16	28252805	However, these effects also damage adjacent normal cells and tissue, leading to the potential toxicities that can be seen with radiation therapy.	('effects', 'Var', (15, 22))	('damage', 'Reg', (28, 34))	('toxicities', 'Disease', (94, 104))	('toxicities', 'Disease', 'MESH:D064420', (94, 104))	('leading to', 'Reg', (69, 79))
147	25528763	Mouse models of primary soft tissue sarcoma and spontaneous lung metastasis were obtained by orthotopic intra-muscular injection of HT1080-RFP human fibrosarcoma cells.	('HT1080-RFP', 'Var', (132, 142))	('HT1080-RFP', 'CellLine', 'CVCL:0317', (132, 142))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (24, 43))	('soft tissue sarcoma', 'Disease', (24, 43))	('human', 'Species', '9606', (143, 148))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (149, 161))	('fibrosarcoma', 'Disease', 'MESH:D005354', (149, 161))	('spontaneous lung metastasis', 'CPA', (48, 75))	('Mouse', 'Species', '10090', (0, 5))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (24, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('fibrosarcoma', 'Disease', (149, 161))
159	25528763	S. typhimurium A1-R has no other apparent attenuating mutations S. typhimurium A1-R could eradicate primary and metastatic tumors as monotherapy in nude mice with prostate, breast, lung and pancreatic cancers, including pancreatic cancer stem cells and pancreatic cancer patient-derived orthotopic xenografts [PDOX], as well as sarcoma and glioma.	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('pancreatic cancers', 'Disease', (190, 208))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('glioma', 'Disease', 'MESH:D005910', (340, 346))	('patient', 'Species', '9606', (271, 278))	('breast', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('pancreatic cancer', 'Disease', (253, 270))	('eradicate', 'NegReg', (90, 99))	('pancreatic cancer', 'Disease', (220, 237))	('pancreatic cancers', 'Disease', 'MESH:D010190', (190, 208))	('S. typhimurium A1-R', 'Var', (64, 83))	('glioma', 'Phenotype', 'HP:0009733', (340, 346))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('S. typhimurium', 'Species', '90371', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('nude mice', 'Species', '10090', (148, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (190, 207))	('lung', 'Disease', (181, 185))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (253, 270))	('sarcoma', 'Disease', 'MESH:D012509', (328, 335))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('S. typhimurium', 'Species', '90371', (64, 78))	('sarcoma', 'Disease', (328, 335))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('prostate', 'Disease', (163, 171))	('tumors', 'Disease', (123, 129))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (190, 208))	('pancreatic cancer', 'Disease', 'MESH:D010190', (190, 207))	('pancreatic cancer', 'Disease', 'MESH:D010190', (253, 270))	('glioma', 'Disease', (340, 346))	('sarcoma', 'Phenotype', 'HP:0100242', (328, 335))
175	25528763	In the present study, we determined the efficacy of S. typhimurium A1-R on primary tumors and experimental and spontaneous metastasis in mouse models of human soft-tissue sarcoma.	('primary tumors', 'Disease', 'MESH:D009369', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('S. typhimurium', 'Species', '90371', (52, 66))	('mouse', 'Species', '10090', (137, 142))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (159, 178))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('sarcoma', 'Disease', 'MESH:D012509', (171, 178))	('S. typhimurium', 'Var', (52, 66))	('human', 'Species', '9606', (153, 158))	('sarcoma', 'Disease', (171, 178))	('primary tumors', 'Disease', (75, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))
177	25528763	GFP-expressing S. typhimurium A1-R invaded the fibrosarcoma cells (Fig.	('fibrosarcoma', 'Disease', (47, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('S. typhimurium', 'Species', '90371', (15, 29))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (47, 59))	('fibrosarcoma', 'Disease', 'MESH:D005354', (47, 59))	('S. typhimurium', 'Var', (15, 29))
185	25528763	Mice transplanted with HT1080-RFP cells in the leg muscle developed primary soft tissue tumor and lung metastasis (Fig.	('HT1080-RFP', 'Var', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('HT1080-RFP', 'CellLine', 'CVCL:0317', (23, 33))	('lung metastasis', 'CPA', (98, 113))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (88, 93))
197	25528763	Fluorescence imaging demonstrated that S. typhimurium A1-R strongly inhibited lung metastases (Fig.	('S. typhimurium', 'Species', '90371', (39, 53))	('inhibited', 'NegReg', (68, 77))	('lung metastases', 'Disease', (78, 93))	('lung metastases', 'Disease', 'MESH:D009362', (78, 93))	('S. typhimurium A1-R', 'Var', (39, 58))
200	25528763	Kaplan-Meier analysis with the log rank test demonstrated that S. typhimurium A1-R significantly improved the survival of the treated mice (P = 0.004; Fig.	('mice', 'Species', '10090', (134, 138))	('S. typhimurium', 'Species', '90371', (63, 77))	('improved', 'PosReg', (97, 105))	('S. typhimurium A1-R', 'Var', (63, 82))	('survival', 'CPA', (110, 118))
202	25528763	In the orthotopic spontaneous metastasis model of soft tissue sarcoma, S. typhimurium A1-R significantly inhibited primary tumor growth and spontaneous lung metastases.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('tumor', 'Disease', (123, 128))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (50, 69))	('inhibited', 'NegReg', (105, 114))	('lung metastases', 'Disease', (152, 167))	('S. typhimurium', 'Species', '90371', (71, 85))	('A1-R', 'Var', (86, 90))	('lung metastases', 'Disease', 'MESH:D009362', (152, 167))	('soft tissue sarcoma', 'Disease', (50, 69))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('S. typhimurium', 'Var', (71, 85))
205	25528763	Furthermore, S. typhimurium A1-R significantly improved the survival of the mice.	('improved', 'PosReg', (47, 55))	('survival of the mice', 'CPA', (60, 80))	('S. typhimurium', 'Var', (13, 27))	('mice', 'Species', '10090', (76, 80))	('S. typhimurium', 'Species', '90371', (13, 27))
206	25528763	Thus, S. typhimurium A1-R directly inhibits primary tumor growth and metastasis of soft-tissue sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('metastasis', 'CPA', (69, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('tumor', 'Disease', (52, 57))	('inhibits', 'NegReg', (35, 43))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (83, 102))	('S. typhimurium', 'Var', (6, 20))	('sarcoma', 'Disease', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('S. typhimurium', 'Species', '90371', (6, 20))
262	33498238	On the other hand, non-synonymous somatic mutations are coding for neoantigens, exclusively expressed by cancer cells, which could induce potent immune responses, because the quality of the T-cell repertoire recognizing these antigens in the context of particular major histocompatibility complex (MHC) alleles is not affected by central T-cell tolerance.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
263	33498238	Some subtypes such as undifferentiated pleomorphic sarcoma (UPS) have a higher number of non-synonymous mutations and greater TMB opening a window of opportunity for immunotherapeutic approaches such as vaccines and anti-PD-1/PD-L1 therapies.	('non-synonymous mutations', 'Var', (89, 113))	('TMB', 'Chemical', '-', (126, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (22, 58))	('UPS', 'Disease', 'MESH:D017118', (60, 63))	('undifferentiated pleomorphic sarcoma', 'Disease', (22, 58))	('TMB', 'MPA', (126, 129))	('UPS', 'Disease', (60, 63))
271	33498238	In addition, around a 20% of sarcomas are associated to chromosomal translocations, which create oncogenic fusion genes encoding for fusion proteins.	('associated', 'Reg', (42, 52))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('sarcomas', 'Disease', (29, 37))	('chromosomal translocations', 'Var', (56, 82))
276	33498238	Administration of anti-PD-1 and/or anti-PD-L1 monoclonal antibodies (MAbs) unblocks immune inhibition via PD-1/PD-L1 bridging and enhances tumor cell killing by the CD8 + CTLs.	('unblocks', 'NegReg', (75, 83))	('immune inhibition', 'MPA', (84, 101))	('anti-PD-L1', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('anti-PD-1', 'Var', (18, 27))	('enhances', 'PosReg', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('CD8', 'Gene', (165, 168))	('bridging', 'Interaction', (117, 125))	('CD8', 'Gene', '925', (165, 168))
281	33498238	PD-L1 can be expressed in tumor cells as a result of genetic modifications including PTEN loss, EGFR mutations, MYC overexpression, mutations in the PI3K/AKT signaling pathway and PDJ amplification.	('mutations', 'Var', (101, 110))	('loss', 'NegReg', (90, 94))	('EGFR', 'Gene', (96, 100))	('AKT', 'Gene', '207', (154, 157))	('MYC', 'Gene', '4609', (112, 115))	('mutations', 'Var', (132, 141))	('overexpression', 'PosReg', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('AKT', 'Gene', (154, 157))	('PTEN', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('PTEN', 'Gene', '5728', (85, 89))	('MYC', 'Gene', (112, 115))	('PDJ', 'Gene', (180, 183))	('EGFR', 'Gene', '1956', (96, 100))
282	33498238	Interestingly, in a recent report it was shown that not PD-L1 per se, but rather the composition of the TME in which PD-L1 is induced, determines tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('PD-L1', 'Var', (117, 122))	('determines', 'Reg', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
288	33498238	In recent years, high-throughput sequencing technologies have made it possible to detect somatic mutations in tumors and to identify TMB profiles.	('TMB', 'Chemical', '-', (133, 136))	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))
289	33498238	Accumulated evidence indicates large heterogeneity of TMB among sarcoma subtypes ranging from very low (0.15 m/MB) to high (29 m/MB).	('0.15 m/MB', 'Var', (104, 113))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('TMB', 'Gene', (54, 57))	('sarcoma', 'Disease', (64, 71))	('TMB', 'Chemical', '-', (54, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('29 m/MB', 'Var', (124, 131))
293	33498238	In a homogeneous study including tissue samples from 26 cardiac sarcomas, whole exome sequencing and NGS analysis identified high TMB in 92.3% of patients.	('cardiac sarcomas', 'Phenotype', 'HP:0031350', (56, 72))	('cardiac sarcomas', 'Disease', (56, 72))	('cardiac sarcomas', 'Disease', 'MESH:D006331', (56, 72))	('high TMB', 'Var', (125, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('patients', 'Species', '9606', (146, 154))	('TMB', 'Chemical', '-', (130, 133))
299	33498238	Another recent report indicated that patients with TMB high and elevated effector immune cells infiltrate exhibited the highest survival.	('elevated', 'PosReg', (64, 72))	('patients', 'Species', '9606', (37, 45))	('TMB', 'Chemical', '-', (51, 54))	('effector immune cells infiltrate', 'CPA', (73, 105))	('TMB high', 'Var', (51, 59))
312	33498238	Results of ongoing studies with ganitumab in combination with palbociclib (NCT04129151) and chemotherapy (NCT02306161) are awaited.	('NCT02306161', 'Var', (106, 117))	('ganitumab', 'Chemical', 'MESH:C545764', (32, 41))	('NCT04129151', 'Var', (75, 86))
322	33498238	High TMB has been suggested to associate with microsatellite instability and increased immunogenicity which confer substantial clinical responses to anti-PD1 treatment.	('High', 'Var', (0, 4))	('microsatellite instability', 'MPA', (46, 72))	('immunogenicity', 'MPA', (87, 101))	('increased', 'PosReg', (77, 86))	('TMB', 'Chemical', '-', (5, 8))
365	33498238	Table 3 presents ongoing CAR-T cell clinical trials aiming to explore the targeting of surface antigens of sarcoma cells with modified memory T cells such as 4SCAR-IgT cells (NCT03356782), CCT301-59 T cells (NCT03960060), C7R-GD2 T cells (NCT03635632) or NY-ESO-1 T cells (NCT03638206).	('NY-ESO-1', 'Gene', (255, 263))	('NCT03960060', 'Var', (208, 219))	('memory T', 'Disease', (135, 143))	('CAR', 'Gene', (160, 163))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))	('CAR', 'Gene', '9970', (160, 163))	('NCT03356782', 'Var', (175, 186))	('CAR', 'Gene', (25, 28))	('sarcoma', 'Disease', (107, 114))	('CAR', 'Gene', '9970', (25, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('NCT03635632', 'Var', (239, 250))	('CAR-T', 'Disease', 'MESH:D056733', (25, 30))	('NCT03638206', 'Var', (273, 284))	('memory T', 'Disease', 'MESH:D008569', (135, 143))	('NY-ESO-1', 'Gene', '246100', (255, 263))	('CAR-T', 'Disease', (25, 30))
367	33498238	The latter is based on the hypothesis that CD19 + B cells serve in their normal role as antigen presenting cells to T cells and are expected to promote the expansion and persistence of the CAR T cells with specificity against EGFR (NCT03618381).	('NCT03618381', 'Var', (232, 243))	('CD19 + B cells', 'Var', (43, 57))	('persistence', 'CPA', (170, 181))	('CAR', 'Gene', (189, 192))	('promote', 'PosReg', (144, 151))	('CAR', 'Gene', '9970', (189, 192))	('EGFR', 'Gene', '1956', (226, 230))	('EGFR', 'Gene', (226, 230))
368	33498238	Another study is exploring the effect of HER2 (Human Epidermal Growth Factor Receptor 2) CAR T cells that in addition contains CD28, which stimulates T cells and make them last longer (NCT00902044).	('CAR', 'Gene', (89, 92))	('CAR', 'Gene', '9970', (89, 92))	('T cells', 'CPA', (150, 157))	('Human Epidermal Growth Factor Receptor 2', 'Gene', '2064', (47, 87))	('stimulates', 'PosReg', (139, 149))	('Human Epidermal Growth Factor Receptor 2', 'Gene', (47, 87))	('CD28', 'Var', (127, 131))
374	33498238	In the same study the genetic modification of NK cells to overexpress the activating receptors, DNAM-1 or NKG2D, elicited a dynamic increase in NK cell degranulation against all sarcoma explants in vitro.	('NKG2D', 'Gene', (106, 111))	('increase', 'PosReg', (132, 140))	('NK cell', 'CPA', (144, 151))	('overexpress', 'PosReg', (58, 69))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('DNAM-1', 'Gene', (96, 102))	('degranulation', 'MPA', (152, 165))	('genetic modification', 'Var', (22, 42))	('NKG2D', 'Gene', '22914', (106, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('sarcoma', 'Disease', (178, 185))	('DNAM-1', 'Gene', '10666', (96, 102))
389	33498238	The patient with TGCT achieved a long-lasting response, an expected effect due to the recurrent translocation t (1; 2) (p11; q35-36) leading to the fusion of CSF1 to COL6A3 that characterized this tumor.	('p11', 'Gene', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('patient', 'Species', '9606', (4, 11))	('CSF1', 'Gene', '1435', (158, 162))	('p11', 'Gene', '6281', (120, 123))	('CSF1', 'Gene', (158, 162))	('COL6A3', 'Gene', (166, 172))	('COL6A3', 'Gene', '1293', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('fusion', 'Var', (148, 154))	('tumor', 'Disease', (197, 202))
509	28454377	However, a study of osteosarcoma revealed that macrophages were associated with a good clinical outcome.	('osteosarcoma', 'Disease', (20, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (20, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('osteosarcoma', 'Disease', 'MESH:D012516', (20, 32))	('macrophages', 'Var', (47, 58))
589	32518213	While TP53 and PTEN disruption is also characteristic of LMS, their frequency of alteration is lower in LMS compared to many other cancer types (Fig.	('cancer', 'Disease', (131, 137))	('lower', 'NegReg', (95, 100))	('TP53', 'Gene', '7157', (6, 10))	('LMS', 'Disease', (104, 107))	('TP53', 'Gene', (6, 10))	('LMS', 'Phenotype', 'HP:0100243', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('disruption', 'Var', (20, 30))	('PTEN', 'Gene', (15, 19))	('PTEN', 'Gene', '5728', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('LMS', 'Phenotype', 'HP:0100243', (57, 60))
595	32518213	Compared to non-mesenchymal cancer subtypes, LMS demonstrates a higher proportion of copy number alterations in tumor suppressors and putative oncogenes, which is a characteristic shared with other sarcomas.	('LMS', 'Phenotype', 'HP:0100243', (45, 48))	('copy number alterations', 'Var', (85, 108))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('sarcomas', 'Disease', 'MESH:D012509', (198, 206))	('sarcomas', 'Disease', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', (28, 34))	('LMS', 'Disease', (45, 48))
653	32518213	With the commonality of RB1 alterations in LMS, E2F1 proceeds with an unchecked oncogenic program, and targeting this pathway represents a challenging but promising strategy in this disease.	('E2F1', 'Gene', (48, 52))	('RB1', 'Gene', (24, 27))	('alterations', 'Var', (28, 39))	('RB1', 'Gene', '5925', (24, 27))	('LMS', 'Disease', (43, 46))	('LMS', 'Phenotype', 'HP:0100243', (43, 46))	('E2F1', 'Gene', '1869', (48, 52))
664	32518213	Further, in early clinical trials utilizing combination treatment with mTOR and IGF1R inhibition, some patients with LMS derived benefit.	('IGF1R', 'Gene', (80, 85))	('LMS', 'Disease', (117, 120))	('IGF1R', 'Gene', '3480', (80, 85))	('LMS', 'Phenotype', 'HP:0100243', (117, 120))	('mTOR', 'Gene', '2475', (71, 75))	('inhibition', 'Var', (86, 96))	('mTOR', 'Gene', (71, 75))	('patients', 'Species', '9606', (103, 111))
665	32518213	Based on early clinical experience and these data, additional preclinical studies with combination therapy utilizing IGF1R inhibition in this LMS subtype are warranted.	('IGF1R', 'Gene', '3480', (117, 122))	('LMS', 'Disease', (142, 145))	('LMS', 'Phenotype', 'HP:0100243', (142, 145))	('inhibition', 'Var', (123, 133))	('IGF1R', 'Gene', (117, 122))
680	28018820	Despite an R1-resection and adjuvant chemotherapy, the patient is in good clinical health and free of tumor relapse 1 year after the surgery.	('R1-resection', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('patient', 'Species', '9606', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
790	27279906	Then, sections were stained for CD99 (dilution 1:500; Signet antibodies, SIG-3620) and Collagen 1 (dilution 1:500; Abcam, ab34710).	('dilution 1:500', 'Var', (99, 113))	('CD99', 'Gene', (32, 36))	('CD99', 'Gene', '4267', (32, 36))
822	27279906	The rate of degradation was much slower for Col1-HA LMW than Col1-HA HMW scaffolds, presumably due to the higher density of chemical cross-links (Fig.	('HMW', 'Gene', (69, 72))	('Col1-HA LMW', 'Var', (44, 55))	('degradation', 'MPA', (12, 23))	('chemical', 'Interaction', (124, 132))	('HA', 'Chemical', 'MESH:D006820', (66, 68))	('HA', 'Chemical', 'MESH:D006820', (49, 51))	('higher', 'PosReg', (106, 112))	('HMW', 'Gene', '57587', (69, 72))	('slower', 'NegReg', (33, 39))
824	27279906	In previous studies, LMW HA was shown to play a role in tumor progression in a number of cancers.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HA', 'Chemical', 'MESH:D006820', (25, 27))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumor', 'Disease', (56, 61))	('LMW HA', 'Var', (21, 27))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
900	27279906	Epigenetic changes such as gene promoter methylation in stromal cells have been associated with malignancy.	('gene promoter methylation', 'Var', (27, 52))	('associated', 'Reg', (80, 90))	('malignancy', 'Disease', (96, 106))	('malignancy', 'Disease', 'MESH:D009369', (96, 106))
901	27279906	However, histone modifications (i.e., H3K27me3 established by EZH2) and chromatin remodeling in the cells comprising tumor microenvironment remain largely unknown and will require further studies.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('EZH2', 'Gene', '2146', (62, 66))	('EZH2', 'Gene', (62, 66))	('H3K27me3', 'Var', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
964	24705963	Gene sequencing (exome sequencing using the Illumina platform [Illumina Inc., San Diego, Calif] to compare 50 million bases of tumor and normal DNA) revealed a mutation in Janus kinase 2 (JAK2) as well as cyclin-dependent kinase 4 (CDK4) and mouse double minute 2 homolog (MDM2) copy number alterations, both of which are commonly detected in liposarcomas.	('rat', 'Species', '10116', (295, 298))	('cyclin-dependent kinase 4', 'Gene', (205, 230))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('liposarcomas', 'Disease', 'MESH:D008080', (343, 355))	('MDM2', 'Gene', (273, 277))	('sarcomas', 'Phenotype', 'HP:0100242', (347, 355))	('cyclin-dependent kinase 4', 'Gene', '12567', (205, 230))	('copy number alterations', 'Var', (279, 302))	('mutation', 'Var', (160, 168))	('liposarcomas', 'Phenotype', 'HP:0012034', (343, 355))	('JAK2', 'Gene', (188, 192))	('CDK4', 'Gene', (232, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (347, 354))	('liposarcoma', 'Phenotype', 'HP:0012034', (343, 354))	('mouse', 'Species', '10090', (242, 247))	('Janus kinase 2', 'Gene', '16452', (172, 186))	('tumor', 'Disease', (127, 132))	('liposarcomas', 'Disease', (343, 355))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Janus kinase 2', 'Gene', (172, 186))
966	24705963	The patient commenced daily treatment with a CDK4 inhibitor (350 mg P1446A-05), which, at first, inhibited the rapid growth of the tumors, as detected by computed tomography (CT) scans.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('350 mg P1446A-05', 'Var', (61, 77))	('patient', 'Species', '9606', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('inhibited', 'NegReg', (97, 106))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('CDK4', 'Gene', (45, 49))	('P1446A', 'Mutation', 'p.P1446A', (68, 74))
984	24705963	The tumor was positive for the Ewing sarcoma/Fli-1 proto-oncogene, ETS transcription factor (EWS-FLI1) fusion gene rearrangement.	('tumor', 'Disease', (4, 9))	('EWS-FLI1', 'Gene', '2130;2313', (93, 101))	('positive', 'Reg', (14, 22))	('fusion gene rearrangement', 'Var', (103, 128))	('Ewing sarcoma', 'Disease', (31, 44))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (31, 44))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (31, 44))	('EWS-FLI1', 'Gene', (93, 101))
1034	24705963	For example, among the subpopulation of metastatic colorectal cancers that carry the wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) allele, objective responses to antiepidermal growth factor receptor therapeutics is still confined to 13% to 17% of patients.	('rat', 'Species', '10116', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('sarcoma', 'Disease', (107, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('colorectal cancers', 'Disease', 'MESH:D015179', (51, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('colorectal cancers', 'Disease', (51, 69))	('patients', 'Species', '9606', (261, 269))	('allele', 'Var', (145, 151))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))
1035	24705963	Although the identification of v-raf murine sarcoma viral oncogene homolog B (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), neuroblastoma v-ras oncogene homolog (NRAS), and rare KRAS mutations may increase this percentage, there is a lack of standard therapeutic options, and the issue of tumor and/or patient heterogeneity in clinical trials remains important.	('BRAF', 'Gene', '109880', (78, 82))	('NRAS', 'Gene', '18176', (205, 209))	('NRAS', 'Gene', (205, 209))	('PIK3CA', 'Gene', (158, 164))	('neuroblastoma', 'Disease', 'MESH:D009447', (167, 180))	('KRAS', 'Gene', (221, 225))	('BRAF', 'Gene', (78, 82))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (31, 76))	('neuroblastoma', 'Disease', (167, 180))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', (31, 76))	('mutations', 'Var', (226, 235))	('patient', 'Species', '9606', (345, 352))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('neuroblastoma', 'Phenotype', 'HP:0003006', (167, 180))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('PIK3CA', 'Gene', '18706', (158, 164))	('tumor', 'Disease', (332, 337))
1036	24705963	Moreover, only a small fraction of tumors harbor these specific alterations, meaning that the majority of patients with advanced cancer will receive no benefit from these therapies.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('alterations', 'Var', (64, 75))	('rat', 'Species', '10116', (68, 71))	('patients', 'Species', '9606', (106, 114))
1043	24705963	The TumorGraft models used here include the tumor microenvironment present in the human host and maintain the features of the transplanted tumor, including gene expression profiles, copy number variants, and, most important, treatment response.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('copy number variants', 'Var', (182, 202))	('Tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('human', 'Species', '9606', (82, 87))
1184	28145886	Epidermal growth factor receptor signaling is known to support FDC-S proliferation; mutations affecting the nuclear factor kappa B pathway and cell cycle regulation were recently identified, by targeted next generation sequencing, in a subgroup of FDC-S. Data on whole genome and whole transcriptome sequencing on this tumor are still lacking.	('tumor', 'Disease', (319, 324))	('cell', 'CPA', (143, 147))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('affecting', 'Reg', (94, 103))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('nuclear factor kappa B pathway', 'Pathway', (108, 138))
1191	28145886	According to the histological evidence of a higher T-cell infiltrate, "T-cell activation" (P00053) was increased in the transcriptome of case #1 while "Integrin Signalling" (P00034) and "Epidermal growth factor receptor (EGFR) signalling" pathway (P00018) were overrepresented in case #2, consistent with previous observations of activated EGFR signalling in FDC-S..	('FDC-S..', 'Disease', (359, 366))	('P00018', 'Var', (248, 254))	('EGFR', 'Gene', (340, 344))	('increased', 'PosReg', (103, 112))	('Epidermal growth factor receptor', 'Gene', '1956', (187, 219))	('EGFR', 'Gene', '1956', (221, 225))	('overrepresented', 'PosReg', (261, 276))	('P00034', 'Var', (174, 180))	('Integrin Signalling', 'MPA', (152, 171))	('EGFR', 'Gene', (221, 225))	('Epidermal growth factor receptor', 'Gene', (187, 219))	('EGFR', 'Gene', '1956', (340, 344))
1291	20646841	Seventeen of 32 (53%) operative bed recurrences occurred in patients whose treatment deviated from the RT guidelines, including 9 who did not receive RT, 2 with dose deviations (major), 5 with volume deviations (3 major and 2 minor), and 1 with both a dose and volume deviation (major).	('patients', 'Species', '9606', (60, 68))	('dose deviations', 'Var', (161, 176))	('operative bed recurrences', 'CPA', (22, 47))
1309	20646841	These data suggest that adherence to RT guidelines would lead to fewer operative bed recurrences and improved local-regional control as observed on IRS IV where the local-regional control rate of 95% was associated with protocol compliance similar to what would be expected for all Group II patients.	('operative bed recurrences', 'CPA', (71, 96))	('local-regional control', 'CPA', (110, 132))	('adherence', 'Var', (24, 33))	('improved', 'PosReg', (101, 109))	('patients', 'Species', '9606', (291, 299))	('IRS', 'Gene', '3376', (148, 151))	('IRS', 'Gene', (148, 151))	('fewer', 'NegReg', (65, 70))
1347	20646841	Operative bed recurrence in children with microscopic residual disease is associated with a lower rate of RT protocol guideline compliance than would be expected for Group II patients treated on rhabdomyosarcoma protocols as reviewed at QARC.	('children', 'Species', '9606', (28, 36))	('microscopic residual disease', 'Var', (42, 70))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (195, 211))	('rhabdomyosarcoma', 'Disease', (195, 211))	('patients', 'Species', '9606', (175, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (195, 211))	('Operative bed', 'Disease', (0, 13))	('lower', 'NegReg', (92, 97))
1354	25649062	The diagnosis was confirmed by the presence of a germ-line STK11 mutation.	('presence', 'Reg', (35, 43))	('mutation', 'Var', (65, 73))	('STK11', 'Gene', (59, 64))	('STK11', 'Gene', '6794', (59, 64))
1365	25649062	This genetic condition is caused by a germline mutation in the tumor suppressor gene serine threonine kinase 11 gene (STK11, also known as LKB1).	('tumor', 'Disease', (63, 68))	('STK11', 'Gene', '6794', (118, 123))	('serine threonine kinase 11 gene', 'Gene', (85, 116))	('caused by', 'Reg', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('LKB1', 'Gene', (139, 143))	('germline mutation', 'Var', (38, 55))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('STK11', 'Gene', (118, 123))	('LKB1', 'Gene', '6794', (139, 143))	('serine threonine kinase 11 gene', 'Gene', '6794', (85, 116))
1366	25649062	It is thought that all patients with PJS have a deleterious mutation in STK11, but current technology detects a mutation in only 75% of cases.	('mutation', 'Var', (60, 68))	('PJS', 'Gene', '6794', (37, 40))	('patients', 'Species', '9606', (23, 31))	('STK11', 'Gene', (72, 77))	('PJS', 'Gene', (37, 40))	('STK11', 'Gene', '6794', (72, 77))
1391	25649062	Full gene sequencing and deletion/duplication analysis of the STK11 gene was completed so that predictive testing could be offered to the patient's daughter; this genetic testing was not needed to make the diagnosis of PJS in our patient.	('STK11', 'Gene', (62, 67))	('deletion/duplication', 'Var', (25, 45))	('patient', 'Species', '9606', (230, 237))	('PJS', 'Gene', '6794', (219, 222))	('patient', 'Species', '9606', (138, 145))	('PJS', 'Gene', (219, 222))	('STK11', 'Gene', '6794', (62, 67))
1425	25649062	We attempted to identify a "second hit" somatic tumor mutation to conclusively link the tumor to the patient's PJS diagnosis and germline STK11 mutation.	('PJS', 'Gene', '6794', (111, 114))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('PJS', 'Gene', (111, 114))	('STK11', 'Gene', (138, 143))	('mutation', 'Var', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('STK11', 'Gene', '6794', (138, 143))	('patient', 'Species', '9606', (101, 108))	('tumor', 'Disease', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
1429	25649062	Identification of STK11 gene mutations in PJS have allowed for the development of targeted molecular therapy.	('mutations', 'Var', (29, 38))	('STK11', 'Gene', (18, 23))	('PJS', 'Gene', '6794', (42, 45))	('STK11', 'Gene', '6794', (18, 23))	('PJS', 'Gene', (42, 45))
1430	25649062	STK11 mutations are associated with activation of the mTOR pathway.	('associated', 'Reg', (20, 30))	('STK11', 'Gene', (0, 5))	('STK11', 'Gene', '6794', (0, 5))	('mTOR', 'Gene', '2475', (54, 58))	('mTOR', 'Gene', (54, 58))	('mutations', 'Var', (6, 15))
1443	21625565	Genome rearrangements and associated gene fusions are known to be important oncogenic events in some cancers.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Genome rearrangements', 'Var', (0, 21))
1446	21625565	Gene fusions are known to play an important role in the development of haematalogical disorders and childhood sarcomas, while the recent discovery of ETS gene fusions in prostate cancer has also prompted renewed interest in gene fusions in solid tumors.	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('prostate cancer', 'Disease', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('Gene fusions', 'Var', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('haematalogical disorders', 'Disease', (71, 95))	('solid tumors', 'Disease', (240, 252))	('prostate cancer', 'Disease', 'MESH:D011471', (170, 185))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('sarcomas', 'Disease', (110, 118))	('prostate cancer', 'Phenotype', 'HP:0012125', (170, 185))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('solid tumors', 'Disease', 'MESH:D009369', (240, 252))	('haematalogical disorders', 'Disease', 'MESH:D030342', (71, 95))
1448	21625565	The discovery of the EML4-ALK fusion in non-small-cell lung cancer and the ETV6-NTRK3 fusion in human secretory breast carcinoma suggest that gene fusions are also recurrent at low levels in other solid tumor types.	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (40, 66))	('fusion', 'Var', (30, 36))	('tumor', 'Disease', (203, 208))	('EML4', 'Gene', (21, 25))	('EML4', 'Gene', '27436', (21, 25))	('lung cancer', 'Disease', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('breast carcinoma', 'Disease', 'MESH:D001943', (112, 128))	('human', 'Species', '9606', (96, 101))	('ALK', 'Gene', '238', (26, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('ALK', 'Gene', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('breast carcinoma', 'Phenotype', 'HP:0003002', (112, 128))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (44, 66))	('breast carcinoma', 'Disease', (112, 128))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (75, 92))	('ETV6-NTRK3 fusion', 'Gene', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
1449	21625565	For ETS gene fusions in prostate cancer, the androgen-responsive regulatory elements of TMPRSS2 drive the expression of the ETS family member to which TMPRSS2 is fused.	('TMPRSS2', 'Gene', (88, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (24, 39))	('expression', 'MPA', (106, 116))	('prostate cancer', 'Phenotype', 'HP:0012125', (24, 39))	('TMPRSS2', 'Gene', (151, 158))	('TMPRSS2', 'Gene', '7113', (88, 95))	('fusions', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('drive', 'PosReg', (96, 101))	('ETS', 'Gene', (4, 7))	('TMPRSS2', 'Gene', '7113', (151, 158))	('prostate cancer', 'Disease', (24, 39))
1473	21625565	As a training set, we compiled a list of all ovarian and sarcoma fusions for which validation was attempted, and added to this list the 11 melanoma fusions, the three K-562 fusions and the TMPRSS2-ERG fusion in NCI-H660.	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('K-562 fusions', 'Var', (167, 180))	('melanoma', 'Disease', (139, 147))	('NCI-H660', 'Gene', (211, 219))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('K-562', 'CellLine', 'CVCL:0004', (167, 172))	('TMPRSS2', 'Gene', (189, 196))	('ERG', 'Gene', '2078', (197, 200))	('NCI-H660', 'CellLine', 'CVCL:1576', (211, 219))	('ERG', 'Gene', (197, 200))	('ovarian and sarcoma', 'Disease', 'MESH:D010051', (45, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('TMPRSS2', 'Gene', '7113', (189, 196))
1490	21625565	The remaining 15 expression-interrupting fusions represent either biallelic inactivations (for example, HNF1A described below) or dominant expression of the fusion allele (for example, RREB1-TFE3 described below).	('RREB1', 'Gene', '6239', (185, 190))	('HNF1A', 'Gene', (104, 109))	('TFE3', 'Gene', '7030', (191, 195))	('expression-interrupting', 'PosReg', (17, 40))	('biallelic inactivations', 'Var', (66, 89))	('HNF1A', 'Gene', '6927', (104, 109))	('fusions', 'Var', (41, 48))	('RREB1', 'Gene', (185, 190))	('TFE3', 'Gene', (191, 195))
1493	21625565	For the FRYL-SH2D1A fusion in HGS3, a marked coincidence between the fusion boundary and an expression changepoint implies that only the fused copy of SH2D1A is expressed (Figure 6).	('fusion', 'Var', (20, 26))	('SH2D1A', 'Gene', (13, 19))	('FRYL', 'Gene', '285527', (8, 12))	('SH2D1A', 'Gene', (151, 157))	('FRYL', 'Gene', (8, 12))	('SH2D1A', 'Gene', '4068', (13, 19))	('HGS3', 'Gene', (30, 34))	('SH2D1A', 'Gene', '4068', (151, 157))
1500	21625565	Although generally considered a breast cancer rearrangement, amplification of ERBB2 has also been shown to occur in mucinous ovarian tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Disease', (32, 45))	('ERBB2', 'Gene', '2064', (78, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('ovarian tumors', 'Phenotype', 'HP:0100615', (125, 139))	('ERBB2', 'Gene', (78, 83))	('mucinous ovarian tumors', 'Phenotype', 'HP:0031494', (116, 139))	('ovarian tumor', 'Phenotype', 'HP:0100615', (125, 138))	('occur', 'Reg', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('amplification', 'Var', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mucinous ovarian tumors', 'Disease', 'MESH:D010051', (116, 139))	('mucinous ovarian tumors', 'Disease', (116, 139))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))
1507	21625565	Biallelic inactivation of HNF1A has been previously reported to lead to aberrant activation of signalling pathways involved in tumorigenesis in human hepatocellular adenomas.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('signalling pathways', 'Pathway', (95, 114))	('HNF1A', 'Gene', '6927', (26, 31))	('human', 'Species', '9606', (144, 149))	('tumor', 'Disease', (127, 132))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (150, 173))	('activation', 'PosReg', (81, 91))	('HNF1A', 'Gene', (26, 31))	('Biallelic inactivation', 'Var', (0, 22))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (150, 173))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('hepatocellular adenomas', 'Disease', (150, 173))
1508	21625565	The RREB1-TFE3 gene fusion found in the intermediate grade myofibroblastic sarcoma SARC3 fuses the first eight exons of RREB1 to the last nine exons of TFE3, preserving the open reading frame of both RREB1 and TFE3.	('TFE3', 'Gene', '7030', (10, 14))	('RREB1', 'Gene', '6239', (4, 9))	('fusion', 'Var', (20, 26))	('TFE3', 'Gene', '7030', (210, 214))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('RREB1', 'Gene', (200, 205))	('TFE3', 'Gene', '7030', (152, 156))	('sarcoma', 'Disease', (75, 82))	('RREB1', 'Gene', '6239', (200, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('open', 'MPA', (173, 177))	('TFE3', 'Gene', (210, 214))	('TFE3', 'Gene', (10, 14))	('RREB1', 'Gene', (120, 125))	('RREB1', 'Gene', (4, 9))	('TFE3', 'Gene', (152, 156))	('RREB1', 'Gene', '6239', (120, 125))
1512	21625565	Finally, the SMARCB1-WASF2 gene fusion found in SARC2 is predicted to produce a transcript that preserves the reading frame of both SMARCB1 and WASF2.	('WASF2', 'Gene', (21, 26))	('SMARCB1', 'Gene', (132, 139))	('SMARCB1', 'Gene', '6598', (132, 139))	('reading frame', 'MPA', (110, 123))	('WASF2', 'Gene', '10163', (144, 149))	('SMARCB1', 'Gene', '6598', (13, 20))	('WASF2', 'Gene', '10163', (21, 26))	('SMARCB1', 'Gene', (13, 20))	('fusion', 'Var', (32, 38))	('WASF2', 'Gene', (144, 149))
1516	21625565	Importantly, the validated fusions in ovarian cancer represent the first reported gene fusions in that tumor type.	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('ovarian cancer', 'Disease', 'MESH:D010051', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('fusions', 'Var', (27, 34))	('ovarian cancer', 'Disease', (38, 52))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
1595	20708326	Overproduction of the cytokine IL-6, either native or virally encoded, has been hypothesized to drive plasma cell proliferation and can explain the systemic manifestations in patients with the plasma cell type of CD.	('IL-6', 'Gene', (31, 35))	('IL-6', 'Gene', '3569', (31, 35))	('plasma cell proliferation', 'CPA', (102, 127))	('man', 'Species', '9606', (157, 160))	('patients', 'Species', '9606', (175, 183))	('Overproduction', 'Var', (0, 14))	('drive', 'PosReg', (96, 101))
1596	20708326	It is suggested that HHV-8 infection may initiate aberrant IL-6 activity causing both Castleman's lymphoproliferation and the plasma cell dyscrasia of POEMS syndrome.	("Castleman's lymphoproliferation", 'Disease', 'MESH:C536362', (86, 117))	('HHV-8 infection', 'Disease', 'MESH:C537372', (21, 36))	('causing', 'Reg', (73, 80))	('HHV-8 infection', 'Disease', (21, 36))	('activity', 'MPA', (64, 72))	('IL-6', 'Gene', (59, 63))	("Castleman's lymphoproliferation", 'Disease', (86, 117))	('dyscrasia of POEMS syndrome', 'Disease', (138, 165))	('aberrant', 'Var', (50, 58))	('IL-6', 'Gene', '3569', (59, 63))	('dyscrasia of POEMS syndrome', 'Disease', 'MESH:D016878', (138, 165))
1722	31993928	Radioactivity clearance from the liver was more evident for RD-ES- than for SK-N-AS-bearing animals.	('RD-ES-', 'Var', (60, 66))	('RD-ES', 'Chemical', '-', (60, 65))	('SK-N-AS', 'Chemical', '-', (76, 83))	('Radioactivity clearance', 'MPA', (0, 23))
1740	31993928	The present work extends previously published results by reporting on the full synthesis process and in vitro assessment of [111In]CHX-DTPA-scFv78-Fc, by evaluating an additional tumor model of human neuroblastoma and by providing human dose extrapolations from mice biodistribution data.	('neuroblastoma', 'Disease', (200, 213))	('CHX-DTPA', 'Chemical', 'MESH:C408383', (131, 139))	('mice', 'Species', '10090', (262, 266))	('neuroblastoma', 'Phenotype', 'HP:0003006', (200, 213))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('human', 'Species', '9606', (194, 199))	('scFv78-Fc', 'Chemical', '-', (140, 149))	('human', 'Species', '9606', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('neuroblastoma', 'Disease', 'MESH:D009447', (200, 213))	('[111In]', 'Var', (124, 131))	('tumor', 'Disease', (179, 184))
1756	31993928	In particular, according to our extrapolations, [111In]CHX-DTPA-scFv78-Fc would deliver a 22 % higher absorbed dose to the liver (0.570 vs. 0.467 mGy/MBq) and a 5 % lower dose to the kidneys (0.298 vs. 0.315 mGy/MBq) compared with [111In]Ibritumomab-tiuxetan.	('tiuxetan', 'Chemical', 'MESH:C077295', (250, 258))	('higher', 'PosReg', (95, 101))	('Ibritumomab', 'Chemical', 'MESH:C422802', (238, 249))	('absorbed dose', 'MPA', (102, 115))	('scFv78-Fc', 'Chemical', '-', (64, 73))	('CHX-DTPA', 'Chemical', 'MESH:C408383', (55, 63))	('[111In]CHX-DTPA-scFv78-Fc', 'Var', (48, 73))
1757	31993928	A larger discrepancy of 89 % would be observed for the spleen (0.876 vs. 0.464 mGy/MBq for [111In]CHX-DTPA-scFv78-Fc and [111In]Ibritumomab-tiuxetan, respectively).	('scFv78-Fc', 'Chemical', '-', (107, 116))	('[111In]', 'Var', (121, 128))	('tiuxetan', 'Chemical', 'MESH:C077295', (140, 148))	('CHX-DTPA', 'Chemical', 'MESH:C408383', (98, 106))	('[111In]CHX-DTPA-scFv78-Fc', 'Var', (91, 116))	('Ibritumomab', 'Chemical', 'MESH:C422802', (128, 139))
1759	31993928	Nevertheless, the total-body absorbed dose would be 53 % lower for [111In]CHX-DTPA-scFv78-Fc compared with [111In]Ibritumomab-tiuxetan (0.058 vs. 0.124 mGy/MBq).	('CHX-DTPA', 'Chemical', 'MESH:C408383', (74, 82))	('[111In]CHX-DTPA-scFv78-Fc', 'Var', (67, 92))	('tiuxetan', 'Chemical', 'MESH:C077295', (126, 134))	('Ibritumomab', 'Chemical', 'MESH:C422802', (114, 125))	('scFv78-Fc', 'Chemical', '-', (83, 92))	('lower', 'NegReg', (57, 62))
1778	29156834	Here we report that Reolysin triggered a striking induction of the anti-angiogenic chemokine interferon-gamma-inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) in both wild type and RAS mutant STS cells.	('CXCL10', 'Gene', '100050993', (139, 145))	('STS', 'Phenotype', 'HP:0030448', (205, 208))	('CXCL10', 'Gene', (139, 145))	('mutant', 'Var', (198, 204))	('induction', 'PosReg', (50, 59))
1787	29156834	Recent studies have demonstrated that reoviruses specifically replicate only in certain cancer cell types, such as those with mutant RAS.	('reovirus', 'Species', '10891', (38, 46))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('rat', 'Species', '10116', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('RAS', 'Gene', (133, 136))	('mutant', 'Var', (126, 132))
1791	29156834	The preferential replication of reovirus in cancer cells with mutant RAS has been attributed to its ability to inhibit double stranded RNA-activated protein kinase (PKR) activity.	('preferential', 'PosReg', (4, 16))	('inhibit', 'NegReg', (111, 118))	('mutant', 'Var', (62, 68))	('replication', 'MPA', (17, 28))	('RAS', 'Gene', (69, 72))	('cancer', 'Disease', (44, 50))	('activity', 'MPA', (170, 178))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('reovirus', 'Species', '10891', (32, 40))	('double stranded', 'MPA', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
1796	29156834	We investigated the ability of oncolytic reovirus to replicate in sarcoma cell lines with mutant and wild type (WT) RAS status and investigated its anticancer activity in both in vitro and in vivo models.	('sarcoma', 'Disease', (66, 73))	('RAS', 'Gene', (116, 119))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('mutant', 'Var', (90, 96))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('reovirus', 'Species', '10891', (41, 49))
1797	29156834	In agreement with prior reports in various solid tumor models, reovirus replicated much more efficiently in cancer cells with mutant RAS.	('reovirus', 'Species', '10891', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('solid tumor', 'Disease', (43, 54))	('replicated', 'MPA', (72, 82))	('more efficiently', 'PosReg', (88, 104))	('mutant', 'Var', (126, 132))	('solid tumor', 'Disease', 'MESH:D009369', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('RAS', 'Gene', (133, 136))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
1802	29156834	Previous studies have reported that reovirus selectively replicates in cells that harbor a RAS mutation or an activated RAS pathway through upstream stimulation.	('mutation', 'Var', (95, 103))	('reovirus', 'Species', '10891', (36, 44))	('RAS', 'Gene', (91, 94))	('RAS pathway', 'Pathway', (120, 131))
1804	29156834	The NRAS mutant HT-1080 cell line displayed hypersensitivity to Reolysin treatment as demonstrated by a significantly greater reduction in cell viability (Figure 1A) and induction of apoptosis (Figure 1B) compared with the WT RAS cell lines (A673, RH30, and SK-LMS-1).	('mutant', 'Var', (9, 15))	('HT-1080', 'CellLine', 'CVCL:0317', (16, 23))	('cell viability', 'CPA', (139, 153))	('RH30', 'Gene', (248, 252))	('RH30', 'Gene', '6007', (248, 252))	('hypersensitivity', 'Disease', (44, 60))	('reduction', 'NegReg', (126, 135))	('NRAS', 'Gene', (4, 8))	('hypersensitivity', 'Disease', 'MESH:D004342', (44, 60))	('rat', 'Species', '10116', (93, 96))	('apoptosis', 'CPA', (183, 192))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (258, 266))	('NRAS', 'Gene', '4893', (4, 8))
1809	29156834	To further characterize the effects of Reolysin on sarcoma cells, we evaluated gene expression changes following reovirus infection in mutant (HT-1080) and WT (SK-LMS-1) RAS sarcoma models by microarray analysis (Supplymentary Tables 2 and 3).	('HT-1080', 'CellLine', 'CVCL:0317', (143, 150))	('sarcoma', 'Disease', (51, 58))	('reovirus infection', 'Disease', 'MESH:D012088', (113, 131))	('reovirus infection', 'Disease', (113, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('mutant', 'Var', (135, 141))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('gene expression', 'MPA', (79, 94))	('sarcoma', 'Disease', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('SK-LMS-1) RAS sarcoma', 'Disease', 'MESH:C535903', (160, 181))
1818	29156834	Consistent with the role of CXCL10 in reducing angiogenesis, neutralizing CXCL10 decreased the ability of Reolysin to block tube formation in endothelial cells (Figure 3C).	('decreased', 'NegReg', (81, 90))	('neutralizing', 'Var', (61, 73))	('tube formation in', 'CPA', (124, 141))	('ability', 'MPA', (95, 102))	('CXCL10', 'Gene', '100050993', (74, 80))	('CXCL10', 'Gene', (74, 80))	('CXCL10', 'Gene', '100050993', (28, 34))	('CXCL10', 'Gene', (28, 34))
1849	29156834	This has led to its evaluation in patients with a variety of tumor types with a high prevalence of constitutive RAS signaling due to activating RAS point mutations or mutations in upstream pathway regulators such as epidermal growth factor receptor (EGFR).	('tumor', 'Disease', (61, 66))	('activating', 'PosReg', (133, 143))	('constitutive RAS signaling', 'MPA', (99, 125))	('RAS', 'Gene', (144, 147))	('epidermal growth factor receptor', 'Gene', (216, 248))	('mutations', 'Var', (167, 176))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('epidermal growth factor receptor', 'Gene', '1956', (216, 248))	('EGFR', 'Gene', '1956', (250, 254))	('patients', 'Species', '9606', (34, 42))	('EGFR', 'Gene', (250, 254))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('point mutations', 'Var', (148, 163))
1851	29156834	At first look, our sarcoma data is supportive of this theory and consistent with data that we and other investigators have obtained in other tumor types in that the reovirus replication and in vitro anticancer efficacy was most pronounced in the mutant RAS HT-1080 fibrosarcoma cell line.	('reovirus', 'Species', '10891', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('reovirus', 'Protein', (165, 173))	('fibrosarcoma', 'Disease', (265, 277))	('pronounced', 'PosReg', (228, 238))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (270, 277))	('HT-1080', 'CellLine', 'CVCL:0317', (257, 264))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('mutant', 'Var', (246, 252))	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('cancer', 'Disease', (203, 209))	('sarcoma', 'Disease', (19, 26))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (265, 277))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('sarcoma', 'Disease', 'MESH:D012509', (270, 277))	('tumor', 'Disease', (141, 146))	('sarcoma', 'Disease', (270, 277))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('fibrosarcoma', 'Disease', 'MESH:D005354', (265, 277))
1854	29156834	Indeed, gene expression analyses on the RAS mutant and sensitive HT-1080 and WT RAS and insensitive SK-LMS-1 sarcoma cell lines following in vitro reovirus infection showed that the anti-angiogenic factor CXCL10 was one of the most significant and dramatically upregulated genes in both sarcoma cell lines.	('SK-LMS-1 sarcoma cell lines', 'Disease', (100, 127))	('HT-1080', 'CellLine', 'CVCL:0317', (65, 72))	('CXCL10', 'Gene', '100050993', (205, 211))	('CXCL10', 'Gene', (205, 211))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('reovirus infection', 'Disease', 'MESH:D012088', (147, 165))	('reovirus infection', 'Disease', (147, 165))	('sarcoma', 'Disease', 'MESH:D012509', (287, 294))	('upregulated', 'PosReg', (261, 272))	('sarcoma', 'Disease', (287, 294))	('sarcoma', 'Disease', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('mutant', 'Var', (44, 50))	('SK-LMS-1 sarcoma cell lines', 'Disease', 'MESH:C535903', (100, 127))
1874	29156834	This important property is mutant RAS-independent, reovirus replication-independent, and opens up broad opportunities for this well tolerated agent to be used more effectively in combination with FDA approved conventional and targeted anticancer therapies for the treatment of highly angiogenic malignancies.	('malignancies', 'Disease', 'MESH:D009369', (295, 307))	('reovirus', 'Species', '10891', (51, 59))	('mutant', 'Var', (27, 33))	('malignancies', 'Disease', (295, 307))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('rat', 'Species', '10116', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
2008	28978047	An abundant infiltrate of TAM (F4/80+) was detected in tumors from untreated mice with a strong predominance of CD206+ M2 over CD86+ M1 macrophages (Figure 5C).	('rat', 'Species', '10116', (18, 21))	('mice', 'Species', '10090', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('TAM', 'Chemical', '-', (26, 29))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('F4/80+)', 'Gene', '13733', (31, 38))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('F4/80+', 'Gene', (31, 37))	('CD206+ M2', 'Var', (112, 121))
2013	28978047	The co-distribution of v-ATPases and CD206 or CD86 was very high, both in tumors from untreated and esomeprazole plus sulfasalazine-treated mice, even if in treated tumors the amount of CD206+ TAM was highly decreased (compare panels a-c with d-f).	('amount', 'MPA', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('decreased', 'NegReg', (208, 217))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('sulfasalazine', 'Chemical', 'MESH:D012460', (118, 131))	('mice', 'Species', '10090', (140, 144))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('esomeprazole', 'Chemical', 'MESH:D064098', (100, 112))	('CD86', 'Gene', (46, 50))	('TAM', 'Chemical', '-', (193, 196))	('v-ATPase', 'Gene', (23, 31))	('tumors', 'Disease', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('v-ATPase', 'Gene', '242341', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('co-distribution', 'MPA', (4, 19))	('CD206', 'Var', (37, 42))	('tumors', 'Disease', (74, 80))
2036	28978047	The double treatment also strongly decreased the number of TAM displaying the M2 marker CD206, which heavily infiltrate 3-MCA sarcoma from untreated mice, whereas the few CD86+ TAM present were unaffected by the therapy.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('rat', 'Species', '10116', (115, 118))	('MCA', 'Gene', '22092', (122, 125))	('decreased', 'NegReg', (35, 44))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('mice', 'Species', '10090', (149, 153))	('TAM', 'Chemical', '-', (59, 62))	('CD206', 'Var', (88, 93))	('MCA', 'Gene', (122, 125))	('sarcoma', 'Disease', (126, 133))	('TAM', 'Chemical', '-', (177, 180))
2053	28978047	The synergy shown by the two drugs may be due also to the redox-dependency of esomeprazole-mediated v-ATPase inhibition: esomeprazole blocks v-ATPases by covalent bonding at a cysteine residue, a reaction counteracted by GSH that restores the activity of the inhibited proton pump.	('esomeprazole', 'Chemical', 'MESH:D064098', (78, 90))	('blocks', 'NegReg', (134, 140))	('cysteine', 'Chemical', 'MESH:D003545', (176, 184))	('covalent', 'Var', (154, 162))	('proton pump', 'Gene', (269, 280))	('esomeprazole', 'Var', (121, 133))	('v-ATPase', 'Gene', (100, 108))	('activity', 'MPA', (243, 251))	('GSH', 'Chemical', 'MESH:D005978', (221, 224))	('v-ATPase', 'Gene', '242341', (100, 108))	('proton pump', 'Gene', '11944', (269, 280))	('esomeprazole', 'Chemical', 'MESH:D064098', (121, 133))	('v-ATPase', 'Gene', (141, 149))	('v-ATPase', 'Gene', '242341', (141, 149))
2060	28978047	The following reagents and Antibodies were used: Esomeprazole, 3-methylcholanthrene, DTNB, Cristal violet, Sulfasalazine and LPS (Sigma-Aldrich); sCPG (Tocris Bioscience); LysoSensor Green DND-189, BCECF-AM and CFSE (Thermo Fisher Scientific);Cisplatin (Accord Healthcare); Mouse IFN-gamma, IL-4 and recombinant GM-CSF (Relia Tech GmbH), rabbit anti-human xCT, mAbs anti-human Cytokeratin 14 (LL002) and Cytokeratin 18 (LDK 18) (Abcam); rabbit anti v-ATPase (TCIRG1, Proteintech); mAb anti-human thioredoxin (clone 2B1) kindly provided by Dr F. Clarke (University of Brisbane, Australia); mAbs to human Vimentin (V9) and Smooth Muscle Actin (1A4) (Thermofisher); rat anti-mouse CD206, CD86 (AbD Serotec), F4/80, CD86-FITC, F4/80-FITC (Biolegend) and CD206-FITC (Bio-Rad Laboratories).	('rabbit', 'Species', '9986', (338, 344))	('DTNB', 'Chemical', 'MESH:D004228', (85, 89))	('v-ATPase', 'Gene', '242341', (449, 457))	('F4/80', 'Gene', (705, 710))	('LPS', 'Disease', (125, 128))	('IL-4', 'Gene', (291, 295))	('rat', 'Species', '10116', (383, 386))	('CD86', 'Var', (685, 689))	('Cytokeratin 14', 'Gene', (377, 391))	('human', 'Species', '9606', (350, 355))	('CD206-FITC', 'Gene', '4360', (750, 760))	('human', 'Species', '9606', (597, 602))	('Cisplatin', 'Chemical', 'MESH:D002945', (243, 252))	('LPS', 'Disease', 'MESH:C536528', (125, 128))	('mouse', 'Species', '10090', (672, 677))	('IL-4', 'Gene', '16189', (291, 295))	('F4/80', 'Gene', '13733', (723, 728))	('BCECF-AM', 'Chemical', 'MESH:C057433', (198, 206))	('Tocris Bioscience', 'Disease', 'None', (152, 169))	('TCIRG1', 'Gene', '27060', (459, 465))	('Sulfasalazine', 'Chemical', 'MESH:D012460', (107, 120))	('IFN-gamma', 'Gene', '15978', (280, 289))	('rat', 'Species', '10116', (410, 413))	('IFN-gamma', 'Gene', (280, 289))	('rabbit', 'Species', '9986', (437, 443))	('Cytokeratin 18', 'Gene', (404, 418))	('F4/80', 'Gene', (723, 728))	('Mouse', 'Species', '10090', (274, 279))	('GM-CSF', 'Gene', '12981', (312, 318))	('rat', 'Species', '10116', (663, 666))	('CD86-FITC', 'Var', (712, 721))	('human', 'Species', '9606', (490, 495))	('Cytokeratin 14', 'Gene', '16664', (377, 391))	('GM-CSF', 'Gene', (312, 318))	('3-methylcholanthrene', 'Chemical', 'MESH:D008748', (63, 83))	('v-ATPase', 'Gene', (449, 457))	('human', 'Species', '9606', (371, 376))	('F4/80', 'Gene', '13733', (705, 710))	('rat', 'Species', '10116', (774, 777))	('Esomeprazole', 'Chemical', 'MESH:D064098', (49, 61))	('Cytokeratin 18', 'Gene', '16668', (404, 418))	('CD206-FITC', 'Gene', (750, 760))	('Tocris Bioscience', 'Disease', (152, 169))	('TCIRG1', 'Gene', (459, 465))
2085	28978047	In the syngenic transplantation model, MCA (0,2x106) and B16 (0,2x106) cells were subcutaneously (s.c.) implanted in the hind flank of immunocompetent syngeneic Balb/C and C57Bl/6J mice, respectively.	('MCA', 'Gene', '22092', (39, 42))	('mice', 'Species', '10090', (181, 185))	('0,2x106', 'Var', (44, 51))	('MCA', 'Gene', (39, 42))	('0,2x106', 'Var', (62, 69))
2101	28978047	Cells were harvested after 48 hours and stained with Ab directed to markers of mature macrophage (anti-F4/80), M1 (anti-CD86) and M2 (anti-CD206) macrophages by flow cytometry or fixed for immunohystochemical assays.	('F4/80', 'Gene', '13733', (103, 108))	('anti-CD86', 'Var', (115, 124))	('F4/80', 'Gene', (103, 108))	('anti-CD206', 'Var', (134, 144))
2154	28101168	RECIST guidelines (version 1.1) were used to assess the efficiency, as follows: Complete response (CR), disappearance of all target lesions; Partial response (PR), at least a 30% reduction in the sum of diameters of target lesions; stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD); and PD, at least a 20% increase in the sum of diameters of target lesions.	('sum of diameters', 'MPA', (196, 212))	('stable disease', 'Disease', (232, 246))	('PD', 'Disease', 'MESH:D010300', (360, 362))	('SD', 'Disease', 'MESH:D029461', (248, 250))	('PD', 'Disease', 'MESH:D010300', (369, 371))	('reduction', 'NegReg', (179, 188))	('Partial response', 'Var', (141, 157))	('disappearance', 'NegReg', (104, 117))
2176	28101168	The P-values of alpha-fetoprotein and TBil were 0.023 and 0.015 (Table II), which were P<0.05 and were considered statistically significant.	('alpha-fetoprotein', 'Gene', (16, 33))	('TBil', 'Chemical', '-', (38, 42))	('alpha-fetoprotein', 'Gene', '174', (16, 33))	('0.015', 'Var', (58, 63))	('TBil', 'MPA', (38, 42))
2223	28101168	Since the 125I provides a source of continuous low dose radiation, it may be more effective than daily pulsed high dose irradiation in treating the hypoxic portion of large, slow-growing necrotic tumors.	('necrotic tumors', 'Disease', (187, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('hypoxic', 'MPA', (148, 155))	('125I', 'Var', (10, 14))	('125I', 'Chemical', 'MESH:C000614960', (10, 14))	('necrotic tumors', 'Disease', 'MESH:D009369', (187, 202))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
2236	28101168	With TACE, embolization of the tumor feeding vessels slows blood flow, creates ischemia and increases the contact time between the chemotherapeutic agent and the tumor cells.	('TACE', 'Chemical', '-', (5, 9))	('creates', 'Reg', (71, 78))	('blood flow', 'MPA', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('contact time', 'MPA', (106, 118))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (31, 36))	('slows', 'NegReg', (53, 58))	('embolization', 'Var', (11, 23))	('ischemia', 'Disease', (79, 87))	('increases', 'PosReg', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('ischemia', 'Disease', 'MESH:D007511', (79, 87))
2243	28101168	Currently, the majority of interstitial brachytherapy treatments are delivered using different radioactive sources, such as 192Ir, 103Pd and 125I.	('125I', 'Chemical', 'MESH:C000614960', (141, 145))	('192Ir', 'Var', (124, 129))	('103Pd', 'Var', (131, 136))	('125I', 'Var', (141, 145))
2249	28101168	Furthermore, the dose homogeneity inside the target volume is very high with 125I.	('125I', 'Var', (77, 81))	('dose homogeneity', 'MPA', (17, 33))	('125I', 'Chemical', 'MESH:C000614960', (77, 81))
2253	28101168	Although it also offers the practical advantage of low energy, reducing the dose to surrounding organs and minimizing shielding requirements, the difference of the half-lives between 103Pd (17 days) and 125I (61 days) is marked.	('125I', 'Var', (203, 207))	('125I', 'Chemical', 'MESH:C000614960', (203, 207))	('103Pd', 'Var', (183, 188))
2258	28101168	Compared with ERBT, 125I implantation has an advantage as brachytherapy inflicts less radiation damage to adjacent structures such as the bowel and genitourinary tract.	('ERBT', 'Chemical', '-', (14, 18))	('bowel', 'Disease', 'MESH:D015212', (138, 143))	('125I', 'Var', (20, 24))	('bowel', 'Disease', (138, 143))	('125I', 'Chemical', 'MESH:C000614960', (20, 24))
2262	28101168	Compared with other radioactivity sources, 125I has a long half-life, a low level of radiant energy that is steadily released over 200 days following implantation and is suitable for targeting slowly growing tumors such as RSTS.	('RSTS', 'Disease', (223, 227))	('STS', 'Phenotype', 'HP:0030448', (224, 227))	('125I', 'Var', (43, 47))	('125I', 'Chemical', 'MESH:C000614960', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('RSTS', 'Chemical', '-', (223, 227))
2300	25008066	The most common are predominantly balanced t(11;22)(q24;q12) and t(21;22)(q22;q12) translocations, resulting in EWS-FLI1 and EWS-ERG fusion gene formation, respectively.	('t(11;22)(q24;q12', 'Var', (43, 59))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (43, 60))	('EWS-FLI1', 'Gene', (112, 120))	('EWS', 'Gene', (125, 128))	('EWS', 'Gene', '2130', (125, 128))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (65, 82))	('EWS', 'Gene', '2130', (112, 115))	('EWS', 'Gene', (112, 115))	('EWS-FLI1', 'Gene', '2130;2313', (112, 120))	('ERG', 'Gene', '2078', (129, 132))	('ERG', 'Gene', (129, 132))	('t(21;22)(q22;q12', 'Var', (65, 81))
2304	25008066	In the most prevalent fusion variants, EWS exon 7 is fused to FLI1 exon 6 (type 1), FLI1 exon 5 (type 2), or ERG exon 9.	('FLI1', 'Gene', (62, 66))	('FLI1', 'Gene', '2313', (62, 66))	('EWS', 'Gene', '2130', (39, 42))	('variants', 'Var', (29, 37))	('EWS', 'Gene', (39, 42))	('FLI1', 'Gene', (84, 88))	('ERG', 'Gene', '2078', (109, 112))	('FLI1', 'Gene', '2313', (84, 88))	('ERG', 'Gene', (109, 112))
2306	25008066	Detection of EWS rearrangements by RT-PCR and/or fluorescence in situ hybridization (FISH) in formalin-fixed paraffin-embedded tissue specimens has become a routine practice in molecular diagnosis of ES.	('formalin', 'Chemical', 'MESH:D005557', (94, 102))	('ES', 'Phenotype', 'HP:0012254', (200, 202))	('rearrangements', 'Var', (17, 31))	('paraffin', 'Chemical', 'MESH:D010232', (109, 117))	('EWS', 'Gene', '2130', (13, 16))	('EWS', 'Gene', (13, 16))
2311	25008066	Biopsy may also cause discomfort suffered by the patient and subsequent surgical complications.	('Biopsy', 'Var', (0, 6))	('patient', 'Species', '9606', (49, 56))	('cause', 'Reg', (16, 21))
2313	25008066	Several groups have already shown that circulating tumor cells (CTCs) carrying EWS-FLI1/ERG fusion transcripts may be detected in 6-43 % of the peripheral blood (PB) specimens of ES patients at the time of diagnosis but the prognostic significance of these findings remains disputable.	('ES', 'Phenotype', 'HP:0012254', (179, 181))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('EWS-FLI1', 'Gene', '2130;2313', (79, 87))	('ERG', 'Gene', '2078', (88, 91))	('patients', 'Species', '9606', (182, 190))	('EWS-FLI1', 'Gene', (79, 87))	('ERG', 'Gene', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('fusion transcripts', 'Var', (92, 110))
2381	25008066	We demonstrated the presence of CTCs carrying oncogenic EWS-FLI1/ERG fusions in only 19 % (n = 3) of ES patients with confirmed EWS/FLI1 rearrangements in tumor specimen.	('rearrangements', 'Var', (137, 151))	('EWS', 'Gene', '2130', (56, 59))	('tumor', 'Disease', (155, 160))	('fusions', 'Var', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('EWS-FLI1', 'Gene', '2130;2313', (56, 64))	('EWS', 'Gene', (128, 131))	('FLI1', 'Gene', (132, 136))	('FLI1', 'Gene', (60, 64))	('EWS', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ERG', 'Gene', (65, 68))	('FLI1', 'Gene', '2313', (132, 136))	('FLI1', 'Gene', '2313', (60, 64))	('patients', 'Species', '9606', (104, 112))	('EWS', 'Gene', '2130', (128, 131))	('ERG', 'Gene', '2078', (65, 68))	('ES', 'Phenotype', 'HP:0012254', (101, 103))	('EWS-FLI1', 'Gene', (56, 64))
2388	25008066	NFKB1 codes for a DNA-binding subunit of the NF-kappa-B (NFkappaB) protein complex transcription regulator, and altered expression of this gene is associated with cancer and many inflammatory diseases.	('NFkappaB', 'Gene', (57, 65))	('NFKB1', 'Gene', (0, 5))	('expression', 'MPA', (120, 130))	('associated', 'Reg', (147, 157))	('NFkappaB', 'Gene', '4790', (57, 65))	('NF-kappa-B', 'Gene', '4790', (45, 55))	('NF-kappa-B', 'Gene', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('inflammatory diseases', 'Disease', (179, 200))	('NFKB1', 'Gene', '4790', (0, 5))	('altered', 'Var', (112, 119))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
2459	24361229	Since there were no differences in FFS by chemotherapy regimen used on COG D9803, both chemotherapy arms and the non-randomized VAC arm were combined for analysis.	('FFS', 'Chemical', '-', (35, 38))	('COG', 'Var', (71, 74))	('VAC', 'Chemical', '-', (128, 131))	('D9803', 'Var', (75, 80))	('COG', 'Chemical', '-', (71, 74))
2481	24361229	In CWS-81, CWS-86, and CWS-91, patients with poor response to induction chemotherapy had inferior FFS than those who achieved a good response.	('CWS-91', 'Var', (23, 29))	('CWS-86', 'Var', (11, 17))	('inferior', 'NegReg', (89, 97))	('FFS', 'CPA', (98, 101))	('patients', 'Species', '9606', (31, 39))	('FFS', 'Chemical', '-', (98, 101))
2494	24361229	The combined results from IRS-IV and D9803 imply that institutional anatomic imaging assessments of response by change in tumor size are unable to predict outcome in RMS and should not be used to tailor patient therapy.	('D9803', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('patient', 'Species', '9606', (203, 210))	('RMS', 'Disease', (166, 169))	('RMS', 'Phenotype', 'HP:0002859', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
2505	24361229	D9803 encouraged surgical excision of the primary tumor after week 12 if it was feasible and the tumor was in a select site (extremity, dome of the bladder, trunk).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('D9803', 'Var', (0, 5))	('tumor', 'Disease', (50, 55))
2508	24361229	Only 20% of all Group III patients in D9803 underwent delayed primary excision, the response rate at week 12 was similar between patients who did and did not have a delayed primary excision, and the local failure rate with this strategy was similar to that of IRS-IV.	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (26, 34))	('local failure', 'Disease', (199, 212))	('local failure', 'Disease', 'MESH:D012594', (199, 212))	('D9803', 'Var', (38, 43))
2515	21106507	To determine the effect of CAV1 on the migratory and invasive capabilities of ESFT cells, we knocked down CAV1 expression in TC252 and A673 cells by stably transfecting a previously validated shRNA construct.	('TC252', 'CellLine', 'CVCL:S866', (125, 130))	('CAV1', 'Gene', (106, 110))	('knocked', 'Var', (93, 100))
2517	21106507	In contrast, animals injected with CAV1 knocked-down cells showed either no incidence of metastasis or developed lung metastases after a significant delay (P<0.0001).	('knocked-down', 'Var', (40, 52))	('developed', 'Reg', (103, 112))	('lung metastases', 'Disease', (113, 128))	('lung metastases', 'Disease', 'MESH:D009362', (113, 128))	('metastasis', 'CPA', (89, 99))	('CAV1', 'Gene', (35, 39))
2526	21106507	The EWS/FLI-1 fusion is required for Ewing's sarcoma oncogenesis, as inhibition of its function results in the loss of transformation of ESFT cells.	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('FLI-1', 'Gene', '2313', (8, 13))	('FLI-1', 'Gene', (8, 13))	("Ewing's sarcoma oncogenesis", 'Disease', 'MESH:C563168', (37, 64))	('loss of', 'NegReg', (111, 118))	('function', 'MPA', (87, 95))	("Ewing's sarcoma oncogenesis", 'Disease', (37, 64))	('inhibition', 'Var', (69, 79))	('ESFT', 'Disease', (137, 141))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (37, 52))
2538	21106507	To determine the effect of CAV1 on the migratory and invasive capabilities of ESFT cells, we knocked down CAV1 expression in TC252 and A673 cells (Fig.	('TC252', 'CellLine', 'CVCL:S866', (125, 130))	('CAV1', 'Gene', (106, 110))	('knocked', 'Var', (93, 100))
2540	21106507	As the acquisition of an invasive phenotype by cancer cells is a critical step for tumor progression, we also examined the effects of CAV1 downregulation on the invasive ability of CAV1 knocked-down ESFT cells derived from both cell lines.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', (83, 88))	('cancer', 'Disease', (47, 53))	('CAV1', 'Gene', (181, 185))	('CAV1', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('knocked-down', 'Var', (186, 198))	('downregulation', 'NegReg', (139, 153))
2546	21106507	Interestingly, the band detected at 100 kDa corresponding to the pro-MMP9 precursor form that became active during the zymography, was found substantially decreased in all CAV1 knocked-down cell lines.	('MMP9', 'Gene', '4318', (69, 73))	('MMP9', 'Gene', (69, 73))	('knocked-down', 'Var', (177, 189))	('decreased', 'NegReg', (155, 164))	('CAV1', 'Gene', (172, 176))
2547	21106507	Furthermore, a faster migrating gelatinolytic form of MMP2, was present only in the control cells, but was undetectable in CAV1 knocked-down cells, suggesting that CAV1 expression is required for MMP9 production and MMP2 activation.	('CAV1', 'Gene', (123, 127))	('MMP2', 'Gene', '4313', (54, 58))	('MMP2', 'Gene', '4313', (216, 220))	('knocked-down', 'Var', (128, 140))	('MMP2', 'Gene', (54, 58))	('faster migrating gelatinolytic', 'MPA', (15, 45))	('MMP9', 'Gene', '4318', (196, 200))	('MMP9', 'Gene', (196, 200))	('MMP2', 'Gene', (216, 220))
2549	21106507	BiPS induced a significant reduction in the invasiveness of A673 and TC252 cells (Supplementary Fig.	('BiPS', 'Var', (0, 4))	('TC252', 'CellLine', 'CVCL:S866', (69, 74))	('invasiveness', 'CPA', (44, 56))	('TC252', 'Gene', (69, 74))	('reduction', 'NegReg', (27, 36))
2552	21106507	As shown in Figure 3C, only MMP9 mRNA was downregulated as a consequence of CAV1 knockdown, suggesting that CAV1 regulates MMP9 expression differently from the way it affects other MMPs.	('MMP9', 'Gene', '4318', (28, 32))	('MMP9', 'Gene', (28, 32))	('regulates', 'Reg', (113, 122))	('knockdown', 'Var', (81, 90))	('expression', 'MPA', (128, 138))	('MMP9', 'Gene', '4318', (123, 127))	('MMP9', 'Gene', (123, 127))
2570	21106507	In contrast, SPARC downregulation did not provoke a decrease of MMP9 suggesting that, SPARC knocked-down cells invaded better than CAV1 knocked-down cells in part because MMP9 was unaffected and thus remained active despite the low cellular levels of SPARC.	('knocked-down', 'Var', (92, 104))	('invaded', 'CPA', (111, 118))	('MMP9', 'Gene', (64, 68))	('SPARC', 'Gene', (86, 91))	('MMP9', 'Gene', '4318', (64, 68))	('MMP9', 'Gene', '4318', (171, 175))	('MMP9', 'Gene', (171, 175))
2579	21106507	Intriguingly, CAV1 knockdown induced the downregulation of MMP9 but not MMP2 or TIMP2.	('MMP9', 'Gene', '4318', (59, 63))	('MMP9', 'Gene', (59, 63))	('TIMP2', 'Gene', '7077', (80, 85))	('knockdown', 'Var', (19, 28))	('MMP2', 'Gene', (72, 76))	('TIMP2', 'Gene', (80, 85))	('CAV1', 'Gene', (14, 18))	('downregulation', 'NegReg', (41, 55))	('MMP2', 'Gene', '4313', (72, 76))
2592	21106507	Similar to MMP9, SPARC mRNA was affected by CAV1 knockdown suggesting that in ESFT expression of both genes might be regulated by CAV1.	('knockdown', 'Var', (49, 58))	('MMP9', 'Gene', (11, 15))	('MMP9', 'Gene', '4318', (11, 15))	('expression', 'MPA', (83, 93))	('affected', 'Reg', (32, 40))
2595	21106507	Zymography analysis showed that as in CAV1 knockdown cells MMP2 activity was reduced as a consequence of SPARC knockdown, in contrast, MMP9 production was unaffected explaining why SPARC knockdown did not induced the same level of invasive inhibition than CAV1 knockdown.	('SPARC', 'Gene', (105, 110))	('MMP2', 'Gene', (59, 63))	('knockdown', 'Var', (111, 120))	('MMP9', 'Gene', '4318', (135, 139))	('MMP9', 'Gene', (135, 139))	('activity', 'MPA', (64, 72))	('reduced', 'NegReg', (77, 84))	('MMP2', 'Gene', '4313', (59, 63))
2668	21977086	In Ewing's sarcoma, the most consistent finding in immunohistochemistry is positivity for vimentin.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (3, 18))	('vimentin', 'Gene', '7431', (90, 98))	("Ewing's sarcoma", 'Disease', (3, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('vimentin', 'Gene', (90, 98))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (3, 18))	('positivity', 'Var', (75, 85))
2690	33926503	URL of Trial registry record: https://clinicaltrials.gov/ct2/show/NCT02948088?term=NCT02948088&draw=2.	('ct2', 'Gene', '386757', (57, 60))	('term=NCT02948088', 'Var', (78, 94))	('ct2', 'Gene', (57, 60))
2693	33926503	From the molecular point of view, both subtypes usually share the presence of a fusion involving the colony stimulating factor (CSF) gene, which drives tumor growth.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('colony stimulating factor', 'Gene', (101, 126))	('CSF', 'Gene', '1437', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('drives', 'PosReg', (145, 151))	('fusion', 'Var', (80, 86))	('colony stimulating factor', 'Gene', '1437', (101, 126))	('CSF', 'Gene', (128, 131))
2797	33926503	In a like manner, this suggests that dt-TGCT increases social costs.	('social costs', 'CPA', (55, 67))	('dt-TGCT', 'Chemical', '-', (37, 44))	('dt-TGCT', 'Var', (37, 44))	('increases', 'PosReg', (45, 54))
2801	33926503	In addition, patients referred to such sarcoma centers are generally more impaired by dt-TGCT, and the lack of patients treated in non-specialized centers could give an overestimation of the disease burden and healthcare utilization.	('dt-TGCT', 'Var', (86, 93))	('impaired', 'NegReg', (74, 82))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('patients', 'Species', '9606', (13, 21))	('dt-TGCT', 'Chemical', '-', (86, 93))	('sarcoma', 'Disease', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('patients', 'Species', '9606', (111, 119))
2826	29691299	Both focal and arm-level copy number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high risk tumors.	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('copy number alterations', 'Var', (25, 48))	('loss', 'NegReg', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('gain', 'PosReg', (71, 75))
2827	29691299	Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a five-year event free survival of 20%.	('gain of 1q', 'Var', (32, 42))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('loss', 'NegReg', (17, 21))
2828	29691299	GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q=0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q=0.07).	('CDKN2A', 'Gene', '1029', (90, 96))	('CDKN2B', 'Gene', (101, 107))	('FGF1', 'Gene', '2246', (54, 58))	('amplification', 'Var', (37, 50))	('CDKN2B', 'Gene', '1030', (101, 107))	('FGF1', 'Gene', (54, 58))	('loss', 'NegReg', (82, 86))	('CDKN2A', 'Gene', (90, 96))
2830	29691299	A high-risk subset of patients whose tumors have copy number loss of 1p and gain of 1q was identified with only 20% survival.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('copy number loss of 1p', 'Var', (49, 71))	('patients', 'Species', '9606', (22, 30))	('gain of 1q', 'PosReg', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
2831	29691299	Oncogenic fusions are common in UDS and next generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers.	('UDS', 'Chemical', '-', (106, 109))	('UDS', 'Chemical', '-', (32, 35))	('children', 'Species', '9606', (92, 100))	('UDS', 'Disease', (32, 35))	('Oncogenic', 'Var', (0, 9))
2839	29691299	Previous Children's Oncology Group (COG) Ewing sarcoma protocols did not require confirmation of an EWSR1-FLI1 fusion or any of the less common recognized Ewing sarcoma variant fusions (e.g., fusion of EWSR1 with another ETS family member or involvement of FUS rather than EWSR1) for eligibility, and thus these studies likely enrolled some patients with Ewing-like or round cell undifferentiated sarcoma.	('variant', 'Var', (169, 176))	('EWSR1', 'Gene', '2130', (273, 278))	('patients', 'Species', '9606', (341, 349))	('involvement', 'Reg', (242, 253))	('enrolled', 'Reg', (327, 335))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (397, 404))	('EWSR1', 'Gene', '2130', (202, 207))	('Ewing sarcoma', 'Disease', (155, 168))	('FUS', 'Gene', '2521', (257, 260))	('EWSR1', 'Gene', (100, 105))	('Ewing sarcoma', 'Disease', (41, 54))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (380, 404))	('Children', 'Species', '9606', (9, 17))	('EWSR1', 'Gene', (273, 278))	('undifferentiated sarcoma', 'Disease', (380, 404))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('EWSR1', 'Gene', (202, 207))	('fusion', 'Var', (192, 198))	('Oncology', 'Phenotype', 'HP:0002664', (20, 28))	('Ewing-like', 'Disease', (355, 365))	('FLI1', 'Gene', (106, 110))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (155, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (41, 54))	('EWSR1', 'Gene', '2130', (100, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (41, 54))	('FUS', 'Gene', (257, 260))	('FLI1', 'Gene', '2313', (106, 110))
2845	29691299	Recently, BCOR-CCNB3 fusions and fusions of CIC with either DUX4 or its paralog DUX4L10 have been found in Ewing-like and undifferentiated round cell sarcomas.	('BCOR', 'Gene', '54880', (10, 14))	('found', 'Reg', (98, 103))	('CCNB3', 'Gene', (15, 20))	('DUX4L10', 'Gene', '440013', (80, 87))	('DUX4', 'Gene', (80, 84))	('fusions', 'Var', (21, 28))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('BCOR', 'Gene', (10, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))	('sarcomas', 'Disease', (150, 158))	('CIC', 'Gene', (44, 47))	('DUX4', 'Gene', '100288687', (80, 84))	('DUX4', 'Gene', (60, 64))	('DUX4L10', 'Gene', (80, 87))	('CCNB3', 'Gene', '85417', (15, 20))	('DUX4', 'Gene', '100288687', (60, 64))	('CIC', 'Gene', '23152', (44, 47))	('Ewing-like', 'Disease', (107, 117))	('fusions', 'Var', (33, 40))
2850	29691299	Although we report a favorable outcome for the majority of these patients, we also identify poor outcomes for those with copy number changes involving chromosome 1, and very frequent oncogenic fusions in the subset that were analyzed by next generation sequencing.	('oncogenic', 'CPA', (183, 192))	('copy number changes', 'Var', (121, 140))	('patients', 'Species', '9606', (65, 73))
2890	29691299	There was a non-statistically significant trend toward lower event free and overall survival in patients with spindle cell morphology (p>0.16, Figure 2D,E).	('overall', 'CPA', (76, 83))	('lower', 'NegReg', (55, 60))	('patients', 'Species', '9606', (96, 104))	('spindle cell morphology', 'Var', (110, 133))	('event free', 'MPA', (61, 71))
2892	29691299	Each of these alterations was more common in patients classified as intermediate or high risk: 1p loss occurred in one of nine (11%) low risk patients versus six of 23 (23%) high risk patients, 1q gain occurred in one of nine (11%) low risk patients versus seven of 23 (30%) high risk patients, gain of chromosome 2 occurred in one of nine (11%) low risk patients versus four of 23 (17%) high risk patients, and gain of chromosome 8 occurred in no low risk patients versus eight of 23 (35%) high risk patients.	('alterations', 'Var', (14, 25))	('patients', 'Species', '9606', (355, 363))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (501, 509))	('loss', 'NegReg', (98, 102))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (285, 293))	('gain', 'PosReg', (197, 201))	('patients', 'Species', '9606', (398, 406))	('patients', 'Species', '9606', (457, 465))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (241, 249))	('gain', 'PosReg', (295, 299))
2895	29691299	Similarly, patients with gain of 1q had worse event free survival (p=0.02) and overall survival (p=0.003) than those without (Figure 4B).	('gain', 'Var', (25, 29))	('overall survival', 'CPA', (79, 95))	('patients', 'Species', '9606', (11, 19))	('event free survival', 'CPA', (46, 65))	('worse', 'NegReg', (40, 45))
2897	29691299	While patients with gain of chromosome 8 had worse overall survival (p=0.04), there were no other associations with outcome in patients with gain of chromosomes 2 or 8 (Figure 4C,D).	('gain', 'Var', (20, 24))	('worse', 'NegReg', (45, 50))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (6, 14))	('overall survival', 'MPA', (51, 67))
2898	29691299	They included recurrent amplification of FGF1 on 5q31.3 (q=0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q=0.07).	('FGF1', 'Gene', (41, 45))	('loss', 'NegReg', (69, 73))	('CDKN2B', 'Gene', (88, 94))	('CDKN2A', 'Gene', (77, 83))	('CDKN2A', 'Gene', '1029', (77, 83))	('CDKN2B', 'Gene', '1030', (88, 94))	('FGF1', 'Gene', '2246', (41, 45))	('amplification', 'Var', (24, 37))
2904	29691299	Given the potential oncogenic fusions we identified using the CNA data, as well as recent published reports of other fusions identified in undifferentiated sarcomas, we turned to next generation sequencing approaches to more robustly investigate oncogenic fusions as well as point mutations/small indels that were not evaluable from the CNA data.	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (139, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('undifferentiated sarcomas', 'Disease', (139, 164))	('point mutations/small', 'Var', (275, 296))	('investigate', 'Reg', (234, 245))
2908	29691299	Four of the five patients whose tumors harbored BCOR-CCNB3 or CIC-DUX4 fusions were classified as intermediate or high risk and treated with ifosfamide, doxorubicin and radiation.	('CIC', 'Gene', (62, 65))	('fusions', 'Var', (71, 78))	('ifosfamide', 'Chemical', 'MESH:D007069', (141, 151))	('BCOR', 'Gene', '54880', (48, 52))	('CCNB3', 'Gene', (53, 58))	('DUX4', 'Gene', (66, 70))	('DUX4', 'Gene', '100288687', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('CIC', 'Gene', '23152', (62, 65))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('doxorubicin', 'Chemical', 'MESH:D004317', (153, 164))	('BCOR', 'Gene', (48, 52))	('CCNB3', 'Gene', '85417', (53, 58))
2911	29691299	Importantly, one patient with a 3.7 cm pelvic tumor harboring a BCOR-CCNB3 fusion that was completely resected was observed on the low risk arm without chemotherapy or radiation and is alive without disease recurrence eight years later.	('CCNB3', 'Gene', (69, 74))	('fusion', 'Var', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patient', 'Species', '9606', (17, 24))	('tumor', 'Disease', (46, 51))	('BCOR', 'Gene', (64, 68))	('CCNB3', 'Gene', '85417', (69, 74))	('pelvic tumor', 'Phenotype', 'HP:0031501', (39, 51))	('BCOR', 'Gene', '54880', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
2912	29691299	In addition to these 5 fusions, NGS analysis confirmed the COL1A1-PDGFB fusion in sample 4 suggested by the CNA analysis, and identified a KIAA1549-BRAF fusion common in pilocytic astrocytomas, and a SAMD5-SASH1 fusion associated with skull base chordoma in one case each (Table 2).	('chordoma', 'Phenotype', 'HP:0010762', (246, 254))	('SAMD5', 'Gene', '389432', (200, 205))	('COL1A1', 'Gene', (59, 65))	('associated', 'Reg', (219, 229))	('PDGFB', 'Gene', (66, 71))	('KIAA1549-BRAF', 'Disease', 'None', (139, 152))	('SASH1', 'Gene', '23328', (206, 211))	('chordoma', 'Disease', (246, 254))	('COL1A1', 'Gene', '1277', (59, 65))	('pilocytic astrocytomas', 'Disease', (170, 192))	('fusion', 'Var', (72, 78))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (170, 192))	('KIAA1549-BRAF', 'Disease', (139, 152))	('chordoma', 'Disease', 'MESH:D002817', (246, 254))	('PDGFB', 'Gene', '5155', (66, 71))	('SAMD5', 'Gene', (200, 205))	('SASH1', 'Gene', (206, 211))
2914	29691299	Interestingly, in a fusion-negative, undifferentiated sarcoma arising from the kidney (sample 31), WES identified an activating PDGFRA D842V mutation, a variant of uncertain significance in TP53 (A138V), and a DICER1 E1813D mutation that has been reported in anaplastic sarcoma of the kidney (Table 2).	('D842V', 'Mutation', 'rs121908585', (135, 140))	('E1813D', 'Var', (217, 223))	('D842V', 'Var', (135, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (270, 277))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (270, 291))	('DICER1', 'Gene', '23405', (210, 216))	('activating', 'PosReg', (117, 127))	('TP53', 'Gene', '7157', (190, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('A138V', 'Mutation', 'rs750600586', (196, 201))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (270, 291))	('DICER1', 'Gene', (210, 216))	('E1813D', 'Mutation', 'p.E1813D', (217, 223))	('sarcoma of the kidney', 'Disease', (270, 291))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (37, 61))	('PDGFRA', 'Gene', '5156', (128, 134))	('PDGFRA', 'Gene', (128, 134))	('TP53', 'Gene', (190, 194))	('undifferentiated sarcoma', 'Disease', (37, 61))
2915	29691299	In summary, while overall numbers are small, a large fraction (90%) of undifferentiated sarcoma samples subjected to next generation sequencing had either recognized oncogenic fusions or point mutations suggestive of a more specific diagnosis and, potentially, alternative therapeutic approaches.	('undifferentiated sarcoma', 'Disease', (71, 95))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (71, 95))	('point mutations', 'Var', (187, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
2927	29691299	This finding is similar to that reported in Ewing sarcoma in which a recurrent secondary unbalanced translocation der(16)t(1;16) is associated with gain of 1q material and poor outcome.	('Ewing sarcoma', 'Disease', (44, 57))	('der', 'Var', (114, 117))	('1q material', 'MPA', (156, 167))	('gain', 'PosReg', (148, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (44, 57))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (44, 57))
2928	29691299	In neuroblastoma, 1p loss is associated with high risk features and decreased event free survival.	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('decreased', 'NegReg', (68, 77))	('1p loss', 'Var', (18, 25))	('neuroblastoma', 'Disease', 'MESH:D009447', (3, 16))	('neuroblastoma', 'Disease', (3, 16))	('event', 'MPA', (78, 83))
2936	29691299	Interestingly, our GISTIC analysis finding focal, recurrent amplification of FGF1, suggests that FGF1-FGFR signaling may be important in undifferentiated sarcoma.	('FGF1', 'Gene', '2246', (97, 101))	('amplification', 'Var', (60, 73))	('FGF1', 'Gene', (97, 101))	('FGF1', 'Gene', '2246', (77, 81))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (137, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('FGF1', 'Gene', (77, 81))	('undifferentiated sarcoma', 'Disease', (137, 161))
2938	29691299	Of ten cases analyzed, next generation sequencing suggested a more specific diagnosis in seven: one with DFSP, three with BCOR-CCNB3 sarcoma, two with CIC-DUX4 sarcoma, and one with a DICER1 mutation found in anaplastic sarcoma of the kidney.	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('BCOR', 'Gene', (122, 126))	('sarcoma', 'Disease', 'MESH:D012509', (220, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('sarcoma', 'Disease', (133, 140))	('CIC-DUX4 sarcoma', 'Disease', (151, 167))	('CCNB3', 'Gene', (127, 132))	('sarcoma', 'Disease', (220, 227))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (220, 241))	('DICER1', 'Gene', '23405', (184, 190))	('mutation', 'Var', (191, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('DICER1', 'Gene', (184, 190))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (220, 241))	('DFSP', 'Disease', 'MESH:D018223', (105, 109))	('CIC-DUX4 sarcoma', 'Disease', 'MESH:D012509', (151, 167))	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('CCNB3', 'Gene', '85417', (127, 132))	('sarcoma', 'Disease', (160, 167))	('sarcoma of the kidney', 'Disease', (220, 241))	('BCOR', 'Gene', '54880', (122, 126))	('DFSP', 'Disease', (105, 109))
2940	29691299	Recent reports of other BRAF fusions in pediatric spindle cell sarcomas suggest that this was not an isolated finding.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('fusions', 'Var', (29, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcomas', 'Disease', (63, 71))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('sarcomas', 'Disease', 'MESH:D012509', (63, 71))
2941	29691299	While we cannot definitively consider these false positives, these data highlight the need for complimentary methods to both identify and confirm potential fusions especially as the unconfirmed NTRK3 fusions would have been considered highly actionable.	('NTRK3', 'Gene', '4916', (194, 199))	('NTRK3', 'Gene', (194, 199))	('fusions', 'Var', (156, 163))
2942	29691299	Next generation sequencing identified potentially targetable molecular alterations in three cases which could guide therapeutic choices for primary treatment or in the event of future tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('alterations', 'Var', (71, 82))	('tumor', 'Disease', (184, 189))	('guide', 'Reg', (110, 115))
2943	29691299	The patient with undifferentiated sarcoma harboring a COL1A1-PDGFB fusion, characteristic of DFSP, died after bony recurrence of her tumor as previously described.	('undifferentiated sarcoma', 'Disease', (17, 41))	('PDGFB', 'Gene', '5155', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('COL1A1', 'Gene', '1277', (54, 60))	('COL1A1', 'Gene', (54, 60))	('PDGFB', 'Gene', (61, 66))	('tumor', 'Disease', (133, 138))	('DFSP', 'Disease', (93, 97))	('DFSP', 'Disease', 'MESH:D018223', (93, 97))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (17, 41))	('fusion', 'Var', (67, 73))
2947	29691299	Finally, the renal tumor harboring a DICER1 mutation also was found to have an activating D842V mutation in PDGFRA.	('renal tumor', 'Disease', 'MESH:D007674', (13, 24))	('mutation', 'Var', (44, 52))	('activating', 'PosReg', (79, 89))	('D842V', 'Mutation', 'rs121908585', (90, 95))	('renal tumor', 'Disease', (13, 24))	('PDGFRA', 'Gene', '5156', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PDGFRA', 'Gene', (108, 114))	('D842V', 'Var', (90, 95))	('DICER1', 'Gene', (37, 43))	('DICER1', 'Gene', '23405', (37, 43))	('renal tumor', 'Phenotype', 'HP:0009726', (13, 24))
2949	29691299	However, preclinical studies demonstrate sensitivity to crenolanib, and a clinical trial of this agent in PDGFRA D842V mutant GIST is ongoing (NCT02847429), further illustrating that careful tumor profiling may uncover potentially useful targeted therapies.	('PDGFRA', 'Gene', '5156', (106, 112))	('D842V mutant', 'Var', (113, 125))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('D842V', 'Mutation', 'rs121908585', (113, 118))	('mutant', 'Var', (119, 125))	('crenolanib', 'Chemical', 'MESH:C577197', (56, 66))	('PDGFRA', 'Gene', (106, 112))
2950	29691299	Recent reports of exceptionally high response rates to TRK inhibitors across a diverse range of tumors harboring TRK fusions, including undifferentiated sarcoma, confirm the value of thorough genomic profiling of pediatric sarcomas.	('fusions', 'Var', (117, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TRK', 'Gene', (113, 116))	('pediatric sarcomas', 'Disease', (213, 231))	('TRK', 'Gene', '4914', (113, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (213, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('TRK', 'Gene', (55, 58))	('TRK', 'Gene', '4914', (55, 58))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (136, 160))	('undifferentiated sarcoma', 'Disease', (136, 160))
2951	29691299	Further, since DICER1 and other mutations found in sarcomas may occur in the germline, thorough genomic characterization of tumors may uncover underlying cancer predisposition syndromes.	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Disease', (51, 59))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (124, 130))	('DICER1', 'Gene', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DICER1', 'Gene', '23405', (15, 21))
2975	30305054	Some studies have reported recurrent activating mutations in angiogenesis signaling genes, especially VEGF receptors, and in other genes encoding proteins associated with regulation of VEGF receptors, such as PTPRB and PLCG1.	('VEGF', 'Gene', '7422', (102, 106))	('PLCG1', 'Gene', (219, 224))	('PLCG1', 'Gene', '5335', (219, 224))	('PTPRB', 'Gene', '5787', (209, 214))	('VEGF', 'Gene', '7422', (185, 189))	('PTPRB', 'Gene', (209, 214))	('VEGF', 'Gene', (102, 106))	('angiogenesis signaling genes', 'Gene', (61, 89))	('activating', 'PosReg', (37, 47))	('mutations', 'Var', (48, 57))	('VEGF', 'Gene', (185, 189))
2976	30305054	In vitro, blockade of the VEGF pathway inhibits tumor growth by decreasing proliferation and increasing apoptosis in tumor cell.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (117, 122))	('inhibits', 'NegReg', (39, 47))	('decreasing', 'NegReg', (64, 74))	('blockade', 'Var', (10, 18))	('VEGF', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('apoptosis', 'CPA', (104, 113))	('increasing', 'PosReg', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('VEGF', 'Gene', '7422', (26, 30))
3038	30305054	Low level of circulating VEGF-C was associated with poor outcome (Table 3).	('Low level', 'Var', (0, 9))	('VEGF-C', 'Gene', '7424', (25, 31))	('VEGF-C', 'Gene', (25, 31))
3129	28002805	Expression of PSMA in tumor neovasculature of high grade sarcomas including synovial sarcoma, rhabdomyosarcoma, undifferentiated sarcoma and MPNST PSMA (prostate specific membrane antigen) is physiologically expressed in normal prostate tissue.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (94, 110))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('PSMA', 'Gene', (147, 151))	('synovial sarcoma', 'Disease', 'MESH:D013584', (76, 92))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (94, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (76, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (112, 136))	('undifferentiated sarcoma', 'Disease', (112, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('MPNST', 'Var', (141, 146))	('PSMA', 'Gene', '2346', (14, 18))	('rhabdomyosarcoma', 'Disease', (94, 110))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('PSMA', 'Gene', (14, 18))	('tumor', 'Disease', (22, 27))	('synovial sarcoma', 'Disease', (76, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('PSMA', 'Gene', '2346', (147, 151))	('sarcomas', 'Disease', (57, 65))
3156	28002805	Analyzing only tumors with strong neovascular PSMA expression (labelling index 2), malignant tumors with a high PSMA expression were more frequent (39/599; 6.51%) compared to tumors of intermediate biological potential (3/148; 2.03%) and benign tumors (1/32; 3.13%) (p = 0.078, Fisher s exact test, malignant vs. intermediate/benign tumors).	('tumors', 'Disease', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('malignant tumors', 'Disease', 'MESH:D018198', (83, 99))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (333, 339))	('benign tumors', 'Disease', 'MESH:D009369', (326, 339))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PSMA', 'Gene', '2346', (112, 116))	('malignant tumors', 'Disease', (83, 99))	('tumors', 'Disease', (245, 251))	('tumors', 'Disease', (15, 21))	('benign tumors', 'Disease', 'MESH:D009369', (238, 251))	('tumors', 'Disease', 'MESH:D009369', (333, 339))	('PSMA', 'Gene', (112, 116))	('PSMA', 'Gene', '2346', (46, 50))	('tumors', 'Disease', (93, 99))	('benign tumors', 'Disease', (326, 339))	('high', 'Var', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('PSMA', 'Gene', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('benign tumors', 'Disease', (238, 251))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))
3199	28002805	The authors concluded that high PSMA expression increases uptake of BIND-014 in certain tumors, pointing towards a potential utility of PSMA expression as a predictive biomarker for responsiveness to BIND-014.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('increases', 'PosReg', (48, 57))	('PSMA', 'Gene', (136, 140))	('PSMA', 'Gene', '2346', (32, 36))	('high', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('uptake', 'MPA', (58, 64))	('PSMA', 'Gene', '2346', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('PSMA', 'Gene', (32, 36))
3314	20718987	Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis.	('apoptosis', 'CPA', (67, 76))	('STK10', 'Gene', (26, 31))	('TNK2', 'Gene', (36, 40))	('TNK2', 'Gene', '10188', (36, 40))	('increased', 'PosReg', (57, 66))	('knockdown', 'Var', (13, 22))
3319	20718987	Rearrangement of the EWS gene on chromosome 22q12 with an ETS gene family member is the underlying molecular genetic abnormality for Ewing's sarcoma.	('Rearrangement', 'Var', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (133, 148))	("Ewing's sarcoma", 'Disease', (133, 148))	('EWS', 'Gene', '2130', (21, 24))	('EWS', 'Gene', (21, 24))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (133, 148))
3321	20718987	This translocation can be further subdivided into two separate types, Type I and Type II, with Type I resulting from the translocation fusing EWS exon 7 to FLI-1 exon 6 and Type II resulting from the fusion of EWS exon 7 to FLI1 exon 5.	('EWS', 'Gene', '2130', (210, 213))	('EWS', 'Gene', (210, 213))	('FLI1', 'Gene', (224, 228))	('EWS', 'Gene', '2130', (142, 145))	('EWS', 'Gene', (142, 145))	('resulting from', 'Reg', (181, 195))	('FLI1', 'Gene', '2313', (224, 228))	('Type II', 'Disease', (173, 180))	('fusing', 'Var', (135, 141))	('Type II', 'Disease', (81, 88))	('FLI-1', 'Gene', '2313', (156, 161))	('Type II', 'Disease', 'MESH:D005776', (173, 180))	('FLI-1', 'Gene', (156, 161))	('Type II', 'Disease', 'MESH:D005776', (81, 88))	('resulting from', 'Reg', (102, 116))
3347	20718987	Cells were transfected with 16 nM of TNK2 and STK10 siRNA or non-silencing siRNAs in 6 well plates by reverse transfection as described above.	('TNK2', 'Gene', '10188', (37, 41))	('STK10', 'Var', (46, 51))	('TNK2', 'Gene', (37, 41))
3366	20718987	We confirmed the effects of silencing of STK10, TNK2, and PLK1 on growth and survival of Ewing's sarcoma cells by repeating the cell based assay in 384-well plates using a different lot of siRNA having the same sequences as the kinase library siRNA.	('TNK2', 'Gene', (48, 52))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (89, 104))	('TNK2', 'Gene', '10188', (48, 52))	("Ewing's sarcoma", 'Disease', (89, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('STK10', 'Gene', (41, 46))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (89, 104))	('silencing', 'Var', (28, 37))	('PLK1', 'Gene', (58, 62))
3367	20718987	Silencing of STK10, TNK2 and PLK1 by both siRNA sequences inhibited cell growth in the four Ewing's sarcoma cell lines as measured by cell number (Figure 3A).	('cell growth in', 'CPA', (68, 82))	('TNK2', 'Gene', '10188', (20, 24))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (92, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('PLK1', 'Gene', (29, 33))	('STK10', 'Gene', (13, 18))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (92, 107))	('inhibited', 'NegReg', (58, 67))	('TNK2', 'Gene', (20, 24))	('Silencing', 'Var', (0, 9))	("Ewing's sarcoma", 'Disease', (92, 107))
3369	20718987	The effect of STK10 and TNK2 knockdown on cell growth was very similar to the effect of PLK1 knockdown in these cells (Figure 3B).	('STK10', 'Gene', (14, 19))	('TNK2', 'Gene', '10188', (24, 28))	('TNK2', 'Gene', (24, 28))	('knockdown', 'Var', (29, 38))
3379	20718987	These data indicate that the knockdown of STK10 and TNK2 induce apoptosis of Ewing's sarcoma cells.	('TNK2', 'Gene', (52, 56))	('knockdown', 'Var', (29, 38))	('apoptosis', 'CPA', (64, 73))	('TNK2', 'Gene', '10188', (52, 56))	('STK10', 'Gene', (42, 47))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (77, 92))	("Ewing's sarcoma", 'Disease', (77, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (77, 92))
3380	20718987	Representative images from the cells treated with TNK2_6 siRNA show various apoptotic bodies associated with TNK2 silencing (Figure 5B).	('TNK2', 'Gene', (50, 54))	('TNK2', 'Gene', (109, 113))	('silencing', 'Var', (114, 123))	('TNK2', 'Gene', '10188', (50, 54))	('TNK2', 'Gene', '10188', (109, 113))	('apoptotic bodies', 'CPA', (76, 92))
3386	20718987	Similarly, anti-tumor activity of GSK1904529A, a small-molecule inhibitor of the insulin-like growth factor-I receptor tyrosine kinase was reported in Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (151, 166))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('GSK1904529A', 'Chemical', 'MESH:C000607695', (34, 45))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (151, 166))	('tyrosine kinase', 'Gene', (119, 134))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('GSK1904529A', 'Var', (34, 45))	('tumor', 'Disease', (16, 21))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (151, 166))	('tyrosine kinase', 'Gene', '7294', (119, 134))
3390	20718987	We developed robust siRNA-screening assays for four Ewing's sarcoma cell lines, TC-32, TC-71, SK-ES-1 and RD-ES and performed HT-RNAi screens to generate data on the growth inhibiting effect of targeting 572 kinases (Figure 1).	('targeting', 'Var', (194, 203))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (52, 67))	("Ewing's sarcoma", 'Disease', (52, 67))	('growth', 'CPA', (166, 172))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (52, 67))	('TC-71', 'CellLine', 'CVCL:2213', (87, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('TC-32', 'CellLine', 'CVCL:7151', (80, 85))	('SK-ES-1', 'CellLine', 'CVCL:0627', (94, 101))
3399	20718987	Our results show that MK-STYX knockdown reduces cell survival in Ewing's sarcoma cells.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (65, 80))	('cell survival', 'CPA', (48, 61))	("Ewing's sarcoma", 'Disease', (65, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (65, 80))	('knockdown', 'Var', (30, 39))	('reduces', 'NegReg', (40, 47))	('MK-STYX', 'Gene', (22, 29))	('MK-STYX', 'Gene', '51657', (22, 29))
3404	20718987	Interestingly, siRNAs against AURKB led to significant reduction in growth of type II cell lines (SK-ES-1 and RD-ES) while the type I cell lines (TC-32, TC-71 and the normal fibroblast cells lines remained unaffected.	('AURKB', 'Gene', (30, 35))	('reduction', 'NegReg', (55, 64))	('growth', 'MPA', (68, 74))	('TC-32', 'CellLine', 'CVCL:7151', (146, 151))	('siRNAs', 'Var', (15, 21))	('SK-ES-1', 'CellLine', 'CVCL:0627', (98, 105))	('AURKB', 'Gene', '9212', (30, 35))	('TC-71', 'CellLine', 'CVCL:2213', (153, 158))
3415	20718987	We confirmed that PLK1 knockdown led to increased cell death, but did not appear to be specific to Ewing's sarcoma cells as it was also a significant "hit" for normal fibroblasts (Figure 2D).	("Ewing's sarcoma", 'Disease', (99, 114))	('PLK1', 'Gene', (18, 22))	('cell death', 'CPA', (50, 60))	('knockdown', 'Var', (23, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (99, 114))	('increased', 'PosReg', (40, 49))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (99, 114))
3427	20718987	These observations are in accordance with our data, wherein we show that STK10 knockdown leads to increased apoptosis and cell death of Ewing's sarcoma cells.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (136, 151))	('cell death', 'CPA', (122, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('increased', 'PosReg', (98, 107))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (136, 151))	('STK10', 'Gene', (73, 78))	('knockdown', 'Var', (79, 88))	("Ewing's sarcoma", 'Disease', (136, 151))	('apoptosis', 'CPA', (108, 117))
3428	20718987	Although, there have been no previous reports discussing the role of STK10 in sarcomas, our results clearly demonstrate an important role for STK10 in growth and survival of Ewing's sarcoma cells.	('growth', 'CPA', (151, 157))	('sarcomas', 'Disease', (78, 86))	('survival', 'CPA', (162, 170))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (174, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('STK10', 'Var', (142, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (174, 189))	("Ewing's sarcoma", 'Disease', (174, 189))
3429	20718987	Next, we validated the results for TNK2 knockdown and similar to STK10, TNK2 also led to increased cell death and apoptosis.	('TNK2', 'Gene', (72, 76))	('TNK2', 'Gene', (35, 39))	('cell death', 'CPA', (99, 109))	('TNK2', 'Gene', '10188', (35, 39))	('knockdown', 'Var', (40, 49))	('TNK2', 'Gene', '10188', (72, 76))	('increased', 'PosReg', (89, 98))	('apoptosis', 'CPA', (114, 123))
3436	20718987	This is contrary to our observation in Ewing's sarcoma cells, wherein we showed that TNK2 knockdown is indeed responsible for causing cell death through apoptosis.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (39, 54))	('TNK2', 'Gene', '10188', (85, 89))	('knockdown', 'Var', (90, 99))	('cell death', 'CPA', (134, 144))	('TNK2', 'Gene', (85, 89))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (39, 54))	("Ewing's sarcoma", 'Disease', (39, 54))	('apoptosis', 'CPA', (153, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
3455	32110037	Both ES and pPNET show the same chromosomal translocations such as t(11;22)(q24;q12) and were included in the same category of ES family of tumors (ESFTs) by the World Health Organization Classification in 2002.	('ESFTs', 'Disease', 'MESH:D012512', (148, 153))	('ES', 'Disease', 'MESH:D012512', (127, 129))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('t(11', 'Var', (67, 71))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('ESFTs', 'Disease', (148, 153))	('pPNET', 'Phenotype', 'HP:0030067', (12, 17))	('ES', 'Phenotype', 'HP:0012254', (127, 129))	('ES', 'Phenotype', 'HP:0012254', (148, 150))	('ES', 'Disease', 'MESH:D012512', (148, 150))	('ES', 'Phenotype', 'HP:0012254', (5, 7))	('ES', 'Disease', 'MESH:D012512', (5, 7))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('pPNET', 'Gene', (12, 17))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (67, 84))
3474	32110037	While central PNETs are characterized by mutations of RASSF1A, NOTCH1 and, especially in neuroblastoma, c-MYC amplifications, ESFTs display different genetic changes, which render these lasts histologically and clinically very different from the firsts.	('mutations', 'Var', (41, 50))	('RASSF1A', 'Gene', '11186', (54, 61))	('neuroblastoma', 'Phenotype', 'HP:0003006', (89, 102))	('c-MYC', 'Gene', (104, 109))	('c-MYC', 'Gene', '4609', (104, 109))	('PNETs', 'Phenotype', 'HP:0030065', (14, 19))	('central PNETs', 'Disease', (6, 19))	('neuroblastoma', 'Disease', 'MESH:D009447', (89, 102))	('ESFTs', 'Disease', 'MESH:D012512', (126, 131))	('ES', 'Phenotype', 'HP:0012254', (126, 128))	('neuroblastoma', 'Disease', (89, 102))	('RASSF1A', 'Gene', (54, 61))	('NOTCH1', 'Gene', '4851', (63, 69))	('NOTCH1', 'Gene', (63, 69))	('ESFTs', 'Disease', (126, 131))
3476	32110037	Most commonly, this involves a rearrangement of the EWS and FLI1 genes (85%) or EWS and ERG genes (10%).	('EWS', 'Gene', (80, 83))	('rearrangement', 'Var', (31, 44))	('EWS', 'Gene', (52, 55))	('ERG', 'Gene', '2078', (88, 91))	('ERG', 'Gene', (88, 91))
3478	32110037	The fusion of EWS gene on 22q12 with the FLI1 gene on 11q24 results in a chimeric fusion transcript EWS-FLI1.	('EWS', 'Gene', (14, 17))	('results in', 'Reg', (60, 70))	('fusion', 'Var', (4, 10))	('chimeric fusion', 'MPA', (73, 88))	('EWS-FLI1', 'Gene', (100, 108))	('EWS-FLI1', 'Gene', '2130;2313', (100, 108))
3481	32110037	Moreover, overexpression of FLI1 is observed to promote self-renewal, repress Rb (retinoblastoma) protein, and induce BCL2 expression in erythroid cells with a corresponding enhancement of cell survival.	('retinoblastoma', 'Gene', (82, 96))	('expression', 'MPA', (123, 133))	('FLI1', 'Gene', (28, 32))	('repress', 'NegReg', (70, 77))	('cell survival', 'CPA', (189, 202))	('retinoblastoma', 'Phenotype', 'HP:0009919', (82, 96))	('overexpression', 'Var', (10, 24))	('Rb', 'Gene', '5925', (78, 80))	('BCL2', 'Gene', '596', (118, 122))	('induce', 'PosReg', (111, 117))	('enhancement', 'PosReg', (174, 185))	('self-renewal', 'CPA', (56, 68))	('promote', 'PosReg', (48, 55))	('BCL2', 'Gene', (118, 122))	('retinoblastoma', 'Gene', '5925', (82, 96))
3497	32110037	A pathognomonic genetic feature of ES is a chromosomal translocation generating a fusion protein (WS-FLI1) able to promote cell cycle, angiogenesis and metastasization.	('cell cycle', 'CPA', (123, 133))	('promote', 'PosReg', (115, 122))	('angiogenesis', 'CPA', (135, 147))	('ES', 'Phenotype', 'HP:0012254', (35, 37))	('ES', 'Disease', 'MESH:D012512', (35, 37))	('translocation', 'Var', (55, 68))	('chromosomal', 'Var', (43, 54))	('metastasization', 'CPA', (152, 167))
3503	32110037	Phosphorylation of IGFR subunits, after their dimerization, induces, through the downstream signaling proteins IR substrate (IRS), the activation of the phosphoinositide 3-kinase (PI3K) and MAPK pathway, thus resulting in the stimulation of cellular proliferation, cell motility and inhibition of apoptosis.	('apoptosis', 'CPA', (297, 306))	('induces', 'Reg', (60, 67))	('activation', 'PosReg', (135, 145))	('dimerization', 'MPA', (46, 58))	('stimulation', 'PosReg', (226, 237))	('Phosphorylation', 'Var', (0, 15))	('MAPK pathway', 'Pathway', (190, 202))	('IGFR', 'Gene', (19, 23))	('cell motility', 'CPA', (265, 278))	('cellular proliferation', 'CPA', (241, 263))	('IGFR', 'Gene', '3480', (19, 23))
3505	32110037	Starting from 1990, different preclinical trials demonstrated that IGF1 is expressed in ES carrying a t(11;22) translocation and that blocking the IGF-1 loop inhibits cell growth.	('inhibits', 'NegReg', (158, 166))	('IGF1', 'Gene', (67, 71))	('blocking', 'Var', (134, 142))	('cell growth', 'CPA', (167, 178))	('IGF1', 'Gene', '3479', (67, 71))	('IGF-1', 'Gene', (147, 152))	('IGF-1', 'Gene', '3479', (147, 152))	('ES', 'Phenotype', 'HP:0012254', (88, 90))	('ES', 'Disease', 'MESH:D012512', (88, 90))
3527	28332083	Meanwhile, beyond the targeting of mutated KIT and PDGFRA in gastrointestinal stromal tumours, emergent understanding of underlying molecular pathology has informed certain therapeutic strategies in rarer STS subtypes.	('mutated', 'Var', (35, 42))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (61, 93))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('PDGFRA', 'Gene', '5156', (51, 57))	('gastrointestinal stromal tumours', 'Disease', (61, 93))	('PDGFRA', 'Gene', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('KIT', 'Gene', (43, 46))
3530	28332083	Eribulin disrupts microtubule propagation, conferring anticancer effects that include suppression of cancer cell migration and invasion, induction of vascular remodelling and reversal of epithelial-mesenchymal transition.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('suppression', 'NegReg', (86, 97))	('cancer', 'Disease', (101, 107))	('vascular remodelling', 'CPA', (150, 170))	('cancer', 'Disease', (58, 64))	('microtubule propagation', 'MPA', (18, 41))	('invasion', 'CPA', (127, 135))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('epithelial-mesenchymal transition', 'CPA', (187, 220))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Eribulin', 'Var', (0, 8))	('disrupts', 'NegReg', (9, 17))
3540	28332083	The trial technically did not have sufficient statistical power to test for interaction between eribulin effect and histological subtype, but regulatory bodies and others have interpreted these results as demonstrating that eribulin has a survival benefit over dacarbazine in LPS only.	('eribulin', 'Var', (224, 232))	('LPS', 'Phenotype', 'HP:0012034', (276, 279))	('LPS', 'Disease', (276, 279))	('dacarbazine', 'Chemical', 'MESH:D003606', (261, 272))	('survival benefit', 'CPA', (239, 255))	('LPS', 'Disease', 'MESH:C536528', (276, 279))
3544	28332083	Following encouraging results from three non-comparative studies, the first randomised evidence of trabectedin efficacy in advanced STS was from a phase II study where patients with pre-treated L-sarcomas were randomly allocated to one of two different trabectedin schedules (1.5 mg/m2 over 24 h q3w vs. 0.58 mg/m2 over 2 h weekly for three consecutive weeks in a 4-week cycle).	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('1.5', 'Var', (276, 279))	('L-sarcomas', 'Disease', (194, 204))	('trabectedin', 'Chemical', 'MESH:D000077606', (99, 110))	('L-sarcomas', 'Disease', 'MESH:D012509', (194, 204))	('trabectedin', 'Chemical', 'MESH:D000077606', (253, 264))	('patients', 'Species', '9606', (168, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (196, 204))
3546	28332083	The efficacy of trabectedin in translocation-associated sarcomas was established by a Japanese randomised phase II trial, where trabectedin (24-h infusion) conferred a large PFS benefit compared to best supportive care alone (median PFS 5.6 vs 0.9 m; HR 0.07; 95% CI 0.03-0.16; p < 0.0001) .	('benefit', 'PosReg', (178, 185))	('trabectedin', 'Chemical', 'MESH:D000077606', (128, 139))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('trabectedin', 'Chemical', 'MESH:D000077606', (16, 27))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('trabectedin', 'Var', (128, 139))	('sarcomas', 'Disease', (56, 64))
3560	28332083	Efforts to improve the efficacy of alkylating drugs in STS chemotherapy regimens whilst reducing ifosfamide-specific toxicities led to the development of palifosfamide, the active DNA-alkylating metabolite of ifosfamide.	('ifosfamide', 'Chemical', 'MESH:D007069', (209, 219))	('ifosfamide', 'Chemical', 'MESH:D007069', (157, 167))	('palifosfamide', 'Chemical', 'MESH:C027061', (154, 167))	('toxicities', 'Disease', (117, 127))	('ifosfamide', 'Chemical', 'MESH:D007069', (97, 107))	('toxicities', 'Disease', 'MESH:D064420', (117, 127))	('palifosfamide', 'Var', (154, 167))
3577	28332083	Despite protocol-mandated use of primary GCSF prophylaxis in the combination arm, higher rates of febrile neutropaenia were seen with doxorubicin-evofosfamide compared to doxorubicin alone (18.2 vs 11.0%), whilst greater levels of grade 3-4 fatigue, GI disturbance and nutritional disorder were also seen with combination treatment.	('febrile neutropaenia', 'Disease', 'MESH:D064147', (98, 118))	('GI disturbance and nutritional disorder', 'Disease', 'MESH:D009748', (250, 289))	('fatigue', 'Disease', (241, 248))	('GCSF', 'Gene', '1440', (41, 45))	('doxorubicin-evofosfamide', 'Var', (134, 158))	('doxorubicin', 'Chemical', 'MESH:D004317', (134, 145))	('fatigue', 'Phenotype', 'HP:0012378', (241, 248))	('doxorubicin', 'Chemical', 'MESH:D004317', (171, 182))	('febrile neutropaenia', 'Disease', (98, 118))	('evofosfamide', 'Chemical', 'MESH:C552526', (146, 158))	('GCSF', 'Gene', (41, 45))	('fatigue', 'Disease', 'MESH:D005221', (241, 248))
3627	28332083	One possibility is that variation in assessment of performance status and life expectancy within large international, multi-centre studies results in the enrolment of patients already experiencing an irreversible terminal decline.	('variation', 'Var', (24, 33))	('results in', 'Reg', (139, 149))	('patients', 'Species', '9606', (167, 175))
3628	28332083	Such a phenomenon is not however indicated by trial subgroup data, where little difference in treatment effect is reported between patients of PS 0 compared to those with PS 1 or 2.	('patients', 'Species', '9606', (131, 139))	('PS 0', 'Var', (143, 147))	('PS 1', 'Gene', (171, 175))	('PS 1', 'Gene', '338399', (171, 175))
3649	27418340	In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity.	('IRS1', 'Gene', '3667', (38, 42))	('Akt', 'Gene', (100, 103))	('IRS1', 'Gene', (38, 42))	('increased IGF1R', 'Phenotype', 'HP:0030269', (115, 130))	('inhibition', 'Var', (44, 54))	('IGF1R', 'Gene', '3480', (125, 130))	('increased', 'PosReg', (115, 124))	('IGF1R', 'Gene', '3480', (58, 63))	('Akt', 'Gene', '207', (100, 103))	('expression', 'MPA', (131, 141))	('IGF1R', 'Gene', (58, 63))	('IGF1R', 'Gene', (125, 130))	('decreased', 'NegReg', (75, 84))
3686	27418340	This illustrates that there is limited preclinical rationale for using IGF1R inhibitors for the treatment of chondrosarcoma of bone.	('chondrosarcoma of bone', 'Disease', 'MESH:D002813', (109, 131))	('inhibitors', 'Var', (77, 87))	('IGF1R', 'Gene', (71, 76))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (109, 123))	('IGF1R', 'Gene', '3480', (71, 76))	('chondrosarcoma of bone', 'Disease', (109, 131))	('rat', 'Species', '10116', (11, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('rat', 'Species', '10116', (51, 54))
3691	27418340	The conventional chondrosarcoma cell lines JJ012, SW1353 (ATCC), CH2879, OUMS27, L835 and CH3573, as well as the dedifferentiated chondrosarcoma cell lines L3252B, NDCS1, and L2975 were cultured in RPMI 1640 (Gibco, Invitrogen) supplemented with 1 % Glutamax (Gibco 35050, Invitrogen), 1 % penicillin/streptomycin (PS) (100U/mL) (Gibco, Invitrogen) and 10 % (JJ012, SW1353, CH2879, NDCS1, L2975) or 20 % (L835, L3252B, OUMS27, CH3573) heat-inactivated Fetal Bovine Serum (FBS) (F7524, Sigma-Aldrich).	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('L2975', 'CellLine', 'CVCL:D706', (175, 180))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (130, 144))	('chondrosarcoma cell', 'Disease', (17, 36))	('L3252B', 'Var', (156, 162))	('L2975', 'CellLine', 'CVCL:D706', (389, 394))	('L3252B', 'SUBSTITUTION', 'None', (156, 162))	('Bovine', 'Species', '9913', (458, 464))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (17, 31))	('SW1353', 'CellLine', 'CVCL:0543', (50, 56))	('chondrosarcoma cell', 'Disease', 'MESH:D002813', (130, 149))	('SW1353', 'CellLine', 'CVCL:0543', (366, 372))	('L835', 'Var', (405, 409))	('chondrosarcoma cell', 'Disease', (130, 149))	('PS', 'Chemical', '-', (315, 317))	('FBS', 'Disease', (472, 475))	('L3252B', 'Var', (411, 417))	('chondrosarcoma cell', 'Disease', 'MESH:D002813', (17, 36))	('FBS', 'Disease', 'MESH:D005198', (472, 475))	('L3252B', 'SUBSTITUTION', 'None', (411, 417))
3697	27418340	Rabbit antibodies against IGF1R (#3018), IR (#3025),IRS1 (#2382) and Phospho-S6 Ribosomal Protein (Ser235/236) (2 F9) (#4856) all diluted 1:1000, were obtained from Cell Signaling.	('IRS1', 'Gene', '3667', (52, 56))	('Ser235', 'Chemical', '-', (99, 105))	('IRS1', 'Gene', (52, 56))	('IGF1R', 'Gene', (26, 31))	('#3018', 'Var', (33, 38))	('IR', 'Gene', '3643', (52, 54))	('IR', 'Gene', '3643', (41, 43))	('IGF1R', 'Gene', '3480', (26, 31))	('#3025', 'Var', (45, 50))	('#2382', 'Var', (58, 63))	('Rabbit', 'Species', '9986', (0, 6))
3713	27418340	Because JJ012 and SW1353 are relatively more sensitive to doxorubicin, JJ012 and SW1353 were treated with 0, 1 nM, 10 nM or 100 nM while CH2879 and OUMS27 were treated with 0, 10 nM, 50 nM and 100 nM doxorubicin.	('SW1353', 'CellLine', 'CVCL:0543', (18, 24))	('doxorubicin', 'Chemical', 'MESH:D004317', (200, 211))	('JJ012', 'Var', (71, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (58, 69))	('SW1353', 'Var', (81, 87))	('SW1353', 'CellLine', 'CVCL:0543', (81, 87))	('sensitive', 'MPA', (45, 54))
3720	27418340	The specificities of two IGF1R antibodies (#3018 and #3027, Cell Signaling) were compared by western blot (as described above) and immunohistochemistry on colon tissue (as described in).	('IGF1R', 'Gene', '3480', (25, 30))	('IGF1R', 'Gene', (25, 30))	('#3018', 'Var', (43, 48))
3729	27418340	Immunoprecipitation for IRS1 followed by western blot analyses with a phospo-IRS1 antibody revealed the presence of phosphorylated IRS1 in JJ012 and SW1353, but not in CH2879 (Fig.	('IRS1', 'Gene', '3667', (24, 28))	('IRS1', 'Gene', (24, 28))	('SW1353', 'CellLine', 'CVCL:0543', (149, 155))	('SW1353', 'Var', (149, 155))	('IRS1', 'Gene', '3667', (131, 135))	('IRS1', 'Gene', (77, 81))	('IRS1', 'Gene', (131, 135))	('IRS1', 'Gene', '3667', (77, 81))	('JJ012', 'Var', (139, 144))
3736	27418340	In addition, four chondrosarcoma cell lines and the Ewing sarcoma cell line were treated with two other IGF1R/IR inhibitors (NVP-ADW742 and GSK1838705A) to determine if alternative targeting showed similar effects on cell viability (Fig.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (18, 32))	('chondrosarcoma cell', 'Disease', 'MESH:D002813', (18, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('IGF1R', 'Gene', '3480', (104, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Ewing sarcoma', 'Disease', (52, 65))	('chondrosarcoma cell', 'Disease', (18, 37))	('GSK1838705A', 'Chemical', 'MESH:C546191', (140, 151))	('IR', 'Gene', '3643', (110, 112))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('GSK1838705A', 'Var', (140, 151))	('IGF1R', 'Gene', (104, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
3738	27418340	By adding OSI-906 to the upper chamber of the CIM plates (xCELLigence), we demonstrated that IGF1R signalling was not essential for the migration of JJ012, SW1353, CH2879 and OUMS27 (Fig.	('JJ012', 'Var', (149, 154))	('IGF1R', 'Gene', '3480', (93, 98))	('rat', 'Species', '10116', (139, 142))	('SW1353', 'CellLine', 'CVCL:0543', (156, 162))	('OSI-906', 'Chemical', 'MESH:C551528', (10, 17))	('SW1353', 'Var', (156, 162))	('rat', 'Species', '10116', (82, 85))	('IGF1R', 'Gene', (93, 98))
3750	27418340	To further study the difference in IGF1R expression between primary tumours and cell lines, we stained the primary tumours corresponding to the cell lines L835, CH2879, L3252B and L2975.	('primary tumours', 'Disease', 'MESH:D009369', (107, 122))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('L2975', 'Var', (180, 185))	('IGF1R', 'Gene', '3480', (35, 40))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('primary tumours', 'Disease', (60, 75))	('L3252B', 'Var', (169, 175))	('L2975', 'CellLine', 'CVCL:D706', (180, 185))	('L3252B', 'SUBSTITUTION', 'None', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('primary tumours', 'Disease', (107, 122))	('IGF1R', 'Gene', (35, 40))	('primary tumours', 'Disease', 'MESH:D009369', (60, 75))
3751	27418340	Strikingly, the primary tumours were either completely negative (L835, CH2879) or showed weak staining (L3252B, L2975) for IGF1R (Fig.	('L3252B', 'Var', (104, 110))	('L835', 'Var', (65, 69))	('primary tumours', 'Disease', (16, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('L3252B', 'SUBSTITUTION', 'None', (104, 110))	('L2975', 'Var', (112, 117))	('negative', 'NegReg', (55, 63))	('CH2879', 'Var', (71, 77))	('IGF1R', 'Gene', (123, 128))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('L2975', 'CellLine', 'CVCL:D706', (112, 117))	('primary tumours', 'Disease', 'MESH:D009369', (16, 31))	('IGF1R', 'Gene', '3480', (123, 128))
3781	27418340	Recently, aberrant expression of IGF pathway members was described in osteosarcomas and OSI-906, a dual inhibitor of the IGF1R and the IR, inhibited proliferation in 3 out of 4 osteosarcoma cell lines with IC50 values within the therapeutic range.	('IGF1R', 'Gene', '3480', (121, 126))	('IGF pathway', 'Gene', (33, 44))	('aberrant', 'Var', (10, 18))	('osteosarcoma', 'Disease', (70, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (70, 82))	('osteosarcomas', 'Phenotype', 'HP:0002669', (70, 83))	('IGF1R', 'Gene', (121, 126))	('osteosarcoma', 'Phenotype', 'HP:0002669', (177, 189))	('inhibited', 'NegReg', (139, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('proliferation', 'CPA', (149, 162))	('rat', 'Species', '10116', (156, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('osteosarcomas', 'Disease', 'MESH:D012516', (70, 83))	('osteosarcoma', 'Disease', (177, 189))	('osteosarcoma', 'Disease', 'MESH:D012516', (177, 189))	('OSI-906', 'Chemical', 'MESH:C551528', (88, 95))	('osteosarcomas', 'Disease', (70, 83))	('IR', 'Gene', '3643', (135, 137))
3783	27418340	one myxoid chondrosarcoma was included, which showed a small decrease in tumour size upon IGF1R inhibition.	('tumour', 'Disease', (73, 79))	('decrease', 'NegReg', (61, 69))	('IGF1R', 'Gene', '3480', (90, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('myxoid chondrosarcoma', 'Disease', (4, 25))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (11, 25))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('inhibition', 'Var', (96, 106))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (4, 25))	('IGF1R', 'Gene', (90, 95))
3805	26204295	On cytogenetic studies, these tumors have a t(7;16)(q34;p11) translocation.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('t(7;16)(q34;p11) translocation', 'Var', (44, 74))	('t(7;16)(q34;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
3820	26204295	Tumor signal homogeneity was classified subjectively on both T1- and T2-weighted images as:  "Hypointense" in areas where tumor had signal intensity less than adjacent muscles; "Isointense" in areas with signal intensity the same as muscles; Areas with signal intensity brighter than muscles but less bright than subcutaneous fat; Areas with signal intensity equal to fat.	('less', 'NegReg', (149, 153))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Isointense', 'Var', (178, 188))	('signal intensity', 'MPA', (132, 148))	('tumor', 'Disease', (122, 127))
3824	26204295	Tumors with peritumoral regions having T1 hypointense and T2 hyperintense signals were designated to exhibit peritumoral edema.	('tumor', 'Disease', (113, 118))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('edema', 'Phenotype', 'HP:0000969', (121, 126))	('T1 hypointense', 'Var', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('edema', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (16, 21))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('T2 hyperintense signals', 'Var', (58, 81))	('edema', 'Disease', 'MESH:D004487', (121, 126))
3825	26204295	Areas having T1 hyperintense signal and T2 hyperintense or T2 hypointense signal that did not suppress on fat-saturated images were characterized as internal hemorrhage.	('internal hemorrhage', 'Phenotype', 'HP:0011029', (149, 168))	('hemorrhage', 'Disease', 'MESH:D006470', (158, 168))	('T2 hypointense signal', 'Var', (59, 80))	('T1 hyperintense signal', 'Var', (13, 35))	('T2 hyperintense', 'Var', (40, 55))	('hemorrhage', 'Disease', (158, 168))
3865	26204295	Cytogenetic studies were performed in 5 tumors, all of which showed the characteristic t(7;16)(q34;p11) translocation.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('t(7;16)(q34;p11) translocation', 'Var', (87, 117))	('t(7;16)(q34;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (87, 103))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
3910	25610688	A Case of Acute Myeloid Leukemia (FAB M2) with Inversion 16 Who Presented with Pelvic Myeloid Sarcoma Acute leukemias are the most common childhood cancer in all age groups.	('Pelvic Myeloid Sarcoma', 'Disease', (79, 101))	('Acute leukemias', 'Phenotype', 'HP:0002488', (102, 117))	('Acute Myeloid Leukemia', 'Disease', 'MESH:D015470', (10, 32))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (10, 32))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (16, 32))	('Acute Myeloid Leukemia', 'Disease', (10, 32))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('Sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('leukemias', 'Disease', 'MESH:D007938', (108, 117))	('Leukemia', 'Phenotype', 'HP:0001909', (24, 32))	('Inversion', 'Var', (47, 56))	('leukemias', 'Phenotype', 'HP:0001909', (108, 117))	('Myeloid Sarcoma Acute', 'Phenotype', 'HP:0012324', (86, 107))	('FAB', 'Gene', '2187', (34, 37))	('cancer', 'Disease', (148, 154))	('FAB', 'Gene', (34, 37))	('Pelvic Myeloid Sarcoma', 'Disease', 'MESH:D023981', (79, 101))	('leukemias', 'Disease', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
3961	25610688	Inv(16) and t(16; 16) which are abnormalities of the 16th chromosome are seen in 7-8% of AML cases.	('AML', 'Disease', 'MESH:D015470', (89, 92))	('t(16; 16', 'Var', (12, 20))	('Inv', 'Gene', '27130', (0, 3))	('AML', 'Phenotype', 'HP:0004808', (89, 92))	('Inv', 'Gene', (0, 3))	('AML', 'Disease', (89, 92))
3982	21471610	These translocations are thought to happen early in carcinogenesis, promoting some of the processes that finally lead to the appearance of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('carcinogenesis', 'Disease', 'MESH:D063646', (52, 66))	('cancer', 'Disease', (139, 145))	('carcinogenesis', 'Disease', (52, 66))	('promoting', 'PosReg', (68, 77))	('translocations', 'Var', (6, 20))
3983	21471610	Single gene mutations in certain group of sarcomas encode proteins leading to tumor formation.	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Single gene mutations', 'Var', (0, 21))	('leading to', 'Reg', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('sarcomas encode proteins', 'Disease', (42, 66))	('sarcomas encode proteins', 'Disease', 'MESH:C564021', (42, 66))
3987	21471610	In this category of sarcomas, p53 inactivation seems to be an early and common event in carcinogenesis.	('carcinogenesis', 'Disease', (88, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('inactivation', 'Var', (34, 46))	('sarcomas', 'Disease', (20, 28))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
3996	21471610	Proteins that associate with CAV1 contain the canonical caveolin-1 binding domain, fxfxxxf or fxxxxfxxf (where f= Trp, Phe or Tyr).	('caveolin-1', 'Gene', (56, 66))	('Phe', 'Var', (119, 122))	('Phe', 'Chemical', 'MESH:D010649', (119, 122))	('Tyr', 'Var', (126, 129))	('caveolin-1', 'Gene', '857', (56, 66))	('Trp', 'Chemical', 'MESH:D014364', (114, 117))	('Proteins', 'Protein', (0, 8))	('Tyr', 'Chemical', 'MESH:D014443', (126, 129))
4011	21471610	However, all of the malignant mesenchymal tumors which are poorly differentiated and dedifferentiated, including leiomyosarcoma and liposarcoma, showed weak immunoreactivity or failed to stain with CAV1, suggesting that loss of CAV1 might be a necessary step towards a differentiation block typical of malignancy and visible in most soft tissue sarcomas.	('malignancy', 'Disease', (302, 312))	('soft tissue sarcomas', 'Disease', (333, 353))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('loss', 'Var', (220, 224))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (333, 353))	('liposarcoma', 'Phenotype', 'HP:0012034', (132, 143))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (333, 352))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (113, 127))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (333, 353))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (113, 127))	('liposarcoma', 'Disease', 'MESH:D008080', (132, 143))	('CAV1', 'Gene', (228, 232))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (345, 353))	('immunoreactivity', 'MPA', (157, 173))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('malignant mesenchymal tumors', 'Disease', 'MESH:C535700', (20, 48))	('malignancy', 'Disease', 'MESH:D009369', (302, 312))	('leiomyosarcoma', 'Disease', (113, 127))	('malignant mesenchymal tumors', 'Disease', (20, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (345, 352))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('liposarcoma', 'Disease', (132, 143))
2526	21471610	The EWS/FLI-1 fusion is required for Ewing's sarcoma oncogenesis, as inhibition of its function results in the loss of transformation of ESFT cells.	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('FLI-1', 'Gene', '2313', (8, 13))	('FLI-1', 'Gene', (8, 13))	("Ewing's sarcoma oncogenesis", 'Disease', 'MESH:C563168', (37, 64))	('loss of', 'NegReg', (111, 118))	('function', 'MPA', (87, 95))	("Ewing's sarcoma oncogenesis", 'Disease', (37, 64))	('inhibition', 'Var', (69, 79))	('ESFT', 'Disease', (137, 141))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (37, 52))
4017	21471610	CAV1 knockdown led to up-regulation of Snail and the concomitant loss of E-cadherin expression.	('Snail', 'Gene', (39, 44))	('loss', 'NegReg', (65, 69))	('E-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', '999', (73, 83))	('knockdown', 'Var', (5, 14))	('CAV1', 'Gene', (0, 4))	('up-regulation', 'PosReg', (22, 35))	('expression', 'MPA', (84, 94))	('Snail', 'Gene', '6615', (39, 44))
4018	21471610	Consistently, loss of CAV1 expression inhibited the anchorage-independent growth of EWS cells and markedly reduced the growth of Ewing's sarcoma cell-derived tumors in nude mice xenografts, indicating that CAV1 promotes the malignant phenotype in Ewing's sarcoma carcinogenesis.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('reduced', 'NegReg', (107, 114))	("Ewing's sarcoma carcinogenesis", 'Disease', (247, 277))	('nude mice', 'Species', '10090', (168, 177))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('promotes', 'PosReg', (211, 219))	('tumors', 'Disease', (158, 164))	('loss', 'Var', (14, 18))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (129, 144))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (247, 262))	("Ewing's sarcoma carcinogenesis", 'Disease', 'MESH:C563168', (247, 277))	('anchorage-independent growth', 'CPA', (52, 80))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (129, 144))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (247, 262))	('CAV1', 'Gene', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	("Ewing's sarcoma", 'Disease', (129, 144))	('growth', 'MPA', (119, 125))	('inhibited', 'NegReg', (38, 47))
4022	21471610	CAV1 knockdown in ESFT cells led to decreased phospho-PKCalpha levels and a concomitant sensitization to apoptosis, which were reversed by CAV1 re-expression.	('apoptosis', 'CPA', (105, 114))	('knockdown', 'Var', (5, 14))	('CAV1', 'Gene', (0, 4))	('PKCalpha', 'Gene', '5578', (54, 62))	('PKCalpha', 'Gene', (54, 62))	('sensitization', 'Reg', (88, 101))	('decreased', 'NegReg', (36, 45))
4042	21471610	Alveolar rhabdomyosarcoma is associated in the vast majority of cases with a specific balanced translocation involving chromosomes 2 and 13 [t] or, less commonly, 1 and 13 [t], each of which encodes a novel fusion protein, PAX3/FOXO1 and PAX7/FOXO1, respectively.	('FOXO1', 'Gene', (228, 233))	('FOXO1', 'Gene', '2308', (228, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('FOXO1', 'Gene', '2308', (243, 248))	('balanced translocation', 'Var', (86, 108))	('PAX7', 'Gene', '5081', (238, 242))	('FOXO1', 'Gene', (243, 248))	('Alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (0, 25))	('Alveolar rhabdomyosarcoma', 'Disease', (0, 25))	('Alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (0, 25))	('PAX3', 'Gene', '5077', (223, 227))	('associated', 'Reg', (29, 39))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (9, 25))	('PAX3', 'Gene', (223, 227))	('PAX7', 'Gene', (238, 242))
4059	21471610	In fact, re-expression of CAV1 has successfully reduced the tumor growth of breast cancer cells and the invasive capability of pancreatic and breast cancer cells.	('re-expression', 'Var', (9, 22))	('CAV1', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('reduced', 'NegReg', (48, 55))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('pancreatic', 'Disease', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('pancreatic', 'Disease', 'MESH:D010195', (127, 137))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
4061	21471610	On the other hand, direct targeting of CAV1 using antisense and siRNA, or indirectly by chemical inhibition, or lowering cholesterol (disrupts caveolae) may result of great help in the cases where CAV1 acts as an oncogene.	('antisense', 'Var', (50, 59))	('CAV1', 'Gene', (39, 43))	('lowering', 'NegReg', (112, 120))	('cholesterol', 'MPA', (121, 132))	('lowering cholesterol', 'Phenotype', 'HP:0003146', (112, 132))	('caveolae', 'MPA', (143, 151))	('cholesterol', 'Chemical', 'MESH:D002784', (121, 132))
4062	21471610	Similar to prostate cancer and melanomas, our group successfully showed that targeting CAV1 with shRNAs reduced Ewing's sarcoma progression.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (112, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (11, 26))	('reduced', 'NegReg', (104, 111))	('melanomas', 'Disease', 'MESH:D008545', (31, 40))	('targeting', 'Var', (77, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (11, 26))	('prostate cancer', 'Disease', (11, 26))	('shRNAs', 'Gene', (97, 103))	('melanomas', 'Disease', (31, 40))	('CAV1', 'Gene', (87, 91))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (112, 127))	("Ewing's sarcoma", 'Disease', (112, 127))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
4068	21471610	These therapies may include humanized antibodies, small-molecule inhibitors and targeted siRNAs altogether with improved gene therapy delivery systems.	('human', 'Species', '9606', (28, 33))	('small-molecule', 'Var', (50, 64))	('siRNAs', 'Protein', (89, 95))
4087	21827676	Patients likely to have narrow resection margins, with high grade tumors, large tumor size, and an unfavorable location relative to the neuro-vascular bundles and bone are referred to radiation oncology and medical oncology for consideration of NR or NCR.	('oncology', 'Phenotype', 'HP:0002664', (215, 223))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Disease', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Patients', 'Species', '9606', (0, 8))	('high grade', 'Var', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('oncology', 'Phenotype', 'HP:0002664', (194, 202))
4135	21827676	Patients treated with NCR or NR were significantly more likely to have periosteal or nerve stripping performed compared to SA-treated patients (p = 0.01).	('patients', 'Species', '9606', (134, 142))	('Patients', 'Species', '9606', (0, 8))	('NCR', 'Var', (22, 25))	('periosteal', 'CPA', (71, 81))	('SA', 'Chemical', '-', (123, 125))
4161	21827676	Any-toxicity recorded was significantly higher among NCR-treated patients (21 of 39 patients, 54%) compared to NR-treated patients (10 of 37 patients, 27%; p = 0.02).	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('higher', 'PosReg', (40, 46))	('patients', 'Species', '9606', (84, 92))	('toxicity', 'Disease', (4, 12))	('NCR-treated', 'Var', (53, 64))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (141, 149))
4168	21827676	It also was higher among the NR-treated group compared to SA (p = 0.02).	('SA', 'Chemical', '-', (58, 60))	('NR-treated', 'Var', (29, 39))	('higher', 'PosReg', (12, 18))
4171	21827676	Significantly more limb-preservation patients who were treated with NCR and IOERT/perioperative brachytherapy had wound complications (16 of 30 patients, 53%) compared to NR-treated patients treated with IOERT/perioperative brachytherapy (11 of 25 patients, 44%, p = 0.009).	('limb-preservation', 'CPA', (19, 36))	('wound complications', 'CPA', (114, 133))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (144, 152))	('IOERT/perioperative', 'Var', (76, 95))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (248, 256))	('NCR', 'Var', (68, 71))
4237	32212796	Prieto-Granada et al., (2016) found that H3K27me3 immunohistochemistry has good sensitivity and robust specificity for the diagnosis of MPNST, while others noted loss of expression in other type of sarcomas too, which included radiation-associated angiosarcomas (Mentzel and Kiss, 2018) and dedifferentiated chondrosarcoma (Makise et al., 2019).	('sarcomas', 'Disease', (253, 261))	('MPNST', 'Disease', (136, 141))	('angiosarcomas', 'Disease', (248, 261))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (308, 322))	('MPNST', 'Phenotype', 'HP:0100697', (136, 141))	('sarcomas', 'Disease', 'MESH:D012509', (198, 206))	('sarcomas', 'Phenotype', 'HP:0100242', (253, 261))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('H3K27me3', 'Var', (41, 49))	('sarcomas', 'Disease', 'MESH:D012509', (253, 261))	('sarcomas', 'Phenotype', 'HP:0100242', (198, 206))	('angiosarcomas', 'Phenotype', 'HP:0200058', (248, 261))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('angiosarcomas', 'Disease', 'MESH:D006394', (248, 261))	('sarcoma', 'Phenotype', 'HP:0100242', (315, 322))	('chondrosarcoma', 'Disease', (308, 322))	('chondrosarcoma', 'Disease', 'MESH:D002813', (308, 322))	('sarcomas', 'Disease', (198, 206))
4287	32212796	Here, we could see the role of H3k27me3 in which it showed loss of its expression thus, it confirmed the diagnosis of MPNST especially when the molecular test is not available in the centre to demonstrate the presence of translocation t(X;18) in synovial sarcoma.	('synovial sarcoma', 'Disease', (246, 262))	('expression', 'MPA', (71, 81))	('MPNST', 'Phenotype', 'HP:0100697', (118, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('translocation t(X', 'Var', (221, 238))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (246, 262))	('synovial sarcoma', 'Disease', 'MESH:D013584', (246, 262))	('loss', 'NegReg', (59, 63))	('H3k27me3', 'Var', (31, 39))
4303	32212796	In MPNST, inactivation of polycomb repressive complex II (PRC2) promotes cell proliferation and tumor growth.	('PRC2', 'Gene', (58, 62))	('promotes', 'PosReg', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inactivation', 'Var', (10, 22))	('tumor', 'Disease', (96, 101))	('MPNST', 'Phenotype', 'HP:0100697', (3, 8))	('cell proliferation', 'CPA', (73, 91))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
4304	32212796	Many studies had shown that inactivation of the polycomb repressive complex 2 (PRC2), has recently been identified in 70-90% of malignant peripheral nerve sheath tumour (Lee et al., 2014; Prieto-Granada et al., 2016; Schaefer et al., 2016).	('malignant peripheral nerve sheath tumour', 'Disease', (128, 168))	('PRC2', 'Gene', (79, 83))	('identified', 'Reg', (104, 114))	('malignant peripheral nerve sheath tumour', 'Phenotype', 'HP:0100697', (128, 168))	('inactivation', 'Var', (28, 40))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('malignant peripheral nerve sheath tumour', 'Disease', 'MESH:D018319', (128, 168))
4353	32283684	In these studies, an array of sarcomas from multiple syngeneic mice were generated using MCA.	('sarcomas', 'Disease', (30, 38))	('MCA', 'Var', (89, 92))	('mice', 'Species', '10090', (63, 67))	('MCA', 'Chemical', 'MESH:D008748', (89, 92))	('sarcomas', 'Disease', 'MESH:D012509', (30, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
4368	32283684	Over time, as the cancer acquires additional mutations and as the immune system exerts a selective pressure eliminating immunogenic cells and leaving behind non-immunogenic cells, the cancer eventually fully escapes immune surveillance.	('cancer', 'Disease', (184, 190))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
4380	32283684	Adjustments made to IL-2 dose scheduling would largely combat acute toxicities, the most prominent being capillary leak syndrome and hypovolemia.	('IL-2', 'Gene', (20, 24))	('combat', 'NegReg', (55, 61))	('hypovolemia', 'Disease', 'MESH:D020896', (133, 144))	('Adjustments', 'Var', (0, 11))	('capillary leak syndrome', 'Disease', 'MESH:D019559', (105, 128))	('hypovolemia', 'Disease', (133, 144))	('toxicities', 'Disease', 'MESH:D064420', (68, 78))	('capillary leak', 'Phenotype', 'HP:0030005', (105, 119))	('capillary leak syndrome', 'Disease', (105, 128))	('hypovolemia', 'Phenotype', 'HP:0011106', (133, 144))	('toxicities', 'Disease', (68, 78))	('men', 'Species', '9606', (6, 9))	('IL-2', 'Gene', '3558', (20, 24))
4386	32283684	In support of these claims, phase 1 clinical trials utilizing recombinant IL-15 alone, and in conjunction with B-cell-depleting antibodies, are currently underway for treating both solid and liquid tumors, respectively [NCT01021059, NCT03759184].	('solid', 'Disease', (181, 186))	('[NCT01021059', 'Var', (219, 231))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('NCT03759184]', 'Var', (233, 245))	('tumors', 'Disease', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
4399	32283684	Upregulation of CTLA-4 on both CD4+ and CD8+ T lymphocytes was identified as a negative regulator of T-cell activation and effector functions, while murine models deficient in CTLA-4 experienced massive lymphoproliferation and tissue infiltration due to over-activation of resident T cells.	('Upregulation', 'PosReg', (0, 12))	('murine', 'Species', '10090', (149, 155))	('CTLA-4', 'Gene', (176, 182))	('CD8', 'Gene', '925', (40, 43))	('lymphoproliferation', 'CPA', (203, 222))	('over-activation', 'PosReg', (254, 269))	('CTLA-4', 'Gene', (16, 22))	('tissue infiltration', 'CPA', (227, 246))	('deficient', 'Var', (163, 172))	('CD8', 'Gene', (40, 43))
4401	32283684	Both orthotopic and pre-established tumor cells were rejected following administration of the anti-CTLA-4 antibody, indicating that blockade of inhibitory signals associated with the co-stimulatory pathway can enhance antitumor immunity.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('enhance', 'PosReg', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('inhibitory signals', 'MPA', (144, 162))	('blockade', 'Var', (132, 140))	('tumor', 'Disease', (36, 41))
4407	32283684	Engagement of PD-1 with its ligand prevented T-cell proliferation and cytokine production when synthetically stimulated, identifying it as an intrinsic inhibitory mechanism of autoreactive lymphocyte activation.	('T-cell proliferation', 'CPA', (45, 65))	('cytokine production', 'MPA', (70, 89))	('PD-1', 'Gene', (14, 18))	('prevented', 'NegReg', (35, 44))	('Engagement', 'Var', (0, 10))	('men', 'Species', '9606', (6, 9))
4411	32283684	Within the past 10 years, several high-profile trials employing anti-PD-1/PD-L1 mAbs under various conditions, dosing strategies, and cancer types, have indicated that blockade of this co-inhibitory pathway is both well-tolerated and associated with durable objective responses in patients.	('anti-PD-1/PD-L1', 'Gene', (64, 79))	('patients', 'Species', '9606', (281, 289))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('blockade', 'Var', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
4455	32283684	One such example is vaccination against the mucin 1 (MUC1) antigen in patients at high-risk of colorectal cancer.	('patients', 'Species', '9606', (70, 78))	('colorectal cancer', 'Disease', (95, 112))	('MUC1', 'Gene', (53, 57))	('mucin 1', 'Gene', (44, 51))	('MUC1', 'Gene', '4582', (53, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('mucin 1', 'Gene', '4582', (44, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('vaccination', 'Var', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
4466	32283684	T-VEC is an attenuated herpes simplex virus harboring various genetic deletions and insertions designed to enhance the antitumor immune response, such as the deletion of an immune-evasive viral gene ICP47 and the insertion of a human GM-CSF gene.	('tumor', 'Disease', (123, 128))	('GM-CSF gene', 'Gene', (234, 245))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('insertion', 'Var', (213, 222))	('herpes simplex', 'Phenotype', 'HP:0012302', (23, 37))	('enhance', 'PosReg', (107, 114))	('ICP47', 'Gene', (199, 204))	('deletion', 'Var', (158, 166))	('insertions', 'Var', (84, 94))	('human', 'Species', '9606', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
4467	32283684	Compared to GM-CSF administration alone, T-VEC led to a 4.4 month increase in median survival in a phase III trial in patients with advanced and metastatic melanoma.	('increase', 'PosReg', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('median survival', 'MPA', (78, 93))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('patients', 'Species', '9606', (118, 126))	('T-VEC', 'Var', (41, 46))
4486	32283684	Native TCRs are often limited by their ability to recognize post-translationally or aberrantly modified proteins, such as those observed in tumor-associated antigens of malignant cells.	('proteins', 'Protein', (104, 112))	('tumor', 'Disease', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('aberrantly modified', 'Var', (84, 103))
4527	32283684	The authors are supported, in part, by the Department of Defense Congressionally Directed Medical Research Programs (#W81XWH-17-1-0299, #W81XWH-19-1-0263, and #W81XWH-19-1-0067 to A.E.S.	('#W81XWH-17-1-0299', 'Var', (117, 134))	('men', 'Species', '9606', (49, 52))	('#W81XWH-19-1-0263', 'Var', (136, 153))	('#W81XWH-19-1-0067', 'Var', (159, 176))
4528	32105410	Role of miRNA-542-5p in the tumorigenesis of osteosarcoma Osteosarcoma, one of the most common malignant bone tumors, is characterized by a high rate of metastasis, and the survival rate of patients with metastatic osteosarcoma is poor.	('patients', 'Species', '9606', (190, 198))	('osteosarcoma', 'Disease', (45, 57))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('osteosarcoma', 'Phenotype', 'HP:0002669', (215, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumorigenesis', 'CPA', (28, 41))	('malignant bone tumors', 'Disease', (95, 116))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('bone tumors', 'Phenotype', 'HP:0010622', (105, 116))	('miRNA-542-5p', 'Var', (8, 20))	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('malignant bone tumors', 'Disease', 'MESH:D009369', (95, 116))	('osteosarcoma', 'Disease', (215, 227))	('osteosarcoma', 'Disease', 'MESH:D012516', (215, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('Osteosarcoma', 'Disease', (58, 70))	('Osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))
4534	32105410	Furthermore, we identified a total of 514 down-regulated genes as possible targets of miR-542-5p.	('down-regulated', 'NegReg', (42, 56))	('miR-542-5p', 'Chemical', '-', (86, 96))	('miR-542-5p', 'Var', (86, 96))
4535	32105410	Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the putative target genes of miR-542-5p were most enriched in the cell-cycle process.	('miR-542-5p', 'Chemical', '-', (114, 124))	('miR-542-5p', 'Var', (114, 124))	('cell-cycle process', 'CPA', (151, 169))
4537	32105410	Finally, transfection of the osteosarcoma cell line U2OS with miR-542-5p mimics or inhibitor revealed that miR-542-5p can promote cell proliferation.	('miR-542-5p', 'Var', (107, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('U2OS', 'CellLine', 'CVCL:0042', (52, 56))	('miR-542-5p', 'Chemical', '-', (62, 72))	('miR-542-5p', 'Chemical', '-', (107, 117))	('promote', 'PosReg', (122, 129))	('osteosarcoma', 'Disease', (29, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('cell proliferation', 'CPA', (130, 148))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))
4540	32105410	In this article, we observed that the expression of miR-542-5p was significantly increased in osteosarcoma compared with normal bones, and miR-542-5p promoted proliferation in osteosarcoma cells.	('miR-542-5p', 'Gene', (52, 62))	('miR-542-5p', 'Chemical', '-', (139, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (94, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('expression', 'MPA', (38, 48))	('miR-542-5p', 'Var', (139, 149))	('proliferation', 'CPA', (159, 172))	('osteosarcoma', 'Disease', (176, 188))	('promoted', 'PosReg', (150, 158))	('miR-542-5p', 'Chemical', '-', (52, 62))	('osteosarcoma', 'Disease', (94, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (176, 188))	('osteosarcoma', 'Disease', 'MESH:D012516', (176, 188))	('increased', 'PosReg', (81, 90))	('osteosarcoma', 'Disease', 'MESH:D012516', (94, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
4541	32105410	Therefore, miR-542-5p may be a promising biomarker in the early diagnosis of patients with osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('miR-542-5p', 'Var', (11, 21))	('miR-542-5p', 'Chemical', '-', (11, 21))	('patients', 'Species', '9606', (77, 85))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('osteosarcoma', 'Disease', (91, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (91, 103))
4550	32105410	In our study, data from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database demonstrated that miR-542-5p are significantly up-regulated in osteosarcoma tissues or cell lines compared with the normal bones.	('up-regulated', 'PosReg', (158, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('miR-542-5p', 'Chemical', '-', (129, 139))	('Cancer', 'Disease', (75, 81))	('osteosarcoma', 'Phenotype', 'HP:0002669', (174, 186))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (174, 186))	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('miR-542-5p', 'Var', (129, 139))	('osteosarcoma', 'Disease', (174, 186))
4552	32105410	Hence the objective of this work aimed to evaluate whether miR-542-5p could be a novel biomarker for the early diagnosis of osteosarcoma.	('miR-542-5p', 'Var', (59, 69))	('osteosarcoma', 'Disease', (124, 136))	('miR-542-5p', 'Chemical', '-', (59, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
4577	32105410	The overlapping genes were used for conducting biometric analysis to explore potential molecular mechanisms of miR-542-5p in osteosarcoma.	('miR-542-5p', 'Var', (111, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('miR-542-5p', 'Chemical', '-', (111, 121))	('osteosarcoma', 'Disease', (125, 137))	('osteosarcoma', 'Disease', 'MESH:D012516', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
4585	32105410	The sequences were as follows: miR-542-5p-mimic (5'-TCGGGGATCATCATGTCACGAGA-3'); miR-542-5p-inhibitor (5'-TCTCGTGACATGATGATCCCCGA-3').	('miR-542-5p-inhibitor', 'Var', (81, 101))	('miR-542-5p', 'Chemical', '-', (81, 91))	('miR-542-5p-mimic', 'Var', (31, 47))	('miR-542-5p', 'Chemical', '-', (31, 41))
4593	32105410	2, the expression profiling of miR-542-5p indicated that it was underexpressed in various human cancer types, such as kidney cancer, liver cancer and pancreatic adenocarcinoma.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (150, 175))	('liver cancer', 'Phenotype', 'HP:0002896', (133, 145))	('human', 'Species', '9606', (90, 95))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (150, 175))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('miR-542-5p', 'Var', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('miR-542-5p', 'Chemical', '-', (31, 41))	('cancer', 'Disease', (125, 131))	('pancreatic adenocarcinoma', 'Disease', (150, 175))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('kidney cancer', 'Disease', 'MESH:D007680', (118, 131))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('liver cancer', 'Disease', 'MESH:D006528', (133, 145))	('cancer', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('kidney cancer', 'Phenotype', 'HP:0009726', (118, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('kidney cancer', 'Disease', (118, 131))	('liver cancer', 'Disease', (133, 145))
4594	32105410	Therefore, miR-542-5p might act as tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-542-5p', 'Var', (11, 21))	('miR-542-5p', 'Chemical', '-', (11, 21))	('tumor', 'Disease', (35, 40))
4595	32105410	However, miR-542-5p could promote tumorigenesis in several cancers, including head and neck squamous cell carcinoma, skin cutaneous melanoma and thyroid carcinoma, of which miR-542-5p was found to be higher in the cancer samples than that in the normal one.	('promote', 'PosReg', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', (34, 39))	('cancer', 'Disease', (214, 220))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 140))	('neck squamous cell carcinoma', 'Disease', (87, 115))	('miR-542-5p', 'Var', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('skin cutaneous melanoma', 'Disease', (117, 140))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (87, 115))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (145, 162))	('miR-542-5p', 'Chemical', '-', (173, 183))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('thyroid carcinoma', 'Disease', (145, 162))	('cancers', 'Disease', (59, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (122, 140))	('higher', 'PosReg', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (145, 162))	('miR-542-5p', 'Var', (9, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('miR-542-5p', 'Chemical', '-', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancer', 'Disease', (59, 65))
4600	32105410	4A, the expression of miR-542-5p in osteosarcoma cell lines was significantly overexpressed compared with that of normal bones (P = 0.0297).	('miR-542-5p', 'Chemical', '-', (22, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('osteosarcoma', 'Phenotype', 'HP:0002669', (36, 48))	('miR-542-5p', 'Var', (22, 32))	('expression', 'MPA', (8, 18))	('overexpressed', 'PosReg', (78, 91))	('osteosarcoma', 'Disease', (36, 48))	('osteosarcoma', 'Disease', 'MESH:D012516', (36, 48))
4602	32105410	Furthermore, we explored the differential expression of miR-542-5p in patients with osteosarcoma and adjacent normal tissues based on the S-MED database.	('patients', 'Species', '9606', (70, 78))	('S-MED', 'Chemical', '-', (138, 143))	('miR-542-5p', 'Var', (56, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('miR-542-5p', 'Chemical', '-', (56, 66))	('osteosarcoma', 'Disease', (84, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))
4603	32105410	The database provided expression data for miR-542-5p in four bone-associated sarcomas (Fig.	('miR-542-5p', 'Var', (42, 52))	('miR-542-5p', 'Chemical', '-', (42, 52))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))
4605	32105410	The analysis indicated that miR-542-5p was significantly up-regulated in patients with osteosarcoma in comparison with normal bone and the other three bone-related sarcomas (Fig.	('miR-542-5p', 'Var', (28, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('miR-542-5p', 'Chemical', '-', (28, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('sarcomas', 'Disease', (164, 172))	('osteosarcoma', 'Disease', (87, 99))	('osteosarcoma', 'Disease', 'MESH:D012516', (87, 99))	('up-regulated', 'PosReg', (57, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('patients', 'Species', '9606', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('sarcomas', 'Disease', 'MESH:D012509', (164, 172))
4606	32105410	Therefore, the results mentioned earlier further demonstrated that miR-542-5p was overexpressed in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (99, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('miR-542-5p', 'Var', (67, 77))	('miR-542-5p', 'Chemical', '-', (67, 77))	('overexpressed', 'PosReg', (82, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (99, 111))	('osteosarcoma', 'Disease', (99, 111))
4608	32105410	Eventually, a total of 514 down-regulated genes (P < 0.05 and log2FC < -1) were selected as possible target genes of miR-542-5p.	('miR-542-5p', 'Var', (117, 127))	('miR-542-5p', 'Chemical', '-', (117, 127))	('down-regulated', 'NegReg', (27, 41))
4611	32105410	KEGG pathways analysis demonstrated that the target genes of miR-542-5p were most related to the regulation of cell cycle.	('miR-542-5p', 'Chemical', '-', (61, 71))	('miR-542-5p', 'Var', (61, 71))	('cell cycle', 'CPA', (111, 121))
4612	32105410	7) to explore the potential mechanisms of miR-542-5 in osteosarcoma, which might inspire new insights for targeted therapy.	('miR-542-5', 'Chemical', '-', (42, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('osteosarcoma', 'Disease', (55, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('miR-542-5', 'Var', (42, 51))
4614	32105410	Those 11 interactive hub genes may be the key target genes of miR-542-5p and involved in regulating signal mechanisms of miR-542-5p in osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('miR-542-5p', 'Var', (121, 131))	('miR-542-5p', 'Var', (62, 72))	('miR-542-5p', 'Chemical', '-', (62, 72))	('miR-542-5p', 'Chemical', '-', (121, 131))	('osteosarcoma', 'Disease', (135, 147))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('osteosarcoma', 'Disease', 'MESH:D012516', (135, 147))
4615	32105410	We examined whether miR-542-5p mimic or inhibitor had impacts on osteosarcoma cell line U2OS by CCK-8 assay.	('impacts', 'Reg', (54, 61))	('miR-542-5p', 'Chemical', '-', (20, 30))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('CCK', 'Gene', (96, 99))	('U2OS', 'CellLine', 'CVCL:0042', (88, 92))	('miR-542-5p', 'Var', (20, 30))	('CCK', 'Gene', '885', (96, 99))
4616	32105410	The results indicated that overexpressed miR-542-5p promoted osteosarcoma cell proliferation (Fig.	('osteosarcoma', 'Disease', (61, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('miR-542-5p', 'Var', (41, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('miR-542-5p', 'Chemical', '-', (41, 51))	('promoted', 'PosReg', (52, 60))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))
4617	32105410	Whereas in the opposite way, down-regulation of miR-542-5p inhibited osteosarcoma cell proliferation (Fig.	('miR-542-5p', 'Var', (48, 58))	('down-regulation', 'NegReg', (29, 44))	('miR-542-5p', 'Chemical', '-', (48, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('inhibited', 'NegReg', (59, 68))	('osteosarcoma', 'Disease', (69, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (69, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
4626	32105410	miR-542-5p was selected as the potential candidate in regulating the tumorigenesis of osteosarcoma by overlapping three GEO datasets.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('miR-542-5p', 'Var', (0, 10))	('tumor', 'Disease', (69, 74))	('osteosarcoma', 'Disease', (86, 98))	('miR-542-5p', 'Chemical', '-', (0, 10))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('osteosarcoma', 'Disease', 'MESH:D012516', (86, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
4627	32105410	The differential expression analysis of osteosarcoma and normal specimens demonstrated that miR-542-5p may be a key diagnostic biomarker and potential therapeutic target in osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('miR-542-5p', 'Var', (92, 102))	('osteosarcoma', 'Disease', (173, 185))	('osteosarcoma', 'Disease', (40, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (173, 185))	('miR-542-5p', 'Chemical', '-', (92, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (40, 52))	('osteosarcoma', 'Disease', 'MESH:D012516', (173, 185))	('osteosarcoma', 'Disease', 'MESH:D012516', (40, 52))
4628	32105410	Several studies have described the functions of miR-542-5p in tumors such as lung cancer [29], breast cancer [30] and endometrial carcinosarcoma [31].	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('miR-542-5p', 'Var', (48, 58))	('endometrial carcinosarcoma', 'Disease', 'MESH:D002296', (118, 144))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (95, 108))	('endometrial carcinosarcoma', 'Phenotype', 'HP:0012114', (118, 144))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miR-542-5p', 'Chemical', '-', (48, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('tumors', 'Disease', (62, 68))	('endometrial carcinosarcoma', 'Disease', (118, 144))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('lung cancer', 'Disease', (77, 88))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
4629	32105410	However, the role of miR-542-5p in osteosarcoma remains unclear, and the mechanisms need further investigation.	('miR-542-5p', 'Var', (21, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (35, 47))	('miR-542-5p', 'Chemical', '-', (21, 31))	('osteosarcoma', 'Disease', (35, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (35, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
4630	32105410	We observed that the expression of miR-542-5p was significantly increased in osteosarcoma compared with the normal bones.	('osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('miR-542-5p', 'Var', (35, 45))	('expression', 'MPA', (21, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('miR-542-5p', 'Chemical', '-', (35, 45))	('increased', 'PosReg', (64, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('osteosarcoma', 'Disease', (77, 89))
4631	32105410	To better understand the molecular role of miR-542-5p in osteosarcoma, we investigated GO and KEGG pathway analyses to comprehensively analyze the molecular interactions between the target genes of miR-542-5p.	('osteosarcoma', 'Phenotype', 'HP:0002669', (57, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('osteosarcoma', 'Disease', 'MESH:D012516', (57, 69))	('miR-542-5p', 'Var', (198, 208))	('miR-542-5p', 'Chemical', '-', (198, 208))	('miR-542-5p', 'Chemical', '-', (43, 53))	('osteosarcoma', 'Disease', (57, 69))
4632	32105410	According to the GO analysis, the most directly related terms were cell cycle, mitosis, metabolic process and organelle fission, indicating that miR-542-5p might impact the development of osteosarcoma by participating in the earlier BPs.	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))	('osteosarcoma', 'Disease', (188, 200))	('mitosis', 'Disease', 'None', (79, 86))	('osteosarcoma', 'Disease', 'MESH:D012516', (188, 200))	('miR-542-5p', 'Var', (145, 155))	('miR-542-5p', 'Chemical', '-', (145, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('mitosis', 'Disease', (79, 86))	('impact', 'NegReg', (162, 168))	('development', 'CPA', (173, 184))
4634	32105410	Based on those earlier findings, we speculated that miR-542-5p participated in regulation of cell cycles.	('cell cycles', 'CPA', (93, 104))	('miR-542-5p', 'Chemical', '-', (52, 62))	('miR-542-5p', 'Var', (52, 62))	('participated', 'Reg', (63, 75))
4635	32105410	CDCA5, DNMT1, UNKL, HSPD1, KLC1, CBX2, RPMS17, LAMB1, SLC3A2, PARP12 and COMMD10 were selected as the hub genes, and elucidation of the function of these hub genes might provide new insights into the molecular mechanisms of miR-542-5p in osteosarcoma.	('KLC1', 'Gene', (27, 31))	('HSPD1', 'Gene', (20, 25))	('miR-542-5p', 'Var', (224, 234))	('SLC3A2', 'Gene', (54, 60))	('COMMD10', 'Gene', '51397', (73, 80))	('miR-542-5p', 'Chemical', '-', (224, 234))	('CDCA5', 'Gene', '113130', (0, 5))	('osteosarcoma', 'Phenotype', 'HP:0002669', (238, 250))	('PARP12', 'Gene', (62, 68))	('DNMT1', 'Gene', (7, 12))	('CBX2', 'Gene', '84733', (33, 37))	('UNKL', 'Gene', '64718', (14, 18))	('RPMS17', 'Gene', '51373', (39, 45))	('LAMB1', 'Gene', (47, 52))	('CBX2', 'Gene', (33, 37))	('CDCA5', 'Gene', (0, 5))	('KLC1', 'Gene', '3831', (27, 31))	('osteosarcoma', 'Disease', (238, 250))	('COMMD10', 'Gene', (73, 80))	('UNKL', 'Gene', (14, 18))	('osteosarcoma', 'Disease', 'MESH:D012516', (238, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('DNMT1', 'Gene', '1786', (7, 12))	('RPMS17', 'Gene', (39, 45))	('HSPD1', 'Gene', '3329', (20, 25))	('SLC3A2', 'Gene', '6520', (54, 60))	('PARP12', 'Gene', '64761', (62, 68))	('LAMB1', 'Gene', '3912', (47, 52))
4637	32105410	The results showed that miR-542-5p promoted proliferation in osteosarcoma cells, which is consistent with our previous informatics analysis.	('osteosarcoma', 'Disease', (61, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('miR-542-5p', 'Chemical', '-', (24, 34))	('promoted', 'PosReg', (35, 43))	('miR-542-5p', 'Var', (24, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))	('proliferation', 'CPA', (44, 57))
4639	32105410	We speculated that miR-542-5p may be promising for a new biomarker in the early diagnosis of patients with osteosarcoma based on current research.	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('osteosarcoma', 'Disease', (107, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('miR-542-5p', 'Var', (19, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('patients', 'Species', '9606', (93, 101))	('miR-542-5p', 'Chemical', '-', (19, 29))
4640	32105410	Further molecular mechanism investigation should be carried out to explore signal pathways associated with miR-542-5p in osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('miR-542-5p', 'Var', (107, 117))	('osteosarcoma', 'Phenotype', 'HP:0002669', (121, 133))	('miR-542-5p', 'Chemical', '-', (107, 117))	('osteosarcoma', 'Disease', (121, 133))	('osteosarcoma', 'Disease', 'MESH:D012516', (121, 133))
4649	26855091	Doing so may worsen the prognosis of uterine sarcoma and confer the need for additional treatment.	('Doing', 'Var', (0, 5))	('sarcoma', 'Disease', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (37, 52))	('worsen', 'NegReg', (13, 19))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))
4723	28256570	Recurrent BCOR internal tandem duplication and BCOR or BCL6 expression distinguish primitive myxoid mesenchymal tumor of infancy from congenital infantile fibrosarcoma Primitive myxoid mesenchymal tumor of infancy is a rare sarcoma that preferentially affects infants.	('BCL6', 'Gene', (55, 59))	('BCOR', 'Gene', '54880', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('congenital infantile fibrosarcoma', 'Disease', (134, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('BCOR', 'Gene', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (112, 117))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (155, 167))	('BCL6', 'Gene', '604', (55, 59))	('BCOR', 'Gene', '54880', (47, 51))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (93, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('BCOR', 'Gene', (47, 51))	('myxoid mesenchymal tumor', 'Disease', (93, 117))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (178, 202))	('internal tandem duplication', 'Var', (15, 42))	('sarcoma', 'Disease', 'MESH:D012509', (224, 231))	('sarcoma', 'Disease', (224, 231))	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('myxoid mesenchymal tumor', 'Disease', (178, 202))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('sarcoma', 'Disease', (160, 167))	('infants', 'Species', '9606', (260, 267))	('congenital infantile fibrosarcoma', 'Disease', 'MESH:D005354', (134, 167))	('tumor', 'Disease', (197, 202))
4726	28256570	Internal tandem duplication of B-cell CLL/lymphoma 6 (BCL6)-interacting co-repressor (BCOR) exon 15 has recently been described in clear cell sarcoma of kidney, central nervous system high-grade neuroepithelial tumor with BCOR alteration, and primitive myxoid mesenchymal tumor of infancy.	('described', 'Reg', (118, 127))	('B-cell CLL/lymphoma', 'Phenotype', 'HP:0012191', (31, 50))	('BCL6', 'Gene', (54, 58))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (195, 216))	('lymphoma', 'Phenotype', 'HP:0002665', (42, 50))	('clear cell sarcoma of kidney', 'Phenotype', 'HP:0006770', (131, 159))	('neuroepithelial tumor', 'Disease', (195, 216))	('Internal tandem duplication', 'Var', (0, 27))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (253, 277))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('sarcoma of kidney', 'Phenotype', 'HP:0008663', (142, 159))	('BCOR', 'Gene', '54880', (222, 226))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (195, 216))	('myxoid mesenchymal tumor', 'Disease', (253, 277))	('BCL6', 'Gene', '604', (54, 58))	('BCOR', 'Gene', '54880', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('BCOR', 'Gene', (222, 226))	('B-cell CLL/lymphoma 6', 'Gene', (31, 52))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('BCOR', 'Gene', (86, 90))	('sarcoma of kidney', 'Disease', 'MESH:D007674', (142, 159))	('B-cell CLL/lymphoma 6', 'Gene', '604', (31, 52))	('sarcoma of kidney', 'Disease', (142, 159))
4738	28256570	have recently reported internal tandem duplication of the X-linked BCL6 corepressor (BCOR) gene (BCOR-internal tandem duplication) in 6 of the 7 primitive myxoid mesenchymal tumor of infancy cases examined.	('BCOR', 'Gene', (97, 101))	('BCL6', 'Gene', '604', (67, 71))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (155, 179))	('reported', 'Reg', (14, 22))	('myxoid mesenchymal tumor', 'Disease', (155, 179))	('BCOR', 'Gene', '54880', (97, 101))	('BCOR', 'Gene', (85, 89))	('BCL6', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('internal tandem duplication', 'Var', (23, 50))	('BCOR', 'Gene', '54880', (85, 89))
4768	28256570	Interphase fluorescence in situ hybridization analysis to detect ETV6 rearrangement, as seen in congenital infantile fibrosarcoma, was negative in all 5 primitive myxoid mesenchymal tumors of infancy cases (Table 1).	('fibrosarcoma', 'Phenotype', 'HP:0100244', (117, 129))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('myxoid mesenchymal tumors of infancy', 'Disease', (163, 199))	('ETV6', 'Gene', (65, 69))	('rearrangement', 'Var', (70, 83))	('ETV6', 'Gene', '2120', (65, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('congenital infantile fibrosarcoma', 'Disease', (96, 129))	('congenital infantile fibrosarcoma', 'Disease', 'MESH:D005354', (96, 129))	('myxoid mesenchymal tumors of infancy', 'Disease', 'MESH:C535700', (163, 199))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
4791	28256570	Five distinct types of in-frame BCOR-internal tandem duplication mutants with varying lengths of internal tandem duplication (in base pairs, bp) were identified in a cohort of clear cell sarcomas of kidney: type I, 96 bp (5 cases); type II, 93 bp (3 cases); type III, 90 bp (1 case); type IV, 87 bp (1 case); and type V, 114 bp (1 case), all located within the C-terminal coding region.	('clear cell sarcomas of kidney', 'Phenotype', 'HP:0006770', (176, 205))	('mutants', 'Var', (65, 72))	('BCOR', 'Gene', (32, 36))	('clear cell sarcomas of kidney', 'Disease', 'MESH:D018227', (176, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('clear cell sarcomas of kidney', 'Disease', (176, 205))	('BCOR', 'Gene', '54880', (32, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))
4795	28256570	The molecular characterization of a larger number of primitive myxoid mesenchymal tumors of infancy is required to establish the clinical, biological, and prognostic implications of BCOR gene alteration, and BCOR and BCL6 protein overexpression.	('myxoid mesenchymal tumors of infancy', 'Disease', (63, 99))	('BCL6', 'Gene', (217, 221))	('BCOR', 'Gene', '54880', (182, 186))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('overexpression', 'PosReg', (230, 244))	('alteration', 'Var', (192, 202))	('BCOR', 'Gene', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BCOR', 'Gene', '54880', (208, 212))	('BCL6', 'Gene', '604', (217, 221))	('myxoid mesenchymal tumors of infancy', 'Disease', 'MESH:C535700', (63, 99))	('BCOR', 'Gene', (182, 186))
4797	28256570	Central nervous system-high grade neuroepithelial tumors with BCOR alterations also share some histologic similarities with primitive myxoid mesenchymal tumor of infancy and clear cell sarcomas of kidney.	('sarcomas', 'Phenotype', 'HP:0100242', (185, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('myxoid mesenchymal tumor', 'Disease', (134, 158))	('BCOR', 'Gene', '54880', (62, 66))	('alterations', 'Var', (67, 78))	('neuroepithelial tumors', 'Disease', (34, 56))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (34, 56))	('clear cell sarcomas of kidney', 'Phenotype', 'HP:0006770', (174, 203))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (134, 158))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (34, 56))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (34, 55))	('clear cell sarcomas of kidney', 'Disease', 'MESH:D018227', (174, 203))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('clear cell sarcomas of kidney', 'Disease', (174, 203))	('BCOR', 'Gene', (62, 66))
4799	28256570	This is similar to the triad of extra-renal rhabdoid tumor of soft tissue, rhabdoid tumor of the kidney, and atypical teratoid rhabdoid tumor of the brain, which share similar morphologic features and, in almost all cases, a common genetic alteration affecting the SMARCB1 locus on the long arm of chromosome 22 that results in the loss of SMARCB1 (INI1) protein expression.	('tumor of the brain', 'Phenotype', 'HP:0030692', (136, 154))	('extra-renal rhabdoid tumor', 'Disease', 'MESH:D018335', (32, 58))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (127, 141))	('tumor of the kidney', 'Phenotype', 'HP:0009726', (84, 103))	('SMARCB1', 'Gene', '6598', (265, 272))	('SMARCB1', 'Gene', (265, 272))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (75, 89))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (44, 58))	('INI1', 'Gene', '6598', (349, 353))	('INI1', 'Gene', (349, 353))	('protein', 'Protein', (355, 362))	('alteration', 'Var', (240, 250))	('teratoid rhabdoid tumor', 'Disease', 'MESH:C000597569', (118, 141))	('extra-renal rhabdoid tumor', 'Disease', (32, 58))	('rhabdoid tumor', 'Disease', (75, 89))	('teratoid rhabdoid tumor', 'Disease', (118, 141))	('loss', 'NegReg', (332, 336))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('SMARCB1', 'Gene', '6598', (340, 347))	('SMARCB1', 'Gene', (340, 347))
4824	28249647	Almost all SS have a recurrent t(X;18) chromosomal translocation, resulting in the fusion of SS18 (at 18q11) with either SSX1 or SSX2 or rarely SSX4 (all on Xp11).	('SS18', 'Gene', (93, 97))	('SSX2', 'Gene', '6757', (129, 133))	('SS', 'Phenotype', 'HP:0100242', (144, 146))	('SSX2', 'Gene', (129, 133))	('SSX4', 'Gene', '6759', (144, 148))	('SS', 'Phenotype', 'HP:0100242', (121, 123))	('SSX4', 'Gene', (144, 148))	('SS', 'Phenotype', 'HP:0100242', (11, 13))	('SS18', 'Gene', '6760', (93, 97))	('SSX1', 'Gene', '6756', (121, 125))	('fusion', 'Var', (83, 89))	('SS', 'Phenotype', 'HP:0100242', (93, 95))	('SSX1', 'Gene', (121, 125))	('SS', 'Phenotype', 'HP:0100242', (129, 131))
4831	28249647	In cases where molecular testing was not done, unstained slides were obtained for FISH analysis of SS18 gene abnormalities, as previously described.	('SS18', 'Gene', '6760', (99, 103))	('SS18', 'Gene', (99, 103))	('abnormalities', 'Var', (109, 122))	('SS', 'Phenotype', 'HP:0100242', (99, 101))
5021	30999901	IHC for CD31, CD44, and CD68 was performed by a CLIA-certified laboratory (University Hospital, Minneapolis) using the antibodies JC70 (CD31) (Santa Cruz Biotechnology), DF1485 (CD44, Santa Cruz Biotechnology), and KP-1 (CD68) (Santa Cruz Biotechnology).	('CD68', 'Gene', (24, 28))	('CD68', 'Gene', '968', (24, 28))	('CD31', 'Gene', (8, 12))	('CD68', 'Gene', (221, 225))	('DF1485', 'Var', (170, 176))	('CD68', 'Gene', '968', (221, 225))	('CD31', 'Gene', (136, 140))	('CD31', 'Gene', '5175', (8, 12))	('CD44', 'Gene', '960', (178, 182))	('CD44', 'Gene', '960', (14, 18))	('CD44', 'Gene', (14, 18))	('CD31', 'Gene', '5175', (136, 140))	('CD44', 'Gene', (178, 182))
5024	30999901	For CD68, staining was scored at 100x magnification as the percent of cells, including stroma, that were positive: 0-5%, > 5-25%, > 25-50%, > 50-75%, or > 75%.	('CD68', 'Gene', '968', (4, 8))	('> 5-25%', 'Var', (121, 128))	('CD68', 'Gene', (4, 8))
5146	30999901	Overall, patients whose pre-treatment ALDH1 staining intensity was high had worse survival outcomes, and patients whose post-treatment ALDH1 staining intensity was high had increased tumor growth; however, these correlations were weak.	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (105, 113))	('ALDH1', 'Gene', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('ALDH1', 'Gene', '216', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('worse', 'NegReg', (76, 81))	('survival outcomes', 'CPA', (82, 99))	('ALDH1', 'Gene', '216', (135, 140))	('increased', 'PosReg', (173, 182))	('tumor', 'Disease', (183, 188))	('ALDH1', 'Gene', (38, 43))
5181	27803418	A contrast-enhanced CT scan revealed a perforation in the digestive tract, which was causing his abdominal pain, and he subsequently abdominal surgery.	('pain', 'Phenotype', 'HP:0012531', (107, 111))	('abdominal pain', 'Disease', 'MESH:D015746', (97, 111))	('perforation', 'Var', (39, 50))	('abdominal pain', 'Phenotype', 'HP:0002027', (97, 111))	('abdominal pain', 'Disease', (97, 111))	('causing', 'Reg', (85, 92))
5386	33482769	H3F3A encodes the replication-independent histone H3.3; 49 to 92% of patients with GCTB have mutations in H3F3A (typically G34W); chondroblastoma has been associated with mutations in H3F3B; other giant cell containing tumors had no or few mutations in either of these genes.	('H3F3A', 'Gene', '3020', (0, 5))	('H3F3A', 'Gene', (106, 111))	('H3F3B', 'Gene', '3021', (184, 189))	('chondroblastoma', 'Disease', (130, 145))	('H3F3B', 'Gene', (184, 189))	('patients', 'Species', '9606', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('H3F3A', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mutations', 'Var', (93, 102))	('tumors', 'Disease', (219, 225))	('associated', 'Reg', (155, 165))	('mutations', 'Var', (171, 180))	('H3F3A', 'Gene', '3020', (106, 111))	('chondroblastoma', 'Disease', 'MESH:D002804', (130, 145))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('G34W', 'Mutation', 'p.G34W', (123, 127))	('GCTB', 'Phenotype', 'HP:0011847', (83, 87))	('chondroblastoma', 'Phenotype', 'HP:0030432', (130, 145))
5388	33482769	Because of the high rate of H3F3A mutations in GCTB, patients negative for mutations should be suspected of having other bone tumor types and followed closely.	('H3F3A', 'Gene', '3020', (28, 33))	('patients', 'Species', '9606', (53, 61))	('GCTB', 'Gene', (47, 51))	('H3F3A', 'Gene', (28, 33))	('bone tumor', 'Disease', (121, 131))	('bone tumor', 'Phenotype', 'HP:0010622', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (34, 43))	('bone tumor', 'Disease', 'MESH:D001859', (121, 131))	('GCTB', 'Phenotype', 'HP:0011847', (47, 51))
5389	33482769	One case (Patient 13) showed MDM2 amplification in the malignant transformation but not in the initial GCTB diagnosis, suggesting a possible role of MDM2 amplification in the development of malignancy.	('MDM2', 'Gene', '4193', (29, 33))	('Patient', 'Species', '9606', (10, 17))	('MDM2', 'Gene', (29, 33))	('malignant transformation', 'CPA', (55, 79))	('malignancy', 'Disease', 'MESH:D009369', (190, 200))	('malignancy', 'Disease', (190, 200))	('GCTB', 'Phenotype', 'HP:0011847', (103, 107))	('amplification', 'Var', (34, 47))	('MDM2', 'Gene', '4193', (149, 153))	('MDM2', 'Gene', (149, 153))
5393	33482769	GCTB consists of stromal cells expressing RANKL and osteoclast-like giant cells expressing the RANK receptor, and signaling through the RANK receptor contributes to osteolysis and tumor growth.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('signaling', 'Var', (114, 123))	('contributes', 'Reg', (150, 161))	('osteolysis', 'Disease', 'MESH:D010014', (165, 175))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('GCTB', 'Phenotype', 'HP:0011847', (0, 4))	('tumor', 'Disease', (180, 185))	('osteolysis', 'Phenotype', 'HP:0002797', (165, 175))	('RANKL', 'Gene', '8600', (42, 47))	('RANKL', 'Gene', (42, 47))	('osteolysis', 'Disease', (165, 175))
5437	31807494	SARC 028 expansion cohort included further 30 patients each of pleomorphic undifferentiated sarcoma and liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('expansion', 'Var', (9, 18))	('pleomorphic undifferentiated sarcoma', 'Disease', 'MESH:D002277', (63, 99))	('patients', 'Species', '9606', (46, 54))	('liposarcoma', 'Phenotype', 'HP:0012034', (104, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('SARC 028', 'Gene', (0, 8))	('liposarcoma', 'Disease', (104, 115))	('pleomorphic undifferentiated sarcoma', 'Disease', (63, 99))	('liposarcoma', 'Disease', 'MESH:D008080', (104, 115))
5473	31428099	and Imai and Iwamoto reported that the K562 leukemia cell line genetically modified to express membrane-bound interleukin (IL)-15 and 4.1-BB ligand (K562-mb15-41BBL) specifically activates human NK cells, driving them into the cell cycle to generate highly cytotoxic NK cells.	('human NK cells', 'CPA', (189, 203))	('human', 'Species', '9606', (189, 194))	('cell cycle', 'CPA', (227, 237))	('rat', 'Species', '10116', (245, 248))	('K562-mb15-41BBL', 'Var', (149, 164))	('K562', 'CellLine', 'CVCL:0004', (149, 153))	('activates', 'PosReg', (179, 188))	('leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('leukemia', 'Disease', 'MESH:D007938', (44, 52))	('K562-mb15-41BBL', 'CellLine', 'CVCL:0004', (149, 164))	('K562', 'CellLine', 'CVCL:0004', (39, 43))	('leukemia', 'Disease', (44, 52))
5474	31428099	Furthermore, the K562-mb15-41BBL stimulation method has already been scaled up to large-scale clinical-grade conditions in accordance with good clinical manufacturing practice guidelines, for the production of large numbers of highly cytotoxic NKAE cells, and FDA-approved clinical trials are already underway in patients with hematologic cancers and childhood solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (367, 373))	('K562-mb15-41BBL', 'Var', (17, 32))	('solid tumors', 'Disease', 'MESH:D009369', (361, 373))	('hematologic cancers', 'Disease', (327, 346))	('hematologic cancers', 'Disease', 'MESH:D009369', (327, 346))	('cancers', 'Phenotype', 'HP:0002664', (339, 346))	('K562-mb15-41BBL', 'CellLine', 'CVCL:0004', (17, 32))	('solid tumors', 'Disease', (361, 373))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('patients', 'Species', '9606', (313, 321))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))
5475	31428099	Our team has leaded five clinical trials using adoptive NK cell immunotherapy in patients with pediatric refractory solid tumors (NCT01337544), relapsed or refractory acute leukemia/lymphoma (NCT01944982 and NCT02074657), acute myeloid leukemia (NCT02763475) or multiple myeloma (NCT02481934).	('multiple myeloma', 'Disease', 'MESH:D009101', (262, 278))	('acute myeloid leukemia', 'Disease', (222, 244))	('NCT01944982', 'Var', (192, 203))	('leukemia/lymphoma', 'Disease', (173, 190))	('NCT02074657', 'Var', (208, 219))	('NCT02481934', 'Var', (280, 291))	('solid tumors', 'Disease', (116, 128))	('multiple myeloma', 'Disease', (262, 278))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (222, 244))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))	('leukemia/lymphoma', 'Disease', 'MESH:D007938', (173, 190))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (222, 244))	('leukemia', 'Phenotype', 'HP:0001909', (236, 244))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (228, 244))	('NCT01337544', 'Var', (130, 141))	('relapsed', 'Disease', (144, 152))	('NCT02763475', 'Var', (246, 257))	('solid tumors', 'Disease', 'MESH:D009369', (116, 128))	('acute leukemia', 'Phenotype', 'HP:0002488', (167, 181))	('lymphoma', 'Phenotype', 'HP:0002665', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('multiple myeloma', 'Phenotype', 'HP:0006775', (262, 278))	('patients', 'Species', '9606', (81, 89))
5478	31428099	We present preclinical data showing the ability of NKAE cell therapy to kill sarcoma cells and of MDX1338 mAb to inhibit the migration and invasion of CXCR4+ sarcoma cells in vitro.	('invasion', 'CPA', (139, 147))	('migration', 'CPA', (125, 134))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('inhibit', 'NegReg', (113, 120))	('sarcoma', 'Disease', 'MESH:D012509', (158, 165))	('MDX1338', 'Var', (98, 105))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcoma', 'Disease', (158, 165))	('rat', 'Species', '10116', (128, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
5485	31428099	A4573 and CW9019 were kind gifts from Dr. Javier Alonso (Institute of Health Carlos III) and Dr. Josep Roma (Vall d'Hebron Research Institute), respectively.	('A4573', 'Var', (0, 5))	('CW9019', 'Var', (10, 16))	('Josep Roma', 'Disease', (97, 107))	('Josep Roma', 'Disease', 'None', (97, 107))	('CW9019', 'CellLine', 'CVCL:N820', (10, 16))
5491	31428099	NKAE cells were obtained by co-culturing donor's PBMCs with irradiated K562-mb15-41BBL cells in a 1:1.5 ratio plus 100 U/ml of IL-2 (Miltenyi) over 14-21 days in stem cell growth medium (SCGM, Cellgenix) supplemented with 10% human AB serum (Sigma).	('donor', 'Species', '9606', (41, 46))	('IL-2', 'Gene', (127, 131))	('human', 'Species', '9606', (226, 231))	('K562-mb15-41BBL', 'CellLine', 'CVCL:0004', (71, 86))	('K562-mb15-41BBL', 'Var', (71, 86))	('IL-2', 'Gene', '3558', (127, 131))	('rat', 'Species', '10116', (104, 107))
5493	31428099	Percentage and phenotype of NK cells (CD3-, CD56+), T cells (CD3+, CD56-) and NKT cells (CD3+, CD56+) was weekly monitored by flow cytometry (Navios, Beckman Coulter) (Supplementary Figure 1).	('CD56', 'Gene', (44, 48))	('CD56', 'Gene', (67, 71))	('CD3-', 'Var', (38, 42))	('CD56', 'Gene', (95, 99))	('CD56', 'Gene', '4684', (44, 48))	('CD56', 'Gene', '4684', (67, 71))	('CD56', 'Gene', '4684', (95, 99))
5506	31428099	For migration/invasion neutralization experiments, 105 RH30 cells were mixed with the indicated final concentration of anti CXCR4 MDX1338 mAb or control IgG4 mAb in a final volume of 90 mul of migration buffer and proceeded as above indicated.	('RH30', 'Gene', (55, 59))	('rat', 'Species', '10116', (109, 112))	('rat', 'Species', '10116', (7, 10))	('rat', 'Species', '10116', (196, 199))	('RH30', 'Gene', '6007', (55, 59))	('anti', 'Var', (119, 123))
5532	31428099	We analyzed the surface expression of CXCR4 on confluent cultures of various sarcoma cell lines: RH30, CW9019, A4573, A673, MG-63, and 143B.	('CW9019', 'Var', (103, 109))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('sarcoma', 'Disease', (77, 84))	('CW9019', 'CellLine', 'CVCL:N820', (103, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('RH30', 'Gene', (97, 101))	('RH30', 'Gene', '6007', (97, 101))
5542	31428099	As expected, MDX1338 had no significant effect on the observed cytotoxicity (Supplementary Figure 2A).	('cytotoxicity', 'Disease', (63, 75))	('MDX1338', 'Var', (13, 20))	('cytotoxicity', 'Disease', 'MESH:D064420', (63, 75))
5543	31428099	MDX1338 is a fully human IgG4 anti-CXCR4 mAb, and would not, therefore, be expected to induce ADCC.	('human', 'Species', '9606', (19, 24))	('ADCC', 'Disease', (94, 98))	('MDX1338', 'Var', (0, 7))
5551	31428099	Mice treated with MDX1338 mAb alone developed intraperitoneal tumors slightly smaller than those of the control mice, whereas a control IgG4 mAb had no significant effect.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('MDX1338', 'Var', (18, 25))	('intraperitoneal tumors', 'Disease', (46, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('Mice', 'Species', '10090', (0, 4))	('intraperitoneal tumors', 'Disease', 'MESH:D009369', (46, 68))	('mice', 'Species', '10090', (112, 116))	('smaller', 'NegReg', (78, 85))
5561	31428099	We detected specific chimeric gene transcript PAX3-FOXO1, in untreated, IgG4-, MDX1338- and NKAE-treated mice, whereas we could not detect it in NKAE+MDX1338-treated mice lungs (Supplementary Figure 3).	('PAX3-FOXO1', 'Gene', (46, 56))	('mice', 'Species', '10090', (105, 109))	('mice', 'Species', '10090', (166, 170))	('MDX1338-', 'Var', (79, 87))
5571	31428099	Aberrant CXCR4 expression has been observed in more than 23 human cancers.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('CXCR4 expression', 'MPA', (9, 25))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('observed', 'Reg', (35, 43))	('human', 'Species', '9606', (60, 65))
5573	31428099	In a recent meta-analysis of 12 studies including a total of 997 sarcoma patients, CXCR4 expression was found to be significantly associated with poor overall survival, higher rates of metastasis and higher tumor stage.	('CXCR4 expression', 'Var', (83, 99))	('higher', 'PosReg', (169, 175))	('sarcoma', 'Disease', (65, 72))	('rat', 'Species', '10116', (176, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('metastasis', 'CPA', (185, 195))	('overall survival', 'MPA', (151, 167))	('tumor', 'Disease', (207, 212))	('patients', 'Species', '9606', (73, 81))	('poor', 'NegReg', (146, 150))
5583	31428099	Consistent with these previous findings, our results for MDX1338, a fully human mAb blocking the CXCR4/CXCL12 axis, show that this mAb can efficiently decrease the migration and invasion indices of metastatic RH30 rhabdomyosarcoma cells in vitro.	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (214, 230))	('rhabdomyosarcoma', 'Disease', (214, 230))	('RH30', 'Gene', (209, 213))	('decrease', 'NegReg', (151, 159))	('RH30', 'Gene', '6007', (209, 213))	('invasion indices', 'CPA', (178, 194))	('MDX1338', 'Var', (57, 64))	('rat', 'Species', '10116', (167, 170))	('human', 'Species', '9606', (74, 79))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (214, 230))	('migration', 'CPA', (164, 173))
5598	31428099	In our model, we hypothesize that MDX1338 blocks not only metastatic CXCR4+ sarcoma cells migration to the lungs, but also blocks therapeutic NKAE cells homing to the bone marrow and favors their permanence in the blood stream, where they are more likely to find and kill metastatic neoplastic cells.	('favors', 'PosReg', (183, 189))	('blocks', 'NegReg', (123, 129))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('blocks', 'NegReg', (42, 48))	('sarcoma', 'Disease', (76, 83))	('rat', 'Species', '10116', (93, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('permanence', 'MPA', (196, 206))	('MDX1338', 'Var', (34, 41))
5601	31428099	Our and others' results indicate that both autologous and haploidentical NKAE cell therapies are safe, with no serious adverse effects, and feasible for use in the treatment of various types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (194, 200))	('haploidentical', 'Var', (58, 72))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
5643	28320420	Fluorescein in situ hybridization (FISH) analysis for EWSR1 break apart probe on paraffin-embedded tumor showed evidence of a 22q12 rearrangement in 197 out of 205 (96%) of interphase nuclei scored.	('tumor', 'Disease', (99, 104))	('EWSR1', 'Gene', '2130', (54, 59))	('Fluorescein', 'Chemical', 'MESH:D019793', (0, 11))	('break apart', 'Phenotype', 'HP:0001061', (60, 71))	('22q12 rearrangement', 'Var', (126, 145))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('EWSR1', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('paraffin', 'Chemical', 'MESH:D010232', (81, 89))
5645	28320420	However, EWSR1 gene rearrangement presented as one red and one green separated signal (Fig.	('green separated signal', 'MPA', (63, 85))	('rearrangement', 'Var', (20, 33))	('EWSR1', 'Gene', (9, 14))	('red', 'MPA', (51, 54))	('EWSR1', 'Gene', '2130', (9, 14))
5672	28320420	Antonescu and his team studied 3 cases of CCS of gastrointestinal tract and claimed to be the first to describe a recurrent translocation of EWS (22q12) and CREB1 (2q32.3) resulting in EWS-CREB1 fusion.	('EWS', 'Gene', '2130', (185, 188))	('EWS', 'Gene', (185, 188))	('EWS', 'Gene', (141, 144))	('CREB1', 'Gene', (189, 194))	('EWS', 'Gene', '2130', (141, 144))	('translocation', 'Var', (124, 137))	('CREB1', 'Gene', '1385', (157, 162))	('CCS of gastrointestinal tract', 'Disease', 'MESH:D004067', (42, 71))	('CREB1', 'Gene', '1385', (189, 194))	('CCS of gastrointestinal tract', 'Disease', (42, 71))	('CREB1', 'Gene', (157, 162))
5675	28320420	In one study, translocation involving the gene EWSR1 was detected in 86% (Twelve cases) of the cases described as GNET.	('EWSR1', 'Gene', (47, 52))	('EWSR1', 'Gene', '2130', (47, 52))	('translocation', 'Var', (14, 27))
5677	28320420	Two more studies have described rare EWSR1-CREB1 fusion in non-gastrointestinal CCS of soft tissue, however, these cases expressed melanocytic markers.	('non-gastrointestinal CCS of soft tissue', 'Disease', (59, 98))	('expressed', 'Reg', (121, 130))	('CREB1', 'Gene', '1385', (43, 48))	('EWSR1', 'Gene', (37, 42))	('fusion', 'Var', (49, 55))	('CREB1', 'Gene', (43, 48))	('EWSR1', 'Gene', '2130', (37, 42))
5679	28320420	Some authors regard this entity as CCS in gastrointestinal tract and explain the lack of melanocytic differentiation as being a variant of CCS especially after detecting EWSR1 rearrangement which is involved in CCS.	('EWSR1', 'Gene', (170, 175))	('rearrangement', 'Var', (176, 189))	('EWSR1', 'Gene', '2130', (170, 175))	('melanocytic differentiation', 'CPA', (89, 116))	('gastrointestinal tract', 'Disease', (42, 64))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (42, 64))
5728	27746879	FISH again showed amplification of the MDM2 gene at 12q15, consistent with the subcutaneous metastasis representing dedifferentiated liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('MDM2', 'Gene', (39, 43))	('liposarcoma', 'Disease', (133, 144))	('liposarcoma', 'Disease', 'MESH:D008080', (133, 144))	('liposarcoma', 'Phenotype', 'HP:0012034', (133, 144))	('amplification', 'Var', (18, 31))
5735	27746879	However, MDM2 amplification is not associated with the other liposarcoma subtypes (myxoid and pleomorphic liposarcomas).	('MDM2', 'Gene', (9, 13))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (94, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('associated', 'Reg', (35, 45))	('liposarcomas', 'Phenotype', 'HP:0012034', (106, 118))	('liposarcoma', 'Phenotype', 'HP:0012034', (61, 72))	('pleomorphic liposarcomas', 'Disease', (94, 118))	('liposarcoma subtypes', 'Disease', 'MESH:D008080', (61, 81))	('liposarcoma subtypes', 'Disease', (61, 81))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))	('amplification', 'Var', (14, 27))
5736	27746879	In our case, MDM2 amplification was demonstrated in both the primary retroperitoneal tumor and the subsequent subcutaneous metastasis.	('primary retroperitoneal tumor', 'Disease', 'MESH:D012186', (61, 90))	('primary retroperitoneal tumor', 'Disease', (61, 90))	('MDM2', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('amplification', 'Var', (18, 31))
5748	27746879	Tirumani and colleagues also found a statistically higher incidence of metastases in high grade DDL, but in contrast a prior study of 155 patients by Henricks and colleagues reported no relationship between histologic grade and the risk of metastases.	('metastases', 'Disease', (240, 250))	('metastases', 'Disease', 'MESH:D009362', (240, 250))	('high grade', 'Var', (85, 95))	('metastases', 'Disease', (71, 81))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('patients', 'Species', '9606', (138, 146))
5801	33506101	It is characterised by a balanced chromosomal translocation t(11;22)(q24;q12) which results in the production of the EWS/Friend leukaemia virus integration 1 (FLI-1) fusion gene.	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (60, 77))	('results in', 'Reg', (84, 94))	('FLI-1', 'Gene', '2313', (159, 164))	('EWS/Friend leukaemia virus integration 1', 'Gene', '2313', (117, 157))	('FLI-1', 'Gene', (159, 164))	('t(11;22)(q24;q12', 'Var', (60, 76))	('EWS/Friend leukaemia virus integration 1', 'Gene', (117, 157))
5854	31786124	Patients with non-metastatic >5 cm, high-grade or unresectable tumor of any grade or size have an approximately 50% survival rate and constituted the intermediaterisk group, whereas patients with metastatic disease have a less than 20% survival rate and comprised the high-risk group.	('tumor', 'Disease', (63, 68))	('Patients', 'Species', '9606', (0, 8))	('high-grade', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
5905	31786124	Initiation of each chemotherapy cycle required an absolute neutrophil count >= 750/microliter, platelet count >= 75,000/microliter, total bilirubin <= 1 5x the upper limit of normal, and for doxorubicin-containing cycles except at week 4, a shortening fraction 24% or ejection fraction 50% on echocardiogram or multigated acquisition scan.	('total bilirubin', 'MPA', (132, 147))	('doxorubicin', 'Chemical', 'MESH:D004317', (191, 202))	('ejection fraction', 'MPA', (268, 285))	('bilirubin', 'Chemical', 'MESH:D001663', (138, 147))	('platelet', 'MPA', (95, 103))	('shortening fraction 24%', 'Var', (241, 264))
5941	31786124	Since intermediate-risk patients could undergo tumor resection prior to study entry or in a delayed fashion, we also evaluated whether the timing of surgery and the extent of resection (R0/R1 vs. R2/no resection, R0 vs. R1) influenced EFS/OS.	('influenced', 'Reg', (224, 234))	('R0/R1', 'Var', (186, 191))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('EFS/OS', 'MPA', (235, 241))	('R0 vs. R1', 'Var', (213, 222))	('tumor', 'Disease', (47, 52))	('EFS/OS', 'CellLine', 'CVCL:5I29', (235, 241))
5977	31786124	Isolated local recurrence/progression occurred in 4 of 103 low-grade R0 tumors (4%), 4 of 22 low-grade R1 tumors (18%), 5 of 80 <=5 cm high-grade R0 tumors (9%), and 2 of 17 <=5 cm high-grade R1 tumors (18%).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('local recurrence/progression', 'CPA', (9, 37))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('low-grade R0', 'Var', (59, 71))
5983	31786124	As shown in Table 3, unresectable disease in intermediate-risk patients predicted poor EFS [29 6% (95% CI 9 7-49 5%) for R2/no resection vs. 70 5% (95% CI 63 5-77 4%) for R0/R1 resection, p<0 0001] and OS [58 0% (95% CI 37 6-78 5%) for R2/no resection vs. 82 5% (95% CI 76 7-88 2%) for R0/R1 resection, p<0 0001].	('R2/no', 'Var', (121, 126))	('EFS', 'MPA', (87, 90))	('patients', 'Species', '9606', (63, 71))
6177	28982163	Oncogenic HrasG12V expression plus knockdown of Cdkn2a using ecotropic lentiviral vectors induces high-grade endometrial stromal sarcoma The uterine corpus represents the most common site for tumour development in the female genital system.	('knockdown', 'Var', (35, 44))	('endometrial stromal sarcoma', 'Disease', (109, 136))	('stromal sarcoma The uterine corpus represents', 'Phenotype', 'HP:0000131', (121, 166))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (109, 136))	('sarcoma The uterine', 'Phenotype', 'HP:0010784', (129, 148))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('Cdkn2a', 'Gene', '12578', (48, 54))	('induces', 'Reg', (90, 97))	('tumour', 'Disease', (192, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('Cdkn2a', 'Gene', (48, 54))
6188	28982163	Several studies report that PTEN mutations occur early in the development of type I tumours.	('type I tumours', 'Disease', 'MESH:D017827', (77, 91))	('PTEN', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('PTEN', 'Gene', '19211', (28, 32))	('type I tumours', 'Disease', (77, 91))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
6190	28982163	Tumour onset and severity can be accelerated by combining Pten deletion with Kras activation.	('Tumour onset', 'CPA', (0, 12))	('Kras', 'Gene', (77, 81))	('accelerated', 'PosReg', (33, 44))	('Kras', 'Gene', '16653', (77, 81))	('deletion', 'Var', (63, 71))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Pten', 'Gene', (58, 62))
6195	28982163	In contrast to type I tumours, type II tumours are frequently characterised by early mutations in TP53.	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('mutations', 'Var', (85, 94))	('TP53', 'Gene', '22059', (98, 102))	('type I tumours, type II tumours', 'Disease', 'MESH:D009369', (15, 46))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('TP53', 'Gene', (98, 102))
6196	28982163	The deletion of the Trp53 gene in the mouse endometrium results in the formation of all histological subtypes of type II disease after 14-16 months.	('Trp53', 'Gene', (20, 25))	('mouse', 'Species', '10090', (38, 43))	('deletion', 'Var', (4, 12))	('type II disease', 'Disease', 'MESH:D005776', (113, 128))	('type II disease', 'Disease', (113, 128))	('results in', 'Reg', (56, 66))
6203	28982163	Patients with germline mutations in fumarate hydratase (FH) have an increased risk of developing uterine leiomyosarcomas as well as uterine leiomyomas.	('FH', 'Gene', '2271', (56, 58))	('fumarate hydratase', 'Gene', '2271', (36, 54))	('fumarate hydratase', 'Gene', (36, 54))	('leiomyosarcomas', 'Disease', (105, 120))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (132, 150))	('Patients', 'Species', '9606', (0, 8))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (97, 120))	('leiomyomas', 'Disease', 'MESH:D007889', (140, 150))	('leiomyomas', 'Disease', (140, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (105, 120))	('germline mutations', 'Var', (14, 32))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (105, 120))
6240	28982163	The antibodies used in this study were anti-CD10 antibody (1:2000, PA5-47075, Thermo Fisher Scientific, Waltham, MA), anti-CD31 antibody (1:200, ab28364, abcam, Cambridge, UK), anti-CYCLIN D1 antibody (1:40, SP4, Thermo Fisher Scientific, Waltham, MA), anti-DESMIN antibody (1:100, D1033, Sigma-Aldrich, Darmstadt, Germany), anti-MYOD1 antibody (1:100, M3512, Dako, Santa Clara), anti-MYOGENIN antibody (1:500, M3559, Dako, Santa Clara), anti-alpha-SMOOTH MUSCLE ACTIN antibody (1:5000, ab5694, abcam, Cambridge, UK), anti-H-RAS antibody (1:100, GTX116041, GeneTex, Irvine, CA) and anti-VIMENTIN antibody (1:500, D21H3, Cell Signaling, Danvers, MA).	('SP4', 'Gene', (208, 211))	('DESMIN antibody', 'Phenotype', 'HP:0100300', (258, 273))	('CD31', 'Gene', '18613', (123, 127))	('CD31', 'Gene', (123, 127))	('SP4', 'Gene', '482345', (208, 211))	('1:500', 'Var', (606, 611))	('anti-alpha-SMOOTH MUSCLE ACTIN antibody', 'Phenotype', 'HP:0003262', (438, 477))
6244	28982163	The extended replicative life span which results from the inactivation of the p53 pathway is thought to represent an important event in the multistep process of endometrial carcinoma development.	('endometrial carcinoma', 'Disease', (161, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('inactivation', 'Var', (58, 70))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (161, 182))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '22059', (78, 81))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (161, 182))
6245	28982163	Given this genetic link to human endometrial carcinogenesis and additionally since pEECs fall into senescence with ongoing cultivation on plastic dishes, we tried to immortalise them by using primary epithelial cultures prepared from Trp53fl/fl uteri.	('fall', 'Phenotype', 'HP:0002527', (89, 93))	('Trp53fl/fl', 'Var', (234, 244))	('human', 'Species', '9606', (27, 32))	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (33, 59))	('endometrial carcinogenesis', 'Disease', (33, 59))
6259	28982163	We conclude that while endometrial epithelial cells can be infected by MuLE viruses, albeit at low efficiency, transformation of other stromal cell types present in these cultures occurs efficiently by HrasG12V overexpression and Cdkn2a knockdown.	('Hras', 'Gene', '15461', (202, 206))	('overexpression', 'PosReg', (211, 225))	('Hras', 'Gene', (202, 206))	('MuLE', 'Species', '319699', (71, 75))	('knockdown', 'Var', (237, 246))	('Cdkn2a', 'Gene', (230, 236))
6281	28982163	Since it was not possible to expand and passage pEECs which retain lineage commitment and normal growth, we tried to generate immortalised cell lines through Trp53 tumour suppressor inactivation or Hras oncogene activation with the use of ecotropic lentiviruses.	('Hras', 'Gene', (198, 202))	('inactivation', 'Var', (182, 194))	('Trp53', 'Gene', (158, 163))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('Hras', 'Gene', '15461', (198, 202))
6284	28982163	In this model, uterus-specific deletion of Trp53 was combined with expression of a constitutively active form of Kras.	('Kras', 'Gene', '16653', (113, 117))	('Kras', 'Gene', (113, 117))	('deletion', 'Var', (31, 39))	('Trp53', 'Gene', (43, 48))
6297	28982163	The injection of an adenovirus expressing Cre into the uterus of Ptenfl/fl mice caused Pten deletion in both stromal and epithelial cells, however this treatment caused endometrial carcinoma development, but none of the injected uteri exhibited stromal tumours.	('tumours', 'Phenotype', 'HP:0002664', (253, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('mice', 'Species', '10090', (75, 79))	('deletion', 'Var', (92, 100))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (169, 190))	('caused', 'Reg', (162, 168))	('stromal tumours', 'Disease', (245, 260))	('endometrial carcinoma', 'Disease', (169, 190))	('stromal tumours', 'Disease', 'MESH:D046152', (245, 260))	('Pten', 'Gene', (87, 91))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (169, 190))
6298	28982163	This indicates that the deletion of Pten in stromal cells does not offer an advantage to the cells and therefore is not selected for in terms of causing a tumour.	('Pten', 'Gene', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('deletion', 'Var', (24, 32))	('tumour', 'Disease', (155, 161))
6321	28326149	Modifications of this flap allow considerable tailoring to the defect.	('flap', 'Gene', (22, 26))	('flap', 'Gene', '241', (22, 26))	('Modifications', 'Var', (0, 13))
6501	24300371	Both types of small molecular drugs have been shown to have potent anti-vascular and anti-tumour efficacy in a wide variety of preclinical models and the lead agents have also undergone clinical evaluation.	('anti-vascular', 'CPA', (67, 80))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('small molecular', 'Var', (14, 29))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))
6512	24300371	Susceptibility contrast information on functional blood volume can also be obtained by BOLD by manipulating levels of endogenous deoxygenated haemoglobin, which is paramagnetic like the mentioned contrast agents.	('oxygen', 'Chemical', 'MESH:D010100', (131, 137))	('levels of endogenous deoxygenated haemoglobin', 'MPA', (108, 153))	('manipulating', 'Var', (95, 107))
6534	24300371	The low-molecular Gd-DTPA leaks from physiological blood vessels outside the brain and to a larger extent from hyper-permeable tumour blood vessels.	('tumour blood vessel', 'Disease', (127, 146))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (18, 25))	('low-molecular', 'Var', (4, 17))	('leaks', 'MPA', (26, 31))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('Gd-DTPA', 'Protein', (18, 25))	('tumour blood vessel', 'Disease', 'MESH:D009383', (127, 146))
6554	24300371	This inhibition is achieved by either competing with adenosine triphosphate (ATP), competing with the substrate protein that is to be phosphorylated, or by conformational change leading to allosteric inhibition.	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (53, 75))	('conformational', 'Var', (156, 170))	('adenosine triphosphate', 'MPA', (53, 75))	('allosteric', 'MPA', (189, 199))	('ATP', 'Chemical', 'MESH:D000255', (77, 80))	('rat', 'Species', '10116', (107, 110))
6564	24300371	found that the increase in permeability of the tumour rim was attributed to vasodilation due to VEGF expression.	('expression', 'Var', (101, 111))	('VEGF', 'Gene', '7422', (96, 100))	('permeability', 'MPA', (27, 39))	('increase', 'PosReg', (15, 23))	('tumour rim', 'Disease', 'MESH:C536816', (47, 57))	('tumour rim', 'Disease', (47, 57))	('vasodilation', 'MPA', (76, 88))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('VEGF', 'Gene', (96, 100))
6566	24300371	Both experiments showed a decrease in Ktrans although contrast agents (albumin-Gd-DTPA and P846), treatment schedules and hence imaging schedules were different.	('Ktrans', 'Chemical', '-', (38, 44))	('P846', 'Var', (91, 95))	('-Gd-DTPA', 'Chemical', 'MESH:D019786', (78, 86))	('decrease', 'NegReg', (26, 34))	('Ktrans although contrast agents', 'MPA', (38, 69))
6573	24300371	Vandetanib showed a dose-dependent decrease in Ktrans, which could be due to both perfusion and permeability as this study used the small contrast agent, and ZD4190 showed a reduction of tumour vascular permeability, vascular volume and blood flow.	('tumour vascular', 'Disease', (187, 202))	('ZD4190', 'Var', (158, 164))	('Vandetanib', 'Chemical', 'MESH:C452423', (0, 10))	('Ktrans', 'MPA', (47, 53))	('decrease', 'NegReg', (35, 43))	('vascular volume', 'CPA', (217, 232))	('blood flow', 'CPA', (237, 247))	('tumour vascular', 'Disease', 'MESH:D019043', (187, 202))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('reduction', 'NegReg', (174, 183))	('Vandetanib', 'Gene', (0, 10))	('Ktrans', 'Chemical', '-', (47, 53))
6574	24300371	Axitinib (AG013736), imatinib (STI571), and cediranib (AZD2171) were only used in one study each, involving mice bearing either a human breast cancer (axitinib), a human prostate cancer (imatinib), or different glioblastomas (cediranib).	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', (136, 149))	('mice', 'Species', '10090', (108, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (170, 185))	('prostate cancer', 'Phenotype', 'HP:0012125', (170, 185))	('imatinib', 'Chemical', 'MESH:D000068877', (21, 29))	('AG013736', 'Var', (10, 18))	('STI571', 'Chemical', 'MESH:D000068877', (31, 37))	('prostate cancer', 'Disease', (170, 185))	('imatinib', 'Chemical', 'MESH:D000068877', (187, 195))	('glioblastomas', 'Disease', (211, 224))	('cediranib', 'Chemical', 'MESH:C500926', (226, 235))	('Axitinib', 'Chemical', 'MESH:D000077784', (0, 8))	('glioblastomas', 'Disease', 'MESH:D005909', (211, 224))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cediranib', 'Chemical', 'MESH:C500926', (44, 53))	('human', 'Species', '9606', (164, 169))	('AZD2171', 'Chemical', 'MESH:C500926', (55, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('axitinib', 'Chemical', 'MESH:D000077784', (151, 159))	('glioblastomas', 'Phenotype', 'HP:0012174', (211, 224))	('human', 'Species', '9606', (130, 135))
6591	24300371	The drug KR-31831 has been reported to suppress endothelial cell proliferation, tube formation, invasion, and migration in vitro as well as vessel formation in vivo.	('rat', 'Species', '10116', (72, 75))	('vessel formation', 'CPA', (140, 156))	('migration', 'CPA', (110, 119))	('tube formation', 'CPA', (80, 94))	('rat', 'Species', '10116', (113, 116))	('KR-31831', 'Var', (9, 17))	('invasion', 'CPA', (96, 104))	('suppress', 'NegReg', (39, 47))	('endothelial cell proliferation', 'CPA', (48, 78))
6605	24300371	The different effect of CA4P, OXi4503, and NPI2358 in the C3H mammary carcinoma is shown in Figure 1.	('carcinoma', 'Disease', 'MESH:D002277', (70, 79))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (62, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('CA4P', 'Var', (24, 28))	('CA4P', 'Chemical', 'MESH:C058728', (24, 28))	('OXi4503', 'Enzyme', (30, 37))	('carcinoma', 'Disease', (70, 79))	('OXi4503', 'Chemical', 'MESH:C465018', (30, 37))	('NPI2358', 'Var', (43, 50))
6607	24300371	DCE-MRI studies of CA4P has been done in the rat tumour models P22 carcinosarcoma, 13762NF mammary carcinoma, and R1 liver rhabdomyosarcoma, and in the murine tumour models sarcoma F, RIF-1 fibrosarcoma, SaS sarcoma, SaF sarcoma, C3H mammary carcinoma, KHT sarcoma, and EL4 lymphoma.	('mammary carcinoma', 'Phenotype', 'HP:0003002', (91, 108))	('murine', 'Species', '10090', (152, 158))	('DCE', 'Chemical', '-', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('lymphoma', 'Disease', (274, 282))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (123, 139))	('carcinosarcoma', 'Disease', (67, 81))	('lymphoma', 'Disease', 'MESH:D008223', (274, 282))	('carcinoma', 'Disease', 'MESH:D002277', (242, 251))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (190, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('carcinoma', 'Disease', 'MESH:D002277', (99, 108))	('carcinosarcoma', 'Disease', 'MESH:D002296', (67, 81))	('KHT sarcoma', 'Disease', (253, 264))	('rat', 'Species', '10116', (45, 48))	('liver rhabdomyosarcoma', 'Disease', 'MESH:D012208', (117, 139))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('SaF sarcoma', 'Disease', 'MESH:D012509', (217, 228))	('13762NF', 'Var', (83, 90))	('tumour', 'Disease', (49, 55))	('tumour models sarcoma F, RIF-1 fibrosarcoma, SaS sarcoma', 'Disease', 'MESH:D012509', (159, 215))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (234, 251))	('tumour', 'Disease', (159, 165))	('SaF sarcoma', 'Disease', (217, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('lymphoma', 'Phenotype', 'HP:0002665', (274, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('liver rhabdomyosarcoma', 'Disease', (117, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinoma', 'Disease', (242, 251))	('KHT sarcoma', 'Disease', 'MESH:D012509', (253, 264))	('carcinoma', 'Disease', (99, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('CA4P', 'Chemical', 'MESH:C058728', (19, 23))
6620	24300371	One study in the KHT sarcoma compared CA4P and the other combretastatin derivative OXi4503 showing a slower perfusion recovery after OXi4503 treatment.	('slower', 'NegReg', (101, 107))	('CA4P', 'Var', (38, 42))	('OXi4503', 'Chemical', 'MESH:C465018', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('CA4P', 'Chemical', 'MESH:C058728', (38, 42))	('perfusion recovery', 'MPA', (108, 126))	('OXi4503', 'Chemical', 'MESH:C465018', (133, 140))	('KHT sarcoma', 'Disease', 'MESH:D012509', (17, 28))	('KHT sarcoma', 'Disease', (17, 28))
6641	24300371	The tumour necrosis factor-alpha (TNF-alpha) inducing drug DMXAA (Vadimezan, ASA404) has been investigated by DCE-MRI in the rat GH3 prolactinoma, in a range of murine tumours including MCA205 (methylcholantrene-induced fibrosarcoma) and SaF sarcoma, and in a number of human xenografts in mice including HT29 and LS174T colon adenocarcinomas, FaDu, A253, and patient-derived head and neck carcinomas.	('DMXAA', 'Chemical', 'MESH:C066668', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('patient', 'Species', '9606', (360, 367))	('SaF sarcoma', 'Disease', 'MESH:D012509', (238, 249))	('prolactinoma', 'Disease', 'MESH:D015175', (133, 145))	('DCE', 'Chemical', '-', (110, 113))	('LS174T', 'Var', (314, 320))	('SaF sarcoma', 'Disease', (238, 249))	('tumours', 'Disease', (168, 175))	('mice', 'Species', '10090', (290, 294))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('carcinomas', 'Phenotype', 'HP:0030731', (390, 400))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (220, 232))	('HT29', 'CellLine', 'CVCL:0320', (305, 309))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('human', 'Species', '9606', (270, 275))	('colon adenocarcinomas', 'Disease', (321, 342))	('rat', 'Species', '10116', (125, 128))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (376, 400))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour necrosis', 'Disease', 'MESH:D009336', (4, 19))	('colon adenocarcinomas', 'Disease', 'MESH:D003110', (321, 342))	('neck carcinomas', 'Disease', 'MESH:D006258', (385, 400))	('tumour necrosis', 'Disease', (4, 19))	('prolactinoma', 'Phenotype', 'HP:0040278', (133, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('carcinomas', 'Phenotype', 'HP:0030731', (332, 342))	('fibrosarcoma', 'Disease', 'MESH:D005354', (220, 232))	('neck carcinomas', 'Disease', (385, 400))	('prolactinoma', 'Disease', (133, 145))	('fibrosarcoma', 'Disease', (220, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('murine', 'Species', '10090', (161, 167))
6649	24300371	In the study of Barbera et al., the DMXAA analogues AP/1649 and AP/1897 showed no antivascular effect in the SaF sarcoma as seen by DMXAA.	('SaF sarcoma', 'Disease', (109, 120))	('AP/1897', 'Var', (64, 71))	('DMXAA', 'Chemical', 'MESH:C066668', (36, 41))	('DMXAA', 'Chemical', 'MESH:C066668', (132, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('SaF sarcoma', 'Disease', 'MESH:D012509', (109, 120))	('antivascular effect', 'MPA', (82, 101))
6756	33082266	One study found significantly more emotional problems in patients who underwent amputation for STS when compared with the normative population, while another reported similar depression scores among amputees using Patient Reported Outcome Measurement Information System.	('amputation', 'Var', (80, 90))	('patients', 'Species', '9606', (57, 65))	('more', 'PosReg', (30, 34))	('STS', 'Phenotype', 'HP:0030448', (95, 98))	('men', 'Species', '9606', (246, 249))	('Patient', 'Species', '9606', (214, 221))	('emotional problems', 'MPA', (35, 53))	('depression', 'Disease', 'MESH:D000275', (175, 185))	('depression', 'Phenotype', 'HP:0000716', (175, 185))	('depression', 'Disease', (175, 185))
6884	33082266	Most studies used a generic HRQoL questionnaire (EORTC QLQ-C30, FACT-G) or the EQ5D (measuring not HRQoL but health status), which cover relevant issues but do not capture all of the unique experiences of patients with sarcoma and consequences of treatment, and thus lack content validity.	('sarcoma', 'Disease', (219, 226))	('patients', 'Species', '9606', (205, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('men', 'Species', '9606', (252, 255))	('EORTC QLQ-C30', 'Var', (49, 62))	('sarcoma', 'Disease', 'MESH:D012509', (219, 226))
6924	31417299	Laboratory investigations revealed hemoglobin 5.2 g/dl, leukocytosis with left shift (20,000/cu mm with 90% polymorphs), alanine transaminase (ALT)90IU/L, aspartate aminotransferase (AST)20IU/L, an average random blood glucose (100 mg/dl), elevated serum creatinine (2.84 mg/dl), serum amylase (40 U/L), serum lipase (45 U/L), serum bilirubin 2.5 mg/dl, and increased C-reactive protein levels (140 mg/L).	('alanine transaminase', 'MPA', (121, 141))	('aspartate', 'MPA', (155, 164))	('serum amylase', 'MPA', (280, 293))	('leukocytosis', 'Disease', 'MESH:D007964', (56, 68))	('leukocytosis', 'Phenotype', 'HP:0001974', (56, 68))	('C-reactive protein', 'Gene', (368, 386))	('leukocytosis', 'Disease', (56, 68))	('AST', 'Gene', (183, 186))	('hemoglobin', 'Disease', (35, 45))	('elevated', 'PosReg', (240, 248))	('serum lipase', 'MPA', (304, 316))	('C-reactive protein', 'Gene', '1401', (368, 386))	('serum bilirubin', 'MPA', (327, 342))	('left shift', 'Phenotype', 'HP:0032239', (74, 84))	('elevated serum creatinine', 'Phenotype', 'HP:0003259', (240, 265))	('serum creatinine', 'MPA', (249, 265))	('increased', 'PosReg', (358, 367))	('20,000/cu', 'Var', (86, 95))	('increased C-reactive protein levels', 'Phenotype', 'HP:0011227', (358, 393))	('AST', 'Gene', '26503', (183, 186))
7002	26366341	Fluorescence in situ hybridization analysis using a EWSR1 break-apart probe identified the rearranged EWSR1 gene in both cases.	('EWS', 'Phenotype', 'HP:0012254', (52, 55))	('EWSR1', 'Gene', (52, 57))	('EWSR1', 'Gene', '2130', (102, 107))	('rearranged', 'Var', (91, 101))	('EWSR1', 'Gene', '2130', (52, 57))	('EWS', 'Phenotype', 'HP:0012254', (102, 105))	('EWSR1', 'Gene', (102, 107))
7066	30254189	In a recent phase III study in metastatic STS (PALETTE), the median progression-free survival (PFS) in patients receiving pazopanib was improved to 4.6 months compared with 1.6 months in patients receiving placebo [8].	('patients', 'Species', '9606', (187, 195))	('pazopanib', 'Chemical', 'MESH:C516667', (122, 131))	('pazopanib', 'Var', (122, 131))	('STS', 'Phenotype', 'HP:0030448', (42, 45))	('patients', 'Species', '9606', (103, 111))	('progression-free survival', 'CPA', (68, 93))	('improved', 'PosReg', (136, 144))
7090	30254189	Our result indicates that pazopanib might modulate multiple signaling pathways in a simultaneous manner.	('pazopanib', 'Chemical', 'MESH:C516667', (26, 35))	('modulate', 'Reg', (42, 50))	('pazopanib', 'Var', (26, 35))
7141	30386736	PD-L1 expression on both tumor cells and TILs has been associated with higher probability of response to checkpoint blockade immunotherapy in multiple tumor types, but this has yet to be shown in sarcoma and further studies are needed to identify reliable predictors of response.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('PD-L1', 'Gene', (0, 5))	('sarcoma', 'Disease', 'MESH:D012509', (196, 203))	('PD-L1', 'Gene', '29126', (0, 5))	('expression', 'Var', (6, 16))	('response', 'MPA', (93, 101))	('sarcoma', 'Disease', (196, 203))
7142	30386736	Ongoing clinical trials are studying combined RT plus CBI for UPS (NCT03116529, NCT03307616, NCT03092323).	('CBI', 'Chemical', '-', (54, 57))	('NCT03092323', 'Var', (93, 104))	('NCT03307616', 'Var', (80, 91))	('NCT03116529', 'Var', (67, 78))
7173	27374091	Circulating levels of VEGF-A are elevated on average ten-fold in sarcoma patients compared to controls, and inhibition of VEGF-A or its receptors can effectively suppress tumor angiogenesis in mouse models of sarcoma.	('VEGF-A', 'Gene', (122, 128))	('sarcoma', 'Disease', (65, 72))	('elevated', 'PosReg', (33, 41))	('suppress', 'NegReg', (162, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('Circulating levels', 'MPA', (0, 18))	('sarcoma', 'Disease', 'MESH:D012509', (209, 216))	('tumor', 'Disease', (171, 176))	('sarcoma', 'Disease', (209, 216))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('inhibition', 'Var', (108, 118))	('mouse', 'Species', '10090', (193, 198))	('patients', 'Species', '9606', (73, 81))
7187	27374091	In this study, we hypothesized that the combination of VEGF-A inhibition and HIF-1alpha inhibition would attenuate tumor vasculature and enhance the effects of hypoxia-activated chemotherapy on sarcoma stem-like cells.	('attenuate', 'NegReg', (105, 114))	('enhance', 'PosReg', (137, 144))	('hypoxia', 'Disease', (160, 167))	('hypoxia', 'Disease', 'MESH:D000860', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inhibition', 'NegReg', (88, 98))	('tumor', 'Disease', (115, 120))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('VEGF-A', 'Gene', (55, 61))	('HIF-1alpha', 'Protein', (77, 87))	('sarcoma', 'Disease', (194, 201))	('inhibition', 'Var', (62, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
7196	27374091	After 14 days of treatment, single modality therapy with DC101, evofosfamide, or doxorubicin inhibited tumor growth by 44%, 12%, and 41%, respectively.	('evofosfamide', 'Chemical', 'MESH:C552526', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('doxorubicin', 'Chemical', 'MESH:D004317', (81, 92))	('DC101', 'Var', (57, 62))	('inhibited', 'NegReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
7200	27374091	When tumors were examined for overall apoptosis using TUNEL staining, multimodal therapy resulted in significantly more apoptosis (41.4 cells per 5 fields) than any other single modality (15.4-18.6 cells per 5 fields) or bimodality treatment (17.8-19.2 cells per 5 fields).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('apoptosis', 'CPA', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('multimodal', 'Var', (70, 80))
7209	27374091	We thus created HT1080 fibrosarcoma cell lines transduced with HIF-1alpha shRNA or scrambled control shRNA.	('HIF-1alpha', 'Var', (63, 73))	('fibrosarcoma', 'Disease', (23, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (23, 35))	('HT1080', 'Gene', (16, 22))	('HT1080', 'Gene', '8872', (16, 22))	('fibrosarcoma', 'Disease', 'MESH:D005354', (23, 35))
7210	27374091	We confirmed effective knockdown of HIF-1alpha in HT1080 cells by Western blot analysis (Figure 2A), and then used these HT1080 cell lines to create xenografts in athymic nude mice.	('HT1080', 'Gene', '8872', (121, 127))	('HT1080', 'Gene', (50, 56))	('knockdown', 'Var', (23, 32))	('HT1080', 'Gene', '8872', (50, 56))	('HIF-1alpha', 'Gene', (36, 46))	('nude mice', 'Species', '10090', (171, 180))	('HT1080', 'Gene', (121, 127))
7211	27374091	Once tumors reached 50-100 mm3, mice were additionally treated with DC101 and/or evofosfamide.	('tumors', 'Disease', (5, 11))	('evofosfamide', 'Chemical', 'MESH:C552526', (81, 93))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (32, 36))	('DC101', 'Var', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
7226	27374091	For HT1080 and SK-LMS-1xenografts, tumors were all less than 250 mm3 even at 60 days and 30 days, respectively (Figure 3A, 3B).	('HT1080', 'Gene', '8872', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (15, 23))	('SK-LMS-1xenografts', 'Var', (15, 33))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('HT1080', 'Gene', (4, 10))
7228	27374091	gammaH2AX levels increase in response to DNA double-strand breaks.	('DNA', 'Var', (41, 44))	('increase', 'PosReg', (17, 25))	('gammaH2AX', 'Gene', (0, 9))	('gammaH2AX', 'Gene', '15270', (0, 9))
7250	27374091	Expression of the self-renewal transcription factors Nanog, Oct-4, and Sox2 were significantly increased in CD133(+) cells compared to CD133(-) cells from sarcoma cell lines (Figure 5B).	('Oct-4', 'Gene', '5460', (60, 65))	('sarcoma', 'Disease', (155, 162))	('Nanog', 'Gene', '79923', (53, 58))	('Expression', 'MPA', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('Oct-4', 'Gene', (60, 65))	('Sox2', 'Gene', '6657', (71, 75))	('Nanog', 'Gene', (53, 58))	('Sox2', 'Gene', (71, 75))	('increased', 'PosReg', (95, 104))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('CD133', 'Var', (108, 113))
7274	27374091	Evofosfamide was found to be more effective in cell lines deficient in homologous recombination secondary to mutations in BRCA1 or BRCA2.	('BRCA1', 'Gene', (122, 127))	('BRCA2', 'Gene', (131, 136))	('Evofosfamide', 'Chemical', 'MESH:C552526', (0, 12))	('BRCA2', 'Gene', '675', (131, 136))	('mutations', 'Var', (109, 118))	('BRCA1', 'Gene', '672', (122, 127))
7298	27374091	All sarcoma cell lines were maintained in Dulbecco modified Eagle medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 mug/ml streptomycin, and L-Glutamine 2 mM.	('sarcoma', 'Disease', (4, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('100 U/mL', 'Var', (115, 123))	('L-Glutamine', 'Chemical', 'MESH:D005973', (165, 176))	('streptomycin', 'Chemical', 'MESH:D013307', (147, 159))	('bovine', 'Species', '9913', (101, 107))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('Dulbecco modified Eagle medium', 'Chemical', '-', (42, 72))	('penicillin', 'Chemical', 'MESH:D010406', (124, 134))
7306	27374091	Maximal knockdown of HIF1-alpha occurred 72 to 96 hours after transduction.	('knockdown', 'Var', (8, 17))	('HIF1-alpha', 'Gene', (21, 31))	('HIF1-alpha', 'Gene', '3091', (21, 31))
7308	27374091	Hind limb tumors were generated in LSL-KrasG12D/+/Trp53fl/fl mice with conditional mutations in oncogenic Kras and the Trp53 tumor suppressor gene as previously described.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('limb tumors', 'Disease', (5, 16))	('Kras', 'Gene', (106, 110))	('Trp53', 'Gene', '22059', (119, 124))	('Trp53', 'Gene', (119, 124))	('mice', 'Species', '10090', (61, 65))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Kras', 'Gene', '16653', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('Kras', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutations', 'Var', (83, 92))	('Kras', 'Gene', '16653', (39, 43))	('Trp53', 'Gene', '22059', (50, 55))	('rat', 'Species', '10116', (26, 29))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', (125, 130))	('limb tumors', 'Disease', 'MESH:D017880', (5, 16))	('Trp53', 'Gene', (50, 55))
7330	27374091	Antibodies used were as follows: human anti-gammaH2AX (mouse polyclonal antibody, 1:100, 05-636, EMD Millipore, Billerica, MA), anti-cleaved caspase-3 (rabbit polyclonal antibody, 1:100, #9661, Cell Signaling Technology, Beverly, MA), anti-CD31 (rat monoclonal antibody, 1:00, DIA-310, Dianova, Hamburg, Germany) and anti-CD133 (rabbit polyclonal antibody, 1:100, MBS46020, MyBioSource, USA).	('rat', 'Species', '10116', (246, 249))	('anti-CD133', 'Var', (317, 327))	('rabbit', 'Species', '9986', (152, 158))	('gammaH2AX', 'Gene', '15270', (44, 53))	('mouse', 'Species', '10090', (55, 60))	('human', 'Species', '9606', (33, 38))	('rabbit', 'Species', '9986', (329, 335))	('CD31', 'Gene', (240, 244))	('gammaH2AX', 'Gene', (44, 53))	('CD31', 'Gene', '5175', (240, 244))
7353	25906748	Gene amplification/rearrangement of ALK, cMYC, HER2, PIK3CA, TOPO2A and cMET was relatively uncommon.	('Gene amplification/rearrangement', 'Var', (0, 32))	('cMET', 'Gene', '4233', (72, 76))	('PIK3CA', 'Gene', '5290', (53, 59))	('cMET', 'Gene', (72, 76))	('ALK', 'Gene', '238', (36, 39))	('HER2', 'Gene', (47, 51))	('cMYC', 'Gene', '4609', (41, 45))	('HER2', 'Gene', '2064', (47, 51))	('PIK3CA', 'Gene', (53, 59))	('ALK', 'Gene', (36, 39))	('cMYC', 'Gene', (41, 45))
7354	25906748	EGFR gene amplification occurred at a rate of 16.9%.	('EGFR', 'Gene', '1956', (0, 4))	('amplification', 'Var', (10, 23))	('EGFR', 'Gene', (0, 4))
7356	25906748	Overexpression of TOPO2A was associated with TP53 mutation (P = 0.0001).	('TP53', 'Gene', '7157', (45, 49))	('TP53', 'Gene', (45, 49))	('mutation', 'Var', (50, 58))	('associated', 'Reg', (29, 39))
7367	25906748	Analyses of genetic alterations in sarcoma have generally focused on particular subtypes and frequently employ limited methodologies.	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('genetic alterations', 'Var', (12, 31))	('sarcoma', 'Disease', (35, 42))
7370	25906748	They were able to identify potentially druggable PIK3CA mutations in 18% of myxoid liposarcomas.	('myxoid liposarcomas', 'Disease', (76, 95))	('mutations', 'Var', (56, 65))	('liposarcoma', 'Phenotype', 'HP:0012034', (83, 94))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (76, 95))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (76, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('PIK3CA', 'Gene', (49, 55))	('PIK3CA', 'Gene', '5290', (49, 55))	('liposarcomas', 'Phenotype', 'HP:0012034', (83, 95))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (76, 94))
7371	25906748	Conversely, a separate series, by Cote and colleagues found that when solely using DNA hotspot analysis or whole exome sequencing, mutations were rare and there was no pattern of alterations noted within sarcoma subtypes.	('sarcoma subtypes', 'Disease', (204, 220))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (204, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('mutations', 'Var', (131, 140))
7375	25906748	Using a registry of 2539 patients with bone and soft tissue sarcomas we have catalogued changes in protein expression, gene amplification/translocation, and somatic mutations.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (48, 68))	('changes', 'Reg', (88, 95))	('soft tissue sarcomas', 'Disease', (48, 68))	('patients', 'Species', '9606', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('gene amplification/translocation', 'Var', (119, 151))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (48, 68))	('protein expression', 'MPA', (99, 117))
7412	25906748	Amplification of the ALK, cMYC, PIK3CA and TOPO2A genes were relatively uncommon events.	('Amplification', 'Var', (0, 13))	('PIK3CA', 'Gene', '5290', (32, 38))	('cMYC', 'Gene', '4609', (26, 30))	('TOPO2A', 'Gene', (43, 49))	('ALK', 'Gene', (21, 24))	('cMYC', 'Gene', (26, 30))	('ALK', 'Gene', '238', (21, 24))	('PIK3CA', 'Gene', (32, 38))
7417	25906748	BRCA2 mutations were seen in 17% of LMS, both uterine and non-uterine.	('BRCA2', 'Gene', '675', (0, 5))	('LMS', 'Disease', (36, 39))	('BRCA2', 'Gene', (0, 5))	('seen', 'Reg', (21, 25))	('mutations', 'Var', (6, 15))
7418	25906748	PTEN and RB1 mutations were noted exclusively in non-uterine LMS and not in those of uterine origin.	('RB1', 'Gene', (9, 12))	('non-uterine LMS', 'Disease', (49, 64))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', (0, 4))	('RB1', 'Gene', '5925', (9, 12))	('PTEN', 'Gene', '5728', (0, 4))
7419	25906748	NRAS mutations were detected in 20% of non-breast angiosarcomas, and were not found in those of breast origin.	('detected', 'Reg', (20, 28))	('angiosarcomas', 'Phenotype', 'HP:0200058', (50, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('non-breast angiosarcomas', 'Disease', 'MESH:C536368', (39, 63))	('mutations', 'Var', (5, 14))	('angiosarcoma', 'Phenotype', 'HP:0200058', (50, 62))	('NRAS', 'Gene', (0, 4))	('non-breast angiosarcomas', 'Disease', (39, 63))	('NRAS', 'Gene', '4893', (0, 4))
7420	25906748	The PIK3CA mutations noted in liposarcoma (5 cases) were found in 4 myxoid liposarcomas and in 1 high grade pleomporphic liposarcoma.	('mutations', 'Var', (11, 20))	('liposarcoma', 'Disease', (75, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('liposarcoma', 'Disease', (121, 132))	('liposarcoma', 'Phenotype', 'HP:0012034', (30, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('PIK3CA', 'Gene', (4, 10))	('found', 'Reg', (57, 62))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (68, 86))	('liposarcoma', 'Disease', 'MESH:D008080', (30, 41))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (68, 87))	('liposarcoma', 'Phenotype', 'HP:0012034', (75, 86))	('liposarcoma', 'Phenotype', 'HP:0012034', (121, 132))	('liposarcomas', 'Phenotype', 'HP:0012034', (75, 87))	('liposarcoma', 'Disease', 'MESH:D008080', (75, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('myxoid liposarcomas', 'Disease', (68, 87))	('liposarcoma', 'Disease', 'MESH:D008080', (121, 132))	('liposarcoma', 'Disease', (30, 41))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (68, 87))	('PIK3CA', 'Gene', '5290', (4, 10))
7421	25906748	No EGFR mutations were detected in our series (Figure 2a-d and Supplementary Table 3).	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))
7423	25906748	We detected BRAF, PTEN, p53 and NRAS mutations in angiosarcoma specimens, not previously described in the literature.	('p53', 'Gene', (24, 27))	('NRAS', 'Gene', (32, 36))	('BRAF', 'Gene', (12, 16))	('PTEN', 'Gene', (18, 22))	('BRAF', 'Gene', '673', (12, 16))	('PTEN', 'Gene', '5728', (18, 22))	('angiosarcoma', 'Disease', 'MESH:D006394', (50, 62))	('p53', 'Gene', '7157', (24, 27))	('angiosarcoma', 'Disease', (50, 62))	('NRAS', 'Gene', '4893', (32, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('mutations', 'Var', (37, 46))	('angiosarcoma', 'Phenotype', 'HP:0200058', (50, 62))
7427	25906748	We noted that 85.8% of samples demonstrated both TOPO2A expression by IHC and TP53 mutation (P value = 0.0001).	('TOPO2A', 'Gene', (49, 55))	('mutation', 'Var', (83, 91))	('expression', 'MPA', (56, 66))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))
7428	25906748	Three patient tumor samples had both a PIK3CA mutation and PTEN loss by IHC (myxoid liposarcoma, rhabdomyosarcoma and sarcoma, NOS).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (77, 95))	('PTEN', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('PIK3CA', 'Gene', '5290', (39, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('liposarcoma', 'Phenotype', 'HP:0012034', (84, 95))	('PTEN', 'Gene', '5728', (59, 63))	('patient', 'Species', '9606', (6, 13))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (97, 113))	('loss', 'NegReg', (64, 68))	('mutation', 'Var', (46, 54))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (77, 95))	('PIK3CA', 'Gene', (39, 45))	('tumor', 'Disease', (14, 19))	('myxoid liposarcoma', 'Disease', (77, 95))	('rhabdomyosarcoma and sarcoma', 'Disease', 'MESH:D012208', (97, 125))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
7432	25906748	Indeed, amplification of the TOPO2A gene has not reliably predicted increased protein levels of TOPO2A in other cancers.	('TOPO2A', 'Gene', (29, 35))	('amplification', 'Var', (8, 21))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('protein levels', 'MPA', (78, 92))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('increased', 'PosReg', (68, 77))
7440	25906748	Our analysis also found an association between TOPO2A overexpression by IHC and TP53 mutation status.	('overexpression', 'PosReg', (54, 68))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))	('TOPO2A', 'Gene', (47, 53))
7441	25906748	Indeed, in some studies, breast tumors containing TP53 mutations are exquisitely sensitive to anthracycline based therapy.	('breast tumors', 'Disease', (25, 38))	('mutations', 'Var', (55, 64))	('anthracycline', 'Chemical', 'MESH:D018943', (94, 107))	('TP53', 'Gene', '7157', (50, 54))	('sensitive', 'MPA', (81, 90))	('breast tumors', 'Phenotype', 'HP:0100013', (25, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TP53', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('breast tumors', 'Disease', 'MESH:D001943', (25, 38))
7452	25906748	MGMT gene silencing through promotor methylation confers sensitivity to the alkylating agents in glioblastoma.	('MGMT', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('methylation', 'Var', (37, 48))	('sensitivity', 'MPA', (57, 68))	('silencing', 'NegReg', (10, 19))	('glioblastoma', 'Disease', (97, 109))	('MGMT', 'Gene', '4255', (0, 4))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))
7460	25906748	On the other hand, PTEN promoter methylation appears to be an uncommon event and may not play a major role in down-regulation of PTEN expression.	('methylation', 'Var', (33, 44))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('PTEN', 'Gene', (129, 133))	('PTEN', 'Gene', '5728', (129, 133))
7462	25906748	Disappointingly, targeting this pathway with mTOR inhibitors has been unsuccessful clinically, possibly owing to the fact that preselection of tumors with alterations in the PI3-kinase pathway was not required for trial enrollment.	('alterations', 'Var', (155, 166))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (143, 149))	('mTOR', 'Gene', '2475', (45, 49))	('PI3-kinase pathway', 'Pathway', (174, 192))	('mTOR', 'Gene', (45, 49))
7464	25906748	PTEN mutations were most commonly seen in chondrosarcomas (7.7%), myxoid liposarcomas (16.7%), Ewing's sarcoma and rhabdomyosarcoma (6.3%).	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (42, 56))	('PTEN', 'Gene', '5728', (0, 4))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (42, 57))	('chondrosarcomas', 'Disease', 'MESH:D002813', (42, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	("Ewing's sarcoma and rhabdomyosarcoma", 'Disease', 'MESH:C563168', (95, 131))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (115, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (66, 84))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (95, 110))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('seen', 'Reg', (34, 38))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (66, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('mutations', 'Var', (5, 14))	('chondrosarcomas', 'Disease', (42, 57))	('liposarcomas', 'Phenotype', 'HP:0012034', (73, 85))	('PTEN', 'Gene', (0, 4))	('myxoid liposarcomas', 'Disease', (66, 85))	('liposarcoma', 'Phenotype', 'HP:0012034', (73, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (66, 85))
7465	25906748	Previous work has demonstrated PIK3CA mutations in 14-18% of myxoid and round cell liposarcoma.	('liposarcoma', 'Disease', 'MESH:D008080', (83, 94))	('liposarcoma', 'Phenotype', 'HP:0012034', (83, 94))	('liposarcoma', 'Disease', (83, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('mutations', 'Var', (38, 47))	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', '5290', (31, 37))	('myxoid', 'Disease', (61, 67))
7466	25906748	In our series, PIK3CA mutations were most commonly seen in myxoid liposarcoma (23.5%), as well as in rhabdomyosarcoma (7.4%), solitary fibrous tumor (6.3%) and UPS (5.5%).	('rhabdomyosarcoma', 'Disease', (101, 117))	('seen', 'Reg', (51, 55))	('myxoid liposarcoma', 'Disease', (59, 77))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (101, 117))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('PIK3CA', 'Gene', '5290', (15, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (59, 77))	('UPS', 'Gene', (160, 163))	('solitary fibrous tumor', 'Disease', (126, 148))	('solitary fibrous tumor', 'Disease', 'MESH:D054364', (126, 148))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (101, 117))	('mutations', 'Var', (22, 31))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (59, 77))	('UPS', 'Gene', '3145', (160, 163))	('PIK3CA', 'Gene', (15, 21))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))
7467	25906748	We had 1 case of myxoid liposarcoma with both PTEN loss by IHC and PIK3CA mutation, not previously described in the literature.	('PIK3CA', 'Gene', '5290', (67, 73))	('mutation', 'Var', (74, 82))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (17, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('IHC', 'Gene', (59, 62))	('PTEN', 'Gene', (46, 50))	('PTEN', 'Gene', '5728', (46, 50))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (17, 35))	('myxoid liposarcoma', 'Disease', (17, 35))	('PIK3CA', 'Gene', (67, 73))	('liposarcoma', 'Phenotype', 'HP:0012034', (24, 35))
7468	25906748	We also detected pathogenic PTEN mutations in angiosarcoma specimens, which have not previously been described in the literature.	('PTEN', 'Gene', (28, 32))	('angiosarcoma', 'Disease', 'MESH:D006394', (46, 58))	('PTEN', 'Gene', '5728', (28, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('angiosarcoma', 'Disease', (46, 58))	('mutations', 'Var', (33, 42))	('angiosarcoma', 'Phenotype', 'HP:0200058', (46, 58))	('pathogenic', 'Reg', (17, 27))
7469	25906748	Finally, our data suggests the co-existence of PTEN and TP53 mutations, as well as TP53 mutations and PTEN loss in sarcoma specimens.	('TP53', 'Gene', '7157', (83, 87))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('loss', 'NegReg', (107, 111))	('TP53', 'Gene', (83, 87))	('sarcoma', 'Disease', (115, 122))	('TP53', 'Gene', '7157', (56, 60))	('mutations', 'Var', (88, 97))	('mutations', 'Var', (61, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('TP53', 'Gene', (56, 60))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('PTEN', 'Gene', (102, 106))	('PTEN', 'Gene', '5728', (102, 106))
7477	25906748	Previous work has shown that both PD-1 and PD-L1 positivity were independent prognostic indicators for OS and EFS in sarcoma.	('sarcoma', 'Disease', (117, 124))	('PD-1', 'Gene', (34, 38))	('PD-1', 'Gene', '5133', (34, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('PD-L1', 'Gene', (43, 48))	('positivity', 'Var', (49, 59))	('EFS', 'Disease', (110, 113))	('PD-L1', 'Gene', '29126', (43, 48))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))
7481	25906748	In other solid tumors, there is concordance between protein expression by IHC and mutation or gene amplification as in the cases of cKIT and HER2 respectively.	('IHC', 'Gene', (74, 77))	('HER2', 'Gene', '2064', (141, 145))	('solid tumors', 'Disease', 'MESH:D009369', (9, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('mutation', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('gene amplification', 'Var', (94, 112))	('cKIT', 'Gene', (132, 136))	('cKIT', 'Gene', '3815', (132, 136))	('solid tumors', 'Disease', (9, 21))	('protein', 'MPA', (52, 59))	('HER2', 'Gene', (141, 145))
7487	25906748	In addition, no EGFR mutations were detected in our sarcomas, consistent with other series.	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('EGFR', 'Gene', '1956', (16, 20))	('sarcomas', 'Disease', (52, 60))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
7511	25906748	Prior to the availability of CLIA certified NGS, mutation analysis by Sanger sequencing included selected regions of BRAF, KRAS, cKIT, EGFR, and PIK3CA genes and was performed by using M13-linked PCR primers designed to amplify targeted sequences.	('PIK3CA', 'Gene', '5290', (145, 151))	('cKIT', 'Gene', '3815', (129, 133))	('KRAS', 'Gene', '3845', (123, 127))	('EGFR', 'Gene', '1956', (135, 139))	('mutation', 'Var', (49, 57))	('BRAF', 'Gene', '673', (117, 121))	('EGFR', 'Gene', (135, 139))	('KRAS', 'Gene', (123, 127))	('PIK3CA', 'Gene', (145, 151))	('cKIT', 'Gene', (129, 133))	('CLIA', 'Disease', (29, 33))	('CLIA', 'Disease', 'None', (29, 33))	('BRAF', 'Gene', (117, 121))
7535	26167450	According to CellSearch manufacturer's instructions, a CTC is characterized by positivity for EpCAM, cytokeratins (CKs), nuclear dye (DAPI), and negativity for CD45.	('positivity', 'Var', (79, 89))	('EpCAM', 'Gene', (94, 99))	('CD45', 'Gene', (160, 164))	('DAPI', 'Chemical', '-', (134, 138))	('EpCAM', 'Gene', '4072', (94, 99))	('CD45', 'Gene', '5788', (160, 164))	('negativity', 'Var', (145, 155))
7576	26167450	To date, this channel has been used to study the apoptotic status of CTCs integrating the system with a monoclonal antibody, anti-M30, anti Bcl-2, and anti-M65.	('anti-M30', 'Var', (125, 133))	('Bcl-2', 'Gene', (140, 145))	('anti-M65', 'Var', (151, 159))	('Bcl-2', 'Gene', '596', (140, 145))
7730	20857106	A radical resection is advised only for chondrosarcomas: the 5-year survival rate was 100% for R0 resections compared to 50% for irradical resections.	('R0 resections', 'Var', (95, 108))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (40, 54))	('chondrosarcomas', 'Disease', (40, 55))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (40, 55))	('chondrosarcomas', 'Disease', 'MESH:D002813', (40, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
7861	28732082	Additionally, datasets including germline TP53 variants and susceptibility to osteosarcoma, ezrin immunostaining, ErbB-2 status, telomerase expression, IGF-1/IGF-1R axis, chromosomal instability, and Fas expression allelotype/genotype are available for query.	('IGF-1', 'Gene', (152, 157))	('TP53', 'Gene', '7157', (42, 46))	('variants', 'Var', (47, 55))	('ErbB-2', 'Gene', (114, 120))	('osteosarcoma', 'Disease', 'MESH:D012516', (78, 90))	('chromosomal instability', 'Phenotype', 'HP:0040012', (171, 194))	('TP53', 'Gene', (42, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('IGF-1R', 'Gene', '3480', (158, 164))	('osteosarcoma', 'Phenotype', 'HP:0002669', (78, 90))	('IGF-1R', 'Gene', (158, 164))	('IGF-1', 'Gene', '3479', (158, 163))	('IGF-1', 'Gene', (158, 163))	('ErbB-2', 'Gene', '2064', (114, 120))	('osteosarcoma', 'Disease', (78, 90))	('IGF-1', 'Gene', '3479', (152, 157))
7877	28732082	Given the known chaotic genomic landscape of osteosarcoma, perturbations in multiple signaling pathways are likely in sarcomagenesis, and the finding that IGFBP2 alone does not drive hierarchal clustering is not an unexpected scientific outcome.	('IGFBP2', 'Gene', '3485', (155, 161))	('sarcomagenesis', 'Disease', (118, 132))	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('IGFBP2', 'Gene', (155, 161))	('osteosarcoma', 'Disease', (45, 57))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('perturbations', 'Var', (59, 72))	('sarcomagenesis', 'Disease', 'None', (118, 132))
7883	28732082	We have demonstrated that the influence of IGFBP2 in the circulation have a minimal effect on the global gene expression in the primary tumors and only a small set of genes is differentially expressed between the high and low IGFBP2 groups.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('IGFBP2', 'Gene', '3485', (43, 49))	('low', 'Var', (222, 225))	('IGFBP2', 'Gene', (43, 49))	('primary tumors', 'Disease', (128, 142))	('high', 'Var', (213, 217))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('IGFBP2', 'Gene', '3485', (226, 232))	('primary tumors', 'Disease', 'MESH:D009369', (128, 142))	('IGFBP2', 'Gene', (226, 232))
7941	24627870	Histopathological figure has been shown colonies of proliferation of cells with dysplastic changes such as extensive cytoplasm and large nuclei, prominent small nucleolus, mitotic figures, and polymorphism in stromal connective tissue with wide areas of necrosis [Figure 3].	('necrosis', 'Disease', (254, 262))	('dysplastic', 'Disease', 'MESH:D004416', (80, 90))	('polymorphism', 'Var', (193, 205))	('necrosis', 'Disease', 'MESH:D009336', (254, 262))	('dysplastic', 'Disease', (80, 90))	('mitotic figures', 'CPA', (172, 187))
8122	25805673	The 4 cases with positive cytogenetic abnormalities all had concurrent bone marrow involvement at diagnosis of MS (Table 1): 1 case with t(8;21) (q22;q22) (case 18); 1 case with FLT3-ITD heterozygous mutation and del(22q11) (case 12); 1 case with t(9;22) (q34;q11), inv(17) (q10), and trisomy 8 (case 10); and 2 cases with t(9;22) (q34;q11).	('FLT3', 'Gene', (178, 182))	('del(22q11', 'Var', (213, 222))	('FLT3', 'Gene', '2322', (178, 182))	('bone marrow involvement', 'Disease', 'MESH:D001855', (71, 94))	('bone marrow involvement', 'Disease', (71, 94))
8139	25805673	Rare cases with association of MS and colon adenocarcinoma were previously reported by Rocca et al., proposing the association with p53 deletion in intestinal stem cells.	('colon adenocarcinoma', 'Disease', (38, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (38, 58))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('deletion', 'Var', (136, 144))	('association', 'Interaction', (115, 126))
8155	25805673	Cytogenetic abnormalities, particularly monosomy 7, trisomy 8, MLL rearrangement, and inv(16), can be seen in about 55% of MS cases.	('monosomy 7', 'Var', (40, 50))	('MLL', 'Gene', (63, 66))	('trisomy 8', 'Var', (52, 61))	('MLL', 'Gene', '4297', (63, 66))
8161	25805673	Immunohistochemically, the expression of B-cell markers such as CD20 and CD79a is rarely seen in MS, but it should be noted that cases with t(8;21) (q22;q22) may express PAX5, CD19, and CD79a.	('CD20', 'Gene', (64, 68))	('CD79a', 'Gene', (186, 191))	('CD19', 'Gene', '930', (176, 180))	('PAX5', 'Gene', '5079', (170, 174))	('CD20', 'Gene', '54474', (64, 68))	('t(8;21) (q22;q22', 'Var', (140, 156))	('express', 'Reg', (162, 169))	('CD79a', 'Gene', '973', (73, 78))	('PAX5', 'Gene', (170, 174))	('CD79a', 'Gene', '973', (186, 191))	('CD19', 'Gene', (176, 180))	('CD79a', 'Gene', (73, 78))
8175	24124617	In this present study, we detected the Ewing sarcoma-specific EWS/Fli-1 mRNA in MVs from the culture medium of ES cell lines carrying t(11;22) (q24; 12).	('t(11;22) (q24; 12', 'Var', (134, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (39, 52))	('ES', 'Phenotype', 'HP:0012254', (111, 113))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('EWS/Fli-1', 'Gene', (62, 71))	('Ewing sarcoma', 'Disease', (39, 52))
8180	24124617	The 2 main types of EWS/Fli-1 fusions, a fusion of EWS exon 7 to FLI1 exon 6 (type 1) and that of EWS exon 7 to FLI1 exon 5 (type 2), account for about 60 and 25% of cases, respectively.	('FLI1', 'Gene', '2313', (65, 69))	('FLI1', 'Gene', (65, 69))	('EWS/Fli-1', 'Gene', (20, 29))	('fusions', 'Var', (30, 37))	('FLI1', 'Gene', (112, 116))	('FLI1', 'Gene', '2313', (112, 116))
8185	24124617	TC-135 and A673 produce the EWS/Fli-1 Type 1 fusion, whereas SK-ES-1 has the Type 2 fusion.	('Fli-1 Type 1', 'Gene', (32, 44))	('A673', 'Var', (11, 15))	('TC-135', 'CellLine', 'CVCL:9698', (0, 6))	('Fli-1 Type 1', 'Gene', '2313', (32, 44))	('SK-ES-1', 'CellLine', 'CVCL:0627', (61, 68))	('TC-135', 'Var', (0, 6))	('ES', 'Phenotype', 'HP:0012254', (64, 66))
8198	24124617	EWS/ATF-1 mRNA was amplified by use of primers 5'-GAGGCATGAGCAGAGGTGG-3' (forward) and 5'-GAAGTCCCTGTACTCCATCTGTG-3' (reverse; Figure 2D).	("5'-GAAGTCCCTGTACTCCATCTGTG-3", 'Var', (87, 115))	('EWS/ATF-1', 'Gene', (0, 9))	('EWS/ATF-1', 'Gene', '466;2130', (0, 9))
8199	24124617	Amplification of GAPDH mRNA was achieved with primers 5'-CCACCCATGGCAAATTCCATGGCA-3' (forward) and 5'-TCTAGACGGCAGGTCAGGTCCACC-3' (reverse).	('GAPDH', 'Gene', '2597', (17, 22))	("5'-TCTAGACGGCAGGTCAGGTCCACC-3", 'Var', (99, 128))	('GAPDH', 'Gene', (17, 22))	('Amplification', 'MPA', (0, 13))	("5'-CCACCCATGGCAAATTCCATGGCA-3", 'Var', (54, 83))
8212	24124617	A total of 3.0 x 106 TC135 or A673 cells in 0.1 ml of PBS (Wako, Osaka, Japan) were inoculated subcutaneously, through a 26-gauge needle into the posterior flank and hip of 10 mice (5 weeks old).	('mice', 'Species', '10090', (176, 180))	('PBS', 'Chemical', 'MESH:D007854', (54, 57))	('A673', 'Var', (30, 34))	('TC135', 'Gene', (21, 26))
8231	24124617	On the other hand three of the seven mice inoculated with A673 cells had demonstrable EWS/Fli-1 mRNA in the MVs derived from their blood (Figure 5).	('A673 cells', 'Var', (58, 68))	('mRNA', 'MPA', (96, 100))	('EWS/Fli-1', 'Gene', (86, 95))	('mice', 'Species', '10090', (37, 41))
8362	23077516	Among the treated groups were cells that were Annexin V-FITC positive and PI negative, indicating that they were undergoing apoptosis, and cells that were Annexin V-FITC and PI positive, indicating that they were in end-stage apoptosis or already dead (Figure 2C).	('negative', 'NegReg', (77, 85))	('Annexin V', 'Gene', '308', (155, 164))	('PI positive', 'Var', (174, 185))	('Annexin V', 'Gene', (155, 164))	('Annexin V', 'Gene', '308', (46, 55))	('end-stage apoptosis', 'CPA', (216, 235))	('Annexin V', 'Gene', (46, 55))
8381	23077516	In A431 and Hep2 cells, treatment with the combination of TQ 10 microM and DG 20 microM reduced cell viability remarkably, to 18.87% and 26.61%, respectively, significantly lower than in controls.	('A431', 'CellLine', 'CVCL:0037', (3, 7))	('cell viability', 'CPA', (96, 110))	('DG 20 microM', 'Var', (75, 87))	('TQ', 'Chemical', 'MESH:C003466', (58, 60))	('Hep2', 'CellLine', 'CVCL:1906', (12, 16))	('TQ 10 microM', 'Var', (58, 70))	('lower', 'NegReg', (173, 178))	('reduced', 'NegReg', (88, 95))
8382	23077516	The combination of TQ 20 microM and DG10 microM reduced A431 and Hep2 viability to 21.19% and 21.85%, respectively, again significantly lower than in controls.	('lower', 'NegReg', (136, 141))	('A431', 'CPA', (56, 60))	('Hep2', 'CellLine', 'CVCL:1906', (65, 69))	('reduced', 'NegReg', (48, 55))	('A431', 'CellLine', 'CVCL:0037', (56, 60))	('DG10 microM', 'Var', (36, 47))	('TQ', 'Chemical', 'MESH:C003466', (19, 21))	('Hep2 viability', 'CPA', (65, 79))
8383	23077516	The combination of TQ 20 microM and DG 20 microM at 48 hours reduced viability to 14.71% and 10.38% in A431 and Hep2 cells, respectively (Figure 6A).	('TQ 20 microM', 'Var', (19, 31))	('DG 20 microM', 'Var', (36, 48))	('viability', 'CPA', (69, 78))	('A431', 'CellLine', 'CVCL:0037', (103, 107))	('Hep2', 'CellLine', 'CVCL:1906', (112, 116))	('TQ', 'Chemical', 'MESH:C003466', (19, 21))	('reduced', 'NegReg', (61, 68))
8386	23077516	To confirm the presence of synergism, we determined the CI for two combination treatment groups in both A431 and Hep2 cells; CI<1 indicated a synergistic effect (Figure 6B).	('synergistic', 'Interaction', (142, 153))	('A431', 'CellLine', 'CVCL:0037', (104, 108))	('CI<1', 'Var', (125, 129))	('Hep2', 'CellLine', 'CVCL:1906', (113, 117))
8433	23077516	Inhibition of the MAPK and PI3K/Akt pathway may have the potential to prevent angiogenesis, proliferation, invasion and metastasis of a wide range of tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('Akt', 'Gene', '207', (32, 35))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('angiogenesis', 'CPA', (78, 90))	('Akt', 'Gene', (32, 35))	('prevent', 'NegReg', (70, 77))	('metastasis', 'CPA', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('Inhibition', 'Var', (0, 10))	('invasion', 'CPA', (107, 115))	('proliferation', 'CPA', (92, 105))	('MAPK', 'Pathway', (18, 22))
8441	23077516	We find that TQ+DG show highly significant potential to reduce tumor size and weight in tumor-bearing animals, much higher than either treatment alone or no treatment.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('TQ+DG', 'Var', (13, 18))	('reduce', 'NegReg', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (88, 93))	('TQ+DG', 'Chemical', '-', (13, 18))
8442	23077516	Significant increases in DNA fragmentation and disorganization of F-action filaments are shown by TUNEL assay and DAPI/phalloidin-TRITC staining, respectively, in TQ-, DG- and TQ+DG-treated mice compared to control tumor-bearing mice.	('DNA fragmentation', 'CPA', (25, 42))	('TQ-', 'Var', (163, 166))	('mice', 'Species', '10090', (229, 233))	('DG-', 'Var', (168, 171))	('disorganization', 'CPA', (47, 62))	('TQ', 'Chemical', 'MESH:C003466', (176, 178))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('mice', 'Species', '10090', (190, 194))	('TQ+DG', 'Chemical', '-', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('TQ', 'Chemical', 'MESH:C003466', (163, 165))	('increases', 'PosReg', (12, 21))	('DAPI', 'Chemical', 'MESH:C007293', (114, 118))	('tumor', 'Disease', (215, 220))	('TQ+DG-treated', 'Var', (176, 189))	('F-action filaments', 'CPA', (66, 84))
8468	32481285	The inclusion criteria for STS patients of the extremities or trunk in this study were as follows: Diagnosed with soft tissue sarcoma International Classification of Diseases for Oncology (ICD-O): sarcoma NOS (8880-8806), fibrosarcoma (8810-8815), malignant fibrohistiocytoma (8830), liposarcoma (8850-8857), dedifferentiated liposarcoma (8858), leiomyosarcoma (8890, 8891, 8896), synovial sarcoma (9040-9044), and malignant peripheral nerve sheath tumor (MPNST) (9540, 9561), as primary malignancy between 2010 and 2015.	('malignant peripheral nerve sheath tumor', 'Disease', (415, 454))	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('sarcoma', 'Disease', (197, 204))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('liposarcoma', 'Phenotype', 'HP:0012034', (284, 295))	('liposarcoma', 'Disease', 'MESH:D008080', (326, 337))	('sarcoma', 'Disease', 'MESH:D012509', (330, 337))	('sarcoma', 'Disease', (126, 133))	('malignancy', 'Disease', 'MESH:D009369', (488, 498))	('9540', 'Var', (464, 468))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (415, 454))	('sarcoma', 'Disease', (330, 337))	('8830', 'Var', (277, 281))	('leiomyosarcoma', 'Disease', (346, 360))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (114, 133))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (222, 234))	('sarcoma', 'Disease', 'MESH:D012509', (353, 360))	('liposarcoma', 'Disease', 'MESH:D008080', (284, 295))	('synovial sarcoma', 'Disease', (381, 397))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('sarcoma', 'Disease', 'MESH:D012509', (227, 234))	('sarcoma', 'Disease', (353, 360))	('malignant fibrohistiocytoma', 'Disease', (248, 275))	('synovial sarcoma', 'Disease', 'MESH:D013584', (381, 397))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('8890', 'Var', (362, 366))	('sarcoma', 'Disease', (227, 234))	('liposarcoma', 'Disease', (326, 337))	('sarcoma', 'Phenotype', 'HP:0100242', (330, 337))	('malignancy', 'Disease', (488, 498))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (415, 454))	('sarcoma', 'Disease', 'MESH:D012509', (288, 295))	('Oncology', 'Phenotype', 'HP:0002664', (179, 187))	('fibrosarcoma', 'Disease', 'MESH:D005354', (222, 234))	('tumor', 'Phenotype', 'HP:0002664', (449, 454))	('sarcoma', 'Disease', (288, 295))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (381, 397))	('fibrosarcoma', 'Disease', (222, 234))	('9040-9044', 'Var', (399, 408))	('sarcoma', 'Disease', 'MESH:D012509', (390, 397))	('8850-8857', 'Var', (297, 306))	('liposarcoma', 'Disease', (284, 295))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (346, 360))	('malignant fibrohistiocytoma', 'Disease', 'MESH:D009369', (248, 275))	('8880-8806', 'Var', (210, 219))	('sarcoma', 'Disease', (390, 397))	('8810-8815', 'Var', (236, 245))	('patients', 'Species', '9606', (31, 39))	('liposarcoma', 'Phenotype', 'HP:0012034', (326, 337))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (346, 360))	('8858', 'Var', (339, 343))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))
8469	32481285	Site limited to of the extremity or trunk (C47.1, C47.2, C47.3, C47.6 C49.1, C49.2, C49.6, C49.3, and C76.1.).	('C47.2', 'CellLine', 'CVCL:L675', (50, 55))	('C47.3', 'Var', (57, 62))	('C49.6', 'Var', (84, 89))	('C49.2', 'Var', (77, 82))	('C49.3', 'Var', (91, 96))	('C47.6', 'Var', (64, 69))	('C47.6 C49.1', 'CellLine', 'CVCL:U639', (64, 75))	('C47.3', 'CellLine', 'CVCL:L675', (57, 62))
8620	31742892	Two CpG sites (cg15585341 and cg04126335) around the promoter of ITGA10 showed strong negative correlations with ITGA10 expression (Pearson's r < -0.6).	('ITGA10', 'Gene', (113, 119))	('cg04126335', 'Var', (30, 40))	('expression', 'MPA', (120, 130))	('ITGA10', 'Gene', (65, 71))	('correlations', 'Interaction', (95, 107))	('cg15585341', 'Var', (15, 25))	('negative', 'NegReg', (86, 94))	('ITGA10', 'Gene', '8515', (113, 119))	('cg04126335', 'Chemical', '-', (30, 40))	('ITGA10', 'Gene', '8515', (65, 71))
8632	31742892	Gene-level CNAs were calculated by the method of Genomic Identification of Significant Targets in Cancer 2.0 (GISTIC2),12 in which the alterations were defined as homozygous deletion (-2), heterozygous loss (-1), copy neutral (0), low-level copy gain (+1) and high-level amplification (+2).	('high-level amplification', 'Var', (260, 284))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (98, 104))	('low-level copy gain', 'Var', (231, 250))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('heterozygous loss', 'Var', (189, 206))
8643	31742892	In univariate analysis, larger tumour size, with pharmaceutical drug adjuvant therapy, high FNCLCC grade, increased COL11A1, ITGA10 and KIF26B expression, and decreased CLEC3B, DUOX2, KRT75 and PPP2R2B were risk factors of shorter RFS (Table 1).	('KRT75', 'Gene', (184, 189))	('high', 'Var', (87, 91))	('PPP2R2B', 'Gene', '5521', (194, 201))	('PPP2R2B', 'Gene', (194, 201))	('KIF26B', 'Gene', '55083', (136, 142))	('decreased', 'NegReg', (159, 168))	('COL11A1', 'Gene', '1301', (116, 123))	('KIF26B', 'Gene', (136, 142))	('increased', 'PosReg', (106, 115))	('ITGA10', 'Gene', '8515', (125, 131))	('DUOX2', 'Gene', '50506', (177, 182))	('expression', 'MPA', (143, 153))	('ITGA10', 'Gene', (125, 131))	('FNCLCC grade', 'Gene', (92, 104))	('CLEC3B', 'Gene', '7123', (169, 175))	('KRT75', 'Gene', '9119', (184, 189))	('COL11A1', 'Gene', (116, 123))	('DUOX2', 'Gene', (177, 182))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('CLEC3B', 'Gene', (169, 175))	('tumour', 'Disease', (31, 37))
8653	31742892	Among the 61 UPS/MFS cases, there were 36 amplification, 20 copy neutral and five deletion cases (Figure 3A).	('copy neutral', 'Var', (60, 72))	('deletion', 'Var', (82, 90))	('UPS', 'Disease', 'MESH:D017118', (13, 16))	('MFS', 'Disease', 'MESH:D008382', (17, 20))	('MFS', 'Disease', (17, 20))	('amplification', 'Var', (42, 55))	('UPS', 'Disease', (13, 16))
8655	31742892	There were 2 missense mutations (p.N336S and p.R668Q) and 1 silent mutation (p.G89G) (Figure 3A), suggesting that somatic mutation was not common in this gene.	('p.N336S', 'Var', (33, 40))	('p.R668Q', 'Var', (45, 52))	('p.G89G', 'Var', (77, 83))	('p.G89G', 'SUBSTITUTION', 'None', (77, 83))	('p.N336S', 'Mutation', 'p.N336S', (33, 40))	('p.R668Q', 'Mutation', 'p.R668Q', (45, 52))
8658	31742892	Transcript expression analysis showed that the two dominant transcripts of ITGA10 (ENST00000369304.7 and ENST00000539363.2) in TCGA sarcoma cases contain exon 1 (Figure S2), suggesting that the promoter of ITGA10 transcription locates before this exon.	('ENST00000539363.2', 'Var', (105, 122))	('ENST00000369304.7', 'Var', (83, 100))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))	('sarcoma', 'Disease', (132, 139))	('ITGA10', 'Gene', (206, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('ITGA10', 'Gene', '8515', (75, 81))	('ITGA10', 'Gene', '8515', (206, 212))	('ITGA10', 'Gene', (75, 81))
8659	31742892	By checking the methylation of 5 CpG sites in ITGA10 locus, we found two CpG sites (cg15585341 and cg04126335), the methylation of which showed strong negative correlations with ITGA10 expression (Pearson's r <-0.6, Figure 3D-E, green dotted frame).	('cg04126335', 'Var', (99, 109))	('correlations', 'Interaction', (160, 172))	('ITGA10', 'Gene', (178, 184))	('negative', 'NegReg', (151, 159))	('expression', 'MPA', (185, 195))	('ITGA10', 'Gene', '8515', (46, 52))	('ITGA10', 'Gene', '8515', (178, 184))	('cg15585341', 'Var', (84, 94))	('ITGA10', 'Gene', (46, 52))	('cg04126335', 'Chemical', '-', (99, 109))
8660	31742892	Cg15585341 locates within exon 1, while cg04126335 is in the first intron of ITGA10 (Figure 3D), suggesting that their hypomethylation status might contribute to enhanced transcription of the gene.	('transcription', 'MPA', (171, 184))	('cg04126335', 'Var', (40, 50))	('hypomethylation status', 'MPA', (119, 141))	('Cg15585341', 'Chemical', '-', (0, 10))	('Cg15585341', 'Var', (0, 10))	('ITGA10', 'Gene', '8515', (77, 83))	('enhanced', 'PosReg', (162, 170))	('cg04126335', 'Chemical', '-', (40, 50))	('ITGA10', 'Gene', (77, 83))
8669	31742892	cg15021031, cg25928493, cg25325094 and cg02760293 in the green dotted frame locate at the intron regions before exon 10, while the 10 CpG sites in purple dotted frame scatter across the introns after exon 10 (Figure 4D-E).	('cg25325094', 'Var', (24, 34))	('cg02760293', 'Var', (39, 49))	('cg25928493', 'Var', (12, 22))	('cg15021031', 'Var', (0, 10))	('cg25928493', 'Chemical', '-', (12, 22))	('cg02760293', 'Chemical', '-', (39, 49))	('cg25325094', 'Chemical', '-', (24, 34))	('cg15021031', 'Chemical', '-', (0, 10))
8721	29506492	Fertility preservation treatment failure or suboptimal response can also lead to psychological distress, and loss of hope for future fertility.	('men', 'Species', '9606', (28, 31))	('suboptimal', 'Var', (44, 54))	('loss', 'NegReg', (109, 113))	('lead to', 'Reg', (73, 80))	('psychological distress', 'CPA', (81, 103))
8804	29506492	Loss of these body parts further threatened feminine gender identity: "I'm losing my breasts, ovaries, ability to have children...I guess it removes a lot of your femininity" (Roxanne 25 Breast, 1 year, nulliparous).	('ovaries', 'Disease', 'MESH:D010051', (94, 101))	('Roxanne 25 Breast', 'Var', (176, 193))	('removes', 'NegReg', (141, 148))	('children', 'Species', '9606', (119, 127))	('ovaries', 'Disease', (94, 101))
8877	29506492	Absence of empathy or understanding was also evident in some accounts of inappropriate comments, such as "jokes about having only one ball" (Christian 37 Testicular, 10 year, parous).	('Christian 37 Testicular', 'Var', (141, 164))	('Absence of empathy', 'Disease', 'MESH:D004832', (0, 18))	('men', 'Species', '9606', (90, 93))	('Absence of empathy', 'Disease', (0, 18))	('parous', 'Disease', (175, 181))
8962	29506492	The qualitative analysis presented in the present study provides insight into previous findings that infertility related distress is higher in cancer patients who do not have children, findings also reflected in our analysis of primary outcomes, where nulliparous status was significantly associated with infertility-related distress for both women and men.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('nulliparous status', 'Var', (252, 270))	('infertility', 'Phenotype', 'HP:0000789', (101, 112))	('infertility', 'Disease', 'MESH:D007247', (101, 112))	('higher', 'PosReg', (133, 139))	('women', 'Species', '9606', (343, 348))	('men', 'Species', '9606', (345, 348))	('patients', 'Species', '9606', (150, 158))	('associated', 'Reg', (289, 299))	('infertility', 'Disease', 'MESH:D007247', (305, 316))	('infertility', 'Disease', (101, 112))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('men', 'Species', '9606', (353, 356))	('children', 'Species', '9606', (175, 183))	('infertility', 'Phenotype', 'HP:0000789', (305, 316))	('infertility', 'Disease', (305, 316))	('fertility related distress', 'Phenotype', 'HP:0000144', (103, 129))
8994	29212209	Inhibitors of glutaminase activity have gained attention in the last few years due to their anti-proliferative effect and ability to induce apoptosis in some cancers.	('anti-proliferative effect', 'CPA', (92, 117))	('apoptosis', 'CPA', (140, 149))	('Inhibitors', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('induce', 'Reg', (133, 139))	('glutaminase', 'Protein', (14, 25))
8999	29212209	SiRNA mediated NF1 knockdown in wild-type NF1 cell line shows increased sensitivity to glutaminase inhibition.	('increased', 'PosReg', (62, 71))	('sensitivity to glutaminase inhibition', 'MPA', (72, 109))	('NF1', 'Gene', (15, 18))	('knockdown', 'Var', (19, 28))	('NF1', 'Gene', '4763', (15, 18))	('increased sensitivity to glutaminase', 'Phenotype', 'HP:0025376', (62, 98))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', (42, 45))
9013	29212209	Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused due to the loss and/or mutation of NF1 tumor suppressor gene.	('tumor', 'Disease', (119, 124))	('NF1', 'Gene', (115, 118))	('NF1', 'Gene', '4763', (115, 118))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', '4763', (26, 29))	('autosomal dominant genetic disorder', 'Disease', 'MESH:D030342', (37, 72))	('autosomal dominant genetic disorder', 'Disease', (37, 72))	('Neurofibromatosis type 1', 'Gene', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('loss', 'NegReg', (91, 95))	('Neurofibromatosis type 1', 'Gene', '4763', (0, 24))	('mutation', 'Var', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
9014	29212209	The NF1 gene codes for a Ras GTPase activating protein called Neurofibromin (NF) and mutational inactivation and/or loss of NF1 can lead to altered Ras-MAPK signaling.	('NF1', 'Gene', (124, 127))	('Ras-MAPK signaling', 'MPA', (148, 166))	('GTP', 'Chemical', 'MESH:D006160', (29, 32))	('lead to altered', 'Reg', (132, 147))	('NF', 'Gene', '4763', (77, 79))	('mutational inactivation', 'Var', (85, 108))	('NF1', 'Gene', (4, 7))	('NF', 'Gene', '4763', (4, 6))	('loss', 'NegReg', (116, 120))	('NF1', 'Gene', '4763', (4, 7))	('NF', 'Gene', '4763', (124, 126))	('Neurofibromin', 'Gene', '4763', (62, 75))	('Neurofibromin', 'Gene', (62, 75))	('NF1', 'Gene', '4763', (124, 127))
9025	29212209	MPNST, ST8814 and S462 cell lines used in this study have been shown previously to carry a mutation/deletion in NF1, whereas, STS26T cell line carries wild-type NF1.	('S462', 'CellLine', 'CVCL:1Y70', (18, 22))	('mutation/deletion', 'Var', (91, 108))	('NF1', 'Gene', '4763', (112, 115))	('NF1', 'Gene', (112, 115))	('NF1', 'Gene', (161, 164))	('STS26T', 'CellLine', 'CVCL:8917', (126, 132))	('NF1', 'Gene', '4763', (161, 164))
9026	29212209	LS141 (Liposarcoma) and CHP100 (Ewing Sarcoma) cell lines, on the other hand, have been used extensively and both these cell lines have not been reported to harbor any NF1 mutation/loss (also, personal communication with Kanojia D, Cancer Science Institute, Singapore).	('Liposarcoma) and CHP100 (Ewing Sarcoma', 'Disease', 'MESH:C563168', (7, 45))	('LS141', 'CellLine', 'CVCL:2105', (0, 5))	('Sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('Cancer', 'Phenotype', 'HP:0002664', (232, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (32, 45))	('Liposarcoma', 'Phenotype', 'HP:0012034', (7, 18))	('NF1', 'Gene', (168, 171))	('Kanojia D, Cancer', 'Disease', 'MESH:D009369', (221, 238))	('NF1', 'Gene', '4763', (168, 171))	('mutation/loss', 'Var', (172, 185))
9028	29212209	MPNST cell line shows detectable levels of NF1 expression since it is NF1 mutant, whereas, ST8814 and S462 cell lines do not show any detectable levels of NF1 on the western blot (Figure 1A).	('NF1', 'Gene', '4763', (70, 73))	('NF1', 'Gene', (43, 46))	('NF1', 'Gene', '4763', (43, 46))	('S462', 'CellLine', 'CVCL:1Y70', (102, 106))	('mutant', 'Var', (74, 80))	('NF1', 'Gene', (155, 158))	('NF1', 'Gene', (70, 73))	('NF1', 'Gene', '4763', (155, 158))
9030	29212209	Removal of glutamine from the media significantly (p<0.0005) decreased cell viability (Figure 1B) only in the NF1 mutant/null cell lines, MPNST, ST8814 and S462 compared to wild-type NF1 sarcoma cell lines, LS141, CHP100 and STS26T.	('NF1', 'Gene', (110, 113))	('NF1', 'Gene', (183, 186))	('glutamine', 'Chemical', 'MESH:D005973', (11, 20))	('mutant/null', 'Var', (114, 125))	('NF1', 'Gene', '4763', (110, 113))	('NF1', 'Gene', '4763', (183, 186))	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('S462', 'CellLine', 'CVCL:1Y70', (156, 160))	('sarcoma', 'Disease', (187, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('STS26T', 'CellLine', 'CVCL:8917', (225, 231))	('decreased', 'NegReg', (61, 70))	('cell viability', 'CPA', (71, 85))	('LS141', 'CellLine', 'CVCL:2105', (207, 212))
9031	29212209	A similar decrease in cell viability was observed in an NF1-null metastatic melanoma cell line, MeWo when glutamine was removed from the media, whereas, another melanoma cell line, 92.1, that does not carry any NF1 mutation/deletion did not show any decrease in cell viability after glutamine removal from the media (Supplementary Figure 1, left panel).	('melanoma', 'Disease', (76, 84))	('NF1', 'Gene', '4763', (56, 59))	('mutation/deletion', 'Var', (215, 232))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('NF1', 'Gene', (211, 214))	('glutamine', 'Chemical', 'MESH:D005973', (283, 292))	('NF1', 'Gene', '4763', (211, 214))	('decrease', 'NegReg', (10, 18))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('glutamine', 'Chemical', 'MESH:D005973', (106, 115))	('cell viability', 'CPA', (22, 36))	('melanoma', 'Disease', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('NF1', 'Gene', (56, 59))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
9032	29212209	This clearly suggested that cancer cell lines other than soft-tissue sarcoma carrying NF1 mutation/deletion may also show sensitivity to glutamine deprivation.	('sensitivity to glutamine deprivation', 'MPA', (122, 158))	('mutation/deletion', 'Var', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('sarcoma', 'Disease', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('NF1', 'Gene', '4763', (86, 89))	('glutamine', 'Chemical', 'MESH:D005973', (137, 146))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('NF1', 'Gene', (86, 89))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (57, 76))	('cancer', 'Disease', (28, 34))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))
9033	29212209	Western blot analysis shows that removal of glutamine from the media induced apoptosis (shown as induction of cleaved poly ADP-ribose polymerase, PARP) only in NF1 mutant/null but not in wild-type NF1 cell lines (Figure 1C and Supplementary Figure 1, right panel).	('poly ADP-ribose polymerase', 'Gene', (118, 144))	('PARP', 'Gene', '142', (146, 150))	('NF1', 'Gene', (160, 163))	('apoptosis', 'CPA', (77, 86))	('NF1', 'Gene', (197, 200))	('NF1', 'Gene', '4763', (160, 163))	('NF1', 'Gene', '4763', (197, 200))	('mutant/null', 'Var', (164, 175))	('PARP', 'Gene', (146, 150))	('poly ADP-ribose polymerase', 'Gene', '142', (118, 144))	('glutamine', 'Chemical', 'MESH:D005973', (44, 53))	('induced', 'Reg', (69, 76))
9034	29212209	Since glutaminolysis is known to play an important role in mTORC1 activation, removal of glutamine from media downregulated mTORC1 activity (shown as decreased phosphorylation of S6 ribosomal protein, p-S6 S235/236 and also quantitated in arbitrary densitometric units) in NF1 mutant/null but not wild-type NF1 cell lines (Figure 1C and Supplementary Figure 1).	('phosphorylation', 'MPA', (160, 175))	('mTORC1', 'Gene', (124, 130))	('NF1', 'Gene', '4763', (307, 310))	('NF1', 'Gene', (273, 276))	('p-S6', 'Gene', (201, 205))	('mTORC1', 'Gene', '382056', (59, 65))	('activity', 'MPA', (131, 139))	('mutant/null', 'Var', (277, 288))	('NF1', 'Gene', '4763', (273, 276))	('mTORC1', 'Gene', '382056', (124, 130))	('glutamine', 'Chemical', 'MESH:D005973', (89, 98))	('decreased', 'NegReg', (150, 159))	('mTORC1', 'Gene', (59, 65))	('p-S6', 'Gene', '338413', (201, 205))	('downregulated', 'NegReg', (110, 123))	('NF1', 'Gene', (307, 310))
9037	29212209	As shown in Figure 2A and 2B, both BPTES and CB-839 treatment resulted in a significant decrease (p<0.001) in cell viability only in NF1 mutant/null cell lines (also Supplementary Figure 1, left panel).	('CB-839', 'Gene', (45, 51))	('decrease', 'NegReg', (88, 96))	('CB-839', 'Chemical', 'MESH:C000593334', (45, 51))	('BPTES', 'Chemical', 'MESH:C523193', (35, 40))	('cell viability', 'CPA', (110, 124))	('NF1', 'Gene', (133, 136))	('mutant/null', 'Var', (137, 148))	('NF1', 'Gene', '4763', (133, 136))
9039	29212209	Western blot analysis (Figure 2C) after 48 hours of CB-839 treatment revealed induction of cleaved PARP as well as downregulation of mTORC1 targets such as p-S6 and p-4EBP1 in NF1 mutant/null but not in wild-type NF1 cell lines.	('mutant/null', 'Var', (180, 191))	('NF1', 'Gene', '4763', (176, 179))	('mTORC1', 'Gene', '382056', (133, 139))	('NF1', 'Gene', (176, 179))	('PARP', 'Gene', (99, 103))	('cleaved', 'MPA', (91, 98))	('p-S6', 'Gene', '338413', (156, 160))	('p-S6', 'Gene', (156, 160))	('p-4EBP1', 'Var', (165, 172))	('NF1', 'Gene', (213, 216))	('CB-839', 'Chemical', 'MESH:C000593334', (52, 58))	('mTORC1', 'Gene', (133, 139))	('PARP', 'Gene', '142', (99, 103))	('NF1', 'Gene', '4763', (213, 216))	('downregulation', 'NegReg', (115, 129))
9045	29212209	Only CB-839 but not rapamycin treatment induced cleaved PARP in the NF1-null ST8814 cell line (Supplementary Figure 2).	('CB-839', 'Chemical', 'MESH:C000593334', (5, 11))	('PARP', 'Gene', '142', (56, 60))	('NF1', 'Gene', (68, 71))	('NF1', 'Gene', '4763', (68, 71))	('rapamycin', 'Chemical', 'MESH:D020123', (20, 29))	('CB-839', 'Var', (5, 11))	('PARP', 'Gene', (56, 60))	('cleaved', 'MPA', (48, 55))
9070	29212209	We also carried out siRNA mediated knockdown of NF1 in the wild-type NF1 cell line, STS26T.	('NF1', 'Gene', '4763', (69, 72))	('knockdown', 'Var', (35, 44))	('NF1', 'Gene', '4763', (48, 51))	('STS26T', 'CellLine', 'CVCL:8917', (84, 90))	('NF1', 'Gene', (69, 72))	('NF1', 'Gene', (48, 51))
9071	29212209	As a result of NF1 knockdown, STS26T cell line exhibited decreased cell viability, and reduced mTORC1 activity (p-S6) (Figure 5B).	('NF1', 'Gene', (15, 18))	('p-S6', 'Gene', '338413', (112, 116))	('knockdown', 'Var', (19, 28))	('NF1', 'Gene', '4763', (15, 18))	('reduced', 'NegReg', (87, 94))	('mTORC1', 'Gene', (95, 101))	('STS26T', 'CellLine', 'CVCL:8917', (30, 36))	('p-S6', 'Gene', (112, 116))	('cell viability', 'CPA', (67, 81))	('decreased', 'NegReg', (57, 66))	('mTORC1', 'Gene', '382056', (95, 101))
9073	29212209	CB-839 treatment post NF1 knockdown was able to reduce increased Ras-GTP levels (Figure 5B, western blot, lane 4) clearly suggesting glutamine dependency in these cells when NF1 is knocked down.	('Ras-GTP levels', 'MPA', (65, 79))	('Ras-GTP', 'Chemical', '-', (65, 72))	('NF1', 'Gene', (22, 25))	('CB-839', 'Gene', (0, 6))	('NF1', 'Gene', '4763', (22, 25))	('CB-839', 'Chemical', 'MESH:C000593334', (0, 6))	('increased', 'PosReg', (55, 64))	('NF1', 'Gene', '4763', (174, 177))	('knockdown', 'Var', (26, 35))	('NF1', 'Gene', (174, 177))	('reduce', 'NegReg', (48, 54))	('glutamine', 'Chemical', 'MESH:D005973', (133, 142))
9074	29212209	No changes in the expression levels of GLS1 were observed after SiRNA mediated knockdown of NF1 or post CB-839 treatment (Figure 5B).	('expression levels', 'MPA', (18, 35))	('GLS1', 'Gene', '2744', (39, 43))	('NF1', 'Gene', (92, 95))	('CB-839', 'Chemical', 'MESH:C000593334', (104, 110))	('NF1', 'Gene', '4763', (92, 95))	('knockdown', 'Var', (79, 88))	('GLS1', 'Gene', (39, 43))
9077	29212209	Western blot analysis (Figure 6B) revealed inhibition of downstream signaling pathways including p-ERK1/2 as well as mTORC1 targets such as p-S6 and p-4EBP1, thus, confirming the inhibition observed in vitro.	('p-ERK', 'Gene', '9451', (97, 102))	('inhibition', 'NegReg', (43, 53))	('mTORC1', 'Gene', '382056', (117, 123))	('p-ERK', 'Gene', (97, 102))	('p-S6', 'Gene', '338413', (140, 144))	('p-4EBP1', 'Var', (149, 156))	('ERK1/2', 'Gene', (99, 105))	('mTORC1', 'Gene', (117, 123))	('ERK1/2', 'Gene', '5595;5594', (99, 105))	('p-S6', 'Gene', (140, 144))
9081	29212209	Malignant peripheral nerve sheath tumors or MPNSTs arise in patients with type 1 neurofibromatosis (NF1) and are often associated with activation of the Ras pathway due to loss of function mutations in NF1, a gene which encodes the Ras-GTPase activating protein (GAP), Neurofibromin (NF).	('loss of function', 'NegReg', (172, 188))	('Malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (0, 40))	('NF1', 'Gene', '4763', (100, 103))	('type 1 neurofibromatosis', 'Disease', (74, 98))	('NF', 'Gene', '4763', (284, 286))	('patients', 'Species', '9606', (60, 68))	('Malignant peripheral nerve sheath tumors', 'Disease', (0, 40))	('NF1', 'Gene', (100, 103))	('NF', 'Gene', '4763', (100, 102))	('NF1', 'Gene', '4763', (202, 205))	('mutations', 'Var', (189, 198))	('type 1 neurofibromatosis', 'Disease', 'MESH:C537392', (74, 98))	('Malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (0, 40))	('Neurofibromin', 'Gene', (269, 282))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('activation', 'PosReg', (135, 145))	('NF1', 'Gene', (202, 205))	('NF', 'Gene', '4763', (202, 204))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Ras-GTP', 'Chemical', '-', (232, 239))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (81, 98))	('Ras pathway', 'Pathway', (153, 164))	('Neurofibromin', 'Gene', '4763', (269, 282))
9083	29212209	In addition to NF1 associated MPNSTs, role of NF1 mutations has also been elucidated in other cancer types such as cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('NF1', 'Gene', (15, 18))	('NF1', 'Gene', (46, 49))	('cutaneous melanoma', 'Disease', (115, 133))	('mutations', 'Var', (50, 59))	('NF1', 'Gene', '4763', (15, 18))	('NF1', 'Gene', '4763', (46, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (115, 133))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
9090	29212209	Based on preclinical data, combination trials of CB-839 with EGFR inhibitors in EGFR mutant lung cancer and with proteasome inhibitors in multiple myeloma are now being planned.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('multiple myeloma', 'Phenotype', 'HP:0006775', (138, 154))	('CB-839', 'Gene', (49, 55))	('multiple myeloma', 'Disease', 'MESH:D009101', (138, 154))	('multiple myeloma', 'Disease', (138, 154))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('CB-839', 'Chemical', 'MESH:C000593334', (49, 55))	('mutant', 'Var', (85, 91))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
9094	29212209	When we deprived the NF1 mutant/null cells of glutamine in the media or treated the cells with glutaminase inhibitor, CB-839 and carried out in vitro detection of Ras activity, we observed a significant decrease in active Ras (Ras-GTP), thus, supporting our hypothesis that Ras activity in these cell lines is dependent on glutamine utilization.	('glutamine', 'Chemical', 'MESH:D005973', (323, 332))	('NF1', 'Gene', '4763', (21, 24))	('active Ras', 'MPA', (215, 225))	('Ras-GTP', 'Chemical', '-', (227, 234))	('glutamine', 'Chemical', 'MESH:D005973', (46, 55))	('decrease', 'NegReg', (203, 211))	('NF1', 'Gene', (21, 24))	('mutant/null', 'Var', (25, 36))	('CB-839', 'Chemical', 'MESH:C000593334', (118, 124))
9095	29212209	Moreover, this decrease in Ras activity could be recapitulated when NF1 was knocked down using siRNA in the wild-type NF1 cell line, STS26T.	('decrease', 'NegReg', (15, 23))	('NF1', 'Gene', '4763', (118, 121))	('knocked', 'Var', (76, 83))	('Ras', 'Protein', (27, 30))	('NF1', 'Gene', (68, 71))	('NF1', 'Gene', '4763', (68, 71))	('STS26T', 'CellLine', 'CVCL:8917', (133, 139))	('NF1', 'Gene', (118, 121))
9097	29212209	Taken together, our data strongly suggests that Ras activity in the NF1 mutant/null cell lines is highly dependent on the ability of cells to utilize glutamine.	('dependent', 'Reg', (105, 114))	('activity', 'MPA', (52, 60))	('NF1', 'Gene', (68, 71))	('Ras', 'Protein', (48, 51))	('NF1', 'Gene', '4763', (68, 71))	('glutamine', 'Chemical', 'MESH:D005973', (150, 159))	('mutant/null', 'Var', (72, 83))
9100	29212209	On the other hand, siRNA mediated knockdown of NF1 in wild-type NF1 cell line (STS26T) resulted in increased sensitivity to glutaminase inhibition.	('increased sensitivity to glutaminase', 'Phenotype', 'HP:0025376', (99, 135))	('STS26T', 'CellLine', 'CVCL:8917', (79, 85))	('sensitivity to glutaminase inhibition', 'MPA', (109, 146))	('NF1', 'Gene', (47, 50))	('NF1', 'Gene', (64, 67))	('NF1', 'Gene', '4763', (47, 50))	('NF1', 'Gene', '4763', (64, 67))	('increased', 'PosReg', (99, 108))	('knockdown', 'Var', (34, 43))
9104	29212209	Western blot analysis using tissue lysates obtained from tumor xenograft samples also showed a decrease in p-ERK as well as p-S6 and p-4EBP1, thus, validating the results obtained in vitro.	('decrease', 'NegReg', (95, 103))	('p-ERK', 'Gene', '9451', (107, 112))	('p-S6', 'Gene', (124, 128))	('p-4EBP1', 'Var', (133, 140))	('p-ERK', 'Gene', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p-S6', 'Gene', '338413', (124, 128))	('tumor', 'Disease', (57, 62))
9105	29212209	Loss of NF1 is known to induce Ras activation and our data showing blockade of p-ERK (a critical component of Ras/Raf/ERK pathway) in response to glutaminase inhibition suggested that glutamine metabolism in the NF1 associated tumors is important for Ras activity.	('ERK', 'Gene', '5594', (118, 121))	('NF1', 'Gene', (8, 11))	('p-ERK', 'Gene', (79, 84))	('NF1', 'Gene', '4763', (8, 11))	('glutamine', 'Chemical', 'MESH:D005973', (184, 193))	('ERK', 'Gene', (118, 121))	('Raf', 'Gene', '22882', (114, 117))	('ERK', 'Gene', '5594', (81, 84))	('tumors', 'Disease', (227, 233))	('ERK', 'Gene', (81, 84))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('NF1', 'Gene', (212, 215))	('p-ERK', 'Gene', '9451', (79, 84))	('Loss', 'Var', (0, 4))	('NF1', 'Gene', '4763', (212, 215))	('Raf', 'Gene', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
9113	29212209	More studies need to be undertaken to understand the intricacies of glutamine versus glucose consumption in NF1 mutant/null and NF1 wild-type cell lines.	('NF1', 'Gene', '4763', (108, 111))	('NF1', 'Gene', '4763', (128, 131))	('mutant/null', 'Var', (112, 123))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('glutamine', 'Chemical', 'MESH:D005973', (68, 77))	('NF1', 'Gene', (108, 111))	('NF1', 'Gene', (128, 131))
9115	29212209	Cancer associated mutations in isocitrate dehydrogenase (IDH) often lead to high levels of 2-HG.	('IDH', 'Gene', '3417', (57, 60))	('lead to', 'Reg', (68, 75))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('high levels of 2-HG', 'MPA', (76, 95))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('isocitrate dehydrogenase', 'Gene', (31, 55))	('IDH', 'Gene', (57, 60))	('isocitrate dehydrogenase', 'Gene', '3417', (31, 55))	('mutations', 'Var', (18, 27))
9116	29212209	While the D-isomer of 2-HG is often associated with mutant IDH, L-isomer is produced under hypoxic conditions.	('IDH', 'Gene', (59, 62))	('hypoxic conditions', 'Disease', 'MESH:D009135', (91, 109))	('mutant', 'Var', (52, 58))	('IDH', 'Gene', '3417', (59, 62))	('associated', 'Reg', (36, 46))	('D-isomer', 'MPA', (10, 18))	('hypoxic conditions', 'Disease', (91, 109))
9117	29212209	Moreover, previous mutational genomic analysis of the NF1-null ST8814 and wild-type NF1 carrying LS141 cell lines have not identified any mutations in IDH, therefore, we do not anticipate that the high levels of 2-HG observed in these cell lines are a result of possible IDH mutations.	('mutations', 'Var', (275, 284))	('IDH', 'Gene', (271, 274))	('IDH', 'Gene', '3417', (151, 154))	('IDH', 'Gene', '3417', (271, 274))	('NF1', 'Gene', (84, 87))	('NF1', 'Gene', '4763', (54, 57))	('NF1', 'Gene', (54, 57))	('NF1', 'Gene', '4763', (84, 87))	('LS141', 'CellLine', 'CVCL:2105', (97, 102))	('ST8814', 'Gene', (63, 69))	('IDH', 'Gene', (151, 154))
9118	29212209	Glutamine has been shown to play a major role not only as a carbon and nitrogen source but also contributes to the anti-oxidative pathways and chromatin organization.	('Glutamine', 'Chemical', 'MESH:D005973', (0, 9))	('nitrogen', 'Chemical', 'MESH:D009584', (71, 79))	('anti-oxidative', 'MPA', (115, 129))	('chromatin organization', 'CPA', (143, 165))	('Glutamine', 'Var', (0, 9))	('carbon', 'Chemical', 'MESH:D002244', (60, 66))
9121	29212209	We believe that in our study, NF1 mutant/null cells are highly dependent on glutamine metabolism for proliferation and withdrawal of glutamine from media or inhibition of GLS1 by CB-839 results in decreased glutaminolysis and thus, reduced mTORC1 activity (shown as reduced p-S6 and p-4EBP1).	('glutamine', 'Chemical', 'MESH:D005973', (76, 85))	('GLS1', 'Gene', (171, 175))	('CB-839', 'Chemical', 'MESH:C000593334', (179, 185))	('NF1', 'Gene', '4763', (30, 33))	('mutant/null', 'Var', (34, 45))	('reduced', 'NegReg', (232, 239))	('GLS1', 'Gene', '2744', (171, 175))	('p-S6', 'Gene', '338413', (274, 278))	('NF1', 'Gene', (30, 33))	('p-S6', 'Gene', (274, 278))	('inhibition', 'NegReg', (157, 167))	('mTORC1', 'Gene', (240, 246))	('CB-839', 'Gene', (179, 185))	('mTORC1', 'Gene', '382056', (240, 246))	('glutaminolysis', 'MPA', (207, 221))	('glutamine', 'Chemical', 'MESH:D005973', (133, 142))	('decreased', 'NegReg', (197, 206))	('withdrawal', 'Var', (119, 129))	('reduced', 'NegReg', (266, 273))
9122	29212209	Additionally, we observe that the Ras activity in our NF1 mutant/null cells is highly dependent on glutamine metabolism.	('Ras', 'Protein', (34, 37))	('NF1', 'Gene', '4763', (54, 57))	('NF1', 'Gene', (54, 57))	('glutamine', 'Chemical', 'MESH:D005973', (99, 108))	('glutamine metabolism', 'MPA', (99, 119))	('mutant/null', 'Var', (58, 69))	('dependent', 'Reg', (86, 95))
9123	29212209	Therefore, we believe that the decreased cell proliferation in the NF1 mutant/null cells is a combined result of decreased mTORC1 and Ras activity and this can be rescued either by overexpression of NF1-GRD or exogenous addition of glutamate to the media.	('NF1', 'Gene', (67, 70))	('mTORC1', 'Gene', '382056', (123, 129))	('mutant/null', 'Var', (71, 82))	('Ras', 'Protein', (134, 137))	('NF1', 'Gene', '4763', (67, 70))	('cell proliferation', 'CPA', (41, 59))	('decreased', 'NegReg', (31, 40))	('mTORC1', 'Gene', (123, 129))	('NF1', 'Gene', (199, 202))	('glutamate', 'Chemical', 'MESH:D018698', (232, 241))	('decreased', 'NegReg', (113, 122))	('NF1', 'Gene', '4763', (199, 202))
9124	29212209	In summary, our data shows a strong correlation between NF1 status and glutamine dependency in tumors.	('NF1', 'Gene', '4763', (56, 59))	('status', 'Var', (60, 66))	('dependency in tumors', 'Disease', (81, 101))	('dependency in tumors', 'Disease', 'MESH:D019966', (81, 101))	('glutamine', 'Chemical', 'MESH:D005973', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('correlation', 'Interaction', (36, 47))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('NF1', 'Gene', (56, 59))
9125	29212209	In addition to MPNSTs, a known NF1 associated malignancy, such a correlation was also observed only in NF1 null metastatic melanoma cell line, MeWo but not wild-type NF1 carrying 92.1 cell line.	('NF1', 'Gene', (166, 169))	('NF1', 'Gene', '4763', (103, 106))	('NF1', 'Gene', '4763', (31, 34))	('NF1', 'Gene', '4763', (166, 169))	('MPNSTs', 'Disease', (15, 21))	('null', 'Var', (107, 111))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('malignancy', 'Disease', 'MESH:D009369', (46, 56))	('NF1', 'Gene', (31, 34))	('malignancy', 'Disease', (46, 56))	('NF1', 'Gene', (103, 106))
9128	29212209	In fact based on these results a single agent CB-839 study for patients with NF1 mutant MPNST, as well as a "basket" study for all NF1 mutant patients, are now planned.	('NF1', 'Gene', (131, 134))	('NF1', 'Gene', (77, 80))	('NF1', 'Gene', '4763', (131, 134))	('NF1', 'Gene', '4763', (77, 80))	('mutant', 'Var', (81, 87))	('patients', 'Species', '9606', (63, 71))	('CB-839', 'Chemical', 'MESH:C000593334', (46, 52))	('patients', 'Species', '9606', (142, 150))
9132	29212209	NF1 mutant MPNST cell line has been described elsewhere.	('NF1', 'Gene', '4763', (0, 3))	('mutant', 'Var', (4, 10))	('NF1', 'Gene', (0, 3))
9133	29212209	STS26T, a wild-type NF1 harboring MPNST cell line, was a generous gift by Dr. Steven.	('STS26T', 'CellLine', 'CVCL:8917', (0, 6))	('NF1', 'Gene', '4763', (20, 23))	('STS26T', 'Var', (0, 6))	('NF1', 'Gene', (20, 23))
9156	29212209	The compounds were scanned in EI and spilt less injection mode by selected ion monitoring (SIM) using the following diagnostic ions: succinate, m/z 247; fumarate, m/z 245; alpha ketoglutarate, m/z 288; 2 hydroxyglutaric acid, m/z 247; citrate, m/z 273; glutamate, m/z 246; aspartic acid, m/z 232; asparagine m/z 231; glutamine, m/z 245; and succinate d4, m/z 251.	('fumarate', 'Chemical', 'MESH:D005650', (153, 161))	('m/z', 'Var', (144, 147))	('glutamine', 'MPA', (317, 326))	('asparagine', 'MPA', (297, 307))	('glutamate', 'Chemical', 'MESH:D018698', (253, 262))	('succinate', 'Chemical', 'MESH:D019802', (341, 350))	('m/z 232', 'Var', (288, 295))	('succinate', 'Chemical', 'MESH:D019802', (133, 142))	('SIM', 'Disease', 'None', (91, 94))	('succinate d4', 'Chemical', '-', (341, 353))	('aspartic acid', 'MPA', (273, 286))	('glutamine', 'Chemical', 'MESH:D005973', (317, 326))	('aspartic acid', 'Chemical', 'MESH:D001224', (273, 286))	('m/z 251', 'Var', (355, 362))	('glutamate', 'MPA', (253, 262))	('asparagine', 'Chemical', 'MESH:D001216', (297, 307))	('m/z 246', 'Var', (264, 271))	('m/z 245', 'Var', (328, 335))	('m/z 273', 'Var', (244, 251))	('SIM', 'Disease', (91, 94))	('2 hydroxyglutaric acid', 'Chemical', 'MESH:C019417', (202, 224))
9209	24481407	Xenograft growth was reduced for those mice receiving both racemic and (S)-YK-4-279 over the control (Figure 3D, p=0.02 and p=0.003, respectively).	('reduced', 'NegReg', (21, 28))	('mice', 'Species', '10090', (39, 43))	('S)-YK-4-279 over', 'Var', (72, 88))	('Xenograft growth', 'CPA', (0, 16))
9215	24481407	Both ES models treated with either racemic or (S)-YK-4-279 regressed by 25-30% of tumor volume over 3 days, while tumors grew in control and (R)-YK-4-279 treated animals (Figures 4A and B).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('S)-YK-4-279', 'Var', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (114, 119))	('ES', 'Phenotype', 'HP:0012254', (5, 7))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('regressed', 'NegReg', (59, 68))	('tumor', 'Disease', (82, 87))
9218	24481407	In the (S)-YK-4-279 treated animals (400 mg/kg), the cell death appeared to encompass a much greater amount of the A4573 tumor, consistent with a dosage effect over the racemic treatment (Figure 4C).	('A4573', 'Var', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
9220	24481407	To confirm the apoptotic cell death, sections from A4573 tumors were stained with TUNEL (Figures 4D) and there was a 3 - 4 fold increase in TUNEL-positive cells treated with (S)-YK-4-279 compared to (R)-YK-R-279 treated tumors (Figure 4E).	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('increase', 'PosReg', (128, 136))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('S)-YK-4-279', 'Var', (175, 186))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
9223	24481407	We evaluated the effect of EWS-FLI1 in animals treated with YK-4-279 upon caveolin-1, a recognized direct gene target whose expression is increased by EWS-FLI1.	('increased', 'PosReg', (138, 147))	('EWS-FLI1', 'Var', (151, 159))	('YK-4-279', 'Var', (60, 68))	('caveolin-1', 'Gene', '12389', (74, 84))	('expression', 'MPA', (124, 134))	('caveolin-1', 'Gene', (74, 84))
9226	24481407	Each slide was scored for intensity and distribution confirming significantly decreased caveolin-1 staining in racemic or (S)-YK-4-279 compared to the control animals (Figure 5B, p=0.004 and p=0.04, respectively).	('decreased', 'NegReg', (78, 87))	('caveolin-1', 'Gene', (88, 98))	('S)-YK-4-279', 'Var', (123, 134))	('caveolin-1', 'Gene', '12389', (88, 98))
9244	24481407	This work shows that tumor-specifc translocations can be successfully inhibited in an animal model with a small molecule.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('translocations', 'Var', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', (21, 26))
9250	24481407	In vitro evaluation of the enantiomeric biologic effects demonstrated that (S)-YK-4-279 was not only significantly more potent as an inhibitor, but also demonstrated significant specifcity upon the function of EWS-FLI1 compared to (R)-YK-4-279.	('more', 'PosReg', (115, 119))	('rat', 'Species', '10116', (160, 163))	('rat', 'Species', '10116', (64, 67))	('EWS-FLI1', 'Gene', (210, 218))	('S)-YK-4-279', 'Var', (76, 87))	('function', 'MPA', (198, 206))
9251	24481407	An observation however, with (R)-YK-4-279 treated animals showed a small growth retardation compared to controls, yet they did not die by apoptosis like the (S)-YK-4-279 treated animals.	('R)-YK-4-279', 'Var', (30, 41))	('growth retardation', 'Disease', 'MESH:D006130', (73, 91))	('growth retardation', 'Disease', (73, 91))	('growth retardation', 'Phenotype', 'HP:0001510', (73, 91))
9258	24481407	Because YK-4-279 abrogates function of EWS-FLI1 by disrupting the interaction with a partner, RHA, adequate delivery of YK-4-279 to the tumor cells is imperative for its treatment course.	('interaction', 'Interaction', (66, 77))	('adequate delivery', 'Phenotype', 'HP:0001622', (99, 116))	('function', 'MPA', (27, 35))	('EWS-FLI1', 'Gene', (39, 47))	('RHA', 'Gene', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('disrupting', 'NegReg', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('RHA', 'Gene', '13211', (94, 97))	('rat', 'Species', '10116', (155, 158))	('YK-4-279', 'Var', (8, 16))	('tumor', 'Disease', (136, 141))	('abrogates', 'NegReg', (17, 26))
9269	24481407	After tumor size reaches 0.5 cm3, mice were randomized and received racemic YK-4-279 at a dosage of 25 mg/kg/administration by IV injection at 12-hour intervals through 60 hours following the first administration (T0, T12, T24, T36, T48, and T60).	('rat', 'Species', '10116', (117, 120))	('mice', 'Species', '10090', (34, 38))	('T60', 'Var', (242, 245))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('T12', 'Var', (218, 221))	('T24', 'Var', (223, 226))	('T48', 'Var', (233, 236))	('rat', 'Species', '10116', (206, 209))	('T36', 'Var', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
9272	24481407	Two million A4573 or SK-ES Ewing's sarcoma cells in 0.1 mL were injected into an orthotopic paraosseous location, adjacent to the left proximal tibia, in 5-week-old female severe combined immunodeficient-beige (SCID/bg) mice (Harlan Laboratories, Inc., Indianapolis, IN).	("SK-ES Ewing's sarcoma", 'Disease', 'MESH:C563168', (21, 42))	('SCID', 'Disease', 'MESH:D053632', (211, 215))	('SCID', 'Disease', (211, 215))	('ES', 'Phenotype', 'HP:0012254', (24, 26))	('mice', 'Species', '10090', (220, 224))	('immunodeficient', 'Disease', 'MESH:D007153', (188, 203))	('immunodeficient', 'Disease', (188, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (27, 42))	("SK-ES Ewing's sarcoma", 'Disease', (21, 42))	('rat', 'Species', '10116', (237, 240))	('A4573', 'Var', (12, 17))
9277	24481407	For the pharmacodynamics study mice were randomized and received 6 doses treatment with vehicle control (0.25% Lecithin solution or DMSO), (S)-YK-4-279, (R)-YK-4-279 or racemic YK-4-279 at a dose of 400 mg/kg twice a day (BID).	('Lecithin', 'Chemical', 'MESH:D054709', (111, 119))	('S)-YK-4-279', 'Var', (140, 151))	('R)-YK-4-279', 'Var', (154, 165))	('mice', 'Species', '10090', (31, 35))	('BID', 'Gene', '12122', (222, 225))	('DMSO', 'Chemical', 'MESH:D004121', (132, 136))	('BID', 'Gene', (222, 225))
9304	21559258	5-year EFS and OS was 69.3 +- 4.8% and 80.3 +- 4.3%, respectively, and was similar for AP and PP, In patients with tumors >5 cm, in whom chemotherapy might be considered most appropriate, relapse occurred in 9/19 (47%) with chemotherapy, compared to 17/46 (37%) In those without.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('chemotherapy', 'Var', (224, 236))	('relapse', 'CPA', (188, 195))	('tumor', 'Disease', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
9345	21126363	Results (not presented) differed negligibly when the model was modified by deleting diabetes or by adding asthma history or attained education level.	('asthma', 'Disease', (106, 112))	('asthma', 'Disease', 'MESH:D001249', (106, 112))	('asthma', 'Phenotype', 'HP:0002099', (106, 112))	('deleting', 'Var', (75, 83))	('diabetes', 'Disease', (84, 92))	('diabetes', 'Disease', 'MESH:D003920', (84, 92))
9354	21126363	As shown in Table 1, history of diabetes was much more common in KSHV seronegative compared to seropositive controls (ORadj 4.69, 95% CI 1.97 - 11.17).	('KSHV', 'Species', '37296', (65, 69))	('common', 'Reg', (55, 61))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('seronegative', 'Var', (70, 82))	('ORadj', 'Chemical', '-', (118, 123))	('diabetes', 'Disease', (32, 40))	('KSHV', 'Gene', (65, 69))	('diabetes', 'Disease', 'MESH:D003920', (32, 40))
9358	21126363	When diabetes was eliminated from the model to test for confounding, the associations of KSHV seronegativity with higher cumulative plant exposure and with plant cluster B were essentially unaltered (results not presented).	('KS', 'Phenotype', 'HP:0100726', (89, 91))	('KSHV', 'Species', '37296', (89, 93))	('seronegativity', 'Var', (94, 108))	('KSHV', 'Gene', (89, 93))	('diabetes', 'Disease', (5, 13))	('diabetes', 'Disease', 'MESH:D003920', (5, 13))
9363	21126363	For our secondary objective, we found that KSHV seroprevalence among controls was modestly lower with overall exposure to plants (Table 2).	('lower', 'NegReg', (91, 96))	('KSHV', 'Gene', (43, 47))	('seroprevalence', 'Var', (48, 62))	('KS', 'Phenotype', 'HP:0100726', (43, 45))	('KSHV', 'Species', '37296', (43, 47))
9365	21126363	Because the earlier seroprevalence analysis was adjusted only for sex and age group, we examined whether the discrepancy might relate to adjusting for diabetes, which was strongly associated with KSHV seronegativity (Table 1).	('diabetes', 'Disease', (151, 159))	('KS', 'Phenotype', 'HP:0100726', (196, 198))	('diabetes', 'Disease', 'MESH:D003920', (151, 159))	('seronegativity', 'Var', (201, 215))	('associated', 'Reg', (180, 190))	('KSHV', 'Species', '37296', (196, 200))
9373	21126363	Chromic luvisol was associated with cKS in our previous study but not in the current one.	('associated', 'Reg', (20, 30))	('cKS', 'Disease', (36, 39))	('luvisol', 'Chemical', '-', (8, 15))	('Chromic', 'Var', (0, 7))	('KS', 'Phenotype', 'HP:0100726', (37, 39))	('cKS', 'Chemical', '-', (36, 39))
9374	21126363	Of these, orthic luvisol was strongly associated with decreased cKS risk.	('cKS', 'Chemical', '-', (64, 67))	('orthic luvisol', 'Var', (10, 24))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('cKS', 'Disease', (64, 67))	('decreased', 'NegReg', (54, 63))	('luvisol', 'Chemical', '-', (17, 24))
9416	21126363	Cumulative time working with plants or soils, previously noted to be associated with elevated KSHV seroprevalence among women, was considered but not retained in the core model.	('KS', 'Phenotype', 'HP:0100726', (94, 96))	('KSHV', 'Species', '37296', (94, 98))	('KSHV', 'Gene', (94, 98))	('women', 'Species', '9606', (120, 125))	('elevated', 'PosReg', (85, 93))	('seroprevalence', 'Var', (99, 113))
9487	30397315	Chemical and biological depletion of the BRD9 subunit of ncBAF rapidly attenuates SS and MRT cell proliferation.	('BRD9', 'Gene', (41, 45))	('BAF', 'Gene', '8815', (59, 62))	('BAF', 'Gene', (59, 62))	('depletion', 'Var', (24, 33))	('BRD9', 'Gene', '65980', (41, 45))	('attenuates', 'NegReg', (71, 81))
9492	30397315	Mutations in the genes encoding mSWI/SNF subunits are found in over 20% of human cancers, with specific subunits mutated in specific malignancies, pointing toward subunit- and complex-specific functions.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('malignancies', 'Disease', (133, 145))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('found', 'Reg', (54, 59))	('Mutations', 'Var', (0, 9))	('mutated', 'Var', (113, 120))	('mSWI/SNF', 'Gene', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))
9494	30397315	Furthermore, complex-defining subunits such as ARID1A and PBRM1 are recurrently mutated in distinct cancers, ovarian clear cell carcinoma and renal clear cell carcinoma, respectively.	('ARID1A', 'Gene', '8289', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('ARID1A', 'Gene', (47, 53))	('distinct cancers', 'Disease', (91, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ovarian clear cell carcinoma and renal clear cell carcinoma', 'Disease', 'MESH:C538614', (109, 168))	('mutated', 'Var', (80, 87))	('PBRM1', 'Gene', (58, 63))	('PBRM1', 'Gene', '55193', (58, 63))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('distinct cancers', 'Disease', 'MESH:D009369', (91, 107))
9495	30397315	While the majority of mSWI/SNF gene mutations result in loss-of-function phenotypes, the SS18-SSX fusion hallmark to synovial sarcoma (SS) results in de novo, gain-of-function targeting of BAF complexes, which activates the unique SS gene expression signature.	('SSX', 'Gene', (94, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('BAF', 'Gene', '8815', (189, 192))	('mSWI/SNF gene', 'Gene', (22, 35))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (117, 133))	('SS18', 'Gene', '6760', (89, 93))	('synovial sarcoma', 'Disease', 'MESH:D013584', (117, 133))	('BAF', 'Gene', (189, 192))	('mutations', 'Var', (36, 45))	('gain-of-function', 'PosReg', (159, 175))	('SS18', 'Gene', (89, 93))	('SSX', 'Gene', '6757', (94, 97))	('synovial sarcoma', 'Disease', (117, 133))
9496	30397315	Incorporation of the SS18-SSX oncoprotein into BAF complexes results in protein-level destabilization of SMARCB1 (a feature shared with MRT), but this event is secondary and not required for maintenance of SS gene expression or proliferation.	('BAF', 'Gene', (47, 50))	('Incorporation', 'Var', (0, 13))	('SSX', 'Gene', '6757', (26, 29))	('SS18', 'Gene', '6760', (21, 25))	('destabilization', 'NegReg', (86, 101))	('SSX', 'Gene', (26, 29))	('SMARCB1', 'Gene', '6598', (105, 112))	('protein-level', 'MPA', (72, 85))	('SMARCB1', 'Gene', (105, 112))	('SS18', 'Gene', (21, 25))	('BAF', 'Gene', '8815', (47, 50))
9500	30397315	We find that cancers driven by core cBAF subunit perturbations, such as SS and MRT, are uniquely dependent on ncBAF function.	('BAF', 'Gene', (112, 115))	('MRT', 'Disease', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('BAF', 'Gene', '8815', (112, 115))	('BAF', 'Gene', '8815', (37, 40))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Disease', (13, 20))	('BAF', 'Gene', (37, 40))	('perturbations', 'Var', (49, 62))
9515	30397315	cBAF complexes were most enriched at active enhancers (H3K27ac and H3K4me1) and at primed sites (H3K4me1), suggesting roles for cBAF in enhancer regulation (Fig.	('enhancers', 'PosReg', (44, 53))	('H3K27ac', 'Var', (55, 62))	('H3K4me1', 'Var', (67, 74))	('BAF', 'Gene', '8815', (1, 4))	('BAF', 'Gene', (1, 4))	('BAF', 'Gene', '8815', (129, 132))	('BAF', 'Gene', (129, 132))
9522	30397315	These screens identified significant, selective sensitivity of both SS and MRT cell lines to perturbation of ncBAF complex subunits BRD9, GLTSCR1, and SMARCD1 (Fig.	('BRD9', 'Gene', '65980', (132, 136))	('GLTSCR1', 'Gene', (138, 145))	('perturbation', 'Var', (93, 105))	('BRD9', 'Gene', (132, 136))	('BAF', 'Gene', '8815', (111, 114))	('SMARCD1', 'Gene', '6602', (151, 158))	('GLTSCR1', 'Gene', '29998', (138, 145))	('SMARCD1', 'Gene', (151, 158))	('BAF', 'Gene', (111, 114))
9528	30397315	In SS, loss of proliferative fitness resulting from ncBAF subunit perturbation was comparable to SS18 perturbation, the driver of disease (Fig.	('loss of proliferative fitness', 'Disease', (7, 36))	('perturbation', 'Var', (66, 78))	('SS18', 'Gene', (97, 101))	('SS18', 'Gene', '6760', (97, 101))	('BAF', 'Gene', '8815', (54, 57))	('loss of proliferative fitness', 'Disease', 'MESH:D009220', (7, 36))	('BAF', 'Gene', (54, 57))
9529	30397315	Both SS and MRT cell lines exhibited higher sensitivity to BRD9 loss than AML cell lines, which have been previously been reported to be sensitive to BRD9 knockdown (Fig.	('knockdown', 'Var', (155, 164))	('AML', 'Disease', 'MESH:D015470', (74, 77))	('loss', 'NegReg', (64, 68))	('AML', 'Disease', (74, 77))	('BRD9', 'Gene', '65980', (150, 154))	('BRD9', 'Gene', '65980', (59, 63))	('BRD9', 'Gene', (150, 154))	('BRD9', 'Gene', (59, 63))
9532	30397315	3a, Supplementary Fig 3c), highlighting the selective sensitivity to ncBAF subunit disruption in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (103, 109))	('BAF', 'Gene', '8815', (71, 74))	('BAF', 'Gene', (71, 74))	('disruption', 'Var', (83, 93))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
9535	30397315	dBRD9-treated SS cells exhibited near complete depletion of BRD9 from whole cell lysates and proliferative attenuation, approaching that which results from SS18-SSX oncoprotein knockdown (Fig.	('SS18', 'Gene', (156, 160))	('BRD9', 'Gene', '65980', (1, 5))	('depletion', 'MPA', (47, 56))	('knockdown', 'Var', (177, 186))	('BRD9', 'Gene', '65980', (60, 64))	('SSX', 'Gene', '6757', (161, 164))	('BRD9', 'Gene', (1, 5))	('BRD9', 'Gene', (60, 64))	('SSX', 'Gene', (161, 164))	('SS18', 'Gene', '6760', (156, 160))
9541	30397315	As mSWI/SNF complexes in SS and MRT/ATRT/EpS disease settings exhibit the shared feature of cBAF perturbation and SMARCB1 (BAF47) loss or destabilization, these results unmask a selective ncBAF dependency in two aggressive and intractable BAF-mutant cancer types.	('BAF', 'Gene', (239, 242))	('AT', 'Disease', 'None', (36, 38))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('BAF', 'Gene', (190, 193))	('SMARCB1', 'Gene', '6598', (114, 121))	('BAF47', 'Gene', '6598', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('SMARCB1', 'Gene', (114, 121))	('BAF', 'Gene', (93, 96))	('BAF', 'Gene', '8815', (239, 242))	('loss', 'NegReg', (130, 134))	('BAF', 'Gene', (123, 126))	('perturbation', 'Var', (97, 109))	('BAF', 'Gene', '8815', (190, 193))	('BAF', 'Gene', '8815', (93, 96))	('BAF47', 'Gene', (123, 128))	('cancer', 'Disease', (250, 256))	('destabilization', 'NegReg', (138, 153))	('BAF', 'Gene', '8815', (123, 126))
9545	30397315	Knockout of BRD9 in HEK-293T cells resulted in destabilized ncBAF complexes (Supplementary Fig.	('BAF', 'Gene', (62, 65))	('BRD9', 'Gene', '65980', (12, 16))	('destabilized', 'NegReg', (47, 59))	('BRD9', 'Gene', (12, 16))	('Knockout', 'Var', (0, 8))	('HEK-293T', 'CellLine', 'CVCL:0063', (20, 28))	('BAF', 'Gene', '8815', (62, 65))
9554	30397315	In contrast, guides targeting the bromodomain and DUF3512 of PBAF-specific BRD7, the paralog of BRD9, did not result in reduced fitness (Fig.	('BAF', 'Gene', (62, 65))	('reduced fitness', 'Disease', 'MESH:D015354', (120, 135))	('BAF', 'Gene', '8815', (62, 65))	('BRD7', 'Gene', (75, 79))	('BRD7', 'Gene', '29117', (75, 79))	('DUF3512', 'Var', (50, 57))	('DUF', 'Chemical', '-', (50, 53))	('BRD9', 'Gene', '65980', (96, 100))	('reduced fitness', 'Disease', (120, 135))	('BRD9', 'Gene', (96, 100))
9555	30397315	These data highlight the synthetic lethal specificity for ncBAF components, and demonstrate the importance of the GLTSCR and DUF3512 domains of GLTSCR1/1L and BRD9, respectively, in ncBAF function in SS.	('BRD9', 'Gene', '65980', (159, 163))	('GLTSCR1', 'Gene', '29998', (144, 151))	('BRD9', 'Gene', (159, 163))	('BAF', 'Gene', '8815', (184, 187))	('DUF3512', 'Var', (125, 132))	('DUF', 'Chemical', '-', (125, 128))	('BAF', 'Gene', '8815', (60, 63))	('BAF', 'Gene', (184, 187))	('GLTSCR1', 'Gene', (144, 151))	('BAF', 'Gene', (60, 63))
9556	30397315	To understand the roles of the GLTSCR and DUF3512 domains in ncBAF complexes, we assessed evolutionary conservation of these regions (Fig.	('BAF', 'Gene', '8815', (63, 66))	('BAF', 'Gene', (63, 66))	('DUF3512', 'Var', (42, 49))	('DUF', 'Chemical', '-', (42, 45))
9558	30397315	Indeed, immunoprecipitation followed by immunoblot of N-terminal and C-terminal truncation mutants of mammalian GLTSCR1 demonstrated that this domain is required for interaction with ncBAF complexes and thus serves as an ncBAF-specific binding region (Fig.	('BAF', 'Gene', '8815', (223, 226))	('BAF', 'Gene', (185, 188))	('BAF', 'Gene', (223, 226))	('GLTSCR1', 'Gene', (112, 119))	('interaction', 'Interaction', (166, 177))	('mutants', 'Var', (91, 98))	('mammalian', 'Species', '9606', (102, 111))	('GLTSCR1', 'Gene', '29998', (112, 119))	('BAF', 'Gene', '8815', (185, 188))
9561	30397315	To determine if the DUF3512 is involved in complex-specific binding of the BRD9 and BRD7 subunits, we performed domain swapping experiments in which we fused the C-terminal DUF-containing region of BRD9 to the N-terminus of BRD7 and vice versa (Fig.	('fused', 'Var', (152, 157))	('BRD7', 'Gene', (84, 88))	('DUF', 'Chemical', '-', (20, 23))	('BRD9', 'Gene', '65980', (198, 202))	('BRD7', 'Gene', '29117', (84, 88))	('BRD9', 'Gene', (198, 202))	('BRD9', 'Gene', '65980', (75, 79))	('DUF', 'Chemical', '-', (173, 176))	('BRD7', 'Gene', (224, 228))	('BRD9', 'Gene', (75, 79))	('BRD7', 'Gene', '29117', (224, 228))
9562	30397315	Swapping of BRD9 and BRD7 DUF3512 regions resulted in switched complex specification, with BRD9-(BRD7 DUF) binding PBAF complexes and BRD7-(BRD9 DUF) binding ncBAF complexes (Fig.	('BRD7', 'Gene', '29117', (97, 101))	('BRD9', 'Gene', (140, 144))	('BRD7', 'Gene', (97, 101))	('DUF', 'Chemical', '-', (102, 105))	('Swapping', 'Var', (0, 8))	('BRD9', 'Gene', (12, 16))	('BRD9', 'Gene', '65980', (140, 144))	('BAF', 'Gene', '8815', (160, 163))	('BRD7', 'Gene', '29117', (134, 138))	('binding', 'Interaction', (107, 114))	('BRD7', 'Gene', '29117', (21, 25))	('BRD9', 'Gene', (91, 95))	('BAF', 'Gene', (116, 119))	('BRD9', 'Gene', '65980', (12, 16))	('DUF', 'Chemical', '-', (145, 148))	('BRD9', 'Gene', '65980', (91, 95))	('BRD7', 'Gene', (134, 138))	('BRD7', 'Gene', (21, 25))	('DUF', 'Chemical', '-', (26, 29))	('BAF', 'Gene', (160, 163))	('BAF', 'Gene', '8815', (116, 119))
9563	30397315	Taken together, these results implicate the BRD9 DUF3512 and the GLTSCR1 GLTSCR domains as ncBAF complex binding domains that underlie critical dependencies in SS cell contexts.	('BAF', 'Gene', '8815', (93, 96))	('DUF3512', 'Var', (49, 56))	('BRD9', 'Gene', '65980', (44, 48))	('DUF', 'Chemical', '-', (49, 52))	('GLTSCR1', 'Gene', '29998', (65, 72))	('BAF', 'Gene', (93, 96))	('BRD9', 'Gene', (44, 48))	('GLTSCR1', 'Gene', (65, 72))	('binding', 'Interaction', (105, 112))
9576	30397315	We next sought to define the divergent gene regulatory effects between SS18-SSX1 and BRD9 perturbation.	('SS18', 'Gene', '6760', (71, 75))	('SSX1', 'Gene', (76, 80))	('perturbation', 'Var', (90, 102))	('SS18', 'Gene', (71, 75))	('SSX1', 'Gene', '6756', (76, 80))	('BRD9', 'Gene', '65980', (85, 89))	('BRD9', 'Gene', (85, 89))
9579	30397315	However, fusion-independent sites (sites retained irrespective of SS18-SSX knockdown) are largely marked by H3K4me3 and CTCF (Fig.	('SSX', 'Gene', (71, 74))	('SSX', 'Gene', '6757', (71, 74))	('CTCF', 'Gene', '10664', (120, 124))	('H3K4me3', 'Protein', (108, 115))	('SS18', 'Gene', '6760', (66, 70))	('knockdown', 'Var', (75, 84))	('SS18', 'Gene', (66, 70))	('CTCF', 'Gene', (120, 124))
9581	30397315	We found that genes closest to fusion-dependent sites were strongly downregulated by SS18-SSX knockdown, but expression of these genes did not change with BRD9 degradation (Fig.	('BRD9', 'Gene', '65980', (155, 159))	('knockdown', 'Var', (94, 103))	('SS18', 'Gene', '6760', (85, 89))	('BRD9', 'Gene', (155, 159))	('downregulated', 'NegReg', (68, 81))	('SS18', 'Gene', (85, 89))	('SSX', 'Gene', '6757', (90, 93))	('SSX', 'Gene', (90, 93))
9606	30397315	Similar to SS, these data support a model in which ncBAF complexes, the only mSWI/SNF family complexes not perturbed by SMARCB1 loss, are critical for gene expression maintenance and subsequently the proliferative capacity, of MRT cells.	('loss', 'Var', (128, 132))	('SMARCB1', 'Gene', (120, 127))	('SMARCB1', 'Gene', '6598', (120, 127))	('BAF', 'Gene', '8815', (53, 56))	('BAF', 'Gene', (53, 56))	('proliferative capacity', 'CPA', (200, 222))
9614	30397315	Importantly, we identify a synthetic lethal relationship in specific cancers with perturbations to the core cBAF functional module: synovial sarcoma (driven by the SS18-SSX fusion) and SMARCB1-deficient malignant rhabdoid tumor.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('SMARCB1-deficient malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (185, 227))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (132, 148))	('synovial sarcoma', 'Disease', 'MESH:D013584', (132, 148))	('SSX', 'Gene', '6757', (169, 172))	('SS18', 'Gene', '6760', (164, 168))	('perturbations', 'Var', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('SS18', 'Gene', (164, 168))	('SMARCB1-deficient malignant rhabdoid tumor', 'Disease', (185, 227))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('BAF', 'Gene', '8815', (109, 112))	('synovial sarcoma', 'Disease', (132, 148))	('BAF', 'Gene', (109, 112))	('cancers', 'Disease', (69, 76))	('SSX', 'Gene', (169, 172))
9617	30397315	Our identification of domains within ncBAF-specific subunits that underlie these dependencies, such as the GLTSCR domain of GLTSCR1/1L and the DUF3512 of BRD9, further expands therapeutic opportunities.	('DUF3512', 'Var', (143, 150))	('GLTSCR1', 'Gene', (124, 131))	('DUF', 'Chemical', '-', (143, 146))	('GLTSCR1', 'Gene', '29998', (124, 131))	('BRD9', 'Gene', '65980', (154, 158))	('BAF', 'Gene', '8815', (39, 42))	('BAF', 'Gene', (39, 42))	('BRD9', 'Gene', (154, 158))
9623	30397315	HEK-293T, G401, TTC1240, ESX, IMR-90, BJ Fibroblast, CRL7250, and NCIH-1437 cells were grown in DMEM (Gibco) supplemented with 10% FBS, 1% GlutaMAX (Gibco), and 1% penicillin-streptomycin (Gibco).	('ESX', 'Gene', '1999', (25, 28))	('IMR-90', 'CellLine', 'CVCL:0347', (30, 36))	('DMEM', 'Chemical', '-', (96, 100))	('CRL', 'Gene', '133396', (53, 56))	('G401', 'Var', (10, 14))	('FBS', 'Disease', (131, 134))	('GlutaMAX', 'Chemical', '-', (139, 147))	('BJ', 'CellLine', 'CVCL:6573', (38, 40))	('NCIH-1437', 'CellLine', 'CVCL:U701', (66, 75))	('penicillin', 'Chemical', 'MESH:D010406', (164, 174))	('HEK-293T', 'CellLine', 'CVCL:0063', (0, 8))	('ESX', 'Gene', (25, 28))	('streptomycin', 'Chemical', 'MESH:D013307', (175, 187))	('TTC1240', 'Var', (16, 23))	('FBS', 'Disease', 'MESH:D005198', (131, 134))	('CRL', 'Gene', (53, 56))
9633	30397315	Lentiviral shRNA hairpins targeting BRD9 (RHS4430-200302441), SMARCE1 (RHS4430-200219172), and a non-silencing control (RHS4346) were constitutively expressed from the pGIPZ vector and obtained from GE Dharmacon; hairpins targeting GLTSCR1 were inducibly expressed from the pTRIPZ vector (#RHS4696) from GE Dharmacon.	('RHS4430-200219172', 'Var', (71, 88))	('GLTSCR1', 'Gene', (232, 239))	('BRD9', 'Gene', '65980', (36, 40))	('SMARCE1', 'Gene', (62, 69))	('BRD9', 'Gene', (36, 40))	('GLTSCR1', 'Gene', '29998', (232, 239))	('RHS4430-200302441', 'Var', (42, 59))	('SMARCE1', 'Gene', '6605', (62, 69))	('#RHS4696', 'Var', (289, 297))
9636	30397315	V5-GLTSCR1 and corresponding N-Del and C-Del mutants were synthesized and cloned into a modified pTight vector by GenScript Biotech Corporation.	('GLTSCR1', 'Gene', (3, 10))	('C-Del', 'Var', (39, 44))	('GLTSCR1', 'Gene', '29998', (3, 10))	('N-Del', 'Var', (29, 34))
9652	30397315	Protein domains were obtained from PFAM regions defined for the following UNIPROT identifiers: BRD9 : Q9H8M2, BICRA : Q9NZM4, BRD7 : Q9NPI1, SMARCA2 : P51531, SMARCA4 : Q9HBD4, SMARCB1 : G5E975, SMARCC1 : Q92922, SMARCC2 : Q8TAQ2, SMARCD1 : Q96GM5, SMARCD2 : Q92925, SMARCE1 : Q969G3, SS18 : Q15532, SSX2 : Q16385.	('SMARCD1', 'Gene', (231, 238))	('SMARCD2', 'Gene', '6603', (249, 256))	('SMARCA4', 'Gene', (159, 166))	('BRD9', 'Gene', '65980', (95, 99))	('SMARCC2', 'Gene', (213, 220))	('SSX2', 'Gene', (300, 304))	('SMARCB1', 'Gene', '6598', (177, 184))	('SMARCB1', 'Gene', (177, 184))	('SMARCE1', 'Gene', '6605', (267, 274))	('P51531', 'Var', (151, 157))	('BRD7', 'Gene', '29117', (126, 130))	('SSX2', 'Gene', '6757', (300, 304))	('SMARCC1', 'Gene', '6599', (195, 202))	('SS18', 'Gene', (285, 289))	('SMARCE1', 'Gene', (267, 274))	('SMARCC2', 'Gene', '6601', (213, 220))	('SMARCA4', 'Gene', '6597', (159, 166))	('SMARCC1', 'Gene', (195, 202))	('BRD7', 'Gene', (126, 130))	('SMARCD2', 'Gene', (249, 256))	('SMARCD1', 'Gene', '6602', (231, 238))	('SS18', 'Gene', '6760', (285, 289))	('SMARCA2', 'Gene', (141, 148))	('SMARCA2', 'Gene', '6595', (141, 148))	('BRD9', 'Gene', (95, 99))
9710	31031965	Whereas classically no known genetic predisposition syndromes were linked to ES tumor development, recent evidence suggests that germline mutations in genes regulating DNA damage pathways are associated with an increased risk of developing ES .	('ES', 'Phenotype', 'HP:0012254', (240, 242))	('DNA damage pathways', 'Pathway', (168, 187))	('associated', 'Reg', (192, 202))	('ES tumor', 'Disease', 'MESH:C563168', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ES tumor', 'Disease', (77, 85))	('ES', 'Phenotype', 'HP:0012254', (77, 79))	('mutations', 'Var', (138, 147))
9758	31031965	Aberrant RTK signaling resulting from amplification, mutation, or overexpression has been implicated in many cancers, including ES .	('implicated', 'Reg', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutation', 'Var', (53, 61))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('ES', 'Phenotype', 'HP:0012254', (128, 130))	('overexpression', 'PosReg', (66, 80))	('amplification', 'Var', (38, 51))	('RTK signaling', 'MPA', (9, 22))
9772	31031965	About 13 to 30% of ES tumors have deletions in CDKN2A - .	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('ES tumors', 'Disease', (19, 28))	('CDKN2A', 'Gene', (47, 53))	('deletions', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CDKN2A', 'Gene', '1029', (47, 53))	('ES', 'Phenotype', 'HP:0012254', (19, 21))	('ES tumors', 'Disease', 'MESH:C563168', (19, 28))
9773	31031965	CDKN2A deletion does not appear to be associated with clinical outcome .	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))
9778	31031965	These data provide a rationale for use even in the absence of CDKN2A deletions .	('deletions', 'Var', (69, 78))	('CDKN2A', 'Gene', '1029', (62, 68))	('CDKN2A', 'Gene', (62, 68))
9782	31031965	Furthermore, the significant myelosuppression seen with CDK4/6 inhibitors complicates combinatorial therapy.	('myelosuppression', 'Disease', 'MESH:D001855', (29, 45))	('myelosuppression', 'Disease', (29, 45))	('CDK4/6', 'Gene', '1019;1021', (56, 62))	('inhibitors', 'Var', (63, 73))	('CDK4/6', 'Gene', (56, 62))
9784	31031965	There are other trials in the US combining CDK4/6 inhibitors with agents, including MEK and mTOR inhibitors (ClinicalTrials.gov Identifiers: NCT03387020, NCT03114527, and NCT02703571) - .	('NCT03387020', 'Var', (141, 152))	('CDK4/6', 'Gene', (43, 49))	('NCT03114527', 'Var', (154, 165))	('mTOR', 'Gene', (92, 96))	('mTOR', 'Gene', '2475', (92, 96))	('MEK', 'Gene', '5609', (84, 87))	('MEK', 'Gene', (84, 87))	('CDK4/6', 'Gene', '1019;1021', (43, 49))
9788	31031965	PARP plays a significant role in DNA repair, particularly with single-strand DNA damage.	('PARP', 'Gene', (0, 4))	('single-strand', 'Var', (63, 76))	('PARP', 'Gene', '142', (0, 4))
9789	31031965	Inhibition of PARP proteins can cause persistent single-strand breaks, ultimately resulting in cellular apoptosis.	('cellular apoptosis', 'CPA', (95, 113))	('single-strand breaks', 'MPA', (49, 69))	('PARP', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('cause', 'Reg', (32, 37))	('PARP', 'Gene', '142', (14, 18))	('resulting in', 'Reg', (82, 94))
9796	31031965	Owing to these promising preclinical data, a series of successor trials have evaluated PARP inhibitors in combination with irinotecan, temozolomide, or IT (ClinicalTrials.gov Identifiers: NCT02116777, NCT01858168, NCT02044120, and NCT02392793) - .	('IT', 'Chemical', '-', (152, 154))	('NCT02044120', 'Var', (214, 225))	('irinotecan', 'Chemical', 'MESH:D000077146', (123, 133))	('NCT01858168', 'Var', (201, 212))	('PARP', 'Gene', (87, 91))	('temozolomide', 'Chemical', 'MESH:D000077204', (135, 147))	('NCT02116777', 'Var', (188, 199))	('PARP', 'Gene', '142', (87, 91))
9814	31031965	Currently, there are ongoing trials for patients with ES combining IT with PARP inhibitors or Vigil autologous vaccine (ClinicalTrials.gov Identifiers: NCT02044120, NCT01858168, and NCT03495921) , , , .	('NCT02044120', 'Var', (152, 163))	('PARP', 'Gene', (75, 79))	('patients', 'Species', '9606', (40, 48))	('IT', 'Chemical', '-', (67, 69))	('NCT03495921', 'Var', (182, 193))	('ES', 'Phenotype', 'HP:0012254', (54, 56))	('PARP', 'Gene', '142', (75, 79))
9828	31031965	Examples of these strategies include lysine-specific demethylase 1A (LSD1) inhibition, inhibition of interaction between EWSR1-FLI1 protein with RNA helicase, epigenetic modification of chromatin modeling resulting in EWS-FLI1 suppression, inhibition of transcriptionally active CDKs, and immunotherapy approaches in ES , - .	('inhibition', 'NegReg', (240, 250))	('CDKs', 'Gene', (279, 283))	('EWSR1', 'Gene', '2130', (121, 126))	('EWS', 'Gene', (218, 221))	('FLI1', 'Gene', (222, 226))	('FLI1', 'Gene', '2313', (127, 131))	('RNA helicase', 'Protein', (145, 157))	('inhibition', 'NegReg', (87, 97))	('LSD1', 'Gene', (69, 73))	('LSD1', 'Gene', '23028', (69, 73))	('EWS', 'Gene', (121, 124))	('interaction', 'Interaction', (101, 112))	('lysine-specific demethylase 1A', 'Gene', (37, 67))	('lysine-specific demethylase 1A', 'Gene', '23028', (37, 67))	('epigenetic modification', 'Var', (159, 182))	('FLI1', 'Gene', '2313', (222, 226))	('suppression', 'NegReg', (227, 238))	('ES', 'Phenotype', 'HP:0012254', (317, 319))	('EWSR1', 'Gene', (121, 126))	('inhibition', 'NegReg', (75, 85))	('EWS', 'Gene', '2130', (218, 221))	('EWS', 'Gene', '2130', (121, 124))	('CDKs', 'Gene', '1019;1021;1022;51755', (279, 283))	('FLI1', 'Gene', (127, 131))
9843	29693796	Selective inhibition of VEGFR2 may lead to increased invasiveness and metastasis, and preclinical models suggest that inhibition of VEGFR2 together with c-MET may decrease tumor size, decrease invasiveness and metastases.	('inhibition', 'NegReg', (10, 20))	('tumor', 'Disease', (172, 177))	('metastases', 'Disease', 'MESH:D009362', (210, 220))	('c-MET', 'Gene', (153, 158))	('VEGFR2', 'Gene', '3791', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('metastases', 'Disease', (210, 220))	('invasiveness', 'Disease', (53, 65))	('VEGFR2', 'Gene', (24, 30))	('increased', 'PosReg', (43, 52))	('VEGFR2', 'Gene', '3791', (24, 30))	('decrease', 'NegReg', (163, 171))	('invasiveness', 'Disease', (193, 205))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('invasiveness', 'Disease', 'MESH:D009362', (53, 65))	('inhibition', 'Var', (118, 128))	('decrease', 'NegReg', (184, 192))	('invasiveness', 'Disease', 'MESH:D009362', (193, 205))	('c-MET', 'Gene', '4233', (153, 158))	('VEGFR2', 'Gene', (132, 138))
9907	29693796	AXL, CA9, and PIGF increased on study D21 and D28 versus baseline.	('CA9', 'Gene', '768', (5, 8))	('PIGF', 'Gene', (14, 18))	('PIGF', 'Gene', '5281', (14, 18))	('AXL', 'Gene', (0, 3))	('AXL', 'Gene', '558', (0, 3))	('increased', 'PosReg', (19, 28))	('D28', 'Var', (46, 49))	('CA9', 'Gene', (5, 8))
9908	29693796	OPN, TIMP-1, and VEGFR2 decreased on D21 and D28 versus baseline.	('decreased', 'NegReg', (24, 33))	('OPN', 'Gene', (0, 3))	('OPN', 'Gene', '6696', (0, 3))	('VEGFR2', 'Gene', (17, 23))	('D28', 'Var', (45, 48))	('TIMP-1', 'Gene', (5, 11))	('TIMP-1', 'Gene', '7076', (5, 11))	('D21', 'Var', (37, 40))	('VEGFR2', 'Gene', '3791', (17, 23))
9909	29693796	There were significant changes in AXL, CA9, OPN, PIGF, TIMP-1, and VEGFR2 (p<0.05) at both D21 and D28 versus baseline.	('CA9', 'Gene', '768', (39, 42))	('AXL', 'Gene', (34, 37))	('changes', 'Reg', (23, 30))	('TIMP-1', 'Gene', (55, 61))	('TIMP-1', 'Gene', '7076', (55, 61))	('PIGF', 'Gene', (49, 53))	('PIGF', 'Gene', '5281', (49, 53))	('AXL', 'Gene', '558', (34, 37))	('VEGFR2', 'Gene', '3791', (67, 73))	('OPN', 'Gene', '6696', (44, 47))	('D21', 'Var', (91, 94))	('OPN', 'Gene', (44, 47))	('D28', 'Var', (99, 102))	('CA9', 'Gene', (39, 42))	('VEGFR2', 'Gene', (67, 73))
9913	29693796	PRs were achieved in two patients with MTC at the 40 mg/m2/d dose level (both continued on study at the time of data cut-off, C20 and C25), one patient with Wilms tumor at 55 mg/m2/d received 24 cycles before progressive disease (PD), and one with clear cell sarcoma at 55 mg/m2/d received seven cycles prior to PD.	('PD', 'Disease', 'MESH:D010300', (312, 314))	('PD', 'Disease', 'MESH:D010300', (230, 232))	('C25', 'Var', (134, 137))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (248, 266))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('patient', 'Species', '9606', (144, 151))	('patient', 'Species', '9606', (25, 32))	('Wilms tumor', 'Disease', (157, 168))	('patients', 'Species', '9606', (25, 33))	('C20', 'Var', (126, 129))	('Wilms tumor', 'Disease', 'MESH:D009396', (157, 168))	('MTC', 'Phenotype', 'HP:0002865', (39, 42))	('Wilms tumor', 'Phenotype', 'HP:0002667', (157, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('clear cell sarcoma', 'Disease', (248, 266))
9918	29693796	All had multiple endocrine neoplasia type 2B (MEN2B), a genetic cancer predisposition syndrome caused by germline activating mutations in the RET proto-oncogene.	('multiple endocrine neoplasia type 2B', 'Gene', '5979', (8, 44))	('RET', 'Gene', '5979', (142, 145))	('neoplasia', 'Phenotype', 'HP:0002664', (27, 36))	('genetic cancer', 'Disease', 'MESH:D030342', (56, 70))	('MEN2B', 'Gene', (46, 51))	('caused by', 'Reg', (95, 104))	('MEN2B', 'Gene', '5979', (46, 51))	('RET', 'Gene', (142, 145))	('genetic cancer', 'Disease', (56, 70))	('germline activating mutations', 'Var', (105, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (17, 36))	('multiple endocrine neoplasia type 2B', 'Gene', (8, 44))
10002	33322371	Tumor initiation is the first step of cancer development during which, by rising mutational load, healthy cells transform into cancer cells.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('rising', 'PosReg', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mutational', 'Var', (81, 91))	('cancer', 'Disease', (38, 44))
10009	33322371	Antibody-mediated neutralization of NK cell-activating receptor NKG2D increased mice susceptibility to MCA-induced sarcoma formation.	('neutralization', 'Var', (18, 32))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('increased', 'PosReg', (70, 79))	('NKG2D', 'Gene', (64, 69))	('sarcoma', 'Disease', (115, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('mice', 'Species', '10090', (80, 84))	('MCA', 'Chemical', 'MESH:D008748', (103, 106))
10015	33322371	However, tumors originating in NKp46-/- mice implanted in WT mice induce a potent immune response suggesting a role of NKp46 in tumor immunoediting.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (128, 133))	('NKp46-/-', 'Var', (31, 39))	('mice', 'Species', '10090', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (9, 14))	('tumors', 'Disease', (9, 15))	('mice', 'Species', '10090', (40, 44))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
10017	33322371	The deletion of NRLP3 has a protective effect in the MCA-induced fibrosarcoma model, dependent on NK cells and IFN-gamma.	('protective effect', 'CPA', (28, 45))	('MCA-induced', 'Disease', (53, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('MCA', 'Chemical', 'MESH:D008748', (53, 56))	('NRLP3', 'Gene', (16, 21))	('fibrosarcoma', 'Disease', (65, 77))	('deletion', 'Var', (4, 12))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (65, 77))	('fibrosarcoma', 'Disease', 'MESH:D005354', (65, 77))
10018	33322371	NRLP3 activation was also shown to impede NK cell antimetastatic function by decreasing NK cell tumor homing.	('NK cell tumor', 'Disease', (88, 101))	('impede', 'NegReg', (35, 41))	('decreasing', 'NegReg', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('activation', 'Var', (6, 16))	('NK cell antimetastatic function', 'CPA', (42, 73))	('NRLP3', 'Gene', (0, 5))	('decreasing NK cell', 'Phenotype', 'HP:0040218', (77, 95))	('NK cell tumor', 'Disease', 'MESH:D054066', (88, 101))
10033	33322371	provided evidence of NK cells playing a key role in limiting the L929 TRAIL-sensitive fibrosarcoma progression in a subcutaneous murine model.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (86, 98))	('fibrosarcoma', 'Disease', 'MESH:D005354', (86, 98))	('L929', 'Var', (65, 69))	('limiting', 'NegReg', (52, 60))	('murine', 'Species', '10090', (129, 135))	('fibrosarcoma', 'Disease', (86, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))
10059	33322371	Moreover, NRLP3 and IL-1R8 deficiencies were shown to have an antimetastatic effect attributed to enhanced NK cell function.	('enhanced', 'PosReg', (98, 106))	('deficiencies', 'Var', (27, 39))	('NK cell function', 'CPA', (107, 123))	('antimetastatic effect', 'CPA', (62, 83))	('IL-1R8', 'Gene', '11141', (20, 26))	('IL-1R8', 'Gene', (20, 26))	('NRLP3', 'Gene', (10, 15))
10060	33322371	NK cells can be successfully used in metastases treatment; K562-expanded NK cells effectively eradicate Ewing sarcoma (EWS) metastases with little effect on the primary tumor in a murine model.	('murine', 'Species', '10090', (180, 186))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('metastases', 'Disease', (124, 134))	('K562', 'CellLine', 'CVCL:0004', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('metastases', 'Disease', (37, 47))	('metastases', 'Disease', 'MESH:D009362', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('EWS', 'Phenotype', 'HP:0012254', (119, 122))	('K562-expanded', 'Var', (59, 72))	('tumor', 'Disease', (169, 174))	('Ewing sarcoma', 'Gene', (104, 117))	('metastases', 'Disease', 'MESH:D009362', (37, 47))	('Ewing sarcoma', 'Gene', '14030', (104, 117))	('eradicate', 'NegReg', (94, 103))
10105	33322371	In soft tissue sarcoma patients, high TGF-beta1 intratumoral expression is associated with aggressive disease and shorter disease-specific survival.	('TGF-beta1', 'Gene', '7040', (38, 47))	('TGF-beta1', 'Gene', (38, 47))	('high', 'Var', (33, 37))	('aggressive disease', 'Disease', 'MESH:D001523', (91, 109))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('patients', 'Species', '9606', (23, 31))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (3, 22))	('shorter', 'NegReg', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sarcoma', 'Disease', (15, 22))	('aggressive disease', 'Disease', (91, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('tumor', 'Disease', (53, 58))
10109	33322371	Moreover, it has been shown that EWS treated with anti-GD2 chimeric antigen receptor (CAR)-NK cells developed resistance to the treatment in an HLA-G-dependent manner, which was selectively upregulated on tumor cells only in CAR-treated mice.	('resistance', 'MPA', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('EWS', 'Phenotype', 'HP:0012254', (33, 36))	('mice', 'Species', '10090', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('anti-GD2', 'Var', (50, 58))
10110	33322371	NKG2A knockdown restored CAR-NK lytic function and allowed for effective tumor eradication.	('restored', 'PosReg', (16, 24))	('NKG2A', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('CAR-NK lytic function', 'CPA', (25, 46))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('knockdown', 'Var', (6, 15))	('NKG2A', 'Gene', '3821', (0, 5))
10133	33322371	However, despite the normal phenotype, PD-1+ NK cells demonstrated reduced cytotoxicity and IFN-gamma production ex vivo following the direct triggering of NKp30, NKp46, CD16, or short stimulation with target cells, suggesting a role of PD-1 in KS-mediated NK cell exhaustion.	('cytotoxicity', 'Disease', (75, 87))	('IFN-gamma production', 'MPA', (92, 112))	('CD16', 'Gene', (170, 174))	('reduced', 'NegReg', (67, 74))	('KS', 'Phenotype', 'HP:0100726', (245, 247))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('NKp46', 'Var', (163, 168))	('NKp30', 'Gene', '259197', (156, 161))	('PD-1+', 'Var', (39, 44))	('CD16', 'Gene', '2214', (170, 174))	('NKp30', 'Gene', (156, 161))
10138	33322371	High B7-H3 expression is also associated with shorter survival and disease recurrence.	('B7-H3', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('B7-H3', 'Gene', '80381', (5, 10))	('disease recurrence', 'CPA', (67, 85))	('shorter', 'NegReg', (46, 53))
10140	33322371	Knockout of IL-1R8 has been shown to restore NK cell antitumor function in MCA-induced sarcomas, implicating a role of IL-1R8 in sarcoma-mediated NK cell suppression.	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('MCA', 'Chemical', 'MESH:D008748', (75, 78))	('sarcoma', 'Disease', (87, 94))	('IL-1R8', 'Gene', '11141', (119, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('IL-1R8', 'Gene', (12, 18))	('sarcomas', 'Disease', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('tumor', 'Disease', (57, 62))	('restore', 'PosReg', (37, 44))	('IL-1R8', 'Gene', '11141', (12, 18))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Knockout', 'Var', (0, 8))	('sarcoma', 'Disease', (129, 136))	('IL-1R8', 'Gene', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
10184	33322371	A case report study has also shown haplo-HSCT to be effective in metastases control in two patients with stage IV EWS.	('EWS', 'Phenotype', 'HP:0012254', (114, 117))	('patients', 'Species', '9606', (91, 99))	('haplo-HSCT', 'Var', (35, 45))	('metastases', 'Disease', 'MESH:D009362', (65, 75))	('metastases', 'Disease', (65, 75))
10208	33322371	Interestingly, IGFR-1 inhibition enhances NK cell expansion without impairing the NK cell-mediated lysis of EWS cells.	('inhibition', 'Var', (22, 32))	('EWS', 'Phenotype', 'HP:0012254', (108, 111))	('enhances', 'PosReg', (33, 41))	('IGFR-1', 'Gene', '2209', (15, 21))	('NK cell expansion', 'CPA', (42, 59))	('IGFR-1', 'Gene', (15, 21))
10220	33322371	Besides, although preliminary studies report entinostat-mediated enhancement of NK cell effector function, both HDAC inhibition and DNA hypomethylation have been linked to NK cell cytotoxicity impairment, raising caution against combining them with NK cell-based therapies.	('NK cell effector function', 'CPA', (80, 105))	('enhancement', 'PosReg', (65, 76))	('entinostat', 'Chemical', 'MESH:C118739', (45, 55))	('NK cell cytotoxicity impairment', 'Disease', (172, 203))	('NK cell cytotoxicity impairment', 'Disease', 'MESH:D064420', (172, 203))	('HDAC', 'Gene', (112, 116))	('HDAC', 'Gene', '9734', (112, 116))	('DNA', 'MPA', (132, 135))	('hypomethylation', 'Var', (136, 151))
10226	33322371	Using a specific MMP-9 inhibitor might represent a double-benefit therapy, where it can both inhibit tumor invasion and restore NK cell-mediated antitumor immune response.	('inhibit', 'NegReg', (93, 100))	('MMP-9', 'Gene', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('restore', 'PosReg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('inhibitor', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('MMP-9', 'Gene', '4318', (17, 22))
10268	33322371	Interestingly, a chimeric NKG2D receptor transduced T cells and NK cells were successfully used in preclinical models of EWS and OS.	('chimeric', 'Var', (17, 25))	('NKG2D receptor', 'Gene', (26, 40))	('EWS', 'Disease', (121, 124))	('OS', 'Phenotype', 'HP:0002669', (129, 131))	('NKG2D receptor', 'Gene', '22914', (26, 40))	('EWS', 'Phenotype', 'HP:0012254', (121, 124))
10278	33322371	iPSC-NK cells can be fine-tuned by multiple genetic modifications to achieve more potent effector function, introduce tailored specificities, and promote persistence, and they are therefore attractive candidates for off-the-shelf cancer immunotherapies.	('modifications', 'Var', (52, 65))	('persistence', 'MPA', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('specificities', 'MPA', (127, 140))	('promote', 'PosReg', (146, 153))
10285	33322371	Augmenting NK cell anticancer properties can be achieved through various priming strategies and genetic modifications, which improve cancer cell recognition, tumor homing, and resistance to suppressive factors in the TME.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('modifications', 'Var', (104, 117))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('improve', 'PosReg', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
10314	32790252	Frequency-domain measurements were acquired using six lasers (658, 690, 785, 808, 830, and 850 nm, part numbers: HL6501MG, HL6738MG, L785P100, L808P030, HL8338MG, and L850P030, respectively, all lasers were acquired from Thorlabs, Newton, New Jersey, USA).	('HL6738MG', 'Var', (123, 131))	('men', 'Species', '9606', (24, 27))	('L808P030', 'Var', (143, 151))	('HL6501MG', 'Var', (113, 121))	('HL6501MG', 'CellLine', 'CVCL:2492', (113, 121))	('HL6738MG', 'CellLine', 'CVCL:2492', (123, 131))	('L785P100', 'Var', (133, 141))	('HL8338MG', 'CellLine', 'CVCL:2492', (153, 161))	('HL8338MG', 'Var', (153, 161))	('L850P030', 'Var', (167, 175))
10316	32790252	A commercial network analyzer (E5061B 100 kHz to 1.5 GHz ENA Series Network Analyzer, Agilent Technologies, Santa Clara, California, USA) was used to generate rf and measure detected amplitude and phase.	('E5061B', 'SUBSTITUTION', 'None', (31, 37))	('amplitude', 'MPA', (183, 192))	('E5061B', 'Var', (31, 37))
10450	32551237	A 46-year-old woman, G0P0, presented to the emergency department with chronic vaginal bleeding that had started 5 months previously and acute heavy vaginal bleeding over the past 2 days.	('vaginal bleeding', 'Disease', (78, 94))	('vaginal bleeding', 'Disease', 'MESH:D014592', (78, 94))	('woman', 'Species', '9606', (14, 19))	('vaginal bleeding', 'Disease', 'MESH:D014592', (148, 164))	('G0P0', 'Var', (21, 25))	('vaginal bleeding', 'Disease', (148, 164))
10478	32551237	Compared with undifferentiated endometrial carcinomas, SDUS more frequently shows phyllodiform architecture, and less frequently expresses TP53 mutations, microsatellite instability, and is characterized only by inactivating mutations in SMARCA4.	('SMARCA4', 'Gene', '6597', (238, 245))	('inactivating mutations', 'Var', (212, 234))	('microsatellite instability', 'Var', (155, 181))	('less', 'NegReg', (113, 117))	('undifferentiated endometrial carcinomas', 'Disease', (14, 53))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (31, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('TP53', 'Gene', '7157', (139, 143))	('undifferentiated endometrial carcinomas', 'Disease', 'MESH:D016889', (14, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('SMARCA4', 'Gene', (238, 245))	('TP53', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))	('phyllodiform architecture', 'CPA', (82, 107))
10479	32551237	SDUS and small cell carcinoma of the ovary (hypercalcemic type) both affect young women, are fatal with aggressive clinical behavior and share inactivation of SMARCA4.	('small cell carcinoma', 'Phenotype', 'HP:0030357', (9, 29))	('inactivation', 'Var', (143, 155))	('affect', 'Reg', (69, 75))	('small cell carcinoma of the ovary', 'Disease', (9, 42))	('women', 'Species', '9606', (82, 87))	('SMARCA4', 'Gene', (159, 166))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (104, 132))	('SMARCA4', 'Gene', '6597', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('SDUS', 'Disease', (0, 4))	('small cell carcinoma of the ovary', 'Disease', 'MESH:D010051', (9, 42))
10555	30930990	A total of 2 cases of GNETs document a patient history of hepatoblastoma or Ewing's sarcoma in early childhood, suggesting that genetic aberration in the embryonic stage could be regarded as a risk for the oncogenesis of this tumor.	('patient', 'Species', '9606', (39, 46))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (76, 91))	('genetic aberration', 'Var', (128, 146))	('hepatoblastoma', 'Disease', (58, 72))	("Ewing's sarcoma", 'Disease', (76, 91))	('embryonic', 'Disease', 'MESH:D009373', (154, 163))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (76, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('hepatoblastoma', 'Disease', 'MESH:D018197', (58, 72))	('embryonic', 'Disease', (154, 163))	('tumor', 'Disease', (226, 231))
10566	30930990	Immunohistochemically, S-100 protein positivity has been found in all reported cases.	('S-100', 'Gene', (23, 28))	('found', 'Reg', (57, 62))	('positivity', 'Var', (37, 47))	('S-100', 'Gene', '6271', (23, 28))
10611	28882536	The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]).	('doxorubicin', 'Var', (203, 214))	('fever', 'Phenotype', 'HP:0001945', (310, 315))	('docetaxel', 'Chemical', 'MESH:D000077143', (299, 308))	('neutropenia', 'Disease', 'MESH:D009503', (126, 137))	('neutropenia', 'Phenotype', 'HP:0001875', (126, 137))	('neutropenia', 'Disease', (345, 356))	('neutropenia', 'Disease', 'MESH:D009503', (345, 356))	('patients', 'Species', '9606', (181, 189))	('fever', 'Disease', 'MESH:D005334', (310, 315))	('doxorubicin', 'Chemical', 'MESH:D004317', (203, 214))	('febrile neutropenia', 'Disease', (118, 137))	('gemcitabine', 'Chemical', 'MESH:C056507', (283, 294))	('patients', 'Species', '9606', (261, 269))	('febrile neutropenia', 'Disease', 'MESH:D009503', (118, 137))	('neutropenia', 'Disease', (126, 137))	('neutropenia', 'Phenotype', 'HP:0001875', (345, 356))	('fever', 'Disease', (310, 315))
10647	28882536	A pharmacogenomics study was also done to investigate the influence of single-nucleotide polymorphisms (SNPs) on treatment efficacy and toxicity.	('single-nucleotide polymorphisms', 'Var', (71, 102))	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('toxicity', 'Disease', (136, 144))
10650	28882536	Patients were required to have adequate organ function (absolute neutrophil count >=1 0 x 109 per L; platelet count >=100 x 109 per L; bilirubin <=1 5 x upper limit of normal [ULN]; aspartate transaminase, alanine transaminase, or both <=3 0 x ULN; alkaline phosphatase <=3 0 x ULN [patients were eligible with a higher alkaline phosphatase concentration if this was shown to be due to bone isoenzyme]; measured or calculated creatinine clearance >=30 mL/min; and cardiac ejection fraction within local normal limits).	('cardiac', 'MPA', (464, 471))	('alkaline', 'MPA', (249, 257))	('creatinine clearance', 'MPA', (426, 446))	('higher alkaline phosphatase concentration', 'Phenotype', 'HP:0003155', (313, 354))	('alkaline phosphatase concentration', 'MPA', (320, 354))	('>=100', 'Var', (116, 121))	('patients', 'Species', '9606', (283, 291))	('Patients', 'Species', '9606', (0, 8))	('bilirubin', 'Chemical', 'MESH:D001663', (135, 144))
10735	28882536	Within the doxorubicin group, three of the four SNPs in the SLC22A16 gene, all in linkage disequilibrium with each other, were associated with a worse progression-free survival (appendix pp 12, 15), as was the minor allele of the SLC29A1 SNP (rs9394992, in both heterozygotes and homozygotes; appendix p 14).	('progression-free survival', 'CPA', (151, 176))	('p 14', 'Gene', (302, 306))	('rs9394992', 'Mutation', 'rs9394992', (243, 252))	('p 14', 'Gene', '1029', (302, 306))	('rs9394992', 'Var', (243, 252))	('SLC29A1', 'Gene', (230, 237))	('SLC29A1', 'Gene', '2030', (230, 237))	('worse', 'NegReg', (145, 150))	('SLC22A16', 'Gene', '85413', (60, 68))	('appendix p 14', 'Phenotype', 'HP:0002825', (293, 306))	('doxorubicin', 'Chemical', 'MESH:D004317', (11, 22))	('p 12', 'Gene', (188, 192))	('SLC22A16', 'Gene', (60, 68))	('p 12', 'Gene', '56655', (188, 192))
10736	28882536	By contrast, the PRDX4 SNP (rs518329) minor allele was associated with improved overall survival in the doxorubicin group in both heterozygotes and homozygotes (appendix p 13).	('overall survival', 'MPA', (80, 96))	('rs518329', 'Mutation', 'rs518329', (28, 36))	('PRDX4', 'Gene', '10549', (17, 22))	('rs518329', 'Var', (28, 36))	('p 13', 'Gene', '440926', (170, 174))	('PRDX4', 'Gene', (17, 22))	('doxorubicin', 'Chemical', 'MESH:D004317', (104, 115))	('p 13', 'Gene', (170, 174))	('improved', 'PosReg', (71, 79))
10737	28882536	Analysis of the gemcitabine and docetaxel treatment group indicated a possible association of the ABCB1 rs1045642 minor allele with worse progression-free survival in both heterozygotes and homozygotes (appendix p 12); the CDA rs2072671 SNP was associated with worse overall survival (appendix p 14), and the CMPK1 rs4492666 SNP was associated with improved overall survival in both heterozygotes and homozygotes (appendix p 14).	('ABCB1', 'Gene', (98, 103))	('ABCB1', 'Gene', '5243', (98, 103))	('overall survival', 'MPA', (358, 374))	('CMPK1', 'Gene', '51727', (309, 314))	('p 14', 'Gene', (423, 427))	('improved', 'PosReg', (349, 357))	('p 14', 'Gene', '1029', (423, 427))	('p 14', 'Gene', (294, 298))	('p 14', 'Gene', '1029', (294, 298))	('docetaxel', 'Chemical', 'MESH:D000077143', (32, 41))	('appendix p 14', 'Phenotype', 'HP:0002825', (414, 427))	('gemcitabine', 'Chemical', 'MESH:C056507', (16, 27))	('p 12', 'Gene', (212, 216))	('p 12', 'Gene', '56655', (212, 216))	('rs4492666 SNP', 'Var', (315, 328))	('rs2072671 SNP', 'Var', (227, 240))	('rs1045642', 'Var', (104, 113))	('rs2072671', 'Mutation', 'rs2072671', (227, 236))	('rs1045642', 'Mutation', 'rs1045642', (104, 113))	('rs4492666', 'Mutation', 'rs4492666', (315, 324))	('CMPK1', 'Gene', (309, 314))	('appendix p 14', 'Phenotype', 'HP:0002825', (285, 298))	('overall', 'MPA', (267, 274))
10738	28882536	The SLC22A16 rs723685 minor allele was associated with a reduced frequency of grade 3-4 adverse events compared with wild type (ten [48%] of 21 patients vs 69 [71%] of 97 patients) in the doxorubicin treatment group but not in the gemcitabine and docetaxel group.	('docetaxel', 'Chemical', 'MESH:D000077143', (247, 256))	('SLC22A16', 'Gene', (4, 12))	('gemcitabine', 'Chemical', 'MESH:C056507', (231, 242))	('doxorubicin', 'Chemical', 'MESH:D004317', (188, 199))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (144, 152))	('reduced', 'NegReg', (57, 64))	('rs723685 minor', 'Var', (13, 27))	('SLC22A16', 'Gene', '85413', (4, 12))	('rs723685', 'Mutation', 'rs723685', (13, 21))	('grade 3-4 adverse events', 'MPA', (78, 102))
10787	28882536	The pharmacogenomics data obtained in the current study suggest that SNPs in the organic cation transporter SLC22A16 are associated with reduced efficacy and decreased toxicity following doxorubicin treatment.	('efficacy', 'MPA', (145, 153))	('decreased', 'NegReg', (158, 167))	('toxicity', 'Disease', 'MESH:D064420', (168, 176))	('toxicity', 'Disease', (168, 176))	('SLC22A16', 'Gene', (108, 116))	('SLC22A16', 'Gene', '85413', (108, 116))	('SNPs', 'Var', (69, 73))	('doxorubicin', 'Chemical', 'MESH:D004317', (187, 198))	('reduced', 'NegReg', (137, 144))
10790	28882536	Two other SNPs, SLC29A1 rs9394992 and PRDX4 rs518329, were also associated with outcomes in the doxorubicin group; however, these genes are not known to be involved in the pharmacology of doxorubicin, so further investigation is required to understand these effects.	('associated', 'Reg', (64, 74))	('rs518329', 'Mutation', 'rs518329', (44, 52))	('doxorubicin', 'Chemical', 'MESH:D004317', (188, 199))	('PRDX4', 'Gene', '10549', (38, 43))	('SLC29A1', 'Gene', '2030', (16, 23))	('rs9394992', 'Var', (24, 33))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('PRDX4', 'Gene', (38, 43))	('rs9394992', 'Mutation', 'rs9394992', (24, 33))	('SLC29A1', 'Gene', (16, 23))	('rs518329', 'Var', (44, 52))
10791	28882536	There were indications that three SNPs predicted to affect gemcitabine pharmacokinetics were associated with an effect on overall survival, most notably the CDA rs2072671 SNP, which was associated with reduced overall survival in the gemcitabine and docetaxel group, with worse survival in patients homozygous (rather than heterozygous) for the minor allele (this is referred to as a gene-dose effect).	('overall survival', 'MPA', (210, 226))	('reduced', 'NegReg', (202, 209))	('gemcitabine', 'MPA', (59, 70))	('patients', 'Species', '9606', (290, 298))	('gemcitabine', 'Chemical', 'MESH:C056507', (234, 245))	('gemcitabine', 'Chemical', 'MESH:C056507', (59, 70))	('overall survival', 'MPA', (122, 138))	('docetaxel', 'Chemical', 'MESH:D000077143', (250, 259))	('rs2072671', 'Mutation', 'rs2072671', (161, 170))	('rs2072671', 'Var', (161, 170))	('affect', 'Reg', (52, 58))
10845	20233457	On molecular analysis using the RT-PCR technique, t (11; 22) (q24; q12) (EWSR1-FLI1) turned out positive, thus confirming the diagnosis of primary Ewing's sarcoma or PNET of the vagina.	('FLI1', 'Gene', (79, 83))	('FLI1', 'Gene', '2313', (79, 83))	('PNET of the vagina', 'Disease', (166, 184))	('t (11', 'Var', (50, 55))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (147, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('EWSR1', 'Gene', (73, 78))	("primary Ewing's sarcoma", 'Disease', 'MESH:C563168', (139, 162))	('PNET', 'Phenotype', 'HP:0030065', (166, 170))	('EWSR1', 'Gene', '2130', (73, 78))	("primary Ewing's sarcoma", 'Disease', (139, 162))
10847	20233457	Following our diagnosis of primary Ewing's sarcoma or PNET of the vagina, our patient was subjected to combination chemotherapy for 9 weeks based on institutional protocol for Ewing's family of tumors (EFT) 2001, including drugs such as vincristine (1.5 mg/m2), ifosamide (2.0 g/m2), etoposide (100 mg/m2), cyclophosphamide (600 mg/m2), doxorubicin (60 mg/m2), and actinomycin (1.0 mg/m2).	("Ewing's family of tumors", 'Disease', (176, 200))	('100 mg/m2', 'Var', (295, 304))	("Ewing's family of tumors", 'Disease', 'MESH:C563168', (176, 200))	("primary Ewing's sarcoma", 'Disease', 'MESH:C563168', (27, 50))	('patient', 'Species', '9606', (78, 85))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (307, 323))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (35, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('etoposide', 'Chemical', 'MESH:D005047', (284, 293))	('vincristine', 'Chemical', 'MESH:D014750', (237, 248))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	("primary Ewing's sarcoma", 'Disease', (27, 50))	('ifosamide', 'Chemical', '-', (262, 271))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('PNET', 'Phenotype', 'HP:0030065', (54, 58))	('actinomycin', 'Chemical', 'MESH:D003609', (365, 376))	('doxorubicin', 'Chemical', 'MESH:D004317', (337, 348))
10851	20233457	Both, however, are characterized by a t(11; 22) (q24; q12) chromosomal translocation leading to a chimeric transcript EWS-FLI1 in 85% of reported cases.	('chimeric transcript', 'MPA', (98, 117))	('EWS', 'Gene', '2130', (118, 121))	('EWS', 'Gene', (118, 121))	('leading to', 'Reg', (85, 95))	('t(11; 22) (q24; q12', 'Var', (38, 57))	('FLI1', 'Gene', '2313', (122, 126))	('FLI1', 'Gene', (122, 126))
10859	20233457	Diffuse membranous MIC2 positivity was more in keeping with a Ewing's sarcoma/PNET than neuroendocrine carcinoma and a synovial sarcoma that also shows MIC2 and cytoplasmic expression.	("Ewing's sarcoma", 'Disease', (62, 77))	('MIC2', 'Gene', (152, 156))	('positivity', 'Var', (24, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (62, 77))	('synovial sarcoma', 'Disease', (119, 135))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (88, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('MIC2', 'Gene', (19, 23))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (88, 112))	('neuroendocrine carcinoma', 'Disease', (88, 112))	('synovial sarcoma', 'Disease', 'MESH:D013584', (119, 135))	('PNET', 'Phenotype', 'HP:0030065', (78, 82))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (119, 135))	('MIC2', 'Gene', '4267', (152, 156))	('MIC2', 'Gene', '4267', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (62, 77))
10860	20233457	Meanwhile, MIC2 positivity is also identified in rhabdomyosarcomas and lymphomas.	('MIC2', 'Gene', (11, 15))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('identified', 'Reg', (35, 45))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (49, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (71, 79))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (49, 66))	('MIC2', 'Gene', '4267', (11, 15))	('lymphomas', 'Phenotype', 'HP:0002665', (71, 80))	('positivity', 'Var', (16, 26))	('rhabdomyosarcomas and lymphomas', 'Disease', 'MESH:D012208', (49, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
10902	32106426	We evaluated intra-tumoral kinetics by FLT-PET imaging, to c-MET inhibitors and MDM2 inhibitors in patients with multiple types of sarcoma.	('MDM2', 'Gene', (80, 84))	('tumoral', 'Disease', (19, 26))	('tumoral', 'Disease', 'MESH:D009369', (19, 26))	('FLT', 'Chemical', 'MESH:C002854', (39, 42))	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('inhibitors', 'Var', (85, 95))	('c-MET', 'Gene', '4233', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('sarcoma', 'Disease', (131, 138))	('patients', 'Species', '9606', (99, 107))	('intra-tumor', 'Disease', 'MESH:D009369', (13, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('c-MET', 'Gene', (59, 64))	('MDM2', 'Gene', '4193', (80, 84))	('intra-tumor', 'Disease', (13, 24))
10937	32106426	This patient had two mesenteric lymph node metastases (annotated R (right) and L(left)); with 18F-FLT, the outcome at seven weeks was -25% (R) and +7% (L), whereas 18F-FDG did not show any response (+19% (R) and +21% (L)).	('18F-FLT', 'Var', (94, 101))	('patient', 'Species', '9606', (5, 12))	('18F-FDG', 'Chemical', 'MESH:D019788', (164, 171))	('metastases', 'Disease', (43, 53))	('metastases', 'Disease', 'MESH:D009362', (43, 53))	('18F-FLT', 'Chemical', 'MESH:C002854', (94, 101))
10948	32106426	With 18F-FLT, the outcome at one week was -13% (R), whereas 18F-FDG did not show any response +37%, and SUVmax increased from 8.9 to 12.2.	('18F-FDG', 'Chemical', 'MESH:D019788', (60, 67))	('SUVmax', 'MPA', (104, 110))	('18F-FLT', 'Chemical', 'MESH:C002854', (5, 12))	('increased', 'PosReg', (111, 120))	('18F-FLT', 'Var', (5, 12))
11004	31143880	From February 2015 to May 2016, 14 patients (M/F 7/7), median age 36 years (range 24-70) and median tumor size 12.5 cm (range 7-17 cm), were enrolled.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('M/F 7', 'Var', (45, 50))	('M/F 7', 'SUBSTITUTION', 'None', (45, 50))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
11024	31143880	It arises predominantly in the extremities of young adults and is characterized by a balanced translocation, most commonly t(12;16)(q13;p11) fusing FUS (also named as TLS) with CHOP (also named as DDIT3) and rarely t(12;22)(q13;q12), where EWS (Ewing's Sarcoma protein) substitutes for its homologous FUS.	('CHOP', 'Gene', '1649', (177, 181))	('FUS', 'Gene', '2521', (148, 151))	('DDIT3', 'Gene', (197, 202))	('EWS', 'Gene', (240, 243))	('FUS', 'Gene', (301, 304))	('CHOP', 'Gene', (177, 181))	('t(12;16)(q13', 'Var', (123, 135))	('Sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	("Ewing's Sarcoma protein", 'Gene', '2130', (245, 268))	('FUS', 'Gene', '2521', (301, 304))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (245, 260))	('TLS', 'Gene', (167, 170))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (123, 140))	('EWS', 'Gene', '2130', (240, 243))	('FUS', 'Gene', (148, 151))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (215, 232))	("Ewing's Sarcoma protein", 'Gene', (245, 268))	('DDIT3', 'Gene', '1649', (197, 202))	('TLS', 'Gene', '2521', (167, 170))
11036	31143880	The dose escalation rules proceeded according to the traditional 3 + 3 design being the prespecified dose-limiting toxicity (DLT) as follows: neutrophil count < 0.5 x 109/L during >= 5 days, febrile neutropenia, platelet count < 50 x 109/L and non-haematological toxicity of grade 3 or above, excluding nausea/vomiting without appropriate antiemetic treatment and grade 3 transaminitis if not leading to T delay.	('toxicity', 'Disease', (263, 271))	('vomiting', 'Disease', (310, 318))	('neutrophil', 'Disease', (142, 152))	('< 0.5 x 109/L', 'Var', (159, 172))	('febrile neutropenia', 'Disease', 'MESH:D009503', (191, 210))	('vomiting', 'Disease', 'MESH:D014839', (310, 318))	('vomiting', 'Phenotype', 'HP:0002013', (310, 318))	('nausea', 'Phenotype', 'HP:0002018', (303, 309))	('nausea', 'Disease', (303, 309))	('neutropenia', 'Phenotype', 'HP:0001875', (199, 210))	('nausea', 'Disease', 'MESH:D009325', (303, 309))	('febrile neutropenia', 'Disease', (191, 210))	('< 50 x 109/L', 'Var', (227, 239))	('toxicity', 'Disease', (115, 123))	('toxicity', 'Disease', 'MESH:D064420', (115, 123))	('toxicity', 'Disease', 'MESH:D064420', (263, 271))
11071	31143880	From February 2015 to May 2016, 14 patients (M/F 7/7) with median age of 36-years (range 24-70) and median tumor size of 12.5 cm (range 7-20 cm) were enrolled.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('M/F 7', 'Var', (45, 50))	('M/F 7', 'SUBSTITUTION', 'None', (45, 50))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
11112	31143880	In addition the effect of VEGFR inhibitors against the metastatic risk of localized high risk STS is far from being demonstrated and a limited activity in advanced liposarcoma has consistently been reported for all these compounds.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('inhibitors', 'Var', (32, 42))	('STS', 'Phenotype', 'HP:0030448', (94, 97))	('VEGFR', 'Gene', (26, 31))	('liposarcoma', 'Disease', (164, 175))	('liposarcoma', 'Disease', 'MESH:D008080', (164, 175))	('liposarcoma', 'Phenotype', 'HP:0012034', (164, 175))	('VEGFR', 'Gene', '3791', (26, 31))
11187	30150604	Further to this, in a sub-analysis of literature of pregnant and non-pregnant women, we found that in certain regions of Africa HHV-8 seropositivity was more frequent in non-pregnant women than in pregnant women of comparable age, while the converse was true in other regions (for example, in West Africa).	('HHV-8', 'Gene', (128, 133))	('seropositivity', 'Var', (134, 148))	('women', 'Species', '9606', (183, 188))	('HHV-8', 'Species', '37296', (128, 133))	('women', 'Species', '9606', (78, 83))	('sero', 'Chemical', '-', (134, 138))	('frequent', 'Reg', (158, 166))	('women', 'Species', '9606', (206, 211))
11198	30150604	Intra-genotype variants have also been reported; for example, K1 A5 and K15 M based on allele differences.	('K15 M', 'Mutation', 'p.K15M', (72, 77))	('K1 A5', 'Var', (62, 67))	('K15 M', 'Var', (72, 77))
11209	30167083	Treatment with MG132 demonstrated an accumulation of MST2 in 25% of sarcoma cell lines, indicating that proteosomal degradation regulates MST2 expression.	('MST2', 'Gene', '6788', (53, 57))	('expression', 'MPA', (143, 153))	('MST2', 'Gene', (138, 142))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('MG132', 'Chemical', 'MESH:C072553', (15, 20))	('MST2', 'Gene', '6788', (138, 142))	('MG132', 'Var', (15, 20))	('sarcoma', 'Disease', (68, 75))	('MST2', 'Gene', (53, 57))	('accumulation', 'PosReg', (37, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
11211	30167083	5-azacytidine treatment in sarcoma cell lines modestly reversed expression of predominantly MST1 (8%) and MST2 (17%), indicating CpG island hypermethylation can silence expression of MST1 and MST2.	('MST2', 'Gene', (106, 110))	('sarcoma', 'Disease', (27, 34))	('5-azacytidine', 'Chemical', 'MESH:D001374', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('MST1', 'Gene', (183, 187))	('silence', 'NegReg', (161, 168))	('MST2', 'Gene', '6788', (192, 196))	('MST2', 'Gene', '6788', (106, 110))	('MST1', 'Gene', '4485', (92, 96))	('MST1', 'Gene', '4485', (183, 187))	('expression', 'MPA', (169, 179))	('MST1', 'Gene', (92, 96))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('hypermethylation', 'Var', (140, 156))	('MST2', 'Gene', (192, 196))
11227	30167083	Mutations in the upstream Hippo kinases, MST1, MST2, LATS1, and LATS2 have also been rare.	('MST1', 'Gene', (41, 45))	('MST2', 'Gene', '6788', (47, 51))	('LATS1', 'Gene', (53, 58))	('LATS1', 'Gene', '9113', (53, 58))	('LATS2', 'Gene', (64, 69))	('MST1', 'Gene', '4485', (41, 45))	('LATS2', 'Gene', '26524', (64, 69))	('Mutations', 'Var', (0, 9))	('MST2', 'Gene', (47, 51))
11235	30167083	Several lines of evidence indicate that silencing of the Hippo kinases is necessary for activation of TAZ and YAP.	('YAP', 'Gene', (110, 113))	('TAZ', 'CPA', (102, 105))	('silencing', 'Var', (40, 49))	('YAP', 'Gene', '10413', (110, 113))	('Hippo kinases', 'Enzyme', (57, 70))
11244	30167083	The similar frequency of loss of the Hippo kinases in TAZ/YAP activated sarcomas versus all sarcomas regardless of TAZ/YAP activation status indicates that loss of the Hippo kinases is associated with TAZ/YAP activation the majority of the time.	('YAP', 'Gene', (58, 61))	('associated', 'Reg', (185, 195))	('YAP', 'Gene', '10413', (205, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcomas versus all sarcomas', 'Disease', 'MESH:D012509', (72, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('YAP', 'Gene', '10413', (119, 122))	('loss', 'Var', (156, 160))	('YAP', 'Gene', '10413', (58, 61))	('sarcomas versus all sarcomas', 'Disease', (72, 100))	('YAP', 'Gene', (205, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('YAP', 'Gene', (119, 122))
11256	30167083	With the exception of MOB1A/B, mutations in the upstream Hippo kinases (especially MST1/2) have been reported to be extremely rare.	('mutations', 'Var', (31, 40))	('MOB1A/B', 'Gene', '55233', (22, 29))	('MST1/2', 'Gene', '4485;6788', (83, 89))	('MOB1A/B', 'Gene', (22, 29))	('MST1/2', 'Gene', (83, 89))	('Hippo kinases', 'Enzyme', (57, 70))
11257	30167083	Mutations in TAZ and YAP have also been shown to be extremely rare, with the exception of the WWTR1-CAMTA1 and YAP1-TFE3 gene fusions which are disease defining genetic alterations found in essentially all epithelioid hemangioendotheliomas.	('CAMTA1', 'Gene', '23261', (100, 106))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (206, 238))	('TAZ', 'Gene', (13, 16))	('YAP', 'Gene', (111, 114))	('YAP1', 'Gene', '10413', (111, 115))	('YAP', 'Gene', (21, 24))	('WWTR1', 'Gene', '25937', (94, 99))	('net', 'Gene', (163, 166))	('Mutations', 'Var', (0, 9))	('YAP1', 'Gene', (111, 115))	('CAMTA1', 'Gene', (100, 106))	('epithelioid hemangioendotheliomas', 'Disease', (206, 239))	('YAP', 'Gene', '10413', (111, 114))	('epithelioid hemangioendotheliomas', 'Phenotype', 'HP:0032060', (206, 239))	('YAP', 'Gene', '10413', (21, 24))	('epithelioid hemangioendotheliomas', 'Disease', 'MESH:D018323', (206, 239))	('WWTR1', 'Gene', (94, 99))	('TFE3', 'Gene', (116, 120))	('TFE3', 'Gene', '7030', (116, 120))	('net', 'Gene', '2004', (163, 166))
11259	30167083	To confirm this is the case in sarcomas, we performed targeted PCR-based Sanger sequencing of 12 sarcoma cell lines and GCT (giant cell tumor) for the presence of mutations in the serines in TAZ (S66, 89, 117, and 311) and YAP (S61, 109, 127, 164, and 381) phosphorylated by LATS1/2.	('giant cell tumor', 'Disease', (125, 141))	('sarcoma', 'Disease', (31, 38))	('S66', 'Var', (196, 199))	('LATS1/2', 'Gene', '9113;26524', (275, 282))	('YAP', 'Gene', (223, 226))	('sarcomas', 'Disease', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('LATS1/2', 'Gene', (275, 282))	('giant cell tumor', 'Phenotype', 'HP:0011847', (125, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('YAP', 'Gene', '10413', (223, 226))	('giant cell tumor', 'Disease', 'MESH:D005870', (125, 141))	('TAZ', 'Gene', (191, 194))	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('mutations', 'Var', (163, 172))	('serines', 'Chemical', 'MESH:D012694', (180, 187))	('sarcoma', 'Disease', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
11265	30167083	After 12 hours, MG132 was shown to quantitatively increase expression of MST2 in 3 of the 12 cell lines (25%) (Figure 3 and Supplementary Figure 5B), indicating that enhanced proteosomal degradation leads to decreased Hippo kinase expression in sarcoma cell lines.	('MST2', 'Gene', (73, 77))	('sarcoma', 'Disease', 'MESH:D012509', (245, 252))	('Hippo kinase expression', 'MPA', (218, 241))	('increase', 'PosReg', (50, 58))	('expression', 'MPA', (59, 69))	('MST2', 'Gene', '6788', (73, 77))	('proteosomal degradation', 'MPA', (175, 198))	('sarcoma', 'Disease', (245, 252))	('decreased', 'NegReg', (208, 217))	('enhanced', 'PosReg', (166, 174))	('MG132', 'Var', (16, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('MG132', 'Chemical', 'MESH:C072553', (16, 21))
11266	30167083	In some cell lines in which MST2 expression increased with MG132 treatment, LATS2 expression was found to demonstrate the opposite relationship and decreased.	('MG132', 'Var', (59, 64))	('MG132', 'Chemical', 'MESH:C072553', (59, 64))	('MST2', 'Gene', (28, 32))	('expression', 'MPA', (82, 92))	('decreased', 'NegReg', (148, 157))	('increased', 'PosReg', (44, 53))	('MST2', 'Gene', '6788', (28, 32))	('expression', 'MPA', (33, 43))	('LATS2', 'Gene', (76, 81))	('LATS2', 'Gene', '26524', (76, 81))
11267	30167083	Prior studies in sarcomas have highlighted in silico data emphasizing deletions in NF2 (merlin), a regulatory protein upstream of the Hippo pathway.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('NF2', 'Gene', (83, 86))	('sarcomas', 'Disease', (17, 25))	('merlin', 'Gene', '4771', (88, 94))	('NF2', 'Gene', '4771', (83, 86))	('deletions', 'Var', (70, 79))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('merlin', 'Gene', (88, 94))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
11268	30167083	In silico analysis demonstrated that 0.8% of sarcomas demonstrated genomic deletions of MST2 and LATS2 combined, indicating that deletions are not a common mechanism by which loss of expression of the Hippo kinases occurs (Figure 4A).	('MST2', 'Gene', '6788', (88, 92))	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('deletions', 'Var', (75, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcomas', 'Disease', (45, 53))	('MST2', 'Gene', (88, 92))	('LATS2', 'Gene', (97, 102))	('LATS2', 'Gene', '26524', (97, 102))
11271	30167083	The RD cell line demonstrated a disomic signal for LATS2 in a polyploid cell, indicating a deletion or loss of chromosome 13.	('deletion', 'Var', (91, 99))	('LATS2', 'Gene', (51, 56))	('LATS2', 'Gene', '26524', (51, 56))	('loss', 'NegReg', (103, 107))	('disomic signal', 'MPA', (32, 46))
11273	30167083	Since genomic alterations/deletions of the Hippo kinases was not responsible for decreased expression of the Hippo kinases, and only MST2 appears to be regulated at a protein level, we asked whether the Hippo kinases expression were regulated at a transcriptional level.	('MST2', 'Gene', '6788', (133, 137))	('MST2', 'Gene', (133, 137))	('alterations/deletions', 'Var', (14, 35))
11280	30167083	A modest negative correlation was identified between methylation of CpG islands and RNA expression for MST2 (r = -0.4) (Figure 5B).	('MST2', 'Gene', '6788', (103, 107))	('MST2', 'Gene', (103, 107))	('RNA expression', 'MPA', (84, 98))	('methylation', 'Var', (53, 64))
11284	30167083	Altogether, the data demonstrate that expression of MST1 and MST2 are modestly regulated by methylation of DNA, mirroring the TCGA in silico data.	('methylation', 'Var', (92, 103))	('MST1', 'Gene', (52, 56))	('expression', 'MPA', (38, 48))	('DNA', 'Protein', (107, 110))	('MST2', 'Gene', '6788', (61, 65))	('MST1', 'Gene', '4485', (52, 56))	('MST2', 'Gene', (61, 65))
11287	30167083	Histone deacetylases are known to bind to methylated DNA via the MBD2/3 and MeCP2 adaptor proteins.	('Histone', 'Protein', (0, 7))	('methylated', 'Var', (42, 52))	('MBD2/3', 'Gene', (65, 71))	('MBD2/3', 'Gene', '8932;53615', (65, 71))	('MeCP2', 'Gene', '4204', (76, 81))	('bind', 'Interaction', (34, 38))	('MeCP2', 'Gene', (76, 81))
11291	30167083	Some lines could only tolerate lower levels of trichostatin A, including SJCRH30 (0.125 muM trichostatin A) and SNF02.2 (0.25 muM trichostatin A).	('muM', 'Gene', (88, 91))	('muM', 'Gene', '56925', (126, 129))	('trichostatin A', 'Chemical', 'MESH:C012589', (92, 106))	('trichostatin A', 'Chemical', 'MESH:C012589', (130, 144))	('0.125', 'Var', (82, 87))	('trichostatin A', 'Chemical', 'MESH:C012589', (47, 61))	('muM', 'Gene', (126, 129))	('SJCRH30', 'Chemical', '-', (73, 80))	('muM', 'Gene', '56925', (88, 91))
11305	30167083	This is due to the observation that few mutations of TAZ and YAP or the upstream Hippo kinases are activated.	('Hippo kinases', 'Enzyme', (81, 94))	('TAZ', 'Gene', (53, 56))	('mutations', 'Var', (40, 49))	('YAP', 'Gene', '10413', (61, 64))	('YAP', 'Gene', (61, 64))
11317	30167083	The majority of TAZ/YAP activated clinical sarcoma samples (75%) demonstrated loss of expression of one of the Hippo kinases, while other combinations of loss of expression of the Hippo kinases was much less frequent, suggesting that loss of expression of one of the Hippo kinases may be sufficient to activate TAZ or YAP.	('loss', 'Var', (234, 238))	('YAP', 'Gene', (20, 23))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('YAP', 'Gene', '10413', (318, 321))	('expression', 'MPA', (86, 96))	('loss', 'NegReg', (78, 82))	('activate', 'PosReg', (302, 310))	('YAP', 'Gene', '10413', (20, 23))	('YAP', 'Gene', (318, 321))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('clinical', 'Species', '191496', (34, 42))
11320	30167083	These mechanisms include: regulation by ubiquitin-mediated degradation, as well as two distinct methods of epigenetic regulation, promoter hypermethylation and histone deacetylation (Figure 7B).	('net', 'Gene', '2004', (112, 115))	('ubiquitin-mediated degradation', 'MPA', (40, 70))	('promoter hypermethylation', 'Var', (130, 155))	('histone', 'MPA', (160, 167))	('net', 'Gene', (112, 115))
11322	30167083	The finding that LATS2 expression decreased with MG132 treatment in some sarcoma cell lines suggests that treatment with proteosomal inhibitors for sarcomas with decreased MST2 expression may not be effective.	('decreased', 'NegReg', (34, 43))	('MST2', 'Gene', (172, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('LATS2', 'Gene', (17, 22))	('LATS2', 'Gene', '26524', (17, 22))	('expression', 'MPA', (177, 187))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('sarcomas', 'Disease', 'MESH:D012509', (148, 156))	('sarcoma', 'Disease', (148, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('sarcomas', 'Disease', (148, 156))	('MG132', 'Var', (49, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))	('expression', 'MPA', (23, 33))	('sarcoma', 'Disease', (73, 80))	('decreased', 'NegReg', (162, 171))	('MG132', 'Chemical', 'MESH:C072553', (49, 54))	('MST2', 'Gene', '6788', (172, 176))
11324	30167083	The presence of promoter hypermethylation in the Hippo kinases, including all four of the Hippo kinases has been noted for some time in sarcomas, astrocytomas, and breast cancer.	('sarcomas', 'Disease', (136, 144))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('promoter hypermethylation', 'Var', (16, 41))	('breast cancer', 'Disease', (164, 177))	('astrocytomas', 'Disease', 'MESH:D001254', (146, 158))	('Hippo kinases', 'Enzyme', (49, 62))	('noted', 'Reg', (113, 118))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('astrocytomas', 'Disease', (146, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))
11325	30167083	Our in silico analysis and in vitro experiments demonstrate that promoter hypermethylation modestly regulates Hippo kinase expression, but that it can be reversed in some contexts with DNA methyltransferase inhibitors such as 5-azacytidine.	('5-azacytidine', 'Chemical', 'MESH:D001374', (226, 239))	('expression', 'MPA', (123, 133))	('promoter hypermethylation', 'Var', (65, 90))	('regulates', 'Reg', (100, 109))	('Hippo kinase', 'Enzyme', (110, 122))
11406	29721200	Methionine restriction of cancer results in an S/G2-phase cell-cycle arrest that eventually leads to cancer-cell death.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('Methionine restriction', 'Var', (0, 22))	('S/G2', 'Var', (47, 51))	('cancer-cell death', 'Disease', 'MESH:D003643', (101, 118))	('S/G2', 'SUBSTITUTION', 'None', (47, 51))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer-cell death', 'Disease', (101, 118))	('leads to', 'Reg', (92, 100))
11455	25188299	The understanding gained regarding the molecular pathology of cancer in recent decades suggests that some tumor types exhibit stand-alone recurrent genetic aberrations, such as chromosomal translocations, that result in gene fusions, e.g., SYT-SSX in synovial sarcoma (SS), TLS-CHOP in myxoid/round cell liposarcoma (MLS), and KIF5B-RET in lung adenocarcinoma, or somatic mutations, e.g., KIT in gastrointestinal stromal tumors (GIST) and 26 mutated genes (TP53, KRAS, EGFR, and 23 other genes) in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (498, 517))	('CHOP', 'Gene', '1649', (278, 282))	('TLS', 'Gene', (274, 277))	('tumor', 'Phenotype', 'HP:0002664', (421, 426))	('carcinoma', 'Phenotype', 'HP:0030731', (350, 359))	('SSX', 'Gene', (244, 247))	('RET', 'Gene', '5979', (333, 336))	('tumor', 'Disease', (106, 111))	('mutations', 'Var', (372, 381))	('SYT', 'Gene', (240, 243))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (340, 359))	('KIF5B', 'Gene', '3799', (327, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (508, 517))	('KRAS', 'Gene', '3845', (463, 467))	('liposarcoma', 'Disease', (304, 315))	('TP53', 'Gene', (457, 461))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (498, 517))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (340, 359))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (396, 427))	('TLS', 'Gene', '2521', (274, 277))	('cancer', 'Disease', (62, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('MLS', 'Phenotype', 'HP:0012268', (317, 320))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (396, 427))	('SS', 'Phenotype', 'HP:0012570', (269, 271))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (498, 517))	('CHOP', 'Gene', (278, 282))	('EGFR', 'Gene', (469, 473))	('KRAS', 'Gene', (463, 467))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (286, 315))	('sarcoma', 'Phenotype', 'HP:0100242', (308, 315))	('KIT', 'Gene', (389, 392))	('RET', 'Gene', (333, 336))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SYT', 'Gene', '6760', (240, 243))	('synovial sarcoma', 'Disease', (251, 267))	('KIF5B', 'Gene', (327, 332))	('MLS', 'Disease', 'MESH:C537466', (317, 320))	('MLS', 'Disease', (317, 320))	('liposarcoma', 'Phenotype', 'HP:0012034', (304, 315))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('SS', 'Phenotype', 'HP:0012570', (244, 246))	('tumor', 'Disease', (421, 426))	('synovial sarcoma', 'Disease', 'MESH:D013584', (251, 267))	('SSX', 'Gene', '727837', (244, 247))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (251, 267))	('TP53', 'Gene', '7157', (457, 461))	('tumor', 'Disease', 'MESH:D009369', (421, 426))	('gastrointestinal stromal tumors', 'Disease', (396, 427))	('GIST', 'Phenotype', 'HP:0100723', (429, 433))	('liposarcoma', 'Disease', 'MESH:D008080', (304, 315))	('EGFR', 'Gene', '1956', (469, 473))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (421, 427))	('lung adenocarcinoma', 'Disease', (340, 359))
11662	31852498	With advances in genetic engineering technologies, people have found that cloning the tumor antigen-specific TCRs and transducing the TCRs into normal T cells by lentivirus or retrovirus can quickly imbue normal T cells with antigen-specific recognition abilities.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('people', 'Species', '9606', (51, 57))	('cloning', 'Var', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
11675	31852498	They found that the genetically modified T cells could be activated by the specific virus antigen in vivo, was home to effector sites, and contributed to tumor clearance.	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('contributed', 'Reg', (139, 150))	('genetically modified', 'Var', (20, 40))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('activated', 'PosReg', (58, 67))	('tumor', 'Disease', (154, 159))
11693	31852498	Another method is to introduce mutations into the transferred TCR alpha and beta chains, by generating an extra cysteine bridge into the constant region, mutating key amino acids found at the interfaces between constant regions, or convert the transferred TCR alpha and beta chains into a single-chain TCR (scTCR) structure.	('mutations', 'Var', (31, 40))	('cysteine bridge', 'MPA', (112, 127))	('convert', 'Reg', (232, 239))	('TCR', 'Gene', (256, 259))	('cysteine', 'Chemical', 'MESH:D003545', (112, 120))	('mutating', 'Var', (154, 162))
11695	31852498	The silencing of endogenous TCRs alpha and beta chains can be achieved through the use of small-interfering RNAs (siRNA), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs ), or by clustered regularly interspaced short palindromic repeats (CRISPR) technology (Fig.	('ZFNs', 'Disease', 'None', (145, 149))	('CR', 'Chemical', 'MESH:D002857', (29, 31))	('CR', 'Chemical', 'MESH:D002857', (276, 278))	('ZFNs', 'Disease', (145, 149))	('silencing', 'NegReg', (4, 13))	('small-interfering', 'Var', (90, 107))
11696	31852498	Although the TCR mispairing phenotype has not been observed in a clinic, the silencing of endogenous TCRs was shown to reduce the occurrence of the lethal graft versus host disease (GvHD) in a mouse model.	('graft versus host disease', 'Disease', 'MESH:D006086', (155, 180))	('GvHD', 'Disease', 'MESH:D006086', (182, 186))	('reduce', 'NegReg', (119, 125))	('silencing', 'Var', (77, 86))	('graft versus host disease', 'Disease', (155, 180))	('mouse', 'Species', '10090', (193, 198))	('TCRs', 'Gene', (101, 105))	('GvHD', 'Disease', (182, 186))
11698	31852498	The second group is neoantigens, which are derived from chromosomal and genetic mutations in tumor cells, which include beta-catenin S37F in melanoma, alpha-actinin-4 K122 N in lung cancer, and heat shock protein 70 kilodalton-2 (hsp70-2) F293I in renal cancer.	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('hsp70-2', 'Gene', (230, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('shock', 'Phenotype', 'HP:0031273', (199, 204))	('beta-catenin', 'Gene', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('beta-catenin', 'Gene', '1499', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('alpha-actinin-4', 'Gene', '81', (151, 166))	('S37F', 'Var', (133, 137))	('F293I', 'SUBSTITUTION', 'None', (239, 244))	('alpha-actinin-4', 'Gene', (151, 166))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('melanoma', 'Disease', (141, 149))	('renal cancer', 'Disease', (248, 260))	('F293I', 'Var', (239, 244))	('S37F', 'Mutation', 'p.S37F', (133, 137))	('renal cancer', 'Phenotype', 'HP:0009726', (248, 260))	('lung cancer', 'Disease', (177, 188))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('heat shock protein 70 kilodalton-2', 'Gene', (194, 228))	('tumor', 'Disease', (93, 98))	('K122 N', 'Mutation', 'rs1046044885', (167, 173))	('renal cancer', 'Disease', 'MESH:D007680', (248, 260))	('hsp70-2', 'Gene', '3304', (230, 237))	('heat shock protein 70 kilodalton-2', 'Gene', '3304', (194, 228))
11704	31852498	Moreover, the procedure for identifying genetic mutations and preparing TCR-based therapies for each patient is tedious and expensive, which has hampered the wide application of TCR-based cellular immunotherapies that target oncovirus antigens and neoantigens in a clinic.	('patient', 'Species', '9606', (101, 108))	('mutations', 'Var', (48, 57))	('hampered', 'NegReg', (145, 153))
11707	31852498	Using the RNA electroporation method, they transduced four RNAs, encoding TCRs that recognized MART-1:27-35, gp100:209-217, NY-ESO-1:157-165, and p53:264-272 peptide/human leukocyte antigen (HLA) A2, into the PBMCs of patients (Fig.	('NY-ESO-1', 'Gene', '246100', (124, 132))	('NY-ESO-1', 'Gene', (124, 132))	('patients', 'Species', '9606', (218, 226))	('human', 'Species', '9606', (166, 171))	('MART-1', 'Gene', '2315', (95, 101))	('MART-1', 'Gene', (95, 101))	('p53:264-272', 'Var', (146, 157))
11725	31852498	Thus, they used a highly avid TCR that was generated in HLA A2 transgenic mice, and they found that 3 out of 16 (17%) patients experienced objective clinical responses after receiving the gp100-specific TCR-T cells, with metastatic tumors regressing in multiple organs, including the brain, lung, liver, lymph nodes, and subcutaneous sites.	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('gp100-specific', 'Var', (188, 202))	('transgenic mice', 'Species', '10090', (63, 78))	('patients', 'Species', '9606', (118, 126))	('tumors', 'Disease', (232, 238))
11764	31852498	In addition, 14 of 20 DMF5 patients and 13 of 16 gp100 patients demonstrated the destruction of epidermal melanocytes, starting as early as day 5 after treatment.	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (27, 35))	('destruction of epidermal melanocytes', 'CPA', (81, 117))	('DMF5', 'Var', (22, 26))
11801	31852498	reported the generation of a novel molecule (ALT-801, 264scTCR/IL-2), comprised of an anti-p53 (aa264-272) scTCR fused to an IL-2 molecule.	('IL-2', 'Gene', (63, 67))	('IL-2', 'Gene', '3558', (63, 67))	('IL-2', 'Gene', '3558', (125, 129))	('IL-2', 'Gene', (125, 129))	('anti-p53', 'Var', (86, 94))
11802	31852498	The scTCR can specifically bind to tumor cell surfaces that express p53 peptide and the HLA A2 complex, and IL-2 can activate a broad range of immune cell types, including T cells, B cells, monocytes, macrophages, lymphokine-activated killer (LAK) cells, and natural killer (NK) cells, located in the proximity of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('IL-2', 'Gene', '3558', (108, 112))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (314, 319))	('IL-2', 'Gene', (108, 112))	('activate', 'PosReg', (117, 125))	('p53 peptide', 'Var', (68, 79))
11819	31852498	In vitro-synthesized TCRs tend to be low affinity because of a lack of association with CD3, CD4, and CD8 molecules; however, some genetic engineering can increase the affinity of in vitro-synthesized TCRs, as in ImmTACs.	('genetic engineering', 'Var', (131, 150))	('increase', 'PosReg', (155, 163))	('CD8', 'Gene', (102, 105))	('CD8', 'Gene', '925', (102, 105))	('ImmTAC', 'Chemical', '-', (213, 219))	('CD4', 'Gene', (93, 96))	('CD4', 'Gene', '920', (93, 96))	('affinity', 'MPA', (168, 176))
11848	31852498	In a premelanosome protein (Pmel-1) mouse model, ACT using gp100-specific T cells caused ocular damage, which paralleled the findings in human melanoma patients who received gp100-specific TCR-T therapy.	('mouse', 'Species', '10090', (36, 41))	('human', 'Species', '9606', (137, 142))	('ocular damage', 'CPA', (89, 102))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('patients', 'Species', '9606', (152, 160))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('gp100-specific', 'Var', (59, 73))	('caused', 'Reg', (82, 88))
11858	31852498	This finding indicates that the modulation of the numbers and phenotypes of the transferred tumor antigen-specific TCR-T cells may affect the toxicity associated with TCR-T therapies.	('affect', 'Reg', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('toxicity', 'Disease', (142, 150))	('modulation', 'Var', (32, 42))	('tumor', 'Disease', (92, 97))
11916	30659312	SK-UT-1, SK-UT-1B, MES-SA, ESS-1 (3 x 104 cells/ml) and HSF (1 x 105 cells/ml) cells were platted on 96-well microplates.	('SK-UT-1', 'CellLine', 'CVCL:0533', (0, 7))	('HSF', 'Gene', (56, 59))	('ESS-1', 'Gene', (27, 32))	('SK-UT-1B', 'Var', (9, 17))	('SK-UT-1', 'CellLine', 'CVCL:0533', (9, 16))	('MES-SA', 'Chemical', '-', (19, 25))	('HSF', 'Gene', '3569', (56, 59))	('ESS-1', 'Gene', '7046', (27, 32))
11962	30659312	Taking into consideration the results obtained in this study we can state that fucoidan express not only cytostatic activity but cytotoxic as well (by inducing apoptosis).	('apoptosis', 'CPA', (160, 169))	('inducing', 'PosReg', (151, 159))	('fucoidan', 'Var', (79, 87))	('fucoidan', 'Chemical', 'MESH:C007789', (79, 87))
11983	30513582	Accordingly, we were inspired to question whether IAPS-2 could modulate a TAM phenotype, and further re-educate the tumor microenvironment for tumor immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('TAM', 'Chemical', '-', (74, 77))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('TAM', 'MPA', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('modulate', 'Reg', (63, 71))	('IAPS-2', 'Var', (50, 56))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
11992	30513582	The results indicated that IAPS-2 could promote the secretion of IL-12 and decrease the level of IL-10, compared with the control group (p < 0.05 or p < 0.01) (Figure 1D,E).	('promote', 'PosReg', (40, 47))	('IL-10', 'Gene', (97, 102))	('decrease', 'NegReg', (75, 83))	('IAPS-2', 'Var', (27, 33))	('IL-10', 'Gene', '16153', (97, 102))	('secretion of IL-12', 'MPA', (52, 70))
12008	30513582	After having confirmed the polarization effect of IAPS-2 on TAMs from S180 tumor tissues in vitro, we set out to observe whether IAPS-2 can prevent the immunosuppressive function in tumors and ignite the anti-tumor effect of the immune system in tumor-bearing mice.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('IAPS-2', 'Var', (129, 135))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', (209, 214))	('mice', 'Species', '10090', (260, 264))	('tumors', 'Disease', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('TAMs', 'Chemical', '-', (60, 64))	('prevent', 'NegReg', (140, 147))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('ignite', 'PosReg', (193, 199))	('immunosuppressive function', 'MPA', (152, 178))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
12010	30513582	In particular, IAPS-2 could effectively prolong the survival of the S180 tumor-bearing mice, compared with the other groups (Figure 3F).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mice', 'Species', '10090', (87, 91))	('prolong', 'PosReg', (40, 47))	('tumor', 'Disease', (73, 78))	('survival', 'CPA', (52, 60))	('IAPS-2', 'Var', (15, 21))
12026	30513582	Indeed, high TAMs invasion has been involved in poor prognosis in several cancers, such as breast cancer, prostate carcinoma, colon cancer, and so on.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TAMs', 'Chemical', '-', (13, 17))	('breast cancer', 'Disease', (91, 104))	('high', 'Var', (8, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))	('cancers', 'Disease', (74, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (126, 138))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (106, 124))	('colon cancer', 'Disease', (126, 138))	('prostate carcinoma', 'Disease', (106, 124))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('prostate carcinoma', 'Disease', 'MESH:D011472', (106, 124))
12029	30513582	Therefore, recent research has demonstrated that repolarizing TAMs into M1 type were effective in treating cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TAMs', 'Chemical', '-', (62, 66))	('repolarizing TAMs', 'Var', (49, 66))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
12038	30513582	In particular, the immunofluorescence analysis of CD31 (an endothelial marker) significantly demonstrated that mice treated with IAPS-2 have a lower density of blood vessels (Figure 6A).	('CD31', 'Gene', (50, 54))	('lower', 'NegReg', (143, 148))	('mice', 'Species', '10090', (111, 115))	('density of blood vessels', 'CPA', (149, 173))	('IAPS-2', 'Var', (129, 135))	('CD31', 'Gene', '18613', (50, 54))
12112	30060548	Serp2 is an anti-apoptotic protein and a virulence factor; deletion of this protein from the virus enhances the oncolytic effects of the virus and markedly attenuates pathogenesis in rabbits.	('pathogenesis', 'CPA', (167, 179))	('oncolytic effects', 'CPA', (112, 129))	('attenuates', 'NegReg', (156, 166))	('enhances', 'PosReg', (99, 107))	('Serp2', 'Gene', '100856132', (0, 5))	('Serp2', 'Gene', (0, 5))	('deletion', 'Var', (59, 67))	('rabbits', 'Species', '9986', (183, 190))
12116	30060548	In another study, the same MYXVDeltaserp2 construct was shown to induce increased cytopathic effects in canine cancer cells as compared to wild-type MYXV.	('canine', 'Species', '9615', (104, 110))	('serp2', 'Gene', '100856132', (36, 41))	('increased', 'PosReg', (72, 81))	('MYXV', 'Species', '10273', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('construct', 'Var', (42, 51))	('MYXV', 'Species', '10273', (149, 153))	('serp2', 'Gene', (36, 41))	('cytopathic effects', 'CPA', (82, 100))
12321	33322802	Overall, 25 out of 57 studied biomarkers, including five out of seven genes involved in angiogenesis, were found mutated/positive in at least one patient, of which 23 biomarkers had low prevalence (fewer than eight out of 134 patients), contrasting with H19 (n = 24, 18%), and TP53 (n = 35, 26%).	('H19', 'Gene', '283120', (254, 257))	('H19', 'Gene', (254, 257))	('patient', 'Species', '9606', (226, 233))	('mutated/positive', 'Var', (113, 129))	('patients', 'Species', '9606', (226, 234))	('patient', 'Species', '9606', (146, 153))	('TP53', 'Gene', '7157', (277, 281))	('TP53', 'Gene', (277, 281))
12325	33322802	For decades, palliative chemotherapy with anthracycline (usually doxorubicin) either as monotherapy, or in combination with ifosfamide has been the conventional first-line systemic therapy for metastatic disease, which provides an overall survival (OS) of approximately 18 months.	('anthracycline', 'Var', (42, 55))	('met', 'Gene', '79811', (193, 196))	('ifosfamide', 'Chemical', 'MESH:D007069', (124, 134))	('met', 'Gene', (193, 196))	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))	('anthracycline', 'Chemical', 'MESH:D018943', (42, 55))
12342	33322802	Central translational analyses were performed by the Diagnostic and Research Institute of Pathology Medical University Graz in Austria with an objective to investigate the mutational status (describe which type of mutations: missenses, translocations, amplifications, do you also have the number off gene copies if <to amplification ) in targeted genes as well as in 50 oncogenes and tumor suppressor genes commonly mutated in cancer with the aim to explore potential prognostic and predictive factors for treatment response.	('tumor', 'Disease', (384, 389))	('cancer', 'Disease', (427, 433))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('translocations', 'Var', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('tumor', 'Disease', 'MESH:D009369', (384, 389))	('tumor', 'Phenotype', 'HP:0002664', (384, 389))	('missenses', 'Var', (225, 234))
12349	33322802	Of the above genes, we considered together the seven genes involved in angiogenesis: FLT1, FLT2, FLT3, FLT4, KDR, TEK (TIE2) and VHL, leading to a new variable noted "Angiogenesis pool" coded "mutated" if at least one of the seven genes of the pool was mutated.	('TIE2', 'Gene', (119, 123))	('TIE2', 'Gene', '7010', (119, 123))	('FLT1', 'Gene', '2321', (85, 89))	('KDR', 'Gene', '3791', (109, 112))	('FLT3', 'Gene', (97, 101))	('mutated', 'Var', (193, 200))	('TEK', 'Gene', '7010', (114, 117))	('VHL', 'Gene', (129, 132))	('TEK', 'Gene', (114, 117))	('FLT4', 'Gene', '2324', (103, 107))	('FLT4', 'Gene', (103, 107))	('VHL', 'Gene', '7428', (129, 132))	('KDR', 'Gene', (109, 112))	('FLT1', 'Gene', (85, 89))	('FLT2', 'Gene', (91, 95))	('FLT3', 'Gene', '2322', (97, 101))	('FLT2', 'Gene', '2260', (91, 95))
12355	33322802	Kaplan-Meier curves for PFS and OS were estimated according to the biomarker status (positive versus negative for H19, mutated versus wild type gene for the other biomarkers).	('H19', 'Gene', '283120', (114, 117))	('mutated', 'Var', (119, 126))	('H19', 'Gene', (114, 117))
12358	33322802	The predictive value of each evaluated biomarker was assessed by evaluating the heterogeneity of treatment effect according to the biomarker status, in Cox models, including the following factors: (i) treatment arm effect (Regorafenib versus Placebo), (ii) biomarker effect (positive versus negative, or mutated versus wild type) and (iii) interaction between treatment arm and biomarker.	('mutated', 'Var', (304, 311))	('Regorafenib', 'Chemical', 'MESH:C559147', (223, 234))	('interaction', 'Reg', (340, 351))
12362	33322802	For the genes also evaluated via full sequence, all HotSpot mutations were confirmed via the full sequence analysis (3 genes: KDR, KIT, and TP53).	('KDR', 'Gene', (126, 129))	('TP53', 'Gene', (140, 144))	('KIT', 'Gene', (131, 134))	('KDR', 'Gene', '3791', (126, 129))	('mutations', 'Var', (60, 69))	('TP53', 'Gene', '7157', (140, 144))	('KIT', 'Gene', '3815', (131, 134))
12363	33322802	In addition, for each of the 10 genes evaluated by full sequence analysis, a mutation was reported in at least 1 tumor, including FGFR1 that was found mutated in two tumors, although these was not identified via the HotSpot analysis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (113, 118))	('FGFR1', 'Gene', (130, 135))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutation', 'Var', (77, 85))	('FGFR1', 'Gene', '2260', (130, 135))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('mutated', 'Var', (151, 158))
12366	33322802	TP53 mutation was significantly more frequent in leiomyosarcoma (16/45, 36%), and other sarcomas (13/34, 38%) rather than in liposarcoma (5/38, 13%), and synovial sarcoma (1/17, 6%) (p = 0.009).	('sarcomas', 'Disease', (88, 96))	('synovial sarcoma', 'Disease', (154, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('synovial sarcoma', 'Disease', 'MESH:D013584', (154, 170))	('TP53', 'Gene', '7157', (0, 4))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (154, 170))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (49, 63))	('liposarcoma', 'Disease', 'MESH:D008080', (125, 136))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (49, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('TP53', 'Gene', (0, 4))	('frequent', 'Reg', (37, 45))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('leiomyosarcoma', 'Disease', (49, 63))	('liposarcoma', 'Disease', (125, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('mutation', 'Var', (5, 13))
12367	33322802	At least one of the seven genes considered in the angiogenesis pool was mutated in 20 tumors (15%), with no significant difference between histological subgroups (p = 0.42): five tumors with each FLT1 and FLT4 mutations, two tumors with FLT2 mutation, seven tumors with KDR mutation, three tumors with TEK (TIE2) mutation, and no tumors with FLT3 and VHL mutations.	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('mutations', 'Var', (210, 219))	('KDR', 'Gene', '3791', (270, 273))	('VHL', 'Gene', '7428', (351, 354))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('FLT4', 'Gene', (205, 209))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('FLT4', 'Gene', '2324', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', (86, 92))	('FLT1', 'Gene', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('FLT1', 'Gene', '2321', (196, 200))	('tumors', 'Disease', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('FLT2', 'Gene', (237, 241))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', (330, 336))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('TIE2', 'Gene', (307, 311))	('TEK', 'Gene', (302, 305))	('TIE2', 'Gene', '7010', (307, 311))	('KDR', 'Gene', (270, 273))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('FLT3', 'Gene', (342, 346))	('VHL', 'Gene', (351, 354))	('mutated', 'Var', (72, 79))	('tumors', 'Disease', (290, 296))	('tumors', 'Disease', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('FLT3', 'Gene', '2322', (342, 346))	('TEK', 'Gene', '7010', (302, 305))	('FLT2', 'Gene', '2260', (237, 241))	('tumors', 'Disease', 'MESH:D009369', (330, 336))	('tumors', 'Disease', (225, 231))
12368	33322802	This includes two tumors with two mutations: one tumor with both FLT1 and KDR mutations and one tumor with both TEK (TIE2) and KDR (VEGFR2) mutations.	('FLT1', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('VEGFR2', 'Gene', '3791', (132, 138))	('KDR', 'Gene', '3791', (127, 130))	('tumors', 'Disease', (18, 24))	('FLT1', 'Gene', '2321', (65, 69))	('tumor', 'Disease', (18, 23))	('mutations', 'Var', (78, 87))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('KDR', 'Gene', (74, 77))	('TEK', 'Gene', (112, 115))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (49, 54))	('TIE2', 'Gene', (117, 121))	('TIE2', 'Gene', '7010', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('TEK', 'Gene', '7010', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('KDR', 'Gene', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('KDR', 'Gene', '3791', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('VEGFR2', 'Gene', (132, 138))
12370	33322802	The proportion of H19 positivity significantly differed between histological subgroups, varying from three out of 34 (9%) in sarcomas other than liposarcoma, leiomyosarcoma and synovial sarcoma, to seven of 17 (41%) in synovial sarcoma (p = 0.02).	('synovial sarcoma', 'Disease', 'MESH:D013584', (219, 235))	('H19', 'Gene', (18, 21))	('leiomyosarcoma', 'Disease', (158, 172))	('liposarcoma', 'Disease', (145, 156))	('positivity', 'Var', (22, 32))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (219, 235))	('synovial sarcoma', 'Disease', (177, 193))	('H19', 'Gene', '283120', (18, 21))	('sarcomas', 'Disease', 'MESH:D012509', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('sarcomas', 'Disease', (125, 133))	('synovial sarcoma', 'Disease', 'MESH:D013584', (177, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('liposarcoma', 'Phenotype', 'HP:0012034', (145, 156))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (158, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (177, 193))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (158, 172))	('liposarcoma', 'Disease', 'MESH:D008080', (145, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('synovial sarcoma', 'Disease', (219, 235))
12376	33322802	Most tumors are associated with complex genetic alterations such as gains, losses, and point mutations.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('gains', 'Var', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('losses', 'Var', (75, 81))	('point mutations', 'Var', (87, 102))	('associated', 'Reg', (16, 26))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
12377	33322802	In this translational study, we hypothesized that inter-individual variability of responses to regorafenib might be predominantly associated with alterations of genes responsible for encoding the protein kinases specifically targeted by regorafenib.	('alterations', 'Var', (146, 157))	('regorafenib', 'Chemical', 'MESH:C559147', (237, 248))	('responses', 'MPA', (82, 91))	('regorafenib', 'Chemical', 'MESH:C559147', (95, 106))	('associated', 'Reg', (130, 140))
12384	33322802	In this study, although investigating tumor samples for common hot spot mutations in 50 well established oncogenes and tumor suppressor genes and as well as searching for mutations in the full coding sequence of Regorafinib targets we found no recurrent mutations in a significant subset of cases.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (119, 124))	('mutations', 'Var', (72, 81))	('Regorafinib', 'Chemical', '-', (212, 223))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
12387	33322802	Moreover, the tumors associated with H19 expression seemed to be associated with poor overall survival (HR = 1.60; p = 0.07; see Table 3), nevertheless, because of sample size this difference did not reach the classical level of significance.	('poor', 'NegReg', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('H19', 'Gene', '283120', (37, 40))	('H19', 'Gene', (37, 40))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('expression', 'Var', (41, 51))	('overall survival', 'MPA', (86, 102))
12389	33322802	TP53 mutations are one of most common mutations found in soft tissue sarcomas.	('TP53', 'Gene', '7157', (0, 4))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (57, 76))	('TP53', 'Gene', (0, 4))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('mutations', 'Var', (5, 14))	('sarcomas', 'Disease', (69, 77))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (57, 77))	('sarcomas', 'Disease', 'MESH:D012509', (69, 77))
12390	33322802	According to the method used, the frequency of TP53 mutations is around 10-30%.	('mutations', 'Var', (52, 61))	('met', 'Gene', (17, 20))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))	('met', 'Gene', '79811', (17, 20))
12391	33322802	As an example, we found that frequency of TP53 mutations in liposarcomas is about 13%.	('TP53', 'Gene', '7157', (42, 46))	('liposarcomas', 'Phenotype', 'HP:0012034', (60, 72))	('liposarcomas', 'Disease', 'MESH:D008080', (60, 72))	('TP53', 'Gene', (42, 46))	('liposarcomas', 'Disease', (60, 72))	('mutations', 'Var', (47, 56))	('liposarcoma', 'Phenotype', 'HP:0012034', (60, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
12392	33322802	These mutations occurred in pleomorphic and myxoid/round cell liposarcomas, and not in well differentiated/dedifferentiated liposarcomas.	('liposarcomas', 'Disease', (124, 136))	('pleomorphic', 'Disease', (28, 39))	('liposarcomas', 'Disease', (62, 74))	('liposarcoma', 'Phenotype', 'HP:0012034', (124, 135))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('myxoid/round cell liposarcomas', 'Phenotype', 'HP:0012268', (44, 74))	('liposarcomas', 'Phenotype', 'HP:0012034', (62, 74))	('occurred', 'Reg', (16, 24))	('liposarcomas', 'Phenotype', 'HP:0012034', (124, 136))	('liposarcomas', 'Disease', 'MESH:D008080', (62, 74))	('liposarcomas', 'Disease', 'MESH:D008080', (124, 136))	('mutations', 'Var', (6, 15))
12393	33322802	Most of these mutations are likely somatic ones, since in the present study, the frequency of TP53 mutation was 26% whereas, in a large study of 559 sarcoma patients, Mitchell et al.	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('sarcoma', 'Disease', (149, 156))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('patients', 'Species', '9606', (157, 165))	('mutation', 'Var', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))
12394	33322802	found that the frequency of TP53 germline mutations is about 3.6%.	('germline mutations', 'Var', (33, 51))	('TP53', 'Gene', (28, 32))	('TP53', 'Gene', '7157', (28, 32))
12397	33322802	However, mutations in FLT1, FLT4, FLT2, KDR, and TEK (TIE2) were neither prognostic nor predictive.	('FLT1', 'Gene', '2321', (22, 26))	('TIE2', 'Gene', '7010', (54, 58))	('FLT2', 'Gene', (34, 38))	('TEK', 'Gene', '7010', (49, 52))	('FLT2', 'Gene', '2260', (34, 38))	('mutations', 'Var', (9, 18))	('KDR', 'Gene', '3791', (40, 43))	('TEK', 'Gene', (49, 52))	('FLT4', 'Gene', '2324', (28, 32))	('FLT4', 'Gene', (28, 32))	('FLT1', 'Gene', (22, 26))	('KDR', 'Gene', (40, 43))	('TIE2', 'Gene', (54, 58))
12417	32313727	Non-translocation sarcomas, particularly undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, had significantly higher counts of both CD68+ and CD163+ macrophages than translocation-associated sarcomas.	('liposarcoma', 'Disease', (99, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('CD68', 'Gene', (152, 156))	('Non-translocation', 'Var', (0, 17))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (41, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Disease', 'MESH:D012509', (211, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Phenotype', 'HP:0100242', (211, 219))	('liposarcoma', 'Phenotype', 'HP:0012034', (99, 110))	('CD163+ macrophages', 'MPA', (162, 180))	('sarcomas', 'Disease', (211, 219))	('undifferentiated pleomorphic sarcoma', 'Disease', (41, 77))	('higher', 'PosReg', (130, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('liposarcoma', 'Disease', 'MESH:D008080', (99, 110))	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcomas', 'Disease', (18, 26))	('CD68', 'Gene', '968', (152, 156))
12434	32313727	In leiomyosarcoma, two studies demonstrated an association between higher density of CD68+ or CD163+ macrophage infiltration and poorer clinical outcomes, perhaps explaining the poor outcomes for leiomyosarcomas in lymphocyte-based adaptive immune checkpoint inhibitor clinical trials.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (196, 210))	('higher', 'PosReg', (67, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (196, 211))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (196, 210))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (196, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('leiomyosarcoma', 'Disease', (3, 17))	('leiomyosarcomas', 'Disease', (196, 211))	('CD163+', 'Var', (94, 100))	('leiomyosarcoma', 'Disease', (196, 210))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (3, 17))	('CD68', 'Gene', (85, 89))	('CD68', 'Gene', '968', (85, 89))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (3, 17))
12436	32313727	Anti-CD47 monoclonal antibodies have impressive activity in mouse xenograft models, leading to the opening of clinical trials targeting the CD47/SIRPalpha axis.	('activity', 'MPA', (48, 56))	('Anti-CD47', 'Gene', (0, 9))	('mouse', 'Species', '10090', (60, 65))	('Anti-CD47', 'Var', (0, 9))
12456	32313727	Survival correlates for overall survival (OS) and progression-free survival (PFS) among all non-translocation or translocation-associated sarcomas were evaluated using a Cox proportional hazards multiple regression analysis to generate hazard ratios and corresponding 95% confidence intervals.	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('translocation-associated', 'Var', (113, 137))	('sarcomas', 'Disease', (138, 146))
12462	32313727	Pleomorphic sarcoma types demonstrated the highest counts of both CD68+ and CD163+ macrophages (Figure 2(a,b)), particularly undifferentiated pleomorphic sarcoma (median CD68 = 460/mm2, CD163 = 512/mm2), dedifferentiated liposarcoma (median CD68 = 418/mm2, CD163 = 650/mm2), myxofibrosarcoma (median CD68 = 361/mm2, CD163 = 299/mm2), and leiomyosarcoma (median CD68 = 273/mm2, CD163 = 281/mm2).	('CD68', 'Gene', (66, 70))	('CD68', 'Gene', (241, 245))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (338, 352))	('sarcoma', 'Disease', 'MESH:D012509', (284, 291))	('liposarcoma', 'Phenotype', 'HP:0012034', (221, 232))	('sarcoma', 'Disease', (284, 291))	('CD163 = 512/mm2', 'Var', (186, 201))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('myxofibrosarcoma', 'Disease', 'None', (275, 291))	('CD68', 'Gene', '968', (300, 304))	('sarcoma', 'Disease', (12, 19))	('liposarcoma', 'Disease', 'MESH:D008080', (221, 232))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (284, 291))	('leiomyosarcoma', 'Disease', (338, 352))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (125, 161))	('sarcoma', 'Disease', 'MESH:D012509', (345, 352))	('CD68', 'Gene', (300, 304))	('sarcoma', 'Disease', 'MESH:D012509', (225, 232))	('sarcoma', 'Disease', (225, 232))	('sarcoma', 'Disease', (345, 352))	('CD68', 'Gene', '968', (361, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('CD68', 'Gene', '968', (170, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('liposarcoma', 'Disease', (221, 232))	('undifferentiated pleomorphic sarcoma', 'Disease', (125, 161))	('myxofibrosarcoma', 'Disease', (275, 291))	('CD68', 'Gene', '968', (241, 245))	('CD68', 'Gene', '968', (66, 70))	('CD68', 'Gene', (170, 174))	('CD68', 'Gene', (361, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (345, 352))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (338, 352))
12463	32313727	Angiosarcomas had the highest counts for both macrophage markers (CD68 = 486/mm2, CD163 = 1081/mm2), but these counts were scored from only four patients (Figure 2(a,b)).	('CD68', 'Gene', (66, 70))	('patients', 'Species', '9606', (145, 153))	('Angiosarcomas', 'Disease', (0, 13))	('Angiosarcomas', 'Disease', 'MESH:D006394', (0, 13))	('CD68', 'Gene', '968', (66, 70))	('Angiosarcomas', 'Phenotype', 'HP:0200058', (0, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('CD163 = 1081/mm2', 'Var', (82, 98))
12464	32313727	As a group, sarcomas driven by mutations and/or copy-number alterations (non-translocation-associated sarcomas) had significantly higher (p < .001) macrophage counts (median CD68 = 105/mm2, CD163 = 139/mm2) than did the translocation-associated sarcomas (median CD68 = 36/mm2, CD163 = 59/mm2) or benign mesenchymal tumors (median CD68 = 18/mm2, CD163 = 38/mm2) (Figure S1A).	('macrophage counts', 'CPA', (148, 165))	('CD68', 'Gene', '968', (262, 266))	('sarcomas', 'Disease', 'MESH:D012509', (245, 253))	('copy-number alterations', 'Var', (48, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (245, 253))	('sarcomas', 'Disease', 'MESH:D012509', (102, 110))	('benign mesenchymal tumors', 'Disease', 'MESH:C535700', (296, 321))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('sarcomas', 'Disease', (245, 253))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcomas', 'Disease', (102, 110))	('CD68', 'Gene', '968', (330, 334))	('CD68', 'Gene', '968', (174, 178))	('CD68', 'Gene', (262, 266))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('benign mesenchymal tumors', 'Disease', (296, 321))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('CD68', 'Gene', (174, 178))	('sarcomas', 'Disease', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('CD68', 'Gene', (330, 334))	('mutations', 'Var', (31, 40))	('higher', 'PosReg', (130, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))
12466	32313727	Across the sample set, there was a strong correlation between density of CD68+ and CD163+ macrophages (rS = 0.75, p < .001), possibly reflecting their partial phenotypic overlap.	('CD163+', 'Var', (83, 89))	('CD68', 'Gene', (73, 77))	('CD68', 'Gene', '968', (73, 77))
12473	32313727	Non-translocation sarcomas had a significantly higher adjusted CD68:TIL ratio (mean: 6.7, 95% CI: 5.3-8.0) than was observed among the translocation-associated sarcomas (mean: 1.8, 95% CI: 1.3-2.3)(p < .001, Figure S1B).	('CD68', 'Gene', (63, 67))	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('CD68', 'Gene', '968', (63, 67))	('TIL', 'Gene', (68, 71))	('higher', 'PosReg', (47, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcomas', 'Disease', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcomas', 'Disease', 'MESH:D012509', (160, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('Non-translocation', 'Var', (0, 17))	('sarcomas', 'Disease', (160, 168))	('TIL', 'Gene', '7096', (68, 71))
12484	32313727	Overall, intratumoral heterogeneity showed a significant positive correlation with increasing proportions of macrophages in the immune microenvironment (p < .05), as did measures representing armlevel chromosomal alterations (aneuploidy score), focal chromosomal copy number alterations (number of chromosomal segments altered), and homologous recombination defects.	('aneuploidy', 'Disease', (226, 236))	('tumor', 'Disease', (14, 19))	('focal chromosomal copy number alterations', 'Var', (245, 286))	('aneuploidy', 'Disease', 'MESH:D000782', (226, 236))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
12486	32313727	When the DNA damage scores were correlated with individual proportions of M0-, M1-, and M2- polarized macrophages (Figure 3(c-e)), it was found that the increasing proportions of macrophages in cases with higher intratumoral heterogeneity, increased copy number alterations, or more homologous recombination defects were attributable to increased M2 macrophages infiltrates in these cases (Figure 3(e)); however, leiomyosarcomas also showed increased proportions of M0 macrophages in cases with more frequent copy number alterations and homologous recombination defects (Figure 3(c)).	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('leiomyosarcomas', 'Disease', (413, 428))	('copy number alterations', 'Var', (509, 532))	('sarcomas', 'Phenotype', 'HP:0100242', (420, 428))	('sarcoma', 'Phenotype', 'HP:0100242', (420, 427))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (413, 428))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (413, 428))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (413, 427))
12504	32313727	Among the non-translocation sarcomas, age, grade, and lower SIRPalpha score were associated with worse overall survival (OS) (p < .05), while among the translocation-associated sarcomas only intermediate-to-high grade correlated with worse OS (p = .04).	('sarcomas', 'Disease', (177, 185))	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('overall survival', 'MPA', (103, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('worse', 'NegReg', (97, 102))	('sarcomas', 'Disease', (28, 36))	('sarcomas', 'Disease', 'MESH:D012509', (177, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (177, 185))	('SIRPalpha', 'Gene', (60, 69))	('non-translocation', 'Var', (10, 27))	('lower', 'NegReg', (54, 59))
12505	32313727	For progression-free survival (PFS), grade (p = .04) was associated with worse outcomes (Table S7) among non-translocation sarcomas, while lower CD47 score was associated with worse outcomes among translocation-associated sarcomas (p = .03; Table S7).	('sarcomas', 'Disease', (222, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcomas', 'Disease', (123, 131))	('non-translocation', 'Var', (105, 122))	('CD47', 'Protein', (145, 149))	('sarcomas', 'Disease', 'MESH:D012509', (222, 230))	('sarcomas', 'Disease', 'MESH:D012509', (123, 131))	('lower', 'NegReg', (139, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (222, 230))	('S7', 'Gene', '6264', (95, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('S7', 'Gene', '6264', (247, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
12507	32313727	While the presence of any SIRPalpha+ macrophage was an adverse prognostic factor in both synovial sarcoma and myxofibrosarcoma (Figure 5(a,b)), the prognostic significance of CD47 and tumor-associated macrophages varied depending on tumor type (Figure 5(c,d)).	('synovial sarcoma and myxofibrosarcoma', 'Disease', 'MESH:D013584', (89, 126))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('tumor', 'Disease', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', (184, 189))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (89, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('CD47', 'Var', (175, 179))	('presence', 'Var', (10, 18))
12509	32313727	That said, in solitary fibrous tumors, high CD163 predicted inferior PFS (Figure 5(d)), but in dedifferentiated liposarcoma high CD163 was a positive prognostic indicator (Figure 5(d)).	('inferior', 'NegReg', (60, 68))	('high', 'Var', (39, 43))	('fibrous tumors', 'Disease', 'MESH:D054364', (23, 37))	('CD163', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('liposarcoma', 'Disease', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('fibrous tumors', 'Disease', (23, 37))	('PFS', 'MPA', (69, 72))	('liposarcoma', 'Phenotype', 'HP:0012034', (112, 123))	('liposarcoma', 'Disease', 'MESH:D008080', (112, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
12518	32313727	Our study depicts a widely variable, highly sarcoma-type-specific expression of both CD68+ and CD163+ tumor-associated macrophages.	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('sarcoma', 'Disease', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('CD68', 'Gene', (85, 89))	('CD68', 'Gene', '968', (85, 89))	('tumor', 'Disease', (102, 107))	('CD163+', 'Var', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
12519	32313727	Tumor-associated macrophages were most frequently observed in pleomorphic sarcomas, such as undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, and were most sparse in translocation-associated sarcomas, including synovial sarcoma, myxoid liposarcoma, clear cell sarcoma, and low-grade fibromyxoid sarcoma.	('sarcoma', 'Disease', (261, 268))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sarcoma', 'Disease', (316, 323))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (304, 323))	('liposarcoma', 'Disease', (257, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('myxoid liposarcoma', 'Disease', (250, 268))	('liposarcoma', 'Disease', 'MESH:D008080', (150, 161))	('sarcoma', 'Disease', 'MESH:D012509', (212, 219))	('undifferentiated pleomorphic sarcoma', 'Disease', (92, 128))	('sarcomas', 'Disease', 'MESH:D012509', (212, 220))	('sarcoma', 'Disease', (212, 219))	('sarcomas', 'Phenotype', 'HP:0100242', (212, 220))	('sarcomas', 'Disease', (212, 220))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (250, 268))	('synovial sarcoma', 'Disease', (232, 248))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (62, 82))	('sarcoma', 'Disease', (154, 161))	('synovial sarcoma', 'Disease', 'MESH:D013584', (232, 248))	('sarcoma', 'Disease', 'MESH:D012509', (241, 248))	('liposarcoma', 'Phenotype', 'HP:0012034', (257, 268))	('sarcoma', 'Disease', (241, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('translocation-associated', 'Var', (187, 211))	('liposarcoma', 'Disease', (150, 161))	('fibromyxoid sarcoma', 'Disease', (304, 323))	('pleomorphic sarcomas', 'Disease', (62, 82))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (232, 248))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('sarcoma', 'Disease', 'MESH:D012509', (281, 288))	('sarcoma', 'Disease', (74, 81))	('sarcoma', 'Disease', (281, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('liposarcoma', 'Disease', 'MESH:D008080', (257, 268))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))	('sarcomas', 'Disease', (74, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (241, 248))	('sarcoma', 'Disease', (121, 128))	('liposarcoma', 'Phenotype', 'HP:0012034', (150, 161))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (92, 128))	('sarcoma', 'Disease', 'MESH:D012509', (316, 323))	('sarcoma', 'Disease', 'MESH:D012509', (261, 268))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (250, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
12526	32313727	High levels of CD47 expression have been shown to be an adverse prognostic factor in several lymphomas, ovarian cancer, and glioblastoma.	('High levels', 'Var', (0, 11))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('glioblastoma', 'Disease', (124, 136))	('lymphomas', 'Phenotype', 'HP:0002665', (93, 102))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('CD47', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('lymphomas, ovarian cancer', 'Disease', 'MESH:D008223', (93, 118))
12530	32313727	In pre-clinical trials, anti-CD47/SIRPalpha blockade has shown an anti-tumor effect in a variety of human malignancies via de-repression of macrophage phagocytosis of tumor cells, which in turn promotes the display of tumor neoantigens on antigen-presenting cells, helping to enhance the adaptive anti-tumor response.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('blockade', 'Var', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('malignancies', 'Disease', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('enhance', 'PosReg', (276, 283))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', (167, 172))	('anti-CD47/SIRPalpha', 'Var', (24, 43))	('promotes', 'PosReg', (194, 202))	('de-repression', 'NegReg', (123, 136))	('tumor', 'Disease', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('display', 'MPA', (207, 214))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('human', 'Species', '9606', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
12543	32313727	The relative macrophage fraction seen in sarcomas correlated with increased intratumoral heterogeneity, aneuploidy score, focal chromosomal copy number alterations, and homologous recombination defects (with the strongest associations seen in leiomyosarcoma).	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('increased', 'PosReg', (66, 75))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('aneuploidy', 'Disease', (104, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('leiomyosarcoma', 'Disease', (243, 257))	('focal chromosomal copy number alterations', 'Var', (122, 163))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (243, 257))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('aneuploidy', 'Disease', 'MESH:D000782', (104, 114))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (243, 257))	('tumor', 'Disease', (81, 86))
12580	30791458	In this study, we outline the establishment and characterization of tumors that are the result of carcinogen administration in H-2k CBA/J mice of both sexes, and assess their use for future research.	('rat', 'Species', '10116', (117, 120))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('mice', 'Species', '10090', (138, 142))	('H-2k', 'Var', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
12599	30791458	Additionally, tumors or suspicious tissues were detected, and the primary isolates were re-transplanted in nine other mice (s.c. MNU  , s.c. MCA  , s.c. MCA  , p.o.	('MCA', 'Chemical', 'MESH:D008748', (153, 156))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('MNU', 'Chemical', 'MESH:D008770', (129, 132))	('mice', 'Species', '10090', (118, 122))	('MCA', 'Chemical', 'MESH:D008748', (141, 144))	('s.c. MCA', 'Var', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('s.c. MNU', 'Var', (124, 132))
12662	30791458	Comparing these results with former flow cytometric analyses of seven syngeneic standard in vivo mouse models, MC38-CEA, CT26.WT, LL/2, Clone M3, 4T1, RENCA, or B16.F10 (for details of the models-Figure S2:sMDI), most striking differences were seen regarding a massive infiltration of CD4+ lymphocytes (~3-fold higher) in cMDI JA-2019, JA-2041, and JA-2042, but not in cMDI JA-2011 (Figure 4B).	('CEA', 'Gene', '111518', (116, 119))	('higher', 'PosReg', (311, 317))	('CD4', 'Gene', (285, 288))	('JA', 'Chemical', 'MESH:C011006', (374, 376))	('CD4', 'Gene', '12504', (285, 288))	('JA', 'Chemical', 'MESH:C011006', (349, 351))	('JA', 'Chemical', 'MESH:C011006', (336, 338))	('mouse', 'Species', '10090', (97, 102))	('JA-2042', 'Var', (349, 356))	('CT26', 'CellLine', 'CVCL:7254', (121, 125))	('JA-2019', 'CellLine', 'CVCL:K781', (327, 334))	('JA-2019', 'Var', (327, 334))	('CEA', 'Gene', (116, 119))	('rat', 'Species', '10116', (275, 278))	('JA', 'Chemical', 'MESH:C011006', (327, 329))
12664	30791458	However, in Treg cells, an enhanced (2-3-fold) invasion was seen in JA-2019 and JA-2042.	('JA-2019', 'CellLine', 'CVCL:K781', (68, 75))	('JA-2019', 'Var', (68, 75))	('JA', 'Chemical', 'MESH:C011006', (68, 70))	('JA-2042', 'Var', (80, 87))	('enhanced', 'PosReg', (27, 35))	('invasion', 'CPA', (47, 55))	('JA', 'Chemical', 'MESH:C011006', (80, 82))
12716	30791458	Results showed that JA-2042 cMDI tumors basically display sufficient immunogenicity to become completely inhibited.	('JA', 'Chemical', 'MESH:C011006', (20, 22))	('JA-2042 cMDI', 'Var', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('immunogenicity', 'MPA', (69, 83))	('tumors', 'Disease', (33, 39))
12720	30791458	Compared to the other anti-mCTLA-4 sensitive models, JA-2011 displayed a different pattern of tumor-infiltrating leukocyte populations, with a low infiltration of lymphocytic CD4+ and CD8+ effector cells, and many neutrophils (Figure 4B).	('JA', 'Chemical', 'MESH:C011006', (53, 55))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('JA-2011', 'Var', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CD4', 'Gene', '12504', (175, 178))	('rat', 'Species', '10116', (153, 156))	('rat', 'Species', '10116', (106, 109))	('tumor', 'Disease', (94, 99))	('mCTLA-4', 'Gene', '12477', (27, 34))	('mCTLA-4', 'Gene', (27, 34))	('CD4', 'Gene', (175, 178))
12723	30791458	Former studies have shown that different carcinogens could induce carcinogen-specific mutations, which might then differentially activate various oncogenes and affect progression to malignancy.	('activate', 'PosReg', (129, 137))	('mutations', 'Var', (86, 95))	('malignancy', 'Disease', 'MESH:D009369', (182, 192))	('oncogenes', 'Protein', (146, 155))	('malignancy', 'Disease', (182, 192))	('induce', 'Reg', (59, 65))	('affect', 'Reg', (160, 166))
12728	30791458	Flow cytometry confirmed that enhanced Cd4 gene expression in JA-2042 was actually associated with enhanced CD4+ T cell infiltration by various tumor-infiltrating leukocytes.	('Cd4', 'Gene', '12504', (39, 42))	('tumor', 'Disease', (144, 149))	('rat', 'Species', '10116', (156, 159))	('enhanced', 'PosReg', (30, 38))	('enhanced', 'PosReg', (99, 107))	('CD4', 'Gene', (108, 111))	('JA', 'Chemical', 'MESH:C011006', (62, 64))	('CD4', 'Gene', '12504', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('Cd4', 'Gene', (39, 42))	('rat', 'Species', '10116', (126, 129))	('JA-2042', 'Var', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
12743	30791458	Termination criteria: If the volume of tumors exceeded 2000 mm3 or an edge length of 2 cm, tumor ulcerations, weight loss of >20%, cachectic phenotype (tumor cachexia), remarkably abnormal, non-physiological posture as a sign of pain, apathy (severe inactivity), strongly reduced feed and water intake, severe dyspnea, motor deficit manifestations or paralysis, ascites, persisting diarrhea, massive behavioral changes, or other unexpected signs were observed, indicating an obviously heavy burden of the animals, the mice would be immediately sacrificed, according to the ATBW/GV-SOLAS.	('dyspnea', 'Disease', (310, 317))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('dyspnea', 'Disease', 'MESH:D004417', (310, 317))	('tumor cachexia', 'Disease', (152, 166))	('behavioral changes', 'CPA', (400, 418))	('ascites', 'Disease', 'MESH:D001201', (362, 369))	('tumors', 'Disease', (39, 45))	('motor', 'CPA', (319, 324))	('tumor ulcerations', 'Disease', 'MESH:D014456', (91, 108))	('reduced', 'NegReg', (272, 279))	('behavioral changes', 'Phenotype', 'HP:0000708', (400, 418))	('abnormal', 'Var', (180, 188))	('diarrhea', 'Phenotype', 'HP:0002014', (382, 390))	('apathy', 'Disease', 'None', (235, 241))	('pain', 'Disease', (229, 233))	('tumor cachexia', 'Disease', 'MESH:D002100', (152, 166))	('ascites', 'Phenotype', 'HP:0001541', (362, 369))	('apathy', 'Disease', (235, 241))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('mice', 'Species', '10090', (518, 522))	('paralysis', 'Phenotype', 'HP:0003470', (351, 360))	('dyspnea', 'Phenotype', 'HP:0002094', (310, 317))	('weight loss', 'Disease', 'MESH:D015431', (110, 121))	('paralysis', 'Disease', 'MESH:D010243', (351, 360))	('pain', 'Phenotype', 'HP:0012531', (229, 233))	('cachexia', 'Phenotype', 'HP:0004326', (158, 166))	('apathy', 'Phenotype', 'HP:0000741', (235, 241))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('diarrhea', 'Disease', (382, 390))	('weight loss', 'Phenotype', 'HP:0001824', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('weight loss', 'Disease', (110, 121))	('pain', 'Disease', 'MESH:D010146', (229, 233))	('tumor ulcerations', 'Disease', (91, 108))	('persisting diarrhea', 'Phenotype', 'HP:0002028', (371, 390))	('diarrhea', 'Disease', 'MESH:D003967', (382, 390))	('ascites', 'Disease', (362, 369))	('paralysis', 'Disease', (351, 360))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
12836	30212597	The intensity of the expression pattern was defined as + for mild expression (5% to 20% of cells in one sample positive), ++ for moderate expression (25% to 50% of cells in one sample positive) and +++ for strong expression (>50% of cells in one sample positive).	('strong expression', 'MPA', (206, 223))	('+++', 'Var', (198, 201))	('rat', 'Species', '10116', (133, 136))
12886	30212597	CAMs form a large and diverse group of proteins, and most of the members belong to either the immunoglobulin superfamily, or to the families of integrins, cadherins or selectins.23, 65  Claudin-1, encoded by the CLDN1 gene, is a tight junction protein and contributes to cell-to-cell adhesion by forming continuous seals around cells, serving as a physical barrier to prevent solutes and water from passing freely through the para-cellular space.66, 67 Abberant claudin expression has been reported in several cancer types, including lung, prostate and gastro-intestinal tumors.	('CLDN1', 'Gene', '9076', (212, 217))	('passing freely', 'Phenotype', 'HP:0007185', (399, 413))	('Claudin-1', 'Gene', '9076', (186, 195))	('tumor', 'Phenotype', 'HP:0002664', (571, 576))	('cancer', 'Disease', (510, 516))	('cancer', 'Phenotype', 'HP:0002664', (510, 516))	('prostate', 'Disease', (540, 548))	('Claudin-1', 'Gene', (186, 195))	('expression', 'MPA', (470, 480))	('gastro-intestinal tumors', 'Disease', 'MESH:D007414', (553, 577))	('cancer', 'Disease', 'MESH:D009369', (510, 516))	('CLDN1', 'Gene', (212, 217))	('water', 'Chemical', 'MESH:D014867', (388, 393))	('Abberant', 'Var', (453, 461))	('gastro-intestinal tumors', 'Disease', (553, 577))	('claudin', 'Gene', (462, 469))	('gastro-intestinal tumors', 'Phenotype', 'HP:0007378', (553, 577))	('tumors', 'Phenotype', 'HP:0002664', (571, 577))	('lung', 'Disease', (534, 538))	('reported', 'Reg', (490, 498))
12913	30231931	The tolerability profile of anlotinib is similar to that of other tyrosine kinase inhibitors that target VEGFR and other tyrosine kinase-mediated pathways; however, anlotinib has a significantly lower incidence of grade 3 or higher side effects compared to that of sunitinib.	('anlotinib', 'Var', (165, 174))	('grade 3', 'MPA', (214, 221))	('tyrosine kinase', 'Gene', '7294', (121, 136))	('tyrosine kinase', 'Gene', '7294', (66, 81))	('sunitinib', 'Chemical', 'MESH:D000077210', (265, 274))	('VEGFR', 'Gene', (105, 110))	('lower', 'NegReg', (195, 200))	('anlotinib', 'Chemical', 'MESH:C000625192', (165, 174))	('tyrosine kinase', 'Gene', (121, 136))	('tyrosine kinase', 'Gene', (66, 81))	('anlotinib', 'Chemical', 'MESH:C000625192', (28, 37))	('VEGFR', 'Gene', '3791', (105, 110))
12936	30231931	For these reasons, multi-targeting RTK inhibitors are one of the most popular and important drug classes being studied, and they may play a significant role in the treatment of cancers.	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('multi-targeting', 'Var', (19, 34))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('RTK inhibitors', 'Protein', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
12939	30231931	Anlotinib can inhibit more targets than other RTK inhibitors can, including sorafenib, sunitinib, and pazopanib.	('pazopanib', 'Chemical', 'MESH:C516667', (102, 111))	('sunitinib', 'Chemical', 'MESH:D000077210', (87, 96))	('sorafenib', 'Chemical', 'MESH:D000077157', (76, 85))	('Anlotinib', 'Chemical', 'MESH:C000625192', (0, 9))	('Anlotinib', 'Var', (0, 9))	('inhibit', 'NegReg', (14, 21))
12948	30231931	Anlotinib had broader and better antitumor efficacy than did sunitinib in vivo.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Anlotinib', 'Chemical', 'MESH:C000625192', (0, 9))	('Anlotinib', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('sunitinib', 'Chemical', 'MESH:D000077210', (61, 70))
12949	30231931	In cell lines expressing mutated FGFR2 protein, anlotinib decreased the number of cells.	('anlotinib', 'Chemical', 'MESH:C000625192', (48, 57))	('decreased', 'NegReg', (58, 67))	('number of cells', 'CPA', (72, 87))	('FGFR2', 'Gene', (33, 38))	('FGFR2', 'Gene', '2263', (33, 38))	('protein', 'Protein', (39, 46))	('mutated', 'Var', (25, 32))
12962	30231931	In vivo, anlotinib exerted a significant effect on the induction of CYP2D1 and CYP3A1/2, while it did not have a significant effect on CYP1A2, CYP2D2, or CYP2C6 after oral administration in rats.	('CYP2D2', 'Gene', '25053', (143, 149))	('CYP2D2', 'Gene', (143, 149))	('rat', 'Species', '10116', (180, 183))	('anlotinib', 'Chemical', 'MESH:C000625192', (9, 18))	('rat', 'Species', '10116', (190, 193))	('CYP2C6', 'Gene', '293989', (154, 160))	('CYP1A2', 'Gene', (135, 141))	('CYP1A2', 'Gene', '24297', (135, 141))	('anlotinib', 'Gene', (9, 18))	('CYP2D1', 'Gene', '266684', (68, 74))	('rats', 'Species', '10116', (190, 194))	('CYP2D1', 'Gene', (68, 74))	('CYP3A1/2', 'Var', (79, 87))	('CYP2C6', 'Gene', (154, 160))
12963	30231931	Caution, therefore, is warranted when anlotinib is administered with other drugs that are metabolized by CYP2D1 and CYP3A1/2.	('anlotinib', 'Chemical', 'MESH:C000625192', (38, 47))	('CYP2D1', 'Gene', (105, 111))	('CYP2D1', 'Gene', '266684', (105, 111))	('CYP3A1/2', 'Var', (116, 124))
12969	30231931	Anlotinib has a significantly longer t1/2 in patients than do most tyrosine kinase inhibitors that have been used clinically to date (i.e., 3-60 h).	('tyrosine kinase', 'Gene', (67, 82))	('longer', 'PosReg', (30, 36))	('Anlotinib', 'Chemical', 'MESH:C000625192', (0, 9))	('Anlotinib', 'Var', (0, 9))	('patients', 'Species', '9606', (45, 53))	('tyrosine kinase', 'Gene', '7294', (67, 82))	('t1/2', 'MPA', (37, 41))
12980	30231931	Patients receiving anlotinib had longer PFS than patients receiving placebo (4.8 vs 1.2 months; hazard ratio (HR) = 0.32; 95% confidence interval (CI), 0.20-0.51; P < 0.0001).	('rat', 'Species', '10116', (103, 106))	('anlotinib', 'Chemical', 'MESH:C000625192', (19, 28))	('anlotinib', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (49, 57))	('PFS', 'MPA', (40, 43))
12981	30231931	Moreover, the overall response rate (ORR) in the anlotinib group was greater than that in the placebo group (10.0%; 95% CI 2.4-17.6% vs 0%; 95% CI 0-6.27%; P = 0.028).	('anlotinib', 'Chemical', 'MESH:C000625192', (49, 58))	('response', 'MPA', (22, 30))	('greater', 'PosReg', (69, 76))	('anlotinib', 'Var', (49, 58))	('rat', 'Species', '10116', (31, 34))
12988	30231931	Patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations who were enrolled in the study must have had treatment failure with prior targeted therapies.	('translocations', 'Var', (100, 114))	('EGFR', 'Gene', '1956', (48, 52))	('ALK', 'Gene', (95, 98))	('anaplastic lymphoma kinase', 'Gene', (67, 93))	('mutations', 'Var', (54, 63))	('epidermal growth factor receptor', 'Gene', (14, 46))	('EGFR', 'Gene', (48, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('Patients', 'Species', '9606', (0, 8))	('ALK', 'Gene', '238', (95, 98))	('anaplastic lymphoma kinase', 'Gene', '238', (67, 93))	('epidermal growth factor receptor', 'Gene', '1956', (14, 46))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (67, 86))
12989	30231931	The results showed that anlotinib was more effective than placebo in third-line treatment of patients with advanced NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('anlotinib', 'Var', (24, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('anlotinib', 'Chemical', 'MESH:C000625192', (24, 33))	('NSCLC', 'Disease', (116, 121))	('patients', 'Species', '9606', (93, 101))
12992	30231931	An exploratory subgroup analysis of the ALTER0303 trial showed that anlotinib significantly improved PFS and OS in patients with both sensitive EGFR mutations and wild-type EGFR.	('patients', 'Species', '9606', (115, 123))	('EGFR', 'Gene', (144, 148))	('rat', 'Species', '10116', (8, 11))	('mutations', 'Var', (149, 158))	('PFS', 'Disease', (101, 104))	('EGFR', 'Gene', '1956', (173, 177))	('OS', 'Chemical', '-', (109, 111))	('EGFR', 'Gene', '1956', (144, 148))	('anlotinib', 'Chemical', 'MESH:C000625192', (68, 77))	('EGFR', 'Gene', (173, 177))	('improved', 'PosReg', (92, 100))
12993	30231931	The PFS and OS in patients with sensitive EGFR mutations receiving anlotinib and placebo were 5.57 months and 0.83 months (PFS, HR = 0.15, 95% CI 0.09-0.24, P < 0.0001), respectively, and 10.70 months and 6.27 months (OS, HR = 0.59, 95% CI 0.37-0.93, P = 0.0227), respectively.	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('anlotinib', 'Chemical', 'MESH:C000625192', (67, 76))	('OS', 'Chemical', '-', (218, 220))	('OS', 'Chemical', '-', (12, 14))	('patients', 'Species', '9606', (18, 26))
12994	30231931	Furthermore, the PFS and OS in patients with wild-type EGFR receiving anlotinib and placebo were 5.37 months and 1.57 months (PFS, HR = 0.29, 95% CI 0.22-0.39, P < 0.0001), respectively, and 8.87 months and 6.47 months (OS, HR = 0.73, 95% CI 0.55-0.97, P = 0.0282), respectively.	('EGFR', 'Gene', '1956', (55, 59))	('anlotinib', 'Chemical', 'MESH:C000625192', (70, 79))	('OS', 'Chemical', '-', (25, 27))	('OS', 'Chemical', '-', (220, 222))	('EGFR', 'Gene', (55, 59))	('anlotinib', 'Var', (70, 79))	('patients', 'Species', '9606', (31, 39))
12995	30231931	More recently, the study investigators reported that anlotinib led to a greater improvement in OS time in patients with sensitive EGFR mutations than in those with wild-type EGFR (10.70 vs 8.87, HR = 0.685, 95% CI 0.50-0.95, P = 0.0204).	('EGFR', 'Gene', (174, 178))	('improvement', 'PosReg', (80, 91))	('EGFR', 'Gene', '1956', (130, 134))	('mutations', 'Var', (135, 144))	('anlotinib', 'Chemical', 'MESH:C000625192', (53, 62))	('patients', 'Species', '9606', (106, 114))	('OS', 'Chemical', '-', (95, 97))	('OS time', 'MPA', (95, 102))	('EGFR', 'Gene', (130, 134))	('EGFR', 'Gene', '1956', (174, 178))
13011	30231931	The ORR and DCR in the anlotinib group were significantly higher than those in the control group (ORR 10.13% vs 1.33%, P = 0.0145; DCR 55.7% vs 22.67%, P < 0.0001).	('ORR', 'MPA', (4, 7))	('DCR', 'MPA', (12, 15))	('anlotinib', 'Chemical', 'MESH:C000625192', (23, 32))	('higher', 'PosReg', (58, 64))	('anlotinib', 'Var', (23, 32))	('DCR', 'Chemical', '-', (131, 134))	('DCR', 'Chemical', '-', (12, 15))
13013	30231931	The pathological subtype with the greatest increase in survival was ASPS, whose median PFS was 18.23 months in the anlotinib group compared with 3 months in the control group (HR = 0.14, P < 0.0001).	('ASPS', 'Gene', '79058', (68, 72))	('anlotinib', 'Chemical', 'MESH:C000625192', (115, 124))	('ASPS', 'Phenotype', 'HP:0012218', (68, 72))	('anlotinib', 'Var', (115, 124))	('ASPS', 'Gene', (68, 72))	('increase', 'PosReg', (43, 51))
13028	30231931	More importantly, the incidence of over-grade 3 side effects was lower in the anlotinib group than in the sunitinib group (28.9% vs 55.8%, P = 0.0039), particularly for grade 3 or 4 thrombocytopenia (0 vs 11.6%, P = 0.003) and neutropenia (0.0 vs 9.3%, P = 0.009).	('neutropenia', 'Disease', 'MESH:D009503', (227, 238))	('thrombocytopenia', 'Disease', (182, 198))	('grade 3', 'Disease', (169, 176))	('lower', 'NegReg', (65, 70))	('sunitinib', 'Chemical', 'MESH:D000077210', (106, 115))	('anlotinib', 'Chemical', 'MESH:C000625192', (78, 87))	('neutropenia', 'Phenotype', 'HP:0001875', (227, 238))	('anlotinib', 'Var', (78, 87))	('thrombocytopenia', 'Disease', 'MESH:D013921', (182, 198))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (182, 198))	('neutropenia', 'Disease', (227, 238))
13042	30231931	As the authors indicated, it is noteworthy that anlotinib appeared to cause less and milder diarrhea than did other oral anti-VEGFR TKIs.	('diarrhea', 'Disease', (92, 100))	('anlotinib', 'Chemical', 'MESH:C000625192', (48, 57))	('diarrhea', 'Disease', 'MESH:D003967', (92, 100))	('VEGFR', 'Gene', '3791', (126, 131))	('anlotinib', 'Var', (48, 57))	('VEGFR', 'Gene', (126, 131))	('diarrhea', 'Phenotype', 'HP:0002014', (92, 100))
13048	30231931	Additionally, in patients with mRCC, anlotinib induced significantly fewer cases of grade 3/4 side effects, especially thrombocytopenia and neutropenia, than sunitinib did, but caused a greater incidence of hypercholesterolemia.	('neutropenia', 'Disease', 'MESH:D009503', (140, 151))	('fewer', 'NegReg', (69, 74))	('thrombocytopenia', 'Disease', (119, 135))	('hypercholesterolemia', 'Disease', (207, 227))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('neutropenia', 'Phenotype', 'HP:0001875', (140, 151))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (207, 227))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (207, 227))	('anlotinib', 'Chemical', 'MESH:C000625192', (37, 46))	('patients', 'Species', '9606', (17, 25))	('neutropenia', 'Disease', (140, 151))	('thrombocytopenia', 'Disease', 'MESH:D013921', (119, 135))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (119, 135))	('anlotinib', 'Var', (37, 46))	('grade 3/4 side effects', 'MPA', (84, 106))	('sunitinib', 'Chemical', 'MESH:D000077210', (158, 167))
13052	30231931	Fortunately, several clinical trials have identified circulating biomarkers that predict anlotinib activity, specifically activated circulating endothelial cells (aCECs) and EGFR-sensitizing mutations or T790M mutation.	('EGFR', 'Gene', (174, 178))	('activated', 'PosReg', (122, 131))	('aCEC', 'Chemical', '-', (163, 167))	('T790M', 'Mutation', 'rs121434569', (204, 209))	('anlotinib', 'Chemical', 'MESH:C000625192', (89, 98))	('activity', 'MPA', (99, 107))	('T790M mutation', 'Var', (204, 218))	('anlotinib', 'Gene', (89, 98))	('EGFR', 'Gene', '1956', (174, 178))
13053	30231931	In the ALTER0303 trial, aCECs were measured in 49 patients receiving anlotinib and 30 patients receiving placebo.	('anlotinib', 'Chemical', 'MESH:C000625192', (69, 78))	('anlotinib', 'Var', (69, 78))	('patients', 'Species', '9606', (50, 58))	('aCEC', 'Chemical', '-', (24, 28))	('aCECs', 'MPA', (24, 29))	('patients', 'Species', '9606', (86, 94))
13059	30231931	Moreover, there was no correlation between sensitizing EGFR mutations and PFS in 27 patients (5.53 vs 5.53 months, HR = 1.16, 95% CI 0.73-1.85, P = 0.495).	('EGFR', 'Gene', '1956', (55, 59))	('patients', 'Species', '9606', (84, 92))	('EGFR', 'Gene', (55, 59))	('PFS', 'Disease', (74, 77))	('mutations', 'Var', (60, 69))
13060	30231931	Similarly, the EGFR T790M mutation did not reflect the treatment effectiveness of anlotinib in 17 patients with advanced NSCLC (5.53 vs 5.53 months, HR = 1.35, 95% CI 0.75-2.41, P = 0.253).	('NSCLC', 'Disease', (121, 126))	('patients', 'Species', '9606', (98, 106))	('T790M', 'Mutation', 'rs121434569', (20, 25))	('anlotinib', 'Chemical', 'MESH:C000625192', (82, 91))	('EGFR', 'Gene', '1956', (15, 19))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('EGFR', 'Gene', (15, 19))	('T790M', 'Var', (20, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
13069	30231931	Anlotinib also has potential as a new treatment for other solid tumors, such as mRCC and thyroid carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('solid tumors', 'Disease', (58, 70))	('Anlotinib', 'Chemical', 'MESH:C000625192', (0, 9))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (89, 106))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('Anlotinib', 'Var', (0, 9))	('RCC', 'Disease', (81, 84))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (89, 106))	('solid tumors', 'Disease', 'MESH:D009369', (58, 70))	('thyroid carcinoma', 'Disease', (89, 106))
13097	30231931	Anlotinib has fewer or milder side effects compared to those of other anti-VEGFR TKIs, particularly the thrombocytopenia and neutropenia found with sunitinib.	('thrombocytopenia', 'Disease', 'MESH:D013921', (104, 120))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (104, 120))	('neutropenia', 'Disease', (125, 136))	('sunitinib', 'Chemical', 'MESH:D000077210', (148, 157))	('VEGFR', 'Gene', (75, 80))	('Anlotinib', 'Chemical', 'MESH:C000625192', (0, 9))	('Anlotinib', 'Var', (0, 9))	('thrombocytopenia', 'Disease', (104, 120))	('neutropenia', 'Phenotype', 'HP:0001875', (125, 136))	('neutropenia', 'Disease', 'MESH:D009503', (125, 136))	('VEGFR', 'Gene', '3791', (75, 80))
13280	29370992	Studies have shown that high tumor mutational load correlates with benefit from checkpoint blockade agents in melanoma and lung cancers, however outliers exist.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('melanoma and lung cancers', 'Disease', 'MESH:D008175', (110, 135))	('mutational load', 'Var', (35, 50))	('lung cancers', 'Phenotype', 'HP:0100526', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', (29, 34))	('benefit', 'PosReg', (67, 74))	('high', 'Var', (24, 28))
13282	29370992	In addition, the presence of TILs as well as PD-L1 expression in the TILs has also been described as being potential important biomarkers predictive of benefit in selected malignancies.	('PD-L1', 'Gene', '29126', (45, 50))	('malignancies', 'Disease', 'MESH:D009369', (172, 184))	('benefit', 'PosReg', (152, 159))	('expression', 'MPA', (51, 61))	('presence', 'Var', (17, 25))	('malignancies', 'Disease', (172, 184))	('PD-L1', 'Gene', (45, 50))
13333	29075582	Laboratory exam was significant for hemoglobin of 8.9 g/dl with the normal total lymphocyte count of 5400/ul and elevated serum creatinine 4.6 mg/dl.	('elevated', 'PosReg', (113, 121))	('hemoglobin', 'Var', (36, 46))	('creatinine', 'Chemical', 'MESH:D003404', (128, 138))	('serum creatinine', 'MPA', (122, 138))	('elevated serum creatinine', 'Phenotype', 'HP:0003259', (113, 138))
13369	32646614	Finally, undifferentiated SMARCA4-deficient thoracic sarcomas are defined by SMARCA4 subunit inactivation, leading to SMARCA4 and SMARCA2 loss.	('undifferentiated SMARCA4-deficient thoracic sarcomas', 'Disease', 'MESH:D002277', (9, 61))	('loss', 'NegReg', (138, 142))	('SMARCA2', 'Gene', (130, 137))	('SMARCA2', 'Gene', '6595', (130, 137))	('SMARCA4', 'Gene', '6597', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('inactivation', 'Var', (93, 105))	('SMARCA4', 'Gene', (118, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('SMARCA4', 'Gene', '6597', (118, 125))	('SMARCA4', 'Gene', (26, 33))	('SMARCA4', 'Gene', (77, 84))	('SMARCA4', 'Gene', '6597', (77, 84))
13370	32646614	Rarely, inactivation of alternate but biologically equivalent key regulators can substitute for canonical subunit deficiency, such as SMARCA4 inactivation in cases of SMARCB1-retained epithelioid sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('subunit deficiency', 'Disease', 'MESH:C580233', (106, 124))	('SMARCA4', 'Gene', '6597', (134, 141))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (184, 203))	('epithelioid sarcoma', 'Disease', (184, 203))	('SMARCB1', 'Gene', '6598', (167, 174))	('inactivation', 'Var', (8, 20))	('SMARCB1', 'Gene', (167, 174))	('inactivation', 'Var', (142, 154))	('SMARCA4', 'Gene', (134, 141))	('subunit deficiency', 'Disease', (106, 124))
13373	32646614	As discussed in detail in other articles in this edition of Seminars in Diagnostic Pathology, a significant subset of human cancers harbor SWI/SNF complex perturbations, which impact tumor suppressor or oncogenic functions of one or more SWI/SNF complex subunit.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('human', 'Species', '9606', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('tumor', 'Disease', (183, 188))	('perturbations', 'Var', (155, 168))	('SWI/SNF complex', 'Gene', (139, 154))	('impact', 'Reg', (176, 182))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('oncogenic functions', 'CPA', (203, 222))
13374	32646614	A variety of mutational evens targeting distinct subunits is observed in specific cancers, indicating tissue-specific protective roles.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('mutational', 'Var', (13, 23))
13375	32646614	In soft tissue tumors, the SMARCB1 (INI1, BAF47, hSNF5) core subunit encoded by SMARCB1 on 22q11.23 is most frequently targeted by genomic mutations causing loss of tumor suppressor function.	('INI1', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('hSNF5', 'Gene', '6598', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('SMARCB1', 'Gene', '6598', (27, 34))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('SMARCB1', 'Gene', (27, 34))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (3, 21))	('BAF47', 'Gene', '6598', (42, 47))	('hSNF5', 'Gene', (49, 54))	('tumors', 'Disease', (15, 21))	('tumor', 'Disease', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('SMARCB1', 'Gene', '6598', (80, 87))	('mutations', 'Var', (139, 148))	('BAF47', 'Gene', (42, 47))	('SMARCB1', 'Gene', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('loss', 'NegReg', (157, 161))	('INI1', 'Gene', '6598', (36, 40))
13387	32646614	Given its roles in coordinating cellular differentiation and proliferation, inactivation of the SWI/SNF complex often results in an undifferentiated cellular state, which may be responsible for the universal monotonous undifferentiated cytomorphology in most SWI/SNF-deficient neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (277, 285))	('results in', 'Reg', (118, 128))	('SWI/SNF', 'Gene', (96, 103))	('SNF-deficient neoplasms', 'Disease', (263, 286))	('SNF-deficient neoplasms', 'Disease', 'MESH:D009369', (263, 286))	('neoplasms', 'Phenotype', 'HP:0002664', (277, 286))	('inactivation', 'Var', (76, 88))	('undifferentiated cellular state', 'MPA', (132, 163))
13389	32646614	The SMARCB1 subunit is most frequently targeted by genomic inactivation in soft tissue neoplasms.	('soft tissue neoplasms', 'Disease', (75, 96))	('neoplasm', 'Phenotype', 'HP:0002664', (87, 95))	('soft tissue neoplasms', 'Disease', 'MESH:D012983', (75, 96))	('SMARCB1', 'Gene', '6598', (4, 11))	('neoplasms', 'Phenotype', 'HP:0002664', (87, 96))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (75, 96))	('genomic inactivation', 'Var', (51, 71))	('SMARCB1', 'Gene', (4, 11))
13394	32646614	SMARCB1 genomic perturbations do not only occur as somatic events in cancer, but also in the germ-line setting: SMARCB1 mutations have been identified in several hereditary SWI/SNF deficiency syndromes predisposing to development of malignant rhabdoid tumor (OMIM # 609,322), familial schwannomatosis (OMIM # 162,091) or SWI/SNF-related meningiomas (OMIM # 607,174), which will not be further discussed here.	('mutations', 'Var', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('hereditary SWI/SNF deficiency syndromes', 'Disease', 'MESH:D061325', (162, 201))	('meningiomas', 'Disease', 'MESH:D008577', (337, 348))	('familial schwannomatosis', 'Disease', (276, 300))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('familial schwannomatosis', 'Disease', 'MESH:C536641', (276, 300))	('meningiomas', 'Phenotype', 'HP:0002858', (337, 348))	('hereditary SWI/SNF deficiency syndromes', 'Disease', (162, 201))	('meningiomas', 'Disease', (337, 348))	('SMARCB1', 'Gene', '6598', (112, 119))	('SMARCB1', 'Gene', '6598', (0, 7))	('SMARCB1', 'Gene', (112, 119))	('SNF deficiency', 'Phenotype', 'HP:0025457', (177, 191))	('SMARCB1', 'Gene', (0, 7))	('identified', 'Reg', (140, 150))	('cancer', 'Disease', (69, 75))	('schwannoma', 'Phenotype', 'HP:0100008', (285, 295))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (233, 257))	('malignant rhabdoid tumor', 'Disease', (233, 257))	('meningioma', 'Phenotype', 'HP:0002858', (337, 347))
13395	32646614	Malignant rhabdoid tumor, a rare tumor occurring almost exclusively in infants and young children, is caused by SMARCB1 biallelic inactivation in virtually all cases.	('Malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Malignant rhabdoid tumor', 'Disease', (0, 24))	('caused by', 'Reg', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('SMARCB1', 'Gene', '6598', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('SMARCB1', 'Gene', (112, 119))	('tumor', 'Disease', (19, 24))	('children', 'Species', '9606', (89, 97))	('biallelic inactivation', 'Var', (120, 142))	('infants', 'Species', '9606', (71, 78))
13397	32646614	Inactivating genomic events include point and frameshift mutations, intragenic deletions and duplications, larger deletions including regions both proximal and distal to SMARCB1, 22q deletions or translocations, and monosomy 22.	('monosomy', 'Disease', (216, 224))	('SMARCB1', 'Gene', (170, 177))	('SMARCB1', 'Gene', '6598', (170, 177))	('22q deletions', 'Var', (179, 192))	('deletions', 'Var', (79, 88))	('frameshift mutations', 'Var', (46, 66))	('duplications', 'CPA', (93, 105))	('translocations', 'Var', (196, 210))	('point', 'Var', (36, 41))
13405	32646614	As demonstrated in cases of SMARCB1-deficient soft tissue neoplasms, co-deletions of EWSR1 at 22q12.2 may be incorrectly interpreted as equivalent to EWSR1 rearrangement.	('SMARCB1-deficient soft tissue neoplasms', 'Disease', (28, 67))	('EWSR1', 'Gene', '2130', (85, 90))	('EWSR1', 'Gene', '2130', (150, 155))	('neoplasm', 'Phenotype', 'HP:0002664', (58, 66))	('SMARCB1-deficient soft tissue neoplasms', 'Disease', 'MESH:D012983', (28, 67))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (46, 67))	('co-deletions', 'Var', (69, 81))	('neoplasms', 'Phenotype', 'HP:0002664', (58, 67))	('EWSR1', 'Gene', (150, 155))	('EWSR1', 'Gene', (85, 90))
13434	32646614	EWSR1 gene fusions are found in about 50% of myoepithelial tumors of soft tissue, including t(1;22)(q23;q12) resulting in EWSR1-PBX1 fusion, t(19;22)(q13;q12) resulting in EWSR1-ZNF444 fusion or t(6;22)(p21;q12) resulting in EWSR1-POU5F1 fusion, which might each be associated with distinct morphologies (Table 2).	('ZNF444', 'Gene', (178, 184))	('EWSR1', 'Gene', '2130', (122, 127))	('POU5F1', 'Gene', '5460', (231, 237))	('t(6;22)(p21;q12', 'Var', (195, 210))	('myoepithelial tumors', 'Disease', (45, 65))	('PBX1', 'Gene', (128, 132))	('t(19;22)(q13;q12', 'Var', (141, 157))	('EWSR1', 'Gene', (172, 177))	('PBX1', 'Gene', '5087', (128, 132))	('EWSR1', 'Gene', '2130', (0, 5))	('EWSR1', 'Gene', (225, 230))	('EWSR1', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('t(6;22)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (195, 211))	('ZNF444', 'Gene', '55311', (178, 184))	('POU5F1', 'Gene', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (45, 65))	('EWSR1', 'Gene', (0, 5))	('EWSR1', 'Gene', '2130', (225, 230))	('t(1;22)(q23;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (92, 108))	('EWSR1', 'Gene', '2130', (172, 177))	('resulting', 'Reg', (212, 221))	('t(19;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (141, 158))
13436	32646614	However, the association between EWSR1 fusions and SMARCB1 perturbations in myoepithelial carcinomas remains to be characterized.	('myoepithelial carcinomas', 'Disease', 'MESH:D009208', (76, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('fusions', 'Var', (39, 46))	('myoepithelial carcinomas', 'Disease', (76, 100))	('EWSR1', 'Gene', (33, 38))	('perturbations', 'Var', (59, 72))	('SMARCB1', 'Gene', '6598', (51, 58))	('EWSR1', 'Gene', '2130', (33, 38))	('SMARCB1', 'Gene', (51, 58))
13447	32646614	Two of those 4 SMARCB1-deficient extraskeletal myxoid chondrosarcomas revealed SMARCB1 genomic inactivation through homozygous deletion and frameshift mutation, respectively.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (54, 68))	('SMARCB1', 'Gene', (79, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('SMARCB1', 'Gene', '6598', (15, 22))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (54, 69))	('SMARCB1', 'Gene', (15, 22))	('frameshift mutation', 'Var', (140, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (47, 69))	('SMARCB1', 'Gene', '6598', (79, 86))	('myxoid chondrosarcomas', 'Disease', (47, 69))
13450	32646614	It remains to be determined whether EWSR1-NR4A3 fusions may be found predominantly in the subset of cases showing SMARCB1 deficiency, or whether these genetic perturbations occur independently.	('EWSR1', 'Gene', '2130', (36, 41))	('fusions', 'Var', (48, 55))	('SMARCB1', 'Gene', '6598', (114, 121))	('SMARCB1', 'Gene', (114, 121))	('NR4A3', 'Gene', '8013', (42, 47))	('NR4A3', 'Gene', (42, 47))	('EWSR1', 'Gene', (36, 41))	('deficiency', 'Disease', (122, 132))	('deficiency', 'Disease', 'MESH:D007153', (122, 132))
13453	32646614	Two cases of primary intracranial myxoid sarcomas with SMARCB1 loss and monosomy 22q have been reported, and in a third case with intact SMARCB1, an EWSR1-CREB1 gene fusion was demonstrated by NGS.	('SMARCB1', 'Gene', (55, 62))	('SMARCB1', 'Gene', '6598', (55, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('intracranial myxoid sarcomas', 'Disease', (21, 49))	('CREB1', 'Gene', (155, 160))	('intracranial myxoid sarcomas', 'Disease', 'MESH:D012509', (21, 49))	('EWSR1', 'Gene', (149, 154))	('SMARCB1', 'Gene', '6598', (137, 144))	('monosomy 22q', 'Var', (72, 84))	('SMARCB1', 'Gene', (137, 144))	('EWSR1', 'Gene', '2130', (149, 154))	('loss', 'NegReg', (63, 67))	('CREB1', 'Gene', '1385', (155, 160))
13468	32646614	NGS identified recurrent SMARCB1 genomic inactivation in both entities, through homozygous deletion, nonsense, frameshift or splice site mutations targeting the SMARCB1 gene.	('nonsense', 'Var', (101, 109))	('deletion', 'Var', (91, 99))	('frameshift or splice site mutations', 'Var', (111, 146))	('SMARCB1', 'Gene', '6598', (161, 168))	('SMARCB1', 'Gene', '6598', (25, 32))	('SMARCB1', 'Gene', (161, 168))	('SMARCB1', 'Gene', (25, 32))
13469	32646614	Epithelioid MPNST lacks canonical aberrations of the PRC2 components SUZ12 and EED, in line with retained H3K27me3 expression in these tumors, and less frequently harbors NF1 mutations than conventional MPNST.	('harbors', 'Reg', (163, 170))	('MPNST', 'Phenotype', 'HP:0100697', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SUZ12', 'Gene', '23512', (69, 74))	('SUZ12', 'Gene', (69, 74))	('EED', 'Gene', '8726', (79, 82))	('lacks', 'NegReg', (18, 23))	('EED', 'Gene', (79, 82))	('tumors', 'Disease', (135, 141))	('NF1', 'Gene', (171, 174))	('mutations', 'Var', (175, 184))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('NF1', 'Gene', '4763', (171, 174))	('PRC2', 'Gene', (53, 57))	('MPNST', 'Phenotype', 'HP:0100697', (203, 208))	('Epithelioid MPNST', 'Disease', (0, 17))
13472	32646614	Epithelioid schwannomas behave in a benign fashion, and epithelioid MPNST appear to have a low risk for recurrence and metastasis, irrespective of tumor depth, with a much more favorable prognosis than conventional MPNST.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('schwannomas', 'Phenotype', 'HP:0100008', (12, 23))	('schwannomas', 'Disease', (12, 23))	('tumor depth', 'Disease', (147, 158))	('schwannoma', 'Phenotype', 'HP:0100008', (12, 22))	('MPNST', 'Phenotype', 'HP:0100697', (215, 220))	('tumor depth', 'Disease', 'MESH:D007222', (147, 158))	('MPNST', 'Phenotype', 'HP:0100697', (68, 73))	('epithelioid MPNST', 'Var', (56, 73))	('Epithelioid schwannomas', 'Phenotype', 'HP:0032060', (0, 23))	('metastasis', 'CPA', (119, 129))	('schwannomas', 'Disease', 'MESH:D009442', (12, 23))	('Epithelioid schwannoma', 'Phenotype', 'HP:0032060', (0, 22))
13475	32646614	Although heterozygous SMARCB1 missense mutations have been reported in a small subset of melanomas, such mutations do not lead to SMARCB1 loss as they are not completely inactivating.	('loss', 'NegReg', (138, 142))	('melanomas', 'Disease', (89, 98))	('SMARCB1', 'Gene', '6598', (22, 29))	('missense mutations', 'Var', (30, 48))	('SMARCB1', 'Gene', (130, 137))	('SMARCB1', 'Gene', '6598', (130, 137))	('SMARCB1', 'Gene', (22, 29))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('melanomas', 'Disease', 'MESH:D008545', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))
13476	32646614	SMARCA4 inactivation was identified by RNA sequencing analyses in a subset of undifferentiated malignancies presenting as compressive mediastinal/pulmonary masses in adults with very aggressive clinical behavior and median survival of 7 months.	('SMARCA4', 'Gene', (0, 7))	('undifferentiated malignancies', 'Disease', 'MESH:D008228', (78, 107))	('SMARCA4', 'Gene', '6597', (0, 7))	('compressive mediastinal/pulmonary masses', 'Disease', (122, 162))	('inactivation', 'Var', (8, 20))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (183, 211))	('undifferentiated malignancies', 'Disease', (78, 107))
13479	32646614	SMARCA4 genomic inactivation results from nonsense, frameshift, missense, and splice-site mutations.	('frameshift', 'Var', (52, 62))	('SMARCA4', 'Gene', (0, 7))	('results', 'Reg', (29, 36))	('SMARCA4', 'Gene', '6597', (0, 7))	('splice-site mutations', 'Var', (78, 99))	('nonsense', 'Var', (42, 50))	('missense', 'Var', (64, 72))
13482	32646614	While distinction of undifferentiated SMARCA4-deficient sarcoma from SMARCA4-deficient carcinomas can be challenging, expression of CD34 and lack of claudin-4 help support mesenchymal over epithelial differentiation in this context, although the precise nosologic status of this tumor type remains controversial.	('undifferentiated SMARCA4-deficient sarcoma', 'Disease', (21, 63))	('SMARCA4-deficient carcinomas', 'Disease', (69, 97))	('claudin-4', 'Gene', '1364', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', (279, 284))	('claudin-4', 'Gene', (149, 158))	('mesenchymal over epithelial differentiation', 'CPA', (172, 215))	('SMARCA4-deficient carcinomas', 'Disease', 'MESH:D009369', (69, 97))	('undifferentiated SMARCA4-deficient sarcoma', 'Disease', 'MESH:D002277', (21, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('CD34', 'Gene', '947', (132, 136))	('lack', 'Var', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('CD34', 'Gene', (132, 136))
13486	32646614	ARID1A mutations are demonstrated across a wide range of tumors including ~45% of endometrioid and clear-cell ovarian carcinomas, ~20% of gastric and bladder carcinomas, ~14% of hepatocellular carcinomas, ~10% of colorectal carcinomas and melanomas, and less frequently in lung, pancreatic, and breast carcinomas.	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (178, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('colorectal carcinomas', 'Disease', (213, 234))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (213, 234))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (178, 203))	('breast carcinomas', 'Disease', 'MESH:D001943', (295, 312))	('carcinomas', 'Phenotype', 'HP:0030731', (302, 312))	('breast carcinomas', 'Disease', (295, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('melanomas', 'Disease', 'MESH:D008545', (239, 248))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('hepatocellular carcinomas', 'Disease', (178, 203))	('endometrioid', 'Disease', (82, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('pancreatic', 'Disease', 'MESH:D010195', (279, 289))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))	('melanomas', 'Disease', (239, 248))	('mutations', 'Var', (7, 16))	('clear-cell ovarian carcinomas', 'Disease', 'MESH:D008649', (99, 128))	('breast carcinomas', 'Phenotype', 'HP:0003002', (295, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('ARID1A', 'Gene', (0, 6))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (150, 168))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('bladder carcinomas', 'Disease', 'MESH:D001749', (150, 168))	('pancreatic', 'Disease', (279, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('ARID1A', 'Gene', '8289', (0, 6))	('melanomas', 'Phenotype', 'HP:0002861', (239, 248))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (110, 128))	('tumors', 'Disease', (57, 63))	('clear-cell ovarian carcinomas', 'Disease', (99, 128))	('bladder carcinomas', 'Disease', (150, 168))	('lung', 'Disease', (273, 277))
13487	32646614	ARID1A inactivation is also found in pediatric neuroblastoma, and dedifferentiated meningioma.	('meningioma', 'Phenotype', 'HP:0002858', (83, 93))	('ARID1A', 'Gene', '8289', (0, 6))	('neuroblastoma', 'Disease', 'MESH:D009447', (47, 60))	('inactivation', 'Var', (7, 19))	('meningioma', 'Disease', 'MESH:D008577', (83, 93))	('neuroblastoma', 'Disease', (47, 60))	('ARID1A', 'Gene', (0, 6))	('found', 'Reg', (28, 33))	('neuroblastoma', 'Phenotype', 'HP:0003006', (47, 60))	('meningioma', 'Disease', (83, 93))
13488	32646614	Genomic inactivation of SMARCA4, ARID1A, ARID1B, ARID2 and PBRM1 is also frequent in cancer and includes mutations of SMARCA4 and SMARCA2 in non-small cell lung carcinomas, undifferentiated/rhabdoid carcinomas of the gastrointestinal and urothelial tract and uterus, and in rare sinonasal carcinomas, which are discussed in detail in other articles in this edition.	('ARID1B', 'Gene', (41, 47))	('carcinomas', 'Disease', 'MESH:D009369', (289, 299))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (145, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (289, 299))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (141, 171))	('ARID1B', 'Gene', '57492', (41, 47))	('mutations', 'Var', (105, 114))	('carcinomas', 'Disease', 'MESH:D009369', (199, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('ARID1A', 'Gene', (33, 39))	('carcinomas', 'Disease', 'MESH:D009369', (161, 171))	('ARID2', 'Gene', '196528', (49, 54))	('undifferentiated/rhabdoid carcinomas of the gastrointestinal', 'Disease', 'MESH:D002277', (173, 233))	('SMARCA2', 'Gene', (130, 137))	('SMARCA2', 'Gene', '6595', (130, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('SMARCA4', 'Gene', (24, 31))	('SMARCA4', 'Gene', (118, 125))	('ARID1A', 'Gene', '8289', (33, 39))	('ARID2', 'Gene', (49, 54))	('PBRM1', 'Gene', '55193', (59, 64))	('cancer', 'Disease', (85, 91))	('carcinomas', 'Disease', (289, 299))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('carcinomas', 'Disease', (199, 209))	('lung carcinomas', 'Disease', 'MESH:D008175', (156, 171))	('carcinomas', 'Disease', (161, 171))	('PBRM1', 'Gene', (59, 64))	('lung carcinomas', 'Disease', (156, 171))	('SMARCA4', 'Gene', '6597', (24, 31))	('SMARCA4', 'Gene', '6597', (118, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
13494	32646614	In undifferentiated carcinomas with a complex genomic landscape and high mutational burden, SWI/SNF inactivation may have different implications than in soft tissue neoplasms, in which SWI/SNF mutations often represent one of very few genomic perturbations and may have essential functions in tumor development/progression.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('SWI/SNF', 'Gene', (185, 192))	('neoplasm', 'Phenotype', 'HP:0002664', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('soft tissue neoplasms', 'Disease', 'MESH:D012983', (153, 174))	('mutations', 'Var', (193, 202))	('tumor', 'Disease', (293, 298))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (3, 30))	('neoplasms', 'Phenotype', 'HP:0002664', (165, 174))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (153, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (20, 30))	('soft tissue neoplasms', 'Disease', (153, 174))	('undifferentiated carcinomas', 'Disease', (3, 30))
13495	32646614	In many cancers, SWI/SNF perturbations do not necessarily represent oncogenic drivers but are rather passenger mutations.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('SWI/SNF', 'Gene', (17, 24))	('cancers', 'Disease', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('perturbations', 'Var', (25, 38))
13500	32646614	The wide range of seemingly unrelated tumor types affected by SWI/SNF mutations, and the spectrum of genomic events targeting distinct subunits, highlight the biologic complexity of the roles of SWI/SNF in cancer.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mutations', 'Var', (70, 79))	('SWI/SNF', 'Gene', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
13502	32646614	Future studies are required to systematically determine the frequencies of SWI/SNF subunit inactivation on the genomic and protein level and to generate insights that help characterize in which biologic context these perturbations foster tumor development and/or progression.	('progression', 'CPA', (263, 274))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('foster', 'PosReg', (231, 237))	('SWI/SNF subunit', 'Gene', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('inactivation', 'Var', (91, 103))
13528	33080033	The following antibodies were used in the current study: anti-KLF15 (Proteintech, 66185-1-Ig), anti-TCF4 (Abcam, ab223073), anti-NKX2-2 (Proteintech, 13013-1-AP), anti-FLI-1 (Santa Cruz Biotechnology, sc-53826), anti-ACLY (Abcam, ab40793), anti-FASN (Abcam, ab22759), anti-ACC (Cell Signaling Technology, 4190S), anti-SPTLC1 (Proteintech, 66899-1-Ig), anti-SCD (Proteintech, 23393-1-AP), anti-Actin (Cell Signaling Technology, 4967), anti-mouse IgG-HRP (Santa Cruz Biotechnology, sc-2005), anti-rabbit IgG-HRP (Santa Cruz Biotechnology, sc-2004) and rabbit IgG Isotype Control (Invitrogen, 02-6102), anti-mTOR (Cell Signaling Technology, 2972S), anti-P-mTOR (S2448) (Cell Signaling Technology, 2971S), anti-P-p38 MAPK (T180/Y182) (Cell Signaling Technology, 9216S), anti-p38 MAPK (Cell Signaling Technology, 8690S), anti-Akt (Cell Signaling Technology 4691S), anti-P-Akt (S473) (Cell Signaling Technology, 4060S), anti-p70 S6 Kinase (Cell Signaling Technology, 9202S) and anti-P-p70 S6 Kinase (Cell Signaling Technology, 9205S).	('p38 MAPK', 'Gene', '26416', (709, 717))	('anti-p70', 'Var', (914, 922))	('Akt', 'Gene', '11651', (867, 870))	('mouse', 'Species', '10090', (439, 444))	('p38 MAPK', 'Gene', '26416', (771, 779))	('Akt', 'Gene', (867, 870))	('Akt', 'Gene', '11651', (821, 824))	('p38 MAPK', 'Gene', (709, 717))	('p38 MAPK', 'Gene', (771, 779))	('AP', 'Gene', '16870', (776, 778))	('AP', 'Gene', '16870', (158, 160))	('Akt', 'Gene', (821, 824))	('anti-P-p70 S6', 'Var', (972, 985))	('AP', 'Gene', '16870', (714, 716))	('AP', 'Gene', '16870', (383, 385))
13556	33080033	Therefore, we focused on A673 cell line, a well-characterized Ewing Sarcoma line which had matched H3K27ac and EWS-FLI1 ChIP-Seq results.	('EWS', 'Gene', '2130', (111, 114))	('EWS', 'Gene', (111, 114))	('FLI1', 'Gene', (115, 119))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (62, 75))	('FLI1', 'Gene', '2313', (115, 119))	('Sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('H3K27ac', 'Var', (99, 106))	('Ewing Sarcoma', 'Disease', (62, 75))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (62, 75))
13578	33080033	Based on these 4 candidates, we next sought to reconstruct functionally the CRC model and to determine their regulatory relationship with EWS-FLI1, by silencing of either EWS-FLI1 or each candidate individually.	('EWS', 'Gene', '2130', (138, 141))	('silencing', 'Var', (151, 160))	('EWS', 'Gene', (138, 141))	('FLI1', 'Gene', '2313', (175, 179))	('FLI1', 'Gene', (142, 146))	('FLI1', 'Gene', '2313', (142, 146))	('EWS', 'Gene', '2130', (171, 174))	('EWS', 'Gene', (171, 174))	('FLI1', 'Gene', (175, 179))
13581	33080033	Within the four CRC candidates, knockdown of either KLF15, NKX2-2 or TCF4 decreased the expression of the other two (Figure 1D), but not RREB1.	('RREB1', 'Gene', (137, 142))	('NKX2-2', 'Gene', (59, 65))	('KLF15', 'Gene', (52, 57))	('TCF4', 'Gene', (69, 73))	('knockdown', 'Var', (32, 41))	('decreased', 'NegReg', (74, 83))	('expression', 'MPA', (88, 98))	('RREB1', 'Gene', '6239', (137, 142))
13583	33080033	Consistent with mRNA expression, silencing EWS-FLI1 decreased protein level of KLF15, NKX2-2 and TCF4 in Ewing sarcoma cell lines (Figure 1E).	('FLI1', 'Gene', '2313', (47, 51))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('decreased protein level', 'Phenotype', 'HP:0003075', (52, 75))	('decreased', 'NegReg', (52, 61))	('TCF4', 'Gene', (97, 101))	('silencing', 'Var', (33, 42))	('Ewing sarcoma', 'Disease', (105, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('EWS', 'Gene', '2130', (43, 46))	('EWS', 'Gene', (43, 46))	('FLI1', 'Gene', (47, 51))	('protein level of KLF15', 'MPA', (62, 84))	('NKX2-2', 'MPA', (86, 92))
13593	33080033	Importantly, ectopic expression of EWS-FLI1 converted these regions to super-enhancers with much higher H3K27ac intensity and chromatin accessibility (top 4 tracks in Figure 2B, Supplementary Figure S2).	('intensity', 'MPA', (112, 121))	('EWS', 'Gene', '2130', (35, 38))	('higher', 'PosReg', (97, 103))	('EWS', 'Gene', (35, 38))	('ectopic expression', 'Var', (13, 31))	('chromatin accessibility', 'MPA', (126, 149))	('FLI1', 'Gene', '2313', (39, 43))	('H3K27ac', 'Protein', (104, 111))	('FLI1', 'Gene', (39, 43))
13594	33080033	On the other hand, in A673 cells, knockdown of EWS-FLI1 drastically decreased H3K27ac signal in EWS-FLI1-occupied super-enhancers (bottom 4 tracks in Figure 2B, Supplementary Figure S2).	('EWS', 'Gene', '2130', (96, 99))	('EWS', 'Gene', (96, 99))	('FLI1', 'Gene', (51, 55))	('decreased', 'NegReg', (68, 77))	('FLI1', 'Gene', '2313', (100, 104))	('FLI1', 'Gene', (100, 104))	('FLI1', 'Gene', '2313', (51, 55))	('knockdown', 'Var', (34, 43))	('H3K27ac', 'Protein', (78, 85))	('EWS', 'Gene', '2130', (47, 50))	('EWS', 'Gene', (47, 50))
13601	33080033	To determine the regulation of these enhancers by their occupying TFs, we silenced each TFs, and knockdown of each factor (Figure 2D) markedly reduced the activity of CE1 and CE2.	('CE2', 'Gene', (175, 178))	('activity', 'MPA', (155, 163))	('knockdown', 'Var', (97, 106))	('CE1', 'Gene', '1066', (167, 170))	('CE1', 'Gene', (167, 170))	('CE2', 'Gene', '8824', (175, 178))	('reduced', 'NegReg', (143, 150))
13610	33080033	Importantly, gene set enrichment analyses (GSEA) showed that genes decreased following silencing of KLF15 were strongly and significantly enriched in those also downregulated upon depletion of either TCF4 or NKX2-2 (Figure 3F).	('silencing', 'Var', (87, 96))	('KLF15', 'Gene', (100, 105))	('downregulated', 'NegReg', (161, 174))	('depletion', 'MPA', (180, 189))	('GSEA', 'Chemical', '-', (43, 47))	('decreased', 'NegReg', (67, 76))
13616	33080033	A previous study showed that NKX2-2 silencing suppressed xenograft growth of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (77, 90))	('NKX2-2', 'Gene', (29, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('silencing', 'Var', (36, 45))	('xenograft growth', 'CPA', (57, 73))	('suppressed', 'NegReg', (46, 56))
13618	33080033	To this end, we generated cell line models in which either KLF15 or TCF4 expression could be silenced by doxycycline (DOX)-inducible shRNA (A673-TetshKLF15 or A673-TetshTCF4) (Supplementary Figure S4B, D).	('KLF15', 'Gene', (59, 64))	('silenced', 'NegReg', (93, 101))	('doxycycline', 'Chemical', 'MESH:D004318', (105, 116))	('expression', 'MPA', (73, 83))	('Tet', 'Chemical', 'MESH:D013752', (164, 167))	('DOX', 'Chemical', 'MESH:D004318', (118, 121))	('Tet', 'Chemical', 'MESH:D013752', (145, 148))	('TCF4', 'Gene', (68, 72))	('A673-TetshTCF4', 'Var', (159, 173))
13621	33080033	Finally, immunoblotting of xenograft tumors again confirmed the co-regulation of CRC TFs, as shown by the downregulation of each CRC member upon silencing of either KLF15 or TCF4 (Figure 4F).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('KLF15', 'Gene', (165, 170))	('TCF4', 'Gene', (174, 178))	('downregulation', 'NegReg', (106, 120))	('silencing', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
13632	33080033	The most abundant fatty acyl chains were oleate (C18:1), palmitate (C16:0), stearate (C18:0), palmitoleic (C16:1), arachidonate (C20:4), docosahexaenoic (C22:6).	('palmitate', 'Chemical', 'MESH:D010168', (57, 66))	('C22', 'Chemical', '-', (154, 157))	('C18:0', 'Var', (86, 91))	('arachidonate', 'Chemical', 'MESH:D016718', (115, 127))	('stearate', 'Chemical', 'MESH:D013228', (76, 84))	('C16:1', 'Var', (107, 112))	('C20:4', 'Var', (129, 134))	('docosahexaenoic', 'Chemical', '-', (137, 152))	('C18:1', 'Var', (49, 54))	('palmitoleic', 'Chemical', '-', (94, 105))	('oleate', 'Chemical', 'MESH:D019301', (41, 47))
13633	33080033	In agreement with the pathway enrichment analysis, silencing of each TF caused appreciable changes in the lipid landscape of A673 cells (Figure 5C-E).	('lipid', 'Chemical', 'MESH:D008055', (106, 111))	('changes', 'Reg', (91, 98))	('silencing', 'Var', (51, 60))	('lipid landscape', 'MPA', (106, 121))
13639	33080033	We next examined in detail how lipid metabolism was perturbed by silencing of CRC TFs via integration of RNA-Seq, ChIP-Seq and lipidomic results.	('silencing', 'Var', (65, 74))	('lipid', 'Chemical', 'MESH:D008055', (127, 132))	('lipid', 'Chemical', 'MESH:D008055', (31, 36))	('lipid metabolism', 'MPA', (31, 47))	('perturbed', 'Reg', (52, 61))	('CRC TFs', 'Gene', (78, 85))
13647	33080033	Verifying our RNA-Seq results, qRT-PCR showed knockdown of each single TF reduced the expression of these central enzymes (Figure 6A).	('expression', 'MPA', (86, 96))	('reduced', 'NegReg', (74, 81))	('PC', 'Chemical', 'MESH:D010713', (35, 37))	('knockdown', 'Var', (46, 55))
13648	33080033	In addition, silencing of TCF4 (but not KLF15 or NKX2-2) also reduced the expression of ACC, another key enzyme in fatty-acid synthesis.	('expression', 'MPA', (74, 84))	('reduced', 'NegReg', (62, 69))	('fatty-acid', 'Chemical', 'MESH:D005227', (115, 125))	('ACC', 'Gene', (88, 91))	('TCF4', 'Gene', (26, 30))	('silencing', 'Var', (13, 22))
13654	33080033	Importantly, silencing of SPTLC1 reduced both colony growth and cell proliferation of Ewing sarcoma cells (Figure 6J-L).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 99))	('cell proliferation', 'CPA', (64, 82))	('colony growth', 'CPA', (46, 59))	('Ewing sarcoma', 'Disease', (86, 99))	('reduced', 'NegReg', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('SPTLC1', 'Gene', (26, 32))	('silencing', 'Var', (13, 22))
13658	33080033	Specifically, 32/84 (38%) genes in PI3K/AKT signaling and 23/72 (32%) genes in MAPK signaling were decreased in at least two out of three knockdown groups (Figure 7B), supportive of the notion that CRC factors cooperatively regulate these pathways.	('AP', 'Gene', '16870', (80, 82))	('knockdown', 'Var', (138, 147))	('decreased', 'NegReg', (99, 108))	('AKT', 'Gene', '207', (40, 43))	('AKT', 'Gene', (40, 43))
13660	33080033	Indeed, silencing of either KLF15, TCF4 or NKX2-2 inhibited the expression of these key molecules as validated by qRT-PCR (Figure 7D).	('expression', 'MPA', (64, 74))	('silencing', 'Var', (8, 17))	('PC', 'Chemical', 'MESH:D010713', (118, 120))	('TCF4', 'Gene', (35, 39))	('NKX2-2', 'Gene', (43, 49))	('inhibited', 'NegReg', (50, 59))	('KLF15', 'Gene', (28, 33))
13673	33080033	Indeed, GSEA of RNA-Seq data confirms that downregulated genes upon knockdown of each TF strongly and significantly overlapped with each other.	('downregulated', 'NegReg', (43, 56))	('knockdown', 'Var', (68, 77))	('GSEA', 'Chemical', '-', (8, 12))
13690	33080033	In addition, silencing of either FASN, SCD or SPTLC1 markedly reduced cell proliferation of Ewing sarcoma, further corroborating this conclusion.	('silencing', 'Var', (13, 22))	('cell proliferation', 'CPA', (70, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('reduced', 'NegReg', (62, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('FASN', 'Gene', (33, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('SPTLC1', 'Gene', (46, 52))	('Ewing sarcoma', 'Disease', (92, 105))
13695	33080033	While TCF4 and NKX2-2 have not been involved in these pathways in any cell type, KLF15 is intriguingly reported to inhibit the AKT and MAPK signaling pathways in normal skeletal muscle, cardiomyocytes and kidney.	('inhibit', 'NegReg', (115, 122))	('AP', 'Gene', '16870', (136, 138))	('AKT', 'Gene', '207', (127, 130))	('KLF15', 'Var', (81, 86))	('AKT', 'Gene', (127, 130))
13701	33080033	]; Singapore Ministry of Health's National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute of Singapore; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives; NIH [1R01 CA200992 to H.P.K.	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('NIH [1R01 CA200992', 'Var', (289, 307))	('Cancer', 'Disease', (125, 131))
13702	33080033	]; De-Chen Lin is supported by the Translational Oncology Program Developmental Fund from Cedars-Sinai Cancer; National Natural Science Foundation of China (NSFC) [81670154/H0812, 81470355/H1616 to X.S.	('Cedars-Sinai Cancer', 'Disease', 'MESH:D009369', (90, 109))	('Cedars-Sinai Cancer', 'Disease', (90, 109))	('[81670154/H0812', 'Var', (163, 178))	('81470355/H1616', 'Var', (180, 194))	('Oncology', 'Phenotype', 'HP:0002664', (49, 57))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))
13707	25503558	Here, we report that after systemic injection of tamoxifen, the vast majority of Pax7-expressing cells remain quiescent despite mutation of p53 and Kras.	('quiescent', 'MPA', (110, 119))	('Pax7', 'Gene', (81, 85))	('Pax7', 'Gene', '18509', (81, 85))	('mutation', 'Var', (128, 136))	('Kras', 'Gene', (148, 152))	('p53', 'Gene', (140, 143))	('tamoxifen', 'Chemical', 'MESH:D013629', (49, 58))
13710	25503558	We show that modulating satellite cell quiescence via intramuscular (IM) injection of HGF increases the penetrance of sarcoma formation at the site of injection, which is dependent on its cognate receptor c-MET.	('sarcoma', 'Disease', (118, 125))	('increases', 'PosReg', (90, 99))	('HGF', 'Gene', (86, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('penetrance', 'MPA', (104, 114))	('modulating', 'Var', (13, 23))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
13714	25503558	To study sarcoma development, we utilized Pax7CreER/+; KrasLSL-G12D/+; Trp53flox/flox (P7KP) mice because mutations in the Ras and p53 pathways have been reported in human soft tissue sarcoma.	('Trp53', 'Gene', '22059', (71, 76))	('mice', 'Species', '10090', (93, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Trp53', 'Gene', (71, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('reported', 'Reg', (154, 162))	('human', 'Species', '9606', (166, 171))	('Pax7', 'Gene', '18509', (42, 46))	('G12D', 'Mutation', 'rs121913529', (63, 67))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (172, 191))	('p53 pathways', 'Pathway', (131, 143))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (172, 191))	('sarcoma', 'Disease', 'MESH:D012509', (184, 191))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('soft tissue sarcoma', 'Disease', (172, 191))	('Pax7', 'Gene', (42, 46))	('sarcoma', 'Disease', (184, 191))	('sarcoma', 'Disease', (9, 16))	('mutations', 'Var', (106, 115))
13715	25503558	Following systemic administration of tamoxifen by intraperitoneal (IP) injection, P7KP mice develop sarcomas throughout the animal in 6-8 weeks.	('P7KP', 'Var', (82, 86))	('tamoxifen', 'Chemical', 'MESH:D013629', (37, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Disease', (100, 108))	('mice', 'Species', '10090', (87, 91))	('rat', 'Species', '10116', (27, 30))	('develop', 'PosReg', (92, 99))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
13717	25503558	Similar to other reports, the histology of the sarcomas in P7KP mice exist along a continuum of undifferentiated pleomorphic sarcoma (UPS), myogenic UPS, and embryonal rhabdomyosarcoma.	('UPS', 'Disease', (134, 137))	('UPS', 'Disease', 'MESH:D017118', (134, 137))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (96, 132))	('sarcomas', 'Disease', (47, 55))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (158, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('undifferentiated pleomorphic sarcoma', 'Disease', (96, 132))	('P7KP', 'Var', (59, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('embryonal rhabdomyosarcoma', 'Disease', (158, 184))	('myogenic UPS', 'Disease', 'MESH:D017118', (140, 152))	('mice', 'Species', '10090', (64, 68))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (168, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('UPS', 'Disease', (149, 152))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (158, 184))	('myogenic UPS', 'Disease', (140, 152))	('UPS', 'Disease', 'MESH:D017118', (149, 152))
13722	25503558	Our experiments demonstrate that the fate of Pax7+ cells harboring oncogenic mutations is altered in the setting of muscle injury in a process dependent on HGF/c-MET signaling.	('muscle injury', 'Disease', (116, 129))	('altered', 'Reg', (90, 97))	('rat', 'Species', '10116', (23, 26))	('Pax7', 'Gene', '18509', (45, 49))	('mutations', 'Var', (77, 86))	('muscle injury', 'Disease', 'MESH:D009135', (116, 129))	('Pax7', 'Gene', (45, 49))
13749	25503558	The details of the PCR protocol for detection of recombined and wild type c-Met were kindly provided by Dr. Thorgeirsson.	('recombined', 'Var', (49, 59))	('c-Met', 'Gene', '17295', (74, 79))	('c-Met', 'Gene', (74, 79))
13752	25503558	Primers Met-1 and Met-3 yield a PCR product corresponding to the deleted allele (650 bp).	('Met-1', 'Gene', (8, 13))	('Met-1', 'Gene', '13433', (8, 13))	('650 bp', 'Var', (81, 87))
13765	25503558	Remarkably, 100% of P7KP mice treated with IP tamoxifen and IM DMSO developed a palpable tumor at the IM injection site in a median of 22 days (range 14-29 days) (Figure 2B), similar to the kinetics seen with 4OHT alone (Figure 2A).	('mice', 'Species', '10090', (25, 29))	('P7KP', 'Var', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('DMSO', 'Chemical', 'MESH:D004121', (63, 67))	('tamoxifen', 'Chemical', 'MESH:D013629', (46, 55))	('tumor', 'Disease', (89, 94))
13766	25503558	In P7KP mice treated with IP tamoxifen and IM saline, 50% of mice developed an injection site sarcoma, but the time to tumor was significantly longer (median 41 days, range 40-48 days) (Figure 2B).	('tumor', 'Disease', (119, 124))	('P7KP', 'Var', (3, 7))	('mice', 'Species', '10090', (61, 65))	('tamoxifen', 'Chemical', 'MESH:D013629', (29, 38))	('sarcoma', 'Disease', (94, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('longer', 'PosReg', (143, 149))	('saline', 'Chemical', 'MESH:D012965', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('mice', 'Species', '10090', (8, 12))
13767	25503558	These results reveal that that DMSO accelerates sarcoma formation in P7KP mice.	('accelerates', 'PosReg', (36, 47))	('sarcoma', 'Disease', (48, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('DMSO', 'Var', (31, 35))	('DMSO', 'Chemical', 'MESH:D004121', (31, 35))	('mice', 'Species', '10090', (74, 78))	('rat', 'Species', '10116', (42, 45))	('sarcoma', 'Disease', 'MESH:D012509', (48, 55))
13790	25503558	We counted 400 - 600 satellite cells per mouse and determined the percentage that were EdU+ (Pax7, EdU double positive) as a measure of satellite cell activation.	('EdU+', 'Var', (87, 91))	('Pax7', 'Gene', (93, 97))	('EdU', 'Chemical', 'MESH:C031086', (99, 102))	('mouse', 'Species', '10090', (41, 46))	('Pax7', 'Gene', '18509', (93, 97))	('EdU', 'Chemical', 'MESH:C031086', (87, 90))
13791	25503558	Interestingly, the vast majority of Pax7+ cells were not proliferating in mice treated with IM saline despite deletion of p53 and activation of Kras in Pax7-expressing cells throughout the animal (Figure 4A).	('saline', 'Chemical', 'MESH:D012965', (95, 101))	('Pax7', 'Gene', '18509', (152, 156))	('Pax7', 'Gene', '18509', (36, 40))	('Pax7', 'Gene', (152, 156))	('activation', 'PosReg', (130, 140))	('Kras', 'Gene', (144, 148))	('Pax7', 'Gene', (36, 40))	('rat', 'Species', '10116', (64, 67))	('mice', 'Species', '10090', (74, 78))	('deletion', 'Var', (110, 118))	('p53', 'Gene', (122, 125))
13800	25503558	Of note, the sarcomas arising in HGF-treated mice occur with a median onset of 37 days, which is slower than sarcomas that arise following treatment with cardiotoxin (Figure 4D).	('sarcomas', 'Disease', (13, 21))	('mice', 'Species', '10090', (45, 49))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('HGF-treated', 'Var', (33, 44))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('sarcomas', 'Disease', (109, 117))
13802	25503558	We crossed P7KP mice to c-Metflox/flox mice to cause c-Met deletion by Cre in satellite cells upon tamoxifen treatment.	('c-Met', 'Gene', (24, 29))	('tamoxifen', 'Chemical', 'MESH:D013629', (99, 108))	('c-Met', 'Gene', '17295', (24, 29))	('c-Met', 'Gene', (53, 58))	('deletion', 'Var', (59, 67))	('mice', 'Species', '10090', (16, 20))	('mice', 'Species', '10090', (39, 43))	('c-Met', 'Gene', '17295', (53, 58))
13804	25503558	We observed that P7KP mice with homozygous c-Met deletion no longer had an increased penetrance of tumor formation at the IM HGF injection site as compared to P7KP mice with only one copy of c-Met deleted (Figure 4G).	('tumor', 'Disease', (99, 104))	('c-Met', 'Gene', '17295', (191, 196))	('c-Met', 'Gene', '17295', (43, 48))	('mice', 'Species', '10090', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('c-Met', 'Gene', (43, 48))	('c-Met', 'Gene', (191, 196))	('deletion', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mice', 'Species', '10090', (22, 26))
13805	25503558	Of note, P7KP; c-Metflox/flox mice could not be followed beyond 2-3 months because they developed sarcomas at other sites.	('c-Met', 'Gene', '17295', (15, 20))	('mice', 'Species', '10090', (30, 34))	('sarcomas', 'Disease', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('c-Met', 'Gene', (15, 20))	('P7KP', 'Var', (9, 13))	('sarcomas', 'Disease', 'MESH:D012509', (98, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('developed', 'Reg', (88, 97))
13809	25503558	In P7Y mice injected with IP tamoxifen and IM cardiotoxin and euthanized 3 days after, the number of P-MET+ cells within the YFP+ population was 40-fold higher than in uninjured muscle (Figure 5B).	('P-MET+ cells', 'Var', (101, 113))	('tamoxifen', 'Chemical', 'MESH:D013629', (29, 38))	('higher', 'PosReg', (153, 159))	('mice', 'Species', '10090', (7, 11))
13818	25503558	Notably, sarcomas arising in P7KP; c-Metflox/flox mice had full recombination at both c-Met loci, confirming that sarcomas arise despite the deletion of c-Met (Figure 6D).	('deletion', 'Var', (141, 149))	('c-Met', 'Gene', (86, 91))	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('c-Met', 'Gene', (35, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('c-Met', 'Gene', '17295', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('sarcomas', 'Disease', (114, 122))	('c-Met', 'Gene', (153, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('c-Met', 'Gene', '17295', (35, 40))	('mice', 'Species', '10090', (50, 54))	('sarcomas', 'Disease', (9, 17))	('c-Met', 'Gene', '17295', (153, 158))
13821	25503558	The P7KP mouse model of STS is a unique system to study the role of injury in tumorigenesis because it provides tight control of the timing of both genetic mutation (IP injection of tamoxifen) and injury (IM injection of cardiotoxin) prior to tumor formation.	('genetic mutation', 'Var', (148, 164))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mouse', 'Species', '10090', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tamoxifen', 'Chemical', 'MESH:D013629', (182, 191))	('tumor', 'Disease', (78, 83))	('STS', 'Phenotype', 'HP:0030448', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
13830	25503558	Attempts to generate urothelial tumors in a mouse model containing inducible activation of Kras and loss of p53 resulted in STS at the suture site, though this was reported as an incidental finding as the intent was to generate a genitourinary tumor.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('loss', 'Var', (100, 104))	('p53', 'Gene', (108, 111))	('genitourinary tumor', 'Disease', 'MESH:D014565', (230, 249))	('rat', 'Species', '10116', (16, 19))	('Kras', 'Gene', (91, 95))	('activation', 'PosReg', (77, 87))	('urothelial tumors', 'Disease', 'MESH:D001749', (21, 38))	('STS', 'Phenotype', 'HP:0030448', (124, 127))	('genitourinary tumor', 'Phenotype', 'HP:0007379', (230, 249))	('rat', 'Species', '10116', (223, 226))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('urothelial tumors', 'Disease', (21, 38))	('genitourinary tumor', 'Disease', (230, 249))	('mouse', 'Species', '10090', (44, 49))
13834	25503558	HGF is also able to break quiescence of satellite cells harboring p53 and Kras mutations and promote sarcoma formation (Figure 4A-D and Supplementary Fig.	('Kras', 'Gene', (74, 78))	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('p53', 'Gene', (66, 69))	('sarcoma', 'Disease', (101, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('break', 'NegReg', (20, 25))	('quiescence', 'MPA', (26, 36))	('promote', 'PosReg', (93, 100))	('mutations', 'Var', (79, 88))
13837	25503558	For example, Allen and colleagues demonstrated that cultured rat satellite cells were activated after HGF treatment in a dose-dependent manner.	('HGF', 'Gene', (102, 105))	('treatment', 'Var', (106, 115))	('rat', 'Species', '10116', (61, 64))	('rat', 'Species', '10116', (41, 44))	('activated', 'PosReg', (86, 95))
13838	25503558	Subsequent studies by Tatsumi and colleagues observed that rats treated with HGF had increased satellite cell proliferation, confirming that this effect was relevant in vivo.	('HGF', 'Var', (77, 80))	('rat', 'Species', '10116', (117, 120))	('satellite cell proliferation', 'CPA', (95, 123))	('rats', 'Species', '10116', (59, 63))	('increased', 'PosReg', (85, 94))	('rat', 'Species', '10116', (59, 62))
13839	25503558	Likewise, deletion of the c-MET receptor in Pax7+ cells results in a significant decrease in the recruitment of proliferating satellite cells to the site of cardiotoxin injury.	('c-MET receptor', 'Protein', (26, 40))	('recruitment of', 'MPA', (97, 111))	('decrease', 'NegReg', (81, 89))	('Pax7', 'Gene', '18509', (44, 48))	('rat', 'Species', '10116', (119, 122))	('Pax7', 'Gene', (44, 48))	('deletion', 'Var', (10, 18))	('cardiotoxin injury', 'Disease', 'MESH:D058186', (157, 175))	('cardiotoxin injury', 'Disease', (157, 175))
13849	25503558	Our finding that 21 days can pass between recombination of p53 and Kras and injury by cardiotoxin suggests that satellite cells can harbor oncogenic mutations without progression to sarcoma formation.	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('mutations', 'Var', (149, 158))	('Kras and injury by cardiotoxin', 'Disease', 'MESH:D058186', (67, 97))	('sarcoma', 'Disease', 'MESH:D012509', (182, 189))	('sarcoma', 'Disease', (182, 189))
13850	25503558	The rarity of sarcomas in humans might be partially explained by the requirement for this additional "activation" step, whereby quiescence prevents cells that harbor oncogenic mutations from forming sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (14, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (199, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('mutations', 'Var', (176, 185))	('prevents', 'NegReg', (139, 147))	('quiescence', 'MPA', (128, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (14, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('humans', 'Species', '9606', (26, 32))	('sarcomas', 'Disease', (199, 207))	('sarcomas', 'Disease', (14, 22))	('sarcomas', 'Disease', 'MESH:D012509', (199, 207))
13865	24822132	He had complex cytogenetics (45,XY,der(5)t(5; 7)(q31; q22), add (11)(p15), add (12)(p13), del (17)(p11.2),-22[17]/46,XY[3]) and positive fluorescence in situ hybridization (FISH) for 5q, 7q, and 11q23.	('del (17)(p11.2', 'Var', (90, 104))	('der(5)t(', 'Var', (35, 43))	('add (11)(p15', 'Var', (60, 72))	('45,XY,der(5)', 'STRUCTURAL_ABNORMALITY', 'None', (29, 41))	('45', 'Var', (29, 31))	('add (12)(p13', 'Var', (75, 87))
13883	24822132	Biopsy analysis by short tandem repeats (STR) of the granulocytic sarcoma revealed that 41.2% of the cells where donor in origin.	('short tandem repeats', 'Var', (19, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('granulocytic sarcoma', 'Disease', 'MESH:D023981', (53, 73))	('donor', 'Species', '9606', (113, 118))	('granulocytic sarcoma', 'Disease', (53, 73))
13904	24822132	Limitations for XY-FISH may occur with gains and loss of sex chromosomes that can be seen in patients with leukemia.	('loss', 'NegReg', (49, 53))	('sex', 'Protein', (57, 60))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('leukemia', 'Disease', (107, 115))	('patients', 'Species', '9606', (93, 101))	('gains', 'Var', (39, 44))
13950	33332599	For example, the HR 1-year postoperative for a patient with R0 margin compared to an R1-2 margin is equal to  where tp = 1 and tp 2 = 1.	('R0 margin', 'Var', (60, 69))	('R1-2', 'Gene', '2840;910;913', (85, 89))	('patient', 'Species', '9606', (47, 54))	('R1-2', 'Gene', (85, 89))
14012	32190320	The inadequate margins (R1 or R2) in 4 cases led to recurrence and DOD status in 2 and 1 cases, respectively.	('R1', 'Var', (24, 26))	('DOD', 'Disease', (67, 70))	('DOD', 'Disease', 'MESH:D001926', (67, 70))	('recurrence', 'CPA', (52, 62))
14032	32190320	Previous findings have shown that older age, large tumor size, high grade, lack of neoadjuvant chemotherapy, and positive surgical margin adversely influence prognosis.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('high grade', 'Var', (63, 73))	('influence', 'Reg', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
14035	32190320	Patients with high-grade sarcomas also had poorer 5-year survival rates than those with low-grade tumors.	('5-year survival rates', 'CPA', (50, 71))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('high-grade', 'Var', (14, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Patients', 'Species', '9606', (0, 8))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('poorer', 'NegReg', (43, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))
14044	31078563	We present herein four new cases of small round cell tumor of the bone that harbor NFATc2 rearrangements involving either EWSR1 or FUS genes.	('FUS', 'Gene', '2521', (131, 134))	('EWSR1', 'Gene', '2130', (122, 127))	('NFATc2', 'Gene', (83, 89))	('FUS', 'Gene', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('rearrangements', 'Var', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('EWSR1', 'Gene', (122, 127))	('tumor of the bone', 'Phenotype', 'HP:0010622', (53, 70))	('NFATc2', 'Gene', '4773', (83, 89))
14059	31078563	To date, the information known about NFATc2 rearranged bone tumors is limited to mainly single case reports and sporadic descriptions within Ewing family series of tumors many of them without clinicopathological information.	('NFATc2', 'Gene', '4773', (37, 43))	('tumors', 'Disease', (164, 170))	('rearranged', 'Var', (44, 54))	('bone tumors', 'Disease', (55, 66))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('bone tumors', 'Disease', 'MESH:D001859', (55, 66))	('NFATc2', 'Gene', (37, 43))	('bone tumors', 'Phenotype', 'HP:0010622', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Disease', (60, 66))
14060	31078563	Herein we describe the clinicopathological features of four new cases of malignant small round cell sarcoma of bone that harbor EWSR1/ FUS-NFATc2 translocation gene fusions.	('sarcoma', 'Disease', (100, 107))	('FUS', 'Gene', (135, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('NFATc2', 'Gene', (139, 145))	('FUS', 'Gene', '2521', (135, 138))	('translocation', 'Var', (146, 159))	('EWSR1', 'Gene', (128, 133))	('NFATc2', 'Gene', '4773', (139, 145))	('EWSR1', 'Gene', '2130', (128, 133))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))
14064	31078563	The EWSR1-NFATc2 fusion was investigated by a dual-color FISH assay on interphase nuclei from paraffin-embedded 4-mum-thick sections with Spectrum Green-labeled BAC clones RP11-367E7 and RP11-480L23 corresponding to the EWSR1-5 region and Spectrum Red-labeled BAC clones RP11-2L23 and RP11-73P15 corresponding to the NFATC2-3' region (Empire Genomics, Buffalo, NY).	('RP11-480L23', 'Var', (187, 198))	('EWSR1', 'Gene', '2130', (4, 9))	('EWSR1', 'Gene', (220, 225))	('NFATc2', 'Gene', (10, 16))	('NFATC2', 'Gene', (317, 323))	('Spectrum Green', 'Chemical', '-', (138, 152))	('EWSR1', 'Gene', '2130', (220, 225))	('paraffin', 'Chemical', 'MESH:D010232', (94, 102))	('NFATc2', 'Gene', '4773', (10, 16))	('Spectrum Red', 'Chemical', '-', (239, 251))	('RP11-73P15', 'Var', (285, 295))	('EWSR1', 'Gene', (4, 9))	('NFATC2', 'Gene', '4773', (317, 323))	('RP11-367E7', 'Var', (172, 182))	('RP11-2L23', 'Var', (271, 280))
14089	31078563	All three cases were also confirmed to have an NFATc2 break-apart rearrangement.	('break-apart', 'Var', (54, 65))	('NFATc2', 'Gene', '4773', (47, 53))	('NFATc2', 'Gene', (47, 53))
14091	31078563	The case harboring an FUS-NFATc2 fusion showed a polyploidy signal below the level of amplification, while the remaining EWSR1-NFATc2 case showed no copy gains.	('NFATc2', 'Gene', (127, 133))	('NFATc2', 'Gene', '4773', (26, 32))	('polyploidy', 'Disease', (49, 59))	('EWSR1', 'Gene', (121, 126))	('FUS', 'Gene', (22, 25))	('FUS', 'Gene', '2521', (22, 25))	('polyploidy', 'Disease', 'MESH:D011123', (49, 59))	('EWSR1', 'Gene', '2130', (121, 126))	('NFATc2', 'Gene', (26, 32))	('NFATc2', 'Gene', '4773', (127, 133))	('fusion', 'Var', (33, 39))
14092	31078563	Targeting RNA sequencing identified EWSR1-NFATc2 fusion in two cases and FUS-NFATc2 fusion gene in one case.	('EWSR1', 'Gene', '2130', (36, 41))	('FUS', 'Gene', '2521', (73, 76))	('NFATc2', 'Gene', '4773', (77, 83))	('NFATc2', 'Gene', (42, 48))	('FUS', 'Gene', (73, 76))	('NFATc2', 'Gene', '4773', (42, 48))	('NFATc2', 'Gene', (77, 83))	('fusion', 'Var', (49, 55))	('EWSR1', 'Gene', (36, 41))
14100	31078563	The flag bearer of this group of tumors is Ewing sarcoma which harbors rearrangement of EWSR1; however, this genetic abnormality is also present in other tumor types including Ewing-like sarcoma defined by EWSR1 fusions with non-TET/ETS gene partners, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, clear cell sarcoma, and desmoplastic small round cell tumor, amongst others.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('tumor', 'Disease', (368, 373))	('EWSR1', 'Gene', (206, 211))	('genetic abnormality', 'Disease', (109, 128))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (298, 312))	('fusions', 'Var', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('sarcoma', 'Phenotype', 'HP:0100242', (325, 332))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Disease', (154, 159))	('EWSR1', 'Gene', '2130', (88, 93))	('Ewing sarcoma', 'Disease', (43, 56))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (252, 275))	('clear cell sarcoma', 'Disease', (314, 332))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('myoepithelial carcinoma', 'Disease', (252, 275))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Ewing-like sarcoma', 'Disease', (176, 194))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (291, 312))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (176, 194))	('extraskeletal', 'Disease', (277, 290))	('EWSR1', 'Gene', '2130', (206, 211))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (176, 194))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (338, 373))	('desmoplastic small round cell tumor', 'Disease', (338, 373))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('EWSR1', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))	('rearrangement', 'Var', (71, 84))	('myxoid chondrosarcoma', 'Disease', (291, 312))	('genetic abnormality', 'Disease', 'MESH:D030342', (109, 128))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (314, 332))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (33, 39))
14104	31078563	The EWSR1-NFATc2 fusion that corresponds to t(20;22) (q13.2;q12.2) results in a truncated NFATc2 protein with loss of the first 2 exons, which encode the regulatory region.	('loss', 'NegReg', (110, 114))	('EWSR1', 'Gene', '2130', (4, 9))	('NFATc2', 'Gene', (90, 96))	('NFATc2', 'Gene', (10, 16))	('fusion', 'Var', (17, 23))	('NFATc2', 'Gene', '4773', (10, 16))	('protein', 'Protein', (97, 104))	('truncated', 'MPA', (80, 89))	('NFATc2', 'Gene', '4773', (90, 96))	('EWSR1', 'Gene', (4, 9))
14113	31078563	Subsequently, investigators have postulated that round cell tumors with this gene fusion should constitute a distinct clinicopathological entity.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('gene fusion', 'Var', (77, 88))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
14123	31078563	Originally, some hypothesized it may be a type of myoepithelial carcinoma because of the morphology, rearrangement of EWSR1, and expression of epithelial markers - cytokeratin or EMA expression have been documented in 14 of 24 cases tested (58.3%) (Cases 7, 8, 13, 30, 32, 33, 34, 36, 40-45); however, this classification has not been confirmed or excluded.	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (50, 73))	('myoepithelial carcinoma', 'Disease', (50, 73))	('EWSR1', 'Gene', (118, 123))	('rearrangement', 'Var', (101, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('EWSR1', 'Gene', '2130', (118, 123))
14129	31078563	All additional genetic lesions we report in our cases are felt to be secondary to the EWSR1/FUS-NFATc2 rearrangement and likely represent genetic instability in these tumors.	('EWSR1', 'Gene', (86, 91))	('NFATc2', 'Gene', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('FUS', 'Gene', (92, 95))	('rearrangement', 'Var', (103, 116))	('FUS', 'Gene', '2521', (92, 95))	('EWSR1', 'Gene', '2130', (86, 91))	('NFATc2', 'Gene', '4773', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
14133	31078563	Regarding the candidate FOXO1-NKAIN2 fusion, NKAIN2 is a poorly characterized candidate tumor suppressor gene; fusions and translocations that have been previously reported for this protein are typically either inactivating or out-of-frame.	('NKAIN2', 'Gene', (30, 36))	('inactivating', 'NegReg', (211, 223))	('fusions', 'Var', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('NKAIN2', 'Gene', (45, 51))	('NKAIN2', 'Gene', '154215', (45, 51))	('FOXO1', 'Gene', '2308', (24, 29))	('FOXO1', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('out-of-frame', 'NegReg', (227, 239))	('translocations', 'Var', (123, 137))	('tumor', 'Disease', (88, 93))	('NKAIN2', 'Gene', '154215', (30, 36))
14134	31078563	FOXO1 fusions to PAX3 or PAX7 include the FOXO1 C-terminal transcriptional activation domain (TAD), aberrantly activating PAX3/7 targets.	('FOXO1', 'Gene', (0, 5))	('FOXO1', 'Gene', '2308', (0, 5))	('PAX3', 'Gene', (17, 21))	('PAX7', 'Gene', (25, 29))	('PAX3', 'Gene', '5077', (122, 126))	('FOXO1', 'Gene', (42, 47))	('activating', 'PosReg', (111, 121))	('PAX3', 'Gene', (122, 126))	('PAX3', 'Gene', '5077', (17, 21))	('FOXO1', 'Gene', '2308', (42, 47))	('PAX7', 'Gene', '5081', (25, 29))	('fusions', 'Var', (6, 13))
14135	31078563	Given the lack of the FOXO1 TAD in this N-terminal FOXO1 fusion, it is difficult to imagine a similar function for this fusion, and we therefore speculate that this is a passenger aberration.	('FOXO1', 'Gene', (22, 27))	('FOXO1', 'Gene', '2308', (22, 27))	('FOXO1', 'Gene', (51, 56))	('FOXO1', 'Gene', '2308', (51, 56))	('fusion', 'Var', (57, 63))
14227	29744030	Knocking down of PD-L1 in both tumors spontaneously resulted in tumor growth in their models, whereas therapeutic PD-L1 blockade augmented anti-tumor T cell responses and further extended survival, suggesting that PD-L1 expression by both the tumor and host plays distinct, partial roles in regulating anti-tumor immunity.	('PD-L1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (307, 312))	('PD-L1', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('survival', 'CPA', (188, 196))	('tumors', 'Disease', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('resulted in', 'Reg', (52, 63))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('blockade', 'Var', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('extended', 'PosReg', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (64, 69))	('Knocking down', 'Var', (0, 13))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('augmented', 'PosReg', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
14234	29744030	PD-L1 knockout by CRISPR-Cas9 technology in both cell types rendered tumors slower growth than their WT counterpart cells.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('PD-L1', 'Gene', (0, 5))	('slower', 'NegReg', (76, 82))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('knockout', 'Var', (6, 14))
14235	29744030	Moreover, PD-1 or PD-L1 blockade with therapeutical antibodies still effectively eradiated the outgrowing tumors, which suggests an additional role for PD-L1 on host-derived immune cells within the tumor microenvironment.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('eradiated', 'NegReg', (81, 90))	('tumors', 'Disease', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('PD-1', 'Gene', (10, 14))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('blockade', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (198, 203))	('PD-L1', 'Gene', (18, 23))	('tumor', 'Disease', (106, 111))
14246	29744030	Using real-time imaging in whole tumor tissues, they observed that anti-PD-L1 antibody accumulated in tumor tissues, regardless of the status of PD-L1 expression on tumor cells.	('accumulated', 'PosReg', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('anti-PD-L1', 'Var', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (165, 170))
14248	29744030	In particular, via CD11b-DTR/PD-L1-/- mixed bone marrow chimera mice model, they elegantly demonstrated that blocking PD-L1 on CD11b+ myeloid cells is indispensable for effective antitumor immunity in PD-L1 blockade therapy.	('blocking', 'Var', (109, 117))	('DTR', 'Gene', (25, 28))	('PD-L1', 'Gene', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('DTR', 'Gene', '15200', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('mice', 'Species', '10090', (64, 68))
14251	29744030	While WT mice bearing various tumors had effective response to PD-L1 blockade, anti-PD-L1 treatment had no antitumor effect in NSG and Rag1-/- mice.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (111, 116))	('NSG', 'Disease', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Rag1', 'Gene', '19373', (135, 139))	('mice', 'Species', '10090', (9, 13))	('anti-PD-L1', 'Var', (79, 89))	('tumor', 'Disease', (30, 35))	('Rag1', 'Gene', (135, 139))	('mice', 'Species', '10090', (143, 147))
14255	29744030	Additionally, they observed a well correlation between expression of PD-L1 on dendritic cells (DCs)/macrophages and the efficacy of treatments with either anti-PD-1 alone or in combination with anti-CTLA-4 in ovarian cancer and melanoma patients.	('ovarian cancer', 'Disease', 'MESH:D010051', (209, 223))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('CTLA-4', 'Gene', '1493', (199, 205))	('anti-PD-1', 'Var', (155, 164))	('melanoma', 'Disease', (228, 236))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('ovarian cancer', 'Disease', (209, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (209, 223))	('patients', 'Species', '9606', (237, 245))	('CTLA-4', 'Gene', (199, 205))	('PD-L1', 'Gene', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
14258	29744030	All the studies employed gene silencing technologies to knock out of PD-L1 in tumors, and these tumors were inoculated to WT immune competent hosts to test the roles of PD-L1 in tumor immune escape (Fig.	('tumors', 'Disease', (78, 84))	('tumor', 'Disease', (178, 183))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('knock out', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('PD-L1 in tumors', 'Disease', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('PD-L1 in tumors', 'Disease', 'MESH:D010300', (69, 84))
14265	29744030	demonstrated the critical role of host-derived PD-L1 by treating the host with anti-PD-L1 antibody, which resulted in significant tumor regression.	('anti-PD-L1', 'Var', (79, 89))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))
14267	29744030	demonstrated evidence of PD-L1 on MC38 cells in inhibiting CD8+ T cell cytotoxicity and suppressing antitumor immunity in their model, Tang et al.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('suppressing', 'NegReg', (88, 99))	('cytotoxicity', 'Disease', (71, 83))	('inhibiting', 'NegReg', (48, 58))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))	('PD-L1', 'Var', (25, 30))
14270	29744030	observed that when WT mice were challenged with increasing numbers of T3DeltaPDL1 tumor cells, the number of mice with progressively growing tumors increased.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('T3DeltaPDL1', 'Var', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mice', 'Species', '10090', (109, 113))	('tumor', 'Disease', (82, 87))	('mice', 'Species', '10090', (22, 26))
14287	29744030	Since simultaneous deletion of PD-L1 from both tumor and host compartments led to most profound frequency of tumor regressions, this unique work from Lau et al.	('deletion', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('PD-L1', 'Gene', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (109, 114))
14294	29744030	showed that PD-L1 on MC38 tumor cells is sufficient to directly suppress activated tumor-infiltrated antigen-specific CD8+ cytotoxic T lymphocytes (CTLs), and is dominant in suppression of antitumor immunity in their mouse model.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mouse', 'Species', '10090', (217, 222))	('PD-L1', 'Var', (12, 17))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('suppress', 'NegReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
14296	29744030	Their work extends the mechanisms of action of PD-1/PD-L1 blockade therapy into the tumor microenvironment, and largely supports the concept that PD-L1 acts as a molecular shield on both tumor cells and host immune cells to prevent tumors from cytolysis by T cells.	('PD-L1', 'Var', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', (232, 237))	('tumors', 'Disease', (232, 238))
14300	29744030	Recently, we reported that inactivation of mTORC1 (the mammalian target of rapamycin, complex 1) signaling in hematopoietic stem/progenitor cells causes a massive expansion of previously uncharacterized CD11b+ PD-L1+ innate myelolymphoblastoid effector cells (IMLECs).	('CD11b+', 'Protein', (203, 209))	('inactivation', 'Var', (27, 39))	('mTORC1', 'Gene', (43, 49))	('mammalian', 'Species', '9606', (55, 64))	('mTORC1', 'Gene', '382056', (43, 49))
14307	24289252	After the establishment of the novel myxofibrosarcoma cell lines MUG-Myx1, cells were characterized using short tandem repeat (STR), copy number variation (CNV), and genotype/loss-of-heterozygosity (LOH) analyses.	('genotype/loss-of-heterozygosity', 'NegReg', (166, 197))	('copy', 'Var', (133, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('myxofibrosarcoma', 'Disease', (37, 53))	('myxofibrosarcoma', 'Disease', 'None', (37, 53))
14311	24289252	The frozen primary parental tumour tissue and the MUG-Myx1 cell line showed the same STR profile at the markers D3S1358, TH01, D21S11, D18S51, Penta E, D5S818, D13S317, D7S820, D16S539, CSF1PO, Penta D, Amelogenin, D8S1179, TPOX, and FGY.	('D16S539', 'Var', (177, 184))	('D5S818', 'Var', (152, 158))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('D21S11', 'Var', (127, 133))	('parental tumour', 'Disease', (19, 34))	('parental tumour', 'Disease', 'MESH:D063129', (19, 34))	('D3S1358', 'Var', (112, 119))	('D18S51', 'Var', (135, 141))	('TPOX', 'Disease', (224, 228))	('D8S1179', 'Var', (215, 222))	('D7S820', 'Var', (169, 175))	('D13S317', 'Var', (160, 167))
14373	24289252	The following primers were used for RT-qPCR: QuantiTect primer assays (Qiagen) for ABCB1 (ID QT00081928), ABCG2 (ID QT00073206), c-Myc (ID QT00062069), SOX-2 (ID QT00237601), and E-cadherin (ID QT00080143).	('ABCG2', 'Gene', '9429', (106, 111))	('SOX-2', 'Gene', (152, 157))	('SOX-2', 'Gene', '6657', (152, 157))	('c-Myc', 'Gene', '4609', (129, 134))	('ABCB1', 'Gene', (83, 88))	('ID QT00237601', 'Var', (159, 172))	('E-cadherin', 'Gene', (179, 189))	('ABCB1', 'Gene', '5243', (83, 88))	('E-cadherin', 'Gene', '999', (179, 189))	('c-Myc', 'Gene', (129, 134))	('ID QT00081928', 'Var', (90, 103))	('ABCG2', 'Gene', (106, 111))	('ID QT00080143', 'Var', (191, 204))	('ID QT00062069', 'Var', (136, 149))	('ID QT00073206', 'Var', (113, 126))
14384	24289252	To characterize the MUG-Myx1 cell line, the following analyses were carried out: definition of the ploidy status, tumourigenicity in NOD/SCID mice, short tandem repeat (STR) analysis, copy number variation (CNV), and genotype/loss-of-heterozygosity (LOH) analysis.	('tumour', 'Disease', (114, 120))	('NOD', 'Gene', '1822', (133, 136))	('SCID', 'Gene', '19090', (137, 141))	('mice', 'Species', '10090', (142, 146))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('SCID', 'Gene', (137, 141))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('NOD', 'Gene', (133, 136))	('copy', 'Var', (184, 188))
14391	24289252	The frozen primary parental tumour tissue and the MUG-Myx1 cell line (p2 and p43) showed the same STR profile at the markers D3S1358, TH01, D21S11, D18S51, Penta E, D5S818, D13S317, D7S820, D16S539, CSF1PO, Penta D, Amelogenin, D8S1179, TPOX and FGY.	('TPOX', 'Disease', (237, 241))	('D21S11', 'Var', (140, 146))	('p43', 'Gene', '9255', (77, 80))	('D16S539', 'Var', (190, 197))	('TH01', 'Var', (134, 138))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('parental tumour', 'Disease', (19, 34))	('D3S1358', 'Var', (125, 132))	('D7S820', 'Var', (182, 188))	('p43', 'Gene', (77, 80))	('D8S1179', 'Var', (228, 235))	('D18S51', 'Var', (148, 154))	('D5S818', 'Var', (165, 171))	('parental tumour', 'Disease', 'MESH:D063129', (19, 34))	('D13S317', 'Var', (173, 180))
14392	24289252	A CNV and LOH analysis of the cell line reveals gains, losses and copy neutral LOHs (uniparental disomy), as are summarized in Figure  2 and Tables  2 and 3.	('losses', 'NegReg', (55, 61))	('uniparental disomy', 'Disease', (85, 103))	('uniparental disomy', 'Disease', 'MESH:D024182', (85, 103))	('copy neutral', 'Var', (66, 78))	('gains', 'PosReg', (48, 53))
14406	24289252	After five weeks, the ALDH1high cells formed significantly larger tumours with the same cell amount and same latency period as in the mice injected with ALDH1low cells.	('mice', 'Species', '10090', (134, 138))	('larger', 'PosReg', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('ALDH1high cells', 'Var', (22, 37))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))
14409	24289252	Using the ImageScope software, Ki-67 tissue samples ALDH1low and ALDH1high tumour slides were quantified after IHC staining.	('ALDH1high', 'Var', (65, 74))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('tumour', 'Disease', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
14417	24289252	This result is in concordance with Huang et al., who found aneuploid or tetraploid DNA ploidy status in 75 well-characterized myxofibrosarcomas .	('tetraploid DNA', 'Var', (72, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('aneuploid', 'Disease', (59, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('myxofibrosarcomas', 'Disease', 'None', (126, 143))	('myxofibrosarcomas', 'Disease', (126, 143))	('aneuploid', 'Disease', 'MESH:D000782', (59, 68))
14419	24289252	Gains in gene copy number drive the expression of oncogenes, whereas decreased gene dosage by hemizygous and/or homozygous deletion result in the inactivation of tumour suppressor genes .	('Gains', 'PosReg', (0, 5))	('tumour', 'Disease', (162, 168))	('gene dosage', 'MPA', (79, 90))	('gene copy number', 'MPA', (9, 25))	('inactivation', 'NegReg', (146, 158))	('decreased', 'NegReg', (69, 78))	('deletion', 'Var', (123, 131))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumour', 'Disease', 'MESH:D009369', (162, 168))	('expression', 'MPA', (36, 46))	('oncogenes', 'MPA', (50, 59))
14420	24289252	There is mounting evidence that regional gains and/or high-level amplifications on chromosomal arm 7q are recurrently found in various types of bone and soft tissue sarcomas, including myxofibrosarcomas .	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (153, 172))	('myxofibrosarcomas', 'Disease', (185, 202))	('gains', 'PosReg', (41, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (153, 173))	('chromosomal arm 7q', 'Gene', (83, 101))	('found', 'Reg', (118, 123))	('amplifications', 'Var', (65, 79))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (153, 173))	('soft tissue sarcomas', 'Disease', (153, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('myxofibrosarcomas', 'Disease', 'None', (185, 202))
14423	24289252	CDK6 protein overexpression and gene amplification were both univariately associated with worse outcomes .	('CDK6', 'Gene', '1021', (0, 4))	('overexpression', 'PosReg', (13, 27))	('CDK6', 'Gene', (0, 4))	('gene amplification', 'Var', (32, 50))
14438	24289252	The ALDH1high population showed a significantly higher tumour formation capacity and proliferation rate, consistent with the characteristics of the high ALDH1 activity phenotype in other cancer cells , which may indicate that ALDH1high cells are partially responsible for tumour metastasis and recurrence and should be targeted during the cancer therapy.	('tumour', 'Disease', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('ALDH1high', 'Var', (4, 13))	('cancer', 'Disease', (187, 193))	('tumour metastasis', 'Disease', (272, 289))	('tumour', 'Phenotype', 'HP:0002664', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('tumour', 'Disease', 'MESH:D009369', (272, 278))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (339, 345))	('higher', 'PosReg', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('proliferation rate', 'CPA', (85, 103))	('tumour', 'Disease', (272, 278))	('tumour metastasis', 'Disease', 'MESH:D009362', (272, 289))
14723	30918552	All cases of the Facial DFSP showed positivity for vimentin and CD34 which confirmed a diagnosis of DFSP.	('vimentin', 'Gene', (51, 59))	('DFSP', 'Disease', (24, 28))	('vimentin', 'Gene', '7431', (51, 59))	('DFSP', 'Disease', (100, 104))	('CD34', 'Gene', (64, 68))	('CD34', 'Gene', '947', (64, 68))	('DFSP', 'Disease', 'MESH:D018223', (24, 28))	('DFSP', 'Disease', 'MESH:D018223', (100, 104))	('Facial DFSP', 'Disease', (17, 28))	('positivity', 'Var', (36, 46))	('Facial DFSP', 'Disease', 'MESH:D018223', (17, 28))
14832	31013172	AEs were more frequent in the regorafenib arm than in the placebo arm.	('AEs', 'Disease', (0, 3))	('regorafenib', 'Var', (30, 41))	('regorafenib', 'Chemical', 'MESH:C559147', (30, 41))
14853	31013172	The placebo arms of this trial and the REGOBONE study demonstrate similar rapid progression: 10% 16-week PFS in SARC024 and 0% 12-week PFS in REGOBONE.	('PFS', 'Var', (105, 108))	('REGOBONE', 'Chemical', '-', (39, 47))	('SARC024', 'Gene', (112, 119))	('REGOBONE', 'Chemical', '-', (142, 150))
14894	28042470	pleomorphism, cellularity, necrosis).	('cellularity', 'CPA', (14, 25))	('necrosis', 'Disease', 'MESH:D009336', (27, 35))	('pleomorphism', 'Var', (0, 12))	('necrosis', 'Disease', (27, 35))
14922	28042470	Immunohistochemistry showed strong expression of epithelial membrane antigen (EMA) and P63; there was also focal expression of cytokeratin (CK7+, CK20-), nuclear staining for IN-1, and a high Ki-67 fraction.	('epithelial membrane antigen', 'Gene', '4582', (49, 76))	('epithelial membrane antigen', 'Gene', (49, 76))	('CK20', 'Gene', (146, 150))	('CK20', 'Gene', '54474', (146, 150))	('P63', 'Gene', '8626', (87, 90))	('EMA', 'Gene', '4582', (78, 81))	('CK7+', 'Var', (140, 144))	('EMA', 'Gene', (78, 81))	('P63', 'Gene', (87, 90))
14952	28042470	It should be noted that in more diagnostically challenging cases certain genetic/cytogenetic abnormalities such as inactivating mutations of NF2, monosomy 22, as well as specific alterations in gene expression, may also be useful in establishing the diagnosis of metastatic meningioma.	('meningioma', 'Disease', (274, 284))	('NF2', 'Gene', (141, 144))	('inactivating mutations', 'Var', (115, 137))	('meningioma', 'Phenotype', 'HP:0002858', (274, 284))	('NF2', 'Gene', '4771', (141, 144))	('meningioma', 'Disease', 'MESH:D008577', (274, 284))	('alterations', 'Reg', (179, 190))	('monosomy', 'Var', (146, 154))
15031	27776324	Cytogenetic analyses can be helpful in the diagnosis of ES/PENT showing Ewing sarcoma (EWS) gene and ETS translocation.The translocation of t (11:22) (q24:q12) have been detected in more than 90% of the ES/PNET of the kidney.	('ES', 'Phenotype', 'HP:0012254', (203, 205))	('translocation', 'Var', (123, 136))	('ES/PNET', 'Disease', (203, 210))	('ES', 'Phenotype', 'HP:0012254', (56, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('EWS', 'Gene', '2130', (87, 90))	('EWS', 'Gene', (87, 90))	('detected', 'Reg', (170, 178))	('PENT', 'Gene', (59, 63))	('Ewing sarcoma', 'Gene', '2130', (72, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('Ewing sarcoma', 'Gene', (72, 85))	('PENT', 'Gene', '5409', (59, 63))	('EWS', 'Phenotype', 'HP:0012254', (87, 90))
15120	21724502	This leads to the uptake at the cylindrical coordinate (r, theta, h) being described by  where betah >= 0, phih >= 0, and tauh represent long-axis slice-specific adjustments of the amplitude, scale and phase of the uptake.	('c', 'Chemical', 'MESH:D002244', (150, 151))	('uptake', 'MPA', (18, 24))	('c', 'Chemical', 'MESH:D002244', (44, 45))	('betah', 'Chemical', '-', (95, 100))	('phih >= 0', 'Var', (107, 116))	('c', 'Chemical', 'MESH:D002244', (78, 79))	('c', 'Chemical', 'MESH:D002244', (193, 194))	('c', 'Chemical', 'MESH:D002244', (32, 33))	('c', 'Chemical', 'MESH:D002244', (40, 41))	('tauh', 'Chemical', '-', (122, 126))	('c', 'Chemical', 'MESH:D002244', (156, 157))	('betah >= 0', 'Var', (95, 105))	('c', 'Chemical', 'MESH:D002244', (160, 161))
15365	21724502	These variations, while not immediately critical for sarcoma, could prove useful in the context of other uptake structures.	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('variations', 'Var', (6, 16))	('c', 'Chemical', 'MESH:D002244', (62, 63))	('c', 'Chemical', 'MESH:D002244', (45, 46))	('sarcoma', 'Disease', (53, 60))	('c', 'Chemical', 'MESH:D002244', (88, 89))	('c', 'Chemical', 'MESH:D002244', (56, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('c', 'Chemical', 'MESH:D002244', (116, 117))	('c', 'Chemical', 'MESH:D002244', (40, 41))
15469	25163595	The only randomized trial comparing different local treatment approaches in retroperitoneal sarcoma showed a clear benefit favouring a combination of postoperative EBRT (35-40 Gy) and IORT (20 Gy) compared to postoperative EBRT alone (50-55 Gy) in terms of local control (60% vs. 20%) and gastrointestinal toxicity, while neurological toxicity was markedly increased in the IORT arm.	('gastrointestinal toxicity', 'Disease', (289, 314))	('local control', 'CPA', (257, 270))	('neurological toxicity', 'Disease', (322, 343))	('retroperitoneal sarcoma', 'Disease', 'MESH:D012186', (76, 99))	('35-40', 'Var', (170, 175))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (289, 314))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('neurological toxicity', 'Disease', 'MESH:D020258', (322, 343))	('retroperitoneal sarcoma', 'Disease', (76, 99))
15510	25163595	described a significant reduction of neuropathy with intraoperative doses of less than 12.5 Gy in a recently updated series of rectal cancer treated with IORT, indicating that our dose constraint seemed reasonable.	('less', 'Var', (77, 81))	('rectal cancer', 'Disease', 'MESH:D012004', (127, 140))	('reduction of neuropathy', 'Disease', (24, 47))	('rectal cancer', 'Disease', (127, 140))	('rectal cancer', 'Phenotype', 'HP:0100743', (127, 140))	('neuropathy', 'Phenotype', 'HP:0009830', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('reduction of neuropathy', 'Disease', 'MESH:D009422', (24, 47))
15516	21343597	The frequency was 100% for osteochondromas induced by conditional inactivation of exostoses (multiple) 1 (Ext1) in chondrocytes, osteosarcomas induced by tibial intramedullary inoculation of Moloney's murine sarcoma virus, and osteosarcomas induced by conditional inactivation of Trp53-with or without inactivation of Rb1-in osteoblast precursors.	('osteochondromas', 'Disease', (27, 42))	('osteosarcomas', 'Disease', 'MESH:D012516', (129, 142))	('induced', 'Reg', (43, 50))	('Ext1', 'Gene', (106, 110))	('osteosarcomas', 'Disease', (227, 240))	('Rb1', 'Gene', (318, 321))	('murine sarcoma virus', 'Species', '11809', (201, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('osteochondromas', 'Phenotype', 'HP:0030431', (27, 42))	('osteosarcomas', 'Disease', (129, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('osteosarcomas', 'Phenotype', 'HP:0002669', (227, 240))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('Ext1', 'Gene', '14042', (106, 110))	('conditional inactivation', 'Var', (54, 78))	('conditional inactivation', 'Var', (252, 276))	('osteosarcomas', 'Phenotype', 'HP:0002669', (129, 142))	('exostoses', 'Gene', (82, 91))	('osteochondromas', 'Disease', 'MESH:D015831', (27, 42))	('Moloney', 'Species', '11809', (191, 198))	('Trp53-with', 'Gene', (280, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('osteosarcoma', 'Phenotype', 'HP:0002669', (227, 239))	('osteochondroma', 'Phenotype', 'HP:0030431', (27, 41))	('Rb1', 'Gene', '19645', (318, 321))	('osteosarcomas', 'Disease', 'MESH:D012516', (227, 240))	('exostoses', 'Phenotype', 'HP:0100777', (82, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (232, 240))
15521	21343597	Histologically, non-osteogenic neoplasms were similar across strains and mutant stocks; osteogenic neoplasms exhibited greater diversity.	('neoplasm', 'Phenotype', 'HP:0002664', (99, 107))	('osteogenic neoplasms', 'Disease', (88, 108))	('neoplasm', 'Phenotype', 'HP:0002664', (31, 39))	('non-osteogenic neoplasms', 'Phenotype', 'HP:0010622', (16, 40))	('osteogenic neoplasms', 'Disease', 'MESH:D012516', (20, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (99, 108))	('mutant', 'Var', (73, 79))	('non-osteogenic neoplasms', 'Disease', 'MESH:D012516', (16, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (31, 40))	('non-osteogenic neoplasms', 'Disease', (16, 40))	('stocks', 'Species', '3724', (80, 86))	('osteogenic neoplasms', 'Disease', 'MESH:D012516', (88, 108))
15547	21343597	If the loss or inactivation of a gene resulted in the development of a bone neoplasm in a mouse model, that gene was considered as down regulated and assigned a hypothetical fold-change score of -99 (e.g.	('loss', 'NegReg', (7, 11))	('resulted in', 'Reg', (38, 49))	('mouse', 'Species', '10090', (90, 95))	('down regulated', 'NegReg', (131, 145))	('neoplasm', 'Phenotype', 'HP:0002664', (76, 84))	('bone neoplasm', 'Disease', 'MESH:D001859', (71, 84))	('bone neoplasm', 'Disease', (71, 84))	('bone neoplasm', 'Phenotype', 'HP:0010622', (71, 84))	('inactivation', 'Var', (15, 27))
15574	21343597	Chondromas were reported in C57BL/10J (0.1% frequency in females)  and a single case was found in a NOD.129P2(B6)-B2mtm1Unc/J mouse (Figs.	('mouse', 'Species', '10090', (126, 131))	('C57BL/10J', 'Var', (28, 37))	('Chondromas', 'Disease', 'MESH:D002812', (0, 10))	('Chondromas', 'Disease', (0, 10))
15584	21343597	Spontaneous chondrosarcomas were reported in B6C3F1 (0.13% frequency in females),  C57BL/10J (0.03% frequency in females)  and in ST/Eh (single case) mice, and observed in a 325 day-old male C57BL/6J mouse (Figs.	('C57BL/10J', 'Var', (83, 92))	('Spontaneous', 'Disease', (0, 11))	('mice', 'Species', '10090', (150, 154))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (12, 26))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (12, 27))	('mouse', 'Species', '10090', (200, 205))	('chondrosarcomas', 'Disease', (12, 27))	('chondrosarcomas', 'Disease', 'MESH:D002813', (12, 27))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('B6C3F1', 'Var', (45, 51))
15598	21343597	In another study on the carcinogenic potential of cyclosporine A in OF-1 mice, a 26.3% frequency was reported in cyclosporine treated mice (14.7% in males and 38% in females) and 35% in controls (20% in males and 30% in females) at 40 to 78 weeks of age.	('mice', 'Species', '10090', (134, 138))	('cyclosporine A', 'Chemical', 'MESH:D016572', (50, 64))	('mice', 'Species', '10090', (73, 77))	('cyclosporine', 'Chemical', 'MESH:D016572', (50, 62))	('carcinogenic', 'Disease', 'MESH:D063646', (24, 36))	('cyclosporine', 'Var', (113, 125))	('cyclosporine', 'Chemical', 'MESH:D016572', (113, 125))	('carcinogenic', 'Disease', (24, 36))
15602	21343597	At The Jackson Laboratory osteomas were diagnosed in A/J, C57BL/6J (Fig.	('osteoma', 'Phenotype', 'HP:0100246', (26, 33))	('C57BL/6J', 'Var', (58, 66))	('osteomas', 'Disease', (26, 34))	('osteomas', 'Phenotype', 'HP:0100246', (26, 34))	('Laboratory osteomas', 'Phenotype', 'HP:0025027', (15, 34))	('osteomas', 'Disease', 'MESH:D010016', (26, 34))
15603	21343597	5), DBA/2J, B6C3F1/J, C3.SW-H2b/SnJ, and C57BL6/J-Tg(Amy1Tag)501Knw/J (Figs.	('C3.SW-H2b/SnJ', 'Var', (22, 35))	('B6C3F1/J', 'Var', (12, 20))	('C57BL6/J-Tg', 'Var', (41, 52))	('C3.SW', 'CellLine', 'CVCL:R777', (22, 27))
15623	21343597	Osteosarcomas induced by intraperitoneal administration of bone seeking radionuclides 224Ra, 223Ra, and 227Th were reported in C3H/HeEl.102, (BALB/c x CBA) F2, (C3Hx101) F1, and NMRI mice,  and by external irradiation with 90Sr-90Y beta rays in ICR mice.	('Osteosarcomas', 'Disease', (0, 13))	('HeEl', 'CellLine', 'CVCL:8686', (131, 135))	('223Ra', 'Var', (93, 98))	('rays', 'Species', '255564', (237, 241))	('Osteosarcomas', 'Phenotype', 'HP:0002669', (0, 13))	('radionuclides', 'Chemical', 'MESH:D011868', (72, 85))	('mice', 'Species', '10090', (183, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('Osteosarcomas', 'Disease', 'MESH:D012516', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('mice', 'Species', '10090', (249, 253))
15625	21343597	Strains of mice varied widely with respect to metastases of osteosarcomas and metastases were infrequent or non-existent in some.Metastases of spontaneous osteosarcomas were noted in BALB/c,  C3Hf/Sed;CB17-Prkdcscid/Prkdcscid,  C57BL/6J,  C57BL/10J,  C57BL/Icrf,  CF-1,  NZB/Bl,  and RF/Un(MTB) mice.	('C57BL/6J', 'Var', (228, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('RF', 'Disease', 'MESH:C538347', (284, 286))	('MTB', 'Gene', (290, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('osteosarcomas', 'Phenotype', 'HP:0002669', (60, 73))	('Metastases of spontaneous osteosarcomas', 'Disease', 'MESH:D009362', (129, 168))	('C57BL/Icrf', 'Var', (251, 261))	('spontaneous osteosarcomas', 'Phenotype', 'HP:0025027', (143, 168))	('osteosarcomas', 'Phenotype', 'HP:0002669', (155, 168))	('Metastases of spontaneous osteosarcomas', 'Disease', (129, 168))	('osteosarcoma', 'Phenotype', 'HP:0002669', (155, 167))	('metastases of osteosarcomas', 'Disease', (46, 73))	('mice', 'Species', '10090', (11, 15))	('metastases', 'Disease', 'MESH:D009362', (46, 56))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('MTB', 'Gene', '76044', (290, 293))	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('mice', 'Species', '10090', (295, 299))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('metastases', 'Disease', (46, 56))	('metastases of osteosarcomas', 'Disease', 'MESH:D009362', (46, 73))	('metastases', 'Disease', (78, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))
15626	21343597	Metastases were quite infrequent in NOD/ShiLtJ and NOD-derived mice,  and absent in AKR  and B6C3F1  mice.	('NOD/ShiLtJ', 'Var', (36, 46))	('mice', 'Species', '10090', (63, 67))	('mice', 'Species', '10090', (101, 105))	('Metastases', 'Disease', (0, 10))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))
15627	21343597	Among virally induced osteosarcomas, metastases were prominent in BALB/c and CD-1 mice inoculated with Moloney Murine Sarcoma Virus  and CzechII/EiJ and CZC3F1 mice inoculated with Murine polyoma virus.	('mice', 'Species', '10090', (82, 86))	('osteosarcomas', 'Disease', 'MESH:D012516', (22, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('CD-1', 'Gene', '111334', (77, 81))	('Moloney', 'Var', (103, 110))	('Sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('metastases', 'Disease', (37, 47))	('Murine polyoma virus', 'Disease', (181, 201))	('CD-1', 'Gene', (77, 81))	('mice', 'Species', '10090', (160, 164))	('metastases', 'Disease', 'MESH:D009362', (37, 47))	('osteosarcomas', 'Phenotype', 'HP:0002669', (22, 35))	('Murine polyoma virus', 'Disease', 'MESH:D012192', (181, 201))	('Moloney Murine Sarcoma Virus', 'Species', '11809', (103, 131))	('osteosarcomas', 'Disease', (22, 35))	('osteosarcoma', 'Phenotype', 'HP:0002669', (22, 34))
15629	21343597	At The Jackson Laboratory osteosarcomas were diagnosed in 129Sv/J, A/J, AKR/J (Figs.	('osteosarcomas', 'Phenotype', 'HP:0002669', (26, 39))	('osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('osteosarcomas', 'Disease', 'MESH:D012516', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('AKR/J', 'Var', (72, 77))	('129Sv', 'Species', '10090', (58, 63))	('osteosarcomas', 'Disease', (26, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
15632	21343597	Osteosarcomas were also found in mice transgenic for the Simian Virus 40 Tumor antigen (SV40 Tag)  and in mice bearing targeted mutations of Trp53 (Trp53tm1TyJ),  in agreement with previous reports in the literature.	('Osteosarcomas', 'Disease', (0, 13))	('mice', 'Species', '10090', (106, 110))	('SV40', 'Species', '1891767', (88, 92))	('mutations', 'Var', (128, 137))	('Trp53', 'Gene', (141, 146))	('Simian Virus 40', 'Species', '1891767', (57, 72))	('Osteosarcomas', 'Phenotype', 'HP:0002669', (0, 13))	('Tumor', 'Phenotype', 'HP:0002664', (73, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('mice', 'Species', '10090', (33, 37))	('Osteosarcomas', 'Disease', 'MESH:D012516', (0, 13))	('transgenic', 'Species', '10090', (38, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('found', 'Reg', (24, 29))
15645	21343597	Hemangiosarcomas of bone were found in CD-1, DBA/2J, HRS/J, FVB/NJ-Trp53tm1TyJ/J, B6;129-Oxttm1Wsy/J, B6.CAST-Gpi-1a/EiJ and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (Figs.	('B6', 'Var', (82, 84))	('Hemangiosarcomas of bone', 'Phenotype', 'HP:0002833', (0, 24))	('CD-1', 'Gene', '111334', (39, 43))	('HRS', 'Disease', (53, 56))	('angiosarcoma', 'Phenotype', 'HP:0200058', (3, 15))	('HRS', 'Disease', 'MESH:D020191', (53, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('CD-1', 'Gene', (39, 43))	('Hemangiosarcomas of bone', 'Disease', (0, 24))	('B6.CAST-Gpi-1a/EiJ', 'Var', (102, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('Hemangiosarcomas of bone', 'Disease', 'MESH:D006394', (0, 24))
15663	21343597	Germline loss-of-function mutations in EXT1 and EXT2 were associated with cartilaginous tumors and multiple hereditary exostoses in humans.	('humans', 'Species', '9606', (132, 138))	('multiple hereditary exostoses', 'Phenotype', 'HP:0002762', (99, 128))	('exostoses', 'Phenotype', 'HP:0100777', (119, 128))	('EXT1', 'Gene', (39, 43))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (74, 94))	('mutations', 'Var', (26, 35))	('cartilaginous tumors', 'Disease', (74, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('EXT2', 'Gene', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('loss-of-function', 'NegReg', (9, 25))
15665	21343597	Mice with a targeted mutation of Ext2 (Ext2tm1Werb) were shown to develop foci of chondrocyte hypertrophy by 2 weeks of age that progress to osteochondromas.	('Ext2tm1Werb', 'Gene', (39, 50))	('progress', 'PosReg', (129, 137))	('Ext2', 'Gene', '14043', (39, 43))	('Ext2tm1Werb', 'Gene', '14043', (39, 50))	('osteochondromas', 'Disease', (141, 156))	('hypertrophy', 'Disease', (94, 105))	('mutation', 'Var', (21, 29))	('osteochondromas', 'Disease', 'MESH:D015831', (141, 156))	('hypertrophy', 'Disease', 'MESH:D006984', (94, 105))	('Ext2', 'Gene', (33, 37))	('Mice', 'Species', '10090', (0, 4))	('osteochondroma', 'Phenotype', 'HP:0030431', (141, 155))	('Ext2', 'Gene', (39, 43))	('osteochondromas', 'Phenotype', 'HP:0030431', (141, 156))	('Ext2', 'Gene', '14043', (33, 37))
15667	21343597	Enchondromas were shown to develop with high frequency in mice with transgenic over-expression of the GLI-Kruppel family member oncogene (Gli2) in chondrocytes and expression of a mutant form of the human parathyroid hormone/parathyroid hormone related protein receptor (R150CPTHR1) in growth plates, both regulated by the Collagen 2a1 (Col2a1) promoter.	('human', 'Species', '9606', (199, 204))	('over-expression', 'PosReg', (79, 94))	('Enchondromas', 'Phenotype', 'HP:0030038', (0, 12))	('Enchondromas', 'Disease', (0, 12))	('mutant', 'Var', (180, 186))	('mice', 'Species', '10090', (58, 62))	('parathyroid hormone/parathyroid hormone related protein receptor', 'Gene', '5745', (205, 269))	('Gli2', 'Gene', (138, 142))	('Enchondromas', 'Disease', 'MESH:D002812', (0, 12))	('transgenic', 'Species', '10090', (68, 78))	('Gli2', 'Gene', '14633', (138, 142))	('R150CPTHR1', 'Var', (271, 281))
15670	21343597	In the chondrosarcoma model, overexpression of Gli2 and deficiency of Trp53 additively down regulate Insulin like growth factor binding protein 3 (Igfbp3), which in turn inhibits chondrocyte apoptosis to facilitate proliferation and transformation.	('Igfbp3', 'Gene', (147, 153))	('chondrosarcoma', 'Disease', (7, 21))	('chondrosarcoma', 'Disease', 'MESH:D002813', (7, 21))	('Gli2', 'Gene', (47, 51))	('Insulin like growth factor binding protein 3', 'Gene', (101, 145))	('Trp53', 'Gene', (70, 75))	('Gli2', 'Gene', '14633', (47, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('facilitate', 'PosReg', (204, 214))	('Insulin like growth factor binding protein 3', 'Gene', '16009', (101, 145))	('down regulate', 'NegReg', (87, 100))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (7, 21))	('chondrocyte apoptosis', 'CPA', (179, 200))	('Igfbp3', 'Gene', '16009', (147, 153))	('inhibits', 'NegReg', (170, 178))	('deficiency', 'Var', (56, 66))
15671	21343597	Mice with targeted mutations in the Nfatc2 gene (Nfatc2tm1Glm) were shown to develop cartilaginous proliferations resembling chondrosarcoma.	('Nfatc2', 'Gene', (36, 42))	('chondrosarcoma', 'Disease', 'MESH:D002813', (125, 139))	('chondrosarcoma', 'Disease', (125, 139))	('Nfatc2tm1Glm', 'Gene', (49, 61))	('mutations', 'Var', (19, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('cartilaginous proliferations', 'Disease', (85, 113))	('develop', 'PosReg', (77, 84))	('Mice', 'Species', '10090', (0, 4))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (125, 139))	('cartilaginous proliferations', 'Disease', 'MESH:D015831', (85, 113))
15675	21343597	Mice with mutations of Trp53 in tandem with mutations of Rb1 specifically in osteoblast precursors are among the most successful models of osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('Rb1', 'Gene', (57, 60))	('Trp53', 'Gene', (23, 28))	('Rb1', 'Gene', '19645', (57, 60))	('Mice', 'Species', '10090', (0, 4))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('mutations', 'Var', (10, 19))	('osteosarcoma', 'Disease', (139, 151))	('osteosarcoma', 'Disease', 'MESH:D012516', (139, 151))
15676	21343597	In one study mice with conditional alleles of Trp53 (Trp53tm1Brn) and Rb1 (Rb1tm3TyJ) developed tumors that ranged in histology from fibroblastic with little osteoid or mineral, to osteoblastic with abundant osteoid and mineral.	('osteoid', 'CPA', (158, 165))	('mice', 'Species', '10090', (13, 17))	('Rb1', 'Gene', (70, 73))	('Rb1', 'Gene', '19645', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Rb1', 'Gene', (75, 78))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Trp53', 'Gene', (46, 51))	('Rb1', 'Gene', '19645', (75, 78))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('osteoblastic', 'CPA', (181, 193))	('Trp53tm1Brn', 'Var', (53, 64))	('fibroblastic', 'CPA', (133, 145))
15679	21343597	Between both studies, the average age of tumor occurrence varied from 125 days in Trp53 and Rb1 double null mice to 338 days in mice heterozygous for Trp53 (Trp53+/-, Rb1+/+).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('mice', 'Species', '10090', (108, 112))	('Rb1', 'Gene', (92, 95))	('Rb1', 'Gene', '19645', (92, 95))	('mice', 'Species', '10090', (128, 132))	('Trp53+/-', 'Var', (157, 165))	('Trp53', 'Gene', (82, 87))	('Rb1', 'Gene', (167, 170))	('Rb1', 'Gene', '19645', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
15683	21343597	In SV40 Tag induced osteosarcomas, sequestration and inactivation of the P53 and RB1 proteins by the SV40 Tumor Antigen (usually large T antigen) resulted in tumorigenesis in a promoter independent manner.	('osteosarcomas', 'Disease', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sequestration', 'MPA', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('SV40', 'Species', '1891767', (101, 105))	('SV40', 'Var', (101, 105))	('osteosarcomas', 'Phenotype', 'HP:0002669', (20, 33))	('RB1', 'Gene', '19645', (81, 84))	('RB1', 'Gene', (81, 84))	('SV40', 'Species', '1891767', (3, 7))	('Tumor', 'Phenotype', 'HP:0002664', (106, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('tumor', 'Disease', (158, 163))	('osteosarcoma', 'Phenotype', 'HP:0002669', (20, 32))	('osteosarcomas', 'Disease', 'MESH:D012516', (20, 33))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('inactivation', 'NegReg', (53, 65))	('P53', 'Gene', (73, 76))	('P53', 'Gene', '22059', (73, 76))
15698	21343597	The most popular inbred strains of mice currently available through The Jackson Laboratory are 129S1/SvImJ, 129X1/SvJ, A/J, AKR/J, BALB/cByJ, BALB/cJ, C3H/HeJ, C57BL/6J, C57BL/6NJ, C57BL/10J, CBA/J, DBA/1J, DBA/2J, FVB/NJ, NOD/ShiLtJ and SJL/J (JAX  Mice; http://www.jaxmice.org/; September 2010).	('C3H/HeJ', 'Var', (151, 158))	('Mice', 'Species', '10090', (250, 254))	('mice', 'Species', '10090', (35, 39))	('C57BL/6NJ', 'Var', (170, 179))	('mice', 'Species', '10090', (270, 274))	('129X1/SvJ', 'Var', (108, 117))	('C57BL/6J', 'Var', (160, 168))	('HeJ', 'CellLine', 'CVCL:0030', (155, 158))	('C57BL/10J', 'Var', (181, 190))
15699	21343597	Among these 129S1/SvImJ, C57BL/10J, DBA/1J, FVB/NJ, and SJL/J mice had no documented bone neoplasms in the diagnostic necropsy archives.	('neoplasms', 'Phenotype', 'HP:0002664', (90, 99))	('bone neoplasms', 'Disease', (85, 99))	('C57BL/10J', 'Var', (25, 34))	('mice', 'Species', '10090', (62, 66))	('bone neoplasms', 'Phenotype', 'HP:0010622', (85, 99))	('bone neoplasm', 'Phenotype', 'HP:0010622', (85, 98))	('neoplasm', 'Phenotype', 'HP:0002664', (90, 98))	('bone neoplasms', 'Disease', 'MESH:D001859', (85, 99))
15703	21343597	In this context it is worth noting that chondrogenic tumors were produced by targeted mutations of Nfatc2 in mice,  but no correlative mutations of NFAT1 were identified in a set of human chondrosarcomas and enchondromas.	('chondrogenic tumors', 'Disease', (40, 59))	('chondrosarcomas', 'Disease', 'MESH:D002813', (188, 203))	('enchondroma', 'Phenotype', 'HP:0030038', (208, 219))	('NFAT1', 'Gene', '18019', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('chondrosarcomas', 'Disease', (188, 203))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('chondrogenic tumors', 'Disease', 'MESH:D009369', (40, 59))	('enchondromas', 'Disease', (208, 220))	('mutations', 'Var', (86, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (195, 203))	('Nfatc2', 'Gene', (99, 105))	('human', 'Species', '9606', (182, 187))	('chondrogenic tumors', 'Phenotype', 'HP:0030431', (40, 59))	('enchondromas', 'Phenotype', 'HP:0030038', (208, 220))	('NFAT1', 'Gene', (148, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (188, 202))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (188, 203))	('mice', 'Species', '10090', (109, 113))	('enchondromas', 'Disease', 'MESH:D002812', (208, 220))
15710	21343597	CZC3F1 mice in this study exhibited metastases suggesting dominance of the metastatic phenotype.	('CZC3F1', 'Var', (0, 6))	('mice', 'Species', '10090', (7, 11))	('metastases', 'Disease', (36, 46))	('exhibited', 'Reg', (26, 35))	('metastases', 'Disease', 'MESH:D009362', (36, 46))
15711	21343597	In studies on spontaneous osteosarcomas, metastases were evident in "black" strains of mice such as C57BL/Icrf,  C57BL/6J  and C57BL/10J,  and absent in B6C3F1mice.	('osteosarcomas', 'Phenotype', 'HP:0002669', (26, 39))	('C57BL/6J', 'Var', (113, 121))	('C57BL/10J', 'Var', (127, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('C57BL/Icrf', 'Var', (100, 110))	('osteosarcomas', 'Disease', 'MESH:D012516', (26, 39))	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('spontaneous osteosarcomas', 'Phenotype', 'HP:0025027', (14, 39))	('mice', 'Species', '10090', (87, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))	('mice', 'Species', '10090', (159, 163))	('osteosarcomas', 'Disease', (26, 39))	('metastases', 'Disease', (41, 51))
15717	30756308	We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor.	('FAK', 'Gene', '5747', (91, 94))	('FAK', 'Gene', (91, 94))	('BI 853520', 'Chemical', '-', (46, 55))	('human', 'Species', '9606', (23, 28))	('BI 853520', 'Var', (46, 55))
15728	30756308	BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('malignancies', 'Disease', 'MESH:D009369', (175, 187))	('BI 853520', 'Var', (0, 9))	('tumor', 'Disease', (87, 92))	('malignancies', 'Disease', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patients', 'Species', '9606', (128, 136))	('BI 853520', 'Chemical', '-', (0, 9))
15737	30756308	Preclinical studies have demonstrated antitumor activity with FAK blockade, and several orally bioavailable, adenosine triphosphate (ATP)-competitive, small-molecule inhibitors of FAK are undergoing evaluation in early-phase clinical trials in patients with cancer, including VS-6063, GSK2256098, and PF-00562271.	('FAK', 'Gene', (180, 183))	('ATP', 'Chemical', 'MESH:D000255', (133, 136))	('tumor', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (109, 131))	('GSK2256098', 'Chemical', 'MESH:C000600809', (285, 295))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('PF-00562271', 'Var', (301, 312))	('FAK', 'Gene', '5747', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('FAK', 'Gene', (62, 65))	('VS-6063', 'Var', (276, 283))	('cancer', 'Disease', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('FAK', 'Gene', '5747', (180, 183))	('patients', 'Species', '9606', (244, 252))
15738	30756308	BI 853520 is a novel, potent, highly selective, ATP-competitive inhibitor of FAK that has demonstrated activity in a variety of preclinical human tumor xenograft models.	('FAK', 'Gene', '5747', (77, 80))	('human', 'Species', '9606', (140, 145))	('activity', 'MPA', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('FAK', 'Gene', (77, 80))	('BI 853520', 'Var', (0, 9))	('tumor', 'Disease', (146, 151))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('BI 853520', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
15739	30756308	In vitro, BI 853520 inhibited recombinant FAK with a half maximal (50%) inhibitory concentration (IC50) of 1 nM, which is largely comparable to the IC50 values reported for VS-6063 (0.6 nM), PF-00562271 (1.5 nM), and GSK2256098 (2-15 nM).	('BI 853520', 'Chemical', '-', (10, 19))	('FAK', 'Gene', '5747', (42, 45))	('BI 853520', 'Var', (10, 19))	('inhibited', 'NegReg', (20, 29))	('FAK', 'Gene', (42, 45))	('GSK2256098', 'Chemical', 'MESH:C000600809', (217, 227))
15741	30756308	The antitumor activity of BI 853520 was found to vary widely across a diverse panel of 16 murine subcutaneous adenocarcinoma xenograft models, from complete tumor inhibition to an absolute lack of sensitivity.	('tumor', 'Disease', (157, 162))	('BI 853520', 'Var', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('adenocarcinoma', 'Disease', (110, 124))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('BI 853520', 'Chemical', '-', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))	('murine', 'Species', '10090', (90, 96))
15742	30756308	Biomarker analysis suggests that the in vivo efficacy of BI 853520 in these models is linked to a mesenchymal tumor phenotype characterized by low E-cadherin messenger RNA (mRNA) and protein levels, and by low expression of the microRNA hsa-miR-200c-3p, an epithelial-specific microRNA that promotes E-cadherin expression.	('BI 853520', 'Var', (57, 66))	('low', 'NegReg', (143, 146))	('expression', 'MPA', (210, 220))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mesenchymal tumor', 'Disease', (98, 115))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (98, 115))	('BI 853520', 'Chemical', '-', (57, 66))
15743	30756308	All xenograft models that were highly sensitive to BI 853520, including kidney, lung, ovary, pancreas and prostate adenocarcinomas, were found to lack E-cadherin expression or to express low levels of E-cadherin.	('lack', 'NegReg', (146, 150))	('BI 853520', 'Chemical', '-', (51, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('expression', 'MPA', (162, 172))	('BI 853520', 'Var', (51, 60))	('pancreas and prostate adenocarcinomas', 'Disease', 'MESH:D010190', (93, 130))	('E-cadherin', 'Protein', (151, 161))
15745	30756308	In murine breast cancer models, BI 853520 most effectively prevented the establishment of metastases in tumors in which E-cadherin was either deficient or downregulated.	('BI 853520', 'Var', (32, 41))	('deficient', 'Disease', 'MESH:D007153', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('prevented', 'NegReg', (59, 68))	('metastases in tumors', 'Disease', 'MESH:D009362', (90, 110))	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('deficient', 'Disease', (142, 151))	('breast cancer', 'Disease', (10, 23))	('murine', 'Species', '10090', (3, 9))	('downregulated', 'NegReg', (155, 168))	('E-cadherin', 'Protein', (120, 130))	('metastases in tumors', 'Disease', (90, 110))	('BI 853520', 'Chemical', '-', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
15746	30756308	We report here the first-in-human phase I study of BI 853520, which comprised a dose-escalation phase followed by an expansion phase in patients with advanced nonhematologic cancers.	('human', 'Species', '9606', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('BI 853520', 'Chemical', '-', (51, 60))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('BI 853520', 'Var', (51, 60))	('patients', 'Species', '9606', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
15801	30756308	Table 5 summarizes the PK parameters for BI 853520, and unbound BI 853520, after single- and multiple-dose administration (200 mg QD; see Electronic Supplementary Tables 2-5 for all dose groups).	('BI 853520', 'Chemical', '-', (41, 50))	('BI 853520', 'Var', (64, 73))	('BI 853520', 'Var', (41, 50))	('BI 853520', 'Chemical', '-', (64, 73))
15813	30756308	This phase I trial demonstrated that continuous monotherapy with BI 853520 is feasible in heavily pretreated patients with advanced or metastatic nonhematologic malignancies; the MTD is determined at 200 mg QD.	('patients', 'Species', '9606', (109, 117))	('BI 853520', 'Chemical', '-', (65, 74))	('malignancies', 'Disease', (161, 173))	('BI 853520', 'Var', (65, 74))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
15814	30756308	The tolerability profile for BI 853520 is acceptable and is similar to that observed with other FAK inhibitors [e.g.	('BI 853520', 'Var', (29, 38))	('BI 853520', 'Chemical', '-', (29, 38))	('FAK', 'Gene', '5747', (96, 99))	('FAK', 'Gene', (96, 99))
15821	30756308	To date, no predisposing or risk factors for the development of BI 853520-associated proteinuria have been identified, and no clear correlation was identified with prior nephrotoxic therapy.	('nephrotoxic', 'Disease', 'MESH:D007674', (170, 181))	('BI 853520', 'Chemical', '-', (64, 73))	('nephrotoxic', 'Disease', (170, 181))	('proteinuria', 'Disease', (85, 96))	('BI 853520-associated', 'Var', (64, 84))	('proteinuria', 'Phenotype', 'HP:0000093', (85, 96))	('proteinuria', 'Disease', 'MESH:D011507', (85, 96))
15825	30756308	Proteinuria has also been reported as an AE following treatment with GSK2256098 and PF-00562271.	('GSK2256098', 'Var', (69, 79))	('GSK2256098', 'Chemical', 'MESH:C000600809', (69, 79))	('Proteinuria', 'Disease', 'MESH:D011507', (0, 11))	('PF-00562271', 'Var', (84, 95))	('Proteinuria', 'Phenotype', 'HP:0000093', (0, 11))	('Proteinuria', 'Disease', (0, 11))
15826	30756308	PK analysis demonstrated that BI 853520 was rapidly absorbed and exhibited at least biphasic disposition kinetics.	('BI 853520', 'Var', (30, 39))	('biphasic', 'MPA', (84, 92))	('BI 853520', 'Chemical', '-', (30, 39))
15829	30756308	The PK data demonstrate oral bioavailability of BI 853520 and support a QD dosing schedule.	('oral bioavailability', 'MPA', (24, 44))	('BI 853520', 'Var', (48, 57))	('BI 853520', 'Chemical', '-', (48, 57))
15830	30756308	In five of eight cases, including three patients with soft tissue sarcoma, the ratio of active pFAK/total FAK was substantially reduced at the end of the first cycle, thus providing clinical evidence supporting target engagement with BI 853520 in patients treated with the 200 mg QD dose.	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('BI 853520', 'Chemical', '-', (234, 243))	('reduced', 'NegReg', (128, 135))	('BI 853520', 'Var', (234, 243))	('ratio', 'MPA', (79, 84))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (54, 73))	('patients', 'Species', '9606', (40, 48))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (54, 73))	('patients', 'Species', '9606', (247, 255))	('FAK', 'Gene', (106, 109))	('FAK', 'Gene', '5747', (106, 109))	('FAK', 'Gene', (96, 99))	('soft tissue sarcoma', 'Disease', (54, 73))	('FAK', 'Gene', '5747', (96, 99))
15836	30756308	Given the cytostatic activity of BI 853520, the combination with other compounds such as immunotherapy should be considered for further development.	('BI 853520', 'Chemical', '-', (33, 42))	('BI 853520', 'Var', (33, 42))	('cytostatic activity', 'MPA', (10, 29))
15841	30756308	These data demonstrate that BI 853520 has a manageable and acceptable safety profile, favorable PK, and preliminary antitumor activity, including, for some patients, SD lasting >= 150 days, and PD modulation at the MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies.	('patients', 'Species', '9606', (156, 164))	('PD', 'Disease', 'MESH:D010300', (194, 196))	('BI 853520', 'Chemical', '-', (28, 37))	('patients', 'Species', '9606', (235, 243))	('BI 853520', 'Var', (28, 37))	('malignancies', 'Disease', 'MESH:D009369', (282, 294))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('modulation', 'Var', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('malignancies', 'Disease', (282, 294))	('tumor', 'Disease', (120, 125))
15875	28781811	Biopsy results revealed atypical spindle or oval cells with hyperchromatic abnormal nuclei accompanied by fibrous tissue, suggestive of sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('hyperchromatic abnormal', 'Var', (60, 83))	('sarcoma', 'Disease', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))
15936	28717701	We are aware of the clear association of anti-CD20-based therapy in lymphomas with HBVr as opposed to solid tumors, where such therapy is not used.	('anti-CD20-based therapy', 'Var', (41, 64))	('lymphomas', 'Phenotype', 'HP:0002665', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('HBVr', 'Disease', (83, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('lymphomas', 'Disease', (68, 77))	('lymphomas', 'Disease', 'MESH:D008223', (68, 77))
15942	24704979	Microsatellites with Macro-Influence in Ewing Sarcoma Numerous molecular abnormalities contribute to the genetic derangements involved in tumorigenesis.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (40, 53))	('tumor', 'Disease', (138, 143))	('Ewing Sarcoma', 'Disease', (40, 53))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('Sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('Numerous molecular abnormalities', 'Disease', 'MESH:C567116', (54, 86))	('Numerous molecular abnormalities', 'Disease', (54, 86))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Microsatellites', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
15943	24704979	EWS/ETS fusions in Ewing sarcoma are a prime example of this, resulting in potent chimeric oncoproteins with novel biological properties and a unique transcriptional signature essential for oncogenesis.	('chimeric', 'MPA', (82, 90))	('fusions', 'Var', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (19, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (19, 32))	('EWS', 'Gene', '2130', (0, 3))	('ETS', 'Chemical', '-', (4, 7))	('oncoproteins', 'Protein', (91, 103))	('Ewing sarcoma', 'Disease', (19, 32))	('EWS', 'Gene', (0, 3))
15945	24704979	These GGAA microsatellites function as enhancer elements, are sites of epigenetic regulation and are necessary for EWS/FLI DNA binding and upregulation of principal oncogenic targets.	('microsatellites', 'Var', (11, 26))	('FLI', 'Gene', (119, 122))	('EWS', 'Gene', '2130', (115, 118))	('EWS', 'Gene', (115, 118))	('enhancer', 'PosReg', (39, 47))	('FLI', 'Gene', '2314', (119, 122))
15947	24704979	Historically regarded as junk DNA, this emerging evidence clearly demonstrates that microsatellite DNA plays an instrumental role in EWS/FLI-mediated transcriptional regulation and oncogenesis in Ewing sarcoma.	('FLI', 'Gene', '2314', (137, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('microsatellite DNA', 'Var', (84, 102))	('FLI', 'Gene', (137, 140))	('oncogenesis', 'CPA', (181, 192))	('Ewing sarcoma', 'Disease', (196, 209))	('EWS', 'Gene', '2130', (133, 136))	('EWS', 'Gene', (133, 136))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (196, 209))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (196, 209))
15948	24704979	This unprecedented role of GGAA microsatellite DNA in Ewing sarcoma provides a unique opportunity to expand our mechanistic understanding of how EWS/ETS fusions influence cancer susceptibility, prognosis and transcriptional regulation.	('fusions', 'Var', (153, 160))	('EWS', 'Gene', '2130', (145, 148))	('EWS', 'Gene', (145, 148))	('transcriptional', 'MPA', (208, 223))	('prognosis', 'CPA', (194, 203))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (54, 67))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (54, 67))	('influence', 'Reg', (161, 170))	('cancer', 'Disease', (171, 177))	('ETS', 'Chemical', '-', (149, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Ewing sarcoma', 'Disease', (54, 67))
15949	24704979	Aberrant chromosomal translocations are common observations in cancer and in many instances these events give rise to chimeric fusion products with novel biological and cellular functions.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Aberrant chromosomal translocations', 'Var', (0, 35))	('chimeric fusion', 'MPA', (118, 133))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('give rise to', 'Reg', (105, 117))	('cancer', 'Disease', (63, 69))
15956	24704979	In Ewing sarcoma, chimeric EWS/ETS fusion products function as an aberrant oncogenic transcription factor, mediated by the transcriptional activating amino-terminus of EWS fused in frame to the DNA binding carboxy-terminus of the ETS transcription factor (Figure 2).	('chimeric', 'Var', (18, 26))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('Ewing sarcoma', 'Disease', (3, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('ETS', 'Chemical', '-', (230, 233))	('ETS', 'Chemical', '-', (31, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('activating', 'PosReg', (139, 149))	('EWS', 'Gene', '2130', (168, 171))	('EWS', 'Gene', (168, 171))	('EWS', 'Gene', '2130', (27, 30))	('EWS', 'Gene', (27, 30))
15962	24704979	In many instances, these rearrangements position the androgen-receptor regulatory element, TMPRSS2, directly upstream of the ETS-member, ERG, resulting in a hormone-driven overexpression of this transcription factor in prostate cells.	('ERG', 'Gene', (137, 140))	('TMPRSS2', 'Gene', '7113', (91, 98))	('rearrangements', 'Var', (25, 39))	('overexpression', 'PosReg', (172, 186))	('ERG', 'Gene', '2078', (137, 140))	('TMPRSS2', 'Gene', (91, 98))	('ETS', 'Chemical', '-', (125, 128))
15963	24704979	In contrast, as this review will expand upon, fusion of the ETS-DNA binding to the transcriptional activating domain of EWS in Ewing sarcoma results in a transcription factor with unique biological properties responsible for oncogenic transformation.	('results in', 'Reg', (141, 151))	('ETS', 'Chemical', '-', (60, 63))	('transcription factor', 'MPA', (154, 174))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (127, 140))	('Ewing sarcoma', 'Disease', (127, 140))	('EWS', 'Gene', '2130', (120, 123))	('EWS', 'Gene', (120, 123))	('fusion', 'Var', (46, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (127, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
15975	24704979	Given the predominance of EWS/FLI fusions in Ewing sarcoma, the biology of wild type and fusion-associated FLI has been most thoroughly characterized.	('FLI', 'Gene', '2314', (30, 33))	('FLI', 'Gene', (30, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('EWS', 'Gene', (26, 29))	('FLI', 'Gene', '2314', (107, 110))	('Ewing sarcoma', 'Disease', (45, 58))	('EWS', 'Gene', '2130', (26, 29))	('FLI', 'Gene', (107, 110))	('fusions', 'Var', (34, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 58))
15979	24704979	Additionally, ectopic expression of EWS/FLI in NIH 3T3 fibroblasts induces oncogenic transformation whereas wild-type FLI does not.	('FLI', 'Gene', (40, 43))	('EWS', 'Gene', '2130', (36, 39))	('EWS', 'Gene', (36, 39))	('oncogenic transformation', 'CPA', (75, 99))	('NIH 3T3', 'CellLine', 'CVCL:0594', (47, 54))	('FLI', 'Gene', '2314', (118, 121))	('induces', 'Reg', (67, 74))	('FLI', 'Gene', (118, 121))	('FLI', 'Gene', '2314', (40, 43))	('ectopic expression', 'Var', (14, 32))
15980	24704979	Silencing of EWS/FLI expression in patient-derived Ewing sarcoma cell lines reverses the oncogenic phenotype.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('FLI', 'Gene', '2314', (17, 20))	('FLI', 'Gene', (17, 20))	('patient', 'Species', '9606', (35, 42))	('Ewing sarcoma', 'Disease', (51, 64))	('EWS', 'Gene', '2130', (13, 16))	('EWS', 'Gene', (13, 16))	('Silencing', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
15991	24704979	Additional functional assessments have shown that in patient-derived Ewing sarcoma cell lines, dysregulated NR0B1 expression is necessary for oncogenic transformation.	('NR0B1', 'Gene', (108, 113))	('Ewing sarcoma', 'Disease', (69, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('dysregulated', 'Var', (95, 107))	('oncogenic transformation', 'CPA', (142, 166))	('NR0B1', 'Gene', '190', (108, 113))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (69, 82))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (69, 82))	('patient', 'Species', '9606', (53, 60))
16005	24704979	Importantly, beyond a threshold of 4-6 repeats, an increasing number of GGAA motifs results in a proportional increase in EWS/FLI-mediated gene expression in both synthetic reporter constructs and bona fide targets, such as NR0B1 (Figure 3).	('increase', 'PosReg', (110, 118))	('NR0B1', 'Gene', (224, 229))	('FLI', 'Gene', '2314', (126, 129))	('FLI', 'Gene', (126, 129))	('motifs', 'Var', (77, 83))	('GGAA', 'Gene', (72, 76))	('NR0B1', 'Gene', '190', (224, 229))	('EWS', 'Gene', '2130', (122, 125))	('EWS', 'Gene', (122, 125))
16006	24704979	Genome-wide localization data further supports these observations, as sites of EWS/FLI enrichment are greatest in regions with microsatellite elements containing 12-14 consecutive GGAA motifs.	('EWS', 'Gene', '2130', (79, 82))	('EWS', 'Gene', (79, 82))	('FLI', 'Gene', '2314', (83, 86))	('microsatellite elements', 'Var', (127, 150))	('FLI', 'Gene', (83, 86))
16007	24704979	Collectively, these findings demonstrate an unprecedented role for microsatellite elements as direct EWS/FLI-transcriptional response elements in Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (146, 159))	('FLI', 'Gene', (105, 108))	('microsatellite elements', 'Var', (67, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (146, 159))	('EWS', 'Gene', '2130', (101, 104))	('EWS', 'Gene', (101, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('Ewing sarcoma', 'Disease', (146, 159))	('FLI', 'Gene', '2314', (105, 108))
16008	24704979	Because an increasing number of GGAA motifs substantially augments target gene expression, it is possible that the EWS/FLI chimeric protein has an increased affinity for larger microsatellites.	('target gene expression', 'MPA', (67, 89))	('FLI', 'Gene', (119, 122))	('EWS', 'Gene', '2130', (115, 118))	('EWS', 'Gene', (115, 118))	('motifs', 'Var', (37, 43))	('augments', 'NegReg', (58, 66))	('FLI', 'Gene', '2314', (119, 122))
16009	24704979	Alternatively, larger microsatellites may facilitate the recruitment of additional EWS/FLI homodimers to produce a synergistic effect on transcriptional activation.	('FLI', 'Gene', (87, 90))	('EWS', 'Gene', '2130', (83, 86))	('EWS', 'Gene', (83, 86))	('facilitate', 'PosReg', (42, 52))	('recruitment', 'MPA', (57, 68))	('FLI', 'Gene', '2314', (87, 90))	('microsatellites', 'Var', (22, 37))	('transcriptional activation', 'MPA', (137, 163))
16015	24704979	Dysregulation of CAV1 has been associated with the metastases in other cancer models and expression of CAV1 is necessary for maintenance of oncogenic transformation in patient-derived Ewing sarcoma cell lines.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (184, 197))	('CAV1', 'Gene', '857', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (184, 197))	('CAV1', 'Gene', (17, 21))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (71, 77))	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('patient', 'Species', '9606', (168, 175))	('associated', 'Reg', (31, 41))	('CAV1', 'Gene', (103, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Ewing sarcoma', 'Disease', (184, 197))	('CAV1', 'Gene', '857', (17, 21))	('metastases', 'Disease', (51, 61))
16018	24704979	Overexpression of this protein also increases chemoresistance to a chemotherapeutic agent commonly used in Ewing sarcoma, etoposide.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (107, 120))	('etoposide', 'Chemical', 'MESH:D005047', (122, 131))	('chemoresistance to a chemotherapeutic', 'MPA', (46, 83))	('Ewing sarcoma', 'Disease', (107, 120))	('Overexpression', 'Var', (0, 14))	('increases', 'PosReg', (36, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (107, 120))
16024	24704979	Instead, as predicted from numerous in vitro assays, the number of GGAA motifs within the microsatellite had a greater influence on EWS/FLI occupancy and gene expression, which was most pronounced at genomic sites with >9 GGAA motifs.	('gene expression', 'MPA', (154, 169))	('FLI', 'Gene', '2314', (136, 139))	('motifs', 'Var', (72, 78))	('EWS', 'Gene', (132, 135))	('EWS', 'Gene', '2130', (132, 135))	('influence', 'Reg', (119, 128))	('FLI', 'Gene', (136, 139))
16025	24704979	a combination of ChIP-seq and formaldehyde-assisted isolation of regulatory elements (FAIRE) produced a detailed mapping of EWS/FLI enrichment sites: 40% of EWS/FLI binding sites contained a GGAA microsatellite, >60% of these microsatellite elements were located within intergenic regions and global EWS/FLI-enrichment favored microsatellite elements containing 8-14 consecutive GGAA motifs.	('EWS', 'Gene', '2130', (124, 127))	('EWS', 'Gene', (124, 127))	('FLI', 'Gene', (304, 307))	('microsatellite elements', 'Var', (327, 350))	('FLI', 'Gene', '2314', (161, 164))	('formaldehyde', 'Chemical', 'MESH:D005557', (30, 42))	('EWS', 'Gene', '2130', (300, 303))	('EWS', 'Gene', (300, 303))	('contained', 'Reg', (179, 188))	('FLI', 'Gene', '2314', (128, 131))	('FLI', 'Gene', '2314', (304, 307))	('FLI', 'Gene', (161, 164))	('FLI', 'Gene', (128, 131))	('EWS', 'Gene', '2130', (157, 160))	('EWS', 'Gene', (157, 160))
16028	24704979	Silencing of EWS/FLI rapidly restored nucleosome occupancy and a closed chromatin configuration at these GGAA microsatellites.	('closed chromatin configuration', 'MPA', (65, 95))	('FLI', 'Gene', '2314', (17, 20))	('FLI', 'Gene', (17, 20))	('nucleosome occupancy', 'MPA', (38, 58))	('EWS', 'Gene', '2130', (13, 16))	('EWS', 'Gene', (13, 16))	('restored', 'PosReg', (29, 37))	('Silencing', 'Var', (0, 9))
16038	24704979	Microsatellite DNA has been previously investigated as a potential marker of cancer susceptibility, genomic instability, and prognosis.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Microsatellite DNA', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
16041	24704979	In hereditary non-polyposis colorectal carcinomas (HNPCC) and sporadic colorectal carcinomas, inherited or acquired alterations of the DNA mismatch repair system give rise to a mutator phenotype characterized by length expansions or contractions of multiple mono- and di-nucleotide microsatellites, respectively.	('mutator', 'MPA', (177, 184))	('non-polyposis colorectal carcinomas (HNPCC) and sporadic colorectal carcinomas', 'Disease', 'MESH:D015179', (14, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('length', 'MPA', (212, 218))	('alterations', 'Var', (116, 127))	('mono- and di-nucleotide', 'Chemical', '-', (258, 281))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('contractions', 'NegReg', (233, 245))
16043	24704979	Detection of MSI and defects in the DNA mismatch repair system in colorectal cancer has become instrumental for the diagnosis of HNPCC, whereas in sporadic colorectal carcinomas, MSI provides an important prognostic molecular marker.	('colorectal carcinomas', 'Disease', (156, 177))	('MSI', 'Disease', 'None', (179, 182))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (156, 177))	('MSI', 'Disease', (13, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('HNPCC', 'Disease', 'None', (129, 134))	('MSI', 'Disease', (179, 182))	('DNA', 'Gene', (36, 39))	('HNPCC', 'Disease', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('defects', 'Var', (21, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('MSI', 'Disease', 'None', (13, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
16044	24704979	However, instability of these microsatellite sequences is more a manifestation of cancer-related genomic instability and these genetic elements do not appear to mediate specific oncogenic transcriptional signatures.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('instability', 'MPA', (9, 20))	('microsatellite', 'Var', (30, 44))
16047	24704979	In addition to MSI, microsatellite polymorphisms associated with various genetic loci have also been associated to cancer susceptibility and pathogenesis.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('microsatellite polymorphisms', 'Var', (20, 48))	('MSI', 'Disease', 'None', (15, 18))	('associated', 'Reg', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('MSI', 'Disease', (15, 18))
16051	24704979	An increasing number of CAG motifs has been shown to reduce the transcriptional activity of the androgen receptor.	('reduce', 'NegReg', (53, 59))	('androgen receptor', 'Gene', (96, 113))	('CAG motifs', 'Var', (24, 34))	('androgen receptor', 'Gene', '367', (96, 113))	('transcriptional activity', 'MPA', (64, 88))
16062	24704979	Our initial hypothesis favored larger GGAA microsatellites in Europeans given the disproportionately high incidence of Ewing sarcoma in this population.	('Ewing sarcoma', 'Disease', (119, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (119, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (119, 132))	('microsatellites', 'Var', (43, 58))
16067	24704979	These results were opposite to our original hypothesis, but considering the transcriptional implications of an increasing number of GGAA motifs in these EWS/FLI response elements, these results provoke several biologically intriguing hypotheses: It is possible that the massive NR0B1 microsatellites commonly observed in Africans do not permit a stoichiometrically favorable environment for EWS/FLI binding and are therefore protective of EWS/FLI-mediated NR0B1 gene activation.	('FLI', 'Gene', '2314', (443, 446))	('FLI', 'Gene', '2314', (157, 160))	('NR0B1', 'Gene', (278, 283))	('FLI', 'Gene', '2314', (395, 398))	('NR0B1', 'Gene', (456, 461))	('FLI', 'Gene', (443, 446))	('FLI', 'Gene', (157, 160))	('NR0B1', 'Gene', '190', (278, 283))	('FLI', 'Gene', (395, 398))	('EWS', 'Gene', '2130', (153, 156))	('EWS', 'Gene', (153, 156))	('microsatellites', 'Var', (284, 299))	('NR0B1', 'Gene', '190', (456, 461))	('EWS', 'Gene', (439, 442))	('EWS', 'Gene', '2130', (439, 442))	('EWS', 'Gene', '2130', (391, 394))	('EWS', 'Gene', (391, 394))
16075	24704979	Chromosomal translocations are common molecular events in cancer, often producing novel fusion proteins with oncogenic properties.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('fusion', 'Protein', (88, 94))	('Chromosomal translocations', 'Var', (0, 26))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('producing', 'Reg', (72, 81))	('cancer', 'Disease', (58, 64))
16078	24704979	This not only highlights how chimerism vastly alters the biological attributes of involved ETS-members, but also brings to attention a completely unappreciated role of microsatellite DNA in oncogenic transcriptional regulation.	('ETS', 'Chemical', '-', (91, 94))	('microsatellite', 'Var', (168, 182))	('chimerism', 'Var', (29, 38))	('biological', 'MPA', (57, 67))	('alters', 'Reg', (46, 52))
16080	24704979	These GGAA microsatellites are also highly polymorphic in human populations, and given that EWS/ETS-mediated gene expression is highly dependent on the length of these repetitive elements, GGAA microsatellite polymorphisms may also provide a unique opportunity to improve our mechanistic understanding of disease susceptibility and prognosis in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (345, 358))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (345, 358))	('human', 'Species', '9606', (58, 63))	('polymorphisms', 'Var', (209, 222))	('microsatellite', 'Var', (194, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (351, 358))	('ETS', 'Chemical', '-', (96, 99))	('EWS', 'Gene', (92, 95))	('EWS', 'Gene', '2130', (92, 95))	('Ewing sarcoma', 'Disease', (345, 358))
16088	33671291	In a mouse sarcoma S180 solid tumor model, HA-es-ZnPP as polymeric micelles exhibited a prolonged systemic circulation time and the consequent tumor-selective accumulation based on the enhanced permeability and retention (EPR) effect was evidenced.	('permeability', 'MPA', (194, 206))	('sarcoma', 'Disease', (11, 18))	('HA-es-ZnPP', 'Var', (43, 53))	('HA-es-ZnPP', 'Chemical', '-', (43, 53))	('polymer', 'Chemical', 'MESH:D011108', (57, 64))	('tumor', 'Disease', (143, 148))	('es', 'Chemical', 'MESH:D004540', (73, 75))	('enhanced', 'PosReg', (185, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('es', 'Chemical', 'MESH:D004540', (46, 48))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('sarcoma', 'Disease', 'MESH:D012509', (11, 18))	('mouse', 'Species', '10090', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (30, 35))	('mice', 'Species', '10090', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
16089	33671291	Consequently, a remarkable anticancer PDT effect was achieved using HA-es-ZnPP and a xenon light source, without apparent side effects.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('HA-es-ZnPP', 'Chemical', '-', (68, 78))	('HA-es-ZnPP', 'Var', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('xenon', 'Chemical', 'MESH:D014978', (85, 90))	('cancer', 'Disease', (31, 37))
16093	33671291	However, the tumor heterogeneity, diversity, and frequent mutation of tumor-related molecules largely limit the application and availability of molecular target drugs.	('limit', 'NegReg', (102, 107))	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('es', 'Chemical', 'MESH:D004540', (91, 93))	('mutation', 'Var', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
16103	33671291	Consequently, a superior antitumor effect, as well as greatly lowered side effects, could be achieved for nanomedicines compared to conventional low molecular anticancer drugs.	('side', 'MPA', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('nanomedicines', 'Var', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Disease', (29, 34))	('cancer', 'Disease', (163, 169))	('es', 'Chemical', 'MESH:D004540', (117, 119))
16190	33671291	The decreased absorbance of ZnPP supported the micelle formation in PBS compared to that in DMSO (Figure 2B).	('decreased', 'NegReg', (4, 13))	('DMSO', 'Chemical', 'MESH:D004121', (92, 96))	('ZnPP', 'Chemical', 'MESH:C017803', (28, 32))	('PBS', 'Chemical', '-', (68, 71))	('PBS', 'Var', (68, 71))	('absorbance of', 'MPA', (14, 27))	('micelle', 'MPA', (47, 54))	('ZnPP', 'Protein', (28, 32))	('mice', 'Species', '10090', (47, 51))
16191	33671291	More pieces of evidence were obtained by quenching of fluorescence from HA-es-ZnPP in an aqueous solution (i.e., PBS) compared to the strong fluorescence of DMSO solution of HA-es-ZnPP (Figure 2C,D).	('es', 'Chemical', 'MESH:D004540', (146, 148))	('HA-es-ZnPP', 'Var', (72, 82))	('DMSO', 'Chemical', 'MESH:D004121', (157, 161))	('es', 'Chemical', 'MESH:D004540', (177, 179))	('PBS', 'Chemical', '-', (113, 116))	('es', 'Chemical', 'MESH:D004540', (75, 77))	('HA-es-ZnPP', 'Chemical', '-', (174, 184))	('es', 'Chemical', 'MESH:D004540', (9, 11))	('HA-es-ZnPP', 'Chemical', '-', (72, 82))	('quenching', 'NegReg', (41, 50))	('fluorescence', 'MPA', (54, 66))	('es', 'Chemical', 'MESH:D004540', (59, 61))
16204	33671291	Compared to free ZnPP, HA-es-ZnPP exhibited a slower but constant uptake by C26 cells, at 8 h after incubation, the intracellular fluorescence from internalized ZnPP in cells treated with HA-es-ZnPP was one-third of that in free ZnPP treated cells (Figure 5A).	('intracellular fluorescence', 'MPA', (116, 142))	('ZnPP', 'Chemical', 'MESH:C017803', (161, 165))	('ZnPP', 'Chemical', 'MESH:C017803', (17, 21))	('es', 'Chemical', 'MESH:D004540', (135, 137))	('C26', 'CellLine', 'CVCL:0240', (76, 79))	('es', 'Chemical', 'MESH:D004540', (191, 193))	('HA-es-ZnPP', 'Var', (188, 198))	('HA-es-ZnPP', 'Chemical', '-', (23, 33))	('HA-es-ZnPP', 'Chemical', '-', (188, 198))	('es', 'Chemical', 'MESH:D004540', (26, 28))	('ZnPP', 'Chemical', 'MESH:C017803', (229, 233))	('ZnPP', 'Chemical', 'MESH:C017803', (29, 33))	('ZnPP', 'Chemical', 'MESH:C017803', (194, 198))
16207	33671291	Compared to free ZnPP, HA-es-ZnPP itself exhibited lower cytotoxicity with an IC50 of 50 mug/ml (ZnPP equivalent).	('ZnPP', 'Chemical', 'MESH:C017803', (17, 21))	('HA-es-ZnPP', 'Var', (23, 33))	('cytotoxicity', 'Disease', (57, 69))	('HA-es-ZnPP', 'Chemical', '-', (23, 33))	('ZnPP', 'Chemical', 'MESH:C017803', (97, 101))	('lower', 'NegReg', (51, 56))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))	('ZnPP', 'Chemical', 'MESH:C017803', (29, 33))
16212	33671291	Compared with native ZnPP which showed very low or negligible distribution in all tested tissues, including tumor (Figure 7A), HA-es-ZnPP exhibited a significantly prolonged circulation time, while the blood concentration of HA-es-ZnPP was 2.5-times more than that of ZnPP (Figure 7A).	('more', 'PosReg', (250, 254))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('es', 'Chemical', 'MESH:D004540', (94, 96))	('HA-es-ZnPP', 'Chemical', '-', (225, 235))	('es', 'Chemical', 'MESH:D004540', (228, 230))	('HA-es-ZnPP', 'Var', (127, 137))	('ZnPP', 'Chemical', 'MESH:C017803', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('prolonged', 'PosReg', (164, 173))	('HA-es-ZnPP', 'Chemical', '-', (127, 137))	('es', 'Chemical', 'MESH:D004540', (130, 132))	('circulation', 'MPA', (174, 185))	('blood concentration', 'MPA', (202, 221))	('es', 'Chemical', 'MESH:D004540', (83, 85))	('ZnPP', 'Chemical', 'MESH:C017803', (133, 137))	('ZnPP', 'Chemical', 'MESH:C017803', (21, 25))	('ZnPP', 'Chemical', 'MESH:C017803', (268, 272))	('es', 'Chemical', 'MESH:D004540', (247, 249))
16213	33671291	More importantly, tumor accumulation of HA-es-ZnPP was 10-times higher than that of free ZnPP (Figure 7A).	('tumor', 'Disease', (18, 23))	('HA-es-ZnPP', 'Var', (40, 50))	('HA-es-ZnPP', 'Chemical', '-', (40, 50))	('higher', 'PosReg', (64, 70))	('ZnPP', 'Chemical', 'MESH:C017803', (89, 93))	('es', 'Chemical', 'MESH:D004540', (43, 45))	('es', 'Chemical', 'MESH:D004540', (61, 63))	('ZnPP', 'Chemical', 'MESH:C017803', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
16214	33671291	Moreover, the amount of HA-es-ZnPP in the tumor was higher than those in most of the normal tissues except the liver, which is rich in reticuloendothelial systems and is the primary organ for the protoporphrin metabolism.	('es', 'Chemical', 'MESH:D004540', (27, 29))	('tumor', 'Disease', (42, 47))	('es', 'Chemical', 'MESH:D004540', (97, 99))	('HA-es-ZnPP', 'Var', (24, 34))	('HA-es-ZnPP', 'Chemical', '-', (24, 34))	('higher', 'PosReg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
16215	33671291	These findings suggest a preferentially targeted delivery of HA-es-ZnPP in the tumor by taking advantage of the EPR effect.	('HA-es-ZnPP', 'Var', (61, 71))	('tumor', 'Disease', (79, 84))	('HA-es-ZnPP', 'Chemical', '-', (61, 71))	('es', 'Chemical', 'MESH:D004540', (2, 4))	('es', 'Chemical', 'MESH:D004540', (19, 21))	('es', 'Chemical', 'MESH:D004540', (64, 66))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
16216	33671291	The tumor-selective delivery of HA-es-ZnPP was also visualized and confirmed by using fluorescence imaging involving detecting the fluorescence from ZnPP, during which much-intensified fluorescence was detected in tumors from mice treated by HA-es-ZnPP compared to those in free ZnPP treated mice (inset of Figure 6).	('tumor', 'Disease', (4, 9))	('fluorescence', 'MPA', (185, 197))	('HA-es-ZnPP', 'Chemical', '-', (242, 252))	('es', 'Chemical', 'MESH:D004540', (190, 192))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('mice', 'Species', '10090', (292, 296))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumors', 'Disease', (214, 220))	('mice', 'Species', '10090', (226, 230))	('ZnPP', 'Chemical', 'MESH:C017803', (279, 283))	('es', 'Chemical', 'MESH:D004540', (245, 247))	('ZnPP', 'Chemical', 'MESH:C017803', (248, 252))	('much-intensified', 'PosReg', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('HA-es-ZnPP', 'Chemical', '-', (32, 42))	('es', 'Chemical', 'MESH:D004540', (91, 93))	('tumor', 'Disease', (214, 219))	('HA-es-ZnPP', 'Var', (242, 252))	('es', 'Chemical', 'MESH:D004540', (35, 37))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('ZnPP', 'Chemical', 'MESH:C017803', (38, 42))	('ZnPP', 'Chemical', 'MESH:C017803', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('es', 'Chemical', 'MESH:D004540', (136, 138))
16217	33671291	In addition, the pictures shown in the inset of Figure 6 were the cross-sectional view of tumors, which clearly showed a strong fluorescence of HA-es-ZnPP in the core of the tumor (inset of Figure 6).	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('fluorescence', 'MPA', (128, 140))	('tumors', 'Disease', (90, 96))	('HA-es-ZnPP', 'Var', (144, 154))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('HA-es-ZnPP', 'Chemical', '-', (144, 154))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('es', 'Chemical', 'MESH:D004540', (23, 25))	('es', 'Chemical', 'MESH:D004540', (133, 135))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('es', 'Chemical', 'MESH:D004540', (147, 149))
16221	33671291	Moreover, three injections of HA-es-ZnPP alone without light irradiation, or light irradiation alone without HA-es-ZnPP did not show apparent tumor suppression (Supplemental data Figure S1).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('es', 'Chemical', 'MESH:D004540', (33, 35))	('tumor', 'Disease', (142, 147))	('HA-es-ZnPP', 'Var', (30, 40))	('HA-es-ZnPP', 'Chemical', '-', (30, 40))	('HA-es-ZnPP', 'Chemical', '-', (109, 119))	('es', 'Chemical', 'MESH:D004540', (153, 155))	('es', 'Chemical', 'MESH:D004540', (112, 114))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
16226	33671291	In this context, HA-es-ZnPP behaves as micelles of ~40 nm (Figure 2A) and maintains the stable micelle formation in an aqueous solution as evidenced by the fluorescence quenching (Figure 2C,D).	('mice', 'Species', '10090', (95, 99))	('es', 'Chemical', 'MESH:D004540', (33, 35))	('HA-es-ZnPP', 'Var', (17, 27))	('HA-es-ZnPP', 'Chemical', '-', (17, 27))	('fluorescence', 'MPA', (156, 168))	('stable micelle formation', 'MPA', (88, 112))	('es', 'Chemical', 'MESH:D004540', (20, 22))	('es', 'Chemical', 'MESH:D004540', (161, 163))	('mice', 'Species', '10090', (39, 43))	('es', 'Chemical', 'MESH:D004540', (45, 47))
16229	33671291	injection, indicating a much longer blood half-life of HA-es-ZnPP than native ZnPP (Figure 6).	('blood half-life', 'MPA', (36, 51))	('ZnPP', 'Chemical', 'MESH:C017803', (61, 65))	('HA-es-ZnPP', 'Var', (55, 65))	('longer', 'PosReg', (29, 35))	('ZnPP', 'Chemical', 'MESH:C017803', (78, 82))	('HA-es-ZnPP', 'Chemical', '-', (55, 65))
16230	33671291	In accordance with this finding, HA-es-ZnPP remarkably accumulated in the tumor, which showed a 10-times higher concentration than that of native ZnPP (Figure 6).	('accumulated', 'PosReg', (55, 66))	('HA-es-ZnPP', 'Chemical', '-', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('es', 'Chemical', 'MESH:D004540', (36, 38))	('tumor', 'Disease', (74, 79))	('ZnPP', 'Chemical', 'MESH:C017803', (146, 150))	('ZnPP', 'Chemical', 'MESH:C017803', (39, 43))	('es', 'Chemical', 'MESH:D004540', (102, 104))	('HA-es-ZnPP', 'Var', (33, 43))
16234	33671291	Together, these findings strongly indicate the preferable properties of HA-es-ZnPP as a nanomedicine to target tumors by the EPR effect.	('es', 'Chemical', 'MESH:D004540', (66, 68))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('es', 'Chemical', 'MESH:D004540', (12, 14))	('ether', 'Chemical', 'MESH:D004986', (3, 8))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('es', 'Chemical', 'MESH:D004540', (75, 77))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('HA-es-ZnPP', 'Chemical', '-', (72, 82))	('HA-es-ZnPP', 'Var', (72, 82))
16241	33671291	As expected, the covalent bond of HA-es-ZnPP ensures little release of ZnPP in water solutions, but ZnPP release could be triggered in the presence of esterase as well as FBS (Figure 3), indicating that HA-es-ZnPP will release ZnPP in circulation and more importantly, in tumor tissues.	('HA-es-ZnPP', 'Chemical', '-', (34, 44))	('ZnPP', 'Chemical', 'MESH:C017803', (227, 231))	('release ZnPP', 'MPA', (219, 231))	('es', 'Chemical', 'MESH:D004540', (206, 208))	('es', 'Chemical', 'MESH:D004540', (151, 153))	('es', 'Chemical', 'MESH:D004540', (141, 143))	('ZnPP', 'Chemical', 'MESH:C017803', (209, 213))	('tumor', 'Disease', (272, 277))	('es', 'Chemical', 'MESH:D004540', (37, 39))	('es', 'Chemical', 'MESH:D004540', (283, 285))	('water', 'Chemical', 'MESH:D014867', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('ZnPP', 'Chemical', 'MESH:C017803', (40, 44))	('HA-es-ZnPP', 'Var', (203, 213))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('ZnPP', 'Chemical', 'MESH:C017803', (71, 75))	('ZnPP', 'Chemical', 'MESH:C017803', (100, 104))	('ester', 'Chemical', 'MESH:D004952', (151, 156))	('es', 'Chemical', 'MESH:D004540', (50, 52))	('HA-es-ZnPP', 'Chemical', '-', (203, 213))
16245	33671291	Our previous studies also showed that polymer conjugated ZnPP with covalent bonds exhibited much lower intracellular uptake than the corresponding native drugs.	('covalent bonds', 'Var', (67, 81))	('ZnPP', 'Chemical', 'MESH:C017803', (57, 61))	('es', 'Chemical', 'MESH:D004540', (18, 20))	('intracellular uptake', 'MPA', (103, 123))	('polymer', 'Chemical', 'MESH:D011108', (38, 45))	('lower', 'NegReg', (97, 102))	('es', 'Chemical', 'MESH:D004540', (137, 139))
16247	33671291	By use of the ester bond, in this study, we found that although the intracellular uptake of HA-es-ZnPP was slower and lower than free ZnPP, the uptake increased gradually in a time-dependent manner, which reached a level of one-third of that of ZnPP after 8 h (Figure 5).	('ZnPP', 'Chemical', 'MESH:C017803', (134, 138))	('ester', 'Chemical', 'MESH:D004952', (14, 19))	('HA-es-ZnPP', 'Var', (92, 102))	('HA-es-ZnPP', 'Chemical', '-', (92, 102))	('slower', 'NegReg', (107, 113))	('ZnPP', 'Chemical', 'MESH:C017803', (245, 249))	('lower', 'NegReg', (118, 123))	('intracellular uptake', 'MPA', (68, 88))	('ZnPP', 'Chemical', 'MESH:C017803', (98, 102))
16248	33671291	This result is partly parallel with the release profiles in the presence of FBS (Figure 3), suggesting that effective internalization of active drug (ZnPP) could be achieved in HA-es-ZnPP by benefiting from the esterase-dependent cleavage of ester bond and release of ZnPP.	('es', 'Chemical', 'MESH:D004540', (96, 98))	('HA-es-ZnPP', 'Var', (177, 187))	('ester', 'Chemical', 'MESH:D004952', (242, 247))	('ester', 'Chemical', 'MESH:D004952', (211, 216))	('HA-es-ZnPP', 'Chemical', '-', (177, 187))	('es', 'Chemical', 'MESH:D004540', (180, 182))	('ZnPP', 'MPA', (268, 272))	('ZnPP', 'Chemical', 'MESH:C017803', (183, 187))	('release', 'MPA', (257, 264))	('es', 'Chemical', 'MESH:D004540', (54, 56))	('es', 'Chemical', 'MESH:D004540', (6, 8))	('es', 'Chemical', 'MESH:D004540', (242, 244))	('es', 'Chemical', 'MESH:D004540', (211, 213))	('es', 'Chemical', 'MESH:D004540', (66, 68))	('ZnPP', 'Chemical', 'MESH:C017803', (150, 154))	('ZnPP', 'Chemical', 'MESH:C017803', (268, 272))	('esterase-dependent', 'Enzyme', (211, 229))	('internalization', 'MPA', (118, 133))	('cleavage of ester bond', 'MPA', (230, 252))
16251	33671291	More importantly, after light irradiation, the cytotoxicities of both free ZnPP and HA-es-ZnPP were remarkably (10-15 times) augmented (Figure 5B).	('HA-es-ZnPP', 'Var', (84, 94))	('HA-es-ZnPP', 'Chemical', '-', (84, 94))	('es', 'Chemical', 'MESH:D004540', (121, 123))	('ZnPP', 'Chemical', 'MESH:C017803', (75, 79))	('es', 'Chemical', 'MESH:D004540', (87, 89))	('cytotoxicities', 'Disease', (47, 61))	('augmented', 'PosReg', (125, 134))	('ZnPP', 'Chemical', 'MESH:C017803', (90, 94))	('cytotoxicities', 'Disease', 'MESH:D064420', (47, 61))	('es', 'Chemical', 'MESH:D004540', (59, 61))
16255	33671291	In this regard, HA-es-ZnPP, as a micellar type nanomedicine, exhibited much higher accumulation in tumors than most normal tissues, which could not be seen in case of small molecule free ZnPP (Figure 6).	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('HA-es-ZnPP', 'Var', (16, 26))	('HA-es-ZnPP', 'Chemical', '-', (16, 26))	('es', 'Chemical', 'MESH:D004540', (128, 130))	('ZnPP', 'Chemical', 'MESH:C017803', (187, 191))	('mice', 'Species', '10090', (33, 37))	('es', 'Chemical', 'MESH:D004540', (19, 21))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ZnPP', 'Chemical', 'MESH:C017803', (22, 26))	('higher accumulation', 'PosReg', (76, 95))	('tumors', 'Disease', (99, 105))
16256	33671291	In addition, interestingly, we found that HA-es-ZnPP in micellar form did not emit 1O2 as well as fluorescence under light irradiation (Figure 2 and Figure 4).	('es', 'Chemical', 'MESH:D004540', (18, 20))	('fluorescence', 'MPA', (98, 110))	('mice', 'Species', '10090', (56, 60))	('HA-es-ZnPP', 'Var', (42, 52))	('HA-es-ZnPP', 'Chemical', '-', (42, 52))	('1O2', 'Chemical', '-', (83, 86))	('es', 'Chemical', 'MESH:D004540', (103, 105))	('es', 'Chemical', 'MESH:D004540', (45, 47))
16257	33671291	This was probably due to a pi-pi stacked structure of ZnPP in the core of micelles, in which excited fluorochrome dissipates the energy.	('energy', 'MPA', (129, 135))	('es', 'Chemical', 'MESH:D004540', (80, 82))	('dissipates', 'NegReg', (114, 124))	('pi-pi stacked', 'Var', (27, 40))	('es', 'Chemical', 'MESH:D004540', (122, 124))	('ZnPP', 'Chemical', 'MESH:C017803', (54, 58))	('mice', 'Species', '10090', (74, 78))	('ZnPP', 'Gene', (54, 58))
16262	33671291	Thus, the PDT using HA-es-ZnPP will confer a superior therapeutic effect over conventional PDT using low molecular weight PS as well the improved safety of the treatment and quality of life in patients.	('patients', 'Species', '9606', (193, 201))	('safety', 'CPA', (146, 152))	('HA-es-ZnPP', 'Var', (20, 30))	('HA-es-ZnPP', 'Chemical', '-', (20, 30))	('therapeutic effect', 'CPA', (54, 72))	('improved', 'PosReg', (137, 145))
16263	33671291	As expected, we found significant suppression of tumor growth by PDT using HA-es-ZnPP (Figure 7A), whereas we did not observe body weight loss in this treatment regimen that indicates no apparent side effects (Figure 7B).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('weight loss', 'Phenotype', 'HP:0001824', (131, 142))	('HA-es-ZnPP', 'Var', (75, 85))	('HA-es-ZnPP', 'Chemical', '-', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('es', 'Chemical', 'MESH:D004540', (39, 41))	('weight loss', 'Disease', 'MESH:D015431', (131, 142))	('tumor', 'Disease', (49, 54))	('es', 'Chemical', 'MESH:D004540', (78, 80))	('weight loss', 'Disease', (131, 142))	('suppression', 'NegReg', (34, 45))	('es', 'Chemical', 'MESH:D004540', (181, 183))
16268	33671291	Moreover, because of the extensive tumor accumulation of HA-es-ZnPP (Figure 6), it may become possible to visualize tumors, especially tiny metastatic tumor nodules and disseminated cancer by using fluorescence imaging, as indicated in Figure 6 (inset).	('HA-es-ZnPP', 'Var', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('HA-es-ZnPP', 'Chemical', '-', (57, 67))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Disease', (182, 188))	('es', 'Chemical', 'MESH:D004540', (203, 205))	('tumors', 'Disease', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('es', 'Chemical', 'MESH:D004540', (124, 126))	('es', 'Chemical', 'MESH:D004540', (60, 62))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('es', 'Chemical', 'MESH:D004540', (162, 164))	('tumor', 'Disease', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
16273	33671291	On the other hand, the micelle formation imposes a prolonged circulation time and tumor-selective accumulation upon HA-es-ZnPP based on the EPR effect (Figure 6).	('HA-es-ZnPP', 'Var', (116, 126))	('HA-es-ZnPP', 'Chemical', '-', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('es', 'Chemical', 'MESH:D004540', (46, 48))	('micelle', 'MPA', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('circulation', 'MPA', (61, 72))	('tumor', 'Disease', (82, 87))	('es', 'Chemical', 'MESH:D004540', (119, 121))	('mice', 'Species', '10090', (23, 27))
16274	33671291	Consequently, a remarkable anticancer PDT effect is achieved both in vitro (Figure 5) and in vivo (Figure 7), suggesting the potential of HA-es-ZnPP as a candidate anticancer nanomedicine for PDT.	('HA-es-ZnPP', 'Chemical', '-', (138, 148))	('es', 'Chemical', 'MESH:D004540', (141, 143))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('es', 'Chemical', 'MESH:D004540', (114, 116))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (31, 37))	('HA-es-ZnPP', 'Var', (138, 148))
16282	31756779	Ewing sarcoma with FEV gene rearrangements is a rare subset with predilection for extra-skeletal locations and aggressive behavior The molecular hallmark of Ewing sarcoma (ES) is a fusion involving the EWSR1 gene and a member of the ETS family of transcription factors.	('FEV', 'Gene', '54738', (19, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('aggressive behavior', 'Disease', (111, 130))	('EWSR1', 'Gene', (202, 207))	('aggressive behavior', 'Phenotype', 'HP:0000718', (111, 130))	('Ewing sarcoma', 'Disease', (157, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('fusion', 'Var', (181, 187))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('EWSR1', 'Gene', '2130', (202, 207))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (157, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('FEV', 'Gene', (19, 22))	('ES', 'Phenotype', 'HP:0012254', (172, 174))	('aggressive behavior', 'Disease', 'MESH:D001523', (111, 130))
16286	31756779	In this study, we investigate the clinicopathologic and molecular features of 10 ES patients with FEV-rearrangements, either fused to EWSR1 (n = 4) or to FUS (n = 6).	('EWSR1', 'Gene', '2130', (134, 139))	('fused', 'Var', (125, 130))	('patients', 'Species', '9606', (84, 92))	('FEV', 'Gene', '54738', (98, 101))	('FUS', 'Gene', '2521', (154, 157))	('FUS', 'Gene', (154, 157))	('ES', 'Phenotype', 'HP:0012254', (81, 83))	('EWSR1', 'Gene', (134, 139))	('FEV', 'Gene', (98, 101))
16298	31756779	In addition to the genetically defined EWSR1-ETS-positive ES, an Ewing sarcoma-like group of tumors characterized by fusions between EWSR1 and non-ETS partners such as PATZ1, SP3, NFATC2, and SMARCA5 is emerging.	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('fusions', 'Var', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SMARCA5', 'Gene', (192, 199))	('Ewing sarcoma', 'Disease', (65, 78))	('PATZ1', 'Gene', '23598', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('EWSR1', 'Gene', '2130', (39, 44))	('EWSR1', 'Gene', '2130', (133, 138))	('SP3', 'Gene', (175, 178))	('NFATC2', 'Gene', (180, 186))	('PATZ1', 'Gene', (168, 173))	('tumors', 'Disease', (93, 99))	('SMARCA5', 'Gene', '8467', (192, 199))	('EWSR1', 'Gene', (133, 138))	('SP3', 'Gene', '6670', (175, 178))	('EWSR1', 'Gene', (39, 44))	('NFATC2', 'Gene', '4773', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (65, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))	('ES', 'Phenotype', 'HP:0012254', (58, 60))
16300	31756779	In this study we focus on a group of ES displaying rare EWSR1/FUS-FEV gene fusion variants.	('variants', 'Var', (82, 90))	('EWSR1', 'Gene', (56, 61))	('FEV', 'Gene', (66, 69))	('FEV', 'Gene', '54738', (66, 69))	('EWSR1', 'Gene', '2130', (56, 61))	('ES', 'Phenotype', 'HP:0012254', (37, 39))	('FUS', 'Gene', (62, 65))	('FUS', 'Gene', '2521', (62, 65))
16320	31756779	This assay involves all exons and selected introns of up to 468 oncogenes and tumor-suppressor genes, allowing the detection of point mutations, small and large insertions or deletions, and rearrangements.	('tumor-suppressor', 'Gene', '7248', (78, 94))	('insertions', 'Var', (161, 171))	('deletions', 'Var', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor-suppressor', 'Gene', (78, 94))	('rearrangements', 'Var', (190, 204))	('point mutations', 'Var', (128, 143))
16327	31756779	Of 286 ES cases confirmed in the authors' database to have EWSR1 or FUS gene rearrangements and a known gene partner, FEV-rearrangement was found in 10 (3.5%) cases.	('EWSR1', 'Gene', (59, 64))	('EWSR1', 'Gene', '2130', (59, 64))	('FUS', 'Gene', (68, 71))	('FEV', 'Gene', (118, 121))	('FUS', 'Gene', '2521', (68, 71))	('FEV', 'Gene', '54738', (118, 121))	('rearrangements', 'Var', (77, 91))	('ES', 'Phenotype', 'HP:0012254', (7, 9))
16351	31756779	Eight patients were tested by FISH showing gene rearrangements in EWSR1 and FEV genes in four cases or FUS and FEV in four cases.	('FUS', 'Gene', (103, 106))	('EWSR1', 'Gene', (66, 71))	('gene rearrangements', 'Var', (43, 62))	('FUS', 'Gene', '2521', (103, 106))	('FEV', 'Gene', (76, 79))	('EWSR1', 'Gene', '2130', (66, 71))	('patients', 'Species', '9606', (6, 14))	('FEV', 'Gene', (111, 114))	('FEV', 'Gene', '54738', (76, 79))	('FEV', 'Gene', '54738', (111, 114))
16353	31756779	In one case, targeted RNA sequencing revealed fusion of EWSR1 exon 8 and FEV exon 2.	('EWSR1', 'Gene', (56, 61))	('revealed', 'Reg', (37, 45))	('FEV', 'Gene', (73, 76))	('EWSR1', 'Gene', '2130', (56, 61))	('FEV', 'Gene', '54738', (73, 76))	('fusion', 'Var', (46, 52))
16356	31756779	By MSK-IMPACT, three missense mutations of CCND1, ICOSLG, MSH6, and one deletion of ZFHX3 were detected in patient# 6 (FUS-FEV).	('MSH6', 'Gene', (58, 62))	('FEV', 'Gene', '54738', (123, 126))	('ICOSLG', 'Gene', (50, 56))	('FUS', 'Gene', (119, 122))	('missense mutations', 'Var', (21, 39))	('CCND1', 'Gene', (43, 48))	('MSH6', 'Gene', '2956', (58, 62))	('detected', 'Reg', (95, 103))	('FUS', 'Gene', '2521', (119, 122))	('patient', 'Species', '9606', (107, 114))	('ZFHX3', 'Gene', '463', (84, 89))	('ICOSLG', 'Gene', '23308', (50, 56))	('CCND1', 'Gene', '595', (43, 48))	('ZFHX3', 'Gene', (84, 89))	('FEV', 'Gene', (123, 126))
16357	31756779	Three missense mutations of ARIDA1, KMT2D, and PREX2 were found in patient# 9 (FUS-FEV).	('FUS', 'Gene', '2521', (79, 82))	('patient', 'Species', '9606', (67, 74))	('KMT2D', 'Gene', (36, 41))	('PREX2', 'Gene', (47, 52))	('missense mutations', 'Var', (6, 24))	('ARIDA1', 'Gene', (28, 34))	('FEV', 'Gene', (83, 86))	('KMT2D', 'Gene', '8085', (36, 41))	('PREX2', 'Gene', '80243', (47, 52))	('FEV', 'Gene', '54738', (83, 86))	('found', 'Reg', (58, 63))	('FUS', 'Gene', (79, 82))
16365	31756779	Three cases had more detailed molecular findings including the fusion transcript type, including two cases with EWSR1 exon 7 fused to FEV exon 2 and one case with FUS exon 10 fused to FEV exon 2 (Table 1).	('FUS', 'Gene', '2521', (163, 166))	('fused', 'Var', (125, 130))	('FEV', 'Gene', (134, 137))	('FEV', 'Gene', '54738', (134, 137))	('EWSR1', 'Gene', (112, 117))	('FEV', 'Gene', (184, 187))	('FEV', 'Gene', '54738', (184, 187))	('EWSR1', 'Gene', '2130', (112, 117))	('FUS', 'Gene', (163, 166))
16366	31756779	All together, including present and published data, of eight cases with available data, the EWSR1 breakpoints included exon 7 in two cases and exon 8 or 9 in one; while the FUS breakpoints were exon 10 in two cases and exon 3 or 7 in one.	('EWSR1', 'Gene', '2130', (92, 97))	('FUS', 'Gene', (173, 176))	('FUS', 'Gene', '2521', (173, 176))	('exon', 'Var', (219, 223))	('EWSR1', 'Gene', (92, 97))	('exon 7', 'Var', (119, 125))	('exon', 'Var', (143, 147))
16368	31756779	The control group included 80 ES patients from our prospective research database, harboring the canonical EWSR1-FLI1 (n = 67) or EWSR1-ERG (n = 13) fusions.	('fusions', 'Var', (148, 155))	('EWSR1', 'Gene', '2130', (106, 111))	('patients', 'Species', '9606', (33, 41))	('ERG', 'Gene', '2078', (135, 138))	('ES', 'Phenotype', 'HP:0012254', (30, 32))	('EWSR1', 'Gene', (129, 134))	('ERG', 'Gene', (135, 138))	('EWSR1', 'Gene', (106, 111))	('FLI1', 'Gene', (112, 116))	('EWSR1', 'Gene', '2130', (129, 134))	('FLI1', 'Gene', '2313', (112, 116))
16369	31756779	ES patients with FEV gene rearrangements (n=18) had a significantly higher proportion of extra-skeletal tumors, compared to patients with the typical EWSR1-FLI1 or EWSR1-ERG fusions (94% vs 35%, respectively, p <0.001, Table 3).	('FEV', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Disease', (104, 110))	('patients', 'Species', '9606', (124, 132))	('EWSR1', 'Gene', (164, 169))	('FLI1', 'Gene', (156, 160))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('ERG', 'Gene', (170, 173))	('skeletal tumors', 'Phenotype', 'HP:0010622', (95, 110))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('EWSR1', 'Gene', '2130', (150, 155))	('higher', 'PosReg', (68, 74))	('ERG', 'Gene', '2078', (170, 173))	('FLI1', 'Gene', '2313', (156, 160))	('patients', 'Species', '9606', (3, 11))	('EWSR1', 'Gene', '2130', (164, 169))	('FEV', 'Gene', '54738', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('EWSR1', 'Gene', (150, 155))	('rearrangements', 'Var', (26, 40))
16372	31756779	ES with FEV gene rearrangements were associated with distinct clinical features compared to the common ES with canonical EWSR1-FLI1 or EFSR1-ERG fusions.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('ES', 'Phenotype', 'HP:0012254', (103, 105))	('rearrangements', 'Var', (17, 31))	('ERG', 'Gene', '2078', (141, 144))	('EWSR1', 'Gene', (121, 126))	('ERG', 'Gene', (141, 144))	('FEV', 'Gene', (8, 11))	('EWSR1', 'Gene', '2130', (121, 126))	('FEV', 'Gene', '54738', (8, 11))	('FLI1', 'Gene', '2313', (127, 131))	('FLI1', 'Gene', (127, 131))
16374	31756779	In contrast, nearly 80% of ES patients with the common FLI1/ERG variants are younger than 20 years of age, with a peak age incidence in the second decade of life.	('FLI1', 'Gene', (55, 59))	('ES', 'Phenotype', 'HP:0012254', (27, 29))	('FLI1', 'Gene', '2313', (55, 59))	('patients', 'Species', '9606', (30, 38))	('ERG', 'Gene', '2078', (60, 63))	('variants', 'Var', (64, 72))	('ERG', 'Gene', (60, 63))
16391	31756779	Of the patients in our cohort with FEV gene rearrangements and available follow-up, 33% presented with disseminated disease at diagnosis and died of disease, while 83% of patients overall developed distant metastases.	('presented', 'Reg', (88, 97))	('disseminated disease', 'Disease', (103, 123))	('developed', 'PosReg', (188, 197))	('FEV', 'Gene', (35, 38))	('metastases', 'Disease', 'MESH:D009362', (206, 216))	('died of disease', 'Disease', 'MESH:D003643', (141, 156))	('patients', 'Species', '9606', (171, 179))	('FEV', 'Gene', '54738', (35, 38))	('metastases', 'Disease', (206, 216))	('patients', 'Species', '9606', (7, 15))	('rearrangements', 'Var', (44, 58))	('died of disease', 'Disease', (141, 156))
16397	31756779	In conclusion, this is the largest study to date investigating one of the rarest ES molecular subsets, characterized by FEV gene rearrangements.	('FEV', 'Gene', '54738', (120, 123))	('rearrangements', 'Var', (129, 143))	('FEV', 'Gene', (120, 123))	('ES', 'Phenotype', 'HP:0012254', (81, 83))
16398	31756779	This is also the first molecular investigation to establish the prevalence of ES with FEV-related fusions among Ewing sarcoma (3.5%).	('Ewing sarcoma', 'Disease', (112, 125))	('FEV', 'Gene', (86, 89))	('FEV', 'Gene', '54738', (86, 89))	('fusions', 'Var', (98, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (112, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (112, 125))	('ES', 'Phenotype', 'HP:0012254', (78, 80))
16408	29849478	Cases of STS can be identified more comprehensively in cancer registries using ICD-O-3 codes than using ICD-10 codes.	('ICD-O-3 codes', 'Var', (79, 92))	('STS', 'Phenotype', 'HP:0030448', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('STS', 'Disease', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
16421	29849478	According to the current estimates, averaged across the years 2003 (or start of registry) through 2012, the nine federal states achieved an estimated completeness of at least 90% across all cancers combined and also specifically across sarcomas (identified by ICD-10 codes C40-C41 and C45-C49).	('sarcomas', 'Disease', (236, 244))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('C45-C49', 'Var', (285, 292))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('sarcomas', 'Disease', 'MESH:D012509', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('sarcomas', 'Phenotype', 'HP:0100242', (236, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('C40-C41', 'Var', (273, 280))
16434	29849478	We calculated the number of deaths attributable to cancer (C00-C97 and D00-D48) among the study cohort in 2012, stratified by age and sex, in the four states (Bavaria, Bremen, Saarland, and Schleswig-Holstein) that consistently reported the cause of death to the ZfKD.	('death', 'Disease', 'MESH:D003643', (250, 255))	('death', 'Disease', (250, 255))	('death to the ZfKD', 'Disease', (250, 267))	('D00-D48', 'Var', (71, 78))	('death to the ZfKD', 'Disease', 'MESH:D003643', (250, 267))	('death', 'Disease', 'MESH:D003643', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('death', 'Disease', (28, 33))	('C00-C97', 'Var', (59, 66))	('men', 'Species', '9606', (171, 174))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
16435	29849478	We used all cancer-attributed causes of death in this analysis because restricting to those coded C46-C49, which do not apply to approximately half of STS cases, would have resulted in substantial underestimation of the number of STS-related deaths in the study cohort.	('death', 'Disease', 'MESH:D003643', (242, 247))	('death', 'Disease', (242, 247))	('death', 'Disease', 'MESH:D003643', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('death', 'Disease', (40, 45))	('cancer', 'Disease', (12, 18))	('STS', 'Phenotype', 'HP:0030448', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('STS', 'Phenotype', 'HP:0030448', (230, 233))	('C46-C49', 'Var', (98, 105))	('underestimation', 'NegReg', (197, 212))
16455	29849478	Of note for later discussion, among the 2,898 STS cases with a cancer-specific cause of death, 1,455 (50.2%) were attributed to an ICD-10 code C46-C49.	('STS', 'Phenotype', 'HP:0030448', (46, 49))	('death', 'Disease', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('C46-C49', 'Var', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('death', 'Disease', 'MESH:D003643', (88, 93))	('cancer', 'Disease', (63, 69))
16456	29849478	However, this underestimates the proportion of deaths related to STS in the study population because, as had been expected (see Introduction) and as reported previously, only 61.0% of non-DCO cases in the study population were associated with an ICD-10 code C46-C49 at the time of diagnosis.	('non-DCO', 'Disease', (184, 191))	('death', 'Disease', 'MESH:D003643', (47, 52))	('death', 'Disease', (47, 52))	('associated', 'Reg', (227, 237))	('STS', 'Phenotype', 'HP:0030448', (65, 68))	('C46-C49', 'Var', (258, 265))
16457	29849478	Therefore, it is more informative to consider that among the 2,898 STS cases with a cancer-specific cause of death, 1,794 (61.9%) were associated with a code C46-C49 at diagnosis.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('STS', 'Phenotype', 'HP:0030448', (67, 70))	('death', 'Disease', 'MESH:D003643', (109, 114))	('cancer', 'Disease', (84, 90))	('death', 'Disease', (109, 114))	('associated', 'Reg', (135, 145))	('C46-C49', 'Var', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
16458	29849478	Among these 1,794 cases, 1,325 (73.9%) had a code C46-C49 recorded as their cause of death.	('death', 'Disease', 'MESH:D003643', (85, 90))	('death', 'Disease', (85, 90))	('C46-C49', 'Var', (50, 57))
16470	29849478	We assume that a similar proportion of cases not associated with a code C46-C49 at diagnosis also may have died of an unrelated malignancy.	('code C46-C49', 'Var', (67, 79))	('malignancy', 'Disease', 'MESH:D009369', (128, 138))	('malignancy', 'Disease', (128, 138))
16472	29849478	However, restriction of the analysis to cases associated with a code C46-C49 would have resulted in substantial underestimation of the number of STS-related deaths and the number of new cases of advanced STS in 2012 because these codes do not identify a large proportion of the STS cases included in the study.	('death', 'Disease', 'MESH:D003643', (157, 162))	('STS', 'Phenotype', 'HP:0030448', (204, 207))	('C46-C49', 'Var', (69, 76))	('underestimation', 'NegReg', (112, 127))	('death', 'Disease', (157, 162))	('code C46-C49', 'Var', (64, 76))	('STS', 'Phenotype', 'HP:0030448', (278, 281))	('STS', 'Phenotype', 'HP:0030448', (145, 148))
16531	29100369	On multivariate analysis, high SUVmax remained independent predictor of worst OS (p=0.02) and PFS (p=0.019), metastatic disease of worst PFS (p=0.01) and high SUVpeak of worst OS (p=0.01).	('PFS', 'Disease', (94, 97))	('OS', 'Chemical', '-', (176, 178))	('high', 'Var', (26, 30))	('worst OS', 'Disease', (72, 80))	('metastatic disease', 'Disease', (109, 127))	('high', 'Var', (154, 158))	('OS', 'Chemical', '-', (78, 80))
16560	29100369	Indeed, high SUVmax, SUVpeak, and SUVmean40% significantly adversely affected PFS and OS.	('high', 'Var', (8, 12))	('PFS', 'CPA', (78, 81))	('OS', 'Chemical', '-', (86, 88))	('affected', 'Reg', (69, 77))	('adversely', 'NegReg', (59, 68))	('SUVmean40%', 'Var', (34, 44))
16562	29100369	Discretization of SUVmax showed that 3-years PFS and OS survival of patients with baseline SUVmax>=17 were decreased compared to patient with lower SUVmax (OS: 21% vs 72%, respectively; p=0.004; PFS: 0% vs 41%, respectively; p=0.001).	('patient', 'Species', '9606', (68, 75))	('>=17', 'Var', (97, 101))	('decreased', 'NegReg', (107, 116))	('OS', 'Chemical', '-', (156, 158))	('OS', 'Chemical', '-', (53, 55))	('PFS', 'CPA', (45, 48))	('patients', 'Species', '9606', (68, 76))	('OS survival', 'CPA', (53, 64))	('patient', 'Species', '9606', (129, 136))
16576	29100369	In the non-metastatic sub-group of patients, all patients with SUVpeak>=12.5 relapsed or progressed during the first 12 months of follow-up, while those with SUVpeak<12.5 had 2-years PFS survival of 80% (p=0.002).	('SUVpeak', 'Var', (63, 70))	('progressed', 'CPA', (89, 99))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (49, 57))
16590	29100369	For our part, in exclusively adult population, in multivariate analysis, high SUVmax value was an independent and unfavorable factor for OS (p=0.02) but no discriminating cut off was found.	('high', 'Var', (73, 77))	('SUVmax value', 'MPA', (78, 90))	('OS', 'Chemical', '-', (137, 139))
16595	29100369	MTV and TLG seem to be useful for the FDG-PET/CT's therapeutic response evaluation of various tumors and high MTV or TLG has an unfavorable prognostic value at baseline in many solid tumors like breast, lung or esophageal cancers.	('TLG', 'Gene', (117, 120))	('solid tumors', 'Disease', 'MESH:D009369', (177, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', (183, 189))	('breast', 'Disease', (195, 201))	('esophageal cancers', 'Disease', 'MESH:D004938', (211, 229))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('TLG', 'Chemical', '-', (8, 11))	('FDG', 'Chemical', 'MESH:D019788', (38, 41))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('solid tumors', 'Disease', (177, 189))	('MTV', 'Chemical', '-', (0, 3))	('high', 'Var', (105, 109))	('MTV', 'Chemical', '-', (110, 113))	('lung', 'Disease', (203, 207))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('TLG', 'Chemical', '-', (117, 120))	('esophageal cancers', 'Disease', (211, 229))	('MTV', 'Gene', (110, 113))
16599	29100369	For MTV, one can hypothesize that the prognosis is possibly less impacted by MTV than the detection of the most intense pixels (SUVmax, SUVpeak), that correspond to the most aggressive cell clusters with prognostic consequence.	('less', 'NegReg', (60, 64))	('MTV', 'Chemical', '-', (4, 7))	('MTV', 'Var', (77, 80))	('MTV', 'Chemical', '-', (77, 80))
16727	24481401	In those cases of positive margins, recurring tumours infiltrated critical anatomic structures, such as large-extremity nerves, or were too advanced and widespread for complete resection.	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('tumours', 'Disease', (46, 53))	('positive', 'Var', (18, 26))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('infiltrated', 'Reg', (54, 65))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
16821	29848707	All adult patients were selected from nine combined SEER registries who were diagnosed with WD/DD liposarcoma [International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) histology codes 8851.3 for WD and 8858.3 for DD] between 1973-2012.	('8851.3', 'Var', (204, 210))	('WD', 'Disease', 'MESH:D006527', (92, 94))	('WD', 'Disease', 'MESH:D006527', (215, 217))	('Oncology', 'Phenotype', 'HP:0002664', (156, 164))	('liposarcoma', 'Phenotype', 'HP:0012034', (98, 109))	('patients', 'Species', '9606', (10, 18))	('WD/DD liposarcoma', 'Disease', 'MESH:D006527', (92, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('WD/DD liposarcoma', 'Disease', (92, 109))
16847	29848707	WD/DD liposarcoma is characterized by 12q13-15 amplification, a hallmark genetic feature in this disease.	('12q13-15 amplification', 'Var', (38, 60))	('WD/DD liposarcoma', 'Disease', 'MESH:D006527', (0, 17))	('liposarcoma', 'Phenotype', 'HP:0012034', (6, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('WD/DD liposarcoma', 'Disease', (0, 17))
16850	29848707	found that in a large combined cohort of 1,162 patients with sarcoma, using targeted exon sequencing, more than half were actually found to have an excess of pathogenic germline monogenic and polygenic variants.	('germline monogenic', 'Var', (169, 187))	('polygenic variants', 'Var', (192, 210))	('patients', 'Species', '9606', (47, 55))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('pathogenic', 'Reg', (158, 168))	('sarcoma', 'Disease', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
16851	29848707	These variants were associated with earlier age of onset, and suggested that a large percentage of sarcomas may in fact have some underlying hereditary and genetic component.	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('variants', 'Var', (6, 14))	('sarcomas', 'Disease', (99, 107))	('sarcomas', 'Disease', 'MESH:D012509', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
16852	29848707	in a similar study of an Asian cohort of patients with sarcoma, which found that 13.6% of patients with sporadic sarcomas exhibited at least one pathogenic germline mutation in 10 cancer-associated genes.	('sporadic sarcomas', 'Disease', (104, 121))	('sarcoma', 'Disease', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('patients', 'Species', '9606', (41, 49))	('sarcoma', 'Disease', (113, 120))	('sporadic sarcomas', 'Disease', 'MESH:D012509', (104, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', (180, 186))	('germline mutation', 'Var', (156, 173))
16943	31417921	In this phase III randomised trial patients were randomly selected to receive 51Gy external beam pelvic radiation or observation.	('51Gy', 'Var', (78, 82))	('patients', 'Species', '9606', (35, 43))	('external beam pelvic radiation', 'CPA', (83, 113))
17031	30970016	To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas.	('atrx', 'Gene', (92, 96))	('knocked out', 'Var', (80, 91))	('peripheral nerve sheath tumors', 'Disease', 'MESH:D010524', (181, 211))	('peripheral nerve sheath tumors', 'Disease', (181, 211))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('develops', 'PosReg', (162, 170))	('zebrafish', 'Species', '7955', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('gliomas', 'Disease', 'MESH:D005910', (216, 223))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('gliomas', 'Phenotype', 'HP:0009733', (216, 223))	('gliomas', 'Disease', (216, 223))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (171, 211))	('mutations', 'Var', (48, 57))
17034	30970016	These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types.	('ATRX', 'Gene', (98, 102))	('human', 'Species', '9606', (212, 217))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (218, 224))	('human', 'Species', '9606', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutant', 'Var', (91, 97))	('zebrafish', 'Species', '7955', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('associated', 'Reg', (75, 85))	('cancer', 'Disease', (6, 12))
17035	30970016	RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples.	('telomerase', 'Enzyme', (87, 97))	('atrx-deficient tumors', 'Disease', 'MESH:D009369', (32, 53))	('atrx-mutant', 'Var', (155, 166))	('atrx-deficient tumors', 'Disease', (32, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('down-regulation', 'NegReg', (68, 83))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('atrx-mutant', 'Gene', (155, 166))
17036	30970016	Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.	('cancer', 'Disease', (145, 151))	('inactivating mutations', 'Var', (10, 32))	('PRC2 dysfunction', 'Disease', (125, 141))	('disturbed', 'Reg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('PRC2-target gene', 'Gene', (51, 67))	('atrx', 'Gene', (36, 40))	('PRC2 dysfunction', 'Disease', 'MESH:D006331', (125, 141))
17039	30970016	Thus, we analyzed the tumor suppressive role of atrx in zebrafish that already harbored inactivating mutations of p53 and nf1.	('p53', 'Gene', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('zebrafish', 'Species', '7955', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('inactivating mutations', 'Var', (88, 110))	('tumor', 'Disease', (22, 27))	('nf1', 'Gene', (122, 125))
17041	30970016	Most of the cancer types we identified correspond to human tumors in the ATRX-mutant tumor sample cohort within the AACR Genie database, attesting to the relevance of our findings to human cancer.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('ATRX-mutant', 'Gene', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('ATRX-mutant', 'Var', (73, 84))	('human', 'Species', '9606', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('human', 'Species', '9606', (53, 58))	('cancer', 'Disease', (189, 195))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumors', 'Disease', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
17042	30970016	Further analysis revealed downregulation of telomerase during the lengthening of the telomeres through the ALT pathway, and disturbed function of the polycomb repressive complex 2 as key mechanistic components underlying atrx-linked tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('disturbed', 'Var', (124, 133))	('function', 'MPA', (134, 142))	('downregulation', 'NegReg', (26, 40))	('tumor', 'Disease', (233, 238))	('telomerase', 'Enzyme', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('ALT pathway', 'Pathway', (107, 118))
17043	30970016	These results demonstrate how a p53/nf1 compromised genetic background combined with ATRX haploinsufficiency leads to a broad spectrum of sarcomas and carcinomas associated with loss of this chromatin modulator.	('sarcomas and carcinomas', 'Disease', 'MESH:D012509', (138, 161))	('haploinsufficiency', 'Disease', (90, 108))	('loss', 'Var', (178, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (151, 161))	('ATRX', 'Gene', (85, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('haploinsufficiency', 'Disease', 'MESH:D058495', (90, 108))	('p53/nf1', 'Gene', (32, 39))	('leads to', 'Reg', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
17046	30970016	In humans, germline loss of ATRX function causes mental retardation and alpha thalassemia that is associated with reduced alpha globin expression levels, lower blood-oxygen levels and hypochromia, anisocytosis, and poikilocytosis of red blood cells.	('thalassemia', 'Disease', (78, 89))	('mental retardation', 'Disease', (49, 67))	('reduced', 'NegReg', (114, 121))	('expression levels', 'MPA', (135, 152))	('globin', 'Gene', (128, 134))	('oxygen', 'Chemical', 'MESH:D010100', (166, 172))	('hypochromia', 'Phenotype', 'HP:0032231', (184, 195))	('lower', 'NegReg', (154, 159))	('thalassemia', 'Disease', 'MESH:D013789', (78, 89))	('globin', 'Gene', '30601', (128, 134))	('ATRX', 'Gene', (28, 32))	('poikilocytosis', 'Phenotype', 'HP:0004447', (215, 229))	('hypochromia', 'Disease', 'None', (184, 195))	('loss', 'Var', (20, 24))	('humans', 'Species', '9606', (3, 9))	('poikilocytosis', 'CPA', (215, 229))	('mental retardation', 'Phenotype', 'HP:0001249', (49, 67))	('anisocytosis', 'Phenotype', 'HP:0011273', (197, 209))	('mental retardation', 'Disease', 'MESH:D008607', (49, 67))	('anisocytosis', 'MPA', (197, 209))	('causes', 'Reg', (42, 48))	('hypochromia', 'Disease', (184, 195))	('blood-oxygen levels', 'MPA', (160, 179))	('lower blood-oxygen levels', 'Phenotype', 'HP:0012418', (154, 179))
17047	30970016	Because the ATRX gene is located on the X-chromosome in humans, females can carry a mutant allele heterozygously, without developing symptoms.	('mutant', 'Var', (84, 90))	('humans', 'Species', '9606', (56, 62))	('ATRX', 'Gene', (12, 16))
17053	30970016	Over the past 5 years, it has become apparent that mutations in epigenetic regulator genes are involved in the onset and progression of a large number of malignancies.	('mutations', 'Var', (51, 60))	('malignancies', 'Disease', 'MESH:D009369', (154, 166))	('epigenetic regulator genes', 'Gene', (64, 90))	('malignancies', 'Disease', (154, 166))	('involved', 'Reg', (95, 103))
17054	30970016	The loss of ATRX in gliomas, neuroendocrine tumors and various sarcoma types facilitates alternative lengthening of the telomeres (ALT) and thereby stabilizes the genome of cancer cells during cancer development, a crucial step in the immortalization of cancer cells in general and a requirement for the formation of malignant tumors in humans.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('sarcoma', 'Disease', (63, 70))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (29, 50))	('gliomas', 'Disease', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('humans', 'Species', '9606', (337, 343))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('ATRX', 'Gene', (12, 16))	('loss', 'Var', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (173, 179))	('neuroendocrine tumors', 'Disease', (29, 50))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('malignant tumors', 'Disease', 'MESH:D018198', (317, 333))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('facilitates', 'PosReg', (77, 88))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (29, 50))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('malignant tumors', 'Disease', (317, 333))
17064	30970016	Thus, we knocked out ATRX in the germline of the previously published p53- and nf1-deficient zebrafish model, in which mutants develop malignant peripheral nerve sheath tumors (MPNSTs) and high-grade gliomas.	('develop', 'PosReg', (127, 134))	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('gliomas', 'Disease', (200, 207))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('zebrafish', 'Species', '7955', (93, 102))	('peripheral nerve sheath tumors', 'Disease', 'MESH:D010524', (145, 175))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (135, 175))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('peripheral nerve sheath tumors', 'Disease', (145, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('mutants', 'Var', (119, 126))
17066	30970016	To create loss-of-function (lof) mutations in atrx in zebrafish germline, we induced frameshift-mutations in exon 4 of atrx using CRISPR/Cas9 (S1 Fig and S1 Table).	('atrx', 'Gene', (119, 123))	('loss-of-function', 'NegReg', (10, 26))	('mutations', 'Var', (33, 42))	('zebrafish', 'Species', '7955', (54, 63))	('frameshift-mutations', 'Var', (85, 105))	('atrx', 'Gene', (46, 50))
17068	30970016	Mutant alleles were generated in both wildtype (strain AB) zebrafish and in the previously published nf1/p53-deficient zebrafish line that expresses the green fluorescent protein (GFP) marker under the control of the zebrafish sox10 promoter (sox10:GFP).	('zebrafish', 'Species', '7955', (59, 68))	('sox10', 'Gene', (243, 248))	('zebrafish', 'Species', '7955', (119, 128))	('zebrafish', 'Species', '7955', (217, 226))	('sox10', 'Gene', '140616', (243, 248))	('sox10', 'Gene', '140616', (227, 232))	('sox10', 'Gene', (227, 232))	('Mutant', 'Var', (0, 6))
17071	30970016	All our here presented knockout lines carry frameshift mutations in atrx in germline and thus model a total loss of ATRX, as it is frequently observed in human tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('atrx', 'Gene', (68, 72))	('loss', 'NegReg', (108, 112))	('human', 'Species', '9606', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('frameshift mutations', 'Var', (44, 64))	('ATRX', 'MPA', (116, 120))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
17075	30970016	Previous reports from human patients have shown that ATRX mutations are associated with reduced alpha-globin expression and lead to alpha-thalassemia myelodysplasia syndrome (ATMDS).	('mutations', 'Var', (58, 67))	('globin', 'Gene', (102, 108))	('ATRX', 'Gene', (53, 57))	('expression', 'MPA', (109, 119))	('human', 'Species', '9606', (22, 27))	('alpha-thalassemia', 'Disease', (132, 149))	('reduced', 'NegReg', (88, 95))	('myelodysplasia', 'Phenotype', 'HP:0002863', (150, 164))	('thalassemia myelodysplasia syndrome', 'Disease', 'MESH:C563023', (138, 173))	('globin', 'Gene', '30601', (102, 108))	('reduced alpha-globin expression', 'Phenotype', 'HP:0004315', (88, 119))	('alpha-thalassemia', 'Disease', 'MESH:D017085', (132, 149))	('thalassemia myelodysplasia syndrome', 'Disease', (138, 173))	('lead to', 'Reg', (124, 131))	('patients', 'Species', '9606', (28, 36))
17076	30970016	To investigate the globin expression in atrx mutant zebrafish, we performed whole-mount in situ hybridization (WISH) using alpha-e1 and beta-e1 globin probes.	('beta-e1 globin', 'Gene', '81538', (136, 150))	('mutant', 'Var', (45, 51))	('zebrafish', 'Species', '7955', (52, 61))	('beta-e1 globin', 'Gene', (136, 150))	('globin', 'Gene', '30601', (19, 25))	('globin', 'Gene', '30601', (144, 150))	('globin', 'Gene', (19, 25))	('globin', 'Gene', (144, 150))
17077	30970016	The results showed that the expression levels of alpha-e1 globin, but not beta-e1 globin, were significantly reduced in atrx-/- homozygous mutants compared to atrx+/- heterozygous and wildtype siblings.	('atrx-/-', 'Gene', (120, 127))	('globin', 'Gene', (82, 88))	('globin', 'Gene', (58, 64))	('expression levels', 'MPA', (28, 45))	('beta-e1 globin', 'Gene', '81538', (74, 88))	('beta-e1 globin', 'Gene', (74, 88))	('mutants', 'Var', (139, 146))	('reduced', 'NegReg', (109, 116))	('globin', 'Gene', '30601', (82, 88))	('globin', 'Gene', '30601', (58, 64))
17080	30970016	The expression levels of c-myb at both 36 hpf and 5 dpf did not show significant differences between atrx-/- homozygous mutants and wildtype embryos (S2A-S2C Fig), indicating that the development of hematopoietic stem/progenitor cells was not affected in atrx-/- homozygous mutants.	('c-myb', 'Gene', (25, 30))	('c-myb', 'Gene', '30519', (25, 30))	('mutants', 'Var', (120, 127))	('atrx-/-', 'Gene', (101, 108))
17081	30970016	To study the effects of reduced globin expression on erythropoiesis, we bred the zebrafish atrx+/- mutant with the Tg(gata1:GFP) transgenic line.	('zebrafish', 'Species', '7955', (81, 90))	('reduced globin', 'Phenotype', 'HP:0001903', (24, 38))	('globin', 'Gene', '30601', (32, 38))	('gata1', 'Gene', (118, 123))	('globin', 'Gene', (32, 38))	('mutant', 'Var', (99, 105))	('atrx+/-', 'Gene', (91, 98))	('gata1', 'Gene', '30481', (118, 123))
17083	30970016	At both 7 dpf and 12 dpf, atrx-/- homozygous mutants showed a remarkable increase in GFP-expressing cells in the heart, kidney marrow and caudal hematopoietic tissue (CHT) compared to wildtype fish (Figs 2D and S2D), indicating the accumulation of erythroid progenitors in these regions.	('mutants', 'Var', (45, 52))	('increase', 'PosReg', (73, 81))	('GFP-expressing cells', 'MPA', (85, 105))	('kidney marrow', 'Disease', (120, 133))	('kidney marrow', 'Disease', 'MESH:D001855', (120, 133))	('accumulation', 'PosReg', (232, 244))
17085	30970016	The rounded erythrocytes indicate the presence of circulating erythroid progenitors in the atrx-/- homozygous mutants, reflecting a block in erythroid cell differentiation resulting from the lack of alpha-globin expression.	('mutants', 'Var', (110, 117))	('expression', 'MPA', (212, 222))	('globin', 'Gene', '30601', (205, 211))	('block', 'NegReg', (132, 137))	('lack', 'NegReg', (191, 195))	('globin', 'Gene', (205, 211))	('atrx-/-', 'Gene', (91, 98))	('erythroid cell differentiation', 'CPA', (141, 171))
17086	30970016	Taken together, these data indicate that the zebrafish atrx knockout model closely resembles the phenotype of human thalassemia patients with ATRX mutation, showing reduced globin expression and the accumulation of erythroid progenitors.	('erythroid progenitors', 'CPA', (215, 236))	('thalassemia', 'Disease', (116, 127))	('accumulation', 'PosReg', (199, 211))	('mutation', 'Var', (147, 155))	('reduced globin', 'Phenotype', 'HP:0001903', (165, 179))	('globin', 'Gene', '30601', (173, 179))	('thalassemia', 'Disease', 'MESH:D013789', (116, 127))	('zebrafish', 'Species', '7955', (45, 54))	('human', 'Species', '9606', (110, 115))	('globin', 'Gene', (173, 179))	('ATRX', 'Gene', (142, 146))	('patients', 'Species', '9606', (128, 136))	('reduced', 'NegReg', (165, 172))
17089	30970016	Loss of NF1 removes a major source of GTPase-activation affecting RAS and thus prolongs and strengthens RAS-MAPK signaling, thus enhancing the proliferation and survival of tumor cells.	('GTPase-activation', 'Protein', (38, 55))	('NF1', 'Gene', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('survival', 'CPA', (161, 169))	('RAS', 'Protein', (66, 69))	('strengthens', 'PosReg', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('affecting', 'Reg', (56, 65))	('RAS-MAPK signaling', 'MPA', (104, 122))	('Loss', 'Var', (0, 4))	('enhancing', 'PosReg', (129, 138))	('proliferation', 'CPA', (143, 156))
17090	30970016	The loss of nf1 has previously been shown to synergize with p53 mutation in a zebrafish model of MPNSTs and high-grade gliomas.	('mutation', 'Var', (64, 72))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('nf1', 'Gene', (12, 15))	('gliomas', 'Disease', (119, 126))	('p53', 'Gene', (60, 63))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('zebrafish', 'Species', '7955', (78, 87))	('loss', 'Var', (4, 8))
17098	30970016	Both, atrx+/+ and artx+/- fish of this line developed visually identical tumors located in the eye, gill, head, tail and predominantly in the abdomen (Fig 3A).	('artx+/-', 'Var', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('artx', 'Chemical', '-', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors located in the eye', 'Phenotype', 'HP:0100012', (73, 98))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
17103	30970016	Immunofluorescence staining using an H3K27me3-specific antibody revealed that this epigenetic mark was clearly present in atrx+/- and atrx+/+ tumors in the p53/nf1-deficient background (S3B Fig).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('atrx+/+', 'Var', (134, 141))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('atrx+/-', 'Var', (122, 129))
17115	30970016	Moreover, in the AACR Genie database, ATRX mutations are annotated in 49 cancer type categories (S3 Table), representing at least 45 distinct malignancies.	('ATRX', 'Gene', (38, 42))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (43, 52))	('49 cancer type categories', 'Disease', 'OMIM:617237', (70, 95))	('malignancies', 'Disease', (142, 154))	('49 cancer type categories', 'Disease', (70, 95))
17116	30970016	Within these, uterine sarcoma and glioma have the highest proportion of ATRX-mutant samples (19.60% and 16.74% respectively), whereas soft tissue sarcomas are ranked 15th with 6.42%.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('ATRX-mutant', 'Var', (72, 83))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('sarcoma', 'Disease', (146, 153))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('sarcomas', 'Disease', (146, 154))	('ATRX-mutant', 'Gene', (72, 83))	('sarcoma', 'Disease', (22, 29))	('glioma', 'Disease', (34, 40))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (14, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (134, 154))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
17122	30970016	This cooperation between lof in p53 and atrx in our model is supported by previous data on the combined lof mutations in ATRX and p53 in high-grade gliomas and leiomyosarcomas.	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (160, 175))	('sarcomas', 'Phenotype', 'HP:0100242', (167, 175))	('gliomas', 'Phenotype', 'HP:0009733', (148, 155))	('gliomas', 'Disease', (148, 155))	('mutations', 'Var', (108, 117))	('lof', 'NegReg', (104, 107))	('gliomas', 'Disease', 'MESH:D005910', (148, 155))	('leiomyosarcomas', 'Disease', (160, 175))	('ATRX', 'Gene', (121, 125))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('p53', 'Gene', (130, 133))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (160, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
17123	30970016	In the AACR Genie database, the overall p53 mutation rate considering all tumor samples analyzed is 38.64%, whereas among the ATRX-mutant samples 55.04% are co-mutants for p53 (Fig 6A).	('mutation', 'Var', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('p53', 'Gene', (40, 43))	('tumor', 'Disease', (74, 79))
17124	30970016	Gliomas, the tumors with the second highest prevalence of ATRX-mutation in the database (S3 Table) carry about twice as often a mutation in p53 if they have a mutation in ATRX (Fig 6A).	('Gliomas', 'Disease', (0, 7))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('p53', 'Gene', (140, 143))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('mutation', 'Var', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('ATRX-mutation', 'Gene', (58, 71))
17125	30970016	In ATRX-mutant soft tissue sarcomas p53 mutations are observed almost 2.5 times as often as in the overall cohort.	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcomas', 'Disease', (27, 35))	('observed', 'Reg', (54, 62))	('p53', 'Gene', (36, 39))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (15, 35))	('mutations', 'Var', (40, 49))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))
17126	30970016	Together, these relationships indicate a selection advantage during the development of these particular tumor types for malignant clones with combined deficiencies in ATRX and p53.	('ATRX', 'Gene', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('deficiencies', 'Var', (151, 163))	('p53', 'Gene', (176, 179))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
17127	30970016	This does not extend as clearly to the loss of NF1 in soft tissue sarcomas, gliomas, and serous ovarian cancer (Fig 6B).	('serous ovarian cancer', 'Disease', 'MESH:D010051', (89, 110))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('gliomas', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('NF1', 'Gene', (47, 50))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (54, 74))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('sarcomas', 'Disease', (66, 74))	('loss', 'Var', (39, 43))	('serous ovarian cancer', 'Disease', (89, 110))
17128	30970016	However, when again all tumor samples were considered, similar results as for p53 were observed with 6.4% NF1-mutation rate in all tumor samples and 16.28% in the ATRX-mutated cohort.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('NF1-mutation', 'Gene', (106, 118))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('NF1-mutation', 'Var', (106, 118))
17130	30970016	In hepatobiliary cancer in particular, there is a threefold higher incidence of nf1 mutations in atrx-mutant samples (Fig 6B).	('atrx-mutant', 'Var', (97, 108))	('atrx-mutant', 'Gene', (97, 108))	('higher', 'PosReg', (60, 66))	('hepatobiliary cancer', 'Disease', 'MESH:D004066', (3, 23))	('nf1', 'Gene', (80, 83))	('hepatobiliary cancer', 'Disease', (3, 23))	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
17131	30970016	Thus loss of nf1b, and therefore RAS-MAPK pathway activation, appears to synergize with atrx deficiency in this cancer type.	('RAS-MAPK pathway', 'Pathway', (33, 49))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('activation', 'PosReg', (50, 60))	('atrx deficiency', 'Disease', (88, 103))	('nf1b', 'Gene', (13, 17))	('loss', 'Var', (5, 9))	('atrx deficiency', 'Disease', 'MESH:D007153', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('nf1b', 'Gene', '564518', (13, 17))
17136	30970016	The observation of an undiminished H3K27me3 signal in MPNSTs upon heterozygous atrx knockout in our model fits well to the fact that patients with MPNSTs retaining the H3K27me3 mark have a better prognosis.	('fits', 'Disease', (106, 110))	('patients', 'Species', '9606', (133, 141))	('H3K27me3', 'Protein', (35, 43))	('H3K27me3', 'Var', (168, 176))	('fits', 'Disease', 'MESH:D012640', (106, 110))
17141	30970016	Since ATRX loss in humans is associated with ALT, we used fluorescence in situ hybridization with a telomere-specific probe (TelC-FISH) to visualize the telomeres of atrx+/- and atrx+/+ tumors in our line.	('loss', 'NegReg', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('ATRX', 'Gene', (6, 10))	('atrx+/-', 'Var', (166, 173))	('humans', 'Species', '9606', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('atrx+/+', 'Var', (178, 185))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('associated', 'Reg', (29, 39))	('ALT', 'Disease', (45, 48))
17143	30970016	This indicates that longer telomeres associated with atrx depletion-mediated ALT triggers a downregulation of tert.	('atrx', 'Gene', (53, 57))	('downregulation', 'NegReg', (92, 106))	('depletion-mediated', 'Var', (58, 76))	('tert', 'Gene', '796551', (110, 114))	('tert', 'Gene', (110, 114))
17149	30970016	Thus, in zebrafish, shortening of the telomeres promotes tumor onset, which can be explained by the need in early tumorigenesis to increase the mutational burden by genomic instability in order to develop a malignant cancer.	('mutational', 'MPA', (144, 154))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('increase', 'PosReg', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (114, 119))	('promotes', 'PosReg', (48, 56))	('malignant cancer', 'Disease', 'MESH:D009369', (207, 223))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('develop', 'PosReg', (197, 204))	('zebrafish', 'Species', '7955', (9, 18))	('shortening', 'Var', (20, 30))	('malignant cancer', 'Disease', (207, 223))	('tumor', 'Disease', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
17152	30970016	In this context, induction of ALT due to the loss of atrx would not be expected to accelerate the onset of tumors, but rather facilitate later phases of their progression.	('atrx', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('ALT', 'Disease', (30, 33))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('loss', 'Var', (45, 49))	('facilitate', 'PosReg', (126, 136))
17156	30970016	In this survey, we found the enrichment of notch1-targets (one gene set) and jak-stat-signaling (one gene set), epithelial differentiation (three gene sets) and PRC2-function (11 gene sets) in p53/nf1/atrx-deficient tumors compared to the atrx wildtype controls (Figs 7F and S5, S7 and S8 Tables).	('atrx-deficient tumors', 'Disease', 'MESH:D009369', (201, 222))	('jak-stat-signaling', 'MPA', (77, 95))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('atrx-deficient tumors', 'Disease', (201, 222))	('epithelial', 'MPA', (112, 122))	('notch1', 'Gene', '30718', (43, 49))	('notch1', 'Gene', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('PRC2-function', 'Var', (161, 174))
17157	30970016	Interestingly, 10 of 11 PRC2-related gene sets showed a significant up-regulation of PRC2-targets, SUZ12-targets or H3K27me3 marked genes from various stem and progenitor cell types.	('SUZ12', 'Gene', (99, 104))	('H3K27me3', 'Var', (116, 124))	('PRC2-related gene sets', 'Gene', (24, 46))	('SUZ12', 'Gene', '794171', (99, 104))	('up-regulation', 'PosReg', (68, 81))	('PRC2-targets', 'Gene', (85, 97))
17160	30970016	This observation is consistent with a previous study in human cells where loss of ATRX was found to displace PCR2-deposited H3K27me3 silencing marks away from the target gene promoters to the intergenic space leading to their re-expression.	('ATRX', 'Gene', (82, 86))	('re-expression', 'MPA', (226, 239))	('silencing', 'NegReg', (133, 142))	('human', 'Species', '9606', (56, 61))	('displace', 'NegReg', (100, 108))	('H3K27me3', 'Protein', (124, 132))	('loss', 'Var', (74, 78))
17161	30970016	In this study, we show the consequences of inactivation of atrx in the zebrafish germline, which resulted in the first zebrafish model atrx deficiency causing alpha-thalassemia and the contribution of loss of atrx to carcinogenesis in the background of p53 loss and RAS-MAPK pathway activation.	('loss of atrx to carcinogenesis', 'Disease', (201, 231))	('activation', 'PosReg', (283, 293))	('causing', 'Reg', (151, 158))	('zebrafish', 'Species', '7955', (119, 128))	('atrx', 'Gene', (59, 63))	('atrx deficiency', 'Disease', (135, 150))	('alpha-thalassemia', 'Disease', (159, 176))	('alpha-thalassemia', 'Disease', 'MESH:D017085', (159, 176))	('atrx deficiency', 'Disease', 'MESH:D007153', (135, 150))	('p53', 'Gene', (253, 256))	('loss of atrx to carcinogenesis', 'Disease', 'MESH:D063646', (201, 231))	('loss', 'NegReg', (257, 261))	('zebrafish', 'Species', '7955', (71, 80))	('inactivation', 'Var', (43, 55))	('RAS-MAPK pathway', 'Pathway', (266, 282))
17164	30970016	Our data are consistent with a negative feedback loop downregulating telomerase upon loss of atrx, causing alternative lengthening of the telomeres, and indicate that the role of atrx-deficiency in tumor initiation may also be linked to disturbed PRC2-mediated gene silencing.	('loss', 'Var', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('atrx-deficiency in tumor initiation', 'Disease', (179, 214))	('atrx', 'Gene', (93, 97))	('downregulating', 'NegReg', (54, 68))	('atrx-deficiency in tumor initiation', 'Disease', 'MESH:D009369', (179, 214))	('telomerase', 'Enzyme', (69, 79))
17169	30970016	The p53/nf1-deficient fish carried a frameshift mutation in exon 26 of nf1a and in exon 17 of nf1b which truncate the Nf1 protein before its functional GRD domain, as published in a previous study.	('p53/nf1-deficient', 'Disease', (4, 21))	('nf1b', 'Gene', (94, 98))	('Nf1', 'Gene', '326708', (118, 121))	('nf1b', 'Gene', '564518', (94, 98))	('frameshift mutation in', 'Var', (37, 59))	('nf1a', 'Gene', (71, 75))	('Nf1', 'Gene', (118, 121))	('nf1a', 'Gene', '326708', (71, 75))
17196	30970016	As primary antibodies were used: pan-cytokeratin AE1/AE3 (Novus Biologicals, Littleton, CO, USA), H3K27me3 C36B11 (Cell Signaling Technology, Danvers, MA, USA).	('H3K27me3 C36B11', 'Var', (98, 113))	('cytokeratin', 'Gene', (37, 48))	('AE1', 'Gene', (49, 52))	('AE3', 'Gene', '100333073', (53, 56))	('cytokeratin', 'Gene', '794486', (37, 48))	('AE3', 'Gene', (53, 56))	('AE1', 'Gene', '84703', (49, 52))
17275	30868006	Second, RANKL expression upregulates nuclear factor IB (NFIB), which is associated with decreased vulnerability to various nuclear oncogenes.	('RANKL', 'Gene', '8600', (8, 13))	('RANKL', 'Gene', (8, 13))	('expression', 'Var', (14, 24))	('NFIB', 'Gene', (56, 60))	('upregulates', 'PosReg', (25, 36))	('nuclear factor IB', 'Gene', (37, 54))	('NFIB)', 'Gene', '4781', (56, 61))
17277	30868006	Third, RANKL expression upregulates semaphorin 3A gene expression in osteosarcoma cell lines, and knockout of this gene stimulates deregulated bone and cartilage growth.	('cartilage growth', 'Disease', 'MESH:D006130', (152, 168))	('semaphorin 3A gene', 'Gene', (36, 54))	('knockout', 'Var', (98, 106))	('stimulates', 'PosReg', (120, 130))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('osteosarcoma', 'Disease', (69, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (69, 81))	('expression', 'MPA', (55, 65))	('RANKL', 'Gene', '8600', (7, 12))	('RANKL', 'Gene', (7, 12))	('cartilage growth', 'Disease', (152, 168))	('upregulates', 'PosReg', (24, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
17305	29343911	With the exception of AC, the most common variant bladder cancer histologies are all independently associated with worse DSS relative to UCC in patients undergoing radical cystectomy.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('DSS', 'Chemical', '-', (121, 124))	('DSS', 'Disease', (121, 124))	('bladder cancer', 'Disease', (50, 64))	('patients', 'Species', '9606', (144, 152))	('variant', 'Var', (42, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))
17314	29343911	Histology ICD-O-3 codes were used to identify the most commonly observed bladder cancer histology cell types: UCC (8120, 8130), squamous cell carcinoma (SCC) (8070, 8076), adenocarcinoma (AC) (8140, 8144, 8255, 8260, 8263, 8310, 8323, 8480, 8481, 8570, 8574, 8575), sarcoma (8801-8802, 8810, 8890, 8896, 8880), small cell carcinoma (8041, 8446), signet ring carcinoma (8490), and spindle cell carcinoma (8030, 8031, 8122).	('8140', 'Var', (193, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (311, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('8041, 8446', 'Var', (333, 343))	('ring carcinoma', 'Disease', (353, 367))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))	('spindle cell carcinoma', 'Disease', 'MESH:D002277', (380, 402))	('bladder cancer', 'Disease', (73, 87))	('sarcoma', 'Disease', 'MESH:D012509', (266, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('8570', 'Var', (247, 251))	('adenocarcinoma', 'Disease', (172, 186))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('ring carcinoma', 'Disease', 'MESH:D012303', (353, 367))	('sarcoma', 'Disease', (266, 273))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('small cell carcinoma', 'Disease', (311, 331))	('8801-8802', 'Var', (275, 284))	('8030', 'Var', (404, 408))	('spindle cell carcinoma', 'Disease', (380, 402))	('small cell carcinoma', 'Disease', 'MESH:D018288', (311, 331))	('SCC', 'Gene', '6317', (153, 156))	('squamous cell carcinoma', 'Disease', (128, 151))	('8490', 'Var', (369, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('SCC', 'Gene', (153, 156))	('adenocarcinoma', 'Disease', 'MESH:D000230', (172, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (393, 402))	('UCC', 'Disease', (110, 113))
17330	29343911	Compared to urothelial carcinoma, there was an increased risk of disease-specific death associated with all variants except AC (HR 1.01, 95% CI: 0.82-1.23, P = 0.92) and small cell (HR 1.40, 95% CI: 1.00-1.97, P = 0.49).	('death', 'Disease', 'MESH:D003643', (82, 87))	('urothelial carcinoma', 'Disease', (12, 32))	('death', 'Disease', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('variants', 'Var', (108, 116))	('small cell', 'Disease', (170, 180))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (12, 32))	('disease-specific', 'Disease', (65, 81))
17334	29343911	The present study is the first to perform a comparative survival analysis for multiple histologic variants relative to urothelial carcinoma while controlling for age and other adverse pathologic characteristics.	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (119, 139))	('urothelial carcinoma', 'Disease', (119, 139))	('variants', 'Var', (98, 106))
17336	29343911	Similar to patients with pure UCC, patients with variant histology bladder cancer tended to be males although the patient population with SCC was nearly equal in terms of gender composition.	('SCC', 'Gene', (138, 141))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('patient', 'Species', '9606', (35, 42))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('SCC', 'Gene', '6317', (138, 141))	('patient', 'Species', '9606', (11, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('patient', 'Species', '9606', (114, 121))	('patients', 'Species', '9606', (11, 19))	('variant', 'Var', (49, 56))	('patients', 'Species', '9606', (35, 43))
17349	29343911	Besides AC and small cell carcinoma, the remaining analyzed histologic variants were associated with worse OS and DSS following radical cystectomy.	('variants', 'Var', (71, 79))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (15, 35))	('associated with', 'Reg', (85, 100))	('OS', 'Chemical', '-', (107, 109))	('small cell carcinoma', 'Disease', (15, 35))	('worse OS', 'Disease', (101, 109))	('small cell carcinoma', 'Disease', 'MESH:D018288', (15, 35))	('DSS', 'Chemical', '-', (114, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('DSS', 'Disease', (114, 117))
17421	33707617	One patient had a mutation of ARID2 in the recurrence of the GCTB under treatment with denosumab.	('GCTB', 'Phenotype', 'HP:0011847', (61, 65))	('denosumab', 'Chemical', 'MESH:D000069448', (87, 96))	('patient', 'Species', '9606', (4, 11))	('ARID2', 'Gene', '196528', (30, 35))	('GCTB', 'Gene', (61, 65))	('mutation', 'Var', (18, 26))	('ARID2', 'Gene', (30, 35))
17423	33707617	Sequencing revealed a persisting H3F3A mutation in the osteosarcoma while the pleomorphic sarcoma lost the H3F3A mutation; however, a FGFR1 mutation, both in the recurrence and in the pleomorphic sarcoma persisted.	('H3F3A', 'Gene', (33, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('lost', 'NegReg', (98, 102))	('mutation', 'Var', (39, 47))	('FGFR1', 'Gene', (134, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('pleomorphic sarcoma', 'Disease', 'MESH:D012509', (184, 203))	('osteosarcoma', 'Disease', (55, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('FGFR1', 'Gene', '2260', (134, 139))	('H3F3A', 'Gene', '3020', (107, 112))	('pleomorphic sarcoma', 'Disease', (184, 203))	('pleomorphic sarcoma', 'Disease', 'MESH:D012509', (78, 97))	('H3F3A', 'Gene', '3020', (33, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('H3F3A', 'Gene', (107, 112))	('pleomorphic sarcoma', 'Disease', (78, 97))
17430	33707617	The stroma cells are the neoplastic component of GCTB and harbour a characteristic point mutation at the histone gene H3F3A leading to a substitution of glycine by tryptophan at position 34 (G34W).	('substitution', 'Var', (137, 149))	('GCTB', 'Phenotype', 'HP:0011847', (49, 53))	('H3F3A', 'Gene', (118, 123))	('H3F3A', 'Gene', '3020', (118, 123))	('glycine by tryptophan at position 34', 'Mutation', 'p.G34W', (153, 189))	('G34W', 'Mutation', 'p.G34W', (191, 195))
17440	33707617	A biopsy was performed and the diagnosis of GCTB was confirmed by detection of the H3F3A G34W mutation.	('H3F3A', 'Gene', '3020', (83, 88))	('G34W', 'Var', (89, 93))	('H3F3A', 'Gene', (83, 88))	('G34W', 'Mutation', 'p.G34W', (89, 93))	('GCTB', 'Phenotype', 'HP:0011847', (44, 48))
17445	33707617	The tumor mass was resected in 07/2017 and a high-grade osteosarcoma with angioinvasion harbouring the H3F3A G34W mutation was diagnosed.	('tumor', 'Disease', (4, 9))	('G34W', 'Var', (109, 113))	('G34W', 'Mutation', 'p.G34W', (109, 113))	('H3F3A', 'Gene', '3020', (103, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('osteosarcoma', 'Disease', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('H3F3A', 'Gene', (103, 108))	('osteosarcoma', 'Disease', 'MESH:D012516', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
17453	33707617	Immunohistochemistry was performed as described using a mutation specific monoclonal antibody for detection of the H3F3A G34W mutation (Anti H3.3 G34W clone 31-1145-00; RevMab Biosciences, San Francisco, CA, USA; dilution 1:400); for detection of proliferation indices the Ki-67 antibody (M7240, Dako, Glostrup, Denmark; dilution 1:200) was applied.	('H3F3A', 'Gene', '3020', (115, 120))	('G34W', 'Var', (121, 125))	('H3F3A', 'Gene', (115, 120))	('G34W', 'Mutation', 'p.G34W', (146, 150))	('G34W', 'Mutation', 'p.G34W', (121, 125))
17459	33707617	We further performed Sanger-Sequencing for H3F3A G34W for all tissue samples of patient 1 and patient 3.	('H3F3A', 'Gene', (43, 48))	('G34W', 'Var', (49, 53))	('patient', 'Species', '9606', (94, 101))	('G34W', 'Mutation', 'p.G34W', (49, 53))	('H3F3A', 'Gene', '3020', (43, 48))	('patient', 'Species', '9606', (80, 87))
17462	33707617	Single nucleotide polymorphisms (SNP) detected in non-tumor-tissue were excluded from further analysis.	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
17465	33707617	The primary tumor showed a strong positivity for the H3.3 G34W detecting antibody in the nuclei of the stromal compartment.	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('G34W', 'Var', (58, 62))	('H3.3', 'Protein', (53, 57))	('tumor', 'Disease', (12, 17))	('G34W', 'Mutation', 'p.G34W', (58, 62))
17467	33707617	A second mononuclear cell population was detected being negative for H3.3 G34W which most probably presents osteoclastic precursors.	('osteoclastic', 'Disease', 'MESH:D001862', (108, 120))	('osteoclastic', 'Disease', (108, 120))	('G34W', 'Mutation', 'p.G34W', (74, 78))	('H3.3 G34W', 'Var', (69, 78))
17470	33707617	We detected an intermingled spindle cell compartment negative for H3.3 G34W.	('H3.3', 'Gene', (66, 70))	('G34W', 'Mutation', 'p.G34W', (71, 75))	('G34W', 'Var', (71, 75))
17471	33707617	The presence of the H3F3A G34W mutation was further proven by Sanger sequencing.	('G34W', 'Mutation', 'p.G34W', (26, 30))	('H3F3A', 'Gene', (20, 25))	('G34W', 'Var', (26, 30))	('H3F3A', 'Gene', '3020', (20, 25))
17472	33707617	Panel sequencing of microdissected tissue of the resected tumor and the biopsy of the recurrence revealed a mutation of ARID2 (chromosome 12; position (GRCh37) 46205208, c.292G > A; p.E98K) with an allele frequency of 48% in the tumor recurrence under denosumab treatment.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('c.292G > A', 'Mutation', 'rs140285438', (170, 180))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('ARID2', 'Gene', '196528', (120, 125))	('c.292G > A', 'Var', (170, 180))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('ARID2', 'Gene', (120, 125))	('denosumab', 'Chemical', 'MESH:D000069448', (252, 261))	('p.E98K', 'Mutation', 'rs140285438', (182, 188))
17475	33707617	Immunochemistry and sequencing confirmed the diagnosis of GCTB with positive staining for the mutation H3F3A G34W.	('G34W', 'Var', (109, 113))	('G34W', 'Mutation', 'p.G34W', (109, 113))	('H3F3A', 'Gene', '3020', (103, 108))	('GCTB', 'Phenotype', 'HP:0011847', (58, 62))	('H3F3A', 'Gene', (103, 108))
17478	33707617	The sarcoma harboured the H3F3A G34W mutation as shown by immunohistochemistry in all tumor cells and a Ki-67 index of 90% (Fig.	('H3F3A', 'Gene', '3020', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('sarcoma', 'Disease', (4, 11))	('H3F3A', 'Gene', (26, 31))	('G34W', 'Mutation', 'p.G34W', (32, 36))	('tumor', 'Disease', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('G34W', 'Var', (32, 36))
17479	33707617	This presence of the mutation was further confirmed by Sanger sequencing for H3F3A G34W mutation.	('H3F3A', 'Gene', '3020', (77, 82))	('G34W', 'Mutation', 'p.G34W', (83, 87))	('G34W', 'Var', (83, 87))	('H3F3A', 'Gene', (77, 82))
17484	33707617	Sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine that was below the detection threshold as shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('G34W-negative', 'Var', (58, 71))	('thymine', 'Chemical', 'MESH:D013941', (126, 133))	('H3F3A', 'Gene', '3020', (52, 57))	('H3F3A', 'Gene', (52, 57))	('G34W', 'Mutation', 'p.G34W', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutation-specific', 'Reg', (108, 125))
17485	33707617	In the panel-sequencing we found a mutation of FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118) in the resection specimen of the GCTB and in the sarcoma with an allele frequency of 10%, which was not found in the biopsy.	('c354G > A', 'Var', (96, 105))	('FGFR1', 'Gene', (47, 52))	('FGFR1', 'Gene', '2260', (47, 52))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('GCTB', 'Phenotype', 'HP:0011847', (148, 152))	('sarcoma', 'Disease', (164, 171))	('c354G > A', 'Mutation', 'c.354G>A', (96, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
17506	33707617	This finding suggests that mutated ARID2 is a marker during tumor progression under denosumab treatment in this H3F3A-mutated GCTB, although no sarcomatous transformation is present.	('ARID2', 'Gene', '196528', (35, 40))	('mutated', 'Var', (27, 34))	('ARID2', 'Gene', (35, 40))	('H3F3A', 'Gene', (112, 117))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (144, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('GCTB', 'Phenotype', 'HP:0011847', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('sarcomatous transformation', 'Disease', 'MESH:D018316', (144, 170))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('H3F3A', 'Gene', '3020', (112, 117))	('tumor', 'Disease', (60, 65))	('denosumab', 'Chemical', 'MESH:D000069448', (84, 93))	('sarcomatous transformation', 'Disease', (144, 170))
17507	33707617	In line with this finding is that ARID2 was identified to play a critical role in the differentiation of osteoblasts and that a mutation may interfere in this process.	('differentiation of osteoblasts', 'CPA', (86, 116))	('interfere', 'NegReg', (141, 150))	('ARID2', 'Gene', '196528', (34, 39))	('mutation', 'Var', (128, 136))	('ARID2', 'Gene', (34, 39))
17508	33707617	The second patient reported was characterized by a persisting H3F3A mutation in the relapse as well as in the osteosarcoma arising in the sacrum.	('mutation', 'Var', (68, 76))	('osteosarcoma', 'Disease', (110, 122))	('H3F3A', 'Gene', '3020', (62, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (110, 122))	('patient', 'Species', '9606', (11, 18))	('osteosarcoma', 'Disease', 'MESH:D012516', (110, 122))	('H3F3A', 'Gene', (62, 67))
17510	33707617	In rare cases, H3F3A mutations have been described in osteosarcoma of the epiphyseal region of mostly older patients as shown by Koelsche et al..	('osteosarcoma of the epiphyseal', 'Disease', (54, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('described', 'Reg', (41, 50))	('H3F3A', 'Gene', (15, 20))	('H3F3A', 'Gene', '3020', (15, 20))	('patients', 'Species', '9606', (108, 116))	('osteosarcoma', 'Phenotype', 'HP:0002669', (54, 66))	('osteosarcoma of the epiphyseal', 'Disease', 'MESH:D012516', (54, 84))	('mutations', 'Var', (21, 30))
17515	33707617	In addition, we detected a mutation in AKT2 and NRAS in the sarcoma.	('NRAS', 'Gene', '4893', (48, 52))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('AKT2', 'Gene', (39, 43))	('mutation', 'Var', (27, 35))	('sarcoma', 'Disease', (60, 67))	('AKT2', 'Gene', '208', (39, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('detected', 'Reg', (16, 24))	('NRAS', 'Gene', (48, 52))
17516	33707617	This may point to the evolution of a high-grade sarcoma from a H3F3A-negative, but FGFR1-positive subclone with acquisition of additional mutations in AKT2 and NRAS during tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('NRAS', 'Gene', (160, 164))	('H3F3A', 'Gene', '3020', (63, 68))	('tumor', 'Disease', (172, 177))	('sarcoma', 'Disease', (48, 55))	('NRAS', 'Gene', '4893', (160, 164))	('H3F3A', 'Gene', (63, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('FGFR1', 'Gene', (83, 88))	('AKT2', 'Gene', (151, 155))	('FGFR1', 'Gene', '2260', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('AKT2', 'Gene', '208', (151, 155))	('sarcoma', 'Disease', 'MESH:D012509', (48, 55))	('mutations', 'Var', (138, 147))
17518	33707617	Although the detected mutations in NRAS and AKT2 are intronic in the presented GCTB with no effect on the cDNA level these two genes have been shown to play a role in bone physiology and osteosarcomas.	('play', 'Reg', (152, 156))	('NRAS', 'Gene', (35, 39))	('osteosarcomas', 'Phenotype', 'HP:0002669', (187, 200))	('role', 'Reg', (159, 163))	('AKT2', 'Gene', (44, 48))	('NRAS', 'Gene', '4893', (35, 39))	('osteosarcoma', 'Phenotype', 'HP:0002669', (187, 199))	('GCTB', 'Phenotype', 'HP:0011847', (79, 83))	('AKT2', 'Gene', '208', (44, 48))	('mutations', 'Var', (22, 31))	('bone physiology', 'Disease', (167, 182))	('osteosarcomas', 'Disease', (187, 200))	('osteosarcomas', 'Disease', 'MESH:D012516', (187, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
17519	33707617	While NRAS mutations have been described in dysplastic bone formation, AKT2 has been shown to play a role in tumor growth by inhibiting cisplatin-induced apoptosis in primary osteosarcomas.	('mutations', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('primary osteosarcomas', 'Disease', 'MESH:D012516', (167, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('NRAS', 'Gene', '4893', (6, 10))	('osteosarcoma', 'Phenotype', 'HP:0002669', (175, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('dysplastic bone', 'Disease', (44, 59))	('dysplastic bone', 'Disease', 'MESH:D001859', (44, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('primary osteosarcomas', 'Disease', (167, 188))	('AKT2', 'Gene', '208', (71, 75))	('NRAS', 'Gene', (6, 10))	('cisplatin-induced apoptosis', 'MPA', (136, 163))	('osteosarcomas', 'Phenotype', 'HP:0002669', (175, 188))	('AKT2', 'Gene', (71, 75))	('dysplastic bone', 'Phenotype', 'HP:0002652', (44, 59))	('inhibiting', 'NegReg', (125, 135))	('tumor', 'Disease', (109, 114))
17522	33707617	Large studies with a total of 2315 patients with GCTB have shown a cumulative incidence of primary malignant giant cell tumor of Bone (PMGCTB) of 1.6% in GCTB compared with 2.4% for secondary malignant giant cell tumor of bone (SMGCTB) following radiotherapy.	('malignant giant cell tumor', 'Disease', (192, 218))	('giant cell tumor', 'Phenotype', 'HP:0011847', (109, 125))	('GCTB', 'Phenotype', 'HP:0011847', (137, 141))	('GCTB', 'Var', (154, 158))	('GCTB', 'Phenotype', 'HP:0011847', (154, 158))	('giant cell tumor', 'Phenotype', 'HP:0011847', (202, 218))	('GCTB', 'Phenotype', 'HP:0011847', (230, 234))	('malignant giant cell tumor', 'Disease', 'MESH:D005870', (99, 125))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (202, 226))	('malignant giant cell tumor', 'Disease', 'MESH:D005870', (192, 218))	('giant cell tumor of Bone', 'Phenotype', 'HP:0011847', (109, 133))	('GCTB', 'Phenotype', 'HP:0011847', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor of bone', 'Phenotype', 'HP:0010622', (213, 226))	('malignant giant cell tumor', 'Disease', (99, 125))
17649	29484083	Fluorescence in situ hybridization using dual-color break-apart probes showed the presence of translocation of the Ewing sarcoma breakpoint region 1 (EWSR1) gene at chromosome 22q12, and the reverse transcriptase polymerase chain reaction studies were positive for the EWSR1-FLI1 fusion transcript, all of which strongly suggested the diagnosis of ES/PNET in the adrenal gland.	('Ewing sarcoma breakpoint region 1', 'Gene', (115, 148))	('FLI1', 'Gene', '2313', (275, 279))	('positive', 'Reg', (252, 260))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (115, 148))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (115, 128))	('EWSR1', 'Gene', '2130', (150, 155))	('ES/PNET', 'Disease', (348, 355))	('EWSR1', 'Gene', (269, 274))	('PNET', 'Phenotype', 'HP:0030065', (351, 355))	('suggested', 'Reg', (321, 330))	('ES', 'Phenotype', 'HP:0012254', (348, 350))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('translocation', 'Var', (94, 107))	('EWSR1', 'Gene', (150, 155))	('EWSR1', 'Gene', '2130', (269, 274))	('FLI1', 'Gene', (275, 279))
17656	29484083	These malignant neoplasms characteristically have a nonrandom translocation of the EWSR1 gene on chromosome 22q12 with resultant chimeric genes including t(11;22)(q24;q12) and an EWSR1-FLI1 chimeric gene.	('FLI1', 'Gene', (185, 189))	('EWSR1', 'Gene', (83, 88))	('t(11;22)(q24;q12', 'Var', (154, 170))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (154, 171))	('FLI1', 'Gene', '2313', (185, 189))	('neoplasms', 'Phenotype', 'HP:0002664', (16, 25))	('EWSR1', 'Gene', '2130', (179, 184))	('EWSR1', 'Gene', '2130', (83, 88))	('malignant neoplasms', 'Disease', 'MESH:D009369', (6, 25))	('malignant neoplasms', 'Disease', (6, 25))	('EWSR1', 'Gene', (179, 184))
17664	29484083	Although EWSR1 translocation indicates the presence of ES/PNET, desmoplastic small round-cell tumors or myxoid liposarcoma can also express this type of translocation, whereas <1% of ES/PNET have no translocation at all.	('myxoid liposarcoma', 'Disease', (104, 122))	('ES', 'Phenotype', 'HP:0012254', (55, 57))	('liposarcoma', 'Phenotype', 'HP:0012034', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PNET', 'Phenotype', 'HP:0030065', (58, 62))	('ES', 'Phenotype', 'HP:0012254', (183, 185))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (104, 122))	('EWSR1', 'Gene', (9, 14))	('ES/PNET', 'Var', (55, 62))	('PNET', 'Phenotype', 'HP:0030065', (186, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('EWSR1', 'Gene', '2130', (9, 14))	('desmoplastic small round-cell tumors', 'Disease', 'MESH:D058405', (64, 100))	('desmoplastic small round-cell tumors', 'Disease', (64, 100))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (104, 122))
17670	29484083	Wilms' tumor stains usually with CD56, CD57, CK22, CK18, EMA, and SMA, and in most cases, there is no genetic mutation except that, in 20%-30% of the cases, mutations of the WT1 gene on chromosome 11p13 and inactivation of a gene on the X chromosome, WTX can be encountered.	('SMA', 'Gene', (66, 69))	('CD57', 'Gene', (39, 43))	('CK18', 'Gene', (51, 55))	('WT1', 'Gene', '7490', (174, 177))	('WT1', 'Gene', (174, 177))	('CD57', 'Gene', '27087', (39, 43))	('SMA', 'Gene', '6606', (66, 69))	("Wilms' tumor", 'Disease', (0, 12))	('CK18', 'Gene', '3875', (51, 55))	('WTX', 'Gene', (251, 254))	("Wilms' tumor", 'Disease', 'MESH:D009396', (0, 12))	('CD56', 'Gene', '4684', (33, 37))	('mutations', 'Var', (157, 166))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (0, 12))	('WTX', 'Gene', '139285', (251, 254))	('CD56', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
17671	29484083	Immunostaining for desmin, positive staining for antibody against WT1 protein, and demonstration of a EWS-WT1 gene fusion suggest desmoplastic small round-cell tumors.	('desmin', 'Gene', '1674', (19, 25))	('EWS-WT1', 'Gene', (102, 109))	('WT1', 'Gene', '7490', (106, 109))	('WT1', 'Gene', (106, 109))	('WT1', 'Gene', '7490', (66, 69))	('WT1', 'Gene', (66, 69))	('desmoplastic small round-cell tumors', 'Disease', (130, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('fusion', 'Var', (115, 121))	('desmoplastic small round-cell tumors', 'Disease', 'MESH:D058405', (130, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('EWS-WT1', 'Gene', '7490', (102, 109))	('desmin', 'Gene', (19, 25))
17673	29484083	For the diagnosis of solitary fibrous tumors, immunostaining for CD34 and STAT6 can be helpful, and demonstration of fusions of the 2 genes, NGFI-A binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, further confirms the diagnosis.	('fusions', 'Var', (117, 124))	('NGFI-A binding protein 2', 'Gene', '4665', (141, 165))	('NAB2', 'Gene', '4665', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('NGFI-A binding protein 2', 'Gene', (141, 165))	('STAT6', 'Gene', (74, 79))	('solitary fibrous tumors', 'Disease', (21, 44))	('STAT6', 'Gene', (177, 182))	('NAB2', 'Gene', (167, 171))	('STAT6', 'Gene', '6778', (74, 79))	('CD34', 'Gene', '947', (65, 69))	('CD34', 'Gene', (65, 69))	('solitary fibrous tumors', 'Disease', 'MESH:D054364', (21, 44))	('STAT6', 'Gene', '6778', (177, 182))
17677	29484083	Demonstration of mutations in the MC1R gene and of the MDM2 SNP309 gene may further help confirm the diagnosis.	('MC1R', 'Gene', '4157', (34, 38))	('MC1R', 'Gene', (34, 38))	('MDM2', 'Gene', '4193', (55, 59))	('MDM2', 'Gene', (55, 59))	('mutations', 'Var', (17, 26))
17738	29099001	Other factors are male gender, extensive tumor necrosis, high grade, large number of mitotic figures (>10/hpf), and syt-ssx1 variant.	('ssx1', 'Gene', '6756', (120, 124))	('variant', 'Var', (125, 132))	('tumor necrosis', 'Disease', 'MESH:D009336', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor necrosis', 'Disease', (41, 55))	('syt', 'Gene', '6857', (116, 119))	('syt', 'Gene', (116, 119))	('ssx1', 'Gene', (120, 124))
17740	29099001	SYT-SSX1 variant is associated with more aggressive phenotype and more tumor cell proliferation.	('tumor cell proliferation', 'CPA', (71, 95))	('variant', 'Var', (9, 16))	('SSX1', 'Gene', '6756', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('more', 'PosReg', (66, 70))	('SSX1', 'Gene', (4, 8))
17807	22982899	The majority, particularly those with a classic low-grade histologic appearance, contain a genetic fusion involving JAZF1 and members of polycomb complex gene (SUZ12, PHF1, EPC1) most frequently resulting from a chromosomal translocation, t(7;17).	('PHF1', 'Gene', (167, 171))	('PHF1', 'Gene', '5252', (167, 171))	('EPC1', 'Gene', '80314', (173, 177))	('JAZF1', 'Gene', (116, 121))	('JAZF1', 'Gene', '221895', (116, 121))	('genetic fusion', 'Var', (91, 105))	('SUZ12', 'Gene', (160, 165))	('SUZ12', 'Gene', '23512', (160, 165))	('EPC1', 'Gene', (173, 177))	('resulting from', 'Reg', (195, 209))
17808	22982899	We recently described and characterized a series of ESS with YWHAE-FAM22A/B (YWHAE-FAM22) genetic fusion resulting from t(10;17)(q22;p13).	('YWHAE', 'Gene', (77, 82))	('t(10;17)(q22;p13', 'Var', (120, 136))	('YWHAE', 'Gene', '7531', (77, 82))	('YWHAE', 'Gene', '7531', (61, 66))	('FAM22A/B', 'Gene', (67, 75))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (120, 137))	('FAM22A/B', 'Gene', '728118;729262', (67, 75))	('YWHAE', 'Gene', (61, 66))
17820	22982899	Formalin-fixed paraffin-embedded tumor tissues were obtained from ESS in which FISH studies had demonstrated either YWHAE-FAM22 rearrangement (n=12), JAZF1/SUZ12/PHF1/EPC1 rearrangement (n=34) or no demonstrable genetic rearrangement (n=21); these were from the pathology archives at Brigham and Women's Hospital, Massachusetts General Hospital, Vancouver General Hospital and Toronto General Hospital.	('YWHAE', 'Gene', (116, 121))	('EPC1', 'Gene', (167, 171))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('EPC1', 'Gene', '80314', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('JAZF1', 'Gene', (150, 155))	('Women', 'Species', '9606', (296, 301))	('PHF1', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('YWHAE', 'Gene', '7531', (116, 121))	('SUZ12', 'Gene', '23512', (156, 161))	('tumor', 'Disease', (33, 38))	('rearrangement', 'Var', (128, 141))	('JAZF1', 'Gene', '221895', (150, 155))	('PHF1', 'Gene', '5252', (162, 166))	('SUZ12', 'Gene', (156, 161))
17844	22982899	All 13 UES with nuclear pleomorphism (UES-P) showed focal (<20%) cyclin D1 staining (Figure 5D).	('cyclin D1', 'Gene', (65, 74))	('nuclear pleomorphism', 'Var', (16, 36))	('cyclin D1', 'Gene', '595', (65, 74))
17883	22982899	In the case of mantle cell lymphoma, genetic rearrangement between IGH@ and CCND1 results in upregulated cyclin D1 expression at mRNA and protein levels.	('IGH@', 'Gene', '3492', (67, 71))	('cell lymphoma', 'Phenotype', 'HP:0012191', (22, 35))	('CCND1', 'Gene', (76, 81))	('genetic rearrangement', 'Var', (37, 58))	('CCND1', 'Gene', '595', (76, 81))	('cyclin D1', 'Gene', '595', (105, 114))	('lymphoma', 'Phenotype', 'HP:0002665', (27, 35))	('expression', 'MPA', (115, 125))	('cyclin D1', 'Gene', (105, 114))	('IGH@', 'Gene', (67, 71))	('upregulated', 'PosReg', (93, 104))	('mantle cell lymphoma', 'Disease', (15, 35))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (15, 35))
17885	22982899	The mechanisms underlying cyclin D1 upregulation in tumors include chromosomal translocation, amplification and increased protein stability.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('upregulation', 'PosReg', (36, 48))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cyclin D1', 'Gene', '595', (26, 35))	('cyclin D1', 'Gene', (26, 35))	('increased', 'PosReg', (112, 121))	('amplification', 'MPA', (94, 107))	('chromosomal translocation', 'Var', (67, 92))	('protein stability', 'MPA', (122, 139))
18031	20573854	The hit-and-run hypothesis proposes that cumulative host mutations can allow viral genomes to be lost entirely, such that cancers remaining virus-positive represent only a fraction of those to which infection contributes.	('mutations', 'Var', (57, 66))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('lost', 'NegReg', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))
18034	20573854	Vaccination with a non-persistent MuHV-4 mutant nonetheless conferred complete protection.	('MuHV-4', 'Species', '33708', (34, 40))	('MuHV-4', 'Gene', (34, 40))	('mutant', 'Var', (41, 47))
18043	20573854	However, cancers accumulate vast numbers of host mutations, some of which will inevitably promote more autonomous growth.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('mutations', 'Var', (49, 58))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('promote', 'PosReg', (90, 97))
18088	20573854	with ORF73-Cre- MuHV-4, which lacks episome maintenance and so fails to persist in vivo.	('ORF73-Cre-', 'Var', (5, 15))	('lacks', 'NegReg', (30, 35))	('MuHV-4', 'Species', '33708', (16, 22))	('episome maintenance', 'MPA', (36, 55))
18094	20573854	It also protected against the milder histological changes induced by Cre+ MuHV-4 in p53flox/flox mice (Fig.	('MuHV-4', 'Species', '33708', (74, 80))	('mice', 'Species', '10090', (97, 101))	('protected', 'Reg', (8, 17))	('Cre+ MuHV-4', 'Var', (69, 80))
18098	20573854	Most analyses of human cancers have focused on examples of genome retention.	('human', 'Species', '9606', (17, 22))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('genome retention', 'Var', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
18105	20573854	In contrast, host mutations drive non-immunogenic cell proliferation even when the viral growth programme is turned off.	('rat', 'Species', '10116', (62, 65))	('mutations', 'Var', (18, 27))	('drive', 'Reg', (28, 33))	('non-immunogenic cell proliferation', 'CPA', (34, 68))
18133	20573854	Replication-deficient, Cre+ MuHV-4 was made by digesting a HincII genomic fragment (63844-70433) in pUC9 with BsmI (67792) and ClaI (69177) to remove most of ORF50 exon 2 (67661-69376).	('MuHV-4', 'Species', '33708', (28, 34))	('ORF50 exon', 'Gene', (158, 168))	('67661-69376', 'Var', (172, 183))	('63844-70433', 'Var', (84, 95))
18146	33836796	Undifferentiated colonic neoplasm with SMARCA4 germline gene mutation and loss of SMARCA4 protein expression: a case report and literature review Nonsense mutation or inactivation of SMARCA4 (BRG1) is associated with a monomorphic undifferentiated histological appearance in tumors at different sites.	('Nonsense mutation', 'Var', (146, 163))	('mutation', 'Var', (61, 69))	('SMARCA4', 'Gene', (183, 190))	('BRG1', 'Gene', '6597', (192, 196))	('Undifferentiated colonic neoplasm', 'Disease', (0, 33))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('loss', 'NegReg', (74, 78))	('BRG1', 'Gene', (192, 196))	('SMARCA4', 'Gene', (39, 46))	('SMARCA4', 'Gene', '6597', (82, 89))	('neoplasm', 'Phenotype', 'HP:0002664', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Disease', (275, 281))	('Undifferentiated colonic neoplasm', 'Disease', 'MESH:D003110', (0, 33))	('SMARCA4', 'Gene', '6597', (183, 190))	('inactivation', 'Var', (167, 179))	('colonic neoplasm', 'Phenotype', 'HP:0100273', (17, 33))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('associated', 'Reg', (201, 211))	('SMARCA4', 'Gene', '6597', (39, 46))	('SMARCA4', 'Gene', (82, 89))
18147	33836796	The association between SMARCA4 alteration and undifferentiated colonic carcinoma needs to be further elucidated.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('alteration', 'Var', (32, 42))	('undifferentiated colonic carcinoma', 'Disease', (47, 81))	('SMARCA4', 'Gene', (24, 31))	('SMARCA4', 'Gene', '6597', (24, 31))	('undifferentiated colonic carcinoma', 'Disease', 'MESH:D003110', (47, 81))
18156	33836796	We presented a rare case of undifferentiated colonic neoplasm with loss of SMARCA4 protein expression and germline SMARCA4 mutation.	('expression', 'MPA', (91, 101))	('mutation', 'Var', (123, 131))	('colonic neoplasm', 'Phenotype', 'HP:0100273', (45, 61))	('protein', 'Protein', (83, 90))	('SMARCA4', 'Gene', (115, 122))	('undifferentiated colonic neoplasm', 'Disease', (28, 61))	('loss', 'NegReg', (67, 71))	('SMARCA4', 'Gene', (75, 82))	('neoplasm', 'Phenotype', 'HP:0002664', (53, 61))	('SMARCA4', 'Gene', '6597', (115, 122))	('undifferentiated colonic neoplasm', 'Disease', 'MESH:D003110', (28, 61))	('SMARCA4', 'Gene', '6597', (75, 82))
18161	33836796	Inactivation of SMARCA4 and other subunits of the SWI/SNF complex have been associated with a monomorphic undifferentiated histological appearance in tumors at different sites.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('associated with', 'Reg', (76, 91))	('SMARCA4', 'Gene', (16, 23))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SMARCA4', 'Gene', '6597', (16, 23))	('Inactivation', 'Var', (0, 12))
18162	33836796	SMARCA4 is frequently inactivated by mutations or other mechanisms in malignancies, such as non-small cell lung cancer, thoracic sarcoma, and malignant rhabdoid tumors.	('thoracic sarcoma', 'Disease', 'MESH:D012509', (120, 136))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (142, 167))	('SMARCA4', 'Gene', (0, 7))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))	('thoracic sarcoma', 'Disease', (120, 136))	('malignant rhabdoid tumors', 'Disease', (142, 167))	('malignancies', 'Disease', 'MESH:D009369', (70, 82))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('lung cancer', 'Disease', (107, 118))	('malignancies', 'Disease', (70, 82))	('inactivated', 'NegReg', (22, 33))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('SMARCA4', 'Gene', '6597', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
18163	33836796	SMARCA4 mutations (both somatic and germline mutations) are currently recognized as genetic driver events in almost all small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), which is the most common undifferentiated ovarian malignancy in women under 40 years of age.	('SMARCA4', 'Gene', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('women', 'Species', '9606', (249, 254))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (120, 141))	('SMARCA4', 'Gene', '6597', (0, 7))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (120, 140))	('hypercalcemic type', 'Disease', (156, 174))	('mutations', 'Var', (8, 17))	('undifferentiated ovarian malignancy', 'Disease', 'MESH:D008228', (210, 245))	('ovarian malignancy', 'Phenotype', 'HP:0100615', (227, 245))	('SCCOHT', 'Chemical', '-', (176, 182))	('undifferentiated ovarian malignancy', 'Disease', (210, 245))	('carcinomas of the ovary', 'Disease', (131, 154))	('carcinomas of the ovary', 'Phenotype', 'HP:0100615', (131, 154))	('carcinomas of the ovary', 'Disease', 'MESH:D010051', (131, 154))
18166	33836796	The association between undifferentiated carcinoma and SMARCA4 alterations, especially the genetic alterations, has not been elucidated.	('undifferentiated carcinoma', 'Disease', (24, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('alterations', 'Var', (63, 74))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (24, 50))	('SMARCA4', 'Gene', (55, 62))	('SMARCA4', 'Gene', '6597', (55, 62))
18167	33836796	We reported a rare case of a 61-year-old man diagnosed with undifferentiated colonic neoplasm with a heterogeneous pattern of loss expression of SMARCA4 and germline SMARCA4 mutation, as well as predictive markers for potential immunotherapy or targeted therapy.	('colonic neoplasm', 'Phenotype', 'HP:0100273', (77, 93))	('undifferentiated colonic neoplasm', 'Disease', (60, 93))	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))	('loss expression', 'NegReg', (126, 141))	('undifferentiated colonic neoplasm', 'Disease', 'MESH:D003110', (60, 93))	('mutation', 'Var', (174, 182))	('SMARCA4', 'Gene', (145, 152))	('SMARCA4', 'Gene', '6597', (145, 152))	('SMARCA4', 'Gene', (166, 173))	('SMARCA4', 'Gene', '6597', (166, 173))
18168	33836796	Moreover, the role of SMARCA4 alterations in diagnosing and treating other tumors was also discussed.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('alterations', 'Var', (30, 41))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('SMARCA4', 'Gene', (22, 29))	('SMARCA4', 'Gene', '6597', (22, 29))
18180	33836796	NGS showed a germline SMARCA4 c.3277C>T(p.R1093*)mutation and no abnormal SMARCB1 gene.	('c.3277C>T', 'Mutation', 'c.3277C>T', (30, 39))	('SMARCB1', 'Gene', '6598', (74, 81))	('p.R1093*', 'Mutation', 'p.R1093*', (40, 48))	('SMARCB1', 'Gene', (74, 81))	('p.R1093*', 'Var', (40, 48))	('SMARCA4', 'Gene', (22, 29))	('SMARCA4', 'Gene', '6597', (22, 29))
18181	33836796	The tumor exhibited microsatellite stability (tumor mutation burden (TMB) of 1.68muts/Mb) and negative PD-L1 expression (tumor proportion score less than 1% and combined positive score less than 1) (Table 1).	('tumor', 'Disease', (4, 9))	('PD-L1', 'Gene', '29126', (103, 108))	('expression', 'MPA', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (121, 126))	('TMB', 'Chemical', '-', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('PD-L1', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('negative', 'NegReg', (94, 102))	('microsatellite', 'Var', (20, 34))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
18185	33836796	SMARCA4 inactivation has been identified as the main genetic driver event in several malignancies, such as SMARCA4-deficient undifferentiated uterine sarcoma, SCCOHT, SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS), and SMARCA4-deficient NSCLC.	('SMARCA4-deficient NSCLC', 'Disease', 'MESH:D002289', (221, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('SMARCA4', 'Gene', (167, 174))	('SMARCA4', 'Gene', (0, 7))	('SMARCA4-deficient NSCLC', 'Disease', (221, 244))	('SMARCA4', 'Gene', '6597', (203, 210))	('SMARCA4', 'Gene', '6597', (107, 114))	('SMARCA4', 'Gene', (221, 228))	('SMARCA4-deficient undifferentiated uterine sarcoma', 'Disease', (107, 157))	('SMARCA4-deficient undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (107, 157))	('inactivation', 'Var', (8, 20))	('SMARCA4-deficient thoracic sarcoma', 'Disease', 'MESH:D012509', (167, 201))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (142, 157))	('SMARCA4-deficient thoracic sarcoma', 'Disease', (167, 201))	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('SMARCA4', 'Gene', '6597', (167, 174))	('SMARCA4', 'Gene', (203, 210))	('SMARCA4', 'Gene', '6597', (0, 7))	('malignancies', 'Disease', (85, 97))	('SCCOHT', 'Disease', (159, 165))	('SMARCA4', 'Gene', (107, 114))	('SCCOHT', 'Chemical', '-', (159, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('SMARCA4', 'Gene', '6597', (221, 228))
18192	33836796	Moreover, previous studies reported that loss of SMARCA4 expression caused tumor cells to undergo an epithelial-to-mesenchymal transition in lung adenocarcinoma and human mammary epithelial cells.	('lung adenocarcinoma', 'Disease', (141, 160))	('loss', 'Var', (41, 45))	('human', 'Species', '9606', (165, 170))	('SMARCA4', 'Gene', (49, 56))	('epithelial-to-mesenchymal transition', 'CPA', (101, 137))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('SMARCA4', 'Gene', '6597', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('undergo', 'Reg', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('tumor', 'Disease', (75, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
18194	33836796	We present an undifferentiated colonic neoplasm with loss of SMARCA4 expression and germline SMARCA4 nonsense mutation where tumor cells were focally positive for CK, CK8, and CK18, but diffusely positive for vimentin.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CK', 'Gene', '51727', (167, 169))	('colonic neoplasm', 'Phenotype', 'HP:0100273', (31, 47))	('loss', 'NegReg', (53, 57))	('SMARCA4', 'Gene', '6597', (93, 100))	('vimentin', 'Gene', '7431', (209, 217))	('nonsense mutation', 'Var', (101, 118))	('vimentin', 'Gene', (209, 217))	('SMARCA4', 'Gene', '6597', (61, 68))	('CK8', 'Gene', '3856', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('CK8', 'Gene', (167, 170))	('CK18', 'Gene', (176, 180))	('SMARCA4', 'Gene', (93, 100))	('CK18', 'Gene', '3875', (176, 180))	('CK', 'Gene', '51727', (163, 165))	('undifferentiated colonic neoplasm', 'Disease', 'MESH:D003110', (14, 47))	('SMARCA4', 'Gene', (61, 68))	('expression', 'MPA', (69, 79))	('tumor', 'Disease', (125, 130))	('undifferentiated colonic neoplasm', 'Disease', (14, 47))	('CK', 'Gene', '51727', (176, 178))	('neoplasm', 'Phenotype', 'HP:0002664', (39, 47))
18202	33836796	Inactivating mutations in the SMARCA4 gene led to the loss of the SMARCA4 protein.	('SMARCA4', 'Gene', (66, 73))	('SMARCA4', 'Gene', '6597', (66, 73))	('Inactivating mutations', 'Var', (0, 22))	('loss', 'NegReg', (54, 58))	('protein', 'Protein', (74, 81))	('SMARCA4', 'Gene', (30, 37))	('SMARCA4', 'Gene', '6597', (30, 37))
18203	33836796	SMARCA4 mutations were detected mainly in SMARCA4-lost and heterogeneous pattern of SMARCA4-lost gastric cancer, while ARIDIA mutations mainly in SMARCA4-reduced and heterogenous pattern of SMARCA4-reduced gastric cancer, which is consistent with the finding report in the current study case.	('gastric cancer', 'Disease', (97, 111))	('SMARCA4', 'Gene', (42, 49))	('gastric cancer', 'Disease', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SMARCA4', 'Gene', '6597', (84, 91))	('SMARCA4', 'Gene', (0, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('SMARCA4', 'Gene', '6597', (146, 153))	('SMARCA4', 'Gene', (190, 197))	('mutations', 'Var', (126, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (206, 220))	('reduced gastric cancer', 'Phenotype', 'HP:0006753', (198, 220))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('SMARCA4', 'Gene', '6597', (42, 49))	('SMARCA4', 'Gene', (84, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('SMARCA4', 'Gene', '6597', (0, 7))	('SMARCA4', 'Gene', (146, 153))	('detected', 'Reg', (23, 31))	('SMARCA4', 'Gene', '6597', (190, 197))
18204	33836796	We showed that germline SMARCA4 mutations were detected in an undifferentiated colonic neoplasm with a heterogeneous pattern of SMARCA4 loss expression.	('neoplasm', 'Phenotype', 'HP:0002664', (87, 95))	('SMARCA4', 'Gene', (24, 31))	('SMARCA4', 'Gene', (128, 135))	('SMARCA4', 'Gene', '6597', (24, 31))	('mutations', 'Var', (32, 41))	('undifferentiated colonic neoplasm', 'Disease', (62, 95))	('colonic neoplasm', 'Phenotype', 'HP:0100273', (79, 95))	('expression', 'MPA', (141, 151))	('loss', 'NegReg', (136, 140))	('detected', 'Reg', (47, 55))	('SMARCA4', 'Gene', '6597', (128, 135))	('undifferentiated colonic neoplasm', 'Disease', 'MESH:D003110', (62, 95))
18206	33836796	reported that SMARCA4 mutations were detected by NGS in 6% of small bowel adenocarcinoma.	('SMARCA4', 'Gene', (14, 21))	('SMARCA4', 'Gene', '6597', (14, 21))	('detected', 'Reg', (37, 45))	('mutations', 'Var', (22, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('small bowel adenocarcinoma', 'Disease', (62, 88))	('small bowel adenocarcinoma', 'Disease', 'MESH:D000230', (62, 88))
18208	33836796	Somatic SMARCA4 mutations occur in lung adenocarcinomas, lymphomas, and medulloblastomas.	('lymphomas', 'Phenotype', 'HP:0002665', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (35, 55))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (35, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('mutations', 'Var', (16, 25))	('medulloblastomas', 'Disease', 'MESH:D008527', (72, 88))	('lymphomas', 'Disease', (57, 66))	('lymphomas', 'Disease', 'MESH:D008223', (57, 66))	('SMARCA4', 'Gene', (8, 15))	('SMARCA4', 'Gene', '6597', (8, 15))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (35, 54))	('medulloblastomas', 'Disease', (72, 88))	('occur', 'Reg', (26, 31))	('lung adenocarcinomas', 'Disease', (35, 55))
18209	33836796	In NSCLC, somatic SMARCA4 mutations were detected in 10% NSCLC.	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('mutations', 'Var', (26, 35))	('SMARCA4', 'Gene', (18, 25))	('SMARCA4', 'Gene', '6597', (18, 25))	('NSCLC', 'Disease', (57, 62))	('detected', 'Reg', (41, 49))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
18210	33836796	Forty-five percent of SMARCA4 mutant NSCLC reported the loss of SMARCA4 expression, and 90% had truncating SMARCA4 mutation.	('SMARCA4', 'Gene', '6597', (64, 71))	('loss', 'NegReg', (56, 60))	('SMARCA4', 'Gene', (64, 71))	('expression', 'MPA', (72, 82))	('NSCLC', 'Disease', (37, 42))	('SMARCA4', 'Gene', (107, 114))	('SMARCA4', 'Gene', '6597', (107, 114))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('mutant', 'Var', (30, 36))	('SMARCA4', 'Gene', (22, 29))	('SMARCA4', 'Gene', '6597', (22, 29))	('truncating', 'MPA', (96, 106))
18211	33836796	In other words, truncating SMARCA4 mutations are the key genetic event accounting for the SMARCA4-deficient NSCLC.	('SMARCA4-deficient NSCLC', 'Disease', (90, 113))	('SMARCA4', 'Gene', (27, 34))	('SMARCA4', 'Gene', (90, 97))	('SMARCA4', 'Gene', '6597', (27, 34))	('mutations', 'Var', (35, 44))	('SMARCA4', 'Gene', '6597', (90, 97))	('SMARCA4-deficient NSCLC', 'Disease', 'MESH:D002289', (90, 113))
18212	33836796	Rhabdoid Tumor Predisposition Syndrome (RTPS) are due to pathogenic variant in genes of SMARCB1 (PTRS1, commonly,) or SMARCA4(PTRS2, rarely), which are inherited in an autosomal dominant fashion.	('Rhabdoid Tumor Predisposition Syndrome', 'Disease', 'MESH:C563738', (0, 38))	('SMARCB1', 'Gene', '6598', (88, 95))	('Tumor', 'Phenotype', 'HP:0002664', (9, 14))	('SMARCA4', 'Gene', (118, 125))	('variant', 'Var', (68, 75))	('SMARCB1', 'Gene', (88, 95))	('SMARCA4', 'Gene', '6597', (118, 125))	('Rhabdoid Tumor Predisposition Syndrome', 'Disease', (0, 38))
18218	33836796	In SCCOHT, at least one germline or somatic deleterious SMARCA4 mutation was detected in 94% of cases.	('SMARCA4', 'Gene', (56, 63))	('SMARCA4', 'Gene', '6597', (56, 63))	('SCCOHT', 'Chemical', '-', (3, 9))	('mutation', 'Var', (64, 72))
18228	33836796	Somatic APC mutation p.R216* was also detected in 31% of tumor cells in this case.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('p.R216*', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('APC', 'Disease', 'MESH:D011125', (8, 11))	('p.R216*', 'Mutation', 'p.R216*', (21, 28))	('tumor', 'Disease', (57, 62))	('APC', 'Disease', (8, 11))
18230	33836796	Somatic APC mutations are detected in at least 80% of sporadic colorectal tumors.	('colorectal tumors', 'Disease', 'MESH:D015179', (63, 80))	('colorectal tumors', 'Disease', (63, 80))	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('APC', 'Disease', 'MESH:D011125', (8, 11))	('APC', 'Disease', (8, 11))
18232	33836796	Moreover, the role of SMARCA4 alterations in diagnosing and treating other tumors was also summarized.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('alterations', 'Var', (30, 41))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('SMARCA4', 'Gene', (22, 29))	('SMARCA4', 'Gene', '6597', (22, 29))
18300	30683671	Insight into the etiology of undifferentiated soft tissue sarcomas from a novel mouse model Aberrant activation of the Hedgehog (Hh) signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS).	('activation', 'PosReg', (101, 111))	('sarcoma', 'Disease', 'MESH:D012509', (245, 252))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('mouse', 'Species', '10090', (80, 85))	('sarcoma', 'Disease', (245, 252))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (254, 280))	('linked', 'Reg', (160, 166))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('embryonal rhabdomyosarcoma', 'Disease', (254, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('sarcoma', 'Disease', (58, 65))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (46, 65))	('eRMS', 'Phenotype', 'HP:0006743', (282, 286))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (264, 280))	('sarcoma', 'Disease', 'MESH:D012509', (273, 280))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (46, 66))	('cancer', 'Disease', (196, 202))	('sarcoma', 'Disease', (273, 280))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (254, 280))	('sarcomas', 'Disease', 'MESH:D012509', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Aberrant', 'Var', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('sarcomas', 'Disease', (58, 66))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (233, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))
18314	30683671	As more data accumulates related to gene fusions identified in other sarcoma variants, such as CIC-DUX4, FUS-NFATc2, and BCOR-CCNB3 for example, it will be important to test their respective activities in mouse model design.	('DUX4', 'Gene', (99, 103))	('variants', 'Var', (77, 85))	('FUS', 'Gene', '233908', (105, 108))	('BCOR', 'Gene', (121, 125))	('sarcoma', 'Disease', (69, 76))	('FUS', 'Gene', (105, 108))	('DUX4', 'Gene', '664783', (99, 103))	('CCNB3', 'Gene', '209091', (126, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('NFATc2', 'Gene', '18019', (109, 115))	('BCOR', 'Gene', '71458', (121, 125))	('mouse', 'Species', '10090', (205, 210))	('CCNB3', 'Gene', (126, 131))	('NFATc2', 'Gene', (109, 115))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))
18373	30683671	However, to our surprise, these Pcp2-cre; CLEG2 (PCG2) animals developed soft tissue tumors (Figure 1A) similar to human small round cell sarcomas, displaying cohesive sheets of small round cells with high nuclear to cytoplasmic (n/c) ratio and geographic necrosis (Figures 1A and S1B).	('PCG', 'Gene', '57390', (49, 52))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('Pcp2-cre', 'Var', (32, 40))	('soft tissue tumors', 'Disease', 'MESH:D012983', (73, 91))	('necrosis', 'Disease', 'MESH:D009336', (256, 264))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (73, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('human', 'Species', '9606', (115, 120))	('sarcomas', 'Disease', (138, 146))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('necrosis', 'Disease', (256, 264))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('PCG', 'Gene', (49, 52))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (73, 90))	('soft tissue tumors', 'Disease', (73, 91))
18392	30683671	Immunostaining confirmed positivity for Nkx2.2 protein in all tumors analyzed (n > 25), while PtchlacZ eRMS were consistently negative (Figure 2B).	('Nkx2.2', 'Gene', '18088', (40, 46))	('protein', 'Protein', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('positivity', 'Var', (25, 35))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('eRMS', 'Phenotype', 'HP:0006743', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('Nkx2.2', 'Gene', (40, 46))
18412	30683671	However, activity of the oncogene was apparent, as all Pcp2-cre; EWSEWS-FLI1 mice displayed ataxia and exopthalmia (not shown), consistent with cerebellar and retinal expression of Pcp2-cre, and apoptosis induced by EWS-FLI1 in certain tissues.	('FLI1', 'Gene', (220, 224))	('EWS', 'Gene', (65, 68))	('EWSEWS-FLI1', 'Gene', (65, 76))	('mice', 'Species', '10090', (77, 81))	('ataxia and exopthalmia', 'Disease', 'MESH:D001259', (92, 114))	('cerebellar', 'Disease', 'MESH:D002526', (144, 154))	('EWS', 'Gene', '14030', (68, 71))	('FLI1', 'Gene', (72, 76))	('EWS', 'Gene', '14030', (216, 219))	('EWS', 'Gene', '14030', (65, 68))	('EWS', 'Gene', (68, 71))	('FLI1', 'Gene', '14247', (220, 224))	('EWSEWS-FLI1', 'Gene', '14247', (65, 76))	('FLI1', 'Gene', '14247', (72, 76))	('Pcp2-cre', 'Var', (55, 63))	('EWS', 'Gene', (216, 219))	('ataxia', 'Phenotype', 'HP:0001251', (92, 98))	('cerebellar', 'Disease', (144, 154))
18421	30683671	Since many sarcomas are defined by chromosomal translocation, we tested whether such changes accompany tumorigenesis in PCG2 mice.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('tumor', 'Disease', (103, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcomas', 'Disease', (11, 19))	('mice', 'Species', '10090', (125, 129))	('PCG', 'Gene', '57390', (120, 123))	('chromosomal translocation', 'Var', (35, 60))	('PCG', 'Gene', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tested', 'Reg', (65, 71))
18423	30683671	Spectral karyotyping (SKY) of PCG2M226 cells revealed amplifications, deletions, and a t(1;7) translocation (Figure S3E).	('PCG', 'Gene', '57390', (30, 33))	('deletions', 'Var', (70, 79))	('PCG', 'Gene', (30, 33))	('M226', 'CellLine', 'CVCL:J621', (34, 38))
18432	30683671	EWS102 was a tumor of the femur with a novel FUS-NFATc2 fusion, and EWS140 was a soft tissue tumor of the thigh with no detected gene fusion (Figure 3B), but both were clinically diagnosed as ES.	('NFATc2', 'Gene', '18019', (49, 55))	('tumor', 'Disease', (13, 18))	('ES', 'Phenotype', 'HP:0012254', (192, 194))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('NFATc2', 'Gene', (49, 55))	('EWS', 'Gene', '14030', (68, 71))	('tumor', 'Disease', (93, 98))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (81, 98))	('fusion', 'Var', (56, 62))	('EWS', 'Gene', '14030', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('EWS', 'Gene', (68, 71))	('FUS', 'Gene', '233908', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('FUS', 'Gene', (45, 48))	('EWS', 'Gene', (0, 3))
18449	30683671	Interestingly, aggressiveness in a subset of ES with more frequent nuclear beta-Catenin appears to be driven through activation of Wnt/beta-Catenin signaling concomitant with upregulation of the extracellular matrix component and known EWS-FLI1 target gene, Tenascin-C (TNC).	('beta-Catenin', 'Gene', (75, 87))	('upregulation', 'PosReg', (175, 187))	('beta-Catenin', 'Gene', '12387', (135, 147))	('Tenascin-C', 'Gene', (258, 268))	('FLI1', 'Gene', '14247', (240, 244))	('aggressiveness', 'Disease', (15, 29))	('EWS', 'Gene', '14030', (236, 239))	('beta-Catenin', 'Gene', (135, 147))	('aggressiveness', 'Phenotype', 'HP:0000718', (15, 29))	('EWS', 'Gene', (236, 239))	('aggressiveness', 'Disease', 'MESH:D001523', (15, 29))	('Tenascin-C', 'Gene', '21923', (258, 268))	('activation', 'PosReg', (117, 127))	('FLI1', 'Gene', (240, 244))	('ES', 'Phenotype', 'HP:0012254', (45, 47))	('nuclear', 'Var', (67, 74))	('beta-Catenin', 'Gene', '12387', (75, 87))	('TNC', 'Gene', '21923', (270, 273))	('extracellular matrix component', 'MPA', (195, 225))	('TNC', 'Gene', (270, 273))
18454	30683671	To achieve this end, we performed genetically-inducible fate-mapping (GIFM) to mark Pcp2-lineage cells with indelible reporters that express either cytoplasmic eYFP (R26ReYFP) or tdTomato (Ai9).	('tdTomato', 'Disease', (179, 187))	('R26ReYFP', 'Var', (166, 174))	('tdTomato', 'Disease', 'None', (179, 187))
18462	30683671	~50% of the resulting M5G2 animals formed aggressive soft tissue tumors by four weeks of age that were indistinguishable from PCG2 tumors in terms of pathology and molecular marker profile (n=11, p = 0.0016) (Figure 5G).	('aggressive soft tissue tumors', 'Disease', 'MESH:D012983', (42, 71))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (53, 70))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('PCG', 'Gene', '57390', (126, 129))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (53, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('aggressive soft tissue tumors', 'Disease', (42, 71))	('PCG', 'Gene', (126, 129))	('M5G2', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
18633	27800093	Fisher et al emphasize the importance of using immunohistochemicals markers to the diagnostic of specific soft tissue tumors specially co-expression of CD34 and cytokeratins in PES cells.	('CD34', 'Gene', (152, 156))	('CD34', 'Gene', '947', (152, 156))	('cytokeratins', 'Protein', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('PES', 'Chemical', '-', (177, 180))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('co-expression', 'Var', (135, 148))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (106, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
18681	24132910	Stability in the incidence of childhood cancers in Costa Rica for 1984-1992 (collection period with data available by ICCC-3 diagnosis group), compared to 1998-2002 (the most recent collection period), was confirmed by searching the Cancer Incidence in Five Continents (CI5) online database for males and females 0-14 years of age, for "all sites" (C00-96) and "bone" (C40-41).	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('childhood cancers', 'Disease', (30, 47))	('C00-96', 'Var', (349, 355))	('Cancer', 'Phenotype', 'HP:0002664', (233, 239))	('childhood cancers', 'Disease', 'MESH:C536928', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
18750	29238848	mutation, duplication, translocation) occurring during MSC differentiation increase the risk of their transformation to cancerous cells and result in the emergence of malignant osteoblastic or chondroblastic malignant cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('MSC', 'Gene', (55, 58))	('mutation', 'Var', (0, 8))	('malignant osteoblastic', 'Disease', (167, 189))	('cancerous', 'Disease', (120, 129))	('malignant osteoblastic', 'Disease', 'MESH:D009369', (167, 189))	('duplication', 'Var', (10, 21))	('translocation', 'Var', (23, 36))	('transformation', 'CPA', (102, 116))	('MSC', 'Gene', '9242', (55, 58))	('cancerous', 'Disease', 'MESH:D009369', (120, 129))
18759	29238848	Indeed, Ewing sarcoma cells are characterised by the expression of a fusion protein resulting from a chromosomal translocation between the EWS gene on chromosome 2 and a gene of the ETS family and consequently have been initially associated with the primitive neuroectodermal family of tumours.	('primitive neuroectodermal family', 'Disease', (250, 282))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (8, 21))	('tumours', 'Disease', (286, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (8, 21))	('tumour', 'Phenotype', 'HP:0002664', (286, 292))	('associated', 'Reg', (230, 240))	('EWS', 'Gene', '2130', (139, 142))	('EWS', 'Gene', (139, 142))	('chromosomal translocation', 'Var', (101, 126))	('tumours', 'Phenotype', 'HP:0002664', (286, 293))	('tumours', 'Disease', 'MESH:D009369', (286, 293))	('Ewing sarcoma', 'Disease', (8, 21))
18783	29238848	used next-generation sequencing (Ion AmpliSeq  Cancer Hotspot Panel v2) to identify a series of five new mutations (KDR, STK11, MLH1, KRAS and PTPN11) related to a higher proliferation index and revealing a higher tumour heterogeneity than initially suspected.	('PTPN11', 'Gene', (143, 149))	('mutations', 'Var', (105, 114))	('KDR', 'Gene', (116, 119))	('PTPN11', 'Gene', '5781', (143, 149))	('higher', 'PosReg', (164, 170))	('STK11', 'Gene', (121, 126))	('rat', 'Species', '10116', (14, 17))	('proliferation index', 'CPA', (171, 190))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('KDR', 'Gene', '3791', (116, 119))	('MLH1', 'Gene', (128, 132))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('rat', 'Species', '10116', (178, 181))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('STK11', 'Gene', '6794', (121, 126))	('KRAS', 'Gene', '3845', (134, 138))	('tumour', 'Disease', (214, 220))	('MLH1', 'Gene', '4292', (128, 132))	('KRAS', 'Gene', (134, 138))
18794	29238848	In addition to mutations in IDH1, IDH2, EXT (exostosin) and more conventional genes associated with cancer progression such as TP53 or Rb1, Tarpey et al.	('exostosin', 'Gene', '2131', (45, 54))	('Rb1', 'Gene', (135, 138))	('IDH2', 'Gene', '3418', (34, 38))	('IDH1', 'Gene', '3417', (28, 32))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('EXT', 'Gene', '2131', (40, 43))	('EXT', 'Gene', (40, 43))	('Rb1', 'Gene', '5925', (135, 138))	('IDH2', 'Gene', (34, 38))	('exostosin', 'Gene', (45, 54))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('TP53', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (127, 131))	('IDH1', 'Gene', (28, 32))
18795	29238848	identified COL2A1 mutations (insertions, deletions and rearrangements) in the third cases.	('COL2A1', 'Gene', '1280', (11, 17))	('rearrangements', 'Var', (55, 69))	('COL2A1', 'Gene', (11, 17))	('deletions', 'Var', (41, 50))	('mutations', 'Var', (18, 27))
18811	29238848	mutation, deletion, amplification) could increase with the proliferation rate of the cells of interest such as MSCs/osteoblasts during bone growth.	('MSC', 'Gene', '9242', (111, 114))	('proliferation rate', 'CPA', (59, 77))	('MSC', 'Gene', (111, 114))	('mutation', 'Var', (0, 8))	('deletion', 'Var', (10, 18))	('rat', 'Species', '10116', (66, 69))	('increase', 'PosReg', (41, 49))	('rat', 'Species', '10116', (73, 76))
18817	29238848	Recent data investigated at the single-cell level showed intercellular communications through gap junctions between osteosarcoma cells and various other cell types.	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('intercellular', 'Reg', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('gap', 'Var', (94, 97))	('osteosarcoma', 'Disease', (116, 128))
18820	29238848	Gap junctions are clearly involved in the tumour development and the loss of connexin43 expression in Ewing sarcoma cells favours the development of the primary tumour growth.	('tumour growth', 'Disease', (161, 174))	('Ewing sarcoma', 'Disease', (102, 115))	('connexin43', 'Gene', '2697', (77, 87))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('loss', 'Var', (69, 73))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('tumour growth', 'Disease', 'MESH:D006130', (161, 174))	('favours', 'PosReg', (122, 129))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('connexin43', 'Gene', (77, 87))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('tumour', 'Disease', (161, 167))	('tumour', 'Disease', (42, 48))
18899	29238848	Based on these observations, the assessment of two anti-PD1 antibodies, pembrolizumab (NCT02301039) and nivolumab (NCT02304458) are in progress in osteosarcoma (Fig.	('osteosarcoma', 'Disease', (147, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (147, 159))	('pembrolizumab', 'Chemical', 'MESH:C582435', (72, 85))	('PD1', 'Gene', '5133', (56, 59))	('osteosarcoma', 'Disease', 'MESH:D012516', (147, 159))	('NCT02301039', 'Var', (87, 98))	('PD1', 'Gene', (56, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('NCT02304458', 'Var', (115, 126))	('nivolumab', 'Chemical', 'MESH:D000077594', (104, 113))
18913	29238848	Based on the pre-clinical data on EWS-Fli1 silencing, a phase I clinical trial has been designed for the treatment of Ewing sarcoma patients by a shRNA EWS/Fli1 type lipoplex (NCT02736565, Table 2).	('EWS', 'Gene', (34, 37))	('Fli1', 'Gene', '2313', (156, 160))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (118, 131))	('EWS', 'Gene', '2130', (152, 155))	('EWS', 'Gene', (152, 155))	('NCT02736565', 'Var', (176, 187))	('Fli1', 'Gene', (156, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('Fli1', 'Gene', '2313', (38, 42))	('Fli1', 'Gene', (38, 42))	('Ewing sarcoma', 'Disease', (118, 131))	('patients', 'Species', '9606', (132, 140))	('EWS', 'Gene', '2130', (34, 37))
18915	29238848	Similarly, TK216 is a chemical compound developed to inhibit downstream effects of the EWS-FLi1 transcription factor (NCT02657005, Table 2).	('inhibit', 'NegReg', (53, 60))	('EWS', 'Gene', '2130', (87, 90))	('EWS', 'Gene', (87, 90))	('FLi1', 'Gene', '2313', (91, 95))	('FLi1', 'Gene', (91, 95))	('TK216', 'Var', (11, 16))
18937	29238848	IDH-1 or -2 are frequently mutated in malignant cartilaginous tumours and two phase I clinical trials are in progress with AG-120, a mutant IDH-1 inhibitor (NCT02073994) and AG-221, a mutant IDH2 inhibitor (NCT02273739).	('AG-120', 'Chemical', 'MESH:C000627630', (123, 129))	('malignant cartilaginous tumours', 'Disease', 'MESH:D009369', (38, 69))	('IDH-1', 'Gene', (0, 5))	('IDH-1 or -2', 'Gene', (0, 11))	('NCT02273739', 'Var', (207, 218))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('IDH2', 'Gene', '3418', (191, 195))	('IDH-1 or -2', 'Gene', '3417;3418', (0, 11))	('malignant cartilaginous tumours', 'Disease', (38, 69))	('NCT02073994', 'Var', (157, 168))	('IDH2', 'Gene', (191, 195))	('AG-221', 'Chemical', 'MESH:C000605269', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('mutant', 'Var', (133, 139))	('IDH-1', 'Gene', '3417', (0, 5))	('IDH-1', 'Gene', '3417', (140, 145))	('IDH-1', 'Gene', (140, 145))
18954	29238848	Nowadays, it is widely accepted that the stromal component is "the tumoural" element of the tissue and its dysregulation leads to the recruitment, proliferation and differentiation of macrophages.	('differentiation', 'CPA', (165, 180))	('recruitment', 'CPA', (134, 145))	('rat', 'Species', '10116', (154, 157))	('tumoural', 'Disease', 'MESH:D009369', (67, 75))	('dysregulation', 'Var', (107, 120))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumoural', 'Disease', (67, 75))	('proliferation', 'CPA', (147, 160))
19012	28571564	Dermatofibrosarcoma protuberans (DFSP) is marked by a translocation resulting in the COL1A1/PDGFB fusion gene, responsible for platelet derived growth factor beta-receptor (PDGFRB) activation.	('DFSP', 'Disease', 'MESH:D018223', (33, 37))	('Dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (0, 31))	('fusion', 'Var', (98, 104))	('Dermatofibrosarcoma protuberans', 'Disease', (0, 31))	('PDGFB', 'Gene', '5155', (92, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('PDGFRB', 'Gene', (173, 179))	('PDGFRB', 'Gene', '5159', (173, 179))	('COL1A1', 'Gene', '1277', (85, 91))	('COL1A1', 'Gene', (85, 91))	('DFSP', 'Disease', (33, 37))	('PDGFB', 'Gene', (92, 97))	('platelet derived growth factor beta-receptor', 'Gene', '5159', (127, 171))	('platelet derived growth factor beta-receptor', 'Gene', (127, 171))
19033	28571564	Among liposarcomas, an extremely heterogeneous family of STS, myxoid liposarcoma is known to be marked by the t(12;16)(q13;p11), detected in more than 90% of cases.	('liposarcoma', 'Phenotype', 'HP:0012034', (6, 17))	('myxoid liposarcoma', 'Disease', (62, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (10, 18))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (110, 127))	('liposarcoma', 'Phenotype', 'HP:0012034', (69, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (62, 80))	('STS', 'Phenotype', 'HP:0030448', (57, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('liposarcomas', 'Disease', 'MESH:D008080', (6, 18))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (62, 80))	('liposarcomas', 'Disease', (6, 18))	('t(12;16)(q13;p11', 'Var', (110, 126))
19034	28571564	In this subtype, the drug has been proven to exert an additional 'targeted' mechanism of action, promoting tumour differentiation through the inactivation of the FUS-CHOP oncogene.	('CHOP', 'Gene', (166, 170))	('promoting', 'PosReg', (97, 106))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('inactivation', 'Var', (142, 154))	('CHOP', 'Gene', '1649', (166, 170))	('tumour', 'Disease', (107, 113))
19060	28571564	Additionally, the hepatocyte growth factor receptor (MET) and anaplastic lymphoma kinase (ALK) are TK-receptors, whose disruption promotes cellular proliferation, angiogenesis and disease spreading in many solid cancers, including STS.	('disruption', 'Var', (119, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('solid cancers', 'Disease', 'MESH:D009369', (206, 219))	('ALK', 'Gene', '238', (90, 93))	('disease spreading', 'CPA', (180, 197))	('hepatocyte growth factor receptor', 'Gene', '4233', (18, 51))	('ALK', 'Gene', (90, 93))	('solid cancers', 'Disease', (206, 219))	('promotes', 'PosReg', (130, 138))	('cellular proliferation', 'CPA', (139, 161))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('hepatocyte growth factor receptor', 'Gene', (18, 51))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (62, 81))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('angiogenesis', 'CPA', (163, 175))	('MET', 'Gene', (53, 56))	('STS', 'Phenotype', 'HP:0030448', (231, 234))	('anaplastic lymphoma kinase', 'Gene', '238', (62, 88))	('anaplastic lymphoma kinase', 'Gene', (62, 88))
19069	28571564	Conflicting results have been described for STS of all types on the association between mTOR and IGF1R inhibitors, with more convincing evidence for Ewing sarcoma.	('association', 'Interaction', (68, 79))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('IGF1R', 'Gene', '3480', (97, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (149, 162))	('STS', 'Phenotype', 'HP:0030448', (44, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('inhibitors', 'Var', (103, 113))	('Ewing sarcoma', 'Disease', (149, 162))	('IGF1R', 'Gene', (97, 102))
19077	28571564	In a proof-of-mechanism study from a French group, 20 patients with chemotherapy-naive primary or relapsed WDLS/DDLS, MDM2 amplified and eligible for resection, received RG7112, a MDM2-antagonist, with one response and 14 stable disease cases being reported, albeit with a significant gastrointestinal and bone-marrow toxicity.	('MDM2', 'Gene', '4193', (180, 184))	('bone-marrow toxicity', 'Disease', 'MESH:D001855', (306, 326))	('MDM2', 'Gene', '4193', (118, 122))	('MDM2', 'Gene', (118, 122))	('gastrointestinal', 'Disease', 'MESH:D005767', (285, 301))	('patients', 'Species', '9606', (54, 62))	('bone-marrow toxicity', 'Disease', (306, 326))	('received', 'Reg', (161, 169))	('RG7112', 'Var', (170, 176))	('gastrointestinal', 'Disease', (285, 301))	('MDM2', 'Gene', (180, 184))
19078	28571564	A phase 1b/2 study (NCT01605526) is currently evaluating the tolerability and activity of a potentially less toxic compound, RO5045337, in association with doxorubicin.	('RO5045337', 'Var', (125, 134))	('activity', 'MPA', (78, 86))	('doxorubicin', 'Chemical', 'MESH:D004317', (156, 167))	('RO5045337', 'Chemical', '-', (125, 134))
19126	26330997	On the basis of these observations, a definitive diagnosis was made of MS 46XY, FLT3-ITD and NPM1-mutant involving the peritoneum and pleural cavity.	('NPM1', 'Gene', '4869', (93, 97))	('FLT3', 'Gene', '2322', (80, 84))	('FLT3', 'Gene', (80, 84))	('MS 46XY', 'Var', (71, 78))	('pleural', 'Disease', 'MESH:D010995', (134, 141))	('NPM1', 'Gene', (93, 97))	('pleural', 'Disease', (134, 141))
19196	24840521	PARPi were developed for cancer therapy based on the simple premise that cancer therapy damages DNA, and DNA repair compromises the therapeutic efficacy; therefore, inhibiting DNA repair should increase the efficacy.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('inhibiting', 'Var', (165, 175))	('PARP', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('therapeutic', 'MPA', (132, 143))	('increase', 'PosReg', (194, 202))	('compromises', 'NegReg', (116, 127))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('DNA', 'MPA', (96, 99))	('cancer', 'Disease', (25, 31))	('PARP', 'Gene', '142', (0, 4))
19206	24840521	The tumour suppressors BRCA1 and BRCA2 play important roles in HRR and mutations in these genes are associated with breast, ovarian and some other cancers.	('breast, ovarian', 'Disease', 'MESH:D010051', (116, 131))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('BRCA2', 'Gene', (33, 38))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('associated', 'Reg', (100, 110))	('mutations', 'Var', (71, 80))	('BRCA2', 'Gene', '675', (33, 38))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('BRCA1', 'Gene', '672', (23, 28))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('cancers', 'Disease', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('BRCA1', 'Gene', (23, 28))
19218	24840521	Interestingly, in cell invasion assays, siRNAs against PARP-1 and EWS reduced cell invasion, but knock-down of other key DNA repair enzymes (XRCC1; base excision repair; XRCC3; HRR and XRCC4; nonhomologous end joining) had no effect.	('XRCC3', 'Gene', (170, 175))	('XRCC3', 'Gene', '7517', (170, 175))	('PARP-1', 'Gene', (55, 61))	('reduced', 'NegReg', (70, 77))	('PARP-1', 'Gene', '142', (55, 61))	('cell invasion', 'CPA', (78, 91))	('cell invasion', 'CPA', (18, 31))	('XRCC1', 'Gene', '7515', (141, 146))	('XRCC4', 'Gene', (185, 190))	('base excision', 'MPA', (148, 161))	('XRCC4', 'Gene', '7518', (185, 190))	('siRNAs', 'Var', (40, 46))	('XRCC1', 'Gene', (141, 146))
19220	24840521	Finally, they demonstrated that EWS-FLI1 maintains PARP-1 mRNA expression, as knockdown of EWS-FLI1 decreased PARP-1 protein expression and promotor activity.	('PARP-1', 'Gene', (51, 57))	('EWS-FLI1', 'Gene', (91, 99))	('PARP-1', 'Gene', (110, 116))	('knockdown', 'Var', (78, 87))	('PARP-1', 'Gene', '142', (51, 57))	('EWS-FLI1', 'Gene', '2130;2313', (91, 99))	('EWS-FLI1', 'Gene', '2130;2313', (32, 40))	('PARP-1', 'Gene', '142', (110, 116))	('decreased', 'NegReg', (100, 109))	('promotor activity', 'CPA', (140, 157))	('EWS-FLI1', 'Gene', (32, 40))
19223	24840521	In cell viability and clonogenic assys, cell lines carrying the EWS-FLI1 translocation were significantly more sensitive to two PARPi (olaparib and rucaparib), than their EWS-FLI1-negative controls.	('PARP', 'Gene', '142', (128, 132))	('EWS-FLI1', 'Gene', (64, 72))	('EWS-FLI1', 'Gene', (171, 179))	('more', 'PosReg', (106, 110))	('olaparib', 'Chemical', 'MESH:C531550', (135, 143))	('EWS-FLI1', 'Gene', '2130;2313', (64, 72))	('translocation', 'Var', (73, 86))	('PARP', 'Gene', (128, 132))	('EWS-FLI1', 'Gene', '2130;2313', (171, 179))	('rucaparib', 'Chemical', 'MESH:C531549', (148, 157))
19226	24840521	Cells transformed with EWS-FLI1 were as sensitive as human Ewing sarcoma cell lines to olaparib, whereas FUS-CHOP transformed cells were resistant, and transient depletion of EWS-FLI1 in Ewing sarcoma cells led to reduced PARPi sensitivity.	('PARP', 'Gene', (222, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('EWS-FLI1', 'Gene', (23, 31))	('Ewing sarcoma', 'Disease', (59, 72))	('depletion', 'Var', (162, 171))	('Ewing sarcoma', 'Disease', (187, 200))	('EWS-FLI1', 'Gene', '2130;2313', (175, 183))	('sensitive', 'MPA', (40, 49))	('olaparib', 'Chemical', 'MESH:C531550', (87, 95))	('EWS-FLI1', 'Gene', '2130;2313', (23, 31))	('human', 'Species', '9606', (53, 58))	('reduced', 'NegReg', (214, 221))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (187, 200))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (187, 200))	('EWS-FLI1', 'Gene', (175, 183))	('PARP', 'Gene', '142', (222, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))
19257	24840521	However, combinations of PARPi with temozolomide, topoisomerase I poisons and/or radiotherapy have shown excellent in-vivo results and are therefore currently the most favoured strategy for upcoming clinical trials.	('PARP', 'Gene', (25, 29))	('topoisomerase I', 'Enzyme', (50, 65))	('poisons', 'Var', (66, 73))	('combinations', 'Interaction', (9, 21))	('temozolomide', 'Chemical', 'MESH:D000077204', (36, 48))	('PARP', 'Gene', '142', (25, 29))
19292	24455604	Despite these similarities, CCS represents a unique entity characterized by a distinct and recurrent chromosomal translocation t (12; 22) (q13, q12) leading to fusion of ATF1 gene on 12q13 to the EWSR1 gene at 22q12 in 90% cases.	('EWSR1', 'Gene', (196, 201))	('EWSR1', 'Gene', '2130', (196, 201))	('ATF1', 'Gene', (170, 174))	('ATF1', 'Gene', '466', (170, 174))	('CCS', 'Disease', (28, 31))	('fusion', 'Var', (160, 166))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (91, 126))
19294	24455604	Recent reports have shown a high incidence of BRAF mutations in malignant melanoma while it is rare in CCS.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('mutations', 'Var', (51, 60))	('malignant melanoma', 'Disease', 'MESH:D008545', (64, 82))	('malignant melanoma', 'Disease', (64, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('malignant melanoma', 'Phenotype', 'HP:0002861', (64, 82))
19295	24455604	demonstrated mutation in BRAF and NRAS in the two of twenty two CCS.	('mutation', 'Var', (13, 21))	('BRAF', 'Gene', '673', (25, 29))	('NRAS', 'Gene', (34, 38))	('BRAF', 'Gene', (25, 29))	('NRAS', 'Gene', '4893', (34, 38))
19299	24455604	EWS-ATF1 deregulates MITF expression by directly binding to the cyclic AMP response element located in the melanocyte-specific MITF promoter resulting in albinism from defective pigment production within viable melanocytes.	('albinism', 'Disease', (154, 162))	('binding', 'Interaction', (49, 56))	('MITF', 'Gene', '4286', (127, 131))	('MITF', 'Gene', (127, 131))	('EWS-ATF1', 'Gene', (0, 8))	('albinism', 'Phenotype', 'HP:0001022', (154, 162))	('resulting in', 'Reg', (141, 153))	('MITF', 'Gene', (21, 25))	('deregulates', 'Var', (9, 20))	('defective', 'NegReg', (168, 177))	('EWS-ATF1', 'Gene', '466;2130', (0, 8))	('MITF', 'Gene', '4286', (21, 25))	('cyclic AMP', 'Chemical', 'MESH:D000242', (64, 74))
19300	24455604	Inhibition of MITF activity in clear cell sarcoma decreases both pigmentation and the expression of markers of melanocytic differentiation previously demonstrated to be MITF targets.	('sarcoma decreases both pigmentation', 'Disease', (42, 77))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (31, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('sarcoma decreases both pigmentation', 'Disease', 'MESH:D012509', (42, 77))	('expression', 'MPA', (86, 96))	('MITF', 'Gene', '4286', (14, 18))	('MITF', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('clear cell sarcoma', 'Disease', (31, 49))	('MITF', 'Gene', '4286', (169, 173))	('MITF', 'Gene', (169, 173))
19327	24369450	All patients were required to have adequate renal function as determined by either 24-hour creatinine clearance or EDTA, PS < 2, albumin > 30 g/L.	('EDTA', 'MPA', (115, 119))	('albumin', 'MPA', (129, 136))	('EDTA', 'Chemical', 'MESH:D004492', (115, 119))	('PS <', 'Var', (121, 125))	('creatinine', 'Chemical', 'MESH:D003404', (91, 101))
19347	23209418	Hsp90 Inhibitors Are Efficacious against Kaposi Sarcoma by Enhancing the Degradation of the Essential Viral Gene LANA, of the Viral Co-Receptor EphA2 as well as Other Client Proteins Heat-shock protein 90 (Hsp90) inhibitors exhibit activity against human cancers.	('Hsp90', 'Gene', '3320', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('Kaposi Sarcoma', 'Disease', (41, 55))	('cancers', 'Disease', (255, 262))	('Hsp90', 'Gene', (0, 5))	('Enhancing', 'PosReg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('LANA', 'Gene', (113, 117))	('Kaposi Sarcoma', 'Disease', 'MESH:D012514', (41, 55))	('Sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('Hsp90', 'Gene', '3320', (206, 211))	('LANA', 'Gene', '4961527', (113, 117))	('Degradation', 'MPA', (73, 84))	('Hsp90', 'Gene', (206, 211))	('Inhibitors', 'Var', (6, 16))	('Kaposi Sarcoma', 'Phenotype', 'HP:0100726', (41, 55))	('cancers', 'Disease', 'MESH:D009369', (255, 262))	('shock', 'Phenotype', 'HP:0031273', (188, 193))	('EphA2', 'Gene', (144, 149))	('EphA2', 'Gene', '1969', (144, 149))	('human', 'Species', '9606', (249, 254))
19349	23209418	All Hsp90 inhibitors exhibited nanomolar EC50 in culture and AUY922 reduced tumor burden in a xenograft model of KS.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Hsp90', 'Protein', (4, 9))	('AUY922', 'Var', (61, 67))	('reduced', 'NegReg', (68, 75))	('AUY922', 'Chemical', 'MESH:C528044', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
19351	23209418	We identified the viral latency associated nuclear antigen (LANA) as a novel client protein of Hsp90 and demonstrate that the Hsp90 inhibitors diminish the level of LANA through proteasomal degradation.	('inhibitors', 'Var', (132, 142))	('LANA', 'Gene', (60, 64))	('proteasomal degradation', 'MPA', (178, 201))	('LANA', 'Gene', '4961527', (60, 64))	('LANA', 'Gene', (165, 169))	('rat', 'Species', '10116', (112, 115))	('LANA', 'Gene', '4961527', (165, 169))	('diminish', 'NegReg', (143, 151))	('Hsp90', 'Protein', (126, 131))	('level', 'MPA', (156, 161))
19354	23209418	Further, both molecules are required for KS tumor formation and both were downregulated in response to Hsp90 inhibitors.	('inhibitors', 'Var', (109, 119))	('KS tumor', 'Disease', 'MESH:D009369', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('KS tumor', 'Disease', (41, 49))	('downregulated', 'NegReg', (74, 87))	('Hsp90', 'Protein', (103, 108))
19370	23209418	For instance, Hsp90 is involved in NFkappaB activation by IKK in normal and lymphoma cells, including in the Kaposi sarcoma-associated herpesvirus (KSHV) driven lymphoma cell lines.	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (109, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (76, 84))	('herpesvirus', 'Species', '39059', (135, 146))	('lymphoma', 'Disease', (161, 169))	('KSHV', 'Species', '37296', (148, 152))	('IKK', 'Var', (58, 61))	('NFkappaB', 'Protein', (35, 43))	('activation', 'PosReg', (44, 54))	('Kaposi sarcoma', 'Disease', (109, 123))	('lymphoma', 'Disease', 'MESH:D008223', (161, 169))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (109, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (161, 169))	('lymphoma', 'Disease', (76, 84))	('lymphoma', 'Disease', 'MESH:D008223', (76, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('Hsp90', 'Protein', (14, 19))
19401	23209418	Rat anti-LANA monoclonal LN53 was purchased from Advanced Biotechnology Inc., anti-LANA polyclonal rabbit antiserum YT041 was raised again the LANA repeat region, and mouse anti-LANA (13B10) was from Leica Biosystems Newcastle Ltd. Rabbit cleaved PARP (Asp214, D64E10), Cleaved caspase-3 (Asp175, 5A1E), rabbit Anti-Akt and phospho-Akt (Ser473, D9E) were purchased from Cell Signaling.	('Ser473', 'Chemical', '-', (337, 343))	('Rat', 'Species', '10116', (0, 3))	('caspase-3', 'Gene', '836', (278, 287))	('Rabbit', 'Species', '9986', (232, 238))	('rabbit', 'Species', '9986', (99, 105))	('LANA', 'Gene', (83, 87))	('Akt', 'Gene', '207', (316, 319))	('Akt', 'Gene', (332, 335))	('caspase-3', 'Gene', (278, 287))	('LANA', 'Gene', '4961527', (83, 87))	('Akt', 'Gene', '207', (332, 335))	('LANA', 'Gene', (178, 182))	('Asp214', 'Var', (253, 259))	('rabbit', 'Species', '9986', (304, 310))	('LANA', 'Gene', '4961527', (178, 182))	('Asp214', 'Chemical', '-', (253, 259))	('LANA', 'Gene', (9, 13))	('LANA', 'Gene', '4961527', (9, 13))	('LANA', 'Gene', (143, 147))	('Akt', 'Gene', (316, 319))	('LANA', 'Gene', '4961527', (143, 147))	('Asp175', 'Chemical', '-', (289, 295))	('mouse', 'Species', '10090', (167, 172))
19408	23209418	Both tagged LANA mutants were transfected into BJAB cells with lipofectamin 2000 (Invitrogen).	('LANA', 'Gene', (12, 16))	('BJAB', 'CellLine', 'CVCL:5711', (47, 51))	('LANA', 'Gene', '4961527', (12, 16))	('lipofectamin 2000', 'Chemical', '-', (63, 80))	('mutants', 'Var', (17, 24))
19413	23209418	A series of full length or FLAG-LANA mutant expressing plasmids (pDD1928 (aa1-329), pDD1931 (aa930-1162) and pDD775) were obtained from Dr. Diane Hayward.	('LANA', 'Gene', '4961527', (32, 36))	('pDD775', 'Var', (109, 115))	('pDD1931', 'Var', (84, 91))	('pDD1928', 'Var', (65, 72))	('LANA', 'Gene', (32, 36))
19422	23209418	Endogenous peroxidase activity was quenched with 3% H2O2 in 10% methanol, then sections were blocked in solution B (10% horse serum [Vector laboratory], 5% BSA and 0.3% Triton X-100 in PBS) for 1 hour at RT, followed by incubation overnight at 4 C with primary antibodies: phospho-Akt (S473, 1:100), LANA (ABI, 1:200), and ephrin B2 (1:100); solution B was used as negative control.	('LANA', 'Gene', '4961527', (300, 304))	('S473', 'Var', (286, 290))	('H2O2', 'Chemical', 'MESH:D006861', (52, 56))	('Akt', 'Gene', '207', (281, 284))	('methanol', 'Chemical', 'MESH:D000432', (64, 72))	('rat', 'Species', '10116', (144, 147))	('ephrin B2', 'Gene', '1948', (323, 332))	('PBS', 'Chemical', 'MESH:D007854', (185, 188))	('quenched', 'NegReg', (35, 43))	('horse', 'Species', '9796', (120, 125))	('activity', 'MPA', (22, 30))	('LANA', 'Gene', (300, 304))	('Triton X-100', 'Chemical', 'MESH:D017830', (169, 181))	('Akt', 'Gene', (281, 284))	('ephrin B2', 'Gene', (323, 332))
19431	23209418	Different concentrations of Hsp90 inhibitors (17-DMAG, PU-H71, NVP-AUY922, BIIB021 and NVP-BEP800) or vehicle were added to the plate after 20 hours of cellular growth.	('17-DMAG', 'Chemical', 'MESH:C448659', (46, 53))	('PU-H71', 'Chemical', 'MESH:C526550', (55, 61))	('NVP-AUY922', 'Var', (63, 73))	('AUY922', 'Chemical', 'MESH:C528044', (67, 73))	('rat', 'Species', '10116', (17, 20))	('17-DMAG', 'Var', (46, 53))	('Hsp90', 'Protein', (28, 33))
19434	23209418	400 L1T2 cells were seeded after counting in 10 cm dish with growth media (as above) supplemented either with vehicle or drugs at serially diluted concentrations (0, 10, 20, 40 and 80 nM for 17-DMAG, PU-H71 and BIB021; 0, 20, 40, 80 and 160 nM for NVP-BEP800; 0, 1, 2, 4 and 8 nM for AUY922).	('BIB021; 0', 'Var', (211, 220))	('17-DMAG', 'Chemical', 'MESH:C448659', (191, 198))	('PU-H71', 'Chemical', 'MESH:C526550', (200, 206))	('rat', 'Species', '10116', (154, 157))	('L1T2', 'CellLine', 'CVCL:9576', (4, 8))	('PU-H71', 'Var', (200, 206))	('AUY922', 'Chemical', 'MESH:C528044', (284, 290))
19456	23209418	We identified heat shock protein Hsp90-beta (NP_0310381).	('shock', 'Phenotype', 'HP:0031273', (19, 24))	('Hsp90-beta', 'Gene', '3326', (33, 43))	('NP_0310381', 'Var', (45, 55))	('Hsp90-beta', 'Gene', (33, 43))
19459	23209418	To confirm our experiments and because of potential non-specific interactions with the central repeat region we generated a stable BJAB cell line expressing a mutant LANA protein, which had a deletion of the central repeat region, and which was engineered to have both a FLAG and HA tag at the N-terminus ( Figure 1A ).	('LANA', 'Gene', '4961527', (166, 170))	('mutant', 'Var', (159, 165))	('deletion', 'Var', (192, 200))	('rat', 'Species', '10116', (116, 119))	('BJAB', 'CellLine', 'CVCL:5711', (131, 135))	('protein', 'Protein', (171, 178))	('LANA', 'Gene', (166, 170))
19463	23209418	To investigate the interaction between LANA and Hsp90, we used WT FLAG-tagged LANA and FLAG-tagged mutant derivatives, the N-terminal or C-terminal of LANA (or both).	('LANA', 'Gene', (78, 82))	('LANA', 'Gene', (39, 43))	('LANA', 'Gene', '4961527', (39, 43))	('LANA', 'Gene', '4961527', (78, 82))	('LANA', 'Gene', (151, 155))	('LANA', 'Gene', '4961527', (151, 155))	('mutant', 'Var', (99, 105))
19464	23209418	After co-transfection of full-length FLAG tagged LANA (or LANA mutants) and HA-tagged-Hsp90 in HeLa cells, immunoprecipitation was performed with anti-FLAG antibody to bait Hsp90 complexes; the complexes separated by SDS-PAGE and associated protein detected with anti-HA antibody.	('rat', 'Species', '10116', (208, 211))	('mutants', 'Var', (63, 70))	('LANA', 'Gene', (49, 53))	('LANA', 'Gene', (58, 62))	('HeLa', 'CellLine', 'CVCL:0030', (95, 99))	('SDS', 'Chemical', 'MESH:D012967', (217, 220))	('LANA', 'Gene', '4961527', (49, 53))	('LANA', 'Gene', '4961527', (58, 62))
19482	23209418	To confirm the 17-DMAG results we used the new highly specific, ATP-competitive inhibitor of Hsp90 AUY922.	('Hsp90', 'Protein', (93, 98))	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('17-DMAG', 'Chemical', 'MESH:C448659', (15, 22))	('AUY922', 'Var', (99, 105))	('AUY922', 'Chemical', 'MESH:C528044', (99, 105))
19483	23209418	BCBL-1 cells were treated with AUY922 for 24 hours at increasing concentrations, followed by immune precipitation using anti-Hsp90 antibody and immunoblotting with anti-LANA antibody.	('anti-Hsp90', 'Protein', (120, 130))	('rat', 'Species', '10116', (72, 75))	('AUY922', 'Var', (31, 37))	('LANA', 'Gene', '4961527', (169, 173))	('AUY922', 'Chemical', 'MESH:C528044', (31, 37))	('LANA', 'Gene', (169, 173))
19484	23209418	AUY922 disrupted the LANA-Hsp90 complexes in BCBL-1 cells at 10-100 nM ( Figure 3B ).	('AUY922', 'Var', (0, 6))	('AUY922', 'Chemical', 'MESH:C528044', (0, 6))	('LANA', 'Gene', (21, 25))	('disrupted', 'NegReg', (7, 16))	('LANA', 'Gene', '4961527', (21, 25))
19500	23209418	MG-132 also increased in endogenous LANA levels in the BCBL-1 PEL cell line after treatment with AUY922 ( Figure 4G ).	('LANA', 'Gene', (36, 40))	('LANA', 'Gene', '4961527', (36, 40))	('increased', 'PosReg', (12, 21))	('AUY922', 'Var', (97, 103))	('AUY922', 'Chemical', 'MESH:C528044', (97, 103))	('MG-132', 'Chemical', 'MESH:C072553', (0, 6))
19510	23209418	Inhibition of Hsp90 changed the characteristic nuclear punctuate pattern of LANA.	('LANA', 'Gene', '4961527', (76, 80))	('Inhibition', 'Var', (0, 10))	('LANA', 'Gene', (76, 80))	('Hsp90', 'Protein', (14, 19))
19513	23209418	To determine whether Hsp90 inhibitors affect LANA transcription, we examined mRNA levels of LANA.	('LANA', 'Gene', '4961527', (45, 49))	('LANA', 'Gene', (92, 96))	('LANA', 'Gene', '4961527', (92, 96))	('LANA', 'Gene', (45, 49))	('mRNA', 'MPA', (77, 81))	('inhibitors', 'Var', (27, 37))	('Hsp90', 'Protein', (21, 26))	('affect', 'Reg', (38, 44))
19538	23209418	BC3 and BCBL-1 have wild-type functional p53 and were more sensitive to 17-DMAG, BCP-1 and BC-1 have mutant p53 and were less sensitive to 17-DMAG.	('p53', 'Gene', '7157', (41, 44))	('p53', 'Gene', (108, 111))	('17-DMAG', 'Chemical', 'MESH:C448659', (139, 146))	('p53', 'Gene', '7157', (108, 111))	('BCP', 'Chemical', '-', (81, 84))	('BC-1', 'Gene', (91, 95))	('sensitive', 'MPA', (59, 68))	('mutant', 'Var', (101, 107))	('17-DMAG', 'Chemical', 'MESH:C448659', (72, 79))	('p53', 'Gene', (41, 44))
19548	23209418	The p53 wild type BC-3 was the most sensitive and the p53 mutant BCP-1 the least sensitive cell line independent of drug and concentration (p<=0.015 for BCP-1, p<=0.003 for BC3, based on ANOVA.	('mutant', 'Var', (58, 64))	('p53', 'Gene', '7157', (4, 7))	('rat', 'Species', '10116', (132, 135))	('BCP', 'Chemical', '-', (153, 156))	('p53', 'Gene', (54, 57))	('p53', 'Gene', '7157', (54, 57))	('BCP-1', 'Gene', (65, 70))	('p53', 'Gene', (4, 7))	('BCP', 'Chemical', '-', (65, 68))
19551	23209418	All PEL lines seemed more sensitive to AUY922 than to the other two drugs, though this did not reach a level of statistical significance at a 95% family-wise confidence level ( Figure 6F ).	('AUY922', 'Var', (39, 45))	('sensitive', 'Reg', (26, 35))	('AUY922', 'Chemical', 'MESH:C528044', (39, 45))
19553	23209418	Hsp90 protein levels were dramatically reduced compared to untreated cells upon specific shRNA transduction with either sh-A or sh-B, but not irrelevant control ( Figure 7 ).	('sh-B', 'Gene', '6461', (128, 132))	('sh-A', 'Var', (120, 124))	('sh-B', 'Gene', (128, 132))	('reduced', 'NegReg', (39, 46))	('Hsp90', 'Protein', (0, 5))
19554	23209418	Upon depletion of Hsp90, the protein levels of LANA and the host control client protein Akt were decreased compared to controls.	('Akt', 'Gene', '207', (88, 91))	('Hsp90', 'Protein', (18, 23))	('depletion', 'Var', (5, 14))	('LANA', 'Gene', (47, 51))	('protein levels', 'MPA', (29, 43))	('LANA', 'Gene', '4961527', (47, 51))	('decreased', 'NegReg', (97, 106))	('Akt', 'Gene', (88, 91))
19557	23209418	This demonstrates that Hsp90 is essential for the survival of PEL and that direct inhibition of Hsp90 rather than off target effect of the drugs mediate the therapeutic efficacy of Hsp90 inhibitors against PEL.	('Hsp90', 'Protein', (96, 101))	('inhibitors', 'Var', (187, 197))	('rat', 'Species', '10116', (12, 15))	('PEL', 'Disease', (206, 209))	('rat', 'Species', '10116', (102, 105))	('inhibition', 'NegReg', (82, 92))	('Hsp90', 'Protein', (181, 186))
19564	23209418	Actin protein levels were used as control for loading and remained constant independent of the dose of AUY922.	('AUY922', 'Chemical', 'MESH:C528044', (103, 109))	('Actin protein levels', 'MPA', (0, 20))	('AUY922', 'Var', (103, 109))
19578	23209418	EphrinB2 protein levels were decreased in the different KS cell lines after treatment with Hsp90 inhibitors, in a dose- and time-dependent fashion ( Figure 8 ).	('EphrinB2', 'Gene', (0, 8))	('protein levels', 'MPA', (9, 23))	('Hsp90', 'Protein', (91, 96))	('EphrinB2', 'Gene', '1948', (0, 8))	('decreased', 'NegReg', (29, 38))	('inhibitors', 'Var', (97, 107))
19580	23209418	Similar to PEL before, we also found that total Akt protein levels and phosphorylated Akt (S473) were decreased in L1T2 cells upon exposure to AUY922.	('Akt', 'Gene', (86, 89))	('Akt', 'Gene', (48, 51))	('AUY922', 'Chemical', 'MESH:C528044', (143, 149))	('Akt', 'Gene', '207', (86, 89))	('phosphorylated', 'MPA', (71, 85))	('Akt', 'Gene', '207', (48, 51))	('L1T2', 'CellLine', 'CVCL:9576', (115, 119))	('decreased', 'NegReg', (102, 111))	('AUY922', 'Var', (143, 149))
19595	23209418	In sum, Hsp90 inhibitors repress KS tumor cell proliferation at nanomolar concentrations.	('repress', 'NegReg', (25, 32))	('rat', 'Species', '10116', (81, 84))	('rat', 'Species', '10116', (54, 57))	('KS tumor', 'Disease', 'MESH:D009369', (33, 41))	('Hsp90', 'Protein', (8, 13))	('KS tumor', 'Disease', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('inhibitors', 'Var', (14, 24))
19598	23209418	AUY922 significantly retarded tumor growth compared to the mock-treated mice (p<=0.05 by repeated measurements analysis of variance (ANOVA)) ( Figure 9C ).	('AUY922', 'Var', (0, 6))	('AUY922', 'Chemical', 'MESH:C528044', (0, 6))	('retarded tumor', 'Disease', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mice', 'Species', '10090', (72, 76))	('retarded tumor', 'Disease', 'MESH:D009369', (21, 35))
19601	23209418	The phosphorylation level of Akt was substantially reduced after AUY922 treatment.	('AUY922', 'Var', (65, 71))	('reduced', 'NegReg', (51, 58))	('Akt', 'Gene', '207', (29, 32))	('AUY922', 'Chemical', 'MESH:C528044', (65, 71))	('phosphorylation level', 'MPA', (4, 25))	('Akt', 'Gene', (29, 32))
19604	23209418	Ephrin B2 levels were significantly decreased after AUY922 treatment.	('AUY922', 'Var', (52, 58))	('AUY922', 'Chemical', 'MESH:C528044', (52, 58))	('Ephrin B2', 'Gene', '1948', (0, 9))	('Ephrin B2', 'Gene', (0, 9))	('decreased', 'NegReg', (36, 45))
19608	23209418	ATP-competitive Hsp90 inhibitors disrupt this interaction and reduce the half-life of LANA by accelerating ubiquitin-mediated, proteasomal degradation of LANA.	('inhibitors', 'Var', (22, 32))	('LANA', 'Gene', '4961527', (86, 90))	('disrupt', 'NegReg', (33, 40))	('half-life', 'MPA', (73, 82))	('ubiquitin-mediated', 'MPA', (107, 125))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('reduce', 'NegReg', (62, 68))	('Hsp90', 'Protein', (16, 21))	('LANA', 'Gene', (154, 158))	('LANA', 'Gene', '4961527', (154, 158))	('interaction', 'Interaction', (46, 57))	('accelerating', 'PosReg', (94, 106))	('LANA', 'Gene', (86, 90))	('rat', 'Species', '10116', (100, 103))
19636	23209418	AUY922 had the lowest IC50 (2 nM) against a battery of KS cell lines.	('AUY922', 'Chemical', 'MESH:C528044', (0, 6))	('lowest', 'NegReg', (15, 21))	('AUY922', 'Var', (0, 6))
19638	23209418	AUY922 inhibited a tumor growth in a xenograft KSHV tumor model with similar efficacy as reported previously for other anti-KS compounds.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('AUY922', 'Var', (0, 6))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('AUY922', 'Chemical', 'MESH:C528044', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('KSHV tumor', 'Disease', 'MESH:C537372', (47, 57))	('inhibited', 'NegReg', (7, 16))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('KSHV tumor', 'Disease', (47, 57))
19643	23209418	Our studies showed that EphA2 was expressed abundantly in L1T2, SLK-KSHV, and KS-IMM cells and that Hsp90 inhibitors reduced EphA2 expression.	('EphA2', 'Gene', (125, 130))	('Hsp90', 'Protein', (100, 105))	('EphA2', 'Gene', '1969', (24, 29))	('reduced', 'NegReg', (117, 124))	('L1T2', 'CellLine', 'CVCL:9576', (58, 62))	('expression', 'MPA', (131, 141))	('EphA2', 'Gene', '1969', (125, 130))	('inhibitors', 'Var', (106, 116))	('KSHV', 'Species', '37296', (68, 72))	('EphA2', 'Gene', (24, 29))
19647	23209418	We found that Hsp90 inhibitors significantly decreased the expression of Ephrin-B2 in multiple KS tumor models (L1T2, SLK-KSHV), which suggests that downregulation of ephrin interactions through Hsp90 inhibitors contributes to their effectiveness in the endothelial lineage tumor KS.	('Ephrin-B2', 'Gene', (73, 82))	('L1T2', 'CellLine', 'CVCL:9576', (112, 116))	('KS tumor', 'Disease', 'MESH:D009369', (95, 103))	('expression', 'MPA', (59, 69))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (274, 279))	('downregulation', 'NegReg', (149, 163))	('Hsp90', 'Protein', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('interactions', 'Interaction', (174, 186))	('inhibitors', 'Var', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('KSHV', 'Species', '37296', (122, 126))	('Ephrin-B2', 'Gene', '1948', (73, 82))	('ephrin', 'Protein', (167, 173))	('decreased', 'NegReg', (45, 54))	('KS tumor', 'Disease', (95, 103))
19648	22723308	EWS/FLI1 regulates EYA3 in Ewing's sarcoma via modulation of microRNA-708, resulting in increased cell survival and chemoresistance Ewing's sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histological response to initial chemotherapy have a poor overall prognosis.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (132, 147))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (27, 42))	('patients', 'Species', '9606', (220, 228))	('cell survival', 'CPA', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (27, 42))	('EYA3', 'Gene', '2140', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	("Ewing's sarcoma", 'Disease', (132, 147))	('EYA3', 'Gene', (19, 23))	('chemoresistance', 'CPA', (116, 131))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('EWS', 'Gene', (0, 3))	('FLI1', 'Gene', (4, 8))	('aggressive pediatric cancer', 'Disease', (154, 181))	("Ewing's sarcoma", 'Disease', (27, 42))	('increased', 'PosReg', (88, 97))	('modulation', 'Var', (47, 57))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('aggressive pediatric cancer', 'Disease', 'MESH:D009369', (154, 181))	('tumors', 'Disease', (235, 241))	('FLI1', 'Gene', '2313', (4, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('microRNA-708', 'Gene', (61, 73))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (132, 147))	('cancer of the bone', 'Phenotype', 'HP:0010622', (175, 193))	('EWS', 'Gene', '2130', (0, 3))
19652	22723308	Because EYA proteins are important for cell survival during development, we examine, and demonstrate, that loss of EYA3 decreases survival of Ewing's sarcoma cells.	('survival', 'CPA', (130, 138))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (142, 157))	('loss', 'Var', (107, 111))	("Ewing's sarcoma", 'Disease', (142, 157))	('EYA3', 'Gene', (115, 119))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (142, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('decreases', 'NegReg', (120, 129))
19653	22723308	Most importantly, knockdown of EYA3 in Ewing's sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing's sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts.	('knockdown', 'Var', (18, 27))	('sensitization', 'MPA', (70, 83))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (143, 158))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (39, 54))	("Ewing's sarcoma", 'Disease', (143, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('repair DNA damage', 'MPA', (232, 249))	('EYA3', 'Gene', (31, 35))	('EYA3', 'Gene', (211, 215))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (39, 54))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (143, 158))	("Ewing's sarcoma", 'Disease', (39, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
19684	22723308	We used primary antibodies against EYA3 (Santa Cruz Biotechnology; #SC-15101), FLI1 (BD Biosciences; #554266), cleaved PARP (BD Biosciences; #8111KC), beta-actin (Sigma-Aldrich; #A5316), and tubulin (Sigma-Aldrich; #T4026).	('FLI1', 'Gene', (79, 83))	('tubulin', 'Protein', (191, 198))	('FLI1', 'Gene', '2313', (79, 83))	('PARP', 'Gene', (119, 123))	('cleaved', 'Var', (111, 118))	('EYA3', 'Gene', (35, 39))	('beta-actin', 'Gene', '728378', (151, 161))	('beta-actin', 'Gene', (151, 161))	('PARP', 'Gene', '1302', (119, 123))
19694	22723308	Further, the miR-145 and miR-708 seed sequence sites were mutated in the EYA3 3'UTR using site-directed mutagenesis II XL kit (Stratagene).	('miR-708', 'Gene', (25, 32))	('miR-708', 'Gene', '100126333', (25, 32))	('miR-145', 'Gene', (13, 20))	('miR-145', 'Gene', '406937', (13, 20))	('mutated', 'Var', (58, 65))
19701	22723308	A673-shscramble, A673-shEYA3#1, and A673-shEYA3#5 cells were grown to about 30-40 percent confluency in 6-cm dishes and then treated with 10muM etoposide for 48h.	('muM', 'Gene', '56925', (140, 143))	('A673-shEYA3', 'Var', (36, 47))	('muM', 'Gene', (140, 143))	('A673-shEYA3', 'Var', (17, 28))	('etoposide', 'Chemical', 'MESH:D005047', (144, 153))
19705	22723308	A673-shscramble, A673-shEYA3#1, and A673-shEYA3#5 cells were grown to be about 40-60 percent confluent in 6-cm dishes and then treated with 100muM etoposide for 2 hours.	('muM', 'Gene', '56925', (143, 146))	('muM', 'Gene', (143, 146))	('A673-shEYA3', 'Var', (36, 47))	('A673-shEYA3', 'Var', (17, 28))	('etoposide', 'Chemical', 'MESH:D005047', (147, 156))
19722	22723308	Importantly, EYA3 mRNA and protein levels were decreased in a manner proportional to the extent of EWS/FLI1 knockdown (Figure 2b and 2c).	('knockdown', 'Var', (108, 117))	('FLI1', 'Gene', (103, 107))	('FLI1', 'Gene', '2313', (103, 107))	('EWS', 'Gene', '2130', (99, 102))	('EWS', 'Gene', (99, 102))	('decreased', 'NegReg', (47, 56))
19727	22723308	Indeed, knockdown of EWS/FLI1 in A673 cells led to a substantial increase in miR-145 and miR-708 levels, and also moderately increased miR-28-5p levels (Figure 3b), confirming the regulation of these miRs by EWS/FLI1.	('miR', 'Gene', (135, 138))	('miR', 'Gene', (77, 80))	('FLI1', 'Gene', '2313', (25, 29))	('increased', 'PosReg', (125, 134))	('miR-145', 'Gene', '406937', (77, 84))	('miR-708', 'Gene', (89, 96))	('miR-28', 'Gene', '407020', (135, 141))	('FLI1', 'Gene', (212, 216))	('EWS', 'Gene', '2130', (21, 24))	('miR-145', 'Gene', (77, 84))	('miR', 'Gene', '220972', (89, 92))	('EWS', 'Gene', (208, 211))	('FLI1', 'Gene', '2313', (212, 216))	('miR', 'Gene', '220972', (200, 203))	('miR', 'Gene', (89, 92))	('miR-708', 'Gene', '100126333', (89, 96))	('miR-28', 'Gene', (135, 141))	('EWS', 'Gene', (21, 24))	('miR', 'Gene', '220972', (135, 138))	('miR', 'Gene', '220972', (77, 80))	('FLI1', 'Gene', (25, 29))	('increase', 'PosReg', (65, 73))	('miR', 'Gene', (200, 203))	('knockdown', 'Var', (8, 17))	('EWS', 'Gene', '2130', (208, 211))
19728	22723308	As expected, this response correlated with the efficiency of EWS/FLI1 knockdown.	('knockdown', 'Var', (70, 79))	('FLI1', 'Gene', '2313', (65, 69))	('FLI1', 'Gene', (65, 69))	('EWS', 'Gene', '2130', (61, 64))	('EWS', 'Gene', (61, 64))
19741	22723308	Because EYA3 is important for Ewing's sarcoma cell survival, and because EYA3 contributes to DNA repair in response to DNA damage in human embryonic kidney cells, we asked whether inhibition of EYA3 could sensitize Ewing's sarcoma cells to DNA-damaging chemotherapeutics.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (30, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('sensitize', 'Reg', (205, 214))	('inhibition', 'Var', (180, 190))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (215, 230))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (30, 45))	("Ewing's sarcoma", 'Disease', (215, 230))	('EYA3', 'Gene', (194, 198))	('human', 'Species', '9606', (133, 138))	("Ewing's sarcoma", 'Disease', (30, 45))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (215, 230))
19743	22723308	Indeed, knockdown of EYA3 sensitized cells to etoposide and doxorubicin, as shown by a decrease in viability using an MTS assay (Figure 5a and 5b).	('EYA3', 'Gene', (21, 25))	('doxorubicin', 'Chemical', 'MESH:D004317', (60, 71))	('knockdown', 'Var', (8, 17))	('etoposide', 'Chemical', 'MESH:D005047', (46, 55))	('viability', 'MPA', (99, 108))	('decrease', 'NegReg', (87, 95))	('doxorubicin', 'MPA', (60, 71))	('sensitized', 'Reg', (26, 36))
19747	22723308	Further, miR-708 expression sensitizes A673 cells to etoposide (Supplementary Figure 7c).	('miR-708', 'Gene', '100126333', (9, 16))	('etoposide', 'Chemical', 'MESH:D005047', (53, 62))	('miR-708', 'Gene', (9, 16))	('expression', 'Var', (17, 27))	('sensitizes', 'Reg', (28, 38))
19748	22723308	Because disease relapse is an important clinical outcome associated with chemoresistance, among other factors, we examined our Ewing's sarcoma tumor samples and although our sample numbers were limited, we observed a clear trend that patients with low levels of miR-708 and high levels of EYA3 have a worse 3-year relapse-free survival (Supplementary Figure 8).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (127, 142))	('miR-708', 'Gene', (262, 269))	('relapse-free survival', 'CPA', (314, 335))	("Ewing's sarcoma tumor", 'Disease', (127, 148))	("Ewing's sarcoma tumor", 'Disease', 'MESH:C563168', (127, 148))	('patients', 'Species', '9606', (234, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('high levels', 'Var', (274, 285))	('miR-708', 'Gene', '100126333', (262, 269))	('worse', 'NegReg', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
19749	22723308	Thus, we asked whether the mechanism by which EYA3 mediates chemoresistance in Ewing's sarcoma cells is via its ability to increase DNA repair.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (79, 94))	('EYA3', 'Var', (46, 50))	("Ewing's sarcoma", 'Disease', (79, 94))	('chemoresistance', 'CPA', (60, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (79, 94))	('increase', 'PosReg', (123, 131))	('DNA repair', 'MPA', (132, 142))
19751	22723308	Importantly, EYA3 knockdown cells had statistically larger tail moments than their control counterpart, indicative of increased DNA damage in response to etoposide treatment (Figure 6a).	('knockdown', 'Var', (18, 27))	('DNA damage', 'MPA', (128, 138))	('increased', 'PosReg', (118, 127))	('etoposide', 'Chemical', 'MESH:D005047', (154, 163))	('larger', 'PosReg', (52, 58))	('tail', 'MPA', (59, 63))	('EYA3', 'Gene', (13, 17))
19762	22723308	EYA2 is a required SIX1 co-factor to enable the induction of cancer stem cell characteristics and TGF-ss signaling, and patients who have high levels of EYA2 in addition to high levels of SIX1 have an especially poor prognosis.	('SIX1', 'Gene', (19, 23))	('EYA2', 'Gene', (153, 157))	('SIX1', 'Gene', (188, 192))	('SIX1', 'Gene', '6495', (19, 23))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('EYA2', 'Gene', '2139', (153, 157))	('SIX1', 'Gene', '6495', (188, 192))	('cancer', 'Disease', (61, 67))	('TGF-ss signaling', 'MPA', (98, 114))	('EYA2', 'Gene', (0, 4))	('high levels', 'Var', (138, 149))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('EYA2', 'Gene', '2139', (0, 4))
19764	22723308	However, EYA has recently been shown to have functions outside of its role as a transcription co-factor, and indeed there is evidence that in some contexts, EYA is tumor suppressive rather than tumor promotional, although the dependence of EYA on SIX1 in this context is unknown.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('SIX1', 'Gene', '6495', (247, 251))	('EYA', 'Var', (157, 160))	('SIX1', 'Gene', (247, 251))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
19765	22723308	For example, EYA4 is hypermethylated in colon cancer and esophageal adenocarcinoma.	('EYA4', 'Gene', (13, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('esophageal adenocarcinoma', 'Disease', (57, 82))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (57, 82))	('colon cancer', 'Disease', (40, 52))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (57, 82))	('hypermethylated', 'Var', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('EYA4', 'Gene', '2070', (13, 17))
19768	22723308	For these studies, we used the A673 human tumor-derived Ewing's sarcoma cell line, where we see high levels of EYA3 expression, and show that knockdown of EWS/FLI1 in these cells results in a concomitant decrease in EYA3 mRNA and protein expression.	('decrease', 'NegReg', (204, 212))	('EWS', 'Gene', '2130', (155, 158))	('EWS', 'Gene', (155, 158))	('tumor', 'Disease', (42, 47))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (56, 71))	('FLI1', 'Gene', (159, 163))	("Ewing's sarcoma", 'Disease', (56, 71))	('EYA3', 'Protein', (216, 220))	('FLI1', 'Gene', '2313', (159, 163))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (56, 71))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('human', 'Species', '9606', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('knockdown', 'Var', (142, 151))
19772	22723308	Additionally, EWS/FLI1 often regulates critical target genes via GGAA microsatellite repeats.	('EWS', 'Gene', '2130', (14, 17))	('EWS', 'Gene', (14, 17))	('FLI1', 'Gene', '2313', (18, 22))	('FLI1', 'Gene', (18, 22))	('microsatellite repeats', 'Var', (70, 92))	('regulates', 'Reg', (29, 38))
19783	22723308	recently demonstrated that miR-708 expression is lost in human renal cell carcinomas (RCC) and described loss of miR-708 as important for cell survival, among other things, in this disease.	('miR-708', 'Gene', (27, 34))	('renal cell carcinomas', 'Disease', (63, 84))	('miR-708', 'Gene', '100126333', (113, 120))	('lost', 'NegReg', (49, 53))	('expression', 'MPA', (35, 45))	('loss', 'Var', (105, 109))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (63, 84))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (63, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('miR-708', 'Gene', (113, 120))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('human', 'Species', '9606', (57, 62))	('miR-708', 'Gene', '100126333', (27, 34))
19786	22723308	These data suggest that miR-708 replacement may serve as a potential Ewing's sarcoma therapy.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (69, 84))	('miR-708', 'Gene', (24, 31))	("Ewing's sarcoma", 'Disease', (69, 84))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (69, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('miR-708', 'Gene', '100126333', (24, 31))	('replacement', 'Var', (32, 43))
19788	22723308	Importantly, EYA3 knockdown leads to an increase in PARP cleavage and an increase in Annexin V positivity, suggesting that EYA3 is required for survival even in the absence of any death-inducing stimuli.	('knockdown', 'Var', (18, 27))	('Annexin V', 'Gene', (85, 94))	('increase', 'PosReg', (73, 81))	('PARP', 'Gene', '1302', (52, 56))	('increase', 'PosReg', (40, 48))	('PARP', 'Gene', (52, 56))	('death', 'Disease', 'MESH:D003643', (180, 185))	('death', 'Disease', (180, 185))	('EYA3', 'Gene', (13, 17))	('Annexin V', 'Gene', '308', (85, 94))
19789	22723308	Because of the newly described role of EYA3 as a mediator of efficient DNA repair through its ED tyrosine phosphatase activity, we further asked whether EYA3 knockdown would lead to a decrease in survival following treatment with DNA-damaging chemotherapeutics that are used to treat Ewing's sarcoma clinically.	('decrease', 'NegReg', (184, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('ED tyrosine phosphatase activity', 'MPA', (94, 126))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (284, 299))	('EYA3', 'Gene', (153, 157))	('knockdown', 'Var', (158, 167))	('survival', 'MPA', (196, 204))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (284, 299))	("Ewing's sarcoma", 'Disease', (284, 299))
19790	22723308	Indeed, EYA3 knockdown significantly sensitizes cells to etoposide and doxorubicin, and this phenotype results from a decreased ability to repair the DNA damage inflicted by these chemotherapeutics when EYA3 levels are decreased.	('sensitizes', 'Reg', (37, 47))	('DNA damage', 'MPA', (150, 160))	('etoposide', 'Chemical', 'MESH:D005047', (57, 66))	('EYA3', 'Gene', (8, 12))	('decreased', 'NegReg', (118, 127))	('knockdown', 'Var', (13, 22))	('ability', 'MPA', (128, 135))	('doxorubicin', 'Chemical', 'MESH:D004317', (71, 82))
19795	22723308	These data thus suggest that inhibitors of EYA3, and/or re-introduction of miR-708, have the potential to sensitize Ewing's sarcomas to DNA-damaging chemotherapeutics and to improve relapse-free survival, and indeed, small molecule inhibitors of EYA are currently under development by our group and others.	('inhibitors', 'Var', (29, 39))	('improve', 'PosReg', (174, 181))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (116, 131))	('miR-708', 'Gene', '100126333', (75, 82))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (116, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('sensitize', 'Reg', (106, 115))	('miR-708', 'Gene', (75, 82))	('DNA-damaging', 'MPA', (136, 148))	("Ewing's sarcomas", 'Disease', (116, 132))	('relapse-free survival', 'CPA', (182, 203))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (116, 132))	('EYA3', 'Gene', (43, 47))
19800	22723308	Furthermore, we have demonstrated that EYA3 mediates chemoresistance and cell survival in this cancer, and this is the first report to demonstrate that EYA mediates chemoresistance in any cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cell survival', 'CPA', (73, 86))	('chemoresistance', 'CPA', (53, 68))	('cancer', 'Disease', (95, 101))	('EYA3', 'Var', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('mediates', 'Reg', (44, 52))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
19840	33653335	Among them, high expression levels of SMARCC1, SRSF10, PRPF38A, JARID2, GNAI3, miR-301a-3p, miR-106b-5p, miRNA-130b-3p, miR-423-3p and LINC01296 and low expression levels of ARF3 and PRKCB were associated with shorter overall survival in sarcomas (Fig.	('ARF3', 'Gene', '377', (174, 178))	('expression levels', 'MPA', (17, 34))	('GNAI3', 'Gene', '2773', (72, 77))	('PRPF38A', 'Gene', '84950', (55, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('expression', 'MPA', (153, 163))	('SRSF10', 'Gene', (47, 53))	('PRKCB', 'Gene', '5579', (183, 188))	('SMARCC1', 'Gene', '6599', (38, 45))	('JARID2', 'Gene', (64, 70))	('PRPF38A', 'Gene', (55, 62))	('miR-106b', 'Gene', '406900', (92, 100))	('miR-423-3p', 'Var', (120, 130))	('shorter', 'NegReg', (210, 217))	('SRSF10', 'Gene', '10772', (47, 53))	('SMARCC1', 'Gene', (38, 45))	('LINC01296', 'Gene', (135, 144))	('miR-106b', 'Gene', (92, 100))	('GNAI3', 'Gene', (72, 77))	('miR-301a', 'Gene', (79, 87))	('LINC01296', 'Gene', '642477', (135, 144))	('miR-301a', 'Gene', '407027', (79, 87))	('sarcomas', 'Disease', 'MESH:D012509', (238, 246))	('ARF3', 'Gene', (174, 178))	('JARID2', 'Gene', '3720', (64, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (238, 246))	('PRKCB', 'Gene', (183, 188))	('overall survival', 'MPA', (218, 234))	('sarcomas', 'Disease', (238, 246))	('miRNA-130b-3p', 'Var', (105, 118))
19846	33653335	However, the high expressions of ARF3 and PRKCB were significantly associated with longer overall survival (P = 0.0018 and P = 0.0162), indicating that ARF3 and PRKCB overexpression could be positive prognostic factors in sarcoma patients.	('PRKCB', 'Gene', (42, 47))	('PRKCB', 'Gene', '5579', (161, 166))	('high', 'Var', (13, 17))	('PRKCB', 'Gene', '5579', (42, 47))	('overall', 'MPA', (90, 97))	('sarcoma', 'Disease', 'MESH:D012509', (222, 229))	('ARF3', 'Gene', '377', (152, 156))	('patients', 'Species', '9606', (230, 238))	('ARF3', 'Gene', '377', (33, 37))	('longer', 'PosReg', (83, 89))	('sarcoma', 'Disease', (222, 229))	('ARF3', 'Gene', (152, 156))	('ARF3', 'Gene', (33, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('PRKCB', 'Gene', (161, 166))
19853	33653335	In addition, in the ceRNA network, both GNAI3 and ARF3 can be regulated by miR-133b and miR-133a-3p, which are at the center of the regulatory network and interact with lncRNAs including NONHSAT001973.2, NONHSAT203034.1, SNHG12 and ZNF37BP.	('ZNF37BP', 'Gene', '100129482', (232, 239))	('SNHG12', 'Gene', (221, 227))	('miR-133a-3p', 'Var', (88, 99))	('ARF3', 'Gene', '377', (50, 54))	('GNAI3', 'Gene', (40, 45))	('ZNF37BP', 'Gene', (232, 239))	('SNHG12', 'Gene', '85028', (221, 227))	('miR-133b', 'Gene', '442890', (75, 83))	('regulated', 'Reg', (62, 71))	('ARF3', 'Gene', (50, 54))	('GNAI3', 'Gene', '2773', (40, 45))	('miR-133b', 'Gene', (75, 83))
19854	33653335	Recent research has demonstrated that SNHG12 was significantly overexpressed in osteosarcoma, and high expression of SNHG12 tended to lead to a poor prognosis of osteosarcoma patients.	('overexpressed', 'PosReg', (63, 76))	('lead to', 'Reg', (134, 141))	('SNHG12', 'Gene', '85028', (38, 44))	('SNHG12', 'Gene', '85028', (117, 123))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))	('high', 'Var', (98, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('osteosarcoma', 'Disease', (162, 174))	('patients', 'Species', '9606', (175, 183))	('osteosarcoma', 'Disease', (80, 92))	('osteosarcoma', 'Phenotype', 'HP:0002669', (162, 174))	('osteosarcoma', 'Disease', 'MESH:D012516', (162, 174))	('SNHG12', 'Gene', (38, 44))	('SNHG12', 'Gene', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
19857	33653335	Additionally, ARF3 could also be regulated by miR-378a-3p and miR-422a, and among them, miR-378a-3p targeted LINC01296.	('miR-422a', 'Gene', (62, 70))	('regulated', 'Reg', (33, 42))	('LINC01296', 'Gene', (109, 118))	('ARF3', 'Gene', (14, 18))	('LINC01296', 'Gene', '642477', (109, 118))	('miR-378a-3p', 'Var', (46, 57))	('miR-422a', 'Gene', '494334', (62, 70))	('miR-378a-3p', 'Var', (88, 99))	('ARF3', 'Gene', '377', (14, 18))
19858	33653335	It has been revealed that the high expressions were significantly associated with shorter overall survival of sarcoma patients (P = 0.0297) through our survival analysis.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('sarcoma', 'Disease', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('overall survival', 'MPA', (90, 106))	('high expressions', 'Var', (30, 46))	('patients', 'Species', '9606', (118, 126))	('shorter', 'NegReg', (82, 89))
19859	33653335	The high expressions of miRNA-301a-3p, miRNA-106b-5p, miRNA-130b-3p, and miRNA-423-3p were significantly associated with a shorter overall survival of sarcoma patients (P < 0.0001, P = 0.0046, P = 0.0128, and P = 0.0147, respectively).	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('miRNA-423-3p', 'Var', (73, 85))	('shorter', 'NegReg', (123, 130))	('overall survival', 'CPA', (131, 147))	('miRNA-301a-3p', 'Var', (24, 37))	('miRNA-130b-3p', 'Var', (54, 67))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('miRNA-106b-5p', 'Var', (39, 52))	('patients', 'Species', '9606', (159, 167))	('sarcoma', 'Disease', (151, 158))
19865	33653335	Until now, there is no study that reports the association of miRNA-423-3p and miRNA-106b-5p with sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('miRNA-106b-5p', 'Var', (78, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('miRNA-423-3p', 'Var', (61, 73))	('sarcomas', 'Disease', (97, 105))
19946	26909278	This translocation leads to the production of an aberrant transcription factor that promotes tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('aberrant', 'Var', (49, 57))	('tumor', 'Disease', (93, 98))	('leads to', 'Reg', (19, 27))	('promotes', 'PosReg', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
19957	26909278	Transgenic mice overexpressing OPG exhibit an osteopetrotic phenotype, whereas OPG-knockout mice have severe osteoporosis.	('osteoporosis', 'Phenotype', 'HP:0000939', (109, 121))	('osteopetrotic', 'Disease', (46, 59))	('OPG', 'Var', (31, 34))	('mice', 'Species', '10090', (11, 15))	('osteoporosis', 'Disease', (109, 121))	('severe osteoporosis', 'Phenotype', 'HP:0005897', (102, 121))	('osteopetrotic', 'Disease', 'None', (46, 59))	('osteoporosis', 'Disease', 'MESH:D010024', (109, 121))	('Transgenic mice', 'Species', '10090', (0, 15))	('mice', 'Species', '10090', (92, 96))
19977	26909278	Groups of 6-8 mice were assigned as control vectors (F68/pcDNA3.1 alone) and hOPG1-194 (F68/pcDNA3.1-OPG1-194).	('F68/pcDNA3.1-OPG1-194', 'Var', (88, 109))	('mice', 'Species', '10090', (14, 18))	('hOPG', 'Gene', '4982', (77, 81))	('hOPG', 'Gene', (77, 81))
19978	26909278	F68 alone or associated with the empty vector pcDNA3.1 does not affect tumor development as compared to non-treated mice that develop the Ewing sarcoma model (data not shown).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (138, 151))	('mice', 'Species', '10090', (116, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Ewing sarcoma', 'Disease', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('F68', 'Var', (0, 3))	('tumor', 'Disease', (71, 76))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (138, 151))
20018	26909278	These cells are CD105+, CD90+, CD45- and CD90-.	('CD90', 'Gene', (41, 45))	('CD45', 'Gene', (31, 35))	('CD45', 'Gene', '5788', (31, 35))	('CD105+', 'Var', (16, 22))	('CD90', 'Gene', '7070', (24, 28))	('CD90', 'Gene', '7070', (41, 45))	('CD90', 'Gene', (24, 28))
20047	26909278	A preventive protocol of non-viral gene transfer using the synthetic copolymer vector F68 from the Lutrol family was designed to determine the potential protective effect of hOPG1-194 on TC-71 ES tumor progression (n=6).	('ES tumor', 'Disease', 'MESH:C563168', (193, 201))	('hOPG', 'Gene', (174, 178))	('ES tumor', 'Disease', (193, 201))	('TC-71 ES', 'Chemical', '-', (187, 195))	('copolymer', 'Chemical', '-', (69, 78))	('ES', 'Phenotype', 'HP:0012254', (193, 195))	('hOPG', 'Gene', '4982', (174, 178))	('synthetic', 'Species', '2005392', (59, 68))	('TC-71', 'Var', (187, 192))	('Lutrol', 'Chemical', 'MESH:C506200', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
20050	26909278	For example at day 38 post-tumor cell injection, the mean tumor volume is diminished in hOPG-treated mice 1647.8+-1122 mm3 as compared to pcDNA3.1 control mice 2658.9.5+-1090.6 mm3 (Fig.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('hOPG', 'Gene', '4982', (88, 92))	('diminished', 'NegReg', (74, 84))	('tumor', 'Disease', (27, 32))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('hOPG', 'Gene', (88, 92))	('mice', 'Species', '10090', (155, 159))	('1647.8+-1122', 'Var', (106, 118))
20058	26909278	These results were confirmed and quantified by bone micro-architecture analysis, showing an intense bone remodeling in the pcDNA3.1 group while micro-architecture is preserved in hOPG treated animals (Fig.	('pcDNA3.1', 'Var', (123, 131))	('hOPG', 'Gene', (179, 183))	('bone remodeling', 'CPA', (100, 115))	('hOPG', 'Gene', '4982', (179, 183))
20077	26909278	Accordingly, inhibition of osteoclast activity represents a promising approach to block the vicious cycle, inhibiting indirectly local cancer growth.	('cancer', 'Disease', (135, 141))	('osteoclast activity', 'CPA', (27, 46))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('inhibiting', 'NegReg', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
20100	26909278	Several in vitro studies have even suggested that OPG could represent a protumoral factor for cancer cells, by inhibiting the pro-apoptosis activity of TRAIL.	('TRAIL', 'Gene', '8743', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TRAIL', 'Gene', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('inhibiting', 'NegReg', (111, 121))	('OPG', 'Var', (50, 53))	('pro-apoptosis activity', 'MPA', (126, 148))	('tumor', 'Disease', (75, 80))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
20126	25265230	The HIV-CAUSAL Collaboration has recently reported an increase in tuberculosis incidence shortly after cART initiation which was particularly marked in patients with CD4 counts below 50 cells/microL, a pattern strongly suggestive of unmasking IRIS.	('tuberculosis', 'Disease', 'MESH:D014376', (66, 78))	('increase', 'PosReg', (54, 62))	('below 50', 'Var', (177, 185))	('CD4', 'Gene', (166, 169))	('CD4', 'Gene', '920', (166, 169))	('tuberculosis', 'Disease', (66, 78))	('HIV', 'Species', '12721', (4, 7))	('patients', 'Species', '9606', (152, 160))
20165	25265230	The risk of tuberculosis up to 3 months after cART initiation was 1.77 (0.78,4.00) in patients with baseline CD4 count <50 cells/mm3, 2.10 (1.07,4.11) in patients with age>50 years and 1.21 (0.84,1.74) in males.	('tuberculosis', 'Disease', 'MESH:D014376', (12, 24))	('patients', 'Species', '9606', (154, 162))	('<50', 'Var', (119, 122))	('CD4', 'Gene', (109, 112))	('CD4', 'Gene', '920', (109, 112))	('tuberculosis', 'Disease', (12, 24))	('patients', 'Species', '9606', (86, 94))
20253	25071266	The proposed pathogenesis is due to defective oxygen and carbon dioxide perfusion which leads to secretion of vascular endothelial growth factors which causes proliferation of endothelial cells and fibroblasts, leading to hypertrophy and dermatitis changes.	('defective', 'Var', (36, 45))	('hypertrophy', 'Disease', (222, 233))	('oxygen', 'Chemical', 'MESH:D010100', (46, 52))	('hypertrophy', 'Disease', 'MESH:D006984', (222, 233))	('carbon dioxide', 'Chemical', 'MESH:D002245', (57, 71))	('leading to', 'Reg', (211, 221))	('dermatitis', 'Disease', (238, 248))	('dermatitis', 'Disease', 'MESH:D003872', (238, 248))	('secretion', 'MPA', (97, 106))	('dermatitis', 'Phenotype', 'HP:0011123', (238, 248))	('causes', 'Reg', (152, 158))
20312	32585948	Ultimately, the 60 s CAP treatment of the medium achieved a similar effect to that of the direct CAP treatment of the cells (MNNG/HOS: 68% +- 8%, p = 0.004; U 2 OS: 69% +- 8%, p < 0.001; A673: 87% +- 4%, p < 0.001; RD-ES: 94% +- 2%, p < 0.001; Figure 2I-L).	('med', 'Gene', '1299', (42, 45))	('CAP', 'Chemical', '-', (97, 100))	('A673', 'Var', (187, 191))	('med', 'Gene', (42, 45))	('CAP', 'Chemical', '-', (21, 24))
20321	32585948	Compared to control cells, with the exception of MNNG/HOS cells (103 +- 9%, p = 0.956), a modest but significant increase of the release of fluorescein was detected after CAP treatment (U-2 OS: 107 +- 4%, p = 0.029; A673: 106 +- 6%, p = 0.032; RD-ES: 113 +- 5%, p = 0.025; Figure 3E-H).	('CAP', 'Chemical', '-', (171, 174))	('increase', 'PosReg', (113, 121))	('release of fluorescein', 'MPA', (129, 151))	('A673', 'Var', (216, 220))	('fluorescein', 'Chemical', 'MESH:D019793', (140, 151))	('U-2 OS', 'CellLine', 'CVCL:0042', (186, 192))
20327	32585948	The FITC area/cell was up to several hundred times higher than in argon gas control-treated cells (MNNG/HOS: 813-fold, p = 0.007; U-2 OS: 60-fold, p = 0.005; A673: 616-fold, p < 0.001; RD-ES: 4627-fold, p = 0.049; Figure 4I-L).	('U-2 OS', 'CellLine', 'CVCL:0042', (130, 136))	('FITC', 'MPA', (4, 8))	('higher', 'PosReg', (51, 57))	('A673', 'Var', (158, 162))	('FITC', 'Chemical', '-', (4, 8))	('argon', 'Chemical', 'MESH:D001128', (66, 71))
20363	32585948	In addition, the caspase assay performed with H2O2 show a tendency of the increased apoptotic processes in both bone sarcoma entities.	('med', 'Gene', (37, 40))	('bone sarcoma entities', 'Disease', (112, 133))	('H2O2', 'Chemical', 'MESH:D006861', (46, 50))	('H2O2', 'Var', (46, 50))	('bone sarcoma', 'Phenotype', 'HP:0002669', (112, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('med', 'Gene', '1299', (37, 40))	('increased', 'PosReg', (74, 83))	('apoptotic processes', 'CPA', (84, 103))	('bone sarcoma entities', 'Disease', 'MESH:D012509', (112, 133))
20397	32585948	If components of CAP lead to modifications of the cytoskeleton, however, it can be assumed that, in addition to changes in the cytoplasmic membrane, modifications of the cytoskeleton structure affect cellular functionality and physiology.	('cellular functionality', 'CPA', (200, 222))	('med', 'Gene', '1299', (87, 90))	('modifications', 'Reg', (29, 42))	('modifications', 'Var', (149, 162))	('affect', 'Reg', (193, 199))	('physiology', 'CPA', (227, 237))	('med', 'Gene', (87, 90))	('CAP', 'Chemical', '-', (17, 20))
20547	25888631	Deregulation of dicer and mir-155 expression in liposarcoma Liposarcoma (LPS) is the most common soft tissue sarcoma.	('mir-155', 'Gene', (26, 33))	('LPS', 'Phenotype', 'HP:0012034', (73, 76))	('liposarcoma', 'Phenotype', 'HP:0012034', (48, 59))	('expression', 'MPA', (34, 44))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('mir-155', 'Gene', '406947', (26, 33))	('sarcoma', 'Disease', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (97, 116))	('liposarcoma', 'Disease', 'MESH:D008080', (48, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('Liposarcoma', 'Phenotype', 'HP:0012034', (60, 71))	('LPS', 'Disease', (73, 76))	('sarcoma', 'Disease', (52, 59))	('dicer', 'Gene', (16, 21))	('liposarcoma', 'Disease', (48, 59))	('Liposarcoma', 'Disease', 'MESH:D008080', (60, 71))	('Deregulation', 'Var', (0, 12))	('dicer', 'Gene', '23405', (16, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('LPS', 'Disease', 'MESH:C536528', (73, 76))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Disease', (64, 71))	('Liposarcoma', 'Disease', (60, 71))
20568	25888631	Furthermore, some data suggest that knockdown of mir-155 delayed tumor cell growth, decreased colony formation and induced G1-S cell cycle arrest in vitro and blocked tumor growth in murine xenografts in vivo.	('colony formation', 'CPA', (94, 110))	('delayed', 'NegReg', (57, 64))	('murine', 'Species', '10090', (183, 189))	('G1-S cell cycle arrest', 'CPA', (123, 145))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('induced', 'Reg', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mir-155', 'Gene', (49, 56))	('knockdown', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('decreased', 'NegReg', (84, 93))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (128, 145))	('tumor', 'Disease', (167, 172))	('blocked', 'NegReg', (159, 166))
20596	25888631	Thus, Dicer deregulation may be site specific and its role may differ in different tumors and in different subtypes.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('deregulation', 'Var', (12, 24))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Dicer', 'Gene', '23405', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Dicer', 'Gene', (6, 11))
20613	25888631	In all samples, inventoried TaqMan Gene Expression Assays for Dicer (Hs00229023_m1), Drosha (Hs00203008_m1), PPIA (Hs99999904_m1), mir-155 (002623) and mir-RNU6B (001093) were used.	('RNU6B', 'Gene', '26826', (156, 161))	('Dicer', 'Gene', '23405', (62, 67))	('Dicer', 'Gene', (62, 67))	('PPIA', 'Gene', '5478', (109, 113))	('002623', 'Var', (140, 146))	('Drosha', 'Gene', (85, 91))	('RNU6B', 'Gene', (156, 161))	('Hs00229023_m1', 'Var', (69, 82))	('Hs00203008_m1', 'Var', (93, 106))	('Hs99999904_m1', 'Var', (115, 128))	('PPIA', 'Gene', (109, 113))	('Drosha', 'Gene', '29102', (85, 91))
20638	33486908	We included the data of patients from 2007 to 2016 with "Korean Standard Classification of Diseases Diagnostic Code" of C18, C19, or C20, which indicate malignancy of the colon and rectum.	('malignancy of the colon', 'Phenotype', 'HP:0100273', (153, 176))	('C18', 'Gene', '27241', (120, 123))	('malignancy of the colon', 'Disease', (153, 176))	('C19', 'Var', (125, 128))	('C20', 'Var', (133, 136))	('indicate', 'Reg', (144, 152))	('malignancy of the colon', 'Disease', 'MESH:D015179', (153, 176))	('Classification of Diseases', 'Disease', (73, 99))	('C18', 'Gene', (120, 123))	('Classification of Diseases', 'Disease', 'MESH:D008310', (73, 99))
20667	31123606	A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes.	('patients', 'Species', '9606', (145, 153))	('pazopanib', 'Chemical', 'MESH:C516667', (91, 100))	('improved', 'PosReg', (51, 59))	('pazopanib', 'Var', (91, 100))	('progression-free survival', 'CPA', (60, 85))	('STS', 'Phenotype', 'HP:0030448', (159, 162))
20673	31123606	This approval was based on the results of a double-blind, placebo-controlled randomized phase III trial that demonstrated significant prolongation of progression-free survival (PFS) in patients with pretreated advanced STS who received pazopanib.	('progression-free survival', 'CPA', (150, 175))	('pazopanib', 'Var', (236, 245))	('prolongation', 'PosReg', (134, 146))	('STS', 'Phenotype', 'HP:0030448', (219, 222))	('patients', 'Species', '9606', (185, 193))	('pazopanib', 'Chemical', 'MESH:C516667', (236, 245))
20684	31123606	In vitro inhibition of ligand-mediated phosphorylation of KIT and PDGFRB by pazopanib was also shown in human lung cancer and foreskin fibroblast cells, respectively, although the drug had no effect on proliferation in an unspecified panel of tumor cells.	('inhibition', 'NegReg', (9, 19))	('PDGFRB', 'Gene', '5159', (66, 72))	('pazopanib', 'Var', (76, 85))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('unspecified', 'Species', '32644', (222, 233))	('ligand-mediated phosphorylation', 'MPA', (23, 54))	('PDGFRB', 'Gene', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('human', 'Species', '9606', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('pazopanib', 'Chemical', 'MESH:C516667', (76, 85))	('KIT', 'Gene', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
20693	31123606	A later study in the same breast cancer xenograft model showed that the inhibition of brain metastasis growth by pazopanib was accompanied by a reduction in the number of PDGFRB-expressing, metastasis-associated astrocytes, suggesting a possible role for pazopanib-mediated therapeutic modulation of the tumor microenvironment (TME).	('PDGFRB', 'Gene', (171, 177))	('brain metastasis growth', 'CPA', (86, 109))	('breast cancer', 'Disease', (26, 39))	('pazopanib', 'Chemical', 'MESH:C516667', (113, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('pazopanib', 'Chemical', 'MESH:C516667', (255, 264))	('pazopanib', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('PDGFRB', 'Gene', '5159', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumor', 'Disease', (304, 309))	('reduction', 'NegReg', (144, 153))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('inhibition', 'NegReg', (72, 82))
20694	31123606	In follow-on studies, a panel of breast cancer and melanoma cell lines with varying BRAF mutational status were used in orthotopic xenograft models that were then treated with pazopanib.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('pazopanib', 'Chemical', 'MESH:C516667', (176, 185))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutational', 'Var', (89, 99))	('melanoma', 'Disease', (51, 59))	('breast cancer', 'Disease', (33, 46))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
20695	31123606	Here, xenografts with either wildtype or exon-11-mutated BRAF showed significant sensitivity to pazopanib and a corresponding reduction of MAPK pathway activation in tumor cells and reduced angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('angiogenesis', 'CPA', (190, 202))	('activation', 'PosReg', (152, 162))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('BRAF', 'Gene', '673', (57, 61))	('exon-11-mutated', 'Var', (41, 56))	('MAPK pathway', 'Pathway', (139, 151))	('BRAF', 'Gene', (57, 61))	('tumor', 'Disease', (166, 171))	('pazopanib', 'Chemical', 'MESH:C516667', (96, 105))	('reduction', 'NegReg', (126, 135))	('sensitivity to pazopanib', 'MPA', (81, 105))	('exon-11', 'Chemical', '-', (41, 48))	('reduced', 'NegReg', (182, 189))
20708	31123606	Subsequent randomized phase III trials in mRCC demonstrated superior PFS with pazopanib vs. placebo in pretreated patients and noninferior disease control and survival.	('pazopanib', 'Var', (78, 87))	('PFS', 'MPA', (69, 72))	('superior', 'PosReg', (60, 68))	('mRCC', 'Disease', (42, 46))	('pazopanib', 'Chemical', 'MESH:C516667', (78, 87))	('patients', 'Species', '9606', (114, 122))
20733	31123606	This sample size would also provide 90% power to detect HR 0.67 for OS, which was included in secondary endpoints along with toxicity and quality-of-life measures.	('OS', 'Chemical', '-', (68, 70))	('toxicity', 'Disease', 'MESH:D064420', (125, 133))	('HR 0.67', 'Var', (56, 63))	('toxicity', 'Disease', (125, 133))
20740	31123606	A small excess in decreased left ventricular ejection fraction, thromboembolic events, and pneumothorax was observed in the pazopanib arm.	('thromboembolic', 'Disease', 'MESH:D013923', (64, 78))	('left ventricular ejection fraction', 'MPA', (28, 62))	('decreased', 'NegReg', (18, 27))	('pneumothorax', 'Phenotype', 'HP:0002107', (91, 103))	('thromboembolic', 'Disease', (64, 78))	('pazopanib', 'Chemical', 'MESH:C516667', (124, 133))	('thromboembolic events', 'Phenotype', 'HP:0001907', (64, 85))	('pazopanib', 'Var', (124, 133))	('pneumothorax', 'Disease', (91, 103))
20751	31123606	Compared to patients with uterine sarcomas who received placebo within the PALETTE study, patients randomized to pazopanib had a significantly longer median PFS (3.0 vs. 0.8 m, p < 0.001) and median OS (17.5 vs. 7.9 m, p = 0.038).	('OS', 'Chemical', '-', (199, 201))	('patients', 'Species', '9606', (12, 20))	('pazopanib', 'Chemical', 'MESH:C516667', (113, 122))	('PFS', 'MPA', (157, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('sarcomas', 'Disease', (34, 42))	('longer', 'PosReg', (143, 149))	('pazopanib', 'Var', (113, 122))	('sarcomas', 'Disease', 'MESH:D012509', (34, 42))	('patients', 'Species', '9606', (90, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (34, 42))
20774	31123606	Predictive analysis did not detect a significant interaction between histological subtype and pazopanib benefit, with improved PFS with pazopanib vs. placebo seen in all three histological subgroups (LMS, SS, other).	('pazopanib', 'Chemical', 'MESH:C516667', (136, 145))	('PFS', 'MPA', (127, 130))	('improved', 'PosReg', (118, 126))	('pazopanib', 'Var', (136, 145))	('LMS', 'Phenotype', 'HP:0100243', (200, 203))	('pazopanib', 'Chemical', 'MESH:C516667', (94, 103))	('SS', 'Phenotype', 'HP:0012570', (205, 207))
20800	31123606	A prospective cohort study of patients with mRCC or advanced STS/GIST treated with TKIs including pazopanib demonstrated that dose optimization in response to suboptimal trough drug levels was successful in attaining subsequent adequate trough levels, indicating that dose monitoring and adjustment could represent a path to improved clinical effectiveness of these drugs.	('pazopanib', 'Chemical', 'MESH:C516667', (98, 107))	('trough levels', 'MPA', (237, 250))	('GIST', 'Phenotype', 'HP:0100723', (65, 69))	('STS', 'Phenotype', 'HP:0030448', (61, 64))	('patients', 'Species', '9606', (30, 38))	('suboptimal', 'Var', (159, 169))
20819	31123606	Other studies have investigated tumor-based pazopanib biomarkers, including retrospective assessment of gene expression-based mRCC molecular subgroups, hypoxia-inducible factor (HIF) levels or von Hippel-Lindau tumor suppressor gene (VHL) mutational status in tissue series.	('pazopanib', 'Chemical', 'MESH:C516667', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('VHL', 'Disease', 'MESH:D006623', (234, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('VHL', 'Disease', (234, 237))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (193, 216))	('von Hippel-Lindau tumor', 'Disease', (193, 216))	('mutational', 'Var', (239, 249))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', (32, 37))	('hypoxia', 'Disease', 'MESH:D000860', (152, 159))	('hypoxia', 'Disease', (152, 159))
20824	31123606	High NLR has been shown to be a negative prognostic marker in multiple solid tumor types.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('High', 'Var', (0, 4))
20831	31123606	TP53 and RB1 were the only two genes found to be altered in >20% (in 10 and 6 patients, respectively), with all detected mutations of TP53 predicted to confer loss-of-function (missense mutation of DNA binding and/or tetramerization domain, or homozygous deletion).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (121, 130))	('TP53', 'Gene', (134, 138))	('patients', 'Species', '9606', (78, 86))	('RB1', 'Gene', (9, 12))	('loss-of-function', 'NegReg', (159, 175))	('DNA', 'Protein', (198, 201))	('RB1', 'Gene', '5925', (9, 12))	('TP53', 'Gene', '7157', (134, 138))	('tetramerization domain', 'MPA', (217, 239))
20839	31123606	Dual pharmacological inhibition or genetic silencing using RNA interference (RNAi) of these targets led to a synergistic increase in tumor cell apoptosis.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('increase', 'PosReg', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('genetic', 'Var', (35, 42))	('tumor', 'Disease', (133, 138))
20842	31123606	These cells were no longer dependent upon PDGFRA signaling but remained sensitive to FGFR1 inhibition, indicating that loss of PDGFRA could serve as a marker of acquired pazopanib resistance that could potentially be therapeutically targeted with inhibitors of FGFR1.	('PDGFRA', 'Gene', (127, 133))	('PDGFRA', 'Gene', '5156', (42, 48))	('PDGFRA', 'Gene', (42, 48))	('PDGFRA', 'Gene', '5156', (127, 133))	('FGFR1', 'Gene', (85, 90))	('pazopanib', 'Chemical', 'MESH:C516667', (170, 179))	('FGFR1', 'Gene', '2260', (85, 90))	('FGFR1', 'Gene', (261, 266))	('FGFR1', 'Gene', '2260', (261, 266))	('loss', 'Var', (119, 123))	('pazopanib resistance', 'MPA', (170, 190))
20870	27761754	Li-Fraumeni syndrome (LFS) is the most common syndrome predisposing to pediatric sarcomas and involves a germline mutation of the TP53 gene.	('germline mutation', 'Var', (105, 122))	('sarcomas', 'Disease', (81, 89))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('LFS', 'Disease', 'MESH:D016864', (22, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('TP53', 'Gene', '7157', (130, 134))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('LFS', 'Disease', (22, 25))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('TP53', 'Gene', (130, 134))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
20874	27761754	Mutations at TP53 represent the most frequently identified genetic alterations in human cancers.	('TP53', 'Gene', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TP53', 'Gene', '7157', (13, 17))	('human', 'Species', '9606', (82, 87))
20878	27761754	Loss of pRb induces unregulated cell cycle progression.	('pRb', 'Gene', (8, 11))	('Loss', 'Var', (0, 4))	('cell cycle progression', 'CPA', (32, 54))	('pRb', 'Gene', '5925', (8, 11))
20879	27761754	Germline loss of RB1 in 13q14 microdeletion syndrome (hereditary retinoblastoma) is associated with an increased risk for retinoblastoma and, to a lesser degree, soft-tissue sarcomas, melanoma, and OS.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (54, 79))	('sarcomas', 'Disease', (174, 182))	('melanoma', 'Disease', (184, 192))	('RB1', 'Gene', '5925', (17, 20))	('OS', 'Phenotype', 'HP:0002669', (198, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('retinoblastoma', 'Gene', (65, 79))	('hereditary retinoblastoma', 'Disease', (54, 79))	('associated', 'Reg', (84, 94))	('retinoblastoma', 'Gene', '5925', (122, 136))	('retinoblastoma', 'Phenotype', 'HP:0009919', (122, 136))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (162, 182))	('RB1', 'Gene', (17, 20))	('retinoblastoma', 'Gene', '5925', (65, 79))	('loss', 'Var', (9, 13))	('retinoblastoma', 'Phenotype', 'HP:0009919', (65, 79))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('retinoblastoma', 'Gene', (122, 136))
20882	27761754	Loss of other genes in this pathway are functionally equivalent to loss of RB1 and have been identified in OS tumors lacking RB1 alterations.	('OS tumors', 'Disease', 'MESH:C567932', (107, 116))	('RB1', 'Gene', (75, 78))	('RB1', 'Gene', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Loss', 'NegReg', (0, 4))	('RB1', 'Gene', '5925', (125, 128))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('loss', 'Var', (67, 71))	('RB1', 'Gene', '5925', (75, 78))	('OS tumors', 'Disease', (107, 116))	('OS', 'Phenotype', 'HP:0002669', (107, 109))
20883	27761754	Germline mutations in genes in the RecQ family give rise to the rare autosomal recessive cancer predisposition disorders (e.g., Bloom's syndrome, Werner's syndrome, and Rothmund-Thomson syndrome), which are all associated with increased incidence of OS.	('Germline mutations', 'Var', (0, 18))	("Werner's syndrome", 'Disease', 'MESH:D014898', (146, 163))	('RecQ', 'Gene', (35, 39))	("Werner's syndrome", 'Disease', (146, 163))	('Rothmund-Thomson syndrome', 'Disease', (169, 194))	('give rise', 'Reg', (47, 56))	('autosomal recessive cancer', 'Disease', (69, 95))	('OS', 'Phenotype', 'HP:0002669', (250, 252))	('Rothmund-Thomson syndrome', 'Disease', 'MESH:D011038', (169, 194))	('autosomal recessive cancer', 'Disease', 'MESH:D009369', (69, 95))	("Bloom's syndrome", 'Disease', (128, 144))	("Bloom's syndrome", 'Disease', 'MESH:D001816', (128, 144))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
20884	27761754	In addition to genetic alterations due to chromosomal instability and loss of tumor suppressor genes, OS can also have disruptions in major signaling pathways, creating a bone microenvironment that promotes proliferation and metastasis.	('chromosomal instability', 'Phenotype', 'HP:0040012', (42, 65))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('disruptions', 'Var', (119, 130))	('proliferation', 'CPA', (207, 220))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('metastasis', 'CPA', (225, 235))	('OS', 'Phenotype', 'HP:0002669', (102, 104))	('major signaling pathways', 'Pathway', (134, 158))	('tumor', 'Disease', (78, 83))	('promotes', 'PosReg', (198, 206))
20888	27761754	Alterations in the insulin-like growth factor-I (IGF-RI) receptor pathway have been identified in the development of OS.	('IGF-RI', 'Gene', (49, 55))	('Alterations', 'Var', (0, 11))	('insulin-like growth factor-I', 'Gene', '3479', (19, 47))	('identified', 'Reg', (84, 94))	('OS', 'Phenotype', 'HP:0002669', (117, 119))	('insulin-like growth factor-I', 'Gene', (19, 47))	('IGF-RI', 'Gene', '3479', (49, 55))
20894	27761754	Metastatic OS has its own set of identifiable genetic alterations that allow tumor cells to migrate into the bloodstream, avoid apoptosis and immune destruction, and adhere and proliferate in distant tissues.	('Metastatic OS', 'Disease', (0, 13))	('proliferate', 'CPA', (177, 188))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('adhere', 'CPA', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('alterations', 'Var', (54, 65))	('OS', 'Phenotype', 'HP:0002669', (11, 13))	('tumor', 'Disease', (77, 82))	('apoptosis', 'CPA', (128, 137))	('allow', 'Reg', (71, 76))
20904	27761754	Another multi-institution genome-wide scan in 935 patients with metastatic OS found significance in a mutation of the NF1B gene.	('patients', 'Species', '9606', (50, 58))	('OS', 'Phenotype', 'HP:0002669', (75, 77))	('mutation', 'Var', (102, 110))	('NF1B', 'Gene', (118, 122))	('significance', 'Reg', (84, 96))	('NF1B', 'Gene', '4781', (118, 122))
20905	27761754	The mutation decreased NF1B activity, leading to increased OS cell migration, proliferation, and colony formation.	('decreased', 'NegReg', (13, 22))	('colony formation', 'CPA', (97, 113))	('NF1B', 'Gene', '4781', (23, 27))	('activity', 'MPA', (28, 36))	('OS cell migration', 'CPA', (59, 76))	('decreased NF1B activity', 'Phenotype', 'HP:0032423', (13, 36))	('increased', 'PosReg', (49, 58))	('mutation', 'Var', (4, 12))	('proliferation', 'CPA', (78, 91))	('NF1B', 'Gene', (23, 27))	('OS', 'Phenotype', 'HP:0002669', (59, 61))
21007	27761754	As discussed earlier, inhibition of the Fas pathway helps OS cells avoid apoptosis and immune-mediated destruction.	('inhibition', 'Var', (22, 32))	('Fas', 'Chemical', 'MESH:C038178', (40, 43))	('apoptosis', 'CPA', (73, 82))	('Fas pathway', 'Pathway', (40, 51))	('OS', 'Phenotype', 'HP:0002669', (58, 60))
21010	27761754	In a recent Children's Oncology Group (COG) phase III trial, liposomal MTP-PE improved overall survival regardless of treatment regimen.	('MTP', 'Gene', (71, 74))	('Oncology', 'Phenotype', 'HP:0002664', (23, 31))	('MTP', 'Gene', '4490', (71, 74))	('liposomal', 'Var', (61, 70))	('Children', 'Species', '9606', (12, 20))	('improved', 'PosReg', (78, 86))	('overall survival', 'MPA', (87, 103))
21012	27761754	Besides their effects on osteoclast activity, bisphosphonates also act to inhibit cell growth and proliferation, can induce apoptosis, and downregulate angiogenic growth factors.	('downregulate', 'NegReg', (139, 151))	('bisphosphonates', 'Var', (46, 61))	('osteoclast activity', 'CPA', (25, 44))	('inhibit', 'NegReg', (74, 81))	('induce', 'PosReg', (117, 123))	('angiogenic growth factors', 'CPA', (152, 177))	('cell growth', 'CPA', (82, 93))	('apoptosis', 'CPA', (124, 133))	('bisphosphonates', 'Chemical', 'MESH:D004164', (46, 61))
21016	27761754	Their work identified polymorphisms in the ABCC3 gene, a member of the multi-drug resistance protein family, and ABCB1, which encodes for an ATP-mediated efflux pump.	('polymorphisms', 'Var', (22, 35))	('ABCB1', 'Gene', (113, 118))	('ABCB1', 'Gene', '5243', (113, 118))	('ATP', 'Chemical', 'MESH:D000255', (141, 144))	('ABCC3', 'Gene', (43, 48))	('drug resistance', 'Phenotype', 'HP:0020174', (77, 92))	('ABCC3', 'Gene', '8714', (43, 48))
21027	27506465	The continued presence of EWSR1 rearrangement in both the blue round cell component and the ganglioneuroblastoma-like component was shown by FISH analysis.	('EWSR1', 'Gene', '2130', (26, 31))	('ganglioneuroblastoma', 'Phenotype', 'HP:0006747', (92, 112))	('ganglioneuroblastoma', 'Disease', (92, 112))	('EWSR1', 'Gene', (26, 31))	('rearrangement', 'Var', (32, 45))	('neuroblastoma', 'Phenotype', 'HP:0003006', (99, 112))	('ganglioneuroblastoma', 'Disease', 'MESH:D018305', (92, 112))
21048	27506465	To confirm the continued presence of the fusion gene FISH analysis was performed showing rearrangement of EWSR1 in both the small blue round cell component and the ganglioneuroblastoma-like component.	('EWSR1', 'Gene', '2130', (106, 111))	('rearrangement', 'Var', (89, 102))	('ganglioneuroblastoma', 'Disease', 'MESH:D018305', (164, 184))	('EWSR1', 'Gene', (106, 111))	('ganglioneuroblastoma', 'Phenotype', 'HP:0006747', (164, 184))	('ganglioneuroblastoma', 'Disease', (164, 184))	('neuroblastoma', 'Phenotype', 'HP:0003006', (171, 184))
21054	27506465	demonstrated the presence of the EWSR1-FLI1 fusion gene in both pre- and post-treatment specimens, as we did in our case.	('fusion', 'Var', (44, 50))	('EWSR1', 'Gene', '2130', (33, 38))	('presence', 'Reg', (17, 25))	('EWSR1', 'Gene', (33, 38))	('FLI1', 'Gene', '2313', (39, 43))	('FLI1', 'Gene', (39, 43))
21136	33465147	Intra-host changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Kaposi sarcoma', 'Disease', (91, 105))	('Kaposi sarcoma', 'Disease', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', (117, 122))	('treatment responses', 'CPA', (173, 192))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (91, 105))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (22, 36))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (22, 36))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('influence', 'Reg', (142, 151))	('cancers', 'Disease', (220, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (91, 105))	('variants', 'Var', (129, 137))
21140	33465147	The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences.	('tumor', 'Disease', (63, 68))	('impacting', 'Reg', (126, 135))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('protein-coding sequences', 'MPA', (136, 160))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('KSHV', 'Gene', (80, 84))
21142	33465147	These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements.	('rearrangements', 'Var', (185, 199))	('deletions', 'Var', (171, 180))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('IR1', 'Gene', '11188', (138, 141))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('K8.1', 'Gene', '3887', (35, 39))	('IR1', 'Gene', (138, 141))	('inactivation', 'NegReg', (15, 27))	('K8.1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
21143	33465147	Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes.	('KSHV', 'Gene', (139, 143))	('rearranged', 'Var', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('metastatic spread', 'CPA', (107, 124))
21144	33465147	These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis.	('aberrant', 'Var', (151, 159))	('contribute', 'Reg', (177, 187))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('KS tumor', 'Disease', 'MESH:D009369', (202, 210))	('KS tumor', 'Disease', (202, 210))	('KSHV', 'Gene', (160, 164))
21147	33465147	While strain differences or mutations in other tumor viruses are known to affect the risk and progression of their associated cancers, whether genetic variation in KSHV is important to the natural history of KS is unclear.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('affect', 'Reg', (74, 80))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', (47, 52))
21151	33465147	However, KSHV genome aberrations and gene-inactivating mutations were found to be common in KS tumors, often impacting the same genes and genomic regions across individuals.	('KS tumors', 'Disease', 'MESH:D009369', (92, 101))	('impacting', 'Reg', (109, 118))	('gene-inactivating mutations', 'Var', (37, 64))	('KS tumors', 'Disease', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('KSHV', 'Gene', (9, 13))
21152	33465147	Whether theses mutations influence KS tumorigenesis or result from genomic instability commonly found in tumors warrants further study.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('KS tumor', 'Disease', 'MESH:D009369', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('genomic instability', 'MPA', (67, 86))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('influence', 'Reg', (25, 34))	('result', 'Reg', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('KS tumor', 'Disease', (35, 43))
21153	33465147	Lastly, aberrant KSHV genomes were found to be shared by distinct tumors within individuals, suggesting the capacity of KS tumor cells to metastasize and seed new lesions.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('metastasize', 'CPA', (138, 149))	('KSHV', 'Gene', (17, 21))	('seed new lesions', 'CPA', (154, 170))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('aberrant', 'Var', (8, 16))	('KS tumor', 'Disease', 'MESH:D009369', (120, 128))	('KS tumor', 'Disease', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
21158	33465147	Studies of other human oncogenic viruses have revealed that viral genetic variation or de novo mutations may be important to their pathogenicity, as is the case for cancers associated with human papilloma viruses and Merkel cell polyomavirus.	('papilloma viruses', 'Disease', 'MESH:D010212', (195, 212))	('papilloma viruses', 'Disease', (195, 212))	('Merkel cell polyomavirus', 'Species', '493803', (217, 241))	('human', 'Species', '9606', (189, 194))	('human', 'Species', '9606', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('papilloma', 'Phenotype', 'HP:0012740', (195, 204))	('mutations', 'Var', (95, 104))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('Merkel cell polyomavirus', 'Disease', (217, 241))
21164	33465147	For example, polymorphisms in the microRNA (miRNA) region of KSHV have been correlated with the development of multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome with and without KS.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('inflammatory cytokine syndrome', 'Disease', 'MESH:D000080424', (162, 192))	('KSHV', 'Gene', (61, 65))	('multicentric Castleman disease', 'Disease', 'MESH:C537372', (111, 141))	('polymorphisms', 'Var', (13, 26))	('correlated with', 'Reg', (76, 91))	('cytokine syndrome', 'Phenotype', 'HP:0031407', (175, 192))	('multicentric Castleman disease', 'Disease', (111, 141))	('inflammatory cytokine syndrome', 'Disease', (162, 192))
21199	33465147	The diversity of the bait library was further increased by including K1, ORF75, K15, ORF26 and TR sequences of strains JSC-1 (Genbank ID: GQ994935.1), DG1 (Genbank ID: JQ619843.1), BC-1 (Genbank ID: U75698.1), BCBL-1 (Genbank ID: HQ404500.1), Sau3A (Genbank ID: U93872.2), and of all Western and African isolates in (Genbank ID: AF130259, AF130266, AF130267, AF130281, AF130305, AF133039, AF133040, AF133043, AF133044, AF151687, AF171057, AF178780, AF178810, AF220292, AF220293, AY329032, KT271453-KT271468).	('AF130281', 'Var', (359, 367))	('AF130267', 'Var', (349, 357))	('ORF75', 'Gene', '4961476', (73, 78))	('AF133040', 'Var', (389, 397))	('ORF75', 'Gene', (73, 78))	('AF178810', 'Var', (449, 457))	('AF133043', 'Var', (399, 407))	('ORF26', 'Gene', (85, 90))	('ORF26', 'Gene', '440829', (85, 90))	('AF151687', 'Var', (419, 427))	('DG1', 'Gene', '1828', (151, 154))	('AF133044', 'Var', (409, 417))	('AF171057', 'Var', (429, 437))	('AY329032', 'Var', (479, 487))	('K15', 'Gene', '3866', (80, 83))	('K15', 'Gene', (80, 83))	('AF130305', 'Var', (369, 377))	('AF220293', 'Var', (469, 477))	('AF130266', 'Var', (339, 347))	('DG1', 'Gene', (151, 154))	('TR', 'Gene', '2149', (95, 97))	('AF220292', 'Var', (459, 467))	('AF133039', 'Var', (379, 387))	('AF178780', 'Var', (439, 447))
21202	33465147	For some tumor samples with low KSHV copy numbers and all oral swab samples, a second library enrichment was performed.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('low', 'Var', (28, 31))	('KSHV', 'Gene', (32, 36))
21224	33465147	Intra-individual single nucleotide differences between tumor and oral swabs ranged in number from 0-2 across entire ~131-kb genomes, not counting the major repeat regions.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('single nucleotide differences', 'Var', (17, 46))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))
21228	33465147	While K1 and K15 are the most variable KSHV genes, polymorphisms along the rest of the genome have been reported to contribute more in aggregate to the total diversity of KSHV.	('polymorphisms', 'Var', (51, 64))	('K15', 'Gene', '3866', (13, 16))	('KSHV', 'Gene', (39, 43))	('K15', 'Gene', (13, 16))
21236	33465147	Inversion of the 60-kb 3' end of the U003-C genome, starting inside K8.1, is a parsimonious explanation for the breakpoints.	('Inversion', 'Var', (0, 9))	('K8.1', 'Gene', '3887', (68, 72))	('K8.1', 'Gene', (68, 72))
21238	33465147	U008-B had 1.7X greater read coverage over a 14.8-kb segment from inside K3 to inside ORF19 (GK18 reference positions 19,168 to 33,980, Fig 6A), including IR1 (masked).	('ORF19', 'Gene', '79783', (86, 91))	('U008-B', 'Var', (0, 6))	('IR1', 'Gene', '11188', (155, 158))	('greater', 'PosReg', (16, 23))	('ORF19', 'Gene', (86, 91))	('IR1', 'Gene', (155, 158))	('read coverage', 'MPA', (24, 37))
21241	33465147	In a parallel study of viral transcriptomes, abundant expression of a chimeric Kaposin transcript fused to the same 14.8-kb segment was found in tumor U008-B, consistent with the viral genome structure we observed.	('expression', 'MPA', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('chimeric', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('Kaposin', 'Gene', (79, 86))
21256	33465147	PCR amplification and Sanger sequencing of this region showed that the U030-C tumor did contain some copies of the entire M-allele K15 sequence.	('K15', 'Gene', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('U030-C', 'Var', (71, 77))	('K15', 'Gene', '3866', (131, 134))
21258	33465147	In the parallel RNAseq study of tumors of this same participant, U030-B and C, transcripts of K15 were also lacking, unlike tumors from all other participants.	('participant', 'Species', '9606', (146, 157))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('participant', 'Species', '9606', (52, 63))	('transcripts', 'MPA', (79, 90))	('lacking', 'NegReg', (108, 115))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('U030-B', 'Var', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('participants', 'Species', '9606', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('K15', 'Gene', '3866', (94, 97))	('K15', 'Gene', (94, 97))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
21259	33465147	In the case of U008-B and U008-D, two tumors biopsied from distinct lesions on the left leg (S5 Fig and S2 Table), full-length genome sequencing showed that they had the same 14.8 kb KSHV subgenomic sequence duplicated in IR2 (Fig 6F).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('U008-D', 'Var', (26, 32))	('U008-B', 'Var', (15, 21))
21264	33465147	In the remaining participant, U004, the sample-consensus KSHV genome in one tumor was identical to that in oral but the second tumor had mutations.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('KSHV', 'Gene', (57, 61))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutations', 'Var', (137, 146))	('participant', 'Species', '9606', (17, 28))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
21265	33465147	The mutations unique to tumors were typically nonsynonymous point mutations resulting in highly dissimilar residues or were mutations that might disrupt their expression (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('disrupt', 'NegReg', (145, 152))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('expression', 'MPA', (159, 169))	('nonsynonymous point mutations', 'Var', (46, 75))	('resulting in', 'Reg', (76, 88))	('highly dissimilar residues', 'MPA', (89, 115))	('mutations', 'Var', (4, 13))
21266	33465147	Several of the mutations or genome aberrations observed in tumors occurred in structural genes (S3 Table), and frequently involved the K8.1 gene, which encodes an envelope glycoprotein: The U003 inversion breakpoint cleaved the K8.1 gene; U004-D had an R56Q mutation in its ORF32 tegument protein coding sequence, as well as a 28-nt deletion in the promoter region of K8.1 (S6A Fig).	('K8.1', 'Gene', (228, 232))	('R56Q', 'Mutation', 'rs767996886', (253, 257))	('U004-D', 'Var', (239, 245))	('K8.1', 'Gene', '3887', (368, 372))	('envelope glycoprotein', 'Gene', '100616444', (163, 184))	('ORF32', 'Gene', '4961479', (274, 279))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('K8.1', 'Gene', '3887', (135, 139))	('K8.1', 'Gene', (368, 372))	('deletion', 'Var', (333, 341))	('envelope glycoprotein', 'Gene', (163, 184))	('K8.1', 'Gene', '3887', (228, 232))	('R56Q', 'Var', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('ORF32', 'Gene', (274, 279))	('K8.1', 'Gene', (135, 139))
21267	33465147	The deletion was after the K8.1 core promoter sequence, but encompassed the K8.1 transcription start site; the ORF25 major capsid protein in U020-B had a Q594K mutation, in addition to the U020-B genomic deletion that started further downstream inside ORF25; U020-C had a nonsense mutation at the beginning of the second K8.1 exon; and U032-B had a T848A mutation in ORF63, a tegument protein.	('T848A', 'Mutation', 'c.848T>A', (349, 354))	('K8.1', 'Gene', '3887', (27, 31))	('ORF63', 'Gene', (367, 372))	('Q594K', 'Var', (154, 159))	('K8.1', 'Gene', (321, 325))	('ORF25', 'Gene', (252, 257))	('K8.1', 'Gene', '3887', (76, 80))	('K8.1', 'Gene', (27, 31))	('Q594K', 'Mutation', 'p.Q594K', (154, 159))	('ORF25', 'Gene', '4961452', (111, 116))	('T848A', 'Var', (349, 354))	('ORF63', 'Gene', '4961466', (367, 372))	('ORF25', 'Gene', '4961452', (252, 257))	('ORF25', 'Gene', (111, 116))	('U032-B', 'Var', (336, 342))	('K8.1', 'Gene', (76, 80))	('K8.1', 'Gene', '3887', (321, 325))
21283	33465147	Given that herpesviruses have among the lowest replication error rates among viruses, next-generation sequencing errors would have corresponded to a greater proportion of suspected mutations and confounded discernment of any rare variants in a potentially heterogeneous mixture, regardless of read depth.	('herpesvirus', 'Species', '39059', (11, 22))	('errors', 'Var', (113, 119))	('mutations', 'Var', (181, 190))	('replication', 'MPA', (47, 58))
21285	33465147	There are reports of intra-host KSHV variability in certain KSHV-endemic populations, in children, in iatrogenic settings and in blood of AIDS-KS patients, but these findings were arrived at by Sanger sequencing of PCR amplicon clones of hypervariable regions in K1 or other genes.	('variability', 'Var', (37, 48))	('AIDS-KS', 'Disease', 'MESH:D000163', (138, 145))	('children', 'Species', '9606', (89, 97))	('AIDS-KS', 'Disease', (138, 145))	('patients', 'Species', '9606', (146, 154))	('KSHV', 'Gene', (32, 36))
21291	33465147	A striking finding in our study was the frequency of aberrant KSHV genomes in KS tumors, summarized in Fig 9.	('KS tumors', 'Disease', 'MESH:D009369', (78, 87))	('KS tumors', 'Disease', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('KSHV genomes', 'Gene', (62, 74))	('aberrant', 'Var', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
21292	33465147	At least 4 of the 7 participants whose samples were examined had KSHV with major inversions, deletions or duplications in their tumors.	('duplications', 'Var', (106, 118))	('participants', 'Species', '9606', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('KSHV', 'Gene', (65, 69))	('deletions', 'Var', (93, 102))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
21293	33465147	Moreover, aberrant genomes comprised the majority of the KSHV genomes in the tumors in which they were detected, from 1.7-fold (U008-B) to 30-fold (U020-C) more aberrant genomes than full-length intact KSHV genomes (Table 2 and Fig 7A and 7B).	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('aberrant genomes', 'Var', (10, 26))	('aberrant', 'Var', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('more', 'PosReg', (156, 160))
21296	33465147	The fact that aberrant KSHV genomes were only observed in tumor samples is intriguing yet their significance is unclear, since it is well known that tumor cells suffer substantial genomic instability.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('KSHV genomes', 'Gene', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('aberrant', 'Var', (14, 22))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
21299	33465147	A PCR screen for some KSHV genes showed that some KS tumors and KSHV-infected B-cell lines can harbor deleted KSHV genomes, and one such B-cell line proliferated faster than the parental BCBL-1 line.	('deleted', 'Var', (102, 109))	('proliferated', 'CPA', (149, 161))	('faster', 'PosReg', (162, 168))	('KS tumors and KSHV-infected', 'Disease', 'MESH:D007239', (50, 77))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('KSHV genomes', 'Gene', (110, 122))
21300	33465147	The genomic locations and character of tumor-associated mutations we observed suggest that mutations that propagated to high copy numbers may not have been random.	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (39, 44))
21302	33465147	Given that the KSHV genome densely encodes many immunomodulatory, angiogenic and anti-apoptotic factors, it is therefore possible that some mutations observed here could contribute to KS disease, or could involve viral genes that are unnecessary within established KS tumors, or contribute to immune evasion of transformed host cells.	('KS tumors', 'Disease', (265, 274))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('contribute', 'Reg', (170, 180))	('involve', 'Reg', (205, 212))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('immune evasion', 'MPA', (293, 307))	('KS tumors', 'Disease', 'MESH:D009369', (265, 274))	('mutations', 'Var', (140, 149))	('contribute', 'Reg', (279, 289))	('KS disease', 'Disease', (184, 194))	('KSHV', 'Gene', (15, 19))	('KS disease', 'Disease', 'MESH:D003141', (184, 194))
21304	33465147	For example, tumors U008-B and U008-D had a 14.8-kb portion of their genomes, from inside K3 to ORF19, duplicated into within IR2 (Fig 6).	('U008-B', 'Var', (20, 26))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('U008-D', 'Var', (31, 37))	('ORF19', 'Gene', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('ORF19', 'Gene', '79783', (96, 101))
21306	33465147	Distinct deletions were observed in tumors U020-B and U020-C from another participant, but the genomic regions retained, aside from TR sequences, again included the IR1 region (Fig 7).	('U020-C', 'Var', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('TR', 'Gene', '2149', (132, 134))	('IR1', 'Gene', '11188', (165, 168))	('U020-B', 'Var', (43, 49))	('IR1', 'Gene', (165, 168))	('participant', 'Species', '9606', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
21312	33465147	There is evidence to suggest that KSHV lytic gene expression is crucial to KS pathogenesis, and that residual lytic gene expression plays a role in latent KSHV persistence in vivo, so it is possible that viral mutations in lytic genes could impact viral persistence or KS disease.	('lytic genes', 'Gene', (223, 234))	('mutations', 'Var', (210, 219))	('impact', 'Reg', (241, 247))	('KS disease', 'Disease', (269, 279))	('viral persistence', 'CPA', (248, 265))	('KS disease', 'Disease', 'MESH:D003141', (269, 279))
21314	33465147	U003-C had an inversion breakpoint at the K8.1 intron, U004-D had a 28-bp deletion ending at 4 bases upstream of the first K8.1 exon, and the U020-C full-length minor genome had a nonsense mutation at the start of the second K8.1 exon.	('K8.1', 'Gene', (225, 229))	('K8.1', 'Gene', '3887', (42, 46))	('U003-C', 'Var', (0, 6))	('K8.1', 'Gene', (123, 127))	('K8.1', 'Gene', '3887', (225, 229))	('K8.1', 'Gene', (42, 46))	('K8.1', 'Gene', '3887', (123, 127))	('U004-D', 'Var', (55, 61))	('U020-C', 'Var', (142, 148))
21316	33465147	Interestingly, truncations in K8.1 had been reported previously, and all were from KS tumor isolates.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('K8.1', 'Gene', '3887', (30, 34))	('truncations', 'Var', (15, 26))	('K8.1', 'Gene', (30, 34))	('KS tumor', 'Disease', 'MESH:D009369', (83, 91))	('KS tumor', 'Disease', (83, 91))
21321	33465147	It is therefore conceivable that the preponderance of K8.1 mutations might be due to potent immune targeting of cells expressing K8.1 glycoproteins.	('K8.1', 'Gene', (129, 133))	('K8.1', 'Gene', (54, 58))	('K8.1', 'Gene', '3887', (129, 133))	('K8.1', 'Gene', '3887', (54, 58))	('mutations', 'Var', (59, 68))
21322	33465147	Evading immune responses by omission of K8.1 expression may confer better survival of the host tumor cell.	('survival', 'CPA', (74, 82))	('tumor', 'Disease', (95, 100))	('omission', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('expression', 'MPA', (45, 55))	('Evading', 'PosReg', (0, 7))	('immune responses', 'CPA', (8, 24))	('K8.1', 'Gene', '3887', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('better', 'PosReg', (67, 73))	('K8.1', 'Gene', (40, 44))
21329	33465147	This suggests that the genomic inversion and K8.1 loss of function was not too detrimental to KS tumor persistence and implies a capacity for tumor-associated KSHV to continually seed tumors in other anatomic sites.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('K8.1', 'Gene', '3887', (45, 49))	('genomic inversion', 'Var', (23, 40))	('KS tumor', 'Disease', 'MESH:D009369', (94, 102))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('KS tumor', 'Disease', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (184, 190))	('K8.1', 'Gene', (45, 49))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('loss of function', 'NegReg', (50, 66))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
21336	33465147	Future studies characterizing KSHV genomes in multiple tumors within individuals among a larger cohort of KS studies will help determine if tumor-associated KSHV mutations similar to those observed in our study result from tumor-associated genome instability, or contribute to KS tumorigenesis, or are associated with KS clinical presentation or clinical outcomes.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('associated', 'Reg', (302, 312))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('KS tumor', 'Disease', (277, 285))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', (55, 61))	('KS tumor', 'Disease', 'MESH:D009369', (277, 285))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (280, 285))	('tumor', 'Disease', (223, 228))	('KSHV', 'Gene', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('mutations', 'Var', (162, 171))	('result from', 'Reg', (211, 222))	('contribute to', 'Reg', (263, 276))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('genome', 'MPA', (240, 246))	('tumor', 'Disease', (140, 145))
21345	33465147	Variants calling was performed and reported to be non-synonymous, which were mostly inconsistent between the matching oral and tumor samples.	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Variants', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))
21353	33465147	The authors also showed that there are however point mutations, sequence deletions, and gene rearrangements in the KS tissues in some of the patients, and in some cases in more than one lesion but not all the lesions analyzed within the same patients.	('gene rearrangements', 'Var', (88, 107))	('point mutations', 'Var', (47, 62))	('sequence deletions', 'Var', (64, 82))	('patients', 'Species', '9606', (141, 149))	('patients', 'Species', '9606', (242, 250))
21355	33465147	Further discussion with emphasis on whether these mutations in KSHV caused tumorigenesis, or whether the rapid replication of cancer cells caused mutations in KSHV genomes, will be helpful.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (146, 155))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('KSHV', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('KSHV', 'Gene', (159, 163))	('tumor', 'Disease', (75, 80))	('caused', 'Reg', (68, 74))
21369	33465147	Line 460-462- This reviewer agrees that the genomic aberrations are profoundly interesting and COULD be important causally, but it was unclear (perhaps my fault) what the frequency of such aberrations were of the total KSHV genomes from within a given tumor harboring those mutations.	('mutations', 'Var', (274, 283))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))
21375	33465147	The authors has focused the discussion on the significance of the role of alternation of the KSHV sequences in KS tumorigenesis and potential immune escape mechanisms by the virus.	('KS tumor', 'Disease', 'MESH:D009369', (111, 119))	('alternation', 'Var', (74, 85))	('KS tumor', 'Disease', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('KSHV', 'Gene', (93, 97))
21379	33465147	The authors have suggested that since K8.1 can generate an effective immune response and thus alternations in K8.1 gene could provide an advantage for viral escape, pathogenesis and tumor growth.	('K8.1', 'Gene', '3887', (38, 42))	('advantage', 'PosReg', (137, 146))	('tumor', 'Disease', (182, 187))	('alternations', 'Var', (94, 106))	('pathogenesis', 'CPA', (165, 177))	('K8.1', 'Gene', '3887', (110, 114))	('viral escape', 'CPA', (151, 163))	('K8.1', 'Gene', (110, 114))	('K8.1', 'Gene', (38, 42))	('immune response', 'CPA', (69, 84))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
21382	33465147	The result showing that in some cases more than one tumor lesion in the same patient harbors the same KSHV alternations is interesting.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor lesion', 'Disease', (52, 64))	('tumor lesion', 'Disease', 'MESH:D009369', (52, 64))	('patient', 'Species', '9606', (77, 84))	('alternations', 'Var', (107, 119))
21384	33465147	The author's reference a previously described duplication in BAC-36 in line 261, and have incorrectly reported the duplication size as 19kb, instead of 9kb.	('duplication', 'Var', (46, 57))	('BAC-36', 'Gene', (61, 67))	('line 261', 'CellLine', 'CVCL:2490', (71, 79))
21400	33465147	Most notably, please discuss in more depth the possibility that the deletions, duplications and changes detected in the tumor cells could be due to the genome instability of the cells, rather than being the cause of tumorigenesis.	('tumor', 'Disease', (216, 221))	('deletions', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('duplications', 'Var', (79, 91))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (120, 125))
21405	33465147	The authors here found that there were gene duplications, inversions and mutations in the tumors from 4 out of the 7 cases.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('inversions', 'Var', (58, 68))	('mutations', 'Var', (73, 82))	('gene duplications', 'Var', (39, 56))
21406	33465147	This reviewer agrees with the previous reviewers that the findings on the deletions, duplications and changes are most likely due to the result of genome instability of the tumor cells rather than the cause of tumorigenesis.	('deletions', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('changes', 'Var', (102, 109))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('duplications', 'Var', (85, 97))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
21407	33465147	Similar changes in multiple lesions can be the results of the metastases of tumor cells harboring the mutations in the KSHV genome.	('metastases of tumor', 'Disease', 'MESH:D009362', (62, 81))	('metastases of tumor', 'Disease', (62, 81))	('KSHV', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (102, 111))
21429	31980651	For example, many oncogenic mutations result in enhanced glucose metabolism, reflecting its importance to tumour cell proliferation.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('enhanced', 'PosReg', (48, 56))	('glucose metabolism', 'MPA', (57, 75))	('glucose', 'Chemical', 'MESH:D005947', (57, 64))	('tumour', 'Disease', (106, 112))	('oncogenic', 'Gene', (18, 27))	('mutations', 'Var', (28, 37))
21447	31980651	Notably, STSs expressing high GLS exhibit increased dependency on glutamine, required to support the TCA cycle, aspartate production, and subsequently, nucleotide synthesis for tumour cell growth.	('increased', 'PosReg', (42, 51))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('aspartate', 'Chemical', 'None', (112, 121))	('tumour', 'Disease', (177, 183))	('aspartate production', 'MPA', (112, 132))	('dependency on glutamine', 'MPA', (52, 75))	('STSs', 'Phenotype', 'HP:0030448', (9, 13))	('nucleotide synthesis', 'MPA', (152, 172))	('high GLS', 'Var', (25, 33))	('TCA cycle', 'MPA', (101, 110))	('increased dependency on glutamine', 'Phenotype', 'HP:0003217', (42, 75))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('TCA', 'Chemical', 'MESH:C000589078', (101, 104))	('glutamine', 'Chemical', 'MESH:C578860', (66, 75))
21454	31980651	Injection of adenovirus expressing Cre-recombinase (AdCre) into hindlimb musculature induces mutant Kras expression, Trp53 loss, and development of UPS tumours (Fig.	('Trp53', 'Gene', (117, 122))	('development', 'CPA', (133, 144))	('UPS tumours', 'Disease', 'MESH:D017118', (148, 159))	('Kras', 'Gene', (100, 104))	('mutant', 'Var', (93, 99))	('loss', 'NegReg', (123, 127))	('Kras', 'Gene', '16653', (100, 104))	('Trp53', 'Gene', '22059', (117, 122))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('UPS tumours', 'Disease', (148, 159))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('expression', 'MPA', (105, 115))
21455	31980651	We previously expanded upon this model with additional HIF-2alpha loss to generate LSL-KrasG12D/+;Trp53fl/fl;Epas1fl/fl (KPH2) animals, and determined HIF-2alpha surprisingly suppresses tumourigenesis (Fig.	('tumour', 'Disease', (186, 192))	('HIF-2alpha', 'Gene', (55, 65))	('loss', 'NegReg', (66, 70))	('Trp53', 'Gene', '22059', (98, 103))	('suppresses', 'NegReg', (175, 185))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('HIF-2alpha', 'Var', (151, 161))	('Kras', 'Gene', (87, 91))	('Kras', 'Gene', '16653', (87, 91))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('Trp53', 'Gene', (98, 103))
21480	31980651	In contrast, C2C12s, KP-6634s, and KPH2-7215s exhibited a critical dependency on glutamine with a decrease in both proliferation and cell viability (Fig.	('C2C12s', 'Var', (13, 19))	('cell viability', 'CPA', (133, 147))	('glutamine', 'MPA', (81, 90))	('decrease', 'NegReg', (98, 106))	('KP-6634s', 'Chemical', 'MESH:C067980', (21, 29))	('KPH2-7215s', 'Var', (35, 45))	('proliferation', 'CPA', (115, 128))	('glutamine', 'Chemical', 'MESH:C578860', (81, 90))	('KPH2-7215s', 'Chemical', 'MESH:C021591', (35, 45))	('KP-6634s', 'Var', (21, 29))
21481	31980651	Interestingly, C2C12s are also glucose dependent, as its withdrawal significantly inhibited cell proliferation, unlike KP-6634s and KPH2-7215s.	('inhibited', 'NegReg', (82, 91))	('C2C12s', 'Var', (15, 21))	('cell proliferation', 'CPA', (92, 110))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (119, 142))
21483	31980651	Notably, upon differentiation into myotubes, C2C12s became resistant to glutamine withdrawal (Fig.	('glutamine', 'Chemical', 'MESH:C578860', (72, 81))	('C2C12s', 'Var', (45, 51))	('resistant to glutamine withdrawal', 'MPA', (59, 92))
21487	31980651	In contrast, while glucose withdrawal affected the proliferation of LPS246s, SW872s were unaffected by either metabolite, although proliferation decreased when both were removed.	('SW872', 'CellLine', 'CVCL:1730', (77, 82))	('proliferation', 'MPA', (51, 64))	('LPS246s', 'Var', (68, 75))	('glucose', 'Chemical', 'MESH:D005947', (19, 26))
21490	31980651	HT1080s and SW872s proliferated at similar rates with differential responses to glutamine deprivation.	('SW872s', 'Var', (12, 18))	('glutamine', 'Chemical', 'MESH:C578860', (80, 89))	('proliferated', 'CPA', (19, 31))	('SW872', 'CellLine', 'CVCL:1730', (12, 17))	('HT1080', 'Gene', (0, 6))	('HT1080', 'Gene', '8872', (0, 6))
21497	31980651	However, while pyruvate provided the greatest rescue of C2C12 proliferation, DKG supplementation was most effective in KP-6634s and KPH2-7215s (Fig.	('KP-6634s', 'Var', (119, 127))	('KPH2-7215s', 'Var', (132, 142))	('C2C12', 'Protein', (56, 61))	('pyruvate', 'Chemical', 'MESH:D011773', (15, 23))	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (119, 142))
21503	31980651	However, NAC improved SK-LMS-1 proliferation upon glutamine withdrawal (Supplementary Fig.	('glutamine', 'Chemical', 'MESH:C578860', (50, 59))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (22, 30))	('SK-LMS-1 proliferation', 'CPA', (22, 44))	('NAC', 'Var', (9, 12))	('NAC', 'Chemical', 'MESH:C086501', (9, 12))	('improved', 'PosReg', (13, 21))
21507	31980651	Although KP-6634s and KPH2-7215s contributed similar levels of glutamine-derived carbon into the TCA cycle (citrate, succinate, fumarate, and malate) to C2C12s (Fig.	('succinate', 'Chemical', 'MESH:D013386', (117, 126))	('KP-6634s', 'Var', (9, 17))	('malate', 'Chemical', 'MESH:D008293', (142, 148))	('citrate', 'Chemical', 'MESH:C102006', (108, 115))	('carbon', 'Chemical', 'MESH:D002244', (81, 87))	('TCA', 'Chemical', 'MESH:C000589078', (97, 100))	('fumarate', 'Chemical', 'MESH:D005650', (128, 136))	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (9, 32))	('succinate', 'MPA', (117, 126))	('glutamine', 'Chemical', 'MESH:C578860', (63, 72))	('glutamine-derived carbon', 'MPA', (63, 87))	('KPH2-7215s', 'Var', (22, 32))
21508	31980651	2d), incorporation into aspartate was significantly higher in KP-6634s and KPH2-7215s (Fig.	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (62, 85))	('aspartate', 'Chemical', 'None', (24, 33))	('incorporation into aspartate', 'MPA', (5, 33))	('higher', 'PosReg', (52, 58))	('KPH2-7215s', 'Var', (75, 85))	('KP-6634s', 'Var', (62, 70))
21513	31980651	Similar to carbon-labelled glutamine, nitrogen contribution to aspartate was increased in KP-6634s and KPH2-7215s compared to C2C12s (Supplementary Fig.	('KP-6634s', 'Var', (90, 98))	('carbon', 'Chemical', 'MESH:D002244', (11, 17))	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (90, 113))	('KPH2-7215s', 'Var', (103, 113))	('aspartate', 'Chemical', 'None', (63, 72))	('nitrogen contribution to aspartate', 'MPA', (38, 72))	('nitrogen', 'Chemical', 'MESH:D009584', (38, 46))	('increased', 'PosReg', (77, 86))	('glutamine', 'Chemical', 'MESH:C578860', (27, 36))
21524	31980651	Total adenine concentrations were elevated in KP-6634s and KPH2-7215s (Fig.	('adenine', 'Chemical', 'MESH:D000225', (6, 13))	('KP-6634s', 'Var', (46, 54))	('KPH2-7215s', 'Var', (59, 69))	('Total adenine concentrations', 'MPA', (0, 28))	('elevated', 'PosReg', (34, 42))	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (46, 69))
21527	31980651	Culturing KP-6634s and KPH2-7215s under low glutamine with nucleosides increased cell proliferation, with more dramatic effects on KPH2-7215s than KP-6634s (Fig.	('cell proliferation', 'CPA', (81, 99))	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (10, 33))	('KP-6634s', 'Chemical', 'MESH:C067980', (147, 155))	('nucleosides', 'Chemical', 'MESH:D009705', (59, 70))	('glutamine', 'Chemical', 'MESH:C578860', (44, 53))	('low glutamine', 'Phenotype', 'HP:0500147', (40, 53))	('KPH2-7215s', 'Var', (131, 141))	('KPH2-7215s', 'Chemical', 'MESH:C021591', (23, 33))	('KP-6634s', 'Chemical', 'MESH:C067980', (10, 18))	('increased', 'PosReg', (71, 80))	('KP-6634s', 'Var', (10, 18))	('low glutamine with nucleosides', 'MPA', (40, 70))	('KPH2-7215s', 'Chemical', 'MESH:C021591', (131, 141))	('KPH2-7215s', 'Var', (23, 33))
21534	31980651	In addition, KP-6634s and KPH2-7215s as well as KP and KPH2 tumours showed higher Gls mRNA and protein compared to C2C12s and gastrocnemius muscle, respectively (Fig.	('Gls', 'Gene', (82, 85))	('KPH2-7215s', 'Var', (26, 36))	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (13, 36))	('higher', 'PosReg', (75, 81))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('Gls', 'Gene', '216456', (82, 85))	('KP-6634s', 'Var', (13, 21))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
21535	31980651	Human HT1080s, SK-LMS-1s, SK-UT-1Bs, CCL-136s, LPS246s, and T778s exhibited high GLS expression (GAC isoform; * band) compared to SW872s (Supplementary Fig.	('Human', 'Species', '9606', (0, 5))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (15, 23))	('GLS expression', 'MPA', (81, 95))	('LPS246s', 'Var', (47, 54))	('SW872', 'CellLine', 'CVCL:1730', (130, 135))	('HT1080', 'Gene', (6, 12))	('HT1080', 'Gene', '8872', (6, 12))	('T778s', 'Var', (60, 65))
21536	31980651	Altogether, this suggests different mechanisms for resistance to glutamine deprivation observed in LPS246s and SW872s (Supplementary Fig.	('SW872s', 'Var', (111, 117))	('glutamine', 'Chemical', 'MESH:C578860', (65, 74))	('SW872', 'CellLine', 'CVCL:1730', (111, 116))	('LPS246s', 'Var', (99, 106))
21550	31980651	Consistent with glutamine deficiency, KP-6634s, KPH2-7215s, HT1080s, SK-LMS-1s, SK-UT-1Bs, CCL-136s, and T778s were highly responsive to CB-839 treatment, i.e.	('glutamine deficiency', 'Disease', (16, 36))	('KP-6634s, KPH2-7215s', 'Chemical', 'MESH:C067980', (38, 58))	('KPH2-7215s', 'Var', (48, 58))	('HT1080', 'Gene', (60, 66))	('HT1080', 'Gene', '8872', (60, 66))	('glutamine deficiency', 'Phenotype', 'HP:0500147', (16, 36))	('T778s', 'Var', (105, 110))	('KP-6634s', 'Var', (38, 46))	('glutamine deficiency', 'Disease', 'MESH:C536832', (16, 36))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (69, 77))
21555	31980651	5b) and human LPS246s and SW872s (Supplementary Fig.	('SW872s', 'Var', (26, 32))	('human', 'Species', '9606', (8, 13))	('SW872', 'CellLine', 'CVCL:1730', (26, 31))	('LPS246s', 'Var', (14, 21))
21563	31980651	Importantly, glutamate or DKG addition rescued cell proliferation and viability upon GLS inhibition in KP-6634s, KPH2-7215s, HT1080s, and SK-LMS-1s (Fig.	('KPH2-7215s', 'Var', (113, 123))	('KP-6634s', 'Var', (103, 111))	('rescued', 'PosReg', (39, 46))	('HT1080', 'Gene', '8872', (125, 131))	('glutamate', 'Chemical', 'None', (13, 22))	('KP-6634s, KPH2-7215s', 'Chemical', 'MESH:C067980', (103, 123))	('viability', 'CPA', (70, 79))	('inhibition', 'NegReg', (89, 99))	('GLS', 'Protein', (85, 88))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (138, 146))	('HT1080', 'Gene', (125, 131))	('cell proliferation', 'CPA', (47, 65))
21567	31980651	Our findings suggest that GLS inhibition suppresses proliferation and viability of tumour-derived UPS, HT1080, and SK-LMS-1 cells in vitro.	('tumour', 'Disease', (83, 89))	('proliferation', 'CPA', (52, 65))	('HT1080', 'Gene', '8872', (103, 109))	('inhibition', 'Var', (30, 40))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (115, 123))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('viability', 'CPA', (70, 79))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('suppresses', 'NegReg', (41, 51))	('GLS', 'Protein', (26, 29))	('HT1080', 'Gene', (103, 109))
21572	31980651	6a) and final tumour mass in both KP-6634 and KPH2-7215 allografts (Fig.	('tumour mass', 'Disease', 'MESH:C536030', (14, 25))	('KP-6634', 'Chemical', 'MESH:C067980', (34, 41))	('tumour mass', 'Disease', (14, 25))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('final tumour', 'Disease', 'MESH:D009369', (8, 20))	('KP-6634', 'Var', (34, 41))	('final tumour', 'Disease', (8, 20))	('KPH2-7215', 'Var', (46, 55))
21583	31980651	CT-quantified tumour size strongly correlated with tumour mass, and CB-839 treatment significantly reduced final tumour weight in KP and KPH2 animals compared to vehicle-treated mice (Fig.	('KPH2', 'Var', (137, 141))	('tumour', 'Disease', (14, 20))	('tumour mass', 'Disease', 'MESH:C536030', (51, 62))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('mice', 'Species', '10090', (178, 182))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour mass', 'Disease', (51, 62))	('tumour', 'Disease', (113, 119))	('final tumour weight', 'Disease', 'MESH:D015431', (107, 126))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('final tumour weight', 'Disease', (107, 126))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('CB-839', 'Gene', (68, 74))	('reduced', 'NegReg', (99, 106))	('tumour', 'Disease', (51, 57))
21599	31980651	Sequencing UPS patient samples identified mutated genes correlated with cell cycle, PI3K/mTOR, and RAS/MAPK signalling pathways, suggesting that GLS may be mTORC1/Myc-driven in UPS.	('mTOR', 'Gene', '2475', (89, 93))	('patient', 'Species', '9606', (15, 22))	('mutated', 'Var', (42, 49))	('mTORC1', 'Gene', (156, 162))	('correlated', 'Reg', (56, 66))	('mTOR', 'Gene', (156, 160))	('mTOR', 'Gene', '2475', (156, 160))	('Myc', 'Gene', '4609', (163, 166))	('Myc', 'Gene', (163, 166))	('mTORC1', 'Gene', '382056', (156, 162))	('cell', 'CPA', (72, 76))	('RAS/MAPK signalling pathways', 'Pathway', (99, 127))	('mTOR', 'Gene', (89, 93))
21611	31980651	UPS and leiomyosarcoma) reliant on exogenous sources, sensitizing them to CB-839, in contrast to lung and PDAC, or STS subtypes that do not express GLS, such as liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (8, 22))	('liposarcoma', 'Disease', 'MESH:D008080', (161, 172))	('liposarcoma', 'Disease', (161, 172))	('sensitizing', 'Reg', (54, 65))	('PD', 'Disease', 'MESH:D010300', (106, 108))	('PDAC', 'Phenotype', 'HP:0006725', (106, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('UPS and leiomyosarcoma', 'Disease', 'MESH:D017118', (0, 22))	('liposarcoma', 'Phenotype', 'HP:0012034', (161, 172))	('CB-839', 'Var', (74, 80))
21614	31980651	For leiomyosarcomas, deletions or mutations of TP53, RB1, and PTEN were found.	('PTEN', 'Gene', (62, 66))	('RB1', 'Gene', '19645', (53, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('PTEN', 'Gene', '19211', (62, 66))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (4, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('deletions', 'Var', (21, 30))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (4, 19))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (4, 19))	('RB1', 'Gene', (53, 56))	('TP53', 'Gene', '22059', (47, 51))	('mutations', 'Var', (34, 43))	('leiomyosarcomas', 'Disease', (4, 19))	('TP53', 'Gene', (47, 51))
21616	31980651	While the majority of glutamine-dependent and CB-839-sensitive cell lines express GLS, LPS246s are resistant to glutamine starvation and CB-839 treatment despite having comparable GLS levels (unlike SW872s; Supplementary Fig.	('LPS246s', 'Var', (87, 94))	('glutamine', 'Chemical', 'MESH:C578860', (112, 121))	('glutamine', 'Chemical', 'MESH:C578860', (22, 31))	('GLS', 'Protein', (82, 85))	('GLS', 'MPA', (180, 183))	('SW872', 'CellLine', 'CVCL:1730', (199, 204))
21620	31980651	For example, GLS inhibition increases radiotherapy response in lung tumour xenografts and synergy with poly(ADP-ribose) polymerase (PARP) inhibition was investigated in renal carcinoma cells, where GLS inhibitors led to nucleoside depletion and DNA replication stress.	('increases', 'PosReg', (28, 37))	('radiotherapy response', 'CPA', (38, 59))	('PARP', 'Gene', (132, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('DNA replication stress', 'MPA', (245, 267))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('renal carcinoma', 'Disease', 'MESH:D002292', (169, 184))	('nucleoside depletion', 'MPA', (220, 240))	('inhibition', 'Var', (17, 27))	('GLS', 'Gene', (13, 16))	('renal carcinoma', 'Disease', (169, 184))	('renal carcinoma', 'Phenotype', 'HP:0005584', (169, 184))	('lung tumour', 'Disease', (63, 74))	('lung tumour', 'Disease', 'MESH:D008175', (63, 74))	('poly(ADP-ribose) polymerase', 'Gene', (103, 130))	('poly(ADP-ribose) polymerase', 'Gene', '11545', (103, 130))	('lung tumour', 'Phenotype', 'HP:0100526', (63, 74))	('nucleoside', 'Chemical', 'MESH:D009705', (220, 230))	('inhibitors', 'Var', (202, 212))	('PARP', 'Gene', '11545', (132, 136))
21645	31980651	HT1080, SK-LMS-1, SK-UT-1B, CCL-136, SW872, 94T778 (T778), and C2C12 cells were purchased from ATCC and authenticated by the manufacturer by short tandem repeat.	('SK-LMS-1', 'CellLine', 'CVCL:0628', (8, 16))	('SW872', 'Var', (37, 42))	('SW872', 'CellLine', 'CVCL:1730', (37, 42))	('HT1080', 'Gene', (0, 6))	('HT1080', 'Gene', '8872', (0, 6))
21647	31980651	KP-6634s and KPH2-7215s were derived from UPS mouse tumours.	('KPH2-7215s', 'Var', (13, 23))	('KP-6634s and KPH2-7215s', 'Chemical', 'MESH:C067980', (0, 23))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('KP-6634s', 'Var', (0, 8))	('UPS mouse tumours', 'Disease', 'MESH:D017118', (42, 59))	('UPS mouse tumours', 'Disease', (42, 59))
21663	31980651	Taqman primers were obtained from Life Technologies: Gls (Mm01257297_m1), Gls2 (Mm01164862_m1), GLS (Hs00248163_m1), and GLS2 (Hs00998733_m1).	('Gls', 'Gene', (53, 56))	('Mm01257297_m1', 'Var', (58, 71))	('Gls', 'Gene', (74, 77))	('Gls2', 'Gene', (74, 78))	('Hs00998733_m1', 'Var', (127, 140))	('GLS2', 'Gene', '216456', (121, 125))	('Gls', 'Gene', '216456', (74, 77))	('Gls', 'Gene', '216456', (53, 56))	('Hs00248163_m1', 'Var', (101, 114))	('Gls2', 'Gene', '216456', (74, 78))	('Mm01164862_m1', 'Var', (80, 93))	('GLS2', 'Gene', (121, 125))
21671	31980651	For labelling studies, C2C12s, KP-6634s, and KPH2-7215s were plated in 10 cm dishes and allowed to adhere overnight.	('KPH2-7215s', 'Var', (45, 55))	('KP-6634s', 'Chemical', 'MESH:C067980', (31, 39))	('KP-6634s', 'Var', (31, 39))	('KPH2-7215s', 'Chemical', 'MESH:C021591', (45, 55))	('C2C12s', 'Var', (23, 29))
21678	31980651	In studies with 13C-labelled glutamine, isotopic enrichment in 13C-glutamate isotopomers was monitored using ions at m/z 432, 433, 434, 435, 436, and 437 for M0, M1, M2, M3, M4, and M5 (containing one to five 13C atoms above M0, the natural abundance), respectively.	('13C-glutamate', 'Chemical', 'None', (63, 76))	('13C', 'Chemical', 'MESH:C513342', (63, 66))	('435', 'Var', (136, 139))	('433', 'Var', (126, 129))	('glutamine', 'Chemical', 'MESH:C578860', (29, 38))	('m/z', 'Var', (117, 120))	('437', 'Var', (150, 153))	('13C', 'Chemical', 'MESH:C513342', (16, 19))	('13C', 'Chemical', 'MESH:C513342', (209, 212))	('434', 'Var', (131, 134))	('436', 'Var', (141, 144))
21680	31980651	Isotopic enrichment in 13C malate isotopomers was evaluated using ions at m/z 419, 420, 421, 422, and 423 for M0, M1, M2, M3, and M4 (containing one to four 13C atoms above natural abundance), respectively.	('malate', 'Chemical', 'MESH:D008293', (27, 33))	('421', 'Var', (88, 91))	('13C', 'Chemical', 'MESH:C513342', (23, 26))	('m/z 419', 'Var', (74, 81))	('13C', 'Chemical', 'MESH:C513342', (157, 160))
21681	31980651	Isotopic enrichment in 13C fumarate isotopomers was monitored using ions at m/z 287, 288, 289, 290, and 291 for M0, M1, M2, M3, and M4 (containing one to four 13C atoms above natural abundance), respectively.	('13C', 'Chemical', 'MESH:C513342', (159, 162))	('fumarate', 'Chemical', 'MESH:D005650', (27, 35))	('13C', 'Chemical', 'MESH:C513342', (23, 26))	('291', 'Var', (104, 107))	('289', 'Var', (90, 93))
21684	31980651	In glutamate, m/z 432 and 433 for M0 and M1, respectively, and aspartate, m/z 418 and 419 for M0 and M1, respectively.	('aspartate', 'MPA', (63, 72))	('m/z 418', 'Var', (74, 81))	('aspartate', 'Chemical', 'None', (63, 72))	('glutamate', 'Chemical', 'None', (3, 12))	('m/z 432', 'Var', (14, 21))	('glutamate', 'MPA', (3, 12))
21688	31980651	Measurements were performed with LC-MS/MS, using MRM ions-pairing 136-119 for adenine and 132-114 for IS.	('132-114', 'Var', (90, 97))	('adenine', 'Chemical', 'MESH:D000225', (78, 85))	('adenine', 'MPA', (78, 85))
21770	28667207	Another secondary outcome includes the proportion of patients classified as 'cases' by a cut-off equalling or exceeding the threshold of 5 on the depression subscale, the threshold of 7 on the anxiety scale and the threshold of 13 on total score.	('anxiety', 'Disease', 'MESH:D001008', (193, 200))	('patients', 'Species', '9606', (53, 61))	('depression', 'Disease', 'MESH:D000275', (146, 156))	('depression', 'Phenotype', 'HP:0000716', (146, 156))	('anxiety', 'Disease', (193, 200))	('anxiety', 'Phenotype', 'HP:0000739', (193, 200))	('cut-off', 'Var', (89, 96))	('depression', 'Disease', (146, 156))
21841	26712767	Inhibition of Myb is therefore emerging as a potential therapeutic strategy for these diseases.	('c', 'Gene', '1051', (65, 66))	('Myb', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('Myb', 'Gene', '4602', (14, 17))
21894	26712767	Crucially, JS6 effectively suppressed metastatic progression in in vivo models bearing human metastatic MDA-MB-231 cells.	('c', 'Gene', '1051', (47, 48))	('C', 'Gene', '1051', (0, 1))	('JS6', 'Var', (11, 14))	('human', 'Species', '9606', (87, 92))	('c', 'Gene', '1051', (3, 4))	('suppressed', 'NegReg', (27, 37))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (104, 114))	('S', 'Chemical', 'MESH:D013455', (12, 13))	('c', 'Gene', '1051', (115, 116))	('c', 'Gene', '1051', (19, 20))	('c', 'Gene', '1051', (102, 103))
21986	26712767	A dysregulation of the cellular acetylation level has been associated with human diseases e.g., cancer, neurodegerenative and metabolic diseases which makes a modulation of sirtuin activity a promising strategy for pharmaceutical intervention (Hoffmann, G., et al.	('c', 'Gene', '1051', (63, 64))	('c', 'Gene', '1051', (96, 97))	('c', 'Gene', '1051', (221, 222))	('cancer', 'Disease', (96, 102))	('c', 'Gene', '1051', (23, 24))	('c', 'Gene', '1051', (134, 135))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('c', 'Gene', '1051', (182, 183))	('metabolic diseases', 'Disease', 'MESH:D008659', (126, 144))	('c', 'Gene', '1051', (226, 227))	('dysregulation', 'Var', (2, 15))	('modulation', 'Var', (159, 169))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('c', 'Gene', '1051', (33, 34))	('c', 'Gene', '1051', (148, 149))	('metabolic diseases', 'Disease', (126, 144))	('c', 'Gene', '1051', (99, 100))	('neurodegerenative', 'Disease', (104, 121))	('human', 'Species', '9606', (75, 80))
22017	26712767	These hot spot predictions were used to design peptides that were supposed to inhibit Hsp90 dimerization.	('Hsp90', 'Gene', (86, 91))	('c', 'Gene', '1051', (20, 21))	('peptides', 'Var', (47, 55))	('Hsp90', 'Gene', '3320', (86, 91))	('inhibit', 'NegReg', (78, 85))	('dimerization', 'MPA', (92, 104))
22077	26712767	Development of ABCG2 inhibitors can be used in combination with anticancer drugs to block the drug secretion from cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('c', 'Gene', '1051', (47, 48))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('c', 'Gene', '1051', (68, 69))	('ABCG2', 'Gene', (15, 20))	('c', 'Gene', '1051', (117, 118))	('c', 'Gene', '1051', (71, 72))	('inhibitors', 'Var', (21, 31))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('c', 'Gene', '1051', (87, 88))	('c', 'Gene', '1051', (121, 122))	('c', 'Gene', '1051', (114, 115))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (68, 74))	('c', 'Gene', '1051', (101, 102))	('ABCG2', 'Gene', '9429', (15, 20))	('c', 'Gene', '1051', (32, 33))	('cancer', 'Disease', (114, 120))
22079	26712767	2012, 20, 2282-2289) and be converted into ABCG2 inhibitors with an IC50 in the submicromolar range upon specific substitutions on the C- and/or D-ring(s) (Gozzi, G.J., et al.	('c', 'Gene', '1051', (112, 113))	('c', 'Gene', '1051', (85, 86))	('substitutions', 'Var', (114, 127))	('C', 'Gene', '1051', (69, 70))	('c', 'Gene', '1051', (28, 29))	('C', 'Gene', '1051', (45, 46))	('c', 'Gene', '1051', (108, 109))	('ABCG2', 'Gene', (43, 48))	('C', 'Gene', '1051', (135, 136))	('ABCG2', 'Gene', '9429', (43, 48))
22121	26712767	Altered activity of protein kinases is associated with numerous disease states, including cancer.	('numerous disease', 'Disease', 'MESH:D004194', (55, 71))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('numerous disease', 'Disease', (55, 71))	('Altered', 'Var', (0, 7))	('c', 'Gene', '1051', (90, 91))	('c', 'Gene', '1051', (93, 94))	('protein kinases', 'Enzyme', (20, 35))	('c', 'Gene', '1051', (9, 10))	('c', 'Gene', '1051', (82, 83))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('c', 'Gene', '1051', (43, 44))
22150	26712767	Thus, inhibitors of this enzyme may represent novel anti-cancer agents.	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('inhibitors', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
22157	26712767	Furthermore, anandamide was found to possess anti-tumorigenic properties and apart from its anti-proliferative and pro-apoptotic action, it may affect tumor cell angiogenesis and metastasization (Ravi, J., et al.	('anandamide', 'Var', (13, 23))	('anandamide', 'Chemical', 'MESH:C078814', (13, 23))	('c', 'Gene', '1051', (157, 158))	('c', 'Gene', '1051', (60, 61))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('c', 'Gene', '1051', (127, 128))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('metastasization', 'CPA', (179, 194))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('c', 'Gene', '1051', (148, 149))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('c', 'Gene', '1051', (130, 131))
22160	26712767	Inhibitors of FAAH may provide novel options for the treatment of pain, inflammation and cancer, since inhibition of FAAH prolongs and enhances the action of anandamide.	('inflammation', 'Disease', (72, 84))	('c', 'Gene', '1051', (89, 90))	('pain', 'Disease', (66, 70))	('cancer', 'Disease', (89, 95))	('prolongs', 'PosReg', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('FAAH', 'Gene', (14, 18))	('pain', 'Phenotype', 'HP:0012531', (66, 70))	('FAAH', 'Gene', (117, 121))	('inhibition', 'Var', (103, 113))	('c', 'Gene', '1051', (149, 150))	('FAAH', 'Gene', '2166', (14, 18))	('c', 'Gene', '1051', (92, 93))	('c', 'Gene', '1051', (140, 141))	('FAAH', 'Gene', '2166', (117, 121))	('pain', 'Disease', 'MESH:D010146', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('c', 'Gene', '1051', (100, 101))	('inflammation', 'Disease', 'MESH:D007249', (72, 84))	('anandamide', 'Chemical', 'MESH:C078814', (158, 168))
22164	26712767	The results of these structural variations are presented together with computational docking studies, describing the interactions between these inhibitors and the active site of FAAH.	('FAAH', 'Gene', (178, 182))	('c', 'Gene', '1051', (123, 124))	('c', 'Gene', '1051', (164, 165))	('c', 'Gene', '1051', (25, 26))	('c', 'Gene', '1051', (87, 88))	('variations', 'Var', (32, 42))	('FAAH', 'Gene', '2166', (178, 182))	('c', 'Gene', '1051', (71, 72))	('c', 'Gene', '1051', (105, 106))
22168	26712767	Inhibitors of this enzyme are at current in clinical trials indicating its druggability (Trembley, J.H., et al.	('c', 'Gene', '1051', (44, 45))	('druggability', 'MPA', (75, 87))	('c', 'Gene', '1051', (64, 65))	('Inhibitors', 'Var', (0, 10))	('c', 'Gene', '1051', (49, 50))	('c', 'Gene', '1051', (33, 34))
22255	26712767	For this purpose P-gp overexpressing A2780adr and MRP1 overexpressing H69 AR cell lines were used.	('H69', 'CellLine', 'CVCL:8121', (70, 73))	('MRP1', 'Gene', '4363', (50, 54))	('P-gp', 'Gene', (17, 21))	('A2780adr', 'Var', (37, 45))	('MRP1', 'Gene', (50, 54))	('P-gp', 'Gene', '5243', (17, 21))	('c', 'Gene', '1051', (77, 78))
22296	26712767	Of a diverse range of heterocyclic derivatives, 3-vinyl and 3-hydroxy analogues displayed the highest potency in human MCF-7 breast cancer cells with IC50 values of 9-20 nM, comparable to combretastatin A-4.	('3-vinyl', 'Var', (48, 55))	('C', 'Gene', '1051', (120, 121))	('A-4', 'Gene', '50617', (203, 206))	('c', 'Gene', '1051', (135, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('human', 'Species', '9606', (113, 118))	('MCF-7', 'CellLine', 'CVCL:0031', (119, 124))	('c', 'Gene', '1051', (174, 175))	('C', 'Gene', '1051', (151, 152))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('A-4', 'Gene', (203, 206))	('c', 'Gene', '1051', (30, 31))	('c', 'Gene', '1051', (188, 189))	('c', 'Gene', '1051', (28, 29))	('c', 'Gene', '1051', (107, 108))	('c', 'Gene', '1051', (139, 140))	('c', 'Gene', '1051', (132, 133))	('combretastatin', 'Chemical', 'MESH:C040105', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('c', 'Gene', '1051', (33, 34))
22347	26712767	Since CK2 is essential for cell survival, inhibition of CK2 results in apoptosis (Litchfield, D.W. Biochem.	('C', 'Gene', '1051', (6, 7))	('c', 'Gene', '1051', (85, 86))	('apoptosis', 'CPA', (71, 80))	('c', 'Gene', '1051', (3, 4))	('c', 'Gene', '1051', (27, 28))	('results in', 'Reg', (60, 70))	('inhibition', 'Var', (42, 52))	('C', 'Gene', '1051', (56, 57))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('c', 'Gene', '1051', (102, 103))
22389	26712767	44077 Nantes-Cedex, France 5 Institut de Cancerologie de l'Ouest, Comprehensive Cancer Center R. Gauducheau, 44805 Nantes, France.	('c', 'Gene', '1051', (44, 45))	('44077', 'Var', (0, 5))	('c', 'Gene', '1051', (24, 25))	('C', 'Gene', '1051', (13, 14))	('C', 'Gene', '1051', (41, 42))	('c', 'Gene', '1051', (127, 128))	('C', 'Gene', '1051', (87, 88))	('c', 'Gene', '1051', (83, 84))	('C', 'Gene', '1051', (66, 67))	('44805', 'Var', (109, 114))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('C', 'Gene', '1051', (80, 81))	('Cedex', 'Chemical', 'MESH:D000077722', (13, 18))	('c', 'Gene', '1051', (102, 103))
22391	26712767	Apoptosis control defect such as the deregulation of Bcl-2 family members expression is frequently involved in chemoresistance.	('expression', 'MPA', (74, 84))	('c', 'Gene', '1051', (22, 23))	('c', 'Gene', '1051', (54, 55))	('involved', 'Reg', (99, 107))	('Bcl-2', 'Gene', (53, 58))	('c', 'Gene', '1051', (27, 28))	('c', 'Gene', '1051', (10, 11))	('Bcl-2', 'Gene', '596', (53, 58))	('c', 'Gene', '1051', (111, 112))	('Apoptosis', 'CPA', (0, 9))	('c', 'Gene', '1051', (124, 125))	('deregulation', 'Var', (37, 49))
22474	26712767	Therefore, inhibitors of these enzymes may represent new drug candidates for the treatment of inflammation.	('c', 'Gene', '1051', (62, 63))	('inflammation', 'Disease', 'MESH:D007249', (94, 106))	('inhibitors', 'Var', (11, 21))	('inflammation', 'Disease', (94, 106))
22722	23036164	NF1 results from an autosomal dominant process that leads to improper function of the NF1 gene, which is responsible for producing Neurofibromin.	('Neurofibromin', 'Gene', (131, 144))	('results from', 'Reg', (4, 16))	('NF1', 'Gene', (86, 89))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (86, 89))	('NF1', 'Gene', '4763', (0, 3))	('improper', 'Var', (61, 69))	('Neurofibromin', 'Gene', '4763', (131, 144))
22730	23036164	Thus, mutations in TP53 can lead to the early development of sarcomas and other tumors through the acquisition of genomic instability.	('sarcomas', 'Disease', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('genomic', 'MPA', (114, 121))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('TP53', 'Gene', (19, 23))	('lead to', 'Reg', (28, 35))	('men', 'Species', '9606', (53, 56))	('sarcomas', 'Disease', 'MESH:D012509', (61, 69))	('TP53', 'Gene', '7157', (19, 23))	('mutations', 'Var', (6, 15))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
22731	23036164	In fact, children with the soft tissue sarcoma rhabdomyosarcoma presenting at less than 3 years of age appear to have an increased likelihood of harboring TP53 germline mutations.	('soft tissue sarcoma', 'Disease', (27, 46))	('TP53', 'Gene', '7157', (155, 159))	('germline mutations', 'Var', (160, 178))	('sarcoma rhabdomyosarcoma', 'Disease', (39, 63))	('children', 'Species', '9606', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('TP53', 'Gene', (155, 159))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (27, 46))	('sarcoma rhabdomyosarcoma', 'Disease', 'MESH:D012208', (39, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (27, 46))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (47, 63))
22732	23036164	It is also important to note that roughly 30-60% of non-LFS soft tissue sarcomas will have somatic mutations of the TP53 gene.	('TP53', 'Gene', (116, 120))	('LFS', 'Disease', 'MESH:D016864', (56, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (60, 80))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (60, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (60, 80))	('mutations', 'Var', (99, 108))	('LFS', 'Disease', (56, 59))	('TP53', 'Gene', '7157', (116, 120))	('soft tissue sarcomas', 'Disease', (60, 80))
22738	23036164	Rb develops by means of germline mutations that lead to inactivation of an allele in the tumor suppressor gene, RB1.	('RB1', 'Gene', '5925', (112, 115))	('inactivation', 'MPA', (56, 68))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Rb', 'Phenotype', 'HP:0009919', (0, 2))	('Rb', 'Gene', '5925', (0, 2))	('RB1', 'Gene', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
22741	23036164	Other familial predisposition syndromes associated with osteosarcoma risk include the very rare, autosomal recessive DNA helicase syndromes including: Rothmund Thomson II (REQ4 mutations), RAPADILINO Syndrome (RA: RAdial aplasia or hypoplasia, PA: PAtellae aplasia or hypoplasia and cleft or high arched PAlate, DI: DIarrhea and DIslocated joints, LI: LIttle size and LImb malformations, NO: long, slender NOse and NOrmal intelligence, REQ4 mutations), Werner (WRN mutations), and Bloom Syndrome (BLM mutations).	('RA', 'Disease', 'MESH:D001172', (210, 212))	('high arched PAlate', 'Phenotype', 'HP:0002705', (292, 310))	('WRN', 'Gene', (461, 464))	('WRN', 'Gene', '7486', (461, 464))	('Bloom Syndrome', 'Disease', (481, 495))	('PAtellae aplasia or hypoplasia', 'Disease', 'MESH:C535568', (248, 278))	('PAtellae aplasia', 'Phenotype', 'HP:0006443', (248, 264))	('REQ4', 'Gene', (436, 440))	('PAtellae aplasia or hypoplasia', 'Disease', (248, 278))	('PAtellae aplasia or hypoplasia', 'Phenotype', 'HP:0006498', (248, 278))	('BLM', 'Disease', 'MESH:D001816', (497, 500))	('DIslocated joints', 'Phenotype', 'HP:0001373', (329, 346))	('RA', 'Disease', 'MESH:D001172', (214, 216))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('RAdial aplasia or hypoplasia', 'Disease', (214, 242))	('slender NOse', 'Phenotype', 'HP:0000417', (398, 410))	('LImb malformations', 'Disease', 'MESH:D000014', (368, 386))	('RAdial aplasia or hypoplasia', 'Phenotype', 'HP:0006501', (214, 242))	('RAdial aplasia', 'Phenotype', 'HP:0003974', (214, 228))	('cleft', 'Disease', 'MESH:D002972', (283, 288))	('RAdial aplasia or hypoplasia', 'Disease', 'MESH:C535281', (214, 242))	('LImb malformations', 'Disease', (368, 386))	('DIarrhea', 'Disease', 'MESH:D003967', (316, 324))	('BLM', 'Disease', (497, 500))	('Rothmund Thomson II', 'Disease', (151, 170))	('LImb malformations', 'Phenotype', 'HP:0002813', (368, 386))	('RA', 'Disease', 'MESH:D001172', (189, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('cleft', 'Disease', (283, 288))	('DIarrhea', 'Disease', (316, 324))	('osteosarcoma', 'Disease', (56, 68))	('DIarrhea', 'Phenotype', 'HP:0002014', (316, 324))	('mutations', 'Var', (441, 450))	('osteosarcoma', 'Disease', 'MESH:D012516', (56, 68))
22745	23036164	A recent publication has reported that common variants near TARDBP and EGR2 are associated with susceptibility to Ewing's sarcoma.	('EGR2', 'Gene', (71, 75))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (114, 129))	("Ewing's sarcoma", 'Disease', (114, 129))	('susceptibility', 'Reg', (96, 110))	('TARDBP', 'Gene', '23435', (60, 66))	('variants', 'Var', (46, 54))	('associated', 'Reg', (80, 90))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (114, 129))	('TARDBP', 'Gene', (60, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('EGR2', 'Gene', '1959', (71, 75))
22766	23036164	A pooled analysis included 434 osteosarcoma cases and 1,000 controls studies, reported a significant association between osteosarcoma risk and high birth weight (> = 4,046 g), compared to an average birth weight (2,665-4,045 g) (adjusted OR = 1.35, 95% CI 1.01, 1.79).	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('high birth weight (> = 4,046 g', 'Var', (143, 173))	('osteosarcoma', 'Phenotype', 'HP:0002669', (31, 43))	('osteosarcoma', 'Disease', (31, 43))	('osteosarcoma', 'Disease', 'MESH:D012516', (31, 43))	('osteosarcoma', 'Phenotype', 'HP:0002669', (121, 133))	('osteosarcoma', 'Disease', (121, 133))	('high birth weight', 'Phenotype', 'HP:0001520', (143, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('osteosarcoma', 'Disease', 'MESH:D012516', (121, 133))
22773	23036164	Furthermore, a recent case-control study in Germany with 97 malignant bone cases and 137 soft tissue sarcoma cases found no significant increase in sarcoma risk among those classified as small-for-gestational age, nor those classified as being large-for-gestational age.	('small-for-gestational', 'Var', (187, 208))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('sarcoma', 'Disease', (148, 155))	('sarcoma', 'Disease', (101, 108))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (89, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (89, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('soft tissue sarcoma', 'Disease', (89, 108))
22851	23036164	(2006) reported that radiotherapy appears to be associated with an increased risk of developing sarcomas, especially among younger patients under the age of 55 (SIR =4.2, 95% CI 2.9, 5.8).	('patients', 'Species', '9606', (131, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('sarcomas', 'Disease', (96, 104))	('radiotherapy', 'Var', (21, 33))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))
23325	32694968	After the Institutional Research Board approval, immunohistochemical experiments on tissue microarray slides containing 32 archived Ewing's sarcoma tumor samples were performed with antibodies against IGF1Rb and p-S6K.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('IGF1R', 'Gene', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('p-S6K', 'Var', (212, 217))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (132, 147))	('IGF1R', 'Gene', '3480', (201, 206))	('p-S6K', 'Mutation', 'p.S6K', (212, 217))	("Ewing's sarcoma tumor", 'Disease', (132, 153))	("Ewing's sarcoma tumor", 'Disease', 'MESH:C563168', (132, 153))
23328	32694968	High expression of IGF1Rb and p-S6K, defined as staining stronger than positive control, was identified in 25% and 68.75% of cases, respectively.	('IGF1R', 'Gene', (19, 24))	('p-S6K', 'Var', (30, 35))	('IGF1R', 'Gene', '3480', (19, 24))	('p-S6K', 'Mutation', 'p.S6K', (30, 35))	('High expression of IGF1Rb', 'Phenotype', 'HP:0030269', (0, 25))
23329	32694968	Statistical analysis revealed that IGF1Rb high expression had a significant association with adverse outcome, shorter OS (P < 0.05), and near significant association with advanced stage tumors (P = 0.0534).	('shorter OS', 'CPA', (110, 120))	('IGF1R', 'Gene', '3480', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('high expression', 'Var', (42, 57))	('adverse', 'Disease', (93, 100))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('IGF1R', 'Gene', (35, 40))
23350	32694968	Sections for IHC were stained with antibodies for the signaling proteins, IGF1Rb (Leica Biosystems, Buffalo Grove, IL) and p-S6K (Cell Signaling, Danvers, MA) according to the manufacturer's specifications.	('IGF1R', 'Gene', '3480', (74, 79))	('IGF1R', 'Gene', (74, 79))	('p-S6K', 'Mutation', 'p.S6K', (123, 128))	('p-S6K', 'Var', (123, 128))
23375	32694968	In many clinical trials, EST treatment with various IGF1R inhibitors has resulted in resistance with less satisfactory results.	('inhibitors', 'Var', (58, 68))	('IGF1R', 'Gene', (52, 57))	('resistance', 'MPA', (85, 95))	('IGF1R', 'Gene', '3480', (52, 57))
23376	32694968	Although more than 1 mechanism can explain this resistance as outlined earlier, cross-signaling and cross-talk with other signaling molecules may result in the activation of other downstream pathways, bypassing IGF1R inhibition and leading to the maintenance of tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('IGF1R', 'Gene', (211, 216))	('leading to', 'Reg', (232, 242))	('activation', 'PosReg', (160, 170))	('tumor', 'Disease', (262, 267))	('bypassing', 'NegReg', (201, 210))	('IGF1R', 'Gene', '3480', (211, 216))	('cross-talk', 'Interaction', (100, 110))	('cross-signaling', 'Var', (80, 95))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
23377	32694968	In this regard, we examined the expression of p-S6K in EST and highlighted a trend association with worse survival indicating a potential marker of poor prognosis in EST.	('p-S6K', 'Mutation', 'p.S6K', (46, 51))	('worse survival', 'MPA', (100, 114))	('p-S6K', 'Var', (46, 51))
23379	32694968	A previous study has revealed that S6K phosphorylation is linked to AKT apoptosis pathway and is decreased significantly with silencing or inhibition of the AKT substrate, PRAS40, which is another target of insulin action.	('AKT', 'Gene', (157, 160))	('insulin', 'Gene', (207, 214))	('phosphorylation', 'MPA', (39, 54))	('linked', 'Reg', (58, 64))	('inhibition', 'NegReg', (139, 149))	('insulin', 'Gene', '3630', (207, 214))	('S6K', 'Gene', (35, 38))	('PRAS40', 'Gene', '84335', (172, 178))	('S6K', 'Gene', '6198', (35, 38))	('AKT', 'Gene', '207', (157, 160))	('AKT', 'Gene', '207', (68, 71))	('decreased', 'NegReg', (97, 106))	('PRAS40', 'Gene', (172, 178))	('silencing', 'Var', (126, 135))	('AKT', 'Gene', (68, 71))
23382	32694968	On the other hand, inhibition of S6K increases the sensitivity of colon carcinoma cells to IGF1R inhibitor.	('S6K', 'Gene', '6198', (33, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('inhibition', 'Var', (19, 29))	('IGF1R', 'Gene', (91, 96))	('colon carcinoma', 'Disease', (66, 81))	('sensitivity', 'MPA', (51, 62))	('IGF1R', 'Gene', '3480', (91, 96))	('increases', 'PosReg', (37, 46))	('S6K', 'Gene', (33, 36))	('colon carcinoma', 'Disease', 'MESH:D003110', (66, 81))
23402	31293656	Overall survival was significantly higher for CREB3L1 high-expression patients than for CREB3L1 low-expression patients, especially for those also treated with the MAID (AI) regimen.	('patients', 'Species', '9606', (70, 78))	('high-expression', 'Var', (54, 69))	('CREB3L1', 'Gene', '90993', (46, 53))	('CREB3L1', 'Gene', (88, 95))	('CREB3L1', 'Gene', (46, 53))	('CREB3L1', 'Gene', '90993', (88, 95))	('Overall survival', 'MPA', (0, 16))	('higher', 'PosReg', (35, 41))	('patients', 'Species', '9606', (111, 119))
23422	31293656	These findings led us to hypothesize that the presence of CREB3L1 may predict clinical responses to doxorubicin-based chemotherapy in advanced soft-tissue sarcomas.	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (143, 163))	('predict', 'Reg', (70, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('presence', 'Var', (46, 54))	('soft-tissue sarcomas', 'Disease', (143, 163))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (143, 163))	('doxorubicin', 'Chemical', 'MESH:D004317', (100, 111))	('CREB3L1', 'Gene', (58, 65))	('clinical', 'Species', '191496', (78, 86))	('CREB3L1', 'Gene', '90993', (58, 65))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (143, 162))
23475	31293656	The relative mRNA levels of CREB3L1 were significantly higher in specimens with high CREB3L1 protein expression (mRNA 4.87 +- 0.05; Figure 2).	('CREB3L1', 'Gene', '90993', (28, 35))	('protein', 'Protein', (93, 100))	('CREB3L1', 'Gene', (85, 92))	('CREB3L1', 'Gene', '90993', (85, 92))	('higher', 'PosReg', (55, 61))	('high', 'Var', (80, 84))	('CREB3L1', 'Gene', (28, 35))
23480	31293656	Thirty of forty-seven (63.8 %) patients with high CREB3L1 expression and forty-four of one hundred and five (41.9 %) patients with low CREB3L1 expression exhibited an overall response (P = 0.012; Table 2).	('CREB3L1', 'Gene', (50, 57))	('CREB3L1', 'Gene', '90993', (135, 142))	('CREB3L1', 'Gene', (135, 142))	('CREB3L1', 'Gene', '90993', (50, 57))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (117, 125))
23481	31293656	For the MAID (AI) regimen, the response rate of patients with high CREB3L1 expression (57.7 %; 15 of 26) was greater than that for low CREB3L1 expression (25.0 %; 14 of 56) (Table 7; P = 0.004).	('CREB3L1', 'Gene', '90993', (67, 74))	('CREB3L1', 'Gene', (67, 74))	('CREB3L1', 'Gene', '90993', (135, 142))	('CREB3L1', 'Gene', (135, 142))	('response', 'MPA', (31, 39))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('greater', 'PosReg', (109, 116))
23482	31293656	For the CAV/IE alternating regimen, although there was no significant association observed between the CREB3L1 expression and response rate (P = 0.414), 15 of 21 (71.4 %) CREB3L1 high-expression patients exhibited overall responses compared with 30 of 49 (61.2 %) CREB3L1 low-expression patients.	('CAV', 'Gene', (8, 11))	('CREB3L1', 'Gene', '90993', (103, 110))	('CREB3L1', 'Gene', (264, 271))	('CREB3L1', 'Gene', (103, 110))	('CAV', 'Gene', '858', (8, 11))	('CREB3L1', 'Gene', '90993', (264, 271))	('patients', 'Species', '9606', (287, 295))	('CREB3L1', 'Gene', '90993', (171, 178))	('CREB3L1', 'Gene', (171, 178))	('patients', 'Species', '9606', (195, 203))	('high-expression', 'Var', (179, 194))	('responses', 'MPA', (222, 231))
23483	31293656	Overall survival was significantly longer for CREB3L1 high-expression patients than for CREB3L1 low-expression patients (Figure 4A; P < 0.001).	('patients', 'Species', '9606', (70, 78))	('high-expression', 'Var', (54, 69))	('CREB3L1', 'Gene', '90993', (46, 53))	('CREB3L1', 'Gene', (88, 95))	('CREB3L1', 'Gene', (46, 53))	('CREB3L1', 'Gene', '90993', (88, 95))	('longer', 'PosReg', (35, 41))	('Overall survival', 'MPA', (0, 16))	('patients', 'Species', '9606', (111, 119))
23487	31293656	The overall survival for CREB3L1 high-expression patients was significantly longer than that for CREB3L1 low-expression patients in both the MAID (AI) regimen (Figure 4B; P = 0.002) and the CAV/IE alternating regimen subgroups (Figure 4C; P = 0.008).	('CAV', 'Gene', '858', (190, 193))	('high-expression', 'Var', (33, 48))	('CREB3L1', 'Gene', '90993', (97, 104))	('CREB3L1', 'Gene', (97, 104))	('CAV', 'Gene', (190, 193))	('longer', 'PosReg', (76, 82))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (49, 57))	('CREB3L1', 'Gene', '90993', (25, 32))	('CREB3L1', 'Gene', (25, 32))
23511	31293656	reported the role of CREB3L1 as a metastasis suppressor in breast cancer and demonstrated that epigenetic silencing is a major regulator of CREB3L1 expression loss.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('loss', 'NegReg', (159, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('metastasis', 'CPA', (34, 44))	('CREB3L1', 'Gene', (21, 28))	('epigenetic silencing', 'Var', (95, 115))	('CREB3L1', 'Gene', '90993', (140, 147))	('expression', 'MPA', (148, 158))	('CREB3L1', 'Gene', (140, 147))	('CREB3L1', 'Gene', '90993', (21, 28))
23522	31293656	Therefore, advanced soft-tissue sarcoma patients with high CREB3L1 expression may benefit from doxorubicin-based chemotherapy, while those with low CREB3L1 expression may fare better with other chemotherapeutic regimens, radiotherapy or combined treatment.	('doxorubicin', 'Chemical', 'MESH:D004317', (95, 106))	('CREB3L1', 'Gene', (148, 155))	('high', 'Var', (54, 58))	('patients', 'Species', '9606', (40, 48))	('soft-tissue sarcoma', 'Disease', (20, 39))	('CREB3L1', 'Gene', '90993', (148, 155))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (20, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('CREB3L1', 'Gene', '90993', (59, 66))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (20, 39))	('benefit', 'PosReg', (82, 89))	('CREB3L1', 'Gene', (59, 66))
23595	31236276	This trial shows that pazopanib increased significantly median progression-free survival to 4.6 months compared to 1.6 months for placebo, although OS was not significantly different.	('progression-free', 'MPA', (63, 79))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))	('pazopanib', 'Var', (22, 31))	('increased', 'PosReg', (32, 41))
23625	30845695	We isolated eSZ cells from stylopod and zeugopod (i.e., tibia/fibula, radius/ulna) bones, from wild-type and Hoxd13 mutant embryos, and tested the impact of EWS-FLI1 transduction on cell proliferation, gene expression, and tumorigenicity.	('tibia', 'Disease', (56, 61))	('EWS-FLI1', 'Gene', '14030;14247', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tested', 'Reg', (136, 142))	('EWS-FLI1', 'Gene', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('mutant', 'Var', (116, 122))	('tibia', 'Disease', 'MESH:C535563', (56, 61))
23627	30845695	Significantly, loss of Hoxd13 had no impact, showing that it is dispensable for the initiation of EWS-FLI1-induced transformation in mouse MSCs.	('EWS-FLI1', 'Gene', (98, 106))	('Hoxd13', 'Gene', (23, 29))	('loss', 'Var', (15, 19))	('mouse', 'Species', '10090', (133, 138))	('EWS-FLI1', 'Gene', '14030;14247', (98, 106))
23641	30845695	We recently reported that high expression of posterior Homeobox D gene cluster (HOXD) genes is a hallmark of Ewing sarcoma and that ectopic expression of EWS-FLI1 in neural crest-derived MSCs hijacks normal epigenetic regulation of HOXD10, HOXD11, and HOXD13.	('ectopic expression', 'Var', (132, 150))	('hallmark of Ewing sarcoma', 'Disease', 'MESH:C563168', (97, 122))	('hallmark of Ewing sarcoma', 'Disease', (97, 122))	('high', 'PosReg', (26, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('EWS-FLI1', 'Gene', (154, 162))	('expression', 'MPA', (31, 41))	('hijacks', 'Reg', (192, 199))	('epigenetic regulation', 'MPA', (207, 228))	('EWS-FLI1', 'Gene', '14030;14247', (154, 162))
23691	30845695	Human Ewing sarcoma tumors over-express HOXD10, HOXD11, and HOXD13 and maintenance of the tumorigenic Ewing sarcoma state requires continued high-level expression of HOXD13.	('Human', 'Species', '9606', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumorigenic Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 115))	('over-express', 'PosReg', (27, 39))	('Ewing sarcoma tumors', 'Disease', (6, 26))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (6, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (6, 19))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumorigenic Ewing sarcoma', 'Disease', (90, 115))	('HOXD10', 'Var', (40, 46))
23715	30845695	In addition, our studies with Hoxd13 mutant eSZ cells demonstrate that susceptibility to EWS-FLI1-induced transformation is not impacted by loss of Hoxd13 revealing that, either the murine cellular context differs from human or, that Hoxd13 is critical for tumor maintenance but dispensable for tumor initiation.	('EWS-FLI1', 'Gene', '14030;14247', (89, 97))	('tumor', 'Disease', (257, 262))	('human', 'Species', '9606', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('Hoxd13', 'Gene', (30, 36))	('EWS-FLI1', 'Gene', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('mutant', 'Var', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('murine', 'Species', '10090', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Disease', (295, 300))
23720	30845695	Study of stylopod MSCs from Hoxd10 mutant mice, alone and in combination with loss of function mutations in other posterior HoxD loci, will be useful to definitively establish the requirement of each of these genes to the initiation of the EWS-FLI1 transformed phenotype.	('Hoxd10', 'Gene', '15430', (28, 34))	('EWS-FLI1', 'Gene', '14030;14247', (240, 248))	('mice', 'Species', '10090', (42, 46))	('mutant', 'Var', (35, 41))	('Hoxd10', 'Gene', (28, 34))	('EWS-FLI1', 'Gene', (240, 248))
23728	30845695	Therefore, a difference in chromatin state around key oncogenic genes could impact the ability of EWS-FLI1 to induce transformation in different cell populations.	('transformation', 'CPA', (117, 131))	('EWS-FLI1', 'Gene', (98, 106))	('ability', 'MPA', (87, 94))	('impact', 'NegReg', (76, 82))	('difference', 'Var', (13, 23))	('EWS-FLI1', 'Gene', '14030;14247', (98, 106))
23736	30845695	Forelimbs of E18.5 Hoxa11GFP/+; Pthrp-lacz embryos were formalin fixed and embedded in OCT. 18 micron sections were collected on slides.	('Pthrp', 'Gene', (32, 37))	('Pthrp', 'Gene', '19227', (32, 37))	('Hoxa11', 'Gene', '15396', (19, 25))	('E18.5', 'Var', (13, 18))	('Hoxa11', 'Gene', (19, 25))	('formalin', 'Chemical', 'MESH:D005557', (56, 64))
23747	30845695	The following Taqman assays from Thermo Fisher (Waltham, MA, USA) were utilized in real-time quantitative PCR: mouse Hprt Mm03024075_m1, mouse Hoxd10 Mm00442839_m1, mouse Hoxd11 Mm02602515_mH, mouse Hoxd13 Mm00433973_m1, mouse Dkk2 Mm01322146_m1, mouse Prckb Mm00435749_m1, mouse Gli1 Mm00494654_m1, and human EWSR1-F Hs03024497.	('Mm01322146_m1', 'Var', (232, 245))	('mouse', 'Species', '10090', (247, 252))	('mouse', 'Species', '10090', (137, 142))	('mouse', 'Species', '10090', (111, 116))	('mouse', 'Species', '10090', (221, 226))	('Mm00442839_m1', 'Var', (150, 163))	('Gli1', 'Gene', '14632', (280, 284))	('mouse', 'Species', '10090', (165, 170))	('Hoxd10', 'Gene', '15430', (143, 149))	('Hoxd11', 'Gene', (171, 177))	('Gli1', 'Gene', (280, 284))	('Hoxd10', 'Gene', (143, 149))	('EWSR1', 'Gene', '2130', (310, 315))	('Hoxd11', 'Gene', '15431', (171, 177))	('Dkk2', 'Gene', (227, 231))	('Mm02602515_mH', 'Var', (178, 191))	('Mm00435749_m1', 'Var', (259, 272))	('mouse', 'Species', '10090', (274, 279))	('Mm00494654_m1', 'Var', (285, 298))	('Hprt', 'Gene', '15452', (117, 121))	('Hprt', 'Gene', (117, 121))	('EWSR1', 'Gene', (310, 315))	('Dkk2', 'Gene', '56811', (227, 231))	('mouse', 'Species', '10090', (193, 198))	('human', 'Species', '9606', (304, 309))
23762	30845695	Additional funding was provided by the National Cancer Institute under award numbers T32 CA 009676 (A.A.), R01 CA215981 (E.R.L.	('R01 CA215981', 'Var', (107, 119))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', (48, 54))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('T32 CA 009676', 'Var', (85, 98))	('T32 CA', 'Mutation', 'c.32T>CA', (85, 91))
23763	30845695	), P30 CA046592; the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number P30 AR069620 and R01 AR061402 (D.M.W.	('P30', 'Gene', '15289', (3, 6))	('Arthritis and Musculoskeletal', 'Disease', 'MESH:D009140', (43, 72))	('R01 AR061402', 'Var', (164, 176))	('Arthritis', 'Phenotype', 'HP:0001369', (43, 52))	('P30', 'Gene', (147, 150))	('P30', 'Gene', (3, 6))	('P30', 'Gene', '15289', (147, 150))
23770	29997151	We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion.	('transcriptional profile', 'MPA', (17, 40))	('KDM1A', 'Gene', (76, 81))	('SP-2509', 'Chemical', 'MESH:C000594309', (51, 58))	('SP-2509', 'Var', (51, 58))	('KDM1A', 'Gene', '23028', (76, 81))
23771	29997151	Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum (ER) stress pathway.	('SP-2509', 'Chemical', 'MESH:C000594309', (48, 55))	('SP-2509', 'Var', (48, 55))	('apoptosis', 'CPA', (71, 80))
23781	29997151	However, there is growing appreciation that dysregulation of epigenetic machinery and chromatin modifications are important mechanisms utilized by tumors to favorably modulate DNA repair, cell cycle control, and apoptosis-promoting genes.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cell cycle control', 'CPA', (188, 206))	('dysregulation', 'Var', (44, 57))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('apoptosis-promoting genes', 'Gene', (212, 237))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('modulate', 'Reg', (167, 175))	('DNA', 'MPA', (176, 179))
23782	29997151	This is particularly pertinent for ES, as recent high throughput screening efforts have shown that this malignancy possesses one of the lowest mutation rates amongst all cancers (0.15 mutations/Mb), yielding a paucity of pharmacologically actionable mutations.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('ES', 'Phenotype', 'HP:0012254', (35, 37))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('mutations/Mb', 'Var', (184, 196))	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('malignancy', 'Disease', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
23783	29997151	KDM1A (LSD1/BHC110), was the first flavine adenine dinucleotide (FAD)-dependent lysine specific demethylase identified to regulate chromatin states through the removal of mono and dimethyl groups (H3K4 or H3K9).	('LSD1', 'Gene', '23028', (7, 11))	('flavine adenine dinucleotide', 'Chemical', 'MESH:D005182', (35, 63))	('chromatin states', 'MPA', (131, 147))	('KDM1A', 'Gene', '23028', (0, 5))	('regulate', 'Reg', (122, 130))	('BHC110', 'Gene', '23028', (12, 18))	('BHC110', 'Gene', (12, 18))	('H3K9', 'Var', (205, 209))	('KDM1A', 'Gene', (0, 5))	('FAD', 'Chemical', 'MESH:D005182', (65, 68))	('LSD1', 'Gene', (7, 11))	('H3K4', 'Var', (197, 201))
23786	29997151	These observations have led to the active development of several small molecule KDM1A inhibitors, with Tranylcypomine (NCT02273102, NCT02261779), GSK-LSD1 (NCT02177812, NCT02034123) and ORY-1001 (2013-002447-29) currently undergoing phase I/II clinical evaluation in patients with acute myeloid leukemia (AML) and small cell lung carcinoma (SCLC).	('myeloid leukemia', 'Phenotype', 'HP:0012324', (287, 303))	('GSK-LSD1', 'Gene', (146, 154))	('KDM1A', 'Gene', (80, 85))	('SCLC', 'Gene', '7864', (341, 345))	('SCLC', 'Gene', (341, 345))	('NCT02261779', 'Var', (132, 143))	('Tranylcypomine', 'Chemical', '-', (103, 117))	('KDM1A', 'Gene', '23028', (80, 85))	('GSK-LSD1', 'Gene', '23028', (146, 154))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (281, 303))	('patients', 'Species', '9606', (267, 275))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (314, 339))	('acute myeloid leukemia', 'Disease', (281, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('AML', 'Disease', 'MESH:D015470', (305, 308))	('small cell lung carcinoma', 'Disease', (314, 339))	('SCLC', 'Phenotype', 'HP:0030357', (341, 345))	('AML', 'Disease', (305, 308))	('NCT02177812', 'Var', (156, 167))	('NCT02273102', 'Var', (119, 130))	('AML', 'Phenotype', 'HP:0004808', (305, 308))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (281, 303))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (314, 339))	('leukemia', 'Phenotype', 'HP:0001909', (295, 303))
23789	29997151	However the precise mechanism by which SP-2509 induces apoptosis remains unknown.	('SP-2509', 'Chemical', 'MESH:C000594309', (39, 46))	('SP-2509', 'Var', (39, 46))	('apoptosis', 'CPA', (55, 64))
23808	29997151	To amplify unspliced and spliced XBP1 variants, 50ng of total RNA was reverse transcribed and amplified using iTaq Universal SYBR Green 1 Step Reaction Mix (Bio-Rad) and the following primers: Forward: 5' TTACGAGAGAAAACTCATGGCC'3, Reverse 5' GGGTCCAAGTTGTCCAGAATGC '3.	('XBP1', 'Gene', '7494', (33, 37))	('variants', 'Var', (38, 46))	('XBP1', 'Gene', (33, 37))	('Rad', 'Gene', '6236', (161, 164))	('Rad', 'Gene', (161, 164))
23820	29997151	Notably, high KDM1A expression was significantly correlated with worse overall survival (Postel-Vinay 2012, P=0.033) and a worse overall survival trend in two additional small studies (Ohali 2004, P=0.054 and Volchenboum 2015, P=0.052) (Fig.	('worse', 'NegReg', (65, 70))	('expression', 'MPA', (20, 30))	('high', 'Var', (9, 13))	('overall survival', 'MPA', (71, 87))	('KDM1A', 'Gene', '23028', (14, 19))	('KDM1A', 'Gene', (14, 19))
23821	29997151	In contrast high KDM1A expression was significantly correlated with poor event free survival only in 1/4 studies (Ohali 2004, P=0.016) (Supplementary Fig.	('high', 'Var', (12, 16))	('KDM1A', 'Gene', '23028', (17, 22))	('event free', 'MPA', (73, 83))	('KDM1A', 'Gene', (17, 22))	('expression', 'MPA', (23, 33))
23824	29997151	Together, although the clinical ES cohorts are small, our findings suggest that high KDM1A expression levels are associated worse overall survival, and that targeting KDM1A has broad utility for this aggressive malignancy.	('overall survival', 'CPA', (130, 146))	('KDM1A', 'Gene', '23028', (167, 172))	('KDM1A', 'Gene', '23028', (85, 90))	('ES', 'Phenotype', 'HP:0012254', (32, 34))	('expression levels', 'MPA', (91, 108))	('KDM1A', 'Gene', (85, 90))	('malignancy', 'Disease', 'MESH:D009369', (211, 221))	('KDM1A', 'Gene', (167, 172))	('malignancy', 'Disease', (211, 221))	('high', 'Var', (80, 84))
23825	29997151	We previously demonstrated targeted inhibition of KDM1A with SP-2509 significantly impairs the tumorigenic growth properties of ES cell lines.	('SP-2509', 'Chemical', 'MESH:C000594309', (61, 68))	('KDM1A', 'Gene', '23028', (50, 55))	('inhibition', 'NegReg', (36, 46))	('ES', 'Phenotype', 'HP:0012254', (128, 130))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('KDM1A', 'Gene', (50, 55))	('SP-2509', 'Var', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('impairs', 'NegReg', (83, 90))	('tumor', 'Disease', (95, 100))
23827	29997151	shRNA retroviral knockdown of KDM1A significantly impaired the anchorage-independent growth of A673 and TTC-466 (95.2/18.5 fold reduction in colony number respectively) ES cell lines in soft agar (Fig.	('reduction', 'NegReg', (128, 137))	('knockdown', 'Var', (17, 26))	('impaired', 'NegReg', (50, 58))	('KDM1A', 'Gene', '23028', (30, 35))	('ES', 'Phenotype', 'HP:0012254', (169, 171))	('colony number', 'CPA', (141, 154))	('anchorage-independent growth', 'CPA', (63, 91))	('KDM1A', 'Gene', (30, 35))
23829	29997151	Correspondingly, silencing of KDM1A significantly reduced the proliferative capacity of both cell lines as shown through IncuCyte live imaging analysis.	('KDM1A', 'Gene', '23028', (30, 35))	('proliferative capacity', 'CPA', (62, 84))	('reduced', 'NegReg', (50, 57))	('KDM1A', 'Gene', (30, 35))	('silencing', 'Var', (17, 26))
23838	29997151	In total 195 repressed genes (11.2%) were commonly induced upon KDM1A-EWS/FLI knockdown, which were highly enriched for hepatic stellate cell activation (P=3.56x10-11) and HMGB1 signaling (P=7.69x10-08).	('EWS', 'Gene', '2130', (70, 73))	('EWS', 'Gene', (70, 73))	('FLI', 'Gene', (74, 77))	('induced', 'PosReg', (51, 58))	('knockdown', 'Var', (78, 87))	('HMGB1', 'Gene', (172, 177))	('KDM1A', 'Gene', '23028', (64, 69))	('HMGB1', 'Gene', '3146', (172, 177))	('repressed genes', 'Gene', (13, 28))	('KDM1A', 'Gene', (64, 69))	('FLI', 'Gene', '2314', (74, 77))
23840	29997151	chi2 analysis revealed a statistically significant overlap (P<0.0001) between genes activated/repressed following A673 treatment with SP-2509 (2muM) and KDM1A knockdown.	('KDM1A', 'Gene', '23028', (153, 158))	('muM', 'Gene', '56925', (144, 147))	('KDM1A', 'Gene', (153, 158))	('SP-2509', 'Var', (134, 141))	('muM', 'Gene', (144, 147))	('activated/repressed', 'PosReg', (84, 103))	('SP-2509', 'Chemical', 'MESH:C000594309', (134, 141))
23841	29997151	In total 162 genes were commonly induced upon SP-2509/KDM1A knockdown (KDM1A repressed genes) with 107 genes commonly down-regulated (KDM1A activated genes) (Supplementary Fig.	('KDM1A', 'Gene', '23028', (54, 59))	('KDM1A', 'Gene', (134, 139))	('KDM1A', 'Gene', '23028', (71, 76))	('KDM1A', 'Gene', '23028', (134, 139))	('KDM1A', 'Gene', (54, 59))	('knockdown', 'Var', (60, 69))	('KDM1A', 'Gene', (71, 76))	('SP-2509', 'Chemical', 'MESH:C000594309', (46, 53))	('down-regulated', 'NegReg', (118, 132))	('induced', 'PosReg', (33, 40))
23845	29997151	GSEA showed significant correlation (P<0.001) for genes both up- and downregulated upon KDM1A knockdown in the SP-2509-regulated gene list.	('knockdown', 'Var', (94, 103))	('KDM1A', 'Gene', '23028', (88, 93))	('up-', 'PosReg', (61, 64))	('KDM1A', 'Gene', (88, 93))	('downregulated', 'NegReg', (69, 82))	('SP-2509', 'Chemical', 'MESH:C000594309', (111, 118))	('GSEA', 'Chemical', '-', (0, 4))
23847	29997151	We next sought to elucidate the molecular basis of SP-2509 induced apoptotic cytotoxicity.	('cytotoxicity', 'Disease', (77, 89))	('SP-2509', 'Var', (51, 58))	('SP-2509', 'Chemical', 'MESH:C000594309', (51, 58))	('cytotoxicity', 'Disease', 'MESH:D064420', (77, 89))
23850	29997151	Importantly primary hMSC cells, a putative ES cell of origin and TIP5 fibroblasts remained unaffected at these low concentrations, SP-2509 IC50 of >4muM and 18.2muM respectively.	('SP-2509', 'Var', (131, 138))	('muM', 'Gene', (161, 164))	('muM', 'Gene', '56925', (149, 152))	('ES', 'Phenotype', 'HP:0012254', (43, 45))	('muM', 'Gene', (149, 152))	('SP-2509', 'Chemical', 'MESH:C000594309', (131, 138))	('TIP5', 'Gene', (65, 69))	('TIP5', 'Gene', '11176', (65, 69))	('muM', 'Gene', '56925', (161, 164))
23852	29997151	ES cell lines were significantly more sensitive (range: 2.1-11.4 fold greater) to SP-2509 compared to all other cancer subtypes (Supplementary Fig.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('SP-2509', 'Var', (82, 89))	('sensitive', 'MPA', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SP-2509', 'Chemical', 'MESH:C000594309', (82, 89))
23853	29997151	To determine the antitumor activity associated with catalytic inhibition of KDM1A, a panel of ES cell lines was also treated with the irreversible KDM1A inhibitors tranylcypromine (72hrs) and its more specific next generation analogue derivative GSK-LSD1 (144hrs).	('144hrs', 'Var', (256, 262))	('GSK-LSD1', 'Gene', (246, 254))	('ES', 'Phenotype', 'HP:0012254', (94, 96))	('KDM1A', 'Gene', (76, 81))	('tumor', 'Disease', (21, 26))	('GSK-LSD1', 'Gene', '23028', (246, 254))	('tranylcypromine', 'Chemical', 'MESH:D014191', (164, 179))	('KDM1A', 'Gene', '23028', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('KDM1A', 'Gene', '23028', (76, 81))	('KDM1A', 'Gene', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
23855	29997151	Strikingly, the low dose rapid cytotoxicity profile of SP-2509 was not recapitulated with either compound (Supplementary Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (31, 43))	('SP-2509', 'Chemical', 'MESH:C000594309', (55, 62))	('cytotoxicity', 'Disease', (31, 43))	('SP-2509', 'Var', (55, 62))
23864	29997151	To confirm that GSK-LSD1 has no effect on the proliferative growth of ES cell lines, A673, TC252 and ES-2 cells were treated with SP-2509, GSK-LSD1 or the ES chemotherapeutic agent Doxorubicin for 96hrs.	('GSK-LSD1', 'Gene', (16, 24))	('SP-2509', 'Chemical', 'MESH:C000594309', (130, 137))	('GSK-LSD1', 'Gene', (139, 147))	('ES', 'Phenotype', 'HP:0012254', (155, 157))	('GSK-LSD1', 'Gene', '23028', (139, 147))	('ES', 'Phenotype', 'HP:0012254', (70, 72))	('SP-2509', 'Var', (130, 137))	('GSK-LSD1', 'Gene', '23028', (16, 24))	('ES', 'Phenotype', 'HP:0012254', (101, 103))	('proliferative growth', 'CPA', (46, 66))	('Doxorubicin', 'Chemical', 'MESH:D004317', (181, 192))	('TC252', 'CellLine', 'CVCL:S866', (91, 96))
23871	29997151	Despite that 3/5 hypersensitive SP-2509 cells lines (IC50 <500nM) (SK-N-MC, A673 and SK-ES-1) harbor null/mutant TP53, no correlation between TP53 mutational status and SP-2509 sensitivity was observed (P=0.256).	('hypersensitive', 'Disease', (17, 31))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('SK-ES-1', 'CellLine', 'CVCL:0627', (85, 92))	('TP53', 'Gene', '7157', (113, 117))	('null/mutant', 'Var', (101, 112))	('SP-2509', 'Chemical', 'MESH:C000594309', (169, 176))	('SK-N-MC', 'CellLine', 'CVCL:0530', (67, 74))	('ES', 'Phenotype', 'HP:0012254', (88, 90))	('SP-2509', 'Chemical', 'MESH:C000594309', (32, 39))	('TP53', 'Gene', (113, 117))	('hypersensitive', 'Disease', 'MESH:D004342', (17, 31))
23877	29997151	In addition, although strong protein expression of KDM1A was evident across the entire cell line cohort, no significant association between SP-2509 sensitivity and KDM1A, KDM1B, FLI and p53 protein levels as well as cell doubling time or whether the cell line was obtained from chemotherapy-naive or treated tumors, was observed (Fig.	('SP-2509 sensitivity', 'Var', (140, 159))	('SP-2509', 'Chemical', 'MESH:C000594309', (140, 147))	('KDM1B', 'Gene', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('KDM1A', 'Gene', (51, 56))	('FLI', 'Gene', '2314', (178, 181))	('KDM1B', 'Gene', '221656', (171, 176))	('FLI', 'Gene', (178, 181))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('p53', 'Gene', (186, 189))	('KDM1A', 'Gene', '23028', (164, 169))	('p53', 'Gene', '7157', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('KDM1A', 'Gene', '23028', (51, 56))	('KDM1A', 'Gene', (164, 169))	('tumors', 'Disease', (308, 314))
23879	29997151	Four unique KDM1A isoforms generated through either single or double insertion of two alternatively spliced exons (2a and 8a) in the unstructured amino-terminus and amino oxidase domains of KDM1A respectively have been identified.	('KDM1A', 'Gene', '23028', (190, 195))	('double insertion', 'Var', (62, 78))	('KDM1A', 'Gene', '23028', (12, 17))	('KDM1A', 'Gene', (190, 195))	('KDM1A', 'Gene', (12, 17))
23883	29997151	Our data demonstrates that regardless of KDM1A expression levels, ES cells are susceptible to the cytotoxic effects of SP-2509, thereby strengthening the broad utility of targeted KDM1A inhibition for the treatment of ES.	('SP-2509', 'Chemical', 'MESH:C000594309', (119, 126))	('KDM1A', 'Gene', (41, 46))	('KDM1A', 'Gene', (180, 185))	('ES', 'Phenotype', 'HP:0012254', (218, 220))	('SP-2509', 'Var', (119, 126))	('KDM1A', 'Gene', '23028', (180, 185))	('KDM1A', 'Gene', '23028', (41, 46))	('ES', 'Phenotype', 'HP:0012254', (66, 68))
23884	29997151	To assess whether SP-2509 treatment directly modulates KDM1A, KDM1B and EWS/FLI mRNA and protein levels, a panel of eight ES cell lines of varying sensitivity were treated with SP-2509 (2muM) for 48hrs.	('SP-2509', 'Chemical', 'MESH:C000594309', (177, 184))	('KDM1A', 'Gene', (55, 60))	('SP-2509', 'Var', (177, 184))	('modulates', 'Reg', (45, 54))	('EWS', 'Gene', (72, 75))	('EWS', 'Gene', '2130', (72, 75))	('KDM1A', 'Gene', '23028', (55, 60))	('muM', 'Gene', '56925', (187, 190))	('KDM1B', 'Gene', (62, 67))	('SP-2509', 'Chemical', 'MESH:C000594309', (18, 25))	('ES', 'Phenotype', 'HP:0012254', (122, 124))	('KDM1B', 'Gene', '221656', (62, 67))	('FLI', 'Gene', '2314', (76, 79))	('muM', 'Gene', (187, 190))	('FLI', 'Gene', (76, 79))
23894	29997151	Finally to elucidate whether small molecule modulation of EWS/FLI protein levels also affects KDM1A and KDM1B expression, A673, TC252 and ES-2 cells were also treated with the nucleoside analog ARA-C (cytosine arabinoside), a known modulator of EWS/FLI protein but not transcript levels.	('EWS', 'Gene', '2130', (245, 248))	('ES', 'Phenotype', 'HP:0012254', (138, 140))	('FLI', 'Gene', (62, 65))	('nucleoside', 'Chemical', 'MESH:D009705', (176, 186))	('modulation', 'Var', (44, 54))	('ARA-C', 'Chemical', 'MESH:D003561', (194, 199))	('KDM1A', 'Gene', (94, 99))	('FLI', 'Gene', '2314', (62, 65))	('KDM1B', 'Gene', (104, 109))	('EWS', 'Gene', '2130', (58, 61))	('KDM1A', 'Gene', '23028', (94, 99))	('cytosine arabinoside', 'Chemical', 'MESH:D003561', (201, 221))	('EWS', 'Gene', (245, 248))	('expression', 'MPA', (110, 120))	('TC252', 'CellLine', 'CVCL:S866', (128, 133))	('KDM1B', 'Gene', '221656', (104, 109))	('FLI', 'Gene', (249, 252))	('affects', 'Reg', (86, 93))	('EWS', 'Gene', (58, 61))	('FLI', 'Gene', '2314', (249, 252))
23897	29997151	Together, these findings suggest that the ability of SP-2509 to modulate KDM1A, KDM1B and EWS/FLI expression levels is a direct affect, and not simply a cellular stress response to cytotoxic agents.	('EWS', 'Gene', (90, 93))	('SP-2509', 'Var', (53, 60))	('EWS', 'Gene', '2130', (90, 93))	('KDM1A', 'Gene', '23028', (73, 78))	('KDM1A', 'Gene', (73, 78))	('modulate', 'Reg', (64, 72))	('FLI', 'Gene', '2314', (94, 97))	('FLI', 'Gene', (94, 97))	('expression levels', 'MPA', (98, 115))	('KDM1B', 'Gene', (80, 85))	('SP-2509', 'Chemical', 'MESH:C000594309', (53, 60))	('KDM1B', 'Gene', '221656', (80, 85))
23903	29997151	Interestingly, knockdown of KDM1B significantly reduced the proliferative capacity of both A673 and EWS-502 cells compared to non-targeting control (iLuc).	('knockdown', 'Var', (15, 24))	('proliferative capacity', 'CPA', (60, 82))	('reduced', 'NegReg', (48, 55))	('KDM1B', 'Gene', (28, 33))	('KDM1B', 'Gene', '221656', (28, 33))	('EWS', 'Gene', '2130', (100, 103))	('EWS', 'Gene', (100, 103))
23907	29997151	Following 72hrs of treatment, KDM1B knockdown significantly reduced the sensitivity of A673 cells to SP-2509 compared to controls by 2.3 and 4.3 fold, shRNA #3 and shRNA #7 respectively.	('KDM1B', 'Gene', (30, 35))	('KDM1B', 'Gene', '221656', (30, 35))	('sensitivity', 'MPA', (72, 83))	('knockdown', 'Var', (36, 45))	('reduced', 'NegReg', (60, 67))	('SP-2509', 'Chemical', 'MESH:C000594309', (101, 108))
23911	29997151	Unsupervised hierarchical clustering analysis of these transcriptomes showed that those cell lines that were highly sensitive to SP-2509 shared similar basal gene expression profiles and clustered separately from the sensitive cell lines (Supplementary Fig.	('basal gene expression profiles', 'MPA', (152, 182))	('SP-2509', 'Chemical', 'MESH:C000594309', (129, 136))	('SP-2509', 'Var', (129, 136))
23915	29997151	To complement and extend these analyses, we next sought to identify which core subset of genes were specifically induced and repressed in our hypersensitive but not sensitive ES cell lines following SP-2509 treatment (Supplementary Fig.	('hypersensitive', 'Disease', 'MESH:D004342', (142, 156))	('SP-2509', 'Chemical', 'MESH:C000594309', (199, 206))	('hypersensitive', 'Disease', (142, 156))	('SP-2509', 'Var', (199, 206))	('induced', 'PosReg', (113, 120))	('ES', 'Phenotype', 'HP:0012254', (175, 177))
23921	29997151	On the basis that SP-2509 resistance was not observed in our ES cell line cohort, we next examined which genes are commonly induced and repressed across all cell lines to mediate SP-2509 cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (187, 199))	('SP-2509', 'Chemical', 'MESH:C000594309', (179, 186))	('SP-2509', 'Chemical', 'MESH:C000594309', (18, 25))	('ES', 'Phenotype', 'HP:0012254', (61, 63))	('cytotoxicity', 'Disease', (187, 199))	('SP-2509', 'Var', (179, 186))
23923	29997151	Interestingly 30/103 (29.1%) and 33/82 (40.2%) of these genes overlapped with known EWS/FLI regulated targets, corroborating our previous findings that SP-2509 reverses the EWS/ETS-driven transcriptional program in ES (Supplementary Table S2).	('FLI', 'Gene', (88, 91))	('SP-2509', 'Var', (152, 159))	('EWS', 'Gene', '2130', (173, 176))	('EWS', 'Gene', (173, 176))	('reverses', 'NegReg', (160, 168))	('EWS', 'Gene', (84, 87))	('EWS', 'Gene', '2130', (84, 87))	('SP-2509', 'Chemical', 'MESH:C000594309', (152, 159))	('ES', 'Phenotype', 'HP:0012254', (215, 217))	('FLI', 'Gene', '2314', (88, 91))
23924	29997151	In addition, the majority of genes modulated by SP-2509 were protein coding (80.6% and 69.5%), followed by long coding RNA's (17.5% and 15.9% up/down-regulated respectively) (Fig.	('SP-2509', 'Chemical', 'MESH:C000594309', (48, 55))	('up/down-regulated', 'PosReg', (142, 159))	('protein', 'Protein', (61, 68))	('SP-2509', 'Var', (48, 55))
23929	29997151	To confirm that SP-2509 activates the ER-stress response pathway, TC252 cells were treated with SP-2509 (2muM), vehicle control or thapsigargin (50nM), a chemical agent known to activate the UPR stress response by blocking ER calcium ATPase pumps, leading to depletion of ER calcium stores.	('muM', 'Gene', '56925', (106, 109))	('SP-2509', 'Var', (16, 23))	('depletion of ER calcium stores', 'MPA', (259, 289))	('muM', 'Gene', (106, 109))	('SP-2509', 'Chemical', 'MESH:C000594309', (96, 103))	('blocking', 'NegReg', (214, 222))	('TC252', 'CellLine', 'CVCL:S866', (66, 71))	('calcium', 'Chemical', 'MESH:D002118', (226, 233))	('SP-2509', 'Var', (96, 103))	('ER calcium ATPase pumps', 'Protein', (223, 246))	('calcium', 'Chemical', 'MESH:D002118', (275, 282))	('SP-2509', 'Chemical', 'MESH:C000594309', (16, 23))	('thapsigargin', 'Chemical', 'MESH:D019284', (131, 143))	('ER-stress response pathway', 'Pathway', (38, 64))
23935	29997151	Finally, mRNA levels of 12 known UPR pathway genes was assessed to determine whether hypersensitive cell lines are basally primed for greater robust apoptotic responses following SP-2509 treatment.	('hypersensitive', 'Disease', (85, 99))	('SP-2509', 'Chemical', 'MESH:C000594309', (179, 186))	('SP-2509', 'Var', (179, 186))	('hypersensitive', 'Disease', 'MESH:D004342', (85, 99))
23941	29997151	In contrast, similar to HSPA5, DDIT3 and ERN1, significant induction of spliced XBP1 was only observed 24hrs post SP-2509 treatment with peak induction observed 48hrs post drug exposure (22.3 fold increase from vehicle control).	('XBP1', 'Gene', '7494', (80, 84))	('DDIT3', 'Gene', (31, 36))	('ERN1', 'Gene', '2081', (41, 45))	('HSPA5', 'Gene', '3309', (24, 29))	('SP-2509', 'Var', (114, 121))	('DDIT3', 'Gene', '1649', (31, 36))	('HSPA5', 'Gene', (24, 29))	('XBP1', 'Gene', (80, 84))	('ERN1', 'Gene', (41, 45))	('SP-2509', 'Chemical', 'MESH:C000594309', (114, 121))
23942	29997151	PCR analysis of the spliced (263bp) and un-spliced (289bp) XBP1 variants following thapsigargin and SP-2509 corroborated these findings.	('XBP1', 'Gene', (59, 63))	('SP-2509', 'Chemical', 'MESH:C000594309', (100, 107))	('thapsigargin', 'Chemical', 'MESH:D019284', (83, 95))	('XBP1', 'Gene', '7494', (59, 63))	('variants', 'Var', (64, 72))
23945	29997151	Taken together these results reveal that SP-2509 induces the UPR and ER-stress response, although at a slower kinetic rate than known UPR inducing agents.	('ER-stress response', 'CPA', (69, 87))	('UPR', 'MPA', (61, 64))	('SP-2509', 'Chemical', 'MESH:C000594309', (41, 48))	('induces', 'Reg', (49, 56))	('SP-2509', 'Var', (41, 48))
23948	29997151	As ERN1 expression was notably induced across all six ES cell lines following SP-2509 treatment (Fig.	('SP-2509', 'Chemical', 'MESH:C000594309', (78, 85))	('ERN1', 'Gene', '2081', (3, 7))	('induced', 'PosReg', (31, 38))	('SP-2509', 'Var', (78, 85))	('ES', 'Phenotype', 'HP:0012254', (54, 56))	('ERN1', 'Gene', (3, 7))	('expression', 'MPA', (8, 18))
23949	29997151	5A/D) and is responsible for the cleavage of XBP1, we next investigated whether stable retroviral knockdown of ERN1 mitigates SP-2509 cytotoxicity.	('ERN1', 'Gene', (111, 115))	('5A/D', 'SUBSTITUTION', 'None', (0, 4))	('XBP1', 'Gene', (45, 49))	('SP-2509', 'Chemical', 'MESH:C000594309', (126, 133))	('knockdown', 'Var', (98, 107))	('cytotoxicity', 'Disease', (134, 146))	('ERN1', 'Gene', '2081', (111, 115))	('mitigates', 'NegReg', (116, 125))	('XBP1', 'Gene', '7494', (45, 49))	('cytotoxicity', 'Disease', 'MESH:D064420', (134, 146))	('5A/D', 'Var', (0, 4))
23951	29997151	Following 72hr treatment with SP-2509 (0-4muM), shRNA knockdown of ERN1 (shRNA #2) significantly increased the concentration of SP-2509 required to reduce viability by 50% (2.06 fold increase).	('increased', 'PosReg', (97, 106))	('knockdown', 'Var', (54, 63))	('ERN1', 'Gene', (67, 71))	('muM', 'Gene', '56925', (42, 45))	('concentration', 'MPA', (111, 124))	('muM', 'Gene', (42, 45))	('SP-2509', 'Chemical', 'MESH:C000594309', (128, 135))	('ERN1', 'Gene', '2081', (67, 71))	('SP-2509', 'Chemical', 'MESH:C000594309', (30, 37))
23955	29997151	In contrast, a significant dose dependent reduction in 2-deoxyglucose-6-phosphate (2DG6P) uptake was observed in both A673 and TC252 cells following treatment with SP-2509 (48/72hrs) suggesting that SP-2509 may engage the accumulation of misfolded proteins through nutrient deprivation.	('SP-2509', 'Chemical', 'MESH:C000594309', (164, 171))	('SP-2509', 'Chemical', 'MESH:C000594309', (199, 206))	('TC252', 'CellLine', 'CVCL:S866', (127, 132))	('SP-2509', 'Var', (164, 171))	('2DG6P', 'Chemical', 'MESH:C015785', (83, 88))	('SP-2509', 'Var', (199, 206))	('2-deoxyglucose-6-phosphate', 'Chemical', 'MESH:C015785', (55, 81))	('reduction', 'NegReg', (42, 51))
23963	29997151	In addition we demonstrate that induction of the UPR response mediates SP-2509 cytotoxicity in ES, a pathway previously unlinked with KDM1A blockade.	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('SP-2509', 'Var', (71, 78))	('KDM1A', 'Gene', '23028', (134, 139))	('cytotoxicity', 'Disease', (79, 91))	('ES', 'Phenotype', 'HP:0012254', (95, 97))	('SP-2509', 'Chemical', 'MESH:C000594309', (71, 78))	('KDM1A', 'Gene', (134, 139))
23965	29997151	Furthermore, SP-2509 specific induction of KDM1B following treatment was also predictive of SP-2509 hypersensitivity (Supplementary Fig.	('SP-2509', 'Chemical', 'MESH:C000594309', (92, 99))	('hypersensitivity', 'Disease', (100, 116))	('hypersensitivity', 'Disease', 'MESH:D004342', (100, 116))	('induction', 'PosReg', (30, 39))	('SP-2509', 'Chemical', 'MESH:C000594309', (13, 20))	('KDM1B', 'Gene', '221656', (43, 48))	('SP-2509', 'Var', (92, 99))	('KDM1B', 'Gene', (43, 48))
23973	29997151	Amplification of KDM1B has been observed in breast, bladder urothelia carcinoma, and neuroendocrine prostate cancer, with stable shRNA silencing of KDM1B significantly reducing the colony formation capacity of breast cancer cell lines.	('silencing', 'Var', (135, 144))	('bladder urothelia carcinoma', 'Disease', 'MESH:D001749', (52, 79))	('reducing', 'NegReg', (168, 176))	('KDM1B', 'Gene', (17, 22))	('breast', 'Disease', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('KDM1B', 'Gene', '221656', (17, 22))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (85, 115))	('colony formation capacity', 'CPA', (181, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('KDM1B', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('neuroendocrine prostate cancer', 'Disease', (85, 115))	('bladder urothelia carcinoma', 'Disease', (52, 79))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('breast cancer', 'Disease', (210, 223))	('KDM1B', 'Gene', '221656', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
23979	29997151	Indeed our results demonstrated that knockdown of KDM1B only in the hypersensitive SP-2509 cell line A673 but not EWS-502 (sensitive) significantly reduced the cytotoxic effects of SP-2509.	('KDM1B', 'Gene', (50, 55))	('EWS', 'Gene', '2130', (114, 117))	('EWS', 'Gene', (114, 117))	('cytotoxic effects of', 'CPA', (160, 180))	('KDM1B', 'Gene', '221656', (50, 55))	('SP-2509', 'Chemical', 'MESH:C000594309', (181, 188))	('reduced', 'NegReg', (148, 155))	('knockdown', 'Var', (37, 46))	('SP-2509', 'Chemical', 'MESH:C000594309', (83, 90))	('hypersensitive', 'Disease', 'MESH:D004342', (68, 82))	('hypersensitive', 'Disease', (68, 82))
23981	29997151	To date, the precise mechanism by which SP-2509 drives ES cells towards an apoptotic fate remains unanswered.	('apoptotic', 'CPA', (75, 84))	('ES', 'Phenotype', 'HP:0012254', (55, 57))	('SP-2509', 'Var', (40, 47))	('drives', 'PosReg', (48, 54))	('SP-2509', 'Chemical', 'MESH:C000594309', (40, 47))
23994	29997151	Interestingly we show that SP-2509 significantly attenuates glucose uptake in ES cell lines.	('attenuates', 'NegReg', (49, 59))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('SP-2509', 'Chemical', 'MESH:C000594309', (27, 34))	('SP-2509', 'Var', (27, 34))	('ES', 'Phenotype', 'HP:0012254', (78, 80))	('glucose uptake', 'CPA', (60, 74))
23996	29997151	Inactivation of KDM1A (chemical and genetic depletion) has been shown to suppress glucose uptake and glycolytic activity, with concurrent activation of mitochondrial respiration.	('suppress', 'NegReg', (73, 81))	('KDM1A', 'Gene', '23028', (16, 21))	('KDM1A', 'Gene', (16, 21))	('mitochondrial respiration', 'MPA', (152, 177))	('glucose', 'Chemical', 'MESH:D005947', (82, 89))	('Inactivation', 'Var', (0, 12))	('glucose', 'CPA', (82, 89))	('activation', 'PosReg', (138, 148))	('glycolytic activity', 'MPA', (101, 120))
24001	29997151	For this reason, further studies are required to define mechanism(s) of SP-2509 resistance, a key unanswered question which will be essential to guide combinatorial treatment methods to circumvent patient drug resistance and define more selective inclusion criteria required for KDM1A inhibitor clinical trials.	('KDM1A', 'Gene', (279, 284))	('SP-2509', 'Chemical', 'MESH:C000594309', (72, 79))	('drug resistance', 'Phenotype', 'HP:0020174', (205, 220))	('SP-2509', 'Var', (72, 79))	('KDM1A', 'Gene', '23028', (279, 284))	('patient', 'Species', '9606', (197, 204))
24148	28559816	We have treated 16 patients with soft-tissue sarcoma with pazopanib, and 2 of these patients (12.5%) experienced pneumothorax complications.	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (37, 52))	('sarcoma', 'Disease', (45, 52))	('pneumothorax', 'Disease', (113, 125))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('pazopanib', 'Chemical', 'MESH:C516667', (58, 67))	('pneumothorax', 'Phenotype', 'HP:0002107', (113, 125))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('pazopanib', 'Var', (58, 67))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (33, 52))
24180	28335496	The majority of latently infected KS spindle and PEL cells express a number of KSHV genes in the viral latency locus at the right end of the genome, including K12 Kaposin (T0.7 RNA), ORF71 (K13; vFLIP), ORF72 (vCyc) and ORF73, the latency-associated nuclear antigen (LANA).	('K12', 'Var', (159, 162))	('ORF71', 'Gene', (183, 188))	('ORF73', 'Gene', (220, 225))	('KSHV', 'Species', '37296', (79, 83))	('vFLIP', 'Gene', '4961494', (195, 200))	('LANA', 'Gene', (267, 271))	('ORF71', 'Gene', '4961494', (183, 188))	('LANA', 'Gene', '4961527', (267, 271))	('vFLIP', 'Gene', (195, 200))	('KSHV genes', 'Gene', (79, 89))	('ORF73', 'Gene', '4961527', (220, 225))	('K13', 'Gene', '4961494', (190, 193))	('ORF72', 'Gene', '4961471', (203, 208))	('ORF72', 'Gene', (203, 208))	('K13', 'Gene', (190, 193))
24214	28335496	Less than 2% of the Vero cells showed evidence of spontaneous reactivation with expression of ORF59 (Figure 1B, red).	('ORF59', 'Gene', '4961492', (94, 99))	('expression', 'Var', (80, 90))	('ORF59', 'Gene', (94, 99))
24247	28335496	These reads delineated the extent of the ORF6 mRNA transcript (Figure 4A; representative data from the LEC-K1 infection), extending from a putative transcription start signal (TSS) at bp 3132 to a transcription termination at bp 6974 (graphically visualized in Figure 4B).	('ORF6', 'Gene', (41, 45))	('ORF6', 'Gene', '4961521', (41, 45))	('bp 3132', 'Var', (184, 191))
24266	28335496	This analysis showed that the ORF6 transcript levels in the duplicate TIME-K2 and -K3 infections were quite similar with an average of 5367 TPM +- 9%, similar to that seen in the Vero infection (5313 TPM) (Figure 5D; Table S1).	('5367 TPM +-', 'Var', (135, 146))	('ORF6', 'Gene', '4961521', (30, 34))	('ORF6', 'Gene', (30, 34))
24291	28335496	In the endothelial infections, the primary transcripts from the ORF8 promoter (1397-1478 TPM) were more abundant than the primary transcripts from the promoters of ORF9 (766-844 TPM) and ORF10 (451-649 TPM) (Table 1; Figure 5D and Figure S2A-C).	('abundant', 'PosReg', (104, 112))	('ORF8', 'Gene', '4961501', (64, 68))	('ORF9', 'Gene', (164, 168))	('ORF9', 'Gene', '54097', (164, 168))	('1397-1478 TPM', 'Var', (79, 92))	('endothelial infections', 'Disease', (7, 29))	('ORF8', 'Gene', (64, 68))
24293	28335496	Similarly, for the ORF2 and ORFK2 locus, higher levels of reads mapped to the polyA-proximal ORFK2 compared to polyA-distal ORF2 in all cells (Table S1).	('ORFK2', 'Gene', (28, 33))	('polyA-proximal', 'Var', (78, 92))	('ORF2', 'Gene', '4961454', (19, 23))	('ORFK2', 'Gene', (93, 98))	('ORF2', 'Gene', (19, 23))	('higher', 'PosReg', (41, 47))	('ORF2', 'Gene', '4961454', (124, 128))	('ORF2', 'Gene', (124, 128))
24321	28335496	A low level of reads mapping to the ORF17 transcript was observed in all of the infected cells, ranging from 1276 to 2069 TPM) (Table S3).	('ORF17', 'Gene', '4961478', (36, 41))	('1276', 'Var', (109, 113))	('ORF17', 'Gene', (36, 41))
24324	28335496	Transcription from this locus has been extensively used to detect lytic replication, as ORF50 is the replication transactivator (RTA), considered to be the central regulator of the lytic replication cycle, ORFK8 (K-bZIP) is an early protein implicated in KSHV replication, and ORFK8.1 is a late lytic cycle enveloped glycoprotein on the infectious virion.	('ORF50', 'Gene', '4961526', (88, 93))	('replication transactivator', 'Gene', (101, 127))	('replication transactivator', 'Gene', '4961526', (101, 127))	('RTA', 'Gene', (129, 132))	('ORFK8.1', 'Gene', (277, 284))	('RTA', 'Gene', '4961526', (129, 132))	('ORF50', 'Gene', (88, 93))	('ORFK8', 'Var', (206, 211))	('KSHV', 'Species', '37296', (255, 259))
24325	28335496	Overlapping spliced transcripts are produced from promoters upstream of ORF50 (~71,627 bp), ORFK8 (~74,592 bp) and ORFK8.1 (~75,966 bp), which all terminate after a single poly(A) signal (76,813 bp) (Figure 8B; Table 2).	('ORF50', 'Gene', (72, 77))	('~71,627', 'Var', (79, 86))	('ORFK8', 'Gene', (92, 97))	('~74,592', 'Var', (99, 106))	('poly(A)', 'Chemical', 'MESH:D011061', (172, 179))	('ORF50', 'Gene', '4961526', (72, 77))	('ORFK8.1', 'Gene', (115, 122))
24334	28335496	Consistent low levels of reads mapped to both the ORF49 and ORF50 UCDS features in all five of the infected cell types, ranging from 884/1470 TPM in Vero cells to 1412/2477 TPM in TIME-K1 cells, for ORF49 and ORF50 respectively (Figure 8D and Figure S4; Tables S4 and S5).	('1412/2477 TPM', 'Var', (163, 176))	('ORF50', 'Gene', '4961526', (60, 65))	('ORF50', 'Gene', '4961526', (209, 214))	('ORF50', 'Gene', (60, 65))	('ORF49', 'Var', (199, 204))	('ORF50', 'Gene', (209, 214))	('ORF49', 'Gene', (50, 55))
24339	28335496	The remaining 45% of the transcripts mapped to ORF50 antisense transcripts.	('ORF50', 'Gene', (47, 52))	('ORF50', 'Gene', '4961526', (47, 52))	('antisense', 'Var', (53, 62))
24346	28335496	In contrast, no ORF50 spliced reads were detected in the latently infected BCBL-1 cells, which had only a low level of sense-strand ORF50 transcripts (1387 TPM).	('ORF50', 'Gene', '4961526', (132, 137))	('ORF50', 'Gene', '4961526', (16, 21))	('ORF50', 'Gene', (132, 137))	('ORF50', 'Gene', (16, 21))	('1387 TPM', 'Var', (151, 159))	('BCBL-1', 'CellLine', 'CVCL:0165', (75, 81))
24350	28335496	A moderate level of split reads identifying this transcript were found in the LEC-K1-3, BEC-K1-3 and TIME-K2, 3 infections (29-71 reads), but not in the TIME-K1, VERO or uninduced BCBL-1 infections (Figure 9D).	('BCBL-1 infections', 'Disease', (180, 197))	('BCBL-1 infections', 'Disease', 'MESH:D007239', (180, 197))	('rat', 'Species', '10116', (6, 9))	('LEC-K1-3', 'Var', (78, 86))
24354	28335496	RNA-seq analysis of the stranded libraries for BCBL-1, LEC-K1, BEC-K1 and TIME-K1 revealed only a low level of reads mapping antisense to ORF49 (58-112 TPM) providing minimal evidence for the unspliced transcript 50.2.	('BCBL-1', 'CellLine', 'CVCL:0165', (47, 53))	('ORF49', 'Gene', (138, 143))	('antisense', 'Var', (125, 134))
24369	28335496	While the adjacent ORF59/58 bicistronic transcript showed high levels of expression (20-28,000 TPM) in the infected endothelial cells (Figure 11A,D), the vIRF transcript levels were much lower ranging from 804 TPM (vIRF-2/K11) to 3514 TPM (vIRF-4/K10) (Figure 11D).	('vIRF-2', 'Gene', '4961491', (215, 221))	('vIRF-4', 'Gene', '4961495', (240, 246))	('vIRF-4', 'Gene', (240, 246))	('3514 TPM', 'Var', (230, 238))	('ORF59', 'Gene', (19, 24))	('expression', 'MPA', (73, 83))	('ORF59', 'Gene', '4961492', (19, 24))	('lower', 'NegReg', (187, 192))	('vIRF-2', 'Gene', (215, 221))
24372	28335496	Transcripts lacking intron "f" are generated by splicing the exon encoding the N-terminal DNA binding domain of K10 to a variant splice acceptor site 2 bp downstream of the major acceptor site within the major vIRF-4 exon (Figure 11B).	('vIRF-4', 'Gene', '4961495', (210, 216))	('vIRF-4', 'Gene', (210, 216))	('K10', 'Gene', (112, 115))	('rat', 'Species', '10116', (39, 42))	('splicing', 'Var', (48, 56))
24377	28335496	This transcript would encode the same vIRF-3/C-terminal cysteine-rich domain fusion protein as the previous transcript with a further deletion of 120 aa from the vIRF-3 ORF in the major exon, herein designated K10.7 (predicted sequence provided in Figure S6).	('vIRF-3', 'Gene', '4961493', (38, 44))	('encode', 'Reg', (22, 28))	('cysteine', 'Chemical', 'MESH:D003545', (56, 64))	('vIRF-3', 'Gene', (162, 168))	('vIRF-3', 'Gene', '4961493', (162, 168))	('deletion', 'Var', (134, 142))	('vIRF-3', 'Gene', (38, 44))
24382	28335496	In the vIRF-2 and vIRF-3 loci, the unspliced transcripts would encode only the putative DNA binding domains in the first exon (K11.1: 163 aa; K10.6: 152 aa), as a translation stop signal is present immediately after the unused splice donor site (sequence provided in Figure S6).	('binding', 'Interaction', (92, 99))	('vIRF-2', 'Gene', (7, 13))	('vIRF-3', 'Gene', (18, 24))	('vIRF-3', 'Gene', '4961493', (18, 24))	('vIRF-2', 'Gene', '4961491', (7, 13))	('K11.1: 163 aa; K10.6: 152 aa', 'Var', (127, 155))	('donor', 'Species', '9606', (234, 239))
24394	28335496	While no evidence for a transcript from the ORF58 promoter was observed in the infected endothelial or BCBL-1 cells, a low level of the ORF58 primary transcript was detected in Vero cells (794 TPM) (Figure 12D; Table S7).	('ORF58', 'Gene', '4961480', (44, 49))	('ORF58', 'Gene', (44, 49))	('BCBL-1', 'CellLine', 'CVCL:0165', (103, 109))	('ORF58', 'Gene', (136, 141))	('794', 'Var', (189, 192))	('ORF58', 'Gene', '4961480', (136, 141))
24399	28335496	The RNA reads mapping to the K12A, DR5 and DR6 UCDS features in all five cell types could be derived from the different transcripts encoding K12 Kaposin A, B and C (Figure 13C).	('DR5', 'Gene', (35, 38))	('DR6', 'Gene', '27242', (43, 46))	('DR5', 'Gene', '8795', (35, 38))	('K12A', 'Mutation', 'p.K12A', (29, 33))	('Kaposin A', 'Gene', (145, 154))	('DR6', 'Gene', (43, 46))	('K12', 'Var', (141, 144))
24401	28335496	The high level of reads mapping to K12A, DR5 and DR6 UCDS features are consistent with a high level of unspliced transcripts encoding either K12 Kaposin A (T0.7A) or variants of the DR5/6 repeats encoding Kaposin B/C (T1.5A) (Figure 13C).	('DR5', 'Gene', '8795', (41, 44))	('DR5/6', 'Gene', '8795;27242', (182, 187))	('K12A', 'Mutation', 'p.K12A', (35, 39))	('DR5', 'Gene', '8795', (182, 185))	('variants', 'Var', (166, 174))	('DR6', 'Gene', '27242', (49, 52))	('DR5', 'Gene', (182, 185))	('DR5', 'Gene', (41, 44))	('DR5/6', 'Gene', (182, 187))	('K12', 'Var', (141, 144))	('DR6', 'Gene', (49, 52))
24404	28335496	Previous studies indicated that ORF73 transcripts are tricistronic with ORF72 and ORF71 with a poly(A) termination site downstream of ORF71 (Figure 13C; transcripts: T5.2B, T5.4B, T5.5B, T5.7B).	('ORF72', 'Gene', '4961471', (72, 77))	('ORF73', 'Gene', '4961527', (32, 37))	('ORF71', 'Gene', (82, 87))	('ORF71', 'Gene', (134, 139))	('ORF71', 'Gene', '4961494', (82, 87))	('poly(A)', 'Chemical', 'MESH:D011061', (95, 102))	('ORF71', 'Gene', '4961494', (134, 139))	('T5.2B', 'Var', (166, 171))	('ORF73', 'Gene', (32, 37))	('T5.5B', 'Var', (180, 185))	('ORF72', 'Gene', (72, 77))	('T5.4B', 'Var', (173, 178))	('T5.7B', 'Var', (187, 192))
24415	28335496	However, moderate levels of transcripts were detected antisense to the DR1 repeat region, and ORFs K6, 29A, 29B, 50, 68, and 69 in the five latently infected cell lines (Table S6).	('DR1', 'Gene', '1810', (71, 74))	('rat', 'Species', '10116', (13, 16))	('DR1', 'Gene', (71, 74))	('antisense', 'Var', (54, 63))
24420	28335496	Similar levels of reads (901 and 1083 TPM, respectively) mapped antisense to ORF29A in the infected LEC and BEC cells (Table S6), indicating the presence of an additional transcript upstream and in the same orientation as ORF34 (see Figure 3).	('ORF34', 'Gene', (222, 227))	('ORF2', 'Gene', '4961454', (77, 81))	('ORF34', 'Gene', '54954', (222, 227))	('ORF2', 'Gene', (77, 81))	('antisense', 'Var', (64, 73))
24421	28335496	Moderate levels of reads in all five cell types were also detected antisense to ORFs 68/69 and ORFK6 (Table S6).	('ORFK6', 'Gene', (95, 100))	('antisense', 'Var', (67, 76))	('ORFs 68/69', 'Gene', (80, 90))	('rat', 'Species', '10116', (4, 7))
24425	28335496	Moderate levels of RNA reads from the stranded libraries mapped antisense to ORFK6 and ORFK5 in the infected LEC, BEC and BCBL cell types (Table S6), indicating the presence of the ORFK6AS transcript.	('rat', 'Species', '10116', (4, 7))	('ORFK5', 'Gene', (87, 92))	('ORFK6', 'Gene', (77, 82))	('antisense', 'Var', (64, 73))
24438	28335496	A set of primary transcripts with reads mapping to UCDS features for K4, K8.1, ORF59, K12A, PAN and DR5 in Group VII, and ORF6, K4.2A, K5, ORF17.5, K8, ORF52, ORF57, ORF61, ORF65, DR6, K12Aa, and ORF72 in Group VI were highly expressed in all of the latently infected endothelial cell cultures (Figure 16, shaded red).	('ORF17', 'Gene', '4961478', (139, 144))	('ORF6', 'Gene', '4961521', (166, 170))	('ORF72', 'Gene', '4961471', (196, 201))	('ORF6', 'Gene', (173, 177))	('ORF65', 'Gene', '4961451', (173, 178))	('ORF6', 'Gene', '4961521', (173, 177))	('ORF57', 'Gene', (159, 164))	('ORF59', 'Gene', (79, 84))	('ORF6', 'Gene', (122, 126))	('ORF17', 'Gene', (139, 144))	('DR5', 'Gene', '8795', (100, 103))	('K12A', 'Mutation', 'p.K12A', (86, 90))	('ORF59', 'Gene', '4961492', (79, 84))	('K4.2A', 'Var', (128, 133))	('ORF57', 'Gene', '4961525', (159, 164))	('K12A', 'Var', (86, 90))	('ORF65', 'Gene', (173, 178))	('ORF6', 'Gene', '4961521', (122, 126))	('K12Aa', 'Var', (185, 190))	('DR6', 'Gene', '27242', (180, 183))	('DR5', 'Gene', (100, 103))	('K4, K8.1', 'Gene', '3851;3887', (69, 77))	('DR6', 'Gene', (180, 183))	('ORF6', 'Gene', (166, 170))	('ORF72', 'Gene', (196, 201))	('K12A', 'Mutation', 'p.K12A', (185, 189))
24439	28335496	The most highly expressed transcript PAN, and transcripts for K4, K4.2A, and K5 are considered to be from lytic genes transcribed from the left end of the genome proximal to the long inverted repeat LIR1 (see Figure 3).	('LIR1', 'Gene', '10859', (199, 203))	('LIR1', 'Gene', (199, 203))	('K4.2A', 'Var', (66, 71))	('highly expressed', 'PosReg', (9, 25))
24440	28335496	The transcripts detected with UCDS features for K12A, DR5, DR6, ORF72 and K12Aa are transcribed from the latency locus proximal to the long inverted repeated LIR2 at the right end of the genome.	('K12A', 'Mutation', 'p.K12A', (48, 52))	('DR6', 'Gene', (59, 62))	('LIR2', 'Gene', (158, 162))	('K12Aa', 'Var', (74, 79))	('K12A', 'Var', (48, 52))	('ORF72', 'Gene', '4961471', (64, 69))	('ORF72', 'Gene', (64, 69))	('LIR2', 'Gene', '10288', (158, 162))	('DR5', 'Gene', (54, 57))	('K12A', 'Mutation', 'p.K12A', (74, 78))	('DR6', 'Gene', '27242', (59, 62))	('DR5', 'Gene', '8795', (54, 57))
24465	28335496	Interestingly, the expression of the spliced homologs of the viral interferon regulatory factor, vIRF-4 (K10), vIRF-3 (K10.5) and vIRF-2 (K11) and the Kaposin complex (K12A, DR5 and DR6) also correlated with the late virion and membrane-associated genes in Cluster 5 (Figure 17B).	('expression', 'MPA', (19, 29))	('K12A', 'Mutation', 'p.K12A', (168, 172))	('vIRF-3', 'Gene', (111, 117))	('vIRF-2', 'Gene', '4961491', (130, 136))	('vIRF-3', 'Gene', '4961493', (111, 117))	('vIRF-4', 'Gene', '4961495', (97, 103))	('DR6', 'Gene', '27242', (182, 185))	('K12A', 'Var', (168, 172))	('vIRF-4', 'Gene', (97, 103))	('correlated', 'Reg', (192, 202))	('DR6', 'Gene', (182, 185))	('vIRF-2', 'Gene', (130, 136))	('DR5', 'Gene', (174, 177))	('DR5', 'Gene', '8795', (174, 177))
24485	28335496	In cells undergoing long-term latency, such as BCBL-1 cells and the drug-selected LEC.219 and BEC.219 cell lines, the presence of ORF59 protein has been attributed to spontaneous reactivation of viral latency.	('ORF59', 'Gene', '4961492', (130, 135))	('presence', 'Var', (118, 126))	('viral latency', 'MPA', (195, 208))	('BEC.219', 'CellLine', 'CVCL:G580', (94, 101))	('ORF59', 'Gene', (130, 135))	('BCBL-1', 'CellLine', 'CVCL:0165', (47, 53))	('protein', 'Protein', (136, 143))
24496	28335496	Our studies confirmed the expression of a spliced transcript removing the C-terminus of the ORF57 transactivator and detected evidence for novel spliced transcripts of the viral interferon regulatory factors, K10, K10.5 and K11 in the different infected cells.	('ORF57', 'Gene', (92, 97))	('K10.5', 'Var', (214, 219))	('C-terminus', 'MPA', (74, 84))	('ORF57', 'Gene', '4961525', (92, 97))	('K11', 'Var', (224, 227))	('K10', 'Var', (209, 212))
24524	28335496	Although the majority of these transcripts appeared to be unspliced, produced from promoters upstream of K12 and DR5/DR6, moderate levels of spliced transcripts containing K12 and DR5/6 were produced from the ORF72 promoter.	('DR5/6', 'Gene', (180, 185))	('DR5', 'Gene', (180, 183))	('DR6', 'Gene', (117, 120))	('K12', 'Var', (105, 108))	('ORF72', 'Gene', '4961471', (209, 214))	('DR5', 'Gene', '8795', (180, 183))	('ORF72', 'Gene', (209, 214))	('DR5/6', 'Gene', '8795;27242', (180, 185))	('DR5', 'Gene', (113, 116))	('DR5', 'Gene', '8795', (113, 116))	('rat', 'Species', '10116', (126, 129))	('K12', 'Var', (172, 175))	('DR6', 'Gene', '27242', (117, 120))
24635	27589063	CD99 expression confirmed ex vivo cultures to be Ewing sarcoma using immunocytochemistry and flow cytometry with FITC-labeled anti-CD99 antibody (#561986, BD Biosciences, Franklin Lakes, NJ, USA) versus the isotype control antibody (#555573).	('CD99', 'Gene', '4267', (0, 4))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('CD99', 'Gene', (0, 4))	('FITC', 'Chemical', 'MESH:D016650', (113, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('CD99', 'Gene', '4267', (131, 135))	('#561986', 'Var', (146, 153))	('Ewing sarcoma', 'Disease', (49, 62))	('CD99', 'Gene', (131, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))
24666	27589063	Primary antibodies used were directed against CASP3 (#9662, Cell Signaling Technology, Danvers, MN, USA), PARP1 (#9542, Cell Signaling Technology), CLSPN (#2800, Cell Signaling Technology), BIRC5 (#2803, Cell Signaling Technology), TP53 (sc-73566, Santa Cruz Biotechnology, Santa Cruz, CA, USA), PMAIP1 (sc-56169, Santa Cruz Biotechnology) and MCL1 (sc-819, Santa Cruz Biotechnology), XIAP (#610716, BD Biosciences) and ss-actin (#A3854, Sigma-Aldrich).	('MCL1', 'Gene', (344, 348))	('MCL1', 'Gene', '4170', (344, 348))	('CLSPN', 'Gene', '63967', (148, 153))	('PMAIP1', 'Gene', '5366', (296, 302))	('XIAP', 'Gene', (385, 389))	('BIRC5', 'Gene', '332', (190, 195))	('MN', 'CellLine', 'CVCL:U508', (96, 98))	('#610716', 'Var', (391, 398))	('XIAP', 'Gene', '331', (385, 389))	('BIRC5', 'Gene', (190, 195))	('CLSPN', 'Gene', (148, 153))	('CASP3', 'Gene', '836', (46, 51))	('CASP3', 'Gene', (46, 51))	('TP53', 'Gene', '7157', (232, 236))	('PARP1', 'Gene', '142', (106, 111))	('TP53', 'Gene', (232, 236))	('PMAIP1', 'Gene', (296, 302))	('PARP1', 'Gene', (106, 111))
24691	27589063	Z-VAD-FMK efficiently decreased apoptotic induction by up to 70% in cells treated with viscumTT or viscum and 30% in cells treated with TT (Fig 3B and S1 Table), validating the essential role of caspases in viscumTT- and viscum-induced apoptosis.	('Z-VAD-FMK', 'Var', (0, 9))	('caspases', 'Gene', '841;842', (195, 203))	('TT', 'Chemical', '-', (93, 95))	('caspases', 'Gene', (195, 203))	('TT', 'Chemical', '-', (136, 138))	('TT', 'Chemical', '-', (213, 215))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (0, 9))	('decreased', 'NegReg', (22, 31))	('apoptotic', 'CPA', (32, 41))
24746	27589063	Mistletoe extracts also suppressed TP53 expression in Ewing sarcoma cell lines, but this effect is less meaningful since TC-71 expresses an inactive TP53 mutant protein and MHH-ES-1 harbors an in-frame deletion of Ser215 in the TP53 transactivation domain.	('TC-71', 'Chemical', '-', (121, 126))	('protein', 'Protein', (161, 168))	('Ser215', 'Var', (214, 220))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (54, 67))	('TP53', 'Gene', '7157', (149, 153))	('TP53', 'Gene', '7157', (35, 39))	('suppressed', 'NegReg', (24, 34))	('TP53', 'Gene', (35, 39))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (54, 67))	('ES-1', 'CellLine', 'CVCL:1198', (177, 181))	('TP53', 'Gene', (149, 153))	('TP53', 'Gene', '7157', (228, 232))	('TP53', 'Gene', (228, 232))	('Ser215', 'Chemical', '-', (214, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('Ewing sarcoma', 'Disease', (54, 67))	('mutant', 'Var', (154, 160))
24777	32415267	PLEUROPULMONARY BLASTOMA-LIKE PERITONEAL SARCOMA Since the original description of pathogenic germline DICER1 variation underlying PPB, the spectrum of extrapulmonary neoplasms known to be associated with DICER1 has continued to expand and now includes tumors of the ovary, thyroid, kidney, eye and brain among other sites.	('SARCOMA', 'Phenotype', 'HP:0100242', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('variation', 'Var', (110, 119))	('DICER1', 'Gene', (205, 211))	('neoplasms', 'Disease', (167, 176))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('tumors of the ovary', 'Phenotype', 'HP:0100615', (253, 272))	('tumors of the ovary', 'Disease', 'MESH:D010051', (253, 272))	('PPB', 'Disease', (131, 134))	('tumors of the ovary', 'Disease', (253, 272))	('neoplasms', 'Phenotype', 'HP:0002664', (167, 176))	('DICER1', 'Gene', '23405', (103, 109))	('PLEUROPULMONARY BLASTOMA', 'Phenotype', 'HP:0100528', (0, 24))	('neoplasm', 'Phenotype', 'HP:0002664', (167, 175))	('PPB', 'Phenotype', 'HP:0100528', (131, 134))	('DICER1', 'Gene', (103, 109))	('extrapulmonary neoplasms', 'Phenotype', 'HP:0032271', (152, 176))	('DICER1', 'Gene', '23405', (205, 211))	('neoplasms', 'Disease', 'MESH:D009369', (167, 176))
24782	32415267	All had a pathogenic DICER1 variation identified in germline and/or tumor DNA.	('tumor', 'Disease', (68, 73))	('DICER1', 'Gene', (21, 27))	('pathogenic', 'Reg', (10, 20))	('DICER1', 'Gene', '23405', (21, 27))	('variation', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
24783	32415267	PPB-like peritoneal tumors represent a newly described manifestation of DICER1 pathogenic variation whose pathologic features are also recapitulated in DICER1-related renal sarcoma, cervical embryonal rhabdomyosarcoma, and some Sertoli-Leydig cell tumors with heterologous elements.	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (228, 254))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (228, 254))	('PPB-like', 'Disease', (0, 8))	('PPB', 'Phenotype', 'HP:0100528', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (191, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (201, 217))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('renal sarcoma', 'Phenotype', 'HP:0008663', (167, 180))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (236, 254))	('embryonal rhabdomyosarcoma', 'Disease', (191, 217))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (236, 253))	('DICER1', 'Gene', '23405', (72, 78))	('variation', 'Var', (90, 99))	('DICER1', 'Gene', '23405', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('Sertoli-Leydig cell tumors', 'Disease', (228, 254))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (228, 253))	('renal sarcoma', 'Disease', (167, 180))	('DICER1', 'Gene', (72, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('DICER1', 'Gene', (152, 158))	('peritoneal tumors', 'Disease', (9, 26))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (191, 217))	('renal sarcoma', 'Disease', 'MESH:D007674', (167, 180))	('peritoneal tumors', 'Disease', 'MESH:D010534', (9, 26))
24786	32415267	Since the initial recognition of the connection between pleuropulmonary blastoma (PPB) and DICER1 in 2009, this neoplasm has been a pathognomonic manifestation of DICER1 mutations.	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (56, 80))	('pleuropulmonary blastoma', 'Disease', (56, 80))	('mutations', 'Var', (170, 179))	('PPB', 'Phenotype', 'HP:0100528', (82, 85))	('DICER1', 'Gene', (163, 169))	('DICER1', 'Gene', '23405', (163, 169))	('DICER1', 'Gene', (91, 97))	('neoplasm', 'Disease', (112, 120))	('neoplasm', 'Phenotype', 'HP:0002664', (112, 120))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (56, 80))	('DICER1', 'Gene', '23405', (91, 97))	('neoplasm', 'Disease', 'MESH:D009369', (112, 120))
24789	32415267	It is now appreciated that not all lung cysts in an individual with germline DICER1 variants progress.	('lung cyst', 'Phenotype', 'HP:0032445', (35, 44))	('lung cysts', 'Disease', (35, 45))	('DICER1', 'Gene', (77, 83))	('variants', 'Var', (84, 92))	('DICER1', 'Gene', '23405', (77, 83))	('lung cysts', 'Phenotype', 'HP:0032445', (35, 45))
24792	32415267	In addition, a case of intra-abdominal sarcoma with DICER1 mutation was recently reported.	('DICER1', 'Gene', (52, 58))	('intra-abdominal sarcoma', 'Disease', 'MESH:D059413', (23, 46))	('intra-abdominal sarcoma', 'Disease', (23, 46))	('DICER1', 'Gene', '23405', (52, 58))	('mutation', 'Var', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))
24794	32415267	Previous work has shown that identification of germline pathogenic variants or mosaicism may result in earlier identification of DICER1-related cancers.	('DICER1', 'Gene', '23405', (129, 135))	('mosaicism', 'Var', (79, 88))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('DICER1', 'Gene', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (144, 151))
24796	32415267	All had germline and/or tumor DICER1 mutations, a finding with relevance for the individual and family members.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('mutations', 'Var', (37, 46))	('DICER1', 'Gene', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('DICER1', 'Gene', '23405', (30, 36))
24803	32415267	DICER1 gene sequencing was performed on blood and/or saliva and tumor tissue using either Sanger sequencing or a next generation sequencing assay designed to detect base substitutions and small insertions/deletions in both coding and intron/exon flanking regions.	('DICER1', 'Gene', (0, 6))	('DICER1', 'Gene', '23405', (0, 6))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('base substitutions', 'Var', (165, 183))	('insertions/deletions', 'Var', (194, 214))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
24807	32415267	All six tumors with available DNA showed biallelic loss of function and RNase IIIb DICER1 mutations.	('mutations', 'Var', (90, 99))	('DICER1', 'Gene', (83, 89))	('DICER1', 'Gene', '23405', (83, 89))	('loss of function', 'NegReg', (51, 67))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
24808	32415267	Four of five individuals tested had germline DICER1 mutations.	('mutations', 'Var', (52, 61))	('DICER1', 'Gene', (45, 51))	('DICER1', 'Gene', '23405', (45, 51))
24815	32415267	A 13-year-old girl with history of Type II PPB at age 5, thyroid carcinoma at age 8, nasal chondromesenchymal hamartoma at age 13 and known germline DICER1 pathogenic variation presented with lower abdominal pain.	('abdominal pain', 'Disease', 'MESH:D015746', (198, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('hamartoma', 'Disease', (110, 119))	('pain', 'Phenotype', 'HP:0012531', (208, 212))	('Type II PPB', 'Disease', (35, 46))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (57, 74))	('PPB', 'Phenotype', 'HP:0100528', (43, 46))	('DICER1', 'Gene', (149, 155))	('DICER1', 'Gene', '23405', (149, 155))	('hamartoma', 'Phenotype', 'HP:0010566', (110, 119))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (57, 74))	('abdominal pain', 'Phenotype', 'HP:0002027', (198, 212))	('hamartoma', 'Disease', 'MESH:D006222', (110, 119))	('thyroid carcinoma', 'Disease', (57, 74))	('abdominal pain', 'Disease', (198, 212))	('girl', 'Species', '9606', (14, 18))	('variation', 'Var', (167, 176))	('Type II PPB', 'Disease', 'MESH:C537516', (35, 46))
24824	32415267	Further testing of the tumor tissue confirmed biallelic pathogenic mutations in DICER1.	('biallelic', 'Var', (46, 55))	('DICER1', 'Gene', (80, 86))	('DICER1', 'Gene', '23405', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))
24844	32415267	Biallelic loss of function and RNase IIIb (hotspot) mutations were identified in the tumor tissue.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', (85, 90))	('loss of function', 'NegReg', (10, 26))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('RNase IIIb', 'Protein', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
24854	32415267	Identification of DICER1 pathogenic variation impacts clinical care and individual and family surveillance.	('impacts', 'Reg', (46, 53))	('DICER1', 'Gene', (18, 24))	('DICER1', 'Gene', '23405', (18, 24))	('pathogenic', 'Reg', (25, 35))	('variation', 'Var', (36, 45))
24855	32415267	PPB-like peritoneal sarcoma is the latest recognized manifestation of DICER1 pathogenic variation.	('sarcoma', 'Disease', (20, 27))	('DICER1', 'Gene', (70, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('DICER1', 'Gene', '23405', (70, 76))	('PPB', 'Phenotype', 'HP:0100528', (0, 3))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('variation', 'Var', (88, 97))
24865	32415267	Adenosarcoma and the extrauterine DICER1 peritoneal sarcoma share in common not only pathologic features but pathogenic hotspot DICER1 mutations.	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('sarcoma', 'Disease', (52, 59))	('Adenosarcoma', 'Disease', 'MESH:D018195', (0, 12))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('DICER1', 'Gene', (128, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('mutations', 'Var', (135, 144))	('DICER1', 'Gene', '23405', (128, 134))	('sarcoma', 'Disease', (5, 12))	('Adenosarcoma', 'Disease', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('DICER1', 'Gene', (34, 40))	('DICER1', 'Gene', '23405', (34, 40))
24869	32415267	Importantly, this tumor description, reflecting uncommon sites of origin, also broadens the differential diagnosis for an individual with a predisposing DICER1 variant who presents with a pelvic mass.	('pelvic mass', 'Disease', (188, 199))	('variant', 'Var', (160, 167))	('tumor', 'Disease', (18, 23))	('pelvic mass', 'Phenotype', 'HP:0031501', (188, 199))	('DICER1', 'Gene', (153, 159))	('DICER1', 'Gene', '23405', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
24870	32415267	Although Sertoli-Leydig cell tumor or gynandroblastoma are more common manifestations of an underlying DICER1 mutation, a mass arising from the Fallopian tube or elsewhere in the peritoneum cannot be assumed to be primary ovarian or metastatic disease.	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (9, 34))	('DICER1', 'Gene', (103, 109))	('ovarian or metastatic disease', 'Disease', (222, 251))	('DICER1', 'Gene', '23405', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('gynandroblastoma', 'Disease', (38, 54))	('mutation', 'Var', (110, 118))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (17, 34))	('Sertoli-Leydig cell tumor', 'Disease', (9, 34))	('gynandroblastoma', 'Disease', 'MESH:D018312', (38, 54))	('ovarian or metastatic disease', 'Disease', 'MESH:D010049', (222, 251))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (9, 34))
24871	32415267	Likewise, some Fallopian tube cysts may represent a regressed tumor analogous to thoracic type Ir PPB, and their presence may be a clue to an underlying DICER1 mutation.	('Fallopian tube cysts', 'Phenotype', 'HP:0012883', (15, 35))	('mutation', 'Var', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PPB', 'Phenotype', 'HP:0100528', (98, 101))	('tumor', 'Disease', (62, 67))	('DICER1', 'Gene', (153, 159))	('DICER1', 'Gene', '23405', (153, 159))	('Fallopian tube cysts', 'Disease', 'MESH:D005184', (15, 35))	('Fallopian tube cysts', 'Disease', (15, 35))	('tube cysts', 'Phenotype', 'HP:0200040', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
24874	32415267	Fortunately, in situations where the clinical picture is difficult to elucidate, for example when a new pelvic mass is identified in a young woman with an underlying DICER1 mutation and a remote history of ovarian neoplasm, genetic testing of the tumor samples, in particular sequencing of the "second hit" in the RNase IIIb domain, will generally differentiate between recurrent and metachronous disease.	('ovarian neoplasm', 'Disease', 'MESH:D010051', (206, 222))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('ovarian neoplasm', 'Disease', (206, 222))	('tumor', 'Disease', (247, 252))	('metachronous disease', 'Disease', (384, 404))	('differentiate', 'Reg', (348, 361))	('DICER1', 'Gene', (166, 172))	('ovarian neoplasm', 'Phenotype', 'HP:0100615', (206, 222))	('metachronous disease', 'Disease', 'MESH:D016609', (384, 404))	('DICER1', 'Gene', '23405', (166, 172))	('neoplasm', 'Phenotype', 'HP:0002664', (214, 222))	('pelvic mass', 'Phenotype', 'HP:0031501', (104, 115))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('woman', 'Species', '9606', (141, 146))	('mutation', 'Var', (173, 181))
24875	32415267	It should be noted, however, that in the rare instance of a predisposing mutation in the RNase IIIb domain, the loss of function mutation would instead vary between different tumors.	('mutation in', 'Var', (73, 84))	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('RNase IIIb', 'Protein', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
24876	32415267	If a germline DICER1 mutation is identified, individual surveillance strategies and family testing are available to maximize the chance to find additional tumors in their earliest and most curable form.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('DICER1', 'Gene', (14, 20))	('DICER1', 'Gene', '23405', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('mutation', 'Var', (21, 29))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))
24879	30777875	Alisertib (MLN8237) is a potent and selective AAK inhibitor.	('MLN8237', 'Chemical', 'MESH:C550258', (11, 18))	('MLN8237', 'Var', (11, 18))	('AAK', 'Enzyme', (46, 49))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))
24883	30777875	Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed.	('AURK gene', 'Gene', (57, 66))	('UGT1A1', 'Gene', (98, 104))	('polymorphisms', 'Var', (36, 49))	('UGT1A1', 'Gene', '54658', (98, 104))
24894	30777875	The Aurora A kinase gene (AURK) has 2 two common polymorphisms; the phe31Ile polymorphism, which alters the kinase function and is associated with tumorigenesis or advanced cancers; and the Va571Ile polymorphism that in combination with phe31IIe may be associated with an increased risk of cancer or treatment related adverse events.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('Va571Ile', 'Var', (190, 198))	('phe31IIe', 'Chemical', '-', (237, 245))	('tumor', 'Disease', (147, 152))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('kinase function', 'MPA', (108, 123))	('Aurora A', 'Gene', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('phe31Ile', 'Chemical', '-', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('associated', 'Reg', (253, 263))	('cancer', 'Disease', (173, 179))	('cancers', 'Disease', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('alters', 'Reg', (97, 103))	('Aurora A', 'Gene', '6790', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cancer', 'Disease', (290, 296))	('associated with', 'Reg', (131, 146))	('phe31Ile', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
24895	30777875	Alisertib (MLN8237) is a potent and selective AAK inhibitor previously investigated alone and in combination with chemotherapy as a potential treatment for patients with relapsed/refractory peripheral T-cell lymphoma as well as advanced solid tumors.	('patients', 'Species', '9606', (156, 164))	('refractory peripheral T-cell lymphoma', 'Disease', (179, 216))	('lymphoma', 'Phenotype', 'HP:0002665', (208, 216))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('cell lymphoma', 'Phenotype', 'HP:0012191', (203, 216))	('refractory peripheral T-cell lymphoma', 'Disease', 'MESH:D016411', (179, 216))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))	('solid tumors', 'Disease', (237, 249))	('MLN8237', 'Chemical', 'MESH:C550258', (11, 18))	('MLN8237', 'Var', (11, 18))	('AAK', 'Enzyme', (46, 49))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (201, 216))	('solid tumors', 'Disease', 'MESH:D009369', (237, 249))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
24899	30777875	Although the major metabolic pathway of alisertib is glucuronidation via the UDP-glucuronosyltransferase, UGT1A1, alisertib CL/F was not altered in adult subjects with UGT1A1*28 polymorphisms.	('UGT1A1', 'Gene', '54658', (106, 112))	('UGT1A1', 'Gene', '54658', (168, 174))	('UGT1A1', 'Gene', (106, 112))	('F', 'Chemical', 'MESH:D005461', (127, 128))	('UGT1A1', 'Gene', (168, 174))	('alisertib', 'Chemical', 'MESH:C550258', (114, 123))	('polymorphisms', 'Var', (178, 191))	('glucuronidation', 'MPA', (53, 68))	('alisertib', 'Chemical', 'MESH:C550258', (40, 49))
24904	30777875	In addition, alisertib was active in p53-wildtype, therapy-refractory NBL cell lines, as a result of disruption of the Aurora-A/N-Myc complex resulting in inhibition of N-Myc dependent transcription.	('N-Myc', 'Gene', (169, 174))	('Aurora-A', 'Gene', '6790', (119, 127))	('N-Myc', 'Gene', (128, 133))	('inhibition', 'NegReg', (155, 165))	('Aurora-A', 'Gene', (119, 127))	('disruption', 'Var', (101, 111))	('N-Myc', 'Gene', '4613', (128, 133))	('N-Myc', 'Gene', '4613', (169, 174))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('alisertib', 'Chemical', 'MESH:C550258', (13, 22))
24905	30777875	Alisertib has also been shown to induce cell death and augment radiation sensitivity in atypical teratoid rhabdoid (ATRT) cell lines that overexpress AAK and have mutations in SMARCB1 (SNF5/INI1), a tumor suppressor and component of chromatin remodeling.	('tumor', 'Disease', (199, 204))	('SNF5/INI1', 'Gene', (185, 194))	('SMARCB1', 'Gene', '6598', (176, 183))	('mutations', 'Var', (163, 172))	('SMARCB1', 'Gene', (176, 183))	('SNF5/INI1', 'Gene', '6598', (185, 194))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))	('augment', 'PosReg', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('death', 'Disease', 'MESH:D003643', (45, 50))	('death', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('radiation sensitivity', 'CPA', (63, 84))	('induce', 'PosReg', (33, 39))
24944	30777875	Consenting patients provided whole blood in EDTA tubes prior to day 7 of the first cycle for genotyping of patients for germline polymorphisms in UGT1A1 or aurora AAK gene (AURK, Phe31Ile and Val57Ile).	('polymorphisms', 'Var', (129, 142))	('Val57Ile', 'Var', (192, 200))	('Phe31Ile', 'Var', (179, 187))	('Val57Ile', 'Mutation', 'rs1047972', (192, 200))	('EDTA', 'Chemical', 'MESH:D004492', (44, 48))	('UGT1A1', 'Gene', '54658', (146, 152))	('patients', 'Species', '9606', (11, 19))	('UGT1A1', 'Gene', (146, 152))	('patients', 'Species', '9606', (107, 115))	('Phe31Ile', 'SUBSTITUTION', 'None', (179, 187))	('AURK', 'Var', (173, 177))
24945	30777875	For UGT1A1 *28 (rs8175347), the number of TA repeats in the promoter region were detected and quantified by a modification of the method described by Akaba et al.	('UGT1A1', 'Gene', '54658', (4, 10))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('UGT1A1', 'Gene', (4, 10))	('rs8175347', 'Mutation', 'rs8175347', (16, 25))	('rs8175347', 'Var', (16, 25))
24946	30777875	UGT1A1 polymorphisms rs4124874 and rs10929302 were evaluated with PCR amplification and dye-terminator sequencing.	('rs4124874', 'Var', (21, 30))	('rs4124874', 'Mutation', 'rs4124874', (21, 30))	('UGT1A1', 'Gene', '54658', (0, 6))	('CR', 'Chemical', '-', (67, 69))	('UGT1A1', 'Gene', (0, 6))	('rs10929302', 'Var', (35, 45))	('rs10929302', 'Mutation', 'rs10929302', (35, 45))
24948	30777875	For AURKA, genotyping for the G>A polymorphism (rs1047972 in codon 57) and T>A polymorphism (rs2273535 in codon 31) was performed by amplification and detected on a Bio-Rad CFX384 Real-Time PCR detection system (Hercules CA).	('rs1047972', 'Var', (48, 57))	('rs2273535', 'Mutation', 'rs2273535', (93, 102))	('AURKA', 'Gene', (4, 9))	('rs1047972', 'Mutation', 'rs1047972', (48, 57))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('F', 'Chemical', 'MESH:D005461', (174, 175))	('CR', 'Chemical', '-', (191, 193))	('rs2273535', 'Var', (93, 102))	('AURKA', 'Gene', '6790', (4, 9))
24952	30777875	The AURKA haplotypes were determined using the Phe31Ile and val57Ile SNPs as described by Ishikawa et al.	('AURKA', 'Gene', (4, 9))	('Phe31Ile', 'Var', (47, 55))	('val57Ile', 'SUBSTITUTION', 'None', (60, 68))	('val57Ile', 'Var', (60, 68))	('Phe31Ile', 'SUBSTITUTION', 'None', (47, 55))	('AURKA', 'Gene', '6790', (4, 9))
24999	30777875	A total of 87 patients underwent genotyping for AURKA and UGT1A1 (Table 4A).	('UGT1A1', 'Gene', '54658', (58, 64))	('AURKA', 'Gene', (48, 53))	('UGT1A1', 'Gene', (58, 64))	('patients', 'Species', '9606', (14, 22))	('genotyping', 'Var', (33, 43))	('AURKA', 'Gene', '6790', (48, 53))
25000	30777875	There was no relationship between cycle 1 toxicity and either the Phe31Ile or Val57Ile single nucleotide polymorphisms (SNP) in the AURKA genotype or in the AURKA haplotypes (Table 4B).	('Phe31Ile', 'SUBSTITUTION', 'None', (66, 74))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('AURKA', 'Gene', '6790', (132, 137))	('Val57Ile', 'Mutation', 'rs1047972', (78, 86))	('Phe31Ile', 'Var', (66, 74))	('toxicity', 'Disease', (42, 50))	('AURKA', 'Gene', '6790', (157, 162))	('AURKA', 'Gene', (132, 137))	('Val57Ile single nucleotide polymorphisms', 'Var', (78, 118))	('AURKA', 'Gene', (157, 162))
25001	30777875	There was no relationship between >= grade 2 toxicities and AURKA genotype for the Ile31Phe SNP or the AURKA haplotypes.	('toxicities', 'Disease', (45, 55))	('AURKA', 'Gene', (103, 108))	('Ile31Phe', 'Mutation', 'rs2273535', (83, 91))	('AURKA', 'Gene', '6790', (103, 108))	('AURKA', 'Gene', '6790', (60, 65))	('toxicities', 'Disease', 'MESH:D064420', (45, 55))	('Ile31Phe', 'Var', (83, 91))	('AURKA', 'Gene', (60, 65))
25002	30777875	However, patients that were heterozygous (WV) for the Val57Ile SNP appeared to have fewer >= grade 2 toxicities (Table 4B).	('patients', 'Species', '9606', (9, 17))	('Val57Ile', 'Var', (54, 62))	('Val57Ile', 'Mutation', 'rs1047972', (54, 62))	('toxicities', 'Disease', (101, 111))	('fewer', 'NegReg', (84, 89))	('toxicities', 'Disease', 'MESH:D064420', (101, 111))
25009	30777875	While alisertib trough concentrations were statistically significantly higher for IM/PM patients, there did not appear to be a relationship with the occurrence of >= grade 2 toxicity (p-value = 0.86).	('higher', 'PosReg', (71, 77))	('IM/PM', 'Var', (82, 87))	('alisertib', 'MPA', (6, 15))	('toxicity', 'Disease', (174, 182))	('patients', 'Species', '9606', (88, 96))	('alisertib', 'Chemical', 'MESH:C550258', (6, 15))	('trough concentrations', 'MPA', (16, 37))	('toxicity', 'Disease', 'MESH:D064420', (174, 182))
25022	30777875	The higher alisertib trough concentration in patients with intermediate and poor metabolizer UGT1A1 phenotypes compared to the extensive metabolizer phenotype was statistically significant.	('alisertib', 'Chemical', 'MESH:C550258', (11, 20))	('poor', 'NegReg', (76, 80))	('intermediate', 'Var', (59, 71))	('UGT1A1', 'Gene', '54658', (93, 99))	('higher', 'PosReg', (4, 10))	('patients', 'Species', '9606', (45, 53))	('phenotypes', 'Var', (100, 110))	('alisertib trough concentration', 'MPA', (11, 41))	('UGT1A1', 'Gene', (93, 99))
25025	30777875	Pharmacogenomic profiling of germline AURKA in adults has focused on cancer susceptibility and early adverse reactions.	('AURKA', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('AURKA', 'Gene', '6790', (38, 43))	('germline', 'Var', (29, 37))	('cancer', 'Disease', (69, 75))
25048	30777875	Aurora A dysregulation has been implicated in cancer, and as such, is a rational therapeutic target.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('Aurora A', 'Gene', '6790', (0, 8))	('cancer', 'Disease', (46, 52))	('implicated', 'Reg', (32, 42))	('Aurora A', 'Gene', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('dysregulation', 'Var', (9, 22))
25049	30777875	This phase 2 study of alisertib (MLN2837), an oral small molecular inhibitor of Aurora A kinase, was evaluated in 137 pediatric patients with relapsed/refractory solid tumors or acute leukemia.	('acute leukemia', 'Disease', 'MESH:D015470', (178, 192))	('acute leukemia', 'Disease', (178, 192))	('Aurora A', 'Gene', (80, 88))	('solid tumors', 'Disease', 'MESH:D009369', (162, 174))	('MLN2837', 'Var', (33, 40))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('Aurora A', 'Gene', '6790', (80, 88))	('solid tumors', 'Disease', (162, 174))	('alisertib', 'Chemical', 'MESH:C550258', (22, 31))	('MLN2837', 'Chemical', '-', (33, 40))	('acute leukemia', 'Phenotype', 'HP:0002488', (178, 192))	('patients', 'Species', '9606', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
25062	30382078	These pathways govern metabolic processes, including autophagy, and their disruption shifts metabolism toward cancer cell-associated glycolysis and hyper-proliferation.	('govern', 'Reg', (15, 21))	('hyper-proliferation', 'Disease', (148, 167))	('cancer', 'Disease', (110, 116))	('metabolic processes', 'CPA', (22, 41))	('disruption', 'Var', (74, 84))	('metabolism', 'MPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('autophagy', 'CPA', (53, 62))	('shifts', 'Reg', (85, 91))	('hyper-proliferation', 'Disease', 'MESH:C565054', (148, 167))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
25064	30382078	These findings support the use of epigenetic modulators to treat human UPS.	('human', 'Species', '9606', (65, 70))	('human UPS', 'Disease', (65, 74))	('epigenetic modulators', 'Var', (34, 55))
25070	30382078	YAP1 is unusually stable in UPS and potentially other sarcomas due to epigenetic silencing of its inhibitor, Angiomotin (AMOT), and Hippo kinase copy number loss.	('YAP1', 'Gene', (0, 4))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('epigenetic silencing', 'Var', (70, 90))	('Hippo', 'Protein', (132, 137))	('sarcomas', 'Disease', (54, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('copy number', 'Var', (145, 156))	('AMOT', 'Gene', '154796', (121, 125))	('loss', 'NegReg', (157, 161))	('AMOT', 'Gene', (121, 125))	('Angiomotin', 'Gene', '154796', (109, 119))	('Angiomotin', 'Gene', (109, 119))
25078	30382078	Here we report that inhibition of YAP1 and/or NF-kappaB recapitulates several key aspects of SAHA/JQ1-mediated differentiation.	('inhibition', 'Var', (20, 30))	('YAP1', 'Protein', (34, 38))	('NF-kappaB', 'Protein', (46, 55))	('SAHA', 'Chemical', '-', (93, 97))
25080	30382078	Importantly, a growing body of literature suggests that disruption of circadian oscillation promotes tumorigenesis in a variety of cancer settings.	('cancer', 'Disease', (131, 137))	('circadian oscillation', 'MPA', (70, 91))	('promotes', 'PosReg', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('disruption', 'Var', (56, 66))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
25104	30382078	Drugs were refreshed for any cells treated for longer than 48 h. shRNA-mediated knockdown of Per1: TRCN0000075403; Arntl: TRCN0000095055; Txnip: TRCN0000182360; Ddit3: TRCN0000103709; RelA: TRCN0000055344, TRCN0000055346; and Yap1: TRCN0000095864, TRCN0000095865 were obtained as glycerol stocks from Dharmacon.	('Arntl', 'Gene', (115, 120))	('glycerol', 'Chemical', 'MESH:D005990', (280, 288))	('stocks', 'Species', '3724', (289, 295))	('TRCN0000095865', 'Var', (248, 262))	('Arntl', 'Gene', '406', (115, 120))	('RelA', 'Gene', (184, 188))	('RelA', 'Gene', '5970', (184, 188))
25113	30382078	Cells were transfected using the Addgene plasmids ATF4 5: 5'ATF4:GFP (#21852) and pEGFP-ATF6 (#32955).	('ATF4', 'Gene', (50, 54))	('#32955', 'Var', (94, 100))	('ATF4', 'Gene', (60, 64))	('ATF4', 'Gene', '468', (50, 54))	('pEGFP-ATF6', 'Gene', (82, 92))	('ATF4', 'Gene', '468', (60, 64))	('pEGFP-ATF6', 'Gene', '22926', (82, 92))	('#21852', 'Var', (70, 76))
25149	30382078	Adenovirus expressing Cre recombinase injected into the gastrocnemius muscle activates oncogenic Kras expression and deletes p53 in muscle progenitor cells, resulting in tumors that recapitulate human UPS.	('human', 'Species', '9606', (195, 200))	('expression', 'MPA', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('p53', 'Gene', (125, 128))	('deletes', 'Var', (117, 124))	('p53', 'Gene', '7157', (125, 128))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('oncogenic', 'MPA', (87, 96))	('activates', 'PosReg', (77, 86))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (170, 176))	('Kras', 'Gene', (97, 101))	('Kras', 'Gene', '3845', (97, 101))
25157	30382078	Therefore, we hypothesized that loss of clock gene expression results in de-differentiation and sarcomagenesis.	('de-differentiation', 'CPA', (73, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('clock gene expression', 'Gene', (40, 61))	('results', 'Reg', (62, 69))	('loss', 'Var', (32, 36))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('sarcoma', 'Disease', (96, 103))
25160	30382078	We investigated the relationship between long-term survival and clock gene expression and found that low levels of CRY2 are associated with poor survival (Fig.	('low levels', 'Var', (101, 111))	('CRY2', 'Gene', (115, 119))	('CRY2', 'Gene', '1408', (115, 119))	('poor survival', 'CPA', (140, 153))
25170	30382078	To determine whether YAP1 inhibition activates clock function we performed a Bmal luciferase reporter assay in KP cells using Yap1-specific siRNA, shRNA, and SAHA/JQ1.	('inhibition', 'Var', (26, 36))	('Yap1-specific', 'Gene', (126, 139))	('SAHA', 'Chemical', '-', (158, 162))
25174	30382078	We bred Relafl/fl mice into our KP model and found that genetic deletion of NF-kappaB, encoded by the Rela gene, prevents outgrowth of tumors (Fig.	('NF-kappaB', 'Gene', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('prevents', 'NegReg', (113, 121))	('deletion', 'Var', (64, 72))	('mice', 'Species', '10090', (18, 22))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
25176	30382078	Both KP tumors and subcutaneous xenografts of human UPS cells stain positively for YAP1 and phospho-p65 (Fig.	('KP tumors', 'Disease', 'MESH:D009369', (5, 14))	('YAP1', 'Gene', (83, 87))	('KP tumors', 'Disease', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('human', 'Species', '9606', (46, 51))	('phospho-p65', 'Var', (92, 103))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
25182	30382078	Slower proliferation rates (KP > HT-1080 > STS-109) correlate with shorter time to maximal USP31 induction by SAHA/JQ1.	('Slower proliferation rates', 'CPA', (0, 26))	('KP > HT-1080 > STS-109', 'Var', (28, 50))	('SAHA', 'Chemical', '-', (110, 114))	('USP31', 'Gene', '57478', (91, 96))	('HT-1080', 'CellLine', 'CVCL:0317', (33, 40))	('USP31', 'Gene', (91, 96))
25198	30382078	To ascertain the functional role of key UPR targets in SAHA/JQ1-induced differentiation we silenced Txnip and Ddit3 with specific shRNAs.	('SAHA', 'Chemical', '-', (55, 59))	('Ddit3', 'Gene', (110, 115))	('silenced', 'Var', (91, 99))	('Txnip', 'Gene', (100, 105))
25208	30382078	We hypothesized that reactivation of clock gene expression would alter the metabolic phenotype in sarcoma cells.	('metabolic phenotype', 'MPA', (75, 94))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('alter', 'Reg', (65, 70))	('reactivation', 'Var', (21, 33))	('sarcoma', 'Disease', (98, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
25222	30382078	Together, these data show that the Yap1/NF-kappaB axis promotes cancer-associated metabolism and that inhibition of this pathway allows expression of muscle markers and muscle-associated metabolism.	('expression', 'MPA', (136, 146))	('muscle-associated metabolism', 'MPA', (169, 197))	('cancer', 'Disease', (64, 70))	('inhibition', 'Var', (102, 112))	('promotes', 'PosReg', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('muscle markers', 'MPA', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
25229	30382078	Consistently, shRNA-mediated depletion of Yap1 enhanced LC3A/B expression in BAF-treated cells (Fig.	('depletion', 'Var', (29, 38))	('enhanced', 'PosReg', (47, 55))	('LC3A/B', 'Gene', (56, 62))	('BAF', 'Chemical', '-', (77, 80))	('expression', 'MPA', (63, 73))	('LC3A/B', 'Gene', '84557;81631', (56, 62))	('Yap1', 'Gene', (42, 46))
25243	30382078	Using our autochthonous mouse models, we showed that Yap1-mediated NF-kappaB activity disrupts normal circadian oscillation by suppressing Per1, Per2, and Cry2 levels.	('normal circadian oscillation', 'MPA', (95, 123))	('mouse', 'Species', '10090', (24, 29))	('activity', 'Var', (77, 85))	('Cry2 levels', 'MPA', (155, 166))	('Per1', 'MPA', (139, 143))	('Per2', 'MPA', (145, 149))	('NF-kappaB', 'Protein', (67, 76))	('suppressing', 'NegReg', (127, 138))	('disrupts', 'NegReg', (86, 94))	('Yap1-mediated', 'Gene', (53, 66))
25253	30382078	Now we appreciate that aberrant YAP1 stabilization impacts these processes in muscle-derived sarcomas and potentially other contexts as well.	('stabilization', 'MPA', (37, 50))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcomas', 'Disease', (93, 101))	('YAP1', 'Gene', (32, 36))	('impacts', 'Reg', (51, 58))	('aberrant', 'Var', (23, 31))
25256	30382078	Finally we sought to determine the utility of epigenetic modulation in the treatment of muscle-derived sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('epigenetic modulation', 'Var', (46, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Disease', (103, 111))
25258	30382078	designed the study, designed and performed most of the experiments, analyzed the data, and helped write the manuscript; G.M., S.E., G.C., S.C., Y.L., J.P., P.M.P., K.P., J.S.C., F.T., and N.M.L.	('P.M.P.', 'Var', (156, 162))	('scr', 'Gene', (112, 115))	('K.P.', 'Var', (164, 168))	('G.C.', 'Var', (132, 136))	('scr', 'Gene', '109559', (112, 115))	('F.T.', 'Var', (178, 182))	('J.S.C.', 'Var', (170, 176))	('J.P.', 'Var', (150, 154))	('Y.L.', 'Var', (144, 148))	('S.C.', 'Var', (138, 142))
25263	23691490	Cytogenetic analysis showed the presence of CYT-SSX1 mutation, and CT scan showed non-specific pleural micro-nodules with a size of 7.5 mm.	('mutation', 'Var', (53, 61))	('SSX1', 'Gene', '6756', (48, 52))	('pleural', 'Disease', 'MESH:D010995', (95, 102))	('presence', 'Reg', (32, 40))	('SSX1', 'Gene', (48, 52))	('pleural', 'Disease', (95, 102))
25304	23691490	Translocation (X;18) resulting in CYT-SSX gene fusion is the cytogenetic characteristic.	('SSX', 'Gene', (38, 41))	('SSX', 'Gene', '6757', (38, 41))	('Translocation', 'Var', (0, 13))
25325	22852096	Downregulation of p21Cip1 and higher expression of CDK4-cyclinD1 and CDK2-cyclinE could accelerate cell cycle in sarcomas.	('CDK2', 'Gene', '362817', (69, 73))	('Downregulation', 'NegReg', (0, 14))	('p21Cip1', 'Var', (18, 25))	('cyclinE', 'Gene', '25729', (74, 81))	('CDK4', 'Gene', (51, 55))	('rat', 'Species', '10116', (94, 97))	('higher', 'PosReg', (30, 36))	('cell cycle in', 'CPA', (99, 112))	('cyclinD1', 'Gene', (56, 64))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('expression', 'MPA', (37, 47))	('sarcomas', 'Disease', (113, 121))	('CDK2', 'Gene', (69, 73))	('CDK4', 'Gene', '94201', (51, 55))	('cyclinD1', 'Gene', '58919', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('accelerate', 'PosReg', (88, 98))	('cyclinE', 'Gene', (74, 81))
25342	22852096	Both rat osteosarcoma cell line COS1NR and malignant fibrous histiocytoma MFH1NR were established from chemically induced osteosarcoma in Fischer 344 rats by 4-hydroxy quinolone 1-oxide in our laboratory and revealed those bearing p53 mutation.	('osteosarcoma', 'Disease', (122, 134))	('mutation', 'Var', (235, 243))	('osteosarcoma', 'Phenotype', 'HP:0002669', (122, 134))	('rats', 'Species', '10116', (150, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('rat', 'Species', '10116', (197, 200))	('osteosarcoma', 'Disease', 'MESH:D012516', (122, 134))	('p53', 'Gene', (231, 234))	('rat', 'Species', '10116', (150, 153))	('rat', 'Species', '10116', (5, 8))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('histiocytoma', 'Phenotype', 'HP:0012315', (61, 73))	('osteosarcoma', 'Disease', (9, 21))	('4-hydroxy quinolone 1-oxide', 'Chemical', '-', (158, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
25367	22852096	This indicated that the cell cycle regulation was upregulated in sarcomas which possessed the p53 mutation, compared to MSCs (Figure 7).	('upregulated', 'PosReg', (50, 61))	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('p53', 'Gene', (94, 97))	('mutation', 'Var', (98, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('sarcomas', 'Disease', (65, 73))	('cell cycle regulation', 'CPA', (24, 45))
25369	22852096	Frequently identified genetic alterations in osteosarcoma and MFH are p53 and Rb mutation, MDM2 amplification, loss of function of p16, and CDK4-cyclinD amplification.	('amplification', 'Var', (96, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('p53', 'Gene', (70, 73))	('osteosarcoma', 'Disease', (45, 57))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('p16', 'Gene', '25163', (131, 134))	('MDM2', 'Gene', (91, 95))	('mutation', 'Var', (81, 89))	('CDK4', 'Gene', '94201', (140, 144))	('MDM2', 'Gene', '314856', (91, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('CDK4', 'Gene', (140, 144))	('loss of function', 'NegReg', (111, 127))	('rat', 'Species', '10116', (34, 37))	('p16', 'Gene', (131, 134))
25370	22852096	The direct evidence for induction of sarcomas by application of these genetic changes was demonstrated by the Prx1-Cre;p53fl/fl mice that developed osteosarcoma, rhabdomyosarcomas as well as undifferentiated sarcomas in vivo.	('rat', 'Species', '10116', (97, 100))	('genetic changes', 'Var', (70, 85))	('changes', 'Var', (78, 85))	('osteosarcoma', 'Disease', (148, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('osteosarcoma', 'Disease', 'MESH:D012516', (148, 160))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('sarcomas', 'Disease', (37, 45))	('sarcomas', 'Disease', (171, 179))	('developed', 'PosReg', (138, 147))	('mice', 'Species', '10090', (128, 132))	('osteosarcoma', 'Phenotype', 'HP:0002669', (148, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('Prx1', 'Gene', '18477', (110, 114))	('Prx1', 'Gene', (110, 114))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (162, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('rhabdomyosarcomas', 'Disease', (162, 179))	('sarcomas', 'Disease', 'MESH:D012509', (208, 216))	('sarcomas', 'Phenotype', 'HP:0100242', (208, 216))	('sarcomas', 'Disease', (208, 216))
25371	22852096	Furthermore, deletion of one Rb allele in these mice increased the frequency of osteosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('mice', 'Species', '10090', (48, 52))	('osteosarcomas', 'Disease', (80, 93))	('deletion', 'Var', (13, 21))	('increased', 'PosReg', (53, 62))	('osteosarcomas', 'Phenotype', 'HP:0002669', (80, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('osteosarcomas', 'Disease', 'MESH:D012516', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
25376	22852096	Rubio reported that deleting p53 in MSC induced leiomyosarcoma.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (48, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('p53', 'Gene', (29, 32))	('deleting', 'Var', (20, 28))	('leiomyosarcoma', 'Disease', (48, 62))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (48, 62))
25377	22852096	MFH also could be induced by inactivation of the Wnt signaling pathway or chemical treatment of 3-methylcholanthrene.	('Wnt', 'Gene', '114487', (49, 52))	('3-methylcholanthrene', 'Chemical', 'MESH:D008748', (96, 116))	('MFH', 'Disease', (0, 3))	('Wnt', 'Gene', (49, 52))	('induced', 'Reg', (18, 25))	('inactivation', 'Var', (29, 41))
25381	22852096	Several studies have suggested that inactivation of Wnt signaling might be involved in osteosarcoma tumorigenesis as well as MFH as described above.	('involved', 'Reg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Wnt', 'Gene', '114487', (52, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('inactivation', 'Var', (36, 48))	('osteosarcoma tumorigenesis', 'Disease', 'MESH:D012516', (87, 113))	('Wnt', 'Gene', (52, 55))	('osteosarcoma tumorigenesis', 'Disease', (87, 113))
25384	22852096	These findings suggest that genetic alteration is independent of Wnt signaling such as p53, Hedgehog may mask the function of the Wnt pathway in sarcomagenesis, or alteration of Wnt signaling may occur at some late stage of neoplastic progression.	('Hedgehog', 'Gene', (92, 100))	('sarcoma', 'Disease', (145, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('alteration', 'Var', (36, 46))	('mask', 'NegReg', (105, 109))	('Wnt', 'Gene', (178, 181))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('rat', 'Species', '10116', (40, 43))	('Wnt', 'Gene', (130, 133))	('function', 'MPA', (114, 122))	('rat', 'Species', '10116', (168, 171))	('Wnt', 'Gene', (65, 68))	('Wnt', 'Gene', '114487', (178, 181))	('Wnt', 'Gene', '114487', (130, 133))	('alteration', 'Reg', (164, 174))	('Wnt', 'Gene', '114487', (65, 68))
25385	22852096	Meanwhile, aberrant activation of Hedgehog signaling is associated with various types of cancers, in which deregulation of cellular growth, survival, and adult stem cell maintenance is believed to be involved.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('aberrant', 'Var', (11, 19))	('associated', 'Reg', (56, 66))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('activation', 'PosReg', (20, 30))	('Hedgehog signaling', 'Pathway', (34, 52))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
25388	22852096	Overexpression of Gli2 in human MSCs increases cell proliferation and progression through cell cycle regulation, and inhibition of Gli2 disrupted the growth of osteosarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('disrupted', 'NegReg', (136, 145))	('Gli2', 'Gene', '2736', (18, 22))	('increases', 'PosReg', (37, 46))	('inhibition', 'Var', (117, 127))	('Gli2', 'Gene', (18, 22))	('progression through cell cycle regulation', 'CPA', (70, 111))	('Gli2', 'Gene', '2736', (131, 135))	('osteosarcoma', 'Disease', (160, 172))	('growth', 'CPA', (150, 156))	('rat', 'Species', '10116', (59, 62))	('osteosarcoma', 'Disease', 'MESH:D012516', (160, 172))	('osteosarcoma', 'Phenotype', 'HP:0002669', (160, 172))	('human', 'Species', '9606', (26, 31))	('Gli2', 'Gene', (131, 135))	('cell proliferation', 'CPA', (47, 65))
25391	22852096	In addition, the disruption of Hedgehog signaling by small interfering RNA against Gli1 induced p21/Cip1 expression that resulted in suppression of cell proliferation in a p53-independent mechanism.	('Gli1', 'Gene', (83, 87))	('p21', 'Gene', '24525', (96, 99))	('induced', 'Reg', (88, 95))	('p21', 'Gene', (96, 99))	('rat', 'Species', '10116', (160, 163))	('Cip1', 'Gene', '114851', (100, 104))	('cell proliferation', 'CPA', (148, 166))	('disruption', 'Var', (17, 27))	('Gli1', 'Gene', '140589', (83, 87))	('suppression', 'NegReg', (133, 144))	('Cip1', 'Gene', (100, 104))	('expression', 'MPA', (105, 115))	('small interfering', 'Var', (53, 70))
25398	22852096	Disruption of p53 such as point mutation or MDM2 amplification and activation of Hedgehog signaling may lead to cell cycle acceleration through downregulation of p21 and upregulation of CDK and cyclins.	('CDK', 'Protein', (186, 189))	('cyclins', 'Protein', (194, 201))	('amplification', 'Var', (49, 62))	('MDM2', 'Gene', (44, 48))	('p53', 'Gene', (14, 17))	('activation', 'PosReg', (67, 77))	('upregulation', 'PosReg', (170, 182))	('MDM2', 'Gene', '314856', (44, 48))	('rat', 'Species', '10116', (129, 132))	('downregulation', 'NegReg', (144, 158))	('p21', 'Gene', '24525', (162, 165))	('Hedgehog signaling', 'Pathway', (81, 99))	('p21', 'Gene', (162, 165))	('cell cycle acceleration', 'CPA', (112, 135))	('point mutation', 'Var', (26, 40))
25399	22852096	In addition, inactivation of the Wnt signaling pathway may lead to the deregulation of differentiation as well as focal adhesion function in MSC, which might be required for normal stem cell maintenance.	('focal', 'MPA', (114, 119))	('inactivation', 'Var', (13, 25))	('MSC', 'Disease', (141, 144))	('Wnt', 'Gene', (33, 36))	('differentiation', 'MPA', (87, 102))	('Wnt', 'Gene', '114487', (33, 36))	('lead to', 'Reg', (59, 66))	('deregulation', 'MPA', (71, 83))
25401	22852096	Wnt and Hedgehog signaling may change during the process of differentiation and might result in cell cycle acceleration in conjunction with p53 mutations as well as DNA replication.	('result in', 'Reg', (86, 95))	('acceleration', 'PosReg', (107, 119))	('cell cycle', 'CPA', (96, 106))	('rat', 'Species', '10116', (113, 116))	('change', 'Reg', (31, 37))	('Wnt', 'Gene', (0, 3))	('Hedgehog signaling', 'MPA', (8, 26))	('mutations', 'Var', (144, 153))	('p53', 'Gene', (140, 143))	('Wnt', 'Gene', '114487', (0, 3))
25418	31942159	A 55-year-old female, P3003, presented with postmenopausal spotting on and off for the past 6 months, cough with expectoration, and significant weight loss for past 2 months.	('spotting', 'Disease', (59, 67))	('weight loss', 'Disease', (144, 155))	('weight loss', 'Phenotype', 'HP:0001824', (144, 155))	('cough', 'Phenotype', 'HP:0012735', (102, 107))	('cough', 'Disease', (102, 107))	('weight loss', 'Disease', 'MESH:D015431', (144, 155))	('P3003', 'Var', (22, 27))
25450	31942159	Women with low-grade ESS usually present with leiomyoma-like symptoms such as abnormal uterine bleeding, abdominal or pelvic pain or pressure symptoms due to enlarging abdomen, abnormal or foul-smelling vaginal discharge, or postmenopausal bleeding.	('abnormal uterine bleeding', 'Disease', 'MESH:D014592', (78, 103))	('Women', 'Species', '9606', (0, 5))	('pain', 'Phenotype', 'HP:0012531', (125, 129))	('enlarging', 'PosReg', (158, 167))	('abdomen', 'Disease', (168, 175))	('low-grade', 'Var', (11, 20))	('abnormal uterine bleeding', 'Disease', (78, 103))	('postmenopausal bleeding', 'Disease', (225, 248))	('ESS', 'Disease', 'MESH:D018203', (21, 24))	('abnormal uterine', 'Phenotype', 'HP:0000130', (78, 94))	('leiomyoma', 'Disease', (46, 55))	('leiomyoma', 'Disease', 'MESH:D007889', (46, 55))	('ESS', 'Disease', (21, 24))	('pelvic pain', 'Disease', 'MESH:D017699', (118, 129))	('pressure symptoms', 'Disease', (133, 150))	('abnormal uterine bleeding', 'Phenotype', 'HP:0100608', (78, 103))	('postmenopausal bleeding', 'Disease', 'MESH:D015663', (225, 248))	('pelvic pain', 'Disease', (118, 129))
25501	25538389	Alveolar RMS have chromosomal translocations (2; 13) (q35; q14) or (1; 13) (p36; q14).	('2; 13) (q35; q14', 'Var', (46, 62))	('RMS', 'Phenotype', 'HP:0002859', (9, 12))	('Alveolar RMS', 'CPA', (0, 12))	('p36', 'Gene', '51251', (76, 79))	('p36', 'Gene', (76, 79))
25631	21437186	EBV-SMT of the gastrointestinal tract, for example, may present with bleeding, abdominal pain, obstruction and perforation.	('abdominal pain', 'Phenotype', 'HP:0002027', (79, 93))	('obstruction', 'Disease', 'MESH:D000402', (95, 106))	('abdominal pain', 'Disease', (79, 93))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (15, 37))	('present', 'Reg', (56, 63))	('abdominal pain', 'Disease', 'MESH:D015746', (79, 93))	('obstruction', 'Disease', (95, 106))	('bleeding', 'Disease', 'MESH:D006470', (69, 77))	('pain', 'Phenotype', 'HP:0012531', (89, 93))	('EBV-SMT of', 'Var', (0, 10))	('bleeding', 'Disease', (69, 77))	('perforation', 'Disease', (111, 122))	('gastrointestinal tract', 'Disease', (15, 37))
25674	21437186	The presence of high copy numbers of EBV in tumor cells by quantitative PCR was found to be consistent with results of in situ hybridization tests.	('EBV', 'Gene', (37, 40))	('high copy numbers', 'Var', (16, 33))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('EBV', 'Species', '10376', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
25833	32633035	Known risk factors for KS-related mortality include recipient HHV-8 seronegativity and older age.	('KS', 'Phenotype', 'HP:0100726', (23, 25))	('HHV-8', 'Species', '37296', (62, 67))	('HHV-8', 'Protein', (62, 67))	('mortality', 'Disease', 'MESH:D003643', (34, 43))	('seronegativity', 'Var', (68, 82))	('mortality', 'Disease', (34, 43))
25867	31898537	Loss of Stag2 cooperates with EWS-FLI1 to transform murine Mesenchymal stem cells Ewing sarcoma is a malignancy of primitive cells, possibly of mesenchymal origin.	('FLI1', 'Gene', (34, 38))	('Ewing sarcoma', 'Disease', (82, 95))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (82, 95))	('EWS', 'Gene', '14030', (30, 33))	('Stag2', 'Gene', (8, 13))	('FLI1', 'Gene', '14247', (34, 38))	('EWS', 'Gene', (30, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('transform', 'Reg', (42, 51))	('murine', 'Species', '10090', (52, 58))	('Loss', 'Var', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('Stag2', 'Gene', '20843', (8, 13))
25869	31898537	Sequencing studies identified STAG2 mutations in approximately 15% of cases in humans.	('STAG2', 'Gene', (30, 35))	('humans', 'Species', '9606', (79, 85))	('mutations', 'Var', (36, 45))
25870	31898537	In the present study, we hypothesize that loss of Stag2 cooperates with EWS-FLI1 in generating sarcomas derived from murine mesenchymal stem cells (MSCs).	('MSC', 'Gene', '17681', (148, 151))	('loss', 'Var', (42, 46))	('MSC', 'Gene', (148, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('sarcomas', 'Disease', 'MESH:D012509', (95, 103))	('Stag2', 'Gene', (50, 55))	('EWS-FLI1', 'Gene', '14030;14247', (72, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('murine', 'Species', '10090', (117, 123))	('EWS-FLI1', 'Gene', (72, 80))	('sarcomas', 'Disease', (95, 103))
25873	31898537	EWS-FLI1 induction and Stag2 knockdown were achieved in vitro by adenovirus-Cre and shRNA-bearing pGIPZ lentiviral infection, respectively.	('EWS-FLI1', 'Gene', '14030;14247', (0, 8))	('knockdown', 'Var', (29, 38))	('EWS-FLI1', 'Gene', (0, 8))
25875	31898537	Primary murine MSCs with the genotype EWS-FLI1 p53-/- were resistant to transformation and did not form tumors in syngeneic mice without irradiation.	('p53-/-', 'Var', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('EWS-FLI1', 'Gene', '14030;14247', (38, 46))	('MSC', 'Gene', '17681', (15, 18))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MSC', 'Gene', (15, 18))	('mice', 'Species', '10090', (124, 128))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('EWS-FLI1', 'Gene', (38, 46))	('murine', 'Species', '10090', (8, 14))
25878	31898537	Stag2 knockdown reduced survival of mice in Kaplan-Meier analysis (p < .001).	('survival', 'CPA', (24, 32))	('reduced', 'NegReg', (16, 23))	('Stag2', 'Gene', (0, 5))	('mice', 'Species', '10090', (36, 40))	('knockdown', 'Var', (6, 15))
25880	31898537	Loss of Stag2 has a synergistic effect with EWS-FLI1 in the production of sarcomas from murine MSCs, but the mechanism may not relate to increased proliferation or chromosomal instability.	('sarcomas', 'Disease', (74, 82))	('murine', 'Species', '10090', (88, 94))	('MSC', 'Gene', '17681', (95, 98))	('EWS-FLI1', 'Gene', (44, 52))	('Stag2', 'Gene', (8, 13))	('MSC', 'Gene', (95, 98))	('chromosomal instability', 'Phenotype', 'HP:0040012', (164, 187))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('EWS-FLI1', 'Gene', '14030;14247', (44, 52))	('Loss', 'Var', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
25885	31898537	Recent studies have identified STAG2 mutation as one of the most common associated anomalies in Ewing sarcoma, occurring in approximately 15% of tumor samples.	('STAG2', 'Gene', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('mutation', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('associated', 'Reg', (72, 82))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (96, 109))	('tumor', 'Disease', (145, 150))	('Ewing sarcoma', 'Disease', (96, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))
25887	31898537	Its mutational inactivation or loss of expression have been documented in a variety of solid and hematologic malignancies, including glioblastoma, lymphomas, colorectal, prostate, urothelial bladder cancers, and Ewing sarcoma.	('lymphomas', 'Disease', (147, 156))	('glioblastoma', 'Disease', (133, 145))	('hematologic malignancies', 'Disease', 'MESH:D019337', (97, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('mutational inactivation', 'Var', (4, 27))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('loss of', 'NegReg', (31, 38))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (212, 225))	('colorectal', 'Disease', (158, 168))	('bladder cancers', 'Phenotype', 'HP:0009725', (191, 206))	('expression', 'MPA', (39, 49))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('bladder cancer', 'Phenotype', 'HP:0009725', (191, 205))	('lymphomas', 'Disease', 'MESH:D008223', (147, 156))	('solid and', 'Disease', (87, 96))	('lymphomas', 'Phenotype', 'HP:0002665', (147, 156))	('prostate', 'Disease', (170, 178))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (212, 225))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (180, 206))	('Ewing sarcoma', 'Disease', (212, 225))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('colorectal', 'Disease', 'MESH:D015179', (158, 168))	('hematologic malignancies', 'Disease', (97, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('urothelial bladder cancers', 'Disease', (180, 206))
25893	31898537	Using this new system, we present in vitro and in vivo data that support a synergistic effect between Stag2 inhibition, EWS-FLI1 expression, and p53 mutation in the transformation of primary MSCs.	('MSC', 'Gene', '17681', (191, 194))	('MSC', 'Gene', (191, 194))	('p53', 'Gene', (145, 148))	('Stag2', 'Gene', (102, 107))	('EWS-FLI1', 'Gene', (120, 128))	('mutation', 'Var', (149, 157))	('EWS-FLI1', 'Gene', '14030;14247', (120, 128))
25938	31898537	Cells subsequently underwent fluorescence-activated cell sorting (FACS) to isolate the GFP negative, EWS-FLI1 p53-/- cell population.	('p53-/-', 'Var', (110, 116))	('EWS-FLI1', 'Gene', '14030;14247', (101, 109))	('EWS-FLI1', 'Gene', (101, 109))
25942	31898537	Using a retroviral GIPZ construct, we expressed Stag2 shRNA or random control (Ctrl) shRNA in the EWS-FLI1 p53-/- MSCs (henceforth designated "Stag2 shRNA" and "Ctrl shRNA" cells, respectively).	('MSC', 'Gene', '17681', (114, 117))	('MSC', 'Gene', (114, 117))	('EWS-FLI1', 'Gene', (98, 106))	('Stag2', 'Var', (48, 53))	('EWS-FLI1', 'Gene', '14030;14247', (98, 106))
25943	31898537	Using metaphase chromosomal spreads to examine the effect of Stag2 inhibition, we noted greater aberrations in Ctrl shRNA and Stag2 shRNA cells (both of which express EWS-FLI1 and carry a p53-/- null mutation) when compared with MSCs derived from normal wild-type C57/Bl6 mice.	('MSC', 'Gene', '17681', (229, 232))	('MSC', 'Gene', (229, 232))	('p53-/-', 'Var', (188, 194))	('mice', 'Species', '10090', (272, 276))	('EWS-FLI1', 'Gene', (167, 175))	('EWS-FLI1', 'Gene', '14030;14247', (167, 175))
25944	31898537	Anchorage-independent growth, as determined by colony formation in soft agar, did not occur in EWS-FLI1 p53-/- MSCs, even after Stag2 knockdown.	('EWS-FLI1', 'Gene', (95, 103))	('MSC', 'Gene', '17681', (111, 114))	('MSC', 'Gene', (111, 114))	('p53-/-', 'Var', (104, 110))	('EWS-FLI1', 'Gene', '14030;14247', (95, 103))
25952	31898537	Furthermore, the mRNA expression of the cohesin complex genes Smc1a, Smc1b, Smc3, and Rad21, which are coordinately expressed with Stag2, was diminished in Stag2 shRNA+10Gy cells compared to Ctrl shRNA+10Gy cells (Fig.	('Smc3', 'Gene', (76, 80))	('Smc1b', 'Gene', '140557', (69, 74))	('Smc1b', 'Gene', (69, 74))	('Smc1a', 'Gene', (62, 67))	('Stag2 shRNA+10Gy', 'Var', (156, 172))	('Smc1a', 'Gene', '24061', (62, 67))	('mRNA expression', 'MPA', (17, 32))	('Smc3', 'Gene', '13006', (76, 80))	('Rad21', 'Gene', '19357', (86, 91))	('Rad21', 'Gene', (86, 91))	('diminished', 'NegReg', (142, 152))
25954	31898537	After intra-muscular injection of cells, 5 of 23 mice (22%) with Ctrl shRNA+10Gy cells developed tumors, whereas 19 of 21 mice (91%) injected with Stag2 shRNA+10Gy cells developed tumors (p < .001, Fig.	('mice', 'Species', '10090', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mice', 'Species', '10090', (49, 53))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Ctrl shRNA+10Gy cells', 'Var', (65, 86))
25955	31898537	Mean time for tumor development was 1.2 months (range 0.8-1.8 months) for Stag2 shRNA+10Gy cells with Stag2 knockdown and 3.1 months (range 1.6-5.5 months) for Ctrl shRNA+10Gy cells without Stag2 knockdown (p < .001).	('knockdown', 'Var', (108, 117))	('tumor', 'Disease', (14, 19))	('Stag2', 'Gene', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
25959	31898537	Taken together, the results indicate that synergy exists between Stag2 inhibition, p53 mutation, and EWS-FLI1 expression in the process of sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('p53', 'Gene', (83, 86))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('EWS-FLI1', 'Gene', '14030;14247', (101, 109))	('expression', 'MPA', (110, 120))	('sarcoma', 'Disease', (139, 146))	('Stag2', 'Gene', (65, 70))	('mutation', 'Var', (87, 95))	('EWS-FLI1', 'Gene', (101, 109))
25960	31898537	To determine whether loss of Stag2 might enable MSCs to acquire certain properties of transformed cells, we performed Transwell migration and invasion assays.	('loss', 'Var', (21, 25))	('Stag2', 'Gene', (29, 34))	('enable', 'Reg', (41, 47))	('MSC', 'Gene', '17681', (48, 51))	('MSC', 'Gene', (48, 51))
25961	31898537	Similarly, inhibition of Stag2 increased the invasive properties of MSCs compared to cells receiving control shRNA (Fig.	('increased', 'PosReg', (31, 40))	('invasive properties', 'CPA', (45, 64))	('MSC', 'Gene', '17681', (68, 71))	('MSC', 'Gene', (68, 71))	('inhibition', 'Var', (11, 21))	('Stag2', 'Gene', (25, 30))
25964	31898537	In our previous murine model, we found that conditional expression of EWS-FLI1 alone in the limb bud did not produce sarcomas in mice, but loss of p53 together with induction of EWS-FLI1 accelerated sarcoma formation.	('EWS-FLI1', 'Gene', '14030;14247', (178, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('murine', 'Species', '10090', (16, 22))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('p53', 'Gene', (147, 150))	('sarcoma', 'Disease', (117, 124))	('EWS-FLI1', 'Gene', '14030;14247', (70, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcomas', 'Disease', (117, 125))	('EWS-FLI1', 'Gene', (178, 186))	('loss', 'Var', (139, 143))	('mice', 'Species', '10090', (129, 133))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('EWS-FLI1', 'Gene', (70, 78))	('sarcoma', 'Disease', (199, 206))	('accelerated', 'PosReg', (187, 198))
25966	31898537	Nevertheless, it is intriguing that approximately 15% of Ewing sarcoma samples exhibited mutations in the STAG2 gene, making it one of the most commonly mutated genes in the disease.	('Ewing sarcoma', 'Disease', (57, 70))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('STAG2', 'Gene', (106, 111))	('mutations', 'Var', (89, 98))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (57, 70))	('exhibited', 'Reg', (79, 88))
25967	31898537	In this study, we explored the question of whether loss of Stag2 might also cooperate with EWS-FLI1 and p53 loss in sarcomagenesis.	('p53', 'Gene', (104, 107))	('loss', 'NegReg', (108, 112))	('loss', 'Var', (51, 55))	('EWS-FLI1', 'Gene', (91, 99))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('EWS-FLI1', 'Gene', '14030;14247', (91, 99))	('Stag2', 'Gene', (59, 64))	('sarcoma', 'Disease', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
25968	31898537	We used MSCs from genetically modified mice bearing the silent EWS-FLI1 gene as the starting material for this study.	('silent', 'Var', (56, 62))	('MSC', 'Gene', (8, 11))	('EWS-FLI1', 'Gene', '14030;14247', (63, 71))	('EWS-FLI1', 'Gene', (63, 71))	('mice', 'Species', '10090', (39, 43))	('MSC', 'Gene', '17681', (8, 11))
25973	31898537	In fact, the combination of p53 null mutation, EWS-FLI1 expression, and Stag2 inhibition did not immediately confer tumor-forming capability to the cells.	('p53', 'Gene', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('EWS-FLI1', 'Gene', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('null mutation', 'Var', (32, 45))	('tumor', 'Disease', (116, 121))	('EWS-FLI1', 'Gene', '14030;14247', (47, 55))
25976	31898537	Thus, we concluded that Stag2 knockdown had a synergistic effect with EWS-FLI1 in the production of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Disease', (100, 108))	('EWS-FLI1', 'Gene', '14030;14247', (70, 78))	('Stag2', 'Gene', (24, 29))	('knockdown', 'Var', (30, 39))	('EWS-FLI1', 'Gene', (70, 78))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
25983	31898537	The main finding that we would stress in the current study is that both p53 mutation and Stag2 loss could accelerate tumorigenesis with EWS-FLI1.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('EWS-FLI1', 'Gene', '14030;14247', (136, 144))	('tumor', 'Disease', (117, 122))	('p53', 'Gene', (72, 75))	('EWS-FLI1', 'Gene', (136, 144))	('accelerate', 'PosReg', (106, 116))	('Stag2', 'Gene', (89, 94))	('loss', 'NegReg', (95, 99))	('mutation', 'Var', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
25985	31898537	Researchers have tried to decipher the mechanism by which loss of STAG2 promotes tumorigenesis.	('STAG2', 'Gene', (66, 71))	('loss', 'Var', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('promotes', 'PosReg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
25986	31898537	As part of the cohesin complex that regulates chromatid segregation, STAG2 was initially believed to prevent aneuploidy.	('STAG2', 'Var', (69, 74))	('aneuploidy', 'Disease', (109, 119))	('aneuploidy', 'Disease', 'MESH:D000782', (109, 119))
25989	31898537	Theoretically, EWS-FLI1 might also contribute to chromosomal rearrangements, but sequencing data in human tumors indicate that mutations are relatively uncommon in Ewing sarcoma, so that most of the changes would be attributed to p53 null mutation.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('EWS-FLI1', 'Gene', (15, 23))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Ewing sarcoma', 'Disease', (164, 177))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (164, 177))	('human', 'Species', '9606', (100, 105))	('changes', 'Var', (199, 206))	('EWS-FLI1', 'Gene', '14030;14247', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mutations', 'Var', (127, 136))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (164, 177))	('p53', 'Gene', (230, 233))
25990	31898537	In our model system, we did not observe tumor formation in the cohort of mice carrying 3 genetic changes (EWS-FLI1, p53 null mutation, and Stag2 loss) without irradiation.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('EWS-FLI1', 'Gene', '14030;14247', (106, 114))	('loss', 'NegReg', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mice', 'Species', '10090', (73, 77))	('EWS-FLI1', 'Gene', (106, 114))	('null mutation', 'Var', (120, 133))	('tumor', 'Disease', (40, 45))	('p53', 'Gene', (116, 119))
25991	31898537	If indeed Stag2 deficiency results in impairment of DNA repair, one might predict that the simultaneous presence of Stag2 and P53 loss would increase the accumulation of mutations and enable tumors to become more aggressive.	('impairment', 'NegReg', (38, 48))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('enable', 'Reg', (184, 190))	('increase', 'PosReg', (141, 149))	('accumulation', 'MPA', (154, 166))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('P53', 'Gene', (126, 129))	('Stag2', 'Gene', (116, 121))	('DNA repair', 'MPA', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('loss', 'NegReg', (130, 134))	('tumors', 'Disease', (191, 197))	('mutations', 'MPA', (170, 179))	('deficiency', 'Var', (16, 26))
25992	31898537	It is interesting to note that in human Ewing sarcoma, tumors harboring both STAG2 and P53 mutations have the worst prognosis and shortest survival.	('Ewing sarcoma', 'Disease', 'MESH:D012512', (40, 53))	('human', 'Species', '9606', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Ewing sarcoma', 'Disease', (40, 53))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('STAG2', 'Gene', (77, 82))	('shortest', 'NegReg', (130, 138))	('mutations', 'Var', (91, 100))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('P53', 'Gene', (87, 90))
25995	31898537	While the literature on mutational changes in pleomorphic sarcomas is sparse, a recent study on human soft tissue sarcomas found only occasional mutations in the cohesin complex, suggesting that STAG2 mutation is not a common mechanism for the development of pleomorphic sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('pleomorphic sarcomas', 'Disease', 'MESH:D008228', (46, 66))	('mutation', 'Var', (201, 209))	('human', 'Species', '9606', (96, 101))	('pleomorphic sarcomas', 'Disease', (46, 66))	('pleomorphic sarcomas', 'Disease', 'MESH:D008228', (259, 279))	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('sarcomas', 'Disease', (114, 122))	('pleomorphic sarcomas', 'Disease', (259, 279))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (102, 122))	('sarcomas', 'Disease', 'MESH:D012509', (271, 279))	('STAG2', 'Gene', (195, 200))	('sarcomas', 'Disease', 'MESH:D012509', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (271, 279))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('sarcomas', 'Disease', (271, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', (58, 66))
25996	31898537	STAG2 is expressed broadly in many different cell types, and yet STAG2 mutation is especially frequent in certain malignancies, including bladder cancer, uterine cancer, and Ewing sarcoma.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', (162, 168))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (174, 187))	('certain malignancies', 'Disease', 'MESH:D009369', (106, 126))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('certain malignancies', 'Disease', (106, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('frequent', 'Reg', (94, 102))	('Ewing sarcoma', 'Disease', (174, 187))	('mutation', 'Var', (71, 79))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (174, 187))	('uterine cancer', 'Phenotype', 'HP:0010784', (154, 168))	('STAG2', 'Gene', (65, 70))
25997	31898537	In a mouse model of leukemia, Stag2 mutation seems to affect genes involved in hematopoietic stem cell renewal and differentiation.	('leukemia', 'Disease', (20, 28))	('leukemia', 'Phenotype', 'HP:0001909', (20, 28))	('leukemia', 'Disease', 'MESH:D007938', (20, 28))	('Stag2', 'Gene', (30, 35))	('affect', 'Reg', (54, 60))	('mouse', 'Species', '10090', (5, 10))	('mutation', 'Var', (36, 44))
26000	31898537	Loss of Stag2 alone produced no tumors, and other genetic changes were clearly needed.	('Stag2', 'Gene', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('Loss', 'Var', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
26002	31898537	Interestingly, in U2OS cells, the truncating R216 mutation of STAG2 reduces proliferation but increases invasiveness of cells, which parallels our findings.	('truncating R216', 'Var', (34, 49))	('STAG2', 'Gene', (62, 67))	('U2OS', 'CellLine', 'CVCL:0042', (18, 22))	('proliferation', 'CPA', (76, 89))	('increases', 'PosReg', (94, 103))	('invasiveness of cells', 'CPA', (104, 125))	('reduces', 'NegReg', (68, 75))
26003	31898537	More recent work has shown that loss of STAG2 increases telomere recombination and postpones replicative senescence in cultured normal human cells.	('increases', 'PosReg', (46, 55))	('postpones', 'NegReg', (83, 92))	('human', 'Species', '9606', (135, 140))	('loss', 'Var', (32, 36))	('replicative senescence', 'CPA', (93, 115))	('STAG2', 'Gene', (40, 45))	('telomere', 'CPA', (56, 64))
26004	31898537	Another interesting observation is that germline mutation or loss of the gene results in mental retardation and craniofacial defects.	('gene', 'Gene', (73, 77))	('craniofacial defects', 'Disease', 'MESH:D019465', (112, 132))	('craniofacial defects', 'Disease', (112, 132))	('germline mutation', 'Var', (40, 57))	('results in', 'Reg', (78, 88))	('mental retardation', 'Phenotype', 'HP:0001249', (89, 107))	('mental retardation', 'Disease', (89, 107))	('loss', 'NegReg', (61, 65))	('mental retardation', 'Disease', 'MESH:D008607', (89, 107))
26008	31898537	In particular, it would be informative to determine whether the effects of Stag2 might be independent of p53, since some human Ewing tumors carry STAG2 mutation without P53 mutation.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('STAG2', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('human', 'Species', '9606', (121, 126))	('Ewing tumors', 'Phenotype', 'HP:0012254', (127, 139))	('Ewing tumors', 'Disease', 'MESH:D012512', (127, 139))	('Ewing tumors', 'Disease', (127, 139))	('mutation', 'Var', (152, 160))
26011	31898537	In summary, we show that loss of Stag2 cooperates with EWS-FLI1 and p53 mutation to promote sarcomagenesis in murine MSCs.	('MSC', 'Gene', '17681', (117, 120))	('MSC', 'Gene', (117, 120))	('loss', 'Var', (25, 29))	('promote', 'PosReg', (84, 91))	('Stag2', 'Gene', (33, 38))	('EWS-FLI1', 'Gene', '14030;14247', (55, 63))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('sarcoma', 'Disease', (92, 99))	('p53', 'Gene', (68, 71))	('mutation', 'Var', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('EWS-FLI1', 'Gene', (55, 63))	('murine', 'Species', '10090', (110, 116))
26085	31789001	2) The decision on the operative method in laparoscopic surgery is made according to the basic policy described in CQ01, CQ03, and CQ04.	('CQ03', 'Var', (121, 125))	('CQ04', 'Var', (131, 135))	('CQ01', 'CellLine', 'CVCL:Z240', (115, 119))	('CQ01', 'Var', (115, 119))
26165	28834194	In the small subset with incidental HCC, the numerically higher 10-year graft (64.1% versus 40.5%; P = 0.441, NS) and patient (85% versus 48.3%; P = 0.168, NS) survival was NS when compared with survival in the primary HCC subset.	('incidental', 'Var', (25, 35))	('graft', 'CPA', (72, 77))	('HCC', 'Gene', '619501', (36, 39))	('higher', 'PosReg', (57, 63))	('HCC', 'Gene', (219, 222))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('HCC', 'Gene', '619501', (219, 222))	('HCC', 'Gene', (36, 39))	('HCC', 'Phenotype', 'HP:0001402', (219, 222))	('patient', 'Species', '9606', (118, 125))
26167	28834194	It is also noteworthy that 10-year patient survival for incidental HCC (85%; 95% CI, 70.6%-100%) was similar to that for BA (89.9%; 95% CI, 88.7%-91%).	('incidental', 'Var', (56, 66))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('HCC', 'Gene', '619501', (67, 70))	('patient', 'Species', '9606', (35, 42))	('HCC', 'Gene', (67, 70))	('BA', 'Phenotype', 'HP:0005912', (121, 123))
26262	27375743	The neoplastic cells were positive for S100 with scattered expression of Melan A. Florescence in situ hybridization revealed a translocation at the EWRS1 locus.	('S100', 'Gene', (39, 43))	('translocation', 'Var', (127, 140))	('S100', 'Gene', '6271', (39, 43))	('Melan A', 'Gene', '2315', (73, 80))	('Melan A', 'Gene', (73, 80))	('EWRS1', 'Gene', (148, 153))
26312	27375743	CCS also lack BRAF mutations which are commonly found in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('mutations', 'Var', (19, 28))	('melanoma', 'Disease', (57, 65))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('lack', 'NegReg', (9, 13))
26314	27375743	Fluorescence in situ hybridization (FISH) is the gold standard test to detect the t(12;22) translocation that is pathognomonic of clear cell sarcoma.	('clear cell sarcoma', 'Disease', (130, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (130, 148))	('translocation', 'Var', (91, 104))
26411	23420076	Furthermore, RRV infects rhesus macaques and induces MCD and non-Hodgkin's lymphoma-like diseases in immunodeficient rhesus macaques, which is similar to KSHV-associated malignancies in individuals coinfected by HIV and KSHV.	('KS', 'Phenotype', 'HP:0100726', (154, 156))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (65, 83))	('KS', 'Phenotype', 'HP:0100726', (220, 222))	('rhesus macaques', 'Species', '9544', (117, 132))	('RRV', 'Var', (13, 16))	('induces', 'Reg', (45, 52))	('rhesus macaques', 'Species', '9544', (25, 40))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	("non-Hodgkin's lymphoma-like diseases", 'Disease', 'MESH:D008228', (61, 97))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (61, 83))	("non-Hodgkin's lymphoma-like diseases", 'Disease', (61, 97))	('MCD', 'Disease', (53, 56))
26423	23420076	DC-SIGN facilitates KSHV entry in human acute monocytic leukemia cell line THP-1, activated primary B lymphocytes, myeloid dendritic cells, and macrophages.	('KS', 'Phenotype', 'HP:0100726', (20, 22))	('monocytic leukemia', 'Disease', (46, 64))	('monocytic leukemia', 'Disease', 'MESH:D007951', (46, 64))	('DC-SIGN', 'Var', (0, 7))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('facilitates', 'PosReg', (8, 19))	('acute monocytic leukemia', 'Phenotype', 'HP:0004845', (40, 64))	('THP-1', 'Gene', '2736', (75, 80))	('THP-1', 'Gene', (75, 80))	('KSHV entry', 'MPA', (20, 30))
26427	23420076	Furthermore, transfection of nonpermissive CHO cells with human alpha3 rendered them susceptible to KSHV infection.	('susceptible', 'MPA', (85, 96))	('transfection', 'Var', (13, 25))	('KS', 'Phenotype', 'HP:0100726', (100, 102))	('alpha3', 'Protein', (64, 70))	('CHO', 'CellLine', 'CVCL:0213', (43, 46))
26454	23420076	Adenovirus has been shown to activate Rac and CDC42 through PI3K, and stimulate actin remodeling and the formation of lamellipodia to facilitate its endocytosis.	('endocytosis', 'MPA', (149, 160))	('Rac', 'Protein', (38, 41))	('actin', 'MPA', (80, 85))	('CDC42', 'Gene', '998', (46, 51))	('CDC42', 'Gene', (46, 51))	('facilitate', 'PosReg', (134, 144))	('PI3K', 'Var', (60, 64))	('stimulate', 'PosReg', (70, 79))	('Adenovirus', 'Protein', (0, 10))	('activate', 'PosReg', (29, 37))
26460	23420076	Activation of AP-1 also leads to induction of several proinflammatory and angiogenic cytokines, including matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, IL-6 and angiopoietin-2, which promote the progression of KSHV-induced malignancies, and possibly dissemination of infectious viruses in vivo.	('malignancies', 'Disease', (225, 237))	('MMP-2', 'Gene', (140, 145))	('KS', 'Phenotype', 'HP:0100726', (212, 214))	('AP-1', 'Gene', (14, 18))	('KSHV-induced malignancies', 'Disease', (212, 237))	('angiopoietin-2', 'Gene', '285', (163, 177))	('angiopoietin-2', 'Gene', (163, 177))	('promote', 'PosReg', (185, 192))	('MMP-9', 'Var', (147, 152))
26461	23420076	Interestingly, KSHV entry induces VE-cadherin degradation and increases vascular permeability.	('increases', 'PosReg', (62, 71))	('VE-cadherin', 'Gene', (34, 45))	('vascular permeability', 'MPA', (72, 93))	('VE-cadherin', 'Gene', '1003', (34, 45))	('KSHV entry', 'Var', (15, 25))	('KS', 'Phenotype', 'HP:0100726', (15, 17))
26462	23420076	Nevertheless, it has been shown that disruption of adherens junction liberates the entry receptor nectin-1, facilitating cell entry of HSV-1 and pseudorabies virus.	('facilitating', 'PosReg', (108, 120))	('disruption', 'Var', (37, 47))	('cell entry', 'CPA', (121, 131))	('adherens junction', 'Protein', (51, 68))	('liberates', 'NegReg', (69, 78))	('pseudorabies', 'Gene', (145, 157))	('pseudorabies virus', 'Species', '10345', (145, 163))
26486	22174504	The tumor was positive for t (11; 22) (q24; q12) translocation detected by fluorescent in situ hybridization (FISH) in the tumor biopsy sample.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('t (11', 'Var', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
26742	31508194	On univariate analysis (Figure 2), we identified negative prognostic factors for OS including RAS (p < 0.001), trunk as primary site of tumor (p < 0.001), higher T stage (p = 0.04), metastasis (p = 0.04), AJCC stage 4 (p = 0.02), microscopic positive margin (p < 0.001) and subtotal or marginal resection with residual tumor (R2; p < 0.001).	('metastasis', 'Disease', (182, 192))	('tumor', 'Disease', (319, 324))	('RAS', 'Disease', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('microscopic', 'Var', (230, 241))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('OS', 'Chemical', '-', (81, 83))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('tumor', 'Disease', (136, 141))
26743	31508194	Multivariate analysis (Table 3) identified older age (HR = 1.04 per year, p = 0.04), RAS (HR = 306, p < 0.001), undetermined margins (HR = 748, p = 0.001), metastasis (HR = 6.53, p = 0.01), and subtotal resection (HR = 232, p < 0.001) as independent predictors of worse OS.	('subtotal resection', 'Var', (194, 212))	('metastasis', 'CPA', (156, 166))	('OS', 'Chemical', '-', (270, 272))	('RAS', 'Disease', (85, 88))
26790	28304377	NGS mutation analysis revealed corresponding mutations in the FGFR3, KIT, KDR and TP53 genes.	('KIT', 'Gene', (69, 72))	('TP53', 'Gene', (82, 86))	('mutations', 'Var', (45, 54))	('FGFR3', 'Gene', '2261', (62, 67))	('KDR', 'Gene', '3791', (74, 77))	('FGFR3', 'Gene', (62, 67))	('TP53', 'Gene', '7157', (82, 86))	('KDR', 'Gene', (74, 77))
26791	28304377	In contrast, the MUG-Myx2a cell lines showed an additional PTEN mutation.	('mutation', 'Var', (64, 72))	('Myx', 'Gene', (21, 24))	('Myx', 'Gene', '83463', (21, 24))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))
26804	28304377	Genomic instability generates a high level of intercellular genetic heterogeneity and has been linked to both drug resistance and poor prognosis in cancer, because therapeutic procedures rely on single tumour biopsy samples.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumour', 'Disease', (202, 208))	('drug resistance', 'Phenotype', 'HP:0020174', (110, 125))	('Genomic instability', 'Var', (0, 19))	('linked', 'Reg', (95, 101))	('intercellular genetic heterogeneity', 'MPA', (46, 81))
26822	28304377	The original tissue and cell lines showed the same STR profile for the markers TH01, D21S11, Penta E, D5S818, D13S317, D7S820, CSF1PO, Penta D, Amelogenin, D8S1179, TPOX, and FGA.	('D21S11', 'Var', (85, 91))	('CSF1PO', 'Var', (127, 133))	('FGA', 'Gene', '2243', (175, 178))	('D7S820', 'Var', (119, 125))	('FGA', 'Gene', (175, 178))	('D5S818', 'Var', (102, 108))	('D8S1179', 'Var', (156, 163))	('D13S317', 'Var', (110, 117))
26825	28304377	After treatment with 0-25 muM doxorubicin, 0-25 muM Verinostat, and 0-25 nM bortezomib for 48 h, cell viability was measured by the MTS assay.	('muM', 'Gene', (26, 29))	('Verinostat', 'Chemical', '-', (52, 62))	('muM', 'Gene', '56925', (48, 51))	('doxorubicin', 'Chemical', 'MESH:D004317', (30, 41))	('bortezomib', 'Chemical', 'MESH:D000069286', (76, 86))	('muM', 'Gene', (48, 51))	('muM', 'Gene', '56925', (26, 29))	('cell viability', 'CPA', (97, 111))	('0-25 nM', 'Var', (68, 75))
26837	28304377	Mutation Analysis of 50 genes by NGS revealed that the primary patient's tumour tissue and MUG-Myx2b showed identical mutations in the FGFR3, KIT, KDR, and TP53 genes.	('KDR', 'Gene', (147, 150))	('KIT', 'Gene', (142, 145))	('tumour', 'Disease', (73, 79))	('mutations', 'Var', (118, 127))	('FGFR3', 'Gene', '2261', (135, 140))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('KDR', 'Gene', '3791', (147, 150))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('Myx', 'Gene', '83463', (95, 98))	('patient', 'Species', '9606', (63, 70))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('FGFR3', 'Gene', (135, 140))	('Myx', 'Gene', (95, 98))
26838	28304377	Conversely, the MUG-Myx2a cell line showed the same mutations as MUG-Myx2b and the primary patient tumour, but had an additional mutation in the PTEN gene (Table 2).	('mutations', 'Var', (52, 61))	('Myx', 'Gene', '83463', (20, 23))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('PTEN', 'Gene', (145, 149))	('mutation', 'Var', (129, 137))	('Myx', 'Gene', '83463', (69, 72))	('PTEN', 'Gene', '5728', (145, 149))	('tumour', 'Disease', (99, 105))	('Myx', 'Gene', (20, 23))	('Myx', 'Gene', (69, 72))	('patient', 'Species', '9606', (91, 98))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
26839	28304377	Low coverage whole genome sequencing was used to determine chromosomal gains and losses in the primary tumour tissue as well as in both MUG-Myx2 cell lines.	('Myx', 'Gene', '83463', (140, 143))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('Myx', 'Gene', (140, 143))	('losses', 'NegReg', (81, 87))	('primary tumour', 'Disease', (95, 109))	('primary tumour', 'Disease', 'MESH:D009369', (95, 109))	('chromosomal gains', 'Var', (59, 76))
26847	28304377	Both MUG-Myx2 cell lines showed a similar pattern of CNVs in these genes and shared the distinct loss of CDKN2a and MLH1, as well as a gain of FGFR1, with the primary tumor tissue (Fig.	('loss', 'NegReg', (97, 101))	('MLH1', 'Gene', (116, 120))	('MLH1', 'Gene', '4292', (116, 120))	('CDKN2a', 'Gene', '1029', (105, 111))	('FGFR1', 'Gene', (143, 148))	('Myx', 'Gene', '83463', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('CNVs', 'Var', (53, 57))	('gain', 'PosReg', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('FGFR1', 'Gene', '2260', (143, 148))	('Myx', 'Gene', (9, 12))	('tumor', 'Disease', (167, 172))	('CDKN2a', 'Gene', (105, 111))
26861	28304377	Gains in gene copy number can drive the expression of oncogenes, whereas decreased gene dosage by hemizygous and/or homozygous deletion may inactivate tumour suppressor genes.	('expression', 'MPA', (40, 50))	('Gains', 'PosReg', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('decreased', 'NegReg', (73, 82))	('gene', 'MPA', (9, 13))	('gene dosage', 'MPA', (83, 94))	('drive', 'PosReg', (30, 35))	('inactivate', 'NegReg', (140, 150))	('deletion', 'Var', (127, 135))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Disease', (151, 157))	('oncogenes', 'MPA', (54, 63))
26868	28304377	FGFR1 amplification is a common feature of several tumour types and activates the cell cycle via the RAS pathway.	('cell cycle', 'CPA', (82, 92))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('activates', 'PosReg', (68, 77))	('amplification', 'Var', (6, 19))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))	('RAS pathway', 'Pathway', (101, 112))
26871	28304377	Our NGS data revealed, that both MUG-Myx2a and MUG-Myx2b cells possessed the p53 mutation R213Q, whereas, only MUG-Myx2a showed the PTEN R173H mutation.	('R213Q', 'Mutation', 'rs587778720', (90, 95))	('PTEN', 'Gene', (132, 136))	('Myx', 'Gene', '83463', (51, 54))	('PTEN', 'Gene', '5728', (132, 136))	('Myx', 'Gene', '83463', (115, 118))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('Myx', 'Gene', (51, 54))	('R213Q', 'Var', (90, 95))	('Myx', 'Gene', '83463', (37, 40))	('R173H', 'Mutation', 'rs121913294', (137, 142))	('Myx', 'Gene', (115, 118))	('Myx', 'Gene', (37, 40))
26874	28304377	Furthermore, mutations in p53 have also been identified as the most common genetic alterations in sarcoma.	('p53', 'Gene', (26, 29))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcoma', 'Disease', (98, 105))	('p53', 'Gene', '7157', (26, 29))	('mutations', 'Var', (13, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('common', 'Reg', (68, 74))
26878	28304377	The combined inactivation pf p53 and PTEN could greatly accelerate tumour development.	('inactivation pf', 'Var', (13, 28))	('tumour', 'Disease', (67, 73))	('accelerate', 'PosReg', (56, 66))	('p53', 'Gene', (29, 32))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('p53', 'Gene', '7157', (29, 32))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (67, 73))
26879	28304377	Mutational analysis of p53 and PTEN in STS tissue samples revealed an incidence of 25.6% (22 out of 86) p53 mutations but only 2.3% (2 out of 86) PTEN mutations.	('PTEN', 'Gene', (31, 35))	('p53', 'Gene', (104, 107))	('PTEN', 'Gene', (146, 150))	('PTEN', 'Gene', '5728', (31, 35))	('PTEN', 'Gene', '5728', (146, 150))	('mutations', 'Var', (108, 117))	('p53', 'Gene', '7157', (104, 107))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))
26881	28304377	This mutation reduces PTEN activity by 50%.	('reduces', 'NegReg', (14, 21))	('PTEN', 'Gene', (22, 26))	('mutation', 'Var', (5, 13))	('PTEN', 'Gene', '5728', (22, 26))
26885	28304377	Several studies have reported the genetic polymorphism of the KDR gene and the implicated risk of coronary artery diseases.	('coronary artery diseases', 'Disease', (98, 122))	('KDR', 'Gene', '3791', (62, 65))	('coronary artery diseases', 'Disease', 'MESH:D003324', (98, 122))	('genetic polymorphism', 'Var', (34, 54))	('KDR', 'Gene', (62, 65))
26887	28304377	Mutations in the KIT receptor tyrosine kinase, which are commonly present in gastrointestinal stromal tumours (GISTs; 70-80% of all cases) are clustered in four exons.	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (77, 109))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('receptor tyrosine kinase', 'Gene', (21, 45))	('gastrointestinal stromal tumours', 'Disease', (77, 109))	('receptor tyrosine kinase', 'Gene', '5979', (21, 45))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('Mutations', 'Var', (0, 9))
26888	28304377	The FGFR3 F386L polymorphism has been reported in association with low-grade tumours and early disease stage in prostate cancer.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('F386L', 'Mutation', 'rs17881656', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('association', 'Reg', (50, 61))	('prostate cancer', 'Disease', (112, 127))	('tumours', 'Disease', (77, 84))	('FGFR3', 'Gene', (4, 9))	('F386L', 'Var', (10, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))	('FGFR3', 'Gene', '2261', (4, 9))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
27109	26217552	For seven studies which evaluated for PFS or MFS, the presence of SS18-SSX1 may indicate a lower survival probability than that of SS18-SSX2, although the effect did not reach a level of statistical significance (P = 0.09).	('lower', 'NegReg', (91, 96))	('SSX2', 'Gene', '6757', (136, 140))	('SS18', 'Gene', (131, 135))	('SSX1', 'Gene', (71, 75))	('survival probability', 'CPA', (97, 117))	('presence', 'Var', (54, 62))	('SS18', 'Gene', '6760', (66, 70))	('SSX2', 'Gene', (136, 140))	('SS18', 'Gene', '6760', (131, 135))	('SSX1', 'Gene', '6756', (71, 75))	('SS18', 'Gene', (66, 70))
27116	26217552	The extent of the prognostic significance of SS18T-SSX fusion gene variant remains unclear.	('SS18', 'Gene', '6760', (45, 49))	('variant', 'Var', (67, 74))	('SSX', 'Gene', '6757', (51, 54))	('SSX', 'Gene', (51, 54))	('SS18', 'Gene', (45, 49))
27155	21373757	Results from experiments involving the ectopic expression of a Myc-tagged CAV1 protein in EWS cells as well as the supplementation of culture media with purified CAV1 protein followed by its intracellular localization using immunofluorescence demonstrated that EWS cells secrete CAV1, that they are able to take up the secreted protein, and that extracellular CAV1 enhances EWS cell proliferation.	('EWS', 'Gene', '2130', (374, 377))	('EWS', 'Gene', (90, 93))	('EWS', 'Gene', '2130', (261, 264))	('extracellular', 'Var', (346, 359))	('Myc', 'Gene', (63, 66))	('EWS', 'Phenotype', 'HP:0012254', (90, 93))	('CAV1', 'Gene', '857', (162, 166))	('CAV1', 'Gene', '857', (74, 78))	('CAV1', 'Gene', '857', (360, 364))	('EWS', 'Gene', (374, 377))	('EWS', 'Gene', (261, 264))	('enhances', 'PosReg', (365, 373))	('CAV1', 'Gene', '857', (279, 283))	('EWS', 'Gene', '2130', (90, 93))	('Myc', 'Gene', '4609', (63, 66))	('EWS', 'Phenotype', 'HP:0012254', (374, 377))	('CAV1', 'Gene', (162, 166))	('EWS', 'Phenotype', 'HP:0012254', (261, 264))	('CAV1', 'Gene', (74, 78))	('CAV1', 'Gene', (360, 364))	('CAV1', 'Gene', (279, 283))
27158	21373757	Most Ewing's sarcoma tumors are characterized by a t(11;22)(q24;q12) chromosomal translocation, which generates the chimeric EWS/FLI protein by fusion of the EWSR1 gene on chromosome 22 and the FLI1 gene on chromosome 11.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (5, 20))	('EWS', 'Phenotype', 'HP:0012254', (125, 128))	('EWS', 'Gene', '2130', (125, 128))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('EWS', 'Gene', (158, 161))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (51, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('EWSR1', 'Gene', '2130', (158, 163))	('fusion', 'Var', (144, 150))	('FLI1', 'Gene', (194, 198))	("Ewing's sarcoma tumors", 'Disease', 'MESH:C563168', (5, 27))	('EWS', 'Phenotype', 'HP:0012254', (158, 161))	('FLI', 'Gene', (194, 197))	("Ewing's sarcoma tumors", 'Disease', (5, 27))	('FLI', 'Gene', (129, 132))	('EWS', 'Gene', (125, 128))	('FLI1', 'Gene', '2313', (194, 198))	('EWS', 'Gene', '2130', (158, 161))	('FLI', 'Gene', '2314', (194, 197))	('FLI', 'Gene', '2314', (129, 132))	('EWSR1', 'Gene', (158, 163))
27163	21373757	Genes transcriptionally regulated by EWS/FLI1 have been cited often as important mediators of oncogenesis, suggesting that targeting them may improve EWS treatment.	('FLI1', 'Gene', '2313', (41, 45))	('EWS', 'Phenotype', 'HP:0012254', (37, 40))	('EWS', 'Phenotype', 'HP:0012254', (150, 153))	('EWS', 'Gene', '2130', (150, 153))	('targeting', 'Var', (123, 132))	('EWS', 'Gene', (150, 153))	('EWS', 'Gene', '2130', (37, 40))	('EWS', 'Gene', (37, 40))	('improve', 'PosReg', (142, 149))	('FLI1', 'Gene', (41, 45))
27169	21373757	Knocking CAV1 down increased the sensitivity of EWS cells to clinically relevant agents such as doxorubicin and cisplatin, with a concurrent induction of apoptosis.	('EWS', 'Gene', (48, 51))	('CAV1', 'Gene', (9, 13))	('EWS', 'Phenotype', 'HP:0012254', (48, 51))	('EWS', 'Gene', '2130', (48, 51))	('down', 'NegReg', (14, 18))	('induction', 'Reg', (141, 150))	('cisplatin', 'MPA', (112, 121))	('apoptosis', 'CPA', (154, 163))	('CAV1', 'Gene', '857', (9, 13))	('increased', 'PosReg', (19, 28))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('sensitivity', 'MPA', (33, 44))	('Knocking', 'Var', (0, 8))
27175	21373757	Elevated CAV1 secretion has been detected in parallel to the increased aggressiveness of prostate cancer cell lines, and the secreted CAV1 has been associated with proangiogenic activities and stimulation of proliferation and progression of prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (241, 256))	('CAV1', 'Gene', (9, 13))	('prostate cancer', 'Phenotype', 'HP:0012125', (241, 256))	('increased', 'PosReg', (61, 70))	('prostate cancer', 'Disease', (241, 256))	('prostate cancer', 'Disease', 'MESH:D011471', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('secreted', 'Var', (125, 133))	('CAV1', 'Gene', (134, 138))	('secretion', 'MPA', (14, 23))	('aggressiveness of prostate cancer', 'Disease', (71, 104))	('aggressiveness', 'Phenotype', 'HP:0000718', (71, 85))	('CAV1', 'Gene', '857', (9, 13))	('aggressiveness of prostate cancer', 'Disease', 'MESH:D011471', (71, 104))	('associated', 'Reg', (148, 158))	('progression', 'CPA', (226, 237))	('proliferation', 'CPA', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('stimulation', 'PosReg', (193, 204))	('CAV1', 'Gene', '857', (134, 138))	('proangiogenic activities', 'CPA', (164, 188))
27185	21373757	The CAV1 knocked-down A4573/shCAV1 cells were generated and maintained as described earlier.	('CAV1', 'Gene', (30, 34))	('CAV1', 'Gene', (4, 8))	('knocked-down', 'Var', (9, 21))	('CAV1', 'Gene', '857', (30, 34))	('CAV1', 'Gene', '857', (4, 8))
27227	21373757	After 48 h under these conditions, the CAV1 knocked-down cells were harvested, lysed and the lysates subjected to SDS-PAGE and CAV1 immunodetection with anti-CAV1 antibodies.	('CAV1', 'Gene', '857', (158, 162))	('knocked-down', 'Var', (44, 56))	('CAV1', 'Gene', (39, 43))	('CAV1', 'Gene', (127, 131))	('CAV1', 'Gene', (158, 162))	('CAV1', 'Gene', '857', (39, 43))	('CAV1', 'Gene', '857', (127, 131))	('SDS', 'Chemical', 'MESH:D012967', (114, 117))
27238	21373757	Following the detection of expressed MD-CAV1 in the culture fluids of EWS cells, we investigated the possible uptake of the ectopically expressed, tagged CAV1 by A4573 cells.	('CAV1', 'Gene', (40, 44))	('EWS', 'Phenotype', 'HP:0012254', (70, 73))	('EWS', 'Gene', '2130', (70, 73))	('EWS', 'Gene', (70, 73))	('CAV1', 'Gene', (154, 158))	('CAV1', 'Gene', '857', (40, 44))	('investigated', 'Reg', (84, 96))	('tagged', 'Var', (147, 153))	('CAV1', 'Gene', '857', (154, 158))
27262	21373757	Interestingly, there does not seem to be a correlation between the total endogenous levels of CAV1 present in the three EWS cell lines and the relative levels of CAV1 that they secrete, as A4573 cells contain the highest levels of cellular CAV1 protein, whereas the largest amounts of secreted CAV1 were found in conditioned media from SK-ES-1 cell cultures.	('CAV1', 'Gene', (294, 298))	('CAV1', 'Gene', '857', (240, 244))	('A4573', 'Var', (189, 194))	('CAV1', 'Gene', '857', (162, 166))	('CAV1', 'Gene', (240, 244))	('CAV1', 'Gene', '857', (94, 98))	('CAV1', 'Gene', '857', (294, 298))	('SK-ES-1', 'CellLine', 'CVCL:0627', (336, 343))	('EWS', 'Phenotype', 'HP:0012254', (120, 123))	('EWS', 'Gene', '2130', (120, 123))	('EWS', 'Gene', (120, 123))	('CAV1', 'Gene', (162, 166))	('CAV1', 'Gene', (94, 98))
27263	21373757	Culturing A4573/shCav1 cells, which were engineered to express diminished levels of CAV1 by shRNA-mediated CAV1 knockdown, with conditioned medium prepared from A4573 cell culture fluids resulted in an increase in the levels of intracellular CAV1, strongly suggesting that the secreted protein was taken up by the A4573/shCav1 cells (Fig.	('CAV1', 'Gene', (84, 88))	('CAV1', 'Gene', '857', (107, 111))	('CAV1', 'Gene', '857', (84, 88))	('knockdown', 'Var', (112, 121))	('CAV1', 'Gene', '857', (242, 246))	('increase', 'PosReg', (202, 210))	('CAV1', 'Gene', (107, 111))	('CAV1', 'Gene', (242, 246))
27272	21373757	Although additional studies are needed to characterize the mechanism by which CAV1 enters the secretory pathway and other pathways influenced by it, as well as the mechanisms by which CAV1 is taken up by EWS cells, the current study clearly shows that CAV1 is secreted by EWS cells, that EWS cells are able to take up the secreted protein, and that secreted CAV1 enhances the proliferation of EWS cells.	('EWS', 'Phenotype', 'HP:0012254', (393, 396))	('EWS', 'Phenotype', 'HP:0012254', (204, 207))	('EWS', 'Gene', (288, 291))	('CAV1', 'Gene', '857', (252, 256))	('EWS', 'Gene', (272, 275))	('EWS', 'Gene', '2130', (393, 396))	('CAV1', 'Gene', (78, 82))	('EWS', 'Gene', '2130', (204, 207))	('EWS', 'Phenotype', 'HP:0012254', (288, 291))	('EWS', 'Phenotype', 'HP:0012254', (272, 275))	('CAV1', 'Gene', '857', (358, 362))	('CAV1', 'Gene', '857', (184, 188))	('CAV1', 'Gene', (252, 256))	('enhances', 'PosReg', (363, 371))	('proliferation', 'CPA', (376, 389))	('EWS', 'Gene', '2130', (288, 291))	('EWS', 'Gene', '2130', (272, 275))	('EWS', 'Gene', (393, 396))	('EWS', 'Gene', (204, 207))	('secreted', 'Var', (349, 357))	('CAV1', 'Gene', '857', (78, 82))	('CAV1', 'Gene', (358, 362))	('CAV1', 'Gene', (184, 188))
27273	21373757	In light of these results, it seems possible that secreted CAV1 may promote the growth of metastases in vivo, and this additional molecular insight raises even further the possibility of using CAV1 as a therapeutic target for Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (226, 241))	('metastases', 'Disease', (90, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('promote', 'PosReg', (68, 75))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (226, 241))	('CAV1', 'Gene', '857', (193, 197))	('CAV1', 'Gene', (59, 63))	('secreted', 'Var', (50, 58))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (226, 241))	('CAV1', 'Gene', (193, 197))	('CAV1', 'Gene', '857', (59, 63))
27298	28536479	MicroRNA-214 (miR-214) and microRNA-126 (miR-126) regulate angiogenesis, proliferation, migration, and cell death of cancer cells; and thus, dysregulation of these 2 miRNAs critically influences tumour progression.	('regulate', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('proliferation', 'CPA', (73, 86))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('death of cancer', 'Disease', (108, 123))	('tumour', 'Disease', (195, 201))	('migration', 'CPA', (88, 97))	('microRNA-126', 'Gene', (27, 39))	('influences', 'Reg', (184, 194))	('death of cancer', 'Disease', 'MESH:D003643', (108, 123))	('angiogenesis', 'CPA', (59, 71))	('dysregulation', 'Var', (141, 154))	('MicroRNA-214', 'Gene', '100886064', (0, 12))	('MicroRNA-214', 'Gene', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('microRNA-126', 'Gene', '100886141', (27, 39))
27306	28536479	The purpose of this study was to assess the potential of circulating miRNA-214 and -126 for use as diagnostic and prognostic biomarkers in various canine neoplastic diseases, as well as for obtaining referential information for exploring novel biomarkers in human cancers.	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('neoplastic diseases', 'Disease', (154, 173))	('human', 'Species', '9606', (258, 263))	('cancers', 'Disease', (264, 271))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('neoplastic disease', 'Phenotype', 'HP:0002664', (154, 172))	('miRNA-214', 'Var', (69, 78))	('canine', 'Species', '9615', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('neoplastic diseases', 'Disease', 'MESH:D009386', (154, 173))
27320	28536479	For the accurate detection and quantification of these short miRNAs having only 22 nucleotides, we performed a looped-primer RT-qPCR using the TaqMan  MicroRNA Assays (Applied Biosystems , Thermo Fisher Scientific, MA, USA) for miR-214 (AB Assay ID 002306), miR-126 (AB Assay ID 002228) and miR-16 (AB Assay ID 000391) with the TaqMan  MicroRNA Reverse Transcription Kit (Applied Biosystems ).	('miR-16', 'Gene', '51573', (291, 297))	('miR-16', 'Gene', (291, 297))	('miR-214', 'Var', (228, 235))
27364	28536479	On the other hand, the epithelial tumour cases with high circulating miR-126 had a significantly shorter survival duration (P = 0.041) than those with low miR-126 (Fig.	('high circulating', 'Var', (52, 68))	('epithelial tumour', 'Disease', 'MESH:D000077216', (23, 40))	('epithelial tumour', 'Disease', (23, 40))	('epithelial tumour', 'Phenotype', 'HP:0031492', (23, 40))	('miR-126', 'Gene', (69, 76))	('shorter', 'NegReg', (97, 104))	('survival duration', 'CPA', (105, 122))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
27369	28536479	As a result, the non-epithelial tumour cases with a high level of circulating miR-214 showed a significantly shorter survival duration when the osteosarcoma cases were excluded (Fig.	('epithelial tumour', 'Phenotype', 'HP:0031492', (21, 38))	('high level', 'Var', (52, 62))	('osteosarcoma', 'Disease', (144, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (144, 156))	('miR-214', 'Gene', (78, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (144, 156))	('survival duration', 'CPA', (117, 134))	('epithelial tumour', 'Disease', 'MESH:D000077216', (21, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('epithelial tumour', 'Disease', (21, 38))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('shorter', 'NegReg', (109, 116))
27372	28536479	As to melanoma cases, adenocarcinoma cases with high miR-126 levels had a significantly shorter survival duration, whilst those cases with high miR-214 levels did not (Fig.	('shorter', 'NegReg', (88, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('adenocarcinoma', 'Disease', 'MESH:D000230', (22, 36))	('high miR-126 levels', 'Var', (48, 67))	('survival duration', 'CPA', (96, 113))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('adenocarcinoma', 'Disease', (22, 36))
27374	28536479	Taken together, these results showed that the cases with high miR-214 levels had a shorter survival duration in the group of non-epithelial tumours excluding osteosarcomas and in the adenocarcinomas of the epithelial group; furthermore, the adenocarcinoma and melanoma cases with high miR-126 levels had a shorter survival time than those with low levels.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('survival duration', 'CPA', (91, 108))	('osteosarcomas', 'Phenotype', 'HP:0002669', (158, 171))	('high', 'Var', (57, 61))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('shorter', 'NegReg', (83, 90))	('non-epithelial tumours', 'Disease', (125, 147))	('shorter', 'NegReg', (306, 313))	('survival time', 'CPA', (314, 327))	('adenocarcinoma and melanoma', 'Disease', 'MESH:D008545', (241, 268))	('osteosarcoma', 'Phenotype', 'HP:0002669', (158, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('osteosarcomas', 'Disease', 'MESH:D012516', (158, 171))	('sarcomas', 'Phenotype', 'HP:0100242', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('adenocarcinomas', 'Disease', 'MESH:D000230', (183, 198))	('adenocarcinomas', 'Disease', (183, 198))	('miR-126', 'Gene', (285, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('high', 'Var', (280, 284))	('osteosarcomas', 'Disease', (158, 171))	('epithelial tumour', 'Phenotype', 'HP:0031492', (129, 146))	('non-epithelial tumours', 'Disease', 'MESH:D000077216', (125, 147))	('miR-214', 'Gene', (62, 69))
27382	28536479	These specificities and sensitivities were relatively high compared to several biomarkers established in human medicine, such as CEA for colorectal cancer (specificity, 87%; sensitivity, 36%) and pancreatic carcinoma (specificities, 66.4-87.3%; sensitivities, 48.4-71.0%), the combination of CEA, NSE, CYFRA21-1, and CA-125 for lung cancer (specificity, 83.9%; sensitivity, 34.8%), and AFP for hepatocellular carcinoma (specificity, 80-94%; sensitivity, 41-65%).	('AFP', 'Gene', (386, 389))	('CEA', 'Gene', '1084', (292, 295))	('AFP', 'Gene', '174', (386, 389))	('colorectal cancer', 'Disease', (137, 154))	('CYFRA21-1', 'Var', (302, 311))	('CA-125', 'Gene', '94025', (317, 323))	('lung cancer', 'Disease', 'MESH:D008175', (328, 339))	('human', 'Species', '9606', (105, 110))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (394, 418))	('lung cancer', 'Phenotype', 'HP:0100526', (328, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('NSE', 'Gene', '2026', (297, 300))	('CEA', 'Gene', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('hepatocellular carcinoma', 'Disease', (394, 418))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (196, 216))	('NSE', 'Gene', (297, 300))	('CA-125', 'Gene', (317, 323))	('pancreatic carcinoma', 'Disease', (196, 216))	('CEA', 'Gene', '1084', (129, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (409, 418))	('CEA', 'Gene', (292, 295))	('lung cancer', 'Disease', (328, 339))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (394, 418))
27386	28536479	Circulating miR-214 has been suggested to be a diagnostic and prognostic biomarker for various human cancers.	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('miR-214', 'Gene', (12, 19))	('Circulating', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
27394	28536479	It was reported that miR-214 regulates osteoblastic differentiation of mesenchymal stem cells, and the level of circulating miR-214 is increased in a genetically engineered mouse model of osteosarcoma and in human osteosarcoma patients.	('osteosarcoma', 'Disease', (188, 200))	('osteosarcoma', 'Disease', 'MESH:D012516', (214, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('osteosarcoma', 'Disease', 'MESH:D012516', (188, 200))	('osteosarcoma', 'Phenotype', 'HP:0002669', (214, 226))	('patients', 'Species', '9606', (227, 235))	('increased', 'PosReg', (135, 144))	('mouse', 'Species', '10090', (173, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('miR-214', 'Gene', (21, 28))	('human', 'Species', '9606', (208, 213))	('osteosarcoma', 'Disease', (214, 226))	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))	('regulates', 'Reg', (29, 38))	('miR-214', 'Var', (124, 131))
27396	28536479	Adenocarcinoma cases with high levels of circulating miR-214 had a significantly shorter survival time, although only a few cases of them classified into the group with a high or moderate increase of circulating miR-214 in the cluster analysis.	('Adenocarcinoma', 'Disease', (0, 14))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('miR-214', 'Gene', (53, 60))	('survival time', 'CPA', (89, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('high levels', 'Var', (26, 37))	('shorter', 'NegReg', (81, 88))
27398	28536479	Given that exosomal miR-214 induces angiogenesis, abundant extracellular miR-214 may contribute to the local invasion and metastasis through accelerating tumour angiogenesis in canine adenocarcinomas.	('adenocarcinomas', 'Disease', (184, 199))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('miR-214', 'Var', (73, 80))	('exosomal', 'Var', (11, 19))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('induces', 'PosReg', (28, 35))	('angiogenesis', 'CPA', (36, 48))	('canine', 'Species', '9615', (177, 183))	('local invasion', 'CPA', (103, 117))	('tumour', 'Disease', (154, 160))	('contribute', 'Reg', (85, 95))	('accelerating', 'PosReg', (141, 153))	('adenocarcinomas', 'Disease', 'MESH:D000230', (184, 199))	('metastasis', 'CPA', (122, 132))	('miR-214', 'Gene', (20, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
27399	28536479	Circulating miR-126, as well as miR-214, has been suggested to be a diagnostic biomarker for human neoplastic disease.	('human', 'Species', '9606', (93, 98))	('miR-214', 'Var', (32, 39))	('neoplastic disease', 'Phenotype', 'HP:0002664', (99, 117))	('neoplastic disease', 'Disease', 'MESH:D009386', (99, 117))	('neoplastic disease', 'Disease', (99, 117))	('miR-126', 'Gene', (12, 19))
27422	28536479	Although we demonstrated that the other established clinical parameters did not show strong correlation with the levels of circulating miR-214 and -126 in this study, it is still possible that the levels of these circulating miRNAs might increase or decrease in other non-neoplastic diseases: several studies examining human diseases reported that the level of circulating miR-214 is decreased in coronary artery disease, as well as that circulating miR-126 is increased in moyamoya disease, allergic rhinitis, and asthma but decreased in atherosclerosis, atrial fibrillation, heart failure, and type-2 diabetes mellitus.	('neoplastic diseases', 'Disease', (272, 291))	('decreased', 'NegReg', (384, 393))	('moyamoya disease', 'Disease', 'MESH:D009072', (474, 490))	('decreased', 'NegReg', (526, 535))	('asthma', 'Disease', (515, 521))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (556, 575))	('miR-214 and -126', 'Gene', '100886064;100886141', (135, 151))	('allergic rhinitis', 'Disease', 'MESH:D065631', (492, 509))	('coronary artery disease', 'Disease', 'MESH:D003324', (397, 420))	('human', 'Species', '9606', (319, 324))	('allergic rhinitis', 'Phenotype', 'HP:0003193', (492, 509))	('circulating miR-126', 'Var', (438, 457))	('heart failure', 'Phenotype', 'HP:0001635', (577, 590))	('heart failure', 'Disease', 'MESH:D006333', (577, 590))	('type-2 diabetes mellitus', 'Disease', (596, 620))	('non-neoplastic disease', 'Disease', (268, 290))	('coronary artery disease', 'Disease', (397, 420))	('type-2 diabetes mellitus', 'Disease', 'MESH:D003924', (596, 620))	('atrial fibrillation', 'Disease', 'MESH:D001281', (556, 575))	('moyamoya disease', 'Phenotype', 'HP:0011834', (474, 490))	('atrial fibrillation', 'Disease', (556, 575))	('neoplastic disease', 'Phenotype', 'HP:0002664', (272, 290))	('neoplastic diseases', 'Disease', 'MESH:D009386', (272, 291))	('non-neoplastic disease', 'Disease', 'MESH:D000073296', (268, 290))	('atherosclerosis', 'Disease', 'MESH:D050197', (539, 554))	('heart failure', 'Disease', (577, 590))	('rhinitis', 'Phenotype', 'HP:0012384', (501, 509))	('atherosclerosis', 'Disease', (539, 554))	('increased', 'PosReg', (461, 470))	('2 diabetes', 'Phenotype', 'HP:0005978', (601, 611))	('atherosclerosis', 'Phenotype', 'HP:0002621', (539, 554))	('clinical', 'Species', '191496', (52, 60))	('asthma', 'Disease', 'MESH:D001249', (515, 521))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (603, 620))	('asthma', 'Phenotype', 'HP:0002099', (515, 521))	('moyamoya disease', 'Disease', (474, 490))	('allergic rhinitis', 'Disease', (492, 509))
27434	27783944	An interaction with Ewing's sarcoma breakpoint protein EWS defines a specific oncogenic mechanism of ETS factors rearranged in prostate cancer More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor.	('chromosomal rearrangement', 'Var', (183, 208))	('prostate cancer', 'Disease', 'MESH:D011471', (127, 142))	("Ewing's sarcoma", 'Disease', (20, 35))	('EWS', 'Gene', (55, 58))	('prostate tumors', 'Disease', (160, 175))	('EWS', 'Gene', '2130', (55, 58))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (20, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (20, 35))	('prostate tumor', 'Phenotype', 'HP:0100787', (160, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('rearranged', 'Var', (113, 123))	('prostate cancer', 'Disease', (127, 142))	('prostate tumors', 'Disease', 'MESH:D011471', (160, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('expression', 'MPA', (231, 241))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
27443	27783944	ETV1 and ETV4 rearrangements occur in an additional 5-10% of tumors.	('ETV4', 'Gene', '2118', (9, 13))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ETV1', 'Gene', (0, 4))	('ETV1', 'Gene', '2115', (0, 4))	('rearrangements', 'Var', (14, 28))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('ETV4', 'Gene', (9, 13))
27464	27783944	This study investigated the role of the wild-type EWS protein in the oncogenic mechanism of ETS genes rearranged in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('rearranged', 'Var', (102, 112))	('prostate cancer', 'Disease', (116, 131))	('ETS genes', 'Gene', (92, 101))	('EWS', 'Gene', '2130', (50, 53))	('EWS', 'Gene', (50, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (116, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))
27466	27783944	Fusion of the EWS N-terminus with any ETS protein promoted prostate cell migration indicating that this interaction is sufficient for an oncogenic phenotype.	('Fusion', 'Var', (0, 6))	('promoted', 'PosReg', (50, 58))	('EWS', 'Gene', '2130', (14, 17))	('EWS', 'Gene', (14, 17))	('prostate cell migration', 'CPA', (59, 82))
27467	27783944	Furthermore, using both a knockdown of EWS, and a point mutation in ERG that fails to interact with EWS, we demonstrate that the EWS-ETS interaction is critical for oncogenic ETS proteins to activate gene expression and drive cell migration and transformation in prostate cells.	('point mutation', 'Var', (50, 64))	('ERG', 'Gene', (68, 71))	('transformation', 'CPA', (245, 259))	('drive', 'PosReg', (220, 225))	('cell migration', 'CPA', (226, 240))	('EWS', 'Gene', (39, 42))	('EWS', 'Gene', (129, 132))	('activate', 'PosReg', (191, 199))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', '2130', (129, 132))	('ERG', 'Gene', '2078', (68, 71))	('gene expression', 'MPA', (200, 215))	('EWS', 'Gene', '2130', (100, 103))	('EWS', 'Gene', (100, 103))
27491	27783944	However, in Ewing's sarcoma, both FLI1 and ERG are oncogenic when fused to the N-terminus of EWS due to a chromosomal rearrangement.	('FLI1', 'Gene', (34, 38))	('fused', 'Var', (66, 71))	('EWS', 'Gene', '2130', (93, 96))	('EWS', 'Gene', (93, 96))	('FLI1', 'Gene', '2130', (34, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (12, 27))	("Ewing's sarcoma", 'Disease', (12, 27))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (12, 27))	('ERG', 'Gene', '2078', (43, 46))	('ERG', 'Gene', (43, 46))
27506	27783944	However, expression of both ERG and myristoylated AKT together resulted in a dramatic increase in clonogenic survival (Figure 2C).	('myristoylated', 'Var', (36, 49))	('ERG', 'Gene', '2078', (28, 31))	('increase', 'PosReg', (86, 94))	('AKT', 'Gene', '207', (50, 53))	('ERG', 'Gene', (28, 31))	('AKT', 'Gene', (50, 53))	('clonogenic survival', 'CPA', (98, 117))
27507	27783944	Similar to the cell migration phenotype, FLI1 expression with activated AKT caused significantly lower increases in clonogenic growth than ERG with activated AKT, but EWS fused to FLI1 was similar to ERG (Figure 2C).	('AKT', 'Gene', '207', (72, 75))	('expression', 'Var', (46, 56))	('increases', 'PosReg', (103, 112))	('clonogenic growth', 'CPA', (116, 133))	('EWS', 'Gene', (167, 170))	('AKT', 'Gene', (72, 75))	('ERG', 'Gene', '2078', (200, 203))	('FLI1', 'Gene', '2130', (41, 45))	('FLI1', 'Gene', (180, 184))	('FLI1', 'Gene', '2130', (180, 184))	('AKT', 'Gene', '207', (158, 161))	('lower', 'NegReg', (97, 102))	('ERG', 'Gene', '2078', (139, 142))	('EWS', 'Gene', '2130', (167, 170))	('ERG', 'Gene', (200, 203))	('ERG', 'Gene', (139, 142))	('FLI1', 'Gene', (41, 45))	('AKT', 'Gene', (158, 161))
27510	27783944	A deletion of the C-terminus of ERG after amino acid 391 resulted in a loss of EWS binding.	('EWS', 'Gene', '2130', (79, 82))	('EWS', 'Gene', (79, 82))	('deletion', 'Var', (2, 10))	('ERG', 'Gene', '2078', (32, 35))	('loss', 'NegReg', (71, 75))	('ERG', 'Gene', (32, 35))
27513	27783944	A deletion analysis of ETV5 identified a region necessary for EWS interaction that was N-terminal to the ETS domain spanning amino acids 357-368 (Figure 3B).	('interaction', 'Interaction', (66, 77))	('deletion', 'Var', (2, 10))	('ETV5', 'Gene', '2119', (23, 27))	('ETV5', 'Gene', (23, 27))	('EWS', 'Gene', '2130', (62, 65))	('EWS', 'Gene', (62, 65))
27521	27783944	To test if the P436A mutation disrupted the ERG-EWS interaction in cells, Flag-ERG and Flag-ERG P436A were expressed in RWPE1 cells and immunoprecipitated with anti-ERG antibody.	('EWS', 'Gene', (48, 51))	('ERG', 'Gene', (92, 95))	('ERG', 'Gene', '2078', (79, 82))	('ERG', 'Gene', '2078', (165, 168))	('EWS', 'Gene', '2130', (48, 51))	('ERG', 'Gene', (165, 168))	('ERG', 'Gene', (79, 82))	('P436A', 'Mutation', 'p.P436A', (96, 101))	('disrupted', 'NegReg', (30, 39))	('ERG', 'Gene', '2078', (44, 47))	('ERG', 'Gene', '2078', (92, 95))	('RWPE1', 'CellLine', 'CVCL:3791', (120, 125))	('ERG', 'Gene', (44, 47))	('P436A', 'Mutation', 'p.P436A', (15, 20))	('P436A mutation', 'Var', (15, 29))	('P436A', 'Var', (96, 101))
27527	27783944	This indicated that the EWS interaction was not only necessary for this ERG function, but that loss of the EWS interaction reversed ERG's function.	('EWS', 'Gene', '2130', (24, 27))	('EWS', 'Gene', (24, 27))	('EWS', 'Gene', '2130', (107, 110))	('EWS', 'Gene', (107, 110))	('ERG', 'Gene', '2078', (132, 135))	('ERG', 'Gene', '2078', (72, 75))	('ERG', 'Gene', (72, 75))	('ERG', 'Gene', (132, 135))	('loss', 'Var', (95, 99))
27528	27783944	A similar result was observed in the clonogenic growth assay, where the P436A mutation abrogated the ability of ERG to promote colony formation (Figure 4B).	('ERG', 'Gene', (112, 115))	('colony formation', 'CPA', (127, 143))	('clonogenic growth assay', 'CPA', (37, 60))	('P436A', 'Mutation', 'p.P436A', (72, 77))	('ERG', 'Gene', '2078', (112, 115))	('P436A', 'Var', (72, 77))	('abrogated', 'NegReg', (87, 96))
27532	27783944	EWS knockdown significantly decreased migration of PC3 cells, but not DU145 cells (Figure 4C and Figure S4C).	('decreased', 'NegReg', (28, 37))	('PC3', 'Gene', '3853', (51, 54))	('knockdown', 'Var', (4, 13))	('PC3', 'Gene', (51, 54))	('DU145', 'CellLine', 'CVCL:0105', (70, 75))	('migration', 'CPA', (38, 47))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
27534	27783944	EWS knockdown had no effect on PC3 or DU145 cell proliferation (Figure S4D).	('PC3', 'Gene', '3853', (31, 34))	('DU145', 'CellLine', 'CVCL:0105', (38, 43))	('knockdown', 'Var', (4, 13))	('PC3', 'Gene', (31, 34))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
27537	27783944	The necessity of EWS for this migration was compared by EWS knockdown in RWPE1-ERG and RWPE1-KRAS cells.	('KRAS', 'Gene', (93, 97))	('EWS', 'Gene', '2130', (56, 59))	('EWS', 'Gene', (56, 59))	('ERG', 'Gene', '2078', (79, 82))	('ERG', 'Gene', (79, 82))	('RWPE1', 'CellLine', 'CVCL:3791', (73, 78))	('KRAS', 'Gene', '3845', (93, 97))	('knockdown', 'Var', (60, 69))	('EWS', 'Gene', '2130', (17, 20))	('EWS', 'Gene', (17, 20))	('RWPE1', 'CellLine', 'CVCL:3791', (87, 92))
27538	27783944	EWS knockdown significantly reduced migration in ERG over-expressing cells, but not the KRAS over-expressing cells (Figure 4D and Figure S4C).	('reduced', 'NegReg', (28, 35))	('over-expressing', 'PosReg', (53, 68))	('ERG', 'Gene', '2078', (49, 52))	('reduced migration in ERG', 'Phenotype', 'HP:0000654', (28, 52))	('ERG', 'Gene', (49, 52))	('KRAS', 'Gene', (88, 92))	('migration', 'CPA', (36, 45))	('KRAS', 'Gene', '3845', (88, 92))	('knockdown', 'Var', (4, 13))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
27539	27783944	EWS knockdown had no effect on RWPE1-ERG or RWPE1-KRAS cell proliferation (Figure S4E).	('RWPE1', 'CellLine', 'CVCL:3791', (31, 36))	('KRAS', 'Gene', (50, 54))	('KRAS', 'Gene', '3845', (50, 54))	('RWPE1', 'CellLine', 'CVCL:3791', (44, 49))	('ERG', 'Gene', '2078', (37, 40))	('knockdown', 'Var', (4, 13))	('ERG', 'Gene', (37, 40))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
27541	27783944	The oncogenic ETS protein ETV4 is required for anchorage independent growth of PC3 prostate cancer cells, and loss of EWS significantly inhibited growth of PC3 cells in soft agar (Figure 4F and Figure S4G).	('ETV4', 'Gene', (26, 30))	('loss', 'Var', (110, 114))	('PC3', 'Gene', '3853', (79, 82))	('EWS', 'Gene', (118, 121))	('EWS', 'Gene', '2130', (118, 121))	('inhibited', 'NegReg', (136, 145))	('ETV4', 'Gene', '2118', (26, 30))	('PC3 prostate cancer', 'Disease', (79, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('growth', 'CPA', (146, 152))	('PC3', 'Gene', '3853', (156, 159))	('PC3 prostate cancer', 'Disease', 'MESH:D053549', (79, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PC3', 'Gene', (79, 82))	('PC3', 'Gene', (156, 159))
27543	27783944	EWS knockdown reduced soft-agar growth of both of these cell lines (Figure 4F and Figure S4G).	('reduced', 'NegReg', (14, 21))	('soft-agar growth', 'CPA', (22, 38))	('knockdown', 'Var', (4, 13))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
27550	27783944	Importantly, the P436A point mutation of ERG abrogated this oncogenic function (Figures 5B and Figure S5A).	('ERG', 'Gene', '2078', (41, 44))	('abrogated', 'NegReg', (45, 54))	('ERG', 'Gene', (41, 44))	('P436A', 'Mutation', 'p.P436A', (17, 22))	('oncogenic function', 'CPA', (60, 78))	('P436A point', 'Var', (17, 28))
27553	27783944	If EWS is recruited by ERG to target sites as a co-activator, we would expect the EWS binding mutant, ERG P436A, to bind target sites, but fail to recruit EWS resulting in loss of transcriptional activation.	('transcriptional activation', 'MPA', (180, 206))	('EWS', 'Gene', (155, 158))	('loss', 'NegReg', (172, 176))	('ERG', 'Gene', (102, 105))	('EWS', 'Gene', '2130', (155, 158))	('P436A', 'Mutation', 'p.P436A', (106, 111))	('P436A', 'Var', (106, 111))	('EWS', 'Gene', '2130', (82, 85))	('EWS', 'Gene', (82, 85))	('ERG', 'Gene', '2078', (102, 105))	('ERG', 'Gene', '2078', (23, 26))	('EWS', 'Gene', '2130', (3, 6))	('EWS', 'Gene', (3, 6))	('ERG', 'Gene', (23, 26))
27554	27783944	To test this hypothesis, ERG and ERG P436A were expressed in RWPE1 cells and genomic occupancy of ERG and EWS was assayed by ChIP.	('ERG', 'Gene', (98, 101))	('ERG', 'Gene', '2078', (25, 28))	('ERG', 'Gene', (25, 28))	('EWS', 'Gene', '2130', (106, 109))	('P436A', 'Var', (37, 42))	('RWPE1', 'CellLine', 'CVCL:3791', (61, 66))	('P436A', 'Mutation', 'p.P436A', (37, 42))	('ERG', 'Gene', '2078', (33, 36))	('ERG', 'Gene', '2078', (98, 101))	('ERG', 'Gene', (33, 36))	('EWS', 'Gene', (106, 109))
27562	27783944	Together, these data indicate that the P436A mutation in ERG does not disrupt ERG chromatin occupancy, but results in decreased EWS recruitment.	('ERG', 'Gene', (78, 81))	('ERG', 'Gene', (57, 60))	('EWS', 'Gene', '2130', (128, 131))	('EWS', 'Gene', (128, 131))	('P436A', 'Var', (39, 44))	('decreased', 'NegReg', (118, 127))	('ERG', 'Gene', '2078', (78, 81))	('P436A', 'Mutation', 'p.P436A', (39, 44))	('ERG', 'Gene', '2078', (57, 60))
27571	27783944	In Ewing's sarcoma, EWS-FLI1 activates transcription via cis-regulatory elements consisting of microsatellite repeats of the core ETS binding sequence, GGAA, and these GGAA repeats regulate the expression of genes that promote transformation and cancer cell survival.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (3, 18))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	("Ewing's sarcoma", 'Disease', (3, 18))	('genes', 'Gene', (208, 213))	('transformation', 'CPA', (227, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('cancer', 'Disease', (246, 252))	('activates', 'PosReg', (29, 38))	('microsatellite repeats', 'Var', (95, 117))	('promote', 'PosReg', (219, 226))	('EWS-FLI1', 'Gene', (20, 28))	('regulate', 'Reg', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('expression', 'MPA', (194, 204))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (3, 18))	('EWS-FLI1', 'Gene', '2130;2313', (20, 28))	('transcription', 'MPA', (39, 52))
27582	27783944	Mutation of each GGAA repeat to GAGA, or mutation of the single ETS binding sequence in the ETS/AP-1 reporter eliminated activation by ETV4 and ERG (Figures 7D and E), indicating that an ETS binding sequence was required.	('ERG', 'Gene', '2078', (144, 147))	('ETV4', 'Gene', '2118', (135, 139))	('activation', 'MPA', (121, 131))	('ERG', 'Gene', (144, 147))	('Mutation', 'Var', (0, 8))	('mutation', 'Var', (41, 49))	('ETV4', 'Gene', (135, 139))	('eliminated', 'NegReg', (110, 120))
27584	27783944	Furthermore, the fusion of EWS to FLI1 (EWS-FLI1) activated the reporters significantly more than FLI1, and to a similar extent as ERG.	('FLI1', 'Gene', '2130', (44, 48))	('FLI1', 'Gene', (34, 38))	('FLI1', 'Gene', '2130', (98, 102))	('EWS-FLI1', 'Gene', (40, 48))	('activated', 'PosReg', (50, 59))	('reporters', 'MPA', (64, 73))	('FLI1', 'Gene', '2130', (34, 38))	('fusion', 'Var', (17, 23))	('EWS', 'Gene', '2130', (40, 43))	('EWS', 'Gene', (40, 43))	('ERG', 'Gene', '2078', (131, 134))	('EWS-FLI1', 'Gene', '2130;2313', (40, 48))	('ERG', 'Gene', (131, 134))	('FLI1', 'Gene', (44, 48))	('FLI1', 'Gene', (98, 102))	('EWS', 'Gene', '2130', (27, 30))	('EWS', 'Gene', (27, 30))
27587	27783944	First, ERG and ETV4 activation were tested in cell lines with EWS shRNA knockdowns (Figure 7F).	('ETV4', 'Gene', '2118', (15, 19))	('ERG', 'Gene', (7, 10))	('EWS', 'Gene', (62, 65))	('EWS', 'Gene', '2130', (62, 65))	('knockdowns', 'Var', (72, 82))	('ETV4', 'Gene', (15, 19))	('ERG', 'Gene', '2078', (7, 10))
27591	27783944	Interestingly, EWS shRNA, ERG P436A, and FLI1 showed a similar ~50% lower activation of GGAA-repeat reporters compared to the ERG control (Figures 7 D, G, and I), indicating that the difference between ERG and FLI1 transcriptional activation could be the ability of ERG to interact with EWS.	('P436A', 'Mutation', 'p.P436A', (30, 35))	('ERG', 'Gene', (126, 129))	('EWS', 'Gene', '2130', (15, 18))	('ERG', 'Gene', '2078', (126, 129))	('ERG', 'Gene', (266, 269))	('lower', 'NegReg', (68, 73))	('GGAA-repeat reporters', 'Protein', (88, 109))	('ERG', 'Gene', (202, 205))	('FLI1', 'Gene', '2130', (210, 214))	('activation', 'PosReg', (74, 84))	('ERG', 'Gene', '2078', (266, 269))	('EWS', 'Gene', (287, 290))	('ERG', 'Gene', (26, 29))	('ERG', 'Gene', '2078', (202, 205))	('FLI1', 'Gene', (210, 214))	('FLI1', 'Gene', '2130', (41, 45))	('EWS', 'Gene', (15, 18))	('ERG', 'Gene', '2078', (26, 29))	('FLI1', 'Gene', (41, 45))	('P436A', 'Var', (30, 35))	('EWS', 'Gene', '2130', (287, 290))
27604	27783944	First, it is possible that FLI1 rearrangements are passenger mutations and not oncogenic.	('FLI1', 'Gene', '2130', (27, 31))	('rearrangements', 'Var', (32, 46))	('FLI1', 'Gene', (27, 31))
27607	27783944	There were 1329 genes rearranged more often than FLI1 in these tumors, and it is likely that many of these are passenger mutations.	('FLI1', 'Gene', (49, 53))	('rearranged', 'Var', (22, 32))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('FLI1', 'Gene', '2130', (49, 53))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
27614	27783944	ETV1 plays important roles in melanoma, where 40% of tumors have copy gains of the ETV1 gene.	('ETV1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('ETV1', 'Gene', '2115', (0, 4))	('ETV1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('copy gains', 'Var', (65, 75))	('ETV1', 'Gene', '2115', (83, 87))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('melanoma', 'Disease', (30, 38))	('tumors', 'Disease', (53, 59))
27620	27783944	In some cancers, the FET member in the fusion appears interchangeable, as in TLS-CHOP or EWS-CHOP fusions in myxoid liposarcoma, EWS-CHN or TAF15-CHN fusions in myxoid chondrosarcoma, and EWS-CIZ and TAF15-CIZ fusions in acute leukemia.	('TLS-CHOP', 'Disease', (77, 85))	('TAF15-CHN', 'Disease', (140, 149))	('myxoid chondrosarcoma', 'Disease', (161, 182))	('CHOP', 'Gene', '1649', (81, 85))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (109, 127))	('acute leukemia', 'Phenotype', 'HP:0002488', (221, 235))	('EWS', 'Gene', (89, 92))	('CIZ', 'Gene', (206, 209))	('EWS', 'Gene', (129, 132))	('EWS', 'Gene', '2130', (188, 191))	('TLS-CHOP', 'Disease', 'None', (77, 85))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('cancers', 'Disease', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('TAF15', 'Gene', (140, 145))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('CHOP', 'Gene', '1649', (93, 97))	('CHOP', 'Gene', (81, 85))	('TAF15', 'Gene', '8148', (140, 145))	('liposarcoma', 'Phenotype', 'HP:0012034', (116, 127))	('CHN', 'Gene', (133, 136))	('CHN', 'Gene', '8013', (133, 136))	('CIZ', 'Gene', '171017', (192, 195))	('fusions', 'Var', (98, 105))	('acute leukemia', 'Disease', (221, 235))	('leukemia', 'Phenotype', 'HP:0001909', (227, 235))	('EWS', 'Gene', '2130', (129, 132))	('EWS', 'Gene', (188, 191))	('TAF15', 'Gene', (200, 205))	('EWS', 'Gene', '2130', (89, 92))	('CHOP', 'Gene', (93, 97))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (109, 127))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('TAF15', 'Gene', '8148', (200, 205))	('CIZ', 'Gene', '171017', (206, 209))	('fusions', 'Var', (150, 157))	('CIZ', 'Gene', (192, 195))	('CHN', 'Gene', (146, 149))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (161, 182))	('myxoid liposarcoma', 'Disease', (109, 127))	('acute leukemia', 'Disease', 'MESH:D015470', (221, 235))	('CHN', 'Gene', '8013', (146, 149))	('TAF15-CHN', 'Disease', 'MESH:C535301', (140, 149))
27638	27783944	Antibodies for immunoblotting were ERG (CM 421, Biocare), EWS (sc-28327, Santa Cruz Biotechnology), ETV4 (ARP32263_P050, Aviva Systems Biology), pAKT (#4060, Cell signaling), Tubulin (T9026, Sigma), and FLAG (F1804, Sigma).	('AKT', 'Gene', '207', (146, 149))	('T9026', 'Var', (184, 189))	('ERG', 'Gene', '2078', (35, 38))	('ERG', 'Gene', (35, 38))	('ETV4', 'Gene', (100, 104))	('#4060', 'Var', (151, 156))	('AKT', 'Gene', (146, 149))	('ETV4', 'Gene', '2118', (100, 104))	('EWS', 'Gene', (58, 61))	('EWS', 'Gene', '2130', (58, 61))
27645	27783944	2x106 RWPE1 epithelial cells expressing either ERG, activated Akt (Myr-Akt), both ERG and Akt (ERG/Myr-Akt), mutant ERG with Akt (P436A/Myr-Akt), or vector control (All as described above) were combined with an equal volume of Matrigel and 0.5x106 cancer-associated fibroblast cells and were injected subcutaneously on the flanks of nude mice.	('Akt', 'Gene', '207', (71, 74))	('yr-Akt', 'Gene', (137, 143))	('Akt', 'Gene', (103, 106))	('P436A', 'Var', (130, 135))	('Akt', 'Gene', '207', (62, 65))	('Akt', 'Gene', '207', (103, 106))	('ERG', 'Gene', '2078', (47, 50))	('cancer', 'Disease', (248, 254))	('ERG', 'Gene', (116, 119))	('Akt', 'Gene', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('nude mice', 'Species', '10090', (333, 342))	('yr-Akt', 'Gene', '207', (100, 106))	('Akt', 'Gene', (140, 143))	('Akt', 'Gene', '207', (125, 128))	('ERG', 'Gene', '2078', (116, 119))	('ERG', 'Gene', (82, 85))	('Akt', 'Gene', (90, 93))	('yr-Akt', 'Gene', '207', (68, 74))	('Akt', 'Gene', '207', (140, 143))	('yr-Akt', 'Gene', (100, 106))	('RWPE1', 'CellLine', 'CVCL:3791', (6, 11))	('mutant', 'Var', (109, 115))	('ERG', 'Gene', '2078', (82, 85))	('P436A', 'SUBSTITUTION', 'None', (130, 135))	('ERG', 'Gene', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('Akt', 'Gene', '207', (90, 93))	('yr-Akt', 'Gene', (68, 74))	('yr-Akt', 'Gene', '207', (137, 143))	('Akt', 'Gene', (71, 74))	('ERG', 'Gene', '2078', (95, 98))	('Akt', 'Gene', (62, 65))	('ERG', 'Gene', (47, 50))
27728	27214230	Therefore, although low values (primarily from cutaneous lymphoma) might lower the overall value, the greater concern is perhaps an inability to identify how many of the dogs with high TK1 might have had T-cell lymphoma, thus suggesting some utility in that disease.	('lymphoma', 'Phenotype', 'HP:0002665', (211, 219))	('cutaneous lymphoma', 'Disease', (47, 65))	('TK1', 'Gene', (185, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (57, 65))	('cutaneous lymphoma', 'Disease', 'MESH:D016410', (47, 65))	('cell lymphoma', 'Phenotype', 'HP:0012191', (206, 219))	('dogs', 'Species', '9615', (170, 174))	('cutaneous lymphoma', 'Phenotype', 'HP:0012192', (47, 65))	('lower', 'NegReg', (73, 78))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (204, 219))	('high', 'Var', (180, 184))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (204, 219))	('T-cell lymphoma', 'Disease', (204, 219))
27769	24742094	This finding further supports the potential risk of patients with Lynch syndrome to develop a MFH as a consequence of the underlying MMR gene germline mutation.	('MMR gene', 'Gene', (133, 141))	('Lynch syndrome', 'Disease', 'MESH:D003123', (66, 80))	('patients', 'Species', '9606', (52, 60))	('develop', 'PosReg', (84, 91))	('MFH', 'Disease', (94, 97))	('germline mutation', 'Var', (142, 159))	('Lynch syndrome', 'Disease', (66, 80))
27841	23388086	found a lack of Birbeck granules in Langerhans cells to be associated with a mutation in the langerin gene.	('mutation', 'Var', (77, 85))	('langerin', 'Gene', (93, 101))	('langerin', 'Gene', '50489', (93, 101))	('associated', 'Reg', (59, 69))
27859	23388086	However, cutaneous squamous cell carcinoma or metastatic cancer shows an obvious nest structure with epithelial phenotype, such as pan-cytokeratin, CK7 or CK20.	('CK7', 'Gene', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('CK20', 'Gene', (155, 159))	('CK20', 'Gene', '54474', (155, 159))	('CK7', 'Gene', '3855', (148, 151))	('pan-cytokeratin', 'Var', (131, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('cutaneous squamous cell carcinoma', 'Disease', (9, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (19, 42))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (9, 42))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (9, 42))
27949	23148739	Factors determining a worse prognosis include tumor diameter > 5cm, inadequate surgical resection, local recurrence, patient age over 20 years, monophasic variant and high mitotic activity .	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('monophasic variant', 'Var', (144, 162))	('patient', 'Species', '9606', (117, 124))	('local', 'CPA', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
28070	32847839	There are also a number of prospective trials currently being conducted: NCT02048722 (Daily Oral Regorafenib for Chemotherapy-Refractory, Metastatic and Locally Advanced Angiosarcoma) is active and recruiting, while NCT01462630 (Pazopanib Hydrochloride in Treating Patients With Advanced Angiosarcoma) is active having completed recruitment.	('Angiosarcoma', 'Disease', 'MESH:D006394', (288, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (288, 300))	('Pazopanib Hydrochloride', 'Chemical', 'MESH:C516667', (229, 252))	('NCT02048722', 'Var', (73, 84))	('Regorafenib', 'Chemical', 'MESH:C559147', (97, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('Angiosarcoma', 'Disease', (170, 182))	('Patients', 'Species', '9606', (265, 273))	('Angiosarcoma', 'Disease', 'MESH:D006394', (170, 182))	('Angiosarcoma', 'Disease', (288, 300))	('Locally Advanced Angiosarcoma', 'Phenotype', 'HP:0200059', (153, 182))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (170, 182))
28220	32375822	The pathogenesis of HCC comprises a multistep process that involves genetic and epigenetic events of multiple genes.	('HCC', 'Gene', (20, 23))	('HCC', 'Gene', '619501', (20, 23))	('epigenetic', 'Var', (80, 90))
28274	30012492	For instance, modifying drugs with poly(ethylene glycol) is a common method for improving hydrophilicity and circulation of a drug by making it larger than the renal size cutoff.	('poly(ethylene glycol)', 'Chemical', 'MESH:D011092', (35, 56))	('improving', 'PosReg', (80, 89))	('circulation', 'MPA', (109, 120))	('modifying', 'Var', (14, 23))	('larger than the renal size', 'Phenotype', 'HP:0000105', (144, 170))	('hydrophilicity', 'MPA', (90, 104))
28298	30012492	They observed that cancer cells expressing oncogenic Ras, an inner plasma membrane protein whose aberrant activation is associated with virtually all aspects of the malignant cancer phenotype, more highly utilize extracellular proteins as a source of amino acids to drive cellular growth .	('malignant cancer', 'Disease', 'MESH:D009369', (165, 181))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', (19, 25))	('malignant cancer', 'Disease', (165, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('oncogenic Ras', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('extracellular proteins', 'MPA', (213, 235))	('activation', 'PosReg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
28309	30012492	This hypothesis was centered around the notion that the presence of SPARC in the tumor environment would concentrate nab-P and thus possibly enhance its therapeutic effect.	('presence', 'Var', (56, 64))	('nab-P', 'Gene', (117, 122))	('enhance', 'PosReg', (141, 148))	('therapeutic effect', 'CPA', (153, 171))	('concentrate', 'Interaction', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('nab', 'Chemical', '-', (117, 120))	('tumor', 'Disease', (81, 86))
28338	30012492	The primary method for in situ covalent attachment to albumin leverages the cysteine-34 amino acid of albumin.	('albumin', 'Gene', (102, 109))	('albumin', 'Gene', '213', (102, 109))	('leverages', 'Var', (62, 71))	('cysteine-34 amino acid', 'MPA', (76, 98))	('cysteine-34 amino acid', 'Chemical', '-', (76, 98))	('albumin', 'Gene', '213', (54, 61))	('albumin', 'Gene', (54, 61))
28349	30012492	Finally, both ruthenium-based anticancer complexes and copper pro-drugs have been synthesized to bind endogenously to the large hydrophobic cavity at the IIA subdomain of albumin, followed by subsequent exchange with the N-donor residues of Lys 199 and His 242 to form a stable albumin complex,.	('His', 'Chemical', 'MESH:D006639', (253, 256))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('albumin', 'Gene', (171, 178))	('albumin', 'Gene', '213', (171, 178))	('copper', 'Chemical', 'MESH:D003300', (55, 61))	('ruthenium', 'Chemical', 'MESH:D012428', (14, 23))	('albumin', 'Gene', '213', (278, 285))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('albumin', 'Gene', (278, 285))	('exchange', 'Var', (203, 211))	('Lys', 'Chemical', 'MESH:D008239', (241, 244))	('N', 'Chemical', 'MESH:D009584', (221, 222))	('donor', 'Species', '9606', (223, 228))
28360	30012492	Mansour and colleagues introduced an octapeptide, Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln, that has been shown to be effectively cleaved by MMPs 2 and 9 when used to link doxorubicin and an albumin-binding maleimide group.	('albumin', 'Gene', (182, 189))	('Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln', 'Chemical', '-', (50, 81))	('albumin', 'Gene', '213', (182, 189))	('link', 'Interaction', (158, 162))	('maleimide', 'Chemical', 'MESH:C043592', (198, 207))	('MMPs 2 and 9', 'Gene', '4313;4318', (132, 144))	('doxorubicin', 'Chemical', 'MESH:D004317', (163, 174))	('Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln', 'Var', (50, 81))
28373	30012492	This approach involved using simple and specific "click" chemistry to conjugate modified siRNA to a PEGylated diacyl lipid, and resulted in a 5.7-fold increase in half-life with Kd~1.38 muMu.	('modified', 'Var', (80, 88))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('siRNA', 'Gene', (89, 94))	('half-life', 'MPA', (163, 172))	('diacyl lipid', 'Chemical', '-', (110, 122))	('increase', 'PosReg', (151, 159))	('PEG', 'Chemical', 'MESH:D011092', (100, 103))
28381	30012492	For instance, truncated EB conjugated to the diabetes drug Exendin-3 resulted in markedly improved half-life (5 to 32 hours) and yielded improvement in hypoglycemic effects.	('diabetes', 'Disease', (45, 53))	('truncated', 'Var', (14, 23))	('diabetes', 'Disease', 'MESH:D003920', (45, 53))	('improved', 'PosReg', (90, 98))	('EB', 'Chemical', 'MESH:D005070', (24, 26))	('improvement', 'PosReg', (137, 148))	('hypoglycemic effects', 'MPA', (152, 172))
28389	30012492	Modifications with these simple albumin-binding moieties are a synthetically appealing approach for improving drug pharmacokinetic properties.	('drug pharmacokinetic properties', 'MPA', (110, 141))	('Modifications', 'Var', (0, 13))	('albumin', 'Gene', (32, 39))	('albumin', 'Gene', '213', (32, 39))	('improving', 'PosReg', (100, 109))
28444	30012492	One such example employed covalent coupling of DI17E6, a monoclonal antibody directed against alphanu integrins, which are cell membrane-spanning matrix adhesion domains that are highly expressed in a various cancer lines.	('alphanu integrins', 'Protein', (94, 111))	('DI17E6', 'Chemical', 'MESH:C000592911', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('DI17E6', 'Var', (47, 53))	('cancer', 'Disease', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
28445	30012492	Inhibitors of alphanubeta3 have been shown to inhibit growth and angiogenesis in melanoma.	('inhibit', 'NegReg', (46, 53))	('Inhibitors', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('alphanubeta3', 'Protein', (14, 26))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
28460	30012492	Other interesting albumin-polymer investigations have shown that modifiying albumin with cationic polymers can be used to improve cell penetration in breast cancer and using thermosensitive polymer-conjugated albumin can be used to thermally target cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('albumin', 'Gene', '213', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('albumin', 'Gene', (209, 216))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Disease', (150, 163))	('albumin', 'Gene', (76, 83))	('polymer', 'Chemical', 'MESH:D011108', (26, 33))	('polymer', 'Chemical', 'MESH:D011108', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('albumin', 'Gene', (18, 25))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('albumin', 'Gene', '213', (209, 216))	('improve', 'PosReg', (122, 129))	('modifiying', 'Var', (65, 75))	('cell penetration', 'CPA', (130, 146))	('albumin', 'Gene', '213', (76, 83))	('polymers', 'Chemical', 'MESH:D011108', (98, 106))	('polymer', 'Chemical', 'MESH:D011108', (190, 197))
28468	30012492	Their self- assembled formulation included a cell penetrating peptide, low molecular weight protamine, on the outside of the particle to aid in tissue penetration and two hydrophobic chemotherapeutics, paclitaxel and fenretinide.	('paclitaxel', 'Chemical', 'MESH:D017239', (202, 212))	('low molecular weight', 'Var', (71, 91))	('aid', 'PosReg', (137, 140))	('fenretinide', 'Chemical', 'MESH:D017313', (217, 228))	('tissue penetration', 'CPA', (144, 162))	('amine', 'Chemical', 'MESH:D000588', (96, 101))
28473	30012492	Briefly, this involved thiolating doxorubicin and modifying HSA with a maleimide (sulfo-SMCC linker).	('thiol', 'Chemical', 'MESH:D013438', (23, 28))	('doxorubicin', 'Chemical', 'MESH:D004317', (34, 45))	('thiolating', 'Var', (23, 33))	('modifying', 'Reg', (50, 59))	('sulfo-SMCC', 'Chemical', 'MESH:C071675', (82, 92))	('HSA', 'Protein', (60, 63))	('maleimide', 'Chemical', 'MESH:C043592', (71, 80))
28477	30012492	Additionally, histological samples of the lung specimens from H226- implanted mice demonstrated that TRAIL/Dox HSA-NP not only decreased lesion numbers and sizes, but exhibited significant induction of apoptosis whereas mice treated with TRAIL or Dox particles did not.	('decreased', 'NegReg', (127, 136))	('Dox', 'Chemical', 'MESH:D004317', (107, 110))	('mice', 'Species', '10090', (220, 224))	('HSA-NP', 'Chemical', '-', (111, 117))	('TRAIL/Dox', 'Var', (101, 110))	('Dox', 'Chemical', 'MESH:D004317', (247, 250))	('mice', 'Species', '10090', (78, 82))
28484	30012492	The administration of this conjugate labeled with Cy5 in lieu of doxorubicin resulted in significant accumulation in tumors with fluorescent intensity decreasing in other organs.	('Cy5', 'Var', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('fluorescent intensity', 'MPA', (129, 150))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('Cy5', 'Chemical', 'MESH:C085321', (50, 53))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('accumulation', 'PosReg', (101, 113))	('decreasing', 'NegReg', (151, 161))	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))
28492	30012492	These conjugates were evaluated in seven nude mouse human tumor xenograft models including bladder, breast, lung, osteosarcoma, soft tissue sarcoma, and prostate cancers, Notably, in soft tissue sarcoma SXF 1301, MTX- HSA treatment resulted in complete remission after a single injection at 12.5 mg/kg whereas an equivalent drug dose of free MTX resulted in short-lasting, partial tumor regression.	('N', 'Chemical', 'MESH:D009584', (171, 172))	('mouse', 'Species', '10090', (46, 51))	('prostate cancers', 'Disease', 'MESH:D011471', (153, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('MTX-', 'Var', (213, 217))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (183, 202))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (183, 202))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (128, 147))	('tumor', 'Disease', (58, 63))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (128, 147))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('bladder', 'Disease', (91, 98))	('breast', 'Disease', (100, 106))	('soft tissue sarcoma', 'Disease', (183, 202))	('soft tissue sarcoma', 'Disease', (128, 147))	('osteosarcoma', 'Disease', (114, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (114, 126))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('prostate cancers', 'Phenotype', 'HP:0012125', (153, 169))	('prostate cancers', 'Disease', (153, 169))	('lung', 'Disease', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('MTX- HSA', 'Chemical', '-', (213, 221))	('tumor', 'Disease', (381, 386))	('osteosarcoma', 'Phenotype', 'HP:0002669', (114, 126))	('human', 'Species', '9606', (52, 57))	('MTX', 'Chemical', 'MESH:D008727', (213, 216))	('MTX', 'Chemical', 'MESH:D008727', (342, 345))	('tumor', 'Disease', 'MESH:D009369', (381, 386))
28493	30012492	Additionally, in the prostate-cancer model PRXF PC3M, MTX-HSA demonstrated 92.8% growth inhibition of control.	('prostate-cancer', 'Disease', (21, 36))	('growth', 'MPA', (81, 87))	('MTX-HSA', 'Chemical', '-', (54, 61))	('prostate-cancer', 'Disease', 'MESH:D011471', (21, 36))	('MTX-HSA', 'Var', (54, 61))	('prostate-cancer', 'Phenotype', 'HP:0012125', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
28505	30012492	Short interfering RNA has also been delivered to tumor cells via albumin nanocarriers,.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Short interfering', 'Var', (0, 17))	('albumin', 'Gene', (65, 72))	('albumin', 'Gene', '213', (65, 72))	('tumor', 'Disease', (49, 54))
28507	30012492	Tail vein injection of 50 mg of Cy5-labeled nanocomplex to SCC7 tumor-bearing mice resulted in 1.7 times the signal intensity in tumor tissue 12 hours post-injection than thiolated siRNA alone.	('N', 'Chemical', 'MESH:D009584', (184, 185))	('tumor', 'Disease', (64, 69))	('Cy5', 'Chemical', 'MESH:C085321', (32, 35))	('signal intensity', 'MPA', (109, 125))	('thiol', 'Chemical', 'MESH:D013438', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('SCC7', 'Gene', (59, 63))	('Cy5-labeled', 'Var', (32, 43))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (129, 134))	('SCC7', 'Gene', '109433', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mice', 'Species', '10090', (78, 82))
28513	30012492	Albumin-mediated delivery of antisense oligonucleotides (ASO) has also been investigated in the context of cancer treatment.	('antisense', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Albumin', 'Gene', '213', (0, 7))	('oligonucleotides', 'Chemical', 'MESH:D009841', (39, 55))	('Albumin', 'Gene', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ASO', 'Chemical', 'MESH:D016376', (57, 60))	('cancer', 'Disease', (107, 113))
28517	30012492	The albuleukin fusion protein of recombinant interleukin-2 and human serum albumin showed the ability of genetic fusion to albumin to confer its remarkable pharmacokinetic properties.	('serum albumin', 'Gene', '213', (69, 82))	('serum albumin', 'Gene', (69, 82))	('albumin', 'Gene', (123, 130))	('human', 'Species', '9606', (63, 68))	('albumin', 'Gene', '213', (123, 130))	('interleukin-2', 'Gene', (45, 58))	('interleukin-2', 'Gene', '3558', (45, 58))	('albuleukin', 'Protein', (4, 14))	('albumin', 'Gene', (75, 82))	('albumin', 'Gene', '213', (75, 82))	('genetic', 'Var', (105, 112))
28527	30012492	By conjugating molecular vaccines to Evans Blue, albumin-binding vaccines that self-assemble in vivo using endogenous albumin were found to be 100-fold more efficient at the co-delivery of CpG and antigens to lymph nodes.	('more efficient', 'PosReg', (152, 166))	('Evans Blue', 'Chemical', 'MESH:D005070', (37, 47))	('albumin', 'Gene', (49, 56))	('albumin', 'Gene', '213', (49, 56))	('co-delivery', 'MPA', (174, 185))	('albumin', 'Gene', (118, 125))	('albumin', 'Gene', '213', (118, 125))	('CpG', 'Var', (189, 192))
28560	30012492	Median progression-free survival time was significantly improved (5.6 vs 2.7 months) with aldoxorubicin compared to doxorubicin as well as the rate of 6-month progression-free survival (46% and 23%).	('aldoxorubicin', 'Var', (90, 103))	('progression-free survival', 'CPA', (7, 32))	('doxorubicin', 'Chemical', 'MESH:D004317', (92, 103))	('doxorubicin', 'Chemical', 'MESH:D004317', (116, 127))	('improved', 'PosReg', (56, 64))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (90, 103))
28573	30012492	While it is clear that binding to albumin can extend circulation half-life through mechanisms such as the FcRn and megalin/cubilin reabsorption, what remains only partly elucidated is how albumin binding impacts cellular entry and subsequent intracellular trafficking of its bound cargo.	('albumin', 'Gene', '213', (188, 195))	('cubilin', 'Gene', (123, 130))	('impacts', 'Reg', (204, 211))	('albumin', 'Gene', (188, 195))	('intracellular trafficking', 'MPA', (242, 267))	('albumin', 'Gene', (34, 41))	('albumin', 'Gene', '213', (34, 41))	('binding', 'Var', (23, 30))	('FcRn', 'Gene', (106, 110))	('megalin', 'Gene', (115, 122))	('megalin', 'Gene', '4036', (115, 122))	('circulation half-life', 'MPA', (53, 74))	('extend', 'PosReg', (46, 52))	('cubilin', 'Gene', '8029', (123, 130))	('FcRn', 'Gene', '2217', (106, 110))	('cellular entry', 'MPA', (212, 226))	('binding', 'Var', (196, 203))
28604	27403082	A DLT was defined as the presence of one of the following toxicities during the first cycle of treatment: absolute neutrophil count <0.5 * 109/L lasting for >=7 days; absolute neutrophil count <0.5 * 109/L with fever >39 C; platelet count <25 * 109/L; and any other drug-related grade 3 or 4 nonhaematological toxicity (with the exception of alopecia, brief nausea and vomiting, diarrhoea, rash, arthralgia, and myalgia).	('arthralgia', 'Disease', 'MESH:D018771', (396, 406))	('alopecia', 'Phenotype', 'HP:0001596', (342, 350))	('myalgia', 'Phenotype', 'HP:0003326', (412, 419))	('arthralgia', 'Disease', (396, 406))	('<0.5 * 109/L', 'Var', (132, 144))	('nausea', 'Phenotype', 'HP:0002018', (358, 364))	('<0.5 * 109/L', 'Var', (193, 205))	('rash', 'Phenotype', 'HP:0000988', (390, 394))	('brief nausea', 'Disease', (352, 364))	('diarrhoea', 'Phenotype', 'HP:0002014', (379, 388))	('myalgia', 'Disease', (412, 419))	('alopecia', 'Disease', (342, 350))	('absolute neutrophil', 'Var', (167, 186))	('vomiting', 'Disease', 'MESH:D014839', (369, 377))	('rash', 'Disease', (390, 394))	('fever', 'Disease', 'MESH:D005334', (211, 216))	('fever', 'Disease', (211, 216))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (358, 377))	('vomiting', 'Phenotype', 'HP:0002013', (369, 377))	('vomiting', 'Disease', (369, 377))	('myalgia', 'Disease', 'MESH:D063806', (412, 419))	('fever', 'Phenotype', 'HP:0001945', (211, 216))	('diarrhoea', 'Disease', (379, 388))	('diarrhoea', 'Disease', 'MESH:D003967', (379, 388))	('arthralgia', 'Phenotype', 'HP:0002829', (396, 406))
28612	27403082	The recognized ability of HDAC inhibitors to affect the expression of genes involved in DNA-damage is thought to be the cause of the synergy with cytotoxic agents that specifically determine DNA-damage, such as doxorubicin, a topoisomerase II inhibitor.	('affect', 'Reg', (45, 51))	('inhibitors', 'Var', (31, 41))	('expression', 'MPA', (56, 66))	('synergy', 'Disease', 'None', (133, 140))	('genes', 'Gene', (70, 75))	('synergy', 'Disease', (133, 140))
28624	25109853	Though previously considered to be distinct clinical entities, given subtle variation in their presenting sites and immunophenotype, the World Health Organization now advocates a simplified nomenclature using ES to represent the aforementioned tumors, as they consistently have a round cell morphology, ubiquitously express CD99, and harbor a near-universal pathognomonic chromosomal translocation:affixing the N-terminal EWSR1 gene to a C-terminal ETS gene.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('EWSR1', 'Gene', '2130', (422, 427))	('ES', 'Phenotype', 'HP:0012254', (209, 211))	('clinical', 'Species', '191496', (44, 52))	('affixing', 'Var', (398, 406))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('CD99', 'Gene', (324, 328))	('EWSR1', 'Gene', (422, 427))
28675	25109853	That human PSCs intrinsically retain the capacity to self-assemble into spatially-complex higher-ordered organ-like structures ex vivo is truly amazing and suggests the genomic or epigenetic information contained within the PSCs is enough to drive organ-level differentiation if augmented by the 'correct' microenvironmental cues.	('organ-level differentiation', 'CPA', (248, 275))	('genomic', 'Var', (169, 176))	('epigenetic information', 'Var', (180, 202))	('human', 'Species', '9606', (5, 10))	('drive', 'Reg', (242, 247))
28713	25109853	As previously reported, diffusion gradients within tumor spheroids have been shown to produce this type of varied cell structure and are widely used to study the growth kinetics and hypoxic effects of tumor cells present within avascular tumor micro-regions within irregular tumor vasculature.	('avascular tumor', 'Disease', (228, 243))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('hypoxic', 'Disease', (182, 189))	('tumor', 'Disease', (275, 280))	('hypoxic', 'Disease', 'MESH:D000860', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('avascular tumor', 'Disease', 'MESH:D010020', (228, 243))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (238, 243))	('tumor', 'Disease', (201, 206))	('diffusion gradients', 'Var', (24, 43))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
28719	25109853	Illustrating this fact, our laboratory confirmed that ES cells acquire an in vivo-like round cell morphology when they are placed within PCL scaffolds and continue to express immunohistochemical biomarkers normally expressed by human ES tumors (CD99+, IGF-1R+, keratin-, and SMA-).	('ES', 'Phenotype', 'HP:0012254', (234, 236))	('rat', 'Species', '10116', (6, 9))	('rat', 'Species', '10116', (32, 35))	('ES tumors', 'Disease', 'MESH:C563168', (234, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('rat', 'Species', '10116', (263, 266))	('CD99+', 'Var', (245, 250))	('IGF-1R+', 'Gene', '3480', (252, 259))	('labor', 'Disease', (28, 33))	('ES', 'Phenotype', 'HP:0012254', (54, 56))	('IGF-1R+', 'Gene', (252, 259))	('ES tumors', 'Disease', (234, 243))	('PCL', 'Chemical', 'MESH:C016240', (137, 140))	('labor', 'Disease', 'MESH:D048949', (28, 33))	('human', 'Species', '9606', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
28733	25109853	Since E-cadherin-dependent co-expression of ErbB4 in ES spheroids appears to up regulate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and secondarily resistance to anoikis and cytotoxic chemotherapy, it is intriguing whether a similar phenomenon is occurring in our 3D PCL-based scaffold architecture.	('up regulate', 'PosReg', (77, 88))	('phosphatidylinositol 3-kinase', 'Gene', (93, 122))	('ErbB4', 'Gene', '2066', (44, 49))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (93, 122))	('ES', 'Phenotype', 'HP:0012254', (53, 55))	('Akt', 'Gene', '207', (130, 133))	('co-expression', 'Var', (27, 40))	('E-cadherin', 'Gene', (6, 16))	('Akt', 'Gene', (130, 133))	('E-cadherin', 'Gene', '999', (6, 16))	('ErbB4', 'Gene', (44, 49))	('PCL', 'Chemical', 'MESH:C016240', (278, 281))
28774	25109853	Unexpectedly, even before a mature vascular network is formed, ECs can affect co-cultured cells and influence the surrounding microenvironment.	('ECs', 'Var', (63, 66))	('affect', 'Reg', (71, 77))	('ECs', 'Chemical', 'MESH:C001390', (63, 66))	('influence', 'Reg', (100, 109))	('co-cultured cells', 'CPA', (78, 95))
28775	25109853	When mixed with MSCs, for example, ECs enhance osteogenic matrix production within 3D PCL scaffolds.	('MSC', 'Gene', '9242', (16, 19))	('ECs', 'Var', (35, 38))	('osteogenic matrix production', 'CPA', (47, 75))	('MSC', 'Gene', (16, 19))	('PCL', 'Chemical', 'MESH:C016240', (86, 89))	('ECs', 'Chemical', 'MESH:C001390', (35, 38))	('enhance', 'PosReg', (39, 46))
28779	25109853	Indirectly tied to VEGF expression, the insulin like growth factor-1 receptor (IGF-1R) has also been implicated in the modulation of angiogenesis and vasculogenesis and dual targeting of IGF-1R and its ligand elicits anti-angiogenic effects.	('dual targeting', 'Var', (169, 183))	('implicated', 'Reg', (101, 111))	('IGF-1R', 'Gene', (187, 193))	('vasculogenesis', 'CPA', (150, 164))	('angiogenesis', 'CPA', (133, 145))	('IGF-1R', 'Gene', (79, 85))	('VEGF', 'Gene', (19, 23))	('insulin like growth factor-1 receptor', 'Gene', '3480', (40, 77))	('anti-angiogenic effects', 'CPA', (217, 240))	('VEGF', 'Gene', '7422', (19, 23))	('insulin like growth factor-1 receptor', 'Gene', (40, 77))
28798	25109853	Though ES cells intrinsically harbor the capacity to metastasize and can gain even greater metastatic potential by acquiring genetic aberrations, the surrounding stromal cells and ECM are critical partners that influence this continuum from bone to lung.	('genetic aberrations', 'Var', (125, 144))	('gain', 'PosReg', (73, 77))	('metastasize', 'CPA', (53, 64))	('metastatic potential', 'CPA', (91, 111))	('rat', 'Species', '10116', (137, 140))	('ES', 'Phenotype', 'HP:0012254', (7, 9))
28807	25109853	A partial solution to this problem has been to extensively profile each patient's tumor to identify dysregulated proteomic pathways, genomic mutations, or other '-omic' aberrations responsible for tumorigenesis and to isolate mechanisms of de novo and acquired drug resistance.	('rat', 'Species', '10116', (173, 176))	('mutations', 'Var', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('drug resistance', 'Phenotype', 'HP:0020174', (261, 276))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('patient', 'Species', '9606', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (197, 202))
28859	23894528	Differential Disruption of EWS-FLI1 Binding by DNA-Binding Agents Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an aberrant gene expression program responsible for the development of Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (210, 223))	('Disruption', 'NegReg', (13, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('aberrant gene expression program', 'MPA', (142, 174))	('FLI1', 'Gene', (31, 35))	('Fusion', 'Var', (66, 72))	('FLI1', 'Gene', '2313', (92, 96))	('EWS', 'Gene', (80, 83))	('FLI1', 'Gene', '2313', (31, 35))	('Binding', 'Interaction', (36, 43))	('EWS', 'Gene', '2130', (80, 83))	('FLI1', 'Gene', (92, 96))	('Ewing sarcoma', 'Disease', (210, 223))	('drives', 'PosReg', (132, 138))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (210, 223))	('EWS', 'Gene', '2130', (27, 30))	('EWS', 'Gene', (27, 30))
28869	23894528	The chimeric EWS-FLI1 oncoprotein alters the regulation of wild type FLI1 transcriptional targets.	('regulation', 'MPA', (45, 55))	('FLI1', 'Gene', (69, 73))	('alters', 'Reg', (34, 40))	('FLI1', 'Gene', '2313', (69, 73))	('EWS', 'Gene', '2130', (13, 16))	('EWS', 'Gene', (13, 16))	('chimeric', 'Var', (4, 12))	('FLI1', 'Gene', (17, 21))	('FLI1', 'Gene', '2313', (17, 21))
28872	23894528	For example, polyamide-based compounds have been shown to be able to bind DNA in a sequence-preferential manner, and to block the binding of transcription factors such as NF-kappaB and hypoxia-inducible factor.	('bind', 'Interaction', (69, 73))	('NF-kappaB', 'Gene', '4790', (171, 180))	('polyamide', 'Chemical', 'MESH:D009757', (13, 22))	('polyamide-based', 'Var', (13, 28))	('NF-kappaB', 'Gene', (171, 180))	('hypoxia', 'Disease', (185, 192))	('hypoxia', 'Disease', 'MESH:D000860', (185, 192))	('transcription', 'MPA', (141, 154))	('DNA', 'Protein', (74, 77))	('block', 'NegReg', (120, 125))	('binding', 'Interaction', (130, 137))
28914	23894528	Epirubicin, a DNA intercalating anthracycline and Ebselen, a mimic of glutathione peroxidase, also demonstrated some separation in disruption of EWS-FLI1 binding (IC50 42 nM and 631 nM respectively) in comparison to p53 (IC50 389 nM and >10,000 nM respectively).	('Ebselen', 'Chemical', 'MESH:C042986', (50, 57))	('binding', 'Interaction', (154, 161))	('EWS', 'Gene', '2130', (145, 148))	('EWS', 'Gene', (145, 148))	('glutathione', 'Chemical', 'MESH:D005978', (70, 81))	('FLI1', 'Gene', (149, 153))	('IC50', 'Var', (163, 167))	('p53', 'Gene', '7157', (216, 219))	('FLI1', 'Gene', '2313', (149, 153))	('anthracycline', 'Chemical', 'MESH:D018943', (32, 45))	('Epirubicin', 'Chemical', 'MESH:D015251', (0, 10))	('p53', 'Gene', (216, 219))
28932	23894528	Genes whose expression was reduced at least 50% after knock-down of EWS-FLI1 (Table S1) were collated to form a gene set of EWS-FLI1 activated genes in A673 cells.	('reduced', 'NegReg', (27, 34))	('EWS', 'Gene', (124, 127))	('knock-down', 'Var', (54, 64))	('EWS', 'Gene', '2130', (124, 127))	('FLI1', 'Gene', '2313', (128, 132))	('FLI1', 'Gene', (72, 76))	('FLI1', 'Gene', (128, 132))	('FLI1', 'Gene', '2313', (72, 76))	('EWS', 'Gene', '2130', (68, 71))	('EWS', 'Gene', (68, 71))	('expression', 'MPA', (12, 22))
28934	23894528	Enrichment for E2F target genes was likely due to the anti-proliferative effects of EWS-FLI1 depletion.	('anti-proliferative effects', 'MPA', (54, 80))	('EWS', 'Gene', '2130', (84, 87))	('EWS', 'Gene', (84, 87))	('FLI1', 'Gene', '2313', (88, 92))	('FLI1', 'Gene', (88, 92))	('depletion', 'Var', (93, 102))
28970	32929561	Targeting Gal-3 would serve as a novel immune checkpoint inhibitor candidate in patients afflicted with aggressive musculoskeletal tumors.	('aggressive musculoskeletal tumors', 'Disease', 'MESH:D009140', (104, 137))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aggressive musculoskeletal tumors', 'Disease', (104, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Targeting', 'Var', (0, 9))
28989	32929561	In patients with osteosarcoma, a higher expression of Gal-3 was reported to be positively correlated with advanced stage, since cytoplasmic Gal-3 enhances the malignant phenotype of osteosarcoma.	('enhances', 'PosReg', (146, 154))	('expression', 'MPA', (40, 50))	('osteosarcoma', 'Disease', (17, 29))	('higher', 'PosReg', (33, 39))	('osteosarcoma', 'Disease', (182, 194))	('osteosarcoma', 'Phenotype', 'HP:0002669', (182, 194))	('osteosarcoma', 'Disease', 'MESH:D012516', (17, 29))	('osteosarcoma', 'Disease', 'MESH:D012516', (182, 194))	('cytoplasmic Gal-3', 'Var', (128, 145))	('patients', 'Species', '9606', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('malignant phenotype of', 'CPA', (159, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))
28995	32929561	On the other hand, the cleaved form of Gal-3 is more abundant in prostate cancer bone metastases, and the shift to cleaved Gal-3 attenuates the osteoclast differentiation.	('attenuates', 'NegReg', (129, 139))	('osteoclast differentiation', 'CPA', (144, 170))	('Gal-3', 'Gene', (123, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('prostate cancer bone metastases', 'Disease', (65, 96))	('shift', 'Var', (106, 111))	('cleaved', 'Var', (115, 122))	('prostate cancer bone metastases', 'Disease', 'MESH:D011471', (65, 96))	('more', 'PosReg', (48, 52))	('Gal-3', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
29001	32929561	These evidences imply that inhibition of Gal-3 may suppress the aggressive behavior of Ewing's sarcoma.	('suppress', 'NegReg', (51, 59))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (87, 102))	('aggressive behavior', 'CPA', (64, 83))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (87, 102))	("Ewing's sarcoma", 'Disease', (87, 102))	('inhibition', 'Var', (27, 37))	('aggressive behavior', 'Phenotype', 'HP:0000718', (64, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('Gal-3', 'Protein', (41, 46))
29007	32929561	Although the Gal-3 function(s) in most soft tissue sarcoma is yet to be established, it should be emphasized that Gal-3 inhibition suppresses angiosarcoma proliferation in vitro, implying that Gal-3 may contribute to malignant phenotype of soft tissue sarcoma.	('sarcoma', 'Disease', (51, 58))	('sarcoma', 'Disease', 'MESH:D012509', (252, 259))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (39, 58))	('inhibition', 'Var', (120, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('angiosarcoma', 'Phenotype', 'HP:0200058', (142, 154))	('angiosarcoma proliferation', 'Disease', 'MESH:D006394', (142, 168))	('contribute', 'Reg', (203, 213))	('sarcoma', 'Disease', (252, 259))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (240, 259))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('angiosarcoma proliferation', 'Disease', (142, 168))	('sarcoma', 'Disease', (147, 154))	('Gal-3', 'Gene', (114, 119))	('suppresses', 'NegReg', (131, 141))
29019	32929561	These evidences suggest that Gal-3 plays a crucial role in the immune checkpoint, and the notion leads to the clinical significance that suppression of Gal-3 enhances the tumor-specific immune response.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('suppression', 'Var', (137, 148))	('Gal-3', 'Gene', (152, 157))	('enhances', 'PosReg', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
29027	32929561	Simultaneously, since cancer patients produce autoantibodies to Gal-3, Gal-3 hinders cancer detection/recognition by the endogenous antibodies and/or immunotherapeutic agents, termed the phenomena as "cancer stealth" effect.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('patients', 'Species', '9606', (29, 37))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (201, 207))	('Gal-3', 'Gene', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('hinders', 'NegReg', (77, 84))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('autoantibodies', 'Var', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Gal-3', 'Gene', (71, 76))
29033	32929561	In conclusion, Gal-3 serves as an immune checkpoint, whereby targeting Gal-3 may suppress the aggressive potential of malignant musculoskeletal tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('malignant musculoskeletal tumors', 'Disease', 'MESH:D009140', (118, 150))	('malignant musculoskeletal tumors', 'Disease', (118, 150))	('targeting', 'Var', (61, 70))	('suppress', 'NegReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Gal-3', 'Gene', (71, 76))
29142	33036589	The large mass with a diameter more than 10 cm, iso-hypo intensity/density on AP and pattern of persistent or progressive enhancement might alert us to the possibility of PHS.	('men', 'Species', '9606', (129, 132))	('iso-hypo', 'Var', (48, 56))	('PHS', 'Gene', '5092', (171, 174))	('PHS', 'Gene', (171, 174))
29185	30867046	Of note, poor CSF inflammatory response is more frequent in patients with HIV infection and CD4 count < 50/mul.	('CD4', 'Gene', '920', (92, 95))	('HIV infection', 'Disease', 'MESH:D015658', (74, 87))	('< 50/mul', 'Var', (102, 110))	('patients', 'Species', '9606', (60, 68))	('HIV infection', 'Disease', (74, 87))	('CD4', 'Gene', (92, 95))
29223	30085879	FS variant is characterized by more spindle cells, greater number of nuclei, and increased mitotic rate; unlike classic variant, immunohistochemically, CD34 expression is weak.	('CD34', 'Gene', (152, 156))	('mitotic rate', 'CPA', (91, 103))	('CD34', 'Gene', '947', (152, 156))	('expression', 'MPA', (157, 167))	('spindle cells', 'CPA', (36, 49))	('greater', 'PosReg', (51, 58))	('variant', 'Var', (3, 10))	('weak', 'NegReg', (171, 175))	('more', 'PosReg', (31, 35))	('increased', 'PosReg', (81, 90))
29307	22287547	Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1-driven mouse xenograft model of ESFT.	('PARP1', 'Gene', (14, 19))	('mouse', 'Species', '10090', (160, 165))	('inhibitor', 'Var', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('temozolamide', 'Chemical', '-', (72, 84))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('EWS-FLI1', 'Gene', (144, 152))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('EWS-FLI1', 'Gene', '2130;2313', (144, 152))	('responses', 'MPA', (106, 115))
29308	22287547	Mechanistic investigations revealed that DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes was potentiated by PARP1 inhibition in ESFT cell lines.	('inhibition', 'NegReg', (135, 145))	('potentiated', 'PosReg', (114, 125))	('ERG', 'Gene', '2078', (93, 96))	('EWS-FLI1', 'Gene', (77, 85))	('ERG', 'Gene', (93, 96))	('PARP1', 'Gene', (129, 134))	('EWS-FLI1', 'Gene', '2130;2313', (77, 85))	('DNA damage', 'MPA', (41, 51))	('expression', 'Var', (63, 73))
29312	22287547	Dysregulation of these chimeric proteins have previously been implicated in abnormal proliferation, invasion, and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('abnormal proliferation', 'CPA', (76, 98))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('invasion', 'CPA', (100, 108))	('implicated', 'Reg', (62, 72))
29315	22287547	Similar to ESFTs, 50% of prostate cancers harbor genomic rearrangements of ETS transcription factors.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('prostate cancers', 'Disease', 'MESH:D011471', (25, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancers', 'Phenotype', 'HP:0012125', (25, 41))	('genomic rearrangements', 'Var', (49, 71))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('prostate cancers', 'Disease', (25, 41))	('ETS transcription factors', 'Gene', (75, 100))
29316	22287547	However, unlike the EWS-FLI or EWS-ERG fusions which produce a multifunctional chimeric protein, prostate cancer rearrangements usually place an androgen-regulated promoter upstream of an ETS gene (ERG or ETV1), resulting in increased ETS transcription factor activity by overexpression.	('prostate cancer', 'Disease', (97, 112))	('ETV1', 'Gene', '2115', (205, 209))	('ERG', 'Gene', '2078', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('ERG', 'Gene', (35, 38))	('increased', 'PosReg', (225, 234))	('FLI', 'Gene', '2314', (24, 27))	('ETV1', 'Gene', (205, 209))	('FLI', 'Gene', (24, 27))	('ERG', 'Gene', '2078', (198, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('overexpression', 'PosReg', (272, 286))	('ERG', 'Gene', (198, 201))	('rearrangements', 'Var', (113, 127))	('ETS transcription factor activity', 'MPA', (235, 268))	('place', 'Reg', (136, 141))
29317	22287547	We have previously demonstrated that PARP1 and DNA-dependent protein kinase (DNA-PKcs) are key ETS cofactors in prostate cancer, and therapeutic inhibition of PARP1 disrupts the growth of ETS positive, but not ETS negative, prostate cancer xenografts.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (224, 239))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PARP1', 'Gene', (159, 164))	('prostate cancer', 'Disease', (224, 239))	('disrupts', 'NegReg', (165, 173))	('prostate cancer', 'Disease', (112, 127))	('DNA-dependent protein kinase', 'Gene', (47, 75))	('DNA-PKcs', 'Gene', '5591', (77, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (224, 239))	('growth', 'MPA', (178, 184))	('ETS', 'Disease', (188, 191))	('inhibition', 'Var', (145, 155))	('DNA-dependent protein kinase', 'Gene', '5591', (47, 75))	('DNA-PKcs', 'Gene', (77, 85))
29320	22287547	PARP1 inhibitors have demonstrated promising activity in early clinical trials, particularly in BRCA-mutant cancers defective in homologous repair (HR), in which they may cause replication fork stalling and subsequent synthetic lethal cell death.	('BRCA', 'Gene', '672', (96, 100))	('cause', 'Reg', (171, 176))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('BRCA', 'Gene', (96, 100))	('replication fork stalling', 'CPA', (177, 202))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('inhibitors', 'Var', (6, 16))	('synthetic lethal cell death', 'CPA', (218, 245))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('PARP1', 'Gene', (0, 5))	('cancers', 'Disease', (108, 115))
29324	22287547	Gene specific knockdown was accomplished using commercially available siRNA duplexes for EWS, ERG, FLI1, DNA-PKcs or PARP-1 (Dharmacon, Lafayette, CO).	('PARP-1', 'Gene', '142', (117, 123))	('DNA-PKcs', 'Gene', '5591', (105, 113))	('ERG', 'Gene', '2078', (94, 97))	('ERG', 'Gene', (94, 97))	('DNA-PKcs', 'Gene', (105, 113))	('knockdown', 'Var', (14, 23))	('PARP-1', 'Gene', (117, 123))
29334	22287547	Overexpression of any of these three ETS fusion genes caused sensitivity to Olaparib (p<0.05 at 3 and 10muM), and the EWS-FLI1 and EWS-ERG fusions were more sensitive than the TMPRSS2-ERG fusion (p<0.05 at 1muM) (Fig.	('EWS-FLI1', 'Gene', '2130;2313', (118, 126))	('TMPRSS2', 'Gene', '7113', (176, 183))	('muM', 'Gene', '56925', (104, 107))	('sensitive', 'MPA', (157, 166))	('fusions', 'Var', (139, 146))	('ERG', 'Gene', '2078', (184, 187))	('sensitivity', 'MPA', (61, 72))	('ERG', 'Gene', '2078', (135, 138))	('muM', 'Gene', (104, 107))	('TMPRSS2', 'Gene', (176, 183))	('muM', 'Gene', '56925', (207, 210))	('ERG', 'Gene', (135, 138))	('caused', 'Reg', (54, 60))	('EWS-FLI1', 'Gene', (118, 126))	('muM', 'Gene', (207, 210))	('ERG', 'Gene', (184, 187))	('Olaparib', 'Chemical', 'MESH:C531550', (76, 84))
29344	22287547	S1B) and knockdown of either EWS-FLI1 or EWS-ERG fusions caused a reduction in COMET tail moment, and significantly decreased the induction of DNA damage after Olaparib treatment (p<0.05) (Fig.	('Olaparib', 'Chemical', 'MESH:C531550', (160, 168))	('ERG', 'Gene', '2078', (45, 48))	('EWS-FLI1', 'Gene', (29, 37))	('knockdown', 'Var', (9, 18))	('ERG', 'Gene', (45, 48))	('induction', 'MPA', (130, 139))	('COMET tail moment', 'MPA', (79, 96))	('COMET', 'Species', '302767', (79, 84))	('EWS-FLI1', 'Gene', '2130;2313', (29, 37))	('DNA damage', 'MPA', (143, 153))	('decreased', 'NegReg', (116, 125))	('reduction', 'NegReg', (66, 75))
29346	22287547	However, siRNA knockdown of XRCC4 (needed for NHEJ) had little effect (Supplementary Fig.	('XRCC4', 'Gene', '7518', (28, 33))	('knockdown', 'Var', (15, 24))	('XRCC4', 'Gene', (28, 33))
29353	22287547	Because PARP1 inhibitors are unlikely to be used clinically as a monotherapy, we also combined PARP1 inhibition with the DNA alkylating agent temozolomide (TMZ) to treat a highly aggressive ESFT xenograft model (RD-ES) harboring an endogenous EWS-FLI1 rearrangement.	('rearrangement', 'Var', (252, 265))	('inhibition', 'NegReg', (101, 111))	('TMZ', 'Chemical', 'MESH:D000077204', (156, 159))	('EWS-FLI1', 'Gene', (243, 251))	('EWS-FLI1', 'Gene', '2130;2313', (243, 251))	('temozolomide', 'Chemical', 'MESH:D000077204', (142, 154))	('RD-ES', 'Chemical', '-', (212, 217))	('PARP1', 'Gene', (95, 100))
29360	22287547	Consistent with this, knockdown of PARP1 or DNA-PKcs, but not other DNA repair proteins, disrupted transcriptional activity to a similar extent as fusion targeting EWS siRNA as evidenced by disruption of consensus EWS-FLI1 target genes (Fig.	('transcriptional activity', 'MPA', (99, 123))	('EWS-FLI1', 'Gene', (214, 222))	('DNA-PKcs', 'Gene', '5591', (44, 52))	('EWS-FLI1', 'Gene', '2130;2313', (214, 222))	('DNA-PKcs', 'Gene', (44, 52))	('knockdown', 'Var', (22, 31))	('disrupted', 'NegReg', (89, 98))
29363	22287547	Likewise, in EFST cells, knockdown of the EWS-FLI1 fusion led to a decrease in PARP1 protein expression and promoter activity (p<0.05), while ERG siRNA did not have these effects in VCaP cells (Fig.	('promoter activity', 'MPA', (108, 125))	('EWS-FLI1', 'Gene', '2130;2313', (42, 50))	('decrease', 'NegReg', (67, 75))	('ERG', 'Gene', '2078', (142, 145))	('ERG', 'Gene', (142, 145))	('VCaP', 'CellLine', 'CVCL:2235', (182, 186))	('EWS-FLI1', 'Gene', (42, 50))	('knockdown', 'Var', (25, 34))	('PARP1', 'Gene', (79, 84))
29369	22287547	Our findings suggest that PARP1 inhibition should be explored as a strategy for targeted therapy in Ewing's sarcoma, which may represent a tumor type that may be as profoundly affected by PARP inhibitors as BRCA1/2 mutated carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (223, 233))	('inhibitors', 'Var', (193, 203))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('PARP', 'Gene', (26, 30))	('PARP', 'Gene', (188, 192))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (100, 115))	('carcinomas', 'Disease', 'MESH:D002277', (223, 233))	("Ewing's sarcoma", 'Disease', (100, 115))	('carcinomas', 'Disease', (223, 233))	('BRCA1/2', 'Gene', (207, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (100, 115))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('PARP', 'Gene', '142', (26, 30))	('PARP', 'Gene', '142', (188, 192))	('BRCA1/2', 'Gene', '672;675', (207, 214))
29374	33648535	These models were marked by amplification of MDM2, CDK4 and HMGA2 genes.	('HMGA2', 'Gene', '8091', (60, 65))	('HMGA2', 'Gene', (60, 65))	('MDM2', 'Gene', (45, 49))	('CDK4', 'Gene', (51, 55))	('CDK4', 'Gene', '1019', (51, 55))	('amplification', 'Var', (28, 41))
29435	33648535	Total/fractioned cellular lysates and immunoprecipitates were separated by SDS-PAGE, transferred onto nitrocellulose membranes and incubated with primary monoclonal antibodies: anti-MDM2 (#86,934, Cell Signaling Technology), anti-HMGA2 (#5269, Cell Signaling Technology), anti-cleaved CCP32 (#9661, Cell Signaling Technology), anti-STAT3 (#4904; Cell Signaling Technology), anti-acetyl-STAT3 (#2523; Cell Signaling Technology), anti-HDAC2 (#5113; Cell Signaling Technology), anti-LC3B (#2775 Cell Signaling), anti-survivin (#ab469; Abcam), anti-XPO1 (#ab24189; Abcam), anti-LC3B (#2775 Cell Signaling Technology), anti-ubiquitin (#ab7780, Abcam), anti-alpha-tubulin (T5168, Merck), anti-p53 (sc-126, Santa Cruz Biotechnology, CA, USA), anti-CDK4 (sc-601, Santa Cruz Biotechnology), anti-p16 (sc-6579, Santa Cruz Biotechnology) and anti-beta-actin (A2066, Merck).	('XPO1', 'Gene', '7514', (545, 549))	('STAT3', 'Gene', (332, 337))	('#ab7780', 'Var', (630, 637))	('LC3B', 'Gene', (480, 484))	('alpha-tubulin', 'Gene', (652, 665))	('anti-p16', 'Var', (782, 790))	('HMGA2', 'Gene', '8091', (230, 235))	('STAT3', 'Gene', '6774', (332, 337))	('CDK4', 'Gene', (741, 745))	('HDAC2', 'Gene', (433, 438))	('LC3B', 'Gene', '81631', (480, 484))	('HDAC2', 'Gene', '3066', (433, 438))	('CA', 'Gene', '12310', (726, 728))	('LC3B', 'Gene', (574, 578))	('survivin', 'Gene', (514, 522))	('LC3B', 'Gene', '81631', (574, 578))	('survivin', 'Gene', '11799', (514, 522))	('anti-ubiquitin', 'Protein', (614, 628))	('XPO1', 'Gene', (545, 549))	('STAT3', 'Gene', (386, 391))	('CDK4', 'Gene', '1019', (741, 745))	('alpha-tubulin', 'Gene', '10376', (652, 665))	('STAT3', 'Gene', '6774', (386, 391))	('HMGA2', 'Gene', (230, 235))	('anti-beta-actin', 'Protein', (831, 846))
29446	33648535	Immunophenotypic profile of models differed from the paired clinical tumours as LS-BP-1 and LS-BZ-1 PDXs lost expression of the myogenic markers Actin 14A and desmin, respectively.	('tumours', 'Disease', (69, 76))	('Actin 14A', 'Protein', (145, 154))	('BP-1', 'Gene', (83, 87))	('BP-1', 'Gene', '474256', (83, 87))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'MPA', (110, 120))	('desmin', 'Protein', (159, 165))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('lost', 'NegReg', (105, 109))	('LS-BZ-1', 'Var', (92, 99))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
29458	33648535	Histopathological evaluation of drug-treated tumors excised from mice immediately after the end of treatment with selinexor or doxorubicin showed no marked differences at the morphological level, but only a slight and focal reduction in cellularity with an increased loose stroma in post-selinexor PDXs (Fig.	('selinexor', 'Chemical', 'MESH:C585161', (288, 297))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('loose stroma', 'CPA', (267, 279))	('increased', 'PosReg', (257, 266))	('cellularity', 'CPA', (237, 248))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('mice', 'Species', '10090', (65, 69))	('doxorubicin', 'Chemical', 'MESH:D004317', (127, 138))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('selinexor', 'Chemical', 'MESH:C585161', (114, 123))	('reduction', 'NegReg', (224, 233))	('post-selinexor', 'Var', (283, 297))
29461	33648535	Western blot analysis, which was performed at the end of treatment with each drug and also after 12 days for selinexor, revealed that the XPO1 inhibitor -but not doxorubicin- reduced the expression of the anti-apoptotic protein survivin and that, in 2 out of 3 PDX models, such a decrease was still appreciable 12 days after the end of treatment (Fig.	('selinexor', 'Chemical', 'MESH:C585161', (109, 118))	('reduced', 'NegReg', (175, 182))	('doxorubicin', 'Chemical', 'MESH:D004317', (162, 173))	('inhibitor', 'Var', (143, 152))	('survivin', 'Gene', '11799', (228, 236))	('XPO1', 'Gene', (138, 142))	('XPO1', 'Gene', '7514', (138, 142))	('survivin', 'Gene', (228, 236))	('expression', 'MPA', (187, 197))	('anti-apoptotic protein', 'MPA', (205, 227))
29466	33648535	In DDLPS cell models, flow cytometric detection of TUNEL-positive cells indicated a dose-dependent induction of apoptosis by both drugs, although the extent of the apoptotic response was consistently greater for selinexor than doxorubicin (Fig.	('selinexor', 'Chemical', 'MESH:C585161', (212, 221))	('apoptosis', 'CPA', (112, 121))	('selinexor', 'Var', (212, 221))	('doxorubicin', 'Chemical', 'MESH:D004317', (227, 238))	('LPS', 'Phenotype', 'HP:0012034', (5, 8))
29473	33648535	Based on a previous report indicating that in triple-negative breast cancer cells the inhibition of XPO1 by selinexor was able to repress BIRC5/survivin gene transcription by inhibiting STAT3 acetylation and blocking STAT3 binding to the survivin promoter, we assessed STAT3 protein expression and acetylation in LS-BZ-1 cells.	('survivin', 'Gene', (238, 246))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('repress', 'NegReg', (130, 137))	('BIRC5', 'Gene', '332', (138, 143))	('survivin', 'Gene', '11799', (238, 246))	('BIRC5', 'Gene', (138, 143))	('transcription', 'MPA', (158, 171))	('survivin', 'Gene', (144, 152))	('STAT3', 'Gene', (269, 274))	('XPO1', 'Gene', (100, 104))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('blocking', 'NegReg', (208, 216))	('survivin', 'Gene', '11799', (144, 152))	('selinexor', 'Chemical', 'MESH:C585161', (108, 117))	('breast cancer', 'Disease', (62, 75))	('inhibiting', 'NegReg', (175, 185))	('STAT3', 'Gene', '6774', (269, 274))	('STAT3', 'Gene', (186, 191))	('inhibition', 'Var', (86, 96))	('STAT3', 'Gene', (217, 222))	('STAT3', 'Gene', '6774', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('binding', 'Interaction', (223, 230))	('XPO1', 'Gene', '7514', (100, 104))	('acetylation', 'MPA', (192, 203))	('STAT3', 'Gene', '6774', (217, 222))
29501	33648535	In addition, selinexor caused marked down-regulation of survivin, with an almost complete abrogation of the protein cytoplasmic pool, which is known to be responsible for survivin anti-apoptotic function.	('survivin', 'Gene', '11799', (56, 64))	('survivin', 'Gene', (171, 179))	('selinexor', 'Chemical', 'MESH:C585161', (13, 22))	('survivin', 'Gene', (56, 64))	('abrogation', 'NegReg', (90, 100))	('down-regulation', 'NegReg', (37, 52))	('survivin', 'Gene', '11799', (171, 179))	('protein cytoplasmic pool', 'MPA', (108, 132))	('selinexor', 'Var', (13, 22))
29522	33038765	Silencing KIF18B enhances radiosensitivity: identification of a promising therapeutic target in sarcoma Sarcomas are rare heterogeneous tumours, derived from primitive mesenchymal stem cells, with more than 100 distinct subtypes.	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('KIF18B', 'Gene', '146909', (10, 16))	('Sarcomas', 'Disease', (104, 112))	('Sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('Sarcomas', 'Disease', 'MESH:D012509', (104, 112))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('tumours', 'Disease', (136, 143))	('KIF18B', 'Gene', (10, 16))	('Sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('radiosensitivity', 'MPA', (26, 42))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('Silencing', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('sarcoma', 'Disease', (96, 103))
29526	33038765	The KIF18B-sensitive drug T0901317 (T09) was further mined to act as radiosensitizer using the Genomics of Drug Sensitivity in Cancer (GDSC) database.	('T09', 'Chemical', 'MESH:C423915', (26, 29))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (107, 123))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Cancer', 'Disease', (127, 133))	('T0901317', 'Var', (26, 34))	('Cancer', 'Disease', 'MESH:D009369', (127, 133))	('T0901317', 'Chemical', 'MESH:C423915', (26, 34))	('T09', 'Chemical', 'MESH:C423915', (36, 39))
29528	33038765	Multivariate Cox regression analysis showed that KIF18B high expression was an independent risk factor for prognosis in sarcoma patients with radiotherapy.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('expression', 'Species', '29278', (61, 71))	('patients', 'Species', '9606', (128, 136))	('KIF18B', 'Gene', (49, 55))	('sarcoma', 'Disease', (120, 127))	('high expression', 'Var', (56, 71))
29529	33038765	Silencing KIF18B or using T09 significantly improved the radiosensitivity of sarcoma cells, delayed tumour growth in subcutaneous and orthotopic xenograft model, and elongated mice survival time.	('delayed', 'NegReg', (92, 99))	('improved', 'PosReg', (44, 52))	('T09', 'Chemical', 'MESH:C423915', (26, 29))	('elongated', 'PosReg', (166, 175))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('mice', 'Species', '10090', (176, 180))	('sarcoma', 'Disease', (77, 84))	('KIF18B', 'Gene', (10, 16))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('radiosensitivity of', 'CPA', (57, 76))	('mice survival time', 'CPA', (176, 194))	('Silencing', 'Var', (0, 9))	('tumour', 'Disease', (100, 106))
29532	33038765	Moreover, the radiosensitivity of sarcomas with overexpressed KIF18B could be effectively improved by silencing KIF18B or using T09, which may provide promising strategies for radiotherapy treatment of sarcoma.	('sarcoma', 'Disease', (34, 41))	('KIF18B', 'Gene', (112, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('overexpressed', 'PosReg', (48, 61))	('radiosensitivity', 'MPA', (14, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('sarcomas', 'Disease', (34, 42))	('improved', 'PosReg', (90, 98))	('KIF18B', 'Gene', (62, 68))	('T09', 'Chemical', 'MESH:C423915', (128, 131))	('sarcoma', 'Disease', 'MESH:D012509', (202, 209))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('silencing', 'Var', (102, 111))	('sarcomas', 'Disease', 'MESH:D012509', (34, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (34, 42))	('sarcoma', 'Disease', (202, 209))
29539	33038765	The study confirmed that silencing KIF18B or using a KIF18B-sensitive drug (T0901317) could reduce the survival rate of clone formation, promote apoptosis and DNA damage, and effectively improve radiosensitivity on high KIF18B expressing sarcoma cells.	('silencing', 'Var', (25, 34))	('T0901317', 'Chemical', 'MESH:C423915', (76, 84))	('survival rate of clone formation', 'CPA', (103, 135))	('radiosensitivity', 'CPA', (195, 211))	('reduce', 'NegReg', (92, 98))	('sarcoma', 'Disease', (238, 245))	('promote', 'PosReg', (137, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('DNA damage', 'CPA', (159, 169))	('KIF18B', 'Gene', (35, 41))	('improve', 'PosReg', (187, 194))	('apoptosis', 'CPA', (145, 154))	('sarcoma', 'Disease', 'MESH:D012509', (238, 245))
29551	33038765	For instance, Gao and Yang showed that KIF18B promoted tumour progression by activating beta-catenin.	('tumour', 'Disease', (55, 61))	('promoted', 'PosReg', (46, 54))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('KIF18B', 'Var', (39, 45))	('beta-catenin', 'Gene', (88, 100))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('activating', 'PosReg', (77, 87))	('beta-catenin', 'Gene', '1499', (88, 100))
29554	33038765	We investigated the radiosensitivity of KIF18B-silenced sarcoma cells, showing that KIF18B was a biomarker for radioresistance.	('sarcoma', 'Disease', (56, 63))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('KIF18B', 'Var', (84, 90))
29557	33038765	The data collection related to osteosarcoma and soft tissue sarcoma were obtained from GEO database on October 15, 2018, in which fifteen datasets (GSE42352, GSE14359, GSE59568, GSE52390, GSE51049, GSE62747, GSE21122, GSE764, GSE68295, GSE6476, GSE42977, GSE28511, GSE62544, GSE2719, and GSE90592) were included in the study based on the following criteria: (1) The study of osteosarcoma or soft tissue sarcoma samples.	('GSE90592', 'Var', (288, 296))	('GSE21122', 'Var', (208, 216))	('sarcoma', 'Disease', 'MESH:D012509', (403, 410))	('GSE62544', 'Var', (265, 273))	('sarcoma', 'Disease', (403, 410))	('osteosarcoma', 'Phenotype', 'HP:0002669', (375, 387))	('GSE42352', 'Var', (148, 156))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (48, 67))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (391, 410))	('sarcoma', 'Phenotype', 'HP:0100242', (380, 387))	('GSE62747', 'Var', (198, 206))	('GSE6476', 'Var', (236, 243))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('osteosarcoma', 'Phenotype', 'HP:0002669', (31, 43))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (403, 410))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Disease', (36, 43))	('GSE764', 'Var', (218, 224))	('GSE14359', 'Var', (158, 166))	('osteosarcoma', 'Disease', (375, 387))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('GSE51049', 'Var', (188, 196))	('osteosarcoma', 'Disease', 'MESH:D012516', (375, 387))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('GSE2719', 'Var', (275, 282))	('osteosarcoma', 'Disease', (31, 43))	('osteosarcoma', 'Disease', 'MESH:D012516', (31, 43))	('sarcoma', 'Disease', 'MESH:D012509', (380, 387))	('GSE28511', 'Var', (255, 263))	('sarcoma', 'Disease', (380, 387))	('GSE68295', 'Var', (226, 234))	('GSE59568', 'Var', (168, 176))	('GSE42977', 'Var', (245, 253))	('GSE52390', 'Var', (178, 186))
29612	33038765	Bone was decalcified with decalcifying solution (G1105, G1107, Servicebio, China) before being embedded in paraffin.	('G1107', 'Var', (56, 61))	('paraffin', 'Chemical', 'MESH:D010232', (107, 115))	('G1105', 'Var', (49, 54))
29621	33038765	Further multivariate Cox regression analysis revealed that high expression of KIF18B (P=0.039) and CCDC69 (P=0.038) were independent risk factors of sarcoma with radiotherapy (Table 4).	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('KIF18B', 'Gene', (78, 84))	('sarcoma', 'Disease', (149, 156))	('CCDC69', 'Gene', (99, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('high', 'Var', (59, 63))	('CCDC69', 'Gene', '26112', (99, 105))	('expression', 'Species', '29278', (64, 74))
29623	33038765	Besides, we found that the OS of patients that had undergone radiotherapy treatment with high KIF18B expression was significantly worse than that of those with low KIF18B expression; however, no significant differences were observed in patients without radiotherapy (Fig.	('worse', 'NegReg', (130, 135))	('patients', 'Species', '9606', (33, 41))	('expression', 'Var', (101, 111))	('patients', 'Species', '9606', (236, 244))	('high', 'Var', (89, 93))	('expression', 'Species', '29278', (101, 111))	('expression', 'Species', '29278', (171, 181))	('KIF18B', 'Gene', (94, 100))
29630	33038765	To verify the relationship between KIF18B expression and radiosensitivity, the expression of KIF18B was disturbed significantly with sh-KIF18B 3 and sh-KIF18B 4 (Fig.	('expression', 'Species', '29278', (79, 89))	('expression', 'Species', '29278', (42, 52))	('expression', 'MPA', (79, 89))	('sh-KIF18B', 'Var', (149, 158))	('disturbed', 'Reg', (104, 113))	('sh-KIF18B', 'Var', (133, 142))	('KIF18B', 'Gene', (93, 99))
29631	33038765	Although KIF18B knockdown also caused a substantial growth inhibition on sarcoma cells without radiation (Fig.	('Alt', 'Gene', '76282', (0, 3))	('sarcoma', 'Disease', (73, 80))	('Alt', 'Gene', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('knockdown', 'Var', (16, 25))	('growth', 'MPA', (52, 58))	('KIF18B', 'Gene', (9, 15))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
29632	33038765	Similarly, the levels of early apoptosis and DNA damage marker (gammaH2AX) significantly increased in the sh-KIF18B+8 Gy group compared with the sh-NC+8 Gy group, but no significant differences were found between the shKIF18B+0Gy group and the shNC+0Gy group (Fig.	('H2AX', 'Gene', (69, 73))	('levels', 'MPA', (15, 21))	('increased', 'PosReg', (89, 98))	('sh-KIF18B+8', 'Var', (106, 117))	('H2AX', 'Gene', '3014', (69, 73))
29635	33038765	These results indicated that silencing KIF18B enhanced the radiosensitivity of sarcoma cells and that KIF18B played a critical role as a potential target in radiotherapy for sarcoma.	('KIF18B', 'Gene', (39, 45))	('sarcoma', 'Disease', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('silencing', 'Var', (29, 38))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('enhanced', 'PosReg', (46, 54))	('sarcoma', 'Disease', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
29638	33038765	Although radiotherapy or sh-KIF18B alone could moderately delay the tumour growth, radiotherapy combined with sh-KIF18B significantly inhibited tumour growth (Fig.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('Alt', 'Gene', '76282', (0, 3))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('inhibited', 'NegReg', (134, 143))	('Alt', 'Gene', (0, 3))	('delay', 'NegReg', (58, 63))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('tumour', 'Disease', (144, 150))	('sh-KIF18B', 'Var', (110, 119))
29639	33038765	By calculating the tumour volume ratio of 8 Gy to 0 Gy, we found that the transplanted tumours in mice of sh-KIF18B group were more sensitive to radiotherapy compared to those in the sh-NC group (Fig.	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('sensitive', 'MPA', (132, 141))	('tumours', 'Disease', (87, 94))	('tumour', 'Disease', (87, 93))	('more', 'PosReg', (127, 131))	('tumour', 'Disease', (19, 25))	('sh-KIF18B', 'Var', (106, 115))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('mice', 'Species', '10090', (98, 102))
29641	33038765	Immunohistochemistry (IHC) analysis confirmed that expression of KIF18B was decreased in the sh-KIF18B group (Fig.	('expression', 'Species', '29278', (51, 61))	('decreased', 'NegReg', (76, 85))	('expression', 'MPA', (51, 61))	('KIF18B', 'Gene', (65, 71))	('sh-KIF18B', 'Var', (93, 102))
29646	33038765	In conclusion, these results suggested that silencing KIF18B was beneficial for the efficacy of radiotherapy for sarcoma in vivo.	('beneficial', 'Reg', (65, 75))	('KIF18B', 'Gene', (54, 60))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('silencing', 'Var', (44, 53))
29648	33038765	We selected drugs whose half-maximal inhibitory concentration (IC50) values were significantly associated with high KIF18B expression.	('expression', 'Species', '29278', (123, 133))	('expression', 'MPA', (123, 133))	('high', 'Var', (111, 115))	('KIF18B', 'Gene', (116, 122))
29649	33038765	Based on IC50 of drugs in cell lines with different KIF18B expression from the GDSC database, we found that T0901317 [T09, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide], an agonist of liver X receptor (LXR), was a drug that was sensitive to high KIF18B-expressing cells (P=0.042, Fig.	('T0901317 [T09', 'Var', (108, 121))	('expression', 'Species', '29278', (59, 69))	('T09', 'Chemical', 'MESH:C423915', (108, 111))	('T09', 'Chemical', 'MESH:C423915', (118, 121))	('KIF18B-expressing', 'Gene', (310, 327))	('T0901317', 'Chemical', 'MESH:C423915', (108, 116))
29651	33038765	6b), indicating that high KIF18B-expressing sarcoma cells were more sensitive to T09.	('T09', 'Chemical', 'MESH:C423915', (81, 84))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('KIF18B-expressing', 'Gene', (26, 43))	('high', 'Var', (21, 25))	('sensitive to T09', 'MPA', (68, 84))	('sarcoma', 'Disease', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))
29655	33038765	These results suggested that T09, as a sensitive drug for KIF18B, could effectively increase the radiosensitivity of high KIF18B-expressing sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('T09', 'Chemical', 'MESH:C423915', (29, 32))	('radiosensitivity', 'CPA', (97, 113))	('high KIF18B-expressing', 'Var', (117, 139))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('increase', 'PosReg', (84, 92))	('sarcoma', 'Disease', (140, 147))
29657	33038765	6e) between the T09 group and the drug-free group after silencing of KIF18B.	('silencing', 'Var', (56, 65))	('KIF18B', 'Gene', (69, 75))	('T09', 'Chemical', 'MESH:C423915', (16, 19))
29658	33038765	These results suggested that T09 could not improve the radiosensitivity of sarcoma cells after silencing of KIF18B.	('T09', 'Chemical', 'MESH:C423915', (29, 32))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('sarcoma', 'Disease', (75, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('silencing', 'Var', (95, 104))	('KIF18B', 'Gene', (108, 114))
29659	33038765	Based on these studies, we speculated that the improvement of radiosensitivity by T09 might be related to KIF18B.	('T09', 'Chemical', 'MESH:C423915', (82, 85))	('radiosensitivity', 'MPA', (62, 78))	('T09', 'Var', (82, 85))	('improvement', 'PosReg', (47, 58))	('KIF18B', 'Var', (106, 112))
29662	33038765	The molecular operating environment (MOE) docking results indicated that T09 could interact with KIF18B stably(S=-6.941) and the analysis of the binding sites showed that KIF18B-protein 267Ser, 269Arg, 304Lys, 349Asn, 352Lys might bind T09 (Fig.	('349Asn', 'Var', (210, 216))	('interact', 'Interaction', (83, 91))	('269Arg', 'Var', (194, 200))	('T09', 'Chemical', 'MESH:C423915', (236, 239))	('T09', 'Chemical', 'MESH:C423915', (73, 76))	('304Lys', 'Var', (202, 208))	('267Ser', 'Var', (186, 192))
29668	33038765	Using the sh-NC sarcoma cells, the tumour volumes in the T09+8Gy group was significantly smaller than the radiotherapy group alone, the T09 group alone, or the untreated group (Fig.	('T09', 'Chemical', 'MESH:C423915', (57, 60))	('T09', 'Chemical', 'MESH:C423915', (136, 139))	('NC sarcoma', 'Disease', 'OMIM:617025', (13, 23))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('T09+8Gy', 'Var', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('NC sarcoma', 'Disease', (13, 23))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('smaller', 'NegReg', (89, 96))	('tumour', 'Disease', (35, 41))
29669	33038765	Similarly, Ki67 expression was significantly lower in the T09 group with radiotherapy (Fig.	('Ki67', 'Protein', (11, 15))	('T09', 'Chemical', 'MESH:C423915', (58, 61))	('lower', 'NegReg', (45, 50))	('T09', 'Var', (58, 61))	('expression', 'Species', '29278', (16, 26))	('expression', 'MPA', (16, 26))
29671	33038765	Additionally, the combination of T09 and radiotherapy significantly extended the survival time of the sarcoma-bearing mice (Fig.	('survival time', 'CPA', (81, 94))	('extended', 'PosReg', (68, 76))	('T09', 'Var', (33, 36))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('sarcoma', 'Disease', (102, 109))	('mice', 'Species', '10090', (118, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('T09', 'Chemical', 'MESH:C423915', (33, 36))
29673	33038765	Tibial xenograft tumour growth was suppressed significantly in the T09 group treated with radiotherapy (Fig.	('T09', 'Var', (67, 70))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('suppressed', 'NegReg', (35, 45))	('tumour', 'Disease', (17, 23))	('T09', 'Chemical', 'MESH:C423915', (67, 70))
29674	33038765	In summary, T09 could significantly enhance the radiosensitivity of sarcoma cells in vivo.	('T09', 'Var', (12, 15))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('T09', 'Chemical', 'MESH:C423915', (12, 15))	('sarcoma', 'Disease', (68, 75))	('enhance', 'PosReg', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
29677	33038765	The results suggested that T09 cannot exert additional radiosensitization in vivo after silencing of KIF18B.	('silencing', 'Var', (88, 97))	('T09', 'Chemical', 'MESH:C423915', (27, 30))	('KIF18B', 'Gene', (101, 107))
29679	33038765	This was consistent with the previous results, indicating that T09 increased the radiosensitivity of sarcoma cells might through interfering with KIF18B rather than inhibiting KIF18B expression.	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('KIF18B', 'Protein', (146, 152))	('sarcoma', 'Disease', (101, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('expression', 'Species', '29278', (183, 193))	('T09', 'Chemical', 'MESH:C423915', (63, 66))	('inhibiting', 'NegReg', (165, 175))	('increased', 'PosReg', (67, 76))	('expression', 'MPA', (183, 193))	('radiosensitivity of', 'CPA', (81, 100))	('KIF18B', 'Gene', (176, 182))	('T09', 'Var', (63, 66))	('interfering', 'NegReg', (129, 140))
29689	33038765	We conducted GSEA and Gene Ontology (GO) analysis of the DEGs as well, and found that the occurrence of sarcoma could be induced by the dysregulation of cell cycle and mitosis (Fig.	('sarcoma', 'Disease', (104, 111))	('dysregulation', 'Var', (136, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('cell cycle', 'CPA', (153, 163))	('GSEA', 'Chemical', '-', (13, 17))	('induced by', 'Reg', (121, 131))	('mitosis', 'Disease', (168, 175))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('mitosis', 'Disease', 'None', (168, 175))
29691	33038765	We confirmed that inhibition of KIF18B could enhance the radiosensitivity of sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('enhance', 'PosReg', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcoma', 'Disease', (77, 84))	('inhibition', 'Var', (18, 28))	('KIF18B', 'Gene', (32, 38))
29693	33038765	Furthermore, we selected T0901317, a drug sensitive to KIF18B, to provide a potential treatment for radiosensitizing sarcoma tumours.	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('radiosensitizing sarcoma tumours', 'Disease', 'MESH:D012509', (100, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('T0901317', 'Var', (25, 33))	('radiosensitizing sarcoma tumours', 'Disease', (100, 132))	('T0901317', 'Chemical', 'MESH:C423915', (25, 33))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))
29702	33038765	Our data also suggested that up-regulation of H2AX phosphorylation and increase of apoptosis played a vital role in KIF18B knockdown-mediated enhancement of radiosensitivity in sarcoma cells.	('enhancement', 'PosReg', (142, 153))	('KIF18B', 'Gene', (116, 122))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('H2AX', 'Gene', '3014', (46, 50))	('sarcoma', 'Disease', (177, 184))	('up-regulation', 'PosReg', (29, 42))	('H2AX', 'Gene', (46, 50))	('radiosensitivity', 'CPA', (157, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('phosphorylation', 'MPA', (51, 66))	('increase', 'PosReg', (71, 79))	('apoptosis', 'CPA', (83, 92))	('knockdown-mediated', 'Var', (123, 141))
29706	33038765	KIF18B is important for microtubule polymerization, and its expression level is maximal at late G2/M-phase, suggesting KIF18B knockdown might exert similar effects like vincristine to regulate cell cycle and to increase radiosensitivity of cells.	('knockdown', 'Var', (126, 135))	('expression', 'Species', '29278', (60, 70))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (211, 236))	('increase', 'PosReg', (211, 219))	('KIF18B', 'Gene', (119, 125))	('vincristine', 'Chemical', 'MESH:D014750', (169, 180))	('radiosensitivity of cells', 'CPA', (220, 245))	('cell cycle', 'CPA', (193, 203))	('regulate', 'Reg', (184, 192))
29707	33038765	In our study, we found that KIF18B knockdown alone (without radiation) exerted an antiproliferative action on sarcoma cells, but not induced apoptosis of cells.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('knockdown', 'Var', (35, 44))	('sarcoma', 'Disease', (110, 117))	('antiproliferative action', 'CPA', (82, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('KIF18B', 'Gene', (28, 34))
29711	33038765	S6), indicating that KIF18B knockdown might not improve chemosensitivity of sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('sarcoma', 'Disease', (76, 83))	('KIF18B', 'Gene', (21, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('knockdown', 'Var', (28, 37))
29716	33038765	Our study proved that T09 could sensitize high-KIF18B expressing sarcoma cells to radiotherapy, whereas it did not exert additive radionsensitization in KIF18B-knockdown sarcoma cells, indicating that the increased radiosensitivity by T09 might be related to KIF18B.	('T09', 'Chemical', 'MESH:C423915', (235, 238))	('sarcoma', 'Disease', 'MESH:D012509', (170, 177))	('sarcoma', 'Disease', (65, 72))	('T09', 'Chemical', 'MESH:C423915', (22, 25))	('high-KIF18B', 'Var', (42, 53))	('T09', 'Var', (22, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('sensitize', 'Reg', (32, 41))	('sarcoma', 'Disease', (170, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (205, 231))
29717	33038765	For example, LXR activation was indirectly related to radioresistance on the head and neck squamous cell carcinomas cell line SCC-61 and radiosensitization linked to LXR inactivation or deficiency in irradiated macrophages.	('SCC-61', 'CellLine', 'CVCL:7118', (126, 132))	('LXR', 'Enzyme', (13, 16))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (91, 115))	('deficiency', 'Disease', (186, 196))	('neck squamous cell carcinomas', 'Disease', (86, 115))	('deficiency', 'Disease', 'MESH:D007153', (186, 196))	('inactivation', 'Var', (170, 182))	('activation', 'PosReg', (17, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (86, 115))	('radioresistance', 'Disease', (54, 69))	('LXR', 'MPA', (166, 169))
29718	33038765	We demonstrated that LXR agonist T09 could effectively increase the radiosensitivity of KIF18B high-expressing sarcoma cells.	('KIF18B', 'Gene', (88, 94))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('increase', 'PosReg', (55, 63))	('T09', 'Var', (33, 36))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('radiosensitivity', 'MPA', (68, 84))	('T09', 'Chemical', 'MESH:C423915', (33, 36))
29721	33038765	Conversely, if T09 increased radiosensitivity through other pathways rather than KIF18B, T09 and sh-KIF18B would exert an additive action, the radiotherapy of the T09+sh-KIF18B group should be more effective than that of the sh-KIF18B group.	('T09', 'Chemical', 'MESH:C423915', (89, 92))	('T09', 'Var', (15, 18))	('radiotherapy', 'CPA', (143, 155))	('radiosensitivity', 'MPA', (29, 45))	('T09', 'Chemical', 'MESH:C423915', (163, 166))	('T09+sh-KIF18B', 'Var', (163, 176))	('T09', 'Chemical', 'MESH:C423915', (15, 18))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (19, 45))
29722	33038765	However, the radiosensitivity of the T09+sh-KIF18B group was similar to that of the sh-KIF18B group, indicating that T09 could not exert additive radiosensitization in sarcoma cells with sh-KIF18B (Fig.	('T09', 'Chemical', 'MESH:C423915', (37, 40))	('T09', 'Var', (117, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('sh-KIF18B', 'Var', (187, 196))	('T09', 'Chemical', 'MESH:C423915', (117, 120))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('sarcoma', 'Disease', (168, 175))
29723	33038765	Therefore, we speculated that T09 improved the curative effect of radiotherapy via affecting KIF18B.	('improved', 'PosReg', (34, 42))	('curative effect', 'CPA', (47, 62))	('T09', 'Var', (30, 33))	('affecting', 'Reg', (83, 92))	('T09', 'Chemical', 'MESH:C423915', (30, 33))	('KIF18B', 'Gene', (93, 99))
29725	33038765	Our study found that the expression of KIF18B in T09 group was not suppressed compared with the drug-free group at 8 Gy (Fig.	('T09', 'Chemical', 'MESH:C423915', (49, 52))	('T09', 'Var', (49, 52))	('KIF18B', 'Gene', (39, 45))	('expression', 'Species', '29278', (25, 35))
29728	33038765	In this study, the crystal structure of KIF18B was simulated by MOE, and the results indicated that T09 might bind KIF18B through 267Ser, 269Arg, 304Lys, 349Asn, and 352Lys to interfere KIF18B.	('267Ser', 'Var', (130, 136))	('T09', 'Chemical', 'MESH:C423915', (100, 103))	('269Arg', 'Var', (138, 144))	('304Lys', 'Var', (146, 152))	('352Lys', 'Var', (166, 172))	('KIF18B', 'Gene', (115, 121))	('349Asn', 'Var', (154, 160))	('interfere', 'NegReg', (176, 185))	('KIF18B', 'Gene', (186, 192))	('bind', 'Interaction', (110, 114))
29729	33038765	We analysed the efficacy and preliminary safety of radiotherapy combined with T09 or KIF18B knockdown in vivo.	('T09', 'Chemical', 'MESH:C423915', (78, 81))	('knockdown', 'Var', (92, 101))	('KIF18B', 'Gene', (85, 91))
29730	33038765	The inhibition of KIF18B induced a robust and long-lasting radiation response, eliminating tumour growth and extending survival time in a subcutaneous xenograft model.	('eliminating', 'NegReg', (79, 90))	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('survival time', 'CPA', (119, 132))	('tumour', 'Disease', (91, 97))	('inhibition', 'Var', (4, 14))	('KIF18B', 'Gene', (18, 24))	('extending', 'PosReg', (109, 118))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
29731	33038765	T09 was also been shown to increase the radiosensitivity of sarcoma in vivo.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('T09', 'Chemical', 'MESH:C423915', (0, 3))	('sarcoma', 'Disease', (60, 67))	('T09', 'Var', (0, 3))	('radiosensitivity', 'MPA', (40, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('increase', 'PosReg', (27, 35))
29735	33038765	The results of this orthotopic tumour model showed that KIF18B-based therapy could increase the sarcoma radiosensitivity, which is consistent with the subcutaneous xenograft model.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('increase', 'PosReg', (83, 91))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('KIF18B-based', 'Var', (56, 68))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('tumour', 'Disease', (31, 37))	('sarcoma', 'Disease', (96, 103))
29737	33038765	In addition, we found that the combination of radiotherapy with KIF18B knockdown could inhibit tumour growth, but it could not induce tumour stasis.	('tumour stasis', 'Disease', 'MESH:D009369', (134, 147))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('KIF18B', 'Gene', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('knockdown', 'Var', (71, 80))	('tumour', 'Disease', (134, 140))	('tumour', 'Disease', (95, 101))	('tumour stasis', 'Disease', (134, 147))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('inhibit', 'NegReg', (87, 94))
29741	33038765	No significant apoptosis was found in sarcoma cells treated with sh-KIF18B at 0Gy, and the results of the bioinformatics analysis and immunohistochemistry showed that KIF18B has almost no expression in most normal tissues (Fig.	('expression', 'Species', '29278', (188, 198))	('sarcoma', 'Disease', (38, 45))	('expression', 'MPA', (188, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('KIF18B', 'Var', (167, 173))	('sh-KIF18B', 'Var', (65, 74))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))
29743	33038765	Moreover, there was no detectable weight loss and no abnormal changes of biochemical indexes (ALT, AST, CRE, UA) and organ pathology in both T09 (+) and T09 (-) groups, indicating that T09 had nearly no toxicity in these mouse models.	('T09', 'Var', (141, 144))	('UA', 'Chemical', 'MESH:D014527', (109, 111))	('ALT', 'Gene', '76282', (94, 97))	('weight loss', 'Disease', (34, 45))	('toxicity', 'Disease', 'MESH:D064420', (203, 211))	('toxicity', 'Disease', (203, 211))	('weight loss', 'Phenotype', 'HP:0001824', (34, 45))	('mouse', 'Species', '10090', (221, 226))	('T09', 'Chemical', 'MESH:C423915', (185, 188))	('T09', 'Chemical', 'MESH:C423915', (141, 144))	('ALT', 'Gene', (94, 97))	('weight loss', 'Disease', 'MESH:D015431', (34, 45))	('CRE', 'Chemical', 'MESH:D003404', (104, 107))	('T09', 'Chemical', 'MESH:C423915', (153, 156))
29747	33038765	Meanwhile, the knockdown of KIF18B or using T09 to target KIF18B could significantly enhance radiosensitivity of sarcoma cells, and could also improve tumour sensitivity to radiotherapy in subcutaneous and orthotopic xenograft models.	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (85, 109))	('knockdown', 'Var', (15, 24))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('improve', 'PosReg', (143, 150))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('KIF18B', 'Gene', (58, 64))	('KIF18B', 'Gene', (28, 34))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('sarcoma', 'Disease', (113, 120))	('tumour', 'Disease', (151, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('T09', 'Chemical', 'MESH:C423915', (44, 47))	('enhance', 'PosReg', (85, 92))
29748	33038765	The mechanism of radiosensitization of T09might be related to that T09 interfering with the functional region of KIF18B.	('T09', 'Var', (67, 70))	('KIF18B', 'Protein', (113, 119))	('functional region', 'MPA', (92, 109))	('radiosensitization', 'MPA', (17, 35))	('interfering', 'NegReg', (71, 82))	('T09', 'Chemical', 'MESH:C423915', (67, 70))	('T09might', 'Var', (39, 47))	('T09', 'Chemical', 'MESH:C423915', (39, 42))
29749	33038765	These results indicated that sarcomas with low expression of KIF18B may benefit from radiotherapy, and the radiosensitivity of sarcoma with high KIF18B expression could be effectively improved by silencing KIF18B or using T09, which may be a window for overcoming radioresistance and provide potential strategies for radiosensitization of sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (339, 346))	('improved', 'PosReg', (184, 192))	('KIF18B', 'Gene', (206, 212))	('radiotherapy', 'CPA', (85, 97))	('sarcoma', 'Disease', (339, 346))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('KIF18B', 'Gene', (61, 67))	('benefit', 'PosReg', (72, 79))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('sarcoma', 'Disease', (29, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcomas', 'Disease', (29, 37))	('expression', 'MPA', (152, 162))	('silencing', 'Var', (196, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (339, 346))	('T09', 'Chemical', 'MESH:C423915', (222, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('KIF18B', 'Gene', (145, 151))	('radiosensitivity', 'CPA', (107, 123))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('expression', 'Species', '29278', (152, 162))	('expression', 'Species', '29278', (47, 57))	('sarcoma', 'Disease', (127, 134))
29753	31935373	Furthermore, disruption of PLP-dependent enzymes ODC1 or GOT2 selectively inhibited AML cell proliferation and their downstream products partially rescued PDXK disruption induced proliferation blockage.	('inhibited', 'NegReg', (74, 83))	('proliferation blockage', 'CPA', (179, 201))	('AML', 'Disease', 'MESH:D015470', (84, 87))	('PLP', 'Gene', (27, 30))	('disruption', 'Var', (13, 23))	('PLP', 'Gene', '57026', (27, 30))	('GOT2', 'Gene', (57, 61))	('AML', 'Phenotype', 'HP:0004808', (84, 87))	('ODC1', 'Gene', (49, 53))	('AML', 'Disease', (84, 87))	('ODC1', 'Gene', '4953', (49, 53))
29761	31935373	Further emphasizing the importance of metabolic reprograming during tumorigenesis, a subset of cancer-causing mutations directly affect metabolic processes.	('tumor', 'Disease', (68, 73))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('affect', 'Reg', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('metabolic', 'MPA', (136, 145))
29762	31935373	These include missense mutations in isocitrate dehydrogenase (IDH) occurring in leukemia, glioma, sarcoma, and cholangiocarcinoma, loss-of-function mutation of succinate dehydrogenase (SDH) in pheochromocytoma and paraganglioma, and hereditary mutations in fumarate hydratase (FH) occurring in renal cell cancer.	('SDH', 'Gene', '6390', (185, 188))	('isocitrate dehydrogenase', 'Gene', '3417', (36, 60))	('hereditary mutations', 'Var', (233, 253))	('renal cell cancer', 'Disease', (294, 311))	('loss-of-function', 'NegReg', (131, 147))	('renal cell cancer', 'Disease', 'MESH:C538614', (294, 311))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('FH', 'Gene', '2271', (277, 279))	('paraganglioma', 'Phenotype', 'HP:0002668', (214, 227))	('glioma', 'Disease', (90, 96))	('renal cell cancer', 'Phenotype', 'HP:0005584', (294, 311))	('pheochromocytoma', 'Disease', 'MESH:D010673', (193, 209))	('SDH', 'Gene', (185, 188))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('fumarate hydratase', 'Gene', (257, 275))	('leukemia', 'Disease', (80, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (111, 129))	('leukemia', 'Disease', 'MESH:D007938', (80, 88))	('succinate dehydrogenase', 'Gene', (160, 183))	('pheochromocytoma', 'Disease', (193, 209))	('cholangiocarcinoma', 'Disease', (111, 129))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (193, 209))	('isocitrate dehydrogenase', 'Gene', (36, 60))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('missense mutations', 'Var', (14, 32))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcoma', 'Disease', (98, 105))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (111, 129))	('paraganglioma', 'Disease', (214, 227))	('glioma', 'Disease', (221, 227))	('fumarate hydratase', 'Gene', '2271', (257, 275))	('paraganglioma', 'Disease', 'MESH:D010235', (214, 227))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('succinate dehydrogenase', 'Gene', '6390', (160, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
29763	31935373	While the clinical success of agents capable of inhibiting the mutant IDH proteins highlights the therapeutic utility of targeting deregulated metabolism in cancer, the vast majority of oncogenic drivers alter metabolism through indirect mechanisms and, as such, metabolic dependencies cannot be inferred from genomic analyses alone.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('metabolism', 'MPA', (210, 220))	('metabolic dependencies', 'Disease', (263, 285))	('mutant', 'Var', (63, 69))	('IDH', 'Gene', (70, 73))	('inhibiting', 'NegReg', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('metabolic dependencies', 'Disease', 'MESH:D008659', (263, 285))	('alter', 'Reg', (204, 209))
29765	31935373	For example, vitamin C and D have recently been implicated in controlling a variety of cancer associated processes, and perturbations in these processes can modulate various cancer phenotypes.	('cancer', 'Disease', (87, 93))	('vitamin C', 'Chemical', 'MESH:D001205', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('perturbations', 'Var', (120, 133))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', (174, 180))	('modulate', 'Reg', (157, 165))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
29776	31935373	To functionally characterize whether these genes are essential for leukemic cell proliferation, a focused CRISPR/Cas9 sgRNA library specifically targeting these 236 genes was constructed and introduced as a pool into Nras(G12D)/MLL-AF9 leukemic cells.	('G12D', 'Var', (222, 226))	('G12D', 'SUBSTITUTION', 'None', (222, 226))	('CRISPR', 'Gene', '70873', (106, 112))	('CRISPR', 'Gene', (106, 112))
29785	31935373	Consistent with CRISPR/Cas9 screening results, knockout of Pdxk using individual sgRNAs inhibited proliferation of Nras(G12D)/MLL-AF9 leukemic cells, but not immortalized mouse embryonic fibroblasts (iMEFs) (Figure 1E-1H).	('inhibited', 'NegReg', (88, 97))	('CRISPR', 'Gene', '70873', (16, 22))	('G12D', 'Var', (120, 124))	('knockout', 'Var', (47, 55))	('CRISPR', 'Gene', (16, 22))	('mouse', 'Species', '10090', (171, 176))	('MEFs', 'CellLine', 'CVCL:9115', (201, 205))	('proliferation', 'CPA', (98, 111))	('iMEF', 'CellLine', 'CVCL:9115', (200, 204))	('G12D', 'SUBSTITUTION', 'None', (120, 124))
29789	31935373	Nras(G12D)/IDH, IDH/Flt3, Nras(G12D)/NPM1, and MLL-AF9) (Figure 1I and 1J), as well as a panel of human leukemic cell lines (MOLM13, ML2, SEMK2, K562, and THP1) (Figure 1K and 1L).	('K562', 'CellLine', 'CVCL:0004', (145, 149))	('THP1', 'CellLine', 'CVCL:0006', (155, 159))	('G12D', 'Var', (5, 9))	('G12D', 'SUBSTITUTION', 'None', (31, 35))	('MOLM13', 'CellLine', 'CVCL:2119', (125, 131))	('G12D', 'SUBSTITUTION', 'None', (5, 9))	('G12D', 'Var', (31, 35))	('human', 'Species', '9606', (98, 103))
29792	31935373	Gene set enrichment analysis of RNA-seq data obtained following Pdxk knockout revealed a significant downregulation of genes associated with "cell cycle progression", "DNA replication", and "nucleotide metabolism" (Figure S3A-S3D and Table S3 and S4).	('downregulation', 'NegReg', (101, 115))	('nucleotide metabolism', 'MPA', (191, 212))	('DNA replication', 'CPA', (168, 183))	('Pdxk', 'Gene', (64, 68))	('3D', 'Chemical', '-', (227, 229))	('knockout', 'Var', (69, 77))
29795	31935373	We previously generated an AML mouse model where Nras(G12D) was co-expressed with luciferase to allow for monitoring of disease progression with bioluminescence imaging.	('AML', 'Phenotype', 'HP:0004808', (27, 30))	('G12D', 'Var', (54, 58))	('mouse', 'Species', '10090', (31, 36))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('G12D', 'SUBSTITUTION', 'None', (54, 58))	('AML', 'Disease', (27, 30))
29796	31935373	These Nras(G12D)/MLL-AF9 leukemic cells were first transduced with viruses encoding control sgRNA or sgRNAs targeting Pdxk with a co-expressed GFP reporter, and subsequently transplanted into sub-lethally irradiated recipient mice.	('G12D', 'Var', (11, 15))	('G12D', 'SUBSTITUTION', 'None', (11, 15))	('sgRNAs', 'Gene', (101, 107))	('mice', 'Species', '10090', (226, 230))
29801	31935373	Similar to the sgRNA approach, Nras(G12D)/MLL-AF9 leukemic cells harboring a reverse tetracycline transactivator (rtTA) were transduced with vectors expressing control or Pdxk shRNAs placed downstream of a tetracycline-responsive element (TRE) promoter and physically linked to GFP.	('tetracycline', 'Chemical', 'MESH:D013752', (85, 97))	('G12D', 'Var', (36, 40))	('shRNAs', 'Gene', (176, 182))	('Pdxk', 'Var', (171, 175))	('G12D', 'SUBSTITUTION', 'None', (36, 40))	('tetracycline', 'Chemical', 'MESH:D013752', (206, 218))
29806	31935373	To determine whether genetic blockade of PDXK activity affected PLP levels in leukemic cells, we developed a high-performance liquid chromatography-mass spectrometry (LC-MS) method to measure intracellular PLP.	('PLP', 'Gene', (206, 209))	('PLP', 'Gene', '57026', (64, 67))	('PLP', 'Gene', '57026', (206, 209))	('genetic blockade', 'Var', (21, 37))	('affected', 'Reg', (55, 63))	('PLP', 'Gene', (64, 67))
29810	31935373	As anticipated, the reduced proliferation of murine and human leukemia cells following genetic inhibition of PDXK was accompanied by a dramatic decrease in PLP levels (Figure 3B-3E).	('reduced', 'NegReg', (20, 27))	('PDXK', 'Gene', (109, 113))	('proliferation', 'CPA', (28, 41))	('decrease', 'NegReg', (144, 152))	('leukemia', 'Disease', (62, 70))	('human', 'Species', '9606', (56, 61))	('genetic inhibition', 'Var', (87, 105))	('leukemia', 'Disease', 'MESH:D007938', (62, 70))	('PLP', 'Gene', (156, 159))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('PLP', 'Gene', '57026', (156, 159))	('murine', 'Species', '10090', (45, 51))
29811	31935373	iMEFs and human sarcoma cells displayed a similar reduction in PLP levels following PDXK disruption (Figure 3F and 3G), despite retaining the ability to proliferate (Figures 1G and S1E).	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('MEFs', 'CellLine', 'CVCL:9115', (1, 5))	('PDXK', 'Gene', (84, 88))	('human', 'Species', '9606', (10, 15))	('reduction', 'NegReg', (50, 59))	('PLP', 'Gene', (63, 66))	('iMEF', 'CellLine', 'CVCL:9115', (0, 4))	('sarcoma', 'Disease', (16, 23))	('disruption', 'Var', (89, 99))	('PLP', 'Gene', '57026', (63, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))
29812	31935373	These results confirm that PDXK disruption reduces intracellular PLP levels and imply that different cell types can have a different biological response to this perturbation.	('disruption', 'Var', (32, 42))	('PLP', 'Gene', '57026', (65, 68))	('PLP', 'Gene', (65, 68))	('PDXK', 'Gene', (27, 31))	('reduces', 'NegReg', (43, 50))
29820	31935373	Wild-type PDXKs or a kinase dead human PDXK mutant were co-expressed with a series of human PDXK-targeting sgRNAs in Cas9-expressing human MOLM13 leukemia cells (Figure 4G-4K).	('human', 'Species', '9606', (86, 91))	('human', 'Species', '9606', (133, 138))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('human', 'Species', '9606', (33, 38))	('leukemia', 'Disease', (146, 154))	('MOLM13', 'CellLine', 'CVCL:2119', (139, 145))	('mutant', 'Var', (44, 50))
29821	31935373	It has been shown previously that mutation of the aspartic acid residue at position 235 in human PDXK to alanine (D235A) eliminates the kinase activity of PDXK while maintaining the overall structure and expression of the protein.	('overall structure', 'MPA', (182, 199))	('maintaining', 'Reg', (166, 177))	('PDXK', 'Enzyme', (155, 159))	('mutation', 'Var', (34, 42))	('eliminates', 'NegReg', (121, 131))	('kinase activity', 'MPA', (136, 151))	('D235A', 'SUBSTITUTION', 'None', (114, 119))	('alanine', 'Chemical', 'MESH:D000409', (105, 112))	('aspartic acid', 'Chemical', 'MESH:D001224', (50, 63))	('expression', 'MPA', (204, 214))	('human', 'Species', '9606', (91, 96))	('D235A', 'Var', (114, 119))
29822	31935373	As expected, enforced expression of wild-type PDXK restored PLP levels and rescued the proliferative defects associated with genetic PDXK reduction (Figure 4G, 4H and 4K).	('proliferative', 'CPA', (87, 100))	('rescued', 'PosReg', (75, 82))	('PLP', 'Gene', '57026', (60, 63))	('restored', 'PosReg', (51, 59))	('genetic', 'Var', (125, 132))	('PLP', 'Gene', (60, 63))	('reduction', 'NegReg', (138, 147))
29823	31935373	By contrast, enforced expression of the kinase dead PDXK mutant (which was expressed at comparable levels to wild-type PDXK) or PDXK with a corresponding deletion did not rescue the proliferative defects or restore PLP levels (Figure 4I-4K and Figure S4E-S4G).	('proliferative defects', 'CPA', (182, 203))	('PLP', 'Gene', '57026', (215, 218))	('deletion', 'Var', (154, 162))	('restore', 'PosReg', (207, 214))	('PLP', 'Gene', (215, 218))	('PDXK', 'Gene', (52, 56))
29837	31935373	Depletion of PNPO decreased PLP, although to a lesser extent than PDXK depletion, while depletion of PDXP did not influence PLP levels (Figure 5B and 5C).	('PDXP', 'Gene', '57026', (101, 105))	('PNPO', 'Gene', (13, 17))	('decreased', 'NegReg', (18, 27))	('PLP', 'Gene', (28, 31))	('Depletion', 'Var', (0, 9))	('PLP', 'Gene', (124, 127))	('PLP', 'Gene', '57026', (28, 31))	('PLP', 'Gene', '57026', (124, 127))	('PDXP', 'Gene', (101, 105))	('PNPO', 'Gene', '55163', (13, 17))
29846	31935373	Metabolomic profiling showed that genetic depletion of PDXK in human MOLM13 leukemia cells altered a wide range of metabolites with nucleotides, their precursors and the polyamine putrescine among the most decreased (Figure 6A and S6A).	('genetic depletion', 'Var', (34, 51))	('human', 'Species', '9606', (63, 68))	('decreased', 'NegReg', (206, 215))	('wide range of metabolites with nucleotides', 'MPA', (101, 143))	('altered', 'Reg', (91, 98))	('putrescine', 'Chemical', 'MESH:D011700', (180, 190))	('MOLM13', 'CellLine', 'CVCL:2119', (69, 75))	('leukemia', 'Disease', (76, 84))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))	('polyamine', 'Chemical', 'MESH:D011073', (170, 179))	('PDXK', 'Gene', (55, 59))
29847	31935373	Genetic depletion of Pdxk in mouse Nras(G12D)/MLL-AF9 leukemia cells displayed qualitatively similar changes (Figure 6B).	('G12D', 'Var', (40, 44))	('MLL-AF9 leukemia', 'Disease', 'MESH:D007938', (46, 62))	('MLL-AF9 leukemia', 'Disease', (46, 62))	('mouse', 'Species', '10090', (29, 34))	('G12D', 'SUBSTITUTION', 'None', (40, 44))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('depletion', 'NegReg', (8, 17))
29848	31935373	Changes in TCA cycle intermediates and glycolytic metabolites were also observed upon PDXK depletion (Figure S6B and S6C).	('TCA', 'Enzyme', (11, 14))	('depletion', 'Var', (91, 100))	('TCA', 'Chemical', 'MESH:D014238', (11, 14))	('glycolytic metabolites', 'MPA', (39, 61))	('Changes', 'Reg', (0, 7))
29851	31935373	In parallel with the metabolomic analyses, we performed a focused CRISPR/Cas9 screen in order to determine whether any of the 27 PLP-dependent enzymes expressed in both murine Nras(G12D)/MLL-AF9 and human MOLM13 AML cells were important for leukemic cell proliferation (Figure 6C).	('PLP', 'Gene', (129, 132))	('PLP', 'Gene', '57026', (129, 132))	('human', 'Species', '9606', (199, 204))	('G12D', 'SUBSTITUTION', 'None', (181, 185))	('murine', 'Species', '10090', (169, 175))	('CRISPR', 'Gene', (66, 72))	('AML', 'Disease', 'MESH:D015470', (212, 215))	('G12D', 'Var', (181, 185))	('leukemic cell proliferation', 'CPA', (241, 268))	('CRISPR', 'Gene', '70873', (66, 72))	('AML', 'Phenotype', 'HP:0004808', (212, 215))	('MOLM13', 'CellLine', 'CVCL:2119', (205, 211))	('AML', 'Disease', (212, 215))
29856	31935373	To further explore the functional relevance of these PLP-dependent enzymes in leukemic cell maintenance, we assessed whether addition of exogenous metabolites could rescue cell proliferation following PLP depletion.	('depletion', 'Var', (205, 214))	('rescue', 'PosReg', (165, 171))	('PLP', 'Gene', '57026', (53, 56))	('cell proliferation', 'CPA', (172, 190))	('PLP', 'Gene', (201, 204))	('PLP', 'Gene', '57026', (201, 204))	('PLP', 'Gene', (53, 56))
29866	31935373	In fact, two prior studies have shown that depletion of GOT1, also a PLP-dependent enzyme, substantially increases aspartate levels.	('GOT1', 'Gene', (56, 60))	('depletion', 'Var', (43, 52))	('aspartate levels', 'MPA', (115, 131))	('PLP', 'Gene', (69, 72))	('PLP', 'Gene', '57026', (69, 72))	('aspartate', 'Chemical', 'MESH:D001224', (115, 124))	('increases', 'PosReg', (105, 114))	('increases aspartate levels', 'Phenotype', 'HP:0500159', (105, 131))
29871	31935373	We transplanted Nras(G12D)/MLL-AF9 cells co-expressing luciferase into sublethally irradiated recipient mice to establish leukemia in vivo (Figure 7A).	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('G12D', 'SUBSTITUTION', 'None', (21, 25))	('mice', 'Species', '10090', (104, 108))	('G12D', 'Var', (21, 25))
29881	31935373	Nonetheless, a dose schedule of 7 mg/kg twice daily, was able to inhibit leukemia expansion in both the Nras(G12D)/MLL-AF9 and AML-ETO leukemia models (Figure S7I-S7N), without disrupting normal hematopoiesis (Figure S7A).	('G12D', 'Var', (109, 113))	('G12D', 'SUBSTITUTION', 'None', (109, 113))	('AML', 'Phenotype', 'HP:0004808', (127, 130))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('AML-ETO leukemia', 'Disease', 'MESH:D015470', (127, 143))	('leukemia', 'Disease', 'MESH:D007938', (73, 81))	('leukemia', 'Disease', (73, 81))	('leukemia', 'Disease', (135, 143))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('leukemia', 'Disease', 'MESH:D007938', (135, 143))	('inhibit', 'NegReg', (65, 72))	('AML-ETO leukemia', 'Disease', (127, 143))
29892	31935373	Conversely, genetic perturbation of ODC1, which is a PLP-dependent enzyme needed for putrescine levels, had a greater effect on AML cells than MEFs.	('putrescine', 'Chemical', 'MESH:D011700', (85, 95))	('AML', 'Disease', (128, 131))	('PLP', 'Gene', '57026', (53, 56))	('ODC1', 'Gene', '4953', (36, 40))	('MEFs', 'CellLine', 'CVCL:9115', (143, 147))	('AML', 'Phenotype', 'HP:0004808', (128, 131))	('AML', 'Disease', 'MESH:D015470', (128, 131))	('perturbation', 'Var', (20, 32))	('ODC1', 'Gene', (36, 40))	('genetic perturbation', 'Var', (12, 32))	('PLP', 'Gene', (53, 56))
29902	31935373	The fact that leukemia cells show a greater dependence than normal cells for vitamin B6 is consistent with recent epidemiological studies suggesting that vitamin B6 is not chemopreventive but instead may increase cancer risk.	('vitamin B6', 'Var', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('vitamin B6', 'Chemical', 'MESH:D025101', (77, 87))	('increase', 'PosReg', (204, 212))	('leukemia', 'Disease', (14, 22))	('vitamin B6', 'Chemical', 'MESH:D025101', (154, 164))	('leukemia', 'Disease', 'MESH:D007938', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('leukemia', 'Phenotype', 'HP:0001909', (14, 22))	('cancer', 'Disease', (213, 219))
29908	31935373	Mouse leukemic cell lines including Nras(G12D)/MLL-AF9, Nras(G12D)/IDH, IDH/Flt3, Nras(G12D)/NPM1, and MLL-AF9 were cultured in RPMI medium supplemented with 10 % Fetal Bovine Serum (FBS), L-glutamine, penicillin streptomycin, recombinant mouse SCF, IL-3, and IL-6.	('SCF', 'Gene', '17311', (245, 248))	('IL-3', 'Gene', '16187', (250, 254))	('G12D', 'SUBSTITUTION', 'None', (61, 65))	('SCF', 'Gene', (245, 248))	('G12D', 'SUBSTITUTION', 'None', (41, 45))	('G12D', 'Var', (61, 65))	('IL-3', 'Gene', (250, 254))	('L-glutamine', 'Chemical', 'MESH:D005973', (189, 200))	('IL-6', 'Gene', (260, 264))	('G12D', 'SUBSTITUTION', 'None', (87, 91))	('G12D', 'Var', (41, 45))	('RPMI medium', 'Chemical', '-', (128, 139))	('Mouse', 'Species', '10090', (0, 5))	('penicillin', 'Chemical', 'MESH:D010406', (202, 212))	('mouse', 'Species', '10090', (239, 244))	('IL-6', 'Gene', '16193', (260, 264))	('G12D', 'Var', (87, 91))	('streptomycin', 'Chemical', 'MESH:D013307', (213, 225))
29918	31935373	For genetic Pdxk depletion or knockdown, Nras(G12D)/MLL-AF9 leukemic cells were infected with viruses encoding sgRNAs or shRNAs either targeting Renilla luciferase or Pdxk before transplantation.	('G12D', 'Var', (46, 50))	('sgRNAs', 'Gene', (111, 117))	('G12D', 'SUBSTITUTION', 'None', (46, 50))	('infected', 'Disease', 'MESH:D007239', (80, 88))	('infected', 'Disease', (80, 88))
29932	31935373	Nras(G12D)/MLL-AF9 leukemic cells were infected with viral sgRNA pool supernatants at 37 C and 1,500 rpm for 60 min.	('G12D', 'Var', (5, 9))	('infected', 'Disease', 'MESH:D007239', (39, 47))	('infected', 'Disease', (39, 47))	('G12D', 'SUBSTITUTION', 'None', (5, 9))
29951	31935373	HSPCs isolated from donor (C57BL/6J mice) were infected with retroviruses expressing shRNAs targeting Renilla luciferase, Pdxk, or Rpa3 and mCherry or GFP in the same transcript.	('infected', 'Disease', (47, 55))	('Rpa3', 'Var', (131, 135))	('Pdxk', 'Var', (122, 126))	('mice', 'Species', '10090', (36, 40))	('infected', 'Disease', 'MESH:D007239', (47, 55))
29961	31935373	For differentiation experiment, Nras(G12D)/MLL-AF9 or MOLM13 cells were infected with viruses encoding sgRNAs targeting either Rosa26 or PDXK.	('MOLM13', 'CellLine', 'CVCL:2119', (54, 60))	('Rosa26', 'Gene', (127, 133))	('G12D', 'Var', (37, 41))	('sgRNAs', 'Gene', (103, 109))	('Rosa26', 'Gene', '14910', (127, 133))	('infected', 'Disease', 'MESH:D007239', (72, 80))	('infected', 'Disease', (72, 80))	('G12D', 'SUBSTITUTION', 'None', (37, 41))
29964	31935373	For cell cycle experiment, Nras(G12D)/MLL-AF9 cells or MOLM13 cells were infected with viruses encoding sgRNAs targeting either Rosa26 or PDXK.	('G12D', 'Var', (32, 36))	('Rosa26', 'Gene', (128, 134))	('infected', 'Disease', 'MESH:D007239', (73, 81))	('sgRNAs', 'Gene', (104, 110))	('MOLM13', 'CellLine', 'CVCL:2119', (55, 61))	('G12D', 'SUBSTITUTION', 'None', (32, 36))	('infected', 'Disease', (73, 81))	('Rosa26', 'Gene', '14910', (128, 134))
29965	31935373	On day 9 and 12 of infection, Nras(G12D)/MLL-AF9 cells or MOLM13 cells were stained with EdU Alexa Fluor 647 Flow Cytometry Assay Kit (Invitrogen C10634).	('Kit', 'Gene', '3815', (130, 133))	('MOLM13', 'CellLine', 'CVCL:2119', (58, 64))	('Alexa Fluor 647', 'Chemical', 'MESH:C569686', (93, 108))	('EdU', 'Chemical', '-', (89, 92))	('infection', 'Disease', (19, 28))	('Kit', 'Gene', (130, 133))	('G12D', 'SUBSTITUTION', 'None', (35, 39))	('infection', 'Disease', 'MESH:D007239', (19, 28))	('G12D', 'Var', (35, 39))
29966	31935373	For apoptosis experiment, Nras(G12D)/MLL-AF9 cells were infected with viruses encoding sgRNAs targeting either Rosa26 or Pdxk.	('Rosa26', 'Gene', (111, 117))	('G12D', 'SUBSTITUTION', 'None', (31, 35))	('infected', 'Disease', 'MESH:D007239', (56, 64))	('Rosa26', 'Gene', '14910', (111, 117))	('G12D', 'Var', (31, 35))	('infected', 'Disease', (56, 64))
29969	31935373	For doxycycline-inducible shRNA mouse models, Nras(G12D)/MLL-AF9 leukemic cells infected with viruses encoding shRNAs targeting either Renilla luciferase or Pdxk.	('Renilla luciferase', 'Enzyme', (135, 153))	('MLL-AF9 leukemic cells infected', 'Disease', 'MESH:D007239', (57, 88))	('G12D', 'SUBSTITUTION', 'None', (51, 55))	('shRNAs', 'Gene', (111, 117))	('doxycycline', 'Chemical', 'MESH:D004318', (4, 15))	('G12D', 'Var', (51, 55))	('mouse', 'Species', '10090', (32, 37))	('MLL-AF9 leukemic cells infected', 'Disease', (57, 88))
29977	31935373	For the compound injection experiment, Nras(G12D)/MLL-AF9 or AML1/ETO leukemic cells were collected and resuspended in PBS at a concentration of 5 million/ml.	('PBS', 'Chemical', 'MESH:D007854', (119, 122))	('ETO', 'Gene', '862', (66, 69))	('AML1', 'Gene', (61, 65))	('G12D', 'Var', (44, 48))	('ETO', 'Gene', (66, 69))	('AML', 'Phenotype', 'HP:0004808', (61, 64))	('AML1', 'Gene', '861', (61, 65))	('G12D', 'SUBSTITUTION', 'None', (44, 48))
29984	31935373	Primary antibodies include anti-PDXK antibody (Sigma HPA030196), anti-GFP antibody (Hypromatrix HM2020), and anti-Actin antibody (Sigma A3854).	('Sigma', 'Var', (47, 52))	('HM2020', 'CellLine', 'CVCL:K782', (96, 102))	('Sigma', 'Var', (130, 135))
29991	31935373	Nras(G12D)/MLL-AF9 cells infected with viruses encoding control or Pdxk shRNAs were harvested after 5 days of doxycycline induction.	('infected', 'Disease', 'MESH:D007239', (25, 33))	('doxycycline', 'Chemical', 'MESH:D004318', (110, 121))	('G12D', 'Var', (5, 9))	('infected', 'Disease', (25, 33))	('G12D', 'SUBSTITUTION', 'None', (5, 9))
30003	31935373	Nras(G12D)/MLL-AF9 or iMEF cells were infected with viruses encoding sgRNAs targeting Cr8 or Pdxk and harvested on day 8 or day 12 respectively.	('Cr8', 'Gene', (86, 89))	('G12D', 'Var', (5, 9))	('iMEF', 'CellLine', 'CVCL:9115', (22, 26))	('infected', 'Disease', 'MESH:D007239', (38, 46))	('sgRNAs', 'Gene', (69, 75))	('infected', 'Disease', (38, 46))	('G12D', 'SUBSTITUTION', 'None', (5, 9))
30004	31935373	8 hr before harvesting the cells, the culture media was substituted with RPMI media containing dialyzed FBS, and the respective tracer (U-[13C]-glucose, U-[13C]-glutamine, [15N]-alpha-glutamine or [15N]-amide-glutamine).	('RPMI media', 'Chemical', '-', (73, 83))	('13C', 'Chemical', 'MESH:C000615229', (156, 159))	('U-[13C]-glutamine', 'Chemical', '-', (153, 170))	('[15N]-alpha-glutamine', 'Var', (172, 193))	('[15N]-alpha-glutamine', 'Chemical', '-', (172, 193))	('13C', 'Chemical', 'MESH:C000615229', (139, 142))	('glucose', 'Chemical', 'MESH:D005947', (144, 151))	('U-[13C]-glutamine', 'Var', (153, 170))	('[15N]-amide-glutamine', 'Chemical', '-', (197, 218))	('[15N]-amide-glutamine', 'Var', (197, 218))	('U-[13C]-glucose', 'Var', (136, 151))
30013	31935373	MS parameters were: gas temp: 200  C; gas flow: 10 L/min; nebulizer pressure: 40 psig; sheath gas temp: 300  C; sheath gas flow: 12 L/min; VCap: 3,000 V; Fragmentor: 125 V; Skimmer: 45 V; Octopole RF: 750 V. Active reference mass correction was performed through a second nebulizer using masses with m/z: 119.03632 and 980.016375.	('m/z: 119.03632', 'Var', (300, 314))	('980.016375', 'Var', (319, 329))	('Octopole', 'Chemical', '-', (188, 196))
30022	31935373	PDXK kinase activity and vitamin B6 are required for leukemic cell proliferation and the disruption of PLP-dependent metabolism results in metabolic changes including reduced nucleotide and polyamine levels.	('disruption', 'Var', (89, 99))	('PLP', 'Gene', (103, 106))	('PLP', 'Gene', '57026', (103, 106))	('metabolic changes', 'MPA', (139, 156))	('vitamin B6', 'Chemical', 'MESH:D025101', (25, 35))	('polyamine', 'Chemical', 'MESH:D011073', (190, 199))	('reduced', 'NegReg', (167, 174))
30105	30027013	Differential diagnoses include other causes of extended PTT, such as treatment with heparin or dabigatran, as well as deficiencies in or acquired inhibitors of various components of the intrinsic pathway, such as factors IX or XI.	('dabigatran', 'Chemical', 'MESH:D000069604', (95, 105))	('heparin', 'Chemical', 'MESH:D006493', (84, 91))	('deficiencies in', 'Var', (118, 133))	('men', 'Species', '9606', (74, 77))	('intrinsic pathway', 'Pathway', (186, 203))	('extended PTT', 'Disease', (47, 59))
30107	30027013	In contrast, lupus anticoagulant can be associated with bleeding, especially in the presence of antibodies against prothrombin.	('bleeding', 'Disease', (56, 64))	('lupus anticoagulant', 'Disease', (13, 32))	('lupus anticoagulant', 'Phenotype', 'HP:0025343', (13, 32))	('antibodies', 'Var', (96, 106))	('prothrombin', 'Gene', (115, 126))	('prothrombin', 'Gene', '2147', (115, 126))	('associated', 'Reg', (40, 50))	('bleeding', 'Disease', 'MESH:D006470', (56, 64))
30124	30027013	The EACH2 reported that complete remission (defined as a complete lack of bleeding, factor VIII activity levels above 50% after suspending all hemostatic agents for 24 hours, inhibitor non-detection, and steroid dosage below 15 mg/day) was more likely for patients who received steroids and cyclophosphamide (80%) as compared to monotherapy with steroids (58%) or rituximab-based therapies (62%).	('complete', 'Disease', (24, 32))	('steroids', 'Chemical', 'MESH:D013256', (346, 354))	('VIII', 'Gene', (91, 95))	('inhibitor', 'MPA', (175, 184))	('VIII', 'Gene', '1351', (91, 95))	('steroid', 'Chemical', 'MESH:D013256', (346, 353))	('bleeding', 'Disease', 'MESH:D006470', (74, 82))	('rituximab', 'Chemical', 'MESH:D000069283', (364, 373))	('bleeding', 'Disease', (74, 82))	('steroids', 'Chemical', 'MESH:D013256', (278, 286))	('lack', 'NegReg', (66, 70))	('activity levels', 'MPA', (96, 111))	('patients', 'Species', '9606', (256, 264))	('steroid', 'Chemical', 'MESH:D013256', (278, 285))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (291, 307))	('steroid', 'Chemical', 'MESH:D013256', (204, 211))	('cyclophosphamide', 'Var', (291, 307))
30136	30027013	A recent phase II/III clinical trial demonstrated the efficacy of B domain deleted recombinant porcine factor VIII in the treatment of severe bleeding episodes in acquired hemophilia.	('bleeding', 'Disease', (142, 150))	('hemophilia', 'Disease', (172, 182))	('bleeding episodes', 'Phenotype', 'HP:0001892', (142, 159))	('VIII', 'Gene', '1351', (110, 114))	('VIII', 'Gene', (110, 114))	('hemophilia', 'Disease', 'MESH:D006467', (172, 182))	('bleeding', 'Disease', 'MESH:D006470', (142, 150))	('men', 'Species', '9606', (127, 130))	('B domain deleted', 'Var', (66, 82))
30204	30023237	Even the areas of associated lymphangiomatosis seen in 4 cases showed CD34 positivity in its lining cells (Fig.	('lymphangioma', 'Phenotype', 'HP:0100764', (29, 41))	('CD34', 'Gene', (70, 74))	('lymphangiomatosis', 'Disease', (29, 46))	('lymphangiomatosis', 'Disease', 'MESH:C537727', (29, 46))	('positivity', 'Var', (75, 85))	('CD34', 'Gene', '947', (70, 74))
30207	30023237	All studied cases of both tumor groups showed alpha-SMA positivity in the walls of well formed blood vessels and in myofibroblastic cells in peritumoral area that worked as internal positive control (Fig.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('positivity', 'Var', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (145, 150))	('alpha-SMA', 'Chemical', '-', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('alpha-SMA', 'Protein', (46, 55))
30249	30023237	who reported that alpha-SMA positivity in KS suggests a differentiation to myofibroblast-like cells.	('alpha-SMA', 'Chemical', '-', (18, 27))	('alpha-SMA', 'Protein', (18, 27))	('positivity', 'Var', (28, 38))	('KS', 'Phenotype', 'HP:0100726', (42, 44))
30262	28938120	Remarkably, in Ewing's sarcoma, the second most common pediatric bone cancer, a chromosomal translocation fuses a large portion of the PrLD of EWSR1 to the transcription factor FLI1 (Figure 1).	('EWSR1', 'Gene', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('EWSR1', 'Gene', '2130', (143, 148))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (15, 30))	('chromosomal translocation', 'Var', (80, 105))	('bone cancer', 'Disease', 'MESH:D001859', (65, 76))	("Ewing's sarcoma", 'Disease', (15, 30))	('fuses', 'NegReg', (106, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (15, 30))	('bone cancer', 'Disease', (65, 76))
30267	28938120	Here, they discover that the pioneer activity of EWS-FLI1 to induce tumor-specific de novo enhancers at GGAA microsatellite repeats is aided by specifically recruiting BAF complexes, which remodel chromatin to spark transcription of EWS-FLI1 target genes.	('tumor', 'Disease', (68, 73))	('enhancers', 'PosReg', (91, 100))	('transcription', 'MPA', (216, 229))	('spark', 'PosReg', (210, 215))	('BAF', 'Chemical', '-', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('EWS-FLI1', 'Gene', (49, 57))	('microsatellite', 'Var', (109, 123))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('BAF', 'Protein', (168, 171))
30273	28938120	Replacement of tyrosine residues with serine in PrLDs alters the molecular grammar of PrLD-mediated phase separation and can reduce fibrillization.	('molecular grammar', 'MPA', (65, 82))	('alters', 'Reg', (54, 60))	('fibrillization', 'MPA', (132, 146))	('serine', 'Chemical', 'MESH:D012694', (38, 44))	('tyrosine', 'Chemical', 'MESH:D014443', (15, 23))	('reduce', 'NegReg', (125, 131))	('Replacement', 'Var', (0, 11))
30274	28938120	Indeed, replacement of 37 tyrosine residues with serine in the EWS-FLI PrLD ablates the ability of EWS-FLI to aggregate in vitro.	('replacement', 'Var', (8, 19))	('37 tyrosine residues with serine', 'Mutation', 'p.Y37S', (23, 55))	('aggregate', 'CPA', (110, 119))	('ablates', 'NegReg', (76, 83))
30275	28938120	Importantly, this tyrosine-replaced EWS-FLI1 variant is also unable to bind GGAA microsatellite repeats and to create active enhancers in mesenchymal stem cells.	('EWS-FLI1', 'Gene', (36, 44))	('tyrosine', 'Chemical', 'MESH:D014443', (18, 26))	('enhancers', 'PosReg', (125, 134))	('bind', 'Interaction', (71, 75))	('variant', 'Var', (45, 52))	('unable', 'NegReg', (61, 67))
30277	28938120	Finally, fusion of short fragments of the EWSR1 PrLD to FLI1 yields proteins that are intrinsically aggregation prone in vitro and phenocopy EWS-FLI1 in inducing the gene-expression program of Ewing's sarcoma (Figure 1).	('EWSR1', 'Gene', '2130', (42, 47))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (193, 208))	("Ewing's sarcoma", 'Disease', (193, 208))	('inducing', 'PosReg', (153, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (193, 208))	('fusion', 'Var', (9, 15))	('gene-expression program', 'MPA', (166, 189))	('EWSR1', 'Gene', (42, 47))
30284	28938120	Finally, portions of the PrLDs of other human RNA-binding proteins such as FUS and TAF15 also get fused to transcription factors via chromosomal translocations that cause other cancers.	('TAF15', 'Gene', '8148', (83, 88))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('FUS', 'Gene', (75, 78))	('cause', 'Reg', (165, 170))	('cancers', 'Disease', (177, 184))	('FUS', 'Gene', '2521', (75, 78))	('TAF15', 'Gene', (83, 88))	('chromosomal translocations', 'Var', (133, 159))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('human', 'Species', '9606', (40, 45))
30298	27303494	In situ hybridization confirmed the translocation of chromosome t(X,18) and a final diagnosis of biphasic synovial sarcoma of the abdomen was made.	('biphasic synovial sarcoma', 'Disease', (97, 122))	('biphasic synovial sarcoma', 'Disease', 'MESH:D013584', (97, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (106, 122))	('translocation', 'Var', (36, 49))
30316	27303494	Cytogenetic studies have found that biphasic tumors predominantly express SYT-SSX1 fusion transcription, while monophasic tumors express either SYT-SSX1 or SYT-SSX2 genetic rearrangement.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('SSX1', 'Gene', (78, 82))	('biphasic tumors', 'Disease', (36, 51))	('express', 'Reg', (66, 73))	('SYT', 'Gene', (74, 77))	('SSX1', 'Gene', '6756', (148, 152))	('SYT', 'Gene', '6760', (156, 159))	('biphasic tumors', 'Disease', 'MESH:D009369', (36, 51))	('SSX1', 'Gene', (148, 152))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('fusion transcription', 'Var', (83, 103))	('SYT', 'Gene', '6760', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('SYT', 'Gene', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (122, 128))	('SYT', 'Gene', '6760', (144, 147))	('SSX2', 'Gene', (160, 164))	('SYT', 'Gene', (156, 159))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('SSX2', 'Gene', '6757', (160, 164))	('SSX1', 'Gene', '6756', (78, 82))
30332	27303494	In addition, it has also been suggested that SYT-SSX2 gene fusion, monophasic synovial sarcoma, size less than 5 cm, less than 15 years of age, and distal extremity location have better prognostic outcomes, although there is still an on-going debate in regard to the significance of these findings.	('gene fusion', 'Var', (54, 65))	('synovial sarcoma', 'Disease', (78, 94))	('SYT', 'Gene', '6760', (45, 48))	('better', 'PosReg', (179, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('SSX2', 'Gene', '6757', (49, 53))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('synovial sarcoma', 'Disease', 'MESH:D013584', (78, 94))	('SSX2', 'Gene', (49, 53))	('SYT', 'Gene', (45, 48))
30341	26010414	In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth.	('slowing sarcoma growth', 'Disease', 'MESH:D006130', (107, 129))	('slowing sarcoma growth', 'Disease', (107, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('mouse', 'Species', '10090', (8, 13))	('inhibition', 'Var', (29, 39))	('VEGF-A', 'Gene', (22, 28))
30345	26010414	The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1alpha activity.	('activity', 'MPA', (210, 218))	('DNA damage', 'MPA', (139, 149))	('decreased', 'NegReg', (189, 198))	('apoptosis', 'CPA', (154, 163))	('increased', 'PosReg', (129, 138))	('VEGF-A', 'Gene', (27, 33))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('TH-302', 'Var', (19, 25))	('inhibition', 'NegReg', (34, 44))	('TH-302', 'Chemical', 'MESH:C552526', (19, 25))	('sarcoma', 'Disease', (98, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('HIF-1alpha', 'Gene', '15251', (199, 209))	('HIF-1alpha', 'Gene', (199, 209))
30358	26010414	Circulating levels of VEGF-A are elevated on average 10-fold in sarcoma patients compared with controls, and inhibition of VEGF-A or its receptors can effectively suppress tumour angiogenesis in mouse models of sarcoma.	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('VEGF-A', 'Gene', (123, 129))	('elevated', 'PosReg', (33, 41))	('inhibition', 'Var', (109, 119))	('suppress', 'NegReg', (163, 171))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('Circulating levels', 'MPA', (0, 18))	('sarcoma', 'Disease', (211, 218))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('tumour', 'Disease', (172, 178))	('sarcoma', 'Disease', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('mouse', 'Species', '10090', (195, 200))	('patients', 'Species', '9606', (72, 80))
30398	26010414	Antibodies used were as follows: human anti-gammaH2AX (mouse polyclonal antibody, 1 : 100, 05-636; EMD Millipore, Billerica, MA, USA), anti-cleaved caspase-3 (rabbit polyclonal antibody, 1 : 100, no.	('rabbit', 'Species', '9986', (159, 165))	('gammaH2AX', 'Gene', '15270', (44, 53))	('mouse', 'Species', '10090', (55, 60))	('human', 'Species', '9606', (33, 38))	('caspase-3', 'Gene', '12367', (148, 157))	('anti-cleaved', 'Var', (135, 147))	('gammaH2AX', 'Gene', (44, 53))	('caspase-3', 'Gene', (148, 157))
30427	26010414	When tumours were examined for overall apoptosis using TUNEL staining, TH-302 alone resulted in very little total apoptosis (4 cells per 5 fields) (Supplementary Figure S1B).	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumours', 'Disease', (5, 12))	('TH-302', 'Chemical', 'MESH:C552526', (71, 77))	('TH-302', 'Var', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
7228	26010414	gammaH2AX levels increase in response to DNA double-strand breaks.	('increase', 'PosReg', (17, 25))	('gammaH2AX', 'Gene', '15270', (0, 9))	('gammaH2AX', 'Gene', (0, 9))	('DNA double-strand breaks', 'Var', (41, 65))
30466	26010414	The combination of TH-302 and radiation did result in increases in DNA damage as measured by gammaH2AX expression (Figure 4C and Supplementary Figure S6C) and apoptosis as measured by cleaved caspase-3 expression (Figure 4D and Supplementary Figure S6D).	('expression', 'MPA', (103, 113))	('DNA damage', 'MPA', (67, 77))	('caspase-3', 'Gene', '12367', (192, 201))	('gammaH2AX', 'Gene', (93, 102))	('TH-302', 'Chemical', 'MESH:C552526', (19, 25))	('TH-302', 'Var', (19, 25))	('increases', 'PosReg', (54, 63))	('gammaH2AX', 'Gene', '15270', (93, 102))	('caspase-3', 'Gene', (192, 201))	('apoptosis', 'CPA', (159, 168))
30485	26010414	In vitro cytotoxicity and clonogenic assays using human cancer cell lines show that TH-302 has little cytotoxic activity under normoxic conditions and greatly enhanced cytotoxic potency under hypoxic conditions.	('hypoxic conditions', 'Disease', (192, 210))	('cytotoxicity', 'Disease', (9, 21))	('enhanced', 'PosReg', (159, 167))	('hypoxic conditions', 'Disease', 'MESH:D009135', (192, 210))	('TH-302', 'Var', (84, 90))	('cytotoxic potency', 'CPA', (168, 185))	('TH-302', 'Chemical', 'MESH:C552526', (84, 90))	('cytotoxicity', 'Disease', 'MESH:D064420', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('human', 'Species', '9606', (50, 55))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
30486	26010414	TH-302 enhances the activity of a wide range of chemotherapy drugs in numerous xenograft models including HT1080 xenografts, and has been found to be a promising agent in combination with doxorubicin for patients with metastatic sarcoma.	('activity', 'MPA', (20, 28))	('TH-302', 'Var', (0, 6))	('patients', 'Species', '9606', (204, 212))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('doxorubicin', 'Chemical', 'MESH:D004317', (188, 199))	('sarcoma', 'Disease', (229, 236))	('HT1080', 'Gene', (106, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('enhances', 'PosReg', (7, 15))	('TH-302', 'Chemical', 'MESH:C552526', (0, 6))	('HT1080', 'Gene', '8872', (106, 112))
30487	26010414	found in two xenograft models that TH-302 combined with chemotherapy increases DNA damage and apoptosis throughout the tumour.	('increases', 'PosReg', (69, 78))	('TH-302', 'Var', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('TH-302', 'Chemical', 'MESH:C552526', (35, 41))	('tumour', 'Disease', (119, 125))	('DNA damage', 'MPA', (79, 89))	('apoptosis', 'CPA', (94, 103))
30488	26010414	TH-302 was found to be more effective in cell lines deficient in homologous recombination secondary to mutations in BRCA1 or BRCA2.	('BRCA2', 'Gene', (125, 130))	('mutations', 'Var', (103, 112))	('BRCA1', 'Gene', (116, 121))	('BRCA2', 'Gene', '12190', (125, 130))	('homologous', 'MPA', (65, 75))	('BRCA1', 'Gene', '12189', (116, 121))	('TH-302', 'Chemical', 'MESH:C552526', (0, 6))
30491	26010414	found that VEGFR-2 inhibition of RIP1-Tag2 mouse pancreatic endocrine tumours led to an increase in intratumoral hypoxia along with increased tumour invasiveness and liver metastases, and found that sunitinib (which targets VEGF and other pathways) increased liver and lung metastases for both experimental and spontaneous metastases.	('sunitinib', 'Chemical', 'MESH:D000077210', (199, 208))	('pancreatic endocrine tumours', 'Disease', (49, 77))	('metastases', 'Disease', (323, 333))	('hypoxia', 'Disease', (113, 120))	('VEGFR-2', 'Gene', '16542', (11, 18))	('tumour invasiveness', 'Disease', (142, 161))	('metastases', 'Disease', (274, 284))	('tumour invasiveness', 'Disease', 'MESH:D009361', (142, 161))	('liver metastases', 'Disease', 'MESH:D009362', (166, 182))	('rat', 'Species', '10116', (103, 106))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('inhibition', 'Var', (19, 29))	('increased', 'PosReg', (132, 141))	('increased', 'PosReg', (249, 258))	('increased liver', 'Phenotype', 'HP:0002240', (249, 264))	('VEGF', 'Gene', (224, 228))	('RIP1', 'Gene', '19766', (33, 37))	('VEGF', 'Gene', (11, 15))	('VEGF', 'Gene', '22339', (224, 228))	('VEGFR-2', 'Gene', (11, 18))	('liver metastases', 'Disease', (166, 182))	('VEGF', 'Gene', '22339', (11, 15))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('pancreatic endocrine tumours', 'Disease', 'MESH:D010190', (49, 77))	('mouse', 'Species', '10090', (43, 48))	('metastases', 'Disease', 'MESH:D009362', (172, 182))	('RIP1', 'Gene', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('metastases', 'Disease', 'MESH:D009362', (323, 333))	('increase', 'PosReg', (88, 96))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('metastases', 'Disease', 'MESH:D009362', (274, 284))	('metastases', 'Disease', (172, 182))
30599	26097321	Most HPC are mostly near diploid and breakpoints in 12q13, 12q24 and 19q13 seem to be very common with recurrent t (12;19) (q13;q13) translocation (Mandahl et al., 1993; Mitelman et al., 2002; Hallen et al., 2002).	('HPC', 'Disease', (5, 8))	('HPC', 'Disease', 'MESH:C537262', (5, 8))	('t (12', 'Var', (113, 118))
30639	25798530	Rare human genetic disorders with mutations in either the catalytic or regulatory subunit of PI3K that result in constitutive activation of the protein predispose to severe herpesvirus infections as well as to virus-associated malignancies.	('herpesvirus infections', 'Phenotype', 'HP:0005353', (173, 195))	('genetic disorders', 'Disease', (11, 28))	('predispose to severe herpesvirus infections', 'Phenotype', 'HP:0005353', (152, 195))	('genetic disorders', 'Disease', 'MESH:D030342', (11, 28))	('malignancies', 'Disease', 'MESH:D009369', (227, 239))	('herpesvirus infections', 'Disease', 'MESH:D006566', (173, 195))	('herpesvirus infection', 'Phenotype', 'HP:0005353', (173, 194))	('predispose', 'Reg', (152, 162))	('activation', 'PosReg', (126, 136))	('herpesvirus infections', 'Disease', (173, 195))	('malignancies', 'Disease', (227, 239))	('PI3K', 'Gene', (93, 97))	('human', 'Species', '9606', (5, 10))	('mutations', 'Var', (34, 43))
30640	25798530	Inhibiting the PI3K/Akt pathway or its downstream proteins using drugs already approved for other diseases can block herpesvirus lytic infection and may reduce malignancies associated with latent herpesvirus infections.	('reduce', 'NegReg', (153, 159))	('herpesvirus infections', 'Disease', 'MESH:D006566', (196, 218))	('malignancies', 'Disease', (160, 172))	('Inhibiting', 'Var', (0, 10))	('herpesvirus infections', 'Disease', (196, 218))	('PI3K/Akt pathway', 'Pathway', (15, 31))	('diseases can block herpesvirus lytic infection', 'Disease', (98, 144))	('herpesvirus infection', 'Phenotype', 'HP:0005353', (196, 217))	('herpesvirus infections', 'Phenotype', 'HP:0005353', (196, 218))	('malignancies', 'Disease', 'MESH:D009369', (160, 172))	('diseases can block herpesvirus lytic infection', 'Disease', 'MESH:D006566', (98, 144))
30647	25798530	Here we highlight recent findings on the ability of human herpesviruses to modulate the PI3K/Akt signaling pathway, the effects of mutations in PI3K on herpesvirus infections in humans, and potential strategies to inhibit PI3K to treat herpesvirus infections and virus-associated malignancies.	('malignancies', 'Disease', (280, 292))	('herpesvirus infections', 'Phenotype', 'HP:0005353', (152, 174))	('human', 'Species', '9606', (178, 183))	('herpesvirus infection', 'Phenotype', 'HP:0005353', (236, 257))	('herpesvirus infections', 'Disease', (152, 174))	('herpesvirus', 'Species', '39059', (152, 163))	('herpesvirus infections', 'Phenotype', 'HP:0005353', (236, 258))	('inhibit', 'NegReg', (214, 221))	('PI3K', 'Gene', (144, 148))	('herpesvirus infections', 'Disease', 'MESH:D006566', (152, 174))	('modulate', 'Reg', (75, 83))	('herpesvirus infections', 'Disease', (236, 258))	('herpesvirus infection', 'Phenotype', 'HP:0005353', (152, 173))	('herpesvirus', 'Species', '39059', (236, 247))	('herpesvirus infections', 'Disease', 'MESH:D006566', (236, 258))	('humans', 'Species', '9606', (178, 184))	('mutations', 'Var', (131, 140))	('human', 'Species', '9606', (52, 57))	('PI3K/Akt signaling pathway', 'Pathway', (88, 114))	('herpesvirus', 'Species', '39059', (58, 69))	('malignancies', 'Disease', 'MESH:D009369', (280, 292))
30657	25798530	Phosphorylation and inactivation of the tuberous sclerosis protein 2 (TSC2) results in mTOR1 activation which in turn phosphorylates and inhibits the translational inhibitor eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and activates S6K1 to stimulate protein synthesis.	('protein synthesis', 'MPA', (276, 293))	('4EBP1', 'Gene', (237, 242))	('activation', 'PosReg', (93, 103))	('TSC2', 'Gene', '7249', (70, 74))	('S6K1', 'Gene', (258, 262))	('tuberous sclerosis protein 2', 'Gene', '7249', (40, 68))	('tuberous sclerosis protein 2', 'Gene', (40, 68))	('inactivation', 'Var', (20, 32))	('Phosphorylation', 'Var', (0, 15))	('S6K1', 'Gene', '6198', (258, 262))	('TSC2', 'Gene', (70, 74))	('4E binding protein 1', 'Gene', '1978', (215, 235))	('4EBP1', 'Gene', '1978', (237, 242))	('mTOR', 'Gene', (87, 91))	('translational inhibitor', 'MPA', (150, 173))	('inhibits', 'NegReg', (137, 145))	('mTOR', 'Gene', '2475', (87, 91))	('activates', 'PosReg', (248, 257))	('stimulate', 'PosReg', (266, 275))	('4E binding protein 1', 'Gene', (215, 235))
30659	25798530	Class I PI3Ks are often involved in the pathogenesis of human cancers and are extensively targeted by viruses.	('PI3Ks', 'Var', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('involved', 'Reg', (24, 32))	('human', 'Species', '9606', (56, 61))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
30663	25798530	Enhanced PI3K/Akt signaling has been identified in many human cancers including mutation or amplification of the genes encoding catalytic subunits of PI3K p110alpha and p110delta the gene product of PIK3CA and PI3KCD, respectively), loss of function of PTEN, and/or INPP4B, or mutation and/or amplification of the proto-oncogenes AKT1 and AKT2.	('AKT2', 'Gene', '208', (339, 343))	('p110delta', 'Gene', '5293', (169, 178))	('loss of function', 'NegReg', (233, 249))	('amplification', 'Var', (293, 306))	('AKT1', 'Gene', '207', (330, 334))	('PIK3CA', 'Gene', '5290', (199, 205))	('amplification', 'Var', (92, 105))	('PTEN', 'Gene', '5728', (253, 257))	('AKT2', 'Gene', (339, 343))	('INPP4B', 'Gene', (266, 272))	('AKT1', 'Gene', (330, 334))	('human', 'Species', '9606', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('Enhanced', 'PosReg', (0, 8))	('p110alpha', 'Gene', '5290', (155, 164))	('PIK3CA', 'Gene', (199, 205))	('p110alpha', 'Gene', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutation', 'Var', (80, 88))	('p110delta', 'Gene', (169, 178))	('mutation', 'Var', (277, 285))	('PI3KCD', 'Var', (210, 216))	('PTEN', 'Gene', (253, 257))	('INPP4B', 'Gene', '8821', (266, 272))	('cancers', 'Disease', 'MESH:D009369', (62, 69))
30669	25798530	Additional glycoproteins are important for entry of specific viruses such as gD for HSV, gp350 and gp42 for EBV, and UL128, UL130, and UL131A for CMV.	('EBV', 'Species', '10376', (108, 111))	('UL130', 'Var', (124, 129))	('UL131A', 'Var', (135, 141))	('UL128', 'Var', (117, 122))	('HSV', 'Disease', (84, 87))	('gp350', 'Var', (89, 94))	('gp42', 'Var', (99, 103))
30671	25798530	Chemical inhibition of PI3K activity with LY294002 blocked HSV entry and fusion mediated by viral glycoproteins (Tiwari and Shukla, 2010).	('LY294002', 'Var', (42, 50))	('fusion', 'CPA', (73, 79))	('HSV entry', 'CPA', (59, 68))	('LY294002', 'Chemical', 'MESH:C085911', (42, 50))	('blocked', 'NegReg', (51, 58))
30673	25798530	PI3K inhibition with LY294002 reduced expression of HSV-1 ICP0 and increased the cleavage of caspase-3, caspase-7, and poly ADP-ribose polymerase (PARP), implying that PI3K may reduce apoptosis in HSV-infected cells.	('poly ADP-ribose', 'MPA', (119, 134))	('HSV-infected', 'Disease', (197, 209))	('expression', 'MPA', (38, 48))	('caspase-3', 'Protein', (93, 102))	('cleavage', 'MPA', (81, 89))	('LY294002', 'Var', (21, 29))	('HSV-1 ICP0', 'Gene', (52, 62))	('ICP0', 'Gene', (58, 62))	('LY294002', 'Chemical', 'MESH:C085911', (21, 29))	('increased', 'PosReg', (67, 76))	('HSV-infected', 'Disease', 'MESH:C536395', (197, 209))	('reduced', 'NegReg', (30, 37))	('HSV-1', 'Species', '10298', (52, 57))	('caspase-7', 'Protein', (104, 113))	('reduce', 'NegReg', (177, 183))	('apoptosis', 'CPA', (184, 193))
30676	25798530	Deletion of HSV glycoprotein D (gD) or gB prevents virus-induced Akt phosphorylation, and Akt interacts directly with gB, but not with gD (Table 1).	('gD', 'Gene', (32, 34))	('HSV', 'Gene', (12, 15))	('glycoprotein D', 'Gene', (16, 30))	('virus-induced Akt phosphorylation', 'MPA', (51, 84))	('glycoprotein D', 'Gene', '2532', (16, 30))	('prevents', 'NegReg', (42, 50))	('interacts', 'Interaction', (94, 103))	('Deletion', 'Var', (0, 8))
30683	25798530	Inhibition of PI3K with LY294002 delays CMV entry, and reduces immediate-early and early gene expression, and viral DNA replication.	('LY294002', 'Var', (24, 32))	('viral DNA replication', 'CPA', (110, 131))	('reduces', 'NegReg', (55, 62))	('delays', 'NegReg', (33, 39))	('LY294002', 'Chemical', 'MESH:C085911', (24, 32))	('CMV entry', 'MPA', (40, 49))
30689	25798530	The interaction of KSHV glycoproteins with integrins induces phosphorylation of FAK and subsequently Src, PI3K, and c-Cbl.	('FAK', 'Gene', (80, 83))	('PI3K', 'Var', (106, 110))	('phosphorylation', 'MPA', (61, 76))	('interaction', 'Interaction', (4, 15))	('FAK', 'Gene', '5747', (80, 83))	('KSHV', 'Species', '37296', (19, 23))	('Src', 'Gene', '6714', (101, 104))	('Src', 'Gene', (101, 104))	('induces', 'Reg', (53, 60))
30692	25798530	PI3K inhibition reduces infectivity and cytoskeletal changes associated with KSHV gB, but does not affect virus binding to cells ( Tiwari and Shukla 2010).	('inhibition reduces', 'NegReg', (5, 23))	('PI3K', 'Var', (0, 4))	('KSHV gB', 'Gene', (77, 84))	('cytoskeletal changes', 'MPA', (40, 60))	('infectivity', 'MPA', (24, 35))	('KSHV', 'Species', '37296', (77, 81))
30693	25798530	KSHV induces phosphorylation of the p85 subunit of PI3K within one minute of infection which return to normal levels 30 minutes after infection.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('phosphorylation', 'MPA', (13, 28))	('p85', 'Gene', '5295', (36, 39))	('PI3K', 'Gene', (51, 55))	('p85', 'Gene', (36, 39))
30695	25798530	VP11/12, the most abundant HSV tegument protein, is phosphorylated by Lck and interacts with the p85 subunit of PI3K.	('p85', 'Gene', '5295', (97, 100))	('interacts', 'Interaction', (78, 87))	('p85', 'Gene', (97, 100))	('Lck', 'Gene', (70, 73))	('Lck', 'Gene', '3932', (70, 73))	('VP11/12', 'Var', (0, 7))
30698	25798530	Phosphorylation of TSC2 by US3 at the same sites as those phosphorylated by Akt results in activation of mTORC1, which enhances protein translation and HSV replication.	('mTORC1', 'Gene', (105, 111))	('activation', 'PosReg', (91, 101))	('Phosphorylation', 'Var', (0, 15))	('HSV replication', 'CPA', (152, 167))	('enhances', 'PosReg', (119, 127))	('TSC2', 'Gene', '7249', (19, 23))	('TSC2', 'Gene', (19, 23))	('protein translation', 'MPA', (128, 147))	('mTORC1', 'Gene', '382056', (105, 111))
30699	25798530	Phosphorylation of GSK3beta by US3 inactivates GSK3beta and promotes stable microtubule formation and virus spread.	('promotes', 'PosReg', (60, 68))	('Phosphorylation', 'Var', (0, 15))	('GSK3beta', 'Gene', (19, 27))	('stable microtubule formation', 'MPA', (69, 97))	('GSK3beta', 'Gene', '2932', (47, 55))	('GSK3beta', 'Gene', (47, 55))	('virus spread', 'CPA', (102, 114))	('GSK3beta', 'Gene', '2932', (19, 27))	('inactivates', 'NegReg', (35, 46))
30700	25798530	VZV infection activates Akt and inhibition of PI3K or Akt reduces VZV replication.	('reduces', 'NegReg', (58, 65))	('inhibition', 'Var', (32, 42))	('Akt', 'Pathway', (24, 27))	('VZV', 'Species', '10335', (0, 3))	('VZV', 'Species', '10335', (66, 69))	('activates', 'PosReg', (14, 23))	('VZV', 'Disease', (66, 69))
30704	25798530	Activation of Akt by ORF12 protein is important for cell cycle progression in VZV-infected cells, since inhibition of Akt activity reduces the differences observed in cell cycle progression with wild-type and ORF12 deleted VZV.	('VZV', 'Species', '10335', (78, 81))	('reduces', 'NegReg', (131, 138))	('VZV', 'Species', '10335', (223, 226))	('ORF12', 'Gene', (209, 214))	('ORF12', 'Gene', '1487655', (209, 214))	('inhibition', 'Var', (104, 114))	('ORF12', 'Gene', (21, 26))	('cell cycle progression', 'CPA', (167, 189))	('ORF12', 'Gene', '1487655', (21, 26))	('activity', 'MPA', (122, 130))
30708	25798530	ICP10PK functions as a constitutively activated growth-factor receptor that activates PI3K/Akt and Ras/ERK pathways.	('PI3K/Akt', 'Pathway', (86, 94))	('activates', 'PosReg', (76, 85))	('ICP10PK', 'Var', (0, 7))	('ERK', 'Gene', (103, 106))	('ERK', 'Gene', '5594', (103, 106))
30709	25798530	While ICP10PK mediated PI3K activation was initially believed to responsible for preventing apoptosis in HSV-2 infected cells, more recent studies indicate that ICP10PK protects cells from apoptosis by binding to caspase-8 and disrupting its interaction with FADD, which is independent of activation of PI3K.	('caspase-8', 'Gene', (213, 222))	('ICP10PK', 'Var', (161, 168))	('HSV-2', 'Species', '10310', (105, 110))	('binding', 'Interaction', (202, 209))	('caspase-8', 'Gene', '841', (213, 222))	('disrupting', 'NegReg', (227, 237))	('apoptosis', 'CPA', (189, 198))	('interaction', 'Interaction', (242, 253))	('FADD', 'Protein', (259, 263))
30711	25798530	PI3K activity is required for upregulation of the anti-apoptotic protein c-FLIP by CMV IEP86.	('c-FLIP', 'Gene', (73, 79))	('CMV IEP86', 'Var', (83, 92))	('upregulation', 'PosReg', (30, 42))	('c-FLIP', 'Gene', '8837', (73, 79))
30719	25798530	PI3K/Akt activation by GPCR also results in phosphorylation of TSC-2, mTOR, 4EPB1, and S6K1 to enhance translation and cell proliferation (Sodhi, Chaisuparat et al.	('GPCR', 'Var', (23, 27))	('activation', 'PosReg', (9, 19))	('phosphorylation', 'MPA', (44, 59))	('enhance', 'PosReg', (95, 102))	('cell proliferation', 'CPA', (119, 137))	('mTOR', 'Gene', (70, 74))	('TSC-2', 'Gene', '7249', (63, 68))	('mTOR', 'Gene', '2475', (70, 74))	('S6K1', 'Gene', (87, 91))	('S6K1', 'Gene', '6198', (87, 91))	('4EPB1', 'Gene', (76, 81))	('PI3K/Akt', 'Pathway', (0, 8))	('TSC-2', 'Gene', (63, 68))	('translation', 'MPA', (103, 114))
30722	25798530	KSHV K1 activation of Akt is associated with phosphorylation and inhibition of FOX01, GSK3beta, and BAD which are important for inhibition of apoptosis, and phosphorylation of mTOR which may increase translation and endothelial cell transformation.	('inhibition', 'NegReg', (65, 75))	('endothelial cell transformation', 'CPA', (216, 247))	('KSHV', 'Species', '37296', (0, 4))	('GSK3beta', 'Gene', (86, 94))	('activation', 'PosReg', (8, 18))	('increase', 'PosReg', (191, 199))	('mTOR', 'Gene', '2475', (176, 180))	('GSK3beta', 'Gene', '2932', (86, 94))	('mTOR', 'Gene', (176, 180))	('Akt', 'Pathway', (22, 25))	('phosphorylation', 'MPA', (45, 60))	('phosphorylation', 'Var', (157, 172))	('KSHV K1', 'Gene', (0, 7))	('translation', 'CPA', (200, 211))	('FOX01', 'Gene', (79, 84))
30730	25798530	Mouse neuroblastoma cells stably expressing LAT have higher levels of phosphorylated and total Akt and are more resistant to apoptosis after serum starvation compared with cells not expressing LAT.	('neuroblastoma', 'Phenotype', 'HP:0003006', (6, 19))	('LAT', 'Var', (44, 47))	('higher', 'PosReg', (53, 59))	('phosphorylated', 'MPA', (70, 84))	('Akt', 'Protein', (95, 98))	('neuroblastoma', 'Disease', 'MESH:D009447', (6, 19))	('Mouse', 'Species', '10090', (0, 5))	('levels', 'MPA', (60, 66))	('neuroblastoma', 'Disease', (6, 19))
30731	25798530	Maintenance of HSV-1 latency requires persistent PI3K activation which is established by binding of nerve growth factor to the TrkA receptor tyrosine kinase (RTK).	('binding', 'Interaction', (89, 96))	('PI3K', 'Var', (49, 53))	('HSV-1', 'Species', '10298', (15, 20))	('tyrosine', 'Chemical', 'MESH:D014443', (141, 149))	('activation', 'PosReg', (54, 64))	('HSV-1', 'Gene', (15, 20))
30738	25798530	Similarly, survival and growth of LMP-1 transgenic B lymphocytes and lymphoma cells requires activation of Akt signaling.	('activation', 'PosReg', (93, 103))	('Akt signaling', 'Pathway', (107, 120))	('lymphoma', 'Disease', (69, 77))	('LMP-1', 'Gene', (34, 39))	('transgenic', 'Species', '10090', (40, 50))	('transgenic', 'Var', (40, 50))	('lymphoma', 'Disease', 'MESH:D008223', (69, 77))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('growth', 'CPA', (24, 30))
30756	25798530	Hypermethylation of the promoter of INPP4B, a phosphatase that inhibits PI3K/Akt signaling, enhances the PI3K/Akt pathway in EBV-positive nasopharyngeal carcinoma cells.	('PI3K/Akt pathway', 'Pathway', (105, 121))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (138, 162))	('EBV', 'Species', '10376', (125, 128))	('enhances', 'PosReg', (92, 100))	('Hypermethylation', 'Var', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('nasopharyngeal carcinoma', 'Disease', (138, 162))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (138, 162))	('INPP4B', 'Gene', '8821', (36, 42))	('INPP4B', 'Gene', (36, 42))
30758	25798530	Inhibition of PI3K reduces EBV reactivation induced by BCR signaling in EBV-positive Burkitt lymphoma cell lines (Iwakiri and Takada 2004, Goswami, Gershburg et al.	('EBV reactivation induced by BCR signaling', 'MPA', (27, 68))	('EBV', 'Species', '10376', (72, 75))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (85, 101))	('Burkitt lymphoma', 'Disease', (85, 101))	('PI3K', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (85, 101))	('EBV', 'Species', '10376', (27, 30))	('reduces', 'NegReg', (19, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))
30759	25798530	Similarly, blocking PI3K impairs TGF-beta-induced reactivation of EBV in Burkitt lymphoma cells and methotrexate-induced EBV reactivation in lymphoblastoid cell lines.	('EBV', 'Species', '10376', (66, 69))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (73, 89))	('PI3K', 'Var', (20, 24))	('EBV', 'Species', '10376', (121, 124))	('EBV', 'Protein', (66, 69))	('reactivation', 'MPA', (50, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('TGF-beta-induced', 'Protein', (33, 49))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (73, 89))	('impairs', 'NegReg', (25, 32))	('blocking PI3K', 'Var', (11, 24))	('Burkitt lymphoma', 'Disease', (73, 89))	('methotrexate', 'Chemical', 'MESH:D008727', (100, 112))
30766	25798530	Inhibition of PI3K reduces KSHV reactivation induced by BCR signaling in KSHV-positive Burkitt lymphoma cell lines, and this effect is associated with reduced expression of KSHV Rta.	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (87, 103))	('reduced', 'NegReg', (151, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (95, 103))	('KSHV', 'Species', '37296', (73, 77))	('Rta', 'Gene', '4961526', (178, 181))	('PI3K', 'Gene', (14, 18))	('expression', 'MPA', (159, 169))	('KSHV reactivation induced by BCR signaling', 'MPA', (27, 69))	('Burkitt lymphoma', 'Disease', (87, 103))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (87, 103))	('Inhibition', 'Var', (0, 10))	('Rta', 'Gene', (178, 181))	('KSHV', 'Species', '37296', (173, 177))	('reduces', 'NegReg', (19, 26))	('KSHV', 'Species', '37296', (27, 31))
30767	25798530	Thus the PI3K/Akt pathway is critical for maintaining HSV, EBV, and KSHV latent infection; inhibition of PI3K/Akt reduces EBV and KSHV reactivation induced by BCR signaling, but enhances reactivation of HSV and of KSHV induced by treatment with other stimuli.	('reactivation', 'MPA', (187, 199))	('inhibition', 'Var', (91, 101))	('EBV', 'CPA', (122, 125))	('reactivation', 'MPA', (135, 147))	('KSHV', 'Species', '37296', (68, 72))	('PI3K/Akt', 'Pathway', (105, 113))	('reduces', 'NegReg', (114, 121))	('enhances', 'PosReg', (178, 186))	('KSHV', 'Species', '37296', (214, 218))	('KSHV latent infection', 'Disease', (68, 89))	('KSHV', 'Species', '37296', (130, 134))	('EBV', 'Species', '10376', (122, 125))	('EBV', 'Species', '10376', (59, 62))	('KSHV latent infection', 'Disease', 'MESH:D055985', (68, 89))
30768	25798530	Recently two immunodeficiencies have been reported in association with mutations in the p110 catalytic or p85 regulatory subunits of PI3K.	('p85', 'Gene', (106, 109))	('PI3K', 'Gene', (133, 137))	('immunodeficiencies', 'Disease', 'MESH:D007153', (13, 31))	('immunodeficiencies', 'Disease', (13, 31))	('immunodeficiencies', 'Phenotype', 'HP:0002721', (13, 31))	('association', 'Reg', (54, 65))	('p110', 'Gene', '100616443', (88, 92))	('mutations in', 'Var', (71, 83))	('p110', 'Gene', (88, 92))	('p85', 'Gene', '5295', (106, 109))
30769	25798530	Two groups have reported patients with severe herpesvirus infections who have heterozygous gain-of-function mutations in PIK3CD, which encodes PI3Kdelta (; Lucas et al., 2014a).	('herpesvirus infections', 'Phenotype', 'HP:0005353', (46, 68))	('PI3Kdelta', 'Gene', '5293', (143, 152))	('gain-of-function', 'PosReg', (91, 107))	('PI3Kdelta', 'Gene', (143, 152))	('mutations', 'Var', (108, 117))	('herpesvirus infection', 'Phenotype', 'HP:0005353', (46, 67))	('herpesvirus infections', 'Disease', 'MESH:D006566', (46, 68))	('PIK3CD', 'Gene', '5293', (121, 127))	('herpesvirus infections', 'Disease', (46, 68))	('patients', 'Species', '9606', (25, 33))	('PIK3CD', 'Gene', (121, 127))
30772	25798530	In each patient a dominant gain-of-function mutation in one allele of PIK3CD resulted in constitutive activation and phosphorylation of Akt and increased activation of mTOR.	('mTOR', 'Gene', (168, 172))	('increased activation', 'PosReg', (144, 164))	('mTOR', 'Gene', '2475', (168, 172))	('mutation', 'Var', (44, 52))	('phosphorylation', 'MPA', (117, 132))	('activation', 'PosReg', (102, 112))	('gain-of-function', 'PosReg', (27, 43))	('PIK3CD', 'Gene', '5293', (70, 76))	('patient', 'Species', '9606', (8, 15))	('PIK3CD', 'Gene', (70, 76))	('Akt', 'Pathway', (136, 139))
30777	25798530	Patients with heterozygous gain-of-function mutations in PIK3R1, which encodes the p85 regulatory subunit of PI3K, were reported with an immunodeficiency syndrome with recurrent bacterial upper and lower respiratory tract infections (; Lucas et al 2014b).	('p85', 'Gene', '5295', (83, 86))	('respiratory tract infections', 'Disease', (204, 232))	('lower respiratory tract infections', 'Phenotype', 'HP:0002783', (198, 232))	('respiratory tract infections', 'Phenotype', 'HP:0011947', (204, 232))	('p85', 'Gene', (83, 86))	('immunodeficiency syndrome', 'Disease', (137, 162))	('gain-of-function', 'PosReg', (27, 43))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (44, 53))	('PIK3R1', 'Gene', (57, 63))	('immunodeficiency syndrome', 'Disease', 'MESH:D007153', (137, 162))	('immunodeficiency', 'Phenotype', 'HP:0002721', (137, 153))	('PIK3R1', 'Gene', '5295', (57, 63))	('respiratory tract infections', 'Disease', 'MESH:D012141', (204, 232))
30779	25798530	Like patients with mutations in PIK3CD, patients with mutations in PIK3R1 also have increased phosphorylation of Akt, increased mTOR signaling, increased IgM, reduced naive T cells, reduced memory B cell function, increased senescent CD8 T cells, and enhanced activation-induced T cell death.	('PIK3CD', 'Gene', (32, 38))	('increased', 'PosReg', (118, 127))	('CD8', 'Gene', (234, 237))	('increased', 'PosReg', (84, 93))	('PIK3R1', 'Gene', (67, 73))	('mTOR', 'Gene', (128, 132))	('patients', 'Species', '9606', (5, 13))	('reduced', 'NegReg', (159, 166))	('mutations', 'Var', (54, 63))	('Akt', 'Pathway', (113, 116))	('phosphorylation', 'MPA', (94, 109))	('reduced', 'NegReg', (182, 189))	('enhanced', 'PosReg', (251, 259))	('mTOR', 'Gene', '2475', (128, 132))	('CD8', 'Gene', '925', (234, 237))	('IgM', 'MPA', (154, 157))	('PIK3R1', 'Gene', '5295', (67, 73))	('activation-induced T cell death', 'CPA', (260, 291))	('PIK3CD', 'Gene', '5293', (32, 38))	('increased IgM', 'Phenotype', 'HP:0003496', (144, 157))	('increased', 'PosReg', (144, 153))	('naive T cells', 'CPA', (167, 180))	('patients', 'Species', '9606', (40, 48))	('increased', 'PosReg', (214, 223))	('memory B cell function', 'CPA', (190, 212))
30784	25798530	Therefore, inhibition of the PI3K/Akt pathway is a potential target for the treatment of EBV and KSHV associated malignancies.	('PI3K/Akt pathway', 'Pathway', (29, 45))	('malignancies', 'Disease', (113, 125))	('KSHV', 'Species', '37296', (97, 101))	('EBV', 'Disease', (89, 92))	('inhibition', 'Var', (11, 21))	('EBV', 'Species', '10376', (89, 92))	('KSHV associated', 'Disease', (97, 112))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))
30802	25798530	A pooled analysis of 19 renal transplant recipients with post-transplant lymphoproliferative disease from multiple European transplant centers showed that substitution of calcineurin inhibitors with sirolimus or everolimus, along with rituximab therapy in six patients and chemotherapy in six patients, resulted in complete remission of disease in 15 patients.	('sirolimus', 'Chemical', 'MESH:D020123', (199, 208))	('lymphoproliferative disease', 'Disease', 'MESH:D008232', (73, 100))	('lymphoproliferative disease', 'Phenotype', 'HP:0005523', (73, 100))	('patients', 'Species', '9606', (260, 268))	('substitution', 'Var', (155, 167))	('patients', 'Species', '9606', (351, 359))	('everolimus', 'Chemical', 'MESH:D000068338', (212, 222))	('patients', 'Species', '9606', (293, 301))	('rituximab', 'Chemical', 'MESH:D000069283', (235, 244))	('lymphoproliferative disease', 'Disease', (73, 100))
30804	25798530	Similarly, an experimental drug that inhibits both PI3K and mTOR was more effective than either PI3K or mTOR inhibitors to inhibit the growth of KSHV-positive primary effusion lymphoma cells in vitro and in a xenograft tumor model ( Human herpesviruses express multiple proteins during the immediate-early, early, and late phases of the virus replication cycle and during latency that activate the PI3K/Akt pathway.	('mTOR', 'Gene', (104, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (176, 184))	('mTOR', 'Gene', '2475', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('PI3K', 'Var', (51, 55))	('effusion lymphoma', 'Disease', (167, 184))	('tumor', 'Disease', (219, 224))	('effusion lymphoma', 'Disease', 'MESH:D054685', (167, 184))	('Human', 'Species', '9606', (233, 238))	('herpesvirus', 'Species', '39059', (239, 250))	('KSHV', 'Species', '37296', (145, 149))	('mTOR', 'Gene', '2475', (60, 64))	('inhibit', 'NegReg', (123, 130))	('mTOR', 'Gene', (60, 64))	('PI3K/Akt pathway', 'Pathway', (398, 414))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('inhibits', 'NegReg', (37, 45))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (159, 184))
30859	23661254	Binding to plasminogen active sites, lysine blocks plasminogen activation into plasmin by tissue plasminogen activator (t-PA).	('tissue plasminogen activator (t-PA', 'Gene', '5327', (90, 124))	('blocks', 'NegReg', (44, 50))	('t-PA', 'Gene', '5327', (120, 124))	('t-PA', 'Gene', (120, 124))	('lysine', 'Var', (37, 43))	('plasminogen activation into plasmin', 'MPA', (51, 86))
30913	23661254	Overexpression of u-PA in sarcoma patients has been correlated with cancer progression, metastasis and poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('metastasis', 'CPA', (88, 98))	('sarcoma', 'Disease', 'MESH:D012509', (26, 33))	('u-PA', 'Gene', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('sarcoma', 'Disease', (26, 33))	('patients', 'Species', '9606', (34, 42))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (68, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('u-PA', 'Gene', '5328', (18, 22))
30922	23661254	For uterine leiomyosarcoma SK-UT-1 cells, a significant negative correlation (r=-0.956) was found between NM modulation of Matrigel invasion inhibition and MMP-9 secretion.	('leiomyosarcoma', 'Disease', (12, 26))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (12, 26))	('Matrigel invasion inhibition', 'CPA', (123, 151))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (4, 26))	('MMP-9', 'Gene', '4318', (156, 161))	('modulation', 'Var', (109, 119))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (12, 26))	('negative', 'NegReg', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('MMP-9', 'Gene', (156, 161))	('NM', 'Chemical', '-', (106, 108))
30929	23661254	In addition, lysine contributes to ECM stability as a natural inhibitor of plasmin-induced proteolysis.	('plasmin', 'Gene', (75, 82))	('lysine', 'Var', (13, 19))	('ECM', 'Gene', '22915', (35, 38))	('plasmin', 'Gene', '5340', (75, 82))	('ECM', 'Gene', (35, 38))	('lysine', 'Chemical', 'MESH:D008239', (13, 19))
31002	23287123	On IHC, tumours were positive for EMA (26/34, 76.4%), CK7(6/10, 60%), CK/MNF116 (6/21, 28.6%), CK19 (3/7, 42.8%), BCL2 (36/37, 97.3%), MIC2 (23/31, 74.1%), calponin (14/14, 100%), vimentin (7/7, 100%), while negative for CD34 in all 21 tumours, wherever performed (Table II).	('CK19', 'Gene', (95, 99))	('calponin', 'Protein', (156, 164))	('CK19', 'Gene', '3880', (95, 99))	('MIC2', 'Gene', (135, 139))	('tumours', 'Disease', (8, 15))	('BCL2', 'Gene', '596', (114, 118))	('EMA', 'Gene', '4582', (34, 37))	('MIC2', 'Gene', '4267', (135, 139))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('CD34', 'Gene', (221, 225))	('tumours', 'Disease', 'MESH:D009369', (8, 15))	('EMA', 'Gene', (34, 37))	('CK7', 'Gene', (54, 57))	('tumours', 'Disease', (236, 243))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('CK/MNF116', 'Var', (70, 79))	('BCL2', 'Gene', (114, 118))	('tumours', 'Phenotype', 'HP:0002664', (236, 243))	('vimentin', 'Gene', '7431', (180, 188))	('tumours', 'Disease', 'MESH:D009369', (236, 243))	('positive', 'Reg', (21, 29))	('vimentin', 'Gene', (180, 188))	('CK7', 'Gene', '3855', (54, 57))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('CD34', 'Gene', '947', (221, 225))
31029	23287123	CK expression in the present study was low as we have MNF116, rather than AE1/AE3 that is a broad spectrum cytokeratin.	('MNF116', 'Var', (54, 60))	('AE3', 'Gene', '6508', (78, 81))	('CK expression', 'MPA', (0, 13))	('AE1', 'Gene', '6521', (74, 77))	('AE3', 'Gene', (78, 81))	('AE1', 'Gene', (74, 77))
31033	23287123	t(X; 20) (p11.2; q13.3) translocation resulting in SSL18L1/SSX has also been documented in a synovial sarcoma.	('translocation', 'Var', (24, 37))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (93, 109))	('synovial sarcoma', 'Disease', 'MESH:D013584', (93, 109))	('SSX', 'Gene', (59, 62))	('SSX', 'Gene', '6757', (59, 62))	('synovial sarcoma', 'Disease', (93, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
31042	23287123	TLE1 positivity was found in 26 out of 70 tumours, leading to an overall specificity of 63.7 per cent.	('positivity', 'Var', (5, 15))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('TLE1', 'Gene', '7088', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('TLE1', 'Gene', (0, 4))	('tumours', 'Disease', (42, 49))
31044	23287123	Among the differential diagnosis of synovial sarcoma, TLE1 positivity was noted in 16.6 per cent MPNSTs, 40 per cent Ewing sarcomas, while its negativity was observed in epithelioid sarcomas and in a single case of a solitary fibrous tumour and adult fibrosarcoma, respectively.	('solitary fibrous tumour', 'Disease', 'MESH:D054364', (217, 240))	('epithelioid sarcomas', 'Disease', (170, 190))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (36, 52))	('solitary fibrous tumour', 'Disease', (217, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('TLE1', 'Gene', (54, 58))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (251, 263))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('adult fibrosarcoma', 'Disease', (245, 263))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (117, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('positivity', 'Var', (59, 69))	('adult fibrosarcoma', 'Disease', 'MESH:D005354', (245, 263))	('MPNSTs', 'Disease', (97, 103))	('synovial sarcoma', 'Disease', (36, 52))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (170, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('TLE1', 'Gene', '7088', (54, 58))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (117, 131))	('synovial sarcoma', 'Disease', 'MESH:D013584', (36, 52))	('Ewing sarcomas', 'Disease', (117, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (117, 131))
31048	23287123	Another example of TLE1 positivity as in malignant mesotheliomas.	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (41, 64))	('positivity', 'Var', (24, 34))	('TLE1', 'Gene', (19, 23))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (41, 64))	('malignant mesotheliomas', 'Disease', (41, 64))	('TLE1', 'Gene', '7088', (19, 23))
31053	23287123	In a recent prospective study, it was observed that utilization of TLE1 for diagnosing synovial sarcomas leads to a considerable reduction in cost and turnaround time, as compared to SYT results by FISH.	('cost', 'MPA', (142, 146))	('SYT', 'Gene', (183, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('utilization', 'Var', (52, 63))	('reduction', 'NegReg', (129, 138))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (87, 104))	('SYT', 'Gene', '6760', (183, 186))	('TLE1', 'Gene', (67, 71))	('synovial sarcomas', 'Disease', 'MESH:D013584', (87, 104))	('synovial sarcomas', 'Disease', (87, 104))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (87, 103))	('TLE1', 'Gene', '7088', (67, 71))
31056	23287123	Apart from its expression in certain tumours, we noted aberrant TLE1 expression in a single case of adenocarcinoma and adamantinoma.	('adenocarcinoma and adamantinoma', 'Disease', 'MESH:D050398', (100, 131))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('aberrant', 'Var', (55, 63))	('tumours', 'Disease', 'MESH:D009369', (37, 44))	('tumours', 'Disease', (37, 44))	('TLE1', 'Gene', (64, 68))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('TLE1', 'Gene', '7088', (64, 68))
31064	23287123	Similar to others, we also noted TLE positivity in non-neoplastic tissues like endothelial cells, basal keratinocytes and adipocytes.	('positivity', 'Var', (37, 47))	('TLE', 'Disease', 'MESH:D004833', (33, 36))	('TLE', 'Disease', (33, 36))
31065	23287123	Besides its diagnostic value, intense TLE1 positivity in most synovial sarcomas and in schwannomas can be presumed to be reflective of neural histogenesis, apart from the epithelial origin of a synovial sarcoma.	('synovial sarcoma', 'Disease', (194, 210))	('schwannomas', 'Disease', (87, 98))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (62, 78))	('synovial sarcoma', 'Disease', 'MESH:D013584', (62, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('synovial sarcomas', 'Disease', 'MESH:D013584', (62, 79))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (194, 210))	('TLE1', 'Gene', '7088', (38, 42))	('schwannomas', 'Disease', 'MESH:D009442', (87, 98))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (62, 79))	('synovial sarcoma', 'Disease', 'MESH:D013584', (194, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('positivity', 'Var', (43, 53))	('synovial sarcomas', 'Disease', (62, 79))	('schwannomas', 'Phenotype', 'HP:0100008', (87, 98))	('TLE1', 'Gene', (38, 42))
31080	22587879	Ewing sarcoma is diagnostically defined by a Ewing sarcoma EWS (chromosome 22) translocation resulting in fusion with an ETS transcription factor, the commonest abnormality (85%) being EWS-FLI1 (chromosome 11).	('EWS', 'Gene', (59, 62))	('EWS', 'Gene', '2130', (185, 188))	('EWS', 'Gene', (185, 188))	('FLI1', 'Gene', '2313', (189, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('FLI1', 'Gene', (189, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('translocation', 'Var', (79, 92))	('fusion', 'MPA', (106, 112))	('Ewing sarcoma', 'Gene', '2130', (0, 13))	('Ewing sarcoma', 'Gene', (0, 13))	('Ewing sarcoma', 'Gene', '2130', (45, 58))	('Ewing sarcoma', 'Gene', (45, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('EWS', 'Gene', '2130', (59, 62))
31124	22587879	Loss of function of cell cycle dependent kinases (p16, p14, p21) and other regulators of the cell cycle through the p53 pathway (MDM2, p53), also appear deregulate in a proportion of tumours and potentially are useful prognostic markers.	('p16', 'Gene', (50, 53))	('MDM2', 'Gene', (129, 133))	('tumours', 'Disease', (183, 190))	('p16', 'Gene', '1029', (50, 53))	('p53', 'Gene', '7157', (135, 138))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('tumours', 'Disease', 'MESH:D009369', (183, 190))	('MDM2', 'Gene', '4193', (129, 133))	('p14', 'Gene', '1029', (55, 58))	('p53', 'Gene', (135, 138))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('cell', 'Enzyme', (20, 24))	('p21', 'Gene', (60, 63))	('p53', 'Gene', '7157', (116, 119))	('p21', 'Gene', '644914', (60, 63))	('p14', 'Gene', (55, 58))	('deregulate', 'Var', (153, 163))	('Loss of function', 'NegReg', (0, 16))	('p53', 'Gene', (116, 119))
31126	22587879	There appears much interest in secondary copy number changes and mutations in Ewing sarcoma, and in particular, chromosome 1 (Table 6).	('Ewing sarcoma', 'Gene', '2130', (78, 91))	('Ewing sarcoma', 'Gene', (78, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('mutations', 'Var', (65, 74))
31127	22587879	For example, recent evidence points to gain of 1q and alteration in abundance of a gene product called CDt2 involved in ubiquitination.	('alteration', 'Var', (54, 64))	('CDt2', 'Gene', '51514', (103, 107))	('CDt2', 'Gene', (103, 107))	('gain', 'PosReg', (39, 43))	('abundance', 'MPA', (68, 77))
31157	31645886	Sarcomas can be broadly divided in three groups, according to their genetic alterations: sarcomas with chromosomal rearrangement, sarcomas with specific genetic mutation and sarcomas with complex and irregular genomic changes.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('sarcomas', 'Disease', (174, 182))	('sarcomas', 'Disease', (130, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('sarcomas', 'Disease', (89, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('sarcomas', 'Disease', 'MESH:D012509', (130, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('chromosomal rearrangement', 'Var', (103, 128))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
31158	31645886	Synovial sarcoma is an example of a sarcoma with chromosomal rearrangement, since it usually harbours t(X;18)(p11.2;q11.2).	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('Synovial sarcoma', 'Disease', (0, 16))	('sarcoma', 'Disease', (9, 16))	('Synovial sarcoma', 'Disease', 'MESH:D013584', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcoma', 'Disease', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('t(X;18)(p11.2;q11.2', 'Var', (102, 121))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (102, 122))
31162	31645886	Their interpretation of the study was that about half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment.	('cancer', 'Disease', (159, 165))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('patients', 'Species', '9606', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('pathogenic', 'Reg', (95, 105))	('polygenic variation', 'Var', (120, 139))	('sarcoma', 'Disease', (71, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
31191	31645886	Patients with high grade STS are at high risk of metastatic disease, most often to the lungs.	('Patients', 'Species', '9606', (0, 8))	('high grade', 'Var', (14, 24))	('metastatic disease', 'CPA', (49, 67))
31247	31645886	This was a phase III study that compared pazopanib versus placebo in non-adipocytic sarcomas and demonstrated an increase in median PFS favouring pazopanib (4.6 versus 1.6 months:HR 0.33:p < 0.0001).	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('pazopanib', 'Chemical', 'MESH:C516667', (146, 155))	('pazopanib', 'Chemical', 'MESH:C516667', (41, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('PFS', 'MPA', (132, 135))	('pazopanib', 'Var', (146, 155))	('sarcomas', 'Disease', (84, 92))
31276	31645886	The use of high dose ifosfamide is associated with worse adverse events including fatigue (85%), nausea and vomiting (80%) myelosuppression (45%), encephalopathy (34%) and renal impairment (14,3%) and should only be prescribed in reference centres.	('nausea and vomiting', 'Phenotype', 'HP:0002017', (97, 116))	('encephalopathy', 'Disease', (147, 161))	('ifosfamide', 'Chemical', 'MESH:D007069', (21, 31))	('renal impairment', 'Disease', 'MESH:D007674', (172, 188))	('renal impairment', 'Phenotype', 'HP:0000083', (172, 188))	('nausea and vomiting', 'Disease', 'MESH:D020250', (97, 116))	('myelosuppression', 'Disease', 'MESH:D001855', (123, 139))	('fatigue', 'Disease', 'MESH:D005221', (82, 89))	('myelosuppression', 'Disease', (123, 139))	('high dose', 'Var', (11, 20))	('vomiting', 'Phenotype', 'HP:0002013', (108, 116))	('encephalopathy', 'Disease', 'MESH:D001927', (147, 161))	('nausea', 'Phenotype', 'HP:0002018', (97, 103))	('fatigue', 'Disease', (82, 89))	('renal impairment', 'Disease', (172, 188))	('fatigue', 'Phenotype', 'HP:0012378', (82, 89))	('encephalopathy', 'Phenotype', 'HP:0001298', (147, 161))
31394	27285983	The crescent tagerability of 131I-Hyp to necrosis was visualized consistently by autoradiography and fluorescence microscopy.	('131I-Hyp', 'Var', (29, 37))	('131I-Hyp', 'Chemical', '-', (29, 37))	('necrosis', 'Disease', 'MESH:D009336', (41, 49))	('necrosis', 'Disease', (41, 49))
31411	27285983	131I-Hyp has also been identified as a potential therapeutic radiopharmaceutical in the field of so-called necrosis target radiotherapy compared with other previously identified specific agents.	('necrosis', 'Disease', (107, 115))	('necrosis', 'Disease', 'MESH:D009336', (107, 115))	('131I-Hyp', 'Var', (0, 8))	('131I-Hyp', 'Chemical', '-', (0, 8))
31414	27285983	Based on the above considerations, we hypothesized that 131I-Hyp could specifically bind to the necrotic liver tumor induced by MWA and further irradiate the surrounding residual viable tumor with persistent cross-fire beta particles.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('131I-Hyp', 'Var', (56, 64))	('irradiate', 'Reg', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('necrotic liver', 'Phenotype', 'HP:0002605', (96, 110))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('rat', 'Species', '10116', (26, 29))	('necrotic liver tumor', 'Disease', 'MESH:D008113', (96, 116))	('liver tumor', 'Phenotype', 'HP:0002896', (105, 116))	('tumor', 'Disease', (186, 191))	('necrotic liver tumor', 'Disease', (96, 116))	('tumor', 'Disease', (111, 116))	('bind', 'Interaction', (84, 88))	('131I-Hyp', 'Chemical', '-', (56, 64))
31425	27285983	At baseline (day 0), tumor volume appeared no significant statistical differences among three groups (211.1306 +- 40.0088, 188.2213 +- 50.0269, 169.8402 +- 16.3967 mm3; p>0.05).	('tumor', 'Disease', (21, 26))	('188.2213 +- 50.0269', 'Var', (123, 142))	('169.8402 +- 16.3967 mm3', 'Var', (144, 167))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
31434	27285983	Over time, radioactivity uptake in normal liver gradually weakened and high radioactivity uptake mainly concentrated in the border of viable tumor and necrosis (Figure 4, B1) 4 days post injection of 131I-Hyp.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('rat', 'Species', '10116', (111, 114))	('radioactivity uptake', 'MPA', (11, 31))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('necrosis', 'Disease', 'MESH:D009336', (151, 159))	('131I-Hyp', 'Var', (200, 208))	('tumor', 'Disease', (141, 146))	('weakened', 'NegReg', (58, 66))	('131I-Hyp', 'Chemical', '-', (200, 208))	('necrosis', 'Disease', (151, 159))
31437	27285983	1 day post injection of 131I-Hyp, fluorescence intensity mainly focused on necrosis and lesser distributed in normal liver and tumor (Figure 4, A4).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('necrosis', 'Disease', 'MESH:D009336', (75, 83))	('fluorescence', 'MPA', (34, 46))	('131I-Hyp', 'Chemical', '-', (24, 32))	('necrosis', 'Disease', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('131I-Hyp', 'Var', (24, 32))
31440	27285983	131I-Hyp could bind to necrotic tumor after MWA and inhibit residual tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inhibit', 'NegReg', (52, 59))	('131I-Hyp', 'Chemical', '-', (0, 8))	('tumor', 'Disease', (69, 74))	('bind', 'Interaction', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('necrotic tumor', 'Disease', (23, 37))	('necrotic tumor', 'Disease', 'MESH:D009369', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('131I-Hyp', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
31445	27285983	Eventually 131I-Hyp presented a persistent and increasing accumulation in necrotic tumor (Figure 2C, 2D), which guaranteed durable cross-fire ionizing radiation around the residual tumor.	('131I-Hyp', 'Var', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', (83, 88))	('accumulation', 'PosReg', (58, 70))	('131I-Hyp', 'Chemical', '-', (11, 19))	('necrotic tumor', 'Disease', (74, 88))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('necrotic tumor', 'Disease', 'MESH:D009369', (74, 88))
31450	27285983	In vitro radioautography and fluorescent microscopy confirmed that 131I-Hyp persistently deposited in the target tissue (necrotic tumor) and rapidly excreted from non-target tissues (normal liver and viable tumor) (Figure 4).	('necrotic tumor', 'Disease', (121, 135))	('necrotic tumor', 'Disease', 'MESH:D009369', (121, 135))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('131I-Hyp', 'Var', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('131I-Hyp', 'Chemical', '-', (67, 75))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (130, 135))
31453	27285983	Tumor inhibition was observed during the 8 day follow-up and 131I-Hyp could persistently concentrate in necrotic areas induced by MWA, significantly prolong TDT and inhibited recurrence of residual tumors compared to the control group.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('necrotic areas', 'Disease', 'MESH:D009336', (104, 118))	('recurrence', 'CPA', (175, 185))	('prolong', 'PosReg', (149, 156))	('inhibited', 'NegReg', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('MWA', 'Gene', (130, 133))	('131I-Hyp', 'Var', (61, 69))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('rat', 'Species', '10116', (96, 99))	('TDT', 'CPA', (157, 160))	('131I-Hyp', 'Chemical', '-', (61, 69))	('necrotic areas', 'Disease', (104, 118))
31466	27285983	Thus, 131I-Hyp can more easily penetrate the tumor tissue microenvironment for the subsequent cross-fire radiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('131I-Hyp', 'Chemical', '-', (6, 14))	('rat', 'Species', '10116', (36, 39))	('tumor', 'Disease', (45, 50))	('131I-Hyp', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
31470	27285983	Our study did demonstrate that 131I-Hyp can persistently bind to necrotic tumor after MWA and further inhibit residual tumor recurrence on rat orthotopic liver allograft sarcoma models.	('necrotic tumor', 'Disease', (65, 79))	('tumor', 'Disease', (119, 124))	('131I-Hyp', 'Chemical', '-', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('necrotic tumor', 'Disease', 'MESH:D009369', (65, 79))	('rat', 'Species', '10116', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('liver allograft sarcoma', 'Disease', (154, 177))	('bind', 'Interaction', (57, 61))	('rat', 'Species', '10116', (21, 24))	('tumor', 'Disease', (74, 79))	('inhibit', 'NegReg', (102, 109))	('liver allograft sarcoma', 'Disease', 'MESH:D008113', (154, 177))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('131I-Hyp', 'Var', (31, 39))
31482	27285983	after 24 h; Group B (n = 10) received intra-operative MWA and vehicle; Group C (n = 10) were blank controls treated with sham ablation and they received surgical interventions but without microwave energy delivery, and then they received vehicle after 24 h. As 131I-Hyp alone has been documented to have little tumoricidal activity, we deliberately did not include a control group of 131I-Hyp treatment alone.	('131I-Hyp', 'Var', (261, 269))	('131I-Hyp', 'Chemical', '-', (384, 392))	('131I-Hyp', 'Chemical', '-', (261, 269))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('rat', 'Species', '10116', (342, 345))	('rat', 'Species', '10116', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('tumor', 'Disease', (311, 316))
31610	29146734	Early-phase clinical trials investigating blockade of the PD-1/PD-L1 signaling pathway have shown positive clinical responses in some patients bearing melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma tumors.	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('patients', 'Species', '9606', (134, 142))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('non-small cell lung cancer', 'Disease', (161, 187))	('melanoma', 'Disease', (151, 159))	('renal cell carcinoma tumors', 'Disease', 'MESH:C538614', (200, 227))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('NSCLC', 'Disease', (189, 194))	('renal cell carcinoma tumors', 'Disease', (200, 227))	('blockade', 'Var', (42, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (161, 187))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (200, 220))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('PD-1/PD-L1', 'Gene', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (161, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (165, 187))
31634	29146734	The PDX tumors that were used in this study include NSCLC: LG0997, LG0978, LG1306, and LG1208; TNBC: BR1126 and BR0744; sarcoma: SA0209; and bladder: BL0293.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('BR1126', 'Var', (101, 107))	('LG1208', 'Var', (87, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('NSCLC', 'Disease', (52, 57))	('BR0744', 'Var', (112, 118))	('PDX tumors', 'Disease', (4, 14))	('BL0293', 'CellLine', 'CVCL:8V90', (150, 156))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('PDX tumors', 'Disease', 'MESH:D009369', (4, 14))	('bladder', 'Disease', (141, 148))	('sarcoma', 'Disease', (120, 127))
31674	29146734	1C) and sarcoma (SA0209P4; Fig.	('SA0209P4;', 'Var', (17, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('sarcoma', 'Disease', (8, 15))
31687	29146734	S1B) of sarcoma (SA0209P4) and NSCLC (LG0997P4) Onco-HuNSG models.	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('NSCLC', 'Disease', (31, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('sarcoma', 'Disease', (8, 15))	('SA0209P4', 'Var', (17, 25))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('LG0997P4', 'Var', (38, 46))
31688	29146734	Analysis of the blood cells revealed that the sarcoma (SA0209P4) and the NSCLC (LG0997P4) Onco-HuNSG mice displayed more circulating CD4+ T cells than CD8+ T cells.	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('more', 'PosReg', (116, 120))	('CD8', 'Gene', (151, 154))	('LG0997P4', 'Var', (80, 88))	('CD8', 'Gene', '925', (151, 154))	('NSCLC', 'Disease', (73, 78))	('sarcoma', 'Disease', (46, 53))	('SA0209P4', 'Var', (55, 63))	('mice', 'Species', '10090', (101, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
31692	29146734	Next, we determined whether anti-PD-1 pembrolizumab would show efficacy in Onco-HuNSG mice.	('mice', 'Species', '10090', (86, 90))	('anti-PD-1', 'Var', (28, 37))	('pembrolizumab', 'Chemical', 'MESH:C582435', (38, 51))	('Onco-HuNSG', 'Disease', (75, 85))
31714	29146734	Next, we collected blood from the NSCLC (LG0978P5) Onco-HuNSG mice, and immune cell populations were analyzed by flow cytometry.	('NSCLC', 'Disease', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('mice', 'Species', '10090', (62, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('LG0978P5', 'Var', (41, 49))
31719	29146734	In all of the tumor models that were tested, including NSCLC (LG1306, LG1208, LG0978), TNBC (MDA-MB-231), and sarcoma (SA0209), we did not find such correlation (data not shown).	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('tumor', 'Disease', (14, 19))	('sarcoma', 'Disease', (110, 117))	('NSCLC', 'Disease', (55, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('LG0978', 'Var', (78, 84))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('LG1306', 'Var', (62, 68))
31725	29146734	In the bladder PDX (BL0293P3) Onco-HuNSG mice, both the responder and the nonresponder HPSC donors had multiple HLA class II loci matched with the bladder PDX tumor, but only the responder donor had 2 HLA class I loci matched with the bladder PDX tumor (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('bladder PDX tumor', 'Disease', 'MESH:D001749', (147, 164))	('mice', 'Species', '10090', (41, 45))	('donor', 'Species', '9606', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BL0293', 'CellLine', 'CVCL:8V90', (20, 26))	('bladder PDX tumor', 'Disease', (235, 252))	('donor', 'Species', '9606', (189, 194))	('bladder PDX tumor', 'Disease', (147, 164))	('BL0293P3', 'Var', (20, 28))	('bladder PDX tumor', 'Disease', 'MESH:D001749', (235, 252))
31726	29146734	In contrast, the responder donor in the lung (LG0978P5) Onco-HuNSG mice had no major HLA class I match with the lung (LG0978P5) PDX tumor (Table 1).	('mice', 'Species', '10090', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('donor', 'Species', '9606', (27, 32))	('LG0978P5', 'Var', (118, 126))
31727	29146734	In the NSCLC (LG0978P5) Onco-HuNSG model, the nonresponder donor (donor 7206) had 4 HLA class II matches but no major HLA class I match with the PDX tumor, which was similar to the matching status of "donor 1" in the TNBC (MDA-MB-231) model.	('NSCLC', 'Disease', (7, 12))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (223, 233))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('donor', 'Species', '9606', (201, 206))	('NSCLC', 'Disease', 'MESH:D002289', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('donor', 'Species', '9606', (59, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (7, 12))	('donor', 'Species', '9606', (66, 71))	('LG0978P5', 'Var', (14, 22))
31729	29146734	In the TNBC (BR1126P5) Onco-HuNSG model, all 3 HPSC donors were partially matched with the TNBC (BR1126P5) PDX tumor at both HLA class I and class II loci, and all 3 HPSC donors responded to pembrolizumab treatment (Supplemental Fig.	('donor', 'Species', '9606', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('responded', 'Reg', (178, 187))	('BR1126P5', 'Var', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('pembrolizumab', 'Chemical', 'MESH:C582435', (191, 204))	('donor', 'Species', '9606', (171, 176))
31762	29146734	The mechanisms for tumor rejection in Onco-HuNSG mice treated with anti-PD-1 remain to be elucidated.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mice', 'Species', '10090', (49, 53))	('tumor', 'Disease', (19, 24))	('anti-PD-1', 'Var', (67, 76))
31774	29146734	We demonstrated herein in Onco-HuNSG mice that pembrolizumab can inhibit tumor growth, not only in CDX but also in various PDX tumor models.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CDX', 'Chemical', '-', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('pembrolizumab', 'Chemical', 'MESH:C582435', (47, 60))	('pembrolizumab', 'Var', (47, 60))	('inhibit', 'NegReg', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mice', 'Species', '10090', (37, 41))	('CDX', 'Disease', (99, 102))
31776	29146734	We found that pembrolizumab increased both CD4+ and CD8+ T-cell numbers in the blood of the 2 NSCLC (LG1306P5 and LG0978P5 responder) Onco-HuNSG models but decreased both CD4+ and CD8+ T-cell numbers in the blood of the TNBC (MDA-MB-231) Onco-HuNSG model (Figs.	('increased', 'PosReg', (28, 37))	('pembrolizumab', 'Chemical', 'MESH:C582435', (14, 27))	('CD8', 'Gene', '925', (180, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (226, 236))	('CD4+', 'MPA', (43, 47))	('NSCLC', 'Disease', (94, 99))	('decreased', 'NegReg', (156, 165))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('CD8', 'Gene', (180, 183))	('CD8', 'Gene', (52, 55))	('LG0978P5', 'Var', (114, 122))	('CD8', 'Gene', '925', (52, 55))
31790	29146734	In the NSCLC (LG0978P5) Onco-HuNSG model, we found higher CD4+ and CD8+ T-cell levels in the anti-PD-1 treatment group compared with vehicle control in responder donor mice peripheral blood (Fig.	('NSCLC', 'Disease', (7, 12))	('NSCLC', 'Disease', 'MESH:D002289', (7, 12))	('mice', 'Species', '10090', (168, 172))	('anti-PD-1', 'Var', (93, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (7, 12))	('higher', 'PosReg', (51, 57))	('CD8', 'Gene', (67, 70))	('donor', 'Species', '9606', (162, 167))	('CD8', 'Gene', '925', (67, 70))
31856	22498582	This review will focus the rationale for targeted therapy in sarcoma, with emphasis on the relevance of specific molecular factors and pathways in both translocation-associated sarcomas and in genetically complex tumors.	('sarcomas', 'Disease', (177, 185))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('translocation-associated', 'Var', (152, 176))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('sarcoma', 'Disease', (177, 184))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('sarcomas', 'Disease', 'MESH:D012509', (177, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('sarcoma', 'Disease', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
31879	22498582	Sarcomas may be broadly classified by genomic events underlying their development as 1) those with specific translocations or gene amplification, 2) those with defining oncogenic mutations and 3) those with complex genomic rearrangements.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('translocations', 'Var', (108, 122))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('gene amplification', 'Var', (126, 144))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
31881	22498582	Specific, recurrent translocations have thus far been identified in 22 types of benign and malignant bone and soft tissue neoplasms, including 19 soft tissue sarcomas (including 4 tumors of at least intermediate (rarely metastasizing) biologic potential).	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('soft tissue neoplasms', 'Disease', 'MESH:D012983', (110, 131))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (146, 166))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (110, 131))	('soft tissue sarcomas', 'Disease', (146, 166))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('identified', 'Reg', (54, 64))	('soft tissue neoplasms', 'Disease', (110, 131))	('translocations', 'Var', (20, 34))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (146, 166))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (146, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
31883	22498582	Typically, recurrent translocations in sarcoma result in chimeric fusion genes which function as transcription factors, as is epitomized by the EWSR1-FLI1 fusion gene in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (170, 183))	('FLI1', 'Gene', '2313', (150, 154))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (170, 183))	('EWSR1', 'Gene', '2130', (144, 149))	('sarcoma', 'Disease', (176, 183))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('chimeric', 'Var', (57, 65))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('result in', 'Reg', (47, 56))	('sarcoma', 'Disease', (39, 46))	('Ewing sarcoma', 'Disease', (170, 183))	('translocations', 'Var', (21, 35))	('EWSR1', 'Gene', (144, 149))	('FLI1', 'Gene', (150, 154))
31884	22498582	Less frequently, translocation results in overexpression or constitutive activation of a growth factor receptor tyrosine kinase (RTK) or other chimeric growth factor signaling protein, as is seen in DFSP, in which wild types PDGFB is overexpressed under the COL1A1 promoter, and inflammatory myofibroblastic tumor (IMT) in which ALK fusion partners promote dimerization of the ALK tyrosine kinase thereby rendering it constitutively active.	('RTK', 'Gene', (129, 132))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (292, 313))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (279, 313))	('DFSP', 'Disease', 'MESH:D018223', (199, 203))	('dimerization', 'MPA', (357, 369))	('ALK', 'Gene', '238', (329, 332))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('COL1A1', 'Gene', '1277', (258, 264))	('ALK', 'Gene', '238', (377, 380))	('RTK', 'Gene', '5979', (129, 132))	('ALK', 'Gene', (329, 332))	('promote', 'PosReg', (349, 356))	('DFSP', 'Disease', (199, 203))	('ALK', 'Gene', (377, 380))	('overexpression', 'PosReg', (42, 56))	('inflammatory myofibroblastic tumor', 'Disease', (279, 313))	('COL1A1', 'Gene', (258, 264))	('PDGFB', 'Gene', '5155', (225, 230))	('activation', 'PosReg', (73, 83))	('receptor tyrosine kinase', 'Gene', '5979', (103, 127))	('translocation', 'Var', (17, 30))	('PDGFB', 'Gene', (225, 230))	('receptor tyrosine kinase', 'Gene', (103, 127))	('overexpressed', 'PosReg', (234, 247))
31885	22498582	Recurrent amplifications have only been identified in a few soft tissue sarcomas, most notably well-differentiated/ dedifferentiated liposarcoma, in which amplification of chromosome 12q13-15, including HDM2 (MDM2) and CDK4 is characteristic.	('amplification', 'Var', (155, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (60, 80))	('HDM2', 'Gene', (203, 207))	('MDM2', 'Gene', '4193', (209, 213))	('liposarcoma', 'Disease', (133, 144))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (60, 79))	('CDK4', 'Gene', (219, 223))	('MDM2', 'Gene', (209, 213))	('HDM2', 'Gene', '4193', (203, 207))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (60, 80))	('liposarcoma', 'Phenotype', 'HP:0012034', (133, 144))	('liposarcoma', 'Disease', 'MESH:D008080', (133, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('soft tissue sarcomas', 'Disease', (60, 80))	('CDK4', 'Gene', '1019', (219, 223))
31887	22498582	Accordingly, amplification and subsequent overexpression of this chromosomal locus results in inhibition of p53-dependent cell-cycle arrest and apoptosis.	('inhibition', 'NegReg', (94, 104))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('apoptosis', 'CPA', (144, 153))	('amplification', 'Var', (13, 26))	('overexpression', 'PosReg', (42, 56))	('arrest', 'Disease', 'MESH:D006323', (133, 139))	('arrest', 'Disease', (133, 139))
31889	22498582	Amplification of MYC has been described in secondary (radiation-induced) angiosarcoma, and may be seen sporadically in other sarcomas.	('angiosarcoma', 'Disease', (73, 85))	('MYC', 'Gene', (17, 20))	('Amplification', 'Var', (0, 13))	('sarcomas', 'Disease', 'MESH:D012509', (125, 133))	('angiosarcoma', 'Phenotype', 'HP:0200058', (73, 85))	('MYC', 'Gene', '4609', (17, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('sarcomas', 'Disease', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('angiosarcoma', 'Disease', 'MESH:D006394', (73, 85))	('described', 'Reg', (30, 39))
31891	22498582	Translocation sarcomas have not yet proven to be as amenable to targeted therapy as had once been hoped, despite a greatly improved understanding of the mechanisms by which chimeric fusion genes promote sarcomagenesis.	('sarcomas', 'Disease', 'MESH:D012509', (14, 22))	('sarcoma', 'Disease', (203, 210))	('sarcoma', 'Disease', (14, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (14, 22))	('Translocation', 'Var', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('chimeric', 'Var', (173, 181))	('sarcomas', 'Disease', (14, 22))	('promote', 'PosReg', (195, 202))	('sarcoma', 'Disease', 'MESH:D012509', (203, 210))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))
31892	22498582	The prototype for this class of sarcomas is DFSP, in which the growth factor PDGFB is fused to the promoter of the constitutively expressed COL1A1 encoding a collagen.	('DFSP', 'Disease', 'MESH:D018223', (44, 48))	('fused', 'Var', (86, 91))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('COL1A1', 'Gene', '1277', (140, 146))	('PDGFB', 'Gene', '5155', (77, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('COL1A1', 'Gene', (140, 146))	('PDGFB', 'Gene', (77, 82))	('sarcomas', 'Disease', (32, 40))	('DFSP', 'Disease', (44, 48))
31893	22498582	Here, inhibition of PDGFR by the RTK- inhibitor (TKI) imatinib mesylate has been shown to dramatically reduce tumor size in previously unresectable cases.	('RTK', 'Gene', '5979', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('RTK', 'Gene', (33, 36))	('reduce', 'NegReg', (103, 109))	('PDGFR', 'Gene', (20, 25))	('inhibition', 'Var', (6, 16))	('PDGFR', 'Gene', '5159', (20, 25))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (54, 71))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
31904	22498582	Early preclinical studies have shown some response to MET-inhibitors in alveolar soft part sarcoma, and clear cell sarcomas, while inhibition of IGF1R may be beneficial in Ewing sarcoma.	('MET-inhibitors', 'MPA', (54, 68))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (72, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('alveolar soft part sarcoma', 'Disease', (72, 98))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (172, 185))	('IGF1R', 'Gene', '3480', (145, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (72, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', (172, 185))	('clear cell sarcomas', 'Disease', 'MESH:D018227', (104, 123))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (81, 98))	('clear cell sarcomas', 'Disease', (104, 123))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (172, 185))	('inhibition', 'Var', (131, 141))	('IGF1R', 'Gene', (145, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
31906	22498582	Preclinical studies have suggested that targeted therapy against FGFR may inhibit growth of synovial sarcoma.	('synovial sarcoma', 'Disease', (92, 108))	('inhibit', 'NegReg', (74, 81))	('growth', 'MPA', (82, 88))	('targeted therapy', 'Var', (40, 56))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (92, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('FGF', 'Gene', (65, 68))	('synovial sarcoma', 'Disease', 'MESH:D013584', (92, 108))	('FGF', 'Gene', '2247', (65, 68))
31907	22498582	It has also been postulated that translocation variants in sarcoma may be predictive of patient outcome, however, the encouraging results of early studies in alveolar rhabdomyosarcoma, Ewing sarcoma and synovial sarcoma have not been clearly validated in more recent reports.	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (158, 183))	('synovial sarcoma', 'Disease', 'MESH:D013584', (203, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (158, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('sarcoma', 'Disease', 'MESH:D012509', (212, 219))	('sarcoma', 'Disease', (212, 219))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (203, 219))	('patient', 'Species', '9606', (88, 95))	('Ewing sarcoma', 'Disease', (185, 198))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('sarcoma', 'Disease', (59, 66))	('alveolar rhabdomyosarcoma', 'Disease', (158, 183))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (167, 183))	('translocation variants', 'Var', (33, 55))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('sarcoma', 'Disease', 'MESH:D012509', (191, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcoma', 'Disease', (176, 183))	('sarcoma', 'Disease', (191, 198))	('synovial sarcoma', 'Disease', (203, 219))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (185, 198))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (185, 198))
31908	22498582	Several sarcomas have been identified in which tumorigenesis is primarily driven by single activating gene mutations.	('sarcomas', 'Disease', 'MESH:D012509', (8, 16))	('mutations', 'Var', (107, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('sarcomas', 'Disease', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
31910	22498582	GISTs require activating mutations in the KIT receptor tyrosine kinase, or less frequently, in PDGFRA for tumor proliferation.	('mutations', 'Var', (25, 34))	('receptor tyrosine kinase', 'Gene', (46, 70))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('activating', 'MPA', (14, 24))	('receptor tyrosine kinase', 'Gene', '5979', (46, 70))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PDGFRA', 'Gene', (95, 101))	('PDGFRA', 'Gene', '5156', (95, 101))	('tumor', 'Disease', (106, 111))
31911	22498582	The majority of cases have mutations in exon 11 of KIT, and respond dramatically to imatinib mesylate therapy, with up to 80% of patients demonstrating at least partial response, while mutations in exon 9 or PDGFRA render tumors resistant.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('KIT', 'Gene', (51, 54))	('patients', 'Species', '9606', (129, 137))	('PDGFRA', 'Gene', (208, 214))	('mutations in exon 11', 'Var', (27, 47))	('PDGFRA', 'Gene', '5156', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (84, 101))
31913	22498582	Unfortunately, GIST frequently develop secondary resistance to imatinib, which in many cases is due to additional activating mutations in KIT or to mutations in PDGFRA.	('mutations', 'Var', (125, 134))	('mutations', 'Var', (148, 157))	('PDGFRA', 'Gene', (161, 167))	('KIT', 'Gene', (138, 141))	('PDGFRA', 'Gene', '5156', (161, 167))	('secondary resistance to imatinib', 'MPA', (39, 71))	('activating', 'PosReg', (114, 124))	('imatinib', 'Chemical', 'MESH:D000068877', (63, 71))
31919	22498582	Complex karyotype sarcomas are thought to occur as a result of genomic instability and failure of DNA repair and maintenance mechanisms.	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('Complex karyotype', 'Var', (0, 17))	('sarcomas', 'Disease', (18, 26))
31920	22498582	While in normal cells, telomere shortening results in cellular senescence, in tumor cells which have circumvented normal cell cycle controls, division continues to occur, with disastrous consequences for chromosomes.	('cellular senescence', 'MPA', (54, 73))	('results in', 'Reg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('telomere shortening', 'Var', (23, 42))
31921	22498582	Telomere loss allows sticky ends of chromosomes to bind to nearby strands of DNA, inducing a cycle of unregulated fusion and breakage, with the end result of bizarre chromosomal inversions, amplifications, duplications, and translocations which characterize high grade malignancies.	('inducing', 'Reg', (82, 90))	('translocations', 'Var', (224, 238))	('unregulated', 'MPA', (102, 113))	('chromosomal inversions', 'Var', (166, 188))	('malignancies', 'Disease', 'MESH:D009369', (269, 281))	('loss', 'NegReg', (9, 13))	('duplications', 'Var', (206, 218))	('malignancies', 'Disease', (269, 281))	('amplifications', 'Var', (190, 204))
31925	22498582	Regardless of the underlying chromosomal events, complex karyotype sarcomas, like carcinomas, seem to develop mutations or activating events in particular cell survival or proliferation pathways, including cell-cycle checkpoints, apoptosis, stress response, and metabolic/proliferative pathways.	('develop', 'PosReg', (102, 109))	('activating', 'PosReg', (123, 133))	('proliferation', 'CPA', (172, 185))	('mutations', 'Var', (110, 119))	('cell-cycle checkpoints', 'CPA', (206, 228))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('apoptosis', 'CPA', (230, 239))	('stress response', 'CPA', (241, 256))	('cell survival', 'CPA', (155, 168))	('metabolic/proliferative pathways', 'Pathway', (262, 294))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('sarcomas', 'Disease', (67, 75))	('carcinomas', 'Disease', (82, 92))	('carcinomas', 'Disease', 'MESH:D002277', (82, 92))
31929	22498582	Hypermethylation of regulatory genes has been identified in a variety of sarcomas compared to non-neoplastic tissue.	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('Hypermethylation', 'Var', (0, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (98, 115))	('sarcomas', 'Disease', (73, 81))	('identified', 'Reg', (46, 56))
31930	22498582	In particular, methylation of MGMT, a DNA repair factor, has been reported to be associated with aggressive tumors.	('methylation', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('aggressive tumors', 'Disease', (97, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('MGMT', 'Gene', (30, 34))	('associated', 'Reg', (81, 91))	('MGMT', 'Gene', '4255', (30, 34))	('aggressive tumors', 'Disease', 'MESH:D001523', (97, 114))
31931	22498582	In addition, hypermethylation of CEBPA, a transcription factor involved in adipocytic differentiation, has been recently identified in 24% of dedifferentiated liposarcoma.	('identified', 'Reg', (121, 131))	('liposarcoma', 'Disease', 'MESH:D008080', (159, 170))	('CEBPA', 'Gene', (33, 38))	('liposarcoma', 'Phenotype', 'HP:0012034', (159, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('CEBPA', 'Gene', '1050', (33, 38))	('liposarcoma', 'Disease', (159, 170))	('hypermethylation', 'Var', (13, 29))
31932	22498582	Moreover, demethylation of CEBPA in dedifferentiated liposarcoma cell lines and xenografts resulted in growth inhibition.	('liposarcoma', 'Disease', (53, 64))	('liposarcoma', 'Disease', 'MESH:D008080', (53, 64))	('liposarcoma', 'Phenotype', 'HP:0012034', (53, 64))	('demethylation', 'Var', (10, 23))	('growth', 'MPA', (103, 109))	('CEBPA', 'Gene', (27, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('CEBPA', 'Gene', '1050', (27, 32))
31936	22498582	Dysregulation of AurKs has been reported in a variety of carcinomas, but little data is available on their role in mesenchymal neoplasms.	('Dysregulation', 'Var', (0, 13))	('AurKs', 'Gene', (17, 22))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (115, 136))	('mesenchymal neoplasms', 'Disease', (115, 136))	('reported', 'Reg', (32, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (127, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('carcinomas', 'Disease', (57, 67))	('carcinomas', 'Disease', 'MESH:D002277', (57, 67))
31937	22498582	Nevertheless, targeted therapy against AurK A and B has shown encouraging anti-tumor effects in in vitro and xenograft studies using Ewing sarcoma-derived cell lines, which appear to overexpress both AurK A and B.	('Ewing sarcoma', 'Disease', (133, 146))	('AurK A and B', 'Gene', '6790;9212', (200, 212))	('tumor', 'Disease', (79, 84))	('targeted', 'Var', (14, 22))	('AurK A and B', 'Gene', '6790;9212', (39, 51))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (133, 146))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (133, 146))	('overexpress', 'PosReg', (183, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
31947	22498582	Inhibition of p53-mediated apoptosis may protect tumor cells against chemotherapy and radiotherapy-mediated cell death.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))	('tumor', 'Disease', (49, 54))	('Inhibition', 'Var', (0, 10))
31948	22498582	Accordingly, preliminary studies targeting this pathway using antisense mRNA-mediated knockdown of bcl-2 have shown that loss of bcl-2 may induce apoptosis or sensitize cells to death from conventional chemotherapy.	('sensitize', 'Reg', (159, 168))	('bcl-2', 'Gene', (99, 104))	('bcl-2', 'Gene', '596', (129, 134))	('loss', 'Var', (121, 125))	('bcl-2', 'Gene', '596', (99, 104))	('induce', 'Reg', (139, 145))	('apoptosis', 'CPA', (146, 155))	('cells to death', 'CPA', (169, 183))	('bcl-2', 'Gene', (129, 134))
31955	22498582	In in vitro studies of malignant peripheral nerve sheath tumors (MPNSTs) treated with HDACis, autophagy has been shown to promote tumor survival, and inhibition of autophagy results in cell death.	('malignant peripheral nerve sheath tumors', 'Disease', (23, 63))	('inhibition', 'Var', (150, 160))	('cell death', 'CPA', (185, 195))	('autophagy', 'CPA', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (23, 63))	('promote', 'PosReg', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (23, 62))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (23, 63))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (130, 135))	('autophagy', 'CPA', (164, 173))
31966	22498582	Both inactivation of Rb or loss of p16INK4a, required to maintain activation of Rb, are frequently observed in UPS/MFH, while loss of RB1 is seen in leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), and osteosarcoma.	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (165, 204))	('MFH', 'Gene', '27086', (115, 118))	('UPS', 'Gene', (111, 114))	('UPS', 'Gene', '3145', (111, 114))	('RB1', 'Gene', (134, 137))	('leiomyosarcoma', 'Disease', (149, 163))	('loss', 'Var', (126, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (165, 204))	('p16INK4a', 'Gene', (35, 43))	('osteosarcoma', 'Disease', (218, 230))	('osteosarcoma', 'Disease', 'MESH:D012516', (218, 230))	('loss', 'Var', (27, 31))	('RB1', 'Gene', '5925', (134, 137))	('MFH', 'Gene', (115, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('p16INK4a', 'Gene', '1029', (35, 43))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (149, 163))	('malignant peripheral nerve sheath tumor', 'Disease', (165, 204))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (149, 163))	('inactivation', 'NegReg', (5, 17))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('osteosarcoma', 'Phenotype', 'HP:0002669', (218, 230))
31967	22498582	Loss of p16INK4a is also associated with tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('associated', 'Reg', (25, 35))	('tumor', 'Disease', (41, 46))	('p16INK4a', 'Gene', '1029', (8, 16))	('p16INK4a', 'Gene', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Loss', 'Var', (0, 4))
31970	22498582	The Akt pathway is normally activated by a growth factor binding to a RTK, but may also be activated by downstream events, including activating mutations in PIK3CA, as is seen in myxoid/round cell liposarcoma, or by loss of the inhibitor PTEN, which has been reported in leiomyosarcoma, and is associated with aggressive behavior.	('PIK3CA', 'Gene', (157, 163))	('liposarcoma', 'Phenotype', 'HP:0012034', (197, 208))	('activated', 'PosReg', (28, 37))	('PTEN', 'Gene', '5728', (238, 242))	('mutations', 'Var', (144, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (278, 285))	('liposarcoma', 'Disease', 'MESH:D008080', (197, 208))	('activated', 'PosReg', (91, 100))	('loss', 'NegReg', (216, 220))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (271, 285))	('Akt', 'Gene', (4, 7))	('activating', 'PosReg', (133, 143))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (271, 285))	('Akt', 'Gene', '207', (4, 7))	('PIK3CA', 'Gene', '5290', (157, 163))	('liposarcoma', 'Disease', (197, 208))	('aggressive behavior', 'Phenotype', 'HP:0000718', (310, 329))	('RTK', 'Gene', (70, 73))	('PTEN', 'Gene', (238, 242))	('leiomyosarcoma', 'Disease', (271, 285))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (179, 208))	('RTK', 'Gene', '5979', (70, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))
31971	22498582	PI3K activation in turn leads to activation of Akt, and subsequently, the mTOR complexes (mTORC) 1 and 2, which regulates protein translation and other cellular processes.	('PI3K', 'Var', (0, 4))	('activation', 'PosReg', (33, 43))	('mTOR complexes (mTORC) 1 and 2', 'Gene', '74343', (74, 104))	('regulates', 'Reg', (112, 121))	('Akt', 'Gene', '207', (47, 50))	('protein translation', 'MPA', (122, 141))	('Akt', 'Gene', (47, 50))
31972	22498582	A variety of RTK are overexpressed or constitutively activated in sarcoma, both in translocation associated sarcomas, as discussed above, and in karyotypically complex tumors.	('sarcoma', 'Disease', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('translocation', 'Var', (83, 96))	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('sarcoma', 'Disease', (108, 115))	('RTK', 'Gene', '5979', (13, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcomas', 'Disease', (108, 116))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('RTK', 'Gene', (13, 16))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
31979	22498582	The RTK MET has been shown to be activated in MPNST, and in preclinical studies, inhibition of MET with the targeted agent XL184 led to reduction of metastatic potential.	('MET', 'Gene', (95, 98))	('inhibition', 'Var', (81, 91))	('metastatic potential', 'CPA', (149, 169))	('RTK', 'Gene', '5979', (4, 7))	('reduction', 'NegReg', (136, 145))	('RTK', 'Gene', (4, 7))
31983	22498582	One difficulty with mTORC1-inhibitors such as sirolimus and temsirolimus is that blockade of mTOR often leads to paradoxical increase in PI3K and Akt activity.	('sirolimus', 'Chemical', 'MESH:D020123', (63, 72))	('mTORC1', 'Gene', '382056', (20, 26))	('mTOR', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (93, 97))	('increase', 'PosReg', (125, 133))	('blockade', 'Var', (81, 89))	('Akt', 'Gene', (146, 149))	('PI3K', 'Pathway', (137, 141))	('sirolimus', 'Chemical', 'MESH:D020123', (46, 55))	('Akt', 'Gene', '207', (146, 149))	('mTORC1', 'Gene', (20, 26))	('temsirolimus', 'Chemical', 'MESH:C401859', (60, 72))	('mTOR', 'Gene', '2475', (20, 24))	('mTOR', 'Gene', (20, 24))
31987	22498582	The Ras pathway is involved in cell proliferation, survival, differentiation and angiogenesis as well as in motility and invasion, and may cross-activate the Akt pathway via PI3K.	('PI3K', 'Var', (174, 178))	('Akt', 'Gene', '207', (158, 161))	('Ras pathway', 'Pathway', (4, 15))	('cross-activate', 'PosReg', (139, 153))	('Akt', 'Gene', (158, 161))
31988	22498582	Activating RAS mutations have been found in leiomyosarcoma and UPS/MFH, and activation of downstream factors MEK and ERK have been described in UPS/MFH, and osteosarcoma, among others.	('Activating', 'PosReg', (0, 10))	('osteosarcoma', 'Disease', (157, 169))	('osteosarcoma', 'Disease', 'MESH:D012516', (157, 169))	('ERK', 'Gene', (117, 120))	('UPS', 'Gene', '3145', (144, 147))	('RAS', 'Protein', (11, 14))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (44, 58))	('UPS', 'Gene', '3145', (63, 66))	('MEK', 'Gene', (109, 112))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (44, 58))	('mutations', 'Var', (15, 24))	('UPS', 'Gene', (63, 66))	('MFH', 'Gene', (67, 70))	('MFH', 'Gene', (148, 151))	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('leiomyosarcoma', 'Disease', (44, 58))	('ERK', 'Gene', '5594', (117, 120))	('MFH', 'Gene', '27086', (67, 70))	('MFH', 'Gene', '27086', (148, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('activation', 'PosReg', (76, 86))	('MEK', 'Gene', '5609', (109, 112))	('UPS', 'Gene', (144, 147))
31989	22498582	BRAF, an intermediary in the Ras pathway, has been shown to be mutated in a minority of GIST lacking KIT or PDGFRA mutations.	('mutated', 'Var', (63, 70))	('mutations', 'Var', (115, 124))	('KIT', 'Gene', (101, 104))	('PDGFRA', 'Gene', '5156', (108, 114))	('PDGFRA', 'Gene', (108, 114))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
31990	22498582	V600E mutant B-raf, as found in a tiny subset of GIST, may be targeted by vemurafenib, which has not been well-studied in sarcoma.	('B-raf', 'Gene', (13, 18))	('B-raf', 'Gene', '673', (13, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('sarcoma', 'Disease', (122, 129))	('vemurafenib', 'Chemical', 'MESH:D000077484', (74, 85))	('V600E', 'Var', (0, 5))
31993	22498582	The data with vemurafenib in V600E mutant melanoma indicate the importance of the specificity of the inhibitor for the driving mutant kinase.	('melanoma', 'Disease', (42, 50))	('V600E', 'Mutation', 'rs113488022', (29, 34))	('vemurafenib', 'Chemical', 'MESH:D000077484', (14, 25))	('V600E', 'Var', (29, 34))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
32006	22498582	Preclinical studies have suggested that inhibition of Notch may reduce the invasiveness of both osteosarcoma and rhabdomyosarcoma, and promote differentiation of rhabdomyosarcoma.	('Notch', 'Gene', (54, 59))	('promote', 'PosReg', (135, 142))	('inhibition', 'Var', (40, 50))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (162, 178))	('reduce', 'NegReg', (64, 70))	('rhabdomyosarcoma', 'Disease', (113, 129))	('osteosarcoma', 'Phenotype', 'HP:0002669', (96, 108))	('osteosarcoma and rhabdomyosarcoma', 'Disease', 'MESH:D012516', (96, 129))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (113, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (162, 178))	('invasiveness', 'CPA', (75, 87))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (113, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('differentiation', 'CPA', (143, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('rhabdomyosarcoma', 'Disease', (162, 178))
32007	22498582	However, the effects of Notch signaling appear to be tumor type-specific, as Notch family members may act as either oncogenes or tumor suppressors, and activation of Notch in Ewing sarcoma cell lines led to growth inhibition.	('growth inhibition', 'CPA', (207, 224))	('Ewing sarcoma', 'Disease', (175, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Notch', 'Gene', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (175, 188))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (175, 188))	('tumor', 'Disease', (53, 58))	('activation', 'Var', (152, 162))	('tumor', 'Disease', (129, 134))
32008	22498582	The gamma secretase inhibitor RO4929097 which blocks notch signaling by preventing cleavage of the activated intracellular domain of Notch from the transmembrane domain is currently in phase I/II trials.	('RO4929097', 'Var', (30, 39))	('cleavage', 'MPA', (83, 91))	('RO4929097', 'Chemical', 'MESH:C545185', (30, 39))
32012	22498582	Moreover, inhibition of hedgehog pathway signaling reduced proliferation of embryonal rhabdomyosarcoma cell lines.	('hedgehog pathway signaling', 'Pathway', (24, 50))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (76, 102))	('reduced', 'NegReg', (51, 58))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (76, 102))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (86, 102))	('inhibition', 'Var', (10, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('embryonal rhabdomyosarcoma', 'Disease', (76, 102))
32018	22498582	Future clinical trials will need to more specifically select patients with appropriate molecular alterations for the therapy tested, and examine groups of specific agents to better achieve the goal of truly personalized treatment for sarcoma.	('sarcoma', 'Disease', (234, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('patients', 'Species', '9606', (61, 69))	('alterations', 'Var', (97, 108))	('sarcoma', 'Disease', 'MESH:D012509', (234, 241))
32105	31164960	We demonstrated that blocking PD-1 results in a greater increase of T-cell mediated killing of EWS-FLI1 low tumor cells as compared to cells with higher EWS-FLI1 expression.	('low tumor', 'Disease', 'MESH:D009800', (104, 113))	('EWS-FLI1', 'Gene', (95, 103))	('increase', 'PosReg', (56, 64))	('PD-1', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('low tumor', 'Disease', (104, 113))	('blocking', 'Var', (21, 29))	('T-cell mediated killing', 'CPA', (68, 91))	('increase of T-cell', 'Phenotype', 'HP:0100828', (56, 74))
32118	31164960	Individual Ewing cells within a tumor can express highly variable levels of the EWS-FLI1 fusion oncoprotein, and this variation in EWS-FLI1 expression can significantly alter tumor cell behavior, with cells harboring lower EWS-FLI1 levels showing increased capability to seed the lung, upregulate tenascin-C expression and metastasize.	('alter', 'Reg', (169, 174))	('expression', 'MPA', (308, 318))	('EWS-FLI1', 'Gene', (131, 139))	('tenascin-C', 'Protein', (297, 307))	('metastasize', 'CPA', (323, 334))	('seed', 'CPA', (271, 275))	('variation', 'Var', (118, 127))	('tumor', 'Disease', (175, 180))	('lower', 'NegReg', (217, 222))	('lung', 'Disease', 'MESH:D008171', (280, 284))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('lung', 'Disease', (280, 284))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('EWS-FLI1', 'Gene', (223, 231))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('upregulate', 'PosReg', (286, 296))
32126	31164960	We hypothesized that since EWS-FLI1 low cells express ICAM-1, these cells would be more capable of T-cell engagement as compared to EWS-FLI1 high cells and as a result, EWS-FLI1 low cells would be more susceptible to T-cell mediated apoptosis.	('T-cell mediated apoptosis', 'CPA', (217, 242))	('ICAM-1', 'Gene', '3383', (54, 60))	('EWS-FLI1 low', 'Var', (27, 39))	('more', 'PosReg', (83, 87))	('T-cell', 'Protein', (99, 105))	('ICAM-1', 'Gene', (54, 60))
32164	31164960	We predicted that EWS-FLI1 'low' cells would be more susceptible to T-cell mediated killing compared to EWS-FLI1 'high' cells given that: 1) EWS-FLI1 'low' cells demonstrate greater basal and IFN-gamma inducible ICAM-1 expression, 2) tumor cell ICAM-1 has been shown to enhance T-cell activation in multiple cancers and 3) blocking tumor ICAM-1 reduces T-cell mediated Ewing tumor cell apoptosis in our system.	('Ewing tumor', 'Disease', (369, 380))	('IFN-gamma', 'Gene', (192, 201))	('multiple cancers', 'Disease', (299, 315))	('tumor', 'Disease', (234, 239))	('IFN-gamma', 'Gene', '3458', (192, 201))	('ICAM-1', 'Gene', '3383', (245, 251))	('T-cell', 'CPA', (278, 284))	('reduces', 'NegReg', (345, 352))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('ICAM-1', 'Gene', '3383', (212, 218))	('ICAM-1', 'Gene', '3383', (338, 344))	('tumor', 'Disease', (375, 380))	('blocking', 'Var', (323, 331))	('enhance T-cell activation', 'Phenotype', 'HP:0005419', (270, 295))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('cancers', 'Phenotype', 'HP:0002664', (308, 315))	('multiple cancers', 'Disease', 'MESH:D009369', (299, 315))	('Ewing tumor', 'Phenotype', 'HP:0012254', (369, 380))	('ICAM-1', 'Gene', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('tumor', 'Disease', (332, 337))	('ICAM-1', 'Gene', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('expression', 'MPA', (219, 229))	('Ewing tumor', 'Disease', 'MESH:C563168', (369, 380))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('ICAM-1', 'Gene', (338, 344))	('enhance', 'PosReg', (270, 277))	('greater', 'PosReg', (174, 181))
32166	31164960	No appreciable difference in tumor cell apoptosis was observed in the absence of T-cells for either control or EWS-FLI1siRNA treated cells (Figure 5E, 5F).	('EWS-FLI1siRNA', 'Var', (111, 124))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))
32177	31164960	We found that following IFN-gamma treatment, both CD274 (PD-L1) and PDCD1LG2 (PD-L2) mRNA is upregulated significantly more in EWS-FLI1 low cells compared to EWS-FLI1 high cells (Figure 6A, 6B).	('IFN-gamma', 'Gene', (24, 33))	('PDCD1LG2', 'Gene', (68, 76))	('CD274', 'Gene', (50, 55))	('EWS-FLI1 low', 'Var', (127, 139))	('mRNA', 'MPA', (85, 89))	('upregulated', 'PosReg', (93, 104))	('CD274', 'Gene', '29126', (50, 55))	('PDCD1LG2', 'Gene', '80380', (68, 76))	('IFN-gamma', 'Gene', '3458', (24, 33))
32179	31164960	We thus examined the impact of PD-1 blockade on the susceptibility of EWS-FLI1 high and low tumor cell susceptibility to T-cell mediated apoptosis and found that PD-1 blockade enhances T-cell mediated tumor cell apoptosis to a greater degree for the EWS-FLI1 low cells (Figure 6C).	('low tumor', 'Disease', 'MESH:D009800', (88, 97))	('blockade', 'Var', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('PD-1', 'Gene', (162, 166))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (201, 206))	('low tumor', 'Disease', (88, 97))	('enhances', 'PosReg', (176, 184))
32193	31164960	Published data has shown that EWS-FLI1 low cells typically represent only a minority of the cells within Ewing tumors (1-2%) and we have now shown that EWS-FLI1 low cells can upregulate PD-L1 and PD-L2 expression and undergo enhanced T-cell mediated tumor cell apoptosis in response to blocking PD-1.	('P', 'Chemical', 'MESH:D010758', (196, 197))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('expression', 'MPA', (202, 212))	('P', 'Chemical', 'MESH:D010758', (186, 187))	('PD-L2', 'Gene', (196, 201))	('tumor', 'Disease', (250, 255))	('Ewing tumors', 'Phenotype', 'HP:0012254', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('low', 'Var', (161, 164))	('Ewing tumors', 'Disease', 'MESH:C563168', (105, 117))	('P', 'Chemical', 'MESH:D010758', (295, 296))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('Ewing tumor', 'Phenotype', 'HP:0012254', (105, 116))	('EWS-FLI1', 'Gene', (152, 160))	('PD-L1', 'Gene', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Ewing tumors', 'Disease', (105, 117))	('upregulate', 'PosReg', (175, 185))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('enhanced', 'PosReg', (225, 233))
32218	31164960	Q-PCR analysis was performed using TaqMan probes (ThermoFisher Scientific: EWS-FLI1 Hs03024497_ft, GAPDH Hs02786624_g1, RPLP0 Hs00420895_gH, ICAM-1 Hs00164932_m1, PD-L1 Hs00204257_m1, PD-L2 Hs00228839), Taqman Universal PCR Master Mix (Applied Biosystems, cat #4304437) and StepOnePlus Real-Time PCR system.	('P', 'Chemical', 'MESH:D010758', (220, 221))	('S', 'Chemical', 'MESH:D013455', (77, 78))	('P', 'Chemical', 'MESH:D010758', (163, 164))	('P', 'Chemical', 'MESH:D010758', (281, 282))	('GAPDH', 'Gene', (99, 104))	('P', 'Chemical', 'MESH:D010758', (123, 124))	('P', 'Chemical', 'MESH:D010758', (296, 297))	('P', 'Chemical', 'MESH:D010758', (121, 122))	('RPLP0', 'Gene', '6175', (120, 125))	('S', 'Chemical', 'MESH:D013455', (274, 275))	('P', 'Chemical', 'MESH:D010758', (184, 185))	('P', 'Chemical', 'MESH:D010758', (2, 3))	('ICAM-1', 'Gene', (141, 147))	('Mix', 'Gene', '83881', (231, 234))	('S', 'Chemical', 'MESH:D013455', (63, 64))	('Mix', 'Gene', (231, 234))	('Hs03024497_ft', 'Var', (84, 97))	('Hs02786624_g1', 'Var', (105, 118))	('P', 'Chemical', 'MESH:D010758', (101, 102))	('GAPDH', 'Gene', '2597', (99, 104))	('ICAM-1', 'Gene', '3383', (141, 147))	('RPLP0', 'Gene', (120, 125))
32224	31164960	Conjugated antibodies used for analysis included ICAM1-APC (Invitrogen cat # L10119, 17-0549-42, L34957), IgG1 isotype control, PD-L1 PE (R&D cat#FAB1561P) and PD-L2 PE (Invitrogen cat #12-5888-42).	('P', 'Chemical', 'MESH:D010758', (160, 161))	('L34957', 'Var', (97, 103))	('P', 'Chemical', 'MESH:D010758', (134, 135))	('ICAM1-APC', 'Disease', 'MESH:D011125', (49, 58))	('P', 'Chemical', 'MESH:D010758', (166, 167))	('ICAM1-APC', 'Disease', (49, 58))	('P', 'Chemical', 'MESH:D010758', (56, 57))	('P', 'Chemical', 'MESH:D010758', (128, 129))	('P', 'Chemical', 'MESH:D010758', (153, 154))
32236	31164960	The LightSwitch Luciferase Assay Kit (#32031), GoClone human ICAM1 promoter reporter (S708388), LightSwitch positive control RPL10 promoter (#32006) and negative control LightSwitch random promoter (#32006) were purchased from Active Motif (Carlsbad, CA, USA) and used in experiments according to the manufacturer's instructions.	('ICAM1', 'Gene', '3383', (61, 66))	('S', 'Chemical', 'MESH:D013455', (86, 87))	('#32031', 'Var', (38, 44))	('ICAM1', 'Gene', (61, 66))	('S', 'Chemical', 'MESH:D013455', (9, 10))	('human', 'Species', '9606', (55, 60))	('S', 'Chemical', 'MESH:D013455', (256, 257))	('RPL10', 'Gene', '6134', (125, 130))	('S', 'Chemical', 'MESH:D013455', (101, 102))	('RPL10', 'Gene', (125, 130))	('#32006', 'Var', (199, 205))	('S708388', 'Var', (86, 93))	('S', 'Chemical', 'MESH:D013455', (175, 176))	('#32006', 'Var', (141, 147))
32257	30378256	Eribulin also blocks the cell cycle at the G2-M phase and is active in taxane-resistant cell lines with beta-tubulin mutations.	('beta-tubulin', 'Protein', (104, 116))	('mutations', 'Var', (117, 126))	('Eribulin', 'Chemical', 'MESH:C490954', (0, 8))	('taxane', 'Chemical', 'MESH:C080625', (71, 77))	('blocks', 'NegReg', (14, 20))	('cell cycle at the G2-M phase', 'CPA', (25, 53))
32266	30378256	The results of this study demonstrated an improved overall survival in the eribulin group (median OS 13.5 months) compared to the dacarbazine group (median OS 11.5 months).	('eribulin', 'Var', (75, 83))	('dacarbazine', 'Chemical', 'MESH:D003606', (130, 141))	('eribulin', 'Chemical', 'MESH:C490954', (75, 83))	('improved', 'PosReg', (42, 50))	('overall survival', 'MPA', (51, 67))
32277	30378256	Based on accrual rates of patients with osteosarcoma from three prior COG studies, ADVL0421, ADVL0524 and ADVL0525, approximately 18 patients (1.5 patients per month) were expected to enroll annually.	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('ADVL0524', 'Chemical', 'MESH:C518174', (93, 101))	('patients', 'Species', '9606', (133, 141))	('ADVL0524', 'Var', (93, 101))	('patients', 'Species', '9606', (26, 34))	('ADVL0421', 'Var', (83, 91))	('patients', 'Species', '9606', (147, 155))	('ADVL0525', 'Var', (106, 114))	('ADVL0421', 'Chemical', 'None', (83, 91))	('osteosarcoma', 'Disease', (40, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (40, 52))	('osteosarcoma', 'Disease', 'MESH:D012516', (40, 52))	('ADVL0525', 'Chemical', 'None', (106, 114))
32351	30410352	In 85% of patients, the FLI1 gene on chromosome 11q24 is involved, leading to an aberrant EWS-ETS transcription factor.	('EWS', 'Gene', (90, 93))	('aberrant', 'Var', (81, 89))	('FLI1', 'Gene', '2313', (24, 28))	('FLI1', 'Gene', (24, 28))	('EWS', 'Gene', '2130', (90, 93))	('patients', 'Species', '9606', (10, 18))
32360	30410352	The mechanisms by which Ewing's sarcoma becomes resistant to chemotherapy are varied and may involve cancer stem cells, proliferative intracellular pathways, and new mutations that allow tumor cells to escape the effect of chemotherapy.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (24, 39))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('mutations', 'Var', (166, 175))	('cancer', 'Disease', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (24, 39))	("Ewing's sarcoma", 'Disease', (24, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
32363	30410352	In the present study, two mRNA microarray datasets, GSE12102 and GSE17679, were downloaded from the Gene Expression Omnibus (GEO) database, and a total of 94 human Ewing's sarcoma samples were selected from these two datasets.	("Ewing's sarcoma", 'Disease', (164, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('human', 'Species', '9606', (158, 163))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (164, 179))	('GSE12102', 'Var', (52, 60))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (164, 179))
32396	30410352	Changes in the TIMELESS gene or its expression may promote the development of various cancers.	('TIMELESS', 'Gene', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TIMELESS', 'Gene', '8914', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('promote', 'PosReg', (51, 58))	('Changes', 'Var', (0, 7))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('expression', 'MPA', (36, 46))
32411	30410352	One report has shown that GAPDH can interact with proteins that recognize these damages and participate in DNA repair.	('GAPDH', 'Gene', '2597', (26, 31))	('interact', 'Interaction', (36, 44))	('participate', 'Reg', (92, 103))	('proteins', 'Protein', (50, 58))	('damages', 'Var', (80, 87))	('DNA', 'CPA', (107, 110))	('GAPDH', 'Gene', (26, 31))
32423	30410352	Elevated EHMT2 induces development and progression of various cancers by regulating cancer metabolism, metastasis, cell survival, and response to hypoxia.	('EHMT2', 'Gene', '10919', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('hypoxia', 'Disease', (146, 153))	('cell survival', 'CPA', (115, 128))	('hypoxia', 'Disease', 'MESH:D000860', (146, 153))	('induces', 'Reg', (15, 22))	('cancer', 'Disease', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('development', 'CPA', (23, 34))	('cancer', 'Disease', (84, 90))	('progression', 'CPA', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('EHMT2', 'Gene', (9, 14))	('regulating', 'Reg', (73, 83))	('Elevated', 'Var', (0, 8))	('metastasis', 'CPA', (103, 113))
32475	29026517	Further studies are needed to determine the exact mechanisms underlying altered PDGF-B expression in the malignant transformation of vascular malformations.	('PDGF-B', 'Gene', (80, 86))	('altered', 'Var', (72, 79))	('PDGF-B', 'Gene', '5155', (80, 86))	('vascular malformations', 'Disease', (133, 155))	('vascular malformations', 'Disease', 'MESH:D000014', (133, 155))
32490	27496711	Similarly, subtypes of NSCLC with EML4-ALK translocation or mutant EGFR respond to crizotinib and erlotinib, respectively, whereas these agents have little impact on survival in unselected patients.	('crizotinib', 'Chemical', 'MESH:D000077547', (83, 93))	('ALK', 'Gene', (39, 42))	('EML4', 'Gene', (34, 38))	('respond', 'Reg', (72, 79))	('erlotinib', 'Chemical', 'MESH:D000069347', (98, 107))	('NSCLC', 'Disease', (23, 28))	('ALK', 'Gene', '238', (39, 42))	('EML4', 'Gene', '27436', (34, 38))	('EGFR', 'Gene', '1956', (67, 71))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('EGFR', 'Gene', (67, 71))	('mutant', 'Var', (60, 66))	('patients', 'Species', '9606', (189, 197))
32499	27496711	In PPTP studies examples of agents for which subsets of tumors are hypersensitive to treatment include the MEK inhibitor, selumetinib, for which a single tumor with a BRAF mutation responded, whereas 45 other models failed to respond; the oncolytic virus NTX-010 for which there was selective sensitivity of neuroblastoma and alveolar rhabdomyosarcoma models, and the PARP inhibitor talazoparib for which xenografts with DNA damage repair defects responded.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutation', 'Var', (172, 180))	('tumors', 'Disease', (56, 62))	('hypersensitive', 'Disease', 'MESH:D004342', (67, 81))	('PARP', 'Gene', '11545', (368, 372))	('tumor', 'Disease', (154, 159))	('neuroblastoma and alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (308, 351))	('MEK', 'Gene', '17242', (107, 110))	('PARP', 'Gene', (368, 372))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('neuroblastoma', 'Phenotype', 'HP:0003006', (308, 321))	('selumetinib', 'Chemical', 'MESH:C517975', (122, 133))	('NTX-010', 'Chemical', '-', (255, 262))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (335, 351))	('tumor', 'Disease', (56, 61))	('talazoparib', 'Chemical', 'MESH:C586365', (383, 394))	('MEK', 'Gene', (107, 110))	('hypersensitive', 'Disease', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PPTP', 'Chemical', '-', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (326, 351))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (344, 351))
32500	27496711	Even within Ewing sarcoma models with a common etiology as a consequence of the oncogenic EWS/FLI1 fusion, only 5 of 10 xenograft models were highly sensitive to combination treatment with temozolomide and a PARP inhibitor and only 1 of 5 xenograft models was sensitive to the IGF-1R inhibitor SCH 717454.	('PARP', 'Gene', (208, 212))	('Ewing sarcoma', 'Disease', (12, 25))	('fusion', 'Var', (99, 105))	('EWS', 'Gene', (90, 93))	('PARP', 'Gene', '11545', (208, 212))	('FLI1', 'Gene', '14247', (94, 98))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (12, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('FLI1', 'Gene', (94, 98))	('SCH 717454', 'Chemical', 'MESH:C573312', (294, 304))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (12, 25))	('temozolomide', 'Chemical', 'MESH:D000077204', (189, 201))	('IGF-1R', 'Gene', (277, 283))	('EWS', 'Gene', '14030', (90, 93))	('IGF-1R', 'Gene', '16001', (277, 283))
32549	27496711	The four models having the highest proportions of accurate predictions were B10, F11, F10 and F2, with correct prediction rates of 84.9%, 85.6%, 86.2% and 87.5% respectively (see Table 1 for tumor line identity and type).	('F10', 'Var', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('B10', 'Gene', (76, 79))	('F11', 'Var', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('B10', 'Gene', '14940', (76, 79))
32557	27496711	Analysis of exomic mutations in the four 'best' and three of the four 'worst' showed a similar low mutation frequency in tumors with good predictive activity (range 2-8 mutations/model) as those with poorer predictive value (range 2-7 mutations/model), Supplemental Table 4).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (121, 127))
32579	27496711	RG7112 was tested in a larger cohort of infant MLL and showed marked activity against all infant-derived models.	('MLL', 'Gene', '4297', (47, 50))	('activity', 'MPA', (69, 77))	('RG7112', 'Var', (0, 6))	('MLL', 'Gene', (47, 50))	('infant', 'Species', '9606', (90, 96))	('infant', 'Species', '9606', (40, 46))
32581	27496711	For antibodies that block ligand binding to the Type 1 insulin-like growth factor receptor (IGF1R), the only meaningful activity was identified in sarcoma models at relatively low frequency (Ewing sarcoma (1 of 5), rhabdomyosarcomas (1 of 5), and osteosarcomas (2 of 6) consistent with clinical data in sarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (247, 259))	('sarcoma', 'Disease', 'MESH:D012509', (252, 259))	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (303, 310))	('sarcoma', 'Disease', (197, 204))	('ligand binding', 'Interaction', (26, 40))	('sarcoma', 'Disease', (252, 259))	('antibodies', 'Var', (4, 14))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (215, 232))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (191, 204))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (191, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('IGF1R', 'Gene', '16001', (92, 97))	('sarcomas', 'Disease', 'MESH:D012509', (252, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('sarcoma', 'Disease', (147, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (252, 260))	('osteosarcoma', 'Disease', (247, 259))	('sarcomas', 'Disease', (252, 260))	('osteosarcoma', 'Disease', 'MESH:D012516', (247, 259))	('growth factor receptor', 'Gene', '20187', (68, 90))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (215, 231))	('sarcoma', 'Disease', 'MESH:D012509', (224, 231))	('sarcoma', 'Disease', 'MESH:D012509', (303, 310))	('Ewing sarcoma', 'Disease', (191, 204))	('sarcomas', 'Disease', 'MESH:D012509', (224, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (224, 232))	('sarcoma', 'Disease', (224, 231))	('sarcoma', 'Disease', (303, 310))	('IGF1R', 'Gene', (92, 97))	('sarcomas', 'Disease', (224, 232))	('growth factor receptor', 'Gene', (68, 90))	('osteosarcomas', 'Phenotype', 'HP:0002669', (247, 260))
32602	27496711	For alveolar rhabdomyosarcoma all 7 xenograft models are characterized by the reciprocal chromosomal translocation t(2;13) encoding the Pax3-Foxo1 chimeric transcription factor, but only one model has an activating mutation in the kinase domain of FGFR4, consistent with clinical data.	('mutation', 'Var', (215, 223))	('FGFR4', 'Gene', (248, 253))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (13, 29))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (4, 29))	('FGFR4', 'Gene', '14186', (248, 253))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (4, 29))	('Foxo1', 'Gene', (141, 146))	('activating', 'PosReg', (204, 214))	('Pax3', 'Gene', '18505', (136, 140))	('Pax3', 'Gene', (136, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('alveolar rhabdomyosarcoma', 'Disease', (4, 29))	('Foxo1', 'Gene', '56458', (141, 146))
32606	27496711	Further, 'exceptional responders' to kinase inhibitors were identified only in models where there was an activating mutation that predisposed the tumor to drug sensitivity.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mutation', 'Var', (116, 124))	('tumor', 'Disease', (146, 151))	('drug', 'MPA', (155, 159))	('predisposed', 'Reg', (130, 141))	('drug sensitivity', 'Phenotype', 'HP:0020174', (155, 171))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
32680	26636923	If glucocorticoids suppress natural killer cell activity, and these cells play an important role against cancer, glucocorticoids might give rise to aberrations in the immune surveillance, which may lead to subsequent conditions favourable to oncogenesis.	('immune surveillance', 'CPA', (167, 186))	('lead to', 'Reg', (198, 205))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('natural killer cell activity', 'CPA', (28, 56))	('suppress', 'NegReg', (19, 27))	('glucocorticoids', 'Var', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('give rise to', 'Reg', (135, 147))	('oncogenesis', 'CPA', (242, 253))
32693	24239359	To investigate the myogenic cell(s) of origin of these sarcomas, we used Pax7-CreER and MyoD-CreER mice to transform Pax7+ and MyoD+ myogenic progenitors by expressing oncogenic KrasG12D and deleting p53 in vivo.	('KrasG12D', 'Var', (178, 186))	('mice', 'Species', '10090', (99, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('p53', 'Gene', (200, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcomas', 'Disease', (55, 63))	('p53', 'Gene', '22059', (200, 203))	('deleting', 'Var', (191, 199))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))
32700	24239359	Here, using inducible CreER mice, we mutate genes relevant to human RMS specifically in Pax7-expressing or MyoD-expressing cells.	('human', 'Species', '9606', (62, 67))	('genes', 'Gene', (44, 49))	('mice', 'Species', '10090', (28, 32))	('RMS', 'Phenotype', 'HP:0002859', (68, 71))	('RMS', 'Disease', (68, 71))	('mutate', 'Var', (37, 43))
32715	24239359	Here, we used mice that express tamoxifen-inducible CreER from either the endogenous Pax7 or MyoD promoters to simultaneously drive expression of oncogenic Kras and delete Trp53.	('delete', 'Var', (165, 171))	('tamoxifen', 'Chemical', 'MESH:D013629', (32, 41))	('Trp53', 'Gene', (172, 177))	('mice', 'Species', '10090', (14, 18))	('drive', 'PosReg', (126, 131))	('expression', 'MPA', (132, 142))	('Kras', 'Gene', (156, 160))
32725	24239359	Therefore, transformation of Pax7+ myogenic progenitors in vivo gives rise to a spectrum of sarcomas ranging from RMS to UPS.	('transformation', 'Var', (11, 25))	('UPS', 'Gene', (121, 124))	('sarcomas', 'Disease', (92, 100))	('RMS', 'Disease', (114, 117))	('RMS', 'Phenotype', 'HP:0002859', (114, 117))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('UPS', 'Gene', '15288', (121, 124))	('gives rise to', 'Reg', (64, 77))
32726	24239359	Given the spectrum of sarcomas that arose in the P7KP mice, we hypothesized that different subpopulations of Pax7+ cells give rise to RMS and UPS because Pax7 is expressed in quiescent satellite cells, activated satellite cells, and myoblasts.	('sarcomas', 'Disease', (22, 30))	('give rise', 'Reg', (121, 130))	('Pax7+', 'Gene', (109, 114))	('RMS', 'Phenotype', 'HP:0002859', (134, 137))	('UPS', 'Gene', (142, 145))	('P7KP', 'Var', (49, 53))	('mice', 'Species', '10090', (54, 58))	('RMS', 'CPA', (134, 137))	('sarcomas', 'Disease', 'MESH:D012509', (22, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('Pax7', 'Gene', (154, 158))	('UPS', 'Gene', '15288', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))
32737	24239359	To ascertain if MyoDCE/+ mice drive tamoxifen-inducible Cre activity in differentiating myogenic progenitors in vivo, we injured the tibialis anterior (TA) muscles of Pax7CE/+;R26mTmG/+ and MyoDCE/+;R26mTmG/mTmG mice to induce satellite cell activation.	('mice', 'Species', '10090', (25, 29))	('mice', 'Species', '10090', (212, 216))	('tamoxifen', 'Chemical', 'MESH:D013629', (36, 45))	('MyoDCE/+;R26mTmG/mTmG', 'Var', (190, 211))	('satellite cell activation', 'CPA', (227, 252))	('Pax7CE/+;R26mTmG/+', 'Var', (167, 185))
32742	24239359	To assess the spectrum of sarcomas generated from MyoD+ cells, we crossed the MyoDCE/+ mice to LSL-KrasG12D/+;Trp53Fl/Fl mice to generate MyoDCE/+; LSL-KrasG12D/+;Trp53Fl/Fl mice, hereafter referred to as MDKP mice.	('sarcomas', 'Disease', (26, 34))	('mice', 'Species', '10090', (210, 214))	('mice', 'Species', '10090', (174, 178))	('mice', 'Species', '10090', (87, 91))	('MyoDCE/+; LSL-KrasG12D/+;Trp53Fl/Fl', 'Var', (138, 173))	('mice', 'Species', '10090', (121, 125))	('sarcomas', 'Disease', 'MESH:D012509', (26, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))
32745	24239359	Interestingly, MDKP mice developed tumors with increased latency with a median tumor-free survival of 153 days compared to P7KP mice, which developed tumors at a median time of 44 days (Figure 1A vs.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mice', 'Species', '10090', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mice', 'Species', '10090', (128, 132))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('MDKP', 'Var', (15, 19))
32750	24239359	The anatomic distribution of the tumors derived from the MDKP mice was similar to the tumors in the PK7P mice and included the extremities, body wall, and the head and neck region (Figure 3F).	('mice', 'Species', '10090', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('MDKP', 'Var', (57, 61))	('mice', 'Species', '10090', (62, 66))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))
32754	24239359	When examining the first principal component scores, we found that the P7KP derived eRMS-like tumors clustered separately from MDKP and P7KP derived UPS-like tumors (Figure 4A).	('tumors', 'Disease', (158, 164))	('RMS', 'Phenotype', 'HP:0002859', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('UPS-like tumors', 'Disease', (149, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('UPS-like tumors', 'Disease', 'MESH:D017118', (149, 164))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('P7KP', 'Var', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
32756	24239359	P7KP derived pRMS-like tumors did not cluster together using the first principal component scores and were distributed evenly throughout the clusters of other subtypes, suggesting that they do not represent a distinct subtype at the molecular level.	('P7KP derived', 'Var', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('RMS', 'Phenotype', 'HP:0002859', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('pRMS-like', 'Disease', (13, 22))
32757	24239359	In good agreement with the PCA results, hierarchical clustering demonstrated that MDKP derived tumors tend to cluster more closely with P7KP derived UPS-like tumors (UPS-like clade) compared to P7KP derived eRMS-like and pRMS-like tumors, which tended to cluster into a separate group (RMS-like clade) (Figure 4B).	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('RMS', 'Phenotype', 'HP:0002859', (222, 225))	('UPS', 'Gene', (149, 152))	('MDKP', 'Var', (82, 86))	('UPS', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('UPS', 'Gene', '15288', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (231, 237))	('tumors', 'Disease', (95, 101))	('UPS', 'Gene', '15288', (166, 169))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('UPS-like tumors', 'Disease', (149, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('UPS-like tumors', 'Disease', 'MESH:D017118', (149, 164))	('RMS', 'Phenotype', 'HP:0002859', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('RMS', 'Phenotype', 'HP:0002859', (286, 289))	('P7KP', 'Var', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
32763	24239359	We defined a gene set comprised of the genes most significantly (p< 0.0001) upregulated in P7KP RMS (eRMS and pRMS) compared to the UPS derived from the MDKP mice (Figure 4C; Figure S4A).	('RMS', 'Phenotype', 'HP:0002859', (102, 105))	('P7KP RMS', 'Var', (91, 99))	('mice', 'Species', '10090', (158, 162))	('UPS', 'Gene', (132, 135))	('RMS', 'Phenotype', 'HP:0002859', (96, 99))	('RMS', 'Phenotype', 'HP:0002859', (111, 114))	('upregulated', 'PosReg', (76, 87))	('UPS', 'Gene', '15288', (132, 135))
32764	24239359	Then, we used GSEA to test whether this gene set upregulated in the P7KP RMS tumors could be used to distinguish between human RMS and other human soft tissue sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (159, 167))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (147, 167))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('RMS tumors', 'Disease', (73, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('RMS', 'Phenotype', 'HP:0002859', (127, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('sarcomas', 'Disease', (159, 167))	('human', 'Species', '9606', (121, 126))	('human', 'Species', '9606', (141, 146))	('upregulated', 'PosReg', (49, 60))	('RMS tumors', 'Disease', 'MESH:D009369', (73, 83))	('RMS', 'Phenotype', 'HP:0002859', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (147, 166))	('P7KP', 'Var', (68, 72))	('GSEA', 'Chemical', '-', (14, 18))	('RMS', 'Disease', (127, 130))
32766	24239359	In good agreement with the histological data, when the gene set comprised of genes upregulated in the P7KP RMS was applied to a human dataset of multiple soft tissue sarcoma subtypes, the P7KP derived mouse RMS enriched in human RMS, validating this system as a model for human RMS (Figure 4C, p=0.002, NES=1.88, FDR=0.024).	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('human', 'Species', '9606', (272, 277))	('human', 'Species', '9606', (223, 228))	('sarcoma', 'Disease', (166, 173))	('RMS', 'Phenotype', 'HP:0002859', (278, 281))	('RMS', 'Phenotype', 'HP:0002859', (229, 232))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (154, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('RMS', 'Phenotype', 'HP:0002859', (107, 110))	('upregulated', 'PosReg', (83, 94))	('RMS', 'Disease', (229, 232))	('mouse', 'Species', '10090', (201, 206))	('human', 'Species', '9606', (128, 133))	('RMS', 'Phenotype', 'HP:0002859', (207, 210))	('P7KP', 'Var', (188, 192))	('P7KP', 'Var', (102, 106))
32767	24239359	To determine whether the P7KP UPS and MDKP UPS sarcomas mimic human sarcoma at the molecular level, we also generated a gene set comprised of the genes most significantly (p< 0.001) upregulated in the mouse UPS from P7KP and MDKP mice compared to the mouse RMS from P7KP mice (Figure 4C; Figure S4B).	('UPS', 'Gene', '15288', (207, 210))	('MDKP UPS sarcomas', 'Disease', 'MESH:D017118', (38, 55))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('UPS', 'Gene', (30, 33))	('sarcoma', 'Disease', (47, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('RMS', 'Phenotype', 'HP:0002859', (257, 260))	('UPS', 'Gene', '15288', (30, 33))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('sarcoma', 'Disease', (68, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('mouse', 'Species', '10090', (251, 256))	('mice', 'Species', '10090', (271, 275))	('MDKP UPS sarcomas', 'Disease', (38, 55))	('human', 'Species', '9606', (62, 67))	('UPS', 'Gene', (43, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('P7KP', 'Var', (216, 220))	('mice', 'Species', '10090', (230, 234))	('UPS', 'Gene', '15288', (43, 46))	('upregulated', 'PosReg', (182, 193))	('UPS', 'Gene', (207, 210))	('mouse', 'Species', '10090', (201, 206))
32770	24239359	We used the CreER-loxP system to express oncogenic Kras and delete p53 specifically in Pax7-expressing or MyoD-expressing cells to show that both Pax7+ and MyoD+ myogenic cells are cells of origin for both myogenic and nonmyogenic soft tissue sarcomas.	('myogenic', 'Disease', (206, 214))	('myogenic soft tissue sarcomas', 'Disease', (222, 251))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (231, 250))	('myogenic soft tissue sarcomas', 'Disease', 'MESH:D012509', (222, 251))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '22059', (67, 70))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (231, 251))	('delete', 'Var', (60, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (243, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))
32771	24239359	Sarcomas generated by Pax7+ myogenic cells displayed histological diversity, ranging from Undifferentiated Pleomorphic Sarcoma (UPS) to differentiated eRMS, whereas MyoD+ cells gave rise to a more restricted UPS phenotype.	('Pax7+', 'Var', (22, 27))	('Sarcoma', 'Disease', (119, 126))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('UPS', 'Gene', '15288', (208, 211))	('UPS', 'Gene', (128, 131))	('Sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('UPS', 'Gene', (208, 211))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('RMS', 'Phenotype', 'HP:0002859', (152, 155))	('Sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('UPS', 'Gene', '15288', (128, 131))	('differentiated eRMS', 'Disease', (136, 155))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
32774	24239359	We used inducible Cre (CreER) alleles for cell of origin studies of sarcomas to temporally activate gene mutations after development.	('sarcomas', 'Disease', (68, 76))	('mutations', 'Var', (105, 114))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
32778	24239359	Here, we used tamoxifen-activated Cre (CreER) alleles, which can be activated after development, to show that mutant Kras, in concert with loss of Trp53, initiates eRMS and UPS in satellite cells, while UPS develops from MyoD expressing cells.	('UPS', 'Gene', (203, 206))	('initiates', 'PosReg', (154, 163))	('UPS', 'Gene', (173, 176))	('RMS', 'Phenotype', 'HP:0002859', (165, 168))	('mutant', 'Var', (110, 116))	('eRMS', 'CPA', (164, 168))	('UPS', 'Gene', '15288', (203, 206))	('tamoxifen', 'Chemical', 'MESH:D013629', (14, 23))	('Kras', 'Gene', (117, 121))	('UPS', 'Gene', '15288', (173, 176))
32779	24239359	By comparing the sarcomas that developed in the P7KP and MDKP mice to each other, we find that Pax7+ and MyoD+ progenitor cells can give rise to distinct and overlapping myogenic soft tissue sarcomas in vivo.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (179, 199))	('myogenic soft tissue sarcomas', 'Disease', 'MESH:D012509', (170, 199))	('sarcomas', 'Disease', (17, 25))	('Pax7+', 'Var', (95, 100))	('mice', 'Species', '10090', (62, 66))	('sarcomas', 'Disease', 'MESH:D012509', (191, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (191, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (179, 198))	('myogenic soft tissue sarcomas', 'Disease', (170, 199))	('give rise to', 'Reg', (132, 144))	('sarcomas', 'Disease', (191, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
32782	24239359	These data imply that the transcriptional profiles of UPS derived from P7KP and MDKP mice are more similar to each other than they are to RMS (eRMS and pRMS) generated in the P7KP mice; in addition, only the Pax7-expressing cells give rise to a spectrum of RMS, suggesting that Pax7+MyoD+ cells are a cell of origin for UPS in vivo.	('mice', 'Species', '10090', (85, 89))	('UPS', 'Gene', '15288', (320, 323))	('UPS', 'Gene', '15288', (54, 57))	('RMS', 'Phenotype', 'HP:0002859', (257, 260))	('UPS', 'Gene', (320, 323))	('RMS', 'Phenotype', 'HP:0002859', (138, 141))	('RMS', 'MPA', (257, 260))	('RMS', 'Phenotype', 'HP:0002859', (144, 147))	('UPS', 'Gene', (54, 57))	('mice', 'Species', '10090', (180, 184))	('P7KP', 'Var', (71, 75))	('spectrum', 'MPA', (245, 253))	('RMS', 'Phenotype', 'HP:0002859', (153, 156))
32783	24239359	These data also raise the possibility that transformation of a myogenic progenitor cell (not the muscle stem cell) gives rise to a more undifferentiated sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('transformation', 'Var', (43, 57))	('gives rise to', 'Reg', (115, 128))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (136, 160))	('undifferentiated sarcoma', 'Disease', (136, 160))
32785	24239359	First, the sarcomas are initiated by mutations in genes that are relevant to human RMS and UPS.	('UPS', 'Gene', '15288', (91, 94))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('initiated by', 'Reg', (24, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('RMS', 'Phenotype', 'HP:0002859', (83, 86))	('sarcomas', 'Disease', (11, 19))	('mutations', 'Var', (37, 46))	('UPS', 'Gene', (91, 94))	('human', 'Species', '9606', (77, 82))
32789	24239359	Second, tamoxifen activates KrasG12D and Trp53 conditional mutations in an inducible fashion via CreER in postnatal Pax7CE/+ and MyoDCE/+ mice.	('Trp53', 'Gene', (41, 46))	('tamoxifen', 'Chemical', 'MESH:D013629', (8, 17))	('mice', 'Species', '10090', (138, 142))	('KrasG12D', 'Gene', (28, 36))	('activates', 'PosReg', (18, 27))	('mutations', 'Var', (59, 68))	('CreER', 'MPA', (97, 102))
32791	24239359	It is possible that initiating mutations in myotubes or myofibers will also give rise to myogenic sarcomas.	('mutations', 'Var', (31, 40))	('myogenic sarcomas', 'Disease', (89, 106))	('give rise to', 'Reg', (76, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('myogenic sarcomas', 'Disease', 'MESH:D012509', (89, 106))
32795	24239359	Taken together, these results suggest that Pax7+MyoD- quiescent satellite cells can be a cell of origin for RMS and that Pax7+MyoD+ cells can be a cell of origin for UPS, at least in the context of Kras and Trp53 mutations.	('Kras', 'Gene', (198, 202))	('UPS', 'Gene', (166, 169))	('RMS', 'Disease', (108, 111))	('RMS', 'Phenotype', 'HP:0002859', (108, 111))	('Trp53', 'Gene', (207, 212))	('mutations', 'Var', (213, 222))	('UPS', 'Gene', '15288', (166, 169))
32820	33230229	However, these effects were not limited to the nephroblastoma cell line but also affected control kidney cell lines and the sarcoma cells; only podocytes are significantly less affected by LCA (at dosages < 200 microm).	('nephroblastoma', 'Phenotype', 'HP:0002667', (47, 61))	('sarcoma', 'Disease', (124, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('LCA', 'Chemical', '-', (189, 192))	('nephroblastoma', 'Disease', 'MESH:D009396', (47, 61))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('nephroblastoma', 'Disease', (47, 61))	('LCA', 'Var', (189, 192))
33025	32560243	This work was supported by the US National Institute of Health, National Cancer Institute grants (U54 CA190155) to CW/JTW, Fogarty International Center grant (K43TW011418) to SJL, and National Institute of General Medical Science grant (P30 GM103509) to CW.	('Cancer', 'Disease', (73, 79))	('P30 GM103509', 'Var', (237, 249))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))
33102	31477141	Historical data from patients irradiated from the 70s to the 90s show an increase in valvular disease for Hodgkin survivors with high RT doses.	('valvular disease', 'Phenotype', 'HP:0001654', (85, 101))	('high', 'Var', (129, 133))	('valvular disease', 'Disease', (85, 101))	('patients', 'Species', '9606', (21, 29))	('valvular disease', 'Disease', 'MESH:D006349', (85, 101))
33119	31477141	Radiotherapy increases the relative lifetime risk for secondary sarcoma depending on the RT-dose and the irradiated area.	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('Radiotherapy', 'Var', (0, 12))	('sarcoma', 'Disease', (64, 71))
33330	29254266	Binding of Gd-LC7-SH to the Cys34 residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI.	('Gd-LC7-SH', 'Chemical', '-', (11, 20))	('retention', 'MPA', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Cys34', 'Var', (28, 33))	('tumor', 'Disease', (123, 128))	('iron', 'Chemical', 'MESH:D007501', (100, 104))	('increases tumor', 'Disease', 'MESH:D009369', (113, 128))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('increases tumor', 'Disease', (113, 128))	('prolongs', 'PosReg', (60, 68))	('Cys34', 'Chemical', '-', (28, 33))	('Binding', 'Interaction', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
33339	29254266	Increases in intratumoral oxidative stress mediated by RRx-001 have previously been measured in vitro with the fluorescent probe 2',7'-dichlorofluorescein diacetate, and by studying the activation of the Nrf2-ARE antioxidant signaling pathways in tumor cells, specifically the nuclear translocation of Nrf2 and the expression of its downstream enzymes HO-1 and NQO1 by RRx-001.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('RRx-001', 'Var', (369, 376))	('Nrf2', 'Gene', '18024', (302, 306))	('tumor', 'Disease', (18, 23))	('RRx-001', 'Chemical', 'MESH:C577469', (55, 62))	('HO-1', 'Gene', (352, 356))	('Nrf2', 'Gene', '18024', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('NQO1', 'Gene', '18104', (361, 365))	('RRx-001', 'Var', (55, 62))	('NQO1', 'Gene', (361, 365))	('tumor', 'Disease', (247, 252))	("2',7'-dichlorofluorescein diacetate", 'Chemical', 'MESH:C029569', (129, 164))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('Nrf2', 'Gene', (302, 306))	('oxidative stress', 'Phenotype', 'HP:0025464', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('expression', 'MPA', (315, 325))	('RRx-001', 'Chemical', 'MESH:C577469', (369, 376))	('HO-1', 'CellLine', 'CVCL:1E42', (352, 356))	('nuclear translocation', 'MPA', (277, 298))	('Nrf2', 'Gene', (204, 208))
33349	29254266	In a careful study of the binding of homocysteine to albumin, Jacobsen and colleagues provide evidence that when reduced homocysteine enters circulation, it attacks albumin-Cys34-S-S-Cys to first form albumin-Cys34 thiolate anion, which then reacts with homocysteine-cysteine mixed disulfide to form albumin-bound homocysteine.	('Cys34-S-S-Cys', 'Chemical', '-', (173, 186))	('albumin-bound homocysteine', 'MPA', (300, 326))	('disulfide', 'Chemical', 'MESH:D004220', (282, 291))	('homocysteine', 'Chemical', 'MESH:D006710', (314, 326))	('homocysteine-cysteine', 'Chemical', '-', (254, 275))	('homocysteine', 'Chemical', 'MESH:D006710', (37, 49))	('homocysteine', 'Chemical', 'MESH:D006710', (254, 266))	('Cys34 thiolate anion', 'Chemical', '-', (209, 229))	('reduced', 'Var', (113, 120))	('homocysteine', 'Chemical', 'MESH:D006710', (121, 133))
33350	29254266	administered Gd-LC7-SH may bind to plasma albumin and subsequently be retained in the tumor interstitium to produce prolonged MRI image enhancement.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('Gd-LC7-SH', 'Var', (13, 22))	('MRI image', 'MPA', (126, 135))	('enhancement', 'PosReg', (136, 147))	('plasma albumin', 'Protein', (35, 49))	('Gd-LC7-SH', 'Chemical', '-', (13, 22))	('bind', 'Interaction', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
33386	29254266	These changes lead to aggregation of the RRx-001-bound RBCs, followed by internalization by tumor vasculature, leading to a release of heme, iron, and oxidized lipid products, that is, ROS and RNS, as well as changes in tumor blood flow.	('RRx-001', 'Chemical', 'MESH:C577469', (41, 48))	('aggregation', 'MPA', (22, 33))	('RBCs', 'Protein', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (220, 225))	('changes', 'Var', (6, 13))	('lead to', 'Reg', (14, 21))	('RNS', 'MPA', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('release of heme', 'MPA', (124, 139))	('heme', 'Chemical', 'MESH:D006418', (135, 139))	('iron', 'Chemical', 'MESH:D007501', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('RNS', 'Chemical', 'MESH:D011886', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('changes', 'Reg', (209, 216))	('internalization', 'MPA', (73, 88))	('lipid', 'Chemical', 'MESH:D008055', (160, 165))	('ROS', 'Chemical', '-', (185, 188))	('iron', 'MPA', (141, 145))	('tumor', 'Disease', (92, 97))	('RRx-001-bound', 'Gene', (41, 54))	('oxidized lipid products', 'MPA', (151, 174))	('ROS', 'MPA', (185, 188))
33393	29254266	One component of an anti-oxidant response would be improved perfusion, and there was a marked increase in the Ktrans parameter calculated from DCE-MRI of CHP-100 Ewing sarcoma xenografts at 1 h post-drug treatment.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (162, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('Ktrans parameter calculated', 'MPA', (110, 137))	('improved', 'PosReg', (51, 59))	('increase', 'PosReg', (94, 102))	('perfusion', 'MPA', (60, 69))	('DCE', 'Chemical', 'MESH:C024565', (143, 146))	('Ktrans', 'Chemical', '-', (110, 116))	('CHP-100 Ewing sarcoma', 'Disease', 'MESH:C563168', (154, 175))	('CHP-100 Ewing sarcoma', 'Disease', (154, 175))	('DCE-MRI', 'Var', (143, 150))	('oxidant response', 'Phenotype', 'HP:0025464', (25, 41))
33404	29254266	In conclusion, MRI enhanced with Gd-LC7-SH provides a non-invasive pharmacodynamic marker of the redox modulatory activity of RRx-001 in three pre-clinical tumor models.	('Gd-LC7-SH', 'Chemical', '-', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('MRI', 'MPA', (15, 18))	('RRx-001', 'Chemical', 'MESH:C577469', (126, 133))	('Gd-LC7-SH', 'Var', (33, 42))
33410	29254266	18 mice were inoculated with each tumor cell line, of which the 12 mice with the most similar mean tumor volumes were stratified into 3 equal treatment groups when the tumors were approximately 250-400 mm3: Gd-LC7-SH MRI group 1 (n = 4), Gd-LC7-SH MRI group 2 (n = 4), and BOLD MRI group 3 (n = 4).	('tumor', 'Disease', (99, 104))	('Gd-LC7-SH', 'Var', (207, 216))	('Gd-LC7-SH', 'Chemical', '-', (238, 247))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Gd-LC7-SH', 'Chemical', '-', (207, 216))	('mice', 'Species', '10090', (3, 7))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mice', 'Species', '10090', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
33445	29254266	Based on the in vivo behavior of a related molecule, Gd-LC6-SH, we have assumed that at   60 min post-injection of Gd-LC7-SH the signal enhancement from the first bolus is essentially time-invariant during the 5 min DCE-MRI measurement following the second bolus.	('Gd-LC6-SH', 'Chemical', '-', (53, 62))	('signal', 'MPA', (129, 135))	('enhancement', 'PosReg', (136, 147))	('Gd-LC7-SH', 'Var', (115, 124))	('DCE', 'Chemical', 'MESH:C024565', (216, 219))	('Gd-LC7-SH', 'Chemical', '-', (115, 124))
33492	24100443	There were six patients with less than 6 months of clinical and radiological follow-up: five patients succumbed to disseminated disease following PET/CT, and in one patient a solitary lung metastasis from STUMP/LMS was confirmed by histological analysis.	('patient', 'Species', '9606', (15, 22))	('patients', 'Species', '9606', (15, 23))	('disseminated disease', 'Disease', (115, 135))	('patient', 'Species', '9606', (165, 172))	('LMS', 'Phenotype', 'HP:0100243', (211, 214))	('patient', 'Species', '9606', (93, 100))	('PET/CT', 'Var', (146, 152))	('patients', 'Species', '9606', (93, 101))
33524	31994243	Regardless of the site of origin, the gold standard in diagnosing a MET relies on demonstrating its 'myoepithelial immunophenotype' of positivity for EMA/CK and S100 protein or GFAP.	('MET', 'Gene', (68, 71))	('GFAP', 'Gene', (177, 181))	('EMA/CK', 'Gene', (150, 156))	('S100', 'Gene', (161, 165))	('S100', 'Gene', '6271', (161, 165))	('positivity', 'Var', (135, 145))	('GFAP', 'Gene', '2670', (177, 181))	('EMA/CK', 'Gene', '4582;51727', (150, 156))	('MET', 'Gene', '79811', (68, 71))
33528	31994243	Genetic analysis was carried out by FISH for EWSR1/FUS rearrangements and potential partners, and/or by targeted RNA sequencing.	('FUS', 'Gene', '2521', (51, 54))	('EWSR1', 'Gene', (45, 50))	('EWSR1', 'Gene', '2130', (45, 50))	('rearrangements', 'Var', (55, 69))	('FUS', 'Gene', (51, 54))
33529	31994243	82% showed EWSR1 rearrangement, while 18% had FUS abnormalities.	('EWSR1', 'Gene', (11, 16))	('rearrangement', 'Var', (17, 30))	('EWSR1', 'Gene', '2130', (11, 16))	('FUS abnormalities', 'Disease', 'MESH:D018376', (46, 63))	('FUS abnormalities', 'Disease', (46, 63))
33531	31994243	In contrast, EWSR1/FUS-PBX1/3 fusions were associated with benign and sclerotic spindle cell morphology.	('EWSR1', 'Gene', '2130', (13, 18))	('PBX1/3', 'Gene', '5087;5090', (23, 29))	('fusions', 'Var', (30, 37))	('FUS', 'Gene', (19, 22))	('PBX1/3', 'Gene', (23, 29))	('FUS', 'Gene', '2521', (19, 22))	('associated', 'Reg', (43, 53))	('EWSR1', 'Gene', (13, 18))
33538	31994243	To complicate things further, the emerging genetic signatures of MET from different sites have suggested a dichotomy of molecular events, with PLAG1 and HMGA2 gene abnormalities being prevalent in salivary gland and skin, while in bone, soft tissue and other viscera recurrent EWSR1 and FUS related gene fusions are detected in half of MET.	('abnormalities', 'Var', (164, 177))	('PLAG1', 'Gene', (143, 148))	('HMGA2', 'Gene', (153, 158))	('prevalent', 'Reg', (184, 193))	('MET', 'Gene', (336, 339))	('MET', 'Gene', '79811', (65, 68))	('MET', 'Gene', (65, 68))	('FUS', 'Gene', (287, 290))	('FUS', 'Gene', '2521', (287, 290))	('EWSR1', 'Gene', (277, 282))	('PLAG1', 'Gene', '5324', (143, 148))	('HMGA2', 'Gene', '8091', (153, 158))	('EWSR1', 'Gene', '2130', (277, 282))	('MET', 'Gene', '79811', (336, 339))
33550	31994243	However, cutaneous myoepithelial tumors with EWSR1-PBX3 fusions diagnostic of syncytial myoepithelioma and benign cutaneous myoepithelial tumors/ benign mixed tumors with PLAG1/HMGA2 gene rearrangements were not included in this investigation.	('fusions', 'Var', (56, 63))	('PBX3', 'Gene', '5090', (51, 55))	('benign cutaneous myoepithelial tumors', 'Disease', (107, 144))	('PBX3', 'Gene', (51, 55))	('cutaneous myoepithelial tumors', 'Disease', (9, 39))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('cutaneous myoepithelial tumors', 'Disease', 'MESH:D009208', (9, 39))	('cutaneous myoepithelial tumors', 'Disease', 'MESH:D009208', (114, 144))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('PLAG1', 'Gene', (171, 176))	('HMGA2', 'Gene', '8091', (177, 182))	('benign cutaneous myoepithelial tumors', 'Disease', 'MESH:D009208', (107, 144))	('EWSR1', 'Gene', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('PLAG1', 'Gene', '5324', (171, 176))	('syncytial myoepithelioma', 'Disease', (78, 102))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('HMGA2', 'Gene', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('EWSR1', 'Gene', '2130', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', (138, 144))	('syncytial myoepithelioma', 'Disease', 'MESH:D009208', (78, 102))	('tumors', 'Disease', (33, 39))
33552	31994243	Tumors were first tested for EWSR1 gene rearrangements, and if negative were subsequently tested for FUS gene abnormalities.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('EWSR1', 'Gene', (29, 34))	('Tumors', 'Disease', (0, 6))	('EWSR1', 'Gene', '2130', (29, 34))	('FUS gene abnormalities', 'Disease', 'MESH:D006623', (101, 123))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('rearrangements', 'Var', (40, 54))	('FUS gene abnormalities', 'Disease', (101, 123))	('tested', 'Reg', (18, 24))
33554	31994243	If no partner was detected, further FISH testing was performed in most cases to exclude alternative diagnoses, including abnormalities in FLI1, ERG, NR4A3, ATF1, CREB1, and CREM genes.	('ERG', 'Gene', '2078', (144, 147))	('abnormalities', 'Var', (121, 134))	('FLI1', 'Gene', '2313', (138, 142))	('FLI1', 'Gene', (138, 142))	('ERG', 'Gene', (144, 147))	('CREB1', 'Gene', (162, 167))	('CREB1', 'Gene', '1385', (162, 167))	('ATF1', 'Gene', (156, 160))	('ATF1', 'Gene', '466', (156, 160))	('NR4A3', 'Gene', (149, 154))	('CREM', 'Gene', '1390', (173, 177))	('NR4A3', 'Gene', '8013', (149, 154))	('CREM', 'Gene', (173, 177))
33561	31994243	The current series included 66 MET which were positive for gene rearrangements or gene fusions typically seen in MET.	('MET', 'Gene', (113, 116))	('MET', 'Gene', '79811', (31, 34))	('MET', 'Gene', (31, 34))	('gene rearrangements', 'Var', (59, 78))	('MET', 'Gene', '79811', (113, 116))	('gene fusions', 'Var', (82, 94))
33566	31994243	By FISH, targeted RNA sequencing, or cytogenetics, EWSR1 rearrangement was found in the large majority of MET, occurring in 54 (82%) cases, while FUS rearrangement was detected in 12 (18%) cases.	('MET', 'Gene', '79811', (106, 109))	('FUS', 'Gene', (146, 149))	('MET', 'Gene', (106, 109))	('EWSR1', 'Gene', (51, 56))	('FUS', 'Gene', '2521', (146, 149))	('found', 'Reg', (75, 80))	('EWSR1', 'Gene', '2130', (51, 56))	('rearrangement', 'Var', (57, 70))	('occurring', 'Reg', (111, 120))
33569	31994243	Among the 12 MET cases with FUS gene rearrangements, only two partners were identified, including the most common KLF17 (n=8, 67%) gene and less frequently POU5F1 (n=2, 17%) (Fig 1).	('FUS', 'Gene', '2521', (28, 31))	('MET', 'Gene', (13, 16))	('POU5F1', 'Gene', '5460', (156, 162))	('POU5F1', 'Gene', (156, 162))	('KLF17', 'Gene', '128209', (114, 119))	('KLF17', 'Gene', (114, 119))	('rearrangements', 'Var', (37, 51))	('FUS', 'Gene', (28, 31))	('MET', 'Gene', '79811', (13, 16))
33585	31994243	Notably, 11/15 (73%) MET with EWSR1-POU5F1 fusions had overtly malignant features, which occurred preferentially in children and young adults, 9 patients being younger than the age of 30.	('patients', 'Species', '9606', (145, 153))	('EWSR1', 'Gene', '2130', (30, 35))	('MET', 'Gene', (21, 24))	('POU5F1', 'Gene', '5460', (36, 42))	('POU5F1', 'Gene', (36, 42))	('fusions', 'Var', (43, 50))	('EWSR1', 'Gene', (30, 35))	('children', 'Species', '9606', (116, 124))	('MET', 'Gene', '79811', (21, 24))
33586	31994243	Morphologically, these 11 malignant MET with EWSR1-POU5F1 fusions consisted of nests and sheets of epithelioid cells, often with clear cell cytoplasm, showing moderate pleomorphism, prominent nucleoli, and increased mitotic activity, but no necrosis (Fig 2).	('EWSR1', 'Gene', (45, 50))	('increased', 'PosReg', (206, 215))	('consisted', 'Reg', (66, 75))	('necrosis', 'Disease', (241, 249))	('mitotic activity', 'CPA', (216, 232))	('EWSR1', 'Gene', '2130', (45, 50))	('fusions', 'Var', (58, 65))	('necrosis', 'Disease', 'MESH:D009336', (241, 249))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (36, 39))	('POU5F1', 'Gene', '5460', (51, 57))	('POU5F1', 'Gene', (51, 57))
33594	31994243	In fact, EWSR1-PBX1/3 fusions were the most common gene fusions in primary skeletal MET, occurring in 7 out of 12 (58%) cases.	('MET', 'Gene', (84, 87))	('PBX1/3', 'Gene', '5087;5090', (15, 21))	('PBX1/3', 'Gene', (15, 21))	('fusions', 'Var', (22, 29))	('EWSR1', 'Gene', (9, 14))	('MET', 'Gene', '79811', (84, 87))	('EWSR1', 'Gene', '2130', (9, 14))
33599	31994243	Eight MET harbored FUS-KLF17 fusions.	('MET', 'Gene', '79811', (6, 9))	('KLF17', 'Gene', (23, 28))	('fusions', 'Var', (29, 36))	('MET', 'Gene', (6, 9))	('FUS', 'Gene', (19, 22))	('FUS', 'Gene', '2521', (19, 22))	('KLF17', 'Gene', '128209', (23, 28))
33605	31994243	Three MET harbored EWSR1-ZNF444 fusions.	('MET', 'Gene', '79811', (6, 9))	('fusions', 'Var', (32, 39))	('ZNF444', 'Gene', (25, 31))	('MET', 'Gene', (6, 9))	('EWSR1', 'Gene', (19, 24))	('ZNF444', 'Gene', '55311', (25, 31))	('EWSR1', 'Gene', '2130', (19, 24))
33616	31994243	The single MET with an EWSR1-KLF17 fusion previously reported represented a benign MET, occurring in the foot of a 20-year-old male.	('MET', 'Gene', '79811', (11, 14))	('MET', 'Gene', (11, 14))	('MET', 'Gene', '79811', (83, 86))	('MET', 'Gene', (83, 86))	('KLF17', 'Gene', '128209', (29, 34))	('EWSR1', 'Gene', (23, 28))	('fusion', 'Var', (35, 41))	('EWSR1', 'Gene', '2130', (23, 28))	('KLF17', 'Gene', (29, 34))
33618	31994243	The molecular abnormalities of bone and soft tissue MET have been recently elucidated as harboring EWSR1/FUS-related gene fusions in at least half of the cases, involving EWSR1 and FUS with various partner genes encoding for transcription factors, including POU5F1, PBX1, PBX3, ZNF444, KLF15 and KLF17.	('FUS', 'Gene', '2521', (181, 184))	('EWSR1', 'Gene', '2130', (99, 104))	('FUS', 'Gene', (105, 108))	('EWSR1', 'Gene', (171, 176))	('ZNF444', 'Gene', (278, 284))	('KLF15', 'Gene', (286, 291))	('PBX3', 'Gene', (272, 276))	('FUS', 'Gene', '2521', (105, 108))	('MET', 'Gene', '79811', (52, 55))	('PBX3', 'Gene', '5090', (272, 276))	('KLF17', 'Gene', '128209', (296, 301))	('KLF17', 'Gene', (296, 301))	('POU5F1', 'Gene', '5460', (258, 264))	('EWSR1', 'Gene', (99, 104))	('KLF15', 'Gene', '28999', (286, 291))	('fusions', 'Var', (122, 129))	('PBX1', 'Gene', (266, 270))	('FUS', 'Gene', (181, 184))	('EWSR1', 'Gene', '2130', (171, 176))	('PBX1', 'Gene', '5087', (266, 270))	('ZNF444', 'Gene', '55311', (278, 284))	('MET', 'Gene', (52, 55))	('POU5F1', 'Gene', (258, 264))
33620	31994243	In contrast, MET arising in the skin and salivary gland frequently show distinct PLAG1 and HMGA2 related gene fusions.	('HMGA2', 'Gene', '8091', (91, 96))	('MET', 'Gene', (13, 16))	('PLAG1', 'Gene', (81, 86))	('HMGA2', 'Gene', (91, 96))	('PLAG1', 'Gene', '5324', (81, 86))	('fusions', 'Var', (110, 117))	('MET', 'Gene', '79811', (13, 16))
33629	31994243	Conversely, some of the tumors that were initially diagnosed as MET based on morphologic findings, immunophenotype and/or EWSR1/FUS gene rearrangements, were reclassified as other mesenchymal neoplasms based on the subsequent NGS or FISH results of variant EWSR1 gene fusions, involving other gene partners such as CREM, ATF1, FLI1, etc.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('ATF1', 'Gene', '466', (321, 325))	('tumors', 'Disease', (24, 30))	('EWSR1', 'Gene', '2130', (122, 127))	('variant', 'Var', (249, 256))	('FLI1', 'Gene', '2313', (327, 331))	('EWSR1', 'Gene', '2130', (257, 262))	('fusions', 'Var', (268, 275))	('CREM', 'Gene', (315, 319))	('FUS', 'Gene', (128, 131))	('MET', 'Gene', (64, 67))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (180, 201))	('EWSR1', 'Gene', (122, 127))	('neoplasm', 'Phenotype', 'HP:0002664', (192, 200))	('CREM', 'Gene', '1390', (315, 319))	('EWSR1', 'Gene', (257, 262))	('FUS', 'Gene', '2521', (128, 131))	('neoplasms', 'Phenotype', 'HP:0002664', (192, 201))	('MET', 'Gene', '79811', (64, 67))	('ATF1', 'Gene', (321, 325))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('FLI1', 'Gene', (327, 331))	('mesenchymal neoplasms', 'Disease', (180, 201))
33632	31994243	In fact, three tumors occurring in children were initially misinterpreted as Ewing sarcoma at the outside institution based on an EWSR1 gene rearrangement positive result and treated with Ewing sarcoma regimens.	('Ewing sarcoma', 'Disease', (188, 201))	('Ewing sarcoma', 'Disease', (77, 90))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('EWSR1', 'Gene', '2130', (130, 135))	('children', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (188, 201))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (188, 201))	('rearrangement', 'Var', (141, 154))	('EWSR1', 'Gene', (130, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('tumors', 'Disease', (15, 21))
33633	31994243	First, MET with EWSR1-POU5F1 fusions represents the most common molecular subset (28%), being prevalent in children or young adults, presenting in the deep soft tissues of the extremities.	('EWSR1', 'Gene', '2130', (16, 21))	('children', 'Species', '9606', (107, 115))	('MET', 'Gene', '79811', (7, 10))	('MET', 'Gene', (7, 10))	('fusions', 'Var', (29, 36))	('POU5F1', 'Gene', '5460', (22, 28))	('POU5F1', 'Gene', (22, 28))	('EWSR1', 'Gene', (16, 21))
33635	31994243	The majority of MET with EWSR1-POU5F1 fusions (11/15; 73%) showed microscopic features in keeping with malignant behavior.	('EWSR1', 'Gene', (25, 30))	('EWSR1', 'Gene', '2130', (25, 30))	('MET', 'Gene', '79811', (16, 19))	('MET', 'Gene', (16, 19))	('POU5F1', 'Gene', '5460', (31, 37))	('POU5F1', 'Gene', (31, 37))	('fusions', 'Var', (38, 45))
33638	31994243	PBX1/3 fusions were most prevalent among skeletal MET, found in more than half of bone tumors.	('prevalent', 'Reg', (25, 34))	('bone tumors', 'Disease', (82, 93))	('bone tumors', 'Disease', 'MESH:D001859', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('bone tumors', 'Phenotype', 'HP:0010622', (82, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('PBX1/3', 'Gene', '5087;5090', (0, 6))	('MET', 'Gene', '79811', (50, 53))	('fusions', 'Var', (7, 14))	('PBX1/3', 'Gene', (0, 6))	('MET', 'Gene', (50, 53))
33639	31994243	Third, chordoma-like morphology (parachordoma) was observed in 6/8 MET with FUS-KLF17 fusions, of which 3 had a benign appearance and 3 had features of malignancy.	('chordoma', 'Phenotype', 'HP:0010762', (37, 45))	('parachordoma', 'Disease', (33, 45))	('MET', 'Gene', (67, 70))	('FUS', 'Gene', (76, 79))	('chordoma', 'Disease', 'MESH:D002817', (7, 15))	('parachordoma', 'Disease', 'None', (33, 45))	('FUS', 'Gene', '2521', (76, 79))	('chordoma', 'Disease', (37, 45))	('chordoma', 'Disease', 'MESH:D002817', (37, 45))	('KLF17', 'Gene', (80, 85))	('MET', 'Gene', '79811', (67, 70))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))	('KLF17', 'Gene', '128209', (80, 85))	('chordoma', 'Phenotype', 'HP:0010762', (7, 15))	('chordoma', 'Disease', (7, 15))	('observed', 'Reg', (51, 59))	('fusions', 'Var', (86, 93))	('malignancy', 'Disease', (152, 162))
33648	31994243	Three other malignant MET with EWSR1-KLF15 fusions and myoepithelial marker expression have been described in the literature.	('EWSR1', 'Gene', (31, 36))	('KLF15', 'Gene', '28999', (37, 42))	('EWSR1', 'Gene', '2130', (31, 36))	('fusions', 'Var', (43, 50))	('MET', 'Gene', '79811', (22, 25))	('KLF15', 'Gene', (37, 42))	('MET', 'Gene', (22, 25))
33654	31994243	Several soft tissue and bone tumors with overlapping morphologic features, including trabecular cords of epithelioid cells in myxoid, myxohyaline or sclerotic stroma, and co-expression of S100 and/or CK/EMA, enter the differential diagnosis of MET.	('co-expression', 'Var', (171, 184))	('S100', 'Gene', (188, 192))	('MET', 'Gene', '79811', (244, 247))	('trabecular cords', 'Phenotype', 'HP:0032465', (85, 101))	('bone tumors', 'Disease', (24, 35))	('bone tumors', 'Disease', 'MESH:D001859', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('S100', 'Gene', '6271', (188, 192))	('CK/EMA', 'Gene', (200, 206))	('MET', 'Gene', (244, 247))	('bone tumors', 'Phenotype', 'HP:0010622', (24, 35))	('CK/EMA', 'Gene', '51727;4582', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('sclerotic stroma', 'Disease', 'MESH:C538213', (149, 165))	('sclerotic stroma', 'Disease', (149, 165))	('myxohyaline', 'Disease', (134, 145))
33664	31994243	The large majority of OFMT show recurrent PHF1 gene rearrangements which can confirm the diagnosis in challenging cases.	('rearrangements', 'Var', (52, 66))	('PHF1', 'Gene', '5252', (42, 46))	('PHF1', 'Gene', (42, 46))
33667	31994243	However, SOX10 expression and loss of SMARCB1 do not exclude MET.	('SOX10', 'Gene', (9, 14))	('MET', 'Gene', (61, 64))	('SMARCB1', 'Gene', '6598', (38, 45))	('MET', 'Gene', '79811', (61, 64))	('loss', 'Var', (30, 34))	('SOX10', 'Gene', '6663', (9, 14))	('SMARCB1', 'Gene', (38, 45))
33669	31994243	A further pitfall can occur if a positive EWSR1 or FUS gene rearrangement is documented.	('FUS', 'Gene', '2521', (51, 54))	('EWSR1', 'Gene', '2130', (42, 47))	('rearrangement', 'Var', (60, 73))	('FUS', 'Gene', (51, 54))	('EWSR1', 'Gene', (42, 47))
33731	30245009	Further, we demonstrate that de novo acetate production sustains Ac-CoA pools and cell proliferation in limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (150, 175))	('mitochondrial dysfunction', 'Disease', (150, 175))	('cell proliferation', 'CPA', (82, 100))	('acetate', 'Chemical', 'MESH:D000085', (37, 44))	('de novo acetate production', 'MPA', (29, 55))	('ATP citrate lyase', 'Gene', '47', (179, 196))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (150, 175))	('ATP citrate lyase', 'Gene', (179, 196))	('deficiency', 'Var', (204, 214))	('Ac-CoA pools', 'MPA', (65, 77))	('Ac-CoA', 'Chemical', 'MESH:C059703', (65, 71))
33758	30245009	Treatment with SAHA suppressed histone deacetylation (Figure 1G), indicated by the increase of total Histone 3 acetylation (H3_ac) as well as acetylation of H3 on lysines 9 (H3K9ac) and 27 (H3K27ac) of Histone H3.	('increase', 'PosReg', (83, 91))	('lysines', 'Chemical', 'MESH:C114808', (163, 170))	('acetyl', 'Chemical', 'MESH:C011632', (41, 47))	('H3K9ac', 'Var', (174, 180))	('SAHA', 'Chemical', 'MESH:C111237', (15, 19))	('suppressed', 'NegReg', (20, 30))	('acetyl', 'Chemical', 'MESH:C011632', (111, 117))	('acetyl', 'Chemical', 'MESH:C011632', (142, 148))	('Histone', 'Protein', (101, 108))	('histone deacetylation', 'MPA', (31, 52))	('acetylation', 'MPA', (142, 153))
33765	30245009	As expected, the 13C labeled Ac-CoA, Ac-carnitine (reversibly converted from Ac-CoA) and citrate (the first intermediate in the TCA cycle) were decreased by UK5099 treatment (Figures S1E-1G).	('citrate', 'Chemical', 'MESH:C102006', (89, 96))	('decreased', 'NegReg', (144, 153))	('Ac-carnitine', 'MPA', (37, 49))	('Ac-carnitine', 'Chemical', 'MESH:D002331', (37, 49))	('13C labeled', 'MPA', (17, 28))	('Ac-CoA', 'Chemical', 'MESH:C059703', (77, 83))	('TCA', 'Chemical', 'MESH:C000589078', (128, 131))	('UK5099', 'Var', (157, 163))	('citrate', 'MPA', (89, 96))	('Ac-CoA', 'Chemical', 'MESH:C059703', (29, 35))
33777	30245009	We then identified (Figure 2D) and quantified (Figure 2E) [18O1]-acetate providing a direct observation in intact cells of the formation of [18O2]-H2O2 and oxidative decarboxylation of pyruvate by H2O2.	('oxidative decarboxylation of pyruvate', 'MPA', (156, 193))	('H2O2', 'Chemical', 'MESH:D014867', (197, 201))	('[18O2]-H2O2', 'Chemical', 'MESH:D014867', (140, 151))	('formation', 'MPA', (127, 136))	('pyruvate', 'Chemical', 'MESH:D011773', (185, 193))	('H2O2', 'Chemical', 'MESH:D014867', (147, 151))	('H2O2', 'Var', (197, 201))	('[18O1]-acetate', 'Chemical', 'MESH:D000085', (58, 72))
33778	30245009	Inhibiting the mitochondrial pyruvate carrier with UK5099 or addition of pyruvate to the culture medium substantially increased the contribution of H2O2 to acetate production from pyruvate (Figure 2E).	('acetate', 'Chemical', 'MESH:D000085', (156, 163))	('pyruvate', 'Chemical', 'MESH:D011773', (29, 37))	('Inhibiting', 'NegReg', (0, 10))	('acetate production from pyruvate', 'MPA', (156, 188))	('contribution', 'MPA', (132, 144))	('increased', 'PosReg', (118, 127))	('pyruvate', 'Chemical', 'MESH:D011773', (73, 81))	('H2O2', 'Chemical', 'MESH:D014867', (148, 152))	('mitochondrial pyruvate carrier', 'Enzyme', (15, 45))	('pyruvate', 'Chemical', 'MESH:D011773', (180, 188))	('UK5099', 'Var', (51, 57))
33779	30245009	To further test this mechanism, inhibition of superoxide dismutase (SOD), which converts superoxides to H2O2 (Figure 2F), with tetrathiomolybdate (TTM), was done to decrease endogenous H2O2 levels.	('inhibition', 'Var', (32, 42))	('endogenous H2O2 levels', 'MPA', (174, 196))	('superoxide dismutase', 'Gene', '6647', (46, 66))	('tetrathiomolybdate', 'Chemical', 'MESH:C020809', (127, 145))	('SOD', 'Gene', '6647', (68, 71))	('decrease', 'NegReg', (165, 173))	('H2O2', 'Chemical', 'MESH:D014867', (104, 108))	('superoxide dismutase', 'Gene', (46, 66))	('H2O2', 'Chemical', 'MESH:D014867', (185, 189))	('superoxides', 'Chemical', 'MESH:D013481', (89, 100))	('SOD', 'Gene', (68, 71))
33780	30245009	Indeed, the presence of TTM decreased 18O incorporation into H2O2-coupled reactions, including methionine sulfoxide (Figure 2G) and acetate (Figures 2H and 2I).	('TTM', 'Var', (24, 27))	('acetate', 'MPA', (132, 139))	('decreased', 'NegReg', (28, 37))	('H2O2', 'Chemical', 'MESH:D014867', (61, 65))	('18O incorporation', 'MPA', (38, 55))	('presence', 'Var', (12, 20))	('H2O2-coupled', 'Enzyme', (61, 73))	('2I', 'Chemical', 'MESH:D007455', (156, 158))	('methionine sulfoxide', 'Chemical', 'MESH:C013111', (95, 115))	('18O', 'Chemical', 'MESH:D013481', (38, 41))	('methionine sulfoxide', 'MPA', (95, 115))	('acetate', 'Chemical', 'MESH:D000085', (132, 139))
33781	30245009	These findings together demonstrate that endogenous H2O2 contributes to acetate formation from pyruvate in cellular conditions.	('H2O2', 'Var', (52, 56))	('acetate', 'Chemical', 'MESH:D000085', (72, 79))	('H2O2', 'Chemical', 'MESH:D014867', (52, 56))	('pyruvate', 'Chemical', 'MESH:D011773', (95, 103))	('acetate formation from pyruvate', 'MPA', (72, 103))
33784	30245009	The reaction followed second order kinetics (k = 0.19 +/- 0.05 mM-1min-1) and could be accelerated with catalysts present in high concentrations in cells such as Cu2+, as Cu2+ stabilizes the intermediate of pyruvate decarboxylation (Figures S2B and C).	('Cu2+', 'Var', (171, 175))	('intermediate', 'MPA', (191, 203))	('Cu2+', 'Chemical', 'MESH:D003300', (171, 175))	('pyruvate', 'Chemical', 'MESH:D011773', (207, 215))	('Cu2+', 'Chemical', 'MESH:D003300', (162, 166))
33787	30245009	Additionally, HCT116 cells pre-incubated with [13C6]-glucose and then treated with [18O2]-H2O2 showed a transient increase in the amount of [18O1]-acetate peaking around five minutes post induction of ROS with subsequent decay kinetics corresponding to the clearance of the ROS (Figure 2J).	('[13C6]-glucose', 'Var', (46, 60))	('increase', 'PosReg', (114, 122))	('[18O1]-acetate', 'Chemical', 'MESH:D000085', (140, 154))	('[13C6]-glucose', 'Chemical', 'MESH:D005947', (46, 60))	('HCT116', 'CellLine', 'CVCL:0291', (14, 20))	('[18O2]-H2O2', 'Chemical', 'MESH:D014867', (83, 94))	('amount of [18O1]-acetate', 'MPA', (130, 154))	('ROS', 'Gene', (201, 204))
33808	30245009	Indeed, [13C2]-acetate, [13C2]-acetaldehyde and [13C2]-Ac-GSH were quickly formed in HCT116 cells within a few minutes after [13C6]-glucose media were added (Figure 4A) and further confirmed with tandem mass spectrometry (Figure S4A).	('HCT116', 'CellLine', 'CVCL:0291', (85, 91))	('[13C6]-glucose', 'Chemical', 'MESH:D005947', (125, 139))	('[13C2]-acetate', 'Var', (8, 22))	('[13C2]-acetaldehyde', 'Chemical', 'MESH:D000079', (24, 43))	('[13C2]-acetate', 'Chemical', 'MESH:C513342', (8, 22))	('[13C2]-acetaldehyde', 'Var', (24, 43))	('[13C2]-Ac-GSH', 'Var', (48, 61))	('[13C2]-Ac-GSH', 'Chemical', 'MESH:C513342', (48, 61))
33809	30245009	The intracellular concentration of [13C2]-acetaldehyde was found to be higher than the intracellular [13C2]-acetate concentration, and also much higher than the concentration of [13C2]-acetaldehyde excreted into the media (Figure 4B).	('higher', 'PosReg', (71, 77))	('[13C2]-acetaldehyde', 'Chemical', 'MESH:D000079', (178, 197))	('[13C2]-acetaldehyde', 'Chemical', 'MESH:D000079', (35, 54))	('[13C2]-acetate', 'Chemical', 'MESH:C513342', (101, 115))	('[13C2]-acetaldehyde', 'Var', (35, 54))	('intracellular concentration', 'MPA', (4, 31))	('higher', 'PosReg', (145, 151))
33817	30245009	Thiamine deprivation for 4 days caused the depletion of thiamine, thiamine pyrophosphate (TPP), and alterations in the levels of TCA intermediates in HCT116 cells (Figure S4D), which is consistent with the hypothesis that thiamine depletion inactivates keto acid dehydrogenases (PDH and aKGDH).	('TPP', 'Chemical', 'MESH:D013835', (90, 93))	('depletion', 'MPA', (43, 52))	('thiamine depletion', 'Phenotype', 'HP:0100503', (222, 240))	('aKGDH', 'Gene', (287, 292))	('alterations', 'Reg', (100, 111))	('levels of TCA intermediates', 'MPA', (119, 146))	('PDH', 'Gene', '54704', (279, 282))	('keto acid', 'Chemical', 'MESH:D007651', (253, 262))	('TCA', 'Chemical', 'MESH:C000589078', (129, 132))	('inactivates', 'NegReg', (241, 252))	('Thiamine', 'Chemical', 'MESH:D013831', (0, 8))	('HCT116', 'CellLine', 'CVCL:0291', (150, 156))	('thiamine pyrophosphate', 'Chemical', 'MESH:D013835', (66, 88))	('thiamine', 'Chemical', 'MESH:D013831', (66, 74))	('depletion of thiamine', 'Phenotype', 'HP:0100503', (43, 64))	('keto acid dehydrogenases', 'Enzyme', (253, 277))	('aKGDH', 'Gene', '4967', (287, 292))	('thiamine', 'Chemical', 'MESH:D013831', (56, 64))	('deprivation', 'Var', (9, 20))	('PDH', 'Gene', (279, 282))	('thiamine', 'Chemical', 'MESH:D013831', (222, 230))
33821	30245009	In addition, CPI-613, a lipoate analogue and a PDH inhibitor, increased the formation of Ac-GSH (Fig.	('increased', 'PosReg', (62, 71))	('CPI-613', 'Var', (13, 20))	('PDH', 'Gene', (47, 50))	('Ac-GSH', 'Chemical', 'MESH:D005978', (89, 95))	('PDH', 'Gene', '54704', (47, 50))	('formation of Ac-GSH', 'MPA', (76, 95))
33834	30245009	As shown in Figures 5G-H, ACSS2 knockdown is detrimental to the fitness of MEF cells with ACLY deficiency, so the co-culture time was shortened to 30 hrs when ACSS2 knockdown cells were used, and the co-culture with HCT116 cells ablated the rescue of cell proliferation.	('HCT116', 'CellLine', 'CVCL:0291', (216, 222))	('cell proliferation', 'CPA', (251, 269))	('knockdown', 'Var', (32, 41))	('ACSS2', 'Gene', (26, 31))	('ACLY deficiency', 'Disease', 'None', (90, 105))	('ACLY deficiency', 'Disease', (90, 105))	('ablated', 'NegReg', (229, 236))
33835	30245009	Consistent with prior findings, [13C6]-glucose contributed minimally to fatty acid synthesis in ACLY KO cells (Figure 5I).	('[13C6]-glucose', 'Chemical', 'MESH:D005947', (32, 46))	('[13C6]-glucose', 'Var', (32, 46))	('fatty acid', 'Chemical', 'MESH:D005227', (72, 82))	('fatty acid synthesis', 'MPA', (72, 92))
33839	30245009	ACLY knockdown had minor effects on de novo lipogenesis (Figures 6A-C), while knockdown or inhibition using a small molecule inhibitor of ACSS2 had larger effects on de novo lipogenesis (Figures 6B-C) when there is no additional acetate in the medium.	('acetate', 'Chemical', 'MESH:D000085', (229, 236))	('de novo lipogenesis', 'MPA', (36, 55))	('knockdown', 'Var', (5, 14))	('ACSS2', 'Gene', (138, 143))	('de novo lipogenesis', 'MPA', (166, 185))
33840	30245009	Furthermore, to evaluate the contribution of ROS-mediated acetate production to intracellular Ac-CoA pools, we measured the labeling patterns of surrogate products of Ac-CoA (Figure 6D), and we saw the incorporation of 18O into Ac-carnitine (Figure 6E) and the increase in [13C2,18O2]- labeled acetylated molecules, including Ac-aspartate in the presence of UK5099 (Figure 6F).	('Ac-CoA', 'Chemical', 'MESH:C059703', (94, 100))	('Ac-carnitine', 'MPA', (228, 240))	('Ac-aspartate', 'MPA', (326, 338))	('Ac-carnitine', 'Chemical', 'MESH:D002331', (228, 240))	('18O', 'Chemical', 'MESH:D013481', (219, 222))	('incorporation', 'MPA', (202, 215))	('Ac-CoA', 'Chemical', 'MESH:C059703', (167, 173))	('18O', 'MPA', (219, 222))	('acetate', 'Chemical', 'MESH:D000085', (58, 65))	('Ac-aspartate', 'Chemical', 'None', (326, 338))	('[13C2,18O2]', 'Chemical', 'MESH:C513342', (273, 284))	('18O', 'Chemical', 'MESH:D013481', (279, 282))	('acetyl', 'Chemical', 'MESH:C011632', (294, 300))	('increase', 'PosReg', (261, 269))	('acetylated molecules', 'MPA', (294, 314))	('UK5099', 'Var', (358, 364))
33841	30245009	Nevertheless, the net effect was that lipogenesis is decreased by exogenous ROS and increased by the presence of catalase (Figures S5A-B), which was likely attributed to the activity of lipogenesis enzymes also being affected by oxidative stress.	('exogenous', 'Var', (66, 75))	('catalase', 'Gene', '847', (113, 121))	('lipogenesis', 'MPA', (38, 49))	('increased', 'PosReg', (84, 93))	('catalase', 'Gene', (113, 121))	('ROS', 'Protein', (76, 79))	('decreased', 'NegReg', (53, 62))	('oxidative stress', 'Phenotype', 'HP:0025464', (229, 245))
33854	30245009	It has also been demonstrated  that the absence of either CoA or NAD+ causes the accumulation of hydroxyethyl-TPP (HETPP), which is the product of the E1 and the substrate of the E2 component.	('absence', 'Var', (40, 47))	('NAD', 'Chemical', 'MESH:D009243', (65, 68))	('CoA', 'Chemical', 'MESH:C065987', (58, 61))	('HETPP', 'Chemical', 'None', (115, 120))	('NAD+', 'Gene', (65, 69))	('hydroxyethyl-TPP', 'Chemical', 'MESH:C047467', (97, 113))	('CoA', 'Gene', (58, 61))	('accumulation', 'PosReg', (81, 93))	('hydroxyethyl-TPP', 'MPA', (97, 113))
33858	30245009	Therefore, although acetate production was depleted by thiamine starvation, neither PDH deletion nor mitochondrial pyruvate carrier inhibition alone was sufficient to completely remove acetate production.	('PDH', 'Gene', (84, 87))	('thiamine', 'Chemical', 'MESH:D013831', (55, 63))	('acetate production', 'MPA', (20, 38))	('acetate production', 'MPA', (185, 203))	('deletion', 'Var', (88, 96))	('remove', 'NegReg', (178, 184))	('PDH', 'Gene', '54704', (84, 87))	('acetate', 'Chemical', 'MESH:D000085', (185, 192))	('acetate', 'Chemical', 'MESH:D000085', (20, 27))	('pyruvate', 'Chemical', 'MESH:D011773', (115, 123))
33862	30245009	ROS levels are dynamic and at steady state, intracellular concentrations of H2O2 vary from nM to muM, while extracellular concentrations of H2O2 may be 10 to 100 times higher under certain circumstances, such as inflammation.	('H2O2', 'Var', (76, 80))	('muM', 'Gene', '56925', (97, 100))	('H2O2', 'Chemical', 'MESH:D014867', (140, 144))	('inflammation', 'Disease', 'MESH:D007249', (212, 224))	('muM', 'Gene', (97, 100))	('inflammation', 'Disease', (212, 224))	('H2O2', 'Chemical', 'MESH:D014867', (76, 80))
33863	30245009	Consistent with this pathway, cancer cells have been shown to produce H2O2 at a rate of around 1 nmol/104 cells/hour , while the combined pyruvate generation and secretion rate (Figure 1B) was found to be around 1 nmol/104 cells/hour.	('H2O2', 'Var', (70, 74))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('pyruvate', 'Chemical', 'MESH:D011773', (138, 146))	('H2O2', 'Chemical', 'MESH:D014867', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
33867	30245009	Nevertheless, ROS can also impair the activity of certain proteins, such as those with active sites containing cysteine residues.	('proteins', 'Protein', (58, 66))	('activity', 'MPA', (38, 46))	('cysteine', 'Chemical', 'MESH:D003545', (111, 119))	('impair', 'NegReg', (27, 33))	('ROS', 'Var', (14, 17))
33868	30245009	For such reasons, exogenous ROS increased ROS-derived acetate production and the incorporation into cellular acetyl groups, but didn't cause a net increase in lipogenesis in cells subjected to ROS.	('exogenous', 'Var', (18, 27))	('ROS-derived acetate production', 'MPA', (42, 72))	('acetate', 'Chemical', 'MESH:D000085', (54, 61))	('incorporation into cellular acetyl groups', 'MPA', (81, 122))	('ROS', 'Protein', (28, 31))	('lipogenesis', 'MPA', (159, 170))	('increased', 'PosReg', (32, 41))	('acetyl', 'Chemical', 'MESH:C011632', (109, 115))
33884	30245009	After overnight incubation in full growth medium, for UK5099 treatment, the old medium was removed and cells were briefly washed with glucose free RPMI 1640 before 1.5 ml of RPMI 1640 (supplemented with 10 % dialyzed FBS) with 0.025 % DMSO or 5 muM UK5099 (final DMSO content 0.025 %) was added to each well.	('glucose free RPMI', 'Disease', 'MESH:D018149', (134, 151))	('glucose free RPMI', 'Disease', (134, 151))	('DMSO', 'Chemical', 'MESH:D004121', (235, 239))	('DMSO', 'Chemical', 'MESH:D004121', (263, 267))	('UK5099', 'Var', (54, 60))	('muM', 'Gene', '56925', (245, 248))	('muM', 'Gene', (245, 248))
33894	30245009	Mouse models of soft tissue sarcoma were generated in a mixed 129/SVJae and C57BL/6 background (The Jackson Laboratory) using a combination of alleles: Pax7CreER-T2, p53fl/fl, LSL-NrasG12D.	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (16, 35))	('soft tissue sarcoma', 'Disease', (16, 35))	('Mouse', 'Species', '10090', (0, 5))	('Pax7CreER-T2', 'Var', (152, 164))	('p53fl/fl', 'Var', (166, 174))	('LSL-NrasG12D', 'Var', (176, 188))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (16, 35))
33899	30245009	siRNA transfection was performed following manufacturer's instructions with Lipofectamine RNAiMAX (Invitrogen), using siRNA pools targeting human ACLY (Dharmacon #L-004915-00), mouse ACSS2 (Dharmacon #L-065412-01), human ACSS2 (Dharmacon #L-010396-00) or a non-targeting control (Dharmacon #D-001810-10-20) at a concentration of 20 nM for ACLY and control, and 5 nM for ACSS2 in growth medium (RPMI 1640 with 10 % FBS).	('Dharmacon', 'Var', (228, 237))	('D-001810-10-20', 'Chemical', 'MESH:C480634', (291, 305))	('human', 'Species', '9606', (140, 145))	('L-010396-00', 'Chemical', 'MESH:D014800', (239, 250))	('Dharmacon #L-065412-01', 'Var', (190, 212))	('L-004915-00', 'Chemical', 'MESH:D014800', (163, 174))	('L-065412-01', 'Chemical', 'MESH:C519584', (201, 212))	('mouse', 'Species', '10090', (177, 182))	('Dharmacon', 'Var', (152, 161))	('human', 'Species', '9606', (215, 220))
33912	30245009	The gradient consisted of 5 to 33% B from 0 to 45 mins and 33 to 98% B from 45 to 50 mins, holding at 98% B until 60 mins with a flow rate of 300 nl/min, 0.1% formic acid in water serving as solvent A, and 80% acetonitrile with 0.1% formic acid serving as solvent B. Peptides were analyzed with an Orbitrap Fusion mass spectrometer (ThermFisher Scientific) operating in positive profile mode with the following full scan settings: 60 000 resolution, mass range 300-1100 m/z, AGC target 2e5, maximum injection time 100 ms. After one full scan in the orbitrap, eight data-independent acquisition (DIA) MS/MS scans of isolation width 50 m/z centered on 325.4125, 375.4375, 425.4625, 475.4875, 525.5125, 575.5375, 625.5625, and 675.5875 m/z were acquired in the ion trap in centroid mode, followed by another full scan, followed by another eight DIA MS/MS scans centered on 725.6125, 775.6375, 825.6625, 875.6875, 925.7125, 975.7375, 1025.7625, and 1075.7875 m/z.	('mum', 'Gene', (495, 498))	('825.6625', 'Var', (890, 898))	('725.6125', 'Var', (870, 878))	('975.7375', 'Var', (920, 928))	('1075.7875 m/z', 'Var', (945, 958))	('1025.7625', 'Var', (930, 939))	('formic acid', 'Chemical', 'MESH:C030544', (233, 244))	('775.6375', 'Var', (880, 888))	('925.7125', 'Var', (910, 918))	('mum', 'Gene', '56925', (495, 498))	('formic acid', 'Chemical', 'MESH:C030544', (159, 170))	('875.6875', 'Var', (900, 908))	('acetonitrile', 'Chemical', 'MESH:C032159', (210, 222))
33958	30245009	Reaction buffer in Eppendorf tube (without [13C3]-pyruvate) was incubated in 37  C water bath for 1 min, and the reaction was initiated by adding [13C3]-pyruvate (final concentration: 200 muM) or the mixture of [13C3]-pyruvate and alpha ketoglutarate (final concentration: 200 muM).	('[13C3]', 'Var', (146, 152))	('muM', 'Gene', (277, 280))	('muM', 'Gene', (188, 191))	('[13C3]-pyruvate', 'Chemical', 'MESH:C513342', (146, 161))	('alpha ketoglutarate', 'Chemical', 'MESH:C029743', (231, 250))	('[13C3]-pyruvate', 'Chemical', 'MESH:C513342', (211, 226))	('[13C3]-pyruvate', 'Chemical', 'MESH:C513342', (43, 58))	('muM', 'Gene', '56925', (277, 280))	('muM', 'Gene', '56925', (188, 191))
33963	30245009	Mouse primary sarcoma cell lines were generated from Pax7CreER-T2; p53fl/fl; LSL-NrasG12D tumors as described previously.	('p53fl/fl', 'Var', (67, 75))	('sarcoma', 'Disease', (14, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Mouse', 'Species', '10090', (0, 5))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))
34031	28215838	Among 48 cases who received chemotherapy/radiotherapy, local-recurrence risk was lower in WPRT-based therapy than ICBT alone although it did not demonstrate statistical significance (5-year cumulative rates, 3.5% versus 9.1%, P = 0.48).	('WPRT', 'Chemical', '-', (90, 94))	('lower', 'NegReg', (81, 86))	('WPRT-based therapy', 'Var', (90, 108))	('local-recurrence', 'CPA', (55, 71))
34049	28215838	In our analysis of stage IA disease, however, non-chemotherapy treatment had increased risk of both local- and distant-recurrences compared to a chemotherapy-based counterpart.	('non-chemotherapy treatment', 'Var', (46, 72))	('stage IA disease', 'Disease', (19, 35))	('stage IA disease', 'Disease', 'MESH:D058625', (19, 35))
34077	32789120	According to the latest soft tissue and bone tumours classification, presented by the World Health Organization (WHO), PNETs are considered to be Ewing sarcomas, since identical chromosomal translocation (t(11;22)(q24;q12)) has been detected in Ewing sarcomas and in more than 85% of PNETs .	('bone tumours', 'Disease', (40, 52))	('PNETs', 'Phenotype', 'HP:0030065', (119, 124))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (251, 259))	('PNETs', 'Phenotype', 'HP:0030065', (284, 289))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (245, 258))	('bone tumours', 'Disease', 'MESH:D001859', (40, 52))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (146, 160))	('Ewing sarcomas', 'Disease', (146, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (146, 160))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (245, 259))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (205, 222))	('Ewing sarcomas', 'Disease', (245, 259))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (146, 159))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (245, 259))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('t(11;22)(q24;q12', 'Var', (205, 221))	('bone tumour', 'Phenotype', 'HP:0010622', (40, 51))
34165	27562075	The relative gene expression of MMP-2, -3 and -9 was quantified by real-time polymerase chain reaction (PCR) using a thermo cycler with TaqMan  Array and specific primers (MMP-2: Hs01548727_m1; MMP-3: Hs01548727_m1; MMP-9: Hs01548727_m1; glyceraldehyde 3-phosphate dehydrogenase (GAPDH): NM_002046.3) (Applied Biosystems, Grand Island, USA).	('MMP-9', 'Gene', (216, 221))	('MMP-3', 'Gene', '4314', (194, 199))	('MMP-3', 'Gene', (194, 199))	('MMP-2', 'Gene', '4313', (32, 37))	('MMP-2', 'Gene', (172, 177))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (238, 278))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (238, 278))	('MMP-2', 'Gene', '4313', (172, 177))	('Hs01548727_m1', 'Var', (223, 236))	('MMP-2, -3 and -9', 'Gene', '4313;4314;4318', (32, 48))	('MMP-9', 'Gene', '4318', (216, 221))	('GAPDH', 'Gene', '2597', (280, 285))	('MMP-2', 'Gene', (32, 37))	('GAPDH', 'Gene', (280, 285))
34221	27439614	FOXM1 interruption by siRNA increased the chemosensitivity for DOX in both SS cell lines.	('increased', 'PosReg', (28, 37))	('interruption', 'Var', (6, 18))	('DOX', 'Chemical', 'MESH:D004317', (63, 66))	('chemosensitivity for DOX', 'MPA', (42, 66))	('FOXM1', 'Gene', (0, 5))	('SS', 'Phenotype', 'HP:0012570', (75, 77))
34229	27439614	Silencing FOXM1 expression suppressed the proliferation of both cancer and sarcoma cell lines.	('proliferation', 'CPA', (42, 55))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('cancer', 'Disease', (64, 70))	('suppressed', 'NegReg', (27, 37))	('sarcoma', 'Disease', (75, 82))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('Silencing', 'Var', (0, 9))	('FOXM1', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
34260	27439614	; GAPDH Hs99999905_m1.	('Hs99999905_m1', 'Var', (8, 21))	('GAPDH', 'Gene', '2597', (2, 7))	('GAPDH', 'Gene', (2, 7))
34283	27439614	In the present study's univariate analysis, FOXM1 expression was revealed to be correlated with poor prognosis for OS and EFS among the SS patients treated with chemotherapy, and the multivariate analysis adjusted for surgical stage, sex and age showed that FOXM1 expression was an independent prognostic factor.	('SS', 'Phenotype', 'HP:0012570', (136, 138))	('patients', 'Species', '9606', (139, 147))	('EFS', 'Disease', (122, 125))	('expression', 'Var', (50, 60))	('FOXM1', 'Gene', (44, 49))
34291	27439614	reported that the survival of SS patients with a high expression of topoisomerase IIalpha was worse than that of SS patients with a lower expression.	('SS', 'Phenotype', 'HP:0012570', (113, 115))	('patients', 'Species', '9606', (33, 41))	('SS', 'Phenotype', 'HP:0012570', (30, 32))	('patients', 'Species', '9606', (116, 124))	('high expression', 'Var', (49, 64))	('worse', 'NegReg', (94, 99))	('topoisomerase IIalpha', 'Enzyme', (68, 89))
34293	27439614	Interruption of FOXM1 reduced the survivin expression in leukemia and osteosarcoma cell lines and inhibited cell-cycle progression.	('survivin', 'Protein', (34, 42))	('leukemia', 'Disease', (57, 65))	('inhibited', 'NegReg', (98, 107))	('osteosarcoma cell lines', 'Disease', (70, 93))	('Interruption', 'Var', (0, 12))	('osteosarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('FOXM1', 'Gene', (16, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('reduced', 'NegReg', (22, 29))	('osteosarcoma cell lines', 'Disease', 'MESH:D012516', (70, 93))	('expression', 'MPA', (43, 53))	('cell-cycle progression', 'CPA', (108, 130))	('leukemia', 'Phenotype', 'HP:0001909', (57, 65))	('leukemia', 'Disease', 'MESH:D007938', (57, 65))
34294	27439614	Survivin also associated with DNA damage response, it may facilitate recruitment of repair proteins at sites of DNA damage and inhibition of survivin mediate the increase chemosensivity for DOX in leukemia cell line.	('recruitment', 'MPA', (69, 80))	('leukemia', 'Disease', 'MESH:D007938', (197, 205))	('facilitate', 'PosReg', (58, 68))	('increase', 'PosReg', (162, 170))	('DOX', 'Chemical', 'MESH:D004317', (190, 193))	('associated', 'Reg', (14, 24))	('survivin', 'Gene', (141, 149))	('inhibition', 'Var', (127, 137))	('leukemia', 'Disease', (197, 205))	('chemosensivity for DOX', 'MPA', (171, 193))	('leukemia', 'Phenotype', 'HP:0001909', (197, 205))
34299	27439614	FOXM1 interruption by siRNA caused a reduction in cell proliferation, significantly so in the cell line SYO-1.	('interruption', 'Var', (6, 18))	('SYO-1', 'Gene', '55027', (104, 109))	('reduction', 'NegReg', (37, 46))	('SYO-1', 'Gene', (104, 109))	('FOXM1', 'Gene', (0, 5))	('cell proliferation', 'CPA', (50, 68))
34300	27439614	FOXM1 interruption caused decreasing viability treated with DOX in both the SYO-1 and HS-SY-II cells.	('interruption', 'Var', (6, 18))	('SYO-1', 'Gene', '55027', (76, 81))	('HS-SY-II', 'CellLine', 'CVCL:8719', (86, 94))	('viability', 'MPA', (37, 46))	('decreasing', 'NegReg', (26, 36))	('SYO-1', 'Gene', (76, 81))	('FOXM1', 'Gene', (0, 5))	('DOX', 'Chemical', 'MESH:D004317', (60, 63))
34308	27439614	This deference effect of FOXM1 interruption between the two cell lines, suggested that the FOXM1 involved in SS tumor progression in a variety of ways.	('SS tumor', 'Disease', (109, 117))	('involved in', 'Reg', (97, 108))	('SS', 'Phenotype', 'HP:0012570', (109, 111))	('interruption', 'Var', (31, 43))	('FOXM1', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SS tumor', 'Disease', 'MESH:D009369', (109, 117))	('FOXM1', 'Gene', (25, 30))
34313	27439614	The proteasome inhibitor MG132 has shown antitumor activity for SS cell lines in vitro, However, the results from a Phase II trial of a single use of bortezomib against a variety of relapsed or metastatic sarcomas including SS have been discouraging.	('bortezomib', 'Chemical', 'MESH:D000069286', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('SS', 'Phenotype', 'HP:0012570', (64, 66))	('MG132', 'Chemical', 'MESH:C072553', (25, 30))	('tumor', 'Disease', (45, 50))	('sarcomas', 'Disease', 'MESH:D012509', (205, 213))	('MG132', 'Var', (25, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (205, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('relapsed', 'Disease', (182, 190))	('SS', 'Phenotype', 'HP:0012570', (224, 226))	('sarcomas', 'Disease', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
34317	27439614	We have elucidated that FOXM1 inhibition is a candidate treatment option for SS, based on our clinicopathologic assessment and in vitro study, using siRNA and thiostrepton on two SS cell lines.	('SS', 'Phenotype', 'HP:0012570', (77, 79))	('inhibition', 'Var', (30, 40))	('SS', 'Phenotype', 'HP:0012570', (179, 181))	('thiostrepton', 'Chemical', 'MESH:D013883', (159, 171))	('FOXM1', 'Gene', (24, 29))
34500	23839490	To superexpand the gene-modified T cells, 2 x 107 cells were transferred to gas-permeable culture devices with 500 ml capacity (Wilson Wolf Manufacturing, New Brighton, MN, USA) in 400 ml of medium containing IL-2 (50 U ml-1) on day 5 after the prestimulation.	('gene-modified', 'Var', (19, 32))	('MN', 'CellLine', 'CVCL:U508', (169, 171))	('Wilson Wolf Manufacturing', 'Disease', (128, 153))	('Wilson Wolf Manufacturing', 'Disease', 'MESH:D006527', (128, 153))
34545	23839490	Mice receiving gene-modified T-cell therapy had lower numbers of pulmonary tumours than control mice (Figure 4B).	('pulmonary tumours', 'Disease', 'MESH:D008175', (65, 82))	('mice', 'Species', '10090', (96, 100))	('gene-modified', 'Var', (15, 28))	('lower', 'NegReg', (48, 53))	('Mice', 'Species', '10090', (0, 4))	('pulmonary tumours', 'Disease', (65, 82))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
34605	28193671	eBAT, a bispecific EGF-urokinase angiotoxin, was developed as a targeted, second generation bispecific biologic drug consisting of human EGF (targeting EGFR), human amino terminal transferase (ATF is the high affinity binding moiety of human urokinase, targeting uPAR), and genetically modified Pseudomonas exotoxin, mutated to reduce immunogenicity and facilitate ER retention.	('human', 'Species', '9606', (236, 241))	('mutated', 'Var', (317, 324))	('ATF', 'Gene', '2668', (193, 196))	('ATF', 'Gene', (193, 196))	('facilitate', 'PosReg', (354, 364))	('immunogenicity', 'MPA', (335, 349))	('human', 'Species', '9606', (131, 136))	('human', 'Species', '9606', (159, 164))	('eBAT', 'Chemical', '-', (0, 4))
34618	28193671	We report on the impact of bispecific targeting on the toxicity risks associated with targeting of EGFR.	('toxicity', 'Disease', (55, 63))	('EGFR', 'Gene', (99, 103))	('targeting', 'Var', (86, 95))	('toxicity', 'Disease', 'MESH:D064420', (55, 63))
34620	28193671	Furthermore, our findings support our belief that bispecificity reduces overall toxicity risks associated with EGFR targeting.	('bispecificity', 'Var', (50, 63))	('EGFR', 'Gene', (111, 115))	('toxicity', 'Disease', 'MESH:D064420', (80, 88))	('reduces', 'NegReg', (64, 71))	('toxicity', 'Disease', (80, 88))
34696	28193671	Since other studies have shown that EGFR-targeted therapies are associated with significant dose-limiting cutaneous and gastrointestinal toxicities, we further examined the safety of eBAT versus EGF-toxin alone in normal C57BL/6 mice.	('EGFR-targeted', 'Gene', (36, 49))	('gastrointestinal toxicities', 'Disease', (120, 147))	('mice', 'Species', '10090', (229, 233))	('gastrointestinal toxicities', 'Disease', 'MESH:D005767', (120, 147))	('eBAT', 'Chemical', '-', (183, 187))	('therapies', 'Var', (50, 59))
34720	28193671	In fact, dogs receiving eBAT had longer survival times than dogs treated with any other contemporary experimental therapy.	('dogs', 'Species', '9615', (60, 64))	('dogs', 'Species', '9615', (9, 13))	('eBAT', 'Chemical', '-', (24, 28))	('survival times', 'CPA', (40, 54))	('eBAT', 'Var', (24, 28))	('longer', 'PosReg', (33, 39))
34756	26568679	Accordingly, discovery of many disease-associated genetic risk variants requires exceedingly large cohorts in genome-wide association studies, as recently exemplified in a large-size cohort analysis of lung adenocarcinoma, wherein 26 research departments from several countries pulled their resources together to conduct the study.	('lung adenocarcinoma', 'Disease', (202, 221))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('variants', 'Var', (63, 71))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('men', 'Species', '9606', (249, 252))
34761	26568679	Since heterogeneity can increase through time and/or in cases wherein tumors are exposed to different microenvironments, heterogeneity can be high when comparing metastases to primary tumors, particularly in cases whereby metastases take up to several decades to evolve allowing time for stochastic genotypic or epigenetic changes.	('metastases', 'Disease', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('men', 'Species', '9606', (114, 117))	('metastases to primary tumors', 'Disease', (162, 190))	('epigenetic changes', 'Var', (312, 330))	('metastases', 'Disease', (222, 232))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('metastases', 'Disease', 'MESH:D009362', (222, 232))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('metastases to primary tumors', 'Disease', 'MESH:D009362', (162, 190))
34802	26568679	Similarly, these methods would be ineffectual in inferring significance of tumor drivers harboring activating mutations and whose gene expression remained unchanged.	('activating', 'PosReg', (99, 109))	('mutations', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
34844	30617281	Although the use of a more objective RMS classification scheme based on presence or absence of the t(2;13) or t(1;13) translocations or expression of PAX3-FOXO1 or PAX7-FOXO1 fusion transcript may clarify this matter, that information has not been captured by SEER or many other large cancer registries.	('translocations', 'Var', (118, 132))	('PAX7', 'Gene', '5081', (164, 168))	('PAX7', 'Gene', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (285, 291))	('PAX3-FOXO1', 'Gene', (150, 160))	('t(2;13', 'Gene', (99, 105))	('t(1;13', 'Gene', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
34849	30617281	Syndromes that are most commonly seen in children with ERMS include Li-Fraumeni syndrome (germline mutation of TP53, a tumour suppressor); Neurofibromatosis type I (deletions in the NF1 gene) ; Costello syndrome (HRAS mutation) ; Noonan syndrome (germline genetic variants activating RAS-MAPK pathways) ; Beckwith-Wiedemann syndrome , and DICER1 syndrome (germline DICER1 mutations)  (Table 1).	('DICER1', 'Gene', '23405', (339, 345))	('HRAS', 'Gene', (213, 217))	('NF1', 'Gene', (182, 185))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (305, 332))	('Costello syndrome', 'Disease', 'MESH:D056685', (194, 211))	('children', 'Species', '9606', (41, 49))	('DICER1', 'Gene', (339, 345))	('Neurofibromatosis type I', 'Disease', (139, 163))	('RAS-MAPK pathways', 'Pathway', (284, 301))	('TP53', 'Gene', '7157', (111, 115))	('Noonan syndrome', 'Disease', (230, 245))	('Costello syndrome', 'Disease', (194, 211))	('Li-Fraumeni syndrome', 'Disease', (68, 88))	('DICER1', 'Gene', '23405', (365, 371))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (68, 88))	('Noonan syndrome', 'Disease', 'MESH:D009634', (230, 245))	('activating', 'PosReg', (273, 283))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('Neurofibromatosis type I', 'Disease', 'MESH:C537392', (139, 163))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('Beckwith-Wiedemann syndrome', 'Disease', (305, 332))	('DICER1', 'Gene', (365, 371))	('deletions', 'Var', (165, 174))	('TP53', 'Gene', (111, 115))	('tumour', 'Disease', (119, 125))	('NF1', 'Gene', '4763', (182, 185))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (139, 156))	('HRAS', 'Gene', '3265', (213, 217))
34852	30617281	This finding seems to contrast experimental studies showing that germline loss of specific tumor suppressors facilitates PAX3-FOXO1-driven neoplasia in genetically-engineered mouse models .	('neoplasia', 'Disease', (139, 148))	('PAX3-FOXO1-driven', 'Var', (121, 138))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('loss', 'NegReg', (74, 78))	('neoplasia', 'Disease', 'MESH:D009369', (139, 148))	('neoplasia', 'Phenotype', 'HP:0002664', (139, 148))	('men', 'Species', '9606', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('mouse', 'Species', '10090', (175, 180))	('facilitates', 'PosReg', (109, 120))
34853	30617281	Importantly, large population-based studies are required to systematically characterize mutations (Table 1) in children with RMS and to evaluate differences by fusion-protein status.	('RMS', 'Disease', (125, 128))	('mutations', 'Var', (88, 97))	('children', 'Species', '9606', (111, 119))
34869	30617281	The t(2;13) and t(1;13) translocations respectively generate PAX3-FOXO1 and PAX7-FOXO1 fusion genes that are expressed as fusion transcripts and translated into neomorphic fusion proteins.	('PAX7', 'Gene', '5081', (76, 80))	('PAX3-FOXO1', 'Gene', (61, 71))	('fusion', 'Var', (87, 93))	('PAX7', 'Gene', (76, 80))	('translocations', 'Var', (24, 38))
34874	30617281	Some of these sites, such as AKT kinase-dependent phosphorylation sites at S437 and S500, regulate the subcellular localization and degradation of wild-type FOXO1 but not PAX3-FOXO1 .	('S437', 'Var', (75, 79))	('degradation', 'MPA', (132, 143))	('AKT', 'Gene', '207', (29, 32))	('FOXO1', 'Gene', (157, 162))	('subcellular localization', 'MPA', (103, 127))	('S500', 'Var', (84, 88))	('AKT', 'Gene', (29, 32))	('regulate', 'Reg', (90, 98))
34875	30617281	Expression of the PAX3-FOXO1 fusion protein is stabilized by S503 phosphorylation mediated by the serine/threonine protein kinase PLK1 and by K426 and K429 acetylation mediated by the histone acetyltransferase KAT2B.	('acetylation', 'MPA', (156, 167))	('K429', 'Var', (151, 155))	('serine', 'Chemical', 'MESH:D012694', (98, 104))	('Expression', 'MPA', (0, 10))	('KAT2B', 'Gene', '8850', (210, 215))	('PAX3-FOXO1', 'Gene', (18, 28))	('K426', 'Var', (142, 146))	('PLK1', 'Gene', (130, 134))	('PLK1', 'Gene', '5347', (130, 134))	('KAT2B', 'Gene', (210, 215))	('S503', 'Var', (61, 65))
34882	30617281	By interacting with these transcription factors and chromatin-related proteins, PAX3-FOXO1 likely reprograms the chromatin landscape and establishes super-enhancers that associate with target gene promoters by three-dimensional looping.	('PAX3-FOXO1', 'Var', (80, 90))	('chromatin landscape', 'MPA', (113, 132))	('interacting', 'Interaction', (3, 14))	('reprograms', 'Reg', (98, 108))	('men', 'Species', '9606', (218, 221))
34883	30617281	The PAX3-FOXO1 and PAX7-FOXO1 fusion proteins function as oncoproteins by dysregulating multiple cellular pathways (Table 3).	('fusion', 'Var', (30, 36))	('PAX3-FOXO1', 'Gene', (4, 14))	('PAX7', 'Gene', '5081', (19, 23))	('dysregulating', 'Reg', (74, 87))	('PAX7', 'Gene', (19, 23))
34884	30617281	Following gene transfer into several mammalian cell types, exogenous PAX3-FOXO1 expression is associated with transforming activity, including loss of contact inhibition of proliferation and gain of anchorage independence.	('transforming activity', 'CPA', (110, 131))	('PAX3-FOXO1', 'Gene', (69, 79))	('contact', 'MPA', (151, 158))	('anchorage independence', 'CPA', (199, 221))	('mammalian', 'Species', '9606', (37, 46))	('gain', 'PosReg', (191, 195))	('loss', 'NegReg', (143, 147))	('exogenous', 'Var', (59, 68))
34886	30617281	Moreover, a mouse knock-in model that conditionally expresses a Pax3-Foxo1 fusion in cells of the myogenic lineage develops ARMS-like tumors, and tumor susceptibility is greatly increased in animals lacking tumor suppressors encoded by either the p53 or Cdkn2a genes .	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('Pax3', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('p53', 'Gene', (247, 250))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('ARMS-like tumors', 'Disease', (124, 140))	('fusion', 'Var', (75, 81))	('Foxo1', 'Gene', (69, 74))	('ARMS-like tumors', 'Disease', 'MESH:D009369', (124, 140))	('Foxo1', 'Gene', '56458', (69, 74))	('increased', 'PosReg', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Cdkn2a', 'Gene', '12578', (254, 260))	('Pax3', 'Gene', '18505', (64, 68))	('mouse', 'Species', '10090', (12, 17))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('lacking', 'NegReg', (199, 206))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Cdkn2a', 'Gene', (254, 260))
34888	30617281	These assays have revealed that 60% of patients with ARMS express PAX3-FOXO1, 20% express PAX7-FOXO1, and 20% are FN .	('patients', 'Species', '9606', (39, 47))	('PAX7', 'Gene', '5081', (90, 94))	('PAX3-FOXO1', 'Var', (66, 76))	('ARMS', 'Disease', (53, 57))	('PAX7', 'Gene', (90, 94))
34890	30617281	Nucleic acid sequencing has shown that patients with FN ARMS do not express fusion proteins but instead show genetic changes in tumour cells that are similar to ERMS tumors, such as whole chromosome gains, recurrent point mutations, and 11p15.5 allelic loss .	('tumour', 'Disease', (128, 134))	('FN ARMS', 'Disease', 'None', (53, 60))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('whole chromosome gains', 'CPA', (182, 204))	('FN ARMS', 'Disease', (53, 60))	('point mutations', 'Var', (216, 231))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('ERMS tumors', 'Disease', (161, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('ERMS tumors', 'Disease', 'MESH:D009369', (161, 172))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('11p15.5', 'Gene', (237, 244))
34893	30617281	Approximately one third of patients with FN RMS are reported to have activating mutations in key components of the RAS pathway, including mutations in NRAS, KRAS, and HRAS.	('KRAS', 'Gene', '3845', (157, 161))	('RAS pathway', 'Pathway', (115, 126))	('activating', 'PosReg', (69, 79))	('patients', 'Species', '9606', (27, 35))	('FN RMS', 'Disease', (41, 47))	('HRAS', 'Gene', '3265', (167, 171))	('KRAS', 'Gene', (157, 161))	('NRAS', 'Gene', (151, 155))	('HRAS', 'Gene', (167, 171))	('NRAS', 'Gene', '4893', (151, 155))	('mutations', 'Var', (138, 147))
34894	30617281	NRAS mutations are predominant in adolescents and KRAS and HRAS mutations are more frequent in infants aged <1 year .	('infants', 'Species', '9606', (95, 102))	('HRAS', 'Gene', '3265', (59, 63))	('HRAS', 'Gene', (59, 63))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', (50, 54))	('KRAS', 'Gene', '3845', (50, 54))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
34895	30617281	Mutations in genes encoding proteins associated with RAS pathway intracellular signaling, such as protein tyrosine phosphatase, non-receptor type 11 (PTPN11), NF1, the B-Raf proto-oncogene, BRAF (encoding a serine/threonine kinase) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, protein is also known as PI3Kalpha), are also described.	('NF1', 'Gene', '4763', (159, 162))	('Raf', 'Gene', (170, 173))	('BRAF', 'Gene', (190, 194))	('PTPN11', 'Gene', (150, 156))	('PIK3CA', 'Gene', (308, 314))	('PIK3CA', 'Gene', '5290', (308, 314))	('PI3Kalpha', 'Gene', '5290', (341, 350))	('PI3Kalpha', 'Gene', (341, 350))	('Mutations', 'Var', (0, 9))	('Raf', 'Gene', '673;5894', (170, 173))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (236, 306))	('serine', 'Chemical', 'MESH:D012694', (207, 213))	('protein tyrosine phosphatase, non-receptor type 11', 'Gene', '5781', (98, 148))	('NF1', 'Gene', (159, 162))	('PTPN11', 'Gene', '5781', (150, 156))	('BRAF', 'Gene', '673', (190, 194))
34896	30617281	Overall, >50% of patients with FN RMS harbor a mutation expected to impact RAS-RAF-MAPK (mitogen-activated protein kinase 1) and/or PI3K-AKT (serine-threonine kinase 1)-mTOR (mammalian target of rapamycin) pathways .	('RAF', 'Gene', '673;5894', (79, 82))	('RAF', 'Gene', (79, 82))	('mTOR', 'Gene', '2475', (169, 173))	('mutation', 'Var', (47, 55))	('mammalian target of rapamycin', 'Gene', '2475', (175, 204))	('mammalian target of rapamycin', 'Gene', (175, 204))	('mTOR', 'Gene', (169, 173))	('impact', 'Reg', (68, 74))	('AKT', 'Gene', '207', (137, 140))	('mitogen-activated protein kinase 1', 'Gene', '5594', (89, 123))	('serine', 'Chemical', 'MESH:D012694', (142, 148))	('patients', 'Species', '9606', (17, 25))	('AKT', 'Gene', (137, 140))	('mitogen-activated protein kinase 1', 'Gene', (89, 123))
34899	30617281	Activating mutations in FGFR4 (encoding a fibroblast growth factor receptor), occur in ~7% of patients with FN RMS.	('FGFR4', 'Gene', '2264', (24, 29))	('FGFR4', 'Gene', (24, 29))	('patients', 'Species', '9606', (94, 102))	('Activating mutations', 'Var', (0, 20))	('FN RMS', 'Disease', (108, 114))
34900	30617281	The K535 and E550 FGFR mutants activate RAS and STAT (signal transducer and activator of transcription) signaling pathways and induce tumor growth and metastatic behavior in mouse tumor cells expressing the human protein .	('metastatic behavior', 'CPA', (151, 170))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mouse', 'Species', '10090', (174, 179))	('activate', 'PosReg', (31, 39))	('FGFR', 'Gene', '2263;2264', (18, 22))	('induce', 'PosReg', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('RAS', 'Pathway', (40, 43))	('tumor', 'Disease', (180, 185))	('E550', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('FGFR', 'Gene', (18, 22))	('human', 'Species', '9606', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('K535', 'Var', (4, 8))
34906	30617281	In poor prognosis patients with RMS (that is, those with advanced or metastatic disease), IRS-1 activation appears refractory to normal negative feedback mediated by increased phosphorylated mTOR and S6 Kinase , and inhibiting IGF1R activity can promote compensatory regulatory activity of the SRC family kinase, YES .	('SRC family kinase', 'Enzyme', (294, 311))	('promote', 'PosReg', (246, 253))	('activity', 'MPA', (233, 241))	('compensatory regulatory activity', 'MPA', (254, 286))	('mTOR', 'Gene', (191, 195))	('inhibiting', 'Var', (216, 226))	('increased', 'PosReg', (166, 175))	('mTOR', 'Gene', '2475', (191, 195))	('IRS-1', 'Gene', (90, 95))	('RMS', 'Disease', (32, 35))	('IGF1R', 'Gene', (227, 232))	('patients', 'Species', '9606', (18, 26))	('IGF1R', 'Gene', '3480', (227, 232))	('IRS-1', 'Gene', '3667', (90, 95))
34907	30617281	The epidermal growth factor receptor tyrosine kinase ERBB2 is frequently expressed  and upregulated with associated MAPK signalling in response to IGF1R inhibition .	('ERBB2', 'Gene', '2064', (53, 58))	('upregulated', 'PosReg', (88, 99))	('receptor tyrosine kinase', 'Gene', (28, 52))	('receptor tyrosine kinase', 'Gene', '5979', (28, 52))	('IGF1R', 'Gene', '3480', (147, 152))	('MAPK signalling', 'MPA', (116, 131))	('IGF1R', 'Gene', (147, 152))	('inhibition', 'Var', (153, 163))	('ERBB2', 'Gene', (53, 58))
34908	30617281	Furthermore, knockdown of PIK3CA leads to increased expression of PIK3CA isoforms and elevated RAS pathway signaling in cell line models .	('elevated', 'PosReg', (86, 94))	('increased', 'PosReg', (42, 51))	('RAS pathway', 'Pathway', (95, 106))	('PIK3CA', 'Gene', '5290', (26, 32))	('PIK3CA', 'Gene', (66, 72))	('expression', 'MPA', (52, 62))	('PIK3CA', 'Gene', '5290', (66, 72))	('knockdown', 'Var', (13, 22))	('PIK3CA', 'Gene', (26, 32))
34910	30617281	High PAX7 expression sustains migration and invasiveness in ERMS cells by upregulating the Ephrin receptors A3 (EPHA3) and A1 (EFNA1) .	('invasiveness', 'Disease', (44, 56))	('Ephrin receptors A3', 'Gene', (91, 110))	('upregulating', 'PosReg', (74, 86))	('High', 'Var', (0, 4))	('Ephrin receptors A3', 'Gene', '2042', (91, 110))	('EFNA1', 'Gene', (127, 132))	('invasiveness', 'Disease', 'MESH:D009361', (44, 56))	('sustains', 'PosReg', (21, 29))	('PAX7', 'Gene', '5081', (5, 9))	('migration', 'CPA', (30, 39))	('EPHA3', 'Gene', '2042', (112, 117))	('EFNA1', 'Gene', '1942', (127, 132))	('PAX7', 'Gene', (5, 9))	('EPHA3', 'Gene', (112, 117))
34911	30617281	Moreover, ERMS cell lines deficient in ephrin receptors EPHA2 and EPHB2 have reduced migratory capacity and are induced to differentiate into a myogenic-like phenotype.	('EPHA2', 'Gene', '1969', (56, 61))	('deficient', 'Var', (26, 35))	('induced', 'Reg', (112, 119))	('migratory capacity', 'CPA', (85, 103))	('EPHA2', 'Gene', (56, 61))	('EPHB2', 'Gene', '2048', (66, 71))	('reduced', 'NegReg', (77, 84))	('EPHB2', 'Gene', (66, 71))	('differentiate', 'CPA', (123, 136))
34913	30617281	Platelet-derived growth factor receptor alpha (PDGFRA) gene expression is driven by the fusion protein in FP RMS, and PDGFRA is occasionally mutated in FN RMS, whereas the PDGFRB is primarily expressed in the vascular stroma of RMS .	('mutated', 'Var', (141, 148))	('PDGFRB', 'Gene', (172, 178))	('PDGFRB', 'Gene', '5159', (172, 178))	('Platelet-derived growth factor receptor alpha', 'Gene', (0, 45))	('PDGFRA', 'Gene', (118, 124))	('Platelet-derived growth factor receptor alpha', 'Gene', '5156', (0, 45))	('fusion protein', 'Protein', (88, 102))	('PDGFRA', 'Gene', '5156', (118, 124))	('PDGFRA', 'Gene', (47, 53))	('PDGFRA', 'Gene', '5156', (47, 53))
34915	30617281	Mutation or promoter methylation of the tumour suppressor PTEN can occur in FN RMS and negatively regulates PI3K signaling .	('regulates', 'Reg', (98, 107))	('PTEN', 'Gene', '5728', (58, 62))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (40, 46))	('Mutation', 'Var', (0, 8))	('negatively', 'NegReg', (87, 97))	('PI3K signaling', 'Pathway', (108, 122))	('promoter', 'MPA', (12, 20))	('FN RMS', 'Disease', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('PTEN', 'Gene', (58, 62))
34916	30617281	In a recent targeted re-sequencing study of tumour cells from 631 patients with FN RMS, TP53 mutations were identified at a higher incidence of 12% than had been previously reported ,.	('mutations', 'Var', (93, 102))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('FN RMS', 'Disease', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('patients', 'Species', '9606', (66, 74))
34918	30617281	In addition, promoter methylation, allelic loss and mutation of tumour suppressor cyclin dependent kinase inhibitor 2A (CDKN2A) is frequent.	('cyclin dependent kinase inhibitor 2A', 'Gene', (82, 118))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('CDKN2A', 'Gene', (120, 126))	('tumour', 'Disease', (64, 70))	('allelic loss', 'Var', (35, 47))	('mutation', 'Var', (52, 60))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (82, 118))	('promoter', 'MPA', (13, 21))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
34919	30617281	The finding of p53 pathway disruption or loss of CDKN2A in RMS is concordant with model systems in which these changes are synergistic and critical for increasing penetrance in PAX3-FOXO1 transgenic mouse models (Box 1) .	('mouse', 'Species', '10090', (199, 204))	('RMS', 'Disease', (59, 62))	('disruption', 'Var', (27, 37))	('p53 pathway', 'Pathway', (15, 26))	('CDKN2A', 'Gene', (49, 55))	('loss', 'NegReg', (41, 45))
34920	30617281	The Catenin Beta 1 gene, CTNNB1, is commonly mutated in FN RMS, and beta-Catenin and other proteins associated with canonical WNT signaling (a key pathway involved in development) are expressed in a high proportion of FN and FP RMS tumors .	('CTNNB1', 'Gene', '1499', (25, 31))	('Catenin Beta 1', 'Gene', (4, 18))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('Catenin Beta 1', 'Gene', '1499', (4, 18))	('beta-Catenin', 'Gene', (68, 80))	('CTNNB1', 'Gene', (25, 31))	('beta-Catenin', 'Gene', '1499', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('FN RMS', 'Disease', (56, 62))	('men', 'Species', '9606', (174, 177))	('FN and FP RMS tumors', 'Disease', 'MESH:D009369', (218, 238))	('mutated', 'Var', (45, 52))
34921	30617281	Notably, inhibition of Wnt Family Member 3a (Wnt3a) protein or Glycogen Synthase Kinase 3 Beta (GSK3B) in cultured RMS cells results in the nuclear translocation and transcriptional activation of beta-Catenin in RMS cells, followed by decreased proliferation and the induction of differentiation, which suggests a potential therapeutic approach.	('nuclear translocation', 'MPA', (140, 161))	('Glycogen Synthase Kinase 3 Beta', 'Gene', '2932', (63, 94))	('Wnt3a', 'Gene', '89780', (45, 50))	('Glycogen Synthase Kinase 3 Beta', 'Gene', (63, 94))	('transcriptional', 'MPA', (166, 181))	('GSK3B', 'Gene', '2932', (96, 101))	('proliferation', 'CPA', (245, 258))	('beta-Catenin', 'Gene', (196, 208))	('decreased', 'NegReg', (235, 244))	('GSK3B', 'Gene', (96, 101))	('activation', 'PosReg', (182, 192))	('differentiation', 'CPA', (280, 295))	('Wnt3a', 'Gene', (45, 50))	('beta-Catenin', 'Gene', '1499', (196, 208))	('induction', 'Reg', (267, 276))	('inhibition', 'Var', (9, 19))
34923	30617281	Cross-talk between these developmental pathways and RAS signalling  creates an integrated signalling network that supports the development of RMS .	('RMS', 'Disease', (142, 145))	('development', 'CPA', (127, 138))	('men', 'Species', '9606', (32, 35))	('Cross-talk', 'Var', (0, 10))	('supports', 'PosReg', (114, 122))	('men', 'Species', '9606', (134, 137))
34924	30617281	Mutations in MYOD1 occurring together with mutations in genes of the PI3K-AKT pathway genes define a particularly aggressive form of FN RMS in children and adults .	('AKT', 'Gene', '207', (74, 77))	('FN RMS', 'Disease', (133, 139))	('Mutations', 'Var', (0, 9))	('MYOD1', 'Gene', '4654', (13, 18))	('children', 'Species', '9606', (143, 151))	('AKT', 'Gene', (74, 77))	('MYOD1', 'Gene', (13, 18))
34925	30617281	Interestingly, DNA binding sites of L122R mutant MYOD1 are similar to those of the MYC proto-oncogene protein, potentially explaining a switch from differentiation to proliferation.	('L122R', 'Var', (36, 41))	('switch', 'Reg', (136, 142))	('MYOD1', 'Gene', (49, 54))	('L122R', 'Mutation', 'p.L122R', (36, 41))	('MYC', 'Gene', (83, 86))	('differentiation', 'CPA', (148, 163))	('MYOD1', 'Gene', '4654', (49, 54))	('MYC', 'Gene', '4609', (83, 86))
34926	30617281	In addition, mutations may lead to decreased MYOD1 binding adjacent to critical myogenic genes, which is thought to contribute to reduced expression of the myogenic program in RMS .	('MYOD1', 'Gene', (45, 50))	('binding', 'Interaction', (51, 58))	('myogenic genes', 'Gene', (80, 94))	('decreased', 'NegReg', (35, 44))	('expression', 'MPA', (138, 148))	('reduced', 'NegReg', (130, 137))	('mutations', 'Var', (13, 22))	('MYOD1', 'Gene', '4654', (45, 50))
34930	30617281	Patients with RMS may have mutations in BCOR that inactivate the BCL6 Corepressor, which interacts with histone deacetylases .	('mutations', 'Var', (27, 36))	('BCL6', 'Gene', (65, 69))	('inactivate', 'NegReg', (50, 60))	('RMS', 'Disease', (14, 17))	('BCOR', 'Gene', (40, 44))	('Patients', 'Species', '9606', (0, 8))	('BCOR', 'Gene', '54880', (40, 44))	('BCL6', 'Gene', '604', (65, 69))
34931	30617281	Mutations also occur in the gene encoding ARID1A, a protein involved in the SWI/SNF chromatin remodelling complex .	('occur', 'Reg', (15, 20))	('ARID1A', 'Gene', '8289', (42, 48))	('Mutations', 'Var', (0, 9))	('ARID1A', 'Gene', (42, 48))
34932	30617281	Together with global and specific changes in DNA methylation and histone marks, and expression of microRNAs and other noncoding RNAs , there is increasing evidence for epigenetic regulation shaping RMS development and progression.	('men', 'Species', '9606', (209, 212))	('changes', 'Reg', (34, 41))	('RMS', 'Disease', (198, 201))	('epigenetic regulation', 'Var', (168, 189))
34933	30617281	Early studies of FP RMS suggested that presence of the PAX3-FOXO1 fusion transcript correlated with greater metastasis risk than PAX7-FOXO1, but that initial finding has not been consistently validated in clinical trials.	('PAX7', 'Gene', (129, 133))	('metastasis', 'CPA', (108, 118))	('PAX3-FOXO1', 'Gene', (55, 65))	('PAX7', 'Gene', '5081', (129, 133))	('presence', 'Var', (39, 47))
34939	30617281	Expression of SNAIL and SNAIL2 derails the myogenic differentiation program , which is associated with cell proliferation arrest.	('derails', 'Reg', (31, 38))	('SNAIL2', 'Gene', (24, 30))	('Expression', 'Var', (0, 10))	('SNAIL2', 'Gene', '6591', (24, 30))	('myogenic differentiation program', 'CPA', (43, 75))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('SNAIL', 'Gene', (24, 29))	('SNAIL', 'Gene', '6615', (14, 19))	('SNAIL', 'Gene', (14, 19))	('SNAIL', 'Gene', '6615', (24, 29))	('arrest', 'Disease', (122, 128))
34942	30617281	Large next generation-sequencing studies of RMS have focused on characterizing tumor cell-intrinsic features, like single nucleotide variants and gene copy-number alterations, not the tumor microenvironment or stroma .	('men', 'Species', '9606', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('single nucleotide variants', 'Var', (115, 141))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
34964	30617281	In particular, ARMS is more precisely diagnosed as FP RMS based on detecting the presence of PAX-FOXO1 fusion in tumour cells, observed using FISH, or by detecting the fusion transcript by RT-PCR assays (Figure 5).	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('PAX-FOXO1', 'Gene', (93, 102))	('ARMS', 'Disease', (15, 19))	('fusion', 'Var', (103, 109))	('tumour', 'Disease', (113, 119))
34977	30617281	This research led to a consensus statement advocating for cancer surveillance in children with germline p53 variants , as well as recognition of the need for further study .	('p53', 'Gene', (104, 107))	('men', 'Species', '9606', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('variants', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('children', 'Species', '9606', (81, 89))	('cancer', 'Disease', (58, 64))
34997	30617281	By contrast, the most recent series of COG trials (ARST0331, ARST0431, and ARST0531) incorporated only three risk groups  (Table 5; Figure 6).	('ARST0531', 'Var', (75, 83))	('COG', 'Chemical', '-', (39, 42))	('ARST0331', 'Var', (51, 59))
35027	30617281	Indeed, a recent report showed variant gene fusions involving VGLL2 fusion to either CITED2 or NCOA2 in infants with sclerosing/spindle cell RMS .	('NCOA2', 'Gene', '10499', (95, 100))	('CITED2', 'Gene', '10370', (85, 91))	('fusion', 'Var', (68, 74))	('VGLL2', 'Gene', '245806', (62, 67))	('NCOA2', 'Gene', (95, 100))	('infants', 'Species', '9606', (104, 111))	('VGLL2', 'Gene', (62, 67))	('CITED2', 'Gene', (85, 91))
35063	30617281	Current efforts for targeted re-sequencing of primary RMS biopsy samples will more precisely define the frequency of previously-identified somatic variants; correlation of these variants with clinical features, such as age, anatomic site, and outcome, should lead to better understanding of tumor biology and enable better risk stratification.	('variants', 'Var', (147, 155))	('variants', 'Var', (178, 186))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumor', 'Disease', (291, 296))
35071	30617281	These mutations are relatively common and potentially a marker for more aggressive disease course in those with FN RMS .	('FN RMS', 'Disease', (112, 118))	('mutations', 'Var', (6, 15))	('aggressive disease', 'Disease', 'MESH:D001523', (72, 90))	('aggressive disease', 'Disease', (72, 90))
35082	30617281	For example, expression of the alveolar RMS (ARMS) associated PAX3-FOXO1 fusion protein in a variety of cell types, including human fetal skeletal muscle cells  and mouse mesenchymal stem cells , promotes a malignant in vitro phenotype, which can be increased with other genetic manipulations of tumour suppressors, such as expression of a dominant negative form of p53 or knock-down of INK4A .	('mouse', 'Species', '10090', (165, 170))	('human', 'Species', '9606', (126, 131))	('PAX3-FOXO1', 'Gene', (62, 72))	('promotes', 'PosReg', (196, 204))	('INK4A', 'Gene', '12578', (387, 392))	('knock-down', 'Var', (373, 383))	('tumour', 'Phenotype', 'HP:0002664', (296, 302))	('tumour', 'Disease', 'MESH:D009369', (296, 302))	('INK4A', 'Gene', (387, 392))	('malignant in vitro phenotype', 'CPA', (207, 235))	('tumour', 'Disease', (296, 302))
35083	30617281	Similarly, stable ectopic expression of oncoproteins RASV12G, SV40 T/t Ag, and hTERT in human skeletal muscle progenitor cells fosters the formation of embryonic RMS (ERMS)-like xenografts in immunocompromised mice .	('SV40', 'Var', (62, 66))	('fosters', 'PosReg', (127, 134))	('hTERT', 'Gene', '7015', (79, 84))	('hTERT', 'Gene', (79, 84))	('mice', 'Species', '10090', (210, 214))	('embryonic RMS', 'Disease', 'MESH:D020964', (152, 165))	('formation', 'CPA', (139, 148))	('human', 'Species', '9606', (88, 93))	('RASV12G', 'Var', (53, 60))	('embryonic RMS', 'Disease', (152, 165))
35087	30617281	A heterozygous knockout of Ptch1 (encoding a receptor for sonic hedgehog) in mice causes a high frequency of RMS.	('mice', 'Species', '10090', (77, 81))	('knockout', 'Var', (15, 23))	('causes', 'Reg', (82, 88))	('Ptch1', 'Gene', '19206', (27, 32))	('RMS', 'Disease', (109, 112))	('Ptch1', 'Gene', (27, 32))
35090	30617281	Microarray analysis identified a RAS-induced gene signature in common between the model and human ERMS - an interesting finding as activating mutations in RAS genes are among the most highly recurrent mutations in RMS .	('activating', 'PosReg', (131, 141))	('mutations', 'Var', (142, 151))	('human', 'Species', '9606', (92, 97))	('RAS genes', 'Gene', (155, 164))
35132	32009477	The final histological evaluation confirmed a dedifferentiated liposarcoma, grade 3 with amplification of MDM2 (Figure 4A, B, and C).	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (46, 74))	('dedifferentiated liposarcoma', 'Disease', (46, 74))	('liposarcoma', 'Phenotype', 'HP:0012034', (63, 74))	('MDM2', 'Gene', '4193', (106, 110))	('MDM2', 'Gene', (106, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('amplification', 'Var', (89, 102))
35143	32009477	The final histological evaluation confirmed a dedifferentiated liposarcoma, grade 2 (Figure 5A and B), positive for amplification of MDM2.	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (46, 74))	('dedifferentiated liposarcoma', 'Disease', (46, 74))	('liposarcoma', 'Phenotype', 'HP:0012034', (63, 74))	('MDM2', 'Gene', '4193', (133, 137))	('MDM2', 'Gene', (133, 137))	('amplification', 'Var', (116, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))
35210	32009477	On univariate analysis, unfavorable prognostic factors for disease-specific survival were metastasis at presentation, high tumor grade, large tumor size, incomplete surgical resection, and positive surgical margin.	('high', 'Var', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (123, 128))	('metastasis', 'Disease', (90, 100))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
35215	32009477	Between all subgroups, with univariate analyses, liposarcoma histotype, high histological grade, metastatic disease at diagnosis, a lack of surgical resection, positive surgical margin, and the application of radiotherapy were predictive of unfavorable OS.	('metastatic', 'Disease', (97, 107))	('liposarcoma', 'Phenotype', 'HP:0012034', (49, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('liposarcoma', 'Disease', (49, 60))	('high', 'Var', (72, 76))	('liposarcoma', 'Disease', 'MESH:D008080', (49, 60))
35227	32009477	By mutating already established concepts related to retroperitoneal sarcomas, adjuvant radiotherapy should be considered in case of positive margins, and chemotherapy in case of high risk of distant metastasis (large tumor size, high grade, high proliferative index, and presence of necrosis).	('necrosis', 'Disease', 'MESH:D009336', (283, 291))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('retroperitoneal sarcomas', 'Disease', 'MESH:D012186', (52, 76))	('retroperitoneal sarcomas', 'Phenotype', 'HP:0006729', (52, 76))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('necrosis', 'Disease', (283, 291))	('retroperitoneal sarcomas', 'Disease', (52, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('mutating', 'Var', (3, 11))
35258	31142349	A 58-year-old white woman with a history of emphysema and chronic obstructive pulmonary disease (COPD) secondary to A1AD, who received lung transplantation 4 years prior, presented to dermatology with a 1-year history of painful nodules on the extensor surfaces of her upper extremities and back.	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (58, 95))	('pain', 'Phenotype', 'HP:0012531', (221, 225))	('woman', 'Species', '9606', (20, 25))	('pain', 'Disease', 'MESH:D010146', (221, 225))	('pain', 'Disease', (221, 225))	('A1AD', 'Var', (116, 120))	('COPD', 'Phenotype', 'HP:0006510', (97, 101))	('COPD', 'Disease', 'MESH:D029424', (97, 101))	('emphysema and chronic obstructive pulmonary disease', 'Disease', 'MESH:D011656', (44, 95))	('A1AD', 'Phenotype', 'HP:0032025', (116, 120))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (66, 95))	('COPD', 'Disease', (97, 101))	('emphysema', 'Phenotype', 'HP:0002097', (44, 53))
35284	31142349	Liposomal doxorubicin, however, has shown comparable efficacy and less toxicity compared to traditional doxorubicin and is often used for the treatment of advanced sarcoma in patients with poor performance status.	('toxicity', 'Disease', (71, 79))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('patients', 'Species', '9606', (175, 183))	('doxorubicin', 'Chemical', 'MESH:D004317', (10, 21))	('doxorubicin', 'Chemical', 'MESH:D004317', (104, 115))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('Liposomal', 'Var', (0, 9))	('toxicity', 'Disease', 'MESH:D064420', (71, 79))
35301	31142349	Both immunosuppression and chronic inflammation are well-known drivers of oncogenic cellular changes; one possible explanation is that advancing age is associated with aberrant expression of pro-inflammatory molecules and decreased immune surveillance.	('decreased immune surveillance', 'Phenotype', 'HP:0002721', (222, 251))	('aberrant', 'Var', (168, 176))	('immune surveillance', 'CPA', (232, 251))	('decreased', 'NegReg', (222, 231))	('inflammation', 'Disease', 'MESH:D007249', (35, 47))	('expression', 'MPA', (177, 187))	('inflammation', 'Disease', (35, 47))
35305	31142349	There is also a known association between A1AD and malignancy, and imbalances between alpha-1-antitrypsin and elastase such as those seen in A1AD may lead to persistent inflammation and tissue damage that promote carcinogenesis via chronic activation of the tissue necrosis factor signaling pathway.	('carcinogenesis', 'Disease', 'MESH:D063646', (213, 227))	('tissue necrosis', 'Phenotype', 'HP:0010885', (258, 273))	('tissue damage', 'CPA', (186, 199))	('imbalances', 'Var', (67, 77))	('imbalances', 'Phenotype', 'HP:0002172', (67, 77))	('A1AD', 'Gene', (141, 145))	('activation', 'PosReg', (240, 250))	('promote', 'PosReg', (205, 212))	('malignancy', 'Disease', 'MESH:D009369', (51, 61))	('A1AD', 'Phenotype', 'HP:0032025', (141, 145))	('inflammation', 'Disease', 'MESH:D007249', (169, 181))	('necrosis', 'Disease', 'MESH:D009336', (265, 273))	('necrosis', 'Disease', (265, 273))	('lead to', 'Reg', (150, 157))	('alpha-1-antitrypsin and elastase', 'Gene', '5265', (86, 118))	('inflammation', 'Disease', (169, 181))	('malignancy', 'Disease', (51, 61))	('carcinogenesis', 'Disease', (213, 227))	('A1AD', 'Phenotype', 'HP:0032025', (42, 46))
35308	31142349	UPS/PDS remains a diagnosis of exclusion because of a lack of tumor-specific markers, including genetic rearrangements or signature mutations.	('PDS', 'Disease', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('genetic rearrangements', 'Var', (96, 118))	('tumor', 'Disease', (62, 67))	('PDS', 'Disease', 'MESH:C536648', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
35371	30003043	Some studies based on the clinical trials have demonstrated that pazopanib is associated with a significantly increased risk of liver toxicity.	('liver toxicity', 'Disease', 'MESH:D056486', (128, 142))	('pazopanib', 'Var', (65, 74))	('pazopanib', 'Chemical', 'MESH:C516667', (65, 74))	('liver toxicity', 'Disease', (128, 142))
35374	30003043	It has been suggested that the occurrence of adverse events such as hypertension and/or hypothyroidism after taking tyrosine kinase inhibitors is associated with improved antitumor efficacy and that these events might be markers of a drug's antitumor activity.	('hypertension', 'Disease', 'MESH:D006973', (68, 80))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('hypertension', 'Disease', (68, 80))	('hypothyroidism', 'Disease', 'MESH:D007037', (88, 102))	('hypothyroidism', 'Phenotype', 'HP:0000821', (88, 102))	('hypertension', 'Phenotype', 'HP:0000822', (68, 80))	('improved', 'PosReg', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('hypothyroidism', 'Disease', (88, 102))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tyrosine', 'Var', (116, 124))
35482	29050367	Inhibition of this interaction by anti-PD-1 antibodies can reinstate cytotoxic activity of TLs leading to subsequent killing of tumor cells.	('PD-1', 'Gene', (39, 43))	('cytotoxic activity', 'CPA', (69, 87))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('PD-1', 'Gene', '5133', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (128, 133))	('killing', 'CPA', (117, 124))	('reinstate', 'PosReg', (59, 68))
35490	29050367	Genetically several sarcoma subtypes are characterized by specific gene fusions.	('gene fusions', 'Var', (67, 79))	('sarcoma subtype', 'Disease', (20, 35))	('sarcoma subtype', 'Disease', 'MESH:D012509', (20, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))
35493	29050367	Similar to Ewing sarcoma, DSRCTs present with an EWSR1 translocation that in DSRCTs fuses with the WT1 gene.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('WT1', 'Gene', (99, 102))	('EWSR1', 'Gene', (49, 54))	('translocation', 'Var', (55, 68))	('Ewing sarcoma', 'Disease', (11, 24))	('EWSR1', 'Gene', '2130', (49, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (11, 24))	('WT1', 'Gene', '7490', (99, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (11, 24))
35500	29050367	Expression per subtype ranged from 20-66%, 25-33% and 20-33% for PD-1, PD-L1 and PD-1+PD-L1+, respectively, and no correlation with clinical outcome was observed.	('PD-1', 'Gene', (81, 85))	('PD-1', 'Gene', '5133', (81, 85))	('PD-L1', 'Var', (71, 76))	('PD-1', 'Gene', (65, 69))	('PD-1', 'Gene', '5133', (65, 69))
35504	29050367	However, PD-L1 in combination with high CD8 levels were associated with better survival which further increased if more than 10% of the CD8+ lymphocytes were PD-1+.	('CD8', 'Gene', (136, 139))	('CD8', 'Gene', '925', (40, 43))	('PD-1', 'Gene', '5133', (158, 162))	('PD-1', 'Gene', (158, 162))	('better', 'PosReg', (72, 78))	('CD8', 'Gene', '925', (136, 139))	('survival', 'CPA', (79, 87))	('increased', 'PosReg', (102, 111))	('CD8', 'Gene', (40, 43))	('PD-L1', 'Var', (9, 14))
35508	29050367	Taken together, the above-mentioned studies do suggest a potential therapeutic role for PD-1 inhibitors in (a subgroup of) sarcomas.	('PD-1', 'Gene', '5133', (88, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcomas', 'Disease', (123, 131))	('sarcomas', 'Disease', 'MESH:D012509', (123, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('inhibitors', 'Var', (93, 103))	('PD-1', 'Gene', (88, 92))
35528	29050367	In alveolar rhabdomyosarcoma, PD-L1+ and PD-L1+CD8+ tumors significantly correlated with low IRS grade (p = 0.005; p = 0.033), whereas PD-1+, PD-1+PD-L1+, PD-1+CD8+ and PD-1+PD-L1+CD8+ tumors showed a trend towards a low IRS grade (p = 0.071).	('CD8', 'Gene', '925', (160, 163))	('PD-L1+', 'Var', (30, 36))	('low', 'NegReg', (89, 92))	('tumors', 'Disease', (185, 191))	('PD-1', 'Gene', (155, 159))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (12, 28))	('PD-1', 'Gene', '5133', (155, 159))	('alveolar rhabdomyosarcoma', 'Disease', (3, 28))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('CD8', 'Gene', '925', (47, 50))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('PD-1', 'Gene', (169, 173))	('PD-1', 'Gene', '5133', (169, 173))	('CD8', 'Gene', '925', (180, 183))	('CD8', 'Gene', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (3, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('tumors', 'Disease', (52, 58))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (3, 28))	('PD-1', 'Gene', (142, 146))	('PD-1', 'Gene', '5133', (142, 146))	('PD-1', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('PD-1', 'Gene', '5133', (135, 139))	('CD8', 'Gene', (47, 50))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('CD8', 'Gene', (180, 183))
35531	29050367	PD-L1 expression correlated with better EFS, overall survival (OS) and metastases-free survival (MFS) in alveolar rhabdomyosarcoma (EFS: p = 0.009, OS: p = 0.049, MFS: p = 0.032) (Figure 3A-3C) and there was a trend towards better EFS for combined PD-L1 and CD8 expression (p = 0.069) (Figure 3D).	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (105, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('OS', 'Chemical', '-', (63, 65))	('alveolar rhabdomyosarcoma', 'Disease', (105, 130))	('EFS', 'MPA', (40, 43))	('OS', 'Chemical', '-', (148, 150))	('PD-L1', 'Gene', (0, 5))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (114, 130))	('CD8', 'Gene', (258, 261))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (105, 130))	('CD8', 'Gene', '925', (258, 261))	('metastases-free', 'Disease', 'MESH:D009362', (71, 86))	('expression', 'Var', (6, 16))	('better', 'PosReg', (33, 39))	('metastases-free', 'Disease', (71, 86))	('overall survival', 'CPA', (45, 61))
35545	29050367	Recently, PD-L1 expression was shown to be associated with worse 5-year EFS and higher infiltration of immune cells.	('infiltration of immune cells', 'CPA', (87, 115))	('expression', 'Var', (16, 26))	('EFS', 'CPA', (72, 75))	('PD-L1', 'Gene', (10, 15))	('higher', 'PosReg', (80, 86))	('rat', 'Species', '10116', (93, 96))
35568	29050367	In addition, PD-L1 alone or co-expression with CD8 significantly correlated with a lower IRS grade and PD-L1 expression alone correlated with the absence of metastases (Table 4).	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('CD8', 'Gene', (47, 50))	('IRS grade', 'CPA', (89, 98))	('CD8', 'Gene', '925', (47, 50))	('lower', 'NegReg', (83, 88))	('co-expression', 'Var', (28, 41))	('metastases', 'Disease', (157, 167))
35583	29050367	Interestingly, similar to Ewing sarcoma, DSRCT has a characteristic translocation involving EWSR1, calling for investigation into the effects of this gene on PD-1 expression.	('Ewing sarcoma', 'Disease', (26, 39))	('EWSR1', 'Gene', '2130', (92, 97))	('translocation', 'Var', (68, 81))	('PD-1', 'Gene', '5133', (158, 162))	('PD-1', 'Gene', (158, 162))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('DSRCT', 'Disease', (41, 46))	('EWSR1', 'Gene', (92, 97))
35610	29050367	Expression in >= 50% of the tumor cells and > 50 CD8+ cells in the tumor were considered high expression (PD-1high, PD-L1high, CD8high).	('tumor', 'Disease', (28, 33))	('PD-1', 'Gene', '5133', (106, 110))	('CD8', 'Gene', (127, 130))	('1h', 'Chemical', '-', (120, 122))	('PD-1', 'Gene', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('1h', 'Chemical', '-', (109, 111))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CD8', 'Gene', '925', (127, 130))	('CD8', 'Gene', (49, 52))	('CD8', 'Gene', '925', (49, 52))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('PD-L1high', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
35649	27803813	Despite reexcision, the risk of local recurrence is significant and is associated with high-grade tumors, residual tumor, marginal reexcisions, and deep tumors.	('marginal reexcisions', 'Var', (122, 142))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('residual', 'Disease', (106, 114))	('local', 'CPA', (32, 37))	('deep tumors', 'Disease', 'MESH:D057887', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('high-grade tumors', 'CPA', (87, 104))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('deep tumors', 'Disease', (148, 159))
35671	21552124	Ninety percent of WDLS and DDLS have amplification of chromosome 12q13-15, which contains the oncogenes MDM2, HMGA2, and CDK4; additional genes located on this amplicon may also play a role in liposarcomagenesis.	('role', 'Reg', (185, 189))	('HMGA2', 'Gene', (110, 115))	('CDK4', 'Gene', '1019', (121, 125))	('liposarcoma', 'Phenotype', 'HP:0012034', (193, 204))	('liposarcoma', 'Disease', 'MESH:D008080', (193, 204))	('amplification', 'Var', (37, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('MDM2', 'Gene', '4193', (104, 108))	('MDM2', 'Gene', (104, 108))	('HMGA2', 'Gene', '8091', (110, 115))	('play', 'Reg', (178, 182))	('liposarcoma', 'Disease', (193, 204))	('WD', 'Disease', 'MESH:D006527', (18, 20))	('CDK4', 'Gene', (121, 125))
35690	21552124	This defect causes MDM2 and CDK4 to accumulate in DDLS cells, so immunohistochemical staining for these proteins allows definitive diagnosis of a soft tissue sarcoma as DDLS.	('CDK4', 'Gene', '1019', (28, 32))	('MDM2', 'Gene', '4193', (19, 23))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (146, 165))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (146, 165))	('MDM2', 'Gene', (19, 23))	('soft tissue sarcoma', 'Disease', (146, 165))	('defect', 'Var', (5, 11))	('accumulate', 'PosReg', (36, 46))	('CDK4', 'Gene', (28, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
35694	21552124	If, however, DDLS encases components of the neurovascular bundle, it may be necessary to sacrifice these structures, or, in extremely rare cases, to amputate.	('DDLS', 'Var', (13, 17))	('amputate', 'Chemical', '-', (149, 157))	('encases', 'Reg', (18, 25))	('neurovascular bundle', 'Disease', (44, 64))	('neurovascular bundle', 'Disease', 'MESH:D013901', (44, 64))
35733	21552124	MDM2 amplification is, therefore, thought to result in reduced levels of p53 and thus to induce transformation of the progenitor cell.	('induce', 'Reg', (89, 95))	('transformation', 'CPA', (96, 110))	('reduced', 'NegReg', (55, 62))	('amplification', 'Var', (5, 18))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))
35739	21552124	In vitro, inhibition of CDK4 protein leads to proliferation arrest.	('proliferation arrest', 'Disease', 'MESH:D006323', (46, 66))	('CDK4', 'Gene', '1019', (24, 28))	('inhibition', 'Var', (10, 20))	('CDK4', 'Gene', (24, 28))	('proliferation arrest', 'Disease', (46, 66))
35742	21552124	Thus, CDK4 may be essential for progression, but not initiation, of liposarcoma, and inhibiting CDK4 may not be sufficient to induce tumor cell death.	('CDK4', 'Gene', '1019', (6, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('liposarcoma', 'Disease', (68, 79))	('death', 'Disease', 'MESH:D003643', (144, 149))	('death', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('liposarcoma', 'Disease', 'MESH:D008080', (68, 79))	('tumor', 'Disease', (133, 138))	('CDK4', 'Gene', (6, 10))	('liposarcoma', 'Phenotype', 'HP:0012034', (68, 79))	('CDK4', 'Gene', (96, 100))	('inhibiting', 'Var', (85, 95))	('CDK4', 'Gene', '1019', (96, 100))
35743	21552124	Instead, CDK4 inhibitors may slow tumor growth, be effective in only a subset of patients, or prove to be ineffective as single agents.	('slow', 'NegReg', (29, 33))	('CDK4', 'Gene', (9, 13))	('tumor', 'Disease', (34, 39))	('CDK4', 'Gene', '1019', (9, 13))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('inhibitors', 'Var', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
35756	21552124	Fifty DDLS samples were examined to identify not only aberrantly expressed genes, but also copy number alterations and somatic mutations that could contribute to liposarcoma initiation and progression.	('contribute', 'Reg', (148, 158))	('liposarcoma', 'Phenotype', 'HP:0012034', (162, 173))	('liposarcoma initiation', 'Disease', 'MESH:D008080', (162, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('aberrantly expressed genes', 'Var', (54, 80))	('liposarcoma initiation', 'Disease', (162, 184))	('mutations', 'Var', (127, 136))	('copy number alterations', 'Var', (91, 114))
35757	21552124	Point mutations were identified in CTNNB1 (beta-catenin), CDH1 (E-cadherin), EPHA1 (ephrin A1), and FBXW7 (a component of the ubiquitin protein ligase complex), each of which has potential oncogenic effects on the liposarcoma cell.	('CTNNB1', 'Gene', '1499', (35, 41))	('FBXW7', 'Gene', '55294', (100, 105))	('liposarcoma', 'Phenotype', 'HP:0012034', (214, 225))	('EPHA1', 'Gene', '1942', (77, 82))	('liposarcoma', 'Disease', 'MESH:D008080', (214, 225))	('CTNNB1', 'Gene', (35, 41))	('Point mutations', 'Var', (0, 15))	('ephrin A1', 'Gene', '1942', (84, 93))	('EPHA1', 'Gene', (77, 82))	('CDH1', 'Gene', '999', (58, 62))	('FBXW7', 'Gene', (100, 105))	('ephrin A1', 'Gene', (84, 93))	('CDH1', 'Gene', (58, 62))	('liposarcoma', 'Disease', (214, 225))	('E-cadherin', 'Gene', (64, 74))	('E-cadherin', 'Gene', '999', (64, 74))	('beta-catenin', 'Gene', (43, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('beta-catenin', 'Gene', '1499', (43, 55))
35759	21552124	For 27 genes, including CDK4, shRNA knockdown inhibited proliferation of cell lines, identifying these genes as potential oncogenes (Table 1).	('knockdown', 'Var', (36, 45))	('CDK4', 'Gene', '1019', (24, 28))	('CDK4', 'Gene', (24, 28))	('inhibited', 'NegReg', (46, 55))	('shRNA', 'Gene', (30, 35))
35807	32312843	This analysis led to the observation that 1) regardless of the immunogen used, essentially all conventionally prepared mouse antisera contained complement-dependent cytotoxic antibodies recognizing the murine leukemia virus (MuLV) gp70 envelope protein and 2) the BALB/c sarcomas, with the significant exceptions of Meth A and two newly induced sarcomas, CMS4 and CMS5, expressed MuLV and gp70.	('CMS4', 'Chemical', '-', (355, 359))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('MuLV', 'Var', (380, 384))	('CMS5', 'Gene', (364, 368))	('mouse', 'Species', '10090', (119, 124))	('MuLV', 'Species', '11786', (380, 384))	('gp70', 'Gene', (231, 235))	('Meth A', 'Chemical', '-', (316, 322))	('gp70', 'Gene', (389, 393))	('sarcomas', 'Disease', 'MESH:D012509', (345, 353))	('CMS5', 'Gene', '8292', (364, 368))	('murine leukemia virus', 'Species', '11786', (202, 223))	('sarcomas', 'Phenotype', 'HP:0100242', (345, 353))	('sarcomas', 'Disease', (345, 353))	('MuLV', 'Species', '11786', (225, 229))	('sarcomas', 'Disease', 'MESH:D012509', (271, 279))	('sarcomas', 'Phenotype', 'HP:0100242', (271, 279))	('gp70', 'Gene', '133418', (231, 235))	('leukemia', 'Phenotype', 'HP:0001909', (209, 217))	('sarcomas', 'Disease', (271, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (345, 352))	('gp70', 'Gene', '133418', (389, 393))
35808	32312843	Interestingly, normal fibroblasts of C57BL/6J but not BALB/cJ origin expressed gp70 in the absence of virion expression.	('gp70', 'Gene', (79, 83))	('gp70', 'Gene', '133418', (79, 83))	('C57BL/6J', 'Var', (37, 45))
35826	32312843	We probed a wide range of murine tumors and leukemias of chemical and viral origin as well as spontaneous tumors and normal tissues for the presence of the p53 kDa species.	('leukemias', 'Disease', 'MESH:D007938', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('murine', 'Species', '10090', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('p53 kDa', 'Var', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('leukemias', 'Phenotype', 'HP:0001909', (44, 53))	('leukemias', 'Disease', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('tumors', 'Disease', (33, 39))
35832	32312843	First, trypsin digestion of p53 from chemically-induced tumors, but not virally-induced tumors showed distinct peptides, implying that genetic alterations in p53, namely mutations, occurred during chemical carcinogenesis, but not viral oncogenesis.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (170, 179))	('carcinogenesis', 'Disease', 'MESH:D063646', (206, 220))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('p53', 'Gene', (158, 161))	('tumors', 'Disease', (88, 94))	('carcinogenesis', 'Disease', (206, 220))
35840	32312843	Given the advances in T-cell immunology, Old's group showed that the Meth A p53 mutation at codon 234 (M to I) could be incorporated as a 9-mer mutant p53232-240 peptide that was able to bind to H-2Kd molecules.	('Meth A', 'Chemical', '-', (69, 75))	('mutant', 'Gene', (144, 150))	('Meth A p53', 'Gene', (69, 79))	('bind', 'Interaction', (187, 191))	('H-2Kd', 'Gene', (195, 200))	('H-2Kd', 'Gene', '14972', (195, 200))	('mutant', 'Gene', '17850', (144, 150))	('mutation', 'Var', (80, 88))	('p53232-240', 'Var', (151, 161))
35841	32312843	A vaccine consisting of the incomplete Freund's adjuvant and the Meth A mutant p53232-240 peptide was then used to induce H-2Kd-restricted, Meth A mutant p53232-240 peptide-specific cytotoxic T-cell lymphocyte (CTL) cells in mice with subsequent rejection of Meth A sarcoma.	('mutant', 'Gene', '17850', (147, 153))	('Meth A', 'Chemical', '-', (259, 265))	('mutant', 'Gene', '17850', (72, 78))	('Meth A', 'Chemical', '-', (65, 71))	('mutant', 'Gene', (147, 153))	('H-2Kd', 'Gene', (122, 127))	('H-2Kd', 'Gene', '14972', (122, 127))	('Meth A', 'Chemical', '-', (140, 146))	('Meth A sarcoma', 'Disease', (259, 273))	('mutant', 'Gene', (72, 78))	('mice', 'Species', '10090', (225, 229))	('Meth A sarcoma', 'Disease', 'MESH:D012509', (259, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('p53232-240', 'Var', (154, 164))	("incomplete Freund's adjuvant", 'Chemical', 'MESH:C114843', (28, 56))
35846	32312843	More interestingly, the DC-based wild-type sequence p53232-240 peptide vaccine also was shown to be able to induce in vitro and in vivo a wild type sequence p53232-240 peptide-specific CTL and immunity to CMS4 sarcoma, which did not express the p53 234 mutation.	('p53232-240', 'Var', (52, 62))	('sarcoma', 'Disease', (210, 217))	('CTL', 'CPA', (185, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('CMS4', 'Chemical', '-', (205, 209))	('immunity', 'CPA', (193, 201))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('induce', 'PosReg', (108, 114))	('p53232-240', 'Var', (157, 167))
35847	32312843	Additional studies focused on various vehicles to deliver the Meth A mutant p53232-240 epitope.	('Meth A', 'Chemical', '-', (62, 68))	('mutant', 'Gene', (69, 75))	('p53232-240', 'Var', (76, 86))	('mutant', 'Gene', '17850', (69, 75))
35849	32312843	In sum, the results of these studies demonstrated the potential translational use of DC-based p53 vaccines to target p53 mutations or non-mutated, wild-type sequence or "self" p53 epitopes for cancer therapy and, perhaps, prevention.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('mutations', 'Var', (121, 130))	('p53', 'Gene', (117, 120))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
35852	32312843	These CTLs recognized HLA-A2+ tumors expressing p53 molecules with mutations outside of the p53264-272 epitope.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('p53 molecules', 'Var', (48, 61))
35853	32312843	In vitro, using the autologous SCCHN patient/tumor PCI-13 system available at UPCI, DCs pulsed with the wild type sequence p53264-272 peptide induced anti-PCI-13 CTL from the patient's lymphocytes as well.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patient', 'Species', '9606', (37, 44))	('patient', 'Species', '9606', (175, 182))	('tumor', 'Disease', (45, 50))	('p53264-272 peptide', 'Var', (123, 141))	('anti-PCI-13 CTL', 'MPA', (150, 165))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
35855	32312843	The variant peptides LLGRNTFEV and LLGRNSWEV were determined to be immunogenic using lymphocytes from donors non-responsive to the parental peptide and they induced anti-p53 peptide CTL recognizing HLA-A2+ tumor cells presenting the wild type sequence LLGRNSFEV p53264-272 epitope and making it an ideal candidate for clinical vaccine use.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('anti-p53', 'MPA', (165, 173))	('induced', 'Reg', (157, 164))	('variant', 'Var', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
35857	32312843	Specifically, the HLA-A2+ SCCHN patients who had tetramer+ p53264-272 CD8+ T cells or in vitro-inducible p53264-272 CD8+ T lymphocytes in their peripheral blood also had tumors that either expressed mutations within this epitope or at codon 273, thereby evading their T lymphocyte activity.	('T lymphocyte activity', 'CPA', (268, 289))	('patients', 'Species', '9606', (32, 40))	('CD8', 'Gene', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CD8', 'Gene', '925', (116, 119))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('CD8', 'Gene', (70, 73))	('mutations', 'Var', (199, 208))	('CD8', 'Gene', '925', (70, 73))	('tumors', 'Disease', (170, 176))	('p53264-272', 'Var', (105, 115))	('evading', 'NegReg', (254, 261))
35858	32312843	In other studies of anti-p53264-272 CTL in SCCHN patients, we determined that patients with a high frequency of p53 tetramer+ CD8+ T cells in their peripheral circulation had a naive phenotype, while those with a lower frequency of p53 tetramer+ CD8+ T cells had mature and terminally differentiated phenotypes, the effector phenotypes.	('CD8', 'Gene', '925', (246, 249))	('CD8', 'Gene', (126, 129))	('CD8', 'Gene', '925', (126, 129))	('p53', 'Var', (112, 115))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (49, 57))	('lower frequency of p53 tetramer+ CD8+ T cells', 'Phenotype', 'HP:0005415', (213, 258))	('CD8', 'Gene', (246, 249))
35859	32312843	In addition, the frequency of p53 tetramer+ CD8+ T cells negatively correlated with p53 expression and tumor stage.	('CD8', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CD8', 'Gene', '925', (44, 47))	('p53', 'Var', (30, 33))	('tumor', 'Disease', (103, 108))	('p53', 'Protein', (84, 87))	('negatively', 'NegReg', (57, 67))	('expression', 'MPA', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
35861	32312843	We also studied the immunogenicity of HLA-2-restricted, CTL-defined p53 epitopes that were identified in tumors of HLA-A2+ SCCHN patients that expressed mutations in non-anchor codon missense mutations.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (153, 162))	('patients', 'Species', '9606', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('non-anchor codon missense mutations', 'Var', (166, 201))
35862	32312843	Of the six p53 mutant peptide epitopes studied, the p53217-225 peptide bearing the codon mutation Y220C, that had been further modified by Appella to eliminate disulfide linkages, was found to be immunogenic in vitro and the induced p53 Y220C peptide-specific CTL recognized an HLA-A2+ SCCHN tumor cell line expressing the p53 Y220C mutation.	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('Y220C', 'Mutation', 'rs121912666', (98, 103))	('p53 Y220C', 'Var', (233, 242))	('Y220C', 'Var', (98, 103))	('disulfide', 'Chemical', 'MESH:D004220', (160, 169))	('p53217-225', 'Var', (52, 62))	('Y220C', 'Mutation', 'rs121912666', (237, 242))	('SCCHN tumor', 'Disease', (286, 297))	('Y220C', 'Mutation', 'rs121912666', (327, 332))	('SCCHN tumor', 'Disease', 'MESH:D009369', (286, 297))	('mutant', 'Gene', '17850', (15, 21))	('disulfide', 'MPA', (160, 169))	('mutant', 'Gene', (15, 21))
35863	32312843	Our analysis of p53 mutations detected the p53 Y220C in 6/50 (12%) of HLA-A2+ SCCHN tumors.	('Y220C', 'Mutation', 'rs121912666', (47, 52))	('SCCHN tumors', 'Disease', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('p53', 'Gene', (16, 19))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('p53 Y220C', 'Var', (43, 52))	('SCCHN tumors', 'Disease', 'MESH:D009369', (78, 90))
35864	32312843	This unexpectedly high frequency of the p53 Y220C mutation in HLA-A2+ SCCHN suggested at the time that a p53 mutation-specific vaccine could be expected to induce anti-tumor immune responses in these HLA-A2+ patients and be more widely applicable than envisioned at that time for any given p53 missense mutation.	('Y220C', 'Mutation', 'rs121912666', (44, 49))	('patients', 'Species', '9606', (208, 216))	('tumor', 'Disease', (168, 173))	('Y220C', 'Var', (44, 49))	('p53', 'Gene', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('induce', 'PosReg', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
35866	32312843	This time the question was whether administering the DC/wild type sequence p53232-240 peptide-based vaccine in the preventive and/or therapy setting could prevent chemical carcinogenesis in mice.	('p53232-240', 'Var', (75, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('prevent', 'NegReg', (155, 162))	('mice', 'Species', '10090', (190, 194))	('carcinogenesis', 'Disease', (172, 186))
35868	32312843	This finding is consistent with the demonstrated immunosuppressive effects of MCA as well as progressive tumor growth, and with what we now recognize as the tumor immunosuppressive/pro-inflammatory activities of loss of function p53 as well.	('tumor', 'Disease', (157, 162))	('MCA', 'Chemical', '-', (78, 81))	('loss of function', 'Var', (212, 228))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('p53', 'Gene', (229, 232))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (105, 110))
35871	32312843	To avoid CTL recognition, the outgrowing tumors either lost the expression of H-2Kd or expressed mutations within the p53232-240 epitope.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (97, 106))	('expression', 'MPA', (64, 74))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('expressed', 'Reg', (87, 96))	('H-2Kd', 'Gene', (78, 83))	('H-2Kd', 'Gene', '14972', (78, 83))	('tumors', 'Disease', (41, 47))	('lost', 'NegReg', (55, 59))	('p53232-240', 'Var', (118, 128))	('tumors', 'Disease', 'MESH:D009369', (41, 47))
35872	32312843	The effort to identify the repertoire of p53 peptide epitopes available for vaccine use was pioneered by Melief and co-workers starting from their initial identification in the 1990's of the human p53274-272 as an HLA-A2-restricted wild type sequence p53 peptide capable of being identified by CD8+ T cells.	('human', 'Species', '9606', (191, 196))	('CD8', 'Gene', '925', (294, 297))	('p53274-272', 'Var', (197, 207))	('CD8', 'Gene', (294, 297))
35876	32312843	in which vaccines consisting of a patient's peripheral blood lymphocytes pulsed with 17-mer peptides incorporating the p53 mutations identified in that patient's tumor were administered and immune responses studied.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutations', 'Var', (123, 132))	('tumor', 'Disease', (162, 167))	('patient', 'Species', '9606', (34, 41))	('p53', 'Gene', (119, 122))	('patient', 'Species', '9606', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
35878	32312843	From extensive molecular analysis of the T-cell receptor repertoire in tumor infiltrating lymphocytes, a panel of class I and class II MHC-restricted peptide epitopes, defined as "neoantigens", were identified, which included frequently occurring p53 "hot spot" mutations, such as p53 R175H and p53 Y220C mutations.	('R175H', 'Mutation', 'rs28934578', (285, 290))	('Y220C mutations', 'Var', (299, 314))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Y220C', 'Mutation', 'rs121912666', (299, 304))	('p53 R175H', 'Var', (281, 290))	('p53', 'Gene', (295, 298))	('tumor', 'Disease', (71, 76))	('p53', 'Gene', (247, 250))
35879	32312843	Most importantly, this approach demonstrated that peptides containing these p53 "hot spot" mutations could be processed and presented as MHC complexes by a variety of types of human tumor cells.	('tumor', 'Disease', (182, 187))	('p53', 'Gene', (76, 79))	('human', 'Species', '9606', (176, 181))	('mutations', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
35885	32312843	Our own experience in this regard was in evaluating the ability of CP-31398 and PRIMA-1 to enhance p53-based immunotherapy of MCA-treated mice in a prevention and/or therapy setting.	('PRIMA-1', 'Gene', '170952', (80, 87))	('PRIMA-1', 'Gene', (80, 87))	('MCA', 'Chemical', '-', (126, 129))	('mice', 'Species', '10090', (138, 142))	('p53-based', 'Protein', (99, 108))	('CP-31398', 'Var', (67, 75))	('enhance', 'PosReg', (91, 98))	('CP-31398', 'Chemical', 'MESH:C402665', (67, 75))
35900	32312843	TLR genes expressed on lymphocytes, dendritic cells and macrophages are p53 targets and changes in their regulation are associated with a range of autoimmune diseases, while p53 also regulates NK cell ligands, influencing their efficacy in anti-tumor response.	('autoimmune diseases', 'Disease', 'MESH:D001327', (147, 166))	('associated', 'Reg', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('autoimmune diseases', 'Disease', (147, 166))	('changes', 'Var', (88, 95))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('TLR genes', 'Gene', (0, 9))	('regulation', 'MPA', (105, 115))	('tumor', 'Disease', (245, 250))	('regulates', 'Reg', (183, 192))
35902	32312843	In tumor cells lacking p53 or expressing mutp53, MHC I expression is low and PD-L1 is high, resulting in inhibition of the CTL upon binding to the PD-1 receptor.	('tumor', 'Disease', (3, 8))	('inhibition', 'NegReg', (105, 115))	('CTL', 'Protein', (123, 126))	('low', 'NegReg', (69, 72))	('binding', 'Interaction', (132, 139))	('mutp53', 'Var', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
35903	32312843	In tumor cells harboring p53mut, upregulation of just the NF-kB signaling pathway, one of many that are influenced by p53, results in increased cytokine production and activation of immune cells.	('NF-kB signaling pathway', 'Pathway', (58, 81))	('cytokine production', 'MPA', (144, 163))	('tumor', 'Disease', (3, 8))	('increased cytokine', 'Phenotype', 'HP:0031407', (134, 152))	('immune cells', 'CPA', (182, 194))	('p53mut', 'Var', (25, 31))	('upregulation', 'PosReg', (33, 45))	('activation', 'PosReg', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('increased', 'PosReg', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
35905	32312843	Furthermore, mutp53 cells shed miR-1246-enriched exosomes with a concomitant uptake by macrophages, triggering an anti-inflammatory immunosuppression state.	('mutp53', 'Var', (13, 19))	('triggering', 'Reg', (100, 110))	('miR-1246-enriched', 'Gene', (31, 48))	('miR-1246', 'Chemical', '-', (31, 39))
35907	32312843	Therefore, loss of p53 function not only promotes cellular transformation by altering control of the cell cycle but also facilitates tumor growth by enhancing pro-inflammatory conditions and suppressing components of the innate and adaptive immune systems in the tumor microenvironment.	('suppressing', 'NegReg', (191, 202))	('altering', 'Reg', (77, 85))	('pro-inflammatory conditions', 'MPA', (159, 186))	('cellular transformation', 'CPA', (50, 73))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('loss', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('facilitates', 'PosReg', (121, 132))	('promotes', 'PosReg', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('control of the cell cycle', 'MPA', (86, 111))	('p53', 'Gene', (19, 22))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', (133, 138))	('enhancing', 'PosReg', (149, 158))
36099	32085747	The current concepts demonstrate that ASPS is characterized by the translocation t(X;17) p (11.2;q25), which results in the chimeric ASPSCR1-TFE3 transcription factor, which drives tumorigenesis and provides an important clue for the diagnosis of ASPS.	('chimeric', 'Var', (124, 132))	('ASPS', 'Gene', '79058', (247, 251))	('ASPS', 'Phenotype', 'HP:0012218', (247, 251))	('ASPSCR1', 'Gene', '79058', (133, 140))	('ASPS', 'Gene', (133, 137))	('ASPS', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('drives', 'PosReg', (174, 180))	('ASPS', 'Gene', '79058', (133, 137))	('ASPSCR1', 'Gene', (133, 140))	('ASPS', 'Gene', '79058', (38, 42))	('ASPS', 'Phenotype', 'HP:0012218', (133, 137))	('ASPS', 'Phenotype', 'HP:0012218', (38, 42))	('ASPS', 'Gene', (247, 251))	('TFE3', 'Gene', (141, 145))	('tumor', 'Disease', (181, 186))	('TFE3', 'Gene', '7030', (141, 145))	('results in', 'Reg', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
36129	30187985	Importantly, some soft tissue tumors in children are characterized by recurrent gene fusions involving either growth factors (eg, PDGFB) or protein kinases (eg, ALK, ROS, NTRK, BRAF), which have paved the way for new targeted treatments that block the respective upregulated downstream pathways.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('ALK', 'Gene', (161, 164))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (18, 36))	('PDGFB', 'Gene', '5155', (130, 135))	('children', 'Species', '9606', (40, 48))	('gene fusions', 'Var', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (18, 35))	('PDGFB', 'Gene', (130, 135))	('ALK', 'Gene', '238', (161, 164))
36130	30187985	However, the majority of gene fusions or mutations detected in soft tissue tumors result in an abnormal function of transcription factors or chromatin remodeling.	('abnormal', 'Reg', (95, 103))	('mutations', 'Var', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('chromatin remodeling', 'CPA', (141, 161))	('gene fusions', 'Var', (25, 37))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (63, 81))	('result in', 'Reg', (82, 91))	('function', 'MPA', (104, 112))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (63, 80))	('tumors', 'Disease', (75, 81))	('transcription factors', 'Protein', (116, 137))
36138	30187985	A subset of childhood sarcomas that strongly resemble IFS by morphologic criteria (IFS-like sarcomas) harbor recurrent chromosomal abnormalities other than ETV6-NTRK3, including EML4-NTRK3 variant fusions and rearrangements of the kinase genes BRAF, and NTRK1 (Figure 1), summarized in Table 1.	('NTRK3', 'Gene', '4916', (183, 188))	('childhood sarcomas', 'Disease', (12, 30))	('recurrent chromosomal abnormalities', 'Phenotype', 'HP:0040012', (109, 144))	('NTRK3', 'Gene', (183, 188))	('chromosomal abnormalities', 'Disease', (119, 144))	('variant fusions', 'Var', (189, 204))	('ETV6', 'Gene', (156, 160))	('sarcomas', 'Disease', 'MESH:D012509', (22, 30))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('BRAF', 'Gene', (244, 248))	('BRAF', 'Gene', '673', (244, 248))	('NTRK1', 'Gene', '4914', (254, 259))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('NTRK1', 'Gene', (254, 259))	('sarcomas', 'Disease', (22, 30))	('sarcomas', 'Disease', (92, 100))	('EML4', 'Gene', (178, 182))	('NTRK3', 'Gene', '4916', (161, 166))	('EML4', 'Gene', '27436', (178, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('rearrangements', 'Var', (209, 223))	('NTRK3', 'Gene', (161, 166))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (119, 144))	('childhood sarcomas', 'Disease', 'MESH:D012509', (12, 30))	('ETV6', 'Gene', '2120', (156, 160))
36141	30187985	More recently, a few cases of IFS have been reported to demonstrate compound intragenic BRAF deletions associated with tandem duplication of exon 2.	('BRAF', 'Gene', (88, 92))	('deletions', 'Var', (93, 102))	('BRAF', 'Gene', '673', (88, 92))	('associated', 'Reg', (103, 113))
36143	30187985	Interestingly, in that study, 2 of 3 IFS with BRAF intragenic deletions show coexisting ETV6-NTRK3 fusions.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('ETV6', 'Gene', '2120', (88, 92))	('NTRK3', 'Gene', (93, 98))	('deletions', 'Var', (62, 71))	('ETV6', 'Gene', (88, 92))	('NTRK3', 'Gene', '4916', (93, 98))
36148	30187985	Moreover, the tumor showed strong and diffuse S100 expression, whereas S0X10 was negative and H3K27me3 retained, an immunoprofile inconsistent with a diagnosis of malignant peripheral nerve sheath tumor (MPNST).	('MPNST', 'Phenotype', 'HP:0100697', (204, 209))	('tumor', 'Disease', (14, 19))	('H3K27me3', 'Var', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (163, 202))	('MPNST', 'Disease', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('S100', 'Gene', '6285', (46, 50))	('expression', 'MPA', (51, 61))	('MPNST', 'Disease', 'MESH:D009442', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('malignant peripheral nerve sheath tumor', 'Disease', (163, 202))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D009442', (163, 202))	('tumor', 'Disease', (197, 202))	('S100', 'Gene', (46, 50))
36150	30187985	Compared to translocation-negative variants of congenital mesoblastic nephroma with classic or mixed histology, the cellular variant with ETV6-NTRK3 fusion carries a far better prognosis in terms of relapse free and overall survival.	('mesoblastic nephroma', 'Phenotype', 'HP:0100881', (58, 78))	('NTRK3', 'Gene', (143, 148))	('overall survival', 'CPA', (216, 232))	('ETV6', 'Gene', (138, 142))	('fusion', 'Var', (149, 155))	('ETV6', 'Gene', '2120', (138, 142))	('relapse free', 'CPA', (199, 211))	('congenital mesoblastic nephroma', 'Phenotype', 'HP:0100881', (47, 78))	('NTRK3', 'Gene', '4916', (143, 148))	('congenital mesoblastic nephroma', 'Disease', (47, 78))	('better', 'PosReg', (170, 176))	('congenital mesoblastic nephroma', 'Disease', 'MESH:D018201', (47, 78))
36151	30187985	Some of the genetic alterations found in pediatric IFS-like sarcomas have also been described in subsets of CMN, including EML4-NTRK3, LMNA-NTRK1, and BRAF intragenic deletions, providing further evidence that IFS and CMN are histogenetically related entities.	('NTRK3', 'Gene', '4916', (128, 133))	('BRAF', 'Gene', '673', (151, 155))	('N', 'Chemical', 'MESH:D009584', (140, 141))	('described', 'Reg', (84, 93))	('BRAF', 'Gene', (151, 155))	('NTRK3', 'Gene', (128, 133))	('N', 'Chemical', 'MESH:D009584', (220, 221))	('alterations', 'Var', (20, 31))	('EML4', 'Gene', (123, 127))	('CMN', 'Disease', (108, 111))	('EML4', 'Gene', '27436', (123, 127))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('LMNA', 'Gene', (135, 139))	('sarcomas', 'Disease', (60, 68))	('deletions', 'Var', (167, 176))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('N', 'Chemical', 'MESH:D009584', (128, 129))	('LMNA', 'Gene', '4000', (135, 139))	('NTRK1', 'Gene', '4914', (140, 145))	('NTRK1', 'Gene', (140, 145))	('N', 'Chemical', 'MESH:D009584', (110, 111))
36152	30187985	Lipofibromatosis-like neural tumor (LPF-NT) is a recently defined entity based on its recurrent NTRK1 gene fusions.	('LPF', 'Disease', (36, 39))	('Lipofibromatosis-like neural tumor', 'Disease', (0, 34))	('fusions', 'Var', (107, 114))	('NTRK1', 'Gene', (96, 101))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('NTRK1', 'Gene', '4914', (96, 101))	('LPF', 'Disease', 'None', (36, 39))	('Lipofibromatosis-like neural tumor', 'Disease', 'MESH:C536408', (0, 34))	('fibroma', 'Phenotype', 'HP:0010614', (4, 11))
36153	30187985	The descriptive designation, LPF-NT, was used to emphasize its close resemblance to lipofibromatosis (LPF) and its incomplete neural immunophenotype with S100 positivity but negative S0X10.	('lipofibromatosis', 'Disease', (84, 100))	('LPF', 'Disease', 'None', (102, 105))	('S100', 'Gene', '6285', (154, 158))	('LPF', 'Disease', (29, 32))	('lipofibromatosis', 'Disease', 'None', (84, 100))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('S100', 'Gene', (154, 158))	('LPF', 'Disease', (102, 105))	('positivity', 'Var', (159, 169))	('fibroma', 'Phenotype', 'HP:0010614', (88, 95))	('LPF', 'Disease', 'None', (29, 32))
36159	30187985	Molecularly, LPF-NTs harbor activating NTRK1 fusions, common gene partners including LMNA, TPR, and TPM3, resulting mostly from intrachromosomal interstitial deletions or inversions.	('TPR', 'Gene', '7175', (91, 94))	('TPM3', 'Gene', '7170', (100, 104))	('LMNA', 'Gene', (85, 89))	('NTRK1', 'Gene', '4914', (39, 44))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('activating', 'PosReg', (28, 38))	('LPF', 'Disease', (13, 16))	('LPF', 'Disease', 'None', (13, 16))	('NTRK1', 'Gene', (39, 44))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('LMNA', 'Gene', '4000', (85, 89))	('TPR', 'Gene', (91, 94))	('fusions', 'Var', (45, 52))	('TPM3', 'Gene', (100, 104))
36166	30187985	Genetic studies to date have not revealed recurrent abnormalities, including no NTRK1 fusions.	('NTRK1', 'Gene', (80, 85))	('recurrent abnormalities', 'Disease', 'None', (42, 65))	('fusions', 'Var', (86, 93))	('recurrent abnormalities', 'Disease', (42, 65))	('NTRK1', 'Gene', '4914', (80, 85))
36169	30187985	However, these lesions are consistently negative for S100 and harbor in nearly all cases a recurrent COL1A1-PDFGB fusion, resulting in autocrine activation of PDGFRB, which can be targeted with imatinib therapy in advanced/inoperable cases.	('S100', 'Gene', (53, 57))	('autocrine activation', 'MPA', (135, 155))	('PDGFRB', 'Gene', '5159', (159, 165))	('COL1A1', 'Gene', '1277', (101, 107))	('COL1A1', 'Gene', (101, 107))	('imatinib', 'Chemical', 'MESH:C097613', (194, 202))	('PDGFRB', 'Gene', (159, 165))	('fusion', 'Var', (114, 120))	('S100', 'Gene', '6285', (53, 57))
36170	30187985	About half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor ALK gene rearrangements and overexpress ALK protein.	('ALK', 'Gene', '238', (96, 99))	('inflammatory myofibroblastic tumors', 'Disease', (14, 49))	('ALK', 'Gene', (136, 139))	('harbor', 'Reg', (89, 95))	('IMTs', 'Disease', 'MESH:D009369', (51, 55))	('IMTs', 'Disease', (51, 55))	('ALK', 'Gene', (96, 99))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (27, 49))	('overexpress', 'PosReg', (124, 135))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (14, 49))	('rearrangements', 'Var', (105, 119))	('ALK', 'Gene', '238', (136, 139))
36174	30187985	In our recent series of 62 IMTs (25 presenting in children), gene rearrangements involving kinases were found in two-thirds of cases, including ALK fusions in 56%, ROS1 in 10%, and one case with RET rearrangement.	('RET', 'Gene', '5979', (195, 198))	('found', 'Reg', (104, 109))	('ALK', 'Gene', '238', (144, 147))	('ROS1', 'Gene', (164, 168))	('children', 'Species', '9606', (50, 58))	('RET', 'Gene', (195, 198))	('ALK', 'Gene', (144, 147))	('IMTs', 'Disease', (27, 31))	('ROS1', 'Gene', '6098', (164, 168))	('IMTs', 'Disease', 'MESH:D009369', (27, 31))	('gene rearrangements', 'Var', (61, 80))
36175	30187985	Furthermore, most IMT with EML4-ALK fusions occurred in children, including 2 newborns (range 0-39 years, mean 15).	('ALK', 'Gene', (32, 35))	('EML4', 'Gene', (27, 31))	('children', 'Species', '9606', (56, 64))	('occurred', 'Reg', (44, 52))	('fusions', 'Var', (36, 43))	('ALK', 'Gene', '238', (32, 35))	('EML4', 'Gene', '27436', (27, 31))
36178	30187985	Additionally, a handful of cases of IMT with ETV6-NTRK3 fusions have also been reported.	('fusions', 'Var', (56, 63))	('ETV6', 'Gene', '2120', (45, 49))	('NTRK3', 'Gene', '4916', (50, 55))	('NTRK3', 'Gene', (50, 55))	('ETV6', 'Gene', (45, 49))
36179	30187985	Importantly, a subset of IMTs with ALK or other kinase fusions show durable response to the ALK inhibitor Crizotinib.	('Crizotinib', 'Chemical', 'MESH:C551994', (106, 116))	('ALK', 'Gene', '238', (35, 38))	('ALK', 'Gene', (92, 95))	('IMTs', 'Disease', 'MESH:D009369', (25, 29))	('IMTs', 'Disease', (25, 29))	('ALK', 'Gene', (35, 38))	('ALK', 'Gene', '238', (92, 95))	('fusions', 'Var', (55, 62))
36184	30187985	The genetic hallmark of FHI, recently coined by NGS and targeted Sanger sequencing, represents a somatic EGFR exon 20 insertion/duplication (Figure 3), likely resulting in oncogenic EGFR activation.	('insertion/duplication', 'Var', (118, 139))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('activation', 'PosReg', (187, 197))	('NGS', 'Disease', (48, 51))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', (105, 109))	('NGS', 'Disease', 'None', (48, 51))	('FHI', 'Disease', (24, 27))
36187	30187985	No EGFR mutations were noted in other fibrolipomatous control cases tested.	('N', 'Chemical', 'MESH:D009584', (0, 1))	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))
36198	30187985	An EWSR1-SMAD3 fusion was recently identified as the genetic hallmark of a novel benign fibroblastic neoplasm with predilection for acral soft tissues.	('fusion', 'Var', (15, 21))	('EWSR1', 'Gene', '2130', (3, 8))	('neoplasm', 'Disease', (101, 109))	('neoplasm', 'Disease', 'MESH:D009369', (101, 109))	('SMAD3', 'Gene', '4088', (9, 14))	('SMAD3', 'Gene', (9, 14))	('neoplasm', 'Phenotype', 'HP:0002664', (101, 109))	('EWSR1', 'Gene', (3, 8))
36203	30187985	Unsupervised clustering of the whole transcriptome data showed that the EWSR1-SMAD3 fusion positive tumor clustered together with other fibroblastic tumors, including a CAF with FN1-EGF fusion, a LPF lacking genetic abnormalities, and a LPF-NT with TPR-NTRK1 fusion.	('fibroblastic tumors', 'Disease', (136, 155))	('genetic abnormalities', 'Disease', (208, 229))	('TPR', 'Gene', '7175', (249, 252))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('N', 'Chemical', 'MESH:D009584', (179, 180))	('LPF', 'Disease', (196, 199))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('CAF', 'Disease', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('EWSR1', 'Gene', '2130', (72, 77))	('N', 'Chemical', 'MESH:D009584', (241, 242))	('SMAD3', 'Gene', '4088', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('LPF', 'Disease', 'None', (237, 240))	('FN1', 'Gene', '2335', (178, 181))	('NTRK1', 'Gene', '4914', (253, 258))	('NTRK1', 'Gene', (253, 258))	('SMAD3', 'Gene', (78, 83))	('EWSR1', 'Gene', (72, 77))	('LPF', 'Disease', 'None', (196, 199))	('N', 'Chemical', 'MESH:D009584', (253, 254))	('FN1', 'Gene', (178, 181))	('CAF', 'Disease', 'MESH:D005350', (169, 172))	('LPF', 'Disease', (237, 240))	('tumor', 'Disease', (149, 154))	('fibroblastic tumors', 'Disease', 'MESH:D009369', (136, 155))	('fusion', 'Var', (84, 90))	('genetic abnormalities', 'Disease', 'MESH:D030342', (208, 229))	('TPR', 'Gene', (249, 252))
36216	30187985	Subsequently, various activating PDGFRB mutations were detected in cases of nonfamilial myofibromatosis and in the majority of sporadic myofibromas encountered in infants (75%) and adults (69%), with N666K mutation being detected in about half of the cases.	('sporadic myofibromas', 'Disease', (127, 147))	('fibroma', 'Phenotype', 'HP:0010614', (91, 98))	('N666K', 'Var', (200, 205))	('myofibromatosis', 'Phenotype', 'HP:0020135', (88, 103))	('PDGFRB', 'Gene', '5159', (33, 39))	('myofibromatosis', 'Disease', (88, 103))	('mutations', 'Var', (40, 49))	('sporadic myofibromas', 'Phenotype', 'HP:0020135', (127, 147))	('N666K', 'Mutation', 'rs864309711', (200, 205))	('infants', 'Species', '9606', (163, 170))	('fibroma', 'Phenotype', 'HP:0010614', (139, 146))	('PDGFRB', 'Gene', (33, 39))	('sporadic myofibromas', 'Disease', 'MESH:D047708', (127, 147))	('myofibromatosis', 'Disease', 'MESH:D018224', (88, 103))	('activating', 'PosReg', (22, 32))
36217	30187985	These activation mutations are mostly located in the juxtamembrane and kinase domains of the PDGFRB receptor and were shown to be sensitive to tyrosine kinase receptor inhibition in experimental models.	('PDGFRB', 'Gene', '5159', (93, 99))	('tyrosine', 'Chemical', 'None', (143, 151))	('PDGFRB', 'Gene', (93, 99))	('activation', 'PosReg', (6, 16))	('mutations', 'Var', (17, 26))
36220	30187985	Not surprisingly, NOTCH rearrangements and fusions associated with MIR143 have been implicated in more than half of glomus tumors; the incidence being much higher in malignant examples.	('MIR143', 'Gene', '406935', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('implicated', 'Reg', (84, 94))	('MIR143', 'Gene', (67, 73))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('glomus tumors', 'Disease', 'MESH:D005918', (116, 129))	('fusions', 'Var', (43, 50))	('glomus tumors', 'Disease', (116, 129))	('NOTCH rearrangements', 'Var', (18, 38))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
36221	30187985	In addition to myofibroma(tosis), RNA sequencing also revealed PDGFRB mutations in myopericytoma and myopericytomatosis, a condition presenting in the lower extremity of adults, characterized by diffuse dermal and/or subcutaneous involvement by myopericytomatous nodules.	('mutations', 'Var', (70, 79))	('fibroma', 'Phenotype', 'HP:0010614', (18, 25))	('PDGFRB', 'Gene', '5159', (63, 69))	('lower extremity', 'Phenotype', 'HP:0006385', (151, 166))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('myopericytoma', 'Disease', (83, 96))	('PDGFRB', 'Gene', (63, 69))	('myopericytoma', 'Disease', 'None', (83, 96))	('myopericytoma', 'Disease', 'None', (101, 114))	('myopericytoma', 'Disease', 'None', (245, 258))	('myopericytoma and myopericytomatosis', 'Disease', 'None', (83, 119))	('myopericytoma', 'Disease', (101, 114))	('myofibroma(tosis', 'Disease', 'MESH:D047708', (15, 31))	('myopericytoma', 'Disease', (245, 258))
36228	30187985	The large majority of alveolar RMS harbors PAX3/7-FOXO1 fusions, while embryonal RMS lack a recurrent genetic abnormality.	('fusions', 'Var', (56, 63))	('FOXO1', 'Gene', '2308', (50, 55))	('FOXO1', 'Gene', (50, 55))	('PAX3', 'Gene', (43, 47))	('RMS', 'Disease', (31, 34))	('PAX3', 'Gene', '5077', (43, 47))	('genetic abnormality', 'Disease', (102, 121))	('RMS', 'Disease', 'MESH:D012208', (81, 84))	('RMS', 'Phenotype', 'HP:0002859', (31, 34))	('genetic abnormality', 'Disease', 'MESH:D030342', (102, 121))	('RMS', 'Disease', (81, 84))	('RMS', 'Disease', 'MESH:D012208', (31, 34))	('RMS', 'Phenotype', 'HP:0002859', (81, 84))
36238	30187985	Despite their overlapping morphologic features, at least three genomic groups have been defined in the pediatric age group, including: an infantile subset of spindle cell RMS harboring VGLL2-related gene fusions, a MYOD1-mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities.	('genetic abnormalities', 'Disease', (314, 335))	('VGLL2', 'Gene', '245806', (185, 190))	('RMS', 'Phenotype', 'HP:0002859', (171, 174))	('fusions', 'Var', (204, 211))	('spindle cell RMS', 'Disease', 'MESH:D002277', (158, 174))	('MYOD1', 'Gene', '4654', (215, 220))	('infant', 'Species', '9606', (138, 144))	('VGLL2', 'Gene', (185, 190))	('associated', 'Reg', (244, 254))	('MYOD1', 'Gene', (215, 220))	('spindle cell RMS', 'Disease', (158, 174))	('genetic abnormalities', 'Disease', 'MESH:D030342', (314, 335))
36245	30187985	The presence of transactivating MYOD1 mutations have been described in both spindle cell and sclerosing RMS, providing a strong molecular basis in support for their classification as a single pathologic entity.	('spindle cell', 'Disease', (76, 88))	('MYOD1', 'Gene', '4654', (32, 37))	('RMS', 'Disease', (104, 107))	('transactivating', 'PosReg', (16, 31))	('RMS', 'Phenotype', 'HP:0002859', (104, 107))	('MYOD1', 'Gene', (32, 37))	('mutations', 'Var', (38, 47))	('RMS', 'Disease', 'MESH:D012208', (104, 107))
36246	30187985	At the molecular level, most tumors harbor a MYOD1 homozygous mutation in exon 1 (p.L122R), while a smaller subset shows a heterozygous genotype (Figure 4).	('p.L122R', 'Mutation', 'p.L122R', (82, 89))	('tumors', 'Disease', (29, 35))	('MYOD1', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('p.L122R', 'Var', (82, 89))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('MYOD1', 'Gene', '4654', (45, 50))
36249	30187985	RMS patients with MYOD1 mutations, with or without accompanying PIK3CA mutations, follow a highly aggressive course with high mortality despite multimodality therapy.	('RMS', 'Disease', (0, 3))	('PIK3CA', 'Gene', (64, 70))	('MYOD1', 'Gene', (18, 23))	('RMS', 'Phenotype', 'HP:0002859', (0, 3))	('PIK3CA', 'Gene', '5290', (64, 70))	('RMS', 'Disease', 'MESH:D012208', (0, 3))	('patients', 'Species', '9606', (4, 12))	('mutations', 'Var', (24, 33))	('MYOD1', 'Gene', '4654', (18, 23))
36250	30187985	In a recent study, MYOD1 mutations were the most common genetic abnormality in pediatric spindle cell/sclerosing RMS, occurring in 64% of children beyond one year of age, and suggesting that it can be used as a molecular biomarker to stratify these high risk patients.	('RMS', 'Phenotype', 'HP:0002859', (113, 116))	('mutations', 'Var', (25, 34))	('children', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (259, 267))	('MYOD1', 'Gene', '4654', (19, 24))	('RMS', 'Disease', 'MESH:D012208', (113, 116))	('MYOD1', 'Gene', (19, 24))	('RMS', 'Disease', (113, 116))	('genetic abnormality', 'Disease', 'MESH:D030342', (56, 75))	('genetic abnormality', 'Disease', (56, 75))
36252	30187985	This group encompasses the "genetically negative" group, lacking gene fusions or MYOD1 mutations, often presenting intra-abdominally or para-testicular.	('lacking', 'NegReg', (57, 64))	('gene fusions', 'Var', (65, 77))	('MYOD1', 'Gene', '4654', (81, 86))	('MYOD1', 'Gene', (81, 86))	('mutations', 'Var', (87, 96))
36254	30187985	The presence of EWSR1/FUS-TFCP2 fusions has been recently reported in 3 tumors from young adult females occuring with predilection at skeletal sites (pelvis, chest wall, sphenoid bone).	('EWSR1', 'Gene', '2130', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('fusions', 'Var', (32, 39))	('TFCP2', 'Gene', (26, 31))	('FUS', 'Gene', (22, 25))	('reported', 'Reg', (58, 66))	('FUS', 'Gene', '2521', (22, 25))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('EWSR1', 'Gene', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('TFCP2', 'Gene', '7024', (26, 31))
36262	30187985	Undifferentiated sarcomas characterized by BCOR genetic alterations, spanning both gene fusions and internal tandem duplications (ITD), share similarities at the morphologic and immunohistochemical levels, despite the wide spectrum of clinical presentations and pathologic entities involved.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcomas', 'Disease', (17, 25))	('BCOR', 'Gene', (43, 47))	('BCOR', 'Gene', '54880', (43, 47))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('internal tandem duplications', 'Var', (100, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
36266	30187985	Regardless of the specific gene alterations, BCOR family of tumors show significant upregulation of BCOR and SATB2 mRNA, resulting into protein overexpression and immunopositivity for BCOR and SATB2, which can be used as reliable diagnostic markers.	('mRNA', 'MPA', (115, 119))	('protein', 'MPA', (136, 143))	('BCOR', 'Gene', '54880', (184, 188))	('SATB2', 'Gene', (193, 198))	('BCOR', 'Gene', (184, 188))	('SATB2', 'Gene', '23314', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('BCOR', 'Gene', '54880', (45, 49))	('BCOR', 'Gene', '54880', (100, 104))	('upregulation', 'PosReg', (84, 96))	('alterations', 'Var', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('overexpression', 'PosReg', (144, 158))	('BCOR', 'Gene', (45, 49))	('BCOR', 'Gene', (100, 104))	('tumors', 'Disease', (60, 66))	('SATB2', 'Gene', (109, 114))	('SATB2', 'Gene', '23314', (109, 114))	('N', 'Chemical', 'MESH:D009584', (117, 118))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
36272	30187985	Moreover, as BCOR ITD alterations were described recently as the leading pathogenetic mechanism of clear cell sarcoma of kidney (CCSK), a comparative histologic and genomic analysis of the 2 tumor types showed significant overlap with the infantile soft tissue tumors harboring a similar genotype.	('clear cell sarcoma of kidney', 'Disease', (99, 127))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (249, 266))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (249, 267))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('CCSK', 'Disease', (129, 133))	('infantile soft tissue tumors', 'Disease', (239, 267))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('CCSK', 'Disease', 'MESH:D018227', (129, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('BCOR', 'Gene', '54880', (13, 17))	('clear cell sarcoma of kidney', 'Disease', 'MESH:D018227', (99, 127))	('tumor', 'Disease', (191, 196))	('BCOR', 'Gene', (13, 17))	('sarcoma of kidney', 'Phenotype', 'HP:0008663', (110, 127))	('infantile soft tissue tumors', 'Disease', 'MESH:D012983', (239, 267))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (261, 266))	('alterations', 'Var', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
36278	30187985	The genetic hallmark consists of a paracentric inversion on the short arm of chromosome X, resulting in the fusion of 2 nearby genes, BCOR and CCNB3 (10 Mb apart), leading to CCNB3 overexpression.	('BCOR', 'Gene', '54880', (134, 138))	('CCNB3', 'Gene', '85417', (175, 180))	('overexpression', 'PosReg', (181, 195))	('CCNB3', 'Gene', '85417', (143, 148))	('short arm', 'Phenotype', 'HP:0009824', (64, 73))	('fusion', 'Var', (108, 114))	('BCOR', 'Gene', (134, 138))	('CCNB3', 'Gene', (175, 180))	('CCNB3', 'Gene', (143, 148))
36287	30187985	Tumors with these fusions were shown to share significant morphologic and immuno-histochemical features with other members of the BCOR-family tumors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('fusions', 'Var', (18, 25))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BCOR', 'Gene', (130, 134))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('BCOR', 'Gene', '54880', (130, 134))
36394	24717189	The factors independently associated with attrition after simultaneous adjustment of all confounders were male sex, low BMI, WHO clinical stage 3 or 4, and later year of enrollment (Fig.	('men', 'Species', '9606', (176, 179))	('men', 'Species', '9606', (77, 80))	('low BMI', 'Phenotype', 'HP:0045082', (116, 123))	('low', 'Var', (116, 119))	('BMI', 'MPA', (120, 123))
36572	33207697	Notably, modulation of immune inhibitory pathways using checkpoint inhibitors has produced durable clinical responses in a sizable subset of patients, leading to their accelerated approval for the treatment of several cancers such as melanoma and renal cell cancer.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('modulation', 'Var', (9, 19))	('cancers', 'Disease', (218, 225))	('renal cell cancer', 'Phenotype', 'HP:0005584', (247, 264))	('melanoma and renal cell cancer', 'Disease', 'MESH:C538614', (234, 264))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('patients', 'Species', '9606', (141, 149))
36576	33207697	Immunosurveillance against tumours depends on immune cell recognition of tumour cells through neoantigens generated by somatic mutations or aberrant expression of non-mutated antigens on tumour cells.	('tumour', 'Disease', (187, 193))	('tumour', 'Disease', (73, 79))	('aberrant expression', 'Var', (140, 159))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumour', 'Disease', (27, 33))	('tumours', 'Disease', (27, 34))	('tumour', 'Disease', 'MESH:D009369', (187, 193))
36586	33207697	GIST with KIT and PDGFRA activating mutations were shown to promote ligand-independent proliferation thereby contributing to the formation of these tumours.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('promote', 'PosReg', (60, 67))	('tumours', 'Disease', (148, 155))	('PDGFRA', 'Gene', '5156', (18, 24))	('PDGFRA', 'Gene', (18, 24))	('ligand-independent proliferation', 'CPA', (68, 100))	('mutations', 'Var', (36, 45))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('KIT', 'Gene', '3815', (10, 13))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('contributing', 'Reg', (109, 121))	('KIT', 'Gene', (10, 13))
36589	33207697	This phenomenon was also observed in patient samples where an increase in the ratio of intratumoural CD8+ T cells to Treg cells was detected in imatinib-sensitive tumours compared to untreated tumours.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (92, 98))	('tumours', 'Disease', (193, 200))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))	('tumour', 'Disease', (163, 169))	('increase', 'PosReg', (62, 70))	('tumours', 'Disease', 'MESH:D009369', (193, 200))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('CD8', 'Gene', '925', (101, 104))	('tumour', 'Disease', (193, 199))	('imatinib-sensitive', 'Var', (144, 162))	('tumours', 'Disease', (163, 170))	('patient', 'Species', '9606', (37, 44))	('imatinib', 'Chemical', 'MESH:D000068877', (144, 152))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumours', 'Disease', 'MESH:D009369', (163, 170))	('CD8', 'Gene', (101, 104))
36591	33207697	examined 82 samples of primary naive GIST and found that GIST with KIT and PDGFRA mutations have higher immune infiltration of CD4+ and CD8+ T cells compared to wildtype GIST.	('immune infiltration', 'CPA', (104, 123))	('higher', 'PosReg', (97, 103))	('GIST', 'Phenotype', 'HP:0100723', (57, 61))	('CD4', 'Gene', '920', (127, 130))	('CD8', 'Gene', (136, 139))	('KIT', 'Gene', (67, 70))	('GIST', 'Phenotype', 'HP:0100723', (37, 41))	('CD8', 'Gene', '925', (136, 139))	('mutations', 'Var', (82, 91))	('PDGFRA', 'Gene', (75, 81))	('GIST', 'Phenotype', 'HP:0100723', (170, 174))	('PDGFRA', 'Gene', '5156', (75, 81))	('CD4', 'Gene', (127, 130))	('KIT', 'Gene', '3815', (67, 70))
36594	33207697	Inhibition of Hedgehog and WNT/beta-catenin signalling pathways could reverse "immune cold" to "immune hot" GIST.	('beta-catenin', 'Gene', '1499', (31, 43))	('GIST', 'Phenotype', 'HP:0100723', (108, 112))	('beta-catenin', 'Gene', (31, 43))	('Inhibition', 'Var', (0, 10))
36600	33207697	Blockade of CTLA-4 on Tregs has been shown to abrogate the inhibitory restraints of Tregs on T cells.	('inhibitory restraints', 'MPA', (59, 80))	('Tregs', 'Chemical', '-', (22, 27))	('Tregs', 'Chemical', '-', (84, 89))	('abrogate', 'NegReg', (46, 54))	('Blockade', 'Var', (0, 8))	('CTLA-4', 'Gene', (12, 18))
36601	33207697	The potential of inhibiting CTLA-4 for cancer therapy was observed in vivo when administration of anti-CTLA-4 antibodies resulted in rejection of murine colon carcinoma and fibrosarcoma and generation of immunological memory.	('colon carcinoma and fibrosarcoma', 'Disease', 'MESH:D003110', (153, 185))	('murine', 'Species', '10090', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('cancer', 'Disease', (39, 45))	('anti-CTLA-4 antibodies', 'Var', (98, 120))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (173, 185))	('immunological memory', 'Disease', (204, 224))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('anti-CTLA-4', 'Gene', (98, 109))	('immunological memory', 'Disease', 'MESH:D007153', (204, 224))	('rejection', 'CPA', (133, 142))	('antibodies', 'Var', (110, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
36620	33207697	Synergistic effects were observed in preclinical studies where tumour-bearing mice were treated with the combination of imatinib and anti-CTLA-4 antibody.	('anti-CTLA-4', 'Var', (133, 144))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('imatinib', 'Chemical', 'MESH:D000068877', (120, 128))	('mice', 'Species', '10090', (78, 82))	('tumour', 'Disease', (63, 69))
36621	33207697	The combination of imatinib and CTLA-4 blockade significantly reduced tumour size compared to mice treated with monotherapies.	('blockade', 'Var', (39, 47))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('CTLA-4', 'Gene', (32, 38))	('imatinib', 'Chemical', 'MESH:D000068877', (19, 27))	('mice', 'Species', '10090', (94, 98))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))	('reduced', 'NegReg', (62, 69))
36645	33207697	examined PD-L1 expression in patient tumour samples with tissue microarray (TMA) analysis carried out with three different antibody clones: >=1% of PD-L1 expression was observed in 20%, 17.6% and 16.3% of undifferentiated pleomorphic sarcomas with PD-L1 22C3, SP263 and SP142 antibodies, respectively.	('patient', 'Species', '9606', (29, 36))	('TMA', 'Disease', 'MESH:D000783', (76, 79))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (205, 242))	('undifferentiated pleomorphic sarcomas', 'Disease', (205, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('tumour', 'Disease', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (234, 242))	('SP142 antibodies', 'Var', (270, 286))	('TMA', 'Disease', (76, 79))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('SP263', 'Var', (260, 265))	('PD-L1', 'Gene', (148, 153))	('PD-L1 22C3', 'Var', (248, 258))
36686	33207697	also showed antibody-mediated PD-L1 blockade significantly increased survival in tumour-bearing mice and reduced the number of lung metastases compared to control mice.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('mice', 'Species', '10090', (96, 100))	('survival', 'CPA', (69, 77))	('tumour', 'Disease', (81, 87))	('PD-L1', 'Gene', (30, 35))	('mice', 'Species', '10090', (163, 167))	('reduced', 'NegReg', (105, 112))	('lung metastases', 'Disease', (127, 142))	('increased', 'PosReg', (59, 68))	('lung metastases', 'Disease', 'MESH:D009362', (127, 142))	('blockade', 'Var', (36, 44))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
36687	33207697	Currently, there are several clinical trials using immune checkpoint inhibitors being conducted in patients with osteosarcoma, such as NCT03006848 and NCT02982486.	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('NCT03006848', 'Var', (135, 146))	('NCT02982486', 'Var', (151, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('patients', 'Species', '9606', (99, 107))	('osteosarcoma', 'Disease', (113, 125))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))
36693	33207697	Furthermore, tumours with low immune infiltration had a higher prevalence of deletions, including MHC-encoding genes, whereas adaptive resistance pathways were expressed in tumours with high immune infiltration.	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('deletions', 'Var', (77, 86))	('tumours', 'Disease', (173, 180))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Disease', (13, 20))	('MHC-encoding genes', 'Gene', (98, 116))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))
36696	33207697	Combination treatment with PD-L1 and CTLA-4 antibodies resulted in complete control of metastatic osteosarcoma in 50% of mice and drastically improved the long-term disease-free survival to 60% compared to 0% observed in mice receiving anti-PD-L1 monotherapy.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('antibodies', 'Var', (44, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('CTLA-4', 'Gene', (37, 43))	('improved', 'PosReg', (142, 150))	('mice', 'Species', '10090', (221, 225))	('mice', 'Species', '10090', (121, 125))	('PD-L1', 'Gene', (27, 32))	('osteosarcoma', 'Disease', (98, 110))
36697	33207697	Combination therapy was also found to increase tumour specific TIL function as compared to monotherapies and induce T cell memory-mediated protection against tumour rechallenge.	('increase', 'PosReg', (38, 46))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('Combination', 'Var', (0, 11))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('tumour', 'Disease', (47, 53))	('T cell memory-mediated protection', 'CPA', (116, 149))	('tumour', 'Disease', (158, 164))	('induce', 'PosReg', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
36734	33207697	Data from this study led to the activation of a phase II trial of ADP-A2M4 SPEAR T cells in advanced synovial sarcoma or myxoid/ round cell liposarcoma (NCT04044768).	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (101, 117))	('liposarcoma', 'Disease', (140, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('synovial sarcoma', 'Disease', 'MESH:D013584', (101, 117))	('ADP-A2M4', 'Var', (66, 74))	('liposarcoma', 'Phenotype', 'HP:0012034', (140, 151))	('liposarcoma', 'Disease', 'MESH:D008080', (140, 151))	('synovial sarcoma', 'Disease', (101, 117))
36744	33207697	Despite being able to control GD2 positive neuroblastoma effectively in vivo, anti-GD2 CAR T cells showed minimal anti-tumour effect against osteosarcoma tumours in a xenograft mouse model and no improvement in survival was observed.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('osteosarcoma tumours', 'Disease', 'MESH:D012516', (141, 161))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('neuroblastoma', 'Disease', 'MESH:D009447', (43, 56))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('neuroblastoma', 'Disease', (43, 56))	('osteosarcoma tumours', 'Disease', (141, 161))	('tumour', 'Disease', (154, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('osteosarcoma', 'Phenotype', 'HP:0002669', (141, 153))	('tumour', 'Disease', (119, 125))	('minimal', 'NegReg', (106, 113))	('mouse', 'Species', '10090', (177, 182))	('neuroblastoma', 'Phenotype', 'HP:0003006', (43, 56))	('anti-GD2', 'Var', (78, 86))
36747	33207697	Combination therapy using ATRA and anti-GD2 CAR T cells significantly enhanced anti-tumour efficacy and improved survival in sarcoma-bearing mice without inducing an increase in Tregs.	('survival', 'CPA', (113, 121))	('tumour', 'Disease', (84, 90))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('anti-GD2', 'Var', (35, 43))	('improved', 'PosReg', (104, 112))	('ATRA', 'Chemical', 'MESH:D014212', (26, 30))	('sarcoma', 'Disease', (125, 132))	('Tregs', 'Chemical', '-', (178, 183))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('enhanced', 'PosReg', (70, 78))	('mice', 'Species', '10090', (141, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
36748	33207697	also examined the efficacy of anti-GD2 CAR T cells against GD2 positive osteosarcoma in vitro and reported anti-GD2 CAR T cells were able to effectively lyse osteosarcoma cells expressing high levels of GD2.	('osteosarcoma', 'Phenotype', 'HP:0002669', (158, 170))	('osteosarcoma', 'Disease', (158, 170))	('GD2', 'Gene', (59, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('anti-GD2', 'Var', (107, 115))	('osteosarcoma', 'Disease', (72, 84))	('osteosarcoma', 'Disease', 'MESH:D012516', (158, 170))	('osteosarcoma', 'Phenotype', 'HP:0002669', (72, 84))	('osteosarcoma', 'Disease', 'MESH:D012516', (72, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
36755	33207697	This study demonstrated the potential of anti-HER2 CAR T therapy in tumours that do not express sufficient level of HER2 to be recognised by monoclonal antibodies.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('tumours', 'Disease', (68, 75))	('anti-HER2', 'Var', (41, 50))
36762	33207697	Anti-IGF1R CAR T cells and anti-ROR1 CAR T cells generated from a sarcoma patient were able to significantly reduce tumour growth in osteosarcoma xenograft mice models.	('sarcoma', 'Disease', (66, 73))	('ROR1', 'Gene', (32, 36))	('patient', 'Species', '9606', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcoma', 'Disease', (138, 145))	('Anti-IGF1R', 'Var', (0, 10))	('reduce', 'NegReg', (109, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('tumour growth in osteosarcoma', 'Disease', (116, 145))	('tumour growth in osteosarcoma', 'Disease', 'MESH:D012516', (116, 145))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('mice', 'Species', '10090', (156, 160))	('ROR1', 'Gene', '4919', (32, 36))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))
36767	33207697	Anti-B7-H3 CAR T therapy was also able to prolong survival in the metastatic osteosarcoma mice model, suggesting the potential of this therapy in established and metastatic osteosarcoma.	('prolong', 'PosReg', (42, 49))	('osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('Anti-B7-H3 CAR', 'Var', (0, 14))	('mice', 'Species', '10090', (90, 94))	('osteosarcoma', 'Disease', (173, 185))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('osteosarcoma', 'Phenotype', 'HP:0002669', (173, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('survival', 'CPA', (50, 58))	('osteosarcoma', 'Disease', 'MESH:D012516', (173, 185))	('osteosarcoma', 'Disease', (77, 89))
36779	33207697	Moreover, cases expressing low levels of PD-L1 in tumour cells showed enhanced intra-tumour infiltration of NK cells and better survival rates.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('intra-tumour', 'Disease', (79, 91))	('tumour', 'Disease', (50, 56))	('survival rates', 'CPA', (128, 142))	('tumour', 'Disease', (85, 91))	('better', 'PosReg', (121, 127))	('low levels', 'Var', (27, 37))	('enhanced', 'PosReg', (70, 78))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('intra-tumour', 'Disease', 'MESH:D009369', (79, 91))	('PD-L1', 'Gene', (41, 46))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
36808	33207697	Currently, there are several clinical trials investigating the safety and efficacy of NK immunotherapy in sarcoma such as NCT02409576 and NCT02849366.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('NCT02849366', 'Var', (138, 149))	('sarcoma', 'Disease', (106, 113))	('NCT02409576', 'Var', (122, 133))
36812	33207697	reported that hu3F8-BsAb was able to suppress tumour progression thus prolonging survival in murine neuroblastoma and melanoma xenograft models.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('survival', 'CPA', (81, 89))	('neuroblastoma', 'Disease', (100, 113))	('murine', 'Species', '10090', (93, 99))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', (46, 52))	('neuroblastoma', 'Phenotype', 'HP:0003006', (100, 113))	('suppress', 'NegReg', (37, 45))	('hu3F8-BsAb', 'Var', (14, 24))	('tumour', 'Disease', 'MESH:D009369', (46, 52))	('neuroblastoma', 'Disease', 'MESH:D009447', (100, 113))	('prolonging', 'NegReg', (70, 80))
36813	33207697	Hu3F8-BsAb was also found to induce T cells and monocytes infiltration into tumour stroma.	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour stroma', 'Disease', 'MESH:D009369', (76, 89))	('tumour stroma', 'Disease', (76, 89))	('induce', 'PosReg', (29, 35))	('Hu3F8-BsAb', 'Var', (0, 10))
36818	33207697	Sarcomas are thought to be ideal for cancer vaccine targets due to the expression of immunogenic antigens such as CTAs, gangliosides and sarcoma-specific fusion proteins generated by chromosomal translocations that are often seen in synovial sarcoma and myxoid/round cell liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('sarcoma', 'Disease', 'MESH:D012509', (276, 283))	('sarcoma', 'Disease', (276, 283))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (233, 249))	('sarcoma', 'Disease', 'MESH:D012509', (242, 249))	('chromosomal translocations', 'Var', (183, 209))	('sarcoma', 'Disease', (242, 249))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('liposarcoma', 'Disease', (272, 283))	('cancer', 'Disease', (37, 43))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('sarcoma', 'Disease', (137, 144))	('Sarcomas', 'Disease', (0, 8))	('liposarcoma', 'Phenotype', 'HP:0012034', (272, 283))	('synovial sarcoma', 'Disease', (233, 249))	('gangliosides', 'Chemical', 'MESH:D005732', (120, 132))	('CTAs', 'Chemical', '-', (114, 118))	('synovial sarcoma', 'Disease', 'MESH:D013584', (233, 249))	('liposarcoma', 'Disease', 'MESH:D008080', (272, 283))
36827	33207697	Chromosomal translocation occurring in distinct subtypes of sarcoma, such as t(X;18)(p11;q11) in synovial sarcoma and t(12;16)(q13;p11) in myxoid/ round cell liposarcoma, can generate tumour-specific immunogenic epitopes that are promising candidates as vaccine targets.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('t(X;18)(p11;q11', 'Var', (77, 92))	('liposarcoma', 'Disease', 'MESH:D008080', (158, 169))	('synovial sarcoma', 'Disease', (97, 113))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (77, 93))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('synovial sarcoma', 'Disease', 'MESH:D013584', (97, 113))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (118, 135))	('sarcoma', 'Disease', (60, 67))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('liposarcoma', 'Disease', (158, 169))	('sarcoma', 'Disease', (162, 169))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (97, 113))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('sarcoma', 'Disease', (106, 113))	('t(12;16)(q13;p11', 'Var', (118, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('liposarcoma', 'Phenotype', 'HP:0012034', (158, 169))
36828	33207697	The chromosomal translocation in synovial sarcoma results in a SS18-SSX fusion protein and it has been demonstrated that circulating CD8+ T cells of HLA-A24+ synovial sarcoma patients can recognise the SS18-SSX peptides and mediate tumour-specific immune responses.	('HLA-A', 'Gene', (149, 154))	('chromosomal translocation', 'Var', (4, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('synovial sarcoma', 'Disease', (33, 49))	('CD8', 'Gene', '925', (133, 136))	('results in', 'Reg', (50, 60))	('synovial sarcoma', 'Disease', 'MESH:D013584', (33, 49))	('SSX', 'Gene', (68, 71))	('SSX', 'Gene', '727837', (207, 210))	('HLA-A', 'Gene', '3105', (149, 154))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumour', 'Disease', 'MESH:D009369', (232, 238))	('tumour', 'Disease', (232, 238))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (33, 49))	('synovial sarcoma', 'Disease', (158, 174))	('SSX', 'Gene', (207, 210))	('synovial sarcoma', 'Disease', 'MESH:D013584', (158, 174))	('CD8', 'Gene', (133, 136))	('mediate', 'Reg', (224, 231))	('patients', 'Species', '9606', (175, 183))	('SSX', 'Gene', '727837', (68, 71))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (158, 174))
36839	33207697	This study reported that administration of LM8-pulsed DCs generated increased antigen-specific cytotoxic T cells activity, enhanced proliferation of CD4+ and CD8+ T cells and increased serum IFN-gamma levels.	('enhanced', 'PosReg', (123, 131))	('LM8-pulsed', 'Var', (43, 53))	('CD8', 'Gene', (158, 161))	('CD4', 'Gene', (149, 152))	('CD8', 'Gene', '925', (158, 161))	('proliferation', 'CPA', (132, 145))	('antigen-specific cytotoxic T cells activity', 'CPA', (78, 121))	('IFN-gamma', 'Gene', '3458', (191, 200))	('IFN-gamma', 'Gene', (191, 200))	('CD4', 'Gene', '920', (149, 152))	('LM8', 'Chemical', '-', (43, 46))	('increased', 'PosReg', (175, 184))	('increased', 'PosReg', (68, 77))	('DCs', 'Gene', (54, 57))
36853	33207697	Further investigations on how to increase efficacy include combination of DC-based vaccines with a demethylating chemotherapy drug, decitabine, to increase CTAs expression in high-risk sarcomas (NCT01241162) and combination of DC-based vaccines with gemcitabine to inhibit MDSCs (NCT01803152).	('sarcomas', 'Phenotype', 'HP:0100242', (185, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('MDSCs', 'Gene', (273, 278))	('expression', 'MPA', (161, 171))	('sarcomas', 'Disease', (185, 193))	('decitabine', 'Chemical', 'MESH:D000077209', (132, 142))	('gemcitabine', 'Chemical', 'MESH:C056507', (250, 261))	('sarcomas', 'Disease', 'MESH:D012509', (185, 193))	('NCT01241162', 'Var', (195, 206))	('increase', 'PosReg', (147, 155))	('inhibit', 'NegReg', (265, 272))	('NCT01803152', 'Var', (280, 291))	('CTAs', 'Protein', (156, 160))	('CTAs', 'Chemical', '-', (156, 160))
36866	33207697	This study showed that treatments with anti-CTLA-4 antibody alone and tumour lysate-pulsed DCs alone led to increased intra-tumour infiltration of CD8+ T cells, decreased frequency of Treg cells, increased IFN-gamma serum levels, reduced burden of pulmonary metastases and prolonged survival.	('decreased', 'NegReg', (161, 170))	('CD8', 'Gene', (147, 150))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('pulmonary metastases', 'Disease', (248, 268))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('tumour', 'Disease', (124, 130))	('increased', 'PosReg', (196, 205))	('intra-tumour', 'Disease', 'MESH:D009369', (118, 130))	('IFN-gamma', 'Gene', '3458', (206, 215))	('IFN-gamma', 'Gene', (206, 215))	('increased', 'PosReg', (108, 117))	('anti-CTLA-4', 'Gene', (39, 50))	('survival', 'CPA', (283, 291))	('reduced', 'NegReg', (230, 237))	('Treg cells', 'CPA', (184, 194))	('anti-CTLA-4', 'Var', (39, 50))	('pulmonary metastases', 'Disease', 'MESH:D009362', (248, 268))	('CD8', 'Gene', '925', (147, 150))	('prolonged', 'PosReg', (273, 282))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('intra-tumour', 'Disease', (118, 130))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))
36873	33207697	These engineered viruses mediate anti-tumour responses either directly by incorporating viruses into tumour cells which leads to tumour cell lysis or indirectly by promoting anti-tumour immune response as immune cells get exposed to TAA from dying tumour cells (Figure 2E).	('viruses', 'Var', (88, 95))	('tumour cell lysis', 'Disease', (129, 146))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('promoting', 'PosReg', (164, 173))	('tumour cell lysis', 'Disease', 'MESH:D015275', (129, 146))	('tumour', 'Disease', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('tumour', 'Disease', (179, 185))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Disease', (129, 135))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('tumour', 'Disease', 'MESH:D009369', (248, 254))	('tumour', 'Disease', (248, 254))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('tumour', 'Disease', (38, 44))
36883	33207697	This study showed that MSCs loaded with oncolytic virus were able to induce higher tumour killing and decrease tumour burden than treatment with oncolytic virus alone.	('oncolytic virus', 'Var', (40, 55))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumour killing and decrease tumour', 'Disease', 'MESH:D009369', (83, 117))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('higher', 'PosReg', (76, 82))
36904	33207697	The lack of anti-PD-1 efficacy in the murine rhabdomyosarcoma model was due to the recruitment of MDSCs to the tumour bed, and disrupting the migration of these MDSCs significantly improved the efficacy of PD-1 blockade.	('efficacy', 'MPA', (194, 202))	('disrupting', 'Var', (127, 137))	('migration', 'CPA', (142, 151))	('improved', 'PosReg', (181, 189))	('PD-1', 'Protein', (206, 210))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (45, 61))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('rhabdomyosarcoma', 'Disease', (45, 61))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (45, 61))	('murine', 'Species', '10090', (38, 44))	('tumour', 'Disease', (111, 117))
36988	29771965	Robust DNA and RNA extraction protocols are required for accurate identification and quantification of somatic variants in FFPE tissue specimens, and this will improve both research and routine clinical management of cancer.	('FFPE', 'Gene', (123, 127))	('clinical', 'Species', '191496', (194, 202))	('variants', 'Var', (111, 119))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('improve', 'PosReg', (160, 167))
36993	29771965	In addition to quantity and quality of the nucleic acids extracted, performance on HTS applications using Agilent SureSelect XT (Agilent Technologies, Santa Clara, CA, US) for variant detection in DNA and Archer FusionPlex Sarcoma Assay (ArcherDX, Boulder, CO, USA) for fusion detection in RNA were evaluated.	('Sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('Sarcoma', 'Disease', (223, 230))	('variant', 'Var', (176, 183))	('Sarcoma', 'Disease', 'MESH:D012509', (223, 230))
37037	28439495	The first group is characterized by a simple karyotype associated with specific tumor genetic alterations that include chromosomal translocations, oncogenetic mutations, and recurrent gene amplifications.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('chromosomal translocations', 'Var', (119, 145))	('tumor', 'Disease', (80, 85))
37052	28439495	Inhibition of this axis enables the immune system to quickly adapt to cancer resistances thus allowing durable responses with ICI.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('allowing', 'Reg', (94, 102))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
37053	28439495	Sarcomas mainly occur either secondary to the activation of oncogenes via translocations and inversions, or secondary to the natural expression of germ cell peptides.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('activation', 'PosReg', (46, 56))	('inversions', 'Var', (93, 103))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('translocations', 'Var', (74, 88))	('oncogenes', 'Protein', (60, 69))	('Sarcomas', 'Disease', (0, 8))
37058	28439495	Alternatively, lymphocyte T-cells may be genetically engineered either by modifying a T-cell receptor for cancer antigen (transgenic TCR) or by adding a chimeric antigen receptor (CAR) that recognizes a specific cancer antigen.	('CAR', 'Gene', '9970', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('chimeric antigen receptor', 'Gene', (153, 178))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('chimeric antigen receptor', 'Gene', '9970', (153, 178))	('CAR', 'Gene', (180, 183))	('modifying', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
37091	28439495	The available results reported a failure of Pembrolizumab in multiple soft tissue sarcomas (NCT02301039) and Nivolumab in metastatic uterine leiomyosarcoma (NCT0 2428192) despite the promising findings encountered with Nivolumab in retrospective experiences.	('Nivolumab', 'Chemical', 'MESH:D000077594', (109, 118))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (141, 155))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (141, 155))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (70, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Nivolumab', 'Chemical', 'MESH:D000077594', (219, 228))	('Pembrolizumab in multiple soft tissue sarcomas', 'Disease', 'MESH:D012509', (44, 90))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (133, 155))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (70, 89))	('leiomyosarcoma', 'Disease', (141, 155))	('NCT02301039', 'Var', (92, 103))	('Pembrolizumab in multiple soft tissue sarcomas', 'Disease', (44, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
37102	30777851	Inhibition of this pathway led to a decrease in migration along the hypoxic gradients.	('migration', 'CPA', (48, 57))	('rat', 'Species', '10116', (51, 54))	('Inhibition', 'Var', (0, 10))	('decrease', 'NegReg', (36, 44))
37125	30777851	Recently, we have shown that hypoxic gradients, which are present in sarcoma ECM, induce cell migration in the direction of higher oxygen, by modifying the ECM..These modifications can impact mechanical properties of the matrix, one of which is stress relaxation.	('mechanical', 'MPA', (192, 202))	('rat', 'Species', '10116', (97, 100))	('sarcoma ECM', 'Disease', (69, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcoma ECM', 'Disease', 'MESH:D012509', (69, 80))	('modifications', 'Var', (167, 180))	('oxygen', 'Chemical', 'MESH:D010100', (131, 137))	('impact', 'Reg', (185, 191))
37141	30777851	To alter the stress relaxation, gels were incubated with PBS 24 mg/mL microbial transglutaminase (mTG) for 2 hours at room temperature.	('mTG', 'Gene', (98, 101))	('PBS', 'Chemical', 'MESH:D007854', (57, 60))	('PBS', 'Var', (57, 60))	('alter', 'Reg', (3, 8))	('stress relaxation', 'MPA', (13, 30))	('rat', 'Species', '10116', (128, 131))	('mTG', 'Gene', '22073', (98, 101))
37189	30777851	KIA cells, expressing GFP or GpNLuc that were encapsulated in quick and slow stress relaxation hypoxic hydrogels as reported above, were subcutaneously implanted in 8-10 week in nude mice.	('GpNLuc', 'Var', (29, 35))	('GFP', 'Var', (22, 25))	('nude mice', 'Species', '10090', (178, 187))
37272	30777851	Additionally, to further confirm the effect of PLOD2 on stress relaxation, subcutaneous tumors were generated in nude mice using the KIA scramble control cells (KIA Scr) and KIA cells with a PLOD2 knockdown (PLOD2(-)).	('Scr', 'Gene', (165, 168))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('Scr', 'Gene', '109559', (165, 168))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (75, 94))	('PLOD2', 'Var', (191, 196))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (75, 93))	('nude mice', 'Species', '10090', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('rat', 'Species', '10116', (104, 107))
37276	30777851	Overall, when PLOD2 crosslinking is knockdown the tumor has a slower stress relaxation time.	('slower', 'NegReg', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('knockdown', 'Var', (36, 45))	('stress relaxation time', 'MPA', (69, 91))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
37278	30777851	As previously loss of PLOD2 expression disrupts pulmonary metastasis and since lungs are the main metastatic sight for sarcoma, we next examined the impact of stress relaxation on lung metastasis.	('loss', 'Var', (14, 18))	('disrupts pulmonary metastasis', 'Disease', (39, 68))	('PLOD2', 'Gene', (22, 27))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('disrupts pulmonary metastasis', 'Disease', 'MESH:D009362', (39, 68))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))
37291	30777851	Interestingly, we could detect a small but significant decrease in disease free survival for high PLOD2 expressing patients; and a significant increase in mortality rates, from 40% for low expressing PLOD2 patients to 20% for high expressing PLOD2 patients (Figure 6D).	('patients', 'Species', '9606', (115, 123))	('mortality', 'Disease', (155, 164))	('rat', 'Species', '10116', (165, 168))	('decrease', 'NegReg', (55, 63))	('patients', 'Species', '9606', (206, 214))	('disease free survival', 'CPA', (67, 88))	('mortality', 'Disease', 'MESH:D003643', (155, 164))	('high PLOD2', 'Var', (93, 103))	('patients', 'Species', '9606', (248, 256))
37300	30777851	This enhanced crosslinking quickens the stress relaxation time of the collagen matrix, which in turn stimulates TGF-beta- shuttling of SMAD2 to the nucleus, further increasing PLOD2 expression.	('TGF-beta', 'Gene', '7039', (112, 120))	('crosslinking', 'Var', (14, 26))	('stimulates', 'PosReg', (101, 111))	('PLOD2', 'Gene', (176, 181))	('stress relaxation time', 'MPA', (40, 62))	('expression', 'MPA', (182, 192))	('quickens', 'PosReg', (27, 35))	('SMAD2', 'Gene', (135, 140))	('SMAD2', 'Gene', '4087', (135, 140))	('increasing', 'PosReg', (165, 175))	('TGF-beta', 'Gene', (112, 120))
37321	30777851	Moreover, when generating tumors from PLOD2 knockdown KIA cells, we could not observe change in tumor volume and stiffness but found slower stress relaxation compared with control tumors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('slower', 'NegReg', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('stress relaxation', 'MPA', (140, 157))	('PLOD2', 'Gene', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Disease', (180, 186))	('knockdown', 'Var', (44, 53))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', (180, 185))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
37322	30777851	This confirms that loss of PLOD2 crosslinking affect stress relaxation in sarcoma, similarly to what we observed in the in-vitro experiment, and with tumors generated from hydrogel implantation.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('stress relaxation', 'MPA', (53, 70))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('affect', 'Reg', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('loss', 'Var', (19, 23))	('rat', 'Species', '10116', (161, 164))	('PLOD2 crosslinking', 'Protein', (27, 45))	('sarcoma', 'Disease', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
37325	30777851	We found a dramatic decrease in patient survival in those who had high expression levels of PLOD2.	('decrease', 'NegReg', (20, 28))	('PLOD2', 'Gene', (92, 97))	('high expression levels', 'Var', (66, 88))	('patient survival', 'CPA', (32, 48))	('patient', 'Species', '9606', (32, 39))
37428	30723546	The most common genetic abnormality in low-grade ESS is t(7,17)(p15;q21) resulting in the fusion of JAZF1 and SUZ12 (JJAZ1) genes at 7p15 and 17q21 respectively.	('genetic abnormality', 'Disease', (16, 35))	('JJAZ1', 'Gene', '23512', (117, 122))	('JAZF1', 'Gene', '221895', (100, 105))	('SUZ12', 'Gene', '23512', (110, 115))	('low-grade ESS', 'Disease', (39, 52))	('JJAZ1', 'Gene', (117, 122))	('fusion', 'Var', (90, 96))	('SUZ12', 'Gene', (110, 115))	('JAZF1', 'Gene', (100, 105))	('genetic abnormality', 'Disease', 'MESH:D030342', (16, 35))
37460	29871905	The functional loss of the WT1 tumor suppressor protein and the oncogenic effects caused by the aberrant 59 kDa fusion protein results in hundreds to thousands of nodules coating the intraabdominal serosal and subdiaphragmatic surfaces.	('WT1', 'Gene', '7490', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('oncogenic effects', 'CPA', (64, 81))	('WT1', 'Gene', (27, 30))	('loss', 'NegReg', (15, 19))	('nodules coating the intraabdominal serosal', 'Disease', (163, 205))	('nodules coating the intraabdominal serosal', 'Disease', 'MESH:D058456', (163, 205))	('results in', 'Reg', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('aberrant 59 kDa', 'Var', (96, 111))
37471	29871905	Specialist pathologists used clinical information, immunohistochemistry, and cytogenetic analysis for the EWSR1-WT1 fusion to confirm the DSRCT diagnoses.	('DSRCT', 'Disease', 'MESH:D058405', (138, 143))	('WT1', 'Gene', '7490', (112, 115))	('fusion', 'Var', (116, 122))	('EWSR1', 'Gene', '2130', (106, 111))	('WT1', 'Gene', (112, 115))	('DSRCT', 'Disease', (138, 143))	('EWSR1', 'Gene', (106, 111))
37511	29871905	Almost half the patients received variants of the Children Oncology Group's alternating VAC/IE (VAC/Ifosfamide and Etoposide) protocol (AEWS-0031), VAI, Europe's VIDE (EURO-EWING99) protocol, or less frequently the P6 protocol when the patients were referred from other cancer centers (Fig 2A), and no regimen proved superior to another (Supplemental Figure S1).	('EURO', 'Species', '9319', (168, 172))	('variants', 'Var', (34, 42))	('VID', 'Disease', 'None', (162, 165))	('patients', 'Species', '9606', (16, 24))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('Etoposide', 'Chemical', 'MESH:D005047', (115, 124))	('patients', 'Species', '9606', (236, 244))	('Oncology', 'Phenotype', 'HP:0002664', (59, 67))	('VID', 'Disease', (162, 165))	('Children', 'Species', '9606', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('N', 'Chemical', 'MESH:D009584', (176, 177))	('Ifosfamide', 'Chemical', 'MESH:D007069', (100, 110))
37532	29871905	At the time of this writing, we are unaware of any DSRCT patients who have responded to immunotherapy, and to the extent one can draw from the sarcoma community's experience with ES and other translocation-positive sarcomas that have otherwise relatively quiescent genomes, current evidence suggests limited clinical effect.	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('DSRCT', 'Disease', 'MESH:D058405', (51, 56))	('ES', 'Disease', 'MESH:D012512', (179, 181))	('patients', 'Species', '9606', (57, 65))	('sarcoma', 'Disease', 'MESH:D012509', (215, 222))	('translocation-positive', 'Var', (192, 214))	('sarcomas', 'Disease', 'MESH:D012509', (215, 223))	('sarcoma', 'Disease', (215, 222))	('sarcoma', 'Disease', 'MESH:D012509', (143, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('DSRCT', 'Disease', (51, 56))	('sarcomas', 'Disease', (215, 223))	('sarcoma', 'Disease', (143, 150))
37589	24330865	Fluorescence in situ hybridization demonstrated gene rearrangement at chromosome 22q12 which confirmed the diagnosis of Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (120, 135))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (120, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('gene rearrangement at', 'Var', (48, 69))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (120, 135))
37593	24330865	ESFTs characteristically express CD99 (Mic2 antigen) and the defining characteristic translocation is t(11;22)(q24;q12).	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('t(11;22)(q24;q12', 'Var', (102, 118))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (102, 119))	('Mic2', 'Gene', '4267', (39, 43))	('CD99', 'Gene', '4267', (33, 37))	('Mic2', 'Gene', (39, 43))	('CD99', 'Gene', (33, 37))
37606	24330865	Fluorescence in situ hybridization (FISH) confirmed Ewing sarcoma region 1 (EWSR1) gene rearrangement at chromosome 22q12 (Figure 3) and hence a final diagnosis of ES/PNET was made.	('rearrangement at', 'Var', (88, 104))	('EWSR1', 'Gene', (76, 81))	('Ewing sarcoma', 'Disease', (52, 65))	('PNET', 'Phenotype', 'HP:0030065', (167, 171))	('ES', 'Phenotype', 'HP:0012254', (164, 166))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('ES/PNET', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
37849	23717796	However, positivity of AE1 in normal or neoplastic astrocytes, possibly due to cross-reactivity with GFAP limits its use in CNS lesions.	('CNS', 'Disease', (124, 127))	('neoplastic astrocytes', 'Phenotype', 'HP:0009592', (40, 61))	('GFAP', 'Gene', '2670', (101, 105))	('positivity', 'Var', (9, 19))	('AE1', 'Gene', '6521', (23, 26))	('limits', 'NegReg', (106, 112))	('AE1', 'Gene', (23, 26))	('GFAP', 'Gene', (101, 105))
37881	23717796	There are reports of TTF-1 positivity in primary CNS neoplasms, although in most diagnostic considerations for metastatic NUP, TTF-1 is negative or only weakly and focally positive.	('TTF-1', 'Gene', '7080', (21, 26))	('TTF-1', 'Gene', (21, 26))	('TTF-1', 'Gene', (127, 132))	('positivity', 'Var', (27, 37))	('neoplasms', 'Phenotype', 'HP:0002664', (53, 62))	('neoplasm', 'Phenotype', 'HP:0002664', (53, 61))	('CNS neoplasms', 'Phenotype', 'HP:0100006', (49, 62))	('neoplasms', 'Disease', 'MESH:D009369', (53, 62))	('neoplasms', 'Disease', (53, 62))	('TTF-1', 'Gene', '7080', (127, 132))
37906	23717796	Negative conversion of HER2 overexpression may provide an opportunity to reconsider the treatment strategy, and the presence of newly identified HER2 overexpression [Figure 10c] or gene amplification [Figure 10d] provides a new treatment option with trastuzumab, although the poor blood-brain barrier permeability of trastuzumab remains a potential limitation.	('HER2', 'Gene', (145, 149))	('HER2', 'Gene', '2064', (145, 149))	('HER2', 'Gene', (23, 27))	('overexpression', 'PosReg', (150, 164))	('HER2', 'Gene', '2064', (23, 27))	('trastuzumab', 'Chemical', 'MESH:D000068878', (317, 328))	('presence', 'Var', (116, 124))	('trastuzumab', 'Chemical', 'MESH:D000068878', (250, 261))	('gene amplification', 'Var', (181, 199))
37907	23717796	Activating epidermal growth factor receptor (EGFR) mutations are present up to 25% of nonsmall cell carcinomas, mainly in adenocarcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('Activating', 'PosReg', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('mutations', 'Var', (51, 60))	('epidermal growth factor receptor', 'Gene', (11, 43))	('EGFR', 'Gene', (45, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('adenocarcinomas', 'Disease', 'MESH:D000230', (122, 137))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (89, 110))	('adenocarcinomas', 'Disease', (122, 137))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (89, 109))	('nonsmall cell carcinomas', 'Disease', (86, 110))	('epidermal growth factor receptor', 'Gene', '1956', (11, 43))	('nonsmall cell carcinomas', 'Disease', 'MESH:D002289', (86, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('EGFR', 'Gene', '1956', (45, 49))
37910	23717796	Other relatively well-studied molecular testing in human neoplasms is BRAF, most commonly V600E mutations.	('V600E', 'Mutation', 'rs113488022', (90, 95))	('neoplasms', 'Phenotype', 'HP:0002664', (57, 66))	('human', 'Species', '9606', (51, 56))	('neoplasms', 'Disease', 'MESH:D009369', (57, 66))	('V600E mutations', 'Var', (90, 105))	('neoplasms', 'Disease', (57, 66))	('BRAF', 'Gene', '673', (70, 74))	('neoplasm', 'Phenotype', 'HP:0002664', (57, 65))	('BRAF', 'Gene', (70, 74))
37911	23717796	The BRAF mutation status can be tested with DNA-based methods and immunohistochemistry using a V600E mutation-specific antibody.	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('V600E', 'Mutation', 'rs113488022', (95, 100))	('V600E', 'Var', (95, 100))
37913	23717796	BRAF mutations can be detected in and thus far, there has been good concordance between primary tumors and their metastases.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('metastases', 'Disease', (113, 123))	('metastases', 'Disease', 'MESH:D009362', (113, 123))	('primary tumors', 'Disease', (88, 102))	('BRAF', 'Gene', (0, 4))	('primary tumors', 'Disease', 'MESH:D009369', (88, 102))
37914	23717796	As such, samples of brain metastases could be tested for BRAF mutations when metastatic tissue is the only available tissue.	('tested', 'Reg', (46, 52))	('brain metastases', 'Disease', 'MESH:D009362', (20, 36))	('BRAF', 'Gene', '673', (57, 61))	('brain metastases', 'Disease', (20, 36))	('BRAF', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
37971	31786484	KIT-positive melanomas represent a significant diagnostic pitfall; KIT mutations are seen in ~10% melanomas arising at mucosal, acral, and chronically sun-exposed sites, and these tumors tend to overexpress KIT.	('KIT', 'Gene', '3815', (207, 210))	('KIT', 'Gene', (67, 70))	('melanomas', 'Disease', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('overexpress', 'PosReg', (195, 206))	('KIT', 'Gene', '3815', (0, 3))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanomas', 'Disease', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('mutations', 'Var', (71, 80))	('tumors', 'Disease', (180, 186))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('KIT', 'Gene', '3815', (67, 70))	('KIT', 'Gene', (207, 210))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('KIT', 'Gene', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))
37988	31786484	Often, the diagnostic challenge lies in successfully identifying scant tumor and then distinguishing the deceptively bland glands from reactive change (not the subject of this review, though mutant-pattern p53 staining is useful in this setting).	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mutant-pattern', 'Var', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
37990	31786484	Loss of SMAD4/DPC4 is seen in up to 60% of pancreatic ductal carcinomas (Figure 11), and, although it is less well-studied, is probably seen in no more than 15% of primary small intestinal adenocarcinomas.	('SMAD4', 'Gene', (8, 13))	('DPC4', 'Gene', '4089', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('DPC4', 'Gene', (14, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('pancreatic ductal carcinomas', 'Disease', 'MESH:D021441', (43, 71))	('intestinal adenocarcinomas', 'Phenotype', 'HP:0040273', (178, 204))	('intestinal adenocarcinomas', 'Disease', 'MESH:D000230', (178, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('SMAD4', 'Gene', '4089', (8, 13))	('pancreatic ductal carcinomas', 'Disease', (43, 71))	('Loss', 'Var', (0, 4))	('intestinal adenocarcinomas', 'Disease', (178, 204))
38059	31786484	When faced with diagnostic uncertainty on the initial H&E, it is best to start by trying to assign the broad tumor class with screening markers such as pankeratin, S100 or SOX10, and CD20 or CD45.	('H&E', 'Chemical', '-', (54, 57))	('CD45', 'Gene', (191, 195))	('S100', 'Gene', (164, 168))	('CD20', 'Gene', '54474', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CD20', 'Gene', (183, 187))	('and', 'Var', (179, 182))	('CD45', 'Gene', '5788', (191, 195))	('S100', 'Gene', '6271', (164, 168))	('pankeratin', 'Chemical', '-', (152, 162))	('SOX10', 'Gene', '6663', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('SOX10', 'Gene', (172, 177))	('tumor', 'Disease', (109, 114))
38096	31935107	For AFA sonication, deparaffinized samples were transferred to Covaris microTUBE-130 AFA Fiber Screw-Caps (520216) and sonicated in a Covaris S220 AFA in the Screw-Cap microTUBE-130 holder (500339).	('500339', 'Var', (190, 196))	('AFA', 'Gene', (85, 88))	('520216', 'Var', (107, 113))	('AFA', 'Gene', (4, 7))	('AFA', 'Gene', '170', (85, 88))	('AFA', 'Gene', (147, 150))	('AFA', 'Gene', '170', (147, 150))	('AFA', 'Gene', '170', (4, 7))	('paraffin', 'Chemical', 'MESH:D010232', (22, 30))
38290	24716831	Cells at the early (P3/P4) and late (P10) passages were collected for the in vitro analyses including: sequencing of genes frequently mutated in OS and EWS, evaluation of telomerase activity, assessment of the gene expression profile and activity of major cancer pathways, cytogenetic analysis on synchronous MSCs, and molecular karyotyping using a comparative genomic hybridization (CGH) array.	('P10', 'Gene', '6281', (37, 40))	('OS', 'Phenotype', 'HP:0002669', (145, 147))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('P10', 'Gene', (37, 40))	('EWS', 'Gene', '2130', (152, 155))	('EWS', 'Gene', (152, 155))	('EWS', 'Phenotype', 'HP:0012254', (152, 155))	('cancer', 'Disease', (256, 262))	('mutated', 'Var', (134, 141))	('MSC', 'Gene', '9242', (309, 312))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('MSC', 'Gene', (309, 312))
38299	24716831	The etiology of OS is not well understood, as well as a clear link between OS and inherited genetic mutations or specific genetic changes has not been established, although patients with Li-Fraumeni syndrome have a high risk of developing OS by inheriting mutations that silence the p53 tumor suppressor gene (for a comprehensive review see).	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (187, 207))	('OS', 'Phenotype', 'HP:0002669', (16, 18))	('OS', 'Phenotype', 'HP:0002669', (75, 77))	('patients', 'Species', '9606', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('OS', 'Phenotype', 'HP:0002669', (239, 241))	('p53', 'Gene', (283, 286))	('tumor', 'Disease', (287, 292))	('Li-Fraumeni syndrome', 'Disease', (187, 207))	('mutations', 'Var', (256, 265))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('p53', 'Gene', '7157', (283, 286))
38301	24716831	The most common mutation associated with EWS involves a translocation of chromosomes 22 and 11 (t (11;22)), which fuses a portion of the EWSR1 gene with a portion of the FLI1 gene to create a EWS/FLI-1 fusion.	('EWSR1', 'Gene', (137, 142))	('fuses', 'Var', (114, 119))	('FLI-1', 'Gene', '2313', (196, 201))	('mutation', 'Var', (16, 24))	('FLI-1', 'Gene', (196, 201))	('EWSR1', 'Gene', '2130', (137, 142))	('FLI1', 'Gene', (170, 174))	('EWS', 'Phenotype', 'HP:0012254', (192, 195))	('FLI1', 'Gene', '2313', (170, 174))	('create', 'Reg', (183, 189))	('EWS', 'Phenotype', 'HP:0012254', (137, 140))	('EWS', 'Phenotype', 'HP:0012254', (41, 44))	('EWS', 'Gene', '2130', (192, 195))	('EWS', 'Gene', (192, 195))	('EWS', 'Gene', '2130', (137, 140))	('EWS', 'Gene', (137, 140))	('EWS', 'Gene', '2130', (41, 44))	('EWS', 'Gene', (41, 44))
38319	24716831	Potential hallmarks of tumorigenic transformation were assessed by characterizing MSC morphology and immunophenotype, osteogenic and adipogenic differentiation, sequencing genes frequently mutated in OS and EWS, evaluating telomerase activity, assessing the gene expression profile of major cancer pathways, as well as cytogenetic analysis on synchronous MSCs, and molecular karyotyping using a comparative genomic hybridization (CGH) array.	('mutated', 'Var', (189, 196))	('EWS', 'Phenotype', 'HP:0012254', (207, 210))	('MSC', 'Gene', (355, 358))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('MSC', 'Gene', '9242', (82, 85))	('EWS', 'Gene', '2130', (207, 210))	('EWS', 'Gene', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('MSC', 'Gene', (82, 85))	('tumor', 'Disease', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('MSC', 'Gene', '9242', (355, 358))	('OS', 'Phenotype', 'HP:0002669', (200, 202))
38327	24716831	MSCs were labeled with monoclonal antibodies against CD34, CD45, CD44, CD90, CD105, CD166 (Beckman Coulter, Fullerton, CA, USA) and CD146 (Miltenyi Biotech, Bergisch Gladbach, Germany).	('CD166', 'Gene', (84, 89))	('CD34', 'Gene', (53, 57))	('CD34', 'Gene', '947', (53, 57))	('CD45', 'Gene', '5788', (59, 63))	('CD166', 'Gene', '214', (84, 89))	('CD146', 'Gene', '4162', (132, 137))	('CD90', 'Gene', '7070', (71, 75))	('CD146', 'Gene', (132, 137))	('CD105', 'Var', (77, 82))	('MSC', 'Gene', (0, 3))	('MSC', 'Gene', '9242', (0, 3))	('CD90', 'Gene', (71, 75))	('CD45', 'Gene', (59, 63))	('CD44', 'Gene', '960', (65, 69))	('CD44', 'Gene', (65, 69))
38354	24716831	The 11 exons of TP53, the 3 exons of CDKN1A along with exon-intron junctions, and SNP309 (rs2279744) in MDM2 were PCR-amplified using primer sequences that will be available upon request.	('CDKN1A', 'Gene', (37, 43))	('rs2279744', 'Mutation', 'rs2279744', (90, 99))	('CDKN1A', 'Gene', '1026', (37, 43))	('rs2279744', 'Var', (90, 99))	('TP53', 'Gene', '7157', (16, 20))	('MDM2', 'Gene', '4193', (104, 108))	('MDM2', 'Gene', (104, 108))	('TP53', 'Gene', (16, 20))
38363	24716831	FACS analysis documented that > 80% of the MSC-CTRL and MSC-SAR expressed the typical MSC markers CD44, CD90, CD105, CD146, CD166, whereas the expression of the hematopoietic markers CD45 and CD34 was <10%.	('CTRL', 'Gene', (47, 51))	('MSC', 'Gene', (56, 59))	('CD44', 'Gene', '960', (98, 102))	('CD34', 'Gene', (192, 196))	('CD44', 'Gene', (98, 102))	('SAR', 'Gene', '1757', (60, 63))	('MSC', 'Gene', '9242', (86, 89))	('MSC', 'Gene', '9242', (56, 59))	('CD45', 'Gene', (183, 187))	('CD166', 'Gene', '214', (124, 129))	('CD105', 'Var', (110, 115))	('CD45', 'Gene', '5788', (183, 187))	('CD90', 'Gene', (104, 108))	('CD34', 'Gene', '947', (192, 196))	('MSC', 'Gene', (43, 46))	('CD90', 'Gene', '7070', (104, 108))	('CD166', 'Gene', (124, 129))	('CD146', 'Gene', '4162', (117, 122))	('CD146', 'Gene', (117, 122))	('MSC', 'Gene', '9242', (43, 46))	('SAR', 'Gene', (60, 63))	('CTRL', 'Gene', '1506', (47, 51))	('MSC', 'Gene', (86, 89))
38380	24716831	Deficiencies in TP53 and CDKN1A, the primary regulators of cell cycle progression and apoptosis normally involved in protection against tumorigenesis, can be the origin of some mesodermic tumors.	('tumor', 'Disease', (188, 193))	('mesodermic tumors', 'Disease', (177, 194))	('Deficiencies', 'Var', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('origin', 'Reg', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('CDKN1A', 'Gene', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('TP53', 'Gene', '7157', (16, 20))	('mesodermic tumors', 'Disease', 'MESH:D002296', (177, 194))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('CDKN1A', 'Gene', '1026', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (136, 141))	('TP53', 'Gene', (16, 20))
38381	24716831	Since MDM2 encodes an important negative regulator of the p53 protein, we also assessed the status of MDM2 SNP309 (rs2279744), which is located in the MDM2 promoter.	('rs2279744', 'Mutation', 'rs2279744', (115, 124))	('MDM2', 'Gene', '4193', (102, 106))	('rs2279744', 'Var', (115, 124))	('MDM2', 'Gene', (102, 106))	('MDM2', 'Gene', '4193', (151, 155))	('MDM2', 'Gene', (151, 155))	('MDM2', 'Gene', '4193', (6, 10))	('MDM2', 'Gene', (6, 10))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
38382	24716831	All donors analyzed showed the presence of exonic and/or intronic polymorphisms in TP53 (Table 2).	('TP53', 'Gene', '7157', (83, 87))	('exonic', 'Var', (43, 49))	('presence', 'Reg', (31, 39))	('TP53', 'Gene', (83, 87))	('donor', 'Species', '9606', (4, 9))	('intronic polymorphisms', 'Var', (57, 79))
38383	24716831	All of these variants were reported in the TP53 database as benign sequence variations.	('TP53', 'Gene', '7157', (43, 47))	('variants', 'Var', (13, 21))	('TP53', 'Gene', (43, 47))
38384	24716831	CDKN1A sequencing revealed only one sequence variant in MSC-SAR 4 (rs1059234), which had been described previously, and is not associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CDKN1A', 'Gene', '1026', (0, 6))	('MSC', 'Gene', (56, 59))	('associated', 'Reg', (127, 137))	('rs1059234', 'Mutation', 'rs1059234', (67, 76))	('rs1059234', 'Var', (67, 76))	('SAR', 'Gene', '1757', (60, 63))	('CDKN1A', 'Gene', (0, 6))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('SAR', 'Gene', (60, 63))	('MSC', 'Gene', '9242', (56, 59))
38385	24716831	The heterozygous presence of SNP309 (rs2279744 T > G) in MDM2 was detected in three donors (Table 2).	('SNP309 (rs2279744 T > G', 'Var', (29, 52))	('MDM2', 'Gene', '4193', (57, 61))	('rs2279744', 'Mutation', 'rs2279744', (37, 46))	('donor', 'Species', '9606', (84, 89))	('MDM2', 'Gene', (57, 61))
38386	24716831	Notably, all TP53, CDKN1A, and MDM2 variants identified in each donor were detected in all DNA samples analyzed.	('TP53', 'Gene', (13, 17))	('CDKN1A', 'Gene', (19, 25))	('MDM2', 'Gene', '4193', (31, 35))	('CDKN1A', 'Gene', '1026', (19, 25))	('variants', 'Var', (36, 44))	('donor', 'Species', '9606', (64, 69))	('detected', 'Reg', (75, 83))	('TP53', 'Gene', '7157', (13, 17))	('MDM2', 'Gene', (31, 35))
38404	24716831	The functional results of prostheses and osteoarticular grafts are not satisfactory because of limited durability, joint instability, incongruity, and gross distortion of the normal anatomy.	('osteoarticular', 'Disease', (41, 55))	('incongruity', 'Var', (134, 145))	('joint instability', 'Phenotype', 'HP:0001388', (115, 132))	('joint instability', 'CPA', (115, 132))	('osteoarticular', 'Disease', 'MESH:D014394', (41, 55))
38426	24716831	While the expression of these 15 genes was altered in U2OS compared to MSC-CTRL, there was no difference between MSC-SAR and MSC-CTRL.	('MSC', 'Gene', '9242', (125, 128))	('MSC', 'Gene', '9242', (71, 74))	('SAR', 'Gene', (117, 120))	('CTRL', 'Gene', (75, 79))	('SAR', 'Gene', '1757', (117, 120))	('MSC', 'Gene', (125, 128))	('U2OS', 'CellLine', 'CVCL:0042', (54, 58))	('MSC', 'Gene', '9242', (113, 116))	('MSC', 'Gene', (71, 74))	('expression', 'MPA', (10, 20))	('MSC', 'Gene', (113, 116))	('OS', 'Phenotype', 'HP:0002669', (56, 58))	('CTRL', 'Gene', '1506', (129, 133))	('CTRL', 'Gene', '1506', (75, 79))	('CTRL', 'Gene', (129, 133))	('altered', 'Reg', (43, 50))	('U2OS', 'Var', (54, 58))
38504	31260471	The SW982 cell line was treated with LL-37 (ProSpec) 12.5 ng/mL and/or IL17A (ProSpec) 10 ng/mL, or BAY11-7082 (Calbiochem) 20 muM, for exactly 10 min.	('muM', 'Gene', (127, 130))	('SW982', 'CellLine', 'CVCL:1734', (4, 9))	('LL-37', 'Gene', (37, 42))	('muM', 'Gene', '56925', (127, 130))	('BAY11-7082', 'Var', (100, 110))	('LL-37', 'Gene', '820', (37, 42))
38527	31260471	The CDH11 gene was induced by both LL-37 and IL17A alone, although when combined they did not increase gene expression (Fig 5C).	('CDH11', 'Gene', '1009', (4, 9))	('CDH11', 'Gene', (4, 9))	('LL-37', 'Gene', (35, 40))	('LL-37', 'Gene', '820', (35, 40))	('IL17A', 'Var', (45, 50))
38537	31260471	LL-37 alone slightly increased the phosphorylation of IKK and p65 but not IkappaB, whereas IL17A alone significantly boosted the phosphorylation of both IkappaB and p65 and slightly increased that of IKK.	('IKK', 'Protein', (54, 57))	('increased', 'PosReg', (21, 30))	('phosphorylation', 'MPA', (129, 144))	('IkappaB', 'Protein', (153, 160))	('IL17A', 'Var', (91, 96))	('boosted', 'PosReg', (117, 124))	('LL-37', 'Gene', '820', (0, 5))	('p65', 'Gene', (165, 168))	('p65', 'Gene', (62, 65))	('phosphorylation', 'MPA', (35, 50))	('LL-37', 'Gene', (0, 5))	('p65', 'Gene', '5970', (62, 65))	('p65', 'Gene', '5970', (165, 168))
38542	31260471	Although cell invasion was strengthened by co-treatment with LL-37 and IL17A, the regulation of apoptosis and cell cycle was not influenced.	('LL-37', 'Gene', '820', (61, 66))	('strengthened', 'PosReg', (27, 39))	('IL17A', 'Gene', (71, 76))	('cell invasion', 'CPA', (9, 22))	('co-treatment', 'Var', (43, 55))	('LL-37', 'Gene', (61, 66))
38579	31260471	Moreover, the combination of LL-37 and IL17A enhanced the gene expression of PTGS2 and TNF, while increasing the levels of PGE2 and TNF for approximately two- and three-fold, respectively.	('PGE2', 'Chemical', 'MESH:D015232', (123, 127))	('PTGS2', 'Gene', '5743', (77, 82))	('LL-37', 'Gene', '820', (29, 34))	('TNF', 'Gene', (87, 90))	('IL17A', 'Var', (39, 44))	('increasing', 'PosReg', (98, 108))	('combination', 'Var', (14, 25))	('enhanced', 'PosReg', (45, 53))	('TNF', 'Gene', (132, 135))	('gene expression', 'MPA', (58, 73))	('LL-37', 'Gene', (29, 34))	('TNF', 'Gene', '7124', (87, 90))	('levels', 'MPA', (113, 119))	('TNF', 'Gene', '7124', (132, 135))	('PTGS2', 'Gene', (77, 82))
38586	31260471	It is found that exogenous LL-37 decreased TNF and IL17A expression while inducing anti-inflammatory IL-10 and TGF-beta production in dendritic cells in allergy and inhibit LMW-hyaluronan-induced cytokine release in skin fibroblast.	('LMW', 'Chemical', '-', (173, 176))	('allergy', 'Disease', 'MESH:D004342', (153, 160))	('inducing', 'PosReg', (74, 82))	('TNF', 'Gene', (43, 46))	('decreased', 'NegReg', (33, 42))	('allergy', 'Disease', (153, 160))	('expression', 'MPA', (57, 67))	('allergy', 'Phenotype', 'HP:0012393', (153, 160))	('IL-10', 'Gene', '3586', (101, 106))	('LL-37', 'Gene', '820', (27, 32))	('inhibit', 'NegReg', (165, 172))	('hyaluronan', 'Chemical', 'MESH:D006820', (177, 187))	('TNF', 'Gene', '7124', (43, 46))	('IL-10', 'Gene', (101, 106))	('exogenous', 'Var', (17, 26))	('TGF-beta', 'Gene', '7040', (111, 119))	('LL-37', 'Gene', (27, 32))	('IL17A', 'Gene', (51, 56))	('TGF-beta', 'Gene', (111, 119))
38588	31260471	Additionally, our results suggest that the combination of LL-37 with IL17A may relate to the chronic inflammatory processes by enhancing the production of proinflammatory cytokines, especially TNF, together with the proinflammatory mediator, PGE2.	('production of proinflammatory cytokines', 'MPA', (141, 180))	('enhancing', 'PosReg', (127, 136))	('TNF', 'Gene', (193, 196))	('LL-37', 'Gene', '820', (58, 63))	('TNF', 'Gene', '7124', (193, 196))	('PGE2', 'Chemical', 'MESH:D015232', (242, 246))	('combination', 'Var', (43, 54))	('relate', 'Reg', (79, 85))	('LL-37', 'Gene', (58, 63))	('IL17A', 'Gene', (69, 74))
38595	31260471	TLR4, another important receptor for HA, showed response to IL17A at higher concentration, but not to LL-37.	('TLR4', 'Gene', (0, 4))	('LL-37', 'Gene', '820', (102, 107))	('IL17A', 'Var', (60, 65))	('HA', 'Chemical', 'MESH:D006820', (37, 39))	('LL-37', 'Gene', (102, 107))	('response', 'MPA', (48, 56))	('TLR4', 'Gene', '7099', (0, 4))
38601	31260471	Our results showed that LL-37 slightly increased the phosphorylation of both IKK and p65, which was clearly enhanced by the co-treatment with IL17A, whereas IL17A was found to be a better inducer for IkappaB phosphorylation.	('IKK', 'Protein', (77, 80))	('LL-37', 'Gene', (24, 29))	('p65', 'Gene', (85, 88))	('LL-37', 'Gene', '820', (24, 29))	('enhanced', 'PosReg', (108, 116))	('p65', 'Gene', '5970', (85, 88))	('increased', 'PosReg', (39, 48))	('IL17A', 'Var', (142, 147))	('phosphorylation', 'MPA', (53, 68))
38604	31260471	The gene of cadherin11, CDH11, was found to be upregulated by both LL-37 and IL17A alone, but not by their combination, suggesting that the combined LL-37 and IL17A may provide an additional selective cascade to enhance cell invasion via upregulation of fibronectin expression.	('expression', 'MPA', (266, 276))	('CDH11', 'Gene', '1009', (24, 29))	('LL-37', 'Gene', '820', (67, 72))	('cadherin11', 'Gene', (12, 22))	('cell invasion', 'CPA', (220, 233))	('fibronectin', 'Gene', (254, 265))	('upregulation', 'PosReg', (238, 250))	('enhance', 'PosReg', (212, 219))	('upregulated', 'PosReg', (47, 58))	('CDH11', 'Gene', (24, 29))	('LL-37', 'Gene', (149, 154))	('LL-37', 'Gene', (67, 72))	('fibronectin', 'Gene', '2335', (254, 265))	('cadherin11', 'Gene', '1009', (12, 22))	('IL17A', 'Var', (159, 164))	('LL-37', 'Gene', '820', (149, 154))
38605	31260471	Immunoblotting showed that the combined LL-37 and IL17A increase the phosphorylation of the NF-kappaB signaling pathway.	('increase', 'PosReg', (56, 64))	('IL17A', 'Var', (50, 55))	('LL-37', 'Gene', '820', (40, 45))	('LL-37', 'Gene', (40, 45))	('NF-kappaB signaling pathway', 'Pathway', (92, 119))	('phosphorylation', 'MPA', (69, 84))
38633	31213834	Furthermore, knockdown of EWSR/FLI1 fusion in ES cell line A673 down-regulates the expression of the 4 key genes was revealed by GDS4962.	('down-regulates', 'NegReg', (64, 78))	('FLI1', 'Gene', (31, 35))	('FLI1', 'Gene', '2313', (31, 35))	('ES', 'Phenotype', 'HP:0012254', (46, 48))	('expression', 'MPA', (83, 93))	('fusion', 'Var', (36, 42))
38638	31213834	Accumulating evidence strongly documented that chromosomal translocation comprising the Ewing sarcoma breakpoint region (EWSR) gene on chromosome 22 and a member of the ETS family of transcription factors implicated in the ES pathogenetic process, which could encode tumor-specific fusion protein EWSR/FLI and was a distinct and well-defined phenotype for ES genetical characterization.	('EWSR', 'Gene', (121, 125))	('ES', 'Phenotype', 'HP:0012254', (223, 225))	('chromosomal translocation', 'Var', (47, 72))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('FLI', 'Gene', '2314', (302, 305))	('tumor', 'Disease', (267, 272))	('ES', 'Phenotype', 'HP:0012254', (356, 358))	('FLI', 'Gene', (302, 305))	('Ewing sarcoma', 'Disease', (88, 101))
38639	31213834	Moreover, previous researches revealed that ~13% of patients with ES harbor rare inactivating variants or mutations in DNA damage repair genes consisting of the same genes that are enriched in hereditary breast cancer (such as BRCA1).	('BRCA1', 'Gene', '672', (227, 232))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (193, 217))	('BRCA1', 'Gene', (227, 232))	('ES', 'Phenotype', 'HP:0012254', (66, 68))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('hereditary breast cancer', 'Disease', (193, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))	('patients', 'Species', '9606', (52, 60))
38643	31213834	For example, highly expressed ERBB4 would facilitate tumor metastasis, invasion and suppress apoptosis by activating the phosphoinositide 3-kinase/AKT and focal adhesion kinase pathways in metastatic ES cells.	('tumor metastasis', 'Disease', 'MESH:D009362', (53, 69))	('ERBB4', 'Gene', '2066', (30, 35))	('facilitate', 'PosReg', (42, 52))	('ES', 'Phenotype', 'HP:0012254', (200, 202))	('tumor metastasis', 'Disease', (53, 69))	('activating', 'PosReg', (106, 116))	('ERBB4', 'Gene', (30, 35))	('suppress', 'NegReg', (84, 92))	('invasion', 'CPA', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('apoptosis', 'CPA', (93, 102))	('AKT', 'Gene', '207', (147, 150))	('focal adhesion kinase pathways', 'Pathway', (155, 185))	('highly expressed', 'Var', (13, 29))	('AKT', 'Gene', (147, 150))
38647	31213834	GDS4962 dataset containing gene expression profile of ES cell line with inducible EWSR/FLI knockdown were employed to analyze the impact of ESWR/FLI1 knock down over key genes.	('FLI1', 'Gene', (145, 149))	('FLI', 'Gene', '2314', (145, 148))	('FLI', 'Gene', '2314', (87, 90))	('ES', 'Phenotype', 'HP:0012254', (54, 56))	('FLI1', 'Gene', '2313', (145, 149))	('knock down', 'Var', (150, 160))	('FLI', 'Gene', (145, 148))	('FLI', 'Gene', (87, 90))	('ES', 'Phenotype', 'HP:0012254', (140, 142))
38655	31213834	GEO dataset GDS4962 containing 16 samples of A673 ES cell line with or without inducible EWSR/FLI1 knockdown in time course was employed to explore whether EWSR/FLI1 could regulate the expression level of these key genes.	('FLI1', 'Gene', '2313', (161, 165))	('FLI1', 'Gene', (94, 98))	('FLI1', 'Gene', '2313', (94, 98))	('ES', 'Phenotype', 'HP:0012254', (50, 52))	('knockdown', 'Var', (99, 108))	('regulate', 'Reg', (172, 180))	('expression level', 'MPA', (185, 201))	('FLI1', 'Gene', (161, 165))
38664	31213834	The result suggested that high expression of MSH2, MSH6, RPA2, and RFC2 was associated with poor overall and event-free survival of ES patients (Figure 4A-H).	('RPA2', 'Gene', (57, 61))	('patients', 'Species', '9606', (135, 143))	('RFC2', 'Gene', '5982', (67, 71))	('high', 'Var', (26, 30))	('MSH2', 'Gene', (45, 49))	('ES', 'Phenotype', 'HP:0012254', (132, 134))	('RPA2', 'Gene', '6118', (57, 61))	('poor', 'NegReg', (92, 96))	('RFC2', 'Gene', (67, 71))	('MSH6', 'Gene', '2956', (51, 55))	('MSH2', 'Gene', '4436', (45, 49))	('MSH6', 'Gene', (51, 55))
38668	31213834	EWSR/FLI1 expression is closely associated with ES cell viability, and EWSR/FLI1 knockdown promotes the ES cell survival.	('promotes', 'PosReg', (91, 99))	('ES', 'Phenotype', 'HP:0012254', (48, 50))	('ES cell survival', 'CPA', (104, 120))	('ES', 'Phenotype', 'HP:0012254', (104, 106))	('FLI1', 'Gene', '2313', (76, 80))	('FLI1', 'Gene', (76, 80))	('knockdown', 'Var', (81, 90))	('FLI1', 'Gene', (5, 9))	('FLI1', 'Gene', '2313', (5, 9))	('associated', 'Reg', (32, 42))
38670	31213834	The result revealed the expression of EWSR and FLI1 was obviously downregulated with time (Figure 6A and B); moreover, the level of MSH2, MSH6, RPA2, and RFC2 decreased first and then slightly increased, and all expression level was significantly lower in EWSR/FLI1 knockdown cell group compared to control group (Figure 6C-F).	('RFC2', 'Gene', '5982', (154, 158))	('downregulated', 'NegReg', (66, 79))	('RPA2', 'Gene', (144, 148))	('RFC2', 'Gene', (154, 158))	('FLI1', 'Gene', (47, 51))	('level', 'MPA', (123, 128))	('expression', 'MPA', (24, 34))	('FLI1', 'Gene', (261, 265))	('knockdown', 'Var', (266, 275))	('MSH2', 'Gene', (132, 136))	('FLI1', 'Gene', '2313', (47, 51))	('MSH6', 'Gene', (138, 142))	('FLI1', 'Gene', '2313', (261, 265))	('lower', 'NegReg', (247, 252))	('MSH6', 'Gene', '2956', (138, 142))	('RPA2', 'Gene', '6118', (144, 148))	('increased', 'PosReg', (193, 202))	('MSH2', 'Gene', '4436', (132, 136))	('expression', 'MPA', (212, 222))	('EWSR', 'Gene', (38, 42))
38685	31213834	Also, the RPA2 inhibitor can synergize with DNA-damaging agents to affect chemotherapy response in lung and ovarian cancer cell lines.	('chemotherapy response', 'CPA', (74, 95))	('affect', 'Reg', (67, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('RPA2', 'Gene', (10, 14))	('lung and ovarian cancer', 'Disease', 'MESH:D010051', (99, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('inhibitor', 'Var', (15, 24))	('RPA2', 'Gene', '6118', (10, 14))
38695	31213834	Heisey et al found that EWSR/FLI1 fusion would increase BCL-2 expression, and thereby induce drug resistant to PARP inhibitors, and BCL-2 and BCL-XL inhibition could significantly reverse the drug resistance in ES FOXO1 is a cancer suppressor in multiple cancer types, which significantly inhibited cell proliferation and clone formation ability in ES cell.	('FOXO1', 'Gene', '2308', (214, 219))	('cancer', 'Disease', (225, 231))	('clone formation ability', 'CPA', (322, 345))	('cancer', 'Disease', (255, 261))	('increase', 'PosReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('FOXO1', 'Gene', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('fusion', 'Var', (34, 40))	('BCL-2', 'Gene', '596', (56, 61))	('drug resistance', 'MPA', (192, 207))	('FLI1', 'Gene', (29, 33))	('BCL-2', 'Gene', (56, 61))	('BCL-XL', 'Gene', (142, 148))	('ES', 'Phenotype', 'HP:0012254', (349, 351))	('inhibited', 'NegReg', (289, 298))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('drug resistance', 'Phenotype', 'HP:0020174', (192, 207))	('expression', 'MPA', (62, 72))	('induce', 'PosReg', (86, 92))	('reverse', 'NegReg', (180, 187))	('PARP', 'Gene', '1302', (111, 115))	('FLI1', 'Gene', '2313', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('BCL-XL', 'Gene', '598', (142, 148))	('ES', 'Phenotype', 'HP:0012254', (211, 213))	('PARP', 'Gene', (111, 115))	('cell proliferation', 'CPA', (299, 317))	('BCL-2', 'Gene', '596', (132, 137))	('BCL-2', 'Gene', (132, 137))
38697	31213834	Furthermore, knockdown of ESW/FLI1 impairs tumorigenesis of ES in vivo.	('FLI1', 'Gene', '2313', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('impairs', 'NegReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ES', 'Phenotype', 'HP:0012254', (26, 28))	('ES', 'Phenotype', 'HP:0012254', (60, 62))	('tumor', 'Disease', (43, 48))	('knockdown', 'Var', (13, 22))	('FLI1', 'Gene', (30, 34))
38699	31213834	EWSR/FLI knockdown in A673 cell line results in the downregulation of the four key genes, and the expression pattern of EWSR and FLI1 are closely related with the four key genes, which indicated that the upregulation of the four genes may be partially regulated by EWSR/FLI1 fusion.	('FLI', 'Gene', '2314', (5, 8))	('FLI', 'Gene', (5, 8))	('FLI', 'Gene', (270, 273))	('knockdown', 'Var', (9, 18))	('FLI', 'Gene', (129, 132))	('upregulation', 'PosReg', (204, 216))	('FLI1', 'Gene', '2313', (270, 274))	('EWSR', 'Gene', (120, 124))	('FLI1', 'Gene', (270, 274))	('FLI1', 'Gene', (129, 133))	('downregulation', 'NegReg', (52, 66))	('FLI1', 'Gene', '2313', (129, 133))	('FLI', 'Gene', '2314', (270, 273))	('FLI', 'Gene', '2314', (129, 132))
38777	31106141	Figures 6, 7 show examples of tumors with high/low cellularity and high/low fat fraction, respectively.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('fat', 'Gene', '2195', (76, 79))	('high/low', 'Var', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('fat', 'Gene', (76, 79))	('high/low cellularity', 'Var', (42, 62))
38793	31106141	The correlation between restricted diffusion (low ADC or D) and high cellularity (high nuclear-to-stromal ratio) demonstrates that the degree of restricted diffusion relates to the density of tumor cells.	('tumor', 'Disease', (192, 197))	('low', 'Var', (46, 49))	('restricted diffusion', 'MPA', (24, 44))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
38828	28571582	Question 34: Why is epidermal growth factor receptor (EGFR) 19 Del-positive tumor more sensitive to targeted therapy than EGFR 21 L858R-positive tumor in patients with non-small cell lung cancer?	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('L858R', 'Mutation', 'rs121434568', (130, 135))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('patients', 'Species', '9606', (154, 162))	('tumor', 'Disease', (145, 150))	('Del-positive', 'Var', (63, 75))	('sensitive', 'MPA', (87, 96))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (168, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('non-small cell lung cancer', 'Disease', (168, 194))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
38860	28571582	chenmy@sysucc.org.cn Among the patients with advanced NSCLC who underwent EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment, the patients with EGFR exon 19 deletion (19 Del)-positive tumor had a higher objective response rate, longer progression-free survival duration, and longer overall survival duration than those with exon 21 L858R mutation (21 L858R)-positive tumor.	('tumor', 'Disease', (368, 373))	('objective response rate', 'CPA', (204, 227))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('rat', 'Species', '10116', (223, 226))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('progression-free survival', 'CPA', (236, 261))	('tumor', 'Disease', (185, 190))	('rat', 'Species', '10116', (302, 305))	('exon', 'Var', (150, 154))	('higher', 'PosReg', (197, 203))	('EGFR', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('overall survival', 'CPA', (283, 299))	('NSCLC', 'Disease', (54, 59))	('L858R', 'Mutation', 'rs121434568', (352, 357))	('patients', 'Species', '9606', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('deletion (19 Del)-positive', 'Var', (158, 184))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('L858R', 'Mutation', 'rs121434568', (333, 338))	('patients', 'Species', '9606', (31, 39))	('rat', 'Species', '10116', (264, 267))	('longer', 'PosReg', (276, 282))	('longer', 'PosReg', (229, 235))
38870	28571582	buw@niaid.nih.gov; jcohen@niaid.nih.gov Carcinomas commonly metastasize via the lymphatic system followed by the involvement of the blood vessel system, whereas sarcomas commonly spread via the blood vessel system in the first place.	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcomas', 'Disease', (161, 169))	('niaid.nih.gov', 'Var', (26, 39))	('metastasize', 'CPA', (60, 71))	('Carcinomas', 'Disease', (40, 50))	('Carcinomas', 'Disease', 'MESH:D002277', (40, 50))	('Carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))
38891	28571582	Diffuse LGGs are characterized by mutually exclusive telomerase reverse transcriptase (TERT) and ATRX mutations, one of the best defined characteristic gene mutations such as isocitrate dehydrogenase 1,2 (IDH1/2) and tumor protein p53 (TP53) mutations and the combined deletion of 1p/19q regions.	('p53', 'Gene', '7157', (231, 234))	('IDH1/2', 'Gene', '3417;3418', (205, 211))	('TP53', 'Gene', (236, 240))	('tumor', 'Disease', (217, 222))	('IDH1/2', 'Gene', (205, 211))	('p53', 'Gene', (231, 234))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('rat', 'Species', '10116', (181, 184))	('ATRX', 'Gene', (97, 101))	('telomerase reverse transcriptase', 'Gene', (53, 85))	('TP53', 'Gene', '7157', (236, 240))	('ATRX', 'Gene', '546', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('mutations', 'Var', (242, 251))	('TERT', 'Gene', (87, 91))	('LGGs', 'Disease', (8, 12))	('telomerase reverse transcriptase', 'Gene', '7015', (53, 85))	('TERT', 'Gene', '7015', (87, 91))
38892	28571582	The IDH mutations are very early genetic events and are frequent in diffuse gliomas.	('IDH', 'Gene', '3417', (4, 7))	('gliomas', 'Disease', (76, 83))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('mutations', 'Var', (8, 17))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('frequent', 'Reg', (56, 64))	('IDH', 'Gene', (4, 7))
38895	28571582	Followed by the mutations in characteristic genes, the acquisition of epigenetic modifications may reinforce the classification criteria of LGG subtypes with astrocytic and oligodendroglial origins which otherwise are less likely to be established by histological features alone.	('astrocytic', 'Disease', (158, 168))	('reinforce', 'PosReg', (99, 108))	('epigenetic modifications', 'Var', (70, 94))	('astrocytic', 'Disease', 'MESH:D001254', (158, 168))	('LGG subtypes', 'Disease', (140, 152))
38897	28571582	This standardized and rigorously validated classifier by integrating genetic, epigenetic, and histological features of LGG should be superior to histological classification alone.	('epigenetic', 'Var', (78, 88))	('rat', 'Species', '10116', (62, 65))	('LGG', 'Disease', (119, 122))
38914	24312142	On the other hand, vitamin E supplementation induces a higher differentiation of immature T cells via increased positive selection by thymic epithelial cells, which results in the improvement of decreased cellular immunity in the aged.	('cellular immunity', 'CPA', (205, 222))	('supplementation', 'Var', (29, 44))	('differentiation', 'CPA', (62, 77))	('decreased cellular immunity', 'Phenotype', 'HP:0002843', (195, 222))	('positive selection', 'CPA', (112, 130))	('improvement', 'PosReg', (180, 191))	('increased', 'PosReg', (102, 111))	('vitamin E', 'Chemical', 'MESH:D014810', (19, 28))	('higher', 'PosReg', (55, 61))	('decreased', 'NegReg', (195, 204))
38928	24312142	Mice were randomly divided into vitamin C and vitamin E-treated groups, respectively, to receive vitamin C (100; 200 mg/kg/day for 7 days in 1 ml of normal saline) administered orally and vitamin E (100; 200 mg/kg/day for 8 days in 1 ml of normal saline) by oral administration.	('vitamin E', 'Chemical', 'MESH:D014810', (188, 197))	('vitamin C', 'Chemical', 'MESH:D001205', (97, 106))	('rat', 'Species', '10116', (271, 274))	('100;', 'Var', (108, 112))	('vitamin C', 'Chemical', 'MESH:D001205', (32, 41))	('100; 200', 'Var', (199, 207))	('Mice', 'Species', '10090', (0, 4))	('vitamin E', 'Chemical', 'MESH:D014810', (46, 55))
38953	22243975	Recent studies have suggested that signals transmitted through p38 mitogen-activated protein kinase (MAPK) can increase or decrease hTERT transcription in human cells.	('decrease', 'NegReg', (123, 131))	('human', 'Species', '9606', (155, 160))	('hTERT', 'Gene', '7015', (132, 137))	('MAPK', 'Gene', (101, 105))	('hTERT', 'Gene', (132, 137))	('p38', 'Var', (63, 66))
38954	22243975	The purpose of this study was to analyse the correlation between p38 MAPK and hTERT in sarcoma samples.	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('hTERT', 'Gene', '7015', (78, 83))	('p38 MAPK', 'Var', (65, 73))	('hTERT', 'Gene', (78, 83))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
38956	22243975	Quantitative detection of hTERT and p38 MAPK was performed by RT-PCR.	('p38', 'Var', (36, 39))	('hTERT', 'Gene', (26, 31))	('hTERT', 'Gene', '7015', (26, 31))
38957	22243975	There was a significant positive correlation between the values of hTERT and p38 MAPK in all samples (r = 0.445, p = 0.0001), soft tissue MFH (r = 0.352, p = 0.0352), LS (r = 0.704, p = 0.0001) and bone MFH samples (r = 0.802, p = 0.0093).	('hTERT', 'Gene', '7015', (67, 72))	('p38', 'Var', (77, 80))	('LS', 'Phenotype', 'HP:0012034', (167, 169))	('hTERT', 'Gene', (67, 72))
38958	22243975	Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis than other patients (p = 0.0036).	('patients', 'Species', '9606', (109, 117))	('p38', 'Var', (53, 56))	('higher', 'PosReg', (19, 25))	('Patients', 'Species', '9606', (0, 8))	('expression', 'MPA', (39, 49))
38959	22243975	p38 MAPK may play a role in up-regulation of hTERT, and therefore, p38 MAPK may be a useful marker in the assessment of hTERT and patients' prognosis in sarcomas.	('p38', 'Var', (67, 70))	('hTERT', 'Gene', '7015', (45, 50))	('hTERT', 'Gene', (45, 50))	('sarcomas', 'Disease', 'MESH:D012509', (153, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('patients', 'Species', '9606', (130, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('p38', 'Var', (0, 3))	('hTERT', 'Gene', '7015', (120, 125))	('sarcomas', 'Disease', (153, 161))	('up-regulation', 'PosReg', (28, 41))	('hTERT', 'Gene', (120, 125))
38967	22243975	This study was undertaken to analyze the clinical significance of p38 MAPK and hTERT expression in primary tumor samples from soft tissue malignant fibrous histiocytomas (MFH), liposarcomas (LS) and bone MFH patients.	('patients', 'Species', '9606', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('hTERT', 'Gene', (79, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('liposarcomas', 'Disease', 'MESH:D008080', (177, 189))	('liposarcomas', 'Phenotype', 'HP:0012034', (177, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('liposarcomas', 'Disease', (177, 189))	('p38', 'Var', (66, 69))	('LS', 'Phenotype', 'HP:0012034', (191, 193))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('hTERT', 'Gene', '7015', (79, 84))	('soft tissue malignant fibrous histiocytomas', 'Disease', (126, 169))
38968	22243975	In addition, with the broader aim of discovering regulation factors of hTERT in sarcomas, we investigated whether there is a correlation between hTERT and p38 MAPK.	('sarcomas', 'Disease', (80, 88))	('hTERT', 'Gene', '7015', (145, 150))	('sarcomas', 'Disease', 'MESH:D012509', (80, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('hTERT', 'Gene', (145, 150))	('hTERT', 'Gene', '7015', (71, 76))	('p38', 'Var', (155, 158))	('hTERT', 'Gene', (71, 76))
38975	22243975	Quantitative detection of hTERT mRNA and p38 MAPK was performed with the LightCycler TaqMan Master using the LightCycler instrument (Roche Molecular System, Alameda, CA).	('hTERT', 'Gene', (26, 31))	('p38', 'Var', (41, 44))	('hTERT', 'Gene', '7015', (26, 31))
38981	22243975	p38 MAPK expression was demonstrated in 84.1% (58 of 69) and hTERT mRNA expression was demonstrated in 91.3% (63 of 69) of all 69 samples.	('hTERT', 'Gene', '7015', (61, 66))	('p38 MAPK', 'Var', (0, 8))	('hTERT', 'Gene', (61, 66))
38982	22243975	The levels of p38 MAPK were 13.4 +- 27.7 (range: 0-191.1) and those of hTERT were 336.5 +- 554.8 (range: 0-2656.0) in all samples.	('p38', 'Var', (14, 17))	('hTERT', 'Gene', (71, 76))	('hTERT', 'Gene', '7015', (71, 76))
38985	22243975	Patients who had a higher than average expression of p38 MAPK had a significantly worse prognosis (5-year survival rate; 38.1%) than other patients overall (73.8%) (p = 0.0036) (Figure 2).	('patients', 'Species', '9606', (139, 147))	('p38', 'Var', (53, 56))	('higher', 'PosReg', (19, 25))	('Patients', 'Species', '9606', (0, 8))	('expression', 'MPA', (39, 49))	('worse', 'NegReg', (82, 87))
38987	22243975	p38 MAPK expression was demonstrated in 77.8% (28 of 36) and hTERT mRNA expression was demonstrated in 88.9% (32 of 36) of soft tissue MFH samples.	('hTERT', 'Gene', '7015', (61, 66))	('p38 MAPK', 'Var', (0, 8))	('hTERT', 'Gene', (61, 66))
38988	22243975	The levels of p38 MAPK were 9.60 +- 17.5 (range: 0-71.1) and those of hTERT were 371.6 +- 695.9 (range: 0-2656.0).	('p38', 'Var', (14, 17))	('hTERT', 'Gene', (70, 75))	('hTERT', 'Gene', '7015', (70, 75))
38990	22243975	There were no significant differences in prognosis between patients who had a higher than average expression of p38 MAPK (5-year survival rate: 41.7%) and those who did not (65.0%) (p = 0.213).	('p38', 'Var', (112, 115))	('higher', 'PosReg', (78, 84))	('patients', 'Species', '9606', (59, 67))	('expression', 'MPA', (98, 108))
38992	22243975	p38 MAPK expression was demonstrated in 95.8% (23 of 24) and hTERT mRNA expression was demonstrated in 91.7% (22 of 24) of LS samples.	('hTERT', 'Gene', '7015', (61, 66))	('LS', 'Phenotype', 'HP:0012034', (123, 125))	('p38', 'Var', (0, 3))	('hTERT', 'Gene', (61, 66))
38993	22243975	The levels of p38 MAPK were 6.81 +- 11.5 (range: 0-38.2) and those of hTERT were 171.3 +- 189.9 (range: 0-726.6) in LS samples.	('p38', 'Var', (14, 17))	('hTERT', 'Gene', (70, 75))	('hTERT', 'Gene', '7015', (70, 75))	('LS', 'Phenotype', 'HP:0012034', (116, 118))
38995	22243975	Patients who had a higher than average expression of p38 MAPK (5-year survival rate: 50.0%) had a significantly worse prognosis than other patients (88.9%) (p = 0.0448) in LS patients.	('patients', 'Species', '9606', (139, 147))	('p38', 'Var', (53, 56))	('higher', 'PosReg', (19, 25))	('LS', 'Phenotype', 'HP:0012034', (172, 174))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (175, 183))	('expression', 'MPA', (39, 49))
38997	22243975	p38 MAPK expression was demonstrated in 77.8% (7 of 9) and hTERT expression was demonstrated in all (9 of 9) of bone MFH samples.	('hTERT', 'Gene', '7015', (59, 64))	('p38', 'Var', (0, 3))	('hTERT', 'Gene', (59, 64))
38998	22243975	The levels of p38 MAPK were 46.4 +- 58.2 (range: 0-191) and the levels of hTERT were 636.5 +- 453.3 (range: 241.7-1405.4) in bone MFH samples.	('p38', 'Var', (14, 17))	('hTERT', 'Gene', (74, 79))	('hTERT', 'Gene', '7015', (74, 79))
39000	22243975	Patients who had a higher than average expression of p38 MAPK (5-year survival rate: 0%) had a worse prognosis than other patients (66.7%), but did not reach significant differences (p = 0.202).	('p38', 'Var', (53, 56))	('higher', 'PosReg', (19, 25))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (122, 130))	('expression', 'MPA', (39, 49))
39010	22243975	p38 MAPK is shown to induce a wide variety of intracellular responses, with roles in tumorigenesis, cell-cycle regulation, development, inflammation and apoptosis.	('tumor', 'Disease', (85, 90))	('intracellular responses', 'MPA', (46, 69))	('development', 'CPA', (123, 134))	('induce', 'Reg', (21, 27))	('p38 MAPK', 'Var', (0, 8))	('cell-cycle regulation', 'CPA', (100, 121))	('inflammation', 'Disease', 'MESH:D007249', (136, 148))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('inflammation', 'Disease', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('apoptosis', 'CPA', (153, 162))
39014	22243975	p38 MAPK may play an important role in the activation of the hTERT promoter by the upstream stimulatory factor (USF) in tumor cells.	('activation', 'PosReg', (43, 53))	('p38 MAPK', 'Var', (0, 8))	('hTERT', 'Gene', '7015', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('USF', 'Gene', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('hTERT', 'Gene', (61, 66))	('USF', 'Gene', '7391', (112, 115))	('tumor', 'Disease', (120, 125))
39015	22243975	In the present study, there was a significant positive correlation between the values of p38 MAPK expression and hTERT, with increased p38 MAPK expression with higher hTERT in sarcoma samples.	('hTERT', 'Gene', (113, 118))	('p38', 'Var', (135, 138))	('increased', 'PosReg', (125, 134))	('sarcoma', 'Disease', (176, 183))	('expression', 'MPA', (144, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('hTERT', 'Gene', '7015', (167, 172))	('hTERT', 'Gene', '7015', (113, 118))	('p38 MAPK', 'Protein', (89, 97))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('hTERT', 'Gene', (167, 172))
39016	22243975	This is the first report to show a correlation between the levels of hTERT mRNA expression and the levels of p38 MAPK in human sarcomas, and these results may suggest that p38 MAPK plays a role in up-regulation of hTERT in soft tissue MFH, liposarcomas, and bone MFH, while we do not have a clear understanding if some factor regulates both p38 MAPK and hTERT expression.	('soft tissue MFH', 'Disease', (223, 238))	('sarcomas', 'Disease', (127, 135))	('hTERT', 'Gene', '7015', (214, 219))	('human', 'Species', '9606', (121, 126))	('p38', 'Var', (172, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('hTERT', 'Gene', '7015', (69, 74))	('sarcomas', 'Disease', 'MESH:D012509', (244, 252))	('sarcomas', 'Phenotype', 'HP:0100242', (244, 252))	('sarcomas', 'Disease', (244, 252))	('hTERT', 'Gene', (214, 219))	('bone MFH', 'Disease', (258, 266))	('liposarcomas', 'Disease', 'MESH:D008080', (240, 252))	('hTERT', 'Gene', '7015', (354, 359))	('hTERT', 'Gene', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('up-regulation', 'PosReg', (197, 210))	('liposarcomas', 'Phenotype', 'HP:0012034', (240, 252))	('hTERT', 'Gene', (354, 359))	('sarcomas', 'Disease', 'MESH:D012509', (127, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('liposarcomas', 'Disease', (240, 252))
39017	22243975	Recent studies have demonstrated that p38 MAPK has diverse roles in the pathogenesis of several cancers and have shown that they are also involved in regulating other functions including the differentiation and proliferation of various cell types.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('roles', 'Reg', (59, 64))	('differentiation', 'CPA', (191, 206))	('involved', 'Reg', (138, 146))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('p38', 'Var', (38, 41))	('cancers', 'Disease', (96, 103))	('proliferation of various cell types', 'CPA', (211, 246))
39020	22243975	In terms of sarcoma cells, inhibition of p38 MAPK activity rescues the antitumor agent fenretinide-mediated cell death in Ewing's sarcoma family of tumors, and inhibition of p38 signals results showing a significant reduction in chondrosarcoma cell proliferation mediated by complex effects of p38 signaling on cell-cycle gene expression, which suggests that p38 MAPK may play an important role in tumorigenesis in these sarcomas.	('sarcoma', 'Disease', 'MESH:D012509', (236, 243))	('inhibition', 'Var', (27, 37))	('sarcoma', 'Disease', (236, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (421, 428))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (122, 137))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('sarcoma', 'Disease', (12, 19))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('reduction', 'NegReg', (216, 225))	('sarcoma', 'Disease', (130, 137))	('chondrosarcoma', 'Disease', 'MESH:D002813', (229, 243))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('chondrosarcoma', 'Disease', (229, 243))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (122, 137))	('tumor', 'Disease', (398, 403))	('inhibition', 'Var', (160, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('tumor', 'Disease', 'MESH:D009369', (398, 403))	('tumors', 'Disease', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	("Ewing's sarcoma", 'Disease', (122, 137))	('sarcoma', 'Disease', 'MESH:D012509', (421, 428))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (229, 243))	('tumor', 'Disease', (148, 153))	('sarcomas', 'Disease', 'MESH:D012509', (421, 429))	('sarcoma', 'Disease', (421, 428))	('sarcomas', 'Phenotype', 'HP:0100242', (421, 429))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('sarcomas', 'Disease', (421, 429))	('tumor', 'Phenotype', 'HP:0002664', (398, 403))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('fenretinide', 'Chemical', 'MESH:D017313', (87, 98))
39022	22243975	In terms of bone and soft tissue MFH, there were no significant differences in prognosis between patients who had a higher than average expression of p38 MAPK and those who did not.	('expression', 'MPA', (136, 146))	('p38', 'Var', (150, 153))	('patients', 'Species', '9606', (97, 105))
39023	22243975	However, patients who had above average p38 (5-year survival rate: soft tissue MFH; 41.7%, bone MFH; 0%) had a worse prognosis than other patients (5-year survival rate: soft tissue MFH; 65.0%, bone MFH; 66.7%), but did not reach significant differences.	('soft tissue', 'Disease', (170, 181))	('patients', 'Species', '9606', (9, 17))	('p38', 'Var', (40, 43))	('patients', 'Species', '9606', (138, 146))
39025	22243975	Therefore, high expression of p38 MAPK may correlate with a worse prognosis especially for LS patients.	('LS', 'Phenotype', 'HP:0012034', (91, 93))	('high', 'PosReg', (11, 15))	('patients', 'Species', '9606', (94, 102))	('p38', 'Var', (30, 33))
39026	22243975	p38 MAPK may be a useful marker in the assessment of hTERT and prognosis.	('hTERT', 'Gene', (53, 58))	('hTERT', 'Gene', '7015', (53, 58))	('p38 MAPK', 'Var', (0, 8))
39027	22243975	Given that more than 80% of sarcomas express p38 MAPK and hTERT, elucidation of the pathways and target genes of p38 MAPK in sarcomas will yield additional understandings into the pathogenesis of several sarcomas and may lead to novel therapeutic strategies for their treatment.	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('hTERT', 'Gene', (58, 63))	('p38', 'Var', (113, 116))	('sarcomas', 'Disease', 'MESH:D012509', (125, 133))	('sarcomas', 'Disease', 'MESH:D012509', (204, 212))	('sarcomas', 'Disease', (28, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('sarcomas', 'Disease', (125, 133))	('p38 MAPK', 'Var', (45, 53))	('sarcomas', 'Disease', (204, 212))	('hTERT', 'Gene', '7015', (58, 63))	('lead', 'Reg', (221, 225))
39028	33471866	Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7 Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma that is etiologically linked to Kaposi's sarcoma-associated herpesvirus (KSHV).	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	("Kaposi's sarcoma", 'Disease', (0, 16))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (223, 239))	("Kaposi's sarcoma", 'Disease', (223, 239))	('FBW7', 'Gene', (121, 125))	('lymphoma', 'Phenotype', 'HP:0002665', (143, 151))	('P', 'Chemical', 'MESH:D010758', (153, 154))	('targeting', 'Var', (111, 120))	('Primary effusion lymphoma', 'Phenotype', 'HP:0030069', (126, 151))	('aggressive B cell lymphoma', 'Disease', (164, 190))	("Kaposi's sarcoma-associated herpesvirus", 'Species', '37296', (0, 39))	("Kaposi's sarcoma-associated herpesvirus", 'Species', '37296', (223, 262))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (175, 190))	('lymphoma', 'Phenotype', 'HP:0002665', (182, 190))	('aggressive B cell lymphoma', 'Disease', 'MESH:D016393', (164, 190))	('Primary effusion lymphoma', 'Disease', 'MESH:D054685', (126, 151))	('KSHV', 'Species', '37296', (264, 268))	('P', 'Chemical', 'MESH:D010758', (126, 127))	('Primary effusion lymphoma', 'Disease', (126, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (0, 16))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (223, 239))
39032	33471866	Consequently, LANA-FBW7 interaction enhances the stability of MCL-1 by preventing its proteasome-mediated degradation, which inhibits caspase-3-mediated apoptosis in PEL cells.	('interaction', 'Var', (24, 35))	('proteasome-mediated degradation', 'MPA', (86, 117))	('enhances', 'PosReg', (36, 44))	('preventing', 'NegReg', (71, 81))	('stability', 'MPA', (49, 58))	('caspase-3', 'Gene', (134, 143))	('inhibits', 'NegReg', (125, 133))	('P', 'Chemical', 'MESH:D010758', (166, 167))	('caspase-3', 'Gene', '836', (134, 143))
39041	33471866	These results suggest that LANA acts as a proto-oncogene via deregulating tumor suppressor FBW7, which upregulates anti-apoptotic MCL-1 expression.	('deregulating', 'Var', (61, 73))	('upregulates', 'PosReg', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('anti-apoptotic MCL-1 expression', 'MPA', (115, 146))
39044	33471866	Dysregulation of the components of this elaborate network leads to human diseases such as cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Dysregulation', 'Var', (0, 13))	('leads to', 'Reg', (58, 66))	('human', 'Species', '9606', (67, 72))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
39063	33471866	Furthermore, depletion of MCL-1 by small interfering RNA (siRNA) or pharmacological inhibition of MCL-1 using the small-molecule inhibitor AT-101 markedly suppressed proliferation and colony formation on soft agar by several PEL cell lines.	('agar', 'Chemical', 'MESH:D000362', (209, 213))	('small', 'Var', (35, 40))	('proliferation', 'CPA', (166, 179))	('AT-101', 'Chemical', 'MESH:C028178', (139, 145))	('suppressed', 'NegReg', (155, 165))	('depletion', 'MPA', (13, 22))	('P', 'Chemical', 'MESH:D010758', (225, 226))	('colony formation on soft agar', 'CPA', (184, 213))
39064	33471866	Remarkably, AT-101 effectively inhibited tumor development and growth in PEL-derived mouse xenograft model.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Disease', (41, 46))	('AT-101', 'Var', (12, 18))	('growth', 'CPA', (63, 69))	('P', 'Chemical', 'MESH:D010758', (73, 74))	('inhibited', 'NegReg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('AT-101', 'Chemical', 'MESH:C028178', (12, 18))
39070	33471866	To further identify the significant phosphorylation sites that are responsible for LANA-FBW7 interaction, we performed IP assays after generating three different phosphorylation-dead LANA mutants: LANAT177A (designated as LANA-P1), LANAS219A/S223A (designated as LANA-P2/P3), and LANAT117A/S219A/S223A (designated as LANA-P1/P2/P3).	('S219A', 'Var', (236, 241))	('LANA-P1', 'Chemical', '-', (222, 229))	('S219A', 'Var', (290, 295))	('P', 'Chemical', 'MESH:D010758', (325, 326))	('P', 'Chemical', 'MESH:D010758', (120, 121))	('S223A', 'Mutation', 'p.S223A', (296, 301))	('T177A', 'Mutation', 'c.177T>A', (201, 206))	('P', 'Chemical', 'MESH:D010758', (271, 272))	('LANA-P1', 'Chemical', '-', (317, 324))	('P', 'Chemical', 'MESH:D010758', (268, 269))	('P', 'Chemical', 'MESH:D010758', (227, 228))	('S219A', 'SUBSTITUTION', 'None', (236, 241))	('S223A', 'Mutation', 'p.S223A', (242, 247))	('S219A', 'SUBSTITUTION', 'None', (290, 295))	('LANAT177A', 'Var', (197, 206))	('P', 'Chemical', 'MESH:D010758', (322, 323))	('P', 'Chemical', 'MESH:D010758', (328, 329))
39076	33471866	To examine this, we generated tetracycline-inducible TREx/BJAB cell lines that ectopically expressed Au-tagged LANA or LANA-P1.	('LANA-P1', 'Chemical', '-', (119, 126))	('LANA-P1', 'Gene', (119, 126))	('BJAB', 'CellLine', 'CVCL:5711', (58, 62))	('Au-tagged', 'Var', (101, 110))	('tetracycline', 'Chemical', 'MESH:D013752', (30, 42))
39079	33471866	In contrast, both LANA-WT and LANA-P1 elevated the intracellular domain of Notch-1 (ICN) expression (Fig 2B).	('Notch-1', 'Gene', (75, 82))	('Notch-1', 'Gene', '4851', (75, 82))	('expression', 'MPA', (89, 99))	('LANA-P1', 'Var', (30, 37))	('intracellular domain', 'MPA', (51, 71))	('elevated', 'PosReg', (38, 46))	('LANA-P1', 'Chemical', '-', (30, 37))
39085	33471866	To address this, we performed competitive protein-binding assays with cells transiently expressing different combinations of LANA-WT, LANA-P1, MCL-1, and FBW7 (Fig 3A).	('FBW7', 'Var', (154, 158))	('LANA-P1', 'Chemical', '-', (134, 141))	('LANA-P1', 'Var', (134, 141))
39088	33471866	Using K48R (Lysine 48 to Arginine) ubiquitin mutant, MCL-1 polyubiquitination was marginally increased when FBW7 was simultaneously overexpressed (Fig 3B lower panel, compared lane 3 with lane 4) and there was no effect by either LANA or LANA-P1 expression (Fig 3B lower panel, compared lane 4 with lanes 5 & 6).	('FBW7', 'Gene', (108, 112))	('Lysine 48 to Arginine', 'Mutation', 'p.K48R', (12, 33))	('K48R', 'SUBSTITUTION', 'None', (6, 10))	('increased', 'PosReg', (93, 102))	('MCL-1 polyubiquitination', 'MPA', (53, 77))	('ubiquitin', 'Protein', (35, 44))	('K48R', 'Var', (6, 10))	('overexpressed', 'PosReg', (132, 145))	('LANA-P1', 'Chemical', '-', (238, 245))
39095	33471866	Additionally, we observed that cleaved caspase-3 levels were greatly diminished in LANA-expressing cells than compared to vector and LANA-P1-expressing cells (Fig 4B).	('LANA-P1', 'Chemical', '-', (133, 140))	('caspase-3', 'Gene', (39, 48))	('diminished', 'NegReg', (69, 79))	('caspase-3', 'Gene', '836', (39, 48))	('LANA-expressing', 'Var', (83, 98))
39100	33471866	In order to examine the effect of LANA-mediated stabilization of MCL-1 in the context of the KSHV infection, we first generated a LANA-P1 mutant KSHV by replacing Theronine at amino acid 177 in LANA encoded in KSHV BAC16 to Alanine (rKSHV-BAC16-LANA-P1) via "scarless" mutagenesis.	('KSHV', 'Species', '37296', (234, 238))	('LANA-P1', 'Gene', (130, 137))	('replacing', 'Var', (153, 162))	('KSHV', 'Species', '37296', (210, 214))	('BAC16', 'Chemical', '-', (215, 220))	('KSHV infection', 'Disease', (93, 107))	('KSHV', 'Species', '37296', (93, 97))	('mutant', 'Var', (138, 144))	('KSHV', 'Species', '37296', (145, 149))	('LANA-P1', 'Chemical', '-', (130, 137))	('Alanine', 'Chemical', 'MESH:D000409', (224, 231))	('KSHV infection', 'Disease', 'MESH:D007239', (93, 107))	('Theronine', 'Chemical', '-', (163, 172))	('BAC16', 'Chemical', '-', (239, 244))	('LANA-P1', 'Chemical', '-', (245, 252))
39103	33471866	We then determined the effect of LANA-P1 mutant on the viral gene expression as well as production of infectious virus.	('LANA-P1', 'Chemical', '-', (33, 40))	('LANA-P1', 'Gene', (33, 40))	('viral gene expression', 'MPA', (55, 76))	('mutant', 'Var', (41, 47))
39104	33471866	To this end, we induced lytic reactivation of KSHV in iSLK cells, harboring rKSHV-BAC16-LANA-P1, rKSHV-BAC16-Rev, and rKSHV-BAC16, and measured both virus production and the expression of the immediate-early (RTA), early (ORF6, ORF45, K2), and late (K8.1) viral proteins.	('RTA', 'Gene', (209, 212))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('KSHV', 'Species', '37296', (46, 50))	('ORF6', 'Gene', '4961521', (222, 226))	('K8.1', 'Gene', (250, 254))	('RTA', 'Gene', '116535', (209, 212))	('BAC16', 'Chemical', '-', (124, 129))	('KSHV', 'Species', '37296', (77, 81))	('S', 'Chemical', 'MESH:D013455', (99, 100))	('BAC16', 'Chemical', '-', (82, 87))	('KSHV', 'Gene', (46, 50))	('LANA-P1', 'Chemical', '-', (88, 95))	('expression', 'MPA', (174, 184))	('ORF45', 'Gene', '4961474', (228, 233))	('S', 'Chemical', 'MESH:D013455', (120, 121))	('K8.1', 'Gene', '3887', (250, 254))	('KSHV', 'Species', '37296', (98, 102))	('rKSHV-BAC16-LANA-P1', 'Var', (76, 95))	('K2', 'Protein', (235, 237))	('BAC16', 'Chemical', '-', (103, 108))	('S', 'Chemical', 'MESH:D013455', (78, 79))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('KSHV', 'Species', '37296', (119, 123))	('ORF45', 'Gene', (228, 233))	('ORF6', 'Gene', (222, 226))
39105	33471866	We found that LANA-P1 mutant KSHV produce comparable amount of virus compared to WT KSHV (S2B Fig).	('S', 'Chemical', 'MESH:D013455', (90, 91))	('LANA-P1', 'Chemical', '-', (14, 21))	('KSHV', 'Species', '37296', (29, 33))	('S', 'Chemical', 'MESH:D013455', (85, 86))	('mutant', 'Var', (22, 28))	('S', 'Chemical', 'MESH:D013455', (30, 31))	('KSHV', 'Species', '37296', (84, 88))	('LANA-P1', 'Gene', (14, 21))
39106	33471866	Accordingly, the expression levels of viral proteins tested did not appear to be affected by LANA-P1 mutant either (S2C Fig), suggesting that LANA-P1 mutant does not affect virus production and viral gene expression.	('mutant', 'Var', (101, 107))	('LANA-P1', 'Chemical', '-', (93, 100))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('LANA-P1', 'Chemical', '-', (142, 149))	('LANA-P1', 'Gene', (93, 100))
39107	33471866	To examine whether LANA also has the ability to induce MCL-1 stabilization in KSHV-infected cells, we established BJAB cell lines with rKSHV-BAC16, rKSHV-BAC16-LANA-P1, and rKSHV-BAC16-Rev (S2D Fig).	('S', 'Chemical', 'MESH:D013455', (79, 80))	('rKSHV-BAC16-LANA-P1', 'Var', (148, 167))	('BAC16', 'Chemical', '-', (154, 159))	('rKSHV-BAC16-Rev', 'Var', (173, 188))	('KSHV-infected', 'Disease', (78, 91))	('BAC16', 'Chemical', '-', (179, 184))	('LANA-P1', 'Chemical', '-', (160, 167))	('S', 'Chemical', 'MESH:D013455', (190, 191))	('KSHV-infected', 'Disease', 'MESH:D007239', (78, 91))	('BAC16', 'Chemical', '-', (141, 146))	('KSHV', 'Species', '37296', (149, 153))	('KSHV', 'Species', '37296', (78, 82))	('S', 'Chemical', 'MESH:D013455', (175, 176))	('S', 'Chemical', 'MESH:D013455', (150, 151))	('S', 'Chemical', 'MESH:D013455', (137, 138))	('KSHV', 'Species', '37296', (136, 140))	('KSHV', 'Species', '37296', (174, 178))	('BJAB', 'CellLine', 'CVCL:5711', (114, 118))
39116	33471866	Thus, elevated expression of MCL-1 in PEL cells prompted us to assess the therapeutic potential of MCL-1 inhibitors AT-101 and A-1210477.	('A-1210477', 'Var', (127, 136))	('P', 'Chemical', 'MESH:D010758', (38, 39))	('A-1210477', 'Chemical', 'MESH:C000611392', (127, 136))	('expression', 'MPA', (15, 25))	('elevated', 'PosReg', (6, 14))	('AT-101', 'Chemical', 'MESH:C028178', (116, 122))
39117	33471866	AT-101 is a pan-BCL-2 inhibitor with anti-MCL-1 activity, while A-1210477 is a selective MCL-1 small-molecule inhibitor.	('BCL-2', 'Gene', (16, 21))	('anti-MCL-1 activity', 'MPA', (37, 56))	('AT-101', 'Chemical', 'MESH:C028178', (0, 6))	('A-1210477', 'Chemical', 'MESH:C000611392', (64, 73))	('BCL-2', 'Gene', '596', (16, 21))	('AT-101', 'Var', (0, 6))	('A-1210477', 'Var', (64, 73))
39118	33471866	Treatment of BJAB and PEL cells with AT-101 or A-1210477 suppressed cell growth and induced cell death in KSHV+ PEL cells but had very marginal effect on BJAB cells (Figs 6D, S4B, S4C and S4D).	('P', 'Chemical', 'MESH:D010758', (112, 113))	('AT-101', 'Var', (37, 43))	('BJAB', 'CellLine', 'CVCL:5711', (13, 17))	('P', 'Chemical', 'MESH:D010758', (22, 23))	('BJAB', 'CellLine', 'CVCL:5711', (154, 158))	('S', 'Chemical', 'MESH:D013455', (107, 108))	('S', 'Chemical', 'MESH:D013455', (180, 181))	('A-1210477', 'Chemical', 'MESH:C000611392', (47, 56))	('cell growth', 'CPA', (68, 79))	('AT-101', 'Chemical', 'MESH:C028178', (37, 43))	('A-1210477', 'Var', (47, 56))	('S', 'Chemical', 'MESH:D013455', (175, 176))	('death', 'Disease', 'MESH:D003643', (97, 102))	('S', 'Chemical', 'MESH:D013455', (188, 189))	('death', 'Disease', (97, 102))	('KSHV', 'Species', '37296', (106, 110))	('suppressed', 'NegReg', (57, 67))
39121	33471866	Notably, both co-treatment of BCBL-1 cells with MCL-1 inhibitors and treatment of cells with MCL-1 inhibitors after colony formation led to marked inhibition of colony formation (Fig 7 upper panel and S5A Fig upper panel), whereas BJAB cells successively formed colonies in soft agar in the presence or absence of MCL-1 inhibitors (Fig 7 bottom panel and S5A Fig bottom panel).	('S', 'Chemical', 'MESH:D013455', (355, 356))	('inhibitors', 'Var', (54, 64))	('colony formation', 'CPA', (161, 177))	('S', 'Chemical', 'MESH:D013455', (201, 202))	('agar', 'Chemical', 'MESH:D000362', (279, 283))	('inhibition', 'NegReg', (147, 157))	('BJAB', 'CellLine', 'CVCL:5711', (231, 235))	('BCBL-1', 'CellLine', 'CVCL:0165', (30, 36))
39127	33471866	We observed abdominal distention in DMSO-treated mice but not in AT-101-treated mice (Fig 8A).	('DMSO', 'Chemical', 'MESH:D004121', (36, 40))	('DMSO-treated', 'Var', (36, 48))	('abdominal distention', 'CPA', (12, 32))	('AT-101', 'Chemical', 'MESH:C028178', (65, 71))	('mice', 'Species', '10090', (49, 53))	('mice', 'Species', '10090', (80, 84))	('abdominal distention', 'Phenotype', 'HP:0003270', (12, 32))
39129	33471866	On average, 1.77 ml ascites were collected from DMSO-treated mice versus 0.12 ml from AT-101-treated mice (Fig 8B).	('DMSO', 'Chemical', 'MESH:D004121', (48, 52))	('mice', 'Species', '10090', (61, 65))	('AT-101', 'Chemical', 'MESH:C028178', (86, 92))	('ascites', 'Disease', (20, 27))	('ascites', 'Phenotype', 'HP:0001541', (20, 27))	('mice', 'Species', '10090', (101, 105))	('ascites', 'Disease', 'MESH:D001201', (20, 27))	('DMSO-treated', 'Var', (48, 60))
39131	33471866	Previous studies reported that mice injected with KSHV+ PEL cells, including BCBL-1 cells, exhibited notable splenomegaly when compared with normal NOD/SCID mice due to infiltration of anaplastic cells.	('SCID', 'Disease', 'MESH:D053632', (152, 156))	('NOD', 'Gene', '1822', (148, 151))	('infiltration', 'PosReg', (169, 181))	('splenomegaly', 'Phenotype', 'HP:0001744', (109, 121))	('anaplastic cells', 'CPA', (185, 201))	('mice', 'Species', '10090', (157, 161))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('splenomegaly', 'Disease', (109, 121))	('KSHV+ PEL', 'Var', (50, 59))	('mice', 'Species', '10090', (31, 35))	('NOD', 'Gene', (148, 151))	('P', 'Chemical', 'MESH:D010758', (56, 57))	('KSHV', 'Species', '37296', (50, 54))	('BCBL-1', 'CellLine', 'CVCL:0165', (77, 83))	('splenomegaly', 'Disease', 'MESH:D013163', (109, 121))	('SCID', 'Disease', (152, 156))
39132	33471866	Notably, the size of the spleen in AT-101-treated mice was obviously reduced compared to the DMSO-treated control mice (Fig 8D).	('AT-101-treated', 'Var', (35, 49))	('reduced', 'NegReg', (69, 76))	('AT-101', 'Chemical', 'MESH:C028178', (35, 41))	('mice', 'Species', '10090', (50, 54))	('mice', 'Species', '10090', (114, 118))	('DMSO', 'Chemical', 'MESH:D004121', (93, 97))	('size of the spleen', 'CPA', (13, 31))
39133	33471866	KSHV+ PEL cells, including BCBL-1 cells isolated originally from patients typically expressed CD45 and CD38, but are usually negative for B-cell markers such as CD19, CD20, CD79, and PAX5.	('KSHV', 'Species', '37296', (0, 4))	('CD20', 'Gene', '54474', (167, 171))	('BCBL-1', 'CellLine', 'CVCL:0165', (27, 33))	('CD20', 'Gene', (167, 171))	('CD38', 'Gene', (103, 107))	('P', 'Chemical', 'MESH:D010758', (6, 7))	('CD45', 'Gene', (94, 98))	('CD19', 'Gene', (161, 165))	('PAX5', 'Gene', '5079', (183, 187))	('CD38', 'Gene', '952', (103, 107))	('expressed', 'Reg', (84, 93))	('CD45', 'Gene', '5788', (94, 98))	('P', 'Chemical', 'MESH:D010758', (183, 184))	('patients', 'Species', '9606', (65, 73))	('PAX5', 'Gene', (183, 187))	('CD19', 'Gene', '930', (161, 165))	('CD79', 'Var', (173, 177))
39141	33471866	Furthermore, siRNA-mediated inhibition of MCL-1 and small-molecule inhibitors (AT-101 and A-1210477) effectively suppressed the anti-apoptotic function of MCL-1, eventually promoting PEL cell death.	('suppressed', 'NegReg', (113, 123))	('anti-apoptotic function', 'MPA', (128, 151))	('A-1210477', 'Var', (90, 99))	('death', 'Disease', 'MESH:D003643', (192, 197))	('death', 'Disease', (192, 197))	('AT-101', 'Chemical', 'MESH:C028178', (79, 85))	('promoting', 'PosReg', (173, 182))	('P', 'Chemical', 'MESH:D010758', (183, 184))	('A-1210477', 'Chemical', 'MESH:C000611392', (90, 99))
39146	33471866	Since most of the FBW7 substrates are proto-oncogenes, relocalization of FBW7 is also likely to derive transformation.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('FBW7', 'Gene', (73, 77))	('relocalization', 'Var', (55, 69))	('FBW7', 'Gene', (18, 22))
39222	33471866	4 Aug 2020  Dear Hey-Ra, Thank you very much for submitting your manuscript "Kaposi's Sarcoma-associated Herpesvirus Latency-associated Nuclear Antigen Dysregulates Expression of MCL-1 by Targeting FBW7" for consideration at PLOS Pathogens.	('FBW7" for consideration', 'Gene', (198, 221))	('P', 'Chemical', 'MESH:D010758', (230, 231))	('S', 'Chemical', 'MESH:D013455', (86, 87))	('Sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	("Kaposi's Sarcoma-associated Herpesvirus", 'Species', '37296', (77, 116))	('Expression', 'MPA', (165, 175))	('S', 'Chemical', 'MESH:D013455', (228, 229))	('P', 'Chemical', 'MESH:D010758', (225, 226))	('Targeting', 'Reg', (188, 197))	('Dysregulates', 'Var', (152, 164))	("Kaposi's Sarcoma", 'Phenotype', 'HP:0100726', (77, 93))
39235	33471866	therefore contributes two important aspects to the KSHV literature: (i) it shows that KSHV LANA stabilises MCL-1 by binding to and thereby diverting the E3 ligase FBW7, which normally downregulates MCL-1; (ii) it describes two further MCL-1 or FBW-7 inhibitors that potently inhibit PEL growth in an in vivo preclinical model and thereby extends a previous report on another MCL-1 inhibitor, S63845, which had been shown by others to markedly inhibit the growth of of PEL cells in tissue culture.	('FBW-7', 'Gene', (244, 249))	('S', 'Chemical', 'MESH:D013455', (52, 53))	('KSHV', 'Species', '37296', (51, 55))	('inhibitors', 'Var', (250, 260))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('PEL growth', 'CPA', (283, 293))	('S', 'Chemical', 'MESH:D013455', (392, 393))	('FBW-7', 'Gene', '55294', (244, 249))	('P', 'Chemical', 'MESH:D010758', (468, 469))	('KSHV', 'Species', '37296', (86, 90))	('inhibit', 'NegReg', (443, 450))	('growth of of PEL cells in tissue culture', 'CPA', (455, 495))	('S63845', 'Var', (392, 398))	('inhibit', 'NegReg', (275, 282))	('P', 'Chemical', 'MESH:D010758', (283, 284))
39238	33471866	So, it is not appreciated how important LANA, in particular, via sequestering FBW7, contributes to the elevated expression of MCL-1 in KSHV-infected PEL cell lines as shown in Figure 5A.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('KSHV-infected', 'Disease', (135, 148))	('sequestering', 'Var', (65, 77))	('FBW7', 'Gene', (78, 82))	('KSHV-infected', 'Disease', 'MESH:D007239', (135, 148))	('P', 'Chemical', 'MESH:D010758', (149, 150))	('S', 'Chemical', 'MESH:D013455', (136, 137))	('elevated', 'PosReg', (103, 111))	('MCL-1', 'Gene', (126, 131))	('expression', 'MPA', (112, 122))
39256	33471866	1F therefore only shows that the LANA P1 mutant localises to the nucleus, not that it 'co-localises' with FBW7 (line 161 in the text).	('localises', 'MPA', (48, 57))	('P', 'Chemical', 'MESH:D010758', (38, 39))	('LANA P1', 'Gene', (33, 40))	('mutant', 'Var', (41, 47))
39257	33471866	I assume that the authors may only have wanted to make the point that the LANA P1 mutant has a nuclear localisation.	('LANA P1', 'Gene', (74, 81))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('nuclear localisation', 'MPA', (95, 115))	('mutant', 'Var', (82, 88))
39261	33471866	5D, text line 256: the text states that AT101 induced cell death in PEL cells but not in BJAB; according to fig.	('AT101', 'Var', (40, 45))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('BJAB', 'CellLine', 'CVCL:5711', (89, 93))	('death', 'Disease', 'MESH:D003643', (59, 64))	('death', 'Disease', (59, 64))
39263	33471866	AT1210477 also reduces the growth rate of BJAB in fig.	('growth rate of BJAB in', 'CPA', (27, 49))	('AT1210477', 'Chemical', '-', (0, 9))	('BJAB', 'CellLine', 'CVCL:5711', (42, 46))	('AT1210477', 'Var', (0, 9))	('reduces', 'NegReg', (15, 22))
39286	33471866	therefore contributes two important aspects to the KSHV literature: (i) it shows that KSHV LANA stabilizes MCL-1 by binding to and thereby diverting the E3 ligase FBW7, which normally downregulates MCL-1; (ii) it describes two further MCL-1 or FBW-7 inhibitors that potently inhibit PEL growth in an in vivo preclinical model and thereby extends a previous report on another MCL- 1 inhibitor, S63845, which had been shown by others to markedly inhibit the growth of PEL cells in tissue culture.	('FBW-7', 'Gene', (244, 249))	('S', 'Chemical', 'MESH:D013455', (52, 53))	('KSHV', 'Species', '37296', (51, 55))	('inhibitors', 'Var', (250, 260))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('PEL growth', 'CPA', (283, 293))	('FBW-7', 'Gene', '55294', (244, 249))	('S', 'Chemical', 'MESH:D013455', (393, 394))	('S63845', 'Var', (393, 399))	('inhibit', 'NegReg', (444, 451))	('KSHV', 'Species', '37296', (86, 90))	('P', 'Chemical', 'MESH:D010758', (466, 467))	('inhibit', 'NegReg', (275, 282))	('P', 'Chemical', 'MESH:D010758', (283, 284))	('growth of PEL cells in tissue culture', 'CPA', (456, 493))
39292	33471866	16 Dec 2020  Dear Dr. Lee, We are delighted to inform you that your manuscript, "Kaposi's Sarcoma-associated Herpesvirus Latency-associated Nuclear Antigen Dysregulates Expression of MCL-1 by Targeting FBW7," has been formally accepted for publication in PLOS Pathogens.	('P', 'Chemical', 'MESH:D010758', (260, 261))	('S', 'Chemical', 'MESH:D013455', (258, 259))	('S', 'Chemical', 'MESH:D013455', (90, 91))	("Kaposi's Sarcoma", 'Phenotype', 'HP:0100726', (81, 97))	('Sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('MCL-1', 'Gene', (183, 188))	('P', 'Chemical', 'MESH:D010758', (255, 256))	('Expression', 'MPA', (169, 179))	("Kaposi's Sarcoma-associated Herpesvirus", 'Species', '37296', (81, 120))	('FBW7', 'Gene', (202, 206))	('Targeting', 'Reg', (192, 201))	('Dysregulates', 'Var', (156, 168))
39308	31331295	Moreover, anti-PDGFRA treatment, both as a single agent as well as combined with doxorubicin, did not result in inhibition of the downstream MAPK and PI3K/AKT signaling pathways.	('AKT', 'Gene', (155, 158))	('PI3', 'Gene', '5266', (150, 153))	('doxorubicin', 'Chemical', 'MESH:D004317', (81, 92))	('inhibition', 'NegReg', (112, 122))	('PI3', 'Gene', (150, 153))	('anti-PDGFRA', 'Var', (10, 21))	('AKT', 'Gene', '207', (155, 158))
39326	31331295	Therefore, olaratumab could theoretically have both a direct cytostatic effect by inhibiting tumor cell growth, as well as an indirect effect by reducing reactive stromal cells and inhibiting neo-angiogenesis.	('neo-angiogenesis', 'CPA', (192, 208))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('inhibiting', 'NegReg', (82, 92))	('inhibiting', 'NegReg', (181, 191))	('reactive stromal cells', 'CPA', (154, 176))	('tumor', 'Disease', (93, 98))	('reducing', 'NegReg', (145, 153))	('olaratumab', 'Var', (11, 21))	('olaratumab', 'Chemical', 'MESH:C000589393', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
39327	31331295	Indeed, olaratumab as single agent significantly delayed tumor growth in osteosarcoma and malignant rhabdoid tumor xenografts; combination of olaratumab with doxorubicin or cisplatin resulted in disease stabilization in osteosarcoma xenografts.	('olaratumab', 'Chemical', 'MESH:C000589393', (8, 18))	('osteosarcoma', 'Phenotype', 'HP:0002669', (73, 85))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('osteosarcoma xenografts', 'Disease', 'MESH:D012516', (220, 243))	('osteosarcoma and malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (73, 114))	('doxorubicin', 'Chemical', 'MESH:D004317', (158, 169))	('olaratumab', 'Chemical', 'MESH:C000589393', (142, 152))	('delayed', 'NegReg', (49, 56))	('disease stabilization', 'CPA', (195, 216))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('tumor', 'Disease', (57, 62))	('osteosarcoma', 'Phenotype', 'HP:0002669', (220, 232))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('combination', 'Var', (127, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('osteosarcoma xenografts', 'Disease', (220, 243))	('tumor', 'Disease', (109, 114))
39353	31331295	A total of 95 adult (10-12 weeks old), female, partially immunodeficient NMRI nu/nu mice were engrafted bilaterally with UZLX-STS22p.18 (n = 24), UZLX-STS39p.15 (n = 24), UZLX-STS59p.19 (n = 24) and UZLX-STS84p.10 (n = 23) tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('UZLX-STS22p.18', 'Var', (121, 135))	('STS', 'Phenotype', 'HP:0030448', (204, 207))	('STS', 'Phenotype', 'HP:0030448', (126, 129))	('STS', 'Phenotype', 'HP:0030448', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('mice', 'Species', '10090', (84, 88))	('STS', 'Phenotype', 'HP:0030448', (176, 179))
39385	31331295	Models UZLX-STS22p.11, UZLX-STS59p.14 and UZLX-STS84p.10 showed high intensity immunopositivity in 100% of the tumor cells, whereas UZLX-STS39p.9 showed positivity in 50% of tumor cells.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('STS', 'Phenotype', 'HP:0030448', (28, 31))	('STS', 'Phenotype', 'HP:0030448', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('UZLX-STS22p.11', 'Var', (7, 21))	('tumor', 'Disease', (111, 116))	('STS', 'Phenotype', 'HP:0030448', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('STS', 'Phenotype', 'HP:0030448', (137, 140))	('UZLX-STS84p.10', 'Var', (42, 56))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('UZLX-STS59p.14', 'Var', (23, 37))
39395	31331295	In the PDX models UZLX-STS39 and -STS59 a significant reduction of proliferation compared to control was observed in the combination treatment arm, however, combining doxorubicin and anti-PDGFRA treatment did not lead to an additive anti-proliferative effect compared to the doxorubicin single agent treatment (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (167, 178))	('reduction', 'NegReg', (54, 63))	('STS', 'Phenotype', 'HP:0030448', (23, 26))	('anti-proliferative effect', 'CPA', (233, 258))	('proliferation', 'CPA', (67, 80))	('UZLX-STS39', 'Var', (18, 28))	('doxorubicin', 'Chemical', 'MESH:D004317', (275, 286))	('STS', 'Phenotype', 'HP:0030448', (34, 37))
39396	31331295	In the PDX models UZLX-STS39, -STS59 and -STS84 we observed an increase in apoptotic activity in the doxorubicin and combination treatment arms (p < 0.05 for UZLX-STS39, p < 0.005 for UZLX-STS59 and -STS84).	('increase', 'PosReg', (63, 71))	('STS', 'Phenotype', 'HP:0030448', (163, 166))	('apoptotic activity', 'CPA', (75, 93))	('STS', 'Phenotype', 'HP:0030448', (23, 26))	('UZLX-STS39', 'Var', (18, 28))	('STS', 'Phenotype', 'HP:0030448', (189, 192))	('STS', 'Phenotype', 'HP:0030448', (42, 45))	('STS', 'Phenotype', 'HP:0030448', (31, 34))	('doxorubicin', 'Chemical', 'MESH:D004317', (101, 112))
39400	31331295	In accordance with the immunohistochemical findings, Western blot analysis showed PDGFRA expression in the control tumors of the UZLX-STS22 and -STS84 models, but not in UZLX-STS39 and -STS59.	('PDGFRA', 'Gene', (82, 88))	('STS', 'Phenotype', 'HP:0030448', (145, 148))	('expression', 'MPA', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('STS', 'Phenotype', 'HP:0030448', (186, 189))	('STS', 'Phenotype', 'HP:0030448', (175, 178))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('STS', 'Phenotype', 'HP:0030448', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('UZLX-STS22', 'Var', (129, 139))
39417	31331295	Nevertheless, there was no correlation between the presence of PDGFRA and response to olaratumab.	('PDGFRA', 'Gene', (63, 69))	('olaratumab', 'Chemical', 'MESH:C000589393', (86, 96))	('presence', 'Var', (51, 59))
39445	31331295	Patients in the combination arm of the clinical trial were more likely to receive gemcitabine/docetaxel, pazopanib or trabectedin, all agents which are known to be active second line treatments, associated with a significant prolongation in PFS in randomized clinical studies.	('prolongation', 'PosReg', (225, 237))	('pazopanib', 'Chemical', 'MESH:C516667', (105, 114))	('PFS', 'MPA', (241, 244))	('docetaxel', 'Chemical', 'MESH:D000077143', (94, 103))	('trabectedin', 'Chemical', 'MESH:D000077606', (118, 129))	('pazopanib', 'Var', (105, 114))	('Patients', 'Species', '9606', (0, 8))	('gemcitabine', 'Chemical', 'MESH:C056507', (82, 93))
39452	31331295	We did not demonstrate significant antitumor effect of anti-PDGFRA treatment, neither alone nor in combination with doxorubicin.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('doxorubicin', 'Chemical', 'MESH:D004317', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('anti-PDGFRA', 'Var', (55, 66))
39461	31049020	 EWSR1-NFATC2 and FUS-NFATC2 Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review The spectrum of mesenchymal tumors associated with rearrangements of the EWSR1 gene has been growing in recent years due to progress in molecular detection techniques.	('NFATC2', 'Gene', '4773', (22, 28))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (140, 158))	('Tumors', 'Phenotype', 'HP:0002664', (64, 70))	('EWSR1', 'Gene', '2130', (1, 6))	('EWSR1', 'Gene', (197, 202))	('FUS', 'Gene', (18, 21))	('Mesenchymal Tumors', 'Disease', 'MESH:C535700', (52, 70))	('Tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mesenchymal tumors', 'Disease', (140, 158))	('NFATC2', 'Gene', (7, 13))	('FUS', 'Gene', '2521', (18, 21))	('EWSR1', 'Gene', (1, 6))	('NFATC2', 'Gene', (22, 28))	('EWSR1', 'Gene', '2130', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('NFATC2', 'Gene', '4773', (7, 13))	('Mesenchymal Tumors', 'Disease', (52, 70))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('rearrangements', 'Var', (175, 189))
39463	31049020	The NFATC2 gene is one of the many translocation partners of EWSR1 in gene fusions in a morphologically typical, albeit rare, subgroup of mesenchymal tumors.	('EWSR1', 'Gene', '2130', (61, 66))	('NFATC2', 'Gene', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('man', 'Species', '9606', (30, 33))	('gene fusions', 'Var', (70, 82))	('NFATC2', 'Gene', '4773', (4, 10))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (138, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('EWSR1', 'Gene', (61, 66))	('mesenchymal tumors', 'Disease', (138, 156))
39473	31049020	EWSR1 fusions with genes from the ETS transcription factor family lead to the development of ES, a highly aggressive, undifferentiated, round cell tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('EWSR1', 'Gene', '2130', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('lead to', 'Reg', (66, 73))	('EWSR1', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))
39474	31049020	In contrast, rearrangements of EWSR1 with other partners are found in a morphological and clinical spectrum of entities, ranging from highly aggressive (clear cell sarcoma (CCS) and round cell-containing myxoid liposarcoma (RMLPS)) to less aggressive tumors (pure myxoid liposarcoma (MLPS) or extraskeletal myxoid chondrosarcoma (EMC)).	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (204, 222))	('EWSR1', 'Gene', (31, 36))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (264, 282))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (153, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('myxoid liposarcoma', 'Disease', (264, 282))	('MLPS', 'Disease', (225, 229))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('liposarcoma', 'Phenotype', 'HP:0012034', (211, 222))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (264, 282))	('MLPS', 'Disease', 'None', (284, 288))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('aggressive tumors', 'Disease', (240, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('rearrangements', 'Var', (13, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('clear cell sarcoma', 'Disease', (153, 171))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (293, 328))	('EWSR1', 'Gene', '2130', (31, 36))	('extraskeletal myxoid chondrosarcoma', 'Disease', (293, 328))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (204, 222))	('aggressive tumors', 'Disease', 'MESH:D001523', (240, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (321, 328))	('liposarcoma', 'Phenotype', 'HP:0012034', (271, 282))	('MLPS', 'Disease', (284, 288))	('myxoid liposarcoma', 'Disease', (204, 222))	('MLPS', 'Disease', 'None', (225, 229))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (314, 328))
39475	31049020	Some undifferentiated, round cell tumors without the classic EWSR1 fusions to genes from the ETS family have been designated Ewing sarcoma-like tumors (ESLTs).	('tumors', 'Disease', (144, 150))	('EWSR1', 'Gene', '2130', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('fusions', 'Var', (67, 74))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('Ewing sarcoma-like tumors', 'Disease', (125, 150))	('Ewing sarcoma-like tumors', 'Disease', 'MESH:C563168', (125, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('EWSR1', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
39479	31049020	Rare mesenchymal tumors carrying EWSR1-NFATC2 fusions have been assigned to ESLTs, probably due to partial CD99 expression and/or involvement of the EWSR1.	('mesenchymal tumors', 'Disease', (5, 23))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('ESLTs', 'Disease', (76, 81))	('fusions', 'Var', (46, 53))	('CD99', 'Gene', '4267', (107, 111))	('EWSR1', 'Gene', (149, 154))	('EWSR1', 'Gene', (33, 38))	('NFATC2', 'Gene', (39, 45))	('CD99', 'Gene', (107, 111))	('EWSR1', 'Gene', '2130', (149, 154))	('EWSR1', 'Gene', '2130', (33, 38))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (5, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('NFATC2', 'Gene', '4773', (39, 45))
39481	31049020	Little is known about the malignant potential of mesenchymal tumors carrying rearrangements of the NFATC2, since even if reported and studied at the molecular level, the more detailed information of clinical course is given only for very few patients.	('NFATC2', 'Gene', '4773', (99, 105))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (49, 67))	('mesenchymal tumors', 'Disease', (49, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('NFATC2', 'Gene', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('rearrangements', 'Var', (77, 91))	('patients', 'Species', '9606', (242, 250))
39494	31049020	Cases with detectable rearrangements of the NFATC2 were retrieved from the files of the Institute of Pathology, University Hospital, Zurich, Switzerland.	('rearrangements', 'Var', (22, 36))	('NFATC2', 'Gene', '4773', (44, 50))	('NFATC2', 'Gene', (44, 50))
39507	31049020	The immunophenotype was nonspecific (CK-, S100-, Des-, and CD45-); however diffuse CD99 expression was found.	('CD99', 'Gene', '4267', (83, 87))	('CK-', 'Var', (37, 40))	('CD45', 'Gene', '5788', (59, 63))	('S100', 'Gene', (42, 46))	('CD99', 'Gene', (83, 87))	('S100', 'Gene', '6271', (42, 46))	('CD45', 'Gene', (59, 63))
39535	31049020	As both categories may show rearrangement of the EWSR1, FISH was performed revealing rearrangement with low-level amplification of the red signal.	('EWSR1', 'Gene', (49, 54))	('EWSR1', 'Gene', '2130', (49, 54))	('rearrangement', 'Var', (28, 41))
39551	31049020	A FUS-NFATC2 gene fusion was detected on NGS performed independently and metachronically, both on the core biopsy as well as the curettage specimen.	('NFATC2', 'Gene', (6, 12))	('FUS', 'Gene', (2, 5))	('FUS', 'Gene', '2521', (2, 5))	('NFATC2', 'Gene', '4773', (6, 12))	('fusion', 'Var', (18, 24))
39571	31049020	Following the recognition that Ewing sarcoma is pathogenically caused by translocations of a gene located on chromosome 22q12 (subsequently called Ewing sarcoma gene) to partner genes of the ETS family of transforming factors, a subgroup of mostly aggressive sarcomas not carrying this translocation type has been identified and designed as "Ewing sarcoma-like tumors" (ESLT).	('Ewing sarcoma', 'Disease', (147, 160))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (342, 355))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (342, 355))	('translocations', 'Var', (73, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (348, 355))	('sarcomas', 'Phenotype', 'HP:0100242', (259, 267))	('tumors', 'Phenotype', 'HP:0002664', (361, 367))	('Ewing sarcoma-like tumors', 'Disease', (342, 367))	('caused by', 'Reg', (63, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (31, 44))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('mostly aggressive sarcomas', 'Disease', (241, 267))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (147, 160))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (147, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('mostly aggressive sarcomas', 'Disease', 'MESH:D012509', (241, 267))	('Ewing sarcoma-like tumors', 'Disease', 'MESH:C563168', (342, 367))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('Ewing sarcoma', 'Disease', (31, 44))
39573	31049020	EWSR1 rearrangements are involved in the pathogenesis of several well-established clinically and morphologically obviously non-ES, non-ESLT, entities such as MLPS, CCS, AFH, and a subgroup of myoepithelial tumors of soft tissue.	('myoepithelial tumors', 'Disease', 'MESH:D009208', (192, 212))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('MLPS', 'Disease', 'None', (158, 162))	('rearrangements', 'Var', (6, 20))	('involved', 'Reg', (25, 33))	('myoepithelial tumors', 'Disease', (192, 212))	('EWSR1', 'Gene', '2130', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('AFH', 'Disease', (169, 172))	('MLPS', 'Disease', (158, 162))	('CCS', 'Disease', (164, 167))	('EWSR1', 'Gene', (0, 5))
39576	31049020	Several studies (Table 1) describe tumors carrying EWSR1-NFATC2 fusion, mostly identified among tumors at first classified as ESLTs.	('NFATC2', 'Gene', '4773', (57, 63))	('fusion', 'Var', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('EWSR1', 'Gene', (51, 56))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('NFATC2', 'Gene', (57, 63))	('EWSR1', 'Gene', '2130', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
39578	31049020	Rearrangements of EWSR1 with various partners have been described in a subgroup of soft tissue myoepithelial tumors.	('EWSR1', 'Gene', (18, 23))	('myoepithelial tumors', 'Disease', (95, 115))	('described', 'Reg', (56, 65))	('Rearrangements', 'Var', (0, 14))	('EWSR1', 'Gene', '2130', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (95, 115))
39579	31049020	Other subgroups of myoepithelial tumors of soft tissue are associated with alternative genetic aberrations such as rearrangements of other genes (e.g., PLAG1) or homozygous deletion of the INI1/SMARCB1 gene, while in a large proportion, the genetic background is not yet known.	('myoepithelial tumors', 'Disease', 'MESH:D009208', (19, 39))	('myoepithelial tumors', 'Disease', (19, 39))	('PLAG1', 'Gene', (152, 157))	('rearrangements', 'Var', (115, 129))	('associated', 'Reg', (59, 69))	('SMARCB1', 'Gene', '6598', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('SMARCB1', 'Gene', (194, 201))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('INI1', 'Gene', (189, 193))	('INI1', 'Gene', '6598', (189, 193))	('homozygous deletion', 'Var', (162, 181))	('PLAG1', 'Gene', '5324', (152, 157))
39580	31049020	In fact, one of the tumors of the current series was initially diagnosed as a myoepithelial carcinoma due to the expression of cytokeratins and the presence of the EWSR1 rearrangement.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('EWSR1', 'Gene', '2130', (164, 169))	('myoepithelial carcinoma', 'Disease', (78, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (78, 101))	('rearrangement', 'Var', (170, 183))	('presence', 'Reg', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('EWSR1', 'Gene', (164, 169))	('cytokeratins', 'Protein', (127, 139))
39581	31049020	The intra-abdominal tumor of patient 3 was initially considered to be either a myoepithelial tumor or an EMC based on the rearrangement of the EWSR1.	('patient', 'Species', '9606', (29, 36))	('EWSR1', 'Gene', (143, 148))	('rearrangement', 'Var', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('EWSR1', 'Gene', '2130', (143, 148))	('myoepithelial tumor', 'Disease', 'MESH:D009208', (79, 98))	('intra-abdominal tumor', 'Disease', 'None', (4, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('intra-abdominal tumor', 'Disease', (4, 25))	('myoepithelial tumor', 'Disease', (79, 98))
39585	31049020	The molecular hallmark of the EWSR1-NFATC2 fusion is the accompanying secondary structural aberration of the fusion product, which leads to low-level amplification of the centromeric portion of the probe on the break-apart FISH.	('EWSR1', 'Gene', '2130', (30, 35))	('NFATC2', 'Gene', '4773', (36, 42))	('low-level amplification', 'MPA', (140, 163))	('NFATC2', 'Gene', (36, 42))	('leads to', 'Reg', (131, 139))	('EWSR1', 'Gene', (30, 35))	('fusion', 'Var', (43, 49))
39596	31049020	The 5' transactivation domain of FUS and EWSR1 seems to be interchangeable in terms of transforming potential, and the fusion proteins resulting from EWSR1 or FUS rearrangements with any given partner seem to exert identical biological effects.	('FUS', 'Gene', '2521', (159, 162))	('EWSR1', 'Gene', (41, 46))	('EWSR1', 'Gene', '2130', (150, 155))	('FUS', 'Gene', (33, 36))	('rearrangements', 'Var', (163, 177))	('FUS', 'Gene', '2521', (33, 36))	('EWSR1', 'Gene', '2130', (41, 46))	('EWSR1', 'Gene', (150, 155))	('FUS', 'Gene', (159, 162))
39651	24755886	On the other hand, cells deficient in homologous recombination (HR) (e.g., with mutations of BRCA1 or BRCA2 genes) are sensitive to trabectedin as well as to platinum compounds.	('mutations', 'Var', (80, 89))	('trabectedin', 'Chemical', 'MESH:D000077606', (132, 143))	('BRCA1', 'Gene', '672', (93, 98))	('sensitive', 'MPA', (119, 128))	('BRCA1', 'Gene', (93, 98))	('BRCA2', 'Gene', (102, 107))	('platinum', 'Chemical', 'MESH:D010984', (158, 166))	('BRCA2', 'Gene', '675', (102, 107))
39668	24755886	Modulation of transcription by trabectedin has also been shown in Ewing's sarcoma, a neoplasm driven by the oncogenic fusion gene EWS-FLI1.	('Modulation', 'Var', (0, 10))	('FLI1', 'Gene', (134, 138))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (66, 81))	('trabectedin', 'Chemical', 'MESH:D000077606', (31, 42))	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))	("Ewing's sarcoma", 'Disease', (66, 81))	('neoplasm', 'Disease', 'MESH:D009369', (85, 93))	('transcription', 'MPA', (14, 27))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (66, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('FLI1', 'Gene', '2313', (134, 138))	('EWS', 'Gene', '2130', (130, 133))	('EWS', 'Gene', (130, 133))	('neoplasm', 'Disease', (85, 93))
39679	24755886	It was also shown that short exposure to trabectedin caused a strong decrease in the production of several cytokines and chemokines secreted by monocytes/macrophages and tumour cells.	('tumour', 'Disease', (170, 176))	('trabectedin', 'Var', (41, 52))	('decrease', 'NegReg', (69, 77))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('trabectedin', 'Chemical', 'MESH:D000077606', (41, 52))
39684	24755886	The results clearly indicated that the macrophage-targeted effect was sufficient to significantly reduce neoplastic growth, under conditions where tumour cells were unresponsive to the drug.	('neoplastic growth', 'CPA', (105, 122))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('reduce', 'NegReg', (98, 104))	('macrophage-targeted', 'Var', (39, 58))	('tumour', 'Disease', (147, 153))
39694	24755886	Also, the high sensitivity of cells that are deficient in HR repair mechanisms suggests that the drug can be particularly effective against breast or ovarian tumours with BRCA1 or BRCA2 mutations.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('BRCA1', 'Gene', (171, 176))	('mutations', 'Var', (186, 195))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('BRCA2', 'Gene', '675', (180, 185))	('BRCA1', 'Gene', '672', (171, 176))	('breast or ovarian tumours', 'Disease', 'MESH:D010051', (140, 165))	('breast or ovarian tumours', 'Disease', (140, 165))	('BRCA2', 'Gene', (180, 185))
39726	32736533	Correlating known genetic aberrations such as copy number variations (CNVs) associated with tumor prognosis and physiological states allows for accurate and reliable assessment of patient outlook.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('copy number variations', 'Var', (46, 68))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('patient', 'Species', '9606', (180, 187))
39781	32736533	IMC Imaging mass cytometry CTCs Circulating tumor cells t-SNE t-Distributed Stochastic Neighbor Embedding PDX Patient-derived xenograft CNV Copy number variations FACS Fluorescence associated cell-sorting FNA Fine needle aspirates CyTOF Cytometry time-of-flight CSV Cell surface vimentin SMA Smooth muscle actin IB - Experimental design, sample preparation, data analysis, manuscript preparation.	('Patient', 'Species', '9606', (110, 117))	('vimentin', 'Gene', (279, 287))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('variations', 'Var', (152, 162))	('vimentin', 'Gene', '7431', (279, 287))	('tumor', 'Disease', (44, 49))
39789	28364003	In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('PS-1001', 'Chemical', '-', (61, 68))	('enhanced', 'PosReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('increased', 'PosReg', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('infiltration of macrophages', 'CPA', (120, 147))	('CIVO', 'Chemical', '-', (5, 9))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', (94, 99))	('doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('rat', 'Species', '10116', (171, 174))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('rat', 'Species', '10116', (126, 129))	('tumors', 'Disease', (53, 59))	('PS-1001', 'Var', (61, 68))
39868	28364003	One hundred twenty-three out of 144 potential injection sites (85%) resulted in identification of micro-injected FTM (Fig.	('micro-injected', 'Var', (98, 112))	('FTM', 'Gene', (113, 116))	('FTM', 'Gene', '23322', (113, 116))
39871	28364003	As observed previously, CIVO-microinjected drugs resulted in spatially localized tumor response zones (generally < 3.0 mm in diameter) with induction of histologic phenotypes specific to the known mechanism(s) of each introduced agent (Fig.	('drugs', 'Var', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CIVO', 'Chemical', '-', (24, 28))	('tumor', 'Disease', (81, 86))
39889	28364003	A potential reason that doxorubicin has historically outperformed other agents in the STS clinic is that exposure to doxorubicin induces changes in the immune microenvironment that result in multiple, potentially coordinated, tumoricidal activities in addition to direct cancer cell-autonomous effects.	('doxorubicin', 'Var', (117, 128))	('STS', 'Phenotype', 'HP:0030448', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('changes', 'Reg', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('doxorubicin', 'Chemical', 'MESH:D004317', (24, 35))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('result in', 'Reg', (181, 190))	('immune microenvironment', 'MPA', (152, 175))	('doxorubicin', 'Chemical', 'MESH:D004317', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('cancer', 'Disease', (271, 277))	('tumor', 'Disease', (226, 231))
39903	28364003	To do so, we used gammaH2AX positivity as a surrogate biomarker of doxorubicin distribution and loss of vimentin-positive cells as a measure of tumor responsiveness.	('tumor', 'Disease', (144, 149))	('vimentin', 'Gene', '7431', (104, 112))	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('vimentin', 'Gene', (104, 112))	('positivity', 'Var', (28, 38))	('gammaH2AX', 'Protein', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('gammaH2AX', 'Chemical', '-', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('loss', 'NegReg', (96, 100))
39904	28364003	By plotting tumor response versus the maximum doxorubicin distribution and applying K-means clustering analysis, patient tumors were classified into three distinct groups: (i) drug sensitive: characterized by high gammaH2AX distribution (mean +- SD: 1.044 +- 0.152 mm) and high vimentin clearance (0.645 +- 0.137 mm), (ii) poor distribution: characterized by low gammaH2AX distribution (0.498 +- 0.154 mm) and low vimentin clearance (0.210 +- 0.092 mm), and (iii) drug resistant: characterized by high gammaH2AX distribution (0.978 +- 0.097 mm) and low vimentin clearance (0.137 +- 0.090 mm; Fig.	('patient', 'Species', '9606', (113, 120))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Disease', (12, 17))	('low', 'NegReg', (359, 362))	('gammaH2AX', 'Chemical', '-', (214, 223))	('gammaH2AX', 'Chemical', '-', (363, 372))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('vimentin', 'Gene', '7431', (414, 422))	('tumor', 'Disease', (121, 126))	('vimentin', 'Gene', (414, 422))	('doxorubicin', 'Chemical', 'MESH:D004317', (46, 57))	('vimentin', 'Gene', '7431', (278, 286))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('vimentin', 'Gene', (278, 286))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('0.978 +-', 'Var', (526, 534))	('gammaH2AX', 'MPA', (363, 372))	('vimentin', 'Gene', '7431', (553, 561))	('low', 'NegReg', (410, 413))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('vimentin', 'Gene', (553, 561))	('tumors', 'Disease', (121, 127))	('gammaH2AX', 'Chemical', '-', (502, 511))
39915	28364003	Consistent with anticipated activity as an autophagy inhibitor, localized microinjection of PS-1001 induced the appearance of LC3-positive puncta, indicative of immature autophagosomes that are unable to fuse with the lysosome (Fig.	('LC3-positive puncta', 'MPA', (126, 145))	('microinjection', 'Var', (74, 88))	('PS-1001', 'Chemical', '-', (92, 99))	('PS-1001', 'Gene', (92, 99))
39919	28364003	Thus, PS-1001 does not appear to affect barriers to doxorubicin penetration, but enhances the antitumor effect of doxorubicin by either neutralizing a cell-autonomous mechanism of STS tumor cell resistance to chemotherapy exposure, or by enhancing a doxorubicin-induced antitumor immune response, or both.	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (274, 279))	('enhancing', 'PosReg', (238, 247))	('STS', 'Phenotype', 'HP:0030448', (180, 183))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('PS-1001', 'Chemical', '-', (6, 13))	('neutralizing', 'NegReg', (136, 148))	('tumor', 'Disease', (184, 189))	('enhances', 'PosReg', (81, 89))	('rat', 'Species', '10116', (69, 72))	('PS-1001', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('doxorubicin', 'Chemical', 'MESH:D004317', (250, 261))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('doxorubicin', 'Chemical', 'MESH:D004317', (52, 63))	('doxorubicin', 'Chemical', 'MESH:D004317', (114, 125))
39925	28364003	However, 2 of 6 doxorubicin-sensitive tumors that received the PS-1001 + doxorubicin combination also exhibited increased macrophage infiltration at sites of drug combination exposure, suggesting that increased cell death is not the only mechanism underlying the impact of PS-1001 on macrophage recruitment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('doxorubicin', 'Chemical', 'MESH:D004317', (16, 27))	('tumors', 'Disease', (38, 44))	('PS-1001', 'Chemical', '-', (273, 280))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('PS-1001', 'Var', (63, 70))	('rat', 'Species', '10116', (139, 142))	('increased macrophage infiltration', 'Phenotype', 'HP:0004311', (112, 145))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('PS-1001', 'Chemical', '-', (63, 70))	('increased', 'PosReg', (112, 121))	('doxorubicin', 'Chemical', 'MESH:D004317', (73, 84))	('macrophage infiltration', 'CPA', (122, 145))
39930	28364003	Consistent with PS-1001 promoting M1 polarization, the localized MAC387-positive infiltrate was highly positive for the M1 biomarker pSTAT1 but devoid of the M2 biomarker c-Maf (Fig.	('STAT1', 'Gene', '6772', (134, 139))	('promoting', 'PosReg', (24, 33))	('c-Maf', 'Gene', '4094', (171, 176))	('MAC387', 'Gene', (65, 71))	('M1 polarization', 'CPA', (34, 49))	('PS-1001', 'Var', (16, 23))	('MAC387', 'Gene', '6280', (65, 71))	('PS-1001', 'Chemical', '-', (16, 23))	('c-Maf', 'Gene', (171, 176))	('STAT1', 'Gene', (134, 139))	('rat', 'Species', '10116', (87, 90))
39932	28364003	In agreement with the CIVO results, and consistent with a direct M1-promoting effect of PS-1001, expression of the M1 markers IL6, iNOS (Nos2), and Socs3 were markedly enhanced, while expression of the M2 markers, Arg1, Ym2, Mrc1, and Socs1 were significantly suppressed in RAW264.7 cells exposed to PS-1001 (Fig.	('PS-1001', 'Chemical', '-', (88, 95))	('RAW264.7', 'CellLine', 'CVCL:0493', (274, 282))	('PS-1001', 'Chemical', '-', (300, 307))	('PS-1001', 'Var', (88, 95))	('IL6', 'Gene', '16193', (126, 129))	('Arg1', 'Gene', '11846', (214, 218))	('expression', 'MPA', (184, 194))	('Ym2', 'Gene', (220, 223))	('Mrc1', 'Gene', '17533', (225, 229))	('PS-1001', 'Var', (300, 307))	('Mrc1', 'Gene', (225, 229))	('iNOS', 'Gene', '18126', (131, 135))	('enhanced', 'PosReg', (168, 176))	('expression', 'MPA', (97, 107))	('Socs1', 'Gene', (235, 240))	('Nos2', 'Gene', '18126', (137, 141))	('Arg1', 'Gene', (214, 218))	('Socs3', 'Gene', '12702', (148, 153))	('Ym2', 'Gene', '104183', (220, 223))	('iNOS', 'Gene', (131, 135))	('CIVO', 'Chemical', '-', (22, 26))	('Nos2', 'Gene', (137, 141))	('Socs1', 'Gene', '12703', (235, 240))	('Socs3', 'Gene', (148, 153))	('IL6', 'Gene', (126, 129))
39937	28364003	Taken together, these data indicate that in concert with doxorubicin, PS-1001 increases macrophage recruitment, skews this population of immune cells toward the antitumorigenic M1 polarization state, and that this proimmunogenic influence correlates with enhanced antitumor activity in a subset of patient tumors identified by CIVO.	('macrophage', 'CPA', (88, 98))	('CIVO', 'Chemical', '-', (327, 331))	('enhanced', 'PosReg', (255, 263))	('PS-1001', 'Chemical', '-', (70, 77))	('tumor', 'Disease', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('PS-1001', 'Var', (70, 77))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('skews', 'Reg', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumors', 'Disease', (306, 312))	('increases', 'PosReg', (78, 87))	('tumor', 'Disease', (165, 170))	('patient', 'Species', '9606', (298, 305))	('tumor', 'Disease', (268, 273))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('doxorubicin', 'Chemical', 'MESH:D004317', (57, 68))
39942	28364003	These responses may be due in part to modulation of the immune microenvironment as the addition of PS-1001 to doxorubicin increased recruitment of myeloid cells and skewed polarization of macrophage toward the proimmunogenic/antitumorigenic M1 state.	('PS-1001', 'Chemical', '-', (99, 106))	('recruitment', 'MPA', (132, 143))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('addition', 'Var', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('PS-1001', 'Gene', (99, 106))	('increased', 'PosReg', (122, 131))	('doxorubicin', 'Chemical', 'MESH:D004317', (110, 121))	('skewed', 'Reg', (165, 171))
39953	28364003	Interestingly, CIVO identified a potential subgroup of tumors where exposure to PS-1001 may provide the most benefit.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('CIVO', 'Chemical', '-', (15, 19))	('PS-1001', 'Var', (80, 87))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('PS-1001', 'Chemical', '-', (80, 87))
40039	25710169	In addition, point mutations that abrogate the ORF57 interaction with REF/Aly support viral replication.	('ORF57', 'Gene', (47, 52))	('point mutations', 'Var', (13, 28))	('Aly', 'Gene', (74, 77))	('support', 'PosReg', (78, 85))	('viral replication', 'CPA', (86, 103))	('Aly', 'Gene', '10189', (74, 77))	('interaction', 'Interaction', (53, 64))	('abrogate', 'NegReg', (34, 42))	('ORF57', 'Gene', '4961525', (47, 52))
40041	25710169	This function was first suggested by the observation that the levels of the polyadenylated nuclear (PAN) RNA is up-regulated by co-expression of ORF57 in transient transfections.	('levels', 'MPA', (62, 68))	('ORF57', 'Gene', '4961525', (145, 150))	('up-regulated', 'PosReg', (112, 124))	('ORF57', 'Gene', (145, 150))	('co-expression', 'Var', (128, 141))
40042	25710169	Direct determination of PAN RNA half-lives further showed increases in PAN RNA levels upon co-expression of ORF57.	('increases', 'PosReg', (58, 67))	('co-expression', 'Var', (91, 104))	('ORF57', 'Gene', '4961525', (108, 113))	('PAN RNA levels', 'MPA', (71, 85))	('ORF57', 'Gene', (108, 113))
40046	25710169	Therefore, the apparent specificity of ORF57 for intronless RNAs may be dictated by their susceptibility to this RNA decay pathway, but this has yet to be formally tested.	('ORF57', 'Gene', (39, 44))	('intronless', 'Var', (49, 59))	('RNA', 'MPA', (113, 116))	('ORF57', 'Gene', '4961525', (39, 44))
40089	25710169	The presence of such mutations within a putative binding site increases confidence that the identified CLIP tags are bona fide binding sites.	('CLIP', 'Gene', '7461', (103, 107))	('CLIP', 'Gene', (103, 107))	('mutations', 'Var', (21, 30))
40090	25710169	We determined whether any classes of mutations were overrepresented in the CLIP tag clusters compared to the input clusters.	('mutations', 'Var', (37, 46))	('overrepresented', 'PosReg', (52, 67))	('CLIP', 'Gene', (75, 79))	('CLIP', 'Gene', '7461', (75, 79))
40091	25710169	Using various criteria, we defined T C transitions and nucleotide deletions to be characteristic to ORF57 crosslinking (see Materials and Methods).	('ORF57', 'Gene', '4961525', (100, 105))	('nucleotide deletions', 'Var', (55, 75))	('ORF57', 'Gene', (100, 105))
40094	25710169	Second, the presence of T C transitions or nucleotide deletions in the CLIP tag clusters provided additional statistical weight, but not all enriched clusters contain mutations.	('CLIP', 'Gene', (71, 75))	('nucleotide deletions', 'Var', (43, 63))	('CLIP', 'Gene', '7461', (71, 75))
40109	25710169	We show other viral enriched clusters mapping to the K10, ORF18, and bicistronic ORF21-ORF22 and K14-vGPCR loci (Fig.	('ORF21-ORF22', 'Gene', (81, 92))	('K14-vGPCR', 'Var', (97, 106))	('K10', 'Gene', '3858', (53, 56))	('K10', 'Gene', (53, 56))
40128	25710169	BTG1 negatively regulates cell proliferation and BTG1 mutations are associated with leukemias.	('BTG1', 'Gene', '694', (49, 53))	('BTG1', 'Gene', (0, 4))	('associated', 'Reg', (68, 78))	('regulates', 'Reg', (16, 25))	('leukemias', 'Phenotype', 'HP:0001909', (84, 93))	('BTG1', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('leukemias', 'Disease', (84, 93))	('leukemias', 'Disease', 'MESH:D007938', (84, 93))	('cell proliferation', 'CPA', (26, 44))	('BTG1', 'Gene', '694', (0, 4))
40198	25710169	In contrast, 15 minutes following induction the presence of ORF57 increases the pre-mRNA and mRNA levels by 2.4 and 1.5-fold, respectively and these changes are not statistically significant (p-value>0.05).	('ORF57', 'Gene', '4961525', (60, 65))	('ORF57', 'Gene', (60, 65))	('presence', 'Var', (48, 56))	('mRNA levels', 'MPA', (93, 104))	('increases', 'PosReg', (66, 75))
40223	25710169	Importantly, ORF57 expression was sufficient to increase the pre-mRNA levels of BTG1, ZFP36, EGR1, as well as EGR1 mRNA, but had little effect on BTG1 or ZFP36 mRNA abundance.	('EGR1', 'Gene', (110, 114))	('ORF57', 'Gene', '4961525', (13, 18))	('ZFP36', 'Gene', '7538', (154, 159))	('BTG1', 'Gene', '694', (146, 150))	('EGR1', 'Gene', (93, 97))	('BTG1', 'Gene', '694', (80, 84))	('ZFP36', 'Gene', (86, 91))	('ORF57', 'Gene', (13, 18))	('expression', 'Var', (19, 29))	('BTG1', 'Gene', (146, 150))	('pre-mRNA levels', 'MPA', (61, 76))	('BTG1', 'Gene', (80, 84))	('ZFP36', 'Gene', '7538', (86, 91))	('EGR1', 'Gene', '1958', (110, 114))	('EGR1', 'Gene', '1958', (93, 97))	('increase', 'PosReg', (48, 56))	('ZFP36', 'Gene', (154, 159))
40285	25710169	8A and 8B), HEK293 cells were transfected in a 12-well plate with a combination of pcDNA3 and pcFl-ORF57II totaling 800 ng.	('ORF57', 'Gene', '4961525', (99, 104))	('ORF57', 'Gene', (99, 104))	('pcDNA3', 'Var', (83, 89))	('HEK293', 'CellLine', 'CVCL:0045', (12, 18))
40297	25710169	Briefly, immunoprecipitated cross-linked RNAs were 5 -end-labeled with PNK and gamma32P-ATP.	('gamma32P-ATP', 'Var', (79, 91))	('gamma32P-ATP', 'Chemical', '-', (79, 91))	('PNK', 'Gene', '8566', (71, 74))	('PNK', 'Gene', (71, 74))
40305	25710169	Deletions and T C mutations were chosen as characteristic RT-induced mutations of ORF57 binding according to comparative analysis of all the 12 types of substitutions, deletions and insertions (see below).	('ORF57', 'Gene', '4961525', (82, 87))	('ORF57', 'Gene', (82, 87))	('deletions', 'Var', (168, 177))	('Deletions', 'Var', (0, 9))
40309	25710169	In order to identify reverse transcription mutations that are characteristic of ORF57 crosslinking sites, we performed several analyses (S7 Fig.).	('ORF57', 'Gene', (80, 85))	('mutations', 'Var', (43, 52))	('ORF57', 'Gene', '4961525', (80, 85))
40312	25710169	In this case, deletion mutations showed the largest increase when we compared pellet to input, but T C and A G mutations have the larger absolute mutation rates in HITS-CLIP samples.	('CLIP', 'Gene', '7461', (169, 173))	('CLIP', 'Gene', (169, 173))	('T C', 'Gene', (99, 102))	('A G mutations', 'Gene', (107, 120))	('deletion mutations', 'Var', (14, 32))
40314	25710169	Based on all of these analyses, we chose deletion and T C mutations as characteristic mutations for the ORF57 protein binding sites.	('deletion', 'Var', (41, 49))	('ORF57', 'Gene', '4961525', (104, 109))	('ORF57', 'Gene', (104, 109))
40329	23110793	Immunohistochemical stains of EZH2, H3K27me3, and Ki-67 were performed on tissue microarrays containing cores from 6 poorly differentiated, 39 monophasic and 10 biphasic synovial sarcomas, and evaluated by pre-established scoring criteria.	('H3K27me3', 'Var', (36, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('EZH2', 'Gene', '2146', (30, 34))	('biphasic synovial sarcomas', 'Disease', 'MESH:D013584', (161, 187))	('EZH2', 'Gene', (30, 34))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (170, 186))	('biphasic synovial sarcomas', 'Disease', (161, 187))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (170, 187))
40334	23110793	Cases with high EZH2 score were characterized by larger tumor size (>= 5cm), distant metastasis, and poor prognosis.	('EZH2', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('distant metastasis', 'CPA', (77, 95))	('high', 'Var', (11, 15))	('EZH2', 'Gene', '2146', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
40338	23110793	Importantly, high EZH2 expression is predictive of developing distant metastasis even in the better-differentiated subtypes.	('developing', 'PosReg', (51, 61))	('high', 'Var', (13, 17))	('EZH2', 'Gene', '2146', (18, 22))	('EZH2', 'Gene', (18, 22))	('distant metastasis', 'CPA', (62, 80))	('expression', 'MPA', (23, 33))
40349	23110793	High expression of EZH2 is generally associated with advanced stages of tumor progression, aggressive tumor behavior, and dismal clinical outcome .	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('associated with', 'Reg', (37, 52))	('High expression', 'Var', (0, 15))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (91, 116))	('tumor', 'Disease', (72, 77))	('aggressive tumor behavior', 'Disease', (91, 116))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('EZH2', 'Gene', '2146', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('EZH2', 'Gene', (19, 23))
40351	23110793	The chromosomal translocation t(X;18)(p11;q11) can be demonstrated in over 95% of cases by fluorescence in situ hybridization (FISH) or real-time PCR (RT-PCR) and produces one of the fusion genes SYT-SSX1, SYT-SSX2 or, rarely, SYT-SSX4 .	('SYT', 'Gene', (227, 230))	('SYT', 'Gene', '6760', (196, 199))	('t(X;18)(p11;q11', 'Var', (30, 45))	('SSX', 'Gene', '6757', (210, 213))	('SYT', 'Gene', '6760', (227, 230))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 46))	('produces', 'Reg', (163, 171))	('SSX', 'Gene', (210, 213))	('SSX2', 'Gene', (210, 214))	('SYT', 'Gene', (206, 209))	('SSX', 'Gene', '6757', (200, 203))	('SSX', 'Gene', '6757', (231, 234))	('SSX2', 'Gene', '6757', (210, 214))	('SSX1', 'Gene', '6756', (200, 204))	('SYT', 'Gene', (196, 199))	('SSX1', 'Gene', (200, 204))	('SSX', 'Gene', (200, 203))	('SSX', 'Gene', (231, 234))	('SYT', 'Gene', '6760', (206, 209))
40355	23110793	Although high EZH2 expression was shown to be generally associated with poor prognosis in soft tissue sarcomas , neither differential expression of EZH2 in the various histological subtypes of synovial sarcoma nor the association of EZH2 with H3K27 trimethylation, tumor behavior, and clinical parameters has been investigated in this particular tumor type.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (90, 110))	('EZH2', 'Gene', '2146', (233, 237))	('synovial sarcoma', 'Disease', 'MESH:D013584', (193, 209))	('EZH2', 'Gene', (233, 237))	('associated', 'Reg', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('tumor behavior', 'Disease', 'MESH:D001523', (265, 279))	('expression', 'MPA', (19, 29))	('tumor', 'Disease', (265, 270))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (193, 209))	('high', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('EZH2', 'Gene', (148, 152))	('EZH2', 'Gene', '2146', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('soft tissue sarcomas', 'Disease', (90, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('tumor behavior', 'Disease', (265, 279))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (90, 110))	('synovial sarcoma', 'Disease', (193, 209))	('tumor', 'Disease', (346, 351))
40383	23110793	There were 35 cases associated with SYT-SSX1 fusion gene and 20 cases with SYT-SSX2.	('SSX1', 'Gene', (40, 44))	('associated', 'Reg', (20, 30))	('SYT', 'Gene', '6760', (75, 78))	('SYT', 'Gene', (75, 78))	('SYT', 'Gene', (36, 39))	('SSX2', 'Gene', '6757', (79, 83))	('SYT', 'Gene', '6760', (36, 39))	('SSX2', 'Gene', (79, 83))	('SSX1', 'Gene', '6756', (40, 44))	('fusion gene', 'Var', (45, 56))
40388	23110793	Furthermore, scores of EZH2 and H3K27me3, but not of Ki-67, were significantly higher in patients with larger tumor size, and all three markers were significantly higher in those with distant metastasis (Table 1).	('distant metastasis', 'CPA', (184, 202))	('H3K27me3', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patients', 'Species', '9606', (89, 97))	('EZH2', 'Gene', '2146', (23, 27))	('higher', 'PosReg', (79, 85))	('higher', 'PosReg', (163, 169))	('EZH2', 'Gene', (23, 27))
40390	23110793	Thus, EZH2 and H3K27me3 may be regarded as auxiliary markers of the poorly differentiated subtype, although the potential of EZH2 and H3K27me3 immunostaining to discriminate between PDSS and the other subtypes was inferior to that of Ki-67 (sensitivities, specificities, and positive predictive values for EZH2: 1.00, 0.82, 0.4; H3K27me3: 1.00, 0.90, 0.54; Ki-67, 1.00, 0.96, 0.75, respectively).	('EZH2', 'Gene', '2146', (6, 10))	('EZH2', 'Gene', (6, 10))	('H3K27me3', 'Var', (134, 142))	('PDSS', 'Disease', (182, 186))	('EZH2', 'Gene', '2146', (306, 310))	('EZH2', 'Gene', '2146', (125, 129))	('EZH2', 'Gene', (125, 129))	('EZH2', 'Gene', (306, 310))
40393	23110793	Kaplan-Meier curves generated by separating patients on the basis of high versus low EZH2 and H3K27me3 scores were similar to the one based on Ki-67 score (Figure 4).	('EZH2', 'Gene', '2146', (85, 89))	('low', 'NegReg', (81, 84))	('patients', 'Species', '9606', (44, 52))	('EZH2', 'Gene', (85, 89))	('H3K27me3 scores', 'Var', (94, 109))
40394	23110793	However, Ki-67 was a superior predictor of tumor-associated death, since the hazard ratios referring to high EZH2, H3K27me3, and Ki-67 expression were 4.48, 5.65, and 6.32, respectively.	('H3K27me3', 'Var', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Ki-67', 'Gene', (129, 134))	('EZH2', 'Gene', '2146', (109, 113))	('tumor', 'Disease', (43, 48))	('EZH2', 'Gene', (109, 113))
40395	23110793	Nevertheless, high EZH2 score also proved to be a valuable predictor of disease outcome, since it was significantly associated with larger tumor size and the presence of distant metastasis.	('distant metastasis', 'CPA', (170, 188))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('high', 'Var', (14, 18))	('EZH2', 'Gene', '2146', (19, 23))	('EZH2', 'Gene', (19, 23))	('associated', 'Reg', (116, 126))
40397	23110793	In contrast, high H3K23me3 failed to show such associations, and high Ki-67 was associated with larger tumor size in all patients only (Table 2) indicating that EZH2 may be useful in the stratification of MPSS and BPSS patients into low and high risk prognostic groups with respect to the likelihood of developing distant metastasis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('EZH2', 'Gene', '2146', (161, 165))	('distant metastasis', 'CPA', (314, 332))	('Ki-67', 'Gene', (70, 75))	('EZH2', 'Gene', (161, 165))	('tumor', 'Disease', (103, 108))	('BPSS', 'Chemical', '-', (214, 218))	('high', 'Var', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('patients', 'Species', '9606', (219, 227))	('H3K23me3', 'Protein', (18, 26))	('patients', 'Species', '9606', (121, 129))
40398	23110793	In our study, high expression of EZH2 was predominantly found in the poorly differentiated histological subtype of synovial sarcoma, which was associated with aggressive clinical behavior.	('associated', 'Reg', (143, 153))	('expression', 'MPA', (19, 29))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (115, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('synovial sarcoma', 'Disease', 'MESH:D013584', (115, 131))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (159, 187))	('high', 'Var', (14, 18))	('EZH2', 'Gene', '2146', (33, 37))	('synovial sarcoma', 'Disease', (115, 131))	('EZH2', 'Gene', (33, 37))	('found', 'Reg', (56, 61))
40405	23110793	Once overexpressed, EZH2 places epigenetic marks that prevent RNA polymerase II-dependent transcriptional elongation and lead to silencing of the downstream genes.	('epigenetic marks', 'Var', (32, 48))	('EZH2', 'Gene', '2146', (20, 24))	('EZH2', 'Gene', (20, 24))	('RNA', 'Protein', (62, 65))	('silencing', 'MPA', (129, 138))	('lead to', 'Reg', (121, 128))	('prevent', 'NegReg', (54, 61))
40407	23110793	H3K27me3 produced by PRC2 is recognized by PRC1 which, in turn, monoubiquitylates lysine 119 of histone H2A.	('PRC2', 'Gene', (21, 25))	('H3K27me3', 'Var', (0, 8))	('lysine', 'Chemical', 'MESH:D008239', (82, 88))	('histone H2A', 'Protein', (96, 107))	('PRC1', 'Gene', (43, 47))	('PRC1', 'Gene', '9055', (43, 47))	('monoubiquitylates lysine 119', 'MPA', (64, 92))
40416	23110793	The activating somatic mutation Y641 of EZH2 leads to high H3K27 trimethylation in lymphomas , and high levels of H3K27me3 consequent to EZH2 hyperactivity have been reported in hepatocellular carcinoma and esophageal squamous cell carcinoma .	('EZH2', 'Gene', (137, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (178, 202))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('hyperactivity', 'Disease', (142, 155))	('lymphomas', 'Disease', 'MESH:D008223', (83, 92))	('lymphomas', 'Phenotype', 'HP:0002665', (83, 92))	('H3K27me3', 'Protein', (114, 122))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (178, 202))	('H3K27', 'Protein', (59, 64))	('esophageal squamous cell carcinoma', 'Disease', (207, 241))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('Y641', 'Var', (32, 36))	('hepatocellular carcinoma', 'Disease', (178, 202))	('hyperactivity', 'Phenotype', 'HP:0000752', (142, 155))	('lymphomas', 'Disease', (83, 92))	('activating', 'PosReg', (4, 14))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (207, 241))	('hyperactivity', 'Disease', 'MESH:D006948', (142, 155))	('EZH2', 'Gene', '2146', (137, 141))
40417	23110793	It is all the more intriguing why in certain tumors, such as carcinomas of the breast, ovary, and pancreas, no clear correlation between EZH2 expression and H3K27 trimethylation was found; rather, quite counterintuitively, both high EZH2 and low H3K27me3 turned out to have adverse prognostic significance .	('H3K27me3', 'Protein', (246, 254))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('EZH2', 'Gene', (137, 141))	('pancreas', 'Disease', (98, 106))	('low', 'Var', (242, 245))	('EZH2', 'Gene', '2146', (233, 237))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('EZH2', 'Gene', (233, 237))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('pancreas', 'Disease', 'MESH:D010190', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('carcinomas', 'Disease', 'MESH:D002277', (61, 71))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (61, 85))	('carcinomas', 'Disease', (61, 71))	('EZH2', 'Gene', '2146', (137, 141))
40421	23110793	Although Ki-67 distinguished more accurately between PDSS and the better-differentiated subtypes, both high EZH2 and high H3K27me3 were preferentially associated with PDSS.	('PDSS', 'Disease', (167, 171))	('PDSS', 'Disease', (53, 57))	('associated with', 'Reg', (151, 166))	('high H3K27me3', 'Var', (117, 130))	('EZH2', 'Gene', (108, 112))	('EZH2', 'Gene', '2146', (108, 112))
40422	23110793	Further, whereas Ki-67 as a well-established prognostic marker in soft tissue sarcomas proved to be a superior predictor of overall survival , high EZH2 status - but not high H3K27me3 or high Ki-67 - was found to be predictive of distant metastasis in the MPSS+BPSS group.	('BPSS', 'Chemical', '-', (261, 265))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (66, 86))	('soft tissue sarcomas', 'Disease', (66, 86))	('high', 'Var', (143, 147))	('distant metastasis', 'CPA', (230, 248))	('EZH2', 'Gene', (148, 152))	('EZH2', 'Gene', '2146', (148, 152))	('MPSS+BPSS', 'Disease', (256, 265))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (66, 86))
40423	23110793	Thus, while not sufficiently specific when applied alone, both EZH2 and H3K27me3 can be used as auxiliary immunohistochemical markers of the poorly differentiated subtype in doubtful cases (e.g., better-differentiated histomorphology coupled with high mitotic rate, or vice versa).	('H3K27me3', 'Var', (72, 80))	('better-differentiated', 'PosReg', (196, 217))	('EZH2', 'Gene', '2146', (63, 67))	('mitotic rate', 'CPA', (252, 264))	('EZH2', 'Gene', (63, 67))
40429	23110793	Successful repression of EZH2 was achieved by small interfering RNA (siRNA) as well as using the small-molecule pharmacologic inhibitor 3-deazaneplanocin A in neuroblastoma cells .	('neuroblastoma', 'Disease', (159, 172))	('EZH2', 'Gene', '2146', (25, 29))	('EZH2', 'Gene', (25, 29))	('3-deazaneplanocin A', 'Chemical', 'MESH:C048460', (136, 155))	('neuroblastoma', 'Phenotype', 'HP:0003006', (159, 172))	('repression', 'NegReg', (11, 21))	('small interfering', 'Var', (46, 63))	('neuroblastoma', 'Disease', 'MESH:D009447', (159, 172))
40431	23110793	Importantly, high EZH2 expression is predictive of developing distant metastasis even in the better-differentiated MPSS and BPSS subtypes.	('BPSS', 'Chemical', '-', (124, 128))	('developing', 'PosReg', (51, 61))	('high', 'Var', (13, 17))	('EZH2', 'Gene', '2146', (18, 22))	('EZH2', 'Gene', (18, 22))	('distant metastasis', 'CPA', (62, 80))	('expression', 'MPA', (23, 33))
40434	23110793	Later, overexpressed EZH2 may become a therapeutic target in synovial sarcoma, especially when inhibited in combination with other pro-oncogenic epigenetic modulators.	('overexpressed', 'Var', (7, 20))	('EZH2', 'Gene', (21, 25))	('EZH2', 'Gene', '2146', (21, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('synovial sarcoma', 'Disease', (61, 77))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (61, 77))	('synovial sarcoma', 'Disease', 'MESH:D013584', (61, 77))
40452	33907565	In recent years, long non-coding RNA (lncRNA) has attracted great attention as a potential diagnostic, prognostic, and predictive biomarkers in the treatment of various cancers.	('cancers', 'Disease', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('long non-coding', 'Var', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
40454	33907565	Accumulating evidence has demonstrated an association between the altered expression of some lncRNAs with various cancer types.	('lncRNAs', 'Gene', (93, 100))	('expression', 'MPA', (74, 84))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('altered', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('association', 'Reg', (42, 53))	('cancer', 'Disease', (114, 120))
40465	33907565	These include SW872 (liposarcoma), HT1080 (fibrosarcoma), SK-LMS-1 (leiomyosarcoma), A204 (rhabdomyosarcoma), RD (rhabdomyosarcoma), ISO-HAS-B (angiosarcoma), HS-sch2 (malignant peripheral nerve sheath tumor, MPNST), FMS-1 (MPNST), SFT8611 (MPNST), SFT9817 (MPNST), YST-1 (MPNST), S462 (NF-1 associated MPNST), HS-SY-II (synovial sarcoma), Yamato-SS (synovial sarcoma), SaOs2 (osteosarcoma), and MG63 (osteosarcoma).	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (91, 107))	('fibrosarcoma', 'Disease', 'MESH:D005354', (43, 55))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (68, 82))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (321, 337))	('synovial sarcoma', 'Disease', (351, 367))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (68, 82))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (91, 107))	('liposarcoma', 'Phenotype', 'HP:0012034', (21, 32))	('ISO-HAS-B', 'Chemical', '-', (133, 142))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (114, 130))	('osteosarcoma', 'Disease', (377, 389))	('fibrosarcoma', 'Disease', (43, 55))	('osteosarcoma', 'Disease', 'MESH:D012516', (377, 389))	('malignant peripheral nerve sheath tumor', 'Disease', (168, 207))	('osteosarcoma', 'Disease', (402, 414))	('synovial sarcoma', 'Disease', 'MESH:D013584', (351, 367))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (114, 130))	('osteosarcoma', 'Disease', 'MESH:D012516', (402, 414))	('liposarcoma', 'Disease', 'MESH:D008080', (21, 32))	('NF-1 associated MPNST', 'Gene', '4763', (287, 308))	('angiosarcoma', 'Disease', 'MESH:D006394', (144, 156))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (58, 66))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (168, 207))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (351, 367))	('angiosarcoma', 'Phenotype', 'HP:0200058', (144, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('SFT9817', 'Var', (249, 256))	('leiomyosarcoma', 'Disease', (68, 82))	('MG63', 'CellLine', 'CVCL:0426', (396, 400))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('HT1080', 'CellLine', 'CVCL:0317', (35, 41))	('angiosarcoma', 'Disease', (144, 156))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('synovial sarcoma', 'Disease', (321, 337))	('SW872', 'CellLine', 'CVCL:1730', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('osteosarcoma', 'Phenotype', 'HP:0002669', (377, 389))	('rhabdomyosarcoma', 'Disease', (91, 107))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (168, 207))	('osteosarcoma', 'Phenotype', 'HP:0002669', (402, 414))	('liposarcoma', 'Disease', (21, 32))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (43, 55))	('synovial sarcoma', 'Disease', 'MESH:D013584', (321, 337))	('HS-SY-II', 'CellLine', 'CVCL:8719', (311, 319))	('rhabdomyosarcoma', 'Disease', (114, 130))	('NF-1 associated MPNST', 'Gene', (287, 308))
40472	33907565	SFT8611 and SFT 9817 were maintained in a DMEM/F12 medium.	('DMEM', 'Chemical', '-', (42, 46))	('F12 medium', 'Chemical', '-', (47, 57))	('SFT 9817', 'Var', (12, 20))	('SFT8611', 'Var', (0, 7))
40493	33907565	We classified the differentially expressed probes between responders and non-responders, either with FC >1.5 or <0.67 (P<0.1), as the lncRNAs that might be related to pazopanib sensitivity.	('related', 'Reg', (156, 163))	('pazopanib', 'Chemical', 'MESH:C516667', (167, 176))	('<0.67', 'Var', (112, 117))
40494	33907565	HS-SY-II and Yamato-SS cells were used in the HAR1B knockdown assay to determine whether alterations in HAR1B expression affected cellular sensitivity to pazopanib treatment.	('HS-SY-II', 'CellLine', 'CVCL:8719', (0, 8))	('HAR1B', 'Gene', '768097', (104, 109))	('HAR1B', 'Gene', '768097', (46, 51))	('pazopanib', 'Chemical', 'MESH:C516667', (154, 163))	('cellular sensitivity to pazopanib treatment', 'MPA', (130, 173))	('affected', 'Reg', (121, 129))	('HAR1B', 'Gene', (104, 109))	('HAR1B', 'Gene', (46, 51))	('alterations', 'Var', (89, 100))
40522	33907565	This level of HAR1B knockdown led to a modest but statistically significant increase in the viability of cells treated with 2-microM pazopanib (69 vs. 59%, P=0.003, Fig.	('increase', 'PosReg', (76, 84))	('HAR1B', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('HAR1B', 'Gene', '768097', (14, 19))	('pazopanib', 'Chemical', 'MESH:C516667', (133, 142))
40523	33907565	In another sensitive cell line Yamato-SS, knockdown of HAR1B also led to a modest but statistically significant increase in the viability of cells treated with 2-microM pazopanib (68 vs. 62%, P=0.005, Fig.	('HAR1B', 'Gene', '768097', (55, 60))	('HAR1B', 'Gene', (55, 60))	('increase', 'PosReg', (112, 120))	('pazopanib', 'Chemical', 'MESH:C516667', (169, 178))	('knockdown', 'Var', (42, 51))
40524	33907565	In contrast, in the pazopanib-resistant cell line SW872, HAR1B knockdown did not affect pazopanib sensitivity (data not shown).	('HAR1B', 'Gene', (57, 62))	('pazopanib sensitivity', 'MPA', (88, 109))	('pazopanib', 'Chemical', 'MESH:C516667', (20, 29))	('HAR1B', 'Gene', '768097', (57, 62))	('SW872', 'CellLine', 'CVCL:1730', (50, 55))	('knockdown', 'Var', (63, 72))	('pazopanib', 'Chemical', 'MESH:C516667', (88, 97))
40534	33907565	We made the following observations: Multiplex qPCR analysis identified 12 lncRNAs that were differentially expressed between pazopanib-sensitive and pazopanib-resistant cells; comprehensive gene and lncRNA expression analyses revealed that HAR1B and HOTAIR were also differentially expressed between responders and non-responders who received pazopanib therapy; we clarified the functional role HAR1B through knockdown by siRNA, which led to an increased pazopanib resistance in sarcoma cell lines; and gene expression profiles related to pazopanib sensitivity include various cellular molecular pathways, including von-Willebrand factor-related signaling.	('HOTAIR', 'Gene', (250, 256))	('pazopanib', 'Chemical', 'MESH:C516667', (455, 464))	('knockdown', 'Var', (409, 418))	('HAR1B', 'Gene', '768097', (395, 400))	('HAR1B', 'Gene', (395, 400))	('von-Willebrand', 'Disease', 'MESH:D014842', (616, 630))	('von-Willebrand', 'Disease', (616, 630))	('pazopanib', 'Chemical', 'MESH:C516667', (343, 352))	('sarcoma', 'Disease', 'MESH:D012509', (479, 486))	('sarcoma', 'Disease', (479, 486))	('HAR1B', 'Gene', '768097', (240, 245))	('pazopanib', 'Chemical', 'MESH:C516667', (539, 548))	('HAR1B', 'Gene', (240, 245))	('pazopanib', 'Chemical', 'MESH:C516667', (125, 134))	('HOTAIR', 'Gene', '100124700', (250, 256))	('pazopanib', 'Chemical', 'MESH:C516667', (149, 158))	('cellular molecular pathways', 'Pathway', (577, 604))	('increased', 'PosReg', (445, 454))	('sarcoma', 'Phenotype', 'HP:0100242', (479, 486))
40539	33907565	We have shown in our study that HAR1B is upregulated in pazopanib-sensitive cells and in responders, and the HAR1B knockdown confers resistance to pazopanib, but the exact mechanisms underlying this altered expression are unknown.	('HAR1B', 'Gene', (109, 114))	('pazopanib', 'Chemical', 'MESH:C516667', (147, 156))	('HAR1B', 'Gene', '768097', (32, 37))	('pazopanib', 'Chemical', 'MESH:C516667', (56, 65))	('upregulated', 'PosReg', (41, 52))	('HAR1B', 'Gene', '768097', (109, 114))	('resistance to pazopanib', 'MPA', (133, 156))	('HAR1B', 'Gene', (32, 37))	('knockdown', 'Var', (115, 124))
40547	33907565	These findings suggest that altered expressions of HAR1A and HAR1B are somehow involved in the tumorigenesis of various cancers, and that their clinical significance depends differentially on cancer type.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('altered', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (120, 126))	('HAR1B', 'Gene', '768097', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('HAR1A', 'Gene', (51, 56))	('involved', 'Reg', (79, 87))	('cancers', 'Disease', (120, 127))	('cancer', 'Disease', (192, 198))	('HAR1A', 'Gene', '768096', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('HAR1B', 'Gene', (61, 66))
40660	31721459	This result indicates that marginal resection might increase the risk of recurrence but not the risk of death.	('recurrence', 'MPA', (73, 83))	('marginal resection', 'Var', (27, 45))	('death', 'Disease', 'MESH:D003643', (104, 109))	('death', 'Disease', (104, 109))
40689	30868512	We reviewed the relevant literature and international guidelines, and, based on the Oslo criteria, proposed the following six definitions for 'tumor rupture': (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; or (6) incisional biopsy.	('ascites', 'Disease', (209, 216))	('tumor', 'Disease', (258, 263))	('intralesional', 'Var', (325, 338))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor fracture', 'Disease', 'MESH:D050723', (163, 177))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	("'tumor rupture", 'Disease', 'MESH:D012421', (142, 156))	('ascites', 'Disease', 'MESH:D001201', (209, 216))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('gastrointestinal perforation', 'Disease', (222, 250))	('tumor fracture', 'Disease', (163, 177))	("'tumor rupture", 'Disease', (142, 156))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('ascites', 'Phenotype', 'HP:0001541', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (143, 148))	('spillage', 'CPA', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
40699	30868512	Although the goal of surgery for localized, resectable disease is a macroscopically complete resection, surgical manipulation with any incision into, or disruption of, the tumor capsule may result in potential dissemination of tumor cells into the peritoneal cavity.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('result in', 'Reg', (190, 199))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', (172, 177))	('dissemination', 'CPA', (210, 223))	('surgical manipulation', 'Var', (104, 125))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
40712	30868512	Tumor rupture may be associated with biological aggressiveness, such as large tumor size, high mitotic count, and KIT exon 11 deletion mutations involving codons 557 and 558.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor rupture', 'Disease', 'MESH:D012421', (0, 13))	('aggressiveness', 'Disease', 'MESH:D001523', (48, 62))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('KIT exon 11', 'Gene', (114, 125))	('aggressiveness', 'Disease', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('deletion mutations', 'Var', (126, 144))	('Tumor rupture', 'Disease', (0, 13))	('tumor', 'Disease', (78, 83))	('aggressiveness', 'Phenotype', 'HP:0000718', (48, 62))
40751	30868512	Preoperative genotyping can also be considered in certain patients since gastric GISTs harboring a KIT exon 11 deletion involving codon 557 or 558 have increased risk of rupture (and could benefit from imatinib neoadjuvant treatment under appropriate circumstances).	('GISTs', 'Phenotype', 'HP:0100723', (81, 86))	('codon 557 or 558', 'Var', (130, 146))	('rupture', 'CPA', (170, 177))	('benefit', 'Reg', (189, 196))	('KIT exon 11', 'Gene', (99, 110))	('patients', 'Species', '9606', (58, 66))	('imatinib', 'Chemical', 'MESH:D000068877', (202, 210))
40776	26846095	We present an unusual case of retro-orbital myeloid sarcoma as an initial presentation of acute myeloid leukemia in a 43-year-old Caucasian man, with rearrangement of chromosome 11q23 involving the MLL gene.	('retro-orbital myeloid sarcoma', 'Disease', 'MESH:D023981', (30, 59))	('rearrangement', 'Var', (150, 163))	('MLL', 'Gene', (198, 201))	('retro-orbital myeloid sarcoma', 'Disease', (30, 59))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (90, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('man', 'Species', '9606', (140, 143))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (90, 112))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (96, 112))	('acute myeloid leukemia', 'Disease', (90, 112))	('MLL', 'Gene', '4297', (198, 201))
40777	26846095	We present an unusual case of retro-orbital myeloid sarcoma as an initial presentation of acute myeloid leukemia in a 43-year-old man, with rearrangement of chromosome 11q23 involving the MLL gene.	('retro-orbital myeloid sarcoma', 'Disease', 'MESH:D023981', (30, 59))	('MLL', 'Gene', (188, 191))	('retro-orbital myeloid sarcoma', 'Disease', (30, 59))	('rearrangement', 'Var', (140, 153))	('MLL', 'Gene', '4297', (188, 191))	('man', 'Species', '9606', (130, 133))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (90, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (90, 112))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (96, 112))	('acute myeloid leukemia', 'Disease', (90, 112))
40801	26846095	A cytogenetic study using florescent in situ hybridization analysis revealed a rearrangement of chromosome 11q23 involving the MLL gene.	('MLL', 'Gene', '4297', (127, 130))	('rearrangement', 'Var', (79, 92))	('MLL', 'Gene', (127, 130))
40812	26846095	While several variants of AML have few or no cells of granulocytic lineage, the broader term "myeloid sarcoma" is currently preferred.	('AML', 'Disease', 'MESH:D015470', (26, 29))	('variants', 'Var', (14, 22))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (94, 109))	('AML', 'Phenotype', 'HP:0004808', (26, 29))	('AML', 'Disease', (26, 29))	('myeloid sarcoma', 'Disease', (94, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
40813	26846095	MSs are most common in certain subtypes of AML, particularly M5a (monoblastic), M5b (monocytic), M4 (myelomonocytic), and M2 (myeloblastic with maturation).	('M5b', 'Var', (80, 83))	('AML', 'Disease', 'MESH:D015470', (43, 46))	('M5a', 'Disease', (61, 64))	('AML', 'Phenotype', 'HP:0004808', (43, 46))	('AML', 'Disease', (43, 46))	('common', 'Reg', (13, 19))
40820	26846095	To the best of our knowledge, since 1993 a total of 11 cases of GS preceding AML in adults have been reported, most of them presenting with the cytogenic t(8:21) translocation and a fair prognosis.	('AML', 'Disease', 'MESH:D015470', (77, 80))	('AML', 'Disease', (77, 80))	('t(8:21) translocation', 'Var', (154, 175))	('GS', 'Disease', 'MESH:D011125', (64, 66))	('AML', 'Phenotype', 'HP:0004808', (77, 80))	('presenting with', 'Reg', (124, 139))
40821	26846095	In the present report, we describe a very aggressive case of AML positive for CD34 and CD117 and a rearrangement of chromosome 11q23 involving the MLL gene that resulted in death.	('MLL', 'Gene', (147, 150))	('rearrangement', 'Var', (99, 112))	('CD34', 'Gene', (78, 82))	('CD117', 'Gene', '3815', (87, 92))	('MLL', 'Gene', '4297', (147, 150))	('AML', 'Disease', 'MESH:D015470', (61, 64))	('CD117', 'Gene', (87, 92))	('CD34', 'Species', '1151260', (78, 82))	('AML', 'Disease', (61, 64))	('death', 'Disease', 'MESH:D003643', (173, 178))	('AML', 'Phenotype', 'HP:0004808', (61, 64))	('death', 'Disease', (173, 178))
40830	26846095	The present case is noteworthy because we describe a very aggressive case of AML with rearrangement of chromosome 11q23 involving the MLL gene that resulted in death.	('death', 'Disease', 'MESH:D003643', (160, 165))	('death', 'Disease', (160, 165))	('AML', 'Disease', 'MESH:D015470', (77, 80))	('MLL', 'Gene', (134, 137))	('MLL', 'Gene', '4297', (134, 137))	('AML', 'Disease', (77, 80))	('rearrangement', 'Var', (86, 99))	('AML', 'Phenotype', 'HP:0004808', (77, 80))
40889	23738095	Microchips have been shown to elicit sarcomas in mice.	('elicit', 'Reg', (30, 36))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('mice', 'Species', '10090', (49, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('Microchips', 'Var', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcomas', 'Disease', (37, 45))
40916	23738095	In these cancers, chromosomal damage and mutations, including mutations in the p53 suppressor gene have been found, and these may be due to oxygen radicals persistently produced by the cells characteristic of chronic inflammation, notably by macrophages, neutrophils, and eosinophils.	('mutations', 'Var', (41, 50))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('due', 'Reg', (133, 136))	('chromosomal damage', 'Disease', 'MESH:D004194', (18, 36))	('chromosomal damage', 'Disease', (18, 36))	('chronic inflammation', 'Disease', 'MESH:D007249', (209, 229))	('chronic inflammation', 'Disease', (209, 229))	('oxygen radicals', 'Chemical', 'MESH:D017382', (140, 155))	('p53 suppressor', 'Gene', (79, 93))	('mutations', 'Var', (62, 71))
40933	23738095	In human cancers, there is a high rate of mutations in the p53 gene and inactivation of p53 thus facilitates tumorigenesis in humans and in animals.	('p53', 'Gene', (59, 62))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('human', 'Species', '9606', (126, 131))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('humans', 'Species', '9606', (126, 132))	('p53', 'Gene', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('inactivation', 'Var', (72, 84))	('facilitates', 'PosReg', (97, 108))	('rat', 'Species', '10116', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (109, 114))
40934	23738095	In human skin carcinogenesis, inactivation of the p53 gene and the onset of genomic instability are the earliest events in the process.	('inactivation', 'Var', (30, 42))	('genomic instability', 'CPA', (76, 95))	('human', 'Species', '9606', (3, 8))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (9, 28))	('p53', 'Gene', (50, 53))	('skin carcinogenesis', 'Disease', (9, 28))
40948	23738095	Interestingly, microchips resulted in sarcomas at the site of microchip implantation in heterozygous p53+/- mice; this was associated with increased oxidative and nitrative stress.	('resulted in', 'Reg', (26, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('rat', 'Species', '10116', (166, 169))	('oxidative and nitrative stress', 'Phenotype', 'HP:0025464', (149, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('increased', 'PosReg', (139, 148))	('sarcomas', 'Disease', (38, 46))	('mice', 'Species', '10090', (108, 112))	('sarcomas', 'Disease', 'MESH:D012509', (38, 46))	('microchips', 'Var', (15, 25))
40950	23738095	Loss of p53 heterozygosity and loss of p53 function has been observed in Trp53+/- mice implanted with subcutaneous plastic plates.	('mice', 'Species', '10090', (82, 86))	('function', 'MPA', (43, 51))	('loss', 'NegReg', (31, 35))	('p53', 'Protein', (8, 11))	('Trp53', 'Gene', (73, 78))	('Loss', 'NegReg', (0, 4))	('p53', 'Gene', (39, 42))	('Trp53', 'Gene', '22059', (73, 78))	('heterozygosity', 'Var', (12, 26))
40956	23738095	Mutations of p53 have been found in some feline and canine soft-tissue sarcomas.	('Mutations', 'Var', (0, 9))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (59, 79))	('sarcomas', 'Disease', 'MESH:D012509', (71, 79))	('p53', 'Gene', (13, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('found', 'Reg', (27, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('canine', 'Species', '9615', (52, 58))	('sarcomas', 'Disease', (71, 79))
40957	23738095	Nanosized titanium dioxide has been shown to be cytotoxic to PC12 cells (derived from rat adrenal medulla pheochromocytoma) and results in oxidative stress, probably through the accumulation of reactive oxygen species, and apoptosis, a situation which may mimic the effects of vaccine adjuvants in vivo.	('results in', 'Reg', (128, 138))	('titanium dioxide', 'Chemical', 'MESH:C009495', (10, 26))	('oxidative stress', 'Phenotype', 'HP:0025464', (139, 155))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (194, 217))	('PC12', 'CellLine', 'CVCL:0481', (61, 65))	('oxidative stress', 'MPA', (139, 155))	('pheochromocytoma', 'Disease', (106, 122))	('apoptosis', 'CPA', (223, 232))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (106, 122))	('pheochromocytoma', 'Disease', 'MESH:D010673', (106, 122))	('rat', 'Species', '10116', (86, 89))	('adrenal medulla pheochromocytoma', 'Phenotype', 'HP:0006748', (90, 122))	('accumulation', 'PosReg', (178, 190))	('Nanosized', 'Var', (0, 9))
40975	32728828	For this special issue on Mutant KRAS: Hidden Secrets in Tumor Progression, the Guest Editor, Jozsef Timar, asked me to write a retrospective piece on the important contributions to RAS research by my proteges, Chris Marshall and Alan Hall, who have sadly predeceased me.	('Tumor', 'Phenotype', 'HP:0002664', (57, 62))	('KRAS', 'Gene', '3845', (33, 37))	('KRAS', 'Gene', (33, 37))	('Mutant', 'Var', (26, 32))
40981	32728828	The transformation of cells in culture by RSV was found to be due to the prototypic oncogene, src, which, while not contributing to viral replication, proved to be essential for cell transformation.	('RSV', 'Var', (42, 45))	('RSV', 'Species', '11886', (42, 45))	('src', 'Gene', '6714', (94, 97))	('src', 'Gene', (94, 97))
40993	32728828	Ki-MSV evolved by mutation and complex recombination events of c-ras in rats with endogenous retroviral elements in rats and with the exogenous MLV.	('rats', 'Species', '10116', (116, 120))	('MLV', 'Species', '11786', (144, 147))	('c-ras', 'Protein', (63, 68))	('rats', 'Species', '10116', (72, 76))	('MSV', 'Species', '11809', (3, 6))	('mutation', 'Var', (18, 26))
41013	32728828	Then, if one of the millions of retinoblasts developed a somatic mutation in the wild-type allele, no functional Rb1 protein would be expressed, and a clonal tumor developed from that mutant cell.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutant', 'Var', (184, 190))	('developed', 'Reg', (164, 173))	('Rb1', 'Gene', (113, 116))	('protein', 'Protein', (117, 124))	('mutation', 'Var', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Rb1', 'Gene', '5925', (113, 116))
41017	32728828	It was observed by David Lane and Lionel Crawford, and by Daniel Linzer and Arnie Levine, that immunoprecipitation of the oncogene product of SV40, large T (tumor) antigen, co-precipitated a cellular protein of 53,000-54,000 Da, now known as TSp53.	('tumor', 'Disease', (157, 162))	('SV40', 'Var', (142, 146))	('p53', 'Gene', (244, 247))	('p53', 'Gene', '7157', (244, 247))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('SV40', 'Species', '1891767', (142, 146))
41018	32728828	The TSp53 protein was not merely a contaminant of the precipitates and gels, but was specifically bound to large T. It was found that large T blocks TSp53 function, just as somatic mutations in TSp53, can contribute to malignant transformation, thus preventing TSp53 to act as what Lane dubbed the "Guardian of the genome".	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('contribute', 'Reg', (205, 215))	('malignant transformation', 'CPA', (219, 243))	('p53', 'Gene', '7157', (151, 154))	('p53', 'Gene', (263, 266))	('function', 'MPA', (155, 163))	('large T blocks', 'Var', (134, 148))	('preventing', 'NegReg', (250, 260))	('p53', 'Gene', '7157', (263, 266))	('p53', 'Gene', '7157', (196, 199))	('p53', 'Gene', (151, 154))	('p53', 'Gene', (196, 199))
41020	32728828	Not only does polyoma large T abrogate TSp53 function but also E1B of adenovirus, E6 of cervical human papilloma viruses and latent nuclear antigen of Kaposi's sarcoma virus.	('s sarcoma virus', 'Species', '11970', (158, 173))	('p53', 'Gene', '7157', (41, 44))	('papilloma viruses', 'Disease', 'MESH:D010212', (103, 120))	('papilloma viruses', 'Disease', (103, 120))	('function', 'MPA', (45, 53))	('human', 'Species', '9606', (97, 102))	('p53', 'Gene', (41, 44))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (151, 167))	('abrogate', 'NegReg', (30, 38))	('polyoma', 'Disease', (14, 21))	('papilloma', 'Phenotype', 'HP:0012740', (103, 112))	('polyoma', 'Disease', 'None', (14, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('adenovirus', 'Species', '10508', (70, 80))	('E1B', 'Var', (63, 66))
41028	32728828	Meanwhile, I gained a grant to search for oncogenes in human tumors by DNA transfection, which had not yet been reported by other research groups.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('transfection', 'Var', (75, 87))	('human', 'Species', '9606', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('DNA transfection', 'Var', (71, 87))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
41043	32728828	Somatic mutations, particularly in and around amino-acid residues 12 and 61, prevent degradation by GTP hydrolysis, and therefore, RAS becomes locked into a constitutively active signaling state.	('prevent', 'NegReg', (77, 84))	('GTP', 'Chemical', 'MESH:D006160', (100, 103))	('mutations', 'Var', (8, 17))	('GTP hydrolysis', 'MPA', (100, 114))	('degradation', 'MPA', (85, 96))
41235	30717777	The results of blood coagulation analysis of the third day after surgery was significantly improved over preoperative results: prothrombin time (12.8 s), prothrombin activity (78%), fibrinogen (400 mg/dL), D-dimmer (835 ng/ml).	('prothrombin', 'Gene', '2147', (127, 138))	('improved', 'PosReg', (91, 99))	('prothrombin', 'Gene', (127, 138))	('D-dimmer', 'MPA', (206, 214))	('fibrinogen', 'Gene', '2244', (182, 192))	('blood coagulation', 'Disease', 'MESH:D001778', (15, 32))	('fibrinogen', 'Gene', (182, 192))	('blood coagulation', 'Disease', (15, 32))	('prothrombin', 'Gene', (154, 165))	('400 mg/dL', 'Var', (194, 203))	('prothrombin', 'Gene', '2147', (154, 165))
41384	29881584	Some authors have used a diagnostic algorithm based on patient age, LDH levels, endometrial cytological findings, and MRI to determine if morcellation is appropriate;53, 54, 55 however, others in a meta-analysis have indicated that morcellation increases the overall and intra-abdominal recurrence rate as well as death rate in uterine leiomyosarcomas 49.	('leiomyosarcomas 49', 'Disease', (336, 354))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (328, 351))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (336, 351))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (328, 350))	('death', 'CPA', (314, 319))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (336, 350))	('sarcoma', 'Phenotype', 'HP:0100242', (343, 350))	('increases', 'PosReg', (245, 254))	('morcellation', 'Var', (232, 244))	('patient', 'Species', '9606', (55, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (343, 351))	('leiomyosarcomas 49', 'Disease', 'MESH:D007890', (336, 354))
41407	29881584	All procedures were performed at major cancer centers by experienced gynecologic oncologists; however, it should be kept in mind that the gynecologic oncology group (GOG) defines optimal cytoreduction as <10 mm 75, while surgical oncologist considers <2.5 mm as the optimal goal for completeness of cytoreduction 76.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('oncology', 'Phenotype', 'HP:0002664', (150, 158))	('<10 mm', 'Var', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
41495	26298731	Experimental models in mice have shown that loss of PTEN and INK4A/ARF results in histiocytic sarcoma.	('histiocytic sarcoma', 'Disease', (82, 101))	('INK4A/ARF', 'Gene', (61, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('INK4A/ARF', 'Gene', '12578', (61, 70))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (82, 101))	('loss', 'Var', (44, 48))	('mice', 'Species', '10090', (23, 27))	('PTEN', 'Protein', (52, 56))
41496	26298731	Interestingly, genomic sequencing studies of Langerhans cell histiocytosis, which is a histiocytic neoplasm that arises from a specialised dendritic cell known as the Langerhans cell, has revealed mutually exclusive driving mutations of BRAF V600E and MAP2K1 mutations that implicate MAP kinase signalling cascade in the pathogenesis of this disorder.	('neoplasm', 'Phenotype', 'HP:0002664', (99, 107))	('V600E', 'Mutation', 'rs113488022', (242, 247))	('MAP2K1', 'Gene', '5604', (252, 258))	('neoplasm', 'Disease', 'MESH:D009369', (99, 107))	('V600E', 'Var', (242, 247))	('MAP2K1', 'Gene', (252, 258))	('histiocytosis', 'Phenotype', 'HP:0100727', (61, 74))	('BRAF', 'Gene', '673', (237, 241))	('neoplasm', 'Disease', (99, 107))	('BRAF', 'Gene', (237, 241))
41497	26298731	Furthermore, genomic sequencing studies of Erdheim-Chester disease, a non-Langerhans cell histiocytic (LCH) neoplasm of monocyte/macrophage origin, has demonstrated mutations in BRAF V600E and NRAS, which can activate the MAP kinase pathway.	('mutations', 'Var', (165, 174))	('NRAS', 'Gene', (193, 197))	('BRAF', 'Gene', '673', (178, 182))	('neoplasm', 'Disease', (108, 116))	('V600E', 'Mutation', 'rs113488022', (183, 188))	('neoplasm', 'Phenotype', 'HP:0002664', (108, 116))	('activate', 'PosReg', (209, 217))	('NRAS', 'Gene', '4893', (193, 197))	('neoplasm', 'Disease', 'MESH:D009369', (108, 116))	('BRAF', 'Gene', (178, 182))	('Erdheim-Chester disease', 'Disease', 'MESH:D031249', (43, 66))	('Erdheim-Chester disease', 'Disease', (43, 66))	('MAP kinase pathway', 'Pathway', (222, 240))
41617	21559205	This theory was supported by molecular studies of giant cell tumors of pancreas and liver showing the same K-ras mutations in the tumor cells and their precursor lesions.	('K-ras', 'Gene', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumors of pancreas', 'Phenotype', 'HP:0002894', (61, 79))	('giant cell tumor', 'Phenotype', 'HP:0011847', (50, 66))	('mutations', 'Var', (113, 122))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('giant cell tumors of pancreas', 'Disease', 'MESH:D005870', (50, 79))	('K-ras', 'Gene', '16653', (107, 112))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (61, 66))	('giant cell tumors', 'Phenotype', 'HP:0011847', (50, 67))	('giant cell tumors of pancreas', 'Disease', (50, 79))
41633	21559205	The negativity of CD117 (c-kit) also ruled out the possibility of malignant gastrointestinal stromal tumor with osteoclast-like giant cells.	('CD117', 'Gene', (18, 23))	('malignant gastrointestinal stromal tumor', 'Disease', (66, 106))	('c-kit', 'Gene', (25, 30))	('ruled', 'Reg', (37, 42))	('c-kit', 'Gene', '16590', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (76, 106))	('negativity', 'Var', (4, 14))	('malignant gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (66, 106))	('CD117', 'Gene', '16590', (18, 23))
41638	21559205	To the best of our knowledge, this is the first report of a case showing an undifferentiated endometrial sarcoma with nuclear pleomorphism associated with presence of osteoclast-like giant cells and no true osteochondromatous differentiation, which further expands the spectrum of this rare uterine neoplasms.	('endometrial sarcoma', 'Disease', 'MESH:D018203', (93, 112))	('neoplasm', 'Phenotype', 'HP:0002664', (299, 307))	('neoplasms', 'Disease', 'MESH:D009369', (299, 308))	('osteochondromatous differentiation', 'Disease', (207, 241))	('endometrial sarcoma', 'Disease', (93, 112))	('neoplasms', 'Disease', (299, 308))	('nuclear pleomorphism', 'Var', (118, 138))	('associated', 'Reg', (139, 149))	('uterine neoplasm', 'Phenotype', 'HP:0010784', (291, 307))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('uterine neoplasms', 'Phenotype', 'HP:0010784', (291, 308))	('osteochondromatous differentiation', 'Phenotype', 'HP:0030431', (207, 241))	('neoplasms', 'Phenotype', 'HP:0002664', (299, 308))	('osteochondromatous differentiation', 'Disease', 'MESH:D012734', (207, 241))	('osteoclast-like giant cells', 'CPA', (167, 194))
41648	33510813	A significant association was also found between the number of M-MDSCs and progression-free survival (PFS) time in patients with metastasis.	('M-MDSCs', 'Var', (63, 70))	('patients', 'Species', '9606', (115, 123))	('progression-free survival', 'CPA', (75, 100))
41667	33510813	Previous studies have shown higher quantities of MDSCs to be associated with poor outcomes in patients with certain solid tumors, such as colon cancer, melanoma, hepatocellular carcinoma and breast cancer.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('colon cancer', 'Disease', (138, 150))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('patients', 'Species', '9606', (94, 102))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (162, 186))	('MDSCs', 'Var', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (138, 150))	('colon cancer', 'Disease', 'MESH:D015179', (138, 150))	('associated', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))	('melanoma, hepatocellular carcinoma and breast cancer', 'Disease', 'MESH:D001943', (152, 204))
41724	33510813	The data indicated that the number of M-MDSC, NKG2D+ CD8+ T cells and Tim-3+ CD8+ T cells was significantly associated with DFS based on the Kaplan-Meier method and the comparisons performed using the log-rank test (Fig.	('CD8', 'Gene', (77, 80))	('CD8', 'Gene', (53, 56))	('CD8', 'Gene', '925', (77, 80))	('M-MDSC', 'Var', (38, 44))	('NKG2D', 'Gene', '22914', (46, 51))	('CD8', 'Gene', '925', (53, 56))	('Tim-3', 'Gene', (70, 75))	('NKG2D', 'Gene', (46, 51))	('associated', 'Reg', (108, 118))	('Tim-3', 'Gene', '84868', (70, 75))	('DFS', 'Disease', (124, 127))
41725	33510813	High numbers of M-MDSC and Tim-3+ CD8+ T cells were significantly associated with poor DFS times (P=0.04 and 0.02, respectively), while high levels of NKG2D+ CD8+ T cells were significantly associated with longer DFS times (P=0.04).	('NKG2D', 'Gene', '22914', (151, 156))	('DFS times', 'MPA', (87, 96))	('CD8', 'Gene', (158, 161))	('Tim-3', 'Gene', (27, 32))	('CD8', 'Gene', (34, 37))	('CD8', 'Gene', '925', (158, 161))	('Tim-3', 'Gene', '84868', (27, 32))	('NKG2D', 'Gene', (151, 156))	('poor', 'NegReg', (82, 86))	('CD8', 'Gene', '925', (34, 37))	('M-MDSC', 'Var', (16, 22))
41733	33510813	A higher number of M-MDSCs and Tim-3+ CD8+ T cells was significantly associated with poor DFS times, while a higher number of NKG2D+ CD8+ T cells was significantly associated with longer DFS times.	('NKG2D', 'Gene', (126, 131))	('M-MDSCs', 'Var', (19, 26))	('CD8', 'Gene', (133, 136))	('CD8', 'Gene', '925', (133, 136))	('Tim-3', 'Gene', (31, 36))	('DFS times', 'MPA', (90, 99))	('CD8', 'Gene', (38, 41))	('Tim-3', 'Gene', '84868', (31, 36))	('CD8', 'Gene', '925', (38, 41))	('NKG2D', 'Gene', '22914', (126, 131))
41735	33510813	In previous studies, high quantities of M-MDSCs in peripheral blood samples were identified as a poor prognostic factor for various types of cancer, such as melanoma, hepatocellular carcinoma, colorectal cancer and non-small cell lung cancer.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('colorectal cancer', 'Disease', 'MESH:D015179', (193, 210))	('hepatocellular carcinoma', 'Disease', (167, 191))	('colorectal cancer', 'Disease', (193, 210))	('M-MDSCs', 'Var', (40, 47))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (215, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (167, 191))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('non-small cell lung cancer', 'Disease', (215, 241))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (167, 191))	('colorectal cancer', 'Phenotype', 'HP:0003003', (193, 210))	('cancer', 'Disease', (235, 241))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (219, 241))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (215, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
41782	31514752	Both high- and low-grade ESS demonstrated T2 hypointense bands, marginal nodules, intratumoral nodules, and worm-like intra-myometrial nodules, and their tumor apparent diffusion coefficient (ADC) values were significantly lower than those of T2-hyperintense leiomyomas (P < .001).	('leiomyomas', 'Disease', 'MESH:D007889', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('lower', 'NegReg', (223, 228))	('tumor', 'Disease', (87, 92))	('leiomyomas', 'Disease', (259, 269))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumoral', 'Disease', 'MESH:D009369', (87, 94))	('tumoral', 'Disease', (87, 94))	('T2 hypointense', 'Var', (42, 56))	('tumor', 'Disease', (154, 159))
41848	30889380	We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('USARC', 'Disease', (78, 83))	('tumor', 'Disease', (84, 89))	('whole genome duplication', 'Var', (14, 38))
41853	30889380	They identify tumors with high mutation burdens, which are enriched for activation of immune pathways and have good prognoses, and deduce four tumorigenic routes, all of which begin with driver mutations before whole genome duplication.	('activation', 'PosReg', (72, 82))	('tumor', 'Disease', (14, 19))	('immune pathways', 'Pathway', (86, 101))	('tumor', 'Disease', (143, 148))	('mutation burdens', 'Var', (31, 47))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
41863	30889380	The ability to probe this complexity is important because genomic instability is a key catalyst in cancer evolution, fuels tumor heterogeneity, and is relevant therapeutically.	('tumor', 'Disease', (123, 128))	('genomic instability', 'Var', (58, 77))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
41875	30889380	Of the 45 tumors demonstrating 15,000 or fewer SNV/indel mutations across the genome, 33 patients harbored 100 or more rearrangements per tumor (mutLo-rearrHi group).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('rearrangements', 'MPA', (119, 133))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (10, 15))	('tumors', 'Disease', (10, 16))	('SNV/indel mutations', 'Var', (47, 66))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
41878	30889380	We found somatic driver SNVs within MSH2 in two cases (PD26873a and PD26876a), both with somatic copy-number loss of the wild-type allele (Table S1).	('PD26876a', 'Var', (68, 76))	('MSH2', 'Gene', (36, 40))	('PD26873a', 'Chemical', '-', (55, 63))	('MSH2', 'Gene', '4436', (36, 40))
41879	30889380	However, we also observed aberrations in MSH2, including promoter methylation (PD26868a; Figure S2A) and a predicted disruptive translocation on the forward strand in intron two associated with loss of heterozygosity (LOH) (PD26866a Figure S2B).	('disruptive', 'NegReg', (117, 127))	('PD26868a', 'Var', (79, 87))	('MSH2', 'Gene', (41, 45))	('MSH2', 'Gene', '4436', (41, 45))	('promoter methylation', 'MPA', (57, 77))	('PD26866a', 'Var', (224, 232))	('loss of', 'NegReg', (194, 201))
41880	30889380	A fifth patient (PD31196a) was found to have a pathogenic germline mutation in MSH6 (p.V878A) with somatic loss of the wild-type allele in the tumor.	('p.V878A', 'Var', (85, 92))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('MSH6', 'Gene', '2956', (79, 83))	('pathogenic', 'Reg', (47, 57))	('patient', 'Species', '9606', (8, 15))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('p.V878A', 'Mutation', 'rs2020912', (85, 92))	('MSH6', 'Gene', (79, 83))
41882	30889380	Sample PD31203a showed a mutational signature (signature 30) that strongly matched the base excision repair NTHL1 deficiency pattern (Figure S2E), previously only seen in a breast cancer and an osteosarcoma.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('osteosarcoma', 'Disease', 'MESH:D012516', (194, 206))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('osteosarcoma', 'Phenotype', 'HP:0002669', (194, 206))	('NTHL1', 'Gene', '4913', (108, 113))	('osteosarcoma', 'Disease', (194, 206))	('PD31203a', 'Var', (7, 15))	('NTHL1', 'Gene', (108, 113))	('breast cancer', 'Disease', (173, 186))
41883	30889380	A rare pathogenic germline heterozygous nonsense mutation of NTHL1 (pQ90*) with somatic loss of the wild-type allele was confirmed in this patient.	('NTHL1', 'Gene', (61, 66))	('NTHL1', 'Gene', '4913', (61, 66))	('pQ90*', 'Var', (68, 73))	('pathogenic', 'Reg', (7, 17))	('patient', 'Species', '9606', (139, 146))
41884	30889380	Finally, PD26882a showed more than 28,000 mutations with strong activity of signature 1 with almost pure C > T transitions in a CpG context, likely caused by spontaneous deamination of methylated cytosines.	('mutations', 'Var', (42, 51))	('activity', 'MPA', (64, 72))	('signature 1', 'Gene', (76, 87))	('cytosines', 'Chemical', 'MESH:D003596', (196, 205))
41886	30889380	This was confirmed by the discovery of biallelic inactivation of the DNA glycosylase gene MBD4 (Figure S2F).	('MBD4', 'Gene', (90, 94))	('MBD4', 'Gene', '8930', (90, 94))	('biallelic inactivation', 'Var', (39, 61))
41888	30889380	To the best of our knowledge, this is the first description of defective MBD4-associated DNA repair in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('defective', 'Var', (63, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Disease', (103, 111))	('MBD4', 'Gene', '8930', (73, 77))	('MBD4', 'Gene', (73, 77))
41892	30889380	We identified 51 recurrently rearranged genes, 9 of which are known tumor suppressor genes (Table S1).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('rearranged', 'Var', (29, 39))
41895	30889380	These data suggest that chromothripsis is an infrequent mechanism of TP53 disruption in USARCs and that inactivation of tumor suppressor genes rather than activation of oncogenes is the sine qua non of the USARC rearrangement phenotype.	('chromothripsis', 'Disease', (24, 38))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('disruption', 'Var', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
41898	30889380	By overlapping the genomic positions of the boundaries of structural breakpoints with the dbSUPER database of 91 human and mouse tissue types, we identified that of the 13 rearrangements (8 translocations, 4 inversions, and 1 tandem-duplication; 7 downstream, 5 upstream, and 1 within TERT) within 100 kb of TERT, 8 rearrangements have a partner region that directly overlaps or is within 500 kb of a super enhancer in all tissues or muscle tissues only.	('rearrangements', 'Var', (172, 186))	('mouse', 'Species', '10090', (123, 128))	('translocations', 'Var', (190, 204))	('human', 'Species', '9606', (113, 118))
41899	30889380	We also found evidence for increased telomere length (tumor:normal ratio) in the majority of samples and disruption in either ATRX or DAXX or in the TERT promoter (Figures S3D and S3E).	('increased telomere length', 'Phenotype', 'HP:0031413', (27, 52))	('increased', 'PosReg', (27, 36))	('disruption', 'Var', (105, 115))	('DAXX', 'Gene', (134, 138))	('ATRX', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ATRX', 'Gene', '546', (126, 130))	('tumor', 'Disease', (54, 59))	('DAXX', 'Gene', '1616', (134, 138))	('telomere length', 'CPA', (37, 52))
41905	30889380	MEN1 mutations have not previously been reported in sarcomas and have been described only occasionally in benign smooth muscle tumors and rarely in lipomas.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('muscle tumors', 'Disease', 'MESH:D009217', (120, 133))	('lipomas', 'Disease', (148, 155))	('muscle tumors', 'Disease', (120, 133))	('MEN1', 'Gene', '4221', (0, 4))	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('benign smooth muscle tumors', 'Phenotype', 'HP:0031460', (106, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('mutations', 'Var', (5, 14))	('sarcomas', 'Disease', (52, 60))	('lipomas', 'Phenotype', 'HP:0012032', (148, 155))	('rarely in lipomas', 'Phenotype', 'HP:0001012', (138, 155))	('lipomas', 'Disease', 'MESH:D008067', (148, 155))	('MEN1', 'Gene', (0, 4))
41906	30889380	These mutations included two frameshift deletions (PD26863a p.F370Sfs*65; PD26873a p.R521Gfs*43), a nonsense mutation (PD31196a p.R532*) and an in-frame deletion (PD26877a p.G168_L173delinsV).	('p.R521Gfs*43', 'Mutation', 'rs794728642', (83, 95))	('p.G168_L173delinsV', 'Mutation', 'p.168,173delinsG,V', (172, 190))	('p.R521Gfs*43', 'Var', (83, 95))	('PD26877a p.G168_L173delinsV', 'Var', (163, 190))	('PD31196a p.R532*', 'Var', (119, 135))	('PD26863a p.F370Sfs*65; PD26873a p.R521Gfs*43', 'Var', (51, 95))	('p.F370Sfs*65', 'Mutation', 'p.F370SfsX65', (60, 72))	('p.R532*', 'Var', (128, 135))	('PD26873a', 'Chemical', '-', (74, 82))	('p.R532*', 'Mutation', 'p.R532*', (128, 135))
41907	30889380	Copy-number calling (Table S2) followed by recurrent copy-number analysis revealed significant recurrent altered regions of the USARC genome including amplification of the known sarcoma driver oncogenes JUN and RICTOR, and deletion of cancer driver genes such as TP53, RB1, CDKN2A, CBFA2T3, STK11, TCF3, and CYLD (GISTIC, q < 0.1; Figure 2A; Table S2).	('STK11', 'Gene', (291, 296))	('TCF3', 'Gene', (298, 302))	('RB1', 'Gene', (269, 272))	('RICTOR', 'Gene', (211, 217))	('CDKN2A', 'Gene', (274, 280))	('TP53', 'Gene', '7157', (263, 267))	('TCF3', 'Gene', '6929', (298, 302))	('deletion', 'Var', (223, 231))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('RB1', 'Gene', '5925', (269, 272))	('STK11', 'Gene', '6794', (291, 296))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('CDKN2A', 'Gene', '1029', (274, 280))	('sarcoma', 'Disease', (178, 185))	('CYLD', 'Gene', (308, 312))	('CBFA2T3', 'Gene', (282, 289))	('TP53', 'Gene', (263, 267))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('CBFA2T3', 'Gene', '863', (282, 289))	('CYLD', 'Gene', '1540', (308, 312))	('cancer', 'Disease', (235, 241))	('RICTOR', 'Gene', '253260', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
41909	30889380	Furthermore, from a potential therapeutic standpoint, mutational profiling and manual curation of driver variants revealed that 33% (n = 17) of tumors harbored mutations in genes encoding proteins upstream of mammalian target of rapamycin (mTOR) in the signaling cascade.	('tumors', 'Disease', (144, 150))	('mTOR', 'Gene', '2475', (240, 244))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('mutations', 'Var', (160, 169))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('mammalian target of rapamycin', 'Gene', '2475', (209, 238))	('mammalian target of rapamycin', 'Gene', (209, 238))	('variants', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mTOR', 'Gene', (240, 244))
41910	30889380	These included truncating events in PTEN (n = 10), TSC1 (n = 2), and TSC2 (n = 2), as well as a hotspot mutation in PIK3CA (p.H1047R).	('PIK3CA', 'Gene', (116, 122))	('TSC2', 'Gene', '7249', (69, 73))	('TSC2', 'Gene', (69, 73))	('p.H1047R', 'Var', (124, 132))	('truncating events', 'MPA', (15, 32))	('PIK3CA', 'Gene', '5290', (116, 122))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('TSC1', 'Gene', '7248', (51, 55))	('p.H1047R', 'Mutation', 'rs121913279', (124, 132))	('TSC1', 'Gene', (51, 55))
41913	30889380	We also found three hypermutated samples (~19%) in the extension cohort, one of which harbored a nonsense mutation of PALB2 (pE331*).	('PALB2', 'Gene', '79728', (118, 123))	('pE331*', 'Var', (125, 131))	('PALB2', 'Gene', (118, 123))
41920	30889380	CNS3 is a signature of hypodiploid tumors (no evidence of WGD) with a large proportion of unaltered segments, and some small amplifications and large deletions.	('deletions', 'Var', (150, 159))	('hypodiploid tumors', 'Disease', (23, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('hypodiploid tumors', 'Disease', 'MESH:D009369', (23, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('amplifications', 'Var', (125, 139))	('CNS3', 'Gene', (0, 4))
41922	30889380	Furthermore, our earlier integrative mutational analysis revealed that 68% of tumors harbored a putative disruptive event in TP53, and that abrogation of TP53 was significantly associated with activity of CNS1 (LOH with two or more WGDs) (Kruskal-Wallis test, p = 9.2 x 10-4, q = 1.3 x 10-2; Figure 5D).	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('CNS1', 'Gene', (205, 209))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('TP53', 'Gene', (154, 158))	('TP53', 'Gene', '7157', (125, 129))	('activity', 'MPA', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TP53', 'Gene', (125, 129))	('abrogation', 'Var', (140, 150))	('TP53', 'Gene', '7157', (154, 158))
41923	30889380	PTEN mutations are associated with an increased activity of the signature of copy neutral LOH, CNS4 (Kruskal-Wallis test, p = 3.9 x 10-3, q = 4.3 x 10-2), and activity of CNS4 is also correlated with tumor mutational burden (linear regression, p = 5.3 x 10-3, q = 5.1 x 10-2).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('activity', 'MPA', (159, 167))	('activity', 'MPA', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('PTEN', 'Gene', '5728', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', (200, 205))	('CNS4', 'Gene', (95, 99))	('PTEN', 'Gene', (0, 4))	('increased', 'PosReg', (38, 47))
41926	30889380	Further, linear modeling of gene expression in genes of interest identified a significant relationship between gene expression and copy number in five genes (TP53, RB1, CDKN2A, PTEN, and TERT; q < 0.05), but no significant association between promoter methylation and gene expression once copy number is accounted for (q > 0.05).	('TP53', 'Gene', '7157', (158, 162))	('CDKN2A', 'Gene', (169, 175))	('TP53', 'Gene', (158, 162))	('copy number', 'Var', (131, 142))	('RB1', 'Gene', '5925', (164, 167))	('CDKN2A', 'Gene', '1029', (169, 175))	('PTEN', 'Gene', (177, 181))	('PTEN', 'Gene', '5728', (177, 181))	('RB1', 'Gene', (164, 167))	('gene expression', 'MPA', (111, 126))
41934	30889380	We found that 14 tumors (27%) in our USARC cohort demonstrate widespread LOH (>50% genome LOH) and that 3 tumors exhibit striking near-genome-scale haploidy (>90% genome LOH).	('14 tumors', 'Disease', 'MESH:C567448', (14, 23))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('haploidy', 'Var', (148, 156))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('14 tumors', 'Disease', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('LOH', 'NegReg', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
41936	30889380	Large-scale haploidy has previously been described using SNP arrays in low-grade chondrosarcoma and in other sarcoma subtypes of various grades.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (81, 95))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('haploidy', 'Var', (12, 20))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('chondrosarcoma', 'Disease', 'MESH:D002813', (81, 95))	('sarcoma', 'Disease', (109, 116))	('chondrosarcoma', 'Disease', (81, 95))	('sarcoma', 'Disease', (88, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
41945	30889380	Our data indicate that polyploidization is a key event in USARC tumorigenesis except for a small outlier group of high-grade tumors without evidence of WGD as estimated by WGS (CNS3).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('polyploidization', 'Var', (23, 39))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
41950	30889380	Furthermore, hypermutation and the recurrence of mutations in mTOR signaling genes open up alternative avenues for stratification and immunotherapy clinical trial design for these patients.	('mTOR', 'Gene', '2475', (62, 66))	('mutations', 'Var', (49, 58))	('mTOR', 'Gene', (62, 66))	('hypermutation', 'Var', (13, 26))	('patients', 'Species', '9606', (180, 188))
41951	30889380	By integrating the results from copy-number signatures, mutational timing, and ploidy analysis we deduced four potential routes to USARC tumorigenesis, all beginning with early driver mutations, preceding any WGD event (Figure 8C).	('tumor', 'Disease', (137, 142))	('mutations', 'Var', (184, 193))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('USARC', 'Disease', (131, 136))
41952	30889380	Live cell-imaging experiments of chromosomally unstable cells have demonstrated that mis-segregation during anaphase can lead to two aberrant daughter cells; one that is hypoploid, and another that is hyperploid due to sequestration of a lagging chromosome in a micronucleus, which may be susceptible to chromothripsis.	('hypoploid', 'Disease', 'None', (170, 179))	('lead to', 'Reg', (121, 128))	('mis-segregation', 'Var', (85, 100))	('hypoploid', 'Disease', (170, 179))
41955	30889380	On a permissive background of TP53 or RB1 inactivation, such widespread genomic loss could lead to a precursor cell state with a near-haploid genome as seen, for example, in samples PD31196a and PD26920a.	('lead to', 'Reg', (91, 98))	('TP53', 'Gene', (30, 34))	('PD26920a', 'Var', (195, 203))	('RB1', 'Gene', (38, 41))	('loss', 'NegReg', (80, 84))	('RB1', 'Gene', '5925', (38, 41))	('inactivation', 'Var', (42, 54))	('PD31196a', 'Var', (182, 190))	('TP53', 'Gene', '7157', (30, 34))
41960	30889380	These new models of sarcoma development demonstrate likely punctuated evolutionary trajectories and provide insights into how patterns of LOH and copy-number gain sculpt the sarcoma genome.	('sarcoma', 'Disease', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('copy-number gain', 'Var', (146, 162))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('sarcoma', 'Disease', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))
41961	30889380	Future work on larger cohorts collected prospectively may elucidate other mechanisms underpinning the aberrant copy-number landscape in sarcomas and may yield further undiscovered copy-number signatures.	('sarcomas', 'Disease', (136, 144))	('copy-number', 'Var', (111, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))
42002	30889380	Variants observed in the CIVIC, Sanger, Genie or Memorial Sloane Kettering Cancer Center cancer hotspots database (MSKCC) were categorized as "High confidence".	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Variants', 'Var', (0, 8))	('Memorial Sloane Kettering Cancer Center cancer', 'Disease', 'MESH:D009369', (49, 95))	('Memorial Sloane Kettering Cancer Center cancer', 'Disease', (49, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
42003	30889380	Variants observed in >1 patient wass categorized as "Medium confidence", otherwise "Low confidence".	('Variants', 'Var', (0, 8))	('patient', 'Species', '9606', (24, 31))	('Low', 'NegReg', (84, 87))
42005	30889380	UTR-UTR, single intron or ambiguous flags were classified as "Unknown significance".	('ambiguous flags', 'Disease', (26, 41))	('single intron', 'Var', (9, 22))	('UTR-UTR', 'Disease', (0, 7))	('flags', 'Species', '34205', (36, 41))
42021	30889380	The method for determining clustered or unclustered rearrangements was altered from; we determine clustered rearrangements as those falling in a piecewise constant fit segment with an average distance between rearrangements less than 0.1x the mean distance between rearrangements across the data set, rather than 0.1x the mean distance between rearrangements in a given sample as is the case in.	('falling', 'Disease', 'MESH:C537863', (132, 139))	('falling', 'Phenotype', 'HP:0002527', (132, 139))	('less', 'Var', (224, 228))	('fall', 'Phenotype', 'HP:0002527', (132, 136))	('falling', 'Disease', (132, 139))
42024	30889380	This model was used because the Cox proportional hazards model's assumption of proportional hazards is violated by several key covariates: resection margins, metastasis status, RB1 mutation status and ATRX mutation status.	('ATRX', 'Gene', '546', (201, 205))	('RB1', 'Gene', '5925', (177, 180))	('RB1', 'Gene', (177, 180))	('mutation', 'Var', (181, 189))	('ATRX', 'Gene', (201, 205))	('metastasis', 'CPA', (158, 168))
42028	30889380	An AFT model for overall survival was fit with covariates: size of tumor (mm), resection margins (Complete, Marginal, Incomplete), metastasis status (Metastasis at diagnosis, Metastasis after diagnosis, No metastasis, Unknown) and burden group (mutLo-rearrLo, mutLo-rearrHi, mutHi-rearrLo).	('Metastasis', 'Disease', 'MESH:D009362', (150, 160))	('Metastasis', 'Disease', (150, 160))	('mutLo-rearrLo', 'Var', (245, 258))	('Metastasis', 'Disease', (175, 185))	('Metastasis', 'Disease', 'MESH:D009362', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mutLo-rearrHi', 'Var', (260, 273))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
42029	30889380	AFT models for metastasis-free survival and progression-free survival were fit with covariates: size of tumor (mm), resection margins (Complete, Marginal, Incomplete) and burden group (mutLo-rearrLo, mutLo-rearrHi, mutHi-rearrLo).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('mutHi-rearrLo', 'Var', (215, 228))	('mutLo-rearrLo', 'Var', (185, 198))	('mutLo-rearrHi', 'Var', (200, 213))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
42031	30889380	Briefly, the most likely multiplicity of an SNV muSNV, given the purity of the sample rho, the underlying total tumor copy number ntot,t,SNV and the variant allele fraction of the SNV fSNV is the integer bound by the underlying major allele state of the tumor nmajor ,t,SNV, inferred as:where ntot,n,SNV=2 is the total copy number of the normal diploid contaminant.	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('variant', 'Var', (149, 156))
42033	30889380	a whole genome duplication tWGD1 in a patient whose age at diagnosis was a, the real-time timing of the WGD rtWGD1 becomesand the WGD occurred tbdWGD1 years before diagnosis We verified that the number of spontaneous (C>T)pG were correlated with the age at diagnosis (Figure S7C), as well as strongly correlated with the total number of mutations NSNV (Figure S7D), and NSNV were therefore also correlated with the age of the patients (Figure S7E).	('C>T)pG', 'Var', (218, 224))	('duplication', 'Var', (15, 26))	('patient', 'Species', '9606', (426, 433))	('patient', 'Species', '9606', (38, 45))	('correlated', 'Reg', (301, 311))	('tWGD1', 'Gene', (27, 32))	('patients', 'Species', '9606', (426, 434))
42062	29225486	Most of these tumors contain t(11;22) (p13;q12) translocation, and it is possible that EWS-WT1 functions as a transcription factor, possibly through WT1 targets.	('WT1', 'Gene', (91, 94))	('t(11', 'Var', (29, 33))	('p13', 'Gene', '440926', (39, 42))	('EWS-WT1', 'Gene', '7490', (87, 94))	('tumors', 'Disease', (14, 20))	('EWS-WT1', 'Gene', (87, 94))	('WT1', 'Gene', '7490', (149, 152))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('WT1', 'Gene', (149, 152))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('WT1', 'Gene', '7490', (91, 94))	('p13', 'Gene', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
42073	29225486	Hyperintense T1 signal and fluid/fluid levels may suggest recent hemorrhage in a tumor.	('T1 signal', 'MPA', (13, 22))	('hemorrhage', 'Disease', (65, 75))	('fluid/fluid levels', 'MPA', (27, 45))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('hemorrhage', 'Disease', 'MESH:D006470', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Hyperintense', 'Var', (0, 12))	('tumor', 'Disease', (81, 86))
42104	29225486	Some of these cases express full-length WT1 or have variant transcripts (KTS+), resulting in atypical staining patterns.	('variant', 'Var', (52, 59))	('WT1', 'Gene', '7490', (40, 43))	('staining patterns', 'MPA', (102, 119))	('WT1', 'Gene', (40, 43))
42106	29225486	The oncogenic potential of both can be unmasked by p53 loss as seen by nuclear localization of p53, and copy-number amplification and gene-set enrichment analysis demonstrated augmentation of the WNT pathway.	('men', 'Species', '9606', (179, 182))	('WNT pathway', 'Pathway', (196, 207))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('loss', 'NegReg', (55, 59))	('men', 'Species', '9606', (149, 152))	('copy-number', 'Var', (104, 115))	('augmentation', 'PosReg', (176, 188))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))
42118	29225486	Previous work has shown that both PD-1 positivity and PD-L1 positivity were independent prognostic indicators of OS and EFS in sarcoma.	('positivity', 'Var', (60, 70))	('EFS', 'Disease', (120, 123))	('PD-1', 'Gene', (34, 38))	('PD-L1', 'Gene', (54, 59))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('positivity', 'Var', (39, 49))	('PD-L1', 'Gene', '29126', (54, 59))	('sarcoma', 'Disease', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
42120	29225486	PD-1 positivity and PD-L1 expression are associated with advanced clinicopathological parameters and presence of distant metastasis, and both PD-1 positivity and PD-L1 positivity are independent prognostic indicators of overall survival (OS).	('positivity', 'Var', (5, 15))	('associated', 'Reg', (41, 51))	('PD-1', 'Gene', (0, 4))	('positivity', 'Var', (147, 157))	('overall', 'MPA', (220, 227))	('PD-L1', 'Gene', '29126', (162, 167))	('distant metastasis', 'CPA', (113, 131))	('PD-L1', 'Gene', (20, 25))	('PD-1', 'Gene', (142, 146))	('PD-L1', 'Gene', '29126', (20, 25))	('PD-L1', 'Gene', (162, 167))
42176	29225486	IGF-1R inhibition has been seen to mitigate mTOR activation and is supported by preclinical data supporting its additive antitumor effects by combining them.	('mitigate', 'NegReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('inhibition', 'Var', (7, 17))	('mTOR', 'Gene', (44, 48))	('mTOR', 'Gene', '2475', (44, 48))	('IGF-1R', 'Gene', '3480', (0, 6))	('IGF-1R', 'Gene', (0, 6))	('combining', 'Interaction', (142, 151))
42182	29225486	Single-agent anti-PD-1 antibodies have had limited efficacy across sarcomas to date.	('anti-PD-1', 'Var', (13, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('sarcomas', 'Disease', (67, 75))
42185	29225486	The composite of tumoral PD-L1 positivity and PD-1 positivity among tumor-infiltrating lymphocytes has been suggested as an indicator of prognosis in soft tissue sarcoma patients.	('tumor', 'Disease', (68, 73))	('patients', 'Species', '9606', (170, 178))	('tumor', 'Disease', (17, 22))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (150, 169))	('sarcoma', 'Disease', (162, 169))	('positivity', 'Var', (51, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('positivity', 'Var', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumoral PD-L1', 'Disease', 'MESH:D010300', (17, 30))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('PD-1', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumoral PD-L1', 'Disease', (17, 30))
42210	24802970	High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options.	('osteosarcoma', 'Disease', (147, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (147, 159))	('osteosarcoma', 'Disease', (41, 53))	('High', 'Var', (0, 4))	('CD49f', 'Gene', (5, 10))	('associated', 'Reg', (25, 35))	('osteosarcoma tumor', 'Disease', (41, 59))	('osteosarcoma', 'Disease', 'MESH:D012516', (147, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (41, 53))	('osteosarcoma', 'Disease', 'MESH:D012516', (41, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patient', 'Species', '9606', (87, 94))	('CD49f', 'Gene', '3655', (5, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('osteosarcoma tumor', 'Disease', 'MESH:D012516', (41, 59))	('OS', 'Phenotype', 'HP:0002669', (161, 163))
42218	24802970	Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability.	('inhibiting', 'Var', (45, 55))	('decreased', 'NegReg', (62, 71))	('CD49f', 'Gene', '3655', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CD49f', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
42225	24802970	Compounding the problem, many of these cultures have been immortalized in vitro, adding significant mutations to cell cultures that may already be too far separated from the original tumors.	('mutations', 'Var', (100, 109))	('original tumors', 'Disease', 'MESH:D009369', (174, 189))	('original tumors', 'Disease', (174, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
42301	24802970	The high expression of CD44, CD90, and CD105 as well as the low expression of CD117 and CD49f confirms the mesenchymal origin of the cell cultures.	('CD44', 'Gene', '960', (23, 27))	('mesenchymal origin of the cell cultures', 'CPA', (107, 146))	('CD44', 'Gene', (23, 27))	('CD90', 'Gene', '7070', (29, 33))	('CD49f', 'Gene', (88, 93))	('CD105', 'Var', (39, 44))	('CD90', 'Gene', (29, 33))	('CD117', 'Gene', '3815', (78, 83))	('CD117', 'Gene', (78, 83))	('CD49f', 'Gene', '3655', (88, 93))
42333	24802970	The KHOS-GFP and KHOS-GFP-shCD49f groups were observed to have an enriched and diminished CD49f expression, respectively, and were selected for additional in vivo studies (Fig.4).	('CD49f', 'Gene', '3655', (28, 33))	('CD49f', 'Gene', (90, 95))	('OS', 'Phenotype', 'HP:0002669', (19, 21))	('expression', 'MPA', (96, 106))	('diminished', 'NegReg', (79, 89))	('KHOS', 'Chemical', '-', (17, 21))	('CD49f', 'Gene', '3655', (90, 95))	('KHOS', 'Chemical', '-', (4, 8))	('CD49f', 'Gene', (28, 33))	('shCD49f', 'Chemical', '-', (26, 33))	('KHOS-GFP', 'Var', (4, 12))	('OS', 'Phenotype', 'HP:0002669', (6, 8))
42337	24802970	After day 30, the KHOS-GFP-shCD49f group showed a reduction in tumor size, whereas the KHOS-GFP group was observed to plateau in tumor size, suggesting less aggressive tumor proliferation capability (Fig.4B-D).	('aggressive tumor', 'Disease', (157, 173))	('OS', 'Phenotype', 'HP:0002669', (20, 22))	('tumor', 'Disease', (129, 134))	('KHOS', 'Chemical', '-', (18, 22))	('less', 'NegReg', (152, 156))	('shCD49f', 'Chemical', '-', (27, 34))	('reduction', 'NegReg', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('KHOS', 'Chemical', '-', (87, 91))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (168, 173))	('OS', 'Phenotype', 'HP:0002669', (89, 91))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('aggressive tumor', 'Disease', 'MESH:D001523', (157, 173))	('KHOS-GFP-shCD49f', 'Var', (18, 34))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
42339	24802970	Interestingly, the intake and take of phase was similar in both CD49f knock down cells and control cells.	('knock down', 'Var', (70, 80))	('CD49f', 'Gene', '3655', (64, 69))	('CD49f', 'Gene', (64, 69))
42349	24802970	Our data suggest a significant (P = 0.001) reduction in clonogenicity abilities between the KHOS shCD49f group and the control group (Fig.5D).	('KHOS shCD49f', 'Var', (92, 104))	('reduction', 'NegReg', (43, 52))	('KHOS shCD49f', 'Chemical', '-', (92, 104))	('clonogenicity abilities', 'CPA', (56, 79))	('OS', 'Phenotype', 'HP:0002669', (94, 96))
42358	24802970	Second, cancer evolves through a process of stepwise accumulation of genetic alterations that result in uncontrolled cell proliferation and a lack of response to normal apoptotic stimuli.	('genetic alterations', 'Var', (69, 88))	('cancer', 'Disease', (8, 14))	('lack', 'NegReg', (142, 146))	('response to normal apoptotic', 'MPA', (150, 178))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
42362	24802970	Our results demonstrate that there is a positive correlation between a high CD49f expression and aggressive tumor progression.	('CD49f', 'Gene', (76, 81))	('expression', 'MPA', (82, 92))	('high', 'Var', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('aggressive tumor', 'Disease', 'MESH:D001523', (97, 113))	('CD49f', 'Gene', '3655', (76, 81))	('aggressive tumor', 'Disease', (97, 113))
42370	24802970	Upon transfection of this construct into KHOS cell line, the expression studies showed a knockdown CD49f expression levels (Fig.4A) and a concomitant significant reduction in tumor development over a period of 34 days (Fig.4B).	('CD49f', 'Gene', '3655', (99, 104))	('reduction', 'NegReg', (162, 171))	('tumor', 'Disease', (175, 180))	('OS', 'Phenotype', 'HP:0002669', (43, 45))	('CD49f', 'Gene', (99, 104))	('expression levels', 'MPA', (105, 122))	('KHOS', 'Chemical', '-', (41, 45))	('knockdown', 'Var', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
42377	24802970	This suggests that the presence of CD49f plays a role in the establishment and progression of cancer cells.	('CD49f', 'Gene', (35, 40))	('plays', 'Reg', (41, 46))	('CD49f', 'Gene', '3655', (35, 40))	('establishment', 'CPA', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('presence', 'Var', (23, 31))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
42378	24802970	In vivo data (Fig.4B) illustrate that limited tumor progression was observed when CD49f was under-expressed or knocked down using shRNA.	('knocked', 'Var', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CD49f', 'Gene', (82, 87))	('tumor', 'Disease', (46, 51))	('CD49f', 'Gene', '3655', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
42430	25326696	Because the patient had factors indicating a poor PPSS prognosis, including her age (>20 years), sex, and the presence of the SYT-SSX1 variant gene, we recommended chemotherapy with a combination of ifosfamide and doxorubicin.	('presence', 'Var', (110, 118))	('ifosfamide', 'Chemical', 'MESH:D007069', (199, 209))	('variant', 'Var', (135, 142))	('doxorubicin', 'Chemical', 'MESH:D004317', (214, 225))	('patient', 'Species', '9606', (12, 19))	('SYT-SSX1', 'Gene', (126, 134))	('SYT-SSX1', 'Gene', '6760;6756', (126, 134))
42458	25326696	Factors that indicate a poor prognosis include age >20 years, female sex, tumor size >5 cm, positive resection margin, extensive tumor necrosis, high number of mitoses (>10 per 10 high-power fields), neurovascular invasion, and the presence of the SYT-SSX1 variant gene .	('SYT-SSX1', 'Gene', (248, 256))	('tumor necrosis', 'Disease', (129, 143))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('neurovascular invasion', 'CPA', (200, 222))	('SYT-SSX1', 'Gene', '6760;6756', (248, 256))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor necrosis', 'Disease', 'MESH:D009336', (129, 143))	('tumor', 'Disease', (74, 79))	('variant', 'Var', (257, 264))	('tumor', 'Disease', (129, 134))	('presence', 'Reg', (232, 240))
42461	25326696	We also suggested pazopanib, which interferes with vascular endothelial growth factor and platelet-derived growth factor pathways.	('interferes', 'NegReg', (35, 45))	('pazopanib', 'Chemical', 'MESH:C516667', (18, 27))	('vascular endothelial growth factor', 'Gene', (51, 85))	('platelet-derived growth factor pathways', 'Pathway', (90, 129))	('vascular endothelial growth factor', 'Gene', '7422', (51, 85))	('pazopanib', 'Var', (18, 27))
42587	25313997	The mean African POS pain score was significantly higher for patients prescribed morphine (3.7, SE: 0.2) than for patients prescribed codeine or a non-opioid analgesic (2.1, SE: 0.3) (p<0.001) (Table 3).	('POS pain', 'Disease', (17, 25))	('higher', 'PosReg', (50, 56))	('morphine', 'Chemical', 'MESH:D009020', (81, 89))	('patients', 'Species', '9606', (61, 69))	('POS pain', 'Disease', 'MESH:D010146', (17, 25))	('codeine', 'Chemical', 'MESH:D003061', (134, 141))	('SE', 'Disease', 'None', (174, 176))	('patients', 'Species', '9606', (114, 122))	('pain', 'Phenotype', 'HP:0012531', (21, 25))	('morphine', 'Var', (81, 89))	('SE', 'Disease', 'None', (96, 98))
42678	25313997	In South Africa, for example, food insecurity was associated with greater HIV symptom severity, and in a survey of PLHIV from four Southern African countries, fewer disease symptoms were reported among study participants who had a modicum of socioeconomic security.	('food insecurity', 'Var', (30, 45))	('HIV', 'Disease', (74, 77))	('participants', 'Species', '9606', (208, 220))	('greater', 'PosReg', (66, 73))
42764	32189912	Although the histogenesis of MPNST remains unclear, its development is thought to be a multistep and multigene process with etiology being the loss of chromosomal arm 17q sequence, including complete inactivation of NF1 gene.	('NF1', 'Gene', '4763', (216, 219))	('NF', 'Phenotype', 'HP:0001067', (216, 218))	('NF1', 'Gene', (216, 219))	('MPNST', 'Disease', 'MESH:D009442', (29, 34))	('chromosomal', 'Gene', (151, 162))	('loss', 'Var', (143, 147))	('MPNST', 'Disease', (29, 34))
42797	32189912	The diagnosis of MPNST is favored by the positivity for S-100, nestin, HMGA2, and SOX10 Treatment of choice for MPNST is surgical intervention.	('MPNST', 'Disease', (112, 117))	('S-100', 'Gene', '6271', (56, 61))	('positivity', 'Var', (41, 51))	('HMGA2', 'Gene', (71, 76))	('MPNST', 'Disease', 'MESH:D009442', (17, 22))	('SOX10', 'Gene', (82, 87))	('SOX10', 'Gene', '6663', (82, 87))	('MPNST', 'Disease', (17, 22))	('S-100', 'Gene', (56, 61))	('MPNST', 'Disease', 'MESH:D009442', (112, 117))	('nestin', 'Gene', (63, 69))	('HMGA2', 'Gene', '8091', (71, 76))
42966	28629371	The most sensitive cell lines were the DDLPS cell lines IB111 and IB115, characterized by MDM2 gene amplification, and the extraskeletal osteosarcoma cell line IB128, with no alteration in MDM2 copy number.	('osteosarcoma', 'Phenotype', 'HP:0002669', (137, 149))	('osteosarcoma', 'Disease', (137, 149))	('amplification', 'Var', (100, 113))	('osteosarcoma', 'Disease', 'MESH:D012516', (137, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('MDM2', 'Gene', (90, 94))	('gene amplification', 'Var', (95, 113))
42969	28629371	The sensitivity differences between the two dedifferentiated LPS cell lines could be explained by the basal expression of CDKs, particularly the expression of CDK4 and CDK6, which was significantly lower in IB111 cells than in IB115 cells (Fig.	('CDK4', 'Gene', (159, 163))	('CDKs', 'Gene', (122, 126))	('CDKs', 'Gene', '1019;1021', (122, 126))	('IB111', 'Var', (207, 212))	('expression', 'MPA', (145, 155))	('CDK6', 'Gene', (168, 172))	('CDK6', 'Gene', '1021', (168, 172))	('lower', 'NegReg', (198, 203))
42975	28629371	Palbociclib (PD0332991) is the first highly selective CDK4/6 inhibitor to be evaluated in humans and has been approved for the treatment of breast cancer.	('PD0332991', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('PD0332991', 'Chemical', 'MESH:C500026', (13, 22))	('humans', 'Species', '9606', (90, 96))
42988	28289810	Facial deformity and functional impairment may be the result of asymmetric facial growth related to the lesion itself or to its treatment.	('facial growth', 'CPA', (75, 88))	('asymmetric', 'Var', (64, 74))	('Facial deformity and functional impairment', 'Disease', 'MESH:D003072', (0, 42))	('asymmetric facial', 'Phenotype', 'HP:0000324', (64, 81))
43033	28289810	The pathogenesis of LCH is not known, and some arguments support the reactive nature while other arguments, such as the presence of BRAF V600E and MAP2K1 gene mutations, rather suggest a neoplastic process.	('MAP2K1', 'Gene', (147, 153))	('V600E', 'Mutation', 'p.V600E', (137, 142))	('LCH', 'Disease', (20, 23))	('neoplastic process', 'Phenotype', 'HP:0002664', (187, 205))	('BRAF V600E', 'Var', (132, 142))	('MAP2K1', 'Gene', '5604', (147, 153))
43043	28289810	In conjunction with the age of presentation, the combination of well-defined lesions on CT, high signal on T2, strong contrast enhancement, and ADC values >1.2 x 10-3 mm2/s is strongly evocative of LCH, especially when patients present with multifocal involvement or diabetes insipidus (Fig.	('diabetes insipidus', 'Phenotype', 'HP:0000873', (267, 285))	('high', 'Var', (92, 96))	('multifocal involvement', 'Disease', (241, 263))	('diabetes insipidus', 'Disease', (267, 285))	('diabetes insipidus', 'Disease', 'MESH:D003919', (267, 285))	('LCH', 'Disease', (198, 201))	('patients', 'Species', '9606', (219, 227))	('evocative', 'Reg', (185, 194))	('ADC', 'MPA', (144, 147))	('multifocal involvement', 'Disease', 'None', (241, 263))
43054	28289810	Mutations in the CTNNB1 gene encoding beta-catenin and the APC gene cause beta-catenin delocalization and accumulation in the nuclei, demonstrated by immunohistochemistry.	('beta-catenin', 'Gene', (38, 50))	('accumulation', 'PosReg', (106, 118))	('APC', 'Phenotype', 'HP:0005227', (59, 62))	('CTNNB1', 'Gene', (17, 23))	('delocalization', 'MPA', (87, 101))	('cause', 'Reg', (68, 73))	('APC', 'Disease', 'MESH:D011125', (59, 62))	('beta-catenin', 'Gene', '1499', (38, 50))	('NB', 'Phenotype', 'HP:0003006', (20, 22))	('Mutations', 'Var', (0, 9))	('beta-catenin', 'Gene', (74, 86))	('APC', 'Disease', (59, 62))	('CTNNB1', 'Gene', '1499', (17, 23))	('beta-catenin', 'Gene', '1499', (74, 86))
43055	28289810	DFs only occasionally show beta catenin and, contrary to desmoid-type fibromatosis of soft tissue, do not display mutations in exon 3 of CTNNB1.	('show', 'Reg', (22, 26))	('mutations in', 'Var', (114, 126))	('fibroma', 'Phenotype', 'HP:0010614', (70, 77))	('desmoid-type fibromatosis', 'Disease', (57, 82))	('NB', 'Phenotype', 'HP:0003006', (140, 142))	('beta catenin', 'Protein', (27, 39))	('CTNNB1', 'Gene', (137, 143))	('CTNNB1', 'Gene', '1499', (137, 143))	('desmoid-type fibromatosis', 'Disease', 'MESH:C535944', (57, 82))
43066	28289810	The rearrangement of the anaplastic lymphoma kinase (ALK) gene at chromosome 2p23, which can be demonstrated by fluorescence in situ hybridization, is now regarded as pathognomonic for the definitive diagnosis.	('ALK', 'Gene', (53, 56))	('lymphoma', 'Phenotype', 'HP:0002665', (36, 44))	('rearrangement', 'Var', (4, 17))	('anaplastic lymphoma kinase', 'Gene', '238', (25, 51))	('ALK', 'Gene', '238', (53, 56))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (25, 44))	('anaplastic lymphoma kinase', 'Gene', (25, 51))
43134	28289810	NBs have many chromosomal and molecular abnormalities, such as amplification of the MYCN oncogene (more common in advanced stage disease); overexpression of the HRAS oncogene (more common in lower-stage disease); chromosome 1p deletion; allelic losses of chromosomes 11q, 14q, and 17q; and variable expression of neurotrophin receptor gene products.	('overexpression', 'PosReg', (139, 153))	('HRAS', 'Gene', (161, 165))	('molecular abnormalities', 'Disease', 'MESH:C567116', (30, 53))	('NB', 'Phenotype', 'HP:0003006', (0, 2))	('amplification', 'MPA', (63, 76))	('losses', 'NegReg', (245, 251))	('expression', 'MPA', (299, 309))	('MYCN', 'Gene', (84, 88))	('chromosome', 'Var', (213, 223))	('molecular abnormalities', 'Disease', (30, 53))	('HRAS', 'Gene', '3265', (161, 165))	('MYCN', 'Gene', '4613', (84, 88))
43191	22738416	The following diagnostic groups were specified a priori for analysis: (i) osteosarcoma (ICD-O-3 topography codes for sites classified as bones and joint: C400-C403, C408-C414, C418-419 and associated morphology codes 9180/3; 9181/3, 9182/3, 9183/3, 9184/3, 9185/3, 9186/3, 9187/3, 9192/3, 9193/3, 9194/3, 9195/3) and (ii) Ewing sarcoma (ICD-O-3 topography codes for sites classified as bones and joint: C400-C403, C408-C414; C418-C419, C760-C768 and associated morphology code 9260/3; 9261/3).	('osteosarcoma', 'Disease', 'MESH:D012516', (74, 86))	('Ewing sarcoma', 'Disease', (322, 335))	('osteosarcoma', 'Phenotype', 'HP:0002669', (74, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (322, 335))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (322, 335))	('sarcoma', 'Phenotype', 'HP:0100242', (328, 335))	('C408-C414', 'Var', (165, 174))	('C400-C403', 'Var', (403, 412))	('C418-419', 'Var', (176, 184))	('C418-C419, C760-C768', 'Disease', 'None', (425, 445))	('C400-C403', 'Var', (154, 163))	('osteosarcoma', 'Disease', (74, 86))
43308	30776883	The main location for the total STS group was in "other connective and soft tissues" (C49xx, 67.3%) and the second main location was in "retroperitoneum and peritoneum" (C48xx, 24.5%), while the remaining locations (C47xx, C223, C224, and C542) represented minor figures (< 10%).	('C224', 'Chemical', 'MESH:C513950', (229, 233))	('C47xx', 'Var', (216, 221))	('STS', 'Phenotype', 'HP:0030448', (32, 35))	('C48', 'Gene', '55755', (170, 173))	('STS', 'Disease', (32, 35))	('C48', 'Gene', (170, 173))	('STS', 'Disease', 'MESH:D012509', (32, 35))
43310	30776883	However, the advanced STS group showed that tumors were located in different areas (C49xx, 58.6%; C48xx, 31.5%).	('tumors', 'Disease', (44, 50))	('C48', 'Gene', (98, 101))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('STS', 'Phenotype', 'HP:0030448', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('C49xx', 'Var', (84, 89))	('STS', 'Disease', (22, 25))	('C48', 'Gene', '55755', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('STS', 'Disease', 'MESH:D012509', (22, 25))
43326	30776883	When the CD group was re-classified according to the treatment they received and then analyzed by treatment modalities, the 5-year survival rates after diagnosis by treatment were 74% for OP+CD-OP, 70.1% for RT+CD-RT, 53.1% for Pre/Post-OP+CD-Pre/Post-OP, 28.6% for CTx/CCRT+CD-CTx/CCRT and 0% for CD-No Tx.	('CTx', 'Gene', '1593', (266, 269))	('CTx', 'Gene', (266, 269))	('RT+CD-RT', 'Var', (208, 216))	('OP+CD-OP', 'Var', (188, 196))	('CTx', 'Gene', '1593', (278, 281))	('CTx', 'Gene', (278, 281))
43355	30776883	However, this last report only includes ICD-10 diagnosis C47 and C49, and they do not report C48, C223, C224, or C542 cases.	('C48', 'Gene', '55755', (93, 96))	('C49', 'Var', (65, 68))	('C224', 'Chemical', 'MESH:C513950', (104, 108))	('C47', 'Var', (57, 60))	('C48', 'Gene', (93, 96))
43361	30776883	Regarding anatomical location at the time of diagnosis, the advanced STS ratios at C47 and C49 were 43% and 39%, respectively, while the advanced STS ratio at C48 was 58%.	('STS', 'Phenotype', 'HP:0030448', (146, 149))	('STS', 'Disease', (69, 72))	('STS', 'Disease', (146, 149))	('C48', 'Gene', (159, 162))	('STS', 'Disease', 'MESH:D012509', (69, 72))	('STS', 'Phenotype', 'HP:0030448', (69, 72))	('STS', 'Disease', 'MESH:D012509', (146, 149))	('C49', 'Var', (91, 94))	('C47', 'Var', (83, 86))	('C48', 'Gene', '55755', (159, 162))
43362	30776883	C47 and C49 are associated with extremity STS, and early detection and treatment are relatively easy, whereas C48 is located in the peritoneum or retroperitoneum, which makes early detection difficult, and even if it is found, surgical treatment options are limited.	('C48', 'Gene', '55755', (110, 113))	('STS', 'Disease', (42, 45))	('C49', 'Var', (8, 11))	('STS', 'Disease', 'MESH:D012509', (42, 45))	('C48', 'Gene', (110, 113))	('C47', 'Var', (0, 3))	('STS', 'Phenotype', 'HP:0030448', (42, 45))	('associated', 'Reg', (16, 26))
43418	31073193	DsRed+ A673 or Luc+ A673 cells were then loaded in VITVO and grown for 72 hours to repopulate the 3D matrix and obtain a consistent tumor bulk.	('Luc+ A673', 'Var', (15, 24))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))
43442	31073193	Tumor mass growth was monitored during the experiment, and after 28 days, a statistically significative reduction in tumor volume compared with untreated group was observed only in the E:T 1:10 group.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('reduction', 'NegReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('E:T 1:10', 'Var', (185, 193))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
43486	31073193	: primary tumor specimens procurement, data analysis and interpretation; V.M., C.S., T.P.	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('C.S.', 'Var', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
43563	32651197	suz12 inactivation in p53- and nf1-deficient zebrafish accelerates the onset of malignant peripheral nerve sheath tumors and expands the spectrum of tumor types Polycomb repressive complex 2 (PRC2) is an epigenetic regulator of gene expression that possesses histone methyltransferase activity.	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (80, 120))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('inactivation', 'Var', (6, 18))	('p53', 'Gene', '30590', (22, 25))	('onset', 'CPA', (71, 76))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (80, 120))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (114, 119))	('malignant peripheral nerve sheath tumors', 'Disease', (80, 120))	('suz12', 'Gene', '794171', (0, 5))	('accelerates', 'PosReg', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('p53', 'Gene', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('nf1', 'Gene', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('suz12', 'Gene', (0, 5))	('zebrafish', 'Species', '7955', (45, 54))	('tumor', 'Disease', (149, 154))	('nf1', 'Gene', '326708', (31, 34))
43565	32651197	Loss-of-function mutations in the PRC2 core subunit SUZ12 have been identified in a variety of tumors, including malignant peripheral nerve sheath tumors (MPNSTs).	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('malignant peripheral nerve sheath tumors', 'Disease', (113, 153))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('SUZ12', 'Gene', (52, 57))	('MPNSTs', 'Phenotype', 'HP:0100697', (155, 161))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (113, 153))	('mutations', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (113, 153))	('tumors', 'Disease', (95, 101))	('PRC2', 'Gene', (34, 38))
43568	32651197	Loss of suz12 significantly accelerated the onset and increased the penetrance of MPNSTs compared to that in control zebrafish.	('penetrance', 'MPA', (68, 78))	('MPNSTs', 'Phenotype', 'HP:0100697', (82, 88))	('zebrafish', 'Species', '7955', (117, 126))	('increased', 'PosReg', (54, 63))	('onset', 'MPA', (44, 49))	('Loss', 'Var', (0, 4))	('suz12', 'Gene', (8, 13))	('accelerated', 'PosReg', (28, 39))
43570	32651197	The suz12-knockout tumors displayed reduced or abolished H3K27me3 epigenetic marks and upregulation of gene sets reported to be targeted by PRC2.	('PRC2', 'Gene', (140, 144))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('H3K27me3', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('suz12-knockout', 'Gene', (4, 18))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('abolished', 'NegReg', (47, 56))	('upregulation', 'PosReg', (87, 99))
43571	32651197	Thus, these zebrafish lines with inactivation of suz12 in combination with loss of p53/nf1 provide a model of human MPNSTs and multiple other tumor types, which will be useful for mechanistic studies of molecular pathogenesis and targeted therapy with small molecule inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MPNSTs', 'Phenotype', 'HP:0100697', (116, 122))	('tumor', 'Disease', (142, 147))	('p53/nf1', 'Gene', (83, 90))	('human', 'Species', '9606', (110, 115))	('suz12', 'Gene', (49, 54))	('zebrafish', 'Species', '7955', (12, 21))	('inactivation', 'Var', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
43572	32651197	Summary: In p53- and nf1-deficient zebrafish, onset of MPNSTs, as well as diverse other tumors, is accelerated by loss of the suz12 tumor suppressor, accompanied by global reduction in H3K27me3 marks and increased Ras-Mapk signaling.	('suz12', 'Gene', (126, 131))	('Ras-Mapk signaling', 'MPA', (214, 232))	('zebrafish', 'Species', '7955', (35, 44))	('increased', 'PosReg', (204, 213))	('tumor', 'Disease', (132, 137))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('reduction', 'NegReg', (172, 181))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('MPNSTs', 'CPA', (55, 61))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('accelerated', 'PosReg', (99, 110))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('H3K27me3', 'Protein', (185, 193))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('loss', 'Var', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('p53-', 'Gene', (12, 16))	('nf1-deficient', 'Gene', (21, 34))	('MPNSTs', 'Phenotype', 'HP:0100697', (55, 61))	('tumors', 'Disease', (88, 94))
43573	32651197	Alterations in genes encoding epigenetic regulators of gene expression have become increasingly important in cancer biology.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
43583	32651197	In neurofibromatosis type 1, loss of PRC2 activity reduces the levels of H3K27me3 and leads to elevated RAS-dependent transcription that facilitates transformation of benign plexiform neurofibroma precursor lesions into MPNSTs.	('neurofibromatosis type 1', 'Disease', (3, 27))	('neurofibroma', 'Phenotype', 'HP:0001067', (3, 15))	('activity', 'MPA', (42, 50))	('neurofibroma', 'Disease', 'MESH:D009455', (3, 15))	('reduces', 'NegReg', (51, 58))	('RAS-dependent transcription', 'MPA', (104, 131))	('neurofibroma', 'Phenotype', 'HP:0001067', (184, 196))	('MPNSTs', 'Phenotype', 'HP:0100697', (220, 226))	('neurofibroma', 'Disease', 'MESH:D009455', (184, 196))	('plexiform neurofibroma', 'Phenotype', 'HP:0009732', (174, 196))	('loss', 'Var', (29, 33))	('PRC2', 'Gene', (37, 41))	('facilitates', 'PosReg', (137, 148))	('neurofibroma', 'Disease', (3, 15))	('elevate', 'Disease', (95, 102))	('neurofibroma', 'Disease', (184, 196))	('neurofibromatosis type 1', 'Disease', 'MESH:C537392', (3, 27))	('transformation', 'MPA', (149, 163))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (3, 20))	('levels of H3K27me3', 'MPA', (63, 81))	('elevate', 'Disease', 'MESH:D006973', (95, 102))
43587	32651197	In T cell acute lymphoblastic leukemia (leukemia), loss of PRC2 core subunits was reported to occur by mutation or deletion in about 25% of all cases, and in a NOTCH1-induced genetic mouse model of leukemia, NOTCH1 antagonizes PRC2 function, leading to a loss of H3K27me3.	('T cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (3, 38))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (16, 38))	('mouse', 'Species', '10090', (183, 188))	('loss', 'NegReg', (51, 55))	('leukemia', 'Phenotype', 'HP:0001909', (198, 206))	('leukemia', 'Disease', (40, 48))	('leukemia', 'Disease', 'MESH:D007938', (40, 48))	('leukemia', 'Disease', (198, 206))	('leukemia', 'Disease', 'MESH:D007938', (198, 206))	('loss', 'NegReg', (255, 259))	('PRC2', 'Gene', (59, 63))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('antagonizes', 'NegReg', (215, 226))	('mutation', 'Var', (103, 111))	('T cell acute lymphoblastic leukemia', 'Disease', (3, 38))	('deletion', 'Var', (115, 123))	('NOTCH1', 'Var', (208, 214))	('H3K27me3', 'Protein', (263, 271))	('leukemia', 'Disease', (30, 38))	('leukemia', 'Disease', 'MESH:D007938', (30, 38))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (10, 38))	('T cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (3, 38))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))
43589	32651197	In the absence of ATRX, the deposition of H3K27me3 is misplaced to ectopic sites in the intergenic space and at non-canonical sites in the target genes, which impairs the maintenance of silenced genes.	('H3K27me3', 'Var', (42, 50))	('ATRX', 'Gene', (18, 22))	('ATRX', 'Gene', '323299', (18, 22))	('impairs', 'NegReg', (159, 166))	('maintenance', 'MPA', (171, 182))
43590	32651197	In a previous atrx-knockout model in zebrafish, we observed the re-expression of PRC2 target genes upon Atrx depletion, despite initial H3K27me3 deposition.	('zebrafish', 'Species', '7955', (37, 46))	('Atrx', 'Gene', (104, 108))	('depletion', 'Var', (109, 118))	('H3K27me3', 'Protein', (136, 144))	('atrx', 'Gene', (14, 18))	('PRC2 target genes', 'Gene', (81, 98))	('Atrx', 'Gene', '323299', (104, 108))	('atrx', 'Gene', '323299', (14, 18))	('re-expression', 'MPA', (64, 77))
43591	32651197	In this study, we report the consequences of loss of suz12 in a p53/nf1-deficient zebrafish tumor model that is suitable for drug testing.	('nf1-deficient zebrafish tumor', 'Disease', 'MESH:C537392', (68, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('suz12', 'Gene', (53, 58))	('loss', 'Var', (45, 49))	('nf1-deficient zebrafish tumor', 'Disease', (68, 97))
43593	32651197	We dissect the consequences of suz12 depletion on oncogenic Ras-Mapk signaling and indicate MEK inhibition as an effective strategy in p53/nf1/suz12-deficient MPNSTs.	('depletion', 'Var', (37, 46))	('MPNSTs', 'Phenotype', 'HP:0100697', (159, 165))	('suz12', 'Gene', (31, 36))	('deficient MPNSTs', 'Disease', (149, 165))	('deficient MPNSTs', 'Disease', 'MESH:D018319', (149, 165))	('oncogenic', 'MPA', (50, 59))
43595	32651197	To create knockout mutations in the suz12 tumor suppressor gene using CRISPR-Cas9, we designed sgRNAs to target exon 1 directly after the start of the coding sequence (Fig.	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (42, 47))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
43598	32651197	This procedure efficiently resulted in germline mutations, which were passed from primary injected F0 zebrafish into the F1 generation .	('resulted in', 'Reg', (27, 38))	('germline mutations', 'Var', (39, 57))	('zebrafish', 'Species', '7955', (102, 111))
43601	32651197	Our previously established model based on combinatorial loss of p53 and nf1 is prone to gliomas at low penetrance and MPNSTs at high penetrance.	('nf1', 'Gene', (72, 75))	('loss', 'Var', (56, 60))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('p53', 'Gene', (64, 67))	('MPNSTs', 'Phenotype', 'HP:0100697', (118, 124))	('prone', 'Reg', (79, 84))
43603	32651197	Because a total loss of nf1 is lethal in developing fish, one allele of nf1a is preserved, which after inbreeding leads to a mixed population of p53m/m, nf1b-/-, nf1a+/- and p53m/m, nf1b-/-, nf1a+/+ progeny.	('nf1', 'Gene', (24, 27))	('nf1a', 'Gene', (162, 166))	('nf1b', 'Gene', '564518', (182, 186))	('nf1b', 'Gene', (153, 157))	('nf1a', 'Gene', (191, 195))	('nf1a', 'Gene', (72, 76))	('leads to', 'Reg', (114, 122))	('nf1a', 'Gene', '326708', (162, 166))	('p53m/m', 'Var', (145, 151))	('loss', 'NegReg', (16, 20))	('p53m/m', 'Var', (174, 180))	('nf1b', 'Gene', '564518', (153, 157))	('nf1a', 'Gene', '326708', (191, 195))	('nf1a', 'Gene', '326708', (72, 76))	('nf1b', 'Gene', (182, 186))
43605	32651197	To assess the biological impact of introducing a suz12 LOF mutation, we monitored tumor onset and penetrance in developing offspring.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('suz12', 'Gene', (49, 54))	('mutation', 'Var', (59, 67))	('tumor', 'Disease', (82, 87))	('LOF', 'NegReg', (55, 58))
43606	32651197	Zebrafish harboring suz12 mutations of both genotypes developed tumors in abdomen, head, tail and anal sites (Fig.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('suz12', 'Gene', (20, 25))	('mutations', 'Var', (26, 35))	('developed', 'Reg', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('Zebrafish', 'Species', '7955', (0, 9))
43607	32651197	Histopathologic analysis of paraffin-embedded tumor tissue revealed that the suz12 disruption diversified the spectrum of tumor types considerably (Fig.	('suz12', 'Gene', (77, 82))	('paraffin', 'Chemical', 'MESH:D010232', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('disruption', 'Var', (83, 93))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
43608	32651197	In p53m/m, nf1b-/-, nf1a+/- and p53m/m, nf1b-/- and nf1a+/+ control fish, only MPNSTs were detected.	('nf1a', 'Gene', (20, 24))	('nf1b', 'Gene', (11, 15))	('nf1a', 'Gene', (52, 56))	('p53m/m', 'Var', (3, 9))	('nf1a', 'Gene', '326708', (20, 24))	('nf1b', 'Gene', (40, 44))	('nf1a', 'Gene', '326708', (52, 56))	('nf1b', 'Gene', '564518', (11, 15))	('nf1b', 'Gene', '564518', (40, 44))	('MPNSTs', 'Phenotype', 'HP:0100697', (79, 85))	('p53m/m', 'Var', (32, 38))
43610	32651197	In the p53m/m, nf1b-/-, nf1a+/-, suz12-mutant cohort, all 28 tumor-bearing fish that were sectioned displayed MPNSTs, one of which also displayed the sole case of pancreatic adenocarcinoma (3.6%).	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (163, 188))	('nf1a', 'Gene', '326708', (24, 28))	('MPNSTs', 'Phenotype', 'HP:0100697', (110, 116))	('nf1b', 'Gene', (15, 19))	('p53m/m', 'Var', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (163, 188))	('nf1b', 'Gene', '564518', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('pancreatic adenocarcinoma', 'Disease', (163, 188))	('nf1a', 'Gene', (24, 28))	('tumor', 'Disease', (61, 66))
43611	32651197	In the p53m/m, nf1b-/-, nf1a+/+, suz12-mutant population, 22 of the 24 tumor-bearing fish (91.7%) had MPNSTs, five displayed leukemia (20.8%), and a single fish showed soft tissue sarcoma or adenosarcoma (4.2%) .	('nf1a', 'Gene', '326708', (24, 28))	('MPNSTs', 'Phenotype', 'HP:0100697', (102, 108))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (168, 187))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (168, 187))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('soft tissue sarcoma', 'Disease', (168, 187))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('leukemia', 'Disease', 'MESH:D007938', (125, 133))	('leukemia', 'Disease', (125, 133))	('adenosarcoma', 'Disease', 'MESH:D018195', (191, 203))	('adenosarcoma', 'Disease', (191, 203))	('tumor', 'Disease', (71, 76))	('nf1a', 'Gene', (24, 28))	('nf1b', 'Gene', (15, 19))	('p53m/m', 'Var', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('nf1b', 'Gene', '564518', (15, 19))
43614	32651197	Thus, the loss of suz12 alone was insufficient to drive tumorigenesis in our model within the time frame of our analysis.	('loss', 'Var', (10, 14))	('drive', 'Reg', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('suz12', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
43615	32651197	Tumor onset was markedly accelerated overall in both the p53m/m, nf1b-/-, nf1a+/- (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor onset', 'CPA', (0, 11))	('nf1b', 'Gene', '564518', (65, 69))	('nf1a', 'Gene', '326708', (74, 78))	('nf1a', 'Gene', (74, 78))	('accelerated', 'PosReg', (25, 36))	('p53m/m', 'Var', (57, 63))	('nf1b', 'Gene', (65, 69))
43616	32651197	2A) and the p53m/m, nf1b-/-, nf1a+/+ backgrounds (Fig.	('nf1b', 'Gene', '564518', (20, 24))	('nf1a', 'Gene', (29, 33))	('nf1b', 'Gene', (20, 24))	('nf1a', 'Gene', '326708', (29, 33))	('p53m/m', 'Var', (12, 18))
43617	32651197	Acceleration of tumor onset in suz12-mutant zebrafish compared to wild-type controls were significant for all suz12-mutant populations, independent of whether one (suz12+/+/+/-), two (suz12+/+/-/-) or three (suz12+/-/-/-) alleles in any combination were disrupted.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('suz12-mutant', 'Var', (110, 122))	('suz12-mutant', 'Gene', (31, 43))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('suz12-mutant', 'Gene', (110, 122))	('suz12+/+/+/-', 'Var', (164, 176))	('Acceleration', 'PosReg', (0, 12))	('zebrafish', 'Species', '7955', (44, 53))
43619	32651197	A significant proportion of p53/nf1/suz12-mutant fish developed multiple tumor foci that were cleanly distinguishable by the expression of the sox10:GFP marker gene (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('sox10', 'Gene', (143, 148))	('sox10', 'Gene', '140616', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('developed', 'PosReg', (54, 63))	('tumor', 'Disease', (73, 78))	('p53/nf1/suz12-mutant', 'Var', (28, 48))
43620	32651197	In all p53m/m, nf1b-/-, nf1a+/-, suz12-mutant populations, multiple tumor foci were observed in 10-70% of the tumor-bearing fish.	('tumor', 'Disease', (68, 73))	('nf1a', 'Gene', '326708', (24, 28))	('observed', 'Reg', (84, 92))	('nf1b', 'Gene', (15, 19))	('tumor', 'Disease', (110, 115))	('p53m/m', 'Var', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('nf1b', 'Gene', '564518', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('nf1a', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
43621	32651197	In p53m/m, nf1b-/-, nf1a+/+, suz12-mutant fish the incidence of multiple tumors was much lower, in the range of 0-35%.	('nf1a', 'Gene', (20, 24))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('lower', 'NegReg', (89, 94))	('nf1b', 'Gene', (11, 15))	('p53m/m', 'Var', (3, 9))	('nf1a', 'Gene', '326708', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('nf1b', 'Gene', '564518', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('suz12-mutant', 'Var', (29, 41))	('tumors', 'Disease', (73, 79))
43624	32651197	Because of the low incidence of multifocal tumors in the nf1a+/+ cohort, loss of suz12 did not significantly affect tumor onset.	('multifocal tumors', 'Disease', 'None', (32, 49))	('suz12', 'Gene', (81, 86))	('loss', 'Var', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('multifocal tumors', 'Disease', (32, 49))	('nf1a', 'Gene', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (116, 121))	('nf1a', 'Gene', '326708', (57, 61))
43628	32651197	1C), the spectrum of tumorigenesis was diversified after disruption of suz12 in the p53/nf1-deficient background.	('disruption', 'Var', (57, 67))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('suz12', 'Gene', (71, 76))
43629	32651197	To determine whether the additional tumor types were consistent with those observed in human patients, we examined the SUZ12 mutant sample cohort of the AACR Genie database.	('SUZ12', 'Gene', (119, 124))	('mutant', 'Var', (125, 131))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('patients', 'Species', '9606', (93, 101))	('tumor', 'Disease', (36, 41))
43630	32651197	Mutations in SUZ12 are annotated in 35 tumor types in the AACR Genie database (v4.0), which include MPNST, pancreatic cancer, leukemia and soft tissue sarcoma .	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (139, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('pancreatic cancer', 'Disease', (107, 124))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('SUZ12', 'Gene', (13, 18))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Mutations', 'Var', (0, 9))	('leukemia and soft tissue sarcoma', 'Disease', 'MESH:D012509', (126, 158))	('MPNST', 'Disease', (100, 105))	('tumor', 'Disease', (39, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))
43631	32651197	The most frequently recorded SUZ12-mutated or SUZ12-deleted cancer type category is 'nerve sheath tumor', including MPNSTs (5.56% and 4.21%, respectively).	('MPNSTs', 'Phenotype', 'HP:0100697', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('SUZ12-deleted', 'Var', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('SUZ12-mutated', 'Var', (29, 42))
43632	32651197	Pancreatic cancer, leukemia and soft tissue sarcoma were also found within the sample cohort of the database for combined p53/SUZ12 mutations.	('leukemia and soft tissue sarcoma', 'Disease', 'MESH:D012509', (19, 51))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (32, 51))	('mutations', 'Var', (132, 141))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('p53/SUZ12', 'Gene', (122, 131))	('found', 'Reg', (62, 67))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))	('leukemia', 'Phenotype', 'HP:0001909', (19, 27))
43637	32651197	By contrast, the mixed epithelial/mesenchymal adenosarcoma case displayed a heterogeneous H3K27me3 status with a strong signal in the epithelial glandular cytokeratin-positive compartment and a lack of H3K27me3 in the mesenchymal spindle-like cells (Fig.	('mesenchymal adenosarcoma', 'Disease', (34, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('cytokeratin', 'Gene', '445051', (155, 166))	('mesenchymal adenosarcoma', 'Disease', 'MESH:D018195', (34, 58))	('cytokeratin', 'Gene', (155, 166))	('H3K27me3', 'Var', (90, 98))
43638	32651197	Thus, we performed RNA-seq on p53m/m, nf1b-/-, nf1a+/-, suz12-mutant MPNSTs (n=4) and p53m/m, nf1b-/-, nf1a+/-, suz12-wild-type control MPNSTs (n=3).	('nf1a', 'Gene', '326708', (47, 51))	('p53m/m', 'Var', (30, 36))	('nf1b', 'Gene', '564518', (38, 42))	('nf1a', 'Gene', (103, 107))	('MPNSTs', 'Phenotype', 'HP:0100697', (136, 142))	('nf1b', 'Gene', (94, 98))	('nf1b', 'Gene', '564518', (94, 98))	('MPNSTs', 'Phenotype', 'HP:0100697', (69, 75))	('nf1a', 'Gene', '326708', (103, 107))	('p53m/m', 'Var', (86, 92))	('nf1a', 'Gene', (47, 51))	('nf1b', 'Gene', (38, 42))
43639	32651197	The results demonstrated elevated expression of gene sets representing PRC2 targets and gene sets related to oncogenic Ras signaling in suz12-deficient MPNSTs compared to suz12-wild-type MPNSTs in the p53m/m, nf1b-/-, nf1a+/- background (Table 2,  and ).	('elevate', 'Disease', 'MESH:D006973', (25, 32))	('expression', 'MPA', (34, 44))	('deficient MPNSTs', 'Disease', (142, 158))	('deficient MPNSTs', 'Disease', 'MESH:D018319', (142, 158))	('elevate', 'Disease', (25, 32))	('nf1a', 'Gene', (218, 222))	('MPNSTs', 'Phenotype', 'HP:0100697', (152, 158))	('nf1b', 'Gene', (209, 213))	('p53m/m', 'Var', (201, 207))	('MPNSTs', 'Phenotype', 'HP:0100697', (187, 193))	('nf1a', 'Gene', '326708', (218, 222))	('nf1b', 'Gene', '564518', (209, 213))
43640	32651197	Similar results were obtained when we compared the gene expression profile of p53/nf1/suz12-deficient and p53/nf1/atrx-deficient tumor samples derived from a previous study (Table 2,  and ).	('atrx-deficient tumor', 'Disease', (114, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('p53/nf1/suz12-deficient', 'Var', (78, 101))	('atrx-deficient tumor', 'Disease', 'MESH:D009369', (114, 134))
43641	32651197	To assess Ras-Mapk pathway signaling in suz12 mutant MPNSTs compared to wild-type MPNSTs, we performed immunohistochemistry staining to qualitatively detect phosphorylation levels of Erk, S6 (Rps6) and Akt (p-Erk, p-S6 and p-Akt).	('MPNSTs', 'Phenotype', 'HP:0100697', (53, 59))	('Akt', 'Pathway', (202, 205))	('Rps6', 'Gene', '445028', (192, 196))	('suz12', 'Gene', (40, 45))	('Rps6', 'Gene', (192, 196))	('MPNSTs', 'Phenotype', 'HP:0100697', (82, 88))	('Erk', 'Protein', (183, 186))	('mutant', 'Var', (46, 52))
43643	32651197	Thus, in our suz12-knockout zebrafish model, impaired PRC2-mediated gene silencing cooperates with loss of nf1 to increase signaling through the Ras-Mapk pathway.	('nf1', 'Gene', (107, 110))	('increase', 'PosReg', (114, 122))	('zebrafish', 'Species', '7955', (28, 37))	('signaling', 'MPA', (123, 132))	('PRC2-mediated gene', 'Gene', (54, 72))	('loss', 'Var', (99, 103))	('impaired', 'NegReg', (45, 53))	('Ras-Mapk pathway', 'Pathway', (145, 161))
43644	32651197	This indicated a potentially increased vulnerability of p53m/m, nf1b-/-, nf1a+/-, suz12-mutant tumors towards pharmacological inhibition of this pathway.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('nf1a', 'Gene', (73, 77))	('vulnerability', 'MPA', (39, 52))	('nf1a', 'Gene', '326708', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('increased', 'PosReg', (29, 38))	('nf1b', 'Gene', (64, 68))	('p53m/m', 'Var', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('nf1b', 'Gene', '564518', (64, 68))	('tumors', 'Disease', (95, 101))
43646	32651197	For this assay, single cells were isolated from two groups of matched MPNST tumors: (1) p53m/m, nf1b-/-, nf1a+/-, suz12-mutant MPNSTs and (2) p53m/m, nf1b-/-, nf1a+/-, suz12-wild-type MPNSTs.	('nf1b', 'Gene', '564518', (96, 100))	('MPNSTs', 'Phenotype', 'HP:0100697', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('nf1a', 'Gene', (159, 163))	('nf1a', 'Gene', '326708', (105, 109))	('nf1a', 'Gene', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('nf1b', 'Gene', '564518', (150, 154))	('MPNSTs', 'Phenotype', 'HP:0100697', (127, 133))	('MPNST tumors', 'Disease', (70, 82))	('nf1b', 'Gene', (150, 154))	('p53m/m', 'Var', (142, 148))	('nf1a', 'Gene', '326708', (159, 163))	('nf1b', 'Gene', (96, 100))	('p53m/m', 'Var', (88, 94))	('MPNST tumors', 'Disease', 'MESH:D018319', (70, 82))
43650	32651197	We observed that MEK inhibition resulted in a decreased tumor size for both p53m/m, nf1b-/-, nf1a+/-, suz12-mutant MPNSTs and p53m/m, nf1b-/-, nf1a+/-, suz12-wild-type MPNSTs (Fig.	('nf1b', 'Gene', '564518', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('nf1a', 'Gene', (93, 97))	('nf1b', 'Gene', (84, 88))	('p53m/m', 'Var', (76, 82))	('nf1b', 'Gene', '564518', (84, 88))	('MPNSTs', 'Phenotype', 'HP:0100697', (115, 121))	('nf1a', 'Gene', '326708', (93, 97))	('decreased', 'NegReg', (46, 55))	('suz12-mutant', 'Var', (102, 114))	('inhibition', 'NegReg', (21, 31))	('tumor', 'Disease', (56, 61))	('MPNSTs', 'Phenotype', 'HP:0100697', (168, 174))	('MEK', 'Enzyme', (17, 20))	('nf1a', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('p53m/m', 'Var', (126, 132))	('nf1b', 'Gene', (134, 138))	('nf1a', 'Gene', '326708', (143, 147))
43651	32651197	However, when the responses of the MEK inhibitor-treated suz12-mutant tumors were compared to the suz12-wild-type tumors at 7 dpf, the suz12-mutant tumors were significantly smaller (Fig.	('suz12-mutant', 'Gene', (57, 69))	('smaller', 'NegReg', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('suz12-mutant', 'Var', (135, 147))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
43652	32651197	Knockout of suz12a and suz12b in the zebrafish germline using CRISPR-Cas9 was highly efficient, and the vast majority of F1 fish examined carried a target-locus mutation in both genes, consisting mainly of deletions spanning less than 10 bp.	('suz12b', 'Gene', '561871', (23, 29))	('suz12b', 'Gene', (23, 29))	('suz12a', 'Gene', (12, 18))	('suz12a', 'Gene', '794171', (12, 18))	('mutation', 'Var', (161, 169))	('Knockout', 'Var', (0, 8))	('deletions', 'Var', (206, 215))	('zebrafish', 'Species', '7955', (37, 46))
43654	32651197	Both suz12-deficient lines demonstrated a strongly accelerated overall tumor onset and penetrance, in both the p53m/m, nf1b-/-, nf1a+/+ and the p53m/m, nf1b-/-, nf1a+/- backgrounds.	('p53m/m', 'Var', (144, 150))	('accelerated', 'PosReg', (51, 62))	('nf1a', 'Gene', (128, 132))	('nf1b', 'Gene', (152, 156))	('nf1a', 'Gene', '326708', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('nf1b', 'Gene', (119, 123))	('p53m/m', 'Var', (111, 117))	('nf1b', 'Gene', '564518', (152, 156))	('nf1a', 'Gene', '326708', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('nf1b', 'Gene', '564518', (119, 123))	('tumor', 'Disease', (71, 76))	('nf1a', 'Gene', (161, 165))
43658	32651197	Based on previous studies, it is clear that p53-deficient zebrafish are already prone to delayed-onset MPNSTs and that the additional loss of nf1 accelerates MPNST formation.	('p53-deficient', 'Gene', (44, 57))	('nf1', 'Gene', (142, 145))	('prone', 'Reg', (80, 85))	('zebrafish', 'Species', '7955', (58, 67))	('delayed-onset', 'MPA', (89, 102))	('MPNST formation', 'CPA', (158, 173))	('MPNSTs', 'Phenotype', 'HP:0100697', (103, 109))	('loss', 'Var', (134, 138))	('accelerates', 'PosReg', (146, 157))
43659	32651197	However, the p53m/m, nf1b-/-, nf1a+/+ genotype is only subtly more oncogenic than the p53m/m background.	('nf1a', 'Gene', '326708', (30, 34))	('nf1b', 'Gene', '564518', (21, 25))	('p53m/m', 'Var', (13, 19))	('oncogenic', 'CPA', (67, 76))	('nf1b', 'Gene', (21, 25))	('nf1a', 'Gene', (30, 34))
43661	32651197	Interestingly, we found that a reduction in suz12 gene dosage of only 25% is sufficient in zebrafish to cause a significantly accelerated onset and increased penetrance of tumors in the context of loss of both nf1 and p53, regardless of which of the two suz12 genes was inactivated on one allele (Fig.	('suz12', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('increased', 'PosReg', (148, 157))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('accelerated', 'PosReg', (126, 137))	('loss', 'Var', (197, 201))	('p53', 'Gene', (218, 221))	('penetrance', 'CPA', (158, 168))	('onset', 'CPA', (138, 143))	('nf1', 'Gene', (210, 213))	('zebrafish', 'Species', '7955', (91, 100))
43662	32651197	2) had rather little additional effect over mutating just one allele on the time of tumor onset or tumor penetrance.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutating', 'Var', (44, 52))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
43663	32651197	Apparently, the optimal concentration of Suz12 proteins in the cell is rate limiting, such that a threshold concentration expressed from all four alleles of suz12 is critical for formation of the PRC2 complex, which contains Ezh2, Suz12, Eed and Rbap48.	('Suz12', 'Var', (231, 236))	('Ezh2', 'Gene', (225, 229))	('suz12', 'Gene', (157, 162))	('Eed', 'Gene', '550463', (238, 241))	('Eed', 'Gene', (238, 241))	('Ezh2', 'Gene', '768133', (225, 229))
43664	32651197	These tumor onset curves suggest that after one suz12 allele is lost, there will be little selection pressure in somatic cells to drive the outgrowth of clones that have lost additional alleles through somatic mutation or silencing.	('lost', 'NegReg', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('suz12', 'Gene', (48, 53))	('silencing', 'Var', (222, 231))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
43665	32651197	Seemingly, loss of one allele representing a quarter of the normal gene dosage is sufficient to deplete the PRC2 complex, relax repression of self-renewal and proliferation genes, and thus promote the onset of tumors in the nf1/p53-depleted background.	('PRC2', 'Protein', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('relax', 'NegReg', (122, 127))	('repression', 'MPA', (128, 138))	('loss', 'Var', (11, 15))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('self-renewal', 'Gene', (142, 154))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('promote', 'PosReg', (189, 196))	('onset', 'PosReg', (201, 206))	('deplete', 'NegReg', (96, 103))
43671	32651197	Among the tumors in suz12 mutant fish, only an adenosarcoma with loss of two alleles had high levels of staining for H3K27me3.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutant', 'Var', (26, 32))	('adenosarcoma', 'Disease', (47, 59))	('adenosarcoma', 'Disease', 'MESH:D018195', (47, 59))	('suz12', 'Gene', (20, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('H3K27me3', 'Protein', (117, 125))	('staining', 'MPA', (104, 112))
43674	32651197	Moreover, multiple tumor foci were observed only in zebrafish within the suz12-deficient cohort, and this result was only significant in p53m/m, nf1b-/-, nf1a+/-, suz12-mutant populations.	('nf1a', 'Gene', '326708', (154, 158))	('p53m/m', 'Var', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('nf1b', 'Gene', (145, 149))	('zebrafish', 'Species', '7955', (52, 61))	('nf1b', 'Gene', '564518', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('nf1a', 'Gene', (154, 158))
43676	32651197	Loss of SUZ12 has been linked directly to increased metastasis in gastric cancer and non-small cell lung cancer, suggesting that the multiple tumor foci with the same histology could in part be due to early dissemination from a single primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (243, 248))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (85, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('increased', 'PosReg', (42, 51))	('metastasis', 'CPA', (52, 62))	('tumor', 'Disease', (142, 147))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (85, 111))	('gastric cancer', 'Disease', (66, 80))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('non-small cell lung cancer', 'Disease', (85, 111))	('SUZ12', 'Gene', (8, 13))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
43677	32651197	In the p53m/m, nf1b-/-, nf1a+/+ or nf1a-/+ backgrounds, we observed a strong diversification of tumorigenesis upon loss of the important epigenetic regulator tumor suppressor suz12.	('tumor', 'Disease', (158, 163))	('nf1a', 'Gene', '326708', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss', 'NegReg', (115, 119))	('nf1a', 'Gene', (35, 39))	('nf1b', 'Gene', (15, 19))	('tumor', 'Disease', (96, 101))	('p53m/m', 'Var', (7, 13))	('nf1a', 'Gene', '326708', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('nf1b', 'Gene', '564518', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('nf1a', 'Gene', (24, 28))
43678	32651197	By contrast, loss of the Ras-inactivating tumor suppressor nf1 in suz12-wild-type fish mainly accelerated the onset of MPNSTs, while inducing none of the other neoplasms observed in our study.	('nf1', 'Gene', (59, 62))	('neoplasms', 'Phenotype', 'HP:0002664', (160, 169))	('tumor', 'Disease', (42, 47))	('MPNSTs', 'Phenotype', 'HP:0100697', (119, 125))	('onset', 'MPA', (110, 115))	('neoplasms', 'Disease', 'MESH:D009369', (160, 169))	('neoplasms', 'Disease', (160, 169))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('loss', 'Var', (13, 17))	('inducing', 'Reg', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('accelerated', 'PosReg', (94, 105))
43679	32651197	Notably, a recently described zebrafish model based solely on the full deletion of p53 (p53del/del) was prone to generate a broad spectrum of tumors, including leukemias.	('generate', 'PosReg', (113, 121))	('leukemias', 'Phenotype', 'HP:0001909', (160, 169))	('p53del/del', 'Var', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('leukemias', 'Disease', (160, 169))	('p53', 'Gene', (83, 86))	('p53del/del', 'Mutation', 'p53del/del', (88, 98))	('leukemias', 'Disease', 'MESH:D007938', (160, 169))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('leukemia', 'Phenotype', 'HP:0001909', (160, 168))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('zebrafish', 'Species', '7955', (30, 39))
43680	32651197	Loss of SUZ12 promotes the onset of a variety of malignancies, including blood cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('blood cancer', 'Disease', (73, 85))	('blood cancer', 'Disease', 'MESH:D007022', (73, 85))	('promotes', 'PosReg', (14, 22))	('malignancies', 'Disease', (49, 61))	('SUZ12', 'Gene', (8, 13))	('Loss', 'Var', (0, 4))	('blood cancer', 'Phenotype', 'HP:0001909', (73, 85))
43682	32651197	Moreover, the leukemia penetrance of 20% provides a workable model of human leukemia with these mutations for future studies and the potential to specify leukemia subtypes.	('leukemia', 'Phenotype', 'HP:0001909', (154, 162))	('leukemia', 'Disease', 'MESH:D007938', (154, 162))	('leukemia', 'Disease', (154, 162))	('leukemia', 'Disease', (14, 22))	('leukemia', 'Phenotype', 'HP:0001909', (14, 22))	('leukemia', 'Disease', 'MESH:D007938', (14, 22))	('human', 'Species', '9606', (70, 75))	('leukemia', 'Disease', (76, 84))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))	('mutations', 'Var', (96, 105))
43683	32651197	In the tumors, it is likely that additional suz12 alleles are inactivated either by somatically acquired mutations, deletions or silencing.	('suz12', 'Gene', (44, 49))	('deletions', 'Var', (116, 125))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('silencing', 'Var', (129, 138))	('mutations', 'Var', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
43684	32651197	4, reflects the strong selection against these suppressive epigenetic marks in the multistep clonal selection that occurred during transformation of these primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('epigenetic marks', 'Var', (59, 75))	('tumors', 'Disease', 'MESH:D009369', (163, 169))
43686	32651197	As expected, zebrafish tumors with loss of suz12 exhibited decreased H3K27me3 and upregulation of PRC2 target gene sets.	('PRC2 target gene sets', 'Gene', (98, 119))	('zebrafish', 'Species', '7955', (13, 22))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('decreased', 'NegReg', (59, 68))	('loss', 'Var', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('H3K27me3', 'Protein', (69, 77))	('upregulation', 'PosReg', (82, 94))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('suz12', 'Gene', (43, 48))
43687	32651197	As described previously, MPNSTs characterized by H3K27me3 loss have worse survival rates than tumors retaining this epigenetic mark.	('loss', 'NegReg', (58, 62))	('worse', 'NegReg', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('MPNSTs', 'Phenotype', 'HP:0100697', (25, 31))	('survival rates', 'CPA', (74, 88))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('H3K27me3', 'Var', (49, 57))
43703	32651197	It is known from the murine system that diminished PRC2 function caused by Suz12 knockout leads to elevated RAS signaling, which promotes MPNST development by amplifying RAS-driven transcription due to modulation of the chromatin structure.	('PRC2', 'Gene', (51, 55))	('diminished', 'NegReg', (40, 50))	('promotes', 'PosReg', (129, 137))	('elevate', 'Disease', (99, 106))	('RAS signaling', 'MPA', (108, 121))	('knockout', 'Var', (81, 89))	('function', 'MPA', (56, 64))	('modulation', 'Reg', (202, 212))	('Suz12', 'Gene', (75, 80))	('MPNST development', 'CPA', (138, 155))	('RAS-driven transcription', 'MPA', (170, 194))	('amplifying', 'PosReg', (159, 169))	('elevate', 'Disease', 'MESH:D006973', (99, 106))	('murine', 'Species', '10090', (21, 27))
43705	32651197	It is reasonable to conclude that increased RAS-MAPK signaling initiated by the loss of PRC2-mediated transcriptional repression synergizes in tumorigenesis with loss of NF1, a potent deactivator of oncogenic RAS, because in this situation elevated RAS activation is combined with an impaired ability of cells to turn off RAS.	('elevate', 'Disease', 'MESH:D006973', (240, 247))	('NF1', 'Gene', (170, 173))	('RAS', 'Protein', (249, 252))	('PRC2-mediated transcriptional repression', 'Gene', (88, 128))	('tumor', 'Disease', (143, 148))	('RAS-MAPK signaling', 'MPA', (44, 62))	('loss', 'Var', (162, 166))	('activation', 'PosReg', (253, 263))	('loss', 'Var', (80, 84))	('elevate', 'Disease', (240, 247))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('increased', 'PosReg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
43708	32651197	It has previously been described in the murine system that Suz12 acts as a tumor suppressor in Nf1-deficient but not in Nf1-wild-type tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Nf1', 'Gene', (120, 123))	('Nf1', 'Gene', '18015', (95, 98))	('murine', 'Species', '10090', (40, 46))	('Suz12', 'Var', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Nf1', 'Gene', '18015', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Nf1', 'Gene', (95, 98))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', (134, 139))
43709	32651197	In combination with our findings, this indicates that simultaneous loss-of-function mutations or deletions of the tumor suppressors SUZ12 and NF1 might be a marker for the clinical use of molecular targeted drugs against MPNSTs that inhibit the RAS-MAPK pathway, for example MEK inhibitors such as Trametinib, Cobimetinib, and Binimetinib.	('RAS-MAPK pathway', 'Pathway', (245, 261))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Cobimetinib', 'Chemical', 'MESH:C574276', (310, 321))	('MPNSTs', 'Phenotype', 'HP:0100697', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('mutations', 'Var', (84, 93))	('MEK', 'Enzyme', (275, 278))	('inhibit', 'NegReg', (233, 240))	('deletions', 'Var', (97, 106))	('loss-of-function', 'NegReg', (67, 83))	('Trametinib', 'Chemical', 'MESH:C560077', (298, 308))	('SUZ12', 'Gene', (132, 137))	('NF1', 'Gene', (142, 145))	('Binimetinib', 'Chemical', 'MESH:C581313', (327, 338))
43710	32651197	In mice, it is known that combined deficiencies in Tp53 and Nf1 synergize in the onset of MPNSTs and high-grade gliomas, and that the combined loss of Suz12 and Nf1 cooperate in the initiation of MPNSTs without loss of Tp53.	('Suz12', 'Gene', (151, 156))	('Nf1', 'Gene', (161, 164))	('deficiencies', 'Var', (35, 47))	('Tp53', 'Gene', (51, 55))	('Tp53', 'Gene', (219, 223))	('mice', 'Species', '10090', (3, 7))	('Nf1', 'Gene', '18015', (60, 63))	('Tp53', 'Gene', '22059', (51, 55))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('Tp53', 'Gene', '22059', (219, 223))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('MPNSTs', 'Phenotype', 'HP:0100697', (196, 202))	('Nf1', 'Gene', '18015', (161, 164))	('MPNSTs', 'CPA', (90, 96))	('MPNSTs', 'Phenotype', 'HP:0100697', (90, 96))	('loss', 'Var', (143, 147))	('Nf1', 'Gene', (60, 63))
43712	32651197	The mutational and deletional inactivation of all three of these genes occurs in at least 28% of human MPNST tumors, making this a very important genotype in MPNST biology.	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('human', 'Species', '9606', (97, 102))	('deletional inactivation', 'Var', (19, 42))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MPNST tumors', 'Disease', (103, 115))	('mutational', 'Var', (4, 14))	('MPNST tumors', 'Disease', 'MESH:D018319', (103, 115))
43714	32651197	It is known that the combined deficiencies in p53 and nf1 synergize in the onset of MPNSTs and high-grade gliomas, and that the combined deficiencies in Suz12 and Nf1 cooperate in widespread tumor development in mice.	('MPNSTs', 'CPA', (84, 90))	('deficiencies', 'Var', (30, 42))	('mice', 'Species', '10090', (212, 216))	('Suz12', 'Gene', (153, 158))	('cooperate', 'Reg', (167, 176))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('p53', 'Gene', (46, 49))	('nf1', 'Gene', (54, 57))	('Nf1', 'Gene', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('MPNSTs', 'Phenotype', 'HP:0100697', (84, 90))	('deficiencies', 'Var', (137, 149))	('Nf1', 'Gene', '18015', (163, 166))
43716	32651197	The inactivation of one or more alleles of suz12 in zebrafish with an nf1/p53 sensitized genetic background accelerates tumor onset and expands the spectrum of tumors in a fashion consistent with genetic abnormalities found in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('inactivation', 'Var', (4, 16))	('genetic abnormalities', 'Disease', 'MESH:D030342', (196, 217))	('expands', 'PosReg', (136, 143))	('genetic abnormalities', 'Disease', (196, 217))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('tumor', 'Disease', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('suz12', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('accelerates', 'PosReg', (108, 119))	('tumor', 'Disease', (160, 165))	('zebrafish', 'Species', '7955', (52, 61))	('human', 'Species', '9606', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancers', 'Disease', (233, 240))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
43717	32651197	Thus, the consequences of loss of H3K27me3 marks maintained by PRC2 during oncogenesis might be conserved between zebrafish and humans, raising the possibility that important strategies to counteract these epigenetic alterations can be investigated in zebrafish models, ultimately leading to the identification of specific molecules that antagonize the cancer-promoting effects of PRC2 deficiency.	('PRC2', 'Gene', (63, 67))	('antagonize', 'NegReg', (338, 348))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('H3K27me3', 'Protein', (34, 42))	('cancer', 'Disease', (353, 359))	('zebrafish', 'Species', '7955', (114, 123))	('humans', 'Species', '9606', (128, 134))	('loss', 'NegReg', (26, 30))	('zebrafish', 'Species', '7955', (252, 261))	('PRC2', 'Gene', (381, 385))	('deficiency', 'Var', (386, 396))
43718	32651197	However, zebrafish is unlikely to be a good model of some tumors commonly associated with suz12 mutations, such as penile, endometrial, and bladder carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('penile', 'Disease', (115, 121))	('bladder carcinomas', 'Disease', 'MESH:D001749', (140, 158))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (140, 158))	('zebrafish', 'Species', '7955', (9, 18))	('suz12', 'Gene', (90, 95))	('endometrial', 'Disease', (123, 134))	('bladder carcinomas', 'Disease', (140, 158))	('mutations', 'Var', (96, 105))
43735	32651197	The sox10:GFP zebrafish were genotyped for mutations in nf1a, suz12a and/or suz12b at age 2-3 months and sorted into separate tanks by genotype.	('sox10', 'Gene', (4, 9))	('sox10', 'Gene', '140616', (4, 9))	('nf1a', 'Gene', (56, 60))	('zebrafish', 'Species', '7955', (14, 23))	('suz12b', 'Gene', '561871', (76, 82))	('nf1a', 'Gene', '326708', (56, 60))	('suz12a', 'Gene', (62, 68))	('suz12b', 'Gene', (76, 82))	('mutations', 'Var', (43, 52))	('suz12a', 'Gene', '794171', (62, 68))
43746	32651197	Immunohistochemistry staining was performed as described previously using the following primary antibodies: phospho-p44/42 MAPK (ERK1/2) (Thr202/Tyr204; Cell Signaling Technology #4370; 1:150), phospho-AKT (Ser473; Cell Signaling Technology #4060; 1:100), phospho-S6 ribosomal protein (Ser240/244; Cell Signaling Technology #4838; 1:100).	('Ser473', 'Var', (207, 213))	('Ser240', 'Chemical', '-', (286, 292))	('Ser473', 'Chemical', '-', (207, 213))	('Tyr204', 'Chemical', '-', (145, 151))	('Thr202', 'Chemical', '-', (138, 144))	('ERK1/2', 'Gene', (129, 135))	('ERK1/2', 'Gene', '399480;360144', (129, 135))	('Ser240/244;', 'Var', (286, 297))
43748	32651197	Primary antibodies used were pan-cytokeratin (AE1/AE3; Novus Biologicals #NBP2-29429; 1:200) and tri-methyl-Histone H3 (Lys27) (C36B11; Cell Signaling Technology #9733; 1:400).	('Histone H3', 'Gene', (108, 118))	('Histone H3', 'Gene', '100000930', (108, 118))	('cytokeratin', 'Gene', (33, 44))	('AE1', 'Gene', '84703', (46, 49))	('AE3', 'Gene', '100333073', (50, 53))	('AE3', 'Gene', (50, 53))	('AE1', 'Gene', (46, 49))	('C36B11;', 'Var', (128, 135))	('Lys27', 'Chemical', '-', (120, 125))	('cytokeratin', 'Gene', '445051', (33, 44))
43751	32651197	Four p53m/m, nf1b-/-, nf1a+/-, suz12-mutant (two p53m/m, nf1b-/-, nf1a+/-, suz12a+/-, suz12b+/- and two p53m/m, nf1b-/-, nf1a+/-, suz12a+/-, suz12b-/-) were analysed, as previously described.	('suz12a', 'Gene', '794171', (130, 136))	('suz12a', 'Gene', '794171', (75, 81))	('suz12b', 'Gene', (141, 147))	('suz12b', 'Gene', (86, 92))	('nf1a', 'Gene', (22, 26))	('nf1a', 'Gene', '326708', (22, 26))	('nf1a', 'Gene', (66, 70))	('nf1a', 'Gene', (121, 125))	('suz12b', 'Gene', '561871', (141, 147))	('suz12b', 'Gene', '561871', (86, 92))	('nf1b', 'Gene', (57, 61))	('p53m/m', 'Var', (49, 55))	('nf1b', 'Gene', (112, 116))	('nf1b', 'Gene', '564518', (57, 61))	('nf1b', 'Gene', '564518', (112, 116))	('suz12a', 'Gene', (130, 136))	('suz12a', 'Gene', (75, 81))	('nf1a', 'Gene', '326708', (66, 70))	('nf1a', 'Gene', '326708', (121, 125))	('nf1b', 'Gene', (13, 17))	('nf1b', 'Gene', '564518', (13, 17))
43752	32651197	As control samples, the RNA-seq data of three p53m/m, nf1b-/-, nf1a+/-, suz12-wild-type tumors of a previous study were used (Oppel et al., 2019).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('nf1a', 'Gene', (63, 67))	('nf1b', 'Gene', (54, 58))	('p53m/m', 'Var', (46, 52))	('nf1a', 'Gene', '326708', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('nf1b', 'Gene', '564518', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
43773	30622826	A 21-year-old, G0P0 woman presented with a four-month history of excessive and prolonged bleeding per vagina, as well as a palpated mass at the lower abdomen that was rapidly increasing in size.	('bleeding', 'Disease', 'MESH:D006470', (89, 97))	('woman', 'Species', '9606', (20, 25))	('bleeding', 'Disease', (89, 97))	('G0P0', 'Var', (15, 19))
43807	30622826	The unique clinical behavior and treatment responses of this subset of ESS therefore merit pathologic evaluation to confirm the presence of the t(10;17)(q22;p13) translocation in cases of morphologically suspected HG-ESS.	('t(10;17)(q22;p13', 'Var', (144, 160))	('HG-ESS', 'Disease', (214, 220))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (144, 161))
43828	30140378	Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy.	('malignancy', 'Disease', (120, 130))	('resulting in', 'Reg', (79, 91))	('gene expression', 'MPA', (62, 77))	('cellular transformation', 'CPA', (92, 115))	('epigenetic balance', 'MPA', (16, 34))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))	('Perturbation', 'Var', (0, 12))	('lead to alterations', 'Reg', (39, 58))
43842	30140378	The most frequent gene mutations involve STAG2 and TP53, and copy number alteration events such as gains of chromosome 1q, 2, 8 and 12, and losses of 9p (affecting CDKN2A) and 16q.	('STAG2', 'Gene', (41, 46))	('TP53', 'Gene', (51, 55))	('STAG2', 'Gene', '10735', (41, 46))	('losses', 'NegReg', (140, 146))	('mutations', 'Var', (23, 32))	('CDKN2A', 'Gene', (164, 170))	('gains', 'PosReg', (99, 104))	('copy number alteration', 'Var', (61, 83))	('CDKN2A', 'Gene', '1029', (164, 170))	('TP53', 'Gene', '7157', (51, 55))
43843	30140378	Recently, some publications have shed light on the role of the epigenome in oncogenesis and tumor progression in ES and have contributed to deeply understand how EWS-FLI1 participates in these processes.	('ES', 'Phenotype', 'HP:0012254', (113, 115))	('EWS-FLI1', 'Gene', '2130;2313', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('epigenome', 'Var', (63, 72))	('participates', 'Reg', (171, 183))	('oncogenesis', 'CPA', (76, 87))	('tumor', 'Disease', (92, 97))	('EWS-FLI1', 'Gene', (162, 170))
43850	30140378	On the other hand, specific inhibitors of LSD1 have been proposed as a potential alternative due to the aberrant expression of LSD1 in several types of cancer such as breast, colorectal, neuroblastoma, osteosarcoma, rhabdomyosarcoma, and synovial sarcoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (187, 200))	('rhabdomyosarcoma', 'Disease', (216, 232))	('colorectal', 'Disease', (175, 185))	('aberrant', 'Var', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('synovial sarcoma', 'Disease', (238, 254))	('cancer', 'Disease', (152, 158))	('osteosarcoma', 'Disease', (202, 214))	('osteosarcoma', 'Disease', 'MESH:D012516', (202, 214))	('synovial sarcoma', 'Disease', 'MESH:D013584', (238, 254))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (216, 232))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (238, 254))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (216, 232))	('breast', 'Disease', (167, 173))	('LSD1', 'Gene', (42, 46))	('osteosarcoma', 'Phenotype', 'HP:0002669', (202, 214))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('LSD1', 'Gene', '23028', (42, 46))	('neuroblastoma', 'Disease', (187, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('neuroblastoma', 'Phenotype', 'HP:0003006', (187, 200))	('LSD1', 'Gene', (127, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (247, 254))	('LSD1', 'Gene', '23028', (127, 131))
43851	30140378	Specifically, HCI-2509, a reversible LSD1 inhibitor, disrupted the oncogenic activity of EWS-ETS fusions, impaired cell viability, and induced apoptosis as a single agent in ES cell lines.	('disrupted', 'NegReg', (53, 62))	('fusions', 'Var', (97, 104))	('induced', 'Reg', (135, 142))	('HCI-2509', 'Chemical', '-', (14, 22))	('cell viability', 'CPA', (115, 129))	('oncogenic activity', 'CPA', (67, 85))	('LSD1', 'Gene', (37, 41))	('impaired', 'NegReg', (106, 114))	('apoptosis', 'CPA', (143, 152))	('EWS', 'Gene', (89, 92))	('LSD1', 'Gene', '23028', (37, 41))	('EWS', 'Gene', '2130', (89, 92))	('ES', 'Phenotype', 'HP:0012254', (174, 176))
43858	30140378	Moreover, a reduction of tumor growth in ES patient-derived xenograft (ES-PDX) mouse models with this epigenetic drug combination was observed.	('mouse', 'Species', '10090', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('patient', 'Species', '9606', (44, 51))	('ES', 'Phenotype', 'HP:0012254', (41, 43))	('reduction', 'NegReg', (12, 21))	('tumor', 'Disease', (25, 30))	('ES', 'Phenotype', 'HP:0012254', (71, 73))	('epigenetic drug combination', 'Var', (102, 129))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
43866	30140378	There were no significant differences in IC50 values between cells bearing EWS-FLI1 fusions with respect to those with other gene fusions (Supplementary Figure 1A and 1B).	('EWS-FLI1', 'Gene', (75, 83))	('IC50 values', 'MPA', (41, 52))	('EWS-FLI1', 'Gene', '2130;2313', (75, 83))	('fusions', 'Var', (84, 91))
43867	30140378	We also evaluated the impact of the gain of chromosome 1q on the response to both drugs since 1qG has been shown to have a strong negative impact on clinical outcome of ES patients; no statistically significant differences were found (Supplementary Figure 1C and 1D).	('patients', 'Species', '9606', (172, 180))	('1qG', 'Var', (94, 97))	('ES', 'Phenotype', 'HP:0012254', (169, 171))	('negative', 'NegReg', (130, 138))
43892	30140378	Thus, a functional primary effect on EWS-FLI1 expression is achieved by these epigenetic drugs.	('EWS-FLI1', 'Gene', '2130;2313', (37, 45))	('epigenetic drugs', 'Var', (78, 94))	('expression', 'MPA', (46, 56))	('EWS-FLI1', 'Gene', (37, 45))
43912	30140378	We performed survival studies in four ES PDX models: HSJD-ES-001, HSJD-ES-004, HSJD-ES-006 and HSJD-ES-011 after drug treatment.	('ES', 'Phenotype', 'HP:0012254', (38, 40))	('ES', 'Phenotype', 'HP:0012254', (100, 102))	('HSJD-ES-001', 'Disease', (53, 64))	('HSJD-ES-004', 'Var', (66, 77))	('ES', 'Phenotype', 'HP:0012254', (84, 86))	('ES', 'Phenotype', 'HP:0012254', (71, 73))	('HSJD-ES-001', 'Disease', 'MESH:C563168', (53, 64))	('HSJD-ES-011', 'Var', (95, 106))	('HSJD-ES-006', 'Var', (79, 90))	('ES', 'Phenotype', 'HP:0012254', (58, 60))
43913	30140378	Safe doses were administered both for SAHA (100 mg/kg) and HCI-2509 (30 mg/kg) once daily (5 days on, 2 days off) intraperitoneal injection for three weeks.	('HCI-2509', 'Chemical', '-', (59, 67))	('100 mg/kg', 'Var', (44, 53))	('HCI-2509', 'Gene', (59, 67))	('SAHA', 'Chemical', 'MESH:D000077337', (38, 42))
43916	30140378	Taking into account the tumor volume at the end of treatment (21 days), we observed that tumors in the combination groups were significantly smaller in the four models with respect to the control group (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('combination', 'Var', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('smaller', 'NegReg', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
43918	30140378	Despite the differences in the tumor volume at day 21, tumors from HSJD-ES-001, HSJD-ES-006 and HSJD-ES-011 progressed after three cycles of treatment (Figure 3B).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('HSJD-ES-001, HSJD-ES-006', 'Disease', 'MESH:C563168', (67, 91))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('HSJD-ES-011', 'Var', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (55, 60))	('ES', 'Phenotype', 'HP:0012254', (101, 103))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('ES', 'Phenotype', 'HP:0012254', (85, 87))	('progressed', 'PosReg', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('ES', 'Phenotype', 'HP:0012254', (72, 74))
43930	30140378	Moreover, a synergistic reduction of EWS-FLI1 was observed in cases treated with the drug combination compared to any other experimental condition.	('reduction', 'NegReg', (24, 33))	('EWS-FLI1', 'Gene', (37, 45))	('drug combination', 'Var', (85, 101))	('EWS-FLI1', 'Gene', '2130;2313', (37, 45))
43935	30140378	The first generation of epigenetic drugs, such as SAHA, has shown modest anti-tumor efficacy in Phase I and II clinical trials in patients with solid tumors in monotherapy, as well as in acute myeloid leukemia.	('SAHA', 'Chemical', 'MESH:D000077337', (50, 54))	('acute myeloid leukemia', 'Disease', (187, 209))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('solid tumors', 'Disease', (144, 156))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (187, 209))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (130, 138))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (193, 209))	('leukemia', 'Phenotype', 'HP:0001909', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (78, 83))	('solid tumors', 'Disease', 'MESH:D009369', (144, 156))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (187, 209))	('epigenetic drugs', 'Var', (24, 40))	('tumor', 'Disease', (150, 155))
43965	30140378	recently proposed a model in which EWS-FLI1 low levels drive ES cells dissemination.	('ES cells dissemination', 'CPA', (61, 83))	('low', 'Var', (44, 47))	('drive', 'Reg', (55, 60))	('ES', 'Phenotype', 'HP:0012254', (61, 63))	('EWS-FLI1', 'Gene', (35, 43))	('EWS-FLI1', 'Gene', '2130;2313', (35, 43))
44012	29757938	A knockdown of PIEZO1 with siRNA in SW982 cells abolished Yoda1-induced Ca2+ response and significantly reduced cell cell-viability.	('cell cell-viability', 'CPA', (112, 131))	('reduced', 'NegReg', (104, 111))	('SW982', 'CellLine', 'CVCL:1734', (36, 41))	('knockdown', 'Var', (2, 11))	('abolished', 'NegReg', (48, 57))	('Ca2+', 'Chemical', 'MESH:D000069285', (72, 76))	('PIEZO1', 'Gene', (15, 21))	('Yoda1-induced Ca2+ response', 'MPA', (58, 85))
44013	29757938	Because PIEZO1 is highly expressed in SW982 cells and its knockdown affects cell-viability, this gene is a potential target against synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (132, 148))	('synovial sarcoma', 'Disease', 'MESH:D013584', (132, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('affects', 'Reg', (68, 75))	('PIEZO1', 'Gene', (8, 14))	('SW982', 'CellLine', 'CVCL:1734', (38, 43))	('cell-viability', 'CPA', (76, 90))	('synovial sarcoma', 'Disease', (132, 148))	('knockdown', 'Var', (58, 67))
44020	29757938	Moreover, PIEZO1 is involved in red blood cell function, because mutations in this gene cause dehydrated hereditary xerocytosis.	('mutations', 'Var', (65, 74))	('dehydrated hereditary xerocytosis', 'Disease', 'MESH:C536764', (94, 127))	('dehydrated hereditary xerocytosis', 'Disease', (94, 127))	('cause', 'Reg', (88, 93))
44027	29757938	Because PIEZO1 is also known as Fam38A, an integrin-interacting protein, we hypothesized that its dysfunction may affect cancer cell survival.	('dysfunction', 'Var', (98, 109))	('Fam38A', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('affect', 'Reg', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('Fam38A', 'Gene', '9780', (32, 38))
44028	29757938	Here, by employing PIEZO1 agonist Yoda1 and siRNA technology, we demonstrate that PIEZO1 is highly expressed in human synovial sarcoma SW982 cells and its knockdown affects the cell-viability.	('knockdown', 'Var', (155, 164))	('PIEZO1', 'Gene', (82, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('synovial sarcoma SW982', 'Disease', (118, 140))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (118, 134))	('synovial sarcoma SW982', 'Disease', 'MESH:D013584', (118, 140))	('affects', 'Reg', (165, 172))	('human', 'Species', '9606', (112, 117))	('cell-viability', 'CPA', (177, 191))
44042	29757938	To test the function of PIEZO1 in synovial sarcoma, we next knocked down PIEZO1 in SW982 cells using stealth small interfering RNA (siRNA).	('knocked', 'Var', (60, 67))	('synovial sarcoma', 'Disease', (34, 50))	('PIEZO1', 'Gene', (73, 79))	('SW982', 'CellLine', 'CVCL:1734', (83, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (34, 50))	('synovial sarcoma', 'Disease', 'MESH:D013584', (34, 50))
44048	29757938	As shown in Figure 4E, PIEZO1 knockdown in SW982 cells effectively reduced cell-viability, suggesting that this protein is a functional regulator of cell-viability in SW982 synovial sarcoma cells.	('synovial sarcoma', 'Disease', (173, 189))	('PIEZO1', 'Gene', (23, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('SW982', 'CellLine', 'CVCL:1734', (43, 48))	('synovial sarcoma', 'Disease', 'MESH:D013584', (173, 189))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (173, 189))	('SW982', 'CellLine', 'CVCL:1734', (167, 172))	('reduced', 'NegReg', (67, 74))	('knockdown', 'Var', (30, 39))	('cell-viability', 'CPA', (75, 89))
44050	29757938	Knocking down PIEZO1 expression reduced SW982 cell-viability as well as Yoda1-induced Ca2+ response, suggesting that PIEZO1 is a potential regulator of cancer cell-viability.	('cancer', 'Disease', (152, 158))	('Yoda1-induced Ca2+ response', 'MPA', (72, 99))	('Knocking down', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('SW982', 'CellLine', 'CVCL:1734', (40, 45))	('PIEZO1', 'Gene', (14, 20))	('reduced', 'NegReg', (32, 39))	('Ca2+', 'Chemical', 'MESH:D000069285', (86, 90))	('SW982', 'MPA', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
44056	29757938	The conductance of Yoda1-induced intrinsic channel was identical to that of mechanical stress sensitive channel (21.6 pS, Figure 2C): Yoda1 at 3 muM and 10 muM had little effect on HEK-hTRPC4 cells and HEK-cont cells (Supplementary Figure S1).	('muM', 'Gene', '56925', (145, 148))	('HEK-cont', 'CellLine', 'CVCL:4W25', (202, 210))	('HEK-hTRPC4', 'CellLine', 'CVCL:2I01', (181, 191))	('Yoda1', 'Var', (134, 139))	('muM', 'Gene', (145, 148))	('muM', 'Gene', '56925', (156, 159))	('muM', 'Gene', (156, 159))
44061	29757938	In the present study, the knockdown of PIEZO1 significantly reduced the cell-viability of SW982 cells.	('cell-viability of SW982 cells', 'CPA', (72, 101))	('reduced', 'NegReg', (60, 67))	('knockdown', 'Var', (26, 35))	('PIEZO1', 'Gene', (39, 45))	('SW982', 'CellLine', 'CVCL:1734', (90, 95))
44067	29757938	A smooth muscle cell-specific loss of PIEZO1 causes the deficit of arterial remodeling upon hypertension.	('PIEZO1', 'Gene', (38, 44))	('hypertension', 'Disease', (92, 104))	('hypertension', 'Phenotype', 'HP:0000822', (92, 104))	('arterial remodeling', 'CPA', (67, 86))	('loss', 'Var', (30, 34))	('hypertension', 'Disease', 'MESH:D006973', (92, 104))
44093	29757938	The following are available online at , Figure S1: Yoda1 has no effect on membrane currents in HEK-hTRPC4 and HEK-cont cells.	('HEK-hTRPC4', 'CellLine', 'CVCL:2I01', (95, 105))	('membrane currents', 'MPA', (74, 91))	('HEK-cont', 'CellLine', 'CVCL:4W25', (110, 118))	('Yoda1', 'Var', (51, 56))
44095	29757938	Right panel: A typical I-V exhibited before and after the application of 3 muM Yoda1, and before and after the application of 100 nM EA.	('Yoda1', 'Var', (79, 84))	('muM', 'Gene', '56925', (75, 78))	('muM', 'Gene', (75, 78))
44126	28186981	Using these cutoffs, patients with higher 18F-FDG SUVs had worse OS (p = 0.007) and a trend toward worse PFS (p = 0.11) than patients with a lower 18F-FDG SUVs (Figure 4).	('patients', 'Species', '9606', (125, 133))	('18F-FDG SUVs', 'Var', (42, 54))	('OS', 'Chemical', '-', (65, 67))	('patients', 'Species', '9606', (21, 29))	('FDG', 'Chemical', 'MESH:D019788', (46, 49))	('PFS', 'MPA', (105, 108))	('FDG', 'Chemical', 'MESH:D019788', (151, 154))	('worse', 'NegReg', (99, 104))
44132	28186981	Despite heterogeneity in treatment regimens, disease stages, and histological types in the patients examined in this retrospective study, 18F-FDG/18F-FES SUV ratio was correlated with both PFS (p = 0.007) and OS (p = 0.005).	('18F-FES', 'Chemical', '-', (146, 153))	('PFS', 'Disease', (189, 192))	('patients', 'Species', '9606', (91, 99))	('FDG', 'Chemical', 'MESH:D019788', (142, 145))	('OS', 'Chemical', '-', (209, 211))	('correlated', 'Reg', (168, 178))	('18F-FDG/18F-FES', 'Var', (138, 153))
44318	25886606	The dissemination of EBG was associated with a limited improvement in sarcoma management when measured in this before-after population-based study, and this improvement was dependent on the primary location of the tumour.	('men', 'Species', '9606', (62, 65))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('sarcoma', 'Disease', (70, 77))	('tumour', 'Disease', (214, 220))	('dissemination', 'Var', (4, 17))	('EBG', 'Gene', (21, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('EBG', 'Chemical', '-', (21, 24))	('men', 'Species', '9606', (84, 87))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('men', 'Species', '9606', (164, 167))
44334	25886606	The sarcoma morphologies that were included in the present study were as follows (coded with International Classification of Diseases for Oncology - third edition - ICD-O 3): 8710/3, 8711/3, 8800/3-8933/3, 8935/3-8940/3, 8950/3-8951/3, 8963/3-8964/3, 8980/3-8991/3, 9040/3-9044/3, 9120/3-9260/3, 9290/3, 9330/3,9342/3, 9364/3, 9365/3, 9473/3, 9480/3, 9508/3 and 9539/3-9581/3.	('colo', 'Species', '307630', (140, 144))	('sarcoma', 'Disease', (4, 11))	('8710/3', 'Var', (175, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Oncology', 'Phenotype', 'HP:0002664', (138, 146))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))
44358	25886606	Improvements in the management of adult sarcoma were observed for soft tissue and bone sarcomas (Table 3): we observed a statistically significant increase in the proportion of EIC discussions (50.0 vs 74.4%, p = 0.020), EIC discussions within 90 days after diagnosis (76.2 vs 100%, p = 0.007) and R0 resections (57.9 vs 91.4%, p = 0.002).	('EIC discussions', 'Var', (177, 192))	('bone sarcomas', 'Disease', 'MESH:D001847', (82, 95))	('bone sarcoma', 'Phenotype', 'HP:0002669', (82, 94))	('EIC discussions', 'Var', (221, 236))	('bone sarcomas', 'Disease', (82, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('bone sarcomas', 'Phenotype', 'HP:0002669', (82, 95))	('men', 'Species', '9606', (26, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('increase', 'PosReg', (147, 155))	('adult sarcoma', 'Disease', 'MESH:D012509', (34, 47))	('men', 'Species', '9606', (7, 10))	('soft tissue and bone sarcoma', 'Phenotype', 'HP:0030448', (66, 94))	('soft tissue and bone sarcomas', 'Phenotype', 'HP:0030448', (66, 95))	('adult sarcoma', 'Disease', (34, 47))
44517	20964813	Testing for JAK2 mutation was negative as was flow cytometry.	('JAK2', 'Gene', (12, 16))	('mutation', 'Var', (17, 25))	('JAK2', 'Gene', '3717', (12, 16))
44526	20964813	Eosinophilia is defined as mild (350 to 1,500 cells/muL), moderate (1,500 to 5000 cells/uL), or severe (>5,000 cells/muL).	('Eosinophilia', 'Phenotype', 'HP:0001880', (0, 12))	('Eosinophilia', 'Disease', (0, 12))	('Eosinophilia', 'Disease', 'MESH:D004802', (0, 12))	('1,500 to 5000 cells/uL', 'Var', (68, 90))	('muL', 'Gene', '4591', (117, 120))	('muL', 'Gene', '4591', (52, 55))	('muL', 'Gene', (117, 120))	('muL', 'Gene', (52, 55))
44624	33114111	Inactivation of polycomb repressive complex 2 subunit EED or SUZ12 in a majority of MPNSTs leads to loss of tri-methylation at the 27th lysine residue of the histone H3 protein, which can be detected by loss of immunoreactivity for the H3K27me3 antibody, a highly specific biomarker of MPNSTs.	('EED', 'Gene', '8726', (54, 57))	('SUZ12', 'Gene', (61, 66))	('EED', 'Gene', (54, 57))	('histone H3 protein', 'Protein', (158, 176))	('tri-methylation at the 27th lysine residue', 'MPA', (108, 150))	('lysine', 'Chemical', 'MESH:D008239', (136, 142))	('SUZ12', 'Gene', '23512', (61, 66))	('Inactivation', 'Var', (0, 12))	('loss', 'NegReg', (100, 104))
44638	33114111	Approximately 50% of myoepithelial neoplasms harbor EWSR1 fusions with a variety of partner genes (PBX1, PBX3, ZNF44, POU5F1, and ATF1).	('POU5F1', 'Gene', '5460', (118, 124))	('EWSR1', 'Gene', (52, 57))	('myoepithelial neoplasms', 'Disease', (21, 44))	('POU5F1', 'Gene', (118, 124))	('ATF1', 'Gene', '466', (130, 134))	('PBX1', 'Gene', (99, 103))	('neoplasm', 'Phenotype', 'HP:0002664', (35, 43))	('myoepithelial neoplasms', 'Disease', 'MESH:D009208', (21, 44))	('PBX3', 'Gene', '5090', (105, 109))	('fusions', 'Var', (58, 65))	('EWSR1', 'Gene', '2130', (52, 57))	('myoepithelial neoplasms', 'Phenotype', 'HP:0031492', (21, 44))	('PBX3', 'Gene', (105, 109))	('ZNF44', 'Gene', '51710', (111, 116))	('ZNF44', 'Gene', (111, 116))	('neoplasms', 'Phenotype', 'HP:0002664', (35, 44))	('PBX1', 'Gene', '5087', (99, 103))	('ATF1', 'Gene', (130, 134))
44653	33114111	The latest "WHO classification of soft tissue and bone tumor" classifies the undifferentiated small round cell sarcomas of bone and soft tissue into three diagnostic categories: round cell sarcomas with EWSR1non-ETS fusions, capicua transcriptional repressor (CIC)-rearranged sarcomas, and sarcoma with Bcl6 corepressor (BCOR) genetic alterations.	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('sarcomas', 'Disease', 'MESH:D012509', (111, 119))	('sarcoma', 'Disease', 'MESH:D012509', (276, 283))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('sarcomas', 'Disease', 'MESH:D012509', (276, 284))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Disease', (276, 283))	('Bcl6 corepressor', 'Gene', (303, 319))	('BCOR', 'Gene', (321, 325))	('CIC', 'Gene', (260, 263))	('bone tumor', 'Disease', 'MESH:D001859', (50, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (276, 284))	('sarcomas', 'Disease', (111, 119))	('sarcomas', 'Disease', (276, 284))	('capicua transcriptional repressor', 'Gene', (225, 258))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))	('EWSR1', 'Gene', (203, 208))	('sarcomas', 'Disease', 'MESH:D012509', (189, 197))	('sarcomas', 'Phenotype', 'HP:0100242', (189, 197))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('sarcoma', 'Disease', (189, 196))	('sarcoma', 'Disease', 'MESH:D012509', (290, 297))	('genetic alterations', 'Var', (327, 346))	('sarcomas', 'Disease', (189, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('sarcoma', 'Disease', (290, 297))	('CIC', 'Gene', '23152', (260, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('Bcl6 corepressor', 'Gene', '54880', (303, 319))	('capicua transcriptional repressor', 'Gene', '23152', (225, 258))	('bone tumor', 'Phenotype', 'HP:0010622', (50, 60))	('bone tumor', 'Disease', (50, 60))	('EWSR1', 'Gene', '2130', (203, 208))	('BCOR', 'Gene', '54880', (321, 325))
44666	33114111	Chromosome translocations involving the FOS gene have been identified as a genetic hallmark of epithelioid hemangioma, whilst rearrangements involving FOSB have been detected in pseudomyogenic hemangioendothelioma and in a subset of epithelioid hemangioma, defined as cellular/atypical variant.	('FOS', 'Gene', (40, 43))	('hemangioma', 'Disease', (107, 117))	('rearrangements', 'Var', (126, 140))	('FOS', 'Gene', '2353', (40, 43))	('hemangioma', 'Phenotype', 'HP:0001028', (245, 255))	('FOS', 'Gene', (151, 154))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (233, 255))	('hemangioma', 'Disease', 'MESH:D006391', (245, 255))	('FOS', 'Gene', '2353', (151, 154))	('pseudomyogenic hemangioendothelioma', 'Disease', 'MESH:D006390', (178, 213))	('pseudomyogenic hemangioendothelioma', 'Disease', (178, 213))	('FOSB', 'Gene', '2354', (151, 155))	('hemangioma', 'Phenotype', 'HP:0001028', (107, 117))	('Chromosome translocations', 'Var', (0, 25))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (95, 117))	('hemangioma', 'Disease', (245, 255))	('hemangioma', 'Disease', 'MESH:D006391', (107, 117))	('hallmark of epithelioid hemangioma', 'Disease', 'MESH:D006391', (83, 117))	('detected', 'Reg', (166, 174))	('hallmark of epithelioid hemangioma', 'Disease', (83, 117))	('FOSB', 'Gene', (151, 155))
44667	33114111	Thus, these alterations represent important diagnostic markers that can help to single out these two entities from other vascular tumors.	('alterations', 'Var', (12, 23))	('vascular tumors', 'Disease', 'MESH:D019043', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('vascular tumor', 'Phenotype', 'HP:0100742', (121, 135))	('vascular tumors', 'Phenotype', 'HP:0100742', (121, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('vascular tumors', 'Disease', (121, 136))
44670	33114111	Interestingly, these fusions lead to the mutually exclusive nuclear accumulation of CAMTA1 or TFE3, making IHC a reliable read out for both variants of epithelioid hemangioendothelioma.	('CAMTA1', 'Gene', (84, 90))	('lead to', 'Reg', (29, 36))	('CAMTA1', 'Gene', '23261', (84, 90))	('TFE3', 'Gene', '7030', (94, 98))	('nuclear accumulation', 'MPA', (60, 80))	('epithelioid hemangioendothelioma', 'Disease', (152, 184))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (152, 184))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (152, 184))	('fusions', 'Var', (21, 28))	('TFE3', 'Gene', (94, 98))
44678	33114111	As reported, MFH patients were generally older than patients with high grade osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('patients', 'Species', '9606', (17, 25))	('MFH', 'Var', (13, 16))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('patients', 'Species', '9606', (52, 60))	('osteosarcoma', 'Disease', (77, 89))
44766	32882761	LCH cases with BRAF V600E mutation showed no significant difference in clinicopathologic and prognostic factors from those with wild-type BRAF (Supplementary Table 2, only online).	('BRAF', 'Gene', '673', (15, 19))	('V600E', 'Mutation', 'p.V600E', (20, 25))	('BRAF', 'Gene', (15, 19))	('BRAF', 'Gene', (138, 142))	('BRAF', 'Gene', '673', (138, 142))	('V600E', 'Var', (20, 25))
44794	32882761	In our LCH cases, BRAF V600E mutations were noted in 25% (4/16) of the tested cases, and there was no significant difference in clinicopathologic and prognostic factors between LCH cases with the mutation and those with wild-type BRAF.	('BRAF', 'Gene', '673', (230, 234))	('V600E', 'Var', (23, 28))	('BRAF', 'Gene', '673', (18, 22))	('BRAF', 'Gene', (230, 234))	('V600E', 'Mutation', 'p.V600E', (23, 28))	('BRAF', 'Gene', (18, 22))
44795	32882761	Most of the samples in the LCH group included the bone and were decalcified in the tissue preparation processes; therefore, we could not comprehensively perform BRAF V600E mutation tests.	('V600E', 'Var', (166, 171))	('BRAF', 'Gene', '673', (161, 165))	('V600E', 'Mutation', 'p.V600E', (166, 171))	('BRAF', 'Gene', (161, 165))
44799	32882761	In a recent East Asian study, no BRAF V600E mutations were noted.	('V600E', 'Var', (38, 43))	('BRAF', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (33, 37))	('V600E', 'Mutation', 'p.V600E', (38, 43))
44801	32882761	Although BRAF V600E mutation status may predict responses to targeted treatment, the clinical and prognostic implications of this mutation are still controversial, and further research is required.	('V600E', 'Mutation', 'p.V600E', (14, 19))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (9, 13))	('predict', 'Reg', (40, 47))	('BRAF', 'Gene', '673', (9, 13))
44804	32882761	However, BRAF immunohistochemistry for BRAF V600E mutation has been reported to have low sensitivity and specificity in LCH or other histiocytic and dendritic cell neoplasms.	('BRAF', 'Gene', '673', (39, 43))	('dendritic cell neoplasm', 'Phenotype', 'HP:0020178', (149, 172))	('BRAF', 'Gene', (9, 13))	('neoplasm', 'Phenotype', 'HP:0002664', (164, 172))	('BRAF', 'Gene', (39, 43))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (149, 173))	('neoplasms', 'Phenotype', 'HP:0002664', (164, 173))	('dendritic cell neoplasms', 'Disease', (149, 173))	('V600E', 'Mutation', 'p.V600E', (44, 49))	('LCH', 'Disease', (120, 123))	('V600E', 'Var', (44, 49))	('BRAF', 'Gene', '673', (9, 13))
44819	32882761	BRAF mutations were noted in the LCH and ECD cases, although the prognostic implications thereof remain uncertain.	('ECD', 'Disease', (41, 44))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('LCH', 'Disease', (33, 36))	('BRAF', 'Gene', (0, 4))
44910	31083265	Extensive studies established that: first, VEGF is a key driver of sprouting angiogenesis, second, VEGF is overexpressed in most solid malignant tumors, and third, inhibition of VEGF can suppress tumor growth in animal models.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('malignant tumors', 'Disease', 'MESH:D018198', (135, 151))	('tumor', 'Disease', (196, 201))	('suppress', 'NegReg', (187, 195))	('VEGF', 'Gene', '7422', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('inhibition', 'Var', (164, 174))	('VEGF', 'Gene', '7422', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (145, 150))	('VEGF', 'Gene', (43, 47))	('VEGF', 'Gene', '7422', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('VEGF', 'Gene', (99, 103))	('VEGF', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('malignant tumors', 'Disease', (135, 151))
44952	31083265	Results of this study showed that the most common AEs were hypertension (with the incidence rate of 72.73%) in the HD group (659 mg/qd) and rash (56.25%) in the LD group (516 mg/qd) (Table 3).	('AEs', 'Chemical', '-', (50, 53))	('hypertension', 'Disease', 'MESH:D006973', (59, 71))	('rash', 'Disease', 'MESH:D005076', (140, 144))	('HD', 'Disease', 'MESH:D006816', (115, 117))	('659 mg/qd', 'Var', (125, 134))	('rash', 'Disease', (140, 144))	('LD', 'Chemical', '-', (161, 163))	('hypertension', 'Disease', (59, 71))	('rash', 'Phenotype', 'HP:0000988', (140, 144))	('hypertension', 'Phenotype', 'HP:0000822', (59, 71))
44963	31083265	In this study, ORR, DCR, PFS, and OS were not statistically significant with the following administered doses of apatinib: 500 and 750 mg/qd.	('750 mg/qd', 'Var', (131, 140))	('OS', 'Chemical', 'MESH:D009992', (34, 36))	('apatinib', 'Chemical', 'MESH:C553458', (113, 121))	('apatinib', 'Gene', (113, 121))
44970	30926641	Using a panel of Ewing sarcoma cell lines and patient-derived xenograft lines, we demonstrated that IGF1R inhibitors synergistically increased sensitivities to BET inhibitors and induced potent apoptosis when combined with BET inhibitors.	('patient', 'Species', '9606', (46, 53))	('apoptosis', 'CPA', (194, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sensitivities', 'MPA', (143, 156))	('Ewing sarcoma', 'Disease', (17, 30))	('inhibitors', 'Var', (106, 116))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (17, 30))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (17, 30))	('increased', 'PosReg', (133, 142))	('IGF1R', 'Gene', (100, 105))
44983	30926641	BET inhibitors or depletion of BET expression impedes the EWS-FLI1-dependent transcription program, leading to compromised cellular proliferation, survival, and xenograft tumor growth.	('EWS-FLI1', 'Gene', '2130;2313', (58, 66))	('BET', 'Gene', (31, 34))	('survival', 'CPA', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('compromised', 'NegReg', (111, 122))	('EWS-FLI1', 'Gene', (58, 66))	('inhibitors', 'Var', (4, 14))	('depletion', 'Var', (18, 27))	('cellular proliferation', 'CPA', (123, 145))	('tumor', 'Disease', (171, 176))	('impedes', 'NegReg', (46, 53))
44985	30926641	Our data show that inhibition of BET proteins dramatically decreases EWS-FLI1-driven transcription of IGF1 and attenuates the IGF1R-mediated kinase cascade in Ewing sarcoma cells.	('BET proteins', 'Protein', (33, 45))	('transcription', 'MPA', (85, 98))	('IGF1', 'Gene', '3479', (126, 130))	('EWS-FLI1', 'Gene', '2130;2313', (69, 77))	('decreases', 'NegReg', (59, 68))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (159, 172))	('inhibition', 'Var', (19, 29))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (159, 172))	('IGF1', 'Gene', (102, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('attenuates', 'NegReg', (111, 121))	('IGF1', 'Gene', (126, 130))	('EWS-FLI1', 'Gene', (69, 77))	('IGF1', 'Gene', '3479', (102, 106))	('Ewing sarcoma', 'Disease', (159, 172))
44993	30926641	Anti-IGF1R therapy for Ewing sarcoma is supported by strong biological rationales and encouraging preclinical results.	('Ewing sarcoma', 'Disease', (23, 36))	('Anti-IGF1R', 'Var', (0, 10))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (23, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (23, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))
45002	30926641	Antibodies against phospho-IGF1R (#3024), total IGF1R (#9750), and BRD4 (#13440) was purchased from Cell Signaling.	('BRD4', 'Gene', (67, 71))	('#3024', 'Var', (34, 39))	('#9750', 'Var', (55, 60))	('BRD4', 'Gene', '23476', (67, 71))	('#13440', 'Var', (73, 79))
45021	30926641	Our previous work has shown that BET inhibition impaired the IGF1 autocrine loop in Ewing sarcoma and attenuated IGF1R-mediated signaling.	('impaired', 'NegReg', (48, 56))	('IGF1', 'Gene', (113, 117))	('attenuated', 'NegReg', (102, 112))	('inhibition', 'Var', (37, 47))	('Ewing sarcoma', 'Disease', (84, 97))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('IGF1', 'Gene', (61, 65))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('IGF1', 'Gene', '3479', (113, 117))	('IGF1', 'Gene', '3479', (61, 65))
45027	30926641	Our results demonstrated that the GI50 value, defined as drug concentrations required to reduce cell viability by 50%, for a potent and selective BET bromodomain inhibitor, NHWD870, was increased by approximately 60 times following Myr-AKT1 expression in TC32 cells (Figure 1B).	('cell viability', 'CPA', (96, 110))	('increased', 'PosReg', (186, 195))	('NHWD870', 'Chemical', '-', (173, 180))	('expression', 'Var', (241, 251))	('AKT1', 'Gene', '207', (236, 240))	('AKT1', 'Gene', (236, 240))
45033	30926641	In both TC32 and TC71 cells, the combination of BMS754807 and NHWD870 was more much effective than either agent alone to reduce cell viability.	('NHWD870', 'Chemical', '-', (62, 69))	('BMS754807', 'Chemical', 'MESH:C545990', (48, 57))	('NHWD870', 'Gene', (62, 69))	('BMS754807', 'Var', (48, 57))	('cell viability', 'CPA', (128, 142))	('reduce', 'NegReg', (121, 127))	('TC71', 'CellLine', 'CVCL:2213', (17, 21))
45035	30926641	As exemplified in TC32 and TC71 cells, the CI values of NHWD870 and BMS754807 were significantly lower than 1 across concentrations of at least two orders of magnitude, indicating strong drug synergism (Figure 2A and 2B).	('BMS754807', 'Var', (68, 77))	('NHWD870', 'Chemical', '-', (56, 63))	('BMS754807', 'Chemical', 'MESH:C545990', (68, 77))	('NHWD870', 'Var', (56, 63))	('lower', 'NegReg', (97, 102))	('TC71', 'CellLine', 'CVCL:2213', (27, 31))
45037	30926641	Cell cycle analyses indicated that the combination of NHWD870 and BMS754807 made more cells accumulated in G1 phase compared with single agents (Figure 2C and Supplemental Figure S2C).	('cells accumulated', 'CPA', (86, 103))	('BMS754807', 'Var', (66, 75))	('NHWD870', 'Chemical', '-', (54, 61))	('more', 'PosReg', (81, 85))	('BMS754807', 'Chemical', 'MESH:C545990', (66, 75))	('NHWD870', 'Var', (54, 61))
45039	30926641	Following transient exposure to NHWD870 or BMS754807 alone, some Ewing sarcoma cells retained the abilities to form colonies (Figure 2E).	('abilities', 'MPA', (98, 107))	('BMS754807', 'Chemical', 'MESH:C545990', (43, 52))	('Ewing sarcoma', 'Disease', (65, 78))	('NHWD870', 'Chemical', '-', (32, 39))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (65, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('NHWD870', 'Var', (32, 39))	('form colonies', 'CPA', (111, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))	('BMS754807', 'Var', (43, 52))
45040	30926641	These results collectively demonstrate that combining IGF1R inhibitors with BET inhibitors compromises the key prosurvival mechanisms and induces synergistic cytotoxic effects, leading to sustained damage to tumorigenicity of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (226, 239))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('inhibitors', 'Var', (60, 70))	('IGF1R', 'Gene', (54, 59))	('compromises', 'NegReg', (91, 102))	('synergistic', 'MPA', (146, 157))	('induces', 'Reg', (138, 145))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (226, 239))	('damage', 'NegReg', (198, 204))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (226, 239))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('tumor', 'Disease', (208, 213))	('prosurvival mechanisms', 'CPA', (111, 133))
45042	30926641	To more broadly test the hypothesis that IGF1R and the downstream PI3K/AKT/mTOR pathway regulates responsiveness to BET inhibitors in Ewing sarcoma cells, we examined the efficacy of NHWD870 and BMS754807 alone or in combination in additional Ewing sarcoma cell lines and low-passage cultures dissociated from PDX tumors.	('Ewing sarcoma', 'Disease', (243, 256))	('mTOR', 'Gene', (75, 79))	('AKT', 'Gene', '207', (71, 74))	('BMS754807', 'Var', (195, 204))	('PDX tumors', 'Disease', (310, 320))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (134, 147))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (134, 147))	('mTOR', 'Gene', '2475', (75, 79))	('PDX tumors', 'Disease', 'MESH:D009369', (310, 320))	('NHWD870', 'Gene', (183, 190))	('BMS754807', 'Chemical', 'MESH:C545990', (195, 204))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('NHWD870', 'Chemical', '-', (183, 190))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (243, 256))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (243, 256))	('responsiveness', 'MPA', (98, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Ewing sarcoma', 'Disease', (134, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('AKT', 'Gene', (71, 74))
45047	30926641	Not surprisingly, trametinib, a MEK inhibitor, selectively augmented response to BET inhibitors in A673 but not in TC71 (Supplemental Figure S4A and S4B).	('augmented', 'PosReg', (59, 68))	('TC71', 'CellLine', 'CVCL:2213', (115, 119))	('trametinib', 'Chemical', 'MESH:C560077', (18, 28))	('response to BET inhibitors', 'MPA', (69, 95))	('MEK', 'Gene', (32, 35))	('A673', 'Var', (99, 103))	('MEK', 'Gene', '5609', (32, 35))
45052	30926641	In line with the deficient IGF1R and AKT activities, CHLA-32 was one of the most BET inhibition-sensitive Ewing sarcoma cell lines, with an IC50 value of NHWD870 that was about100 folds less than that of A673.	('NHWD870', 'Var', (154, 161))	('CHLA-32', 'Chemical', '-', (53, 60))	('Ewing sarcoma', 'Disease', (106, 119))	('AKT', 'Gene', '207', (37, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('AKT', 'Gene', (37, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('NHWD870', 'Chemical', '-', (154, 161))	('deficient IGF1R', 'Phenotype', 'HP:0030269', (17, 32))
45053	30926641	In contrast, CHLA-32 did not respond to the IGF1R inhibitor BMS754807 in the presence or absence of BET inhibitors (Figure 3C).	('BMS754807', 'Chemical', 'MESH:C545990', (60, 69))	('CHLA-32', 'Chemical', '-', (13, 20))	('BMS754807', 'Var', (60, 69))	('IGF1R', 'Gene', (44, 49))
45060	30926641	In TC32 cells, EWS-FLI1 mRNA did not significantly change following the treatment of NHWD870 +- BMS754807 (Figure 4A).	('EWS-FLI1', 'Gene', (15, 23))	('EWS-FLI1', 'Gene', '2130;2313', (15, 23))	('NHWD870 +- BMS754807', 'Var', (85, 105))	('BMS754807', 'Chemical', 'MESH:C545990', (96, 105))	('NHWD870', 'Chemical', '-', (85, 92))
45061	30926641	The protein levels of EWS-FLI1 also remained largely consistent whether treated with NHWD870, BMS754807, or the combination (Figure 4B).	('protein levels', 'MPA', (4, 18))	('EWS-FLI1', 'Gene', (22, 30))	('BMS754807', 'Chemical', 'MESH:C545990', (94, 103))	('BMS754807', 'Var', (94, 103))	('EWS-FLI1', 'Gene', '2130;2313', (22, 30))	('NHWD870', 'Chemical', '-', (85, 92))	('NHWD870', 'Var', (85, 92))
45063	30926641	In contrast, antiapoptotic genes, such as BCL2 and BIRC3, were significantly downregulated by NHWD870, while the proapoptotic BIM was upregulated by NHWD870 (Figure 4C and 4D).	('BIRC3', 'Gene', (51, 56))	('downregulated', 'NegReg', (77, 90))	('NHWD870', 'Chemical', '-', (94, 101))	('BCL2', 'Gene', '596', (42, 46))	('BIRC3', 'Gene', '330', (51, 56))	('NHWD870', 'Chemical', '-', (149, 156))	('upregulated', 'PosReg', (134, 145))	('BCL2', 'Gene', (42, 46))	('NHWD870', 'Var', (94, 101))	('NHWD870', 'Var', (149, 156))	('BIM', 'Gene', '10018', (126, 129))	('antiapoptotic genes', 'Gene', (13, 32))	('BIM', 'Gene', (126, 129))
45064	30926641	Some of these effects were strengthened by concurrent treatment of BMS754807.	('BMS754807', 'Var', (67, 76))	('BMS754807', 'Chemical', 'MESH:C545990', (67, 76))	('strengthened', 'PosReg', (27, 39))
45066	30926641	In addition, MYC was not responsive to either BET inhibitors or IGF1R inhibitors (Supplemental Figure S5B).	('MYC', 'Gene', '4609', (13, 16))	('S5B', 'Gene', (102, 105))	('IGF1R', 'Gene', (64, 69))	('inhibitors', 'Var', (70, 80))	('S5B', 'Gene', '5711', (102, 105))	('MYC', 'Gene', (13, 16))
45067	30926641	Collectively, these data suggest that modulation of EWS-FLI1 is unlikely implicated in the synergistic interaction between BET inhibitors and IGF1R inhibitors, whereas changes in expression of apoptotic regulators may contribute to the combinatorial effects.	('modulation', 'Var', (38, 48))	('EWS-FLI1', 'Gene', (52, 60))	('IGF1R', 'Gene', (142, 147))	('EWS-FLI1', 'Gene', '2130;2313', (52, 60))
45069	30926641	Administration of NHWD870 alone greatly reduced TC32 tumor growth, which was consistent with the observations in our previous study using the prototypical BET inhibitor, JQ1 (Figure 5A).	('NHWD870', 'Chemical', '-', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NHWD870', 'Var', (18, 25))	('reduced', 'NegReg', (40, 47))	('tumor', 'Disease', (53, 58))
45070	30926641	BMS754807 also significantly impaired tumor growth (Figure 5A).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('BMS754807', 'Var', (0, 9))	('BMS754807', 'Chemical', 'MESH:C545990', (0, 9))	('impaired tumor', 'Disease', (29, 43))	('impaired tumor', 'Disease', 'MESH:D060825', (29, 43))
45077	30926641	COG-352 tumors that expressed EWS-ERG were less sensitive to NHWD870 and BMS754807, as neither of these compounds alone has any significant impact on tumor growth (Figure 5B).	('ERG', 'Gene', '2078', (34, 37))	('ERG', 'Gene', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('COG', 'Chemical', '-', (0, 3))	('BMS754807', 'Chemical', 'MESH:C545990', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('less', 'NegReg', (43, 47))	('BMS754807', 'Var', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumor', 'Disease', (8, 13))	('NHWD870', 'Chemical', '-', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', (150, 155))
45080	30926641	Immunohistochemical analysis identified modest increases of the proliferative marker, Ki67, in the BMS754807-treated arm in both xenograft tumor models, which was antagonized by BET inhibitors (Figure 5C and Supplementary Figure S6C).	('BMS754807', 'Chemical', 'MESH:C545990', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('proliferative marker', 'MPA', (64, 84))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('BMS754807-treated', 'Var', (99, 116))	('Ki67', 'Gene', '17345', (86, 90))	('increases', 'PosReg', (47, 56))	('Ki67', 'Gene', (86, 90))
45083	30926641	Taken together, these findings suggest that the combination of BET inhibitors and IGF1R inhibitors has the potential to generate strong therapeutic response in Ewing sarcoma, at least in part, through induction of apoptotic cell death.	('inhibitors', 'Var', (67, 77))	('apoptotic cell death', 'CPA', (214, 234))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (160, 173))	('IGF1R', 'Gene', (82, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (160, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('Ewing sarcoma', 'Disease', (160, 173))	('inhibitors', 'Var', (88, 98))
45089	30926641	Our work showed that BET inhibition in Ewing sarcoma cells using JQ1 only affected about 10% of genes sensitive to knockdown of EWS-FLI1.	('EWS-FLI1', 'Gene', '2130;2313', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (39, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('Ewing sarcoma', 'Disease', (39, 52))	('BET', 'MPA', (21, 24))	('EWS-FLI1', 'Gene', (128, 136))	('knockdown', 'Var', (115, 124))
45092	30926641	Our results further demonstrated that combining IGF1R inhibitors with BET inhibitors synergistically killed Ewing sarcoma cells and induced tumor regression in xenograft models.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('inhibitors', 'Var', (54, 64))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('killed', 'NegReg', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('IGF1R', 'Gene', (48, 53))	('Ewing sarcoma', 'Disease', (108, 121))	('tumor', 'Disease', (140, 145))
45098	30926641	A different strategy showed that chronic exposure to BET inhibitors activated an array of oncogenic kinase cascades in ovarian cancer cells.	('inhibitors', 'Var', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (119, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('activated', 'PosReg', (68, 77))	('ovarian cancer', 'Disease', (119, 133))	('oncogenic kinase cascades', 'Pathway', (90, 115))
45102	30926641	The MEK/ERK pathway was not significantly activated by the blockade of IGF1R signaling in TC32 and TC71 cells.	('ERK', 'Gene', (8, 11))	('ERK', 'Gene', '2048', (8, 11))	('MEK', 'Gene', (4, 7))	('MEK', 'Gene', '5609', (4, 7))	('IGF1R signaling', 'Gene', (71, 86))	('blockade', 'Var', (59, 67))	('TC71', 'CellLine', 'CVCL:2213', (99, 103))
45106	30926641	Although clinical outcomes of IGF1R neutralizing antibodies and small molecule kinase inhibitors in Ewing sarcoma patients were rather disappointing, a small subset of patients had response, supporting the significance of this pathway in this disease.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (100, 113))	('neutralizing', 'Var', (36, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (100, 113))	('IGF1R', 'Gene', (30, 35))	('Ewing sarcoma', 'Disease', (100, 113))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (114, 122))
45236	25147782	We found that JS-K robustly decreased Ewing sarcoma cell viability and xenograft tumor growth and improved overall survival of xenograft mice.	('JS-K', 'Var', (14, 18))	('xenograft tumor', 'Disease', (71, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('decreased', 'NegReg', (28, 37))	('xenograft tumor', 'Disease', 'MESH:D009369', (71, 86))	('Ewing sarcoma cell viability', 'Disease', 'MESH:C563168', (38, 66))	('Ewing sarcoma cell viability', 'Disease', (38, 66))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('improved', 'PosReg', (98, 106))	('mice', 'Species', '10090', (137, 141))
45237	25147782	Our data suggest that GSTM4 is a novel therapeutic target for the treatment of high GSTM4-expressing Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('GSTM4', 'Gene', (84, 89))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('GSTM4', 'Gene', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('GSTM4', 'Gene', '2948', (84, 89))	('high', 'Var', (79, 83))	('GSTM4', 'Gene', '2948', (22, 27))	('Ewing sarcoma', 'Disease', (101, 114))
45245	25147782	Consistently, high MGST1 expression in Ewing sarcoma correlates with poor prognosis due to doxorubicin resistance.	('doxorubicin resistance', 'MPA', (91, 113))	('MGST1', 'Gene', (19, 24))	('doxorubicin', 'Chemical', 'MESH:D004317', (91, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('expression', 'MPA', (25, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (39, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('high', 'Var', (14, 18))	('MGST1', 'Gene', '4257', (19, 24))	('Ewing sarcoma', 'Disease', (39, 52))
45255	25147782	Most cases of Ewing sarcoma are driven by the fusion oncoprotein EWS/FLI that results from a chromosomal translocation between chromosomes 11 and 22.	('EWS', 'Gene', '2130', (65, 68))	('EWS', 'Gene', (65, 68))	('results from', 'Reg', (78, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('Ewing sarcoma', 'Disease', (14, 27))	('FLI', 'Gene', '2314', (69, 72))	('chromosomal translocation', 'Var', (93, 118))	('FLI', 'Gene', (69, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (14, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (14, 27))	('driven by', 'Reg', (32, 41))
45274	25147782	Anti-ASK1 (sc-5294 and sc-390275) and anti-Myc (sc-40) antibodies were from Santa Cruz Biotechnology (Dallas, TX, USA).	('Anti-ASK1', 'Var', (0, 9))	('sc-390275', 'Var', (23, 32))	('Myc', 'Gene', '4609', (43, 46))	('Myc', 'Gene', (43, 46))
45301	25147782	Our previous observation that GSTM4 is required for oncogenic transformation and mediates etoposide resistance of Ewing sarcoma cells, led us to hypothesize that GSTM4 inhibitory agents might be cytotoxic and increase the sensitivity of Ewing sarcoma cells to etoposide.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('etoposide', 'Chemical', 'MESH:D005047', (90, 99))	('GSTM4', 'Gene', '2948', (162, 167))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (114, 127))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (237, 250))	('GSTM4', 'Gene', (30, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (237, 250))	('Ewing sarcoma', 'Disease', (237, 250))	('GSTM4', 'Gene', (162, 167))	('etoposide', 'Chemical', 'MESH:D005047', (260, 269))	('Ewing sarcoma', 'Disease', (114, 127))	('increase', 'PosReg', (209, 217))	('GSTM4', 'Gene', '2948', (30, 35))	('inhibitory agents', 'Var', (168, 185))	('sensitivity', 'MPA', (222, 233))
45304	25147782	We found drastic decrease in cell proliferation in RH30, A673, and TC71, but not HEK293 cells in response to NBDHEX treatment (Figure 2A).	('NBDHEX', 'Chemical', 'MESH:C528479', (109, 115))	('HEK293', 'CellLine', 'CVCL:0045', (81, 87))	('decrease', 'NegReg', (17, 25))	('RH30', 'Gene', (51, 55))	('RH30', 'Gene', '6007', (51, 55))	('A673', 'Var', (57, 61))	('TC71', 'CellLine', 'CVCL:2213', (67, 71))	('cell proliferation', 'CPA', (29, 47))
45307	25147782	These results indicate that inhibition of GSTM4 decreases cellular proliferation and abolishes oncogenic transformation.	('oncogenic transformation', 'CPA', (95, 119))	('GSTM4', 'Gene', '2948', (42, 47))	('decreases', 'NegReg', (48, 57))	('abolishes', 'NegReg', (85, 94))	('inhibition', 'Var', (28, 38))	('GSTM4', 'Gene', (42, 47))	('cellular proliferation', 'CPA', (58, 80))
45308	25147782	The data are in agreement with our previous finding that GSTM4 knockdown inhibits oncogenic transformation.	('oncogenic transformation', 'CPA', (82, 106))	('GSTM4', 'Gene', (57, 62))	('inhibits', 'NegReg', (73, 81))	('GSTM4', 'Gene', '2948', (57, 62))	('knockdown', 'Var', (63, 72))
45309	25147782	We previously found that knockdown of GSTM4 renders Ewing sarcoma cells more sensitive to etoposide.	('GSTM4', 'Gene', '2948', (38, 43))	('etoposide', 'Chemical', 'MESH:D005047', (90, 99))	('Ewing sarcoma', 'Disease', (52, 65))	('GSTM4', 'Gene', (38, 43))	('more', 'PosReg', (72, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('sensitive to etoposide', 'MPA', (77, 99))	('knockdown', 'Var', (25, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
45326	25147782	We found that etoposide treatment led to higher JNK activation in GSTM4 knockdown (GSTM4-4 and GSTM4-5 RNAi) cells compared with control (Luc-RNAi) cells (Figure 3A), indicating that GSTM4 inhibits JNK activation induced by etoposide.	('etoposide', 'Chemical', 'MESH:D005047', (14, 23))	('GSTM4-5', 'Gene', '2948;2949', (95, 102))	('GSTM4', 'Gene', (66, 71))	('JNK', 'Gene', (48, 51))	('JNK', 'Gene', '5599', (48, 51))	('GSTM4', 'Gene', '2948', (83, 88))	('JNK', 'Gene', (198, 201))	('GSTM4-4', 'Gene', '2948', (83, 90))	('JNK', 'Gene', '5599', (198, 201))	('GSTM4-4', 'Gene', (83, 90))	('GSTM4', 'Gene', '2948', (66, 71))	('GSTM4', 'Gene', (183, 188))	('GSTM4', 'Gene', (95, 100))	('knockdown', 'Var', (72, 81))	('etoposide', 'Chemical', 'MESH:D005047', (224, 233))	('GSTM4-5', 'Gene', (95, 102))	('GSTM4', 'Gene', '2948', (183, 188))	('GSTM4', 'Gene', (83, 88))	('higher', 'PosReg', (41, 47))	('GSTM4', 'Gene', '2948', (95, 100))
45334	25147782	To identify the key GSTM4 region responsible for interaction with ASK1, we generated GSTM4 deletion mutants, GSTM4-NT and GSTM4-CT, in which the substrate binding site and GSH binding site of GSTM4 are absent, respectively (Figure 3D, upper panel).	('GSH', 'Chemical', 'MESH:D005978', (172, 175))	('deletion mutants', 'Var', (91, 107))	('absent', 'NegReg', (202, 208))	('GSTM4', 'Gene', '2948', (192, 197))	('mutants', 'Var', (100, 107))	('substrate', 'MPA', (145, 154))	('GSTM4', 'Gene', '2948', (20, 25))	('GSTM4', 'Gene', (122, 127))	('GSTM4', 'Gene', (109, 114))	('GSTM4', 'Gene', (20, 25))	('binding', 'Interaction', (176, 183))	('GSTM4', 'Gene', (85, 90))	('GSTM4', 'Gene', (192, 197))	('GSTM4', 'Gene', '2948', (85, 90))	('GSTM4', 'Gene', '2948', (122, 127))	('GSTM4', 'Gene', '2948', (109, 114))
45335	25147782	Immunoprecipitation studies using these deletion mutants showed that the C-terminal end of GSTM4 is required for interaction with ASK1 (Figure 3D, lower panel).	('deletion', 'Var', (40, 48))	('GSTM4', 'Gene', '2948', (91, 96))	('GSTM4', 'Gene', (91, 96))	('interaction', 'Interaction', (113, 124))
45342	25147782	JS-K has shown promise as a novel cancer therapeutic agent in a number of studies, but its utility for the treatment of pediatric cancers has not been previously evaluated.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancer', 'Disease', (130, 136))	('pediatric cancers', 'Disease', 'MESH:D009369', (120, 137))	('pediatric cancers', 'Disease', (120, 137))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('JS-K', 'Var', (0, 4))
45343	25147782	Our initial studies showed that JS-K inhibits the proliferation of A673 and TC71 Ewing sarcoma cells in a dose-dependent fashion (Figure 4A).	('Ewing sarcoma', 'Disease', (81, 94))	('TC71', 'CellLine', 'CVCL:2213', (76, 80))	('JS-K', 'Var', (32, 36))	('proliferation', 'CPA', (50, 63))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('inhibits', 'NegReg', (37, 45))
45344	25147782	To assess whether GSTM4 is required for this response, we knocked down GSTM4 in A673 and TC71 cells and then treated control- or GSTM4-silenced cells with increasing concentrations of JS-K. We found that limiting JS-K metabolism by silencing GSTM4 decreased sensitivity to the drug (Figure 4B).	('TC71', 'CellLine', 'CVCL:2213', (89, 93))	('sensitivity to the drug', 'MPA', (258, 281))	('GSTM4', 'Gene', '2948', (18, 23))	('GSTM4', 'Gene', (242, 247))	('decreased', 'NegReg', (248, 257))	('GSTM4', 'Gene', (71, 76))	('GSTM4', 'Gene', (129, 134))	('GSTM4', 'Gene', '2948', (129, 134))	('GSTM4', 'Gene', '2948', (242, 247))	('silencing', 'Var', (232, 241))	('GSTM4', 'Gene', '2948', (71, 76))	('GSTM4', 'Gene', (18, 23))
45346	25147782	We next assessed whether JS-K decreases tumor growth in xenograft models.	('decreases tumor', 'Disease', (30, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('decreases tumor', 'Disease', 'MESH:D009369', (30, 45))	('JS-K', 'Var', (25, 29))
45348	25147782	We found that treatment with JS-K significantly reduced tumor growth (Figure 4C, ANOVA Test p = 0.023) and increased overall survival (Figure 4D, Mantel-Cox Test, p = 0.0002), strongly suggesting that this GSTM4 pro-drug has anti-tumorigenic effects that can be exploited for the treatment of Ewing sarcoma.	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (293, 306))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('increased', 'PosReg', (107, 116))	('GSTM4', 'Gene', '2948', (206, 211))	('reduced', 'NegReg', (48, 55))	('overall survival', 'CPA', (117, 133))	('tumor', 'Disease', (56, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (293, 306))	('JS-K', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('Ewing sarcoma', 'Disease', (293, 306))	('Cox', 'Gene', '1351', (153, 156))	('Cox', 'Gene', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('GSTM4', 'Gene', (206, 211))
45366	25147782	Molecular analyses in cellular models showed that JS-K inhibits the growth of Ewing sarcoma cells in a GSTM4-dependent fashion, and that this feature is recapitulated in in vivo settings.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('GSTM4', 'Gene', '2948', (103, 108))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('inhibits', 'NegReg', (55, 63))	('JS-K', 'Var', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('growth', 'CPA', (68, 74))	('GSTM4', 'Gene', (103, 108))	('Ewing sarcoma', 'Disease', (78, 91))
45370	25147782	Second, we demonstrated that the C-terminus of GSTM4 directly or indirectly interacts with the apoptosis-inducing kinase ASK1, limiting phosphorylation of MKK4 by ASK1.	('phosphorylation', 'MPA', (136, 151))	('ASK1', 'Var', (163, 167))	('GSTM4', 'Gene', (47, 52))	('MKK4', 'Gene', (155, 159))	('GSTM4', 'Gene', '2948', (47, 52))	('MKK4', 'Gene', '6416', (155, 159))	('limiting', 'NegReg', (127, 135))
45377	25147782	Thirdly, specific disruption of GSTM4/ASK1 interactions can potentially reactivate apoptosis, thus decreasing chemoresistance to existing therapeutic agents.	('chemoresistance', 'CPA', (110, 125))	('interactions', 'Interaction', (43, 55))	('GSTM4', 'Gene', (32, 37))	('decreasing', 'NegReg', (99, 109))	('GSTM4', 'Gene', '2948', (32, 37))	('apoptosis', 'CPA', (83, 92))	('disruption', 'Var', (18, 28))	('reactivate', 'Reg', (72, 82))
45439	22629492	Again, combination of chemo-radiation and total/subtotal surgery reduced the rate of distant metastasis in CNS-PNET patients (chi2, P < 0.05) but not in primary intraspinal EES/pPNET group (chi2, P = 0.163) [Table 9].	('reduced', 'NegReg', (65, 72))	('PNET', 'Phenotype', 'HP:0030065', (178, 182))	('patients', 'Species', '9606', (116, 124))	('PNET', 'Phenotype', 'HP:0030065', (111, 115))	('distant metastasis', 'CPA', (85, 103))	('CNS-PNET', 'Var', (107, 115))	('ES', 'Phenotype', 'HP:0012254', (174, 176))
45583	21157568	This family of tumors shares common cytogenetic and molecular changes which involve the translocation of Ewing's sarcoma gene on chromosome 22 (22q12) on to a number of other genes like fli-1 on chromosome 11 (11q24) in 90% of cases and erg on chromosome 21 (21q22).	('erg', 'Gene', (237, 240))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('fli-1', 'Gene', (186, 191))	('fli-1', 'Gene', '2313', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (105, 120))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('translocation', 'Var', (88, 101))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (105, 120))	("Ewing's sarcoma", 'Disease', (105, 120))	('tumors', 'Disease', (15, 21))
46034	29302306	Since it has been discovered that ASPSs are characterized by a tumor-specific der(17)t(X;17) (p11;q25) that fuses the transcription factor 3 (TFE3) gene at Xp11 to the ASPL gene at 17q25, creating an ASPL-TFE3 fusion protein.	('p11', 'Gene', (157, 160))	('ASPS', 'Phenotype', 'HP:0012218', (34, 38))	('ASPS', 'Disease', 'MESH:D018234', (34, 38))	('transcription factor 3', 'Gene', '6929', (118, 140))	('ASPL', 'Gene', (200, 204))	('transcription factor 3', 'Gene', (118, 140))	('ASPS', 'Disease', (34, 38))	('TFE3', 'Gene', (142, 146))	('ASPL', 'Gene', (168, 172))	('TFE3', 'Gene', (205, 209))	('fuses', 'Var', (108, 113))	('tumor', 'Disease', (63, 68))	('TFE3', 'Gene', '7030', (142, 146))	('TFE3', 'Gene', '7030', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ASPL', 'Gene', '79058', (200, 204))	('p11', 'Gene', '6281', (94, 97))	('ASPL', 'Gene', '79058', (168, 172))	('p11', 'Gene', (94, 97))	('p11', 'Gene', '6281', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
46039	29302306	On the other hand, nuclear expression of TFE3 can be seen in a variety of different tumors, most of which harbor TFE3 gene fusions, including ASPS, Xp11 translocation renal cell carcinoma, 'melanotic' Xp11 translocation renal cell carcinoma and a subset of PEComas and epithelioid hemangioendotheliomas.	('TFE3', 'Gene', (113, 117))	('epithelioid hemangioendotheliomas', 'Phenotype', 'HP:0032060', (269, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('epithelioid hemangioendotheliomas', 'Disease', 'MESH:D018323', (269, 302))	('TFE3', 'Gene', (41, 45))	('TFE3', 'Gene', '7030', (113, 117))	('PEComas', 'Disease', 'MESH:D054973', (257, 264))	('p11', 'Gene', '6281', (202, 205))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (167, 187))	('TFE3', 'Gene', '7030', (41, 45))	('PEComas', 'Disease', (257, 264))	("'melanotic' Xp11 translocation renal cell carcinoma", 'Disease', 'MESH:C538614', (189, 240))	('p11', 'Gene', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('fusions', 'Var', (123, 130))	('tumors', 'Disease', (84, 90))	('ASPS', 'Phenotype', 'HP:0012218', (142, 146))	('ASPS', 'Disease', 'MESH:D018234', (142, 146))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (220, 240))	('renal cell carcinoma', 'Disease', (167, 187))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('ASPS', 'Disease', (142, 146))	('p11', 'Gene', '6281', (149, 152))	('p11', 'Gene', (149, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('epithelioid hemangioendotheliomas', 'Disease', (269, 302))	('renal cell carcinoma', 'Disease', (220, 240))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (220, 240))
46080	28840102	LV-only pacing might cause reverse dyssynchrony compared with right ventricular-only pacing.	('dyssynchrony', 'Disease', (35, 47))	('dyssynchrony', 'Disease', 'None', (35, 47))	('LV-only pacing', 'Var', (0, 14))
46083	28840102	In a large retrospective registry a higher incidence of malignancies was detected in patients with PM implants, although no excess risk was found for sarcomas.	('PM implants', 'Var', (99, 110))	('sarcomas', 'Disease', (150, 158))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('patients', 'Species', '9606', (85, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('malignancies', 'Disease', (56, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))
46110	26517673	In vivo serial transplantation assays showed that CD146+ cells are highly tumorigenic, capable of self-renewal and thus enriches for the TPC population.	('self-renewal', 'CPA', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CD146+ cells', 'Var', (50, 62))	('tumor', 'Disease', (74, 79))
46113	26517673	Inhibition of one of these upregulated pathways, Notch signaling, significantly reduced tumor growth and self-renewal.	('self-renewal', 'CPA', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Notch', 'Gene', '18128', (49, 54))	('Notch', 'Gene', (49, 54))	('reduced', 'NegReg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (88, 93))
46133	26517673	We found CD146 (also known as MCAM or MUC18), can reliability enrich for TPCs in osteosarcoma and UPS.	('TPCs', 'MPA', (73, 77))	('osteosarcoma', 'Disease', (81, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('MUC18', 'Gene', '4162', (38, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('CD146', 'Var', (9, 14))	('MCAM', 'Gene', (30, 34))	('MUC18', 'Gene', (38, 43))	('MCAM', 'Gene', '4162', (30, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))
46134	26517673	Importantly, we showed that CD146+ and SP cells are independently tumorigenic and represent overlapping and distinct populations of sarcoma TPCs.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('sarcoma TPCs', 'Disease', 'MESH:D012509', (132, 144))	('SP', 'Chemical', '-', (39, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma TPCs', 'Disease', (132, 144))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CD146+', 'Var', (28, 34))
46142	26517673	Specifically, 25.13% (+-13.64%SEM) of the SP population expressed CD31, 29.51% (+-15.01% SEM) expressed CD66, 11.02% (+-3.46% SEM) expressed CD104, 36.34% (+-24.27% SEM) expressed CD144 and 16.60% expressed CD146 (+-8.10% SEM).	('CD31', 'Gene', '5175', (66, 70))	('SP', 'Chemical', '-', (42, 44))	('CD144', 'Gene', '1003', (180, 185))	('CD66', 'Var', (104, 108))	('CD144', 'Gene', (180, 185))	('CD104', 'Gene', '3691', (141, 146))	('CD104', 'Gene', (141, 146))	('CD146', 'Var', (207, 212))	('CD31', 'Gene', (66, 70))
46143	26517673	In the NSP population, 1.37% (+-0.52 SEM) expressed CD31, 0.75% (+-0.24% SEM) expressed CD66, 2.47% (+- 1.63% SEM) expressed CD104, 0.95% (+-0.62%) expressed CD144, and 4.62% (+-1.47%) expressed CD146.	('CD31', 'Gene', '5175', (52, 56))	('CD104', 'Gene', '3691', (125, 130))	('SP', 'Chemical', '-', (8, 10))	('CD146', 'Var', (195, 200))	('CD104', 'Gene', (125, 130))	('CD144', 'Gene', (158, 163))	('CD144', 'Gene', '1003', (158, 163))	('CD31', 'Gene', (52, 56))	('CD66', 'Var', (88, 92))
46147	26517673	CD31+, CD66+, CD104+ and CD144+ cells did not show higher tumor initiating ability compared to their respective marker negative populations or bulk tumor cells (data not show).	('CD104', 'Gene', '3691', (14, 19))	('tumor', 'Disease', (58, 63))	('CD66+', 'Var', (7, 12))	('CD144', 'Gene', '1003', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CD144', 'Gene', (25, 30))	('tumor', 'Disease', (148, 153))	('CD104', 'Gene', (14, 19))	('CD31', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('CD31', 'Gene', '5175', (0, 4))
46150	26517673	The expression of CD146 was significantly enriched in the SP population compared to the NSP cells (P < 0.001), with 53.2% (+-9.51% SEM) of SP cells expressing CD146, and 2.98% (+-0.90% SEM) of NSP cells expressing CD146 (Figure 1A, 1B).	('SP', 'Chemical', '-', (58, 60))	('CD146', 'Gene', (18, 23))	('CD146', 'Var', (159, 164))	('SP', 'Chemical', '-', (139, 141))	('SP', 'Chemical', '-', (194, 196))	('SP', 'Chemical', '-', (89, 91))
46153	26517673	In osteosarcoma, the mean percentage SP and CD146+ cells is 0.68% (+- 0.28 SEM) and 4.92% (+-0.90 SEM) respectively.	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('SP', 'Chemical', '-', (37, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('CD146+ cells', 'Var', (44, 56))
46160	26517673	As few as 10 CD146+ cells in UPS formed tumors at high frequency.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('CD146+ cells', 'Var', (13, 25))
46162	26517673	Similarly, the CD146+ cells in osteosarcoma exhibited substantially higher tumor-forming capacity compared to the CD146- cells (Table 2).	('osteosarcoma', 'Phenotype', 'HP:0002669', (31, 43))	('osteosarcoma', 'Disease', (31, 43))	('osteosarcoma', 'Disease', 'MESH:D012516', (31, 43))	('higher', 'PosReg', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CD146+ cells', 'Var', (15, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('tumor', 'Disease', (75, 80))
46166	26517673	Furthermore, hematoxylin and eosin staining of tumors xenograft derived from CD146+ cells resembled the patient tumor in both UPS and osteosarcoma (Figure 2A).	('osteosarcoma', 'Phenotype', 'HP:0002669', (134, 146))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('hematoxylin', 'Chemical', 'MESH:D006416', (13, 24))	('eosin', 'Chemical', 'MESH:D004801', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patient', 'Species', '9606', (104, 111))	('UPS and osteosarcoma', 'Disease', 'MESH:D017118', (126, 146))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (112, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))	('CD146+ cells', 'Var', (77, 89))
46172	26517673	We found that the NSP CD146+ population was significantly more tumorigenic than the NSP CD146- population over serial transplants (Table 3, P = 9.58e-13).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CD146+', 'Var', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('SP', 'Chemical', '-', (19, 21))	('more', 'PosReg', (58, 62))	('SP', 'Chemical', '-', (85, 87))
46173	26517673	Therefore, despite the overlap between SP and CD146+ population, CD146+ cells depleted of SP remain enriched for tumor propagating capacity, suggesting that CD146 enrich for a subpopulation of TPCs in sarcoma that both overlap with, but also distinct from SP cells.	('tumor', 'Disease', (113, 118))	('sarcoma', 'Disease', 'MESH:D012509', (201, 208))	('SP', 'Chemical', '-', (90, 92))	('SP', 'Chemical', '-', (39, 41))	('sarcoma', 'Disease', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('SP', 'Chemical', '-', (256, 258))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CD146', 'Var', (157, 162))
46175	26517673	Four separate populations of CD146+, CD146-, SP and NSP were sorted from 3 osteosarcoma samples, and their expression profiles were analyzed.	('osteosarcoma', 'Disease', (75, 87))	('CD146-', 'Var', (37, 43))	('SP', 'Chemical', '-', (45, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('CD146+', 'Var', (29, 35))	('SP', 'Chemical', '-', (53, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))
46176	26517673	Using a 1.5 fold change and a P < 0.05 as thresholds, we identified 3763 differentially expressed genes between CD146+ versus CD146- cells and 757 differentially expressed genes between SP versus NSP cell.	('differentially expressed genes', 'MPA', (73, 103))	('SP', 'Chemical', '-', (186, 188))	('SP', 'Chemical', '-', (197, 199))	('CD146+', 'Var', (112, 118))
46178	26517673	This analysis identified multiple targetable pathways that were similarly affected in the SP and CD146+ populations (Figure S2).	('affected', 'Reg', (74, 82))	('SP', 'Chemical', '-', (90, 92))	('CD146+', 'Var', (97, 103))
46185	26517673	On the other hand, extracellular matrix remodeling, cell migration, hypoxia response and angiogenesis associated pathways were enriched only in the CD146+ cells (Figure.	('cell migration', 'CPA', (52, 66))	('CD146+', 'Var', (148, 154))	('hypoxia', 'Disease', (68, 75))	('hypoxia', 'Disease', 'MESH:D000860', (68, 75))	('angiogenesis', 'CPA', (89, 101))	('extracellular matrix remodeling', 'CPA', (19, 50))
46200	26517673	CD146+ cells in sarcomas are relatively more abundant representing 3.61% of UPS and 4.91% of osteosarcoma.	('CD146+', 'Var', (0, 6))	('sarcomas', 'Disease', (16, 24))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('osteosarcoma', 'Disease', (93, 105))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('osteosarcoma', 'Disease', 'MESH:D012516', (93, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('UPS', 'Disease', (76, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
46201	26517673	The ability of CD146+ to initiate tumors over multiple transplantations suggests it indeed enriches for TPCs with self-renewal ability.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('CD146+', 'Var', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
46212	26517673	In addition, we found other self-renewal pathways activated in SP and CD146+ cells.	('SP', 'Chemical', '-', (63, 65))	('CD146+', 'Var', (70, 76))	('activated', 'PosReg', (50, 59))	('self-renewal pathways', 'CPA', (28, 49))
46216	26517673	Furthermore, our pathway analysis showed that metabolic pathways, especially, glucose metabolism are upregulated in the SP and CD146+ cells.	('glucose', 'Chemical', 'MESH:D005947', (78, 85))	('metabolic pathways', 'Pathway', (46, 64))	('SP', 'Chemical', '-', (120, 122))	('CD146+', 'Var', (127, 133))	('glucose metabolism', 'MPA', (78, 96))	('upregulated', 'PosReg', (101, 112))
46217	26517673	The increased glucose uptake of TPCs compared to bulk tumor cells may contribute to their survival advantage.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('survival advantage', 'CPA', (90, 108))	('tumor', 'Disease', (54, 59))	('TPCs', 'Var', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('increased glucose', 'Phenotype', 'HP:0003074', (4, 21))	('glucose uptake', 'MPA', (14, 28))	('increased', 'PosReg', (4, 13))	('glucose', 'Chemical', 'MESH:D005947', (14, 21))
46225	26517673	Using in vivo model, we demonstrated that CD146+ tumor cells show increased tumorigenicity, self-renewal ability, and can initiate tumors that resemble the primary patient tumor.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('CD146+', 'Var', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('increased', 'PosReg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patient', 'Species', '9606', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (49, 54))	('tumors', 'Disease', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('initiate', 'PosReg', (122, 130))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('self-renewal ability', 'CPA', (92, 112))
46238	26517673	Since the stromal cells are likely derived from the mouse, removing the H-2k+ cells allow us to deplete the stromal cells from the tumor.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mouse', 'Species', '10090', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('H-2k+', 'Var', (72, 77))	('tumor', 'Disease', (131, 136))
46260	26517673	Three independent human osteosarcoma xenografts were sorted for SP, NSP, CD146+ and CD146- fractions.	('SP', 'Chemical', '-', (69, 71))	('osteosarcoma', 'Phenotype', 'HP:0002669', (24, 36))	('human', 'Species', '9606', (18, 23))	('osteosarcoma', 'Disease', (24, 36))	('osteosarcoma', 'Disease', 'MESH:D012516', (24, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('CD146- fractions', 'Var', (84, 100))	('SP', 'Chemical', '-', (64, 66))
46292	26018727	Overall, HR GTV contour agreement was substantial for RPS1 (kappa 0.66), substantial for RPS2 (kappa 0.61), and moderate for RPS3 (kappa 0.52).	('RPS2', 'Gene', (89, 93))	('RPS3', 'Gene', (125, 129))	('RPS2', 'Gene', '6187', (89, 93))	('RPS3', 'Gene', '6188', (125, 129))	('RPS1', 'Var', (54, 58))
46293	26018727	Maximum, minimum, mean (+-standard deviation) and STAPLE95 consensus HR GTV volumes were 1399.2, 689.7, 947 (+-29 %), and 1100.8 cc for RPS1; 419.1, 173.2, 290.2 (+-27 %), and 316.5 cc for RPS2; and 921.7, 174.2, 414.4 (+-60 %), and 434.9 cc for RPS3.	('RPS3', 'Gene', '6188', (246, 250))	('1399.2', 'Var', (89, 95))	('RPS2', 'Gene', (189, 193))	('RPS2', 'Gene', '6187', (189, 193))	('RPS3', 'Gene', (246, 250))
46294	26018727	Median volume overlap for HR GTV contours is the intersection volume common to all teams as a percentage of the mean volume, and these values are 44 % for RPS1, 26 % for RPS2, and 60 % for RPS3.	('RPS3', 'Gene', (189, 193))	('RPS2', 'Gene', (170, 174))	('RPS1', 'Var', (155, 159))	('RPS2', 'Gene', '6187', (170, 174))	('RPS3', 'Gene', '6188', (189, 193))
46342	20406839	Human soft tissue sarcoma cell lines HT1080 (fibrosarcoma; wild type p53) and SKLMS1 (leiomyosarcoma; mutated p53)were obtained from ATCC.	('Human', 'Species', '9606', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('leiomyosarcoma', 'Disease', (86, 100))	('mutated', 'Var', (102, 109))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('HT1080', 'Gene', (37, 43))	('sarcoma', 'Disease', (93, 100))	('HT1080', 'Gene', '8872', (37, 43))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (45, 57))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (6, 25))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (86, 100))	('fibrosarcoma', 'Disease', 'MESH:D005354', (45, 57))	('SKLMS1', 'CellLine', 'CVCL:0628', (78, 84))	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('sarcoma', 'Disease', (18, 25))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (86, 100))	('fibrosarcoma', 'Disease', (45, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))
46380	20406839	Five of the most vascularized areas within a tumor ("hot spots") identified based on CD31 positivity were chosen at low magnification and vessels were counted in a representative high-magnification (X400) field in each of these areas.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('CD31', 'Gene', (85, 89))	('positivity', 'Var', (90, 100))	('CD31', 'Gene', '5175', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
46385	20406839	SKLMS1 harbors a mutated p53 (a common mutation in complex karyotype STS) and HT1080 harbors a NRAS mutation but is p53 wild type (www.sanger.ac.uk/genetics/CGP/cosmic).	('p53', 'Gene', (25, 28))	('SKLMS1', 'CellLine', 'CVCL:0628', (0, 6))	('NRAS', 'Gene', (95, 99))	('HT1080', 'Gene', (78, 84))	('HT1080', 'Gene', '8872', (78, 84))	('NRAS', 'Gene', '4893', (95, 99))	('mutated', 'Var', (17, 24))
46394	20406839	Treatment with low-dose doxorubicin alone resulted in a small, non-statistically significant decrease in tumor growth; the average tumor volume of doxorubicin treated tumors at study termination was 1453 mm3 +- 481 compared 1738 mm3 +- 533 for controls (p=0.33, Fig 2A).	('doxorubicin', 'Var', (147, 158))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('doxorubicin', 'Chemical', 'MESH:D004317', (147, 158))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (131, 136))	('doxorubicin', 'Chemical', 'MESH:D004317', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('decrease', 'NegReg', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (105, 110))	('tumors', 'Disease', (167, 173))	('tumor', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
46414	20406839	Similarly, an increase in DR5 was seen in doxorubicin treated tumors and to the highest extent in combination treated samples.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('doxorubicin', 'Var', (42, 53))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('DR5', 'Gene', (26, 29))	('DR5', 'Gene', '8795', (26, 29))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('increase', 'PosReg', (14, 22))
46432	20406839	Similarly, a statistically significant (p<0.005) decrease in IL-8 mRNA expression was observed in combination therapy tumors, but not in tumors treated with either compound alone.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('IL-8', 'Gene', '3576', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('IL-8', 'Gene', (61, 65))	('decrease', 'NegReg', (49, 57))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mRNA expression', 'MPA', (66, 81))	('combination therapy', 'Var', (98, 117))	('tumors', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
46434	20406839	The functional impact of decreased in IL8, one of the most important chemotactic factors for neutrophils, was further reflected by a statistically significant decrease in the number of tumor infiltrating neutrophils identified in combination treated samples (p<0.05; Figure 5D).	('tumor', 'Disease', (185, 190))	('decreased', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('decrease', 'NegReg', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('IL8', 'Gene', (38, 41))	('IL8', 'Gene', '3576', (38, 41))
46451	20406839	Importantly, our findings show that the doxorubicin/TRAIL combination effect is independent of p53 mutation status: significant anti-tumor effects were observed in STS harboring either wild type or mutated p53.	('p53', 'Gene', (206, 209))	('doxorubicin', 'Chemical', 'MESH:D004317', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutated', 'Var', (198, 205))	('tumor', 'Disease', (133, 138))
46466	20406839	Furthermore, treatment induced changes in these cytokines can potentially affect tumor growth by impacting additional tumor microenvironment constituents such as neutrophils and macrophages in favor of tumor inhibition.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (118, 123))	('affect', 'Reg', (74, 80))	('changes', 'Var', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('impacting', 'Reg', (97, 106))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
46469	20406839	Taken together, our studies suggest that doxorubicin/TRAIL combination has significant anti-STS effects resulting in both tumor cell apoptosis and anti-angiogenic impact.	('doxorubicin/TRAIL', 'Var', (41, 58))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('anti-angiogenic impact', 'CPA', (147, 169))	('doxorubicin', 'Chemical', 'MESH:D004317', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('anti-STS effects', 'CPA', (87, 103))	('tumor', 'Disease', (122, 127))
46542	31427377	Additionally, patients with inherited homozygous mutations in ATM, human cell lines lacking functional ATM, and Atm knockout mice are hypersensitive to radiation.	('a', 'Gene', '11820', (70, 71))	('mice', 'Species', '10090', (125, 129))	('hypersensitive', 'Disease', (134, 148))	('A', 'Gene', '11820', (112, 113))	('a', 'Gene', '11820', (85, 86))	('patients', 'Species', '9606', (14, 22))	('hypersensitive to radiation', 'Phenotype', 'HP:0011133', (134, 161))	('A', 'Gene', '11820', (0, 1))	('a', 'Gene', '11820', (52, 53))	('a', 'Gene', '11820', (100, 101))	('A', 'Gene', '11820', (103, 104))	('a', 'Gene', '11820', (108, 109))	('a', 'Gene', '11820', (156, 157))	('a', 'Gene', '11820', (130, 131))	('A', 'Gene', '11820', (62, 63))	('hypersensitive', 'Disease', 'MESH:D004342', (134, 148))	('a', 'Gene', '11820', (153, 154))	('a', 'Gene', '11820', (15, 16))	('homozygous', 'Var', (38, 48))	('a', 'Gene', '11820', (8, 9))	('human', 'Species', '9606', (67, 72))
46543	31427377	Therefore, genetic deletion of Atm in either primary tumor or endothelial cells can be utilized to radiosensitize specific cell populations in order to define the roles of these cell types during tumor response to radiotherapy.	('a', 'Gene', '11820', (133, 134))	('Atm', 'Gene', (31, 34))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('a', 'Gene', '11820', (100, 101))	('a', 'Gene', '11820', (223, 224))	('genetic deletion', 'Var', (11, 27))	('a', 'Gene', '11820', (49, 50))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (53, 58))	('a', 'Gene', '11820', (215, 216))	('a', 'Gene', '11820', (71, 72))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('a', 'Gene', '11820', (81, 82))
46545	31427377	In this model, viral delivery of Flp recombinase initiated tumorigenesis by deleting FRTed alleles of the tumor suppressor p53 and drove expression of the mutated oncogene KrasG12D by deleting an upstream FRTed STOP cassette at the endogenous promoter.	('a', 'Gene', '11820', (158, 159))	('p53', 'Gene', '22060', (123, 126))	('tumor', 'Disease', (59, 64))	('a', 'Gene', '11820', (174, 175))	('a', 'Gene', '11820', (127, 128))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('a', 'Gene', '11820', (54, 55))	('tumor', 'Disease', (106, 111))	('expression', 'MPA', (137, 147))	('a', 'Gene', '11820', (45, 46))	('a', 'Gene', '11820', (225, 226))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('a', 'Gene', '11820', (91, 92))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('a', 'Gene', '11820', (217, 218))	('a', 'Gene', '11820', (18, 19))	('a', 'Gene', '11820', (202, 203))	('drove', 'PosReg', (131, 136))	('a', 'Gene', '11820', (193, 194))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('deleting', 'Var', (76, 84))	('Flp', 'Gene', (33, 36))	('p53', 'Gene', (123, 126))	('deleting', 'Var', (184, 192))
46546	31427377	Cre recombinase was not used to initiate the primary tumor in this system, but instead was expressed under the control of the VE-Cadherin promoter to direct Cre expression to endothelial cells in order to delete floxed Atm alleles specifically in the vasculature without affecting Atm gene expression in the primary tumor cells (Table 1).	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('a', 'Gene', '11820', (84, 85))	('VE-Cadherin', 'Gene', (126, 137))	('a', 'Gene', '11820', (37, 38))	('a', 'Gene', '11820', (252, 253))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('a', 'Gene', '11820', (330, 331))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Cre', 'Gene', '2777477', (0, 3))	('a', 'Gene', '11820', (312, 313))	('Cre', 'Gene', (0, 3))	('a', 'Gene', '11820', (12, 13))	('a', 'Gene', '11820', (130, 131))	('a', 'Gene', '11820', (257, 258))	('a', 'Gene', '11820', (184, 185))	('Cre', 'Gene', '2777477', (157, 160))	('a', 'Gene', '11820', (88, 89))	('Cre', 'Gene', (157, 160))	('VE-Cadherin', 'Gene', '12562', (126, 137))	('a', 'Gene', '11820', (17, 18))	('a', 'Gene', '11820', (271, 272))	('a', 'Gene', '11820', (223, 224))	('tumor', 'Disease', (316, 321))	('a', 'Gene', '11820', (49, 50))	('delete', 'Var', (205, 211))	('tumor', 'Disease', (53, 58))	('floxed Atm', 'Gene', (212, 222))	('a', 'Gene', '11820', (239, 240))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
46548	31427377	Cre expression in tumor initiating cells activated expression of oncogenic KrasG12D by deleting a floxed STOP cassette and deleted floxed alleles of the tumor suppressor p53 in addition to Atm.	('floxed', 'MPA', (98, 104))	('a', 'Gene', '11820', (119, 120))	('p53', 'Gene', (170, 173))	('expression', 'MPA', (51, 61))	('a', 'Gene', '11820', (29, 30))	('deleting', 'Var', (87, 95))	('p53', 'Gene', '22060', (170, 173))	('a', 'Gene', '11820', (46, 47))	('a', 'Gene', '11820', (77, 78))	('tumor', 'Disease', (18, 23))	('a', 'Gene', '11820', (138, 139))	('tumor', 'Disease', (153, 158))	('Cre', 'Gene', '2777477', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('Cre', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('a', 'Gene', '11820', (177, 178))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('a', 'Gene', '11820', (41, 42))	('a', 'Gene', '11820', (111, 112))	('a', 'Gene', '11820', (96, 97))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('deleted', 'Var', (123, 130))
46568	31427377	As a positive control for the ability to modulate rates of tumor eradication with SBRT, we also deleted Atm specifically in tumor parenchymal cells.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('a', 'Gene', '11820', (46, 47))	('a', 'Gene', '11820', (116, 117))	('a', 'Gene', '11820', (30, 31))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('A', 'Gene', '11820', (0, 1))	('deleted', 'Var', (96, 103))	('A', 'Gene', '11820', (104, 105))	('a', 'Gene', '11820', (139, 140))	('a', 'Gene', '11820', (131, 132))	('a', 'Gene', '11820', (67, 68))	('a', 'Gene', '11820', (91, 92))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('a', 'Gene', '11820', (3, 4))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('a', 'Gene', '11820', (51, 52))	('rat', 'Species', '10116', (50, 53))	('a', 'Gene', '11820', (71, 72))	('SBRT', 'Chemical', '-', (82, 86))
46569	31427377	Pax7-CreER; LoxP-STOP-LoxP (LSL)-KrasG12D; p53FL/FL; AtmFL/+ (P7KPAFL/+) and AtmFL/FL (P7KPAFL/FL) mice were injected into the gastrocnemius muscle with 4-hydroxy-tamoxifen to activate Cre recombinase to initiate sarcomagenesis and delete Atm within the same cell population.	('FL', 'Chemical', 'MESH:D005459', (92, 94))	('KPAFL', 'Chemical', '-', (64, 69))	('sarcomagenesis', 'Disease', 'None', (213, 227))	('FL', 'Chemical', 'MESH:D005459', (83, 85))	('4-hydroxy-tamoxifen', 'Chemical', 'MESH:C016601', (153, 172))	('a', 'Gene', '11820', (269, 270))	('a', 'Gene', '11820', (228, 229))	('Cre', 'Gene', '2777477', (185, 188))	('Cre', 'Gene', (185, 188))	('a', 'Gene', '11820', (197, 198))	('a', 'Gene', '11820', (219, 220))	('a', 'Gene', '11820', (164, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('FL', 'Chemical', 'MESH:D005459', (56, 58))	('FL', 'Chemical', 'MESH:D005459', (49, 51))	('FL', 'Chemical', 'MESH:D005459', (80, 82))	('delete', 'Var', (232, 238))	('Atm', 'Gene', (239, 242))	('FL', 'Chemical', 'MESH:D005459', (95, 97))	('mice', 'Species', '10090', (99, 103))	('a', 'Gene', '11820', (209, 210))	('a', 'Gene', '11820', (176, 177))	('a', 'Gene', '11820', (35, 36))	('Pax7', 'Gene', '18509', (0, 4))	('sarcomagenesis', 'Disease', (213, 227))	('a', 'Gene', '11820', (1, 2))	('FL', 'Chemical', 'MESH:D005459', (46, 48))	('KPAFL', 'Chemical', '-', (89, 94))	('Cre', 'Gene', '2777477', (5, 8))	('a', 'Gene', '11820', (255, 256))	('a', 'Gene', '11820', (128, 129))	('Cre', 'Gene', (5, 8))	('a', 'Gene', '11820', (73, 74))	('FL', 'Chemical', 'MESH:D005459', (67, 69))	('a', 'Gene', '11820', (214, 215))	('a', 'Gene', '11820', (181, 182))	('Pax7', 'Gene', (0, 4))
46570	31427377	Deletion of both floxed alleles of Atm (P7KPAFL/FL) within the tumor cells of the primary sarcoma resulted in enhanced radiosensitivity.	('tumor', 'Disease', (63, 68))	('a', 'Gene', '11820', (113, 114))	('a', 'Gene', '11820', (24, 25))	('sarcoma', 'Disease', (90, 97))	('FL', 'Chemical', 'MESH:D005459', (45, 47))	('FL', 'Chemical', 'MESH:D005459', (48, 50))	('a', 'Gene', '11820', (86, 87))	('KPAFL', 'Chemical', '-', (42, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('a', 'Gene', '11820', (96, 97))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (110, 135))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('a', 'Gene', '11820', (91, 92))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))	('a', 'Gene', '11820', (120, 121))	('Deletion', 'Var', (0, 8))
46583	31427377	Disruption of ATM signaling enhanced lung cancer cell radiosensitivity in a colony survival assay in vitro.	('lung cancer', 'Disease', (37, 48))	('cell radiosensitivity', 'Phenotype', 'HP:0010997', (49, 70))	('a', 'Gene', '11820', (89, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('a', 'Gene', '11820', (31, 32))	('a', 'Gene', '11820', (55, 56))	('cancer cell radiosensitivity', 'Phenotype', 'HP:0010997', (42, 70))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('a', 'Gene', '11820', (74, 75))	('a', 'Gene', '11820', (22, 23))	('a', 'Gene', '11820', (92, 93))	('a', 'Gene', '11820', (43, 44))	('a', 'Gene', '11820', (95, 96))	('Disruption', 'Var', (0, 10))
46584	31427377	Radiosensitization of lung tumor cells in KPAFL/FL mice translated to a significant decrease in tumor volume 6 and 8 weeks after 15 Gy irradiation to the whole thorax.	('a', 'Gene', '11820', (62, 63))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('a', 'Gene', '11820', (70, 71))	('lung tumor', 'Disease', 'MESH:D008175', (22, 32))	('a', 'Gene', '11820', (141, 142))	('a', 'Gene', '11820', (13, 14))	('a', 'Gene', '11820', (164, 165))	('mice', 'Species', '10090', (51, 55))	('a', 'Gene', '11820', (138, 139))	('tumor', 'Disease', (27, 32))	('FL', 'Chemical', 'MESH:D005459', (48, 50))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('Radiosensitization of lung', 'Phenotype', 'HP:0010997', (0, 26))	('a', 'Gene', '11820', (123, 124))	('lung tumor', 'Disease', (22, 32))	('a', 'Gene', '11820', (58, 59))	('KPAFL', 'Chemical', '-', (42, 47))	('tumor', 'Disease', (96, 101))	('a', 'Gene', '11820', (1, 2))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('lung tumor', 'Phenotype', 'HP:0100526', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('a', 'Gene', '11820', (89, 90))	('FL', 'Chemical', 'MESH:D005459', (45, 47))	('a', 'Gene', '11820', (111, 112))	('KPAFL/FL', 'Var', (42, 50))	('a', 'Gene', '11820', (80, 81))
46597	31427377	Radiosensitization of the endothelial cells through the deletion of Atm further disrupted AngioSense accumulation and blood flow into sarcomas, indicating an impairment of vascular function.	('A', 'Gene', '11820', (68, 69))	('a', 'Gene', '11820', (149, 150))	('A', 'Gene', '11820', (90, 91))	('a', 'Gene', '11820', (101, 102))	('a', 'Gene', '11820', (173, 174))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('a', 'Gene', '11820', (140, 141))	('deletion', 'Var', (56, 64))	('a', 'Gene', '11820', (13, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('sarcomas', 'Disease', (134, 142))	('a', 'Gene', '11820', (155, 156))	('a', 'Gene', '11820', (108, 109))	('a', 'Gene', '11820', (161, 162))	('disrupted', 'NegReg', (80, 89))	('blood flow', 'CPA', (118, 128))	('a', 'Gene', '11820', (178, 179))	('a', 'Gene', '11820', (35, 36))	('a', 'Gene', '11820', (114, 115))	('a', 'Gene', '11820', (1, 2))	('a', 'Gene', '11820', (135, 136))
46649	31885975	However, genetic testing revealed no pathogenic mutations in the TP53 gene or any other known mutations.	('TP53', 'Gene', '7157', (65, 69))	('mutations', 'Var', (48, 57))	('TP53', 'Gene', (65, 69))
46653	31885975	The patient was started on a regimen consisting of ifosfamide (3750 mg/m2 days 1-2 each 21-day cycle) and doxorubicin (30 mg/m2 days 1-2 each 21-day cycle), continuation of bevacizumab (10 mg/kg every 2 weeks; 4 additional cycles), and initiation of NovoTTF (Optune) treatment for the malignant glioma.	('glioma', 'Phenotype', 'HP:0009733', (295, 301))	('bevacizumab', 'Chemical', 'MESH:D000068258', (173, 184))	('patient', 'Species', '9606', (4, 11))	('ifosfamide', 'Chemical', 'MESH:D007069', (51, 61))	('doxorubicin', 'Chemical', 'MESH:D004317', (106, 117))	('3750', 'Var', (63, 67))	('malignant glioma', 'Disease', (285, 301))	('malignant glioma', 'Disease', 'MESH:D005910', (285, 301))
46677	31885975	The range of radiation dosages reported was 3600-6300 cGy, with most sarcomas occurring after treatment with 5100-6000 cGy (11/23, 47.8%).	('occurring', 'Reg', (78, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('5100-6000 cGy', 'Var', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcomas', 'Disease', (69, 77))	('sarcomas', 'Disease', 'MESH:D012509', (69, 77))
46686	31885975	Li-Fraumeni is a rare hereditary disorder linked to mutations of the tumor protein p53 (TP53) gene and increases the risk of developing multiple cancers early in life (commonly, breast cancers, sarcomas, and brain tumors).	('cancers', 'Disease', (145, 152))	('p53', 'Gene', (83, 86))	('Li-Fraumeni', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('TP53', 'Gene', '7157', (88, 92))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('brain tumors', 'Disease', 'MESH:D001932', (208, 220))	('brain tumors', 'Phenotype', 'HP:0030692', (208, 220))	('breast cancers', 'Disease', 'MESH:D001943', (178, 192))	('breast cancers', 'Disease', (178, 192))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('breast cancers', 'Phenotype', 'HP:0003002', (178, 192))	('increases', 'PosReg', (103, 112))	('brain tumors', 'Disease', (208, 220))	('sarcomas', 'Disease', 'MESH:D012509', (194, 202))	('tumor', 'Disease', (214, 219))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('sarcomas', 'Disease', (194, 202))	('hereditary disorder', 'Disease', (22, 41))	('TP53', 'Gene', (88, 92))	('mutations', 'Var', (52, 61))	('p53', 'Gene', '7157', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', (69, 74))	('hereditary disorder', 'Disease', 'MESH:D030342', (22, 41))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('linked', 'Reg', (42, 48))
46692	31885975	The patient's tumor was negative for IDH-1, which is found to be mutated in 43% of diffuse low-grade astrocytomas and is associated with better outcomes.	('astrocytomas', 'Disease', (101, 113))	('tumor', 'Disease', (14, 19))	('patient', 'Species', '9606', (4, 11))	('IDH-1', 'Gene', '3417', (37, 42))	('astrocytomas', 'Disease', 'MESH:D001254', (101, 113))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('IDH-1', 'Gene', (37, 42))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutated', 'Var', (65, 72))
46693	31885975	Of additional interest is the MGMT promoter and 1p/19q status, which was not available for this patient because coverage for the tests was denied by the patient's insurance carrier.	('patient', 'Species', '9606', (96, 103))	('1p/19q status', 'Var', (48, 61))	('patient', 'Species', '9606', (153, 160))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', '4255', (30, 34))
46694	31885975	Deleted 1p/19q and/or MGMT hypermethylation in anaplastic gliomas imparts better prognosis for patients treated with radiotherapy or chemotherapy.	('better', 'PosReg', (74, 80))	('Deleted 1p/19q', 'Var', (0, 14))	('patients', 'Species', '9606', (95, 103))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('MGMT', 'Gene', (22, 26))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('MGMT', 'Gene', '4255', (22, 26))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))
46697	31885975	For example, an EGFR mutation that occurs in roughly 40% of glioblastomas and also known to be highly expressed in many sarcomas would be an ideal target.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('glioblastomas', 'Disease', 'MESH:D005909', (60, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('sarcomas', 'Disease', (120, 128))	('glioblastomas', 'Disease', (60, 73))	('mutation', 'Var', (21, 29))	('EGFR', 'Gene', '1956', (16, 20))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('EGFR', 'Gene', (16, 20))	('glioblastomas', 'Phenotype', 'HP:0012174', (60, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
46711	31579490	Fusion between the 5' segment of the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the 3' portion of the Friend leukemia virus integration site 1 (FLI1) gene is detected in around 85% cases of Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (198, 213))	('Fusion', 'Var', (0, 6))	('EWSR1', 'Gene', (72, 77))	('Friend leukemia virus integration site 1', 'Gene', (110, 150))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (198, 213))	('Ewing sarcoma breakpoint region 1', 'Gene', (37, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('detected', 'Reg', (166, 174))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (37, 70))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('FLI1', 'Gene', '2313', (152, 156))	('FLI1', 'Gene', (152, 156))	('EWSR1', 'Gene', '2130', (72, 77))	('Friend leukemia virus integration site 1', 'Gene', '2313', (110, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	("Ewing's sarcoma", 'Disease', (198, 213))
46713	31579490	Translocations give rise to chimeric genes, which act as aberrant transcription factors and promote tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('promote', 'PosReg', (92, 99))	('Translocations', 'Var', (0, 14))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('chimeric', 'Var', (28, 36))
46736	31579490	These translocations are t(11;22)(q24;q12), t(21;22)(q22;q12), t(7;22)(q22;q12), t(17;22)(q21;q12), and t(2,22)(q35;q12) which give rise to the fusion genes EWSR1- FLI1 (85% of cases), EWSR1-ERG (10% of cases), EWSR1-ETV1 (<1% of cases), EWSR1-ETV4 (<1% of case), and EWS1- FEV (<1% of cases), respectively.	('EWSR1', 'Gene', '2130', (211, 216))	('EWSR1', 'Gene', '2130', (185, 190))	('EWS', 'Gene', '2130', (157, 160))	('EWS', 'Gene', (185, 188))	('EWS', 'Gene', '2130', (268, 271))	('EWS', 'Gene', (238, 241))	('ETV1', 'Gene', (217, 221))	('ETV4', 'Gene', (244, 248))	('t(21;22)(q22;q12', 'Var', (44, 60))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (44, 61))	('t(7;22)(q22;q12', 'Var', (63, 78))	('EWSR1', 'Gene', (211, 216))	('EWS', 'Gene', '2130', (211, 214))	('t(7;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (63, 79))	('EWSR1', 'Gene', (185, 190))	('EWSR1', 'Gene', '2130', (238, 243))	('t(2,22)(q35;q12', 'Var', (104, 119))	('FLI1', 'Gene', (164, 168))	('EWSR1', 'Gene', '2130', (157, 162))	('t(17;22)(q21;q12', 'Var', (81, 97))	('t(11;22)(q24;q12', 'Var', (25, 41))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (25, 42))	('ETV1', 'Gene', '2115', (217, 221))	('ETV4', 'Gene', '2118', (244, 248))	('EWS', 'Gene', (157, 160))	('EWS', 'Gene', '2130', (185, 188))	('FLI1', 'Gene', '2313', (164, 168))	('EWS', 'Gene', (268, 271))	('EWS', 'Gene', '2130', (238, 241))	('t(17;22)(q21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (81, 98))	('EWS', 'Gene', (211, 214))	('EWSR1', 'Gene', (238, 243))	('EWSR1', 'Gene', (157, 162))
46737	31579490	The resultant fusion gene functions as a constitutively active transcription factor, encodes a chimeric protein and regulates numerous other genes, responsible for the oncogenic behavior of Ewing's sarcoma.	('fusion', 'Var', (14, 20))	("Ewing's sarcoma", 'Disease', (190, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (190, 205))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (190, 205))
46749	31579490	Hence, identification of chromosomal translocations and chimeric genes specific to Ewing's sarcoma, as discussed earlier, via molecular techniques fluorescence in situ hybridization, and polymerase chain reaction is considered the gold standard of diagnosis.	('chimeric genes', 'Var', (56, 70))	("Ewing's sarcoma", 'Disease', (83, 98))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (83, 98))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (83, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))
46762	31579490	Molecular diagnostics to detect abnormal expression of various genes/proteins and transcription factors/modulators, promoting tumorigenesis in Ewing's sarcoma patients, could help create a personalized chemotherapy regimen, consisting of novel targeted agents along with standard anticancer agents.	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (143, 158))	("Ewing's sarcoma", 'Disease', (143, 158))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (143, 158))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('abnormal', 'Var', (32, 40))	('promoting', 'PosReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Disease', (126, 131))
46885	28622153	Fluorescence in situ hybridization (FISH) was used to detect amplification of Mouse double minute 2 homolog (MDM2) in all cases of retroperitoneal located tumors to rule out dedifferentiated liposarcoma.	('MDM2', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('Mouse double minute 2 homolog', 'Gene', '17246', (78, 107))	('liposarcoma', 'Disease', 'MESH:D008080', (191, 202))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('liposarcoma', 'Phenotype', 'HP:0012034', (191, 202))	('amplification', 'Var', (61, 74))	('tumors', 'Disease', (155, 161))	('Mouse double minute 2 homolog', 'Gene', (78, 107))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('liposarcoma', 'Disease', (191, 202))
46972	29116117	Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma The lack of useful biomarkers is a crucial problem for patients with soft tissue sarcomas (STSs).	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (153, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('STSs', 'Phenotype', 'HP:0030448', (175, 179))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (153, 173))	('patients', 'Species', '9606', (139, 147))	('Sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (67, 83))	('STS', 'Phenotype', 'HP:0030448', (175, 178))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (153, 173))	('soft tissue sarcomas', 'Disease', (153, 173))	('MicroRNA-92b-3p', 'Var', (12, 27))	('Sarcoma', 'Disease', (76, 83))	('Sarcoma', 'Disease', 'MESH:D012509', (76, 83))
46987	29116117	Accumulating evidence indicates that miRNAs may function as either tumour suppressors or oncogenes that regulates growth and apoptosis.	('miRNAs', 'Var', (37, 43))	('tumour', 'Disease', (67, 73))	('growth', 'CPA', (114, 120))	('apoptosis', 'CPA', (125, 134))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (67, 73))
46994	29116117	Then, miR-92b-3p, miR-150-3p, miR-4701-5p and miR-4728-3p, for which qPCR reporter probes were available, were selected for the further detailed analysis.	('miR-92b-3', 'Gene', '407047', (6, 15))	('miR-4701-5p', 'Var', (30, 41))	('miR-150-3p', 'Chemical', '-', (18, 28))	('miR-92b-3', 'Gene', (6, 15))	('miR-4728-3p', 'Var', (46, 57))	('miR-150-3p', 'Var', (18, 28))
46997	29116117	On the other hand, miR-92b-3p expression in the culture media of all SS cell lines examined and miR-150-3p expression in the culture medium of YaFuSS was significantly higher than that of hMSCs (p < 0.05, Fig.	('expression', 'MPA', (30, 40))	('miR-92b-3', 'Gene', (19, 28))	('miR-150-3p', 'Chemical', '-', (96, 106))	('SS', 'Phenotype', 'HP:0012570', (147, 149))	('higher', 'PosReg', (168, 174))	('miR-150-3p', 'Var', (96, 106))	('SS', 'Phenotype', 'HP:0012570', (69, 71))	('miR-92b-3', 'Gene', '407047', (19, 28))
46998	29116117	1E), suggesting that miR-92b-3p and miR-150-3p are abundantly secreted from SS-cells.	('miR-92b-3', 'Gene', (21, 30))	('miR-150-3p', 'Var', (36, 46))	('miR-92b-3', 'Gene', '407047', (21, 30))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('miR-150-3p', 'Chemical', '-', (36, 46))
47097	26947017	Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('copy number', 'Var', (89, 100))	('gain', 'PosReg', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
47107	26947017	Synovial sarcoma cells have been shown consistently to bear a balanced t(X;18) chromosomal translocation that generates a fusion between SS18 (formerly called SYT) and an SSX gene.	('fusion', 'Var', (122, 128))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('generates', 'Reg', (110, 119))	('SSX', 'Gene', '6757', (171, 174))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('SSX', 'Gene', (171, 174))	('SYT', 'Gene', '268996', (159, 162))	('SS18', 'Gene', (137, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SYT', 'Gene', (159, 162))
47111	26947017	Epigenetic mechanisms have been described wherein SS18-SSX fusion oncoproteins serve as master regulators of transcription in synovial sarcoma cell lines.	('synovial sarcoma', 'Disease', 'MESH:D013584', (126, 142))	('synovial sarcoma', 'Disease', (126, 142))	('Epigenetic', 'Var', (0, 10))	('SSX', 'Gene', '6757', (55, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (126, 142))	('SSX', 'Gene', (55, 58))
47113	26947017	This hypothesis has been supported by limited comparative genomic hybridization and sequencing data that identified few copy number variations and mutations in most synovial sarcomas.	('mutations', 'Var', (147, 156))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (165, 182))	('synovial sarcomas', 'Disease', 'MESH:D013584', (165, 182))	('synovial sarcomas', 'Disease', (165, 182))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (165, 181))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))
47133	26947017	Targeted, deeper sequencing was used for validation of all mutations that had an allelic fraction of at least 10% in the tumor and no more than a single read in the germline control tissue.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
47134	26947017	Most identified mutations demonstrated variant allele fractions well below 40 percent, which in light of the greater than 85 percent typical histologically-determined tumor cell density in the samples, suggests that the mutations were sub-clonal across the neoplasm and therefore had not contributed to initial malignant transformation.	('neoplasm', 'Disease', 'MESH:D009369', (257, 265))	('neoplasm', 'Phenotype', 'HP:0002664', (257, 265))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('neoplasm', 'Disease', (257, 265))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (220, 229))	('tumor', 'Disease', (167, 172))
47135	26947017	Transcriptome sequencing demonstrated that most mutations also arose in genes that were minimally expressed in the mutated-allele-bearing tumor and minimally expressed in the other tumors that lacked the mutation.	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', (138, 143))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('arose', 'Reg', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
47136	26947017	Notably, comparison of hSS1- and hSS2-induced tumors found a slight increase in the number of these passenger mutations in the former, which also developed and were harvested at an older age (Mean 262 versus 168 days).	('hSS2', 'Gene', '56244', (33, 37))	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('increase', 'PosReg', (68, 76))	('hSS1', 'Gene', '3123', (23, 27))	('tumors', 'Disease', (46, 52))	('hSS1', 'Gene', (23, 27))	('hSS2', 'Gene', (33, 37))
47140	26947017	Thus, the only genetic change that frequently contributes to mouse synovial sarcomagenesis is amplification of part or all of chromosome 6, consistently including the fusion gene expression locus.	('amplification', 'Var', (94, 107))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (67, 83))	('synovial sarcoma', 'Disease', 'MESH:D013584', (67, 83))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (67, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('mouse', 'Species', '10090', (61, 66))	('synovial sarcoma', 'Disease', (67, 83))
47146	26947017	In each induction model, hSS1 expression resulted in slightly fewer, but comparably located tumors, at longer latencies (Fig.	('fewer', 'NegReg', (62, 67))	('expression', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('hSS1', 'Gene', '3123', (25, 29))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('hSS1', 'Gene', (25, 29))
47151	26947017	Early human patient series correlated the SS18-SSX1 fusion genotype with worse prognosis.	('human', 'Species', '9606', (6, 11))	('SSX1', 'Gene', (47, 51))	('fusion', 'Var', (52, 58))	('patient', 'Species', '9606', (12, 19))	('SSX1', 'Gene', '6756', (47, 51))
47158	26947017	This demonstrated a statistically significant reduction in BSS histology cases in synovial sarcomas of the SS18-SSX2 fusion genotype (p < 0.0001, Fisher exact test; Supplementary Table 5).	('synovial sarcomas', 'Phenotype', 'HP:0012570', (82, 99))	('reduction', 'NegReg', (46, 55))	('synovial sarcomas', 'Disease', 'MESH:D013584', (82, 99))	('SSX2', 'Gene', '6757', (112, 116))	('synovial sarcomas', 'Disease', (82, 99))	('BSS', 'Disease', (59, 62))	('fusion', 'Var', (117, 123))	('SSX2', 'Gene', (112, 116))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (82, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))
47177	26947017	First, the t(X;18) translocation in a human synovial sarcoma disrupts one allele of the involved, native SSX gene, whose 3' exons it repurposes in the fusion gene.	('t(X;18', 'Gene', (11, 17))	('allele', 'MPA', (74, 80))	('SSX', 'Gene', (105, 108))	('synovial sarcoma disrupts', 'Disease', (44, 69))	('human', 'Species', '9606', (38, 43))	('SSX', 'Gene', '6757', (105, 108))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (44, 60))	('synovial sarcoma disrupts', 'Disease', 'MESH:D013584', (44, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('translocation', 'Var', (19, 32))
47178	26947017	This could be especially impactful in males, in which the fusion disrupts the only copy of the involved SSX gene.	('fusion', 'Var', (58, 64))	('disrupts', 'NegReg', (65, 73))	('SSX', 'Gene', '6757', (104, 107))	('SSX', 'Gene', (104, 107))	('only copy', 'MPA', (78, 87))
47182	26947017	We are therefore left to only hypothesis-generating experiments to explain a role for the loss of native SSX2 in either reduced synovial sarcomas in males or reduced BSS histology.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (128, 144))	('BSS histology', 'CPA', (166, 179))	('SSX2', 'Gene', (105, 109))	('loss', 'Var', (90, 94))	('reduced synovial sarcomas', 'Disease', 'MESH:D013584', (120, 145))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (128, 145))	('reduced synovial sarcomas', 'Disease', (120, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('reduced', 'NegReg', (158, 165))	('SSX2', 'Gene', '6757', (105, 109))
47183	26947017	Knock-down of SSX2 expression by small interfering RNA (siRNA) in human synovial sarcoma cell lines hampered proliferation compared to a non-target control siRNA (Fig.	('hampered', 'NegReg', (100, 108))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (72, 88))	('synovial sarcoma', 'Disease', 'MESH:D013584', (72, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('human', 'Species', '9606', (66, 71))	('SSX2', 'Gene', '6757', (14, 18))	('SSX2', 'Gene', (14, 18))	('proliferation', 'CPA', (109, 122))	('small interfering', 'Var', (33, 50))	('synovial sarcoma', 'Disease', (72, 88))
47190	26947017	Exome sequencing demonstrated a striking absence of mutations that by allele fraction and gene transcription levels likely contributed to synovial sarcomagenesis.	('mutations', 'Var', (52, 61))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (138, 154))	('synovial sarcoma', 'Disease', 'MESH:D013584', (138, 154))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (138, 161))	('synovial sarcoma', 'Disease', (138, 154))	('contributed', 'Reg', (123, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
47192	26947017	The only recurrent genetic change in tumors, beyond the activation of the hSS1 or hSS2 fusion gene, was amplification of part or all of chromosome 6.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('hSS2', 'Gene', (82, 86))	('hSS2', 'Gene', '56244', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('hSS1', 'Gene', '3123', (74, 78))	('hSS1', 'Gene', (74, 78))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('amplification', 'Var', (104, 117))
47194	26947017	While chromosome 6 trisomy may impact many genes, the partial chromosomal gains always included the Rosa26 locus and every copy number gain was an increase in the targeted allele.	('Rosa26', 'Gene', (100, 106))	('genes', 'Gene', (43, 48))	('partial chromosomal gains', 'Var', (54, 79))	('impact', 'Reg', (31, 37))	('Rosa26', 'Gene', '14910', (100, 106))	('trisomy', 'Var', (19, 26))	('included', 'Reg', (87, 95))
47195	26947017	The increased expression by copy number gain is likely an artifact of expression from other than the native Ss18 locus.	('Ss18', 'Gene', '268996', (108, 112))	('expression', 'MPA', (14, 24))	('Ss18', 'Gene', (108, 112))	('copy number gain', 'Var', (28, 44))	('increased', 'PosReg', (4, 13))
47212	26947017	The fact that both tumorigenesis and BSS histology seem to be limited more profoundly in males also fits with an effect mediated by loss of native SSX2, on the X-chromosome.	('fits', 'Disease', 'MESH:D012640', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('SSX2', 'Gene', '6757', (147, 151))	('loss', 'Var', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('fits', 'Disease', (100, 104))	('tumor', 'Disease', (19, 24))	('SSX2', 'Gene', (147, 151))
47219	26947017	Demonstrating that modulation of SSX2 levels impacts proliferation in human synovial sarcoma cell lines suggests that SSX2 may function as an oncogene.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (76, 92))	('SSX2', 'Gene', (118, 122))	('SSX2', 'Gene', (33, 37))	('synovial sarcoma', 'Disease', 'MESH:D013584', (76, 92))	('human', 'Species', '9606', (70, 75))	('proliferation', 'CPA', (53, 66))	('impacts', 'Reg', (45, 52))	('synovial sarcoma', 'Disease', (76, 92))	('SSX2', 'Gene', '6757', (118, 122))	('modulation', 'Var', (19, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('SSX2', 'Gene', '6757', (33, 37))
47221	26947017	Certainly, prospective experiments are warranted, as the capacity to generate translocations and assay transformation and tumorgenesis from them in normal human cells in vitro are developed.	('transformation', 'CPA', (103, 117))	('human', 'Species', '9606', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('translocations', 'Var', (78, 92))	('tumor', 'Disease', (122, 127))
47232	26947017	The mice bearing Rosa26-targeted conditional SS18-SSX2, were previously described, as were Rosa26-CreER, Myf5-Cre and Hprt-Cre mice.	('mice', 'Species', '10090', (127, 131))	('Myf5', 'Gene', (105, 109))	('mice', 'Species', '10090', (4, 8))	('Hprt', 'Gene', '15452', (118, 122))	('Hprt', 'Gene', (118, 122))	('Rosa26', 'Gene', '14910', (91, 97))	('SSX2', 'Gene', (50, 54))	('conditional', 'Var', (33, 44))	('Rosa26', 'Gene', '14910', (17, 23))	('Myf5', 'Gene', '17877', (105, 109))	('Rosa26', 'Gene', (91, 97))	('Rosa26', 'Gene', (17, 23))	('SSX2', 'Gene', '6757', (50, 54))
47262	25970220	Gastrointestinal toxicosis was identified in only 16% of dogs receiving vinorelbine in one of the aforementioned studies, whereas the other studies revealed mild to moderate gastrointestinal toxic effects in 11 of 24 (46%) treated dogs or after 44 of 89 (49%) total administered doses.	('vinorelbine', 'Var', (72, 83))	('vinorelbine', 'Chemical', 'MESH:D000077235', (72, 83))	('gastrointestinal toxic', 'Disease', 'MESH:D005767', (174, 196))	('Gastrointestinal toxicosis', 'Disease', (0, 26))	('Gastrointestinal toxicosis', 'Disease', 'MESH:D005767', (0, 26))	('dogs', 'Species', '9615', (231, 235))	('gastrointestinal toxic', 'Disease', (174, 196))	('dogs', 'Species', '9615', (57, 61))
47480	25044961	These 34 soft tissue sarcomas were extracted from the NCDB using the appropriate second and third editions of the WHO International Classification of Disease for Oncology (ICD-0-2/3) site (C40.0-C40.9, C41.0-C41.9) and histology codes.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (9, 29))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (9, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('C40.0-C40.9', 'Var', (189, 200))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (9, 29))	('soft tissue sarcomas', 'Disease', (9, 29))	('C41.0-C41.9', 'Var', (202, 213))	('C41', 'CellLine', 'CVCL:2253', (208, 211))	('Oncology', 'Phenotype', 'HP:0002664', (162, 170))	('C41', 'CellLine', 'CVCL:2253', (202, 205))
47610	23050205	Histopathological analysis showed a primitive neuroectodermal tumor, and immunohistochemical analysis showed positivity for CD99, synaptophysin, and EMA and negativity for desmin, myogenin, S-100 protein, and pancytokeratin AE1/AE3, favoring the diagnosis of pPNET.	('pPNET', 'Disease', (259, 264))	('myogenin', 'Gene', (180, 188))	('negativity', 'Var', (157, 167))	('synaptophysin', 'Gene', '6855', (130, 143))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (46, 67))	('positivity', 'Var', (109, 119))	('neuroectodermal tumor', 'Disease', (46, 67))	('desmin', 'Gene', (172, 178))	('AE3', 'Gene', '6508', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('AE1', 'Gene', '6521', (224, 227))	('myogenin', 'Gene', '4656', (180, 188))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (46, 67))	('AE1', 'Gene', (224, 227))	('desmin', 'Gene', '1674', (172, 178))	('CD99', 'Gene', (124, 128))	('S-100', 'Gene', (190, 195))	('PNET', 'Phenotype', 'HP:0030065', (260, 264))	('CD99', 'Gene', '4267', (124, 128))	('synaptophysin', 'Gene', (130, 143))	('S-100', 'Gene', '6271', (190, 195))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (36, 67))	('AE3', 'Gene', (228, 231))
47644	30992672	Whole exome sequencing demonstrated that the main somatic mutation was a non-synonymous mutation of KRAS (c.182A>G), and this result did not show any indications for targeted drugs.	('KRAS', 'Gene', (100, 104))	('c.182A>G', 'Var', (106, 114))	('c.182A>G', 'Mutation', 'rs121913240', (106, 114))	('KRAS', 'Gene', '3845', (100, 104))
47651	30992672	Previous studies have demonstrated that testis-specific protein Y-linked (TSPY ) gene expression and sex-determining region Y (SRY), Wilms tumor 1 (WT1), and SRY box 9 (SOX9) gene mutations are associated with tumor development.	('Wilms tumor', 'Disease', (133, 144))	('tumor', 'Disease', (139, 144))	('sex-determining region Y', 'Gene', '6736', (101, 125))	('WT1', 'Gene', '7490', (148, 151))	('testis-specific protein Y-linked', 'Gene', '7258', (40, 72))	('TSPY', 'Gene', (74, 78))	('sex-determining region Y', 'Gene', (101, 125))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('TSPY', 'Gene', '7258', (74, 78))	('tumor', 'Disease', (210, 215))	('SRY', 'Gene', '6736', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('SRY', 'Gene', '6736', (127, 130))	('SRY box 9', 'Gene', (158, 167))	('mutations', 'Var', (180, 189))	('Wilms tumor', 'Disease', 'MESH:D009396', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('associated', 'Reg', (194, 204))	('SOX9', 'Gene', (169, 173))	('SRY box 9', 'Gene', '6662', (158, 167))	('SRY', 'Gene', (158, 161))	('SRY', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('testis-specific protein Y-linked', 'Gene', (40, 72))	('Wilms tumor', 'Phenotype', 'HP:0002667', (133, 144))	('SOX9', 'Gene', '6662', (169, 173))	('WT1', 'Gene', (148, 151))
47710	30992672	Although the mechanism of tumorigenesis in 46, XY PGD is still unclear, studies have found that tumor development is associated with TSPY gene expression and certain gene mutations, such as SRY, SOX9, and WT1.	('PGD', 'Phenotype', 'HP:0000133', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SOX9', 'Gene', (195, 199))	('associated', 'Reg', (117, 127))	('SOX9', 'Gene', '6662', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (96, 101))	('SRY', 'Gene', '6736', (190, 193))	('TSPY', 'Gene', '7258', (133, 137))	('WT1', 'Gene', '7490', (205, 208))	('TSPY', 'Gene', (133, 137))	('mutations', 'Var', (171, 180))	('tumor', 'Disease', (26, 31))	('WT1', 'Gene', (205, 208))	('SRY', 'Gene', (190, 193))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
47711	30992672	In this report, germline gene mutation demonstrated copy-number variations of the FGF9 gene and frameshift mutation of the MAP3K1 gene, which may explain why this patient had the diagnosis of 46, XY PGD.	('frameshift mutation', 'Var', (96, 115))	('FGF9', 'Gene', '2254', (82, 86))	('MAP3K1', 'Gene', (123, 129))	('MAP3K1', 'Gene', '4214', (123, 129))	('patient', 'Species', '9606', (163, 170))	('PGD', 'Phenotype', 'HP:0000133', (199, 202))	('copy-number variations', 'Var', (52, 74))	('FGF9', 'Gene', (82, 86))
47714	30992672	However, with regard to genes associated with gonadal tumorigenesis, the molecular genetic testing revealed that the only pathogenic driver gene mutation was in KRAS.	('gonadal tumor', 'Phenotype', 'HP:0010785', (46, 59))	('gonadal tumorigenesis', 'Phenotype', 'HP:0010785', (46, 67))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('gonadal tumor', 'Disease', 'MESH:D006058', (46, 59))	('KRAS', 'Gene', (161, 165))	('gonadal tumor', 'Disease', (46, 59))	('KRAS', 'Gene', '3845', (161, 165))	('mutation', 'Var', (145, 153))
47722	30992672	In this case, we performed the molecular genetic testing for samples of the primary tumor and the metastatic tumors, and the results revealed the same non-synonymous KRAS gene mutation.	('revealed', 'Reg', (133, 141))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('non-synonymous', 'Var', (151, 165))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('KRAS', 'Gene', (166, 170))	('KRAS', 'Gene', '3845', (166, 170))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('tumor', 'Disease', (109, 114))
47743	30992672	Ras genes are the most common target of somatic mutations in human cancers, of which KRAS is the most frequently mutated isoform.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('Ras genes', 'Gene', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('KRAS', 'Gene', (85, 89))	('human', 'Species', '9606', (61, 66))	('KRAS', 'Gene', '3845', (85, 89))	('mutations', 'Var', (48, 57))
47745	30992672	With regard to therapeutic strategies, first, Ras activation could reduce the clinical efficacy of EGFR inhibitors; that is, mutant KRAS is not suitable for EGFR inhibitors.	('reduce', 'NegReg', (67, 73))	('EGFR', 'Gene', (157, 161))	('EGFR', 'Gene', (99, 103))	('KRAS', 'Gene', (132, 136))	('mutant', 'Var', (125, 131))	('KRAS', 'Gene', '3845', (132, 136))	('EGFR', 'Gene', '1956', (157, 161))	('EGFR', 'Gene', '1956', (99, 103))	('clinical efficacy', 'MPA', (78, 95))
47832	28630763	SS is a mesenchymal spindle-cell tumour which displays variable epithelial differentiation, including glandular formation and has a specific chromosomal translocation t(X;18) (p11;q11).	('tumour', 'Disease', (33, 39))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('t(X;18) (p11;q11', 'Var', (167, 183))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (33, 39))
47963	22312495	An SS18 rearrangement was observed in 49/50 nuclei examined, confirming the diagnosis of synovial sarcoma (Figure 4).	('synovial sarcoma', 'Disease', (89, 105))	('SS18', 'Gene', '6760', (3, 7))	('observed', 'Reg', (26, 34))	('rearrangement', 'Var', (8, 21))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (89, 105))	('SS18', 'Gene', (3, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('synovial sarcoma', 'Disease', 'MESH:D013584', (89, 105))
47980	22312495	Additionally the diagnosis of synovial sarcoma can be confirmed genetically with the detection of t(X;18)(p11.2;q11.2).	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('synovial sarcoma', 'Disease', (30, 46))	('t(X;18)(p11.2;q11.2', 'Var', (98, 117))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (98, 118))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (30, 46))	('synovial sarcoma', 'Disease', 'MESH:D013584', (30, 46))
48027	28039162	Our data provide preclinical rationale for the utility of PD-1/PD-L1 inhibition as a therapeutic option in this malignancy.	('PD-1', 'Gene', (58, 62))	('PD-1', 'Gene', '5133', (58, 62))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('inhibition', 'Var', (69, 79))	('malignancy', 'Disease', (112, 122))
48095	28039162	However, we found that PD-1 density in the tumor invasive margin was significantly associated with lower PFS, and CD8 and PD-L1 densities in the invasive margin also approached significance in this association, as well.	('PD-1', 'Gene', (23, 27))	('lower', 'NegReg', (99, 104))	('PD-1', 'Gene', '5133', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('PFS', 'Disease', (105, 108))	('density', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CD8', 'Gene', (114, 117))	('CD8', 'Gene', '925', (114, 117))	('tumor', 'Disease', (43, 48))
48098	28039162	Given that our prior experience with melanoma demonstrated that the presence of CD8 TILs at the tumor invasive margin (along with concomitant proximal PD-1 and PD-L1 induction) predicted clinical response to PD-1 inhibition, it is reasonable to extrapolate that this pattern might predict clinical response to PD-1 inhibition in other tumor types as well.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('CD8', 'Gene', '925', (80, 83))	('predicted', 'Reg', (177, 186))	('tumor', 'Disease', (335, 340))	('PD-1', 'Gene', (208, 212))	('PD-1', 'Gene', '5133', (208, 212))	('PD-1', 'Gene', (151, 155))	('PD-1', 'Gene', '5133', (151, 155))	('tumor', 'Disease', (96, 101))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('presence', 'Var', (68, 76))	('PD-1', 'Gene', (310, 314))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('PD-1', 'Gene', '5133', (310, 314))	('CD8', 'Gene', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))
48106	28039162	Further studies at the genomic and transcriptomic level may reveal baseline tumor mutations, as well as novel tumor antigens or neoepitopes resulting from nonsynonymous mutations, which collectively are responsible for the immunogenicity of certain subsets of synovial sarcoma.	('synovial sarcoma', 'Disease', 'MESH:D013584', (260, 276))	('nonsynonymous mutations', 'Var', (155, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (110, 115))	('synovial sarcoma', 'Disease', (260, 276))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mutations', 'Var', (82, 91))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (260, 276))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
48112	28039162	Although whole tumor or wedge resection analysis allows for a more complete representation of PD-L1, PD-1 or CD8 density variations within the tumor invasive margin, we recognize that prospective wedge resection and subsequent analysis of lung metastases to determine likelihood of treatment success with PD-1/PD-L1 inhibitors may not be technically feasible in every patient.	('PD-L1', 'Gene', (94, 99))	('CD8', 'Gene', (109, 112))	('PD-1', 'Gene', (305, 309))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (143, 148))	('PD-1', 'Gene', '5133', (305, 309))	('CD8', 'Gene', '925', (109, 112))	('variations', 'Var', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('patient', 'Species', '9606', (368, 375))	('tumor', 'Disease', (15, 20))	('lung metastases', 'Disease', (239, 254))	('PD-1', 'Gene', (101, 105))	('lung metastases', 'Disease', 'MESH:D009362', (239, 254))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('PD-1', 'Gene', '5133', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
48137	20396630	could detect strong immunoreactivity with murine double minute 2 (MDM2) in the absence of p53 mutations in one case, pointing to a possible role of MDM2 overexpression in tumorigenesis of SEF.	('p53', 'Gene', (90, 93))	('mutations', 'Var', (94, 103))	('MDM2', 'Gene', (148, 152))	('MDM2', 'Gene', '17246', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('MDM2', 'Gene', '17246', (148, 152))	('p53', 'Gene', '22060', (90, 93))	('tumor', 'Disease', (171, 176))	('murine', 'Species', '10090', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('MDM2', 'Gene', (66, 70))	('immunoreactivity', 'MPA', (20, 36))
48221	33348683	Radiological tumor response also predicted overall survival (OS) (Figure 4a-d) using three of the four methods (p1D-RECIST = 0.0304, p2D-WHO = 0.0794, p3D-EpSSG = 0.002 and p3D-Osirix = 0.0087).	('tumor', 'Disease', (13, 18))	('p3D-Osirix', 'Disease', (173, 183))	('p3D-Osirix', 'Disease', 'None', (173, 183))	('p2D-WHO', 'Var', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('overall survival', 'MPA', (43, 59))	('2D-WHO', 'Chemical', '-', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
48225	33348683	For EFS, the adjusted HRs were considerably higher with the 3D-EpSSG and the 3D-Osirix than with the 1D-RECIST or the 2D-WHO, with no remarkable overlap in the corresponding 95% CIs.	('3D-EpSSG', 'Var', (60, 68))	('HRs', 'MPA', (22, 25))	('higher', 'PosReg', (44, 50))	('3D-Osirix', 'Disease', 'None', (77, 86))	('2D-WHO', 'Chemical', '-', (118, 124))	('3D-Osirix', 'Disease', (77, 86))
48294	32002123	At 20 days after treatment, tumours from the combination treated mice were significantly smaller than those from untreated and single drug treated mice.	('mice', 'Species', '10090', (147, 151))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('combination', 'Var', (45, 56))	('mice', 'Species', '10090', (65, 69))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))	('smaller', 'NegReg', (89, 96))
48310	32002123	Dysregulation of this pathway plays a major role in many different cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
48321	32002123	Therefore, the inactivation of HKII-VDAC-ANT is an appealing anti-metabolic target, as blocking it inhibits HKII's preferential access to newly synthesised ATP, increases superoxide production, triggers mitochondrial depolarisation and initiates apoptosis.	('mitochondrial depolarisation', 'Phenotype', 'HP:0030059', (203, 231))	('HKII', 'Gene', (108, 112))	('apoptosis', 'CPA', (246, 255))	('HKII', 'Gene', (31, 35))	('preferential access to newly synthesised ATP', 'MPA', (115, 159))	('HKII', 'Gene', '3099', (31, 35))	('blocking', 'Var', (87, 95))	('HKII', 'Gene', '3099', (108, 112))	('ATP', 'Chemical', 'MESH:D000255', (156, 159))	('increases', 'PosReg', (161, 170))	('triggers', 'Reg', (194, 202))	('ANT', 'Gene', (41, 44))	('superoxide', 'Chemical', 'MESH:D013481', (171, 181))	('ANT', 'Gene', '293', (41, 44))	('mitochondrial depolarisation', 'MPA', (203, 231))	('initiates', 'Reg', (236, 245))	('inhibits', 'NegReg', (99, 107))	('increases superoxide production', 'Phenotype', 'HP:0025464', (161, 192))	('superoxide production', 'MPA', (171, 192))	('inactivation', 'Var', (15, 27))
48326	32002123	PENAO's trivalent arsenical moiety cross-links unpaired cysteine residues Cys57 and Cys257 located on the peptide loop of ANT that protrude into the matrix.	('ANT', 'Gene', (122, 125))	('Cys257', 'Var', (84, 90))	('Cys', 'Chemical', 'MESH:C046557', (74, 77))	('ANT', 'Gene', '293', (122, 125))	('arsenic', 'Chemical', 'MESH:D001151', (18, 25))	('cysteine', 'Chemical', 'MESH:D003545', (56, 64))	('Cys', 'Chemical', 'MESH:C046557', (84, 87))	('Cys57', 'Var', (74, 79))	('PENAO', 'Chemical', 'None', (0, 5))
48343	32002123	Calculation by CalcuSyn software (Biosoft, Cambridge, UK) showed that combination treatments were synergistic (combination index CI < 1) in terms of proliferation inhibition on HOS, HT1080 and SW982 (Figure 3D).	('inhibition', 'NegReg', (163, 173))	('SW982', 'CellLine', 'CVCL:1734', (193, 198))	('SW982', 'Var', (193, 198))	('proliferation', 'CPA', (149, 162))	('HT1080', 'CellLine', 'CVCL:0317', (182, 188))	('HOS', 'CellLine', 'CVCL:0312', (177, 180))
48385	32002123	PENAO, similarly as CAO, enters the mitochondrial matrix and inactivates ANT in the mitochondrial inner membrane and triggers Ca2+-dependent MPTP, by cross-linking the matrix facing thiols of Cys57 and Cys257 in ANT.	('ANT', 'Gene', (212, 215))	('Ca2+', 'Chemical', 'MESH:D002118', (126, 130))	('Cys57', 'Var', (192, 197))	('thiols', 'Chemical', 'MESH:D013438', (182, 188))	('MPTP', 'Chemical', 'MESH:D015632', (141, 145))	('cross-linking', 'Reg', (150, 163))	('inactivates', 'NegReg', (61, 72))	('ANT', 'Gene', '293', (212, 215))	('Cys', 'Chemical', 'MESH:C046557', (192, 195))	('ANT', 'Gene', (73, 76))	('Ca2+-dependent MPTP', 'MPA', (126, 145))	('Cys', 'Chemical', 'MESH:C046557', (202, 205))	('Cys257', 'Var', (202, 208))	('PENAO', 'Chemical', 'None', (0, 5))	('triggers', 'Reg', (117, 125))	('ANT', 'Gene', '293', (73, 76))
48386	32002123	Inactivation of ANT causes proliferation arrest, ATP depletion, superoxide level increase, mitochondrial depolarization and apoptosis in proliferating endothelial and tumour cells.	('ATP depletion', 'MPA', (49, 62))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Disease', (167, 173))	('proliferation arrest', 'Disease', (27, 47))	('superoxide level', 'MPA', (64, 80))	('mitochondrial depolarization', 'CPA', (91, 119))	('ATP', 'Chemical', 'MESH:D000255', (49, 52))	('ANT', 'Gene', '293', (16, 19))	('superoxide', 'Chemical', 'MESH:D013481', (64, 74))	('ANT', 'Gene', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('increase', 'PosReg', (81, 89))	('proliferation arrest', 'Disease', 'MESH:D006323', (27, 47))	('apoptosis', 'CPA', (124, 133))	('Inactivation', 'Var', (0, 12))
48399	32002123	By contrast PENAO and Gefitinib combination treatment significantly induced early and late apoptosis on HOS cells when compared to the control and single drug treatment groups.	('induced', 'Reg', (68, 75))	('PENAO', 'Chemical', 'None', (12, 17))	('HOS', 'CellLine', 'CVCL:0312', (104, 107))	('combination', 'Var', (32, 43))	('Gefitinib', 'Chemical', 'MESH:C419708', (22, 31))
48402	32002123	Our group has reported that, in seven STS cell lines, EGFR-targeted monotherapy strikingly inhibited the activities of EGFR and downstream PI3K/AKT, despite showing limited anti-proliferation.	('AKT', 'Gene', (144, 147))	('inhibited', 'NegReg', (91, 100))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', '1956', (119, 123))	('activities', 'MPA', (105, 115))	('AKT', 'Gene', '207', (144, 147))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', (119, 123))	('monotherapy', 'Var', (68, 79))
48412	32002123	It is postulated that mitochondrial perturbations resulting in increased ECAR are early events in the process of proliferation arrest and cell death.	('increased', 'PosReg', (63, 72))	('proliferation arrest', 'Disease', (113, 133))	('perturbations', 'Var', (36, 49))	('proliferation arrest', 'Disease', 'MESH:D006323', (113, 133))	('ECAR', 'MPA', (73, 77))
48421	32002123	The GCT, HT1080, SW872, SW982, Saos-2 and MG63 were purchased from the American Type Culture Collection (VA, USA).	('HT1080', 'CellLine', 'CVCL:0317', (9, 15))	('SW982', 'CellLine', 'CVCL:1734', (24, 29))	('SW872', 'Var', (17, 22))	('SW982', 'Var', (24, 29))
48517	22993336	Our data demonstrate a 37% improvement in 3- year DRFS in patients with pathCR compared to those without pathCR.	('pathCR', 'Var', (72, 78))	('improvement', 'PosReg', (27, 38))	('patients', 'Species', '9606', (58, 66))	('DRFS', 'MPA', (50, 54))
48518	22993336	With a median follow-up of 40 months, we observed no local or distant recurrences among the patients with pathCR, a time period during which the majority of STS recurrences are known to occur.	('pathCR', 'Var', (106, 112))	('STS', 'Phenotype', 'HP:0030448', (157, 160))	('patients', 'Species', '9606', (92, 100))	('local', 'CPA', (53, 58))
48521	23046583	Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis Mutations in the gene encoding the RNA-binding protein fused in sarcoma (FUS) can cause familial and sporadic amyotrophic lateral sclerosis (ALS) and rarely frontotemproal dementia (FTD).	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('Fused in sarcoma', 'Gene', (14, 30))	('ALS', 'Gene', (293, 296))	('RNA-binding protein', 'Gene', '27303', (187, 206))	('sporadic amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (253, 291))	('Fused in sarcoma', 'Gene', '233908', (14, 30))	('mice', 'Species', '10090', (44, 48))	('Mutations', 'Var', (152, 161))	('fused in sarcoma', 'Gene', (207, 223))	('FTD', 'Disease', 'MESH:C563003', (334, 337))	('ALS', 'Gene', '6647', (293, 296))	('dementia', 'Phenotype', 'HP:0000726', (324, 332))	('FUS proteinopathies', 'Disease', 'MESH:C563476', (85, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('FUS proteinopathies', 'Disease', (85, 104))	('RNA-binding protein', 'Gene', (187, 206))	('cause', 'Reg', (234, 239))	('FTD', 'Disease', (334, 337))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (262, 291))	('dementia', 'Disease', (324, 332))	('frontotemproal dementia', 'Phenotype', 'HP:0002145', (309, 332))	('dementia', 'Disease', 'MESH:D003704', (324, 332))	('fused in sarcoma', 'Gene', '233908', (207, 223))	('sporadic amyotrophic lateral sclerosis', 'Disease', (253, 291))
48522	23046583	FUS accumulates in neuronal cytoplasmic inclusions (NCIs) in ALS patients with FUS mutations.	('mutations', 'Var', (83, 92))	('ALS', 'Gene', (61, 64))	('patients', 'Species', '9606', (65, 73))	('ALS', 'Gene', '6647', (61, 64))	('FUS', 'Gene', (79, 82))
48525	23046583	It is unknown how FUS mutations cause disease and the role of FUS in FTD-FUS cases, which do not have FUS mutations.	('FTD', 'Disease', 'MESH:C563003', (69, 72))	('disease', 'Disease', (38, 45))	('FTD', 'Disease', (69, 72))	('mutations', 'Var', (22, 31))	('cause', 'Reg', (32, 37))	('FUS', 'Gene', (18, 21))
48526	23046583	In this paper we report the development of somatic brain transgenic (SBT) mice using recombinant adeno-associated virus (rAAV) to investigate how FUS mutations lead to neurodegeneration.	('lead to', 'Reg', (160, 167))	('neurodegeneration', 'Disease', (168, 185))	('neurodegeneration', 'Disease', 'MESH:D019636', (168, 185))	('FUS', 'Gene', (146, 149))	('neurodegeneration', 'Phenotype', 'HP:0002180', (168, 185))	('mutations', 'Var', (150, 159))	('mice', 'Species', '10090', (74, 78))	('adeno-associated virus', 'Species', '272636', (97, 119))
48527	23046583	We compared SBT mice expressing wild-type human FUS (FUSWT), and two ALS-linked mutations: FUSR521C and FUSDelta14, which lacks the nuclear localization signal.	('ALS', 'Gene', '6647', (69, 72))	('FUSWT', 'Gene', 'None', (53, 58))	('ALS', 'Gene', (69, 72))	('human', 'Species', '9606', (42, 47))	('FUSDelta14', 'Gene', (104, 114))	('FUSR521C', 'Mutation', 'rs121909668', (91, 99))	('FUSR521C', 'Var', (91, 99))	('mice', 'Species', '10090', (16, 20))	('FUSDelta14', 'Chemical', '-', (104, 114))	('FUSWT', 'Gene', (53, 58))
48528	23046583	Both FUS mutants accumulated in the cytoplasm relative to FUSWT.	('FUSWT', 'Gene', (58, 63))	('mutants', 'Var', (9, 16))	('FUSWT', 'Gene', 'None', (58, 63))
48530	23046583	Mice expressing the most aggressive mutation, FUSDelta14, recapitulated many aspects of FUS proteinopathies, including insoluble FUS, basophilic and eosiniphilic NCIs, and other pathologic markers, including ubiquitin, p62/SQSTM1, alpha-internexin, and the poly-adenylate(A)-binding protein 1 (PABP-1).	('FUSDelta14', 'Chemical', '-', (46, 56))	('FUS proteinopathies', 'Disease', (88, 107))	('eosiniphilic NCIs', 'Disease', 'None', (149, 166))	('eosiniphilic NCIs', 'Disease', (149, 166))	('FUSDelta14', 'Var', (46, 56))	('insoluble FUS', 'MPA', (119, 132))	('Mice', 'Species', '10090', (0, 4))	('FUS proteinopathies', 'Disease', 'MESH:C563476', (88, 107))
48531	23046583	Our data supports the hypothesis that ALS or FTD-linked FUS mutations cause neurodegeneration by increasing cyotplasmic FUS.	('ALS', 'Gene', '6647', (38, 41))	('cyotplasmic FUS', 'MPA', (108, 123))	('neurodegeneration', 'Phenotype', 'HP:0002180', (76, 93))	('ALS', 'Gene', (38, 41))	('neurodegeneration', 'Disease', (76, 93))	('neurodegeneration', 'Disease', 'MESH:D019636', (76, 93))	('cause', 'Reg', (70, 75))	('mutations', 'Var', (60, 69))	('FTD-linked FUS', 'Disease', 'MESH:C563003', (45, 59))	('increasing', 'PosReg', (97, 107))	('FTD-linked FUS', 'Disease', (45, 59))
48533	23046583	Identification of mutations in other genes that cause ALS/FTD, such as C9ORF72, sentaxin, and angiogenin, lends support to the idea that defective RNA metabolism is a critical pathogenic pathway.	('angiogenin', 'Gene', '11727', (94, 104))	('C9ORF72', 'Gene', (71, 78))	('angiogenin', 'Gene', (94, 104))	('FTD', 'Disease', (58, 61))	('sentaxin', 'Gene', (80, 88))	('ALS', 'Gene', '6647', (54, 57))	('RNA metabolism', 'MPA', (147, 161))	('ALS', 'Gene', (54, 57))	('FTD', 'Disease', 'MESH:C563003', (58, 61))	('mutations', 'Var', (18, 27))
48534	23046583	The SBT FUS mice described here will provide a valuable platform for dissecting the pathogenic mechanism of FUS mutations, define the relationship between FTD and ALS-FUS, and help identify therapeutic targets that are desperately needed for these devastating neurodegenerative disorders.	('ALS-FUS', 'Disease', (163, 170))	('FUS', 'Gene', (108, 111))	('FTD', 'Disease', 'MESH:C563003', (155, 158))	('rat', 'Species', '10116', (271, 274))	('FTD', 'Disease', (155, 158))	('mutations', 'Var', (112, 121))	('ALS-FUS', 'Disease', 'MESH:D008113', (163, 170))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (260, 287))	('mice', 'Species', '10090', (12, 16))	('rat', 'Species', '10116', (224, 227))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (260, 287))	('neurodegenerative disorders', 'Disease', (260, 287))
48535	23046583	Mutations in the Fused in Sarcoma (FUS) gene were recently discovered in some cases of familial and sporadic amyotrophic lateral sclerosis (ALS) and more rarely fronto-temproal dementia (FTD) .	('dementia', 'Phenotype', 'HP:0000726', (177, 185))	('Fused in Sarcoma', 'Gene', (17, 33))	('dementia', 'Disease', (177, 185))	('sporadic amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (100, 138))	('sporadic amyotrophic lateral sclerosis', 'Disease', (100, 138))	('dementia', 'Disease', 'MESH:D003704', (177, 185))	('FTD', 'Disease', 'MESH:C563003', (187, 190))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (109, 138))	('ALS', 'Gene', '6647', (140, 143))	('fronto-temproal dementia', 'Phenotype', 'HP:0002145', (161, 185))	('Mutations', 'Var', (0, 9))	('Sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('discovered', 'Reg', (59, 69))	('FUS', 'Gene', (35, 38))	('FTD', 'Disease', (187, 190))	('ALS', 'Gene', (140, 143))	('Fused in Sarcoma', 'Gene', '233908', (17, 33))
48538	23046583	The identification of FUS mutations and accumulation of FUS within ubiquitin-positive neuronal cytoplasmic inclusions (NCI) in a portion of ALS cases led to the re-examination of other neurological diseases with NCI of unknown origin.	('FUS', 'Gene', (22, 25))	('neurological diseases', 'Disease', (185, 206))	('neurological diseases', 'Disease', 'MESH:D020271', (185, 206))	('ubiquitin-positive neuronal cytoplasmic inclusions', 'Phenotype', 'HP:0012083', (67, 117))	('ALS', 'Gene', '6647', (140, 143))	('mutations', 'Var', (26, 35))	('ALS', 'Gene', (140, 143))
48544	23046583	In this report we have utilized a technique called somatic brain transgenesis (SBT) to investigate how FUS mutations lead to neurodegeneration.	('FUS', 'Gene', (103, 106))	('mutations', 'Var', (107, 116))	('neurodegeneration', 'Disease', (125, 142))	('neurodegeneration', 'Disease', 'MESH:D019636', (125, 142))	('lead to', 'Reg', (117, 124))	('neurodegeneration', 'Phenotype', 'HP:0002180', (125, 142))
48546	23046583	We compared over expression of wild-type human FUS (FUSWT), and two mutations associated with ALS: FUSR521C, or FUSDelta14.	('FUSDelta14', 'Chemical', '-', (112, 122))	('FUSR521C', 'Var', (99, 107))	('FUSR521C', 'Mutation', 'rs121909668', (99, 107))	('ALS', 'Gene', (94, 97))	('ALS', 'Gene', '6647', (94, 97))	('FUSDelta14', 'Var', (112, 122))	('human', 'Species', '9606', (41, 46))	('FUSWT', 'Gene', (52, 57))	('FUSWT', 'Gene', 'None', (52, 57))
48547	23046583	Expression of both FUS mutants led to increased FUS protein in the neuronal cytoplasm, the degree of which correlated with the severity of the mutation as reflected by disease onset in humans.	('FUS protein', 'Protein', (48, 59))	('FUS', 'Gene', (19, 22))	('mutants', 'Var', (23, 30))	('humans', 'Species', '9606', (185, 191))	('increased', 'PosReg', (38, 47))
48548	23046583	Mice expressing the most aggressive mutation, FUSDelta14, recapitulated many aspects of human FUS proteinopathies, including insoluble FUS protein, basophilic and eosiniphilic neuronal cytoplasmic inclusions (NCI), and presence of other pathologic markers, including ubiquitin, p62/SQSTM1, alpha-internexin, and the polyadenylate-binding protein 1 (PABP-1).	('insoluble FUS', 'MPA', (125, 138))	('polyadenylate-binding protein 1', 'Gene', (316, 347))	('FUSDelta14', 'Chemical', '-', (46, 56))	('polyadenylate-binding protein 1', 'Gene', '26986', (316, 347))	('eosin', 'Chemical', 'MESH:D004801', (163, 168))	('FUSDelta14', 'Var', (46, 56))	('FUS proteinopathies', 'Disease', 'MESH:C563476', (94, 113))	('FUS proteinopathies', 'Disease', (94, 113))	('Mice', 'Species', '10090', (0, 4))	('human', 'Species', '9606', (88, 93))	('ubiquitin', 'Disease', (267, 276))	('alpha-internexin', 'Protein', (290, 306))
48549	23046583	We utilized SBT to express wild type human FUS and two FUS mutations associated with ALS in the brains of mice to investigate the role of FUS in neurodegeneration using an in vivo model.	('mice', 'Species', '10090', (106, 110))	('neurodegeneration', 'Disease', (145, 162))	('associated', 'Reg', (69, 79))	('neurodegeneration', 'Disease', 'MESH:D019636', (145, 162))	('ALS', 'Gene', '6647', (85, 88))	('mutations', 'Var', (59, 68))	('human', 'Species', '9606', (37, 42))	('ALS', 'Gene', (85, 88))	('FUS', 'Gene', (55, 58))	('neurodegeneration', 'Phenotype', 'HP:0002180', (145, 162))
48550	23046583	In this experimental paradigm, newly born (P0) litters of mice were administered recombinant AAV1 encoding FUSWT, FUSR521C, or FUSDelta14, through bilateral intracerebroventricular injection.	('FUSR521C', 'Var', (114, 122))	('mice', 'Species', '10090', (58, 62))	('FUSR521C', 'Mutation', 'rs121909668', (114, 122))	('FUSDelta14', 'Chemical', '-', (127, 137))	('FUSWT', 'Gene', (107, 112))	('AAV1', 'Gene', (93, 97))	('FUSWT', 'Gene', 'None', (107, 112))	('AAV1', 'Species', '85106', (93, 97))
48551	23046583	The FUS R521C mutation, which has been identified in 16 ALS families to date, occurs within the PY nuclear localization signal (PY-NLS) region, and results in an average age of onset of 40 years .	('ALS', 'Gene', (56, 59))	('FUS R521C', 'Var', (4, 13))	('R521C', 'Mutation', 'rs121909668', (8, 13))	('ALS', 'Gene', '6647', (56, 59))
48552	23046583	The third model, FUSDelta14,was based on a de novo mutation found in a patient with sporadic ALS that we reported previously .	('ALS', 'Gene', '6647', (93, 96))	('ALS', 'Gene', (93, 96))	('mutation', 'Var', (51, 59))	('FUSDelta14', 'Chemical', '-', (17, 27))	('patient', 'Species', '9606', (71, 78))
48553	23046583	Briefly, a mutation in intron 13 of the FUS gene (g.10747A>G) causes skipping of exon 14, a frame shift, and premature termination in exon 15, leading to a truncated FUS protein of 478 amino acids that lacks the C-terminal PY-NLS (Figure  1A).	('FUS protein', 'Protein', (166, 177))	('g.10747A>G', 'Mutation', 'g.10747A>G', (50, 60))	('skipping', 'MPA', (69, 77))	('FUS', 'Gene', (40, 43))	('truncated', 'MPA', (156, 165))	('g.10747A>G', 'Var', (50, 60))
48557	23046583	Based on V5 immunohistochemistry FUSWT, FUSR521C, and FUSDelta14 mice had widespread FUS protein expression, throughout the brain, with the highest levels in the cerebral cortex and the hippocampus (Figure  1B-G).	('FUSWT', 'Gene', 'None', (33, 38))	('levels', 'MPA', (148, 154))	('FUSDelta14', 'Chemical', '-', (54, 64))	('mice', 'Species', '10090', (65, 69))	('FUS protein', 'Protein', (85, 96))	('FUSDelta14', 'Var', (54, 64))	('FUSR521C', 'Var', (40, 48))	('FUSR521C', 'Mutation', 'rs121909668', (40, 48))	('FUSWT', 'Gene', (33, 38))
48559	23046583	FUSR521C mice had marked increases in FUS immunoreactivity in the neuronal cytoplasm.	('FUSR521C', 'Mutation', 'rs121909668', (0, 8))	('FUSR521C', 'Var', (0, 8))	('increases', 'PosReg', (25, 34))	('FUS immunoreactivity', 'MPA', (38, 58))	('mice', 'Species', '10090', (9, 13))
48561	23046583	Despite increased cytoplasmic levels of FUSR521C, no obvious inclusions or aggregates of FUS were observed in mice injected with FUSWT or FUSR521C.	('FUSWT', 'Gene', (129, 134))	('FUSWT', 'Gene', 'None', (129, 134))	('FUSR521C', 'Var', (138, 146))	('FUSR521C', 'Mutation', 'rs121909668', (138, 146))	('mice', 'Species', '10090', (110, 114))	('increased', 'PosReg', (8, 17))	('cytoplasmic levels', 'MPA', (18, 36))	('FUSR521C', 'Var', (40, 48))	('FUSR521C', 'Mutation', 'rs121909668', (40, 48))
48562	23046583	FUSDelta14 mice showed the greatest cytoplasmic redistribution, with some neurons showing no nuclear FUS reactivity but strong labelling of the cell body and processes in cortex.	('mice', 'Species', '10090', (11, 15))	('FUSDelta14', 'Chemical', '-', (0, 10))	('labelling', 'MPA', (127, 136))	('FUSDelta14', 'Var', (0, 10))
48563	23046583	A portion of neurons in FUSDelta14 mice contained FUS-positive neuronal cytoplasmic inclusions (NCIs), which bared striking resemblance to the NCIs that are a characteristic pathologic feature of ALS and FTD-FUS (Figure  1D and 1G).	('FTD', 'Disease', (204, 207))	('ALS', 'Gene', (196, 199))	('FTD', 'Disease', 'MESH:C563003', (204, 207))	('FUSDelta14', 'Chemical', '-', (24, 34))	('mice', 'Species', '10090', (35, 39))	('FUSDelta14', 'Var', (24, 34))	('ALS', 'Gene', '6647', (196, 199))
48564	23046583	In cortex, the percentage of transduced neurons with cytoplasmic distribution of FUS significantly increased in FUSR521C and FUSDelta14 mice (Figure  1H).	('mice', 'Species', '10090', (136, 140))	('FUSDelta14', 'Var', (125, 135))	('increased', 'PosReg', (99, 108))	('FUSDelta14', 'Chemical', '-', (125, 135))	('FUSR521C', 'Var', (112, 120))	('FUSR521C', 'Mutation', 'rs121909668', (112, 120))
48572	23046583	Comparison of the ratio of soluble cytoplasmic to nuclear FUS protein using densitometry confirmed that the steady state levels of the FUS mutants are higher in the cytoplasm, with FUSDelta14 showing the strongest shift (Figure.	('rat', 'Species', '10116', (18, 21))	('FUSDelta14', 'Chemical', '-', (181, 191))	('higher', 'PosReg', (151, 157))	('mutants', 'Var', (139, 146))	('FUSDelta14', 'Var', (181, 191))
48575	23046583	No FUSWT, but a portion of FUSR521C protein was also detected in the insoluble fraction.	('FUSR521C', 'Var', (27, 35))	('FUSR521C', 'Mutation', 'rs121909668', (27, 35))	('FUSWT', 'Gene', (3, 8))	('protein', 'Protein', (36, 43))	('FUSWT', 'Gene', 'None', (3, 8))
48577	23046583	Sections from eGFP, FUSWT and FUSR521C mice had diffuse ubiquitin staining with no detectable inclusions (Figure  3A, E and I).	('diffuse', 'MPA', (48, 55))	('FUSR521C', 'Mutation', 'rs121909668', (30, 38))	('FUSWT', 'Gene', (20, 25))	('FUSWT', 'Gene', 'None', (20, 25))	('mice', 'Species', '10090', (39, 43))	('FUSR521C', 'Var', (30, 38))
48578	23046583	In contrast, FUSDelta14 mice had frequent ubiquitin-positive NCIs (Figure  3M and Additional file 4: Figure S4).	('FUSDelta14', 'Chemical', '-', (13, 23))	('FUSDelta14', 'Var', (13, 23))	('ubiquitin-positive', 'MPA', (42, 60))	('mice', 'Species', '10090', (24, 28))
48580	23046583	We did not observe an increase in high molecular weight smearing of FUS, an indicator of poly-ubiquitination, on immunoblots of brain tissue of FUSDelta14 compared to FUSWT (data not shown).	('FUSWT', 'Gene', (167, 172))	('FUSWT', 'Gene', 'None', (167, 172))	('high molecular weight smearing', 'MPA', (34, 64))	('FUSDelta14', 'Chemical', '-', (144, 154))	('FUSDelta14', 'Var', (144, 154))
48581	23046583	Furthermore, immunoblots directly for poly-ubiquitin did not detect a difference between FUSWT, FUSR521C or FUSDelta14 mice, suggesting that FUS is not robustly ubiquitinated (data not shown).	('mice', 'Species', '10090', (119, 123))	('FUSR521C', 'Mutation', 'rs121909668', (96, 104))	('FUSR521C', 'Var', (96, 104))	('FUSWT', 'Gene', (89, 94))	('FUSWT', 'Gene', 'None', (89, 94))	('FUSDelta14', 'Chemical', '-', (108, 118))
48583	23046583	Many of the NCI in FUSDelta14 mice were basophilic by H&E staining, similar to the NCI found in BIBD, aFTLD-U, and NIFID cases (Figure  3N) .	('H&E', 'Chemical', '-', (54, 57))	('mice', 'Species', '10090', (30, 34))	('NIFID', 'Disease', 'None', (115, 120))	('FUSDelta14', 'Chemical', '-', (19, 29))	('FUSDelta14', 'Var', (19, 29))	('aFTLD', 'Disease', (102, 107))	('aFTLD', 'Disease', 'None', (102, 107))	('NIFID', 'Disease', (115, 120))
48588	23046583	There was diffuse cytoplasmic staining of PABP-1 in eGFP, FUSWT or FUSR521C mice, but no obvious NCI (Figure  3D, H and L).	('PABP-1', 'Gene', (42, 48))	('FUSWT', 'Gene', (58, 63))	('mice', 'Species', '10090', (76, 80))	('FUSWT', 'Gene', 'None', (58, 63))	('FUSR521C', 'Var', (67, 75))	('FUSR521C', 'Mutation', 'rs121909668', (67, 75))
48592	23046583	OPTN immunostaining was diffuse and widespread in the neuronal cytoplasm of FUSWT, FUSR521C, as well as FUSDelta14 mice.	('FUSR521C', 'Mutation', 'rs121909668', (83, 91))	('FUSR521C', 'Var', (83, 91))	('mice', 'Species', '10090', (115, 119))	('FUSWT', 'Gene', (76, 81))	('FUSDelta14', 'Chemical', '-', (104, 114))	('FUSWT', 'Gene', 'None', (76, 81))
48593	23046583	We found occasional increased OPTN staining in the neuronal cytoplasm in brain regions of FUSDelta14 mice with ubiquitin positive NCI, but no definite labelling of NCIs (Additional file 6: Figure S6).	('increased', 'PosReg', (20, 29))	('FUSDelta14', 'Var', (90, 100))	('OPTN staining', 'MPA', (30, 43))	('mice', 'Species', '10090', (101, 105))	('FUSDelta14', 'Chemical', '-', (90, 100))
48594	23046583	We did not find any evidence of TDP-43 redistribution from the nucleus to the cytoplasm or presence of TDP-43 within NCI in FUSWT, FUSR521C and FUSDelta14 mice (Figure  6A, B and C).	('TDP-43', 'Gene', (103, 109))	('FUSDelta14', 'Chemical', '-', (144, 154))	('FUSR521C', 'Var', (131, 139))	('FUSWT', 'Gene', (124, 129))	('mice', 'Species', '10090', (155, 159))	('FUSR521C', 'Mutation', 'rs121909668', (131, 139))	('FUSWT', 'Gene', 'None', (124, 129))
48595	23046583	In contrast, over expression of TDP-43 with a mutated nuclear localization signal in mice using SBT leads to cytoplasmic accumulation of TDP-43 (Additional file 7: Figure S7).	('mice', 'Species', '10090', (85, 89))	('over expression', 'PosReg', (13, 28))	('TDP-43', 'Gene', (32, 38))	('mutated', 'Var', (46, 53))	('cytoplasmic accumulation', 'MPA', (109, 133))	('TDP-43', 'Gene', (137, 143))
48596	23046583	Double-label immunofluorescence data also showed TDP-43 predominantly distributed in the nucleus in eGFP, FUSWT, FUSR521C and FUSDelta14 mice, even in neurons with well-defined NCIs (Additional file 8: Figure S8 and Figure  6C-J).	('FUSR521C', 'Mutation', 'rs121909668', (113, 121))	('FUSWT', 'Gene', (106, 111))	('TDP-43', 'Gene', (49, 55))	('FUSWT', 'Gene', 'None', (106, 111))	('FUSDelta14', 'Chemical', '-', (126, 136))	('distributed', 'Reg', (70, 81))	('FUSDelta14', 'Var', (126, 136))	('mice', 'Species', '10090', (137, 141))	('FUSR521C', 'Var', (113, 121))
48597	23046583	Our study is the first to use SBT to model FUS gene mutations in the mammalian central nervous system.	('mutations', 'Var', (52, 61))	('FUS gene', 'Gene', (43, 51))	('mammalian', 'Species', '9606', (69, 78))
48598	23046583	The SBT paradigm was chosen because 1) mice can be generated quickly (a few months) compared to traditional transgenic techniques (a few years), 2) gene expression reaches a maximum ~3 weeks after birth, potentially avoiding toxicity during development, as has been recently observed for TDP-43 , and 3) recombinant AAV vectors can be rapidly generated to test different constructs in vivo, such as alternative promoters or putative disease associated mutations.	('rat', 'Species', '10116', (347, 350))	('mice', 'Species', '10090', (39, 43))	('mutations', 'Var', (452, 461))	('toxicity', 'Disease', 'MESH:D064420', (225, 233))	('rat', 'Species', '10116', (55, 58))	('toxicity', 'Disease', (225, 233))
48599	23046583	A key question in the field is how mutations in FUS cause neurodegeneration in ALS or FTD.	('FTD', 'Disease', 'MESH:C563003', (86, 89))	('ALS', 'Gene', (79, 82))	('ALS', 'Gene', '6647', (79, 82))	('neurodegeneration', 'Disease', 'MESH:D019636', (58, 75))	('cause', 'Reg', (52, 57))	('FTD', 'Disease', (86, 89))	('neurodegeneration', 'Phenotype', 'HP:0002180', (58, 75))	('FUS', 'Gene', (48, 51))	('neurodegeneration', 'Disease', (58, 75))	('mutations', 'Var', (35, 44))
48601	23046583	Over expression of either FUSWT, FUSR521C, or FUSDelta14 was not overtly toxic to mice on an organismal level after 3 months.	('mice', 'Species', '10090', (82, 86))	('FUSDelta14', 'Chemical', '-', (46, 56))	('FUSWT', 'Gene', (26, 31))	('FUSWT', 'Gene', 'None', (26, 31))	('FUSDelta14', 'Var', (46, 56))	('FUSR521C', 'Var', (33, 41))	('FUSR521C', 'Mutation', 'rs121909668', (33, 41))
48602	23046583	Similarly, transgenic rats expressing wild-type human FUS do not have acute neuronal degeneration or behavioural impairment up to the first year of life; although transgenic lines expressing FUSR521C have rapid motor impairment and neuronal degeneration .	('human', 'Species', '9606', (48, 53))	('rapid motor impairment', 'CPA', (205, 227))	('neuronal degeneration', 'Disease', 'MESH:D009410', (76, 97))	('neuronal degeneration', 'Disease', (76, 97))	('FUSR521C', 'Var', (191, 199))	('FUSR521C', 'Mutation', 'rs121909668', (191, 199))	('neuronal degeneration', 'Disease', (232, 253))	('behavioural impairment', 'Phenotype', 'HP:0000708', (101, 123))	('neuronal degeneration', 'Disease', 'MESH:D009410', (232, 253))	('rats', 'Species', '10116', (22, 26))
48603	23046583	Despite this ALS-like phenotype, FUS R521C rat lines did not have classic neuropathology associated with FUS proteinopathies.	('FUS R521C', 'Var', (33, 42))	('R521C', 'Mutation', 'rs121909668', (37, 42))	('rat', 'Species', '10116', (43, 46))	('ALS', 'Gene', '6647', (13, 16))	('FUS proteinopathies', 'Disease', 'MESH:C563476', (105, 124))	('ALS', 'Gene', (13, 16))	('FUS proteinopathies', 'Disease', (105, 124))
48604	23046583	Intriguingly, both FUS WT and R521C rats accumulated ubiquitin; however FUS did not co-localize with ubiquitin and there was no formation of distinct NCI .	('ubiquitin', 'MPA', (53, 62))	('R521C', 'Var', (30, 35))	('R521C', 'Mutation', 'rs121909668', (30, 35))	('rats', 'Species', '10116', (36, 40))	('accumulated', 'PosReg', (41, 52))
48606	23046583	In contrast, SBT generated FUSDelta14 mice have FUS and ubiquitin positive NCI, suggesting that we observed a much greater accumulation of neuropathology due to the use of this mutation, which causes a dramatic redistribution of FUS into the cytoplasm .	('mutation', 'Var', (177, 185))	('mice', 'Species', '10090', (38, 42))	('FUS into the', 'MPA', (229, 241))	('FUSDelta14', 'Chemical', '-', (27, 37))	('rat', 'Species', '10116', (21, 24))	('redistribution', 'MPA', (211, 225))
48607	23046583	One deficiency of the SBT FUSR521C or FUSDelta14 mice we have described is the lack of a motor phenotype or neurodegeneration.	('neurodegeneration', 'Phenotype', 'HP:0002180', (108, 125))	('FUSR521C', 'Var', (26, 34))	('FUSR521C', 'Mutation', 'rs121909668', (26, 34))	('neurodegeneration', 'Disease', (108, 125))	('neurodegeneration', 'Disease', 'MESH:D019636', (108, 125))	('mice', 'Species', '10090', (49, 53))	('FUSDelta14', 'Chemical', '-', (38, 48))	('FUSDelta14', 'Var', (38, 48))
48610	23046583	To date 46 mutations in FUS that are associated with ALS or FTD have been discovered, but the mechanism of their toxicity is still being deciphered .	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('mutations', 'Var', (11, 20))	('FTD', 'Disease', (60, 63))	('FTD', 'Disease', 'MESH:C563003', (60, 63))	('ALS', 'Gene', (53, 56))	('associated', 'Reg', (37, 47))	('ALS', 'Gene', '6647', (53, 56))	('FUS', 'Gene', (24, 27))
48611	23046583	Our data provide the first in vivo evidence in mouse neurons that both ALS mutations studied, FUSR521C and FUSDelta14, translocate to the cytoplasm at higher levels compared to control.	('FUSDelta14', 'Var', (107, 117))	('translocate', 'MPA', (119, 130))	('FUSR521C', 'Var', (94, 102))	('higher', 'PosReg', (151, 157))	('ALS', 'Gene', (71, 74))	('ALS', 'Gene', '6647', (71, 74))	('FUSDelta14', 'Chemical', '-', (107, 117))	('FUSR521C', 'Mutation', 'rs121909668', (94, 102))	('mouse', 'Species', '10090', (47, 52))
48612	23046583	FUSDelta14, which lacks the entire PY-NLS domain, had the highest levels of FUS in the neuronal cytoplasm, lowest levels in the nucleus, and was the only mutation that developed robust inclusions and insoluble FUS.	('levels', 'MPA', (66, 72))	('FUS', 'MPA', (76, 79))	('FUSDelta14', 'Chemical', '-', (0, 10))	('lowest', 'NegReg', (107, 113))	('FUSDelta14', 'Var', (0, 10))
48613	23046583	The degree of FUS re-localization caused by a mutation and age of disease onset has been interpreted to mean that cytoplasmic accumulation of FUS is a primary event that drives neurodegneration .	('rat', 'Species', '10116', (187, 190))	('mutation', 'Var', (46, 54))	('neurodegneration', 'Disease', (177, 193))
48616	23046583	Our observation that FUSDelta14, which produces the earliest disease onset in humans, accumulates at the highest levels in the cytoplasm and rapidly induces multiple pathological features of FUS proteinopathies, broadly supports the hypothesis that cytoplasmic FUS is toxic .	('humans', 'Species', '9606', (78, 84))	('FUSDelta14', 'Chemical', '-', (21, 31))	('FUS proteinopathies', 'Disease', 'MESH:C563476', (191, 210))	('induces', 'Reg', (149, 156))	('FUS proteinopathies', 'Disease', (191, 210))	('FUSDelta14', 'Var', (21, 31))
48621	23046583	NCIs containing ubiquitin and p62 are common to all sub-types of FTD and ALS-FUS.	('FTD', 'Disease', 'MESH:C563003', (65, 68))	('p62', 'Var', (30, 33))	('FTD', 'Disease', (65, 68))	('ALS-FUS', 'Disease', 'MESH:D008113', (73, 80))	('ubiquitin', 'Protein', (16, 25))	('ALS-FUS', 'Disease', (73, 80))
48622	23046583	More informative is the frequent presence of basophilic NCI in FUSDelta14 mice, which are numerous in BIBD cases, but also present in aFTLD-U and NIFID to a lesser extent .	('FUSDelta14', 'Var', (63, 73))	('aFTLD', 'Disease', (134, 139))	('FUSDelta14', 'Chemical', '-', (63, 73))	('mice', 'Species', '10090', (74, 78))	('aFTLD', 'Disease', 'None', (134, 139))	('NIFID', 'Disease', 'None', (146, 151))	('NIFID', 'Disease', (146, 151))
48637	23046583	Taken together, we hypothesize that accumulation of FUSDelta14 into NCI recruits other protein(s) that are ubiquitinated.	('accumulation', 'PosReg', (36, 48))	('FUSDelta14', 'Var', (52, 62))	('FUSDelta14', 'Chemical', '-', (52, 62))
48643	23046583	PABP-1 labels NCI in ALS-FUS with a R521C mutation, as well as NCI in FTLD-FUS, BIBD and NIFID .	('ALS-FUS', 'Disease', 'MESH:D008113', (21, 28))	('R521C', 'Mutation', 'rs121909668', (36, 41))	('NIFID', 'Disease', (89, 94))	('ALS-FUS', 'Disease', (21, 28))	('R521C', 'Var', (36, 41))	('NIFID', 'Disease', 'None', (89, 94))	('FTLD-FUS', 'Disease', (70, 78))	('FTLD-FUS', 'Disease', 'MESH:D057174', (70, 78))
48648	23046583	Mutations in FUS were first identified in ALS cases because sequencing of the FUS gene was prioritized based on its functional similarity to TDP-43, another RNA-binding protein that had been discovered to harbour causative mutations in ALS patients.	('ALS', 'Gene', '6647', (42, 45))	('ALS', 'Gene', (42, 45))	('ALS', 'Gene', '6647', (236, 239))	('FUS', 'Gene', (78, 81))	('Mutations', 'Var', (0, 9))	('FUS', 'Gene', (13, 16))	('ALS', 'Gene', (236, 239))	('patients', 'Species', '9606', (240, 248))	('RNA-binding protein', 'Gene', '27303', (157, 176))	('RNA-binding protein', 'Gene', (157, 176))
48649	23046583	Abnormal function of FUS, TDP-43, and other RNA-binding proteins has been recently proposed to be part of a common pathway linking defects in RNA quality control to neurodegeneration in ALS and FTLD .	('neurodegeneration', 'Disease', 'MESH:D019636', (165, 182))	('defects', 'Var', (131, 138))	('ALS', 'Gene', '6647', (186, 189))	('FTLD', 'Disease', 'MESH:D057174', (194, 198))	('TDP-43', 'Gene', (26, 32))	('RNA-binding protein', 'Gene', (44, 63))	('RNA-binding protein', 'Gene', '27303', (44, 63))	('ALS', 'Gene', (186, 189))	('neurodegeneration', 'Phenotype', 'HP:0002180', (165, 182))	('FTLD', 'Disease', (194, 198))	('FUS', 'Gene', (21, 24))	('neurodegeneration', 'Disease', (165, 182))
48654	23046583	Thus in our mouse model, FUS and TDP-43 aggregation appear distinct, and lead us to speculate that despite their many similarities , FUS and TDP-43 have unique biological functions and their dysfunction may cause neurodegeneration through RNA dysfunction, but the precise targets and pathways are distinct.	('cause', 'Reg', (207, 212))	('FUS', 'Gene', (133, 136))	('dysfunction', 'Var', (191, 202))	('mouse', 'Species', '10090', (12, 17))	('neurodegeneration', 'Phenotype', 'HP:0002180', (213, 230))	('RNA dysfunction', 'Disease', (239, 254))	('neurodegeneration', 'Disease', (213, 230))	('neurodegeneration', 'Disease', 'MESH:D019636', (213, 230))	('TDP-43', 'Gene', (141, 147))
48656	23046583	We find that expression of a disease-associated FUS mutation (FUSDelta14) validates it as a pathogenic mutation, because expression of this mutation produced a number of pathological features of FUS proteinopathies.	('FUS proteinopathies', 'Disease', (195, 214))	('mutation', 'Var', (140, 148))	('produced', 'Reg', (149, 157))	('FUSDelta14', 'Chemical', '-', (62, 72))	('FUS proteinopathies', 'Disease', 'MESH:C563476', (195, 214))
48657	23046583	The finding that FUSDelta14 expression can reproduce many pathologic features observed in subtypes of FTLD and ALS FUS proteinopathies was surprising, and provides additional evidence that these diseases may share a common disease mechanism.	('ALS FUS proteinopathies', 'Disease', (111, 134))	('FTLD', 'Disease', 'MESH:D057174', (102, 106))	('FUSDelta14', 'Chemical', '-', (17, 27))	('ALS FUS proteinopathies', 'Disease', 'MESH:C563476', (111, 134))	('FTLD', 'Disease', (102, 106))	('FUSDelta14', 'Var', (17, 27))
48659	23046583	Expression of the ALS mutation FUSR521C was also not obviously toxic to animals at 3 months.	('FUSR521C', 'Var', (31, 39))	('ALS', 'Gene', '6647', (18, 21))	('FUSR521C', 'Mutation', 'rs121909668', (31, 39))	('ALS', 'Gene', (18, 21))
48660	23046583	Although FUSR521C mice did not have distinct NCI, they did have a large increase in the amount of FUS present in the cell bodies and processes of neurons, as well as accumulation of biochemically insoluble FUS.	('biochemically insoluble FUS', 'MPA', (182, 209))	('increase', 'PosReg', (72, 80))	('mice', 'Species', '10090', (18, 22))	('amount', 'MPA', (88, 94))	('FUSR521C', 'Var', (9, 17))	('accumulation', 'PosReg', (166, 178))	('FUSR521C', 'Mutation', 'rs121909668', (9, 17))	('FUS', 'MPA', (98, 101))
48662	23046583	Alternatively, the insoluble nature of a portion of FUSR521C may indicate that small NCIs or oligomers of FUS may already be present in these animals, but are not detectable using classic immunohistochemistry.	('insoluble', 'MPA', (19, 28))	('FUSR521C', 'Var', (52, 60))	('FUSR521C', 'Mutation', 'rs121909668', (52, 60))
48664	23046583	In summary, our data supports the hypothesis that many ALS/FTD-linked mutations cause disease by increasing the cyotplasmic levels of FUS, with unknown consequences.	('ALS', 'Gene', '6647', (55, 58))	('mutations', 'Var', (70, 79))	('ALS', 'Gene', (55, 58))	('FTD-linked', 'Disease', (59, 69))	('cause', 'Reg', (80, 85))	('cyotplasmic levels of FUS', 'MPA', (112, 137))	('FTD-linked', 'Disease', 'MESH:C563003', (59, 69))	('disease', 'Disease', (86, 93))	('increasing', 'PosReg', (97, 107))
48667	23046583	The recent identification of an expanded hexanucleotide repeat in C9ORF72 as a frequent cause of the ALS/FTD clinical spectrum in addition to causative mutations in RNA-binding proteins, including TDP-43, FUS, sentaxin, and angiogenin, strongly implicates defects in RNA metabolism as a critical pathogenic pathway in both ALS and FTD .	('RNA-binding protein', 'Gene', '27303', (165, 184))	('RNA-binding protein', 'Gene', (165, 184))	('mutations', 'Var', (152, 161))	('ALS', 'Gene', (323, 326))	('ALS', 'Gene', '6647', (323, 326))	('ALS', 'Gene', '6647', (101, 104))	('TDP-43', 'Gene', (197, 203))	('FTD', 'Disease', 'MESH:C563003', (105, 108))	('expanded hexanucleotide repeat', 'Var', (32, 62))	('FTD', 'Disease', 'MESH:C563003', (331, 334))	('ALS', 'Gene', (101, 104))	('hexanucleotide', 'Chemical', '-', (41, 55))	('cause', 'Reg', (88, 93))	('FTD', 'Disease', (331, 334))	('C9ORF72', 'Gene', (66, 73))	('FTD', 'Disease', (105, 108))	('angiogenin', 'Gene', (224, 234))	('angiogenin', 'Gene', '11727', (224, 234))
48668	23046583	The SBT FUS mice described in this manuscript will provide a valuable platform for further dissecting the pathogenic mechanism of FUS mutations, define the relationship between FTD and ALS-FUS, and help identify therapeutic targets that are desperately needed for these devastating neurodegenerative disorders.	('rat', 'Species', '10116', (246, 249))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (282, 309))	('neurodegenerative disorders', 'Disease', (282, 309))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (282, 309))	('ALS-FUS', 'Disease', 'MESH:D008113', (185, 192))	('FTD', 'Disease', 'MESH:C563003', (177, 180))	('FUS', 'Gene', (130, 133))	('mutations', 'Var', (134, 143))	('FTD', 'Disease', (177, 180))	('mice', 'Species', '10090', (12, 16))	('ALS-FUS', 'Disease', (185, 192))	('rat', 'Species', '10116', (293, 296))
48669	23046583	The generation of the N-terminally V5 tagged FUS constructs, AAV1-wild type human FUS (FUSWT), AAV1-human pR521C mutant FUS (FUSR521C) and AAV1-human p.G466VfsX14 truncated FUS (FUSDelta14) was previously described .	('AAV1', 'Species', '85106', (139, 143))	('rat', 'Species', '10116', (8, 11))	('human', 'Species', '9606', (144, 149))	('R521C', 'Mutation', 'rs121909668', (128, 133))	('FUSDelta14', 'Chemical', '-', (178, 188))	('AAV1', 'Species', '85106', (61, 65))	('p.G466VfsX14', 'Var', (150, 162))	('pR521C mutant', 'Var', (106, 119))	('AAV1', 'Species', '85106', (95, 99))	('human', 'Species', '9606', (100, 105))	('p.G466VfsX14', 'Mutation', 'rs35711706', (150, 162))	('FUSWT', 'Gene', (87, 92))	('human', 'Species', '9606', (76, 81))	('FUSWT', 'Gene', 'None', (87, 92))	('FUSR521C', 'Mutation', 'rs121909668', (125, 133))	('R521C', 'Mutation', 'rs121909668', (107, 112))
48677	23046583	Three groups of wild type B6C3F1 mice were injected with virus encoding FUSWT (n=9), FUSR521C (n=16) and FUSDelta14 (n=11).	('FUSR521C', 'Var', (85, 93))	('FUSDelta14', 'Chemical', '-', (105, 115))	('FUSR521C', 'Mutation', 'rs121909668', (85, 93))	('FUSDelta14', 'Var', (105, 115))	('FUSWT', 'Gene', (72, 77))	('mice', 'Species', '10090', (33, 37))	('FUSWT', 'Gene', 'None', (72, 77))
48809	28288693	It was reported that translocation of t(10;17), including the YWHAE gene, was detected in a uterine sarcoma that was diagnosed as a poorly differentiated uterine tumor with t(10;17) translocation and neuroectodermal phenotype.	('sarcoma', 'Disease', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (92, 107))	('translocation', 'Var', (21, 34))	('tumor', 'Disease', (162, 167))	('uterine tumor', 'Phenotype', 'HP:0010784', (154, 167))	('t(10;17', 'Gene', (38, 45))	('detected', 'Reg', (78, 86))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
48810	28288693	The c-kit positivity seen in the current case might possibly be suggestive of a uterine GIST.	('c-kit', 'Gene', (4, 9))	('c-kit', 'Gene', '16590', (4, 9))	('GIST', 'Phenotype', 'HP:0100723', (88, 92))	('uterine GIST', 'Disease', (80, 92))	('positivity', 'Var', (10, 20))
48819	26474460	Tumor cells and their stromal compartments acquire many genetic and/or epigenetic alternations to facilitate tumor growth and metastasis.	('epigenetic alternations', 'Var', (71, 94))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('genetic', 'Var', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('facilitate', 'PosReg', (98, 108))	('tumor', 'Disease', (109, 114))
48829	26474460	All of these studies in mouse models suggest that progenitor cells contribute to the CSC pool by genetic and/or epigenetic hits.	('genetic', 'Var', (97, 104))	('mouse', 'Species', '10090', (24, 29))	('CSC', 'Disease', (85, 88))	('epigenetic hits', 'Var', (112, 127))
48830	26474460	Mani et al., discovered that the ectopic expression of transcription factors, such as Twist1 and Snail, or treatment with TGF-beta in mammary epithelial cells or cancer cells can induce stem cell-like or cancer stem cell-like phenotypes.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('ectopic expression', 'Var', (33, 51))	('cancer', 'Disease', (162, 168))	('Twist1', 'Gene', (86, 92))	('induce', 'PosReg', (179, 185))	('Mani', 'Species', '156483', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('stem cell-like', 'CPA', (186, 200))	('TGF-beta', 'Gene', (122, 130))
48834	26474460	Thus, the acquisition and accumulation of genetic and/or epigenetic alterations can covert cancer cells, even some normal cells, to a stemness state by dedifferentiation, indicating that this dedifferentiation program can generate CSCs.	('stemness', 'Disease', 'MESH:D020295', (134, 142))	('stemness', 'Disease', (134, 142))	('cancer', 'Disease', (91, 97))	('epigenetic alterations', 'Var', (57, 79))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('genetic', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
48856	26474460	Silencing SS18-SSX genes in synovial sarcoma stem cells induces multiple-lineage differentiation in vitro that is similar to MSCs.	('multiple-lineage differentiation', 'CPA', (64, 96))	('synovial sarcoma', 'Disease', 'MESH:D013584', (28, 44))	('SS18', 'Gene', '6760', (10, 14))	('induces', 'Reg', (56, 63))	('synovial sarcoma', 'Disease', (28, 44))	('Silencing', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('SS18', 'Gene', (10, 14))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (28, 44))
48874	26474460	Indeed, CD105+ renal CSCs can generate endothelial cells in vitro and give rise to vessels with a human origin in vivo.	('give rise', 'Reg', (70, 79))	('CD105+', 'Var', (8, 14))	('human', 'Species', '9606', (98, 103))	('endothelial cells', 'CPA', (39, 56))
48876	26474460	The authors employed mammosphere culture to enrich the breast CSCs and successfully obtained breast CSC-derived endothelial cells that express several endothelial markers (e.g., CD31, VE-Cadherin, CD105 and vWF).	('VE-Cadherin', 'Gene', '1003', (184, 195))	('CD31', 'Gene', (178, 182))	('vWF', 'Gene', '7450', (207, 210))	('CD105', 'Var', (197, 202))	('vWF', 'Gene', (207, 210))	('CD31', 'Gene', '5175', (178, 182))	('VE-Cadherin', 'Gene', (184, 195))
48883	26474460	Ricci-Vitiani et al., reported that a large proportion of the endothelial cells in GBM harbors the same chromosomal alterations as in tumor cells.	('chromosomal alterations', 'Var', (104, 127))	('GBM', 'Disease', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))	('tumor', 'Disease', (134, 139))
48897	26474460	By analyzing patients' GBM samples, the authors found that vast majority of tumor pericytes carry the same genetic alternations as neoplastic cells.	('GBM', 'Phenotype', 'HP:0012174', (23, 26))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('genetic alternations', 'Var', (107, 127))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
48915	26474460	Recent studies reveal that constitutively activating EMT suppresses the stemness of human epithelial CSCs in vitro and inhibits their metastatic colonization abilities in vivo; however, transiently inducing EMT at primary site enhances local invasion and blood entry.	('local invasion', 'CPA', (236, 250))	('blood entry', 'CPA', (255, 266))	('suppresses', 'NegReg', (57, 67))	('transiently', 'Var', (186, 197))	('inhibits', 'NegReg', (119, 127))	('stemness', 'Disease', 'MESH:D020295', (72, 80))	('EMT', 'Gene', (207, 210))	('human', 'Species', '9606', (84, 89))	('enhances', 'PosReg', (227, 235))	('stemness', 'Disease', (72, 80))	('metastatic colonization abilities', 'CPA', (134, 167))
48942	26474460	Some cancer cells display components of the phenotypes of neurons; for example, breast-to-brain metastatic cells exhibit GABAergic characteristics that are similar to neuronal cells to promote their metastatic growth, indicating that CSCs may gain some phenotypes of neural cells in the tumor microenvironment.	('metastatic growth', 'CPA', (199, 216))	('breast-to-brain metastatic cells', 'CPA', (80, 112))	('CSCs', 'Var', (234, 238))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('cancer', 'Disease', (5, 11))	('promote', 'PosReg', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (287, 292))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('gain', 'PosReg', (243, 247))
48972	26474460	Differentiated cancer cells can dedifferentiate into CSCs or CSC-like cells through transcriptional regulation, post-transcriptional regulation, microenvironment signal stimulation, epigenetic modification and metabolic reprogramming.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('epigenetic modification', 'Var', (182, 205))	('post-transcriptional', 'MPA', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
49074	24349382	Especially, the PD1/PD-L1 interaction attenuates the immune response by decreasing cytokine production and inducing T lymphocyte anergy and apoptosis.	('attenuates', 'NegReg', (38, 48))	('inducing', 'PosReg', (107, 115))	('apoptosis', 'CPA', (140, 149))	('T lymphocyte anergy', 'CPA', (116, 135))	('cytokine production', 'MPA', (83, 102))	('interaction', 'Var', (26, 37))	('PD1/PD-L1', 'Gene', '5133;29126', (16, 25))	('PD1/PD-L1', 'Gene', (16, 25))	('decreasing', 'NegReg', (72, 82))	('immune response', 'CPA', (53, 68))
49075	24349382	The expression rate of PD-L1 in human malignant tumors has been reported to vary from 19% to 92% and the expression of PD-L1 was associated with progression and poor prognosis of various human cancers.	('associated with', 'Reg', (129, 144))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('PD-L1', 'Gene', (23, 28))	('cancers', 'Disease', (193, 200))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('expression', 'Var', (105, 115))	('PD-L1', 'Gene', (119, 124))	('malignant tumors', 'Disease', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('human', 'Species', '9606', (187, 192))	('human', 'Species', '9606', (32, 37))	('malignant tumors', 'Disease', 'MESH:D018198', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
49087	24349382	PD-L1 expressing tumor cells escape from the lysis by activated T lymphocytes and the expression of PD-L1 in tumor cells associated with progression of human malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', (168, 173))	('associated with', 'Reg', (121, 136))	('malignant tumors', 'Disease', (158, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('human', 'Species', '9606', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('expression', 'Var', (86, 96))	('malignant tumors', 'Disease', 'MESH:D018198', (158, 174))	('PD-L1', 'Gene', (100, 105))	('tumor', 'Disease', (109, 114))
49091	24349382	When we performed additional analysis by combining PD1- and PD-L1-positivity (the PD1/PD-L1 pattern), it was significantly associated with the age of patients, tumor stage, depth of sarcoma, distant metastasis, histologic grade, tumor differentiation, mitotic count, and tumor necrosis (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('patients', 'Species', '9606', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('distant metastasis', 'CPA', (191, 209))	('mitotic count', 'CPA', (252, 265))	('PD1/PD-L1', 'Gene', '5133;29126', (82, 91))	('PD1-', 'Var', (51, 55))	('tumor', 'Disease', (271, 276))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor necrosis', 'Disease', 'MESH:D009336', (271, 285))	('associated', 'Reg', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('PD-L1-positivity', 'Gene', (60, 76))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('sarcoma', 'Disease', 'MESH:D012509', (182, 189))	('tumor necrosis', 'Disease', (271, 285))	('PD1/PD-L1', 'Gene', (82, 91))	('sarcoma', 'Disease', (182, 189))
49094	24349382	Intra-tumoral infiltration of PD1-positive lymphocytes predicted shorter OS (P < 0.001, HR; 5.068, 95% confidence interval [95% CI]; 2.518-10.201) and EFS (P < 0.001, HR; 3.830, 95% CI; 2.157-6.803) (Figure 2 B).	('PD1-positive', 'Var', (30, 42))	('EFS', 'CPA', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('shorter OS', 'CPA', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
49097	24349382	The five-year survival rates of the PD1-/PD-L1-, (PD1+/PD-L1- or PD1-/PD-L1+), and PD1+/PD-L1+ groups were 90%, 74%, and 13%, respectively.	('PD-L1+', 'Gene', (88, 94))	('PD-L1+', 'Gene', '29126', (88, 94))	('PD-L1+', 'Gene', (70, 76))	('PD1-/PD-L1-', 'Var', (36, 47))	('PD-L1+', 'Gene', '29126', (70, 76))
49116	24349382	Recent preliminary data for immunotherapy with an anti-PD1 antibody resulted in response in 27 - 31% of renal cell carcinoma, 28% of melanoma, and 18% of non-small cell lung cancer patients.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (154, 180))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (104, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cell lung cancer', 'Disease', (164, 180))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('patients', 'Species', '9606', (181, 189))	('cell lung cancer', 'Disease', 'MESH:D008175', (164, 180))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (158, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('renal cell carcinoma', 'Disease', (104, 124))	('anti-PD1', 'Var', (50, 58))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))
49119	24349382	In addition to the prognostic significance of intra-tumoral infiltration of PD1-positive lymphocytes, our data also show that the expression of PD-L1 in STS is an independent indicator of poor prognosis of STS patients.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('intra-tumoral', 'Disease', 'MESH:D009369', (46, 59))	('expression', 'Var', (130, 140))	('STS', 'Phenotype', 'HP:0030448', (153, 156))	('intra-tumoral', 'Disease', (46, 59))	('PD-L1', 'Gene', (144, 149))	('patients', 'Species', '9606', (210, 218))	('STS', 'Phenotype', 'HP:0030448', (206, 209))
49120	24349382	In agreement with our results, the expression of PD-L1 has predicted poor survival of breast cancer, esophageal cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, urothelial cancer, and renal cell carcinoma patients.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('urothelial cancer', 'Disease', (181, 198))	('renal cell carcinoma', 'Disease', (204, 224))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (204, 224))	('esophageal cancer', 'Disease', (101, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('PD-L1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('breast cancer', 'Disease', (86, 99))	('expression', 'Var', (35, 45))	('gastric cancer', 'Disease', (139, 153))	('hepatocellular carcinoma', 'Disease', (155, 179))	('patients', 'Species', '9606', (225, 233))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (204, 224))	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('urothelial cancer', 'Disease', 'MESH:D014523', (181, 198))	('poor', 'NegReg', (69, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('pancreatic cancer', 'Disease', (120, 137))
49128	24349382	Despite the importance of the PD1/PD-L1 interaction in tumor evasion, the exact mechanism of how the PD1/PD-L1 interaction affects the tumor microenvironment to promote the escape of tumor cells from anti-tumor immunolosurveillance is not clear.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('PD1/PD-L1', 'Gene', '5133;29126', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('promote', 'PosReg', (161, 168))	('tumor immunolosurveillance', 'Disease', 'MESH:D009369', (205, 231))	('PD1/PD-L1', 'Gene', '5133;29126', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('interaction', 'Var', (111, 122))	('affects', 'Reg', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('escape', 'CPA', (173, 179))	('PD1/PD-L1', 'Gene', (101, 110))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('PD1/PD-L1', 'Gene', (30, 39))	('tumor immunolosurveillance', 'Disease', (205, 231))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (205, 210))
49163	33479225	While the determination of characteristic molecular alterations most often consisting of translocations that generate gene fusions has become a diagnostic standard for many sarcoma types, approximately half of the sarcoma entities lack unequivocal molecular hallmarks.	('sarcoma entities', 'Disease', 'MESH:D012509', (214, 230))	('mark', 'Gene', (262, 266))	('mark', 'Gene', '4139', (262, 266))	('sarcoma', 'Disease', (173, 180))	('sarcoma', 'Disease', 'MESH:D012509', (214, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('sarcoma entities', 'Disease', (214, 230))	('sarcoma', 'Disease', (214, 221))	('translocations', 'Var', (89, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))
49181	33479225	Unifying features of cases mapping to this class are rhabdomyoblast-like cells and DICER1 mutations.	('DICER1', 'Gene', (83, 89))	('rhabdomyoblast-like cells', 'CPA', (53, 78))	('DICER1', 'Gene', '23405', (83, 89))	('mutations', 'Var', (90, 99))
49182	33479225	Methylation class SARC (MPNST-like) was reported as a subset of malignant peripheral nerve sheath tumours.	('malignant peripheral nerve sheath tumours', 'Disease', (64, 105))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('Methylation', 'Var', (0, 11))	('malignant peripheral nerve', 'Phenotype', 'HP:0100697', (64, 90))	('malignant peripheral nerve sheath tumours', 'Disease', 'MESH:D018319', (64, 105))
49192	33479225	However, because some sarcomas with low calibrated classifier scores carried unique molecular alterations such as ONECUT1-NUTM1 or EWSR1-TFCP2 gene fusions we favour considering these as epigenetic subsets not yet covered by the current classifier version.	('ONECUT1', 'Gene', (114, 121))	('sarcomas', 'Disease', (22, 30))	('NUTM1', 'Gene', '256646', (122, 127))	('ONECUT1', 'Gene', '3175', (114, 121))	('carried', 'Reg', (69, 76))	('NUTM1', 'Gene', (122, 127))	('EWSR1', 'Gene', (131, 136))	('TFCP2', 'Gene', (137, 142))	('sarcomas', 'Disease', 'MESH:D012509', (22, 30))	('EWSR1', 'Gene', '2130', (131, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('gene fusions', 'Var', (143, 155))	('TFCP2', 'Gene', '7024', (137, 142))
49193	33479225	Independent from the methylation patterns used for classification, high-density DNA methylation arrays allow for determining copy number alterations, the detection of which is of major diagnostic relevance for sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (210, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('copy number alterations', 'Var', (125, 148))	('sarcomas', 'Disease', (210, 218))	('sarcomas', 'Disease', 'MESH:D012509', (210, 218))
49195	33479225	Frequently encountered alterations include MDM2 amplification for well-/dedifferentiated liposarcomas, MYC amplification for radiation induced angiosarcoma or segmental chromosomal deletions on chromosome 22q encompassing SMARCB1 for rhabdoid tumours.	('tumours', 'Phenotype', 'HP:0002664', (243, 250))	('liposarcomas', 'Disease', (89, 101))	('amplification', 'Var', (107, 120))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('segmental chromosomal deletions on', 'Var', (159, 193))	('MDM2', 'Gene', (43, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('angiosarcoma', 'Disease', 'MESH:D006394', (143, 155))	('rhabdoid tumours', 'Disease', (234, 250))	('angiosarcoma', 'Phenotype', 'HP:0200058', (143, 155))	('MDM2', 'Gene', '4193', (43, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('MYC', 'Gene', (103, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('liposarcomas', 'Disease', 'MESH:D008080', (89, 101))	('liposarcoma', 'Phenotype', 'HP:0012034', (89, 100))	('angiosarcoma', 'Disease', (143, 155))	('amplification', 'Var', (48, 61))	('liposarcomas', 'Phenotype', 'HP:0012034', (89, 101))	('SMARCB1', 'Gene', (222, 229))	('SMARCB1', 'Gene', '6598', (222, 229))	('rhabdoid tumours', 'Disease', 'MESH:D018335', (234, 250))	('MYC', 'Gene', '4609', (103, 106))
49196	33479225	While these alterations often are characteristic for distinct sarcoma entities, they usually are not pathognomonic because of their occasional occurrence also in other entities.	('alterations', 'Var', (12, 23))	('sarcoma entities', 'Disease', (62, 78))	('sarcoma entities', 'Disease', 'MESH:D012509', (62, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))
49243	33479225	A patent for a DNA methylation-based method for classifying tumour species of the brain has been applied for by the Deutsches Krebsforschungszentrum Stiftung des offentlichen Rechts and Ruprecht-Karls-Universitat Heidelberg (EP 3067432 A1) with S.M.P., A.v.D., D.T.W.J., D.C., V.Ho., M.Si., M.B.H.	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('EP 3067432 A1', 'Var', (225, 238))	('tumour', 'Disease', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (60, 66))
49313	31662931	Occult malignancy is more common than previously thought, and power morcellation poses a risk of spreading occult malignant tissue, which worsens patients' long-term survival.	('Occult malignancy', 'Disease', (0, 17))	('power morcellation', 'Var', (62, 80))	('Occult malignancy', 'Disease', 'MESH:D009382', (0, 17))	('worsens', 'NegReg', (138, 145))	('patient', 'Species', '9606', (146, 153))	('patients', 'Species', '9606', (146, 154))
49419	26549645	The stimulatory effect on tumor cell proliferation, survival and migration, as well as angiogenesis in these tumors is mediated by two NPY receptors, Y2R and Y5R, which are expressed in either a constitutive or inducible manner.	('Y5R', 'Gene', '18168', (158, 161))	('migration', 'CPA', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (109, 115))	('Y2R', 'Var', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (26, 31))	('survival', 'CPA', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('Y5R', 'Gene', (158, 161))	('angiogenesis', 'CPA', (87, 99))	('NPY', 'Protein', (135, 138))	('tumor', 'Disease', (109, 114))
49450	26549645	Importantly, despite differences in tumor localization and degree of neuronal differentiation, the common feature of Ewing sarcoma tumors is the presence of a characteristic chromosomal translocation leading to the fusion of the Ewing sarcoma breakpoint region1 (EWSR1) gene with an E26 transformation-specific (ETS) transcription factor (EWS-ETS), most often Friend leukemia integration 1 transcription factor (FLI1).	('tumor', 'Disease', (131, 136))	('EWS', 'Gene', '2130', (339, 342))	('tumor', 'Disease', (36, 41))	('EWSR1', 'Gene', '2130', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('FLI1', 'Gene', (412, 416))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (229, 242))	('EWS', 'Gene', (263, 266))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (117, 137))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (117, 130))	('Friend leukemia integration 1 transcription factor', 'Gene', (360, 410))	('FLI1', 'Gene', '2313', (412, 416))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Friend leukemia integration 1 transcription factor', 'Gene', '2313', (360, 410))	('EWSR1', 'Gene', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('EWS', 'Gene', (339, 342))	('Ewing sarcoma breakpoint region1', 'Gene', '2130', (229, 261))	('fusion', 'Var', (215, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('leukemia', 'Phenotype', 'HP:0001909', (367, 375))	('EWS', 'Gene', '2130', (263, 266))	('Ewing sarcoma breakpoint region1', 'Gene', (229, 261))	('Ewing sarcoma tumors', 'Disease', (117, 137))
49451	26549645	This aberrant transcriptional activity of EWS-FLI1 fusion protein is believed to trigger a malignant transformation of Ewing sarcoma, but also induce a neuronal phenotype of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (174, 187))	('induce', 'Reg', (143, 149))	('Ewing sarcoma', 'Disease', (119, 132))	('trigger', 'Reg', (81, 88))	('transcriptional activity', 'MPA', (14, 38))	('FLI1', 'Gene', (46, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('malignant transformation', 'CPA', (91, 115))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (174, 187))	('FLI1', 'Gene', '2313', (46, 50))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (119, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (119, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (174, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('aberrant', 'Var', (5, 13))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
49468	26549645	Associations of high systemic NPY with adverse disease phenotype observed in various malignancies raised a question as to its potential role in tumor growth and progression.	('tumor', 'Disease', (144, 149))	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('high systemic', 'Var', (16, 29))	('adverse disease', 'Disease', 'MESH:D064420', (39, 54))	('malignancies', 'Disease', (85, 97))	('adverse disease', 'Disease', (39, 54))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
49475	26549645	Paradoxically, our initial studies indicated that simultaneous activation of Y1R and Y5R triggers Ewing sarcoma cell death (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (98, 111))	('Y5R', 'Gene', (85, 88))	('Ewing sarcoma cell death', 'Disease', (98, 122))	('Ewing sarcoma cell death', 'Disease', 'MESH:C563168', (98, 122))	('Y1R', 'Var', (77, 80))	('Y5R', 'Gene', '18168', (85, 88))	('activation', 'PosReg', (63, 73))
49489	26549645	For example, NPY acting via Y1R also expressed in breast cancer cells has been shown to inhibit estrogen-induced proliferation.	('Y1R', 'Var', (28, 31))	('inhibit', 'NegReg', (88, 95))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('NPY', 'Var', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('estrogen-induced proliferation', 'CPA', (96, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
49492	26549645	We have found that in addition to its role in augmenting proliferative effects of Y2R, Y5R acts as a survival factor for neuroblastoma cells.	('Y5R', 'Gene', (87, 90))	('neuroblastoma', 'Gene', (121, 134))	('Y2R', 'Var', (82, 85))	('neuroblastoma', 'Phenotype', 'HP:0003006', (121, 134))	('Y5R', 'Gene', '18168', (87, 90))	('neuroblastoma', 'Gene', '230972', (121, 134))	('augmenting', 'PosReg', (46, 56))	('proliferative effects', 'MPA', (57, 78))
49494	26549645	As these factors up-regulate NPY expression and release as well, these coordinated changes lead to activation of the NPY/Y5R pathway, which promotes neuroblastoma cell survival and resistance to chemotherapy via activation of the p44/42 MAPK pathway (Fig.	('release', 'MPA', (48, 55))	('up-regulate', 'PosReg', (17, 28))	('Y5R', 'Gene', (121, 124))	('neuroblastoma', 'Gene', (149, 162))	('NPY', 'Gene', (29, 32))	('promotes', 'PosReg', (140, 148))	('Y5R', 'Gene', '18168', (121, 124))	('neuroblastoma', 'Phenotype', 'HP:0003006', (149, 162))	('p44', 'Gene', (230, 233))	('neuroblastoma', 'Gene', '230972', (149, 162))	('resistance to chemotherapy', 'CPA', (181, 207))	('p44', 'Gene', '2966', (230, 233))	('expression', 'MPA', (33, 43))	('changes', 'Var', (83, 90))
49506	26549645	Consequently, blocking Y5R signaling inhibits the ability of BDNF to promote neuroblastoma cell survival and resistance to therapy.	('neuroblastoma', 'Gene', '230972', (77, 90))	('Y5R', 'Gene', '18168', (23, 26))	('promote', 'PosReg', (69, 76))	('BDNF', 'Gene', '627', (61, 65))	('Y5R', 'Gene', (23, 26))	('blocking', 'Var', (14, 22))	('BDNF', 'Gene', (61, 65))	('neuroblastoma', 'Phenotype', 'HP:0003006', (77, 90))	('neuroblastoma', 'Gene', (77, 90))	('resistance to therapy', 'CPA', (109, 130))	('inhibits', 'NegReg', (37, 45))
49513	26549645	Interestingly, the association of high NPY levels with future relapse has also been reported in prostate cancer (Tab.	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('high', 'Var', (34, 38))	('prostate cancer', 'Disease', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NPY levels', 'MPA', (39, 49))
49515	26549645	In addition to its direct effects on tumor cells, NPY can also affect the tumor microenvironment.	('affect', 'Reg', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('NPY', 'Var', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (74, 79))
49528	26549645	In line with this, NPY treatment in breast cancer cells stimulated VEGF release.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('treatment', 'Var', (23, 32))	('NPY', 'Gene', (19, 22))	('VEGF', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('VEGF', 'Gene', '7422', (67, 71))	('stimulated', 'PosReg', (56, 66))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
49536	26549645	Moreover, high tissue NPY was associated with an invasive phenotype of melanoma and prostate cancer.	('NPY', 'Protein', (22, 25))	('high tissue', 'Var', (10, 21))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma and prostate cancer', 'Disease', 'MESH:D011471', (71, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('associated with', 'Reg', (30, 45))
49541	26549645	Expression of Y2R, in turn, was elevated in tissues derived from local relapses, suggesting its role in tumor cell invasiveness.	('elevated', 'PosReg', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Expression', 'MPA', (0, 10))	('tumor', 'Disease', (104, 109))	('Y2R', 'Var', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
49542	26549645	While Y5R was highly expressed in all human Ewing sarcoma tissues, immunostaining for Y2R was variable and its high levels tended to associate with worse patient survival.	('Y5R', 'Gene', '18168', (6, 9))	('Ewing sarcoma', 'Disease', (44, 57))	('human', 'Species', '9606', (38, 43))	('patient', 'Species', '9606', (154, 161))	('worse', 'NegReg', (148, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (44, 57))	('high levels', 'MPA', (111, 122))	('Y2R', 'Var', (86, 89))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (44, 57))	('Y5R', 'Gene', (6, 9))	('associate with', 'Reg', (133, 147))
49544	26549645	However, we have also observed an NPY-induced increase in invasiveness of neuroblastoma cells, which express Y2R and Y5R (Fig.	('Y2R', 'Var', (109, 112))	('increase', 'PosReg', (46, 54))	('Y5R', 'Gene', (117, 120))	('invasiveness of neuroblastoma', 'Disease', (58, 87))	('Y5R', 'Gene', '18168', (117, 120))	('invasiveness of neuroblastoma', 'Disease', 'MESH:D009447', (58, 87))	('neuroblastoma', 'Phenotype', 'HP:0003006', (74, 87))	('NPY-induced', 'Gene', (34, 45))
49553	26549645	In support of this hypothesis, we reported that the degree of bone destruction in Ewing sarcoma primary tumors derived from our in vivo xenograft model correlated with the level of NPY release from these tumors and was significantly reduced by NPY shRNA.	('reduced', 'NegReg', (233, 240))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('NPY release', 'MPA', (181, 192))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Ewing sarcoma primary tumors', 'Disease', (82, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('Ewing sarcoma primary tumors', 'Disease', 'MESH:C563168', (82, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('bone destruction', 'CPA', (62, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('bone destruction', 'Phenotype', 'HP:0002797', (62, 78))	('NPY', 'Var', (244, 247))
49563	26549645	For example, activation of Y2R in neuroblastoma cells has been shown to stimulate glycolysis, the main metabolic pathway activated in hypoxic cells to produce ATP under low oxygen conditions.	('neuroblastoma', 'Phenotype', 'HP:0003006', (34, 47))	('neuroblastoma', 'Gene', '230972', (34, 47))	('activation', 'Var', (13, 23))	('Y2R', 'Var', (27, 30))	('glycolysis', 'MPA', (82, 92))	('ATP', 'Chemical', 'MESH:D000255', (159, 162))	('stimulate', 'PosReg', (72, 81))	('neuroblastoma', 'Gene', (34, 47))	('oxygen', 'Chemical', 'MESH:D010100', (173, 179))
49573	26549645	Using in vivo xenograft models, we have already demonstrated that treatment with Y2R antagonist inhibits angiogenesis in both pediatric tumor types, while in neuroblastoma Y2R and Y5R antagonists inhibit tumor growth via their anti-proliferative and anti-apoptotic activities, respectively.	('neuroblastoma', 'Gene', '230972', (158, 171))	('inhibits', 'NegReg', (96, 104))	('Y2R', 'Var', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('angiogenesis', 'CPA', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Y5R', 'Gene', (180, 183))	('neuroblastoma', 'Gene', (158, 171))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (204, 209))	('inhibit', 'NegReg', (196, 203))	('Y5R', 'Gene', '18168', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('anti-proliferative', 'CPA', (227, 245))	('anti-apoptotic activities', 'CPA', (250, 275))	('tumor', 'Disease', (136, 141))	('neuroblastoma', 'Phenotype', 'HP:0003006', (158, 171))
49582	26549645	On the other hand, blocking Y2R in the periphery shifts the energy balance from fat accumulation to an increase in lean mass, the loss of which is the main problem in cachexic patients.	('patients', 'Species', '9606', (176, 184))	('increase', 'PosReg', (103, 111))	('energy balance', 'MPA', (60, 74))	('lean mass', 'MPA', (115, 124))	('fat accumulation', 'MPA', (80, 96))	('Y2R', 'Var', (28, 31))
49592	26549645	For example, as described above, in breast cancer, activation of Y5R stimulates cancer cell proliferation and migration.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('Y5R', 'Gene', (65, 68))	('breast cancer', 'Disease', (36, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('migration', 'CPA', (110, 119))	('Y5R', 'Gene', '18168', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('activation', 'Var', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('stimulates', 'PosReg', (69, 79))	('cancer', 'Disease', (80, 86))
49617	22382690	Inhibition of such activation prevents cell death and Fas/Fas L upregulation.	('Fas L', 'Gene', '356', (58, 63))	('Fas', 'Chemical', 'MESH:C038178', (54, 57))	('Fas L', 'Gene', (58, 63))	('prevents', 'NegReg', (30, 38))	('upregulation', 'PosReg', (64, 76))	('Fas', 'Chemical', 'MESH:C038178', (58, 61))	('Inhibition', 'Var', (0, 10))	('cell death', 'CPA', (39, 49))
49697	22382690	In the case of A4573 there was an ~3-fold increase over the control after 8 h of treatment and a markedly higher increase after 24 h of treatment (6- to 7-fold greater than the control).	('to 7', 'Species', '1214577', (150, 154))	('A4573', 'Chemical', '-', (15, 20))	('increase', 'PosReg', (113, 121))	('A4573', 'Var', (15, 20))	('increase', 'PosReg', (42, 50))
49721	22382690	Similarly, inhibitors of metalloproteinases induce apoptosis in Ewing's sarcoma cell lines by avoiding the cleavage of transmembrane Fas L, thus increasing the level of transmembrane Fas L, as well as that of its receptor Fas.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (64, 79))	('avoiding', 'NegReg', (94, 102))	('Fas L', 'Gene', (133, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('Fas', 'Chemical', 'MESH:C038178', (222, 225))	('Fas', 'Chemical', 'MESH:C038178', (133, 136))	('Fas', 'Chemical', 'MESH:C038178', (183, 186))	('Fas L', 'Gene', '356', (183, 188))	('inhibitors', 'Var', (11, 21))	('apoptosis', 'CPA', (51, 60))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (64, 79))	('cleavage', 'MPA', (107, 115))	('Fas L', 'Gene', '356', (133, 138))	('increasing', 'PosReg', (145, 155))	("Ewing's sarcoma", 'Disease', (64, 79))	('Fas L', 'Gene', (183, 188))
49723	22382690	This is supported by the finding of inhibition of melatonin-induced cell death by Fas- and Fas L-neutralising antibodies as well as by the lipooxigenase inhibitor NDGA, which has been associated with the inhibition of cell death mediated by Fas.	('Fas L', 'Gene', (91, 96))	('cell death', 'CPA', (68, 78))	('Fas', 'Chemical', 'MESH:C038178', (91, 94))	('inhibition', 'NegReg', (36, 46))	('Fas', 'Chemical', 'MESH:C038178', (82, 85))	('melatonin-induced', 'Gene', (50, 67))	('NDGA', 'Chemical', 'MESH:D009637', (163, 167))	('Fas', 'Chemical', 'MESH:C038178', (241, 244))	('Fas L', 'Gene', '356', (91, 96))	('antibodies', 'Var', (110, 120))	('melatonin', 'Chemical', 'MESH:D008550', (50, 59))
49744	22382690	In fact, we have recently published that melatonin induces cell death in human leukaemia cells in correlation with an increase in Fas and Fas L expression.	('melatonin', 'Var', (41, 50))	('leukaemia', 'Disease', (79, 88))	('Fas L', 'Gene', '356', (138, 143))	('increase', 'PosReg', (118, 126))	('Fas', 'Chemical', 'MESH:C038178', (130, 133))	('Fas L', 'Gene', (138, 143))	('Fas', 'Protein', (130, 133))	('human', 'Species', '9606', (73, 78))	('cell death', 'CPA', (59, 69))	('leukaemia', 'Disease', 'MESH:D007938', (79, 88))	('melatonin', 'Chemical', 'MESH:D008550', (41, 50))	('Fas', 'Chemical', 'MESH:C038178', (138, 141))
49751	31672974	We identify four molecular subtypes that resemble those observed in endometrial carcinoma: POLE-mutated, microsatellite instability, copy number high, and copy number low subtypes.	('endometrial carcinoma', 'Disease', (68, 89))	('POLE-mutated', 'Var', (91, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('copy number high', 'Var', (133, 149))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (68, 89))	('microsatellite instability', 'MPA', (105, 131))	('copy number low', 'Var', (155, 170))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (68, 89))
49752	31672974	These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes.	('DNA', 'Disease', (41, 44))	('linked', 'Reg', (29, 35))	('deficiencies', 'Var', (52, 64))	('patient', 'Species', '9606', (153, 160))
49768	31672974	Microsatellite instability, caused by defective mismatch repair, is observed in 20-40% of endometrial endometrioid carcinoma and is associated with higher histological grade and more lymphovascular space invasion but better prognosis.	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (90, 124))	('mismatch repair', 'Protein', (48, 63))	('defective', 'Var', (38, 47))	('observed', 'Reg', (68, 76))	('Microsatellite instability', 'Disease', (0, 26))	('lymphovascular space invasion', 'CPA', (183, 212))	('endometrial endometrioid carcinoma', 'Disease', (90, 124))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (102, 124))
49769	31672974	The ultramutated phenotype, resulting from mutations in the exonuclease domain of DNA polymerase epsilon (POLE), is present in several cancer types, including endometrial cancer, and linked with diseases at an earlier stage and with a more favorable prognosis.	('linked with', 'Reg', (183, 194))	('cancer', 'Disease', (135, 141))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations in', 'Var', (43, 55))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('POLE', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('present', 'Reg', (116, 123))
49770	31672974	Copy number aberration is a dominant characteristic of the genome in endometrial and ovarian serous carcinoma, and is associated with a more advanced disease and poor patient outcomes.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('patient', 'Species', '9606', (167, 174))	('Copy number aberration', 'Var', (0, 22))	('endometrial and ovarian serous carcinoma', 'Disease', 'MESH:D010051', (69, 109))	('advanced disease', 'Disease', (141, 157))	('associated', 'Reg', (118, 128))	('advanced disease', 'Disease', 'MESH:D020178', (141, 157))
49777	31672974	We used a modified version of the molecular subtyping method based on genomic aberration profiling (described in the Methods) on 109 uterine and ovarian CS samples, and then used a decision tree to classify samples into four molecular subtypes: POLE-mutated (POLE), microsatellite instability (MSI), copy number high (CNH), and copy number low (CNL) subtypes.	('ovarian CS', 'Disease', (145, 155))	('copy number', 'Var', (328, 339))	('ovarian CS', 'Disease', 'MESH:D010049', (145, 155))	('microsatellite', 'MPA', (266, 280))	('copy', 'Var', (300, 304))
49779	31672974	MSI tumors exhibited numerous indels (range: 10-63, median: 27) and a moderately increased number of SNVs (range: 8-207, median: 55) but fewer CNVs (range: 0-7, median: 2).	('MSI tumors', 'Disease', (0, 10))	('indels', 'Var', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SNVs', 'MPA', (101, 105))	('CNVs', 'MPA', (143, 147))	('MSI tumors', 'Disease', 'MESH:D009369', (0, 10))
49780	31672974	The remaining tumors were assigned as CNL subtype, with few SNVs, indels, or CNVs (Fig.	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('CNVs', 'Var', (77, 81))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('indels', 'Var', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
49788	31672974	The ovarian CS and endometrial carcinoma share a subset of SNVs/indels, including the POLE p.P286R mutation.	('ovarian CS', 'Disease', (4, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('p.P286R', 'Var', (91, 98))	('ovarian CS', 'Disease', 'MESH:D010049', (4, 14))	('endometrial carcinoma', 'Disease', (19, 40))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (19, 40))	('p.P286R', 'Mutation', 'p.P286R', (91, 98))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (19, 40))
49792	31672974	Moreover, the multivariate Cox regression analysis with FIGO stage, tumor size, and primary tumor anatomical site confirmed that each of these genomic aberration subtypes was independent (POLE: p = 0.9985 and 0.9987, HR = 0.0000 and 0.0000; MSI: p = 0.0068 and 0.0205, HR = 0.1937 and 0.0937; CNH: p = 0.0007 and 0.0296, HR = 3.9048 and 2.6047; CNL: p = 0.1782 and 0.0025, HR = 1.9214 and 4.1512).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('0.0937', 'Var', (285, 291))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
49795	31672974	We curated gene sets for mismatch repair (MMR) and homologous recombination (HR) pathways that were relevant for hereditary breast, endometrial, and ovarian cancer, and subsequently assessed whether a tumor retained a germline and/or somatic mutation or CpG-site hypermethylation in the selected genes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ovarian cancer', 'Disease', (149, 163))	('endometrial', 'Disease', (132, 143))	('hereditary breast', 'Disease', (113, 130))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('endometrial', 'Disease', 'MESH:D016889', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))	('tumor', 'Disease', (201, 206))	('hereditary breast', 'Disease', 'MESH:D061325', (113, 130))	('CpG-site hypermethylation', 'Var', (254, 279))
49798	31672974	Defective MMR was observed in the MSI subtype, including MLH1 promoter hypermethylation and germline/somatic mutations in MLH1, MSH2, MSH6, or PMS2 loci.	('MLH1', 'Gene', '4292', (57, 61))	('PMS2', 'Gene', '5395', (143, 147))	('MLH1', 'Gene', (57, 61))	('MSH6', 'Gene', '2956', (134, 138))	('MLH1', 'Gene', (122, 126))	('MLH1', 'Gene', '4292', (122, 126))	('MSH2', 'Gene', (128, 132))	('MSH2', 'Gene', '4436', (128, 132))	('hypermethylation', 'Var', (71, 87))	('MSH6', 'Gene', (134, 138))	('PMS2', 'Gene', (143, 147))
49799	31672974	HR deficiency was a distinctive feature of the CNH subtype, as exemplified by (1) BRCA1 and RAD51C promoter hypermethylation; (2) germline inactivation plus loss of heterozygosity (LOH) in the loci of BRCA1/2, ATM, RAD50, and BLM; and (3) somatic mutation of the PTEN gene.	('inactivation', 'Var', (139, 151))	('BRCA1', 'Gene', (82, 87))	('ATM', 'Gene', '472', (210, 213))	('BRCA1/2', 'Gene', (201, 208))	('HR deficiency', 'Disease', (0, 13))	('PTEN', 'Gene', (263, 267))	('RAD51C', 'Gene', (92, 98))	('BRCA1/2', 'Gene', '672;675', (201, 208))	('PTEN', 'Gene', '5728', (263, 267))	('ATM', 'Gene', (210, 213))	('RAD51C', 'Gene', '5889', (92, 98))	('BRCA1', 'Gene', '672', (201, 206))	('BRCA1', 'Gene', '672', (82, 87))	('HR deficiency', 'Disease', 'MESH:D001919', (0, 13))	('loss of', 'NegReg', (157, 164))	('RAD50', 'Gene', (215, 220))	('RAD50', 'Gene', '10111', (215, 220))	('BRCA1', 'Gene', (201, 206))
49801	31672974	CCNE1 amplification and homozygous deletions of RB1 and NF1 loci were previously reported to be involved in chromosomal instability through a distinct mechanism not involving HR deficiency (non-HRD).	('chromosomal instability', 'MPA', (108, 131))	('RB1', 'Gene', (48, 51))	('NF1', 'Gene', '4763', (56, 59))	('HRD', 'Disease', 'MESH:C537157', (194, 197))	('CCNE1', 'Gene', '898', (0, 5))	('HR deficiency', 'Disease', (175, 188))	('involved', 'Reg', (96, 104))	('HRD', 'Disease', (194, 197))	('CCNE1', 'Gene', (0, 5))	('RB1', 'Gene', '5925', (48, 51))	('HR deficiency', 'Disease', 'MESH:D001919', (175, 188))	('chromosomal instability', 'Phenotype', 'HP:0040012', (108, 131))	('amplification', 'Var', (6, 19))	('NF1', 'Gene', (56, 59))	('homozygous deletions', 'Var', (24, 44))
49802	31672974	Within the CNH subtype, 17 (26.6%) of 64 CNH tumors (15 CCNE1 amplification and 2 RB1 deletion) exhibited this non-HRD-type chromosomal instability.	('RB1', 'Gene', '5925', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('exhibited', 'Reg', (96, 105))	('HRD', 'Disease', (115, 118))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('CNH tumors', 'Disease', 'MESH:D009369', (41, 51))	('chromosomal instability', 'Phenotype', 'HP:0040012', (124, 147))	('CCNE1', 'Gene', '898', (56, 61))	('CCNE1', 'Gene', (56, 61))	('RB1', 'Gene', (82, 85))	('amplification', 'Var', (62, 75))	('HRD', 'Disease', 'MESH:C537157', (115, 118))	('CNH tumors', 'Disease', (41, 51))	('deletion', 'Var', (86, 94))
49803	31672974	The CNH subtype with non-HRD chromosomal instability showed worse prognosis than CNH tumors with HRD in terms of overall survival (p = 0.0427 by Gehan-Breslow-Wilcoxon test; Fig.	('CNH tumors', 'Disease', 'MESH:D009369', (81, 91))	('CNH tumors', 'Disease', (81, 91))	('HRD', 'Disease', 'MESH:C537157', (25, 28))	('chromosomal instability', 'Var', (29, 52))	('chromosomal instability', 'Phenotype', 'HP:0040012', (29, 52))	('HRD', 'Disease', 'MESH:C537157', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('HRD', 'Disease', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('worse', 'NegReg', (60, 65))	('HRD', 'Disease', (97, 100))
49807	31672974	Also, by GISTIC analysis of SNP6 data, copy number amplification was highly significant for MECOM, MYC, and CCNE1.	('copy number amplification', 'Var', (39, 64))	('MECOM', 'Gene', (92, 97))	('MYC', 'Disease', (99, 102))	('MECOM', 'Gene', '2122', (92, 97))	('CCNE1', 'Gene', '898', (108, 113))	('CCNE1', 'Gene', (108, 113))
49825	31672974	The phylogenetic trees of the CNL and CNH subtype tumors had a high proportion of trunks: the carcinoma and sarcoma components shared most of the SNVs/indels of the 596 genes (Fig.	('CNH subtype tumors', 'Disease', 'MESH:C535673', (38, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('CNH subtype tumors', 'Disease', (38, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('SNVs/indels', 'Var', (146, 157))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (94, 115))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
49827	31672974	Whereas none of the 26 (0%) and only 2 of the 12 (16.7%) drivers on the carcinoma- or sarcoma-branches were clonal among the POLE and MSI subtypes, 21 of 43 (48.8%) and 9 of 12 (75.0%) driver mutations on the trunk were clonal, respectively (Fig.	('carcinoma- or sarcoma-branches', 'Disease', (72, 102))	('carcinoma- or sarcoma-branches', 'Disease', 'MESH:D012509', (72, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('mutations', 'Var', (192, 201))
49829	31672974	CS tumors of the CNH subtype frequently had longer trunks with shorter branches for both carcinoma and sarcoma components, and this branching pattern was also confirmed with tree analyses with SNVs/indels from the exome data (when available) and with CNVs of the target panel or exome data (Supplementary Fig.	('CS tumors', 'Disease', 'MESH:D006223', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('longer', 'PosReg', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (89, 110))	('CS tumors', 'Disease', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('shorter', 'NegReg', (63, 70))	('SNVs/indels', 'Var', (193, 204))	('CNH', 'Disease', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
49835	31672974	However, in the CNH subtype (GY030 tumor), similarities between T2 (carcinoma-dominant) and T3 (sarcoma-dominant), and between T4 (carcinoma-dominant) and T6 (sarcoma-dominant) suggest parallel evolution of the bimodal T2/T3 and T4/T6 regions.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('carcinoma-dominant', 'Disease', 'MESH:D002277', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinoma-dominant', 'Disease', (68, 86))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('sarcoma-dominant', 'Disease', (96, 112))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (159, 175))	('CNH', 'Disease', (16, 19))	('sarcoma-dominant', 'Disease', (159, 175))	('tumor', 'Disease', (35, 40))	('carcinoma-dominant', 'Disease', 'MESH:D002277', (131, 149))	('carcinoma-dominant', 'Disease', (131, 149))	('GY030', 'Var', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (96, 112))
49839	31672974	No recurrent genetic mutations in SNVs/indels or CNVs were differentially detected between carcinoma- and sarcoma-dominant regions with multi-regional sequenced data of 3 cases (EN676, GY030, and EN558; the data from EN482 were not used for this purpose since sarcoma-dominant region sequenced data was not available for the case; also described in Supplementary Note 3).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('sarcoma-dominant', 'Disease', (106, 122))	('EN558', 'Var', (196, 201))	('sarcoma-dominant', 'Disease', (260, 276))	('carcinoma- and sarcoma-dominant regions', 'Disease', 'MESH:D012509', (91, 130))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (106, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('EN676', 'Var', (178, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('GY030', 'Var', (185, 190))	('sarcoma-dominant', 'Disease', 'MESH:D012509', (260, 276))
49867	31672974	ARID1A mutation was correlated with better patient outcomes when all cases were included in the analysis, because it was more frequently mutated in POLE and MSI subtypes, which show an intrinsically more favorable prognosis.	('ARID1A', 'Gene', '8289', (0, 6))	('ARID1A', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('patient', 'Species', '9606', (43, 50))
49868	31672974	On the contrary, in the CNH subgroup, patients with ARID1A mutant tumors showed substantially poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutant', 'Var', (59, 65))	('tumors', 'Disease', (66, 72))	('ARID1A', 'Gene', '8289', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('ARID1A', 'Gene', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (38, 46))	('poor', 'NegReg', (94, 98))
49869	31672974	Since ARID1A has been reported to be involved in DNA double-strand break repair, there is a possible interaction between DNA copy number aberration and ARID1A protein loss in CS aggressiveness.	('protein loss', 'Disease', 'MESH:D058495', (159, 171))	('ARID1A', 'Gene', '8289', (152, 158))	('aggressiveness', 'Disease', (178, 192))	('DNA', 'Gene', (121, 124))	('ARID1A', 'Gene', '8289', (6, 12))	('ARID1A', 'Gene', (6, 12))	('copy number aberration', 'Var', (125, 147))	('aggressiveness', 'Phenotype', 'HP:0000718', (178, 192))	('protein loss', 'Disease', (159, 171))	('ARID1A', 'Gene', (152, 158))	('aggressiveness', 'Disease', 'MESH:D001523', (178, 192))
49875	31672974	Whereas CTNNB1-activating mutations have long been recognized as a driving mechanism of EMT in multiple cancer types, including uterine endometrioid carcinoma, in the current CS cohort and contrary to our expectations, the mutational status was independent of the EMT score but, instead, associated with hypomethylation of the miR-200a/200b/429 and miR-141/200c promotors.	('hypomethylation', 'MPA', (304, 319))	('mutational', 'Var', (223, 233))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('endometrioid carcinoma', 'Disease', (136, 158))	('miR-141', 'Gene', (349, 356))	('CTNNB1', 'Gene', '1499', (8, 14))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('miR-200a', 'Gene', '406983', (327, 335))	('miR-200a', 'Gene', (327, 335))	('miR-141', 'Gene', '406933', (349, 356))	('endometrioid carcinoma', 'Disease', 'MESH:D018269', (136, 158))	('CTNNB1', 'Gene', (8, 14))	('cancer', 'Disease', (104, 110))	('associated with', 'Reg', (288, 303))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (136, 158))
49881	31672974	In the current cohort, 2 cases (OV594 and OV343) had synchronous endometrial and ovarian carcinomas (SEOC) and were associated with endometriosis in the ovary.	('ovarian carcinomas', 'Disease', (81, 99))	('associated with', 'Reg', (116, 131))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('endometriosis', 'Phenotype', 'HP:0030127', (132, 145))	('OV343', 'Var', (42, 47))	('OV594', 'Var', (32, 37))	('synchronous endometrial', 'Disease', 'MESH:D016889', (53, 76))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (81, 99))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (81, 98))	('endometriosis', 'Disease', 'MESH:D004715', (132, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('endometriosis', 'Disease', (132, 145))	('synchronous endometrial', 'Disease', (53, 76))
49915	31672974	Loss of heterozygosity (LOH) in copy number was determined by the number of variant sequence reads compared with the wildtype in the tumor DNA.	('variant', 'Var', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Loss', 'NegReg', (0, 4))	('tumor', 'Disease', (133, 138))
49921	31672974	The timing of a driver event is inferred from the cancer cell fraction calculated from the mutant allele frequency of a SNV/indel and the copy number state where the SNV/indel resides.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutant', 'Var', (91, 97))	('SNV/indel', 'Gene', (120, 129))
49925	31672974	Samples were first categorized by POLE hotspot mutations in the exonuclease domain (POLE mutated; POLE) and then by MSI-high status (microsatellite instability; MSI), which was determined by deviations from paired normal control in electropherograms of 2 or more among 6 DNA markers (BAT25, BAT26, D2S123, D5S346, D17S250, and BAT40), as previously described.	('D17S250', 'Var', (314, 321))	('D2S123', 'Chemical', 'MESH:C492712', (298, 304))	('BAT25', 'Var', (284, 289))	('BAT40', 'Var', (327, 332))	('D2S123', 'Var', (298, 304))	('D5S346', 'Var', (306, 312))	('BAT26', 'Var', (291, 296))
49927	31672974	We used another molecular subtyping method based on major driver mutations observed in carcinomas with endometrioid or serous histology.	('endometrioid', 'Disease', (103, 115))	('carcinomas', 'Disease', 'MESH:D002277', (87, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('carcinomas', 'Disease', (87, 97))	('serous', 'Disease', (119, 125))	('mutations', 'Var', (65, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
49928	31672974	For this analysis, samples with PTEN or ARID1A mutations were assigned as endometrioid-like, samples with TP53 or PPP2R1A mutations were classified as serous-like, and the remaining samples lacking any mutation in these four genes were assigned to the unclassified group.	('ARID1A', 'Gene', (40, 46))	('ARID1A', 'Gene', '8289', (40, 46))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('mutations', 'Var', (47, 56))	('PPP2R1A', 'Gene', (114, 121))	('PPP2R1A', 'Gene', '5518', (114, 121))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))	('endometrioid-like', 'Disease', (74, 91))
50014	30121085	In addition, insurance rates are significantly lower in AYA patients.	('lower', 'NegReg', (47, 52))	('patients', 'Species', '9606', (60, 68))	('AYA', 'Chemical', '-', (56, 59))	('insurance rates', 'CPA', (13, 28))	('AYA', 'Var', (56, 59))
50053	26806808	In recent years, specific gene fusion/mutations and gene over-expression/activation have been shown to drive sarcoma pathogenesis and development.	('development', 'CPA', (134, 145))	('gene fusion/mutations', 'Var', (26, 47))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('over-expression/activation', 'PosReg', (57, 83))	('drive', 'PosReg', (103, 108))	('sarcoma', 'Disease', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))
50056	26806808	Given that sarcoma is believed to develop as a result of genetic alterations in mesenchymal progenitor/stem cells, CRISPR-Cas9 genome editing technologies hold extensive application potentials in sarcoma models and therapies.	('sarcoma', 'Disease', (11, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('genetic', 'Var', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcoma', 'Disease', 'MESH:D012509', (196, 203))	('sarcoma', 'Disease', 'MESH:D012509', (11, 18))	('sarcoma', 'Disease', (196, 203))
50064	26806808	KIT and/or platelet-derived growth factor receptor-alpha (PDGFR-alpha) mutations in gastrointestinal stromal tumors (GIST)), DNA copy number alterations (e.g.	('gastrointestinal stromal tumors', 'Disease', (84, 115))	('PDGFR-alpha', 'Gene', '18595', (58, 69))	('mutations', 'Var', (71, 80))	('PDGFR-alpha', 'Gene', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (84, 115))	('platelet-derived growth factor receptor-alpha', 'Gene', (11, 56))	('platelet-derived growth factor receptor-alpha', 'Gene', '18595', (11, 56))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (84, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
50067	26806808	More commonly, sarcoma pathogenesis is the result of complex chromosomal abnormalities, as in the case of osteosarcomas and high grade undifferentiated pleomorphic sarcomas (neurofibromin 1 (NF1) gene deletions, point mutations and indels such as P53 and RB).	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('neurofibromin 1', 'Gene', (174, 189))	('NF1', 'Gene', (191, 194))	('indels', 'Var', (232, 238))	('point mutations', 'Var', (212, 227))	('osteosarcomas', 'Disease', 'MESH:D012516', (106, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('sarcoma', 'Disease', (15, 22))	('sarcoma', 'Disease', (164, 171))	('osteosarcomas', 'Disease', (106, 119))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (61, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('osteosarcomas', 'Phenotype', 'HP:0002669', (106, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (135, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('undifferentiated pleomorphic sarcomas', 'Disease', (135, 172))	('chromosomal abnormalities', 'Disease', (61, 86))	('result', 'Reg', (43, 49))	('neurofibromin 1', 'Gene', '18015', (174, 189))	('P53', 'Gene', (247, 250))	('NF1', 'Gene', '18015', (191, 194))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
50068	26806808	In addition, a variety of protein kinases including receptor tyrosine kinases (RTKs) are overexpressed or constitutively activated in sarcoma, both in translocation associated sarcomas, such as GIST discussed above, and in karyotypically complex tumors, for instance osteosarcoma.	('translocation', 'Var', (151, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('osteosarcoma', 'Disease', (267, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('tumors', 'Disease', (246, 252))	('osteosarcoma', 'Disease', 'MESH:D012516', (267, 279))	('sarcomas', 'Disease', (176, 184))	('protein kinases', 'Enzyme', (26, 41))	('activated', 'PosReg', (121, 130))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('overexpressed', 'PosReg', (89, 102))	('sarcoma', 'Disease', 'MESH:D012509', (272, 279))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('osteosarcoma', 'Phenotype', 'HP:0002669', (267, 279))	('sarcoma', 'Disease', (272, 279))	('sarcomas', 'Disease', 'MESH:D012509', (176, 184))	('sarcoma', 'Disease', (176, 183))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('sarcoma', 'Disease', (134, 141))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))
50074	26806808	Much of the power of the Cre-loxP system derives from the potential to generate conditional mutants.	('lox', 'Gene', '16948', (29, 32))	('lox', 'Gene', (29, 32))	('conditional mutants', 'Var', (80, 99))
50079	26806808	Sarcoma pathogenesis is a multistep process that involves many genetic alterations and epigenetic changes.	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('epigenetic changes', 'Var', (87, 105))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))
50080	26806808	Genome sequencing studies have identified a large collection of genetic and epigenetic alterations that occur in different types of human sarcomas.	('genetic', 'Var', (64, 71))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('sarcomas', 'Disease', (138, 146))	('human', 'Species', '9606', (132, 137))	('epigenetic alterations', 'Var', (76, 98))
50083	26806808	The CRISPR-Cas9 genome editing technology has revolutionized the field of genetic engineering and may overcome many of the limitations of earlier techniques including Cre-loxP, ZFNs, and TALENS, on carrying out deletions, insertions, translocations, and inversions at specific sites in the DNA of cells.	('deletions', 'Var', (211, 220))	('lox', 'Gene', (171, 174))	('lox', 'Gene', '16948', (171, 174))	('insertions', 'Var', (222, 232))	('inversions', 'Var', (254, 264))	('translocations', 'Var', (234, 248))
50085	26806808	Genome sequencing studies have identified multiple driver gene mutations in human sarcomas.	('mutations', 'Var', (63, 72))	('human', 'Species', '9606', (76, 81))	('sarcomas', 'Disease', 'MESH:D012509', (82, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcomas', 'Disease', (82, 90))
50088	26806808	Hematopoietic stem cells were also derived from mice with knock-in of the FLT3 internal tandem duplication (FLT3-ITD) mutation.	('FLT3', 'Gene', '14255', (74, 78))	('FLT3', 'Gene', (108, 112))	('mice', 'Species', '10090', (48, 52))	('FLT3', 'Gene', '14255', (108, 112))	('FLT3', 'Gene', (74, 78))	('mutation', 'Var', (118, 126))
50089	26806808	Using cooperating LOF mutations in genes encoding epigenetic modifiers, transcription factors, and mediators of cytokine signaling (such as TET2, DNMT3A, RUNX1, NF1, SMC3, P53, ASXL1, and EZH2), researchers were able to generate models of acute myeloid leukemia (AML).	('acute myeloid leukemia', 'Disease', (239, 261))	('ASXL1', 'Gene', '228790', (177, 182))	('TET2', 'Gene', (140, 144))	('EZH2', 'Gene', '14056', (188, 192))	('leukemia', 'Phenotype', 'HP:0001909', (253, 261))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (245, 261))	('SMC3', 'Gene', (166, 170))	('AML', 'Disease', 'MESH:D015470', (263, 266))	('RUNX1', 'Gene', (154, 159))	('AML', 'Phenotype', 'HP:0004808', (263, 266))	('AML', 'Disease', (263, 266))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (239, 261))	('LOF', 'NegReg', (18, 21))	('DNMT3A', 'Gene', (146, 152))	('EZH2', 'Gene', (188, 192))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (239, 261))	('DNMT3A', 'Gene', '13435', (146, 152))	('mutations', 'Var', (22, 31))	('SMC3', 'Gene', '13006', (166, 170))	('NF1', 'Gene', '18015', (161, 164))	('TET2', 'Gene', '214133', (140, 144))	('RUNX1', 'Gene', '12394', (154, 159))	('ASXL1', 'Gene', (177, 182))	('NF1', 'Gene', (161, 164))
50091	26806808	A recent study has identified that deregulation of APC, P53, KRAS, and SMAD4 is sufficient for transformation of cultured mouse colon cells into colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('deregulation', 'Var', (35, 47))	('SMAD4', 'Gene', (71, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('transformation', 'Reg', (95, 109))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('KRAS', 'Gene', (61, 65))	('APC', 'Disease', (51, 54))	('colorectal cancer', 'Disease', (145, 162))	('P53', 'Gene', (56, 59))	('mouse', 'Species', '10090', (122, 127))
50092	26806808	CRISPR-Cas9 was utilized to induce LOF mutations in APC, P53, and SMAD4, and GOF mutation in KRAS in cultured human intestinal stem cells.	('APC', 'Disease', (52, 55))	('P53', 'Gene', (57, 60))	('mutations', 'Var', (39, 48))	('human', 'Species', '9606', (110, 115))	('APC', 'Disease', 'MESH:D011125', (52, 55))	('SMAD4', 'Gene', (66, 71))	('LOF', 'NegReg', (35, 38))
50093	26806808	To introduce the GOF mutation, an oligonucleotide with the KRAS mutation and two silent mutations was designed to serve as a template for HDR.	('oligonucleotide', 'Chemical', 'MESH:D009841', (34, 49))	('KRAS', 'Gene', (59, 63))	('mutation', 'Var', (64, 72))	('mutation', 'Var', (21, 29))
50095	26806808	Upon xenotransplantation into mice, quadruple mutants grew as tumors with features of invasive carcinoma.	('invasive carcinoma', 'Disease', 'MESH:D009361', (86, 104))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('invasive carcinoma', 'Disease', (86, 104))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('quadruple mutants', 'Var', (36, 53))
50096	26806808	Another colorectal cancer model using CRISPR-Cas9-mediated engineering of human intestinal organoids has been established by Matano et al.. By modulating the culture conditions to mimic the intestinal environment, LOF mutations of APC, P53, SMAD4, and GOF mutations of KRAS and PIK3CA were introduced into organoids derived from normal human intestinal epithelium.	('APC', 'Disease', (231, 234))	('mutations', 'Var', (218, 227))	('KRAS', 'Gene', (269, 273))	('GOF', 'PosReg', (252, 255))	('PIK3CA', 'Gene', (278, 284))	('LOF', 'NegReg', (214, 217))	('colorectal cancer', 'Disease', 'MESH:D015179', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (256, 265))	('colorectal cancer', 'Phenotype', 'HP:0003003', (8, 25))	('SMAD4', 'Gene', (241, 246))	('human', 'Species', '9606', (74, 79))	('APC', 'Disease', 'MESH:D011125', (231, 234))	('P53', 'Gene', (236, 239))	('colorectal cancer', 'Disease', (8, 25))	('human', 'Species', '9606', (336, 341))
50098	26806808	They then selected the isogenic organoids that carried mutations in the tumor suppressor genes APC, P53, and SMAD4, and the oncogenes KRAS and/or PIK3CA.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutations', 'Var', (55, 64))	('APC', 'Disease', (95, 98))	('tumor', 'Disease', (72, 77))	('SMAD4', 'Gene', (109, 114))	('P53', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('APC', 'Disease', 'MESH:D011125', (95, 98))
50099	26806808	Organoids engineered to express all five mutations grew independently of niche factors in vitro, and an adenocarcinoma sequence model was formed after implantation under the kidney subcapsule in mice.	('mutations', 'Var', (41, 50))	('mice', 'Species', '10090', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('adenocarcinoma', 'Disease', (104, 118))	('adenocarcinoma', 'Disease', 'MESH:D000230', (104, 118))
50102	26806808	As a result, when PTEN was mutated by CRISPR, elevated AKT phosphorylation and lipid accumulation in hepatocytes were observed, while simultaneous mutation of PTEN and P53 induced liver tumors.	('mutated', 'Var', (27, 34))	('PTEN', 'Gene', (18, 22))	('elevated', 'PosReg', (46, 54))	('induced', 'PosReg', (172, 179))	('PTEN', 'Gene', (159, 163))	('lipid', 'Chemical', 'MESH:D008055', (79, 84))	('mutation', 'Var', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('AKT', 'CPA', (55, 58))	('P53', 'Gene', (168, 171))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('lipid accumulation in hepatocytes', 'Phenotype', 'HP:0006561', (79, 112))	('liver tumors', 'Disease', 'MESH:D008113', (180, 192))	('liver tumors', 'Phenotype', 'HP:0002896', (180, 192))	('liver tumors', 'Disease', (180, 192))	('lipid accumulation', 'MPA', (79, 97))
50103	26806808	Furthermore, the feasibility of inducing GOF mutations by CRISPR-Cas9 in the liver was also determined by co-injection of Cas9-sgRNA plasmids targeting beta-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations, which led to the generation of hepatocytes with nuclear localization of beta-catenin.	('mutations', 'Var', (45, 54))	('CRISPR-Cas9', 'Gene', (58, 69))	('oligonucleotide', 'Chemical', 'MESH:D009841', (196, 211))	('beta-catenin', 'Gene', (327, 339))	('beta-catenin', 'Gene', (152, 164))	('donor', 'Species', '9606', (212, 217))	('beta-catenin', 'Gene', '1499', (327, 339))	('beta-catenin', 'Gene', '1499', (152, 164))	('inducing', 'Reg', (32, 40))	('hepatocytes with nuclear localization', 'MPA', (286, 323))
50110	26806808	To demonstrate that cooperative genetic tumor modeling can be achieved using CRISPR-Cas9, they generated tetracistronic MuLE vectors designed to express either scrambled sgRNA or sgRNA targeting P53 exon 7 or exon 8, as well as H-RASG12V, hCas9, and puromycin resistance.	('H-RASG12V', 'CellLine', 'CVCL:V247', (228, 237))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('hCas9', 'Var', (239, 244))	('MuLE', 'Species', '319699', (120, 124))	('sgRNA', 'Gene', (179, 184))	('puromycin', 'Chemical', 'MESH:D011691', (250, 259))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('H-RASG12V', 'Var', (228, 237))
50117	26806808	In addition to modeling chromosomal rearrangements in cell lines, mouse models of EML4-ALK gene rearrangement by CRISPR-Cas9 in non-small-cell lung cancers (NSCLCs) were generated.	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('EML4', 'Gene', (82, 86))	('mouse', 'Species', '10090', (66, 71))	('ALK', 'Gene', '11682', (87, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('rearrangement', 'Var', (96, 109))	('lung cancers', 'Disease', 'MESH:D008175', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lung cancers', 'Phenotype', 'HP:0100526', (143, 155))	('NSCLC', 'Disease', (157, 162))	('EML4', 'Gene', '78798', (82, 86))	('ALK', 'Gene', (87, 90))	('lung cancers', 'Disease', (143, 155))
50123	26806808	While various types of sarcomas show characteristic translocations, gene fusions generated from these translocations are the initiating events of many sarcomas and are likely essential in some subtypes of these tumors.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('translocations', 'Var', (52, 66))	('sarcomas', 'Disease', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('initiating', 'Reg', (125, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('sarcomas', 'Disease', 'MESH:D012509', (23, 31))	('translocations', 'Var', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('sarcomas', 'Disease', (23, 31))
50124	26806808	Alveolar rhabdomyosarcoma (A-RMS), the third most common soft-tissue sarcoma in children, is typified by a translocation that fuses the PAX3 gene on chromosome 2 to the FOXO1 gene on chromosome 13.	('FOXO1', 'Gene', (169, 174))	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (61, 76))	('sarcoma', 'Disease', (18, 25))	('sarcoma', 'Disease', (69, 76))	('A-RMS', 'Phenotype', 'HP:0006779', (27, 32))	('translocation', 'Var', (107, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('children', 'Species', '9606', (80, 88))	('PAX3', 'Gene', (136, 140))	('Alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (0, 25))	('Alveolar rhabdomyosarcoma', 'Disease', (0, 25))	('Alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (0, 25))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (9, 25))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))
50141	26806808	Interestingly, this study generated mutations that not only caused loss of P53 protein but also novel mutant P53 proteins that could promote lymphoma development.	('mutant', 'Var', (102, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (141, 149))	('P53', 'Gene', (109, 112))	('protein', 'Protein', (79, 86))	('promote', 'PosReg', (133, 140))	('loss', 'NegReg', (67, 71))	('proteins', 'Protein', (113, 121))	('lymphoma', 'Disease', (141, 149))	('lymphoma', 'Disease', 'MESH:D008223', (141, 149))	('P53 protein', 'Protein', (75, 86))
50144	26806808	This study provides a roadmap for in vivo Cas9 screens and makes genome-scale CRISPR screening feasible using a transplant model with virtually any cell line or genetic background (e.g., mutations in KRAS, CDKN2A, P53, PTEN, etc.).	('P53', 'Gene', (214, 217))	('KRAS', 'Gene', (200, 204))	('mutations', 'Var', (187, 196))	('CDKN2A', 'Gene', '12578', (206, 212))	('CDKN2A', 'Gene', (206, 212))	('PTEN', 'Gene', (219, 223))
50146	26806808	For example, mutant KRAS expression and P53 loss cooperate in the development of undifferentiated pleomorphic sarcomas.	('mutant', 'Var', (13, 19))	('P53', 'Gene', (40, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('loss', 'NegReg', (44, 48))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (81, 118))	('undifferentiated pleomorphic sarcomas', 'Disease', (81, 118))	('KRAS expression', 'Protein', (20, 35))
50151	26806808	In a new mouse model of ARF-/- Emu-myc B-cell lymphoma, CRISPR-Cas9-mediated disruption of p53 conferred cells with resistance to doxorubicin treatment.	('lymphoma', 'Phenotype', 'HP:0002665', (46, 54))	('disruption', 'Var', (77, 87))	('doxorubicin', 'Chemical', 'MESH:D004317', (130, 141))	('ARF', 'Gene', '12578', (24, 27))	('mouse', 'Species', '10090', (9, 14))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '22059', (91, 94))	('ARF', 'Gene', (24, 27))	('lymphoma', 'Disease', (46, 54))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (39, 54))	('conferred', 'Reg', (95, 104))	('lymphoma', 'Disease', 'MESH:D008223', (46, 54))
50156	26806808	Furthermore, the migration and invasion activity was markedly reduced by CDK11 knockout, indicating that CDK11 maybe a novel therapeutic target for osteosarcoma.	('CDK11', 'Gene', (73, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('osteosarcoma', 'Disease', (148, 160))	('osteosarcoma', 'Phenotype', 'HP:0002669', (148, 160))	('knockout', 'Var', (79, 87))	('osteosarcoma', 'Disease', 'MESH:D012516', (148, 160))	('reduced', 'NegReg', (62, 69))
50159	26806808	Overexpression of MDR1 results in an active efflux of anti-cancer agents from cells, thus lowering intracellular drug concentrations and inducing cancer cell resistance to chemotherapeutic drugs, such as doxorubicin and paclitaxel.	('active efflux of', 'MPA', (37, 53))	('MDR1', 'Gene', '18669', (18, 22))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('paclitaxel', 'Chemical', 'MESH:D017239', (220, 230))	('doxorubicin', 'Chemical', 'MESH:D004317', (204, 215))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MDR1', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('intracellular drug concentrations', 'MPA', (99, 132))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('lowering', 'NegReg', (90, 98))	('inducing', 'Reg', (137, 145))
50160	26806808	Similar to targeting CDK11 as described above, the CRISPR-Cas9 system can also be applied to knockout MDR1 in drug resistant sarcoma cells to reverse drug resistance.	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('reverse', 'Reg', (142, 149))	('MDR1', 'Gene', (102, 106))	('sarcoma', 'Disease', (125, 132))	('drug resistance', 'MPA', (150, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('MDR1', 'Gene', '18669', (102, 106))	('drug resistance', 'Phenotype', 'HP:0020174', (150, 165))	('knockout', 'Var', (93, 101))
50169	26806808	To validate this drug-target interaction, CRISPR-Cas9 was adopted to introduce a single XPO1 C528S mutation in acute T cell leukemia Jurkat cells.	('C528S', 'Var', (93, 98))	('leukemia Jurkat', 'CellLine', 'CVCL:0065', (124, 139))	('leukemia', 'Phenotype', 'HP:0001909', (124, 132))	('C528S', 'Mutation', 'p.C528S', (93, 98))	('T cell leukemia', 'Phenotype', 'HP:0005517', (117, 132))	('XPO1', 'Gene', (88, 92))
50170	26806808	As expected, this mutation prevented Selinexor-meditated functional inhibition of XPO1 by blocking XPO1-Selinexor binding.	('XPO1', 'Gene', (82, 86))	('Selinexor', 'Chemical', 'MESH:C585161', (104, 113))	('Selinexor-meditated functional inhibition', 'MPA', (37, 78))	('Selinexor', 'Chemical', 'MESH:C585161', (37, 46))	('blocking', 'NegReg', (90, 98))	('prevented', 'NegReg', (27, 36))	('binding', 'Interaction', (114, 121))	('mutation', 'Var', (18, 26))	('XPO1-Selinexor', 'Protein', (99, 113))
50174	26806808	Sequencing studies and bioinformatics analysis suggest that mutations in the Ala133 residue of KSP may be responsible for ispinesib resistance.	('Ala133', 'Chemical', '-', (77, 83))	('ispinesib', 'Chemical', 'MESH:C508757', (122, 131))	('KSP', 'Gene', (95, 98))	('mutations in', 'Var', (60, 72))	('responsible', 'Reg', (106, 117))	('ispinesib resistance', 'MPA', (122, 142))
50177	26806808	The results showed that the A133P substitution conferred >150-fold resistance to ispinesib, which validated previous results from sequencing and bioinformatics studies.	('ispinesib', 'Chemical', 'MESH:C508757', (81, 90))	('A133P', 'Var', (28, 33))	('conferred', 'Reg', (47, 56))	('A133P', 'Mutation', 'rs373785777', (28, 33))	('resistance to ispinesib', 'MPA', (67, 90))
50179	26806808	Vemurafenib, a therapeutic Braf inhibitor, demonstrated efficacy in some tumors carrying the Braf V600E mutation.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('Braf', 'Gene', (93, 97))	('Braf', 'Gene', '109880', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Braf', 'Gene', '109880', (93, 97))	('tumors', 'Disease', (73, 79))	('Braf', 'Gene', (27, 31))	('V600E', 'Var', (98, 103))
50186	26806808	In addition, paired Cas9 nickases are highly specific in human cells, and can generate two single-stand breaks or nicks on different DNA strands.	('single-stand', 'MPA', (91, 103))	('nickases', 'Var', (25, 33))	('stand breaks', 'Phenotype', 'HP:0003698', (98, 110))	('generate', 'Reg', (78, 86))	('Cas9 nickases', 'Var', (20, 33))	('nicks', 'MPA', (114, 119))	('human', 'Species', '9606', (57, 62))
50192	26806808	In sarcoma, epigenetic abnormalities and genomic mutations are two sides of one coin.	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('genomic mutations', 'Var', (41, 58))	('epigenetic abnormalities', 'Disease', (12, 36))	('epigenetic abnormalities', 'Disease', 'MESH:D000014', (12, 36))	('sarcoma', 'Disease', 'MESH:D012509', (3, 10))	('sarcoma', 'Disease', (3, 10))
50256	31806415	ESOS represents approximately 4% of osteosarcomas and less than 1% of soft tissue sarcomas (STS).	('osteosarcomas', 'Disease', 'MESH:D012516', (36, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('OS', 'Phenotype', 'HP:0002669', (2, 4))	('sarcomas', 'Disease', (41, 49))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (70, 90))	('STS', 'Phenotype', 'HP:0030448', (92, 95))	('ESOS', 'Var', (0, 4))	('osteosarcomas', 'Phenotype', 'HP:0002669', (36, 49))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (70, 89))	('sarcomas', 'Disease', 'MESH:D012509', (82, 90))	('osteosarcoma', 'Phenotype', 'HP:0002669', (36, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('osteosarcomas', 'Disease', (36, 49))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))	('sarcomas', 'Disease', (82, 90))
50269	31806415	Treatment details collected included type of surgery and margin status according to the R classification: R0 - negative margin, no tumor at the inked margin; R1 - microscopically positive margin, tumor present at the inked margin; R2 - grossly positive margin.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('R2 -', 'Var', (231, 235))	('R1 - microscopically', 'Var', (158, 178))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
50424	31423237	The results revealed that the combination of metformin and itraconazole significantly altered the physicochemical and pathohistological characteristics of the hamster fibrosarcoma tumors, including absolute and relative weight, volume, density, length, surface area, surface to volume ratio, Ki-67-positivity and the immunoexpression of cytoplasmic markers, without indications of toxicity.	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('altered', 'Reg', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('surface to volume ratio', 'CPA', (267, 290))	('surface area', 'CPA', (253, 265))	('toxicity', 'Disease', (381, 389))	('itraconazole', 'Chemical', 'MESH:D017964', (59, 71))	('toxicity', 'Disease', 'MESH:D064420', (381, 389))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('Ki-67-positivity', 'Var', (292, 308))	('hamster fibrosarcoma tumors', 'Disease', 'MESH:D005354', (159, 186))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (167, 179))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('Ki-67', 'Chemical', '-', (292, 297))	('hamster fibrosarcoma tumors', 'Disease', (159, 186))
50429	31423237	Notably, metformin exerts anticancer effects in vitro via the following main mechanisms: Inhibition of AMP-activated protein kinase (AMPK)/serine/threonine- protein kinase mTOR signaling, anti-angiogenesis, or folate and autophagy inhibition.	('Inhibition', 'NegReg', (89, 99))	('mTOR', 'Gene', (172, 176))	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('anti-angiogenesis', 'CPA', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('folate', 'Chemical', 'MESH:D005492', (210, 216))	('AMPK', 'Gene', '5564', (133, 137))	('folate', 'CPA', (210, 216))	('AMPK', 'Gene', (133, 137))	('mTOR', 'Gene', '2475', (172, 176))	('AMP-activated protein kinase', 'Gene', '5564', (103, 131))	('AMP-activated protein kinase', 'Gene', (103, 131))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('metformin', 'Var', (9, 18))	('autophagy inhibition', 'CPA', (221, 241))
50435	31423237	The in vitro anticancer functions of itraconazole in cancer cell cultures include the following: Inhibition of AMPK/mTOR signaling, anti-angiogenesis, antilymphangiogenesis, folate and autophagy inhibition, inhibition of Hedgehog signaling, inhibition of P-glycoprotein (P-gp), chemosensitization (reversed multiple drug resistance, particularly to cytotoxic antitumor drugs), inhibition of the transportation and pumping of cholesterol, and inhibition of the Wnt/beta-catenin signaling pathway.	('P-glycoprotein', 'Gene', '5243', (255, 269))	('antilymphangiogenesis', 'CPA', (151, 172))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Hedgehog', 'Protein', (221, 229))	('inhibition', 'Var', (241, 251))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('cancer', 'Disease', (17, 23))	('mTOR', 'Gene', '2475', (116, 120))	('anti-angiogenesis', 'CPA', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('inhibition', 'NegReg', (442, 452))	('P-gp', 'Gene', (271, 275))	('pumping of cholesterol', 'MPA', (414, 436))	('inhibition', 'NegReg', (195, 205))	('folate', 'CPA', (174, 180))	('transportation', 'MPA', (395, 409))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (363, 368))	('inhibition', 'NegReg', (377, 387))	('AMPK', 'Gene', (111, 115))	('autophagy', 'CPA', (185, 194))	('P-gp', 'Gene', '5243', (271, 275))	('AMPK', 'Gene', '5564', (111, 115))	('beta-catenin', 'Gene', (464, 476))	('folate', 'Chemical', 'MESH:D005492', (174, 180))	('P-glycoprotein', 'Gene', (255, 269))	('drug resistance', 'Phenotype', 'HP:0020174', (316, 331))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('beta-catenin', 'Gene', '1499', (464, 476))	('cholesterol', 'Chemical', 'MESH:D002784', (425, 436))	('mTOR', 'Gene', (116, 120))	('itraconazole', 'Chemical', 'MESH:D017964', (37, 49))
50443	31423237	Organic cation transporters 1 and 3 are active transporters of metformin; therefore, as a potent P-gp and CYP3A4 inhibitor, itraconazole can increase the plasma concentrations of P-gp and CYP3A4 substrates, including metformin, and enhance their effects.	('CYP3A4', 'Gene', (106, 112))	('itraconazole', 'Var', (124, 136))	('increase', 'PosReg', (141, 149))	('CYP3A4', 'Gene', (188, 194))	('P-gp', 'Gene', (179, 183))	('plasma concentrations', 'MPA', (154, 175))	('CYP3A4', 'Gene', '1576', (106, 112))	('itraconazole', 'Chemical', 'MESH:D017964', (124, 136))	('CYP3A4', 'Gene', '1576', (188, 194))	('P-gp', 'Gene', '5243', (97, 101))	('metformin', 'MPA', (217, 226))	('metformin', 'Chemical', 'MESH:D008687', (63, 72))	('metformin', 'Chemical', 'MESH:D008687', (217, 226))	('enhance', 'PosReg', (232, 239))	('Organic cation transporters 1 and 3', 'Gene', '6580;100049579', (0, 35))	('P-gp', 'Gene', '5243', (179, 183))	('P-gp', 'Gene', (97, 101))	('effects', 'MPA', (246, 253))
50527	31423237	Perioral co-treatment with metformin and itraconazole significantly inhibited tumor growth at 2 and 3 weeks, as indicated by significant decreases in tumor weight, relative weight, volume, density, length, surface area and S/V ratio, as well as by the decreased proliferation status of tumor cells, as demonstrated by Ki-67 staining of the hamster tumor sections at 2 and 3 weeks (Tables II and III; Figs.	('proliferation status', 'CPA', (262, 282))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('volume', 'CPA', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('density', 'CPA', (189, 196))	('itraconazole', 'Var', (41, 53))	('itraconazole', 'Chemical', 'MESH:D017964', (41, 53))	('inhibited', 'NegReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('decreases', 'NegReg', (137, 146))	('metformin', 'Chemical', 'MESH:D008687', (27, 36))	('surface', 'MPA', (206, 213))	('relative weight', 'CPA', (164, 179))	('hamster tumor', 'Disease', (340, 353))	('tumor', 'Disease', (286, 291))	('tumor', 'Disease', (78, 83))	('S/V ratio', 'MPA', (223, 232))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Disease', (150, 155))	('decreased', 'NegReg', (252, 261))	('Ki-67', 'Chemical', '-', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('hamster tumor', 'Disease', 'MESH:D009369', (340, 353))	('tumor', 'Disease', (348, 353))
50539	31423237	The combination of metformin and itraconazole in the present study resulted in reductions in fibrosarcoma tumor weight, relative weight, volume, density, length, surface area, S/V ratio, proliferation, vasculature and tissue penetration.	('fibrosarcoma tumor', 'Disease', (93, 111))	('tissue penetration', 'CPA', (218, 236))	('fibrosarcoma tumor', 'Disease', 'MESH:D005354', (93, 111))	('relative weight', 'CPA', (120, 135))	('metformin', 'Chemical', 'MESH:D008687', (19, 28))	('itraconazole', 'Var', (33, 45))	('density', 'CPA', (145, 152))	('S/V ratio', 'MPA', (176, 185))	('combination', 'Interaction', (4, 15))	('itraconazole', 'Chemical', 'MESH:D017964', (33, 45))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (93, 105))	('surface area', 'CPA', (162, 174))	('volume', 'CPA', (137, 143))	('reductions', 'NegReg', (79, 89))	('proliferation', 'CPA', (187, 200))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('vasculature', 'CPA', (202, 213))	('length', 'CPA', (154, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
50615	30916474	Among patients with a simple genetic alteration, translocation alterations were more frequent in long-term survivors (90% vs 65%), as well as activating mutation (5% vs 0.7%, respectively); in contrast to amplification (5% vs 31%) and inactivating mutation (0% vs 2%; P = 0.017).	('translocation alterations', 'Var', (49, 74))	('patients', 'Species', '9606', (6, 14))	('activating mutation', 'Var', (142, 161))
50626	30916474	We observed that 23 patients alive at 5 years (59%) were enrolled in a clinical trial in metastatic setting (NCT01771458, NCT01494688, NCT00796120, NCT00410462, ET-743, EORTC 62043, PALETTE - VEG110727, PALSAR, EORTC 62043, BP29428, EORTC-62012, AP23573 - ARIAD, SUCCEED, REGO-SARC1214, IMCLONE CP13-0707, NP27872, EFC 10145).	('ET-743', 'Var', (161, 167))	('CP13-0707', 'Var', (295, 304))	('NCT01771458', 'Var', (109, 120))	('ARIAD', 'Disease', 'None', (256, 261))	('BP29428', 'Var', (224, 231))	('NCT00410462', 'Var', (148, 159))	('NCT01494688', 'Var', (122, 133))	('EORTC-62012', 'Var', (233, 244))	('NP27872', 'Var', (306, 313))	('patients', 'Species', '9606', (20, 28))	('ARIAD', 'Disease', (256, 261))	('NCT00796120', 'Var', (135, 146))
50647	30916474	Also, we noted a significant predominance of simple genomic sarcoma in long-term survivor (54%) and, more specifically, of translocation-related sarcoma (90%) especially SSX-SS18 or JAZF1 fusion transcript, consistently with frequent synovial sarcomas and endometrial stromal sarcomas.	('SS18', 'Gene', '6760', (174, 178))	('endometrial stromal sarcomas', 'Disease', (256, 284))	('sarcoma', 'Disease', 'MESH:D012509', (276, 283))	('sarcoma', 'Disease', (276, 283))	('synovial sarcomas', 'Disease', 'MESH:D013584', (234, 251))	('sarcomas', 'Phenotype', 'HP:0100242', (276, 284))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (234, 250))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Disease', 'MESH:D012509', (243, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('sarcoma', 'Disease', (243, 250))	('sarcomas', 'Phenotype', 'HP:0100242', (243, 251))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('sarcoma', 'Disease', (145, 152))	('SS18', 'Gene', (174, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('fusion transcript', 'Var', (188, 205))	('JAZF1', 'Gene', '221895', (182, 187))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (234, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('synovial sarcomas', 'Disease', (234, 251))	('JAZF1', 'Gene', (182, 187))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (256, 284))
50658	30916474	However, these combinations improved PFS and tumor response, a clinically important outcome in patient with locally advanced and symptomatic STS inoperable in first intention, but whose tumor could be resectable after sufficient size reduction.4, 15, 16 Histology is also associated with polychemotherapy efficacy.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patient', 'Species', '9606', (95, 102))	('PFS', 'CPA', (37, 40))	('improved', 'PosReg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('combinations', 'Var', (15, 27))
50694	27012530	In transplant recipients nonmalignant pathologic events as cytopenias and acute hepatitis syndromes can be provoked by KSHV.	('acute hepatitis', 'Phenotype', 'HP:0200119', (74, 89))	('hepatitis', 'Phenotype', 'HP:0012115', (80, 89))	('hepatitis syndromes', 'Disease', 'MESH:D056486', (80, 99))	('cytopenias', 'Disease', 'MESH:D006402', (59, 69))	('hepatitis syndromes', 'Disease', (80, 99))	('cytopenias', 'Disease', (59, 69))	('KSHV', 'Species', '37296', (119, 123))	('KSHV', 'Var', (119, 123))	('KS', 'Phenotype', 'HP:0100726', (119, 121))
50718	27012530	Treatment continued with low-dose BEAM (bis-chloroethylnitrosourea 60 mg/m2 on day 1, etoposide 15 mg/m2 on day 2,3,4 and 5, cytarabine 2 x 100 mg/m2 on day 2,3,4 and 5, and melphalan 30 mg/m2 on day 6) followed by autologous stem cell rescue, resulting in a partial response.	('etoposide', 'Chemical', 'MESH:D005047', (86, 95))	('bis-chloroethylnitrosourea', 'Chemical', '-', (40, 66))	('autologous stem cell rescue', 'CPA', (215, 242))	('melphalan', 'Chemical', 'MESH:D008558', (174, 183))	('men', 'Species', '9606', (5, 8))	('cytarabine', 'Chemical', 'MESH:D003561', (125, 135))	('bis-chloroethylnitrosourea', 'Var', (40, 66))
50809	31537896	Expanding the spectrum of dicer1-associated sarcomas DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations.	('DICER1', 'Gene', (147, 153))	('DICER1', 'Gene', '23405', (147, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('hereditary cancer predisposition syndrome', 'Disease', (74, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('caused by', 'Reg', (116, 125))	('hereditary cancer predisposition syndrome', 'Disease', 'MESH:D061325', (74, 115))	('DICER1', 'Gene', (53, 59))	('dicer1', 'Gene', '23405', (26, 32))	('sarcomas', 'Disease', 'MESH:D012509', (44, 52))	('mutations', 'Var', (154, 163))	('DICER1', 'Gene', '23405', (53, 59))	('sarcomas', 'Disease', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('dicer1', 'Gene', (26, 32))
50816	31537896	In addition to expanding the phenotypic spectrum of DICER1-associated conditions, identification of pathogenic DICER1 variants facilitates optimized genetic counseling, caregiver education and judicious imaging-based surveillance.	('DICER1', 'Gene', (52, 58))	('DICER1', 'Gene', (111, 117))	('DICER1', 'Gene', '23405', (111, 117))	('DICER1', 'Gene', '23405', (52, 58))	('variants', 'Var', (118, 126))
50818	31537896	Dysregulation of miRNA by DICER1 mutations causes activation of oncogenes.	('DICER1', 'Gene', '23405', (26, 32))	('miRNA', 'MPA', (17, 22))	('activation', 'PosReg', (50, 60))	('mutations', 'Var', (33, 42))	('Dysregulation', 'MPA', (0, 13))	('DICER1', 'Gene', (26, 32))	('oncogenes', 'CPA', (64, 73))
50819	31537896	Characteristic "hotspot" somatic mutations (E1705, E1813, D1709, D1810, or G1809) at the four metal-binding sites of the RNase IIIb domain that affect the catalytic activity of DICER1 have been identified in DICER1-associated tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('G1809', 'Var', (75, 80))	('E1705', 'Var', (44, 49))	('D1810', 'Var', (65, 70))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('DICER1', 'Gene', (177, 183))	('DICER1', 'Gene', (208, 214))	('DICER1', 'Gene', '23405', (208, 214))	('metal', 'Chemical', 'MESH:D008670', (94, 99))	('D1709', 'Var', (58, 63))	('DICER1', 'Gene', '23405', (177, 183))	('affect', 'Reg', (144, 150))	('E1813', 'Var', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('catalytic activity', 'MPA', (155, 173))
50820	31537896	In addition, DICER1 mosaicism may occur as a result of postzygotic acquisition of a de novo mutation and can result in two genetically distinct populations of cells.	('mosaicism', 'Var', (20, 29))	('DICER1', 'Gene', '23405', (13, 19))	('mutation', 'Var', (92, 100))	('result in', 'Reg', (109, 118))	('DICER1', 'Gene', (13, 19))
50827	31537896	performed a similar study and identified DICER1 somatic mutations in the RNase IIIb domain in 14/197 nonepithelial tumors, including 9/28 sex cord-stromal tumors, 5/118 gonadal germ cell tumors, and 0/43 extragonadal germ cell tumors.	('RNase', 'Gene', (73, 78))	('germ cell tumor', 'Phenotype', 'HP:0100728', (217, 232))	('germ cell tumors', 'Phenotype', 'HP:0100728', (217, 233))	('germ cell tumor', 'Phenotype', 'HP:0100728', (177, 192))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (138, 161))	('germ cell tumors', 'Phenotype', 'HP:0100728', (177, 193))	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('DICER1', 'Gene', '23405', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', (187, 193))	('cord-stromal tumors', 'Disease', 'MESH:D018312', (142, 161))	('DICER1', 'Gene', (41, 47))	('cord-stromal tumors', 'Disease', (142, 161))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (187, 193))
50833	31537896	Our aims in the present study are to expand the phenotypic spectrum of DICER1-associated sarcomas and to highlight the importance of detailed molecular profiling in determining the true association of a condition with DICER1 mutation.	('sarcomas', 'Disease', (89, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('DICER1', 'Gene', (218, 224))	('DICER1', 'Gene', (71, 77))	('DICER1', 'Gene', '23405', (71, 77))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('DICER1', 'Gene', '23405', (218, 224))	('mutation', 'Var', (225, 233))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
50886	31537896	1A7, 1C6) positivity supported rhabdomyoblastic differentiation in all three patients.	('supported', 'Reg', (21, 30))	('rhabdomyoblastic differentiation', 'Disease', 'MESH:D012734', (31, 63))	('positivity', 'Var', (10, 20))	('patients', 'Species', '9606', (77, 85))	('rhabdomyoblastic differentiation', 'Disease', (31, 63))
50890	31537896	Two DICER1 variants of strong clinical significance were identified in this patient's tumor specimen; a DICER1 c.2223_2230del (p.Ser742Thrfs*16) frameshift inactivating mutation and a DICER1 c.5425G>A (p.Gly1809Arg) missense mutation; confirming the diagnosis of a DICER1-associated sarcoma.	('c.5425G>A (p.Gly1809Arg', 'Var', (191, 214))	('c.5425G>A', 'Mutation', 'c.5425G>A', (191, 200))	('sarcoma', 'Disease', 'MESH:D012509', (283, 290))	('sarcoma', 'Disease', (283, 290))	('c.2223_2230del', 'Var', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('frameshift', 'Var', (145, 155))	('c.2223_2230del', 'Mutation', 'c.2223_2230del', (111, 125))	('DICER1', 'Gene', '23405', (4, 10))	('DICER1', 'Gene', '23405', (184, 190))	('DICER1', 'Gene', '23405', (265, 271))	('sarcoma', 'Phenotype', 'HP:0100242', (283, 290))	('DICER1', 'Gene', (4, 10))	('DICER1', 'Gene', (184, 190))	('DICER1', 'Gene', (265, 271))	('DICER1', 'Gene', '23405', (104, 110))	('p.Ser742Thrfs*16', 'FRAMESHIFT', 'None', (127, 143))	('p.Ser742Thrfs*16', 'Var', (127, 143))	('DICER1', 'Gene', (104, 110))	('tumor', 'Disease', (86, 91))	('patient', 'Species', '9606', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('p.Gly1809Arg', 'Mutation', 'p.G1809R', (202, 214))
50891	31537896	Sanger sequencing for these two DICER1 mutations performed on the peripheral blood revealed that the patient was heterozygous for the DICER1 c.2223_2230del (p.Ser742Thrfs*16) frameshift mutation.	('c.2223_2230del', 'Mutation', 'c.2223_2230del', (141, 155))	('DICER1', 'Gene', (32, 38))	('DICER1', 'Gene', '23405', (32, 38))	('p.Ser742Thrfs*16', 'FRAMESHIFT', 'None', (157, 173))	('DICER1', 'Gene', (134, 140))	('patient', 'Species', '9606', (101, 108))	('p.Ser742Thrfs*16', 'Var', (157, 173))	('DICER1', 'Gene', '23405', (134, 140))
50893	31537896	Two DICER1 variants of strong clinical significance were detected in the tumor at similar variant allele frequencies:a DICER1 c.3682C>T (p.Gln1228Ter) nonsense mutation and a hotspot DICER1 c.5428G>T (p.Asp1810Tyr) missense mutation; confirming the diagnosis of a DICER1-associated sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('c.3682C>T', 'Mutation', 'c.3682C>T', (126, 135))	('DICER1', 'Gene', '23405', (4, 10))	('p.Asp1810Tyr', 'Mutation', 'p.D1810Y', (201, 213))	('p.Gln1228Ter', 'Mutation', 'p.Q1228X', (137, 149))	('sarcoma', 'Disease', 'MESH:D012509', (282, 289))	('DICER1', 'Gene', (4, 10))	('c.5428G>T', 'Var', (190, 199))	('sarcoma', 'Disease', (282, 289))	('DICER1', 'Gene', '23405', (183, 189))	('DICER1', 'Gene', '23405', (264, 270))	('tumor', 'Disease', (73, 78))	('c.3682C>T', 'Var', (126, 135))	('DICER1', 'Gene', '23405', (119, 125))	('c.5428G>T', 'Mutation', 'c.5428G>T', (190, 199))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('DICER1', 'Gene', (264, 270))	('DICER1', 'Gene', (183, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('DICER1', 'Gene', (119, 125))
50894	31537896	In addition, an activating missense mutation was identified in the NRAS proto-oncogene:NRAS c.181C>A (p.Gln61Lys).	('c.181C>A', 'Mutation', 'rs121913254', (92, 100))	('NRAS', 'Gene', '4893', (87, 91))	('NRAS', 'Gene', (67, 71))	('c.181C>A', 'Var', (92, 100))	('p.Gln61Lys', 'Mutation', 'rs121913254', (102, 112))	('NRAS', 'Gene', '4893', (67, 71))	('activating', 'PosReg', (16, 26))	('NRAS', 'Gene', (87, 91))
50896	31537896	The tumor specimen contained a DICER1 c.5439G>C (p.Glu1813Asp) frameshift inactivating mutation of strong clinical significance, with 97% variant allele frequency.	('tumor', 'Disease', (4, 9))	('DICER1', 'Gene', (31, 37))	('DICER1', 'Gene', '23405', (31, 37))	('c.5439G>C', 'Var', (38, 47))	('p.Glu1813Asp', 'Mutation', 'p.E1813D', (49, 61))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('c.5439G>C', 'Mutation', 'c.5439G>C', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
50897	31537896	In addition, variants of unknown clinical significance were observed in GLI2, IGF1R, and TSC2.	('TSC2', 'Gene', '7249', (89, 93))	('variants', 'Var', (13, 21))	('TSC2', 'Gene', (89, 93))	('GLI2', 'Gene', (72, 76))	('IGF1R', 'Gene', (78, 83))	('GLI2', 'Gene', '2736', (72, 76))	('IGF1R', 'Gene', '3480', (78, 83))
50898	31537896	Chromosomal microarray from this tumor specimen demonstrated a variety of copy number alterations and regional loss of heterozygosity.	('copy number alterations', 'Var', (74, 97))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('loss of', 'NegReg', (111, 118))	('tumor', 'Disease', (33, 38))
50900	31537896	A key finding was a deletion of the distal long arm of chromosome 14 that includes the DICER1 gene.	('DICER1', 'Gene', '23405', (87, 93))	('deletion', 'Var', (20, 28))	('DICER1', 'Gene', (87, 93))
50902	31537896	The molecular and cytogenetic findings affecting DICER1 may be the result of a heterozygous germline DICER1 c.5439 (p.Glu1813Asp) variant followed by somatic deletion affecting the wild-type DICER1 allele; highly suggestive of the diagnosis of a DICER1 -associated sarcoma.	('result', 'Reg', (67, 73))	('sarcoma', 'Disease', (265, 272))	('DICER1', 'Gene', (49, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('p.Glu1813Asp', 'Mutation', 'p.E1813D', (116, 128))	('DICER1', 'Gene', (191, 197))	('DICER1', 'Gene', '23405', (49, 55))	('DICER1', 'Gene', (246, 252))	('DICER1', 'Gene', (101, 107))	('DICER1', 'Gene', '23405', (101, 107))	('DICER1', 'Gene', '23405', (191, 197))	('DICER1', 'Gene', '23405', (246, 252))	('sarcoma', 'Disease', 'MESH:D012509', (265, 272))	('c.5439 (p.Glu1813Asp', 'Var', (108, 128))
50908	31537896	Pathogenic germline DICER1 variants or characteristic somatic "hotspot" mutations are key mutational events in DICER1-associated tumorigenesis.	('variants', 'Var', (27, 35))	('DICER1', 'Gene', (111, 117))	('DICER1', 'Gene', '23405', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('DICER1', 'Gene', (20, 26))	('DICER1', 'Gene', '23405', (20, 26))
50909	31537896	Patients with germline or mosaic DICER1 gene mutations are at an increased risk of developing a range of childhood-, adolescent, and young adult-onset tumors, infrequently including sarcomas like genitourinary embryonal rhabdomyosarcoma of the bladder or uterine cervix and anaplastic sarcoma of the kidney.	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (220, 236))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (285, 306))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('anaplastic sarcoma of the kidney', 'Disease', 'MESH:D012509', (274, 306))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('mosaic', 'Var', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('tumors', 'Disease', (151, 157))	('sarcomas', 'Disease', (182, 190))	('Patients', 'Species', '9606', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('DICER1', 'Gene', '23405', (33, 39))	('childhood-', 'Disease', (105, 115))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (210, 236))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('DICER1', 'Gene', (33, 39))	('germline', 'Var', (14, 22))	('mutations', 'Var', (45, 54))	('embryonal rhabdomyosarcoma of the bladder', 'Disease', 'MESH:D001745', (210, 251))	('anaplastic sarcoma of the kidney', 'Disease', (274, 306))	('embryonal rhabdomyosarcoma of the bladder', 'Disease', (210, 251))	('uterine cervix', 'Phenotype', 'HP:0030160', (255, 269))
50924	31537896	There were no confirmed associations reported between DICER1 mutation and alveolar rhabdomyosarcoma in the literature.	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (74, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('mutation', 'Var', (61, 69))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (83, 99))	('alveolar rhabdomyosarcoma', 'Disease', (74, 99))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (74, 99))	('DICER1', 'Gene', (54, 60))	('DICER1', 'Gene', '23405', (54, 60))
50926	31537896	The histologic patterns of DICER1-associated sarcomas in this report strongly resembles that of pleuropulmonary blastoma, more than 70% of which are associated with an underlying DICER1 mutation.	('DICER1', 'Gene', (27, 33))	('pleuropulmonary blastoma', 'Disease', (96, 120))	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('DICER1', 'Gene', (179, 185))	('DICER1', 'Gene', '23405', (179, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('DICER1', 'Gene', '23405', (27, 33))	('sarcomas', 'Disease', (45, 53))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (96, 120))	('associated', 'Reg', (149, 159))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (96, 120))	('mutation', 'Var', (186, 194))
50934	31537896	In our literature review (Supplementary Table 2), all patients had either somatic (n = 51), germline (n = 15), or both (n = 20) DICER1 mutations reported.	('DICER1', 'Gene', '23405', (128, 134))	('DICER1', 'Gene', (128, 134))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (135, 144))
50935	31537896	In our review, frequently reported additional genomic alterations include TP53 (n = 22), KRAS (n = 11), NRAS (n = 5), and NF1 (n = 9) mutations (Supplementary Table 2).	('NRAS', 'Gene', '4893', (104, 108))	('TP53', 'Gene', '7157', (74, 78))	('NF1', 'Gene', (122, 125))	('mutations', 'Var', (134, 143))	('NRAS', 'Gene', (104, 108))	('NF1', 'Gene', '4763', (122, 125))	('KRAS', 'Gene', (89, 93))	('TP53', 'Gene', (74, 78))	('KRAS', 'Gene', '3845', (89, 93))
50936	31537896	Exome sequencing of pleuropulmonary blastoma has previously demonstrated frequent biallelic loss of TP53 and some cases with mutations of NRAS or BRAF in addition to the mutation(s) in the DICER1 gene.	('mutations', 'Var', (125, 134))	('BRAF', 'Gene', (146, 150))	('TP53', 'Gene', '7157', (100, 104))	('NRAS', 'Gene', '4893', (138, 142))	('DICER1', 'Gene', (189, 195))	('TP53', 'Gene', (100, 104))	('DICER1', 'Gene', '23405', (189, 195))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (20, 44))	('loss', 'NegReg', (92, 96))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (20, 44))	('BRAF', 'Gene', '673', (146, 150))	('pleuropulmonary blastoma', 'Disease', (20, 44))	('NRAS', 'Gene', (138, 142))
50937	31537896	Copy number changes in critical genomic regions including PTEN, ATM, and WT1 are also common.	('ATM', 'Gene', '472', (64, 67))	('PTEN', 'Gene', '5728', (58, 62))	('Copy number changes', 'Var', (0, 19))	('ATM', 'Gene', (64, 67))	('WT1', 'Gene', '7490', (73, 76))	('WT1', 'Gene', (73, 76))	('PTEN', 'Gene', (58, 62))
50938	31537896	Identification of pathogenic somatic, germline, and mosaic mutations in the DICER1 gene is imperative to discern the true causality of DICER1-associated conditions.	('pathogenic', 'Reg', (18, 28))	('DICER1', 'Gene', (76, 82))	('DICER1', 'Gene', (135, 141))	('DICER1', 'Gene', '23405', (76, 82))	('DICER1', 'Gene', '23405', (135, 141))	('mosaic mutations', 'Var', (52, 68))
50940	31537896	Subsequently, extensive molecular profiling demonstrated a somatic hotspot mutation in exon 25 (c.5438A>G, p.E1813G) and a frameshift mutation in exon 15 (c.2392_2393insA, p.T798Nfs*33) DICER1 mutation in the pleuropulmonary blastoma tumor tissue and none in the atypical choroid plexus papilloma tumor tissue or in normal lung tissue.	('p.T798Nfs*33', 'Mutation', 'rs886037690', (172, 184))	('choroid plexus papilloma', 'Phenotype', 'HP:0200022', (272, 296))	('choroid plexus papilloma tumor', 'Disease', 'MESH:D020288', (272, 302))	('c.5438A>G', 'Var', (96, 105))	('DICER1', 'Gene', '23405', (186, 192))	('c.2392_2393insA', 'Mutation', 'rs886037690', (155, 170))	('DICER1', 'Gene', (186, 192))	('p.E1813G', 'Var', (107, 115))	('c.5438A>G', 'Mutation', 'c.5438A>G', (96, 105))	('choroid plexus papilloma tumor', 'Disease', (272, 302))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (209, 233))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('pleuropulmonary blastoma tumor', 'Disease', 'MESH:C537516', (209, 239))	('p.E1813G', 'Mutation', 'p.E1813G', (107, 115))	('pleuropulmonary blastoma tumor', 'Disease', (209, 239))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('c.2392_2393insA', 'Var', (155, 170))	('p.T798Nfs*33', 'Var', (172, 184))	('hotspot', 'PosReg', (67, 74))	('papilloma', 'Phenotype', 'HP:0012740', (287, 296))
50941	31537896	Whole exome sequencing demonstrated a pathogenic variant in c.263dupT, p.(I88*fs) in SBDS, which is unlikely to be a plausible cause for the atypical choroid plexus papilloma.	('c.263dupT', 'Mutation', 'c.263dupT', (60, 69))	('SBDS', 'Gene', (85, 89))	('SBDS', 'Gene', '51119', (85, 89))	('p.(I88*', 'SUBSTITUTION', 'None', (71, 78))	('papilloma', 'Phenotype', 'HP:0012740', (165, 174))	('c.263dupT', 'Var', (60, 69))	('choroid plexus papilloma', 'Phenotype', 'HP:0200022', (150, 174))	('pathogenic', 'Reg', (38, 48))	('choroid plexus papilloma', 'Disease', (150, 174))	('choroid plexus papilloma', 'Disease', 'MESH:D020288', (150, 174))
50946	31537896	Given that DICER1 mutations underlie the genetic basis of only a small fraction of sarcomas, identification of this unique histologic pattern should raise the suspicion for the presence of a pathogenic DICER1 mutation(s), warranting a detailed review of the family history and DICER1 mutation analysis.	('DICER1', 'Gene', (202, 208))	('DICER1', 'Gene', '23405', (202, 208))	('DICER1', 'Gene', (11, 17))	('DICER1', 'Gene', '23405', (11, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('pathogenic', 'Reg', (191, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcomas', 'Disease', (83, 91))	('mutation', 'Var', (209, 217))	('DICER1', 'Gene', (277, 283))	('DICER1', 'Gene', '23405', (277, 283))	('sarcomas', 'Disease', 'MESH:D012509', (83, 91))	('mutations', 'Var', (18, 27))
50947	31537896	Identification of pathogenic DICER1 variants would facilitate optimized genetic counseling and germline testing, individual and caregiver education, and judicious imaging-based surveillance.	('pathogenic', 'Reg', (18, 28))	('DICER1', 'Gene', (29, 35))	('DICER1', 'Gene', '23405', (29, 35))	('variants', 'Var', (36, 44))
50950	24842792	Genetic and epigenetic evidences link aberrant activation of the Wnt signaling to growth and progression of human sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('aberrant', 'Var', (38, 46))	('activation', 'PosReg', (47, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', (114, 122))	('Wnt signaling', 'Pathway', (65, 78))	('human', 'Species', '9606', (108, 113))
50958	24842792	Deregulated Wnt signaling has been associated with a variety of human pathologies affecting different cell types and tissues including several types of cancer, diseases of the central nervous system and of the bone.	('human', 'Species', '9606', (64, 69))	('Wnt signaling', 'Pathway', (12, 25))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Deregulated', 'Var', (0, 11))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('diseases of the central nervous system', 'Disease', 'MESH:D002493', (160, 198))	('diseases of the central nervous system', 'Disease', (160, 198))
50965	24842792	Specifically, canonical Wnt pathway activation in osteosarcoma and in other soft tissue sarcomas (STS) has been described involving mutations and/or altered expression levels of key pathway regulators (autocrine activation).	('expression levels', 'MPA', (157, 174))	('sarcomas', 'Disease', (88, 96))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (76, 96))	('altered', 'Reg', (149, 156))	('mutations', 'Var', (132, 141))	('STS', 'Phenotype', 'HP:0030448', (98, 101))	('activation', 'PosReg', (36, 46))	('canonical Wnt pathway', 'Pathway', (14, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('osteosarcoma', 'Disease', (50, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('osteosarcoma', 'Disease', 'MESH:D012516', (50, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
50967	24842792	Consistent with a role in these tumors, reduction of in vitro and in vivo tumor growth and metastasis in osteosarcoma and fibrosarcoma respectively was achieved through ectopic expression of negative secreted modulators of the canonical Wnt pathway, such as of Wnt inhibitory factor 1 (WIF1) and the secreted Frizzled-related protein 3 (sFRP3).	('WIF1', 'Gene', (286, 290))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (74, 79))	('fibrosarcoma', 'Disease', 'MESH:D005354', (122, 134))	('tumors', 'Disease', (32, 38))	('secreted Frizzled-related protein 3', 'Gene', (300, 335))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('secreted Frizzled-related protein 3', 'Gene', '2487', (300, 335))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('fibrosarcoma', 'Disease', (122, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('Wnt inhibitory factor 1', 'Gene', (261, 284))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('Wnt inhibitory factor 1', 'Gene', '11197', (261, 284))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('sFRP3', 'Gene', (337, 342))	('ectopic expression', 'Var', (169, 187))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('metastasis', 'CPA', (91, 101))	('tumor', 'Disease', (32, 37))	('sFRP3', 'Gene', '2487', (337, 342))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('reduction', 'NegReg', (40, 49))	('WIF1', 'Gene', '11197', (286, 290))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (122, 134))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('canonical Wnt pathway', 'Pathway', (227, 248))
50973	24842792	Using U2OS cells as a model, SEN461 treatment resulted in decreased Wnt transcriptional signaling activity, modulation of well reported Wnt target genes (AXIN2 and CDC25A), Axin1 stabilization and increased amount of phosphorylated beta-catenin associated with Axin1 within the destruction complex.	('Wnt', 'Pathway', (68, 71))	('AXIN2', 'Gene', (154, 159))	('AXIN2', 'Gene', '8313', (154, 159))	('Axin1', 'Gene', '8312', (173, 178))	('U2OS', 'CellLine', 'CVCL:0042', (6, 10))	('decreased', 'NegReg', (58, 67))	('SEN461', 'Chemical', '-', (29, 35))	('increased', 'PosReg', (197, 206))	('beta-catenin', 'Gene', (232, 244))	('stabilization', 'MPA', (179, 192))	('CDC25A', 'Gene', (164, 170))	('SEN461', 'Var', (29, 35))	('modulation', 'MPA', (108, 118))	('Axin1', 'Gene', (261, 266))	('CDC25A', 'Gene', '993', (164, 170))	('Axin1', 'Gene', (173, 178))	('beta-catenin', 'Gene', '1499', (232, 244))	('Axin1', 'Gene', '8312', (261, 266))
50975	24842792	In the fibrosarcoma cell line HT-1080, the acute stabilization of the Axin1 protein, sustained by SEN461 treatment, negatively impacts the expression of the proto-oncoprotein c-Myc, an important mediator of sarcoma growth, in vitro and in vivo.	('SEN461', 'Chemical', '-', (98, 104))	('Axin1', 'Gene', '8312', (70, 75))	('c-Myc', 'Gene', '4609', (175, 180))	('SEN461', 'Var', (98, 104))	('negatively impacts', 'NegReg', (116, 134))	('sarcoma growth', 'Disease', (207, 221))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (7, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('Axin1', 'Gene', (70, 75))	('fibrosarcoma', 'Disease', (7, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('HT-1080', 'CellLine', 'CVCL:0317', (30, 37))	('expression', 'MPA', (139, 149))	('stabilization', 'MPA', (49, 62))	('sarcoma growth', 'Disease', 'MESH:D006130', (207, 221))	('c-Myc', 'Gene', (175, 180))	('fibrosarcoma', 'Disease', 'MESH:D005354', (7, 19))
51023	24842792	When U2OS cells, transiently transfected with GFP-tagged Axin1, were stimulated with Wnt3a exogenously provided in conditioned medium (Wnt3a-CM) containing SEN461, an increase in the amount of phosphorylated beta-catenin associated with Axin1 was observed (Figure 1C and 1D).	('GFP-tagged', 'Var', (46, 56))	('increase', 'PosReg', (167, 175))	('Axin1', 'Gene', (237, 242))	('Axin1', 'Gene', '8312', (57, 62))	('beta-catenin', 'Gene', (208, 220))	('SEN461', 'Var', (156, 162))	('beta-catenin', 'Gene', '1499', (208, 220))	('SEN461', 'Chemical', '-', (156, 162))	('Axin1', 'Gene', '8312', (237, 242))	('U2OS', 'CellLine', 'CVCL:0042', (5, 9))	('Axin1', 'Gene', (57, 62))
51025	24842792	Moreover, the mRNA levels for the Wnt/beta-catenin target gene AXIN2, induced by Wnt3a CM, was inhibited by SEN461 treatment (Figure 1E).	('beta-catenin', 'Gene', (38, 50))	('Wnt3a CM', 'Var', (81, 89))	('AXIN2', 'Gene', (63, 68))	('inhibited', 'NegReg', (95, 104))	('AXIN2', 'Gene', '8313', (63, 68))	('beta-catenin', 'Gene', '1499', (38, 50))	('mRNA levels for the', 'MPA', (14, 33))	('SEN461', 'Chemical', '-', (108, 114))
51028	24842792	These data support previously results obtained in glioblastoma cells and in the colorectal cancer cell line DLD1 (Figure S1), thus confirming that SEN461 is a bona fide an inhibitor of Wnt/beta-catenin signaling.	('beta-catenin', 'Gene', (189, 201))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('SEN461', 'Chemical', '-', (147, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('SEN461', 'Var', (147, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('beta-catenin', 'Gene', '1499', (189, 201))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('glioblastoma', 'Disease', (50, 62))
51053	24842792	We found that SEN461 did not affect either Myc mediated activation or the basal activity of the reporter assay (Figure S4), arguing that SEN461 effect on c-Myc might occur at the post-transcriptional level.	('c-Myc', 'Gene', (154, 159))	('SEN461', 'Chemical', '-', (137, 143))	('Myc', 'Gene', (43, 46))	('SEN461', 'Chemical', '-', (14, 20))	('Myc', 'Gene', '4609', (43, 46))	('c-Myc', 'Gene', '4609', (154, 159))	('Myc', 'Gene', '4609', (156, 159))	('Myc', 'Gene', (156, 159))	('SEN461', 'Var', (137, 143))
51056	24842792	Conversely XAV939 did not affect c-Myc protein level (Figure 3G).	('c-Myc', 'Gene', (33, 38))	('XAV939', 'Chemical', 'MESH:C544261', (11, 17))	('c-Myc', 'Gene', '4609', (33, 38))	('XAV939', 'Var', (11, 17))
51070	24842792	All animals receiving SEN461 twice a day for seven days, maintained their body weight with no significant changes (Figure S5A), correlating with absence of gross histological changes in the architecture of gastrointestinal tract (Figure S5B).	('maintained', 'PosReg', (57, 67))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (206, 228))	('histological changes in the architecture of gastrointestinal tract', 'Phenotype', 'HP:0012718', (162, 228))	('body', 'MPA', (74, 78))	('gastrointestinal tract', 'Disease', (206, 228))	('SEN461', 'Var', (22, 28))	('SEN461', 'Chemical', '-', (22, 28))
51073	24842792	Here, we demonstrated that SEN461 reduces the tumorigenic potential of osteosarcoma and fibrosarcoma cell lines and confirm this activity is mediated largely through Axin stabilization.	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SEN461', 'Var', (27, 33))	('reduces', 'NegReg', (34, 41))	('SEN461', 'Chemical', '-', (27, 33))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (88, 100))	('tumor', 'Disease', (46, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('fibrosarcoma', 'Disease', 'MESH:D005354', (88, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('osteosarcoma', 'Disease', (71, 83))	('fibrosarcoma', 'Disease', (88, 100))
51074	24842792	SEN461 affects Wnt transcriptional activity, influences the amount of beta-catenin levels and modulates Wnt pathway components in the examined osteosarcoma cell lines.	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('osteosarcoma', 'Disease', (143, 155))	('osteosarcoma', 'Disease', 'MESH:D012516', (143, 155))	('SEN461', 'Chemical', '-', (0, 6))	('SEN461', 'Var', (0, 6))	('beta-catenin', 'Gene', (70, 82))	('influences', 'Reg', (45, 55))	('affects', 'Reg', (7, 14))	('Wnt pathway components', 'Pathway', (104, 126))	('modulates', 'Reg', (94, 103))	('beta-catenin', 'Gene', '1499', (70, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Wnt transcriptional activity', 'MPA', (15, 43))
51080	24842792	This makes c-Myc a relevant "driver" for tumorigenicity in the fibrosarcoma HT-1080 cells, as reported by the proliferation effect induced by gene knock-down, and explains the reduced tumorigenic potential evoked by SEN461 treatment.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('c-Myc', 'Gene', (11, 16))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('reduced', 'NegReg', (176, 183))	('SEN461', 'Chemical', '-', (216, 222))	('knock-down', 'Var', (147, 157))	('fibrosarcoma', 'Disease', (63, 75))	('tumor', 'Disease', (184, 189))	('HT-1080', 'CellLine', 'CVCL:0317', (76, 83))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (63, 75))	('fibrosarcoma', 'Disease', 'MESH:D005354', (63, 75))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('c-Myc', 'Gene', '4609', (11, 16))
51081	24842792	In fact, Myc modulation was also previously reported to be able to reverse the process of transformation even in tumors with high genomic complexity like sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (154, 162))	('sarcomas', 'Disease', (154, 162))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('Myc', 'Gene', '4609', (9, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('modulation', 'Var', (13, 23))	('sarcomas', 'Disease', 'MESH:D012509', (154, 162))	('Myc', 'Gene', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
51084	24842792	down regulation of c-Myc protein level) between XAV939 and SEN461 suggest that they act similarly but not identically.	('XAV939', 'Var', (48, 54))	('SEN461', 'Gene', (59, 65))	('down', 'NegReg', (0, 4))	('c-Myc', 'Gene', '4609', (19, 24))	('XAV939', 'Chemical', 'MESH:C544261', (48, 54))	('SEN461', 'Chemical', '-', (59, 65))	('c-Myc', 'Gene', (19, 24))
51091	23936513	All cases displayed CD105 and weak c-KIT positivity in the endothelial cells.	('c-KIT', 'Gene', (35, 40))	('c-KIT', 'Gene', '3815', (35, 40))	('CD105', 'Var', (20, 25))
51149	23936513	as a fibroblast-like cell population of the bone marrow ("marrow stromal cells"), which express CD105, CD90, and CD73 antibodies.	('CD90', 'Gene', '7070', (103, 107))	('CD105', 'Var', (96, 101))	('CD90', 'Gene', (103, 107))	('CD73', 'Gene', '4907', (113, 117))	('CD73', 'Gene', (113, 117))
51151	23936513	The PMCs express CD105, CD90, CD34 and SMA but are negative for c-KIT and also for CD3, CD4, and CD8.	('c-KIT', 'Gene', (64, 69))	('CD105', 'Var', (17, 22))	('CD4', 'Gene', '920', (88, 91))	('c-KIT', 'Gene', '3815', (64, 69))	('CD34', 'Gene', (30, 34))	('CD34', 'Gene', '947', (30, 34))	('CD8', 'Gene', (97, 100))	('CD4', 'Gene', (88, 91))	('CD90', 'Gene', '7070', (24, 28))	('CD8', 'Gene', '925', (97, 100))	('CD90', 'Gene', (24, 28))
51267	32280747	Acquisition parameters have previously been described in detail and are as follows:   Following the acquisition of nonenhanced scans, T1 contrast enhancement was achieved via injection of Gd-DTPA at 0.5 mmol/kg via the tail vein catheter, which was placed under anesthesia before imaging.	('Gd-DTPA', 'Var', (188, 195))	('T1 contrast', 'MPA', (134, 145))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (188, 195))	('enhancement', 'PosReg', (146, 157))
51282	32280747	These networks iterated combinations of 3 parameters: Dice versus cross entropy loss functions, networks with skip connections versus those without, and multicontrast versus T2-only MR images as inputs.	('Dice', 'Gene', '319565', (54, 58))	('cross entropy loss functions', 'Disease', (66, 94))	('skip connections', 'Var', (110, 126))	('cross entropy loss functions', 'Disease', 'MESH:C537866', (66, 94))	('Dice', 'Gene', (54, 58))
51299	32280747	Dice and VOE scores are shown to be significantly higher for the network with skip connections.	('skip connections', 'Var', (78, 94))	('higher', 'PosReg', (50, 56))	('Dice', 'Gene', (0, 4))	('Dice', 'Gene', '319565', (0, 4))	('VOE scores', 'CPA', (9, 19))
51321	32280747	These changes alter tumor signal patterns in each of the MR contrasts, contributing to heterogeneity of the tumor radiomics features that differentiate the pre- and post-RT MRI data.	('contributing to', 'Reg', (71, 86))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('alter', 'Reg', (14, 19))	('changes', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
51356	24362521	KDM3A depletion further results in augmentation of the levels of the repressive H3K9me2 histone mark, and downregulation of pro-oncogenic factors in Ewing Sarcoma.	('Ewing Sarcoma', 'Disease', (149, 162))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('Sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('downregulation', 'NegReg', (106, 120))	('KDM3A', 'Gene', (0, 5))	('augmentation', 'PosReg', (35, 47))	('levels of the repressive', 'MPA', (55, 79))	('H3K9me2', 'Protein', (80, 87))	('depletion', 'Var', (6, 15))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (149, 162))
51367	24362521	Epigenetic modifiers have recently emerged as playing key roles in cancer, with particular importance in the pathogenesis of pediatric tumors.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('pediatric tumors', 'Disease', (125, 141))	('cancer', 'Disease', (67, 73))	('Epigenetic modifiers', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('pediatric tumors', 'Disease', 'MESH:D063766', (125, 141))
51370	24362521	Together, our studies reveal a new miR-regulated, epigenetic, tumor-promotional pathway in Ewing Sarcoma, downstream of the EWS/Fli1 oncoprotein.	('EWS', 'Gene', '2130', (124, 127))	('Fli1', 'Gene', (128, 132))	('EWS', 'Gene', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('Ewing Sarcoma', 'Disease', (91, 104))	('Sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumor', 'Disease', (62, 67))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('epigenetic', 'Var', (50, 60))	('miR', 'Gene', (35, 38))	('Fli1', 'Gene', '2313', (128, 132))	('miR', 'Gene', '22877', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
51404	24362521	Thus, KDM3A is growth promoting in Ewing Sarcoma.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('Sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('KDM3A', 'Var', (6, 11))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('Ewing Sarcoma', 'Disease', (35, 48))
51406	24362521	To begin to understand mechanisms by which KDM3A promotes the oncogenic phenotype in Ewing Sarcoma, we first verified that KDM3A depletion results in increased levels of H3K9 methylation (Figure 4a).	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('KDM3A', 'Gene', (123, 128))	('depletion', 'Var', (129, 138))	('Ewing Sarcoma', 'Disease', (85, 98))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('Sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('increased', 'PosReg', (150, 159))	('H3K9', 'Protein', (170, 174))
51421	24362521	Epigenetic modifications, as a class, are emerging as a powerful driving force in cancer.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Epigenetic modifications', 'Var', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))
51422	24362521	In pediatric cancers, which tend to harbor fewer mutations than their adult counterparts, epigenetic modifications may make a disproportionate contribution to initiation and maintenance of the oncogenic state, as suggested by recent studies in retinoblastoma, and pointed out by others.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('retinoblastoma', 'Disease', 'MESH:D012175', (244, 258))	('retinoblastoma', 'Disease', (244, 258))	('mutations', 'Var', (49, 58))	('pediatric cancers', 'Disease', 'MESH:D009369', (3, 20))	('pediatric cancers', 'Disease', (3, 20))	('epigenetic modifications', 'Var', (90, 114))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('retinoblastoma', 'Phenotype', 'HP:0009919', (244, 258))
51428	24362521	Interestingly, Cyclin D1 expression is silenced via H3K9 methylation in differentiating cardiomyocytes, suggesting that modulation of the H3K9 methyl mark may be a more general mechanism of regulation of this pivotal oncogene.	('Cyclin D1', 'Gene', '595', (15, 24))	('Cyclin D1', 'Gene', (15, 24))	('expression', 'MPA', (25, 35))	('H3K9', 'Var', (138, 142))	('silenced', 'NegReg', (39, 47))	('H3K9', 'Var', (52, 56))
51429	24362521	Further examination of the biology of KDM3A and related factors will help determine whether modulation of H3K9 methylation should be pursued as a therapeutic approach in Ewing Sarcoma, and potentially other cancers.	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('H3K9', 'Protein', (106, 110))	('cancers', 'Disease', (207, 214))	('Sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('modulation', 'Var', (92, 102))	('Ewing Sarcoma', 'Disease', (170, 183))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (170, 183))
51463	25520709	Two specific inverted nested PCRs were used afterwards with primer pairs I_Buddha_F1/I_Buddha_R3 (TCCCGACACAAATAATCGGACAACC) and I_Buddha_R1/I_Buddha_F3 (GACGTGCTTTGTTAGAATCTGTTCCTG) during the first step and I_Buddha_F2/I_Buddha_R4 (GAAATTTGAATTTCCATCTTAGCTTGAGTC) and I_Buddha_R2/I_Buddha_F4 (CAAACCCTGCAATGGTGTGTAGATG) during the second amplification step.	('ACG', 'Chemical', 'MESH:C023716', (155, 158))	('I_Buddha_R1/I_Buddha_F3', 'Var', (129, 152))	('I_Buddha_R2/I_Buddha_F4', 'Var', (270, 293))
51471	25520709	Renal tubules contained eosinophilic droplets in the epithelial cells, as is often seen in mice with histiocytic sarcoma, although the cause is not known.	('eosin', 'Chemical', 'MESH:D004801', (24, 29))	('mice', 'Species', '10090', (91, 95))	('eosinophilic', 'Var', (24, 36))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (101, 120))	('histiocytic sarcoma', 'Disease', (101, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
51496	25520709	Although the full process of tumorigenesis is not completely understood, it is known that accumulation of mutations in proto-oncogenes (such as those involved in the regulation or suppression of cell replication or tumors) or the effect of viral infections are involved in the progression (Bergers and Benjamin,; McAloose and Newton,).	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('involved', 'Reg', (261, 269))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (29, 34))	('viral infections', 'Disease', (240, 256))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', (215, 220))	('viral infections', 'Disease', 'MESH:D001102', (240, 256))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))
51517	25520709	It is known that parvoviruses can establish latency by integrating in their hosts' genome (Schnepp et al.,; Kapoor et al.,), and an integration event might cause the disruption of important onco-suppressors and be one of the initial causes for tumor development.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cause', 'Reg', (156, 161))	('tumor', 'Disease', (244, 249))	('onco-suppressors', 'CPA', (190, 206))	('integration', 'Var', (132, 143))	('disruption', 'MPA', (166, 176))	('parvovirus', 'Species', '10798', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
51521	25520709	In fact it is known that certain viruses, called oncolytic viruses, have tropism for specific cancer cells and they can even lead to "spontaneous regression" of malignancies (Butt and Miggin,; Sze et al.,).	('malignancies', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))	('viruses', 'Var', (33, 40))	('lead to', 'Reg', (125, 132))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
51525	25520709	Although more studies are required to provide a conclusive answer, the infection with Sl.L-PV-1 might have delayed tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('infection', 'Var', (71, 80))	('Sl.L-PV-1', 'Gene', (86, 95))	('tumor', 'Disease', (115, 120))	('delayed', 'NegReg', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
51592	24959221	Secondly, impairment in the DNA repair proteins could lead to an increased susceptibility to radiation-induced carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('lead', 'Reg', (54, 58))	('DNA repair proteins', 'Protein', (28, 47))	('impairment', 'Var', (10, 20))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('susceptibility to radiation', 'Phenotype', 'HP:0011133', (75, 102))	('radiation-induced', 'CPA', (93, 110))
51600	24959221	In a large study, patients with MFH of the extremities who underwent limb sparing surgery followed by radiation experienced a 10-year relapse-free survival rate of 62% and an overall survival rate of 80%, which was higher than that in earlier studies.	('relapse-free survival', 'CPA', (134, 155))	('patients', 'Species', '9606', (18, 26))	('MFH', 'Var', (32, 35))
51619	22606446	Therefore, surgical treatment was planned under the diagnosis of T4aN2bM0, stage III-C malignant melanoma according to the American Joint Committee on Cancer classification.	('malignant melanoma', 'Phenotype', 'HP:0002861', (87, 105))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))	('malignant melanoma', 'Disease', (87, 105))	('malignant melanoma', 'Disease', 'MESH:D008545', (87, 105))	('T4aN2bM0', 'Var', (65, 73))
51937	23762651	Prognosis is adversely affected by a tumor size of more than 5 cm, tumor site, age over 60 years, high grade malignancy, and the presence of metastatic disease.	('malignancy', 'Disease', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('high', 'Var', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('metastatic disease', 'CPA', (141, 159))	('tumor', 'Disease', (67, 72))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))
51946	21216937	Subsequently we identified and validated (in vitro and in vivo) a two gene set signature (high CUGBP2; low RHOJ) that associated with the synergistic phenotype.	('CUGBP2', 'Gene', '10659', (95, 101))	('CUGBP2', 'Gene', (95, 101))	('RHOJ', 'Gene', (107, 111))	('associated', 'Reg', (118, 128))	('high', 'Var', (90, 94))	('RHOJ', 'Gene', '57381', (107, 111))
51947	21216937	We further uncover that the epigenetic synergism leading to specific upregulation of CDKI p21 in specific cell lines is a function of the differences in the degree of baseline chromatin modification.	('p21', 'Gene', '1026', (90, 93))	('epigenetic synergism', 'Var', (28, 48))	('upregulation', 'PosReg', (69, 81))	('p21', 'Gene', (90, 93))
51952	21216937	However, there is no obvious mechanistic link between epigenetic modification and either of these two tumor types that would necessarily exclude other cancer subtypes from responding based on a similar concept of epigenetic modulation, be it global or specific.	('epigenetic modification', 'Var', (54, 77))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
51959	21216937	Uterine leiomyosarcomas have characteristic suppression of BRCA1 via DNA promoter methylation.	('BRCA1', 'Gene', '672', (59, 64))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (8, 22))	('leiomyosarcomas', 'Disease', (8, 23))	('methylation', 'Var', (82, 93))	('BRCA1', 'Gene', (59, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('Uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (0, 23))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (8, 23))	('suppression', 'NegReg', (44, 55))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (8, 23))
51987	21216937	Antibodies: AV40323 (Sigma) Anti-CUGBP2; (Abcam) Mouse Anti-RHOJ Monoclonal Antibody.	('RHOJ', 'Gene', (60, 64))	('CUGBP2', 'Gene', '10659', (33, 39))	('CUGBP2', 'Gene', (33, 39))	('RHOJ', 'Gene', '57381', (60, 64))	('AV40323', 'Var', (12, 19))	('Mouse', 'Species', '10090', (49, 54))
51988	21216937	IHC was performed as previously described by us using the following antibodies: Ki67 (Dako; Cat # M7240), p21/waf1 (Calbiochem, Cat # OP64), AcH3 (Cell Signaling, Cat # 9677S).	('OP64', 'CellLine', 'CVCL:4398', (134, 138))	('p21/waf1', 'Gene', (106, 114))	('AcH3', 'Gene', (141, 145))	('p21/waf1', 'Gene', '1026', (106, 114))	('Ki67', 'Var', (80, 84))
52005	21216937	To examine whether the decrease in cellular growth observed in the presence of epigenetic agents was cytostatic or cytotoxic, we performed crystal violet staining (data not shown), viability (trypan blue exclusion), cell cycle, and caspase activity assays on all cell lines using the five HDACIs (at a wide spectrum of doses) in the presence and absence of decitabine.	('decrease', 'NegReg', (23, 31))	('decitabine', 'Chemical', 'MESH:D000077209', (357, 367))	('crystal violet', 'Chemical', 'MESH:D005840', (139, 153))	('cellular', 'MPA', (35, 43))	('epigenetic', 'Var', (79, 89))	('trypan blue', 'Chemical', 'MESH:D014343', (192, 203))
52007	21216937	Since our data indicated that DNA-MIs were augmenting an HDACI mediated decrease in cellular growth, we focused on examining the status of p21, a well-studied cell cycle inhibitor known to be responsive to HDACIs, in ESR and non-ESR cell lines.	('cellular growth', 'CPA', (84, 99))	('MI', 'Chemical', 'MESH:C011506', (34, 36))	('p21', 'Gene', '1026', (139, 142))	('DNA-MIs', 'Var', (30, 37))	('p21', 'Gene', (139, 142))	('decrease', 'NegReg', (72, 80))
52056	21216937	This conclusion is based mainly on our observations that siRNA knockdown strategies either against CUGBP2 in an attempt to downregulate CUGBP2 in a cell line (SAOS2) that is initially responsive to epigenetic synergism in order to make it non-responsive; or vice versa, siRNA against RHOJ, in an attempt to make a cell line that is initially non-responsive to epigenetic treatment become sensitive did not result in the intended effect.	('CUGBP2', 'Gene', '10659', (99, 105))	('CUGBP2', 'Gene', '10659', (136, 142))	('RHOJ', 'Gene', '57381', (284, 288))	('downregulate', 'NegReg', (123, 135))	('CUGBP2', 'Gene', (99, 105))	('CUGBP2', 'Gene', (136, 142))	('knockdown', 'Var', (63, 72))	('RHOJ', 'Gene', (284, 288))
52072	20176037	AM1241, a CB2 agonist, does not demonstrate central nervous system side-effects seen with CB1 agonists such as hypothermia and catalepsy.	('catalepsy', 'Disease', (127, 136))	('hypothermia', 'Disease', (111, 122))	('CB1', 'Gene', (90, 93))	('catalepsy', 'Disease', 'MESH:D002375', (127, 136))	('hypothermia', 'Phenotype', 'HP:0002045', (111, 122))	('rat', 'Species', '10116', (39, 42))	('AM1241', 'Var', (0, 6))	('AM1241', 'Chemical', 'MESH:C439263', (0, 6))	('CB1', 'Gene', '12801', (90, 93))	('hypothermia', 'Disease', 'MESH:D007035', (111, 122))
52075	20176037	In contrast, CB2 selective agonists have been shown to reduce bone loss associated with a model of osteoporosis.	('bone loss', 'Phenotype', 'HP:0002797', (62, 71))	('bone loss', 'Disease', (62, 71))	('osteoporosis', 'Phenotype', 'HP:0000939', (99, 111))	('bone loss', 'Disease', 'MESH:D016301', (62, 71))	('CB2', 'Gene', (13, 16))	('osteoporosis', 'Disease', 'MESH:D010024', (99, 111))	('reduce', 'NegReg', (55, 61))	('osteoporosis', 'Disease', (99, 111))	('agonists', 'Var', (27, 35))
52080	20176037	The systemic administration of AM1241 acutely or for 7 days significantly attenuated spontaneous and evoked pain in the inoculated limb.	('pain', 'Phenotype', 'HP:0012531', (108, 112))	('pain', 'Disease', 'MESH:D010146', (108, 112))	('pain', 'Disease', (108, 112))	('AM1241', 'Var', (31, 37))	('rat', 'Species', '10116', (21, 24))	('AM1241', 'Chemical', 'MESH:C439263', (31, 37))	('attenuated', 'NegReg', (74, 84))
52081	20176037	Sustained AM1241 significantly reduced bone loss and decreased the incidence of cancer-induced bone fractures.	('bone loss', 'Disease', 'MESH:D016301', (39, 48))	('bone fractures', 'Disease', 'MESH:D050723', (95, 109))	('reduced', 'NegReg', (31, 38))	('bone fractures', 'Phenotype', 'HP:0020110', (95, 109))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bone fracture', 'Phenotype', 'HP:0020110', (95, 108))	('bone loss', 'Phenotype', 'HP:0002797', (39, 48))	('AM1241', 'Var', (10, 16))	('bone fractures', 'Disease', (95, 109))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('decreased', 'NegReg', (53, 62))	('bone loss', 'Disease', (39, 48))	('AM1241', 'Chemical', 'MESH:C439263', (10, 16))	('cancer', 'Disease', (80, 86))
52085	20176037	Destruction of the bone causes chronic pain, which often leads to pathological fractures and/or hypercalcemia.	('fractures', 'Disease', 'MESH:D050723', (79, 88))	('hypercalcemia', 'Phenotype', 'HP:0003072', (96, 109))	('Destruction of the bone', 'Phenotype', 'HP:0002797', (0, 23))	('hypercalcemia', 'Disease', (96, 109))	('pathological fractures', 'Phenotype', 'HP:0002756', (66, 88))	('fractures', 'Disease', (79, 88))	('pain', 'Phenotype', 'HP:0012531', (39, 43))	('hypercalcemia', 'Disease', 'MESH:D006934', (96, 109))	('Destruction', 'Var', (0, 11))	('pain', 'Disease', 'MESH:D010146', (39, 43))	('chronic pain', 'Phenotype', 'HP:0012532', (31, 43))	('pain', 'Disease', (39, 43))	('leads to', 'Reg', (57, 65))
52092	20176037	Recently, we demonstrated that murine bone cancer models treated with sustained morphine not only intensifies pain after a week of treatment but also accelerates bone destruction when compared to vehicle treated animals.	('rat', 'Species', '10116', (156, 159))	('accelerates', 'PosReg', (150, 161))	('pain', 'Disease', 'MESH:D010146', (110, 114))	('pain', 'Disease', (110, 114))	('bone cancer', 'Disease', 'MESH:D001859', (38, 49))	('morphine', 'Var', (80, 88))	('bone cancer', 'Disease', (38, 49))	('morphine', 'Chemical', 'MESH:D009020', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('intensifies', 'PosReg', (98, 109))	('bone destruction', 'CPA', (162, 178))	('pain', 'Phenotype', 'HP:0012531', (110, 114))	('murine', 'Species', '10090', (31, 37))	('bone destruction', 'Phenotype', 'HP:0002797', (162, 178))	('rat', 'Species', '10116', (20, 23))
52100	20176037	In animal pain models, AM1241 is consistently reported as a CB2 agonist, as effects are blocked by CB2 but not CB1 selective antagonists and not seen in CB2-/- mice..	('pain', 'Disease', 'MESH:D010146', (10, 14))	('pain', 'Disease', (10, 14))	('AM1241', 'Var', (23, 29))	('AM1241', 'Chemical', 'MESH:C439263', (23, 29))	('mice', 'Species', '10090', (160, 164))	('CB1', 'Gene', (111, 114))	('CB1', 'Gene', '12801', (111, 114))	('pain', 'Phenotype', 'HP:0012531', (10, 14))
52146	20176037	At day 10, tumor bearing mice with AM1241 showed a reduction in flinching when compared to tumor bearing treated mice with vehicle (i.p.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('reduction', 'NegReg', (51, 60))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('AM1241', 'Var', (35, 41))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('AM1241', 'Chemical', 'MESH:C439263', (35, 41))	('flinching', 'MPA', (64, 73))
52147	20176037	treatment of AM1241 resulted in a decrease in guarding by day 14 in sarcoma treated mice when compared to vehicle treated animals (p<0.05) (Figure 1B).	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('decrease', 'NegReg', (34, 42))	('AM1241', 'Var', (13, 19))	('guarding', 'MPA', (46, 54))	('AM1241', 'Chemical', 'MESH:C439263', (13, 19))	('sarcoma', 'Disease', (68, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('mice', 'Species', '10090', (84, 88))
52149	20176037	On day 7 after sarcoma inoculation and prior to either AM1241 or vehicle, animals' mechanical thresholds were not different from baseline values on day 0.	('sarcoma inoculation', 'Disease', (15, 34))	('sarcoma inoculation', 'Disease', 'MESH:D002372', (15, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('AM1241', 'Var', (55, 61))	('AM1241', 'Chemical', 'MESH:C439263', (55, 61))
52152	20176037	More importantly is that the animals treated with sustained AM1241 demonstrated a significant block of sarcoma-induced mechanical hypersensitivity (p<0.001) (Figure 2A).	('AM1241', 'Var', (60, 66))	('sarcoma', 'Disease', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('block', 'NegReg', (94, 99))	('rat', 'Species', '10116', (74, 77))	('AM1241', 'Chemical', 'MESH:C439263', (60, 66))	('hypersensitivity', 'Disease', 'MESH:D004342', (130, 146))	('hypersensitivity', 'Disease', (130, 146))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))
52155	20176037	Sarcoma-induced animals treated with both vehicle and AM1241 displayed limping by day 10, yet by day 14, there was a significant difference in movement-evoked pain between AM1241 and vehicle treated groups.	('pain', 'Phenotype', 'HP:0012531', (159, 163))	('AM1241', 'Var', (54, 60))	('Sarcoma', 'Disease', (0, 7))	('AM1241', 'Var', (172, 178))	('AM1241', 'Chemical', 'MESH:C439263', (54, 60))	('pain', 'Disease', 'MESH:D010146', (159, 163))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('pain', 'Disease', (159, 163))	('limp', 'Phenotype', 'HP:0031955', (71, 75))	('limping', 'Phenotype', 'HP:0031955', (71, 78))	('AM1241', 'Chemical', 'MESH:C439263', (172, 178))	('limping', 'CPA', (71, 78))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
52157	20176037	Sustained administration of AM1241 from day 7 until day 14, significantly reversed the sarcoma-induced loss of limb use by day 14 (P<0.001) (Figure 2B).	('rat', 'Species', '10116', (18, 21))	('sarcoma-induced loss of limb', 'Disease', (87, 115))	('sarcoma-induced loss of limb', 'Disease', 'MESH:D012509', (87, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('AM1241', 'Var', (28, 34))	('AM1241', 'Chemical', 'MESH:C439263', (28, 34))	('loss of limb', 'Phenotype', 'HP:0040064', (103, 115))
52158	20176037	These data suggest that sustained AM1241 significantly reduces sarcoma-induced evoked pain.	('pain', 'Phenotype', 'HP:0012531', (86, 90))	('sarcoma', 'Disease', (63, 70))	('pain', 'Disease', 'MESH:D010146', (86, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('pain', 'Disease', (86, 90))	('AM1241', 'Var', (34, 40))	('reduces', 'NegReg', (55, 62))	('AM1241', 'Chemical', 'MESH:C439263', (34, 40))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
52164	20176037	Sustained AM1241 from days 7 until day 14 significantly reduced the amount of sarcoma-induced bone loss when compared to the vehicle treated animals (P<0.001) (Figure 3D).	('sarcoma-induced bone loss', 'Disease', (78, 103))	('sarcoma-induced bone loss', 'Disease', 'MESH:D016301', (78, 103))	('reduced', 'NegReg', (56, 63))	('bone loss', 'Phenotype', 'HP:0002797', (94, 103))	('AM1241', 'Var', (10, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('AM1241', 'Chemical', 'MESH:C439263', (10, 16))
52166	20176037	Sustained AM1241 from day 7 until day 14 significantly reduced bone loss by blind scoring with only 2 out of 10 animals demonstrating unicortical bone loss (Figure 3E).	('bone loss', 'Phenotype', 'HP:0002797', (63, 72))	('bone loss', 'Disease', (63, 72))	('reduced', 'NegReg', (55, 62))	('bone loss', 'Phenotype', 'HP:0002797', (146, 155))	('bone loss', 'Disease', (146, 155))	('bone loss', 'Disease', 'MESH:D016301', (63, 72))	('AM1241', 'Var', (10, 16))	('rat', 'Species', '10116', (127, 130))	('bone loss', 'Disease', 'MESH:D016301', (146, 155))	('AM1241', 'Chemical', 'MESH:C439263', (10, 16))
52167	20176037	Flinching and guarding behaviors were observed in order to determine the acute effects of AM1241 on sarcoma-induced spontaneous pain.	('sarcoma', 'Disease', (100, 107))	('pain', 'Phenotype', 'HP:0012531', (128, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('spontaneous pain', 'Phenotype', 'HP:0010833', (116, 132))	('pain', 'Disease', 'MESH:D010146', (128, 132))	('pain', 'Disease', (128, 132))	('AM1241', 'Var', (90, 96))	('AM1241', 'Chemical', 'MESH:C439263', (90, 96))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))
52171	20176037	However, 30 minutes and 60 minutes following injection with AM1241 animals showed a significant reduction in flinching (p<0.001) and guarding (30 min, p<0.05) (60 min, p<0.001) when compared to vehicle treated mice (Figure 4A and 4B).	('mice', 'Species', '10090', (210, 214))	('AM1241', 'Var', (60, 66))	('flinching', 'CPA', (109, 118))	('AM1241', 'Chemical', 'MESH:C439263', (60, 66))	('guarding', 'CPA', (133, 141))	('reduction', 'NegReg', (96, 105))
52173	20176037	resulted in a significant attenuation of the AM1241 effects (p<0.001) in both flinching and guarding (Figure 4A and 4B) demonstrating that the reduction of sarcoma-induced spontaneous pain by AM1241 is CB2 receptor mediated.	('sarcoma', 'Disease', 'MESH:D012509', (156, 163))	('pain', 'Phenotype', 'HP:0012531', (184, 188))	('flinching', 'CPA', (78, 87))	('attenuation', 'NegReg', (26, 37))	('pain', 'Disease', 'MESH:D010146', (184, 188))	('pain', 'Disease', (184, 188))	('sarcoma', 'Disease', (156, 163))	('AM1241', 'Var', (192, 198))	('AM1241', 'Var', (45, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('rat', 'Species', '10116', (127, 130))	('reduction', 'NegReg', (143, 152))	('spontaneous pain', 'Phenotype', 'HP:0010833', (172, 188))	('guarding', 'CPA', (92, 100))	('AM1241', 'Chemical', 'MESH:C439263', (192, 198))	('AM1241', 'Chemical', 'MESH:C439263', (45, 51))
52177	20176037	Animals treated with acute AM1241 demonstrated a significant attenuation of sarcoma-induced touch evoked hypersensitivity compared to control (vehicle) (Figure 4C).	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('attenuation', 'NegReg', (61, 72))	('sarcoma', 'Disease', (76, 83))	('rat', 'Species', '10116', (41, 44))	('AM1241', 'Var', (27, 33))	('hypersensitivity', 'Disease', (105, 121))	('hypersensitivity', 'Disease', 'MESH:D004342', (105, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('AM1241', 'Chemical', 'MESH:C439263', (27, 33))
52178	20176037	Although 30 minutes following AM1241 injection did not result in a significant attenuation of evoked responses the 60 minute time point resulted in a significant attenuation of evoked responses (p<0.05) when compared to vehicle treated animals and/or baseline thresholds (Figure 4C).	('attenuation', 'NegReg', (162, 173))	('evoked responses', 'MPA', (177, 193))	('AM1241', 'Chemical', 'MESH:C439263', (30, 36))	('AM1241', 'Var', (30, 36))
52179	20176037	resulted in a significant attenuation of the AM1241 effects (p<0.001) in evoked responses (Figure 4C) demonstrating that the reduction of sarcoma-induced evoked pain by AM1241 is CB2 receptor mediated.	('reduction', 'NegReg', (125, 134))	('AM1241', 'Var', (169, 175))	('AM1241', 'Chemical', 'MESH:C439263', (169, 175))	('sarcoma', 'Disease', (138, 145))	('attenuation', 'NegReg', (26, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('AM1241', 'Var', (45, 51))	('evoked responses', 'MPA', (73, 89))	('rat', 'Species', '10116', (109, 112))	('pain', 'Phenotype', 'HP:0012531', (161, 165))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('AM1241', 'Chemical', 'MESH:C439263', (45, 51))	('pain', 'Disease', 'MESH:D010146', (161, 165))	('pain', 'Disease', (161, 165))
52202	20176037	Studies here demonstrate that sustained CB2 agonist maintain bone integrity when compared to vehicle treated animals.	('bone integrity', 'CPA', (61, 75))	('CB2', 'Gene', (40, 43))	('agonist', 'Var', (44, 51))	('rat', 'Species', '10116', (20, 23))
52203	20176037	There was a significant reduction in sarcoma-induced bone loss and a reduction in the number of unicortical fractures due to the administration of the AM1241.	('sarcoma-induced bone loss', 'Disease', (37, 62))	('fractures', 'Disease', 'MESH:D050723', (108, 117))	('sarcoma-induced bone loss', 'Disease', 'MESH:D016301', (37, 62))	('rat', 'Species', '10116', (137, 140))	('AM1241', 'Var', (151, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('fractures', 'Disease', (108, 117))	('bone loss', 'Phenotype', 'HP:0002797', (53, 62))	('reduction', 'NegReg', (24, 33))	('reduction', 'NegReg', (69, 78))	('AM1241', 'Chemical', 'MESH:C439263', (151, 157))
52210	20176037	Bone density in CB2 knockout mice was significantly lower when compared to wild type littermates (Karsak et al.	('Bone density', 'CPA', (0, 12))	('CB2', 'Gene', (16, 19))	('lower', 'NegReg', (52, 57))	('knockout', 'Var', (20, 28))	('mice', 'Species', '10090', (29, 33))
52211	20176037	In addition, CB2 knockout mice displayed a markedly accelerated age-related trabecular and cortical bone remodeling.	('knockout', 'Var', (17, 25))	('rat', 'Species', '10116', (58, 61))	('CB2', 'Gene', (13, 16))	('accelerated', 'PosReg', (52, 63))	('mice', 'Species', '10090', (26, 30))
52230	31427882	The genetic hallmark of MLPS is the t(12;16)(q13;p11) translocation that is present in nearly 95% of cases and generates a novel fusion protein, FUS-CHOP.	('generates', 'Reg', (111, 120))	('MLPS', 'Disease', 'None', (24, 28))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (36, 53))	('t(12;16)(q13;p11', 'Var', (36, 52))	('MLPS', 'Disease', (24, 28))	('MLPS', 'Phenotype', 'HP:0012268', (24, 28))
52234	31427882	Interestingly, experiments in transgenic mice showed that expression of the truncated form of FUS in the presence of aberrant CHOP was sufficient to generate tumors.	('tumors', 'Disease', (158, 164))	('FUS', 'Gene', (94, 97))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('truncated', 'Var', (76, 85))	('transgenic mice', 'Species', '10090', (30, 45))	('generate', 'PosReg', (149, 157))
52236	31427882	These experiments suggest a synergistic mechanism of tumorigenesis resulting from abnormal FUS and CHOP expression in MLPS.	('MLPS', 'Disease', (118, 122))	('MLPS', 'Phenotype', 'HP:0012268', (118, 122))	('FUS', 'Protein', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CHOP', 'Gene', (99, 103))	('MLPS', 'Disease', 'None', (118, 122))	('tumor', 'Disease', (53, 58))	('abnormal', 'Var', (82, 90))
52249	31427882	Rosa26 LSL-FUS-CHOP/+ mice were generated by taking the human 7-2 FUS-CHOP translocation variant cDNA from the NCBI database and generating a targeting vector for the Rosa26 locus.	('Rosa26', 'Gene', '14910', (167, 173))	('Rosa26', 'Gene', (0, 6))	('variant', 'Var', (89, 96))	('Rosa26', 'Gene', (167, 173))	('human', 'Species', '9606', (56, 61))	('Rosa26', 'Gene', '14910', (0, 6))	('mice', 'Species', '10090', (22, 26))
52260	31427882	Mice lacking Cre expression were injected with an adenovirus expressing Cre, Ad5CMVCre (University of Iowa Viral Vector Core, VVC-U of Iowa-5), to activate recombination via Cre recombinase.	('recombination', 'MPA', (156, 169))	('activate', 'PosReg', (147, 155))	('adenovirus', 'Species', '10519', (50, 60))	('Ad5CMVCre', 'Var', (77, 86))	('Mice', 'Species', '10090', (0, 4))
52289	31427882	The membranes were washed three times in TBS-T for 5 min before secondary antibody incubation with goat anti-rabbit IRDye800 (Li-Cor Biosciences, P/N 925-32211) and goat anti-mouse IRDye680 (Li-Cor Biosciences, P/N 925-68070) both at 1 : 10,000 dilutions in TBS-T for 1 h at room temperature.	('P/N 925', 'SUBSTITUTION', 'None', (211, 218))	('goat', 'Species', '9925', (99, 103))	('rabbit', 'Species', '9986', (109, 115))	('goat', 'Species', '9925', (165, 169))	('P/N 925', 'SUBSTITUTION', 'None', (146, 153))	('mouse', 'Species', '10090', (175, 180))	('P/N 925', 'Var', (146, 153))	('P/N 925', 'Var', (211, 218))
52292	31427882	TaqMan probes from Thermo Fisher were used for PCR: Gapdh (MM99999915), Trp53 (Mm01731290), Cdkn1a (Mm00432448), Bbc3 (Mm0051926), Mdm2 (Mm01233136), and Bax (Mm00432051).	('Mdm2', 'Gene', (131, 135))	('Mm01731290', 'Var', (79, 89))	('Bbc3', 'Gene', (113, 117))	('Trp53', 'Gene', (72, 77))	('Cdkn1a', 'Gene', '12575', (92, 98))	('Bbc3', 'Gene', '170770', (113, 117))	('Bax', 'Gene', (154, 157))	('Mm01233136', 'Var', (137, 147))	('Cdkn1a', 'Gene', (92, 98))	('MM99999915', 'Var', (59, 69))	('Mm00432448', 'Var', (100, 110))	('Trp53', 'Gene', '22059', (72, 77))	('Mdm2', 'Gene', '17246', (131, 135))	('Mm0051926', 'Var', (119, 128))	('Bax', 'Gene', '12028', (154, 157))	('Mm00432051', 'Var', (159, 169))	('MM99999915', 'CellLine', 'CVCL:H241', (59, 69))
52310	31427882	The 7-2 translocation variant, which was the first reported variant of the translocation to be discovered in MLPS, joins the first 7 exons of FUS in frame with exon 2 of CHOP via a short translated linker region originally part of the 5'UTR of CHOP.	('MLPS', 'Disease', (109, 113))	('variant', 'Var', (22, 29))	('MLPS', 'Phenotype', 'HP:0012268', (109, 113))	('7-2', 'Gene', (4, 7))	('MLPS', 'Disease', 'None', (109, 113))
52333	31427882	In contrast, tumors from a mouse model of undifferentiated pleomorphic sarcoma in LSL-Kras G12D; p53fl/fl mice do not express FUS-CHOP (Figure 2(e)).	('mice', 'Species', '10090', (106, 110))	('p53', 'Gene', (97, 100))	('pleomorphic sarcoma', 'Disease', (59, 78))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('mouse', 'Species', '10090', (27, 32))	('G12D', 'Mutation', 'p.G12D', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('p53', 'Gene', '22059', (97, 100))	('G12D', 'Var', (91, 95))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (59, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
52339	31427882	Intramuscular injection of an adenovirus expressing Cre recombinase (AdCre) into mice with conditional activation of oncogenic Kras G12D and deletion of p53 (LSL-Kras G12D; p53fl/fl) generates primary soft tissue sarcomas with high penetrance as we previously reported.	('G12D', 'Mutation', 'p.G12D', (167, 171))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (201, 220))	('deletion', 'Var', (141, 149))	('mice', 'Species', '10090', (81, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (213, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('p53', 'Gene', (173, 176))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (201, 221))	('sarcomas', 'Disease', (213, 221))	('adenovirus', 'Species', '10519', (30, 40))	('p53', 'Gene', '22059', (173, 176))	('G12D', 'Mutation', 'p.G12D', (132, 136))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '22059', (153, 156))	('sarcomas', 'Disease', 'MESH:D012509', (213, 221))
52344	31427882	Interestingly, activation of FUS-CHOP with simultaneous deletion of p53 via AdCre delivery in Rosa26 LSL-FUS-CHOP/+, p53fl/fl mice was sufficient to generate tumors (Table 2).	('deletion', 'Var', (56, 64))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('generate', 'Reg', (149, 157))	('p53', 'Gene', (117, 120))	('mice', 'Species', '10090', (126, 130))	('p53', 'Gene', '22059', (117, 120))	('Rosa26', 'Gene', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '22059', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Rosa26', 'Gene', '14910', (94, 100))
52345	31427882	Similarly, when two copies of FUS-CHOP were activated with p53 co-deletion, tumors also formed.	('p53', 'Gene', '22059', (59, 62))	('p53', 'Gene', (59, 62))	('co-deletion', 'Var', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
52346	31427882	Most importantly, because tumors did not form in Rosa26 LSL-FUS-CHOP/+ or Rosa26 LSL-FUS-CHOP/LSL-FUS-CHOP mice in the presence of intact p53, these data suggest that FUS-CHOP-driven sarcomas in mice are dependent on inactivation of p53 or the p53 pathway.	('p53', 'Gene', (138, 141))	('Rosa26', 'Gene', (49, 55))	('FUS-CHOP-driven sarcomas', 'Disease', 'MESH:D012509', (167, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('mice', 'Species', '10090', (195, 199))	('p53', 'Gene', '22059', (244, 247))	('Rosa26', 'Gene', '14910', (74, 80))	('mice', 'Species', '10090', (107, 111))	('Rosa26', 'Gene', '14910', (49, 55))	('p53', 'Gene', '22059', (233, 236))	('p53', 'Gene', '22059', (138, 141))	('LSL-FUS-CHOP/LSL-FUS-CHOP', 'Disease', (81, 106))	('tumors', 'Disease', (26, 32))	('inactivation', 'Var', (217, 229))	('LSL-FUS-CHOP/LSL-FUS-CHOP', 'Disease', 'None', (81, 106))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('p53', 'Gene', (244, 247))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('FUS-CHOP-driven sarcomas', 'Disease', (167, 191))	('Rosa26', 'Gene', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('p53', 'Gene', (233, 236))
52347	31427882	To avoid keratoacanthomas and to temporally and spatially restrict tumor formation to develop a preclinical model to study FUS-CHOP-driven sarcomagenesis in vivo, we generated the Rosa26 FUS-CHOP; p53 (FCP) model, which delivers a plasmid (pSECC-sgp53) that contains Cre to activate expression of FUS-CHOP, and Cas9 and a p53 single guide RNA (sgRNA), sgp53, to create insertions/deletions (indels) in p53 (Figure 3).	('p53', 'Gene', '22059', (197, 200))	('tumor', 'Disease', (67, 72))	('p53', 'Gene', '22059', (402, 405))	('keratoacanthomas', 'Disease', (9, 25))	('p53', 'Gene', (248, 251))	('Rosa26', 'Gene', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('p53', 'Gene', '22059', (354, 357))	('p53', 'Gene', '22059', (322, 325))	('insertions/deletions', 'Var', (369, 389))	('FUS-CHOP-driven sarcomagenesis', 'Disease', 'None', (123, 153))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('p53', 'Gene', (197, 200))	('Rosa26', 'Gene', '14910', (180, 186))	('p53', 'Gene', (402, 405))	('keratoacanthomas', 'Phenotype', 'HP:0031525', (9, 25))	('p53', 'Gene', (354, 357))	('p53', 'Gene', '22059', (248, 251))	('FUS-CHOP-driven sarcomagenesis', 'Disease', (123, 153))	('p53', 'Gene', (322, 325))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('keratoacanthomas', 'Disease', 'MESH:D007636', (9, 25))
52360	31427882	In contrast, tumors 1650, 2148, 2149, and 2150 were formed with CRISPR-mediated indels in p53.	('p53', 'Gene', (90, 93))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('p53', 'Gene', '22059', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('indels', 'Var', (80, 86))
52378	31427882	In addition to generating genetically engineered mouse models for the conditional expression of FUS-CHOP in a tissue-specific manner, we also devised a strategy to generate endogenous Fus-Chop chromosomal rearrangements in vivo using CRISPR/Cas9 technology (Figure 5).	('Fus', 'Gene', '233908', (184, 187))	('chromosomal', 'Var', (193, 204))	('Fus', 'Gene', (184, 187))	('mouse', 'Species', '10090', (49, 54))
52382	31427882	NIH-3T3 cells were transfected with pX333-FC, and genomic DNA was assayed using Surveyor endonuclease to detect mutations and confirm Cas9 activity at the targeted loci (Figure 5(b)).	('mutations', 'Var', (112, 121))	('NIH-3T3', 'CellLine', 'CVCL:0594', (0, 7))	('Cas9', 'Gene', (134, 138))	('activity', 'MPA', (139, 147))
52383	31427882	This experiment demonstrated that pX333-FC can be used to generate the Fus-Chop translocation in NIH-3T3 cells.	('Fus', 'Gene', (71, 74))	('pX333-FC', 'Var', (34, 42))	('NIH-3T3', 'CellLine', 'CVCL:0594', (97, 104))	('Fus', 'Gene', '233908', (71, 74))
52398	31427882	Because our prior experiments suggested that p53 inactivation is important for FUS-CHOP-driven tumorigenesis in mice, we attempted to initiate tumors by generating a t(7;10) in p53fl/fl mice by co-administering AdCre, to delete p53, and AdFC, to engineer the translocation.	('p53', 'Gene', (45, 48))	('FUS-CHOP-driven tumor', 'Disease', (79, 100))	('p53', 'Gene', '22059', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('p53', 'Gene', (177, 180))	('tumors', 'Disease', (143, 149))	('p53', 'Gene', (228, 231))	('p53', 'Gene', '22059', (177, 180))	('delete', 'Var', (221, 227))	('p53', 'Gene', '22059', (228, 231))	('FUS-CHOP-driven tumor', 'Disease', 'MESH:D009369', (79, 100))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('mice', 'Species', '10090', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mice', 'Species', '10090', (112, 116))
52403	31427882	Specific sarcoma subtypes harbor specific gene fusions, which likely drive sarcomagenesis in these tumors.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('gene fusions', 'Var', (42, 54))	('sarcoma subtype', 'Disease', (9, 24))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('drive', 'Reg', (69, 74))	('sarcoma', 'Disease', (75, 82))	('sarcoma', 'Disease', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcoma subtype', 'Disease', 'MESH:D012509', (9, 24))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
52413	31427882	We discovered that early embryonic expression of FUS-CHOP in Meox2-Cre and PdgfRalpha-Cre mice was lethal.	('Meox2', 'Gene', (61, 66))	('mice', 'Species', '10090', (90, 94))	('FUS-CHOP', 'Var', (49, 57))	('Meox2', 'Gene', '17286', (61, 66))
52432	31427882	Administration of AdCre successfully generated tumors only in mice that had floxed p53 alleles and p53 deleted in tumors.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '22059', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('floxed', 'Var', (76, 82))	('mice', 'Species', '10090', (62, 66))	('p53', 'Gene', '22059', (99, 102))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('p53', 'Gene', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
52436	31427882	While it is well established that p53 is important for preventing tumorigenesis, conditional site-specific deletion or knockout of p53 is not sufficient for sarcomagenesis in mice.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '22059', (34, 37))	('mice', 'Species', '10090', (175, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('tumor', 'Disease', (66, 71))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '22059', (131, 134))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('deletion', 'Var', (107, 115))	('sarcoma', 'Disease', (157, 164))
52444	31427882	Based on our prior findings, we also hypothesized that the lack of simultaneous p53 inactivation may have prevented tumor formation.	('prevented', 'NegReg', (106, 115))	('tumor', 'Disease', (116, 121))	('lack', 'NegReg', (59, 63))	('p53', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('p53', 'Gene', '22059', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inactivation', 'Var', (84, 96))
52510	28744773	ASPS is most commonly known to be isointense to hyperintense on T1WI and characteristically hyperintense on T2WI, but this is in comparison to muscle.	('ASPS', 'Gene', '79058', (0, 4))	('ASPS', 'Phenotype', 'HP:0012218', (0, 4))	('ASPS', 'Gene', (0, 4))	('hyperintense', 'Var', (48, 60))
52514	28744773	Of the seven other cases of primary ASPS, five documented MRI characteristics, where the tumours were all described as either hypo- to isointense on T1WI and markedly hyperintense on T2WI when compared to grey matter.	('T1WI', 'MPA', (149, 153))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('hypo-', 'Var', (126, 131))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('ASPS', 'Phenotype', 'HP:0012218', (36, 40))	('ASPS', 'Gene', (36, 40))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumours', 'Disease', (89, 96))	('ASPS', 'Gene', '79058', (36, 40))
52541	28744773	A pre-surgical KPS of 70 and above has been reported as a good prognostic indicator associated with a higher median survival in those with metastatic sarcoma of the brain.	('sarcoma of the brain', 'Disease', (150, 170))	('sarcoma of the brain', 'Disease', 'MESH:D012509', (150, 170))	('higher', 'PosReg', (102, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('KPS', 'Var', (15, 18))
52660	25199839	In this review, we will focus on the recent advances to our understanding of the molecular basis of oncogenic virus-induced progression of tumor metastasis by deregulation of Nm23-H1.	('tumor metastasis', 'Disease', (139, 155))	('deregulation', 'Var', (159, 171))	('Nm23-H1', 'Gene', '4830', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor metastasis', 'Disease', 'MESH:D009362', (139, 155))	('Nm23-H1', 'Gene', (175, 182))
52666	25199839	A small number of tumorigenic cells can accumulate the full complement of alterations which enables them to disseminate from the primary tumor site.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (18, 23))	('alterations', 'Var', (74, 85))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
52727	25199839	In this study, LMP2A expression in primary tonsil epithelial cells induced migration and invasiveness of the tumor cells.	('LMP2', 'Gene', '5698', (15, 19))	('invasiveness of the tumor', 'Disease', 'MESH:D009369', (89, 114))	('invasiveness of the tumor', 'Disease', (89, 114))	('induced', 'PosReg', (67, 74))	('expression', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('migration', 'CPA', (75, 84))	('LMP2', 'Gene', (15, 19))
52740	25199839	showed that the KSHV vIL-6 enhanced the expression of DNA methyltransferase 1 (DNMT1) in endothelial cells which increased the global methylation of genomic DNA and promoted cell proliferation and migration.	('genomic', 'Protein', (149, 156))	('expression', 'MPA', (40, 50))	('cell proliferation', 'CPA', (174, 192))	('vIL-6', 'Gene', (21, 26))	('global methylation', 'MPA', (127, 145))	('enhanced', 'PosReg', (27, 35))	('vIL-6', 'Gene', '4961449', (21, 26))	('migration', 'CPA', (197, 206))	('promoted', 'PosReg', (165, 173))	('increased', 'PosReg', (113, 122))	('DNMT1', 'Gene', (79, 84))	('KS', 'Phenotype', 'HP:0100726', (16, 18))	('KSHV', 'Species', '37296', (16, 20))	('KSHV', 'Var', (16, 20))
52782	25199839	Other reports showed that knockdown of Nm23-H1 reduced proliferation and increased the percentage of cells arrested in the G0/G1 phase of the cell cycle.	('increased', 'PosReg', (73, 82))	('Nm23-H1', 'Gene', '4830', (39, 46))	('proliferation', 'CPA', (55, 68))	('Nm23-H1', 'Gene', (39, 46))	('knockdown', 'Var', (26, 35))	('reduced', 'NegReg', (47, 54))
52791	25199839	Identification of onco-Dbl resulted in the cloning of the proto-oncogene pDbl.	('Dbl', 'Gene', '4168', (23, 26))	('Dbl', 'Gene', (74, 77))	('Dbl', 'Gene', (23, 26))	('cloning', 'Var', (43, 50))	('Dbl', 'Gene', '4168', (74, 77))
52796	25199839	Several in vitro studies showed that overexpression of gelsolin stimulated tumor cell motility and invasion through the modulation of different signaling pathways, including EGFR, PI3K, and Ras-PI3K-Rac.	('EGFR', 'Gene', (174, 178))	('overexpression', 'PosReg', (37, 51))	('modulation', 'Reg', (120, 130))	('stimulated', 'PosReg', (64, 74))	('gelsolin', 'Gene', (55, 63))	('EGFR', 'Gene', '1956', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('invasion', 'CPA', (99, 107))	('PI3K', 'Var', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('gelsolin', 'Gene', '2934', (55, 63))
52818	25199839	Of note, Nm23-H1/H-Prune interaction is facilitated through casein kinase phosphorylation of Ser120, Ser122, and Ser125 of Nm23-H1.	('Ser122', 'Chemical', '-', (101, 107))	('casein kinase', 'Enzyme', (60, 73))	('facilitated', 'PosReg', (40, 51))	('Nm23-H1', 'Gene', (9, 16))	('Nm23-H1', 'Gene', '4830', (123, 130))	('H-Prune', 'Gene', '58497', (17, 24))	('Ser122', 'Var', (101, 107))	('Ser120', 'Var', (93, 99))	('Ser120', 'Chemical', '-', (93, 99))	('H-Prune', 'Gene', (17, 24))	('Nm23-H1', 'Gene', (123, 130))	('Ser125', 'Chemical', '-', (113, 119))	('Nm23-H1', 'Gene', '4830', (9, 16))	('Ser125', 'Var', (113, 119))
52880	25199839	Collectively, these studies established a role for additional metastasis suppressor genes in KS-associated pathogenesis and that regulation of Nm23-H1 by KSHV may synergize with other mechanisms to promote KS progression.	('KS', 'Phenotype', 'HP:0100726', (154, 156))	('Nm23-H1', 'Gene', '4830', (143, 150))	('promote', 'PosReg', (198, 205))	('KS', 'Phenotype', 'HP:0100726', (206, 208))	('KSHV', 'Gene', (154, 158))	('regulation', 'Var', (129, 139))	('metastasis suppressor genes', 'Gene', (62, 89))	('KS', 'Phenotype', 'HP:0100726', (93, 95))	('Nm23-H1', 'Gene', (143, 150))	('KS-associated', 'Disease', (93, 106))	('KSHV', 'Species', '37296', (154, 158))
52886	25199839	Followed by Nm23-H1 inhibition, HPV-16 E7-expressing HaCaT cells acquire invasiveness capabilities and resistance to granzyme A-induced apoptosis.	('Nm23-H1', 'Gene', (12, 19))	('HaCaT', 'CellLine', 'CVCL:0038', (53, 58))	('HPV-16', 'Species', '333760', (32, 38))	('E7-expressing', 'Var', (39, 52))	('invasiveness capabilities', 'CPA', (73, 98))	('granzyme A', 'Gene', (117, 127))	('granzyme A', 'Gene', '3001', (117, 127))	('Nm23-H1', 'Gene', '4830', (12, 19))	('HPV-16', 'Gene', (32, 38))
52890	25199839	Furthermore, loss of Nm23-H1 might allow HPV-16 E7 to promote cell transformation and tumor progression.	('cell transformation', 'CPA', (62, 81))	('promote', 'PosReg', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('Nm23-H1', 'Gene', '4830', (21, 28))	('HPV-16', 'Species', '333760', (41, 47))	('Nm23-H1', 'Gene', (21, 28))	('loss', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
52894	25199839	Necdin has been associated with genetic inactivation in human Prader-Willi syndrome (PWS).	('human', 'Species', '9606', (56, 61))	('PWS', 'Disease', 'MESH:D011218', (85, 88))	('Prader-Willi syndrome', 'Disease', (62, 83))	('PWS', 'Disease', (85, 88))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (62, 83))	('genetic inactivation', 'Var', (32, 52))
52919	25199839	Different studies suggested that tumor metastasis is the primary cause of death in cancer patients and modulation of nm23-H1 gene expression can be useful to understand the underlying mechanisms of metastatic invasion in malignant tumors.	('tumor metastasis', 'Disease', (33, 49))	('nm23-H1', 'Gene', (117, 124))	('modulation', 'Var', (103, 113))	('nm23-H1', 'Gene', '4830', (117, 124))	('malignant tumors', 'Disease', 'MESH:D018198', (221, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('death in cancer', 'Disease', 'MESH:D003643', (74, 89))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('death in cancer', 'Disease', (74, 89))	('tumor metastasis', 'Disease', 'MESH:D009362', (33, 49))	('patients', 'Species', '9606', (90, 98))	('malignant tumors', 'Disease', (221, 237))
52925	25199839	Experimental evidence showed that MPA induces Nm23 expression levels at higher dose in human breast carcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('breast carcinoma', 'Phenotype', 'HP:0003002', (93, 109))	('human', 'Species', '9606', (87, 92))	('expression levels', 'MPA', (51, 68))	('MPA', 'Var', (34, 37))	('Nm23', 'Gene', '4830', (46, 50))	('breast carcinoma', 'Disease', 'MESH:D001943', (93, 109))	('breast carcinoma', 'Disease', (93, 109))	('Nm23', 'Gene', (46, 50))
52926	25199839	Interestingly, high-dose-MPA exposure led to a reduction in anchorage-independent colonization which is further abrogated by Nm23-H1 antiserum transfection, suggesting an important role of MPA role for elevating Nm23 levels.	('Nm23', 'Gene', '4830', (212, 216))	('Nm23', 'Gene', (212, 216))	('Nm23-H1', 'Gene', (125, 132))	('transfection', 'Var', (143, 155))	('reduction', 'NegReg', (47, 56))	('anchorage-independent colonization', 'CPA', (60, 94))	('Nm23', 'Gene', '4830', (125, 129))	('Nm23-H1', 'Gene', '4830', (125, 132))	('abrogated', 'NegReg', (112, 121))	('Nm23', 'Gene', (125, 129))
52927	25199839	Silencing of Nm23-H1 also has consequences for several biological activities, including interruption of E-cadherin-mediated cell-to-cell adhesion, resulting in beta-catenin nuclear translocation, T cell factor transactivation, deregulated cellularmotility, and extracellular matrix invasion.	('deregulated cellularmotility', 'CPA', (227, 255))	('Nm23-H1', 'Gene', '4830', (13, 20))	('T cell factor transactivation', 'MPA', (196, 225))	('beta-catenin', 'Gene', (160, 172))	('consequences', 'Reg', (30, 42))	('Nm23-H1', 'Gene', (13, 20))	('interruption', 'NegReg', (88, 100))	('beta-catenin', 'Gene', '1499', (160, 172))	('extracellular matrix invasion', 'CPA', (261, 290))	('Silencing', 'Var', (0, 9))	('E-cadherin', 'Gene', (104, 114))	('E-cadherin', 'Gene', '999', (104, 114))
52932	25199839	Other evidence suggested a role for KSHV in regulating Nm23-H1 which may be an important mechanism for KSHV induction, and targeting Nm23-H1 could be a possible therapeutic approach for the treatment of KS.	('Nm23-H1', 'Gene', (55, 62))	('Nm23-H1', 'Gene', '4830', (133, 140))	('KSHV', 'Species', '37296', (103, 107))	('KS', 'Phenotype', 'HP:0100726', (203, 205))	('KS', 'Phenotype', 'HP:0100726', (103, 105))	('targeting', 'Var', (123, 132))	('Nm23-H1', 'Gene', (133, 140))	('KSHV', 'Species', '37296', (36, 40))	('Nm23-H1', 'Gene', '4830', (55, 62))	('KS', 'Phenotype', 'HP:0100726', (36, 38))
52937	28843265	Poly-L-Lysine Inhibits Tumor Angiogenesis and Induces Apoptosis in Ehrlich Ascites Carcinoma and in Sarcoma S-180 Tumor This study focuses on the role of Poly-L-lysine (PLL), an essential amino acid, on molecular changes of tumor angiogenesis suppression, pro-apoptotic and anti-apoptotic gene expression after treatment on Ehrlich ascites carcinoma (EAC) and solid sarcoma-180 tumor cells bearing mice.	('tumor', 'Disease', (378, 383))	('Ehrlich ascites carcinoma', 'Disease', 'MESH:D002286', (324, 349))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('Ehrlich Ascites Carcinoma', 'Disease', 'MESH:D002286', (67, 92))	('essential amino acid', 'Chemical', 'MESH:D000601', (178, 198))	('tumor', 'Disease', 'MESH:D009369', (378, 383))	('sarcoma-180 tumor', 'Disease', 'MESH:D012510', (366, 383))	('Tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Sarcoma S-180 Tumor', 'Disease', 'MESH:D012510', (100, 119))	('PLL', 'Chemical', '-', (169, 172))	('Ehrlich ascites carcinoma', 'Disease', (324, 349))	('Sarcoma S-180 Tumor', 'Disease', (100, 119))	('ascites', 'Phenotype', 'HP:0001541', (332, 339))	('Carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (340, 349))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('Sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Poly-L-Lysine', 'Chemical', '-', (0, 13))	('Poly-L-lysine', 'Chemical', '-', (154, 167))	('Poly-L-Lysine', 'Var', (0, 13))	('tumor', 'Disease', (224, 229))	('Inhibits', 'NegReg', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('Induces', 'Reg', (46, 53))	('sarcoma-180 tumor', 'Disease', (366, 383))	('mice', 'Species', '10090', (398, 402))	('Apoptosis', 'CPA', (54, 63))	('Tumor Angiogenesis', 'CPA', (23, 41))	('EAC', 'Chemical', '-', (351, 354))	('Tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Ascites', 'Phenotype', 'HP:0001541', (75, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (366, 373))	('Ehrlich Ascites Carcinoma', 'Disease', (67, 92))
52942	28843265	Precisely, PLL had cytotoxic effect on K562; A549; U937 and B16F10 cancer cells.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('U937', 'CellLine', 'CVCL:0007', (51, 55))	('cancer', 'Disease', (67, 73))	('A549', 'CellLine', 'CVCL:0023', (45, 49))	('PLL', 'Var', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('B16F10', 'CellLine', 'CVCL:0159', (60, 66))	('PLL', 'Chemical', '-', (11, 14))	('cytotoxic effect', 'CPA', (19, 35))	('K562', 'CellLine', 'CVCL:0004', (39, 43))
52951	28843265	Inhibiting tumor angiogenesis may halt tumor growth and decrease their metastatic potential.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Inhibiting', 'Var', (0, 10))	('halt', 'NegReg', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('metastatic potential', 'CPA', (71, 91))	('tumor', 'Disease', (39, 44))	('decrease', 'NegReg', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
52952	28843265	The cytokine vascular endothelial growth factor (VEGF) is the most important angiogenic factor associated closely with induction and maintenance of neovasculature structure in tumor (Bussolino et al., 1997; McMahon et al., 2000), so the inhibition of VEGF expression is known to have an impact on angiogenesis dependent tumor growth and metastasis.	('VEGF', 'Gene', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('vascular endothelial growth factor', 'Gene', (13, 47))	('impact', 'Reg', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('vascular endothelial growth factor', 'Gene', '22339', (13, 47))	('tumor', 'Disease', (176, 181))	('VEGF', 'Gene', '22339', (251, 255))	('inhibition', 'Var', (237, 247))	('VEGF', 'Gene', '22339', (49, 53))	('tumor', 'Disease', (320, 325))	('VEGF', 'Gene', (251, 255))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
52954	28843265	It has now been revealed that oncogenic mutations disrupt apoptosis, leading to tumor initiation, progression or metastasis.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('progression', 'CPA', (98, 109))	('tumor initiation', 'Disease', 'MESH:D009369', (80, 96))	('mutations', 'Var', (40, 49))	('tumor initiation', 'Disease', (80, 96))	('metastasis', 'CPA', (113, 123))	('apoptosis', 'CPA', (58, 67))	('leading to', 'Reg', (69, 79))
52961	28843265	For many years now, poly-L-lysine, PLL, has been known to have unusual biological properties, an early report indicating that PLL has some activity against murine tumors.	('PLL', 'Chemical', '-', (35, 38))	('murine', 'Species', '10090', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('activity', 'MPA', (139, 147))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('poly-L-lysine', 'Var', (20, 33))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('poly-L-lysine', 'Chemical', '-', (20, 33))	('PLL', 'Chemical', '-', (126, 129))
52971	28843265	In the present communication, we demonstrate the efficacy of the PLL amino acid on murine mammary Ehrlich ascites tumor (liquid tumour) and sarcoma-180 (solid tumor) cell lines at the molecular level to demonstrate its potential anti-tumor, apoptosis and angio-preventive activities.	('tumor', 'Disease', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('sarcoma-180', 'Disease', 'MESH:D012510', (140, 151))	('PLL amino acid', 'Var', (65, 79))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('solid tumor', 'Disease', 'MESH:D009369', (153, 164))	('sarcoma-180', 'Disease', (140, 151))	('tumor', 'Disease', (114, 119))	('Ehrlich ascites tumor', 'Disease', (98, 119))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('PLL', 'Chemical', '-', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('angio-preventive activities', 'CPA', (255, 282))	('tumor', 'Disease', (159, 164))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('apoptosis', 'CPA', (241, 250))	('Ehrlich ascites tumor', 'Disease', 'MESH:D002286', (98, 119))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('murine', 'Species', '10090', (83, 89))	('tumour', 'Disease', (128, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ascites', 'Phenotype', 'HP:0001541', (106, 113))	('solid tumor', 'Disease', (153, 164))
53140	28843265	Therefore, PLL reduced the ability of Bcl-2 to bind to Bax and enhanced the translocation of Bax from cytosol to mitochondria, further increasing the susceptibility of the cells to apoptosis (ZuKe et al., 2005).	('Bax', 'Gene', (93, 96))	('enhanced', 'PosReg', (63, 71))	('Bax', 'Gene', '12028', (55, 58))	('PLL', 'Chemical', '-', (11, 14))	('PLL', 'Var', (11, 14))	('apoptosis', 'CPA', (181, 190))	('reduced', 'NegReg', (15, 22))	('ability', 'MPA', (27, 34))	('Bax', 'Gene', '12028', (93, 96))	('bind', 'Interaction', (47, 51))	('Bax', 'Gene', (55, 58))	('translocation', 'MPA', (76, 89))	('susceptibility', 'MPA', (150, 164))	('increasing', 'PosReg', (135, 145))
53146	28843265	Inhibition of fluid accumulation, tumor growth, and microvessel density by neutralization of VEGF has demonstrated the importance of VEGF in malignant ascites formation (Kim et al., 1993; Colombo et al., 2002).	('VEGF', 'Gene', '22339', (133, 137))	('fluid accumulation', 'Phenotype', 'HP:0000969', (14, 32))	('VEGF', 'Gene', (93, 97))	('tumor', 'Disease', (34, 39))	('microvessel density', 'CPA', (52, 71))	('malignant ascites', 'Disease', (141, 158))	('neutralization', 'Var', (75, 89))	('malignant ascites', 'Disease', 'MESH:D001201', (141, 158))	('ascites', 'Phenotype', 'HP:0001541', (151, 158))	('VEGF', 'Gene', '22339', (93, 97))	('VEGF', 'Gene', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('fluid accumulation', 'CPA', (14, 32))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
53147	28843265	Our studies show that PLL inhibited tumor angiogenesis by inhibiting the secretion of VEGF dose dependently and prevented the formation of tumor directed capillaries resulting in reduced peritoneal angiogenesis in EAC bearing mice.	('prevented', 'NegReg', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('PLL', 'Var', (22, 25))	('mice', 'Species', '10090', (226, 230))	('inhibited', 'NegReg', (26, 35))	('VEGF', 'Gene', (86, 90))	('PLL', 'Chemical', '-', (22, 25))	('inhibiting', 'NegReg', (58, 68))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('peritoneal angiogenesis', 'CPA', (187, 210))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('VEGF', 'Gene', '22339', (86, 90))	('EAC', 'Chemical', '-', (214, 217))	('formation of', 'MPA', (126, 138))	('tumor', 'Disease', (36, 41))	('reduced', 'NegReg', (179, 186))
53153	28843265	Further in PLL treated cells there was a marked reduction in the density and size of surface microvilli.	('PLL treated', 'Var', (11, 22))	('reduction', 'NegReg', (48, 57))	('PLL', 'Chemical', '-', (11, 14))
53163	28843265	These results clearly indicate that PLL significantly inhibits cell viability in a dose dependent manner in EAC & Sarcoma-180 cells.	('Sarcoma-180', 'Disease', (114, 125))	('PLL', 'Var', (36, 39))	('Sarcoma-180', 'Disease', 'MESH:D012510', (114, 125))	('PLL', 'Chemical', '-', (36, 39))	('EAC', 'Chemical', '-', (108, 111))	('Sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('cell viability', 'CPA', (63, 77))	('inhibits', 'NegReg', (54, 62))
53164	28843265	PLL also changes the morphology of cells and is able to induce Bcl-2 dependent apoptosis in both ascites EAC and solid Sarcoma-180 tumor via an intrinsic mitochondrial pathway.	('Sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('ascites', 'Phenotype', 'HP:0001541', (97, 104))	('Bcl-2 dependent', 'MPA', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ascites', 'Disease', 'MESH:D001201', (97, 104))	('PLL', 'Var', (0, 3))	('induce', 'PosReg', (56, 62))	('apoptosis', 'CPA', (79, 88))	('EAC', 'Chemical', '-', (105, 108))	('ascites', 'Disease', (97, 104))	('PLL', 'Chemical', '-', (0, 3))	('Sarcoma-180 tumor', 'Disease', (119, 136))	('Sarcoma-180 tumor', 'Disease', 'MESH:D012510', (119, 136))	('changes', 'Reg', (9, 16))	('morphology', 'MPA', (21, 31))
53165	28843265	Our investigations demonstrate the expression of both p53 and Bax in the tumor cells increase significantly with the treatment of PLL, but reduce the level of Bcl-2, thereby resulting in increase of Bcl-2/Bax ratio, associated with sub-G1 phase cell cycle arrest, substantiating apoptosis.	('sub-G1 phase cell cycle', 'CPA', (232, 255))	('Bax', 'Gene', (205, 208))	('Bax', 'Gene', '12028', (62, 65))	('increase', 'PosReg', (187, 195))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (245, 262))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('level of Bcl-2', 'MPA', (150, 164))	('PLL', 'Var', (130, 133))	('expression', 'MPA', (35, 45))	('p53', 'Gene', (54, 57))	('Bax', 'Gene', '12028', (205, 208))	('tumor', 'Disease', (73, 78))	('Bax', 'Gene', (62, 65))	('PLL', 'Chemical', '-', (130, 133))	('reduce', 'NegReg', (139, 145))	('increase', 'PosReg', (85, 93))	('p53', 'Gene', '22060', (54, 57))
53167	28843265	Our results indicate PLL inhibits tumor cell proliferations via apoptotic pathway and tumor angiogenesis suppression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('inhibits', 'NegReg', (25, 33))	('tumor', 'Disease', (86, 91))	('PLL', 'Var', (21, 24))	('apoptotic pathway', 'Pathway', (64, 81))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PLL', 'Chemical', '-', (21, 24))
53176	27132463	Each of the sarcoma sub-types has a distinct genetic profile and phenotype with some such as osteosarcoma characterized by a highly unstable and complex genome while others such as Ewing sarcoma characterized by a translocation between EWSR1 gene and a variety of ETS partners as the single major oncogenic driver.	('EWSR1', 'Gene', '2130', (236, 241))	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('Ewing sarcoma', 'Disease', (181, 194))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('sarcoma', 'Disease', (12, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('sarcoma', 'Disease', (187, 194))	('osteosarcoma', 'Disease', (93, 105))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (93, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (181, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('sarcoma', 'Disease', (98, 105))	('EWSR1', 'Gene', (236, 241))	('translocation', 'Var', (214, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (181, 194))
53186	27132463	These include: 1) establishment of better measures to identify patient prognosis and response to therapy by analysis of circulating tumor DNA; 2) analysis of a variety of germline genetic alterations such as in the gene TP53 that may impact development and progression of sarcomas; and 3) development of novel techniques of freezing tissue samples that would allow for creation of patient derived xenografts (PDXs) in the context of standard therapy or clinical trials.	('TP53', 'Gene', '7157', (220, 224))	('TP53', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (272, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('sarcomas', 'Disease', (272, 280))	('progression', 'CPA', (257, 268))	('patient', 'Species', '9606', (381, 388))	('DNA; 2', 'Gene', '1763', (138, 144))	('tumor', 'Disease', (132, 137))	('impact', 'Reg', (234, 240))	('development', 'CPA', (241, 252))	('alterations', 'Var', (188, 199))	('patient', 'Species', '9606', (63, 70))	('DNA; 2', 'Gene', (138, 144))	('sarcomas', 'Disease', 'MESH:D012509', (272, 280))
53193	27132463	The most commonly mutated gene is TP53 often through an inactivating translocation in intron 1.	('inactivating translocation', 'Var', (56, 82))	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))
53202	27132463	In summary, the challenges that remain with the work completed so far include lack of potentially targetable mutations in any significant frequency to validate in a clinical trial, potential clonal heterogeneity within tumors, lack of understanding of epigenetic events, and lack of genomic data in relapsed or refractory tumors as well as metastatic tumors in osteosarcoma.	('tumors', 'Disease', 'MESH:D009369', (322, 328))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('tumors', 'Disease', (351, 357))	('tumors', 'Disease', 'MESH:D009369', (351, 357))	('osteosarcoma', 'Phenotype', 'HP:0002669', (361, 373))	('osteosarcoma', 'Disease', (361, 373))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('sarcoma', 'Phenotype', 'HP:0100242', (366, 373))	('mutations', 'Var', (109, 118))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('tumors', 'Disease', (322, 328))	('osteosarcoma', 'Disease', 'MESH:D012516', (361, 373))
53206	27132463	Two novel loci associated with risk of osteosarcoma achieved genome-wide significance: rs1906953 at 6p21.3, which maps to the GRM4 gene and rs7591996 in a gene desert on 2p25.	('osteosarcoma', 'Phenotype', 'HP:0002669', (39, 51))	('rs1906953', 'Var', (87, 96))	('rs7591996', 'Mutation', 'rs7591996', (140, 149))	('rs7591996', 'Var', (140, 149))	('rs1906953', 'Mutation', 'rs1906953', (87, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('osteosarcoma', 'Disease', (39, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (39, 51))	('GRM4', 'Gene', '2914', (126, 130))	('GRM4', 'Gene', (126, 130))
53209	27132463	This study identified a genome-wide significant SNP, rs7034162, in the NFIB gene at 9p24.1 strongly associated with metastasis in European osteosarcoma patients, as well as in patients of African and Brazilian ancestry.	('patients', 'Species', '9606', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('rs7034162', 'Mutation', 'rs7034162', (53, 62))	('associated with', 'Reg', (100, 115))	('NFIB', 'Gene', (71, 75))	('NFIB', 'Gene', '4781', (71, 75))	('metastasis', 'CPA', (116, 126))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('osteosarcoma', 'Disease', 'MESH:D012516', (139, 151))	('osteosarcoma', 'Disease', (139, 151))	('rs7034162', 'Var', (53, 62))	('patients', 'Species', '9606', (152, 160))
53210	27132463	The rs7034162 risk allele was also significantly associated with worse overall survival.	('overall', 'MPA', (71, 78))	('worse', 'NegReg', (65, 70))	('rs7034162', 'Var', (4, 13))	('rs7034162', 'Mutation', 'rs7034162', (4, 13))
53212	27132463	Importantly, this study suggests a connection between germline genetics and osteosarcoma metastasis at diagnosis, the leading cause of death in osteosarcoma patients.	('osteosarcoma metastasis', 'Disease', (76, 99))	('osteosarcoma metastasis', 'Disease', 'MESH:D009362', (76, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (144, 156))	('death in osteosarcoma', 'Disease', (135, 156))	('patients', 'Species', '9606', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('death in osteosarcoma', 'Disease', 'MESH:D012516', (135, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('germline genetics', 'Var', (54, 71))
53213	27132463	Osteosarcoma is a hallmark of certain inherited cancer syndromes such as Li-Fraumeni syndrome (LFS), which is caused by autosomal dominant, germline TP53 mutations.	('caused by', 'Reg', (110, 119))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (73, 93))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('LFS', 'Disease', 'MESH:D016864', (95, 98))	('TP53', 'Gene', '7157', (149, 153))	('Li-Fraumeni syndrome', 'Disease', (73, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('Osteosarcoma', 'Disease', (0, 12))	('TP53', 'Gene', (149, 153))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mutations', 'Var', (154, 163))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('LFS', 'Disease', (95, 98))
53215	27132463	A large study was conducted to determine the prevalence of germline TP53 mutations in unselected osteosarcoma cases.	('germline', 'Var', (59, 67))	('osteosarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('osteosarcoma', 'Disease', (97, 109))	('osteosarcoma', 'Disease', 'MESH:D012516', (97, 109))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('mutations', 'Var', (73, 82))
53216	27132463	They observed a high frequency of young osteosarcoma cases (<=29 years of age) carrying a known LFS or likely LFS-associated mutation (3.4%) or rare exonic variant (5.7%), compared with none observed in cases 30 years of age or older.	('LFS', 'Disease', 'MESH:D016864', (110, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('LFS', 'Disease', (96, 99))	('LFS', 'Disease', (110, 113))	('osteosarcoma', 'Disease', (40, 52))	('LFS', 'Disease', 'MESH:D016864', (96, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (40, 52))	('mutation', 'Var', (125, 133))	('osteosarcoma', 'Disease', 'MESH:D012516', (40, 52))
53224	27132463	Beyond the characteristic translocation, variants that are relatively common include mutations in the tumor suppressors STAG2 and TP53 as well as CDKN2A deletions (Figure 1).	('CDKN2A', 'Gene', (146, 152))	('tumor', 'Disease', (102, 107))	('CDKN2A', 'Gene', '1029', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mutations', 'Var', (85, 94))	('STAG2', 'Gene', (120, 125))	('STAG2', 'Gene', '10735', (120, 125))	('TP53', 'Gene', '7157', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('TP53', 'Gene', (130, 134))	('deletions', 'Var', (153, 162))
53225	27132463	While alterations in TP53 and CDKN2A had previously been known to be present in Ewing sarcoma, they have not thus far proven to be prognostic when evaluated in a subset of patients treated with multi-agent interval compressed chemotherapy.	('TP53', 'Gene', (21, 25))	('alterations', 'Var', (6, 17))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('CDKN2A', 'Gene', (30, 36))	('CDKN2A', 'Gene', '1029', (30, 36))	('Ewing sarcoma', 'Disease', (80, 93))	('patients', 'Species', '9606', (172, 180))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))	('TP53', 'Gene', '7157', (21, 25))
53228	27132463	Ewing sarcoma provides a unique opportunity for serial disease monitoring through circulating tumor cells or cell free circulating tumor DNA due to the presence of a known translocation that is tumor specific.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('translocation', 'Var', (172, 185))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Ewing sarcoma', 'Disease', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (131, 136))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('tumor', 'Disease', (194, 199))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))
53232	27132463	Some of this risk may be related to the GGAA microsatellite polymorphisms in the NROB1 gene or other GGAA microsatellite regions across the genome.	('NROB1', 'Gene', '190', (81, 86))	('NROB1', 'Gene', (81, 86))	('microsatellite polymorphisms', 'Var', (45, 73))
53233	27132463	Recently, a susceptibility variant in the enhancer region of EGR2 has been identified representing the first such germline determinant that predisposes to development of Ewing sarcoma, and this also may be related to its impact on GGAA microsatellite length.	('predisposes to', 'Reg', (140, 154))	('EGR2', 'Gene', '1959', (61, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (170, 183))	('EGR2', 'Gene', (61, 65))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (170, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('Ewing sarcoma', 'Disease', (170, 183))	('variant', 'Var', (27, 34))	('susceptibility', 'Reg', (12, 26))
53241	27132463	Fusion negative tumors frequently acquire mutations along the receptor tyrosine kinase/RAS/PI3K pathway, including in NRAS, HRAS, KRAS, PIK3CA, NF1 and FGFR4, which are potentially amenable to targeted therapy.	('HRAS', 'Gene', '3265', (124, 128))	('FGFR4', 'Gene', '2264', (152, 157))	('PIK3CA', 'Gene', '5290', (136, 142))	('HRAS', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('acquire', 'Reg', (34, 41))	('tumors', 'Disease', (16, 22))	('NF1', 'Gene', (144, 147))	('KRAS', 'Gene', '3845', (130, 134))	('FGFR4', 'Gene', (152, 157))	('KRAS', 'Gene', (130, 134))	('NRAS', 'Gene', '4893', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('PIK3CA', 'Gene', (136, 142))	('receptor tyrosine kinase/RAS/PI3K pathway', 'Pathway', (62, 103))	('NRAS', 'Gene', (118, 122))	('NF1', 'Gene', '4763', (144, 147))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mutations', 'Var', (42, 51))
53242	27132463	Additional observations include recurrent mutations in BCOR and FBXW7 but their clinical significance remains to be determined.	('FBXW7', 'Gene', '55294', (64, 69))	('BCOR', 'Gene', (55, 59))	('BCOR', 'Gene', '54880', (55, 59))	('FBXW7', 'Gene', (64, 69))	('mutations', 'Var', (42, 51))
53243	27132463	A subset of rhabdomyosarcoma tumors harbor point mutations in the muscle development transcription factor MYOD1.	('rhabdomyosarcoma tumors', 'Disease', 'MESH:D012208', (12, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('point mutations', 'Var', (43, 58))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('MYOD1', 'Gene', '4654', (106, 111))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (12, 28))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('rhabdomyosarcoma tumors', 'Disease', (12, 35))	('MYOD1', 'Gene', (106, 111))
53244	27132463	Interestingly, these mutations appear to lead to a muscle development block and are associated with activating mutations in PIK3CA, which confers an aggressive phenotype of embryonal rhabdomyosarcoma.	('mutations', 'Var', (111, 120))	('mutations', 'Var', (21, 30))	('embryonal rhabdomyosarcoma', 'Disease', (173, 199))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (173, 199))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (173, 199))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (183, 199))	('activating', 'PosReg', (100, 110))	('PIK3CA', 'Gene', (124, 130))	('associated', 'Reg', (84, 94))	('lead to', 'Reg', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('PIK3CA', 'Gene', '5290', (124, 130))	('muscle development block', 'CPA', (51, 75))
53245	27132463	Recently, dystrophin has been identified as a tumor suppressor gene and an intragenic deletion in this gene leads to progression of myogenic tumors to aggressive sarcomas.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('dystrophin', 'Gene', '1756', (10, 20))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (141, 146))	('leads to', 'Reg', (108, 116))	('myogenic tumors to aggressive sarcomas', 'Disease', 'MESH:D012509', (132, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('progression', 'PosReg', (117, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('myogenic tumors to aggressive sarcomas', 'Disease', (132, 170))	('dystrophin', 'Gene', (10, 20))	('deletion', 'Var', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
53246	27132463	Dystrophin inactivation has been found in 100% of embryonal rhabdomyosarcoma tumors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('Dystrophin', 'Gene', '1756', (0, 10))	('found', 'Reg', (33, 38))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (60, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('inactivation', 'Var', (11, 23))	('embryonal rhabdomyosarcoma tumors', 'Disease', (50, 83))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (50, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('embryonal rhabdomyosarcoma tumors', 'Disease', 'MESH:D018233', (50, 83))	('Dystrophin', 'Gene', (0, 10))
53249	27132463	The authors identified loss of heterozygosity as an early event within the development of fusion negative tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('negative', 'NegReg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('loss of heterozygosity', 'Var', (23, 45))
53250	27132463	In addition, they identify mutation of PKN1, which confers a developmental block, as an early event in a small subset of tumors.	('PKN1', 'Gene', '5585', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('PKN1', 'Gene', (39, 43))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('mutation', 'Var', (27, 35))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('developmental block', 'Disease', 'MESH:D006327', (61, 80))	('developmental block', 'Disease', (61, 80))
53259	27132463	While continued characterization of both germline and somatic variations is vital to improving our understanding of the fundamental biology of sarcomas, there is also a clear understanding that this genomic analysis will not provide a complete explanation of pathogenesis for sarcomas nor will genomics reveal all possible avenues for new therapies.	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcomas', 'Disease', (143, 151))	('variations', 'Var', (62, 72))	('sarcomas', 'Disease', 'MESH:D012509', (276, 284))	('sarcomas', 'Phenotype', 'HP:0100242', (276, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('sarcomas', 'Disease', (276, 284))	('sarcomas', 'Disease', 'MESH:D012509', (143, 151))
53263	27132463	Epigenetic modifications have been shown to be the driving force in several cancers especially pediatric cancers that have hallmark translocations leading to fusion proteins.	('force', 'Reg', (59, 64))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers especially pediatric cancers', 'Disease', 'MESH:D009369', (76, 112))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('fusion', 'MPA', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Epigenetic modifications', 'Var', (0, 24))	('cancers especially pediatric cancers', 'Disease', (76, 112))
53266	27132463	Data from sequencing studies show that more than 20% of human tumors have mutations in mSWI/SNF (BAF complexes).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BAF', 'Gene', '8815', (97, 100))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('mutations', 'Var', (74, 83))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('human', 'Species', '9606', (56, 61))	('mSWI/SNF', 'Gene', (87, 95))	('BAF', 'Gene', (97, 100))	('human', 'Disease', (56, 61))
53295	27132463	Data on 15 pediatric and young adult sarcoma patients accumulated from prospective clinical testing using MSK-IMPACT clinical next generation sequencing (NGS) assay, showed examples of RAS-mutated embryonal rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, and MYOD1 L122R positive rhabdomyosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('sarcoma', 'Disease', 'MESH:D012509', (245, 252))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (239, 252))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (239, 252))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (197, 223))	('patients', 'Species', '9606', (45, 53))	('sarcoma', 'Disease', (245, 252))	('rhabdomyosarcoma', 'Disease', (279, 295))	('rhabdomyosarcoma', 'Disease', (207, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('sarcoma', 'Disease', 'MESH:D012509', (37, 44))	('osteosarcoma', 'Disease', (225, 237))	('sarcoma', 'Disease', (37, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('osteosarcoma', 'Disease', 'MESH:D012516', (225, 237))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (279, 295))	('Ewing sarcoma', 'Disease', (239, 252))	('MYOD1', 'Gene', (258, 263))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (207, 223))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (279, 295))	('RAS-mutated', 'Var', (185, 196))	('sarcoma', 'Disease', 'MESH:D012509', (288, 295))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (197, 223))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (207, 223))	('sarcoma', 'Disease', 'MESH:D012509', (216, 223))	('sarcoma', 'Disease', (288, 295))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcoma', 'Disease', (216, 223))	('embryonal rhabdomyosarcoma', 'Disease', (197, 223))	('L122R', 'Mutation', 'p.L122R', (264, 269))	('sarcoma', 'Disease', 'MESH:D012509', (230, 237))	('MYOD1', 'Gene', '4654', (258, 263))	('osteosarcoma', 'Phenotype', 'HP:0002669', (225, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('sarcoma', 'Disease', (230, 237))
53296	27132463	In addition, the NGS data generated by MSK-IMPACT can pinpoint the genomic EWSR1-FLI1 or EWSR1-ERG rearrangement in a given patient with Ewing sarcoma which can then be used to design patient-specific PCR assays for circulating tumor DNA detection by digital PCR, enabling longitudinal disease monitoring in the context of an ongoing research protocol.	('EWSR1', 'Gene', '2130', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('FLI1', 'Gene', '2313', (81, 85))	('patient', 'Species', '9606', (184, 191))	('Ewing sarcoma', 'Disease', (137, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('rearrangement', 'Var', (99, 112))	('EWSR1', 'Gene', '2130', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('EWSR1', 'Gene', (75, 80))	('longitudinal disease', 'Disease', (273, 293))	('patient', 'Species', '9606', (124, 131))	('EWSR1', 'Gene', (89, 94))	('ERG', 'Gene', (95, 98))	('longitudinal disease', 'Disease', 'MESH:D017887', (273, 293))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (137, 150))	('tumor', 'Disease', (228, 233))	('ERG', 'Gene', '2078', (95, 98))	('FLI1', 'Gene', (81, 85))
53299	27132463	Profile has demonstrated good specificity and sensitivity for point mutations, amplifications and deletions across tumor types.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('point mutations', 'Var', (62, 77))	('amplifications', 'Var', (79, 93))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('deletions', 'Var', (98, 107))
53300	27132463	Several diagnoses were changed after the sequencing results reveled a translocation or set of mutations that lead to better characterization of the tumor type with obvious therapeutic implications as well.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', (148, 153))	('translocation', 'Var', (70, 83))	('changed', 'Reg', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
53301	27132463	Approximately 60% of adult patients who had their tumors profiled showed a mutation with potential clinical utility, which included both mutations that are necessary for cancer development or those that may be useful in the context of a particular tumor.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Disease', (170, 176))	('mutation', 'Var', (75, 83))	('mutations', 'Var', (137, 146))	('patients', 'Species', '9606', (27, 35))	('particular tumor', 'Disease', 'MESH:D009369', (237, 253))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('particular tumor', 'Disease', (237, 253))
53304	27132463	iCAT (individualized cancer therapy) 1 was a multi-institutional protocol prospectively enrolling pediatric patients with relapsed/refractory non-CNS solid tumors with the primary objective of determining the feasibility of identifying genetic alterations in patient tumors to be able to make a clinical therapeutic recommendation.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('solid tumors', 'Disease', (150, 162))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('genetic alterations', 'Var', (236, 255))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('solid tumors', 'Disease', 'MESH:D009369', (150, 162))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('patients', 'Species', '9606', (108, 116))	('patient', 'Species', '9606', (108, 115))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (267, 273))	('tumors', 'Disease', (156, 162))	('patient', 'Species', '9606', (259, 266))	('tumors', 'Disease', 'MESH:D009369', (267, 273))
53316	27132463	The data from the first 150 patients enrolled on this study revealed approximately 25% of tumor reports to include somatic mutations classified as being of established or potential clinical utility, and about 8% of germline reports identifying pathogenic or potentially pathogenic germline mutations in cancer susceptibility genes.	('pathogenic', 'Reg', (244, 254))	('cancer', 'Disease', (303, 309))	('germline mutations', 'Var', (281, 299))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('patients', 'Species', '9606', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
53328	27132463	Study subjects will have a tumor biopsy at the time of disease recurrence in order to provide tissue for sequencing on a targeted cancer gene mutation panel.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Disease', (27, 32))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mutation', 'Var', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
53343	27132463	A summary of proceedings from translational research workshop on pediatric sarcomas Discusses biology advancements in pediatric sarcomas Discusses ongoing/planned precision medicine trials in pediatric oncology Outlines key areas of future research in pediatric sarcomas These include- evaluate circulating tumor DNA, germline variants and develop PDXs	('pediatric sarcomas', 'Disease', 'MESH:D063766', (118, 136))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('sarcomas', 'Phenotype', 'HP:0100242', (262, 270))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (252, 270))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (262, 269))	('oncology', 'Phenotype', 'HP:0002664', (202, 210))	('tumor', 'Disease', (307, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('pediatric sarcomas', 'Disease', (118, 136))	('pediatric sarcomas', 'Disease', (65, 83))	('PDXs', 'Disease', (348, 352))	('germline variants', 'Var', (318, 335))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (65, 83))	('pediatric sarcomas', 'Disease', (252, 270))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
53537	20979180	EWS-FLI1 expression is essential for Ewing sarcoma cells, as targeting of EWS-FLI1 with antisense oligonucleotides or RNAi inhibits proliferation, survival, and oncogenic transformation.	('Ewing sarcoma', 'Disease', (37, 50))	('oncogenic transformation', 'CPA', (161, 185))	('EWS-FLI1', 'Gene', (74, 82))	('survival', 'CPA', (147, 155))	('targeting', 'Var', (61, 70))	('antisense', 'Var', (88, 97))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (37, 50))	('oligonucleotides', 'Chemical', 'MESH:D009841', (98, 114))	('proliferation', 'CPA', (132, 145))	('inhibits', 'NegReg', (123, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
53569	20979180	All tumors progressed on treatment including A673, although the growth rate of this line was inhibited ~50%.	('growth rate', 'CPA', (64, 75))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('progressed', 'PosReg', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('inhibited', 'NegReg', (93, 102))	('A673', 'Var', (45, 49))
53570	20979180	While the increase in time to event was statistically significant for CHLA258 and A673, this did not meet criteria for intermediate activity (EFS (T/C) >=2), thus had "low" activity by all criteria (Table II).	('CHLA258', 'Var', (70, 77))	('CHLA258', 'Chemical', '-', (70, 77))	('time', 'MPA', (22, 26))	('A673', 'Var', (82, 86))	('increase', 'PosReg', (10, 18))
53579	26545119	Aberrant miRNA expression contributes to the development of many types of cancer.	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('expression', 'Species', '29278', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('contributes to', 'Reg', (26, 40))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
53586	26545119	While single-knockout mutants still showed a marked reduction in SMAD2 expression, TIVE cells infected by a double-knockout mutant virus were fully restored for SMAD2 expression, compared to non-infected TIVE cells.	('reduction', 'NegReg', (52, 61))	('expression', 'MPA', (71, 81))	('SMAD2', 'Gene', (65, 70))	('SMAD2', 'Gene', '4087', (161, 166))	('SMAD2', 'Gene', '4087', (65, 70))	('mutant', 'Var', (124, 130))	('expression', 'Species', '29278', (167, 177))	('expression', 'Species', '29278', (71, 81))	('expression', 'MPA', (167, 177))	('SMAD2', 'Gene', (161, 166))
53589	26545119	Manipulation of the TGF-beta pathway via host miRNAs represents a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS.	('TGF-beta', 'Gene', (20, 28))	('KSHV', 'Disease', (108, 112))	('miR', 'Gene', (46, 49))	('angiogenesis', 'CPA', (131, 143))	('tumor', 'Disease', (113, 118))	('KSHV', 'Species', '37296', (108, 112))	('KS', 'Phenotype', 'HP:0100726', (108, 110))	('KS', 'Phenotype', 'HP:0100726', (159, 161))	('Manipulation', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('miR', 'Gene', '220972', (46, 49))
53591	26545119	Dysregulation of miRNAs is a hallmark of many human cancers.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('human', 'Species', '9606', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
53603	26545119	Furthermore, vFLIP does not just block the extrinsic signal but also induces NF-kappaB signaling, which is important for viral latency and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('vFLIP', 'Chemical', '-', (13, 18))	('NF-kappaB signaling', 'MPA', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('induces', 'Reg', (69, 76))	('tumor', 'Disease', (139, 144))	('vFLIP', 'Var', (13, 18))	('block', 'NegReg', (33, 38))	('extrinsic signal', 'MPA', (43, 59))
53614	26545119	Dysregulation of miRNAs is not only a hallmark of many human malignancies but is also involved in the development and progression of cancer.	('malignancies', 'Disease', 'MESH:D009369', (61, 73))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('malignancies', 'Disease', (61, 73))	('human', 'Species', '9606', (55, 60))	('cancer', 'Disease', (133, 139))	('involved', 'Reg', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
53618	26545119	Amplification of this region is found in several types of lymphomas and lung cancer and overexpression in transgenic mice causes B cell lymphomas.	('B cell lymphomas', 'Disease', (129, 145))	('Amplification', 'Var', (0, 13))	('lymphomas', 'Phenotype', 'HP:0002665', (136, 145))	('lymphomas', 'Phenotype', 'HP:0002665', (58, 67))	('found', 'Reg', (32, 37))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (129, 145))	('B cell lymphomas', 'Disease', 'MESH:D016393', (129, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('transgenic mice', 'Species', '10090', (106, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (58, 66))	('expression', 'Species', '29278', (92, 102))	('lymphomas and lung cancer', 'Disease', 'MESH:D008175', (58, 83))
53620	26545119	With respect to cell cycle control, the miR-17-92 cluster miRNAs target the E2F transcription factor family but are also activated by E2F, thereby establishing a negative feedback loop.	('miR', 'Gene', '220972', (40, 43))	('E2F', 'Var', (134, 137))	('miR', 'Gene', (40, 43))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('E2F transcription factor family', 'Pathway', (76, 107))	('activated', 'PosReg', (121, 130))	('target', 'Reg', (65, 71))
53664	26545119	However, transfection of vFLIP or vCyclin diminished the response to the TGF-beta measured by luciferase activity (Fig 3B and 3C).	('vCyclin', 'Gene', (34, 41))	('vFLIP', 'Chemical', '-', (25, 30))	('diminished', 'NegReg', (42, 52))	('vCyclin', 'Gene', '4961471', (34, 41))	('response to the TGF-beta', 'MPA', (57, 81))	('luciferase', 'Enzyme', (94, 104))	('transfection', 'Var', (9, 21))
53672	26545119	To generate single or double knock-out mutant viruses of vFLIP or vCyclin, KSHV BAC16 was used.	('vCyclin', 'Gene', (66, 73))	('vCyclin', 'Gene', '4961471', (66, 73))	('mutant', 'Var', (39, 45))	('KS', 'Phenotype', 'HP:0100726', (75, 77))	('KSHV', 'Species', '37296', (75, 79))	('vFLIP', 'Chemical', '-', (57, 62))
53674	26545119	To mutate vFLIP or vCyclin without affecting the complex RNA expression pattern in this locus, we mutated start codons rather than deleting open reading frames.	('vFLIP', 'Chemical', '-', (10, 15))	('vCyclin', 'Gene', '4961471', (19, 26))	('mutate', 'Var', (3, 9))	('expression', 'Species', '29278', (61, 71))	('mutated', 'Var', (98, 105))	('vCyclin', 'Gene', (19, 26))
53677	26545119	Infection of iSLK cells with the DeltavFLIP mutant resulted in a detectable but significantly lower expression level of SMAD2.	('SMAD2', 'Gene', (120, 125))	('SMAD2', 'Gene', '4087', (120, 125))	('expression level', 'MPA', (100, 116))	('DeltavFLIP mutant', 'Var', (33, 50))	('vFLIP', 'Chemical', '-', (38, 43))	('expression', 'Species', '29278', (100, 110))	('lower', 'NegReg', (94, 99))
53678	26545119	In contrast, infection with the DeltavCyclin mutant virus restored SMAD2 protein levels similar to that seen in uninfected iSLK cells.	('mutant', 'Var', (45, 51))	('vCyclin', 'Gene', '4961471', (37, 44))	('infection', 'Disease', (13, 22))	('infection', 'Disease', 'MESH:D007239', (13, 22))	('restored', 'PosReg', (58, 66))	('SMAD2', 'Gene', '4087', (67, 72))	('SMAD2', 'Gene', (67, 72))	('vCyclin', 'Gene', (37, 44))
53681	26545119	Wt or mutant virus-infected iSLK cells, which express the RTA gene as an inducible transgene, were used to generate high titer virus that after quantification was used to stably infect TIVE cells.	('mutant', 'Var', (6, 12))	('RTA', 'Gene', '23543', (58, 61))	('RTA', 'Gene', (58, 61))
53686	26545119	Infection of TIVE cells with the DeltavFLIP/DeltavCyc mutant fully restored the SMAD2 expression to levels observed in uninfected TIVE cells (Fig 5B).	('vFLIP', 'Chemical', '-', (38, 43))	('expression', 'Species', '29278', (86, 96))	('expression', 'MPA', (86, 96))	('SMAD2', 'Gene', (80, 85))	('SMAD2', 'Gene', '4087', (80, 85))	('restored', 'PosReg', (67, 75))	('DeltavFLIP/DeltavCyc', 'Var', (33, 53))
53692	26545119	Steady-state SMAD2 mRNA levels were not significantly changed in KSHV infected TIVE cells, compared to mock infected cells (Fig 5C).	('KSHV', 'Species', '37296', (65, 69))	('SMAD2', 'Gene', '4087', (13, 18))	('SMAD2', 'Gene', (13, 18))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('mRNA levels', 'MPA', (19, 30))	('KSHV infected', 'Var', (65, 78))
53693	26545119	We observed a slight increase in SMAD2 mRNA in cells infected with single knock-out mutant.	('mRNA', 'MPA', (39, 43))	('mutant', 'Var', (84, 90))	('SMAD2', 'Gene', '4087', (33, 38))	('SMAD2', 'Gene', (33, 38))	('increase', 'PosReg', (21, 29))
53702	26545119	Complete loss of SMAD2 was not only observed in SLK cells over-expressing vFLIP and vCyc by transfection, but also in WT KSHV infected cells of both epithelial (SLK) and endothelial (TIVE) origin (Figs 3A, 5A and 5B).	('transfection', 'Var', (92, 104))	('SMAD2', 'Gene', (17, 22))	('SMAD2', 'Gene', '4087', (17, 22))	('KS', 'Phenotype', 'HP:0100726', (121, 123))	('KSHV', 'Species', '37296', (121, 125))	('loss', 'NegReg', (9, 13))	('over-expressing', 'PosReg', (58, 73))	('vFLIP', 'Chemical', '-', (74, 79))	('vFLIP', 'Gene', (74, 79))
53704	26545119	In latently infected SLK cells, deletion of vCyc was sufficient to restore SMAD2 expression to nearly wt levels whereas deletion of vFLIP did not restore SMAD2.	('SMAD2', 'Gene', (75, 80))	('SMAD2', 'Gene', (154, 159))	('deletion', 'Var', (32, 40))	('SMAD2', 'Gene', '4087', (154, 159))	('vCyc', 'Gene', (44, 48))	('vFLIP', 'Chemical', '-', (132, 137))	('expression', 'Species', '29278', (81, 91))	('SMAD2', 'Gene', '4087', (75, 80))	('restore', 'PosReg', (67, 74))	('expression', 'MPA', (81, 91))
53720	26545119	Molluscum Contagiosum Virus (MCV) is a poxvirus that encodes two FLIP proteins termed MC159 and MC160, which encode two DED domains but contrary to KSHV vFLIP do not induce NFkB but rather inhibit it.	('vFLIP', 'Var', (153, 158))	('KSHV', 'Species', '37296', (148, 152))	('vFLIP', 'Chemical', '-', (153, 158))	('Molluscum Contagiosum', 'Phenotype', 'HP:0032163', (0, 21))	('NFkB', 'MPA', (173, 177))	('KS', 'Phenotype', 'HP:0100726', (148, 150))	('induce', 'Reg', (166, 172))	('Molluscum Contagiosum Virus', 'Species', '10279', (0, 27))	('MCV', 'Species', '10279', (29, 32))	('inhibit', 'NegReg', (189, 196))
53722	26545119	Hence, in addition to inhibiting apoptosis, modulating NFkB positively or negatively, and inhibiting IRF-3, viral FLIP proteins also induce the oncogenic miR-17-92 cluster.	('apoptosis', 'CPA', (33, 42))	('induce', 'PosReg', (133, 139))	('oncogenic miR-17-92', 'CPA', (144, 163))	('modulating', 'Var', (44, 54))	('IRF-3', 'Gene', (101, 106))	('IRF-3', 'Gene', '3661', (101, 106))	('inhibiting', 'NegReg', (90, 100))	('NFkB', 'Gene', (55, 59))	('inhibiting', 'NegReg', (22, 32))
53727	26545119	At high levels of TGF-beta, signaling occurs through phosphorylation of SMAD2, 3, and 4, which in endothelial cells is antiangiogenic and in fully transformed cells is associated with NF-kB activation.	('TGF-beta', 'Gene', (18, 26))	('antiangiogenic', 'CPA', (119, 133))	('SMAD2, 3', 'Gene', '4087;4088', (72, 80))	('phosphorylation', 'Var', (53, 68))
53728	26545119	Conversely, at low concentrations of TGF-beta, signaling occurs through phosphorylation of SMAD 1,5, and 8 which is proangiogenic and induces proliferation and migration associated with high levels of ID1 known to be activated in KSHV latently infected cells.	('KS', 'Phenotype', 'HP:0100726', (230, 232))	('proliferation', 'CPA', (142, 155))	('ID1', 'Gene', (201, 204))	('migration', 'CPA', (160, 169))	('TGF-beta', 'Gene', (37, 45))	('induces', 'PosReg', (134, 141))	('KSHV', 'Species', '37296', (230, 234))	('phosphorylation', 'Var', (72, 87))
53739	26545119	iSLK or TIVE cells, infected with KSHV BAC16 wild type or mutant viruses, were treated with 50 mug/mL Hygromycin for maintaining latently infected cells.	('mutant', 'Var', (58, 64))	('KSHV', 'Species', '37296', (34, 38))	('KS', 'Phenotype', 'HP:0100726', (34, 36))	('KSHV BAC16', 'Gene', (34, 44))	('Hygromycin', 'Chemical', 'MESH:C026273', (102, 112))
53843	23326300	NLGP can activate T cells, NK cells, inhibit Tregs, promote type 1 cytokine microenvironment and rectify altered chemokine signaling, thereby, inducing antigen-specific tumor cell killing.	('inducing', 'PosReg', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('activate', 'PosReg', (9, 17))	('inhibit', 'NegReg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Tregs', 'CPA', (45, 50))	('altered chemokine signaling', 'MPA', (105, 132))	('tumor', 'Disease', (169, 174))	('type 1 cytokine microenvironment', 'MPA', (60, 92))	('Treg', 'Chemical', '-', (45, 49))	('NK cells', 'CPA', (27, 35))	('NLGP', 'Var', (0, 4))	('promote', 'PosReg', (52, 59))	('T cells', 'CPA', (18, 25))
53850	23326300	Again, the number of regresser plus tumor free animals is significantly more in mice group that received NLGP once a week for 4 weeks in total through s.c. route (13/24 (54.2%)) than those that received PBS only (4/24 (16.6%)).	('NLGP', 'Var', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PBS', 'Chemical', 'MESH:D007854', (203, 206))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('more', 'PosReg', (72, 76))	('tumor', 'Disease', (36, 41))
53871	23326300	CD8 depletion following tumor inoculation resulted in increase in tumor growth in NLGP-treated mice (p<0.01), suggesting that NLGP mediated tumor growth inhibition is CD8+ T cell dependent (Figure 2F).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mice', 'Species', '10090', (95, 99))	('tumor inoculation', 'Disease', 'MESH:D002372', (24, 41))	('tumor', 'Disease', (24, 29))	('CD8', 'Gene', (167, 170))	('tumor', 'Disease', (66, 71))	('CD8', 'Gene', '925', (167, 170))	('increase', 'PosReg', (54, 62))	('depletion', 'Var', (4, 13))	('CD8', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor inoculation', 'Disease', (24, 41))	('CD8', 'Gene', '925', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (140, 145))
53933	23326300	CD4 depletion in sarcoma bearing mice compromised the NLGP mediated tumor growth restriction particularly at a later stage (data not shown).	('tumor', 'Disease', (68, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('compromised', 'NegReg', (38, 49))	('CD4', 'Gene', '12504', (0, 3))	('depletion', 'Var', (4, 13))	('sarcoma', 'Disease', 'MESH:D012509', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('growth restriction', 'Phenotype', 'HP:0001510', (74, 92))	('mice', 'Species', '10090', (33, 37))	('NLGP', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sarcoma', 'Disease', (17, 24))	('CD4', 'Gene', (0, 3))
53940	23326300	Over-expression of CCR5 on antigen presenting cells, like, monocytes/macrophages, may help to move these cells towards TME, where, they can present tumor derived peptide fragments to CD8+ T cells for cytotoxicity.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CD8', 'Gene', '925', (183, 186))	('CCR5', 'Gene', '12774', (19, 23))	('tumor', 'Disease', (148, 153))	('cytotoxicity', 'Disease', 'MESH:D064420', (200, 212))	('Over-expression', 'Var', (0, 15))	('CCR5', 'Gene', (19, 23))	('CD8', 'Gene', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cytotoxicity', 'Disease', (200, 212))	('present', 'Interaction', (140, 147))
54037	23326300	Afterwards, endogenous peroxidase was inhibited with 0.3% H2O2 and blocked with 5% BSA in a humid chamber for 30 min each, followed by incubation with primary mouse anti-CD8 antibody (Biolegend, clone 53-6.7).	('H2O2', 'Chemical', 'MESH:D006861', (58, 62))	('H2O2', 'Var', (58, 62))	('endogenous peroxidase', 'Enzyme', (12, 33))	('mouse', 'Species', '10090', (159, 164))	('inhibited', 'NegReg', (38, 47))	('CD8', 'Gene', (170, 173))	('CD8', 'Gene', '925', (170, 173))
54049	29541203	Cancer is a genetic disease characterized by genomic abnormalities that alter the transcriptome and influence the pathways that control proliferation and survival.	('transcriptome', 'MPA', (82, 95))	('abnormalities', 'Var', (53, 66))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('pathways', 'Pathway', (114, 122))	('alter', 'Reg', (72, 77))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic disease', 'Disease', (12, 27))	('genetic disease', 'Disease', 'MESH:D030342', (12, 27))	('influence', 'Reg', (100, 109))	('proliferation', 'CPA', (136, 149))
54076	29541203	The breast cancer (GSE31448), CRC (GSE17538, GSE41258, GSE39396), Ewing's sarcoma (GSE17679), glioma (GSE16011), hepatocellular carcinoma (GSE20140), leukemia (GSE12417), lung cancer (GSE3141), lymphoma (GSE10846), melanoma (GSE65904) and ovarian cancer (GSE32062) datasets, and the respective clinical information were obtained from the GEO repository.	('lymphoma', 'Phenotype', 'HP:0002665', (194, 202))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('melanoma', 'Disease', (215, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('GSE17538', 'Var', (35, 43))	('GSE39396', 'Var', (55, 63))	('GSE12417', 'Var', (160, 168))	('GSE31448', 'Var', (19, 27))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (66, 81))	('GSE20140', 'Var', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (113, 137))	('lymphoma', 'Disease', (194, 202))	('lymphoma', 'Disease', 'MESH:D008223', (194, 202))	('GSE65904', 'Var', (225, 233))	('leukemia', 'Disease', (150, 158))	('ovarian cancer', 'Disease', 'MESH:D010051', (239, 253))	("Ewing's sarcoma", 'Disease', (66, 81))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('lung cancer', 'Disease', (171, 182))	('leukemia', 'Disease', 'MESH:D007938', (150, 158))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('GSE3141', 'Var', (184, 191))	('breast cancer', 'Disease', (4, 17))	('GSE32062', 'Var', (255, 263))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (113, 137))	('GSE16011', 'Var', (102, 110))	('GSE10846', 'Var', (204, 212))	('glioma', 'Disease', (94, 100))	('CRC', 'Disease', (30, 33))	('ovarian cancer', 'Disease', (239, 253))	('GSE17679', 'Var', (83, 91))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('hepatocellular carcinoma', 'Disease', (113, 137))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('ovarian cancer', 'Phenotype', 'HP:0100615', (239, 253))
54077	29541203	For metastasis and relapse analysis, the sarcoma (GSE21050), breast cancer (GSE1456), hepatocellular carcinoma (GSE10140), gastric cancer (GSE26253) and prostate cancer (GSE46691) datasets were obtained from the GEO database.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (86, 110))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (153, 168))	('GSE1456', 'Var', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('prostate cancer', 'Disease', (153, 168))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))	('hepatocellular carcinoma', 'Disease', (86, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('GSE21050', 'Var', (50, 58))	('GSE1456', 'Chemical', '-', (76, 83))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('breast cancer', 'Disease', (61, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('GSE26253', 'Var', (139, 147))	('gastric cancer', 'Disease', (123, 137))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('sarcoma', 'Disease', (41, 48))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (86, 110))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('GSE10140', 'Var', (112, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))
54156	27570681	For example, in clinical trial NCT00035308, for criterion "malignant disease or immunodeficiency syndrome," we extracted two UMLS concepts, "malignant disease"(CUI=C0442867) and "immunodeficiency syndrome" (CUI= C002105).	('immunodeficiency syndrome', 'Disease', (80, 105))	('immunodeficiency syndrome', 'Disease', 'MESH:D007153', (179, 204))	('immunodeficiency', 'Phenotype', 'HP:0002721', (80, 96))	('malignant disease', 'Disease', (141, 158))	('malignant disease', 'Disease', 'MESH:D009369', (59, 76))	('immunodeficiency syndrome', 'Disease', 'MESH:D007153', (80, 105))	('immunodeficiency', 'Phenotype', 'HP:0002721', (179, 195))	('malignant disease', 'Disease', (59, 76))	('malignant disease', 'Disease', 'MESH:D009369', (141, 158))	('immunodeficiency syndrome', 'Disease', (179, 204))	('CUI=C0442867', 'Var', (160, 172))
54204	27570681	Amplification of this protein converts cultured cells into a cancerous phe- notypes, which is known to occur in 15-20% of breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('Amplification', 'Var', (0, 13))	('breast cancers', 'Disease', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancerous', 'Disease', (61, 70))	('phe', 'Chemical', 'MESH:D010649', (71, 74))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancerous', 'Disease', 'MESH:D009369', (61, 70))
54251	23136578	Immunohistochemically, the stromal cells were diffusely and strongly positive for vimentin (1:200, Zymed, San Francisco, CA, USA), CD10 (1:50, Novocastra, Newcastle, UK) (Fig.	('1:200', 'Var', (92, 97))	('CD10', 'Gene', (131, 135))	('positive', 'Reg', (69, 77))	('CD10', 'Gene', '4311', (131, 135))	('vimentin', 'Gene', '7431', (82, 90))	('vimentin', 'Gene', (82, 90))
54253	23136578	However, the stromal cells were negative for the estrogen receptor (ER; 1:200, Neomarkers), desmin (1:200, Dako, Glostrup, Denmark), S-100 protein (1:500, Zymed), and CD34 (1:500, Immunotech, Marseille, France).	('estrogen receptor', 'Gene', (49, 66))	('desmin', 'Gene', '1674', (92, 98))	('estrogen receptor', 'Gene', '2099', (49, 66))	('CD34', 'Gene', '947', (167, 171))	('CD34', 'Gene', (167, 171))	('S-100', 'Gene', '6271', (133, 138))	('1:200', 'Var', (100, 105))	('desmin', 'Gene', (92, 98))	('S-100', 'Gene', (133, 138))
54321	27740934	Potential approaches to the treatment of Ewing's sarcoma Ewing's sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the transcription factor FLI1 gene.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('Ewing sarcoma breakpoint region 1', 'Gene', (194, 227))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('ES', 'Phenotype', 'HP:0012254', (74, 76))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (57, 72))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (194, 227))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (41, 56))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (57, 72))	('chromosomal fusion', 'Var', (163, 181))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (41, 56))	('EWSR1', 'Gene', '2130', (229, 234))	("Ewing's sarcoma", 'Disease', (57, 72))	('caused by', 'Reg', (151, 160))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (194, 207))	('children', 'Species', '9606', (125, 133))	("Ewing's sarcoma", 'Disease', (41, 56))	('EWSR1', 'Gene', (229, 234))	('tumor', 'Disease', (116, 121))
54328	27740934	The reciprocal chromosomal translocation t (11;22) (q24;q12) is found in 85% of these tumors, which leads to the fusion between the 5' segment of the Ewing sarcoma breakpoint region 1 gene (EWSR1) on the chromosome 22 and the 3' portion of Friend leukemia virus integration site 1 (FLI1) on the chromosome 11.	('Friend leukemia virus integration site 1', 'Gene', (240, 280))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('leukemia', 'Phenotype', 'HP:0001909', (247, 255))	('leads to', 'Reg', (100, 108))	('FLI1', 'Gene', (282, 286))	('fusion', 'Var', (113, 119))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (150, 183))	('EWSR1', 'Gene', (190, 195))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Ewing sarcoma breakpoint region 1', 'Gene', (150, 183))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (150, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('EWSR1', 'Gene', '2130', (190, 195))	('Friend leukemia virus integration site 1', 'Gene', '2313', (240, 280))
54329	27740934	In addition to FLI1, fusions between EWSR1 and other ETS family transcription factors, including ATF-1, ERG, and WT1, occur in ES.	('ATF-1', 'Gene', (97, 102))	('WT1', 'Gene', (113, 116))	('ATF-1', 'Gene', '466', (97, 102))	('EWSR1', 'Gene', (37, 42))	('fusions', 'Var', (21, 28))	('occur', 'Reg', (118, 123))	('WT1', 'Gene', '7490', (113, 116))	('EWSR1', 'Gene', '2130', (37, 42))	('ES', 'Phenotype', 'HP:0012254', (127, 129))
54330	27740934	These translocations produce the chimeric proteins EWS-ETSs, which function as aberrant transcription factors, accounting for the tumorigenic potential of ES.	('ES', 'Phenotype', 'HP:0012254', (155, 157))	('EWS-ETSs', 'Gene', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('translocations', 'Var', (6, 20))
54335	27740934	Abnormal RTK signaling often leads to cell transformation, which is observed in a wide variety of malignancies.	('malignancies', 'Disease', (98, 110))	('RTK signaling', 'MPA', (9, 22))	('Abnormal', 'Var', (0, 8))	('leads to', 'Reg', (29, 37))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('cell transformation', 'CPA', (38, 57))
54342	27740934	Interference with the IGF1R pathways in ES cells suppresses growth, increases apoptosis both in vitro and in vivo, and significantly decreases migration, invasion and metastases.	('increases', 'PosReg', (68, 77))	('apoptosis', 'CPA', (78, 87))	('IGF1R', 'Gene', (22, 27))	('metastases', 'Disease', (167, 177))	('Interference', 'Var', (0, 12))	('migration', 'CPA', (143, 152))	('ES', 'Phenotype', 'HP:0012254', (40, 42))	('growth', 'CPA', (60, 66))	('decreases', 'NegReg', (133, 142))	('metastases', 'Disease', 'MESH:D009362', (167, 177))	('suppresses', 'NegReg', (49, 59))
54344	27740934	Anti-IGF1R monoclonal antibodies induce responses in a subset of patients with ES.	('ES', 'Phenotype', 'HP:0012254', (79, 81))	('patients', 'Species', '9606', (65, 73))	('responses', 'MPA', (40, 49))	('Anti-IGF1R', 'Var', (0, 10))
54345	27740934	R1507 inhibits the growth of ES cells expressing high levels of IGF2, and exhibits an overall 10% response rate in patients with recurrent or refractory ES.	('patients', 'Species', '9606', (115, 123))	('growth', 'MPA', (19, 25))	('IGF2', 'Gene', '3481', (64, 68))	('inhibits', 'NegReg', (6, 14))	('ES', 'Phenotype', 'HP:0012254', (29, 31))	('ES', 'Phenotype', 'HP:0012254', (153, 155))	('IGF2', 'Gene', (64, 68))	('R1507', 'Var', (0, 5))
54346	27740934	Data from phase I clinical trials suggest that MK-0646 is safe, well tolerated, and significantly inhibits tumor cell proliferation.	('MK-0646', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('clinical', 'Species', '191496', (18, 26))	('MK-0646', 'Chemical', 'MESH:C569480', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('inhibits', 'NegReg', (98, 106))
54357	27740934	Combination of ADW742 and usual chemotherapeutic agents, such as imatinib, vincristine, ordoxorubicin synergistically augmented the effect on ES cells.	('imatinib', 'Chemical', 'MESH:D000068877', (65, 73))	('effect', 'MPA', (132, 138))	('ES', 'Phenotype', 'HP:0012254', (142, 144))	('ADW742', 'Var', (15, 21))	('augmented', 'PosReg', (118, 127))	('ordoxorubicin', 'Chemical', '-', (88, 101))	('vincristine', 'Chemical', 'MESH:D014750', (75, 86))
54358	27740934	NVP-AEW541 induces G1 cell cycle block in ES cells, and inhibits migration, metastasis, vasculogenicity, and angiogenesis in ES mouse xenografts.	('metastasis', 'CPA', (76, 86))	('migration', 'CPA', (65, 74))	('vasculogenicity', 'CPA', (88, 103))	('ES', 'Phenotype', 'HP:0012254', (42, 44))	('G1 cell cycle block', 'CPA', (19, 38))	('ES', 'Phenotype', 'HP:0012254', (125, 127))	('angiogenesis', 'CPA', (109, 121))	('inhibits', 'NegReg', (56, 64))	('NVP-AEW541', 'Var', (0, 10))	('mouse', 'Species', '10090', (128, 133))
54386	27740934	Either antisense oligodeoxynucleotides or siRNAs could reduce the expression levels of EWS-FLI1, resulting in decreased proliferation of ES cells in vitro, and regression of tumors in nude mice.	('proliferation', 'CPA', (120, 133))	('nude mice', 'Species', '10090', (184, 193))	('EWS-FLI1', 'Gene', '2130;2313', (87, 95))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (17, 38))	('expression levels', 'MPA', (66, 83))	('regression', 'NegReg', (160, 170))	('decreased', 'NegReg', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('reduce', 'NegReg', (55, 61))	('antisense oligodeoxynucleotides', 'Var', (7, 38))	('ES', 'Phenotype', 'HP:0012254', (137, 139))	('EWS-FLI1', 'Gene', (87, 95))
54394	27740934	Small molecule YK-4-279, which has been shown to interrupt the binding of EWS-FLI1 to RHA, induces apoptosis in ES cells and reduces growth in ES xenografts (Figure 3).	('RHA', 'Gene', (86, 89))	('EWS-FLI1', 'Gene', (74, 82))	('binding', 'Interaction', (63, 70))	('growth in ES xenografts', 'CPA', (133, 156))	('reduces', 'NegReg', (125, 132))	('apoptosis', 'CPA', (99, 108))	('interrupt', 'NegReg', (49, 58))	('EWS-FLI1', 'Gene', '2130;2313', (74, 82))	('RHA', 'Gene', '1660', (86, 89))	('ES', 'Phenotype', 'HP:0012254', (143, 145))	('ES', 'Phenotype', 'HP:0012254', (112, 114))	('induces', 'Reg', (91, 98))	('YK-4-279', 'Var', (15, 23))
54402	27740934	In ES, EWS-FLI1 expression induces the epigenetic alterations to reprogram cells into the malignancy through activating HDACs.	('HDACs', 'MPA', (120, 125))	('expression', 'Var', (16, 26))	('EWS-FLI1', 'Gene', '2130;2313', (7, 15))	('malignancy', 'Disease', 'MESH:D009369', (90, 100))	('epigenetic alterations', 'MPA', (39, 61))	('induces', 'Reg', (27, 34))	('malignancy', 'Disease', (90, 100))	('EWS-FLI1', 'Gene', (7, 15))	('ES', 'Phenotype', 'HP:0012254', (3, 5))	('activating', 'PosReg', (109, 119))
54403	27740934	EWS-FLI1 knockdown in ES led to widespread epigenetic changes in promoters, enhancers, and super-enhancers; histone H3K27 acetylation was the most affected mark.	('epigenetic changes', 'MPA', (43, 61))	('knockdown', 'Var', (9, 18))	('histone H3K27 acetylation', 'MPA', (108, 133))	('EWS-FLI1', 'Gene', (0, 8))	('ES', 'Phenotype', 'HP:0012254', (22, 24))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))
54406	27740934	Lysine-specific demethylase 1 (LSD1, also known as KDM1A, AOF2 and BHC110), specifically catalyzes oxidative demethylation of mono- and dimethyl-lysine at histone H3 lysines 4 and 9 (H3K4me1/2 and H3K9me1/2).	('H3K9me1/2', 'Var', (197, 206))	('AOF2', 'Gene', (58, 62))	('oxidative demethylation', 'MPA', (99, 122))	('KDM1A', 'Gene', (51, 56))	('LSD1', 'Gene', '23028', (31, 35))	('LSD1', 'Gene', (31, 35))	('lysines', 'Chemical', 'MESH:D008239', (166, 173))	('AOF2', 'Gene', '23028', (58, 62))	('mono- and dimethyl-lysine', 'Chemical', '-', (126, 151))	('BHC110', 'Gene', '23028', (67, 73))	('Lysine-specific demethylase 1', 'Gene', '23028', (0, 29))	('BHC110', 'Gene', (67, 73))	('KDM1A', 'Gene', '23028', (51, 56))	('Lysine-specific demethylase 1', 'Gene', (0, 29))
54409	27740934	Treatment of ES cells with the LSD1 inhibitor HCI-2509, comprehensively reverses the transcriptional profiles driven by both EWS-FLI and EWS-ERG, and markedly delays tumorigenesis in vivo.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('FLI', 'Gene', (129, 132))	('LSD1', 'Gene', '23028', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('LSD1', 'Gene', (31, 35))	('tumor', 'Disease', (166, 171))	('reverses', 'NegReg', (72, 80))	('delays', 'NegReg', (159, 165))	('HCI-2509', 'Chemical', '-', (46, 54))	('transcriptional profiles', 'MPA', (85, 109))	('EWS-ERG', 'Var', (137, 144))	('FLI', 'Gene', '2314', (129, 132))	('ES', 'Phenotype', 'HP:0012254', (13, 15))
54411	27740934	Mithramycin suppresses growth of ES cells and xenograft tumors, and prolongs survival of mice with ES xenografts.	('xenograft tumors', 'Disease', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('suppresses', 'NegReg', (12, 22))	('Mithramycin', 'Var', (0, 11))	('survival', 'CPA', (77, 85))	('ES', 'Phenotype', 'HP:0012254', (99, 101))	('mice', 'Species', '10090', (89, 93))	('prolongs', 'NegReg', (68, 76))	('ES', 'Phenotype', 'HP:0012254', (33, 35))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('xenograft tumors', 'Disease', 'MESH:D009369', (46, 62))	('Mithramycin', 'Chemical', 'MESH:D008926', (0, 11))	('growth', 'CPA', (23, 29))
54418	27740934	Overexpression of Aurora kinase A (AURKA) is associated with tumorigenesis.	('AURKA', 'Gene', '6790', (35, 40))	('Aurora kinase A', 'Gene', (18, 33))	('AURKA', 'Gene', (35, 40))	('associated', 'Reg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Overexpression', 'Var', (0, 14))	('Aurora kinase A', 'Gene', '6790', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
54420	27740934	The in vitro and in vivo antitumor activities of an AURKA inhibitor MLN8237 (alisertib) have been reported in ES, whereas significant response was not observed in a phase I trial including ES patients.	('AURKA', 'Gene', '6790', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('MLN8237', 'Chemical', 'MESH:C550258', (68, 75))	('ES', 'Phenotype', 'HP:0012254', (189, 191))	('ES', 'Phenotype', 'HP:0012254', (110, 112))	('AURKA', 'Gene', (52, 57))	('patients', 'Species', '9606', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('MLN8237', 'Var', (68, 75))	('alisertib', 'Chemical', 'MESH:C550258', (77, 86))	('tumor', 'Disease', (29, 34))
54429	27740934	When Gli1 was knocked down, or SUFU, which inhibits Gli1 was overexpressed, the transformed phenotype was decreased, indicating that Gli1 functions downstream of EWS-FLI1 and mediates the transformation induced by EWS-FLI1.	('decreased', 'NegReg', (106, 115))	('SUFU', 'Gene', '51684', (31, 35))	('EWS-FLI1', 'Gene', (214, 222))	('EWS-FLI1', 'Gene', '2130;2313', (162, 170))	('SUFU', 'Gene', (31, 35))	('EWS-FLI1', 'Gene', '2130;2313', (214, 222))	('Gli1', 'Gene', (133, 137))	('EWS-FLI1', 'Gene', (162, 170))	('mediates', 'Reg', (175, 183))	('knocked', 'Var', (14, 21))
54430	27740934	In ES cells, EWS-FLI1 knockdown produced a reduction of Gli1 expression and the transformed phenotype.	('reduction', 'NegReg', (43, 52))	('EWS-FLI1', 'Gene', (13, 21))	('Gli1', 'Gene', (56, 60))	('knockdown', 'Var', (22, 31))	('EWS-FLI1', 'Gene', '2130;2313', (13, 21))	('transformed phenotype', 'CPA', (80, 101))	('ES', 'Phenotype', 'HP:0012254', (3, 5))	('expression', 'MPA', (61, 71))
54439	27740934	CCK mRNA levels were upregulated by ectopic expression of EWS-FLI1, and downregulated by EWS-FLI1 knockdown.	('EWS-FLI1', 'Gene', '2130;2313', (58, 66))	('upregulated', 'PosReg', (21, 32))	('ectopic expression', 'Var', (36, 54))	('EWS-FLI1', 'Gene', (89, 97))	('CCK', 'Gene', '885', (0, 3))	('EWS-FLI1', 'Gene', (58, 66))	('CCK', 'Gene', (0, 3))	('downregulated', 'NegReg', (72, 85))	('EWS-FLI1', 'Gene', '2130;2313', (89, 97))
54443	27740934	However, a specific antagonist of the CCKBR (L365 260) did not show any effect on ES cell proliferation or viability.	('L365 260', 'Var', (45, 53))	('CCKBR', 'Gene', '887', (38, 43))	('ES', 'Phenotype', 'HP:0012254', (82, 84))	('CCKBR', 'Gene', (38, 43))
54453	27740934	NKX2.2 is expressed in ES, and NKX2.2 silencing decreases ES cellular growth and tumor formation in ES xenograft models.	('NKX2.2', 'Gene', '4821', (0, 6))	('NKX2.2', 'Gene', '4821', (31, 37))	('ES', 'Phenotype', 'HP:0012254', (100, 102))	('ES cellular growth', 'CPA', (58, 76))	('decreases', 'NegReg', (48, 57))	('NKX2.2', 'Gene', (0, 6))	('NKX2.2', 'Gene', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('silencing', 'Var', (38, 47))	('ES', 'Phenotype', 'HP:0012254', (23, 25))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('ES', 'Phenotype', 'HP:0012254', (58, 60))
54455	27740934	DAX1 silencing induces growth arrest in ES cells, and severely impairs their growth in semisolid medium and tumor growth in immunodeficient mice.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('growth arrest', 'Disease', (23, 36))	('mice', 'Species', '10090', (140, 144))	('growth arrest', 'Disease', 'MESH:D006323', (23, 36))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('silencing', 'Var', (5, 14))	('immunodeficient', 'Disease', 'MESH:D007153', (124, 139))	('growth arrest', 'Phenotype', 'HP:0001510', (23, 36))	('tumor', 'Disease', (108, 113))	('DAX1', 'Gene', (0, 4))	('ES', 'Phenotype', 'HP:0012254', (40, 42))	('impairs', 'NegReg', (63, 70))	('immunodeficient', 'Disease', (124, 139))	('growth in semisolid medium', 'MPA', (77, 103))
54457	27740934	PRAS40 silencing induces the apoptosis of ES cells through regulating the insulin receptor/Akt and mTOR signaling pathways.	('apoptosis', 'CPA', (29, 38))	('ES', 'Phenotype', 'HP:0012254', (42, 44))	('Akt', 'Gene', '207', (91, 94))	('insulin receptor', 'Gene', '3643', (74, 90))	('Akt', 'Gene', (91, 94))	('PRAS40', 'Gene', '84335', (0, 6))	('PRAS40', 'Gene', (0, 6))	('regulating', 'Reg', (59, 69))	('mTOR', 'Gene', '2475', (99, 103))	('insulin receptor', 'Gene', (74, 90))	('mTOR', 'Gene', (99, 103))	('silencing', 'Var', (7, 16))
54459	27740934	EGR2 is a target gene of EWS-FLI1, and EGR2 knockdown inhibits ES cell proliferation, clonogenicity and spheroidal growth, and induces regression of ES xenografts.	('ES xenografts', 'CPA', (149, 162))	('ES', 'Phenotype', 'HP:0012254', (63, 65))	('induces', 'Reg', (127, 134))	('EGR2', 'Gene', '1959', (0, 4))	('EGR2', 'Gene', (0, 4))	('regression', 'CPA', (135, 145))	('ES', 'Phenotype', 'HP:0012254', (149, 151))	('spheroidal growth', 'CPA', (104, 121))	('EWS-FLI1', 'Gene', (25, 33))	('ES cell proliferation', 'CPA', (63, 84))	('inhibits', 'NegReg', (54, 62))	('knockdown', 'Var', (44, 53))	('EWS-FLI1', 'Gene', '2130;2313', (25, 33))	('EGR2', 'Gene', '1959', (39, 43))	('EGR2', 'Gene', (39, 43))
54461	27740934	CRM1 shRNA-mediated silencing or a small-molecule inhibitor KPT-330 treatment in ES cells, dramatically decreases cell growth while inducing apoptosis and cell cycle arrest.	('apoptosis', 'CPA', (141, 150))	('cell growth', 'CPA', (114, 125))	('decreases', 'NegReg', (104, 113))	('cell cycle arrest', 'CPA', (155, 172))	('inducing', 'NegReg', (132, 140))	('ES', 'Phenotype', 'HP:0012254', (81, 83))	('CRM1', 'Gene', '7514', (0, 4))	('silencing', 'Var', (20, 29))	('CRM1', 'Gene', (0, 4))	('KPT-330', 'Gene', (60, 67))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (155, 172))
54462	27740934	CRM1 silencing markedly reduces EWS-FLI1 protein level and upregulates the expression of IGFBP3.	('IGFBP3', 'Gene', (89, 95))	('CRM1', 'Gene', (0, 4))	('reduces', 'NegReg', (24, 31))	('EWS-FLI1', 'Gene', '2130;2313', (32, 40))	('silencing', 'Var', (5, 14))	('IGFBP3', 'Gene', '3486', (89, 95))	('upregulates', 'PosReg', (59, 70))	('CRM1', 'Gene', '7514', (0, 4))	('protein level', 'MPA', (41, 54))	('expression', 'MPA', (75, 85))	('EWS-FLI1', 'Gene', (32, 40))
54473	27740934	Cytotoxic T lymphocytes (CTLs) specific for LIPI-derived peptides LDYTDAKFV and NLLKHGASL could lyse HLA-A2 positive ES cells in vitro.	('ES', 'Phenotype', 'HP:0012254', (117, 119))	('Cytotoxic T', 'Disease', (0, 11))	('LIPI', 'Gene', (44, 48))	('NLLKHGASL', 'Var', (80, 89))	('lyse', 'MPA', (96, 100))	('LDYTDAKFV', 'Var', (66, 75))	('Cytotoxic T', 'Disease', 'MESH:D064420', (0, 11))	('LIPI', 'Gene', '149998', (44, 48))
54492	27740934	A systemic delivery of vesicular stomatitis virus (VSVDeltaM51) resulted in a significant decrease of tumor burden in ES bearing mice, and tumor-specific killing of resistant ES cells.	('stomatitis', 'Phenotype', 'HP:0010280', (33, 43))	('vesicular stomatitis virus', 'Species', '11276', (23, 49))	('VSVDeltaM51', 'Var', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (102, 107))	('ES', 'Phenotype', 'HP:0012254', (118, 120))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('mice', 'Species', '10090', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('decrease', 'NegReg', (90, 98))	('ES', 'Phenotype', 'HP:0012254', (175, 177))
54499	27740934	In athymic nude mice, the combined treatments with anti-CD99 0662 monoclonal antibody and doxorubicin (DXR) were remarkably effective against both local growth and metastases of ES xenografts, and the survival rate of mice was also increased.	('metastases', 'Disease', 'MESH:D009362', (164, 174))	('DXR', 'Chemical', 'MESH:D004317', (103, 106))	('ES', 'Phenotype', 'HP:0012254', (178, 180))	('survival rate', 'CPA', (201, 214))	('metastases', 'Disease', (164, 174))	('increased', 'PosReg', (232, 241))	('doxorubicin', 'Chemical', 'MESH:D004317', (90, 101))	('anti-CD99 0662', 'Var', (51, 65))	('mice', 'Species', '10090', (218, 222))	('mice', 'Species', '10090', (16, 20))	('nude mice', 'Species', '10090', (11, 20))	('local growth', 'CPA', (147, 159))
54506	24356813	Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically-modified chicken DT40 and human cancer cell lines.	('PARP2', 'Gene', '10038', (92, 97))	('PARP2', 'Gene', (92, 97))	('PARP', 'Gene', '142', (29, 33))	('PARP', 'Gene', '142', (92, 96))	('chicken', 'Species', '9031', (225, 232))	('PARP', 'Gene', (29, 33))	('cancer', 'Disease', (248, 254))	('PARP', 'Gene', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('BMN', 'Var', (45, 48))	('PARP', 'Gene', '142', (82, 86))	('PARP', 'Gene', '142', (122, 126))	('rucaparib', 'Chemical', 'MESH:C531549', (152, 161))	('PARP', 'Gene', (82, 86))	('PARP', 'Gene', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('BMN 673', 'Chemical', 'MESH:C586365', (45, 52))	('olaparib', 'Chemical', 'MESH:C531550', (139, 147))	('human', 'Species', '9606', (242, 247))
54507	24356813	Although BMN 673, olaparib and rucaparib are comparable at inhibiting PARP catalytic activity, BMN 673 is ~100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as single agent than olaparib, while olaparib and rucaparib show similar potencies in trapping PARP-DNA complexes.	('PARP', 'Gene', (273, 277))	('rucaparib', 'Chemical', 'MESH:C531549', (228, 237))	('PARP', 'Gene', '142', (70, 74))	('trapping', 'MPA', (131, 139))	('PARP', 'Gene', (140, 144))	('olaparib', 'Chemical', 'MESH:C531550', (199, 207))	('PARP', 'Gene', '142', (273, 277))	('inhibiting', 'NegReg', (59, 69))	('olaparib', 'Chemical', 'MESH:C531550', (18, 26))	('BMN 673', 'Chemical', 'MESH:C586365', (9, 16))	('PARP', 'Gene', '142', (140, 144))	('PARP', 'Gene', (70, 74))	('BMN 673', 'Var', (95, 102))	('BMN 673', 'Chemical', 'MESH:C586365', (95, 102))	('olaparib', 'Chemical', 'MESH:C531550', (215, 223))	('rucaparib', 'Chemical', 'MESH:C531549', (31, 40))
54509	24356813	Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient.	('BMN 673', 'Var', (23, 30))	('stereospecific', 'MPA', (39, 53))	('BMN 673', 'Chemical', 'MESH:C586365', (23, 30))	('binding', 'Interaction', (54, 61))	('PARP1', 'Gene', (65, 70))
54517	24356813	Accordingly, PARP inhibition results in the accumulation of recombinogenic substrates marked by RAD51 and gammaH2AX nuclear foci.	('inhibition', 'NegReg', (18, 28))	('recombinogenic substrates', 'MPA', (60, 85))	('RAD51', 'Gene', (96, 101))	('PARP', 'Gene', (13, 17))	('RAD51', 'Gene', '5888', (96, 101))	('gammaH2AX', 'Var', (106, 115))	('PARP', 'Gene', '142', (13, 17))	('accumulation', 'PosReg', (44, 56))
54524	24356813	Indeed, veliparib is a highly potent catalytic PARP inhibitor with relatively limited trapping of PARP-DNA complexes in comparison with niraparib and olaparib.	('PARP', 'Gene', (47, 51))	('veliparib', 'Chemical', 'MESH:C521013', (8, 17))	('PARP', 'Gene', (98, 102))	('olaparib', 'Chemical', 'MESH:C531550', (150, 158))	('veliparib', 'Var', (8, 17))	('PARP', 'Gene', '142', (47, 51))	('niraparib', 'Chemical', 'MESH:C545685', (136, 145))	('PARP', 'Gene', '142', (98, 102))
54528	24356813	PARP1-/- avian B-lymphoblast DT40 cells are equivalent to PARP1 and PARP2 double-knockout cells, and do not have detectable level of poly(ADP-ribosyl)ation.	('PARP1-/-', 'Var', (0, 8))	('ADP', 'Chemical', 'MESH:D000244', (138, 141))	('PARP2', 'Gene', '10038', (68, 73))	('PARP2', 'Gene', (68, 73))
54558	24356813	Figure 1C and Table 1 show a quantitative analysis using the clinically validated PAR ELISA assay with IC50 (inhibitory concentration 50%) and IC90 (inhibitory concentration 90%) for all three drugs in DT40 cells and human prostate DU145 cancer cells.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('IC50', 'Var', (103, 107))	('human', 'Species', '9606', (217, 222))	('DU145', 'CellLine', 'CVCL:0105', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('IC90', 'Var', (143, 147))
54562	24356813	These results demonstrate that BMN 673, olaparib and rucaparib are highly potent PARP inhibitors at low nanomolar concentrations, and they are indistinguishable above 0.1 muM since PAR levels are almost zero under these conditions.	('PARP', 'Gene', (81, 85))	('rucaparib', 'Chemical', 'MESH:C531549', (53, 62))	('BMN 673', 'Chemical', 'MESH:C586365', (31, 38))	('BMN', 'Var', (31, 34))	('PARP', 'Gene', '142', (81, 85))	('olaparib', 'Chemical', 'MESH:C531550', (40, 48))
54571	24356813	The IC90 of wild type DT40 cells to BMN 673 was 6-10 times lower than for the other two PARP inhibitors.	('lower', 'NegReg', (59, 64))	('PARP', 'Gene', '142', (88, 92))	('BMN 673', 'Var', (36, 43))	('IC90', 'MPA', (4, 8))	('BMN 673', 'Chemical', 'MESH:C586365', (36, 43))	('PARP', 'Gene', (88, 92))
54572	24356813	We also confirmed by flow cytometry analyses the higher cytotoxicity of BMN 673 compared to olaparib and rucaparib (Figure S3A).	('olaparib', 'Chemical', 'MESH:C531550', (92, 100))	('BMN', 'Var', (72, 75))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('BMN 673', 'Chemical', 'MESH:C586365', (72, 79))	('rucaparib', 'Chemical', 'MESH:C531549', (105, 114))	('cytotoxicity', 'Disease', (56, 68))	('higher', 'PosReg', (49, 55))
54573	24356813	The IC90 of BRCA2tr/- cells toBMN 673 was 25-33 times lower than for olaparib and rucaparib (Figure 2A, bottom panel).	('rucaparib', 'Chemical', 'MESH:C531549', (82, 91))	('olaparib', 'Chemical', 'MESH:C531550', (69, 77))	('BRCA2tr/- cells toBMN 673', 'Var', (12, 37))	('IC90', 'MPA', (4, 8))	('lower', 'NegReg', (54, 59))	('BMN 673', 'Chemical', 'MESH:C586365', (30, 37))
54574	24356813	Moreover, LT674, the inactive stereoisomer of BMN 673, was markedly less cytotoxic (~100-fold) even in the BRCA2-deficient cells (Figure S4).	('LT674', 'Var', (10, 15))	('cytotoxic', 'CPA', (73, 82))	('BMN 673', 'Chemical', 'MESH:C586365', (46, 53))	('less', 'NegReg', (68, 72))
54579	24356813	The IC90 of BMN 673 was 10- and 5-fold lower than that of olaparib in DU145 and EW8 cells, respectively (Figure 2B, bottom panel).	('BMN 673', 'Var', (12, 19))	('olaparib', 'Chemical', 'MESH:C531550', (58, 66))	('DU145', 'CellLine', 'CVCL:0105', (70, 75))	('IC90', 'MPA', (4, 8))	('BMN 673', 'Chemical', 'MESH:C586365', (12, 19))	('lower', 'NegReg', (39, 44))
54581	24356813	Consistently, the flow cytometry analyses revealed higher cytotoxic effect in BMN 673 compared to olaparib and rucaparib (Figure S3B).	('olaparib', 'Chemical', 'MESH:C531550', (98, 106))	('cytotoxic effect', 'CPA', (58, 74))	('BMN 673', 'Var', (78, 85))	('higher', 'PosReg', (51, 57))	('rucaparib', 'Chemical', 'MESH:C531549', (111, 120))	('BMN 673', 'Chemical', 'MESH:C586365', (78, 85))
54582	24356813	These results indicate that BMN 673 produces greater PARP-mediated cytotoxicity than olaparib and rucaparib.	('PARP', 'Gene', (53, 57))	('BMN 673', 'Var', (28, 35))	('rucaparib', 'Chemical', 'MESH:C531549', (98, 107))	('olaparib', 'Chemical', 'MESH:C531550', (85, 93))	('cytotoxicity', 'Disease', (67, 79))	('BMN 673', 'Chemical', 'MESH:C586365', (28, 35))	('PARP', 'Gene', '142', (53, 57))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))
54588	24356813	Notably, the IC50 of BMN 673 was overall lower than that of olaparib in the olaparib-sensitive cell lines, which is consistent with the fact that BMN 673 has higher PARP-mediated cytotoxicity than olaparib.	('BMN 673', 'Var', (21, 28))	('BMN 673', 'Chemical', 'MESH:C586365', (21, 28))	('PARP', 'Gene', (165, 169))	('BMN 673', 'Var', (146, 153))	('lower', 'NegReg', (41, 46))	('cytotoxicity', 'Disease', (179, 191))	('higher', 'PosReg', (158, 164))	('BMN 673', 'Chemical', 'MESH:C586365', (146, 153))	('olaparib', 'Chemical', 'MESH:C531550', (76, 84))	('PARP', 'Gene', '142', (165, 169))	('olaparib', 'Chemical', 'MESH:C531550', (197, 205))	('cytotoxicity', 'Disease', 'MESH:D064420', (179, 191))	('IC50', 'MPA', (13, 17))	('olaparib', 'Chemical', 'MESH:C531550', (60, 68))
54592	24356813	DT40 cells only have PARP1 (no PARP2) (Figure 4A) whereas DU145 have both PARP1 and PARP2 (Figure 4B).	('PARP2', 'Gene', '10038', (31, 36))	('DU145', 'CellLine', 'CVCL:0105', (58, 63))	('PARP2', 'Gene', (31, 36))	('PARP1', 'Var', (21, 26))	('PARP2', 'Gene', '10038', (84, 89))	('PARP2', 'Gene', (84, 89))
54598	24356813	Figure 5B shows that both PARP inhibitors enhanced the fluorescence anisotropy signal, which reflects the stabilization of PARP1-DNA complexes.	('PARP', 'Gene', (123, 127))	('PARP', 'Gene', (26, 30))	('enhanced', 'PosReg', (42, 50))	('PARP', 'Gene', '142', (123, 127))	('PARP', 'Gene', '142', (26, 30))	('fluorescence anisotropy signal', 'MPA', (55, 85))	('inhibitors', 'Var', (31, 41))
54600	24356813	Time-course experiments following NAD+ addition also showed that BMN 673 slowed the dissociation of PARP1-DNA complexes more efficiently than olaparib (Figure 5C).	('PARP1-DNA', 'Protein', (100, 109))	('BMN 673', 'Var', (65, 72))	('BMN 673', 'Chemical', 'MESH:C586365', (65, 72))	('NAD+', 'Chemical', 'MESH:D009243', (34, 38))	('dissociation of', 'MPA', (84, 99))	('olaparib', 'Chemical', 'MESH:C531550', (142, 150))	('slowed', 'NegReg', (73, 79))
54601	24356813	Together, these results demonstrate that BMN 673 is markedly more effective at trapping PARP than olaparib and rucaparib.	('BMN 673', 'Var', (41, 48))	('olaparib', 'Chemical', 'MESH:C531550', (98, 106))	('BMN 673', 'Chemical', 'MESH:C586365', (41, 48))	('PARP', 'Gene', '142', (88, 92))	('trapping', 'MPA', (79, 87))	('rucaparib', 'Chemical', 'MESH:C531549', (111, 120))	('PARP', 'Gene', (88, 92))
54603	24356813	As expected from the well-established role of PARylation for SSB repair, PARP1-/- cells were hypersensitive to MMS (compare open and closed circles in panels A and B, Figure 6).	('hypersensitive', 'Disease', 'MESH:D004342', (93, 107))	('SSB', 'Gene', '6741', (61, 64))	('SSB', 'Gene', (61, 64))	('PARP1-/-', 'Var', (73, 81))	('hypersensitive', 'Disease', (93, 107))	('MMS', 'Chemical', 'MESH:D008741', (111, 114))
54606	24356813	Notably, the MMS sensitivity of wild type cells treated with 0.1 muM olaparib, 0.1 muM rucaparib or 0.001 muM BMN 673 was greater than that of PARP1-/-cells (Figure 6, compare upper three A panels and the B panel).	('greater', 'PosReg', (122, 129))	('olaparib', 'Chemical', 'MESH:C531550', (69, 77))	('BMN 673', 'Chemical', 'MESH:C586365', (110, 117))	('0.1 muM', 'Var', (79, 86))	('0.1', 'Var', (61, 64))	('MMS sensitivity', 'MPA', (13, 28))	('MMS', 'Chemical', 'MESH:D008741', (13, 16))	('rucaparib', 'Chemical', 'MESH:C531549', (87, 96))
54607	24356813	These results indicate that BMN 673 induces PARP-mediated cytotoxicity ~100 times more efficiently than olaparib or rucaparib and that its cytotoxicity is mediated not only by PARP catalytic inhibition but also by trapping PARP-DNA complexes.	('PARP', 'Gene', (44, 48))	('BMN 673', 'Var', (28, 35))	('PARP', 'Gene', '142', (176, 180))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))	('cytotoxicity', 'Disease', 'MESH:D064420', (139, 151))	('BMN 673', 'Chemical', 'MESH:C586365', (28, 35))	('PARP', 'Gene', '142', (44, 48))	('PARP', 'Gene', (223, 227))	('rucaparib', 'Chemical', 'MESH:C531549', (116, 125))	('cytotoxicity', 'Disease', (58, 70))	('olaparib', 'Chemical', 'MESH:C531550', (104, 112))	('catalytic', 'MPA', (181, 190))	('PARP', 'Gene', (176, 180))	('PARP', 'Gene', '142', (223, 227))	('induces', 'Reg', (36, 43))	('cytotoxicity', 'Disease', (139, 151))
54612	24356813	Figure 6D shows that all three PARP inhibitors enhanced the cytotoxicity of temozolomide, with BMN 673 being markedly more potent than olaparib and rucaparib.	('cytotoxicity', 'Disease', (60, 72))	('PARP', 'Gene', '142', (31, 35))	('enhanced', 'PosReg', (47, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))	('temozolomide', 'Chemical', 'MESH:D000077204', (76, 88))	('PARP', 'Gene', (31, 35))	('olaparib', 'Chemical', 'MESH:C531550', (135, 143))	('BMN 673', 'Chemical', 'MESH:C586365', (95, 102))	('rucaparib', 'Chemical', 'MESH:C531549', (148, 157))	('BMN', 'Var', (95, 98))
54613	24356813	These results demonstrate that BMN 673 is the most potent drug among the three PARP inhibitors tested in combination with temozolomide.	('temozolomide', 'Chemical', 'MESH:D000077204', (122, 134))	('BMN 673', 'Chemical', 'MESH:C586365', (31, 38))	('BMN', 'Var', (31, 34))	('PARP', 'Gene', (79, 83))	('PARP', 'Gene', '142', (79, 83))
54615	24356813	It is approximately 2 orders of magnitude more potent than olaparib both in prostate cancer DU145 and lymphoma DT40 cells for both PARP1 and PARP2 (see Figure 4).	('PARP1', 'Var', (131, 136))	('lymphoma', 'Disease', (102, 110))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('lymphoma', 'Disease', 'MESH:D008223', (102, 110))	('DU145', 'CellLine', 'CVCL:0105', (92, 97))	('olaparib', 'Chemical', 'MESH:C531550', (59, 67))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('PARP2', 'Gene', '10038', (141, 146))	('prostate cancer', 'Disease', (76, 91))	('PARP2', 'Gene', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
54619	24356813	Our data indicate that BMN 673 is only slightly more potent than olaparib and rucaparib at inhibiting PARP catalytic activity.	('inhibiting', 'NegReg', (91, 101))	('rucaparib', 'Chemical', 'MESH:C531549', (78, 87))	('PARP', 'Gene', (102, 106))	('olaparib', 'Chemical', 'MESH:C531550', (65, 73))	('BMN 673', 'Var', (23, 30))	('PARP', 'Gene', '142', (102, 106))	('BMN 673', 'Chemical', 'MESH:C586365', (23, 30))
54624	24356813	Notably, LT674, the inactive enantiomer of BMN 673, is markedly less active than BMN 673 both at PARP-mediated cytotoxicity and at inhibiting its catalytic activity.	('BMN 673', 'Chemical', 'MESH:C586365', (81, 88))	('PARP', 'Gene', '142', (97, 101))	('BMN 673', 'Chemical', 'MESH:C586365', (43, 50))	('catalytic activity', 'MPA', (146, 164))	('less', 'NegReg', (64, 68))	('cytotoxicity', 'Disease', 'MESH:D064420', (111, 123))	('PARP', 'Gene', (97, 101))	('inhibiting', 'NegReg', (131, 141))	('cytotoxicity', 'Disease', (111, 123))	('LT674', 'Var', (9, 14))
54626	24356813	We believe that BMN 673 can now be viewed not only as a valuable anticancer agent but also as a molecular tool to elucidate PARP allosteric regulation.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PARP', 'Gene', (124, 128))	('BMN 673', 'Chemical', 'MESH:C586365', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('BMN', 'Var', (16, 19))	('cancer', 'Disease', (69, 75))	('PARP', 'Gene', '142', (124, 128))
54628	24356813	The nanomolar cytotoxicity of BMN 673 is notably greater than that of rucaparib or olaparib (>=10-fold in lymphoma DT40 and prostate cancer DU145 and >= 5-fold in Ewing's sarcoma EW8 cells) (see Figure 2).	('cytotoxicity', 'Disease', 'MESH:D064420', (14, 26))	('BMN', 'Var', (30, 33))	('lymphoma DT40 and prostate cancer', 'Disease', 'MESH:D011471', (106, 139))	('greater', 'PosReg', (49, 56))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (163, 178))	('rucaparib', 'Chemical', 'MESH:C531549', (70, 79))	("Ewing's sarcoma", 'Disease', (163, 178))	('olaparib', 'Chemical', 'MESH:C531550', (83, 91))	('DU145', 'CellLine', 'CVCL:0105', (140, 145))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (163, 178))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('cytotoxicity', 'Disease', (14, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (106, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('nanomolar', 'MPA', (4, 13))	('BMN 673', 'Chemical', 'MESH:C586365', (30, 37))
54631	24356813	The potency of BMN 673 observed across the NCI60 cell line panel (see Figure 3) showed significant correlation between BMN 673 and olaparib (Table 2).	('BMN', 'Var', (119, 122))	('BMN 673', 'Chemical', 'MESH:C586365', (15, 22))	('olaparib', 'Chemical', 'MESH:C531550', (131, 139))	('NCI60', 'CellLine', 'CVCL:A592', (43, 48))	('correlation', 'Interaction', (99, 110))	('BMN 673', 'Chemical', 'MESH:C586365', (119, 126))
54632	24356813	The greater cytotoxic potency of BMN 673 over olaparib and rucaparib can be related to the trapping of PARP-DNA complexes because knocking out PARP1 in lymphoma DT40 cells, which by itself is well-tolerated in spite of the fact that DT40 cells also lack PARP2, conferred extreme resistance to BMN 673 (and olaparib) (see Figure 2).	('rucaparib', 'Chemical', 'MESH:C531549', (59, 68))	('lack', 'NegReg', (249, 253))	('lymphoma', 'Phenotype', 'HP:0002665', (152, 160))	('olaparib', 'Chemical', 'MESH:C531550', (46, 54))	('BMN 673', 'Chemical', 'MESH:C586365', (33, 40))	('PARP2', 'Gene', '10038', (254, 259))	('BMN 673', 'Chemical', 'MESH:C586365', (293, 300))	('PARP', 'Gene', '142', (143, 147))	('PARP2', 'Gene', (254, 259))	('lymphoma', 'Disease', (152, 160))	('lymphoma', 'Disease', 'MESH:D008223', (152, 160))	('resistance', 'MPA', (279, 289))	('PARP', 'Gene', '142', (254, 258))	('PARP', 'Gene', '142', (103, 107))	('PARP', 'Gene', (143, 147))	('PARP', 'Gene', (254, 258))	('PARP', 'Gene', (103, 107))	('knocking out', 'Var', (130, 142))	('olaparib', 'Chemical', 'MESH:C531550', (306, 314))
54633	24356813	Moreover, the greater cytotoxicity of BMN 673 compared to olaparib is correlated with the greater potency of BMN 673 at trapping PARP (see Figures 4 and 5) while both drugs are equally effective at inhibiting PARP catalytic activity (see Figure 2).	('PARP', 'Gene', (209, 213))	('BMN 673', 'Chemical', 'MESH:C586365', (38, 45))	('PARP', 'Gene', '142', (129, 133))	('potency', 'MPA', (98, 105))	('cytotoxicity', 'Disease', (22, 34))	('olaparib', 'Chemical', 'MESH:C531550', (58, 66))	('cytotoxicity', 'Disease', 'MESH:D064420', (22, 34))	('PARP', 'Gene', '142', (209, 213))	('BMN 673', 'Var', (109, 116))	('BMN 673', 'Chemical', 'MESH:C586365', (109, 116))	('PARP', 'Gene', (129, 133))
54637	24356813	We speculate that the inhibition of tankyrases may contribute to the broader cytotoxicity of rucaparib as tankyrase-1 RNAi results in mitotic arrest.	('RNAi', 'Var', (118, 122))	('mitotic arrest', 'Disease', (134, 148))	('tankyrase-1', 'Gene', '8658', (106, 117))	('tankyrase-1', 'Gene', (106, 117))	('mitotic arrest', 'Disease', 'MESH:D006323', (134, 148))	('cytotoxicity', 'Disease', (77, 89))	('results in', 'Reg', (123, 133))	('cytotoxicity', 'Disease', 'MESH:D064420', (77, 89))	('rucaparib', 'Chemical', 'MESH:C531549', (93, 102))	('contribute', 'Reg', (51, 61))
54639	24356813	As single agent in BRCA-deficient cells, we found that BMN 673 demonstrates   30-fold greater potency in isogenic BRCA2-deficient lymphoma DT40 cells (see Figure 2).	('BRCA2-deficient lymphoma', 'Disease', (114, 138))	('greater', 'PosReg', (86, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('BMN 673', 'Chemical', 'MESH:C586365', (55, 62))	('BMN', 'Var', (55, 58))	('potency', 'MPA', (94, 101))	('BRCA-deficient', 'Disease', (19, 33))	('BRCA2-deficient lymphoma', 'Disease', 'MESH:D008223', (114, 138))	('BRCA-deficient', 'Disease', 'OMIM:604370', (19, 33))
54640	24356813	BMN 673 is also significantly more potent than olaparib in combination with temozolomide or MMS (see Figure 6), which is consistent with the enhanced trapping of PARP by BMN 673 and olaparib in the presence of MMS (see Figure 4).	('olaparib', 'Chemical', 'MESH:C531550', (47, 55))	('PARP', 'Gene', '142', (162, 166))	('BMN 673', 'Chemical', 'MESH:C586365', (0, 7))	('MMS', 'Chemical', 'MESH:D008741', (210, 213))	('olaparib', 'Chemical', 'MESH:C531550', (182, 190))	('potent', 'MPA', (35, 41))	('trapping', 'MPA', (150, 158))	('BMN 673', 'Var', (170, 177))	('temozolomide', 'Chemical', 'MESH:D000077204', (76, 88))	('enhanced', 'PosReg', (141, 149))	('PARP', 'Gene', (162, 166))	('BMN 673', 'Chemical', 'MESH:C586365', (170, 177))	('MMS', 'Chemical', 'MESH:D008741', (92, 95))
54641	24356813	In spite of the fact that BMN 673 is a highly potent drug by inducing PARP-DNA complexes, it is surprising that half of the NCI60 cell lines are resistant even at 100 muM of BMN 673 (see Figure 3).	('BMN 673', 'Chemical', 'MESH:C586365', (174, 181))	('PARP', 'Gene', '142', (70, 74))	('NCI60', 'CellLine', 'CVCL:A592', (124, 129))	('BMN 673', 'Var', (26, 33))	('PARP', 'Gene', (70, 74))	('BMN 673', 'Chemical', 'MESH:C586365', (26, 33))	('inducing', 'Reg', (61, 69))
54644	24356813	It will also be important to determine whether the resistant cells exhibit preferential homologous recombination by 53BP1 inactivation.	('53BP1', 'Gene', (116, 121))	('53BP1', 'Gene', '7158', (116, 121))	('inactivation', 'Var', (122, 134))	('homologous recombination', 'MPA', (88, 112))	('preferential', 'PosReg', (75, 87))
54664	32145827	In high-resource settings, pegylated liposomal doxorubicin and paclitaxel have been shown to be highly effective in inducing regression of advanced AIDS-associated Kaposi sarcoma.	('paclitaxel', 'Chemical', 'MESH:D017239', (63, 73))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (164, 178))	('pegylated liposomal', 'Var', (27, 46))	('doxorubicin', 'Chemical', 'MESH:D004317', (47, 58))	('regression', 'MPA', (125, 135))	('Kaposi sarcoma', 'Disease', (164, 178))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (164, 178))	('AIDS', 'Disease', 'MESH:D000163', (148, 152))	('AIDS', 'Disease', (148, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))
54718	32145827	Descriptive summaries of changes in CD4 cell counts were made with medians and IQRs, and with HIV-1 RNA levels with percentages (<200, 200-1000, >1000 copies per mL) by study week.	('CD4', 'Gene', (36, 39))	('CD4', 'Gene', '920', (36, 39))	('HIV-1', 'Species', '11676', (94, 99))	('<200', 'Var', (129, 133))
54732	32145827	Although the differences in the death rates failed to reach statistical significance, the rates of IERC-confirmed Kaposi sarcoma progression or death, and the rates of death by week 48 were higher in the etoposide plus ART and bleomycin and vincristine plus ART arms than in the paclitaxel plus ART arm (figure 2).	('ART', 'Chemical', '-', (219, 222))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (114, 128))	('ART', 'Chemical', '-', (258, 261))	('death', 'Disease', (144, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('death', 'Disease', (168, 173))	('Kaposi sarcoma', 'Disease', (114, 128))	('death', 'Disease', (32, 37))	('etoposide', 'Chemical', 'MESH:D005047', (204, 213))	('etoposide', 'Var', (204, 213))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (114, 128))	('ART', 'Chemical', '-', (295, 298))	('paclitaxel', 'Chemical', 'MESH:D017239', (279, 289))	('death', 'Disease', 'MESH:D003643', (144, 149))	('death', 'Disease', 'MESH:D003643', (168, 173))	('vincristine', 'Chemical', 'MESH:D014750', (241, 252))	('death', 'Disease', 'MESH:D003643', (32, 37))	('bleomycin', 'Chemical', 'MESH:D001761', (227, 236))	('higher', 'PosReg', (190, 196))
54733	32145827	Similarly, although the time to death analysis did not show a significant difference between arms, the time to death and the time to progression or death analyses showed higher risk for both etoposide plus ART and bleomycin and vincristine plus ART than for paclitaxel plus ART (figure 3).	('bleomycin', 'Chemical', 'MESH:D001761', (214, 223))	('death', 'Disease', (32, 37))	('ART', 'Chemical', '-', (206, 209))	('death', 'Disease', 'MESH:D003643', (111, 116))	('ART', 'Chemical', '-', (245, 248))	('etoposide', 'Chemical', 'MESH:D005047', (191, 200))	('ART', 'Chemical', '-', (274, 277))	('death', 'Disease', 'MESH:D003643', (148, 153))	('death', 'Disease', (148, 153))	('vincristine', 'Chemical', 'MESH:D014750', (228, 239))	('etoposide', 'Var', (191, 200))	('death', 'Disease', (111, 116))	('death', 'Disease', 'MESH:D003643', (32, 37))	('paclitaxel', 'Chemical', 'MESH:D017239', (258, 268))
54763	32145827	In addition to the unexpected finding that paclitaxel plus ART was superior to both investigational arms with respect to the primary outcome, PFS at 48 weeks, we found that participants who received paclitaxel as their initial chemotherapy showed a superior outcome compared with participants who received either etoposide or bleomycin and vincristine with respect to overall response rate, response duration, and the composite of time to death or progression.	('participants', 'Species', '9606', (173, 185))	('ART', 'Chemical', '-', (59, 62))	('paclitaxel', 'Var', (199, 209))	('death', 'Disease', 'MESH:D003643', (439, 444))	('death', 'Disease', (439, 444))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('vincristine', 'Chemical', 'MESH:D014750', (340, 351))	('bleomycin', 'Chemical', 'MESH:D001761', (326, 335))	('paclitaxel', 'Chemical', 'MESH:D017239', (199, 209))	('etoposide', 'Chemical', 'MESH:D005047', (313, 322))	('participants', 'Species', '9606', (280, 292))
54825	31817469	These TRAIL formulations include highly stable TRAIL trimers, fusion proteins with single-chain variable antibody fragments (scFv) that active target TRAIL to cancer cells or immune cells, mutant variants with specificity to DR5, and different types of nanoparticles.	('mutant variants', 'Var', (189, 204))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('scFv', 'Gene', '652070', (125, 129))	('DR5', 'Gene', (225, 228))	('DR5', 'Gene', '8795', (225, 228))	('scFv', 'Gene', (125, 129))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('variants', 'Var', (196, 204))
54827	31817469	We already demonstrated that LUV-TRAIL exhibited an enhanced anti-tumor activity when compared to soluble TRAIL (sTRAIL) against leukemic cells resistant to TRAIL or to chemotherapeutic drugs, and on epithelial carcinoma cells both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (200, 220))	('leukemic', 'Disease', (129, 137))	('tumor', 'Disease', (66, 71))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (200, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('enhanced', 'PosReg', (52, 60))	('leukemic', 'Disease', 'MESH:D007938', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('LUV-TRAIL', 'Var', (29, 38))	('epithelial carcinoma', 'Disease', (200, 220))
54828	31817469	The increased cytotoxicity of LUV-TRAIL relied on its ability to induce an improved DR5 clustering leading to an enhanced DISC recruitment in comparison to sTRAIL.	('improved', 'PosReg', (75, 83))	('cytotoxicity', 'Disease', 'MESH:D064420', (14, 26))	('DISC recruitment', 'CPA', (122, 138))	('LUV-TRAIL', 'Var', (30, 39))	('DR5', 'Gene', (84, 87))	('cytotoxicity', 'Disease', (14, 26))	('DR5', 'Gene', '8795', (84, 87))	('enhanced', 'PosReg', (113, 121))
54847	31817469	Thus, DOX molecules passively diffuse from the media to the liposomal lumen, where the low pH induces a protonation of the DOX molecule, rendering it insoluble and therefore unable to cross the lipid barrier, being entrapped inside the liposomes.	('DOX', 'Chemical', 'MESH:D004317', (6, 9))	('insoluble', 'MPA', (150, 159))	('induces', 'Reg', (94, 101))	('protonation', 'MPA', (104, 115))	('low pH', 'Var', (87, 93))	('DOX', 'Chemical', 'MESH:D004317', (123, 126))
54871	31817469	It is worth noting that LDT also induced a quick and strong activation of caspase-9.	('caspase-9', 'Gene', '842', (74, 83))	('activation', 'PosReg', (60, 70))	('LDT', 'Var', (24, 27))	('caspase-9', 'Gene', (74, 83))
54872	31817469	Overall, while LD did not induce any noticeable activation of any of the three caspases analyzed, LDT induced a clear and strong activation of the three caspases even from the 30-minute time point.	('caspases', 'Gene', (153, 161))	('LDT', 'Var', (98, 101))	('caspases', 'Gene', '841;842', (79, 87))	('activation', 'PosReg', (129, 139))	('caspases', 'Gene', (79, 87))	('caspases', 'Gene', '841;842', (153, 161))
54877	31817469	Having corroborated that LDT induced a strong caspase activation, we next checked if caspases were the main driver of LDT cytotoxicity.	('caspase', 'Gene', (46, 53))	('LDT', 'Var', (25, 28))	('caspase', 'Gene', (85, 92))	('caspases', 'Gene', (85, 93))	('LDT cytotoxicity', 'Disease', (118, 134))	('LDT cytotoxicity', 'Disease', 'MESH:D064420', (118, 134))	('activation', 'PosReg', (54, 64))	('caspase', 'Gene', '841;842', (46, 53))	('caspase', 'Gene', '841;842', (85, 92))	('caspases', 'Gene', '841;842', (85, 93))
54883	31817469	In this line, silencing caspase-8 in SKBR3 cells completely abrogated LDT-induced cell death (Supplementary Figure S2b).	('caspase-8', 'Gene', (24, 33))	('silencing', 'Var', (14, 23))	('SKBR3', 'CellLine', 'CVCL:0033', (37, 42))	('LDT-induced cell death', 'CPA', (70, 92))	('caspase-8', 'Gene', '841', (24, 33))	('abrogated', 'NegReg', (60, 69))
54905	31817469	Interestingly, pre-treatment with z-VAD-fmk also decreased the amount of DOX into the nuclei, although to a lesser extent than DYN.	('amount of DOX into the nuclei', 'MPA', (63, 92))	('DOX', 'Chemical', 'MESH:D004317', (73, 76))	('decreased', 'NegReg', (49, 58))	('z-VAD-fmk', 'Var', (34, 43))	('DYN', 'Chemical', 'MESH:C059508', (127, 130))
54908	31817469	As expected, caspase activation was reduced after z-VAD-fmk treatment.	('caspase', 'Gene', '841;842', (13, 20))	('z-VAD-fmk', 'Var', (50, 59))	('activation', 'MPA', (21, 31))	('caspase', 'Gene', (13, 20))	('reduced', 'NegReg', (36, 43))
54912	31817469	Importantly, both DYN and z-IETD-fmk were able to abrogate apoptosis induced by LDT or by the combination of LT and LD.	('DYN', 'Chemical', 'MESH:C059508', (18, 21))	('abrogate', 'NegReg', (50, 58))	('apoptosis', 'CPA', (59, 68))	('LDT', 'Disease', (80, 83))	('combination', 'Interaction', (94, 105))	('z-IETD-fmk', 'Var', (26, 36))
54918	31817469	Toxicity was similar on both CD4+ and CD8+ 6-day T-cell blasts subpopulations (Figure S3c,d), and it was clearly due to DOX, since LD exhibited a similar cytotoxicity pattern.	('DOX', 'Chemical', 'MESH:D004317', (120, 123))	('cytotoxicity', 'Disease', (154, 166))	('Toxicity', 'Disease', (0, 8))	('Toxicity', 'Disease', 'MESH:D064420', (0, 8))	('CD8+', 'Var', (38, 42))	('cytotoxicity', 'Disease', 'MESH:D064420', (154, 166))
54935	31817469	On the other hand, tumors of mice treated with LDT took significantly longer to reach 25%, 50%, and 75% of the tumor volume when compared to both the control and LT groups.	('tumors', 'Disease', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (19, 24))	('mice', 'Species', '10090', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('LDT', 'Var', (47, 50))
54937	31817469	In this regard, we have demonstrated in the present study that LDT exhibited a greatly improved cytotoxicity against a broad panel of cancer cells from distinct origins, overcoming resistance to sTRAIL or to LT, while LD alone did not show a remarkable cytotoxic effect in the case of epithelial cells, in which cytotoxicity was dependent on the presence of TRAIL.	('cytotoxicity', 'Disease', (312, 324))	('improved', 'PosReg', (87, 95))	('LDT', 'Var', (63, 66))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cytotoxicity', 'Disease', (96, 108))	('cytotoxicity', 'Disease', 'MESH:D064420', (312, 324))	('overcoming', 'PosReg', (170, 180))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cytotoxicity', 'Disease', 'MESH:D064420', (96, 108))
54938	31817469	In the case of sarcoma cells, LD contributed to the cytotoxic effect, but the presence of TRAIL enhanced cytotoxicity even more.	('enhanced', 'PosReg', (96, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (105, 117))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcoma', 'Disease', (15, 22))	('cytotoxic effect', 'MPA', (52, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('presence', 'Var', (78, 86))	('cytotoxicity', 'Disease', (105, 117))
54970	31817469	At the same time, liver, kidney, spleen, and ovaries were also surgically extracted to perform a histological analysis of any possible tissular damage induced by LDT 1/10.	('ovaries', 'Disease', 'MESH:D010051', (45, 52))	('tissular damage', 'Disease', 'MESH:D009422', (135, 150))	('tissular damage', 'Disease', (135, 150))	('ovaries', 'Disease', (45, 52))	('LDT', 'Var', (162, 165))
54973	31817469	Therefore, it could be concluded that LDT 1/10 did not induce any systemic toxicity on any tissue analyzed, validating their use in vivo.	('LDT', 'Var', (38, 41))	('toxicity', 'Disease', 'MESH:D064420', (75, 83))	('toxicity', 'Disease', (75, 83))
54975	31817469	LDT 1/10 was able to slow down the tumor growth in a significant manner when compared to untreated animals and most importantly, when compared to LT.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('LDT', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('slow down', 'NegReg', (21, 30))	('tumor', 'Disease', (35, 40))
55050	30783599	These neoplasms are composed of small round blue cells of neuroectodermal origin, and about 85% of Ewing sarcomas are associated with translocation t(11;22)(q24.1;q12.2).	('translocation t(11;22)(q24.1;q12.2', 'Var', (134, 168))	('neoplasms', 'Disease', 'MESH:D009369', (6, 15))	('neoplasms', 'Disease', (6, 15))	('neoplasm', 'Phenotype', 'HP:0002664', (6, 14))	('t(11;22)(q24.1;q12.2)', 'STRUCTURAL_ABNORMALITY', 'None', (148, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('Ewing sarcomas', 'Disease', (99, 113))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (99, 113))	('neoplasms', 'Phenotype', 'HP:0002664', (6, 15))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (99, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('associated', 'Reg', (118, 128))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (99, 113))
55097	27843394	Between October 2013 and December 2014 ten patients with translocation-positive pediatric-type refractory and end-stage sarcomas with no conventional treatment options left started treatment at our institutions with an off-label compassionate use chemotherapy, combining trabectedin and irinotecan based on preclinical observations.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('end-stage sarcomas', 'Disease', 'MESH:D007676', (110, 128))	('translocation-positive', 'Var', (57, 79))	('Oct', 'Gene', '5362', (8, 11))	('pediatric-type refractory', 'Disease', (80, 105))	('Oct', 'Gene', (8, 11))	('end-stage sarcomas', 'Disease', (110, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
55099	27843394	Four had other translocation-positive soft tissue sarcomas: two alveolar rhabdomyosarcomas, one synovial sarcoma, and one desmoplastic small round cell tumor.	('synovial sarcoma', 'Disease', 'MESH:D013584', (96, 112))	('desmoplastic small round cell tumor', 'Disease', (122, 157))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (64, 90))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (38, 58))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (73, 89))	('synovial sarcoma', 'Disease', (96, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (96, 112))	('alveolar rhabdomyosarcomas', 'Disease', (64, 90))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (73, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (64, 90))	('translocation-positive', 'Var', (15, 37))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (122, 157))
55170	24397743	The risk of soft-tissue sarcoma and basalioma in the metal-on-metal cohort was higher than in the non-metal-on-metal cohort (SIR/SIR ratio = 2.6, CI: 1.02-6.4 for soft-tissue sarcoma; SIR/SIR ratio = 1.3, CI: 1.1-1.5 for basalioma).	('sarcoma', 'Disease', (175, 182))	('sarcoma', 'Disease', (24, 31))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (163, 182))	('on-metal', 'Chemical', '-', (99, 107))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (12, 31))	('basalioma', 'Phenotype', 'HP:0002671', (36, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('basalioma', 'Disease', 'None', (221, 230))	('basalioma', 'Disease', (36, 45))	('metal-on-metal', 'Chemical', '-', (102, 116))	('metal-on-metal', 'Var', (53, 67))	('basalioma', 'Phenotype', 'HP:0002671', (221, 230))	('sarcoma and basalioma', 'Disease', 'MESH:D012509', (24, 45))	('on-metal', 'Chemical', '-', (108, 116))	('metal-on-metal', 'Chemical', '-', (53, 67))	('basalioma', 'Disease', (221, 230))	('on-metal', 'Chemical', '-', (59, 67))	('sarcoma', 'Disease', 'MESH:D012509', (175, 182))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('basalioma', 'Disease', 'None', (36, 45))
55171	24397743	The overall risk of death in the metal-on-metal cohort was less than that in the non-metal-on-metal cohort (RR = 0.78, CI: 0.69-0.88).	('on-metal', 'Chemical', '-', (91, 99))	('on-metal', 'Chemical', '-', (39, 47))	('on-metal', 'Chemical', '-', (82, 90))	('metal-on-metal', 'Chemical', '-', (85, 99))	('metal-on-metal', 'Var', (33, 47))	('death', 'Disease', 'MESH:D003643', (20, 25))	('death', 'Disease', (20, 25))	('less', 'NegReg', (59, 63))	('metal-on-metal', 'Chemical', '-', (33, 47))
55203	24397743	A Poisson regression model was also used for comparison of the risk of death in the metal-on-metal cohort and in the non-metal-on-metal cohort.	('metal-on-metal', 'Var', (84, 98))	('death', 'Disease', 'MESH:D003643', (71, 76))	('death', 'Disease', (71, 76))	('on-metal', 'Chemical', '-', (127, 135))	('metal-on-metal', 'Chemical', '-', (121, 135))	('on-metal', 'Chemical', '-', (90, 98))	('on-metal', 'Chemical', '-', (118, 126))	('metal-on-metal', 'Chemical', '-', (84, 98))
55208	24397743	In the regression model, the overall cancer risk in the metal-on-metal cohort was not any higher than that in the non-metal-on-metal cohort (RR = 0.9, CI: 0.8-1.0; p = 0.1).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('on-metal', 'Chemical', '-', (115, 123))	('cancer', 'Disease', (37, 43))	('on-metal', 'Chemical', '-', (62, 70))	('on-metal', 'Chemical', '-', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('metal-on-metal', 'Chemical', '-', (56, 70))	('metal-on-metal', 'Var', (56, 70))	('metal-on-metal', 'Chemical', '-', (118, 132))
55209	24397743	Risk of basalioma in the metal-on-metal cohort was higher than in the Finnish population (SIR = 1.4, CI: 1.2-1.6; p < 0.001) (Table 2).	('basalioma', 'Phenotype', 'HP:0002671', (8, 17))	('basalioma', 'Disease', 'None', (8, 17))	('metal-on-metal', 'Chemical', '-', (25, 39))	('basalioma', 'Disease', (8, 17))	('metal-on-metal', 'Var', (25, 39))
55210	24397743	Risk of basalioma in the metal-on-metal cohort was also higher than in the non-metal-on-metal cohort, both in the non-stratified analysis (SIR/SIR ratio = 1.3, CI: 1.1-1.5) (Table 3) and in the stratified regression analysis (RR = 1.3, CI: 1.1-1.5; p = 0.01).	('on-metal', 'Chemical', '-', (31, 39))	('on-metal', 'Chemical', '-', (76, 84))	('on-metal', 'Chemical', '-', (85, 93))	('metal-on-metal', 'Chemical', '-', (79, 93))	('basalioma', 'Phenotype', 'HP:0002671', (8, 17))	('basalioma', 'Disease', 'None', (8, 17))	('metal-on-metal', 'Chemical', '-', (25, 39))	('higher', 'PosReg', (56, 62))	('basalioma', 'Disease', (8, 17))	('metal-on-metal', 'Var', (25, 39))
55214	24397743	The risk of soft-tissue sarcoma in the metal-on-metal cohort was higher than in the non-metal-on-metal cohort (RR = 2.6, CI: 1.0-6.4) (Table 3).	('metal-on-metal', 'Chemical', '-', (88, 102))	('sarcoma', 'Disease', (24, 31))	('metal-on-metal', 'Var', (39, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('on-metal', 'Chemical', '-', (85, 93))	('on-metal', 'Chemical', '-', (45, 53))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (12, 31))	('on-metal', 'Chemical', '-', (94, 102))	('metal-on-metal', 'Chemical', '-', (39, 53))
55220	24397743	The overall risk of death in the metal-on-metal cohort was less than that in the non-metal-on-metal cohort (RR = 0.78, CI: 0.69-0.88; p < 0.001).	('on-metal', 'Chemical', '-', (91, 99))	('on-metal', 'Chemical', '-', (39, 47))	('on-metal', 'Chemical', '-', (82, 90))	('metal-on-metal', 'Chemical', '-', (85, 99))	('metal-on-metal', 'Var', (33, 47))	('death', 'Disease', 'MESH:D003643', (20, 25))	('death', 'Disease', (20, 25))	('less', 'NegReg', (59, 63))	('metal-on-metal', 'Chemical', '-', (33, 47))
55224	24397743	The SMR for cardiovascular deaths in a follow-up time of 5 years or more since operation was 0.81 (CI: 0.50-1.2) in the metal-on-metal cohort and 0.98 (CI: 0.90-1.1) in the non-metal-on-metal cohort relative to that in the Finnish population.	('metal-on-metal', 'Chemical', '-', (177, 191))	('on-metal', 'Chemical', '-', (174, 182))	('metal-on-metal', 'Chemical', '-', (120, 134))	('on-metal', 'Chemical', '-', (126, 134))	('cardiovascular deaths', 'Disease', 'MESH:D002318', (12, 33))	('metal-on-metal', 'Var', (120, 134))	('cardiovascular deaths', 'Disease', (12, 33))	('on-metal', 'Chemical', '-', (183, 191))
55226	24397743	The risk of cardiovascular deaths in the metal-on-metal cohort was less than that in the non-metal-on-metal cohort (RR = 0.79, CI: 0.64-0.97; p = 0.02).	('on-metal', 'Chemical', '-', (47, 55))	('less', 'NegReg', (67, 71))	('on-metal', 'Chemical', '-', (99, 107))	('metal-on-metal', 'Chemical', '-', (41, 55))	('on-metal', 'Chemical', '-', (90, 98))	('metal-on-metal', 'Chemical', '-', (93, 107))	('cardiovascular deaths', 'Disease', (12, 33))	('cardiovascular deaths', 'Disease', 'MESH:D002318', (12, 33))	('metal-on-metal', 'Var', (41, 55))
55227	24397743	Separately analyzed risk for ischemic heart disease deaths in the metal-on-metal cohort was not any higher than in the non-metal-on-metal cohort (RR = 0.78, CI: 0.60-1.02; p = 0.07).	('on-metal', 'Chemical', '-', (129, 137))	('on-metal', 'Chemical', '-', (120, 128))	('ischemic heart disease deaths', 'Disease', (29, 58))	('metal-on-metal', 'Chemical', '-', (123, 137))	('ischemic heart disease deaths', 'Disease', 'MESH:D003324', (29, 58))	('on-metal', 'Chemical', '-', (72, 80))	('metal-on-metal', 'Chemical', '-', (66, 80))	('metal-on-metal', 'Var', (66, 80))
55228	24397743	The risk of death from cancer in the metal-on-metal cohort was less than in the non-metal-on-metal cohort (RR = 0.78, CI: 0.63-0.97; p = 0.02).	('death', 'Disease', (12, 17))	('metal-on-metal', 'Chemical', '-', (37, 51))	('on-metal', 'Chemical', '-', (43, 51))	('on-metal', 'Chemical', '-', (81, 89))	('metal-on-metal', 'Var', (37, 51))	('metal-on-metal', 'Chemical', '-', (84, 98))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('on-metal', 'Chemical', '-', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('death', 'Disease', 'MESH:D003643', (12, 17))	('less', 'NegReg', (63, 67))
55229	24397743	The risks of death from respiratory disease and of death from accidents and violence in the metal-on-metal cohort were similar to those in the non-metal-on-metal cohort (RR = 0.86, CI: 0.42-1.74; p = 0.7; and RR = 0.92, CI: 0.61-1.39; p = 0.7, respectively).	('on-metal', 'Chemical', '-', (153, 161))	('metal-on-metal', 'Chemical', '-', (92, 106))	('respiratory disease', 'Disease', (24, 43))	('on-metal', 'Chemical', '-', (98, 106))	('respiratory disease', 'Phenotype', 'HP:0011947', (24, 43))	('metal-on-metal', 'Var', (92, 106))	('death', 'Disease', 'MESH:D003643', (13, 18))	('respiratory disease', 'Disease', 'MESH:D012131', (24, 43))	('death', 'Disease', (13, 18))	('on-metal', 'Chemical', '-', (144, 152))	('metal-on-metal', 'Chemical', '-', (147, 161))	('death', 'Disease', 'MESH:D003643', (51, 56))	('death', 'Disease', (51, 56))
55234	24397743	the healthy-patient effect:had an appreciable influence on overall and site-specific risk of death during the first years of follow-up, both in the metal-on-metal and in the non-metal-on-metal cohorts.	('influence', 'Reg', (46, 55))	('metal-on-metal', 'Var', (148, 162))	('on-metal', 'Chemical', '-', (175, 183))	('on-metal', 'Chemical', '-', (154, 162))	('metal-on-metal', 'Chemical', '-', (178, 192))	('death', 'Disease', 'MESH:D003643', (93, 98))	('death', 'Disease', (93, 98))	('patient', 'Species', '9606', (12, 19))	('on-metal', 'Chemical', '-', (184, 192))	('metal-on-metal', 'Chemical', '-', (148, 162))
55235	24397743	The overall and site-specific risk of death was not higher in the metal-on-metal cohort than in the non-metal-on-metal cohort, not even after the patient selection bias had ceased after the first 5 years of follow-up.	('death', 'Disease', 'MESH:D003643', (38, 43))	('on-metal', 'Chemical', '-', (110, 118))	('death', 'Disease', (38, 43))	('on-metal', 'Chemical', '-', (72, 80))	('metal-on-metal', 'Chemical', '-', (66, 80))	('metal-on-metal', 'Chemical', '-', (104, 118))	('metal-on-metal', 'Var', (66, 80))	('patient', 'Species', '9606', (146, 153))	('on-metal', 'Chemical', '-', (101, 109))
55248	24397743	Male patients with metal-on-metal Birmingham hip resurfacing had a lower risk of death than those with a conventional hip device.	('death', 'Disease', 'MESH:D003643', (81, 86))	('patients', 'Species', '9606', (5, 13))	('metal-on-metal', 'Var', (19, 33))	('death', 'Disease', (81, 86))	('Birmingham hip resurfacing', 'CPA', (34, 60))	('metal-on-metal', 'Chemical', '-', (19, 33))
55261	24397743	The risk of soft-tissue sarcoma in the metal-on-metal cohort was increased in our previous report, but not statistically significantly.	('sarcoma', 'Disease', (24, 31))	('metal-on-metal', 'Var', (39, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (12, 31))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('metal-on-metal', 'Chemical', '-', (39, 53))
55274	24397743	In the study based on the National Joint Registry of England and Wales, the risk of melanoma was not higher in metal-on-metal patients than in patients with other bearing options in the first 7 years after arthroplasty.	('metal-on-metal', 'Var', (111, 125))	('arthroplasty', 'Disease', 'None', (206, 218))	('arthroplasty', 'Disease', (206, 218))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (126, 134))	('metal-on-metal', 'Chemical', '-', (111, 125))
55288	31307426	In contrast, for patients with carcinosarcoma, total mortality risk was significantly decreased with EBRT, brachytherapy, and combination radiotherapy compared with no radiotherapy.	('brachytherapy', 'Var', (107, 120))	('carcinosarcoma', 'Disease', 'MESH:D002296', (31, 45))	('mortality', 'MPA', (53, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('EBRT', 'Var', (101, 105))	('decreased', 'NegReg', (86, 95))	('patients', 'Species', '9606', (17, 25))	('carcinosarcoma', 'Disease', (31, 45))	('EBRT', 'Chemical', '-', (101, 105))
55315	31307426	The SEER database was examined to identify patients with primary uterine sarcoma according to codes of the International Classification of Diseases for Oncology (ICD-O) for anatomic sites (PRIMSITE = C54.0-C54.3, C54.8-C54.9, C55.9) who underwent total hysterectomy (SURGPRIF = 40, 50).	('Oncology', 'Phenotype', 'HP:0002664', (152, 160))	('C54.0-C54.3', 'Var', (200, 211))	('patients', 'Species', '9606', (43, 51))	('sarcoma', 'Disease', (73, 80))	('C54.8-C54.9', 'Var', (213, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (65, 80))	('C55.9', 'Var', (226, 231))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
55348	31307426	In contrast, for patients with carcinosarcoma, the risk of overall mortality was significantly decreased with EBRT alone (aHR = 0.72, 95% CI: 0.53, 0.99, P = 0.042), brachytherapy alone (aHR = 0.55, 95% CI: 0.37, 0.80, P = 0.002), and combination radiotherapy (aHR = 0.47, 95% CI: 0.29, 0.77, P = 0.003) as compared with no radiotherapy (Table 2).	('decreased', 'NegReg', (95, 104))	('carcinosarcoma', 'Disease', 'MESH:D002296', (31, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('brachytherapy', 'Var', (166, 179))	('EBRT', 'Chemical', '-', (110, 114))	('patients', 'Species', '9606', (17, 25))	('carcinosarcoma', 'Disease', (31, 45))	('combination radiotherapy', 'Var', (235, 259))
55349	31307426	In addition, for patients with carcinosarcoma, the risk of cancer-specific mortality was significantly decreased with brachytherapy alone (aHR = 0.51, 95% CI: 0.31, 0.84, P = 0.009), combination radiotherapy (aHR = 0.53, 95% CI: 0.29, 0.95, P = 0.034) as compared to no radiotherapy (Table 2).	('carcinosarcoma', 'Disease', 'MESH:D002296', (31, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('decreased', 'NegReg', (103, 112))	('combination radiotherapy', 'Var', (183, 207))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (17, 25))	('carcinosarcoma', 'Disease', (31, 45))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
55355	31307426	For patients with carcinosarcoma, propensity score matching showed the risk of overall mortality was significantly decreased with EBRT alone (aHR = 0.65, 95% CI: 0.45, 0.93, P = 0.020), brachytherapy alone (aHR = 0.62, 95% CI: 0.40, 0.95, P = 0.029), and combination radiotherapy (aHR = 0.47, 95% CI: 0.26, 0.85, P = 0.013) as compared with no radiotherapy (Table 3).	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('EBRT', 'Chemical', '-', (130, 134))	('brachytherapy', 'Var', (186, 199))	('decreased', 'NegReg', (115, 124))	('carcinosarcoma', 'Disease', 'MESH:D002296', (18, 32))	('patients', 'Species', '9606', (4, 12))	('combination radiotherapy', 'Var', (255, 279))	('carcinosarcoma', 'Disease', (18, 32))
55375	31307426	The locoregional failure rate was lower for patients who received adjuvant radiotherapy than for those who did not (17.5% vs. 28.5%, P = 0.107), and adjuvant radiotherapy was associated with longer locoregional recurrence-free survival in patients who did not undergo pelvic lymph node dissection (52.7% vs. 18.7%, P < 0.001).	('locoregional failure rate', 'CPA', (4, 29))	('patients', 'Species', '9606', (44, 52))	('lower', 'NegReg', (34, 39))	('patients', 'Species', '9606', (239, 247))	('adjuvant', 'Var', (149, 157))	('locoregional recurrence-free survival', 'CPA', (198, 235))	('longer', 'PosReg', (191, 197))
55380	31307426	analyzed the SEER data of 1855 patients with uterine carcinosarcoma and found that lymphadenectomy was associated with improved OS in patients with stage I-III disease as compared to no lymphadenectomy.	('carcinosarcoma', 'Disease', (53, 67))	('OS', 'Chemical', '-', (128, 130))	('carcinosarcoma', 'Disease', 'MESH:D002296', (53, 67))	('patients', 'Species', '9606', (134, 142))	('II disease', 'Disease', (157, 167))	('patients', 'Species', '9606', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (45, 67))	('improved', 'PosReg', (119, 127))	('II disease', 'Disease', 'MESH:D005776', (157, 167))	('lymphadenectomy', 'Var', (83, 98))
55382	31307426	For women who received adjuvant radiotherapy as compared to those who did not, the 5-year OS rates were 41.5 and 33.2%, respectively (P < 0.001), and uterine-specific survival rates were 56.0 and 50.8%, respectively (P = 0.005).	('uterine-specific survival', 'CPA', (150, 175))	('women', 'Species', '9606', (4, 9))	('radiotherapy', 'Var', (32, 44))	('OS', 'Chemical', '-', (90, 92))
55383	31307426	Radiotherapy was associated with better OS in patients with stage I-III disease (HR = 0.87, P = 0.03), and with better OS (HR = 0.63, P < 0.001) and uterine-specific survival (HR = 0.63, P = 0.004) in patients with stage IV disease.	('patients', 'Species', '9606', (201, 209))	('patients', 'Species', '9606', (46, 54))	('II disease', 'Disease', 'MESH:D005776', (69, 79))	('Radiotherapy', 'Var', (0, 12))	('uterine-specific survival', 'CPA', (149, 174))	('OS', 'Chemical', '-', (40, 42))	('II disease', 'Disease', (69, 79))	('OS', 'Chemical', '-', (119, 121))	('better', 'PosReg', (33, 39))	('better', 'PosReg', (112, 118))
55403	30913212	To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of:function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME).	('mice', 'Species', '10090', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('HPK1', 'Gene', (100, 104))	('loss-of:function', 'NegReg', (148, 164))	('tumor', 'Disease', (307, 312))	('point mutation in', 'Var', (165, 182))
55404	30913212	Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses.	('suppressive functions', 'MPA', (84, 105))	('HKP1', 'Gene', (37, 41))	('inactivation', 'Var', (189, 201))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('Tregs', 'Chemical', '-', (178, 183))	('elicit', 'Reg', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('HKP1', 'Gene', '15278', (37, 41))	('HPK1', 'Gene', (109, 113))	('tumor', 'Disease', (256, 261))
55410	30913212	HPK1 ablation resulted in enhanced T cell activation and immune functions, as demonstrated by the increased susceptibility of HPK1 KO mice to experimental autoimmune encephalomyelitis.	('enhanced', 'PosReg', (26, 34))	('enhanced T cell', 'Phenotype', 'HP:0100828', (26, 41))	('mice', 'Species', '10090', (134, 138))	('HPK1', 'Gene', (0, 4))	('HPK1', 'Gene', (126, 130))	('ablation', 'Var', (5, 13))	('T cell activation', 'CPA', (35, 52))	('enhanced T cell activation', 'Phenotype', 'HP:0005419', (26, 52))	('autoimmune encephalomyelitis', 'Disease', (155, 183))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (155, 183))	('immune functions', 'CPA', (57, 73))
55412	30913212	Consistently, studies also demonstrated that mice received adoptive transfer of HPK1 KO T cells became resistant to Lewis lung carcinoma (LLC) tumor growth via mounting effective anti-tumor immune responses, suggesting that inhibition of HPK1 could be a viable approach for cancer immune therapy by promoting effector functions of T cells.	('promoting', 'PosReg', (299, 308))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('mice', 'Species', '10090', (45, 49))	('resistant', 'CPA', (103, 112))	('effector functions', 'CPA', (309, 327))	('tumor', 'Disease', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancer', 'Disease', (274, 280))	('HPK1', 'Gene', (80, 84))	('tumor', 'Disease', (184, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('inhibition', 'Var', (224, 234))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('Lewis lung carcinoma (LLC) tumor', 'Disease', 'MESH:D018827', (116, 148))	('HPK1', 'Gene', (238, 242))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
55421	30913212	Our data provide novel evidence that blockade of HPK1 kinase activity is sufficient to beneficial effect on enabling an optimal "cancer-immunity cycle", supporting that pharmacological intervention of HPK1 kinase activity could serve as a novel immunomodulatory approach to anticancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('blockade', 'Var', (37, 45))	('HPK1', 'Gene', (49, 53))	('enabling', 'PosReg', (108, 116))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Disease', (278, 284))
55424	30913212	The targeting strategy allows the generation of a constitutive Knock-In of a point mutation (KI-PM) in the Map4k1 gene.	('Map4k1', 'Gene', '26411', (107, 113))	('point mutation', 'Var', (77, 91))	('Map4k1', 'Gene', (107, 113))
55428	30913212	This KI-PM allele was demonstrated to express the mutated Map4k1 K46M protein.	('protein', 'Protein', (70, 77))	('mutated', 'Var', (50, 57))	('Map4k1', 'Gene', (58, 64))	('K46M', 'Var', (65, 69))	('Map4k1', 'Gene', '26411', (58, 64))	('K46M', 'Mutation', 'p.K46M', (65, 69))
55452	30913212	The point mutation K46M was constitutively introduced into the kinase domain of the mouse HPK1 gene, resulting in a kinase-inactive HPK1.	('K46M', 'Var', (19, 23))	('K46M', 'Mutation', 'p.K46M', (19, 23))	('mouse', 'Species', '10090', (84, 89))	('HPK1', 'Gene', (90, 94))	('kinase-inactive HPK1', 'MPA', (116, 136))
55459	30913212	The splenocytes were stained with anti-B220, anti-CD3, anti-CD4, anti-CD8, anti-pan-NK, and anti-CD11b monoclonal antibodies followed by measurement via FACS to evaluate various immune cell populations.	('CD3', 'Gene', '12501', (50, 53))	('anti-CD8', 'Var', (65, 73))	('FACS', 'Gene', (153, 157))	('CD11b', 'Gene', (97, 102))	('CD11b', 'Gene', '16409', (97, 102))	('FACS', 'Gene', '14081', (153, 157))	('anti-CD4', 'Var', (55, 63))	('CD3', 'Gene', (50, 53))	('anti-B220', 'Var', (34, 43))
55465	30913212	The inactivation of HPK1 kinase led to significant enhancement of IL-2 and IFNgamma release by both CD4+ and CD8+ T cells (Fig 2A-2D).	('enhancement', 'PosReg', (51, 62))	('inactivation', 'Var', (4, 16))	('IL-2 and IFNgamma', 'Gene', '16183;15978', (66, 83))	('HPK1', 'Gene', (20, 24))
55466	30913212	Further analysis of T cell proliferation by [3H]-thymidine incorporation revealed a hyper-proliferative response upon inactivation of HPK1 kinase (Fig 2E-2F).	('inactivation', 'Var', (118, 130))	('HPK1', 'Gene', (134, 138))	('[3H]-thymidine', 'Chemical', '-', (44, 58))	('hyper-proliferative', 'PosReg', (84, 103))
55478	30913212	Significant enhancement of OT1 cell proliferation was observed with BMDCs from HPK1 KD mice (S3 Fig).	('HPK1 KD', 'Var', (79, 86))	('enhancement', 'PosReg', (12, 23))	('BMDC', 'Chemical', '-', (68, 72))	('mice', 'Species', '10090', (87, 91))	('OT1 cell proliferation', 'CPA', (27, 49))
55485	30913212	The inactivation of HPK1 kinase led to significant resistance to the impairment of splenocyte proliferation by PGE2 and NECA (Fig 3A-3B).	('inactivation', 'Var', (4, 16))	('HPK1', 'Gene', (20, 24))	('splenocyte proliferation', 'CPA', (83, 107))	('resistance', 'NegReg', (51, 61))	('PGE2', 'Chemical', 'MESH:D015232', (111, 115))	('NECA', 'Chemical', 'MESH:D019830', (120, 124))
55486	30913212	The suppression of IL-2 release by PGE2 and adenosine was also significantly weakened with HPK1 KD (Fig 3C-3D), suggesting that the kinase activity of HPK1 plays a critical role in attenuating the suppressive functions of PGE2 and adenosine.	('PGE2', 'Chemical', 'MESH:D015232', (222, 226))	('suppression', 'NegReg', (4, 15))	('kinase activity', 'MPA', (132, 147))	('weakened', 'NegReg', (77, 85))	('IL-2', 'Gene', '16183', (19, 23))	('adenosine', 'Chemical', 'MESH:D000241', (231, 240))	('HPK1 KD', 'Var', (91, 98))	('IL-2', 'Gene', (19, 23))	('PGE2', 'Chemical', 'MESH:D015232', (35, 39))	('adenosine', 'Chemical', 'MESH:D000241', (44, 53))	('attenuating', 'NegReg', (181, 192))	('suppressive', 'MPA', (197, 208))
55493	30913212	With high levels of release of both PGE2 and inosine (adenosine) from 1956 sarcoma cells, we selected this tumor model to assess the potential anti-tumor benefit afforded by the inactivation of HPK1 kinase activity.	('inactivation', 'Var', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (148, 153))	('adenosine', 'Chemical', 'MESH:D000241', (54, 63))	('sarcoma', 'Disease', (75, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('HPK1', 'Gene', (194, 198))	('inosine', 'Chemical', 'MESH:D007288', (45, 52))	('PGE2', 'Chemical', 'MESH:D015232', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
55496	30913212	These results suggest that inactivation of HPK1 kinase contributes to the improvement of anti-tumor immune response in a tumor model containing relevant immune suppressive factors, e.g.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('inactivation', 'Var', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (94, 99))	('improvement', 'PosReg', (74, 85))	('HPK1', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
55501	30913212	Significantly higher CD69 levels, in both CD4+ and CD8+ cell populations, were observed in the HPK1 KD group in comparison with WT group (Fig 5A-5B), indicating that HPK1 KD leads to augmentation of T cell activation in the tumor bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('CD69', 'Gene', '12515', (21, 25))	('tumor', 'Disease', (224, 229))	('HPK1 KD', 'Var', (166, 173))	('CD69', 'Gene', (21, 25))	('augmentation', 'PosReg', (183, 195))	('HPK1 KD', 'Var', (95, 102))	('mice', 'Species', '10090', (238, 242))	('T cell activation', 'CPA', (199, 216))	('higher', 'PosReg', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
55503	30913212	The magnitude of the cytokine release was markedly higher in HPK1 KD groups (Fig 5C-5D), with over 30 fold higher levels of IFNgamma in the tumor bearing mice compared with naive mice (Fig 2D and Fig 5C).	('mice', 'Species', '10090', (154, 158))	('cytokine release', 'MPA', (21, 37))	('mice', 'Species', '10090', (179, 183))	('IFNgamma', 'Gene', '15978', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('higher', 'PosReg', (51, 57))	('higher', 'PosReg', (107, 113))	('IFNgamma', 'Gene', (124, 132))	('HPK1 KD', 'Var', (61, 68))	('tumor', 'Disease', (140, 145))
55505	30913212	The HPK1 KD T cells, in comparison with HPK1 WT T cells, exhibited remarkably higher cytolytic activities against the previously experienced syngeneic tumors (Fig 5E), suggesting that HPK1 KD could improve the antigen recall response of CD8+ T cells.	('HPK1 WT T', 'Disease', 'MESH:C536751', (40, 49))	('improve', 'PosReg', (198, 205))	('HPK1 KD T', 'Disease', 'MESH:C537017', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('higher', 'PosReg', (78, 84))	('HPK1 WT T', 'Disease', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('antigen recall response', 'CPA', (210, 233))	('HPK1 KD', 'Var', (184, 191))	('syngeneic tumors', 'Disease', 'MESH:D009369', (141, 157))	('syngeneic tumors', 'Disease', (141, 157))	('cytolytic activities', 'MPA', (85, 105))	('HPK1 KD T', 'Disease', (4, 13))
55508	30913212	A modest reduction of tumor volume was observed in HPK1 KD mice post 10-day tumor implantation (Fig 6A).	('mice', 'Species', '10090', (59, 63))	('HPK1 KD', 'Var', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('reduction', 'NegReg', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
55509	30913212	Further analysis revealed significant reduction of regulatory T cells, an increased ratio of CD8+ to regulatory T cells in the TME of HPK1 KD mice, whereas the percentage of CD8+ Ki67+ T cell populations remained similar between WT and KD groups (Fig 6B-6D).	('regulatory T cells', 'CPA', (51, 69))	('mice', 'Species', '10090', (142, 146))	('reduction', 'NegReg', (38, 47))	('increased', 'PosReg', (74, 83))	('HPK1 KD', 'Var', (134, 141))
55510	30913212	The dLN analysis from HPK1 KD mice demonstrated a markedly higher percentage of CD4+Ki67+ and CD8+Ki67+ T cells as well as reduction of the regulatory T cell population (Fig 6E-6G).	('mice', 'Species', '10090', (30, 34))	('CD8+Ki67+', 'Var', (94, 103))	('HPK1', 'Var', (22, 26))	('reduction', 'NegReg', (123, 132))	('regulatory T cell population', 'CPA', (140, 168))	('higher', 'PosReg', (59, 65))	('CD4+Ki67+', 'CPA', (80, 89))
55512	30913212	Importantly, under HPK1 KD conditions, the dLN appear to be better orchestrated to generate a more robust anti-tumor immune reservoir as demonstrated by the augmented levels of CD4+Ki67+ and CD8+Ki67+ T cells.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CD8+Ki67+', 'Var', (191, 200))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('CD4+Ki67+', 'MPA', (177, 186))	('levels', 'MPA', (167, 173))	('augmented', 'PosReg', (157, 166))
55515	30913212	In comparison with HPK1 WT mice, a significant reduction of pSLP76 was observed in both CD4+ and CD8+ T cells in the peripheral blood of the HPK1 KD group (Fig 7A), with markedly higher IFNgamma messenger levels in HPK1 KD group (Fig 7B).	('SLP76', 'Gene', (61, 66))	('SLP76', 'Gene', '16822', (61, 66))	('IFNgamma', 'Gene', (186, 194))	('IFNgamma', 'Gene', '15978', (186, 194))	('HPK1 KD', 'Var', (141, 148))	('mice', 'Species', '10090', (27, 31))	('reduction', 'NegReg', (47, 56))	('higher', 'PosReg', (179, 185))
55519	30913212	Under tumor challenge conditions, significant immune modulatory effects were observed in HPK1 KD group compared with WT group (S4 Fig).	('immune modulatory effects', 'MPA', (46, 71))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('HPK1 KD', 'Var', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
55520	30913212	The results revealed that various immune cell types and pathways were affected in HPK1 KD mice, including T effector cells, dendritic cells, regulatory T cells, natural killer cells and neutrophils.	('mice', 'Species', '10090', (90, 94))	('affected', 'Reg', (70, 78))	('HPK1 KD', 'Var', (82, 89))	('immune cell types', 'CPA', (34, 51))
55521	30913212	Notably, HPK1 KD mice showed markedly increased pro-inflammatory pathways in response to priming with tumor antigens as shown by the enhanced related gene expression, e.g.	('enhanced', 'PosReg', (133, 141))	('mice', 'Species', '10090', (17, 21))	('pro-inflammatory', 'MPA', (48, 64))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('response', 'MPA', (77, 85))	('HPK1 KD', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('increased', 'PosReg', (38, 47))
55528	30913212	Through the studies in KO mice, the beneficial effects of HPK1 deletion on the improvement of TCR signaling, antigen presentation ability and resistance to PGE2 immunosuppression have been well documented.	('improvement', 'PosReg', (79, 90))	('TCR', 'Gene', (94, 97))	('HPK1', 'Gene', (58, 62))	('TCR', 'Gene', '328483', (94, 97))	('antigen presentation ability', 'MPA', (109, 137))	('deletion', 'Var', (63, 71))	('PGE2', 'Chemical', 'MESH:D015232', (156, 160))	('mice', 'Species', '10090', (26, 30))
55532	30913212	We demonstrated that HPK1 KD exhibits significant impact on both CD4+ and CD8+ T effector cells with enhanced cytokine secretion and proliferation under in vitro and in vivo settings, as well as under polyclonal stimulation conditions with anti-CD3 or an antigen specific manner with OVA administration.	('CD3', 'Gene', '12501', (245, 248))	('HPK1 KD', 'Var', (21, 28))	('enhanced', 'PosReg', (101, 109))	('CD3', 'Gene', (245, 248))	('proliferation', 'CPA', (133, 146))	('cytokine secretion', 'MPA', (110, 128))
55534	30913212	The CD4+ T cells with HPK1 KD could improve the priming phase of CD8+ T-cell activation and the differentiation of CD8+ effector cells into memory cells, via direct cell-cell interaction and/or IL-2 provision.	('improve', 'PosReg', (36, 43))	('differentiation', 'CPA', (96, 111))	('CD8+ T-cell activation', 'CPA', (65, 87))	('HPK1 KD', 'Var', (22, 29))	('priming', 'CPA', (48, 55))	('IL-2', 'Gene', '16183', (194, 198))	('IL-2', 'Gene', (194, 198))
55536	30913212	Strikingly, our current study revealed a marked augmentation of CD4+Ki67+ and CD8+Ki67+ T cells in tumor dLN in HPK1 KD mice, further support the positive interplay between CD4+ and CD8+ T cells upon inactivation of HPK1 kinase in tumor bearing mice.	('HPK1', 'Gene', (112, 116))	('tumor', 'Disease', (99, 104))	('CD4+Ki67+', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('mice', 'Species', '10090', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('augmentation', 'PosReg', (48, 60))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mice', 'Species', '10090', (245, 249))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('inactivation', 'Var', (200, 212))
55538	30913212	Consistently, our data here demonstrated a significant enhanced IFNgamma secretion with CD4+ T cells from HPK1 KD mice.	('enhanced', 'PosReg', (55, 63))	('IFNgamma', 'Gene', (64, 72))	('IFNgamma', 'Gene', '15978', (64, 72))	('mice', 'Species', '10090', (114, 118))	('CD4+', 'Var', (88, 92))	('HPK1 KD', 'Var', (106, 113))
55541	30913212	Moreover, a significantly better recall response was demonstrated with HPK1 KD splenocytes upon ex vivo re-challenge with syngeneic tumor cells.	('recall response', 'CPA', (33, 48))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('HPK1 KD', 'Var', (71, 78))	('better', 'PosReg', (26, 32))
55550	30913212	Adenosine and PGE2 thereby cooperatively diminishes lymphocyte activities.	('Adenosine', 'Chemical', 'MESH:D000241', (0, 9))	('diminishes', 'NegReg', (41, 51))	('Adenosine', 'Var', (0, 9))	('lymphocyte activities', 'CPA', (52, 73))	('PGE2', 'Chemical', 'MESH:D015232', (14, 18))	('PGE2', 'Gene', (14, 18))	('diminishes lymphocyte', 'Phenotype', 'HP:0001888', (41, 62))
55555	30913212	Our data strongly support that the inhibition of the kinase activity of HPK1 could facilitate the maintenance of effective anti-tumor immune responses and overcome immune resistance mediated by immune suppressive factors.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('kinase activity', 'MPA', (53, 68))	('immune', 'MPA', (164, 170))	('facilitate', 'PosReg', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('HPK1', 'Gene', (72, 76))	('tumor', 'Disease', (128, 133))	('inhibition', 'Var', (35, 45))
55558	30913212	In HPK1 KD mice, tumor progression was significantly retarded and an enhanced ratio of CD8+/Treg in the TME was observed.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('retarded', 'Disease', 'MESH:D008607', (53, 61))	('Treg', 'Chemical', '-', (92, 96))	('enhanced', 'PosReg', (69, 77))	('HPK1 KD', 'Var', (3, 10))	('mice', 'Species', '10090', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('ratio', 'MPA', (78, 83))	('retarded', 'Disease', (53, 61))
55562	30913212	A significant reduction of the Treg population in the TME of HPK1 KD mice was observed, potentially via intervention of the TGFss-HPK1-JNK and/or PGE2-HPK1 cascades.	('JNK', 'Gene', (135, 138))	('Treg population', 'CPA', (31, 46))	('PGE2-HPK1', 'Gene', (146, 155))	('PGE2-HPK1', 'Gene', '26411', (146, 155))	('mice', 'Species', '10090', (69, 73))	('JNK', 'Gene', '5599', (135, 138))	('reduction', 'NegReg', (14, 23))	('HPK1 KD', 'Var', (61, 68))	('Treg', 'Chemical', '-', (31, 35))
55563	30913212	Additionally, loss of HPK1 kinase activity is likely to re-shape the immune cell repertoire/balance via modulating the plasticity of Tregs and promoting the conversion of Treg into T effector cells.	('activity', 'MPA', (34, 42))	('promoting', 'PosReg', (143, 152))	('loss', 'Var', (14, 18))	('plasticity', 'MPA', (119, 129))	('Tregs', 'Chemical', '-', (133, 138))	('Treg', 'Chemical', '-', (133, 137))	('modulating', 'Reg', (104, 114))	('Treg', 'Chemical', '-', (171, 175))	('conversion', 'CPA', (157, 167))	('HPK1', 'Gene', (22, 26))
55566	30913212	Depletion of Treg cells in the TME would shift the balance from immune suppression to immune activation towards tumor cells.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Treg', 'Chemical', '-', (13, 17))	('Depletion', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('shift', 'Reg', (41, 46))	('tumor', 'Disease', (112, 117))
55567	30913212	In constant Treg supportive TME with Treg populations being constantly replenished by conversion of conventional CD4+CD25- T cells into CD4+CD25+ Treg upon exposure to TGF-beta or PGE2, inhibition of HPK1 could combat Treg suppression via several venues as demonstrated by our studies here.	('TGF-beta', 'Gene', (168, 176))	('Treg', 'Chemical', '-', (12, 16))	('Treg', 'Chemical', '-', (218, 222))	('CD25', 'Gene', (140, 144))	('Treg', 'Chemical', '-', (37, 41))	('CD25', 'Gene', '16184', (117, 121))	('CD25', 'Gene', '16184', (140, 144))	('CD25', 'Gene', (117, 121))	('PGE2', 'Chemical', 'MESH:D015232', (180, 184))	('HPK1', 'Gene', (200, 204))	('TGF-beta', 'Gene', '21803', (168, 176))	('inhibition', 'Var', (186, 196))	('Treg', 'Chemical', '-', (146, 150))	('Treg suppression', 'CPA', (218, 234))
55575	30734606	Preliminary structure-activity relationships (SARs) analysis indicated that: (1) C1-methylation and C7-methoxylation were favorable for increased activities; (2) 3-Pyridyl or 2-thienyl group substituent into position-1 of the beta-carboline core, and the aryl substituent into another beta-carboline ring might be detrimental to cytotoxic effects of this class compounds.	('aryl substituent', 'Var', (255, 271))	('C', 'Chemical', 'MESH:D002244', (100, 101))	('beta-carboline', 'Chemical', 'MESH:C010262', (226, 240))	('C7-methoxylation', 'MPA', (100, 116))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('S', 'Chemical', 'MESH:D013455', (46, 47))	('C1-methylation', 'MPA', (81, 95))	('beta-carboline', 'Chemical', 'MESH:C010262', (285, 299))
55586	30734606	Previous investigations has shown that some dimer antitumor agents via an appropriate linker could lead to significantly improved antitumor activities (100- to 500-fold improvement over the corresponding monomers).	('improvement', 'PosReg', (169, 180))	('improved', 'PosReg', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('dimer', 'Var', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (134, 139))
55587	30734606	Therefore, bivalent beta-carbolines were expected to exhibit more potent antitumor efficacies than monomers.	('bivalent', 'Var', (11, 19))	('beta-carbolines', 'Chemical', 'MESH:D002243', (20, 35))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
55591	30734606	The pharmacological mechanisms showed that the angiogenesis inhibitor B-9-3 selectively induces apoptosis of endothelial cells, in part through disruption of VEGF-A/VEGFR2 signaling.	('induces', 'Reg', (88, 95))	('VEGF-A', 'Gene', (158, 164))	('VEGF-A', 'Gene', '22339', (158, 164))	('VEGFR2', 'Gene', (165, 171))	('apoptosis', 'CPA', (96, 105))	('disruption', 'NegReg', (144, 154))	('B-9-3', 'Chemical', '-', (70, 75))	('VEGFR2', 'Gene', '16542', (165, 171))	('B-9-3', 'Var', (70, 75))
55593	30734606	Here, we designed and synthesized a series of novel N9-heterobivalent beta-carboline derivatives as potent antitumor agents.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('beta-carboline', 'Chemical', 'MESH:C010262', (70, 84))	('N9-heterobivalent', 'Var', (52, 69))
55637	30734606	calcd for C33H29N5: C, 79.97; H, 5.90; N, 14.13; found C 79.11, H 5.88, N 13.90.	('C 79.11', 'Var', (55, 62))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('C33H29N5: C', 'Var', (10, 21))	('C33H29N5', 'Chemical', '-', (10, 18))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('C', 'Chemical', 'MESH:D002244', (10, 11))
55641	30734606	calcd for C34H31N5: C, 80.13; H, 6.13; N, 13.74; found C 79.72, H 6.14, N 13.32.	('C 79.72', 'Var', (55, 62))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('C34H31N5', 'Chemical', '-', (10, 18))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('C34H31N5', 'Var', (10, 18))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('C', 'Chemical', 'MESH:D002244', (10, 11))
55681	30734606	calcd for C37H28ClN5: C, 76.87; H, 4.88; N, 12.11; found C 76.38, H 4.85, N 11.75.	('N', 'Chemical', 'MESH:D009584', (74, 75))	('C 76.38', 'Var', (57, 64))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('C37H28ClN5', 'Chemical', '-', (10, 20))	('C37H28ClN5: C', 'Var', (10, 23))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('C', 'Chemical', 'MESH:D002244', (10, 11))
55709	30734606	calcd for C33H29N5O: C, 77.47; H, 5.71; N, 13.69; found C, 76.67; H, 5.75; N, 13.05.	('C', 'Chemical', 'MESH:D002244', (21, 22))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('C, 76.67', 'Var', (56, 64))	('C33H29N5O: C', 'Var', (10, 22))	('C33H29N5O', 'Chemical', '-', (10, 19))	('C', 'Chemical', 'MESH:D002244', (10, 11))
55753	30734606	All the 24 novel synthesized N9-heterobivalent beta-carbolines (5a-x) were screened for their in vitro cytotoxic activities against six different cancer cell lines, namely BGC-823 (gastric carcinoma), HepG2 (liver carcinoma), MCF-7 (breast carcinoma), HT-29 (colon carcinoma), Eca-109 (esophageal carcinoma) and LLC (Lewis lung carcinoma).	('cancer', 'Disease', (146, 152))	('C', 'Chemical', 'MESH:D002244', (227, 228))	('N9-heterobivalent', 'Var', (29, 46))	('HepG2', 'CellLine', 'CVCL:0027', (201, 206))	('C', 'Chemical', 'MESH:D002244', (314, 315))	('Lewis lung carcinoma', 'Disease', (317, 337))	('esophageal carcinoma', 'Disease', (286, 306))	('breast carcinoma', 'Phenotype', 'HP:0003002', (233, 249))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('gastric carcinoma', 'Disease', 'MESH:D013274', (181, 198))	('breast carcinoma', 'Disease', (233, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('gastric carcinoma', 'Disease', (181, 198))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (317, 337))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (286, 306))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (181, 198))	('liver carcinoma', 'Phenotype', 'HP:0001402', (208, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('MCF-7', 'CellLine', 'CVCL:0031', (226, 231))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('liver carcinoma', 'Disease', (208, 223))	('beta-carbolines', 'Chemical', 'MESH:D002243', (47, 62))	('liver carcinoma', 'Disease', 'MESH:D006528', (208, 223))	('C', 'Chemical', 'MESH:D002244', (174, 175))	('colon carcinoma', 'Disease', (259, 274))	('breast carcinoma', 'Disease', 'MESH:D001943', (233, 249))	('HT-29', 'CellLine', 'CVCL:0320', (252, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (286, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('colon carcinoma', 'Disease', 'MESH:D015179', (259, 274))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
55767	30734606	These results suggested that 3-pyridyl or 2-thienyl group substituent into position-1 of the beta-carboline core, and in another beta-carboline ring, the methyl substituent into R1' facilitated cytotoxic potency, and the aryl substituent into R1' might be detrimental to cytotoxic effects.	('beta-carboline', 'Chemical', 'MESH:C010262', (129, 143))	('substituent', 'Var', (58, 69))	('facilitated', 'PosReg', (182, 193))	('beta-carboline', 'Chemical', 'MESH:C010262', (93, 107))	('cytotoxic potency', 'CPA', (194, 211))
55780	30734606	In summary, a total analysis of the cytotoxic activities of N9-heterobivalent beta-carbolines in vitro clearly suggest that: (1) C1-methylation and C7-methoxylation were favorable for increased activities; (2) 3-Pyridyl or 2-thienyl group substituent into position-1 of the beta-carboline core, and the aryl (electron withdrawing and donating groups) substituent into position-1' of another beta-carboline ring might be detrimental to cytotoxic effects of this class of compounds.	('beta-carbolines', 'Chemical', 'MESH:D002243', (78, 93))	('3-Pyridyl', 'Var', (210, 219))	('aryl', 'Var', (303, 307))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('beta-carboline', 'Chemical', 'MESH:C010262', (78, 92))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('beta-carboline', 'Chemical', 'MESH:C010262', (274, 288))	('beta-carboline', 'Chemical', 'MESH:C010262', (391, 405))	('C', 'Chemical', 'MESH:D002244', (129, 130))
55788	30734606	Based on the in vitro assay results, we further tested the antitumor activity of four N9-heterobivalent beta-carbolines in vivo against mice bearing Sarcoma 180 and Lewis lung cancer, respectively, and the reference drugs Cyclophosphamide (CTX).	('tumor', 'Disease', (63, 68))	('mice', 'Species', '10090', (136, 140))	('CTX', 'Gene', '57276', (240, 243))	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (222, 238))	('Sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Lewis lung cancer', 'Disease', (165, 182))	('beta-carbolines', 'Chemical', 'MESH:D002243', (104, 119))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Sarcoma', 'Disease', (149, 156))	('tested', 'Reg', (48, 54))	('CTX', 'Gene', (240, 243))	('N', 'Chemical', 'MESH:D009584', (86, 87))	('Lewis lung cancer', 'Disease', 'MESH:D018827', (165, 182))	('N9-heterobivalent', 'Var', (86, 103))
55791	30734606	As shown in Table 2, all the tested N9-heterobivalent beta-carbolines displayed moderate to strong antitumor activities in animal model.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('tumor', 'Disease', (103, 108))	('N9-heterobivalent', 'Var', (36, 53))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('beta-carbolines', 'Chemical', 'MESH:D002243', (54, 69))
55807	30734606	Although most N9-heterodimeric beta-carbolines presented here showed modest cytotoxic activities, the investigations of these structural modifications and preliminary SARs would be helpful to further design and develop more potent compounds.	('beta-carbolines', 'Chemical', 'MESH:D002243', (31, 46))	('N9-heterodimeric', 'Var', (14, 30))	('cytotoxic activities', 'CPA', (76, 96))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('S', 'Chemical', 'MESH:D013455', (167, 168))
55867	27482375	MCs are present mainly at the tumour edge and are likely to contribute to osteolysis and tumour invasion.	('tumour edge', 'Disease', (30, 41))	('MCs', 'Var', (0, 3))	('tumour edge', 'Disease', 'MESH:D009369', (30, 41))	('osteolysis', 'Phenotype', 'HP:0002797', (74, 84))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('contribute', 'Reg', (60, 70))	('osteolysis and tumour', 'Disease', 'MESH:D010014', (74, 95))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
55878	27482375	MCs have also been shown to influence the extent of the DC, TAM and lymphocyte infiltrate through the release of mediators which enhance migration and proliferation of these cells.	('MCs', 'Var', (0, 3))	('proliferation', 'CPA', (151, 164))	('TAM', 'Chemical', '-', (60, 63))	('influence', 'Reg', (28, 37))	('migration', 'CPA', (137, 146))	('enhance', 'PosReg', (129, 136))
55912	27482375	However, MCs (+/++) were commonly found at the periphery of invasive bone tumours in the fibrous pseudocapsule at the soft tissue margin and at the host bone-tumour interface where there was osteolysis (Fig.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('MCs (+/++', 'Var', (9, 18))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('host bone-tumour', 'Disease', (148, 164))	('osteolysis', 'Disease', (191, 201))	('invasive bone tumours', 'Disease', (60, 81))	('invasive bone tumours', 'Disease', 'MESH:D001859', (60, 81))	('bone tumour', 'Phenotype', 'HP:0010622', (69, 80))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('osteolysis', 'Disease', 'MESH:D010014', (191, 201))	('host bone-tumour', 'Disease', 'MESH:D001859', (148, 164))	('osteolysis', 'Phenotype', 'HP:0002797', (191, 201))
55940	27482375	The suppression of DC antigen and function can induce immune tolerance to tumour antigens in sarcomas; specifically, the alteration of carbohydrates on the cell surface is thought to influence the interaction between C-type lectins on DCs and tumour cells, thus interfering with antigen presentation.	('function', 'MPA', (34, 42))	('immune', 'MPA', (54, 60))	('interfering', 'NegReg', (262, 273))	('antigen presentation', 'MPA', (279, 299))	('interaction', 'Interaction', (197, 208))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('influence', 'Reg', (183, 192))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('tumour', 'Disease', 'MESH:D009369', (243, 249))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('tumour', 'Disease', (243, 249))	('sarcomas', 'Disease', (93, 101))	('alteration', 'Var', (121, 131))	('induce', 'Reg', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('C-type lectins', 'Protein', (217, 231))	('carbohydrates', 'Chemical', 'MESH:D002241', (135, 148))	('suppression', 'NegReg', (4, 15))	('DC antigen', 'Protein', (19, 29))
55946	27482375	Mechanisms whereby MCs may influence tumour progression include stimulation of the release of growth factors essential for tumour growth and suppression of the host immune response to tumour cells.	('tumour growth', 'Disease', (123, 136))	('stimulation', 'PosReg', (64, 75))	('tumour', 'Disease', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('tumour growth', 'Disease', 'MESH:D006130', (123, 136))	('tumour', 'Disease', (123, 129))	('release of growth factors', 'MPA', (83, 108))	('influence', 'Reg', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('MCs', 'Var', (19, 22))	('tumour', 'Disease', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
55956	27482375	MCs are likely to contribute to tumour osteolysis as they are almost exclusively found at the tumour-bone interface.	('MCs', 'Var', (0, 3))	('tumour osteolysis', 'Disease', 'MESH:D010014', (32, 49))	('tumour osteolysis', 'Disease', (32, 49))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour-bone', 'Disease', 'MESH:D001859', (94, 105))	('tumour-bone', 'Disease', (94, 105))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('contribute', 'Reg', (18, 28))	('osteolysis', 'Phenotype', 'HP:0002797', (39, 49))
55964	32164354	These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by EWSR1-ERG-positive EwS.	('EWSR1', 'Gene', '2130', (222, 227))	('CD99', 'Gene', (77, 81))	('high', 'Var', (33, 37))	('EwS', 'Gene', (164, 167))	('BCL11B', 'Gene', (38, 44))	('EwS', 'Gene', (241, 244))	('ERG', 'Gene', '2078', (228, 231))	('GLG1', 'Gene', '2734', (52, 56))	('EWSR1', 'Gene', (222, 227))	('BCL11B', 'Gene', '64919', (38, 44))	('ERG', 'Gene', (228, 231))	('EwS', 'Gene', '2130', (241, 244))	('EwS', 'Phenotype', 'HP:0012254', (164, 167))	('CD99', 'Gene', '4267', (77, 81))	('EwS', 'Phenotype', 'HP:0012254', (241, 244))	('EwS', 'Gene', '2130', (164, 167))	('GLG1', 'Gene', (52, 56))
55976	32164354	Since fusions of the FET family of genes comprising FUS, EWSR1, and potentially TAF15, with members of the ETS family of transcription factors (including FLI1, ERG, ETV1/4/6 and FEV) are largely pathognomonic for EwS, molecular identification of such fusions is the most reliable diagnostic test for EwS to date.	('FUS', 'Gene', (52, 55))	('TAF15', 'Gene', '8148', (80, 85))	('EwS', 'Gene', '2130', (300, 303))	('EwS', 'Phenotype', 'HP:0012254', (213, 216))	('fusions', 'Var', (6, 13))	('EWSR1', 'Gene', '2130', (57, 62))	('EwS', 'Gene', (213, 216))	('pathognomonic', 'Reg', (195, 208))	('FUS', 'Gene', '2521', (52, 55))	('ETV1/4/6', 'Gene', '2115;2118;2120', (165, 173))	('FET family', 'Gene', (21, 31))	('EwS', 'Phenotype', 'HP:0012254', (300, 303))	('ETV1/4/6', 'Gene', (165, 173))	('EwS', 'Gene', (300, 303))	('EWSR1', 'Gene', (57, 62))	('ERG', 'Gene', (160, 163))	('EwS', 'Gene', '2130', (213, 216))	('FLI1', 'Gene', (154, 158))	('ERG', 'Gene', '2078', (160, 163))	('TAF15', 'Gene', (80, 85))	('FLI1', 'Gene', '2313', (154, 158))
55993	32164354	Therefore, if such histology is present and EwS is suspected, fluorescence in situ hybridization (FISH) for detection of EWSR1 break-apart and immunohistochemical CD99 stains are commonly performed in pathological routine diagnostics for exclusion or diagnosis of EwS.	('EwS', 'Phenotype', 'HP:0012254', (264, 267))	('EwS', 'Gene', '2130', (264, 267))	('EWSR1', 'Gene', (121, 126))	('CD99', 'Gene', '4267', (163, 167))	('EwS', 'Phenotype', 'HP:0012254', (44, 47))	('EwS', 'Gene', '2130', (44, 47))	('EwS', 'Gene', (264, 267))	('EWSR1', 'Gene', '2130', (121, 126))	('break-apart', 'Var', (127, 138))	('CD99', 'Gene', (163, 167))	('EwS', 'Gene', (44, 47))
55994	32164354	Yet, EWSR1 break-apart occurs in several morphological mimics of EwS such as DSRCT harboring a pathognomonic EWSR1-WT1 fusion, and angiomatoid fibrous histiocytoma (AFH) commonly positive for EWSR1-ATF1 fusions (Figure 1).	('EwS', 'Gene', '2130', (65, 68))	('EWSR1', 'Gene', '2130', (109, 114))	('angiomatoid fibrous histiocytoma', 'Disease', (131, 163))	('DSRCT', 'Disease', (77, 82))	('EWSR1', 'Gene', '2130', (192, 197))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (131, 163))	('fusion', 'Var', (119, 125))	('EwS', 'Gene', (65, 68))	('EwS', 'Phenotype', 'HP:0012254', (65, 68))	('EWSR1', 'Gene', (5, 10))	('WT1', 'Gene', '7490', (115, 118))	('ATF1', 'Gene', (198, 202))	('histiocytoma', 'Phenotype', 'HP:0012315', (151, 163))	('EWSR1', 'Gene', (109, 114))	('EWSR1', 'Gene', '2130', (5, 10))	('ATF1', 'Gene', '466', (198, 202))	('EWSR1', 'Gene', (192, 197))	('WT1', 'Gene', (115, 118))
56022	32164354	As shown in Supplementary Figure S1a, knockdown of EWSR1-ERG was accompanied by downregulation of BCL11B and GLG1 expression in all three cell lines tested, suggesting that these markers are also upregulated by EWSR1-ERG in EwS harboring this fusion (around 10% of cases).	('EWSR1', 'Gene', '2130', (211, 216))	('EwS', 'Phenotype', 'HP:0012254', (224, 227))	('BCL11B', 'Gene', (98, 104))	('upregulated', 'PosReg', (196, 207))	('EwS', 'Gene', (224, 227))	('EWSR1', 'Gene', '2130', (51, 56))	('expression', 'MPA', (114, 124))	('GLG1', 'Gene', (109, 113))	('EWSR1', 'Gene', (211, 216))	('GLG1', 'Gene', '2734', (109, 113))	('EwS', 'Gene', '2130', (224, 227))	('EWSR1', 'Gene', (51, 56))	('ERG', 'Gene', (217, 220))	('ERG', 'Gene', (57, 60))	('ERG', 'Gene', '2078', (217, 220))	('ERG', 'Gene', '2078', (57, 60))	('BCL11B', 'Gene', '64919', (98, 104))	('knockdown', 'Var', (38, 47))	('downregulation', 'NegReg', (80, 94))
56041	32164354	The diagnosis of EwS can be confidently established in case of high BCL11B immunoreactivity (IRS >6; i.e., moderate nuclear staining intensity in at least 80% of tumor cells, or strong nuclear staining intensity in at least 60% of tumor cells) and/or high GLG1 immunoreactivity (IRS >9; i.e., strong perinuclear staining in at least 80% of tumor cells).	('EwS', 'Gene', (17, 20))	('tumor', 'Disease', (162, 167))	('GLG1', 'Gene', (256, 260))	('immunoreactivity', 'MPA', (75, 91))	('high', 'Var', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('GLG1', 'Gene', '2734', (256, 260))	('tumor', 'Disease', (231, 236))	('EwS', 'Gene', '2130', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('BCL11B', 'Gene', '64919', (68, 74))	('tumor', 'Disease', (340, 345))	('BCL11B', 'Gene', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('EwS', 'Phenotype', 'HP:0012254', (17, 20))	('nuclear staining intensity', 'MPA', (116, 142))
56052	32164354	However, due to the large variety of existing FET-ETS fusions in EwS, many of the currently used multiplex PCR sets likely do not cover all possible FET-ETS fusions.	('EwS', 'Gene', '2130', (65, 68))	('fusions', 'Var', (54, 61))	('EwS', 'Gene', (65, 68))	('FET-ETS', 'Gene', (46, 53))	('EwS', 'Phenotype', 'HP:0012254', (65, 68))
56055	32164354	While FLI1 is unable to confirm EwS cases with FET-non-FLI1 translocations, NKX2-2 and PAX7 lack specificity and can be even strongly expressed in close morphological mimics such as EWSR1-NFATc2-positive sarcomas.	('EWSR1', 'Gene', (182, 187))	('FLI1', 'Gene', (55, 59))	('NKX2-2', 'Gene', (76, 82))	('EwS', 'Phenotype', 'HP:0012254', (32, 35))	('EwS', 'Gene', (32, 35))	('FLI1', 'Gene', (6, 10))	('FLI1', 'Gene', '2313', (55, 59))	('sarcomas', 'Disease', 'MESH:D012509', (204, 212))	('specificity', 'MPA', (97, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('sarcomas', 'Disease', (204, 212))	('NFATc2', 'Gene', (188, 194))	('FLI1', 'Gene', '2313', (6, 10))	('EwS', 'Gene', '2130', (32, 35))	('EWSR1', 'Gene', '2130', (182, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('PAX7', 'Gene', '5081', (87, 91))	('NFATc2', 'Gene', '4773', (188, 194))	('NKX2-2', 'Gene', '4821', (76, 82))	('PAX7', 'Gene', (87, 91))	('translocations', 'Var', (60, 74))	('lack', 'NegReg', (92, 96))
56062	32164354	Using IHC in a series of 47 EwS and 127 non-EwS tumors from 11 distinct entities, we found that high BCL11B and/or high GLG1 expression in CD99-positive cases may be diagnostic for EwS, while ATP1A1 did neither raise the specificity nor sensitivity of this marker combination further.	('CD99', 'Gene', '4267', (139, 143))	('EwS', 'Gene', '2130', (44, 47))	('GLG1', 'Gene', (120, 124))	('GLG1', 'Gene', '2734', (120, 124))	('EwS', 'Gene', '2130', (28, 31))	('ATP1A1', 'Gene', (192, 198))	('EwS', 'Phenotype', 'HP:0012254', (181, 184))	('ATP1A1', 'Gene', '476', (192, 198))	('EwS', 'Gene', (181, 184))	('BCL11B', 'Gene', '64919', (101, 107))	('EwS', 'Phenotype', 'HP:0012254', (44, 47))	('EwS tumors', 'Disease', 'MESH:C563168', (44, 54))	('diagnostic', 'Reg', (166, 176))	('BCL11B', 'Gene', (101, 107))	('EwS', 'Phenotype', 'HP:0012254', (28, 31))	('EwS', 'Gene', (44, 47))	('high', 'Var', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('EwS', 'Gene', (28, 31))	('high', 'Var', (96, 100))	('EwS tumors', 'Disease', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('CD99', 'Gene', (139, 143))	('EwS', 'Gene', '2130', (181, 184))
56066	32164354	Also, EwS cases with EWSR1-ERG fusions exhibited high marker immunoreactivity.	('EwS', 'Gene', '2130', (6, 9))	('high marker immunoreactivity', 'MPA', (49, 77))	('EWSR1', 'Gene', (21, 26))	('ERG', 'Gene', '2078', (27, 30))	('ERG', 'Gene', (27, 30))	('EwS', 'Gene', (6, 9))	('EWSR1', 'Gene', '2130', (21, 26))	('fusions', 'Var', (31, 38))	('EwS', 'Phenotype', 'HP:0012254', (6, 9))
56070	32164354	As tumor material is often limited, heterogeneously expressed markers can lead to misdiagnoses depending on the tumor fraction captured in a given sample.	('tumor', 'Disease', (3, 8))	('lead to', 'Reg', (74, 81))	('heterogeneously', 'Var', (36, 51))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
56100	32164354	Total RNA was extracted from these EwS cell lines 96 h after induction of EWSR1-ERG knockdown using the NucleoSpin RNA kit (Macherey-Nagel, Duren, Germany).	('EwS', 'Phenotype', 'HP:0012254', (35, 38))	('EwS', 'Gene', '2130', (35, 38))	('EwS', 'Gene', (35, 38))	('knockdown', 'Var', (84, 93))	('ERG', 'Gene', '2078', (80, 83))	('EWSR1', 'Gene', (74, 79))	('kit', 'Gene', (119, 122))	('EWSR1', 'Gene', '2130', (74, 79))	('ERG', 'Gene', (80, 83))	('kit', 'Gene', '3815', (119, 122))
56106	32164354	The following are available online at , Figure S1: EWSR-ERG knockdown leads to decrease of BCL11B and GLG1 expression in EwS cell line models and PDX EwS models exhibit high immunoreactivity for BCL11B and GLG1; Figure S2: BCL11B and GLG1 show moderate intra-tumoral staining heterogeneity in EwS.	('EwS', 'Phenotype', 'HP:0012254', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('ERG', 'Gene', '2078', (56, 59))	('BCL11B', 'Gene', (223, 229))	('EwS', 'Gene', (121, 124))	('EwS', 'Phenotype', 'HP:0012254', (150, 153))	('GLG1', 'Gene', (206, 210))	('EwS', 'Gene', (150, 153))	('EwS', 'Phenotype', 'HP:0012254', (293, 296))	('GLG1', 'Gene', '2734', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('immunoreactivity', 'MPA', (174, 190))	('GLG1', 'Gene', (102, 106))	('knockdown', 'Var', (60, 69))	('EwS', 'Gene', (293, 296))	('BCL11B', 'Gene', '64919', (195, 201))	('BCL11B', 'Gene', (195, 201))	('GLG1', 'Gene', '2734', (102, 106))	('EwS', 'Gene', '2130', (121, 124))	('EwS', 'Gene', '2130', (150, 153))	('BCL11B', 'Gene', '64919', (91, 97))	('GLG1', 'Gene', (234, 238))	('BCL11B', 'Gene', (91, 97))	('EwS', 'Gene', '2130', (293, 296))	('GLG1', 'Gene', '2734', (234, 238))	('expression', 'MPA', (107, 117))	('decrease', 'NegReg', (79, 87))	('ERG', 'Gene', (56, 59))	('tumor', 'Disease', (259, 264))	('BCL11B', 'Gene', '64919', (223, 229))
56110	32164354	UD is supported by the German Cancer Aid (DKH-108128, DKH-70112018, DKH-701134219), the Barbara und Hubertus Trettner foundation, and the Gert & Susanna Mayer foundation.	('Aid', 'Gene', (37, 40))	('Cancer', 'Disease', 'MESH:D009369', (30, 36))	('Cancer', 'Disease', (30, 36))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('DKH-108128', 'Var', (42, 52))	('DKH-701134219', 'Var', (68, 81))	('Aid', 'Gene', '57379', (37, 40))
56121	27391784	Interestingly, members of both of these complexes are frequently genetically altered in cancer and these mutations can create an imbalance in the antagonistic function between these two complexes.	('imbalance in the antagonistic function', 'MPA', (129, 167))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('imbalance', 'Phenotype', 'HP:0002172', (129, 138))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('create', 'Reg', (119, 125))
56123	27391784	The loss of SMARCB1 results in unregulated PRC2-mediated gene repression in these tumors, thus preventing the de-repression of genes involved in differentiation and other anti-tumorigenic functions.	('de-repression', 'MPA', (110, 123))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('SMARCB1', 'Gene', (12, 19))	('unregulated', 'NegReg', (31, 42))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('preventing', 'NegReg', (95, 105))	('PRC2-mediated gene repression', 'MPA', (43, 72))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('loss', 'Var', (4, 8))
56125	27391784	Additional mutations in the SWI/SNF complex are observed in a variety of tumor types, including mutations in SMARCA4, SMARCA2, ARID1A and others.	('mutations', 'Var', (11, 20))	('SWI/SNF complex', 'Gene', (28, 43))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('ARID1A', 'Gene', '8289', (127, 133))	('ARID1A', 'Gene', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('observed', 'Reg', (48, 56))	('tumor', 'Disease', (73, 78))	('SMARCA2', 'Gene', (118, 125))	('SMARCA2', 'Gene', '6595', (118, 125))	('SMARCA4', 'Gene', (109, 116))	('mutations', 'Var', (96, 105))	('SMARCA4', 'Gene', '6597', (109, 116))
56126	27391784	In synovial sarcoma a recurrent chromosomal translocation fuses the SS18 gene (a subunit of the SWI/SNF chromatin remodeling complex) on chromosome 18 to one of three related genes on the X chromosome, SSX1, SSX2 and rarely SSX4, resulting in the expression of a SS18-SSX fusion protein.	('synovial sarcoma', 'Disease', 'MESH:D013584', (3, 19))	('SSX', 'Gene', '6757', (202, 205))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (3, 19))	('SSX', 'Gene', (268, 271))	('SSX1', 'Gene', '6756', (202, 206))	('expression', 'MPA', (247, 257))	('SSX1', 'Gene', (202, 206))	('translocation fuses', 'Var', (44, 63))	('SSX', 'Gene', (202, 205))	('SSX', 'Gene', '6757', (224, 227))	('SSX', 'Gene', '6757', (208, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('fuses', 'Var', (58, 63))	('SSX4', 'Gene', (224, 228))	('SSX', 'Gene', (224, 227))	('SSX', 'Gene', (208, 211))	('SSX2', 'Gene', (208, 212))	('synovial sarcoma', 'Disease', (3, 19))	('SS18', 'Gene', (68, 72))	('SSX4', 'Gene', '6759', (224, 228))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (22, 57))	('SSX2', 'Gene', '6757', (208, 212))	('SSX', 'Gene', '6757', (268, 271))
56179	27391784	Tumor fragments (5 mm x 5 mm x 5 mm) were harvested from donor animals, each implanted from a specific passage lot (CTG-0331 and CTG-0771 at P4).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('donor', 'Species', '9606', (57, 62))	('CTG-0771', 'Var', (129, 137))	('CTG', 'Chemical', '-', (129, 132))	('CTG', 'Chemical', '-', (116, 119))	('CTG-0331', 'Var', (116, 124))
56184	27391784	For the CTG-0771 and CTG-0331 models, 3 to 5 mice per group with the largest tumors were euthanized by carbon dioxide inhalation on day 35 for blood and tissue sampling, and the 7 remaining mice were followed for an additional 25 days as animal survival study.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('CTG', 'Chemical', '-', (8, 11))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CTG', 'Chemical', '-', (21, 24))	('carbon dioxide', 'Chemical', 'MESH:D002245', (103, 117))	('mice', 'Species', '10090', (190, 194))	('CTG-0331', 'Var', (21, 29))
56209	27391784	ATF3, SOX2, EGR1, CDKN2A, and GAPDH expression were analyzed by using the TaqMan Gene Expression Assays (Life technologies) and the TaqMan probes (Hs00231069_m1, Hs01053049_s1, Hs00152928_m1, Hs00233365_m1, and Hs99999905_m1, respectively).	('CDKN2A', 'Gene', '1029', (18, 24))	('SOX2', 'Gene', '6657', (6, 10))	('Hs00152928_m1', 'Var', (177, 190))	('Hs99999905_m1', 'Var', (211, 224))	('Hs01053049_s1', 'Var', (162, 175))	('Hs00233365_m1', 'Var', (192, 205))	('ATF3', 'Gene', '467', (0, 4))	('EGR1', 'Gene', (12, 16))	('GAPDH', 'Gene', '2597', (30, 35))	('EGR1', 'Gene', '1958', (12, 16))	('Hs00231069_m1', 'Var', (147, 160))	('CDKN2A', 'Gene', (18, 24))	('ATF3', 'Gene', (0, 4))	('SOX2', 'Gene', (6, 10))	('GAPDH', 'Gene', (30, 35))
56223	27391784	Additionally, the absence of mutations in EZH2 in these two synovial sarcoma cell lines was confirmed by sequencing (S1A Fig).	('synovial sarcoma', 'Disease', (60, 76))	('mutations', 'Var', (29, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('EZH2', 'Gene', (42, 46))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (60, 76))	('synovial sarcoma', 'Disease', 'MESH:D013584', (60, 76))
56234	27391784	Alterations in SWI/SNF and PRC2 activity is thought to induce tumorigenesis through altered epigenetic regulation of gene transcription.	('PRC2', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Alterations', 'Var', (0, 11))	('epigenetic regulation of gene transcription', 'MPA', (92, 135))	('tumor', 'Disease', (62, 67))	('induce', 'Reg', (55, 61))	('altered', 'Reg', (84, 91))	('SWI/SNF', 'Gene', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
56235	27391784	Several pathways have been implicated in synovial sarcoma, including altered ATF2-mediated transcription, aberrant cell cycle inhibition and modulation of SOX2 expression.	('expression', 'MPA', (160, 170))	('synovial sarcoma', 'Disease', 'MESH:D013584', (41, 57))	('SOX2', 'Gene', '6657', (155, 159))	('SOX2', 'Gene', (155, 159))	('modulation', 'Var', (141, 151))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (41, 57))	('altered', 'Reg', (69, 76))	('synovial sarcoma', 'Disease', (41, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('ATF2', 'Gene', (77, 81))	('aberrant cell cycle', 'Phenotype', 'HP:0011018', (106, 125))	('ATF2', 'Gene', '1386', (77, 81))	('cell cycle inhibition', 'CPA', (115, 136))
56255	27391784	Both tazemetostat and EPZ011989 alone were well tolerated with minimal effect on body weight; however, some body weight loss was observed in mice receiving doxorubicin (S2A Fig).	('weight loss', 'Disease', (113, 124))	('doxorubicin', 'Chemical', 'MESH:D004317', (156, 167))	('weight loss', 'Phenotype', 'HP:0001824', (113, 124))	('tazemetostat', 'Chemical', 'MESH:C000593333', (5, 17))	('EPZ011989', 'Chemical', '-', (22, 31))	('mice', 'Species', '10090', (141, 145))	('weight loss', 'Disease', 'MESH:D015431', (113, 124))	('EPZ011989', 'Var', (22, 31))
56256	27391784	In the fast growing Fuji xenograft model, treatment with 250 mg/kg or 500 mg/kg BID tazemetostat led to a dose-dependent decrease in tumor volume, and treatment with 500 mg/kg BID EPZ011989 also inhibited tumor growth (Fig 3A).	('EPZ011989', 'Chemical', '-', (180, 189))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tazemetostat', 'Chemical', 'MESH:C000593333', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('inhibited', 'NegReg', (195, 204))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EPZ011989', 'Var', (180, 189))	('tazemetostat', 'Gene', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', (133, 138))	('decrease', 'NegReg', (121, 129))
56267	27391784	MBand analysis further found that the HS-SY-II cell line has variable numbers of t(x;18) fusions (mode number of 2) along with many other clonal and non-clonal chromosomal abnormalities involving chromosomes X and 18 (S4B Fig).	('t(x;18', 'Gene', (81, 87))	('HS-SY-II', 'CellLine', 'CVCL:8719', (38, 46))	('fusions', 'Var', (89, 96))	('chromosomal abnormalities', 'Disease', (160, 185))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (160, 185))
56292	27391784	To further examine the gene expression patterns induced by EZH2 inhibition, we performed RNA-seq analysis on the three in vivo models that were sensitive to EZH2 inhibition (CTG-0331, CTG-0771, and Fuji).	('CTG-0771', 'Var', (184, 192))	('CTG', 'Chemical', '-', (184, 187))	('CTG', 'Chemical', '-', (174, 177))	('CTG-0331', 'Var', (174, 182))
56311	27391784	Furthermore, other members of the SWI/SNF complex are frequently lost or mutated in cancers, and it will be of interest to investigate whether altered SWI/SNF activity through mutation or expression changes of a given complex subunit in general predicts sensitivity to EZH2 inhibition.	('mutated', 'Var', (73, 80))	('activity', 'MPA', (159, 167))	('sensitivity', 'MPA', (254, 265))	('predicts', 'Reg', (245, 253))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutation', 'Var', (176, 184))
56312	27391784	The mechanism(s) by which SS18-SSX translocations lead to tumorigenesis is currently being investigated by different groups, with at least two mechanisms currently suggested.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('translocations', 'Var', (35, 49))	('lead to', 'Reg', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('SSX', 'Gene', '6757', (31, 34))	('SSX', 'Gene', (31, 34))
56320	27391784	This increased binding at the SOX2 loci results in a decrease in H3K27Me3 levels at the promoter, suggesting that the aberrant SWI/SNF complex displaces PRC2/EZH2 leading to the loss of repressive chromatin marks.	('SWI/SNF', 'Gene', (127, 134))	('H3K27', 'Gene', (65, 70))	('SOX2', 'Gene', (30, 34))	('H3K27', 'Gene', '126961', (65, 70))	('decrease', 'NegReg', (53, 61))	('displaces', 'NegReg', (143, 152))	('PRC2/EZH2', 'Gene', (153, 162))	('repressive chromatin marks', 'MPA', (186, 212))	('aberrant', 'Var', (118, 126))	('increased', 'PosReg', (5, 14))	('SOX2', 'Gene', '6657', (30, 34))	('binding', 'Interaction', (15, 22))	('loss', 'NegReg', (178, 182))
56331	25614485	Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma with important therapeutic implications.	('SOX9', 'Gene', '20682', (107, 111))	('DLK1', 'Gene', (102, 106))	('aberrant', 'Var', (89, 97))	('SOX9', 'Gene', (107, 111))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (143, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('DLK1', 'Gene', '13388', (102, 106))	('undifferentiated sarcoma', 'Disease', (143, 167))
56346	25614485	Loss of p53 has been firmly implicated in the pathogenesis of undifferentiated sarcomas in human.	('p53', 'Gene', (8, 11))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (62, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('undifferentiated sarcomas', 'Disease', (62, 87))	('implicated', 'Reg', (28, 38))	('Loss', 'Var', (0, 4))	('human', 'Species', '9606', (91, 96))
56348	25614485	Surprisingly, however, p53KO MSCs did not show signs of neoplastic transformation in hypoxic growth conditions in vitro, such as the ability to form foci of transformation in the dedicated assay or sizable colonies in soft agar (Fig.	('hypoxic growth conditions', 'Disease', 'MESH:D006130', (85, 110))	('agar', 'Chemical', 'MESH:D000362', (223, 227))	('p53KO', 'Var', (23, 28))	('hypoxic growth conditions', 'Disease', (85, 110))
56349	25614485	In order to test their tumorigenic potential in vivo, we next seeded p53KO MSCs into scaffolds and transplanted them subcutaneously in syngeneic C57BL/6, or nude mice (1rst recipients).	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('nude mice', 'Species', '10090', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('p53KO', 'Var', (69, 74))	('tumor', 'Disease', (23, 28))
56358	25614485	In addition, in vitro hypoxic growth conditions, by maintaining genomic stability of primary adult p53-null MSCs and by preventing their spontaneous neoplastic transformation, might represent the cornerstone for the development of a tightly controlled genetic platform aimed at identifying specific genetic alterations that, in combination with p53 loss, could dictate adult MSCs transformation and development of undifferentiated sarcomas.	('hypoxic growth conditions', 'Disease', (22, 47))	('adult MSCs transformation', 'CPA', (369, 394))	('dictate', 'Reg', (361, 368))	('p53-null', 'Gene', (99, 107))	('alterations', 'Var', (307, 318))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (414, 439))	('sarcomas', 'Phenotype', 'HP:0100242', (431, 439))	('hypoxic growth conditions', 'Disease', 'MESH:D006130', (22, 47))	('preventing', 'NegReg', (120, 130))	('loss', 'NegReg', (349, 353))	('undifferentiated sarcomas', 'Disease', (414, 439))	('sarcoma', 'Phenotype', 'HP:0100242', (431, 438))	('spontaneous neoplastic transformation', 'CPA', (137, 174))
56359	25614485	To test this hypothesis, we decided to challenge our platform with oncogenic stresses previously implicated in sarcomagenesis, and assess their capacity to transform p53-null MSCs.	('p53-null', 'Var', (166, 174))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', (111, 118))
56360	25614485	Specifically, in p53-null MSCs maintained in hypoxic conditions we over-expressed c-myc, K-RasG12V and IDH2R172K, while we knocked-down Pten.	('K-RasG12V', 'Var', (89, 98))	('hypoxic conditions', 'Disease', (45, 63))	('Pten', 'Gene', (136, 140))	('Pten', 'Gene', '19211', (136, 140))	('c-myc', 'Protein', (82, 87))	('over-expressed', 'PosReg', (67, 81))	('hypoxic conditions', 'Disease', 'MESH:D009135', (45, 63))	('IDH2R172K', 'Var', (103, 112))
56361	25614485	The expression of c-myc and K-RasG12V, as well as the loss of Pten (but not the expression of IDH2R172K) were indeed able to trigger p53-null MSCs transformation in vitro, and represented proofs of principle for the validity of our approach (Fig.	('c-myc', 'Var', (18, 23))	('K-RasG12V', 'Var', (28, 37))	('loss', 'Var', (54, 58))	('Pten', 'Gene', (62, 66))	('Pten', 'Gene', '19211', (62, 66))	('p53-null MSCs transformation', 'CPA', (133, 161))	('trigger', 'Reg', (125, 132))
56363	25614485	Since undifferentiated sarcomas have been suggested to originate through the combined deregulation in adult MSCs of genes involved in cellular proliferation/apoptosis (such as p53), and genes implicated in the regulation of stem cell differentiation, we decided to couple two known regulators of stem cells maintenance and differentiation with the loss of p53.	('undifferentiated sarcomas', 'Disease', (6, 31))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (6, 31))	('loss', 'Var', (348, 352))	('deregulation', 'NegReg', (86, 98))	('originate', 'Reg', (55, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('p53', 'Gene', (356, 359))
56365	25614485	While Pml knockdown in p53-null MSCs did not trigger neoplastic transformation, adult p53-null MSCs knocked down for Lrf, showed features of neoplastic transformation in vitro (Fig.	('neoplastic transformation', 'CPA', (141, 166))	('knocked down', 'Var', (100, 112))	('Pml', 'Gene', (6, 9))	('Pml', 'Gene', '18854', (6, 9))
56385	25614485	For this reason, we first investigated the possibility that Lrf could trigger sarcomagenesis by blocking the differentiation capacity of MSCs.	('blocking', 'NegReg', (96, 104))	('differentiation capacity of MSCs', 'CPA', (109, 141))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('trigger', 'Reg', (70, 77))	('sarcoma', 'Disease', (78, 85))	('Lrf', 'Var', (60, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))
56390	25614485	3A), and accordingly, the expression of Ppargamma and Fabp4 during differentiation was significantly lower in CRE-cells compared to CTR-cells (Fig.	('expression', 'MPA', (26, 36))	('Ppargamma', 'Gene', (40, 49))	('CTR', 'Gene', (132, 135))	('Fabp4', 'Gene', '11770', (54, 59))	('CRE-cells', 'Var', (110, 119))	('lower', 'NegReg', (101, 106))	('Fabp4', 'Gene', (54, 59))	('CTR', 'Gene', '12311', (132, 135))	('Ppargamma', 'Gene', '19016', (40, 49))
56405	25614485	Similarly, the knock-down of LRF in hMSCs resulted in the up-regulation of SOX9-activity (Figure 4B).	('SOX9', 'Gene', (75, 79))	('up-regulation', 'PosReg', (58, 71))	('LRF', 'Gene', (29, 32))	('SOX9', 'Gene', '20682', (75, 79))	('knock-down', 'Var', (15, 25))
56406	25614485	Next, in order to address the critical question of whether Lrf mediates MSC commitment through Sox9, CRE-cells were knocked down for Sox9 (Supplementary Fig.	('Sox9', 'Gene', (133, 137))	('Sox9', 'Gene', (95, 99))	('knocked down', 'Var', (116, 128))	('Sox9', 'Gene', '20682', (133, 137))	('Sox9', 'Gene', '20682', (95, 99))
56412	25614485	Similarly, knock-down of LRF resulted in the up-regulation of DLK1 in hMSCs (Figure 4F).	('DLK1', 'Gene', '13388', (62, 66))	('up-regulation', 'PosReg', (45, 58))	('knock-down', 'Var', (11, 21))	('DLK1', 'Gene', (62, 66))	('LRF', 'Gene', (25, 28))
56418	25614485	In order to functionally validate the Lrf/Dlk1 axis in MSC commitment, we knocked down Dlk1 in CRE-cells, and induced the generated cells to differentiate toward adipocytes and osteoblasts.	('Dlk1', 'Gene', '13386', (42, 46))	('Dlk1', 'Gene', (42, 46))	('differentiate', 'CPA', (141, 154))	('osteoblasts', 'CPA', (177, 188))	('knocked', 'Var', (74, 81))	('induced', 'Reg', (110, 117))	('Dlk1', 'Gene', (87, 91))	('Dlk1', 'Gene', '13386', (87, 91))
56419	25614485	As expected, CRE-shSCR-cells failed to differentiate compared to CTR-shSCR-cells; but, critically, the concomitant inactivation of Dlk1 (CRE-shDlk1-cells) rescued their defects of adipogenesis (Fig.	('Dlk1', 'Gene', (131, 135))	('CTR', 'Gene', (65, 68))	('Dlk1', 'Gene', '13386', (131, 135))	('adipogenesis', 'MPA', (180, 192))	('Dlk1', 'Gene', (143, 147))	('CTR', 'Gene', '12311', (65, 68))	('inactivation', 'Var', (115, 127))	('Dlk1', 'Gene', '13386', (143, 147))
56446	25614485	Thus, the use of neutralizing antibodies against DLK1, alone or in combination with inhibitors of SOX9 down-stream factors may offer a window of opportunity for the development of novel therapeutic strategies for this lethal form of cancer.	('SOX9', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('DLK1', 'Gene', (49, 53))	('neutralizing', 'Var', (17, 29))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('SOX9', 'Gene', '20682', (98, 102))	('DLK1', 'Gene', '13388', (49, 53))
56468	25614485	The following antibodies were used: anti-CD45 FITC, anti-CD31 FITC, anti-Ter119 FITC, anti-Sca1 Pacific Blue, anti-PDGFRalpha PE (all purchased from Biolegend); Annexin-V PE (BD, pharmingen).	('Sca1', 'Gene', (91, 95))	('FITC', 'Chemical', 'MESH:D016650', (62, 66))	('FITC', 'Chemical', 'MESH:D016650', (46, 50))	('anti-Ter119', 'Var', (68, 79))	('CD31', 'Gene', (57, 61))	('FITC', 'Chemical', 'MESH:D016650', (80, 84))	('CD31', 'Gene', '18613', (57, 61))	('Sca1', 'Gene', '110454', (91, 95))	('CD45', 'Gene', '19264', (41, 45))	('anti-PDGFRalpha', 'Var', (110, 125))	('CD45', 'Gene', (41, 45))
56504	25614485	The mutated version of this plasmid was generated by utilizing the Dlk1 3'UTR as template and modifying the putative Lrf binding sites using the QuikChange II XL Site-Directed Mutagenesis Kit.	('Lrf', 'Protein', (117, 120))	('binding sites', 'Interaction', (121, 134))	('Dlk1', 'Gene', (67, 71))	('Dlk1', 'Gene', '13386', (67, 71))	('modifying', 'Var', (94, 103))
56530	22437667	After initial surgery, microscopic residual disease in the tumor bed will cause a local recurrence in approximately 33% of patients with sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('local recurrence', 'CPA', (82, 98))	('tumor', 'Disease', (59, 64))	('microscopic', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('patients', 'Species', '9606', (123, 131))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('sarcoma', 'Disease', (137, 144))	('cause', 'Reg', (74, 79))
56553	22437667	To test this hypothesis, we used genetically engineered mice with conditional mutations in B-raf and p53 that develop primary sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('B-raf', 'Gene', (91, 96))	('sarcomas', 'Disease', (126, 134))	('develop', 'PosReg', (110, 117))	('mutations', 'Var', (78, 87))	('p53', 'Gene', (101, 104))	('mice', 'Species', '10090', (56, 60))	('B-raf', 'Gene', '109880', (91, 96))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))	('p53', 'Gene', '22060', (101, 104))
56560	22437667	The mouse genotypes that were used to generate sarcomas included LSL-KrasG12D/+; p53Flox/Flox, LSL-YFP;LSL-KrasG12D/+;p53Flox/Flox10, BrafCa/+; p53Flox/Flox, and BrafCa/Ca;p53Flox/Flox.	('mouse', 'Species', '10090', (4, 9))	('sarcomas', 'Disease', (47, 55))	('p53', 'Gene', '22060', (81, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('p53', 'Gene', (118, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('p53', 'Gene', '22060', (172, 175))	('p53', 'Gene', '22060', (144, 147))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '22060', (118, 121))	('LSL-KrasG12D/+', 'Var', (103, 117))	('p53', 'Gene', (144, 147))	('p53', 'Gene', (172, 175))
56566	22437667	Mice with primary soft tissue sarcomas were injected with 2 nmol of Prosense 680, Prosense 750, MMPSense 680, Noncleavable Prosense 680 Control, Cat K 680 FAST, or VM249 (all from Perkin Elmer, Waltham, Mass) through the tail vein.	('MMPSense 680', 'Var', (96, 108))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (18, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('primary soft tissue sarcomas', 'Disease', (10, 38))	('VM249', 'Var', (164, 169))	('primary soft tissue sarcomas', 'Disease', 'MESH:D012509', (10, 38))	('Cat K', 'Gene', '13038', (145, 150))	('Mice', 'Species', '10090', (0, 4))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (18, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('Cat K', 'Gene', (145, 150))
56567	22437667	Twenty-four hours after injection for Noncleavable Prosense 680 Control, Prosense 680, Prosense 750, and MMPsense 680 or 6 hours after Cat K 680 FAST and VM249, multiple sections of the tumor were removed surgically and imaged with the device.	('Cat K', 'Gene', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('MMPsense 680', 'Var', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('Cat K', 'Gene', '13038', (135, 140))
56573	22437667	Before surgery, mice with primary soft tissue sarcomas >=200 mm3 were injected with 2 nmol of Cat K 680 FAST or VM249.	('Cat K', 'Gene', (94, 99))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (34, 54))	('primary soft tissue sarcomas', 'Disease', 'MESH:D012509', (26, 54))	('VM249', 'Var', (112, 117))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (34, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('Cat K', 'Gene', '13038', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('mice', 'Species', '10090', (16, 20))	('primary soft tissue sarcomas', 'Disease', (26, 54))
56581	22437667	LSL-YFP;LSL-Kras;p53Flox/Flox mice with yellow fluorescent protein (YFP)-expressing sarcomas were injected with 2 nmol Prosense 680, Cat K 680 FAST, or VM249.	('Cat K', 'Gene', '13038', (133, 138))	('mice', 'Species', '10090', (30, 34))	('Cat K', 'Gene', (133, 138))	('p53', 'Gene', '22060', (17, 20))	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('p53', 'Gene', (17, 20))	('sarcomas', 'Disease', (84, 92))	('VM249', 'Var', (152, 157))
56594	22437667	The average tumor-to-muscle fluorescence signal ratio (+-standard deviation) for Prosense 680, Prosense 750, and MMPSense 680 was approximately 12 +- 2.4, 5 +- 1.0, and 8 +- 3.5, respectively (Fig.	('tumor', 'Disease', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('MMPSense 680', 'Var', (113, 125))
56597	22437667	Significant Prosense 680 activation was apparent only in the tumor from the mouse that was injected with Prosense 680 and not in normal muscle from the same animal or in tissues from the animal that was injected with the noncleavable Prosense 680 (Fig.	('Prosense 680', 'Gene', (12, 24))	('Prosense 680', 'Var', (105, 117))	('mouse', 'Species', '10090', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('activation', 'PosReg', (25, 35))	('tumor', 'Disease', (61, 66))
56621	22437667	The presence of residual fluorescence above this threshold was correlated with YFP-positive cells present in the tumor bed for both Cat K 680 FAST and VM249 (Fig.	('tumor', 'Disease', (113, 118))	('Cat K', 'Gene', (132, 137))	('fluorescence', 'MPA', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('VM249', 'Var', (151, 156))	('Cat K', 'Gene', '13038', (132, 137))
56627	22437667	Mice were injected with Cat K 680 FAST (n = 13) or VM249 (n = 12) 6 hours before surgery.	('Cat K', 'Gene', '13038', (24, 29))	('VM249', 'Var', (51, 56))	('Cat K', 'Gene', (24, 29))	('Mice', 'Species', '10090', (0, 4))
56631	22437667	In mice that were injected with either Cat K 680 FAST or VM249 and underwent multiple resections, the removal of all residual fluorescence significantly improved local control (Fig.	('removal', 'Var', (102, 109))	('Cat K', 'Gene', (39, 44))	('local', 'MPA', (162, 167))	('VM249', 'Var', (57, 62))	('mice', 'Species', '10090', (3, 7))	('improved', 'PosReg', (153, 161))	('Cat K', 'Gene', '13038', (39, 44))
56646	22437667	Like limb-sparing resections, amputations for these tumors can result in wide, marginal, or intralesional margins based on the amputation level in relation to the proximal aspect of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (52, 57))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('amputations', 'Var', (30, 41))
56685	22928122	Flow cytometry results showed CD34 98%, HLA-DR 98%, CD13 96%, CD33 99%, CD11 97% with negativity for CD10 and CD22 in 71% cells gated, thus confirming acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (151, 173))	('CD33', 'Gene', '945', (62, 66))	('CD33', 'Gene', (62, 66))	('CD10', 'Gene', '4311', (101, 105))	('leukemia', 'Phenotype', 'HP:0001909', (165, 173))	('CD10', 'Gene', (101, 105))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (157, 173))	('CD34', 'Gene', (30, 34))	('CD34', 'Gene', '947', (30, 34))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (151, 173))	('CD22', 'Gene', (110, 114))	('CD13', 'Gene', '290', (52, 56))	('CD22', 'Gene', '933', (110, 114))	('acute myeloid leukemia', 'Disease', (151, 173))	('CD11 97%', 'Var', (72, 80))	('CD13', 'Gene', (52, 56))
56706	21559405	ERG and ETV1 are the most common ETS members observed in these genetic alterations.	('ERG', 'Gene', '2078', (0, 3))	('ERG', 'Gene', (0, 3))	('genetic', 'Var', (63, 70))	('ETV1', 'Gene', (8, 12))	('ETV1', 'Gene', '2115', (8, 12))
56707	21559405	The high prevalence of these rearrangements and their biological significance represents a novel therapeutic target for the treatment of prostate cancer.	('men', 'Species', '9606', (38, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	('men', 'Species', '9606', (129, 132))	('prostate cancer', 'Disease', (137, 152))	('rearrangements', 'Var', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))
56712	21559405	YK-4-279 reduced the motility of LNCaP cells in a scratch assay and the invasive phenotype of both LNCaP and VCaP cells in a HUVEC invasion assay.	('invasive phenotype', 'CPA', (72, 90))	('LNCaP', 'CellLine', 'CVCL:0395', (33, 38))	('VCa', 'CellLine', 'CVCL:2235', (109, 112))	('HUVEC', 'CellLine', 'CVCL:2959', (125, 130))	('LNCaP', 'CellLine', 'CVCL:0395', (99, 104))	('YK-4-279', 'Var', (0, 8))	('reduced', 'NegReg', (9, 16))	('motility', 'CPA', (21, 29))
56714	21559405	SiRNA mediated ERG knockdown in VCaP cells resulted in a loss of drug responsiveness.	('VCa', 'CellLine', 'CVCL:2235', (32, 35))	('loss of drug responsiveness', 'Phenotype', 'HP:0020174', (57, 84))	('knockdown', 'Var', (19, 28))	('ERG', 'Gene', '2078', (15, 18))	('ERG', 'Gene', (15, 18))	('loss', 'NegReg', (57, 61))	('drug responsiveness', 'MPA', (65, 84))
56717	21559405	Therefore, YK-4-279 may have an impact on metastasis in prostate cancer and it may be further evaluated for its clinical applications in prostate cancer in addition to Ewing's sarcoma.	('impact', 'Reg', (32, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	("Ewing's sarcoma", 'Disease', (168, 183))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (168, 183))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('prostate cancer', 'Disease', (137, 152))	('YK-4-279', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (168, 183))	('metastasis', 'CPA', (42, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))	('prostate cancer', 'Disease', (56, 71))
56719	21559405	Chromosomal translocations involving the ETS family of transcription factors are present in 40-70% of prostate cancers, including the most clinically aggressive forms.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('prostate cancers', 'Phenotype', 'HP:0012125', (102, 118))	('Chromosomal translocations', 'Var', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('prostate cancers', 'Disease', (102, 118))	('ETS family of transcription factors', 'Gene', (41, 76))	('prostate cancers', 'Disease', 'MESH:D011471', (102, 118))	('present', 'Reg', (81, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))
56720	21559405	These translocations produce chimeric genes, which fuse the promoter region of an androgen responsive gene, such as TMPRSS2, to the coding region of ETS factors, most frequently ETV1 or ERG .	('ETV1', 'Gene', (178, 182))	('TMPRSS2', 'Gene', (116, 123))	('ETV1', 'Gene', '2115', (178, 182))	('ERG', 'Gene', '2078', (186, 189))	('TMPRSS2', 'Gene', '7113', (116, 123))	('ERG', 'Gene', (186, 189))	('translocations', 'Var', (6, 20))
56722	21559405	Over-expression of ETS factors in prostate cancer cells increase cell invasion and induces prostatic intraepithelial neoplasia (PIN) in transgenic mouse models.	('mouse', 'Species', '10090', (147, 152))	('increase', 'PosReg', (56, 64))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (91, 126))	('cell invasion', 'CPA', (65, 78))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (101, 126))	('neoplasia', 'Phenotype', 'HP:0002664', (117, 126))	('prostate cancer', 'Disease', (34, 49))	('induces', 'Reg', (83, 90))	('ETS factors', 'Gene', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Over-expression', 'Var', (0, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (34, 49))	('prostatic intraepithelial neoplasia', 'Disease', (91, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))
56723	21559405	ERG and ETV1 depletion also result in reduced tumor growth in vivo .	('ERG', 'Gene', '2078', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ERG', 'Gene', (0, 3))	('reduced', 'NegReg', (38, 45))	('tumor', 'Disease', (46, 51))	('depletion', 'Var', (13, 22))	('ETV1', 'Gene', (8, 12))	('ETV1', 'Gene', '2115', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
56730	21559405	Our results indicate that YK-4-279 can inhibit ERG and ETV1 dependent transcriptional activity and consequently leads to reduced cell motility and invasion.	('cell motility', 'CPA', (129, 142))	('inhibit', 'NegReg', (39, 46))	('YK-4-279', 'Var', (26, 34))	('reduced', 'NegReg', (121, 128))	('invasion', 'CPA', (147, 155))	('ETV1', 'Gene', (55, 59))	('transcriptional activity', 'MPA', (70, 94))	('ETV1', 'Gene', '2115', (55, 59))	('ERG', 'Gene', '2078', (47, 50))	('ERG', 'Gene', (47, 50))
56734	21559405	The VCaP cell-line harbors a TMPRSS2-ERG rearrangement, which occurs via interstitial deletion of the 3 Mb region between TMPRSS2 and ERG on chromosome 21 (Fig.	('TMPRSS2', 'Gene', (29, 36))	('ERG', 'Gene', (134, 137))	('TMPRSS2', 'Gene', (122, 129))	('TMPRSS2', 'Gene', '7113', (29, 36))	('men', 'Species', '9606', (50, 53))	('VCa', 'CellLine', 'CVCL:2235', (4, 7))	('ERG', 'Gene', '2078', (37, 40))	('TMPRSS2', 'Gene', '7113', (122, 129))	('ERG', 'Gene', (37, 40))	('ERG', 'Gene', '2078', (134, 137))	('deletion', 'Var', (86, 94))
56751	21559405	Promoter activity was reduced by simultaneous treatment of the cells with YK-4-279, without any appreciable decrease in ERG protein levels (Fig.	('ERG', 'Gene', (120, 123))	('men', 'Species', '9606', (51, 54))	('Promoter activity', 'MPA', (0, 17))	('decrease in ERG', 'Phenotype', 'HP:0000654', (108, 123))	('reduced', 'NegReg', (22, 29))	('ERG', 'Gene', '2078', (120, 123))	('YK-4-279', 'Var', (74, 82))
56755	21559405	Exposure of VCaP cells to 10 microM YK-4-279 for 48 hours resulted in significantly reduced mRNA and protein levels of several ERG target genes, such as PLAU, PLAT and ADAM29.	('ERG', 'Gene', '2078', (127, 130))	('ADAM29', 'Gene', (168, 174))	('VCa', 'CellLine', 'CVCL:2235', (12, 15))	('ERG', 'Gene', (127, 130))	('ADAM29', 'Gene', '11086', (168, 174))	('PLAT', 'Gene', '5327', (159, 163))	('reduced', 'NegReg', (84, 91))	('PLAT', 'Gene', (159, 163))	('PLAU', 'Gene', (153, 157))	('PLAU', 'Gene', '5328', (153, 157))	('YK-4-279', 'Var', (36, 44))
56756	21559405	The level of down-regulation was comparable to that obtained by siRNA mediated ERG knock-down in VCaP cells (Fig.	('ERG', 'Gene', '2078', (79, 82))	('ERG', 'Gene', (79, 82))	('down-regulation', 'NegReg', (13, 28))	('knock-down', 'Var', (83, 93))	('VCa', 'CellLine', 'CVCL:2235', (97, 100))
56757	21559405	Similarly, YK-4-279 resulted in down-regulation of ETV1 target gene MMP-13 in LNCaP cells (Fig.	('MMP-13', 'Gene', (68, 74))	('down-regulation', 'NegReg', (32, 47))	('LNCaP', 'CellLine', 'CVCL:0395', (78, 83))	('ETV1', 'Gene', (51, 55))	('ETV1', 'Gene', '2115', (51, 55))	('YK-4-279', 'Var', (11, 19))	('MMP-13', 'Gene', '4322', (68, 74))
56759	21559405	These results suggest that YK-4-279 is able to inhibit ERG and ETV1 transcriptional activity in prostate cancer cells, leading to decreased expression of genes that are involved in breakdown of extracellular matrix and metastasis.	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('ERG', 'Gene', '2078', (55, 58))	('ERG', 'Gene', (55, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('YK-4-279', 'Var', (27, 35))	('ETV1', 'Gene', (63, 67))	('inhibit', 'NegReg', (47, 54))	('ETV1', 'Gene', '2115', (63, 67))	('prostate cancer', 'Disease', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('expression of genes', 'MPA', (140, 159))	('decreased', 'NegReg', (130, 139))	('transcriptional activity', 'MPA', (68, 92))
56760	21559405	Previous studies have suggested that ETS gene rearrangements mediate invasion in prostate cancer.	('men', 'Species', '9606', (55, 58))	('prostate cancer', 'Disease', (81, 96))	('mediate', 'Reg', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('invasion', 'CPA', (69, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('ETS gene', 'Gene', (37, 45))	('rearrangements', 'Var', (46, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))
56761	21559405	To address the question whether YK-4-279 is able to inhibit ERG and ETV1 mediated invasion, we utilized an impedance based endothelial cell invasion assay.	('ETV1', 'Gene', (68, 72))	('inhibit', 'NegReg', (52, 59))	('ETV1', 'Gene', '2115', (68, 72))	('ERG', 'Gene', '2078', (60, 63))	('ERG', 'Gene', (60, 63))	('YK-4-279', 'Var', (32, 40))
56767	21559405	Treating these cells with YK-4-279 resulted in significantly decreased invasion of HUVEC cells by LNCaP and VCaP cells.	('invasion of HUVEC cells', 'CPA', (71, 94))	('HUVEC', 'CellLine', 'CVCL:2959', (83, 88))	('LNCaP', 'CellLine', 'CVCL:0395', (98, 103))	('YK-4-279', 'Var', (26, 34))	('VCa', 'CellLine', 'CVCL:2235', (108, 111))	('decreased', 'NegReg', (61, 70))
56773	21559405	Treatment with YK-4-279 significantly inhibited the ERG mediated increase in invasion (Fig.	('increase', 'PosReg', (65, 73))	('invasion', 'CPA', (77, 85))	('ERG', 'Gene', '2078', (52, 55))	('inhibited', 'NegReg', (38, 47))	('ERG', 'Gene', (52, 55))	('men', 'Species', '9606', (5, 8))	('YK-4-279', 'Var', (15, 23))
56774	21559405	Together, these results suggest that YK-4-279 is able to inhibit ETS-mediated invasion of prostate cancer cells, both in cells with endogenous and exogenous high expression of ETS proteins.	('YK-4-279', 'Var', (37, 45))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('ETS-mediated invasion of', 'CPA', (65, 89))	('inhibit', 'NegReg', (57, 64))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
56785	21559405	S3) These findings suggest that the effects of YK-4-279 on LNCaP cells in scratch assay is not due to cytotoxicity, but solely due to inhibition of cell motility.	('YK-4-279', 'Var', (47, 55))	('cytotoxicity', 'Disease', (102, 114))	('LNCaP', 'CellLine', 'CVCL:0395', (59, 64))	('inhibition', 'NegReg', (134, 144))	('cell motility', 'CPA', (148, 161))	('cytotoxicity', 'Disease', 'MESH:D064420', (102, 114))	('LNCaP cells in scratch assay', 'CPA', (59, 87))
56792	21559405	Furthermore, chromatin immunoprecipitation was performed to evaluate ERG binding to PLAU promoter in the presence of YK-4-279.	('PLAU', 'Gene', '5328', (84, 88))	('ERG', 'Gene', '2078', (69, 72))	('ERG', 'Gene', (69, 72))	('binding', 'Interaction', (73, 80))	('YK-4-279', 'Var', (117, 125))	('PLAU', 'Gene', (84, 88))
56793	21559405	Results confirmed Biacore findings that YK-4-279 does not interfere with ERG DNA binding (Fig S5b).	('ERG', 'Gene', '2078', (73, 76))	('YK-4-279', 'Var', (40, 48))	('ERG', 'Gene', (73, 76))
56794	21559405	ETS translocations in prostate cancer, on the other hand, result in the expression of an almost full-length ETS family member.	('translocations', 'Var', (4, 18))	('prostate cancer', 'Disease', (22, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('expression', 'MPA', (72, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (22, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('ETS', 'Gene', (0, 3))	('result in', 'Reg', (58, 67))
56795	21559405	Therefore, we hypothesize that YK-4-279 may inhibit ETV1 and ERG function in prostate cancer cells by preventing protein-protein interactions that are different than EWS-FLI1 partners in Ewing's Sarcoma.	("Ewing's Sarcoma", 'Disease', (187, 202))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (187, 202))	('inhibit', 'NegReg', (44, 51))	('prostate cancer', 'Disease', (77, 92))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (187, 202))	('Sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ETV1', 'Gene', (52, 56))	('YK-4-279', 'Var', (31, 39))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('preventing', 'NegReg', (102, 112))	('ETV1', 'Gene', '2115', (52, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('ERG', 'Gene', '2078', (61, 64))	('protein-protein', 'Protein', (113, 128))	('ERG', 'Gene', (61, 64))
56796	21559405	Hence, further investigation is required to determine the exact molecular mechanism of YK-4-279 mediated inhibition of ERG and ETV1 function in prostate cancer cells.	('prostate cancer', 'Phenotype', 'HP:0012125', (144, 159))	('ETV1', 'Gene', (127, 131))	('prostate cancer', 'Disease', (144, 159))	('inhibition', 'NegReg', (105, 115))	('ETV1', 'Gene', '2115', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('YK-4-279', 'Var', (87, 95))	('ERG', 'Gene', '2078', (119, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (144, 159))	('ERG', 'Gene', (119, 122))
56801	21559405	Recent reports have suggested that ETS knock-down in prostate cancer cells may result in decreased proliferation in cells expressing these oncoproteins.	('prostate cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('knock-down', 'Var', (39, 49))	('ETS', 'Gene', (35, 38))	('proliferation', 'CPA', (99, 112))	('decreased', 'NegReg', (89, 98))
56802	21559405	Although the experiments in this manuscript were performed at doses and time intervals that were not toxic to the cells, there does appear to be a direct correlation between the expression of ETS proteins and YK-4-279 cytotoxicity.	('cytotoxicity', 'Disease', (218, 230))	('YK-4-279', 'Var', (209, 217))	('cytotoxicity', 'Disease', 'MESH:D064420', (218, 230))	('men', 'Species', '9606', (19, 22))	('ETS proteins', 'Protein', (192, 204))
56809	21559405	Thus, the successful development of small molecule inhibitors of ERG and ETV1, such as YK-4-279, will represent a novel line of therapeutics aimed at preventing or treating metastatic disease, while saving patients the long-term effects of therapies targeting the androgen pathway.	('ERG', 'Gene', '2078', (65, 68))	('metastatic disease', 'Disease', (173, 191))	('men', 'Species', '9606', (28, 31))	('ERG', 'Gene', (65, 68))	('ETV1', 'Gene', (73, 77))	('small molecule inhibitors', 'Var', (36, 61))	('androgen pathway', 'Pathway', (264, 280))	('patients', 'Species', '9606', (206, 214))	('ETV1', 'Gene', '2115', (73, 77))	('inhibitors', 'Var', (51, 61))
56825	21559405	Cos-7 cells were co-transfected with a lentiviral plasmid expressing the most-commonly found truncated ERG mRNA, and a vector containing Id2 gene promoter driving expression of a luciferase gene.	('ERG', 'Gene', '2078', (103, 106))	('truncated', 'Var', (93, 102))	('Id2', 'Gene', (137, 140))	('ERG', 'Gene', (103, 106))	('Cos-7', 'CellLine', 'CVCL:0224', (0, 5))	('Id2', 'Gene', '3398', (137, 140))
56845	21045144	Unexpectedly, dendritic cells (DC) in the progressive tumor microenvironment (TME) acquire OX40 expression and bind fluorescently-labeled OX40L-Fc.	('acquire', 'PosReg', (83, 90))	('OX40 expression', 'MPA', (91, 106))	('bind', 'Interaction', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('OX40L-Fc', 'Var', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
56849	21045144	Notably, these vascular alterations were maintained in Rag-/- mice, indicating that the OX40L-Fc-mediated activation of both DC and VEC occur in a T cell-independent manner.	('OX40L-Fc-mediated', 'Var', (88, 105))	('vascular alterations', 'Phenotype', 'HP:0002597', (15, 35))	('VEC', 'Gene', (132, 135))	('mice', 'Species', '10090', (62, 66))	('VEC', 'Gene', '12562', (132, 135))	('activation', 'PosReg', (106, 116))	('rat', 'Species', '10116', (28, 31))
56860	21045144	Indeed, recent studies have demonstrated that agonist signaling through OX40 inhibits the suppressor function of natural Foxp3+ Treg, prevents the induction of Treg from CD4+ T effector cells, and confers resistance to effector cells against Treg-mediated inhibition.	('suppressor function', 'CPA', (90, 109))	('confers', 'Reg', (197, 204))	('prevents', 'NegReg', (134, 142))	('OX40', 'Var', (72, 76))	('rat', 'Species', '10116', (35, 38))	('resistance', 'CPA', (205, 215))	('inhibits', 'NegReg', (77, 85))
56862	21045144	We observed that the progressive growth of well-established day 17 sarcomas was inhibited by a short course of OX40L-Fc therapy, with complete tumor regression or extended disease stabilization (i.e.	('tumor', 'Disease', (143, 148))	('progressive growth', 'CPA', (21, 39))	('OX40L-Fc', 'Var', (111, 119))	('disease stabilization', 'CPA', (172, 193))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('sarcomas', 'Disease', (67, 75))	('inhibited', 'NegReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
56867	21045144	Six to ten week old female C57BL/6 (H-2b), B6.129S7-Rag1tm1Mom (Rag-/-; H-2b) and BALB/cJ (H-2d) mice were purchased from The Jackson Laboratory and maintained in the pathogen-free animal facility in the Biomedical Sciences Tower at the University of Pittsburgh.	('rat', 'Species', '10116', (138, 141))	('B6.129S7', 'CellLine', 'CVCL:C319', (43, 51))	('H-2d', 'Gene', '83772', (91, 95))	('mice', 'Species', '10090', (97, 101))	('B6.129S7-Rag1tm1Mom', 'Var', (43, 62))	('H-2d', 'Gene', (91, 95))
56899	21045144	In contrast, OX40L-Fc-treated mice exhibited reduced, stabilized tumor size by day 27 that was durable through day 40.	('mice', 'Species', '10090', (30, 34))	('reduced', 'NegReg', (45, 52))	('tumor', 'Disease', (65, 70))	('OX40L-Fc-treated', 'Var', (13, 29))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
56901	21045144	Similar therapeutic benefits were observed in the CMS4 (H-2d) sarcoma model, where over 80% of animals rejected their tumors after OX40L-Fc treatment on days 17 and 20 (Fig.	('H-2d', 'Gene', '83772', (56, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('H-2d', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('OX40L-Fc', 'Var', (131, 139))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('tumors', 'Disease', (118, 124))	('sarcoma', 'Disease', (62, 69))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
56902	21045144	Despite the superior efficacy observed for OX40L-Fc in the CMS4 model, all remaining data were collected in the MCA205 tumor model due to the tendency of progressor CMS4 tumors to ulcerate, necessitating pre-mature euthanasia per IACUC regulations.	('OX40L-Fc', 'Var', (43, 51))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('rat', 'Species', '10116', (184, 187))	('tumor', 'Disease', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (170, 176))	('CMS4', 'Gene', (165, 169))
56904	21045144	While OX40 was barely detectable on CD4+Foxp3- and CD8+ T cells in the TDLN, approximately 50% of CD4+Foxp3+ T cells expressed OX40 (Fig.	('CD8', 'Gene', (51, 54))	('OX40', 'Var', (127, 131))	('CD4+Foxp3+', 'Var', (98, 108))	('CD8', 'Gene', '925', (51, 54))
56907	21045144	Furthermore, FITC-labeled OX40L-Fc was found to bind to TIDC, but not to TDLN-localized DC (Fig.	('FITC', 'Chemical', 'MESH:D016650', (13, 17))	('bind', 'Interaction', (48, 52))	('OX40L-Fc', 'Var', (26, 34))
56908	21045144	These data suggest that although CD4+Foxp3+ T cells may represent the exclusive expressors of OX40 in the periphery, CD4+Foxp3- and CD8+ T effector cells, as well as DC, contain substantial OX40+ populations in the TME, making each of these cell types plausible targets of OX40L-Fc-based therapy.	('CD8', 'Gene', (132, 135))	('CD4+Foxp3-', 'Var', (117, 127))	('CD8', 'Gene', '925', (132, 135))
56909	21045144	Given the observed high levels of OX40 expressed by TIDC in untreated tumor-bearing mice, we next evaluated how DC populations were altered in response to OX40L-Fc treatment.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('OX40L-Fc', 'Var', (155, 163))	('TIDC', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mice', 'Species', '10090', (84, 88))
56910	21045144	By day 3 after the first OX40L-Fc treatment, TIDC expression of the costimulatory molecules CD80 and CD86 was augmented (data not shown), and a concordant increase in CD11c+CD11b+ DC within the TDLN was observed when compared to isotype mAb-treated control mice (Fig.	('CD80', 'Gene', (92, 96))	('increase', 'PosReg', (155, 163))	('OX40L-Fc', 'Var', (25, 33))	('mice', 'Species', '10090', (257, 261))	('CD11c', 'Gene', '16411', (167, 172))	('CD11c', 'Gene', (167, 172))	('CD80', 'Gene', '12519', (92, 96))	('augmented', 'PosReg', (110, 119))	('CD11b', 'Gene', (173, 178))	('CD11b', 'Gene', '16409', (173, 178))	('CD86', 'Gene', (101, 105))	('CD86', 'Gene', '12524', (101, 105))	('expression', 'MPA', (50, 60))
56912	21045144	Moreover, enrichment of DC upon OX40L-Fc treatment was similarly observed in the TDLN of Rag-/- mice bearing established MCA205 tumors (Fig.	('mice', 'Species', '10090', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('MCA205 tumors', 'Disease', 'MESH:D009369', (121, 134))	('MCA205 tumors', 'Disease', (121, 134))	('OX40L-Fc', 'Var', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
56913	21045144	These data are consistent with the T cell-independent activation/maturation of OX40+ TIDC to become competent for trafficking to the TDLN within the initial 3 days of OX40L-Fc-based therapy.	('OX40+', 'Var', (79, 84))	('trafficking', 'MPA', (114, 125))	('rat', 'Species', '10116', (69, 72))
56918	21045144	Indeed, 7 days after initiating OX40L-Fc treatment, highly significant up-regulation in expression of the proliferation marker Ki67 was observed for both CD4+ and CD8+ T cell subsets within the TDLN (P < 0.01; Fig.	('rat', 'Species', '10116', (113, 116))	('Ki67', 'Gene', (127, 131))	('Ki67', 'Gene', '17345', (127, 131))	('up-regulation', 'PosReg', (71, 84))	('OX40L-Fc', 'Var', (32, 40))	('CD8', 'Gene', (163, 166))	('expression', 'MPA', (88, 98))	('CD8', 'Gene', '925', (163, 166))
56922	21045144	S3B, we found that the CXCR3+ sub-population of CD4+ and CD8+ T cells was increased after OX40L-Fc versus control mAb treatment.	('S3B', 'Gene', '11778', (0, 3))	('CD8', 'Gene', (57, 60))	('CXCR3', 'Gene', '12766', (23, 28))	('CD8', 'Gene', '925', (57, 60))	('increased', 'PosReg', (74, 83))	('S3B', 'Gene', (0, 3))	('OX40L-Fc', 'Var', (90, 98))	('CXCR3', 'Gene', (23, 28))
56925	21045144	Although increased frequencies of CD4+Foxp3- and CD8+ T effector cells were detected in the TME throughout the observation period, a highly significant increase versus control mAb-treated animals was noted for CD4+Foxp3- TIL at days 7 and 10 post-treatment and CD8+ TIL at day 10 post-treatment (P < 0.01; Fig.	('increase', 'PosReg', (152, 160))	('CD8', 'Gene', (261, 264))	('CD4+Foxp3- TIL', 'Var', (210, 224))	('CD8', 'Gene', (49, 52))	('CD8', 'Gene', '925', (49, 52))	('CD8', 'Gene', '925', (261, 264))
56926	21045144	The change in percentages of T effector cells correlated with increases in the number of CD4+Foxp3- and CD8+ TIL per gram of tumor tissue (Fig.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('increases', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('CD8', 'Gene', (104, 107))	('CD8', 'Gene', '925', (104, 107))	('CD4+Foxp3-', 'Var', (89, 99))
56939	21045144	Although minimal alterations were observed in the expression of any of these four transcripts on days 3 and 7 post-treatment, by day 10 post-treatment, at a time when increased frequencies of TIL were observed, transcript levels for all 4 gene products were dramatically enhanced in the OX40L-Fc treatment group.	('rat', 'Species', '10116', (21, 24))	('transcript levels', 'MPA', (211, 228))	('OX40L-Fc', 'Var', (287, 295))	('enhanced', 'PosReg', (271, 279))
56942	21045144	To ensure that alterations in IFN-gamma RNA expression correlated with alterations at the protein level, TIL were isolated on days 3-10 post-treatment and stimulated in vitro prior to analysis of IFN-gamma secretion levels by ELISA.	('expression', 'MPA', (44, 54))	('IFN-gamma', 'Gene', (196, 205))	('IFN-gamma', 'Gene', '15978', (30, 39))	('rat', 'Species', '10116', (75, 78))	('alterations', 'Var', (15, 26))	('rat', 'Species', '10116', (19, 22))	('IFN-gamma', 'Gene', '15978', (196, 205))	('IFN-gamma', 'Gene', (30, 39))
56943	21045144	Interestingly, TIL production of IFN-gamma was not elevated, and perhaps even slightly reduced on day 3 after treatment with OX40L-Fc versus isotype mAb (Fig.	('IFN-gamma', 'Gene', '15978', (33, 42))	('reduced', 'NegReg', (87, 94))	('IFN-gamma', 'Gene', (33, 42))	('OX40L-Fc', 'Var', (125, 133))
56944	21045144	In contrast, TIL isolated 7 and 10 days after initiating OX40L-Fc-based therapy produced significantly higher levels of IFN-gamma protein versus TIL harvested from control mAb-treated mice at these same time points.	('OX40L-Fc-based', 'Var', (57, 71))	('higher', 'PosReg', (103, 109))	('IFN-gamma', 'Gene', '15978', (120, 129))	('IFN-gamma', 'Gene', (120, 129))	('mice', 'Species', '10090', (184, 188))
56949	21045144	by day 3) and maintain VCAM-1 expression through day 10 as a consequence of treatment with OX40L-Fc (Fig.	('expression', 'MPA', (30, 40))	('OX40L-Fc', 'Var', (91, 99))	('VCAM-1', 'Gene', (23, 29))	('VCAM-1', 'Gene', '22329', (23, 29))
56952	21045144	6A data suggest that additional (non-VEC) stromal cells in the TME produce CXCL9 in wild-type, but not Rag-/- mice (most strikingly on day 7 post-treatment with OX40L-Fc).	('OX40L-Fc', 'Var', (161, 169))	('CXCL9', 'Gene', '17329', (75, 80))	('mice', 'Species', '10090', (110, 114))	('VEC', 'Gene', (37, 40))	('CXCL9', 'Gene', (75, 80))	('VEC', 'Gene', '12562', (37, 40))
56954	21045144	We also observed a pronounced reorganization of the tumor vasculature after OX40L-Fc treatment, consistent with what has previously been described as a more "normalized" phenotype.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('OX40L-Fc', 'Var', (76, 84))	('reorganization', 'Reg', (30, 44))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
56955	21045144	While CD31+ VEC density increased coordinately with disease progression in the tumors of isotype control mAb-treated mice, vessel density in OX40L-Fc-treated tumors was significantly diminished by day 10 post-treatment (Fig.	('diminished', 'NegReg', (183, 193))	('OX40L-Fc-treated', 'Var', (141, 157))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('VEC', 'Gene', (12, 15))	('mice', 'Species', '10090', (117, 121))	('tumors', 'Disease', (79, 85))	('CD31', 'Gene', (6, 10))	('VEC', 'Gene', '12562', (12, 15))	('CD31', 'Gene', '18613', (6, 10))	('vessel density', 'MPA', (123, 137))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('increased', 'PosReg', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
56957	21045144	normalized) morphology of OX40L-Fc- versus control mAb-treated tumor vasculature (Fig.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('OX40L-Fc-', 'Var', (26, 35))
56960	21045144	on days 17 and 20 post-tumor inoculation, OX40L-Fc treatment inhibited tumor growth, resulting in disease stabilization or complete regression in the majority of treated animals.	('inhibited', 'NegReg', (61, 70))	('disease stabilization', 'CPA', (98, 119))	('OX40L-Fc', 'Var', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (71, 76))
56961	21045144	In the TDLN of mice bearing well-established MCA205 sarcomas, OX40 expression was restricted to CD4+Foxp3+ T cells, whereas CD4+Foxp3- and CD8+ T effector cells, as well as DC and potentially VEC, were observed to be OX40+ in the TME.	('CD8', 'Gene', (139, 142))	('VEC', 'Gene', '12562', (192, 195))	('CD8', 'Gene', '925', (139, 142))	('OX40', 'MPA', (62, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('MCA205 sarcomas', 'Disease', 'MESH:D012509', (45, 60))	('CD4+Foxp3+', 'Var', (96, 106))	('MCA205 sarcomas', 'Disease', (45, 60))	('mice', 'Species', '10090', (15, 19))	('VEC', 'Gene', (192, 195))
56962	21045144	Expression of OX40 has also been reported to be up-regulated by T cells in primary tumors, but not in the tumor-free lymph nodes of human cancer patients.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (138, 144))	('Expression', 'MPA', (0, 10))	('tumor', 'Disease', (83, 88))	('up-regulated', 'PosReg', (48, 60))	('tumors', 'Disease', (83, 89))	('OX40', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('human', 'Species', '9606', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Disease', (106, 111))
56963	21045144	In alternative disease models, T cell up-regulation of OX40 has been observed at sites of inflammation during the onset of experimental autoimmune encephalomyelitis, and within the synovial fluid, but not the peripheral blood of patients with rheumatoid arthritis.	('up-regulation', 'PosReg', (38, 51))	('patients', 'Species', '9606', (229, 237))	('inflammation', 'Disease', 'MESH:D007249', (90, 102))	('arthritis', 'Phenotype', 'HP:0001369', (254, 263))	('inflammation', 'Disease', (90, 102))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (243, 263))	('autoimmune encephalomyelitis', 'Disease', (136, 164))	('OX40', 'Var', (55, 59))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (136, 164))	('rheumatoid arthritis', 'Disease', (243, 263))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (243, 263))
56967	21045144	Numerous studies have indicated that both CD4+ and CD8+ T effector cells play instrumental roles in anti-tumor immunity stimulated by OX40 agonists in vivo.	('OX40', 'Var', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('CD8', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('CD8', 'Gene', '925', (51, 54))	('tumor', 'Disease', (105, 110))
56970	21045144	the conversion of OX40+ TIDC into transport-competent APC (deduced from the subsequent enrichment of CD11c+CCR7+ myeloid DC in the TDLN by day 3 post-treatment).	('CCR7', 'Gene', (107, 111))	('CD11c', 'Gene', '16411', (101, 106))	('CD11c', 'Gene', (101, 106))	('OX40+ TIDC', 'Var', (18, 28))	('CCR7', 'Gene', '12775', (107, 111))
56977	21045144	OX40L-Fc could conceivably mediate vascular activation in the TME of Rag-/- mice via: i.)	('mice', 'Species', '10090', (76, 80))	('OX40L-Fc', 'Var', (0, 8))	('vascular', 'CPA', (35, 43))
56980	21045144	TNF-alpha) by OX40+ TIDC upon OX40L-Fc treatment may induce CXCL9 and VCAM-1 expression in the TME, allowing for the recruitment of Type-1 polarized T effector cells that produce IFN-gamma (a potent inducer of CXCL9 and other angiostatic chemokines), resulting in further remodeling of the tumor vasculature and enhanced T cell infiltration.	('TNF-alpha', 'Gene', (0, 9))	('CXCL9', 'Gene', '17329', (60, 65))	('VCAM-1', 'Gene', (70, 76))	('IFN-gamma', 'Gene', '15978', (179, 188))	('rat', 'Species', '10116', (334, 337))	('CXCL9', 'Gene', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('TNF-alpha', 'Gene', '21926', (0, 9))	('OX40+ TIDC', 'Var', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('CXCL9', 'Gene', '17329', (210, 215))	('VCAM-1', 'Gene', '22329', (70, 76))	('CXCL9', 'Gene', (60, 65))	('IFN-gamma', 'Gene', (179, 188))	('T cell infiltration', 'CPA', (321, 340))	('tumor', 'Disease', (290, 295))	('enhanced', 'PosReg', (312, 320))
56981	21045144	Based on the tumor growth curves of OX40L-Fc- versus control mAb-treated mice, the impact of therapy only becomes apparent by 7-10 days after the initiation of therapy.	('tumor', 'Disease', (13, 18))	('OX40L-Fc-', 'Var', (36, 45))	('mice', 'Species', '10090', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
56983	21045144	As OX40 signaling has been previously shown to enhance recall responses and to preferentially expand CD44hi memory T cells upon antigen rechallenge, this may suggest that OX40L-Fc treatment leads to the expansion of a tumor antigen-experienced, rather than naive, T effector cell population in the TDLN, and subsequent trafficking of these T cells to the TME.	('enhance', 'PosReg', (47, 54))	('CD44hi', 'Gene', (101, 107))	('OX40L-Fc', 'Var', (171, 179))	('recall responses', 'CPA', (55, 71))	('trafficking', 'CPA', (319, 330))	('rat', 'Species', '10116', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('CD44hi', 'Gene', '12505', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))
56987	21045144	Overall, the therapeutic benefits demonstrated for OX40L-Fc in our well-established sarcoma models strongly supports the continued translation of OX40 agonists, particularly those based on a recombinant form of OX40L, into human clinical trials.	('human', 'Species', '9606', (223, 228))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('OX40L-Fc', 'Var', (51, 59))	('sarcoma', 'Disease', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('rat', 'Species', '10116', (41, 44))
56988	21045144	Moving forward, it will be important to better delineate how the various OX40+ target cell populations within the TME (and elsewhere) are impacted by OX40-mediated signals in order to select potential co-therapeutic agents and to define a strategically-rational schedule for the administration of each modality to yield maximal treatment benefit.	('OX40-mediated', 'Var', (150, 163))	('impacted', 'Reg', (138, 146))	('rat', 'Species', '10116', (253, 256))	('rat', 'Species', '10116', (287, 290))	('rat', 'Species', '10116', (241, 244))
56992	26684580	While some of the fusions appear to be passenger mutations caused by the increased genetic instability that is a hallmark of many malignant neoplasms, others constitute strong driver alterations.	('increased', 'PosReg', (73, 82))	('malignant neoplasms', 'Disease', (130, 149))	('fusions', 'Var', (18, 25))	('malignant neoplasms', 'Disease', 'MESH:D009369', (130, 149))	('caused', 'Reg', (59, 65))	('neoplasms', 'Phenotype', 'HP:0002664', (140, 149))	('genetic instability', 'MPA', (83, 102))
56998	26684580	While there are recent reviews on general, technological, or clinical aspects of gene fusions in STT and other neoplasms, a comprehensive review of their biological features is missing.	('STT', 'Disease', (97, 100))	('STT', 'Phenotype', 'HP:0031459', (97, 100))	('neoplasms', 'Disease', 'MESH:D009369', (111, 120))	('neoplasms', 'Disease', (111, 120))	('gene fusions', 'Var', (81, 93))	('neoplasms', 'Phenotype', 'HP:0002664', (111, 120))
56999	26684580	The Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer was queried on September 24, 2015 for gene fusions reported in tumors that are included in the latest WHO classification of soft tissue and bone tumors and that originated in soft tissues.	('bone tumors', 'Phenotype', 'HP:0010622', (215, 226))	('bone tumors', 'Disease', 'MESH:D001859', (215, 226))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (68, 74))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('gene fusions', 'Var', (113, 125))	('bone tumors', 'Disease', (215, 226))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
57001	26684580	Using these criteria, gene fusions were found in 40 different tumor types, representing all major subgroups except smooth muscle tumors, gastrointestinal stromal tumors, and peripheral nerve sheath tumors (Table 1).	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (137, 168))	('tumor', 'Disease', (162, 167))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (137, 168))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('muscle tumors', 'Disease', (122, 135))	('peripheral nerve sheath tumors', 'Disease', (174, 204))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (137, 167))	('gastrointestinal stromal tumors', 'Disease', (137, 168))	('gene fusions', 'Var', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('found', 'Reg', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('peripheral nerve sheath tumors', 'Disease', 'MESH:D010524', (174, 204))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('muscle tumors', 'Disease', 'MESH:D009217', (122, 135))
57002	26684580	For instance, six separate genes (ATF1, DDIT2, GLI1, HMGA2, NAB2, and STAT6) that map to chromosome bands 12q13-q15 are recurrently involved in different types of STT; in addition, there are numerous nonrecurrent gene fusions affecting other genes in chromosome arm 12q, typically resulting from the intrachromosomal rearrangements that are associated with the amplification events that are characteristic for certain subtypes of STT (Table 1).	('STT', 'Disease', (163, 166))	('gene fusions', 'Var', (213, 225))	('STT', 'Phenotype', 'HP:0031459', (163, 166))	('STAT6', 'Gene', (70, 75))	('DDIT2', 'Gene', (40, 45))	('STAT6', 'Gene', '6778', (70, 75))	('GLI1', 'Gene', '2735', (47, 51))	('DDIT2', 'Gene', '10912', (40, 45))	('NAB2', 'Gene', (60, 64))	('resulting', 'Reg', (281, 290))	('STT', 'Disease', (430, 433))	('STT', 'Phenotype', 'HP:0031459', (430, 433))	('involved', 'Reg', (132, 140))	('GLI1', 'Gene', (47, 51))	('NAB2', 'Gene', '4665', (60, 64))
57004	26684580	Indeed, several recurrent gene fusions that were recently detected by NGS, such as the NAB2-STAT6 fusion in solitary fibrous tumor, strongly suggest that fusions of neighboring genes are pathogenetically significant also in STT.	('fibrous tumor', 'Disease', 'MESH:D054364', (117, 130))	('significant', 'Reg', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('STT', 'Disease', (224, 227))	('fusions', 'Var', (154, 161))	('STAT6', 'Gene', (92, 97))	('NAB2', 'Gene', '4665', (87, 91))	('STAT6', 'Gene', '6778', (92, 97))	('fibrous tumor', 'Disease', (117, 130))	('STT', 'Phenotype', 'HP:0031459', (224, 227))	('NAB2', 'Gene', (87, 91))
57005	26684580	Recurrent gene fusions seem to be particularly prevalent among tumors of uncertain differentiation or histo-genesis, involving close to half of the tumor types (Table 1).	('tumor', 'Disease', (63, 68))	('gene fusions', 'Var', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('prevalent', 'Reg', (47, 56))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
57006	26684580	In general, the absence or presence of gene fusions is not related to basic clinicopathologic features such as grade of malignancy or degree of differentiation: gene fusions may be found in completely benign, highly differentiated lesions, such as conventional lipoma, as well as in undifferentiated, extremely aggressive tumors, like Ewing sarcoma and undifferentiated small round cell sarcomas (Table 1).	('lipoma', 'Disease', (261, 267))	('sarcomas', 'Disease', (387, 395))	('sarcomas', 'Disease', 'MESH:D012509', (387, 395))	('malignancy', 'Disease', (120, 130))	('lipoma', 'Phenotype', 'HP:0012032', (261, 267))	('Ewing sarcoma', 'Disease', (335, 348))	('aggressive tumors', 'Disease', 'MESH:D001523', (311, 328))	('sarcomas', 'Phenotype', 'HP:0100242', (387, 395))	('sarcoma', 'Phenotype', 'HP:0100242', (341, 348))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('aggressive tumors', 'Disease', (311, 328))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (335, 348))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (335, 348))	('lipoma', 'Disease', 'MESH:D008067', (261, 267))	('gene fusions', 'Var', (161, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (387, 394))
57011	26684580	For instance, in-depth genomic analysis of embryonal rhabdomyosarcomas has disclosed that they, in contrast to alveolar rhabdomyosarcomas, develop through characteristic combinations of point mutations and chromosomal and allelic imbalances, while some tumors, like desmoid-type fibromatosis or gastrointestinal stromal tumor, display near-universal mutations of a limited set of genes.	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('imbalances', 'Phenotype', 'HP:0002172', (230, 240))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (111, 137))	('embryonal rhabdomyosarcomas', 'Disease', (43, 70))	('embryonal rhabdomyosarcomas', 'Phenotype', 'HP:0006743', (43, 70))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (53, 69))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (295, 325))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (120, 137))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (295, 325))	('point mutations', 'Var', (186, 201))	('tumors', 'Disease', (253, 259))	('alveolar rhabdomyosarcomas', 'Disease', (111, 137))	('gastrointestinal stromal tumor', 'Disease', (295, 325))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('desmoid-type fibromatosis', 'Disease', (266, 291))	('develop', 'Reg', (139, 146))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (120, 136))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (53, 70))	('embryonal rhabdomyosarcomas', 'Disease', 'MESH:D018233', (43, 70))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (111, 137))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('desmoid-type fibromatosis', 'Disease', 'MESH:C535944', (266, 291))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (111, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
57014	26684580	The findings in these tumors are in line with the observation that gene fusions often are formed as a by-product of the extensive reshuffling of genetic material that is associated with gene amplification.	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('gene fusions', 'Var', (67, 79))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
57020	26684580	Many STT are already known to display several related, recurrent as well as nonrecurrent, gene fusions, a variation that often seems to have little or no discernible impact on the morphology or biology of the tumor.	('tumor', 'Disease', (209, 214))	('STT', 'Disease', (5, 8))	('STT', 'Phenotype', 'HP:0031459', (5, 8))	('gene fusions', 'Var', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
57022	26684580	The best example is probably alveolar rhabdomyosarcoma, in which the PAX3-FOXO1 and PAX7-FOXO1 fusions account for some 65 and 20%, respectively, of all cases.	('PAX7', 'Gene', (84, 88))	('PAX3-FOXO1', 'Gene', (69, 79))	('alveolar rhabdomyosarcoma', 'Disease', (29, 54))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (38, 54))	('PAX7', 'Gene', '5081', (84, 88))	('fusions', 'Var', (95, 102))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (29, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (29, 54))
57025	26684580	This could then explain why, e.g., FUS-DDIT3 is so much more common than EWSR1-DDIT3 in myxoid liposarcoma and an SS18-SSX3 has never been found in synovial sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (88, 106))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (148, 164))	('SSX3', 'Gene', (119, 123))	('myxoid liposarcoma', 'Disease', (88, 106))	('synovial sarcoma', 'Disease', 'MESH:D013584', (148, 164))	('FUS-DDIT3', 'Var', (35, 44))	('common', 'Reg', (61, 67))	('SSX3', 'Gene', '10214', (119, 123))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (88, 106))	('liposarcoma', 'Phenotype', 'HP:0012034', (95, 106))	('synovial sarcoma', 'Disease', (148, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
57028	26684580	Thus, interphase FISH with a break-apart probe for EWSR1, DDIT3 or PLAG1 readily identifies all recurrent gene fusions in Ewing sarcoma, myxoid liposarcoma, or lipoblastoma, respectively.	('gene fusions', 'Var', (106, 118))	('Ewing sarcoma', 'Disease', (122, 135))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (137, 155))	('PLAG1', 'Gene', '5324', (67, 72))	('lipoblastoma', 'Disease', 'MESH:D062689', (160, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (137, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (122, 135))	('lipoblastoma', 'Disease', (160, 172))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (122, 135))	('PLAG1', 'Gene', (67, 72))	('liposarcoma', 'Phenotype', 'HP:0012034', (144, 155))	('myxoid liposarcoma', 'Disease', (137, 155))
57031	26684580	Because there is good reason to believe that these gene fusions are strong driver mutations, the morphologic and clinical differences between the tumor types must be explained either by different sets of additional mutations and/or different cellular origins.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('fusions', 'Var', (56, 63))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
57036	26684580	Thus, no less than 14 of the recurrent gene fusions that have been described in STT have also been described in primary intraskeletal tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('STT', 'Disease', (80, 83))	('intraskeletal tumors', 'Disease', (120, 140))	('intraskeletal tumors', 'Disease', 'MESH:D009369', (120, 140))	('STT', 'Phenotype', 'HP:0031459', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('gene fusions', 'Var', (39, 51))	('described', 'Reg', (99, 108))
57038	26684580	For example, some ALK fusions in inflammatory myofibroblastic tumor are shared with malignant lymphomas and lung cancer, and TFE3 fusions in alveolar soft part sarcoma, PEComa, and epithelioid hemangioendothelioma are found also in kidney cancer (Table 2).	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (141, 167))	('fusions', 'Var', (22, 29))	('lymphomas', 'Phenotype', 'HP:0002665', (94, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('kidney cancer', 'Disease', 'MESH:D007680', (232, 245))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('epithelioid hemangioendothelioma', 'Disease', (181, 213))	('inflammatory myofibroblastic tumor', 'Disease', (33, 67))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (181, 213))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('alveolar soft part sarcoma', 'Disease', (141, 167))	('malignant lymphomas', 'Disease', 'MESH:D008223', (84, 103))	('PEComa', 'Disease', 'MESH:D054973', (169, 175))	('lung cancer', 'Disease', (108, 119))	('kidney cancer', 'Phenotype', 'HP:0009726', (232, 245))	('PEComa', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('kidney cancer', 'Disease', (232, 245))	('ALK', 'Gene', '238', (18, 21))	('ALK', 'Gene', (18, 21))	('TFE3', 'Gene', (125, 129))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (181, 213))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('TFE3', 'Gene', '7030', (125, 129))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (150, 167))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (141, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (33, 67))	('malignant lymphomas', 'Disease', (84, 103))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (46, 67))
57050	26684580	Furthermore, highly recurrent gene fusions in congenital spindle cell rhabdomyosarcoma involve critical transcriptional activators of muscle-specific genes, such as VGLL2, TEAD1, and SRF.	('VGLL2', 'Gene', '245806', (165, 170))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (70, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('TEAD1', 'Gene', '7003', (172, 177))	('gene fusions', 'Var', (30, 42))	('VGLL2', 'Gene', (165, 170))	('TEAD1', 'Gene', (172, 177))	('SRF', 'Gene', '6722', (183, 186))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (70, 86))	('transcriptional activators', 'MPA', (104, 130))	('SRF', 'Gene', (183, 186))	('involve', 'Reg', (87, 94))	('rhabdomyosarcoma', 'Disease', (70, 86))
57059	26684580	Yet another scenario is illustrated by conventional lipoma; some 75% of these tumors have a rearrangement of the HMGA2 gene, resulting in either an in-frame fusion transcript or in truncation of the gene, typically after the first three exons that encode the AT-hook domains.	('lipoma', 'Disease', (52, 58))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('lipoma', 'Phenotype', 'HP:0012032', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('truncation', 'MPA', (181, 191))	('in-frame fusion transcript', 'MPA', (148, 174))	('HMGA2', 'Gene', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lipoma', 'Disease', 'MESH:D008067', (52, 58))	('rearrangement', 'Var', (92, 105))
57062	26684580	Indeed, the high incidence of fusions involving Ets family proteins also in prostate cancer has spurred interest, and several promising studies are on-going.	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('Ets family proteins', 'Protein', (48, 67))	('fusions', 'Var', (30, 37))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
57067	26684580	An indication that the involvement of a particular PK is less tissue-specific than for TFs could be gleaned from the fact that several of the STT-associated gene fusions are seen in many other types of neoplasia, ETV6-NTRK3 and EML4-ALK constituting the most prominent examples (Table 2).	('ETV6', 'Gene', (213, 217))	('fusions', 'Var', (162, 169))	('EML4', 'Gene', '27436', (228, 232))	('STT-associated', 'Gene', (142, 156))	('neoplasia', 'Disease', 'MESH:D009369', (202, 211))	('neoplasia', 'Phenotype', 'HP:0002664', (202, 211))	('ETV6', 'Gene', '2120', (213, 217))	('ALK', 'Gene', '238', (233, 236))	('NTRK3', 'Gene', '4916', (218, 223))	('ALK', 'Gene', (233, 236))	('NTRK3', 'Gene', (218, 223))	('EML4', 'Gene', (228, 232))	('neoplasia', 'Disease', (202, 211))	('STT', 'Phenotype', 'HP:0031459', (142, 145))
57068	26684580	Furthermore, the PK that is most often involved in STT-associated chimeras:ALK:is activated by numerous other fusions, as well as other types of mutation, in a large number of neoplasms.	('ALK', 'Gene', (75, 78))	('neoplasms', 'Disease', (176, 185))	('activated', 'PosReg', (82, 91))	('neoplasms', 'Disease', 'MESH:D009369', (176, 185))	('ALK', 'Gene', '238', (75, 78))	('neoplasms', 'Phenotype', 'HP:0002664', (176, 185))	('STT', 'Phenotype', 'HP:0031459', (51, 54))	('fusions', 'Var', (110, 117))	('mutation', 'Var', (145, 153))
57073	26684580	Thus, the chimeric PKs here, as in other malignancies with receptor tyrosine kinases activated by gene fusions/mutations, offer an excellent therapeutic target .	('malignancies', 'Disease', 'MESH:D009369', (41, 53))	('tyrosine kinase', 'Gene', (68, 83))	('malignancies', 'Disease', (41, 53))	('tyrosine kinase', 'Gene', '7294', (68, 83))	('fusions/mutations', 'Var', (103, 120))
57075	26684580	Gene fusions resulting in distorted chromatin regulation have been recognized in leukemias for two decades, with fusions involving the KMT2A (previously known as MLL) gene as a well-known example.	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('KMT2A', 'Gene', (135, 140))	('leukemias', 'Disease', 'MESH:D007938', (81, 90))	('KMT2A', 'Gene', '4297', (135, 140))	('distorted', 'Reg', (26, 35))	('fusions', 'Var', (113, 120))	('leukemias', 'Phenotype', 'HP:0001909', (81, 90))	('chromatin regulation', 'MPA', (36, 56))	('MLL', 'Gene', (162, 165))	('leukemias', 'Disease', (81, 90))	('MLL', 'Gene', '4297', (162, 165))
57076	26684580	Thus, STT with gene fusions affecting chromatin regulation are either undifferentiated, as exemplified by undifferentiated round cell sarcomas with the BCOR-CCNB3 fusion, or display disparate lines of differentiation, such as synovial sarcoma with SS18-SSX fusions or ossifying fibromyxoid tumor with PHF1 fusions.	('fibromyxoid tumor', 'Disease', (278, 295))	('SSX', 'Gene', (253, 256))	('BCOR', 'Gene', '54880', (152, 156))	('CCNB3', 'Gene', (157, 162))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (226, 242))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('PHF1', 'Gene', '5252', (301, 305))	('sarcomas', 'Disease', (134, 142))	('BCOR', 'Gene', (152, 156))	('STT', 'Phenotype', 'HP:0031459', (6, 9))	('fusions', 'Var', (20, 27))	('fusions', 'Var', (306, 313))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('CCNB3', 'Gene', '85417', (157, 162))	('SSX', 'Gene', '6757', (253, 256))	('synovial sarcoma', 'Disease', (226, 242))	('fibromyxoid tumor', 'Disease', 'MESH:D009369', (278, 295))	('PHF1', 'Gene', (301, 305))	('synovial sarcoma', 'Disease', 'MESH:D013584', (226, 242))
57080	26684580	Two gene fusions involve growth factors:the COL1A1-PDGFB fusion in dermatofibrosarcoma protuberans/giant cell fibroblastoma and the COL6A3-CSF1 fusion in tenosyno-vial giant cell tumor:that result in constitutive activation of their respective tyrosine kinase receptors, PDGFRB and CSF1R.	('dermatofibrosarcoma protuberans', 'Disease', (67, 98))	('PDGFB', 'Gene', (51, 56))	('COL6A3', 'Gene', (132, 138))	('CSF1R', 'Gene', '1436', (282, 287))	('COL6A3', 'Gene', '1293', (132, 138))	('tyrosine kinase', 'Gene', (244, 259))	('CSF1R', 'Gene', (282, 287))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('tyrosine kinase', 'Gene', '7294', (244, 259))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (67, 98))	('COL1A1', 'Gene', '1277', (44, 50))	('CSF1', 'Gene', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('fusion', 'Var', (57, 63))	('CSF1', 'Gene', (139, 143))	('COL1A1', 'Gene', (44, 50))	('activation', 'PosReg', (213, 223))	('giant cell fibroblastoma', 'Disease', (99, 123))	('CSF1', 'Gene', '1435', (282, 286))	('PDGFB', 'Gene', '5155', (51, 56))	('PDGFRB', 'Gene', '5159', (271, 277))	('giant cell fibroblastoma', 'Disease', 'MESH:D018223', (99, 123))	('tenosyno-vial giant cell tumor', 'Disease', 'MESH:D005870', (154, 184))	('CSF1', 'Gene', '1435', (139, 143))	('PDGFRB', 'Gene', (271, 277))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (74, 86))	('giant cell tumor', 'Phenotype', 'HP:0011847', (168, 184))	('tenosyno-vial giant cell tumor', 'Disease', (154, 184))
57084	26684580	Similar USP6 fusions have been described also in primary aneurysmal bone cyst and in giant cell reparative granuloma of the hands and feet, but with other or unknown 5'-partners.	('granuloma', 'Phenotype', 'HP:0032252', (107, 116))	('described', 'Reg', (31, 40))	('granuloma of the hands', 'Disease', 'MESH:D006099', (107, 129))	('aneurysmal bone cyst', 'Phenotype', 'HP:0012063', (57, 77))	('granuloma of the hands', 'Disease', (107, 129))	('aneurysmal bone cyst', 'Disease', 'MESH:D017824', (57, 77))	('fusions', 'Var', (13, 20))	('USP6', 'Gene', (8, 12))	('bone cyst', 'Phenotype', 'HP:0012062', (68, 77))	('USP6', 'Gene', '9098', (8, 12))	('aneurysmal bone cyst', 'Disease', (57, 77))
57087	26684580	If also malignant STT, as has been shown for other types of malignancy, turn out to display fusions activating ubiquitin-specific proteases, promising treatment options have emerged.	('malignancy', 'Disease', (60, 70))	('malignant STT', 'Disease', (8, 21))	('fusions', 'Var', (92, 99))	('activating', 'PosReg', (100, 110))	('ubiquitin-specific', 'Protein', (111, 129))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))	('STT', 'Phenotype', 'HP:0031459', (18, 21))
57088	26684580	An exception to the rule that recurrent fusion proteins in STT affect the transcription of other genes was recently provided by, who identified a TRIO-TERT chimera in two dedifferentiated liposarcomas.	('affect', 'Reg', (63, 69))	('TERT', 'Gene', (151, 155))	('liposarcomas', 'Phenotype', 'HP:0012034', (188, 200))	('liposarcomas', 'Disease', 'MESH:D008080', (188, 200))	('fusion proteins', 'Var', (40, 55))	('liposarcomas', 'Disease', (188, 200))	('STT', 'Gene', (59, 62))	('TERT', 'Gene', '7015', (151, 155))	('liposarcoma', 'Phenotype', 'HP:0012034', (188, 199))	('STT', 'Phenotype', 'HP:0031459', (59, 62))	('transcription', 'MPA', (74, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
57089	26684580	STT typically maintain telomere length through mutations in the promoter region of the TERT gene or by alternative lengthening of telomeres.	('STT', 'Phenotype', 'HP:0031459', (0, 3))	('telomere', 'MPA', (23, 31))	('mutations', 'Var', (47, 56))	('TERT', 'Gene', (87, 91))	('maintain', 'Reg', (14, 22))	('TERT', 'Gene', '7015', (87, 91))
57095	26684580	An important step in this endeavour is the creation of transgenic mouse models, which so far exist for only four gene fusions (EWSR1-ATF1, FUS-DDIT3, PAX3-FOXO1, and SS18-SSX2) and truncated HMGA2; all of these models develop the corresponding human tumors.	('truncated', 'Var', (181, 190))	('human', 'Species', '9606', (244, 249))	('SSX2', 'Gene', '6757', (171, 175))	('HMGA2', 'Gene', (191, 196))	('mouse', 'Species', '10090', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('SSX2', 'Gene', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('develop', 'PosReg', (218, 225))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))	('transgenic', 'Species', '10090', (55, 65))
57106	27635231	The oncogenic phenotype is primarily driven by one underlying prototypical chromosomal translocation, fusion of the EWS gene on chromosome 22q24 with one of five E-twenty-six (ETS) transcription factor gene family members ( FLI , ERG , ETV1 , E1AF , , and FEV ).	('ETV1', 'Gene', (236, 240))	('ERG', 'Gene', (230, 233))	('ETV1', 'Gene', '2115', (236, 240))	('fusion', 'Var', (102, 108))	('FLI', 'Gene', '2314', (224, 227))	('FLI', 'Gene', (224, 227))	('E1AF', 'Gene', (243, 247))	('E1AF', 'Gene', '2118', (243, 247))	('EWS', 'Gene', '2130', (116, 119))	('EWS', 'Gene', (116, 119))	('driven by', 'Reg', (37, 46))	('ERG', 'Gene', '2078', (230, 233))
57119	27635231	Reduction of EWS/FLI fusion levels through anti-sense/small interfering RNA (siRNA) or oligodeoxynucleotides significantly impairs the proliferative, invasive, and tumorigenic phenotype of Ewing sarcoma both in vitro and in vivo - .	('tumor', 'Disease', (164, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('impairs', 'NegReg', (123, 130))	('FLI', 'Gene', '2314', (17, 20))	('proliferative', 'CPA', (135, 148))	('FLI', 'Gene', (17, 20))	('Ewing sarcoma', 'Disease', (189, 202))	('Reduction', 'NegReg', (0, 9))	('EWS', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('invasive', 'CPA', (150, 158))	('EWS', 'Gene', '2130', (13, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (189, 202))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('anti-sense/small interfering', 'Var', (43, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (189, 202))
57130	27635231	Although YK-4-279 was first thought to directly impede EWS/FLI-driven transcriptional activation, Selvanathan et al.	('EWS', 'Gene', '2130', (55, 58))	('EWS', 'Gene', (55, 58))	('FLI', 'Gene', '2314', (59, 62))	('FLI', 'Gene', (59, 62))	('impede', 'NegReg', (48, 54))	('YK-4-279', 'Var', (9, 17))
57147	27635231	Interestingly, of the four Ewing sarcoma cell lines tested, 5838 cells harboring the EWS/ERG translocation were the least sensitive.	('ERG', 'Gene', (89, 92))	('translocation', 'Var', (93, 106))	('Ewing sarcoma', 'Disease', (27, 40))	('ERG', 'Gene', '2078', (89, 92))	('EWS', 'Gene', (85, 88))	('EWS', 'Gene', '2130', (85, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (27, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (27, 40))
57171	27635231	This reversal of EWS/FLI gene expression pattern was exclusively mirrored through siRNA-mediated knockdown of BRD3 and BRD4 but not BRD2, suggesting that BRD3 and BRD4 may be critical epigenetic regulators in Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('BRD3', 'Gene', '8019', (110, 114))	('EWS', 'Gene', (17, 20))	('BRD4', 'Gene', (119, 123))	('Ewing sarcoma', 'Disease', (209, 222))	('FLI', 'Gene', (21, 24))	('BRD4', 'Gene', '23476', (163, 167))	('BRD2', 'Gene', '6046', (132, 136))	('knockdown', 'Var', (97, 106))	('FLI', 'Gene', '2314', (21, 24))	('BRD2', 'Gene', (132, 136))	('BRD3', 'Gene', (154, 158))	('EWS', 'Gene', '2130', (17, 20))	('BRD4', 'Gene', '23476', (119, 123))	('BRD3', 'Gene', '8019', (154, 158))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (209, 222))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (209, 222))	('BRD3', 'Gene', (110, 114))	('BRD4', 'Gene', (163, 167))
57172	27635231	Although complete Ewing sarcoma xenograft tumor response was not observed following single-agent JQ1 treatment, these early preclinical findings suggest that combination treatment with epigenetic inhibitors that block BET bromodomain activity and the associated EWS/FLI transcriptional program may represent a potential therapeutic platform for Ewing sarcoma.	('EWS', 'Gene', '2130', (262, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (351, 358))	('Ewing sarcoma xenograft tumor', 'Disease', 'MESH:C563168', (18, 47))	('Ewing sarcoma', 'Disease', (345, 358))	('epigenetic inhibitors', 'Var', (185, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('BET', 'Gene', (218, 221))	('FLI', 'Gene', (266, 269))	('EWS', 'Gene', (262, 265))	('Ewing sarcoma xenograft tumor', 'Disease', (18, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('FLI', 'Gene', '2314', (266, 269))	('activity', 'MPA', (234, 242))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (345, 358))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (345, 358))	('BET', 'Gene', '92737', (218, 221))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (18, 31))	('block', 'NegReg', (212, 217))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (18, 31))
57180	27635231	Currently, three irreversible LSD1 inhibitory agents:tranylcypromine, GSK-2879552, and ORY-100:are undergoing clinical evaluation primarily in patients with acute myeloid leukemia , and clinical formulations of HCI-2509 are expected to enter phase I testing in 2017.	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (157, 179))	('GSK', 'Chemical', '-', (70, 73))	('GSK-2879552', 'Gene', (70, 81))	('acute myeloid leukemia', 'Disease', (157, 179))	('HCI-2509', 'Chemical', '-', (211, 219))	('LSD1', 'Gene', '23028', (30, 34))	('patients', 'Species', '9606', (143, 151))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (157, 179))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (163, 179))	('LSD1', 'Gene', (30, 34))	('ORY-100', 'Var', (87, 94))	('tranylcypromine', 'Chemical', 'MESH:D014191', (53, 68))
57186	27635231	In addition, mutations in PARP-1 and PARP-2 are seldom observed in Ewing sarcoma ( Table 2).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('PARP-2', 'Gene', (37, 43))	('PARP-1', 'Gene', (26, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('PARP-1', 'Gene', '142', (26, 32))	('mutations', 'Var', (13, 22))	('observed', 'Reg', (55, 63))	('PARP-2', 'Gene', '10038', (37, 43))	('Ewing sarcoma', 'Disease', (67, 80))
57187	27635231	Recent whole genome/exome sequencing studies of Ewing sarcoma tumors , , -  identified PARP-1/2 mutations in only 1 out of 279 (0.36%) and 2 out of 279 (0.72%) patient tumor samples, respectively.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (48, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PARP-1', 'Gene', (87, 93))	('tumor', 'Disease', (168, 173))	('PARP-1', 'Gene', '142', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('Ewing sarcoma tumors', 'Disease', (48, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('patient', 'Species', '9606', (160, 167))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (48, 68))	('mutations', 'Var', (96, 105))
57190	27635231	identified a highly significant association between the presence of the EWS/FLI rearrangement and olaparib (Lynparza) sensitivity (geometric mean IC 50 for EWS/FLI = 4.7 versus 64 muM for non-EWS/FLI lines).	('FLI', 'Gene', (160, 163))	('olaparib', 'Chemical', 'MESH:C531550', (98, 106))	('presence', 'Var', (56, 64))	('olaparib', 'MPA', (98, 106))	('FLI', 'Gene', '2314', (196, 199))	('EWS', 'Gene', (72, 75))	('EWS', 'Gene', (156, 159))	('FLI', 'Gene', (196, 199))	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', '2130', (156, 159))	('FLI', 'Gene', '2314', (160, 163))	('FLI', 'Gene', '2314', (76, 79))	('EWS', 'Gene', '2130', (192, 195))	('EWS', 'Gene', (192, 195))	('FLI', 'Gene', (76, 79))
57207	27635231	Inhibitors of PARP have emerged as a novel class of agents to treat Ewing sarcoma, and several clinical studies are underway ( Table 1).	('Ewing sarcoma', 'Disease', (68, 81))	('Inhibitors', 'Var', (0, 10))	('PARP', 'Gene', (14, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (68, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
57250	31775680	Following features were evaluated: type of modality (CT, MRI), maximum size (largest diameter in mm, defined on the slide with the largest tumor appearance), number of lesions, localization, imaging appearance (hypodense/hypointense, isodense/isointense, hyperdense/hyperintense in comparison to surrounding muscle tissue) and type of enhancement (no enhancement; homogenous or heterogeneous enhancement).	('hypodense/hypointense', 'Var', (211, 232))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('isodense/isointense', 'MPA', (234, 253))	('hyperdense/hyperintense', 'MPA', (255, 278))
57263	31775680	On T1-weighted images, MS were hypointense in 22/54 cases (40.7%), isointense in 30/54 cases (55.6%) and hyperintense in 2/54 cases (3.7%) compared to the adjacent muscle tissue.	('hyperintense', 'Var', (105, 117))	('MS', 'Disease', 'MESH:D023981', (23, 25))	('isointense', 'Var', (67, 77))	('hypointense', 'Var', (31, 42))
57367	28125078	Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma Germline mutations in Ewing sarcoma Ewing sarcoma is a highly malignant small round blue cell tumor that predominantly affects the adolescent and young adult population.	('DNA repair genes', 'Gene', (44, 60))	('inactivating', 'NegReg', (9, 21))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (114, 127))	('tumor', 'Disease', (186, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('Ewing sarcoma', 'Disease', (114, 127))	('mutations', 'Var', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('Ewing sarcoma', 'Disease', (128, 141))	('Ewing sarcoma', 'Disease', (78, 91))	('patients', 'Species', '9606', (64, 72))
57370	28125078	Pathogenic mutations were highly enriched for genes involved with DNA damage repair and for genes associated with cancer predisposition syndromes.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
57377	28125078	Germline mutations in cancer predisposition genes have recently been described in 8.5-12% of pediatric cancer cases across a range of cancer types.	('Germline mutations', 'Var', (0, 18))	('described', 'Reg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
57382	28125078	WGS/WES were processed and mapped and variants called using methods employed previously by our group with very high validation rates.	('WGS', 'Disease', 'None', (0, 3))	('WGS', 'Disease', (0, 3))	('variants', 'Var', (38, 46))
57383	28125078	To perform burden testing for genes with pathogenic/likely pathogenic variants, we compared the rate of these classes of variants in these genes in our Ewing sarcoma cohort to that in the ExAC population database, minus samples contributed from TCGA.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (152, 165))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('variants', 'Var', (121, 129))	('variants', 'Var', (70, 78))	('Ewing sarcoma', 'Disease', (152, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
57384	28125078	In the cohort of 175 Ewing sarcoma patients analyzed, we identified 52 Tier 1 variants for further manual classification.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('Ewing sarcoma', 'Disease', (21, 34))	('patients', 'Species', '9606', (35, 43))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('variants', 'Var', (78, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))
57386	28125078	The nine remaining variants we placed in a separate category as truncating mutations in a tumor suppressor gene that is not reported to be a germline cancer predisposition gene (Table S4).	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('truncating mutations', 'Var', (64, 84))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Disease', (90, 95))	('cancer', 'Disease', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
57387	28125078	The pathogenic/likely pathogenic variants were all mutually exclusive by patient, and were therefore found in 13.1% of the population studied.	('patient', 'Species', '9606', (73, 80))	('pathogenic/likely', 'Reg', (4, 21))	('variants', 'Var', (33, 41))
57388	28125078	These variants were found in similar percentages amongst the different cohorts studied (NCI 14.3% vs. ICGC 12.0% vs. PCGP 15.8%, p=0.85), between WGS and WES samples (12.0% vs. 16.0%, p = 0.62) and between matched sequencing and tumor-only sequencing (12.3% vs. 16.2%, p=0.58).	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('variants', 'Var', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('WGS', 'Disease', 'None', (146, 149))	('WGS', 'Disease', (146, 149))
57389	28125078	Truncating mutations in non-syndromic tumor suppressor genes, however, were much more commonly observed in tumor-only sequencing samples (19.4% vs. 2.2%, p=0.003), suggesting that some of these mutations are likely somatic variants that have not been previously reported simply because they are not highly recurrent in this tumor type (Table S4).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', (324, 329))	('mutations', 'Var', (194, 203))	('non-syndromic tumor', 'Disease', (24, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('non-syndromic tumor', 'Disease', 'MESH:D009369', (24, 43))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
57392	28125078	We identified 1367 pathogenic/likely pathogenic variants in this population, or 2.57%, which is significantly lower than the 13.1% affected in the Ewing sarcoma cohort (p=2e-10).	('pathogenic/likely', 'Reg', (19, 36))	('Ewing sarcoma', 'Disease', (147, 160))	('pathogenic', 'Reg', (37, 47))	('variants', 'Var', (48, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (147, 160))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (147, 160))
57396	28125078	There were no significant differences between patients with a pathogenic/likely pathogenic germline mutation and those without with regards to rates of somatic mutations in STAG2 (18.1% vs. 17.8%, p=1.0), CDKN2A (13.6% vs. 12.3%, p=1.0), or TP53 (9.1% vs. 8.9%, p=1.0).	('patients', 'Species', '9606', (46, 54))	('pathogenic', 'Reg', (80, 90))	('mutations', 'Var', (160, 169))	('TP53', 'Gene', '7157', (241, 245))	('CDKN2A', 'Gene', (205, 211))	('TP53', 'Gene', (241, 245))	('STAG2', 'Gene', (173, 178))	('STAG2', 'Gene', '10735', (173, 178))	('pathogenic/likely', 'Reg', (62, 79))	('CDKN2A', 'Gene', '1029', (205, 211))
57397	28125078	Interestingly, we noted that the two patients with a somatic mutation in TP53 in the pathogenic/likely pathogenic group include the two patients with germline mutations in either TP53 itself or the TP53-associated gene WRAP53, suggesting a germline/somatic oncogenic synergy in these two cases.	('WRAP53', 'Gene', (219, 225))	('TP53', 'Gene', '7157', (73, 77))	('WRAP53', 'Gene', '55135', (219, 225))	('patients', 'Species', '9606', (37, 45))	('mutation', 'Var', (61, 69))	('TP53', 'Gene', (73, 77))	('TP53', 'Gene', '7157', (198, 202))	('patients', 'Species', '9606', (136, 144))	('TP53', 'Gene', (198, 202))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (179, 183))
57400	28125078	There was a trend towards younger age amongst patients with pathogenic/likely pathogenic germline mutation than those without (57.1% vs. 42.3% under age 12, 42.9% vs. 50.8% age 12-24, 0 vs. 6.9% over age 24), but this result did not reach statistical significance (p=0.31).	('germline', 'Gene', (89, 97))	('pathogenic', 'Reg', (78, 88))	('patients', 'Species', '9606', (46, 54))	('pathogenic/likely', 'Var', (60, 77))
57405	28125078	For example, we considered heterozygous deleterious mutation in any member of the Fanconi anemia gene family to likely predispose to solid malignancies and thus considered these as likely pathogenic in our population.	('malignancies', 'Disease', (139, 151))	('anemia', 'Phenotype', 'HP:0001903', (90, 96))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (82, 96))	('Fanconi anemia', 'Disease', (82, 96))	('malignancies', 'Disease', 'MESH:D009369', (139, 151))	('heterozygous deleterious mutation', 'Var', (27, 60))	('predispose', 'Reg', (119, 129))	('Fanconi anemia', 'Disease', 'MESH:D005199', (82, 96))
57406	28125078	Next generation sequencing has increasingly identified heterozygous deleterious mutation of members of this gene family outside of the more well established BRCA1 and BRCA2 as predisposing to solid tumors , supporting our choice.	('heterozygous deleterious mutation', 'Var', (55, 88))	('BRCA1', 'Gene', (157, 162))	('solid tumors', 'Disease', (192, 204))	('predisposing', 'Reg', (176, 188))	('BRCA2', 'Gene', (167, 172))	('solid tumors', 'Disease', 'MESH:D009369', (192, 204))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('BRCA2', 'Gene', '675', (167, 172))	('BRCA1', 'Gene', '672', (157, 162))
57408	28125078	We found that pathogenic germline mutations in Ewing sarcoma are not highly recurrent in a single gene, but rather spread across a number of genes with potentially similar functional clustering.	('pathogenic', 'Reg', (14, 24))	('Ewing sarcoma', 'Disease', (47, 60))	('germline', 'Var', (25, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (47, 60))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (47, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))
57409	28125078	We found that second somatic hits in the same genes were uncommon, which is consistent with one previous report in which 0 of 5 Ewing sarcoma patients with pathogenic/likely pathogenic germline mutation had a second somatic hit .	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('germline', 'Var', (185, 193))	('Ewing sarcoma', 'Disease', (128, 141))	('patients', 'Species', '9606', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
57410	28125078	Given that gain of a somatic EWS-ETS fusion is believed to be the seminal event in Ewing sarcoma development , we speculate that the pathogenic germline mutations observed may be permissive to the development of DNA breaks and subsequent translocation.	('mutations', 'Var', (153, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('EWS', 'Gene', (29, 32))	('Ewing sarcoma', 'Disease', (83, 96))	('EWS', 'Gene', '2130', (29, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (83, 96))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (83, 96))	('translocation', 'CPA', (238, 251))
57411	28125078	Previous work has also noted a similar association between deleterious germline mutation in DNA repair genes and other translocation-associated sarcomas .	('sarcomas', 'Phenotype', 'HP:0100242', (144, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('sarcomas', 'Disease', (144, 152))	('deleterious germline mutation', 'Var', (59, 88))	('DNA repair', 'Gene', (92, 102))	('sarcomas', 'Disease', 'MESH:D012509', (144, 152))
57412	28125078	We do caution that similar gene classes of pathogenic germline mutations have been described in the previously aforementioned pediatric malignancies studies that were not Ewing sarcoma-specific.	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('Ewing sarcoma', 'Disease', (171, 184))	('malignancies', 'Disease', (136, 148))	('germline mutations', 'Var', (54, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (171, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (171, 184))
57418	28125078	Given the high rates of pathogenic germline mutations in this population, we believe referral to a genetic specialist should be considered for all patients and families affected by this disease.	('patients', 'Species', '9606', (147, 155))	('germline mutations', 'Var', (35, 53))	('pathogenic', 'Reg', (24, 34))
57419	28125078	Though screening for Ewing sarcoma itself is unlikely to be undertaken given the rarity of the disease even in those with a predisposing mutation, patients that survive their cancer and/or potentially family members may benefit from existing risk management strategies for those with deleterious mutations in genes such as APC or BRCA1 that are associated with cancer syndromes that have a screening or surgical risk reduction management option.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BRCA1', 'Gene', '672', (330, 335))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))	('Ewing sarcoma', 'Disease', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('mutations', 'Var', (296, 305))	('patients', 'Species', '9606', (147, 155))	('BRCA1', 'Gene', (330, 335))	('APC', 'Disease', 'MESH:D011125', (323, 326))	('APC', 'Disease', (323, 326))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('cancer', 'Disease', (361, 367))	('cancer', 'Disease', 'MESH:D009369', (361, 367))
57420	28125078	For the patients themselves, many of these germline variants may also influence cancer treatment or at least suggest the use of novel therapies, ideally in the setting of clinical trial.	('influence', 'Reg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('suggest', 'Reg', (109, 116))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('germline variants', 'Var', (43, 60))	('cancer', 'Disease', (80, 86))	('patients', 'Species', '9606', (8, 16))
57421	28125078	As examples, carriers of germline BRCA1 or BRCA2 mutations, even outside of breast or ovarian cancer, may benefit from treatment with PARP inhibitors, while Hedgehog pathway inhibitors have activity in tumors associated with germline mutations in PTCH1 or PTCH2.	('PARP', 'Gene', (134, 138))	('PTCH1', 'Gene', (247, 252))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('breast or ovarian cancer', 'Disease', (76, 100))	('BRCA2', 'Gene', '675', (43, 48))	('benefit', 'PosReg', (106, 113))	('BRCA1', 'Gene', '672', (34, 39))	('mutations', 'Var', (49, 58))	('BRCA1', 'Gene', (34, 39))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (76, 100))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PTCH1', 'Gene', '5727', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumors', 'Disease', (202, 208))	('PTCH2', 'Gene', '8643', (256, 261))	('BRCA2', 'Gene', (43, 48))	('PARP', 'Gene', '142', (134, 138))	('PTCH2', 'Gene', (256, 261))
57433	26267867	Expansion of ART in Botswana was associated with decreased age-specific cancer risk.	('Botswana', 'Gene', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('decreased', 'NegReg', (49, 58))	('Expansion of ART', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('ART', 'Chemical', '-', (13, 16))	('cancer', 'Disease', (72, 78))
57521	26267867	In the US, ART was associated with sharp declines in both Kaposi's and non-Hodgkin's lymphoma.	("Kaposi's and non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (58, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (85, 93))	('ART', 'Var', (11, 14))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (75, 93))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (71, 93))	('ART', 'Chemical', '-', (11, 14))	('declines', 'NegReg', (41, 49))
57577	22811667	The peptides contained the following 16 amino acids: Asp, Thr, Ser, Glu, Gly, Ala, Cys, Val, Met, Ile, Leu, Phe, Lys, His, Arg, and Pro.	('Val', 'Var', (88, 91))	('Thr', 'MPA', (58, 61))	('Ile', 'Var', (98, 101))	('Glu', 'MPA', (68, 71))	('Lys', 'Chemical', 'MESH:D008239', (113, 116))	('Pro', 'Chemical', 'MESH:D011392', (132, 135))	('Met', 'Chemical', 'MESH:D008715', (93, 96))	('Cys', 'Chemical', 'MESH:D003545', (83, 86))	('Lys', 'Var', (113, 116))	('Cys', 'MPA', (83, 86))	('Thr', 'Chemical', 'MESH:D013912', (58, 61))	('Val', 'Chemical', 'MESH:D014633', (88, 91))	('Gly', 'MPA', (73, 76))	('Leu', 'Var', (103, 106))	('Met', 'Var', (93, 96))	('Asp', 'Chemical', 'MESH:D001224', (53, 56))	('Phe', 'Chemical', 'MESH:D010649', (108, 111))	('Asp', 'Var', (53, 56))	('Glu', 'Chemical', 'MESH:D018698', (68, 71))	('His', 'MPA', (118, 121))	('Ser', 'Chemical', 'MESH:D012694', (63, 66))	('Leu', 'Chemical', 'MESH:D007930', (103, 106))	('Arg', 'MPA', (123, 126))	('Ser', 'MPA', (63, 66))	('Phe', 'Var', (108, 111))	('Arg', 'Chemical', 'MESH:D001120', (123, 126))	('Ala', 'Chemical', 'MESH:D000409', (78, 81))	('His', 'Chemical', 'MESH:D006639', (118, 121))	('Gly', 'Chemical', 'MESH:D005998', (73, 76))	('Ile', 'Chemical', 'MESH:D007532', (98, 101))	('Ala', 'MPA', (78, 81))
57620	22811667	The serum levels of IL-2, IFN-gamma, and TNF-alpha were markedly increased in S180-bearing mice administrated with Gl-BSP (200 mg kg-1), compared with that in S180-bearing control mice administrated with physiological saline (Table 7).	('BSP', 'Gene', (118, 121))	('increased', 'PosReg', (65, 74))	('S180-bearing', 'Var', (78, 90))	('mice', 'Species', '10090', (91, 95))	('IL-2', 'Gene', (20, 24))	('Gl', 'Chemical', 'MESH:C015905', (115, 117))	('IFN-gamma', 'Gene', '15978', (26, 35))	('BSP', 'Gene', '103993', (118, 121))	('TNF-alpha', 'Gene', (41, 50))	('mice', 'Species', '10090', (180, 184))	('IFN-gamma', 'Gene', (26, 35))	('saline', 'Chemical', 'MESH:D012965', (218, 224))	('serum levels', 'MPA', (4, 16))	('IL-2', 'Gene', '16183', (20, 24))	('TNF-alpha', 'Gene', '21926', (41, 50))
57650	22811667	Thus, less than 100 mg kg-1 Gl-BSP may represent a real dose and further study is needed to confirm this assumption.	('Gl', 'Chemical', 'MESH:C015905', (28, 30))	('BSP', 'Gene', (31, 34))	('less than 100 mg', 'Var', (6, 22))	('BSP', 'Gene', '103993', (31, 34))
57699	32932909	Numerous reports have shown direct evidence of the anthelmintic effects of C. intybus viz., decreased worm egg numbers in feces, decreased abomasal worm burdens, decreased male worms in parasitized animals, and decreased ability of infective larvae.	('male worms in parasitized', 'CPA', (172, 197))	('C. intybus', 'Var', (75, 85))	('decreased abomasal', 'Disease', 'MESH:D002303', (129, 147))	('decreased', 'NegReg', (162, 171))	('ability of infective larvae', 'CPA', (221, 248))	('decreased', 'NegReg', (211, 220))	('decreased', 'NegReg', (92, 101))	('decreased abomasal', 'Disease', (129, 147))	('C. intybus', 'Species', '13427', (75, 85))	('worm egg numbers', 'CPA', (102, 118))
57706	32932909	Cichorin D (1) was isolated as a white solid and the IR spectrum demonstrated the presence of a benzene ring (1580 and 1420 cm-1), hydroxyl (3390 cm-1), and carbonyl group (1630 cm-1) (see Experimental section).	('carbon', 'Chemical', 'MESH:D002244', (157, 163))	('3390 cm-1', 'Var', (141, 150))	('benzene ring', 'MPA', (96, 108))	('hydroxyl', 'MPA', (131, 139))	('benzene', 'Chemical', 'MESH:D001554', (96, 103))	('1630 cm-1', 'Var', (173, 182))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('1580', 'Var', (110, 114))
57709	32932909	The COSY correlations further confirmed that two protons viz., deltaH 7.62 (H-5) and 6.98 (H-6) were coupled together through ortho coupling (J = 8.0 Hz), while the two protons viz., deltaH 6.98 (H-6) and 6.82 (H-8) were coupled to each other via meta coupling (J = 2.6 Hz) as well as ortho coupling (J = 8.0 Hz).	('meta coupling', 'MPA', (247, 260))	('C', 'Chemical', 'MESH:D002244', (4, 5))	('deltaH', 'Var', (63, 69))
57713	32932909	The 13C NMR spectrum displayed signals for a ketone at deltaC 205.2 along with a saturated quaternary carbon at deltaC 76.5 and from these peaks, the proposed structure for this compound is one that possesses a 1,2-dihydronaphthalane skeleton.	('carbon', 'Chemical', 'MESH:D002244', (102, 108))	('signals', 'Reg', (31, 38))	('deltaC', 'Chemical', '-', (55, 61))	('ketone', 'Chemical', 'MESH:D007659', (45, 51))	('ketone', 'MPA', (45, 51))	('1,2-dihydronaphthalane', 'Chemical', '-', (211, 233))	('deltaC', 'Chemical', '-', (112, 118))	('13C', 'Chemical', 'MESH:C000615229', (4, 7))	('deltaC', 'Var', (55, 61))
57719	32932909	Furthermore, the AB olefin spin system protons at deltaH 7.37, d, J = 9.0 Hz and at 6.27 d, J = 9.0 Hz represent H-4 and H-3, respectively, of ring B, which is evident from HMBC correlations depicted in Figure 3.	('AB olefin spin system protons', 'MPA', (17, 46))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('C', 'Chemical', 'MESH:D002244', (176, 177))	('F', 'Chemical', 'MESH:D005461', (203, 204))	('AB olefin', 'Chemical', '-', (17, 26))	('deltaH 7.37', 'Var', (50, 61))
57741	32932909	In addition, the signal at deltaH 7.34 (H-4) is meta-coupled (J = 2.0 Hz) with the proton signal at deltaH 6.76 and thus this signal is assigned to H-2 based on the COSY correlation as well.	('C', 'Chemical', 'MESH:D002244', (165, 166))	('deltaH 7.34', 'Var', (27, 38))	('meta-coupled', 'MPA', (48, 60))
57791	32932909	While solid; [alpha]D25 = +11.2 (c 0.26, CH2Cl2); IR (KBr) vmax: 3410, 2950, 1600, 1420, 1000 cm-1; For 1H 13C NMR: see Table 1; ESI-MS (m/z): 227.2 [M + Na]+, C12H12NaO3; HRESIMS: m/z 205.0862 [M + H]: (calcd for C12H13O3, 205.0865).	('13C', 'Chemical', 'MESH:C000615229', (107, 110))	('CH2Cl2', 'Chemical', '-', (41, 47))	('C12H12NaO3', 'Chemical', '-', (160, 170))	('1H', 'Chemical', '-', (104, 106))	('m/z 205.0862 [M', 'Var', (181, 196))	('F', 'Chemical', 'MESH:D005461', (100, 101))	('C12H13O3', 'Var', (214, 222))	('C12H13O3', 'Chemical', '-', (214, 222))
57793	32932909	Yellow solid; IR (KBr) vmax: 1600, 1420, 1000 cm-1; For 1H 13C NMR: see Table 2; ESI-MS (m/z): 349.2 [M + Na]+, C19H18NaO5; HRESIMS: m/z 327.1238 [M + H]: (calcd for C19H19O5, 327.1232).	('C19H18NaO5', 'Chemical', '-', (112, 122))	('C19H18NaO5', 'Var', (112, 122))	('C19H19O5', 'Var', (166, 174))	('1H', 'Chemical', '-', (56, 58))	('C19H19O5', 'Chemical', '-', (166, 174))	('F', 'Chemical', 'MESH:D005461', (52, 53))	('13C', 'Chemical', 'MESH:C000615229', (59, 62))
57846	31186774	Fluoresence in situ hybridization (FISH) analysis with EWS break-apart kit revealed fusion of EWS gene (Fig.	('EWS', 'Gene', '2130', (94, 97))	('EWS', 'Gene', (55, 58))	('EWS', 'Gene', (94, 97))	('EWS', 'Gene', '2130', (55, 58))	('fusion', 'Var', (84, 90))
57855	31186774	Formalin-fixed, paraffin-embedded biopsy blocks from the specimen were analyzed for the detection of translocations involving the EWSR gene at 22q12.2.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('translocations', 'Var', (101, 115))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('EWS', 'Gene', '2130', (130, 133))	('EWS', 'Gene', (130, 133))
57863	31186774	These results confirm the presence EWSR1 gene translocations (Fig.	('EWSR1', 'Gene', (35, 40))	('gene translocations', 'Var', (41, 60))	('EWSR1', 'Gene', '2130', (35, 40))
58005	24293303	NF1 is commonly an autosomal dominant genetic disorder due to mutation of chromosome 17.	('autosomal dominant genetic disorder', 'Disease', 'MESH:D030342', (19, 54))	('autosomal dominant genetic disorder', 'Disease', (19, 54))	('NF', 'Phenotype', 'HP:0001067', (0, 2))	('mutation', 'Var', (62, 70))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))
58054	33719644	The aetiology of SFT is still unknown, while some molecular changes are thought to be related to tumour progression, such as changes to NGFI-A binding protein 2 (NAB2)-signal transducer and activator of transcription 6 (STAT6) fusion and tumour protein 53 (TP53).	('NAB2', 'Gene', (162, 166))	('tumour protein 53', 'Gene', (238, 255))	('NAB2', 'Gene', '4665', (162, 166))	('tumour protein 53', 'Gene', '7157', (238, 255))	('changes', 'Var', (125, 132))	('TP53', 'Gene', (257, 261))	('SFT', 'Disease', (17, 20))	('STAT6', 'Gene', (220, 225))	('NGFI-A binding protein 2', 'Gene', (136, 160))	('signal transducer and activator of transcription 6', 'Gene', '6778', (168, 218))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Disease', 'MESH:D009369', (238, 244))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('NGFI-A binding protein 2', 'Gene', '4665', (136, 160))	('TP53', 'Gene', '7157', (257, 261))	('tumour', 'Disease', (97, 103))	('tumour', 'Disease', (238, 244))	('STAT6', 'Gene', '6778', (220, 225))
58084	33719644	Although 18F-FDG PET/CT may be helpful in diagnosing MSFT, its diagnostic utility remains debatable due to its imperfect sensitivity.	('18F-FDG', 'Var', (9, 16))	('18F-FDG', 'Chemical', 'MESH:D019788', (9, 16))	('MSFT', 'Chemical', '-', (53, 57))	('MSFT', 'Disease', (53, 57))
58085	33719644	The criteria in some countries for distinguishing MSFT is as follows: (1) high cellularity and mitotic activity (mitotic index: > 4 mitotic figures in 10 high power fields); (2) pleomorphism; (3) haemorrhage; and (4) necrosis.	('mitotic activity', 'CPA', (95, 111))	('haemorrhage', 'Disease', (196, 207))	('pleomorphism', 'Var', (178, 190))	('necrosis', 'Disease', (217, 225))	('necrosis', 'Disease', 'MESH:D009336', (217, 225))	('haemorrhage', 'Disease', 'MESH:D006470', (196, 207))	('high cellularity', 'CPA', (74, 90))	('MSFT', 'Chemical', '-', (50, 54))	('MSFT', 'Disease', (50, 54))
58087	33719644	Lesions in the chest may cause respiratory symptoms, such as cough and chest pain.	('cough', 'Disease', 'MESH:D003371', (61, 66))	('respiratory symptoms', 'Disease', (31, 51))	('chest pain', 'Disease', 'MESH:D002637', (71, 81))	('cough', 'Phenotype', 'HP:0012735', (61, 66))	('chest pain', 'Disease', (71, 81))	('pain', 'Phenotype', 'HP:0012531', (77, 81))	('cough', 'Disease', (61, 66))	('respiratory symptoms', 'Phenotype', 'HP:0011947', (31, 51))	('cause', 'Reg', (25, 30))	('respiratory symptoms', 'Disease', 'MESH:D012818', (31, 51))	('chest pain', 'Phenotype', 'HP:0100749', (71, 81))	('Lesions', 'Var', (0, 7))
58097	33719644	SFT is often positive for STAT6, CD99, CD34, Bcl-2, and TP53; and negative for S-100, SMA, and EMA; and the Ki67 positive rate is often week, but is higher in the malignant lesions.	('positive', 'Reg', (13, 21))	('higher', 'Reg', (149, 155))	('malignant lesions', 'Disease', 'MESH:D009369', (163, 180))	('Bcl-2', 'Gene', (45, 50))	('CD34', 'Gene', (39, 43))	('TP53', 'Gene', '7157', (56, 60))	('Bcl-2', 'Gene', '596', (45, 50))	('CD34', 'Gene', '947', (39, 43))	('S-100', 'Gene', (79, 84))	('Ki67', 'Var', (108, 112))	('TP53', 'Gene', (56, 60))	('CD99', 'Gene', '4267', (33, 37))	('Ki67', 'Chemical', '-', (108, 112))	('malignant lesions', 'Disease', (163, 180))	('STAT6', 'Gene', (26, 31))	('S-100', 'Gene', '6271', (79, 84))	('STAT6', 'Gene', '6778', (26, 31))	('CD99', 'Gene', (33, 37))
58372	22961750	Following signed informed consent by patient, parent, or guardian, chemotherapy with vincristine and dactinomycin (VA) was begun according to the Grouping system used to indicate the presence of residual disease (Group II, microscopic tumor at the margins; or Group III, gross residual disease +- tumor-involved regional lymph nodes).	('vincristine', 'Chemical', 'MESH:D014750', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('patient', 'Species', '9606', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('microscopic', 'Var', (223, 234))	('VA', 'Chemical', '-', (115, 117))	('tumor', 'Disease', (235, 240))	('dactinomycin', 'Chemical', 'MESH:D003609', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', (297, 302))
58546	29892685	In fact, accumulating evidence suggested that morcellation worsens survival outcomes of patients affected by uterine confined sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('morcellation', 'Var', (46, 58))	('uterine confined', 'Phenotype', 'HP:0000139', (109, 125))	('patients', 'Species', '9606', (88, 96))	('survival outcomes', 'CPA', (67, 84))	('worsens', 'NegReg', (59, 66))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('sarcoma', 'Disease', (126, 133))
58643	24190483	For example, increased expression of MMP-9 has been found to correlate with osteosarcoma metastasis in patients and inhibitors of MMPs, such as TIMP-1 have been shown to inhibit invasiveness of osteosarcoma tumor cells in vitro.	('MMP-9', 'Gene', '4318', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('MMP-9', 'Gene', (37, 42))	('increased', 'PosReg', (13, 22))	('TIMP-1', 'Gene', (144, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('invasiveness of osteosarcoma tumor', 'Disease', (178, 212))	('osteosarcoma metastasis', 'Disease', 'MESH:D009362', (76, 99))	('inhibitors', 'Var', (116, 126))	('expression', 'MPA', (23, 33))	('inhibit', 'NegReg', (170, 177))	('osteosarcoma metastasis', 'Disease', (76, 99))	('MMPs', 'Gene', (130, 134))	('MMPs', 'Gene', '4312;4313;4314;4318', (130, 134))	('invasiveness of osteosarcoma tumor', 'Disease', 'MESH:D012516', (178, 212))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (194, 206))	('patients', 'Species', '9606', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('TIMP-1', 'Gene', '7076', (144, 150))
30929	24190483	In addition, lysine contributes to ECM stability as a natural inhibitor of plasmin-induced proteolysis.	('plasmin', 'Gene', (75, 82))	('lysine', 'Var', (13, 19))	('ECM', 'Gene', '22915', (35, 38))	('plasmin', 'Gene', '5340', (75, 82))	('ECM', 'Gene', (35, 38))	('lysine', 'Chemical', 'MESH:D008239', (13, 19))
58723	32629676	The sensitivity and specificity of qualitative features which showed significant difference between high- and low-grade sarcomas were as follows: 67.7% and 72.7% for hyperintensity on T1-weighted images; 74.2% and 72.7% for poorly-defined margin on T2-weighted images; 80.6% and 72.7% for poorly-defined margin on CE T1-weighted images; and 80.6% and 63.6% for peritumoral enhancement.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('tumoral', 'Disease', (365, 372))	('tumoral', 'Disease', 'MESH:D009369', (365, 372))	('hyperintensity', 'Var', (166, 180))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('sarcomas', 'Disease', (120, 128))	('poorly-defined', 'Var', (224, 238))	('poorly-defined', 'Var', (289, 303))	('men', 'Species', '9606', (380, 383))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
58727	32629676	In texture features based on GLCM, CE T1 difference variance and CE T1 contrast demonstrated significant differences, which were higher in high-grade than in low-grade sarcomas (.239 +- .086 vs .175 +- .064, P = .031; .430 +- .130 vs .354 +- .162, P = .027).	('sarcomas', 'Disease', 'MESH:D012509', (168, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('sarcomas', 'Disease', (168, 176))	('higher', 'PosReg', (129, 135))	('GLCM', 'Chemical', '-', (29, 33))	('.239 +- .086', 'Var', (178, 190))
58791	30538569	Patients with histologically confirmed Ewing sarcoma (EWS, 9260/3), PNET (9364/3) or Askin tumor (9365/3) according to the International Classification of Disease for Oncology, third revision were eligible for the study.	('9365/3', 'Var', (98, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('EWS', 'Gene', '2130', (54, 57))	('EWS', 'Gene', (54, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('Oncology', 'Phenotype', 'HP:0002664', (167, 175))	('PNET', 'Disease', (68, 72))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Askin tumor', 'Disease', 'MESH:C563168', (85, 96))	('Askin tumor', 'Disease', (85, 96))	('PNET', 'Phenotype', 'HP:0030065', (68, 72))	('Ewing sarcoma', 'Disease', (39, 52))
58896	30249211	We additionally found that at least focal hyalinization was present in 93% of post-treatment samples and that patients whose tumors demonstrated > 5% hyalinization following completion of neoadjuvant radiation therapy had better 3-year recurrence-free survival and a trend towards improved overall survival, suggesting that hyalinization could be used as a surrogate for outcomes.	('improved', 'PosReg', (281, 289))	('hyalinization', 'Var', (150, 163))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('3-year recurrence-free survival', 'CPA', (229, 260))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('overall survival', 'CPA', (290, 306))	('better', 'PosReg', (222, 228))	('patients', 'Species', '9606', (110, 118))
58929	30249211	Additional genomic analyses may also be performed as sarcomas are rich in copy number alterations which have been correlated with immunotherapy response in melanoma.	('copy number alterations', 'Var', (74, 97))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcomas', 'Disease', (53, 61))
58949	30249211	Analysis of copy number alterations also identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade, particularly relevant in UPS and DDLPS where copy number alterations (particularly losses) are much more common relevant to point mutations.	('copy number', 'Var', (71, 82))	('PD-1', 'Gene', '5133', (119, 123))	('CTLA-4', 'Gene', (108, 114))	('UPS', 'Disease', (159, 162))	('DDLPS', 'Disease', (167, 172))	('loss', 'NegReg', (83, 87))	('CTLA-4', 'Gene', '1493', (108, 114))	('PD-1', 'Gene', (119, 123))
59053	29416348	The ethmoid sinus and frontal sinus were filled with high T2 lesions, arousing our suspicion of secondary sinusitis due to the tumor (Figure 1C and D).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('high T2 lesions', 'Var', (53, 68))	('secondary sinusitis', 'Disease', (96, 115))	('secondary sinusitis', 'Disease', 'MESH:D012852', (96, 115))	('sinusitis', 'Phenotype', 'HP:0000246', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
59113	28777778	Specifically, the dysregulation of recombination signal binding protein for Jk (RBP-Jk), a Notch pathway component and transcriptional regulator, has proven to be essential in the switch from latency to lytic reactivation.	('RBP-Jk', 'Gene', (80, 86))	('dysregulation', 'Var', (18, 31))	('Notch', 'Gene', (91, 96))	('Notch', 'Gene', '31293', (91, 96))
59120	28777778	The glycoprotein gB interacts with the cellular receptor integrin alpha3beta1 to mediate viral entry, while K8.1, a protein commonly used as a marker of viral reactivation, interacts with host cells by binding heparan sulfate-like moieties.	('viral', 'CPA', (89, 94))	('interacts', 'Interaction', (173, 182))	('binding', 'Interaction', (202, 209))	('heparan sulfate', 'Chemical', 'MESH:D006497', (210, 225))	('K8.1', 'Var', (108, 112))	('heparan sulfate-like', 'Protein', (210, 230))	('interacts', 'Interaction', (20, 29))	('glycoprotein', 'Protein', (4, 16))
59129	28777778	Interestingly, 81 consensus and additional non-consensus RBP-Jk DNA binding sites have been identified within the KSHV genome (Lukac Lab, Unpublished observations), suggesting that KSHV might manipulate the host Notch transcriptional pathway to regulate the expression of its own genes.	('KSHV', 'Species', '37296', (181, 185))	('KSHV', 'Var', (181, 185))	('regulate', 'Reg', (245, 253))	('Notch', 'Gene', (212, 217))	('KS', 'Phenotype', 'HP:0100726', (181, 183))	('expression', 'MPA', (258, 268))	('manipulate', 'Reg', (192, 202))	('Notch', 'Gene', '31293', (212, 217))	('KS', 'Phenotype', 'HP:0100726', (114, 116))	('KSHV', 'Species', '37296', (114, 118))
59143	28777778	It is evident that the dysregulation of the Notch signaling pathway, specifically through viral use of the RBP-Jk component, is essential for successful KSHV infection.	('dysregulation', 'Var', (23, 36))	('Notch', 'Gene', (44, 49))	('KSHV infection', 'Disease', 'MESH:C537372', (153, 167))	('Notch', 'Gene', '31293', (44, 49))	('KSHV infection', 'Disease', (153, 167))	('KS', 'Phenotype', 'HP:0100726', (153, 155))
59160	28777778	As previously mentioned, KSHV is the causative agent of two human cancers, Kaposi's sarcoma and Multicentric Castleman's disease (MCD), and a lymphoproliferation, primary effusion lymphoma (PEL).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (163, 188))	('KSHV', 'Var', (25, 29))	("Multicentric Castleman's disease", 'Disease', (96, 128))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('MCD', 'Disease', 'MESH:D012514', (130, 133))	('KS', 'Phenotype', 'HP:0100726', (25, 27))	('MCD', 'Disease', (130, 133))	('PEL', 'Phenotype', 'HP:0030069', (190, 193))	("Multicentric Castleman's disease", 'Disease', 'MESH:C537372', (96, 128))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (75, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (163, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (180, 188))	('KSHV', 'Species', '37296', (25, 29))	('men', 'Species', '9606', (14, 17))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (75, 91))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('primary effusion lymphoma', 'Disease', (163, 188))	('cancers', 'Disease', (66, 73))	("Kaposi's sarcoma", 'Disease', (75, 91))	('human', 'Species', '9606', (60, 65))
59176	28777778	KSHV also causes KS, the disease in which the virus was discovered and identified as a separate entity from HIV.	('KS', 'Phenotype', 'HP:0100726', (17, 19))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('HIV', 'Species', '12721', (108, 111))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('causes', 'Reg', (10, 16))
59196	28777778	While the majority of infected cells within a KS tumor are latently infected, the expression of viral lytic genes promotes KS development (reviewed in).	('KS', 'Phenotype', 'HP:0100726', (123, 125))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('KS tumor', 'Disease', 'MESH:D009369', (46, 54))	('KS tumor', 'Disease', (46, 54))	('expression', 'Var', (82, 92))	('promotes', 'PosReg', (114, 122))	('men', 'Species', '9606', (133, 136))	('KS', 'Phenotype', 'HP:0100726', (46, 48))	('KS development', 'CPA', (123, 137))
59203	28777778	Transcripts from this region include: LANA (latency-associated nuclear antigen) encoded by ORF73, v-Cyclin encoded by ORF72, v-FLIP encoded by ORF71, Kaposin encoded by K12, and 12 pre-microRNAs.	('ORF72', 'Gene', (118, 123))	('ORF71', 'Var', (143, 148))	('K12', 'Gene', (169, 172))	('Cyclin', 'Gene', '5111', (100, 106))	('LANA', 'Gene', (38, 42))	('K12', 'Gene', '3859', (169, 172))	('ORF73', 'Gene', (91, 96))	('LANA', 'Gene', '4961527', (38, 42))	('Cyclin', 'Gene', (100, 106))
59208	28777778	LANA's interaction with RBP-Jk represses the transactivation of the Rta promoter, as mutations to RBP-Jk binding sites within the Rta promoter induce both a decrease in Rta expression and KSHV genomes.	('KS', 'Phenotype', 'HP:0100726', (188, 190))	('transactivation', 'MPA', (45, 60))	('LANA', 'Gene', '4961527', (0, 4))	('Rta', 'Gene', (169, 172))	('decrease', 'NegReg', (157, 165))	('Rta', 'Gene', '23543', (169, 172))	('LANA', 'Gene', (0, 4))	('mutations', 'Var', (85, 94))	('Rta', 'Gene', (68, 71))	('RBP-Jk', 'Gene', (98, 104))	('KSHV', 'Species', '37296', (188, 192))	('Rta', 'Gene', (130, 133))	('Rta', 'Gene', '23543', (68, 71))	('Rta', 'Gene', '23543', (130, 133))
59210	28777778	As was observed when LANA expression was not properly induced in de novo infection, LANA mutants with defective RBP-Jk interactions fail to support episome persistence.	('LANA', 'Gene', (84, 88))	('episome persistence', 'MPA', (148, 167))	('infection', 'Disease', (73, 82))	('LANA', 'Gene', '4961527', (84, 88))	('infection', 'Disease', 'MESH:D007239', (73, 82))	('LANA', 'Gene', (21, 25))	('mutants', 'Var', (89, 96))	('LANA', 'Gene', '4961527', (21, 25))	('interactions', 'Interaction', (119, 131))
59223	28777778	Furthermore, the phorbol ester, TPA, reactivates KSHV through the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway.	('ERK', 'Gene', (145, 148))	('reactivates', 'Var', (37, 48))	('KSHV', 'Species', '37296', (49, 53))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('KSHV', 'Gene', (49, 53))	('ERK', 'Gene', '5594', (145, 148))	('TPA', 'Chemical', '-', (32, 35))	('phorbol ester', 'Chemical', 'MESH:D010703', (17, 30))
59225	28777778	Presumably, Rta is a key pathogenic factor, since its expression leads to the release of mature virions with the potential to infect endothelial cells and cause KS.	('KS', 'Phenotype', 'HP:0100726', (161, 163))	('release of mature virions', 'MPA', (78, 103))	('expression', 'Var', (54, 64))	('leads to', 'Reg', (65, 73))	('Rta', 'Gene', (12, 15))	('Rta', 'Gene', '23543', (12, 15))	('infect', 'Reg', (126, 132))	('cause', 'Reg', (155, 160))
59226	28777778	The immediate early genes include: Rta, ORF45, K8alpha, K8.2, K4.1, K4, ORF48, ORF29b, K3, and ORF70.	('Rta', 'Gene', (35, 38))	('Rta', 'Gene', '23543', (35, 38))	('K8alpha', 'Var', (47, 54))	('ORF45', 'Gene', (40, 45))	('ORF70', 'Gene', (95, 100))	('K4.1', 'Var', (62, 66))	('ORF29b', 'Gene', (79, 85))	('ORF48', 'Gene', (72, 77))
59229	28777778	Studies from our lab indicate that the presence of Mta enhances reactivation by Rta and that the expression of Mta is tightly associated with complete viral reactivation.	('Rta', 'Gene', (80, 83))	('presence', 'Var', (39, 47))	('reactivation', 'MPA', (64, 76))	('Rta', 'Gene', '23543', (80, 83))	('Mta', 'Gene', (51, 54))	('enhances', 'PosReg', (55, 63))
59230	28777778	Furthermore, the knockout of Mta has been shown to disrupt the expression of lytic genes ORF59, K-bZIP, and K8.1, and decrease the amount of virus produced.	('amount of virus produced', 'MPA', (131, 155))	('Mta', 'Gene', (29, 32))	('ORF59', 'Gene', '4961492', (89, 94))	('disrupt', 'NegReg', (51, 58))	('expression', 'MPA', (63, 73))	('knockout', 'Var', (17, 25))	('K-bZIP', 'Gene', (96, 102))	('K8.1', 'Gene', (108, 112))	('decrease', 'NegReg', (118, 126))	('ORF59', 'Gene', (89, 94))
59235	28777778	Conversely, K-bZIP has also been shown to repress Rta-mediated transactivation, suggesting that cooperation is promoter-specific.	('Rta', 'Gene', '23543', (50, 53))	('K-bZIP', 'Var', (12, 18))	('Rta', 'Gene', (50, 53))
59256	28777778	Gel filtration chromatography proved that these complexes include Rta tetramers, and Rta mutants that exclusively form tetramers retain WT transactivation and reactivation functions.	('WT transactivation', 'MPA', (136, 154))	('Rta', 'Gene', '23543', (66, 69))	('Rta', 'Gene', (85, 88))	('Rta', 'Gene', '23543', (85, 88))	('mutants', 'Var', (89, 96))	('Rta', 'Gene', (66, 69))	('reactivation functions', 'MPA', (159, 181))
59257	28777778	Because the deletion of the leucine rich region of Rta prevented Rta STAD from competing with full length Rta for transactivation, this region was implicated in participating in Rta:Rta interactions.	('deletion', 'Var', (12, 20))	('Rta', 'Gene', (182, 185))	('Rta', 'Gene', '23543', (178, 181))	('transactivation', 'MPA', (114, 129))	('leucine', 'Chemical', 'MESH:D007930', (28, 35))	('Rta', 'Gene', '23543', (65, 68))	('Rta', 'Gene', '23543', (51, 54))	('Rta', 'Gene', (65, 68))	('Rta', 'Gene', (178, 181))	('Rta', 'Gene', (106, 109))	('interactions', 'Interaction', (186, 198))	('prevented', 'NegReg', (55, 64))	('Rta', 'Gene', '23543', (182, 185))	('Rta', 'Gene', (51, 54))	('Rta', 'Gene', '23543', (106, 109))
59259	28777778	Although the mutant containing amino acids 1-272 contained the leucine rich region, only truncated Rta containing amino acids 1-414 was precipitated by WT Rta, indicating that the leucine rich region alone was not sufficient for Rta:Rta interactions.	('Rta', 'Gene', (155, 158))	('Rta', 'Gene', '23543', (155, 158))	('amino acids', 'Var', (31, 42))	('Rta', 'Gene', (229, 232))	('leucine rich region', 'MPA', (63, 82))	('interactions', 'Interaction', (237, 249))	('leucine', 'Chemical', 'MESH:D007930', (63, 70))	('Rta', 'Gene', (99, 102))	('Rta', 'Gene', '23543', (229, 232))	('Rta', 'Gene', '23543', (99, 102))	('leucine', 'Chemical', 'MESH:D007930', (180, 187))	('Rta', 'Gene', (233, 236))	('Rta', 'Gene', '23543', (233, 236))
59265	28777778	However, unlike NICD's stable interaction with a single domain of RBP-Jk, two independent domains of RBP-Jk, amino acids 1-180 and 179-500 of RBP-Jk, were each necessary and sufficient to bind to Rta.	('RBP-Jk', 'Gene', (142, 148))	('Rta', 'Gene', '23543', (196, 199))	('amino acids 1-180', 'Var', (109, 126))	('bind', 'Interaction', (188, 192))	('Rta', 'Gene', (196, 199))
59271	28777778	Furthermore, this region contains the leucine rich repeat region, which, when deleted, severely compromises Rta:RBP-Jk complex formation, indicating that the entirety of this region is necessary for Rta:RBP-Jk interactions.	('Rta', 'Gene', (108, 111))	('Rta', 'Gene', '23543', (199, 202))	('Rta', 'Gene', '23543', (108, 111))	('leucine', 'Chemical', 'MESH:D007930', (38, 45))	('interactions', 'Interaction', (210, 222))	('deleted', 'Var', (78, 85))	('compromises', 'NegReg', (96, 107))	('Rta', 'Gene', (199, 202))
59273	28777778	Mutations made within the 118-207 amino acid region of Rta rendered Rta unable to degrade both nuclear and cytoplasmic IRF7, indicating that this region is essential for this function, while amino acids 401-500 contribute to the interaction with ORF59 and viral replication.	('Rta', 'Gene', (55, 58))	('Rta', 'Gene', '23543', (55, 58))	('contribute', 'Reg', (211, 221))	('degrade', 'NegReg', (82, 89))	('unable', 'NegReg', (72, 78))	('ORF59', 'Gene', (246, 251))	('Mutations', 'Var', (0, 9))	('Rta', 'Gene', (68, 71))	('IRF7', 'Gene', (119, 123))	('interaction', 'Interaction', (229, 240))	('ORF59', 'Gene', '4961492', (246, 251))	('IRF7', 'Gene', '3665', (119, 123))	('Rta', 'Gene', '23543', (68, 71))
59292	28777778	Furthermore, transactivation deficient Rta (Rta STAD) is sufficient to rescue transactivation by RBP-Jk fused to a VP16 activation domain, and stimulates RBP-Jk DNA binding.	('Rta', 'Gene', '23543', (44, 47))	('fused', 'Var', (104, 109))	('RBP-Jk', 'Gene', (97, 103))	('Rta', 'Gene', (44, 47))	('Rta', 'Gene', (39, 42))	('stimulates', 'PosReg', (143, 153))	('rescue', 'PosReg', (71, 77))	('deficient Rta', 'Disease', (29, 42))	('deficient Rta', 'Disease', 'MESH:D000141', (29, 42))	('Rta', 'Gene', '23543', (39, 42))	('transactivation', 'MPA', (78, 93))	('RBP-Jk DNA binding', 'Interaction', (154, 172))
59298	28777778	Rta mutated to ensure tetramer formation was able to activate the transcription of the K-bZIP viral promoter at levels similar to that of wild-type Rta.	('mutated', 'Var', (4, 11))	('Rta', 'Gene', (148, 151))	('Rta', 'Gene', '23543', (148, 151))	('transcription', 'MPA', (66, 79))	('Rta', 'Gene', (0, 3))	('activate', 'PosReg', (53, 61))	('Rta', 'Gene', '23543', (0, 3))
59303	28777778	Indeed, a DNA binding mutant of Rta has been described that retains its ability to bind RBP-Jk but is reactivation deficient.	('bind', 'Interaction', (83, 87))	('Rta', 'Gene', (32, 35))	('RBP-Jk', 'Protein', (88, 94))	('Rta', 'Gene', '23543', (32, 35))	('ability', 'MPA', (72, 79))	('mutant', 'Var', (22, 28))	('reactivation', 'MPA', (102, 114))
59310	28777778	Furthermore, Rta mutants were unable to inhibit the accumulation of IRF7 in 293 cells.	('inhibit', 'NegReg', (40, 47))	('Rta', 'Gene', (13, 16))	('IRF7', 'Gene', (68, 72))	('accumulation', 'MPA', (52, 64))	('IRF7', 'Gene', '3665', (68, 72))	('Rta', 'Gene', '23543', (13, 16))	('mutants', 'Var', (17, 24))	('293 cells', 'CellLine', 'CVCL:0045', (76, 85))
59319	28777778	The effects of Notch pathway dysregulation were first observed in female Drosophila containing a mutant Notch allele.	('Notch', 'Gene', '31293', (104, 109))	('Notch', 'Gene', '31293', (15, 20))	('mutant', 'Var', (97, 103))	('Notch', 'Gene', (104, 109))	('Notch', 'Gene', (15, 20))	('Drosophila', 'Species', '7227', (73, 83))
59339	28777778	Activating mutations within this domain were discovered in T-ALL, resulting in constitutively active Notch.	('Notch', 'Gene', '31293', (101, 106))	('mutations', 'Var', (11, 20))	('Notch', 'Gene', (101, 106))	('constitutively', 'MPA', (79, 93))
59349	28777778	It is also of note that the Notch RAM domain contains the PhiPPhiW motif, which is conserved in the EBV transactivator EBNA2, but not in Rta.	('PhiPPhiW', 'Var', (58, 66))	('EBNA2', 'Gene', '17494192', (119, 124))	('Notch', 'Gene', (28, 33))	('EBNA2', 'Gene', (119, 124))	('Rta', 'Gene', (137, 140))	('Notch', 'Gene', '31293', (28, 33))	('Rta', 'Gene', '23543', (137, 140))	('EBV', 'Species', '10376', (100, 103))
59351	28777778	Numerous studies have discovered mutations within this domain in cancer derived cells, all of which have been found to increase the stability of Notch.	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Notch', 'Gene', (145, 150))	('stability', 'MPA', (132, 141))	('increase', 'PosReg', (119, 127))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('Notch', 'Gene', '31293', (145, 150))
59405	28777778	Using immunofluorescence of both Rta and another viral protein LANA, coupled with fluorescence-activated cell sorting (FACS) analysis and extracellular viral DNA amplification via PCR, it was shown that expression of ectopic NICD 1 is sufficient to induce viral reactivation in infected B cells.	('NICD 1', 'Gene', (225, 231))	('ectopic', 'Var', (217, 224))	('Rta', 'Gene', (33, 36))	('LANA', 'Gene', (63, 67))	('Rta', 'Gene', '23543', (33, 36))	('viral reactivation', 'MPA', (256, 274))	('induce', 'Reg', (249, 255))	('LANA', 'Gene', '4961527', (63, 67))
59412	28777778	In that work, we inhibited Notch through the use of DAPT, siRNAs, and the ectopic expression of a dominant negative mastermind mutant, all of which decreased the amount of infectious virus produced in response to HDACi or ectopic Rta (Lukac Lab, Unpublished).	('mutant', 'Var', (127, 133))	('Rta', 'Gene', '23543', (230, 233))	('ectopic', 'Var', (222, 229))	('decreased', 'NegReg', (148, 157))	('Notch', 'Gene', (27, 32))	('amount', 'MPA', (162, 168))	('DAPT', 'Chemical', '-', (52, 56))	('Notch', 'Gene', '31293', (27, 32))	('HD', 'Disease', 'MESH:D006816', (213, 215))	('Rta', 'Gene', (230, 233))
59430	24204904	Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression.	('SNF5', 'Gene', (189, 193))	('function', 'MPA', (34, 42))	('increased expression of fibroblast', 'Phenotype', 'HP:0410157', (59, 93))	('FGFR', 'Gene', (237, 241))	('SNF5', 'Gene', (29, 33))	('expression', 'MPA', (69, 79))	('FGFRs', 'Gene', (119, 124))	('primary tumors', 'Disease', (148, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('repression', 'NegReg', (223, 233))	('re-expression', 'Var', (172, 185))	('increased', 'PosReg', (59, 68))	('primary tumors', 'Disease', 'MESH:D009369', (148, 162))	('loss', 'NegReg', (21, 25))	('expression', 'MPA', (242, 252))
59432	24204904	In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model.	('NVP-BGJ398', 'Var', (24, 34))	('BGJ398', 'Chemical', 'MESH:C568950', (28, 34))	('murine', 'Species', '10090', (88, 94))	('blocks', 'NegReg', (64, 70))
59434	24204904	MRTs are characterized by loss of function of the tumor suppressor SNF5 (also known as SMARCB1, INI1 or BAF47) due to inactivating mutations or deletions of the SNF5 gene.	('SMARCB1', 'Gene', (87, 94))	('deletions', 'Var', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('BAF47', 'Gene', (104, 109))	('BAF47', 'Gene', '6598', (104, 109))	('inactivating mutations', 'Var', (118, 140))	('SNF5', 'Gene', (67, 71))	('INI1', 'Gene', (96, 100))	('MRTs', 'Disease', (0, 4))	('INI1', 'Gene', '6598', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SNF5', 'Gene', (161, 165))	('loss of function', 'NegReg', (26, 42))	('SMARCB1', 'Gene', '6598', (87, 94))	('tumor', 'Disease', (50, 55))
59438	24204904	Thus, abrogation of SNF5 function leads to hyperphosphorylation of pRb and E2F-mediated cell cycle activation.	('E2F-mediated cell cycle activation', 'CPA', (75, 109))	('SNF5', 'Gene', (20, 24))	('function', 'MPA', (25, 33))	('pRb', 'Gene', '5925', (67, 70))	('pRb', 'Gene', (67, 70))	('hyperphosphorylation', 'MPA', (43, 63))	('abrogation', 'Var', (6, 16))
59439	24204904	In addition, inactivation of SNF5 results in the upregulation of multiple oncogenic pathways, such as Hedgehog and Aurora A signaling and the induction of the Polycomb gene EZH2 .	('Hedgehog', 'MPA', (102, 110))	('inactivation', 'Var', (13, 25))	('oncogenic pathways', 'Pathway', (74, 92))	('Aurora A', 'Gene', (115, 123))	('Aurora A', 'Gene', '6790', (115, 123))	('SNF5', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (173, 177))	('upregulation', 'PosReg', (49, 61))	('EZH2', 'Gene', (173, 177))
59440	24204904	To this end, we have utilized the Cancer Cell Line Encyclopedia (CCLE), a collection of almost 1000 cancer cell lines of multiple tumor types comprehensively annotated in terms of genome-scale mRNA expression, gene copy number alterations and gene mutations (23), and for which pharmacological profiles for over 2000 compounds with defined modes of action (MoAs) have been generated.	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (34, 63))	('mutations', 'Var', (248, 257))	('multiple tumor', 'Disease', 'MESH:D009369', (121, 135))	('gene', 'Gene', (243, 247))	('CCLE', 'Chemical', '-', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer Cell Line Encyclopedia', 'Disease', (34, 63))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('multiple tumor', 'Disease', (121, 135))	('mRNA expression', 'MPA', (193, 208))
59441	24204904	By means of an unbiased computational approach designed to identify chemical vulnerabilities that are selectively active in a defined subset of cell lines, we have found that FGFR inhibitors are significantly more active in MRT cell lines compared to the rest of soft tissue sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (275, 283))	('MRT', 'Disease', (224, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('FGFR', 'Gene', (175, 179))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (263, 282))	('more', 'PosReg', (209, 213))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (263, 283))	('sarcomas', 'Disease', (275, 283))	('active', 'MPA', (214, 220))	('inhibitors', 'Var', (180, 190))	('sarcomas', 'Disease', 'MESH:D012509', (275, 283))
59442	24204904	In particular, MRT lines showed sensitivity to NVP-BGJ398, a novel and highly selective pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer indications.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('BGJ398', 'Chemical', 'MESH:C568950', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('sensitivity', 'Reg', (32, 43))	('cancer', 'Disease', (157, 163))	('NVP-BGJ398', 'Var', (47, 57))
59444	24204904	Moreover, de-regulated FGF/FGFR activity due to genetic alterations occurring in various members of this family has been linked to several diseases including cancer.	('FGF/FGFR', 'Protein', (23, 31))	('de-regulated', 'NegReg', (10, 22))	('linked', 'Reg', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('activity', 'MPA', (32, 40))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('genetic alterations', 'Var', (48, 67))
59455	24204904	Probesets analyzed were 211535_s_at for FGFR1, 208228_s_at for FGFR2 and 212167_s_at for SNF5.	('211535_s_at', 'Var', (24, 35))	('212167_s_at', 'Var', (73, 84))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('FGFR2', 'Gene', '2263', (63, 68))	('FGFR2', 'Gene', (63, 68))	('208228_s_at', 'Var', (47, 58))
59457	24204904	Proteins were visualized using antibodies to total-ERK1/2 (#9102, Cell Signaling), phospho-ERK1/2 (#9101, Cell Signaling), phospho-Fibroblast growth factor receptor substrate 2 (phospho-FRS2) (#3861, Cell Signaling), SNF5 (#A301-087A, Bethyl), FGFR1 ((#sc-57132, Santa Cruz), FGFR2 ((#sc-122, Santa Cruz), appropriate horseradish peroxidase-labeled secondary antibodies (Amersham and Jackson ImmunoResearch) and a chemiluminescence detection reagent (Pierce).	('FRS2', 'Gene', '10818', (186, 190))	('#A301-087A', 'Var', (223, 233))	('FGFR2', 'Gene', (276, 281))	('FGFR2', 'Gene', '2263', (276, 281))	('FRS2', 'Gene', (186, 190))	('(#sc-122', 'Var', (283, 291))	('FGFR1', 'Gene', (244, 249))	('horseradish', 'Species', '3704', (318, 329))	('FGFR1', 'Gene', '2260', (244, 249))
59458	24204904	Anti-beta-tubulin (T4026, Sigma) or anti-alpha-actinin ((#05-384, Millipore) was used as a loading control.	('alpha-actinin', 'Gene', (41, 54))	('alpha-actinin', 'Gene', '87', (41, 54))	('T4026', 'Var', (19, 24))
59466	24204904	Primers sequences used to monitor enrichment of FGFR2 promoter DNA were f-AGGCTGAAAGCACACAGTTG and r-CCTGGTCTCAGTGGGAGTTT (-9133), f-TGCGAAGAAAAGAGACCTCA and r-AAGGGCAGAAAAGCCAGTAA (-2420), f- AACTTAAGCACGGCTGCTC and r- CAACTGCACACCAAGCTGTA (-1021), f- AACATTTCCAAGTGGCTTCC and r-ACTTTAAAATGCGCCTGCTT (-462), f-CTCTGAGCCTTCGCAACTC and r- AAGAAAGGACTCAGGCTTGG (+207), f- AGGACCACTCTTCTGCGTTT and r- GATTACCTTGAATGGCAACG (+397), f-TCTGTGGCTGCATAGGTGAT and r-TAGCAGAGGCAGAACTTCCA (+639), f-CGAACTGGACCGACTTTTTC and r-AATGAGCGCGCAAGTTAGA (+1108), f-TGCTTTTGTAGTTGCCCTTG and r-CTCAGATACGTGCAGCCACT (+4118).	('FGFR2', 'Gene', (48, 53))	('FGFR2', 'Gene', '2263', (48, 53))	('+397', 'Var', (420, 424))	('+1108', 'Var', (535, 540))	('AT', 'Disease', 'None', (256, 258))	('AT', 'Disease', 'None', (288, 290))	('AT', 'Disease', 'None', (447, 449))	('AT', 'Disease', 'None', (409, 411))	('+639', 'Var', (478, 482))	('AT', 'Disease', 'None', (515, 517))	('AT', 'Disease', 'None', (577, 579))	('AT', 'Disease', 'None', (440, 442))	('AT', 'Disease', 'None', (399, 401))
59477	24204904	Primary mouse MRT samples were derived from SNF5-heterozygous mice, which develop tumors upon spontaneous inactivation of the functional allele.	('inactivation', 'Var', (106, 118))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('mice', 'Species', '10090', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mouse', 'Species', '10090', (8, 13))
59484	24204904	Specifically, we performed an unbiased selectivity analysis of small molecule inhibitors among a panel of 17 soft tissue cancer lines present in the CCLE, including three lines of the MRT subtype - G401, G402 and A204.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('A204', 'Var', (213, 217))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CCLE', 'Chemical', '-', (149, 153))	('soft tissue cancer', 'Phenotype', 'HP:0031459', (109, 127))	('cancer', 'Disease', (121, 127))	('G402', 'Var', (204, 208))
59490	24204904	In addition to the high-throughput analysis, we tested FGFR-dependence of the three MRT lines using NVP-BGJ398 in manual colorimetric proliferation assays and found that NVP-BGJ398 impaired proliferation of G402 cells with an IC50 of 249.9 nM.	('BGJ398', 'Chemical', 'MESH:C568950', (104, 110))	('impaired', 'NegReg', (181, 189))	('proliferation', 'CPA', (190, 203))	('tested', 'Reg', (48, 54))	('NVP-BGJ398', 'Var', (170, 180))	('BGJ398', 'Chemical', 'MESH:C568950', (174, 180))
59491	24204904	In G401 and A204 cells, treatment with NVP-BGJ398 induced a strong growth inhibition with IC50 values of 15.0 nM and 40.5 nM, respectively (Fig.	('NVP-BGJ398', 'Var', (39, 49))	('growth inhibition', 'CPA', (67, 84))	('BGJ398', 'Chemical', 'MESH:C568950', (43, 49))
59494	24204904	However, analysis of Affymetrix transcript expression data revealed that within the CCLE dataset, A204 and G402 were among the lines with the highest expression levels of FGFR1 and the G401 line displayed high levels of FGFR2 (Fig.	('FGFR2', 'Gene', (220, 225))	('FGFR2', 'Gene', '2263', (220, 225))	('G401', 'Var', (185, 189))	('FGFR1', 'Gene', (171, 176))	('CCLE', 'Chemical', '-', (84, 88))	('FGFR1', 'Gene', '2260', (171, 176))	('A204', 'Var', (98, 102))	('G402', 'Var', (107, 111))	('expression levels', 'MPA', (150, 167))
59498	24204904	MRTs are characterized by loss of the tumor suppressor SNF5, a component of the SWI/SNF complex, which we confirmed in the three rhabdoid cell lines A204, G401 and G402 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('loss of the tumor', 'Disease', 'MESH:D009369', (26, 43))	('SNF5', 'Gene', (55, 59))	('rhabdoid', 'Disease', 'MESH:D018335', (129, 137))	('G402', 'Var', (164, 168))	('loss of the tumor', 'Disease', (26, 43))	('G401', 'Var', (155, 159))	('rhabdoid', 'Disease', (129, 137))	('MRTs', 'Disease', (0, 4))
59499	24204904	In both G401 and G402 we found that re-expression of SNF5 abrogated elevated protein expression of FGFR2 and FGFR1, respectively, which was paralleled by a decrease in mRNA levels (Fig.	('abrogated', 'NegReg', (58, 67))	('G402', 'Var', (17, 21))	('FGFR1', 'Gene', (109, 114))	('re-expression', 'Var', (36, 49))	('FGFR2', 'Gene', '2263', (99, 104))	('FGFR1', 'Gene', '2260', (109, 114))	('elevated', 'PosReg', (68, 76))	('SNF5', 'Gene', (53, 57))	('protein expression', 'MPA', (77, 95))	('G401', 'Var', (8, 12))	('decrease', 'NegReg', (156, 164))	('mRNA levels', 'MPA', (168, 179))	('FGFR2', 'Gene', (99, 104))
59503	24204904	Re-expression of SNF5 causes cell cycle arrest associated with activation of p16INK4A and inhibition of the CDK4/RB/E2F pathway.	('CDK4', 'Gene', '1019', (108, 112))	('inhibition', 'NegReg', (90, 100))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (29, 46))	('p16INK4A', 'Gene', (77, 85))	('Re-expression', 'Var', (0, 13))	('cell cycle arrest', 'CPA', (29, 46))	('RB', 'Disease', 'MESH:D012175', (113, 115))	('p16INK4A', 'Gene', '1029', (77, 85))	('CDK4', 'Gene', (108, 112))	('SNF5', 'Gene', (17, 21))	('activation', 'PosReg', (63, 73))
59507	24204904	We tested the effect of siRNA-mediated SNF5-knockdown in a panel of non-MRT sarcoma cell lines with low or moderate FGFR1 and FGFR2 levels, as well as in BJ cells, a non-immortalized human fibroblast line, previously reported to have a functional SWI/SNF complex.	('FGFR2', 'Gene', '2263', (126, 131))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('BJ', 'CellLine', 'CVCL:6573', (154, 156))	('FGFR1', 'Gene', (116, 121))	('FGFR1', 'Gene', '2260', (116, 121))	('tested', 'Reg', (3, 9))	('sarcoma', 'Disease', (76, 83))	('human', 'Species', '9606', (183, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('low', 'NegReg', (100, 103))	('SNF5-knockdown', 'Var', (39, 53))	('SNF5-knockdown', 'Gene', (39, 53))	('FGFR2', 'Gene', (126, 131))
59509	24204904	The transcriptional induction of FGFR2 upon SNF5 knockdown was paralleled by an increase in FGFR2 protein levels (Fig.	('transcriptional', 'MPA', (4, 19))	('knockdown', 'Var', (49, 58))	('increase', 'PosReg', (80, 88))	('protein levels', 'MPA', (98, 112))	('FGFR2', 'Gene', (33, 38))	('SNF5', 'Gene', (44, 48))	('FGFR2', 'Gene', (92, 97))	('FGFR2', 'Gene', '2263', (92, 97))	('FGFR2', 'Gene', '2263', (33, 38))
59510	24204904	Since SNF5 is a core component of the SWI/SNF chromatin remodeling complex, we tested whether inhibition of SWI/SNF function by knockdown of the ATPase core subunit BRG1 would similarly affect FGFR2 expression in BJ cells and found that loss of BRG1 function also led to induction of FGFR2 (Fig.	('affect', 'Reg', (186, 192))	('BRG1', 'Gene', (245, 249))	('expression', 'MPA', (199, 209))	('loss', 'Var', (237, 241))	('induction', 'Reg', (271, 280))	('BJ', 'CellLine', 'CVCL:6573', (213, 215))	('BRG1', 'Gene', '6597', (245, 249))	('ATP', 'Chemical', 'MESH:D000255', (145, 148))	('BRG1', 'Gene', (165, 169))	('FGFR2', 'Gene', (193, 198))	('FGFR2', 'Gene', '2263', (193, 198))	('FGFR2', 'Gene', (284, 289))	('FGFR2', 'Gene', '2263', (284, 289))	('BRG1', 'Gene', '6597', (165, 169))	('tested', 'Reg', (79, 85))
59515	24204904	At this site, we found an approximately 10-fold enrichment of ChIP-DNA compared to the basal enrichment levels present at distal sites and the negative control locus IGX1A, and similar to the fold enrichment observed for the known SNF5 target gene CDKN1A (Fig.	('CDKN1A', 'Gene', (248, 254))	('CDKN1A', 'Gene', '1026', (248, 254))	('ChIP-DNA', 'Var', (62, 70))
59527	24204904	This data suggests that upregulation of FGFR1 or FGFR2 occurs upon loss of SNF5 also in human MRTs and highlights the clinical relevance of our finding.	('FGFR1', 'Gene', (40, 45))	('FGFR2', 'Gene', (49, 54))	('FGFR2', 'Gene', '2263', (49, 54))	('FGFR1', 'Gene', '2260', (40, 45))	('SNF5 also', 'Gene', (75, 84))	('loss', 'Var', (67, 71))	('human', 'Species', '9606', (88, 93))	('upregulation', 'PosReg', (24, 36))
59532	24204904	Besides genomic alterations leading to SNF5 loss of function, truncating deletions of BRG1 are present in a small subset of MRTs, further indicating that alterations in SWI/SNF function are causative for the development of this tumor type.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('BRG1', 'Gene', '6597', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('truncating deletions', 'Var', (62, 82))	('SNF5', 'Gene', (39, 43))	('tumor', 'Disease', (228, 233))	('BRG1', 'Gene', (86, 90))	('loss of function', 'NegReg', (44, 60))
59538	24204904	Since siRNA-mediated knock-down of both SNF5 and the SWI/SNF ATPase subunit BRG1 led to increased expression of FGFR2, the repressive function of SNF5 potentially includes the recruitment of the SWI/SNF complex to specific target genes and corresponding changes in nucleosome architecture.	('BRG1', 'Gene', (76, 80))	('ATP', 'Chemical', 'MESH:D000255', (61, 64))	('BRG1', 'Gene', '6597', (76, 80))	('knock-down', 'Var', (21, 31))	('SNF5', 'Gene', (40, 44))	('increased', 'PosReg', (88, 97))	('FGFR2', 'Gene', (112, 117))	('FGFR2', 'Gene', '2263', (112, 117))	('recruitment', 'PosReg', (176, 187))	('changes', 'Reg', (254, 261))	('nucleosome architecture', 'MPA', (265, 288))	('expression', 'MPA', (98, 108))
59539	24204904	Indeed, in the case of GLI1, the absence of SNF5 correlated with an open chromatin structure of the promoter region, while the TSS of the GLI1 promoter was more densely packed with nucleosomes in the presence of SNF5.	('GLI1', 'Gene', '2735', (138, 142))	('absence', 'Var', (33, 40))	('open chromatin structure of the promoter', 'MPA', (68, 108))	('GLI1', 'Gene', (138, 142))	('SNF5', 'Gene', (44, 48))	('GLI1', 'Gene', '2735', (23, 27))	('GLI1', 'Gene', (23, 27))
59542	24204904	Here, the presence of SNF5 correlates with increased levels of trimethylated histone H3 lysine 4 (H3K4) at the CDKN1A locus.	('levels of', 'MPA', (53, 62))	('lysine', 'Chemical', 'MESH:D008239', (88, 94))	('trimethylated histone H3', 'Chemical', '-', (63, 87))	('SNF5', 'Gene', (22, 26))	('increased', 'PosReg', (43, 52))	('CDKN1A', 'Gene', (111, 117))	('presence', 'Var', (10, 18))	('CDKN1A', 'Gene', '1026', (111, 117))
59545	24204904	This is supported by our finding that inactivation of SNF5 in a panel of non-MRT sarcoma cell lines had no effect on FGFR expression, but led to increased FGFR2 levels in non-immortalized human fibroblasts, in line with the cell type specific activity of SNF5 on Aurora A kinase expression.	('human', 'Species', '9606', (188, 193))	('Aurora A', 'Gene', (263, 271))	('FGFR2', 'Gene', (155, 160))	('inactivation', 'Var', (38, 50))	('FGFR2', 'Gene', '2263', (155, 160))	('increased', 'PosReg', (145, 154))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('SNF5', 'Gene', (54, 58))	('Aurora A', 'Gene', '6790', (263, 271))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
59548	24204904	For instance, homozygous deletions of the SNF5 locus 22q11.2 are found in small-cell hepatoblastomas and poorly differentiated chordomas and inactivating mutations and/or deletion of SNF5 are observed in extraskeletal myxoid chondrosarcomas, undifferentiated sarcomas, epitheliod sarcomas and meningiomas.	('extraskeletal myxoid chondrosarcomas', 'Disease', (204, 240))	('found', 'Reg', (65, 70))	('chordomas', 'Disease', (127, 136))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (225, 240))	('sarcomas', 'Phenotype', 'HP:0100242', (259, 267))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (242, 267))	('SNF5', 'Gene', (42, 46))	('SNF5', 'Gene', (183, 187))	('epitheliod sarcomas and meningiomas', 'Disease', 'MESH:D008577', (269, 304))	('deletion', 'Var', (171, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (280, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('small-cell hepatoblastomas', 'Disease', 'MESH:D018197', (74, 100))	('small-cell hepatoblastomas', 'Disease', (74, 100))	('extraskeletal myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (204, 240))	('inactivating mutations', 'Var', (141, 163))	('observed', 'Reg', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('chordomas', 'Disease', 'MESH:D002817', (127, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (280, 287))	('meningiomas', 'Phenotype', 'HP:0002858', (293, 304))	('sarcomas', 'Phenotype', 'HP:0100242', (232, 240))	('undifferentiated sarcomas', 'Disease', (242, 267))
59556	24204904	In this regard, it may be of interest to test drug combinations in future studies, e. g. using inhibitors to FGFRs, Aurora A kinase and CDK4, which might lead the way to an effective clinical therapy for this lethal pediatric cancer.	('inhibitors', 'Var', (95, 105))	('CDK4', 'Gene', (136, 140))	('Aurora A', 'Gene', (116, 124))	('lead', 'Reg', (154, 158))	('cancer', 'Disease', (226, 232))	('CDK4', 'Gene', '1019', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('FGFRs', 'Gene', (109, 114))	('Aurora A', 'Gene', '6790', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
59609	22951975	To test the relevance of specific oncogenic mutations on miRNA biogenesis in sarcoma, we used primary soft tissue sarcomas expressing either BrafV600E or KrasG12D.	('soft tissue sarcomas', 'Disease', (102, 122))	('BrafV600E', 'Mutation', 'rs113488022', (141, 150))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('sarcoma', 'Disease', (114, 121))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (102, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('Kras', 'Gene', (154, 158))	('Kras', 'Gene', '16653', (154, 158))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (102, 121))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (102, 122))	('BrafV600E', 'Var', (141, 150))
59610	22951975	We find that BrafV600E mutant tumors, which have increased MAPK signaling, have higher levels of mature miRNAs and enhanced miRNA processing.	('miRNA processing', 'MPA', (124, 140))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('increased', 'PosReg', (49, 58))	('MAPK', 'Gene', (59, 63))	('MAPK', 'Gene', '5594;26413;26417', (59, 63))	('BrafV600E', 'Mutation', 'rs113488022', (13, 22))	('enhanced', 'PosReg', (115, 123))	('BrafV600E', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('higher', 'PosReg', (80, 86))	('levels of mature miRNAs', 'MPA', (87, 110))
59611	22951975	To investigate the relevance of oncogene dependent alterations in miRNA biogenesis, we introduce conditional mutations in Dicer and show that Dicer haploinsufficiency promotes the development of distant metastases in an oncogene dependent manner.	('metastases', 'Disease', 'MESH:D009362', (203, 213))	('development', 'CPA', (180, 191))	('Dicer', 'Gene', (142, 147))	('Dicer', 'Gene', '23405', (142, 147))	('promotes', 'PosReg', (167, 175))	('Dicer haploinsufficiency', 'Disease', (142, 166))	('Dicer haploinsufficiency', 'Disease', 'MESH:D058495', (142, 166))	('Dicer', 'Gene', '23405', (122, 127))	('Dicer', 'Gene', (122, 127))	('mutations', 'Var', (109, 118))	('metastases', 'Disease', (203, 213))
59612	22951975	These results demonstrate that a specific oncogenic mutation can cooperate with mutation in Dicer to promote tumor progression in vivo.	('promote', 'PosReg', (101, 108))	('Dicer', 'Gene', '23405', (92, 97))	('Dicer', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutation', 'Var', (80, 88))	('tumor', 'Disease', (109, 114))
59622	22951975	Mutations in a number of enzymes that process pri-miRNA transcripts into mature miRNAs have been identified in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('human', 'Species', '9606', (111, 116))	('identified', 'Reg', (97, 107))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (117, 123))
59623	22951975	For example, DICER mutations have been identified in ovarian cancer and soft tissue sarcomas including UPS and rhabdomyosarcoma.	('ovarian cancer', 'Disease', (53, 67))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (72, 91))	('DICER', 'Gene', '23405', (13, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('soft tissue sarcomas', 'Disease', (72, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('identified', 'Reg', (39, 49))	('rhabdomyosarcoma', 'Disease', (111, 127))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (72, 92))	('DICER', 'Gene', (13, 18))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (72, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (111, 127))	('mutations', 'Var', (19, 28))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (111, 127))	('UPS', 'Disease', (103, 106))	('UPS', 'Disease', 'MESH:D017118', (103, 106))
59624	22951975	Moreover, loss of one allele of Dicer is a common feature of many other malignancies.	('loss', 'Var', (10, 14))	('Dicer', 'Gene', '23405', (32, 37))	('Dicer', 'Gene', (32, 37))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('malignancies', 'Disease', (72, 84))
59630	22951975	Mutations in growth factor receptors, Ras, or within the MAPK pathway itself can activate the MAPK pathway leading to cell proliferation.	('activate', 'PosReg', (81, 89))	('MAPK', 'Gene', '5594;26413;26417', (57, 61))	('Ras', 'Protein', (38, 41))	('Mutations', 'Var', (0, 9))	('MAPK', 'Gene', (94, 98))	('cell proliferation', 'CPA', (118, 136))	('MAPK', 'Gene', (57, 61))	('MAPK', 'Gene', '5594;26413;26417', (94, 98))	('growth', 'Protein', (13, 19))
59632	22951975	Here we show that specific oncogenic mutations can regulate miRNA biogenesis in sarcomas in vivo.	('miRNA biogenesis', 'MPA', (60, 76))	('sarcomas', 'Disease', 'MESH:D012509', (80, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('mutations', 'Var', (37, 46))	('regulate', 'Reg', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcomas', 'Disease', (80, 88))
59633	22951975	Using complementary primary mouse models of soft tissue sarcoma, we find that tumors initiated by BrafV600E, compared to tumors expressing KrasG12D, have increased pERK, miRNA processing, and expression of mature miRNAs.	('BrafV600E', 'Var', (98, 107))	('pERK', 'Gene', (164, 168))	('miRNA processing', 'MPA', (170, 186))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('Kras', 'Gene', '16653', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('expression', 'MPA', (192, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('increased', 'PosReg', (154, 163))	('pERK', 'Gene', '13666', (164, 168))	('tumors', 'Disease', (78, 84))	('mouse', 'Species', '10090', (28, 33))	('BrafV600E', 'Mutation', 'rs113488022', (98, 107))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (44, 63))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (44, 63))	('soft tissue sarcoma', 'Disease', (44, 63))	('Kras', 'Gene', (139, 143))
59635	22951975	However, deletion of one allele of Dicer in BrafV600E driven tumors does not increase tumor proliferation or the rate of distant metastases.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('Dicer', 'Gene', '23405', (35, 40))	('Dicer', 'Gene', (35, 40))	('increase tumor', 'Disease', (77, 91))	('deletion', 'Var', (9, 17))	('BrafV600E', 'Mutation', 'rs113488022', (44, 53))	('BrafV600E', 'Var', (44, 53))	('metastases', 'Disease', (129, 139))	('increase tumor', 'Disease', 'MESH:D009369', (77, 91))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('metastases', 'Disease', 'MESH:D009362', (129, 139))
59636	22951975	These results indicate that, in cancer, the consequences of a mutation in a component of the miRNA biogenesis machinery depend on specific oncogenic mutations.	('cancer', 'Disease', (32, 38))	('mutation', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))
59656	22951975	Because mutations in upstream receptor tyrosine kinases and KrasG12D, but not BrafV600E, induce Sprouty and other suppressors of MAPK signaling, we hypothesized that BrafV600E mutant sarcomas would have increased MAPK signaling compared to KrasG12D mutant sarcomas.	('BrafV600E', 'Mutation', 'rs113488022', (166, 175))	('sarcomas', 'Disease', (256, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('Kras', 'Gene', '16653', (60, 64))	('BrafV600E', 'Mutation', 'rs113488022', (78, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('Kras', 'Gene', (240, 244))	('MAPK', 'Gene', (129, 133))	('increased', 'PosReg', (203, 212))	('MAPK', 'Gene', '5594;26413;26417', (129, 133))	('mutations', 'Var', (8, 17))	('Kras', 'Gene', '16653', (240, 244))	('BrafV600E', 'Var', (166, 175))	('Sprouty', 'MPA', (96, 103))	('Kras', 'Gene', (60, 64))	('sarcomas', 'Disease', 'MESH:D012509', (183, 191))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('MAPK', 'Gene', (213, 217))	('MAPK', 'Gene', '5594;26413;26417', (213, 217))	('sarcomas', 'Disease', (183, 191))	('sarcomas', 'Disease', 'MESH:D012509', (256, 264))	('sarcomas', 'Phenotype', 'HP:0100242', (256, 264))
59657	22951975	Intramuscular injection of an adenovirus expressing Cre recombinase into BrafCA/+; p53Fl/Fl mice (referred to here as BP mice), results in Cre dependent activation of the BrafV600E allele and deletion of p53, causing soft tissue sarcomas.	('Braf', 'Gene', (73, 77))	('p53', 'Gene', (83, 86))	('soft tissue sarcomas', 'Disease', (217, 237))	('Braf', 'Gene', '109880', (171, 175))	('BP', 'Chemical', '-', (118, 120))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (217, 237))	('p53', 'Gene', '22060', (83, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (229, 237))	('mice', 'Species', '10090', (92, 96))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (217, 237))	('activation', 'PosReg', (153, 163))	('BrafV600E', 'Mutation', 'rs113488022', (171, 180))	('Braf', 'Gene', '109880', (73, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('causing', 'Reg', (209, 216))	('mice', 'Species', '10090', (121, 125))	('Braf', 'Gene', (171, 175))	('p53', 'Gene', (204, 207))	('deletion', 'Var', (192, 200))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (217, 236))	('p53', 'Gene', '22060', (204, 207))
59667	22951975	We found an increased ratio of mature:pri-miRNA in the BrafV600E mutant sarcomas in miRNAs upregulated, or downregulated, in sarcomas from KP mice (Figure 1F).	('upregulated', 'PosReg', (91, 102))	('BrafV600E', 'Mutation', 'rs113488022', (55, 64))	('BrafV600E', 'Var', (55, 64))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('sarcomas', 'Disease', 'MESH:D012509', (125, 133))	('increased', 'PosReg', (12, 21))	('mice', 'Species', '10090', (142, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('sarcomas', 'Disease', (125, 133))	('downregulated', 'NegReg', (107, 120))	('sarcomas', 'Disease', (72, 80))	('ratio', 'MPA', (22, 27))
59671	22951975	Dicer haploinsufficiency has been observed in a number of human cancers, and specific mutations in Dicer have been identified in several subtypes of soft tissue sarcoma.	('mutations', 'Var', (86, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('human', 'Species', '9606', (58, 63))	('Dicer', 'Gene', '23405', (99, 104))	('identified', 'Reg', (115, 125))	('soft tissue sarcoma', 'Disease', (149, 168))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (149, 168))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('Dicer', 'Gene', '23405', (0, 5))	('Dicer', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('observed', 'Reg', (34, 42))	('Dicer', 'Gene', (99, 104))	('Dicer haploinsufficiency', 'Disease', 'MESH:D058495', (0, 24))	('Dicer haploinsufficiency', 'Disease', (0, 24))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (149, 168))
59680	22951975	Taken together, these results suggest that oncogene dependent alterations in MAPK signaling, such as differences in pERK, resulting from specific mutations in Kras or Braf, can regulate miRNA biogenesis in vivo.	('pERK', 'Gene', (116, 120))	('MAPK', 'Gene', (77, 81))	('miRNA biogenesis', 'MPA', (186, 202))	('mutations', 'Var', (146, 155))	('Kras', 'Gene', '16653', (159, 163))	('regulate', 'Reg', (177, 185))	('MAPK', 'Gene', '5594;26413;26417', (77, 81))	('Braf', 'Gene', '109880', (167, 171))	('Braf', 'Gene', (167, 171))	('pERK', 'Gene', '13666', (116, 120))	('Kras', 'Gene', (159, 163))
59681	22951975	Previous studies have suggested that decreased miRNA expression from knockdown of Dicer or other components of the miRNA biogenesis machinery enhances tumor cell proliferation both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('miRNA expression', 'MPA', (47, 63))	('Dicer', 'Gene', '23405', (82, 87))	('Dicer', 'Gene', (82, 87))	('decreased', 'NegReg', (37, 46))	('knockdown', 'Var', (69, 78))	('enhances', 'PosReg', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
59697	22951975	Our results in a primary mouse model of soft tissue sarcoma show that mutations in components of the miRNA biogenesis machinery can alter the natural history of tumors by increasing cell proliferation and the development of distant metastases in an oncogene dependent manner.	('mutations', 'Var', (70, 79))	('tumors', 'Disease', (161, 167))	('increasing', 'PosReg', (171, 181))	('cell proliferation', 'CPA', (182, 200))	('metastases', 'Disease', (232, 242))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (40, 59))	('mouse', 'Species', '10090', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (40, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('natural', 'MPA', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('soft tissue sarcoma', 'Disease', (40, 59))	('metastases', 'Disease', 'MESH:D009362', (232, 242))	('alter', 'Reg', (132, 137))
59701	22951975	For instance, increased MAPK signaling can be provided by oncogenic mutations that strongly activate the MAPK cascade such as mutations in Braf, which are less susceptible to feedback inhibition from downstream Sprouty and other proteins.	('increased', 'PosReg', (14, 23))	('MAPK', 'Gene', '5594;26413;26417', (105, 109))	('MAPK', 'Gene', (24, 28))	('Braf', 'Gene', (139, 143))	('MAPK', 'Gene', '5594;26413;26417', (24, 28))	('mutations', 'Var', (126, 135))	('MAPK', 'Gene', (105, 109))	('activate', 'PosReg', (92, 100))	('Braf', 'Gene', '109880', (139, 143))
59703	22951975	Although we did identify a few Kras mutant sarcomas with higher levels of mature miRNAs, these tumors also had elevated pERK.	('elevated', 'PosReg', (111, 119))	('Kras', 'Gene', '16653', (31, 35))	('pERK', 'Gene', (120, 124))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('higher', 'PosReg', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('levels of mature miRNAs', 'MPA', (64, 87))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('mutant', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Kras', 'Gene', (31, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('tumors', 'Disease', (95, 101))	('pERK', 'Gene', '13666', (120, 124))	('sarcomas', 'Disease', (43, 51))
59704	22951975	It is possible that additional molecular alterations, such as downregulation or mutation of Sprouty or Spred proteins, may lead to increased MAPK signaling and higher levels of mature miRNAs within these tumors.	('Spred', 'Gene', '114716', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('increased', 'PosReg', (131, 140))	('higher', 'PosReg', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Spred', 'Gene', (103, 108))	('MAPK', 'Gene', (141, 145))	('downregulation', 'NegReg', (62, 76))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('MAPK', 'Gene', '5594;26413;26417', (141, 145))	('mutation', 'Var', (80, 88))
59705	22951975	Conversely, mutations that decrease MAPK signaling within Braf tumors may lead to the opposite phenotype.	('decrease', 'NegReg', (27, 35))	('mutations', 'Var', (12, 21))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Braf', 'Gene', '109880', (58, 62))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('MAPK', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MAPK', 'Gene', '5594;26413;26417', (36, 40))	('Braf', 'Gene', (58, 62))
59706	22951975	Therefore, as we have observed in primary sarcomas in mice, Kras mutant tumors, may be more susceptible to mutations in other components of the miRNA biogenesis pathway, such as Dicer, resulting in decreased miRNA levels that promote tumor proliferation and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (234, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Kras', 'Gene', '16653', (60, 64))	('tumors', 'Disease', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('primary sarcomas', 'Disease', 'MESH:D012509', (34, 50))	('mutant', 'Var', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('decreased', 'NegReg', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('metastasis', 'CPA', (258, 268))	('tumor', 'Disease', (72, 77))	('Dicer', 'Gene', '23405', (178, 183))	('primary sarcomas', 'Disease', (34, 50))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Dicer', 'Gene', (178, 183))	('miRNA levels', 'MPA', (208, 220))	('Kras', 'Gene', (60, 64))	('mutations', 'Var', (107, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('promote', 'PosReg', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mice', 'Species', '10090', (54, 58))
59707	22951975	It is likely that as additional mechanisms that regulate miRNA biogenesis are uncovered, more mutations in pathways commonly perturbed in cancer will be identified that alter regulation of miRNA processing.	('alter', 'Reg', (169, 174))	('cancer', 'Disease', (138, 144))	('miRNA processing', 'MPA', (189, 205))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('regulation', 'MPA', (175, 185))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
59710	22951975	These results suggest that specific p53 mutations such as point-mutations versus deletion, may lead to alterations in miRNA biogenesis and sensitize cells to loss of function mutations in Dicer or other components of the miRNA biogenesis machinery.	('alterations', 'Reg', (103, 114))	('loss of function', 'NegReg', (158, 174))	('p53', 'Gene', (36, 39))	('deletion', 'Var', (81, 89))	('mutations', 'Var', (175, 184))	('Dicer', 'Gene', '23405', (188, 193))	('Dicer', 'Gene', (188, 193))	('miRNA biogenesis', 'MPA', (118, 134))	('p53', 'Gene', '22060', (36, 39))	('point-mutations', 'Var', (58, 73))
59711	22951975	The ability of mutations in Dicer to increase cell proliferation and metastasis is likely to be due to the combined downregulation of a number of miRNAs rather than loss of a specific miRNA.	('metastasis', 'CPA', (69, 79))	('cell proliferation', 'CPA', (46, 64))	('downregulation', 'NegReg', (116, 130))	('mutations', 'Var', (15, 24))	('increase', 'PosReg', (37, 45))	('Dicer', 'Gene', '23405', (28, 33))	('Dicer', 'Gene', (28, 33))
59719	32923894	Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant Genomic alterations in the Ewing sarcoma family of tumors (EFT) were discovered > 30 years ago with the identification of the reciprocal translocation, t(11;22)(q24;q12), otherwise known as EWS-FL1.	('CCNB3', 'Gene', (87, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('BCOR', 'Gene', (82, 86))	('CDKN2B', 'Gene', '1030', (113, 119))	('Ewing sarcoma', 'Disease', (155, 168))	('Sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (280, 297))	('EWS', 'Gene', (318, 321))	('Sarcoma', 'Disease', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('t(11;22)(q24;q12', 'Var', (280, 296))	('Sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('CCNB3', 'Gene', '85417', (87, 92))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (155, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('tumors', 'Disease', (179, 185))	('EWS', 'Gene', '2130', (318, 321))	('CDKN2B', 'Gene', (113, 119))	('BCOR', 'Gene', '54880', (82, 86))
59739	32923894	The mutational burden of the tumor was relatively low at 75,046 somatic mutations, with only 88 somatic mutations mapping to protein coding regions (Circos plot in Fig 2A).	('mutations', 'Var', (72, 81))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))
59741	32923894	Additionally, an undescribed somatic mutation in the SMO gene (SMO N476S) was identified in the tumor, and germline sequencing revealed a CDKN2B N41D missense variant, which was heterozygous in both the germline and tumor genomes of this patient.	('tumor', 'Disease', (216, 221))	('SMO', 'Gene', '6608', (63, 66))	('SMO', 'Gene', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('CDKN2B', 'Gene', '1030', (138, 144))	('N41D', 'SUBSTITUTION', 'None', (145, 149))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('N476S', 'Mutation', 'p.N476S', (67, 72))	('SMO', 'Gene', '6608', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('SMO', 'Gene', (53, 56))	('patient', 'Species', '9606', (238, 245))	('N41D', 'Var', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('CDKN2B', 'Gene', (138, 144))
59744	32923894	The BCOR gene itself can fuse to a number of 3' partner genes in round cell sarcomas or additionally have internal tandem duplications, which have been reported to drive similar transcriptional patterns in a variety of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('sarcomas', 'Disease', (76, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('BCOR', 'Gene', '54880', (4, 8))	('sarcomas', 'Disease', 'MESH:D012509', (76, 84))	('sarcomas', 'Disease', (219, 227))	('sarcomas', 'Phenotype', 'HP:0100242', (76, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('fuse', 'Reg', (25, 29))	('internal tandem duplications', 'Var', (106, 134))	('BCOR', 'Gene', (4, 8))	('sarcomas', 'Disease', 'MESH:D012509', (219, 227))
59752	32923894	This congenital tumor also harbored a SMARCB1/INI1 gene deletion common to malignant rhabdoid tumor, epithelioid sarcomas, and epithelioid malignant peripheral nerve sheath tumor that also, when found germline, is known to cause rhabdoid tumor predisposition syndrome.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (139, 178))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('cause', 'Reg', (223, 228))	('deletion', 'Var', (56, 64))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (229, 243))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (139, 178))	('rhabdoid tumor', 'Disease', (229, 243))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('tumor', 'Disease', (238, 243))	('tumor', 'Disease', (16, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('SMARCB1', 'Gene', '6598', (38, 45))	('INI1', 'Gene', (46, 50))	('sarcomas', 'Disease', (113, 121))	('INI1', 'Gene', '6598', (46, 50))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (75, 99))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('malignant rhabdoid tumor', 'Disease', (75, 99))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (173, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('malignant peripheral nerve sheath tumor', 'Disease', (139, 178))	('SMARCB1', 'Gene', (38, 45))
59755	32923894	Our patient also harbored a germline heterozygous missense variant, CDKN2B N41D.	('N41D', 'Var', (75, 79))	('patient', 'Species', '9606', (4, 11))	('CDKN2B', 'Gene', (68, 74))	('N41D', 'SUBSTITUTION', 'None', (75, 79))	('CDKN2B', 'Gene', '1030', (68, 74))
59756	32923894	It is unclear what role this germline CDKN2B N41D variant could play in sarcomagenesis, as cancer risks associated with CDKN2A/B gene variants include melanoma, pancreatic cancer, and astrocytomas.	('astrocytomas', 'Disease', (184, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('CDKN2B', 'Gene', (38, 44))	('CDKN2A/B', 'Gene', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('astrocytomas', 'Disease', 'MESH:D001254', (184, 196))	('CDKN2B', 'Gene', '1030', (38, 44))	('sarcomagenesis', 'Disease', (72, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (161, 178))	('N41D', 'Var', (45, 49))	('CDKN2A/B', 'Gene', '1029;1030', (120, 128))	('cancer', 'Disease', (172, 178))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('pancreatic cancer', 'Disease', (161, 178))	('N41D', 'SUBSTITUTION', 'None', (45, 49))	('variants', 'Var', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (91, 97))	('sarcomagenesis', 'Disease', 'None', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
59757	32923894	There is a recent short report from Jouenne et al that found an increased risk of soft tissue sarcoma development with germline loss of CDKN2A, though no data exist confirming this risk with CDKN2B variants.	('CDKN2B', 'Gene', (191, 197))	('sarcoma', 'Disease', (94, 101))	('loss', 'Var', (128, 132))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (82, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('CDKN2B', 'Gene', '1030', (191, 197))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))
59759	32923894	Sunita et al showed that the specific CDKN2B N41D variant, which encodes p15(INK4B), is unable to bind to the CDK6 protein, leading to loss of function of CDKN2B, which could lead to dysregulated control of S-phase entry.	('N41D', 'SUBSTITUTION', 'None', (45, 49))	('CDKN2B', 'Gene', '1030', (155, 161))	('S-phase entry', 'MPA', (207, 220))	('INK4B', 'Gene', (77, 82))	('control', 'MPA', (196, 203))	('CDKN2B', 'Gene', '1030', (38, 44))	('lead', 'Reg', (175, 179))	('N41D', 'Var', (45, 49))	('unable', 'NegReg', (88, 94))	('CDK6', 'Gene', (110, 114))	('CDK6', 'Gene', '1021', (110, 114))	('CDKN2B', 'Gene', (38, 44))	('INK4B', 'Gene', '1030', (77, 82))	('loss of function', 'NegReg', (135, 151))	('CDKN2B', 'Gene', (155, 161))
59760	32923894	Though this variant's contribution to tumorigenesis is intriguing, CKDN2B was normally expressed in our patient's tumor, and there are no data suggesting that this impaired binding to CDK6 leads to mRNA overexpression along multiple levels of the CDK4/6 pathway.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('variant', 'Var', (12, 19))	('CDK4/6', 'Gene', '1019;1021', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mRNA', 'MPA', (198, 202))	('tumor', 'Disease', (114, 119))	('CDK4/6', 'Gene', (247, 253))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('binding', 'Interaction', (173, 180))	('overexpression', 'PosReg', (203, 217))	('patient', 'Species', '9606', (104, 111))	('CDK6', 'Gene', (184, 188))	('CDK6', 'Gene', '1021', (184, 188))	('impaired', 'NegReg', (164, 172))
59762	32923894	In a preclinical Ewing sarcoma orthotopic xenograft model with CDKN2A deletion, palbociclib was able to greatly suppress growth despite doxorubicin resistance of this model.	('deletion', 'Var', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('CDKN2A', 'Gene', '1029', (63, 69))	('doxorubicin', 'Chemical', 'MESH:D004317', (136, 147))	('palbociclib', 'Chemical', 'MESH:C500026', (80, 91))	('Ewing sarcoma', 'Disease', (17, 30))	('suppress', 'NegReg', (112, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (17, 30))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (17, 30))	('growth despite doxorubicin', 'MPA', (121, 147))	('CDKN2A', 'Gene', (63, 69))
59767	32923894	To summarize, 3 independent observations supported consideration of therapeutic inhibition of the CDK4/6-RB1 pathway for this patient: (1) the presence of the BCOR-CCNB3 gene fusion believed to drive entry into the cell cycle, (2) direct detection of an active CDK4/6-RB1 pathway, and (3) the presence of a germline CDKN2B variant.	('CDKN2B', 'Gene', '1030', (316, 322))	('variant', 'Var', (323, 330))	('CDK4/6', 'Gene', '1019;1021', (98, 104))	('RB1', 'Gene', (268, 271))	('BCOR', 'Gene', (159, 163))	('CCNB3', 'Gene', '85417', (164, 169))	('patient', 'Species', '9606', (126, 133))	('CDK4/6', 'Gene', '1019;1021', (261, 267))	('BCOR', 'Gene', '54880', (159, 163))	('RB1', 'Gene', (105, 108))	('CDK4/6', 'Gene', (98, 104))	('RB1', 'Gene', '5925', (268, 271))	('RB1', 'Gene', '5925', (105, 108))	('CDK4/6', 'Gene', (261, 267))	('presence', 'Var', (143, 151))	('CCNB3', 'Gene', (164, 169))	('drive', 'PosReg', (194, 199))	('CDKN2B', 'Gene', (316, 322))
59791	31949491	As such, over-abundance may play a role in pathogenesis of various diseases, including human neoplastic disorders.	('neoplastic disorders', 'Disease', 'MESH:D009386', (93, 113))	('over-abundance', 'Var', (9, 23))	('human', 'Species', '9606', (87, 92))	('neoplastic disorders', 'Disease', (93, 113))	('play', 'Reg', (28, 32))
59800	31949491	Patients were selected according to the following criteria: 1) categorized into homogenous groups of sarcoma patients; and 2) they had a well-established pathological diagnosis performed by expert pathologists specialized in sarcoma diagnostics and confirmed by molecular testing (i.e., cytogenetics results showing translocation of t(X;18) and t(11;22), which is characteristic of SSs and ESs, respectively, and genotyping revealing the presence of oncogenic KIT and PDGFRA driver mutations in GISTs).	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('patients', 'Species', '9606', (109, 117))	('sarcoma', 'Disease', 'MESH:D012509', (225, 232))	('PDGFRA', 'Gene', '5156', (468, 474))	('sarcoma', 'Disease', (101, 108))	('PDGFRA', 'Gene', (468, 474))	('sarcoma', 'Disease', (225, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('mutations', 'Var', (482, 491))	('Patients', 'Species', '9606', (0, 8))	('GISTs', 'Disease', 'MESH:D046152', (495, 500))	('KIT', 'Gene', '3815', (460, 463))	('GISTs', 'Disease', (495, 500))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('ES', 'Disease', 'MESH:D012512', (390, 392))	('SS', 'Disease', 'MESH:D013584', (382, 384))	('KIT', 'Gene', (460, 463))
59841	31949491	DNA methylation, histone deacetylation, changes in DNA copy number, and gene mutations affect proteins involved in miRNA processing and maturation.	('affect', 'Reg', (87, 93))	('histone deacetylation', 'MPA', (17, 38))	('proteins', 'Protein', (94, 102))	('mutations', 'Var', (77, 86))	('miR', 'Gene', '220972', (115, 118))	('miR', 'Gene', (115, 118))
59843	31949491	Therefore, dysregulated miRNA expression may play roles in the pathogenesis of numerous human disorders, including cancer development and progression.	('cancer', 'Disease', (115, 121))	('dysregulated', 'Var', (11, 23))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('human', 'Species', '9606', (88, 93))	('play roles', 'Reg', (45, 55))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
59852	31949491	We found that most c-miRNAs dysregulated in pre-therapeutic serum samples were sarcoma type-specific; only three were found in all sarcoma types.	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('sarcoma', 'Disease', (79, 86))	('dysregulated', 'Var', (28, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('sarcoma', 'Disease', (131, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
59859	31949491	Most aberrantly expressed c-miRNAs discriminated OS patients from healthy volunteers with high specificity and sensitivity; therefore, they were considered promising diagnostic and prognostic biomarkers for patients with advanced tumors.	('patients', 'Species', '9606', (207, 215))	('discriminated', 'Reg', (35, 48))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('aberrantly', 'Var', (5, 15))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('patients', 'Species', '9606', (52, 60))
59871	31949491	Alterations in expression of miRNA in ES involve both EWS/Ets oncogenic fusion-dependent and -independent mechanisms, which contribute to a malignant phenotype.	('ES', 'Disease', 'MESH:D012512', (38, 40))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('Alterations', 'Var', (0, 11))	('EWS', 'Gene', '2130', (54, 57))	('EWS', 'Gene', (54, 57))	('expression', 'MPA', (15, 25))
59880	31949491	They show well-characterized molecular features related to activating mutations in theKIT or PDGFRA genes.	('KIT', 'Gene', (86, 89))	('mutations', 'Var', (70, 79))	('activating', 'PosReg', (59, 69))	('PDGFRA', 'Gene', (93, 99))	('PDGFRA', 'Gene', '5156', (93, 99))	('KIT', 'Gene', '3815', (86, 89))
59913	30648052	A meta-analysis of congestive heart failure (CHF) with VEGF-TKI shows a relative risk of all grade and high-grade CHF for the VEGF-TKI vs. no VEGF-TKI arms was 2.69 and 1.65, respectively.	('CHF', 'Phenotype', 'HP:0001635', (114, 117))	('congestive heart failure', 'Disease', 'MESH:D006333', (19, 43))	('CHF', 'Disease', (45, 48))	('VEGF-TKI', 'Gene', (55, 63))	('HF', 'Phenotype', 'HP:0001635', (46, 48))	('CHF', 'Disease', 'MESH:D006333', (45, 48))	('congestive heart failure', 'Disease', (19, 43))	('CHF', 'Disease', 'MESH:D006333', (114, 117))	('CHF', 'Disease', (114, 117))	('VEGF-TKI', 'Var', (126, 134))	('heart failure', 'Phenotype', 'HP:0001635', (30, 43))	('CHF', 'Phenotype', 'HP:0001635', (45, 48))	('HF', 'Phenotype', 'HP:0001635', (115, 117))	('congestive heart failure', 'Phenotype', 'HP:0001635', (19, 43))
59920	30648052	This thus suggests that VEGF and PDGF receptor inhibition could induce cardiomyocyte apoptosis and prevent cardiac remodeling, resulting in ventricular dysfunction.	('ventricular dysfunction', 'Disease', (140, 163))	('VEGF', 'Protein', (24, 28))	('induce', 'PosReg', (64, 70))	('ventricular dysfunction', 'Phenotype', 'HP:0005162', (140, 163))	('resulting in', 'Reg', (127, 139))	('cardiomyocyte apoptosis', 'CPA', (71, 94))	('prevent', 'NegReg', (99, 106))	('inhibition', 'Var', (47, 57))	('cardiac remodeling', 'Disease', (107, 125))	('ventricular dysfunction', 'Disease', 'MESH:D018754', (140, 163))	('cardiac remodeling', 'Disease', 'MESH:D020257', (107, 125))	('PDGF receptor', 'Protein', (33, 46))
59922	30648052	There is some evidence to suggest that TKI interruption along with optimal guideline-directed cardiovascular treatment leads to improvement in cardiac status and such patients can be eligible to resume TKI therapy.	('interruption', 'Var', (43, 55))	('improvement', 'PosReg', (128, 139))	('patients', 'Species', '9606', (167, 175))	('cardiac status', 'MPA', (143, 157))	('TKI', 'Gene', (39, 42))
59925	30648052	The PALETTE trial showed a 1% rate of symptomatic left ventricular systolic dysfunction in people treated with Pazopanib, while 99% of patients had received anthracyclines.	('ventricular systolic dysfunction', 'Disease', 'MESH:D018754', (55, 87))	('patients', 'Species', '9606', (135, 143))	('Pazopanib', 'Var', (111, 120))	('ventricular systolic dysfunction', 'Disease', (55, 87))	('ventricular systolic dysfunction', 'Phenotype', 'HP:0025169', (55, 87))	('anthracyclines', 'Chemical', 'MESH:D018943', (157, 171))	('left ventricular systolic dysfunction', 'Phenotype', 'HP:0025169', (50, 87))	('systolic dysfunction', 'Phenotype', 'HP:0006673', (67, 87))	('Pazopanib', 'Chemical', 'MESH:C516667', (111, 120))	('people', 'Species', '9606', (91, 97))
59926	30648052	This again supports the hypothesis that Pazopanib causes cardiotoxicity independent of prior exposure to anthracyclines.	('Pazopanib', 'Chemical', 'MESH:C516667', (40, 49))	('anthracyclines', 'Chemical', 'MESH:D018943', (105, 119))	('Pazopanib', 'Var', (40, 49))	('cardiotoxicity', 'Disease', 'MESH:D066126', (57, 71))	('cardiotoxicity', 'Disease', (57, 71))
59927	30648052	We believe this case report will add to the available literature about this potentially life-threatening complication associated with VEGF-TKI therapy while demonstrating the potential reversibility of cardiotoxicity with cessation of therapy.	('VEGF-TKI', 'Gene', (134, 142))	('therapy', 'Var', (143, 150))	('cardiotoxicity', 'Disease', (202, 216))	('cardiotoxicity', 'Disease', 'MESH:D066126', (202, 216))
59949	30613391	That article described the discovery of epidermal growth factor receptor ( EGFR) exon 20 insertion/duplication mutations in 12 cases of FHI, casting a cloud over their status as true "hamartomas" and suggesting that the distinction from neoplasia may be arbitrary.	('hamartomas', 'Disease', (184, 194))	('neoplasia', 'Disease', 'MESH:D009369', (237, 246))	('neoplasia', 'Phenotype', 'HP:0002664', (237, 246))	('epidermal growth factor receptor', 'Gene', '1956', (40, 72))	('hamartomas', 'Disease', 'MESH:D006222', (184, 194))	('hamartoma', 'Phenotype', 'HP:0010566', (184, 193))	('insertion/duplication mutations', 'Var', (89, 120))	('hamartomas', 'Phenotype', 'HP:0010566', (184, 194))	('FHI', 'Disease', (136, 139))	('EGFR', 'Gene', '1956', (75, 79))	('neoplasia', 'Disease', (237, 246))	('epidermal growth factor receptor', 'Gene', (40, 72))	('EGFR', 'Gene', (75, 79))
59968	30613391	described recurrent PDGFRB mutations in sporadic infantile and adult myofibromas but not in angioleiomyomas and myopericytomas, based on mutations found in congenital inherited IM.	('mutations', 'Var', (27, 36))	('fibroma', 'Phenotype', 'HP:0010614', (72, 79))	('angioleiomyomas and myopericytomas', 'Disease', 'MESH:D000077777', (92, 126))	('adult myofibromas', 'Disease', (63, 80))	('adult myofibromas', 'Disease', 'MESH:D047708', (63, 80))	('IM', 'Phenotype', 'HP:0020135', (177, 179))	('PDGFRB', 'Gene', '5159', (20, 26))	('PDGFRB', 'Gene', (20, 26))
59969	30613391	sequenced PDGFRB in a series of 16 IM samples of sporadic IM.	('PDGFRB', 'Gene', '5159', (10, 16))	('IM', 'Phenotype', 'HP:0020135', (35, 37))	('PDGFRB', 'Gene', (10, 16))	('IM', 'Phenotype', 'HP:0020135', (58, 60))	('sequenced', 'Var', (0, 9))
59970	30613391	Mutations in the coding sequence of PDGFRB were found in six out of eight cases of multicentric IM and one out of eight unifocal IM.	('multicentric IM', 'Disease', (83, 98))	('IM', 'Phenotype', 'HP:0020135', (129, 131))	('IM', 'Phenotype', 'HP:0020135', (96, 98))	('PDGFRB', 'Gene', '5159', (36, 42))	('Mutations', 'Var', (0, 9))	('PDGFRB', 'Gene', (36, 42))	('found', 'Reg', (48, 53))
59983	30613391	In an archival series of 14 cases, 10 showed NTRK1 rearrangement by fluorescence in situ hybridization (FISH).	('NTRK1', 'Gene', '4914', (45, 50))	('rearrangement', 'Var', (51, 64))	('NTRK1', 'Gene', (45, 50))
59984	30613391	The LMNA-NTRK1 fusion resulted from an interstitial deletion (0.7 Mb apart) on 1q22, and in four cases there was inversion.	('fusion', 'Var', (15, 21))	('NTRK1', 'Gene', '4914', (9, 14))	('LMNA', 'Gene', (4, 8))	('NTRK1', 'Gene', (9, 14))	('resulted from', 'Reg', (22, 35))	('LMNA', 'Gene', '4000', (4, 8))	('deletion', 'Var', (52, 60))
59991	30613391	Immunohistochemical testing of ESFT reveals a distinctive ERG positivity, and FISH of tested cases showed EWSR1 rearrangement.	('EWSR1', 'Gene', '2130', (106, 111))	('EWSR1', 'Gene', (106, 111))	('ERG positivity', 'MPA', (58, 72))	('rearrangement', 'Var', (112, 125))
59994	30613391	reported the discovery of an LMNA-NTRK1 fusion in four patients with an HPC-like sarcoma, including two infants and two adults.	('LMNA', 'Gene', (29, 33))	('NTRK1', 'Gene', (34, 39))	('fusion', 'Var', (40, 46))	('LMNA', 'Gene', '4000', (29, 33))	('infants', 'Species', '9606', (104, 111))	('patients', 'Species', '9606', (55, 63))	('NTRK1', 'Gene', '4914', (34, 39))	('HPC-like sarcoma', 'Disease', (72, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('HPC-like sarcoma', 'Disease', 'MESH:C537262', (72, 88))
60000	30613391	Four of these tumors contained TMP1-NTRK1 fusions, one a LMNA-NTRK1 fusion and one a variant EML4-NTRK3 fusion.	('LMNA', 'Gene', (57, 61))	('NTRK1', 'Gene', (62, 67))	('NTRK3', 'Gene', '4916', (98, 103))	('NTRK1', 'Gene', '4914', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('NTRK1', 'Gene', '4914', (62, 67))	('LMNA', 'Gene', '4000', (57, 61))	('EML4', 'Gene', (93, 97))	('contained', 'Reg', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('NTRK1', 'Gene', (36, 41))	('fusions', 'Var', (42, 49))	('EML4', 'Gene', '27436', (93, 97))	('NTRK3', 'Gene', (98, 103))
60004	30613391	Thirty tumors demonstrated EVT6 or NTRK rearrangement, and negative controls included 50 cases of non- NRTK-rearranged pediatric soft tissue lesions.	('TRK', 'Gene', (36, 39))	('EVT6', 'Var', (27, 31))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('TRK', 'Gene', '7170', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
60014	30613391	Recurring internal tandem duplication (ITD) of BCOR exon 16 was found in nine out of 22 URCS and six out of seven PMMTI as well as three out of four CCSK tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('URCS', 'Disease', (88, 92))	('internal tandem duplication', 'Var', (10, 37))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('BCOR', 'Gene', (47, 51))	('found', 'Reg', (64, 69))	('CCSK', 'Chemical', '-', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('BCOR', 'Gene', '54880', (47, 51))
60018	30613391	BCOR and SATB2 expression was also reported in most cases with BCOR or YWHAE-NUTM2B fusions and was seen in about one third to one half of synovial sarcomas.	('YWHAE', 'Gene', (71, 76))	('BCOR', 'Gene', (63, 67))	('NUTM2B', 'Gene', '729262', (77, 83))	('synovial sarcomas', 'Disease', 'MESH:D013584', (139, 156))	('BCOR', 'Gene', '54880', (0, 4))	('synovial sarcomas', 'Disease', (139, 156))	('fusions', 'Var', (84, 91))	('BCOR', 'Gene', '54880', (63, 67))	('SATB2', 'Gene', '23314', (9, 14))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (139, 155))	('YWHAE', 'Gene', '7531', (71, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('NUTM2B', 'Gene', (77, 83))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (139, 156))	('SATB2', 'Gene', (9, 14))	('BCOR', 'Gene', (0, 4))
60028	30613391	Subsequent testing of nine additional IFS-like pediatric sarcomas disclosed four additional tumors with BRAF rearrangements.	('rearrangements', 'Var', (109, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('BRAF', 'Gene', '673', (104, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('BRAF', 'Gene', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('sarcomas', 'Disease', (57, 65))
60032	30613391	The tumor responded to adjuvant chemotherapy with ifosfamide, vincristine, and actinomycin D. FusionSeq revealed a TFG-MET fusion, validated by reverse transcription-polymerase chain reaction (RT-PCR) and FISH.	('tumor', 'Disease', (4, 9))	('fusion', 'Var', (123, 129))	('TFG', 'Gene', '10342', (115, 118))	('vincristine', 'Chemical', 'MESH:D014750', (62, 73))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('TFG', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ifosfamide', 'Chemical', 'MESH:D007069', (50, 60))	('actinomycin D', 'Chemical', 'MESH:D003609', (79, 92))
60042	30613391	It has been recognized that SCRMS is not a good diagnosis in adults , 2013, and one factor appears to be a distinctive MYOD1 L122R mutation that characterizes these lesions , .	('L122R', 'Mutation', 'p.L122R', (125, 130))	('L122R', 'Var', (125, 130))	('MYOD1', 'Gene', '4654', (119, 124))	('MYOD1', 'Gene', (119, 124))
60043	30613391	MYOD1 mutation is not limited to adult SCRMS, as shown by Agaram et al.	('MYOD1', 'Gene', '4654', (0, 5))	('MYOD1', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))
60046	30613391	In one study of infantile SCRMS , SRF-NCOA2 and TEAD1-NCOA2 studies were found, and another study  found recurrent NCOA2 rearrangements as well as VGLL2 rearrangements ( VGLL2-CITED in four tumors and VGLL2-NCOA2 in two).	('NCOA2', 'Gene', '10499', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('TEAD1', 'Gene', (48, 53))	('VGLL2', 'Gene', '245806', (170, 175))	('tumors', 'Disease', (190, 196))	('NCOA2', 'Gene', '10499', (54, 59))	('NCOA2', 'Gene', (207, 212))	('VGLL2', 'Gene', '245806', (147, 152))	('TEAD1', 'Gene', '7003', (48, 53))	('NCOA2', 'Gene', (38, 43))	('VGLL2', 'Gene', '245806', (201, 206))	('NCOA2', 'Gene', '10499', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('VGLL2', 'Gene', (170, 175))	('NCOA2', 'Gene', (54, 59))	('VGLL2', 'Gene', (147, 152))	('VGLL2', 'Gene', (201, 206))	('NCOA2', 'Gene', (115, 120))	('SRF', 'Gene', '6722', (34, 37))	('rearrangements', 'Var', (121, 135))	('SRF', 'Gene', (34, 37))	('rearrangements', 'Var', (153, 167))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('NCOA2', 'Gene', '10499', (207, 212))
60053	30613391	COL1A1-PDGFB fusion is seen in both DFSP and GCF, but about 4% of lesions with typical histology and CD34 positivity are negative on routine screening .	('PDGFB', 'Gene', (7, 12))	('DFSP', 'Disease', 'MESH:D018223', (36, 40))	('fusion', 'Var', (13, 19))	('GCF', 'Disease', (45, 48))	('seen', 'Reg', (23, 27))	('DFSP', 'Disease', (36, 40))	('PDGFB', 'Gene', '5155', (7, 12))	('CD34', 'Gene', '947', (101, 105))	('COL1A1', 'Gene', '1277', (0, 6))	('COL1A1', 'Gene', (0, 6))	('CD34', 'Gene', (101, 105))
60060	30613391	found FN1-EGF fusions in a series of nine CAF cases.	('FN1', 'Gene', '2335', (6, 9))	('EGF', 'Gene', (10, 13))	('FN1', 'Gene', (6, 9))	('fusions', 'Var', (14, 21))	('EGF', 'Gene', '1950', (10, 13))
60106	29141017	In the Phase 3 PALETTE study in patients with progressive, metastatic STS, those treated with pazopanib demonstrated significantly longer median progression-free survival (PFS) compared with those in the placebo group (4.6 months versus 1.6 months).	('patients', 'Species', '9606', (32, 40))	('progression-free survival', 'CPA', (145, 170))	('pazopanib', 'Chemical', 'MESH:C516667', (94, 103))	('longer', 'PosReg', (131, 137))	('pazopanib', 'Var', (94, 103))	('STS', 'Phenotype', 'HP:0030448', (70, 73))
60107	29141017	Importantly, in preclinical and translational studies, pazopanib inhibited activation of both phosphoinositide 3-kinase (PI3K) and MAPK/extracellular signal-regulated kinase (ERK) pathways, along with the above-mentioned oncogenic pathways in multiple tumor types.	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('ERK', 'Gene', '5595;5594;5595', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('inhibited', 'NegReg', (65, 74))	('pazopanib', 'Chemical', 'MESH:C516667', (55, 64))	('ERK', 'Gene', (175, 178))	('phosphoinositide 3-kinase', 'Gene', '5293', (94, 119))	('tumor', 'Disease', (252, 257))	('phosphoinositide 3-kinase', 'Gene', (94, 119))	('pazopanib', 'Var', (55, 64))
60108	29141017	Thus, if a cancer cell relies on the activation of PI3K and MAPK pathways for its survival, pazopanib may have enhanced anti-tumor efficacy.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('pazopanib', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('activation', 'PosReg', (37, 47))	('tumor', 'Disease', (125, 130))	('enhanced', 'PosReg', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('PI3K', 'Pathway', (51, 55))	('cancer', 'Disease', (11, 17))	('MAPK pathways', 'Pathway', (60, 73))	('pazopanib', 'Chemical', 'MESH:C516667', (92, 101))
60114	29141017	We thus hypothesize that during progression on pazopanib, the tumor cells have begun developing escape pathways around the tyrosine kinase inhibition.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('pazopanib', 'Var', (47, 56))	('escape', 'MPA', (96, 102))	('tyrosine kinase inhibition', 'MPA', (123, 149))	('pazopanib', 'Chemical', 'MESH:C516667', (47, 56))
60123	29141017	Furthermore, in glioma cell lines there is a suggestion that cediranib, a highly potent VEGFR inhibitor (VEGFRi), enhanced the effectiveness of temozolomide.	('cediranib', 'Var', (61, 70))	('VEGFR', 'Gene', (105, 110))	('VEGFR', 'Gene', (88, 93))	('temozolomide', 'Chemical', 'MESH:D000077204', (144, 156))	('glioma', 'Disease', (16, 22))	('enhanced', 'PosReg', (114, 122))	('cediranib', 'Chemical', 'MESH:C500926', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('effectiveness', 'MPA', (127, 140))	('VEGFR', 'Gene', '3791', (88, 93))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('VEGFR', 'Gene', '3791', (105, 110))
60153	29141017	Inhibition of VEGFR and other tyrosine kinase receptors with pazopanib has been shown to improve PFS relative to placebo in patients with STS and also alter signaling through PI3K/Akt and MAPK pathways.	('improve', 'PosReg', (89, 96))	('MAPK pathways', 'Pathway', (188, 201))	('signaling', 'MPA', (157, 166))	('VEGFR', 'Gene', '3791', (14, 19))	('Akt', 'Gene', (180, 183))	('STS', 'Phenotype', 'HP:0030448', (138, 141))	('pazopanib', 'Gene', (61, 70))	('PFS', 'MPA', (97, 100))	('Inhibition', 'Var', (0, 10))	('alter', 'Reg', (151, 156))	('VEGFR', 'Gene', (14, 19))	('Akt', 'Gene', '207', (180, 183))	('patients', 'Species', '9606', (124, 132))	('pazopanib', 'Chemical', 'MESH:C516667', (61, 70))
60177	29141017	Next generation sequencing could aid in the identification of sarcoma subtype-specific alterations and help elucidate key predictive biomarkers.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('aid', 'Gene', (33, 36))	('alterations', 'Var', (87, 98))	('aid', 'Gene', '57379', (33, 36))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('sarcoma', 'Disease', (62, 69))
60183	28415063	Furthermore, NRSF was genetically knocked out by antisense oligodeoxynucleotide, and the expression of MOR and the effect of morphine were subsequently analyzed.	('antisense oligodeoxynucleotide', 'Var', (49, 79))	('morphine', 'Chemical', 'MESH:D009020', (125, 133))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (59, 79))	('NRSF', 'Gene', (13, 17))	('knocked out', 'NegReg', (34, 45))
60187	28415063	Epigenetically, up-regulation of MOR could substantially improve the effect of system delivery of morphine.	('Epigenetically', 'Var', (0, 14))	('improve', 'PosReg', (57, 64))	('MOR', 'Gene', (33, 36))	('up-regulation', 'PosReg', (16, 29))	('effect of system delivery of morphine', 'MPA', (69, 106))	('morphine', 'Chemical', 'MESH:D009020', (98, 106))
60199	28415063	Previous studies have confirmed that mu-opioid receptor (MOR) expression regulation is involved in the pathogenesis of neuropathic pain, and the modulation of MOR expression is also involved in the nociceptive behavior abnormalities associated with bone cancer pain.	('bone cancer pain', 'Disease', 'MESH:D001859', (249, 265))	('neuropathic pain', 'Disease', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('pain', 'Phenotype', 'HP:0012531', (261, 265))	('nociceptive behavior abnormalities', 'Disease', 'MESH:D059226', (198, 232))	('modulation', 'Var', (145, 155))	('bone cancer pain', 'Disease', (249, 265))	('expression regulation', 'MPA', (62, 83))	('neuropathic pain', 'Disease', 'MESH:D009437', (119, 135))	('bone cancer pain', 'Phenotype', 'HP:0002653', (249, 265))	('pain', 'Phenotype', 'HP:0012531', (131, 135))	('involved', 'Reg', (87, 95))	('involved', 'Reg', (182, 190))	('nociceptive behavior abnormalities', 'Disease', (198, 232))	('mu-opioid', 'Protein', (37, 46))	('MOR', 'Gene', (159, 162))	('behavior abnormalities', 'Phenotype', 'HP:0000708', (210, 232))
60305	28415063	The effects of different doses of intraperitoneal morphine on pain-related behaviors after NRSF knockdown were evaluated.	('knockdown', 'Var', (96, 105))	('pain', 'Disease', 'MESH:D010146', (62, 66))	('pain', 'Disease', (62, 66))	('NRSF', 'Gene', (91, 95))	('morphine', 'Chemical', 'MESH:D009020', (50, 58))	('pain', 'Phenotype', 'HP:0012531', (62, 66))
60310	28415063	administrated morphine were significantly potentiated by NRSF gene knockdown in sarcoma-bearing mice.	('mice', 'Species', '10090', (96, 100))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('morphine', 'Chemical', 'MESH:D009020', (14, 22))	('knockdown', 'Var', (67, 76))	('sarcoma', 'Disease', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('NRSF gene', 'Gene', (57, 66))	('potentiated', 'PosReg', (42, 53))
60335	28415063	Interestingly, although NRSF knockdown significantly rescued the expression of MOR, no significant changes were observed in the baseline pain behaviors of the AS-ODN-treated group.	('knockdown', 'Var', (29, 38))	('pain behaviors', 'Disease', (137, 151))	('pain behaviors', 'Disease', 'MESH:D013001', (137, 151))	('AS-ODN', 'Chemical', '-', (159, 165))	('pain', 'Phenotype', 'HP:0012531', (137, 141))	('expression', 'MPA', (65, 75))	('MOR', 'Gene', (79, 82))	('rescued', 'PosReg', (53, 60))
60353	28415063	Genetic knockdown of NRSF rescues the expression of MOR and potentiates morphine analgesia.	('analgesia', 'Disease', 'MESH:D000699', (81, 90))	('expression', 'MPA', (38, 48))	('knockdown', 'Var', (8, 17))	('MOR', 'MPA', (52, 55))	('morphine', 'Chemical', 'MESH:D009020', (72, 80))	('potentiates', 'PosReg', (60, 71))	('NRSF', 'Gene', (21, 25))	('analgesia', 'Disease', (81, 90))	('rescues', 'PosReg', (26, 33))
60371	25396137	Immunohistochemically, tumor cells showed diffuse and intense positivity for both anti-S-100 and anti-HMB-45 antibodies [Figures 2 and 3].	('S-100', 'Gene', '6271', (87, 92))	('positivity', 'MPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('S-100', 'Gene', (87, 92))	('anti-HMB-45', 'Var', (97, 108))	('tumor', 'Disease', (23, 28))
60383	25396137	In our case, immunohistochemically, tumor cells showed diffuse and intense positivity for both anti-S-100 and anti-HMB-45 antibodies.	('S-100', 'Gene', '6271', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('S-100', 'Gene', (100, 105))	('positivity', 'MPA', (75, 85))	('anti-HMB-45', 'Var', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
60401	21387267	In the absence of clinical trials and treatment guidelines tailored to this population, under-treatment may disadvantage the elderly with increased cancer-related morbidity and mortality.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('disadvantage', 'NegReg', (108, 120))	('under-treatment', 'Var', (88, 103))
60425	21387267	The codes for death from soft tissue malignancy (164.1, 171, C47, C49, C38.0, C45.2) were selected to determine disease-specific survival.	('C49', 'Var', (66, 69))	('soft tissue malignancy', 'Phenotype', 'HP:0031459', (25, 47))	('C47', 'Var', (61, 64))	('C45.2', 'Var', (78, 83))	('164.1', 'Var', (49, 54))	('death', 'Disease', 'MESH:D003643', (14, 19))	('death', 'Disease', (14, 19))	('malignancy', 'Disease', 'MESH:D009369', (37, 47))	('malignancy', 'Disease', (37, 47))	('C38.0', 'Var', (71, 76))
60476	33535618	The conjugation of these antibodies with a fluorescent dye will yield in specific tracers for image-guided surgery of soft tissue sarcomas to improve the success rates of tumor resections.	('sarcomas', 'Disease', (130, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('yield', 'Reg', (64, 69))	('conjugation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (118, 138))	('improve', 'PosReg', (142, 149))	('sarcomas', 'Disease', 'MESH:D012509', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (118, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
60523	33535618	Furthermore, TEM1 expression is associated with enhanced tumor growth, presumably due to tumor-specific angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('TEM1', 'Gene', (13, 17))	('enhanced', 'PosReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('expression', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('TEM1', 'Gene', '57124', (13, 17))
60537	33535618	Additional benefits are its diffuse pattern of expression, the high frequency of positivity (STS 77%, MFS 100%, USTS 81% and SS 71%), and its correlation with advanced tumor grades.	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('positivity', 'Var', (81, 91))	('tumor', 'Disease', (168, 173))
60544	33535618	VEGFR-1 and VEGFR-2 have been clinically targeted by antibodies in STS, in contrast to VEGFR-3.	('VEGFR-3', 'Gene', '2324', (87, 94))	('VEGFR-1', 'Gene', (0, 7))	('VEGFR-2', 'Gene', '3791', (12, 19))	('VEGFR-3', 'Gene', (87, 94))	('VEGFR-1', 'Gene', '2321', (0, 7))	('VEGFR-2', 'Gene', (12, 19))	('antibodies', 'Var', (53, 63))
60562	33535618	Major advantages of VEGFR-1 are the high frequency of positivity in STS (76%), the diffuse pattern of expression in tumors and increasing expression associated with enhanced tumor grade.	('tumor', 'Disease', (174, 179))	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('enhanced', 'PosReg', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('increasing', 'PosReg', (127, 137))	('VEGFR-1', 'Gene', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('expression', 'MPA', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('VEGFR-1', 'Gene', '2321', (20, 27))	('positivity', 'Var', (54, 64))
60609	33535618	In tumor biology, PDGFR activation stimulates cell growth and enhances metastatic behavior by attracting fibroblasts, which secrete factors that promote proliferation and migration of tumor cells.	('PDGFR', 'Gene', '5159', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (3, 8))	('activation', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cell growth', 'CPA', (46, 57))	('met', 'Gene', '79811', (71, 74))	('tumor', 'Disease', (184, 189))	('stimulates', 'PosReg', (35, 45))	('proliferation', 'CPA', (153, 166))	('migration', 'CPA', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('enhances', 'PosReg', (62, 70))	('promote', 'PosReg', (145, 152))	('met', 'Gene', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('PDGFR', 'Gene', (18, 23))
60632	33535618	A phase II clinical trial applying APX005M, a second-generation agonistic CD40 monoclonal antibody, combined with Doxorubicin in STS is currently recruiting participants.	('APX005M', 'Var', (35, 42))	('participants', 'Species', '9606', (157, 169))	('CD40', 'Gene', '958', (74, 78))	('CD40', 'Gene', (74, 78))	('Doxorubicin', 'Chemical', 'MESH:D004317', (114, 125))
60806	30354935	Importantly, results show that ART is associated with improved 12-month QOL in this patient population and that no long-term deleterious effects of chemotherapy were observed in QOL measures.	('ART', 'Var', (31, 34))	('patient', 'Species', '9606', (84, 91))	('improved', 'PosReg', (54, 62))	('QOL', 'Disease', (72, 75))
60939	30709876	Refractory and metastatic infantile fibrosarcoma harboring LMNA-NTRK1 fusion shows complete and durable response to crizotinib Infantile fibrosarcoma (IFS) is a rare soft-tissue sarcoma, which classically presents as an aggressive and rapidly enlarging tumor over the distal extremities of children in their first year of life.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcoma', 'Disease', (142, 149))	('crizotinib', 'Chemical', 'MESH:D000077547', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('IFS', 'Chemical', '-', (151, 154))	('fibrosarcoma', 'Disease', 'MESH:D005354', (137, 149))	('LMNA', 'Gene', '4000', (59, 63))	('fibrosarcoma', 'Disease', (137, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (170, 185))	('sarcoma', 'Disease', (178, 185))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (36, 48))	('NTRK1', 'Gene', '4914', (64, 69))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('tumor', 'Disease', (253, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('NTRK1', 'Gene', (64, 69))	('sarcoma', 'Disease', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('LMNA', 'Gene', (59, 63))	('children', 'Species', '9606', (290, 298))	('fibrosarcoma', 'Disease', 'MESH:D005354', (36, 48))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (137, 149))	('fusion', 'Var', (70, 76))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (166, 185))	('fibrosarcoma', 'Disease', (36, 48))
60947	30709876	Classically, IFS is driven by the t(12;15)(p13;q25) translocation encoding the ETV6-NTRK3 fusion protein, as also seen in congenital mesoblastic nephroma.	('t(12;15)(p13;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (34, 51))	('congenital mesoblastic nephroma', 'Phenotype', 'HP:0100881', (122, 153))	('t(12;15)(p13;q25', 'Var', (34, 50))	('IFS', 'Chemical', '-', (13, 16))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (79, 96))	('ETV6-NTRK3 fusion', 'Gene', (79, 96))	('congenital mesoblastic nephroma', 'Disease', (122, 153))	('congenital mesoblastic nephroma', 'Disease', 'MESH:D018201', (122, 153))
60951	30709876	Given the prevalence of aberrant TRK signaling seen in a number of cancers, TRK inhibition represents an attractive therapeutic target.	('TRK', 'Gene', '4914', (76, 79))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('TRK', 'Gene', (33, 36))	('TRK', 'Gene', '4914', (33, 36))	('aberrant', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TRK', 'Gene', (76, 79))
60954	30709876	Although IFS is typically characterized by ETV6-NTRK3 fusion, herein we present the case of a child with refractory, metastatic IFS whose tumor harbored a noncanonical LMNA-NTRK1 fusion only identified by next-generation sequencing (NGS), who achieved a durable, complete response with crizotinib therapy.	('child', 'Species', '9606', (94, 99))	('LMNA', 'Gene', '4000', (168, 172))	('NTRK1', 'Gene', '4914', (173, 178))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (43, 60))	('tumor', 'Disease', (138, 143))	('IFS', 'Chemical', '-', (9, 12))	('fusion', 'Var', (179, 185))	('ETV6-NTRK3 fusion', 'Gene', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('LMNA', 'Gene', (168, 172))	('NTRK1', 'Gene', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('crizotinib', 'Chemical', 'MESH:D000077547', (286, 296))	('IFS', 'Chemical', '-', (128, 131))
60988	30709876	The results revealed copy loss at Chr 3q, copy gain at Chr 16, and homozygous deletion of CDKN2A and CDKN2B on Chr 9.	('CDKN2A', 'Gene', '1029', (90, 96))	('copy loss', 'Var', (21, 30))	('CDKN2B', 'Gene', (101, 107))	('deletion', 'Var', (78, 86))	('CDKN2B', 'Gene', '1030', (101, 107))	('CDKN2A', 'Gene', (90, 96))	('copy gain', 'Var', (42, 51))
60992	30709876	Herein we present the case of a child with refractory, metastatic IFS harboring an unusual LMNA-NTRK1 fusion, not detected by routine FISH studies, who was successfully treated with crizotinib.	('fusion', 'Var', (102, 108))	('NTRK1', 'Gene', (96, 101))	('LMNA', 'Gene', (91, 95))	('child', 'Species', '9606', (32, 37))	('crizotinib', 'Chemical', 'MESH:D000077547', (182, 192))	('NTRK1', 'Gene', '4914', (96, 101))	('IFS', 'Chemical', '-', (66, 69))	('LMNA', 'Gene', '4000', (91, 95))
60997	30709876	LMNA-NTRK1 fusions have been implicated in a number of malignancies, including Spitz nevi, colorectal cancer, lung cancer, soft-tissue sarcomas, and a rare case of infantile-onset lipofibromatosis-like neural tumor.	('colorectal cancer', 'Disease', (91, 108))	('Spitz nevi', 'Disease', (79, 89))	('soft-tissue sarcomas', 'Disease', (123, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('lung cancer', 'Disease', (110, 121))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (123, 142))	('lipofibromatosis-like neural tumor', 'Disease', (180, 214))	('malignancies', 'Disease', 'MESH:D009369', (55, 67))	('LMNA', 'Gene', (0, 4))	('nevi', 'Phenotype', 'HP:0003764', (85, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('malignancies', 'Disease', (55, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('fusions', 'Var', (11, 18))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (123, 143))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('LMNA', 'Gene', '4000', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('NTRK1', 'Gene', '4914', (5, 10))	('implicated', 'Reg', (29, 39))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (127, 142))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lipofibromatosis-like neural tumor', 'Disease', 'MESH:C536149', (180, 214))	('NTRK1', 'Gene', (5, 10))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))
60998	30709876	Within the past 2 years, there have been additional case reports of LMNA-NTRK1 fusions in pediatric soft-tissue sarcomas and IFS.	('NTRK1', 'Gene', '4914', (73, 78))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (100, 120))	('IFS', 'Chemical', '-', (125, 128))	('LMNA', 'Gene', (68, 72))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (100, 119))	('NTRK1', 'Gene', (73, 78))	('LMNA', 'Gene', '4000', (68, 72))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (104, 119))	('soft-tissue sarcomas', 'Disease', (100, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('fusions', 'Var', (79, 86))
61002	30709876	In a recent large study of pediatric tumor specimens, two cases harbored LMNA-NTRK1 fusions.	('LMNA', 'Gene', '4000', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('fusions', 'Var', (84, 91))	('NTRK1', 'Gene', '4914', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('LMNA', 'Gene', (73, 77))	('tumor', 'Disease', (37, 42))	('NTRK1', 'Gene', (78, 83))
61003	30709876	Of the two patients with LMNA-NTRK1 fusions, one was a 1-yr-old with metastatic fibrosarcoma, the other patient was a 14-yr-old with PNET.	('patients', 'Species', '9606', (11, 19))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (80, 92))	('fibrosarcoma', 'Disease', 'MESH:D005354', (80, 92))	('LMNA', 'Gene', (25, 29))	('NTRK1', 'Gene', '4914', (30, 35))	('fusions', 'Var', (36, 43))	('patient', 'Species', '9606', (11, 18))	('patient', 'Species', '9606', (104, 111))	('NTRK1', 'Gene', (30, 35))	('LMNA', 'Gene', '4000', (25, 29))	('fibrosarcoma', 'Disease', (80, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('metastatic fibrosarcoma', 'Phenotype', 'HP:0200059', (69, 92))
61007	30709876	Of note, as in our case presented here, coincident CDKN2A deletions have been found in a significant number of the above patients who harbor NTRK1 fusions, including three of four cases, two of four cases, three of five cases, and in Wong's case above.	('CDKN2A', 'Gene', '1029', (51, 57))	('found', 'Reg', (78, 83))	('NTRK1', 'Gene', (141, 146))	('deletions', 'Var', (58, 67))	('fusions', 'Var', (147, 154))	('CDKN2A', 'Gene', (51, 57))	('patients', 'Species', '9606', (121, 129))	('NTRK1', 'Gene', '4914', (141, 146))
61008	30709876	NTRK fusions are being increasingly implicated in a number of malignancies in both pediatric and adult patients, including pediatric high-grade glioma, soft-tissue sarcomas, secretory breast cancer, and papillary thyroid cancer, in addition to many other solid tumors.	('implicated', 'Reg', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('thyroid cancer', 'Phenotype', 'HP:0002890', (213, 227))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (156, 171))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (203, 227))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('fusions', 'Var', (5, 12))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (203, 227))	('glioma', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('soft-tissue sarcomas', 'Disease', (152, 172))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('TRK', 'Gene', (1, 4))	('solid tumors', 'Disease', (255, 267))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (152, 171))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('malignancies', 'Disease', (62, 74))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('TRK', 'Gene', '4914', (1, 4))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (152, 172))	('papillary thyroid cancer', 'Disease', (203, 227))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('breast cancer', 'Disease', (184, 197))	('patients', 'Species', '9606', (103, 111))	('solid tumors', 'Disease', 'MESH:D009369', (255, 267))
61011	30709876	There have been three additional patients reported with IFS harboring EML4-NTRK3 fusions rather than the classic ETV6-NTRK3 fusion, as well.	('EML4', 'Gene', (70, 74))	('IFS', 'Chemical', '-', (56, 59))	('EML4', 'Gene', '27436', (70, 74))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (113, 130))	('patients', 'Species', '9606', (33, 41))	('NTRK3', 'Gene', '4916', (118, 123))	('NTRK3', 'Gene', '4916', (75, 80))	('ETV6-NTRK3 fusion', 'Gene', (113, 130))	('fusions', 'Var', (81, 88))	('NTRK3', 'Gene', (118, 123))	('NTRK3', 'Gene', (75, 80))
61012	30709876	Consistently, in a recent article of 10 patients with ETV6-NTRK3 fusion-negative spindle cell sarcomas with pathology reminiscent of IFS, testing revealed one EML4-NTRK3 fusion and one TPM3-NTRK1 fusion.	('TPM3', 'Gene', '7170', (185, 189))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (54, 71))	('ETV6-NTRK3 fusion', 'Gene', (54, 71))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('IFS', 'Chemical', '-', (133, 136))	('NTRK3', 'Gene', '4916', (164, 169))	('NTRK3', 'Gene', '4916', (59, 64))	('TPM3', 'Gene', (185, 189))	('sarcomas', 'Disease', (94, 102))	('fusion', 'Var', (170, 176))	('NTRK3', 'Gene', (59, 64))	('NTRK1', 'Gene', '4914', (190, 195))	('NTRK3', 'Gene', (164, 169))	('NTRK1', 'Gene', (190, 195))	('patients', 'Species', '9606', (40, 48))	('EML4', 'Gene', (159, 163))	('EML4', 'Gene', '27436', (159, 163))
61014	30709876	Given the increasing awareness of aberrant TRK signaling in a wide number of malignancies, selective TRK inhibitors are currently in early-phase clinical trials, with positive initial results.	('TRK', 'Gene', '4914', (101, 104))	('TRK', 'Gene', (43, 46))	('TRK', 'Gene', '4914', (43, 46))	('aberrant', 'Var', (34, 42))	('malignancies', 'Disease', (77, 89))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))	('TRK', 'Gene', (101, 104))
61019	30709876	It is becoming increasingly evident that aberrant NTRK signaling plays a vital role in mediating solid tumors in both pediatric and adult patients.	('solid tumors', 'Disease', 'MESH:D009369', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('aberrant', 'Var', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('solid tumors', 'Disease', (97, 109))	('TRK', 'Gene', (51, 54))	('TRK', 'Gene', '4914', (51, 54))	('patients', 'Species', '9606', (138, 146))
61021	30709876	As NGS technology is not yet easily accessible to all patients, other research groups have published on the feasibility of using pan-Trk immunohistochemistry to identify NTRK rearrangements in pediatric mesenchymal cancers rather than relying on standard FISH and RT-PCR panels, which miss nonclassical NTRK rearrangements, as was the case initially for our patient.	('patient', 'Species', '9606', (54, 61))	('pan', 'Gene', '51816', (271, 274))	('TRK', 'Gene', (304, 307))	('Trk', 'Gene', (133, 136))	('TRK', 'Gene', '4914', (304, 307))	('patients', 'Species', '9606', (54, 62))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('TRK', 'Gene', (171, 174))	('Trk', 'Gene', '4914', (133, 136))	('TRK', 'Gene', '4914', (171, 174))	('pan', 'Gene', (271, 274))	('patient', 'Species', '9606', (358, 365))	('pan', 'Gene', '51816', (129, 132))	('pan', 'Gene', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('pediatric mesenchymal cancers', 'Disease', (193, 222))	('pediatric mesenchymal cancers', 'Disease', 'MESH:D009369', (193, 222))	('rearrangements', 'Var', (175, 189))
61022	30709876	Given the growing recognition of NTRK fusions in a variety of tumors, especially soft-tissue sarcomas, further work will be required to characterize the histologic, molecular, and clinical signatures of such malignancies.	('malignancies', 'Disease', (208, 220))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (85, 100))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('soft-tissue sarcomas', 'Disease', (81, 101))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('TRK', 'Gene', (34, 37))	('TRK', 'Gene', '4914', (34, 37))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (81, 100))	('malignancies', 'Disease', 'MESH:D009369', (208, 220))	('fusions', 'Var', (38, 45))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (81, 101))
61023	30709876	Whether soft-tissue sarcomas of infancy harboring nonclassical NTRK fusions represent a distinct clinical entity from IFS showing the canonical ETV6-NTRK3 fusion also remains to be further investigated.	('IFS', 'Chemical', '-', (118, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('TRK', 'Gene', (150, 153))	('TRK', 'Gene', (64, 67))	('TRK', 'Gene', '4914', (150, 153))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (144, 161))	('TRK', 'Gene', '4914', (64, 67))	('fusions', 'Var', (68, 75))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (8, 28))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (8, 27))	('ETV6-NTRK3 fusion', 'Gene', (144, 161))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (12, 27))	('soft-tissue sarcomas', 'Disease', (8, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
61025	30709876	In pediatric patients with soft-tissue sarcomas harboring NTRK fusions refractory to standard treatments, oral crizotinib may be a reasonable and effective therapeutic option for inducing complete and durable response while eagerly awaiting clinical deployment of selective TRK inhibitors.	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (27, 47))	('TRK', 'Gene', (274, 277))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (27, 46))	('TRK', 'Gene', '4914', (274, 277))	('patients', 'Species', '9606', (13, 21))	('soft-tissue sarcomas', 'Disease', (27, 47))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (31, 46))	('TRK', 'Gene', (59, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('TRK', 'Gene', '4914', (59, 62))	('crizotinib', 'Chemical', 'MESH:D000077547', (111, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('fusions', 'Var', (63, 70))
61039	27098543	Four-month PFS rate was 46 %, and significantly better for patients with ECOG 0 (ECOG 0: 54 % vs ECOG 1: 43 % vs ECOG 2: 0 %; p = 0.003), for patients undergoing metastasectomy after GD (sCR2 75 % vs no-sCR2 40 %, p = 0.02) and for osteosarcoma (osteosarcoma 56 % vs HGS 18 %; p = 0.05), with no differences according to age, line of treatment, and pattern of metastases.	('GD', 'Chemical', '-', (183, 185))	('metastases', 'Disease', 'MESH:D009362', (360, 370))	('HGS', 'Gene', '9146', (267, 270))	('sCR2', 'Gene', (187, 191))	('osteosarcoma', 'Phenotype', 'HP:0002669', (246, 258))	('metastases', 'Disease', (360, 370))	('osteosarcoma', 'Phenotype', 'HP:0002669', (232, 244))	('HGS', 'Gene', (267, 270))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('sCR2', 'Gene', (203, 207))	('PFS', 'MPA', (11, 14))	('patients', 'Species', '9606', (59, 67))	('ECOG 0', 'Var', (73, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('sCR2', 'Gene', '5937', (187, 191))	('better', 'PosReg', (48, 54))	('osteosarcoma', 'Disease', (246, 258))	('osteosarcoma', 'Disease', 'MESH:D012516', (246, 258))	('osteosarcoma', 'Disease', (232, 244))	('osteosarcoma', 'Disease', 'MESH:D012516', (232, 244))	('sCR2', 'Gene', '5937', (203, 207))	('patients', 'Species', '9606', (142, 150))
61233	28651927	Originally, the study was designed to detect a 4-month improvement in median overall survival, assuming a median survival of 10 months in the doxorubicin control group and 14 months in the doxorubicin plus evofosfamide investigational group (eg, a hazard ratio [HR] of 0 714).5,12-15 However, several clinical trials were reported after the study initiation that indicated the median overall survival for patients with sarcoma receiving single-drug doxorubicin in the first-line setting was likely to be longer than 10 months.	('doxorubicin', 'Chemical', 'MESH:D004317', (449, 460))	('sarcoma', 'Disease', (419, 426))	('single-drug', 'Var', (437, 448))	('evofosfamide', 'Chemical', 'MESH:C552526', (206, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (419, 426))	('patients', 'Species', '9606', (405, 413))	('doxorubicin', 'Chemical', 'MESH:D004317', (189, 200))	('sarcoma', 'Disease', 'MESH:D012509', (419, 426))	('doxorubicin', 'Chemical', 'MESH:D004317', (142, 153))
61282	28651927	Plasma concentrations for bromo-isophos-phoramide mustard were roughly 2% of that for evofosfamide.	('bromo-isophos-phoramide', 'Var', (26, 49))	('bromo-isophos-phoramide', 'Chemical', '-', (26, 49))	('evofosfamide', 'Chemical', 'MESH:C552526', (86, 98))	('Plasma concentrations', 'MPA', (0, 21))
61299	28651927	Haematological adverse events were more common in the doxorubicin plus evofosfamide group than in the doxorubicin alone group, with higher overall incidences of anaemia (189 [60%] of 313 vs 104 [34%] of 308), thrombocytopenia (72 [23%] vs 19 [6%]), and febrile neutropenia (57 [18%] vs 34 [11%]).	('febrile neutropenia', 'Disease', 'MESH:D009503', (253, 272))	('thrombocytopenia', 'Disease', 'MESH:D013921', (209, 225))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (209, 225))	('doxorubicin', 'Chemical', 'MESH:D004317', (54, 65))	('evofosfamide', 'Chemical', 'MESH:C552526', (71, 83))	('thrombocytopenia', 'Disease', (209, 225))	('anaemia', 'Disease', 'MESH:D000740', (161, 168))	('doxorubicin', 'Chemical', 'MESH:D004317', (102, 113))	('anaemia', 'Disease', (161, 168))	('neutropenia', 'Phenotype', 'HP:0001875', (261, 272))	('anaemia', 'Phenotype', 'HP:0001903', (161, 168))	('doxorubicin', 'Var', (54, 65))	('febrile neutropenia', 'Disease', (253, 272))
61450	27652195	As a result, many surgeons now inject substances such as n-butyl cyanoacrylate (NBCA), polyvinyl alcohol (PVA), or other substances intraoperatively to further decrease blood loss.	('decrease blood loss', 'Disease', (160, 179))	('NBCA', 'Chemical', 'MESH:D004659', (80, 84))	('decrease blood loss', 'Disease', 'MESH:D006473', (160, 179))	('polyvinyl alcohol', 'Chemical', 'MESH:D011142', (87, 104))	('polyvinyl', 'Var', (87, 96))	('PVA', 'Chemical', 'MESH:D011142', (106, 109))	('n-butyl cyanoacrylate', 'Chemical', 'MESH:D004659', (57, 78))
61543	26384279	Tumor-specific fluorescence detected using FMT yielded a tumor to normal tissue fluorochrome ratio of 6.7 while the tumor to normal tissue fluorescence ratio using a handheld epi-illumination device ranged from 5 to over 20.	('FMT', 'Var', (43, 46))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (116, 121))
61562	26384279	In a subsequent randomized phase III clinical trial of patients with malignant glioma undergoing complete surgical resection, use of 5-ALA fluorescence to guide surgery was associated with a 20% increase in 6-month progression free survival.	('malignant glioma', 'Disease', 'MESH:D005910', (69, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('use', 'Var', (126, 129))	('patients', 'Species', '9606', (55, 63))	('progression free survival', 'CPA', (215, 240))	('5-ALA', 'Chemical', 'MESH:C000614854', (133, 138))	('increase', 'PosReg', (195, 203))	('malignant glioma', 'Disease', (69, 85))
61619	23922114	Inhibition of histone deacetylase (HDAC) provides a novel approach for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('HDAC', 'Gene', (35, 39))	('histone deacetylase', 'Gene', '9734', (14, 33))	('HDAC', 'Gene', '9734', (35, 39))	('Inhibition', 'Var', (0, 10))	('histone deacetylase', 'Gene', (14, 33))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
61621	23922114	Several lines of evidence suggest that aberrant recruitment of HDAC and the resulting modification of chromatin structure may have a role in changes in gene expression seen in transformed cells.	('recruitment', 'MPA', (48, 59))	('HDAC', 'Gene', (63, 67))	('HDAC', 'Gene', '9734', (63, 67))	('chromatin structure', 'MPA', (102, 121))	('changes', 'Reg', (141, 148))	('modification', 'Reg', (86, 98))	('gene expression', 'MPA', (152, 167))	('aberrant', 'Var', (39, 47))
61721	33176817	The definitive diagnosis is made by a NUT monoclonal antibody or gene analysis, but these are not always routinely available.	('NUT', 'Gene', (38, 41))	('NUT', 'Gene', '256646', (38, 41))	('gene analysis', 'Var', (65, 78))
61734	33176817	NUT carcinoma is genetically defined and characterized by chromosomal rearrangements in the NUT gene.	('NUT', 'Gene', '256646', (92, 95))	('NUT carcinoma', 'Disease', (0, 13))	('NUT', 'Gene', (92, 95))	('NUT carcinoma', 'Disease', 'MESH:D009369', (0, 13))	('NUT', 'Gene', (0, 3))	('NUT', 'Gene', '256646', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (4, 13))	('chromosomal rearrangements', 'Var', (58, 84))
61737	33176817	Historically, several epithelial malignancies with chromosomal translocation 15;19 were found to be clinically aggressive.	('malignancies', 'Disease', 'MESH:D009369', (33, 45))	('chromosomal translocation 15;19', 'Var', (51, 82))	('malignancies', 'Disease', (33, 45))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (22, 45))
61857	30782196	Our results showed that high expression levels of HIF-1alpha were associated with poorer OS (overall survival) (HR = 2.61, 95% CI 2.11-3.23, P <  0.001) and shorter DFS (disease-free survival) (HR = 2.02, 95% CI 1.41-2.89, P <  0.001) in bone tumor.	('bone tumor', 'Disease', (238, 248))	('HIF-1alpha', 'Gene', '3091', (50, 60))	('shorter', 'NegReg', (157, 164))	('poorer', 'NegReg', (82, 88))	('bone tumor', 'Disease', 'MESH:D001859', (238, 248))	('DFS', 'MPA', (165, 168))	('HIF-1alpha', 'Gene', (50, 60))	('expression levels', 'MPA', (29, 46))	('high', 'Var', (24, 28))	('OS', 'Chemical', '-', (89, 91))	('bone tumor', 'Phenotype', 'HP:0010622', (238, 248))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
61899	30782196	2, high HIF-1alpha expression was strongly associated with MVD of bone tumor (SMD = 2.34, 95% CI 1.35-3.34, P <  0.001; random effects model: chi2 = 69.97, I2 = 91.4, P <  0.001).	('associated with', 'Reg', (43, 58))	('expression', 'MPA', (19, 29))	('MVD of bone tumor', 'Disease', 'MESH:D001859', (59, 76))	('SMD', 'Disease', 'MESH:C537501', (78, 81))	('HIF-1alpha', 'Gene', (8, 18))	('SMD', 'Disease', (78, 81))	('bone tumor', 'Phenotype', 'HP:0010622', (66, 76))	('high', 'Var', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('MVD of bone tumor', 'Disease', (59, 76))	('HIF-1alpha', 'Gene', '3091', (8, 18))
61901	30782196	3a, high expression level of HIF-1alpha significantly predicted unfavorable OS in bone tumor (HR = 2.61, 95% CI 2.11-3.23, P <  0.001), without any heterogeneity in the data (fixed effects model: chi2 = 5.70, I2 = 0, P = 0.770).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('OS', 'Chemical', '-', (76, 78))	('bone tumor', 'Phenotype', 'HP:0010622', (82, 92))	('bone tumor', 'Disease', (82, 92))	('HIF-1alpha', 'Gene', (29, 39))	('high', 'Var', (4, 8))	('bone tumor', 'Disease', 'MESH:D001859', (82, 92))	('HIF-1alpha', 'Gene', '3091', (29, 39))
61992	29686838	Analysis of a subset group of patients with >= 24-month follow-up revealed that smoking impacted DMFS (p < 0.0001) and PFS (p = 0.0004) on UVA, and DMFS (p = 0.0001, 95% CI 2.14-9.61) and PFS (p = 0.005, 95% CI 1.45-8.21) on MVA.	('DMFS', 'MPA', (97, 101))	('PFS', 'Gene', (119, 122))	('DMFS', 'Var', (148, 152))	('DMFS', 'Chemical', '-', (97, 101))	('patients', 'Species', '9606', (30, 38))	('UVA', 'Disease', (139, 142))	('DMFS', 'Chemical', '-', (148, 152))	('impacted', 'Reg', (88, 96))
61994	29686838	Current smoking impacted DMFS on UVA (p = 0.0005) and MVA (p = 0.0009, 95% CI 1.62-6.50), and PFS on UVA (p = 0.0014) and MVA (p = 0.0109, 95% CI 1.24-5.09).	('DMFS', 'Var', (25, 29))	('DMFS', 'Chemical', '-', (25, 29))	('PFS', 'Var', (94, 97))	('MVA', 'Disease', (54, 57))	('UVA', 'Disease', (33, 36))
62169	29482629	Intratumoral hemorrhage is common and observed in 8 (50.0%) of 16 cases; this feature exhibits hyperdensity on plain CT images, hyperintensity on T1W images, and hypointensity on T2W images.	('hemorrhage', 'Disease', 'MESH:D006470', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('hyper', 'Disease', 'MESH:D053307', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('hyper', 'Disease', (128, 133))	('hyper', 'Disease', 'MESH:D053307', (95, 100))	('tumor', 'Disease', (5, 10))	('hemorrhage', 'Disease', (13, 23))	('hypointensity', 'Var', (162, 175))	('hyper', 'Disease', (95, 100))
62279	27503773	Even by going through the operating holes, sub broken surgery may cause abdominal and pelvic sarcoma metastasis, resulting in a rapid development of this tumor.	('rapid development', 'MPA', (128, 145))	('pelvic sarcoma metastasis', 'Disease', (86, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cause', 'Reg', (66, 71))	('pelvic sarcoma metastasis', 'Disease', 'MESH:D009362', (86, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('sub broken surgery', 'Var', (43, 61))	('tumor', 'Disease', (154, 159))
62309	27503773	Supplemented treatment or even secondary cytoreductive surgery may improve prognosis for patients with tumor recurrence caused by sub-broken surgery.	('prognosis', 'MPA', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('improve', 'PosReg', (67, 74))	('sub-broken surgery', 'Var', (130, 148))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
62371	26161403	To asses MVD in tumors tissues many markers were used, that is, CD34, CD31, CD105, and von Willebrand factor.	('CD31', 'Gene', '5175', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('CD34', 'Gene', (64, 68))	('CD34', 'Gene', '947', (64, 68))	('CD105', 'Var', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('von Willebrand', 'Disease', (87, 101))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('von Willebrand', 'Disease', 'MESH:D014842', (87, 101))	('CD31', 'Gene', (70, 74))
62372	26161403	The undisputed advantage of glycoprotein CD34 is its high sensitivity and specificity, especially in endothelial cells staining.	('glycoprotein', 'Var', (28, 40))	('CD34', 'Gene', '947', (41, 45))	('CD34', 'Gene', (41, 45))
62413	22952867	Using ex-vivo transduction of oncogenic Kras(G12V) into p16/p19-/- bone marrow cells, we generated transplantable leukemia-initiating cells that rapidly induced tumor formation in the skeletal muscle of immunocompromised NOD.SCID mice.	('tumor', 'Disease', (161, 166))	('mice', 'Species', '10090', (230, 234))	('NOD', 'Gene', '1822', (221, 224))	('leukemia', 'Phenotype', 'HP:0001909', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('leukemia', 'Disease', 'MESH:D007938', (114, 122))	('leukemia', 'Disease', (114, 122))	('NOD', 'Gene', (221, 224))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('G12V', 'Mutation', 'rs121913529', (45, 49))	('induced', 'Reg', (153, 160))	('Kras(G12V', 'Var', (40, 49))	('rat', 'Species', '10116', (93, 96))
62414	22952867	In this model, murine histiocytic sarcomas, equivalent to human myeloid sarcomas, emerged at the injection site 30-50 days after cell implantation and consisted of tightly packed monotypic cells that were CD48+, CD47+ and Mac1+, with low or absent expression of other hematopoietic lineage markers.	('CD47+', 'Var', (212, 217))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('CD48+', 'Var', (205, 210))	('human', 'Species', '9606', (58, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('murine', 'Species', '10090', (15, 21))	('sarcomas', 'Disease', (34, 42))	('myeloid sarcomas', 'Disease', 'MESH:D023981', (64, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (22, 41))	('histiocytic sarcoma', 'Disease', (22, 41))	('sarcomas', 'Disease', (72, 80))	('myeloid sarcomas', 'Disease', (64, 80))	('sarcomas', 'Disease', 'MESH:D012509', (34, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (34, 42))
62416	22952867	P16/p19-/-; Kras(G12V) myeloid sarcomas were multi-clonal, with dominant clones selected during secondary transplantation.	('myeloid sarcomas', 'Disease', 'MESH:D023981', (23, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('P16', 'Gene', '12578', (0, 3))	('P16', 'Gene', (0, 3))	('Kras(G12V', 'Var', (12, 21))	('G12V', 'Mutation', 'rs121913529', (17, 21))	('myeloid sarcomas', 'Disease', (23, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
62430	22952867	Moreover, constitutively activated Kras(G12D) combined with p16/p19 deficiency induces aggressive cancers in a number of non-hematopoietic tissues and organs in mice.	('p16/p19', 'Gene', (60, 67))	('mice', 'Species', '10090', (161, 165))	('aggressive cancers', 'Disease', (87, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('deficiency', 'Var', (68, 78))	('aggressive cancers', 'Disease', 'MESH:D009369', (87, 105))	('Kras(G12D', 'Var', (35, 44))	('G12D', 'Mutation', 'rs121913529', (40, 44))	('induces', 'Reg', (79, 86))
62436	22952867	Bone marrow (BM) cells were isolated from p16p19-/- mice, infected with Kras(G12V) in a GFP-tagged pGIPZ lentivirus, and injected retro-orbitally into immunodeficient NOD.SCID mice.	('Kras(G12V', 'Gene', (72, 81))	('mice', 'Species', '10090', (52, 56))	('mice', 'Species', '10090', (176, 180))	('p16p19-/-', 'Var', (42, 51))	('NOD', 'Gene', '1822', (167, 170))	('G12V', 'Mutation', 'rs121913529', (77, 81))	('NOD', 'Gene', (167, 170))
62439	22952867	Likewise, wild-type (WT) C57BL/6 BM cells infected with Kras(G12V) induced leukemias in only 2 out of 10 injected NOD.SCID mice.	('leukemias', 'Disease', 'MESH:D007938', (75, 84))	('induced', 'Reg', (67, 74))	('NOD', 'Gene', (114, 117))	('Kras(G12V', 'Var', (56, 65))	('leukemias', 'Phenotype', 'HP:0001909', (75, 84))	('leukemias', 'Disease', (75, 84))	('G12V', 'Mutation', 'rs121913529', (61, 65))	('leukemia', 'Phenotype', 'HP:0001909', (75, 83))	('mice', 'Species', '10090', (123, 127))	('NOD', 'Gene', '1822', (114, 117))
62440	22952867	Thus, consistent with previous reports, the combination of oncogenic Kras and p16p19-deficiency potently drives leukemogenesis in mouse BM cells, whereas either of these two lesions alone shows limited leukemogenic potential within an 8 to 10- week follow up time.	('p16p19-deficiency potently drives leukemogenesis', 'Disease', (78, 126))	('Kras', 'Var', (69, 73))	('mouse', 'Species', '10090', (130, 135))	('p16p19-deficiency potently drives leukemogenesis', 'Disease', 'MESH:D007153', (78, 126))
62441	22952867	Significantly, prior reports indicate that even with longer follow up (8-9 months), p16p19-deficiency or oncogenic Kras alone produces hematopoietic neoplasms (mostly B- or T-lymphomas and T cell leukemias) with relatively low efficiency.	('Kras', 'Gene', (115, 119))	('p16p19-deficiency', 'Disease', (84, 101))	('p16p19-deficiency', 'Disease', 'MESH:D007153', (84, 101))	('neoplasms', 'Phenotype', 'HP:0002664', (149, 158))	('leukemia', 'Phenotype', 'HP:0001909', (196, 204))	('lymphomas', 'Phenotype', 'HP:0002665', (175, 184))	('produces', 'Reg', (126, 134))	('oncogenic', 'Var', (105, 114))	('hematopoietic neoplasms', 'Disease', 'MESH:D019337', (135, 158))	('T-lymphomas and T cell leukemias', 'Disease', 'MESH:D016399', (173, 205))	('hematopoietic neoplasms', 'Disease', (135, 158))	('hematopoietic neoplasms', 'Phenotype', 'HP:0004377', (135, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (175, 183))	('neoplasm', 'Phenotype', 'HP:0002664', (149, 157))	('leukemias', 'Phenotype', 'HP:0001909', (196, 205))
62442	22952867	The spleen and liver of leukemic mice originally injected with p16p19-/-; Kras(G12V) BM cells, exhibited extramedullary hematopoiesis and massive infiltration by intermediate to large size cells with oval, irregularly folded nuclei, prominent nucleoli, and a moderate to large amount of eosinophilic cytoplasm most consistent with involvement of a non-lymphoid hematopoietic malignancy (Fig.	('liver of leukemic', 'Disease', (15, 32))	('hematopoietic malignancy', 'Phenotype', 'HP:0004377', (361, 385))	('lymphoid hematopoietic malignancy', 'Phenotype', 'HP:0005526', (352, 385))	('liver of leukemic', 'Disease', 'MESH:D007938', (15, 32))	('rat', 'Species', '10116', (152, 155))	('extramedullary hematopoiesis', 'Phenotype', 'HP:0001978', (105, 133))	('non-lymphoid hematopoietic malignancy', 'Disease', 'MESH:D019337', (348, 385))	('rat', 'Species', '10116', (263, 266))	('p16p19-/-', 'Var', (63, 72))	('hematopoiesis', 'Disease', 'MESH:C536227', (120, 133))	('non-lymphoid hematopoietic malignancy', 'Disease', (348, 385))	('mice', 'Species', '10090', (33, 37))	('G12V', 'Mutation', 'rs121913529', (79, 83))	('hematopoiesis', 'Disease', (120, 133))
62445	22952867	Taken together, this constellation of findings is consistent with the development of murine histiocytic leukemia, equivalent to human acute myeloid leukemia, after retro-orbital injection of p16p19-/-; Kras bone marrow cells.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('p16p19-/-', 'Var', (191, 200))	('murine', 'Species', '10090', (85, 91))	('leukemia', 'Disease', (104, 112))	('acute myeloid leukemia', 'Disease', (134, 156))	('leukemia', 'Disease', 'MESH:D007938', (104, 112))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('leukemia', 'Disease', (148, 156))	('human', 'Species', '9606', (128, 133))	('leukemia', 'Disease', 'MESH:D007938', (148, 156))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))
62447	22952867	The majority of GFP+ tumor cells expressed CD48 (99.3+-0.7%), CD47 (89.5+-6.9%) and Mac1 (74.4+-14.7%), while expression of Gr1 (4.73+-2.65%), B220 (1.35+-1.52%), CD4 (18.6+-16.8%), and Ter119 (3.13+-1.6%, Fig.	('CD47', 'Var', (62, 66))	('Ter119', 'Gene', (186, 192))	('Gr1', 'Gene', '546644', (124, 127))	('Gr1', 'Gene', (124, 127))	('tumor', 'Disease', (21, 26))	('Ter119', 'Gene', '104231', (186, 192))	('CD48', 'Var', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
62448	22952867	Variable levels of CD8 (68.8+-14.9%) and CD71 (58.6+-16.8%) were seen in a subset of mice (10 out of 32 animals examined).	('mice', 'Species', '10090', (85, 89))	('CD8', 'Gene', (19, 22))	('CD71', 'Var', (41, 45))	('CD8', 'Gene', '925', (19, 22))
62452	22952867	39 out of 46 animals receiving p16p19-/-; Kras(G12V) BM cells developed tumors at the site of injection within 30-50 days (one additional mouse developed tumor at day 70, Table 1, Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Kras(G12V', 'Var', (42, 51))	('tumor', 'Disease', (72, 77))	('mouse', 'Species', '10090', (138, 143))	('p16p19-/-; Kras(G12V', 'Var', (31, 51))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('G12V', 'Mutation', 'rs121913529', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (154, 159))
62453	22952867	In parallel control experiments, NOD-SCID mice receiving p16p19-/-; Ctrl BM cells (n = 16 mice, 3 independent experiments) or WT; Kras(G12V) BM cells (n = 10 mice, 2 independent experiments) in the cardiotoxin pre-injured gastrocnemius muscles produced no tumors (Table 1), nor did C57BL/6 mice receiving p16p19-/-; Kras(G12V) BM cells in pre-injured muscles (0/10).	('p16p19-/-', 'Var', (57, 66))	('mice', 'Species', '10090', (158, 162))	('mice', 'Species', '10090', (42, 46))	('NOD', 'Gene', '1822', (33, 36))	('G12V', 'Mutation', 'rs121913529', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('G12V', 'Mutation', 'rs121913529', (321, 325))	('mice', 'Species', '10090', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('NOD', 'Gene', (33, 36))	('tumors', 'Disease', (256, 262))	('mice', 'Species', '10090', (290, 294))
62454	22952867	To assess the influence of cardiotoxin pre-injury on subsequent tumor development, p16p19-/-; Kras(G12V) BM cells were injected into the gastrocnemius muscles of an additional cohort of NOD.SCID mice without cardiotoxin pre-injury (n = 10 mice, 2 independent experiments, Table 1).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cardiotoxin pre-injury', 'Disease', 'MESH:D058246', (208, 230))	('mice', 'Species', '10090', (195, 199))	('tumor', 'Disease', (64, 69))	('NOD', 'Gene', '1822', (186, 189))	('cardiotoxin pre-injury', 'Disease', (27, 49))	('p16p19-/-', 'Var', (83, 92))	('G12V', 'Mutation', 'rs121913529', (99, 103))	('cardiotoxin pre-injury', 'Disease', (208, 230))	('cardiotoxin pre-injury', 'Disease', 'MESH:D058246', (27, 49))	('NOD', 'Gene', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mice', 'Species', '10090', (239, 243))
62456	22952867	Phenotypic analyses of tumor samples indicated that tumors arising from p16p19-/-; Kras(G12V) BM cells were comprised mostly of immature GFP+ monocytic cells (61.2+-13.9%, Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('G12V', 'Mutation', 'rs121913529', (88, 92))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('p16p19-/-', 'Var', (72, 81))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
62457	22952867	The immunophenotype of GFP+ tumor cells recovered from muscle was highly similar to that of leukemic cells recovered from mice transplanted retro-orbitally with p16p19-/-; Kras(G12V) cells (Fig.	('mice', 'Species', '10090', (122, 126))	('tumor', 'Disease', (28, 33))	('leukemic', 'Disease', (92, 100))	('p16p19-/-', 'Var', (161, 170))	('G12V', 'Mutation', 'rs121913529', (177, 181))	('leukemic', 'Disease', 'MESH:D007938', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
62459	22952867	One notable exception was the more frequent expression of CD8 by tumor cells recovered from the bone marrow of mice transplanted retro-orbitally with p16p19-/-; Kras-transduced cells (68.8+-14.9% vs. 9.24+-9.05%, Figs.	('p16p19-/-', 'Var', (150, 159))	('expression', 'MPA', (44, 54))	('tumor', 'Disease', (65, 70))	('CD8', 'Gene', (58, 61))	('mice', 'Species', '10090', (111, 115))	('CD8', 'Gene', '925', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
62460	22952867	In general, however, the immunophenotype of the murine histiocytic neoplasm induced from p16p19-/-; Kras(G12V) BM cells appears to be independent of its primary site and particular microenvironment.	('p16p19-/-; Kras(G12V) BM', 'Var', (89, 113))	('G12V', 'Mutation', 'rs121913529', (105, 109))	('neoplasm', 'Disease', (67, 75))	('murine', 'Species', '10090', (48, 54))	('neoplasm', 'Phenotype', 'HP:0002664', (67, 75))	('neoplasm', 'Disease', 'MESH:D009369', (67, 75))
62463	22952867	Immunohistochemical staining of primary tumor samples demonstrated that the tumor cells were GFP+ (consistent with flow cytometry analyses (Fig.	('GFP+', 'Var', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('rat', 'Species', '10116', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
62468	22952867	Based on their morphology and staining pattern, the muscle tumors arising from p16p19-/-; Kras(G12V) BM cells were classified as histiocytic sarcomas (equivalent of human myeloid sarcomas).	('muscle tumors', 'Disease', (52, 65))	('myeloid sarcomas', 'Disease', 'MESH:D023981', (171, 187))	('myeloid sarcomas', 'Disease', (171, 187))	('sarcomas', 'Disease', 'MESH:D012509', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (129, 148))	('sarcomas', 'Disease', (141, 149))	('Kras', 'Var', (90, 94))	('sarcomas', 'Disease', 'MESH:D012509', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('human', 'Species', '9606', (165, 170))	('sarcomas', 'Disease', (179, 187))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('muscle tumors', 'Disease', 'MESH:D009217', (52, 65))	('p16p19-/-; Kras', 'Var', (79, 94))	('G12V', 'Mutation', 'rs121913529', (95, 99))	('histiocytic sarcoma', 'Disease', (129, 148))
62475	22952867	GFP+ cells were CD48hi (95.4+-3.1% in bone marrow, 98.9+-0.9% in spleen), CD47hi (93.4+-6.1% in bone marrow, 89.2+-11.7% in spleen), Mac1mid/hi (79.1+-12.5% in bone marrow, 70.5+-17.9% in spleen), and B220-/lo, CD4-/lo, CD8-/lo, Ter119-/lo, and CD71lo/mid (Fig.	('CD71lo/mid', 'Var', (245, 255))	('CD4-/lo', 'Var', (211, 218))	('Ter119', 'Gene', (229, 235))	('CD8', 'Gene', (220, 223))	('CD48hi', 'Var', (16, 22))	('CD8', 'Gene', '925', (220, 223))	('Ter119', 'Gene', '104231', (229, 235))	('CD47hi', 'Var', (74, 80))
62476	22952867	This immunophenotype is highly consistent with the phenotype of GFP+ cells isolated from primary histiocytic sarcomas induced by intramuscular injection of p16p19-/-; Kras(G12V) BM cells (see Fig.	('Kras(G12V', 'Var', (167, 176))	('G12V', 'Mutation', 'rs121913529', (172, 176))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (97, 116))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('histiocytic sarcoma', 'Disease', (97, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('p16p19-/-; Kras(G12V', 'Var', (156, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcomas', 'Disease', (109, 117))
62477	22952867	2D), as well as the phenotype of GFP+ leukemia cells derived by retro-orbital injection of BM cells modified by the same oncogenetic lesions (see Fig.	('leukemia', 'Disease', (38, 46))	('leukemia', 'Phenotype', 'HP:0001909', (38, 46))	('leukemia', 'Disease', 'MESH:D007938', (38, 46))	('lesions', 'Var', (133, 140))
62479	22952867	The rapid growth of p16p19-/-; Kras(G12V) histiocytic sarcoma suggested that the initial seeding cell population contained clones with leukemia-propagating ability.	('histiocytic sarcoma', 'Disease', (42, 61))	('G12V', 'Mutation', 'rs121913529', (36, 40))	('p16p19-/-; Kras(G12V', 'Var', (20, 40))	('Kras(G12V', 'Var', (31, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('leukemia', 'Disease', (135, 143))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (42, 61))	('leukemia', 'Disease', 'MESH:D007938', (135, 143))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))
62480	22952867	To test directly the tumor-propagating potential of p16p19-/-; Kras(G12V) histiocytic sarcomas, GFP+ cells from primary tumors induced in the muscles of primary NOD.SCID recipients were sorted using FACS and defined numbers of sorted cells were transplanted into the cardiotoxin pre-injured gastrocnemius muscle of secondary NOD.SCID recipients (Fig.	('tumor', 'Disease', (21, 26))	('NOD', 'Gene', '1822', (161, 164))	('G12V', 'Mutation', 'rs121913529', (68, 72))	('p16p19-/-', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('primary tumors', 'Disease', (112, 126))	('NOD', 'Gene', (161, 164))	('sarcomas', 'Disease', 'MESH:D012509', (86, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('NOD', 'Gene', '1822', (325, 328))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (74, 93))	('sarcomas', 'Disease', (86, 94))	('NOD', 'Gene', (325, 328))	('tumor', 'Disease', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('primary tumors', 'Disease', 'MESH:D009369', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('histiocytic sarcoma', 'Disease', (74, 93))
62483	22952867	These studies suggest that the latency of secondary tumor formation is markedly shorter than that of primary tumor formation (30-50 days for tumor induction with 5x106 p16p19-/-; Kras(G12V) BM cells, Table 1).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (52, 57))	('G12V', 'Mutation', 'rs121913529', (184, 188))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('Kras(G12V) BM', 'Var', (179, 192))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (109, 114))
62486	22952867	Based on these data, the average frequency of tumor-propagating cells in p16p19-/-; Kras(G12V) histiocytic sarcomas is 1/3 765 (confidence choice 95%, confidence intervals 1 870-7 578).	('histiocytic sarcoma', 'Disease', (95, 114))	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('tumor', 'Disease', (46, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (95, 114))	('sarcomas', 'Disease', (107, 115))	('p16p19-/-; Kras(G12V', 'Var', (73, 93))	('G12V', 'Mutation', 'rs121913529', (89, 93))	('Kras(G12V', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
62491	22952867	Thus, p16p19-/-; Kras(G12V) induced histiocytic sarcomas are highly transplantable in vivo.	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('Kras(G12V', 'Var', (17, 26))	('p16p19-/-; Kras(G12V', 'Var', (6, 26))	('G12V', 'Mutation', 'rs121913529', (22, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (36, 55))	('sarcomas', 'Disease', (48, 56))	('histiocytic sarcoma', 'Disease', (36, 55))
62493	22952867	We therefore asked if the p16p19-/-; Kras(G12V) histiocytic sarcomas were initiated by a single clone or multiple clones of tumorigenic cells by analysis of proviral integration sites.	('sarcomas', 'Disease', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('histiocytic sarcoma', 'Disease', (48, 67))	('tumor', 'Disease', (124, 129))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('rat', 'Species', '10116', (171, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('p16p19-/-; Kras(G12V', 'Var', (26, 46))	('G12V', 'Mutation', 'rs121913529', (42, 46))	('Kras(G12V', 'Var', (37, 46))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (48, 67))
62497	22952867	Of note, sequencing of LM-PCR products demonstrated that a single clone harboring an insertion in the proximity of Ribosomal Protein S29 (RPS29) was present in one set of matching primary and secondary transplanted tumors (bands 10, 17, 18, Fig.	('Ribosomal Protein S29', 'Gene', (115, 136))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('RPS29', 'Gene', (138, 143))	('rat', 'Species', '10116', (46, 49))	('insertion in', 'Var', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))	('RPS29', 'Gene', '20090', (138, 143))	('Ribosomal Protein S29', 'Gene', '20090', (115, 136))
62502	22952867	The very high rate of induction of histiocytic sarcoma observed using p16p19-/-; Kras(G12V) BM cells as a donor cell population prompted us to ask whether this might be an intrinsic property of this oncogenic combination, or whether histiocytic sarcomas can be introduced in NOD.SCID mice using other leukemogenic systems.	('G12V', 'Mutation', 'rs121913529', (86, 90))	('Kras(G12V', 'Var', (81, 90))	('histiocytic sarcoma', 'Disease', (233, 252))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (35, 54))	('histiocytic sarcoma', 'Disease', (35, 54))	('NOD', 'Gene', (275, 278))	('sarcomas', 'Disease', 'MESH:D012509', (245, 253))	('rat', 'Species', '10116', (14, 17))	('donor', 'Species', '9606', (106, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (245, 253))	('NOD', 'Gene', '1822', (275, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('p16p19-/-; Kras(G12V', 'Var', (70, 90))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (233, 252))	('sarcomas', 'Disease', (245, 253))	('mice', 'Species', '10090', (284, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
62507	22952867	It previously has been reported that the MLL-AF9 retroviral model induces acute myeloid leukemia in mice.	('acute myeloid leukemia', 'Disease', (74, 96))	('induces', 'Reg', (66, 73))	('mice', 'Species', '10090', (100, 104))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (74, 96))	('MLL-AF9', 'Var', (41, 48))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (74, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (80, 96))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))
62510	22952867	Similar to p16p19-/-; Kras(G12V) histiocytic sarcomas (Fig.	('Kras(G12V', 'Var', (22, 31))	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcomas', 'Disease', (45, 53))	('p16p19-/-; Kras(G12V', 'Var', (11, 31))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (33, 52))	('G12V', 'Mutation', 'rs121913529', (27, 31))	('histiocytic sarcoma', 'Disease', (33, 52))
62512	22952867	1E), MLL-AF9/DsRed tumors were CD48hi (95.8+-2.4%), CD47hi (95.3+-2.9%), Mac1hi (83.4+-7.8%), Gr1mid/lo (20.2+-2.4%), and B220- /lo, CD4- /lo, CD8- /lo, Ter119- /lo (Fig.	('CD48hi', 'Var', (31, 37))	('B220- /lo', 'Var', (122, 131))	('Gr1', 'Gene', (94, 97))	('CD47hi', 'Var', (52, 58))	('Ter119', 'Gene', (153, 159))	('Gr1', 'Gene', '546644', (94, 97))	('CD8', 'Gene', (143, 146))	('CD8', 'Gene', '925', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MLL-AF9/DsRed tumors', 'Disease', (5, 25))	('MLL-AF9/DsRed tumors', 'Disease', 'MESH:D009369', (5, 25))	('Ter119', 'Gene', '104231', (153, 159))	('Mac1hi', 'Var', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('CD4- /lo', 'Var', (133, 141))
62516	22952867	The work described here establishes a novel in vivo lentivirus-induced histiocytic/myeloid sarcoma model in immuno-compromised mice, combining ablation of the tumor suppressor gene locus p16p19 and ectopic expression of constitutively active oncogenic Kras(G12V).	('G12V', 'Mutation', 'rs121913529', (257, 261))	('mice', 'Species', '10090', (127, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('ablation', 'Var', (143, 151))	('myeloid sarcoma', 'Disease', (83, 98))	('p16p19', 'Var', (187, 193))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
62517	22952867	P16p19-/-; Kras(G12V) tumor cells exhibit typical features of histiocytic sarcoma, including a predominant lack of expression of lymphocyte markers, positive expression of histiocyte/macrophage markers, and round to oval shaped cells with abundant, eosinophilic cytoplasm and nuclear atypia.	('histiocytic sarcoma', 'Disease', (62, 81))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('P16p19-/-; Kras(G12V', 'Var', (0, 20))	('lack', 'NegReg', (107, 111))	('G12V', 'Mutation', 'rs121913529', (16, 20))	('Kras(G12V', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('expression', 'MPA', (115, 125))	('tumor', 'Disease', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (62, 81))
62518	22952867	P16p19-/-; Kras(G12V) induced murine histiocytic sarcomas are aggressive neoplasms, and all tumor-bearing mice ultimately succumb to progressive leukemic symptoms.	('leukemic symptoms', 'Disease', 'MESH:D007938', (145, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (37, 56))	('aggressive neoplasms', 'Disease', (62, 82))	('P16p19-/-; Kras(G12V', 'Var', (0, 20))	('succumb', 'Reg', (122, 129))	('murine', 'Species', '10090', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('neoplasms', 'Phenotype', 'HP:0002664', (73, 82))	('mice', 'Species', '10090', (106, 110))	('leukemic symptoms', 'Disease', (145, 162))	('aggressive neoplasms', 'Disease', 'MESH:D001523', (62, 82))	('neoplasm', 'Phenotype', 'HP:0002664', (73, 81))	('histiocytic sarcoma', 'Disease', (37, 56))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcomas', 'Disease', (49, 57))	('Kras(G12V', 'Var', (11, 20))	('G12V', 'Mutation', 'rs121913529', (16, 20))	('tumor', 'Disease', (92, 97))
62520	22952867	Murine histiocytic tumors induced by P16p19-/-; Kras(G12V) tumor cells show evidence of a monocytic origin.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('G12V', 'Mutation', 'rs121913529', (53, 57))	('Murine', 'Species', '10090', (0, 6))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('P16p19-/-', 'Var', (37, 46))
62522	22952867	Histiocytic sarcoma also has been observed sporadically in pEmu-Ras transgenic mice, and p16p19-/- mice develop histiocytic sarcoma with homozygous loss of Pten .	('mice', 'Species', '10090', (99, 103))	('Pten', 'Gene', (156, 160))	('Histiocytic sarcoma', 'Disease', (0, 19))	('Pten', 'Gene', '19211', (156, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('p16p19-/-', 'Var', (89, 98))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (112, 131))	('mice', 'Species', '10090', (79, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('develop', 'Reg', (104, 111))	('transgenic mice', 'Species', '10090', (68, 83))	('histiocytic sarcoma', 'Disease', (112, 131))	('Histiocytic sarcoma', 'Disease', 'MESH:D054747', (0, 19))
62525	22952867	In this regard, it is intriguing that in our study, we observed variable expression of the lymphoid marker CD8 in a subset of leukemic mice transplanted intravenously with p16p19-/-; Kras(G12V) cells, whereas CD8 was less frequently expressed in histiocytic sarcomas generated by intramuscular transplantation of the same donor cell population.	('CD8', 'Gene', (209, 212))	('Kras(G12V', 'Var', (183, 192))	('histiocytic sarcoma', 'Disease', (246, 265))	('CD8', 'Gene', (107, 110))	('leukemic', 'Disease', 'MESH:D007938', (126, 134))	('leukemic', 'Disease', (126, 134))	('expression', 'MPA', (73, 83))	('sarcomas', 'Disease', 'MESH:D012509', (258, 266))	('sarcomas', 'Phenotype', 'HP:0100242', (258, 266))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (246, 265))	('sarcomas', 'Disease', (258, 266))	('CD8', 'Gene', '925', (209, 212))	('CD8', 'Gene', '925', (107, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('donor', 'Species', '9606', (322, 327))	('p16p19-/-; Kras(G12V', 'Var', (172, 192))	('G12V', 'Mutation', 'rs121913529', (188, 192))	('mice', 'Species', '10090', (135, 139))	('rat', 'Species', '10116', (271, 274))
62528	22952867	Of note, in both the p16p19-/-; Kras(G12V) and MLL-AF9 sarcoma models studied here, BM cells were cultured with a cytokine cocktail briefly (3 hr) after isolation and prior to intramuscular injection (see Materials and Methods).	('p16p19-/-; Kras(G12V', 'Var', (21, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('G12V', 'Mutation', 'rs121913529', (37, 41))	('MLL-AF9 sarcoma', 'Disease', 'MESH:D012509', (47, 62))	('Kras(G12V', 'Var', (32, 41))	('MLL-AF9 sarcoma', 'Disease', (47, 62))
62533	22952867	These bi-directional interactions are mediated by an array of molecular and cellular signaling pathways, such that perturbations in microenvironmental regulators can influence both normal hematopoiesis and leukemic progression.	('leukemic', 'Disease', 'MESH:D007938', (206, 214))	('influence', 'Reg', (166, 175))	('hematopoiesis', 'Disease', 'MESH:C536227', (188, 201))	('leukemic', 'Disease', (206, 214))	('mediated', 'Reg', (38, 46))	('hematopoiesis', 'Disease', (188, 201))	('perturbations', 'Var', (115, 128))
62535	22952867	Furthermore, mice with AML induced by co-expression of BCR/ABL and the Nup98/HoxA9 fusion protein showed a loss of osteolineage cells in the marrow, which may have contributed to the underlying pancytopenia.	('pancytopenia', 'Disease', 'MESH:D010198', (194, 206))	('osteolineage cells in the', 'MPA', (115, 140))	('mice', 'Species', '10090', (13, 17))	('Nup98', 'Gene', (71, 76))	('HoxA9', 'Gene', '15405', (77, 82))	('loss', 'NegReg', (107, 111))	('AML', 'Disease', 'MESH:D015470', (23, 26))	('co-expression', 'Var', (38, 51))	('AML', 'Phenotype', 'HP:0004808', (23, 26))	('Nup98', 'Gene', '269966', (71, 76))	('BCR/ABL', 'Gene', '110279;11350', (55, 62))	('AML', 'Disease', (23, 26))	('BCR/ABL', 'Gene', (55, 62))	('pancytopenia', 'Phenotype', 'HP:0001876', (194, 206))	('pancytopenia', 'Disease', (194, 206))	('HoxA9', 'Gene', (77, 82))
62536	22952867	Finally, "niche"-specific deletion of the microRNA processing enzyme Dicer (using conditional ablation in mouse osteolineage cells) was shown to be sufficient to drive the development of a hematopoietic malignancy that requires this altered microenvironment for its continued propagation.	('Dicer', 'Gene', (69, 74))	('hematopoietic malignancy', 'Disease', (189, 213))	('hematopoietic malignancy', 'Disease', 'MESH:D019337', (189, 213))	('deletion', 'Var', (26, 34))	('drive', 'PosReg', (162, 167))	('hematopoietic malignancy', 'Phenotype', 'HP:0004377', (189, 213))	('mouse', 'Species', '10090', (106, 111))
62539	22952867	Whether arising initially in the skeletal muscle or hematopoietic tissue, the histiocytic sarcoma and leukemia cells induced by p16p19 deletion and Kras activation share nearly identical morphological, phenotypic, and histopathological features.	('deletion', 'Var', (135, 143))	('leukemia', 'Disease', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('histiocytic sarcoma', 'Disease', (78, 97))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (78, 97))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))	('p16p19', 'Gene', (128, 134))	('leukemia', 'Disease', 'MESH:D007938', (102, 110))
62543	22952867	Also known as Integrin Associated Protein (IAP), CD47 acts as a "don't eat me" signal, such that cells with high surface expression of CD47 escape integrin-mediated phagocytosis and death.	('escape', 'PosReg', (140, 146))	('high surface', 'Var', (108, 120))	('death', 'Disease', 'MESH:D003643', (182, 187))	('death', 'Disease', (182, 187))	('CD47', 'Gene', (135, 139))
62549	22952867	Based on these findings, it is tempting to speculate that differences in the capacity for or consequences of recognition of tumor cell-expressed CD47 by SIRP-alpha-expressing macrophages in NOD.SCID versus C57BL/6 mice may contribute to the ability of intra-muscularly injected p16p19-/-; Kras(G12V) tumor cells to generate histiocytic sarcomas in NOD.SCID but not C57BL/6 recipients, as reported here.	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('histiocytic sarcoma', 'Disease', (324, 343))	('NOD', 'Gene', '1822', (348, 351))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('NOD', 'Gene', '1822', (190, 193))	('SIRP-alpha', 'Gene', (153, 163))	('G12V', 'Mutation', 'rs121913529', (294, 298))	('p16p19-/-', 'Var', (278, 287))	('NOD', 'Gene', (348, 351))	('NOD', 'Gene', (190, 193))	('sarcomas', 'Disease', 'MESH:D012509', (336, 344))	('sarcomas', 'Phenotype', 'HP:0100242', (336, 344))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (324, 343))	('sarcomas', 'Disease', (336, 344))	('tumor', 'Disease', (300, 305))	('rat', 'Species', '10116', (319, 322))	('SIRP-alpha', 'Gene', '19261', (153, 163))	('CD47', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('mice', 'Species', '10090', (214, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))
62551	22952867	Through direct ex vivo modification and transplantation of oncogene-modified hematopoietic lineage cells, we established a rapid and reproducible system for the generation of this extramedullary tumor, and showed that this model recapitulates the natural progression of the disease in leukemia patients.	('tumor', 'Disease', (195, 200))	('modification', 'Var', (23, 35))	('leukemia', 'Phenotype', 'HP:0001909', (285, 293))	('leukemia', 'Disease', 'MESH:D007938', (285, 293))	('patients', 'Species', '9606', (294, 302))	('leukemia', 'Disease', (285, 293))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('rat', 'Species', '10116', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
62582	22952867	The following antibodies were used: PE-CD4 (100408, BioLegend, San Diego, CA), PECy7-CD8 (100722, BioLegend), APC-Mac1 (17-0112-82, eBioscience, San Diego, CA), APCCy7-Gr1 (108424, BioLegend), APC-Ter119 (116212, BioLegend), PE-CD71 (113808, BioLegend), PE-CD48 (103405, BioLegend), APC-CD47 (17-0471, eBioscience).	('CD8', 'Gene', (85, 88))	('CD8', 'Gene', '925', (85, 88))	('APC-Ter119', 'Disease', (193, 203))	('APC-Ter119', 'Disease', 'MESH:D011125', (193, 203))	('Gr1', 'Gene', '546644', (168, 171))	('Gr1', 'Gene', (168, 171))	('103405', 'Var', (263, 269))
62617	32290096	The model that best recapitulates the metastatic biology of human synovial sarcoma is the combined expression of SS18-SSX1 or SS18-SSX2 and the deletion of Pten via the injection of TATCre, a critical tumor suppressor gene that acts to suppress the over-proliferation of tumor cells.	('Pten', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('deletion', 'Var', (144, 152))	('synovial sarcoma', 'Disease', (66, 82))	('SSX1', 'Gene', '6756', (118, 122))	('TATCre', 'Chemical', '-', (182, 188))	('SSX1', 'Gene', (118, 122))	('synovial sarcoma', 'Disease', 'MESH:D013584', (66, 82))	('tumor', 'Disease', (201, 206))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (66, 82))	('SSX2', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (271, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('SSX2', 'Gene', '6757', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('over-proliferation', 'CPA', (249, 267))	('human', 'Species', '9606', (60, 65))
62622	32290096	Pten was concomitantly deleted in all mice using the Ptenlox5/lox5 allele, with the deletion of Pten occurring spatially via the injection of TATCre in hind limbs in order to drive primary tumor development.	('tumor', 'Disease', (189, 194))	('deletion', 'Var', (84, 92))	('mice', 'Species', '10090', (38, 42))	('drive', 'PosReg', (175, 180))	('TATCre', 'Chemical', '-', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('Pten', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
62651	32290096	This gene is intriguing in that it is downstream of RUNX2, a master regulator of bone development and ossification, and a high expression has been correlated to a faster disease progression in a number of cancers (i.e., colon, prostate, breast, head, and neck) due to the overexpression of PTHLH.	('head', 'Disease', (245, 249))	('correlated to', 'Reg', (147, 160))	('PTHLH', 'Gene', (290, 295))	('breast', 'Disease', (237, 243))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('RUNX2', 'Gene', '12393', (52, 57))	('expression', 'MPA', (127, 137))	('high', 'Var', (122, 126))	('cancers', 'Disease', (205, 212))	('colon', 'Disease', (220, 225))	('RUNX2', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('overexpression', 'PosReg', (272, 286))	('prostate', 'Disease', (227, 235))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
62687	32290096	Pten silencing acts as a major step in promoting and maintaining baseline inflammation through PI3K/AKT signal transduction, resulting in the recruitment of macrophages and neutrophils to the tumor microenvironment.	('tumor', 'Disease', (192, 197))	('AKT', 'Gene', (100, 103))	('recruitment', 'MPA', (142, 153))	('silencing', 'Var', (5, 14))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('Pten', 'Gene', (0, 4))	('promoting', 'PosReg', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('AKT', 'Gene', '11651', (100, 103))
62719	32290096	In a controlled comparison of mice with metastatic synovial sarcoma and only the presence or absence of ossification as the differentiating phenotype, we observed that mice with ossification exhibited a 6-week longer survival.	('synovial sarcoma', 'Disease', 'MESH:D013584', (51, 67))	('mice', 'Species', '10090', (30, 34))	('ossification', 'Var', (178, 190))	('mice', 'Species', '10090', (168, 172))	('synovial sarcoma', 'Disease', (51, 67))	('longer', 'PosReg', (210, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (51, 67))
62735	29416716	Ewing sarcoma is characterized by the presence of chimeric EWSR1-ETS fusion oncogenes.	('EWSR1', 'Gene', (59, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('chimeric', 'Var', (50, 58))	('EWSR1', 'Gene', '2130', (59, 64))	('Ewing sarcoma', 'Gene', '2130', (0, 13))	('Ewing sarcoma', 'Gene', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))
62765	29416716	To further explore this regulatory relationship, available gene expression data were assessed, which showed that the ectopic EWSR1-FLI1 expression in embryonic stem cells was sufficient to significantly induce the expression of ATP1A1, BCL11B, and GLG1 (Figure 2A).	('GLG1', 'Gene', (248, 252))	('ATP1A1', 'Gene', (228, 234))	('induce', 'PosReg', (203, 209))	('EWSR1', 'Gene', (125, 130))	('FLI1', 'Gene', (131, 135))	('BCL11B', 'Gene', '64919', (236, 242))	('FLI1', 'Gene', '2313', (131, 135))	('ATP1A1', 'Gene', '476', (228, 234))	('GLG1', 'Gene', '2734', (248, 252))	('EWSR1', 'Gene', '2130', (125, 130))	('ectopic', 'Var', (117, 124))	('BCL11B', 'Gene', (236, 242))	('expression', 'MPA', (214, 224))
62766	29416716	Conversely, the shRNA-mediated knockdown of EWSR1-FLI1 in six different Ewing sarcoma cell lines significantly decreased their expression levels (Figure 2B).	('EWSR1', 'Gene', '2130', (44, 49))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('expression levels', 'MPA', (127, 144))	('decreased', 'NegReg', (111, 120))	('FLI1', 'Gene', '2313', (50, 54))	('Ewing sarcoma', 'Gene', '2130', (72, 85))	('FLI1', 'Gene', (50, 54))	('EWSR1', 'Gene', (44, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('Ewing sarcoma', 'Gene', (72, 85))	('knockdown', 'Var', (31, 40))
62773	29416716	In agreement with previous observations, these EWSR1-FLI1-dependent enhancers showed the typical H3K27ac profile of so-called super-enhancers in the A673 and SK-N-MC Ewing sarcoma cell lines (Figure 3C, Supplementary Tables 1 & 2).	('EWSR1', 'Gene', '2130', (47, 52))	('SK-N-MC Ewing sarcoma', 'Disease', (158, 179))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (166, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('H3K27ac', 'Var', (97, 104))	('FLI1', 'Gene', '2313', (53, 57))	('EWSR1', 'Gene', (47, 52))	('FLI1', 'Gene', (53, 57))	('SK-N-MC Ewing sarcoma', 'Disease', 'MESH:C563168', (158, 179))
62796	29416716	To date, at least 18 types of chimeric EWSR1-FLI1 transcripts have been reported.	('FLI1', 'Gene', (45, 49))	('FLI1', 'Gene', '2313', (45, 49))	('EWSR1', 'Gene', (39, 44))	('chimeric', 'Var', (30, 38))	('EWSR1', 'Gene', '2130', (39, 44))
62802	29416716	Moreover, there is a risk of falsely diagnosing a tumor as Ewing sarcoma based on FISH, because break-apart of the EWSR1 gene can also be observed in other sarcoma entities such as desmoplastic small-round-cell tumor (DSRCT), clear cell sarcoma, angiomatoid fibrous histiocytoma, extraskeletal myxoid chondrosarcoma, and a subset of myxoid liposarcoma.	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (246, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('clear cell sarcoma', 'Disease', (226, 244))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (294, 315))	('sarcoma entities', 'Disease', (156, 172))	('Ewing sarcoma', 'Gene', (59, 72))	('histiocytoma', 'Phenotype', 'HP:0012315', (266, 278))	('tumor', 'Disease', (211, 216))	('liposarcoma', 'Phenotype', 'HP:0012034', (340, 351))	('sarcoma entities', 'Disease', 'MESH:D012509', (156, 172))	('myxoid chondrosarcoma', 'Disease', (294, 315))	('angiomatoid fibrous histiocytoma', 'Disease', (246, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('break-apart', 'Var', (96, 107))	('EWSR1', 'Gene', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('desmoplastic small-round-cell tumor', 'Disease', (181, 216))	('Ewing sarcoma', 'Gene', '2130', (59, 72))	('tumor', 'Disease', (50, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (308, 315))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (301, 315))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (333, 351))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (226, 244))	('myxoid liposarcoma', 'Disease', (333, 351))	('observed', 'Reg', (138, 146))	('desmoplastic small-round-cell tumor', 'Disease', 'MESH:D058405', (181, 216))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (333, 351))	('sarcoma', 'Phenotype', 'HP:0100242', (344, 351))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('EWSR1', 'Gene', '2130', (115, 120))
62823	29416716	All Ewing sarcoma samples were genetically verified to contain a specific EWSR1-ETS translocation as previously described.	('Ewing sarcoma', 'Gene', '2130', (4, 17))	('Ewing sarcoma', 'Gene', (4, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('EWSR1', 'Gene', (74, 79))	('translocation', 'Var', (84, 97))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (4, 17))	('EWSR1', 'Gene', '2130', (74, 79))
62831	29416716	The following samples were used in this study: ENCODE_SKNMC_hg19_DNAseHS_rep2 GSM1517546 SKNMC.shGFP96.FLI1 GSM1517555 SKNMC.shFLI196.FLI1 GSM1517547 SKNMC.shGFP96.H3K27ac GSM1517556 SKNMC.shFLI196.H3K27ac GSM1517569 A673.shGFP48.FLI1 GSM1517572 A673.shFLI148.FLI1 GSM1517571 A673.shGFP96.H3.k27ac GSM1517574 A673.shFLI196.H3K27ac ChIP-seq data of the histone modification H3K27ac in A673 and SK-N-MC Ewing sarcoma cell lines (shGFP96) from a genome-wide chromatin analysis (GSE61944) conducted by Riggi et al.	('FLI1', 'Gene', (230, 234))	('FLI1', 'Gene', (103, 107))	('FLI1', 'Gene', '2313', (191, 195))	('FLI1', 'Gene', (253, 257))	('FLI1', 'Gene', '2313', (127, 131))	('FLI1', 'Gene', (134, 138))	('FLI1', 'Gene', '2313', (230, 234))	('SK-N-MC Ewing sarcoma', 'Disease', (393, 414))	('FLI1', 'Gene', (316, 320))	('FLI1', 'Gene', '2313', (103, 107))	('FLI1', 'Gene', '2313', (253, 257))	('FLI1', 'Gene', (260, 264))	('FLI1', 'Gene', '2313', (134, 138))	('GSM1517569', 'Chemical', '-', (206, 216))	('SK-N-MC Ewing sarcoma', 'Disease', 'MESH:C563168', (393, 414))	('FLI1', 'Gene', '2313', (316, 320))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (401, 414))	('H3K27ac', 'Var', (373, 380))	('FLI1', 'Gene', '2313', (260, 264))	('FLI1', 'Gene', (191, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (407, 414))	('FLI1', 'Gene', (127, 131))
62854	29416716	Microarray data of 166 primary Ewing sarcoma tumors (GSE63157, GSE34620, GSE12102, and GSE17618), which had well-curated clinical annotations available, were downloaded from the GEO.	('GSE34620', 'Var', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('Ewing sarcoma tumors', 'Disease', (31, 51))	('GSE12102', 'Var', (73, 81))	('GSE63157', 'Var', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (31, 51))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (31, 44))
62959	28134926	In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.	('tumor', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Ewing sarcoma', 'Gene', '2130', (89, 102))	('Ewing sarcoma', 'Gene', (89, 102))	('epigenetic heterogeneity', 'Var', (61, 85))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
62969	28134926	Together, these two dimensions established an epigenetic disease spectrum underlying EwS, which was associated partially with somatic mutations in STAG2 and TP53.	('STAG2', 'Gene', (147, 152))	('TP53', 'Gene', (157, 161))	('STAG2', 'Gene', '10735', (147, 152))	('associated', 'Reg', (100, 110))	('EwS', 'Phenotype', 'HP:0012254', (85, 88))	('mutations', 'Var', (134, 143))	('EwS', 'Gene', '2130', (85, 88))	('EwS', 'Gene', (85, 88))	('TP53', 'Gene', '7157', (157, 161))
62971	28134926	In summary, this study provides a comprehensive assessment of DNA methylation heterogeneity in EwS, as well as a resource for studying epigenomic deregulation and tumor heterogeneity in genetically homogeneous cancers.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('methylation', 'Var', (66, 77))	('EwS', 'Phenotype', 'HP:0012254', (95, 98))	('EwS', 'Gene', '2130', (95, 98))	('tumor', 'Disease', (163, 168))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('EwS', 'Gene', (95, 98))	('cancers', 'Disease', (210, 217))
62987	28134926	We identified 2,917 CpGs that were specifically hypomethylated in EwS (Fig.	('EwS', 'Phenotype', 'HP:0012254', (66, 69))	('EwS', 'Gene', (66, 69))	('hypomethylated', 'Var', (48, 62))	('EwS', 'Gene', '2130', (66, 69))
62988	28134926	1e) The EwS-specific hypomethylated CpGs were exclusive to EwS samples and were heavily methylated in essentially all other cell types, whereas the difference was less pronounced for EwS-specific hypermethylated CpGs.	('EwS', 'Gene', '2130', (59, 62))	('EwS', 'Phenotype', 'HP:0012254', (8, 11))	('EwS', 'Phenotype', 'HP:0012254', (183, 186))	('EwS', 'Gene', '2130', (183, 186))	('EwS', 'Gene', '2130', (8, 11))	('EwS', 'Gene', (59, 62))	('EwS', 'Gene', (183, 186))	('EwS', 'Gene', (8, 11))	('hypomethylated', 'Var', (21, 35))	('EwS', 'Phenotype', 'HP:0012254', (59, 62))
62993	28134926	By contrast, EwS-specific hypermethylated CpGs overlapped with developmental regulators of various lineages, including polycomb-repressed regions in pluripotent stem cells, AP-1 binding sites, and binding sites of various developmental transcription factors (Fig.	('EwS', 'Gene', (13, 16))	('CpGs', 'Gene', (42, 46))	('hypermethylated', 'Var', (26, 41))	('EwS', 'Phenotype', 'HP:0012254', (13, 16))	('EwS', 'Gene', '2130', (13, 16))	('binding', 'Interaction', (197, 204))
63044	28134926	For example, PIM identifies regions with a combination of fully methylated and fully unmethylated reads as heterogeneous, whereas PDR does not; by contrast, PDR identifies regions with consistent and reproducible patterns of methylated and unmethylated CpGs as disordered, whereas PIM considers them homogeneous (Fig.	('methylated', 'Var', (225, 235))	('disordered', 'Disease', 'MESH:D030342', (261, 271))	('disordered', 'Disease', (261, 271))	('CpGs', 'Protein', (253, 257))
63048	28134926	Focusing on the 79 EwS tumors that had whole-genome sequencing data (which allowed us to statistically control for differences in tumor purity), we compared the heterogeneity scores defined above (MIRA, PDR, and PIM) with patient annotations such as age, metastatic status at diagnosis, tumor size, tumor location, relapse status, and mutations for STAG2, TP53, and CDKN2A.	('TP53', 'Gene', (356, 360))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutations', 'Var', (335, 344))	('tumor', 'Disease', (130, 135))	('STAG2', 'Gene', '10735', (349, 354))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('EwS tumors', 'Disease', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('CDKN2A', 'Gene', (366, 372))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('STAG2', 'Gene', (349, 354))	('tumor', 'Disease', (287, 292))	('TP53', 'Gene', '7157', (356, 360))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('patient', 'Species', '9606', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CDKN2A', 'Gene', '1029', (366, 372))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('EwS', 'Phenotype', 'HP:0012254', (19, 22))	('EwS tumors', 'Disease', 'MESH:C563168', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', 'MESH:D009369', (299, 304))
63051	28134926	Comparing 16 tumors with a STAG2 mutation to 63 tumors without such a mutation, we observed significantly lower MIRA scores for EWS-FLI1-anti-correlated enhancers in the STAG2 mutated tumors (Wilcoxon P value < 0.01; Fig.	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('lower', 'NegReg', (106, 111))	('EWS', 'Gene', (128, 131))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('FLI1', 'Gene', (132, 136))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('MIRA scores', 'MPA', (112, 123))	('enhancers', 'PosReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mutation', 'Var', (33, 41))	('tumors', 'Disease', (13, 19))	('STAG2', 'Gene', '10735', (170, 175))	('FLI1', 'Gene', '2313', (132, 136))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('STAG2', 'Gene', '10735', (27, 32))	('EWS', 'Gene', '2130', (128, 131))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('STAG2', 'Gene', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mutated', 'Var', (176, 183))	('tumors', 'Disease', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('STAG2', 'Gene', (27, 32))
63052	28134926	This result places the STAG2 mutated tumors in the more stem-like area of the EwS spectrum, which is consistent with recent research showing that cohesin mutants enforce stem cell programs.	('EwS', 'Gene', (78, 81))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('enforce', 'PosReg', (162, 169))	('STAG2', 'Gene', (23, 28))	('STAG2', 'Gene', '10735', (23, 28))	('stem cell programs', 'CPA', (170, 188))	('mutated', 'Var', (29, 36))	('EwS', 'Phenotype', 'HP:0012254', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('mutants', 'Var', (154, 161))	('EwS', 'Gene', '2130', (78, 81))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
63053	28134926	The deletion of CDKN2A, which is a relatively common genetic lesion in EwS, showed no significant association (Wilcoxon P value > 0.1; Supplementary Fig.	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('EwS', 'Phenotype', 'HP:0012254', (71, 74))	('EwS', 'Gene', '2130', (71, 74))	('deletion', 'Var', (4, 12))	('genetic lesion', 'Disease', (53, 67))	('EwS', 'Gene', (71, 74))	('genetic lesion', 'Disease', 'MESH:D020022', (53, 67))
63054	28134926	11), but among the seven TP53-mutated tumors in our cohort, we observed increased MIRA scores for EwS-specific DNaseI elements; this places TP53 mutants in the more Ewing-like area of the spectrum (Wilcoxon P value < 0.03; Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('EwS', 'Gene', (98, 101))	('mutants', 'Var', (145, 152))	('TP53', 'Gene', (25, 29))	('TP53', 'Gene', (140, 144))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('MIRA scores', 'MPA', (82, 93))	('EwS', 'Phenotype', 'HP:0012254', (98, 101))	('EwS', 'Gene', '2130', (98, 101))	('TP53', 'Gene', '7157', (25, 29))	('TP53', 'Gene', '7157', (140, 144))
63061	28134926	But we also observed substantial epigenetic tumor heterogeneity between patients and within tumors, which stands in stark contrast to the genetic homogeneity of EwS.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('EwS', 'Gene', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('epigenetic', 'Var', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('EwS', 'Phenotype', 'HP:0012254', (161, 164))	('tumors', 'Disease', (92, 98))	('tumor', 'Disease', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (44, 49))	('EwS', 'Gene', '2130', (161, 164))	('patients', 'Species', '9606', (72, 80))
63067	28134926	Rather than identifying a small number of distinct subtypes, as observed for many other cancers, we found that DNA methylation differences in EwS gave rise to a continuous disease spectrum along two dimensions.	('differences', 'Var', (127, 138))	('EwS', 'Phenotype', 'HP:0012254', (142, 145))	('EwS', 'Gene', '2130', (142, 145))	('gave rise to', 'Reg', (146, 158))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('methylation differences', 'Var', (115, 138))	('EwS', 'Gene', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
63082	28134926	Specifically, tumor purity was estimated on the basis of the loss of heterozygosity, copy number change, and mutated allele fraction of single-nucleotide variants using established methodology.	('tumor', 'Disease', (14, 19))	('single-nucleotide variants', 'Var', (136, 162))	('heterozygosity', 'MPA', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('loss', 'NegReg', (61, 65))	('copy number change', 'Var', (85, 103))
63218	26713165	In addition, mutation analysis of p53 demonstrated the presence of identical point mutations in the primary and recurrent tumors in both cases.	('point mutations', 'Var', (77, 92))	('tumors', 'Disease', (122, 128))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('mutation', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
63276	26331003	Screening blood tests were suggestive of an iron deficiency anemia [hemoglobin (Hb) 105 g/L, mean corpuscle volume (MCV) 77 fL, ferritin (Fe) 2 umol/L, transferrin saturation 3%] associated with elevated inflammatory markers ESR 73 mm/hr, CRP 45 mg/L and a low vitamin D level.	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (44, 66))	('inflammatory markers', 'MPA', (204, 224))	('vitamin D', 'Chemical', 'MESH:D014807', (261, 270))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (44, 66))	('iron deficiency anemia', 'Disease', (44, 66))	('transferrin', 'Gene', '7018', (152, 163))	('ESR', 'Var', (225, 228))	('CRP', 'Gene', (239, 242))	('transferrin', 'Gene', (152, 163))	('low', 'NegReg', (257, 260))	('CRP', 'Gene', '1401', (239, 242))	('elevated', 'PosReg', (195, 203))	('elevated inflammatory markers', 'Phenotype', 'HP:0012649', (195, 224))	('anemia', 'Phenotype', 'HP:0001903', (60, 66))	('low vitamin D', 'Phenotype', 'HP:0100512', (257, 270))
63370	23844615	One-third of sarcomas show specific genetic alterations and relatively simple karyotypes with translocations which produce defining gene fusions (e.g., EWS-FLI1 in ES, ASPLTFE3 in alveolar soft part sarcoma, JAZF1-JJAZ1 in endome-trial stromal sarcoma and HMGIC fusions in liposarcoma or specific genetic mutations (e.g., c-kit in GIST).	('EWS-FLI1', 'Gene', '2130;2313', (152, 160))	('sarcoma', 'Disease', 'MESH:D012509', (277, 284))	('alterations', 'Var', (44, 55))	('sarcoma', 'Disease', 'MESH:D012509', (13, 20))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (189, 206))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	('sarcoma', 'Disease', (277, 284))	('sarcoma', 'Disease', (13, 20))	('sarcoma', 'Disease', 'MESH:D012509', (244, 251))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('rat', 'Species', '10116', (48, 51))	('sarcomas', 'Disease', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('sarcoma', 'Disease', (244, 251))	('liposarcoma', 'Disease', (273, 284))	('JAZF1', 'Gene', '221895', (208, 213))	('JJAZ1', 'Gene', '23512', (214, 219))	('JJAZ1', 'Gene', (214, 219))	('c-kit', 'Gene', '3815', (322, 327))	('HMGIC', 'Gene', '8091', (256, 261))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('HMGIC', 'Gene', (256, 261))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('JAZF1', 'Gene', (208, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('liposarcoma', 'Phenotype', 'HP:0012034', (273, 284))	('ASPLTFE3', 'Var', (168, 176))	('EWS-FLI1', 'Gene', (152, 160))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (180, 206))	('liposarcoma', 'Disease', 'MESH:D008080', (273, 284))	('c-kit', 'Gene', (322, 327))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('sarcoma', 'Disease', (199, 206))
63371	23844615	The remaining two-thirds of sarcomas show complex karyotypes with multiple chromosomal rearrangements, duplications and deletions (e.g., OS and leiomyosarcoma).	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcoma', 'Disease', (28, 35))	('deletions', 'Var', (120, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('sarcomas', 'Disease', (28, 36))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (144, 158))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('multiple chromosomal rearrangements', 'Phenotype', 'HP:0040012', (66, 101))	('duplications', 'Var', (103, 115))	('sarcoma', 'Disease', (151, 158))
63400	23844615	Validation of these in vivo models by gene expression profiling confirms that gene expression patterns and copy number alterations are preserved in patient-derived OS cell lines and xenograft tumors and are therefore relevant for molecular and drug screening studies.	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('xenograft tumors', 'Disease', (182, 198))	('rat', 'Species', '10116', (123, 126))	('copy number alterations', 'Var', (107, 130))	('patient', 'Species', '9606', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('xenograft tumors', 'Disease', 'MESH:D009369', (182, 198))
63425	23844615	These generally mimic gene deletions (deletion of TP53), gene amplification (overexpression of c-Fos) and point mutations (heterozygous mutation of Nf2) that predispose patients to this disease.	('patients', 'Species', '9606', (169, 177))	('c-Fos', 'Gene', (95, 100))	('TP53', 'Gene', '7157', (50, 54))	('point mutations', 'Var', (106, 121))	('c-Fos', 'Gene', '2353', (95, 100))	('deletion', 'Var', (38, 46))	('TP53', 'Gene', (50, 54))	('Nf2', 'Gene', '4771', (148, 151))	('Nf2', 'Gene', (148, 151))
63427	23844615	Germline and conditional gene ablations for genes which induce aneuploidy, tumor suppressors and factors that function in normal mesenchymal differentiation drive malignant transformations in various mouse models, especially in combinations that silence the p53 and Rb1 pathways.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mouse', 'Species', '10090', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('malignant transformations', 'CPA', (163, 188))	('silence', 'NegReg', (246, 253))	('ablations', 'Var', (30, 39))	('tumor', 'Disease', (75, 80))	('aneuploidy', 'Var', (63, 73))
63429	23844615	Other model systems generated from the conditional inactivation of p53 and Rb1 in osteoblasts and in Sca-1 positive mesenchymal stem/progenitor cells provide appropriate genetic models of inherited disease (Table 1).	('conditional inactivation', 'Var', (39, 63))	('Rb1', 'Gene', (75, 78))	('Sca-1', 'Gene', (101, 106))	('p53', 'Gene', (67, 70))	('inherited disease', 'Disease', 'MESH:D030342', (188, 205))	('Sca-1', 'Gene', '6310', (101, 106))	('rat', 'Species', '10116', (24, 27))	('inherited disease', 'Disease', (188, 205))
63439	23844615	A reciprocal translocation mechanism that results in an EWS-ERG fusion gene has also been described, and FEV, ETV1 and ETV4 fusions have been reported.	('fusion', 'Var', (64, 70))	('ETV4', 'Gene', '2118', (119, 123))	('EWS-ERG', 'Gene', (56, 63))	('ETV1', 'Gene', (110, 114))	('results in', 'Reg', (42, 52))	('ETV1', 'Gene', '2115', (110, 114))	('ETV4', 'Gene', (119, 123))
63454	23844615	IGF-1R targeting antibodies have undergone single-agent and combination testing in ES xenograft models.	('antibodies', 'Var', (17, 27))	('IGF-1R', 'Gene', (0, 6))	('IGF-1R', 'Gene', '3480', (0, 6))
63457	23844615	In another approach, Cre-mediated activation of EWS-FLI1 resulted in rapid development of myeloid/erythroid leukemia in mice suggesting that activation of EWS-FLI1 has a role in this disease.	('activation', 'Var', (34, 44))	('EWS-FLI1', 'Gene', '2130;2313', (48, 56))	('mice', 'Species', '10090', (120, 124))	('myeloid/erythroid leukemia', 'Disease', (90, 116))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('myeloid/erythroid leukemia', 'Phenotype', 'HP:0005531', (90, 116))	('EWS-FLI1', 'Gene', (48, 56))	('EWS-FLI1', 'Gene', (155, 163))	('myeloid/erythroid leukemia', 'Disease', 'MESH:D007951', (90, 116))	('EWS-FLI1', 'Gene', '2130;2313', (155, 163))
63460	23844615	Cooperative interactions between EWS-FLI1 and p53 deletions are also being studied as a potential model.	('EWS-FLI1', 'Gene', (33, 41))	('p53', 'Gene', (46, 49))	('EWS-FLI1', 'Gene', '2130;2313', (33, 41))	('rat', 'Species', '10116', (5, 8))	('deletions', 'Var', (50, 59))
63477	23844615	These include dasatinib (Src inhibitor), SCH717454 (IGF-1R receptor inhibitor), and rapamycin (mTOR inhibitor).	('SCH717454', 'Var', (41, 50))	('rapamycin', 'Chemical', 'MESH:D020123', (84, 93))	('SCH717454', 'Chemical', 'MESH:C573312', (41, 50))	('dasatinib', 'Chemical', 'MESH:D000069439', (14, 23))	('Src', 'Gene', (25, 28))	('Src', 'Gene', '6714', (25, 28))	('IGF-1R', 'Gene', '3480', (52, 58))	('mTOR', 'Gene', (95, 99))	('IGF-1R', 'Gene', (52, 58))	('mTOR', 'Gene', '2475', (95, 99))
63531	20981347	Subsequently, several retrospective studies indicated that by immunohistochemistry features of neural differentiation can also be revealed in ES, using antibodies against proteins such as neuron-specific enolase, Leu 7 (later termed CD57), and S100.	('neuron-specific enolase', 'Gene', (188, 211))	('S100', 'Var', (244, 248))	('Leu 7', 'Gene', (213, 218))	('neural differentiation', 'CPA', (95, 117))	('CD57', 'Gene', (233, 237))	('ES', 'Phenotype', 'HP:0012254', (142, 144))	('neuron-specific enolase', 'Gene', '2026', (188, 211))	('Leu 7', 'Gene', '27087', (213, 218))	('CD57', 'Gene', '27087', (233, 237))
63553	20981347	Modulation of CD99 expression significantly modifies cell growth in anchorage-independent conditions, and it affects cell migration, tumorigenesis, and metastatic activity in other models.	('Modulation', 'Var', (0, 10))	('affects', 'Reg', (109, 116))	('cell growth', 'CPA', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('metastatic activity', 'CPA', (152, 171))	('cell migration', 'CPA', (117, 131))	('modifies', 'Reg', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CD99', 'Gene', (14, 18))	('tumor', 'Disease', (133, 138))
63560	20981347	The combination of CD99 and FLI1 immunostaining appears to improve the specificity of these markers for diagnosis of EWS/FLI1 fusion-positive ESFT.	('FLI1', 'Gene', (28, 32))	('FLI1', 'Gene', (121, 125))	('FLI1', 'Gene', '2313', (28, 32))	('ESFT', 'Disease', (142, 146))	('FLI1', 'Gene', '2313', (121, 125))	('ES', 'Phenotype', 'HP:0012254', (142, 144))	('improve', 'PosReg', (59, 66))	('fusion-positive', 'Var', (126, 141))	('specificity', 'MPA', (71, 82))
63581	20981347	In 99% of cases, molecular fusions of ESFT involve the EWS gene (also known as EWSR1; located on chromosome 22) and a member of the ETS family of transcription factors, which includes FLI1 (on chromosome 11) and ERG (in chromosome 21).	('ES', 'Phenotype', 'HP:0012254', (38, 40))	('EWSR1', 'Gene', (79, 84))	('EWS gene', 'Gene', (55, 63))	('ERG', 'Gene', (212, 215))	('EWSR1', 'Gene', '2130', (79, 84))	('FLI1', 'Gene', (184, 188))	('molecular fusions', 'Var', (17, 34))	('FLI1', 'Gene', '2313', (184, 188))	('ETS', 'Chemical', '-', (132, 135))	('ESFT', 'Gene', (38, 42))
63583	20981347	Although it is a promiscuous gene that creates chimeras in a variety of neoplasms, fusions of EWS to ETS family genes are unique to ESFT.	('EWS', 'Gene', (94, 97))	('ES', 'Phenotype', 'HP:0012254', (132, 134))	('neoplasms', 'Disease', 'MESH:D009369', (72, 81))	('neoplasms', 'Disease', (72, 81))	('neoplasm', 'Phenotype', 'HP:0002664', (72, 80))	('ETS', 'Chemical', '-', (101, 104))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))	('fusions', 'Var', (83, 90))
63584	20981347	The list of variants of ETS family that genes may substitute for FLI1 continues to grow.	('FLI1', 'Gene', '2313', (65, 69))	('FLI1', 'Gene', (65, 69))	('ETS family', 'Gene', (24, 34))	('variants', 'Var', (12, 20))	('ETS', 'Chemical', '-', (24, 27))
63585	20981347	Regardless of the ETS partner involved, variant translocations do not alter the tumor phenotype.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('ETS', 'Chemical', '-', (18, 21))	('variant translocations', 'Var', (40, 62))
63590	20981347	Different combinations of exons from EWS and FLI1 create up to 18 possible types of in-frame EWS-FLI1 chimeric transcripts; these have been termed "type 1", "type 2", and so forth, fusions.	('FLI1', 'Gene', (45, 49))	('FLI1', 'Gene', '2313', (45, 49))	('FLI1', 'Gene', (97, 101))	('FLI1', 'Gene', '2313', (97, 101))	('chimeric', 'Var', (102, 110))
63592	20981347	reported that respective subgroups of 55 and 99 patients with localized ESFT and type 1 EWS-FLI1 fusions had longer relapse-free survival than those with nontype 1 fusions.	('longer', 'PosReg', (109, 115))	('fusions', 'Var', (97, 104))	('relapse-free survival', 'CPA', (116, 137))	('FLI1', 'Gene', (92, 96))	('FLI1', 'Gene', '2313', (92, 96))	('patients', 'Species', '9606', (48, 56))	('ES', 'Phenotype', 'HP:0012254', (72, 74))
63594	20981347	EWS/ERG induces hematopoietic tumors in knock-in mice, suggesting that it can operate in targets other than mesenchymal cells.	('hematopoietic tumors', 'Disease', (16, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('EWS/ERG', 'Var', (0, 7))	('mice', 'Species', '10090', (49, 53))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (16, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('induces', 'Reg', (8, 15))
63601	20981347	The resultant t(16:21)(p11;q24) produces an FUS-ERG fusion with no EWS rearrangement.	('FUS', 'Gene', (44, 47))	('FUS', 'Gene', '2521', (44, 47))	('produces', 'Reg', (32, 40))	('t(16:21)(p11;q24', 'Var', (14, 30))	('t(16:21)(p11;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (14, 31))
63608	20981347	Recent studies have focussed on secondary changes of ESFT, such as mutations and epigenetic alterations, particularly as a means of predicting clinical outcome.	('ES', 'Phenotype', 'HP:0012254', (53, 55))	('mutations', 'Var', (67, 76))	('epigenetic alterations', 'Var', (81, 103))	('ESFT', 'Gene', (53, 57))	('clinical', 'Species', '191496', (143, 151))
63611	20981347	In a study of 62 ESFT by CGH, univariate analysis showed that patients with gains of chromosomes 1q, 2q, 12, and 20 or losses of 16q and 17p have significantly lower overall survival than those without such aberrations.	('gains', 'PosReg', (76, 81))	('overall survival', 'MPA', (166, 182))	('losses', 'Var', (119, 125))	('ES', 'Phenotype', 'HP:0012254', (17, 19))	('patients', 'Species', '9606', (62, 70))	('lower', 'NegReg', (160, 165))
63612	20981347	In this study, patients whose tumors had three or fewer copy number changes had better survival than patients with tumors having a higher number of copy number aberrations.	('tumors', 'Disease', (30, 36))	('patients', 'Species', '9606', (101, 109))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('patients', 'Species', '9606', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('copy number changes', 'Var', (56, 75))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (115, 121))	('survival', 'CPA', (87, 95))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('better', 'PosReg', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
63615	20981347	In a similar study of 27 ESFT, Schaeffer identified genes that were differentially regulated between metastatic and localized tumors and described characteristic gene expression signatures associated with metastases, including signalling pathways for activation of PDGF and WNT1, apoptosis, angiogenesis, alteration of p53, and resistance to chemotherapy.	('ES', 'Phenotype', 'HP:0012254', (25, 27))	('apoptosis', 'CPA', (280, 289))	('p53', 'Gene', '7157', (319, 322))	('alteration', 'Var', (305, 315))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('localized tumors', 'Disease', (116, 132))	('metastases', 'Disease', (205, 215))	('resistance to chemotherapy', 'CPA', (328, 354))	('angiogenesis', 'CPA', (291, 303))	('WNT1', 'Gene', (274, 278))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('metastases', 'Disease', 'MESH:D009362', (205, 215))	('PDGF', 'Gene', (265, 269))	('localized tumors', 'Disease', 'MESH:D009364', (116, 132))	('WNT1', 'Gene', '7471', (274, 278))	('genes', 'Gene', (52, 57))	('p53', 'Gene', (319, 322))	('activation', 'PosReg', (251, 261))
63617	20981347	This work identifies target genes of the fusion protein and suggests that the phenotype is mediated by the t(11;22)(q24;q12).	('mediated', 'Reg', (91, 99))	('t(11;22)(q24;q12', 'Var', (107, 123))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (107, 124))
63621	20981347	However, genetic/epigenetic alteration of factors such as p53 or p16 may determine prognosis.	('p16', 'Gene', '1029', (65, 68))	('genetic/epigenetic alteration', 'Var', (9, 38))	('determine', 'Reg', (73, 82))	('p16', 'Gene', (65, 68))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
63622	20981347	p53 alterations appear to define a small clinical sunset of ESFT with a markedly poor outcome.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('alterations', 'Var', (4, 15))	('sunset of ESFT', 'Phenotype', 'HP:0012470', (50, 64))	('ES', 'Phenotype', 'HP:0012254', (60, 62))	('clinical', 'Species', '191496', (41, 49))	('ESFT', 'Disease', (60, 64))
63631	20981347	Microsatellites have been found to be responsive elements to EWS-FLI1.	('FLI1', 'Gene', (65, 69))	('Microsatellites', 'Var', (0, 15))	('FLI1', 'Gene', '2313', (65, 69))
63638	20981347	In special media, transfection of EWS/FLI1 and repression of the inhibitory effect of miRNA cause hpMSC to assume a neural crest stem cell phenotype and to generate a subpopulation of cells that display ESFT features.	('ES', 'Phenotype', 'HP:0012254', (203, 205))	('FLI1', 'Gene', '2313', (38, 42))	('generate', 'Reg', (156, 164))	('hpMSC', 'Gene', (98, 103))	('FLI1', 'Gene', (38, 42))	('miRNA', 'Gene', (86, 91))	('repression', 'NegReg', (47, 57))	('neural crest stem cell phenotype', 'CPA', (116, 148))	('assume', 'PosReg', (107, 113))	('ESFT features', 'CPA', (203, 216))	('transfection', 'Var', (18, 30))
63658	20981347	In these patients, cooperative group and single institution studies have associated adverse outcome with older age at presentation (>=14 years or >=18 years), large tumor volume, poor response to induction therapy, axial location, elevated LDH, secondary genetic abnormalities, deletion of p16, and mutation of P53.	('LDH', 'MPA', (240, 243))	('patients', 'Species', '9606', (9, 17))	('P53', 'Gene', (311, 314))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('elevated', 'PosReg', (231, 239))	('P53', 'Gene', '7157', (311, 314))	('genetic abnormalities', 'Disease', 'MESH:D030342', (255, 276))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('mutation', 'Var', (299, 307))	('p16', 'Gene', '1029', (290, 293))	('deletion', 'Var', (278, 286))	('genetic abnormalities', 'Disease', (255, 276))	('p16', 'Gene', (290, 293))	('tumor', 'Disease', (165, 170))
63728	20981347	Losses of p161INK4A, mutation of TP53, and deletion of CKDN2A appear to correlate with a poor prognosis.	('CKDN2A', 'Gene', (55, 61))	('Losses', 'NegReg', (0, 6))	('deletion', 'Var', (43, 51))	('TP53', 'Gene', '7157', (33, 37))	('p16', 'Gene', (10, 13))	('mutation', 'Var', (21, 29))	('TP53', 'Gene', (33, 37))	('p16', 'Gene', '1029', (10, 13))
63755	31684956	Patients who underwent resection of a retroperitoneal sarcoma between 1998 and 2012 were identified by the International Classification of Disease for Oncology, 3rd Edition (ICD-O-3) topography codes: 8800, 8801, 8802, 8810, 8830, 8850, 8851, 8852, 8853, 8854, 8858, 8890, 9120, 9540.	('8801', 'Var', (207, 211))	('8858', 'Var', (261, 265))	('8810', 'Var', (219, 223))	('9120', 'Var', (273, 277))	('retroperitoneal sarcoma', 'Disease', 'MESH:D012186', (38, 61))	('8830', 'Var', (225, 229))	('8890', 'Var', (267, 271))	('8851', 'Var', (237, 241))	('8852', 'Var', (243, 247))	('8800', 'Var', (201, 205))	('retroperitoneal sarcoma', 'Disease', (38, 61))	('Patients', 'Species', '9606', (0, 8))	('Oncology', 'Phenotype', 'HP:0002664', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('8854', 'Var', (255, 259))	('8802', 'Var', (213, 217))	('8850', 'Var', (231, 235))
63796	31684956	Longer-term oncologic outcomes were also improved despite higher-grade tumors in the LT/HV group (HR 0.73, p = 0.0009).	('LT/HV', 'Var', (85, 90))	('improved', 'PosReg', (41, 49))	('higher-grade', 'PosReg', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('oncologic outcomes', 'CPA', (12, 30))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
63834	22847205	Lymphocyte subset percentage was abnormal: CD3 84.0% (normal range 67-76%), CD3+DR+ 43.0% (normal range 8-15%), CD4 32% (normal range 38-46%), CD8 52% (normal range 31-40%), CD19 2% (normal range 11-16%), NK 6% (normal range 10-19%).	('CD4', 'Gene', '920', (112, 115))	('CD19', 'Gene', '930', (174, 178))	('CD3+DR+', 'Var', (76, 83))	('CD8', 'Gene', (143, 146))	('CD8', 'Gene', '925', (143, 146))	('CD3', 'Var', (43, 46))	('CD19', 'Gene', (174, 178))	('CD4', 'Gene', (112, 115))
63836	22847205	Immunophenotypic analysis showed cell markers F VIII+, CK AE1/AE3-, CD34+ and CD31+ (Figure 3), demonstrating the endothelial nature of the proliferating tumor cells.	('AE1', 'Gene', '6521', (58, 61))	('AE3', 'Gene', (62, 65))	('AE1', 'Gene', (58, 61))	('CD31', 'Gene', (78, 82))	('CD34', 'Gene', (68, 72))	('CD34', 'Gene', '947', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CD31', 'Gene', '5175', (78, 82))	('F VIII+', 'Var', (46, 53))	('AE3', 'Gene', '6508', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
63850	22847205	The presence of triptolide m/z=359 (M-H-) and tripdiolide m/z=375 (M-H-), 2 major active components of Trypterigium wilfordii Hook F, was confirmed.	('triptolide', 'Chemical', 'MESH:C001899', (16, 26))	('m/z=359', 'Var', (27, 34))	('m/z=375', 'Var', (58, 65))	('tripdiolide', 'Chemical', 'MESH:C001898', (46, 57))
63885	22937465	Exercise capacity was impaired as shown by a 6 min walking distance of 553 meters (69% of predicted) with desaturation from 96 to 90% and by an ergospirometry showing a peak oxygen consumption of 22 ml/min/kg with desaturation from 97 to 83%.	('impaired', 'NegReg', (22, 30))	('oxygen', 'Chemical', 'MESH:D010100', (174, 180))	('Exercise', 'MPA', (0, 8))	('desaturation', 'Var', (106, 118))
63886	22937465	Chest X-ray showed enlarged pulmonary arteries with a right parahilar nodule, perfusion scan multiple lobar and segmental defects, and pulmonary angiography amputations of the right lower lobe and left upper lobe arteries, with multiple aneurysmal dilatations of the branches of the right upper lobe artery (Figure 1).	('amputations', 'Var', (157, 168))	('angiography amputations', 'Phenotype', 'HP:0004950', (145, 168))	('aneurysm', 'Phenotype', 'HP:0002617', (237, 245))	('pulmonary arteries', 'CPA', (28, 46))	('segmental defects', 'Disease', 'MESH:C537538', (112, 129))	('aneurysmal dilatations', 'Phenotype', 'HP:0002617', (237, 259))	('enlarged pulmonary arteries', 'Phenotype', 'HP:0004890', (19, 46))	('multiple aneurysmal dilatations of the branches of the right upper lobe artery', 'Disease', 'MESH:D002532', (228, 306))	('segmental defects', 'Disease', (112, 129))
63915	31837177	EWSR1-WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases.	('mutations', 'Var', (66, 75))	('STAG2', 'Gene', (100, 105))	('WT1', 'Gene', '7490', (6, 9))	('STAG2', 'Gene', '10735', (100, 105))	('EWSR1', 'Gene', '2130', (0, 5))	('WT1', 'Gene', (6, 9))	('TERT', 'Gene', (83, 87))	('TERT', 'Gene', '7015', (83, 87))	('EWSR1', 'Gene', (0, 5))
63928	31837177	Cases 1-4 had sufficient tumor tissue for genetic evaluation on the UCSF500 Cancer Panel, which assesses approximately 500 cancer-associated genes for mutations, copy number alterations, and structural variants including gene fusions (, and Supplementary Table 1).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('copy number alterations', 'Var', (162, 185))	('Cancer', 'Disease', (76, 82))	('cancer', 'Disease', (123, 129))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
63963	31837177	Staining for neuronal markers showed patchy or focal synaptophysin in 4/5 cases, patchy NeuN in 3/3 cases, and strong CD56 staining in 3/3 cases.	('NeuN', 'Gene', '146713', (88, 92))	('synaptophysin', 'Gene', (53, 66))	('synaptophysin', 'Gene', '6855', (53, 66))	('NeuN', 'Gene', (88, 92))	('patchy', 'Var', (37, 43))	('CD56', 'Protein', (118, 122))
63966	31837177	For all cases evaluated by the UCSF500 Cancer panel (case #1, 2, 3, 4), the fusion junction occurred between intron 8-9 of the EWSR1 gene (NM_013986) on chromosome 22q12 and intron 7-8 of the WT1 gene (NM_024426) on chromosome 11p33.	('EWSR1', 'Gene', (127, 132))	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('WT1', 'Gene', '7490', (192, 195))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('WT1', 'Gene', (192, 195))	('NM_013986', 'Var', (139, 148))	('EWSR1', 'Gene', '2130', (127, 132))	('NM_024426', 'Var', (202, 211))	('Cancer', 'Disease', (39, 45))
63970	31837177	Accompanying pathogenic mutations included a TERT promoter hotspot mutation in case #3, and a subclonal STAG2 splice site mutation in case #4 predicted to disrupt gene function (Table 3).	('disrupt', 'NegReg', (155, 162))	('mutation', 'Var', (67, 75))	('TERT', 'Gene', (45, 49))	('mutation', 'Var', (122, 130))	('STAG2', 'Gene', (104, 109))	('STAG2', 'Gene', '10735', (104, 109))	('gene function', 'MPA', (163, 176))	('TERT', 'Gene', '7015', (45, 49))	('mutations', 'Var', (24, 33))
63978	31837177	This case was positive for YAP1 and GAB1, with p53 positivity in 60% of tumor nuclei, mimicking an anaplastic medulloblastoma, SHH-activated and likely TP53 mutant.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SHH', 'Gene', (127, 130))	('YAP1', 'Gene', (27, 31))	('mutant', 'Var', (157, 163))	('YAP1', 'Gene', '10413', (27, 31))	('tumor', 'Disease', (72, 77))	('anaplastic medulloblastoma', 'Disease', (99, 125))	('TP53', 'Gene', '7157', (152, 156))	('GAB1', 'Gene', (36, 40))	('SHH', 'Gene', '6469', (127, 130))	('anaplastic medulloblastoma', 'Disease', 'MESH:D008527', (99, 125))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('medulloblastoma', 'Phenotype', 'HP:0002885', (110, 125))	('TP53', 'Gene', (152, 156))	('p53', 'Gene', (47, 50))	('GAB1', 'Gene', '2549', (36, 40))	('p53', 'Gene', '7157', (47, 50))
63988	31837177	However, one could speculate that a mesencyhmal progenitor cell associated with the meninges, the vasculature, or possibly located within the brain parenchyma due to abnormal developmental differentiation or migration, could acquire genetic and epigenetic alterations resulting in sarcoma tumorigenesis.	('epigenetic alterations', 'Var', (245, 267))	('abnormal developmental differentiation', 'Disease', (166, 204))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('sarcoma tumorigenesis', 'Disease', 'MESH:D063646', (281, 302))	('genetic', 'Var', (233, 240))	('sarcoma tumorigenesis', 'Disease', (281, 302))	('resulting in', 'Reg', (268, 280))	('abnormal developmental differentiation', 'Disease', 'MESH:D012734', (166, 204))	('abnormal developmental differentiation or migration', 'Phenotype', 'HP:0002269', (166, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))
63991	31837177	Desmin positivity, in the context of a polyphenotypic immunoprofile and particularly if there is a globular staining pattern, is highly suggestive of a DSRCT diagnosis.	('Desmin positivity', 'Phenotype', 'HP:0100300', (0, 17))	('positivity', 'Var', (7, 17))	('Desmin', 'Gene', '1674', (0, 6))	('Desmin', 'Gene', (0, 6))	('DSRCT diagnosis', 'Disease', (152, 167))
63994	31837177	Desmin positivity could be very useful as an initial screening test, which would then initiate additional confirmatory molecular testing to evaluate for the presence of an EWSR1-WT1 gene fusion, a matching methylation profile, or surrogate indication of the fusion by WT1 immunostaining.	('Desmin positivity', 'Phenotype', 'HP:0100300', (0, 17))	('EWSR1', 'Gene', (172, 177))	('WT1', 'Gene', '7490', (178, 181))	('WT1', 'Gene', (178, 181))	('EWSR1', 'Gene', '2130', (172, 177))	('Desmin', 'Gene', '1674', (0, 6))	('WT1', 'Gene', (268, 271))	('WT1', 'Gene', '7490', (268, 271))	('fusion', 'Var', (187, 193))	('Desmin', 'Gene', (0, 6))
64005	31837177	Inactivating mutations in STAG2 are the most frequent accompanying somatic mutation in Ewing sarcoma, occurring in approximately 17% of cases, and are associated with poor outcome.	('STAG2', 'Gene', (26, 31))	('associated', 'Reg', (151, 161))	('Inactivating mutations', 'Var', (0, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('Ewing sarcoma', 'Disease', (87, 100))	('STAG2', 'Gene', '10735', (26, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (87, 100))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (87, 100))
64006	31837177	To the best of our knowledge, among the relatively few cases of DSRCT that have either undergone extensive genetic sequencing or sequencing focused specifically on accompanying STAG2 or TP53 mutations, only one additional case with a STAG2 mutation has been reported.	('STAG2', 'Gene', '10735', (234, 239))	('mutations', 'Var', (191, 200))	('TP53', 'Gene', '7157', (186, 190))	('STAG2', 'Gene', (177, 182))	('STAG2', 'Gene', '10735', (177, 182))	('TP53', 'Gene', (186, 190))	('STAG2', 'Gene', (234, 239))
64008	31837177	The prognostic implication of accompanying STAG2 mutations within DSRCT is of uncertain significance.	('STAG2', 'Gene', '10735', (43, 48))	('STAG2', 'Gene', (43, 48))	('mutations', 'Var', (49, 58))
64009	31837177	Within our review of DSRCT sequencing studies available in the literature, whole exome sequencing analysis was performed on seven tumors, a targeted panel of cancer related genes were assessed in one tumor, and 6 tumors were evaluated specifically for accompanying STAG2 or TP53 mutations using a targeted cancer panel.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('STAG2', 'Gene', (265, 270))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('TP53', 'Gene', (274, 278))	('tumor', 'Disease', (130, 135))	('mutations', 'Var', (279, 288))	('tumors', 'Disease', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', (200, 205))	('cancer', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('TP53', 'Gene', '7157', (274, 278))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', (306, 312))	('tumor', 'Disease', (213, 218))	('tumors', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('STAG2', 'Gene', '10735', (265, 270))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('tumor', 'Disease', 'MESH:D009369', (213, 218))
64010	31837177	Mutation of the TERT promoter was either not identified or not assessed in these studies, and would not be detected by sequencing limited to the exome.	('TERT', 'Gene', (16, 20))	('TERT', 'Gene', '7015', (16, 20))	('Mutation', 'Var', (0, 8))
64023	33335088	Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance.	('autochthonous sarcomas', 'Phenotype', 'HP:0031549', (117, 139))	('decreased', 'NegReg', (174, 183))	('blockade', 'Var', (57, 65))	('sarcomas', 'Disease', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('neoantigen expression', 'MPA', (184, 205))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('PD-1', 'Gene', (52, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('sarcomas', 'Disease', (131, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('sarcomas', 'Disease', 'MESH:D012509', (30, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
64031	33335088	Preclinical studies using transplanted tumor models demonstrate that focal RT can synergize with immune checkpoint inhibitors to generate systemic antitumor immune responses.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('focal RT', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
64045	33335088	We injected the gastrocnemius muscle of Trp53fl/fl mice with an adenovirus expressing Cre recombinase (Adeno-Cre) to delete Trp53, followed by injection with the carcinogen 3-methylcholanthrene (MCA).	('mice', 'Species', '10090', (51, 55))	('Trp53', 'Gene', '22059', (40, 45))	('Trp53', 'Gene', (124, 129))	('3-methylcholanthrene', 'Chemical', 'MESH:D008748', (173, 193))	('adenovirus', 'Species', '10508', (64, 74))	('MCA', 'Chemical', 'MESH:D008748', (195, 198))	('Trp53', 'Gene', '22059', (124, 129))	('Trp53', 'Gene', (40, 45))	('delete', 'Var', (117, 123))
64053	33335088	In primary and transplant tumors harvested 3 days after treatment with anti-PD-1 or isotype control antibody and 0 or 20 Gy, we compared paired WES data from the tumor and liver of each mouse to identify somatic mutations within each tumor.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (234, 239))	('transplant tumors', 'Disease', (15, 32))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('transplant tumors', 'Disease', 'MESH:D007674', (15, 32))	('mouse', 'Species', '10090', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('anti-PD-1', 'Var', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
64054	33335088	Primary tumors harbored more nonsynonymous mutations than transplant tumors (Fig.	('transplant tumors', 'Disease', (58, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Primary tumors', 'Disease', 'MESH:D001932', (0, 14))	('transplant tumors', 'Disease', 'MESH:D007674', (58, 75))	('Primary tumors', 'Disease', (0, 14))	('nonsynonymous mutations', 'Var', (29, 52))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
64058	33335088	In primary tumors, treatment with anti-PD-1 antibody decreased the number of nonsynonymous mutations by ~15%, and the addition of RT resulted in an ~40% decrease in nonsynonymous mutations at 3 days post-treatment (Fig.	('anti-PD-1', 'Gene', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('primary tumors', 'Disease', (3, 17))	('anti-PD-1', 'Var', (34, 43))	('nonsynonymous mutations', 'MPA', (165, 188))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('primary tumors', 'Disease', 'MESH:D001932', (3, 17))	('decreased', 'NegReg', (53, 62))	('nonsynonymous mutations', 'MPA', (77, 100))	('decrease', 'NegReg', (153, 161))
64060	33335088	The fraction of nonsynonymous mutations predicted to be neoantigens was significantly lower in primary tumors than transplant tumors but did not change with treatment (Supplementary Fig.	('primary tumors', 'Disease', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('transplant tumors', 'Disease', 'MESH:D007674', (115, 132))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('transplant tumors', 'Disease', (115, 132))	('primary tumors', 'Disease', 'MESH:D001932', (95, 109))	('lower', 'NegReg', (86, 91))	('nonsynonymous mutations', 'Var', (16, 39))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
64076	33335088	This transcriptional immune evasion mechanism was specific to neoantigenic mutations, as no differences were seen in global gene expression in tumors from Rag2-/- and Rag2+/- mice (Supplementary Fig.	('mice', 'Species', '10090', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('Rag2', 'Gene', (167, 171))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('Rag2', 'Gene', '19374', (155, 159))	('mutations', 'Var', (75, 84))	('Rag2', 'Gene', (155, 159))	('Rag2', 'Gene', '19374', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
64082	33335088	Transplant "self" tumors in donor mice were resistant to tumor cure by anti-PD-1 and RT.	('mice', 'Species', '10090', (34, 38))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (57, 62))	('anti-PD-1', 'Var', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
64083	33335088	When the same tumor cell lines were injected into naive mice and treated with anti-PD-1 and RT, more than half of the mice (52%) were cured (Fig.	('tumor', 'Disease', (14, 19))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mice', 'Species', '10090', (118, 122))	('anti-PD-1', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
64093	33335088	To identify the major transcriptional differences between primary and transplant sarcomas, we analyzed bulk tumor RNA harvested 3 days after treatment with either 0 or 20 Gy and anti-PD-1 or isotype control antibody.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('sarcomas', 'Disease', (81, 89))	('anti-PD-1', 'Var', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('tumor', 'Disease', (108, 113))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
64110	33335088	To test whether PD-L1+ macrophages differed between primary and transplant tumors, we used a panel of 37 heavy metal-conjugated antibodies to analyze independent tumor samples by mass cytometry (CyTOF) at 3 days after treatment with isotype control, anti-PD-1, RT, or anti-PD-1 and RT.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('anti-PD-1', 'Var', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('metal', 'Chemical', 'MESH:D008670', (111, 116))	('transplant tumors', 'Disease', 'MESH:D007674', (64, 81))	('transplant tumors', 'Disease', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (75, 80))	('anti-PD-1', 'Var', (250, 259))
64114	33335088	To gain insight into the transcriptional differences in the immune microenvironments of primary and transplant tumors, we performed single-cell RNA sequencing (scRNA-seq) on FACS-sorted CD45+ tumor-infiltrating immune cells from sarcomas harvested 3 days after treatment with either anti-PD-1 antibody or isotype control (primary and transplant) and 0 or 20 Gy (primary tumors only).	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('sarcomas', 'Disease', 'MESH:D012509', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (370, 375))	('sarcomas', 'Phenotype', 'HP:0100242', (229, 237))	('sarcomas', 'Disease', (229, 237))	('tumors', 'Phenotype', 'HP:0002664', (370, 376))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('primary tumors', 'Disease', 'MESH:D001932', (362, 376))	('FACS', 'Gene', (174, 178))	('tumor', 'Disease', (192, 197))	('transplant tumors', 'Disease', 'MESH:D007674', (100, 117))	('transplant tumors', 'Disease', (100, 117))	('tumor', 'Disease', (111, 116))	('CD4', 'Gene', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('FACS', 'Gene', '14081', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('primary tumors', 'Disease', (362, 376))	('CD4', 'Gene', '12504', (186, 189))	('anti-PD-1', 'Var', (283, 292))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', (370, 375))
64119	33335088	Tumor-infiltrating myeloid cells comprise the largest fraction of immune cells in both primary and transplant tumors, and they undergo significant remodeling with anti-PD-1 therapy (Supplementary Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('anti-PD-1', 'Var', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('transplant tumors', 'Disease', (99, 116))	('transplant tumors', 'Disease', 'MESH:D007674', (99, 116))
64132	33335088	In primary tumors, treatment with anti-PD-1 therapy also upregulated genes involved in the type I interferon response (Irf7, Isg15, Ifit1, Ifit3, and Ccl5) and antigen processing machinery (Tap1, Tapbp, and B2m) (Supplementary Fig.	('Tap1', 'Gene', '21354', (190, 194))	('Tap1', 'Gene', (190, 194))	('primary tumors', 'Disease', (3, 17))	('Isg15', 'Gene', (125, 130))	('Ccl5', 'Gene', '20304', (150, 154))	('Tapbp', 'Gene', '21356', (196, 201))	('anti-PD-1', 'Var', (34, 43))	('Tapbp', 'Gene', (196, 201))	('Ifit3', 'Gene', (139, 144))	('B2m', 'Gene', (207, 210))	('Ifit1', 'Gene', '15957', (132, 137))	('Ifit1', 'Gene', (132, 137))	('Isg15', 'Gene', '100038882', (125, 130))	('upregulated', 'PosReg', (57, 68))	('Ccl5', 'Gene', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('Ifit3', 'Gene', '15959', (139, 144))	('primary tumors', 'Disease', 'MESH:D001932', (3, 17))	('type', 'MPA', (91, 95))	('Irf7', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Irf7', 'Gene', '54123', (119, 123))	('B2m', 'Gene', '12010', (207, 210))	('genes', 'Gene', (69, 74))
64134	33335088	PD-1 blockade also induced Stat1 and Irf1, suggesting that despite the immunosuppressive myeloid cell environment in isotype control-treated primary tumors, treatment with PD-1 blockade can induce myeloid cells to adopt an antitumor phenotype.	('blockade', 'Var', (177, 185))	('adopt', 'Reg', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (227, 232))	('primary tumors', 'Disease', (141, 155))	('myeloid cells', 'CPA', (197, 210))	('PD-1', 'Gene', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', (149, 154))	('induce', 'PosReg', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('primary tumors', 'Disease', 'MESH:D001932', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
64135	33335088	In preclinical studies using transplanted tumor models, focal RT can synergize with immune checkpoint inhibitors by increasing tumor immunogenicity and by reinvigorating the antitumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('reinvigorating', 'PosReg', (155, 169))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (127, 132))	('focal RT', 'Var', (56, 64))	('increasing', 'PosReg', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
64136	33335088	To examine the transcriptional effects of RT on the immune microenvironment of radiation-resistant primary tumors, we also performed scRNA-seq on CD45+ cells isolated from primary sarcomas harvested 3 days after treatment with 20 Gy RT and either anti-PD-1 or isotype control antibody.	('anti-PD-1', 'Var', (247, 256))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('primary tumors', 'Disease', 'MESH:D001932', (99, 113))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('CD4', 'Gene', (146, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('CD4', 'Gene', '12504', (146, 149))	('sarcomas', 'Disease', (180, 188))	('primary tumors', 'Disease', (99, 113))
64138	33335088	After RT, myeloid cells from primary tumors treated with isotype control or anti-PD-1 antibody clustered into myeloid subclusters Y2, Y4, and Y6 (Fig.	('primary tumors', 'Disease', 'MESH:D001932', (29, 43))	('anti-PD-1', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('primary tumors', 'Disease', (29, 43))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('Y4, and Y6', 'Gene', '19065', (134, 144))
64144	33335088	Taken together, these data indicate that, despite the immunosuppressive microenvironment of untreated primary tumors, PD-1 blockade and RT successfully repolarize myeloid cells in primary tumors, with the dominant changes being activation of type I and II interferon response pathways.	('blockade', 'Var', (123, 131))	('activation', 'PosReg', (228, 238))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('primary tumors', 'Disease', 'MESH:D001932', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('primary tumors', 'Disease', (180, 194))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('myeloid cells', 'MPA', (163, 176))	('repolarize', 'NegReg', (152, 162))	('PD-1', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('primary tumors', 'Disease', 'MESH:D001932', (180, 194))	('primary tumors', 'Disease', (102, 116))
64153	33335088	Interestingly, we also found that transplant tumor cure by anti-PD-1 and RT was dependent on CD4+ T cells (Fig.	('transplant tumor', 'Disease', (34, 50))	('anti-PD-1', 'Var', (59, 68))	('transplant tumor', 'Disease', 'MESH:D007674', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CD4', 'Gene', (93, 96))	('CD4', 'Gene', '12504', (93, 96))
64160	33335088	Interestingly, within the small number of CD8+ T cells from primary tumors that fell into cluster L0, treatment with anti-PD-1 antibody induced high expression of Tox (Supplementary Fig.	('Tox', 'Gene', (163, 166))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('anti-PD-1', 'Var', (117, 126))	('primary tumors', 'Disease', 'MESH:D001932', (60, 74))	('CD8', 'Gene', (42, 45))	('expression', 'MPA', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CD8', 'Gene', '925', (42, 45))	('primary tumors', 'Disease', (60, 74))	('Tox', 'Gene', '252838', (163, 166))
64169	33335088	Within CD8+ T cells from transplant tumors, treatment with anti-PD-1 antibody increased expression of granzymes (Gzma, Gzmb) and cell proliferation genes (Rps12, Rpl5, Eif4a1, and Top2a), while anti-PD-1 treatment reduced expression of the exhaustion markers Tnfrsf18 (Gitr) and Lag3 (Supplementary Fig.	('transplant tumors', 'Disease', (25, 42))	('anti-PD-1', 'Var', (59, 68))	('Tnfrsf18', 'Gene', '21936', (259, 267))	('transplant tumors', 'Disease', 'MESH:D007674', (25, 42))	('CD8', 'Gene', '925', (7, 10))	('expression', 'MPA', (88, 98))	('Gitr', 'Gene', (269, 273))	('Rpl5', 'Gene', '100503670', (162, 166))	('Gzmb', 'Gene', (119, 123))	('Tnfrsf18', 'Gene', (259, 267))	('Gzma', 'Gene', '14938', (113, 117))	('Gzma', 'Gene', (113, 117))	('Gzmb', 'Gene', '14939', (119, 123))	('Gitr', 'Gene', '21936', (269, 273))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('expression', 'MPA', (222, 232))	('Eif4a1', 'Gene', '13681', (168, 174))	('Top2a', 'Gene', (180, 185))	('Rps12', 'Gene', (155, 160))	('CD8', 'Gene', (7, 10))	('reduced', 'NegReg', (214, 221))	('Lag3', 'Gene', '16768', (279, 283))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Rpl5', 'Gene', (162, 166))	('Eif4a1', 'Gene', (168, 174))	('Lag3', 'Gene', (279, 283))	('increased', 'PosReg', (78, 87))	('Top2a', 'Gene', '21973', (180, 185))	('Rps12', 'Gene', '20042', (155, 160))
64171	33335088	Interestingly, the activity of the Wnt/beta-Catenin signaling pathway in CD8+ T cells increased further after anti-PD-1 treatment in primary tumors but decreased after anti-PD-1 treatment in transplant tumors (Supplementary Fig.	('beta-Catenin', 'Gene', '12387', (39, 51))	('primary tumors', 'Disease', (133, 147))	('increased', 'PosReg', (86, 95))	('transplant tumors', 'Disease', 'MESH:D007674', (191, 208))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('beta-Catenin', 'Gene', (39, 51))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('primary tumors', 'Disease', 'MESH:D001932', (133, 147))	('decreased', 'NegReg', (152, 161))	('activity', 'MPA', (19, 27))	('transplant tumors', 'Disease', (191, 208))	('anti-PD-1', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CD8', 'Gene', (73, 76))	('CD8', 'Gene', '925', (73, 76))	('T cells increased', 'Phenotype', 'HP:0100828', (78, 95))
64186	33335088	Similar proinflammatory myeloid cell remodeling occurs in primary tumors after PD-1 blockade, but this is not accompanied by an increase in activated CD8+ T cells in primary tumors, suggesting that additional mechanisms of immune tolerance are responsible for primary tumor resistance to immunotherapy.	('primary tumors', 'Disease', (58, 72))	('CD8', 'Gene', '925', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (66, 71))	('primary tumors', 'Disease', (166, 180))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CD8', 'Gene', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('primary tumors', 'Disease', 'MESH:D001932', (58, 72))	('PD-1', 'Gene', (79, 83))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('blockade', 'Var', (84, 92))	('primary tumors', 'Disease', 'MESH:D001932', (166, 180))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
64255	33335088	The aligned bam files were post-processed by following the recommended pipeline of Genome Analysis Toolkit (GATK, version 3.8) to generate the analysis-ready BAM files for variant calling.	('kit', 'Gene', (103, 106))	('kit', 'Gene', '16590', (103, 106))	('variant calling', 'Var', (172, 187))
64258	33335088	Variants called by MuTect2 that were present in the dbSNP were removed.	('MuTect2', 'CellLine', 'CVCL:3448', (19, 26))	('Variants', 'Var', (0, 8))	('MuTect2', 'Gene', (19, 26))
64260	33335088	The binding ability between all the mutant peptides and mouse H2-Kb/Db was predicted by netMHC (4.0) with default parameters.	('binding', 'Interaction', (4, 11))	('mouse', 'Species', '10090', (56, 61))	('mutant', 'Var', (36, 42))
64300	33335088	A.J.W., Y.M.M., C.S.H., J.E.H., E.S.X., D.J.C., C.L.K., and L.L.	('C.L.K.', 'Var', (48, 54))	('D.J.C.', 'Var', (40, 46))	('J.E.H', 'CellLine', 'CVCL:0355', (24, 29))	('E.S.X.', 'Var', (32, 38))	('J.E.H.', 'Var', (24, 30))	('C.S.H.', 'Var', (16, 22))
64302	33335088	A.J.W., Y.M.M., C.S.H., J.E.H., R.P., A.M.B., D.J.C., C.L.K., and E.S.X.	('A.M.B.', 'Var', (38, 44))	('J.E.H', 'CellLine', 'CVCL:0355', (24, 29))	('J.E.H.', 'Var', (24, 30))	('R.P.', 'Var', (32, 36))	('C.S.H.', 'Var', (16, 22))	('C.L.K.', 'Var', (54, 60))	('D.J.C.', 'Var', (46, 52))
64358	32335707	Articular surface irregularity potentially may give rise to early osteoarthritis, although there is no long-term data on this outcome as yet.	('osteoarthritis', 'Disease', (66, 80))	('osteoarthritis', 'Disease', 'MESH:D010003', (66, 80))	('give rise', 'Reg', (47, 56))	('early osteoarthritis', 'Phenotype', 'HP:0003088', (60, 80))	('Articular', 'Var', (0, 9))	('osteoarthritis', 'Phenotype', 'HP:0002758', (66, 80))
64401	32335707	Females on denosumab should be advised to avoid pregnancy and take appropriate contraceptive precautions as there is evidence that denosumab is associated with increased stillbirth and decreased body weight gain, growth and development in studies of animal infants exposed in utero.	('decreased body weight gain', 'Disease', (185, 211))	('increased', 'PosReg', (160, 169))	('weight gain', 'Phenotype', 'HP:0004324', (200, 211))	('stillbirth', 'Disease', (170, 180))	('denosumab', 'Chemical', 'MESH:D000069448', (131, 140))	('denosumab', 'Chemical', 'MESH:D000069448', (11, 20))	('infants', 'Species', '9606', (257, 264))	('decreased body weight', 'Phenotype', 'HP:0004325', (185, 206))	('decreased body weight gain', 'Disease', 'MESH:D015430', (185, 211))	('stillbirth', 'Disease', 'MESH:D050497', (170, 180))	('denosumab', 'Var', (131, 140))
64481	28873262	Reactivation of TWIST1 contributes to Ewing sarcoma metastasis Ewing sarcoma is a cancer of bone and soft tissue.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('Ewing sarcoma metastasis', 'Disease', 'MESH:C563168', (38, 62))	('cancer of bone', 'Phenotype', 'HP:0010622', (82, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('cancer', 'Disease', (82, 88))	('Ewing sarcoma', 'Disease', (63, 76))	('Reactivation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TWIST1', 'Gene', (16, 22))	('TWIST1', 'Gene', '7291', (16, 22))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('Ewing sarcoma metastasis', 'Disease', (38, 62))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))
64485	28873262	Ewing sarcoma patients were divided into high or low Twist1 gene expression and survival curves were generated using the R2 microarray-based Genomic Analysis platform (http://r2.amc.nl).	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', (0, 13))	('Twist1', 'Gene', (53, 59))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('low', 'Var', (49, 52))	('patients', 'Species', '9606', (14, 22))
64502	28873262	In fact EWS/FLI knockdown cells tend to seed the lung better than their parental cells with EWS/FLI expression.	('FLI', 'Gene', (12, 15))	('EWS', 'Gene', (8, 11))	('FLI', 'Gene', '2314', (96, 99))	('EWS', 'Gene', '2130', (8, 11))	('knockdown', 'Var', (16, 25))	('EWS', 'Gene', (92, 95))	('seed', 'CPA', (40, 44))	('FLI', 'Gene', (96, 99))	('FLI', 'Gene', '2314', (12, 15))	('EWS', 'Gene', '2130', (92, 95))	('lung', 'CPA', (49, 53))
64509	28873262	Many studies have also shown Twist1 expression was associated with aggressive human cancers including melanomas and neuroblastoma, both of which originate from the neural crest.	('melanomas', 'Disease', (102, 111))	('neuroblastoma', 'Disease', 'MESH:D009447', (116, 129))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('Twist1', 'Gene', (29, 35))	('expression', 'Var', (36, 46))	('cancers', 'Disease', (84, 91))	('neuroblastoma', 'Disease', (116, 129))	('associated', 'Reg', (51, 61))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('neuroblastoma', 'Phenotype', 'HP:0003006', (116, 129))	('human', 'Species', '9606', (78, 83))
64547	28873262	50ul containing 250,000 A673 or TC32 cells were injected intramuscularly into the gastrocnemius muscles of 8 week old nude mice (NU/J strain from the Jackson Laboratory) using a 30 gauge needle.	('A673', 'Var', (24, 28))	('TC32', 'Gene', (32, 36))	('nude mice', 'Species', '10090', (118, 127))	('TC32', 'CellLine', 'CVCL:7151', (32, 36))
64568	28873262	Prior studies suggests upwards of 95% of Ewing sarcoma patients have an EWS rearrangement detected at diagnosis.	('Ewing sarcoma', 'Disease', (41, 54))	('EWS', 'Gene', (72, 75))	('EWS', 'Gene', '2130', (72, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (41, 54))	('rearrangement', 'Var', (76, 89))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (41, 54))	('patients', 'Species', '9606', (55, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
64572	28873262	Furthermore, we found that Twist1 positivity was correlated with poor survival in patients with Ewing sarcoma, consistent with the results from the Dirksen and Savola patient data set (Fig.	('Twist1', 'Gene', (27, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('positivity', 'Var', (34, 44))	('patient', 'Species', '9606', (82, 89))	('patients', 'Species', '9606', (82, 90))	('patient', 'Species', '9606', (167, 174))	('Ewing sarcoma', 'Disease', (96, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('poor', 'NegReg', (65, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))
64573	28873262	Survival curves based on Twist 1 expression was similar to survival curves based on presence of metastasis (Fig.	('Twist 1', 'Gene', (25, 32))	('expression', 'Var', (33, 43))	('Twist 1', 'Gene', '7291', (25, 32))
64584	28873262	We infected GFP expressing-A673 and TC32 Ewing cells with a lentiviral vector carrying either shRNA against Twist1 (shTwist3, shTwist5, or shTwist7) or a control shRNA (shNCT).	('shTwist7', 'Var', (139, 147))	('TC32', 'CellLine', 'CVCL:7151', (36, 40))	('shTwist5', 'Var', (126, 134))
64586	28873262	A673 cells expressing shTwist#3 or shTwist#7 generated primary tumors with similar growth kinetics and similar final weight as the control cells (Fig.	('shTwist#3', 'Var', (22, 31))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('primary tumor', 'Disease', (55, 68))	('shTwist#7', 'Var', (35, 44))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('primary tumor', 'Disease', 'MESH:D009369', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
64587	28873262	However, mice carrying A673 tumors expressing shRNAs against Twist1 presented significantly fewer lung metastases, average 2 nodules per mice, compared to the control xenografts, average 32 nodules per mice (Fig.4B).	('mice', 'Species', '10090', (202, 206))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('fewer', 'NegReg', (92, 97))	('Twist1', 'Gene', (61, 67))	('lung metastases', 'Disease', (98, 113))	('mice', 'Species', '10090', (9, 13))	('lung metastases', 'Disease', 'MESH:D009362', (98, 113))	('mice', 'Species', '10090', (137, 141))	('shRNAs against', 'Var', (46, 60))
64588	28873262	IHC for Twist1 in the primary tumor confirm TWIST1 knockdown in the mice (Fig.4A).	('mice', 'Species', '10090', (68, 72))	('primary tumor', 'Disease', 'MESH:D009369', (22, 35))	('TWIST1', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('primary tumor', 'Disease', (22, 35))	('knockdown', 'Var', (51, 60))
64614	28873262	The addition of targeted therapy against this metastatic pathway instead of additional cytotoxic therapy could minimize long-term sequela of therapy, decrease disease metastasis and recurrence to improve overall survival.	('decrease disease metastasis', 'Disease', 'MESH:D009362', (150, 177))	('improve', 'PosReg', (196, 203))	('metastatic pathway', 'Pathway', (46, 64))	('recurrence', 'CPA', (182, 192))	('decrease disease metastasis', 'Disease', (150, 177))	('targeted', 'Var', (16, 24))
64617	28873262	IHC Immunohistochemistry RCHSD Rady Children's Hospital San Diego CHOC Children's Hospital Orange County NTC Non-target coding GFP Green fluorescent protein EMT Epithelial - mesenchymal transition MET Mesenchymal - epithelial transition	('RCHSD', 'Disease', 'None', (25, 30))	('GFP', 'Var', (127, 130))	('Children', 'Species', '9606', (36, 44))	('Children', 'Species', '9606', (71, 79))	('RCHSD', 'Disease', (25, 30))	('Epithelial', 'CPA', (161, 171))
64669	29051995	Of the six renal cancer patients with low Cmin only one was female.	('renal cancer', 'Disease', (11, 23))	('renal cancer', 'Phenotype', 'HP:0009726', (11, 23))	('renal cancer', 'Disease', 'MESH:D007680', (11, 23))	('patients', 'Species', '9606', (24, 32))	('low Cmin', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
64673	29051995	In soft tissue sarcoma, median progression free survival was 18.7 weeks for patients with high and 8.8 weeks for patients with low Cmin (p = 0.142, log-rank test, see Fig.	('soft tissue sarcoma', 'Disease', (3, 22))	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (113, 121))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (3, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (3, 22))	('high', 'Var', (90, 94))
64692	29051995	However, in the multivariate analysis in sarcoma this difference in progression free survival for patients with Cmin > 20 mg/L was statistically significant (p = 0.011).	('sarcoma', 'Disease', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Cmin', 'Gene', (112, 116))	('patients', 'Species', '9606', (98, 106))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('> 20 mg/L', 'Var', (117, 126))
64717	25453902	Approximately one-third of all sarcomas, the cancers of connective tissue, associate with chromosomal translocations that generate fusion genes.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('chromosomal translocations', 'Var', (90, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('sarcomas', 'Disease', (31, 39))	('cancers of connective tissue', 'Phenotype', 'HP:0100242', (45, 73))	('associate', 'Reg', (75, 84))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('fusion genes', 'MPA', (131, 143))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
64718	25453902	Many of these fusion genes have been shown to serve as primary drivers of sarcomagenesis.	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('sarcoma', 'Disease', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('fusion genes', 'Var', (14, 26))
64742	25453902	Both human and mouse tumors associated with ASPSCR1-TFE3 demonstrated the diagnostic, strong nuclear TFE3 staining (Fig.3G-H), whereas mouse tumors driven by SS18-SSX2 provided the appropriate negative control (data not shown).	('ASPS', 'Phenotype', 'HP:0012218', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('SSX2', 'Gene', (163, 167))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', (21, 27))	('mouse', 'Species', '10090', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('ASPSCR1-TFE3', 'Var', (44, 56))	('mouse', 'Species', '10090', (15, 20))	('human', 'Species', '9606', (5, 10))	('SSX2', 'Gene', '6757', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
64743	25453902	Tumors induced by conditional AT3 expression in the mouse often arose in or near the leptomeninges, along sulci (Fig.3I).	('conditional AT3', 'Gene', (18, 33))	('mouse', 'Species', '10090', (52, 57))	('expression', 'Var', (34, 44))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
64747	25453902	In order to further validate the tumors generated by conditional AT3 expression as a model for human ASPS, we performed a series of transcriptomic analyses.	('conditional AT3 expression', 'Var', (53, 79))	('human', 'Species', '9606', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('ASPS', 'Phenotype', 'HP:0012218', (101, 105))
64768	25453902	Suspecting that the mouse brain might harbor some preferred cell of origin for transformation by AT3 expression, leading to tumorigenesis that was too rapid to allow slower limb tumors to become detectable, we next crossed mice bearing conditional AT3 with mice bearing a lineage-restricted tamoxifen-inducible Cre-recombinase, expressed from a Prx1 promoter (Prx1-CreERT2).	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Disease', (178, 183))	('mice', 'Species', '10090', (257, 261))	('expression', 'Var', (101, 111))	('Prx1', 'Gene', (345, 349))	('AT3', 'Gene', (97, 100))	('Prx1', 'Gene', '18933', (345, 349))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('Prx1', 'Gene', '18933', (360, 364))	('mouse', 'Species', '10090', (20, 25))	('Prx1', 'Gene', (360, 364))	('tamoxifen', 'Chemical', 'MESH:D013629', (291, 300))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('limb tumors', 'Disease', 'MESH:D017880', (173, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('limb tumors', 'Disease', (173, 184))	('mice', 'Species', '10090', (223, 227))
64798	25453902	Surprisingly, ASPSCR1-TFE3-driven tumors demonstrated up-regulation of nearly the entire complement of mitochondrial genes compared to quadriceps muscle controls, in both mouse and human comparisons (Fig.7A-B).	('ASPSCR1-TFE3-driven', 'Var', (14, 33))	('human', 'Species', '9606', (181, 186))	('tumors', 'Disease', (34, 40))	('mitochondrial genes', 'Gene', (103, 122))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('up-regulation', 'PosReg', (54, 67))	('ASPS', 'Phenotype', 'HP:0012218', (14, 18))	('mouse', 'Species', '10090', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
64800	25453902	ASPSCR1-TFE3-driven mouse tumors were more oxidative than comparison mouse tumor types at baseline and responded oxidatively to the administration of lactate substrate (Fig.7C-D).	('responded oxidatively', 'MPA', (103, 124))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('mouse', 'Species', '10090', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('more', 'PosReg', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('ASPS', 'Phenotype', 'HP:0012218', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('oxidative', 'MPA', (43, 52))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('ASPSCR1-TFE3-driven', 'Var', (0, 19))	('tumor', 'Disease', (75, 80))	('tumors', 'Disease', (26, 32))	('mouse', 'Species', '10090', (20, 25))
64816	25453902	As cross-validation of this effect, we cultured the only two described human cancer cell lines that express ASPSCR1-TFE3, FU-UR-1 and ASPS-1 in increasing concentrations of sodium lactate, identifying a proliferative response.	('ASPS-1', 'Var', (134, 140))	('ASPSCR1-TFE3', 'Var', (108, 120))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('ASPS', 'Phenotype', 'HP:0012218', (134, 138))	('sodium lactate', 'Chemical', 'MESH:D019354', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ASPS', 'Phenotype', 'HP:0012218', (108, 112))	('human', 'Species', '9606', (71, 76))
64822	25453902	Previously, members of our group have demonstrated the oncogenicity of the fusion genes that derive from chromosomal translocations in alveolar rhabdomysarcoma (PAX3-FKHR), synovial sarcoma (SS18-SSX2), and clear cell sarcoma (EWSR1-ATF1).	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('SSX2', 'Gene', (196, 200))	('EWSR1', 'Gene', '14030', (227, 232))	('alveolar rhabdomysarcoma', 'Phenotype', 'HP:0006779', (135, 159))	('EWSR1', 'Gene', (227, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('fusion', 'Var', (75, 81))	('FKHR', 'Gene', '56458', (166, 170))	('alveolar rhabdomysarcoma', 'Disease', 'MESH:D002282', (135, 159))	('SSX2', 'Gene', '6757', (196, 200))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (207, 225))	('synovial sarcoma', 'Disease', (173, 189))	('synovial sarcoma', 'Disease', 'MESH:D013584', (173, 189))	('PAX3', 'Gene', (161, 165))	('PAX3', 'Gene', '18505', (161, 165))	('ATF1', 'Gene', (233, 237))	('clear cell sarcoma', 'Disease', (207, 225))	('FKHR', 'Gene', (166, 170))	('ATF1', 'Gene', '11908', (233, 237))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (173, 189))	('alveolar rhabdomysarcoma', 'Disease', (135, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))
64840	25453902	We interpret the anatomic location of mouse tumors induced by expression of ASPSCR1-TFE3 as circumstantial evidence of a preference for high environmental lactate.	('tumors', 'Disease', (44, 50))	('mouse', 'Species', '10090', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('ASPS', 'Phenotype', 'HP:0012218', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lactate', 'Chemical', 'MESH:D019344', (155, 162))	('expression', 'Var', (62, 72))	('ASPSCR1-TFE3', 'Gene', (76, 88))
64847	25453902	Much of ASPS biology has actually been inferred from studies in a clear cell carcinoma cell line that expresses ASPSCR1-TFE3.	('ASPSCR1-TFE3', 'Var', (112, 124))	('ASPS', 'Phenotype', 'HP:0012218', (8, 12))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('ASPS', 'Phenotype', 'HP:0012218', (112, 116))	('carcinoma', 'Disease', (77, 86))
64857	25453902	Human cell lines known to express ASPSCR1-TFE3 proliferated in response to exogenous lactate and increased in nuclear HIF1alpha.	('HIF1alpha', 'Protein', (118, 127))	('Human', 'Species', '9606', (0, 5))	('ASPSCR1-TFE3', 'Var', (34, 46))	('increased', 'PosReg', (97, 106))	('lactate', 'Chemical', 'MESH:D019344', (85, 92))	('response to exogenous lactate', 'MPA', (63, 92))	('ASPS', 'Phenotype', 'HP:0012218', (34, 38))	('proliferated', 'CPA', (47, 59))
64891	23433433	Electroporation is an increase of cell membrane permeability to molecules that otherwise lack efficient transmembrane transport mechanisms.	('increase', 'PosReg', (22, 30))	('Electroporation', 'Var', (0, 15))	('rat', 'Species', '10116', (9, 12))	('cell membrane permeability to molecules', 'MPA', (34, 73))
64892	23433433	Due to membrane electroporation cell membrane conductivity is also increased.	('rat', 'Species', '10116', (25, 28))	('increased', 'PosReg', (67, 76))	('cell membrane conductivity', 'CPA', (32, 58))	('membrane electroporation', 'Var', (7, 31))
64915	23433433	Numerous studies demonstrated that the conductivity is increased due to membrane electroporation and that in calculating the local electric field distribution within treated tissue one needs to account for these tissue conductivity increases.	('conductivity', 'MPA', (39, 51))	('membrane electroporation', 'Var', (72, 96))	('increased', 'PosReg', (55, 64))	('rat', 'Species', '10116', (24, 27))	('rat', 'Species', '10116', (90, 93))
64933	23433433	However, to account for experimentally observed tissue conductivity increase due to electroporation, Eq.	('tissue conductivity', 'MPA', (48, 67))	('electroporation', 'Var', (84, 99))	('increase', 'PosReg', (68, 76))	('rat', 'Species', '10116', (93, 96))
64977	23433433	the initial sigma of non-electroporated tissues for E < Erev), the conductivity increase factor due to tissue electroporation and the threshold values Erev and Eirrev for each of the tissues were selected based on data we published previously and based on the comparison of I [A] calculated in our models to the in vivo measurements.	('rat', 'Species', '10116', (119, 122))	('conductivity', 'MPA', (67, 79))	('E < Erev', 'Var', (52, 60))	('rat', 'Species', '10116', (34, 37))
64982	23433433	We then performed numerical modeling with NPA with smoothed Heaviside relationships of sigma(E) for two predefined baseline electrical conductivities: 0.126 S/m and 0.091 S/m.	('Heaviside', 'Chemical', '-', (60, 69))	('0.126 S/m', 'Var', (151, 160))	('0.091 S/m', 'Var', (165, 174))
64997	23433433	The entire volume of the target tumor tissue (VT_E>Erev = 100%) was exposed to the local electric field above Erev at different applied voltages for different target tumor tissue conductivities sigmaT(E): U = 340 V (for sigmaT1(E)), U = 400 V (for sigmaT2(E)) and U = 440 V (for sigmaT3(E)).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (166, 171))	('U = 400 V', 'Var', (233, 242))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('U = 340 V', 'Var', (205, 214))	('U = 440 V', 'Var', (264, 273))	('tumor', 'Disease', (32, 37))
65000	23433433	We visualized the calculated local electric field distribution within the model of subcutaneous tumor tissue for two different applied voltages U = 176 V and U = 276 V (Figure 10) in XY cross-section plane (see Figure 2).	('U = 176 V', 'Var', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cutaneous tumor', 'Phenotype', 'HP:0008069', (86, 101))	('U = 276 V', 'Var', (158, 167))	('cutaneous tumor', 'Disease', (86, 101))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (83, 101))	('cutaneous tumor', 'Disease', 'MESH:D009369', (86, 101))
65002	23433433	The electric field distribution is calculated for four different conductivities of target tumor tissue sigmaT: Figure 10A sigmaT = const., Figure 10B sigmaT1(E), Figure 10C sigmaT2(E) and Figure 10D sigmaT3(E).	('Figure 10B sigmaT1', 'Var', (139, 157))	('Figure 10D sigmaT3', 'Var', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Figure 10C sigmaT2', 'Var', (162, 180))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
65004	23433433	In a recent study of robustness of electrochemotherapy treatment planning based on analysis of local electric field distribution E the authors show that the uncertainties in predefined dielectric properties of the treated tissues and in the rate of increase in electric conductivity due to the electroporation have large effect on treatment effectiveness, which indicated that more experimental and numerical research is needed.	('electroporation', 'Var', (294, 309))	('rat', 'Species', '10116', (303, 306))	('electric conductivity', 'MPA', (261, 282))	('effect', 'Reg', (321, 327))	('rat', 'Species', '10116', (241, 244))
65043	23433433	We also demonstrated that the electroporation of more conductive tissues resulted in higher values of total electric current I [A] flowing through tissue (Figure 8).	('rat', 'Species', '10116', (15, 18))	('higher', 'PosReg', (85, 91))	('rat', 'Species', '10116', (39, 42))	('total electric current I [A] flowing through', 'MPA', (102, 146))	('electroporation', 'Var', (30, 45))
65046	23433433	Furthermore, the volume of the target tumor tissue VT exposed to the E > Erev in the subcutaneous model with constant conductivities of all tissue was zero (Figure 9A).	('E > Erev', 'Var', (69, 77))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
65085	33525546	One interesting finding of our study is the fact that 7 out of 15 genes harboring somatic mutations (CHL, MEGF10, MEIS2, MYH8, RIMS4, TBPL1 and ZFPM2) are regulated by the same transcription factor, LEF1 (p < 0.001), which, in turn, is regulated by WT1.	('mutations', 'Var', (90, 99))	('MEGF10', 'Gene', '84466', (106, 112))	('ZFPM2', 'Gene', '23414', (144, 149))	('ZFPM2', 'Gene', (144, 149))	('RIMS4', 'Gene', '140730', (127, 132))	('LEF1', 'Gene', '51176', (199, 203))	('TBPL1', 'Gene', '9519', (134, 139))	('TBPL1', 'Gene', (134, 139))	('WT1', 'Gene', (249, 252))	('MEIS2', 'Gene', '4212', (114, 119))	('MYH8', 'Gene', (121, 125))	('WT1', 'Gene', '7490', (249, 252))	('MEIS2', 'Gene', (114, 119))	('MYH8', 'Gene', '4626', (121, 125))	('LEF1', 'Gene', (199, 203))	('MEGF10', 'Gene', (106, 112))	('CHL', 'Gene', (101, 104))	('RIMS4', 'Gene', (127, 132))	('CHL', 'Gene', '200942', (101, 104))
65088	33525546	More recently, the molecular analysis of 6 patients with DSRCT revealed a total of 137 somatic mutations which were related to specific biological processes: DNA damage-response (DDR) network and mesenchymal-epithelial reverse transition/epithelial-mesenchymal transition (MErT/EMT), reinforcing the relevance of these processes in tumor heterogeneity, aggressiveness and drug resistance.	('patients', 'Species', '9606', (43, 51))	('aggressiveness', 'Disease', (353, 367))	('drug resistance', 'Phenotype', 'HP:0020174', (372, 387))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('aggressiveness', 'Phenotype', 'HP:0000718', (353, 367))	('mutations', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('aggressiveness', 'Disease', 'MESH:D001523', (353, 367))	('tumor', 'Disease', (332, 337))
65105	33525546	Nowadays, large fusion panels using RT-PCR are able to help in differentiating small round cell sarcomas from the ES family and new entities are been recognized such as tumors harboring CIC-DUX4, BCOR-CCNB3 and CIC-FOX04 fusions.	('CCNB3', 'Gene', '85417', (201, 206))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('CIC-FOX04', 'Gene', (211, 220))	('fusions', 'Var', (221, 228))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('sarcomas', 'Disease', (96, 104))	('ES', 'Phenotype', 'HP:0012254', (114, 116))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('CCNB3', 'Gene', (201, 206))	('DUX4', 'Gene', (190, 194))	('DUX4', 'Gene', '100288687', (190, 194))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BCOR', 'Gene', (196, 200))	('tumors', 'Disease', (169, 175))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))	('BCOR', 'Gene', '54880', (196, 200))
65135	33525546	Earlier, it was demonstrated that patients who had CR0 or CR1 and HIPEC had significantly longer median survival compared with patients who had HIPEC and gross residual disease greater than 2.5 cm after surgical cytoreduction (63.4 vs. 26.7 months).	('CR1', 'Gene', '1378', (58, 61))	('patients', 'Species', '9606', (127, 135))	('longer', 'PosReg', (90, 96))	('patients', 'Species', '9606', (34, 42))	('CR0', 'Var', (51, 54))	('median survival', 'MPA', (97, 112))	('HIPEC', 'Disease', (66, 71))	('CR1', 'Gene', (58, 61))
65139	33525546	A retrospective study with 187 DSRCT patients confirmed that chemotherapy and CCS remain the cornerstone of treatment, and suggest that prospective randomized studies will be required to prove the unequivocal benefit of HIPEC or WAP RT in the management of DSRCT.	('patients', 'Species', '9606', (37, 45))	('HIPEC', 'Var', (220, 225))	('DSRCT', 'Disease', (257, 262))
65164	33525546	Silencing EWS-WT1 causes proliferation loss, growth arrest and gene expression analysis indicates repression of estrogen signaling and highlights therapeutic genetic vulnerabilities, such as FGFR4, JAK3, mTOR, PDGF, ERG, and TGFB1 genes.	('mTOR', 'Gene', '2475', (204, 208))	('growth arrest', 'Disease', (45, 58))	('Silencing', 'Var', (0, 9))	('JAK3', 'Gene', (198, 202))	('proliferation loss', 'CPA', (25, 43))	('repression', 'NegReg', (98, 108))	('EWS-WT1', 'Gene', (10, 17))	('TGFB1', 'Gene', '7040', (225, 230))	('PDGF', 'Gene', '5156', (210, 214))	('FGFR4', 'Gene', '2264', (191, 196))	('TGFB1', 'Gene', (225, 230))	('ERG', 'Gene', (216, 219))	('FGFR4', 'Gene', (191, 196))	('JAK3', 'Gene', '3718', (198, 202))	('ERG', 'Gene', '2078', (216, 219))	('growth arrest', 'Phenotype', 'HP:0001510', (45, 58))	('EWS-WT1', 'Gene', '7490', (10, 17))	('PDGF', 'Gene', (210, 214))	('mTOR', 'Gene', (204, 208))	('estrogen', 'Protein', (112, 120))	('growth arrest', 'Disease', 'MESH:D006323', (45, 58))
65171	33525546	In this study, it was found that the induction of TRAIL decreases proliferation and induces apoptosis in vitro and decreases tumor growth in vivo.	('TRAIL', 'Gene', (50, 55))	('apoptosis', 'CPA', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('decreases', 'NegReg', (56, 65))	('proliferation', 'CPA', (66, 79))	('decreases tumor growth', 'Disease', (115, 137))	('TRAIL', 'Gene', '8743', (50, 55))	('decreases tumor growth', 'Disease', 'MESH:D006130', (115, 137))	('induction', 'Var', (37, 46))	('induces', 'Reg', (84, 91))
65229	33525546	A phase I trial evaluated the combination of cixutumumab (an IGFR antibody) with temsirolimus, which resulted in stable disease lasting longer than 5 months in two of the three patients with DSRCT of the study.	('IGFR', 'Gene', '3480', (61, 65))	('combination', 'Interaction', (30, 41))	('patients', 'Species', '9606', (177, 185))	('cixutumumab', 'Var', (45, 56))	('temsirolimus', 'Chemical', 'MESH:C401859', (81, 93))	('IGFR', 'Gene', (61, 65))	('cixutumumab', 'Chemical', 'MESH:C557414', (45, 56))
65261	33525546	Around one-third of sarcomas are characterized by single gene translocation that acts as a driver mutation.	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcomas', 'Disease', (20, 28))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('single gene translocation', 'Var', (50, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
65273	33525546	On the other hand, the combination of an anti-PD1 and anti-CTLA4 (ipilimumab) resulted in a better outcome.	('CTLA4', 'Gene', (59, 64))	('CTLA4', 'Gene', '1493', (59, 64))	('ipilimumab', 'Chemical', 'MESH:D000074324', (66, 76))	('anti-PD1', 'Var', (41, 49))
65278	33525546	The neurotrophic tyrosine kinase receptor (NTKR) fusions act as driver mutation is a myriad of neoplasms.	('NTKR', 'Gene', (43, 47))	('neoplasms', 'Phenotype', 'HP:0002664', (95, 104))	('neoplasm', 'Phenotype', 'HP:0002664', (95, 103))	('neoplasms', 'Disease', 'MESH:D009369', (95, 104))	('neoplasms', 'Disease', (95, 104))	('fusions', 'Var', (49, 56))
65302	33478080	According to their genetic alterations, sarcomas can be subdivided in two main categories.	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('genetic alterations', 'Var', (19, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('sarcomas', 'Disease', (40, 48))
65305	33478080	Some of the molecular events found in sarcomas are druggable, such as tyrosine-protein kinase (KIT) mutations in gastrointestinal stromal tumors (GISTs) and in a minority of other mesenchymal tumors.	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (113, 144))	('mutations', 'Var', (100, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('KIT', 'Gene', '3815', (95, 98))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (113, 144))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('sarcomas', 'Disease', (38, 46))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (180, 198))	('KIT', 'Gene', (95, 98))	('GISTs', 'Phenotype', 'HP:0100723', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mesenchymal tumors', 'Disease', (180, 198))	('gastrointestinal stromal tumors', 'Disease', (113, 144))	('GIST', 'Phenotype', 'HP:0100723', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('sarcomas', 'Disease', 'MESH:D012509', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
65328	33478080	For our primary search we used the following three search terms: the first term was "sarcoma" AND the second term was variable, being "immune check point inhibitory therapy" (4 results) OR "immune checkpoint inhibitory therapy" (4 results) OR "immune checkpoint blockade" (0 results) OR "CTLA-4" (33 results) OR "anti-CTLA4" (14 results) OR "PD-L1" (62 results) OR "anti-PD-L1" (14 results) OR "PD-1" (70 results) OR "anti-PD1" (31 results).	('anti-PD1', 'Var', (418, 426))	('PD-L1', 'Gene', (342, 347))	('CTLA-4', 'Gene', '1493', (288, 294))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('PD-L1', 'Gene', (371, 376))	('PD-L1', 'Gene', '29126', (371, 376))	('CTLA-4', 'Gene', (288, 294))	('CTLA4', 'Gene', '1493', (318, 323))	('PD-L1', 'Gene', '29126', (342, 347))	('sarcoma', 'Disease', (85, 92))	('CTLA4', 'Gene', (318, 323))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
65416	33478080	The investigators made here also a comment about UV light exposure DNA mutational signature in cutaneous angiosarcomas, implying that this may interfere with the drug efficacy.	('DNA', 'Reg', (67, 70))	('angiosarcomas', 'Phenotype', 'HP:0200058', (105, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('cutaneous angiosarcomas', 'Disease', (95, 118))	('interfere', 'NegReg', (143, 152))	('mutational', 'Var', (71, 81))	('angiosarcoma', 'Phenotype', 'HP:0200058', (105, 117))	('cutaneous angiosarcomas', 'Disease', 'MESH:D006394', (95, 118))
65470	33478080	The tumor also expressed many novel gene fusions and cancer-testis antigens, which can serve as neoantigens and induce immune response but had a low TMB.	('tumor', 'Disease', (4, 9))	('cancer-testis', 'Disease', 'MESH:D013736', (53, 66))	('TMB', 'Chemical', '-', (149, 152))	('gene fusions', 'Var', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cancer-testis', 'Disease', (53, 66))
65478	33478080	Gastrointestinal stromal tumors (GISTs) nearly always carry activating mutations of c-KIT, a proto-oncogene or platelet-derived growth factor receptor-alpha gene, giving ground to treatment with TKIs.	('GIST', 'Phenotype', 'HP:0100723', (33, 37))	('activating', 'PosReg', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('platelet-derived growth factor receptor-alpha', 'Gene', (111, 156))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (111, 156))	('mutations', 'Var', (71, 80))	('c-KIT', 'Gene', (84, 89))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('GISTs', 'Phenotype', 'HP:0100723', (33, 38))	('Gastrointestinal stromal tumors', 'Disease', (0, 31))	('c-KIT', 'Gene', '3815', (84, 89))
65521	33478080	Desmoid tumors (DT) are known for showing mutations of the CTNNB1 gene, resulting in activation of the beta-catenin pathway.	('CTNNB1', 'Gene', '1499', (59, 65))	('DT', 'Phenotype', 'HP:0100245', (16, 18))	('beta-catenin', 'Gene', (103, 115))	('Desmoid tumors', 'Phenotype', 'HP:0100245', (0, 14))	('beta-catenin', 'Gene', '1499', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('activation', 'PosReg', (85, 95))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('CTNNB1', 'Gene', (59, 65))	('mutations', 'Var', (42, 51))	('Desmoid tumors', 'Disease', 'MESH:C535944', (0, 14))	('Desmoid tumors', 'Disease', (0, 14))
65526	33478080	Moreover, limited response of LMS to ICB is confirmed by the studies SARC028 (NCT02301039) and NCT02428192.	('NCT02428192', 'Var', (95, 106))	('NCT02301039', 'Var', (78, 89))	('ICB', 'Chemical', '-', (37, 40))	('LMS', 'Phenotype', 'HP:0100243', (30, 33))
65527	33478080	Given that PI3K-AKT-mTOR pathway has been proven to be dysregulated via several genetic mechanisms, among them mutations of the PTEN, combination therapy of ICB with PI3K-AKT pathway inhibitors may have a role in the treatment of certain sarcomas.	('mutations', 'Var', (111, 120))	('mTOR', 'Gene', '2475', (20, 24))	('AKT', 'Gene', '207', (16, 19))	('PTEN', 'Gene', (128, 132))	('sarcomas', 'Disease', 'MESH:D012509', (238, 246))	('PTEN', 'Gene', '5728', (128, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (238, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('AKT', 'Gene', '207', (171, 174))	('sarcomas', 'Disease', (238, 246))	('AKT', 'Gene', (16, 19))	('ICB', 'Chemical', '-', (157, 160))	('AKT', 'Gene', (171, 174))	('mTOR', 'Gene', (20, 24))
65536	33478080	The presence of M2/IDO suppressor pathway in sarcomas might lead to resistance in ICIs, according to the PEMBROSARC study (NCT02406781).	('ICIs', 'Disease', (82, 86))	('IDO', 'Gene', '3620', (19, 22))	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('lead to', 'Reg', (60, 67))	('IDO', 'Gene', (19, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcomas', 'Disease', (45, 53))	('resistance', 'Disease', (68, 78))	('presence', 'Var', (4, 12))
65574	33478080	Specific mutations seem to have a predictive role, such as mutations of the CTNNBN1 or PTEN genes.	('CTNNBN1', 'Gene', (76, 83))	('PTEN', 'Gene', (87, 91))	('PTEN', 'Gene', '5728', (87, 91))	('mutations', 'Var', (59, 68))
65593	32326444	The complexity of the somatic genome of OS is a major cause of intra-tumoral heterogeneity, characterized by chromosomal aneuploidy, alteration of genes by mutation and/or variation of copy number, genomic instability featured by massive rearrangement through chromotripsis, and the presence of patterns of localized hypermutated regions, named kataegis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('aneuploidy', 'Disease', (121, 131))	('cause', 'Reg', (54, 59))	('intra-tumoral', 'Disease', (63, 76))	('chromotripsis', 'Disease', (260, 273))	('variation', 'Var', (172, 181))	('rat', 'Species', '10116', (137, 140))	('aneuploidy', 'Disease', 'MESH:D000782', (121, 131))	('alteration', 'Reg', (133, 143))	('chromotripsis', 'Disease', 'None', (260, 273))	('intra-tumoral', 'Disease', 'MESH:D009369', (63, 76))	('mutation', 'Var', (156, 164))
65595	32326444	Recently, a subset of OSs was described with genomic alterations in genes of the DNA repair pathways, reminiscent of BRCA1/2-deficient tumors.	('genomic alterations', 'Var', (45, 64))	('OSs', 'Disease', (22, 25))	('OSs', 'Phenotype', 'HP:0002669', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('rat', 'Species', '10116', (57, 60))	('DNA repair pathways', 'Pathway', (81, 100))	('BRCA1/2-deficient tumors', 'Disease', 'OMIM:612555', (117, 141))	('BRCA1/2-deficient tumors', 'Disease', (117, 141))
65623	32326444	Consequently, RANK-RANKL interaction appears to be bi-directional, dual, and complementary in the coupling of bone resorption and formation: RANK transduction on osteoclasts and precursors activates osteolysis, while RANKL transduction on osteoblasts and precursors activates osteogenesis.	('bone resorption', 'Phenotype', 'HP:0002797', (110, 125))	('osteogenesis', 'Disease', 'MESH:D010013', (276, 288))	('osteolysis', 'Disease', 'MESH:D010014', (199, 209))	('osteogenesis', 'Disease', (276, 288))	('osteolysis', 'Phenotype', 'HP:0002797', (199, 209))	('activates', 'PosReg', (266, 275))	('RANK transduction', 'Var', (141, 158))	('osteolysis', 'Disease', (199, 209))	('activates', 'PosReg', (189, 198))
65648	32326444	reported an important decrease of lung metastases upon using the inhibitor AZD4547 to block FGF receptor signaling following OS induction in mice.	('decrease', 'NegReg', (22, 30))	('AZD4547', 'Var', (75, 82))	('FGF', 'Protein', (92, 95))	('mice', 'Species', '10090', (141, 145))	('lung metastases', 'Disease', (34, 49))	('decrease of lung', 'Phenotype', 'HP:0002089', (22, 38))	('AZD4547', 'Chemical', 'MESH:C572463', (75, 82))	('lung metastases', 'Disease', 'MESH:D009362', (34, 49))
65658	32326444	In another study, whole body deletion of RANKL proteins prevented OS development and lung metastases in genetically predisposed mice while, in contrast, Rank deletion in osteoblasts did not change OS burden, nor lung metastasis.	('deletion', 'Var', (29, 37))	('prevented', 'NegReg', (56, 65))	('mice', 'Species', '10090', (128, 132))	('lung metastases', 'Disease', 'MESH:D009362', (85, 100))	('lung metastases', 'Disease', (85, 100))	('RANKL', 'Gene', (41, 46))	('OS development', 'CPA', (66, 80))	('proteins', 'Protein', (47, 55))
65683	32326444	Hypomethylation on LINE-1 retro-transposons correlates with chromosomal instability and may drive oncogenetic effects.	('correlates with', 'Reg', (44, 59))	('drive', 'PosReg', (92, 97))	('chromosomal instability', 'Phenotype', 'HP:0040012', (60, 83))	('Hypomethylation', 'Var', (0, 15))	('chromosomal instability', 'CPA', (60, 83))	('transposons', 'Species', '2387', (32, 43))	('oncogenetic effects', 'CPA', (98, 117))
65684	32326444	Large genomic studies have demonstrated that high-grade OS presents one of the highest levels of chromosomal instability associated with hyper-mutations.	('hyper-mutations', 'Var', (137, 152))	('chromosomal instability', 'MPA', (97, 120))	('high-grade OS', 'Disease', (45, 58))	('rat', 'Species', '10116', (34, 37))	('chromosomal instability', 'Phenotype', 'HP:0040012', (97, 120))
65729	32326444	Amplification of genes in the VEGF pathway, in particular VEGF-A, has been described in OS patients, and was confirmed at the protein level.	('VEGF-A', 'Gene', '7422', (58, 64))	('Amplification', 'Var', (0, 13))	('patients', 'Species', '9606', (91, 99))	('VEGF-A', 'Gene', (58, 64))	('VEGF pathway', 'Pathway', (30, 42))	('described', 'Reg', (75, 84))
65735	32326444	Beside VEGF, the expression of its receptor VEGFR-2 is increased in OS as compared to normal bone tissues, and high VEGFR-2 expression is associated with poor prognosis.	('VEGFR-2', 'Gene', (44, 51))	('VEGFR-2', 'Gene', (116, 123))	('expression', 'MPA', (17, 27))	('increased', 'PosReg', (55, 64))	('expression', 'MPA', (124, 134))	('VEGFR-2', 'Gene', '3791', (44, 51))	('VEGFR-2', 'Gene', '3791', (116, 123))	('high', 'Var', (111, 115))
65765	32326444	Among them, only one using anti-PD-L1 avelumab (NCT03006848) is recruiting, while three trials using anti-PD-1, penbrolizumab (NCT02301039 and NCT03013127), or nivolumab (NCT02304458) are either not recruiting or suspended, likely due to risk of immune-related side effects such as skin reactions, pneumonitis, colitis, and hepatitis.	('pneumonitis', 'Disease', 'MESH:D011014', (298, 309))	('NCT02304458', 'Var', (171, 182))	('PD-1', 'Gene', '5133', (106, 110))	('colitis', 'Phenotype', 'HP:0002583', (311, 318))	('PD-L1', 'Gene', (32, 37))	('skin reactions', 'Disease', (282, 296))	('PD-1', 'Gene', (106, 110))	('hepatitis', 'Disease', (324, 333))	('hepatitis', 'Phenotype', 'HP:0012115', (324, 333))	('PD-L1', 'Gene', '29126', (32, 37))	('pneumonitis', 'Disease', (298, 309))	('NCT03013127', 'Var', (143, 154))	('colitis', 'Disease', 'MESH:D003092', (311, 318))	('skin reactions', 'Phenotype', 'HP:0011123', (282, 296))	('hepatitis', 'Disease', 'MESH:D056486', (324, 333))	('colitis', 'Disease', (311, 318))	('NCT03006848', 'Var', (48, 59))	('NCT02301039', 'Var', (127, 138))
65897	25737787	Recent published studies showed genetic modification and loss of SMARCB1 protein expression in more than 80% of cases of ES.	('protein', 'Protein', (73, 80))	('genetic modification', 'Var', (32, 52))	('loss', 'NegReg', (57, 61))	('SMARCB1', 'Gene', '6598', (65, 72))	('SMARCB1', 'Gene', (65, 72))	('expression', 'MPA', (81, 91))
65926	24758355	Representative examples include the relationship between mRNA expression and response and survival using antifolates , beta tubulin III mRNA levels and response to tubulin-interacting agents , PTEN methylation and resistance to CPT-11 , and Ras oncogenic activation and resistance to EGFR-interacting agents .	('beta tubulin', 'Protein', (119, 131))	('response', 'MPA', (152, 160))	('CPT-11', 'Chemical', 'MESH:D000077146', (228, 234))	('methylation', 'Var', (198, 209))	('PTEN', 'Gene', (193, 197))	('PTEN', 'Gene', '5728', (193, 197))	('EGFR', 'Gene', '1956', (284, 288))	('mRNA levels', 'MPA', (136, 147))	('EGFR', 'Gene', (284, 288))
65936	24758355	Additionally, Schizosaccharomyces pombe cells containing a RAD51 mutation were found to be extremely sensitive to Zalypsis, suggesting that the compound induces double-strand breaks (DSBs) .	('DSBs', 'Chemical', '-', (183, 187))	('Schizosaccharomyces pombe', 'Species', '4896', (14, 39))	('mutation', 'Var', (65, 73))	('Zalypsis', 'Disease', 'None', (114, 122))	('Zalypsis', 'Disease', (114, 122))	('induces', 'Reg', (153, 160))	('double-strand breaks', 'MPA', (161, 181))	('RAD51', 'Gene', (59, 64))
65993	24758355	We also found that the correlation of high PDGFRalpha expression and resistance to Zalypsis was the only relationship showing a statistically relevant value (p < 0.05) (Figure  2A and B).	('expression', 'MPA', (54, 64))	('high', 'Var', (38, 42))	('Zalypsis', 'Disease', 'None', (83, 91))	('PDGFRalpha', 'Gene', '5156', (43, 53))	('Zalypsis', 'Disease', (83, 91))	('PDGFRalpha', 'Gene', (43, 53))
66008	24758355	The IC50 for Zalypsis in the cell lines showed a rank from 13 nM to 0.6 nM, with SW1990, Calu6, and SKOV3 cells presenting an IC50 above the average.	('SW1990', 'CellLine', 'CVCL:1723', (81, 87))	('Zalypsis', 'Disease', 'None', (13, 21))	('Zalypsis', 'Disease', (13, 21))	('SKOV3', 'CellLine', 'CVCL:0532', (100, 105))	('SW1990', 'Var', (81, 87))
66031	24758355	Activated AKT can phosphorylate the pro-apoptotic Bcl-2 family member Bax at S184, inhibiting its conformational change and its subsequent translocation to mitochondria, thus preventing Bif-1 binding to Bax and alterations in mitochondrial membrane potential, cytochrome c release, caspase activation, and apoptosis .	('Bax', 'Gene', '581', (203, 206))	('activation', 'PosReg', (290, 300))	('Bif-1', 'Gene', (186, 191))	('cytochrome c', 'Gene', (260, 272))	('AKT', 'Gene', '207', (10, 13))	('Bif-1', 'Gene', '9841', (186, 191))	('alterations', 'Reg', (211, 222))	('inhibiting', 'NegReg', (83, 93))	('translocation to mitochondria', 'MPA', (139, 168))	('apoptosis', 'CPA', (306, 315))	('binding', 'Interaction', (192, 199))	('caspase', 'CPA', (282, 289))	('S184', 'Var', (77, 81))	('preventing', 'NegReg', (175, 185))	('Bcl-2', 'Gene', (50, 55))	('cytochrome c', 'Gene', '54205', (260, 272))	('mitochondrial membrane potential', 'MPA', (226, 258))	('Bax', 'Gene', (70, 73))	('conformational change', 'MPA', (98, 119))	('AKT', 'Gene', (10, 13))	('Bax', 'Gene', '581', (70, 73))	('Bcl-2', 'Gene', '596', (50, 55))	('Bax', 'Gene', (203, 206))
66044	24758355	Recently, we have also reported that SNPs in the PDGFRbeta gene are related to increased levels of receptor and signaling, promoting chemotherapy resistance in colorectal cancer patients .	('promoting', 'PosReg', (123, 132))	('increased', 'PosReg', (79, 88))	('chemotherapy resistance', 'CPA', (133, 156))	('SNPs', 'Var', (37, 41))	('PDGFRbeta', 'Gene', (49, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('patients', 'Species', '9606', (178, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('PDGFRbeta', 'Gene', '5159', (49, 58))	('colorectal cancer', 'Disease', (160, 177))
66066	23977394	Gene silencing of KCTD10 increased cell proliferation and invasion, suggesting that KCTD10 has a tumor-suppressive function.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('increased', 'PosReg', (25, 34))	('KCTD10', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('KCTD10', 'Gene', (84, 90))	('KCTD10', 'Gene', '83892', (18, 24))	('tumor', 'Disease', (97, 102))	('cell proliferation', 'CPA', (35, 53))	('Gene silencing', 'Var', (0, 14))	('KCTD10', 'Gene', '83892', (84, 90))	('invasion', 'CPA', (58, 66))
66071	23977394	GIST is characterized by the presence of mutations in receptor tyrosine kinases: activating mutations are present in KIT and PDGFRA in approximately 80% and 10% of GISTs, respectively.	('KIT', 'Gene', (117, 120))	('PDGFRA', 'Gene', '5156', (125, 131))	('PDGFRA', 'Gene', (125, 131))	('GIST', 'Phenotype', 'HP:0100723', (164, 168))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('mutations', 'Var', (92, 101))	('activating', 'PosReg', (81, 91))
66101	23977394	KCTD10-specific siRNAs were purchased from Sigma-Aldrich (HS01-00108591, HS01-00108592, and HS01-00108593, St. Louis, MO), and control stealth siRNA was from Life Technologies.	('HS01-00108592', 'Var', (73, 86))	('KCTD10', 'Gene', '83892', (0, 6))	('HS01', 'CellLine', 'CVCL:W404', (58, 62))	('HS01', 'CellLine', 'CVCL:W404', (73, 77))	('KCTD10', 'Gene', (0, 6))	('HS01', 'CellLine', 'CVCL:W404', (92, 96))
66134	23977394	Cell viability assays revealed that transfection of siRNAs 1 and 3 resulted in an increase of cell growth relative to negative control GIST T1 cells, and siRNA2 transfection did not significantly decrease cell proliferation (Figure 4B).	('siRNAs', 'Gene', (52, 58))	('increase', 'PosReg', (82, 90))	('GIST T1', 'CellLine', 'CVCL:4976', (135, 142))	('transfection', 'Var', (36, 48))	('GIST', 'Phenotype', 'HP:0100723', (135, 139))	('cell growth', 'CPA', (94, 105))
66135	23977394	In addition, siRNA-mediated silencing of KCTD10 significantly increased the invasive ability of GIST T1 cells in the siRNA1 and siRNA3 groups (p = 0.0143 and p = 0.0134, respectively, Figure 4C and D), but not in the siRNA2 group.	('increased', 'PosReg', (62, 71))	('KCTD10', 'Gene', '83892', (41, 47))	('GIST T1', 'CellLine', 'CVCL:4976', (96, 103))	('invasive ability of GIST T1 cells', 'CPA', (76, 109))	('GIST', 'Phenotype', 'HP:0100723', (96, 100))	('silencing', 'Var', (28, 37))	('KCTD10', 'Gene', (41, 47))
66205	22532922	Moreover, mutation of the hSNF5/INI gene on chromosome 22, considered the hallmark of MRT tumors, and the lack of staining of the INI1 gene product, can help to confirm diagnosis with accuracy.	('INI', 'Gene', (32, 35))	('MRT tumors', 'Disease', (86, 96))	('hSNF5', 'Gene', '6598', (26, 31))	('INI1', 'Gene', '6598', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('INI', 'Gene', '84844', (32, 35))	('INI', 'Gene', (130, 133))	('INI1', 'Gene', (130, 134))	('mutation', 'Var', (10, 18))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('MRT tumors', 'Disease', 'MESH:D009369', (86, 96))	('hSNF5', 'Gene', (26, 31))	('INI', 'Gene', '84844', (130, 133))
66209	22532922	More recently, molecular genetics have revealed a mutation of the SMARCB1/hSNF5/INI1 gene which can help confirm diagnosis.	('hSNF5', 'Gene', '6598', (74, 79))	('hSNF5', 'Gene', (74, 79))	('SMARCB1', 'Gene', (66, 73))	('SMARCB1', 'Gene', '6598', (66, 73))	('INI1', 'Gene', (80, 84))	('INI1', 'Gene', '6598', (80, 84))	('mutation', 'Var', (50, 58))
66228	34022967	Mutation of tumor suppressors RB1, TP53, REQL4 and INK4a and/or deregulation of PI3K/mTOR, TGFbeta, RANKL/NF-kappaB and IGF pathways have been linked to OS development.	('NF-kappaB', 'Gene', '4790', (106, 115))	('deregulation', 'Reg', (64, 76))	('RB1', 'Gene', (30, 33))	('mTOR', 'Gene', '2475', (85, 89))	('tumor', 'Disease', (12, 17))	('RANKL', 'Gene', (100, 105))	('REQL4', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('RANKL', 'Gene', '8600', (100, 105))	('RB1', 'Gene', '5925', (30, 33))	('linked', 'Reg', (143, 149))	('OS', 'Phenotype', 'HP:0002669', (153, 155))	('TGFbeta', 'Gene', (91, 98))	('TP53', 'Gene', (35, 39))	('INK4a', 'Gene', (51, 56))	('TGFbeta', 'Gene', '7039', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('men', 'Species', '9606', (163, 166))	('Mutation', 'Var', (0, 8))	('NF-kappaB', 'Gene', (106, 115))	('INK4a', 'Gene', '1029', (51, 56))	('IGF pathways', 'Pathway', (120, 132))	('mTOR', 'Gene', (85, 89))
66232	34022967	Multiple microRNAs including miR-30/9/23b/29c/194/200, proteins including SYT-SSX1/2 fusion proteins and OVOL2, and other factors that inhibit AMF/PGI and LRP5 can suppress either the expression or activity of EMT-TFs to increase epithelial features and inhibit OS metastasis.	('OS', 'Phenotype', 'HP:0002669', (262, 264))	('SSX1', 'Gene', (78, 82))	('increase', 'PosReg', (221, 229))	('SYT', 'Gene', (74, 77))	('OVOL2', 'Gene', (105, 110))	('epithelial features', 'CPA', (230, 249))	('expression', 'MPA', (184, 194))	('inhibit', 'NegReg', (254, 261))	('AMF/PGI', 'Gene', (143, 150))	('inhibit', 'NegReg', (135, 142))	('activity', 'MPA', (198, 206))	('miR-30/9/23b/29c/194/200', 'Var', (29, 53))	('SYT', 'Gene', '6760', (74, 77))	('OS metastasis', 'CPA', (262, 275))	('EMT-TFs', 'Gene', (210, 217))	('LRP5', 'Gene', (155, 159))	('LRP5', 'Gene', '4041', (155, 159))	('suppress', 'NegReg', (164, 172))	('OVOL2', 'Gene', '58495', (105, 110))	('AMF/PGI', 'Gene', '14751', (143, 150))	('SSX1', 'Gene', '6756', (78, 82))
66255	34022967	Individuals carrying germline RB1 mutations have approximately 1000-fold increased risk to develop OS.	('OS', 'Phenotype', 'HP:0002669', (99, 101))	('develop OS', 'Disease', (91, 101))	('RB1', 'Gene', (30, 33))	('mutations', 'Var', (34, 43))	('RB1', 'Gene', '5925', (30, 33))
66256	34022967	Abnormalities in the CDKN2A gene, which codes for p16INK4a, a CDK4 inhibitor, and p14ARF, a p53 stabilizer, also increase the risk of OS development.	('men', 'Species', '9606', (144, 147))	('CDK4', 'Gene', '1019', (62, 66))	('p16INK4a', 'Gene', (50, 58))	('Abnormalities', 'Var', (0, 13))	('p14ARF', 'Gene', (82, 88))	('p16INK4a', 'Gene', '1029', (50, 58))	('OS', 'Phenotype', 'HP:0002669', (134, 136))	('CDKN2A', 'Gene', (21, 27))	('increase', 'PosReg', (113, 121))	('p14ARF', 'Gene', '1029', (82, 88))	('CDKN2A', 'Gene', '1029', (21, 27))	('CDK4', 'Gene', (62, 66))
66270	34022967	Many genomic alterations involved in human OS pathogenesis are also detected in canine OSs, such as the loss-of-function genetic alterations of the TP53, RB and PTEN tumor suppressor genes in both human and canine OSs.	('genetic alterations', 'Var', (121, 140))	('OS', 'Phenotype', 'HP:0002669', (214, 216))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('PTEN tumor', 'Disease', 'MESH:D006223', (161, 171))	('PTEN tumor', 'Disease', (161, 171))	('canine', 'Species', '9615', (207, 213))	('TP53', 'Gene', (148, 152))	('OS', 'Phenotype', 'HP:0002669', (43, 45))	('OSs', 'Phenotype', 'HP:0002669', (214, 217))	('loss-of-function', 'NegReg', (104, 120))	('human', 'Species', '9606', (37, 42))	('human', 'Species', '9606', (197, 202))	('OSs', 'Phenotype', 'HP:0002669', (87, 90))	('OS', 'Phenotype', 'HP:0002669', (87, 89))	('RB', 'Disease', 'MESH:D012175', (154, 156))	('canine', 'Species', '9615', (80, 86))
66275	34022967	For example, rats treated with P32-orthophosphate have been shown to develop OS tumors that histologically resemble human OS.	('rats', 'Species', '10116', (13, 17))	('P32-orthophosphate', 'Var', (31, 49))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('OS tumors', 'Disease', (77, 86))	('OS', 'Phenotype', 'HP:0002669', (77, 79))	('OS', 'Phenotype', 'HP:0002669', (122, 124))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('develop', 'PosReg', (69, 76))	('P32-orthophosphate', 'Chemical', '-', (31, 49))	('OS tumors', 'Disease', 'MESH:C567932', (77, 86))	('human', 'Species', '9606', (116, 121))
66293	34022967	Many murine OS models have been developed to recapitulate p53 and RB mutations in hereditary and sporadic human OSs.	('mutations', 'Var', (69, 78))	('human', 'Species', '9606', (106, 111))	('OS', 'Phenotype', 'HP:0002669', (12, 14))	('OS', 'Phenotype', 'HP:0002669', (112, 114))	('OSs', 'Phenotype', 'HP:0002669', (112, 115))	('hereditary', 'Disease', (82, 92))	('murine OS', 'CellLine', 'CVCL:2860', (5, 14))	('p53', 'Gene', (58, 61))	('RB', 'Disease', 'MESH:D012175', (66, 68))
66294	34022967	Germ-line deletion of p53 results in an OS incidence of 4% in homozygous p53 null mice and 25% in heterozygous p53 mice, indicating the importance of p53 loss in OS development.	('mice', 'Species', '10090', (82, 86))	('OS', 'Phenotype', 'HP:0002669', (162, 164))	('mice', 'Species', '10090', (115, 119))	('OS', 'Phenotype', 'HP:0002669', (40, 42))	('p53', 'Gene', (22, 25))	('deletion', 'Var', (10, 18))	('OS incidence', 'CPA', (40, 52))	('men', 'Species', '9606', (172, 175))
66298	34022967	Deletion of both Tp53 and Rb genes by Osterix-Cre leads to OS development with high penetrance.	('men', 'Species', '9606', (69, 72))	('OS', 'Phenotype', 'HP:0002669', (59, 61))	('Tp53', 'Gene', (17, 21))	('Rb', 'Gene', '19645', (26, 28))	('leads to', 'Reg', (50, 58))	('OS development', 'CPA', (59, 73))	('Deletion', 'Var', (0, 8))
66299	34022967	Mice with Prx-1-Cre mediated deletion of both Tp53 and Rb genes induces OS development, and also generated poorly differentiated soft tissue sarcomas.	('Prx-1', 'Gene', (10, 15))	('deletion', 'Var', (29, 37))	('Rb', 'Gene', '19645', (55, 57))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (129, 148))	('sarcomas', 'Disease', 'MESH:D012509', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('Prx-1', 'Gene', '18933', (10, 15))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('generated', 'Reg', (97, 106))	('sarcomas', 'Disease', (141, 149))	('Tp53', 'Gene', (46, 50))	('Mice', 'Species', '10090', (0, 4))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (129, 149))	('OS', 'Phenotype', 'HP:0002669', (72, 74))	('induces', 'PosReg', (64, 71))	('men', 'Species', '9606', (82, 85))	('OS development', 'CPA', (72, 86))
66303	34022967	In addition to c-fos and p53, other proteins such as TWIST1, p14ARF, p16INK4a, PRKAR1A, and p21CIP have been implicated in OS pathogenesis based on findings from human OS samples, and their involvements in OS development have also been demonstrated in GEM models.	('p16INK4a', 'Gene', '1029', (69, 77))	('men', 'Species', '9606', (216, 219))	('p14ARF', 'Gene', (61, 67))	('PRKAR1A', 'Gene', '5573', (79, 86))	('implicated', 'Reg', (109, 119))	('human', 'Species', '9606', (162, 167))	('men', 'Species', '9606', (197, 200))	('TWIST1', 'Gene', (53, 59))	('GEM', 'Chemical', '-', (252, 255))	('OS', 'Phenotype', 'HP:0002669', (123, 125))	('PRKAR1A', 'Gene', (79, 86))	('p16INK4a', 'Gene', (69, 77))	('p21CIP', 'Var', (92, 98))	('OS', 'Phenotype', 'HP:0002669', (168, 170))	('OS', 'Phenotype', 'HP:0002669', (206, 208))	('TWIST1', 'Gene', '7291', (53, 59))	('p14ARF', 'Gene', '1029', (61, 67))
66327	34022967	Knockdown of SLUG also inhibits the growth of these cell-derived xenografts in an in vivo chick chorioallantoic membrane (CAM) assay model.	('CAM', 'Disease', 'MESH:C535342', (122, 125))	('Knockdown', 'Var', (0, 9))	('SLUG', 'Gene', (13, 17))	('chick', 'Species', '9031', (90, 95))	('CAM', 'Disease', (122, 125))	('growth', 'CPA', (36, 42))	('inhibits', 'NegReg', (23, 31))
66328	34022967	Ectopic expression of SLUG in these OS cells increases the expression level of WNT5A, decreases the expression level of the adhesion molecule osteoblast cadherin (OB-Cad), and increases cell motility by promoting the formation of actin-rich cellular protrusions.	('promoting', 'PosReg', (203, 212))	('increases', 'PosReg', (45, 54))	('OS', 'Phenotype', 'HP:0002669', (36, 38))	('SLUG', 'Gene', (22, 26))	('WNT5A', 'Gene', '7474', (79, 84))	('increases', 'PosReg', (176, 185))	('Ectopic expression', 'Var', (0, 18))	('actin', 'Gene', '396526', (230, 235))	('expression level of the adhesion molecule', 'MPA', (100, 141))	('decreases', 'NegReg', (86, 95))	('actin', 'Gene', (230, 235))	('cell motility', 'CPA', (186, 199))	('expression level', 'MPA', (59, 75))	('WNT5A', 'Gene', (79, 84))
66329	34022967	The expression levels of ZEB1 protein in human sarcoma tissues are also positively correlated with lung metastasis, which is consistent with the finding showing that ZEB1 knockdown in MG-63 cells significantly inhibits cell invasive capability.	('expression levels', 'MPA', (4, 21))	('inhibits', 'NegReg', (210, 218))	('correlated', 'Reg', (83, 93))	('ZEB1', 'Gene', '6935', (166, 170))	('ZEB1', 'Gene', (166, 170))	('human', 'Species', '9606', (41, 46))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('MG-63', 'CellLine', 'CVCL:0426', (184, 189))	('lung metastasis', 'CPA', (99, 114))	('knockdown', 'Var', (171, 180))	('ZEB1', 'Gene', (25, 29))	('cell invasive capability', 'CPA', (219, 243))	('ZEB1', 'Gene', '6935', (25, 29))	('sarcoma', 'Disease', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
66344	34022967	Specifically, blocking Wnt/LDL receptor related protein 5 (LRP5) signaling by a soluble negative dominant form of LRP5 mutant in OS cells markedly upregulates the expression of E-cadherin, an epithelial marker, and downregulates the expression of N-cadherin, a mesenchymal marker.	('Wnt', 'Gene', (23, 26))	('expression', 'MPA', (233, 243))	('LDL receptor related protein 5', 'Gene', '4041', (27, 57))	('LDL receptor related protein 5', 'Gene', (27, 57))	('Wnt', 'Gene', '7474', (23, 26))	('LRP5', 'Gene', '4041', (114, 118))	('LRP5', 'Gene', (59, 63))	('mutant', 'Var', (119, 125))	('E-cadherin', 'Gene', (177, 187))	('N-cadherin', 'Gene', (247, 257))	('E-cadherin', 'Gene', '999', (177, 187))	('OS', 'Phenotype', 'HP:0002669', (129, 131))	('N-cadherin', 'Gene', '1000', (247, 257))	('blocking', 'NegReg', (14, 22))	('downregulates', 'NegReg', (215, 228))	('LRP5', 'Gene', (114, 118))	('expression', 'MPA', (163, 173))	('LRP5', 'Gene', '4041', (59, 63))	('upregulates', 'PosReg', (147, 158))
66345	34022967	Inhibition of the Wnt/LRP5 signaling also downregulates the activity of EMT-TFs such as TWIST1 and SLUG.	('EMT-TFs', 'CPA', (72, 79))	('Wnt', 'Gene', '7474', (18, 21))	('LRP5', 'Gene', '4041', (22, 26))	('TWIST1', 'Gene', (88, 94))	('LRP5', 'Gene', (22, 26))	('Inhibition', 'Var', (0, 10))	('activity', 'MPA', (60, 68))	('downregulates', 'NegReg', (42, 55))	('SLUG', 'CPA', (99, 103))	('TWIST1', 'Gene', '7291', (88, 94))	('Wnt', 'Gene', (18, 21))
66348	34022967	Accordingly, silencing the expression of AMF/PGI can reduce SNAIL activity, which induces terminal differentiation of these OS cells into mature osteoblasts, resulting in suppression of the growth and pulmonary metastasis of these OS cell-derived xenografts in nude mice.	('reduce', 'NegReg', (53, 59))	('induces', 'Reg', (82, 89))	('AMF/PGI', 'Gene', (41, 48))	('SNAIL activity', 'MPA', (60, 74))	('pulmonary metastasis', 'Disease', (201, 221))	('OS', 'Phenotype', 'HP:0002669', (231, 233))	('AMF/PGI', 'Gene', '14751', (41, 48))	('nude mice', 'Species', '10090', (261, 270))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (201, 221))	('suppression', 'NegReg', (171, 182))	('OS', 'Phenotype', 'HP:0002669', (124, 126))	('silencing', 'Var', (13, 22))
66352	34022967	For example, miR-30 and miR-9 can target TWIST1, SNAIL and ZEB1 mRNAs, and miR-23b, miR-29c, miR-194 and miR-200 can downregulate TWIST1 and ZEB1 mRNAs, resulting in upregulation of E-cadherin expression.	('TWIST1', 'Gene', (41, 47))	('E-cadherin', 'Gene', '999', (182, 192))	('miR-194', 'Var', (93, 100))	('downregulate', 'NegReg', (117, 129))	('expression', 'MPA', (193, 203))	('ZEB1', 'Gene', (141, 145))	('miR-29c', 'Gene', '407026', (84, 91))	('upregulation', 'PosReg', (166, 178))	('TWIST1', 'Gene', '7291', (41, 47))	('ZEB1', 'Gene', (59, 63))	('miR-23b', 'Gene', '407011', (75, 82))	('miR-29c', 'Gene', (84, 91))	('TWIST1', 'Gene', (130, 136))	('miR-200', 'Var', (105, 112))	('miR-23b', 'Gene', (75, 82))	('ZEB1', 'Gene', '6935', (141, 145))	('E-cadherin', 'Gene', (182, 192))	('TWIST1', 'Gene', '7291', (130, 136))	('ZEB1', 'Gene', '6935', (59, 63))
66368	34022967	Under these circumstances, inhibition of SNAIL can promote cisplatin sensitivity and prevent cisplatin treatment-induced EMT-like process, which results in diminished OS cell growth and survival.	('diminished', 'NegReg', (156, 166))	('OS cell growth', 'CPA', (167, 181))	('prevent', 'NegReg', (85, 92))	('cisplatin sensitivity', 'MPA', (59, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('men', 'Species', '9606', (108, 111))	('OS', 'Phenotype', 'HP:0002669', (167, 169))	('inhibition', 'Var', (27, 37))	('promote', 'PosReg', (51, 58))	('cisplatin treatment-induced', 'MPA', (93, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('survival', 'CPA', (186, 194))	('SNAIL', 'Gene', (41, 46))	('EMT-like process', 'CPA', (121, 137))
66386	33669307	Rationale for Early Detection of EWSR1 Translocation-Associated Sarcoma Biomarkers in Liquid Biopsy Tumour cells often spread from the primary site to new tissues in a process known as metastasis.	('Sarcoma', 'Disease', (64, 71))	('spread', 'Reg', (119, 125))	('Sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('EWSR1', 'Gene', (33, 38))	('Sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('Tumour', 'Phenotype', 'HP:0002664', (100, 106))	('Translocation-Associated', 'Var', (39, 63))	('EWSR1', 'Gene', '2130', (33, 38))
66390	33669307	This review summarises developments for sarcomas that are associated with the translocation of EWSR1 and similar genes.	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('EWSR1', 'Gene', (95, 100))	('translocation', 'Var', (78, 91))	('sarcomas', 'Disease', (40, 48))
66391	33669307	Sarcomas are mesenchymal tumours that often arise and develop as a result of chromosomal translocations, and for several forms of sarcoma the EWSR1 gene is a frequent translocation partner.	('result', 'Reg', (67, 73))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('EWSR1', 'Gene', (142, 147))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('chromosomal translocations', 'Var', (77, 103))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('sarcoma', 'Disease', (130, 137))	('mesenchymal tumours', 'Disease', 'MESH:D009369', (13, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('mesenchymal tumours', 'Disease', (13, 32))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
66394	33669307	An update is provided on research relevant to the improvement of the early detection of relapse in sarcomas with EWSR1-associated translocations, in the contexts of biology, diagnosis, and liquid biopsy.	('EWSR1-associated', 'Gene', (113, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('sarcomas', 'Disease', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('translocations', 'Var', (130, 144))	('sarcomas', 'Disease', 'MESH:D012509', (99, 107))
66403	33669307	In the context of liquid biopsy, several methylation sites have been described as predictive of prognosis for colorectal cancer, breast cancer, and liver cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('liver cancer', 'Phenotype', 'HP:0002896', (148, 160))	('methylation', 'Var', (41, 52))	('liver cancer', 'Disease', 'MESH:D006528', (148, 160))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('liver cancer', 'Disease', (148, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('colorectal cancer', 'Disease', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
66404	33669307	The methylation status of cfDNA can also be predictive for multiple common cancers, allowing population-wide screening of asymptomatic people at risk.	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('people', 'Species', '9606', (135, 141))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cfDNA', 'Gene', (26, 31))	('methylation status', 'Var', (4, 22))
66412	33669307	While much of the understanding of EWSR1/EWS centres around the chromosomal translocation that causes sarcoma, naturally occurring variants and transgenic mice indicate the diverse roles played this molecule (and closely related genes FUS and TAF15) and highlight challenges for therapeutic targeting in sarcoma.	('causes', 'Reg', (95, 101))	('sarcoma', 'Disease', 'MESH:D012509', (304, 311))	('transgenic mice', 'Species', '10090', (144, 159))	('variants', 'Var', (131, 139))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('sarcoma', 'Disease', (304, 311))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
66413	33669307	Mutations in EWSR1, FUS, and TAF15 have been associated with a minor subset (>=5%) of neuro-degenerative disorders including amyotrophic lateral sclerosis and fronto-temporal dementia.	('neuro-degenerative disorders', 'Disease', 'MESH:D019636', (86, 114))	('dementia', 'Phenotype', 'HP:0000726', (175, 183))	('dementia', 'Disease', (175, 183))	('neuro-degenerative disorders', 'Phenotype', 'HP:0002180', (86, 114))	('associated', 'Reg', (45, 55))	('neuro-degenerative disorders', 'Disease', (86, 114))	('Mutations', 'Var', (0, 9))	('dementia', 'Disease', 'MESH:D003704', (175, 183))	('amyotrophic lateral sclerosis', 'Disease', (125, 154))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (125, 154))	('FUS', 'Gene', (20, 23))	('fronto-temporal dementia', 'Phenotype', 'HP:0002145', (159, 183))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (125, 154))	('TAF15', 'Gene', (29, 34))	('EWSR1', 'Gene', (13, 18))
66415	33669307	A combination of in vivo and in vitro studies have demonstrated that disruption of EWSR1 potentiates a reduction in the number and activity of mitochondria, dysfunctional gametogenesis, and neuronal atrophy, resulting in motor function deficits.	('neuronal atrophy', 'Phenotype', 'HP:0002529', (190, 206))	('neuronal atrophy', 'Disease', (190, 206))	('motor function deficits', 'CPA', (221, 244))	('EWSR1', 'Gene', (83, 88))	('neuronal atrophy', 'Disease', 'MESH:D009410', (190, 206))	('disruption', 'Var', (69, 79))	('reduction', 'NegReg', (103, 112))	('dysfunctional gametogenesis', 'CPA', (157, 184))
66417	33669307	While the involvement of similar EWSR1-associated gene translocations in several forms of sarcoma presents a challenge when distinguishing between subtypes of a particular sarcoma, in the context of the cell of origin, the differing cell phenotypes resulting from each variant permit the determination of the effect of each mutant gene.	('variant', 'Var', (269, 276))	('sarcoma', 'Disease', (172, 179))	('sarcoma', 'Disease', (90, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('translocations', 'Var', (55, 69))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('EWSR1-associated', 'Gene', (33, 49))	('involvement', 'Reg', (10, 21))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
66418	33669307	Angiomatoid fibrous histiocytoma, primary pulmonary myxoid sarcoma, and myoepithelial tumours of soft tissue are exceptionally rare forms of sarcoma that harbour translocations of the EWSR1 gene (EWSR1-CREB, EWSR1-ATF1) or the FUS gene (FUS-AFT1).	('sarcoma', 'Disease', (141, 148))	('ATF1', 'Gene', (214, 218))	('histiocytoma', 'Phenotype', 'HP:0012315', (20, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('soft', 'Gene', (97, 101))	('Angiomatoid fibrous histiocytoma', 'Disease', (0, 32))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('myoepithelial tumours', 'Disease', 'MESH:D009208', (72, 93))	('ATF1', 'Gene', '466', (214, 218))	('sarcoma', 'Disease', (59, 66))	('CREB', 'Gene', (202, 206))	('myoepithelial tumours', 'Disease', (72, 93))	('EWSR1', 'Gene', (184, 189))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('translocations', 'Var', (162, 176))	('pulmonary myxoid sarcoma', 'Disease', (42, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('soft', 'Gene', '25886', (97, 101))	('CREB', 'Gene', '1385', (202, 206))	('Angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (0, 32))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))	('pulmonary myxoid sarcoma', 'Disease', 'MESH:D012509', (42, 66))
66424	33669307	The diagnosis of ES is confirmed after a cytogenetic analysis of the chromosomal translocation using FISH break apart probes; the expression of CD99 by IHC can also confirm diagnosis, as can next generation sequencing (NGS) where necessary.	('break apart', 'Phenotype', 'HP:0001061', (106, 117))	('CD99', 'Gene', (144, 148))	('expression', 'Var', (130, 140))	('ES', 'Phenotype', 'HP:0012254', (17, 19))	('CD99', 'Gene', '4267', (144, 148))
66428	33669307	Unlike the more common osteosarcoma, ES cells have a genomic translocation giving rise to well characterised mutant fusion genes such as EWSR1-FLI1 or EWSR1-ERG, which primarily drive the disease.	('ERG', 'Gene', (157, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('drive', 'Reg', (178, 183))	('ES', 'Phenotype', 'HP:0012254', (37, 39))	('mutant', 'Var', (109, 115))	('osteosarcoma', 'Phenotype', 'HP:0002669', (23, 35))	('FLI1', 'Gene', '2313', (143, 147))	('osteosarcoma', 'Disease', 'MESH:D012516', (23, 35))	('FLI1', 'Gene', (143, 147))	('osteosarcoma', 'Disease', (23, 35))	('ERG', 'Gene', '2078', (157, 160))
66430	33669307	The small number of remaining mutations (<5%) typically comprise fusions of EWSR1-FLI1 or EWSR1-ERG at other exon junctions or EWSR1-ETV1, EWSR1-FEV, and FUS-ERG translocations.	('ETV1', 'Gene', (133, 137))	('ETV1', 'Gene', '2115', (133, 137))	('ERG', 'Gene', '2078', (96, 99))	('ERG', 'Gene', (96, 99))	('ERG', 'Gene', '2078', (158, 161))	('mutations', 'Var', (30, 39))	('comprise', 'Reg', (56, 64))	('FLI1', 'Gene', '2313', (82, 86))	('fusions', 'Var', (65, 72))	('FLI1', 'Gene', (82, 86))	('ERG', 'Gene', (158, 161))
66431	33669307	The phenotypes arising from the more common EWSR1 translocation partners (FLI1 and ERG) are clinically similar, although there may be slightly more overall survival in patients with the EWSR1-FLI1 variant compared to all others.	('EWSR1', 'Gene', (44, 49))	('overall survival', 'MPA', (148, 164))	('more', 'PosReg', (143, 147))	('variant', 'Var', (197, 204))	('ERG', 'Gene', '2078', (83, 86))	('ERG', 'Gene', (83, 86))	('FLI1', 'Gene', '2313', (74, 78))	('patients', 'Species', '9606', (168, 176))	('FLI1', 'Gene', (74, 78))	('FLI1', 'Gene', (192, 196))	('FLI1', 'Gene', '2313', (192, 196))
66433	33669307	The aberrant protein is primarily responsible for the pathology, with few other mutations consistently observed in ES tumours.	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumours', 'Disease', (118, 125))	('aberrant', 'Var', (4, 12))	('ES', 'Phenotype', 'HP:0012254', (115, 117))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('protein', 'Protein', (13, 20))
66435	33669307	Similarly, IGFR activity potentiates ES development (due in part to autocrine IGF-1-mediated activity), but treatment targeting ligation of IGF-1 to the receptor or the consequent receptor kinase activity yielded poor results.	('activity', 'Var', (16, 24))	('IGFR', 'Gene', (11, 15))	('IGF-1', 'Gene', '3479', (78, 83))	('IGF-1', 'Gene', (78, 83))	('ES development', 'CPA', (37, 51))	('ES', 'Phenotype', 'HP:0012254', (37, 39))	('IGF-1', 'Gene', '3479', (140, 145))	('IGF-1', 'Gene', (140, 145))	('IGFR', 'Gene', '3480', (11, 15))	('potentiates', 'PosReg', (25, 36))
66436	33669307	Despite the derivation from tumours of multiple immortalised ES cell lines for each of the most common translocation variants, many avenues of research have terminated in translational cul-de-sacs.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('variants', 'Var', (117, 125))	('ES', 'Phenotype', 'HP:0012254', (61, 63))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))
66444	33669307	The detection of cfRNA EWSR1-FLI1 fusion transcripts by Allegretti M et al.	('FLI1', 'Gene', '2313', (29, 33))	('fusion transcripts', 'Var', (34, 52))	('FLI1', 'Gene', (29, 33))
66447	33669307	The approaches used in these studies to detect early relapse and monitor disease activity are generally applicable to most forms of sarcoma featuring chromosomal translocation.	('chromosomal translocation', 'Var', (150, 175))	('sarcoma', 'Disease', (132, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
66455	33669307	The study of DSRCT has been hampered by the lack of tumour-derived cell lines with only one established so far (JN-DSRCT-1), which harbours one of the less common translocation variants; nevertheless, this cell line displays exosomal similarities to DSCRT explants.	('tumour', 'Disease', (52, 58))	('variants', 'Var', (177, 185))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))
66458	33669307	As with other sarcomas, each case of CCS is primarily driven by a single mutation particular to each tumour and for CCS genomic translocation results in the fusions of EWSR1 with ATF1 or, rarely, with CREB1 (Figure 2).	('sarcomas', 'Disease', 'MESH:D012509', (14, 22))	('EWSR1', 'Gene', (168, 173))	('results in', 'Reg', (142, 152))	('ATF1', 'Gene', (179, 183))	('ATF1', 'Gene', '466', (179, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (14, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('CREB1', 'Gene', '1385', (201, 206))	('tumour', 'Disease', (101, 107))	('sarcomas', 'Disease', (14, 22))	('CREB1', 'Gene', (201, 206))	('fusions', 'Var', (157, 164))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
66486	33669307	Despite a lack of success in the decades-long effort to therapeutically target a relatively small number of a sarcoma-specific gene fusion proteins, the consistency of the mutant mRNA exon boundaries is an opportunity in terms of diagnosis and detection of residual disease that is now being fulfilled.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('mutant', 'Var', (172, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Disease', (110, 117))
66502	33669307	For sarcoma patients, however, the relatively small number of well-characterized fusion proteins encoded by mRNA with specific mutant exon junctions provides an opportunity to establish protocols and infrastructure for future diagnostic platforms.	('mutant', 'Var', (127, 133))	('patients', 'Species', '9606', (12, 20))	('sarcoma', 'Disease', (4, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('mRNA', 'Gene', (108, 112))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))
66576	30627094	In the FAB M4/M5 type of AML, those with certain cytogenetic abnormalities, including a balanced translocation between chromosomes 18 and 21 (t (8; 21)) and inversion 16 (inv(16)), CD56+ blasts, 11q abnormalities, a recent history of allogenic stem cell transplant, and cellular immune dysfunction have higher incidence of Myeloid sarcoma.	('genetic abnormalities', 'Disease', (53, 74))	('CD56', 'Gene', (181, 185))	('11q abnormalities', 'Var', (195, 212))	('inversion 16', 'Var', (157, 169))	('balanced translocation', 'Var', (88, 110))	('Myeloid sarcoma', 'Disease', 'MESH:D023981', (323, 338))	('genetic abnormalities', 'Disease', 'MESH:D030342', (53, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (331, 338))	('AML', 'Disease', 'MESH:D015470', (25, 28))	('AML', 'Phenotype', 'HP:0004808', (25, 28))	('Myeloid sarcoma', 'Disease', (323, 338))	('CD56', 'Gene', '4684', (181, 185))	('AML', 'Disease', (25, 28))
66639	28257516	In the current studies, transient knockdown of ACOX1 and ABCD3 led to cell death in the KSHV latently infected endothelial cells but not the mock-infected control.	('KSHV', 'Species', '37296', (88, 92))	('mock-infected', 'Disease', 'MESH:D007239', (141, 154))	('mock-infected', 'Disease', (141, 154))	('ACOX1', 'Gene', '51', (47, 52))	('cell death', 'CPA', (70, 80))	('ABCD3', 'Gene', (57, 62))	('knockdown', 'Var', (34, 43))	('ABCD3', 'Gene', '5825', (57, 62))	('ACOX1', 'Gene', (47, 52))
66697	28257516	There is an approximately 50% increase in the number of peroxisomes per cell in the KSHV infected endothelial cells as compared to mock infected cells (Fig 4I and 4J).	('KSHV', 'Gene', (84, 88))	('infected', 'Var', (89, 97))	('KSHV', 'Species', '37296', (84, 88))	('increase', 'PosReg', (30, 38))	('peroxisomes', 'MPA', (56, 67))
66712	28257516	To determine if ACOX1 is necessary during KSHV latent infection, small interfering RNA (siRNA) was used to knockdown its gene expression (Fig 6B).	('knockdown', 'Var', (107, 116))	('ACOX1', 'Gene', (16, 21))	('KSHV', 'Species', '37296', (42, 46))	('ACOX1', 'Gene', '51', (16, 21))
66713	28257516	Loss of ACOX1 did not alter the cellular proliferation of uninfected cells or the KSHV infection rates but resulted in a significant increase in cell death of the KSHV infected cells compared to controls at 96 hpi (Fig 6C-6E).	('KSHV', 'Species', '37296', (163, 167))	('ACOX1', 'Gene', (8, 13))	('KSHV infection', 'Disease', 'MESH:C537372', (82, 96))	('increase', 'PosReg', (133, 141))	('ACOX1', 'Gene', '51', (8, 13))	('cell death', 'CPA', (145, 155))	('Loss', 'Var', (0, 4))	('KSHV infection', 'Disease', (82, 96))	('KSHV', 'Species', '37296', (82, 86))
66717	28257516	Similarly, to ACOX1, loss of ABCD3 did not alter cellular proliferation of uninfected cells or KSHV infection rates but resulted in a significant increase in cell death of the KSHV infected cells compared to controls at 96 hpi (Fig 6C-6E).	('loss', 'Var', (21, 25))	('ACOX1', 'Gene', (14, 19))	('ACOX1', 'Gene', '51', (14, 19))	('increase', 'PosReg', (146, 154))	('cell death', 'CPA', (158, 168))	('ABCD3', 'Gene', (29, 34))	('KSHV', 'Species', '37296', (176, 180))	('ABCD3', 'Gene', '5825', (29, 34))	('KSHV infection', 'Disease', 'MESH:C537372', (95, 109))	('KSHV', 'Species', '37296', (95, 99))	('KSHV infection', 'Disease', (95, 109))
66735	28257516	In the KSHV infected cells, there was a significant increase in most of the LCFAs measured.	('increase', 'PosReg', (52, 60))	('FAs', 'Chemical', 'MESH:C038178', (78, 81))	('KSHV', 'Species', '37296', (7, 11))	('KSHV', 'Var', (7, 11))
66806	28257516	MS data files were searched using the COMET algorithm and the output was imported into the Trans-Proteomic Pipeline with the following parameters: variable oxidation of methionine, variable phosphorylation of Serine, Threonine, or Tyrosine, up to 4 variable modifications per peptide, fixed oxidation of Cysteine, and fixed iTRAQ labeling of Lysines and the N-terminus, maximum charge of 7.	('fixed iTRAQ', 'Var', (318, 329))	('modifications', 'Var', (258, 271))	('Tyrosine', 'Chemical', 'MESH:D014443', (231, 239))	('Cysteine', 'Chemical', 'MESH:D003545', (304, 312))	('Lysines', 'Chemical', 'MESH:D008239', (342, 349))	('COMET', 'Species', '302767', (38, 43))	('Serine', 'MPA', (209, 215))	('oxidation', 'MPA', (156, 165))	('Serine', 'Chemical', 'MESH:D012694', (209, 215))	('Threonine', 'Chemical', 'MESH:D013912', (217, 226))	('oxidation', 'MPA', (291, 300))	('methionine', 'Chemical', 'MESH:D008715', (169, 179))	('phosphorylation', 'MPA', (190, 205))
66826	28257516	: K1 (K1_HHV8P), K2 (VIL6_HHV8P), K12A (K12_HHV8P), K12B, K12C, ORF71 (VFLIP_HHV8P), ORF72 (VCYCL_HHV8P), and ORF73 (ORF73_HHV8P).	('K1', 'Gene', '4961511', (2, 4))	('VFLIP', 'Gene', '4961494', (71, 76))	('K12C', 'SUBSTITUTION', 'None', (58, 62))	('ORF72', 'Gene', '4961471', (85, 90))	('K12B', 'Var', (52, 56))	('ORF73', 'Gene', (117, 122))	('K1', 'Gene', '4961511', (40, 42))	('ORF73', 'Gene', (110, 115))	('VFLIP', 'Gene', (71, 76))	('K12C', 'Var', (58, 62))	('ORF73', 'Gene', '4961527', (117, 122))	('K1', 'Gene', '4961511', (52, 54))	('K1', 'Gene', '4961511', (6, 8))	('ORF73', 'Gene', '4961527', (110, 115))	('K12B', 'SUBSTITUTION', 'None', (52, 56))	('ORF72', 'Gene', (85, 90))	('ORF71', 'Gene', '4961494', (64, 69))	('K1', 'Gene', '4961511', (34, 36))	('ORF71', 'Gene', (64, 69))	('K1', 'Gene', '4961511', (58, 60))	('K12A', 'Mutation', 'p.K12A', (34, 38))
66861	27307854	At that time, it was felt that a rotationplasty would result in an increased risk for tumor recurrence, due to the proximity of the tumor to the peroneal nerve and a resultant lack of reasonable tumor-free margins.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('rotationplasty', 'Var', (33, 47))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
66872	27307854	A mutation of the NSD1 gene, located on the 5q35 locus, has been identified in nearly 75% of individuals with Sotos syndrome.	('NSD1', 'Gene', '64324', (18, 22))	('Sotos syndrome', 'Disease', (110, 124))	('mutation', 'Var', (2, 10))	('identified', 'Reg', (65, 75))	('NSD1', 'Gene', (18, 22))	('Sotos syndrome', 'Disease', 'MESH:D058495', (110, 124))
66873	27307854	The NSD1 gene is felt to act as a tumor suppressor, and therefore a mutation in this gene may confer an increased risk of malignancies.	('tumor', 'Disease', (34, 39))	('NSD1', 'Gene', (4, 8))	('malignancies', 'Disease', 'MESH:D009369', (122, 134))	('mutation', 'Var', (68, 76))	('malignancies', 'Disease', (122, 134))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('NSD1', 'Gene', '64324', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
66874	27307854	A recent publication showed that a haploinsufficiency of the NSD1 gene in addition to an NSD1 mutation causes Sotos syndrome.	('NSD1', 'Gene', (61, 65))	('haploinsufficiency', 'Disease', (35, 53))	('Sotos syndrome', 'Disease', (110, 124))	('NSD1', 'Gene', (89, 93))	('causes', 'Reg', (103, 109))	('haploinsufficiency', 'Disease', 'MESH:D058495', (35, 53))	('NSD1', 'Gene', '64324', (89, 93))	('NSD1', 'Gene', '64324', (61, 65))	('Sotos syndrome', 'Disease', 'MESH:D058495', (110, 124))	('mutation', 'Var', (94, 102))
67008	24280108	While osteogenic sarcoma cells increased oxygen consumption and spare respiratory capacity upon MYC suppression, they displayed minimal changes in glucose and glutamine consumption as well as their respective contribution to the citrate pool.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('citrate pool', 'MPA', (229, 241))	('MYC', 'Var', (96, 99))	('increased', 'PosReg', (31, 40))	('glutamine', 'Chemical', 'MESH:D005973', (159, 168))	('oxygen', 'Chemical', 'MESH:D010100', (41, 47))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (6, 24))	('osteogenic sarcoma', 'Disease', (6, 24))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (6, 24))	('citrate', 'Chemical', 'MESH:D019343', (229, 236))	('oxygen consumption', 'MPA', (41, 59))	('glucose', 'Chemical', 'MESH:D005947', (147, 154))	('spare respiratory capacity', 'MPA', (64, 90))
67009	24280108	However, glutamine significantly induced oxygen consumption in the presence of MYC which was dependent on aminotransferases.	('induced', 'Reg', (33, 40))	('glutamine', 'Chemical', 'MESH:D005973', (9, 18))	('oxygen', 'Chemical', 'MESH:D010100', (41, 47))	('glutamine', 'Var', (9, 18))	('oxygen consumption', 'MPA', (41, 59))
67010	24280108	Furthermore, inhibition of aminotransferases selectively diminished cell proliferation and survival of osteogenic sarcoma MYC-expressing cells.	('survival', 'CPA', (91, 99))	('diminished', 'NegReg', (57, 67))	('aminotransferases', 'Enzyme', (27, 44))	('cell proliferation', 'CPA', (68, 86))	('inhibition', 'Var', (13, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (103, 121))	('osteogenic sarcoma', 'Disease', (103, 121))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (103, 121))
67023	24280108	Normal cells induce MYC upon cell surface receptor-dependent signaling to stimulate aerobic glycolysis and glutaminolysis to promote cell proliferation, while cancer cells have deregulated MYC allowing proliferation to occur in a cell-autonomous manner.	('cancer', 'Disease', (159, 165))	('stimulate', 'PosReg', (74, 83))	('glutaminolysis', 'MPA', (107, 121))	('cell proliferation', 'CPA', (133, 151))	('MYC', 'Gene', (189, 192))	('aerobic glycolysis', 'MPA', (84, 102))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('MYC', 'MPA', (20, 23))	('deregulated', 'Var', (177, 188))	('promote', 'PosReg', (125, 132))
67024	24280108	For example, MYC increases glycolysis in part through the regulation of lactate dehydrogenase A (LDHA) and glutaminolysis by upregulating expression of GLS.	('MYC', 'Var', (13, 16))	('glutaminolysis', 'MPA', (107, 121))	('lactate dehydrogenase A', 'Gene', (72, 95))	('increases', 'PosReg', (17, 26))	('lactate dehydrogenase A', 'Gene', '16828', (72, 95))	('GLS', 'Gene', (152, 155))	('GLS', 'Gene', '216456', (152, 155))	('LDHA', 'Gene', '16828', (97, 101))	('LDHA', 'Gene', (97, 101))	('expression', 'MPA', (138, 148))	('upregulating', 'PosReg', (125, 137))	('glycolysis', 'MPA', (27, 37))
67061	24280108	Previous reports indicate that MYC induction can stimulate oxygen consumption.	('oxygen', 'Chemical', 'MESH:D010100', (59, 65))	('oxygen consumption', 'MPA', (59, 77))	('MYC induction', 'Var', (31, 44))	('stimulate', 'PosReg', (49, 58))
67077	24280108	MYC increases cell proliferation in osteogenic sarcoma cells, thereby placing a heavy demand for mitochondrial TCA cycle metabolites for macromolecule synthesis.	('increases', 'PosReg', (4, 13))	('MYC', 'Var', (0, 3))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (36, 54))	('osteogenic sarcoma', 'Disease', (36, 54))	('mito', 'Species', '262676', (97, 101))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (36, 54))	('cell proliferation', 'CPA', (14, 32))	('TCA', 'Chemical', 'MESH:D014238', (111, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
67084	24280108	When cells were cultured with [U-13C]-glucose and unlabeled glutamine for six hours, the osteocytes displayed a significant increase in the unlabeled citrate fraction (m+0) and a decrease in glucose derived m+2, m+4, and m+6 pools indicating that over this time period, a lower fraction of the citrate pool was supplied by glucose metabolism.	('increase', 'PosReg', (124, 132))	('glucose', 'Chemical', 'MESH:D005947', (38, 45))	('glucose', 'Chemical', 'MESH:D005947', (323, 330))	('glucose derived m+2', 'MPA', (191, 210))	('glucose', 'Chemical', 'MESH:D005947', (191, 198))	('citrate', 'Chemical', 'MESH:D019343', (294, 301))	('[U-13C]-glucose', 'Chemical', '-', (30, 45))	('m+4', 'MPA', (212, 215))	('decrease', 'NegReg', (179, 187))	('m+6 pools', 'MPA', (221, 230))	('citrate', 'Chemical', 'MESH:D019343', (150, 157))	('glutamine', 'Chemical', 'MESH:D005973', (60, 69))	('[U-13C]-glucose', 'Var', (30, 45))
67100	24280108	Thus, the deprivation of these nutrients could increase ROS levels, contributing to the increase in cell death.	('deprivation', 'Var', (10, 21))	('ROS levels', 'MPA', (56, 66))	('increase', 'PosReg', (88, 96))	('cell death', 'CPA', (100, 110))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('increase', 'PosReg', (47, 55))	('increase ROS levels', 'Phenotype', 'HP:0025464', (47, 66))
67112	24280108	Glutamine substantially stimulated OCR which was diminished by AOA and rescued by DMK (Figure 5a).	('Glutamine', 'Chemical', 'MESH:D005973', (0, 9))	('DMK', 'Chemical', 'MESH:C541783', (82, 85))	('AOA', 'Chemical', 'MESH:D000625', (63, 66))	('OCR', 'Chemical', '-', (35, 38))	('OCR', 'MPA', (35, 38))	('stimulated', 'PosReg', (24, 34))	('DMK', 'Var', (82, 85))
67115	24280108	AOA induced cell death and decreased cell proliferation, which was rescued by DMK in the MYC-dependent osteogenic sarcoma cells (Figure 5c and 5d).	('cell death', 'CPA', (12, 22))	('decreased', 'NegReg', (27, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('DMK', 'Chemical', 'MESH:C541783', (78, 81))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (103, 121))	('osteogenic sarcoma', 'Disease', (103, 121))	('AOA', 'Chemical', 'MESH:D000625', (0, 3))	('DMK', 'Var', (78, 81))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (103, 121))	('cell proliferation', 'CPA', (37, 55))
67132	24280108	MVE induced cell death in the osteogenic sarcoma cells compared to the control TPP compound (Figure 6g).	('cell death', 'CPA', (12, 22))	('osteogenic sarcoma', 'Disease', (30, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (30, 48))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (30, 48))	('MVE', 'Var', (0, 3))	('TPP', 'Chemical', '-', (79, 82))
67133	24280108	MVE significantly diminished ROS levels but did not cause significant cell death in the differentiated osteocytes compared to the control TPP compound (Figure 6e and 6g).	('TPP', 'Chemical', '-', (138, 141))	('ROS levels', 'MPA', (29, 39))	('MVE', 'Var', (0, 3))	('diminished', 'NegReg', (18, 28))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))
67143	24280108	Furthermore, inhibition of aminotransferases prevents xenograft tumor growth of MDA-MB-231 breast cancer cells and MYC-dependent neuroblastoma cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('breast cancer', 'Disease', (91, 104))	('tumor', 'Disease', (64, 69))	('neuroblastoma', 'Disease', 'MESH:D009447', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('aminotransferases', 'Enzyme', (27, 44))	('inhibition', 'Var', (13, 23))	('neuroblastoma', 'Disease', (129, 142))	('prevents', 'NegReg', (45, 53))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (80, 90))	('neuroblastoma', 'Phenotype', 'HP:0003006', (129, 142))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
67144	24280108	This raises the possibility that inhibition of aminotransferases might be an effective strategy to inhibit MYC-dependent tumorigenesis.	('inhibition', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('inhibit', 'NegReg', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
67146	24280108	ROS, in addition to causing genomic instability, can also increase tumorigenesis by activating signaling pathways that regulate cellular proliferation, angiogenesis, and metastasis.	('angiogenesis', 'CPA', (152, 164))	('cellular proliferation', 'CPA', (128, 150))	('signaling pathways', 'Pathway', (95, 113))	('increase', 'PosReg', (58, 66))	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('metastasis', 'CPA', (170, 180))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('activating', 'Reg', (84, 94))	('tumor', 'Disease', (67, 72))
67151	24280108	While previous studies have demonstrated that NAC is effective in reducing MYC-dependent tumorigenesis, it remains to be determined whether mitochondrial-targeted antioxidants would also prevent tumorigenesis in vivo.	('NAC', 'Chemical', 'MESH:D000111', (46, 49))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('NAC', 'Var', (46, 49))	('reducing', 'NegReg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('MYC-dependent', 'Disease', (75, 88))	('mito', 'Species', '262676', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (89, 94))
67157	24280108	This work is supported by NIH (R01CA123067) to NSC and NIH (R01CA157996) and the Robert A Welch Foundation (I1733) to RJD.	('R01CA123067', 'Var', (31, 42))	('NSC', 'Disease', 'OMIM:617394', (47, 50))	('NSC', 'Disease', (47, 50))	('R01CA157996', 'Var', (60, 71))
67158	24280108	DWF was supported by NIH (R01CA089305) and (R01CA34233).	('R01CA34233', 'Var', (44, 54))	('DWF', 'Chemical', '-', (0, 3))	('R01CA089305', 'Var', (26, 37))
67162	31848295	We compared 10 silvestrol-related rocaglates lacking the dioxanyl ring and found that didesmethylrocaglamide (DDR) and rocaglamide (Roc) had growth-inhibitory activity comparable to silvestrol.	('didesmethylrocaglamide', 'Chemical', '-', (86, 108))	('growth-inhibitory activity', 'MPA', (141, 167))	('dioxanyl', 'Chemical', '-', (57, 65))	('didesmethylrocaglamide', 'Var', (86, 108))	('silvestrol', 'Chemical', 'MESH:C489897', (182, 192))	('DDR', 'Chemical', '-', (110, 113))	('rocaglamide', 'Chemical', 'MESH:C107772', (97, 108))	('rocaglates', 'Chemical', '-', (34, 44))	('silvestrol', 'Chemical', 'MESH:C489897', (15, 25))	('rocaglamide', 'Chemical', 'MESH:C107772', (119, 130))	('Roc', 'Chemical', 'MESH:C107772', (132, 135))
67174	31848295	MPNSTs can occur sporadically or arise from pre-existing plexiform neurofibromas in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome caused by mutations in the NF1 gene which encodes the Ras-GTPase-activating protein neurofibromin.	('neurofibromas', 'Disease', (67, 80))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (57, 80))	('tumor', 'Disease', (132, 137))	('NF1', 'Gene', '4763', (189, 192))	('NF1', 'Gene', '4763', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('patients', 'Species', '9606', (84, 92))	('NF1', 'Gene', (189, 192))	('arise', 'Reg', (33, 38))	('neurofibromin', 'Gene', (246, 259))	('NF1', 'Gene', (124, 127))	('neurofibromatosis type 1', 'Gene', (98, 122))	('neurofibromas', 'Phenotype', 'HP:0001067', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('neurofibromas', 'Disease', 'MESH:D009455', (67, 80))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (98, 115))	('mutations', 'Var', (172, 181))	('neurofibromin', 'Gene', '4763', (246, 259))	('MPNSTs', 'Phenotype', 'HP:0100697', (0, 6))	('caused by', 'Reg', (162, 171))	('neurofibromatosis type 1', 'Gene', '4763', (98, 122))
67175	31848295	Importantly, even sporadic tumors frequently harbor mutations in the NF1 gene or the Ras pathway.	('mutations', 'Var', (52, 61))	('NF1', 'Gene', '4763', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Ras pathway', 'Pathway', (85, 96))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('NF1', 'Gene', (69, 72))
67178	31848295	Additionally, recurrent mutations in the tumor suppressor genes CDKN2A and TP53 and the subunits of the chromatin-modifying polycomb repressor complex-2 (PRC2), SUZ12 and EED, have been identified and are important for MPNST progression.	('PRC2', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('SUZ12', 'Gene', (161, 166))	('EED', 'Gene', '8726', (171, 174))	('tumor', 'Disease', (41, 46))	('CDKN2A', 'Gene', (64, 70))	('EED', 'Gene', (171, 174))	('CDKN2A', 'Gene', '1029', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (24, 33))	('SUZ12', 'Gene', '23512', (161, 166))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
67179	31848295	Inactivation of CDKN2A and TP53 disables the G1/S checkpoint.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('disables', 'NegReg', (32, 40))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('G1/S checkpoint', 'CPA', (45, 60))	('Inactivation', 'Var', (0, 12))
67232	31848295	Similar to previous observations, the substitution of a methoxy group at position 8b, as in 8b-O-methylrocaglaol versus rocaglaol, abolished the activity (Fig.	('8b-O-methylrocaglaol', 'Chemical', '-', (92, 112))	('abolished', 'NegReg', (131, 140))	('rocaglaol', 'Chemical', 'MESH:C510144', (120, 129))	('activity', 'MPA', (145, 153))	('rocaglaol', 'Chemical', 'MESH:C510144', (103, 112))	('substitution', 'Var', (38, 50))
67233	31848295	This methoxy substitution at 8b could be partly mitigated by the addition of a methylenedioxy ring to phenyl ring B. Additionally, the presence of amide or ester groups at position C-2 of the benzofuran scaffold appeared to enhance the activity, as compounds such as DDR, Roc, and methyl rocaglate were more potent than rocaglaol.	('ester', 'Chemical', 'MESH:D004952', (156, 161))	('methyl rocaglate', 'Chemical', 'MESH:C483989', (281, 297))	('enhance', 'PosReg', (224, 231))	('presence', 'Var', (135, 143))	('benzofuran', 'Chemical', 'MESH:C105430', (192, 202))	('Roc', 'Chemical', 'MESH:C107772', (272, 275))	('amide', 'Chemical', 'MESH:D000577', (147, 152))	('rocaglaol', 'Chemical', 'MESH:C510144', (320, 329))	('DDR', 'Chemical', '-', (267, 270))	('activity', 'MPA', (236, 244))
67237	31848295	Phase contrast micrographs taken of cells prior to cell cycle analysis showed increased floating dead cells and debris in DDR or Roc-treated dishes.	('Roc', 'Chemical', 'MESH:C107772', (129, 132))	('floating dead cells', 'CPA', (88, 107))	('DDR', 'Chemical', '-', (122, 125))	('debris', 'CPA', (112, 118))	('increased', 'PosReg', (78, 87))	('DDR', 'Var', (122, 125))
67240	31848295	STS26T cells treated for 3 days with either DDR or Roc exhibited increased cleavage of the executioner caspases-3 and 7 and their downstream substrate PARP (Fig.	('increased', 'PosReg', (65, 74))	('STS26T', 'CellLine', 'CVCL:8917', (0, 6))	('cleavage', 'MPA', (75, 83))	('PARP', 'Gene', (151, 155))	('caspases-3 and 7', 'Gene', '836;840', (103, 119))	('Roc', 'Chemical', 'MESH:C107772', (51, 54))	('DDR', 'Var', (44, 47))	('DDR', 'Chemical', '-', (44, 47))	('PARP', 'Gene', '142', (151, 155))
67245	31848295	Similarly, cleavage of caspase-3 and PARP and induction of gammaH2A.X were also detected in NF1-null ST8814 cells treated with DDR and Roc (Supplementary Fig.	('Roc', 'Chemical', 'MESH:C107772', (135, 138))	('PARP', 'Gene', (37, 41))	('DDR', 'Chemical', '-', (127, 130))	('caspase-3', 'Gene', (23, 32))	('gammaH2A.X', 'Gene', (59, 69))	('NF1', 'Gene', (92, 95))	('detected', 'Reg', (80, 88))	('PARP', 'Gene', '142', (37, 41))	('cleavage', 'MPA', (11, 19))	('NF1', 'Gene', '4763', (92, 95))	('DDR', 'Var', (127, 130))	('caspase-3', 'Gene', '836', (23, 32))
67274	31848295	Also, we observed that DDR consistently exhibited lower IC50 values than Roc in every sarcoma cell line tested.	('sarcoma', 'Disease', (86, 93))	('lower', 'NegReg', (50, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('IC50 values', 'MPA', (56, 67))	('sarcoma', 'Disease', 'MESH:D012509', (86, 93))	('Roc', 'Chemical', 'MESH:C107772', (73, 76))	('DDR', 'Var', (23, 26))	('DDR', 'Chemical', '-', (23, 26))
67277	31848295	Similarly, the average size of Roc-treated osteosarcoma PDX tumors was reduced by ~80% compared to those of vehicle-treated tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Roc-treated', 'Var', (31, 42))	('Roc', 'Chemical', 'MESH:C107772', (31, 34))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('osteosarcoma PDX tumors', 'Disease', 'MESH:D012516', (43, 66))	('tumors', 'Disease', (124, 130))	('reduced', 'NegReg', (71, 78))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('osteosarcoma', 'Phenotype', 'HP:0002669', (43, 55))	('osteosarcoma PDX tumors', 'Disease', (43, 66))	('tumors', 'Disease', (60, 66))
67278	31848295	Also, Roc inhibited the growth of rhabdomyosarcoma PDXs by ~70% (Fig.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (34, 50))	('rhabdomyosarcoma PDXs', 'Disease', 'MESH:D012208', (34, 55))	('Roc', 'Chemical', 'MESH:C107772', (6, 9))	('inhibited', 'NegReg', (10, 19))	('Roc', 'Var', (6, 9))	('growth', 'MPA', (24, 30))	('rhabdomyosarcoma PDXs', 'Disease', (34, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
67301	31848295	Our side-by-side comparison of 10 rocaglates lacking the bulky dioxanyl ring present in silvestrol has allowed us to discern certain structure-activity relationships, particularly the C-8b, C-2, and C-6 positions along the cyclopenta[b]benzofuran core.	('silvestrol', 'Chemical', 'MESH:C489897', (88, 98))	('cyclopenta[b]benzofuran', 'Chemical', '-', (223, 246))	('C-2', 'Var', (190, 193))	('dioxanyl', 'Chemical', '-', (63, 71))	('rocaglates', 'Chemical', '-', (34, 44))	('C-8b', 'Gene', '732', (184, 188))	('C-8b', 'Gene', (184, 188))	('C-6', 'Var', (199, 202))
67304	31848295	Also, the phenyl rings A and B of Roc parallel stack with RNA bases, which may explain our finding that adding a methylenedioxy group to ring B modestly improved the growth inhibitory activity of rocaglates with methylated 8b-OH (Fig.	('Roc', 'Chemical', 'MESH:C107772', (34, 37))	('methylated', 'Var', (212, 222))	('improved', 'PosReg', (153, 161))	('growth inhibitory activity', 'MPA', (166, 192))	('rocaglates', 'Chemical', '-', (196, 206))
67309	31848295	Consistent with this notion, we detected a higher level of MDR1 in ST8814 MPNST cells than that in STS26T cells (Supplementary Fig.	('MDR1', 'MPA', (59, 63))	('STS26T', 'CellLine', 'CVCL:8917', (99, 105))	('ST8814', 'Var', (67, 73))	('higher', 'PosReg', (43, 49))
67316	31848295	Consistently, we observed that Roc and DDR decreased the levels of multiple signaling proteins important for tumor growth and survival, leading to G2/M cell cycle arrest and activation of executioner caspases.	('levels of multiple signaling proteins', 'MPA', (57, 94))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (152, 169))	('arrest', 'Disease', 'MESH:D006323', (163, 169))	('Roc', 'Chemical', 'MESH:C107772', (31, 34))	('Roc', 'Var', (31, 34))	('arrest', 'Disease', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('activation', 'PosReg', (174, 184))	('DDR', 'Var', (39, 42))	('DDR', 'Chemical', '-', (39, 42))	('decreased', 'NegReg', (43, 52))	('tumor', 'Disease', (109, 114))	('executioner caspases', 'Pathway', (188, 208))
67322	31848295	Also, blocking mTOR signaling is associated with activation of bypass signaling pathways that can restore critical survival signals, enabling tumor regrowth.	('restore', 'PosReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('mTOR', 'Gene', (15, 19))	('blocking', 'Var', (6, 14))	('mTOR', 'Gene', '2475', (15, 19))	('bypass signaling pathways', 'Pathway', (63, 88))	('enabling', 'PosReg', (133, 141))	('critical survival signals', 'MPA', (106, 131))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
67323	31848295	Inhibition of eIF4E tends to decrease translation of the mRNAs with 5' terminal oligopyrimidine tracts, which encode ribosomal proteins, elongation factors, lysosomal-related and metabolic-related proteins.	('translation', 'MPA', (38, 49))	('oligopyrimidine', 'Chemical', '-', (80, 95))	('eIF4E', 'Gene', '1977', (14, 19))	('Inhibition', 'Var', (0, 10))	('decrease', 'NegReg', (29, 37))	('eIF4E', 'Gene', (14, 19))
67326	31848295	Thus, blocking eIF4A may have a stronger effect on tumor growth and survival.	('eIF4A', 'Gene', '1974', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('survival', 'CPA', (68, 76))	('tumor', 'Disease', (51, 56))	('blocking', 'Var', (6, 14))	('eIF4A', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
67339	31848295	In summary, we have demonstrated that Roc and DDR, as eIF4A inhibitors, simultaneously suppressed multiple growth-promoting signaling pathways and induced apoptosis in tumor cells.	('induced', 'PosReg', (147, 154))	('tumor', 'Disease', (168, 173))	('growth-promoting signaling pathways', 'Pathway', (107, 142))	('DDR', 'Var', (46, 49))	('eIF4A', 'Gene', '1974', (54, 59))	('Roc', 'Chemical', 'MESH:C107772', (38, 41))	('Roc', 'Var', (38, 41))	('eIF4A', 'Gene', (54, 59))	('DDR', 'Chemical', '-', (46, 49))	('suppressed', 'NegReg', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('apoptosis', 'CPA', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
67441	31377411	On univariate Cox regression analysis, older age, retroperitoneal tumors, tumor size >= 5 cm, positive margin status, presence of lymphovascular invasion, and positive lymph node status were associated with worse overall survival.	('overall survival', 'MPA', (213, 229))	('retroperitoneal tumors', 'Disease', (50, 72))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('worse', 'NegReg', (207, 212))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('lymphovascular invasion', 'CPA', (130, 153))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('tumor', 'Disease', (74, 79))	('retroperitoneal tumors', 'Disease', 'MESH:D012186', (50, 72))	('positive', 'Var', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
67471	29100387	Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties Ewing sarcoma (EWS) is a highly aggressive and metabolically active malignant tumor.	('malignant tumor', 'Disease', (159, 174))	('Ewing sarcoma', 'Gene', '2130', (91, 104))	('Ewing sarcoma', 'Gene', (91, 104))	('modulation', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Ewing sarcoma', 'Gene', '2130', (24, 37))	('Ewing sarcoma', 'Gene', (24, 37))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumor', 'Disease', (169, 174))	('malignant tumor', 'Disease', 'MESH:D018198', (159, 174))	('tumor', 'Disease', (53, 58))	('inhibits', 'NegReg', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
67482	29100387	About 95% of EWS family tumors contain a translocation between the EWS gene on chromosome 11 and the ETS family genes (FLI1 or ERG) on chromosome 22.	('ERG', 'Gene', '2078', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('ERG', 'Gene', (127, 130))	('translocation', 'Var', (41, 54))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('EWS gene', 'Gene', (67, 75))	('FLI1', 'Gene', (119, 123))	('FLI1', 'Gene', '2313', (119, 123))
67497	29100387	2DG binds to glucose transporters and gets phosphorylated by hexokinase to 2DG-6-phosphate, which cannot be metabolized any further, thus blocking the glycolytic pathway.	('hexokinase', 'Gene', '3098', (61, 71))	('2DG', 'Chemical', 'MESH:D003847', (75, 78))	('blocking', 'NegReg', (138, 146))	('glycolytic pathway', 'Pathway', (151, 169))	('2DG-6-phosphate', 'Var', (75, 90))	('2DG-6-phosphate', 'Chemical', 'MESH:C015785', (75, 90))	('glucose transporters', 'Gene', (13, 33))	('2DG', 'Chemical', 'MESH:D003847', (0, 3))	('glucose transporters', 'Gene', '6513', (13, 33))	('hexokinase', 'Gene', (61, 71))	('binds', 'Interaction', (4, 9))
67516	29100387	On the other hand, treatment with 2DG should inhibit aerobic glycolysis, as can be observed by the decrease in lactate production and consequently inhibit tumor cell viability.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('lactate', 'Chemical', 'MESH:D019344', (111, 118))	('lactate production', 'MPA', (111, 129))	('aerobic glycolysis', 'MPA', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('decrease', 'NegReg', (99, 107))	('2DG', 'Chemical', 'MESH:D003847', (34, 37))	('inhibit', 'NegReg', (147, 154))	('inhibit', 'NegReg', (45, 52))	('2DG', 'Var', (34, 37))
67519	29100387	From lactate measurement at the end of 24 hours (normalized to cell numbers), we observed that lactate production was increased for all cell lines under metformin treatment, whereas, with 2DG we observed a decrease in two of the three cell lines, namely MHH and TC71.	('metformin', 'Chemical', 'MESH:D008687', (153, 162))	('lactate', 'Chemical', 'MESH:D019344', (5, 12))	('lactate', 'Chemical', 'MESH:D019344', (95, 102))	('2DG', 'Chemical', 'MESH:D003847', (188, 191))	('increased', 'PosReg', (118, 127))	('lactate production', 'MPA', (95, 113))	('metformin', 'Var', (153, 162))
67537	29100387	Measurement of caspase-3 activity (Figure 3A) showed that in the two out of the three cell lines, 2DG was successful in inducing a strong caspase-3 activity compared to untreated control.	('caspase-3', 'Gene', (138, 147))	('inducing', 'Reg', (120, 128))	('caspase-3', 'Gene', (15, 24))	('caspase-3', 'Gene', '836', (138, 147))	('2DG', 'Chemical', 'MESH:D003847', (98, 101))	('activity', 'MPA', (148, 156))	('2DG', 'Var', (98, 101))	('caspase-3', 'Gene', '836', (15, 24))
67542	29100387	Since 2DG seemed to induce the highest level of apoptosis, we further examined the time dependent induction under the treatment of 2.5 mM 2DG and results show significant increase in apoptotic population from 4 hours onward, reaching a peak at 16h, within a 24h period (Figure 3C).	('increase', 'PosReg', (171, 179))	('apoptotic population', 'CPA', (183, 203))	('2DG', 'Chemical', 'MESH:D003847', (6, 9))	('2DG', 'Chemical', 'MESH:D003847', (138, 141))	('2DG', 'Var', (6, 9))
67543	29100387	Both 2DG and metformin could upregulate AMPK-alpha activation by phosphorylation at threonine 172 residue and could inhibit ACC, as observed by an increase in ACC phosphorylation at serine 79 residue.	('ACC', 'Disease', (124, 127))	('upregulate', 'PosReg', (29, 39))	('2DG', 'Chemical', 'MESH:D003847', (5, 8))	('serine', 'Chemical', 'MESH:D012694', (182, 188))	('AMPK-alpha', 'Protein', (40, 50))	('threonine', 'Var', (84, 93))	('threonine', 'Chemical', 'MESH:D013912', (84, 93))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('inhibit', 'NegReg', (116, 123))	('increase', 'PosReg', (147, 155))	('ACC phosphorylation', 'MPA', (159, 178))	('phosphorylation', 'Var', (65, 80))	('activation', 'PosReg', (51, 61))
67550	29100387	Supporting this hypothesis, flow cytometry based cell cycle analysis with two different EWS cell lines, TC71 and MHH, revealed that 2DG increased the number of cells in G0/G1, while reducing it in S phase, thus inducing G1/S checkpoint arrest (Figure 4B).	('2DG', 'Chemical', 'MESH:D003847', (132, 135))	('2DG', 'Var', (132, 135))	('reducing', 'NegReg', (182, 190))	('inducing', 'PosReg', (211, 219))	('G1/S checkpoint arrest', 'CPA', (220, 242))	('increased', 'PosReg', (136, 145))	('S phase', 'CPA', (197, 204))
67557	29100387	We observed that 2DG and metformin significantly reduced sphere number (Figure 5A & 5B) while 2DG was more effective in reducing the size (Figure 5C) of the spheres when compared to untreated cells.	('the', 'MPA', (129, 132))	('reduced', 'NegReg', (49, 56))	('sphere number', 'CPA', (57, 70))	('while', 'Var', (88, 93))	('2DG', 'Chemical', 'MESH:D003847', (17, 20))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('2DG', 'Chemical', 'MESH:D003847', (94, 97))
67575	29100387	To address this issue, we first examined if treatment with 2DG can add to the efficacy of a routinely used chemotherapeutic drug Doxorubicin and also to a PARP inhibitor, Talazoparib (BMN-673).	('Talazoparib', 'Chemical', 'MESH:C586365', (171, 182))	('PARP', 'Gene', '142', (155, 159))	('Doxorubicin', 'Chemical', 'MESH:D004317', (129, 140))	('efficacy', 'MPA', (78, 86))	('BMN-673', 'Chemical', 'MESH:C586365', (184, 191))	('PARP', 'Gene', (155, 159))	('2DG', 'Chemical', 'MESH:D003847', (59, 62))	('2DG', 'Var', (59, 62))
67576	29100387	We observed that 2DG can significantly increase the inhibitory effect of Doxorubicin (Figure 7A) and BMN-673 (Figure 7B).	('BMN-673', 'Chemical', 'MESH:C586365', (101, 108))	('increase', 'PosReg', (39, 47))	('2DG', 'Chemical', 'MESH:D003847', (17, 20))	('2DG', 'Var', (17, 20))	('Doxorubicin', 'Chemical', 'MESH:D004317', (73, 84))	('inhibitory effect', 'MPA', (52, 69))
67593	29100387	Combination of 2DG and radiation in phase I/II clinical trials have shown at well tolerated levels of 2DG combined with radiotherapy, an increase in survival.	('2DG', 'Chemical', 'MESH:D003847', (15, 18))	('survival', 'MPA', (149, 157))	('2DG', 'Chemical', 'MESH:D003847', (102, 105))	('increase', 'PosReg', (137, 145))	('2DG', 'Var', (102, 105))	('clinical', 'Species', '191496', (47, 55))
67620	29100387	Treatment with 2DG was also very effective in reducing the subpopulation with high ALDHhigh expression, previously shown to be associated with chemotherapy resistant EWS stem cells.	('ALDHhigh', 'Gene', (83, 91))	('high', 'Var', (78, 82))	('2DG', 'Chemical', 'MESH:D003847', (15, 18))
67637	29100387	Cells were grown in a humidified atmosphere containing 5% CO2 at 37 C. 2DG (D6134), Metformin (#D150959-5G), Valinomycin (V0627-10MG), and Staurosporine (89157-676) were purchased from Sigma-Aldrich.	('#D150959-5G', 'Var', (95, 106))	('2DG', 'Chemical', 'MESH:D003847', (71, 74))	('V0627-10MG', 'Var', (122, 132))	('Metformin', 'Chemical', 'MESH:D008687', (84, 93))	('CO2', 'Chemical', '-', (58, 61))	('Valinomycin', 'Chemical', 'MESH:D014634', (109, 120))	('Staurosporine', 'Chemical', 'MESH:D019311', (139, 152))
67638	29100387	Primary antibodies p-Thr172-AMPK-alpha (#2535), AMPK-alpha (#2603), p-Ser79-ACC (#3661), ACC (#3676) were procured from Cell Signaling Technology.	('#2535', 'Var', (40, 45))	('Thr172', 'Chemical', '-', (21, 27))	('Ser79', 'Chemical', '-', (70, 75))	('#2603', 'Var', (60, 65))	('#3661', 'Var', (81, 86))	('p-Ser79-ACC', 'Var', (68, 79))
67682	27577794	Prior genomic studies of myxofibrosarcoma have revealed no single characteristic genetic alteration; instead, single-nucleotide polymorphism (SNP) and array comparative genomic hybridization (CGH) studies have shown that myxofibrosarcoma is among the most highly complex sarcoma types.	('sarcoma', 'Disease', (34, 41))	('sarcoma', 'Disease', (271, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('single-nucleotide polymorphism', 'Var', (110, 140))	('myxofibrosarcoma', 'Disease', (25, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('myxofibrosarcoma', 'Disease', 'None', (25, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('myxofibrosarcoma', 'Disease', (221, 237))	('sarcoma', 'Disease', 'MESH:D012509', (230, 237))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('myxofibrosarcoma', 'Disease', 'None', (221, 237))	('sarcoma', 'Disease', 'MESH:D012509', (271, 278))	('sarcoma', 'Disease', (230, 237))
67683	27577794	The gene most commonly mutated was NF1, mutated in 10.5% of myxofibrosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('myxofibrosarcomas', 'Disease', 'None', (60, 77))	('mutated', 'Var', (23, 30))	('myxofibrosarcomas', 'Disease', (60, 77))	('NF1', 'Gene', (35, 38))	('NF1', 'Gene', '4763', (35, 38))
67721	27577794	Interestingly, knockdown induced growth suppression and apoptosis in all 4 myxofibrosarcoma cell lines, including the one with relatively low ITGA10 expression (MXF8500).	('ITGA10', 'Gene', '8515', (142, 148))	('knockdown', 'Var', (15, 24))	('myxofibrosarcoma cell lines', 'Disease', (75, 102))	('ITGA10', 'Gene', (142, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('myxofibrosarcoma cell lines', 'Disease', 'MESH:C538614', (75, 102))	('apoptosis', 'CPA', (56, 65))	('growth suppression', 'CPA', (33, 51))
67726	27577794	After knockdown of ITGA10, we observed significant downregulation of the activation of both PAK (T423 phosphorylation) and AKT (S473 phosphorylation) (Fig.	('activation', 'PosReg', (73, 83))	('AKT', 'Gene', '207', (123, 126))	('ITGA10', 'Gene', '8515', (19, 25))	('knockdown', 'Var', (6, 15))	('downregulation', 'NegReg', (51, 65))	('AKT', 'Gene', (123, 126))	('ITGA10', 'Gene', (19, 25))
67729	27577794	This experiment confirmed that integrin-alpha10 knockdown inhibited RAC activation (Fig.	('integrin-alpha10', 'Gene', (31, 47))	('RAC', 'Gene', (68, 71))	('inhibited', 'NegReg', (58, 67))	('integrin-alpha10', 'Gene', '8515', (31, 47))	('RAC', 'Gene', '207', (68, 71))	('knockdown', 'Var', (48, 57))
67731	27577794	Because AKT is an upstream activator of the protein complex mTORC1, we also examined the effects of integrin-alpha10 silencing on the two major targets of mTORC1, phospho-S6 and phospho-4EBP, and found that the silencing reduced the levels of these phosphoproteins in myxofibrosarcoma cells but not ASCs (Fig.	('AKT', 'Gene', '207', (8, 11))	('mTORC1', 'Gene', '382056', (60, 66))	('levels', 'MPA', (233, 239))	('AKT', 'Gene', (8, 11))	('mTORC1', 'Gene', '382056', (155, 161))	('mTORC1', 'Gene', (60, 66))	('silencing', 'Var', (211, 220))	('reduced', 'NegReg', (221, 228))	('integrin-alpha10', 'Gene', (100, 116))	('integrin-alpha10', 'Gene', '8515', (100, 116))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (268, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('mTORC1', 'Gene', (155, 161))	('myxofibrosarcoma cells', 'Disease', (268, 290))
67733	27577794	Plating on collagen II induced activation of FAK, AKT, and PAK, and the integrin-alpha10 knockdown abolished this activation of AKT and PAK, but not FAK (Fig.	('abolished', 'NegReg', (99, 108))	('integrin-alpha10', 'Gene', '8515', (72, 88))	('FAK', 'Gene', '5747', (149, 152))	('PAK', 'CPA', (59, 62))	('AKT', 'Gene', '207', (50, 53))	('AKT', 'Gene', (128, 131))	('FAK', 'Gene', '5747', (45, 48))	('AKT', 'Gene', (50, 53))	('activation', 'PosReg', (31, 41))	('knockdown', 'Var', (89, 98))	('integrin-alpha10', 'Gene', (72, 88))	('FAK', 'Gene', (45, 48))	('AKT', 'Gene', '207', (128, 131))	('FAK', 'Gene', (149, 152))
67735	27577794	Because ITGA10 knockdown induced growth suppression and apoptosis in cells that showed no obvious detachment, we hypothesized that the cell death was not caused by loss of adhesion.	('ITGA10', 'Gene', '8515', (8, 14))	('knockdown', 'Var', (15, 24))	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('ITGA10', 'Gene', (8, 14))	('apoptosis', 'CPA', (56, 65))	('growth suppression', 'CPA', (33, 51))
67736	27577794	We therefore directly assessed the effect of ITGA10 knockdown on adhesion to collagen I and collagen II.	('adhesion', 'MPA', (65, 73))	('ITGA10', 'Gene', (45, 51))	('ITGA10', 'Gene', '8515', (45, 51))	('knockdown', 'Var', (52, 61))	('assessed', 'Reg', (22, 30))
67739	27577794	Integrin-alpha10 overexpressed through lentivirus transduction in myxofibrosarcoma cells was consistently found to diffusely localize to the plasma membranes and some lamellipodia, but did not co-localize with vinculin or p-FAK at the typical focal adhesion structures (Supplementary Fig.	('Integrin-alpha10', 'Gene', '8515', (0, 16))	('vinculin', 'Gene', '7414', (210, 218))	('overexpressed', 'PosReg', (17, 30))	('Integrin-alpha10', 'Gene', (0, 16))	('vinculin', 'Gene', (210, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('FAK', 'Gene', '5747', (224, 227))	('diffusely', 'MPA', (115, 124))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (66, 88))	('myxofibrosarcoma cells', 'Disease', (66, 88))	('FAK', 'Gene', (224, 227))	('lentivirus transduction', 'Var', (39, 62))
67742	27577794	To further examine the specific requirement of integrin-alpha10 on myxofibrosarcoma cell survival signaling through AKT and PAK, we knocked down integrin-alpha1 and integrin-alpha2.	('integrin-alpha1', 'Gene', (47, 62))	('integrin-alpha10', 'Gene', (47, 63))	('integrin-alpha1', 'Gene', (145, 160))	('integrin-alpha1', 'Gene', '3672', (47, 62))	('integrin-alpha2', 'Gene', '3673', (165, 180))	('integrin-alpha10', 'Gene', '8515', (47, 63))	('integrin-alpha2', 'Gene', (165, 180))	('AKT', 'Gene', '207', (116, 119))	('myxofibrosarcoma', 'Disease', (67, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('myxofibrosarcoma', 'Disease', 'None', (67, 83))	('integrin-alpha1', 'Gene', '3672', (145, 160))	('AKT', 'Gene', (116, 119))	('knocked', 'Var', (132, 139))
67748	27577794	In our array CGH data, we found that nearly half of the tumors (27 of 64; 42%) possessed co-amplification of TRIO and RICTOR (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('co-amplification', 'Var', (89, 105))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('TRIO', 'Gene', (109, 113))	('TRIO', 'Gene', '7204', (109, 113))
67749	27577794	Co-amplification was significantly associated with worse DSS (Supplementary Fig.	('DSS', 'Chemical', '-', (57, 60))	('associated', 'Reg', (35, 45))	('DSS', 'Disease', (57, 60))	('Co-amplification', 'Var', (0, 16))
67751	27577794	Both RICTOR and TRIO mRNA levels were positively associated with copy number of the genes (Fig.	('TRIO', 'Gene', (16, 20))	('TRIO', 'Gene', '7204', (16, 20))	('RICTOR', 'MPA', (5, 11))	('associated', 'Interaction', (49, 59))	('copy number', 'Var', (65, 76))
67752	27577794	Although in the overall study group expression levels of TRIO and RICTOR were not significantly associated with outcomes, for the subset whose tumors had high ITGA10 expression (n=32), high TRIO expression was significantly associated with worse DSS and distant recurrence-free survival, as was combined expression of TRIO and RICTOR (Fig.	('TRIO', 'Gene', '7204', (318, 322))	('TRIO', 'Gene', (57, 61))	('TRIO', 'Gene', '7204', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('worse', 'NegReg', (240, 245))	('tumors', 'Disease', (143, 149))	('DSS', 'CPA', (246, 249))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('ITGA10', 'Gene', '8515', (159, 165))	('ITGA10', 'Gene', (159, 165))	('high', 'Var', (185, 189))	('DSS', 'Chemical', '-', (246, 249))	('distant recurrence-free survival', 'CPA', (254, 286))	('TRIO', 'Gene', (318, 322))	('TRIO', 'Gene', (190, 194))	('TRIO', 'Gene', '7204', (190, 194))
67757	27577794	In lysates of MXF8000 cells exposed to collagen II, antibody against integrin-alpha10, but not control rabbit IgG, precipitated integrin-alpha10 together with TRIO and RICTOR (Fig.	('rabbit', 'Species', '9986', (103, 109))	('antibody', 'Var', (52, 60))	('integrin-alpha10', 'Gene', '8515', (128, 144))	('integrin-alpha10', 'Gene', (69, 85))	('integrin-alpha10', 'Gene', (128, 144))	('integrin-alpha10', 'Gene', '8515', (69, 85))	('TRIO', 'Gene', (159, 163))	('TRIO', 'Gene', '7204', (159, 163))
67761	27577794	TRIO knockdown suppressed cell growth and induced apoptosis in myxofibrosarcoma cells but not ASCs (Fig.	('myxofibrosarcoma cells', 'Disease', (63, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('knockdown', 'Var', (5, 14))	('cell growth', 'CPA', (26, 37))	('TRIO', 'Gene', (0, 4))	('TRIO', 'Gene', '7204', (0, 4))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (63, 85))	('induced', 'Reg', (42, 49))	('suppressed', 'NegReg', (15, 25))	('apoptosis', 'CPA', (50, 59))
67762	27577794	TRIO knockdown also decreased phospho-PAK levels strongly in myxofibrosarcoma cells but only modestly in ASCs (Fig.	('phospho-PAK levels', 'MPA', (30, 48))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (61, 83))	('decreased', 'NegReg', (20, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('knockdown', 'Var', (5, 14))	('TRIO', 'Gene', (0, 4))	('myxofibrosarcoma cells', 'Disease', (61, 83))	('TRIO', 'Gene', '7204', (0, 4))
67766	27577794	RAC1 knockdown induced robust growth suppression (Fig.	('knockdown', 'Var', (5, 14))	('RAC1', 'Gene', (0, 4))	('growth suppression', 'CPA', (30, 48))	('RAC1', 'Gene', '5879', (0, 4))
67768	27577794	In contrast, in normal ASCs RAC1 knockdown induced modest growth suppression but not apoptosis (Supplementary Fig.	('growth', 'MPA', (58, 64))	('knockdown', 'Var', (33, 42))	('RAC1', 'Gene', '5879', (28, 32))	('RAC1', 'Gene', (28, 32))
67771	27577794	Notably, upon knockdown of TRIO, the phosphorylation of AKT at S473 and T308 was inhibited in both of the myxofibrosarcoma cell lines but not in ASCs, while the phosphorylation of ERK was not inhibited in any of the cell types (Fig.	('AKT', 'Gene', '207', (56, 59))	('ERK', 'Gene', '2048', (180, 183))	('phosphorylation', 'MPA', (37, 52))	('T308', 'Var', (72, 76))	('ERK', 'Gene', (180, 183))	('at S473', 'Var', (60, 67))	('inhibited', 'NegReg', (81, 90))	('AKT', 'Gene', (56, 59))	('myxofibrosarcoma cell lines', 'Disease', (106, 133))	('TRIO', 'Gene', (27, 31))	('TRIO', 'Gene', '7204', (27, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('knockdown', 'Var', (14, 23))	('myxofibrosarcoma cell lines', 'Disease', 'MESH:C538614', (106, 133))	('T308', 'Chemical', '-', (72, 76))
67772	27577794	RAC1 knockdown in myxofibrosarcoma cells similarly inhibited phosphorylation of AKT, as well as inhibiting the phosphorylation of two mTORC1 targets: S6 and 4EBP (Supplementary Fig.	('phosphorylation', 'MPA', (61, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('AKT', 'Gene', '207', (80, 83))	('RAC1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('mTORC1', 'Gene', (134, 140))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (18, 40))	('AKT', 'Gene', (80, 83))	('inhibiting', 'NegReg', (96, 106))	('RAC1', 'Gene', '5879', (0, 4))	('myxofibrosarcoma cells', 'Disease', (18, 40))	('inhibited', 'NegReg', (51, 60))	('phosphorylation', 'MPA', (111, 126))	('mTORC1', 'Gene', '382056', (134, 140))
67775	27577794	RICTOR knockdown induced substantial growth suppression and apoptosis in myxofibrosarcoma cell lines, but not in ASCs (Fig.	('RICTOR', 'Gene', (0, 6))	('myxofibrosarcoma cell lines', 'Disease', 'MESH:C538614', (73, 100))	('apoptosis', 'CPA', (60, 69))	('growth suppression', 'CPA', (37, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('myxofibrosarcoma cell lines', 'Disease', (73, 100))	('knockdown', 'Var', (7, 16))
67777	27577794	RICTOR knockdown in myxofibrosarcoma cell lines reduced phosphorylation of AKT at S473 (Fig.	('AKT', 'Gene', '207', (75, 78))	('myxofibrosarcoma cell lines', 'Disease', (20, 47))	('reduced', 'NegReg', (48, 55))	('AKT', 'Gene', (75, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('myxofibrosarcoma cell lines', 'Disease', 'MESH:C538614', (20, 47))	('phosphorylation', 'MPA', (56, 71))	('RICTOR', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))
67778	27577794	RICTOR knockdown also reduced phosphorylation of mTORC1 targets S6 and 4EBP, indicating that RICTOR/mTORC2 controls mTORC1 activity in myxofibrosarcoma cells.	('activity', 'MPA', (123, 131))	('phosphorylation', 'MPA', (30, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (135, 157))	('myxofibrosarcoma cells', 'Disease', (135, 157))	('mTORC1', 'Gene', '382056', (116, 122))	('mTORC1', 'Gene', (116, 122))	('mTORC1', 'Gene', '382056', (49, 55))	('reduced', 'NegReg', (22, 29))	('mTORC2', 'Gene', '74343', (100, 106))	('mTORC2', 'Gene', (100, 106))	('RICTOR', 'Gene', (0, 6))	('mTORC1', 'Gene', (49, 55))	('knockdown', 'Var', (7, 16))
67779	27577794	In addition, RICTOR knockdown in myxofibrosarcoma cells downregulated phospho-T308 AKT, which is not a direct phosphorylation target of mTORC2, suggesting that RICTOR may regulate AKT partly through an mTOR-independent mechanism.	('AKT', 'Gene', '207', (83, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('myxofibrosarcoma cells', 'Disease', (33, 55))	('regulate', 'Reg', (171, 179))	('AKT', 'Gene', (83, 86))	('mTORC2', 'Gene', (136, 142))	('T308', 'Chemical', '-', (78, 82))	('phospho-T308', 'MPA', (70, 82))	('AKT', 'Gene', (180, 183))	('RICTOR', 'Gene', (13, 19))	('downregulated', 'NegReg', (56, 69))	('mTORC2', 'Gene', '74343', (136, 142))	('knockdown', 'Var', (20, 29))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (33, 55))	('AKT', 'Gene', '207', (180, 183))
67780	27577794	Interestingly, although the extent of RICTOR knockdown was similar in normal ASCs and myxofibrosarcoma cells, knockdown in ASCs had little effect on phospho-S473 and phospho-T308 AKT, suggesting that RICTOR has no major role in AKT phosphorylation in normal mesenchymal stem cells.	('knockdown', 'Var', (110, 119))	('AKT', 'Gene', (179, 182))	('AKT', 'Gene', '207', (228, 231))	('phospho-S473', 'MPA', (149, 161))	('AKT', 'Gene', (228, 231))	('T308', 'Chemical', '-', (174, 178))	('AKT', 'Gene', '207', (179, 182))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (86, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('myxofibrosarcoma cells', 'Disease', (86, 108))	('phospho-T308', 'Var', (166, 178))
67781	27577794	Furthermore, RICTOR knockdown in myxofibrosarcoma cells inhibited phosphorylation of PAK, which suggests tumor-specific cross-talk between the pathways under integrin-alpha10 is bi-directional.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('myxofibrosarcoma cells', 'Disease', (33, 55))	('integrin-alpha10', 'Gene', '8515', (158, 174))	('integrin-alpha10', 'Gene', (158, 174))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('phosphorylation', 'MPA', (66, 81))	('RICTOR', 'Gene', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('PAK', 'Protein', (85, 88))	('knockdown', 'Var', (20, 29))	('inhibited', 'NegReg', (56, 65))	('tumor', 'Disease', (105, 110))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (33, 55))
67782	27577794	To further test requirement for mTOR complexes, we knocked down SIN1, another essential component of mTORC2, and RAPTOR, an essential mTORC1 component.	('mTORC2', 'Gene', (101, 107))	('SIN1', 'Gene', '79109', (64, 68))	('mTORC2', 'Gene', '74343', (101, 107))	('mTORC1', 'Gene', (134, 140))	('knocked', 'Var', (51, 58))	('RAPTOR', 'Gene', (113, 119))	('mTORC1', 'Gene', '382056', (134, 140))	('RAPTOR', 'Gene', '57521', (113, 119))	('SIN1', 'Gene', (64, 68))
67784	27577794	In contrast, RAPTOR knockdown, did not cause cell death in myxofibrosarcoma cells (Supplementary Fig.	('death in myxofibrosarcoma', 'Disease', 'MESH:D003643', (50, 75))	('RAPTOR', 'Gene', '57521', (13, 19))	('death in myxofibrosarcoma', 'Disease', (50, 75))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (59, 81))	('knockdown', 'Var', (20, 29))	('RAPTOR', 'Gene', (13, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('myxofibrosarcoma cells', 'Disease', (59, 81))
67787	27577794	To do this, we tested for rescue of integrin-alpha10 knockdown by constitutively active mutants of RAC1 (RAC1-L61), PAK (PAK1-T423E), and AKT (Myr-AKT).	('RAC1', 'Gene', (105, 109))	('T423E', 'Mutation', 'p.T423E', (126, 131))	('RAC1-L61', 'Gene', '5879', (105, 113))	('RAC1', 'Gene', (99, 103))	('PAK1', 'Gene', (121, 125))	('RAC1', 'Gene', '5879', (105, 109))	('tested', 'Reg', (15, 21))	('integrin-alpha10', 'Gene', '8515', (36, 52))	('RAC1', 'Gene', '5879', (99, 103))	('PAK1', 'Gene', '5058', (121, 125))	('AKT', 'Gene', (147, 150))	('RAC1-L61', 'Gene', (105, 113))	('AKT', 'Gene', (138, 141))	('mutants', 'Var', (88, 95))	('Myr-AKT', 'Gene', '207', (143, 150))	('integrin-alpha10', 'Gene', (36, 52))	('knockdown', 'MPA', (53, 62))	('Myr-AKT', 'Gene', (143, 150))	('AKT', 'Gene', '207', (147, 150))	('AKT', 'Gene', '207', (138, 141))
67795	27577794	NSC27366 and EHop-016 each robustly suppressed growth of MXF8000 cells (Fig.	('suppressed', 'NegReg', (36, 46))	('EHop-016', 'Chemical', '-', (13, 21))	('growth', 'MPA', (47, 53))	('NSC27366', 'Var', (0, 8))	('EHop-016', 'Gene', (13, 21))
67797	27577794	Detection of annexin-V-positive cells and cleaved caspase-3 (Fig.	('annexin-V', 'Gene', '308', (13, 22))	('caspase-3', 'Protein', (50, 59))	('cleaved', 'Var', (42, 49))	('annexin-V', 'Gene', (13, 22))
67798	27577794	In ASCs, treatment with either NSC23766 or EHop-016 exhibited cytostatic effects (Supplementary Fig.	('NSC23766', 'Var', (31, 39))	('EHop-016', 'Chemical', '-', (43, 51))	('EHop-016', 'Gene', (43, 51))	('cytostatic effects', 'CPA', (62, 80))
67799	27577794	This growth inhibition may be explained by fact that NSC23766 and EHop-016 inhibit RAC2 and RAC3 as well as RAC1.	('EHop-016', 'Gene', (66, 74))	('growth', 'MPA', (5, 11))	('RAC1', 'Gene', (108, 112))	('RAC3', 'Gene', (92, 96))	('RAC2', 'Gene', '5880', (83, 87))	('inhibit', 'NegReg', (75, 82))	('RAC2', 'Gene', (83, 87))	('NSC23766', 'Var', (53, 61))	('RAC3', 'Gene', '5881', (92, 96))	('EHop-016', 'Chemical', '-', (66, 74))	('RAC1', 'Gene', '5879', (108, 112))
67802	27577794	To inhibit mTORC2, we used a selective mTOR kinase inhibitor, INK128 (MLN0128).	('MLN0128', 'Var', (70, 77))	('MLN0128', 'Chemical', 'MESH:C572449', (70, 77))	('inhibit', 'NegReg', (3, 10))	('mTORC2', 'Gene', (11, 17))	('INK128', 'Chemical', 'MESH:C572449', (62, 68))	('mTORC2', 'Gene', '74343', (11, 17))
67803	27577794	The treatment of myxofibrosarcoma cells with INK128 for 48 or 96 hours caused dose-dependent growth suppression and induced complete growth arrest by 7 days of treatment (Fig.	('growth arrest', 'Disease', (133, 146))	('growth arrest', 'Disease', 'MESH:D006323', (133, 146))	('INK128', 'Var', (45, 51))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (17, 39))	('growth arrest', 'Phenotype', 'HP:0001510', (133, 146))	('growth suppression', 'CPA', (93, 111))	('myxofibrosarcoma cells', 'Disease', (17, 39))	('INK128', 'Chemical', 'MESH:C572449', (45, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))
67806	27577794	The fact that RICTOR knockdown affects apoptosis whereas mTOR kinase inhibition does not suggests that RICTOR has an mTOR kinase-independent role in myxofibrosarcoma cell survival.	('RICTOR', 'Gene', (14, 20))	('apoptosis', 'CPA', (39, 48))	('myxofibrosarcoma', 'Disease', (149, 165))	('affects', 'Reg', (31, 38))	('myxofibrosarcoma', 'Disease', 'None', (149, 165))	('knockdown', 'Var', (21, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
67808	27577794	We confirmed that INK128 reduced phosphorylation of AKT at S473 to a similar extent as we observed with RICTOR knockdown (Supplementary Fig.	('phosphorylation', 'MPA', (33, 48))	('reduced', 'NegReg', (25, 32))	('AKT', 'Gene', (52, 55))	('INK128', 'Var', (18, 24))	('INK128', 'Chemical', 'MESH:C572449', (18, 24))	('AKT', 'Gene', '207', (52, 55))
67809	27577794	As expected, INK128 also caused complete inhibition of mTORC1 kinase activity, as detected by phospho-S6 and phospho-4EBP.	('INK128', 'Var', (13, 19))	('mTORC1', 'Gene', '382056', (55, 61))	('INK128', 'Chemical', 'MESH:C572449', (13, 19))	('inhibition', 'NegReg', (41, 51))	('mTORC1', 'Gene', (55, 61))
67812	27577794	Because integrin-alpha10 exerts its tumor-specific growth signal through both RAC and mTORC2, we hypothesized that inhibitors of RAC and mTORC2 may have cooperative effects in myxofibrosarcoma cells.	('RAC', 'Gene', '207', (129, 132))	('integrin-alpha10', 'Gene', '8515', (8, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('myxofibrosarcoma cells', 'Disease', (176, 198))	('RAC', 'Gene', (78, 81))	('mTORC2', 'Gene', (137, 143))	('RAC', 'Gene', (129, 132))	('exerts', 'MPA', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mTORC2', 'Gene', '74343', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (176, 198))	('integrin-alpha10', 'Gene', (8, 24))	('mTORC2', 'Gene', (86, 92))	('RAC', 'Gene', '207', (78, 81))	('inhibitors', 'Var', (115, 125))	('tumor', 'Disease', (36, 41))	('mTORC2', 'Gene', '74343', (86, 92))
67823	27577794	Either EHop-016 or INK128 alone significantly suppressed the lung metastasis over the time of the treatment, and again the combination of EHop-016 and INK128 more substantially inhibited the metastatic tumor growth compared to either drug administered alone (Fig.	('inhibited', 'NegReg', (177, 186))	('combination', 'Var', (123, 134))	('INK128', 'Chemical', 'MESH:C572449', (19, 25))	('tumor', 'Disease', (202, 207))	('lung metastasis', 'Disease', (61, 76))	('lung metastasis', 'Disease', 'MESH:D009362', (61, 76))	('EHop-016', 'Chemical', '-', (7, 15))	('EHop-016', 'Var', (138, 146))	('EHop-016', 'Chemical', '-', (138, 146))	('INK128', 'Var', (151, 157))	('INK128', 'Chemical', 'MESH:C572449', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('suppressed', 'NegReg', (46, 56))
67829	27577794	The exquisite dependency of myxofibrosarcoma cells but not normal mesenchymal cells on integrin-alpha10/TRIO/RICTOR signaling circuitry represents a tumor-specific vulnerability and a promising therapeutic target, since inhibiting this circuitry can interfere with myxofibrosarcoma tumor growth and survival with minimum toxicity to normal tissues.	('mum', 'Gene', (317, 320))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (282, 287))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (28, 50))	('myxofibrosarcoma cells', 'Disease', (28, 50))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('TRIO', 'Gene', (104, 108))	('survival', 'CPA', (299, 307))	('integrin-alpha10', 'Gene', (87, 103))	('toxicity', 'Disease', 'MESH:D064420', (321, 329))	('mum', 'Gene', '56925', (317, 320))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('inhibiting', 'Var', (220, 230))	('interfere', 'NegReg', (250, 259))	('TRIO', 'Gene', '7204', (104, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('myxofibrosarcoma tumor', 'Disease', (265, 287))	('toxicity', 'Disease', (321, 329))	('myxofibrosarcoma tumor', 'Disease', 'MESH:D009369', (265, 287))	('tumor', 'Disease', (149, 154))	('integrin-alpha10', 'Gene', '8515', (87, 103))
67841	27577794	Finally, constitutively active RAC, PAK, and AKT rescue the growth inhibition and apoptosis caused by integrin-alpha10 knockdown, demonstrating that much of integrin-alpha10's pro-growth and pro-survival functions are carried out through these proteins.	('AKT', 'Gene', '207', (45, 48))	('apoptosis', 'CPA', (82, 91))	('integrin-alpha10', 'Gene', (157, 173))	('AKT', 'Gene', (45, 48))	('integrin-alpha10', 'Gene', (102, 118))	('growth inhibition', 'CPA', (60, 77))	('RAC', 'Gene', '207', (31, 34))	('integrin-alpha10', 'Gene', '8515', (157, 173))	('knockdown', 'Var', (119, 128))	('integrin-alpha10', 'Gene', '8515', (102, 118))	('RAC', 'Gene', (31, 34))
67851	27577794	This is consistent with the fact that Itga10 knockout chondrocytes adhere to collagen II to the same extent as wild-type cells.	('Itga10', 'Gene', (38, 44))	('Itga10', 'Gene', '8515', (38, 44))	('knockout', 'Var', (45, 53))	('adhere', 'CPA', (67, 73))
67860	27577794	In our study, blocking TRIO's ability to activate RAC with NSC23766 or EHop-016 resulted in prominent growth inhibition and cytotoxicity in myxofibrosarcoma cells.	('EHop-016', 'Chemical', '-', (71, 79))	('NSC23766', 'Var', (59, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (124, 136))	('TRIO', 'Gene', (23, 27))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (140, 162))	('TRIO', 'Gene', '7204', (23, 27))	('growth inhibition', 'CPA', (102, 119))	('RAC', 'Gene', (50, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('myxofibrosarcoma cells', 'Disease', (140, 162))	('EHop-016', 'Gene', (71, 79))	('cytotoxicity', 'Disease', (124, 136))	('RAC', 'Gene', '207', (50, 53))
67869	27577794	In both prostate and breast cancer cells, RICTOR's tumor-specific function is associated with its regulation of AKT phosphorylation at T308 as well as S473, both of which are required for mTORC1 activity in transformed cells.	('T308', 'Chemical', '-', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mTORC1', 'Gene', '382056', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('tumor', 'Disease', (51, 56))	('breast cancer', 'Disease', (21, 34))	('AKT', 'Gene', '207', (112, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('RICTOR', 'Gene', (42, 48))	('mTORC1', 'Gene', (188, 194))	('AKT', 'Gene', (112, 115))	('S473', 'Var', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
67870	27577794	Similarly, in myxofibrosarcoma cells, we demonstrated that RICTOR is required for AKT phosphorylation at T308 and S473 as well as for mTORC1 activity.	('mTORC1', 'Gene', '382056', (134, 140))	('T308', 'Chemical', '-', (105, 109))	('mTORC1', 'Gene', (134, 140))	('S473', 'Var', (114, 118))	('myxofibrosarcoma cells', 'Disease', 'MESH:C538614', (14, 36))	('AKT', 'Gene', '207', (82, 85))	('myxofibrosarcoma cells', 'Disease', (14, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('AKT', 'Gene', (82, 85))
67871	27577794	However, RICTOR knockdown also induced apoptosis, whereas inhibiting mTORC1 and mTORC2 with INK128 did not, suggesting that RICTOR has a pro-survival function independent of its phosphorylation of AKT.	('mTORC2', 'Gene', '74343', (80, 86))	('RICTOR', 'Gene', (9, 15))	('RICTOR', 'Gene', (124, 130))	('apoptosis', 'CPA', (39, 48))	('pro-survival function', 'CPA', (137, 158))	('AKT', 'Gene', '207', (197, 200))	('INK128', 'Chemical', 'MESH:C572449', (92, 98))	('mTORC1', 'Gene', '382056', (69, 75))	('knockdown', 'Var', (16, 25))	('AKT', 'Gene', (197, 200))	('induced', 'Reg', (31, 38))	('mTORC2', 'Gene', (80, 86))	('mTORC1', 'Gene', (69, 75))
67872	27577794	This function might be through the regulation of RAC/PAK, because RICTOR knockdown, but not INK128, suppresses phospho-PAK.	('phospho-PAK', 'MPA', (111, 122))	('RICTOR', 'Gene', (66, 72))	('INK128', 'Chemical', 'MESH:C572449', (92, 98))	('RAC', 'Gene', '207', (49, 52))	('suppresses', 'NegReg', (100, 110))	('knockdown', 'Var', (73, 82))	('RAC', 'Gene', (49, 52))
67875	27577794	Similarly, we observed that TRIO or RAC1 knockdown significantly affects the activation of AKT in myxofibrosarcoma, though not in normal mesenchymal stem cells.	('myxofibrosarcoma', 'Disease', (98, 114))	('RAC1', 'Gene', '5879', (36, 40))	('myxofibrosarcoma', 'Disease', 'None', (98, 114))	('AKT', 'Gene', '207', (91, 94))	('RAC1', 'Gene', (36, 40))	('TRIO', 'Gene', (28, 32))	('TRIO', 'Gene', '7204', (28, 32))	('AKT', 'Gene', (91, 94))	('affects', 'Reg', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('knockdown', 'Var', (41, 50))	('activation', 'MPA', (77, 87))
67877	27577794	Although INK128 alone does not induce apoptosis in myxofibrosarcoma in vitro, it increases EHop-016-induced growth inhibition and potentiates the cytotoxicity of low-dose EHop-016.	('EHop-016', 'Chemical', '-', (171, 179))	('EHop-016-induced', 'Gene', (91, 107))	('myxofibrosarcoma', 'Disease', (51, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (146, 158))	('potentiates', 'PosReg', (130, 141))	('myxofibrosarcoma', 'Disease', 'None', (51, 67))	('INK128', 'Chemical', 'MESH:C572449', (9, 15))	('EHop-016', 'Chemical', '-', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('cytotoxicity', 'Disease', (146, 158))	('growth inhibition', 'CPA', (108, 125))	('INK128', 'Var', (9, 15))	('increases', 'PosReg', (81, 90))
67880	27577794	Indeed, INK128 has demonstrated anti-tumor effects against various sarcoma models, including rhabdomyosarcoma and Ewing sarcoma xenografts and liposarcoma cell lines.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (93, 109))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('liposarcoma', 'Disease', 'MESH:D008080', (143, 154))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('sarcoma', 'Disease', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('sarcoma', 'Disease', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('INK128', 'Chemical', 'MESH:C572449', (8, 14))	('liposarcoma', 'Disease', (143, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('INK128', 'Var', (8, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('Ewing sarcoma xenografts', 'Disease', 'MESH:C563168', (114, 138))	('rhabdomyosarcoma', 'Disease', (93, 109))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('tumor', 'Disease', (37, 42))	('liposarcoma', 'Phenotype', 'HP:0012034', (143, 154))	('Ewing sarcoma xenografts', 'Disease', (114, 138))	('sarcoma', 'Disease', (120, 127))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (93, 109))
67882	27577794	Our data suggest that patients with myxofibrosarcomas at high risk for metastasis could benefit from INK128.	('INK128', 'Chemical', 'MESH:C572449', (101, 107))	('INK128', 'Var', (101, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('patients', 'Species', '9606', (22, 30))	('myxofibrosarcomas', 'Disease', 'None', (36, 53))	('myxofibrosarcomas', 'Disease', (36, 53))
67883	27577794	Importantly, the anti-tumor effects on both primary tumor and lung metastases were greatest with the combination of EHop-016 and INK128, supporting our hypothesis that integrin-alpha10-mediated TRIO/RAC signaling and RICTOR signaling represent promising therapeutic targets.	('integrin-alpha10', 'Gene', '8515', (168, 184))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('combination', 'Var', (101, 112))	('RAC', 'Gene', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TRIO', 'Gene', (194, 198))	('EHop-016', 'Chemical', '-', (116, 124))	('RAC', 'Gene', '207', (199, 202))	('INK128', 'Chemical', 'MESH:C572449', (129, 135))	('integrin-alpha10', 'Gene', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TRIO', 'Gene', '7204', (194, 198))	('INK128', 'Var', (129, 135))	('lung metastases', 'Disease', 'MESH:D009362', (62, 77))	('EHop-016', 'Var', (116, 124))	('tumor', 'Disease', (22, 27))	('lung metastases', 'Disease', (62, 77))
67884	27577794	These results have led to the inclusion of MYXF/PMFH patients in an ALLIANCE-sponsored phase I/II study of INK128 (MLN0128) vs. pazopanib in patients with advanced sarcoma.	('PMFH', 'Disease', 'None', (48, 52))	('patients', 'Species', '9606', (53, 61))	('MLN0128', 'Var', (115, 122))	('PMFH', 'Disease', (48, 52))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('INK128', 'Chemical', 'MESH:C572449', (107, 113))	('pazopanib', 'Chemical', 'MESH:C516667', (128, 137))	('MLN0128', 'Chemical', 'MESH:C572449', (115, 122))	('sarcoma', 'Disease', (164, 171))	('patients', 'Species', '9606', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
67909	27577794	Array CGH was performed on all primary cell lines and compared to array CGH performed on the human tumor tissue from which they were derived so as to verify that the copy number alterations in the cell lines were representative of those found in the original tumor samples.	('tumor', 'Disease', (99, 104))	('copy number', 'Var', (166, 177))	('original tumor', 'Disease', 'MESH:D009369', (250, 264))	('human', 'Species', '9606', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('original tumor', 'Disease', (250, 264))
67915	27577794	The clones used were as follows: ITGA10 (TRCN0000057725, TRCN0000057726), ITGA1 (TRCN0000057748, TRCN0000057749), ITGA2 (TRCN0000057731, TRCN0000308081), TRIO (TRCN0000010561, GIPZ, V2LHS_1430), RAC1 (TRCN0000318430, TRCN0000318375, TRCN0000004870), RICTOR (TRCN0000074288, TRCN0000074289, TRCN0000074290), SIN1 (TRCN0000003152, TRCN0000003153), RAPTOR (TRCN0000039770, TRCN0000039772).	('ITGA10', 'Gene', '8515', (33, 39))	('RAC1', 'Gene', '5879', (195, 199))	('ITGA1', 'Gene', '3672', (74, 79))	('TRCN0000039770', 'Var', (354, 368))	('ITGA2', 'Gene', '3673', (114, 119))	('ITGA10', 'Gene', (33, 39))	('TRCN0000318430', 'Var', (201, 215))	('TRCN0000004870', 'Var', (233, 247))	('TRIO', 'Gene', (154, 158))	('TRCN0000074288, TRCN0000074289, TRCN0000074290), SIN1 (TRCN0000003152, TRCN0000003153', 'Disease', 'None', (258, 343))	('ITGA1', 'Gene', '3672', (33, 38))	('ITGA2', 'Gene', (114, 119))	('TRIO', 'Gene', '7204', (154, 158))	('TRCN0000057748, TRCN0000057749', 'Disease', 'None', (81, 111))	('RAPTOR', 'Gene', '57521', (346, 352))	('ITGA1', 'Gene', (74, 79))	('TRCN0000010561', 'Var', (160, 174))	('TRCN0000057731', 'Var', (121, 135))	('RAPTOR', 'Gene', (346, 352))	('ITGA1', 'Gene', (33, 38))	('RAC1', 'Gene', (195, 199))
67942	27577794	We found that integrin-alpha10 promotes tumor cell survival through activation of TRIO-RAC-RICTOR-mTOR signaling, and that inhibitors of RAC and mTOR have anti-tumor effects in vivo, thus identifying a potential treatment strategy for patients with high-risk myxofibrosarcoma.	('RAC', 'Gene', '207', (137, 140))	('activation', 'PosReg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('integrin-alpha10', 'Gene', '8515', (14, 30))	('RAC', 'Gene', (87, 90))	('TRIO', 'Gene', (82, 86))	('patients', 'Species', '9606', (235, 243))	('RAC', 'Gene', '207', (87, 90))	('myxofibrosarcoma', 'Disease', 'None', (259, 275))	('TRIO', 'Gene', '7204', (82, 86))	('integrin-alpha10', 'Gene', (14, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (160, 165))	('promotes', 'PosReg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('inhibitors', 'Var', (123, 133))	('RAC', 'Gene', (137, 140))	('myxofibrosarcoma', 'Disease', (259, 275))
67953	25446280	Despite encouraging preclinical data, the combination of cixutumumab and temsirolimus did not result in objective responses in this phase II trial of pediatric and young adults with recurrent or refractory sarcoma.	('cixutumumab', 'Var', (57, 68))	('sarcoma', 'Disease', (206, 213))	('temsirolimus', 'Chemical', 'MESH:C401859', (73, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('cixutumumab', 'Chemical', 'MESH:C557414', (57, 68))	('sarcoma', 'Disease', 'MESH:D012509', (206, 213))
67957	25446280	This upstream activation is mediated in part through the insulin-like growth factor-1 receptor (IGF-1R), and antibody blockade of IGF-1R can abrogate this escape pathway and synergize with mTOR inhibitors in preclinical models of pediatric sarcomas.	('activation', 'PosReg', (14, 24))	('pediatric sarcomas', 'Disease', (230, 248))	('abrogate', 'NegReg', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (57, 94))	('IGF-1R', 'Gene', (130, 136))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (230, 248))	('antibody blockade', 'Var', (109, 126))	('IGF-1R', 'Gene', (96, 102))	('insulin-like growth factor-1 receptor', 'Gene', (57, 94))	('escape pathway', 'Pathway', (155, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (240, 248))
67958	25446280	In fact, maintained complete responses have been observed in murine models of osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma when combining non-curative doses of an anti-IGF-1R antibody with an mTOR inhibitor.	('anti-IGF-1R', 'Gene', (168, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (111, 127))	('osteosarcoma', 'Disease', 'MESH:D012516', (78, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('murine', 'Species', '10090', (61, 67))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (111, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('osteosarcoma', 'Phenotype', 'HP:0002669', (78, 90))	('anti-IGF-1R', 'Var', (168, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('osteosarcoma', 'Disease', (78, 90))	('rhabdomyosarcoma', 'Disease', (111, 127))	('Ewing sarcoma', 'Disease', (92, 105))
68025	25446280	Moderate or strong protein expression of IGF-1R, p-AKT, and p-mTOR was seen in 53%, 81%, and 23% of all tumors, respectively.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('AKT', 'Gene', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('protein expression', 'MPA', (19, 37))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('p-mTOR', 'Var', (60, 66))	('IGF-1R', 'Gene', (41, 47))	('AKT', 'Gene', '207', (51, 54))
68046	25446280	It may be that the optimum use of these agents will be in combination with conventional cytotoxic drugs, since both cixutumumab and temsirolimus may affect chemotherapy-induced apoptosis and be synergistic with commonly used chemotherapy drugs such as cyclophosphamide and doxorubicin.	('cixutumumab', 'Var', (116, 127))	('affect', 'Reg', (149, 155))	('doxorubicin', 'Chemical', 'MESH:D004317', (273, 284))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (252, 268))	('temsirolimus', 'Chemical', 'MESH:C401859', (132, 144))	('cixutumumab', 'Chemical', 'MESH:C557414', (116, 127))	('chemotherapy-induced apoptosis', 'CPA', (156, 186))
68157	20525755	ES cohort, EDCL and normal tissue (NT) CEL file data (accession numbers E-MEXP-353, E-MEXP-1142, GSE7007, GSE12102, GSE14543, GSE7007, GSE1133) were extracted from GEO or ArrayExpress.	('GSE7007', 'Var', (97, 104))	('GSE1133', 'Chemical', '-', (135, 142))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('GSE12102', 'Var', (106, 114))	('GSE7007', 'Chemical', '-', (97, 104))	('EDCL', 'Chemical', '-', (11, 15))	('E-MEXP', 'Chemical', '-', (72, 78))	('L', 'Chemical', '-', (14, 15))	('L', 'Chemical', '-', (41, 42))	('E-MEXP', 'Chemical', '-', (84, 90))	('GSE7007', 'Chemical', '-', (126, 133))	('GSE7007', 'Var', (126, 133))	('GSE14543', 'Var', (116, 124))
68168	20525755	qRT-PCR was performed using validated proprietary TaqMan Gene Expression Assays (Applied Biosystems) for CXCR4 (Hs00607978_s1), CXCR7 (Hs00664172_s1), GAPDH (Hs99999905_m1) and ACTB (Hs99999903_m1) on an Applied Biosystems 7900HT system.	('Hs99999903_m1', 'Var', (183, 196))	('CXCR4', 'Gene', '7852', (105, 110))	('CXCR7', 'Gene', (128, 133))	('ACTB', 'Gene', '60', (177, 181))	('ACTB', 'Gene', (177, 181))	('CXCR4', 'Gene', (105, 110))	('Hs99999905_m1', 'Var', (158, 171))	('CXCR7', 'Gene', '57007', (128, 133))	('Hs00664172_s1', 'Var', (135, 148))	('Hs00607978_s1', 'Var', (112, 125))
68205	20525755	These rates were diminished for patients with either high CXCR4 (OS = 54.5%) or CXCR7 (OS = 45.4%) tumor content, and were drastically reduced for patients with high-expressing CXCR4 and CXCR7 tumors (OS = 28.6%; Log-rank test, p = 0.0161; hazard ratio 8.0).	('CXCR7', 'Gene', (187, 192))	('tumor', 'Disease', (99, 104))	('CXCR7 tumors', 'Disease', 'MESH:D009369', (187, 199))	('diminished', 'NegReg', (17, 27))	('CXCR7', 'Gene', '57007', (187, 192))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (193, 198))	('high', 'Var', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('CXCR4', 'Gene', '7852', (58, 63))	('reduced', 'NegReg', (135, 142))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CXCR4', 'Gene', (58, 63))	('CXCR7', 'Gene', (80, 85))	('CXCR7 tumors', 'Disease', (187, 199))	('CXCR4', 'Gene', '7852', (177, 182))	('patients', 'Species', '9606', (32, 40))	('L', 'Chemical', '-', (213, 214))	('CXCR4', 'Gene', (177, 182))	('CXCR7', 'Gene', '57007', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
68206	20525755	Analysis of event-free survival (EFS) rates suggested a trend wherein high CXCR4 and CXCR7 expression might negatively impacted EFS (median EFS in high CXCR4/CXCR7 = 1.5 years versus 5.4 years for patients with low CXCR4/CXCR7; Hazard ratio = 0.34; 95% CI 0.11-1.0), but this correlation did not reach statistical significance (p = 0.0586), presumably owing to the small sample size analyzed.	('CXCR4', 'Gene', (152, 157))	('CXCR7', 'Gene', '57007', (158, 163))	('CXCR4', 'Gene', '7852', (75, 80))	('CXCR4', 'Gene', '7852', (215, 220))	('patients', 'Species', '9606', (197, 205))	('CXCR7', 'Gene', '57007', (85, 90))	('negatively', 'NegReg', (108, 118))	('CXCR4', 'Gene', (215, 220))	('CXCR7', 'Gene', '57007', (221, 226))	('CXCR7', 'Gene', (85, 90))	('CXCR7', 'Gene', (158, 163))	('CXCR4', 'Gene', (75, 80))	('CXCR4', 'Gene', '7852', (152, 157))	('high', 'Var', (70, 74))	('CXCR7', 'Gene', (221, 226))	('EFS', 'MPA', (128, 131))	('impacted', 'Reg', (119, 127))
68344	34045862	With the increased use of virtual MDTs, there has been an increase in MDT functionality that allows for improved patient care.	('patient', 'Species', '9606', (113, 120))	('virtual', 'Var', (26, 33))	('increase', 'PosReg', (58, 66))	('improved', 'PosReg', (104, 112))	('MDT', 'Chemical', '-', (34, 37))	('MDT', 'Chemical', '-', (70, 73))	('MDT functionality', 'MPA', (70, 87))
68430	32542629	K i -67 (MIB1) is a nuclear proliferation marker correlated with mitotic count, cellularity, and histological grade,  expressed at all phases of the cell cycle except the resting G0 stage.	('MIB1', 'Gene', '57534', (9, 13))	('K i -67', 'Var', (0, 7))	('MIB1', 'Gene', (9, 13))
68518	31205436	Immunophenotypically, the tumor cells revealed positivity for vimentin, CD68, caldesmon (focal), and AE1/AE3 (focal).	('CD68', 'Gene', (72, 76))	('vimentin', 'Gene', (62, 70))	('AE3', 'Gene', '6508', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('CD68', 'Gene', '968', (72, 76))	('AE3', 'Gene', (105, 108))	('AE1', 'Gene', '6521', (101, 104))	('AE1', 'Gene', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('vimentin', 'Gene', '7431', (62, 70))	('positivity', 'Var', (47, 57))	('caldesmon', 'Protein', (78, 87))
68555	31205436	Given the CD21 positivity, a diagnosis of FDCS was made.	('FDCS', 'Disease', (42, 46))	('positivity', 'Var', (15, 25))	('CD21', 'Gene', (10, 14))	('CD21', 'Gene', '1380', (10, 14))
68578	31205436	Go et al probed histiocytic and FDCSs for BRAF V600E mutations.	('BRAF', 'Gene', (42, 46))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('BRAF', 'Gene', '673', (42, 46))	('V600E', 'Var', (47, 52))
68579	31205436	They found that in the 27 cases of FDCS in their study, 5 had the BRAF V600E mutations.	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', (66, 70))	('BRAF', 'Gene', '673', (66, 70))	('V600E', 'Mutation', 'rs113488022', (71, 76))
68711	29623256	Cox models were generated to assess the relationship between gene expression in the primary tumor and overall survival from time of surgery, and the Kaplan-Meier method was used to visualize how outcomes differed between PD-L1 positive and negative patients.	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('patients', 'Species', '9606', (249, 257))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('positive', 'Var', (227, 235))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('PD-L1', 'Gene', (221, 226))
68758	29623256	It is thought that mismatch repair leads to a high tumor mutational burden, and hence greater neoantigen expression that can stimulate the immune system and thus be more affected by anti-PD-1 therapy.	('immune', 'MPA', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('greater', 'PosReg', (86, 93))	('neoantigen expression', 'MPA', (94, 115))	('tumor', 'Disease', (51, 56))	('PD-1', 'Gene', (187, 191))	('PD-1', 'Gene', '5133', (187, 191))	('stimulate', 'PosReg', (125, 134))	('mismatch repair', 'Var', (19, 34))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
68927	31618208	At baseline, individuals infected with S. mansoni (detected by microscopy) were more likely to be KSHV seropositive (aOR = 1.86 (1.16, 2.99) p = 0.012) and had higher anti-K8.1 antibody levels (acoefficient = 0.03 (0.01, 0.06) p = 0.02).	('S. mansoni', 'Var', (39, 49))	('higher', 'PosReg', (160, 166))	('KSHV', 'Gene', (98, 102))	('anti-K8.1 antibody levels', 'MPA', (167, 192))	('S. mansoni', 'Species', '6183', (39, 49))	('KSHV', 'Species', '37296', (98, 102))
68928	31618208	In the final survey, S. mansoni (by microscopy, adjusted Odds Ratio (aOR = 1.43 (1.04-1.95), p = 0.028) and malaria parasitaemia (aOR = 3.49 (1.08-11.28), p = 0.038) were positively associated with KSHV seropositivity.	('S. mansoni', 'Species', '6183', (21, 31))	('associated', 'Interaction', (182, 192))	('KSHV', 'Disease', (198, 202))	('seropositivity', 'Var', (203, 217))	('KSHV', 'Species', '37296', (198, 202))	('malaria parasitaemia', 'Disease', (108, 128))	('malaria parasitaemia', 'Disease', 'MESH:D008288', (108, 128))
68961	31618208	The following thresholds were used for classification of S. mansoni infection intensities: 1-99 eggs per gram of stool as light intensity, 100-399 eggs per gram of stool as moderate intensity and greater than 400 eggs per gram of stool as heavy intensity.	('1-99', 'Var', (91, 95))	('mansoni infection', 'Disease', (60, 77))	('mansoni infection', 'Disease', 'MESH:D012555', (60, 77))	('100-399 eggs', 'Var', (139, 151))	('S. mansoni', 'Species', '6183', (57, 67))
69006	31618208	We have previously reported a high KSHV seroprevalence of >95% in adults in the General Population Cohort in rural southwestern Uganda, and a prevalence of 61% amongst mothers in a peri-urban cohort.	('KSHV', 'Gene', (35, 39))	('seroprevalence', 'Var', (40, 54))	('KSHV', 'Species', '37296', (35, 39))
69026	31618208	However, the association with anti-K8.1 (a lytic antigen) but not anti-ORF73 (a latent antigen) antibodies with S. mansoni infection at baseline may imply specific effects of S. mansoni on KSHV reactivation as opposed to non-specific inflammatory effects.	('association', 'Interaction', (13, 24))	('anti-K8.1', 'Var', (30, 39))	('mansoni infection', 'Disease', 'MESH:D012555', (115, 132))	('ORF73', 'Gene', '4961527', (71, 76))	('KSHV', 'Species', '37296', (189, 193))	('ORF73', 'Gene', (71, 76))	('S. mansoni', 'Species', '6183', (112, 122))	('mansoni infection', 'Disease', (115, 132))	('S. mansoni', 'Species', '6183', (175, 185))
69027	31618208	Furthermore, higher anti-Ag85A (a Mycobacteria tuberculosis antigen unrelated to S. mansoni) IgG4, but not IgG, has been reported in S. mansoni infected individuals compared to S. mansoni uninfected individuals.	('S. mansoni', 'Species', '6183', (81, 91))	('Mycobacteria tuberculosis', 'Disease', 'MESH:D014376', (34, 59))	('S. mansoni', 'Species', '6183', (133, 143))	('Mycobacteria tuberculosis', 'Disease', (34, 59))	('mansoni infected', 'Disease', (136, 152))	('anti-Ag85A', 'Var', (20, 30))	('higher', 'PosReg', (13, 19))	('mansoni infected', 'Disease', 'MESH:D012555', (136, 152))	('S. mansoni', 'Species', '6183', (177, 187))
69044	31618208	Plasmodia have also been shown to cause macrophage and dendritic cell dysfunction.	('dendritic cell dysfunction', 'Disease', (55, 81))	('dendritic cell dysfunction', 'Disease', 'MESH:D054740', (55, 81))	('Plasmodia', 'Var', (0, 9))	('cause', 'Reg', (34, 39))
69049	29629425	As pathognomonic genomic events in these respective tumor types, EWSR1 fusions represent robust potential biomarkers for disease monitoring.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('EWSR1', 'Gene', (65, 70))	('tumor', 'Disease', (52, 57))	('fusions', 'Var', (71, 78))	('EWSR1', 'Gene', '2130', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
69050	29629425	To investigate the feasibility of identifying EWSR1 fusions in plasma derived cell-free DNA (cfDNA) from ES and DSRCT patients, we evaluated two complementary approaches in samples from 17 patients with radiographic evidence of disease.	('EWSR1', 'Gene', (46, 51))	('ES', 'Phenotype', 'HP:0012254', (105, 107))	('EWSR1', 'Gene', '2130', (46, 51))	('patients', 'Species', '9606', (189, 197))	('patients', 'Species', '9606', (118, 126))	('fusions', 'Var', (52, 59))
69053	29629425	EWSR1 fusions were identified in 11/11 (100%) ES and 5/6 (83%) DSRCT samples by ddPCR, while 10/11 (91%) and 4/6 (67%) were identified by NGS.	('EWSR1', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('ES', 'Phenotype', 'HP:0012254', (46, 48))	('EWSR1', 'Gene', '2130', (0, 5))
69054	29629425	However, the hybrid capture-based NGS assay identified the precise fusion breakpoints in the majority of cfDNA samples, as well as mutations in TP53 and STAG2, two other recurrent, clinically significant alterations in ES, all without prior knowledge of the tumor sequencing results.	('TP53', 'Gene', '7157', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('TP53', 'Gene', (144, 148))	('mutations', 'Var', (131, 140))	('cfDNA', 'Disease', (105, 110))	('tumor', 'Disease', (258, 263))	('STAG2', 'Gene', (153, 158))	('STAG2', 'Gene', '10735', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('ES', 'Phenotype', 'HP:0012254', (219, 221))
69056	29629425	Both are characterized by fusions involving the EWSR1 gene on chromosome 22q12.	('EWSR1', 'Gene', (48, 53))	('fusions', 'Var', (26, 33))	('EWSR1', 'Gene', '2130', (48, 53))
69057	29629425	The fusions in ES involve EWSR1 and a member of the ETS family.	('ES', 'Phenotype', 'HP:0012254', (15, 17))	('EWSR1', 'Gene', (26, 31))	('fusions', 'Var', (4, 11))	('EWSR1', 'Gene', '2130', (26, 31))
69064	29629425	More recently, studies in various cancer types have demonstrated the potential utility of identifying and following tumor-specific mutations in cell free DNA (cfDNA) isolated from plasma as a marker for subclinical disease.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Disease', (34, 40))	('tumor', 'Disease', (116, 121))
69065	29629425	A study of various different cancer types by Bettegowda et al demonstrated highly variable levels of mutations in baseline cfDNA in patients with different tumor types, suggesting that the utility of cfDNA as a clinically relevant signal for subclinical disease will be partly based on the cancer type itself.	('cfDNA', 'Gene', (123, 128))	('cancer', 'Disease', (29, 35))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('patients', 'Species', '9606', (132, 140))
69066	29629425	These studies all rely on the ability to identify tumor-specific aberrations as a marker of disease burden.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('aberrations', 'Var', (65, 76))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
69067	29629425	Tumors such as ES and DSRCT have very low mutational burdens as it is believed that the pathognomonic EWSR1 fusions are the primary driving oncogenic lesions in these tumor types, with few recurrent secondary alterations.	('DSRCT', 'Disease', (22, 27))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('EWSR1', 'Gene', '2130', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('EWSR1', 'Gene', (102, 107))	('ES', 'Phenotype', 'HP:0012254', (15, 17))	('tumor', 'Disease', (167, 172))	('fusions', 'Var', (108, 115))
69068	29629425	Therefore, the identification of tumor specific EWSR1 fusions in cfDNA as a marker for active disease is an especially attractive option given that these tumors are defined by these translocations.	('EWSR1', 'Gene', (48, 53))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('fusions', 'Var', (54, 61))	('cfDNA', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('EWSR1', 'Gene', '2130', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
69069	29629425	Moreover, issues such as clonal evolution which can affect the detection of certain mutations in cfDNA in other tumor types are less pertinent as these sarcomas maintain these specific fusions through an individual's disease course.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cfDNA', 'Gene', (97, 102))	('sarcomas', 'Disease', 'MESH:D012509', (152, 160))	('fusions', 'MPA', (185, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('mutations', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('sarcomas', 'Disease', (152, 160))	('tumor', 'Disease', (112, 117))
69070	29629425	Importantly, even identical EWSR1 fusion transcripts are the result of genomic breakpoints in the corresponding introns that are unique to each patient.	('fusion', 'Var', (34, 40))	('result', 'Reg', (61, 67))	('patient', 'Species', '9606', (144, 151))	('EWSR1', 'Gene', '2130', (28, 33))	('EWSR1', 'Gene', (28, 33))
69075	29629425	The second approach utilizes next generation sequencing (NGS) via a modified hybridization capture approach to identify EWSR1 fusions as well as potentially prognostic mutations in cfDNA samples.	('EWSR1', 'Gene', (120, 125))	('EWSR1', 'Gene', '2130', (120, 125))	('fusions', 'Var', (126, 133))
69084	29629425	Gene fusions involving EWSR1 were identified in all cases included in this study using DELLY.	('Gene fusions', 'Var', (0, 12))	('EWSR1', 'Gene', (23, 28))	('EWSR1', 'Gene', '2130', (23, 28))
69094	29629425	Additional aberrations, including previously described recurrent mutations of TP53 and STAG2 were also identified by MSK-IMPACT profiling of biopsy material (Table 3).	('STAG2', 'Gene', '10735', (87, 92))	('STAG2', 'Gene', (87, 92))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('mutations', 'Var', (65, 74))
69097	29629425	We identified tumor-specific fusions as evidence of ctDNA in all 11 baseline plasma samples from ES patients (Table 3).	('tumor', 'Disease', (14, 19))	('fusions', 'Var', (29, 36))	('ES', 'Phenotype', 'HP:0012254', (97, 99))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('ctDNA', 'Disease', (52, 57))
69099	29629425	We also identified EWSR1-WT1 fusions in 5 out of 6 DSRCT baseline plasma samples.	('WT1', 'Gene', '7490', (25, 28))	('fusions', 'Var', (29, 36))	('WT1', 'Gene', (25, 28))	('EWSR1', 'Gene', (19, 24))	('EWSR1', 'Gene', '2130', (19, 24))
69101	29629425	By achieving such deep coverage, we achieved high sensitivity for detecting different EWSR1 fusions in a single universal assay, regardless of the precise location of the genomic breakpoint in EWSR1.	('EWSR1', 'Gene', (86, 91))	('fusions', 'Var', (92, 99))	('EWSR1', 'Gene', (193, 198))	('EWSR1', 'Gene', '2130', (86, 91))	('EWSR1', 'Gene', '2130', (193, 198))
69104	29629425	Prior MSK-IMPACT mutation profiling of tumor tissue had previously revealed 4 mutations in TP53 or STAG2 in these cases, with variant allele fractions ranging from 0.53 to 0.74.	('TP53', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('STAG2', 'Gene', (99, 104))	('TP53', 'Gene', '7157', (91, 95))	('STAG2', 'Gene', '10735', (99, 104))
69105	29629425	Furthermore, we identified two additional novel mutations in TP53 in patient ES-2 that had not been seen in the tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ES', 'Phenotype', 'HP:0012254', (77, 79))	('patient', 'Species', '9606', (69, 76))	('tumor', 'Disease', (112, 117))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', '7157', (61, 65))	('mutations', 'Var', (48, 57))
69106	29629425	Altogether this patient harbored 3 TP53 mutations in cfDNA, potentially indicative of convergent tumor evolution characterized by multiple independent mutations in the same gene (Supp.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('tumor', 'Disease', (97, 102))	('mutations', 'Var', (40, 49))	('patient', 'Species', '9606', (16, 23))
69109	29629425	This is the first report to directly compare two complementary methodologies, ddPCR and hybrid-capture NGS, to evaluate tumor specific EWSR1 fusions in cfDNA from patients with ES and DSRCT.	('fusions', 'Var', (141, 148))	('patients', 'Species', '9606', (163, 171))	('EWSR1', 'Gene', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('ES', 'Phenotype', 'HP:0012254', (177, 179))	('cfDNA', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('EWSR1', 'Gene', '2130', (135, 140))	('tumor', 'Disease', (120, 125))
69110	29629425	Tumor specific fusions are particularly attractive target substrates for mutation-based biomarker studies of EWSR1 translocation-associated sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('EWSR1', 'Gene', '2130', (109, 114))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sarcomas', 'Disease', (140, 148))	('translocation-associated', 'Var', (115, 139))	('EWSR1', 'Gene', (109, 114))	('sarcomas', 'Disease', 'MESH:D012509', (140, 148))
69111	29629425	Although tumor cfDNA studies typically target oncogene point mutations, we previously demonstrated the relative scarcity of such recurrent somatic mutations in fusion-associated sarcomas.	('sarcomas', 'Disease', (178, 186))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('point mutations', 'Var', (55, 70))	('sarcomas', 'Disease', 'MESH:D012509', (178, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (178, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
69112	29629425	Specifically, in 75 ES and 24 DSRCT screened for 275 recurrent point mutations in 29 oncogenes frequently mutated across different cancer types, mutations were identified in only 4% of ES samples, and none of the DSRCT samples.	('cancer', 'Disease', (131, 137))	('ES', 'Phenotype', 'HP:0012254', (185, 187))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('oncogenes', 'Gene', (85, 94))	('point mutations', 'Var', (63, 78))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('ES', 'Phenotype', 'HP:0012254', (20, 22))
69114	29629425	Conversely, EWSR1 fusions are defining molecular features of ES and DSRCT, and have never been reported to undergo modification or clonal evolution through a disease course.	('fusions', 'Var', (18, 25))	('DSRCT', 'Disease', (68, 73))	('ES', 'Phenotype', 'HP:0012254', (61, 63))	('EWSR1', 'Gene', (12, 17))	('EWSR1', 'Gene', '2130', (12, 17))
69115	29629425	Previous studies utilizing RT-PCR to identify EWSR1 fusion transcripts in peripheral blood or bone marrow samples from ES patients report successful identification in less than 50% of patients.	('patients', 'Species', '9606', (184, 192))	('EWSR1', 'Gene', (46, 51))	('fusion transcripts', 'Var', (52, 70))	('patients', 'Species', '9606', (122, 130))	('ES', 'Phenotype', 'HP:0012254', (119, 121))	('EWSR1', 'Gene', '2130', (46, 51))
69116	29629425	It is perhaps not surprising that the cfDNA-based approach used in our study yielded more sensitive results, as previous studies attempted to identify rare occult tumor cells through the identification of cellular EWSR1 fusion transcripts.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('EWSR1', 'Gene', (214, 219))	('fusion transcripts', 'Var', (220, 238))	('tumor', 'Disease', (163, 168))	('EWSR1', 'Gene', '2130', (214, 219))
69119	29629425	Therefore a subset of patients whose tumors harbored less common EWSR1-FLI1 fusion types or other EWSR1 fusion partners was uncaptured, reducing the clinical sensitivity of the assay.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('EWSR1', 'Gene', (65, 70))	('EWSR1', 'Gene', '2130', (98, 103))	('clinical sensitivity', 'MPA', (149, 169))	('reducing', 'NegReg', (136, 144))	('EWSR1', 'Gene', '2130', (65, 70))	('patients', 'Species', '9606', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('fusion', 'Var', (76, 82))	('EWSR1', 'Gene', (98, 103))	('FLI1', 'Gene', (71, 75))	('tumors', 'Disease', (37, 43))	('FLI1', 'Gene', '2313', (71, 75))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
69120	29629425	In this study, both platforms were highly sensitive at detecting EWSR1 fusions in baseline cfDNA samples, although ddPCR demonstrated increased sensitivity and was able to detect levels <= 0.1%.	('EWSR1', 'Gene', (65, 70))	('fusions', 'Var', (71, 78))	('EWSR1', 'Gene', '2130', (65, 70))	('detecting', 'Reg', (55, 64))
69122	29629425	The characterization of TP53 alterations as an adverse prognostic finding was proposed based on several retrospective studies but was not confirmed in a recent prospective study.	('TP53', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (24, 28))	('alterations', 'Var', (29, 40))
69123	29629425	However, another recent large-scale genomic profiling study of Ewing Sarcoma identified tumors with co-mutation of STAG2 and TP53 as defining a particularly high-risk subset of patients.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('Sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('TP53', 'Gene', '7157', (125, 129))	('STAG2', 'Gene', (115, 120))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('patients', 'Species', '9606', (177, 185))	('co-mutation', 'Var', (100, 111))	('STAG2', 'Gene', '10735', (115, 120))	('TP53', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Ewing Sarcoma', 'Disease', (63, 76))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
69127	29629425	A similar NGS based approach was recently described in patients with advanced lung cancer, with 88% and 100% sensitivity and specificity for detecting previously characterized mutations present at 0.1% allele frequency or higher.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('mutations', 'Var', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('patients', 'Species', '9606', (55, 63))
69128	29629425	Targeted NGS has the unique advantage of obviating the need for parallel tumor tissue profiling for breakpoint identification.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('parallel tumor', 'Disease', 'MESH:D009369', (64, 78))	('parallel tumor', 'Disease', (64, 78))	('NGS', 'Var', (9, 12))
69129	29629425	Furthermore, NGS provides the ability to capture the heterogeneity of a patient's disease more completely than ddPCR, as reflected in the patient cfDNA sample (ES-2) with multiple TP53 mutations.	('TP53', 'Gene', '7157', (180, 184))	('TP53', 'Gene', (180, 184))	('patient', 'Species', '9606', (72, 79))	('ES', 'Phenotype', 'HP:0012254', (160, 162))	('patient', 'Species', '9606', (138, 145))	('cfDNA', 'Disease', (146, 151))	('mutations', 'Var', (185, 194))
69133	29629425	This will also allow for identification of the precise fusion breakpoint as well as additional TP53 and STAG2 mutational status on the majority of patients without the need to profile tumor material.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('STAG2', 'Gene', (104, 109))	('mutational', 'Var', (110, 120))	('STAG2', 'Gene', '10735', (104, 109))	('tumor', 'Disease', (184, 189))	('patients', 'Species', '9606', (147, 155))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
69135	29629425	First, our approach should capture almost 100% of patients with ES and DSRCT, as the platforms are designed to capture any EWSR1 fusion type including those with rare variant EWSR1 translocations.	('EWSR1', 'Gene', (123, 128))	('patients', 'Species', '9606', (50, 58))	('EWSR1', 'Gene', '2130', (175, 180))	('EWSR1', 'Gene', '2130', (123, 128))	('translocations', 'Var', (181, 195))	('ES', 'Phenotype', 'HP:0012254', (64, 66))	('EWSR1', 'Gene', (175, 180))
69143	28881567	Exploration of the mechanism revealed that Pom blocked lytic down-regulation of MHC-I induced by transfection with K3 but not K5.	('Pom', 'Chemical', 'MESH:C467566', (43, 46))	('MHC-I', 'Gene', (80, 85))	('down-regulation', 'NegReg', (61, 76))	('lytic', 'MPA', (55, 60))	('transfection', 'Var', (97, 109))
69161	28881567	Len and Pom also inhibit NF-kappaB in diffuse large B cell lymphoma (DLBCL) and MM, and this, along with effects on IRF4, is associated with inhibition of cell growth and cellular toxicity.	('large B cell', 'Phenotype', 'HP:0005404', (46, 58))	('NF-kappaB', 'Protein', (25, 34))	('inhibition', 'NegReg', (141, 151))	('B cell lymphoma', 'Disease', 'MESH:D016393', (52, 67))	('Pom', 'Var', (8, 11))	('Len', 'Chemical', 'MESH:D000077269', (0, 3))	('inhibit', 'NegReg', (17, 24))	('toxicity', 'Disease', 'MESH:D064420', (180, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('toxicity', 'Disease', (180, 188))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (52, 67))	('IRF4', 'Gene', '3662', (116, 120))	('cell lymphoma', 'Phenotype', 'HP:0012191', (54, 67))	('IRF4', 'Gene', (116, 120))	('Pom', 'Chemical', 'MESH:C467566', (8, 11))	('B cell lymphoma', 'Disease', (52, 67))	('cell growth', 'CPA', (155, 166))
69194	28881567	KSHV also down-regulates ICAM-1 and B7-2, which are ligands for NK cell-mediated cytotoxicity receptors.	('ICAM-1', 'Gene', '3383', (25, 31))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('cytotoxicity', 'Disease', (81, 93))	('ICAM-1', 'Gene', (25, 31))	('B7-2', 'Gene', '942', (36, 40))	('B7-2', 'Gene', (36, 40))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('down-regulates', 'NegReg', (10, 24))
69202	28881567	By contrast to these effects on ICAM-1 and MHC-I, expression of ICAM-3 and MHC-II, which are not targets of K3 or K5, were unaffected by Pom (Figure 3E and 4E).	('MHC-II', 'Gene', (75, 81))	('Pom', 'Chemical', 'MESH:C467566', (137, 140))	('ICAM-3', 'Gene', (64, 70))	('ICAM-1', 'Gene', '3383', (32, 38))	('Pom', 'Var', (137, 140))	('ICAM-3', 'Gene', '3385', (64, 70))	('ICAM-1', 'Gene', (32, 38))	('expression', 'MPA', (50, 60))
69217	28881567	Expression of GFP-K3 or GFP-K5 in BJAB cells showed a substantial down-regulation of MHC-I expression (Figure 6A and 6C, dashed lines).	('GFP-K5', 'Var', (24, 30))	('expression', 'MPA', (91, 101))	('GFP-K3', 'Var', (14, 20))	('BJAB', 'CellLine', 'CVCL:5711', (34, 38))	('MHC-I', 'Gene', (85, 90))	('down-regulation', 'NegReg', (66, 81))
69253	28881567	Pom was found to decrease K3 mRNA expression in lytic cells, thus providing an additional mechanism by which these drugs can enhance MHC-I expression in lytic cells.	('MHC-I', 'Gene', (133, 138))	('K3 mRNA expression', 'MPA', (26, 44))	('decrease', 'NegReg', (17, 25))	('Pom', 'Chemical', 'MESH:C467566', (0, 3))	('enhance', 'PosReg', (125, 132))	('expression', 'MPA', (139, 149))	('Pom', 'Var', (0, 3))
69257	28881567	The ability of Pom to reverse MHC-I downregulation by K3 transfection, but not K5 transfection, provides some suggestive evidence that it might have a more direct effect on K3-mediated MHC-downregulation.	('MHC-I', 'Gene', (30, 35))	('K3 transfection', 'Var', (54, 69))	('downregulation', 'NegReg', (36, 50))	('Pom', 'Chemical', 'MESH:C467566', (15, 18))
69258	28881567	However, it is possible that the downregulation mediated by K5 transfection of BJAB cells simply overwhelmed the ability of Pom to restore MHC-I.	('BJAB', 'CellLine', 'CVCL:5711', (79, 83))	('K5 transfection', 'Var', (60, 75))	('Pom', 'Chemical', 'MESH:C467566', (124, 127))	('downregulation', 'NegReg', (33, 47))	('MHC-I', 'MPA', (139, 144))
69269	28881567	A knockdown in IRF4 can lead to lytic reactivation of KSHV in PEL cells, and Tha, Len, and Pom have all been reported to cause lytic activation of Epstein Barr virus.	('lytic reactivation', 'MPA', (32, 50))	('KSHV', 'Gene', (54, 58))	('knockdown', 'Var', (2, 11))	('lytic activation', 'MPA', (127, 143))	('KSHV', 'Species', '37296', (54, 58))	('IRF4', 'Gene', '3662', (15, 19))	('IRF4', 'Gene', (15, 19))	('lead to', 'Reg', (24, 31))	('cause', 'Reg', (121, 126))	('Len', 'Chemical', 'MESH:D000077269', (82, 85))	('Tha', 'Chemical', 'MESH:D013792', (77, 80))	('Epstein Barr virus', 'Disease', (147, 165))	('Pom', 'Chemical', 'MESH:C467566', (91, 94))
69276	28881567	In this regard, previous studies have demonstrated that de novo expression of B7-2 and ICAM-1 restores NK cell-mediated killing of K5-expressing cells.	('restores', 'PosReg', (94, 102))	('ICAM-1', 'Gene', '3383', (87, 93))	('B7-2', 'Gene', (78, 82))	('B7-2', 'Gene', '942', (78, 82))	('ICAM-1', 'Gene', (87, 93))	('expression', 'Var', (64, 74))	('NK cell-mediated killing', 'CPA', (103, 127))
69299	28881567	Primers for ICAM-1 and B7-2 were from Biorad (ICAM-1: 10025636, qHsaCED0004281) and (B7-2: 10025636, qHsaCED0043530 (Hercules, CA).	('B7-2', 'Gene', (85, 89))	('ICAM-1', 'Gene', '3383', (12, 18))	('B7-2', 'Gene', (23, 27))	('ICAM-1', 'Gene', '3383', (46, 52))	('qHsaCED0004281', 'Var', (64, 78))	('B7-2', 'Gene', '942', (23, 27))	('B7-2', 'Gene', '942', (85, 89))	('qHsaCED0043530', 'Var', (101, 115))	('ICAM-1', 'Gene', (12, 18))	('ICAM-1', 'Gene', (46, 52))
69342	23391816	Anti-GAPDH antibody (G9545, Sigma-Aldrich, St. Louis, MO) was used as a loading control.	('GAPDH', 'Gene', (5, 10))	('G9545', 'Var', (21, 26))	('GAPDH', 'Gene', '14433', (5, 10))	('Al', 'Chemical', 'MESH:D000535', (34, 36))
69357	23391816	BrafCA;p53Fl/Fl mice were used to generate primary hind limb STS expressing BrafV600E with p53 deletion.	('BrafV600E', 'Var', (76, 85))	('p53', 'Gene', '22060', (7, 10))	('p53', 'Gene', (91, 94))	('STS', 'Phenotype', 'HP:0030448', (61, 64))	('mice', 'Species', '10090', (16, 20))	('p53', 'Gene', (7, 10))	('BrafV600E', 'Mutation', 'rs113488022', (76, 85))	('p53', 'Gene', '22060', (91, 94))
69370	23391816	Fluorescence microscopy of these samples demonstrates both VM249-positive tumor cells and VM249-positive F4/80 stained macrophages (Figure 5A, B).	('VM249-positive', 'Var', (90, 104))	('F4/80', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('VM249-positive tumor', 'Disease', (59, 79))	('VM249-positive tumor', 'Disease', 'MESH:D009369', (59, 79))	('F4/80', 'Gene', '13733', (105, 110))
69409	23226072	Apart from the groundbreaking discovery of KIT expression and activating mutations in gastrointestinal stromal tumors (GISTs) that transformed this chemo-insensitive, routinely fatal disease to one of the most treatable sarcomas, there has been little progress in sarcoma therapy in the past 10 years.	('sarcoma', 'Disease', (220, 227))	('sarcoma', 'Disease', 'MESH:D012509', (264, 271))	('gastrointestinal stromal tumors', 'Disease', (86, 117))	('GISTs', 'Phenotype', 'HP:0100723', (119, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('sarcoma', 'Disease', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('sarcomas', 'Disease', (220, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (86, 117))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (86, 117))	('sarcoma', 'Disease', 'MESH:D012509', (220, 227))	('sarcomas', 'Disease', 'MESH:D012509', (220, 228))	('mutations', 'Var', (73, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (220, 228))
69453	23226072	This leads to inhibition of activated transcription, and trabectedin interacts with the transcription-coupled nucleotide-excision repair, leading to irreversible breaks in DNA strands, cell-cycle arrest, and apoptosis.	('apoptosis', 'CPA', (208, 217))	('arrest', 'Disease', (196, 202))	('breaks', 'Var', (162, 168))	('DNA strands', 'Protein', (172, 183))	('activated transcription', 'MPA', (28, 51))	('trabectedin', 'Chemical', 'MESH:D000077606', (57, 68))	('arrest', 'Disease', 'MESH:D006323', (196, 202))	('interacts', 'Reg', (69, 78))	('inhibition', 'NegReg', (14, 24))
69508	23226072	In addition, studies in xenograft models of sarcoma and non-small cell lung cancer (NSCLC) show that TH-302 adds to the activity of maximally tolerated doses of doxorubicin, leading to tumor regressions and growth delay.	('doxorubicin', 'Chemical', 'MESH:D004317', (161, 172))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (60, 82))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (56, 82))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('activity', 'MPA', (120, 128))	('tumor', 'Disease', (185, 190))	('growth delay', 'CPA', (207, 219))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('TH-302', 'Var', (101, 107))	('NSCLC', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('sarcoma', 'Disease', (44, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('non-small cell lung cancer', 'Disease', (56, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('TH-302', 'Chemical', 'MESH:C552526', (101, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (56, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('growth delay', 'Phenotype', 'HP:0001510', (207, 219))
69551	23226072	Sorafenib (BAY 43-9006; Onyx Pharmaceuticals) is an oral multikinase inhibitor with antiangiogenic and proapoptotic properties, targeting wild-type and mutant B-raf and C-raf kinases, as well as VEGFR-2, PDGFR-beta, fms-like tyrosine kinase 3 (Flt-3), c-KIT and p38a, a member of the MAP kinase family.	('C-raf', 'Gene', '5894', (169, 174))	('PDGFR-beta', 'Gene', (204, 214))	('fms-like tyrosine kinase 3', 'Gene', '2322', (216, 242))	('B-raf', 'Gene', '673', (159, 164))	('c-KIT', 'Gene', (252, 257))	('p38a', 'Gene', '1432', (262, 266))	('c-KIT', 'Gene', '3815', (252, 257))	('VEGFR-2', 'Gene', '3791', (195, 202))	('BAY 43-9006', 'Chemical', 'MESH:D000077157', (11, 22))	('PDGFR-beta', 'Gene', '5159', (204, 214))	('mutant', 'Var', (152, 158))	('C-raf', 'Gene', (169, 174))	('VEGFR-2', 'Gene', (195, 202))	('p38a', 'Gene', (262, 266))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('Flt-3', 'Gene', '2322', (244, 249))	('fms-like tyrosine kinase 3', 'Gene', (216, 242))	('B-raf', 'Gene', (159, 164))	('Flt-3', 'Gene', (244, 249))
69640	23226072	Activating mutations in growth-factor receptors lead to activation of the downstream PI3K/AKT/mTOR pathway.	('growth-factor', 'Protein', (24, 37))	('mutations', 'Var', (11, 20))	('mTOR', 'Gene', (94, 98))	('AKT', 'Gene', (90, 93))	('mTOR', 'Gene', '2475', (94, 98))	('activation', 'PosReg', (56, 66))	('AKT', 'Gene', '207', (90, 93))
69649	23226072	The study met its primary end point, with a statistically significant improvement in PFS of 3.1 weeks (17.7 versus 14.6 weeks) favoring ridaforolimus, but there was no significant improvement in OS.	('PFS', 'MPA', (85, 88))	('ridaforolimus', 'Var', (136, 149))	('OS', 'Chemical', '-', (195, 197))	('ridaforolimus', 'Chemical', 'MESH:C515074', (136, 149))
69663	23226072	These sarcomas are part of a family of diseases that includes angiomyolipomas and lymphangioleiomyomatosis and are seen in patients with tuberous sclerosis, which is associated with mutations in TSC1 and TSC2, which lead to activation of the mTOR pathway.	('angiomyolipomas', 'Disease', 'MESH:D018207', (62, 77))	('lymphangioleiomyomatosis', 'Disease', 'MESH:D018192', (82, 106))	('lymphangioleiomyomatosis', 'Disease', (82, 106))	('TSC2', 'Gene', '7249', (204, 208))	('mTOR', 'Gene', (242, 246))	('angiomyolipomas', 'Disease', (62, 77))	('TSC1', 'Gene', (195, 199))	('sarcomas', 'Disease', 'MESH:D012509', (6, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))	('sarcomas', 'Disease', (6, 14))	('patients', 'Species', '9606', (123, 131))	('TSC1', 'Gene', '7248', (195, 199))	('mTOR', 'Gene', '2475', (242, 246))	('TSC2', 'Gene', (204, 208))	('activation', 'PosReg', (224, 234))	('mutations', 'Var', (182, 191))	('lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (82, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (137, 155))	('tuberous sclerosis', 'Disease', (137, 155))
69673	23226072	Inflammatory myofibroblastic tumor, a rare aggressive sarcoma in young adults and children, is associated with rearrangements in the ALK locus in around 50% of patients.	('children', 'Species', '9606', (82, 90))	('patients', 'Species', '9606', (160, 168))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (13, 34))	('ALK', 'Gene', (133, 136))	('rearrangements', 'Var', (111, 125))	('myofibroblastic tumor', 'Disease', 'MESH:D009369', (13, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('aggressive sarcoma', 'Disease', 'MESH:D012509', (43, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('ALK', 'Gene', '238', (133, 136))	('associated', 'Reg', (95, 105))	('aggressive sarcoma', 'Disease', (43, 61))	('myofibroblastic tumor', 'Disease', (13, 34))
69676	23226072	MDM2 antagonists have demonstrated preclinical activity and are now entering early clinical development, including sarcoma-specific trials in combination with chemotherapy.	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('sarcoma', 'Disease', (115, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('antagonists', 'Var', (5, 16))	('MDM2', 'Gene', (0, 4))
69684	22042973	At the pathway level, we identified a significant enrichment of copy number-altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1R gene itself.	('IGF1R', 'Gene', '3480', (138, 143))	('amplifications', 'MPA', (173, 187))	('IGF1R', 'Gene', (195, 200))	('IGF1R', 'Gene', (138, 143))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (99, 136))	('IGF1R', 'Gene', '3480', (195, 200))	('insulin-like growth factor 1 receptor', 'Gene', (99, 136))	('copy number-altering', 'Var', (64, 84))
69685	22042973	To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using immunohistochemistry.	('worse', 'NegReg', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('IGF1R', 'Gene', (16, 21))	('IGF1R', 'Gene', (92, 97))	('high IGF1R', 'Phenotype', 'HP:0030269', (87, 97))	('IGF1R', 'Gene', '3480', (16, 21))	('IGF1R', 'Gene', '3480', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('high', 'Var', (87, 91))	('tumor', 'Disease', (128, 133))	('MPNSTs', 'Phenotype', 'HP:0100697', (55, 61))	('protein', 'Protein', (98, 105))	('MPNST', 'Phenotype', 'HP:0100697', (55, 60))
69696	22042973	Microarray-based comparative genomic hybridization (aCGH) is a well-established method for detecting chromosomal gains and losses of DNA segments.	('chromosomal gains', 'Var', (101, 118))	('CGH', 'Gene', (53, 56))	('losses', 'NegReg', (123, 129))	('CGH', 'Gene', '3342', (53, 56))
69701	22042973	Genes that have been suggested as targets of common deletions include CDH1, GLTSCR2, EGR1, CTSB, GATA3, SULT2A1, GLTSCR2, HMMR/RHAMM, LICAM2, MMP13, p16/INK4a, RASSF2, NM-23H1, and TP53.	('GATA3', 'Gene', (97, 102))	('TP53', 'Gene', (181, 185))	('HMMR', 'Gene', (122, 126))	('CDH1', 'Gene', '999', (70, 74))	('deletions', 'Var', (52, 61))	('MMP13', 'Gene', '4322', (142, 147))	('RASSF2', 'Gene', '9770', (160, 166))	('SULT2A1', 'Gene', '6822', (104, 111))	('GLTSCR2', 'Gene', '29997', (76, 83))	('CDH1', 'Gene', (70, 74))	('RASSF2', 'Gene', (160, 166))	('GLTSCR2', 'Gene', '29997', (113, 120))	('CTSB', 'Gene', '1508', (91, 95))	('NM-23H1', 'Gene', (168, 175))	('EGR1', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (181, 185))	('EGR1', 'Gene', '1958', (85, 89))	('RHAMM', 'Gene', '3161', (127, 132))	('RHAMM', 'Gene', (127, 132))	('p16', 'Gene', (149, 152))	('SULT2A1', 'Gene', (104, 111))	('INK4a', 'Gene', (153, 158))	('HMMR', 'Gene', '3161', (122, 126))	('CTSB', 'Gene', (91, 95))	('GLTSCR2', 'Gene', (76, 83))	('GLTSCR2', 'Gene', (113, 120))	('p16', 'Gene', '1029', (149, 152))	('GATA3', 'Gene', '2625', (97, 102))	('NM-23H1', 'Gene', '4830', (168, 175))	('INK4a', 'Gene', '1029', (153, 158))	('MMP13', 'Gene', (142, 147))
69702	22042973	Recent reports show that alterations of TOP2A, CDK4, and FOXM1 not only are associated with survival but also are potential therapeutic targets.	('alterations', 'Var', (25, 36))	('survival', 'CPA', (92, 100))	('FOXM1', 'Gene', (57, 62))	('CDK4', 'Gene', (47, 51))	('associated', 'Reg', (76, 86))	('FOXM1', 'Gene', '2305', (57, 62))	('TOP2A', 'Gene', '7153', (40, 45))	('CDK4', 'Gene', '1019', (47, 51))	('TOP2A', 'Gene', (40, 45))
69721	22042973	After that, the CGHcall algorithm was used to give each segment an aberration label: normal, deletion, or amplification.	('amplification', 'Var', (106, 119))	('deletion', 'Var', (93, 101))	('CGH', 'Gene', (16, 19))	('CGH', 'Gene', '3342', (16, 19))
69738	22042973	With approximately 65% of patients affected, we identified focal deletion of 9p21.3 (harboring tumor suppressors CDKN2A and CDKN2B) as the most recurrent genomic event in our data, consistent with a previous study (Fig.	('CDKN2B', 'Gene', '1030', (124, 130))	('CDKN2B', 'Gene', (124, 130))	('CDKN2A', 'Gene', (113, 119))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('CDKN2A', 'Gene', '1029', (113, 119))	('focal deletion', 'Var', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
69740	22042973	More novel chromosomal abnormalities included deletions of 1p, containing TP73 and MIIP, 10q26 containing MGMT, 16p containing MMP15, chromosome 19 with several cancer-related genes including AKT2, BCL3, CEBPA, and ERCC2, and 22q containing GSTT1, MKL1, MYH9, NF2, PDGFB, SMARCB1.	('MKL1', 'Gene', (248, 252))	('PDGFB', 'Gene', (265, 270))	('GSTT1', 'Gene', '2952', (241, 246))	('cancer', 'Disease', (161, 167))	('AKT2', 'Gene', '208', (192, 196))	('NF2', 'Gene', '4771', (260, 263))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('BCL3', 'Gene', '602', (198, 202))	('GSTT1', 'Gene', (241, 246))	('AKT2', 'Gene', (192, 196))	('MYH9', 'Gene', (254, 258))	('NF2', 'Gene', (260, 263))	('MGMT', 'Gene', (106, 110))	('ERCC2', 'Gene', (215, 220))	('MIIP', 'Gene', '60672', (83, 87))	('SMARCB1', 'Gene', (272, 279))	('SMARCB1', 'Gene', '6598', (272, 279))	('MIIP', 'Gene', (83, 87))	('CEBPA', 'Gene', '1050', (204, 209))	('MMP15', 'Gene', '4324', (127, 132))	('ERCC2', 'Gene', '2068', (215, 220))	('TP73', 'Gene', '7161', (74, 78))	('MMP15', 'Gene', (127, 132))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('BCL3', 'Gene', (198, 202))	('MKL1', 'Gene', '57591', (248, 252))	('deletions', 'Var', (46, 55))	('PDGFB', 'Gene', '5155', (265, 270))	('CEBPA', 'Gene', (204, 209))	('MYH9', 'Gene', '4627', (254, 258))	('TP73', 'Gene', (74, 78))	('MGMT', 'Gene', '4255', (106, 110))
69743	22042973	For example, the amplification of MYC was significantly associated with tumor recurrence, and the deletion of AKT1 was associated with the presence of tumor metastases.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('MYC', 'Gene', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('AKT1', 'Gene', '207', (110, 114))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (151, 156))	('deletion', 'Var', (98, 106))	('tumor metastases', 'Disease', (151, 167))	('associated', 'Reg', (56, 66))	('AKT1', 'Gene', (110, 114))	('MYC', 'Gene', '4609', (34, 37))	('tumor metastases', 'Disease', 'MESH:D009362', (151, 167))	('amplification', 'Var', (17, 30))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('associated', 'Reg', (119, 129))
69753	22042973	In addition to IGF1R amplifications, at least one gene in the IGF1R pathway was altered in 82% of the cases making the pathway highly significant.	('IGF1R', 'Gene', '3480', (62, 67))	('IGF1R', 'Gene', (15, 20))	('IGF1R', 'Gene', '3480', (15, 20))	('amplifications', 'Var', (21, 35))	('altered', 'Reg', (80, 87))	('IGF1R', 'Gene', (62, 67))
69755	22042973	Notably, the PTEN signaling pathway was also significantly altered in MPNSTs (Fig 2C).	('altered', 'Reg', (59, 66))	('MPNSTs', 'Var', (70, 76))	('MPNSTs', 'Phenotype', 'HP:0100697', (70, 76))	('PTEN', 'Gene', (13, 17))	('MPNST', 'Phenotype', 'HP:0100697', (70, 75))	('PTEN', 'Gene', '5728', (13, 17))
69759	22042973	Interestingly, we found that the patients in the group with less alterations had a significantly better prognosis than the patients in the other group (P = 0.0379) (Fig 2C).	('patients', 'Species', '9606', (33, 41))	('alterations', 'Var', (65, 76))	('better', 'PosReg', (97, 103))	('patients', 'Species', '9606', (123, 131))
69771	22042973	In ST88-14 cells, treatment with MK-0646 led to a decrease in the activated form of IGF1R as well as a decrease in cell proliferation relative to control (Fig.	('MK-0646', 'Var', (33, 40))	('MK-0646', 'Chemical', 'MESH:C569480', (33, 40))	('IGF1R as', 'Gene', '104472848', (84, 92))	('cell proliferation', 'CPA', (115, 133))	('IGF1R as', 'Gene', (84, 92))	('activated form', 'MPA', (66, 80))	('decrease', 'NegReg', (103, 111))	('decrease', 'NegReg', (50, 58))
69789	22042973	IGF1R inhibitors have already been successfully used to treat some types of cancers.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('IGF1R', 'Gene', (0, 5))	('inhibitors', 'Var', (6, 16))	('IGF1R', 'Gene', '3480', (0, 5))
69791	22042973	Aberrant activation of the IGF1/IGF1R axis has been associated with a worse prognosis in many tumors, including breast, gastric, and prostate cancers.	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('IGF1', 'Gene', (32, 36))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('IGF1R', 'Gene', '3480', (32, 37))	('tumors', 'Disease', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('prostate cancers', 'Disease', 'MESH:D011471', (133, 149))	('IGF1', 'Gene', '3479', (27, 31))	('gastric', 'Disease', (120, 127))	('IGF1R', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('breast', 'Disease', (112, 118))	('prostate cancers', 'Phenotype', 'HP:0012125', (133, 149))	('prostate cancers', 'Disease', (133, 149))	('IGF1', 'Gene', (27, 31))	('IGF1', 'Gene', '3479', (32, 36))
69792	22042973	Furthermore, in pancreatic cancer and anaplastic thyroid carcinomas, IGF1R inhibitors were shown to also reduce vascularization and VEGF expression.	('anaplastic thyroid carcinomas', 'Disease', (38, 67))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('reduce', 'NegReg', (105, 111))	('inhibitors', 'Var', (75, 85))	('VEGF', 'Protein', (132, 136))	('anaplastic thyroid carcinomas', 'Disease', 'MESH:D065646', (38, 67))	('expression', 'Species', '29278', (137, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('IGF1R', 'Gene', (69, 74))	('pancreatic cancer', 'Disease', (16, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (49, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (16, 33))	('anaplastic thyroid carcinomas', 'Phenotype', 'HP:0011779', (38, 67))	('vascularization', 'CPA', (112, 127))	('IGF1R', 'Gene', '3480', (69, 74))
69796	22042973	Furthermore, the combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxic response.	('induced', 'Reg', (75, 82))	('cytotoxic response', 'CPA', (92, 110))	('combination', 'Interaction', (17, 28))	('imatinib', 'Chemical', 'MESH:D000068877', (47, 55))	('NVP-AEW541', 'Var', (32, 42))
69798	22042973	In the current study, the aCGH profile characterized the significant genetic amplifications of IGF1R signaling pathway genes including IGF1R itself.	('IGF1R', 'Gene', '3480', (135, 140))	('genetic amplifications', 'Var', (69, 91))	('IGF1R', 'Gene', (95, 100))	('IGF1R', 'Gene', '3480', (95, 100))	('CGH', 'Gene', (27, 30))	('CGH', 'Gene', '3342', (27, 30))	('IGF1R', 'Gene', (135, 140))
69799	22042973	The deregulation of expression of IGF1R is an independent prognostic factor for this type of sarcoma.	('expression', 'MPA', (20, 30))	('sarcoma', 'Disease', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('IGF1R', 'Gene', (34, 39))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('deregulation of', 'Var', (4, 19))	('IGF1R', 'Gene', '3480', (34, 39))	('expression', 'Species', '29278', (20, 30))
69803	22042973	A major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production.	('enhanced', 'PosReg', (133, 141))	('insulin receptor', 'Gene', (142, 158))	('homodimer', 'Interaction', (166, 175))	('IGF-2', 'Gene', (190, 195))	('IGF-2', 'Gene', '3481', (190, 195))	('insulin receptor', 'Gene', '3643', (142, 158))	('inhibitors', 'Var', (51, 61))	('IGF-1R', 'Gene', (65, 71))	('IGF-1R', 'Gene', '3480', (65, 71))
69806	22042973	For example, different from the results in other tumors, in our study the inhibition of IGF1R did not result in the activation of EGFR pathways in MPNST and the combined inhibition of IGF1R and EGFR did not show additive antitumor effects at the cellular level, suggesting lack of cross-talk between IGF1R and EGFR pathways in MPNSTs.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('IGF1R', 'Gene', '3480', (184, 189))	('EGFR', 'Gene', '1956', (310, 314))	('tumor', 'Disease', (225, 230))	('IGF1R', 'Gene', '3480', (88, 93))	('tumors', 'Disease', (49, 55))	('EGFR', 'Gene', (194, 198))	('EGFR', 'Gene', (130, 134))	('IGF1R', 'Gene', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('inhibition', 'Var', (74, 84))	('IGF1R', 'Gene', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('IGF1R', 'Gene', '3480', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (49, 54))	('EGFR', 'Gene', (310, 314))	('EGFR', 'Gene', '1956', (194, 198))	('EGFR', 'Gene', '1956', (130, 134))	('IGF1R', 'Gene', (300, 305))	('MPNSTs', 'Phenotype', 'HP:0100697', (327, 333))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('MPNST', 'Phenotype', 'HP:0100697', (147, 152))	('MPNST', 'Phenotype', 'HP:0100697', (327, 332))
69839	21029368	Heparanase staining correlated with increased tumour size (P = 0.04) and patient age (P = 0.03), prognostic factors associated with disease severity and a worse outcome.	('staining', 'Var', (11, 19))	('Heparanase', 'Gene', '10855', (0, 10))	('increased tumour', 'Disease', (36, 52))	('Heparanase', 'Gene', (0, 10))	('patient', 'Species', '9606', (73, 80))	('increased tumour', 'Disease', 'MESH:D009369', (36, 52))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))
69904	21029368	Ewing's sarcoma is associated with unique chromosomal translocations that give rise to specific fusion genes comprising the EWS genes and members of the ETS transcription factors, primarily FLI (85%).	("Ewing's sarcoma", 'Disease', (0, 15))	('EWS genes', 'Gene', (124, 133))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('give rise', 'Reg', (74, 83))	('fusion', 'Var', (96, 102))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('FLI', 'Gene', '2314', (190, 193))	('FLI', 'Gene', (190, 193))
69929	21029368	Moreover, tumour xenograft growth was markedly suppressed in mice treated with SST0001 relative to untreated animals (Fig.	('suppressed', 'NegReg', (47, 57))	('mice', 'Species', '10090', (61, 65))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('SST0001', 'Var', (79, 86))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('tumour', 'Disease', (10, 16))
70001	33579340	The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) criteria for the rectum, bladder, and the further bowel will be followed (V50 < 50%, V60 < 35%, V65 < 25%, V70 < 20%, and V75 < 15%).	('a', 'Gene', '351', (6, 7))	('V75 < 15%', 'Var', (197, 206))	('A', 'Gene', '351', (68, 69))	('a', 'Gene', '351', (11, 12))	('A', 'Gene', '351', (17, 18))	('a', 'Gene', '351', (19, 20))	('a', 'Gene', '351', (33, 34))	('a', 'Gene', '351', (193, 194))	('a', 'Gene', '351', (82, 83))	('a', 'Gene', '351', (102, 103))	('V50 < 50%', 'Var', (149, 158))	('a', 'Gene', '351', (109, 110))	('V70 < 20%', 'Var', (182, 191))	('V65 < 25%', 'Var', (171, 180))	('V60 < 35%', 'Var', (160, 169))
70066	33579340	The benefit of particles lies in the steeper dose gradients, which improve the chances of homogeneous target volume coverage and reduction of dose constraints considered relevant for, e.g., diarrhea as V40Gy < 124 cm3, V15Gy < 275 cm3.	('a', 'Gene', '351', (199, 200))	('a', 'Gene', '351', (192, 193))	('V15Gy < 275 cm3', 'Var', (219, 234))	('a', 'Gene', '351', (103, 104))	('a', 'Gene', '351', (121, 122))	('a', 'Gene', '351', (52, 53))	('a', 'Gene', '351', (125, 126))	('a', 'Gene', '351', (175, 176))	('a', 'Gene', '351', (197, 198))	('a', 'Gene', '351', (153, 154))	('diarrhea', 'Phenotype', 'HP:0002014', (190, 198))	('V40Gy < 124 cm3', 'Var', (202, 217))	('a', 'Gene', '351', (16, 17))	('a', 'Gene', '351', (81, 82))	('diarrhea', 'Disease', (190, 198))	('diarrhea', 'Disease', 'MESH:D003967', (190, 198))
70099	33579340	The composite primary endpoint which is not validated consisted of local or distant progression during or after RT, inoperability of tumor or patient defined as ASA score of 3, R2 resection, peritoneal metastases, or local recurrence after resection.	('R2 resection', 'Var', (177, 189))	('a', 'Gene', '351', (199, 200))	('metastases', 'Disease', 'MESH:D009362', (202, 212))	('a', 'Gene', '351', (49, 50))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('a', 'Gene', '351', (80, 81))	('metastases', 'Disease', (202, 212))	('a', 'Gene', '351', (143, 144))	('a', 'Gene', '351', (158, 159))	('a', 'Gene', '351', (70, 71))	('a', 'Gene', '351', (205, 206))	('patient', 'Species', '9606', (142, 149))	('a', 'Gene', '351', (234, 235))	('ASA', 'Chemical', 'MESH:D001241', (161, 164))	('a', 'Gene', '351', (220, 221))	('resection', 'Var', (180, 189))	('a', 'Gene', '351', (45, 46))	('tumor', 'Disease', (133, 138))	('a', 'Gene', '351', (122, 123))	('a', 'Gene', '351', (106, 107))	('a', 'Gene', '351', (18, 19))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('a', 'Gene', '351', (208, 209))
70259	29992013	However, such modification led to graft rejection in approximately half of the patients.	('led to', 'Reg', (27, 33))	('modification', 'Var', (14, 26))	('graft rejection', 'CPA', (34, 49))	('patients', 'Species', '9606', (79, 87))
70510	21933400	Corresponding with previously reported photon data, SAHA lead to an increase of sensitivity to heavy ions along with an increase of DSB and apoptosis in the two sarcoma cell lines.	('SAHA', 'Var', (52, 56))	('sarcoma', 'Disease', (161, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('DSB', 'MPA', (132, 135))	('apoptosis', 'CPA', (140, 149))	('sensitivity to heavy ions', 'MPA', (80, 105))	('increase', 'PosReg', (68, 76))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('increase', 'PosReg', (120, 128))	('SAHA', 'Chemical', 'MESH:D000077337', (52, 56))
70521	21933400	In a previous report, we have shown that SAHA enhances radio-sensitivity to conventional megavoltage photon beam radiation (XRT) in multiple pediatric sarcoma cell lines.	('enhances', 'PosReg', (46, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (141, 158))	('pediatric sarcoma', 'Disease', (141, 158))	('SAHA', 'Chemical', 'MESH:D000077337', (41, 45))	('SAHA', 'Var', (41, 45))
70575	21933400	In the XRT, but even more in the HIT experiments, the KHOS-24OS cell line showed a prolonged presence of gammaH2AX, respectively DSB, which was not observed in A-204.	('gammaH2AX', 'Chemical', '-', (105, 114))	('gammaH2AX', 'Var', (105, 114))	('KHOS-24OS', 'Chemical', '-', (54, 63))	('HIT', 'Disease', (33, 36))	('HIT', 'Disease', 'MESH:D013921', (33, 36))
70579	21933400	The findings showed that gammaH2AX-expression was significantly increased 2 hours after HIT or HIT plus SAHA treatment, compared to the untreated cells in KHOS-24OS, as well as A-204, but not in hFOB1.19 (Figure 6).	('gammaH2AX', 'Chemical', '-', (25, 34))	('KHOS-24OS', 'Chemical', '-', (155, 164))	('gammaH2AX-expression', 'Var', (25, 45))	('HIT plus SAHA', 'Disease', (95, 108))	('HIT', 'Disease', (88, 91))	('HIT plus SAHA', 'Disease', 'MESH:D007625', (95, 108))	('HIT', 'Disease', 'MESH:D013921', (95, 98))	('HIT', 'Disease', (95, 98))	('increased', 'PosReg', (64, 73))	('HIT', 'Disease', 'MESH:D013921', (88, 91))
70582	21933400	All these proteins play a critical role in the repair of DNA-DSB, and are known to be activated by, amongst others, gammaH2AX.	('play', 'Reg', (19, 23))	('DNA-DSB', 'Disease', (57, 64))	('gammaH2AX', 'Chemical', '-', (116, 125))	('gammaH2AX', 'Var', (116, 125))	('activated', 'PosReg', (86, 95))
70593	21933400	In the hFOB1.19 cell line, SAHA also resulted in a slight increase of cells in G0/1 phase, but HIT only, as well as the combination treatment did not induce a G0/1 or G2/M arrest.	('increase', 'PosReg', (58, 66))	('cells in G0/1 phase', 'CPA', (70, 89))	('SAHA', 'Chemical', 'MESH:D000077337', (27, 31))	('HIT', 'Disease', 'MESH:D013921', (95, 98))	('HIT', 'Disease', (95, 98))	('SAHA', 'Var', (27, 31))
70607	21933400	We observed KHOS-24OS after SAHA alone, combination treatment with HIT and SAHA and HIT only.	('KHOS-24OS', 'Var', (12, 21))	('SAHA', 'Chemical', 'MESH:D000077337', (75, 79))	('HIT', 'Disease', 'MESH:D013921', (67, 70))	('HIT', 'Disease', (67, 70))	('KHOS-24OS', 'Chemical', '-', (12, 21))	('HIT', 'Disease', 'MESH:D013921', (84, 87))	('HIT', 'Disease', (84, 87))	('SAHA', 'Chemical', 'MESH:D000077337', (28, 32))
70609	21933400	It has previously been reported that high-LET radiation induces different changes in gene expression as compared to low-LET XRT a possible explanation for this discrepancy; However, the combination of SAHA with either XRT or HIT showed similar effects on the repair kinetics of DSB as measured by gammaH2AX, despite the different reaction on the protein expression level immediately after treatment.	('effects', 'Reg', (244, 251))	('repair', 'MPA', (259, 265))	('gammaH2AX', 'Chemical', '-', (297, 306))	('combination', 'Var', (186, 197))	('HIT', 'Disease', 'MESH:D013921', (225, 228))	('HIT', 'Disease', (225, 228))	('SAHA', 'Chemical', 'MESH:D000077337', (201, 205))
70617	21933400	KHOS-24OS is a tetraploid osteosarcoma cell line with a known p53 mutation, A-204 a diploid and tetraploid rhabdomyosarcoma cell line with wild-type p53.	('osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('p53', 'Gene', (149, 152))	('tetraploid rhabdomyosarcoma', 'Disease', 'MESH:D057891', (96, 123))	('tetraploid osteosarcoma', 'Disease', 'MESH:D057891', (15, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('p53', 'Gene', '7157', (149, 152))	('tetraploid osteosarcoma', 'Disease', (15, 38))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (107, 123))	('mutation', 'Var', (66, 74))	('tetraploid rhabdomyosarcoma', 'Disease', (96, 123))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('KHOS-24OS', 'Chemical', '-', (0, 9))
70618	21933400	KHOS-24OS showed a lower sensitivity to XRT radiation compared to A-204, which is in line to the mutated p53.	('sensitivity', 'MPA', (25, 36))	('lower sensitivity to XRT radiation', 'Phenotype', 'HP:0011133', (19, 53))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('KHOS-24OS', 'Var', (0, 9))	('lower', 'NegReg', (19, 24))	('KHOS-24OS', 'Chemical', '-', (0, 9))
70620	21933400	p53 mutations often lead to XRT resistance.	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (0, 3))	('lead to', 'Reg', (20, 27))	('XRT resistance', 'Disease', (28, 42))	('mutations', 'Var', (4, 13))
70621	21933400	While KHOS-24OS contains mutated p53, A-204 is a p53-wild type cell line.	('KHOS-24OS', 'Chemical', '-', (6, 15))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('mutated', 'Var', (25, 32))
70631	21933400	Interestingly, however, the influence of the combination therapy of SAHA with HIT, as well as XRT on the repair kinetics as represented by the gammaH2AX-response, proved to be higher in A-204 than in KHOS-24OS (Figure 5).	('KHOS-24OS', 'Chemical', '-', (200, 209))	('SAHA', 'Chemical', 'MESH:D000077337', (68, 72))	('repair', 'MPA', (105, 111))	('gammaH2AX', 'Chemical', '-', (143, 152))	('higher', 'PosReg', (176, 182))	('HIT', 'Disease', 'MESH:D013921', (78, 81))	('A-204', 'Var', (186, 191))	('HIT', 'Disease', (78, 81))
70635	21933400	As suggested by Hamada et al., high-LET radiation may be particularly effective in patients with mutated p53 or p53 depleted tumors and the addition of a HDACI may be of additional value.	('depleted', 'NegReg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mutated', 'Var', (97, 104))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('p53', 'Gene', '7157', (112, 115))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('p53', 'Gene', (112, 115))	('patients', 'Species', '9606', (83, 91))	('HDAC', 'Gene', (154, 158))	('HDAC', 'Gene', '9734', (154, 158))
70648	30789359	FISH detected mutually exclusive ZC3H7B-BCOR and YWHAE-NUTM2 fusions in three uniform undifferentiated uterine sarcomas; two pleomorphic tumors harbored YWHAE rearrangement with no known partner.	('YWHAE', 'Gene', '7531', (153, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('YWHAE', 'Gene', (49, 54))	('BCOR', 'Gene', '54880', (40, 44))	('ZC3H7B', 'Gene', (33, 39))	('pleomorphic tumors', 'Disease', 'MESH:C538229', (125, 143))	('YWHAE', 'Gene', '7531', (49, 54))	('ZC3H7B', 'Gene', '23264', (33, 39))	('BCOR', 'Gene', (40, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('fusions', 'Var', (61, 68))	('undifferentiated uterine sarcomas', 'Disease', (86, 119))	('undifferentiated uterine sarcomas', 'Disease', 'MESH:D002277', (86, 119))	('pleomorphic tumors', 'Disease', (125, 143))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (103, 118))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('YWHAE', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('uniform undifferentiated uterine sarcomas', 'Phenotype', 'HP:0000131', (78, 119))
70649	30789359	Targeted RNA sequencing of five FISH-negative uniform undifferentiated uterine sarcomas detected BRD8-PHF1 and YWHAE-NUTM2B fusions and BCOR internal tandem duplication in four of them.	('BRD8', 'Gene', (97, 101))	('undifferentiated uterine sarcomas', 'Disease', (54, 87))	('YWHAE', 'Gene', '7531', (111, 116))	('PHF1', 'Gene', '5252', (102, 106))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (71, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('internal tandem duplication', 'Var', (141, 168))	('YWHAE', 'Gene', (111, 116))	('NUTM2B', 'Gene', '729262', (117, 123))	('uniform undifferentiated uterine sarcomas', 'Phenotype', 'HP:0000131', (46, 87))	('BCOR', 'Gene', (136, 140))	('BRD8', 'Gene', '10902', (97, 101))	('undifferentiated uterine sarcomas', 'Disease', 'MESH:D002277', (54, 87))	('BCOR', 'Gene', '54880', (136, 140))	('fusions', 'Var', (124, 131))	('PHF1', 'Gene', (102, 106))	('NUTM2B', 'Gene', (117, 123))
70654	30789359	Novel YWHAE rearrangements may define a subset of true undifferentiated pleomorphic sarcomas.	('undifferentiated pleomorphic sarcomas', 'Disease', (55, 92))	('YWHAE', 'Gene', (6, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('rearrangements', 'Var', (12, 26))	('YWHAE', 'Gene', '7531', (6, 11))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (55, 92))
70663	30789359	Few early reports suggest that undifferentiated uterine sarcomas have complex karyotypes and frequently harbor TP53 mutations.	('harbor', 'Reg', (104, 110))	('TP53', 'Gene', '7157', (111, 115))	('undifferentiated uterine sarcomas', 'Disease', 'MESH:D002277', (31, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('TP53', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('undifferentiated uterine sarcomas', 'Disease', (31, 64))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (48, 63))
70665	30789359	Those harboring YWHAE and BCOR rearrangements likely represent high-grade endometrial stromal sarcomas that were previously unrecognized due to lack of available novel fusion detection methods at the time of diagnosis.	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (74, 102))	('YWHAE', 'Gene', '7531', (16, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('endometrial stromal sarcomas', 'Disease', (74, 102))	('rearrangements', 'Var', (31, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('BCOR', 'Gene', (26, 30))	('YWHAE', 'Gene', (16, 21))	('BCOR', 'Gene', '54880', (26, 30))
70690	30789359	Rearrangements were detected in 5 of 10 (50%) tumors (Table 1).	('Rearrangements', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
70695	30789359	BCOR exon 15 internal tandem duplication and BRD8-PHF1 fusion (exons 9 and 2) were detected in two and one tumors, respectively (Figures 4 and 5).	('internal tandem duplication', 'Var', (13, 40))	('BCOR', 'Gene', '54880', (0, 4))	('detected', 'Reg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('PHF1', 'Gene', (50, 54))	('BRD8', 'Gene', '10902', (45, 49))	('BRD8', 'Gene', (45, 49))	('PHF1', 'Gene', '5252', (50, 54))	('BCOR', 'Gene', (0, 4))
70723	30789359	Both tumors harboring BCOR exon 15 internal tandem duplication showed similar morphologic features.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('internal tandem duplication', 'Var', (35, 62))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('BCOR', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('BCOR', 'Gene', '54880', (22, 26))
70728	30789359	Both tumors morphologically resembled published reports of high-grade endometrial stromal sarcoma with BCOR internal tandem duplication and were re-classified as such after re-review of the morphology and molecular results.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('BCOR', 'Gene', '54880', (103, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('internal tandem duplication', 'Var', (108, 135))	('endometrial stromal sarcoma', 'Disease', (70, 97))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (70, 97))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('BCOR', 'Gene', (103, 107))
70736	30789359	Given the recent publication of BRD8-PHF1 fusion in a low-grade endometrial stromal sarcoma, the current tumor was re-classified as high-grade endometrial stromal sarcoma based on the fusion status and presence of high-grade histologic features.	('endometrial stromal sarcoma', 'Disease', (64, 91))	('BRD8', 'Gene', '10902', (32, 36))	('PHF1', 'Gene', '5252', (37, 41))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (64, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('endometrial stromal sarcoma', 'Disease', (143, 170))	('fusion', 'Var', (42, 48))	('BRD8', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (143, 170))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('tumor', 'Disease', (105, 110))	('PHF1', 'Gene', (37, 41))
70738	30789359	Known endometrial stromal sarcoma-associated genetic aberrations were detected in 70% of tumors tested and included ZC3H7B-BCOR (n=2), YWHAE-NUTM2 (n=2), and BRD8-PHF1 (n=1) fusions as well as BCOR internal tandem duplications (n=2).	('tumors', 'Disease', (89, 95))	('BCOR', 'Gene', (193, 197))	('detected', 'Reg', (70, 78))	('YWHAE', 'Gene', (135, 140))	('YWHAE', 'Gene', '7531', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('internal tandem duplications', 'Var', (198, 226))	('genetic aberrations', 'Disease', (45, 64))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (6, 33))	('PHF1', 'Gene', (163, 167))	('BRD8', 'Gene', '10902', (158, 162))	('genetic aberrations', 'Disease', 'MESH:D030342', (45, 64))	('PHF1', 'Gene', '5252', (163, 167))	('ZC3H7B', 'Gene', (116, 122))	('BCOR', 'Gene', '54880', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('ZC3H7B', 'Gene', '23264', (116, 122))	('endometrial stromal sarcoma', 'Disease', (6, 33))	('fusions', 'Var', (174, 181))	('BCOR', 'Gene', (123, 127))	('BCOR', 'Gene', '54880', (193, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('BRD8', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
70740	30789359	Novel YWHAE gene rearrangements with no known partner were also detected by FISH in two additional undifferentiated uterine sarcomas with marked nuclear pleomorphism and may represent novel fusions in this sarcoma subtype.	('sarcoma', 'Disease', (206, 213))	('sarcoma', 'Disease', (124, 131))	('YWHAE', 'Gene', (6, 11))	('rearrangements', 'Var', (17, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('undifferentiated uterine sarcomas', 'Disease', (99, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (116, 131))	('detected', 'Reg', (64, 72))	('sarcoma', 'Disease', 'MESH:D012509', (206, 213))	('YWHAE', 'Gene', '7531', (6, 11))	('undifferentiated uterine sarcomas', 'Disease', 'MESH:D002277', (99, 132))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))
70741	30789359	BCOR expression in >=50% of cells corresponded to the presence of gene fusion or internal tandem duplication in 89% (eight of nine) of tumors, suggesting its utility in triaging tumors for molecular confirmation of high-grade endometrial stromal sarcoma-associated genetic abnormalities.	('BCOR', 'Gene', '54880', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('internal tandem duplication', 'Var', (81, 108))	('gene fusion', 'Var', (66, 77))	('tumors', 'Disease', (178, 184))	('endometrial stromal sarcoma', 'Disease', (226, 253))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('genetic abnormalities', 'Disease', 'MESH:D030342', (265, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (226, 253))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('genetic abnormalities', 'Disease', (265, 286))	('BCOR', 'Gene', (0, 4))
70752	30789359	It is not surprising that YWHAE-NUTM2 fusions as well as BCOR gene rearrangements and internal tandem duplications were found among our tumors that demonstrated nuclear isomorphism.	('YWHAE', 'Gene', (26, 31))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('found', 'Reg', (120, 125))	('YWHAE', 'Gene', '7531', (26, 31))	('BCOR', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('BCOR', 'Gene', '54880', (57, 61))	('rearrangements', 'Var', (67, 81))	('internal tandem duplications', 'Var', (86, 114))	('fusions', 'Var', (38, 45))
70753	30789359	Interestingly, however, novel YWHAE gene rearrangements with no known fusion partners were detected by FISH in two undifferentiated uterine sarcomas demonstrating marked nuclear pleomorphism and strong BCOR expression in at least 50% of tumor cells by immunohistochemistry.	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('undifferentiated uterine sarcomas', 'Disease', (115, 148))	('YWHAE', 'Gene', (30, 35))	('tumor', 'Disease', (237, 242))	('rearrangements', 'Var', (41, 55))	('undifferentiated uterine sarcomas', 'Disease', 'MESH:D002277', (115, 148))	('YWHAE', 'Gene', '7531', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('expression', 'MPA', (207, 217))	('BCOR', 'Gene', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (132, 147))	('BCOR', 'Gene', '54880', (202, 206))
70756	30789359	It is possible that in at least one of our cases, the rearrangement detected by FISH involves YWHAE exons 1-4.	('YWHAE', 'Gene', '7531', (94, 99))	('rearrangement', 'Var', (54, 67))	('YWHAE', 'Gene', (94, 99))
70759	30789359	A BRD8-PHF1 fusion was detected by targeted RNA sequencing in one of our tumors that was previously considered an undifferentiated uterine sarcoma due to the absence of YWHAE rearrangement.	('fusion', 'Var', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (114, 146))	('YWHAE', 'Gene', '7531', (169, 174))	('PHF1', 'Gene', (7, 11))	('BRD8', 'Gene', '10902', (2, 6))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('PHF1', 'Gene', '5252', (7, 11))	('detected', 'Reg', (23, 31))	('BRD8', 'Gene', (2, 6))	('YWHAE', 'Gene', (169, 174))	('tumors', 'Disease', (73, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('undifferentiated uterine sarcoma', 'Disease', (114, 146))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (131, 146))
70760	30789359	While PHF1 rearrangements have been well recognized among low-grade endometrial stromal sarcomas, fusion with an alternative partner, BRD8, was only recently described.	('PHF1', 'Gene', (6, 10))	('rearrangements', 'Var', (11, 25))	('PHF1', 'Gene', '5252', (6, 10))	('endometrial stromal sarcomas', 'Disease', (68, 96))	('BRD8', 'Gene', '10902', (134, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('BRD8', 'Gene', (134, 138))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (68, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
70766	30789359	Based on histologic features that exceed those acceptable for low-grade endometrial stromal sarcoma and the presence of an endometrial stromal sarcoma-associated gene fusion, this tumor was ultimately reclassified as a high-grade endometrial stromal sarcoma rather than undifferentiated uterine sarcoma.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('endometrial stromal sarcoma', 'Disease', (123, 150))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (287, 302))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('undifferentiated uterine sarcoma', 'Disease', (270, 302))	('endometrial stromal sarcoma', 'Disease', (230, 257))	('endometrial stromal sarcoma', 'Disease', (72, 99))	('tumor', 'Disease', (180, 185))	('undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (270, 302))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (123, 150))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (230, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (72, 99))	('fusion', 'Var', (167, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (295, 302))
70767	30789359	A larger cohort of BRD8-PHF1 fusion-positive tumors is required to confirm its inclusion among other well-known high-grade endometrial stromal sarcomas.	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (123, 151))	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PHF1', 'Gene', (24, 28))	('BRD8', 'Gene', '10902', (19, 23))	('fusion-positive', 'Var', (29, 44))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('PHF1', 'Gene', '5252', (24, 28))	('BRD8', 'Gene', (19, 23))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('endometrial stromal sarcomas', 'Disease', (123, 151))
70770	30789359	BCOR was informative in all tumors harboring YWHAE rearrangement and BCOR internal tandem duplication and in only one of two tumors harboring BCOR rearrangement, confirming previously published observations.	('BCOR', 'Gene', (69, 73))	('BCOR', 'Gene', (142, 146))	('BCOR', 'Gene', '54880', (0, 4))	('BCOR', 'Gene', '54880', (69, 73))	('BCOR', 'Gene', '54880', (142, 146))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('YWHAE', 'Gene', (45, 50))	('YWHAE', 'Gene', '7531', (45, 50))	('internal tandem duplication', 'Var', (74, 101))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('BCOR', 'Gene', (0, 4))
70773	30789359	Entities that must be considered prior to a diagnosis of undifferentiated uterine sarcoma include high-grade endometrial stromal sarcomas harboring YWHAE, BCOR, and PHF1 rearrangements as well as BCOR internal tandem duplication.	('BCOR', 'Gene', (155, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('PHF1', 'Gene', (165, 169))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (74, 89))	('PHF1', 'Gene', '5252', (165, 169))	('endometrial stromal sarcomas', 'Disease', (109, 137))	('undifferentiated uterine sarcoma', 'Disease', (57, 89))	('BCOR', 'Gene', '54880', (155, 159))	('undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (57, 89))	('internal tandem duplication', 'Var', (201, 228))	('YWHAE', 'Gene', (148, 153))	('rearrangements', 'Var', (170, 184))	('BCOR', 'Gene', (196, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (109, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('YWHAE', 'Gene', '7531', (148, 153))	('BCOR', 'Gene', '54880', (196, 200))
70774	30789359	Novel YWHAE rearrangements may define a subset of bonafide undifferentiated pleomorphic sarcomas.	('YWHAE', 'Gene', (6, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('rearrangements', 'Var', (12, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('YWHAE', 'Gene', '7531', (6, 11))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (59, 96))	('undifferentiated pleomorphic sarcomas', 'Disease', (59, 96))
70778	30212584	Reactivation from latency is driven by the KSHV lytic gene transactivator RTA, and RTA transcription is controlled by epigenetic modifications.	('Reactivation', 'MPA', (0, 12))	('KS', 'Phenotype', 'HP:0100726', (43, 45))	('KSHV', 'Species', '37296', (43, 47))	('epigenetic modifications', 'Var', (118, 142))	('RTA', 'Gene', (83, 86))
70779	30212584	To identify host chromatin-modifying proteins that are involved in the latent to lytic transition, we screened a panel of inhibitors that target epigenetic regulatory proteins for their ability to stimulate KSHV reactivation.	('KSHV reactivation', 'MPA', (207, 224))	('stimulate', 'PosReg', (197, 206))	('inhibitors', 'Var', (122, 132))	('KSHV', 'Species', '37296', (207, 211))	('KS', 'Phenotype', 'HP:0100726', (207, 209))
70782	30212584	Finally, silencing Bmi1 induces KSHV reactivation, indicating that Bmi1, a member of the Polycomb repressive complex 1, is critical for maintaining KSHV latency.	('silencing', 'Var', (9, 18))	('KSHV reactivation', 'MPA', (32, 49))	('Bmi1', 'Gene', '648', (67, 71))	('KSHV', 'Species', '37296', (148, 152))	('Bmi1', 'Gene', '648', (19, 23))	('induces', 'Reg', (24, 31))	('KSHV', 'Species', '37296', (32, 36))	('KS', 'Phenotype', 'HP:0100726', (148, 150))	('KS', 'Phenotype', 'HP:0100726', (32, 34))	('Bmi1', 'Gene', (19, 23))	('Bmi1', 'Gene', (67, 71))
70785	30212584	KSHV reactivation from latency is controlled by epigenetic changes at the promoter of the lytic gene transactivator, RTA.	('KSHV', 'Species', '37296', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('epigenetic changes', 'Var', (48, 66))	('KSHV', 'Gene', (0, 4))	('controlled by', 'Reg', (34, 47))
70804	30212584	To gain further insight into epigenetic control of the latent to lytic switch, we screened a library of known small molecule inhibitors that target epigenetic regulatory proteins such as histone writers, readers, and erasers for their ability to stimulate KSHV reactivation.	('stimulate', 'PosReg', (246, 255))	('KSHV', 'Gene', (256, 260))	('inhibitors', 'Var', (125, 135))	('KSHV', 'Species', '37296', (256, 260))	('KS', 'Phenotype', 'HP:0100726', (256, 258))
70809	30212584	To identify host chromatin-modifying proteins that are essential for maintaining KSHV latency, we screened 62 known small molecule inhibitors that target epigenetic regulatory proteins for their ability to stimulate KSHV reactivation.	('KS', 'Phenotype', 'HP:0100726', (81, 83))	('KS', 'Phenotype', 'HP:0100726', (216, 218))	('KSHV reactivation', 'MPA', (216, 233))	('stimulate', 'PosReg', (206, 215))	('inhibitors', 'Var', (131, 141))	('KSHV', 'Species', '37296', (81, 85))	('KSHV', 'Species', '37296', (216, 220))
70814	30212584	The compounds that induced appreciable KSHV reactivation after 48 hours were the HDAC inhibitors LAQ824 (Dacinostat), Trichostatin A (TSA), SAHA (Vorinostat), CAY10603, Romidepsin, and Panobinostat, where 5-25% of treated cells were RFP positive (Fig 1A).	('CAY10603', 'Var', (159, 167))	('RFP', 'Gene', '5987', (233, 236))	('CAY10603', 'Chemical', '-', (159, 167))	('RFP', 'Gene', (233, 236))	('TSA', 'Chemical', 'MESH:C012589', (134, 137))	('LAQ824', 'Chemical', 'MESH:C477361', (97, 103))	('Trichostatin A', 'Chemical', 'MESH:C012589', (118, 132))	('Panobinostat', 'Chemical', 'MESH:D000077767', (185, 197))	('SAHA', 'Chemical', 'MESH:D000077337', (140, 144))	('Dacinostat', 'Chemical', '-', (105, 115))	('KS', 'Phenotype', 'HP:0100726', (39, 41))	('KSHV', 'Species', '37296', (39, 43))	('Romidepsin', 'Chemical', 'MESH:C087123', (169, 179))	('HDAC', 'Gene', (81, 85))	('KSHV', 'MPA', (39, 43))	('HDAC', 'Gene', '9734', (81, 85))	('Vorinostat', 'Chemical', 'MESH:D000077337', (146, 156))
70826	30212584	Other bromodomain inhibitors that induced reactivation, including PFI-1, Bromosporine, I-BET762 (GSK525762A), I-BET151, and OTX015, were less effective, and stimulated reactivation in 2-3% of treated cells.	('reactivation', 'MPA', (168, 180))	('Bromosporine', 'Chemical', '-', (73, 85))	('I-BET151', 'Var', (110, 118))	('I-BET762', 'Var', (87, 95))	('stimulated', 'PosReg', (157, 167))
70827	30212584	KSHV reactivation was also induced by the JMJD3 histone demethylase inhibitor GSK-J4 and the DNA methyltransferase inhibitor Decitabine in 2% and 4% of treated cells, respectively.	('KSHV', 'Species', '37296', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('KSHV', 'Gene', (0, 4))	('Decitabine', 'Chemical', 'MESH:D000077209', (125, 135))	('JMJD3', 'Var', (42, 47))
70830	30212584	Under the culture conditions tested thus far, the EZH2 inhibitors included in the screen, UNC1999, EPZ-6438, GSK343, GSK126, EI1, and EPZ011989, did not induce appreciable KSHV reactivation.	('EPZ-6438', 'Var', (99, 107))	('KS', 'Phenotype', 'HP:0100726', (172, 174))	('KSHV', 'Species', '37296', (172, 176))	('GSK343', 'Chemical', 'MESH:C586265', (109, 115))	('GSK126', 'Chemical', 'MESH:C577920', (117, 123))	('KSHV', 'MPA', (172, 176))	('EZH2', 'Gene', '2146', (50, 54))	('EZH2', 'Gene', (50, 54))	('EPZ011989', 'Var', (134, 143))
70831	30212584	This was surprising given that H3K27me3 is associated with latent KSHV genomes and suppressed RTA expression, and the EZH2 inhibitor 3-Deazaneplanocin A (DZNep) has previously been demonstrated to induce KSHV reactivation from latency.	('DZNep', 'Chemical', 'MESH:C048460', (154, 159))	('RTA expression', 'MPA', (94, 108))	('KS', 'Phenotype', 'HP:0100726', (66, 68))	('KSHV', 'Species', '37296', (66, 70))	('3-Deazaneplanocin A', 'Chemical', 'MESH:C048460', (133, 152))	('KS', 'Phenotype', 'HP:0100726', (204, 206))	('KSHV', 'Gene', (66, 70))	('H3K27me3', 'Var', (31, 39))	('KSHV', 'Species', '37296', (204, 208))	('associated', 'Reg', (43, 53))	('EZH2', 'Gene', (118, 122))	('EZH2', 'Gene', '2146', (118, 122))	('suppressed', 'NegReg', (83, 93))
70833	30212584	UNC1999 and GSK126 were the most potent inducers of KSHV reactivation, which was stimulated in approximately 35 percent of cells treated with the highest concentration of these inhibitors (Fig 1C).	('GSK126', 'Var', (12, 18))	('KSHV', 'Species', '37296', (52, 56))	('stimulated', 'PosReg', (81, 91))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('inducers', 'Reg', (40, 48))	('KSHV', 'Gene', (52, 56))	('reactivation', 'MPA', (57, 69))	('GSK126', 'Chemical', 'MESH:C577920', (12, 18))	('UNC1999', 'Var', (0, 7))
70835	30212584	EPZ-6438 and GSK343 induced reactivation in 16 and 11 percent of cells, respectively.	('GSK343', 'Gene', (13, 19))	('GSK343', 'Chemical', 'MESH:C586265', (13, 19))	('reactivation', 'MPA', (28, 40))	('EPZ-6438', 'Var', (0, 8))
70836	30212584	DZNep, EI1, and EPZ011989 stimulated KSHV reactivation in 6, 5, and 7 percent of cells, respectively.	('DZNep', 'Chemical', 'MESH:C048460', (0, 5))	('KSHV reactivation', 'MPA', (37, 54))	('stimulated', 'PosReg', (26, 36))	('KS', 'Phenotype', 'HP:0100726', (37, 39))	('KSHV', 'Species', '37296', (37, 41))	('EPZ011989', 'Var', (16, 25))
70838	30212584	To confirm that our compounds of interest, Romidepsin, Panobinostat, (+)-JQ1, and PTC-209, induce KSHV reactivation in PEL cells, various PEL lines were incubated with each compound, NaB+TPA as a positive control, or DMSO, and KSHV lytic transcript levels were analyzed by RT-qPCR.	('PEL', 'Phenotype', 'HP:0030069', (138, 141))	('KS', 'Phenotype', 'HP:0100726', (98, 100))	('PTC-209', 'Chemical', 'MESH:C586999', (82, 89))	('KS', 'Phenotype', 'HP:0100726', (227, 229))	('KSHV', 'Species', '37296', (227, 231))	('PTC-209', 'Var', (82, 89))	('KSHV reactivation', 'MPA', (98, 115))	('PEL', 'Phenotype', 'HP:0030069', (119, 122))	('NaB', 'Chemical', '-', (183, 186))	('Panobinostat', 'Chemical', 'MESH:D000077767', (55, 67))	('TPA', 'Chemical', 'MESH:D013755', (187, 190))	('Romidepsin', 'Chemical', 'MESH:C087123', (43, 53))	('DMSO', 'Chemical', 'MESH:D004121', (217, 221))	('KSHV', 'Species', '37296', (98, 102))
70841	30212584	Furthermore, we observed increased vIL-6 and ORF45 protein levels in NaB+TPA, Romidepsin, and Panobinostat treated cells compared to the control (Fig 2B).	('increased', 'PosReg', (25, 34))	('vIL', 'Gene', '7429', (35, 38))	('NaB', 'Chemical', '-', (69, 72))	('Romidepsin', 'Chemical', 'MESH:C087123', (78, 88))	('ORF45', 'Gene', (45, 50))	('NaB+TPA', 'Var', (69, 76))	('TPA', 'Chemical', 'MESH:D013755', (73, 76))	('vIL', 'Gene', (35, 38))	('Panobinostat', 'Chemical', 'MESH:D000077767', (94, 106))
70842	30212584	Treatment with (+)-JQ1 and PTC-209 also induced KSHV lytic gene expression in all the PEL lines tested, albeit at more modest levels than those induced by NaB+TPA (Fig 2C).	('KSHV lytic gene', 'Gene', (48, 63))	('expression', 'MPA', (64, 74))	('+)-JQ1', 'Var', (16, 22))	('induced', 'Reg', (40, 47))	('KS', 'Phenotype', 'HP:0100726', (48, 50))	('KSHV', 'Species', '37296', (48, 52))	('NaB', 'Chemical', '-', (155, 158))	('TPA', 'Chemical', 'MESH:D013755', (159, 162))	('PTC-209', 'Var', (27, 34))	('PTC-209', 'Chemical', 'MESH:C586999', (27, 34))	('PEL', 'Phenotype', 'HP:0030069', (86, 89))
70844	30212584	In BCBL-1, JSC-1, and BC-3 cells, (+)-JQ1 induced expression of these genes to levels 2- to 30-fold higher than in DMSO treated cells.	('BCBL-1', 'CellLine', 'CVCL:0165', (3, 9))	('JSC-1', 'CellLine', 'CVCL:3728', (11, 16))	('higher', 'PosReg', (100, 106))	('+)-JQ1', 'Var', (35, 41))	('expression', 'MPA', (50, 60))	('DMSO', 'Chemical', 'MESH:D004121', (115, 119))
70846	30212584	Following treatment with PTC-209, vIL-6 expression increased in BCBL-1 and JSC-1 cells by approximately 16- and 2-fold, respectively, and ORF57 and K8.1 expression increased in all the PEL lines tested by 3- to 30-fold.	('expression', 'MPA', (40, 50))	('BCBL-1', 'CellLine', 'CVCL:0165', (64, 70))	('increased', 'PosReg', (51, 60))	('K8.1', 'Gene', '3887', (148, 152))	('PTC-209', 'Chemical', 'MESH:C586999', (25, 32))	('ORF57', 'Gene', (138, 143))	('JSC-1', 'CellLine', 'CVCL:3728', (75, 80))	('PTC-209', 'Var', (25, 32))	('expression', 'MPA', (153, 163))	('K8.1', 'Gene', (148, 152))	('PEL', 'Phenotype', 'HP:0030069', (185, 188))	('vIL', 'Gene', (34, 37))	('vIL', 'Gene', '7429', (34, 37))	('increased', 'PosReg', (164, 173))
70847	30212584	We observed increased vIL-6 protein levels in (+)-JQ1 treated BCBL-1 cells compared to the control, and increased vIL-6 and ORF45 protein levels in PTC-209 treated cells (Fig 2D).	('vIL', 'Gene', (114, 117))	('+)-JQ1', 'Var', (47, 53))	('vIL', 'Gene', (22, 25))	('increased', 'PosReg', (104, 113))	('BCBL-1', 'Gene', (62, 68))	('ORF45 protein levels', 'MPA', (124, 144))	('vIL', 'Gene', '7429', (114, 117))	('BCBL-1', 'CellLine', 'CVCL:0165', (62, 68))	('increased', 'PosReg', (12, 21))	('vIL', 'Gene', '7429', (22, 25))	('PTC-209', 'Chemical', 'MESH:C586999', (148, 155))
70850	30212584	Treatment with each compound induced broad KSHV gene expression compared to DMSO treated cells, confirming that Romidepsin, Panobinostat, (+)-JQ1, and PTC-209 stimulate KSHV lytic gene expression.	('KSHV lytic gene', 'Gene', (169, 184))	('Panobinostat', 'Chemical', 'MESH:D000077767', (124, 136))	('Romidepsin', 'Chemical', 'MESH:C087123', (112, 122))	('PTC-209', 'Chemical', 'MESH:C586999', (151, 158))	('KSHV', 'Species', '37296', (169, 173))	('KS', 'Phenotype', 'HP:0100726', (169, 171))	('KS', 'Phenotype', 'HP:0100726', (43, 45))	('KSHV', 'Species', '37296', (43, 47))	('PTC-209', 'Var', (151, 158))	('stimulate', 'PosReg', (159, 168))	('DMSO', 'Chemical', 'MESH:D004121', (76, 80))
70851	30212584	As a thorough analysis of the mechanism by which (+)-JQ1 stimulates KSHV reactivation from latency has recently been published, we continued our studies with Romidepsin, Panobinostat, and PTC-209.	('Panobinostat', 'Chemical', 'MESH:D000077767', (170, 182))	('Romidepsin', 'Chemical', 'MESH:C087123', (158, 168))	('stimulates', 'PosReg', (57, 67))	('KSHV', 'Gene', (68, 72))	('+)-JQ1', 'Var', (50, 56))	('PTC-209', 'Chemical', 'MESH:C586999', (188, 195))	('KSHV', 'Species', '37296', (68, 72))	('KS', 'Phenotype', 'HP:0100726', (68, 70))
70858	30212584	Similarly, KSHV copy number was increased in PTC-209 treated BCBL-1 cells by 3-fold compared to DMSO treated cells (Fig 4D), and there was a 15-fold difference in KSHV copy number in Vero cells infected with supernatants collected from PTC-209 versus DMSO treated BCBL-1 cells (Fig 4E).	('PTC-209', 'Chemical', 'MESH:C586999', (236, 243))	('KS', 'Phenotype', 'HP:0100726', (11, 13))	('KSHV', 'Species', '37296', (11, 15))	('PTC-209', 'Var', (236, 243))	('BCBL-1', 'CellLine', 'CVCL:0165', (264, 270))	('PTC-209', 'Chemical', 'MESH:C586999', (45, 52))	('DMSO', 'Chemical', 'MESH:D004121', (251, 255))	('KSHV', 'Species', '37296', (163, 167))	('DMSO', 'Chemical', 'MESH:D004121', (96, 100))	('KS', 'Phenotype', 'HP:0100726', (163, 165))	('KSHV', 'Gene', (11, 15))	('increased', 'PosReg', (32, 41))	('PTC-209', 'Var', (45, 52))	('BCBL-1', 'CellLine', 'CVCL:0165', (61, 67))	('KSHV', 'Gene', (163, 167))
70859	30212584	vIL-6, ORF57, and K8.1 were expressed at levels 9- to 30-fold higher in Vero cells infected with supernatants collected from PTC-209 versus DMSO treated BCBL-1 cells (Fig 4F).	('PTC-209', 'Var', (125, 132))	('vIL', 'Gene', '7429', (0, 3))	('K8.1', 'Gene', '3887', (18, 22))	('ORF57', 'Gene', (7, 12))	('higher', 'PosReg', (62, 68))	('DMSO', 'Chemical', 'MESH:D004121', (140, 144))	('BCBL-1', 'CellLine', 'CVCL:0165', (153, 159))	('K8.1', 'Gene', (18, 22))	('vIL', 'Gene', (0, 3))	('PTC-209', 'Chemical', 'MESH:C586999', (125, 132))
70862	30212584	We hypothesized that Romidepsin and Panobinostat treatment would increase levels of acetylated histone 3 (H3Ac) at the RTA promoter, while PTC-209 treatment would reduce levels of H2AK119ub, which is associated with heterochromatin and repressed gene expression.	('increase', 'PosReg', (65, 73))	('Panobinostat', 'Chemical', 'MESH:D000077767', (36, 48))	('PTC-209', 'Chemical', 'MESH:C586999', (139, 146))	('acetylated histone 3', 'MPA', (84, 104))	('H2AK119ub', 'Var', (180, 189))	('Romidepsin', 'Chemical', 'MESH:C087123', (21, 31))	('levels', 'MPA', (170, 176))	('H2AK119ub', 'Chemical', '-', (180, 189))	('levels', 'MPA', (74, 80))	('H3Ac', 'Chemical', '-', (106, 110))	('reduce', 'NegReg', (163, 169))
70865	30212584	Furthermore, ChIP-qPCR analysis following PTC-209 treatment using total H2A, H2AK119ub, or control IgG antibodies revealed a greater than 2-fold reduction in H2AK119ub at the NFKBIA promoter and across the RTA promoter in PTC-209 treated compared to DMSO treated cells (Fig 5B).	('H2AK119ub', 'Chemical', '-', (158, 167))	('IgG antibodies', 'Phenotype', 'HP:0003237', (99, 113))	('PTC-209', 'Chemical', 'MESH:C586999', (222, 229))	('reduction', 'NegReg', (145, 154))	('DMSO', 'Chemical', 'MESH:D004121', (250, 254))	('NFKBIA', 'Gene', (175, 181))	('PTC-209', 'Chemical', 'MESH:C586999', (42, 49))	('H2AK119ub', 'Chemical', '-', (77, 86))	('NFKBIA', 'Gene', '4792', (175, 181))	('H2AK119ub', 'Var', (158, 167))
70867	30212584	To determine if increased levels of H3Ac and decreased levels of H2AK119ub result in changes in chromatin accessibility at the RTA promoter, we probed nucleosome density in this region by FAIRE analysis.	('H2AK119ub', 'Var', (65, 74))	('changes', 'Reg', (85, 92))	('H2AK119ub', 'Chemical', '-', (65, 74))	('decreased', 'NegReg', (45, 54))	('H3Ac', 'Chemical', '-', (36, 40))	('chromatin accessibility at', 'MPA', (96, 122))
70878	30212584	To confirm a role for Bmi1 in maintaining KSHV latency, we silenced Bmi1 using siRNAs and performed immunoblot analysis for KSHV lytic proteins.	('Bmi1', 'Gene', (22, 26))	('silenced', 'Var', (59, 67))	('KS', 'Phenotype', 'HP:0100726', (42, 44))	('KSHV', 'Species', '37296', (42, 46))	('KSHV', 'Species', '37296', (124, 128))	('Bmi1', 'Gene', '648', (68, 72))	('Bmi1', 'Gene', '648', (22, 26))	('KS', 'Phenotype', 'HP:0100726', (124, 126))	('Bmi1', 'Gene', (68, 72))
70880	30212584	Bmi1 depletion resulted in increased levels of vIL-6, ORF45, and K8alpha.	('K8alpha', 'MPA', (65, 72))	('depletion', 'Var', (5, 14))	('increased', 'PosReg', (27, 36))	('Bmi1', 'Gene', (0, 4))	('levels', 'MPA', (37, 43))	('vIL', 'Gene', (47, 50))	('Bmi1', 'Gene', '648', (0, 4))	('ORF45', 'MPA', (54, 59))	('vIL', 'Gene', '7429', (47, 50))
70884	30212584	Romidepsin and Panobinostat, two HDAC inhibitors not previously shown to induce KSHV reactivation, as well as (+)-JQ1, a bromodomain inhibitor, and PTC-209, a Bmi1 inhibitor, induced KSHV lytic gene transcription.	('Panobinostat', 'Chemical', 'MESH:D000077767', (15, 27))	('Bmi1', 'Gene', '648', (159, 163))	('KSHV', 'Species', '37296', (183, 187))	('induced', 'PosReg', (175, 182))	('HDAC', 'Gene', (33, 37))	('KSHV lytic gene transcription', 'Gene', (183, 212))	('Romidepsin', 'Chemical', 'MESH:C087123', (0, 10))	('KSHV', 'Species', '37296', (80, 84))	('HDAC', 'Gene', '9734', (33, 37))	('KS', 'Phenotype', 'HP:0100726', (80, 82))	('KS', 'Phenotype', 'HP:0100726', (183, 185))	('Bmi1', 'Gene', (159, 163))	('+)-JQ1', 'Var', (111, 117))	('PTC-209', 'Chemical', 'MESH:C586999', (148, 155))
70885	30212584	While Romidepsin and Panobinostat stimulated expression of all viral genes (Fig 3A), only a subset of viral genes were induced by (+)-JQ1 and PTC-209 (Fig 3B), suggesting that modulation of different epigenetic signals may activate viral gene transcription through different pathways.	('transcription', 'MPA', (243, 256))	('PTC-209', 'Chemical', 'MESH:C586999', (142, 149))	('Panobinostat', 'Chemical', 'MESH:D000077767', (21, 33))	('activate', 'PosReg', (223, 231))	('Romidepsin', 'Chemical', 'MESH:C087123', (6, 16))	('stimulated', 'PosReg', (34, 44))	('expression', 'MPA', (45, 55))	('viral', 'MPA', (232, 237))	('+)-JQ1', 'Var', (131, 137))	('PTC-209', 'Var', (142, 149))
70889	30212584	Silencing of PRC1 member Bmi1 by siRNA resulted in KSHV reactivation, demonstrating that PRC1 is critical for the maintenance of KSHV latency.	('KSHV', 'Species', '37296', (51, 55))	('Bmi1', 'Gene', (25, 29))	('KS', 'Phenotype', 'HP:0100726', (51, 53))	('KSHV', 'Species', '37296', (129, 133))	('Bmi1', 'Gene', '648', (25, 29))	('Silencing', 'Var', (0, 9))	('KS', 'Phenotype', 'HP:0100726', (129, 131))	('KSHV reactivation', 'MPA', (51, 68))
70892	30212584	For example, Bmi1 phosphorylation by MAPKAP kinase 3 results in dissociation of PRC1 complexes from chromatin.	('MAPKAP kinase 3', 'Gene', (37, 52))	('PRC1 complexes', 'Protein', (80, 94))	('dissociation', 'MPA', (64, 76))	('Bmi1', 'Gene', '648', (13, 17))	('MAPKAP kinase 3', 'Gene', '7867', (37, 52))	('phosphorylation', 'Var', (18, 33))	('Bmi1', 'Gene', (13, 17))
70926	30212584	Supernatants were collected from BCBL-1 cells following treatment with DMSO or 1muM Romidepsin or Panobinostat for five days, or DMSO or 10muM PTC-209 for seven days.	('DMSO', 'Chemical', 'MESH:D004121', (129, 133))	('DMSO', 'Chemical', 'MESH:D004121', (71, 75))	('Panobinostat', 'Chemical', 'MESH:D000077767', (98, 110))	('PTC-209', 'Chemical', 'MESH:C586999', (143, 150))	('muM', 'Gene', '56925', (80, 83))	('muM', 'Gene', '56925', (139, 142))	('Romidepsin', 'Chemical', 'MESH:C087123', (84, 94))	('BCBL-1', 'CellLine', 'CVCL:0165', (33, 39))	('DMSO', 'Var', (129, 133))	('muM', 'Gene', (80, 83))	('muM', 'Gene', (139, 142))
70964	25628845	According to the American Joint Committee on Cancer (AJCC) staging system for soft tissue sarcoma (7th ed, 2010), he had a T2aN0 or stage Ib lesion.	('T2aN0', 'Var', (123, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (78, 97))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (78, 97))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', (45, 51))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('soft tissue sarcoma', 'Disease', (78, 97))
71013	24391834	Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine.	('Ewing sarcoma', 'Disease', (173, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('chemosensitizing', 'CPA', (65, 81))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('metformin', 'Var', (17, 26))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (173, 186))	('metformin', 'Chemical', 'MESH:D008687', (17, 26))	('antiproliferative', 'CPA', (43, 60))	('vincristine', 'Chemical', 'MESH:D014750', (246, 257))
71025	24391834	Over-expression of IR-A is in fact emerging as a feature of cancer cells where it mediates cell survival, proliferation, and migration under insulin and IGF-2 stimulus.	('migration', 'CPA', (125, 134))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('IGF-2', 'Gene', (153, 158))	('cancer', 'Disease', (60, 66))	('Over-expression', 'Var', (0, 15))	('mediates', 'Reg', (82, 90))	('IR-A', 'Gene', (19, 23))	('insulin', 'Gene', (141, 148))	('IGF-2', 'Gene', '3481', (153, 158))	('proliferation', 'CPA', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('insulin', 'Gene', '3630', (141, 148))	('cell survival', 'CPA', (91, 104))
71034	24391834	Indeed, epidemiological investigations report that metformin treatment is associated with a decreased incidence of cancers in several organs, such as breast, prostate, colon, and pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (179, 196))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('prostate', 'Disease', 'MESH:D011472', (158, 166))	('colon', 'Disease', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('metformin', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('prostate', 'Disease', (158, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (179, 196))	('decreased', 'NegReg', (92, 101))	('breast', 'Disease', (150, 156))	('metformin', 'Chemical', 'MESH:D008687', (51, 60))	('pancreatic cancer', 'Disease', (179, 196))
71035	24391834	In addition, in clinical settings, metformin improves outcome of diabetic cancers patients, either as single agent as well as in combination with chemotherapeutic drugs, suggesting a potential role on cancer therapy.	('diabetic cancers', 'Disease', (65, 81))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('metformin', 'Var', (35, 44))	('outcome', 'Disease', (54, 61))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('improves', 'PosReg', (45, 53))	('diabetic cancers', 'Disease', 'MESH:D003920', (65, 81))	('metformin', 'Chemical', 'MESH:D008687', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
71037	24391834	At the cellular level, there is considerable evidence showing that metformin partially inhibits complex-I of the respiratory chain in mitochondria, leading to reduced oxidative phosphorylation and reduced ATP production.	('complex-I of the respiratory chain in', 'Enzyme', (96, 133))	('metformin', 'Chemical', 'MESH:D008687', (67, 76))	('reduced', 'NegReg', (159, 166))	('reduced', 'NegReg', (197, 204))	('inhibits', 'NegReg', (87, 95))	('oxidative phosphorylation', 'MPA', (167, 192))	('ATP', 'Gene', '51761', (205, 208))	('ATP', 'Gene', (205, 208))	('metformin', 'Var', (67, 76))
71054	24391834	The following loci were verified: D16S539, D18S51, D19S433, D21S11, D2S1338, D3S1358, D5S818, D8S1179, FGA, SE33, TH01, TPOX VWA.	('D21S11', 'Var', (60, 66))	('D8S1179', 'Var', (94, 101))	('D3S1358', 'Var', (77, 84))	('D2S1338', 'Var', (68, 75))	('FGA', 'Gene', '2243', (103, 106))	('D5S818', 'Var', (86, 92))	('FGA', 'Gene', (103, 106))	('D18S51', 'Var', (43, 49))	('D16S539', 'Var', (34, 41))	('D19S433', 'Var', (51, 58))
71079	24391834	Mice treated with metformin received the drug either in drinking water (200 mg/Kg, for 3 weeks) or through daily intratumor injection (200 mg/Kg in PBS, 5 days weekly, for 3 weeks) or through daily gavage at 500 mg/kg, 5 days weekly, for 2 weeks.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('PBS', 'Chemical', '-', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('drinking water', 'Chemical', 'MESH:D060766', (56, 70))	('Mice', 'Species', '10090', (0, 4))	('metformin', 'Chemical', 'MESH:D008687', (18, 27))	('200 mg/Kg', 'Var', (135, 144))
71106	24391834	These results demonstrate that, in Ewing sarcoma cells, metformin initiates a strong metabolic stress which very likely leads to direct activation of AMPK.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('metabolic stress', 'MPA', (85, 101))	('AMPK', 'Gene', '5563', (150, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('AMPK', 'Gene', (150, 154))	('metformin', 'Var', (56, 65))	('activation', 'PosReg', (136, 146))	('metformin', 'Chemical', 'MESH:D008687', (56, 65))	('Ewing sarcoma', 'Disease', (35, 48))
71107	24391834	Differences in time-dependent activation of AMPK reflect the variable effectiveness of metformin: in TC-71, the most sensitive cell line, metformin induced phosphorylation of AMPKalpha after 30min of treatment, in SK-N-MC after 1h, while in 6647 we observed increased levels of p-AMPKalpha after 6 h (Figure 3C).	('AMPK', 'Gene', (280, 284))	('AMPK', 'Gene', '5563', (175, 179))	('TC-71', 'Chemical', '-', (101, 106))	('AMPK', 'Gene', (44, 48))	('AMPK', 'Gene', '5563', (44, 48))	('metformin', 'Var', (138, 147))	('AMPK', 'Gene', (175, 179))	('AMPK', 'Gene', '5563', (280, 284))	('metformin', 'Chemical', 'MESH:D008687', (87, 96))	('metformin', 'Chemical', 'MESH:D008687', (138, 147))	('SK-N-MC', 'CellLine', 'CVCL:0530', (214, 221))	('phosphorylation', 'MPA', (156, 171))	('1h', 'Chemical', '-', (228, 230))
71113	24391834	Specifically, metformin was found to decrease the expression of many genes involved in mitosis and may alter cell proliferation or induce cell death depending on the status of p53.	('cell proliferation', 'CPA', (109, 127))	('decrease', 'NegReg', (37, 45))	('mitosis', 'Disease', (87, 94))	('mitosis', 'Disease', 'None', (87, 94))	('p53', 'Gene', (176, 179))	('metformin', 'Var', (14, 23))	('induce', 'Reg', (131, 137))	('p53', 'Gene', '7157', (176, 179))	('cell death', 'CPA', (138, 148))	('alter', 'Reg', (103, 108))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('expression', 'MPA', (50, 60))
71115	24391834	Most of our cell lines display mutated p53 (Table 1) but no induction of apoptosis was observed after metformin exposure (data not shown).	('p53', 'Gene', (39, 42))	('metformin', 'Chemical', 'MESH:D008687', (102, 111))	('p53', 'Gene', '7157', (39, 42))	('mutated', 'Var', (31, 38))
71116	24391834	In contrast, in the Ewing sarcoma cells TC-71, SK-N-MC and 6647, showing a truncation (TC-71) or major deletions (SK-N-MC) inactivating p53 transcriptional activity, or carrying the single point mutation S241F in the DNA binding domain which retains part of the wt-p53 activity (6647), metformin treatment led to accumulation of cells in G1 phase (Figure 3D).	('p53', 'Gene', (265, 268))	('S241F', 'Var', (204, 209))	('Ewing sarcoma', 'Disease', (20, 33))	('accumulation', 'PosReg', (313, 325))	('p53', 'Gene', '7157', (136, 139))	('transcriptional activity', 'MPA', (140, 164))	('S241F', 'Mutation', 'rs28934573', (204, 209))	('p53', 'Gene', (136, 139))	('TC-71', 'Chemical', '-', (87, 92))	('SK-N-MC', 'CellLine', 'CVCL:0530', (47, 54))	('inactivating', 'NegReg', (123, 135))	('G1 phase', 'CPA', (338, 346))	('TC-71', 'Chemical', '-', (40, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (20, 33))	('metformin', 'Chemical', 'MESH:D008687', (286, 295))	('p53', 'Gene', '7157', (265, 268))	('SK-N-MC', 'CellLine', 'CVCL:0530', (114, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))
71120	24391834	Combined treatments with vincristine, doxorubicin, actinomycin-D and ifosfamide, the main drugs currently used in the therapy of sarcoma patients, showed that metformin produced significant increases in the efficacy of chemotherapeutic agents, with synergistic or additive effects (Table 2).	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('efficacy', 'MPA', (207, 215))	('ifosfamide', 'Chemical', 'MESH:D007069', (69, 79))	('increases', 'PosReg', (190, 199))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('patients', 'Species', '9606', (137, 145))	('doxorubicin', 'Chemical', 'MESH:D004317', (38, 49))	('vincristine', 'Chemical', 'MESH:D014750', (25, 36))	('metformin', 'Var', (159, 168))	('sarcoma', 'Disease', (129, 136))	('metformin', 'Chemical', 'MESH:D008687', (159, 168))	('actinomycin-D', 'Chemical', 'MESH:D003609', (51, 64))
71148	24391834	Metformin may represent a possibility that deserves to be explored, particularly in pediatric sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Metformin', 'Var', (0, 9))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('pediatric sarcomas', 'Disease', (84, 102))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (84, 102))
71156	24391834	Polymorphisms or mutations in the genes encoding for these transporters have been described and may affect metformin effects as well as tumor LKB1 expression.	('affect', 'Reg', (100, 106))	('metformin effects', 'MPA', (107, 124))	('expression', 'MPA', (147, 157))	('Polymorphisms', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('LKB1', 'Gene', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('LKB1', 'Gene', '6794', (142, 146))	('metformin', 'Chemical', 'MESH:D008687', (107, 116))	('tumor', 'Disease', (136, 141))	('mutations', 'Var', (17, 26))
71158	24391834	Through these events, and in relation to the level of inhibition in the different cells, metformin reduces cell growth and induces cell-cycle arrest at G1 phase.	('cell growth', 'CPA', (107, 118))	('metformin', 'Var', (89, 98))	('induces', 'Reg', (123, 130))	('cell-cycle arrest at G1 phase', 'CPA', (131, 160))	('metformin', 'Chemical', 'MESH:D008687', (89, 98))	('reduces', 'NegReg', (99, 106))
71159	24391834	Despite that most of sarcoma cell lines display deficient p53 functions metformin fails to induce apoptosis, thus suggesting that the drug may have clinical value in combination with other agents rather than alone.	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('sarcoma', 'Disease', (21, 28))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('deficient', 'Var', (48, 57))	('p53', 'Gene', (58, 61))	('metformin', 'Chemical', 'MESH:D008687', (72, 81))	('p53', 'Gene', '7157', (58, 61))
71162	24391834	Through AMPK-mediated inhibition of IRS-1 phosphorylation, metformin participates to the inhibition of the IGF/insulin pathway and shows potential advantages with respect to other mTOR inhibitors, such as rapamycin.	('metformin', 'Var', (59, 68))	('insulin', 'Gene', '3630', (111, 118))	('mTOR', 'Gene', (180, 184))	('AMPK', 'Gene', (8, 12))	('mTOR', 'Gene', '2475', (180, 184))	('inhibition', 'NegReg', (22, 32))	('metformin', 'Chemical', 'MESH:D008687', (59, 68))	('IRS-1', 'Gene', '3667', (36, 41))	('inhibition', 'NegReg', (89, 99))	('AMPK', 'Gene', '5563', (8, 12))	('advantages', 'PosReg', (147, 157))	('IRS-1', 'Gene', (36, 41))	('insulin', 'Gene', (111, 118))
71168	24391834	This effect together with recent evidence that metformin may protect against doxorubicin-induced cardiotoxicity and that it inhibits P-glycoprotein expression, one of the major adverse biomarkers in osteosarcoma further supported its potential use as adjuvant drug.	('osteosarcoma', 'Disease', (199, 211))	('doxorubicin', 'Chemical', 'MESH:D004317', (77, 88))	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('inhibits', 'NegReg', (124, 132))	('osteosarcoma', 'Phenotype', 'HP:0002669', (199, 211))	('osteosarcoma', 'Disease', 'MESH:D012516', (199, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('cardiotoxicity', 'Disease', 'MESH:D066126', (97, 111))	('cardiotoxicity', 'Disease', (97, 111))	('metformin', 'Var', (47, 56))	('P-glycoprotein', 'Gene', '5243', (133, 147))	('P-glycoprotein', 'Gene', (133, 147))
71187	24391834	It is thus possible that while in normoxia the metformin- induced glycolytic shift is able to generate a stress sufficient for cells to induce direct activation of AMPK, in hypoxia the accumulation of HIF1 may make respiration more efficient and protect cells from damages, including energy perturbations induced by metformin.	('accumulation', 'Var', (185, 197))	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('energy perturbations', 'MPA', (284, 304))	('AMPK', 'Gene', '5563', (164, 168))	('HIF1', 'Gene', '3091', (201, 205))	('respiration', 'MPA', (215, 226))	('more efficient', 'PosReg', (227, 241))	('make', 'PosReg', (210, 214))	('AMPK', 'Gene', (164, 168))	('hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('hypoxia', 'Disease', (173, 180))	('HIF1', 'Gene', (201, 205))	('metformin', 'Chemical', 'MESH:D008687', (316, 325))
71196	31658985	Combining radiotherapy with beta1 or alphaV integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins.	('alphaV integrin', 'Gene', (37, 52))	('monotargeting', 'Var', (53, 66))	('beta1', 'Protein', (28, 33))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('alphaV integrin', 'Gene', '16410', (37, 52))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
71214	31658985	We find that combined beta1/alphaV integrin targeting, but not interference with either integrin subset alone, effectively radiosensitizes and ablates local disease and suppresses metastatic progression.	('ablates local disease', 'Disease', (143, 164))	('suppresses', 'NegReg', (169, 179))	('radiosensitizes', 'NegReg', (123, 138))	('alphaV integrin', 'Gene', '16410', (28, 43))	('metastatic progression', 'CPA', (180, 202))	('targeting', 'Var', (44, 53))	('alphaV integrin', 'Gene', (28, 43))	('ablates local disease', 'Disease', 'MESH:D012594', (143, 164))
71258	31658985	In situ MAPK signaling, which supports cell growth and survival downstream of integrins, was diminished after beta1/beta3 integrin targeting to levels slightly below the stromal background (Fig.	('MAPK signaling', 'MPA', (8, 22))	('beta3', 'Gene', '28883', (116, 121))	('beta3', 'Gene', (116, 121))	('targeting', 'Var', (131, 140))	('diminished', 'NegReg', (93, 103))
71259	31658985	Notably after integrin targeting, the tumor core regressed, whereas the collective invasion zone retained low-level mitotic activity and persisted beyond day 13; however, with increased detachment of cell groups and individual cells as also previously shown in vitro (; Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('targeting', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('detachment', 'CPA', (186, 196))
71261	31658985	This survival advantage, however, was abrogated when beta1 integrin targeting was combined with fractionated IR, disrupting and shrinking the invasion zone (Fig.	('disrupting', 'NegReg', (113, 123))	('targeting', 'Var', (68, 77))	('beta1 integrin', 'Gene', '3688', (53, 67))	('shrinking', 'NegReg', (128, 137))	('beta1 integrin', 'Gene', (53, 67))	('invasion zone', 'CPA', (142, 155))
71272	31658985	Mice bearing emerging macroscopic and exponentially growing tumors were treated with antibodies 4B4 and 17E6, individually or combined, and irradiated using an adjusted, dose-conservative scheme (cumulative 10-15 Gy) to achieve relapsing disease in 70-80% of the cohort receiving nontargeting IgG1 isotypic control antibody (Fig.	('antibodies', 'Var', (85, 95))	('IgG1', 'Gene', (293, 297))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('achieve', 'PosReg', (220, 227))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('Mice', 'Species', '10090', (0, 4))	('relapsing', 'Disease', (228, 237))	('IgG1', 'Gene', '16017', (293, 297))	('tumors', 'Disease', (60, 66))
71297	31658985	This combination potentially targets 15 of 16 integrin members expressed by mesenchymal and epithelial tumor cells and previously tested in clinical trials, including alpha1-11beta1, alphaVbeta3, alphaVbeta5, alphaVbeta6, and alphaVbeta8.	('beta3', 'Gene', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('epithelial tumor', 'Phenotype', 'HP:0031492', (92, 108))	('tumor', 'Disease', (103, 108))	('beta6', 'Gene', '19230', (215, 220))	('beta6', 'Gene', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('beta3', 'Gene', '28883', (189, 194))	('alpha1-11beta1', 'Var', (167, 181))
71309	31658985	ShRNA sequences targeting ITGB1 (beta1 integrin, 5'-AGCCACAGACATTTACATTAAA-3') and ITGB3 (beta3 integrin, 5'-AAGTCACTTTCTTCTTCTTAAA-3') for gene silencing by RNAi were cloned into the lentiviral vector pLBM containing either a puromycin (p-puro) or a neomycin (p-neo) cassette, and lentiviral particles were produced and concentrated by ultracentrifugation, as described.	('p-puro', 'Chemical', '-', (238, 244))	('beta1 integrin', 'Gene', '3688', (33, 47))	('gene', 'Var', (140, 144))	('beta3', 'Gene', '28883', (90, 95))	('puromycin', 'Chemical', 'MESH:D011691', (227, 236))	('neomycin', 'Chemical', 'MESH:D009355', (251, 259))	('beta3', 'Gene', (90, 95))	('beta1 integrin', 'Gene', (33, 47))	('ITGB3', 'Gene', (83, 88))	('p-neo', 'Chemical', '-', (261, 266))	('ITGB1', 'Gene', (26, 31))
71310	31658985	HT-1080 dual-color cells were infected with p-puro or p-neo viruses (vector controls), or with ITGB1 (on p-puro) or ITGB3 targeting (on p-neo) pLBM viruses.	('infected', 'Disease', 'MESH:D007239', (30, 38))	('ITGB1', 'Gene', (95, 100))	('HT-1080', 'CellLine', 'CVCL:0317', (0, 7))	('ITGB3', 'Gene', (116, 121))	('p-neo', 'Chemical', '-', (54, 59))	('p-puro', 'Chemical', '-', (105, 111))	('p-puro', 'Chemical', '-', (44, 50))	('infected', 'Disease', (30, 38))	('p-neo', 'Chemical', '-', (136, 141))	('p-puro', 'Var', (44, 50))
71311	31658985	For generation of double knockdown cells, HT-1080 p-puro or HT-1080 beta1RNAi cells were additionally infected with ITGB3 targeting or p-neo viruses, respectively.	('infected', 'Disease', 'MESH:D007239', (102, 110))	('ITGB3', 'Gene', (116, 121))	('infected', 'Disease', (102, 110))	('p-puro', 'Chemical', '-', (50, 56))	('HT-1080', 'CellLine', 'CVCL:0317', (42, 49))	('p-neo', 'Var', (135, 140))	('HT-1080', 'CellLine', 'CVCL:0317', (60, 67))	('p-neo', 'Chemical', '-', (135, 140))
71363	31658985	Hypoxia and phospho-p44/42-MAPK signals were detected in tumors 7 d after implantation from window-bearing mice.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mice', 'Species', '10090', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('phospho-p44/42-MAPK', 'Var', (12, 31))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
71376	31658985	beta1 integrin knockdown efficiency in HT-1080 cells was detected by protein gel electrophoresis and Western blot analysis using whole-cell lysates.	('beta1 integrin', 'Gene', (0, 14))	('beta1 integrin', 'Gene', '3688', (0, 14))	('knockdown', 'Var', (15, 24))	('HT-1080', 'CellLine', 'CVCL:0317', (39, 46))
71447	31260491	Recently, a study revealed that high serum CRP level was significantly associated with PD-L1 (programmed death-ligand 1) positivity in patients with non-small cell lung cancer.	('PD-L1', 'Gene', '29126', (87, 92))	('non-small cell lung cancer', 'Disease', (149, 175))	('patients', 'Species', '9606', (135, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (153, 175))	('positivity', 'Var', (121, 131))	('CRP', 'Gene', (43, 46))	('high serum CRP', 'Phenotype', 'HP:0011227', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('programmed death-ligand 1', 'Gene', (94, 119))	('programmed death-ligand 1', 'Gene', '29126', (94, 119))	('CRP', 'Gene', '1401', (43, 46))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (149, 175))	('PD-L1', 'Gene', (87, 92))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (149, 175))
71548	25453903	At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters.	('EWS-FLI1', 'Gene', '2130;2313', (108, 116))	('multimers', 'Var', (117, 126))	('induce', 'PosReg', (127, 133))	('enhancers', 'PosReg', (171, 180))	('opening', 'Disease', 'MESH:D005597', (144, 151))	('opening', 'Disease', (144, 151))	('EWS-FLI1', 'Gene', (108, 116))
71555	25453903	This is in sharp contrast to most tumors in adults where the genome-wide analysis of regulatory networks is complicated by many recurrent mutations and genomic instability.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('mutations', 'Var', (138, 147))
71557	25453903	Ewing sarcoma is characterized by chromosomal translocations that generate fusions between the EWS gene and members of the ETS family of transcription factors, by far the most common being FLI1.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('common', 'Reg', (176, 182))	('FLI1', 'Gene', '2313', (189, 193))	('fusions', 'Var', (75, 82))	('FLI1', 'Gene', (189, 193))	('Ewing sarcoma', 'Disease', (0, 13))	('EWS', 'Gene', '2130', (95, 98))	('EWS', 'Gene', (95, 98))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))
71574	25453903	We also mapped these modifications in a set of primary Ewing sarcoma tumors and in MSCs.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('modifications', 'Var', (21, 34))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('MSCs', 'Disease', (83, 87))	('Ewing sarcoma tumors', 'Disease', (55, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (55, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (55, 68))
71576	25453903	1A, 86% of sites are concordant for H3K4me1 and 75% for H3K27ac), but distinct from those in mesenchymal stem cells, suggesting that the cell line models are representative of the native tumor environment at these sites (Fig.	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('H3K4me1', 'Var', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (187, 192))
71579	25453903	However, we observed essentially no overlap between EWS-FLI1 binding sites and H3K27me3, a repressive modification deposited by Polycomb repressive complexes, in either the cell lines or the primary tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('EWS-FLI1', 'Gene', '2130;2313', (52, 60))	('H3K27me3', 'Var', (79, 87))	('primary tumors', 'Disease', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('EWS-FLI1', 'Gene', (52, 60))	('primary tumors', 'Disease', 'MESH:D009369', (191, 205))
71583	25453903	EWS-FLI1 depletion significantly altered global enhancer patterns in the tumor cell lines, such that they more closely resembled the non-transformed MSCs (Fig.	('enhancer', 'PosReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('EWS-FLI1', 'Gene', (0, 8))	('tumor', 'Disease', (73, 78))	('altered', 'Reg', (33, 40))	('global', 'MPA', (41, 47))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('depletion', 'Var', (9, 18))
71584	25453903	In particular,, loss of EWS-FLI1 elicited divergent responses at target sites, with some cis-regulatory elements displaying marked increases in H3K27ac levels and others displaying equally strong decreases in this marker for enhancer activity (Fig.	('decreases', 'NegReg', (196, 205))	('increases', 'PosReg', (131, 140))	('cis-regulatory', 'MPA', (89, 103))	('loss', 'Var', (16, 20))	('H3K27ac levels', 'MPA', (144, 158))	('EWS-FLI1', 'Gene', (24, 32))	('EWS-FLI1', 'Gene', '2130;2313', (24, 32))
71590	25453903	We then mapped p300 binding genome-wide before and after EWS-FLI1 knock-down in the Ewing sarcoma lines.	('EWS-FLI1', 'Gene', (57, 65))	('p300', 'Gene', '2033', (15, 19))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma lines', 'Disease', 'MESH:C563168', (84, 103))	('EWS-FLI1', 'Gene', '2130;2313', (57, 65))	('knock-down', 'Var', (66, 76))	('p300', 'Gene', (15, 19))	('Ewing sarcoma lines', 'Disease', (84, 103))
71595	25453903	GGAA repeats have been previously implicated in Ewing sarcoma on the basis of their association with open chromatin and proximity to some activated genes.	('association', 'Interaction', (84, 95))	('repeats', 'Var', (5, 12))	('GGAA', 'Gene', (0, 4))	('Ewing sarcoma', 'Disease', (48, 61))	('implicated', 'Reg', (34, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('open chromatin', 'MPA', (101, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (48, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (48, 61))
71605	25453903	In contrast to other cell types where expression of EWS-FLI1 leads to growth arrest and apoptosis, induction of the fusion in MSCs results in transformation and activation of a set of genes that closely recapitulate the Ewing sarcoma phenotype.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('fusion', 'Var', (116, 122))	('EWS-FLI1', 'Gene', '2130;2313', (52, 60))	('growth arrest', 'Phenotype', 'HP:0001510', (70, 83))	('Ewing sarcoma', 'Disease', (220, 233))	('arrest', 'Disease', 'MESH:D006323', (77, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (220, 233))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (220, 233))	('activation', 'PosReg', (161, 171))	('EWS-FLI1', 'Gene', (52, 60))	('MSCs', 'Gene', (126, 130))	('arrest', 'Disease', (77, 83))	('transformation', 'MPA', (142, 156))
71609	25453903	Moreover, EWS-FLI1 induction causes significant increases in both H3K4me1 and H3K27ac at 78% of these sites, resulting in an active enhancer-like pattern analogous to their state in Ewing sarcoma cell lines and primary tissues (Fig.	('increases', 'PosReg', (48, 57))	('active', 'MPA', (125, 131))	('Ewing sarcoma', 'Disease', (182, 195))	('H3K27ac', 'Protein', (78, 85))	('EWS-FLI1', 'Gene', (10, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('H3K4me1', 'Protein', (66, 73))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('induction', 'Var', (19, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('enhancer-like', 'PosReg', (132, 145))	('EWS-FLI1', 'Gene', '2130;2313', (10, 18))
71617	25453903	Given that our data point to a direct distal regulatory role for EWS-FLI1 bound GGAA repeats and that variations in repeat size have been proposed as a potential contributor to Ewing sarcoma susceptibility, we also considered whether EWS-FLI1 bound repeat elements may exhibit length variability.	('variations', 'Var', (102, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (177, 190))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (177, 190))	('EWS-FLI1', 'Gene', (234, 242))	('GGAA', 'Protein', (80, 84))	('EWS-FLI1', 'Gene', (65, 73))	('EWS-FLI1', 'Gene', '2130;2313', (234, 242))	('Ewing sarcoma', 'Disease', (177, 190))	('EWS-FLI1', 'Gene', '2130;2313', (65, 73))
71624	25453903	We surveyed ELF1 binding in SKNMC cells by ChIP-seq before and after EWS-FLI1 knock-down (Fig.	('EWS-FLI1', 'Gene', '2130;2313', (69, 77))	('knock-down', 'Var', (78, 88))	('ELF1', 'Gene', '1997', (12, 16))	('ELF1', 'Gene', (12, 16))	('EWS-FLI1', 'Gene', (69, 77))
71627	25453903	A combined analysis of ELF1 and GABPA occupancy changes shows that repressed sites may exhibit increases in either transcription factor separately or a gain of both ELF1 and GABPA together after EWS-FLI1 knock-down (Fig.	('GABPA', 'Gene', (174, 179))	('GABPA', 'Gene', '2551', (32, 37))	('gain', 'PosReg', (152, 156))	('ELF1', 'Gene', '1997', (23, 27))	('increases', 'PosReg', (95, 104))	('GABPA', 'Gene', '2551', (174, 179))	('ELF1', 'Gene', '1997', (165, 169))	('knock-down', 'Var', (204, 214))	('ELF1', 'Gene', (23, 27))	('EWS-FLI1', 'Gene', (195, 203))	('GABPA', 'Gene', (32, 37))	('ELF1', 'Gene', (165, 169))	('EWS-FLI1', 'Gene', '2130;2313', (195, 203))	('transcription factor', 'MPA', (115, 135))
71632	25453903	We performed RNA sequencing (RNA-seq) in the Ewing sarcoma lines before and after EWS-FLI1 knock-down.	('Ewing sarcoma lines', 'Disease', 'MESH:C563168', (45, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('Ewing sarcoma lines', 'Disease', (45, 64))	('EWS-FLI1', 'Gene', (82, 90))	('EWS-FLI1', 'Gene', '2130;2313', (82, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('knock-down', 'Var', (91, 101))
71638	25453903	For example, PRKCB encodes protein kinase C-beta, whose knock-down has previously been shown to induce apoptosis in Ewing cell lines.	('induce', 'Reg', (96, 102))	('knock-down', 'Var', (56, 66))	('C-beta', 'Species', '10703', (42, 48))	('apoptosis', 'CPA', (103, 112))	('PRKCB', 'Gene', (13, 18))
71643	25453903	EWS-FLI1 knock-down markedly reduced VRK1 expression in the cell lines, while EWS-FLI1 induction was sufficient to up-regulate this kinase in MSCs (Fig.	('EWS-FLI1', 'Gene', (78, 86))	('expression', 'MPA', (42, 52))	('EWS-FLI1', 'Gene', (0, 8))	('MSCs', 'Disease', (142, 146))	('reduced', 'NegReg', (29, 36))	('VRK1', 'Gene', '7443', (37, 41))	('up-regulate', 'PosReg', (115, 126))	('knock-down', 'Var', (9, 19))	('EWS-FLI1', 'Gene', '2130;2313', (78, 86))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('VRK1', 'Gene', (37, 41))
71644	25453903	We directly tested the dependence of Ewing sarcoma cell lines on VRK1 by shRNA knock-down (Fig.	('VRK1', 'Gene', '7443', (65, 69))	('Ewing sarcoma', 'Disease', (37, 50))	('tested', 'Reg', (12, 18))	('knock-down', 'Var', (79, 89))	('VRK1', 'Gene', (65, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (37, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
71646	25453903	In contrast, VRK1 depletion in non-Ewing sarcoma cell lines only moderately decreased proliferation and failed to trigger apoptosis, consistent with recent studies of its function in other tumor models.	('tumor', 'Disease', (189, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('proliferation', 'CPA', (86, 99))	('decreased', 'NegReg', (76, 85))	('depletion', 'Var', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('VRK1', 'Gene', '7443', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('non-Ewing sarcoma', 'Disease', 'MESH:C563168', (31, 48))	('non-Ewing sarcoma', 'Disease', (31, 48))	('VRK1', 'Gene', (13, 17))
71647	25453903	Finally, injection of VRK1-depleted SKNMC cells immediately after lentiviral infection resulted in a marked decrease in tumor development in vivo (p-value < 10-5), confirming the critical role of this direct target in sustaining tumor cell proliferation and survival (Fig.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('lentiviral', 'Var', (66, 76))	('infection', 'Disease', 'MESH:D007239', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('VRK1', 'Gene', '7443', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('decrease', 'NegReg', (108, 116))	('VRK1', 'Gene', (22, 26))	('infection', 'Disease', (77, 86))	('tumor', 'Disease', (120, 125))
71658	25453903	EWS-FLI1 expression in mesenchymal stem cells can induce de novo chromatin opening and creation of active enhancers that closely resemble those present in Ewing cells lines and primary tumors.	('expression', 'Var', (9, 19))	('enhancers', 'PosReg', (106, 115))	('primary tumors', 'Disease', 'MESH:D009369', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('EWS-FLI1', 'Gene', (0, 8))	('primary tumors', 'Disease', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('induce', 'Reg', (50, 56))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('opening', 'Disease', 'MESH:D005597', (75, 82))	('opening', 'Disease', (75, 82))
71659	25453903	Interestingly, while enhancers are often populated and driven by the binding of multiple collaborative transcription factors, our data suggest that the configuration of EWS-FLI1 as multimers at repeat sites is on its own sufficient to open chromatin and recruit methyltransferase and acetyltransferase activities to generate de novo active regulatory elements.	('methyltransferase', 'Enzyme', (262, 279))	('recruit', 'PosReg', (254, 261))	('acetyltransferase', 'Enzyme', (284, 301))	('EWS-FLI1', 'Gene', (169, 177))	('EWS-FLI1', 'Gene', '2130;2313', (169, 177))	('configuration', 'Var', (152, 165))	('open chromatin', 'MPA', (235, 249))
71676	25453903	This is exemplified by the association between an aberrant distal regulatory element controlling VRK1 expression and the preferential dependency of Ewing sarcoma cells on this cell-cycle dependent kinase.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (148, 161))	('VRK1', 'Gene', '7443', (97, 101))	('association', 'Interaction', (27, 38))	('VRK1', 'Gene', (97, 101))	('Ewing sarcoma', 'Disease', (148, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('aberrant', 'Var', (50, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (148, 161))
71684	25453903	For knock-down experiments, the following lentiviral shRNAs were obtained from the RNAi Consortium in the pLKO.1 vector: FLI1 (TRCN0000005322), VRK1 (TRCN0000197134, TRCN0000002133).	('VRK1', 'Gene', (144, 148))	('FLI1', 'Gene', (121, 125))	('TRCN0000002133', 'Var', (166, 180))	('FLI1', 'Gene', '2313', (121, 125))	('TRCN0000005322', 'Var', (127, 141))	('TRCN0000197134', 'Var', (150, 164))	('VRK1', 'Gene', '7443', (144, 148))
71692	25453903	Solubilized chromatin was immunoprecipitated with antibodies against H3K4me3 (Millipore), H3K27me3 (Millipore), H3K27ac (Abcam, Active Motif), H3K4me1 (Abcam), FLI1 (Santa Cruz, sc-356), ELF1 (Santa Cruz, sc-631), GABPA (Santa Cruz, sc-22810), p300 (Santa Cruz, sc-585) or WDR5 (Bethyl, A302-429A).	('WDR5', 'Gene', '11091', (273, 277))	('WDR5', 'Gene', (273, 277))	('ELF1', 'Gene', (187, 191))	('ELF1', 'Gene', '1997', (187, 191))	('p300', 'Gene', (244, 248))	('FLI1', 'Gene', (160, 164))	('GABPA', 'Gene', '2551', (214, 219))	('H3K27me3', 'Var', (90, 98))	('p300', 'Gene', '2033', (244, 248))	('FLI1', 'Gene', '2313', (160, 164))	('H3K4me3', 'Var', (69, 76))	('H3K27ac', 'Var', (112, 119))	('H3K4me1', 'Var', (143, 150))	('GABPA', 'Gene', (214, 219))
71694	25453903	Direct enhancer activation or repression by a single aberrant transcription factor Chromatin remodeling at enhancer elements is dictated by underlying DNA sequence Divergent recruitment of chromatin remodeling complexes by EWS-FLI1 De novo enhancers mediate tumor dependencies Cancer genome studies have identified many alterations in transcriptional regulators that have the potential to promote oncogenic gene expression programs.	('Cancer', 'Disease', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('EWS-FLI1', 'Gene', '2130;2313', (223, 231))	('alterations', 'Var', (320, 331))	('Cancer', 'Disease', 'MESH:D009369', (277, 283))	('Cancer', 'Phenotype', 'HP:0002664', (277, 283))	('oncogenic', 'CPA', (397, 406))	('tumor dependencies', 'Disease', 'MESH:D019966', (258, 276))	('tumor dependencies', 'Disease', (258, 276))	('EWS-FLI1', 'Gene', (223, 231))	('promote', 'PosReg', (389, 396))
71695	25453903	The impact of such changes is particularly evident in pediatric malignancies, where they may represent the sole event in tumor initiation.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('changes', 'Var', (19, 26))	('tumor', 'Disease', (121, 126))	('pediatric malignancies', 'Disease', 'MESH:D063766', (54, 76))	('pediatric malignancies', 'Disease', (54, 76))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
71713	31635323	Upregulation of class III beta-tubulin confers taxane resistance in colon, prostate, breast, and ovarian/uterine carcinosarcoma and serous carcinoma, among others, in part due to alterations in the binding pocket conferring reduced affinity of paclitaxel and docetaxel.	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (105, 127))	('serous carcinoma', 'Disease', 'MESH:D018284', (132, 148))	('taxane resistance', 'MPA', (47, 64))	('affinity', 'MPA', (232, 240))	('paclitaxel', 'Chemical', 'MESH:D017239', (244, 254))	('ovarian', 'Disease', 'MESH:D010049', (97, 104))	('taxane', 'Chemical', 'MESH:C080625', (47, 53))	('breast', 'Disease', (85, 91))	('alterations', 'Var', (179, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('reduced', 'NegReg', (224, 231))	('class III beta-tubulin', 'Gene', (16, 38))	('colon', 'Disease', (68, 73))	('carcinosarcoma', 'Disease', (113, 127))	('ovarian', 'Disease', (97, 104))	('carcinosarcoma', 'Disease', 'MESH:D002296', (113, 127))	('Upregulation', 'PosReg', (0, 12))	('binding pocket', 'Interaction', (198, 212))	('serous carcinoma', 'Disease', (132, 148))	('class III beta-tubulin', 'Gene', '10381', (16, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('prostate', 'Disease', (75, 83))	('docetaxel', 'Chemical', 'MESH:C067311', (259, 268))
71715	31635323	Overexpression of class III beta-tubulin has robustly been associated with chemoresistance and poor clinical outcome.	('associated', 'Reg', (59, 69))	('chemoresistance', 'CPA', (75, 90))	('class III beta-tubulin', 'Gene', '10381', (18, 40))	('class III beta-tubulin', 'Gene', (18, 40))	('Overexpression', 'Var', (0, 14))
71726	31635323	Pharmacologic targeting of the EP4 receptor can halt this cascade.	('EP4', 'Gene', '5734', (31, 34))	('EP4', 'Gene', (31, 34))	('Pharmacologic targeting', 'Var', (0, 23))
71730	31635323	In osteosarcoma, a recent meta-analysis found that COX-2 expression predicted reduced 2-year overall and disease-free survival, without significant association with age, gender, tumor location, histology, stage, metastasis, or necrosis.	('COX-2', 'Gene', (51, 56))	('tumor', 'Disease', (178, 183))	('osteosarcoma', 'Disease', (3, 15))	('COX-2', 'Gene', '5743', (51, 56))	('expression', 'Var', (57, 67))	('necrosis', 'Disease', (227, 235))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('necrosis', 'Disease', 'MESH:D009336', (227, 235))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('reduced', 'NegReg', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('disease-free survival', 'CPA', (105, 126))
71760	31635323	As measured by densitometry, EP4 was significantly overexpressed in SK-UT-1 and SK-UT-1B by approximately 9- and 8-fold higher, respectively, compared to PHM1-41 cells (Figure 4B).	('EP4', 'Gene', '5734', (29, 32))	('SK-UT-1B', 'Var', (80, 88))	('higher', 'PosReg', (120, 126))	('overexpressed', 'PosReg', (51, 64))	('EP4', 'Gene', (29, 32))
71767	31635323	Similarly, expression for both class III beta-tubulin and EP4 was significantly increased in the cytoplasmic portions of SK-UT-1 and SK-UT-1B, replicating what was observed for the total protein Western blots.	('expression', 'MPA', (11, 21))	('increased', 'PosReg', (80, 89))	('SK-UT-1B', 'Var', (133, 141))	('EP4', 'Gene', '5734', (58, 61))	('class III beta-tubulin', 'Gene', '10381', (31, 53))	('SK-UT-1', 'Var', (121, 128))	('EP4', 'Gene', (58, 61))	('class III beta-tubulin', 'Gene', (31, 53))
71776	31635323	The EP4 antagonist RQ15986 also lead to a decrease in the migration of SK-UT-1 by 75%; however, for unknown reasons, we did not observe inhibition in a dose responsive manner (10 microM and 3 microM, p < 0.05) (Figure 5A).	('migration', 'CPA', (58, 67))	('RQ15986', 'Chemical', 'MESH:C043461', (19, 26))	('decrease', 'NegReg', (42, 50))	('EP4', 'Gene', (4, 7))	('EP4', 'Gene', '5734', (4, 7))	('RQ15986', 'Var', (19, 26))
71777	31635323	For SK-UT-1B, migration was decreased by up to 50% in a dose-dependent response with either AH23848 or RQ15986; however, we did not reach statistical significance compared to the positive control (Figure 5B).	('migration', 'CPA', (14, 23))	('decreased', 'NegReg', (28, 37))	('AH23848', 'Var', (92, 99))	('RQ15986', 'Var', (103, 110))	('AH23848', 'Chemical', 'MESH:C046926', (92, 99))	('SK-UT-1B', 'Var', (4, 12))	('RQ15986', 'Chemical', 'MESH:C043461', (103, 110))
71779	31635323	Using a DNA content-based assay, we observed negligible effects on proliferation in SK-UT-1 and SK-UT-1B when treated with AH23848 or RQ15986 (Figure 6A,B).	('AH23848', 'Var', (123, 130))	('RQ15986', 'Var', (134, 141))	('AH23848', 'Chemical', 'MESH:C046926', (123, 130))	('RQ15986', 'Chemical', 'MESH:C043461', (134, 141))
71783	31635323	Pre-treatment with EP4 antagonists AH23848 or RQ15986 resulted in a significant increase in sensitivity to treatment with docetaxel in SK-UT-1 cells (Figure 6D).	('sensitivity to treatment with docetaxel', 'MPA', (92, 131))	('docetaxel', 'Chemical', 'MESH:C067311', (122, 131))	('AH23848', 'Chemical', 'MESH:C046926', (35, 42))	('RQ15986', 'Chemical', 'MESH:C043461', (46, 53))	('increase', 'PosReg', (80, 88))	('EP4', 'Gene', (19, 22))	('EP4', 'Gene', '5734', (19, 22))	('RQ15986', 'Var', (46, 53))	('AH23848', 'Var', (35, 42))
71784	31635323	A 2-fold sensitization occurred when cells were treated with AH23848 with a decrease in the IC50 from 1.47 nM for docetaxel as a single agent to 0.6 nM (p < 0.01) when combined with 10 microM AH23848 and 0.46 nM (p < 0.001) when combined with 0.5 microM AH23848.	('AH23848', 'Chemical', 'MESH:C046926', (254, 261))	('AH23848', 'Var', (61, 68))	('IC50', 'MPA', (92, 96))	('AH23848', 'Chemical', 'MESH:C046926', (61, 68))	('decrease', 'NegReg', (76, 84))	('docetaxel', 'Chemical', 'MESH:C067311', (114, 123))	('AH23848', 'Chemical', 'MESH:C046926', (192, 199))
71786	31635323	when treated with 30 microM RQ15986 and 0.66 nM (p < 0.01) when treated with 3 microM RQ15986 compared to an IC50 of 1.47 nM for single agent docetaxel (Figure 6D).	('RQ15986', 'Var', (86, 93))	('RQ15986', 'Var', (28, 35))	('docetaxel', 'Chemical', 'MESH:C067311', (142, 151))	('RQ15986', 'Chemical', 'MESH:C043461', (86, 93))	('RQ15986', 'Chemical', 'MESH:C043461', (28, 35))
71787	31635323	The difference in chemosensitization between SK-UT-1 and SK-UT-1B when pre-treated with EP4 antagonists may be due to differences in EP4 protein expression since SK-UT-1 has higher EP4 expression compared to SK-UT-1B (Figure 6E).	('expression', 'MPA', (185, 195))	('EP4', 'Gene', (88, 91))	('EP4', 'Gene', '5734', (133, 136))	('EP4', 'Gene', '5734', (88, 91))	('higher', 'PosReg', (174, 180))	('EP4', 'Gene', (133, 136))	('EP4', 'Gene', '5734', (181, 184))	('SK-UT-1', 'Var', (162, 169))	('EP4', 'Gene', (181, 184))
71800	31635323	SK-UT-1 and SK-UT-1B represent the malignant mesenchymal and epithelial components from a uterine grade III mesodermal mixed tumor consistent with leiomyosarcoma (carcinosarcoma) derived from a 75-year-old, female, Caucasian patient.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('SK-UT-1B', 'Var', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('carcinosarcoma', 'Disease', 'MESH:D002296', (163, 177))	('tumor', 'Disease', (125, 130))	('leiomyosarcoma', 'Disease', (147, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('patient', 'Species', '9606', (225, 232))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (147, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (147, 161))	('carcinosarcoma', 'Disease', (163, 177))
71803	31635323	Two EP4 antagonists were used AH23848 (Cayman Chemical) and RQ15986 (AskAt, Inc., Japan).	('AH23848', 'Var', (30, 37))	('RQ15986', 'Chemical', 'MESH:C043461', (60, 67))	('EP4', 'Gene', '5734', (4, 7))	('EP4', 'Gene', (4, 7))	('AH23848', 'Chemical', 'MESH:C046926', (30, 37))	('RQ15986', 'Var', (60, 67))
71829	31635323	However, knockdown of TUBB3 only partially recovered sensitivity to eribulin which suggests that class III beta-tubulin is not solely responsible for the observed eribulin resistance in SK-LMS-1.	('knockdown', 'Var', (9, 18))	('LMS', 'Phenotype', 'HP:0100243', (189, 192))	('sensitivity', 'MPA', (53, 64))	('TUBB3', 'Gene', (22, 27))	('TUBB3', 'Gene', '10381', (22, 27))	('class III beta-tubulin', 'Gene', '10381', (97, 119))	('SK-LMS-1', 'CellLine', 'CVCL:7020', (186, 194))	('class III beta-tubulin', 'Gene', (97, 119))
71851	31635323	All LMS (100%) exhibited EP4 expression >=1+; in contrast, negative staining for EP4 was observed in 12.5% of leiomyomatosis/STUMP, 18% of leiomyomas, and 17% of normal myometrium.	('LMS', 'Phenotype', 'HP:0100243', (4, 7))	('EP4', 'Gene', '5734', (81, 84))	('leiomyomas', 'Disease', 'MESH:D007889', (139, 149))	('LMS', 'Disease', 'MESH:D007890', (4, 7))	('EP4', 'Gene', (81, 84))	('EP4', 'Gene', (25, 28))	('leiomyomas', 'Disease', (139, 149))	('leiomyomatosis', 'Disease', 'MESH:D018231', (110, 124))	('EP4', 'Gene', '5734', (25, 28))	('>=1+', 'Var', (40, 44))	('LMS', 'Disease', (4, 7))	('leiomyomatosis', 'Disease', (110, 124))
71856	31635323	In the present study of LMS, low (<1+) cytoplasmic EP4 staining was associated with improved crude overall survival.	('LMS', 'Disease', (24, 27))	('crude overall survival', 'MPA', (93, 115))	('LMS', 'Phenotype', 'HP:0100243', (24, 27))	('LMS', 'Disease', 'MESH:D007890', (24, 27))	('low (<1+', 'Var', (29, 37))	('improved', 'PosReg', (84, 92))	('EP4', 'Gene', '5734', (51, 54))	('EP4', 'Gene', (51, 54))
71857	31635323	Overall, our findings suggest that cytoplasmic EP4 could serve as a biomarker for aggressive LMS.	('LMS', 'Disease', (93, 96))	('EP4', 'Gene', '5734', (47, 50))	('LMS', 'Phenotype', 'HP:0100243', (93, 96))	('LMS', 'Disease', 'MESH:D007890', (93, 96))	('EP4', 'Gene', (47, 50))	('cytoplasmic', 'Var', (35, 46))
71866	31635323	demonstrated in pre-clinical models that treatment with EP4 antagonist GW627368X reduces tumor chemoresistance of breast cancer and colorectal tumors in vivo when used in combination with paclitaxel, thus demonstrating that EP4 antagonists could be a viable addition to chemotherapeutic treatment for a variety of cancers including LMS.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Disease', (314, 321))	('colorectal tumors', 'Disease', (132, 149))	('EP4', 'Gene', '5734', (224, 227))	('EP4', 'Gene', (224, 227))	('reduces', 'NegReg', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('GW627368X', 'Chemical', 'MESH:C515270', (71, 80))	('tumor', 'Disease', (89, 94))	('EP4', 'Gene', '5734', (56, 59))	('EP4', 'Gene', (56, 59))	('colorectal tumors', 'Disease', 'MESH:D015179', (132, 149))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('LMS', 'Disease', 'MESH:D007890', (332, 335))	('tumor', 'Disease', (143, 148))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('LMS', 'Disease', (332, 335))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('paclitaxel', 'Chemical', 'MESH:D017239', (188, 198))	('LMS', 'Phenotype', 'HP:0100243', (332, 335))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('GW627368X', 'Var', (71, 80))	('breast cancer', 'Disease', (114, 127))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
71868	31635323	The potentially interesting finding is that, in spite of this, EP4 antagonists sensitize cells to docetaxel and other chemotherapeutics.	('antagonists', 'Var', (67, 78))	('EP4', 'Gene', '5734', (63, 66))	('sensitize', 'Reg', (79, 88))	('EP4', 'Gene', (63, 66))	('docetaxel', 'Chemical', 'MESH:C067311', (98, 107))
71918	28529743	In a previous study, the results of imaging analysis were non-specific: On MRI, T1-weighted imaging (WI) revealed areas of isointensity or hyperintensity relative to muscle in the tumor masses, and T2WI frequently showed heterogeneous signal intensity, including areas of triple signal intensity involving regions of high signal intensity that appeared fluid, isointense, or hyperintense relative to fat, and hypointense relative to fibrous tissue.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('heterogeneous signal intensity', 'MPA', (221, 251))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('hyperintensity', 'Var', (139, 153))	('tumor', 'Disease', (180, 185))	('isointense', 'MPA', (360, 370))	('hyperintense', 'MPA', (375, 387))
71995	20953407	Ewing's sarcoma cells with EWS-FLI1 knockdown by siRNA exhibit decreased cell proliferation, and tumor xenografts regress in mice.	("Ewing's sarcoma", 'Disease', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('decreased', 'NegReg', (63, 72))	('mice', 'Species', '10090', (125, 129))	('knockdown', 'Var', (36, 45))	('tumor', 'Disease', (97, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('EWS-FLI1', 'Gene', (27, 35))	('cell proliferation', 'CPA', (73, 91))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))
71997	20953407	Fli1 (Friend leukemia virus integration) was originally identified as the gene activated by insertion of the Friend murine leukemia virus (MuLV).	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('Friend leukemia virus', 'Disease', 'MESH:D007938', (6, 27))	('Friend murine leukemia virus', 'Species', '11795', (109, 137))	('Fli1', 'Gene', '14247', (0, 4))	('Friend leukemia virus', 'Disease', (6, 27))	('Fli1', 'Gene', (0, 4))	('leukemia', 'Phenotype', 'HP:0001909', (13, 21))	('insertion', 'Var', (92, 101))
72001	20953407	EWS-FLI1 concomitantly represses genes that induce cell cycle arrest and apoptosis, including TGFB2 , p21, p57kip, and IGFBP3.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('induce', 'PosReg', (44, 50))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (51, 68))	('arrest', 'Disease', (62, 68))	('IGFBP3', 'Gene', '16009', (119, 125))	('p57kip', 'Var', (107, 113))	('p21', 'Gene', '18196', (102, 105))	('apoptosis', 'CPA', (73, 82))	('TGFB2', 'Gene', '21808', (94, 99))	('TGFB2', 'Gene', (94, 99))	('p21', 'Gene', (102, 105))	('IGFBP3', 'Gene', (119, 125))
72009	20953407	Conversely, introduction of EWS-FLI1 into neuroblastoma cell lines has been shown to make the cells less differentiated and acquire characteristics of Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (151, 166))	('introduction', 'Var', (12, 24))	('neuroblastoma', 'Phenotype', 'HP:0003006', (42, 55))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (151, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('EWS-FLI1', 'Gene', (28, 36))	('neuroblastoma', 'Disease', 'MESH:D009447', (42, 55))	('less', 'NegReg', (100, 104))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (151, 166))	('neuroblastoma', 'Disease', (42, 55))
72018	20953407	Several groups have demonstrated that expression of EWS-FLI1 in murine MSCs resulted in transformation of the cells, and when these cells were implanted into mice, sarcomas formed.	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('mice', 'Species', '10090', (158, 162))	('murine', 'Species', '10090', (64, 70))	('sarcomas', 'Disease', (164, 172))	('expression', 'Var', (38, 48))	('transformation', 'CPA', (88, 102))	('resulted in', 'Reg', (76, 87))	('EWS-FLI1', 'Gene', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('sarcomas', 'Disease', 'MESH:D012509', (164, 172))
72020	20953407	In a related set of experiments, expression of EWS-FLI1 in the pluripotential murine cell line C3H10T1/2 inhibited the cells ability to differentiate into osteoblasts and adipocytes while upregulating neural genes.	('C3H10T1', 'CellLine', 'CVCL:0190', (95, 102))	('upregulating', 'PosReg', (188, 200))	('expression', 'Var', (33, 43))	('inhibited', 'NegReg', (105, 114))	('neural genes', 'Gene', (201, 213))	('murine', 'Species', '10090', (78, 84))	('EWS-FLI1', 'Gene', (47, 55))
72029	20953407	Ewing's sarcoma cell lines with knockdown of EWS-FLI1 have a transcription profile similar to that of the human fetal fibroblast cell line IMR-90.	('human', 'Species', '9606', (106, 111))	("Ewing's sarcoma", 'Disease', (0, 15))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('knockdown', 'Var', (32, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('IMR-90', 'CellLine', 'CVCL:0347', (139, 145))	('EWS-FLI1', 'Gene', (45, 53))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('transcription profile', 'MPA', (61, 82))
72030	20953407	This was statistically significant for the subset of genes that were upregulated or downregulated by EWS-FLI1, but it is noteworthy that the overall pattern of gene expression appeared to have distinct differences between MSCs and Ewing's sarcoma cells with EWS-FLI1 knockdown.	('downregulated', 'NegReg', (84, 97))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (231, 246))	('knockdown', 'Var', (267, 276))	('differences', 'Reg', (202, 213))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (231, 246))	('upregulated', 'PosReg', (69, 80))	("Ewing's sarcoma", 'Disease', (231, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('EWS-FLI1', 'Gene', (258, 266))	('EWS-FLI1', 'Gene', (101, 109))
72032	20953407	A complementary set of observations was made by Burns et al., who reported that late passage human mesenchymal cells that spontaneously transformed after introduction of telomerase (hMSC-TERT20) took on an immunohistochemical profile that was reminiscent of Ewing's sarcoma, namely, CD99+, vimentin+, CD45-, cytokeratin-, and desmin-.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (258, 273))	('TERT20', 'CellLine', 'CVCL:Z018', (187, 193))	('CD99+', 'Var', (283, 288))	('human', 'Species', '9606', (93, 98))	('desmin', 'Gene', '1674', (326, 332))	("Ewing's sarcoma", 'Disease', (258, 273))	('vimentin', 'Gene', '7431', (290, 298))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (258, 273))	('CD45', 'Gene', (301, 305))	('vimentin', 'Gene', (290, 298))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('CD45', 'Gene', '5788', (301, 305))	('desmin', 'Gene', (326, 332))
72033	20953407	While these collective data are supportive of a mesenchymal origin of Ewing's sarcoma, it is clear that simple knock-down of EWS-FLI1 in tumor cells does not cause them to revert to a normal mesenchymal cell.	('EWS-FLI1', 'Gene', (125, 133))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (70, 85))	('tumor', 'Disease', (137, 142))	("Ewing's sarcoma", 'Disease', (70, 85))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (70, 85))	('knock-down', 'Var', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
72041	20953407	The Mx1-cre mouse expresses cre recombinase in the liver, spleen, bone marrow, and lymphoid tissues after induction with alpha/beta interferon or polyinosinic*poly(C) (pIpC).	('polyinosinic*poly(C', 'Var', (146, 165))	('pIpC', 'Chemical', '-', (168, 172))	('polyinosinic*poly(C)', 'Chemical', '-', (146, 166))	('mouse', 'Species', '10090', (12, 17))	('Mx1', 'Gene', '17857', (4, 7))	('Mx1', 'Gene', (4, 7))
72046	20953407	While it was once believed that EWS-FLI1 was specific to Ewing's sarcoma, it is now known that EWS-FLI1 and related EWS-ETS fusions occur sporadically in other malignancies, including leukemias and biphenotypic tumors, which have features of both myogenic and neuroectodermal differentiation.	('malignancies', 'Disease', (160, 172))	('EWS-FLI1', 'Gene', (95, 103))	('leukemias', 'Phenotype', 'HP:0001909', (184, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('leukemias and biphenotypic tumors', 'Disease', 'MESH:D015456', (184, 217))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (57, 72))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	("Ewing's sarcoma", 'Disease', (57, 72))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('malignancies', 'Disease', 'MESH:D009369', (160, 172))	('occur', 'Reg', (132, 137))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (57, 72))	('fusions', 'Var', (124, 131))
72052	20953407	However, in this model, sarcomas did not spontaneously form unless the p53 gene was simultaneously mutated.	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcomas', 'Disease', (24, 32))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '22059', (71, 74))	('mutated', 'Var', (99, 106))
72053	20953407	In contrast to the more differentiated osteosarcomas that formed without EWS-FLI1 in mice with conditional mutation of p53 induced by Prx1-cre, the tumors that arose with EWS-FLI1 were undifferentiated sarcomas, similar to Ewing's sarcoma.	('Prx1', 'Gene', (134, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (231, 238))	('mice', 'Species', '10090', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (223, 238))	('sarcomas', 'Disease', 'MESH:D012509', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('p53', 'Gene', (119, 122))	('sarcomas', 'Disease', (44, 52))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (223, 238))	('sarcomas', 'Disease', 'MESH:D012509', (202, 210))	('osteosarcomas', 'Disease', 'MESH:D012516', (39, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (202, 210))	('EWS-FLI1', 'Var', (171, 179))	('sarcomas', 'Disease', (202, 210))	('tumors', 'Disease', (148, 154))	('osteosarcomas', 'Disease', (39, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	("Ewing's sarcoma", 'Disease', (223, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('p53', 'Gene', '22059', (119, 122))	('Prx1', 'Gene', '18933', (134, 138))	('osteosarcomas', 'Phenotype', 'HP:0002669', (39, 52))
72058	20953407	For example, in a knock-in model of alveolar rhabdomyosarcoma, mutations in Ink4A/Arf or Trp53 were needed for the Pax3;Fkhr fusion to transform cells effectively.	('mutations', 'Var', (63, 72))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (45, 61))	('Pax3', 'Gene', (115, 119))	('Fkhr', 'Gene', (120, 124))	('Pax3', 'Gene', '18505', (115, 119))	('alveolar rhabdomyosarcoma', 'Disease', (36, 61))	('Trp53', 'Gene', '22059', (89, 94))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (36, 61))	('Ink4A/Arf', 'Gene', '12578', (76, 85))	('Ink4A/Arf', 'Gene', (76, 85))	('Fkhr', 'Gene', '56458', (120, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (36, 61))	('transform', 'Reg', (135, 144))	('Trp53', 'Gene', (89, 94))
72060	20953407	TRP53, however, is unlikely to be the critical cooperating mutated gene in Ewing's sarcoma since TRP53 mutations are found only in about 10% of Ewing's sarcoma cases.	('mutations', 'Var', (103, 112))	('TRP53', 'Gene', '22059', (97, 102))	('TRP53', 'Gene', (97, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (75, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('TRP53', 'Gene', '22059', (0, 5))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (144, 159))	("Ewing's sarcoma", 'Disease', (75, 90))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (75, 90))	("Ewing's sarcoma", 'Disease', (144, 159))	('TRP53', 'Gene', (0, 5))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (144, 159))
72063	20953407	Instead, EWS-FLI1 tends to cause growth arrest.	('growth arrest', 'Disease', 'MESH:D006323', (33, 46))	('growth arrest', 'Disease', (33, 46))	('growth arrest', 'Phenotype', 'HP:0001510', (33, 46))	('cause', 'Reg', (27, 32))	('EWS-FLI1', 'Var', (9, 17))
72072	31239779	Grade 3-4 adverse events were more common with apatinib plus doxorubicin than with apatinib after doxorubicin, and these included leukopenia (5.45% vs 38.1%, respectively, p=0.001), anemia (7.27% vs 28.57%, respectively, p=0.023), oral mucositis (3.64% vs 19.05%, respectively, p=0.046), transaminase increases (0% vs 14.29%, respectively, p=0.011).	('transaminase increases', 'Phenotype', 'HP:0002910', (288, 310))	('leukopenia', 'Disease', (130, 140))	('oral mucositis', 'Disease', 'MESH:D013280', (231, 245))	('doxorubicin', 'Chemical', 'MESH:D004317', (61, 72))	('doxorubicin', 'Chemical', 'MESH:D004317', (98, 109))	('leukopenia', 'Phenotype', 'HP:0001882', (130, 140))	('oral mucositis', 'Disease', (231, 245))	('apatinib', 'Var', (47, 55))	('apatinib', 'Chemical', 'MESH:C553458', (47, 55))	('anemia', 'Disease', (182, 188))	('transaminase', 'MPA', (288, 300))	('increases', 'PosReg', (301, 310))	('anemia', 'Disease', 'MESH:D000740', (182, 188))	('apatinib', 'Chemical', 'MESH:C553458', (83, 91))	('leukopenia', 'Disease', 'MESH:D007970', (130, 140))	('anemia', 'Phenotype', 'HP:0001903', (182, 188))
72129	31239779	AEs were significantly more prevalent in patients treated with apatinib plus doxorubicin than in those treated with apatinib after doxorubicin (Table 4).	('doxorubicin', 'Chemical', 'MESH:D004317', (131, 142))	('prevalent', 'Reg', (28, 37))	('doxorubicin', 'Chemical', 'MESH:D004317', (77, 88))	('AEs', 'Chemical', '-', (0, 3))	('patients', 'Species', '9606', (41, 49))	('apatinib', 'Var', (63, 71))	('apatinib', 'Chemical', 'MESH:C553458', (116, 124))	('AEs', 'Disease', (0, 3))	('apatinib', 'Chemical', 'MESH:C553458', (63, 71))
72131	31239779	Grade-3/4 AEs were significantly more common in the apatinib plus doxorubicin group than in the apatinib after doxorubicin group, and these included leukopenia (5.45% of vs 38.1%, respectively, p=0.001), anemia (7.27% vs 28.57%, respectively, p=0.023), oral mucositis (3.64% vs 19.05%, respectively, p=0.046), and transaminase increases (0% vs 14.29%, respectively, p=0.011; Table 4).	('leukopenia', 'Phenotype', 'HP:0001882', (149, 159))	('anemia', 'Disease', (204, 210))	('apatinib', 'Chemical', 'MESH:C553458', (52, 60))	('anemia', 'Disease', 'MESH:D000740', (204, 210))	('leukopenia', 'Disease', (149, 159))	('increases', 'PosReg', (327, 336))	('oral mucositis', 'Disease', (253, 267))	('leukopenia', 'Disease', 'MESH:D007970', (149, 159))	('anemia', 'Phenotype', 'HP:0001903', (204, 210))	('transaminase', 'MPA', (314, 326))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('AEs', 'Chemical', '-', (10, 13))	('apatinib', 'Chemical', 'MESH:C553458', (96, 104))	('AEs', 'Disease', (10, 13))	('transaminase increases', 'Phenotype', 'HP:0002910', (314, 336))	('doxorubicin', 'Chemical', 'MESH:D004317', (111, 122))	('apatinib', 'Var', (52, 60))	('oral mucositis', 'Disease', 'MESH:D013280', (253, 267))
72170	30711517	Investigating a chimeric anti-mouse PDGFRalpha antibody as a radiosensitizer in primary mouse sarcomas Olaratumab (LY3012207/IMC-3G3/Lartruvo ) is a fully human monoclonal antibody specific for platelet-derived growth factor receptor alpha (PDGFRalpha).	('PDGFRalpha', 'Gene', '18595', (241, 251))	('platelet-derived growth factor receptor alpha', 'Gene', '18595', (194, 239))	('PDGFRalpha', 'Gene', (241, 251))	('Olaratumab', 'Chemical', 'MESH:C000589393', (103, 113))	('human', 'Species', '9606', (155, 160))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('LY3012207/IMC-3G3/Lartruvo', 'Var', (115, 141))	('PDGFRalpha', 'Gene', '18595', (36, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('mouse', 'Species', '10090', (88, 93))	('platelet-derived growth factor receptor alpha', 'Gene', (194, 239))	('LY3012207', 'Chemical', '-', (115, 124))	('PDGFRalpha', 'Gene', (36, 46))	('sarcomas', 'Disease', (94, 102))	('mouse', 'Species', '10090', (30, 35))
72175	30711517	When tumors reached 70 mm3, mice were allocated into treatment groups: 1) isotype, 2) 1E10Fc, 3) isotype + RT, 4) 1E10Fc + RT.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('1E10Fc + RT', 'Var', (114, 125))	('mice', 'Species', '10090', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('1E10Fc', 'Var', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
72180	30711517	A Chi-square test was performed to compare the development of micrometastases in the lungs after treatment with 1E10Fc or isotype.	('metastases', 'Disease', (67, 77))	('1E10Fc', 'Var', (112, 118))	('metastases', 'Disease', 'MESH:D009362', (67, 77))
72182	30711517	Fewer mice treated with 1E10Fc had micrometastases, but this difference was not statistically significant (p < 0 09).	('metastases', 'Disease', (40, 50))	('1E10Fc', 'Var', (24, 30))	('mice', 'Species', '10090', (6, 10))	('metastases', 'Disease', 'MESH:D009362', (40, 50))
72185	30711517	We focused particularly on the phase I/IIb study by Tap and colleagues in which the combination of olaratumab and doxorubicin improved overall survival compared with doxorubicin alone and additional publications referencing this study, To our knowledge, this work is the first to address whether targeting PDGFRalpha radiosensitizes primary sarcomas in vivo.	('doxorubicin', 'Chemical', 'MESH:D004317', (166, 177))	('improved', 'PosReg', (126, 134))	('Tap', 'Gene', '21354', (52, 55))	('IIb', 'Gene', '50771', (39, 42))	('PDGFRalpha', 'Gene', (306, 316))	('Tap', 'Gene', (52, 55))	('primary sarcomas', 'Disease', 'MESH:D012509', (333, 349))	('sarcoma', 'Phenotype', 'HP:0100242', (341, 348))	('overall', 'MPA', (135, 142))	('IIb', 'Gene', (39, 42))	('olaratumab', 'Chemical', 'MESH:C000589393', (99, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (341, 349))	('primary sarcomas', 'Disease', (333, 349))	('targeting', 'Var', (296, 305))	('doxorubicin', 'Chemical', 'MESH:D004317', (114, 125))
72187	30711517	Although we observed decreased microvessel density with combination treatment with 1E10Fc and radiation therapy, tumor growth was not affected by this treatment combination.	('tumor', 'Disease', (113, 118))	('Alt', 'Gene', '76282', (0, 3))	('decreased', 'NegReg', (21, 30))	('microvessel density', 'CPA', (31, 50))	('Alt', 'Gene', (0, 3))	('1E10Fc', 'Var', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
72188	30711517	Metastasis was not the primary endpoint of this study; however, fewer mice treated with 1E10Fc developed micrometastases in the lung (p = 0 09) [Chi-square test], which supports future pre-clinical studies targeting PDGFRalpha as adjuvant therapy for soft tissue sarcomas.	('soft tissue sarcoma', 'Disease', (251, 270))	('metastases', 'Disease', (110, 120))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (251, 270))	('sarcomas', 'Disease', 'MESH:D012509', (263, 271))	('mice', 'Species', '10090', (70, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (263, 271))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (251, 270))	('fewer', 'NegReg', (64, 69))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (251, 271))	('1E10Fc', 'Var', (88, 94))	('sarcomas', 'Disease', (263, 271))
72206	30711517	Indeed, a previous preclinical study demonstrated that combining PDGFR inhibitor with radiation reduced RT-mediated lung fibrosis.	('lung fibrosis', 'Phenotype', 'HP:0002206', (116, 129))	('PDGFR', 'Gene', '18596', (65, 70))	('lung fibrosis', 'Disease', 'MESH:D005355', (116, 129))	('PDGFR', 'Gene', (65, 70))	('lung fibrosis', 'Disease', (116, 129))	('inhibitor', 'Var', (71, 80))	('reduced', 'NegReg', (96, 103))
72209	30711517	In this project, we use a genetically engineered and carcinogen-induced mouse model of undifferentiated pleomorphic sarcoma (UPS), the most common type of adult soft tissue sarcoma, to investigate the potential effects of 1E10Fc and RT on primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (87, 123))	('soft tissue sarcoma', 'Disease', (161, 180))	('tumors', 'Disease', (247, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('mouse', 'Species', '10090', (72, 77))	('undifferentiated pleomorphic sarcoma', 'Disease', (87, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (161, 180))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (161, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('1E10Fc', 'Var', (222, 228))
72214	30711517	When tumors were detected, they were measured three times per week to assess tumor growth using the following formula: When tumors reached ~70 mm3 (or 5 x 5 mm, Day 0), mice were divided into treatment groups of 1) isotype control, 2) 1E10Fc, 3) isotype + RT, or 4) 1E10Fc + RT.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('1E10Fc', 'Var', (235, 241))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('1E10Fc + RT', 'Var', (266, 277))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('isotype + RT', 'Var', (246, 258))	('tumors', 'Disease', (124, 130))	('mice', 'Species', '10090', (169, 173))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (77, 82))
72215	30711517	Treatments of 1E10Fc or isotype continued biweekly until the tumor reached an endpoint volume of ~900 mm3 (or 12 x 12 mm).	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('1E10Fc', 'Var', (14, 20))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
72216	30711517	On the first day of 1E10Fc treatment (Day 0), mice in the RT groups began a five-fraction image-guided RT protocol to the tumor where clinically relevant 5 Gy fractions were administered daily for five consecutive days (25 Gy total).	('1E10Fc', 'Var', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
72225	30711517	Samples were run on Mini-PROTEAN  TGX  Precast Gels (BioRad) at 100 V for 1.5 h and transferred to nitrocellulose membrane (ThermoFisher) via a wet transfer at 250 mV for 2 h. Membranes were blotted for expression of phosphorylated (1:2000, Cell Signaling #4060) and total AKT (1:1000, Cell Signaling #9272), a downstream target of PDGFRalpha signaling.	('AKT', 'Gene', '11651', (273, 276))	('AKT', 'Gene', (273, 276))	('1:2000', 'Var', (233, 239))	('1:1000', 'Var', (278, 284))
72234	30711517	For each mouse, four representative images were taken of the tumor if it occupied the majority of the slide (for PDGFRalpha staining: n = 19 for isotype, n = 19 for 1E10Fc, n = 20 for isotype + RT, and n = 18 for 1E10Fc + RT; for CD31 staining: n = 19 for isotype, n = 20 for 1E10Fc, n = 20 for isotype + RT, and n = 19 for 1E10Fc + RT).	('1E10Fc', 'Var', (276, 282))	('1E10Fc + RT', 'Var', (324, 335))	('mouse', 'Species', '10090', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CD31', 'Gene', '18613', (230, 234))	('CD31', 'Gene', (230, 234))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('1E10Fc + RT', 'Var', (213, 224))
72249	30711517	Genotyping confirmed the recombination of FRT sites and deletion of p53 in each of the three cell lines derived from these tumors (Fig.	('deletion', 'Var', (56, 64))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('p53', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
72250	30711517	To test whether 1E10Fc was indeed inhibiting PDGFRalpha signaling in the p53/MCA sarcoma model, western blot analysis was performed on cell lines generated from three primary p53/MCA sarcomas.	('inhibiting', 'NegReg', (34, 44))	('MCA sarcomas', 'Disease', 'MESH:D020244', (179, 191))	('MCA sarcoma', 'Disease', 'MESH:D020244', (179, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('MCA sarcomas', 'Disease', (179, 191))	('MCA sarcoma', 'Disease', 'MESH:D020244', (77, 88))	('PDGFRalpha signaling', 'MPA', (45, 65))	('MCA sarcoma', 'Disease', (77, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('1E10Fc', 'Var', (16, 22))
72252	30711517	The ratio of phosphorylated to total AKT was lower in all three cell lines treated with 1E10Fc compared to isotype control (p = 0 0206) [paired t-test], suggesting that 1E10Fc is effectively inhibiting PDGFRalpha signaling in p53/MCA sarcoma cells in vitro.	('MCA sarcoma', 'Disease', 'MESH:D020244', (230, 241))	('inhibiting', 'NegReg', (191, 201))	('MCA sarcoma', 'Disease', (230, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('AKT', 'Gene', '11651', (37, 40))	('PDGFRalpha signaling', 'MPA', (202, 222))	('lower', 'NegReg', (45, 50))	('AKT', 'Gene', (37, 40))	('1E10Fc', 'Var', (169, 175))
72253	30711517	To determine the effects of 1E10Fc on murine primary tumor growth alone or in combination with RT, time to volume quintupling (TTQ) from initial tumor volume was compared across mice treated with isotype control, 1E10Fc, isotype + RT, or 1E10Fc + RT (Fig.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('1E10Fc', 'Var', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('1E10Fc + RT', 'Var', (238, 249))	('mice', 'Species', '10090', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TTQ', 'Chemical', '-', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (53, 58))	('murine', 'Species', '10090', (38, 44))
72255	30711517	2b) [two-way ANOVA], no differences in TTQ were observed in mice treated with isotype and 1E10Fc groups even with the addition of RT.	('mice', 'Species', '10090', (60, 64))	('TTQ', 'MPA', (39, 42))	('TTQ', 'Chemical', '-', (39, 42))	('1E10Fc', 'Var', (90, 96))
72264	30711517	Lower CD31 expression was observed in tumors treated with 1E10Fc + RT as compared to isotype alone (p = 0 03) [one-way ANOVA], but not compared to RT + isotype (n = 19 for isotype, 20 for 1E10Fc, 20 for isotype + RT, and 19 for 1E10Fc + RT) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('1E10Fc + RT', 'Var', (58, 69))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('expression', 'MPA', (11, 21))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('CD31', 'Gene', (6, 10))	('Lower', 'NegReg', (0, 5))	('CD31', 'Gene', '18613', (6, 10))
72265	30711517	This suggests a lower microvessel density in tumors treated with 1E10Fc + RT, though this did not affect primary tumor growth compared to RT alone.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('1E10Fc + RT', 'Var', (65, 76))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('microvessel density', 'CPA', (22, 41))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('lower', 'NegReg', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
72268	30711517	When the mice are grouped by treatment with 1E10Fc (n = 40) vs isotype antibody (n = 40), more mice treated with isotype antibody developed micrometastases (5 vs. 1), but this difference did not reach statistical significance (p = 0 0895) [Chi-square test].	('metastases', 'Disease', (145, 155))	('mice', 'Species', '10090', (95, 99))	('1E10Fc', 'Var', (44, 50))	('metastases', 'Disease', 'MESH:D009362', (145, 155))	('mice', 'Species', '10090', (9, 13))
72270	30711517	While 1E10Fc appeared to inhibit PDGFRalpha signaling using AKT phosphorylation as a surrogate marker, blocking PDGFRalpha did not act as a radiosensitizer in this model of primary STS as measured by tumor growth delay.	('tumor growth delay', 'Disease', 'MESH:D006130', (200, 218))	('PDGFRalpha signaling', 'MPA', (33, 53))	('tumor growth delay', 'Disease', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('1E10Fc', 'Var', (6, 12))	('AKT', 'Gene', '11651', (60, 63))	('growth delay', 'Phenotype', 'HP:0001510', (206, 218))	('inhibit', 'NegReg', (25, 32))	('PDGFRalpha', 'Gene', (112, 122))	('AKT', 'Gene', (60, 63))
72271	30711517	Immunohistochemical analysis of primary murine sarcomas taken at endpoint volume demonstrated a trend toward decreased microvessel density in the tumors treated with 1E10Fc + RT compared to isotype as shown by a reduction in CD31 staining, which provides evidence of 1E10Fc activity in vivo despite the lack of effect on primary sarcoma growth.	('decreased', 'NegReg', (109, 118))	('sarcomas', 'Disease', (47, 55))	('CD31', 'Gene', (225, 229))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('sarcoma growth', 'Disease', 'MESH:D006130', (329, 343))	('murine', 'Species', '10090', (40, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('1E10Fc + RT', 'Var', (166, 177))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('sarcoma growth', 'Disease', (329, 343))	('reduction', 'NegReg', (212, 221))	('tumors', 'Disease', (146, 152))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (329, 336))	('microvessel density', 'CPA', (119, 138))	('CD31', 'Gene', '18613', (225, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
72275	30711517	While p53 is the most commonly mutated gene in human UPS, sarcomas that retain p53 (i.e.	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcomas', 'Disease', (58, 66))	('p53', 'Var', (79, 82))	('human', 'Species', '9606', (47, 52))	('sarcomas', 'Disease', 'MESH:D012509', (58, 66))
72278	30711517	Furthermore, the relatively large sample size in each treatment group (powered to detect a biologically relevant but small difference in tumor growth delay after RT), the use of clinically relevant sophisticated small animal irradiation, and blinding of the experimenter to treatment groups allowed for detailed and unbiased analysis of the combination of 1E10Fc and RT for treatment of primary sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (395, 403))	('1E10Fc', 'Var', (356, 362))	('sarcoma', 'Phenotype', 'HP:0100242', (395, 402))	('tumor growth delay', 'Disease', 'MESH:D006130', (137, 155))	('growth delay', 'Phenotype', 'HP:0001510', (143, 155))	('primary sarcomas', 'Disease', 'MESH:D012509', (387, 403))	('primary sarcomas', 'Disease', (387, 403))	('tumor growth delay', 'Disease', (137, 155))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
72279	30711517	Only 1 of 40 mice treated with 1E10Fc had lesions in the lungs suspicious for micrometastatic disease.	('mice', 'Species', '10090', (13, 17))	('micrometastatic disease', 'Disease', (78, 101))	('1E10Fc', 'Var', (31, 37))
72281	30711517	While our study was not designed to assess for metastasis specifically, our data suggest that neoadjuvant 1E10Fc may delay or prevent the development of lung metastases.	('1E10Fc', 'Var', (106, 112))	('lung metastases', 'Disease', (153, 168))	('prevent', 'NegReg', (126, 133))	('lung metastases', 'Disease', 'MESH:D009362', (153, 168))	('delay', 'NegReg', (117, 122))
72283	30711517	Although beyond the scope of the present study, in future pre-clinical studies it would be interesting to formally test whether neoadjuvant or adjuvant 1E10Fc affects the development and growth of metastasis after surgery achieves local control.	('Alt', 'Gene', '76282', (0, 3))	('development', 'CPA', (171, 182))	('Alt', 'Gene', (0, 3))	('growth', 'CPA', (187, 193))	('1E10Fc', 'Var', (152, 158))	('affects', 'Reg', (159, 166))
72290	30711517	In conclusion, 1E10Fc did not act as a radiosensitizer in this mouse model of primary soft tissue sarcoma.	('1E10Fc', 'Var', (15, 21))	('mouse', 'Species', '10090', (63, 68))	('soft tissue sarcoma', 'Disease', (86, 105))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (86, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (86, 105))
72291	30711517	Although microvessel density was decreased in tumors treated with 1E10Fc + RT, this did not affect primary tumor growth.	('1E10Fc + RT', 'Var', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('Alt', 'Gene', '76282', (0, 3))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumors', 'Disease', (46, 52))	('Alt', 'Gene', (0, 3))	('tumor', 'Disease', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('microvessel density', 'CPA', (9, 28))	('decreased', 'NegReg', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
72292	30711517	Finally, we performed a histologic analysis of the lungs which suggested a potential decrease in micrometastases in mice treated with neoadjuvant 1E10Fc.	('mice', 'Species', '10090', (116, 120))	('decrease', 'NegReg', (85, 93))	('metastases', 'Disease', (102, 112))	('1E10Fc', 'Var', (146, 152))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
72311	28868028	Cytogenetic studies have demonstrated that synovial sarcomas have a consistent, specific chromosomal translocation t(X;18) (p11.2;q11.2) and the consequent fusion gene SYT-SSX.	('synovial sarcomas', 'Phenotype', 'HP:0012570', (43, 60))	('SYT', 'Gene', '6760', (168, 171))	('synovial sarcomas', 'Disease', (43, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('synovial sarcomas', 'Disease', 'MESH:D013584', (43, 60))	('t(X;18) (p11.2', 'Var', (115, 129))	('SSX', 'Gene', (172, 175))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (43, 59))	('SYT', 'Gene', (168, 171))	('SSX', 'Gene', '727837', (172, 175))
72320	28868028	FISH for a SS18 (18q11.2) rearrangement showed a break apart consistent with a translocation involving the SS18 gene characteristic of synovial sarcoma (Fig.	('SS18', 'Gene', (107, 111))	('synovial sarcoma', 'Disease', (135, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('translocation', 'Var', (79, 92))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (135, 151))	('synovial sarcoma', 'Disease', 'MESH:D013584', (135, 151))	('SS18', 'Gene', '6760', (11, 15))	('break apart', 'Phenotype', 'HP:0001061', (49, 60))	('SS18', 'Gene', '6760', (107, 111))	('SS18', 'Gene', (11, 15))
72372	26866881	Other immunomarkers were negative (ALK-1, Bcl-2, CD117, CD34, CD45, Desmin, EMA, MNF116, p63 and S100).	('ALK-1', 'Gene', (35, 40))	('p63', 'Gene', (89, 92))	('Bcl-2', 'Gene', (42, 47))	('CD45', 'Gene', (62, 66))	('Bcl-2', 'Gene', '596', (42, 47))	('ALK-1', 'Gene', '6590', (35, 40))	('MNF116', 'Var', (81, 87))	('p63', 'Gene', '8626', (89, 92))	('CD117', 'Gene', '3815', (49, 54))	('S100', 'Var', (97, 101))	('Desmin', 'Gene', '1674', (68, 74))	('CD34', 'Gene', '947', (56, 60))	('CD117', 'Gene', (49, 54))	('EMA', 'Gene', (76, 79))	('CD45', 'Gene', '5788', (62, 66))	('EMA', 'Gene', '4582', (76, 79))	('Desmin', 'Gene', (68, 74))	('CD34', 'Gene', (56, 60))
72395	26866881	Desmoid tumours appear hypo-intense on T1-weighted MRI and predominantly hyper-intense on T2-weighted MRI, reflecting the proliferation of fibroblasts.	('Desmoid tumours', 'Disease', (0, 15))	('Desmoid tumours', 'Disease', 'MESH:C535944', (0, 15))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('T1-weighted', 'Var', (39, 50))	('Desmoid tumours', 'Phenotype', 'HP:0100245', (0, 15))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))
72501	24042031	Heterogeneity in Intratumor Correlations of 18F-FDG, 18F-FLT, and 61Cu-ATSM PET in Canine Sinonasal Tumors Intratumor heterogeneity in biologic properties and in relationships between various phenotypes may present a challenge for biologically targeted therapies.	('rat', 'Species', '10116', (110, 113))	('Canine Sinonasal Tumors', 'Phenotype', 'HP:0030072', (83, 106))	('Canine', 'Species', '9615', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Sinonasal Tumors', 'Disease', 'MESH:C537344', (90, 106))	('Tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Tumors', 'Phenotype', 'HP:0002664', (100, 106))	('18F-FDG', 'Var', (44, 51))	('Sinonasal Tumors', 'Disease', (90, 106))	('tumor', 'Disease', (22, 27))	('rat', 'Species', '10116', (20, 23))	('tumor', 'Disease', (112, 117))	('FLT', 'Gene', (57, 60))	('FLT', 'Gene', '2321', (57, 60))
72562	24042031	Voxel-based Spearman rank correlation coefficients were calculated for each tracer combination: 18F-FLT-61Cu-ATSM, 18F-FDG-61Cu-ATSM, and 18FFDG-18F-FLT.	('FLT', 'Gene', '2321', (100, 103))	('18F', 'Chemical', 'MESH:C000615276', (145, 148))	('FLT', 'Gene', (100, 103))	('FLT', 'Gene', '2321', (149, 152))	('FLT', 'Gene', (149, 152))	('61Cu-ATSM', 'Chemical', '-', (123, 132))	('18F', 'Chemical', 'MESH:C000615276', (115, 118))	('61Cu-ATSM', 'Chemical', '-', (104, 113))	('18F', 'Chemical', 'MESH:C000615276', (96, 99))	('18F-FDG', 'Chemical', 'MESH:D019788', (115, 122))	('18F', 'Chemical', 'MESH:C000615276', (138, 141))	('18F-FDG-61Cu-ATSM', 'Var', (115, 132))
72588	24042031	For 61Cu-ATSM-18F-FDG and 61Cu-ATSM-18F-FLT overlap, differences between sarcomas and carcinomas were significant at thresholds of 40%-80%, with carcinomas having greater average overlap.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('carcinomas', 'Disease', (86, 96))	('carcinomas', 'Disease', 'MESH:D002277', (145, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('FLT', 'Gene', (40, 43))	('61Cu-ATSM', 'Chemical', '-', (4, 13))	('FLT', 'Gene', '2321', (40, 43))	('sarcomas and carcinomas', 'Disease', 'MESH:D012509', (73, 96))	('18F', 'Chemical', 'MESH:C000615276', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('18F', 'Chemical', 'MESH:C000615276', (36, 39))	('carcinomas', 'Disease', 'MESH:D002277', (86, 96))	('61Cu-ATSM-18F-FDG', 'Var', (4, 21))	('carcinomas', 'Disease', (145, 155))	('61Cu-ATSM', 'Chemical', '-', (26, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('18F-FDG', 'Chemical', 'MESH:D019788', (14, 21))
72595	24042031	As registration inaccuracies can significantly degrade voxelwise correlations between images, canine nasal tumors were chosen for the present study because the nondeformable bony anatomy surrounding the nasal cavity enables accurate image registration, mitigating such errors.	('nasal tumors', 'Phenotype', 'HP:0012720', (101, 113))	('rat', 'Species', '10116', (9, 12))	('canine', 'Species', '9615', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('rat', 'Species', '10116', (228, 231))	('degrade', 'NegReg', (47, 54))	('inaccuracies', 'Var', (16, 28))	('rat', 'Species', '10116', (245, 248))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('nasal tumors', 'Disease', (101, 113))	('nasal tumors', 'Disease', 'MESH:D009669', (101, 113))	('voxelwise correlations between', 'MPA', (55, 85))
72633	24042031	61Cu-ATSM also has a lower binding affinity for serum albumin in dogs than in humans, potentially influencing uptake.	('influencing', 'Reg', (98, 109))	('uptake', 'MPA', (110, 116))	('61Cu-ATSM', 'Chemical', '-', (0, 9))	('dogs', 'Species', '9615', (65, 69))	('lower', 'NegReg', (21, 26))	('humans', 'Species', '9606', (78, 84))	('serum albumin', 'Protein', (48, 61))	('61Cu-ATSM', 'Var', (0, 9))	('binding affinity for', 'Interaction', (27, 47))
72651	22318517	To determine whether T lymphocytes influence tumour development, we adapted a mouse model of human soft tissue sarcomagenesis driven by Cre/LoxP-regulated expression of oncogenic K-rasG12D and deletion of p53 to allow for the control of tumour immunogenicity.	('deletion', 'Var', (193, 201))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('p53', 'Gene', (205, 208))	('human', 'Species', '9606', (93, 98))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('sarcoma', 'Disease', (111, 118))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('tumour', 'Disease', (237, 243))	('G12D', 'Mutation', 'p.G12D', (184, 188))	('mouse', 'Species', '10090', (78, 83))	('tumour', 'Disease', (45, 51))	('soft tissue sarcomagenesis', 'Phenotype', 'HP:0030448', (99, 125))
72655	22318517	We also observed a difference in the penetrance of sarcoma development in KPR versus KP mice by 140 days with Lenti-x (89% versus 43%, respectively), although the difference was less dramatic than observed with Lenti-LucOS (Fig.	('sarcoma', 'Disease', (51, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('Lenti-x', 'Var', (110, 117))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('mice', 'Species', '10090', (88, 92))
72661	22318517	Rag-2 deficiency prevents both T and B lymphocyte development and, therefore, could have pleiotropic effects on the immune response to tumour antigens.	('Rag-2', 'Gene', (0, 5))	('deficiency', 'Var', (6, 16))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('effects', 'Reg', (101, 108))	('prevents', 'NegReg', (17, 25))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('Rag-2', 'Gene', '19374', (0, 5))	('tumour', 'Disease', (135, 141))
72662	22318517	To specifically test the significance of T cell responses, we treated mice with antibodies against CD4 and CD8 to deplete T cells concurrent with, or subsequent to, intramuscular injection of Lenti-LucOS.	('CD4', 'Gene', '12504', (99, 102))	('deplete', 'NegReg', (114, 121))	('mice', 'Species', '10090', (70, 74))	('CD4', 'Gene', (99, 102))	('CD8', 'Gene', (107, 110))	('antibodies', 'Var', (80, 90))
72665	22318517	These mice develop specific tolerance to luciferase and SIY due to weak thymic expression and deletion of reactive T cells (Supplementary Fig.	('SIY', 'Disease', (56, 59))	('deletion', 'Var', (94, 102))	('SIY', 'Disease', 'None', (56, 59))	('mice', 'Species', '10090', (6, 10))	('weak', 'NegReg', (67, 71))	('luciferase', 'Enzyme', (41, 51))	('thymic expression', 'MPA', (72, 89))
72677	22318517	To assay whether autochthonous sarcomas driven by targeted genetic mutations would also display an unedited phenotype, we transplanted independently derived sarcomas from KPR or KP mice into either wild-type or Rag-2-/- mice.	('autochthonous sarcomas', 'Phenotype', 'HP:0031549', (17, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('mice', 'Species', '10090', (181, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcomas', 'Disease', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Rag-2', 'Gene', (211, 216))	('sarcomas', 'Disease', (31, 39))	('mice', 'Species', '10090', (220, 224))	('mutations', 'Var', (67, 76))	('Rag-2', 'Gene', '19374', (211, 216))	('sarcomas', 'Disease', 'MESH:D012509', (157, 165))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
72681	22318517	Interestingly, Lenti-x tumours generated in KPR or KP mice grew equally well when transplanted into wild-type or Rag-2-/- mice (Fig.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('mice', 'Species', '10090', (122, 126))	('Lenti-x tumours', 'Disease', (15, 30))	('KPR', 'Var', (44, 47))	('Lenti-x tumours', 'Disease', 'MESH:C562844', (15, 30))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('mice', 'Species', '10090', (54, 58))	('Rag-2', 'Gene', (113, 118))	('grew', 'CPA', (59, 63))	('Rag-2', 'Gene', '19374', (113, 118))
72682	22318517	It is noteworthy that while autochthonous tumours initiated by Lenti-x appeared partially inhibited by an adaptive immune response (Fig.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('adaptive immune response', 'CPA', (106, 130))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('Lenti-x', 'Var', (63, 70))	('inhibited', 'NegReg', (90, 99))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))
72683	22318517	These cells may be sufficient to eliminate a limited number of nascent tumour cells in the context of transformation by lentiviral infection, but not in response to the transplantation of fully developed tumours.	('lentiviral infection', 'Var', (120, 140))	('tumour', 'Disease', (204, 210))	('tumour', 'Disease', (71, 77))	('tumours', 'Disease', 'MESH:D009369', (204, 211))	('tumours', 'Disease', (204, 211))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumours', 'Phenotype', 'HP:0002664', (204, 211))	('tumour', 'Disease', 'MESH:D009369', (204, 210))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
72687	22318517	In an attempt to introduce immunogenic mutations in Lenti-x tumours, we treated cell lines from these tumours with MCA in vitro.	('Lenti-x tumours', 'Disease', (52, 67))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('mutations', 'Var', (39, 48))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Disease', (102, 109))	('Lenti-x tumours', 'Disease', 'MESH:C562844', (52, 67))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
72692	22318517	Sarcomas from KP mice treated with anti-CD4 and anti-CD8 antibodies at tumour initiation also retained luciferase activity (5/6 sarcomas luc+, Fig.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('mice', 'Species', '10090', (17, 21))	('activity', 'MPA', (114, 122))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('CD4', 'Gene', '12504', (40, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('anti-CD8', 'Var', (48, 56))	('sarcomas', 'Disease', (128, 136))	('tumour initiation', 'Disease', 'MESH:D009369', (71, 88))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('CD4', 'Gene', (40, 43))	('luciferase', 'Enzyme', (103, 113))	('Sarcomas', 'Disease', (0, 8))	('tumour initiation', 'Disease', (71, 88))
72693	22318517	However, fewer sarcomas retained luciferase expression when mice were treated with anti-CD4 and anti-CD8 antibodies beginning 14 days after tumour initiation (1/5 sarcomas luc+), suggesting that immunoediting can occur very early during sarcoma development.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('expression', 'MPA', (44, 54))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('sarcoma', 'Disease', (15, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcomas', 'Disease', (15, 23))	('mice', 'Species', '10090', (60, 64))	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('CD4', 'Gene', '12504', (88, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('sarcoma', 'Disease', (163, 170))	('anti-CD8', 'Var', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('tumour initiation', 'Disease', 'MESH:D009369', (140, 157))	('sarcomas', 'Disease', 'MESH:D012509', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (163, 171))	('sarcomas', 'Disease', (163, 171))	('luciferase', 'Enzyme', (33, 43))	('tumour initiation', 'Disease', (140, 157))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('CD4', 'Gene', (88, 91))	('sarcoma', 'Disease', (237, 244))
72698	22318517	Indeed, re-expression of LucOS led to severely reduced tumour growth (Fig.	('re-expression', 'Var', (8, 21))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('LucOS', 'Protein', (25, 30))	('tumour growth', 'Disease', (55, 68))	('tumour growth', 'Disease', 'MESH:D006130', (55, 68))	('reduced', 'NegReg', (47, 54))
72699	22318517	4d), indicating that loss of antigen expression was the primary means of tumour escape in this setting.	('loss', 'Var', (21, 25))	('tumour', 'Disease', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('antigen', 'Protein', (29, 36))
72700	22318517	Epigenetic silencing of tumour antigen expression via DNA methylation could be responsible for antigen loss and tumour escape.	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('DNA methylation', 'Var', (54, 69))	('tumour', 'Disease', (24, 30))	('Epigenetic silencing', 'Var', (0, 20))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('antigen', 'MPA', (95, 102))	('loss', 'NegReg', (103, 107))
72703	22318517	Therefore, epigenetic silencing of tumour antigens may represent an important mechanism by which tumours can be edited in response to immune surveillance.	('tumour', 'Disease', (97, 103))	('tumour', 'Disease', (35, 41))	('epigenetic silencing', 'Var', (11, 31))	('tumours', 'Disease', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
72707	22318517	The immunogenicity of MCA-induced sarcomas is well-documented, and may be a direct consequence of TSAs that arise from carcinogen-induced mutations of normal genes during tumour development(ref*).	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('sarcomas', 'Disease', (34, 42))	('tumour', 'Disease', (171, 177))	('sarcomas', 'Disease', 'MESH:D012509', (34, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (34, 42))	('mutations', 'Var', (138, 147))
72764	33490136	In cats, extradural lymphoma has been reported to consist of an epidural mass resulting in spinal cord compression, which can extend into and through the adjacent vertebrae as well as into the underlying muscle and has been reported to be T2-hyperintense to white matter, T1-hypointense, with a variable mass effect and homogeneous contrast enhancement.	('spinal cord compression', 'CPA', (91, 114))	('T2-hyperintense', 'Var', (239, 254))	('lymphoma', 'Disease', (20, 28))	('spinal cord compression', 'Phenotype', 'HP:0002176', (91, 114))	('lymphoma', 'Disease', 'MESH:D008223', (20, 28))	('epidural mass', 'Phenotype', 'HP:0100310', (64, 77))	('hyperintense to white matter', 'Phenotype', 'HP:0030890', (242, 270))	('cats', 'Species', '9685', (3, 7))	('lymphoma', 'Phenotype', 'HP:0002665', (20, 28))
72768	33490136	In fact, a previous report in a dog with vertebral osteosarcoma described marked osteolysis and a large soft tissue mass component, whereas a case series evaluating MRI findings in dogs with chondrosarcoma described mixed osteolytic and proliferative masses, which were T2-hyperintense, T1-hypointense, and involved the dorsal compartments of several consecutive vertebrae.	('vertebral osteosarcoma', 'Disease', (41, 63))	('soft tissue mass', 'Phenotype', 'HP:0031459', (104, 120))	('chondrosarcoma', 'Disease', 'MESH:D002813', (191, 205))	('chondrosarcoma', 'Disease', (191, 205))	('osteolytic', 'Disease', 'MESH:D030981', (222, 232))	('dog', 'Species', '9615', (181, 184))	('T1-hypointense', 'Var', (287, 301))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (191, 205))	('osteolysis', 'Phenotype', 'HP:0002797', (81, 91))	('vertebral osteosarcoma', 'Disease', 'MESH:D012516', (41, 63))	('dogs', 'Species', '9615', (181, 185))	('T2-hyperintense', 'Var', (270, 285))	('proliferative masses', 'CPA', (237, 257))	('involved', 'Reg', (307, 315))	('osteolytic', 'Disease', (222, 232))	('dog', 'Species', '9615', (32, 35))	('osteosarcoma', 'Phenotype', 'HP:0002669', (51, 63))	('osteolysis', 'Disease', (81, 91))	('osteolysis', 'Disease', 'MESH:D010014', (81, 91))
72932	33490136	Despite the overlap between tumor classes and types, within the round cell neoplasia tumor class, bone lesions with multiple myeloma were more commonly T1-hyperintense, whereas bone lesions with lymphoma were more commonly T1 isointense.	('neoplasia tumor', 'Disease', (75, 90))	('tumor', 'Disease', (85, 90))	('neoplasia tumor', 'Disease', 'MESH:D009369', (75, 90))	('tumor', 'Disease', (28, 33))	('bone', 'Disease', (98, 102))	('lymphoma', 'Disease', (195, 203))	('T1-hyperintense', 'Var', (152, 167))	('lymphoma', 'Disease', 'MESH:D008223', (195, 203))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('lymphoma', 'Phenotype', 'HP:0002665', (195, 203))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('multiple myeloma', 'Phenotype', 'HP:0006775', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('multiple myeloma', 'Disease', 'MESH:D009101', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('multiple myeloma', 'Disease', (116, 132))
72961	33490136	Two of three dogs of this study with chondrosarcoma had lesions centered on the dorsal aspect of their respective spinous process, with T1 and T2 hypointensity of the spinous processes immediately cranial and caudal to the principal lesion in one of these cases (Figure 8).	('chondrosarcoma', 'Phenotype', 'HP:0006765', (37, 51))	('dogs', 'Species', '9615', (13, 17))	('chondrosarcoma', 'Disease', (37, 51))	('chondrosarcoma', 'Disease', 'MESH:D002813', (37, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('T2 hypointensity', 'Var', (143, 159))
72984	33490136	The combination of features predictive of round cell neoplasia was the preservation of overall shape, homogeneous contrast enhancement, and lesion centering on bone, whereas alteration of overall shape, heterogeneous contrast enhancement, and lesion centering on paraspinal soft tissues were predictive of mesenchymal neoplasia.	('neoplasia', 'Disease', (318, 327))	('alteration', 'Var', (174, 184))	('homogeneous contrast enhancement', 'MPA', (102, 134))	('neoplasia', 'Disease', (53, 62))	('mesenchymal neoplasia', 'Disease', 'MESH:D009369', (306, 327))	('neoplasia', 'Phenotype', 'HP:0002664', (318, 327))	('mesenchymal neoplasia', 'Disease', (306, 327))	('neoplasia', 'Disease', 'MESH:D009369', (53, 62))	('neoplasia', 'Disease', 'MESH:D009369', (318, 327))	('neoplasia', 'Phenotype', 'HP:0002664', (53, 62))	('heterogeneous contrast enhancement', 'MPA', (203, 237))
73049	31059528	Cases were those that died from AIDS related causes of death (with their ICD 10 codes): infectious gastroenteritis (A09), tuberculosis of the lung (A15 and A16), extra-pulmonary tuberculosis (A17 to A19 and A31), certain infectious and parasitic diseases (A41), HIV (B21 to B24), cryptococcosis (B45), pneumocystis (B59), Kaposi's sarcoma (C46), Hodgkin's and non-Hodgkin's lymphoma (C82 and C85), diseases of the blood and blood forming organisms (most of D51 to D89), meningitis (G00, G03, G04, G06 and G08), pneumonia, chronic obstructive pulmonary disease, and lower respiratory tract infections (included in J01-J99), diseases of the digestive system (K72-K74), diseases of skin and bone (included in L03-L95 and M01-M99) and genitourinary conditions (N00-N39).	('diseases', 'Disease', (623, 631))	('respiratory tract infections', 'Phenotype', 'HP:0011947', (571, 599))	('diseases of the blood', 'Disease', (398, 419))	('extra-pulmonary tuberculosis', 'Phenotype', 'HP:0032271', (162, 190))	('pneumonia', 'Phenotype', 'HP:0002090', (511, 520))	('genitourinary conditions', 'Phenotype', 'HP:0000119', (731, 755))	("Hodgkin's and non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (346, 382))	('cryptococcosis', 'Disease', 'MESH:D003453', (280, 294))	('pneumonia', 'Disease', 'MESH:D011014', (511, 520))	('infectious gastroenteritis', 'Disease', 'MESH:D005759', (88, 114))	('parasitic diseases', 'Disease', 'MESH:D010272', (236, 254))	('pneumocystis', 'Disease', (302, 314))	('tuberculosis of the lung', 'Disease', 'MESH:D014376', (122, 146))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (522, 559))	('respiratory tract infections', 'Disease', (571, 599))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (322, 338))	('extra-pulmonary tuberculosis', 'Disease', (162, 190))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (522, 559))	('lymphoma', 'Phenotype', 'HP:0002665', (374, 382))	('diseases', 'Disease', (667, 675))	('pneumonia', 'Disease', (511, 520))	('death', 'Disease', (55, 60))	('pulmonary tuberculosis', 'Phenotype', 'HP:0032262', (168, 190))	('cryptococcosis', 'Disease', (280, 294))	('AIDS', 'Disease', 'MESH:D000163', (32, 36))	('tuberculosis of the lung', 'Disease', (122, 146))	('meningitis', 'Disease', (470, 480))	('digestive system', 'Disease', (639, 655))	('infectious gastroenteritis', 'Disease', (88, 114))	('chronic obstructive pulmonary disease', 'Disease', (522, 559))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (322, 338))	('G00', 'Var', (482, 485))	('sarcoma', 'Phenotype', 'HP:0100242', (331, 338))	('respiratory tract infections', 'Disease', 'MESH:D012141', (571, 599))	("Kaposi's sarcoma", 'Disease', (322, 338))	('diseases of the blood', 'Disease', 'MESH:D006402', (398, 419))	('diseases of the digestive system', 'Phenotype', 'HP:0011024', (623, 655))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (360, 382))	('J01-J99', 'CellLine', 'CVCL:U323', (613, 620))	('parasitic diseases', 'Disease', (236, 254))	('urinary conditions', 'Phenotype', 'HP:0000079', (737, 755))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (530, 559))	('ICD', 'Disease', (73, 76))	('pneumocystis', 'Disease', 'MESH:D016720', (302, 314))	('lower respiratory tract infections', 'Phenotype', 'HP:0002783', (565, 599))	('extra-pulmonary tuberculosis', 'Disease', 'MESH:D014397', (162, 190))	('meningitis', 'Disease', 'MESH:D008581', (470, 480))	('death', 'Disease', 'MESH:D003643', (55, 60))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (364, 382))	('AIDS', 'Disease', (32, 36))	('meningitis', 'Phenotype', 'HP:0001287', (470, 480))	('ICD', 'Disease', 'OMIM:252500', (73, 76))
73077	31059528	and 738k in a study by the Joint United Nations Programme on HIV and AIDS (UNAIDS).	('738k', 'Var', (4, 8))	('AIDS', 'Disease', (77, 81))	('AIDS', 'Disease', 'MESH:D000163', (77, 81))	('AIDS', 'Disease', (69, 73))	('AIDS', 'Disease', 'MESH:D000163', (69, 73))
73199	26550504	Further cytologic evaluation of the pleural and ascitic fluid revealed scattered large atypical lymphoid cells expressing HHV-8, CD30, CD79A, MUM-1, CD56, and CD138 (Figure 2).	('ascitic', 'Disease', (48, 55))	('CD138', 'Var', (159, 164))	('CD79A', 'Var', (135, 140))	('CD30', 'Var', (129, 133))	('HHV-8', 'Gene', (122, 127))	('CD56', 'Var', (149, 153))	('pleural', 'Disease', 'MESH:D010995', (36, 43))	('HHV-8', 'Species', '37296', (122, 127))	('ascitic', 'Disease', 'MESH:D001201', (48, 55))	('pleural', 'Disease', (36, 43))
73201	26550504	The flow cytometry study on the pleural effusion sample also revealed a monoclonal B-cell population consisting of larger lymphocytes expressing CD45, HLA-DR, CD38, and both surface and cytoplasmic lambda light chain.	('pleural effusion', 'Disease', (32, 48))	('CD45', 'Gene', (145, 149))	('CD38', 'Gene', (159, 163))	('HLA-DR', 'Var', (151, 157))	('pleural effusion', 'Disease', 'MESH:D010996', (32, 48))	('pleural effusion', 'Phenotype', 'HP:0002202', (32, 48))	('CD45', 'Gene', '5788', (145, 149))	('CD38', 'Gene', '952', (159, 163))
73222	26550504	As a result of HAART, a smaller proportion of KS patients appear to present with visceral disease.	('visceral disease', 'Disease', (81, 97))	('KS', 'Phenotype', 'HP:0100726', (46, 48))	('visceral disease', 'Disease', 'MESH:D059265', (81, 97))	('patients', 'Species', '9606', (49, 57))	('HAART', 'Var', (15, 20))
73268	24711903	The neoplastic cells showed positivity for desmin (Figure 1D) and vimentin and the mass was designated at that time as pleomorphic rhabdomyosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('desmin', 'Gene', '1674', (43, 49))	('vimentin', 'Gene', '7431', (66, 74))	('positivity', 'Var', (28, 38))	('vimentin', 'Gene', (66, 74))	('pleomorphic rhabdomyosarcoma', 'Disease', (119, 147))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (131, 147))	('desmin', 'Gene', (43, 49))	('pleomorphic rhabdomyosarcoma', 'Disease', 'MESH:D012208', (119, 147))
73327	23596566	However, modulation of LGR5 or exposure to RSPO had no impact on proliferation confirming that Wnt/beta-catenin signaling in ES cells does not recapitulate signaling in epithelial cells.	('RSPO', 'Gene', '284654', (43, 47))	('ES', 'Phenotype', 'HP:0012254', (125, 127))	('LGR5', 'Gene', (23, 27))	('modulation', 'Var', (9, 19))	('RSPO', 'Gene', (43, 47))	('beta-catenin', 'Gene', (99, 111))	('beta-catenin', 'Gene', '1499', (99, 111))
73345	23596566	The LGR5+ colorectal CSC have increased clonogenic and tumorigenic potential compared to bulk tumor cells and lose expression of LGR5 upon in vitro differentiation (Kemper et al.,).	('LGR5', 'Gene', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('colorectal CSC', 'Disease', (10, 24))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (55, 60))	('clonogenic', 'CPA', (40, 50))	('expression', 'MPA', (115, 125))	('increased', 'PosReg', (30, 39))	('lose', 'NegReg', (110, 114))	('LGR5+', 'Var', (4, 9))
73347	23596566	Thus, there is compelling evidence in both human and murine intestinal tumors that LGR5+ stem cells contribute to cancer initiation and progression and that high LGR5 expression is associated with worse clinical outcomes.	('associated', 'Reg', (181, 191))	('intestinal tumors', 'Disease', (60, 77))	('cancer initiation', 'Disease', 'MESH:D009369', (114, 131))	('progression', 'CPA', (136, 147))	('intestinal tumors', 'Disease', 'MESH:D007414', (60, 77))	('murine', 'Species', '10090', (53, 59))	('cancer initiation', 'Disease', (114, 131))	('high', 'Var', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('LGR5', 'Gene', (162, 166))	('expression', 'MPA', (167, 177))	('human', 'Species', '9606', (43, 48))
73383	23596566	Measurements were normalized to mCherry mean fluorescent intensity for cells transduced with the p7TFC vector, otherwise TCF reporter activity was expressed relative to the L-cell CM control.	('p7TFC', 'Var', (97, 102))	('TCF', 'Gene', (121, 124))	('TCF', 'Gene', '3172', (121, 124))
73394	23596566	Therefore, we sought to determine if high expression of LGR5 might also be associated with aggressive disease in ES.	('high expression', 'Var', (37, 52))	('aggressive disease', 'Disease', 'MESH:D001523', (91, 109))	('aggressive disease', 'Disease', (91, 109))	('ES', 'Phenotype', 'HP:0012254', (113, 115))	('LGR5', 'Gene', (56, 60))	('associated', 'Reg', (75, 85))
73413	23596566	In support of this, we observed no significant or reproducible change in the expression of Wnt/beta-catenin target genes following LGR5 knockdown (Figure 4B).	('expression', 'MPA', (77, 87))	('knockdown', 'Var', (136, 145))	('beta-catenin', 'Gene', (95, 107))	('beta-catenin', 'Gene', '1499', (95, 107))	('LGR5', 'Gene', (131, 135))
73414	23596566	In particular, loss of LGR5 did not result in down-regulation of Wnt targets suggesting that, in the context of standard tissue culture (i.e., in the absence of exogenous RSPO), LGR5 has little impact on Wnt/beta-catenin transcriptional activity (Figure 4B).	('RSPO', 'Gene', '284654', (171, 175))	('LGR5', 'Gene', (23, 27))	('LGR5', 'Gene', (178, 182))	('loss', 'Var', (15, 19))	('beta-catenin', 'Gene', (208, 220))	('RSPO', 'Gene', (171, 175))	('beta-catenin', 'Gene', '1499', (208, 220))
73415	23596566	Next, we used TCF-promoter luciferase-reporter assays to directly measure the level of TCF transcriptional activity in CHLA25 ES cells before and after LGR5 knockdown.	('TCF', 'Gene', (14, 17))	('TCF', 'Gene', (87, 90))	('TCF', 'Gene', '3172', (87, 90))	('TCF', 'Gene', '3172', (14, 17))	('CHLA25', 'CellLine', 'CVCL:M152', (119, 125))	('knockdown', 'Var', (157, 166))	('ES', 'Phenotype', 'HP:0012254', (126, 128))
73416	23596566	These assays confirmed that LGR5 knockdown had only minimal impact on basal Wnt/beta-catenin transcriptional activity in standard culture conditions (Figure 4C).	('knockdown', 'Var', (33, 42))	('LGR5', 'Gene', (28, 32))	('beta-catenin', 'Gene', '1499', (80, 92))	('beta-catenin', 'Gene', (80, 92))
73432	23596566	To determine if LGR5 was responsible for mediating this robust RSPO2-dependent potentiation of Wnt/beta-catenin signaling we evaluated the consequences of LGR5 knockdown on this signaling axis in CHLA25 cells.	('RSPO2', 'Gene', (63, 68))	('knockdown', 'Var', (160, 169))	('beta-catenin', 'Gene', (99, 111))	('CHLA25', 'CellLine', 'CVCL:M152', (196, 202))	('LGR5', 'Gene', (155, 159))	('RSPO2', 'Gene', '340419', (63, 68))	('beta-catenin', 'Gene', '1499', (99, 111))
73433	23596566	Significantly, in the context of Wnt3a and RSPO2 ligands, knockdown of LGR5 resulted in reduced potentiation of Wnt/beta-catenin transcriptional activity (Figure 6C).	('LGR5', 'Gene', (71, 75))	('beta-catenin', 'Gene', (116, 128))	('RSPO2', 'Gene', '340419', (43, 48))	('potentiation', 'PosReg', (96, 108))	('reduced', 'NegReg', (88, 95))	('RSPO2', 'Gene', (43, 48))	('knockdown', 'Var', (58, 67))	('beta-catenin', 'Gene', '1499', (116, 128))
73438	23596566	Cellular viability was also measured by trypan blue staining and no change was observed in any of the cell lines following LGR5 knockdown or over-expression (data not shown).	('over-expression', 'Var', (141, 156))	('knockdown', 'Var', (128, 137))	('LGR5', 'Gene', (123, 127))	('trypan blue', 'Chemical', 'MESH:D014343', (40, 51))
73450	23596566	In addition, studies of colorectal and gastric carcinoma, glioblastoma, and esophageal adenocarcinoma have all demonstrated heterogeneity of LGR5 expression and shown that high LGR5 levels are associated with worse outcomes (Becker et al.,; Simon et al.,; Wu et al.,; Nakata et al.,).	('esophageal adenocarcinoma', 'Disease', (76, 101))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('glioblastoma', 'Disease', (58, 70))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (39, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('colorectal and gastric carcinoma', 'Disease', 'MESH:D013274', (24, 56))	('LGR5', 'Gene', (141, 145))	('high', 'Var', (172, 176))	('glioblastoma', 'Disease', 'MESH:D005909', (58, 70))	('LGR5', 'MPA', (177, 181))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))
73451	23596566	Likewise, several studies have found a connection between high LGR5 expression and chemoresistance (Bauer et al.,) and metastasis (Uchida et al.,; Takahashi et al.,; Valladares-Ayerbes et al.,; Wu et al.,) in gastrointestinal malignancies.	('chemoresistance', 'CPA', (83, 98))	('expression', 'MPA', (68, 78))	('LGR5', 'Gene', (63, 67))	('gastrointestinal malignancies', 'Disease', (209, 238))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (209, 238))	('high', 'Var', (58, 62))	('metastasis', 'CPA', (119, 129))
73455	23596566	described a novel splice variant of LGR5 in the context of soft tissue sarcoma and reported that low level expression of this variant transcript (which lacks exon 5) was associated with worse overall and event free survival.	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('splice variant', 'Var', (18, 32))	('sarcoma', 'Disease', (71, 78))	('worse', 'NegReg', (186, 191))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (59, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('event free survival', 'CPA', (204, 223))	('LGR5', 'Gene', (36, 40))
73466	23596566	Thus, although there is still much to be understood about the role of Wnt signaling in ES pathogenesis, the data thus far support a more dominant role for Wnt deregulation in altering cell morphology, motility, and invasion rather than classical beta-catenin-mediated cellular proliferation.	('altering', 'Reg', (175, 183))	('invasion', 'CPA', (215, 223))	('deregulation', 'Var', (159, 171))	('ES', 'Phenotype', 'HP:0012254', (87, 89))	('beta-catenin', 'Gene', (246, 258))	('motility', 'CPA', (201, 209))	('Wnt', 'Gene', (155, 158))	('beta-catenin', 'Gene', '1499', (246, 258))	('cell morphology', 'CPA', (184, 199))
73470	23596566	Likewise, LGR5 knockdown had no discernible impact on the expression of Wnt/beta-catenin target gene expression nor TCF reporter activity under basal conditions.	('TCF', 'Gene', '3172', (116, 119))	('knockdown', 'Var', (15, 24))	('expression', 'MPA', (58, 68))	('beta-catenin', 'Gene', (76, 88))	('LGR5', 'Gene', (10, 14))	('activity', 'MPA', (129, 137))	('beta-catenin', 'Gene', '1499', (76, 88))	('TCF', 'Gene', (116, 119))
73481	23596566	In addition, promoter hypermethylation and loss of function mutations in LGR5 and LGR6 have been discovered in some colorectal tumor samples, again suggesting that these genes could act as tumor suppressors in some contexts (Sjoblom et al.,; Chan et al.,; de Sousa et al.,).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('loss of function', 'NegReg', (43, 59))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', (127, 132))	('LGR6', 'Gene', '59352', (82, 86))	('colorectal tumor', 'Disease', (116, 132))	('LGR5', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('LGR6', 'Gene', (82, 86))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('colorectal tumor', 'Disease', 'MESH:D015179', (116, 132))
73601	32850452	Future treatments with agents that target the epigenetic machinery such as inhibitors against Enhancer of Zeste homolog 2 (EZH2) or histone deactylase may prove even more effective.	('EZH2', 'Gene', (123, 127))	('inhibitors', 'Var', (75, 85))	('Enhancer of Zeste homolog 2', 'Gene', '2146', (94, 121))	('Enhancer of Zeste homolog 2', 'Gene', (94, 121))	('EZH2', 'Gene', '2146', (123, 127))
73645	32850452	Several studies have reported durable tumor responses to KIT inhibition by imatinib, nilotimib, sorafenib, dasatinib, and sunitinib in patients with melanoma harboring KIT mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mutations', 'Var', (172, 181))	('sorafenib', 'Chemical', 'MESH:D000077157', (96, 105))	('patients', 'Species', '9606', (135, 143))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('inhibition', 'NegReg', (61, 71))	('KIT', 'Gene', '3815', (168, 171))	('KIT', 'Gene', '3815', (57, 60))	('dasatinib', 'Chemical', 'MESH:D000069439', (107, 116))	('imatinib', 'Chemical', 'MESH:D000068877', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('KIT', 'Gene', (168, 171))	('KIT', 'Gene', (57, 60))	('nilotimib', 'Chemical', '-', (85, 94))	('sunitinib', 'Chemical', 'MESH:D000077210', (122, 131))
73697	32708251	The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers.	('Epigenetic Alterations', 'Var', (27, 49))	('BRCA1', 'Gene', '672', (139, 144))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('BRCA1', 'Gene', (139, 144))	('Cancers', 'Disease', 'MESH:D009369', (114, 121))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (251, 277))	('found', 'Reg', (231, 236))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('Cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('Breast Cancer', 'Phenotype', 'HP:0003002', (122, 135))	('tumor', 'Disease', (175, 180))	('BARD1', 'Gene', '580', (53, 58))	('BARD1', 'Gene', (53, 58))	('Breast Cancer 1', 'Gene', '672', (122, 137))	('Cancers', 'Disease', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('ovarian cancers', 'Phenotype', 'HP:0100615', (262, 277))	('Cancers', 'Phenotype', 'HP:0002664', (114, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (262, 276))	('women', 'Species', '9606', (240, 245))	('Breast Cancer 1', 'Gene', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('Effects', 'Reg', (4, 11))
73699	32708251	Underscoring the functional significance of the BRCA1 and BARD1 interactions, prevalent mutations in the BRCA1 gene are found in its RING domain, through which it binds the RING domain of BARD1.	('BRCA1', 'Gene', (105, 110))	('BRCA1', 'Gene', '672', (48, 53))	('BRCA1', 'Gene', (48, 53))	('mutations', 'Var', (88, 97))	('binds', 'Interaction', (163, 168))	('BRCA1', 'Gene', '672', (105, 110))
73701	32708251	However, many mutations in both BARD1 and BRCA1 also exist in other domains that significantly affect their biological functions.	('BRCA1', 'Gene', '672', (42, 47))	('BRCA1', 'Gene', (42, 47))	('biological functions', 'MPA', (108, 128))	('BARD1', 'Gene', (32, 37))	('affect', 'Reg', (95, 101))	('mutations', 'Var', (14, 23))
73702	32708251	Intriguingly, recent genome-wide studies have identified various single nucleotide polymorphisms (SNPs), genetic alterations, and epigenetic modifications in or near the BARD1 gene that manifested profound effects on tumorigenesis in a variety of non-breast and non-gynecological cancers.	('effects', 'Reg', (206, 213))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('BARD1', 'Gene', (170, 175))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('single nucleotide polymorphisms', 'Var', (65, 96))	('cancers', 'Disease', (280, 287))	('epigenetic modifications', 'Var', (130, 154))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))
73705	32708251	Furthermore, the pro- and anti-tumorigenic functions of different SNPs and BARD1 variants will also be discussed.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('BARD1', 'Gene', (75, 80))	('SNPs', 'Gene', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('variants', 'Var', (81, 89))
73721	32708251	Due to the pronounced role of BRCA1 and BRCA2 in hereditary breast and ovarian cancer, different mutations and variants of BARD1 were first investigated in breast cancers and various gynecological cancers in the late 1990s and early 2000s.	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (49, 85))	('BRCA1', 'Gene', (30, 35))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('breast cancers', 'Disease', 'MESH:D001943', (156, 170))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('breast cancers', 'Disease', (156, 170))	('BRCA2', 'Gene', (40, 45))	('breast cancers', 'Phenotype', 'HP:0003002', (156, 170))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Disease', (197, 204))	('variants', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('BRCA2', 'Gene', '675', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('BARD1', 'Gene', (123, 128))	('cancers', 'Disease', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('BRCA1', 'Gene', '672', (30, 35))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))
73722	32708251	For example, women with the missense mutation C557S, just before the BRCT1 domain of BARD1, have an increased susceptibility to breast cancer.	('C557S', 'Var', (46, 51))	('missense', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('C557S', 'Mutation', 'rs28997576', (46, 51))	('women', 'Species', '9606', (13, 18))	('BARD1', 'Gene', (85, 90))	('susceptibility', 'Reg', (110, 124))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
73725	32708251	These variations have been well-studied in hereditary breast and ovarian cancers, however, the presence and functional consequences of these alterations in other cancer types are still being investigated.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (162, 168))	('variations', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (43, 80))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('ovarian cancers', 'Phenotype', 'HP:0100615', (65, 80))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))
73728	32708251	Specifically, we will summarize the clinical manifestations of single nucleotide polymorphisms (SNPs) in the BARD1 gene and the expression of BARD1 isoforms in neuroblastoma (NB), gastrointestinal cancers, non-small cell lung cancer (NSCLC), nephroblastoma, Ewing sarcoma, and acute myeloid leukemia (AML).	('gastrointestinal cancers', 'Disease', (180, 204))	('neuroblastoma', 'Disease', (160, 173))	('acute myeloid leukemia', 'Disease', (277, 299))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (206, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('Ewing sarcoma', 'Disease', (258, 271))	('SCLC', 'Phenotype', 'HP:0030357', (235, 239))	('neuroblastoma', 'Phenotype', 'HP:0003006', (160, 173))	('BARD1', 'Gene', (142, 147))	('nephroblastoma', 'Phenotype', 'HP:0002667', (242, 256))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (210, 232))	('neuroblastoma', 'Disease', 'MESH:D009447', (160, 173))	('AML', 'Disease', 'MESH:D015470', (301, 304))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('AML', 'Phenotype', 'HP:0004808', (301, 304))	('AML', 'Disease', (301, 304))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (206, 232))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (277, 299))	('NSCLC', 'Disease', (234, 239))	('leukemia', 'Phenotype', 'HP:0001909', (291, 299))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (277, 299))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (283, 299))	('BARD1', 'Gene', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (234, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (258, 271))	('non-small cell lung cancer', 'Disease', (206, 232))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (258, 271))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (180, 204))	('single nucleotide polymorphisms', 'Var', (63, 94))	('nephroblastoma', 'Disease', 'MESH:D009396', (242, 256))	('NB', 'Phenotype', 'HP:0003006', (175, 177))	('nephroblastoma', 'Disease', (242, 256))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
73729	32708251	We will then discuss how these genetic alterations affect the domain structures of BARD1 and the implications of these changes in BARD1-mediated biological interactions and processes, including tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('affect', 'Reg', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('domain structures', 'MPA', (62, 79))	('BARD1', 'Gene', (83, 88))	('genetic alterations', 'Var', (31, 50))
73733	32708251	The heterodimer formation may be vital for the stabilization of BARD1 and BRCA1 as the loss of one protein drastically decreases the amount of the other protein.	('decreases', 'NegReg', (119, 128))	('loss', 'Var', (87, 91))	('amount of the other protein', 'MPA', (133, 160))	('BRCA1', 'Gene', '672', (74, 79))	('protein', 'Protein', (99, 106))	('BRCA1', 'Gene', (74, 79))
73735	32708251	Loss of BARD1-BRCA1 at this step results in the rapid accumulation of fragmented or extra centrosomes.	('BRCA1', 'Gene', '672', (14, 19))	('accumulation', 'PosReg', (54, 66))	('Loss', 'Var', (0, 4))	('BRCA1', 'Gene', (14, 19))
73757	32708251	Both BARD1 and BRCA1 are capable of physically interacting with RAD51 and DNA; however, it is the BRCA2-DSS1 complex that facilitates the replacement of RPA with RAD51.	('RAD51', 'Gene', '5888', (64, 69))	('facilitates', 'PosReg', (122, 133))	('RPA', 'Gene', '6117', (153, 156))	('DSS1', 'Gene', '7979', (104, 108))	('RAD51', 'Gene', (162, 167))	('replacement', 'Var', (138, 149))	('BRCA1', 'Gene', '672', (15, 20))	('BRCA2', 'Gene', (98, 103))	('RPA', 'Gene', (153, 156))	('DSS1', 'Gene', (104, 108))	('RAD51', 'Gene', '5888', (162, 167))	('BRCA1', 'Gene', (15, 20))	('BRCA2', 'Gene', '675', (98, 103))	('RAD51', 'Gene', (64, 69))
73764	32708251	Mutations therein alter DNA foci in a parallel stepwise manner with BRCA1 mutations impairing the complex from forming entirely.	('BRCA1', 'Gene', (68, 73))	('mutations', 'Var', (74, 83))	('impairing', 'NegReg', (84, 93))	('alter', 'Reg', (18, 23))	('BRCA1', 'Gene', '672', (68, 73))
73770	32708251	BARD1 overexpression induces apoptosis, while the tumor-related mutation, Q564H, diminishes BARD1's pro-apoptotic ability when exposed to genotoxic stress.	('apoptosis', 'CPA', (29, 38))	('pro-apoptotic ability', 'MPA', (100, 121))	('BARD1', 'Gene', (92, 97))	('genotoxic stress', 'Disease', 'MESH:D000079225', (138, 154))	('genotoxic stress', 'Disease', (138, 154))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('BARD1', 'Gene', (0, 5))	('Q564H', 'Var', (74, 79))	('overexpression', 'PosReg', (6, 20))	('Q564H', 'Mutation', 'p.Q564H', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('diminishes', 'NegReg', (81, 91))	('tumor', 'Disease', (50, 55))
73775	32708251	Additionally, mutations associated with breast, ovarian, and uterine malignancies lack sequences in the ANK-BRCT linker region that are vital for BARD1-dependent apoptosis.	('lack', 'NegReg', (82, 86))	('ANK', 'Gene', (104, 107))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('ovarian', 'Disease', (48, 55))	('ANK', 'Gene', '286', (104, 107))	('breast', 'Disease', (40, 46))	('sequences', 'MPA', (87, 96))	('mutations', 'Var', (14, 23))	('uterine malignancies', 'Phenotype', 'HP:0010784', (61, 81))	('malignancies', 'Disease', (69, 81))
73785	32708251	The deletion of its BRCT domain not only limits the ability of BARD1 to bind p53, but it also inhibits its export out of the nucleus and localization to the cytoplasm and mitochondria.	('BRCT', 'Gene', (20, 24))	('bind', 'Interaction', (72, 76))	('inhibits', 'NegReg', (94, 102))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('deletion', 'Var', (4, 12))	('ability', 'MPA', (52, 59))	('export out of the nucleus', 'MPA', (107, 132))	('localization', 'MPA', (137, 149))	('limits', 'NegReg', (41, 47))
73789	32708251	Mutating the NLS of BARD1 results in BRCA1 localizing to the cytoplasm, thus supporting the hypothesis that BARD1 acts as a chaperone to transport BRCA1 into the nucleus.	('Mutating', 'Var', (0, 8))	('BRCA1', 'Gene', '672', (147, 152))	('results in', 'Reg', (26, 36))	('BRCA1', 'Gene', (147, 152))	('localizing', 'MPA', (43, 53))	('BARD1', 'Gene', (20, 25))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA1', 'Gene', (37, 42))
73804	32708251	For example, the Q564H mutation of BARD1 found in ovarian, breast, and uterine tumors, reduces the BARD1-CstF-50 interaction, and prevents their inhibition of polyadenylation.	('BARD1', 'Gene', (35, 40))	('Q564H', 'Var', (17, 22))	('CstF-50', 'Gene', (105, 112))	('reduces', 'NegReg', (87, 94))	('breast', 'Disease', (59, 65))	('inhibition', 'MPA', (145, 155))	('Q564H', 'Mutation', 'p.Q564H', (17, 22))	('uterine tumors', 'Phenotype', 'HP:0010784', (71, 85))	('prevents', 'NegReg', (130, 138))	('tumors', 'Disease', (79, 85))	('ovarian', 'Disease', (50, 57))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('polyadenylation', 'MPA', (159, 174))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('CstF-50', 'Gene', '1477', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('interaction', 'Interaction', (113, 124))
73805	32708251	Interestingly, p53 associates with BARD1-CstF-50, and tumor-related mutations in p53 also result in decreased BARD1-CstF-50 association and inhibition of mRNA cleavage.	('mRNA cleavage', 'MPA', (154, 167))	('CstF-50', 'Gene', '1477', (116, 123))	('CstF-50', 'Gene', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CstF-50', 'Gene', '1477', (41, 48))	('p53', 'Gene', (15, 18))	('association', 'Interaction', (124, 135))	('CstF-50', 'Gene', (41, 48))	('decreased', 'NegReg', (100, 109))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (81, 84))	('inhibition', 'NegReg', (140, 150))	('p53', 'Gene', '7157', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (68, 77))	('tumor', 'Disease', (54, 59))
73809	32708251	Inhibition of PARPs has been implemented in the treatment of BRCA1/2 mutated cancers.	('PARPs', 'Gene', (14, 19))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('PARPs', 'Gene', '142', (14, 19))	('mutated', 'Var', (69, 76))	('cancers', 'Disease', (77, 84))	('BRCA1/2', 'Gene', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BRCA1/2', 'Gene', '672;675', (61, 68))
73812	32708251	Genome-wide association studies (GWAS) in NB have shown that BARD1 acts as a tumor suppressor during its development and that certain variations in a single nucleotide have profound effects on BARD1 protein expression and NB susceptibility (Table 1).	('variations', 'Var', (134, 144))	('protein', 'Protein', (199, 206))	('NB', 'Phenotype', 'HP:0003006', (222, 224))	('NB', 'Phenotype', 'HP:0003006', (42, 44))	('BARD1', 'Gene', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('BARD1', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('expression', 'MPA', (207, 217))	('tumor', 'Disease', (77, 82))	('effects', 'Reg', (182, 189))	('susceptibility', 'Reg', (225, 239))
73813	32708251	identified multiple SNPs in the BARD1 gene from blood samples of NB patients from European American and European populations.	('patients', 'Species', '9606', (68, 76))	('SNPs', 'Var', (20, 24))	('NB', 'Phenotype', 'HP:0003006', (65, 67))	('BARD1', 'Gene', (32, 37))
73814	32708251	One particular SNP, rs6435862 T > G, which is located in intron 1 of the BARD1 gene and results in splicing of exon 2 and 3 and formation of BARD1beta, was most significantly associated with susceptibility to NB.	('associated', 'Reg', (175, 185))	('rs6435862', 'Mutation', 'rs6435862', (20, 29))	('NB', 'Phenotype', 'HP:0003006', (209, 211))	('rs6435862 T > G', 'Var', (20, 35))	('splicing', 'MPA', (99, 107))	('susceptibility', 'Reg', (191, 205))
73815	32708251	Studies also found that rs6435862 was associated with high-risk NB, suggesting that BARD1beta is an oncogene.	('rs6435862', 'Var', (24, 33))	('rs6435862', 'Mutation', 'rs6435862', (24, 33))	('NB', 'Phenotype', 'HP:0003006', (64, 66))	('associated', 'Reg', (38, 48))
73818	32708251	In the Han Chinese population, rs6435862 was associated with stage IV tumors and adrenal gland as the primary site while another study in Han Chinese showed additional associations with stage III disease and the onset of NB after one year of age in patients homozygous for the G risk allele.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('associations', 'Interaction', (168, 180))	('stage III disease', 'Disease', (186, 203))	('patients', 'Species', '9606', (249, 257))	('rs6435862', 'Mutation', 'rs6435862', (31, 40))	('associated', 'Reg', (45, 55))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('stage III disease', 'Disease', 'MESH:D058625', (186, 203))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('adrenal gland', 'Disease', (81, 94))	('NB', 'Phenotype', 'HP:0003006', (221, 223))	('rs6435862', 'Var', (31, 40))
73820	32708251	Knockdown of BARD1beta in NB cell lines, NLF and Nb-Ebc1, which contain rs6435862, resulted in significant inhibition of proliferation and colony formation.	('NB', 'Phenotype', 'HP:0003006', (26, 28))	('proliferation', 'CPA', (121, 134))	('colony formation', 'CPA', (139, 155))	('rs6435862', 'Mutation', 'rs6435862', (72, 81))	('rs6435862', 'Var', (72, 81))	('BARD1beta', 'Gene', (13, 22))	('inhibition', 'NegReg', (107, 117))
73821	32708251	The enhanced proliferation and evasion of apoptosis in NB caused by this variant were through BARD1beta interaction with and stabilization of Aurora kinases A and B.	('proliferation', 'CPA', (13, 26))	('stabilization', 'MPA', (125, 138))	('enhanced', 'PosReg', (4, 12))	('BARD1beta', 'Gene', (94, 103))	('interaction', 'Interaction', (104, 115))	('evasion', 'CPA', (31, 38))	('apoptosis', 'CPA', (42, 51))	('Aurora kinases A and B', 'Gene', '6790;9212', (142, 164))	('NB', 'Phenotype', 'HP:0003006', (55, 57))	('variant', 'Var', (73, 80))
73822	32708251	The mechanisms of BARD1beta were independent of p53 and BRCA1-dependent HR because silencing of BARD1beta did not alter the level of phosphorylated p53 and additional silencing of PARP1 was not lethal to NB cells.	('p53', 'Gene', (48, 51))	('PARP1', 'Gene', '142', (180, 185))	('PARP1', 'Gene', (180, 185))	('p53', 'Gene', (148, 151))	('p53', 'Gene', '7157', (48, 51))	('BRCA1', 'Gene', '672', (56, 61))	('p53', 'Gene', '7157', (148, 151))	('BRCA1', 'Gene', (56, 61))	('silencing', 'Var', (167, 176))	('NB', 'Phenotype', 'HP:0003006', (204, 206))	('BARD1beta', 'Gene', (96, 105))
73826	32708251	Another intronic SNP associated with the development of NB is rs3768716.	('rs3768716', 'Mutation', 'rs3768716', (62, 71))	('NB', 'Phenotype', 'HP:0003006', (56, 58))	('associated', 'Reg', (21, 31))	('rs3768716', 'Var', (62, 71))
73827	32708251	Combined tumor samples from the United Kingdom and the United States found that this variant was associated with high-risk NB with an odds ratio of 1.68.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('variant', 'Var', (85, 92))	('NB', 'Phenotype', 'HP:0003006', (123, 125))	('tumor', 'Disease', (9, 14))	('associated', 'Reg', (97, 107))
73828	32708251	rs3768716 could indicate an aggressive disease phenotype since the SNP was associated with stage III and IV NB, origination at the adrenal gland and diagnosis after 12 months of age.	('IV NB', 'Disease', (105, 110))	('aggressive disease', 'Disease', (28, 46))	('SNP', 'Disease', (67, 70))	('rs3768716', 'Var', (0, 9))	('aggressive disease', 'Disease', 'MESH:D001523', (28, 46))	('rs3768716', 'Mutation', 'rs3768716', (0, 9))	('NB', 'Phenotype', 'HP:0003006', (108, 110))	('stage III', 'Disease', (91, 100))	('associated', 'Reg', (75, 85))
73829	32708251	One of the most common SNPs in the BARD1 gene associated with NB is rs17489363, which is located in the promoter region.	('BARD1', 'Gene', (35, 40))	('rs17489363', 'Var', (68, 78))	('NB', 'Phenotype', 'HP:0003006', (62, 64))	('rs17489363', 'Mutation', 'rs17489363', (68, 78))	('associated', 'Reg', (46, 56))
73831	32708251	Knocking down of BARD1-FL in SHSY5Y and SKNSH, two human NB cell lines, led to increased viability and invasion, which is consistent with the tumor suppression function of BARD1-FL in NB.	('NB', 'Phenotype', 'HP:0003006', (57, 59))	('increased', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('viability', 'CPA', (89, 98))	('Knocking down', 'Var', (0, 13))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('human', 'Species', '9606', (51, 56))	('NB', 'Phenotype', 'HP:0003006', (184, 186))	('BARD1-FL', 'Gene', (17, 25))	('invasion', 'CPA', (103, 111))	('SHSY5Y', 'CellLine', 'CVCL:0019', (29, 35))
73832	32708251	Heat shock factor 1 (HSF1) bound more strongly to the BARD1 gene with homozygous T risk allele of rs17489363 present in the SHSY5Y cell line compared to its homozygous C allele in the SKNAS cell line.	('rs17489363', 'Var', (98, 108))	('strongly', 'PosReg', (38, 46))	('Heat shock factor 1', 'Gene', '3297', (0, 19))	('HSF1', 'Gene', (21, 25))	('SKNAS', 'CellLine', 'CVCL:1700', (184, 189))	('bound', 'Interaction', (27, 32))	('Heat shock factor 1', 'Gene', (0, 19))	('BARD1', 'Gene', (54, 59))	('HSF1', 'Gene', '3297', (21, 25))	('rs17489363', 'Mutation', 'rs17489363', (98, 108))	('shock', 'Phenotype', 'HP:0031273', (5, 10))	('SHSY5Y', 'CellLine', 'CVCL:0019', (124, 130))
73833	32708251	rs6720708, another SNP in the BARD1 gene, has the strongest association with NB arising from the adrenal gland.	('rs6720708', 'Var', (0, 9))	('NB', 'Phenotype', 'HP:0003006', (77, 79))	('rs6720708', 'Mutation', 'rs6720708', (0, 9))	('NB arising', 'Disease', (77, 87))	('BARD1', 'Gene', (30, 35))	('association', 'Interaction', (60, 71))
73834	32708251	Since it is in strong linkage disequilibrium with rs17489363, it is likely that rs17489363 is also associated with this site of origin.	('rs17489363', 'Mutation', 'rs17489363', (80, 90))	('rs17489363', 'Var', (50, 60))	('rs17489363', 'Mutation', 'rs17489363', (50, 60))	('rs17489363', 'Var', (80, 90))	('associated', 'Reg', (99, 109))
73836	32708251	rs17489363 predisposes to NB originating from the adrenal gland by allowing the binding of HSF1 to the BARD1 gene at the promoter region and reducing the transcription of BARD1-FL, thereby affecting its DDR function.	('NB', 'Phenotype', 'HP:0003006', (26, 28))	('transcription', 'MPA', (154, 167))	('HSF1', 'Gene', (91, 95))	('HSF1', 'Gene', '3297', (91, 95))	('rs17489363', 'Var', (0, 10))	('affecting', 'Reg', (189, 198))	('binding', 'Interaction', (80, 87))	('rs17489363', 'Mutation', 'rs17489363', (0, 10))	('BARD1-FL', 'Gene', (171, 179))	('reducing', 'NegReg', (141, 149))	('DDR function', 'MPA', (203, 215))	('BARD1', 'Gene', (103, 108))
73837	32708251	rs7585356, located downstream of the BARD1 gene in the 3' untranslated region (UTR), resulted in overexpression of BARD1-FL.	('overexpression', 'PosReg', (97, 111))	('rs7585356', 'Mutation', 'rs7585356', (0, 9))	('BARD1-FL', 'Gene', (115, 123))	('BARD1', 'Gene', (37, 42))	('rs7585356', 'Var', (0, 9))
73840	32708251	Harboring at least one A allele at rs7585356 was significantly associated with decreased risk of NB in Chinese girls.	('decreased', 'NegReg', (79, 88))	('rs7585356', 'Mutation', 'rs7585356', (35, 44))	('girls', 'Species', '9606', (111, 116))	('rs7585356', 'Var', (35, 44))	('NB', 'Phenotype', 'HP:0003006', (97, 99))
73841	32708251	rs7585356 by conversion of the G allele to an A allele overexpressed BARD1-FL and resulted in better clinical prognosis.	('rs7585356', 'Var', (0, 9))	('better', 'PosReg', (94, 100))	('rs7585356', 'Mutation', 'rs7585356', (0, 9))	('BARD1-FL', 'Gene', (69, 77))
73842	32708251	rs1048108, located in exon 1 of the BARD1 gene near the RING domain, was also negatively associated with NB risk in European Americans, African Americans, Italians, and Chinese people.	('associated', 'Reg', (89, 99))	('NB', 'Phenotype', 'HP:0003006', (105, 107))	('BARD1', 'Gene', (36, 41))	('people', 'Species', '9606', (177, 183))	('rs1048108', 'Mutation', 'rs1048108', (0, 9))	('rs1048108', 'Var', (0, 9))	('negatively', 'NegReg', (78, 88))
73843	32708251	Pathway analysis indicated that rs1048108 repressed cellular development and regulated apoptosis.	('rs1048108', 'Mutation', 'rs1048108', (32, 41))	('regulated', 'Reg', (77, 86))	('cellular development', 'CPA', (52, 72))	('apoptosis', 'CPA', (87, 96))	('rs1048108', 'Var', (32, 41))
73847	32708251	For example, rs16852804 was significantly associated with NB susceptibility, while rs7599060 was significantly associated with high-risk disease.	('rs16852804', 'Var', (13, 23))	('associated', 'Reg', (42, 52))	('rs16852804', 'Mutation', 'rs16852804', (13, 23))	('rs7599060', 'Var', (83, 92))	('associated', 'Reg', (111, 121))	('NB', 'Phenotype', 'HP:0003006', (58, 60))	('rs7599060', 'Mutation', 'rs7599060', (83, 92))
73849	32708251	There are many other single nucleotide variants of BARD1 that are significantly associated with NB susceptibility (Supplemental Table S1), however, the details regarding their role in cancer prognosis still need to be further investigated.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('single nucleotide variants', 'Var', (21, 47))	('NB', 'Phenotype', 'HP:0003006', (96, 98))	('associated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('BARD1', 'Gene', (51, 56))
73851	32708251	BARD1-FL promotes DDR through G2-M checkpoint arrest via downregulation of cyclin B and induction of apoptosis via phosphorylation of p53.	('downregulation', 'NegReg', (57, 71))	('G2-M', 'MPA', (30, 34))	('checkpoint arrest', 'Disease', 'MESH:D006323', (35, 52))	('p53', 'Gene', '7157', (134, 137))	('phosphorylation', 'Var', (115, 130))	('cyclin B', 'Protein', (75, 83))	('p53', 'Gene', (134, 137))	('checkpoint arrest', 'Disease', (35, 52))	('apoptosis', 'CPA', (101, 110))	('BARD1-FL', 'Gene', (0, 8))	('DDR', 'Disease', (18, 21))	('promotes', 'PosReg', (9, 17))
73853	32708251	SNPs in the BARD1 gene have both oncogenic and tumor-suppressing roles.	('BARD1', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('SNPs', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
73854	32708251	In support of BARD1 as a tumor suppressor, rs7585356 leads to the overexpression of BARD1-FL while rs1048108 does not affect BRCA1 binding.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('rs7585356', 'Mutation', 'rs7585356', (43, 52))	('tumor', 'Disease', (25, 30))	('BRCA1', 'Gene', '672', (125, 130))	('rs7585356', 'Var', (43, 52))	('BARD1-FL', 'Gene', (84, 92))	('rs1048108', 'Mutation', 'rs1048108', (99, 108))	('BRCA1', 'Gene', (125, 130))	('overexpression', 'PosReg', (66, 80))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
73855	32708251	Reduced expression of BARD1-FL (rs17489363) and formation of the oncogenic BARD1beta isoform (rs6435862) increase susceptibility to NB and correlate with poor prognostic factors such as stage III and IV disease, older age at diagnosis and tumor originating in the adrenal gland.	('rs17489363', 'Mutation', 'rs17489363', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('IV disease', 'Disease', (200, 210))	('stage III', 'Disease', (186, 195))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('increase', 'PosReg', (105, 113))	('susceptibility', 'MPA', (114, 128))	('rs6435862', 'Mutation', 'rs6435862', (94, 103))	('BARD1-FL', 'Gene', (22, 30))	('tumor', 'Disease', (239, 244))	('expression', 'MPA', (8, 18))	('NB', 'Phenotype', 'HP:0003006', (132, 134))	('rs17489363', 'Var', (32, 42))	('rs6435862', 'Var', (94, 103))
73857	32708251	The proliferation of NB cell lines and xenograft tumors with mutations or deletions in DNA repair genes, including BARD1, were inhibited by the PARP inhibitor (PARPi), Olaparib.	('deletions', 'Var', (74, 83))	('proliferation', 'CPA', (4, 17))	('PARP', 'Gene', '142', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('PARP', 'Gene', (144, 148))	('mutations', 'Var', (61, 70))	('inhibited', 'NegReg', (127, 136))	('NB', 'Phenotype', 'HP:0003006', (21, 23))	('DNA repair genes', 'Gene', (87, 103))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('Olaparib', 'Chemical', 'MESH:C531550', (168, 176))	('PARP', 'Gene', (160, 164))	('PARP', 'Gene', '142', (144, 148))	('BARD1', 'Gene', (115, 120))
73858	32708251	Thus, SNPs leading to oncogenic isoforms or decreased activity of BARD1-FL result in dysregulation of DDR, and those patients could benefit from treatment with Aurora kinase inhibitors or PARP inhibitors.	('PARP', 'Gene', (188, 192))	('BARD1-FL', 'Gene', (66, 74))	('dysregulation', 'MPA', (85, 98))	('oncogenic isoforms', 'MPA', (22, 40))	('SNPs', 'Var', (6, 10))	('decreased', 'NegReg', (44, 53))	('PARP', 'Gene', '142', (188, 192))	('activity', 'MPA', (54, 62))	('patients', 'Species', '9606', (117, 125))	('DDR', 'MPA', (102, 105))	('benefit', 'Reg', (132, 139))
73860	32708251	For example, mutations in the MutS homolog 2 (MSH2), a mismatch repair protein, are prevalent in Hereditary Non-Polyposis Colorectal Cancer as well as sporadic cases.	('MutS homolog 2', 'Gene', (30, 44))	('Hereditary Non-Polyposis Colorectal Cancer', 'Disease', (97, 139))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('MutS homolog 2', 'Gene', '4436', (30, 44))	('prevalent', 'Reg', (84, 93))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (122, 139))	('MSH2', 'Gene', (46, 50))	('mutations', 'Var', (13, 22))	('Hereditary Non-Polyposis Colorectal Cancer', 'Disease', 'MESH:D003123', (97, 139))	('MSH2', 'Gene', '4436', (46, 50))
73865	32708251	Therefore, mutations in BARD1 may play a role in CRC tumorigenesis through the disruption of MMR.	('mutations', 'Var', (11, 20))	('disruption', 'NegReg', (79, 89))	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('MMR', 'Protein', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('play', 'Reg', (34, 38))	('tumor', 'Disease', (53, 58))	('BARD1', 'Gene', (24, 29))	('role', 'Reg', (41, 45))
73867	32708251	Comparison of these matched tissues showed that the variants which removed exon 4 (4a/5, 3/5, 1/5) were decreased in tumor compared to the normal colon; however, in general, variants 4a/5 and 3/5 are more highly expressed in normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('decreased', 'NegReg', (104, 113))	('variants', 'Var', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
73871	32708251	Positive staining for antigens mapped to either exon 3 or exon 4 showed no improvement in survival, suggesting that isoforms beta, kappa, and pi may promote tumor growth in CRC.	('tumor', 'Disease', (157, 162))	('CRC', 'Disease', (173, 176))	('isoforms', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('CRC', 'Phenotype', 'HP:0003003', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('promote', 'PosReg', (149, 156))
73873	32708251	CaCo-2 cells, which express BARD1beta and wild-type BRCA1, showed sensitivity to PARPi with an IC50 of ~17.5 uM.	('BRCA1', 'Gene', '672', (52, 57))	('sensitivity', 'MPA', (66, 77))	('PARP', 'Gene', (81, 85))	('BRCA1', 'Gene', (52, 57))	('CaCo-2', 'CellLine', 'CVCL:0025', (0, 6))	('PARP', 'Gene', '142', (81, 85))	('BARD1beta', 'Var', (28, 37))
73875	32708251	As this trend is similar to the CaCo-2 cells, BARD1beta causes PARPi sensitization likely through disrupting HR.	('PARP', 'Gene', '142', (63, 67))	('CaCo-2', 'CellLine', 'CVCL:0025', (32, 38))	('BARD1beta', 'Var', (46, 55))	('PARP', 'Gene', (63, 67))	('causes', 'Reg', (56, 62))	('disrupting', 'NegReg', (98, 108))
73883	32708251	Given that a multitude of variants in BARD1 have been identified in CRCs and normal colons, both tumorigenic and protective alterations exist.	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('identified', 'Reg', (54, 64))	('BARD1', 'Gene', (38, 43))	('CRCs', 'Disease', (68, 72))	('variants', 'Var', (26, 34))
73887	32708251	Staining patterns with co-expression of only these N- and C-terminal regions is consistent with the delta and phi isoforms, suggesting that these variants may prevent tumor growth.	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('variants', 'Var', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('prevent', 'NegReg', (159, 166))	('tumor', 'Disease', (167, 172))
73890	32708251	Sodium butyrate treatment of SW48 cells showed that BARD1 cleavage occurs early in apoptosis during the G0/G1 phase and is mediated by calpain.	('mediated', 'Reg', (123, 131))	('cleavage', 'Var', (58, 66))	('Sodium butyrate', 'Chemical', 'MESH:D020148', (0, 15))	('SW48', 'CellLine', 'CVCL:1724', (29, 33))	('BARD1', 'Gene', (52, 57))
73891	32708251	The importance of the ANK repeats and the BRCT domain are further supported by pathogenic variants disrupting this region.	('ANK', 'Gene', '286', (22, 25))	('variants', 'Var', (90, 98))	('ANK', 'Gene', (22, 25))
73892	32708251	An extremely rare variant of BARD1 with strong CRC inheritance pattern, c.1811-2A > G, resulted in the removal of exon 9 due to exon skipping, which is part of the BRCT domain.	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('removal', 'NegReg', (103, 110))	('c.1811-2A > G', 'Mutation', 'c.1811-2A>G', (72, 85))	('BARD1', 'Gene', (29, 34))	('exon', 'Protein', (114, 118))	('exon skipping', 'Var', (128, 141))	('c.1811-2A > G', 'Var', (72, 85))
73893	32708251	Missense mutations, BARD1 c.1217G > A p.Arg406Gln (rs587780014) and BARD1 c.1918C > A p.Leu640Ile (rs1553612535), were present in three patients with stage III or IV CRC diagnosed before the age of 50.	('p.Leu640Ile', 'Mutation', 'rs1553612535', (86, 97))	('rs587780014', 'Mutation', 'rs587780014', (51, 62))	('rs1553612535', 'Mutation', 'rs1553612535', (99, 111))	('c.1918C > A', 'Mutation', 'c.1918C>A', (74, 85))	('c.1918C > A p.Leu640Ile (rs1553612535', 'Var', (74, 111))	('rs587780014', 'Var', (51, 62))	('BARD1', 'Gene', (20, 25))	('BARD1', 'Gene', (68, 73))	('patients', 'Species', '9606', (136, 144))	('c.1217G > A', 'Mutation', 'rs587780014', (26, 37))	('CRC', 'Phenotype', 'HP:0003003', (166, 169))	('stage III', 'Disease', (150, 159))	('p.Arg406Gln', 'Mutation', 'rs587780014', (38, 49))	('IV CRC', 'Disease', (163, 169))	('c.1217G > A p.Arg406Gln (rs587780014', 'Var', (26, 62))	('rs1553612535', 'Var', (99, 111))
73894	32708251	As these mutations are located in or near the ANK and BRCT domains, etoposide treatment of patients' lymphoblastoid cells did not hinder BARD1 and BRCA1 colocalization or RAD51 foci formation.	('colocalization', 'Interaction', (153, 167))	('BRCA1', 'Gene', '672', (147, 152))	('patients', 'Species', '9606', (91, 99))	('mutations', 'Var', (9, 18))	('BRCA1', 'Gene', (147, 152))	('ANK', 'Gene', (46, 49))	('etoposide', 'Chemical', 'MESH:D005047', (68, 77))	('BARD1', 'Gene', (137, 142))	('RAD51', 'Gene', (171, 176))	('ANK', 'Gene', '286', (46, 49))	('RAD51', 'Gene', '5888', (171, 176))
73895	32708251	However, the mutants had fewer apoptotic cells after treatment with etoposide compared to the healthy controls.	('etoposide', 'Chemical', 'MESH:D005047', (68, 77))	('mutants', 'Var', (13, 20))	('apoptotic cells', 'CPA', (31, 46))	('fewer', 'NegReg', (25, 30))
73896	32708251	Thus, these variants may inhibit apoptosis through disruption of the interaction between p53 and the ANK repeats and BRCT domain.	('disruption', 'NegReg', (51, 61))	('apoptosis', 'CPA', (33, 42))	('ANK', 'Gene', (101, 104))	('interaction', 'Interaction', (69, 80))	('variants', 'Var', (12, 20))	('p53', 'Gene', (89, 92))	('inhibit', 'NegReg', (25, 32))	('p53', 'Gene', '7157', (89, 92))	('ANK', 'Gene', '286', (101, 104))
73897	32708251	In conclusion, CRC initiation is largely attributed to the inability to repair DNA damage, which can be caused by BARD1 variants that prevent BRCA1 interaction at its RING domain, such as with BARD1beta.	('inability', 'Disease', 'MESH:D007319', (59, 68))	('BARD1', 'Gene', (114, 119))	('prevent', 'NegReg', (134, 141))	('variants', 'Var', (120, 128))	('BRCA1', 'Gene', '672', (142, 147))	('CRC', 'Disease', (15, 18))	('caused', 'Reg', (104, 110))	('inability', 'Disease', (59, 68))	('interaction', 'Interaction', (148, 159))	('BRCA1', 'Gene', (142, 147))	('CRC', 'Phenotype', 'HP:0003003', (15, 18))
73898	32708251	However, mutations in the ANK and BRCT domains have been shown to disrupt other protein-protein interactions, possibly to p53.	('ANK', 'Gene', '286', (26, 29))	('disrupt', 'NegReg', (66, 73))	('mutations', 'Var', (9, 18))	('p53', 'Gene', '7157', (122, 125))	('protein-protein', 'Protein', (80, 95))	('ANK', 'Gene', (26, 29))	('p53', 'Gene', (122, 125))
73899	32708251	Therefore, the pathogenic variants of BARD1 in CRCs could be both BRCA1-dependent and BRCA1-independent.	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('BRCA1', 'Gene', '672', (66, 71))	('BRCA1', 'Gene', '672', (86, 91))	('pathogenic', 'Reg', (15, 25))	('BRCA1', 'Gene', (66, 71))	('BRCA1', 'Gene', (86, 91))	('CRCs', 'Disease', (47, 51))	('BARD1', 'Gene', (38, 43))	('variants', 'Var', (26, 34))
73901	32708251	Cisplatin resistance of Eca109 and TE-1, two ESCC cell lines, was due to the upregulation of integrin alpha5, which activated the PI3K/AKT pathway via phosphorylation of FAK and SRC resulting in survival.	('Cisplatin resistance', 'MPA', (0, 20))	('AKT', 'Gene', '207', (135, 138))	('FAK', 'Gene', (170, 173))	('integrin alpha5', 'Gene', '3678', (93, 108))	('FAK', 'Gene', '5747', (170, 173))	('activated', 'PosReg', (116, 125))	('SRC', 'Gene', (178, 181))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('AKT', 'Gene', (135, 138))	('SRC', 'Gene', '6714', (178, 181))	('phosphorylation', 'Var', (151, 166))	('upregulation', 'PosReg', (77, 89))	('integrin alpha5', 'Gene', (93, 108))
73902	32708251	Additionally, knocking down of Neutrophin Receptor-Interacting MAGE Homolog (NRAGE) led to susceptibility to cisplatin, etoposide, and irradiation.	('NRAGE', 'Gene', (77, 82))	('etoposide', 'MPA', (120, 129))	('knocking down', 'Var', (14, 27))	('Neutrophin Receptor-Interacting MAGE Homolog', 'Gene', '9500', (31, 75))	('Neutrophin Receptor-Interacting MAGE Homolog', 'Gene', (31, 75))	('irradiation', 'CPA', (135, 146))	('susceptibility', 'MPA', (91, 105))	('etoposide', 'Chemical', 'MESH:D005047', (120, 129))	('NRAGE', 'Gene', '9500', (77, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('cisplatin', 'CPA', (109, 118))
73903	32708251	The silencing of NRAGE caused the ubiquitination of RING Finger Protein 8 (RNF8) and BARD1.	('ubiquitination', 'MPA', (34, 48))	('NRAGE', 'Gene', (17, 22))	('RNF8', 'Gene', (75, 79))	('RING Finger Protein 8', 'Gene', (52, 73))	('BARD1', 'Gene', (85, 90))	('RING Finger Protein 8', 'Gene', '9025', (52, 73))	('silencing', 'Var', (4, 13))	('NRAGE', 'Gene', '9500', (17, 22))	('RNF8', 'Gene', '9025', (75, 79))
73908	32708251	The cisplatin-resistant cells showed upregulation of BARD1 and BRCA1, and knocking down of integrin alpha5 resulted in a significant decrease in mRNA expression of both genes.	('decrease', 'NegReg', (133, 141))	('BRCA1', 'Gene', (63, 68))	('integrin alpha5', 'Gene', (91, 106))	('BARD1', 'Gene', (53, 58))	('upregulation', 'PosReg', (37, 49))	('integrin alpha5', 'Gene', '3678', (91, 106))	('knocking down', 'Var', (74, 87))	('mRNA expression', 'MPA', (145, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('BRCA1', 'Gene', '672', (63, 68))
73909	32708251	Similarly, the silencing of NRAGE showed increased gammaH2AX foci, which colocalized with those of BRCA1 and 53BP1.	('increased', 'PosReg', (41, 50))	('53BP1', 'Gene', (109, 114))	('53BP1', 'Gene', '7158', (109, 114))	('BRCA1', 'Gene', (99, 104))	('NRAGE', 'Gene', (28, 33))	('silencing', 'Var', (15, 24))	('gammaH2AX', 'Protein', (51, 60))	('BRCA1', 'Gene', '672', (99, 104))	('NRAGE', 'Gene', '9500', (28, 33))
73911	32708251	This suggests that resistance to chemotherapy and radiation therapy in ESCC is at least partially mediated by enhanced HR likely through the BARD1-BRCA1 complex, however, more studies need to be conducted to confirm whether BARD1 triggered DDR and survival through BRCA1-dependent or -independent mechanisms, or both.	('BARD1', 'Var', (224, 229))	('DDR', 'MPA', (240, 243))	('BRCA1', 'Gene', '672', (147, 152))	('BRCA1', 'Gene', '672', (265, 270))	('ESCC', 'Disease', (71, 75))	('enhanced', 'PosReg', (110, 118))	('BRCA1', 'Gene', (147, 152))	('BRCA1', 'Gene', (265, 270))	('survival', 'CPA', (248, 256))
73914	32708251	Patients with pre-diagnosed HCC had significant hypomethylation of the BARD1 gene compared to healthy patients as measured by a 13.3% difference between the groups.	('patients', 'Species', '9606', (102, 110))	('hypomethylation', 'Var', (48, 63))	('BARD1', 'Gene', (71, 76))	('Patients', 'Species', '9606', (0, 8))	('HCC', 'Disease', (28, 31))	('HCC', 'Phenotype', 'HP:0001402', (28, 31))
73916	32708251	They thus proposed that the BARD1 gene hypomethylation, among epigenetic changes of 8 other genes, can be used as an identifier for the likelihood of HCC with predisposing risk in HBV-negative patients.	('patients', 'Species', '9606', (193, 201))	('HCC', 'Disease', (150, 153))	('HCC', 'Phenotype', 'HP:0001402', (150, 153))	('BARD1', 'Gene', (28, 33))	('hypomethylation', 'Var', (39, 54))
73919	32708251	BARD1 expression was significantly associated with poor prognostic factors such as TNM stage III and IV, Barcelona clinic liver cancer (BCLC) stage B and C, tumor size greater than 5cm, HBV infection (positive HBV surface antigen, or HBsAg) and high serum AFP and aspartate aminotransferase (AST) concentrations.	('tumor', 'Disease', (157, 162))	('liver cancer', 'Phenotype', 'HP:0002896', (122, 134))	('AFP', 'Gene', (256, 259))	('Barcelona clinic liver cancer', 'Disease', (105, 134))	('AFP', 'Gene', '174', (256, 259))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('BARD1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Barcelona clinic liver cancer', 'Disease', 'MESH:D006528', (105, 134))	('TNM stage III', 'Disease', (83, 96))	('HBV infection', 'Disease', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('stage B', 'Disease', (142, 149))	('expression', 'Var', (6, 16))	('HBV infection', 'Disease', 'MESH:D006509', (186, 199))
73921	32708251	Mechanistically, the knocking down of BARD1 in SMMC7721 and Huh7, two HCC cell lines, decreased colony formation, invasion, and migration.	('HCC', 'Phenotype', 'HP:0001402', (70, 73))	('knocking down', 'Var', (21, 34))	('Huh7', 'Gene', '284424', (60, 64))	('migration', 'CPA', (128, 137))	('decreased', 'NegReg', (86, 95))	('colony formation', 'CPA', (96, 112))	('Huh7', 'Gene', (60, 64))	('BARD1', 'Gene', (38, 43))	('invasion', 'CPA', (114, 122))	('SMMC7721', 'CellLine', 'CVCL:0534', (47, 55))
73926	32708251	Sequencing of lymphocyte DNA from 302 PDAC patients with a positive family history of PDAC showed that 11.9% of the patients had pathogenic variants, of which 25% were not known to be associated with PDAC.	('pathogenic', 'Reg', (129, 139))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (116, 124))	('variants', 'Var', (140, 148))
73927	32708251	A novel mutation in the BARD1 gene was discovered in a patient who had 5 family members with PDAC but no other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patient', 'Species', '9606', (55, 62))	('mutation', 'Var', (8, 16))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('PDAC', 'Disease', (93, 97))	('BARD1', 'Gene', (24, 29))
73928	32708251	BARD1 c.632T > A (p.Leu211*) results in a premature stop codon.	('c.632T > A (p.Leu211*', 'Var', (6, 27))	('c.632T > A', 'Mutation', 'c.632T>A', (6, 16))	('results in', 'Reg', (29, 39))	('p.Leu211*', 'Var', (18, 27))	('p.Leu211*', 'Mutation', 'p.L211*', (18, 27))	('BARD1', 'Gene', (0, 5))	('premature stop codon', 'MPA', (42, 62))
73930	32708251	They identified a mutation in BARD1 c.1921C > T p.Arg641X in a PDAC patient who had one relative with pancreatic cancer that resulted in a premature stop.	('c.1921C > T p.Arg641X', 'Var', (36, 57))	('patient', 'Species', '9606', (68, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('c.1921C > T', 'Mutation', 'rs587781948', (36, 47))	('BARD1', 'Gene', (30, 35))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('p.Arg641X', 'Mutation', 'rs587781948', (48, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
73932	32708251	Additionally, analysis of lymphoblasts from 100 familial pancreatic cancer patients detected two SNPs in BARD1, rs2229571 and rs1129804, which had profound effects on its gene expression (greater than 4-fold change).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('gene expression', 'MPA', (171, 186))	('rs2229571', 'Var', (112, 121))	('effects', 'Reg', (156, 163))	('BARD1', 'Gene', (105, 110))	('patients', 'Species', '9606', (75, 83))	('rs1129804', 'Mutation', 'rs1129804', (126, 135))	('rs1129804', 'Var', (126, 135))	('familial pancreatic cancer', 'Disease', (48, 74))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (48, 74))	('rs2229571', 'Mutation', 'rs2229571', (112, 121))
73933	32708251	Although the function of the variants was not investigated, these SNPs are likely associated with susceptibility to familial pancreatic cancer since rs2229571 increased the risk of NB (Supplemental Table S1).	('rs2229571', 'Var', (149, 158))	('familial pancreatic cancer', 'Disease', (116, 142))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (116, 142))	('increased', 'PosReg', (159, 168))	('NB', 'Phenotype', 'HP:0003006', (181, 183))	('rs2229571', 'Mutation', 'rs2229571', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))
73937	32708251	Genetic testing has identified mutations in many genes involved in the BRCA-associated HR pathway.	('BRCA', 'Gene', '672;675', (71, 75))	('mutations', 'Var', (31, 40))	('BRCA', 'Gene', (71, 75))
73938	32708251	One patient with an unremarkable family history for cancer who developed a pancreaticoduodenal tumor with metastasis to the liver and abdominal lymph nodes was found to have a germline alteration in the BARD1 gene: c.69_70delins25 (p.Ala25Glyfs*41).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('pancreaticoduodenal tumor', 'Disease', (75, 100))	('pancreaticoduodenal tumor', 'Disease', 'MESH:D009369', (75, 100))	('p.Ala25Glyfs*41', 'FRAMESHIFT', 'None', (232, 247))	('p.Ala25Glyfs*41', 'Var', (232, 247))	('patient', 'Species', '9606', (4, 11))	('BARD1', 'Gene', (203, 208))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('c.69_70delins25', 'Mutation', 'c.69_70delins25', (215, 230))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))
73939	32708251	Thus, mutations in BARD1 can lead to the development of pancreatic cancers originating from neuroendocrine cells.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('lead to', 'Reg', (29, 36))	('BARD1', 'Gene', (19, 24))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('pancreatic cancers', 'Disease', 'MESH:D010190', (56, 74))	('pancreatic cancers', 'Disease', (56, 74))	('mutations', 'Var', (6, 15))
73940	32708251	Novel germline mutations in the BARD1 gene have been identified in pancreatic cancers, arising from either neuroendocrine or exocrine ductal cells, however, their function and role in susceptibility have yet to be validated.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pancreatic cancers', 'Disease', 'MESH:D010190', (67, 85))	('pancreatic cancers', 'Disease', (67, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('BARD1', 'Gene', (32, 37))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('germline mutations', 'Var', (6, 24))	('identified', 'Reg', (53, 63))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (67, 85))
73944	32708251	Although the susceptibility to PDAC and pancreatic NEN in patients with rare germline mutations in BARD1 remains to be studied, familial inheritance patterns and research evidence suggest that BARD1 may disrupt HR as mutations in BRCA2 and other DDR genes have also been shown to be tumorigenic.	('mutations', 'Var', (86, 95))	('pancreatic NEN', 'Disease', 'MESH:D010195', (40, 54))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('NEN', 'Phenotype', 'HP:0100634', (51, 54))	('BARD1', 'Gene', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('BRCA2', 'Gene', '675', (230, 235))	('BRCA2', 'Gene', (230, 235))	('BARD1', 'Gene', (99, 104))	('tumor', 'Disease', (283, 288))	('pancreatic NEN', 'Disease', (40, 54))	('patients', 'Species', '9606', (58, 66))	('DDR', 'Gene', (246, 249))	('mutations', 'Var', (217, 226))	('disrupt', 'Reg', (203, 210))
73957	32708251	When BARD1beta was overexpressed in A549 cells, it increased cellular proliferation, inhibited apoptosis, and increased the expression of fibronectin, an inducer of EMT, compared to its BARD1-FL expressing counterparts.	('inhibited', 'NegReg', (85, 94))	('fibronectin', 'Gene', (138, 149))	('increased', 'PosReg', (51, 60))	('apoptosis', 'CPA', (95, 104))	('increased', 'PosReg', (110, 119))	('cellular proliferation', 'CPA', (61, 83))	('BARD1beta', 'Var', (5, 14))	('A549', 'CellLine', 'CVCL:0023', (36, 40))	('expression', 'MPA', (124, 134))	('fibronectin', 'Gene', '2335', (138, 149))
73968	32708251	The neddylation E1 inhibitor, MLN4924, decreased BARD1 intensity following laser ablation.	('decreased', 'NegReg', (39, 48))	('MLN4924', 'Chemical', 'MESH:C539933', (30, 37))	('BARD1 intensity', 'MPA', (49, 64))	('MLN4924', 'Var', (30, 37))
73969	32708251	The combination treatment of MLN4924 and Olaparib for 72 h significantly inhibited the proliferation of A549 and H1299 NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('MLN4924', 'Var', (29, 36))	('MLN4924', 'Chemical', 'MESH:C539933', (29, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('Olaparib', 'Chemical', 'MESH:C531550', (41, 49))	('inhibited', 'NegReg', (73, 82))	('H1299', 'CellLine', 'CVCL:0060', (113, 118))	('NSCLC', 'Disease', (119, 124))	('SCLC', 'Phenotype', 'HP:0030357', (120, 124))
73971	32708251	IHC staining of NSCLC tumors showed that the expression of BARD1 did not correlate with that of BRCA1 or p53, suggesting that disruption of BARD1's protein-protein interactions plays a role in tumorigenesis.	('NSCLC tumors', 'Disease', 'MESH:D009369', (16, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('NSCLC tumors', 'Disease', (16, 28))	('disruption', 'Var', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('BRCA1', 'Gene', '672', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('p53', 'Gene', (105, 108))	('BARD1', 'Gene', (140, 145))	('BRCA1', 'Gene', (96, 101))	('protein-protein', 'Protein', (148, 163))	('p53', 'Gene', '7157', (105, 108))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('SCLC', 'Phenotype', 'HP:0030357', (17, 21))
73973	32708251	Although the molecular pathways activated or inhibited by the BARD1 oncogenic isoforms in NSCLC need to be further investigated, inhibition of these mutated proteins, especially isoforms beta, kappa, and pi, may drastically inhibit tumor progression.	('inhibition', 'Var', (129, 139))	('NSCLC', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (232, 237))	('inhibit', 'NegReg', (224, 231))	('SCLC', 'Phenotype', 'HP:0030357', (91, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('BARD1', 'Gene', (62, 67))
73976	32708251	examined whether three variants in the BARD1 gene were associated with 145 nephroblastoma patients compared to 531 cancer-free controls from an ethnic Han population from Southern China.	('cancer', 'Disease', (115, 121))	('nephroblastoma', 'Phenotype', 'HP:0002667', (75, 89))	('BARD1', 'Gene', (39, 44))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('nephroblastoma', 'Disease', 'MESH:D009396', (75, 89))	('variants', 'Var', (23, 31))	('patients', 'Species', '9606', (90, 98))	('nephroblastoma', 'Disease', (75, 89))
73977	32708251	rs7585356 homozygous for the A risk allele significantly increased the risk of nephroblastoma, specifically stage I and II disease, when compared to the wildtype G alleles.	('nephroblastoma', 'Disease', (79, 93))	('rs7585356', 'Mutation', 'rs7585356', (0, 9))	('II disease', 'Disease', (120, 130))	('nephroblastoma', 'Phenotype', 'HP:0002667', (79, 93))	('nephroblastoma', 'Disease', 'MESH:D009396', (79, 93))	('rs7585356', 'Var', (0, 9))	('increased', 'PosReg', (57, 66))	('stage I', 'Disease', (108, 115))
73978	32708251	While there was a trend toward increased risk with an increased number of variants, patients with three risky variants in BARD1 (rs7585356, rs6435862, and rs3768716) were significantly associated with nephroblastoma susceptibility with an odds ratio of 2.21, and subgroup analysis identified increased risk in females and development of stage I and II disease.	('rs3768716', 'Var', (155, 164))	('rs6435862', 'Mutation', 'rs6435862', (140, 149))	('rs3768716', 'Mutation', 'rs3768716', (155, 164))	('associated', 'Reg', (185, 195))	('rs7585356', 'Var', (129, 138))	('patients', 'Species', '9606', (84, 92))	('nephroblastoma', 'Disease', 'MESH:D009396', (201, 215))	('BARD1', 'Gene', (122, 127))	('rs6435862', 'Var', (140, 149))	('nephroblastoma', 'Disease', (201, 215))	('rs7585356', 'Mutation', 'rs7585356', (129, 138))	('nephroblastoma', 'Phenotype', 'HP:0002667', (201, 215))
73979	32708251	This single study highlights the need for identification of functions of aberrant BARD1 in nephroblastoma initiation and progression, particularly by expanding patient samples to include other ethnic groups and analyzing the frequency of more SNPs in the BARD1 gene.	('nephroblastoma', 'Phenotype', 'HP:0002667', (91, 105))	('patient', 'Species', '9606', (160, 167))	('BARD1', 'Gene', (82, 87))	('aberrant', 'Var', (73, 81))	('nephroblastoma initiation', 'Disease', (91, 116))	('BARD1', 'Gene', (255, 260))	('nephroblastoma initiation', 'Disease', 'MESH:D009396', (91, 116))
73981	32708251	The vast majority of Ewing sarcoma patients have chromosomal translocation t(11;22) producing the fusion protein EWS-FLI1.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('FLI1', 'Gene', '2313', (117, 121))	('FLI1', 'Gene', (117, 121))	('Ewing sarcoma', 'Disease', (21, 34))	('chromosomal translocation t', 'Var', (49, 76))	('EWS', 'Gene', '2130', (113, 116))	('EWS', 'Gene', (113, 116))	('patients', 'Species', '9606', (35, 43))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))
73988	32708251	A frameshift mutation in BARD1 c.176_177AG; p.E59Afs*8 occurred in the RING domain.	('p.E59Afs*8', 'Mutation', 'rs1057517589', (44, 54))	('c.176_177AG; p.E59Afs*', 'Var', (31, 53))	('p.E59Afs*', 'Var', (44, 53))	('BARD1', 'Gene', (25, 30))
73990	32708251	This study suggests that the dysfunction of HR may be implicated in the familial inheritance of Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('implicated', 'Reg', (54, 64))	('Ewing sarcoma', 'Disease', (96, 109))	('dysfunction', 'Var', (29, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))
73991	32708251	The interaction of the major oncogenic driver, EWS-FLI1, with the C-terminus of BARD1 as well as a frameshift deletion in the BRCA1-binding region of BARD1 in Ewing sarcoma strongly support the need for more functional studies of impaired DDR in Ewing sarcoma.	('Ewing sarcoma', 'Disease', (246, 259))	('FLI1', 'Gene', (51, 55))	('BARD1', 'Gene', (80, 85))	('interaction', 'Interaction', (4, 15))	('BRCA1', 'Gene', (126, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (159, 172))	('FLI1', 'Gene', '2313', (51, 55))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (159, 172))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (246, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (246, 259))	('BARD1', 'Gene', (150, 155))	('frameshift deletion in', 'Var', (99, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('EWS', 'Gene', '2130', (47, 50))	('EWS', 'Gene', (47, 50))	('Ewing sarcoma', 'Disease', (159, 172))	('BRCA1', 'Gene', '672', (126, 131))
73995	32708251	Further characterization of three BARD1 truncated variants, which they called omega isoforms, in NB4 cells showed loss of the N-terminal region but retaining of the BRCT domain with or without the ANK repeats.	('loss', 'NegReg', (114, 118))	('ANK', 'Gene', '286', (197, 200))	('BRCT domain', 'MPA', (165, 176))	('ANK', 'Gene', (197, 200))	('variants', 'Var', (50, 58))	('BARD1', 'Gene', (34, 39))	('NB', 'Phenotype', 'HP:0003006', (97, 99))	('N-terminal region', 'MPA', (126, 143))
73998	32708251	Knocking down of the BARD1 isoform drastically increased the number of apoptotic cells after Vorinostat treatment.	('increased', 'PosReg', (47, 56))	('BARD1', 'Gene', (21, 26))	('Knocking down', 'Var', (0, 13))	('Vorinostat', 'Chemical', 'MESH:D000077337', (93, 103))
74000	32708251	According to the most recent TCGA database (as of July 2020), 169 BARD1 mutations have been identified in a variety of cancers, including those discussed here.	('mutations', 'Var', (72, 81))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('identified', 'Reg', (92, 102))	('BARD1', 'Gene', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
74001	32708251	Somewhat similar to what was observed in the literature, the majority of genetic mutations occurred in gynecological cancers, specifically uterine cancers, followed by cancers of the gastrointestinal tract, then lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('uterine cancers', 'Phenotype', 'HP:0010784', (139, 154))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('genetic mutations', 'Var', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancers', 'Disease', 'MESH:D008175', (212, 224))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', (117, 124))	('lung cancers', 'Disease', (212, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('occurred', 'Reg', (91, 99))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('lung cancers', 'Phenotype', 'HP:0100526', (212, 224))	('cancers', 'Disease', (147, 154))	('cancers', 'Disease', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
74002	32708251	Mutations in the BARD1 gene were appreciated in 20-25% of tumor samples taken from the pancreas and the adrenal gland; however, the cohorts were very small and may not reflect the true prevalence of BARD1 mutations in pancreatic cancer and NB.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (218, 235))	('mutations', 'Var', (205, 214))	('Mutations', 'Var', (0, 9))	('BARD1', 'Gene', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('NB', 'Phenotype', 'HP:0003006', (240, 242))	('pancreatic cancer', 'Disease', 'MESH:D010190', (218, 235))	('BARD1', 'Gene', (17, 22))	('pancreatic cancer', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
74003	32708251	evaluated 76 possibly pathogenic BARD1 mutations in 24 cancers.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('BARD1', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pathogenic', 'Reg', (22, 32))	('mutations', 'Var', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
74004	32708251	The missense mutations were most prevalent in breast and uterine/endometrial cancers.	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('prevalent', 'Reg', (33, 42))	('missense mutations', 'Var', (4, 22))	('endometrial cancers', 'Disease', 'MESH:D016889', (65, 84))	('breast', 'Disease', (46, 52))	('endometrial cancers', 'Disease', (65, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
74005	32708251	BARD1 variants were also commonly found in cancers of the ovaries, prostate, brain, lung, and gastrointestinal tract.	('gastrointestinal tract', 'Disease', (94, 116))	('found in', 'Reg', (34, 42))	('variants', 'Var', (6, 14))	('prostate', 'Disease', (67, 75))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('brain', 'Disease', (77, 82))	('BARD1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung', 'Disease', (84, 88))	('cancers of the ovaries', 'Phenotype', 'HP:0100615', (43, 65))	('cancers of the ovaries', 'Disease', 'MESH:D010051', (43, 65))	('cancers of the ovaries', 'Disease', (43, 65))
74006	32708251	Surprisingly, none of the variants in the RING domain led to functional loss of HR.	('loss of HR', 'Disease', 'MESH:D001919', (72, 82))	('loss of HR', 'Disease', (72, 82))	('variants', 'Var', (26, 34))
74008	32708251	More functional studies need to be conducted to determine the pathogenicity of different BARD1 variants in various cancer types.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('BARD1', 'Gene', (89, 94))	('variants', 'Var', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
74011	32708251	In CRC and NSCLC, the expression of BARD1-FL was associated with increased survival, while the SNP rs7585356, which overexpressed BARD1-FL, was associated with decreased susceptibility to high-risk NB.	('NSCLC', 'Disease', (11, 16))	('increased', 'PosReg', (65, 74))	('rs7585356', 'Mutation', 'rs7585356', (99, 108))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('NB', 'Phenotype', 'HP:0003006', (198, 200))	('NSCLC', 'Disease', 'MESH:D002289', (11, 16))	('high-risk NB', 'Disease', (188, 200))	('BARD1-FL', 'Gene', (36, 44))	('rs7585356', 'Var', (99, 108))	('survival', 'MPA', (75, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (11, 16))	('decreased', 'NegReg', (160, 169))	('SCLC', 'Phenotype', 'HP:0030357', (12, 16))
74013	32708251	BARD1 isoforms caused by genetic mutations or SNPs are upregulated in many tumors.	('SNPs', 'Var', (46, 50))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('BARD1', 'Gene', (0, 5))	('upregulated', 'PosReg', (55, 66))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('caused', 'Reg', (15, 21))	('tumors', 'Disease', (75, 81))	('genetic mutations', 'Var', (25, 42))
74015	32708251	Therefore, developing inhibitors targeting the pro-tumorigenic BARD1 variants will be beneficial to sensitize those tumors to chemotherapy and radiation therapy, induce synthetic lethality with PARPi, or overcome secondary mutations that confer resistance to DNA damaging agents.	('PARP', 'Gene', (194, 198))	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('synthetic lethality', 'CPA', (169, 188))	('variants', 'Var', (69, 77))	('tumor', 'Disease', (51, 56))	('PARP', 'Gene', '142', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('BARD1', 'Gene', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
74016	32708251	Supplemental Table S2: All reported BARD1 variants in CRC, pancreatic cancer, NSCLC, nephroblastoma, Ewing sarcoma and AML.	('nephroblastoma', 'Phenotype', 'HP:0002667', (85, 99))	('NSCLC', 'Disease', (78, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('variants', 'Var', (42, 50))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('AML', 'Phenotype', 'HP:0004808', (119, 122))	('AML', 'Disease', (119, 122))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('pancreatic cancer', 'Disease', (59, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('nephroblastoma', 'Disease', 'MESH:D009396', (85, 99))	('nephroblastoma', 'Disease', (85, 99))	('SCLC', 'Phenotype', 'HP:0030357', (79, 83))	('CRC', 'Disease', (54, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('BARD1', 'Gene', (36, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))	('Ewing sarcoma', 'Disease', (101, 114))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
74188	21602661	One case from a male patient was a poorly differentiated malignancy with an immunohistochemical profile consistent with malignant mesothelioma (CKMix+, calretinin+, CK7-, CK20-).	('malignancy', 'Disease', (57, 67))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (120, 142))	('calretinin+', 'Var', (152, 163))	('patient', 'Species', '9606', (21, 28))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (120, 142))	('CKMix+', 'Var', (144, 150))	('malignant mesothelioma', 'Disease', (120, 142))	('CK20', 'Gene', '54474', (171, 175))	('CK7', 'Gene', (165, 168))	('malignancy', 'Disease', 'MESH:D009369', (57, 67))	('CK20', 'Gene', (171, 175))	('CK7', 'Gene', '3855', (165, 168))
74228	26814175	While LTC-KMSCs had lower proliferation rates than the uninfected cells, they expressed mixtures of KS markers and displayed differential angiogenic, invasive, and transforming phenotypes.	('angiogenic', 'CPA', (138, 148))	('lower', 'NegReg', (20, 25))	('rat', 'Species', '10116', (40, 43))	('LTC-KMSCs', 'Var', (6, 15))	('KS', 'Phenotype', 'HP:0100726', (100, 102))	('rat', 'Species', '10116', (33, 36))	('expressed', 'Reg', (78, 87))	('transforming', 'CPA', (164, 176))	('invasive', 'CPA', (150, 158))	('mixtures of KS markers', 'MPA', (88, 110))
74299	26814175	Vascular endothelial cell marker von Willebrand factor (vWF) was upregulated in LTC-KMSCa and LTC-KGMSC compared to their controls, while it was expressed at low levels in both MSCbm and LTC-KMSCbm.	('KMSCbm', 'Chemical', '-', (191, 197))	('GMSC', 'Chemical', '-', (99, 103))	('vWF', 'Gene', '7450', (56, 59))	('LTC-KMSCa', 'Var', (80, 89))	('von Willebrand', 'Disease', 'MESH:D014842', (33, 47))	('vWF', 'Gene', (56, 59))	('upregulated', 'PosReg', (65, 76))	('von Willebrand', 'Disease', (33, 47))
74308	26814175	Robust tube-like structures were observed with LTC-KMSCa and LTC-KMSCbm while minimal or no tube-like structures were visible with uninfected MSCa and MSCbm (Fig.	('LTC-KMSCa', 'Var', (47, 56))	('tube-like structures', 'CPA', (7, 27))	('KMSCbm', 'Chemical', '-', (65, 71))	('LTC-KMSCbm', 'Var', (61, 71))
74314	26814175	Interestingly, while LTC-KMSCa had a 4-fold increase over uninfected control cells of cells invading and crossing through the coated membrane, LTC-KMSCbm had only a 1.2-fold increase (Fig.	('LTC-KMSCbm', 'Var', (143, 153))	('increase', 'PosReg', (44, 52))	('KMSCbm', 'Chemical', '-', (147, 153))
74324	26814175	To investigate whether KSHV miRNAs might mediate KSHV-induced angiogenesis in MSCa, we infected them with a mutant virus containing a deletion of a cluster of 10 pre-miRNAs, including pre-miR-K1-9 and -K11 (DeltamiR) and established a long-term MSCa culture infected with this mutant KSHV (LTC-DeltamiRMSCa).	('KS', 'Phenotype', 'HP:0100726', (23, 25))	('KSHV', 'Species', '37296', (49, 53))	('miR', 'Gene', (188, 191))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('miR', 'Gene', '220972', (188, 191))	('miR', 'Gene', '220972', (212, 215))	('miR', 'Gene', '220972', (299, 302))	('miR', 'Gene', (212, 215))	('miR', 'Gene', (299, 302))	('deletion', 'Var', (134, 142))	('KSHV', 'Species', '37296', (284, 288))	('miR', 'Gene', '220972', (28, 31))	('KSHV', 'Species', '37296', (23, 27))	('miR', 'Gene', (28, 31))	('miR', 'Gene', '220972', (166, 169))	('KS', 'Phenotype', 'HP:0100726', (284, 286))	('miR', 'Gene', (166, 169))
74325	26814175	Additionally, we used a retrovirus expressing the KSHV miRNA cluster to rescue the functions of the deleted miRNAs.	('KSHV', 'Gene', (50, 54))	('functions', 'MPA', (83, 92))	('deleted', 'Var', (100, 107))	('miR', 'Gene', '220972', (108, 111))	('KSHV', 'Species', '37296', (50, 54))	('miR', 'Gene', (55, 58))	('miR', 'Gene', (108, 111))	('miR', 'Gene', '220972', (55, 58))	('KS', 'Phenotype', 'HP:0100726', (50, 52))
74326	26814175	Deletion of the miRNA cluster (LTC-DeltamiRMSCa) abolished KSHV-induced tube formation in MSCa (Fig.	('KSHV', 'Species', '37296', (59, 63))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('KS', 'Phenotype', 'HP:0100726', (59, 61))	('abolished', 'NegReg', (49, 58))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))	('Deletion', 'Var', (0, 8))
74329	26814175	To elucidate the signaling pathways that mediate the proangiogenic function of KSHV miRNAs, we screened specific inhibitors of proangiogenic pathways that could block KSHV-induced angiogenesis, including a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), a MEK inhibitor (U0126), a phospholipase C inhibitor (U-73122), and a ROCK inhibitor (Y-27632).	('miR', 'Gene', '220972', (84, 87))	('U-73122', 'Var', (319, 326))	('miR', 'Gene', (84, 87))	('block', 'NegReg', (161, 166))	('KSHV', 'Species', '37296', (167, 171))	('MEK', 'Gene', '5609', (267, 270))	('LY294002', 'Var', (254, 262))	('KSHV', 'Species', '37296', (79, 83))	('U0126', 'Chemical', 'MESH:C113580', (282, 287))	('KS', 'Phenotype', 'HP:0100726', (79, 81))	('Y-27632', 'Chemical', 'MESH:C108830', (351, 358))	('U0126', 'Var', (282, 287))	('U-73122', 'Chemical', 'MESH:C060229', (319, 326))	('LY294002', 'Chemical', 'MESH:C085911', (254, 262))	('KS', 'Phenotype', 'HP:0100726', (167, 169))	('MEK', 'Gene', (267, 270))
74330	26814175	Examination of LTC-KMSCa showed that these cells indeed had a significantly higher level of AKT phosphorylation at T308 than did the uninfected control cells (Fig.	('T308', 'Chemical', '-', (115, 119))	('T308', 'Var', (115, 119))	('AKT', 'Gene', '207', (92, 95))	('higher', 'PosReg', (76, 82))	('AKT', 'Gene', (92, 95))
74331	26814175	KSHV infection did not alter the level of AKT phosphorylation at S473 (Fig.	('S473', 'Var', (65, 69))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('AKT', 'Gene', (42, 45))	('KSHV infection', 'Disease', 'MESH:C537372', (0, 14))	('KSHV infection', 'Disease', (0, 14))	('AKT', 'Gene', '207', (42, 45))
74332	26814175	Treatment with the PI3K inhibitor significantly reduced the level of AKT phosphorylation at T308 (Fig.	('AKT', 'Gene', (69, 72))	('reduced', 'NegReg', (48, 55))	('T308', 'Chemical', '-', (92, 96))	('T308', 'Var', (92, 96))	('AKT', 'Gene', '207', (69, 72))
74333	26814175	Furthermore, deletion of the miRNA cluster (LTC-DeltamiRMSCa) abolished the increased level of AKT phosphorylation at T308, while overexpression of the KSHV miRNA cluster was sufficient to rescue the AKT phosphorylation in LTC-DeltamiRMSCa (Fig.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('abolished', 'NegReg', (62, 71))	('AKT', 'Gene', '207', (200, 203))	('T308', 'Chemical', '-', (118, 122))	('miR', 'Gene', '220972', (157, 160))	('AKT', 'Gene', '207', (95, 98))	('miR', 'Gene', (157, 160))	('deletion', 'Var', (13, 21))	('KS', 'Phenotype', 'HP:0100726', (152, 154))	('AKT', 'Gene', (200, 203))	('KSHV', 'Species', '37296', (152, 156))	('AKT', 'Gene', (95, 98))	('miR', 'Gene', '220972', (232, 235))	('miR', 'Gene', (232, 235))
74350	26814175	Podoplanin was upregulated in MSCa but downregulated in GMSC by KSHV while it remained unchanged in MSCbm following KSHV infection.	('KS', 'Phenotype', 'HP:0100726', (64, 66))	('upregulated', 'PosReg', (15, 26))	('Podoplanin', 'Chemical', '-', (0, 10))	('KSHV', 'Species', '37296', (116, 120))	('KSHV infection', 'Disease', 'MESH:C537372', (116, 130))	('GMSC', 'Chemical', '-', (56, 60))	('KSHV', 'Species', '37296', (64, 68))	('KSHV infection', 'Disease', (116, 130))	('KSHV', 'Var', (64, 68))	('KS', 'Phenotype', 'HP:0100726', (116, 118))	('downregulated', 'NegReg', (39, 52))
74369	26814175	AKT phosphorylation at S473 is carried out by target of rapamycin complex (TORC) 1 and 2 and DNA-activated protein kinase (DNA-PK), which is required for stabilizing the kinase and further increasing the enzymatic activity.	('AKT', 'Gene', (0, 3))	('DNA-PK', 'Gene', (123, 129))	('DNA-activated protein kinase', 'Gene', '5591', (93, 121))	('DNA-PK', 'Gene', '5591', (123, 129))	('target of rapamycin complex (TORC) 1 and 2', 'Gene', '23373;200186', (46, 88))	('S473', 'Var', (23, 27))	('AKT', 'Gene', '207', (0, 3))	('DNA-activated protein kinase', 'Gene', (93, 121))
74370	26814175	However, phosphorylation at S473 alone is insufficient to activate AKT.	('activate', 'PosReg', (58, 66))	('S473', 'Var', (28, 32))	('AKT', 'Gene', (67, 70))	('AKT', 'Gene', '207', (67, 70))
74372	26814175	However, AKT phosphorylation at T308 was induced by KSHV infection, and inhibition of this phosphorylation with LY294002 suppressed the tube formation activity in a dose-dependent manner.	('AKT', 'Gene', '207', (9, 12))	('T308', 'Chemical', '-', (32, 36))	('KSHV infection', 'Disease', (52, 66))	('LY294002', 'Chemical', 'MESH:C085911', (112, 120))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('tube formation activity', 'CPA', (136, 159))	('suppressed', 'NegReg', (121, 131))	('induced', 'Reg', (41, 48))	('AKT', 'Gene', (9, 12))	('LY294002', 'Var', (112, 120))	('KSHV infection', 'Disease', 'MESH:C537372', (52, 66))
74390	26814175	LY294002 (PI3K inhibitor), U0126 (MEK inhibitor), U-73122 (phospholipase C inhibitor), and Y-27632 (ROCK inhibitor) were purchased from Calbiochem (San Diego, CA).	('LY294002', 'Var', (0, 8))	('U0126', 'Chemical', 'MESH:C113580', (27, 32))	('MEK', 'Gene', (34, 37))	('MEK', 'Gene', '5609', (34, 37))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('U0126', 'Var', (27, 32))	('U-73122', 'Chemical', 'MESH:C060229', (50, 57))	('Y-27632', 'Chemical', 'MESH:C108830', (91, 98))	('U-73122', 'Var', (50, 57))
74392	26814175	iSLK-DeltamiR cells harboring recombinant BAC16 with a deletion of 10 KSHV pre-miRNAs, including pre-miR-K1-K9 and -K11, were previously described.	('miR', 'Gene', '220972', (101, 104))	('BAC16', 'Gene', (42, 47))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('KSHV', 'Species', '37296', (70, 74))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('deletion', 'Var', (55, 63))	('KSHV', 'Gene', (70, 74))	('miR', 'Gene', (101, 104))
74459	26558181	In the stromal cells, prominent pleomorphism, stromal overgrowth, increased mitosis (>10 per 10 hpf), and increased stromal cellularity were striking findings and also osseous metaplasia was detected (Fig.	('overgrowth', 'Phenotype', 'HP:0001548', (54, 64))	('osseous metaplasia', 'Disease', 'MESH:D008679', (168, 186))	('increased mitosis', 'Disease', 'MESH:D019586', (66, 83))	('stromal overgrowth', 'CPA', (46, 64))	('pleomorphism', 'Var', (32, 44))	('increased', 'PosReg', (106, 115))	('osseous metaplasia', 'Disease', (168, 186))	('increased mitosis', 'Disease', (66, 83))	('stromal cellularity', 'CPA', (116, 135))
74486	26558181	PASH is a benign lesion, and does not contain atypia; it is possible to treat PASH with wide local excision, and CD34 positivity has diagnostic features.	('AS', 'Phenotype', 'HP:0200058', (79, 81))	('CD34', 'Gene', '947', (113, 117))	('CD34', 'Gene', (113, 117))	('AS', 'Phenotype', 'HP:0200058', (1, 3))	('PASH', 'Disease', (0, 4))	('positivity', 'Var', (118, 128))
74498	26558181	In addition, presence of atypia in fibrosarcoma, cellularity, CD34 positivity in phyllodes tumors, and cleft-like structures covered with epithelium are clues for the differential diagnosis.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (35, 47))	('CD34', 'Gene', '947', (62, 66))	('cleft', 'Disease', 'MESH:D002972', (103, 108))	('phyllodes', 'Chemical', '-', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('atypia in fibrosarcoma', 'Disease', (25, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('positivity', 'Var', (67, 77))	('CD34', 'Gene', (62, 66))	('atypia in fibrosarcoma', 'Disease', 'MESH:D005354', (25, 47))	('cleft', 'Disease', (103, 108))
74516	26558181	CTNNB-1 mutation and nuclear beta-catenin expression are frequently detected in sporadic breast fibromatoses, suggesting as a useful tool for differential diagnosis of breast fibromatoses from other neoplasms (Kim et al.).	('breast fibromatoses', 'Disease', (168, 187))	('neoplasms', 'Disease', 'MESH:D009369', (199, 208))	('neoplasms', 'Disease', (199, 208))	('CTNNB-1', 'Gene', (0, 7))	('breast fibromatoses', 'Disease', 'MESH:D005350', (89, 108))	('breast fibromatoses', 'Disease', 'MESH:D005350', (168, 187))	('CTNNB-1', 'Gene', '1499', (0, 7))	('beta-catenin', 'Gene', (29, 41))	('neoplasms', 'Phenotype', 'HP:0002664', (199, 208))	('detected', 'Reg', (68, 76))	('beta-catenin', 'Gene', '1499', (29, 41))	('mutation', 'Var', (8, 16))	('breast fibromatoses', 'Disease', (89, 108))
74629	25873878	At the molecular level, SCS is characterized by a SYT-SSX gene fusion caused by the rearrangement between the p11.2 and q11.2 portions of chromosomes X and 18, respectively, i.e.	('SYT', 'Gene', '6857', (50, 53))	('caused by', 'Reg', (70, 79))	('SYT', 'Gene', (50, 53))	('SCS', 'Phenotype', 'HP:0012570', (24, 27))	('p11.2', 'Gene', '5707', (110, 115))	('rearrangement', 'Var', (84, 97))	('p11.2', 'Gene', (110, 115))	('SCS', 'Disease', (24, 27))
74643	25873878	Immunohistochemical analysis demonstrated positivity for Bcl-2, CD99, transducin-like enhancer of split 1 (TLE1), vimentin and focal positivity for cytokeratin (CK) 7.	('vimentin', 'Gene', '7431', (114, 122))	('cytokeratin (CK) 7', 'Gene', (148, 166))	('TLE1', 'Gene', (107, 111))	('CD99', 'Gene', (64, 68))	('vimentin', 'Gene', (114, 122))	('positivity', 'Var', (42, 52))	('Bcl-2', 'Gene', '596', (57, 62))	('transducin-like enhancer of split 1', 'Gene', '7088', (70, 105))	('CD99', 'Gene', '4267', (64, 68))	('TLE1', 'Gene', '7088', (107, 111))	('Bcl-2', 'Gene', (57, 62))	('transducin-like enhancer of split 1', 'Gene', (70, 105))	('cytokeratin (CK) 7', 'Gene', '3855', (148, 166))
74646	25873878	A definitive diagnosis was achieved by the confirmation of a SYT gene rearrangement using a SYT dual color break apart probe-based (Z-2097-50; Zytovision, Bremerhaven, Germany) FISH test (fig.	('SYT', 'Gene', '6857', (61, 64))	('SYT', 'Gene', '6857', (92, 95))	('SYT', 'Gene', (92, 95))	('rearrangement', 'Var', (70, 83))	('break apart', 'Phenotype', 'HP:0001061', (107, 118))	('SYT', 'Gene', (61, 64))
74656	25873878	4), the expression of which is strongly predictive of SYT gene rearrangement according to large studies, but still needs molecular confirmation according to data from smaller studies.	('rearrangement', 'Var', (63, 76))	('SYT', 'Gene', '6857', (54, 57))	('SYT', 'Gene', (54, 57))
74657	25873878	Therefore, definitive diagnosis of a renal SCS requires confirmation of rearrangement involving the SYT gene by either reverse transcriptase polymerase chain reaction or applying FISH testing with properly designed probes.	('rearrangement', 'Var', (72, 85))	('renal SCS', 'Disease', 'MESH:D000168', (37, 46))	('SYT', 'Gene', '6857', (100, 103))	('renal SCS', 'Disease', (37, 46))	('SYT', 'Gene', (100, 103))	('SCS', 'Phenotype', 'HP:0012570', (43, 46))
74672	28115911	Apart from affecting prognosis, delays may affect patients' evaluations and give rise to psychological distress and patient complaints.	('rise to psychological distress', 'Disease', (81, 111))	('patient complaints', 'CPA', (116, 134))	('affect', 'Reg', (43, 49))	('rise to psychological distress', 'Disease', 'MESH:D000067073', (81, 111))	('delays', 'Var', (32, 38))
74701	26251617	Our results demonstrated that IGF-1R expression was associated with poor outcome in terms of overall survival in BSTS patients (pooled HR =2.15, 95% CI: 1.06-4.38; P=0.03).	('expression', 'Var', (37, 47))	('patients', 'Species', '9606', (118, 126))	('BSTS', 'Disease', (113, 117))	('IGF-1R', 'Gene', (30, 36))
74718	26251617	In other BSTSs, such as SS, liposarcoma, and rhabdomyosarcoma, IGF-1R was considered to negatively influence survival of patients; at the same time, a study on multiple soft tissue sarcomas showed a significant association between high expression of IGF-1R and favorable outcome, although the numbers of SS, liposarcoma, and rhabdomyosarcoma were small (n=3, 16, and 1, respectively).	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (45, 61))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (169, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (334, 341))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('BSTSs', 'Chemical', '-', (9, 14))	('liposarcoma', 'Phenotype', 'HP:0012034', (308, 319))	('liposarcoma', 'Disease', (28, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('rhabdomyosarcoma', 'Disease', (325, 341))	('liposarcoma', 'Disease', 'MESH:D008080', (308, 319))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('high expression', 'Var', (231, 246))	('liposarcoma', 'Phenotype', 'HP:0012034', (28, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (325, 341))	('rhabdomyosarcoma', 'Disease', (45, 61))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (325, 341))	('patients', 'Species', '9606', (121, 129))	('liposarcoma', 'Disease', 'MESH:D008080', (28, 39))	('liposarcoma', 'Disease', (308, 319))	('influence', 'Reg', (99, 108))	('soft tissue sarcomas', 'Disease', (169, 189))	('IGF-1R', 'Gene', (250, 256))	('favorable', 'Disease', (261, 270))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (45, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (312, 319))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (169, 189))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (169, 188))
74737	26251617	Our further analysis indicated that high expression of IGF-1R in osteosarcoma was significantly related to poor prognosis (pooled HR =2.20, 95% CI: 1.59-3.03; P<0.001).	('IGF-1R', 'Gene', (55, 61))	('high expression', 'Var', (36, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('related', 'Reg', (96, 103))
74743	26251617	Amplification of IGF-1R expression has been shown in many human solid malignancies, including lung cancer, breast cancer, and colorectal cancer, etc, and has been related to poor outcome.	('human', 'Species', '9606', (58, 63))	('lung cancer', 'Disease', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('IGF-1R', 'Gene', (17, 23))	('related', 'Reg', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('shown', 'Reg', (44, 49))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('colorectal cancer', 'Disease', (126, 143))	('malignancies', 'Disease', 'MESH:D009369', (70, 82))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Disease', (107, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('malignancies', 'Disease', (70, 82))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
74748	26251617	A clinical trial indicated that presence of IGF-1R served as a biomarker to predict elevated sensitivity of sarcomas to IGF-1R-targeted therapy.	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('presence', 'Var', (32, 40))	('sarcomas', 'Disease', (108, 116))	('sensitivity', 'MPA', (93, 104))	('IGF-1R', 'Gene', (44, 50))
74754	26251617	We demonstrated that high IGF-1R expression was a marker of aggressive disease, associated with poorer OVS of BSTS patients.	('patients', 'Species', '9606', (115, 123))	('aggressive disease', 'Disease', 'MESH:D001523', (60, 78))	('IGF-1R', 'Gene', (26, 32))	('high', 'Var', (21, 25))	('aggressive disease', 'Disease', (60, 78))	('expression', 'MPA', (33, 43))	('high IGF-1R', 'Phenotype', 'HP:0030269', (21, 32))
74885	30847027	CLEC14A, CD93 and CD248 can bind to MMRN2; however, thrombomodulin does not.	('thrombomodulin', 'Gene', (52, 66))	('bind', 'Interaction', (28, 32))	('thrombomodulin', 'Gene', '7056', (52, 66))	('MMRN2', 'Protein', (36, 41))	('CD93', 'Gene', '22918', (9, 13))	('CD248', 'Var', (18, 23))	('CD93', 'Gene', (9, 13))
74893	30847027	In mouse embryos, CD248-lacZ co-localized with most vimentin-positive cells and a large portion of CD31- or desmin-positive cells.	('co-localized', 'Interaction', (29, 41))	('mouse', 'Species', '10090', (3, 8))	('vimentin-positive', 'Protein', (52, 69))	('CD248-lacZ', 'Var', (18, 28))
74895	30847027	Endosialin-/- mice have no defect in pericyte recruitment, suggesting a role for endosialin in pericyte/endothelial cell cooperation during vascular patterning.Endosialin-/- mice have higher than normal bone mass due to increased osteoblast-mediated bone formation.	('increased', 'PosReg', (220, 229))	('mice', 'Species', '10090', (174, 178))	('osteoblast-mediated bone formation', 'CPA', (230, 264))	('mice', 'Species', '10090', (14, 18))	('increased osteoblast', 'Phenotype', 'HP:0030328', (220, 240))	('bone mass', 'CPA', (203, 212))	('patterning.Endosialin-/-', 'Var', (149, 173))	('higher', 'PosReg', (184, 190))
74901	30847027	The surface marker transcriptome of AMSCs, validated the expression of classical markers, and identified nine non-classical markers (CD36, CD163, CD271, CD200, CD273, CD274, CD146, CD248, and CD140B) that may potentially discriminate AMSCs.	('CD140B', 'Var', (192, 198))	('CD36', 'Species', '42374', (133, 137))	('CD146', 'Var', (174, 179))	('CD274', 'Var', (167, 172))	('CD36', 'Var', (133, 137))	('AMSCs', 'Disease', (234, 239))	('CD248', 'Var', (181, 186))	('CD200', 'Var', (153, 158))	('CD271', 'Var', (146, 151))	('CD163', 'Var', (139, 144))	('CD273', 'Var', (160, 165))
74909	30847027	In mice, wounds treated with CD248+ cells healed faster, and at 7 days, had more re-epithelialization than wounds in other groups.	('mice', 'Species', '10090', (3, 7))	('CD248+ cells', 'Var', (29, 41))	('faster', 'PosReg', (49, 55))	('re-epithelialization', 'CPA', (81, 101))
74924	30847027	CD248 knockout produced high bone mass due to increased osteoblast-mediated bone formation, suggesting targeting CD248 in rheumatoid arthritis.	('bone mass', 'CPA', (29, 38))	('rheumatoid arthritis', 'Disease', (122, 142))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (122, 142))	('increased', 'PosReg', (46, 55))	('CD248', 'Gene', (113, 118))	('CD248', 'Gene', (0, 5))	('osteoblast-mediated bone formation', 'CPA', (56, 90))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (122, 142))	('knockout', 'Var', (6, 14))	('increased osteoblast', 'Phenotype', 'HP:0030328', (46, 66))	('arthritis', 'Phenotype', 'HP:0001369', (133, 142))
74946	30847027	Thus, CD248 stromal cells have a role in renal fibrosis, furthermore, targeting CD248 was effective at inhibiting both microvascular rarefaction and renal fibrosis through modulation of pericyte and stromal cell function.	('renal fibrosis', 'Disease', 'MESH:D005355', (41, 55))	('microvascular rarefaction', 'CPA', (119, 144))	('renal fibrosis', 'Disease', (41, 55))	('renal fibrosis', 'Phenotype', 'HP:0030760', (41, 55))	('inhibiting', 'NegReg', (103, 113))	('renal fibrosis', 'Phenotype', 'HP:0030760', (149, 163))	('renal fibrosis', 'Disease', 'MESH:D005355', (149, 163))	('modulation', 'Reg', (172, 182))	('renal fibrosis', 'Disease', (149, 163))	('targeting', 'Var', (70, 79))	('CD248', 'Gene', (80, 85))
74960	30847027	Collagen deposition and alpha-SMA expression, but not inflammation and neo-angiogenesis, was reduced in CD248 knockout mice compared with control mice after carbon tetrachloride treatment.	('mice', 'Species', '10090', (119, 123))	('inflammation', 'Disease', 'MESH:D007249', (54, 66))	('reduced', 'NegReg', (93, 100))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (157, 177))	('Collagen deposition', 'CPA', (0, 19))	('inflammation', 'Disease', (54, 66))	('mice', 'Species', '10090', (146, 150))	('knockout', 'Var', (110, 118))	('alpha-SMA', 'Gene', (24, 33))	('CD248', 'Gene', (104, 109))	('alpha-SMA', 'Gene', '11475', (24, 33))
75022	30847027	Mixed cell cultures from gliomas expressing high CD56, SOX2, SOX9, and low CD105, CD248, alphaSMA are tumorigenic and express cancer stem cell markers.	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('SOX9', 'Gene', (61, 65))	('cancer', 'Disease', (126, 132))	('gliomas', 'Disease', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SOX2', 'Gene', (55, 59))	('CD248', 'Var', (82, 87))	('SOX2', 'Gene', '6657', (55, 59))	('SOX9', 'Gene', '6662', (61, 65))	('CD56', 'Gene', (49, 53))	('express', 'Reg', (118, 125))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('low CD105', 'Var', (71, 80))	('tumor', 'Disease', (102, 107))	('CD56', 'Gene', '4684', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))
75041	30847027	Genetic inactivation of CD248 resulted in accelerated tumor growth in an inducible mouse hepatocellular carcinoma model.	('Genetic inactivation', 'Var', (0, 20))	('hepatocellular carcinoma', 'Disease', (89, 113))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('mouse', 'Species', '10090', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CD248', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('accelerated', 'PosReg', (42, 53))	('tumor', 'Disease', (54, 59))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (89, 113))
75053	30847027	The osteosarcoma side population cells had high CD248 and CD133, OCT3/4A, Nanog and Nestin, which are responsible for high self-renewal and deregulated cell proliferation.	('osteosarcoma', 'Phenotype', 'HP:0002669', (4, 16))	('osteosarcoma', 'Disease', (4, 16))	('osteosarcoma', 'Disease', 'MESH:D012516', (4, 16))	('OCT3/4A', 'Gene', (65, 72))	('OCT3/4A', 'Gene', '5460', (65, 72))	('CD248', 'Var', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('CD133', 'Gene', (58, 63))	('CD133', 'Gene', '8842', (58, 63))
75059	30847027	In cell lines, CD248 was detected in neuroblastoma lines, including cancer stem cell-like side population cells, but was absent in melanoma and was rare and weak in small cell lung cancer.	('neuroblastoma lines', 'Disease', 'MESH:D009447', (37, 56))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (165, 187))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('CD248', 'Var', (15, 20))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('neuroblastoma lines', 'Disease', (37, 56))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('small cell lung cancer', 'Disease', (165, 187))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('neuroblastoma', 'Phenotype', 'HP:0003006', (37, 50))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (181, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('small cell lung cancer', 'Disease', 'MESH:D055752', (165, 187))
75065	30847027	Biodistribution studies in xenograft-bearing mice confirmed high tumor uptake 89Zr-Ontuxizumab can be used to determine CD248 expression.	('89Zr-Ontuxizumab', 'Var', (78, 94))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('expression', 'MPA', (126, 136))	('CD248', 'Gene', (120, 125))	('high tumor', 'Disease', (60, 70))	('Ontuxizumab', 'Chemical', '-', (83, 94))	('high tumor', 'Disease', 'MESH:D009369', (60, 70))
75088	30847027	A randomized, double-blind, placebo-controlled, phase II study evaluated the safety and efficacy of anti-CD248 ontuxizumab (MORAb-004) in patients with chemo-refractory metastatic colorectal cancer.	('ontuxizumab', 'Chemical', '-', (111, 122))	('patients', 'Species', '9606', (138, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (180, 197))	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('anti-CD248', 'Var', (100, 110))	('colorectal cancer', 'Disease', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('MORAb-004', 'Chemical', 'MESH:C000604563', (124, 133))
75112	30847027	The antibody-drug conjugate anti-CD248-MC-VC-PABC-MMAE, with 3-4 MMAE molecules per ADC, was selectively cytotoxic to CD248-positive cells in culture and produced profound, durable tumor control in human CD248-positive tumor xenografts.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', (219, 224))	('anti-CD248-MC-VC-PABC-MMAE', 'Var', (28, 54))	('MMAE', 'Chemical', '-', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('MC-VC-PABC', 'Chemical', '-', (39, 49))	('human', 'Species', '9606', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cytotoxic', 'NegReg', (105, 114))	('MMAE', 'Chemical', '-', (50, 54))
75113	30847027	The cytotoxicity of anti-CD248-MC-VC-PABC-MMAE was assessed in human cell lines with varied CD248 levels.	('human', 'Species', '9606', (63, 68))	('MC-VC-PABC', 'Chemical', '-', (31, 41))	('anti-CD248-MC-VC-PABC-MMAE', 'Var', (20, 46))	('cytotoxicity', 'Disease', (4, 16))	('MMAE', 'Chemical', '-', (42, 46))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
75117	30847027	The anti-CD248-MC-VC-PABC-MMAE conjugate produced marked prolonged tumor responses in both models.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('MMAE', 'Chemical', '-', (26, 30))	('anti-CD248-MC-VC-PABC-MMAE', 'Var', (4, 30))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MC-VC-PABC', 'Chemical', '-', (15, 25))	('tumor', 'Disease', (67, 72))	('prolonged', 'PosReg', (57, 66))
75129	30847027	Prophylactic immunization of mice with CD248-TT prevented or delayed tumor formation in mice.	('delayed', 'NegReg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('CD248-TT', 'Var', (39, 47))	('mice', 'Species', '10090', (29, 33))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
75131	30847027	CD248-TT vaccination elicited CD8+ cytotoxic T cell responses against tumor-specific antigens indicating that targeting CD248 has therapeutic potential in cancer immunotherapy.	('CD8', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CD8', 'Gene', '925', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('elicited', 'Reg', (21, 29))	('CD248', 'Gene', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (70, 75))	('CD248-TT', 'Var', (0, 8))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
75138	30847027	CD248 knock-down on naive CD8 T cells increased cell proliferation.	('T cells increased', 'Phenotype', 'HP:0100828', (30, 47))	('CD8', 'Gene', '925', (26, 29))	('CD248', 'Gene', (0, 5))	('cell proliferation', 'CPA', (48, 66))	('knock-down', 'Var', (6, 16))	('increased', 'PosReg', (38, 47))	('CD8', 'Gene', (26, 29))
75166	28433655	Sphere formation assay was performed by culturing cells with serum-free medium supplemented with B27 (1x), N2 (1x), bFGF (20 ng/ml), and EGF (20 ng/ml) in the low-attachment plate.	('bFGF', 'Gene', (116, 120))	('N2 (1x', 'Var', (107, 113))	('bFGF', 'Gene', '2247', (116, 120))
75179	28433655	To further characterize this subpopulation of HLA-I(-) cells, we tested five sarcoma cell lines including MFH (undifferentiated pleomorphic sarcoma), CW9019 (rhabdomyosarcoma), SKNEP (Ewing sarcoma), MG63 (osteosarcoma), and LPS141 (liposarcoma).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (184, 197))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (184, 197))	('LPS141', 'Chemical', '-', (225, 231))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (158, 174))	('liposarcoma', 'Disease', (233, 244))	('sarcoma', 'Disease', (190, 197))	('sarcoma', 'Disease', (77, 84))	('MFH', 'Gene', '27086', (106, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('SKNEP', 'Chemical', '-', (177, 182))	('osteosarcoma', 'Phenotype', 'HP:0002669', (206, 218))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('sarcoma', 'Disease', (211, 218))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('liposarcoma', 'Phenotype', 'HP:0012034', (233, 244))	('Ewing sarcoma', 'Disease', (184, 197))	('sarcoma', 'Disease', (140, 147))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (111, 147))	('MG63', 'Chemical', '-', (200, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('rhabdomyosarcoma', 'Disease', (158, 174))	('liposarcoma', 'Disease', 'MESH:D008080', (233, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('MFH', 'Gene', (106, 109))	('osteosarcoma', 'Disease', (206, 218))	('CW9019', 'CellLine', 'CVCL:N820', (150, 156))	('osteosarcoma', 'Disease', 'MESH:D012516', (206, 218))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('undifferentiated pleomorphic sarcoma', 'Disease', (111, 147))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (158, 174))	('CW9019', 'Var', (150, 156))	('sarcoma', 'Disease', (167, 174))	('sarcoma', 'Disease', (237, 244))	('tested', 'Reg', (65, 71))
75180	28433655	HLA-I(-) cells were identified in all cell lines, albeit at low frequencies (MFH: 1.6+-0.6%; CW9019: 3.1+-1.9%; SKNEP: 2.8+-1.4%; MG63: 1.2+-0.3%; and LPS141: 2.6+-1.0%)(Figures 1B and 1C).	('CW9019', 'CellLine', 'CVCL:N820', (93, 99))	('MFH', 'Gene', '27086', (77, 80))	('CW9019', 'Var', (93, 99))	('LPS141', 'Chemical', '-', (151, 157))	('MG63', 'Chemical', '-', (130, 134))	('MFH', 'Gene', (77, 80))	('SKNEP', 'Chemical', '-', (112, 117))
75187	28433655	The calculated tumor initiating cell (TIC) frequencies of HLA-I(-) cells were 1/621 for MFH, and 1/9204 for CW9019; substantially higher (95-and 14-fold, respectively) than their HLA-I(+) counterparts (Figure 2A).	('CW9019', 'CellLine', 'CVCL:N820', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('higher', 'PosReg', (130, 136))	('MFH', 'Gene', '27086', (88, 91))	('TIC', 'Phenotype', 'HP:0100033', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CW9019', 'Var', (108, 114))	('tumor', 'Disease', (15, 20))	('1/9204', 'Var', (97, 103))	('MFH', 'Gene', (88, 91))
75203	28433655	Differential gene expression analysis revealed distinct signatures corresponding to 1,214 over-expressed and 1,293 under-expressed genes in HLA-I(-) TICs when compared to HLA-I(+) non-TICs from the same tumor (>1.5 fold, P<0.05).	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('TIC', 'Phenotype', 'HP:0100033', (149, 152))	('over-expressed', 'PosReg', (90, 104))	('TIC', 'Phenotype', 'HP:0100033', (184, 187))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('HLA-I', 'Var', (140, 145))	('TICs', 'Phenotype', 'HP:0100033', (184, 188))	('TICs', 'Phenotype', 'HP:0100033', (149, 153))
75345	28042471	The degree of PD-1 positivity in tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in tumor specimens from 105 cases of soft tissue sarcomas, has been correlated with a poorer prognosis and more aggressive disease.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (129, 149))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (129, 148))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (129, 149))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (95, 100))	('positivity', 'Var', (19, 29))	('aggressive disease', 'Disease', (204, 222))	('PD-L1', 'Gene', (75, 80))	('PD-1', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PD-1', 'Gene', '5133', (14, 18))	('PD-L1', 'Gene', '29126', (75, 80))	('soft tissue sarcomas', 'Disease', (129, 149))	('aggressive disease', 'Disease', 'MESH:D001523', (204, 222))
75353	28042471	Next generation sequencing to determine the presence of specific mutations in a panel of 50 genes was performed in one patient with a dedifferentiated chondrosarcoma responding to nivolumab alone; the polymerase chain reaction (PCR) product for specific mutations was sequenced on an Ion Torrent PGM instrument (Thermo Fisher Scientific, Waltham, MA).	('chondrosarcoma', 'Disease', 'MESH:D002813', (151, 165))	('patient', 'Species', '9606', (119, 126))	('mutations', 'Var', (254, 263))	('chondrosarcoma', 'Disease', (151, 165))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (151, 165))	('nivolumab', 'Chemical', 'MESH:D000077594', (180, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
75388	28042471	Multiple recent genomic studies have provided better insight into sarcoma biology through a more accurate classification by molecular subtype, identification of recurrent mutations in oncogenic pathways and evidence of epigenetic dysregulation.	('sarcoma', 'Disease', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('mutations', 'Var', (171, 180))	('oncogenic pathways', 'Pathway', (184, 202))
75414	27218413	Since SMARCB1 and EWSR1 genes are located close to each other on chromosome 22, larger SMARCB1 deletions may encompass the EWSR1 locus.	('EWSR1', 'Gene', (123, 128))	('EWSR1', 'Gene', (18, 23))	('SMARCB1', 'Gene', (87, 94))	('deletions', 'Var', (95, 104))	('EWSR1', 'Gene', '2130', (123, 128))	('EWSR1', 'Gene', '2130', (18, 23))	('SMARCB1', 'Gene', '6598', (6, 13))	('SMARCB1', 'Gene', (6, 13))	('SMARCB1', 'Gene', '6598', (87, 94))
75418	27218413	The SMARCB1 FISH revealed homozygous or heterozygous deletions in three and one case, respectively.	('SMARCB1', 'Gene', '6598', (4, 11))	('deletions', 'Var', (53, 62))	('SMARCB1', 'Gene', (4, 11))
75421	27218413	We conclude that in the context of 22q11-12 regional alterations present in SMARCB1-deleted tumors, simultaneous EWSR1 involvement may be misinterpreted as equivalent to EWSR1 rearrangement.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('SMARCB1', 'Gene', '6598', (76, 83))	('EWSR1', 'Gene', '2130', (113, 118))	('SMARCB1', 'Gene', (76, 83))	('EWSR1', 'Gene', (170, 175))	('alterations', 'Var', (53, 64))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('EWSR1', 'Gene', '2130', (170, 175))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('EWSR1', 'Gene', (113, 118))
75424	27218413	The association between SWI/SNF complexes and neoplasia was first recognized nearly two decades ago, with the discovery of SMARCB1 truncating mutations and deletions in malignant rhabdoid tumors at different locations (brain, kidney, soft tissue).	('truncating mutations', 'Var', (131, 151))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (169, 194))	('neoplasia', 'Disease', (46, 55))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('neoplasia', 'Phenotype', 'HP:0002664', (46, 55))	('SMARCB1', 'Gene', '6598', (123, 130))	('neoplasia', 'Disease', 'MESH:D009369', (46, 55))	('SMARCB1', 'Gene', (123, 130))	('malignant rhabdoid tumors', 'Disease', (169, 194))	('deletions', 'Var', (156, 165))
75427	27218413	Remarkably, by whole genome sequencing, 19.6% of all human tumors harbor mutations in various SWI/SNF subunits, a similar rate to TP53 mutation.	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('SWI/SNF subunits', 'Gene', (94, 110))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('human', 'Species', '9606', (53, 58))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('mutations', 'Var', (73, 82))
75428	27218413	Biallelic disruption of the SMARCB1 gene is the molecular hallmark of SMARCB1-deficient tumors and stems from a variety of mechanisms, including inactivating mutations, intragenic or whole-gene deletions, copy number-neutral loss of heterozygosity (LOH), and, infrequently, translocations.	('SMARCB1', 'Gene', (28, 35))	('inactivating mutations', 'Var', (145, 167))	('SMARCB1', 'Gene', '6598', (28, 35))	('Biallelic disruption', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('copy number-neutral loss of heterozygosity', 'Var', (205, 247))	('translocations', 'Var', (274, 288))	('SMARCB1', 'Gene', '6598', (70, 77))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (70, 94))	('SMARCB1-deficient tumors', 'Disease', (70, 94))	('SMARCB1', 'Gene', (70, 77))
75429	27218413	The incidence of homozygous or heterozygous SMARCB1 deletions varies depending on the tumor type and anatomic location of SMARCB1-deficient tumor.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SMARCB1-deficient tumor', 'Disease', (122, 145))	('SMARCB1', 'Gene', '6598', (44, 51))	('tumor', 'Disease', (86, 91))	('SMARCB1', 'Gene', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('SMARCB1-deficient tumor', 'Disease', 'MESH:D009369', (122, 145))	('SMARCB1', 'Gene', '6598', (122, 129))	('deletions', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('SMARCB1', 'Gene', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (140, 145))
75430	27218413	Among malignant rhabdoid tumors, brain tumors often exhibit large deletions or LOH of the whole chromosome arm 22q, while soft tissue counterparts usually harbor regional deletions across 22q11.22-11.23, and the renal tumors have either complex copy number deviation or copy number-neutral LOH.	('brain tumors', 'Phenotype', 'HP:0030692', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('renal tumors', 'Phenotype', 'HP:0009726', (212, 224))	('malignant rhabdoid tumors', 'Disease', (6, 31))	('deletions', 'Var', (171, 180))	('brain tumors', 'Disease', 'MESH:D001932', (33, 45))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('brain tumors', 'Disease', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('renal tumors', 'Disease', 'MESH:D007674', (212, 224))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('LOH', 'NegReg', (79, 82))	('renal tumors', 'Disease', (212, 224))	('deletions', 'Var', (66, 75))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (6, 31))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
75432	27218413	In contrast, epithelioid sarcomas show a complex cytogenetic profile, with frequent aneuploidies, numerous structural aberrations, a high mutation burden and copy number changes.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (13, 33))	('epithelioid sarcomas', 'Disease', (13, 33))	('structural aberrations', 'Var', (107, 129))	('copy number changes', 'Var', (158, 177))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))
75433	27218413	Since the SMARCB1 and EWSR1 genes are located only 5.5 Mb from each other in chromosome bands 22q11.23 and 22q12.2, respectively, secondary EWSR1 regional deletions may occur in SMARCB1-deleted tumors.	('EWSR1', 'Gene', '2130', (22, 27))	('EWSR1', 'Gene', '2130', (140, 145))	('tumors', 'Disease', (194, 200))	('regional deletions', 'Var', (146, 164))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('SMARCB1', 'Gene', '6598', (178, 185))	('EWSR1', 'Gene', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('occur', 'Reg', (169, 174))	('SMARCB1', 'Gene', (178, 185))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('SMARCB1', 'Gene', '6598', (10, 17))	('EWSR1', 'Gene', (140, 145))	('SMARCB1', 'Gene', (10, 17))
75434	27218413	In our previous study, we detected heterozygous telomeric EWSR1 deletions in 25% (9/36) of SMARCB1-deleted epithelioid sarcomas by fluorescence in situ hybridization (FISH).	('SMARCB1', 'Gene', '6598', (91, 98))	('deletions', 'Var', (64, 73))	('SMARCB1', 'Gene', (91, 98))	('EWSR1', 'Gene', '2130', (58, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (107, 127))	('EWSR1', 'Gene', (58, 63))	('epithelioid sarcomas', 'Disease', (107, 127))
75436	27218413	We identified three cases from the consultation files of the senior author (CRA) with a presumed EWSR1 gene rearrangement, which were sent for further classification or in an attempt to identify the EWSR1 fusion partner.	('EWSR1', 'Gene', '2130', (199, 204))	('EWSR1', 'Gene', (97, 102))	('EWSR1', 'Gene', '2130', (97, 102))	('rearrangement', 'Var', (108, 121))	('EWSR1', 'Gene', (199, 204))
75437	27218413	An additional case with similar EWSR1 alteration was retrieved from the archive of MSKCC Surgical Pathology.	('alteration', 'Var', (38, 48))	('EWSR1', 'Gene', (32, 37))	('EWSR1', 'Gene', '2130', (32, 37))
75441	27218413	FISH for SMARCB1 deletion and EWSR1 break-apart assay was applied on formalin-fixed and paraffin-embedded 4 mum-sections in all cases.	('EWSR1', 'Gene', '2130', (30, 35))	('SMARCB1', 'Gene', '6598', (9, 16))	('SMARCB1', 'Gene', (9, 16))	('deletion', 'Var', (17, 25))	('paraffin', 'Chemical', 'MESH:D010232', (88, 96))	('formalin', 'Chemical', 'MESH:D005557', (69, 77))	('EWSR1', 'Gene', (30, 35))
75452	27218413	The FISH assay displayed homozygous SMARCB1 deletion associated with a heterogeneous and complex EWSR1 split pattern (Fig.	('SMARCB1', 'Gene', '6598', (36, 43))	('deletion', 'Var', (44, 52))	('EWSR1', 'Gene', (97, 102))	('SMARCB1', 'Gene', (36, 43))	('EWSR1', 'Gene', '2130', (97, 102))	('associated', 'Reg', (53, 63))
75454	27218413	The T-brachyury immunostain performed in our lab was positive and, corroborated with the homozygous SMARCB1 FISH deletions, was consistent with a diagnosis of poorly differentiated chordoma, rather than an EWSR1-rearranged myoepithelial carcinoma (Fig.	('SMARCB1', 'Gene', (100, 107))	('chordoma', 'Disease', 'MESH:D002817', (181, 189))	('EWSR1', 'Gene', (206, 211))	('deletions', 'Var', (113, 122))	('chordoma', 'Phenotype', 'HP:0010762', (181, 189))	('EWSR1', 'Gene', '2130', (206, 211))	('myoepithelial carcinoma', 'Disease', (223, 246))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (223, 246))	('chordoma', 'Disease', (181, 189))	('SMARCB1', 'Gene', '6598', (100, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
75459	27218413	The outside FISH analysis showed a positive EWSR1 rearrangement, and a diagnosis of an atypical Ewing sarcoma with loss of SMARCB1 expression was entertained.	('EWSR1', 'Gene', '2130', (44, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('loss', 'NegReg', (115, 119))	('SMARCB1', 'Gene', '6598', (123, 130))	('expression', 'MPA', (131, 141))	('Ewing sarcoma', 'Disease', (96, 109))	('SMARCB1', 'Gene', (123, 130))	('rearrangement', 'Var', (50, 63))	('EWSR1', 'Gene', (44, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))
75460	27218413	The combined SMARCB1 and EWSR1 FISH assay demonstrated a homozygous SMARCB1 deletion, accompanied by loss of the telomeric EWSR1 signal on one allele and a split EWSR1 signal on the other allele (Fig.	('EWSR1', 'Gene', (123, 128))	('deletion', 'Var', (76, 84))	('EWSR1', 'Gene', (25, 30))	('EWSR1', 'Gene', (162, 167))	('loss', 'NegReg', (101, 105))	('EWSR1', 'Gene', '2130', (123, 128))	('EWSR1', 'Gene', '2130', (25, 30))	('SMARCB1', 'Gene', (68, 75))	('SMARCB1', 'Gene', '6598', (68, 75))	('SMARCB1', 'Gene', '6598', (13, 20))	('EWSR1', 'Gene', '2130', (162, 167))	('SMARCB1', 'Gene', (13, 20))
75469	27218413	The initial FISH examination reported EWSR1 rearrangement and a presumed diagnosis of myoepithelial carcinoma was rendered.	('rearrangement', 'Var', (44, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('EWSR1', 'Gene', '2130', (38, 43))	('EWSR1', 'Gene', (38, 43))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (86, 109))	('myoepithelial carcinoma', 'Disease', (86, 109))
75470	27218413	Our combined SMARCB1 and EWSR1 assay revealed homozygous SMARCB1 deletion with heterogeneous alterations of the EWSR1 locus (Fig 2C, 2D).	('EWSR1', 'Gene', (25, 30))	('EWSR1', 'Gene', '2130', (25, 30))	('SMARCB1', 'Gene', (57, 64))	('SMARCB1', 'Gene', '6598', (57, 64))	('EWSR1', 'Gene', (112, 117))	('SMARCB1', 'Gene', '6598', (13, 20))	('SMARCB1', 'Gene', (13, 20))	('deletion', 'Var', (65, 73))	('EWSR1', 'Gene', '2130', (112, 117))
75471	27218413	Most tumor cells exhibited deletion of the telomeric EWSR1 region (loss of green signals) on one allele, while the other harbored a 22q11 deletion extending to the centromeric part of EWSR1 region (residual tiny yellow signals)(Fig.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('EWSR1', 'Gene', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('deletion', 'Var', (27, 35))	('loss', 'NegReg', (67, 71))	('EWSR1', 'Gene', (53, 58))	('EWSR1', 'Gene', '2130', (184, 189))	('tumor', 'Disease', (5, 10))	('EWSR1', 'Gene', '2130', (53, 58))
75473	27218413	Overall findings were in keeping with a myoepithelial carcinoma with homozygous SMARCB1 deletion and secondary EWSR1 genetic abnormalities.	('myoepithelial carcinoma', 'Disease', (40, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('SMARCB1', 'Gene', '6598', (80, 87))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (40, 63))	('deletion', 'Var', (88, 96))	('genetic abnormalities', 'Disease', 'MESH:D030342', (117, 138))	('EWSR1', 'Gene', (111, 116))	('SMARCB1', 'Gene', (80, 87))	('EWSR1', 'Gene', '2130', (111, 116))	('genetic abnormalities', 'Disease', (117, 138))
75474	27218413	This case illustrates the complexity and heterogeneity of 22q11-12 regional alterations in SMARCB1-deficient myoepithelial tumors.	('alterations', 'Var', (76, 87))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('SMARCB1-deficient myoepithelial tumors', 'Disease', 'MESH:D009208', (91, 129))	('SMARCB1-deficient myoepithelial tumors', 'Disease', (91, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
75481	27218413	The combined SMARCB1 and EWSR1 FISH assay revealed heterozygous SMARCB1 deletion extending to the telomeric-EWSR1 region (small residual green signals) (Fig.	('EWSR1', 'Gene', (25, 30))	('EWSR1', 'Gene', (108, 113))	('EWSR1', 'Gene', '2130', (25, 30))	('SMARCB1', 'Gene', '6598', (64, 71))	('SMARCB1', 'Gene', '6598', (13, 20))	('EWSR1', 'Gene', '2130', (108, 113))	('SMARCB1', 'Gene', (64, 71))	('SMARCB1', 'Gene', (13, 20))	('deletion', 'Var', (72, 80))
75482	27218413	These heterozygous deletions resulted in a misinterpretation as an unbalanced EWSR1 translocation with centromeric loss, even though the 5'-end of EWSR1 gene is always represented in the EWSR1 chimeric fusion transcript.	('resulted in', 'Reg', (29, 40))	('EWSR1', 'Gene', '2130', (78, 83))	('EWSR1', 'Gene', (147, 152))	('EWSR1', 'Gene', (187, 192))	('EWSR1', 'Gene', '2130', (147, 152))	('EWSR1', 'Gene', (78, 83))	('EWSR1', 'Gene', '2130', (187, 192))	('deletions', 'Var', (19, 28))
75483	27218413	Corroborating all the genetic findings of SMARCB1 deletion and absence of NR4A3 abnormalities the diagnosis was reclassified as a proximal-type epithelioid sarcoma.	('SMARCB1', 'Gene', (42, 49))	('deletion', 'Var', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('NR4A3', 'Gene', (74, 79))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (144, 163))	('epithelioid sarcoma', 'Disease', (144, 163))	('SMARCB1', 'Gene', '6598', (42, 49))
75485	27218413	In the setting of SMARCB1-deficient tumors, FISH can potentially be used to investigate SMARCB1 gene deletions as the size range of the genomic regions (100 kb-18 Mb) involved are often within the resolution of FISH probes (50 kb-2 Mb).	('SMARCB1', 'Gene', (18, 25))	('SMARCB1', 'Gene', '6598', (88, 95))	('SMARCB1', 'Gene', (88, 95))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (18, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('SMARCB1-deficient tumors', 'Disease', (18, 42))	('deletions', 'Var', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('SMARCB1', 'Gene', '6598', (18, 25))
75486	27218413	Although FISH analysis is not suitable to identify other SMARCB1 molecular alterations, such as mutations, small deletions, or LOH, it remains a reliable test in SMARCB1-deficient tumors where large homozygous or heterozygous 22q11-12 deletions predominate.	('SMARCB1', 'Gene', '6598', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('deletions', 'Var', (113, 122))	('SMARCB1', 'Gene', (162, 169))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('SMARCB1', 'Gene', (57, 64))	('SMARCB1', 'Gene', '6598', (57, 64))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (162, 186))	('SMARCB1-deficient tumors', 'Disease', (162, 186))	('mutations', 'Var', (96, 105))
75487	27218413	For example, homozygous SMARCB1 deletions are present in the overwhelming majority of both proximal and distal epithelioid sarcomas (83-90%).	('deletions', 'Var', (32, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (111, 131))	('SMARCB1', 'Gene', '6598', (24, 31))	('epithelioid sarcomas', 'Disease', (111, 131))	('SMARCB1', 'Gene', (24, 31))
75488	27218413	In malignant rhabdoid tumors, the genetic abnormalities are equally divided between homozygous SMARCB1 deletions and SMARCB1 missense mutations with heterozygous deletion or LOH.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('SMARCB1', 'Gene', (117, 124))	('malignant rhabdoid tumors', 'Disease', (3, 28))	('SMARCB1', 'Gene', '6598', (95, 102))	('genetic abnormalities', 'Disease', 'MESH:D030342', (34, 55))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('SMARCB1', 'Gene', (95, 102))	('genetic abnormalities', 'Disease', (34, 55))	('deletions', 'Var', (103, 112))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (3, 28))	('missense mutations', 'Var', (125, 143))	('SMARCB1', 'Gene', '6598', (117, 124))
75489	27218413	Despite limited case numbers, SMARCB1-deficient chordoma and sinonasal rhabdoid/basaloid carcinoma appear to have a comparable high rate of homozygous or heterozygous SMARCB1 deletion.	('basaloid carcinoma', 'Phenotype', 'HP:0002671', (80, 98))	('SMARCB1', 'Gene', '6598', (30, 37))	('SMARCB1', 'Gene', (30, 37))	('SMARCB1', 'Gene', '6598', (167, 174))	('chordoma', 'Phenotype', 'HP:0010762', (48, 56))	('deletion', 'Var', (175, 183))	('SMARCB1', 'Gene', (167, 174))	('SMARCB1-deficient chordoma and sinonasal rhabdoid/basaloid carcinoma', 'Disease', 'MESH:D002817', (30, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))
75490	27218413	At least a small subset of extraskeletal myxoid chondrosarcoma and myoepithelial carcinoma with loss of SMARCB1 expression show concurrent SMARCB1 deletion, although none of the cases reported to date show co-existing NR4A3 or EWSR1 rearrangements, suggesting a mutually exclusive mechanism.	('EWSR1', 'Gene', (227, 232))	('myoepithelial carcinoma', 'Disease', (67, 90))	('SMARCB1', 'Gene', (104, 111))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (27, 62))	('extraskeletal myxoid chondrosarcoma', 'Disease', (27, 62))	('SMARCB1', 'Gene', '6598', (139, 146))	('EWSR1', 'Gene', '2130', (227, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('SMARCB1', 'Gene', (139, 146))	('deletion', 'Var', (147, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (48, 62))	('loss', 'NegReg', (96, 100))	('SMARCB1', 'Gene', '6598', (104, 111))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (67, 90))
75491	27218413	The absence of SMARCB1 deletions by FISH in the settings of SMARCB1-deficient tumors harboring a high rate of SMARCB1 deletions should raise concerns about the correct diagnosis.	('deletions', 'Var', (23, 32))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (60, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('SMARCB1-deficient tumors', 'Disease', (60, 84))	('SMARCB1', 'Gene', (110, 117))	('SMARCB1', 'Gene', '6598', (15, 22))	('SMARCB1', 'Gene', '6598', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SMARCB1', 'Gene', (15, 22))	('SMARCB1', 'Gene', (60, 67))	('deletions', 'Var', (118, 127))	('SMARCB1', 'Gene', '6598', (110, 117))
75494	27218413	By FISH examination no SMARCB1 deletions were identified, which was unusual for an epithelioid sarcoma and alerted us to obtain additional clinical information, which revealed that the patient's sister had sickle cell trait.	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (83, 102))	('epithelioid sarcoma', 'Disease', (83, 102))	('sickle cell trait', 'Disease', (206, 223))	('SMARCB1', 'Gene', '6598', (23, 30))	('patient', 'Species', '9606', (185, 192))	('SMARCB1', 'Gene', (23, 30))	('deletions', 'Var', (31, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))
75495	27218413	Thus a diagnosis of a renal medullary carcinoma was rendered, in which the preferred mechanism of SMARCB1 inactivation is more likely through a SMARCB1 translocation or LOH.	('SMARCB1', 'Gene', (144, 151))	('carcinoma', 'Disease', (38, 47))	('carcinoma', 'Disease', 'MESH:D002277', (38, 47))	('SMARCB1', 'Gene', '6598', (98, 105))	('translocation', 'Var', (152, 165))	('SMARCB1', 'Gene', (98, 105))	('LOH', 'Var', (169, 172))	('SMARCB1', 'Gene', '6598', (144, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('inactivation', 'NegReg', (106, 118))
75498	27218413	Thus the smaller size or centromeric-centered SMARCB1 deletions might result in partial or minimal loss of signal intensity, which can be easily missed by the low FISH resolution.	('deletions', 'Var', (54, 63))	('SMARCB1', 'Gene', (46, 53))	('signal intensity', 'MPA', (107, 123))	('SMARCB1', 'Gene', '6598', (46, 53))
75499	27218413	reported a significantly lower percentage (15/31, 48%) of SMARCB1 deletions in epithelioid sarcoma using the Vysis LSI BCR SpectrumGreen probes (BCR/ABL Dual Color Translocation Probe Set, Abbott Molecular, Illinois, USA).	('epithelioid sarcoma', 'Disease', (79, 98))	('lower', 'NegReg', (25, 30))	('SMARCB1', 'Gene', '6598', (58, 65))	('deletions', 'Var', (66, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (79, 98))	('SMARCB1', 'Gene', (58, 65))
75500	27218413	2 in which the anti-BCR FISH probe failed to identify a SMARCB1 deletion, and thus a diagnosis of rhabdoid tumor was excluded.	('rhabdoid tumor', 'Disease', 'MESH:D018335', (98, 112))	('SMARCB1', 'Gene', (56, 63))	('SMARCB1', 'Gene', '6598', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('rhabdoid tumor', 'Disease', (98, 112))	('deletion', 'Var', (64, 72))
75501	27218413	In contrast, our custom SMARCB1-specific strategy detected homozygous deletion in this case, which also explained the secondary nearby EWSR1 gene abnormalities.	('deletion', 'Var', (70, 78))	('EWSR1', 'Gene', (135, 140))	('EWSR1', 'Gene', '2130', (135, 140))	('SMARCB1', 'Gene', '6598', (24, 31))	('SMARCB1', 'Gene', (24, 31))
75502	27218413	In this regard, we have recently identified that 27% of Ewing sarcoma with EWSR1-ERG fusions show a false negative result by FISH using the EWSR1 break-apart probes, due to a complex pattern of inversions and rearrangements.	('EWSR1', 'Gene', '2130', (75, 80))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('EWSR1', 'Gene', '2130', (140, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('fusions', 'Var', (85, 92))	('Ewing sarcoma', 'Disease', (56, 69))	('EWSR1', 'Gene', (75, 80))	('EWSR1', 'Gene', (140, 145))
75503	27218413	In this study, we describe four cases of SMARCB1-deleted tumors harboring concurrent EWSR1 regional alterations, mimicking either balanced or unbalanced EWSR1 rearrangements.	('SMARCB1', 'Gene', (41, 48))	('EWSR1', 'Gene', '2130', (85, 90))	('EWSR1', 'Gene', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('SMARCB1', 'Gene', '6598', (41, 48))	('EWSR1', 'Gene', '2130', (153, 158))	('EWSR1', 'Gene', (85, 90))	('alterations', 'Var', (100, 111))
75505	27218413	In two cases, the SMARCB1 deletion involved the EWSR1 gene, and the FISH result showed a split signal, although the size of the signals was smaller than the ones seen in a typical balanced rearrangement.	('EWSR1', 'Gene', (48, 53))	('SMARCB1', 'Gene', (18, 25))	('involved', 'Reg', (35, 43))	('deletion', 'Var', (26, 34))	('EWSR1', 'Gene', '2130', (48, 53))	('SMARCB1', 'Gene', '6598', (18, 25))
75506	27218413	In the other two cases, FISH showed a heterozygous deletion of EWSR1 FISH probes.	('EWSR1', 'Gene', '2130', (63, 68))	('deletion', 'Var', (51, 59))	('EWSR1', 'Gene', (63, 68))
75507	27218413	Although our previous study showed one-fourth of SMARCB1-deleted epithelioid sarcoma contained synchronous deletion of telomeric EWSR1 region, the prevalence of concurrent break-apart or heterozygous EWSR1 abnormalities reminiscent of EWSR1 rearrangement in SMARCB1-deleted tumors remains unclear.	('abnormalities', 'Var', (206, 219))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('EWSR1', 'Gene', (235, 240))	('SMARCB1', 'Gene', '6598', (258, 265))	('EWSR1', 'Gene', '2130', (200, 205))	('SMARCB1', 'Gene', (258, 265))	('EWSR1', 'Gene', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('SMARCB1', 'Gene', '6598', (49, 56))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (65, 84))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('SMARCB1', 'Gene', (49, 56))	('EWSR1', 'Gene', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('deletion', 'Var', (107, 115))	('EWSR1', 'Gene', '2130', (235, 240))	('tumors', 'Disease', (274, 280))	('break-apart', 'Var', (172, 183))	('epithelioid sarcoma', 'Disease', (65, 84))	('EWSR1', 'Gene', '2130', (129, 134))
75508	27218413	The single nucleotide polymorphism-based oligonucleotide array showed heterozygous 22q12.2 deletion in 8.5% (3/35) of malignant rhabdoid tumors.	('deletion', 'Var', (91, 99))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (118, 143))	('oligonucleotide', 'Chemical', 'MESH:D009841', (41, 56))	('22q12.2', 'Gene', (83, 90))	('malignant rhabdoid tumors', 'Disease', (118, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
75511	27218413	In two studies, none of the SMARCB1-deficient myoepithelial carcinomas or extraskeletal myxoid chondrosarcomas had concurrent EWSR1 rearrangement and SMARCB1 deletion.	('extraskeletal myxoid chondrosarcoma', 'Disease', (74, 109))	('rearrangement', 'Var', (132, 145))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (74, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('SMARCB1', 'Gene', '6598', (28, 35))	('SMARCB1', 'Gene', (28, 35))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (88, 110))	('myxoid chondrosarcomas', 'Disease', (88, 110))	('deletion', 'Var', (158, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('SMARCB1-deficient myoepithelial carcinomas', 'Disease', (28, 70))	('EWSR1', 'Gene', '2130', (126, 131))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (95, 109))	('SMARCB1', 'Gene', (150, 157))	('SMARCB1', 'Gene', '6598', (150, 157))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (95, 110))	('SMARCB1-deficient myoepithelial carcinomas', 'Disease', 'MESH:D009208', (28, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('EWSR1', 'Gene', (126, 131))
75513	27218413	They often have loss of SMARCB1 protein expression as a result of SMARCB1 deletions.	('expression', 'MPA', (40, 50))	('SMARCB1', 'Gene', '6598', (24, 31))	('deletions', 'Var', (74, 83))	('loss', 'NegReg', (16, 20))	('protein', 'Protein', (32, 39))	('SMARCB1', 'Gene', (66, 73))	('SMARCB1', 'Gene', '6598', (66, 73))	('SMARCB1', 'Gene', (24, 31))
75515	27218413	The initial negative result of T-brachyury immunostaining and FISH positivity for EWSR1 rearrangement favored a myoepithelial carcinoma.	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (112, 135))	('myoepithelial carcinoma', 'Disease', (112, 135))	('EWSR1', 'Gene', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('rearrangement', 'Var', (88, 101))	('EWSR1', 'Gene', '2130', (82, 87))
75516	27218413	However, our FISH findings of SMARCB1 deletions encompassing the EWSR1 locus, as well as the lack of rearrangements in all EWSR1-gene partners described in myoepithelial tumors, questioned the outside EWSR1 gene break-apart result.	('EWSR1', 'Gene', (123, 128))	('EWSR1', 'Gene', (65, 70))	('SMARCB1', 'Gene', '6598', (30, 37))	('EWSR1', 'Gene', '2130', (123, 128))	('EWSR1', 'Gene', '2130', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SMARCB1', 'Gene', (30, 37))	('deletions', 'Var', (38, 47))	('EWSR1', 'Gene', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (156, 176))	('EWSR1', 'Gene', '2130', (201, 206))	('myoepithelial tumors', 'Disease', (156, 176))
75518	27218413	Indeed, chromosomal 22q translocation or mitotic recombination with variable regional deletion, outside the hot spot EWSR1 breakpoints, represents one of the main mechanisms for SMARCB1 inactivation.	('mitotic recombination', 'CPA', (41, 62))	('EWSR1', 'Gene', (117, 122))	('EWSR1', 'Gene', '2130', (117, 122))	('chromosomal 22q translocation', 'Var', (8, 37))	('SMARCB1', 'Gene', '6598', (178, 185))	('SMARCB1', 'Gene', (178, 185))	('inactivation', 'NegReg', (186, 198))
75519	27218413	Rare round cell sarcomas harboring SMARCB1 genetic alterations and consequent loss of expression have been previously described, having a predilection for young children and a favorable outcome.	('sarcomas', 'Disease', (16, 24))	('children', 'Species', '9606', (161, 169))	('expression', 'MPA', (86, 96))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('loss', 'NegReg', (78, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))	('SMARCB1', 'Gene', '6598', (35, 42))	('genetic alterations', 'Var', (43, 62))	('SMARCB1', 'Gene', (35, 42))
75522	27218413	EWSR1 rearrangements were only demonstrated in 2/4 such cases using break-apart FISH strategy, but not confirmed by other methods.	('EWSR1', 'Gene', (0, 5))	('EWSR1', 'Gene', '2130', (0, 5))	('rearrangements', 'Var', (6, 20))
75524	27218413	2, representing rhabdoid tumors with secondary EWSR1 abnormalities due to SMARCB1 deletions.	('rhabdoid tumors', 'Disease', (16, 31))	('deletions', 'Var', (82, 91))	('EWSR1', 'Gene', '2130', (47, 52))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (16, 31))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('SMARCB1', 'Gene', '6598', (74, 81))	('SMARCB1', 'Gene', (74, 81))	('EWSR1', 'Gene', (47, 52))
75525	27218413	Additional FISH or RT-PCR testing to assess FLI1 or ERG gene rearrangements would settle this dilemma as confirming the diagnosis of Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('Ewing sarcoma', 'Disease', (133, 146))	('ERG gene', 'Gene', (52, 60))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (133, 146))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (133, 146))	('rearrangements', 'Var', (61, 75))	('FLI1', 'Gene', (44, 48))
75527	27218413	Our previous study showed homozygous SMARCB1 deletions in three of five myoepithelial carcinomas with SMARCB1 immunonegativity, but none of them harbored EWSR1 gene rearrangement.	('myoepithelial carcinomas', 'Disease', 'MESH:D009208', (72, 96))	('EWSR1', 'Gene', '2130', (154, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('SMARCB1', 'Gene', (37, 44))	('SMARCB1', 'Gene', '6598', (37, 44))	('myoepithelial carcinomas', 'Disease', (72, 96))	('deletions', 'Var', (45, 54))	('SMARCB1', 'Gene', '6598', (102, 109))	('SMARCB1', 'Gene', (102, 109))	('EWSR1', 'Gene', (154, 159))
75528	27218413	Even though reported SMARCB1 deletions in 2/4 SMARCB1-deficient extraskeletal myxoid chondrosarcoma, none of them harbored EWSR1-NR4A3 or TAF2A-NR4A3 fusion transcript by RT-PCR.	('EWSR1', 'Gene', (123, 128))	('SMARCB1-deficient extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (46, 99))	('SMARCB1', 'Gene', '6598', (46, 53))	('EWSR1', 'Gene', '2130', (123, 128))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (85, 99))	('SMARCB1', 'Gene', (46, 53))	('SMARCB1', 'Gene', '6598', (21, 28))	('SMARCB1', 'Gene', (21, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('deletions', 'Var', (29, 38))
75529	27218413	Furthermore, in our prior study, none of seven SMARCB1-deficient extraskeletal myxoid chondrosarcoma with NR4A3 gene rearrangements showed SMARCB1 abnormalities by FISH.	('NR4A3', 'Gene', (106, 111))	('SMARCB1-deficient extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (47, 100))	('rearrangements', 'Var', (117, 131))	('SMARCB1', 'Gene', '6598', (139, 146))	('SMARCB1', 'Gene', '6598', (47, 54))	('SMARCB1', 'Gene', (139, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('SMARCB1', 'Gene', (47, 54))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (86, 100))
75530	27218413	In this setting, we highly recommend evaluation of NR4A3 gene rearrangement by FISH or RT-PCR to confirm the diagnosis of extraskeletal myxoid chondrosarcoma, as EWSR1 gene abnormalities might be secondary to large SMARCB1 deletions.	('EWSR1', 'Gene', (162, 167))	('SMARCB1', 'Gene', '6598', (215, 222))	('NR4A3', 'Gene', (51, 56))	('abnormalities', 'Var', (173, 186))	('SMARCB1', 'Gene', (215, 222))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (143, 157))	('deletions', 'Var', (223, 232))	('extraskeletal myxoid chondrosarcoma', 'Disease', (122, 157))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (122, 157))	('EWSR1', 'Gene', '2130', (162, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))
75531	27218413	Except for the above-mentioned Ewing sarcoma study, there are three additional case reports describing SMARCB1-deficient tumors with co-existing EWSR1 rearrangements, including two myoepithelial carcinomas and one desmoplastic small round cell tumor.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('myoepithelial carcinomas', 'Disease', (181, 205))	('rearrangements', 'Var', (151, 165))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('EWSR1', 'Gene', (145, 150))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (103, 127))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (214, 249))	('Ewing sarcoma', 'Disease', (31, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('EWSR1', 'Gene', '2130', (145, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('SMARCB1-deficient tumors', 'Disease', (103, 127))	('myoepithelial carcinomas', 'Disease', 'MESH:D009208', (181, 205))	('desmoplastic small round cell tumor', 'Disease', (214, 249))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (31, 44))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (31, 44))
75535	27218413	The third case was a cytokeratin and desmin-negative desmoplastic small round cell tumor which by RT-PCR showed an EWSR1-WT1 transcript, but by FISH had one pair of EWSR1 break-apart signals, indicating monosomy 22 or allelic deletion.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('EWSR1', 'Gene', (115, 120))	('EWSR1', 'Gene', '2130', (165, 170))	('monosomy', 'Var', (203, 211))	('EWSR1', 'Gene', '2130', (115, 120))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (53, 88))	('EWSR1', 'Gene', (165, 170))	('desmoplastic small round cell tumor', 'Disease', (53, 88))
75539	27218413	Our results emphasize that a subset of SMARCB1-deleted tumors contain secondary EWSR1 regional alterations by FISH, including break-apart and heterozygous deletions; both of these EWSR1 FISH abnormalities patterns having the potential for misdiagnosis.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SMARCB1', 'Gene', '6598', (39, 46))	('EWSR1', 'Gene', (180, 185))	('EWSR1', 'Gene', (80, 85))	('FISH abnormalities', 'Disease', 'MESH:D000014', (186, 204))	('FISH abnormalities', 'Disease', (186, 204))	('alterations', 'Reg', (95, 106))	('SMARCB1', 'Gene', (39, 46))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('EWSR1', 'Gene', '2130', (180, 185))	('tumors', 'Disease', (55, 61))	('deletions', 'Var', (155, 164))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('EWSR1', 'Gene', '2130', (80, 85))
75541	27218413	Our results corroborated with a careful literature review further emphasizes that most EWSR1 rearranged tumors do not show concurrent SMARCB1 gene inactivations, and most likely represent independent mechanisms of pathogenesis.	('rearranged', 'Var', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('EWSR1', 'Gene', (87, 92))	('SMARCB1', 'Gene', '6598', (134, 141))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('SMARCB1', 'Gene', (134, 141))	('EWSR1', 'Gene', '2130', (87, 92))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
75543	27218413	Additional FISH testing for confirming rearrangements in the potential EWSR1 gene partners or applying complementary methods (RT-PCR, NGS) should be recommended in challenging cases, and close clinicopathologic correlation with the FISH results should be carried out to avoid these pitfalls.	('rearrangements', 'Var', (39, 53))	('EWSR1', 'Gene', (71, 76))	('EWSR1', 'Gene', '2130', (71, 76))
75705	33806182	MTM has been used in the past as a therapeutic agent to treat several cancer types, including Ewing sarcoma, in which MTM was able to inhibit its characteristic EWS-FLI1 transcription factor.	('FLI1', 'Gene', (165, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('inhibit', 'NegReg', (134, 141))	('MTM', 'Chemical', 'MESH:D008926', (118, 121))	('EWS', 'Gene', (161, 164))	('MTM', 'Chemical', 'MESH:D008926', (0, 3))	('MTM', 'Var', (118, 121))	('Ewing sarcoma', 'Disease', (94, 107))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('EWS', 'Gene', '2130', (161, 164))	('FLI1', 'Gene', '2313', (165, 169))
75722	33806182	Poly (lactic-co-glycolic acid) (PLGA) (LG 50:50, Mw 24-38 kDa), Sorbitan monostearate (Span 60, S60) (C24H46O6, MW = 430.62 g/mol), Polisorbate 20 (Tween 20, T20) (C58H114O26, MM = 1227 g/mol) and Cholesterol (Cho) (C27H46O, MW = 386.65 g/mol) were purchased from Sigma Aldrich (USA).	('glycolic acid', 'Chemical', 'MESH:C031149', (16, 29))	('Cho', 'Chemical', 'MESH:D002784', (197, 200))	('Tween 20', 'Chemical', 'MESH:D011136', (148, 156))	('C58H114O26', 'Var', (164, 174))	('C27H46O', 'Var', (216, 223))	('Cho', 'Chemical', 'MESH:D002784', (210, 213))
75764	33806182	It was also observed that EE was higher in PLGA1 (S60:Cho) polymeric micelles (87%), formulated using cholesterol and without PC.	('higher', 'PosReg', (33, 39))	('PLGA1', 'Var', (43, 48))	('cholesterol', 'Chemical', 'MESH:D002784', (102, 113))	('Cho', 'Chemical', 'MESH:D002784', (54, 57))	('PC', 'Chemical', 'MESH:D010713', (126, 128))
75805	33806182	Thus, recent studies have found that the combination of MTM with CDK9 inhibitors or the semisynthetic taxane cabazitaxel resulted in improved anti-tumor activity and/or limited MTM-toxicity in Ewing sarcoma and B-cell acute lymphoblastic leukemia, respectively.	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (224, 246))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (193, 206))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (193, 206))	('-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (212, 246))	('tumor', 'Disease', (147, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('toxicity', 'Disease', 'MESH:D064420', (181, 189))	('inhibitors', 'Var', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('MTM', 'Chemical', 'MESH:D008926', (56, 59))	('improved', 'PosReg', (133, 141))	('CDK9', 'Gene', (65, 69))	('taxane', 'Chemical', 'MESH:C080625', (102, 108))	('Ewing sarcoma', 'Disease', (193, 206))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (224, 246))	('toxicity', 'Disease', (181, 189))	('lymphoblastic leukemia', 'Disease', (224, 246))	('cabazitaxel', 'Chemical', 'MESH:C552428', (109, 120))	('combination', 'Interaction', (41, 52))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (218, 246))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('CDK9', 'Gene', '1025', (65, 69))	('leukemia', 'Phenotype', 'HP:0001909', (238, 246))	('MTM', 'Chemical', 'MESH:D008926', (177, 180))
75840	33806182	We speculate that treatments such as nano-delivered MTM, which are able to simultaneously inhibit several well-known driver oncogenes in sarcoma, may have a higher impact on the patient's outcome.	('inhibit', 'NegReg', (90, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('patient', 'Species', '9606', (178, 185))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('nano-delivered', 'Var', (37, 51))	('MTM', 'Chemical', 'MESH:D008926', (52, 55))	('sarcoma', 'Disease', (137, 144))
75843	33806182	In a similar way, we showed that EC-8042 was able to inhibit the expression of a panel of CSC markers and demonstrated a higher ability to target CSCs in vivo than other chemotherapeutics drugs in sarcoma cells.	('EC-8042', 'Chemical', 'MESH:C576677', (33, 40))	('inhibit', 'NegReg', (53, 60))	('EC-8042', 'Var', (33, 40))	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('sarcoma', 'Disease', (197, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('expression', 'MPA', (65, 75))	('CSC markers', 'Gene', (90, 101))	('higher', 'PosReg', (121, 127))
75852	32933053	A chromosomal rearrangement was identified in 31 (74%) of the cases and a missense mutation in known oncogenes/tumor suppressor genes in 11 (26%).	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('missense mutation', 'Var', (74, 91))
75854	32933053	While YWHAE-NUTM2 fusion genes may be present in both high and low grade ESS, the high-grade presents with additional BCOR or BCORL1 gene mutations.	('BCOR', 'Gene', '54880', (126, 130))	('YWHAE', 'Gene', (6, 11))	('BCOR', 'Gene', (118, 122))	('BCORL1', 'Gene', (126, 132))	('BCOR', 'Gene', '54880', (118, 122))	('YWHAE', 'Gene', '7531', (6, 11))	('BCOR', 'Gene', (126, 130))	('BCORL1', 'Gene', '63035', (126, 132))	('mutations', 'Var', (138, 147))
75864	32933053	Recently, the expression of BCOR using IHC (Immunohistochemistry) was proposed as a criterion to classify HG-ESS carrying a BCOR rearrangement or a YWHAE-NUTM2 fusion.	('rearrangement', 'Var', (129, 142))	('BCOR', 'Gene', (124, 128))	('BCOR', 'Gene', '54880', (28, 32))	('BCOR', 'Gene', '54880', (124, 128))	('YWHAE', 'Gene', (148, 153))	('BCOR', 'Gene', (28, 32))	('YWHAE', 'Gene', '7531', (148, 153))
75866	32933053	This translational study was conducted on a retrospective series of 42 ESS negative for JAZF1 rearrangement (n = 22), YWHAE rearrangement (n = 11) or both (n = 9) (Figure S1).	('JAZF1', 'Gene', (88, 93))	('YWHAE', 'Gene', '7531', (118, 123))	('rearrangement', 'Var', (124, 137))	('JAZF1', 'Gene', '221895', (88, 93))	('rearrangement', 'Var', (94, 107))	('YWHAE', 'Gene', (118, 123))
75877	32933053	Among the latter, two cases (5%) harbored a fusion implicating GLI1 relating them to the previously described "malignant epithelioid neoplasm with GLI1 gene rearrangements", and one case (2%) harbored a LMNA-NTRK1 fusion corresponding to the previously described NTRK-fused uterine sarcomas.	('rearrangements', 'Var', (157, 171))	('GLI1', 'Gene', (147, 151))	('fusion', 'Var', (44, 50))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (274, 289))	('NTRK1', 'Gene', '4914', (208, 213))	('GLI1', 'Gene', (63, 67))	('sarcomas', 'Disease', 'MESH:D012509', (282, 290))	('LMNA-NTRK', 'Gene', '4000', (203, 212))	('LMNA-NTRK', 'Gene', (203, 212))	('sarcomas', 'Phenotype', 'HP:0100242', (282, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('malignant epithelioid neoplasm', 'Disease', (111, 141))	('sarcomas', 'Disease', (282, 290))	('NTRK1', 'Gene', (208, 213))	('malignant epithelioid neoplasm', 'Disease', 'MESH:D009369', (111, 141))	('GLI1', 'Gene', '2735', (147, 151))	('GLI1', 'Gene', '2735', (63, 67))	('neoplasm', 'Phenotype', 'HP:0002664', (133, 141))
75878	32933053	Of note, five (11%) cases harbored complex genomic profiles with numerous gene fusions and/or had mutations involving either TP53, KRAS, NRAS or BRAF, consistent with a diagnosis of UUS, and one case presented a deletion of SMARCA4 (together with a NRAS mutation), consistent with a SMARCA4-deficient undifferentiated uterine sarcoma.	('BRAF', 'Gene', (145, 149))	('NRAS', 'Gene', (249, 253))	('SMARCA4', 'Gene', (224, 231))	('TP53', 'Gene', (125, 129))	('NRAS', 'Gene', (137, 141))	('KRAS', 'Gene', '3845', (131, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (326, 333))	('KRAS', 'Gene', (131, 135))	('SMARCA4-deficient undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (283, 333))	('SMARCA4-deficient undifferentiated uterine sarcoma', 'Disease', (283, 333))	('deletion', 'Var', (212, 220))	('SMARCA4', 'Gene', (283, 290))	('TP53', 'Gene', '7157', (125, 129))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (318, 333))	('SMARCA4', 'Gene', '6597', (224, 231))	('NRAS', 'Gene', '4893', (249, 253))	('NRAS', 'Gene', '4893', (137, 141))	('mutations', 'Var', (98, 107))	('SMARCA4', 'Gene', '6597', (283, 290))	('BRAF', 'Gene', '673', (145, 149))
75888	32933053	Seven cases diagnosed as LG-ESS were reclassified either as HG-ESS with BCOR rearrangement (n = 2), malignant epithelioid neoplasm with GLI1 rearrangement (n = 2), NCOA fusion-positive uterine tumors (n = 2) or uterine leiomyoma (n = 1).	('rearrangement', 'Var', (77, 90))	('BCOR', 'Gene', (72, 76))	('leiomyoma', 'Disease', (219, 228))	('neoplasm', 'Phenotype', 'HP:0002664', (122, 130))	('leiomyoma', 'Disease', 'MESH:D007889', (219, 228))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('BCOR', 'Gene', '54880', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('uterine tumor', 'Phenotype', 'HP:0010784', (185, 198))	('malignant epithelioid neoplasm', 'Disease', (100, 130))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('malignant epithelioid neoplasm', 'Disease', 'MESH:D009369', (100, 130))	('HG-ESS', 'Disease', (60, 66))	('tumors', 'Disease', (193, 199))	('GLI1', 'Gene', '2735', (136, 140))	('GLI1', 'Gene', (136, 140))	('uterine tumors', 'Phenotype', 'HP:0010784', (185, 199))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (211, 228))
75894	32933053	However, the analysis of the two HG showed two nucleotide variation events identified: one mutation in BCOR (CLB_RNA_1514: NM_017745: exon4:c.2570_2571del:p.E857fs; AAR = 0.28, validated by Sanger sequencing) (Figure S7), and one in BCORL1 (CLB_RNA_1512: NM_021946: exon7:c.A4256T:p.K1419I; AAR = 0.67).	('exon4:c.2570_2571del', 'DELETION', 'None', (134, 154))	('c.A4256T:p.K1419I', 'Var', (272, 289))	('exon4:c.2570_2571del', 'Var', (134, 154))	('BCORL1', 'Gene', '63035', (233, 239))	('BCOR', 'Gene', '54880', (233, 237))	('BCOR', 'Gene', '54880', (103, 107))	('c.A4256T:p.K1419I', 'SUBSTITUTION', 'None', (272, 289))	('BCORL1', 'Gene', (233, 239))	('p.E857fs', 'Var', (155, 163))	('BCOR', 'Gene', (233, 237))	('BCOR', 'Gene', (103, 107))	('p.E857fs', 'Mutation', 'p.E857fsX', (155, 163))
75902	32933053	Importantly, a small subset of tumors (composed of a case of UUS that harbored a NRAS G13D mutation, a case of uterine sarcoma with LMNA-NTRK1 fusion and a case of UUS without relevant genomic alteration) stood out consistently from the other tumors.	('mutation', 'Var', (91, 99))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('NRAS', 'Gene', (81, 85))	('G13D mutation', 'Var', (86, 99))	('LMNA-NTRK', 'Gene', '4000', (132, 141))	('NTRK1', 'Gene', '4914', (137, 142))	('LMNA-NTRK', 'Gene', (132, 141))	('NTRK1', 'Gene', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('G13D', 'Mutation', 'rs112445441', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (111, 126))	('tumors', 'Disease', (243, 249))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', (119, 126))	('NRAS', 'Gene', '4893', (81, 85))
75908	32933053	The HG group is composed of ESS harboring a BCOR rearrangement, while the LG group is composed of ESS that harbors a fusion of a PRC2 zinc finger protein (e.g., JAZF1, PHF1).	('PHF1', 'Gene', (168, 172))	('JAZF1', 'Gene', (161, 166))	('BCOR', 'Gene', (44, 48))	('PHF1', 'Gene', '5252', (168, 172))	('BCOR', 'Gene', '54880', (44, 48))	('rearrangement', 'Var', (49, 62))	('JAZF1', 'Gene', '221895', (161, 166))	('PR', 'Gene', '140738', (129, 131))
75929	32933053	Of note, the level of expression of ESR1 was also significantly higher in the C2/3 than in the C1 cluster (HG), which is consistent with the known prognosis of ER in sarcomas.	('level', 'MPA', (13, 18))	('ESR1', 'Gene', '2099', (36, 40))	('higher', 'PosReg', (64, 70))	('sarcomas', 'Disease', 'MESH:D012509', (166, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (166, 174))	('C2/3', 'Var', (78, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('sarcomas', 'Disease', (166, 174))	('ESR1', 'Gene', (36, 40))	('expression', 'MPA', (22, 32))
75932	32933053	Here, we demonstrate that (i) LG-ESS with YWHAE-NUTM2 fusions are not uncommon; (ii) they differ from their HG counterparts not only by the expression of genes involved in cell cycle/proliferation pathways and absence of mutation of the BCOR pathway, but also by those involved in the immune response or angiogenesis and (iii) they may be identified by ER positivity in IHC.	('fusions', 'Var', (54, 61))	('BCOR', 'Gene', '54880', (237, 241))	('YWHAE', 'Gene', (42, 47))	('YWHAE', 'Gene', '7531', (42, 47))	('IHC', 'Disease', (370, 373))	('BCOR', 'Gene', (237, 241))
75934	32933053	Inhibition of HDAC (Histone deacetylases) therefore provides a very interesting approach to treatment for this subtype of sarcoma.	('HDAC', 'Gene', (14, 18))	('HDAC', 'Gene', '9734', (14, 18))	('Histone deacetylases', 'Gene', (20, 40))	('Inhibition', 'Var', (0, 10))	('Histone deacetylases', 'Gene', '9734', (20, 40))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('sarcoma', 'Disease', (122, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
75940	32933053	By showing the molecular landscape of fusions genes in ESS, RNAseq analysis also helps in understanding the biology and the mechanisms of tumorigenesis.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('ESS', 'Disease', (55, 58))	('fusions', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
75943	32933053	The JAZF1-SUZ12 fusion disrupts the PRC2 complex, preventing its binding, and thus impairs the chromatin repression of oncogenes such as HOXA9.	('HOXA9', 'Gene', '3205', (137, 142))	('SUZ12', 'Gene', '23512', (10, 15))	('fusion', 'Var', (16, 22))	('binding', 'Interaction', (65, 72))	('SUZ12', 'Gene', (10, 15))	('HOXA9', 'Gene', (137, 142))	('JAZF1', 'Gene', (4, 9))	('preventing', 'NegReg', (50, 60))	('PR', 'Gene', '140738', (36, 38))	('impairs', 'NegReg', (83, 90))	('JAZF1', 'Gene', '221895', (4, 9))	('chromatin repression', 'MPA', (95, 115))	('disrupts', 'NegReg', (23, 31))
75950	32933053	TET2 increases the activity of HDAC2, and mutations of this gene have previously been described in other neoplasms such as AML (acute myeloid leukemia) with an unfavorable prognostic value.	('TET2', 'Gene', (0, 4))	('acute myeloid leukemia', 'Disease', (128, 150))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('described', 'Reg', (86, 95))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (128, 150))	('leukemia', 'Phenotype', 'HP:0001909', (142, 150))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (134, 150))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('activity', 'MPA', (19, 27))	('TET2', 'Gene', '54790', (0, 4))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (128, 150))	('HDAC2', 'Gene', (31, 36))	('HDAC2', 'Gene', '3066', (31, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (105, 113))	('AML', 'Disease', (123, 126))	('mutations', 'Var', (42, 51))	('neoplasms', 'Disease', 'MESH:D009369', (105, 114))	('neoplasms', 'Disease', (105, 114))
75951	32933053	In one case (CLB_RNA_1372), we detected a KAT6B-KANSL1 fusion that was previously described in two cases of leiomyomas.	('KANSL1', 'Gene', '284058', (48, 54))	('leiomyomas', 'Disease', 'MESH:D007889', (108, 118))	('leiomyomas', 'Disease', (108, 118))	('KAT6B', 'Gene', (42, 47))	('KANSL1', 'Gene', (48, 54))	('fusion', 'Var', (55, 61))	('KAT6B', 'Gene', '23522', (42, 47))
75954	32933053	ARID2 is a subunit of the PBAF chromatin-remodeling complex, and mutations of this gene have been described in various neoplasms (hepatocellular carcinoma, melanoma).	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (130, 154))	('neoplasms', 'Disease', 'MESH:D009369', (119, 128))	('neoplasms', 'Disease', (119, 128))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('ARID2', 'Gene', '196528', (0, 5))	('neoplasms', 'Phenotype', 'HP:0002664', (119, 128))	('described', 'Reg', (98, 107))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('ARID2', 'Gene', (0, 5))	('neoplasm', 'Phenotype', 'HP:0002664', (119, 127))	('mutations', 'Var', (65, 74))	('hepatocellular carcinoma', 'Disease', (130, 154))
76130	30943926	This study of 37 cell lines and four tissue specimens shows the detection of C-terminal ALK or ROS1 proteins could be a comprehensive method to determine ALK or ROS1 fusion, whereas not only the detection of C-terminal RET protein but also other methods would be needed to determine RET fusion.	('ROS1', 'Gene', '6098', (95, 99))	('ROS1', 'Gene', (161, 165))	('ROS1', 'Gene', (95, 99))	('ROS1', 'Gene', '6098', (161, 165))	('ALK', 'Var', (154, 157))
76131	30943926	Molecular subsets of non-small cell lung cancer (NSCLC) have been defined by various types of driver gene mutations involving epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK) gene fusion.	('NSCLC', 'Disease', (49, 54))	('epidermal growth factor receptor', 'Gene', '24329', (126, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (232, 251))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('epidermal growth factor receptor', 'Gene', (126, 158))	('sarcoma', 'Disease', (189, 196))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (21, 47))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (25, 47))	('anaplastic lymphoma kinase', 'Gene', (232, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (21, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (243, 251))	('anaplastic lymphoma kinase', 'Gene', '266802', (232, 258))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('mutations', 'Var', (106, 115))	('non-small cell lung cancer', 'Disease', (21, 47))	('rat', 'Species', '10116', (185, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
76133	30943926	A key issue in identifying patients that would be suitable for the targeted agents is precisely identifying the presence or absence of the driver gene mutations in a molecular diagnosis of the lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('patients', 'Species', '9606', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('lung cancer', 'Disease', (193, 204))	('mutations', 'Var', (151, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))
76134	30943926	In approximately 5% of NSCLC, the rearrangement of the amino-terminal (N-terminal) region of echinoderm microtubule associated protein like 4 (EML4) with the carboxy-terminal (C-terminal) region of ALK occurs by inversion within the short arm of chromosome 2.	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('EML4', 'Gene', (143, 147))	('rearrangement', 'Var', (34, 47))	('echinoderm microtubule associated protein like 4', 'Gene', '27436', (93, 141))	('EML4', 'Gene', '27436', (143, 147))	('NSCLC', 'Disease', (23, 28))	('short arm', 'Phenotype', 'HP:0009824', (233, 242))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('echinoderm microtubule associated protein like 4', 'Gene', (93, 141))
76136	30943926	The ALK IHC method determines whether tumor cells are harboring an ALK fusion using an antibody directed to the C-terminal ALK protein, but unlike FISH tests, it has been reported to show not only positive results in patients with ALK fusion-positive cancer but also false-negative errors in some patients who actually have ALK fusion-positive cancer.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('cancer', 'Disease', (344, 350))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('ALK fusion-positive', 'Var', (231, 250))	('patients', 'Species', '9606', (297, 305))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('patients', 'Species', '9606', (217, 225))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (344, 350))
76137	30943926	In addition to ALK fusion, RET proto-oncogene (RET) or v-ros UR2 sarcoma virus oncogene homolog 1 (ROS1) are rearranged in approximately 1% of NSCLC.	('v-ros UR2 sarcoma virus oncogene homolog 1', 'Gene', (55, 97))	('ROS1', 'Gene', (99, 103))	('NSCLC', 'Disease', (143, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('ROS1', 'Gene', '6098', (99, 103))	('rearranged', 'Var', (109, 119))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('v-ros UR2 sarcoma virus oncogene homolog 1', 'Gene', '25346', (55, 97))
76139	30943926	In this study, we verified the reliability of IHC methods that target ALK, RET, and ROS1 C-terminal protein as diagnostic tools for lung cancer by investigating whether the expression at the C-terminal region is elevated in each of the fusion-positive lung cancer cells compared with that in fusion-negative cells.	('ROS1', 'Gene', '6098', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('fusion-positive', 'Var', (236, 251))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('elevated', 'PosReg', (212, 220))	('lung cancer', 'Disease', 'MESH:D008175', (252, 263))	('lung cancer', 'Disease', (132, 143))	('expression', 'MPA', (173, 183))	('ROS1', 'Gene', (84, 88))	('lung cancer', 'Disease', (252, 263))	('lung cancer', 'Phenotype', 'HP:0100526', (252, 263))
76144	30943926	To examine ALK expression at the C-terminus in lung cancer cells with or without ALK fusion, we used 37 lung cancer cell lines (Table 1) that harbor already-known driver mutations, including ALK fusion and wild-type, to mimic the populations of patients with lung cancer as shown in Korpanty G.J.	('lung cancer', 'Disease', (259, 270))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('patients', 'Species', '9606', (245, 253))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('mutations', 'Var', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('lung cancer', 'Disease', 'MESH:D008175', (259, 270))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
76145	30943926	Both the NCI-H2228 and SNU-2292 cell lines had EML4-ALK variant 3a, and the SNU-2535 cell line had EML4-ALK variant 1 (Additional file 5: Figure S1a and Additional file 6: Figure S2).	('EML4', 'Gene', (47, 51))	('variant', 'Var', (56, 63))	('EML4', 'Gene', (99, 103))	('SNU-2292', 'CellLine', 'CVCL:5036', (23, 31))	('EML4', 'Gene', '27436', (47, 51))	('EML4', 'Gene', '27436', (99, 103))	('EML4-ALK variant 1', 'Gene', '27436', (99, 117))	('SNU-2535', 'CellLine', 'CVCL:R756', (76, 84))	('EML4-ALK variant 1', 'Gene', (99, 117))
76149	30943926	Next, we tested four lung cancer tissue specimens harboring ALK fusion, EGFR mutation, KRAS mutation, or none (Table 2).	('ALK', 'Gene', (60, 63))	('mutation', 'Var', (77, 85))	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('EGFR', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('KRAS', 'Disease', (87, 91))	('tested', 'Reg', (9, 15))
76150	30943926	ILS31007 had EML4-ALK variant 3a, and markedly expressed mRNA, protein, and phosphorylation of C-terminal ALK compared with the other three ALK fusion-negative tissue specimens (Fig.	('ILS31007', 'Var', (0, 8))	('EML4', 'Gene', (13, 17))	('variant 3a', 'Var', (22, 32))	('EML4', 'Gene', '27436', (13, 17))	('expressed', 'PosReg', (47, 56))	('mRNA', 'MPA', (57, 61))	('phosphorylation', 'MPA', (76, 91))	('protein', 'MPA', (63, 70))
76162	30943926	ROS1 is rearranged with genes such as SCL34A2 or CD73 in approximately 1% of lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rearranged', 'Var', (8, 18))	('SCL34A2', 'Gene', (38, 45))	('ROS1', 'Gene', (0, 4))	('CD73', 'Gene', '4907', (49, 53))	('lung cancers', 'Disease', 'MESH:D008175', (77, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (77, 89))	('ROS1', 'Gene', '6098', (0, 4))	('CD73', 'Gene', (49, 53))	('lung cancers', 'Disease', (77, 89))
76166	30943926	In HCC78 cells, the mRNA level of the C-terminal ROS1 region, which is backward from the breakpoint at exon 32 or 34 in ROS1 rearrangement, was elevated by at least 2000-fold more than the median of all 37 cell lines, and high protein expression at the C-terminus was detected (Figs.	('ROS1', 'Gene', (120, 124))	('ROS1', 'Gene', '6098', (120, 124))	('ROS1', 'Gene', (49, 53))	('rearrangement', 'Var', (125, 138))	('HCC78', 'CellLine', 'CVCL:2061', (3, 8))	('elevated', 'PosReg', (144, 152))	('ROS1', 'Gene', '6098', (49, 53))	('mRNA level', 'MPA', (20, 30))
76174	30943926	We found that the promoter of EML4 was constitutively activated in lung cancer as well as normal cells independent of ALK fusion, and C-terminal ALK protein level and phosphorylation were specifically elevated in ALK fusion-positive cancer cells (Figs.	('cancer', 'Disease', (72, 78))	('elevated', 'PosReg', (201, 209))	('activated', 'PosReg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('EML4', 'Gene', (30, 34))	('phosphorylation', 'MPA', (167, 182))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('EML4', 'Gene', '27436', (30, 34))	('ALK fusion-positive', 'Var', (213, 232))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('C-terminal ALK protein level', 'MPA', (134, 162))
76186	30943926	However, in this study, the ROS1 fusion-positive cell line, HCC78, harboring an SLC34A2-ROS1 fusion only showed protein expression at the C-terminal domain and a sensitivity to the ROS1-TKIs by inhibiting ROS1 signaling pathways involving STAT3/AKT/ERK (Figs.	('STAT3', 'Gene', '6774', (239, 244))	('AKT', 'Gene', (245, 248))	('ROS1', 'Gene', '6098', (28, 32))	('ROS1', 'Gene', (205, 209))	('fusion', 'Var', (93, 99))	('inhibiting', 'NegReg', (194, 204))	('SLC34A2', 'Gene', '10568', (80, 87))	('ROS1', 'Gene', (181, 185))	('HCC78', 'CellLine', 'CVCL:2061', (60, 65))	('ERK', 'Gene', (249, 252))	('SLC34A2', 'Gene', (80, 87))	('ROS1', 'Gene', '6098', (88, 92))	('AKT', 'Gene', '207', (245, 248))	('ROS1', 'Gene', (28, 32))	('ERK', 'Gene', '2048', (249, 252))	('ROS1', 'Gene', '6098', (205, 209))	('ROS1', 'Gene', '6098', (181, 185))	('STAT3', 'Gene', (239, 244))	('ROS1', 'Gene', (88, 92))
76189	30943926	Therefore, the C-terminal ROS1 protein level could only be elevated by the strong promoter activity of genes such as SLC34A2 or CD74 in ROS1 fusion-positive lung cancer cells, which suggests that the ROS1 IHC test is a reliable diagnostic test for the detection of patients with lung cancer who have ROS1 fusion.	('ROS1', 'Gene', (26, 30))	('ROS1', 'Gene', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('elevated', 'PosReg', (59, 67))	('lung cancer', 'Disease', 'MESH:D008175', (279, 290))	('fusion', 'Var', (305, 311))	('lung cancer', 'Disease', (157, 168))	('promoter activity', 'MPA', (82, 99))	('CD74', 'Gene', (128, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (279, 290))	('ROS1', 'Gene', (300, 304))	('patients', 'Species', '9606', (265, 273))	('ROS1', 'Gene', '6098', (200, 204))	('SLC34A2', 'Gene', '10568', (117, 124))	('ROS1', 'Gene', '6098', (26, 30))	('ROS1', 'Gene', '6098', (136, 140))	('SLC34A2', 'Gene', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('lung cancer', 'Disease', (279, 290))	('CD74', 'Gene', '972', (128, 132))	('ROS1', 'Gene', '6098', (300, 304))	('ROS1', 'Gene', (200, 204))
76193	30943926	Hyper-methylation of promoter and copy number gain of ROS1 were reported as one of the mechanisms that activate ROS1 expression in fusion-negative carcinomas.	('carcinomas', 'Disease', 'MESH:D002277', (147, 157))	('ROS1', 'Gene', (112, 116))	('ROS1', 'Gene', '6098', (54, 58))	('carcinomas', 'Disease', (147, 157))	('ROS1', 'Gene', '6098', (112, 116))	('Hyper-methylation', 'Var', (0, 17))	('expression', 'MPA', (117, 127))	('copy number', 'Var', (34, 45))	('activate', 'PosReg', (103, 111))	('gain', 'PosReg', (46, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('ROS1', 'Gene', (54, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
76197	30943926	For NSCLC, NGS-based tumor-profiling multiplex gene panels, such as Oncomine Dx target test or FoundationOne CDx, have recently been approved as companion diagnostics to detect mutations of EGFR and BRAF, or fusions of ALK and ROS1 in the US.	('Oncomine Dx', 'Chemical', '-', (68, 79))	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('tumor', 'Disease', (21, 26))	('fusions', 'Var', (208, 215))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('ALK', 'Gene', (219, 222))	('ROS1', 'Gene', (227, 231))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('EGFR', 'Gene', (190, 194))	('BRAF', 'Gene', (199, 203))	('CDx', 'Chemical', '-', (109, 112))	('ROS1', 'Gene', '6098', (227, 231))	('BRAF', 'Gene', '673', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('NSCLC', 'Disease', (4, 9))
76199	30943926	However, evaluations of the usability of diagnosis by NGS compared to IHC or FISH in NSCLC specimens showed that NGS screenings could provide an alternative method of detecting fusion genes to IHC or FISH tests.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('fusion genes', 'Var', (177, 189))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))
76200	30943926	Therefore, further studies of NGS in addition to C-terminal protein expression analysis using NSCLC cell lines would be a strong support to precise selection of NSCLC patients with fusion genes by NGS with or without IHC.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('fusion genes', 'Var', (181, 193))	('patients', 'Species', '9606', (167, 175))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('NSCLC', 'Disease', (161, 166))
76232	29971180	Supporting this theory, similar genetic abnormalities were described in both MH and UESL and especially chromosome 19 aberrations.	('chromosome', 'Var', (104, 114))	('aberrations', 'Var', (118, 129))	('genetic abnormalities', 'Disease', 'MESH:D030342', (32, 53))	('genetic abnormalities', 'Disease', (32, 53))
76233	29971180	TP53 mutations were identified in UESL, suggesting a role in the malignant transformation of the lesion.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
76312	27182479	Postoperative RT improves local control in patients with marginal excisions and in those with residual tumor cells after re-excision.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('patients', 'Species', '9606', (43, 51))	('marginal', 'Var', (57, 65))	('tumor', 'Disease', (103, 108))	('improves', 'PosReg', (17, 25))	('local control', 'CPA', (26, 39))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
76334	27182479	The lack of efficacy might be influenced by the inclusion of patients with non-extremity sarcomas (33%), low- and intermediate-grade tumors (55%), and of tumors smaller than 10 cm (63%), as well as by the low dose of ifosfamide.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('ifosfamide', 'Chemical', 'MESH:D007069', (217, 227))	('tumors', 'Disease', (133, 139))	('non-extremity sarcomas', 'Disease', 'MESH:D012509', (75, 97))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('patients', 'Species', '9606', (61, 69))	('non-extremity sarcomas', 'Disease', (75, 97))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('low-', 'Var', (105, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
76428	27182479	The objective response rate was 6% for pazopanib versus 0% for placebo, with 67% stable diseases in the pazopanib arm versus 38% in the placebo arm.	('pazopanib', 'Var', (104, 113))	('pazopanib', 'Chemical', 'MESH:C516667', (104, 113))	('stable diseases', 'Disease', (81, 96))	('pazopanib', 'Chemical', 'MESH:C516667', (39, 48))
76442	27182479	The median PFS of leimyosarcoma patients was 4 months with regorafenib versus 1.9 months with the placebo (HR = 0.49; 95% CI 0.27-0.89; P = 0.017) and 4.6 months versus 1.0 month with regorafenib and placebo, respectively (HR = 0.38; 95% CI 0.20-0.74; P = 0.002) in other types of STS.	('patients', 'Species', '9606', (32, 40))	('leimyosarcoma', 'Disease', (18, 31))	('regorafenib', 'Chemical', 'MESH:C559147', (59, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('leimyosarcoma', 'Disease', 'None', (18, 31))	('regorafenib', 'Var', (59, 70))	('regorafenib', 'Chemical', 'MESH:C559147', (184, 195))
76446	27182479	The PFS was improved with 52% gain in median PFS (22.4 weeks for ridaforolimus versus 14.7 weeks for placebo; HR = 0.72; P < 0.001).	('PFS', 'Disease', (4, 7))	('ridaforolimus', 'Var', (65, 78))	('PFS', 'MPA', (45, 48))	('ridaforolimus', 'Chemical', 'MESH:C515074', (65, 78))	('gain', 'PosReg', (30, 34))
76448	27182479	Sirolimus, another mTOR inhibitor, has resulted in significant clinical activity in patients with malignant perivascular epithelioid cell tumors (PEComa) through a mechanism involving the mTOR1 pathway, pathologically activated by loss of TSC1/TSC2 tumor suppressor complex in PEComa.	('Sirolimus', 'Chemical', 'MESH:D020123', (0, 9))	('mTOR', 'Gene', (19, 23))	('epithelioid cell tumors', 'Disease', (121, 144))	('patients', 'Species', '9606', (84, 92))	('PEComa', 'Disease', 'MESH:D054973', (146, 152))	('mTOR', 'Gene', '2475', (19, 23))	('epithelioid cell tumors', 'Disease', 'MESH:D054973', (121, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('PEComa', 'Disease', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('PEComa', 'Disease', 'MESH:D054973', (277, 283))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mTOR', 'Gene', (188, 192))	('TSC1/TSC2 tumor', 'Disease', (239, 254))	('TSC1/TSC2 tumor', 'Disease', 'MESH:C565346', (239, 254))	('PEComa', 'Disease', (277, 283))	('clinical activity', 'MPA', (63, 80))	('loss', 'Var', (231, 235))	('mTOR', 'Gene', '2475', (188, 192))
76458	25869102	ES as a malignant entity is genetically characterized by chromosomal translocation involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene.	('chromosomal translocation', 'Var', (57, 82))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (97, 130))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (97, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('EWSR1', 'Gene', (132, 137))	('Ewing sarcoma breakpoint region 1', 'Gene', (97, 130))	('EWSR1', 'Gene', '2130', (132, 137))
76459	25869102	Translocation of EWSR1 on chromosome 22 to chromosome 11 occurs in 85% of ES cases, forming the fusion protein product EWS-FLI1.	('Translocation', 'Var', (0, 13))	('EWS-FLI1', 'Gene', (119, 127))	('EWSR1', 'Gene', '2130', (17, 22))	('EWS-FLI1', 'Gene', '2130;2313', (119, 127))	('ES', 'Phenotype', 'HP:0012254', (74, 76))	('EWSR1', 'Gene', (17, 22))
76461	25869102	The EWSR1 breakpoint appears to be a hot spot for genetic translocations and can promiscuously bind other C-terminal genes in other sarcoma subtypes such as clear cell sarcoma, extraskeletal myxoid chondrosarcoma and others.	('clear cell sarcoma', 'Disease', 'MESH:D018227', (157, 175))	('genetic', 'Var', (50, 57))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (198, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('EWSR1', 'Gene', '2130', (4, 9))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('sarcoma', 'Disease', (132, 139))	('EWSR1', 'Gene', (4, 9))	('sarcoma', 'Disease', (205, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('extraskeletal myxoid chondrosarcoma', 'Disease', (177, 212))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (177, 212))	('clear cell sarcoma', 'Disease', (157, 175))	('sarcoma', 'Disease', (168, 175))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
76480	25869102	These antibodies include human-like IgG1 antibodies AMG 479 , R1507  and cixutumumab  as well as the human-like IgG2 antibody figitumumab .	('cixutumumab', 'Chemical', 'MESH:C557414', (73, 84))	('figitumumab', 'Chemical', 'MESH:C525021', (126, 137))	('AMG', 'Gene', (52, 55))	('R1507', 'Var', (62, 67))	('AMG', 'Gene', '265', (52, 55))	('IgG1', 'Protein', (36, 40))	('human', 'Species', '9606', (25, 30))	('human', 'Species', '9606', (101, 106))
76481	25869102	In a phase I trial using R1507, two (22.2%) of nine ES patients achieved partial responses (PR), and one (11.1%) patient had stable disease (SD) for more than 6 months and no dose-limiting toxicities were identified .	('patient', 'Species', '9606', (113, 120))	('toxicities', 'Disease', (189, 199))	('SD', 'Disease', 'MESH:D029461', (141, 143))	('R1507', 'Var', (25, 30))	('toxicities', 'Disease', 'MESH:D064420', (189, 199))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (55, 63))	('ES', 'Phenotype', 'HP:0012254', (52, 54))	('partial responses', 'MPA', (73, 90))
76491	25869102	In addition, BMS-754807, a reversible ATP-competitive antagonist of the IGF-1R kinase domain demonstrated moderate growth inhibition in in vitro and in vivo ES models.	('rat', 'Species', '10116', (110, 113))	('growth inhibition', 'CPA', (115, 132))	('IGF-1R', 'Gene', (72, 78))	('ATP', 'Chemical', 'MESH:D000255', (38, 41))	('IGF-1R', 'Gene', '3480', (72, 78))	('ES', 'Phenotype', 'HP:0012254', (157, 159))	('rat', 'Species', '10116', (100, 103))	('BMS-754807', 'Var', (13, 23))
76492	25869102	Another small molecule IGF-1R inhibitor, ADW742, has been shown to induce dose-dependent G1 phase blockade and apoptosis in ES cell lines, which demonstrated synergy with the KIT/PDFGR and BCR-ABL tyrosine kinase inhibitor imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (223, 231))	('ES', 'Phenotype', 'HP:0012254', (124, 126))	('G1 phase blockade', 'CPA', (89, 106))	('inhibitor', 'Var', (30, 39))	('rat', 'Species', '10116', (152, 155))	('CR', 'Chemical', '-', (190, 192))	('IGF-1R', 'Gene', '3480', (23, 29))	('IGF-1R', 'Gene', (23, 29))	('ADW742', 'Chemical', 'MESH:C531185', (41, 47))	('apoptosis', 'CPA', (111, 120))	('ADW742', 'Var', (41, 47))
76501	25869102	Genetic and epigenetic aberrations of the PI3K/AKT/mTOR pathway play a critical role in tumorigenesis and cancer progression for many cancer types, and ES is no exception (Figure 1) .	('mTOR', 'Gene', (51, 55))	('AKT', 'Gene', (47, 50))	('mTOR', 'Gene', '2475', (51, 55))	('epigenetic aberrations', 'Var', (12, 34))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('ES', 'Phenotype', 'HP:0012254', (152, 154))	('cancer', 'Disease', (134, 140))	('AKT', 'Gene', '207', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('rat', 'Species', '10116', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
76507	25869102	Inhibitors of mTOR have been shown more effective in combinations such as with IGF-1R than as single agents by our institution and others.	('mTOR', 'Gene', '2475', (14, 18))	('Inhibitors', 'Var', (0, 10))	('combinations', 'Interaction', (53, 65))	('IGF-1R', 'Gene', (79, 85))	('mTOR', 'Gene', (14, 18))	('IGF-1R', 'Gene', '3480', (79, 85))
76508	25869102	mTOR inhibition releases the inhibitory feedback loop on the insulin receptor substrate 1 (IRS-1) and, therefore, upregulates PI3K and Akt in an IGF-1/IGF-1R dependent manner .	('upregulates', 'PosReg', (114, 125))	('inhibition', 'Var', (5, 15))	('Akt', 'Gene', (135, 138))	('insulin receptor substrate 1', 'Gene', '3667', (61, 89))	('IGF-1', 'Gene', '3479', (151, 156))	('Akt', 'Gene', '207', (135, 138))	('PI3K', 'Pathway', (126, 130))	('IRS-1', 'Gene', (91, 96))	('IGF-1R', 'Gene', '3480', (151, 157))	('IGF-1', 'Gene', (145, 150))	('IGF-1R', 'Gene', (151, 157))	('mTOR', 'Gene', (0, 4))	('inhibitory feedback loop', 'MPA', (29, 53))	('mTOR', 'Gene', '2475', (0, 4))	('IGF-1', 'Gene', '3479', (145, 150))	('IRS-1', 'Gene', '3667', (91, 96))	('insulin receptor substrate 1', 'Gene', (61, 89))	('releases', 'PosReg', (16, 24))	('IGF-1', 'Gene', (151, 156))
76513	25869102	Interestingly, one of two patients with the CR had a history of a previous PR when treated with the single-agent IGF-1R antibody R1507 alone, which lasted for nearly 30 months.	('IGF-1R', 'Gene', '3480', (113, 119))	('patients', 'Species', '9606', (26, 34))	('IGF-1R', 'Gene', (113, 119))	('CR', 'Chemical', '-', (44, 46))	('R1507', 'Var', (129, 134))
76519	25869102	In communication with Pharma, one explanation is their concern that IGF-1R inhibitors would not receive FDA approval as a single-agent activity and, therefore, would not be allowed conditional approval in combination with mTOR inhibitors or other agents (personal communication).	('inhibitors', 'Var', (75, 85))	('mTOR', 'Gene', '2475', (222, 226))	('IGF-1R', 'Gene', '3480', (68, 74))	('mTOR', 'Gene', (222, 226))	('IGF-1R', 'Gene', (68, 74))
76528	25869102	In another phase II clinical trial, immunohistochemical evidence of expression >=2+/4+ for either KIT or PDGFRalpha was, in fact, applied as one of the required criteria for patient enrollment.	('patient', 'Species', '9606', (174, 181))	('>=2+/4+', 'Var', (79, 86))	('PDGFRalpha', 'Gene', '5156', (105, 115))	('KIT', 'Gene', (98, 101))	('clinical', 'Species', '191496', (20, 28))	('PDGFRalpha', 'Gene', (105, 115))
76530	25869102	Of interest, the only patients responding to the therapy had the highest expression level of PDGFRalpha and KIT (3+/4+ PDGFRalpha and 3+/4+ KIT) .	('expression level', 'MPA', (73, 89))	('patients', 'Species', '9606', (22, 30))	('PDGFRalpha', 'Gene', '5156', (93, 103))	('KIT', 'MPA', (108, 111))	('PDGFRalpha', 'Gene', (93, 103))	('3+/4+ KIT', 'Var', (134, 143))	('PDGFRalpha', 'Gene', '5156', (119, 129))	('PDGFRalpha', 'Gene', (119, 129))
76536	25869102	Somatic EGFR mutations, which are associated with a salutary response to EGFR inhibitors in non-small cell lung cancer patients, have not been reported in ES.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (92, 118))	('EGFR', 'Gene', '1956', (73, 77))	('ES', 'Phenotype', 'HP:0012254', (155, 157))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('EGFR', 'Gene', (73, 77))	('non-small cell lung cancer', 'Disease', (92, 118))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', (8, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('mutations', 'Var', (13, 22))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))
76546	25869102	One interesting study to date does, however, suggest that specific VEGF germline single nucleotide polymorphisms (VEGF-2578 AA and VEGF-1154 AA) were associated with superior median OS in breast cancer patients treated with a bevacizumab containing therapy, whereas other genotypes (VEGF-634 CC and VEGF-1498 TT) were associated with significantly fewer side effects such as hypertension.	('VEGF', 'Gene', '7422', (283, 287))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('median OS', 'CPA', (175, 184))	('VEGF', 'Gene', (283, 287))	('VEGF', 'Gene', '7422', (131, 135))	('single nucleotide', 'Var', (81, 98))	('VEGF', 'Gene', '7422', (67, 71))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Disease', (188, 201))	('VEGF', 'Gene', (131, 135))	('VEGF', 'Gene', (67, 71))	('patients', 'Species', '9606', (202, 210))	('bevacizumab', 'Chemical', 'MESH:D000068258', (226, 237))	('hypertension', 'Disease', 'MESH:D006973', (375, 387))	('VEGF', 'Gene', '7422', (114, 118))	('hypertension', 'Disease', (375, 387))	('VEGF', 'Gene', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('hypertension', 'Phenotype', 'HP:0000822', (375, 387))	('superior', 'PosReg', (166, 174))	('VEGF', 'Gene', '7422', (299, 303))	('VEGF', 'Gene', (299, 303))
76548	25869102	A study in patients with locally advanced rectal cancer showed that individuals with high concentrations of plasma VEGFR1 did not benefit as much from a bevacizumab-based therapy as patients with lower concentrations .	('rat', 'Species', '10116', (97, 100))	('bevacizumab', 'Chemical', 'MESH:D000068258', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('VEGFR1', 'Gene', '2321', (115, 121))	('high concentrations', 'Var', (85, 104))	('rat', 'Species', '10116', (209, 212))	('VEGFR1', 'Gene', (115, 121))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('rectal cancer', 'Phenotype', 'HP:0100743', (42, 55))	('patients', 'Species', '9606', (11, 19))	('cancer', 'Disease', (49, 55))
76549	25869102	In addition to VEGF polymorphisms and VEGFR1 levels, some VEGFR mutations also contribute to drug response.	('VEGFR1', 'Gene', '2321', (38, 44))	('VEGF', 'Gene', (58, 62))	('VEGFR', 'Gene', '3791', (38, 43))	('VEGFR1', 'Gene', (38, 44))	('VEGF', 'Gene', '7422', (38, 42))	('VEGFR', 'Gene', '3791', (58, 63))	('VEGF', 'Gene', (15, 19))	('contribute', 'Reg', (79, 89))	('VEGF', 'Gene', '7422', (58, 62))	('VEGFR', 'Gene', (38, 43))	('VEGFR', 'Gene', (58, 63))	('mutations', 'Var', (64, 73))	('VEGF', 'Gene', '7422', (15, 19))	('VEGF', 'Gene', (38, 42))	('drug response', 'MPA', (93, 106))
76550	25869102	For example, a VEGFR1 Y1053D mutation was found to be associated with sorafenib resistance.	('Y1053D', 'Var', (22, 28))	('sorafenib', 'Chemical', 'MESH:D000077157', (70, 79))	('Y1053D', 'Mutation', 'p.Y1053D', (22, 28))	('VEGFR1', 'Gene', '2321', (15, 21))	('associated with', 'Reg', (54, 69))	('sorafenib', 'Disease', (70, 79))	('VEGFR1', 'Gene', (15, 21))
76551	25869102	Taken together, VEGF polymorphism, VEGFR1 level and VEGFR somatic mutations can be further investigated as promising biomarkers for drug response in therapies targeting VEGF/VEGFR signaling.	('VEGFR', 'Gene', '3791', (174, 179))	('VEGF', 'Gene', '7422', (52, 56))	('VEGFR', 'Gene', (174, 179))	('VEGF', 'Gene', (52, 56))	('VEGFR', 'Gene', '3791', (52, 57))	('VEGF', 'Gene', '7422', (35, 39))	('VEGF', 'Gene', '7422', (169, 173))	('VEGFR', 'Gene', (52, 57))	('VEGF', 'Gene', (35, 39))	('VEGF', 'Gene', (169, 173))	('VEGFR', 'Gene', '3791', (35, 40))	('VEGFR', 'Gene', (35, 40))	('VEGF', 'Gene', '7422', (16, 20))	('VEGF', 'Gene', '7422', (174, 178))	('VEGFR1', 'Gene', '2321', (35, 41))	('VEGFR1', 'Gene', (35, 41))	('VEGF', 'Gene', (16, 20))	('VEGF', 'Gene', (174, 178))	('polymorphism', 'Var', (21, 33))
76563	25869102	Other than the FLI1 ETS gene, YK-4-279 also inhibited ERG and ETV1 in ETS-expressing prostate cancer, likely through inhibiting RHA .	('inhibited', 'NegReg', (44, 53))	('ETV1', 'Gene', (62, 66))	('RHA', 'Gene', (128, 131))	('YK-4-279', 'Var', (30, 38))	('FLI1', 'Gene', (15, 19))	('ETS-expressing', 'Disease', (70, 84))	('prostate cancer', 'Disease', (85, 100))	('inhibiting', 'NegReg', (117, 127))	('FLI1', 'Gene', '2313', (15, 19))	('ETV1', 'Gene', '2115', (62, 66))	('ERG', 'Gene', '2078', (54, 57))	('RHA', 'Gene', '1660', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('ERG', 'Gene', (54, 57))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))
76565	25869102	Our experience using an oral formulation of YK-4-279 in mouse xenografts bearing ES explants demonstrated significant clinical activity and early phase clinical trials using YK-4-279 or a close analog are in the concept stage (personal communication).	('clinical activity', 'MPA', (118, 135))	('clinical', 'Species', '191496', (118, 126))	('clinical', 'Species', '191496', (152, 160))	('YK-4-279', 'Var', (174, 182))	('mouse', 'Species', '10090', (56, 61))	('ES', 'Phenotype', 'HP:0012254', (81, 83))	('rat', 'Species', '10116', (100, 103))
76569	25869102	Preclinical testing using an aurora kinase A inhibitor MLN8237 showed maintained CRs in pediatric cancer xenograft models including ES.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ES', 'Phenotype', 'HP:0012254', (132, 134))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('CRs', 'Chemical', 'MESH:D002857', (81, 84))	('cancer', 'Disease', (98, 104))	('MLN8237', 'Chemical', 'MESH:C550258', (55, 62))	('CRs', 'CPA', (81, 84))	('aurora kinase A', 'Gene', '6790', (29, 44))	('clinical', 'Species', '191496', (3, 11))	('MLN8237', 'Var', (55, 62))	('aurora kinase A', 'Gene', (29, 44))
76570	25869102	MLN8237 is currently being evaluated in an ongoing phase II trial sponsored by the Children's Oncology Group for young patients with recurrent or refractory solid tumours or leukemia and results are expected soon (Table 3) .	('Oncology', 'Phenotype', 'HP:0002664', (94, 102))	('leukemia', 'Disease', (174, 182))	('leukemia', 'Phenotype', 'HP:0001909', (174, 182))	('leukemia', 'Disease', 'MESH:D007938', (174, 182))	('Children', 'Species', '9606', (83, 91))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('patients', 'Species', '9606', (119, 127))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('MLN8237', 'Var', (0, 7))	('refractory solid tumours', 'Disease', (146, 170))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('refractory solid tumours', 'Disease', 'MESH:D064129', (146, 170))
76586	25869102	In addition to the indirect targeting against ES fusion targets, a preclinical study also found that PARP inhibitors could reduce the viability of human cells depleted for cohesin complexes.	('PARP', 'Gene', '142', (101, 105))	('human', 'Species', '9606', (147, 152))	('clinical', 'Species', '191496', (70, 78))	('reduce', 'NegReg', (123, 129))	('ES', 'Phenotype', 'HP:0012254', (46, 48))	('inhibitors', 'Var', (106, 116))	('PARP', 'Gene', (101, 105))	('cohesin complexes', 'Protein', (172, 189))	('viability', 'CPA', (134, 143))
76588	25869102	Mutation in STAG2 can lead to the truncation of SA2, which causes the structural disruption of the cohesin complex, resulting in chromosomal instability and aneuploidy .	('chromosomal', 'MPA', (129, 140))	('lead to', 'Reg', (22, 29))	('SA2', 'Gene', (48, 51))	('resulting in', 'Reg', (116, 128))	('chromosomal instability', 'Phenotype', 'HP:0040012', (129, 152))	('aneuploidy', 'Disease', 'MESH:D000782', (157, 167))	('Mutation', 'Var', (0, 8))	('truncation', 'MPA', (34, 44))	('STAG2', 'Gene', (12, 17))	('STAG2', 'Gene', '10735', (12, 17))	('causes', 'Reg', (59, 65))	('structural disruption', 'MPA', (70, 91))	('SA2', 'Gene', '10735', (48, 51))	('aneuploidy', 'Disease', (157, 167))
76589	25869102	Because STAG2 mutation is frequently observed in ES tumours, targeting the cohesin complex using PARP inhibitors may benefit this population of ES patients.	('PARP', 'Gene', '142', (97, 101))	('ES', 'Phenotype', 'HP:0012254', (49, 51))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('STAG2', 'Gene', (8, 13))	('STAG2', 'Gene', '10735', (8, 13))	('mutation', 'Var', (14, 22))	('patients', 'Species', '9606', (147, 155))	('PARP', 'Gene', (97, 101))	('ES tumours', 'Disease', 'MESH:C563168', (49, 59))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('ES tumours', 'Disease', (49, 59))	('ES', 'Phenotype', 'HP:0012254', (144, 146))
76598	25869102	Studies have suggested that CD99 inhibits neural differentiation of ES cell lines through the MAPK pathway, contributing to cell proliferation and tumour growth.	('tumour growth', 'Disease', (147, 160))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('MAPK pathway', 'Pathway', (94, 106))	('tumour growth', 'Disease', 'MESH:D006130', (147, 160))	('contributing', 'Reg', (108, 120))	('CD99', 'Var', (28, 32))	('rat', 'Species', '10116', (136, 139))	('cell proliferation', 'CPA', (124, 142))	('neural differentiation', 'CPA', (42, 64))	('inhibits', 'NegReg', (33, 41))	('ES', 'Phenotype', 'HP:0012254', (68, 70))
76615	25869102	Protein tyrosine phosphatase receptor type D (PTPRD) regulates STAT3 through dephosphorylating Y705.	('dephosphorylating', 'MPA', (77, 94))	('Protein tyrosine phosphatase receptor type D', 'Gene', '5789', (0, 44))	('Protein tyrosine phosphatase receptor type D', 'Gene', (0, 44))	('Y705', 'Var', (95, 99))	('STAT3', 'Gene', '6774', (63, 68))	('PTPRD', 'Gene', '5789', (46, 51))	('PTPRD', 'Gene', (46, 51))	('STAT3', 'Gene', (63, 68))
76616	25869102	A PTPRD mutation W775 stop was identified in a patient with ES .	('PTPRD', 'Gene', (2, 7))	('patient', 'Species', '9606', (47, 54))	('W775 stop', 'Var', (17, 26))	('ES', 'Phenotype', 'HP:0012254', (60, 62))	('W775 stop', 'Mutation', 'rs747543296', (17, 26))	('PTPRD', 'Gene', '5789', (2, 7))
76617	25869102	This mutation results in a truncated PTPRD protein, causing accumulation of phosphorylated STAT3, which likely explains the enhanced level of activated STAT3 found in some of the ES samples.	('STAT3', 'Gene', '6774', (152, 157))	('ES', 'Phenotype', 'HP:0012254', (179, 181))	('results in', 'Reg', (14, 24))	('STAT3', 'Gene', (152, 157))	('enhanced', 'PosReg', (124, 132))	('STAT3', 'Gene', '6774', (91, 96))	('mutation', 'Var', (5, 13))	('truncated', 'MPA', (27, 36))	('STAT3', 'Gene', (91, 96))	('PTPRD', 'Gene', '5789', (37, 42))	('accumulation', 'PosReg', (60, 72))	('PTPRD', 'Gene', (37, 42))	('protein', 'Protein', (43, 50))
76624	25869102	There is anecdotal evidence from early phase clinical trials in ESFT that resistance to IGF1R and mTOR targeting therapies can be mediated through KRAS mutation and MAPK pathway activation.	('IGF1R', 'Gene', (88, 93))	('IGF1R', 'Gene', '3480', (88, 93))	('activation', 'PosReg', (178, 188))	('KRAS', 'Protein', (147, 151))	('mTOR', 'Gene', '2475', (98, 102))	('mTOR', 'Gene', (98, 102))	('ES', 'Phenotype', 'HP:0012254', (64, 66))	('MAPK pathway', 'Pathway', (165, 177))	('mutation', 'Var', (152, 160))	('clinical', 'Species', '191496', (45, 53))
76625	25869102	In addition, an NRAS mutation, which activates the MAPK pathway, has been anecdotally reported in patients with ES and the biological implication remains unclear.	('MAPK pathway', 'Pathway', (51, 63))	('NRAS', 'Gene', (16, 20))	('patients', 'Species', '9606', (98, 106))	('mutation', 'Var', (21, 29))	('activates', 'PosReg', (37, 46))	('NRAS', 'Gene', '4893', (16, 20))	('ES', 'Phenotype', 'HP:0012254', (112, 114))
76638	25869102	Our institutional experience from several advanced cancers suggests that therapies matching underlying actionable somatic mutations can improve outcomes compared to unmatched therapies.	('improve', 'PosReg', (136, 143))	('outcomes', 'MPA', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (122, 131))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
76640	25869102	Recently published studies utilizing next-generation sequencing technologies have shown that significant fraction of ES patients have recurrent genetic mutations other than EWSR1-ETS fusion gene product, particularly STAG2 mutations, which may lead to chromosomal structural defect and aneuploidy .	('ES', 'Phenotype', 'HP:0012254', (117, 119))	('STAG2', 'Gene', (217, 222))	('STAG2', 'Gene', '10735', (217, 222))	('mutations', 'Var', (152, 161))	('rat', 'Species', '10116', (46, 49))	('EWSR1', 'Gene', '2130', (173, 178))	('EWSR1', 'Gene', (173, 178))	('lead to', 'Reg', (244, 251))	('patients', 'Species', '9606', (120, 128))	('mutations', 'Var', (223, 232))	('chromosomal structural defect and aneuploidy', 'Disease', 'MESH:D000782', (252, 296))
76642	25869102	First, cancer stem cells are capable of proliferate and generate tumor cells with new sets of mutations which may harbor different protein targets .	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Disease', (65, 70))	('mutations', 'Var', (94, 103))	('rat', 'Species', '10116', (60, 63))	('rat', 'Species', '10116', (47, 50))	('proliferate', 'CPA', (40, 51))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
76684	24829745	Treatment was well tolerated with minimal side effects including a grade 1 nausea, grade 2 alkaline phosphatase (437 IU/L) and grade 3 neutropenia (800/mL).	('nausea', 'Disease', (75, 81))	('nausea', 'Disease', 'MESH:D009325', (75, 81))	('neutropenia', 'Phenotype', 'HP:0001875', (135, 146))	('437 IU/L', 'Var', (113, 121))	('neutropenia', 'Disease', (135, 146))	('alkaline phosphatase', 'MPA', (91, 111))	('neutropenia', 'Disease', 'MESH:D009503', (135, 146))	('nausea', 'Phenotype', 'HP:0002018', (75, 81))
76714	24711713	It assumes that several cancer stem cell (CSC) populations with genetic and epigenetic changes coexist.	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('epigenetic changes', 'Var', (76, 94))
76729	24711713	In addition, anti-LGR5 antibody-mediated modulation of the Wnt reporter suggests a direct role of the R-spondin-LGR5 complex in Wnt pathway regulation, rather than indirectly via a tertiary protein complex together with LRPs or frizzled receptors.	('rat', 'Species', '10116', (152, 155))	('LRP', 'Gene', (220, 223))	('anti-LGR5', 'Var', (13, 22))	('LRP', 'Gene', '16971', (220, 223))	('modulation', 'Reg', (41, 51))	('Wnt pathway', 'Pathway', (128, 139))	('regulation', 'MPA', (140, 150))	('R-spondin', 'Gene', '192199', (102, 111))	('R-spondin', 'Gene', (102, 111))
76734	24711713	Notably, it has recently been reported that a c.376C<T nonsense mutation of human LGR4 results in termination at position 126.	('human', 'Species', '9606', (76, 81))	('c.376C<T', 'Mutation', 'rs587777005', (46, 54))	('LGR4', 'Gene', (82, 86))	('c.376C<T', 'Var', (46, 54))
76741	24711713	293T) cells, LGR5 could compensate for the loss of Wnt signal activities caused by LGR4 knockdown.	('Wnt signal activities', 'MPA', (51, 72))	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('LGR4', 'Gene', (83, 87))	('knockdown', 'Var', (88, 97))
76748	24711713	A decade ago, one of the pioneering studies on LGR5 in cancer reported the overexpression of LGR5 in hepatocellular carcinomas, pointing out the correlation with beta-catenin mutations causing aberrant activation of the canonical Wnt pathway.	('overexpression', 'PosReg', (75, 89))	('beta-catenin', 'Gene', (162, 174))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (101, 126))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('canonical Wnt pathway', 'Pathway', (220, 241))	('hepatocellular carcinomas', 'Disease', (101, 126))	('mutations', 'Var', (175, 184))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (101, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('activation', 'PosReg', (202, 212))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('beta-catenin', 'Gene', '12387', (162, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('LGR5', 'Gene', (93, 97))	('cancer', 'Disease', (55, 61))
76756	24711713	Indeed, specific deletion of the adenomatous polyposis coli gene, known to initiate intestinal cancer by Wnt-pathway-activating mutations, rapidly induced intestinal adenomas in LGR5+ve stem cells, but could not maintain adenomas when introduced to transit amplifying cells.	('intestinal adenomas', 'Disease', 'MESH:D000236', (155, 174))	('adenomas', 'Disease', 'MESH:D000236', (221, 229))	('adenomas', 'Disease', (166, 174))	('intestinal cancer', 'Disease', 'MESH:D007414', (84, 101))	('adenomas', 'Disease', (221, 229))	('intestinal cancer', 'Disease', (84, 101))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (33, 59))	('intestinal adenomas', 'Disease', (155, 174))	('induced', 'Reg', (147, 154))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (33, 59))	('deletion', 'Var', (17, 25))	('adenomatous polyposis coli', 'Disease', (33, 59))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('adenomas', 'Disease', 'MESH:D000236', (166, 174))
76763	24711713	In addition, it was shown that promoter methylation can cause repression of LGR5 expression in some colon cancer cells.	('promoter methylation', 'Var', (31, 51))	('expression', 'MPA', (81, 91))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('colon cancer', 'Disease', 'MESH:D015179', (100, 112))	('cause', 'Reg', (56, 61))	('repression', 'NegReg', (62, 72))	('LGR5', 'Gene', (76, 80))	('colon cancer', 'Disease', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
76764	24711713	Using the lineage tracing system, it was shown that LGR5+ve cells in the bulge region of hair follicles represent the stem cell population, which could generate all cell lineages of hair follicles in vivo (but not of interfollicular epidermis and sebaceous glands) and efficiently generate hair follicles in transplanted nude mice.	('cell lineages of hair follicles', 'CPA', (165, 196))	('rat', 'Species', '10116', (156, 159))	('sebaceous glands', 'Phenotype', 'HP:0032227', (247, 263))	('LGR5+ve', 'Var', (52, 59))	('nude mice', 'Species', '10090', (321, 330))	('hair follicles', 'CPA', (290, 304))	('generate', 'PosReg', (152, 160))	('rat', 'Species', '10116', (285, 288))
76769	24711713	Another group combined LGR5-lineage tracing and a skin SCC mouse model induced by E6/E7 oncogenes from human papilloma virus 16, driven by the K14 promoter.	('mouse', 'Species', '10090', (59, 64))	('induced', 'Reg', (71, 78))	('papilloma', 'Phenotype', 'HP:0012740', (109, 118))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('skin SCC mouse', 'Disease', (50, 64))	('human papilloma virus', 'Species', '10566', (103, 124))	('E6/E7', 'Var', (82, 87))
76776	24711713	Moreover, the report demonstrated that a depletion assay of LGR5-expressing cells using the LGR5-DTR (diphtheria toxin receptor) mouse strain resulted in a significant decrease of the reconstruction potential of mammary glands, unlike in the case of intestinal stem cells.	('reconstruction potential of mammary glands', 'CPA', (184, 226))	('depletion', 'Var', (41, 50))	('decrease', 'NegReg', (168, 176))	('mouse', 'Species', '10090', (129, 134))	('rat', 'Species', '10116', (28, 31))
76781	24711713	It was shown that LGR5 knockdown reduces lung metastases, suggesting a key role of LGR5 in CSC regulation, including metastasis-initiating potentials in breast cancer.	('lung metastases', 'Disease', (41, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('knockdown', 'Var', (23, 32))	('LGR5', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('reduces', 'NegReg', (33, 40))	('lung metastases', 'Disease', 'MESH:D009362', (41, 56))	('breast cancer', 'Disease', (153, 166))
76792	24711713	In line with these observations, inhibition of LGR5 gene expression in glioblastoma stem-like cells causes cell death.	('inhibition', 'Var', (33, 43))	('LGR5', 'Gene', (47, 51))	('glioblastoma', 'Disease', (71, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('cell death', 'CPA', (107, 117))
76795	24711713	Interestingly, inhibition of LGR5 causes a decrease in PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) expression, which was recently identified as an indispensable gene for the glioblastoma stem-like cell survival.	('LGR5', 'Gene', (29, 33))	('decrease', 'NegReg', (43, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (193, 205))	('6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4', 'Gene', '270198', (63, 116))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('PFKFB4', 'Gene', '270198', (55, 61))	('glioblastoma', 'Disease', (193, 205))	('expression', 'MPA', (118, 128))	('inhibition', 'Var', (15, 25))	('PFKFB4', 'Gene', (55, 61))
76798	24711713	Another report on clinical sarcoma samples described a novel splice variant of LGR5 identified in soft tissue sarcoma, of which lower expression was shown to be associated with worse overall survival.	('sarcoma', 'Disease', (27, 34))	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcoma', 'Disease', (110, 117))	('expression', 'MPA', (134, 144))	('clinical', 'Species', '191496', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (98, 117))	('splice variant', 'Var', (61, 75))	('LGR5', 'Gene', (79, 83))	('lower', 'NegReg', (128, 133))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))
76833	22619564	Approximately 80% of aRMSs contain a stable reciprocal translocation involving either the PAX3 or PAX7 transcription factors with the FOXO1 transcription factor, resulting in a fusion gene with altered transcriptional and translational properties, while 80% of eRMSs have loss of heterozygosity in chromosome 11p15.	('PAX3', 'Gene', (90, 94))	('fusion gene', 'Var', (177, 188))	('PAX7', 'Gene', (98, 102))	('RMS', 'Phenotype', 'HP:0002859', (262, 265))	('PAX7', 'Gene', '5081', (98, 102))	('RMS', 'Phenotype', 'HP:0002859', (22, 25))	('altered', 'Reg', (194, 201))
76840	22619564	During this time, the survival rates for patients with low- and intermediate-risk disease improved significantly from a ~25% OS to the most recent studies with mature data for low-risk (IRSG IV) and intermediate-risk RMS (D9803) demonstrating a five-year FFS of 90% and four-year OS of 71%, respectively,.	('RMS', 'Phenotype', 'HP:0002859', (217, 220))	('improved', 'PosReg', (90, 98))	('patients', 'Species', '9606', (41, 49))	('survival', 'MPA', (22, 30))	('RMS (D9803', 'Var', (217, 227))
76851	22619564	These embryonic signaling pathways that are responsible for normal skeletal muscle differentiation may therefore play a critical role in RMS tumorigenesis by stabilizing muscle precursor cells and allowing more opportunities for secondary, cooperating mutations to occur, by directly inhibiting normal differentiation leading to transformation or by promoting dedifferentiation of mature muscle cells.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('inhibiting', 'NegReg', (284, 294))	('RMS', 'Phenotype', 'HP:0002859', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('normal differentiation', 'CPA', (295, 317))	('tumor', 'Disease', (141, 146))	('mutations', 'Var', (252, 261))	('dedifferentiation', 'CPA', (360, 377))	('promoting', 'PosReg', (350, 359))	('RMS', 'Disease', (137, 140))	('transformation', 'CPA', (329, 343))
76856	22619564	In the limb, this occurs between E10.5 and E12.5 in mice.	('E12.5', 'Var', (43, 48))	('E10.5', 'Var', (33, 38))	('mice', 'Species', '10090', (52, 56))
76860	22619564	Given the critical role of these pathways in myogenesis, aberrant expression, activation, or regulation of these pathways may be involved in RMS tumorigenesis and may present novel therapeutic targets in the treatment of RMS.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('RMS', 'Disease', (141, 144))	('involved', 'Reg', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('RMS', 'Phenotype', 'HP:0002859', (141, 144))	('tumor', 'Disease', (145, 150))	('activation', 'PosReg', (78, 88))	('RMS', 'Phenotype', 'HP:0002859', (221, 224))	('aberrant', 'Var', (57, 65))
76876	22619564	showed that inactivation of the Notch pathway results in inappropriate differentiation of myogenic cells and depletion of muscle progenitor cells during embryogenesis.	('Notch', 'Gene', '31293', (32, 37))	('depletion of', 'MPA', (109, 121))	('inappropriate differentiation', 'CPA', (57, 86))	('inactivation', 'Var', (12, 24))	('Notch', 'Gene', (32, 37))
76877	22619564	Similarly, in postnatal muscle repair following injury, inhibition of the Notch pathway reduces the ability of satellite cells to regenerate muscle.	('Notch', 'Gene', '31293', (74, 79))	('ability of satellite cells to regenerate muscle', 'CPA', (100, 147))	('injury', 'Disease', (48, 54))	('injury', 'Disease', 'MESH:D058186', (48, 54))	('inhibition', 'Var', (56, 66))	('reduces', 'NegReg', (88, 95))	('Notch', 'Gene', (74, 79))
76898	22619564	In regenerating muscle, activating or inhibiting the Wnt pathway early (two days) following injury did not alter myogenesis; however, activating the Wnt pathway late (four days) following injury increased myogenic differentiation.	('activating', 'Var', (134, 144))	('injury', 'Disease', 'MESH:D058186', (92, 98))	('increased', 'PosReg', (195, 204))	('injury', 'Disease', (188, 194))	('injury', 'Disease', 'MESH:D058186', (188, 194))	('inhibiting', 'NegReg', (38, 48))	('Wnt pathway', 'Pathway', (149, 160))	('myogenic differentiation', 'CPA', (205, 229))	('injury', 'Disease', (92, 98))
76919	22619564	Recent data suggests that Hedgehog signaling plays a unique role in adult myogenesis because inhibition of Shh via cyclopamine impaired the activation of Myf5 and MyoD in skeletal muscle progenitors and led to a reduction in the number of activated satellite cells and myoblasts following injury in vivo.	('activation', 'MPA', (140, 150))	('Hedgehog', 'Gene', (26, 34))	('Myf5', 'Gene', '4617', (154, 158))	('Hedgehog', 'Gene', '42737', (26, 34))	('MyoD', 'Protein', (163, 167))	('cyclopamine', 'Chemical', 'MESH:C000541', (115, 126))	('Shh', 'Gene', '6469', (107, 110))	('Myf5', 'Gene', (154, 158))	('injury', 'Disease', (289, 295))	('reduction', 'NegReg', (212, 221))	('impaired', 'NegReg', (127, 135))	('injury', 'Disease', 'MESH:D058186', (289, 295))	('inhibition', 'Var', (93, 103))	('Shh', 'Gene', (107, 110))
76926	22619564	They additionally show that in skeletal muscle precursors, aberrant activation of Notch signaling or inactivation of WNT signaling prevents myogenic lineage progression.	('Notch', 'Gene', (82, 87))	('Notch', 'Gene', '31293', (82, 87))	('aberrant activation', 'Var', (59, 78))	('inactivation', 'NegReg', (101, 113))	('WNT', 'Pathway', (117, 120))	('myogenic lineage progression', 'CPA', (140, 168))	('prevents', 'NegReg', (131, 139))
76929	22619564	Briefly, it has been demonstrated in epithelium that loss of Shh in the hair follicle leads to an increase in GSK3beta, suggesting that activated Hedgehog signaling can, given the appropriate cellular context, potentiate Wnt signaling activation via beta-catenin stabilization.	('GSK3beta', 'Gene', '2932', (110, 118))	('Shh', 'Gene', '6469', (61, 64))	('beta-catenin', 'Gene', (250, 262))	('Shh', 'Gene', (61, 64))	('potentiate', 'PosReg', (210, 220))	('Hedgehog', 'Gene', '42737', (146, 154))	('increase', 'PosReg', (98, 106))	('loss', 'Var', (53, 57))	('Hedgehog', 'Gene', (146, 154))	('beta-catenin', 'Gene', '1499', (250, 262))	('GSK3beta', 'Gene', (110, 118))
76952	22619564	The Wnt/beta-catenin pathway was first identified as protumorigenic when an inactivating mutation in APC was described in human colon cancer.	('human', 'Species', '9606', (122, 127))	('APC', 'Gene', '324', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('colon cancer', 'Disease', (128, 140))	('beta-catenin', 'Gene', (8, 20))	('tumor', 'Disease', (56, 61))	('beta-catenin', 'Gene', '1499', (8, 20))	('inactivating mutation', 'Var', (76, 97))	('APC', 'Gene', (101, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
76954	22619564	On the other hand, inactivation of GSK3 (which activates beta-catenin) causes cell cycle arrest in leukemia, decreased cell proliferation in pancreatic cancer, and apoptosis in colorectal cancer.	('leukemia', 'Disease', 'MESH:D007938', (99, 107))	('leukemia', 'Disease', (99, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('pancreatic cancer', 'Disease', 'MESH:D010190', (141, 158))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (57, 69))	('cell cycle arrest', 'CPA', (78, 95))	('colorectal cancer', 'Disease', (177, 194))	('GSK3', 'Gene', (35, 39))	('pancreatic cancer', 'Disease', (141, 158))	('apoptosis', 'CPA', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('inactivation', 'Var', (19, 31))	('cell proliferation', 'CPA', (119, 137))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (78, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (141, 158))	('decreased', 'NegReg', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))
76961	22619564	In aRMS, GSK3 inhibitors, which result in the activation of beta-catenin, appeared to preferentially inhibit cell proliferation and induce apoptosis when compared with eRMS cells.	('cell proliferation', 'CPA', (109, 127))	('RMS', 'Phenotype', 'HP:0002859', (4, 7))	('inhibit', 'NegReg', (101, 108))	('preferentially', 'PosReg', (86, 100))	('GSK3', 'Gene', (9, 13))	('activation', 'PosReg', (46, 56))	('beta-catenin', 'Gene', (60, 72))	('RMS', 'Phenotype', 'HP:0002859', (169, 172))	('beta-catenin', 'Gene', '1499', (60, 72))	('induce', 'PosReg', (132, 138))	('inhibitors', 'Var', (14, 24))	('apoptosis', 'CPA', (139, 148))
76962	22619564	Previous work had demonstrated that inhibiting PAX3-FOXO1 activity through the use of a PAX3-KRAB does inhibit growth of aRMS cells in conditions of low serum or soft agar and inhibits tumor xenograft formation in immunodeficient mice.	('tumor', 'Disease', (185, 190))	('activity', 'MPA', (58, 66))	('mice', 'Species', '10090', (230, 234))	('RMS', 'Phenotype', 'HP:0002859', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('growth of aRMS cells', 'CPA', (111, 131))	('inhibits', 'NegReg', (176, 184))	('inhibit growth of aRMS', 'Phenotype', 'HP:0009824', (103, 125))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('PAX3-FOXO1', 'Gene', (47, 57))	('inhibiting', 'Var', (36, 46))	('immunodeficient', 'Disease', 'MESH:D007153', (214, 229))	('immunodeficient', 'Disease', (214, 229))	('inhibit', 'NegReg', (103, 110))
76965	22619564	Thus, activating the Wnt pathway in RMS tumors may be a promising future strategy for the treatment of both aRMS and eRMS.	('activating', 'Var', (6, 16))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('eRMS', 'Disease', (117, 121))	('Wnt pathway', 'Pathway', (21, 32))	('RMS tumors', 'Disease', (36, 46))	('RMS', 'Phenotype', 'HP:0002859', (118, 121))	('RMS', 'Phenotype', 'HP:0002859', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('RMS', 'Phenotype', 'HP:0002859', (109, 112))	('RMS tumors', 'Disease', 'MESH:D009369', (36, 46))
76967	22619564	Individuals with germline mutations in PTCH1 (Gorlin syndrome) are susceptible to multiple malignancies such as basal cell carcinoma (BCC), medulloblastoma, and to a lesser extent RMS.	('medulloblastoma', 'Disease', 'MESH:D008527', (140, 155))	('susceptible', 'Reg', (67, 78))	('medulloblastoma', 'Phenotype', 'HP:0002885', (140, 155))	('multiple malignancies', 'Disease', 'MESH:D009369', (82, 103))	('multiple malignancies', 'Disease', (82, 103))	('germline mutations', 'Var', (17, 35))	('RMS', 'Disease', (180, 183))	('PTCH1', 'Gene', '5727', (39, 44))	('medulloblastoma', 'Disease', (140, 155))	('RMS', 'Phenotype', 'HP:0002859', (180, 183))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (112, 132))	('basal cell carcinoma', 'Disease', (112, 132))	('BCC', 'Phenotype', 'HP:0002671', (134, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('PTCH1', 'Gene', (39, 44))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (112, 132))
76969	22619564	The role of PTCH1 mutations in sporadic human RMS is less clear.	('PTCH1', 'Gene', '5727', (12, 17))	('RMS', 'Phenotype', 'HP:0002859', (46, 49))	('PTCH1', 'Gene', (12, 17))	('human', 'Species', '9606', (40, 45))	('mutations', 'Var', (18, 27))
76970	22619564	Recent studies in human tumors that searched for mutations in either PTCH1 or SMO have yielded conflicting results.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('PTCH1', 'Gene', '5727', (69, 74))	('mutations', 'Var', (49, 58))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('human', 'Species', '9606', (18, 23))	('PTCH1', 'Gene', (69, 74))	('SMO', 'Gene', (78, 81))
76973	22619564	In addition, a recent study found that 12 out of 34 fetal rhabdomyomas and eRMS lacked PTCH1 immunoreactivity and four of nine tumors examined had LOH at the PTCH1 locus.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('LOH', 'Var', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('PTCH1', 'Gene', '5727', (158, 163))	('rhabdomyomas', 'Disease', 'MESH:D012207', (58, 70))	('PTCH1', 'Gene', (158, 163))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('PTCH1', 'Gene', (87, 92))	('RMS', 'Phenotype', 'HP:0002859', (76, 79))	('lacked', 'NegReg', (80, 86))	('rhabdomyomas', 'Phenotype', 'HP:0009730', (58, 70))	('eRMS', 'Disease', (75, 79))	('PTCH1', 'Gene', '5727', (87, 92))	('rhabdomyomas', 'Disease', (58, 70))
76975	22619564	However, such an approach has proven challenging because even though Ptch1+/- mouse tumors depend on Smo for RMS initiation, the SMO inhibitor cyclopamine does not appear to suppress tumor growth in vivo .	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Smo', 'Gene', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cyclopamine', 'Chemical', 'MESH:C000541', (143, 154))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Smo', 'Gene', '319757', (101, 104))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (183, 188))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('mouse', 'Species', '10090', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('Ptch1+/-', 'Var', (69, 77))	('RMS', 'Phenotype', 'HP:0002859', (109, 112))
76990	22619564	These inhibitors appear to work at different levels of the Wnt pathway; for example, XAV939 inhibits Axin, while iCRT-3, 5, and 14 inhibit the beta-catenin-TCF interaction.	('XAV939', 'Chemical', 'MESH:C544261', (85, 91))	('inhibit', 'NegReg', (131, 138))	('beta-catenin', 'Gene', '1499', (143, 155))	('Axin', 'Gene', '8312', (101, 105))	('TCF', 'Gene', (156, 159))	('TCF', 'Gene', '3172', (156, 159))	('Axin', 'Gene', (101, 105))	('XAV939', 'Var', (85, 91))	('beta-catenin', 'Gene', (143, 155))	('inhibits', 'NegReg', (92, 100))
76995	22619564	Maleimide derivatives SB216763 and SB415286 and indirubin analogs BIO and INO all selectively inhibit GSK3.	('SB415286', 'Var', (35, 43))	('indirubin', 'Chemical', 'MESH:C027185', (48, 57))	('SB216763', 'Var', (22, 30))	('SB415286', 'Chemical', 'MESH:C417520', (35, 43))	('SB216763', 'Chemical', 'MESH:C417521', (22, 30))	('Maleimide', 'Chemical', 'MESH:C043592', (0, 9))	('GSK3', 'Protein', (102, 106))	('inhibit', 'NegReg', (94, 101))
76996	22619564	WAY-316606, a small-molecule inhibitor of SFRP1, was shown to stimulate bone formation in an in vitro model of osteoporosis.	('SFRP1', 'Gene', '6422', (42, 47))	('osteoporosis', 'Phenotype', 'HP:0000939', (111, 123))	('bone formation', 'CPA', (72, 86))	('SFRP1', 'Gene', (42, 47))	('osteoporosis', 'Disease', 'MESH:D010024', (111, 123))	('osteoporosis', 'Disease', (111, 123))	('WAY-316606', 'Var', (0, 10))	('stimulate', 'PosReg', (62, 71))	('WAY-316606', 'Chemical', '-', (0, 10))
76999	22619564	Interestingly, a recent phase I trial demonstrated that GDC-0449 caused a partial or complete response in the majority of patients with BCC and medulloblastoma.	('GDC-0449', 'Var', (56, 64))	('medulloblastoma', 'Disease', 'MESH:D008527', (144, 159))	('medulloblastoma', 'Phenotype', 'HP:0002885', (144, 159))	('medulloblastoma', 'Disease', (144, 159))	('patients', 'Species', '9606', (122, 130))	('BCC', 'Disease', (136, 139))	('BCC', 'Phenotype', 'HP:0002671', (136, 139))	('GDC-0449', 'Chemical', 'MESH:C538724', (56, 64))
77003	22619564	Therapies designed to target aberrant stem cell pathways involved in tumor development may also unwittingly inhibit normal, essential stem cell pathways required for normal growth and development into adulthood, a defining characteristic of the pediatric population.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('aberrant', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('inhibit', 'NegReg', (108, 115))
77005	22619564	Regardless of the precise cell of origin, mutations in embryonic signaling pathways may function as primary events in tumorigenesis, or secondary, cooperating mutations.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('embryonic signaling pathways', 'Pathway', (55, 83))	('tumor', 'Disease', (118, 123))	('function', 'Reg', (88, 96))	('mutations', 'Var', (42, 51))
77027	33262201	Multiple activating single-nucleotide variants (SNVs) could be detected in the RAS/RAF family.	('RAF', 'Gene', '22882', (83, 86))	('RAF', 'Gene', (83, 86))	('single-nucleotide variants', 'Var', (20, 46))	('activating', 'PosReg', (9, 19))
77083	33262201	We identified TP53, RB1 and CDKN2A/B deletions as well as MDM2 amplification (figure 2A).	('deletions', 'Var', (37, 46))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('RB1', 'Gene', '5925', (20, 23))	('CDKN2A/B', 'Gene', (28, 36))	('MDM2', 'Gene', '4193', (58, 62))	('MDM2', 'Gene', (58, 62))	('RB1', 'Gene', (20, 23))	('CDKN2A/B', 'Gene', '1029;1030', (28, 36))
77086	33262201	More specifically regarding TP53, deletions were found in 3 MFS (15.8%) and 2 UPS (9.1%) and single-nucleotide variant (SNV) in 6 MFS (31.6%) and 12 UPS (54.5%).	('single-nucleotide variant', 'Var', (93, 118))	('TP53', 'Gene', (28, 32))	('deletions', 'Var', (34, 43))	('TP53', 'Gene', '7157', (28, 32))
77087	33262201	For RB1 in MFS, three samples had a deletion (15.8%) and one had an SNV (5.3%).	('RB1', 'Gene', '5925', (4, 7))	('RB1', 'Gene', (4, 7))	('deletion', 'Var', (36, 44))
77089	33262201	CDKN2A/B was deleted in four MFS (21.1%) and three UPS (13.6%).	('deleted', 'Var', (13, 20))	('CDKN2A/B', 'Gene', (0, 8))	('CDKN2A/B', 'Gene', '1029;1030', (0, 8))
77092	33262201	Similarly, multiple alterations in this pathway were found within the head and neck samples, with 10 SNV in TP53 (55%), 2 in RB1 (11%) and 1 SNV, 1 DEL in CDKN2A/B (11%).	('CDKN2A/B', 'Gene', (155, 163))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('CDKN2A/B', 'Gene', '1029;1030', (155, 163))	('RB1', 'Gene', (125, 128))	('RB1', 'Gene', '5925', (125, 128))	('SNV', 'Var', (101, 104))	('alterations', 'Reg', (20, 31))
77095	33262201	The only alteration found in the thymoma samples was one deletion of CDKN2A/B.	('thymoma', 'Disease', (33, 40))	('deletion', 'Var', (57, 65))	('CDKN2A/B', 'Gene', (69, 77))	('thymoma', 'Phenotype', 'HP:0100522', (33, 40))	('thymoma', 'Disease', 'MESH:D013945', (33, 40))	('CDKN2A/B', 'Gene', '1029;1030', (69, 77))
77097	33262201	In the YST samples, we found KRAS alterations (D33E and G12V, figure 3A) in two out of nine patients (22%).	('D33E', 'SUBSTITUTION', 'None', (47, 51))	('KRAS', 'Gene', (29, 33))	('patients', 'Species', '9606', (92, 100))	('KRAS', 'Gene', '3845', (29, 33))	('D33E', 'Var', (47, 51))	('G12V', 'Var', (56, 60))	('G12V', 'SUBSTITUTION', 'None', (56, 60))
77098	33262201	We also found a canonical KIT mutation in exon 17, codon 816, which was previously identified as a recurrent mutation for ovarian germ cell tumours and potentially actionable with drugs like avapritinib or ripretinib.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('KIT', 'Gene', '3815', (26, 29))	('ovarian germ cell tumours', 'Disease', 'MESH:D009373', (122, 147))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('ripretinib', 'Chemical', '-', (206, 216))	('ovarian germ cell tumours', 'Disease', (122, 147))	('KIT', 'Gene', (26, 29))	('codon 816', 'Var', (51, 60))	('avapritinib', 'Chemical', '-', (191, 202))
77099	33262201	Regarding the thymoma samples, we identified several mutations in this family: one patient with multiple HRAS canonical mutations: G12V (hotspot, activating mutation), subclonal, G13R (hotspot, activating mutation) and subclonal, K117N (activating mutation); and one patient with a HRAS Q61L mutation conserved between primary and recurrent sample (thymus and pleura, figure 3B).	('Q61L', 'SUBSTITUTION', 'None', (287, 291))	('mutations', 'Var', (120, 129))	('G13R', 'Var', (179, 183))	('HRAS', 'Gene', '3265', (282, 286))	('HRAS', 'Gene', (282, 286))	('HRAS', 'Gene', '3265', (105, 109))	('thymus', 'Disease', 'MESH:D013953', (349, 355))	('HRAS', 'Gene', (105, 109))	('G13R', 'SUBSTITUTION', 'None', (179, 183))	('K117N', 'SUBSTITUTION', 'None', (230, 235))	('G12V', 'Var', (131, 135))	('G12V', 'SUBSTITUTION', 'None', (131, 135))	('mutations', 'Var', (53, 62))	('thymoma', 'Disease', 'MESH:D013945', (14, 21))	('Q61L', 'Var', (287, 291))	('K117N', 'Var', (230, 235))	('patient', 'Species', '9606', (267, 274))	('thymoma', 'Disease', (14, 21))	('patient', 'Species', '9606', (83, 90))	('thymoma', 'Phenotype', 'HP:0100522', (14, 21))	('thymus', 'Disease', (349, 355))
77100	33262201	In this population, we also observed several mutations in the RAF family: one mutation in BRAF V600E (activating mutation) and one in BRAF D594G (impaired kinase activity, figure 3C).	('BRAF', 'Gene', (90, 94))	('D594G', 'Var', (139, 144))	('RAF', 'Gene', (62, 65))	('V600E', 'SUBSTITUTION', 'None', (95, 100))	('D594G', 'SUBSTITUTION', 'None', (139, 144))	('BRAF', 'Gene', '673', (134, 138))	('RAF', 'Gene', (135, 138))	('RAF', 'Gene', '22882', (135, 138))	('BRAF', 'Gene', (134, 138))	('RAF', 'Gene', '22882', (91, 94))	('RAF', 'Gene', (91, 94))	('BRAF', 'Gene', '673', (90, 94))	('RAF', 'Gene', '22882', (62, 65))	('V600E', 'Var', (95, 100))
77101	33262201	Another BRAF mutation (G596C) was identified in a patient with a nasopharynx and paranasal sinus (NPS) adenocarcinoma (head and neck cohort).	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('BRAF', 'Gene', '673', (8, 12))	('paranasal sinus (NPS) adenocarcinoma', 'Disease', 'MESH:D010255', (81, 117))	('BRAF', 'Gene', (8, 12))	('G596C', 'SUBSTITUTION', 'None', (23, 28))	('patient', 'Species', '9606', (50, 57))	('G596C', 'Var', (23, 28))
77102	33262201	This specific mutation is located within the kinase domain of the BRAF protein, and results in decreased BRAF kinase activity, but was shown in vitro to activate downstream MEK and ERK in combination with CRAF.	('ERK', 'Gene', (181, 184))	('decreased', 'NegReg', (95, 104))	('BRAF', 'Gene', '673', (105, 109))	('BRAF', 'Gene', (105, 109))	('CRAF', 'Gene', (205, 209))	('mutation', 'Var', (14, 22))	('CRAF', 'Gene', '5894', (205, 209))	('BRAF', 'Gene', '673', (66, 70))	('MEK', 'Gene', (173, 176))	('activate', 'PosReg', (153, 161))	('MEK', 'Gene', '5609', (173, 176))	('ERK', 'Gene', '2048', (181, 184))	('BRAF', 'Gene', (66, 70))
77106	33262201	Rearrangements (or structural variants) were mostly found in sarcoma (four in MFS: IGH-15q25, KTM2C exon 45, ZMYM3 exon 12, POT1 intron 6; and 5 in UPS: RAD21 exon 8, KTM2C exon 45, TSC2 intron 5, HSP90AA1, PTPRO exon 22), rare histologies of head and neck (three cases: CDK12 exon 12, ARID1A exon 5 and MYB intron 14) as well as one in YST (ARID1A exon 19) (figure 3D).	('TSC2', 'Gene', '7249', (182, 186))	('HSP90AA1', 'Gene', (197, 205))	('RAD21', 'Gene', (153, 158))	('ZMYM3', 'Gene', (109, 114))	('MYB', 'Gene', '4602', (304, 307))	('HSP90AA1', 'Gene', '3320', (197, 205))	('MYB', 'Gene', (304, 307))	('POT1', 'Gene', '25913', (124, 128))	('ARID1A', 'Gene', (342, 348))	('RAD21', 'Gene', '5885', (153, 158))	('TSC2', 'Gene', (182, 186))	('ZMYM3', 'Gene', '9203', (109, 114))	('ARID1A', 'Gene', (286, 292))	('KTM2C exon 45', 'Var', (94, 107))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('CDK12', 'Gene', '51755', (271, 276))	('ARID1A', 'Gene', '8289', (342, 348))	('sarcoma', 'Disease', (61, 68))	('IGH', 'Gene', (83, 86))	('POT1', 'Gene', (124, 128))	('Rearrangements', 'Var', (0, 14))	('PTPRO', 'Gene', (207, 212))	('KTM2C exon', 'Var', (167, 177))	('ARID1A', 'Gene', '8289', (286, 292))	('PTPRO', 'Gene', '5800', (207, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('IGH', 'Gene', '3492', (83, 86))	('CDK12', 'Gene', (271, 276))
77121	33262201	Within this study, only 4.7% of rare cancers had directly actionable mutations, with already tested targeted therapy available within the same disease entity (3 sarcoma cases out of 41 (7.3%) and 1 rare head and neck case out of 14 (7.1%)): 1 patient had a NTRK fusion, 1 patient had an EGFR exon 20 insertion and 2 patients had FGFR fusion/amplification (figure 4A, green bars).	('sarcoma', 'Disease', (161, 168))	('mutations', 'Var', (69, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('patient', 'Species', '9606', (243, 250))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('TRK', 'Gene', (258, 261))	('patient', 'Species', '9606', (316, 323))	('EGFR', 'Gene', '1956', (287, 291))	('TRK', 'Gene', '4914', (258, 261))	('EGFR', 'Gene', (287, 291))	('patient', 'Species', '9606', (272, 279))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('patients', 'Species', '9606', (316, 324))
77125	33262201	A closer look at the type of molecular alterations that were used for treatment recommendation highlighted that for rare cancers, half of the recommendations within the disease type (two out of four cases) are linked to fusions (figure 4B, dark blue bar), one recommendation based on indel and the last one based on amplification.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('linked', 'Reg', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('indel', 'Var', (284, 289))	('fusions', 'Var', (220, 227))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
77126	33262201	However, recommendations based on other disease types are based on SNVs (17 cases, 45.7%), amplification (12 cases, 34.2%), indels (5 cases, 14.2%), rearrangements (1 case, 2.8%) or high TMB (1 case, 2.8%) (figure 4B).	('high TMB', 'Var', (182, 190))	('amplification', 'Var', (91, 104))	('TMB', 'Chemical', '-', (187, 190))	('rearrangements', 'Var', (149, 163))	('indels', 'Var', (124, 130))
77134	33262201	These include multiple SNVs (eg, EGFR or KRAS G12C mutation in non-small-cell lung carcinoma), as well as amplification (ERBB2 in breast cancer).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('KRAS', 'Gene', '3845', (41, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (67, 92))	('G12C', 'Var', (46, 50))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (63, 92))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('ERBB2', 'Gene', '2064', (121, 126))	('G12C', 'SUBSTITUTION', 'None', (46, 50))	('EGFR', 'Gene', '1956', (33, 37))	('amplification', 'Var', (106, 119))	('lung carcinoma', 'Disease', (78, 92))	('lung carcinoma', 'Disease', 'MESH:D008175', (78, 92))	('EGFR', 'Gene', (33, 37))	('KRAS', 'Gene', (41, 45))	('ERBB2', 'Gene', (121, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
77135	33262201	Given the presence of mutations overlapping in haematological and solid tumours, and across solid tumour types, more broad panels encompassing all types of alterations could be proposed for all cancer types.	('cancer', 'Disease', (194, 200))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('solid tumours', 'Disease', (66, 79))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumour', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('mutations', 'Var', (22, 31))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('solid tumours', 'Disease', 'MESH:D009369', (66, 79))
77140	33262201	In YST, we confirmed the low mutational rate and the lack of mutations in the HRD pathways, in contrast to 48% of the high-grade serous carcinoma.	('HRD', 'Disease', 'None', (78, 81))	('serous carcinoma', 'Disease', 'MESH:D018297', (129, 145))	('mutational', 'Var', (29, 39))	('serous carcinoma', 'Disease', (129, 145))	('HRD', 'Disease', (78, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
77142	33262201	The low mutational rate (possibly linked to reduced tumour heterogeneity) is consistent with the encouraging response to chemotherapy, especially platinum-based chemotherapy, seen in this patient population, even in relapse cases.	('patient', 'Species', '9606', (188, 195))	('platinum', 'Chemical', 'MESH:D010984', (146, 154))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('mutational', 'Var', (8, 18))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Disease', (52, 58))
77144	33262201	We did, however, confirm in one out of nine samples (11%) a mutation in KIT (previously described as the most significantly mutated gene in dysgerminomas), and in one out of nine samples (11%), an amplification of genes located in chromosome 12p.	('mutation', 'Var', (60, 68))	('KIT', 'Gene', (72, 75))	('dysgerminomas', 'Disease', 'MESH:D004407', (140, 153))	('dysgerminomas', 'Disease', (140, 153))	('KIT', 'Gene', '3815', (72, 75))
77146	33262201	Finally, we identified alterations in ARID1A in two samples: one rearrangement within exon 19 and one mutation Q538* (on exon 3).	('ARID1A', 'Gene', '8289', (38, 44))	('Q538*', 'Var', (111, 116))	('ARID1A', 'Gene', (38, 44))	('alterations', 'Reg', (23, 34))	('Q538*', 'SUBSTITUTION', 'None', (111, 116))
77148	33262201	to date, no direct treatment is associated with alterations in ARID1A, but ARID1A mutations have been shown to be more frequent in clear cell carcinoma.	('ARID1A', 'Gene', '8289', (63, 69))	('frequent', 'Reg', (119, 127))	('ARID1A', 'Gene', (63, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('mutations', 'Var', (82, 91))	('clear cell carcinoma', 'Disease', (131, 151))	('ARID1A', 'Gene', '8289', (75, 81))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (131, 151))	('ARID1A', 'Gene', (75, 81))
77150	33262201	Similarly, ARID1A mutations have been shown to sensitise ovarian clear cell carcinomas cell lines to BET inhibitors, in vitro and in vivo.	('sensitise ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (47, 86))	('BET', 'Gene', '92737', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ARID1A', 'Gene', '8289', (11, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('ARID1A', 'Gene', (11, 17))	('BET', 'Gene', (101, 104))	('sensitise ovarian clear cell carcinomas', 'Disease', (47, 86))	('mutations', 'Var', (18, 27))
77151	33262201	Mutations in the Ras/Raf pathways were identified in 4 out of 13 patients (30%), identifying a potential therapeutic target, especially in the light of available RAF and more recently KRAS inhibitors.	('Raf', 'Gene', '22882', (21, 24))	('KRAS', 'Gene', (184, 188))	('RAF', 'Gene', (162, 165))	('Raf', 'Gene', (21, 24))	('KRAS', 'Gene', '3845', (184, 188))	('RAF', 'Gene', '22882', (162, 165))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (65, 73))
77163	32222066	 DICER1 screening in 15 paediatric paratesticular sarcomas unveils an unusual DICER1-associated sarcoma Individuals with DICER1 syndrome, a genetic disorder caused by pathogenic germline variants in DICER1, are at increased risk of developing a wide array of predominantly childhood onset conditions, including genitourinary sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('DICER1', 'Gene', (78, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (325, 332))	('DICER1', 'Gene', '23405', (121, 127))	('DICER1', 'Gene', '23405', (199, 205))	('germline variants', 'Var', (178, 195))	('DICER1', 'Gene', (121, 127))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('sarcoma', 'Disease', (50, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('DICER1', 'Gene', '23405', (1, 7))	('sarcomas', 'Disease', (50, 58))	('genetic disorder', 'Disease', 'MESH:D030342', (140, 156))	('sarcoma', 'Disease', (96, 103))	('DICER1', 'Gene', (199, 205))	('child', 'Species', '9606', (273, 278))	('genetic disorder', 'Disease', (140, 156))	('sarcoma', 'Disease', 'MESH:D012509', (325, 332))	('sarcomas', 'Disease', 'MESH:D012509', (325, 333))	('DICER1', 'Gene', (1, 7))	('sarcoma', 'Disease', (325, 332))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (325, 333))	('sarcomas', 'Disease', (325, 333))	('DICER1', 'Gene', '23405', (78, 84))
77166	32222066	He harboured a pathogenic germline DICER1 variant and different somatic hot-spot mutations in each tumour.	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('DICER1', 'Gene', (35, 41))	('pathogenic', 'Reg', (15, 25))	('tumour', 'Disease', (99, 105))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('variant', 'Var', (42, 49))
77171	32222066	In summary, we present the first case of a paratesticular sarcoma associated with DICER1 syndrome, emphasising that paratesticular tumours with an unusual histological appearance may suggest an underlying DICER1 mutation, especially in the presence of a personal or family history of DICER1-associated disease.	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('paratesticular tumours', 'Disease', 'MESH:D009369', (116, 138))	('mutation', 'Var', (212, 220))	('associated', 'Reg', (66, 76))	('paratesticular tumour', 'Phenotype', 'HP:0010788', (116, 137))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('DICER1', 'Gene', (205, 211))	('paratesticular tumours', 'Disease', (116, 138))	('paratesticular sarcoma', 'Disease', (43, 65))	('paratesticular sarcoma', 'Disease', 'MESH:D012509', (43, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
77172	32222066	In this context, DICER1 mutation testing could lead to changes in clinical care including implementation of cancer care surveillance strategies.	('lead to changes', 'Reg', (47, 62))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutation testing', 'Var', (24, 40))	('clinical care', 'MPA', (66, 79))	('DICER1', 'Gene', (17, 23))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
77174	32222066	With respect to sarcomas, the subtypes thus far linked to DICER1 mutations are embryonal rhabdomyosarcomas (ERMS), particularly of the urogenital tract - including bladder 5, ovary 6, cervix 5, 7, 8, 9, anaplastic sarcoma of the kidney 10, 11 and undifferentiated sarcoma of the ovary 12.	('undifferentiated sarcoma of the ovary', 'Disease', 'MESH:D010051', (247, 284))	('sarcoma', 'Disease', 'MESH:D012509', (214, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('sarcoma', 'Disease', (214, 221))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (214, 235))	('sarcomas', 'Disease', (16, 24))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (89, 106))	('undifferentiated sarcoma of the ovary', 'Disease', (247, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('embryonal rhabdomyosarcomas', 'Disease', 'MESH:D018233', (79, 106))	('DICER1', 'Gene', (58, 64))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcomas', 'Disease', 'MESH:D012509', (98, 106))	('sarcoma', 'Disease', (98, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('sarcoma', 'Disease', 'MESH:D012509', (264, 271))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (89, 105))	('sarcomas', 'Disease', (98, 106))	('sarcoma', 'Disease', (264, 271))	('embryonal rhabdomyosarcomas', 'Disease', (79, 106))	('embryonal rhabdomyosarcomas', 'Phenotype', 'HP:0006743', (79, 106))	('sarcoma', 'Disease', (16, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('mutations', 'Var', (65, 74))
77187	32222066	We also evaluated 14 other paediatric paratesticular sarcomas and none had DICER1 mutations or strongly expressed immunohistochemical markers characteristic of Mullerian-derived tumours.	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('paratesticular sarcomas', 'Disease', (38, 61))	('paratesticular sarcomas', 'Disease', 'MESH:D012509', (38, 61))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('mutations', 'Var', (82, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('tumours', 'Disease', (178, 185))	('DICER1', 'Gene', (75, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))
77200	32222066	However, tumour DNA from the unusual paratesticular sarcoma was found to harbour two pathogenic mutations in DICER1 (see case report).	('tumour', 'Disease', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('DICER1', 'Gene', (109, 115))	('paratesticular sarcoma', 'Disease', (37, 59))	('paratesticular sarcoma', 'Disease', 'MESH:D012509', (37, 59))	('mutations', 'Var', (96, 105))
77218	32222066	Instead, this tumour typically carries an internal tandem duplication of the BCOR gene 22.	('tumour', 'Disease', (14, 20))	('internal tandem duplication', 'Var', (42, 69))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('BCOR', 'Gene', (77, 81))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('BCOR', 'Gene', '54880', (77, 81))
77225	32222066	Mullerian adenosarcomas have similar immunohistochemistry expression profiles and a small percentage has been described to harbour DICER1 mutations 13, 26.	('adenosarcomas', 'Disease', 'MESH:D018195', (10, 23))	('DICER1', 'Gene', (131, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('adenosarcomas', 'Disease', (10, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('mutations', 'Var', (138, 147))
77229	32222066	Given the association of CN with DICER1 syndrome, we screened for DICER1 mutations in both lesions and in normal tissue from the child.	('DICER1', 'Gene', (66, 72))	('child', 'Species', '9606', (129, 134))	('screened', 'Reg', (53, 61))	('DICER1 syndrome', 'Disease', (33, 48))	('association', 'Reg', (10, 21))	('mutations', 'Var', (73, 82))
77230	32222066	Molecular analysis showed that the paratesticular sarcoma harboured a deletion of 4 nucleotides in exon 23 of DICER1 (c.4308_4311del, p.A1436fs, Figure 3A) and a missense mutation modifying one of five 'hot-spot' amino acids in the RNase IIIb domain (c.5114A > T, p.E1705V, Figure 3B).	('c.4308_4311del', 'Var', (118, 132))	('p.A1436fs', 'Var', (134, 143))	('c.5114A > T', 'Var', (251, 262))	('p.A1436fs', 'Mutation', 'p.A1436fsX', (134, 143))	('DICER1', 'Gene', (110, 116))	('paratesticular sarcoma', 'Disease', (35, 57))	('paratesticular sarcoma', 'Disease', 'MESH:D012509', (35, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('c.4308_4311del', 'Mutation', 'c.4308_4311del', (118, 132))	('p.E1705V', 'Mutation', 'p.E1705V', (264, 272))	('c.5114A > T', 'Mutation', 'c.5114A>T', (251, 262))
77231	32222066	The CN revealed two mutations in DICER1: the same pathogenic deletion found in the paratesticular sarcoma (c.4308_4311del, p.A1436fs, Figure 3A) and a different missense hot-spot RNAse IIIb mutation (c.5428G > T, p.D1810Y, Figure 3C).	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('p.D1810Y', 'Mutation', 'p.D1810Y', (213, 221))	('p.A1436fs', 'Var', (123, 132))	('c.5428G > T', 'Mutation', 'c.5428G>T', (200, 211))	('paratesticular sarcoma', 'Disease', (83, 105))	('paratesticular sarcoma', 'Disease', 'MESH:D012509', (83, 105))	('c.4308_4311del', 'Mutation', 'c.4308_4311del', (107, 121))	('DICER1', 'Gene', (33, 39))	('p.A1436fs', 'Mutation', 'p.A1436fsX', (123, 132))	('c.5428G > T', 'Var', (200, 211))	('c.4308_4311del', 'Var', (107, 121))
77232	32222066	The CN from the patient showed only focal staining for WT1 (Figure 1C) and negative staining for CD10 (Figure 1D), indicating that the DICER1 mutation was not likely inducing the expression of these two antigens.	('expression', 'MPA', (179, 189))	('CD10', 'Gene', (97, 101))	('WT1', 'Gene', '7490', (55, 58))	('CD10', 'Gene', '4311', (97, 101))	('DICER1', 'Gene', (135, 141))	('inducing', 'Reg', (166, 174))	('WT1', 'Gene', (55, 58))	('mutation', 'Var', (142, 150))	('patient', 'Species', '9606', (16, 23))
77233	32222066	In agreement with this, two other CNs harbouring DICER1 mutations showed only very occasional stromal cells positive for WT1 (both cases) and CD10 (one case).	('CD10', 'Gene', (142, 146))	('mutations', 'Var', (56, 65))	('CD10', 'Gene', '4311', (142, 146))	('DICER1', 'Gene', (49, 55))	('WT1', 'Gene', '7490', (121, 124))	('WT1', 'Gene', (121, 124))
77240	32222066	The child was found to have a germline pathogenic DICER1 variant, coupled with different somatic missense hot-spot mutations affecting metal ion binding residues in the RNase IIIb domain in the paratesticular sarcoma and the CN.	('mutations', 'Var', (115, 124))	('metal', 'Chemical', 'MESH:D008670', (135, 140))	('variant', 'Var', (57, 64))	('child', 'Species', '9606', (4, 9))	('DICER1', 'Gene', (50, 56))	('paratesticular sarcoma', 'Disease', (194, 216))	('paratesticular sarcoma', 'Disease', 'MESH:D012509', (194, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))
77241	32222066	The presence of these mutations in DICER1 indicates a causative role for aberrant DICER1 function in the oncogenesis of this paratesticular tumour and includes it as a novel phenotype of DICER1 syndrome.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('DICER1', 'Gene', (35, 41))	('paratesticular tumour', 'Disease', 'MESH:D009369', (125, 146))	('function', 'MPA', (89, 97))	('paratesticular tumour', 'Disease', (125, 146))	('aberrant', 'Var', (73, 81))	('causative', 'Reg', (54, 63))	('DICER1', 'Gene', (82, 88))	('paratesticular tumour', 'Phenotype', 'HP:0010788', (125, 146))
77249	32222066	Following this description, one might have predicted that the paratesticular ERMS cases with anaplasia would have harboured DICER1 mutations, given that anaplastic sarcoma of the kidney is a known component of the DICER1 syndrome and many of those cases show areas of rhabdomyoblastic differentiation 10, 27.	('mutations', 'Var', (131, 140))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (164, 185))	('anaplasia', 'Disease', 'MESH:D000708', (93, 102))	('anaplasia', 'Disease', (93, 102))	('DICER1', 'Gene', (124, 130))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('paratesticular ERMS', 'Disease', (62, 81))	('rhabdomyoblastic differentiation', 'Disease', 'MESH:D012734', (268, 300))	('rhabdomyoblastic differentiation', 'Disease', (268, 300))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
77250	32222066	Furthermore, PPB tumours, most of which result from DICER1 mutations, characteristically contain areas with rhabdomyoblastic differentiation, often with anaplasia 28.	('DICER1', 'Gene', (52, 58))	('result', 'Reg', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('rhabdomyoblastic differentiation', 'Disease', 'MESH:D012734', (108, 140))	('anaplasia', 'Disease', 'MESH:D000708', (153, 162))	('mutations', 'Var', (59, 68))	('PPB tumours', 'Disease', (13, 24))	('anaplasia', 'Disease', (153, 162))	('PPB tumours', 'Disease', 'MESH:C537516', (13, 24))	('rhabdomyoblastic differentiation', 'Disease', (108, 140))
77252	32222066	Indeed, a group of predominantly paediatric intracranial sarcomas with DICER1 mutations was found to have a distinct methylation signature 14.	('methylation', 'MPA', (117, 128))	('mutations', 'Var', (78, 87))	('intracranial sarcomas', 'Disease', 'MESH:D012509', (44, 65))	('DICER1', 'Gene', (71, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('intracranial sarcomas', 'Disease', (44, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
77253	32222066	In the case of embryonal tumours with multi-layered rosettes (ETMRs, another paediatric brain tumour), although a different methylation pattern has been identified, the cluster includes both DICER1-mutated and DICER1-wild type ETMRs 30.	('rosettes', 'Phenotype', 'HP:0031925', (52, 60))	('DICER1-mutated', 'Var', (191, 205))	('embryonal tumours', 'Disease', (15, 32))	('brain tumour', 'Phenotype', 'HP:0030692', (88, 100))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('brain tumour', 'Disease', 'MESH:D001932', (88, 100))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('DICER1-wild', 'Var', (210, 221))	('brain tumour', 'Disease', (88, 100))	('embryonal tumours', 'Disease', 'MESH:D009373', (15, 32))
77259	32222066	In the setting of DICER1 mutations, over 70% of all sarcomas occur in females, the majority manifesting in female reproductive tract organs 17.	('mutations', 'Var', (25, 34))	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('DICER1', 'Gene', (18, 24))	('sarcomas', 'Disease', (52, 60))
77260	32222066	However, no sarcoma in male reproductive organs has previously been identified with characteristic DICER1 molecular changes 17.	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('sarcoma', 'Disease', (12, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('DICER1', 'Gene', (99, 105))	('molecular changes 17', 'Var', (106, 126))
77266	32222066	Conversely, gynaecological tumours of probable Wolffian origin have not been found to harbour DICER1 mutations (as seen by Mirkovic et al 39 and by our group, unpublished data, n = 2).	('mutations', 'Var', (101, 110))	('DICER1', 'Gene', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumours', 'Disease', (27, 34))
77268	32222066	We postulate that microRNA alterations as a result of DICER1 mutations could result in persistence of Mullerian remnants, through microRNA-mediated inhibition of differentiation, which could predispose to tumour formation in Mullerian-derived structures.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('result', 'Reg', (77, 83))	('tumour', 'Disease', (205, 211))	('inhibition', 'NegReg', (148, 158))	('mutations', 'Var', (61, 70))	('differentiation', 'CPA', (162, 177))	('persistence', 'MPA', (87, 98))	('DICER1', 'Gene', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))
77271	32222066	In these cases, DICER1 testing may be recommended, as the identification of a pathogenic germline variant in DICER1 could lead to changes in clinical care including implementation of cancer surveillance strategies 4.	('cancer', 'Disease', (183, 189))	('lead to changes', 'Reg', (122, 137))	('variant', 'Var', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('pathogenic', 'Reg', (78, 88))	('DICER1', 'Gene', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
77294	31871884	Molecular analysis identified an amplification of chimeric transcript corresponding to the EWS-WT1 gene rearrangement, indicating the presence of t(11;22)(p13: q12) reciprocal translocation.	('amplification', 'MPA', (33, 46))	('p13', 'Gene', (155, 158))	('EWS', 'Phenotype', 'HP:0012254', (91, 94))	('EWS-WT1', 'Gene', '7490', (91, 98))	('rearrangement', 'Var', (104, 117))	('p13', 'Gene', '440926', (155, 158))	('EWS-WT1', 'Gene', (91, 98))	('chimeric transcript', 'MPA', (50, 69))
77346	28899971	A majority of Ewing sarcoma cases are the result of a translocation between chromosomes 11 and 22 resulting in the aberrant transcription factor EWS-FLI1.	('result of', 'Reg', (42, 51))	('EWS', 'Gene', '2130', (145, 148))	('EWS', 'Gene', (145, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('Ewing sarcoma', 'Disease', (14, 27))	('FLI1', 'Gene', (149, 153))	('FLI1', 'Gene', '2313', (149, 153))	('translocation', 'Var', (54, 67))	('aberrant', 'Var', (115, 123))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (14, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (14, 27))
77436	28899971	Among the top targets with signal increase were several markers of apoptosis including cleaved caspase 7, cleaved PARP, and cleaved caspase 3, which were significantly increased at 24 hours.	('increased', 'PosReg', (168, 177))	('caspase 7', 'Gene', (95, 104))	('cleaved', 'Var', (124, 131))	('PARP', 'Gene', '142', (114, 118))	('caspase 7', 'Gene', '840', (95, 104))	('cleaved', 'MPA', (106, 113))	('PARP', 'Gene', (114, 118))	('cleaved', 'MPA', (87, 94))
77461	28899971	PARPis were initially believed to have great potential for Ewing sarcoma, as preclinical data from multiple groups revealed that Ewing sarcoma gene fusions were dependent on the activity of PARP1 and that cell lines expressing these fusions were exquisitely sensitive to PARP inhibition.	('fusions', 'Var', (148, 155))	('Ewing sarcoma', 'Disease', (129, 142))	('PARP', 'Gene', (0, 4))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (129, 142))	('PARP', 'Gene', (271, 275))	('PARP', 'Gene', '142', (190, 194))	('PARP1', 'Gene', '142', (190, 195))	('Ewing sarcoma', 'Disease', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (129, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('PARP1', 'Gene', (190, 195))	('PARP', 'Gene', '142', (271, 275))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))	('activity', 'MPA', (178, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', (190, 194))
77473	28899971	As we demonstrate herein, inhibition of NAMPT clearly alters PARP activity.	('alters', 'Reg', (54, 60))	('PARP', 'Gene', (61, 65))	('inhibition', 'Var', (26, 36))	('NAMPT', 'Gene', (40, 45))	('PARP', 'Gene', '142', (61, 65))
77509	30445938	The results from the laboratory examination were normal, including for tumor markers (CA19-9, CEA, CA125, CA50, and CA242), biochemical, and routine blood tests.	('CA50', 'Var', (106, 110))	('CEA', 'Gene', (94, 97))	('CA19-9', 'Chemical', 'MESH:C086528', (86, 92))	('CA125', 'Gene', '94025', (99, 104))	('CEA', 'Gene', '5670', (94, 97))	('CA242', 'Chemical', '-', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CA242', 'Var', (116, 121))	('CA125', 'Gene', (99, 104))	('CA19-9', 'Var', (86, 92))	('CA50', 'Chemical', '-', (106, 110))	('tumor', 'Disease', (71, 76))
77519	30445938	The immunohistochemical results showed S-100(-), NSE(+), CD117(+), CD34(-), CD99(+), Dog-1(-), SMA(-), EMA(-), CK(-), Vim(+), HMB45(-), and the positive rate of Ki67 was 8% (Fig.	('CD34', 'Gene', '415130', (67, 71))	('Vim', 'Gene', (118, 121))	('CD34', 'Gene', (67, 71))	('Dog', 'Species', '9615', (85, 88))	('Vim', 'Gene', '477991', (118, 121))	('CD99', 'Gene', (76, 80))	('CD99', 'Gene', '609832', (76, 80))	('S-100', 'Var', (39, 44))
77601	29137100	Preoperative serum cancer antigen 125 (CA-125), CA19-9, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and CA72-4 were all in the normal range.	('alpha-fetoprotein', 'Gene', (88, 105))	('carcinoembryonic antigen', 'Gene', (56, 80))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('CA72-4', 'Var', (117, 123))	('cancer', 'Disease', (19, 25))	('CEA', 'Gene', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('alpha-fetoprotein', 'Gene', '174', (88, 105))	('CEA', 'Gene', '1084', (82, 85))	('AFP', 'Gene', (107, 110))	('carcinoembryonic antigen', 'Gene', '1084', (56, 80))	('AFP', 'Gene', '174', (107, 110))
77689	27703957	RT-PCR analysis for EWS-FLI1 fusion proteins was positive for type II 191 pb and negative for type I 125 pb.	('EWS', 'Gene', (20, 23))	('FLI1', 'Gene', '2313', (24, 28))	('FLI1', 'Gene', (24, 28))	('positive', 'Reg', (49, 57))	('type II', 'Var', (62, 69))	('EWS', 'Phenotype', 'HP:0012254', (20, 23))	('EWS', 'Gene', '2130', (20, 23))
77720	27703957	The EWS/FLI1 fusion may be detected directly with the use of RT-PCR or fluorescence in situ hybridization (FISH), otherwise indirectly with standard cytogenetic studies by the t (11; 22) (q 24; q 12) (1).	('fusion', 'Var', (13, 19))	('FLI1', 'Gene', (8, 12))	('FLI1', 'Gene', '2313', (8, 12))	('EWS', 'Phenotype', 'HP:0012254', (4, 7))	('EWS', 'Gene', '2130', (4, 7))	('EWS', 'Gene', (4, 7))
77788	22417062	In these cases, asymmetric radiation of the vertebral body may increase the risk of scoliosis or kyphosis.	('kyphosis', 'Phenotype', 'HP:0002808', (97, 105))	('scoliosis', 'Phenotype', 'HP:0002650', (84, 93))	('scoliosis or kyphosis', 'Disease', (84, 105))	('asymmetric radiation', 'Var', (16, 36))	('scoliosis or kyphosis', 'Disease', 'MESH:D012600', (84, 105))
77791	22417062	Dosimetric studies have been undertaken which suggest that proton RT in medulloblastoma should lead to decreased long-term toxicity.	('toxicity', 'Disease', (123, 131))	('medulloblastoma', 'Disease', 'MESH:D008527', (72, 87))	('decreased', 'NegReg', (103, 112))	('long-term', 'MPA', (113, 122))	('medulloblastoma', 'Phenotype', 'HP:0002885', (72, 87))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))	('medulloblastoma', 'Disease', (72, 87))	('proton RT', 'Var', (59, 68))
77846	22417062	Conversely, the one-third of retinoblastoma patients harboring germline mutations in the Rb gene, standardly present with bilateral involvement, often during the first year of life.	('retinoblastoma', 'Phenotype', 'HP:0009919', (29, 43))	('patients', 'Species', '9606', (44, 52))	('retinoblastoma', 'Disease', 'MESH:D012175', (29, 43))	('retinoblastoma', 'Disease', (29, 43))	('germline mutations', 'Var', (63, 81))
77850	22417062	A separate analysis of three patients treated at the MD Anderson Cancer Center demonstrated superior target coverage and normal tissue sparing, most notably a decrease in dose to the orbital bones, with protons compared to electrons, 3D conformal RT and IMRT.	('patients', 'Species', '9606', (29, 37))	('protons', 'Var', (203, 210))	('target coverage', 'CPA', (101, 116))	('decrease', 'NegReg', (159, 167))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (53, 71))	('dose', 'MPA', (171, 175))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('MD Anderson Cancer', 'Disease', (53, 71))
77878	22417062	A separate dosimetric analysis of two female and one male patient treated at the MD Anderson Cancer Center for pelvic sarcoma demonstrated a marked reduction in ovarian dose with protons compared to both 3D conformal RT and IMRT.	('MD Anderson Cancer', 'Disease', (81, 99))	('pelvic sarcoma', 'Disease', (111, 125))	('reduction', 'NegReg', (148, 157))	('pelvic sarcoma', 'Disease', 'MESH:D034161', (111, 125))	('patient', 'Species', '9606', (58, 65))	('ovarian dose', 'MPA', (161, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('protons', 'Var', (179, 186))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (81, 99))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))
77919	26074722	Primary endpoint was progression-free survival (PFS) at 6 months and would be met if >=17 patients were progression-free at 6 m. Secondary endpoints are response rate, PFS at 3 m, overall survival, and toxicity.	('response', 'CPA', (153, 161))	('toxicity', 'Disease', 'MESH:D064420', (202, 210))	('PFS', 'Var', (168, 171))	('toxicity', 'Disease', (202, 210))	('patients', 'Species', '9606', (90, 98))
78040	29412642	Furthermore, gene expression profiling has identified mRNAs unique (EWS-FLIl) or overexpressed (survivin) in Ewing sarcoma tumors relative to normal tissues that can be targeted for drug activation in our Au-NP system.	('FLIl', 'Gene', '2314', (72, 76))	('FLIl', 'Gene', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (109, 129))	('Au-NP', 'Chemical', '-', (205, 210))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mRNAs', 'Var', (54, 59))	('EWS', 'Gene', (68, 71))	('EWS', 'Gene', '2130', (68, 71))	('Ewing sarcoma tumors', 'Disease', (109, 129))
78048	29412642	The SN-38-oligonucleotide exhibits significant toxicity against Ewing Sarcoma cells at picomolar concentrations (Figure S1B).	('Sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (64, 77))	('toxicity', 'Disease', 'MESH:D064420', (47, 55))	('toxicity', 'Disease', (47, 55))	('Ewing Sarcoma', 'Disease', (64, 77))	('SN-38-oligonucleotide', 'Chemical', '-', (4, 25))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (64, 77))	('SN-38-oligonucleotide', 'Var', (4, 25))
78069	29412642	The viability of all cells treated with SN38-survivin Au-NPs was significantly diminished when compared to the no treatment control and the SN38-scrambled Au-NPs (Figure 4A,B).	('SN38-survivin', 'Var', (40, 53))	('Au-NPs', 'Chemical', '-', (54, 60))	('viability', 'CPA', (4, 13))	('SN38', 'Chemical', 'MESH:D000077146', (40, 44))	('Au-NPs', 'Chemical', '-', (155, 161))	('diminished', 'NegReg', (79, 89))	('SN38', 'Chemical', 'MESH:D000077146', (140, 144))
78071	29412642	The moderate toxicity of SN38-scrambled Au-NPs is likely caused by the nonspecific release of SN-38 conjugated oligonucleotides from the Au-NPs.	('toxicity', 'Disease', 'MESH:D064420', (13, 21))	('Au-NPs', 'Chemical', '-', (40, 46))	('toxicity', 'Disease', (13, 21))	('SN-38', 'Chemical', 'MESH:D000077146', (94, 99))	('Au-NPs', 'Chemical', '-', (137, 143))	('SN38-scrambled', 'Var', (25, 39))	('SN-38', 'Protein', (94, 99))	('SN38', 'Chemical', 'MESH:D000077146', (25, 29))	('release', 'MPA', (83, 90))	('oligonucleotides', 'Chemical', 'MESH:D009841', (111, 127))
78073	29412642	Finally, SN38-conjugated Au-NPs also significantly inhibited the growth of Ewing sarcoma cells in long-term clonogenic growth assays (Figure 5A,B).	('Ewing sarcoma', 'Disease', (75, 88))	('growth', 'CPA', (65, 71))	('SN38', 'Chemical', 'MESH:D000077146', (9, 13))	('Au-NPs', 'Chemical', '-', (25, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('SN38-conjugated', 'Var', (9, 24))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('inhibited', 'NegReg', (51, 60))
78075	29412642	When subcutaneous tumors became palpable they were treated with a single injection of PBS, survivin Au-NP (lacking SN-38), SN38-survivin Au-NP, or SN38-EWS/FLI1 Au-NP.	('SN-38', 'Chemical', 'MESH:D000077146', (115, 120))	('SN38-survivin', 'Var', (123, 136))	('EWS', 'Gene', '2130', (152, 155))	('EWS', 'Gene', (152, 155))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (5, 24))	('FLI1', 'Gene', (156, 160))	('SN38', 'Chemical', 'MESH:D000077146', (123, 127))	('FLI1', 'Gene', '2313', (156, 160))	('tumors', 'Disease', (18, 24))	('Au-NP', 'Chemical', '-', (161, 166))	('PBS', 'Chemical', 'MESH:D007854', (86, 89))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('Au-NP', 'Chemical', '-', (137, 142))	('SN38', 'Chemical', 'MESH:D000077146', (147, 151))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('Au-NP', 'Chemical', '-', (100, 105))
78077	29412642	The viability of the tumors treated with SN38-survivin and SN38-EWS/FLI1 Au-NPs was significantly diminished in comparison to the tumors injected with PBS or Au-NPs lacking SN-38 (Figure 6).	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('diminished', 'NegReg', (98, 108))	('SN38-survivin', 'Var', (41, 54))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Au-NPs', 'Chemical', '-', (73, 79))	('FLI1', 'Gene', (68, 72))	('SN38', 'Chemical', 'MESH:D000077146', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('EWS', 'Gene', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('Au-NPs', 'Chemical', '-', (158, 164))	('viability', 'CPA', (4, 13))	('tumors', 'Disease', (21, 27))	('PBS', 'Chemical', 'MESH:D007854', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SN38', 'Chemical', 'MESH:D000077146', (41, 45))	('FLI1', 'Gene', '2313', (68, 72))	('tumors', 'Disease', (130, 136))	('SN-38', 'Chemical', 'MESH:D000077146', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('EWS', 'Gene', '2130', (64, 67))
78082	29412642	Further supporting the potential clinical applications of this approach, nucleic acid functionalized Au-NPs exhibit favorable therapeutic properties including internalization by multiple cell types including Ewing sarcoma (Figure 1), stability in biological environments, resistance to nucleases, minimal cell toxicity, and low immunogenicity.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (208, 221))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (208, 221))	('Au-NPs', 'Chemical', '-', (101, 107))	('nucleic acid functionalized', 'Var', (73, 100))	('internalization', 'MPA', (159, 174))	('toxicity', 'Disease', 'MESH:D064420', (310, 318))	('toxicity', 'Disease', (310, 318))	('Ewing sarcoma', 'Disease', (208, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))
78083	29412642	Additionally, Au-NPs carrying siRNA or DNA antisense oligonucleotides have exhibited in vivo efficacy following intravenous injection when tested in murine models of gastric and brain tumors.	('oligonucleotides', 'Chemical', 'MESH:D009841', (53, 69))	('brain tumors', 'Disease', 'MESH:D001932', (178, 190))	('brain tumors', 'Phenotype', 'HP:0030692', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('gastric', 'Disease', 'MESH:D013274', (166, 173))	('gastric', 'Disease', (166, 173))	('brain tumors', 'Disease', (178, 190))	('antisense oligonucleotides', 'Var', (43, 69))	('Au-NPs', 'Chemical', '-', (14, 20))	('murine', 'Species', '10090', (149, 155))
78086	29412642	Supported by extensive literature describing the chemical modification and/or encapsulation of SN-38, we hypothesized that conjugation of SN-38 to an oligonucleotide and sequestration to Au-NPs would enhance its solubility and delivery.	('SN-38', 'Gene', (138, 143))	('conjugation', 'Var', (123, 134))	('oligonucleotide', 'Chemical', 'MESH:D009841', (150, 165))	('oligonucleotide', 'Protein', (150, 165))	('solubility', 'MPA', (212, 222))	('delivery', 'MPA', (227, 235))	('sequestration', 'MPA', (170, 183))	('SN-38', 'Chemical', 'MESH:D000077146', (95, 100))	('Au-NPs', 'Chemical', '-', (187, 193))	('enhance', 'PosReg', (200, 207))	('SN-38', 'Chemical', 'MESH:D000077146', (138, 143))
78087	29412642	Importantly, conjugation of SN-38 to an oligonucleotide did not perturb its ability to inhibit topoisomerase I and induce cell death (Figure S1B).	('cell death', 'CPA', (122, 132))	('conjugation', 'Var', (13, 24))	('induce', 'Reg', (115, 121))	('topoisomerase I', 'Enzyme', (95, 110))	('SN-38', 'Chemical', 'MESH:D000077146', (28, 33))	('oligonucleotide', 'Chemical', 'MESH:D009841', (40, 55))	('inhibit', 'NegReg', (87, 94))
78092	29412642	However, SN38-Survivin Au-NPs may cause more toxicity than SN38-EWS-FLI1 Au-NPs as survivin can be expressed in normal tissues, albeit at lower levels than in cancer cells.	('cancer', 'Disease', (159, 165))	('Au-NPs', 'Chemical', '-', (23, 29))	('toxicity', 'Disease', 'MESH:D064420', (45, 53))	('SN38', 'Chemical', 'MESH:D000077146', (9, 13))	('toxicity', 'Disease', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('Au-NPs', 'Chemical', '-', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('FLI1', 'Gene', (68, 72))	('SN38', 'Chemical', 'MESH:D000077146', (59, 63))	('EWS', 'Gene', '2130', (64, 67))	('EWS', 'Gene', (64, 67))	('FLI1', 'Gene', '2313', (68, 72))	('SN38-Survivin', 'Var', (9, 22))
78102	29412642	The moderate toxicity of SN38-scrambled Au-NPs is likely caused by the nonspecific release of SN-38 conjugated oligonucleotides from the Au-NPs or cleavage of the ester linking SN-38 and the oligonucleotide (Figures 1B and 3A).	('toxicity', 'Disease', 'MESH:D064420', (13, 21))	('Au-NPs', 'Chemical', '-', (40, 46))	('toxicity', 'Disease', (13, 21))	('SN-38', 'Chemical', 'MESH:D000077146', (94, 99))	('cleavage', 'Var', (147, 155))	('Au-NPs', 'Chemical', '-', (137, 143))	('SN-38', 'Chemical', 'MESH:D000077146', (177, 182))	('oligonucleotide', 'Chemical', 'MESH:D009841', (111, 126))	('ester', 'Chemical', 'MESH:D004952', (163, 168))	('SN38', 'Chemical', 'MESH:D000077146', (25, 29))	('oligonucleotide', 'Chemical', 'MESH:D009841', (191, 206))	('release', 'MPA', (83, 90))	('oligonucleotides', 'Chemical', 'MESH:D009841', (111, 127))
78105	29412642	In support of systemic delivery, intravenously administered nucleic acid functionalized gold nanoparticles (siRNA and molecular beacons) showed minimal toxicity to normal tissues while accumulating in tumors.	('nucleic', 'Var', (60, 67))	('accumulating', 'PosReg', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('toxicity', 'Disease', 'MESH:D064420', (152, 160))	('toxicity', 'Disease', (152, 160))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
78168	29412642	Ewing sarcoma cells were pretreated for 4h with scrambled Au-NP, SN38-scrambled Au-NP, SN38-Survivin Au-NP, SN38-EWS-FLI1 Au-NP 3 nM, or untreated.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('SN38', 'Chemical', 'MESH:D000077146', (108, 112))	('Au-NP', 'Chemical', '-', (101, 106))	('SN38-scrambled Au-NP', 'Var', (65, 85))	('Au-NP', 'Chemical', '-', (80, 85))	('SN38-Survivin Au-NP', 'Var', (87, 106))	('FLI1', 'Gene', '2313', (117, 121))	('Ewing sarcoma', 'Disease', (0, 13))	('Au-NP', 'Var', (101, 106))	('FLI1', 'Gene', (117, 121))	('Au-NP', 'Chemical', '-', (122, 127))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('EWS', 'Gene', '2130', (113, 116))	('EWS', 'Gene', (113, 116))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('Au-NP', 'Chemical', '-', (58, 63))	('SN38', 'Chemical', 'MESH:D000077146', (87, 91))	('SN38', 'Chemical', 'MESH:D000077146', (65, 69))
78173	29412642	When tumors became palpable, Survivin Au-NP, SN38-Survivin Au-NP, SN38-EWS/FLI1 Au-NP, or PBS was injected into the tumor.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('SN38-Survivin', 'Var', (45, 58))	('Au-NP', 'Chemical', '-', (59, 64))	('PBS', 'Chemical', 'MESH:D007854', (90, 93))	('SN38', 'Chemical', 'MESH:D000077146', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('EWS', 'Gene', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('FLI1', 'Gene', (75, 79))	('SN38', 'Chemical', 'MESH:D000077146', (66, 70))	('tumors', 'Disease', (5, 11))	('Au-NP', 'Chemical', '-', (80, 85))	('EWS', 'Gene', '2130', (71, 74))	('tumor', 'Disease', (5, 10))	('Au-NP', 'Chemical', '-', (38, 43))	('tumor', 'Disease', (116, 121))	('FLI1', 'Gene', '2313', (75, 79))
78220	31523571	These tumors are generally positive for basal cell CK (CK5, CK14), and p63.	('CK14', 'Gene', '3861', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('p63', 'Var', (71, 74))	('positive', 'Reg', (27, 35))	('tumors', 'Disease', (6, 12))	('CK14', 'Gene', (60, 64))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('basal cell CK', 'Disease', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
78343	28099593	In this study, the team investigated the relationship between the presence of HHV-8, as determined by polymerase chain reaction, and angiosarcoma, using samples from patients with epidemic Kaposi's sarcoma as controls.	("epidemic Kaposi's sarcoma", 'Disease', (180, 205))	('presence', 'Var', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('HHV-8', 'Gene', (78, 83))	('angiosarcoma', 'Disease', 'MESH:D006394', (133, 145))	('HHV-8', 'Species', '37296', (78, 83))	('angiosarcoma', 'Disease', (133, 145))	('angiosarcoma', 'Phenotype', 'HP:0200058', (133, 145))	("epidemic Kaposi's sarcoma", 'Disease', 'MESH:D012514', (180, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('patients', 'Species', '9606', (166, 174))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (189, 205))
78364	28099593	These consisted of two different fragments of the ORF-K1 variable-loop region, VR1 (380bp) and VR2 (336bp), and a 407bp fragment of the ORF-K12 region, using modified cycling conditions (initial denaturation of DNA at 95 C for 5 minutes; 40 cycles of 94 C for 50 seconds, 62 C for 50 seconds; and 72 C for 1 minute, followed by a final extension at 72 C for 10 minutes).	('VR2', 'Gene', (95, 98))	('men', 'Species', '9606', (124, 127))	('ORF-K1', 'Gene', (50, 56))	('336bp', 'Var', (100, 105))	('VR1', 'Gene', '56664', (79, 82))	('men', 'Species', '9606', (37, 40))	('380bp', 'Var', (84, 89))	('VR1', 'Gene', (79, 82))	('VR2', 'Gene', '56663', (95, 98))
78381	28099593	In all variants of KS, HHV-8 is implicated as the agent-inducing disease.	('KS', 'Phenotype', 'HP:0100726', (19, 21))	('HHV-8', 'Species', '37296', (23, 28))	('variants', 'Var', (7, 15))	('HHV-8', 'Gene', (23, 28))
78409	25276445	JAK2 V617F mutation was negative.	('V617F', 'SUBSTITUTION', 'None', (5, 10))	('JAK2', 'Gene', '3717', (0, 4))	('JAK2', 'Gene', (0, 4))	('V617F', 'Var', (5, 10))
78413	25276445	In the third week WBC was 64000/mm3, Hb: 7.2 gr/dL, but this time her PLT count was normal, 259000/mm3, and LDH was 654 IU/L.	('PLT', 'Gene', '27163', (70, 73))	('259000/mm3', 'Var', (92, 102))	('PLT', 'Gene', (70, 73))
78414	25276445	JAK2 V617F mutation was repeated too and it was negative.	('V617F', 'SUBSTITUTION', 'None', (5, 10))	('JAK2', 'Gene', (0, 4))	('V617F', 'Var', (5, 10))
78417	25276445	The proliferation of hypermetabolic lesions was also observed in spleen, bones with SUVmax: 2.7 and SUVmax: 2.1, respectively.	('SUVmax', 'Var', (100, 106))	('hypermetabolic lesions', 'Disease', 'MESH:C565498', (21, 43))	('hypermetabolic lesions', 'Disease', (21, 43))	('SUVmax: 2.7', 'Var', (84, 95))
78427	25276445	Immunohistochemistry is very valuable in identifying antigens such as CD13, CD33, CD34, CD43, CD45, CD99, CD117, MPO, CD68, and lysozyme which are associated with myeloid lineage.	('CD13', 'Gene', (70, 74))	('CD99', 'Gene', '4267', (100, 104))	('lysozyme', 'Protein', (128, 136))	('CD33', 'Gene', '945', (76, 80))	('CD45', 'Gene', (94, 98))	('CD33', 'Gene', (76, 80))	('CD68', 'Gene', (118, 122))	('CD43', 'Gene', (88, 92))	('CD34', 'Var', (82, 86))	('CD99', 'Gene', (100, 104))	('CD117', 'Var', (106, 111))	('CD68', 'Gene', '968', (118, 122))	('CD45', 'Gene', '5788', (94, 98))	('CD13', 'Gene', '290', (70, 74))	('MPO', 'Gene', (113, 116))	('CD43', 'Gene', '6693', (88, 92))
78429	25276445	Trisomy 8, inv (16), t(9,11), t(8,21), 11q23, and del(16q) are the chromosomal abnormalities which are found to be related with MS. JAK2 V617F mutation is found in myeloid tumors and in neoplastic proliferation of the hematopoietic cells of myeloproliferative diseases.	('V617F', 'SUBSTITUTION', 'None', (137, 142))	('V617F', 'Var', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('myeloid tumors', 'Disease', 'OMIM:601308', (164, 178))	('neoplastic proliferation', 'CPA', (186, 210))	('del(16q', 'Var', (50, 57))	('MS. JAK2', 'Gene', (128, 136))	('myeloid tumors', 'Disease', (164, 178))	('Trisomy', 'Disease', (0, 7))	('neoplastic proliferation', 'Phenotype', 'HP:0002664', (186, 210))	('Trisomy', 'Disease', 'MESH:D014314', (0, 7))	('found', 'Reg', (155, 160))
78430	25276445	reported a case of myeloid sarcoma with JAK2 V617F.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('V617F', 'Var', (45, 50))	('myeloid sarcoma', 'Disease', (19, 34))	('V617F', 'SUBSTITUTION', 'None', (45, 50))
78478	24503412	The incidence in 3.0 mg/kg males was significantly greater than the vehicle control incidence and exceeded the historical control ranges for dermal studies and for all routes of administration by only one tumor (Table 1).	('3.0 mg/kg', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('greater', 'PosReg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))
78485	24503412	The combined incidence of basal cell adenoma and carcinoma was statistically significant in the 0.3 mg/kg group and exceeded the historical control range for all routes of study (0-8%), but only by a single neoplasm.	('carcinoma', 'Disease', 'MESH:D002277', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('0.3 mg/kg', 'Var', (96, 105))	('neoplasm', 'Disease', (207, 215))	('basal cell adenoma', 'Disease', 'MESH:D000236', (26, 44))	('carcinoma', 'Disease', (49, 58))	('neoplasm', 'Disease', 'MESH:D009369', (207, 215))	('basal cell adenoma', 'Phenotype', 'HP:0002671', (26, 44))	('neoplasm', 'Phenotype', 'HP:0002664', (207, 215))	('basal cell adenoma', 'Disease', (26, 44))
78486	24503412	The increased incidence of basal cell adenoma or basal cell carcinoma (combined) was statistically significant in the 0.3 mg/kg group, the lowest dose group.	('basal cell adenoma', 'Phenotype', 'HP:0002671', (27, 45))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (49, 69))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (49, 69))	('basal cell carcinoma', 'Disease', (49, 69))	('basal cell adenoma', 'Disease', (27, 45))	('0.3 mg/kg', 'Var', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('basal cell adenoma', 'Disease', 'MESH:D000236', (27, 45))
78555	24503412	There was a positive trend in the incidences of mesothelioma; the incidence in 3.0 mg/kg males was significantly greater than in the concurrent vehicle controls receiving acetone.	('acetone', 'Chemical', 'MESH:D000096', (171, 178))	('3.0 mg/kg', 'Var', (79, 88))	('mesothelioma', 'Disease', (48, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('greater', 'PosReg', (113, 120))
78623	33430667	For the gene mutation analysis, each tumor was categorized as mutated or wild-type (WT) on the basis of the occurrence of a given gene mutation.	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutation', 'Var', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (37, 42))
78624	33430667	For the copy number variations, each tumor was categorized as loss (-1, -2), no change (0), or gain (1, 2) on the basis of results generated by GISTIC2.	('loss', 'NegReg', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('copy number variations', 'Var', (8, 30))	('GIST', 'Phenotype', 'HP:0100723', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('gain', 'PosReg', (95, 99))
78635	33430667	The results showed that Tem CD4+ T cells infiltration may be associated with better survival in sarcomas.	('better', 'PosReg', (77, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Tem', 'Chemical', '-', (24, 27))	('sarcomas', 'Disease', (96, 104))	('Tem CD4+ T cells', 'Var', (24, 40))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))
78651	33430667	The sarcoma subtypes were partially overlapped with the TCGA cohort used in our study, and were analyzed using IHC to evaluate the prognostic significance of CD3+, CD4+, CD8+, CD20+, and CD45+ lymphocytes infiltration.	('sarcoma', 'Disease', (4, 11))	('CD8+', 'Var', (170, 174))	('CD4+', 'Var', (164, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('CD3+', 'Var', (158, 162))	('CD20+', 'Var', (176, 181))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))
78687	29737912	While Walsh et al reported that for every 20% increase in Native American ancestry there was a corresponding 20% increase in the risk of B-ALL among Hispanic children, this increase was incompletely accounted for by existed genetic variants which increase ALL risk, some of which have a higher allele frequency among Hispanics.	('ALL', 'Phenotype', 'HP:0006721', (256, 259))	('ALL', 'Phenotype', 'HP:0006721', (139, 142))	('increase', 'PosReg', (46, 54))	('variants', 'Var', (232, 240))	('B-ALL', 'Disease', (137, 142))	('increase', 'PosReg', (113, 121))	('children', 'Species', '9606', (158, 166))
78692	29737912	de Smith et al have found that the presence of activating KIR receptors, which instruct natural killer cells recognize and eliminate cancer cells, were associated with reduced risk of leukemia in Hispanics but not non-Hispanic whites.	('presence', 'Var', (35, 43))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('KIR', 'Gene', '3805', (58, 61))	('cancer', 'Disease', (133, 139))	('KIR', 'Gene', (58, 61))	('leukemia', 'Disease', 'MESH:D007938', (184, 192))	('leukemia', 'Disease', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('activating', 'PosReg', (47, 57))	('reduced', 'NegReg', (168, 175))
78705	29737912	Among children diagnosed with AML, favorable cytogenetics, including inv(16) and t(8;21), are associated with an up to 30% increase in over-all survival (OS) when compared with AML with normal karyotype.	('inv(16', 'Var', (69, 75))	('AML', 'Disease', 'MESH:D015470', (30, 33))	('AML', 'Disease', (177, 180))	('over-all survival', 'CPA', (135, 152))	('AML', 'Phenotype', 'HP:0004808', (177, 180))	('AML', 'Disease', (30, 33))	('increase', 'PosReg', (123, 131))	('t(8;21', 'Var', (81, 87))	('AML', 'Phenotype', 'HP:0004808', (30, 33))	('children', 'Species', '9606', (6, 14))	('AML', 'Disease', 'MESH:D015470', (177, 180))
78713	29737912	A recent study in children with AML showed short blood telomere length at the end of leukemia induction predicts delays in hematopoietic recovery, defined as prolonged neutropenia, in later courses of chemotherapy.	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('AML', 'Disease', 'MESH:D015470', (32, 35))	('leukemia', 'Disease', 'MESH:D007938', (85, 93))	('children', 'Species', '9606', (18, 26))	('neutropenia', 'Disease', 'MESH:D009503', (168, 179))	('leukemia', 'Disease', (85, 93))	('AML', 'Phenotype', 'HP:0004808', (32, 35))	('short blood telomere length', 'Phenotype', 'HP:0031413', (43, 70))	('neutropenia', 'Phenotype', 'HP:0001875', (168, 179))	('AML', 'Disease', (32, 35))	('hematopoietic recovery', 'CPA', (123, 145))	('short', 'Var', (43, 48))	('neutropenia', 'Disease', (168, 179))	('delays', 'NegReg', (113, 119))
78724	29737912	We do know that polymorphic GGAA repeat microsatellites have been associated with Ewing sarcoma somatic transformation, as well as recent GWAS ; in fact, one of the candidate SNPs in recent GWAS for Ewing sarcoma has been linked to GGAA microsatellite region.	('Ewing sarcoma', 'Disease', (82, 95))	('Ewing sarcoma', 'Disease', (199, 212))	('associated', 'Reg', (66, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (82, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (199, 212))	('polymorphic', 'Var', (16, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (199, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
78725	29737912	Since the Disparity Conference, a recent publication has described pathogenic or likely pathogenic germline mutations in 13.1% of a cohort of patients with Ewing Sarcoma (N = 175); these included pathogenic mutations in DNA damage repair genes associated with cancer predisposition syndromes.	('mutations', 'Var', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('pathogenic', 'Reg', (88, 98))	('DNA damage repair genes', 'Gene', (220, 243))	('pathogenic', 'Reg', (67, 77))	('Sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('cancer', 'Disease', (260, 266))	('mutations', 'Var', (207, 216))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (156, 169))	('germline', 'Gene', (99, 107))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('pathogenic', 'Reg', (196, 206))	('Ewing Sarcoma', 'Disease', (156, 169))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (156, 169))
78736	29737912	Notably, the NUDT15 C416T variant was recently identified in a GWAS to be associated with the susceptibility to mercaptopurine (MP) intolerance and explained a large proportion of ancestry-related differences in MP toxicity.	('C416T', 'Mutation', 'c.416C>T', (20, 25))	('NUDT15', 'Gene', (13, 19))	('MP', 'Chemical', 'MESH:D015122', (128, 130))	('mercaptopurine', 'Chemical', 'MESH:D015122', (112, 126))	('C416T', 'Var', (20, 25))	('MP toxicity', 'Disease', 'MESH:D064420', (212, 223))	('MP toxicity', 'Disease', (212, 223))	('MP', 'Chemical', 'MESH:D015122', (212, 214))	('susceptibility', 'Reg', (94, 108))	('NUDT15', 'Gene', '55270', (13, 19))	('associated', 'Reg', (74, 84))
78751	29737912	Prenatal exposure to PAHs significantly predicted presence of chromosomal aberrations such as translocations at birth (in cord blood) in large chromosomes (especially on chromosome 6) including those frequently involved in translocations commonly found in ALL, after adjusting for gender of the child, ethnicity, and exposure to household cigarette smoke.	('ALL', 'Phenotype', 'HP:0006721', (256, 259))	('translocations', 'Var', (94, 108))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (62, 85))	('child', 'Species', '9606', (295, 300))	('chromosomal aberrations', 'Disease', (62, 85))	('chromosomal aberrations', 'Disease', 'MESH:D002869', (62, 85))	('Prenatal exposure', 'Phenotype', 'HP:0031437', (0, 17))	('PAH', 'Chemical', 'MESH:D011084', (21, 24))
78752	29737912	Further, significantly elevated levels of PAH metabolites were found in urine from 5-year-old children who had stable chromosomal aberrations or translocations in concurrent blood samples compared with children without these translocations.	('chromosomal aberrations', 'Disease', 'MESH:D002869', (118, 141))	('translocations', 'Var', (145, 159))	('elevated', 'PosReg', (23, 31))	('PAH', 'Chemical', 'MESH:D011084', (42, 45))	('children', 'Species', '9606', (94, 102))	('levels', 'MPA', (32, 38))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (118, 141))	('chromosomal aberrations', 'Disease', (118, 141))	('children', 'Species', '9606', (202, 210))
78754	29737912	Together, this work suggests that elevated exposures to common air pollutants during pregnancy and early childhood, two periods relevant to pediatric leukemogenesis, are associated with formation of chromosomal translocations, an intermediate step in leukemogenesis, and may disproportionately affect some inner city children.	('chromosomal translocations', 'Var', (199, 225))	('children', 'Species', '9606', (317, 325))	('child', 'Species', '9606', (105, 110))	('pollutants during pregnancy', 'Phenotype', 'HP:0031437', (67, 94))	('associated with', 'Reg', (170, 185))	('child', 'Species', '9606', (317, 322))
78766	29737912	Austin et al reported that Hispanic ethnicity was independently associated with advanced stage disease at presentation for CNS tumors, whereas Black race was associated with advanced stage disease in non-CNS solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('associated', 'Reg', (64, 74))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('Hispanic ethnicity', 'Var', (27, 45))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('solid tumors', 'Disease', 'MESH:D009369', (208, 220))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('advanced stage disease', 'Disease', (80, 102))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('solid tumors', 'Disease', (208, 220))
78772	29737912	Nonadherence to oral chemotherapy is associated with approximately 60% of relapses among Hispanic and NHW children with ALL.	('ALL', 'Phenotype', 'HP:0006721', (120, 123))	('children', 'Species', '9606', (106, 114))	('Nonadherence', 'Var', (0, 12))	('relapses', 'Disease', (74, 82))
78794	30353072	Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation.	('yields', 'Reg', (112, 118))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('chondrogenic tumor', 'Disease', 'MESH:D009369', (143, 161))	('sarcomas', 'Disease', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('chondrogenic tumor', 'Disease', (143, 161))	('cell transformation', 'CPA', (119, 138))	('c-Fos', 'Var', (74, 79))	('chondrogenic tumor', 'Phenotype', 'HP:0030431', (143, 161))
78798	30353072	Murine MPCs (mMPCs) with mutations in p21, p53 and/or Rb serve as cell of origin of fibrosarcoma, leiomyosarcoma and OS.	('mutations', 'Var', (25, 34))	('leiomyosarcoma', 'Disease', (98, 112))	('p21', 'Gene', (38, 41))	('fibrosarcoma', 'Disease', 'MESH:D005354', (84, 96))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (84, 96))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (98, 112))	('p21', 'Gene', '12575', (38, 41))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (98, 112))	('OS', 'Phenotype', 'HP:0002669', (117, 119))	('Murine', 'Species', '10090', (0, 6))	('p53', 'Gene', (43, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('fibrosarcoma', 'Disease', (84, 96))
78800	30353072	Human MPCs (hMPCs) are more resistant to tumoral transformation, and therefore several events need to be combined to achieve an oncogenic phenotype, such as introduction of human telomerase (TERT), expression of HPV-16 E6 and E7 to abrogate the functions of p53 and pRB family members, expression of SV40 small T or large T antigens to inactivate protein phosphatase 2A (PP2A) and therefore stabilize c-Myc, and finally induction of H-RAS, a well-known oncogene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Human', 'Species', '9606', (0, 5))	('protein phosphatase 2A', 'Protein', (347, 369))	('abrogate', 'NegReg', (232, 240))	('stabilize', 'PosReg', (391, 400))	('H-RAS', 'Gene', (433, 438))	('tumoral transformation', 'Disease', 'MESH:D020518', (41, 63))	('H-RAS', 'Gene', '3265', (433, 438))	('inactivate', 'NegReg', (336, 346))	('SV40 small T', 'Var', (300, 312))	('functions', 'MPA', (245, 254))	('human', 'Species', '9606', (173, 178))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('c-Myc', 'Gene', (401, 406))	('tumoral transformation', 'Disease', (41, 63))	('PP2A', 'Gene', (371, 375))	('c-Myc', 'Gene', '4609', (401, 406))	('HPV-16', 'Species', '333760', (212, 218))
78803	30353072	In example, Osteochondroma appears when Ext1 is inactivated in the growth plate's chondrocyte and p53/p16 inactivated in these mice.	('Ext1', 'Gene', (40, 44))	('mice', 'Species', '10090', (127, 131))	('Osteochondroma', 'Phenotype', 'HP:0030431', (12, 26))	('Osteochondroma', 'Disease', (12, 26))	('Osteochondroma', 'Disease', 'MESH:D015831', (12, 26))	('p16', 'Gene', (102, 105))	('Ext1', 'Gene', '14042', (40, 44))	('inactivated', 'Var', (48, 59))	('p16', 'Gene', '12578', (102, 105))
78804	30353072	In the case of central chondrosarcomas, mutations in IDH push MPCs towards chondrogenic differentiation instead of osteogenic differentiation causing enchondromas, and additional mutations are required for progression towards chondrosarcoma.	('central chondrosarcomas', 'Disease', 'MESH:D002813', (15, 38))	('chondrosarcoma', 'Disease', 'MESH:D002813', (23, 37))	('chondrosarcoma', 'Disease', (23, 37))	('enchondromas', 'Disease', 'MESH:D002812', (150, 162))	('mutations', 'Var', (40, 49))	('MPCs', 'Gene', (62, 66))	('chondrosarcoma', 'Disease', 'MESH:D002813', (226, 240))	('chondrosarcoma', 'Disease', (226, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (23, 37))	('IDH', 'Gene', '3417', (53, 56))	('push', 'Reg', (57, 61))	('IDH', 'Gene', (53, 56))	('enchondromas', 'Disease', (150, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (226, 240))	('central chondrosarcomas', 'Disease', (15, 38))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (23, 38))	('enchondromas', 'Phenotype', 'HP:0030038', (150, 162))
78814	30353072	In accordance, c-Fos-transformed hMPCs give rise to chondrogenic tumors upon implantation in immunodeficient mice.	('chondrogenic tumors', 'Phenotype', 'HP:0030431', (52, 71))	('give rise to', 'Reg', (39, 51))	('chondrogenic tumors', 'Disease', 'MESH:D009369', (52, 71))	('c-Fos-transformed', 'Var', (15, 32))	('chondrogenic tumor', 'Phenotype', 'HP:0030431', (52, 70))	('chondrogenic tumors', 'Disease', (52, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('immunodeficient', 'Disease', 'MESH:D007153', (93, 108))	('mice', 'Species', '10090', (109, 113))	('immunodeficient', 'Disease', (93, 108))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
78823	30353072	Those cells, defined as 3 Hits hMPC (3H), overexpresses hTERT and HPV-16 E6/E7, which extend cell lifespan in culture and abrogate p53 and pRB function respectively, although they are no tumorogenic when inoculated in immunodeficient mice (3H in Table 1).	('HPV-16', 'Gene', (66, 72))	('tumor', 'Disease', (187, 192))	('E6/E7', 'Var', (73, 78))	('HPV-16', 'Species', '333760', (66, 72))	('3H', 'Chemical', '-', (37, 39))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('function', 'MPA', (143, 151))	('mice', 'Species', '10090', (234, 238))	('pRB', 'Protein', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('immunodeficient', 'Disease', 'MESH:D007153', (218, 233))	('immunodeficient', 'Disease', (218, 233))	('TERT', 'Gene', (57, 61))	('p53', 'Protein', (131, 134))	('TERT', 'Gene', '7015', (57, 61))	('extend', 'PosReg', (86, 92))	('cell lifespan', 'CPA', (93, 106))	('3H', 'Chemical', '-', (240, 242))	('abrogate', 'NegReg', (122, 130))
78825	30353072	In accordance to our results in primary hMPCs, we observed a significant increase in cell proliferation upon c-Fos expression in 3H-Fos cells (Fig.	('3H', 'Chemical', '-', (129, 131))	('cell proliferation', 'CPA', (85, 103))	('increase', 'PosReg', (73, 81))	('c-Fos', 'Protein', (109, 114))	('expression', 'Var', (115, 125))
78827	30353072	Accordingly, levels of B-Myb and Cyclin A1, which regulate cell cycle progression through G1/S and S/G2/M phases respectively, were also increased in 3H-Fos cells (Fig.	('B-Myb', 'Gene', (23, 28))	('Cyclin A1', 'Gene', '8900', (33, 42))	('cell cycle', 'CPA', (59, 69))	('Cyclin A1', 'Gene', (33, 42))	('S/G2', 'Var', (99, 103))	('increased', 'PosReg', (137, 146))	('S/G2', 'SUBSTITUTION', 'None', (99, 103))	('levels', 'MPA', (13, 19))	('B-Myb', 'Gene', '4605', (23, 28))	('3H', 'Chemical', '-', (150, 152))
78839	30353072	Altogether these data indicate that c-Fos expression increases proliferation rate and S/G2/M accumulation, while promotes in vitro transformation of immortalized hMPCs possibly related to an increased resistance to death and to mitochondrial dysfunction.	('promotes', 'PosReg', (113, 121))	('c-Fos', 'Protein', (36, 41))	('S/G2', 'Var', (86, 90))	('proliferation rate', 'CPA', (63, 81))	('S/G2', 'SUBSTITUTION', 'None', (86, 90))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (228, 253))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (228, 253))	('expression', 'Var', (42, 52))	('increases', 'PosReg', (53, 62))	('mitochondrial dysfunction', 'Disease', (228, 253))
78842	30353072	To test this hypothesis, we first analyzed the rate of random motility of individual cells by time-lapse videomicroscopy and found a markedly decreased cell mobility in 3H-Fos compared to 3H-O cells (Fig.	('3H-Fos', 'Var', (169, 175))	('3H', 'Chemical', '-', (188, 190))	('decreased', 'NegReg', (142, 151))	('3H', 'Chemical', '-', (169, 171))	('cell mobility', 'CPA', (152, 165))
78846	30353072	Accordingly, induction of alkaline phosphatase and RUNX2 mRNA upon osteogenic stimulation was impaired in 3H-Fos comparing with 3H-O cells (Fig.	('3H', 'Chemical', '-', (106, 108))	('impaired', 'NegReg', (94, 102))	('induction', 'MPA', (13, 22))	('3H-Fos', 'Var', (106, 112))	('RUNX2', 'Gene', (51, 56))	('alkaline phosphatase', 'MPA', (26, 46))	('3H', 'Chemical', '-', (128, 130))
78867	30353072	Once the effect of c-Fos in human MPC transformation was assessed, we moved to corroborate our findings in terms of chondral tumor phenotype related to c-Fos expression.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('human', 'Species', '9606', (28, 33))	('chondral tumor', 'Disease', (116, 130))	('c-Fos', 'Var', (152, 157))	('chondral tumor', 'Disease', 'MESH:D009369', (116, 130))
78868	30353072	A previous paper shows tumors arising from transformed mouse p53KO mMPCs switch their phenotype from osteoblastic to chondroblastic when c-Fos is expressed in them.	('p53KO mMPCs', 'Var', (61, 72))	('osteoblastic', 'CPA', (101, 113))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('chondroblastic', 'CPA', (117, 131))	('mouse', 'Species', '10090', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('switch', 'Reg', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
78871	30353072	After p53-/-Rb-/- mMPCs transduction with c-Fos lentiviral vector (mMPC-Fos), the transgene expression was confirmed (Supplementary Fig.	('C-Fos', 'Gene', '2353', (70, 75))	('p53-/-Rb-/- mMPCs', 'Var', (6, 23))	('C-Fos', 'Gene', (70, 75))
78876	30353072	In contraposition, the tibias injected with control p53-/-Rb-/- mMPCs (mMPC-O) showed the expected osteogenic tumors (Fig.	('tibias', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('osteogenic tumors', 'Disease', (99, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tibias', 'Disease', 'MESH:C535563', (23, 29))	('p53-/-Rb-/- mMPCs', 'Var', (52, 69))	('osteogenic tumors', 'Disease', 'MESH:D012516', (99, 116))
78878	30353072	c-Fos is a known oncogene expressed in sarcoma tumors, whose deregulated expression is enough to transform a number of cell types, including cells of mesenchymal origin as fibroblasts.	('deregulated', 'Var', (61, 72))	('sarcoma tumors', 'Disease', (39, 53))	('c-Fos', 'Gene', (0, 5))	('expression', 'MPA', (73, 83))	('sarcoma tumors', 'Disease', 'MESH:D012509', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('transform', 'Reg', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
78881	30353072	Conversely, tumors originated in c-Fos chimeric mice show clear chondrogenic phenotype, indicating preferential c-Fos targeting to chondrogenic cells.	('mice', 'Species', '10090', (48, 52))	('chimeric', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('targeting', 'MPA', (118, 127))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('preferential', 'PosReg', (99, 111))	('c-Fos chimeric', 'Var', (33, 47))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
78884	30353072	Forced expression of c-Fos in mouse embryo limb bud at E10 causes chondrodysplasia, thus indicating a common target cell type in this model and in c-Fos chimeras.	('E10', 'Var', (55, 58))	('chondrodysplasia', 'Disease', (66, 82))	('chondrodysplasia', 'Disease', 'MESH:D010009', (66, 82))	('causes', 'Reg', (59, 65))	('c-Fos', 'Gene', (21, 26))	('mouse', 'Species', '10090', (30, 35))
78894	30353072	We then employed immortalized hMPCs, which accumulate oncogenic modifications in hTERT and HPV-16 E6/E7 genes but still do not display tumorigenic features.	('TERT', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('E6/E7 genes', 'Var', (98, 109))	('HPV-16', 'Species', '333760', (91, 97))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('TERT', 'Gene', '7015', (82, 86))	('modifications', 'Var', (64, 77))	('HPV-16', 'Gene', (91, 97))
78898	30353072	Our data indicate that c-Fos induces higher proliferation rate of both primary and immortalized hMPCs; this correlates with an increase in the percentage of cells in S and M phases, and an increment in B-Myb and cyclin A expression in 3H-Fos comparing with 3H-O.	('3H', 'Chemical', '-', (235, 237))	('higher', 'PosReg', (37, 43))	('cyclin A', 'Gene', (212, 220))	('increment', 'PosReg', (189, 198))	('cyclin A', 'Gene', '890', (212, 220))	('3H', 'Chemical', '-', (257, 259))	('B-Myb', 'Gene', '4605', (202, 207))	('increase', 'PosReg', (127, 135))	('B-Myb', 'Gene', (202, 207))	('proliferation rate', 'CPA', (44, 62))	('expression', 'MPA', (221, 231))	('c-Fos', 'Var', (23, 28))
78906	30353072	When we tested cell function, we observed reduced mobility due to c-Fos expression and we concluded 3H-Fos cells are unable to properly generate actin polymerization and microtube formation, thereby reducing their ability to move and migrate.	('reduced', 'NegReg', (42, 49))	('microtube formation', 'MPA', (170, 189))	('unable', 'NegReg', (117, 123))	('mobility', 'MPA', (50, 58))	('c-Fos expression', 'Protein', (66, 82))	('reducing', 'NegReg', (199, 207))	('3H', 'Chemical', '-', (100, 102))	('actin polymerization', 'MPA', (145, 165))	('3H-Fos', 'Var', (100, 106))
78910	30353072	A recent study suggests c-Fos in p53KO mouse MPCs induces the expression of SOX9, a master regulator of chondrogenesis, and downregulation of RUNX2, a master regulator of osteogenesis.	('p53KO', 'Var', (33, 38))	('c-Fos', 'Var', (24, 29))	('expression', 'MPA', (62, 72))	('SOX9', 'Gene', (76, 80))	('induces', 'PosReg', (50, 57))	('RUNX2', 'Gene', (142, 147))	('mouse', 'Species', '10090', (39, 44))	('downregulation', 'NegReg', (124, 138))
78922	30353072	reported recurrent rearrangement of FOS only in osteoblastoma benign tumors and not in other malignant bone tumors, concluding that in clinic FOS may be genetically altered only in benign bone tumors.	('bone tumors', 'Phenotype', 'HP:0010622', (188, 199))	('OS', 'Phenotype', 'HP:0002669', (37, 39))	('bone tumors', 'Disease', 'MESH:D001859', (103, 114))	('rearrangement', 'Var', (19, 32))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('bone tumors', 'Disease', 'MESH:D001859', (188, 199))	('benign bone tumors', 'Disease', 'MESH:D001859', (181, 199))	('benign bone tumors', 'Disease', (181, 199))	('FOS', 'Gene', (142, 145))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('osteoblastoma', 'Phenotype', 'HP:0011846', (48, 61))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('FOS', 'Gene', '2353', (142, 145))	('osteoblastoma benign tumors', 'Disease', (48, 75))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('osteoblastoma benign tumors', 'Disease', 'MESH:D018215', (48, 75))	('FOS', 'Gene', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('FOS', 'Gene', '2353', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('bone tumors', 'Disease', (103, 114))	('OS', 'Phenotype', 'HP:0002669', (143, 145))	('bone tumors', 'Phenotype', 'HP:0010622', (103, 114))
78943	24019649	Pre-operative MRI was carried out in all patients with acquisition of T1W, T2W, and short tau inversion recovery (STIR) sequences in appropriate planes.	('T1W', 'Var', (70, 73))	('patients', 'Species', '9606', (41, 49))	('T2W', 'Var', (75, 78))
78963	24019649	T1W, T2W fat suppressed, and STIR images were routinely acquired in axial and orthogonal planes in all the patients.	('T2W', 'Var', (5, 8))	('T1W', 'Var', (0, 3))	('patients', 'Species', '9606', (107, 115))
79040	24019649	Thus, the temporal delay yielded an inaccuracy in the calculation of pre-operative staging parameters such as size, number of compartments involved, etc., Differences in the orientation of MR scan planes and in tumor orientation during imaging and pathologic examination may exaggerate disparities.	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Differences', 'Var', (155, 166))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (211, 216))
79056	24019649	They found that interpretations based on combined PET-CT and conventional imaging findings MRI correctly staged tumors in 60 (87%) patients, over staged in 8 (12%) patients and under staged in 1 (1%) patient.	('patients', 'Species', '9606', (131, 139))	('over', 'PosReg', (141, 145))	('MRI', 'Var', (91, 94))	('patient', 'Species', '9606', (164, 171))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patient', 'Species', '9606', (131, 138))	('patients', 'Species', '9606', (164, 172))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('patient', 'Species', '9606', (200, 207))	('tumors', 'Disease', (112, 118))
79084	22640803	In our clinical molecular diagnostic laboratory, pyrosequencing is used for EGFR (codon 719, 746-753, 768, 790 and 858), KRAS (codon 12, 13 and 61) and BRAF (codon 600) mutation tests.	('rat', 'Species', '10116', (41, 44))	('codon', 'Var', (127, 132))	('EGFR', 'Gene', (76, 80))
79104	22640803	Since the wildtype EGFR exon 21 is supposed to have a thymidine (T) at this position, the G peak observed at this position indicates that there is a T to G mutation, which, in fact, is corresponding to the EGFR L858R mutation.	('L858R', 'Mutation', 'rs121434568', (211, 216))	('EGFR', 'Gene', (206, 210))	('thymidine', 'Chemical', 'MESH:D013936', (54, 63))	('T to G', 'Var', (149, 155))	('L858R', 'Var', (211, 216))
79105	22640803	The software analysis algorithm involves multiple steps, which can be illustrated as following, using EGFR mutation as an example.	('mutation', 'Var', (107, 115))	('EGFR', 'Gene', (102, 106))	('rat', 'Species', '10116', (76, 79))
79108	22640803	In the example shown in Figure 1, the peak pattern fits the EGFR L858R mutation.	('L858R', 'Var', (65, 70))	('fits', 'Disease', (51, 55))	('L858R', 'Mutation', 'rs121434568', (65, 70))	('EGFR', 'Gene', (60, 64))	('fits', 'Disease', 'MESH:D012640', (51, 55))
79112	22640803	When the working draft software was used to analyze this pyrogram, the result was positive for BRAF V600E mutation (data not shown).	('V600E', 'Mutation', 'rs113488022', (100, 105))	('BRAF', 'Gene', (95, 99))	('positive', 'Reg', (82, 90))	('V600E mutation', 'Var', (100, 114))
79113	22640803	However, this specimen is actually positive for V600K mutation.	('V600K', 'Mutation', 'rs121913227', (48, 53))	('positive', 'Reg', (35, 43))	('V600K', 'Var', (48, 53))
79116	22640803	Using BRAF mutation as an example (see pyrograms in Figures 2A and 3A), the dispensing order is TCGTATCTGTAG and usually no peak is expected at the dispensing positions 1, 3, and 6.	('mutation', 'Var', (11, 19))	('TCGTATCTGTAG', 'Var', (96, 108))	('TCGTATCTGTAG', 'Chemical', '-', (96, 108))	('BRAF', 'Gene', (6, 10))
79120	22640803	V600E, V600K and V600R.	('V600K', 'Var', (7, 12))	('V600R', 'Var', (17, 22))	('V600K', 'Mutation', 'rs121913227', (7, 12))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('V600R', 'Mutation', 'rs121913227', (17, 22))	('V600E', 'Var', (0, 5))
79132	22640803	An example is BRAF V600K mutation.	('BRAF', 'Gene', (14, 18))	('V600K', 'Mutation', 'rs121913227', (19, 24))	('V600K', 'Var', (19, 24))
79134	22640803	In the case of the V600K mutation, apart from mutant peak T (second peak at dispensing position 4), the fourth peak C and fifth peak T (at the dispensing position 7 and 8) are lower than normal.	('lower', 'NegReg', (176, 181))	('V600K', 'Mutation', 'rs121913227', (19, 24))	('fourth peak C', 'MPA', (104, 117))	('V600K', 'Var', (19, 24))
79139	22640803	During the testing process, it was realized that although such settings can recognize some V600K mutations, but will occasionally misinterpret some V600K cases as V600E.	('V600E', 'Mutation', 'rs113488022', (163, 168))	('V600K', 'Var', (148, 153))	('V600K', 'Mutation', 'rs121913227', (148, 153))	('V600K', 'Var', (91, 96))	('V600K', 'Mutation', 'rs121913227', (91, 96))
79143	22640803	For example, it has been tailored in such a way so that it can distinguish BRAF V600E, V600K and V600R mutations.	('V600K', 'Mutation', 'rs121913227', (87, 92))	('V600R', 'Var', (97, 102))	('V600E', 'Var', (80, 85))	('BRAF', 'Gene', (75, 79))	('V600E', 'Mutation', 'rs113488022', (80, 85))	('V600K', 'Var', (87, 92))	('V600R', 'Mutation', 'rs121913227', (97, 102))
79146	22640803	EGFR, Epidermal growth factor receptor; KRAS, Kirsten rat sarcoma viral oncogene homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B1 mutations.	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (96, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('rat', 'Species', '10116', (54, 57))	('Epidermal growth factor receptor', 'Gene', (6, 38))	('Epidermal growth factor receptor', 'Gene', '24329', (6, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('sarcoma', 'Disease', (109, 116))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '114486', (96, 142))	('sarcoma', 'Disease', (58, 65))	('mutations', 'Var', (143, 152))
79153	22577336	Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('inhibits', 'NegReg', (45, 53))	('MAPK', 'Gene', (30, 34))	('bone sarcomas', 'Phenotype', 'HP:0002669', (124, 137))	('local invasiveness', 'CPA', (69, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('drug resistance', 'CPA', (105, 120))	('proliferation', 'CPA', (54, 67))	('bone sarcomas', 'Disease', 'MESH:D001847', (124, 137))	('drug resistance', 'Phenotype', 'HP:0020174', (105, 120))	('metastasis', 'CPA', (89, 99))	('targeting', 'Var', (35, 44))	('bone sarcomas', 'Disease', (124, 137))	('bone sarcoma', 'Phenotype', 'HP:0002669', (124, 136))
79154	22577336	A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('osteosarcomas', 'Disease', 'MESH:D012516', (98, 111))	('unresectable', 'Disease', (71, 83))	('patients', 'Species', '9606', (57, 65))	('osteosarcomas', 'Phenotype', 'HP:0002669', (98, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('MAPK/ERK', 'Gene', (122, 130))	('benefits', 'PosReg', (45, 53))	('targeting therapy', 'Var', (131, 148))	('osteosarcomas', 'Disease', (98, 111))
79174	22577336	When gain-of-function mutations occur in Ras/Raf, a commonly observed phenomenon in many types of cancers, MEK/MAPK proteins become constitutively activated.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Raf', 'Gene', '22882', (45, 48))	('gain-of-function', 'PosReg', (5, 21))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('MEK', 'Gene', (107, 110))	('MEK', 'Gene', '5609', (107, 110))	('cancers', 'Disease', (98, 105))	('mutations', 'Var', (22, 31))	('Raf', 'Gene', (45, 48))	('ser', 'Chemical', 'MESH:D012694', (63, 66))
79182	22577336	Patients with metastatic gastric cancers expressing p-MAPK/ERK in tumor showed decreased disease-free overall survival (8.5 months) in comparison to nonexpressing cancers (13.7 months) indicating p-MAPK as a negative prognostic indicator in metastatic gastric cancers.	('cancers', 'Disease', 'MESH:D009369', (260, 267))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('decreased', 'NegReg', (79, 88))	('tumor', 'Disease', (66, 71))	('p-MAPK/ERK', 'Var', (52, 62))	('cancers', 'Disease', (33, 40))	('gastric cancers', 'Disease', (25, 40))	('gastric cancers', 'Disease', 'MESH:D013274', (25, 40))	('gastric cancers', 'Phenotype', 'HP:0012126', (25, 40))	('Patients', 'Species', '9606', (0, 8))	('disease-free overall survival', 'CPA', (89, 118))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('cancers', 'Disease', (260, 267))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('gastric cancers', 'Disease', (252, 267))	('gastric cancers', 'Disease', 'MESH:D013274', (252, 267))	('gastric cancers', 'Phenotype', 'HP:0012126', (252, 267))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancers', 'Disease', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
79193	22577336	While most studies suggest that the inhibition of ERK 1/2 leads to increased apoptosis and decreased metastasis, some studies conclude that the activation of RAF/MAPK/MEK/ERK1/2 pathway is required for osteosarcoma cells apoptosis.	('MEK', 'Gene', (167, 170))	('osteosarcoma', 'Phenotype', 'HP:0002669', (202, 214))	('MEK', 'Gene', '5609', (167, 170))	('osteosarcoma', 'Disease', (202, 214))	('ERK 1/2', 'Gene', '5595;5594', (50, 57))	('decreased', 'NegReg', (91, 100))	('apoptosis', 'CPA', (77, 86))	('inhibition', 'Var', (36, 46))	('osteosarcoma', 'Disease', 'MESH:D012516', (202, 214))	('ERK 1/2', 'Gene', (50, 57))	('metastasis', 'CPA', (101, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('RAF', 'Gene', '22882', (158, 161))	('RAF', 'Gene', (158, 161))
79195	22577336	examined the therapeutic effect of PD98059 (an inhibitor of ERK1/2 phosphorylation) on osteosarcoma cell lines in vitro (Figure 2).	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('PD98059', 'Var', (35, 42))	('osteosarcoma', 'Disease', (87, 99))	('osteosarcoma', 'Disease', 'MESH:D012516', (87, 99))	('PD98059', 'Chemical', 'MESH:C093973', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
79198	22577336	ERK1/2 inhibition prevented doxorubicin-induced upregulation of Bcl-2 and Bcl-xL, thereby increasing doxorubicin sensitivity in osteosarcoma cells.	('Bcl-xL', 'Gene', (74, 80))	('Bcl-2', 'Gene', '596', (64, 69))	('ERK1/2', 'Gene', (0, 6))	('osteosarcoma', 'Disease', (128, 140))	('doxorubicin sensitivity', 'MPA', (101, 124))	('prevented', 'NegReg', (18, 27))	('inhibition', 'Var', (7, 17))	('osteosarcoma', 'Phenotype', 'HP:0002669', (128, 140))	('doxorubicin', 'Chemical', 'MESH:D004317', (28, 39))	('osteosarcoma', 'Disease', 'MESH:D012516', (128, 140))	('Bcl-2', 'Gene', (64, 69))	('Bcl-xL', 'Gene', '598', (74, 80))	('increasing', 'PosReg', (90, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('doxorubicin', 'Chemical', 'MESH:D004317', (101, 112))	('upregulation', 'PosReg', (48, 60))
79199	22577336	In human osteosarcoma cell line SaOS-2 cells, MEK/MAPK is a negative regulator of differentiation while p38 MAPK promotes differentiation.	('promotes', 'PosReg', (113, 121))	('differentiation', 'MPA', (122, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('human', 'Species', '9606', (3, 8))	('SaOS-2', 'CellLine', 'CVCL:0548', (32, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('osteosarcoma', 'Disease', (9, 21))	('p38 MAPK', 'Var', (104, 112))	('MEK', 'Gene', (46, 49))	('MEK', 'Gene', '5609', (46, 49))
79201	22577336	pERK inhibitor PD98059 inhibited motility of human osteosarcoma cells in vitro, suggesting that pERK inhibitors impede local invasion and metastasis.	('PD98059', 'Var', (15, 22))	('PD98059', 'Chemical', 'MESH:C093973', (15, 22))	('inhibited', 'NegReg', (23, 32))	('pERK', 'Gene', '9451', (0, 4))	('pERK', 'Gene', (0, 4))	('osteosarcoma', 'Disease', (51, 63))	('pERK', 'Gene', '9451', (96, 100))	('pERK', 'Gene', (96, 100))	('impede', 'NegReg', (112, 118))	('osteosarcoma', 'Disease', 'MESH:D012516', (51, 63))	('human', 'Species', '9606', (45, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('motility', 'CPA', (33, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (51, 63))
79202	22577336	Various targeted inhibitors have been shown to have antitumor effects in osteosarcoma (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('osteosarcoma', 'Phenotype', 'HP:0002669', (73, 85))	('osteosarcoma', 'Disease', (73, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (73, 85))	('inhibitors', 'Var', (17, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
79203	22577336	An in vivo survival study using 143B human osteosarcoma cells with elevated Ras activity demonstrated that pERK targeting with PD98059 resulted in slower tumor growth and prolonged survival by inducing the production of proapoptotic proteins.	('prolonged', 'PosReg', (171, 180))	('osteosarcoma', 'Disease', 'MESH:D012516', (43, 55))	('inducing', 'PosReg', (193, 201))	('PD98059', 'Var', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('production of proapoptotic proteins', 'MPA', (206, 241))	('PD98059', 'Chemical', 'MESH:C093973', (127, 134))	('slower tumor', 'Disease', (147, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('survival', 'CPA', (181, 189))	('pERK', 'Gene', '9451', (107, 111))	('pERK', 'Gene', (107, 111))	('human', 'Species', '9606', (37, 42))	('slower tumor', 'Disease', 'MESH:D009369', (147, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (43, 55))	('osteosarcoma', 'Disease', (43, 55))
79204	22577336	Combinatorial treatment with doxorubicin and PD98059 further prolonged the survival of osteosarcoma-bearing mice.	('survival', 'CPA', (75, 83))	('doxorubicin', 'Chemical', 'MESH:D004317', (29, 40))	('PD98059', 'Var', (45, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('mice', 'Species', '10090', (108, 112))	('osteosarcoma', 'Disease', (87, 99))	('osteosarcoma', 'Disease', 'MESH:D012516', (87, 99))	('PD98059', 'Chemical', 'MESH:C093973', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('prolonged', 'PosReg', (61, 70))
79210	22577336	In osteosarcoma, expression of VEGF-R3 is associated with poor event-free and overall survival while VEGF-B correlated with a poor histological response to chemotherapy.	('VEGF-R3', 'Gene', (31, 38))	('VEGF-B', 'Gene', (101, 107))	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('overall survival', 'CPA', (78, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('VEGF-R3', 'Gene', '2324', (31, 38))	('expression', 'Var', (17, 27))	('poor', 'NegReg', (58, 62))	('VEGF-B', 'Gene', '7423', (101, 107))
79224	22577336	Two major downstream IGF pathways, that are, MAPK and PI3K, play an important role in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 99))	('Ewing sarcoma', 'Disease', (86, 99))	('IGF pathways', 'Pathway', (21, 33))	('PI3K', 'Var', (54, 58))
79226	22577336	PD98059 and U0126 (MEK inhibitor) impaired Ewing sarcoma cell growth by inducing G1 blockage and reducing its migratory effect (Figure 2).	('U0126', 'Var', (12, 17))	('MEK', 'Gene', '5609', (19, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('PD98059', 'Var', (0, 7))	('blockage', 'NegReg', (84, 92))	('inducing', 'PosReg', (72, 80))	('impaired Ewing sarcoma cell', 'Disease', (34, 61))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('migratory effect', 'CPA', (110, 126))	('reducing', 'NegReg', (97, 105))	('U0126', 'Chemical', 'MESH:C113580', (12, 17))	('MEK', 'Gene', (19, 22))	('impaired Ewing sarcoma cell', 'Disease', 'MESH:C563168', (34, 61))
79227	22577336	Another study confirmed that combined administration of U0126 and LY294002 (PI3K inhibitor) enhanced actinomycin-D-induced apoptosis in vitro and in vivo.	('U0126', 'Chemical', 'MESH:C113580', (56, 61))	('LY294002', 'Var', (66, 74))	('actinomycin-D-induced apoptosis', 'MPA', (101, 132))	('U0126', 'Var', (56, 61))	('LY294002', 'Chemical', 'MESH:C085911', (66, 74))	('actinomycin-D', 'Chemical', 'MESH:D003609', (101, 114))	('enhanced', 'PosReg', (92, 100))
79228	22577336	ERK1/2 proteins are constitutively activated in transformed NIH 3T3 cells expressing EWS/FLI-1 and ERK inhibition impaired the ability of EWS/FLI-1 overexpression to transform NIH3T3.	('NIH3T3', 'Gene', (176, 182))	('FLI-1', 'Gene', (142, 147))	('FLI-1', 'Gene', '14247', (142, 147))	('NIH 3T3', 'CellLine', 'CVCL:0594', (60, 67))	('ERK', 'Gene', (99, 102))	('FLI-1', 'Gene', '14247', (89, 94))	('inhibition', 'Var', (103, 113))	('transform', 'MPA', (166, 175))	('FLI-1', 'Gene', (89, 94))	('impaired', 'NegReg', (114, 122))
79233	22577336	NVP-AEW541, a dual pan-PI3K-mTOR inhibitor, inhibited growth of Ewing sarcoma and metastasis in athymic mice.	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('inhibited', 'NegReg', (44, 53))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (64, 77))	('mice', 'Species', '10090', (104, 108))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (64, 77))	('NVP-AEW541', 'Var', (0, 10))	('metastasis', 'CPA', (82, 92))	('growth', 'CPA', (54, 60))	('Ewing sarcoma', 'Disease', (64, 77))
79238	22577336	In phase I trials, IGF-1R inhibitors (R1507, AMG479, CP-751, 871) showed sustained remission in patients with Ewing sarcoma.	('R1507', 'Var', (38, 43))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (110, 123))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (110, 123))	('AMG479', 'Var', (45, 51))	('IGF-1R', 'Gene', (19, 25))	('patients', 'Species', '9606', (96, 104))	('CP-751', 'Chemical', '-', (53, 59))	('CP-751, 871', 'Var', (53, 64))	('Ewing sarcoma', 'Disease', (110, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
79258	22577336	Both PD98059 and U0126 inhibited osteopontin-induced MMP-9 upregulation and migration of human chondrosarcoma cells.	('U0126', 'Chemical', 'MESH:C113580', (17, 22))	('human', 'Species', '9606', (89, 94))	('PD98059', 'Chemical', 'MESH:C093973', (5, 12))	('inhibited', 'NegReg', (23, 32))	('migration', 'CPA', (76, 85))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (95, 109))	('osteopontin', 'Gene', '6696', (33, 44))	('osteopontin', 'Gene', (33, 44))	('chondrosarcoma', 'Disease', 'MESH:D002813', (95, 109))	('MMP-9', 'Gene', '4318', (53, 58))	('U0126', 'Var', (17, 22))	('upregulation', 'PosReg', (59, 71))	('MMP-9', 'Gene', (53, 58))	('chondrosarcoma', 'Disease', (95, 109))	('PD98059', 'Var', (5, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
79264	22577336	alpha5beta1 monoclonal antibody and MEK inhibitors (PD98059 and U0126) inhibited migration of chondrosarcoma cells.	('U0126', 'Chemical', 'MESH:C113580', (64, 69))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (94, 108))	('alpha5beta1 monoclonal', 'Protein', (0, 22))	('inhibited', 'NegReg', (71, 80))	('chondrosarcoma', 'Disease', (94, 108))	('chondrosarcoma', 'Disease', 'MESH:D002813', (94, 108))	('U0126', 'Var', (64, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('MEK', 'Gene', (36, 39))	('PD98059', 'Var', (52, 59))	('PD98059', 'Chemical', 'MESH:C093973', (52, 59))	('MEK', 'Gene', '5609', (36, 39))
79273	22577336	In vitro proof of therapeutic concept studies assures that pMAPK/ERK targeting offers new methods of inhibiting proliferation, invasion, angiogenesis, and inflammation which are the hallmarks of cancers.	('pMAPK/ERK', 'Gene', (59, 68))	('invasion', 'CPA', (127, 135))	('angiogenesis', 'CPA', (137, 149))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('targeting', 'Var', (69, 78))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Disease', (195, 202))	('proliferation', 'CPA', (112, 125))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))	('inflammation', 'Disease', (155, 167))	('inhibiting', 'NegReg', (101, 111))
79279	22034177	Identification of a Novel, Recurrent HEY1-NCOA2 Fusion in Mesenchymal Chondrosarcoma based on a Genome-wide Screen of Exon-level Expression Data Cancer gene fusions that encode a chimeric protein are often characterized by an intragenic discontinuity in the RNA expression levels of the exons that are 5' or 3' to the fusion point in one or both of the fusion partners due to differences in the levels of activation of their respective promoters.	('Chondrosarcoma', 'Phenotype', 'HP:0006765', (70, 84))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('fusions', 'Var', (157, 164))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('si', 'Chemical', 'MESH:D012825', (159, 161))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('HEY1', 'Gene', '15213', (37, 41))	('HEY1', 'Gene', (37, 41))	('Cancer', 'Disease', (145, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('si', 'Chemical', 'MESH:D012825', (355, 357))	('Fusion', 'Var', (48, 54))	('NCOA2', 'Gene', '10499', (42, 47))	('Mesenchymal Chondrosarcoma', 'Disease', (58, 84))	('Cancer', 'Disease', 'MESH:D009369', (145, 151))	('Mesenchymal Chondrosarcoma', 'Disease', 'MESH:D018211', (58, 84))	('si', 'Chemical', 'MESH:D012825', (268, 270))	('NCOA2', 'Gene', (42, 47))	('RNA expression', 'MPA', (258, 272))	('si', 'Chemical', 'MESH:D012825', (320, 322))
79286	22034177	We also identified a NUP107-LGR5 fusion in a dedifferentiated liposarcoma but analysis of 17 additional samples did not confirm it as a recurrent event in this sarcoma type.	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcoma type', 'Disease', 'MESH:D012509', (160, 172))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('liposarcoma', 'Disease', (62, 73))	('NUP107-LGR5', 'Gene', (21, 32))	('sarcoma type', 'Disease', (160, 172))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))	('fusion', 'Var', (33, 39))	('liposarcoma', 'Disease', 'MESH:D008080', (62, 73))
79287	22034177	The novel HEY1-NCOA2 fusion appears to be the defining and diagnostic gene fusion in mesenchymal chondrosarcomas.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (97, 112))	('NCOA2', 'Gene', (15, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('mesenchymal chondrosarcomas', 'Disease', (85, 112))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('fusion', 'Var', (21, 27))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (85, 112))	('NCOA2', 'Gene', '10499', (15, 20))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (97, 111))
79298	22034177	The fundamental rationale for exon-level expression profiling in the detection of fusion genes is based on the observation that most gene fusions that lead to the formation of a chimeric fusion protein cause an intragenic discontinuity in the RNA expression level of the exons that are 5' or 3' to the fusion point in one or both of the fusion partners.	('si', 'Chemical', 'MESH:D012825', (84, 86))	('si', 'Chemical', 'MESH:D012825', (304, 306))	('cause', 'Reg', (202, 207))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('si', 'Chemical', 'MESH:D012825', (253, 255))	('si', 'Chemical', 'MESH:D012825', (339, 341))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('RNA expression level of the exons', 'MPA', (243, 276))	('fusions', 'Var', (138, 145))	('si', 'Chemical', 'MESH:D012825', (189, 191))
79301	22034177	We demonstrate the successful application of this approach in detection of gene fusions without prior knowledge of the genetic background of a given case, and describe the identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma.	('mesenchymal chondrosarcoma', 'Disease', 'MESH:D018211', (230, 256))	('NCOA2', 'Gene', (214, 219))	('mesenchymal chondrosarcoma', 'Disease', (230, 256))	('si', 'Chemical', 'MESH:D012825', (222, 224))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('fusion', 'Var', (220, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('NCOA2', 'Gene', '10499', (214, 219))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (242, 256))
79312	22034177	The fundamental signal pattern of a cancer gene fusion is a sharp change in exon level expression moving from the 5' to the 3' end of one or sometimes both of the translocation partner genes.	('si', 'Chemical', 'MESH:D012825', (93, 95))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('cancer', 'Disease', (36, 42))	('change', 'Reg', (66, 72))	('exon level expression', 'MPA', (76, 97))	('fusion', 'Var', (48, 54))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
79320	22034177	The training set included the known EWSR1-FLI1 and EWSR1-WT1-positive cases (using the genes FLl1 and WT1) in 8 tumor samples TM_HuEx_1_JN_DSCRT, TM_HuEx_1_ExDS1, TM_HuEx_1_ExDS2, TM_HuEx_1_ExDS3, LW_Exon1_SK_PN_DW, TM_HuEx_1_ExES4, TM_HuEx_1_ExES6, and TM_HuEx_1_ExES7 for which the fusion outcome was set to 1 (or 1-epsilon , where epsilon is a small number) and 32 normal samples for which the fusion outcome was set to zero (or epsilon ).	('EWSR1', 'Gene', '2130', (36, 41))	('si', 'Chemical', 'MESH:D012825', (399, 401))	('WT1', 'Gene', '7490', (102, 105))	('FLI1', 'Gene', '2313', (42, 46))	('EWSR1', 'Gene', '2130', (51, 56))	('si', 'Chemical', 'MESH:D012825', (336, 338))	('si', 'Chemical', 'MESH:D012825', (286, 288))	('EWSR1', 'Gene', (36, 41))	('tumor', 'Disease', (112, 117))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('si', 'Chemical', 'MESH:D012825', (434, 436))	('WT1', 'Gene', (57, 60))	('EWSR1', 'Gene', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('TM_HuEx_1_JN_DSCRT', 'Var', (126, 144))	('WT1', 'Gene', '7490', (57, 60))	('FLI1', 'Gene', (42, 46))	('WT1', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('si', 'Chemical', 'MESH:D012825', (320, 322))
79333	22034177	The primer pair HEY1-F1/NCOA2-R3 was also used for screening for HEY1-NCOA2 fusion transcripts in a set of 14 cases diagnosed histologically as mesenchymal chondrosarcoma.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (156, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('NCOA2', 'Gene', '10499', (24, 29))	('NCOA2', 'Gene', '10499', (70, 75))	('mesenchymal chondrosarcoma', 'Disease', (144, 170))	('NCOA2', 'Gene', (24, 29))	('fusion transcripts', 'Var', (76, 94))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('NCOA2', 'Gene', (70, 75))	('mesenchymal chondrosarcoma', 'Disease', 'MESH:D018211', (144, 170))
79337	22034177	NCOA2 probe, a combination of BAC clones RP11-126F11 and RP11-152C15, was labeled in green; HEY1 probe, BAC clone RP11-888F10 was labeled in red.	('NCOA2', 'Gene', (0, 5))	('RP11-152C15', 'Var', (57, 68))	('NCOA2', 'Gene', '10499', (0, 5))	('RP11-126F11', 'Var', (41, 52))
79369	22034177	As BAC clone RP11-888F10, spanning sequences upstream of HEY1, was labeled in red, fused green/red (yellow) signals were expected in HEY1-NCOA2 fusion cases.	('si', 'Chemical', 'MESH:D012825', (146, 148))	('NCOA2', 'Gene', '10499', (138, 143))	('RP11-888F10', 'Var', (13, 24))	('NCOA2', 'Gene', (138, 143))	('si', 'Chemical', 'MESH:D012825', (108, 110))
79396	22034177	Notably, NUP107 is approximately 100 kb centromeric to MDM2 and therefore lies in a common boundary for 12q amplicons in dedifferentiated liposarcomas.	('liposarcomas', 'Disease', (138, 150))	('NUP107', 'Var', (9, 15))	('liposarcoma', 'Phenotype', 'HP:0012034', (138, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('liposarcomas', 'Phenotype', 'HP:0012034', (138, 150))	('MDM2', 'Gene', (55, 59))	('liposarcomas', 'Disease', 'MESH:D008080', (138, 150))
79399	22034177	In addition, we also identified a novel but non-recurrent NUP107-LGR5 fusion in a dedifferentiated liposarcoma case with the same approach.	('liposarcoma', 'Disease', (99, 110))	('NUP107-LGR5', 'Gene', (58, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('liposarcoma', 'Phenotype', 'HP:0012034', (99, 110))	('fusion', 'Var', (70, 76))	('liposarcoma', 'Disease', 'MESH:D008080', (99, 110))	('si', 'Chemical', 'MESH:D012825', (72, 74))
79402	22034177	Specifically, have reported the detection of the TMPRS22-ERG fusion in prostate cancer and demonstrated the detection of the EML4-ALK fusion in lung cancers by exon expression profiling using Affymetrix Human Exon 1.0 ST Arrays.	('fusion', 'Var', (61, 67))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('EML4', 'Gene', (125, 129))	('EML4', 'Gene', '27436', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancers', 'Disease', 'MESH:D008175', (144, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('ALK', 'Gene', '238', (130, 133))	('lung cancers', 'Disease', (144, 156))	('prostate cancer', 'Disease', (71, 86))	('ALK', 'Gene', (130, 133))	('Human', 'Species', '9606', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancers', 'Phenotype', 'HP:0100526', (144, 156))	('ERG', 'Gene', (57, 60))	('si', 'Chemical', 'MESH:D012825', (187, 189))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('ERG', 'Gene', '2078', (57, 60))
79405	22034177	The novel HEY1-NCOA2 fusion reported here is the first recurrent gene fusion identified in mesenchymal chondrosarcoma.	('mesenchymal chondrosarcoma', 'Disease', (91, 117))	('NCOA2', 'Gene', (15, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('fusion', 'Var', (21, 27))	('mesenchymal chondrosarcoma', 'Disease', 'MESH:D018211', (91, 117))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (103, 117))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('NCOA2', 'Gene', '10499', (15, 20))
79411	22034177	Given that HEY1 and NCOA2 are only about 10 Mb apart, respectively mapping to 8q21.1 and 8q13.3, and both are on the reverse strand, this fusion could arise most simply from a small interstitial deletion, del(8)(q13.3q21.1), which would be cryptic in most conventional banding preparations.	('del(8)(q13.3q21.1', 'Var', (205, 222))	('NCOA2', 'Gene', '10499', (20, 25))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('NCOA2', 'Gene', (20, 25))	('arise', 'Reg', (151, 156))	('si', 'Chemical', 'MESH:D012825', (140, 142))
79413	22034177	The consistent detection of the HEY1-NCOA2 fusion in mesenchymal chondrosarcomas and the absence of this fusion in other types of chondrosarcoma identifies it as a characteristic molecular marker for this sarcoma, which should aid in the diagnosis of mesenchymal chondrosarcomas and help us better delineate this entity morphologically and clinically.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (130, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('chondrosarcoma', 'Disease', (65, 79))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('aid', 'Reg', (227, 230))	('chondrosarcoma', 'Disease', 'MESH:D002813', (65, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('sarcoma', 'Disease', (205, 212))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (53, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (270, 277))	('fusion', 'Var', (43, 49))	('NCOA2', 'Gene', '10499', (37, 42))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (263, 277))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (251, 278))	('mesenchymal chondrosarcomas', 'Disease', (53, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('mesenchymal chondrosarcomas', 'Disease', (251, 278))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (65, 79))	('si', 'Chemical', 'MESH:D012825', (7, 9))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (65, 80))	('NCOA2', 'Gene', (37, 42))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (263, 278))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('chondrosarcoma', 'Disease', 'MESH:D002813', (130, 144))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('chondrosarcoma', 'Disease', (130, 144))	('sarcoma', 'Disease', (137, 144))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('si', 'Chemical', 'MESH:D012825', (244, 246))	('sarcoma', 'Disease', (72, 79))	('sarcoma', 'Disease', 'MESH:D012509', (270, 277))	('chondrosarcoma', 'Disease', 'MESH:D002813', (263, 277))	('chondrosarcoma', 'Disease', (263, 277))	('sarcoma', 'Disease', (270, 277))	('sarcomas', 'Phenotype', 'HP:0100242', (270, 278))
79419	22034177	MYST3-NCOA2 was the first NCOA2 fusion identified, being found in a rare subset of AML (acute myeloid leukemia) patients with the chromosome rearrangement inv(8)(p11q13).	('inv(8)(p11q13', 'Var', (155, 168))	('MYST3', 'Gene', (0, 5))	('AML', 'Disease', (83, 86))	('NCOA2', 'Gene', '10499', (26, 31))	('acute myeloid leukemia', 'Disease', (88, 110))	('NCOA2', 'Gene', '10499', (6, 11))	('NCOA2', 'Gene', (26, 31))	('found', 'Reg', (57, 62))	('patients', 'Species', '9606', (112, 120))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (88, 110))	('NCOA2', 'Gene', (6, 11))	('MYST3', 'Gene', '7994', (0, 5))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (88, 110))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (94, 110))	('AML', 'Disease', 'MESH:D015470', (83, 86))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))
79426	22034177	HEY1, the 5' partner of the HEY1-NCOA2 fusion, is a downstream effector of Notch signaling.	('HEY1', 'Gene', (0, 4))	('NCOA2', 'Gene', (33, 38))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('NCOA2', 'Gene', '10499', (33, 38))	('fusion', 'Var', (39, 45))
79434	22034177	In conclusion, the novel HEY1-NCOA2 fusion is the first recurrent gene fusion identified in mesenchymal chondrosarcomas.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (104, 119))	('NCOA2', 'Gene', (30, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('mesenchymal chondrosarcomas', 'Disease', (92, 119))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (104, 118))	('si', 'Chemical', 'MESH:D012825', (38, 40))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (92, 119))	('fusion', 'Var', (36, 42))	('NCOA2', 'Gene', '10499', (30, 35))
79435	22034177	The consistent detection of the HEY1-NCOA2 fusion in this primitive sarcoma identifies it as a marker of potential clinical utility to add to the list of fusion-gene based molecular diagnostic markers in sarcomas.	('NCOA2', 'Gene', (37, 42))	('sarcoma', 'Disease', 'MESH:D012509', (204, 211))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('sarcomas', 'Disease', 'MESH:D012509', (204, 212))	('sarcoma', 'Disease', (204, 211))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('si', 'Chemical', 'MESH:D012825', (7, 9))	('sarcomas', 'Disease', (204, 212))	('sarcoma', 'Disease', (68, 75))	('fusion', 'Var', (43, 49))	('NCOA2', 'Gene', '10499', (37, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('si', 'Chemical', 'MESH:D012825', (45, 47))
79437	22034177	Furthermore, given the recent discovery of IDH1 or IDH2 point mutations in approximately 50% of conventional central and periosteal chondromas and chondrosarcomas, it will be interesting to now assess whether such mutations co-exist with the HEY1-NCOA2 fusion in mesenchymal chondrosarcomas.	('chondromas', 'Disease', (132, 142))	('chondrosarcomas', 'Disease', 'MESH:D002813', (275, 290))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (147, 161))	('point mutations', 'Var', (56, 71))	('NCOA2', 'Gene', (247, 252))	('chondromas', 'Disease', 'MESH:D002812', (132, 142))	('si', 'Chemical', 'MESH:D012825', (255, 257))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (147, 162))	('chondrosarcomas', 'Disease', 'MESH:D002813', (147, 162))	('chondrosarcomas', 'Disease', (275, 290))	('IDH2', 'Gene', (51, 55))	('chondrosarcomas', 'Disease', (147, 162))	('sarcomas', 'Phenotype', 'HP:0100242', (282, 290))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (263, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (154, 162))	('mesenchymal chondrosarcomas', 'Disease', (263, 290))	('NCOA2', 'Gene', '10499', (247, 252))	('IDH1', 'Gene', (43, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (275, 289))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (275, 290))
79551	31307409	In cell proliferation and cell cycle assay revealed that caffeine citrate had most strong effect as a combination drug than caffeine and citric acid in inducing G0/G1 cell-cycle arrest with subsequent suppressed cell proliferation.	('caffeine citrate', 'Chemical', 'MESH:C026189', (57, 73))	('cell proliferation', 'CPA', (212, 230))	('G0/G1 cell-cycle arrest', 'CPA', (161, 184))	('inducing', 'PosReg', (152, 160))	('caffeine', 'Chemical', 'MESH:D002110', (124, 132))	('citric acid', 'Chemical', 'MESH:D019343', (137, 148))	('caffeine', 'Chemical', 'MESH:D002110', (57, 65))	('caffeine', 'Var', (57, 65))	('suppressed', 'NegReg', (201, 211))
79554	31307409	This is the first report demonstrating that caffeine citrate has a significantly greater potentiating effect on cisplatin than adding either caffeine or citric acid.	('potentiating', 'MPA', (89, 101))	('caffeine citrate', 'Chemical', 'MESH:C026189', (44, 60))	('cisplatin', 'MPA', (112, 121))	('caffeine', 'Chemical', 'MESH:D002110', (141, 149))	('caffeine', 'Chemical', 'MESH:D002110', (44, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('citric acid', 'Chemical', 'MESH:D019343', (153, 164))	('caffeine', 'Var', (44, 52))
79573	31307409	Briefly, cells were seeded in 96-well flat-bottomed microplates (5 x 103 cells/well), incubated at 37  C for 24 h, and exposed to various concentrations of cisplatin (0, 0.125, 0.25, 0.5, 1.0, and 2.0 muM) alone or with the addition of 0.5 mM of caffeine, citrate, or caffeine citrate.	('caffeine', 'Chemical', 'MESH:D002110', (268, 276))	('muM', 'Gene', '56925', (201, 204))	('caffeine', 'Var', (268, 276))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('citrate', 'Chemical', 'MESH:D019343', (256, 263))	('caffeine', 'Chemical', 'MESH:D002110', (246, 254))	('caffeine citrate', 'Chemical', 'MESH:C026189', (268, 284))	('citrate', 'Chemical', 'MESH:D019343', (277, 284))	('muM', 'Gene', (201, 204))
79606	31307409	The viability of all cells was inhibited by cisplatin, cisplatin + caffeine, cisplatin + citrate, and cisplatin + caffeine citrate with a dose-dependent manner (Fig.	('cisplatin +', 'Var', (77, 88))	('caffeine', 'Chemical', 'MESH:D002110', (114, 122))	('viability', 'CPA', (4, 13))	('cisplatin + caffeine', 'Var', (102, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('caffeine', 'Chemical', 'MESH:D002110', (67, 75))	('citrate', 'Chemical', 'MESH:D019343', (89, 96))	('cisplatin + caffeine', 'Var', (55, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('inhibited', 'NegReg', (31, 40))	('citrate', 'Chemical', 'MESH:D019343', (123, 130))	('caffeine citrate', 'Chemical', 'MESH:C026189', (114, 130))
79609	31307409	In EdU assay, cisplatin + caffeine citrate resulted in a significant decrease in EdU-positive proliferating cells in the HOS, HT1080, and LM8 cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('cisplatin + caffeine citrate', 'Var', (14, 42))	('caffeine citrate', 'Chemical', 'MESH:C026189', (26, 42))	('HOS', 'Disease', (121, 124))	('EdU', 'Chemical', '-', (81, 84))	('decrease', 'NegReg', (69, 77))	('HT1080', 'Gene', (126, 132))	('EdU-positive proliferating cells', 'CPA', (81, 113))	('HT1080', 'Gene', '8872', (126, 132))	('EdU', 'Chemical', '-', (3, 6))	('HOS', 'Disease', 'MESH:C535326', (121, 124))
79610	31307409	In HOS cells, EdU-positive cells were significantly decreased in cisplatin + caffeine and cisplatin + caffeine citrate relative to the control group, and in cisplatin + caffeine citrate relative to all other treatment groups.	('EdU', 'Chemical', '-', (14, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('decreased', 'NegReg', (52, 61))	('caffeine citrate', 'Chemical', 'MESH:C026189', (102, 118))	('EdU-positive cells', 'CPA', (14, 32))	('caffeine', 'Chemical', 'MESH:D002110', (169, 177))	('cisplatin', 'Var', (65, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('HOS', 'Disease', 'MESH:C535326', (3, 6))	('caffeine', 'Chemical', 'MESH:D002110', (102, 110))	('HOS', 'Disease', (3, 6))	('caffeine citrate', 'Chemical', 'MESH:C026189', (169, 185))	('cisplatin', 'Var', (90, 99))	('caffeine', 'Chemical', 'MESH:D002110', (77, 85))
79611	31307409	In HT1080 cells, EdU-positive cells were significantly decreased in cisplatin + caffeine/caffeine citrate relative to the control group, in cisplatin + caffeine relative to cisplatin and cisplatin + citrate, and in cisplatin + caffeine citrate relative to all other treatment groups.	('EdU-positive cells', 'CPA', (17, 35))	('caffeine citrate', 'Chemical', 'MESH:C026189', (89, 105))	('caffeine', 'Chemical', 'MESH:D002110', (152, 160))	('citrate', 'Chemical', 'MESH:D019343', (236, 243))	('EdU', 'Chemical', '-', (17, 20))	('caffeine', 'Chemical', 'MESH:D002110', (89, 97))	('caffeine', 'Chemical', 'MESH:D002110', (80, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (215, 224))	('cisplatin', 'Var', (140, 149))	('decreased', 'NegReg', (55, 64))	('HT1080', 'Gene', (3, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('citrate', 'Chemical', 'MESH:D019343', (98, 105))	('caffeine citrate', 'Chemical', 'MESH:C026189', (227, 243))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('HT1080', 'Gene', '8872', (3, 9))	('caffeine', 'Chemical', 'MESH:D002110', (227, 235))	('cisplatin', 'Var', (68, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('citrate', 'Chemical', 'MESH:D019343', (199, 206))
79612	31307409	In LM8 cells, EdU-positive cells were significantly decreased in cisplatin + caffeine/citrate/caffeine citrate relative to the control group and cisplatin, and in cisplatin + caffeine citrate relative to all other treatment groups.	('citrate', 'Chemical', 'MESH:D019343', (86, 93))	('EdU', 'Chemical', '-', (14, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('citrate', 'Chemical', 'MESH:D019343', (103, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('decreased', 'NegReg', (52, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('citrate', 'Chemical', 'MESH:D019343', (184, 191))	('EdU-positive cells', 'CPA', (14, 32))	('caffeine citrate', 'Chemical', 'MESH:C026189', (175, 191))	('caffeine', 'Chemical', 'MESH:D002110', (94, 102))	('cisplatin', 'Var', (65, 74))	('caffeine citrate', 'Chemical', 'MESH:C026189', (94, 110))	('caffeine', 'Chemical', 'MESH:D002110', (77, 85))	('caffeine', 'Chemical', 'MESH:D002110', (175, 183))
79613	31307409	In mitochondrial depolarization assay, cisplatin + caffeine citrate significantly decreased cell luminance, indicating a weaker mitochondrial membrane potential in the HOS, HT1080, and LM8 cells (Fig.	('cisplatin', 'Var', (39, 48))	('HT1080', 'Gene', (173, 179))	('mitochondrial membrane potential', 'MPA', (128, 160))	('cell luminance', 'MPA', (92, 106))	('HT1080', 'Gene', '8872', (173, 179))	('caffeine citrate', 'Chemical', 'MESH:C026189', (51, 67))	('HOS', 'Disease', 'MESH:C535326', (168, 171))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('weaker', 'NegReg', (121, 127))	('HOS', 'Disease', (168, 171))	('decreased', 'NegReg', (82, 91))
79615	31307409	In HT1080 cells, the cell luminance was significantly decreased in cisplatin + caffeine/citrate/caffeine citrate relative to the control group and cisplatin alone, and in cisplatin + caffeine citrate relative to cisplatin + caffeine/citrate.	('caffeine', 'Chemical', 'MESH:D002110', (96, 104))	('caffeine', 'Chemical', 'MESH:D002110', (224, 232))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('caffeine', 'Chemical', 'MESH:D002110', (183, 191))	('caffeine', 'Chemical', 'MESH:D002110', (79, 87))	('decreased', 'NegReg', (54, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('citrate', 'Chemical', 'MESH:D019343', (233, 240))	('HT1080', 'Gene', (3, 9))	('citrate', 'Chemical', 'MESH:D019343', (105, 112))	('citrate', 'Chemical', 'MESH:D019343', (192, 199))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('HT1080', 'Gene', '8872', (3, 9))	('cisplatin', 'Var', (67, 76))	('caffeine citrate', 'Chemical', 'MESH:C026189', (96, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('citrate', 'Chemical', 'MESH:D019343', (88, 95))	('caffeine citrate', 'Chemical', 'MESH:C026189', (183, 199))	('cell luminance', 'MPA', (21, 35))
79616	31307409	In LM8 cells, the cell luminance was significantly decreased in all treatment groups relative to the control group, in cisplatin + caffeine/citrate/caffeine + citrate relative to cisplatin alone, and cisplatin + caffeine citrate relative to isplatin + caffeine.	('cisplatin', 'Chemical', 'MESH:D002945', (200, 209))	('decreased', 'NegReg', (51, 60))	('citrate', 'Chemical', 'MESH:D019343', (221, 228))	('isplatin', 'Chemical', '-', (201, 209))	('cisplatin + caffeine', 'Var', (200, 220))	('isplatin', 'Chemical', '-', (241, 249))	('caffeine citrate', 'Chemical', 'MESH:C026189', (212, 228))	('caffeine', 'Chemical', 'MESH:D002110', (212, 220))	('citrate', 'Chemical', 'MESH:D019343', (140, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('cell luminance', 'MPA', (18, 32))	('isplatin', 'Chemical', '-', (120, 128))	('caffeine', 'Chemical', 'MESH:D002110', (148, 156))	('caffeine', 'Chemical', 'MESH:D002110', (252, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('citrate', 'Chemical', 'MESH:D019343', (159, 166))	('caffeine', 'Chemical', 'MESH:D002110', (131, 139))	('isplatin', 'Chemical', '-', (180, 188))	('caffeine + citrate', 'Chemical', 'MESH:C026189', (148, 166))
79618	31307409	After treatment with cisplatin + caffeine, cisplatin + citrate, and cisplatin + caffeine citrate, G2/M fraction was also significantly increased, compared with control group.	('caffeine citrate', 'Chemical', 'MESH:C026189', (80, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('citrate', 'Chemical', 'MESH:D019343', (55, 62))	('cisplatin + caffeine', 'Var', (68, 88))	('cisplatin', 'Var', (43, 52))	('G2/M', 'MPA', (98, 102))	('increased', 'PosReg', (135, 144))	('caffeine', 'Chemical', 'MESH:D002110', (33, 41))	('caffeine', 'Chemical', 'MESH:D002110', (80, 88))	('citrate', 'Chemical', 'MESH:D019343', (89, 96))	('cisplatin', 'Var', (21, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
79624	31307409	After treatment with cisplatin + caffeine citrate, the rate of live cells was significantly lower, compared with any other treatment group.	('caffeine citrate', 'Chemical', 'MESH:C026189', (33, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('lower', 'NegReg', (92, 97))	('cisplatin + caffeine', 'Var', (21, 41))
79625	31307409	After treatment with cisplatin + caffeine and cisplatin + citrate, the rate of live cells was also significantly lower, compared with cisplatin alone.	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('lower', 'NegReg', (113, 118))	('cisplatin + citrate', 'Var', (46, 65))	('cisplatin + caffeine', 'Var', (21, 41))	('rate', 'CPA', (71, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('caffeine', 'Chemical', 'MESH:D002110', (33, 41))	('citrate', 'Chemical', 'MESH:D019343', (58, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))
79626	31307409	After treatment with cisplatin + caffeine citrate, the rate of live cells was significantly higher, compared with any other treatment group.	('caffeine citrate', 'Chemical', 'MESH:C026189', (33, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('higher', 'PosReg', (92, 98))	('cisplatin +', 'Var', (21, 32))
79627	31307409	After treatment with cisplatin + caffeine and cisplatin + citrate, the rate of live cells was also significantly lower, compared with cisplatin alone (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('lower', 'NegReg', (113, 118))	('cisplatin + citrate', 'Var', (46, 65))	('cisplatin + caffeine', 'Var', (21, 41))	('rate', 'CPA', (71, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('caffeine', 'Chemical', 'MESH:D002110', (33, 41))	('citrate', 'Chemical', 'MESH:D019343', (58, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))
79632	31307409	In the results of R2 regimen for LM8, the volume and weight of the tumor treated with caffeine + citrate was significantly reduced, compared with control group.	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('caffeine + citrate', 'Chemical', 'MESH:C026189', (86, 104))	('LM8', 'Var', (33, 36))	('reduced', 'NegReg', (123, 130))
79634	31307409	In the results of R3 regimen for LM8, the volume and weight of the tumor treated with caffeine + citrate was also significantly reduced, compared with control group.	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('reduced', 'NegReg', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('caffeine + citrate', 'Chemical', 'MESH:C026189', (86, 104))	('LM8', 'Var', (33, 36))
79638	31307409	We also demonstrated that cisplatin + caffeine citrate had a significantly greater inhibition of tumor growth than the other treatments given to mice with implanted osteosarcomas or fibrosarcomas.	('cisplatin + caffeine', 'Var', (26, 46))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('inhibition', 'NegReg', (83, 93))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (182, 194))	('osteosarcomas', 'Phenotype', 'HP:0002669', (165, 178))	('osteosarcoma', 'Phenotype', 'HP:0002669', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('implanted osteosarcomas or fibrosarcomas', 'Disease', 'MESH:D005354', (155, 195))	('tumor', 'Disease', (97, 102))	('caffeine citrate', 'Chemical', 'MESH:C026189', (38, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('implanted osteosarcomas or fibrosarcomas', 'Disease', (155, 195))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('mice', 'Species', '10090', (145, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))
79641	31307409	Caffeine overcomes the cisplatinum-induced S/G2 cell-cycle arrest with subsequent increased apoptosis.	('overcomes', 'NegReg', (9, 18))	('S/G2', 'Var', (43, 47))	('Caffeine', 'Gene', '104272', (0, 8))	('S/G2', 'SUBSTITUTION', 'None', (43, 47))	('cisplatinum', 'Chemical', 'MESH:D002945', (23, 34))	('Caffeine', 'Gene', (0, 8))
79643	31307409	In this study, caffeine was stronger, overcame the cisplatinum-induced S/G2 cell-cycle arrest with subsequent increased apoptosis in HOS.	('cisplatinum', 'Chemical', 'MESH:D002945', (51, 62))	('S/G2', 'Var', (71, 75))	('overcame', 'PosReg', (38, 46))	('caffeine', 'Chemical', 'MESH:D002110', (15, 23))	('HOS', 'Disease', 'MESH:C535326', (133, 136))	('S/G2', 'SUBSTITUTION', 'None', (71, 75))	('HOS', 'Disease', (133, 136))
79649	31307409	In this study, citric acid also overcame the cisplatinum-induced S/G2 cell-cycle arrest with subsequent increased apoptosis and induced G0/G1 cell-cycle arrest with subsequent suppressed cell proliferation.	('S/G2', 'SUBSTITUTION', 'None', (65, 69))	('G0/G1 cell-cycle arrest', 'CPA', (136, 159))	('citric acid', 'Chemical', 'MESH:D019343', (15, 26))	('suppressed', 'NegReg', (176, 186))	('overcame', 'PosReg', (32, 40))	('cell proliferation', 'CPA', (187, 205))	('apoptosis', 'CPA', (114, 123))	('cisplatinum', 'Chemical', 'MESH:D002945', (45, 56))	('S/G2', 'Var', (65, 69))
79651	31307409	Finally, caffeine citrate had most strong effect as a combination drug than caffeine and citric acid in both overcoming the cisplatinum-induced S/G2 cell-cycle arrest with subsequent increased apoptosis and inducing G0/G1 cell-cycle arrest with subsequent suppressed cell proliferation.	('suppressed', 'NegReg', (256, 266))	('caffeine citrate', 'Chemical', 'MESH:C026189', (9, 25))	('cisplatinum-induced', 'MPA', (124, 143))	('apoptosis', 'CPA', (193, 202))	('inducing', 'PosReg', (207, 215))	('cisplatinum', 'Chemical', 'MESH:D002945', (124, 135))	('increased', 'PosReg', (183, 192))	('caffeine', 'Chemical', 'MESH:D002110', (9, 17))	('G0/G1 cell-cycle arrest', 'CPA', (216, 239))	('caffeine', 'Chemical', 'MESH:D002110', (76, 84))	('citric acid', 'Chemical', 'MESH:D019343', (89, 100))	('S/G2', 'SUBSTITUTION', 'None', (144, 148))	('cell proliferation', 'CPA', (267, 285))	('S/G2', 'Var', (144, 148))	('overcoming', 'PosReg', (109, 119))
79721	30541504	In time-to-event analysis, the high mitotic index was significantly associated with worse OS (log-rank p = 0.0002, HR = 3.441, 95%CI: 1.649-7.181) (Fig.	('high', 'Var', (31, 35))	('worse OS', 'Disease', (84, 92))	('OS', 'Chemical', '-', (90, 92))	('mitotic index', 'CPA', (36, 49))
79723	30541504	In addition to high mitotic index (HR = 2.687, 95%CI: 1.160-6.471, p = 0.028), the grade 3 differentiation of the sarcoma (HR = 3.426, 95%CI: 1.014-11.569, p = 0.047) was also recognized to be associated with worse DFS in the univariate setting (Table 3).	('mitotic index', 'MPA', (20, 33))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('sarcoma', 'Disease', (114, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('grade 3', 'Var', (83, 90))
79732	30541504	Patients with high tumor grade (grade3), advanced stages, high mitotic index and age over 65 are considered to have worse prognosis.	('high tumor', 'Disease', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('high tumor', 'Disease', 'MESH:D009369', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('high', 'Var', (58, 62))
79803	25960853	More than 85% of Ewing's sarcoma/PNET have characterized by presence of t(11;22) (q24;q12) translocation that results fusion of EWS gene located on chromosome 22 to FLI1 gene on chromosome 11 resulting formation of chimeric product of EWS-FLI1.	('FLI1', 'Gene', (165, 169))	("Ewing's sarcoma", 'Disease', (17, 32))	('EWS', 'Gene', '2130', (128, 131))	('EWS', 'Gene', (128, 131))	('FLI1', 'Gene', (239, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (17, 32))	('EWS', 'Gene', '2130', (235, 238))	('EWS', 'Gene', (235, 238))	('FLI1', 'Gene', '2313', (239, 243))	('PNET', 'Phenotype', 'HP:0030065', (33, 37))	('formation', 'Reg', (202, 211))	('fusion', 'Var', (118, 124))	('chimeric', 'MPA', (215, 223))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (17, 32))	('FLI1', 'Gene', '2313', (165, 169))
79860	25789016	A study by Nishimura et al revealed that AML patients with a t(8;21) translocation presented with extra-medullary sarcomas more frequently affecting the central nervous system.	('translocation', 'Var', (69, 82))	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', (114, 122))	('t(8;21', 'Gene', (61, 67))	('presented', 'Reg', (83, 92))	('AML', 'Disease', 'MESH:D015470', (41, 44))	('patients', 'Species', '9606', (45, 53))	('AML', 'Disease', (41, 44))
79873	25356068	DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions Germline mutations in DICER1 are associated with increased risk for a wide variety of neoplastic conditions, including pleuropulmonary blastoma (PPB), cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors, botryoid embryonal rhabdomyosarcoma of the uterine cervix, ciliary body medulloepithelioma, pineoblastoma, pituitary blastoma and nodular thyroid hyperplasia or thyroid carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('DICER1', 'Gene', (0, 6))	('medulloepithelioma', 'Phenotype', 'HP:0030071', (432, 450))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (521, 538))	('DICER1', 'Gene', (142, 148))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (239, 263))	('Germline', 'Var', (120, 128))	('pleuropulmonary blastoma', 'Disease', (239, 263))	('pineoblastoma', 'Phenotype', 'HP:0030408', (452, 465))	('thyroid carcinoma', 'Disease', (521, 538))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (7, 31))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (379, 395))	('sarcoma', 'Phenotype', 'HP:0100242', (388, 395))	('botryoid embryonal rhabdomyosarcoma', 'Disease', (360, 395))	('pineoblastoma', 'Disease', 'MESH:D010871', (452, 465))	('hamartoma', 'Phenotype', 'HP:0010566', (313, 322))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (369, 395))	('uterine cervix', 'Phenotype', 'HP:0030160', (403, 417))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (340, 357))	('thyroid hyperplasia', 'Phenotype', 'HP:0008249', (498, 517))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (340, 358))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (521, 538))	('neoplastic conditions', 'Disease', 'MESH:D009135', (206, 227))	('cystic nephroma', 'Disease', (271, 286))	('DICER1-pleuropulmonary blastoma familial tumor', 'Disease', (0, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (529, 538))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (239, 263))	('cystic nephroma', 'Disease', 'MESH:D018201', (271, 286))	('botryoid embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (360, 395))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (7, 31))	('neoplastic conditions', 'Disease', (206, 227))	('pineoblastoma', 'Disease', (452, 465))	('ciliary body medulloepithelioma', 'Disease', (419, 450))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('pituitary blastoma and nodular thyroid hyperplasia', 'Disease', 'MESH:D020518', (467, 517))	('ciliary body medulloepithelioma', 'Disease', 'MESH:D008527', (419, 450))	('DICER1', 'Gene', '23405', (0, 6))	('neoplastic conditions', 'Disease', 'MESH:D009135', (98, 119))	('mutations', 'Var', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (332, 358))	('DICER1', 'Gene', '23405', (142, 148))	('associated', 'Reg', (153, 163))	('nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (288, 358))	('DICER1-pleuropulmonary blastoma familial tumor', 'Disease', 'MESH:C537516', (0, 46))	('neoplastic conditions', 'Disease', (98, 119))
79875	25356068	Here we describe the medical history of a child with a heterozygous, loss of function germline DICER1 mutation and multiple tumors associated with the syndrome..	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutation', 'Var', (102, 110))	('loss of function', 'NegReg', (69, 85))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('child', 'Species', '9606', (42, 47))	('DICER1', 'Gene', (95, 101))	('DICER1', 'Gene', '23405', (95, 101))
79876	25356068	Although germline mutations in DICER1 are rare, tumors of these types will be seen by practicing pathologists and should prompt consideration of an underlying DICER1 mutation.	('DICER1', 'Gene', (31, 37))	('DICER1', 'Gene', '23405', (31, 37))	('tumors', 'Disease', (48, 54))	('DICER1', 'Gene', (159, 165))	('DICER1', 'Gene', '23405', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mutation', 'Var', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('germline mutations', 'Var', (9, 27))
79910	25356068	This case illustrates several of the tumor types that may occur in the setting of germline DICER1 mutation, in this case in the same individual.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutation', 'Var', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('DICER1', 'Gene', (91, 97))	('DICER1', 'Gene', '23405', (91, 97))
79911	25356068	Additional tumor types commonly associated with DICER1 mutations and/or PPB include: cystic nephroma (CN), ciliary body medulloepithelioma (CBME), botryoid embryonal rhabdomyosarcoma (ERMS) of the cervix, thyroid nodular hyperplasia and thyroid cancer, pineoblastoma and pituitary blastoma.	('cystic nephroma', 'Disease', 'MESH:D018201', (85, 100))	('thyroid nodular hyperplasia', 'Disease', 'MESH:D020518', (205, 232))	('thyroid cancer', 'Disease', 'MESH:D013964', (237, 251))	('pineoblastoma', 'Phenotype', 'HP:0030408', (253, 266))	('associated', 'Reg', (32, 42))	('medulloepithelioma', 'Phenotype', 'HP:0030071', (120, 138))	('thyroid cancer', 'Phenotype', 'HP:0002890', (237, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('botryoid embryonal rhabdomyosarcoma', 'Disease', (147, 182))	('tumor', 'Disease', (11, 16))	('PPB', 'Gene', (72, 75))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (156, 182))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('pineoblastoma and pituitary blastoma', 'Disease', 'MESH:D010871', (253, 289))	('DICER1', 'Gene', '23405', (48, 54))	('mutations', 'Var', (55, 64))	('botryoid embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (147, 182))	('thyroid nodular hyperplasia', 'Disease', (205, 232))	('ciliary body medulloepithelioma', 'Disease', (107, 138))	('thyroid cancer', 'Disease', (237, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('ciliary body medulloepithelioma', 'Disease', 'MESH:D008527', (107, 138))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('DICER1', 'Gene', (48, 54))	('cystic nephroma', 'Disease', (85, 100))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (166, 182))
79912	25356068	Wilms tumor, neuroblastoma and medulloblastoma have also been seen in children with DICER1 mutations but the prevalence of DICER1 mutations in these latter three tumor types appears to be low.	('tumor', 'Disease', (162, 167))	('medulloblastoma', 'Disease', 'MESH:D008527', (31, 46))	('DICER1', 'Gene', (84, 90))	('medulloblastoma', 'Phenotype', 'HP:0002885', (31, 46))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('DICER1', 'Gene', '23405', (123, 129))	('medulloblastoma', 'Disease', (31, 46))	('Wilms tumor', 'Disease', 'MESH:D009396', (0, 11))	('DICER1', 'Gene', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Wilms tumor', 'Phenotype', 'HP:0002667', (0, 11))	('neuroblastoma', 'Disease', (13, 26))	('tumor', 'Disease', (6, 11))	('neuroblastoma', 'Phenotype', 'HP:0003006', (13, 26))	('children', 'Species', '9606', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('DICER1', 'Gene', '23405', (84, 90))	('mutations', 'Var', (91, 100))	('neuroblastoma', 'Disease', 'MESH:D009447', (13, 26))	('Wilms tumor', 'Disease', (0, 11))
79918	25356068	The penetrance of these various neoplasms in germline DICER1 mutation carriers appears low (Hill, Doros and Stewart unpublished data).	('neoplasms', 'Phenotype', 'HP:0002664', (32, 41))	('mutation', 'Var', (61, 69))	('neoplasm', 'Phenotype', 'HP:0002664', (32, 40))	('neoplasms', 'Disease', 'MESH:D009369', (32, 41))	('neoplasms', 'Disease', (32, 41))	('DICER1', 'Gene', (54, 60))	('DICER1', 'Gene', '23405', (54, 60))
79920	25356068	In PPB, CN, NCMH, papillary thyroid carcinoma and SLCT we know that the second event is a partial loss of function, somatic missense mutation affecting one of six amino acids in the RNase IIIb domain of DICER1.	('papillary thyroid carcinoma', 'Disease', (18, 45))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (18, 45))	('DICER1', 'Gene', '23405', (203, 209))	('loss of function', 'NegReg', (98, 114))	('missense mutation', 'Var', (124, 141))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (18, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('affecting', 'Reg', (142, 151))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (28, 45))	('DICER1', 'Gene', (203, 209))
79922	25356068	As demonstrated by the somatic mutation in the NCMH in this case report and a previous report from our group on CN, somatic missense mutations in DICER1 do not have an obligate conveyance of a malignant phenotype; NCMH and CN typically have a benign course.	('NCMH', 'Disease', (214, 218))	('DICER1', 'Gene', '23405', (146, 152))	('missense mutations', 'Var', (124, 142))	('DICER1', 'Gene', (146, 152))
79923	25356068	Additional genetic events such as loss or mutation of TP53 in PPB may be required for progression.	('TP53', 'Gene', '7157', (54, 58))	('mutation', 'Var', (42, 50))	('loss', 'NegReg', (34, 38))	('TP53', 'Gene', (54, 58))	('PPB', 'Gene', (62, 65))
79924	25356068	Loss of function germline DICER1 mutations are seen in nearly 70% of all children with PPB regardless of family history.	('children', 'Species', '9606', (73, 81))	('mutations', 'Var', (33, 42))	('DICER1', 'Gene', (26, 32))	('DICER1', 'Gene', '23405', (26, 32))	('PPB', 'Disease', (87, 90))
79925	25356068	Some children without germline DICER1 mutations have two somatic mutations in DICER1, one loss of function mutation and one missense mutation affecting 5p miRNA cleavage.	('DICER1', 'Gene', (31, 37))	('DICER1', 'Gene', '23405', (31, 37))	('children', 'Species', '9606', (5, 13))	('DICER1', 'Gene', (78, 84))	('DICER1', 'Gene', '23405', (78, 84))	('mutations', 'Var', (38, 47))	('5p miRNA cleavage', 'MPA', (152, 169))
79927	25356068	Prevalence of germline DICER1 mutations in NCMH, lung cysts, thyroid carcinoma, nodular thyroid hyperplasia, embryonal brain tumors and other ovarian stromal tumors is the subject of a current study.	('DICER1', 'Gene', '23405', (23, 29))	('embryonal brain tumors', 'Disease', 'MESH:D001932', (109, 131))	('lung cysts', 'Disease', 'MESH:D008171', (49, 59))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (61, 78))	('lung cysts', 'Disease', (49, 59))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('thyroid carcinoma', 'Disease', (61, 78))	('DICER1', 'Gene', (23, 29))	('lung cysts', 'Phenotype', 'HP:0032445', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('NCMH', 'Disease', (43, 47))	('brain tumors', 'Phenotype', 'HP:0030692', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('nodular thyroid hyperplasia', 'Disease', (80, 107))	('ovarian stromal tumors', 'Disease', (142, 164))	('nodular thyroid hyperplasia', 'Disease', 'MESH:D020518', (80, 107))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (61, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('embryonal brain tumors', 'Disease', (109, 131))	('mutations', 'Var', (30, 39))	('ovarian stromal tumors', 'Disease', 'MESH:D010051', (142, 164))	('thyroid hyperplasia', 'Phenotype', 'HP:0008249', (88, 107))
79928	25356068	The pathologist making the diagnosis of one of the rare neoplasms in this syndrome may be the first to suggest the association of a particular tumor type with DICER1 mutations to the clinical team.	('neoplasms', 'Phenotype', 'HP:0002664', (56, 65))	('tumor', 'Disease', (143, 148))	('mutations', 'Var', (166, 175))	('neoplasms', 'Disease', (56, 65))	('neoplasms', 'Disease', 'MESH:D009369', (56, 65))	('DICER1', 'Gene', (159, 165))	('DICER1', 'Gene', '23405', (159, 165))	('neoplasm', 'Phenotype', 'HP:0002664', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('association', 'Interaction', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
79929	25356068	The benefit of detecting germline DICER1 mutations in a child includes early identification of malignant conditions in young family members through screening and educating families and their treating physicians about early signs of disease (e.g.	('mutations', 'Var', (41, 50))	('child', 'Species', '9606', (56, 61))	('DICER1', 'Gene', (34, 40))	('DICER1', 'Gene', '23405', (34, 40))
79930	25356068	Recommendations for screening in individuals with DICER1 mutations was summarized in a recent review.	('mutations', 'Var', (57, 66))	('DICER1', 'Gene', (50, 56))	('DICER1', 'Gene', '23405', (50, 56))
79948	25356068	DICER1 somatic mutation testing may also be of benefit in this circumstance.	('somatic mutation testing', 'Var', (7, 31))	('DICER1', 'Gene', (0, 6))	('DICER1', 'Gene', '23405', (0, 6))
79962	25356068	We have seen numerous examples of multilocular lung cysts in older individuals with DICER1 mutations (up to age 62).	('lung cysts', 'Phenotype', 'HP:0032445', (47, 57))	('multilocular lung cysts', 'Disease', (34, 57))	('DICER1', 'Gene', (84, 90))	('DICER1', 'Gene', '23405', (84, 90))	('mutations', 'Var', (91, 100))	('multilocular lung cysts', 'Disease', 'MESH:C536591', (34, 57))
79965	25356068	In other cases, it can be demonstrated by myogenin and/or MyoD1 nuclear immunopositivity From cell cultures of Type I PPB mesenchyme we know there is a clonal subpopulation with a somatic missense mutation in DICER1 on the allele opposite to the one with the germline DICER1 mutation (i.e.	('myogenin', 'Gene', (42, 50))	('MyoD1', 'Gene', (58, 63))	('MyoD1', 'Gene', '4654', (58, 63))	('myogenin', 'Gene', '4656', (42, 50))	('DICER1', 'Gene', (268, 274))	('DICER1', 'Gene', '23405', (268, 274))	('missense mutation', 'Var', (188, 205))	('DICER1', 'Gene', (209, 215))	('DICER1', 'Gene', '23405', (209, 215))
79972	25356068	Occasional cases without cartilage nodules have been seen in individuals with DICER1 mutations.	('cartilage nodules', 'Disease', (25, 42))	('mutations', 'Var', (85, 94))	('DICER1', 'Gene', (78, 84))	('cartilage nodules', 'Disease', 'MESH:D002357', (25, 42))	('DICER1', 'Gene', '23405', (78, 84))
79976	25356068	SLCT in patients with germline DICER1 may be cystic and solid or solid and often contain heterologous epithelial glandular elements as in this case report.	('DICER1', 'Gene', (31, 37))	('DICER1', 'Gene', '23405', (31, 37))	('germline', 'Var', (22, 30))	('contain', 'Reg', (81, 88))	('patients', 'Species', '9606', (8, 16))
79979	25356068	Occasionally we have seen tumors with both Sertoli-Leydig cell and juvenile granulosa cell features in children and young adults with DICER1 mutations.	('mutations', 'Var', (141, 150))	('children', 'Species', '9606', (103, 111))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Sertoli-Leydig cell', 'CPA', (43, 62))	('juvenile granulosa cell features', 'CPA', (67, 99))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('DICER1', 'Gene', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))	('DICER1', 'Gene', '23405', (134, 140))
79980	25356068	CN is the second most common neoplasm we see in children with DICER1 mutations.	('mutations', 'Var', (69, 78))	('children', 'Species', '9606', (48, 56))	('DICER1', 'Gene', '23405', (62, 68))	('neoplasm', 'Disease', (29, 37))	('neoplasm', 'Phenotype', 'HP:0002664', (29, 37))	('neoplasm', 'Disease', 'MESH:D009369', (29, 37))	('DICER1', 'Gene', (62, 68))
79983	25356068	The same somatic missense DICER1 mutations seen in Type I PPB are also seen in CN.	('DICER1', 'Gene', (26, 32))	('missense', 'Var', (17, 25))	('DICER1', 'Gene', '23405', (26, 32))	('mutations', 'Var', (33, 42))
80008	25356068	It is uncertain if DICER1 mutations are associated with better differentiated tumors.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (26, 35))	('DICER1', 'Gene', (19, 25))	('DICER1', 'Gene', '23405', (19, 25))	('associated', 'Reg', (40, 50))
80011	25356068	The finding of rare tumors including PPB, ovarian stromal tumors especially SLCT, NCMH, CBME and ERMS of the uterine cervix especially at an early age or in constellation with other neoplasms should prompt consideration of germline DICER1 mutations, a finding which has importance for individual and family screening.	('ovarian stromal tumors', 'Disease', (42, 64))	('neoplasm', 'Phenotype', 'HP:0002664', (182, 190))	('mutations', 'Var', (239, 248))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('neoplasms', 'Disease', 'MESH:D009369', (182, 191))	('PPB', 'Disease', (37, 40))	('uterine cervix', 'Phenotype', 'HP:0030160', (109, 123))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('DICER1', 'Gene', '23405', (232, 238))	('neoplasms', 'Disease', (182, 191))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('DICER1', 'Gene', (232, 238))	('ovarian stromal tumors', 'Disease', 'MESH:D010051', (42, 64))	('SLCT', 'Disease', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (58, 64))	('neoplasms', 'Phenotype', 'HP:0002664', (182, 191))
80012	25356068	The penetrance and expressivity of germline DICER1 mutations is the focus of ongoing analyses.	('DICER1', 'Gene', '23405', (44, 50))	('mutations', 'Var', (51, 60))	('DICER1', 'Gene', (44, 50))
80035	22427255	However, a chimeric protein created by substituting the N-terminal IGFBP domain of IGFBP-3 with the N-terminal IGFBP domain of CCN3 displayed very weak binding to IGFs similar to that observed for CCN3.	('IGFBP-3', 'Gene', (83, 90))	('substituting', 'Var', (39, 51))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('binding', 'Interaction', (152, 159))	('N', 'Chemical', 'MESH:D009584', (199, 200))	('IGFs', 'Protein', (163, 167))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('weak', 'NegReg', (147, 151))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('IGFBP-3', 'Gene', '3486', (83, 90))
80043	22427255	While the relationship between processing events that have been described in vitro to those that occur naturally need to be further clarified, these cleaved CCN variants and/or their ratio to the full length protein are thought to significantly impact the functions of CCN family members.	('rat', 'Species', '10116', (183, 186))	('variants', 'Var', (161, 169))	('impact', 'Reg', (245, 251))	('CCN', 'Gene', (157, 160))	('CCN', 'Chemical', '-', (157, 160))	('functions', 'MPA', (256, 265))	('CCN', 'Chemical', '-', (269, 272))
80054	22427255	The first CCN3 variant to be described was an amino-terminal truncation that resulted from integration of the MAV virus, which removed the signal peptide and the IGFBP domain, leaving only the lasts three modules (VWC, TSP-1 and CT) (Joliot et al.).	('TSP-1', 'Gene', (219, 224))	('MAV', 'Gene', '11275', (110, 113))	('variant', 'Var', (15, 22))	('MAV', 'Gene', (110, 113))	('leaving', 'Reg', (176, 183))	('TSP-1', 'Gene', '7057', (219, 224))	('signal peptide', 'MPA', (139, 153))	('removed', 'NegReg', (127, 134))	('rat', 'Species', '10116', (96, 99))	('CCN3', 'Gene', (10, 14))
80055	22427255	This CCN3 variant was expressed in chicken embryo fibroblasts and exhibited transforming properties.	('exhibited', 'Reg', (66, 75))	('CCN3', 'Gene', (5, 9))	('chicken', 'Species', '9031', (35, 42))	('variant', 'Var', (10, 17))	('transforming properties', 'CPA', (76, 99))
80078	22427255	Male and female mice, which were heterozygous for the transgene, displayed a 30-35% decrease in trabecular bone volume but exhibited similar numbers of osteoblasts, osteoclasts and similar degrees of bone erosion.	('decrease', 'NegReg', (84, 92))	('osteoclasts', 'CPA', (165, 176))	('osteoblasts', 'CPA', (152, 163))	('bone erosion', 'CPA', (200, 212))	('trabecular bone volume', 'CPA', (96, 118))	('mice', 'Species', '10090', (16, 20))	('transgene', 'Var', (54, 63))
80083	22427255	These mice were engineered to express a CCN3del3 mutant, which encoded a protein lacking the VWC domain (Heath et al.).	('VWC domain', 'MPA', (93, 103))	('CCN3del3 mutant', 'Var', (40, 55))	('encoded', 'Reg', (63, 70))	('mice', 'Species', '10090', (6, 10))	('lacking', 'NegReg', (81, 88))
80084	22427255	In CCN3del3 expressing embryos, the skeleton showed abnormalities such as enlarged vertebrae, elongated long bones and digits.	('enlarged vertebrae', 'Disease', (74, 92))	('enlarged vertebrae', 'Disease', 'MESH:D006529', (74, 92))	('digits', 'CPA', (119, 125))	('CCN3del3 expressing', 'Var', (3, 22))	('enlarged vertebrae', 'Phenotype', 'HP:0004570', (74, 92))	('elongated long bones', 'CPA', (94, 114))
80085	22427255	In addition, joint defects such as fusions, malformations, dislocations and laxity were observed mice expressing CCN3del3.	('joint defects', 'Disease', 'MESH:D007592', (13, 26))	('joint defects', 'Disease', (13, 26))	('dislocations', 'CPA', (59, 71))	('laxity', 'Disease', 'MESH:C535884', (76, 82))	('fusions', 'CPA', (35, 42))	('mice', 'Species', '10090', (97, 101))	('laxity', 'Disease', (76, 82))	('CCN3del3', 'Var', (113, 121))	('malformations', 'Disease', 'MESH:D000014', (44, 57))	('malformations', 'Disease', (44, 57))
80087	22427255	However, the authors could not definitively conclude that skeletal phenotypes observed in the CCN3del3 mice resulted from the loss of CCN3 or to a new function ascribed to the truncated CCN3del3 protein (Heath et al.).	('mice', 'Species', '10090', (103, 107))	('CCN3', 'Gene', (134, 138))	('loss', 'NegReg', (126, 130))	('CCN3del3', 'Var', (94, 102))
80089	22427255	Another CCN3 null mouse has been developed, where the entire coding sequence of CCN3 was deleted (Canalis et al.).	('mouse', 'Species', '10090', (18, 23))	('CCN3', 'Gene', (80, 84))	('deleted', 'Var', (89, 96))
80094	22427255	Moreover, blocking antibodies against CCN1 disrupt fracture healing, providing evidence that CCN family members play a functional role in this process (Athanasopoulos et al.).	('fracture', 'Disease', 'MESH:D050723', (51, 59))	('CCN', 'Chemical', '-', (93, 96))	('antibodies', 'Var', (19, 29))	('fracture', 'Disease', (51, 59))	('CCN1', 'Gene', (38, 42))	('blocking antibodies', 'Var', (10, 29))	('CCN1', 'Gene', '3491', (38, 42))	('CCN', 'Chemical', '-', (38, 41))
80098	22427255	For example, studies on CCN2-/- mice revealed that CCN3 becomes overexpressed in a context of CCN2 knock-out (Kawaki et al.).	('knock-out', 'Var', (99, 108))	('mice', 'Species', '10090', (32, 36))	('CCN2', 'Gene', (94, 98))	('overexpressed', 'PosReg', (64, 77))	('CCN3', 'Gene', (51, 55))
80100	22427255	Using a MC3T3 murine calvarial derived cell model, which can be induced to differentiate into osteoblast-like cells, CCN3 was shown to inhibit osteoblast differentiation by binding to and neutralizing BMP2, a well-known enhancer of osteoblastogenesis (Minamizato et al.).	('murine', 'Species', '10090', (14, 20))	('BMP2', 'Gene', (201, 205))	('CCN3', 'Gene', (117, 121))	('inhibit', 'NegReg', (135, 142))	('neutralizing', 'Var', (188, 200))	('osteoblast differentiation', 'CPA', (143, 169))	('MC3T3', 'CellLine', 'CVCL:0D74', (8, 13))	('binding', 'Interaction', (173, 180))
80102	22427255	In addition, CCN3 was also shown to augment the release of the Notch Intracellular Domain (NICD) from full length Notch, leading to an increase in Hairy/Enhancer of Split (HES) and Hairy/Enhancer of Split with YRPW motif 1 (HEY) transcription and ultimately to impaired osteoblast differentiation (Minamizato et al.).	('release', 'MPA', (48, 55))	('N', 'Chemical', 'MESH:D009584', (114, 115))	('Hairy/Enhancer', 'MPA', (147, 161))	('osteoblast differentiation', 'CPA', (270, 296))	('increase', 'PosReg', (135, 143))	('Notch', 'Gene', (63, 68))	('Notch', 'Gene', '4851;18128', (63, 68))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('Notch', 'Gene', '4851;18128', (114, 119))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('Notch', 'Gene', (114, 119))	('CCN3', 'Var', (13, 17))	('transcription', 'MPA', (229, 242))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('impaired', 'NegReg', (261, 269))	('Hairy/Enhancer', 'MPA', (181, 195))
80110	22427255	When investigating osteoclast differentiation, calvarial cultures from CCN3-/- mice displayed higher numbers of osteoclasts when vitamin D3 was used as an inducer of osteoclastogenesis, raising the possibility that CCN3 suppresses osteoclast differentiation as well (Canalis et al.).	('osteoclasts', 'CPA', (112, 123))	('vitamin D3', 'Chemical', 'MESH:D002762', (129, 139))	('mice', 'Species', '10090', (79, 83))	('higher', 'PosReg', (94, 100))	('CCN3', 'Var', (215, 219))	('osteoclast differentiation', 'CPA', (231, 257))	('suppresses', 'NegReg', (220, 230))	('CCN3-/-', 'Var', (71, 78))
80121	22427255	It is known that osteosarcomas are characterized by impaired osteoblastic differentiation and generally lack markers of terminal differentiation, which has been associated with disrupted Runx2 function (Thomas et al.).	('osteosarcomas', 'Disease', (17, 30))	('lack', 'NegReg', (104, 108))	('impaired osteoblastic differentiation', 'Disease', (52, 89))	('osteosarcomas', 'Phenotype', 'HP:0002669', (17, 30))	('disrupted', 'Var', (177, 186))	('impaired osteoblastic differentiation', 'Disease', 'MESH:D012734', (52, 89))	('Runx2', 'Gene', '860', (187, 192))	('Runx2', 'Gene', (187, 192))	('osteosarcomas', 'Disease', 'MESH:D012516', (17, 30))	('function', 'MPA', (193, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))
80124	22427255	Thus, it has been hypothesized that high CCN3 expression in osteosarcoma might activate Notch signaling, resulting in osteosarcoma cells being locked into an early stage of osteoblastic differentiation.	('osteosarcoma', 'Disease', 'MESH:D012516', (60, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('osteosarcoma cell', 'Disease', 'MESH:D012516', (118, 135))	('activate', 'PosReg', (79, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (118, 130))	('osteosarcoma', 'Disease', (118, 130))	('osteosarcoma cell', 'Disease', (118, 135))	('CCN3', 'Gene', (41, 45))	('osteosarcoma', 'Disease', (60, 72))	('osteosarcoma', 'Disease', 'MESH:D012516', (118, 130))	('Notch', 'Gene', '4851;18128', (88, 93))	('Notch', 'Gene', (88, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('high', 'Var', (36, 40))
80126	22427255	Indeed, high CCN3 expression in osteosarcomas was not associated with osteoblast differentiation markers and, more importantly, correlated with shorter disease free survival (Perbal et al.).	('high', 'Var', (8, 12))	('correlated', 'Reg', (128, 138))	('osteosarcomas', 'Disease', 'MESH:D012516', (32, 45))	('osteosarcomas', 'Phenotype', 'HP:0002669', (32, 45))	('shorter', 'NegReg', (144, 151))	('disease free survival', 'CPA', (152, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('expression', 'MPA', (18, 28))	('osteosarcoma', 'Phenotype', 'HP:0002669', (32, 44))	('CCN3', 'Gene', (13, 17))	('osteosarcomas', 'Disease', (32, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
80127	22427255	This clinical correlation is in agreement with the recent observation that CCN3 can enhance the migratory properties of osteosarcoma cells, which involves alphavbeta5 integrin-mediated upregulation of COX-2 expression (Huang et al.).	('COX-2', 'Gene', '4513', (201, 206))	('COX-2', 'Gene', (201, 206))	('rat', 'Species', '10116', (99, 102))	('CCN3', 'Var', (75, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('osteosarcoma cell', 'Disease', 'MESH:D012516', (120, 137))	('migratory properties of', 'CPA', (96, 119))	('osteosarcoma', 'Phenotype', 'HP:0002669', (120, 132))	('expression', 'MPA', (207, 217))	('upregulation', 'PosReg', (185, 197))	('enhance', 'PosReg', (84, 91))	('osteosarcoma cell', 'Disease', (120, 137))
80137	22427255	Microarray analyses on 30 Ewing's tumors, coupled with immunohistochemistry on 125 cases that possessed sufficient clinical data and follow-up, revealed that low levels of CCN3 expression were associated with better patient prognosis when disease free and overall survival was considered.	('better', 'PosReg', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('low levels', 'Var', (158, 168))	("Ewing's tumors", 'Disease', (26, 40))	('patient', 'Species', '9606', (216, 223))	("Ewing's tumors", 'Disease', 'MESH:C563168', (26, 40))	('expression', 'MPA', (177, 187))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (26, 40))	('CCN3', 'Gene', (172, 176))
80147	22427255	Similarly, high CCN3 expression is also associated with a poor outcome in Ewing's Sarcoma and elicits enhanced migratory and invasive responses in these cells.	('enhanced', 'PosReg', (102, 110))	('rat', 'Species', '10116', (114, 117))	('expression', 'MPA', (21, 31))	("Ewing's Sarcoma", 'Disease', (74, 89))	('CCN3', 'Gene', (16, 20))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (74, 89))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (74, 89))	('Sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('high', 'Var', (11, 15))
80148	22427255	In contrast, CCN3 expression has been associated with a more differentiated phenotype and better prognosis in chondrosarcoma.	('associated', 'Reg', (38, 48))	('chondrosarcoma', 'Disease', 'MESH:D002813', (110, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('chondrosarcoma', 'Disease', (110, 124))	('CCN3', 'Gene', (13, 17))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (110, 124))	('expression', 'Var', (18, 28))
80161	22427255	These studies argue that high CCN3 expression in breast cancers is associated with a better outcome.	('breast cancers', 'Phenotype', 'HP:0003002', (49, 63))	('breast cancers', 'Disease', 'MESH:D001943', (49, 63))	('expression', 'MPA', (35, 45))	('breast cancers', 'Disease', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('high', 'Var', (25, 29))	('CCN3', 'Gene', (30, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
80171	22427255	Rather, CCN3 expression enhanced the ability of MDA-MB-231 cells to form spheroids in 3-D culture through increased intercellular adhesion.	('intercellular adhesion', 'CPA', (116, 138))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (48, 58))	('CCN3', 'Gene', (8, 12))	('enhanced', 'PosReg', (24, 32))	('expression', 'Var', (13, 23))	('increased', 'PosReg', (106, 115))
80172	22427255	Interestingly, full length CCN3 was unable to induce the migration of MDA-MB-231 cells, whereas a CCN3 mutant lacking the CT domain was able to induce a migratory phenotype.	('rat', 'Species', '10116', (156, 159))	('mutant', 'Var', (103, 109))	('rat', 'Species', '10116', (60, 63))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (70, 80))	('CCN3', 'Gene', (98, 102))	('induce', 'Reg', (144, 150))
80178	22427255	We also demonstrated that CCN3 enhanced the bone metastatic ability of 66cl4 cells, which are known only to metastasize to the lungs, without altering their growth in the mammary fat pad (Ouellet et al.).	('rat', 'Species', '10116', (15, 18))	('enhanced', 'PosReg', (31, 39))	('CCN3', 'Var', (26, 30))	('bone metastatic ability', 'CPA', (44, 67))
80181	22427255	In agreement with previous studies, CCN3 was able to impair osteoblast differentiation from primary bone marrow cultures, resulting in higher RANKL/OPG ratios which would enhance osteoclastogenesis.	('osteoclastogenesis', 'CPA', (179, 197))	('osteoblast differentiation', 'CPA', (60, 86))	('enhance', 'PosReg', (171, 178))	('rat', 'Species', '10116', (152, 155))	('CCN3', 'Var', (36, 40))	('OPG', 'Gene', (148, 151))	('OPG', 'Gene', '4982', (148, 151))	('impair', 'NegReg', (53, 59))	('higher', 'PosReg', (135, 141))	('RANKL', 'Gene', '8600', (142, 147))	('RANKL', 'Gene', (142, 147))
80185	22427255	High CCN1/CCN3 or CCN2/CCN3 mRNA ratios were found to be associated with a highly metastatic phenotype in breast cancer cells.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('CCN1', 'Gene', (5, 9))	('breast cancer', 'Disease', (106, 119))	('CCN1', 'Gene', '3491', (5, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('rat', 'Species', '10116', (33, 36))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('CCN2/CCN3', 'Var', (18, 27))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('associated', 'Reg', (57, 67))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
80199	22427255	), coupled with the recent observation that low CCN3 concentrations may enhance osteoblastogenesis, raises the intriguing possibility that CCN3 could play a role in lytic and/or blastic bone metastases formation depending on the level of CCN3 expression.	('CCN3', 'Gene', (48, 52))	('lytic', 'CPA', (165, 170))	('osteoblastogenesis', 'CPA', (80, 98))	('enhance', 'PosReg', (72, 79))	('low', 'Var', (44, 47))	('rat', 'Species', '10116', (60, 63))	('play', 'Reg', (150, 154))	('bone metastases', 'Disease', 'MESH:D009362', (186, 201))	('bone metastases', 'Disease', (186, 201))
80221	22375140	Kaposi's sarcoma-associated herpesvirus and other herpesviruses have a unique feature: KSHV can manipulate cellular machineries, such as cell proliferation, anti-apoptosis, and immune surveillance, by hijacking the cellular ubiquitin system, including polyubiquitin-dependent degradation by the 26S proteasome.	('hijacking', 'PosReg', (201, 210))	('cellular', 'CPA', (107, 115))	('cell proliferation', 'CPA', (137, 155))	('herpesvirus', 'Species', '39059', (50, 61))	('KSHV', 'Species', '37296', (87, 91))	('KSHV', 'Var', (87, 91))	('26S proteasome', 'Enzyme', (295, 309))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (0, 16))	('immune surveillance', 'CPA', (177, 196))	('cellular', 'Pathway', (215, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('manipulate', 'Reg', (96, 106))	('polyubiquitin-dependent degradation', 'MPA', (252, 287))	('herpesvirus', 'Species', '39059', (28, 39))	('anti-apoptosis', 'CPA', (157, 171))	("Kaposi's sarcoma-associated herpesvirus", 'Species', '37296', (0, 39))
80227	22375140	The polyubiquitin chain, linked through Lys48 (K48-linked polyubiquitin), functions as a signal for degradation by the 26S proteasome.	('polyubiquitin chain', 'Protein', (4, 23))	('Lys48', 'Var', (40, 45))	('Lys48', 'Chemical', '-', (40, 45))	('degradation', 'MPA', (100, 111))
80228	22375140	On the other hand, it has been thought that the polyubiquitin chain linked through Lys other than Lys48 (i.e., Lys6, 11, 27, 29, 33, and 63), plays a role in numerous cellular events.	('Lys', 'Chemical', 'MESH:D008239', (83, 86))	('plays', 'Reg', (142, 147))	('Lys6', 'Chemical', '-', (111, 115))	('polyubiquitin chain', 'Protein', (48, 67))	('Lys', 'Chemical', 'MESH:D008239', (111, 114))	('role', 'Reg', (150, 154))	('Lys', 'Chemical', 'MESH:D008239', (98, 101))	('Lys6', 'Var', (111, 115))	('Lys48', 'Chemical', '-', (98, 103))
80239	22375140	Proteins conjugated with a K48-linked polyubiquitin chain are rapidly degraded by the 26S proteasome in an ATP-dependent manner (Figure 1B).	('degraded', 'NegReg', (70, 78))	('K48-linked', 'Var', (27, 37))	('ATP', 'Chemical', 'MESH:D000255', (107, 110))	('Pro', 'Chemical', 'MESH:D011392', (0, 3))	('Proteins', 'Protein', (0, 8))
80252	22375140	The LANA CR region can be further subdivided into three subdomains, based on differences in amino acid (aa) repeat sequences: CR1 (aa 321-428 in ORF73 of the BC-1 sequence, CR2 (aa 430-768), and CR3 (aa 769-937).	('CR1', 'Gene', (126, 129))	('CR', 'Chemical', '-', (126, 128))	('CR2', 'Species', '2498238', (173, 176))	('ORF73', 'Gene', (145, 150))	('CR1', 'Gene', '1378', (126, 129))	('aa 430-768', 'Var', (178, 188))	('CR', 'Chemical', '-', (173, 175))	('LANA', 'Gene', (4, 8))	('CR', 'Chemical', '-', (9, 11))	('aa 321-428', 'Var', (131, 141))	('LANA', 'Gene', '4961527', (4, 8))	('CR', 'Chemical', '-', (195, 197))	('ORF73', 'Gene', '4961527', (145, 150))
80253	22375140	It is known that the subdomain containing CR2CR3 contributes to LANA stability in vitro and in vivo and also retards LANA protein synthesis, minimizing LANA protein levels (Kwun et al.,).	('LANA', 'Gene', '4961527', (117, 121))	('LANA', 'Gene', '4961527', (152, 156))	('CR2CR3', 'Var', (42, 48))	('LANA', 'Gene', (64, 68))	('LANA', 'Gene', '4961527', (64, 68))	('LANA', 'Gene', (117, 121))	('contributes', 'PosReg', (49, 60))	('retards', 'NegReg', (109, 116))	('minimizing', 'NegReg', (141, 151))	('LANA', 'Gene', (152, 156))
80256	22375140	These findings suggest that LANA physically inhibits the proteasome by insertion of the repeats into the proteolytic core particle of the 26S proteasome; however, KSHV and EBV use different mechanisms to evade host CTL-dependent surveillance.	('insertion', 'Var', (71, 80))	('repeats', 'Var', (88, 95))	('KSHV', 'Species', '37296', (163, 167))	('LANA', 'Gene', (28, 32))	('inhibits', 'NegReg', (44, 52))	('LANA', 'Gene', '4961527', (28, 32))
80285	22375140	Moreover, KSHV-encoded vIRF1 also contributes to destabilizing the protein level of p53 by manipulating ATM kinase, which is activated by DNA damage.	('destabilizing', 'NegReg', (49, 62))	('manipulating', 'Var', (91, 103))	('KSHV', 'Species', '37296', (10, 14))	('vIRF1', 'Gene', '4961464', (23, 28))	('vIRF1', 'Gene', (23, 28))	('ATM', 'MPA', (104, 107))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('protein level', 'MPA', (67, 80))
80286	22375140	ATM can phosphorylate the Ser15 residues of p53, and this phosphorylation inhibits the interaction with Mdm2, resulting in p53 stabilization.	('Ser15', 'Chemical', '-', (26, 31))	('interaction', 'Interaction', (87, 98))	('Mdm2', 'Gene', (104, 108))	('p53', 'Gene', (44, 47))	('p53', 'Gene', (123, 126))	('stabilization', 'MPA', (127, 140))	('inhibits', 'NegReg', (74, 82))	('p53', 'Gene', '7157', (44, 47))	('p53', 'Gene', '7157', (123, 126))	('Ser15', 'Var', (26, 31))	('Mdm2', 'Gene', '4193', (104, 108))
80294	22375140	RTA interacts with Hey1 and K-RBP, and RTA mediates polyubiquitination, dependent on the Cys/His-rich domain of RTA, resulting in proteasomal degradation, while the Cys/His-rich domain of RTA is partially necessary for TRIF degradation, and RTA-mediated degradation of TRIF is partially mediated through the ubiquitin system.	('K-RBP', 'Gene', (28, 33))	('TRIF', 'Gene', (219, 223))	('TRIF', 'Gene', (269, 273))	('K-RBP', 'Gene', '79088', (28, 33))	('TRIF', 'Gene', '148022', (219, 223))	('His', 'Chemical', 'MESH:D006639', (93, 96))	('Cys', 'Chemical', 'MESH:D003545', (89, 92))	('Cys/His-rich domain', 'Var', (89, 108))	('His', 'Chemical', 'MESH:D006639', (169, 172))	('mediates', 'Reg', (43, 51))	('proteasomal degradation', 'MPA', (130, 153))	('Cys', 'Chemical', 'MESH:D003545', (165, 168))	('polyubiquitination', 'MPA', (52, 70))	('TRIF', 'Gene', '148022', (269, 273))	('Hey1', 'Gene', '23462', (19, 23))	('Hey1', 'Gene', (19, 23))
80301	22375140	The RING-CH domain of K5 interacts with UbcH5a as an E2 enzyme (Coscoy et al.,), which is involved in K63-, K11-, and K48-linked polyubiquitination (Bosanac et al.,).	('E2 enzyme', 'Gene', '7321;7334', (53, 62))	('K48-linked polyubiquitination', 'Disease', 'MESH:C564433', (118, 147))	('K63-', 'Var', (102, 106))	('UbcH5a', 'Gene', '7321', (40, 46))	('involved', 'Reg', (90, 98))	('UbcH5a', 'Gene', (40, 46))	('E2 enzyme', 'Gene', (53, 62))	('K11-', 'MPA', (108, 112))	('K48-linked polyubiquitination', 'Disease', (118, 147))
80307	22375140	Ubc13 has been implicated in a variety of cellular processes, such as cell signaling and DNA repair, and has the ability to catalyze formation of K63-linked polyubiquitin chains on various substrates.	('implicated', 'Reg', (15, 25))	('K63-linked', 'Var', (146, 156))	('cell signaling', 'CPA', (70, 84))	('Ubc13', 'Gene', '7334', (0, 5))	('Ubc13', 'Gene', (0, 5))	('DNA repair', 'Disease', (89, 99))
80308	22375140	Many substrates of the 26S proteasome are modified by the post-translational modification before their K48-linked polyubiquitination.	('modified', 'Reg', (42, 50))	('K48-linked polyubiquitination', 'Disease', 'MESH:C564433', (103, 132))	('K48-linked polyubiquitination', 'Disease', (103, 132))	('post-translational modification', 'Var', (58, 89))
80317	22375140	More than 70 F-box proteins in humans can be categorized into three types (Figure 3): F-box proteins containing WD40 repeats domain (Fbw/FBXW), F-box proteins containing leucine-rich repeats domain (Fbl/FBXL), and F-box proteins containing other domains (Fbx/FBXO; Nakayama and Nakayama,).	('Fbw', 'Gene', (133, 136))	('Fbl', 'Gene', (199, 202))	('Fbw', 'Gene', '55294', (133, 136))	('Fbl', 'Gene', '2091', (199, 202))	('WD40 repeats domain', 'Var', (112, 131))	('humans', 'Species', '9606', (31, 37))
80319	22375140	beta-TrCP recognizes the conserved DpSGXXpS motif (with phosphorylated serine residues) in the substrate.	('DpSGXXpS', 'Var', (35, 43))	('beta-TrCP', 'Gene', '8945', (0, 9))	('serine', 'Chemical', 'MESH:D012694', (71, 77))	('beta-TrCP', 'Gene', (0, 9))
80325	22375140	As described in the next section, KSHV can also promote the phosphorylation of Thr187 of p27, leading to polyubiquitination of p27.	('phosphorylation', 'MPA', (60, 75))	('p27', 'Gene', (89, 92))	('p27', 'Gene', '3429', (89, 92))	('KSHV', 'Var', (34, 38))	('KSHV', 'Species', '37296', (34, 38))	('p27', 'Gene', (127, 130))	('p27', 'Gene', '3429', (127, 130))	('Thr187', 'Chemical', '-', (79, 85))	('polyubiquitination', 'MPA', (105, 123))	('promote', 'PosReg', (48, 55))
80346	22375140	When a Notch ligand, such as Jagged or Delta, binds the Notch receptor, a gamma-secretase complex, including presenilin, cleaves the intramembrane region of the Notch receptor, Notch-1, 2, 3, and 4, resulting in release of intracellular Notch (ICN, also called the Notch intracellular domain, NICD).	('release', 'MPA', (212, 219))	('cleaves', 'Var', (121, 128))	('intracellular Notch', 'MPA', (223, 242))	('Notch-1, 2, 3, and 4', 'Gene', '4851;4853;4854;4855', (177, 197))
80360	22375140	K63-linked polyubiquitinated NEMO then activates the IKK complex, which phosphorylates IkappaBalpha.	('K63-linked polyubiquitinated', 'Var', (0, 28))	('IkappaBalpha', 'Gene', (87, 99))	('activates', 'PosReg', (39, 48))	('IKK complex', 'Pathway', (53, 64))	('NEMO', 'Gene', (29, 33))	('IkappaBalpha', 'Gene', '4792', (87, 99))	('NEMO', 'Gene', '8517', (29, 33))
80361	22375140	Phosphorylation of Ser32 and Ser36 IkappaBalpha can be a trigger for K48-linked polyubiquitination by SCFbetaTrCP (Figure 3).	('IkappaBalpha', 'Gene', (35, 47))	('Ser32', 'Chemical', '-', (19, 24))	('Ser36', 'Var', (29, 34))	('K48-linked polyubiquitination', 'Disease', (69, 98))	('K48-linked polyubiquitination', 'Disease', 'MESH:C564433', (69, 98))	('SCF', 'Gene', (102, 105))	('IkappaBalpha', 'Gene', '4792', (35, 47))	('SCF', 'Gene', '4254', (102, 105))	('Ser36', 'Chemical', '-', (29, 34))
80367	22375140	In response to TNF-alpha stimuli, receptor-interacting protein (RIP) is modified with K63-linked polyubiquitin chain, and polyubiquitinated RIP recruits NEMO into the IKK complex.	('receptor-interacting protein', 'Gene', '8737', (34, 62))	('receptor-interacting protein', 'Gene', (34, 62))	('polyubiquitinated', 'Var', (122, 139))	('NEMO', 'Gene', '8517', (153, 157))	('RIP', 'Gene', '8737', (64, 67))	('TNF-alpha', 'Gene', '7124', (15, 24))	('RIP', 'Gene', (64, 67))	('RIP', 'Gene', (140, 143))	('RIP', 'Gene', '8737', (140, 143))	('TNF-alpha', 'Gene', (15, 24))	('NEMO', 'Gene', (153, 157))	('K63-linked polyubiquitin chain', 'MPA', (86, 116))
80370	22375140	v-FLIP can activate the IKK complex through interaction with NEMO of the IKK complex, including Hsp90 (Field et al.,) and RIP (Chaudhary et al.,; Liu et al.,).	('NEMO', 'Gene', (61, 65))	('v-FLIP', 'Var', (0, 6))	('Hsp90', 'Gene', (96, 101))	('NEMO', 'Gene', '8517', (61, 65))	('Hsp90', 'Gene', '3320', (96, 101))	('activate', 'PosReg', (11, 19))	('RIP', 'Gene', '8737', (122, 125))	('RIP', 'Gene', (122, 125))	('interaction', 'Interaction', (44, 55))
80382	22375140	Furthermore, K7 expression reduces vGPCR tumorigenicity in nude mice (Feng et al.,).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('reduces', 'NegReg', (27, 34))	('tumor', 'Disease', (41, 46))	('vGPCR', 'Gene', (35, 40))	('K7 expression', 'Var', (13, 26))	('vGPCR', 'Gene', '4961465', (35, 40))	('nude mice', 'Species', '10090', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
80386	22375140	Displacement of GSK-3 from the complex leads to stabilization of beta-catenin, which translocates to the nucleus and forms a complex with Lef (or Tcf4) transcription factors, stimulating the expression of c-Myc, c-Jun, and cyclin D1.	('beta-catenin', 'Gene', '1499', (65, 77))	('stimulating', 'PosReg', (175, 186))	('c-Jun', 'Gene', '3725', (212, 217))	('Tcf4', 'Gene', '6925', (146, 150))	('c-Myc', 'Gene', '4609', (205, 210))	('Displacement', 'Var', (0, 12))	('cyclin D1', 'Gene', '595', (223, 232))	('c-Myc', 'Gene', (205, 210))	('GSK-3', 'Gene', (16, 21))	('Tcf4', 'Gene', (146, 150))	('stabilization', 'MPA', (48, 61))	('c-Jun', 'Gene', (212, 217))	('expression', 'MPA', (191, 201))	('complex', 'Interaction', (125, 132))	('beta-catenin', 'Gene', (65, 77))	('cyclin D1', 'Gene', (223, 232))
80387	22375140	Phosphorylation of beta-catenin is essential for binding SCFbetaTrCP complex, containing the beta-TrCP that recognizes the DpSGXXpS motif in beta-catenin.	('beta-TrCP', 'Gene', (93, 102))	('beta-catenin', 'Gene', (141, 153))	('SCF', 'Gene', (57, 60))	('beta-catenin', 'Gene', '1499', (141, 153))	('beta-catenin', 'Gene', (19, 31))	('SCF', 'Gene', '4254', (57, 60))	('beta-TrCP', 'Gene', '8945', (93, 102))	('beta-catenin', 'Gene', '1499', (19, 31))	('DpSGXXpS motif', 'Var', (123, 137))
80391	22375140	In beta-catenin, phosphorylation of Ser45 by casein kinase I serves as the priming event for GSK-3 kinase, which then phosphorylates the Thr41, Ser37, and Ser33 residues.	('Thr41', 'Var', (137, 142))	('Ser37', 'Chemical', '-', (144, 149))	('beta-catenin', 'Gene', (3, 15))	('beta-catenin', 'Gene', '1499', (3, 15))	('Ser37', 'Var', (144, 149))	('Ser45', 'Chemical', '-', (36, 41))	('Thr41', 'Chemical', '-', (137, 142))	('Ser33', 'Chemical', '-', (155, 160))	('Ser33', 'Var', (155, 160))
80392	22375140	Phosphorylation of Ser33 and Ser37 of beta-catenin is necessary for binding of the SCFbetaTrCP complex and K48-linked polyubiquitination.	('SCF', 'Gene', (83, 86))	('beta-catenin', 'Gene', (38, 50))	('Ser37', 'Var', (29, 34))	('binding', 'Interaction', (68, 75))	('SCF', 'Gene', '4254', (83, 86))	('beta-catenin', 'Gene', '1499', (38, 50))	('K48-linked polyubiquitination', 'Disease', 'MESH:C564433', (107, 136))	('K48-linked polyubiquitination', 'Disease', (107, 136))	('Ser37', 'Chemical', '-', (29, 34))	('Ser33', 'Chemical', '-', (19, 24))
80403	22375140	Inactivation of nuclear GSK-3 by LANA may increase the stability and activity of c-Myc and further contribute to LANA-mediated growth dysregulation.	('LANA', 'Gene', (33, 37))	('growth dysregulation', 'MPA', (127, 147))	('activity', 'MPA', (69, 77))	('LANA', 'Gene', (113, 117))	('contribute', 'Reg', (99, 109))	('LANA', 'Gene', '4961527', (113, 117))	('LANA', 'Gene', '4961527', (33, 37))	('nuclear GSK-3', 'Protein', (16, 29))	('stability', 'MPA', (55, 64))	('c-Myc', 'Gene', '4609', (81, 86))	('c-Myc', 'Gene', (81, 86))	('Inactivation', 'Var', (0, 12))	('increase', 'PosReg', (42, 50))
80443	28389532	Cytoplasmic inclusions of alpha-synuclein in the neurons of the substantia nigra pars compacta and other brain regions are a hallmark feature of PD.	('PD', 'Disease', 'MESH:D010300', (145, 147))	('alpha-synuclein', 'Protein', (26, 41))	('Cytoplasmic', 'Var', (0, 11))
80445	28389532	In HD, a genetic trinucleotide repeat expansion leads to an elongated polyglutamine tract in the protein huntingtin, causing it to form both nuclear and cytoplasmic amyloid inclusions.	('polyglutamine', 'Chemical', 'MESH:C097188', (70, 83))	('elongated', 'Var', (60, 69))	('trinucleotide', 'Chemical', '-', (17, 30))	('polyglutamine tract', 'MPA', (70, 89))	('leads to', 'Reg', (48, 56))	('huntingtin', 'Gene', (105, 115))	('trinucleotide repeat expansion', 'Var', (17, 47))	('HD', 'Disease', 'MESH:D006816', (3, 5))	('amyloid inclusions', 'Phenotype', 'HP:0011034', (165, 183))	('huntingtin', 'Gene', '3064', (105, 115))
80446	28389532	In addition, repeat-associated non-ATG (RAN) translation occurs in several diseases caused by repeat expansions, including spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1, fragile X-associated tremor ataxia syndrome, ALS, and HD.	('HD', 'Disease', 'MESH:D006816', (242, 244))	('SCA8', 'Gene', '724066', (154, 158))	('ataxia', 'Phenotype', 'HP:0001251', (139, 145))	('SCA8', 'Gene', (154, 158))	('myotonic dystrophy', 'Disease', 'MESH:D009223', (161, 179))	('RAN', 'Gene', '5901', (40, 43))	('ALS', 'Gene', (233, 236))	('repeat-associated non-ATG', 'Gene', (13, 38))	('repeat expansions', 'Var', (94, 111))	('ataxia', 'Phenotype', 'HP:0001251', (216, 222))	('caused', 'Reg', (84, 90))	('ALS', 'Gene', '6647', (233, 236))	('fragile X-associated tremor ataxia syndrome', 'Disease', (188, 231))	('spinocerebellar ataxia type 8', 'Disease', (123, 152))	('RAN', 'Gene', (40, 43))	('fragile X-associated tremor ataxia syndrome', 'Disease', 'MESH:C564105', (188, 231))	('repeat-associated non-ATG', 'Gene', '5901', (13, 38))	('myotonic dystrophy', 'Disease', (161, 179))	('tremor', 'Phenotype', 'HP:0001337', (209, 215))	('occurs', 'Reg', (57, 63))	('ALS', 'Phenotype', 'HP:0007354', (233, 236))
80447	28389532	RAN translation in HD, which occurs in multiple reading frames from both sense and antisense transcripts, leads to the accumulation of aggregated polyalanine, polyserine, polyleucine, and polycysteine in the brains of HD patients.	('polyserine', 'Var', (159, 169))	('patients', 'Species', '9606', (221, 229))	('polyalanine', 'Chemical', 'MESH:C019529', (146, 157))	('polyleucine', 'Var', (171, 182))	('polyserine', 'Chemical', 'MESH:C027794', (159, 169))	('polycysteine', 'MPA', (188, 200))	('HD', 'Disease', 'MESH:D006816', (218, 220))	('HD', 'Disease', 'MESH:D006816', (19, 21))	('RAN', 'Gene', (0, 3))	('polyalanine', 'Var', (146, 157))	('RAN', 'Gene', '5901', (0, 3))	('polyleucine', 'Chemical', 'MESH:C027819', (171, 182))	('polycysteine', 'Chemical', 'MESH:C057713', (188, 200))	('accumulation', 'PosReg', (119, 131))
80462	28389532	Deletion of this prion domain precludes access to the prion state, and addition of this region to otherwise innocuous proteins is sufficient to confer prion behavior.	('prion', 'Species', '36469', (54, 59))	('prion', 'Species', '36469', (17, 22))	('prion behavior', 'MPA', (151, 165))	('precludes', 'NegReg', (30, 39))	('prion', 'Species', '36469', (151, 156))	('confer', 'Reg', (144, 150))	('Deletion', 'Var', (0, 8))
80469	28389532	This association began with the identification of a trinucleotide repeat expansion in the gene encoding ataxin 1 (ATXN1) that leads to a polyglutamine protein product and causes SCA1.	('causes', 'Reg', (171, 177))	('leads to', 'Reg', (126, 134))	('ATXN1', 'Gene', (114, 119))	('ATXN1', 'Gene', '6310', (114, 119))	('trinucleotide', 'Chemical', '-', (52, 65))	('polyglutamine protein product', 'MPA', (137, 166))	('polyglutamine', 'Chemical', 'MESH:C097188', (137, 150))	('ataxin 1', 'Gene', '6310', (104, 112))	('SCA1', 'Gene', (178, 182))	('ataxin 1', 'Gene', (104, 112))	('trinucleotide repeat expansion', 'Var', (52, 82))	('SCA1', 'Gene', '6310', (178, 182))
80471	28389532	A similar expansion in ataxin 2 (ATXN2) causes SCA2.	('causes', 'Reg', (40, 46))	('ataxin 2', 'Gene', '6311', (23, 31))	('ATXN2', 'Gene', (33, 38))	('ATXN2', 'Gene', '6311', (33, 38))	('SCA2', 'Gene', (47, 51))	('ataxin 2', 'Gene', (23, 31))	('SCA2', 'Gene', '6311', (47, 51))	('expansion', 'Var', (10, 19))
80479	28389532	Mutations in the gene encoding TDP-43 (TARDBP) have been identified in cases of both familial and sporadic ALS, with mutations segregating with disease in the former, further implicating TDP-43 in the pathogenesis of neurodegeneration.	('familial', 'Disease', (85, 93))	('ALS', 'Gene', '6647', (107, 110))	('TARDBP', 'Gene', '23435', (39, 45))	('neurodegeneration', 'Disease', 'MESH:D019636', (217, 234))	('ALS', 'Phenotype', 'HP:0007354', (107, 110))	('ALS', 'Gene', (107, 110))	('Mutations', 'Var', (0, 9))	('TARDBP', 'Gene', (39, 45))	('identified', 'Reg', (57, 67))	('neurodegeneration', 'Phenotype', 'HP:0002180', (217, 234))	('neurodegeneration', 'Disease', (217, 234))
80480	28389532	TARDBP mutations are also found in rare instances of FTD.	('mutations', 'Var', (7, 16))	('found', 'Reg', (26, 31))	('FTD', 'Disease', 'MESH:C563003', (53, 56))	('TARDBP', 'Gene', '23435', (0, 6))	('TARDBP', 'Gene', (0, 6))	('FTD', 'Disease', (53, 56))
80483	28389532	The TDP-43 PrLD is also crucial for aberrant protein aggregation in vitro and in model systems, and select disease-linked mutations accelerate protein aggregation in vitro and in vivo.	('rat', 'Species', '10116', (138, 141))	('mutations', 'Var', (122, 131))	('protein aggregation', 'MPA', (143, 162))	('accelerate', 'PosReg', (132, 142))
80484	28389532	Deletion of the PrLD eliminates protein toxicity in model organisms, as does disruption of the RNA-binding ability of TDP-43, suggesting roles for both misfolding and RNA engagement in disease pathogenesis.	('toxicity', 'Disease', (40, 48))	('PrLD', 'Gene', (16, 20))	('eliminates', 'NegReg', (21, 31))	('RNA-binding', 'Interaction', (95, 106))	('toxicity', 'Disease', 'MESH:D064420', (40, 48))	('Deletion', 'Var', (0, 8))
80492	28389532	Mutations in FUS have been linked to sporadic and familial cases of ALS, and these patients demonstrate the accumulation of FUS-positive inclusions in the cytoplasm of degenerating neurons and glia, and decreased nuclear FUS.	('linked', 'Reg', (27, 33))	('FUS', 'Gene', '2521', (124, 127))	('FUS', 'Gene', (221, 224))	('decreased', 'NegReg', (203, 212))	('ALS', 'Gene', '6647', (68, 71))	('FUS', 'Gene', '2521', (221, 224))	('patients', 'Species', '9606', (83, 91))	('rat', 'Species', '10116', (99, 102))	('Mutations', 'Var', (0, 9))	('FUS', 'Gene', (13, 16))	('rat', 'Species', '10116', (174, 177))	('FUS', 'Gene', '2521', (13, 16))	('ALS', 'Gene', (68, 71))	('ALS', 'Phenotype', 'HP:0007354', (68, 71))	('FUS', 'Gene', (124, 127))
80493	28389532	FUS mutations have caused the earliest reported onset of juvenile-onset ALS reported in children as young as 11 years old.	('juvenile-onset ALS', 'Phenotype', 'HP:0005681', (57, 75))	('ALS', 'Gene', '6647', (72, 75))	('ALS', 'Phenotype', 'HP:0007354', (72, 75))	('ALS', 'Gene', (72, 75))	('children', 'Species', '9606', (88, 96))	('FUS', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('FUS', 'Gene', '2521', (0, 3))
80496	28389532	Putative pathogenic mutations in FUS cluster in the C-terminal proline-tyrosine nuclear localization signal (PY-NLS), the RGG-rich region, and the PrLD (Figure 3).	('pathogenic', 'Reg', (9, 19))	('FUS', 'Gene', (33, 36))	('proline', 'Chemical', 'MESH:D011392', (63, 70))	('FUS', 'Gene', '2521', (33, 36))	('tyrosine', 'Chemical', 'MESH:D014443', (71, 79))	('mutations', 'Var', (20, 29))
80498	28389532	ALS-linked FUS mutations confer both gain- and loss-of-function phenotypes.	('ALS', 'Phenotype', 'HP:0007354', (0, 3))	('loss-of-function', 'NegReg', (47, 63))	('ALS-linked FUS', 'Disease', (0, 14))	('mutations', 'Var', (15, 24))	('gain-', 'PosReg', (37, 42))	('ALS-linked FUS', 'Disease', 'MESH:D008113', (0, 14))
80501	28389532	Similarly, ALS-linked mutations in FUS increase the association of FUS with SMN, leading to a reduction in the abundance of Gems and altered snRNA levels.	('ALS', 'Phenotype', 'HP:0007354', (11, 14))	('ALS', 'Gene', (11, 14))	('abundance of Gems', 'MPA', (111, 128))	('FUS', 'Gene', (67, 70))	('reduction', 'NegReg', (94, 103))	('FUS', 'Gene', '2521', (67, 70))	('SMN', 'Gene', (76, 79))	('snRNA levels', 'MPA', (141, 153))	('association', 'Interaction', (52, 63))	('increase', 'PosReg', (39, 47))	('SMN', 'Gene', '6606', (76, 79))	('mutations', 'Var', (22, 31))	('FUS', 'Gene', (35, 38))	('ALS', 'Gene', '6647', (11, 14))	('FUS', 'Gene', '2521', (35, 38))	('altered', 'Reg', (133, 140))
80502	28389532	These pathologic mutations simultaneously decrease FUS binding to the U1 snRNP, resulting in splicing disruptions that phenocopy a partial loss of FUS activity.	('FUS', 'Gene', '2521', (51, 54))	('loss', 'NegReg', (139, 143))	('splicing disruptions', 'MPA', (93, 113))	('decrease', 'NegReg', (42, 50))	('FUS', 'Gene', (147, 150))	('U1 snRNP', 'Gene', '26871;55599', (70, 78))	('FUS', 'Gene', '2521', (147, 150))	('mutations', 'Var', (17, 26))	('U1 snRNP', 'Gene', (70, 78))	('FUS', 'Gene', (51, 54))
80507	28389532	Further investigation identified mutations in TAF15 and EWSR1 in patients with sporadic ALS (Figure 4) and revealed that either protein may be found depleted from the nucleus and mislocalized to cytoplasmic neuronal inclusions in ALS and FTD.	('ALS', 'Gene', '6647', (230, 233))	('FTD', 'Disease', 'MESH:C563003', (238, 241))	('EWSR1', 'Gene', (56, 61))	('TAF15', 'Gene', '8148', (46, 51))	('ALS', 'Phenotype', 'HP:0007354', (230, 233))	('mutations', 'Var', (33, 42))	('EWSR1', 'Gene', '2130', (56, 61))	('ALS', 'Gene', (88, 91))	('ALS', 'Gene', '6647', (88, 91))	('FTD', 'Disease', (238, 241))	('TAF15', 'Gene', (46, 51))	('patients', 'Species', '9606', (65, 73))	('ALS', 'Phenotype', 'HP:0007354', (88, 91))	('ALS', 'Gene', (230, 233))
80508	28389532	Additional evidence for pathogenicity came from in vitro studies demonstrating that both proteins are intrinsically aggregation prone, and ALS-linked TAF15 and EWSR1 mutations accelerate aggregation.	('rat', 'Species', '10116', (72, 75))	('ALS-linked TAF15', 'Disease', 'MESH:D008113', (139, 155))	('mutations', 'Var', (166, 175))	('ALS-linked TAF15', 'Disease', (139, 155))	('aggregation', 'MPA', (116, 127))	('accelerate', 'PosReg', (176, 186))	('rat', 'Species', '10116', (182, 185))	('ALS', 'Phenotype', 'HP:0007354', (139, 142))	('EWSR1', 'Gene', (160, 165))	('aggregation', 'MPA', (187, 198))	('EWSR1', 'Gene', '2130', (160, 165))
80509	28389532	In addition, both proteins are toxic when overexpressed in the Drosophila nervous system and disease-associated TAF15 mutations cause a more severe phenotype.	('TAF15', 'Gene', (112, 117))	('Drosophila nervous system', 'Disease', (63, 88))	('Drosophila nervous system', 'Disease', 'MESH:D009421', (63, 88))	('mutations', 'Var', (118, 127))	('TAF15', 'Gene', '8148', (112, 117))	('cause', 'Reg', (128, 133))
80510	28389532	Finally, in cultured mammalian neurons, disease-linked TAF15 and EWSR1 mutations induced formation of cytoplasmic TAF15 and EWSR1 inclusions.	('EWSR1', 'Gene', (65, 70))	('EWSR1', 'Gene', (124, 129))	('cytoplasmic', 'MPA', (102, 113))	('TAF15', 'Gene', '8148', (55, 60))	('TAF15', 'Gene', '8148', (114, 119))	('EWSR1', 'Gene', '2130', (124, 129))	('EWSR1', 'Gene', '2130', (65, 70))	('mutations', 'Var', (71, 80))	('mammalian', 'Species', '9606', (21, 30))	('TAF15', 'Gene', (55, 60))	('TAF15', 'Gene', (114, 119))	('disease-linked', 'Reg', (40, 54))
80519	28389532	VCP mutations have subsequently been identified in patients with isolated ALS, IBM, and PDB.	('PDB', 'Gene', '5131', (88, 91))	('ALS', 'Phenotype', 'HP:0007354', (74, 77))	('VCP', 'Gene', '7415', (0, 3))	('IBM', 'Disease', (79, 82))	('VCP', 'Gene', (0, 3))	('ALS', 'Gene', (74, 77))	('PDB', 'Gene', (88, 91))	('ALS', 'Gene', '6647', (74, 77))	('identified', 'Reg', (37, 47))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (4, 13))
80520	28389532	VCP plays a critical role in the clearance of stress granules via autophagy, and disease-associated VCP variants cause the constitutive formation of stress granules in cell culture, suggesting that aberrant stress granule persistence may contribute to neurodegenerative disease pathogenesis.	('constitutive', 'MPA', (123, 135))	('neurodegenerative disease', 'Disease', 'MESH:D019636', (252, 277))	('contribute', 'Reg', (238, 248))	('neurodegenerative disease', 'Disease', (252, 277))	('cause', 'Reg', (113, 118))	('variants', 'Var', (104, 112))	('VCP', 'Gene', (0, 3))	('VCP', 'Gene', '7415', (0, 3))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (252, 277))	('VCP', 'Gene', '7415', (100, 103))	('VCP', 'Gene', (100, 103))
80521	28389532	Exome sequencing and linkage analysis of two MSP-affected families without VCP mutations uncovered pathogenic mutations in the genes encoding heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2B1 (hnRNPA1 and hnRNPA2B1), two RBPs with PrLDs.	('VCP', 'Gene', (75, 78))	('RNP', 'Gene', (186, 189))	('RBP', 'Gene', (233, 236))	('A2B1', 'Gene', (199, 203))	('hnRNPA1', 'Gene', (205, 212))	('mutations', 'Var', (110, 119))	('RNP', 'Gene', '55599', (186, 189))	('RNP', 'Gene', '55599', (207, 210))	('RBP', 'Gene', '57794', (233, 236))	('hnRNPA1', 'Gene', '3178', (205, 212))	('RNP', 'Gene', (219, 222))	('pathogenic', 'Reg', (99, 109))	('RNP', 'Gene', '55599', (219, 222))	('RNP', 'Gene', (207, 210))	('VCP', 'Gene', '7415', (75, 78))
80522	28389532	MSP can be caused by a D262V substitution in hnRNPA1 or a D290V substitution in hnRNPA2.	('MSP', 'Disease', (0, 3))	('hnRNPA2', 'Gene', '3181', (80, 87))	('D262V', 'Mutation', 'rs397518452', (23, 28))	('D290V', 'Mutation', 'rs397515326', (58, 63))	('hnRNPA2', 'Gene', (80, 87))	('hnRNPA1', 'Gene', (45, 52))	('D262V', 'Var', (23, 28))	('D290V', 'Var', (58, 63))	('caused by', 'Reg', (11, 20))	('hnRNPA1', 'Gene', '3178', (45, 52))
80536	28389532	Importantly, the splicing changes that result from the MSP-causing substitution, D290V, in hnRNPA2B1 in patient fibroblasts are distinct from those that occur due to loss of hnRNPA2B1 function.	('D290V', 'Mutation', 'rs397515326', (81, 86))	('splicing', 'MPA', (17, 25))	('D290V', 'Var', (81, 86))	('patient', 'Species', '9606', (104, 111))	('hnRNPA2B1', 'Gene', (91, 100))	('MSP-causing', 'Reg', (55, 66))
80537	28389532	In contrast, the splicing changes caused by the D290V substitution in hnRNPA2B1 have a ~66% overlap with splicing alterations observed in fibroblasts from patients with an MSP-causing mutation in VCP.	('splicing alterations', 'MPA', (105, 125))	('rat', 'Species', '10116', (118, 121))	('hnRNPA2B1', 'Gene', (70, 79))	('splicing changes', 'MPA', (17, 33))	('VCP', 'Gene', '7415', (196, 199))	('VCP', 'Gene', (196, 199))	('D290V', 'Mutation', 'rs397515326', (48, 53))	('D290V', 'Var', (48, 53))	('patients', 'Species', '9606', (155, 163))
80538	28389532	This finding suggests a possible etiology for the shared disease phenotype caused by mutations in VCP and hnRNPA2B1.	('VCP', 'Gene', '7415', (98, 101))	('VCP', 'Gene', (98, 101))	('mutations', 'Var', (85, 94))	('caused', 'Reg', (75, 81))	('hnRNPA2B1', 'Gene', (106, 115))
80540	28389532	Interestingly, both MSP-linked mutations involve a valine substitution at a conserved gatekeeper aspartate residue in the PrLD that is computationally predicted, by two separate algorithms, to increase prionogenicity (Figure 5).	('prionogenicity', 'MPA', (202, 216))	('mutations', 'Var', (31, 40))	('valine substitution', 'Var', (51, 70))	('increase', 'PosReg', (193, 201))	('valine', 'Chemical', 'MESH:D014633', (51, 57))	('rat', 'Species', '10116', (173, 176))	('MSP-linked', 'Gene', (20, 30))	('prion', 'Species', '36469', (202, 207))	('aspartate', 'Chemical', 'MESH:D001224', (97, 106))	('gatekeeper', 'Species', '111938', (86, 96))
80542	28389532	The aspartate-to-valine substitution in this region is predicted to strengthen a steric zipper, making the protein more prone to fibrillization (Figure 6).	('aspartate-to-valine substitution', 'Var', (4, 36))	('more', 'PosReg', (115, 119))	('steric zipper', 'MPA', (81, 94))	('strengthen', 'PosReg', (68, 78))	('prone', 'MPA', (120, 125))	('protein', 'Protein', (107, 114))	('fibrillization', 'MPA', (129, 143))	('aspartate', 'Chemical', 'MESH:D001224', (4, 13))	('substitution', 'Var', (24, 36))	('valine', 'Chemical', 'MESH:D014633', (17, 23))
80544	28389532	can nucleate the aggregation of soluble protein), thereby reducing the lag phase of assembly, and the disease-associated mutations greatly accelerate fibrillization.	('lag phase of assembly', 'MPA', (71, 92))	('mutations', 'Var', (121, 130))	('reducing', 'NegReg', (58, 66))	('fibrillization', 'MPA', (150, 164))	('aggregation', 'MPA', (17, 28))	('accelerate', 'PosReg', (139, 149))	('rat', 'Species', '10116', (145, 148))
80545	28389532	However, if the presence of the aspartate-to-valine substitution accelerates the misfolding of the mutant protein, and the misfolding of the mutant protein can nucleate the misfolding of the wild-type protein, the presence of the wild-type allele would not be protective against the development of a disease phenotype.	('protein', 'Protein', (106, 113))	('aspartate-to-valine', 'Protein', (32, 51))	('aspartate', 'Chemical', 'MESH:D001224', (32, 41))	('misfolding', 'MPA', (173, 183))	('rat', 'Species', '10116', (71, 74))	('misfolding', 'MPA', (81, 91))	('accelerates', 'PosReg', (65, 76))	('mutant', 'Var', (99, 105))	('substitution', 'Var', (52, 64))	('valine', 'Chemical', 'MESH:D014633', (45, 51))
80546	28389532	Muscle biopsies from MSP patients with mutations in VCP, hnRNPA1, or hnRNPA2B1 share cytopathologic features including the cytoplasmic aggregation of TDP-43, which has also been observed in sporadic IBM in addition to ALS and FTD.	('hnRNPA2B1', 'Gene', (69, 78))	('cytoplasmic', 'MPA', (123, 134))	('FTD', 'Disease', 'MESH:C563003', (226, 229))	('FTD', 'Disease', (226, 229))	('IBM', 'Disease', (199, 202))	('mutations', 'Var', (39, 48))	('ALS', 'Phenotype', 'HP:0007354', (218, 221))	('hnRNPA1', 'Gene', (57, 64))	('patients', 'Species', '9606', (25, 33))	('TDP-43', 'Gene', (150, 156))	('hnRNPA1', 'Gene', '3178', (57, 64))	('ALS', 'Gene', (218, 221))	('VCP', 'Gene', (52, 55))	('ALS', 'Gene', '6647', (218, 221))	('VCP', 'Gene', '7415', (52, 55))
80547	28389532	A biopsy from an affected individual in the family harboring the hnRNPA2D290V variant also demonstrated mislocalization of hnRNPA2 from the nucleus to cytoplasmic inclusions, and in muscle fibers obtained from a patient expressing hnRNPA1D262V, both hnRNPA1 and hnRNPA2 were cleared from myonuclei and localized to sarcoplasmic inclusions.	('hnRNPA2', 'Gene', '3181', (262, 269))	('hnRNPA1', 'Gene', (250, 257))	('hnRNPA1', 'Gene', (231, 238))	('hnRNPA2', 'Gene', (65, 72))	('patient', 'Species', '9606', (212, 219))	('variant', 'Var', (78, 85))	('hnRNPA2', 'Gene', (262, 269))	('hnRNPA1', 'Gene', '3178', (250, 257))	('hnRNPA1', 'Gene', '3178', (231, 238))	('rat', 'Species', '10116', (98, 101))	('hnRNPA2', 'Gene', '3181', (123, 130))	('mislocalization', 'MPA', (104, 119))	('hnRNPA2', 'Gene', (123, 130))	('hnRNPA2', 'Gene', '3181', (65, 72))
80548	28389532	Motor neurons differentiated from iPSCs from MSP patients with hnRNPA2D290V or VCPR155H variants demonstrate nuclear hnRNPA2B1 aggregation.	('hnRNPA2B1', 'Protein', (117, 126))	('aggregation', 'MPA', (127, 138))	('patients', 'Species', '9606', (49, 57))	('VCPR155H', 'Mutation', 'rs121909329', (79, 87))	('variants', 'Var', (88, 96))	('rat', 'Species', '10116', (104, 107))
80552	28389532	Sequencing efforts to uncover pathogenic mutations in familial and sporadic ALS patients have identified additional mutations in hnRNPA1 and hnRNPA2 linked to ALS.	('ALS', 'Gene', '6647', (159, 162))	('patients', 'Species', '9606', (80, 88))	('hnRNPA2', 'Gene', (141, 148))	('ALS', 'Phenotype', 'HP:0007354', (159, 162))	('ALS', 'Gene', (159, 162))	('ALS', 'Gene', (76, 79))	('hnRNPA1', 'Gene', (129, 136))	('ALS', 'Gene', '6647', (76, 79))	('linked', 'Reg', (149, 155))	('ALS', 'Phenotype', 'HP:0007354', (76, 79))	('mutations', 'Var', (116, 125))	('hnRNPA1', 'Gene', '3178', (129, 136))	('hnRNPA2', 'Gene', '3181', (141, 148))
80553	28389532	A substitution (D262N) occurring in a familial case of ALS affects the same aspartate residue implicated in the pathogenesis of MSP.	('D262N', 'SUBSTITUTION', 'None', (16, 21))	('ALS', 'Gene', '6647', (55, 58))	('ALS', 'Phenotype', 'HP:0007354', (55, 58))	('ALS', 'Gene', (55, 58))	('affects', 'Reg', (59, 66))	('D262N', 'Var', (16, 21))	('aspartate residue', 'MPA', (76, 93))	('aspartate', 'Chemical', 'MESH:D001224', (76, 85))
80554	28389532	The D262N substitution in hnRNPA1 introduces a strong steric zipper and strengthens an existing steric zipper (Figure 6).	('D262N', 'Var', (4, 9))	('hnRNPA1', 'Gene', (26, 33))	('D262N', 'SUBSTITUTION', 'None', (4, 9))	('hnRNPA1', 'Gene', '3178', (26, 33))	('steric zipper', 'MPA', (96, 109))	('strengthens', 'PosReg', (72, 83))	('steric zipper', 'MPA', (54, 67))
80555	28389532	Similar to the D262V substitution, D262N significantly reduced the lag phase of fibrillization and accelerated hnRNPA1 aggregation in vitro.	('hnRNPA1', 'Gene', (111, 118))	('rat', 'Species', '10116', (105, 108))	('reduced', 'NegReg', (55, 62))	('accelerated', 'PosReg', (99, 110))	('hnRNPA1', 'Gene', '3178', (111, 118))	('D262V', 'Mutation', 'rs397518452', (15, 20))	('aggregation', 'MPA', (119, 130))	('D262N', 'Var', (35, 40))	('lag phase of fibrillization', 'MPA', (67, 94))	('D262N', 'SUBSTITUTION', 'None', (35, 40))	('D262V', 'Var', (15, 20))
80556	28389532	Several other mutations in hnRNPA1 that have been identified in patients with ALS also introduce or strengthen steric zipper motifs (Figures 5 and 6).	('hnRNPA1', 'Gene', '3178', (27, 34))	('ALS', 'Gene', (78, 81))	('patients', 'Species', '9606', (64, 72))	('strengthen', 'PosReg', (100, 110))	('ALS', 'Gene', '6647', (78, 81))	('introduce', 'Reg', (87, 96))	('hnRNPA1', 'Gene', (27, 34))	('steric zipper motifs', 'MPA', (111, 131))	('ALS', 'Phenotype', 'HP:0007354', (78, 81))	('mutations', 'Var', (14, 23))
80557	28389532	One of these, a substitution in the PY-NLS of hnRNPA1 (P288S) was recently identified as the cause of a familial case of flail-arm ALS (Figure 5).	('hnRNPA1', 'Gene', (46, 53))	('P288S', 'Var', (55, 60))	('hnRNPA1', 'Gene', '3178', (46, 53))	('ALS', 'Gene', (131, 134))	('cause', 'Reg', (93, 98))	('ALS', 'Gene', '6647', (131, 134))	('ALS', 'Phenotype', 'HP:0007354', (131, 134))	('substitution in', 'Var', (16, 31))	('P288S', 'Mutation', 'p.P288S', (55, 60))
80560	28389532	It remains unclear how this disease manifests in such a heterogeneous way among patients with the same mutation, and it would be informative to investigate, via postmortem biopsy, whether patients who developed muscle and bone pathology, for example, but no clinical dementia demonstrated evidence of asymptomatic protein pathology in the frontal cortex.	('dementia', 'Disease', (267, 275))	('patients', 'Species', '9606', (80, 88))	('dementia', 'Disease', 'MESH:D003704', (267, 275))	('rat', 'Species', '10116', (283, 286))	('patients', 'Species', '9606', (188, 196))	('mutation', 'Var', (103, 111))	('dementia', 'Phenotype', 'HP:0000726', (267, 275))
80561	28389532	Also of relevance would be a study of ALS patients with TDP-43 or FUS mutations and pathology to look for co-occurrence of hnRNPA1 or hnRNPA2 pathology.	('mutations', 'Var', (70, 79))	('TDP-43', 'Gene', (56, 62))	('ALS', 'Phenotype', 'HP:0007354', (38, 41))	('ALS', 'Gene', (38, 41))	('hnRNPA2', 'Gene', '3181', (134, 141))	('hnRNPA1', 'Gene', (123, 130))	('hnRNPA2', 'Gene', (134, 141))	('hnRNPA1', 'Gene', '3178', (123, 130))	('FUS', 'Gene', (66, 69))	('patients', 'Species', '9606', (42, 50))	('FUS', 'Gene', '2521', (66, 69))	('ALS', 'Gene', '6647', (38, 41))
80562	28389532	Wild-type TDP-43 aggregates along with hnRNPA1 and hnRNPA2 in MSP, suggesting the possibility that wild-type hnRNPA1 and hnRNPA2 may be present in the inclusions driven by mutations in other RBPs in ALS and FTD patients.	('mutations', 'Var', (172, 181))	('ALS', 'Phenotype', 'HP:0007354', (199, 202))	('ALS', 'Gene', (199, 202))	('hnRNPA2', 'Gene', '3181', (121, 128))	('hnRNPA1', 'Gene', (39, 46))	('hnRNPA1', 'Gene', (109, 116))	('patients', 'Species', '9606', (211, 219))	('hnRNPA2', 'Gene', (51, 58))	('FTD', 'Disease', 'MESH:C563003', (207, 210))	('hnRNPA1', 'Gene', '3178', (39, 46))	('hnRNPA2', 'Gene', (121, 128))	('hnRNPA1', 'Gene', '3178', (109, 116))	('hnRNPA2', 'Gene', '3181', (51, 58))	('RBP', 'Gene', (191, 194))	('RBP', 'Gene', '57794', (191, 194))	('FTD', 'Disease', (207, 210))	('ALS', 'Gene', '6647', (199, 202))
80565	28389532	Thus, VCP mutations are not always accompanied by hnRNPA1 and hnRNPA2 pathology as they can be in MSP.	('hnRNPA2', 'Gene', (62, 69))	('hnRNPA1', 'Gene', (50, 57))	('VCP', 'Gene', '7415', (6, 9))	('VCP', 'Gene', (6, 9))	('hnRNPA1', 'Gene', '3178', (50, 57))	('hnRNPA2', 'Gene', '3181', (62, 69))	('mutations', 'Var', (10, 19))
80566	28389532	Finally, the contribution of hnRNPA1 and hnRNPA2 mutations to the overall landscape of neurodegeneration is currently unknown in that we do not yet know how frequently these mutations occur or how penetrant they are.	('neurodegeneration', 'Disease', (87, 104))	('mutations', 'Var', (49, 58))	('hnRNPA2', 'Gene', (41, 48))	('hnRNPA1', 'Gene', (29, 36))	('neurodegeneration', 'Disease', 'MESH:D019636', (87, 104))	('hnRNPA1', 'Gene', '3178', (29, 36))	('neurodegeneration', 'Phenotype', 'HP:0002180', (87, 104))	('hnRNPA2', 'Gene', '3181', (41, 48))
80567	28389532	The discovery of hnRNPA1 and hnRNPA2 mutations in MSP was rapidly followed by the identification of additional hnRNPA1 and hnRNPA2 mutations in patients with sporadic and familial ALS, and we expect the number of patients suffering from neurodegenerative phenotypes with identified mutations in hnRNPA1 or hnRNPA2 to grow as our knowledge of disease increases.	('hnRNPA2', 'Gene', '3181', (306, 313))	('hnRNPA1', 'Gene', (295, 302))	('patients', 'Species', '9606', (213, 221))	('hnRNPA1', 'Gene', '3178', (17, 24))	('hnRNPA1', 'Gene', (111, 118))	('ALS', 'Gene', (180, 183))	('hnRNPA1', 'Gene', '3178', (295, 302))	('hnRNPA1', 'Gene', '3178', (111, 118))	('ALS', 'Gene', '6647', (180, 183))	('mutations', 'Var', (37, 46))	('hnRNPA2', 'Gene', (29, 36))	('hnRNPA2', 'Gene', (123, 130))	('mutations', 'Var', (282, 291))	('mutations', 'Var', (131, 140))	('hnRNPA2', 'Gene', '3181', (29, 36))	('hnRNPA2', 'Gene', '3181', (123, 130))	('patients', 'Species', '9606', (144, 152))	('ALS', 'Phenotype', 'HP:0007354', (180, 183))	('hnRNPA2', 'Gene', (306, 313))	('hnRNPA1', 'Gene', (17, 24))	('rat', 'Species', '10116', (248, 251))
80569	28389532	Indeed, mutations in the PrLD of hnRNPDL, leading to D378N or D378H substitutions, have now been linked to limb-girdle muscular dystrophy type 1G.	('limb-girdle muscular dystrophy', 'Disease', 'MESH:D049288', (107, 137))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (119, 137))	('hnRNPDL', 'Gene', '9987', (33, 40))	('mutations', 'Var', (8, 17))	('hnRNPDL', 'Gene', (33, 40))	('linked', 'Reg', (97, 103))	('limb-girdle muscular dystrophy', 'Disease', (107, 137))	('D378H', 'Var', (62, 67))	('D378N', 'Mutation', 'rs587777669', (53, 58))	('limb-girdle muscular dystrophy', 'Phenotype', 'HP:0006785', (107, 137))	('D378H', 'SUBSTITUTION', 'None', (62, 67))	('substitutions', 'Var', (68, 81))	('D378N', 'Var', (53, 58))
80585	28389532	A role for the alteration of RNP granule dynamics in neurodegenerative pathology is suggested by studies showing that disease-associated mutant proteins are recruited differently to RNP granules than their wild-type counterparts.	('RNP', 'Gene', (29, 32))	('neurodegenerative pathology', 'Phenotype', 'HP:0002180', (53, 80))	('RNP', 'Gene', '55599', (29, 32))	('RNP', 'Gene', (182, 185))	('rat', 'Species', '10116', (19, 22))	('recruited', 'PosReg', (157, 166))	('RNP', 'Gene', '55599', (182, 185))	('rat', 'Species', '10116', (64, 67))	('proteins', 'Protein', (144, 152))	('mutant', 'Var', (137, 143))
80588	28389532	The D290V substitution also enhances hnRNPA2 recruitment to stress granules in motor neurons derived from MSP-patient iPSCs.	('D290V', 'Mutation', 'rs397515326', (4, 9))	('D290V', 'Var', (4, 9))	('hnRNPA2', 'Gene', '3181', (37, 44))	('patient', 'Species', '9606', (110, 117))	('enhances', 'PosReg', (28, 36))	('hnRNPA2', 'Gene', (37, 44))	('recruitment to stress granules', 'MPA', (45, 75))
80589	28389532	A VCP mutation that also causes MSP has the same effect on hnRNPA2.	('hnRNPA2', 'Gene', (59, 66))	('mutation', 'Var', (6, 14))	('MSP', 'Disease', (32, 35))	('hnRNPA2', 'Gene', '3181', (59, 66))	('VCP', 'Gene', '7415', (2, 5))	('VCP', 'Gene', (2, 5))
80590	28389532	The fact that these mutations promote the targeting of RBPs to stress granules, while VCP mutations can also decrease stress granule clearance, suggests a model in which MSP can be caused by any perturbation that shifts the equilibrium of dynamic stress granule formation and dissolution towards granule formation or persistence.	('decrease', 'NegReg', (109, 117))	('caused', 'Reg', (181, 187))	('mutations', 'Var', (90, 99))	('promote', 'PosReg', (30, 37))	('targeting', 'MPA', (42, 51))	('stress granule clearance', 'MPA', (118, 142))	('RBP', 'Gene', (55, 58))	('VCP', 'Gene', '7415', (86, 89))	('VCP', 'Gene', (86, 89))	('RBP', 'Gene', '57794', (55, 58))	('MSP', 'Disease', (170, 173))	('shifts', 'Reg', (213, 219))	('mutations', 'Var', (20, 29))
80591	28389532	In cultured cells, familial ALS mutations cause increased formation of TDP-43 inclusions that are also positive for stress granule markers after exposure to environmental stress.	('increased', 'PosReg', (48, 57))	('ALS', 'Gene', '6647', (28, 31))	('ALS', 'Phenotype', 'HP:0007354', (28, 31))	('ALS', 'Gene', (28, 31))	('TDP-43', 'Gene', (71, 77))	('formation', 'MPA', (58, 67))	('mutations', 'Var', (32, 41))
80592	28389532	FUS variants, too, show enhanced association with stress granule markers in cytoplasmic inclusions.	('variants', 'Var', (4, 12))	('enhanced', 'PosReg', (24, 32))	('stress granule markers', 'MPA', (50, 72))	('FUS', 'Gene', (0, 3))	('FUS', 'Gene', '2521', (0, 3))	('association', 'Interaction', (33, 44))
80595	28389532	Interestingly, Pbp1 is the yeast homolog of human ATXN2, which bears a polyglutamine expansion in SCA2.	('human', 'Species', '9606', (44, 49))	('polyglutamine expansion', 'Var', (71, 94))	('ATXN2', 'Gene', (50, 55))	('polyglutamine', 'Chemical', 'MESH:C097188', (71, 84))	('SCA2', 'Gene', (98, 102))	('yeast', 'Species', '4932', (27, 32))	('ATXN2', 'Gene', '6311', (50, 55))	('Pbp1', 'Gene', '853089', (15, 19))	('SCA2', 'Gene', '6311', (98, 102))	('Pbp1', 'Gene', (15, 19))
80596	28389532	Deletion of Pbp1 diminishes stress granule formation and suppresses TDP-43 toxicity in yeast, whereas overexpression of Pbp1 enhances TDP-43 toxicity in yeast.	('yeast', 'Species', '4932', (153, 158))	('TDP-43 toxicity', 'Disease', (68, 83))	('Pbp1', 'Gene', (120, 124))	('diminishes', 'NegReg', (17, 27))	('suppresses', 'NegReg', (57, 67))	('stress granule formation', 'MPA', (28, 52))	('Pbp1', 'Gene', '853089', (12, 16))	('TDP-43 toxicity', 'Disease', 'MESH:D057177', (68, 83))	('TDP-43 toxicity', 'Disease', 'MESH:D057177', (134, 149))	('yeast', 'Species', '4932', (87, 92))	('Pbp1', 'Gene', (12, 16))	('TDP-43 toxicity', 'Disease', (134, 149))	('Pbp1', 'Gene', '853089', (120, 124))	('Deletion', 'Var', (0, 8))
80600	28389532	Genetically, mutations in ATXN2 are the most common known risk factor for ALS.	('ATXN2', 'Gene', (26, 31))	('ALS', 'Gene', '6647', (74, 77))	('ALS', 'Gene', (74, 77))	('ATXN2', 'Gene', '6311', (26, 31))	('ALS', 'Phenotype', 'HP:0007354', (74, 77))	('mutations', 'Var', (13, 22))	('risk factor', 'Reg', (58, 69))
80601	28389532	Polyglutamine expansions of >34 repeats cause SCA2, but intermediate length expansions from 27 to 33 glutamines in length were found to increase the likelihood of developing ALS by a factor of ~2.8.	('Polyglutamine', 'Var', (0, 13))	('SCA2', 'Gene', (46, 50))	('SCA2', 'Gene', '6311', (46, 50))	('glutamines', 'Chemical', 'MESH:D005973', (101, 111))	('Polyglutamine', 'Chemical', 'MESH:C097188', (0, 13))	('increase', 'PosReg', (136, 144))	('ALS', 'Gene', '6647', (174, 177))	('ALS', 'Phenotype', 'HP:0007354', (174, 177))	('ALS', 'Gene', (174, 177))
80609	28389532	Deletion of the stress granule protein Pub1 or the P-body protein Lsm7 decreases FUS toxicity in yeast.	('Lsm7', 'Gene', '855575', (66, 70))	('Pub1', 'Gene', (39, 43))	('yeast', 'Species', '4932', (97, 102))	('Pub1', 'Gene', '855716', (39, 43))	('decreases FUS toxicity', 'Disease', 'MESH:D066126', (71, 93))	('decreases FUS toxicity', 'Disease', (71, 93))	('Lsm7', 'Gene', (66, 70))	('Deletion', 'Var', (0, 8))
80614	28389532	Stress granule formation in yeast is diminished by deletion of Pbp1, the yeast homolog of ATXN2, or Pub1, the yeast homolog of the human protein TIA1.	('TIA1', 'Gene', (145, 149))	('TIA1', 'Gene', '7072', (145, 149))	('Pbp1', 'Gene', '853089', (63, 67))	('ATXN2', 'Gene', '6311', (90, 95))	('Stress', 'Disease', (0, 6))	('Pbp1', 'Gene', (63, 67))	('human', 'Species', '9606', (131, 136))	('Pub1', 'Gene', (100, 104))	('yeast', 'Species', '4932', (28, 33))	('Pub1', 'Gene', '855716', (100, 104))	('Stress', 'Disease', 'MESH:D000079225', (0, 6))	('ATXN2', 'Gene', (90, 95))	('deletion', 'Var', (51, 59))	('yeast', 'Species', '4932', (73, 78))	('diminished', 'NegReg', (37, 47))	('yeast', 'Species', '4932', (110, 115))
80618	28389532	A mutation in TIA1 causes Welender distal myopathy, and mutant TIA1 expression leads to increased stress granule abundance in cultured cells, suggesting that altered stress granule dynamics may underpin this slowly progressive, adult-onset disorder.	('myopathy', 'Disease', 'MESH:D009135', (42, 50))	('mutation', 'Var', (2, 10))	('causes', 'Reg', (19, 25))	('distal myopathy', 'Phenotype', 'HP:0003693', (35, 50))	('stress granule abundance', 'MPA', (98, 122))	('adult-onset disorder', 'Disease', (228, 248))	('mutant', 'Var', (56, 62))	('myopathy', 'Disease', (42, 50))	('myopathy', 'Phenotype', 'HP:0003198', (42, 50))	('adult-onset disorder', 'Disease', 'MESH:D004421', (228, 248))	('increased', 'PosReg', (88, 97))	('TIA1', 'Gene', (63, 67))	('TIA1', 'Gene', (14, 18))	('TIA1', 'Gene', '7072', (14, 18))	('TIA1', 'Gene', '7072', (63, 67))
80636	28389532	Mutations in the PrLD of FUS also reduce the reversibility of FUS hydrogel formation.	('reversibility', 'MPA', (45, 58))	('reduce', 'NegReg', (34, 40))	('Mutations', 'Var', (0, 9))	('FUS', 'Gene', (25, 28))	('FUS', 'Gene', (62, 65))	('FUS', 'Gene', '2521', (25, 28))	('FUS', 'Gene', '2521', (62, 65))
80637	28389532	This suggests a model in which disease-causing FUS mutations, which tend to cluster in the PrLD, RGG-rich regions, and NLS, enhance fiber formation within droplets via one of two mechanisms.	('mutations', 'Var', (51, 60))	('enhance', 'PosReg', (124, 131))	('FUS', 'Gene', (47, 50))	('FUS', 'Gene', '2521', (47, 50))	('fiber formation within droplets', 'MPA', (132, 163))
80638	28389532	First, PrLD mutations likely serve to directly increase the propensity of FUS liquids to transition into irreversible aggregates.	('transition', 'MPA', (89, 99))	('mutations', 'Var', (12, 21))	('FUS', 'Gene', (74, 77))	('PrLD', 'Gene', (7, 11))	('FUS', 'Gene', '2521', (74, 77))	('increase', 'PosReg', (47, 55))
80639	28389532	Second, NLS mutations, or frameshift mutations that disrupt the NLS (Figure 3), may function to increase cytoplasmic FUS concentration by decreased nuclear import, driving liquid droplet formation, persistence, and maturation to fibrous structures.	('FUS', 'Gene', (117, 120))	('NLS', 'Gene', (8, 11))	('nuclear import', 'MPA', (148, 162))	('FUS', 'Gene', '2521', (117, 120))	('decreased', 'NegReg', (138, 147))	('mutations', 'Var', (12, 21))	('maturation', 'CPA', (215, 225))	('NLS', 'Gene', (64, 67))	('rat', 'Species', '10116', (219, 222))	('persistence', 'CPA', (198, 209))	('increase', 'PosReg', (96, 104))	('rat', 'Species', '10116', (128, 131))	('driving liquid droplet formation', 'MPA', (164, 196))
80640	28389532	Importantly, though, mutations in the FUS NLS can also directly alter the dynamics of phase transitions.	('dynamics of phase transitions', 'MPA', (74, 103))	('alter', 'Reg', (64, 69))	('FUS', 'Gene', (38, 41))	('FUS', 'Gene', '2521', (38, 41))	('mutations', 'Var', (21, 30))
80641	28389532	When purified FUS with and without mutations in the PY-NLS was induced by a temperature shift to form liquid droplets in vitro, mutant FUS droplets persisted longer than those composed of wild-type FUS.	('FUS', 'Gene', '2521', (14, 17))	('FUS', 'Gene', (135, 138))	('FUS', 'Gene', '2521', (135, 138))	('rat', 'Species', '10116', (81, 84))	('mutant', 'Var', (128, 134))	('FUS', 'Gene', (198, 201))	('FUS', 'Gene', '2521', (198, 201))	('FUS', 'Gene', (14, 17))	('mutations', 'Var', (35, 44))
80642	28389532	Thus, mutations in regions outside the LCD may contribute to pathologic persistence of RNP granules leading to aberrant fibril formation.	('RNP', 'Gene', '55599', (87, 90))	('contribute', 'Reg', (47, 57))	('RNP', 'Gene', (87, 90))	('aberrant fibril', 'MPA', (111, 126))	('mutations', 'Var', (6, 15))
80643	28389532	The most common cause of ALS and FTD is a hexanucleotide repeat expansion in a noncoding region of C9ORF72.	('ALS', 'Phenotype', 'HP:0007354', (25, 28))	('ALS', 'Gene', (25, 28))	('C9ORF72', 'Gene', (99, 106))	('hexanucleotide repeat expansion in', 'Var', (42, 76))	('FTD', 'Disease', 'MESH:C563003', (33, 36))	('hexanucleotide', 'Chemical', '-', (42, 56))	('ALS', 'Gene', '6647', (25, 28))	('C9ORF72', 'Gene', '203228', (99, 106))	('FTD', 'Disease', (33, 36))	('cause', 'Reg', (16, 21))
80644	28389532	This expansion leads to the RAN translation of several dipeptide repeat proteins, including poly-(Pro-Arg) (PR) and poly-(Gly-Arg) (GR), which form nuclear and cytoplasmic inclusions in the brain and spinal cord of ALS/FTD patients harboring this expansion.	('FTD', 'Disease', 'MESH:C563003', (219, 222))	('poly-(Gly-Arg)', 'Chemical', '-', (116, 130))	('RAN', 'Gene', (28, 31))	('PR', 'Gene', '140738', (108, 110))	('RAN', 'Gene', '5901', (28, 31))	('FTD', 'Disease', (219, 222))	('ALS', 'Gene', (215, 218))	('poly-(Gly-Arg', 'Var', (116, 129))	('ALS', 'Gene', '6647', (215, 218))	('dipeptide', 'Chemical', 'MESH:D004151', (55, 64))	('ALS', 'Phenotype', 'HP:0007354', (215, 218))	('leads to', 'Reg', (15, 23))	('poly-(Pro-Arg)', 'Chemical', '-', (92, 106))	('patients', 'Species', '9606', (223, 231))	('dipeptide', 'Protein', (55, 64))
80647	28389532	GR20 or PR20 reduced the concentration required for hnRNPA1 LLPS and led to the formation of droplets with reduced fluidity.	('fluidity', 'MPA', (115, 123))	('rat', 'Species', '10116', (32, 35))	('LLPS', 'Disease', 'None', (60, 64))	('hnRNPA1', 'Gene', '3178', (52, 59))	('LLPS', 'Disease', (60, 64))	('PR', 'Gene', '140738', (8, 10))	('GR20', 'Var', (0, 4))	('formation', 'MPA', (80, 89))	('reduced', 'NegReg', (13, 20))	('concentration required', 'MPA', (25, 47))	('hnRNPA1', 'Gene', (52, 59))
80657	28389532	In a rat model of PD, expression of Hsp104 decreased dopaminergic neuron loss and accumulation of alpha-synuclein aggregates in the substantia nigra of animals expressing a PD-linked alpha-synuclein variant.	('loss', 'NegReg', (73, 77))	('accumulation', 'PosReg', (82, 94))	('decreased dopaminergic neuron', 'Phenotype', 'HP:0012656', (43, 72))	('expression', 'Var', (22, 32))	('alpha-synuclein aggregates', 'MPA', (98, 124))	('rat', 'Species', '10116', (5, 8))	('dopaminergic neuron', 'MPA', (53, 72))	('PD', 'Disease', 'MESH:D010300', (18, 20))	('variant', 'Var', (199, 206))	('neuron loss', 'Phenotype', 'HP:0002529', (66, 77))	('Hsp104', 'Gene', (36, 42))	('PD', 'Disease', 'MESH:D010300', (173, 175))	('decreased', 'NegReg', (43, 52))	('Hsp104', 'Gene', '850633', (36, 42))
80659	28389532	Potentiated Hsp104 variants with enhanced ATPase activity reduce protein aggregation and suppress toxicity of TDP-43, FUS, and alpha-synuclein in S. cerevisiae.	('protein aggregation', 'MPA', (65, 84))	('activity', 'MPA', (49, 57))	('toxicity', 'Disease', 'MESH:D064420', (98, 106))	('FUS', 'Gene', (118, 121))	('toxicity', 'Disease', (98, 106))	('ATPase', 'Gene', (42, 48))	('FUS', 'Gene', '2521', (118, 121))	('S. cerevisiae', 'Species', '4932', (146, 159))	('ATPase', 'Gene', '1769', (42, 48))	('reduce', 'NegReg', (58, 64))	('Hsp104', 'Gene', '850633', (12, 18))	('Hsp104', 'Gene', (12, 18))	('suppress', 'NegReg', (89, 97))	('variants', 'Var', (19, 27))	('enhanced', 'PosReg', (33, 41))
80660	28389532	Enhanced Hsp104 variants also protect against dopaminergic neuron loss in a C. elegans model of PD.	('C. elegans', 'Species', '6239', (76, 86))	('Hsp104', 'Gene', (9, 15))	('PD', 'Disease', 'MESH:D010300', (96, 98))	('Hsp104', 'Gene', '850633', (9, 15))	('variants', 'Var', (16, 24))	('neuron loss', 'Phenotype', 'HP:0002529', (59, 70))	('dopaminergic neuron loss', 'MPA', (46, 70))
80665	28389532	We anticipate that harnessing the power of protein disaggregases could lead to important advances in treating several devastating diseases caused by aberrant phase transitions of RBPs with PrLDs.	('aberrant', 'Var', (149, 157))	('RBP', 'Gene', '57794', (179, 182))	('RBP', 'Gene', (179, 182))
80703	23259075	It has been reported in patients with a thrombophilic prothrombin mutation as discussed by Martin et al., in upper limbs following placement of arteriovenous shunt for hemodialysis as shown by the extensive work by Fernandez et al., in the paralyzed limb as shown by the study of Landthaler et al., and hepatitis C. It is more prevalent in males.	('paralyzed limb', 'Disease', (240, 254))	('hepatitis', 'Phenotype', 'HP:0012115', (303, 312))	('paralyzed limb', 'Disease', 'MESH:D017880', (240, 254))	('arteriovenous', 'Disease', (144, 157))	('mutation', 'Var', (66, 74))	('patients', 'Species', '9606', (24, 32))	('arteriovenous shunt', 'Phenotype', 'HP:0004947', (144, 163))	('prothrombin', 'Gene', (54, 65))	('arteriovenous', 'Disease', 'MESH:D001165', (144, 157))	('prothrombin', 'Gene', '2147', (54, 65))
80724	32161722	The bioengineered nCAR/miR-34a-5p was precisely processed to mature miR-34a-5p in ES cells and subsequently suppressed cell proliferation, attributable to the enhancement of apoptosis and induction of G2 cell cycle arrest through downregulation of SIRT-1, BCL-2 and CDK6 protein levels.	('cell proliferation', 'CPA', (119, 137))	('enhancement', 'PosReg', (159, 170))	('downregulation', 'NegReg', (230, 244))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (204, 221))	('SIRT-1', 'Gene', '93759', (248, 254))	('miR-34a-5p', 'Var', (68, 78))	('apoptosis', 'CPA', (174, 183))	('SIRT-1', 'Gene', (248, 254))	('miR-34a-5p', 'Chemical', '-', (23, 33))	('miR-34a-5p', 'Chemical', '-', (68, 78))	('suppressed', 'NegReg', (108, 118))	('G2 cell cycle arrest', 'CPA', (201, 221))	('ES', 'Phenotype', 'HP:0012254', (82, 84))	('ES', 'Disease', 'MESH:D012512', (82, 84))	('CDK6 protein levels', 'MPA', (266, 285))
80725	32161722	Furthermore, systemic administration of nCAR/miR-34a-5p dramatically suppressed the ES xenograft tumor growth in vivo while showing biocompatibility.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('nCAR/miR-34a-5p', 'Var', (40, 55))	('ES', 'Phenotype', 'HP:0012254', (84, 86))	('tumor', 'Disease', (97, 102))	('ES', 'Disease', 'MESH:D012512', (84, 86))	('suppressed', 'NegReg', (69, 79))	('miR-34a-5p', 'Chemical', '-', (45, 55))
80733	32161722	Genetically, ES is characterized by balanced chromosomal translocations and fusions of the FET gene family with an ETS transcription factor, of which Ewing Sarcoma breakpoint region 1 protein- Friend leukemia integration 1 transcription factor (EWSR1-FLI1) fusion accounts for 85%.	('FLI1', 'Gene', (251, 255))	('ES', 'Disease', 'MESH:D012512', (13, 15))	('Ewing Sarcoma breakpoint region 1', 'Gene', '14030', (150, 183))	('Ewing Sarcoma breakpoint region 1', 'Gene', (150, 183))	('Friend leukemia integration 1 transcription factor', 'Gene', '14247', (193, 243))	('fusion', 'Var', (257, 263))	('FLI1', 'Gene', '14247', (251, 255))	('Friend leukemia integration 1 transcription factor', 'Gene', (193, 243))	('EWSR1', 'Gene', '14030', (245, 250))	('EWSR1', 'Gene', (245, 250))	('Sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (150, 163))	('leukemia', 'Phenotype', 'HP:0001909', (200, 208))	('ES', 'Phenotype', 'HP:0012254', (13, 15))
80734	32161722	Other rare mutations include TP53, STAG2, and CDKN2A deletions.	('CDKN2A', 'Gene', '12578', (46, 52))	('deletions', 'Var', (53, 62))	('STAG2', 'Gene', (35, 40))	('CDKN2A', 'Gene', (46, 52))	('STAG2', 'Gene', '20843', (35, 40))	('TP53', 'Gene', '22059', (29, 33))	('TP53', 'Gene', (29, 33))
80742	32161722	Moreover, it has been demonstrated that reintroduction of miR-34a is effective in suppressing osteosarcoma, liver cancer, prostate cancer, and colorectal cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (122, 137))	('liver cancer', 'Phenotype', 'HP:0002896', (108, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('colorectal cancer', 'Disease', (143, 160))	('osteosarcoma', 'Disease', 'MESH:D012516', (94, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (94, 106))	('suppressing', 'NegReg', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('reintroduction', 'Var', (40, 54))	('liver cancer', 'Disease', 'MESH:D006528', (108, 120))	('prostate cancer', 'Disease', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('osteosarcoma', 'Disease', (94, 106))	('liver cancer', 'Disease', (108, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('miR-34a', 'Gene', (58, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))
80752	32161722	Our in vitro data demonstrated that bioengineered nCAR/miR-34a-5p was precisely processed to target warhead miR-34a-5p and subsequently, suppressed ES cell proliferation.	('miR-34a-5p', 'Chemical', '-', (108, 118))	('miR-34a-5p', 'Chemical', '-', (55, 65))	('suppressed', 'NegReg', (137, 147))	('ES', 'Phenotype', 'HP:0012254', (148, 150))	('ES', 'Disease', 'MESH:D012512', (148, 150))	('warhead miR-34a-5p', 'Var', (100, 118))
80753	32161722	The antiproliferative activity of biologic miR-34a-5p prodrug was associated with the enhancement of apoptosis and the induction of G2 cell cycle arrest through downregulation of SIRT-1, BCL-2 and CDK6 protein levels.	('enhancement', 'PosReg', (86, 97))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('miR-34a-5p', 'Var', (43, 53))	('SIRT-1', 'Gene', (179, 185))	('miR-34a-5p', 'Chemical', '-', (43, 53))	('downregulation', 'NegReg', (161, 175))	('SIRT-1', 'Gene', '93759', (179, 185))	('G2 cell cycle arrest', 'CPA', (132, 152))	('apoptosis', 'CPA', (101, 110))	('CDK6 protein levels', 'MPA', (197, 216))	('antiproliferative activity', 'CPA', (4, 30))
80754	32161722	Furthermore, systemic administration of nCAR/miR-34a-5p dramatically suppressed the ES xenograft tumor growth in vivo while well tolerated in mice (shown in Scheme 1).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('nCAR/miR-34a-5p', 'Var', (40, 55))	('ES', 'Phenotype', 'HP:0012254', (84, 86))	('tumor', 'Disease', (97, 102))	('ES', 'Disease', 'MESH:D012512', (84, 86))	('mice', 'Species', '10090', (142, 146))	('suppressed', 'NegReg', (69, 79))	('miR-34a-5p', 'Chemical', '-', (45, 55))
80795	32161722	The expression of Ki-67 and cleaved-caspase-3 were determined by immunohistochemical (IHC) study using primary antibody against Ki-67 (1:400; 27309-1-AP; Proteintech Group, Inc, Wuhan, China), cleaved-caspase-3 (1:100; AF7022; Affbiotech, OH, USA) and the HRP-goat anti-rabbit secondary antibody (1:50; AS-1110; Aspen, Wuhan, China).	('AS', 'Chemical', 'MESH:D001151', (303, 305))	('Ki-67', 'Gene', '17345', (128, 133))	('Ki-67', 'Gene', (18, 23))	('1:400; 27309-1-AP', 'Var', (135, 152))	('goat', 'Species', '9925', (260, 264))	('rabbit', 'Species', '9986', (270, 276))	('Ki-67', 'Gene', (128, 133))	('Ki-67', 'Gene', '17345', (18, 23))
80802	32161722	The results showed that nCAR/miR-34a-5p reduced the protein levels of SIRT-1, BCL-2 and CDK6 to much lower degrees than control RNA and vehicle treatment (P < 0.0001, two-way ANOVA, Figures 1B,C), supporting the utility of bioengineered nCAR/miR-34a-5p in the modulation of target gene expression.	('nCAR/miR-34a-5p', 'Var', (24, 39))	('miR-34a-5p', 'Chemical', '-', (29, 39))	('miR-34a-5p', 'Chemical', '-', (242, 252))	('SIRT-1', 'Gene', (70, 76))	('BCL-2', 'MPA', (78, 83))	('CDK6', 'MPA', (88, 92))	('reduced', 'NegReg', (40, 47))	('SIRT-1', 'Gene', '93759', (70, 76))	('protein levels', 'MPA', (52, 66))
80804	32161722	The results showed that proliferation of ES A673 cells and RD-ES cells was significantly suppressed by nCAR/miR-34a-5p in a dose-dependent manner, as compared to control RNA (P < 0.001, two-way ANOVA; Figures 1D,E).	('miR-34a-5p', 'Chemical', '-', (108, 118))	('nCAR/miR-34a-5p', 'Var', (103, 118))	('proliferation', 'CPA', (24, 37))	('ES', 'Disease', 'MESH:D012512', (62, 64))	('ES', 'Phenotype', 'HP:0012254', (62, 64))	('ES', 'Phenotype', 'HP:0012254', (41, 43))	('ES', 'Disease', 'MESH:D012512', (41, 43))	('suppressed', 'NegReg', (89, 99))
80807	32161722	Moreover, seeing from the higher tumorigenicity and typicality of A673, it was chosen for further assessments in vitro and in vivo rather than RD-ES.	('A673', 'Var', (66, 70))	('higher', 'PosReg', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('ES', 'Phenotype', 'HP:0012254', (146, 148))	('ES', 'Disease', 'MESH:D012512', (146, 148))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
80811	32161722	In particular, late apoptosis (170.3% increase) was altered to a greater degree than early apoptosis (35.5% increase) by nCAR/miR-34a-5p, compared with control RNA.	('increase', 'PosReg', (38, 46))	('altered', 'Reg', (52, 59))	('late apoptosis', 'CPA', (15, 29))	('miR-34a-5p', 'Chemical', '-', (126, 136))	('nCAR/miR-34a-5p', 'Var', (121, 136))
80817	32161722	Compared with the control RNA or vehicle, nCAR/miR-34a-5p remarkably altered the cell cycle profiles (Figure 3A).	('miR-34a-5p', 'Chemical', '-', (47, 57))	('cell cycle profiles', 'CPA', (81, 100))	('altered', 'Reg', (69, 76))	('nCAR/miR-34a-5p', 'Var', (42, 57))
80818	32161722	Specifically, nCAR/miR-34a-5p led to an accumulation of A673 cells in G2 phase, while the percentages of A673 cells in G0/G1 and S phases were reduced accordingly (P < 0.0001, two-way ANOVA; Figure 3B).	('G2 phase', 'CPA', (70, 78))	('A673', 'Var', (56, 60))	('miR-34a-5p', 'Chemical', '-', (19, 29))	('accumulation', 'PosReg', (40, 52))	('nCAR/miR-34a-5p', 'Var', (14, 29))
80822	32161722	It was obvious that nCAR/miR-34a-5p treatment led to a significant suppression of the outgrowth of viable tumors, compared to the control RNA and vehicle treatments (Figure 4B).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('suppression', 'NegReg', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('nCAR/miR-34a-5p', 'Var', (20, 35))	('miR-34a-5p', 'Chemical', '-', (25, 35))
80824	32161722	From day 21 after inoculation, the mice treated with nCAR/miR-34a-5p had a remarkable decline of the outgrowth of tumor volumes compared with control RNA (P < 0.05, two-way ANOVA; Figure 4D) and vehicle treatments (P < 0.01, two-way ANOVA; Figure 4D).	('decline', 'NegReg', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('nCAR/miR-34a-5p', 'Var', (53, 68))	('tumor', 'Disease', (114, 119))	('mice', 'Species', '10090', (35, 39))	('miR-34a-5p', 'Chemical', '-', (58, 68))
80825	32161722	At the endpoint of study, the tumor volumes of mice with nCAR/miR-34a-5p treatment were smaller than 1/12 of that in control group and 1/14 of that in vehicle group (P < 0.0001, two-way ANOVA; Figure 4D).	('smaller', 'NegReg', (88, 95))	('mice', 'Species', '10090', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('nCAR/miR-34a-5p treatment', 'Var', (57, 82))	('tumor', 'Disease', (30, 35))	('miR-34a-5p', 'Chemical', '-', (62, 72))
80828	32161722	The data showed that Ki-67 contents in the tumor tissues from nCAR/miR-34a-5p-treated animals were significantly lower than those treated with control RNA (P < 0.001, one-way ANOVA; Figures 5A,B) or vehicle (P < 0.0001, one-way ANOVA; Figures 5A,B).	('Ki-67', 'Gene', (21, 26))	('lower', 'NegReg', (113, 118))	('nCAR/miR-34a-5p-treated', 'Var', (62, 85))	('miR-34a-5p', 'Chemical', '-', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Ki-67', 'Gene', '17345', (21, 26))	('tumor', 'Disease', (43, 48))
80831	32161722	The results revealed an elevation of p53 expression in tumors treated with nCAR/miR-34a-5p compared with vehicle or with control RNA (P < 0.0001, one-way ANOVA; Figures 5E,F).	('miR-34a-5p', 'Chemical', '-', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('expression', 'MPA', (41, 51))	('nCAR/miR-34a-5p', 'Var', (75, 90))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('p53', 'Gene', (37, 40))	('elevation', 'PosReg', (24, 33))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('p53', 'Gene', '22059', (37, 40))
80837	32161722	The data showed that none of these blood biomarkers was significantly altered by nCAR/miR-34a-5p therapy, compared to control RNA or vehicle treatments, and all markers were within normal ranges (Figure 7), indicating the absence of hepatic, renal and myocardial toxicity.	('nCAR/miR-34a-5p therapy', 'Var', (81, 104))	('myocardial toxicity', 'Disease', 'MESH:D009202', (252, 271))	('myocardial toxicity', 'Disease', (252, 271))	('hepatic', 'MPA', (233, 240))	('miR-34a-5p', 'Chemical', '-', (86, 96))
80843	32161722	Nevertheless, due to the excessive artificial modifications, there are likely unknown alterations in the structures, activities and toxicities between synthetic and natural RNA molecules, which have not been fully explored yet.	('alterations', 'Reg', (86, 97))	('activities', 'MPA', (117, 127))	('modifications', 'Var', (46, 59))	('toxicities', 'Disease', (132, 142))	('toxicities', 'Disease', 'MESH:D064420', (132, 142))
80853	32161722	Consequently, bioengineered miR-34a-5p prodrug exerted potent antiproliferative activity against ES with an enhancement of apoptosis and induction of G2 cell cycle arrest, attributable to a set of proteins (apoptosis-associated SIRT-1, BCL-2 and cell cycle arrest-associated CDK6) down-regulated by miR-34a-5p prodrug that were assembled into critical tumor regulatory pathways.	('G2 cell cycle arrest', 'CPA', (150, 170))	('antiproliferative activity', 'CPA', (62, 88))	('enhancement', 'PosReg', (108, 119))	('down-regulated', 'NegReg', (281, 295))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('miR-34a-5p', 'Chemical', '-', (299, 309))	('miR-34a-5p', 'Gene', (28, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (153, 170))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (246, 263))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('ES', 'Phenotype', 'HP:0012254', (97, 99))	('SIRT-1', 'Gene', (228, 234))	('ES', 'Disease', 'MESH:D012512', (97, 99))	('apoptosis', 'CPA', (123, 132))	('tumor', 'Disease', (352, 357))	('miR-34a-5p', 'Chemical', '-', (28, 38))	('SIRT-1', 'Gene', '93759', (228, 234))	('miR-34a-5p', 'Var', (299, 309))
80855	32161722	Moreover, miR-34a-5p prodrug therapy did not cause significant body weight loss in the mice.	('weight loss', 'Disease', (68, 79))	('miR-34a-5p', 'Chemical', '-', (10, 20))	('weight loss', 'Phenotype', 'HP:0001824', (68, 79))	('mice', 'Species', '10090', (87, 91))	('weight loss', 'Disease', 'MESH:D015431', (68, 79))	('miR-34a-5p', 'Var', (10, 20))
80858	32161722	It is concluded that therapeutic doses of bioengineered miR-34a-5p prodrug was well-tolerated in tumor-bearing mouse models in vivo.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mouse', 'Species', '10090', (111, 116))	('tumor', 'Disease', (97, 102))	('miR-34a-5p', 'Var', (56, 66))	('miR-34a-5p', 'Chemical', '-', (56, 66))
80862	32161722	As an important regulator in p53 pathway, miR-34a is able to stimulate endogenous p53 activity in a positive feedback-loop through inhibiting the expression of target gene SIRT-1 and thus leads to cell apoptosis.	('SIRT-1', 'Gene', (172, 178))	('cell apoptosis', 'CPA', (197, 211))	('miR-34a', 'Var', (42, 49))	('stimulate', 'PosReg', (61, 70))	('activity', 'MPA', (86, 94))	('p53', 'Gene', (29, 32))	('SIRT-1', 'Gene', '93759', (172, 178))	('p53', 'Gene', (82, 85))	('inhibiting', 'NegReg', (131, 141))	('p53', 'Gene', '22059', (82, 85))	('p53', 'Gene', '22059', (29, 32))	('expression', 'MPA', (146, 156))	('leads to', 'Reg', (188, 196))
80863	32161722	Our results revealed a remarkable down-regulation of SIRT-1 in ES cells and demonstrated obvious tendency of apoptosis both in vitro and in vivo, indicating that exogenous restoration of miR-34a-5p into ES cells could promote p53 activation and succumb ES to a single hit.	('ES', 'Phenotype', 'HP:0012254', (203, 205))	('p53', 'Gene', '22059', (226, 229))	('ES', 'Disease', 'MESH:D012512', (203, 205))	('miR-34a-5p', 'Var', (187, 197))	('ES', 'Phenotype', 'HP:0012254', (63, 65))	('promote', 'PosReg', (218, 225))	('succumb', 'PosReg', (245, 252))	('miR-34a-5p', 'Chemical', '-', (187, 197))	('ES', 'Disease', 'MESH:D012512', (63, 65))	('down-regulation', 'NegReg', (34, 49))	('SIRT-1', 'Gene', (53, 59))	('activation', 'PosReg', (230, 240))	('ES', 'Phenotype', 'HP:0012254', (253, 255))	('p53', 'Gene', (226, 229))	('ES', 'Disease', 'MESH:D012512', (253, 255))	('SIRT-1', 'Gene', '93759', (53, 59))
80869	32161722	The pharmacological effects of miR-34a-5p was attributable to the enhancement of apoptosis and induction of G2 cell cycle arrest through downregulation of SIRT-1, BCL-2 and CDK6 protein levels.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('apoptosis', 'CPA', (81, 90))	('downregulation', 'NegReg', (137, 151))	('SIRT-1', 'Gene', (155, 161))	('G2 cell cycle arrest', 'CPA', (108, 128))	('CDK6 protein levels', 'MPA', (173, 192))	('miR-34a-5p', 'Var', (31, 41))	('SIRT-1', 'Gene', '93759', (155, 161))	('enhancement', 'PosReg', (66, 77))	('miR-34a-5p', 'Chemical', '-', (31, 41))
80870	32161722	In addition, systemic administration of miR-34a-5p prodrug dramatically suppressed the ES xenograft tumor growth in vivo while well-tolerated in mice.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ES', 'Phenotype', 'HP:0012254', (87, 89))	('tumor', 'Disease', (100, 105))	('ES', 'Disease', 'MESH:D012512', (87, 89))	('miR-34a-5p', 'Var', (40, 50))	('miR-34a-5p', 'Chemical', '-', (40, 50))	('suppressed', 'NegReg', (72, 82))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
80871	32161722	The antitumor effect of miR-34a-5p prodrug was associated with a lower degree of tumoral cell proliferation and greater extent of apoptosis.	('tumoral cell proliferation', 'Disease', (81, 107))	('apoptosis', 'CPA', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('lower', 'NegReg', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumoral cell proliferation', 'Disease', 'MESH:C565054', (81, 107))	('miR-34a-5p', 'Var', (24, 34))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('miR-34a-5p', 'Chemical', '-', (24, 34))	('tumor', 'Disease', (81, 86))
80940	31032392	Eighty-five percent of PNETs demonstrate a characteristic rearrangement of the Ewing sarcoma (EWS) gene on chromosome 22, which creates the EWRS1/FLI1 fusion product t(11;22)q24q12.	('EWS', 'Phenotype', 'HP:0012254', (94, 97))	('EWS', 'Gene', '2130', (94, 97))	('EWS', 'Gene', (94, 97))	('t(11;22)q24q12', 'Var', (166, 180))	('FLI1', 'Gene', (146, 150))	('FLI1', 'Gene', '2313', (146, 150))	('Ewing sarcoma', 'Disease', (79, 92))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('creates', 'Reg', (128, 135))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (79, 92))	('PNET', 'Phenotype', 'HP:0030065', (23, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
80941	31032392	Tumors with this gene rearrangement are considered to belong to the EWS/peripheral primitive neuroectodermal tumor (pPNET) spectrum.	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (83, 114))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (93, 114))	('gene rearrangement', 'Var', (17, 35))	('PNET', 'Phenotype', 'HP:0030065', (117, 121))	('pPNET', 'Phenotype', 'HP:0030067', (116, 121))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (93, 114))	('EWS', 'Gene', '2130', (68, 71))	('EWS', 'Gene', (68, 71))	('EWS', 'Phenotype', 'HP:0012254', (68, 71))	('peripheral primitive neuroectodermal tumor', 'Phenotype', 'HP:0030067', (72, 114))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('neuroectodermal tumor', 'Disease', (93, 114))
80942	31032392	Lack of an EWSR1 rearrangement excludes them from this family and are then considered central type PNETs regardless of shared histologic and immunohistochemical findings.	('PNET', 'Phenotype', 'HP:0030065', (99, 103))	('EWSR1', 'Gene', (11, 16))	('rearrangement', 'Var', (17, 30))	('EWSR1', 'Gene', '2130', (11, 16))	('excludes', 'NegReg', (31, 39))	('EWS', 'Phenotype', 'HP:0012254', (11, 14))
80966	31032392	She received tumor directed radiotherapy which consisted of 4500 cGy in 25 fractions to the whole pelvis, followed by 1500 cGy in three fractions to the vaginal cuff.	('tumor', 'Disease', (13, 18))	('4500 cGy', 'Var', (60, 68))	('vaginal cuff', 'Phenotype', 'HP:0000145', (153, 165))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('1500 cGy', 'Var', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
80997	30143749	We highlight recent advances in understanding how viral manipulation of host cellular signalling, DNA damage responses, immunity and microRNA targets promotes the initiation and development of cancer.	('N', 'Chemical', 'MESH:D009584', (139, 140))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('viral manipulation', 'Var', (50, 68))	('cancer', 'Disease', (193, 199))	('promotes', 'PosReg', (150, 158))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('development', 'CPA', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('initiation', 'CPA', (163, 173))
81017	30143749	Dysregulating the tumour suppressor activities of p53 and pRB can benefit virus propagation.	('benefit', 'PosReg', (66, 73))	('Dysregulating', 'Var', (0, 13))	('virus propagation', 'CPA', (74, 91))	('pRB', 'Gene', (58, 61))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('pRB', 'Gene', '5925', (58, 61))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumour', 'Disease', (18, 24))
81023	30143749	Compounding genetic mutations that are acquired by cells in this deteriorating environment could ultimately lead to cancer.	('genetic mutations', 'Var', (12, 29))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('lead to', 'Reg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
81027	30143749	Dysregulation of the PI3K axis can disrupt normal cellular growth control and result in the survival and proliferation of tumour cells.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('survival', 'CPA', (92, 100))	('disrupt', 'NegReg', (35, 42))	('Dysregulation', 'Var', (0, 13))	('result in', 'Reg', (78, 87))	('tumour', 'Disease', (122, 128))	('proliferation', 'CPA', (105, 118))	('PI3K axis', 'Pathway', (21, 30))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
81036	30143749	Inhibition of FOXO3 therefore promotes the survival and proliferation of CD4+ T cells that maintain the capacity to spread infectious HTLV-1 particles.	('O3', 'Chemical', 'MESH:D013481', (17, 19))	('HTLV-1', 'Species', '11908', (134, 140))	('promotes', 'PosReg', (30, 38))	('spread', 'MPA', (116, 122))	('proliferation', 'CPA', (56, 69))	('CD4', 'Gene', (73, 76))	('CD4', 'Gene', '920', (73, 76))	('FOXO3', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('survival', 'CPA', (43, 51))
81053	30143749	In agreement with this finding, inhibition of MAPK/ERK kinase 1 (MeK1) and MEK2 with a cancer drug (trametinib) drastically limits MCPyV infection by blocking MCPyV transcription and/or replication in infected cells, suggesting that activation of the MAPK pathway is needed to support these events in the MCPyV life cycle.	('MCPyV', 'Gene', (159, 164))	('transcription', 'MPA', (165, 178))	('trametinib', 'Chemical', 'MESH:C560077', (100, 110))	('MeK1', 'Gene', (65, 69))	('replication', 'MPA', (186, 197))	('MCPyV', 'Species', '493803', (131, 136))	('cancer', 'Disease', (87, 93))	('limits', 'NegReg', (124, 130))	('inhibition', 'Var', (32, 42))	('MCPyV', 'Species', '493803', (305, 310))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MAPK/ERK kinase 1', 'Gene', '5604', (46, 63))	('MAPK/ERK kinase 1', 'Gene', (46, 63))	('blocking', 'NegReg', (150, 158))	('MCPyV infection', 'Disease', (131, 146))	('MEK2', 'Gene', (75, 79))	('MCPyV', 'Species', '493803', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('MeK1', 'Gene', '5604', (65, 69))	('MCPyV infection', 'Disease', 'MESH:D007239', (131, 146))
81059	30143749	The molecular mechanism by which KSHV activates MAPK pathways is better understood than in EBV infection.	('infection', 'Disease', 'MESH:D007239', (95, 104))	('EBV', 'Species', '10376', (91, 94))	('MAPK pathways', 'Pathway', (48, 61))	('KSHV', 'Species', '37296', (33, 37))	('KSHV', 'Var', (33, 37))	('activates', 'PosReg', (38, 47))	('infection', 'Disease', (95, 104))
81065	30143749	Depending on the cellular environment and tissue context, perturbations in the Notch signalling pathway can either promote or suppress tumorigenesis (box 2).	('promote', 'PosReg', (115, 122))	('Notch signalling pathway', 'Pathway', (79, 103))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('perturbations', 'Var', (58, 71))	('suppress', 'NegReg', (126, 134))	('tumorigenesis', 'CPA', (135, 148))
81067	30143749	By contrast, Notch signalling has a tumour suppressor function in skin epithelia and pancreatic cells.	('skin epithelia', 'Disease', (66, 80))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('skin epithelia', 'Disease', 'MESH:D012871', (66, 80))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('pancreatic', 'Disease', 'MESH:D010195', (85, 95))	('pancreatic', 'Disease', (85, 95))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('Notch', 'Var', (13, 18))
81087	30143749	Hyperactivation of the downstream transcription targets of WNT/beta-catenin signalling can contribute to many growth-related pathologies, including cancer.	('beta-catenin', 'Gene', (63, 75))	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('contribute', 'Reg', (91, 101))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('beta-catenin', 'Gene', '1499', (63, 75))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Hyperactivation', 'Var', (0, 15))	('growth-related pathologies', 'Disease', (110, 136))
81093	30143749	Similarly, continual expression of HTLV-1 HBZ in HTLV-1-induced adult T cell leukaemia cells dysregulates the WNT signalling pathway to promote migration and proliferation.	('dysregulates', 'Var', (93, 105))	('promote', 'PosReg', (136, 143))	('WNT signalling pathway', 'Pathway', (110, 132))	('HBZ', 'Gene', (42, 45))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('adult T cell leukaemia', 'Disease', (64, 86))	('adult T cell leukaemia', 'Disease', 'MESH:D015459', (64, 86))	('HTLV-1', 'Species', '11908', (35, 41))	('HTLV-1', 'Species', '11908', (49, 55))	('HTLV-1-induced', 'Gene', (49, 63))	('HBZ', 'Gene', '3050', (42, 45))	('migration', 'CPA', (144, 153))
81107	30143749	In transgenic mice that express KSHV vFLIP, vFLIP-activated NF-kappaB contributes to enhanced proliferation of lymphocytes and an increased incidence of lymphoma.	('lymphoma', 'Disease', 'MESH:D008223', (153, 161))	('NF-kappaB', 'Gene', '4790', (60, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('enhanced', 'PosReg', (85, 93))	('NF-kappaB', 'Gene', (60, 69))	('KSHV', 'Species', '37296', (32, 36))	('KSHV', 'Var', (32, 36))	('proliferation', 'CPA', (94, 107))	('transgenic mice', 'Species', '10090', (3, 18))	('lymphoma', 'Disease', (153, 161))
81115	30143749	Cells with disrupted DNA damage recognition and repair systems can accumulate genetic mutations that enhance cell survival and proliferation.	('mutations', 'Var', (86, 95))	('proliferation', 'CPA', (127, 140))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('enhance', 'PosReg', (101, 108))	('cell survival', 'CPA', (109, 122))
81119	30143749	Compromised sensing, signalling or repair of damaged DNA may allow cells to acquire mutations that overcome tumour suppressor barriers during oncogenic progression.	('tumour', 'Disease', (108, 114))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('mutations', 'Var', (84, 93))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumour', 'Disease', 'MESH:D009369', (108, 114))
81126	30143749	Although manipulation of the cell cycle and DDR factors can promote a fragile genomic state, appropriate activation of DDRs to viral stressors remains a major barrier for progression to cancer.	('promote', 'PosReg', (60, 67))	('manipulation', 'Var', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('fragile genomic state', 'MPA', (70, 91))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
81129	30143749	Abrogation of ATM and CHK2 kinase activity, however, results in B cell transformation.	('Abrogation', 'Var', (0, 10))	('ATM', 'Gene', '472', (14, 17))	('results in', 'Reg', (53, 63))	('CHK2', 'Gene', (22, 26))	('B cell transformation', 'CPA', (64, 85))	('CHK2', 'Gene', '11200', (22, 26))	('ATM', 'Gene', (14, 17))
81131	30143749	Unlike MCPyV large T antigen expressed in persistent infection, MCPyV proviruses integrated in malignant MCC cells encode large T antigen truncation mutants that almost invariably delete this DDR-activating domain but retain the aminoterminal pRB-inhibiting motif.	('pRB', 'Gene', (243, 246))	('infection', 'Disease', 'MESH:D007239', (53, 62))	('MCPyV', 'Gene', (64, 69))	('MCPyV', 'Species', '493803', (64, 69))	('mutants', 'Var', (149, 156))	('DDR-activating domain', 'MPA', (192, 213))	('persistent infection', 'Phenotype', 'HP:0031035', (42, 62))	('pRB', 'Gene', '5925', (243, 246))	('large', 'Gene', (122, 127))	('MCPyV', 'Species', '493803', (7, 12))	('infection', 'Disease', (53, 62))	('delete', 'NegReg', (180, 186))
81133	30143749	HTLV-1 DNA integration into T cell genomes induces a lengthy latency period, in which a polyclonal expansion of the infected cells progresses to an aggressive monoclonal leukaemia in ~5% of infected individuals.	('aggressive monoclonal leukaemia', 'Disease', (148, 179))	('HTLV-1', 'Gene', (0, 6))	('HTLV-1', 'Species', '11908', (0, 6))	('N', 'Chemical', 'MESH:D009584', (8, 9))	('aggressive monoclonal leukaemia', 'Disease', 'MESH:D001523', (148, 179))	('DNA integration', 'Var', (7, 22))	('progresses to', 'Reg', (131, 144))	('integration', 'Var', (11, 22))
81135	30143749	The same integration pattern was observed in cells at asymptomatic stages as in leukaemia or lymphoma cells, suggesting that provirus-dependent gene perturbations trigger initial polyclonal expansion of the infected clones at non-malignant stages.	('leukaemia or lymphoma', 'Disease', (80, 101))	('leukaemia or lymphoma', 'Disease', 'MESH:D015459', (80, 101))	('polyclonal expansion', 'CPA', (179, 199))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))	('perturbations', 'Var', (149, 162))
81136	30143749	Expression of HTLV-1 Tax protein induces further DNA damage and genomic instability by inhibiting DNA repair pathways and causing DNA repair infidelity, allowing the accumulation of somatic mutations in clones that ultimately progress to malignancy (FIG.	('DNA repair infidelity', 'MPA', (130, 151))	('causing', 'Reg', (122, 129))	('progress', 'PosReg', (226, 234))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('mutations', 'Var', (190, 199))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('HTLV-1', 'Species', '11908', (14, 20))	('HTLV-1', 'Gene', (14, 20))	('malignancy', 'Disease', 'MESH:D009369', (238, 248))	('inhibiting', 'NegReg', (87, 97))	('malignancy', 'Disease', (238, 248))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('DNA repair pathways', 'Pathway', (98, 117))
81139	30143749	RNAi and antisense targeting experiments revealed that the high mutation frequency in HCV infection is caused by the increased expression of error-prone DNA polymerases and activation-induced cytidine deaminase (AID), which cause the hypermutation of cellular genes (FIG.	('HCV infection', 'Disease', (86, 99))	('cytidine', 'Chemical', 'MESH:D003562', (192, 200))	('cellular genes', 'Gene', (251, 265))	('mutation', 'Var', (64, 72))	('increased', 'PosReg', (117, 126))	('expression', 'MPA', (127, 137))	('HCV infection', 'Disease', 'MESH:D006526', (86, 99))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('hypermutation', 'MPA', (234, 247))	('cause', 'Reg', (224, 229))	('N', 'Chemical', 'MESH:D009584', (1, 2))
81140	30143749	Mutations in the tumour suppressors and proto-oncogenes were amplified and selected for in HCV-associated lymphomas and HCCs but not in similar neoplasias originating from other causes.	('lymphomas', 'Phenotype', 'HP:0002665', (106, 115))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('neoplasias', 'Disease', 'MESH:D009369', (144, 154))	('neoplasias', 'Phenotype', 'HP:0002664', (144, 154))	('neoplasias', 'Disease', (144, 154))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('Mutations', 'Var', (0, 9))	('HCV', 'Species', '11103', (91, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (106, 114))	('tumour', 'Disease', (17, 23))	('lymphomas', 'Disease', (106, 115))	('lymphomas', 'Disease', 'MESH:D008223', (106, 115))	('HCC', 'Phenotype', 'HP:0001402', (120, 123))	('HCCs', 'Disease', (120, 124))
81141	30143749	Although HCV-related mutations contribute to the development of HCC, HCV RNA is not found in most of the virus-induced HCC cells, suggesting a 'hit and run' oncogenic mechanism (FIG.	('N', 'Chemical', 'MESH:D009584', (74, 75))	('HCV', 'Species', '11103', (69, 72))	('HCC', 'Disease', (64, 67))	('HCV', 'Species', '11103', (9, 12))	('HCC', 'Phenotype', 'HP:0001402', (119, 122))	('HCV-related', 'Gene', (9, 20))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))	('mutations', 'Var', (21, 30))
81144	30143749	In doing so, HBx derepresses transcriptional inhibition, allowing productive viral gene expression and replication.	('derepresses', 'Var', (17, 28))	('transcriptional inhibition', 'MPA', (29, 55))	('HBx', 'Gene', (13, 16))	('allowing', 'PosReg', (57, 65))	('replication', 'MPA', (103, 114))	('HBx', 'Gene', '944566', (13, 16))
81168	30143749	Given the importance of this pathway in defence against cancer, it is possible that inhibition of cGAS-STING compromises an early barrier to viral oncogenesis.	('cGAS', 'Gene', '115004', (98, 102))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('STING', 'Gene', (103, 108))	('compromises', 'NegReg', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cGAS', 'Gene', (98, 102))	('STING', 'Gene', '340061', (103, 108))	('cancer', 'Disease', (56, 62))	('inhibition', 'Var', (84, 94))
81183	30143749	In addition, KSHV K3 and K5 proteins downregulate cell surface MHC-I display by promoting endocytosis and endolysosomal degradation of class I chains.	('KSHV', 'Var', (13, 17))	('downregulate', 'NegReg', (37, 49))	('cell surface', 'MPA', (50, 62))	('endolysosomal degradation', 'MPA', (106, 131))	('promoting', 'PosReg', (80, 89))	('MHC-I', 'Gene', (63, 68))	('KSHV', 'Species', '37296', (13, 17))	('endocytosis', 'MPA', (90, 101))
81185	30143749	HTLV-1 p12 down-regulates immune modulator intercellular adhesion molecule 1 (ICAM1), ICAM2 and MHC-I on the cell surface, allowing infected cells to escape killing by natural killer cells and cytotoxic T cells.	('ICAM2', 'Gene', (86, 91))	('escape', 'CPA', (150, 156))	('p12', 'Var', (7, 10))	('HTLV-1', 'Gene', (0, 6))	('down-regulates', 'NegReg', (11, 25))	('HTLV-1', 'Species', '11908', (0, 6))	('MHC-I', 'Gene', (96, 101))
81199	30143749	In these instances, viral strategies that normally support infection instead drive uncontrolled cellular proliferation, accumulation of mutations and evasion of antitumour immunity.	('infection', 'Disease', (59, 68))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('infection', 'Disease', 'MESH:D007239', (59, 68))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('mutations', 'Var', (136, 145))	('tumour', 'Disease', (165, 171))
81202	30143749	It was further suggested that, by targeting key cellular components that are at the interface of these signalling pathways, oncogenic viruses disable both the host antiviral and anticancer mechanisms, priming the infected cells for cancerous transformation.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('oncogenic viruses', 'Var', (124, 141))	('cancer', 'Disease', (232, 238))	('cancerous', 'Disease', (232, 241))	('disable', 'NegReg', (142, 149))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Disease', (182, 188))	('cancerous', 'Disease', 'MESH:D009369', (232, 241))
81205	30143749	Recent oncogenic virus research has also revealed that double-stranded DNA introduced by viral infection and DNA damage generated during viral proliferation can stimulate innate immune DNA sensing pathways, leading to the production of cytokines that have both antiviral and antitumour function.	('viral infection', 'Disease', (89, 104))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('stimulate', 'PosReg', (161, 170))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('cytokines', 'MPA', (236, 245))	('innate immune DNA sensing pathways', 'Pathway', (171, 205))	('double-stranded', 'Var', (55, 70))	('N', 'Chemical', 'MESH:D009584', (186, 187))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('tumour', 'Disease', (279, 285))	('production', 'MPA', (222, 232))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('viral infection', 'Disease', 'MESH:D014777', (89, 104))
81221	30143749	A general activator of T cell killing, anti-PD1-PDL1 immune checkpoint blockade in individuals with MCPyV+ MCC improves their survival.	('anti-PD1-PDL1', 'Gene', (39, 52))	('survival', 'CPA', (126, 134))	('MCPyV+', 'Var', (100, 106))	('MCPyV', 'Species', '493803', (100, 105))	('improves', 'PosReg', (111, 119))
81252	30143749	theATM kinase pathway is primarily activated by double-stranded DNa breaks, whereas the ATR kinase pathway responds mostly to single-stranded breaks.	('ATR', 'Gene', '545', (88, 91))	('ATR', 'Gene', (88, 91))	('activated', 'Reg', (35, 44))	('ATM', 'Gene', (3, 6))	('double-stranded DNa breaks', 'Var', (48, 74))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('ATM', 'Gene', '472', (3, 6))
81256	30143749	Dysregulation of miRNA synthesis or processing machinery or the expression of certain individual miRNAs could compromise cellular function and lead to pathological processes, including cancer.	('Dysregulation', 'Var', (0, 13))	('processing', 'MPA', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('miRNA synthesis', 'MPA', (17, 32))	('lead to', 'Reg', (143, 150))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('cellular function', 'CPA', (121, 138))	('cancer', 'Disease', (185, 191))	('compromise', 'NegReg', (110, 120))
81275	30143749	However, some tumour viruses, such as adenovirus and polyomavirus SV40 promote tumorigenesis in other organisms and infect humans but do not cause human cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('promote', 'PosReg', (71, 78))	('cancers', 'Disease', (153, 160))	('human', 'Species', '9606', (147, 152))	('polyomavirus', 'Var', (53, 65))	('human', 'Species', '9606', (123, 128))	('adenovirus', 'Disease', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumour viruses', 'Disease', (14, 28))	('humans', 'Species', '9606', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('polyomavirus', 'Species', '36362', (53, 65))	('tumorigenesis in other organisms', 'CPA', (79, 111))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('SV40', 'Gene', (66, 70))	('tumour viruses', 'Disease', 'MESH:D009369', (14, 28))
81289	30143749	A protein kinase essential to normal cell division and development that is activated by ataxia telangiectasia and Rad3-related protein (ATR) in response to single-stranded DNa to facilitate proper DNA replication, cell cycle progression and response to DNA insults.	('N', 'Chemical', 'MESH:D009584', (173, 174))	('N', 'Chemical', 'MESH:D009584', (198, 199))	('ataxia telangiectasia and Rad3-related protein', 'Gene', '545', (88, 134))	('activated', 'PosReg', (75, 84))	('ATR', 'Gene', '545', (136, 139))	('ATR', 'Gene', (136, 139))	('response', 'MPA', (144, 152))	('cell cycle progression', 'CPA', (214, 236))	('telangiectasia', 'Phenotype', 'HP:0001009', (95, 109))	('N', 'Chemical', 'MESH:D009584', (254, 255))	('single-stranded', 'Var', (156, 171))	('ataxia', 'Phenotype', 'HP:0001251', (88, 94))	('facilitate', 'PosReg', (179, 189))
81291	30143749	A type of endogenous gene that, when overexpressed or abnormally activated as a result of mutation, can promote cancer development, at which point it is referred to as an oncogene.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('promote', 'PosReg', (104, 111))	('mutation', 'Var', (90, 98))
81314	22461510	Phosphoproteomics Identifies Driver Tyrosine Kinases in Sarcoma Cell Lines and Tumors Driver tyrosine kinase mutations are rare in sarcomas, and patterns of tyrosine phosphorylation are poorly understood.	('Sarcoma Cell Lines and Tumors', 'Disease', 'MESH:D012509', (56, 85))	('tyrosine', 'Chemical', 'MESH:D014443', (93, 101))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('Sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (109, 118))	('sarcomas', 'Disease', (131, 139))	('tyrosine', 'Chemical', 'MESH:D014443', (157, 165))
81325	22461510	For example, gastrointestinal stromal tumors (GIST) that harbor activating mutations in the c-KIT gene are sensitive to treatment with imatinib mesylate, a tyrosine kinase inhibitor, whereas those without c-KIT mutations are less sensitive.	('c-KIT', 'Gene', '3815', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (135, 152))	('activating', 'PosReg', (64, 74))	('c-KIT', 'Gene', '3815', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (13, 44))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (13, 44))	('tyrosine', 'Chemical', 'MESH:D014443', (156, 164))	('mutations', 'Var', (75, 84))	('c-KIT', 'Gene', (205, 210))	('c-KIT', 'Gene', (92, 97))	('gastrointestinal stromal tumors', 'Disease', (13, 44))	('sensitive', 'MPA', (107, 116))	('GIST', 'Phenotype', 'HP:0100723', (46, 50))
81328	22461510	Furthermore, many sarcomas harbor balanced translocations that result in unique fusion proteins that have been shown to deregulate various kinases.	('fusion proteins', 'Protein', (80, 95))	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('deregulate', 'Reg', (120, 130))	('kinases', 'MPA', (139, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcomas', 'Disease', (18, 26))	('translocations', 'Var', (43, 57))	('result in', 'Reg', (63, 72))
81341	22461510	These methods can also be used to identify novel tyrosine phosphorylation sites and identify oncogenic proteins resulting from activating mutations in protein tyrosine kinases.	('tyrosine', 'Chemical', 'MESH:D014443', (49, 57))	('tyrosine', 'Chemical', 'MESH:D014443', (159, 167))	('activating', 'PosReg', (127, 137))	('protein tyrosine kinases', 'Enzyme', (151, 175))	('tyrosine phosphorylation sites', 'MPA', (49, 79))	('mutations', 'Var', (138, 147))
81376	22461510	Important signaling proteins such as p130CAS, paxillin, Stat3, and ERK1/2 that are activated by tyrosine phosphorylation were also identified.	('Stat3', 'Gene', (56, 61))	('paxillin', 'Gene', '5829', (46, 54))	('tyrosine', 'Var', (96, 104))	('paxillin', 'Gene', (46, 54))	('ERK1/2', 'Gene', (67, 73))	('ERK1/2', 'Gene', '5595;5594', (67, 73))	('p130CAS', 'Gene', '9564', (37, 44))	('activated', 'PosReg', (83, 92))	('tyrosine', 'Chemical', 'MESH:D014443', (96, 104))	('Stat3', 'Gene', '6774', (56, 61))	('p130CAS', 'Gene', (37, 44))
81384	22461510	To help investigate this further, we screened the same sarcoma cell lines against inhibitors of EGFR (erlotinib), JAK (P6), FGFR (SU5402), MET (PHA665752), IGF1R (OSI868), RET (ZD6474), PDGFR (imatinib and dasatinib), and SRC (dasatinib; refs.).	('IGF1R', 'Gene', (156, 161))	('OSI868', 'Var', (163, 169))	('SU5402', 'Var', (130, 136))	('sarcoma cell lines', 'Disease', (55, 73))	('EGFR', 'Gene', (96, 100))	('SRC', 'Gene', '6714', (222, 225))	('sarcoma cell lines', 'Disease', 'MESH:D012509', (55, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('dasatinib', 'Chemical', 'MESH:D000069439', (206, 215))	('SU5402', 'Chemical', 'MESH:C105686', (130, 136))	('RET', 'Gene', '5979', (172, 175))	('imatinib', 'Chemical', 'MESH:D000068877', (193, 201))	('SRC', 'Gene', (222, 225))	('PHA665752', 'Var', (144, 153))	('erlotinib', 'Chemical', 'MESH:D000069347', (102, 111))	('dasatinib', 'Chemical', 'MESH:D000069439', (227, 236))	('EGFR', 'Gene', '1956', (96, 100))	('ZD6474', 'Chemical', 'MESH:C452423', (177, 183))	('OSI868', 'Chemical', '-', (163, 169))	('PDGFR', 'Gene', (186, 191))	('PDGFR', 'Gene', '5159', (186, 191))	('IGF1R', 'Gene', '3480', (156, 161))	('RET', 'Gene', (172, 175))	('PHA665752', 'Chemical', 'MESH:C480541', (144, 153))
81392	22461510	Validation experiments with RTK array confirmed tyrosine phosphorylated PDGFRalpha, and Western blotting showed overexpression of PDGFRalpha compared with other cell lines studied (see Fig.	('tyrosine', 'Chemical', 'MESH:D014443', (48, 56))	('RTK', 'Gene', (28, 31))	('PDGFRalpha', 'Gene', '5156', (72, 82))	('overexpression', 'PosReg', (112, 126))	('PDGFRalpha', 'Gene', (72, 82))	('RTK', 'Gene', '5979', (28, 31))	('tyrosine', 'Var', (48, 56))	('PDGFRalpha', 'Gene', '5156', (130, 140))	('PDGFRalpha', 'Gene', (130, 140))
81398	22461510	We engineered A204 cells to express a mutant form of PDGFRalpha expressing a gatekeeper mutation that prevents TKI binding to the ATP binding pocket.	('mutant', 'Var', (38, 44))	('mutation', 'Var', (88, 96))	('ATP', 'Chemical', 'MESH:D000255', (130, 133))	('gatekeeper', 'Species', '111938', (77, 87))	('PDGFRalpha', 'Gene', '5156', (53, 63))	('binding', 'Interaction', (115, 122))	('PDGFRalpha', 'Gene', (53, 63))
81399	22461510	3B, cells expressing this mutant form of PDGFRalpha were rescued from the effects of dasatinib compared with cells expressing wild-type PDGFRalpha (Fig.	('PDGFRalpha', 'Gene', (136, 146))	('effects', 'MPA', (74, 81))	('dasatinib', 'Chemical', 'MESH:D000069439', (85, 94))	('PDGFRalpha', 'Gene', '5156', (41, 51))	('rescued', 'PosReg', (57, 64))	('PDGFRalpha', 'Gene', (41, 51))	('PDGFRalpha', 'Gene', '5156', (136, 146))	('mutant', 'Var', (26, 32))
81411	22461510	We identified pY peptides corresponding to MET in 7 of the 10 cells with higher spectral counts (a semiquantitative measure of peptide abundance) in MNNG, SK-LMS1, and Saos2 cells.	('peptides', 'Chemical', 'MESH:D010455', (17, 25))	('SK-LMS1', 'CellLine', 'CVCL:0628', (155, 162))	('MET', 'Var', (43, 46))	('higher', 'PosReg', (73, 79))
81416	22461510	Interestingly, the MNNG cells are known to harbor a gene fusion between TPR and MET leading to constitutive MET signaling and transformation.	('gene fusion', 'Var', (52, 63))	('TPR', 'Gene', (72, 75))	('transformation', 'CPA', (126, 140))	('constitutive MET signaling', 'MPA', (95, 121))	('TPR', 'Gene', '7175', (72, 75))	('MET', 'Gene', (80, 83))
81418	22461510	OSI868 strongly inhibited pAKT and paradoxically increased levels of pERK, perhaps through a cross-talk or adaptive mechanisms (Fig.	('inhibited', 'NegReg', (16, 25))	('AKT', 'Gene', (27, 30))	('increased', 'PosReg', (49, 58))	('pERK', 'Gene', '9451', (69, 73))	('OSI868', 'Var', (0, 6))	('pERK', 'Gene', (69, 73))	('cross-talk', 'Disease', 'MESH:D020922', (93, 103))	('AKT', 'Gene', '207', (27, 30))	('cross-talk', 'Disease', (93, 103))	('OSI868', 'Chemical', '-', (0, 6))
81419	22461510	OSI868 also increased PARP cleavage indicative of cell apoptosis with similar evidence of p27 elevation (Fig.	('PARP', 'Gene', (22, 26))	('OSI868', 'Var', (0, 6))	('increased', 'PosReg', (12, 21))	('p27', 'Gene', '3429', (90, 93))	('p27', 'Gene', (90, 93))	('elevation', 'PosReg', (94, 103))	('PARP', 'Gene', '1302', (22, 26))	('OSI868', 'Chemical', '-', (0, 6))
81459	22461510	Our studies revealed that sarcoma cells and tissues express multiple tyrosine kinases and this may ultimately limit the effectiveness of targeted agents.	('tyrosine', 'Chemical', 'MESH:D014443', (69, 77))	('sarcoma', 'Disease', 'MESH:D012509', (26, 33))	('effectiveness', 'MPA', (120, 133))	('tyrosine kinases', 'Var', (69, 85))	('sarcoma', 'Disease', (26, 33))	('limit', 'NegReg', (110, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))
81563	27523972	We will address five major molecular alterations frequent in sarcoma, including 1) the presence of chimeric transcription factors, in vascular tumors; 2) abnormal kinase signaling, in gastrointestinal stromal tumor; 3) epigenetic deregulation, either by oncometabolites, as a result of metabolic enzyme mutations, or as primary events, in chondrosarcoma, chondroblastoma, and other tumor types; 4) deregulated cell survival and proliferation, due to extreme copy number alterations, in dedifferentiated liposarcoma; and 5) extreme genomic instability in conventional osteosarcoma, as a representative example of sarcomas with highly complex karyotype.	('mutations', 'Var', (303, 312))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('sarcoma', 'Disease', 'MESH:D012509', (507, 514))	('proliferation', 'CPA', (428, 441))	('sarcoma', 'Phenotype', 'HP:0100242', (612, 619))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (184, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (572, 579))	('sarcoma', 'Disease', (507, 514))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', (382, 387))	('liposarcoma', 'Disease', (503, 514))	('chondroblastoma', 'Disease', 'MESH:D002804', (355, 370))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (184, 214))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('vascular tumors', 'Disease', (134, 149))	('sarcoma', 'Disease', 'MESH:D012509', (346, 353))	('osteosarcoma', 'Disease', (567, 579))	('osteosarcoma', 'Disease', 'MESH:D012516', (567, 579))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('sarcoma', 'Disease', (61, 68))	('sarcoma', 'Disease', (346, 353))	('chondrosarcoma', 'Disease', 'MESH:D002813', (339, 353))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('sarcoma', 'Phenotype', 'HP:0100242', (507, 514))	('gastrointestinal stromal tumor', 'Disease', (184, 214))	('chondrosarcoma', 'Disease', (339, 353))	('vascular tumors', 'Phenotype', 'HP:0100742', (134, 149))	('chondroblastoma', 'Phenotype', 'HP:0030432', (355, 370))	('copy number alterations', 'Var', (458, 481))	('liposarcoma', 'Phenotype', 'HP:0012034', (503, 514))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (346, 353))	('chondroblastoma', 'Disease', (355, 370))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('tumor', 'Disease', (143, 148))	('vascular tumors', 'Disease', 'MESH:D019043', (134, 149))	('sarcoma', 'Disease', 'MESH:D012509', (612, 619))	('sarcomas', 'Disease', 'MESH:D012509', (612, 620))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (339, 353))	('sarcoma', 'Disease', (612, 619))	('osteosarcoma', 'Phenotype', 'HP:0002669', (567, 579))	('sarcomas', 'Phenotype', 'HP:0100242', (612, 620))	('liposarcoma', 'Disease', 'MESH:D008080', (503, 514))	('sarcoma', 'Disease', 'MESH:D012509', (572, 579))	('sarcomas', 'Disease', (612, 620))	('deregulated', 'NegReg', (398, 409))	('sarcoma', 'Disease', (572, 579))	('cell survival', 'CPA', (410, 423))
81570	27523972	The molecular correlates of these cytogenetic presentations are recurrent genomic rearrangements and activating gene mutations for sarcomas with relatively simple karyotype, and multiple, diverse genomic events including gene amplifications and non-recurrent rearrangements, for those with complex karyotype.	('mutations', 'Var', (117, 126))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('sarcomas', 'Disease', (131, 139))
81573	27523972	In this review, we summarize the major molecular mechanisms that underlie sarcoma pathogenesis, highlighting those alterations that provide diagnostic, prognostic or predictive information (the so-called "clinically-actionable" alterations).	('sarcoma', 'Disease', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('alterations', 'Var', (115, 126))
81575	27523972	We will address five major molecular alterations, including the presence of chimeric transcription factors, in vascular tumors; deregulated kinase signaling, in gastrointestinal stromal tumor (GIST); epigenetic deregulation by oncometabolites, as a result of metabolic enzyme mutations in chondrosarcoma and other tumor types; deregulated cell survival and proliferation, due to extreme copy number alterations, in dedifferentiated liposarcoma (DDLPS); and extreme genomic instability in conventional osteosarcoma, as a representative example of sarcomas with highly complex karyotype.	('osteosarcoma', 'Phenotype', 'HP:0002669', (501, 513))	('cell survival', 'CPA', (339, 352))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (161, 191))	('liposarcoma', 'Disease', (432, 443))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (314, 319))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (289, 303))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (161, 191))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('sarcoma', 'Phenotype', 'HP:0100242', (436, 443))	('sarcomas', 'Disease', 'MESH:D012509', (546, 554))	('sarcoma', 'Phenotype', 'HP:0100242', (546, 553))	('proliferation', 'CPA', (357, 370))	('mutations', 'Var', (276, 285))	('kinase', 'MPA', (140, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (546, 554))	('gastrointestinal stromal tumor', 'Disease', (161, 191))	('sarcomas', 'Disease', (546, 554))	('liposarcoma', 'Phenotype', 'HP:0012034', (432, 443))	('tumor', 'Disease', (120, 125))	('osteosarcoma', 'Disease', (501, 513))	('vascular tumors', 'Disease', (111, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (501, 513))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (506, 513))	('liposarcoma', 'Disease', 'MESH:D008080', (432, 443))	('vascular tumors', 'Phenotype', 'HP:0100742', (111, 126))	('deregulated', 'PosReg', (327, 338))	('sarcoma', 'Phenotype', 'HP:0100242', (296, 303))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('copy number alterations', 'Var', (387, 410))	('chondrosarcoma', 'Disease', 'MESH:D002813', (289, 303))	('chondrosarcoma', 'Disease', (289, 303))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('vascular tumors', 'Disease', 'MESH:D019043', (111, 126))
81576	27523972	Table 2 provides a non-comprehensive list of clinically-actionable genetic alterations commonly encountered in sarcoma.	('genetic alterations', 'Var', (67, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))
81577	27523972	Sarcomas with simple genomic profiles usually harbor a recurrent molecular aberration, either a balanced chromosomal rearrangement or a mutation in a known oncogene or tumor suppressor gene, which is critical for tumorigenesis and is considered the main oncogenic driver.	('tumor', 'Disease', (213, 218))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('tumor', 'Disease', (168, 173))	('mutation', 'Var', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
81578	27523972	These alterations are usually present in the context of a relatively stable genome, with a low mutational load and a (near) diploid karyotype; additional point mutations or copy number alterations may occur during tumor progression, frequently following reproducible patterns, in contrast with the remarkable variability observed in genomically-complex sarcomas (Figure 1).	('sarcomas', 'Disease', (353, 361))	('point mutations', 'Var', (154, 169))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('sarcomas', 'Disease', 'MESH:D012509', (353, 361))	('tumor', 'Disease', (214, 219))	('sarcomas', 'Phenotype', 'HP:0100242', (353, 361))	('copy number alterations', 'Var', (173, 196))	('occur', 'Reg', (201, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (353, 360))
81579	27523972	An expanding list of mesenchymal tumors contain recurrent balanced chromosomal rearrangements, most often translocations, and most fusion genes produced by these rearrangements encode chimeric transcription factors that cause transcriptional deregulation.	('balanced chromosomal rearrangements', 'Var', (58, 93))	('encode', 'Reg', (177, 183))	('mesenchymal tumors', 'Disease', (21, 39))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (21, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))
81581	27523972	Chimeric transcription factors are thought to deregulate the expression of specific repertoires of target genes, thereby orchestrating several of the defined "hallmarks of cancer".	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Chimeric transcription', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('deregulate', 'Reg', (46, 56))	('expression', 'MPA', (61, 71))
81582	27523972	The group of sarcomas carrying a specific translocation constituted only ~15-20% of all sarcomas in 2007.	('sarcomas', 'Disease', (13, 21))	('sarcomas', 'Disease', (88, 96))	('translocation', 'Var', (42, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
81583	27523972	Examples of the increased resolution of current methods include the detection of fusions by a paracentric inversion in solitary fibrous tumor, and mesenchymal chondrosarcoma, both of which have provided useful diagnostic immunohistochemical or molecular markers for the diagnosis of these entities.	('fibrous tumor', 'Disease', (128, 141))	('mesenchymal chondrosarcoma', 'Disease', 'MESH:D018211', (147, 173))	('fibrous tumor', 'Disease', 'MESH:D054364', (128, 141))	('fusions', 'Var', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('mesenchymal chondrosarcoma', 'Disease', (147, 173))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (159, 173))	('paracentric inversion', 'Var', (94, 115))
81589	27523972	Transcriptome sequencing of epithelioid hemangioma revealed a recurrent translocation breakpoint involving the FOS gene fused to different partners.	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (28, 50))	('hemangioma', 'Phenotype', 'HP:0001028', (40, 50))	('FOS', 'Gene', (111, 114))	('translocation breakpoint', 'Var', (72, 96))	('epithelioid hemangioma', 'Disease', (28, 50))	('epithelioid hemangioma', 'Disease', 'MESH:D006391', (28, 50))	('FOS', 'Gene', '2353', (111, 114))
81591	27523972	Atypical variants of epithelioid hemangioma were shown to harbor ZFP36-FOSB fusions.	('hemangioma', 'Phenotype', 'HP:0001028', (33, 43))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (21, 43))	('fusions', 'Var', (76, 83))	('ZFP36', 'Gene', '7538', (65, 70))	('FOSB', 'Gene', '2354', (71, 75))	('FOSB', 'Gene', (71, 75))	('epithelioid hemangioma', 'Disease', (21, 43))	('epithelioid hemangioma', 'Disease', 'MESH:D006391', (21, 43))	('ZFP36', 'Gene', (65, 70))
81592	27523972	The distinction between epithelioid hemangioma and angiosarcoma can be challenging, and detection of FOS rearrangements may assist in the differential diagnosis.	('FOS', 'Gene', '2353', (101, 104))	('angiosarcoma', 'Disease', (51, 63))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (24, 46))	('angiosarcoma', 'Phenotype', 'HP:0200058', (51, 63))	('hemangioma', 'Phenotype', 'HP:0001028', (36, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('FOS', 'Gene', (101, 104))	('angiosarcoma', 'Disease', 'MESH:D006394', (51, 63))	('epithelioid hemangioma', 'Disease', (24, 46))	('epithelioid hemangioma', 'Disease', 'MESH:D006391', (24, 46))	('rearrangements', 'Var', (105, 119))
81594	27523972	Interestingly, FOSB rearrangements are also the hallmark of pseudomyogenic haemangioendothelioma (epithelioid sarcoma-like hemangioendothelioma), which is a rare, distinctive entity frequently presenting as multiple discontiguous nodules in different tissue planes of a limb in young adult males.	('epithelioid sarcoma-like hemangioendothelioma', 'Phenotype', 'HP:0032060', (98, 143))	('rearrangements', 'Var', (20, 34))	('FOSB', 'Gene', '2354', (15, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('FOSB', 'Gene', (15, 19))	('epithelioid sarcoma-like hemangioendothelioma', 'Disease', (98, 143))	('epithelioid sarcoma-like hemangioendothelioma', 'Disease', 'MESH:D018323', (98, 143))	('hallmark of pseudomyogenic haemangioendothelioma', 'Disease', (48, 96))	('hallmark of pseudomyogenic haemangioendothelioma', 'Disease', 'None', (48, 96))
81599	27523972	A specific entity has been described, focally resembling EHE, with more solid architecture admixed with the formation of well-formed vascular channels, genetically characterized by YAP1-TFE3 fusions.	('fusions', 'Var', (191, 198))	('YAP1', 'Gene', (181, 185))	('YAP1', 'Gene', '10413', (181, 185))	('TFE3', 'Gene', '7030', (186, 190))	('EHE', 'Disease', (57, 60))	('TFE3', 'Gene', (186, 190))
81601	27523972	Future studies should reveal if there is a final common pathway affected by these fusion genes that is involved in the development of these vascular tumors.	('vascular tumors', 'Phenotype', 'HP:0100742', (140, 155))	('vascular tumors', 'Disease', 'MESH:D019043', (140, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('vascular tumors', 'Disease', (140, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('fusion genes', 'Var', (82, 94))
81606	27523972	In addition to MYC amplification, co-amplification of FLT4, or PTPRB and/or PLCG1 mutations can be found in secondary angiosarcomas.	('angiosarcomas', 'Disease', 'MESH:D006394', (118, 131))	('FLT4', 'Gene', (54, 58))	('FLT4', 'Gene', '2324', (54, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('MYC', 'Gene', '4609', (15, 18))	('angiosarcomas', 'Phenotype', 'HP:0200058', (118, 131))	('PLCG1', 'Gene', (76, 81))	('MYC', 'Gene', (15, 18))	('PTPRB', 'Gene', '5787', (63, 68))	('mutations', 'Var', (82, 91))	('co-amplification', 'Var', (34, 50))	('PTPRB', 'Gene', (63, 68))	('angiosarcoma', 'Phenotype', 'HP:0200058', (118, 130))	('PLCG1', 'Gene', '5335', (76, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('angiosarcomas', 'Disease', (118, 131))
81608	27523972	Recently, CIC rearrangements or mutations have been found in 9% of primary angiosarcomas, which were predominantly epithelioid with solid growth and affected younger patients, with an inferior disease-free survival.	('found', 'Reg', (52, 57))	('CIC', 'Gene', (10, 13))	('angiosarcoma', 'Phenotype', 'HP:0200058', (75, 87))	('rearrangements', 'Var', (14, 28))	('angiosarcomas', 'Phenotype', 'HP:0200058', (75, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('mutations', 'Var', (32, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('primary angiosarcomas', 'Disease', (67, 88))	('primary angiosarcomas', 'Disease', 'MESH:D006394', (67, 88))	('patients', 'Species', '9606', (166, 174))
81609	27523972	Deregulation of cellular signaling driving sustained proliferation is a major hallmark of cancer and, as such, contributes to the biology of most sarcoma types.	('hallmark of cancer', 'Disease', 'MESH:D009369', (78, 96))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('sarcoma', 'Disease', (146, 153))	('cellular signaling', 'MPA', (16, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('hallmark of cancer', 'Disease', (78, 96))	('contributes', 'Reg', (111, 122))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
81611	27523972	Prominent examples amongst sarcoma include mutationally-activated receptor tyrosine kinases such as KIT in GIST, recurrent chimeric kinase fusions like ALK oncoproteins in inflammatory myofibroblastic (IMT) and ETV6-NTRK3 in infantile fibrosarcoma, or kinase receptors activated by autocrine mechanisms such as PDGFRA/B in dermatofibrosarcoma protuberans (DFSP).	('KIT', 'Gene', (100, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('chimeric', 'Var', (123, 131))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (323, 354))	('DFSP', 'Disease', 'MESH:D018223', (356, 360))	('ETV6', 'Gene', (211, 215))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (330, 342))	('sarcoma', 'Disease', (27, 34))	('DFSP', 'Disease', (356, 360))	('mutationally-activated', 'Var', (43, 65))	('ALK', 'Gene', '238', (152, 155))	('sarcoma', 'Disease', 'MESH:D012509', (335, 342))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (235, 247))	('NTRK3', 'Gene', '4916', (216, 221))	('sarcoma', 'Disease', (335, 342))	('sarcoma', 'Disease', 'MESH:D012509', (240, 247))	('PDGFRA', 'Gene', '5156', (311, 317))	('ALK', 'Gene', (152, 155))	('PDGFRA', 'Gene', (311, 317))	('infantile fibrosarcoma', 'Disease', (225, 247))	('NTRK3', 'Gene', (216, 221))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (225, 247))	('sarcoma', 'Disease', (240, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (335, 342))	('ETV6', 'Gene', '2120', (211, 215))	('dermatofibrosarcoma protuberans', 'Disease', (323, 354))
81613	27523972	The most remarkable example of clinically effective targeted inhibition of oncogenic kinase mutations in sarcoma is inhibition of KIT/PDGFRA in GIST.	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('mutations', 'Var', (92, 101))	('sarcoma', 'Disease', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('PDGFRA', 'Gene', '5156', (134, 140))	('PDGFRA', 'Gene', (134, 140))
81614	27523972	An additional ~10% of GIST are driven by analogous activating mutations in the receptor tyrosine kinase PDGFRA.	('PDGFRA', 'Gene', (104, 110))	('PDGFRA', 'Gene', '5156', (104, 110))	('activating', 'PosReg', (51, 61))	('GIST', 'MPA', (22, 26))	('mutations', 'Var', (62, 71))
81616	27523972	KIT and PDGFRA mutations, which are mutually exclusive, lead to ligand-independent activation, which in turn activates intracellular signaling pathways controlling cell differentiation, survival and proliferation.	('cell differentiation', 'CPA', (164, 184))	('proliferation', 'CPA', (199, 212))	('survival', 'CPA', (186, 194))	('mutations', 'Var', (15, 24))	('intracellular signaling pathways', 'Pathway', (119, 151))	('PDGFRA', 'Gene', (8, 14))	('activates', 'PosReg', (109, 118))	('PDGFRA', 'Gene', '5156', (8, 14))	('KIT', 'Gene', (0, 3))
81617	27523972	KIT primary mutations usually affect exon 11 (70%), exon 9 (10%), exon 13 (1%) or exon 17 (1%), whereas PDGFRA mutations affect exons 18 (5%), 12 (1%) or 14 (<1%).	('affect', 'Reg', (121, 127))	('PDGFRA', 'Gene', (104, 110))	('mutations', 'Var', (12, 21))	('PDGFRA', 'Gene', '5156', (104, 110))	('affect', 'Reg', (30, 36))
81618	27523972	All of them are activating mutations, but the activation results from different alterations of various functional domains of the protein, which tolerate different kinds of mutational mechanisms (Figure 3): the juxtamembrane domain, encoded by exons 11 in KIT and 12 in PDGFRA, is an autoinhibitory domain that can be disrupted by in-frame deletions, in-frame insertion-deletions, or point mutations.	('in-frame insertion-deletions', 'Var', (350, 378))	('PDGFRA', 'Gene', (269, 275))	('PDGFRA', 'Gene', '5156', (269, 275))	('deletions', 'Var', (339, 348))	('KIT', 'Gene', (255, 258))	('point mutations', 'Var', (383, 398))
81619	27523972	The two domains that form the split kinase, namely the ATP-binding pocket (exons 13 to 15) and the activation loop (exons 17 and 18), are usually activated by point mutations.	('ATP', 'Chemical', 'MESH:D000255', (55, 58))	('activated', 'PosReg', (146, 155))	('point mutations', 'Var', (159, 174))
81620	27523972	The diagnostic value of KIT mutations is limited in GIST, since the diagnosis is often achievable by the detection of KIT and DOG1 expression by immunohistochemistry, in the appropriate morphological and clinical context.	('KIT', 'Gene', (118, 121))	('DOG1', 'Gene', (126, 130))	('DOG1', 'Gene', '55107', (126, 130))	('mutations', 'Var', (28, 37))
81622	27523972	Regarding prognosis, some KIT/PDGFRA mutations are associated with poor clinical outcomes in untreated populations, such as in-frame deletions of codons 557-558 in exon 11.	('mutations', 'Var', (37, 46))	('PDGFRA', 'Gene', '5156', (30, 36))	('PDGFRA', 'Gene', (30, 36))	('codons 557-558', 'Var', (146, 160))
81623	27523972	Most mutant KIT and PDGFRA oncoproteins can be effectively inhibited by small molecule kinase inhibitors such as imatinib.	('KIT', 'Gene', (12, 15))	('imatinib', 'Chemical', 'MESH:D000068877', (113, 121))	('mutant', 'Var', (5, 11))	('PDGFRA', 'Gene', '5156', (20, 26))	('PDGFRA', 'Gene', (20, 26))
81624	27523972	The degree of inhibition, and hence the potential clinical benefit, correlates tightly with the specific mutation: in general, exon 11 KIT mutations are extremely sensitive to imatinib, while exon 9 mutations, typically a 6 nucleotide duplication affecting codons 502 and 503, are less sensitive and require a higher dose of imatinib (usually 800mg, double the standard dose).	('mutations', 'Var', (139, 148))	('imatinib', 'Chemical', 'MESH:D000068877', (176, 184))	('imatinib', 'Chemical', 'MESH:D000068877', (325, 333))	('sensitive to imatinib', 'MPA', (163, 184))	('exon', 'Var', (127, 131))
81626	27523972	Primary drug resistance to imatinib results mostly from PDGFRA D842V point mutation or KIT/PDGFRA wild-type status.	('D842V', 'Mutation', 'rs121908585', (63, 68))	('Primary drug resistance to imatinib', 'MPA', (0, 35))	('PDGFRA', 'Gene', '5156', (56, 62))	('PDGFRA', 'Gene', (56, 62))	('D842V point mutation', 'Var', (63, 83))	('drug resistance', 'Phenotype', 'HP:0020174', (8, 23))	('PDGFRA', 'Gene', (91, 97))	('results', 'Reg', (36, 43))	('imatinib', 'Chemical', 'MESH:D000068877', (27, 35))	('PDGFRA', 'Gene', '5156', (91, 97))
81627	27523972	Of note, PDGFRA D842V mutation is cross-resistant to most tyrosine kinase inhibitors, with the potential exception of crenolanib that has shown activity in vitro.	('crenolanib', 'Chemical', 'MESH:C577197', (118, 128))	('PDGFRA', 'Gene', (9, 15))	('D842V', 'Mutation', 'rs121908585', (16, 21))	('PDGFRA', 'Gene', '5156', (9, 15))	('D842V', 'Var', (16, 21))
81631	27523972	Resistance results in the majority of cases from secondary mutations that affect non-random residues in KIT, typically in either the ATP-binding pocket (exon 13-15), or the kinase activation loop (exons 17 or 18 of KIT and exon 18 of PDGFRA), which occur in cis with the primary mutation (i.e.	('ATP', 'Chemical', 'MESH:D000255', (133, 136))	('KIT', 'Gene', (104, 107))	('PDGFRA', 'Gene', (234, 240))	('PDGFRA', 'Gene', '5156', (234, 240))	('KIT', 'Gene', (215, 218))	('mutations', 'Var', (59, 68))
81632	27523972	In the presence of an active inhibitor, however, activating mutations in these domains are selected, and clonal expansion of tumor cells may result in the presence of different secondary mutations in different tumor cell subpopulations in a single patient.	('result in', 'Reg', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('presence', 'Reg', (155, 163))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (125, 130))	('patient', 'Species', '9606', (248, 255))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
81633	27523972	The predictive nature of KIT mutations in relation to imatinib treatment response extends to sunitinib and regorafenib -and, essentially, to every tyrosine kinase inhibitor.	('sunitinib', 'Chemical', 'MESH:D000077210', (93, 102))	('mutations', 'Var', (29, 38))	('imatinib', 'Chemical', 'MESH:D000068877', (54, 62))	('regorafenib', 'Chemical', 'MESH:C559147', (107, 118))	('KIT', 'Gene', (25, 28))
81634	27523972	Sunitinib is effective against mutations in exons 13-15 of KIT (ATP-binding pocket), but is ineffective against mutations in exons 17-18 (activation loop); while the opposite is true for regorafenib.	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('mutations in exons 13-15', 'Var', (31, 55))	('Sunitinib', 'Chemical', 'MESH:D000077210', (0, 9))	('regorafenib', 'Chemical', 'MESH:C559147', (187, 198))	('KIT', 'Gene', (59, 62))
81635	27523972	Therefore, the sequence of treatment for advanced GIST determined historically, first-line imatinib, followed by sunitinib and third-line regorafenib, is not surprisingly supported by the biology and the natural history of the various KIT/PDGFRA mutations in GIST.	('imatinib', 'Chemical', 'MESH:D000068877', (91, 99))	('mutations', 'Var', (246, 255))	('regorafenib', 'Chemical', 'MESH:C559147', (138, 149))	('PDGFRA', 'Gene', '5156', (239, 245))	('sunitinib', 'Chemical', 'MESH:D000077210', (113, 122))	('PDGFRA', 'Gene', (239, 245))
81639	27523972	KIT exon 11 mutations are typically primary mutations, and are very sensitive to imatinib.	('mutations', 'Var', (12, 21))	('imatinib', 'Chemical', 'MESH:D000068877', (81, 89))	('KIT exon 11', 'Gene', (0, 11))
81640	27523972	The most common PDGFRA mutation in GIST, D842V in exon 18, is imatinib-resistant (and cross-resistant to most tyrosine kinase inhibitors) KIT exon 9 primary mutations, usually dup502_503, respond to higher dose of imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (62, 70))	('D842V', 'Mutation', 'rs121908585', (41, 46))	('imatinib', 'Chemical', 'MESH:D000068877', (214, 222))	('D842V', 'Var', (41, 46))	('PDGFRA', 'Gene', '5156', (16, 22))	('dup502_503', 'Var', (176, 186))	('PDGFRA', 'Gene', (16, 22))
81641	27523972	KIT exon 13 mutation, often K642E, is often a secondary mutation resistant to imatinib.	('KIT exon', 'Gene', (0, 8))	('K642E', 'Mutation', 'rs121913512', (28, 33))	('imatinib', 'Chemical', 'MESH:D000068877', (78, 86))	('K642E', 'Var', (28, 33))
81643	27523972	KIT activation-loop mutations, affecting exon 17, are secondary mutations cross-resistant to imatinib and sunitinib, but may respond to regorafenib.	('regorafenib', 'Chemical', 'MESH:C559147', (136, 147))	('imatinib', 'Chemical', 'MESH:D000068877', (93, 101))	('activation-loop', 'PosReg', (4, 19))	('sunitinib', 'Chemical', 'MESH:D000077210', (106, 115))	('respond', 'Reg', (125, 132))	('KIT', 'Gene', (0, 3))	('mutations', 'Var', (20, 29))
81645	27523972	Various tyrosine kinase inhibitors (sorafenib, dasatinib, nilotinib, crenolanib, ponatinib) are effective against different sets of KIT/PDGFRA mutations.	('dasatinib', 'Chemical', 'MESH:D000069439', (47, 56))	('ponatinib', 'Chemical', 'MESH:C545373', (81, 90))	('nilotinib', 'Chemical', 'MESH:C498826', (58, 67))	('sorafenib', 'Chemical', 'MESH:D000077157', (36, 45))	('PDGFRA', 'Gene', '5156', (136, 142))	('PDGFRA', 'Gene', (136, 142))	('mutations', 'Var', (143, 152))	('crenolanib', 'Chemical', 'MESH:C577197', (69, 79))
81646	27523972	Mutations in metabolic enzymes lead to deregulated cellular energetics in cancer cells and, more importantly, result in the production of metabolites that may alter tightly-regulated physiological processes such as gene expression and epigenetic regulation.	('production of metabolites', 'MPA', (124, 149))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('result in', 'Reg', (110, 119))	('cancer', 'Disease', (74, 80))	('Mutations', 'Var', (0, 9))	('epigenetic regulation', 'MPA', (235, 256))	('metabolic', 'Enzyme', (13, 22))	('deregulated cellular energetics', 'MPA', (39, 70))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('alter', 'Reg', (159, 164))	('gene expression', 'MPA', (215, 230))	('tightly-regulated physiological processes', 'MPA', (165, 206))
81648	27523972	An illustrative example is the metabolic enzyme isocitrate dehydrogenase (IDH), in which somatic mutations were first described in gliomas, followed by other tumors including ~50% of chondrosarcomas.	('tumors', 'Disease', (158, 164))	('mutations', 'Var', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('gliomas', 'Disease', (131, 138))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (183, 198))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('chondrosarcomas', 'Disease', 'MESH:D002813', (183, 198))	('IDH', 'Gene', (74, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (190, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('isocitrate dehydrogenase', 'Gene', (48, 72))	('chondrosarcomas', 'Disease', (183, 198))	('IDH', 'Gene', '3417', (74, 77))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (183, 197))	('isocitrate dehydrogenase', 'Gene', '3417', (48, 72))
81650	27523972	Mutations in IDH cause epigenetic changes by the formation of a neoenzyme that catalyzes the reduction of alpha-ketoglutarate to D-2-hydroxyglutarate (D2HG).	('epigenetic changes', 'MPA', (23, 41))	('IDH', 'Gene', '3417', (13, 16))	('cause', 'Reg', (17, 22))	('Mutations', 'Var', (0, 9))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (106, 125))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (129, 149))	('IDH', 'Gene', (13, 16))
81651	27523972	D2HG is considered an oncometabolite and inhibits alpha-ketoglutarate dependent oxygenases like TET2.	('TET2', 'Gene', (96, 100))	('inhibits', 'NegReg', (41, 49))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (50, 69))	('alpha-ketoglutarate dependent oxygenases', 'Enzyme', (50, 90))	('TET2', 'Gene', '54790', (96, 100))	('D2HG', 'Var', (0, 4))
81652	27523972	Indeed, IDH1 mutations are associated with a hypermethylated phenotype in cartilage tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('IDH1', 'Gene', (8, 12))	('cartilage tumors', 'Disease', (74, 90))	('associated', 'Reg', (27, 37))	('hypermethylated', 'MPA', (45, 60))	('IDH1', 'Gene', '3417', (8, 12))	('cartilage tumors', 'Disease', 'MESH:D002357', (74, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (13, 22))
81653	27523972	D2HG also inhibits other alpha-ketoglutarate dependent oxygenases such as the Jumonji domain histone demethylases, thereby increasing histone methylation as well.	('alpha-ketoglutarate dependent oxygenases', 'Enzyme', (25, 65))	('inhibits', 'NegReg', (10, 18))	('histone methylation', 'MPA', (134, 153))	('increasing', 'PosReg', (123, 133))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (25, 44))	('D2HG', 'Var', (0, 4))
81654	27523972	Indeed, when mesenchymal stem cells are treated with D2HG, or when an IDH mutation is introduced, this results in inhibition of osteogenic differentiation and stimulation of chondrogenic differentiation, explaining the development of enchondromas during bone development.	('mutation', 'Var', (74, 82))	('enchondromas', 'Disease', (234, 246))	('inhibition', 'NegReg', (114, 124))	('chondrogenic differentiation', 'CPA', (174, 202))	('enchondromas', 'Phenotype', 'HP:0030038', (234, 246))	('IDH', 'Gene', (70, 73))	('enchondromas', 'Disease', 'MESH:D002812', (234, 246))	('osteogenic differentiation', 'CPA', (128, 154))	('IDH', 'Gene', '3417', (70, 73))	('enchondroma', 'Phenotype', 'HP:0030038', (234, 245))	('stimulation', 'PosReg', (159, 170))	('D2HG', 'Var', (53, 57))
81659	27523972	Detection of hotspot mutations in IDH1 or IDH2 can be useful in the differential diagnosis of chondrosarcoma versus chordoma or chondroblastic osteosarcoma, which can sometimes be challenging.	('IDH1', 'Gene', '3417', (34, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('chordoma', 'Phenotype', 'HP:0010762', (116, 124))	('hotspot', 'PosReg', (13, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('chondrosarcoma versus chordoma or chondroblastic osteosarcoma', 'Disease', 'MESH:D002817', (94, 155))	('IDH2', 'Gene', (42, 46))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (94, 108))	('IDH1', 'Gene', (34, 38))	('IDH2', 'Gene', '3418', (42, 46))	('mutations', 'Var', (21, 30))
81661	27523972	IDH mutations are present in 87% of Ollier- associated enchondromas, 86% of secondary central chondrosarcoma, 38-70% of primary central chondrosarcoma, ~15% of periosteal chondrosarcoma and 54% of dedifferentiated chondrosarcoma and are absent in peripheral chondrosarcoma, osteosarcoma and in chordoma.	('chondrosarcoma', 'Disease', (214, 228))	('chondrosarcoma', 'Disease', 'MESH:D002813', (214, 228))	('enchondromas', 'Disease', 'MESH:D002812', (55, 67))	('osteosarcoma', 'Disease', (274, 286))	('enchondroma', 'Phenotype', 'HP:0030038', (55, 66))	('osteosarcoma', 'Disease', 'MESH:D012516', (274, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('IDH', 'Gene', (0, 3))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (136, 150))	('chondrosarcoma', 'Disease', (94, 108))	('chondrosarcoma', 'Disease', 'MESH:D002813', (94, 108))	('chondrosarcoma', 'Disease', 'MESH:D002813', (171, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('chondrosarcoma', 'Disease', (171, 185))	('chondrosarcoma', 'Disease', 'MESH:D002813', (258, 272))	('chordoma', 'Phenotype', 'HP:0010762', (294, 302))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (214, 228))	('enchondromas', 'Disease', (55, 67))	('chondrosarcoma', 'Disease', (258, 272))	('chordoma', 'Disease', (294, 302))	('IDH', 'Gene', '3417', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('peripheral chondrosarcoma', 'Disease', 'MESH:D002813', (247, 272))	('mutations', 'Var', (4, 13))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (94, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (274, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (171, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('enchondromas', 'Phenotype', 'HP:0030038', (55, 67))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (258, 272))	('chondrosarcoma', 'Disease', 'MESH:D002813', (136, 150))	('chordoma', 'Disease', 'MESH:D002817', (294, 302))	('chondrosarcoma', 'Disease', (136, 150))	('peripheral chondrosarcoma', 'Disease', (247, 272))
81662	27523972	Other metabolic enzymes, including succinate dehydrogenase (SDH) and fumarate hydratase (FH) are also known to be mutated in cancer and to cause defective energy metabolism as well as epigenetic deregulation in cancer.	('SDH', 'Gene', (60, 63))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('fumarate hydratase', 'Gene', (69, 87))	('mutated', 'Var', (114, 121))	('cancer', 'Disease', (211, 217))	('succinate dehydrogenase', 'Gene', (35, 58))	('succinate dehydrogenase', 'Gene', '6390', (35, 58))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('fumarate hydratase', 'Gene', '2271', (69, 87))	('FH', 'Gene', '2271', (89, 91))	('SDH', 'Gene', '6390', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cause', 'Reg', (139, 144))	('energy metabolism', 'MPA', (155, 172))	('epigenetic', 'MPA', (184, 194))	('defective', 'NegReg', (145, 154))
81663	27523972	Inactivating mutations in subunits of mitochondrial complex II including the succinate dehydrogenase subunit D (SDHD), C (SDHC) and B (SDHB) genes, are found in patients with head and neck paragangliomas and pheochromocytomas.	('SDHC', 'Gene', (122, 126))	('neck paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (184, 225))	('succinate dehydrogenase subunit D', 'Gene', '6392', (77, 110))	('SDHB', 'Gene', '6390', (135, 139))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (208, 225))	('SDHC', 'Gene', '6391', (122, 126))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (175, 203))	('succinate dehydrogenase subunit D', 'Gene', (77, 110))	('paragangliomas', 'Phenotype', 'HP:0002668', (189, 203))	('SDHB', 'Gene', (135, 139))	('Inactivating mutations', 'Var', (0, 22))	('SDHD', 'Gene', (112, 116))	('SDHD', 'Gene', '6392', (112, 116))	('patients', 'Species', '9606', (161, 169))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('found', 'Reg', (152, 157))
81664	27523972	Also, a subset of gastrointestinal stromal tumors, lacking mutations in KIT or PDGFRA, carry mutations in one of the SDH genes or an SDHC epimutation both of which are associated with global hypermethylation.	('SDH', 'Gene', (133, 136))	('SDHC', 'Gene', (133, 137))	('epimutation', 'Var', (138, 149))	('SDH', 'Gene', '6390', (117, 120))	('mutations', 'Var', (93, 102))	('KIT', 'Gene', (72, 75))	('gastrointestinal stromal tumors', 'Disease', (18, 49))	('SDHC', 'Gene', '6391', (133, 137))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (18, 48))	('PDGFRA', 'Gene', '5156', (79, 85))	('lacking', 'NegReg', (51, 58))	('PDGFRA', 'Gene', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (18, 49))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (18, 49))	('SDH', 'Gene', (117, 120))	('SDH', 'Gene', '6390', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))
81666	27523972	Mutations in one of the SDH subunits destabilize the SDH complex, causing degradation and loss of SDHB.	('SDH', 'Gene', '6390', (24, 27))	('SDH', 'Gene', (53, 56))	('SDH', 'Gene', (98, 101))	('loss', 'NegReg', (90, 94))	('destabilize', 'NegReg', (37, 48))	('SDHB', 'Gene', '6390', (98, 102))	('degradation', 'MPA', (74, 85))	('SDHB', 'Gene', (98, 102))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', '6390', (53, 56))	('SDH', 'Gene', (24, 27))	('SDH', 'Gene', '6390', (98, 101))
81667	27523972	Immunohistochemistry for SDHB is therefore a surrogate marker for mutations in one of the SDH subunits (Figure 4D).	('mutations', 'Var', (66, 75))	('SDH', 'Gene', '6390', (90, 93))	('SDH', 'Gene', (25, 28))	('SDH', 'Gene', (90, 93))	('SDHB', 'Gene', '6390', (25, 29))	('SDHB', 'Gene', (25, 29))	('SDH', 'Gene', '6390', (25, 28))
81668	27523972	Inactivating germline mutations of another tricarboxylic acid cycle gene, fumarate hydratase (FH), cause autosomal dominant HLRCC syndrome (hereditary leiomyomas and type 2 papillary renal cell carcinoma), including benign cutaneous and uterine leiomyomas and renal cell cancer, while somatic mutations are rare.	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (237, 255))	('Inactivating germline mutations', 'Var', (0, 31))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (43, 61))	('fumarate hydratase', 'Gene', '2271', (74, 92))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('fumarate hydratase', 'Gene', (74, 92))	('renal cell cancer', 'Phenotype', 'HP:0005584', (260, 277))	('hereditary leiomyomas and type 2 papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (140, 203))	('cause', 'Reg', (99, 104))	('FH', 'Gene', '2271', (94, 96))	('autosomal dominant HLRCC syndrome', 'Disease', 'MESH:C535516', (105, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (183, 203))	('autosomal dominant HLRCC syndrome', 'Disease', (105, 138))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (173, 203))	('cutaneous and uterine leiomyomas', 'Phenotype', 'HP:0007620', (223, 255))	('2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (171, 203))	('leiomyomas and renal cell cancer', 'Disease', 'MESH:C538614', (245, 277))
81669	27523972	The accumulation of fumarate, caused by mutations in FH, leads to aberrant succination of proteins.	('accumulation', 'PosReg', (4, 16))	('fumarate', 'Chemical', 'MESH:D005650', (20, 28))	('mutations', 'Var', (40, 49))	('fumarate', 'MPA', (20, 28))	('FH', 'Gene', '2271', (53, 55))	('succination of proteins', 'MPA', (75, 98))	('leads to', 'Reg', (57, 65))
81671	27523972	Similar to mutations in IDH, FH as well as SDH mutations affect epigenetic signaling, by inhibition of histone demethylases and the TET family of 5 hydroxymethylcytosine (5mC)-hydroxylases by accumulated fumarate and succinate, respectively.	('SDH', 'Gene', (43, 46))	('fumarate', 'MPA', (204, 212))	('IDH', 'Gene', (24, 27))	('mutations', 'Var', (47, 56))	('affect', 'Reg', (57, 63))	('histone demethylases', 'Enzyme', (103, 123))	('succinate', 'MPA', (217, 226))	('inhibition', 'NegReg', (89, 99))	('epigenetic signaling', 'MPA', (64, 84))	('SDH', 'Gene', '6390', (43, 46))	('IDH', 'Gene', '3417', (24, 27))	('fumarate', 'Chemical', 'MESH:D005650', (204, 212))	('TET', 'Chemical', 'MESH:C010349', (132, 135))	('FH', 'Gene', '2271', (29, 31))	('succinate', 'Chemical', 'MESH:D019802', (217, 226))	('5mC', 'Chemical', 'MESH:C011865', (171, 174))	('accumulated', 'PosReg', (192, 203))
81672	27523972	Using immunohistochemistry, loss of 5hmC and increased H3K9me3 can be shown in SDH and FH mutant tumor cells.	('SDH', 'Gene', '6390', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('5hmC', 'Protein', (36, 40))	('increased', 'PosReg', (45, 54))	('FH', 'Gene', '2271', (87, 89))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutant', 'Var', (90, 96))	('H3K9me3', 'Protein', (55, 62))	('tumor', 'Disease', (97, 102))	('5hmC', 'Chemical', '-', (36, 40))	('SDH', 'Gene', (79, 82))	('loss', 'NegReg', (28, 32))
81673	27523972	In SDH mutant GIST, 5-hmC staining is also low to absent.	('SDH', 'Gene', (3, 6))	('mutant', 'Var', (7, 13))	('SDH', 'Gene', '6390', (3, 6))
81674	27523972	Epigenetic deregulation is emerging as a very prevalent oncogenic mechanism in a wide variety of tumors, beyond the effects of metabolic enzymes and oncometabolites.	('Epigenetic deregulation', 'Var', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
81676	27523972	Frequently, epigenetic deregulation is an additional feature in a cancer cell, contributing to a complex genomic environment in which several other oncogenic mechanisms are already in place (e.g.	('epigenetic deregulation', 'Var', (12, 35))	('contributing', 'Reg', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
81677	27523972	mutations in members of the PRC2 complex in malignant peripheral nerve sheath tumors).	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('PRC2', 'Gene', (28, 32))	('malignant peripheral nerve sheath tumors', 'Disease', (44, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (44, 84))	('mutations', 'Var', (0, 9))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (44, 84))
81678	27523972	In some tumor types, however, mutations causing epigenetic deregulation seem to occur as early events, in a background of low mutational rate, and may serve as primary drivers of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('mutations', 'Var', (30, 39))	('epigenetic deregulation', 'Var', (48, 71))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
81679	27523972	Examples include histone mutations in giant cell tumor of bone (GCTB) and chondroblastoma, SMARCB1 homozygous deletions in rhabdoid tumor, and SMARCA4 inactivation in SMARCA4-deficient thoracic sarcomas.	('SMARCB1', 'Gene', '6598', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor of bone', 'Phenotype', 'HP:0010622', (49, 62))	('SMARCB1', 'Gene', (91, 98))	('tumor', 'Disease', (132, 137))	('chondroblastoma', 'Phenotype', 'HP:0030432', (74, 89))	('mutations', 'Var', (25, 34))	('SMARCA4', 'Gene', (167, 174))	('SMARCA4', 'Gene', (143, 150))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('SMARCA4-deficient thoracic sarcomas', 'Disease', 'MESH:D012509', (167, 202))	('SMARCA4-deficient thoracic sarcomas', 'Disease', (167, 202))	('chondroblastoma', 'Disease', (74, 89))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (49, 54))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (123, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('SMARCA4', 'Gene', '6597', (167, 174))	('SMARCA4', 'Gene', '6597', (143, 150))	('inactivation', 'Var', (151, 163))	('histone', 'Protein', (17, 24))	('rhabdoid tumor', 'Disease', (123, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (38, 62))	('chondroblastoma', 'Disease', 'MESH:D002804', (74, 89))
81681	27523972	Mutations in bone tumors affecting epigenetic signaling include histone H3.3 mutations in giant cell tumor of bone (GCTB) and chondroblastoma, both of which are locally aggressive bone tumors predominantly affecting young patients.	('chondroblastoma', 'Disease', (126, 141))	('bone tumors', 'Disease', (13, 24))	('bone tumors', 'Phenotype', 'HP:0010622', (13, 24))	('patients', 'Species', '9606', (222, 230))	('bone tumor', 'Phenotype', 'HP:0010622', (180, 190))	('bone tumors', 'Disease', (180, 191))	('bone tumors', 'Phenotype', 'HP:0010622', (180, 191))	('tumor', 'Disease', (185, 190))	('bone tumors', 'Disease', 'MESH:D001859', (13, 24))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (90, 114))	('tumor', 'Disease', (18, 23))	('bone tumor', 'Phenotype', 'HP:0010622', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor of bone', 'Phenotype', 'HP:0010622', (101, 114))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('bone tumors', 'Disease', 'MESH:D001859', (180, 191))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('histone H3.3', 'Gene', '3021', (64, 76))	('chondroblastoma', 'Disease', 'MESH:D002804', (126, 141))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('chondroblastoma', 'Phenotype', 'HP:0030432', (126, 141))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', (101, 106))	('histone H3.3', 'Gene', (64, 76))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
81682	27523972	In 92% of GCTBs mutations are found in the H3F3A gene, while in 95% of the chondroblastomas mutations were found in the H3F3B gene.	('H3F3B', 'Gene', (120, 125))	('H3F3A', 'Gene', (43, 48))	('found', 'Reg', (30, 35))	('chondroblastomas', 'Disease', (75, 91))	('GCTBs', 'Disease', (10, 15))	('mutations', 'Var', (16, 25))	('chondroblastomas', 'Disease', 'MESH:D002804', (75, 91))	('GCTBs', 'Chemical', '-', (10, 15))	('chondroblastoma', 'Phenotype', 'HP:0030432', (75, 90))	('H3F3A', 'Gene', '3020', (43, 48))	('H3F3B', 'Gene', '3021', (120, 125))
81684	27523972	The exact mechanism by which these histone H3.3 mutations cause the formation of these giant cell containing tumors is currently unknown.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('cause', 'Reg', (58, 63))	('histone H3.3', 'Gene', (35, 47))	('histone H3.3', 'Gene', '3021', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('mutations', 'Var', (48, 57))
81686	27523972	Mutation analysis may be a useful diagnostic tool, in addition to the possible use of S100 or DOG1 immunohistochemistry, of which positivity would favor chondroblastoma.	('Mutation', 'Var', (0, 8))	('chondroblastoma', 'Disease', (153, 168))	('DOG1', 'Gene', '55107', (94, 98))	('chondroblastoma', 'Phenotype', 'HP:0030432', (153, 168))	('DOG1', 'Gene', (94, 98))	('chondroblastoma', 'Disease', 'MESH:D002804', (153, 168))	('S100', 'Gene', (86, 90))	('S100', 'Gene', '6271', (86, 90))
81689	27523972	Sensitivity is therefore highly dependent on the technique used, detecting mutations in H3F3A in 69% of the giant cell tumors of bone using classical Sanger sequencing compared to 92% using a targeted next generation sequencing (NGS) approach.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('giant cell tumors of bone', 'Phenotype', 'HP:0011847', (108, 133))	('tumors of bone', 'Phenotype', 'HP:0010622', (119, 133))	('H3F3A', 'Gene', (88, 93))	('giant cell tumors', 'Disease', (108, 125))	('mutations', 'Var', (75, 84))	('giant cell tumors', 'Disease', 'MESH:D005870', (108, 125))	('detecting', 'Reg', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('H3F3A', 'Gene', '3020', (88, 93))
81694	27523972	The high chromosomal instability occurs in the context of TP53 pathway alterations, very often TP53 mutation, which is likely an early event in tumorigenesis.	('tumor', 'Disease', (144, 149))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('mutation', 'Var', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('chromosomal instability', 'Phenotype', 'HP:0040012', (9, 32))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
81696	27523972	The Rb/E2F pathway is also critical for tumor development and multiple members of the pathway are frequently mutated by different mechanisms.	('Rb/E2F pathway', 'Pathway', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutated', 'Var', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
81698	27523972	Nonetheless, the higher mutational load in these tumors potentially makes them good candidates for immunotherapy, with drugs such as immune checkpoint blockers.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('mutational', 'Var', (24, 34))
81702	27523972	One example is well differentiated/dedifferentiated liposarcoma (WD/DDLPS), whose genome is characterized by multiple copy number changes, mostly gains and amplifications, with multiple intra and interchromosomal rearrangements.	('liposarcoma', 'Phenotype', 'HP:0012034', (52, 63))	('liposarcoma', 'Disease', 'MESH:D008080', (52, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('gains', 'Var', (146, 151))	('WD', 'Disease', 'MESH:D006527', (65, 67))	('liposarcoma', 'Disease', (52, 63))	('amplifications', 'Var', (156, 170))
81708	27523972	The highly recurrent nature of MDM2 and CDK4 amplification provides a useful diagnostic marker.	('CDK4', 'Gene', (40, 44))	('CDK4', 'Gene', '1019', (40, 44))	('MDM2', 'Gene', '4193', (31, 35))	('MDM2', 'Gene', (31, 35))	('amplification', 'Var', (45, 58))
81709	27523972	Detection of MDM2 amplification by FISH is currently the gold standard for diagnosis of WD/DDLPS, while combined immunohistochemical detection of the MDM2 and CDK4 proteins is a very useful diagnostic tool in surgical pathology routine practice.	('CDK4', 'Gene', (159, 163))	('CDK4', 'Gene', '1019', (159, 163))	('MDM2', 'Gene', '4193', (13, 17))	('MDM2', 'Gene', '4193', (150, 154))	('WD', 'Disease', 'MESH:D006527', (88, 90))	('MDM2', 'Gene', (13, 17))	('MDM2', 'Gene', (150, 154))	('amplification', 'Var', (18, 31))
81712	27523972	Biologically, amplification of MDM2 results in inactivation of p53, while CDK4 amplification leads to cell cycle progression.	('MDM2', 'Gene', '4193', (31, 35))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('CDK4', 'Gene', '1019', (74, 78))	('CDK4', 'Gene', (74, 78))	('leads to', 'Reg', (93, 101))	('inactivation', 'NegReg', (47, 59))	('cell cycle progression', 'CPA', (102, 124))	('amplification', 'Var', (79, 92))	('MDM2', 'Gene', (31, 35))	('amplification', 'Var', (14, 27))
81715	27523972	Despite the strong biologic rationale and proven on-target activity, initial clinical experiences demonstrate that few DDLPS patients achieve disease stabilization after MDM2 inhibition, at the expense of substantial adverse effects.	('MDM2', 'Gene', (170, 174))	('disease', 'Disease', (142, 149))	('inhibition', 'Var', (175, 185))	('MDM2', 'Gene', '4193', (170, 174))	('DDLPS', 'Disease', (119, 124))	('patients', 'Species', '9606', (125, 133))
81721	27523972	These high grade sarcomas often harbor aberrations in the Rb or p53 pathway.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('sarcomas', 'Disease', (17, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))	('aberrations', 'Var', (39, 50))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
81724	27523972	At the genetic level osteosarcoma is extremely unstable with many translocations, amplifications, mutations and deletions (Figure 1D).	('osteosarcoma', 'Phenotype', 'HP:0002669', (21, 33))	('osteosarcoma', 'Disease', (21, 33))	('osteosarcoma', 'Disease', 'MESH:D012516', (21, 33))	('deletions', 'Var', (112, 121))	('mutations', 'Var', (98, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))
81728	27523972	Sarcomas with simple genome can be driven by transcriptional deregulation, abnormal kinase signaling, or epigenetic reprogramming.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('epigenetic', 'Var', (105, 115))	('transcriptional deregulation', 'Var', (45, 73))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('driven by', 'Reg', (35, 44))	('abnormal', 'Var', (75, 83))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
81733	27523972	The high mutational load may make these tumors good candidates for immunotherapies dependent on neoantigens.	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('mutational load', 'Var', (9, 24))	('tumors', 'Disease', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
81745	27058531	Several groups have reported association between mutations and tumor suppressor genes.	('tumor', 'Disease', (63, 68))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('association', 'Interaction', (29, 40))
81747	27058531	Mutations in the Rb1 gene and high frequency of allelic loss of Rb1 gene at 13q and p53 gene at 17p have been detected in OS samples.	('detected', 'Reg', (110, 118))	('Rb1', 'Gene', '5925', (17, 20))	('loss', 'NegReg', (56, 60))	('OS', 'Phenotype', 'HP:0002669', (122, 124))	('Rb1', 'Gene', (64, 67))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (84, 87))	('Rb1', 'Gene', (17, 20))	('Rb1', 'Gene', '5925', (64, 67))
81748	27058531	Moreover RB1 inactivation was detected in almost 20%-40% of OS cases and associated with poor prognosis.	('inactivation', 'Var', (13, 25))	('RB1', 'Gene', (9, 12))	('associated', 'Reg', (73, 83))	('OS', 'Phenotype', 'HP:0002669', (60, 62))	('detected', 'Reg', (30, 38))	('RB1', 'Gene', '5925', (9, 12))
81749	27058531	Inactivation or loss of TP53 causes cells to be resistant to DNA damage as well as loss control of cell growth thus resulting in extensive proliferation, transformation, and evade toxic effects of DNA damaging agents.	('resulting in', 'Reg', (116, 128))	('TP53', 'Gene', (24, 28))	('transformation', 'CPA', (154, 168))	('loss', 'Var', (16, 20))	('Inactivation', 'Var', (0, 12))	('TP53', 'Gene', '7157', (24, 28))
81753	27058531	High expression of Myc in bone marrow stromal cells caused loss of adipogenesis and transformation into osteosarcoma.	('Myc', 'Gene', (19, 22))	('transformation', 'Reg', (84, 98))	('High', 'Var', (0, 4))	('osteosarcoma', 'Disease', (104, 116))	('Myc', 'Gene', '4609', (19, 22))	('osteosarcoma', 'Phenotype', 'HP:0002669', (104, 116))	('osteosarcoma', 'Disease', 'MESH:D012516', (104, 116))	('adipogenesis', 'MPA', (67, 79))	('loss', 'NegReg', (59, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))
81780	27058531	Moreover, RTKs have been arraigned as a key factor in growth and progression of several tumors and several gene mutation, amplification have been implicated in the disruption of RTKs signaling cascade.	('mutation', 'Var', (112, 120))	('implicated', 'Reg', (146, 156))	('amplification', 'Var', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (88, 94))
81789	27058531	Phase I/II clinical trial of cixutumumab on children with refractory solid tumors including OS, reported cixutumumab to be well tolerated but with limited single-agent activity.	('cixutumumab', 'Var', (105, 116))	('cixutumumab', 'Chemical', 'MESH:C557414', (29, 40))	('cixutumumab', 'Chemical', 'MESH:C557414', (105, 116))	('OS', 'Phenotype', 'HP:0002669', (92, 94))	('children', 'Species', '9606', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('refractory solid tumors', 'Disease', (58, 81))	('refractory solid tumors', 'Disease', 'MESH:D009369', (58, 81))
81792	27058531	Furthermore, SCH 717454 in combination with cisplatin or cyclophosphamide had demonstrated a remarkable increase in in vivo antitumor activity compared with single agent treatment.	('increase', 'PosReg', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('SCH 717454', 'Chemical', 'MESH:C573312', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (57, 73))	('SCH 717454', 'Var', (13, 23))	('tumor', 'Disease', (128, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))
81793	27058531	However, a phase 1/1B trial of SCH 717454 in combination with different treatment regimens in pediatric patients with advanced solid tumors (NCT00960063 *) and a phase II trial on activity of SCH 717454 in patients with relapsed OS and Ewing's sarcoma (NCT00617890 *) were recently terminated (Table 1).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('NCT00960063 *', 'Var', (141, 154))	('solid tumors', 'Disease', (127, 139))	('OS', 'Phenotype', 'HP:0002669', (229, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('SCH 717454', 'Chemical', 'MESH:C573312', (192, 202))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (236, 251))	('patients', 'Species', '9606', (206, 214))	("Ewing's sarcoma", 'Disease', (236, 251))	('solid tumors', 'Disease', 'MESH:D009369', (127, 139))	('SCH 717454', 'Chemical', 'MESH:C573312', (31, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (236, 251))	('relapsed OS', 'Disease', (220, 231))	('patients', 'Species', '9606', (104, 112))
81794	27058531	Two IGF ligand-neutralizing antibodies against IGF ligands IGF-I and -II have been found: BI836845 and MEDI-573.	('BI836845', 'Var', (90, 98))	('IGF-I', 'Gene', '3479', (59, 64))	('neu', 'Gene', '2064', (15, 18))	('neu', 'Gene', (15, 18))	('IGF-I', 'Gene', (59, 64))
81796	27058531	At present, several phase I trials of BI836845 for patients with solid tumors are ongoing recruitment (Table 1).	('solid tumors', 'Disease', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (51, 59))	('BI836845', 'Var', (38, 46))	('solid tumors', 'Disease', 'MESH:D009369', (65, 77))
81798	27058531	BMS-754807 is a reversible small molecule ATP-competitive inhibitor of IGF-1R.	('IGF-1R', 'Gene', '3480', (71, 77))	('ATP', 'Chemical', 'MESH:D000255', (42, 45))	('IGF-1R', 'Gene', (71, 77))	('BMS-754807', 'Var', (0, 10))
81832	27058531	Further clinical evaluation of sorafenib in combination with bevacizumab (NCT00665990) and irinotecan (NCT01518413) are in progress (Table 1).	('NCT00665990', 'Var', (74, 85))	('sorafenib', 'Chemical', 'MESH:D000077157', (31, 40))	('irinotecan', 'Chemical', 'MESH:D000077146', (91, 101))	('bevacizumab', 'Chemical', 'MESH:D000068258', (61, 72))	('NCT01518413', 'Var', (103, 114))
81856	27058531	Moreover, high level of mTOR in OS patients have been consistently correlated with poorer prognosis.	('correlated', 'Reg', (67, 77))	('OS', 'Phenotype', 'HP:0002669', (32, 34))	('high', 'Var', (10, 14))	('patients', 'Species', '9606', (35, 43))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))
81877	27058531	Preclinical studies on silencing of AURK-A protein expression in osteosarcoma cells revealed that it could induce cell cycle arrest in G2/M and result in cell apoptosis in vitro.	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (114, 131))	('induce', 'Reg', (107, 113))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('AURK-A', 'Gene', '6790', (36, 42))	('cell apoptosis', 'CPA', (154, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('silencing', 'Var', (23, 32))	('cell cycle arrest', 'CPA', (114, 131))	('result in', 'Reg', (144, 153))	('AURK-A', 'Gene', (36, 42))	('protein', 'Protein', (43, 50))
81878	27058531	MLN8237 (alisertib) is a second generation aurora kinase inhibitors, specifically targeting AURK-A via competing with ATP binding.	('targeting', 'Reg', (82, 91))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('AURK-A', 'Gene', '6790', (92, 98))	('alisertib', 'Chemical', 'MESH:C550258', (9, 18))	('MLN8237', 'Var', (0, 7))	('AURK-A', 'Gene', (92, 98))	('ATP', 'Chemical', 'MESH:D000255', (118, 121))
81880	27058531	A recent in vitro study has reported that MLN8237 through aurora kinase inhibition could induce autophagy and apoptotic cell death via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathway and that the reactive oxygen species (ROS) as well as sirtuin-1 pathways are also involved.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (200, 223))	('autophagy', 'CPA', (96, 105))	('induce', 'PosReg', (89, 95))	('MAPK', 'Gene', (154, 158))	('AMPK signaling pathway', 'Pathway', (164, 186))	('MAPK', 'Gene', '5595;5594;5595', (154, 158))	('sirtuin-1', 'Gene', '23411', (241, 250))	('MLN8237', 'Chemical', 'MESH:C550258', (42, 49))	('sirtuin-1', 'Gene', (241, 250))	('OS', 'Phenotype', 'HP:0002669', (226, 228))	('ROS', 'Chemical', 'MESH:D017382', (225, 228))	('MLN8237', 'Var', (42, 49))	('aurora', 'Protein', (58, 64))	('apoptotic cell death', 'CPA', (110, 130))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))	('inhibition', 'NegReg', (72, 82))
81899	27058531	This study indicated that blockade of PD-1/PD-L1 signaling pathway could drastically improve the functions of tumor-infiltrating lymphocytes, reduce the tumor burden and increase survival in OS mouse models.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('OS', 'Phenotype', 'HP:0002669', (191, 193))	('improve', 'PosReg', (85, 92))	('survival', 'CPA', (179, 187))	('increase', 'PosReg', (170, 178))	('tumor', 'Disease', (110, 115))	('blockade', 'Var', (26, 34))	('mouse', 'Species', '10090', (194, 199))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('reduce', 'NegReg', (142, 148))	('PD-1/PD-L1', 'Gene', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
81905	27058531	High expression of miR33a was found in OS cells that are resistant to cisplatin, through down regulation of TWIST and that inhibition of miR33a could increase the cell apoptosis induced by cisplatin Therefore, microRNAs like miR-144, miR132, miR-27a, miR33a and may be able to serve as a diagnostic and therapeutic target for OS treatment.	('miR33a', 'Gene', '407039', (251, 257))	('inhibition', 'Var', (123, 133))	('miR132', 'Gene', '406921', (234, 240))	('increase', 'PosReg', (150, 158))	('miR-27a', 'Gene', (242, 249))	('miR33a', 'Gene', '407039', (19, 25))	('down regulation', 'NegReg', (89, 104))	('miR-144', 'Gene', (225, 232))	('miR33a', 'Gene', '407039', (137, 143))	('miR132', 'Gene', (234, 240))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))	('miR33a', 'Gene', (251, 257))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('TWIST', 'Gene', (108, 113))	('TWIST', 'Gene', '7291', (108, 113))	('OS', 'Phenotype', 'HP:0002669', (39, 41))	('miR-27a', 'Gene', '407018', (242, 249))	('miR33a', 'Gene', (19, 25))	('OS', 'Phenotype', 'HP:0002669', (326, 328))	('cell apoptosis', 'CPA', (163, 177))	('miR33a', 'Gene', (137, 143))	('miR-144', 'Gene', '406936', (225, 232))
81929	27058531	A series of phase I studies on DOXO-EMCH showed it to be safe, stable in circulation without accumulating in body compartments with fewer cases of doxorubicin-associated cardiotoxicity and could induce tumor regressions in tumor types known to be anthracycline-sensitive tumors such as breast cancer, small cell lung cancer and sarcomas.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (271, 277))	('small cell lung cancer', 'Disease', 'MESH:D055752', (301, 323))	('breast cancer', 'Disease', 'MESH:D001943', (286, 299))	('breast cancer', 'Disease', (286, 299))	('small cell lung cancer', 'Disease', (301, 323))	('tumor', 'Disease', (202, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (312, 323))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', (271, 276))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (301, 323))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('cardiotoxicity', 'Disease', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('sarcomas', 'Disease', 'MESH:D012509', (328, 336))	('sarcomas', 'Phenotype', 'HP:0100242', (328, 336))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('induce', 'Reg', (195, 201))	('sarcomas', 'Disease', (328, 336))	('DOXO-EMCH', 'Var', (31, 40))	('anthracycline', 'Chemical', 'MESH:D018943', (247, 260))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('doxorubicin', 'Chemical', 'MESH:D004317', (147, 158))	('cardiotoxicity', 'Disease', 'MESH:D066126', (170, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (286, 299))	('sarcoma', 'Phenotype', 'HP:0100242', (328, 335))	('DOXO-EMCH', 'Chemical', 'MESH:C575867', (31, 40))
81935	27058531	Nab-paclitaxel showed significant antitumor activity against most pediatric solid tumor cell lines including OS, while in OS xenograft model, nab-paclitaxel demonstrated significantly higher tumor inhibition (98.8%) compared to adriamycin (46.1%) and paclitaxel (40.8%).	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (142, 156))	('OS', 'Phenotype', 'HP:0002669', (109, 111))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (82, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('nab-paclitaxel', 'Var', (142, 156))	('adriamycin', 'Chemical', 'MESH:D004317', (228, 238))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (146, 156))	('OS', 'Phenotype', 'HP:0002669', (122, 124))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (191, 196))	('higher', 'PosReg', (184, 190))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('Nab-paclitaxel', 'Chemical', 'MESH:D017239', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('paclitaxel', 'Chemical', 'MESH:D017239', (251, 261))
81965	25415714	A characteristic unbalanced translocation, der(17)t(X:17) (p11;q25) results in the formation of an ASPL-TFE3 fusion protein.	('results in', 'Reg', (68, 78))	('TFE3', 'Gene', '7030', (104, 108))	('der(17)t(X:17) (', 'Var', (43, 59))	('TFE3', 'Gene', (104, 108))
82048	25415714	Other tumors that may appear hyperintense on T1W MRI include hemangioma, clear cell sarcoma, melanoma and hemorrhagic soft tissue tumors including the most common soft-tissue sarcoma in children, rhabdomyosarcoma.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('sarcoma', 'Disease', (175, 182))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (196, 212))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('sarcoma', 'Disease', (205, 212))	('hemangioma', 'Disease', (61, 71))	('children', 'Species', '9606', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (73, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('T1W', 'Var', (45, 48))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Disease', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('hemangioma', 'Phenotype', 'HP:0001028', (61, 71))	('rhabdomyosarcoma', 'Disease', (196, 212))	('tumors', 'Disease', (6, 12))	('hemangioma', 'Disease', 'MESH:D006391', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('tumors', 'Disease', (130, 136))	('clear cell sarcoma', 'Disease', (73, 91))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (167, 182))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (118, 136))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (196, 212))	('melanoma and hemorrhagic soft tissue tumors', 'Disease', 'MESH:D008545', (93, 136))	('sarcoma', 'Disease', 'MESH:D012509', (175, 182))
82085	24013230	The MutSbeta complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double strand break repair and mismatch repair Loss of the DNA mismatch repair protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSbeta (MSH2-MSH3) complex in late onset tumorigenesis.	('tumors', 'Disease', (231, 237))	('mismatch repair Loss', 'Var', (129, 149))	('tumor', 'Disease', (231, 236))	('leads to', 'Reg', (190, 198))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumor', 'Disease', (374, 379))	('DNA mismatch repair protein MSH3', 'Gene', (157, 189))	('Loss', 'Var', (145, 149))	('mice', 'Species', '10090', (241, 245))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (374, 379))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '22060', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('DNA mismatch repair protein MSH3', 'Gene', '17686', (157, 189))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))
82089	24013230	Msh3/p53 tumors showed increased loss of heterozygosity, elevated genome-wide copy number variation, and a moderate microsatellite instability phenotype compared to Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability.	('p53', 'Gene', '22060', (5, 8))	('MSH2-MSH3', 'Var', (197, 206))	('p53', 'Gene', (170, 173))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (218, 223))	('p53', 'Gene', '22060', (170, 173))	('tumors', 'Disease', (174, 180))	('heterozygosity', 'MPA', (41, 55))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('suppresses', 'NegReg', (207, 217))	('elevated', 'PosReg', (57, 65))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('microsatellite instability', 'MPA', (116, 142))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('chromosomal stability', 'MPA', (247, 268))	('p53', 'Gene', (5, 8))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
82092	24013230	Two heterodimeric MutS homolog (MSH) complexes, consisting of either MSH2-MSH6 (MutSalpha) or MSH2-MSH3 (MutSbeta), are responsible for the recognition of these mismatched bases.	('mismatched', 'Var', (161, 171))	('MSH', 'Gene', '17701', (69, 72))	('MSH', 'Gene', (69, 72))	('MSH', 'Gene', (94, 97))	('MSH', 'Gene', '17701', (94, 97))	('MSH', 'Gene', (32, 35))	('responsible', 'Reg', (120, 131))	('MSH', 'Gene', '17701', (32, 35))	('MSH', 'Gene', (74, 77))	('MSH', 'Gene', '17701', (74, 77))	('MSH', 'Gene', '17701', (99, 102))	('MSH', 'Gene', (99, 102))
82093	24013230	Germline mutations in MSH2 and MSH6 but not MSH3 are responsible for hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS); however, an (A)8 tract in the coding region of MSH3 was found to be frequently affected by frameshift mutations in MMR-deficient colorectal tumors, resulting in loss of MSH3 protein expression.	('loss', 'NegReg', (300, 304))	('MMR-deficient colorectal tumors', 'Disease', 'MESH:C536928', (254, 285))	('MMR-deficient colorectal tumors', 'Disease', (254, 285))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('MSH3', 'Gene', (308, 312))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hereditary non-polyposis colorectal cancer', 'Disease', (69, 111))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (69, 111))	('MSH3', 'Gene', (186, 190))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (69, 111))	('MSH2', 'Gene', (22, 26))	('HNPCC', 'Disease', 'None', (128, 133))	('Lynch syndrome', 'Disease', (112, 126))	('HNPCC', 'Disease', (128, 133))	('affected', 'Reg', (218, 226))	('protein', 'Protein', (313, 320))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('Lynch syndrome', 'Disease', 'MESH:D003123', (112, 126))	('frameshift mutations', 'Var', (230, 250))
82099	24013230	Previous observations showed that inactivation of Msh3 in mice leads to a moderate defect in the repair of insertion/deletion but not base-base mismatches, which might explain the absence of MSH3 mutations in HNPCC/LS families.	('repair', 'MPA', (97, 103))	('inactivation', 'Var', (34, 46))	('defect', 'NegReg', (83, 89))	('Msh3', 'Gene', (50, 54))	('mice', 'Species', '10090', (58, 62))	('insertion/deletion', 'Var', (107, 125))	('HNPCC', 'Disease', 'None', (209, 214))	('MSH3', 'Gene', (191, 195))	('HNPCC', 'Disease', (209, 214))
82100	24013230	Among other tumors, Msh3-/- mice developed gastrointestinal tumors late in life, which corresponds with loss of MSH3 expression in late onset sporadic colorectal cancer (CRC) in humans.	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gastrointestinal tumors', 'Disease', (43, 66))	('sporadic colorectal cancer', 'Disease', (142, 168))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (43, 66))	('mice', 'Species', '10090', (28, 32))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('sporadic colorectal cancer', 'Disease', 'MESH:D015179', (142, 168))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('Msh3-/-', 'Var', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('humans', 'Species', '9606', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', (60, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (43, 66))	('MSH3', 'Gene', (112, 116))	('developed', 'PosReg', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
82103	24013230	MSH3 polymorphisms were found to be associated with sporadic colorectal, prostate, and lung cancer.	('sporadic colorectal', 'Disease', (52, 71))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('MSH3', 'Gene', (0, 4))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('associated', 'Reg', (36, 46))	('polymorphisms', 'Var', (5, 18))	('prostate', 'Disease', (73, 81))
82106	24013230	Previous studies in mice showed that loss of Msh2 is sufficient to initiate and significantly accelerate tumorigenesis, especially in p53-deficient mice, and that tumorigenesis is associated with an MSI-high (MSI-H) phenotype.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('Msh2', 'Gene', (45, 49))	('p53', 'Gene', '22060', (134, 137))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('MSI-H', 'Disease', (209, 214))	('mice', 'Species', '10090', (148, 152))	('accelerate', 'PosReg', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (163, 168))	('loss', 'Var', (37, 41))	('MSI-H', 'Disease', 'MESH:D000848', (209, 214))	('p53', 'Gene', (134, 137))	('tumor', 'Disease', (105, 110))
82107	24013230	The MSH2-MSH6 complex is essential for the repair of base/base mismatches, and loss of either MSH2 or MSH6 therefore results in generation of a severe mutator phenotype and early onset cancers.	('MSH6', 'Gene', (102, 106))	('loss', 'Var', (79, 83))	('severe mutator phenotype', 'MPA', (144, 168))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('early', 'Disease', (173, 178))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('MSH2', 'Gene', (94, 98))	('results in', 'Reg', (117, 127))
82108	24013230	In contrast, the absence of MSH3 mutations in early onset HNPCC/LS tumors and the late onset tumor phenotype in Msh3-/- mice indicate that MSH3 is likely not involved in tumor initiation.	('HNPCC/LS tumors', 'Disease', 'MESH:D007888', (58, 73))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('mice', 'Species', '10090', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('HNPCC/LS tumors', 'Disease', (58, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (33, 42))	('tumor initiation', 'Disease', 'MESH:D009369', (170, 186))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('tumor initiation', 'Disease', (170, 186))	('MSH3', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
82111	24013230	We found that due to its role in DSBR rather than MMR, loss of Msh3 alters the tumor spectrum in p53 mutant mice by modulating the characteristics of the chromosomal instability (CIN) phenotype, resulting in elevated sarcomagenesis.	('loss', 'Var', (55, 59))	('mice', 'Species', '10090', (108, 112))	('DSBR', 'Chemical', '-', (33, 37))	('Msh3', 'Gene', (63, 67))	('p53', 'Gene', (97, 100))	('alters', 'Reg', (68, 74))	('CIN', 'Disease', (179, 182))	('sarcoma', 'Disease', 'MESH:D012509', (217, 224))	('p53', 'Gene', '22060', (97, 100))	('sarcoma', 'Disease', (217, 224))	('elevated', 'PosReg', (208, 216))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('modulating', 'Reg', (116, 126))	('CIN', 'Phenotype', 'HP:0040012', (179, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('chromosomal instability', 'Phenotype', 'HP:0040012', (154, 177))	('mutant', 'Var', (101, 107))	('CIN', 'Disease', 'MESH:D007674', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
82112	24013230	We conclude that germline mutations in Msh3 can cause late onset tumorigenesis with various genomic signatures and modulate the tumor spectrum on cancer predisposing backgrounds.	('cancer', 'Disease', (146, 152))	('modulate', 'Reg', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', (65, 70))	('cause', 'Reg', (48, 53))	('germline mutations', 'Var', (17, 35))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Msh3', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
82113	24013230	To accelerate tumorigenesis in Msh3 null mice and study tumor progression, we intercrossed Msh3+/- and p53+/- knockout mice and generated two cohorts of mutant mice carrying homozygous mutations in Msh3 and either homozygous (Msh3-/-p53-/-) or heterozygous (Msh3-/-p53+/-) mutations in p53.	('p53', 'Gene', (265, 268))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('p53', 'Gene', '22060', (233, 236))	('p53', 'Gene', '22060', (265, 268))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Msh3', 'Gene', (198, 202))	('p53', 'Gene', (103, 106))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Disease', (56, 61))	('p53', 'Gene', (286, 289))	('mice', 'Species', '10090', (160, 164))	('p53', 'Gene', '22060', (103, 106))	('p53', 'Gene', '22060', (286, 289))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('mice', 'Species', '10090', (119, 123))	('tumor', 'Disease', (14, 19))	('accelerate', 'PosReg', (3, 13))	('mutations', 'Var', (273, 282))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutations', 'Var', (185, 194))	('p53', 'Gene', (233, 236))
82116	24013230	Msh3-/-p53+/- and p53+/- mice also showed similar survival rates (p = .11), suggesting that loss of Msh3 does not contribute to the initiation or acceleration of tumorigenesis.	('Msh3', 'Gene', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('p53', 'Gene', (18, 21))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('p53', 'Gene', '22060', (7, 10))	('p53', 'Gene', '22060', (18, 21))	('loss', 'Var', (92, 96))	('p53', 'Gene', (7, 10))
82119	24013230	Surprisingly, loss of Msh3 induced a significant shift in the distribution of the various tumor types in p53 mutant mice: twice as many sarcomas were found in Msh3-/-p53-/- (32% vs. 17%, p = .04) and Msh3-/-p53+/- mice (53% vs. 30%, p = .04, Figure 1b) compared to tumors from p53-/- and p53+/- mice, respectively.	('sarcomas', 'Disease', (136, 144))	('p53', 'Gene', (288, 291))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '22060', (288, 291))	('p53', 'Gene', '22060', (105, 108))	('mice', 'Species', '10090', (116, 120))	('loss', 'Var', (14, 18))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', (90, 95))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '22060', (207, 210))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('p53', 'Gene', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('Msh3', 'Gene', (22, 26))	('mutant', 'Var', (109, 115))	('p53', 'Gene', (277, 280))	('p53', 'Gene', '22060', (166, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('mice', 'Species', '10090', (295, 299))	('p53', 'Gene', '22060', (277, 280))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (265, 271))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('mice', 'Species', '10090', (214, 218))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))
82122	24013230	When tumors were analyzed for their MSI phenotype, which is the hallmark of MMR-deficiency, we found that most tumors from Msh2-/-p53-/- or Msh2-/-p53+/- mice showed MSI at the D7Mit91 and D17Mit123 dinucleotide repeats, compared to few tumors with MSI from Msh3-/-p53 mutant mice(Figure 1c).	('p53', 'Gene', (265, 268))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('p53', 'Gene', '22060', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumors', 'Disease', (111, 117))	('p53', 'Gene', '22060', (265, 268))	('p53', 'Gene', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('D7Mit91', 'Var', (177, 184))	('p53', 'Gene', '22060', (130, 133))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('MMR-deficiency', 'Disease', (76, 90))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mice', 'Species', '10090', (154, 158))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('D17Mit123 dinucleotide repeats', 'Var', (189, 219))	('tumors', 'Disease', (5, 11))	('dinucleotide', 'Chemical', 'MESH:D015226', (199, 211))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('mice', 'Species', '10090', (276, 280))	('MMR-deficiency', 'Disease', 'MESH:C536143', (76, 90))	('p53', 'Gene', (147, 150))
82125	24013230	During tumorigenesis, MMR deficiency leads to the accumulation of somatic mutations in tumor suppressor genes and oncogenes.	('deficiency', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (7, 12))	('MMR', 'Gene', (22, 25))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('accumulation', 'PosReg', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
82128	24013230	Consistent with the MMR-deficient phenotype, the majority of Msh2-/-p53+/- tumors (63%, 12/19, Table 1) showed mutation of p53.	('p53', 'Gene', '22060', (123, 126))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('p53', 'Gene', '22060', (68, 71))	('showed', 'Reg', (104, 110))	('p53', 'Gene', (123, 126))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('p53', 'Gene', (68, 71))	('mutation', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
82129	24013230	All p53 exons were sequenced, and mutations were found in exons 4, 5, 7, 8, 9, and 11 of Msh2-/-p53+/- tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('p53', 'Gene', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('p53', 'Gene', '22060', (96, 99))	('p53', 'Gene', '22060', (4, 7))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('p53', 'Gene', (4, 7))	('mutations', 'Var', (34, 43))
82130	24013230	In contrast, no p53 mutations were detected in the Msh3-/-p53+/- tumors (0/8); however, LOH at the wild type p53 allele occurred in almost all of the tumors (86%, 6/7) (Figure 1d and Table 1), suggesting a possible role for MSH3 in CIN.	('tumors', 'Disease', (150, 156))	('p53', 'Gene', '22060', (109, 112))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('CIN', 'Disease', 'MESH:D007674', (232, 235))	('p53', 'Gene', '22060', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('p53', 'Gene', (16, 19))	('CIN', 'Phenotype', 'HP:0040012', (232, 235))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('p53', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('CIN', 'Disease', (232, 235))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '22060', (16, 19))	('LOH', 'Var', (88, 91))
82132	24013230	In yeast, MSH2-MSH3 is involved in the processing of SSA recombination intermediates during certain forms of homologous recombination, and loss of this function might result in defective DSBR and contribute to the LOH phenotype in the tumors of Msh2-/-p53+/- and Msh3-/-p53+/- mice.	('mice', 'Species', '10090', (277, 281))	('p53', 'Gene', '22060', (270, 273))	('defective', 'NegReg', (177, 186))	('DSBR', 'Chemical', '-', (187, 191))	('DSBR', 'MPA', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('p53', 'Gene', '22060', (252, 255))	('loss', 'Var', (139, 143))	('p53', 'Gene', (252, 255))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('p53', 'Gene', (270, 273))	('contribute', 'Reg', (196, 206))	('yeast', 'Species', '4932', (3, 8))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Disease', (235, 241))	('result', 'Reg', (167, 173))
82134	24013230	Msh3-/- and Msh2-/- MEFs both showed a significant increase in chromatid breaks (Figures 2a and 2b), further indicating a defective DSBR response.	('increase', 'PosReg', (51, 59))	('Msh2-/-', 'Var', (12, 19))	('chromatid breaks', 'CPA', (63, 79))	('DSBR', 'Chemical', '-', (132, 136))	('defective', 'NegReg', (122, 131))	('MEFs', 'CellLine', 'CVCL:9115', (20, 24))	('chromatid breaks', 'Phenotype', 'HP:0040012', (63, 79))	('Msh3-/-', 'Var', (0, 7))	('DSBR response', 'CPA', (132, 145))
82137	24013230	We did not observe a difference in the number of gammaH2AX foci one hour after irradiation (Figure S1), which suggests that both wild type and Msh3-/- MEFs had a comparable accumulation of DSBs at early time-points and that gammaH2AX signaling is intact in Msh3-/- cells.	('gammaH2AX', 'Gene', (224, 233))	('DSBs', 'Chemical', 'MESH:C007563', (189, 193))	('gammaH2AX', 'Gene', '15270', (49, 58))	('DSBs', 'MPA', (189, 193))	('gammaH2AX', 'Gene', (49, 58))	('MEFs', 'CellLine', 'CVCL:9115', (151, 155))	('gammaH2AX', 'Gene', '15270', (224, 233))	('accumulation', 'PosReg', (173, 185))	('Msh3-/- MEFs', 'Var', (143, 155))
82140	24013230	Taken together, these data demonstrate a moderate DSBR defect in Msh3-deficient cells that is revealed by a delay in resolving DSBs.	('Msh3-deficient', 'Gene', (65, 79))	('Msh3-deficient', 'Var', (65, 79))	('DSBR', 'Disease', (50, 54))	('defect', 'NegReg', (55, 61))	('DSBR', 'Chemical', '-', (50, 54))	('DSBs', 'Chemical', 'MESH:C007563', (127, 131))
82141	24013230	To examine whether loss of MSH3 does lead to chromosomal instability during tumorigenesis, we used spectral karyotyping (SKY) to determine whether lymphomas of Msh3-deficient mice displayed any gross chromosomal abnormalities.	('mice', 'Species', '10090', (175, 179))	('lymphomas of Msh3-deficient', 'Disease', 'MESH:D008223', (147, 174))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('lead to', 'Reg', (37, 44))	('lymphomas of Msh3-deficient', 'Disease', (147, 174))	('lymphomas', 'Phenotype', 'HP:0002665', (147, 156))	('chromosomal instability', 'Phenotype', 'HP:0040012', (45, 68))	('MSH3', 'Gene', (27, 31))	('lymphoma', 'Phenotype', 'HP:0002665', (147, 155))	('chromosomal abnormalities', 'Disease', (200, 225))	('loss', 'Var', (19, 23))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (200, 225))	('chromosomal instability', 'MPA', (45, 68))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
82143	24013230	However, the type of chromosomal changes between genotypes tended to be different: Msh3-/-p53-/- and Msh2-/-p53-/- tumor cells showed about two times more translocations compared to p53-/- cells (1.2 and 0.9 vs. 0.5 per cell, Table 2), suggesting that the DSBR defect associated with loss of the MSH2-MSH3 complex that was observed earlier contributes to this type of chromosomal rearrangement.	('p53', 'Gene', (90, 93))	('MSH2-MSH3', 'Gene', (296, 305))	('p53', 'Gene', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('p53', 'Gene', '22060', (182, 185))	('tumor', 'Disease', (115, 120))	('p53', 'Gene', '22060', (90, 93))	('p53', 'Gene', '22060', (108, 111))	('loss', 'Var', (284, 288))	('DSBR', 'Chemical', '-', (256, 260))	('translocations', 'MPA', (155, 169))	('p53', 'Gene', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
82144	24013230	In contrast, a trend towards slightly higher numbers of deletions and duplications was observed in Msh3-/-p53-/- and p53-/- cells compared to Msh2-/-p53-/- cells, reflecting the aneuploidy phenotype that is associated with the p53-/- tumor background.	('p53', 'Gene', (227, 230))	('p53', 'Gene', (149, 152))	('tumor', 'Disease', (234, 239))	('p53', 'Gene', (117, 120))	('aneuploidy', 'Disease', 'MESH:D000782', (178, 188))	('p53', 'Gene', '22060', (106, 109))	('p53', 'Gene', '22060', (227, 230))	('deletions', 'Var', (56, 65))	('p53', 'Gene', '22060', (149, 152))	('p53', 'Gene', '22060', (117, 120))	('higher', 'PosReg', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('aneuploidy', 'Disease', (178, 188))	('p53', 'Gene', (106, 109))	('duplications', 'Var', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
82146	24013230	Since loss of Msh3 induces sarcomagenesis we also analyzed two groups of Msh3-/-p53+/- and p53-/- sarcomas (Figure S2).	('sarcoma', 'Disease', (27, 34))	('Msh3', 'Gene', (14, 18))	('sarcomas', 'Disease', (98, 106))	('loss', 'Var', (6, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('p53', 'Gene', (80, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('p53', 'Gene', (91, 94))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcomas', 'Disease', 'MESH:D012509', (98, 106))	('sarcoma', 'Disease', (98, 105))	('p53', 'Gene', '22060', (80, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('induces', 'Reg', (19, 26))	('p53', 'Gene', '22060', (91, 94))
82153	24013230	Taken together, these results confirm that loss of MSH3, but not MSH2, is associated with an increase in overall chromosomal instability in tumor genomes and that the amount of CIN depends on the underlying predisposing genetic background and the tissue-specific context.	('CIN', 'Disease', 'MESH:D007674', (177, 180))	('increase', 'PosReg', (93, 101))	('chromosomal instability', 'MPA', (113, 136))	('CIN', 'Phenotype', 'HP:0040012', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('MSH3', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('loss', 'Var', (43, 47))	('CIN', 'Disease', (177, 180))	('chromosomal instability', 'Phenotype', 'HP:0040012', (113, 136))	('tumor', 'Disease', (140, 145))
82154	24013230	The MMR proteins MSH2, MSH6, MLH1 and PMS2 all play a major and well-described role in mismatch repair, and mutations in these genes have been found in patients with HNPCC/LS.	('mismatch repair', 'MPA', (87, 102))	('MSH2', 'Gene', (17, 21))	('HNPCC', 'Disease', 'None', (166, 171))	('mutations', 'Var', (108, 117))	('HNPCC', 'Disease', (166, 171))	('PMS2', 'Gene', (38, 42))	('PMS2', 'Gene', '5395', (38, 42))	('MSH6', 'Gene', (23, 27))	('found', 'Reg', (143, 148))	('MLH1', 'Gene', '4292', (29, 33))	('patients', 'Species', '9606', (152, 160))	('MLH1', 'Gene', (29, 33))
82156	24013230	Although intestinal tumors developed in Msh3 and Mlh3 knockout mice late in life, these proteins appear to have a less pronounced role in MMR and tumor suppression.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('knockout', 'Var', (54, 62))	('intestinal tumors', 'Disease', 'MESH:D007414', (9, 26))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('mice', 'Species', '10090', (63, 67))	('Mlh3', 'Gene', (49, 53))	('Mlh3', 'Gene', '217716', (49, 53))	('Msh3', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('intestinal tumors', 'Disease', (9, 26))	('tumor', 'Disease', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
82160	24013230	In this study, we showed that in mice loss of Msh3 leads to accumulation of unrepaired DSBs, and to a shift in tumor spectrum with increased CIN on a p53-driven tumor predisposing background.	('loss', 'Var', (38, 42))	('tumor', 'Disease', (161, 166))	('p53', 'Gene', '22060', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('increased', 'PosReg', (131, 140))	('DSBs', 'Chemical', 'MESH:C007563', (87, 91))	('CIN', 'Phenotype', 'HP:0040012', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Msh3', 'Gene', (46, 50))	('shift', 'Reg', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (111, 116))	('p53', 'Gene', (150, 153))	('CIN', 'Disease', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mice', 'Species', '10090', (33, 37))	('CIN', 'Disease', 'MESH:D007674', (141, 144))	('accumulation', 'PosReg', (60, 72))
82161	24013230	As described before, mice with combined Msh2 and p53 ablation show independent segregation of the MSI phenotype compared to p53-/- alone, which suggests that loss of Msh2 is dominant over the p53-/- phenotype.	('loss', 'Var', (158, 162))	('p53', 'Gene', (124, 127))	('p53', 'Gene', (49, 52))	('mice', 'Species', '10090', (21, 25))	('p53', 'Gene', '22060', (192, 195))	('ablation', 'Var', (53, 61))	('Msh2', 'Gene', (166, 170))	('p53', 'Gene', '22060', (49, 52))	('p53', 'Gene', '22060', (124, 127))	('Msh2', 'Gene', (40, 44))	('p53', 'Gene', (192, 195))
82165	24013230	Interestingly, loss of p53 did not accelerate gastrointestinal tumorigenesis of Msh3-/- mice since we only detected a small number of gastrointestinal carcinomas in Msh3/p53 mutant mice (Figure 1b).	('tumor', 'Disease', (63, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (151, 161))	('p53', 'Gene', '22060', (23, 26))	('mice', 'Species', '10090', (181, 185))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (134, 161))	('gastrointestinal carcinomas', 'Disease', 'MESH:D004067', (134, 161))	('gastrointestinal carcinomas', 'Disease', (134, 161))	('p53', 'Gene', (170, 173))	('loss', 'Var', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('p53', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mice', 'Species', '10090', (88, 92))	('p53', 'Gene', '22060', (170, 173))	('mutant', 'Var', (174, 180))
82166	24013230	Since loss of MSH3 is associated with a variety of human cancer types, its effects might be evident on other predisposing backgrounds, implicating MSH3 as a general modulator of cancer phenotypes.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('loss', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (57, 63))	('human', 'Species', '9606', (51, 56))	('cancer', 'Disease', (178, 184))	('MSH3', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('associated', 'Reg', (22, 32))
82167	24013230	The contribution of Msh3 deletion to tumorigenesis, however, depends on the genetic context and subsequent mechanism of tumorigenesis in different tissues, since Msh3-/-Apc1638N mice did not show a different tumor onset or phenotype compared to Apc1638N mice.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('mice', 'Species', '10090', (178, 182))	('mice', 'Species', '10090', (254, 258))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('deletion', 'Var', (25, 33))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Msh3', 'Gene', (20, 24))	('tumor', 'Disease', (120, 125))
82168	24013230	Due to the strong aneuploidy phenotype caused by loss of p53 it was not immediately clear whether loss of Msh3 contributed to the increase in CIN in Msh3-/-p53-/- tumors.	('p53', 'Gene', '22060', (57, 60))	('loss', 'Var', (49, 53))	('aneuploidy', 'Disease', (18, 28))	('CIN', 'Phenotype', 'HP:0040012', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('p53', 'Gene', (156, 159))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('aneuploidy', 'Disease', 'MESH:D000782', (18, 28))	('CIN', 'Disease', (142, 145))	('increase', 'PosReg', (130, 138))	('loss', 'Var', (98, 102))	('p53', 'Gene', (57, 60))	('CIN', 'Disease', 'MESH:D007674', (142, 145))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('p53', 'Gene', '22060', (156, 159))	('Msh3', 'Gene', (106, 110))
82169	24013230	However, although there were not enough tumor samples available for SKY analysis, we observed differences between tumors with combined Msh3/p53 deficiency and single p53 deficiency with a trend towards an increase in the average number of translocations per cell for Msh3-/-p53-/- tumors compared to p53-/- alone, indicating defective DSBR caused by loss of the MSH2-MSH3 complex in these tumors.	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('translocations', 'MPA', (239, 253))	('increase', 'PosReg', (205, 213))	('p53', 'Gene', '22060', (140, 143))	('tumors', 'Disease', (389, 395))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (281, 286))	('DSBR', 'Chemical', '-', (335, 339))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Disease', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (389, 395))	('differences', 'Reg', (94, 105))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('p53', 'Gene', (166, 169))	('tumor', 'Disease', (389, 394))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('p53', 'Gene', '22060', (166, 169))	('tumor', 'Disease', (40, 45))	('deficiency', 'Var', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (389, 394))	('tumors', 'Disease', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('DSBR', 'Disease', (335, 339))	('deficiency', 'Var', (144, 154))	('p53', 'Gene', (300, 303))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('p53', 'Gene', (274, 277))	('tumors', 'Phenotype', 'HP:0002664', (389, 395))	('tumors', 'Disease', (114, 120))	('p53', 'Gene', '22060', (300, 303))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '22060', (274, 277))
82170	24013230	This defect in DSBR was also visible when we counted chromosomal aberrations in metaphase spreads, showing a significant increase in chromatid breaks in Msh3-/- and Msh2-/- MEFs.	('MEFs', 'CellLine', 'CVCL:9115', (173, 177))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (53, 76))	('increase', 'PosReg', (121, 129))	('Msh3-/-', 'Var', (153, 160))	('chromatid breaks', 'Phenotype', 'HP:0040012', (133, 149))	('DSBR', 'Chemical', '-', (15, 19))	('Msh2-/- MEFs', 'Var', (165, 177))	('chromatid breaks', 'CPA', (133, 149))
82171	24013230	Interestingly, here the number of translocations was not significantly different between wild type, Msh3-/- and Msh2-/- MEFs, which might be due to technical difficulties with scoring translocations in regular metaphase spreads.	('Msh2-/-', 'Var', (112, 119))	('MEFs', 'CellLine', 'CVCL:9115', (120, 124))	('Msh3-/-', 'Var', (100, 107))
82172	24013230	Alternatively, this data suggests that loss of MSH2-MSH3-dependent DSBR results in an increase in the number of translocations during the clonal outgrowth of p53-deficient tumors and contributes to p53-driven tumorigenesis.	('tumor', 'Disease', (172, 177))	('p53-deficient tumors', 'Disease', 'MESH:D009369', (158, 178))	('loss', 'Var', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('increase', 'PosReg', (86, 94))	('tumor', 'Disease', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('p53', 'Gene', (158, 161))	('MSH2-MSH3-dependent', 'Gene', (47, 66))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('p53', 'Gene', '22060', (158, 161))	('contributes to', 'Reg', (183, 197))	('p53', 'Gene', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('p53', 'Gene', '22060', (198, 201))	('DSBR', 'Chemical', '-', (67, 71))	('p53-deficient tumors', 'Disease', (158, 178))	('DSBR', 'Gene', (67, 71))
82173	24013230	The amount of chromosomal instability represented by CNV, however, is significantly increased in Msh3-/-p53+/- tumors (Figure 4 and Figure S2) compared to the CNV phenotype in p53+/- tumors from our previous study which indicates that loss of Msh3 is contributing to the chromosomal instability phenotype in Msh3-/-p53+/- tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('chromosomal instability', 'Phenotype', 'HP:0040012', (271, 294))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', (111, 117))	('increased', 'PosReg', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('tumors', 'Disease', (183, 189))	('chromosomal instability', 'MPA', (14, 37))	('p53', 'Gene', (104, 107))	('p53', 'Gene', (176, 179))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('p53', 'Gene', '22060', (104, 107))	('loss', 'Var', (235, 239))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('p53', 'Gene', '22060', (176, 179))	('tumors', 'Disease', (322, 328))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('chromosomal instability', 'Phenotype', 'HP:0040012', (14, 37))	('p53', 'Gene', (315, 318))	('chromosomal instability', 'MPA', (271, 294))	('Msh3', 'Gene', (243, 247))	('tumors', 'Disease', 'MESH:D009369', (322, 328))	('p53', 'Gene', '22060', (315, 318))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
82175	24013230	Msh2-deficient mice display a strong MMR defect with accumulation of mutations and low chromosomal instability, indicating the essential role for MSH2 in MMR.	('mutations', 'Var', (69, 78))	('defect', 'NegReg', (41, 47))	('chromosomal instability', 'Phenotype', 'HP:0040012', (87, 110))	('MMR', 'CPA', (37, 40))	('Msh2-deficient', 'Gene', (0, 14))	('mice', 'Species', '10090', (15, 19))	('chromosomal instability', 'CPA', (87, 110))	('accumulation', 'PosReg', (53, 65))
82178	24013230	Interestingly, loss of MSH3 was shown to be associated with accelerated tumor progression in MLH1-deficient colorectal cancers, and it was suggested that the effect of MSH3 loss on tumor progression might be related to another function of MSH3 unrelated to MMR, implicating its role in DNA DSBR by SSA.	('MLH1-deficient colorectal cancers', 'Disease', (93, 126))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (181, 186))	('MSH3', 'Gene', (23, 27))	('tumor', 'Disease', (72, 77))	('accelerated', 'PosReg', (60, 71))	('MLH1-deficient colorectal cancers', 'Disease', 'MESH:D015179', (93, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('loss', 'Var', (15, 19))	('loss', 'NegReg', (173, 177))	('DSBR', 'Chemical', '-', (290, 294))	('MSH3', 'Gene', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
82181	24013230	Despite the moderate defect in DSBR Msh3 deficient mice showed a significant increase in sarcomagenesis, suggesting that loss of MSH3 targets sarcoma tumor suppressor genes and modulates p53-dependent tumorigenesis.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('sarcoma', 'Disease', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('sarcoma tumor', 'Disease', (142, 155))	('mice', 'Species', '10090', (51, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('increase', 'PosReg', (77, 85))	('tumor', 'Disease', (201, 206))	('sarcoma tumor', 'Disease', 'MESH:D012509', (142, 155))	('DSBR', 'Chemical', '-', (31, 35))	('MSH3', 'Gene', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('tumor', 'Disease', (150, 155))	('p53', 'Gene', (187, 190))	('loss', 'Var', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('p53', 'Gene', '22060', (187, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('modulates', 'Reg', (177, 186))
82184	24013230	This indicates that loss of Msh3 causes a repair defect that contributes to genomic instability in a tissue-specific manner and promotes p53-driven sarcomagenesis.	('contributes', 'Reg', (61, 72))	('Msh3', 'Gene', (28, 32))	('loss', 'Var', (20, 24))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('sarcoma', 'Disease', (148, 155))	('p53', 'Gene', '22060', (137, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('promotes', 'PosReg', (128, 136))	('genomic instability', 'MPA', (76, 95))	('p53', 'Gene', (137, 140))	('repair', 'MPA', (42, 48))
82185	24013230	Since the sarcomas in our mouse cohorts are microsatellite stable, the increase in sarcoma incidence in Msh3/p53 mutant mice is likely caused by loss of Msh3-dependent DSBR which contributes to the moderate CIN that is associated with sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('CIN', 'Phenotype', 'HP:0040012', (207, 210))	('increase', 'PosReg', (71, 79))	('mutant', 'Var', (113, 119))	('DSBR', 'Chemical', '-', (168, 172))	('CIN', 'Disease', 'MESH:D007674', (207, 210))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('sarcoma', 'Disease', (235, 242))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('sarcoma', 'Disease', (83, 90))	('loss', 'NegReg', (145, 149))	('p53', 'Gene', (109, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('sarcoma', 'Disease', 'MESH:D012509', (10, 17))	('sarcomas', 'Disease', 'MESH:D012509', (10, 18))	('CIN', 'Disease', (207, 210))	('p53', 'Gene', '22060', (109, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (10, 18))	('mice', 'Species', '10090', (120, 124))	('sarcoma', 'Disease', (10, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcomas', 'Disease', (10, 18))	('mouse', 'Species', '10090', (26, 31))
82186	24013230	However, loss of Msh3-dependent MMR might also play a role in p53-dependent sarcomagenesis by resulting in a low-level mutator phenotype that might be difficult to detect.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('p53', 'Gene', '22060', (62, 65))	('Msh3-dependent', 'Gene', (17, 31))	('low-level mutator phenotype', 'MPA', (109, 136))	('play', 'Reg', (47, 51))	('loss', 'Var', (9, 13))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('p53', 'Gene', (62, 65))
82188	24013230	In contrast to the MutSalpha complex (MSH2-MSH6), which has a dominant role in genome maintenance by MMR, MSH2-MSH3 functions both in MMR, indicated by an MSI-L phenotype, and DSBR, as has been recently shown in yeast.	('MSH2-MSH3', 'Var', (106, 115))	('MMR', 'Disease', (134, 137))	('DSBR', 'Chemical', '-', (176, 180))	('yeast', 'Species', '4932', (212, 217))
82189	24013230	Loss of MSH3 can therefore contribute to tumorigenesis in two ways: by a mild MMR defect leading to MSI-L and low-level mutation accumulation, and by a DSBR defect that leads to a moderate increase in CIN.	('low-level mutation accumulation', 'MPA', (110, 141))	('MSI-L', 'MPA', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MSH3', 'Gene', (8, 12))	('defect', 'Var', (82, 88))	('CIN', 'Disease', 'MESH:D007674', (201, 204))	('tumor', 'Disease', (41, 46))	('DSBR', 'Chemical', '-', (152, 156))	('CIN', 'Phenotype', 'HP:0040012', (201, 204))	('MMR', 'Gene', (78, 81))	('CIN', 'Disease', (201, 204))	('contribute', 'Reg', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Loss', 'Var', (0, 4))	('increase', 'PosReg', (189, 197))
82198	24013230	For MSI analysis, the D7Mit91 and D17Mit123 microsatellite loci were amplified from normal and tumor DNA and analyzed as previously described.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('D17Mit123', 'Var', (34, 43))	('tumor', 'Disease', (95, 100))	('D7Mit91', 'Var', (22, 29))
82200	24013230	To analyze tumors for p53 mutations, primers amplifying all exons of p53 (including both transcript variants of exon 11) were used as described, followed by DNA sequencing.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('p53', 'Gene', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('p53', 'Gene', (22, 25))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('mutations', 'Var', (26, 35))	('p53', 'Gene', '22060', (69, 72))	('p53', 'Gene', '22060', (22, 25))
82213	24013230	relative copy number increase (gain) or decrease (loss) according to the aCGH data.	('decrease', 'NegReg', (40, 48))	('copy number', 'Var', (9, 20))	('gain', 'Disease', (31, 35))	('increase', 'PosReg', (21, 29))	('gain', 'Disease', 'MESH:D015430', (31, 35))
82222	23761818	This indicated that IIi inhibits mTOR activity and induces autophagy.	('autophagy', 'CPA', (59, 68))	('inhibits', 'NegReg', (24, 32))	('mTOR', 'Gene', '2475', (33, 37))	('induces', 'Reg', (51, 58))	('mTOR', 'Gene', (33, 37))	('IIi', 'Var', (20, 23))
82239	23761818	The present study also showed that IIi inhibits mTOR activity and induces autophagy in breast cancer cells.	('mTOR', 'Gene', '2475', (48, 52))	('mTOR', 'Gene', (48, 52))	('induces', 'Reg', (66, 73))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('autophagy', 'CPA', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('inhibits', 'NegReg', (39, 47))	('IIi', 'Var', (35, 38))
82272	23761818	It has been reported that the mTOR inhibitors produce antitumor activities and induce autophagy, and that beta-elemene also induces autophagy in certain cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', (153, 159))	('autophagy', 'CPA', (86, 95))	('induces', 'Reg', (124, 131))	('autophagy', 'CPA', (132, 141))	('induce', 'Reg', (79, 85))	('beta-elemene', 'Chemical', 'MESH:C445979', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('inhibitors', 'Var', (35, 45))	('mTOR', 'Gene', '2475', (30, 34))	('mTOR', 'Gene', (30, 34))
82282	23761818	Structural modifications have been demonstrated to successfully increase water solubility and/or antitumor activity of several natural compounds, including salvicine, camptothecin and taxol.	('modifications', 'Var', (11, 24))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('taxol', 'Chemical', 'MESH:D017239', (184, 189))	('water solubility', 'MPA', (73, 89))	('camptothecin', 'Chemical', 'MESH:D002166', (167, 179))	('salvicine', 'Chemical', 'MESH:C122096', (156, 165))	('increase', 'PosReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('water', 'Chemical', 'MESH:D014867', (73, 78))
82300	23761818	In the present study, we also showed that IIi induces human cancer cell autophagy, in an identical manner to the mTOR inhibitor, rapamycin.	('IIi', 'Var', (42, 45))	('rapamycin', 'Chemical', 'MESH:D020123', (129, 138))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('mTOR', 'Gene', (113, 117))	('cancer', 'Disease', (60, 66))	('mTOR', 'Gene', '2475', (113, 117))	('induces', 'Reg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))
82392	31951641	We found impoverishment of oral microbial diversity and enrichment of specific microbiota in O-KS individuals compared to O-KSHV or No KSHV individuals.	('men', 'Species', '9606', (62, 65))	('oral microbial diversity', 'CPA', (27, 51))	('KSHV', 'Species', '37296', (124, 128))	('KS', 'Phenotype', 'HP:0100726', (135, 137))	('KSHV', 'Species', '37296', (135, 139))	('KS', 'Phenotype', 'HP:0100726', (124, 126))	('men', 'Species', '9606', (19, 22))	('KS', 'Phenotype', 'HP:0100726', (95, 97))	('O-KS', 'Var', (93, 97))
82393	31951641	These results suggest that HIV/KSHV coinfection and oral microbiota might impact one another and influence the development of oral KS.	('oral KS', 'Disease', (126, 133))	('KS', 'Phenotype', 'HP:0100726', (31, 33))	('KSHV', 'Species', '37296', (31, 35))	('oral KS', 'Disease', 'MESH:D012514', (126, 133))	('impact', 'Reg', (74, 80))	('KS', 'Phenotype', 'HP:0100726', (131, 133))	('coinfection', 'Var', (36, 47))	('men', 'Species', '9606', (118, 121))	('development', 'CPA', (111, 122))	('influence', 'Reg', (97, 106))
82397	31951641	We observed impoverishment of oral microbial diversity and enrichment of specific types of microbes in O-KS individuals compared to O-KSHV or No KSHV individuals.	('KS', 'Phenotype', 'HP:0100726', (134, 136))	('oral microbial diversity', 'CPA', (30, 54))	('KSHV', 'Species', '37296', (134, 138))	('men', 'Species', '9606', (65, 68))	('KS', 'Phenotype', 'HP:0100726', (145, 147))	('KSHV', 'Species', '37296', (145, 149))	('men', 'Species', '9606', (22, 25))	('O-KS', 'Var', (103, 107))	('KS', 'Phenotype', 'HP:0100726', (105, 107))
82398	31951641	Hence, HIV/KSHV coinfection and oral microbiota might impact one another and influence the development of oral KS.	('development', 'CPA', (91, 102))	('oral KS', 'Disease', (106, 113))	('KS', 'Phenotype', 'HP:0100726', (11, 13))	('influence', 'Reg', (77, 86))	('KSHV', 'Species', '37296', (11, 15))	('impact', 'Reg', (54, 60))	('oral KS', 'Disease', 'MESH:D012514', (106, 113))	('coinfection', 'Var', (16, 27))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('men', 'Species', '9606', (98, 101))
82418	31951641	Other studies also showed a positive association between Propionibacterium acnes and the development of prostate cancer.	('men', 'Species', '9606', (96, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('Propionibacterium acnes', 'Species', '1747', (57, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('acnes', 'Phenotype', 'HP:0001061', (75, 80))	('prostate cancer', 'Disease', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Propionibacterium acnes', 'Var', (57, 80))
82450	31951641	We observed a significant diminution of Pasteurellales and Burkholderiales at order level in the O-KS group compared to the O-KSHV and No KSHV groups (Fig 4A).	('O-KS', 'Var', (97, 101))	('KSHV', 'Species', '37296', (126, 130))	('KSHV', 'Species', '37296', (138, 142))	('Pasteurellales', 'CPA', (40, 54))	('KS', 'Phenotype', 'HP:0100726', (138, 140))	('diminution', 'NegReg', (26, 36))	('KS', 'Phenotype', 'HP:0100726', (126, 128))	('KS', 'Phenotype', 'HP:0100726', (99, 101))
82451	31951641	At genus level, the abundances of Aggregibacter and Lautropia were decreased in the O-KS group, whereas those of Corynebacterium and Shuttleworthia were increased (Fig 4C).	('Lautropia', 'Disease', 'None', (52, 61))	('O-KS', 'Var', (84, 88))	('increased', 'PosReg', (153, 162))	('abundances', 'MPA', (20, 30))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('Lautropia', 'Disease', (52, 61))	('decreased', 'NegReg', (67, 76))
82452	31951641	At the species level, the abundances of Dialister and Satelles were increased whereas those of Lautropia and Porphyromonas were decreased in the O-KS group (Fig 4D).	('O-KS', 'Var', (145, 149))	('KS', 'Phenotype', 'HP:0100726', (147, 149))	('Porphyromonas', 'Species', '1924944', (109, 122))	('abundances', 'MPA', (26, 36))	('Lautropia', 'Disease', (95, 104))	('decreased', 'NegReg', (128, 137))	('Lautropia', 'Disease', 'None', (95, 104))	('increased', 'PosReg', (68, 77))
82456	31951641	For examples, the abundance of Bacillales order increased in both O-KSHV and O-KS groups (Fig 4E), whereas those of Gemellaceae family and the Gemella species decreased (Fig 4F and 4G and Fig 5B).	('increased', 'PosReg', (48, 57))	('abundance', 'MPA', (18, 27))	('KS', 'Phenotype', 'HP:0100726', (79, 81))	('Bacillales', 'Protein', (31, 41))	('KSHV', 'Species', '37296', (68, 72))	('O-KSHV', 'Var', (66, 72))	('KS', 'Phenotype', 'HP:0100726', (68, 70))
82464	31951641	We indeed have observed lower CD4+ T cell counts in the O-KS group than the other two groups (Fig 1D).	('lower CD4+ T', 'Phenotype', 'HP:0005407', (24, 36))	('O-KS', 'Var', (56, 60))	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('lower', 'NegReg', (24, 29))	('CD4', 'Gene', (30, 33))	('CD4', 'Gene', '920', (30, 33))
82491	31951641	Also, and perhaps even more important, SCFA, such as sodium butyrate and valproic acid, that act as histone deacetylase (HDAC) inhibitors, can reactivate KSHV, and therefore increased butyrate production, might promote KS tumorigenesis through lytic activation of KSHV.	('KS', 'Phenotype', 'HP:0100726', (154, 156))	('reactivate', 'Var', (143, 153))	('sodium butyrate', 'Chemical', 'MESH:D020148', (53, 68))	('KSHV', 'Species', '37296', (154, 158))	('KSHV', 'Species', '37296', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('KS', 'Phenotype', 'HP:0100726', (219, 221))	('KSHV', 'Gene', (154, 158))	('butyrate', 'Chemical', 'MESH:D002087', (184, 192))	('valproic acid', 'Chemical', 'MESH:D014635', (73, 86))	('butyrate', 'Chemical', 'MESH:D002087', (60, 68))	('KS', 'Phenotype', 'HP:0100726', (264, 266))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('butyrate production', 'MPA', (184, 203))	('tumor', 'Disease', (222, 227))	('increased', 'PosReg', (174, 183))	('promote', 'PosReg', (211, 218))
82517	31567194	Pericytoma with t(7;12) and ACTB-GLI1 Fusion: Reevaluation of an Unusual Entity and its Relationship to the Spectrum of GLI1 Fusion-Related Neoplasms The entity "pericytoma with t(7;12)" was described as a rare, distinct perivascular myoid neoplasm provisionally classified within the family of myopericytic tumors that demonstrates t(7;12)(p22;q13) translocation with resultant ACTB-GLI1 fusion and biologically was felt to behave in an indolent fashion.	('ACTB', 'Gene', '60', (28, 32))	('GLI1', 'Gene', (384, 388))	('Neoplasms', 'Phenotype', 'HP:0002664', (140, 149))	('t(7;12)(p22;q13) translocation', 'Var', (333, 363))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('GLI1', 'Gene', (33, 37))	('GLI1', 'Gene', (120, 124))	('myopericytic tumors', 'Disease', 'MESH:D009369', (295, 314))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('myoid neoplasm', 'Disease', (234, 248))	('Neoplasms', 'Disease', 'MESH:D009369', (140, 149))	('GLI1', 'Gene', '2735', (384, 388))	('myopericytic tumors', 'Disease', (295, 314))	('neoplasm', 'Phenotype', 'HP:0002664', (240, 248))	('t(7;12)(p22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (333, 349))	('GLI1', 'Gene', '2735', (33, 37))	('GLI1', 'Gene', '2735', (120, 124))	('fusion', 'Var', (389, 395))	('myoid neoplasm', 'Disease', 'MESH:D009369', (234, 248))	('Neoplasms', 'Disease', (140, 149))	('ACTB', 'Gene', (379, 383))	('ACTB', 'Gene', '60', (379, 383))	('ACTB', 'Gene', (28, 32))
82518	31567194	However, a recent study showed that tumors with this and similar translocations may have variable morphology and immunohistochemical phenotype with inconsistent myopericytic characteristics and a propensity for metastasis, raising questions regarding the most appropriate classification of these neoplasms.	('translocations', 'Var', (65, 79))	('myopericytic', 'MPA', (161, 173))	('neoplasms', 'Disease', 'MESH:D009369', (296, 305))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('neoplasms', 'Disease', (296, 305))	('neoplasm', 'Phenotype', 'HP:0002664', (296, 304))	('metastasis', 'CPA', (211, 221))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('neoplasms', 'Phenotype', 'HP:0002664', (296, 305))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
82519	31567194	Herein, we report 3 additional patients with tumors harboring t(7;12) and ACTB-GLI1 fusion.	('GLI1', 'Gene', '2735', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GLI1', 'Gene', (79, 83))	('tumors', 'Disease', (45, 51))	('ACTB', 'Gene', '60', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('ACTB', 'Gene', (74, 78))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (31, 39))	('fusion', 'Var', (84, 90))
82527	31567194	in 2004 as a group of soft tissue neoplasms with distinctive pericytic features that shared the t(7;12)(p22;q13) translocation by cytogenetic analysis, the resultant unique ACTB-GLI1 fusion was considered the driving genetic abnormality.	('neoplasms', 'Disease', 'MESH:D009369', (34, 43))	('neoplasms', 'Disease', (34, 43))	('neoplasm', 'Phenotype', 'HP:0002664', (34, 42))	('GLI1', 'Gene', (178, 182))	('ACTB', 'Gene', (173, 177))	('t(7;12)(p22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (96, 112))	('ACTB', 'Gene', '60', (173, 177))	('neoplasms', 'Phenotype', 'HP:0002664', (34, 43))	('soft tissue neoplasm', 'Phenotype', 'HP:0031459', (22, 42))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (22, 43))	('fusion', 'Var', (183, 189))	('GLI1', 'Gene', '2735', (178, 182))
82528	31567194	However, recently, 6 tumors with a round to epithelioid, nested morphology harboring GLI1 gene fusions, including 4 fused to ACTB, 1 to MALAT1 and 1 to PTCH1 gene have been reported.	('PTCH1', 'Gene', '5727', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('fusions', 'Var', (95, 102))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('PTCH1', 'Gene', (152, 157))	('GLI1', 'Gene', '2735', (85, 89))	('ACTB, 1 to MALAT1 and 1', 'Gene', '378938', (125, 148))	('GLI1', 'Gene', (85, 89))
82530	31567194	The constellation of reported findings raises questions about how to best classify these neoplasms and whether tumors with ACTB-GLI1 fusion represent multiple distinct entities or different manifestations of a spectrum of tumors with variable pericytic nature and biologic potential.	('neoplasms', 'Disease', (89, 98))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('GLI1', 'Gene', '2735', (128, 132))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('GLI1', 'Gene', (128, 132))	('fusion', 'Var', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ACTB', 'Gene', '60', (123, 127))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('ACTB', 'Gene', (123, 127))	('neoplasms', 'Phenotype', 'HP:0002664', (89, 98))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('neoplasms', 'Disease', 'MESH:D009369', (89, 98))
82531	31567194	Herein, we describe 3 additional cases of neoplasms with ACTB-GLI1 fusion and expand upon the morphologic, immunophenotypic, and clinical behavior of this evolving entity.	('neoplasms', 'Disease', 'MESH:D009369', (42, 51))	('neoplasms', 'Disease', (42, 51))	('GLI1', 'Gene', (62, 66))	('ACTB', 'Gene', (57, 61))	('neoplasm', 'Phenotype', 'HP:0002664', (42, 50))	('ACTB', 'Gene', '60', (57, 61))	('neoplasms', 'Phenotype', 'HP:0002664', (42, 51))	('fusion', 'Var', (67, 73))	('GLI1', 'Gene', '2735', (62, 66))
82548	31567194	While the overall tumor size was slightly increased on MRI, the intra-osseous component showed non-enhancing, hemorrhagic, cystic components indicative of treatment effect.	('increased', 'PosReg', (42, 51))	('tumor', 'Disease', (18, 23))	('MRI', 'Var', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('hemorrhagic', 'Disease', (110, 121))	('non-enhancing', 'MPA', (95, 108))	('hemorrhagic', 'Disease', 'MESH:D006470', (110, 121))
82563	31567194	An NGS-based assay (FoundationOne , Cambridge, MA) revealed 3 genetic abnormalities: ACTB-GLI1 rearrangement, JAK2 G571S mutation, and NOTCH2 P6fs*27.	('GLI1', 'Gene', '2735', (90, 94))	('GLI1', 'Gene', (90, 94))	('genetic abnormalities', 'Disease', 'MESH:D030342', (62, 83))	('JAK2', 'Gene', '3717', (110, 114))	('NOTCH2', 'Gene', (135, 141))	('G571S', 'Mutation', 'rs139504737', (115, 120))	('ACTB', 'Gene', (85, 89))	('ACTB', 'Gene', '60', (85, 89))	('genetic abnormalities', 'Disease', (62, 83))	('NOTCH2', 'Gene', '4853', (135, 141))	('JAK2', 'Gene', (110, 114))	('rearrangement', 'Var', (95, 108))
82593	31567194	The tumor showed a low mutation burden (2 mutations/Mb), and the only definitive genomic alteration identified was t(7; 12) with GLI1-ACTB rearrangement.	('tumor', 'Disease', (4, 9))	('GLI1', 'Gene', '2735', (129, 133))	('t(7; 12', 'Var', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('GLI1', 'Gene', (129, 133))	('ACTB', 'Gene', '60', (134, 138))	('ACTB', 'Gene', (134, 138))	('rearrangement', 'Var', (139, 152))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
82601	31567194	Postulated to be a distinct subset of myopericytoma is the entity provisionally named "pericytoma with t(7;12)" which harbors a translocation involving ACTB and GLI.	('ACTB', 'Gene', '60', (152, 156))	('myopericytoma', 'Disease', 'MESH:D000077777', (38, 51))	('ACTB', 'Gene', (152, 156))	('myopericytoma', 'Disease', (38, 51))	('GLI', 'Gene', (161, 164))	('translocation', 'Var', (128, 141))	('GLI', 'Gene', '2735', (161, 164))
82607	31567194	recently described 6 tumors with round to epithelioid phenotype showing GLI1 fusions (4 with ACTB-GLI1, 1 with GLI1-MALAT1, and 1 with GLI1-PTCH1) that exhibited significant metastatic potential.	('fusions', 'Var', (77, 84))	('PTCH1', 'Gene', '5727', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('GLI1', 'Gene', (72, 76))	('GLI1', 'Gene', (111, 115))	('GLI1', 'Gene', (135, 139))	('GLI1', 'Gene', '2735', (98, 102))	('MALAT1', 'Gene', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('PTCH1', 'Gene', (140, 145))	('tumors', 'Disease', (21, 27))	('MALAT1', 'Gene', '378938', (116, 122))	('ACTB', 'Gene', (93, 97))	('metastatic', 'CPA', (174, 184))	('ACTB', 'Gene', '60', (93, 97))	('GLI1', 'Gene', '2735', (72, 76))	('GLI1', 'Gene', '2735', (111, 115))	('GLI1', 'Gene', '2735', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('GLI1', 'Gene', (98, 102))
82621	31567194	While the relatively small number of reported cases precludes definitively answering the question of whether GLI1-ACTB fusion in these round and ovoid cell tumors defines a specific entity or whether it is an alteration seen in several different types of neoplasms, it may be informative to attempt to understand how these cases were classified before the molecular information was known.	('neoplasm', 'Phenotype', 'HP:0002664', (255, 263))	('ACTB', 'Gene', '60', (114, 118))	('ovoid cell tumors', 'Disease', 'MESH:D005935', (145, 162))	('ACTB', 'Gene', (114, 118))	('fusion', 'Var', (119, 125))	('neoplasms', 'Disease', 'MESH:D009369', (255, 264))	('ovoid cell tumors', 'Disease', (145, 162))	('neoplasms', 'Disease', (255, 264))	('GLI1', 'Gene', '2735', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('GLI1', 'Gene', (109, 113))	('neoplasms', 'Phenotype', 'HP:0002664', (255, 264))
82626	31567194	One case was considered an unusual pericytic tumor despite positivity for S100 protein and negativity for SMA because of its morphologic resemblance to cellular glomus tumor and the presence of ACTB-GLI1, so it is difficult to be sure how this case would have been characterized without the genetic information.	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GLI1', 'Gene', (199, 203))	('tumor', 'Disease', (168, 173))	('ACTB', 'Gene', (194, 198))	('S100', 'Gene', '6271', (74, 78))	('positivity', 'Var', (59, 69))	('tumor', 'Disease', (45, 50))	('ACTB', 'Gene', '60', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('glomus tumor', 'Disease', (161, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('GLI1', 'Gene', '2735', (199, 203))	('glomus tumor', 'Disease', 'MESH:D005918', (161, 173))	('S100', 'Gene', (74, 78))
82631	31567194	Based on all of the reported cases, ACTB-GLI1 fusions may be characteristic of one entity, but GLI1-rearranged tumors with different fusion partners may represent related but distinct neoplasms.	('GLI1', 'Gene', (41, 45))	('ACTB', 'Gene', '60', (36, 40))	('ACTB', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('fusions', 'Var', (46, 53))	('neoplasms', 'Disease', 'MESH:D009369', (184, 193))	('tumors', 'Disease', (111, 117))	('neoplasms', 'Disease', (184, 193))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('neoplasm', 'Phenotype', 'HP:0002664', (184, 192))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('GLI1', 'Gene', '2735', (95, 99))	('GLI1', 'Gene', '2735', (41, 45))	('GLI1', 'Gene', (95, 99))	('neoplasms', 'Phenotype', 'HP:0002664', (184, 193))
82637	31567194	An increasing number of Ewing-like round cell sarcomas or undifferentiated sarcomas with round cell phenotype have been recognized, including sarcomas associated with translocations of BCOR-CCNB3 and CIC-DUX4 or CIC-FOXO4.	('BCOR', 'Gene', '54880', (185, 189))	('sarcomas', 'Disease', 'MESH:D012509', (142, 150))	('CCNB3', 'Gene', (190, 195))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('undifferentiated sarcomas', 'Disease', (58, 83))	('sarcomas', 'Disease', (142, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('translocations', 'Var', (167, 181))	('sarcomas', 'Disease', (46, 54))	('BCOR', 'Gene', (185, 189))	('associated', 'Reg', (151, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('CIC-DUX4 or CIC-FOXO4', 'Disease', (200, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('Ewing', 'Disease', (24, 29))	('CIC-DUX4 or CIC-FOXO4', 'Disease', 'None', (200, 221))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (58, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('Ewing', 'Disease', 'MESH:C563168', (24, 29))	('sarcomas', 'Disease', 'MESH:D012509', (75, 83))	('CCNB3', 'Gene', '85417', (190, 195))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))	('sarcomas', 'Disease', (75, 83))	('Ewing-like round cell sarcomas', 'Phenotype', 'HP:0012254', (24, 54))
82639	31567194	Immunohistochemically, these sarcomas may demonstrate variable patterns of CD99 positivity, unlike the diffuse, strong, membranous pattern characteristic of Ewing sarcoma.	('CD99', 'Gene', (75, 79))	('Ewing sarcoma', 'Disease', (157, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (157, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('positivity', 'Var', (80, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('sarcomas', 'Disease', (29, 37))	('CD99', 'Gene', '4267', (75, 79))
82649	31567194	While in two of our tumors GLI1-ACTB rearrangement was the only abnormal genetic abnormality detected by NGS, the tibial tumor (patient #1) also demonstrated mutations in Notch2 and JAK2.	('GLI1', 'Gene', (27, 31))	('Notch2', 'Gene', (171, 177))	('tumors', 'Disease', (20, 26))	('ACTB', 'Gene', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tibial tumor', 'Disease', 'MESH:D020429', (114, 126))	('ACTB', 'Gene', '60', (32, 36))	('JAK2', 'Gene', '3717', (182, 186))	('Notch2', 'Gene', '4853', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('patient', 'Species', '9606', (128, 135))	('rearrangement', 'Var', (37, 50))	('mutations', 'Var', (158, 167))	('tibial tumor', 'Disease', (114, 126))	('JAK2', 'Gene', (182, 186))	('GLI1', 'Gene', '2735', (27, 31))
82653	31567194	Lack of Notch signaling has been implicated in epithelial-to-mesenchymal transition, and thus this NOTCH2 mutation may have contributed to the malignant phenotype in this myopericytoma.	('myopericytoma', 'Disease', (171, 184))	('implicated', 'Reg', (33, 43))	('Lack', 'NegReg', (0, 4))	('NOTCH2', 'Gene', '4853', (99, 105))	('contributed', 'Reg', (124, 135))	('myopericytoma', 'Disease', 'MESH:D000077777', (171, 184))	('mutation', 'Var', (106, 114))	('NOTCH2', 'Gene', (99, 105))	('epithelial-to-mesenchymal transition', 'CPA', (47, 83))
82654	31567194	JAK2 encodes Janus kinase 2, a tyrosine kinase that regulates signaling initiated by cytokines and growth factors and is often mutated in hematopoietic and lymphoid malignancies.	('lymphoid malignancies', 'Disease', (156, 177))	('Janus kinase 2', 'Gene', '3717', (13, 27))	('JAK2', 'Gene', '3717', (0, 4))	('regulates signaling initiated by cytokines', 'MPA', (52, 94))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (156, 177))	('JAK2', 'Gene', (0, 4))	('mutated', 'Var', (127, 134))	('Janus kinase 2', 'Gene', (13, 27))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (156, 177))
82655	31567194	Most mutations occur at V617, but G571S has been observed in patients with myeloproliferative neoplasms and erythrocytosis.	('myeloproliferative neoplasms and erythrocytosis', 'Disease', 'MESH:D011086', (75, 122))	('erythrocytosis', 'Phenotype', 'HP:0001901', (108, 122))	('V617', 'Var', (24, 28))	('patients', 'Species', '9606', (61, 69))	('G571S', 'Mutation', 'rs139504737', (34, 39))	('G571S', 'Var', (34, 39))	('neoplasm', 'Phenotype', 'HP:0002664', (94, 102))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (75, 103))	('observed', 'Reg', (49, 57))	('neoplasms', 'Phenotype', 'HP:0002664', (94, 103))
82656	31567194	However, available evidence suggests that the G571S mutation is not a JAK2-activating mutation, and thus this finding may not be a significant contributor to the malignant phenotype of this case.	('JAK2', 'Gene', '3717', (70, 74))	('JAK2', 'Gene', (70, 74))	('G571S', 'Var', (46, 51))	('G571S', 'Mutation', 'rs139504737', (46, 51))
82657	31567194	In summary, we describe 3 new cases of mesenchymal neoplasms with translocations involving ACTB and GLI1 genes, and results support emerging evidence that tumors with this genetic abnormality have the potential to behave in a biologically aggressive fashion.	('GLI1', 'Gene', (100, 104))	('translocations', 'Var', (66, 80))	('neoplasm', 'Phenotype', 'HP:0002664', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('ACTB', 'Gene', '60', (91, 95))	('ACTB', 'Gene', (91, 95))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('mesenchymal neoplasms', 'Disease', (39, 60))	('neoplasms', 'Phenotype', 'HP:0002664', (51, 60))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (39, 60))	('GLI1', 'Gene', '2735', (100, 104))
82661	31567194	This study expands the clinicopathologic and molecular data for this exceedingly rare group of tumors and will contribute to further understanding of tumors harboring ACTB-GLI translocations.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('GLI', 'Gene', '2735', (172, 175))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('ACTB', 'Gene', (167, 171))	('ACTB', 'Gene', '60', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('GLI', 'Gene', (172, 175))	('tumors', 'Disease', (95, 101))	('translocations', 'Var', (176, 190))
82703	26019542	Concentration-response curves were prepared and the effective concentrations of the compounds - CC50 (causing a 50% reduction of cell viability) and/or CC90 (causing a 90% reduction of cell viability) were estimated.	('CC90', 'Var', (152, 156))	('cell viability', 'CPA', (185, 199))	('reduction', 'NegReg', (116, 125))	('rat', 'Species', '10116', (7, 10))	('reduction', 'NegReg', (172, 181))	('rat', 'Species', '10116', (69, 72))
82717	26019542	Among the tested compounds, Cu-UDCA and Ni-UDCA were found to be the most active cytotoxic and cytostatic agents against animal LSCC-SF-Mc29 and LSR-SF-SR cells, while Zn-UDCA was shown to significantly decrease the viability and proliferation of human tumour cell lines.	('viability', 'CPA', (216, 225))	('UDCA', 'Chemical', 'MESH:D014580', (43, 47))	('human', 'Species', '9606', (247, 252))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('UDCA', 'Chemical', 'MESH:D014580', (171, 175))	('tumour', 'Disease', (253, 259))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('decrease', 'NegReg', (203, 211))	('UDCA', 'Chemical', 'MESH:D014580', (31, 35))	('Ni-UDCA', 'Var', (40, 47))	('rat', 'Species', '10116', (237, 240))	('proliferation', 'CPA', (230, 243))	('Zn', 'Chemical', 'MESH:D015032', (168, 170))
82745	32516921	DFSP has characteristic t(17; 22) (q22; q13), resulting in a COL1A1- PDGFB fusion transcripts in more than 90% of DFSPs.	('DFSP', 'Disease', (0, 4))	('fusion', 'Var', (75, 81))	('COL1A1', 'Gene', '1277', (61, 67))	('COL1A1', 'Gene', (61, 67))	('DFSP', 'Disease', 'MESH:D018223', (0, 4))	('DFSP', 'Disease', (114, 118))	('PDGFB', 'Gene', '5155', (69, 74))	('DFSP', 'Disease', 'MESH:D018223', (114, 118))	('PDGFB', 'Gene', (69, 74))
82768	32516921	Cytogenetic and molecular studies have demonstrated that more than 90% of DFSPs are characterized by either supernumerary ring chromosomes derived from chromosomes 17 and 22 or chromosomal translocation t(17; 22) (q22; q13), resulting in the fusion of collagen type 1-alpha 1(COL1A1 at 17q22) and platelet-derived growth factor beta (PDGFB at 22q13) genes.	('PDGFB', 'Gene', '5155', (334, 339))	('PDGFB', 'Gene', (334, 339))	('COL1A1', 'Gene', (276, 282))	('COL1A1', 'Gene', '1277', (276, 282))	('DFSP', 'Disease', (74, 78))	('fusion', 'Var', (242, 248))	('DFSP', 'Disease', 'MESH:D018223', (74, 78))
82775	32516921	FISH analysis revealed genetic translocations involving the CSPG2 gene at 5q14.3 and PTK2B gene at 8p21.2 in a patient of DFSP without the COL1A1-PDGFB fusion transcript.	('DFSP', 'Disease', (122, 126))	('COL1A1', 'Gene', (139, 145))	('PDGFB', 'Gene', (146, 151))	('DFSP', 'Disease', 'MESH:D018223', (122, 126))	('COL1A1', 'Gene', '1277', (139, 145))	('PTK2B', 'Gene', (85, 90))	('CSPG2', 'Gene', '1462', (60, 65))	('patient', 'Species', '9606', (111, 118))	('PTK2B', 'Gene', '2185', (85, 90))	('CSPG2', 'Gene', (60, 65))	('PDGFB', 'Gene', '5155', (146, 151))	('translocations', 'Var', (31, 45))
82777	32516921	Moreover, p53 mutation and overexpression, murine double minute 2 (MDM2) overexpression were reported in fibrosarcomatous variant of DFSP.	('murine double minute 2', 'Gene', '17246', (43, 65))	('murine double minute 2', 'Gene', (43, 65))	('DFSP', 'Disease', 'MESH:D018223', (133, 137))	('MDM2', 'Gene', (67, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('fibrosarcomatous', 'Disease', 'MESH:D018223', (105, 121))	('p53', 'Gene', '22060', (10, 13))	('mutation', 'Var', (14, 22))	('fibrosarcomatous', 'Disease', (105, 121))	('MDM2', 'Gene', '17246', (67, 71))	('DFSP', 'Disease', (133, 137))	('overexpression', 'PosReg', (73, 87))	('p53', 'Gene', (10, 13))
82779	32516921	In addition, pregnancy may increase the risk for the development of DFSP.	('men', 'Species', '9606', (60, 63))	('DFSP', 'Disease', (68, 72))	('DFSP', 'Disease', 'MESH:D018223', (68, 72))	('pregnancy', 'Var', (13, 22))
82816	32516921	These variants reflect the morphologic heterogeneity which is associated with the spindle cell differentiation during tumor development.	('variants', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('men', 'Species', '9606', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))
82832	32516921	Multiple studies have shown that MMS can significantly lower the risk of recurrence of DFSP, compared with WLE.	('DFSP', 'Disease', 'MESH:D018223', (87, 91))	('MMS', 'Var', (33, 36))	('DFSP', 'Disease', (87, 91))	('lower', 'NegReg', (55, 60))
82863	32516921	Imatinib mesylate (IM) is a potent and specific protein tyrosine kinase inhibitor interfering with the phosphorylation and activation of the PDGF receptor beta which is constitutively activated due to translocation and fusion between PDGFB and COL1A1 genes as discussed in Pathogenesis section.	('COL1A1', 'Gene', (244, 250))	('interfering', 'NegReg', (82, 93))	('PDGFB', 'Gene', (234, 239))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('fusion', 'Var', (219, 225))	('COL1A1', 'Gene', '1277', (244, 250))	('PDGF receptor beta', 'Gene', (141, 159))	('activation', 'PosReg', (123, 133))	('phosphorylation', 'MPA', (103, 118))	('PDGFB', 'Gene', '5155', (234, 239))
82872	32516921	The efficacy of IM was observed in localized and metastatic DFSP with t(17; 22), but not in FS-DFSP lacking t(17; 22).	('DFSP', 'Disease', (95, 99))	('DFSP', 'Disease', 'MESH:D018223', (95, 99))	('t(17; 22', 'Var', (70, 78))	('DFSP', 'Disease', (60, 64))	('FS-DFSP', 'Disease', (92, 99))	('FS-DFSP', 'Disease', 'MESH:D018223', (92, 99))	('localized', 'Disease', (35, 44))	('DFSP', 'Disease', 'MESH:D018223', (60, 64))
82890	32516921	In vitro and in vivo studies demonstrated the effectiveness of CDK4/6 inhibitors PD-0332991 and LEE011 in inhibiting DFSP105 proliferation, suggesting that CDK4/6 inhibitors can be potential drugs in p16 negative FS-DFSP.	('DFSP105', 'Gene', (117, 124))	('LEE011', 'Var', (96, 102))	('DFSP105', 'Chemical', '-', (117, 124))	('CDK4/6', 'Gene', (156, 162))	('inhibiting', 'NegReg', (106, 116))	('PD-0332991', 'Chemical', 'MESH:C500026', (81, 91))	('p16', 'Gene', '1029', (200, 203))	('LEE011', 'Chemical', 'MESH:C000589651', (96, 102))	('CDK4/6', 'Gene', '1019;1021', (63, 69))	('FS-DFSP', 'Disease', (213, 220))	('PD-0332991', 'Var', (81, 91))	('FS-DFSP', 'Disease', 'MESH:D018223', (213, 220))	('CDK4/6', 'Gene', '1019;1021', (156, 162))	('p16', 'Gene', (200, 203))	('CDK4/6', 'Gene', (63, 69))
82901	32516921	A vast majority harbor t(17; 22) (q22; q13) resulting in the formation of COL1A1-PDGFB fusion gene transcript, which holds not only diagnostic value, but also therapeutic significance.	('t(17; 22) (q22; q13', 'Var', (23, 42))	('PDGFB', 'Gene', '5155', (81, 86))	('COL1A1', 'Gene', '1277', (74, 80))	('COL1A1', 'Gene', (74, 80))	('PDGFB', 'Gene', (81, 86))	('resulting in', 'Reg', (44, 56))
82957	31054582	We found that nearly all S180 and MDA-MB-231 cancer cells were captured at a zeta potential of + 25 mV, while normal white blood cells (WBCs) were not (Additional file 1: Figure S1).	('MDA-MB-231', 'Gene', (34, 44))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (34, 44))	('S180', 'Var', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
83071	28300912	Phototherapy induces local and systemic immunosuppression by DNA damage, Langerhans cell reduction and altered cellular immunity, with consequent generation of cytokines and T-cells with suppressing activities.	('cellular immunity', 'CPA', (111, 128))	('altered', 'Reg', (103, 110))	('cytokines', 'MPA', (160, 169))	('Langerhans cell reduction', 'Disease', (73, 98))	('Langerhans cell reduction', 'Disease', 'MESH:D054752', (73, 98))	('Phototherapy', 'Var', (0, 12))
83076	24121124	p62 (SQSTM1) is a key component of autophagic machinery which is also involved in signal transduction.	('SQSTM1', 'Gene', (5, 11))	('p62', 'Var', (0, 3))	('SQSTM1', 'Gene', '18412', (5, 11))
83079	24121124	Based on this result, we hypothesized that p62 may be a feasible candidate to be an anti-cancer DNA vaccine.	('p62', 'Var', (43, 46))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
83081	24121124	In mice challenged with Ca755 cells, p62 treatment had dual effect: inhibited tumor growth in some mice and prolonged life in those mice which developed tumor size similar to control.	('mice', 'Species', '10090', (99, 103))	('p62', 'Var', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mice', 'Species', '10090', (3, 7))	('inhibited', 'NegReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('life', 'CPA', (118, 122))	('tumor', 'Disease', (153, 158))	('prolonged', 'PosReg', (108, 117))	('mice', 'Species', '10090', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
83099	24121124	Here we describe a novel DNA vaccine based on p62 protein (sequestome 1) that is critical for cancer and dispensable for normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('p62', 'Var', (46, 49))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
83100	24121124	p62 performs two major functions in the cell - it is involved in autophagy, and serves as a signaling hub for several signal transduction pathways such as NF-kB, p38, TRAF6, protein kinases etc.	('TRAF6', 'Gene', '22034', (167, 172))	('involved', 'Reg', (53, 61))	('autophagy', 'CPA', (65, 74))	('p38', 'Gene', (162, 165))	('protein kinases', 'Pathway', (174, 189))	('p62', 'Var', (0, 3))	('p38', 'Gene', '217737', (162, 165))	('TRAF6', 'Gene', (167, 172))
83102	24121124	Indeed, the absence of p62 in the knockout mice completely prevented the emergence of cancer.	('p62', 'Gene', (23, 26))	('mice', 'Species', '10090', (43, 47))	('absence', 'Var', (12, 19))	('prevented', 'NegReg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('emergence of', 'CPA', (73, 85))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
83105	24121124	Based on high intratumoral p62 level, together with the fact that p62 is indispensable for tumor formation and/or progression, we hypothesized that p62 may provide significant benefits as a potent antigen candidate for selective DNA vaccine, which a cancer would not be able to escape.	('benefits', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Disease', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('p62', 'Var', (148, 151))	('tumor', 'Disease', (91, 96))
83117	24121124	Of note, expression of Ras oncogene in MCF10A cells leads to their transformation.	('expression', 'Var', (9, 19))	('Ras oncogene', 'Gene', (23, 35))	('MCF10A', 'CellLine', 'CVCL:0598', (39, 45))	('leads to', 'Reg', (52, 60))	('transformation', 'CPA', (67, 81))	('MCF10A', 'Gene', (39, 45))
83119	24121124	Thus, elevated levels of p62 in cancers are likely to be a direct consequence of the expression of oncogenes.	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('p62', 'Var', (25, 28))	('levels', 'MPA', (15, 21))	('elevated', 'PosReg', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
83123	24121124	Since human melanoma and lung cancer demonstrated the highest levels of p62 overexpression as compared to normal tissues (see above Fig.	('human', 'Species', '9606', (6, 11))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('p62', 'Var', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
83134	24121124	Administered according to this schedule, p62 DNA vaccine demonstrated significant inhibition of growth of B16 melanoma primary tumors (Fig.	('p62 DNA vaccine', 'Var', (41, 56))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('melanoma primary tumors', 'Disease', 'MESH:D008545', (110, 133))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('melanoma primary tumors', 'Disease', (110, 133))	('B16', 'CPA', (106, 109))	('growth', 'MPA', (96, 102))	('inhibition', 'NegReg', (82, 92))
83139	24121124	Ca755 is a rapidly growing tumor which lead to 50% mortality in control group within 25 days after the challenge (Fig.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Ca755', 'Var', (0, 5))
83140	24121124	In this model, we observed two different effects of p62 DNA vaccination on a primary tumor.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('p62 DNA', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
83146	24121124	Overall, in all four mouse models of solid tumors, p62 vaccine demonstrated potent suppression of tumor growth.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('suppression', 'NegReg', (83, 94))	('p62 vaccine', 'Var', (51, 62))	('mouse', 'Species', '10090', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('solid tumors', 'Disease', 'MESH:D009369', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (43, 48))	('solid tumors', 'Disease', (37, 49))
83154	24121124	Importantly, p62 vaccine decreased both the number of small and large metastases to a similar extent, indicating that the treatment prevents formation of new metastases instead of just inhibiting growth of already established metastases.	('prevents', 'NegReg', (132, 140))	('metastases', 'Disease', 'MESH:D009362', (226, 236))	('growth', 'CPA', (196, 202))	('inhibiting', 'NegReg', (185, 195))	('metastases', 'Disease', (70, 80))	('metastases', 'Disease', 'MESH:D009362', (70, 80))	('decreased', 'NegReg', (25, 34))	('metastases', 'Disease', (158, 168))	('p62 vaccine', 'Var', (13, 24))	('metastases', 'Disease', (226, 236))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
83161	24121124	As seen in Fig.6, p62 vaccine caused significant decrease both the number of lung metastasis, and their size.	('decrease both the number of lung metastasis', 'Disease', 'MESH:D009362', (49, 92))	('decrease both the number of lung metastasis', 'Disease', (49, 92))	('p62 vaccine', 'Var', (18, 29))
83162	24121124	We conclude that p62 may serve as an antigen for a broad-spectrum anti-cancer vaccine.	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('p62', 'Var', (17, 20))
83177	24121124	Tumor cells were injected subcutaneously in the leg in the amount of 7x105 for LLC, 3x105 for B16 melanoma, and 1x106 per mouse for S37 sarcoma and Ca755 breast carcinoma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('S37 sarcoma', 'Disease', 'MESH:D012509', (132, 143))	('breast carcinoma', 'Disease', (154, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('breast carcinoma', 'Disease', 'MESH:D001943', (154, 170))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('Ca755', 'Var', (148, 153))	('melanoma', 'Disease', (98, 106))	('S37 sarcoma', 'Disease', (132, 143))	('breast carcinoma', 'Phenotype', 'HP:0003002', (154, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('mouse', 'Species', '10090', (122, 127))
83182	23323048	Anticancer and Immunopotentiating Activities of Crude Polysaccharides from Pleurotus nebrodensis on Mouse Sarcoma 180 Pleurotus nebrodensis is an edible and commercially available mushroom in Korea.	('Anticancer', 'CPA', (0, 10))	('Mouse', 'Species', '10090', (100, 105))	('Immunopotentiating Activities', 'CPA', (15, 44))	('Sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Sarcoma', 'Disease', (106, 113))	('mushroom', 'Species', '5341', (180, 188))	('Sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('Polysaccharides', 'Chemical', 'MESH:D011134', (54, 69))	('Pleurotus nebrodensis', 'Var', (118, 139))	('Pleurotus nebrodensis', 'Species', '228216', (118, 139))	('Pleurotus nebrodensis', 'Species', '228216', (75, 96))
83199	23323048	Chemical modification has been reported to enhance the immunopotentiation and antitumor activities of polysaccharides, due to the change of substituent groups and chain conformation of polysaccharides.	('substituent groups', 'MPA', (140, 158))	('immunopotentiation', 'CPA', (55, 73))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Chemical modification', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('polysaccharides', 'Chemical', 'MESH:D011134', (102, 117))	('tumor', 'Disease', (82, 87))	('polysaccharides', 'Chemical', 'MESH:D011134', (185, 200))	('enhance', 'PosReg', (43, 50))	('change', 'Reg', (130, 136))
83277	23323048	Maximum cell viabilities on sarcoma 180, HT-29, NIH3T3, and RAW 264.7 of Fr.	('NIH3T3', 'Var', (48, 54))	('sarcoma', 'Disease', (28, 35))	('NIH3T3', 'CellLine', 'CVCL:0594', (48, 54))	('cell viabilities', 'CPA', (8, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('RAW 264.7', 'CellLine', 'CVCL:0493', (60, 69))	('HT-29', 'CellLine', 'CVCL:0320', (41, 46))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))
83307	23323048	The results of this study suggested that beta-glucan of P. nebrodensis can improve the immune response of the host via stimulating proliferation of immune organs, murine spleen cells.	('P. nebrodensis', 'Species', '228216', (56, 70))	('P. nebrodensis', 'Var', (56, 70))	('beta-glucan', 'Protein', (41, 52))	('stimulating', 'Reg', (119, 130))	('proliferation of immune organs', 'CPA', (131, 161))	('beta-glucan', 'Chemical', 'MESH:D047071', (41, 52))	('immune response', 'CPA', (87, 102))	('improve', 'PosReg', (75, 82))	('murine', 'Species', '10090', (163, 169))
83312	23323048	The results of this study demonstrated that beta-glucan of P. nebrodensis can induce an increase in production of NO and can improve the immune response in ICR mice.	('P. nebrodensis', 'Species', '228216', (59, 73))	('P. nebrodensis', 'Var', (59, 73))	('immune response', 'CPA', (137, 152))	('increase', 'PosReg', (88, 96))	('production of NO', 'MPA', (100, 116))	('beta-glucan', 'Chemical', 'MESH:D047071', (44, 55))	('mice', 'Species', '10090', (160, 164))	('improve', 'PosReg', (125, 132))	('beta-glucan', 'Protein', (44, 55))
83332	22438986	Additionally, our data showing that Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('Hiwi', 'Gene', '9271', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('promote', 'PosReg', (212, 219))	('Hiwi', 'Gene', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('Hiwi', 'Gene', '9271', (36, 40))	('tumor', 'Disease', (132, 137))	('Hiwi', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('genomic integrity', 'CPA', (220, 237))	('tumor', 'Disease', (343, 348))	('hyper-methylation', 'Var', (56, 73))
83335	22438986	Specifically, previous studies have shown that transposon-specific DNA-methylation was reduced and transposon activity was elevated following silencing of Hiwi (or its orthologs).	('silencing', 'Var', (142, 151))	('transposon-specific DNA-methylation', 'MPA', (47, 82))	('Hiwi', 'Gene', '9271', (155, 159))	('transposon activity', 'MPA', (99, 118))	('reduced', 'NegReg', (87, 94))	('Hiwi', 'Gene', (155, 159))	('elevated', 'PosReg', (123, 131))
83336	22438986	Although transposons promote evolutionary diversity in lower organisms, their unchecked migration in higher organisms can result in disruption of genomic integrity and thus Piwi proteins may have developed as an evolutionary defense system for multi-cellular species.	('genomic integrity', 'CPA', (146, 163))	('evolutionary diversity', 'CPA', (29, 51))	('promote', 'PosReg', (21, 28))	('transposons', 'Var', (9, 20))	('Piwi', 'Gene', (173, 177))	('Piwi', 'Gene', '9271', (173, 177))
83343	22438986	We go on to show that Hiwi mediated DNA methylation is associated with tumor suppressor gene silencing, thus potentially accounting for Hiwi-mediated tumorigenesis.	('Hiwi', 'Gene', (136, 140))	('tumor suppressor', 'Gene', (71, 87))	('DNA methylation', 'Var', (36, 51))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('Hiwi', 'Gene', '9271', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor suppressor', 'Gene', '7248', (71, 87))	('Hiwi', 'Gene', '9271', (22, 26))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (150, 155))	('Hiwi', 'Gene', (22, 26))	('silencing', 'NegReg', (93, 102))
83366	22438986	Although we realize this is a low tumor incidence, it is still significantly higher than deletion of the retinoblastoma tumor suppressor under the same promoter; suggesting to us that the low incidence rate may under-represent Hiwi's tumorigenic potential in this model.	('retinoblastoma', 'Phenotype', 'HP:0009919', (105, 119))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (34, 39))	('Hiwi', 'Gene', '9271', (227, 231))	('Hiwi', 'Gene', (227, 231))	('tumor suppressor', 'Gene', (120, 136))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('deletion', 'Var', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('low tumor', 'Disease', 'MESH:D009800', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor suppressor', 'Gene', '7248', (120, 136))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (120, 125))	('low tumor', 'Disease', (30, 39))
83424	22438986	Additionally, our data show that Hiwi-mediated methylation is associated with DNA hyper-methylation with subsequent genetic and epigenetic changes that favor a tumorigenic state, reconciling the outstanding conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis.	('genomic integrity', 'CPA', (262, 279))	('Hiwi', 'Gene', '9271', (224, 228))	('favor', 'PosReg', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('Hiwi', 'Gene', (224, 228))	('associated', 'Reg', (62, 72))	('methylation', 'Var', (47, 58))	('tumor', 'Disease', (385, 390))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('Hiwi', 'Gene', '9271', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('promote', 'PosReg', (254, 261))	('Hiwi', 'Gene', (33, 37))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (385, 390))
83438	22438986	DNA methylation at repetitive element regions has been previously reported to result in long distance gene silencing via chromatin remodeling and given previous reports that Piwi proteins associate with small RNAs (piRNAs) with homology to repetitive elements may explain the lack of gene promoter methylation observed in our systems.	('Piwi', 'Gene', (174, 178))	('Piwi', 'Gene', '9271', (174, 178))	('associate', 'Interaction', (188, 197))	('methylation', 'Var', (4, 15))	('gene', 'MPA', (102, 106))	('silencing', 'NegReg', (107, 116))
83440	22438986	To examine the possibility of Hiwi-mediated histone methylation changes, we performed immunofluorescence staining for various histone marks (Figure S13A-F) on our dox-ind-sh-Hiwi MFH cells.	('Hiwi', 'Gene', (30, 34))	('Hiwi', 'Gene', '9271', (174, 178))	('Hiwi', 'Gene', (174, 178))	('MFH', 'Gene', (179, 182))	('S13A', 'SUBSTITUTION', 'None', (148, 152))	('dox-ind', 'Chemical', '-', (163, 170))	('MFH', 'Gene', '27086', (179, 182))	('S13A', 'Var', (148, 152))	('Hiwi', 'Gene', '9271', (30, 34))
83445	22438986	Thus the global hypomethylation observed in cancer is believed to predominantly occur via repetitive element hypomethylation (which accounts for a significant portion of the human genome; reviewed extensively in).	('human', 'Species', '9606', (174, 179))	('repetitive element hypomethylation', 'Var', (90, 124))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
83448	22438986	The data presented here are, to our knowledge, the first to define a causative oncogenic role for Hiwi in human cancer and to elucidate that DNA methylation dependent silencing of tumor suppressor genes accounts for the tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('human', 'Species', '9606', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor suppressor', 'Gene', '7248', (180, 196))	('tumor', 'Disease', (180, 185))	('silencing', 'NegReg', (167, 176))	('methylation', 'Var', (145, 156))	('Hiwi', 'Gene', '9271', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('Hiwi', 'Gene', (98, 102))	('tumor suppressor', 'Gene', (180, 196))
83449	22438986	In doing so, we not only reconcile Hiwi's genomic protective and tumorigenic properties but also provide a therapeutic rationale for treating patients with Hiwi-expressing tumors epigenetically by means of DNA-methyltransferase inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (65, 70))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', (172, 177))	('epigenetically', 'Var', (179, 193))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('Hiwi', 'Gene', '9271', (35, 39))	('Hiwi', 'Gene', '9271', (156, 160))	('Hiwi', 'Gene', (35, 39))	('Hiwi', 'Gene', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
83462	22438986	Nitrocellulose membranes were incubated overnight at 4 C in primary antibody: DNMT1 (1:500, abcam 92453); DNMT3a (1:500, abgent AP1034a); MDB2 (1:1000, abcam 38646); Hiwi (1:500 ProSci 45-735P).	('1:500', 'Var', (85, 90))	('DNMT3a', 'Gene', (106, 112))	('DNMT1', 'Gene', (78, 83))	('DNMT1', 'Gene', '1786', (78, 83))	('1:500', 'Var', (114, 119))	('DNMT3a', 'Gene', '1788', (106, 112))	('Hiwi', 'Gene', '9271', (166, 170))	('Hiwi', 'Gene', (166, 170))	('1:1000', 'Var', (144, 150))
83489	33316779	Soft tissue sarcomas occur with great frequency in patients with specific mutations, such as the APC mutation and TP53 mutation.	('mutation', 'Var', (119, 127))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('TP53', 'Gene', '7157', (114, 118))	('Soft tissue sarcomas', 'Phenotype', 'HP:0030448', (0, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('patients', 'Species', '9606', (51, 59))	('APC', 'Disease', 'MESH:D011125', (97, 100))	('TP53', 'Gene', (114, 118))	('sarcomas', 'Disease', (12, 20))	('APC', 'Disease', (97, 100))
83507	33316779	We explored the relationship between the mutations of these genes and the immune scores and found that the mutation status was not correlated with immune scores (Figure 1D-1I, Student's t test), indicating that the main type of mutation in sarcoma might not cause specific changes in immune infiltration.	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('sarcoma', 'Disease', (240, 247))	('mutation', 'Var', (228, 236))	('sarcoma', 'Disease', 'MESH:D012509', (240, 247))
83508	33316779	Consistently, patients in the low-stromal-score group were significantly worse off in their overall survival times compared to the high-score group (Figure 1K, P=0.035).	('patients', 'Species', '9606', (14, 22))	('worse off', 'NegReg', (73, 82))	('overall survival times', 'CPA', (92, 114))	('low-stromal-score', 'Var', (30, 47))
83542	33316779	For sarcoma patients with low MHC-I expression, their overall survival and event-free survival significantly worsened compared with those in the high-expression group.	('patients', 'Species', '9606', (12, 20))	('sarcoma', 'Disease', (4, 11))	('worsened', 'NegReg', (109, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('low', 'Var', (26, 29))	('overall survival', 'CPA', (54, 70))	('MHC-I', 'Gene', (30, 35))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('event-free survival', 'CPA', (75, 94))	('expression', 'MPA', (36, 46))
83576	32928933	Our findings suggest that genetic variation associated with ancestry may play a stronger role than area-level SES-related factors in the etiology of sarcoma.	('genetic variation', 'Var', (26, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('sarcoma', 'Disease', (149, 156))	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))
83581	32928933	These include genetic predisposition from both rare variants, some of which underlie cancer predisposition syndromes, and common variants.	('underlie', 'Reg', (76, 84))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('variants', 'Var', (52, 60))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
83587	32928933	SES can serve as a proxy for locally varying environmental and lifestyle factors that influence health, whereas racial/ethnic disparities that are independent of SES may indicate that genetic variants associated with ancestry contribute to tumor development.	('tumor', 'Disease', (240, 245))	('contribute', 'Reg', (226, 236))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('genetic variants', 'Var', (184, 200))
83601	32928933	Age at diagnosis was categorized into 9 age-groups (0 - 9 years, 10 - 19 years, 20 - 29 years, 30 - 39 years, 40 - 49 years, 50 - 64 years, 65 - 74 years, 75 - 84 years, 85 +).	('50 - 64 years', 'Var', (125, 138))	('Age', 'Gene', '5973', (0, 3))	('age', 'Gene', '5973', (40, 43))	('age', 'Gene', (40, 43))	('Age', 'Gene', (0, 3))
83619	32928933	However, the results from CT-SES evaluated as an ordinal variable may have obscured a potential non-linear association in the incidence of F/MF tumors; the IRR comparing CT-SES Q2 vs Q1 (IRR: 1.37 ,99% CI: 0.97, 1.94) appeared higher than the IRR comparing CT-SES Q3 vs Q1 (IRR: 1.04, 99% CI: 0.71, 1.52; Supplementary Table 3).	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('CT-SES', 'Chemical', '-', (170, 176))	('CT-SES', 'Var', (170, 176))	('CT-SES', 'Chemical', '-', (26, 32))	('CT-SES', 'Chemical', '-', (257, 263))	('F/MF tumors', 'Disease', 'OMIM:102510', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('F/MF tumors', 'Disease', (139, 150))
83630	32928933	Among AIAN/API children, the IRRs that reached statistical significance (3 of 7 subtypes) were all less than 1, with some subtypes showing incidence rates that were nearly 50% lower in AIAN/API compared to NH-white children (e.g.	('lower', 'NegReg', (176, 181))	('children', 'Species', '9606', (15, 23))	('AIAN/API', 'Var', (185, 193))	('children', 'Species', '9606', (215, 223))
83634	32928933	For example, the incidence of UPS was lower in older adults identified as NH-black (IRR: 0.48, 99% CI: 0.35, 0.64) and Hispanic (IRR: 0.65, 95% CI 0.52, 0.8) compared to NH-white older adults, but showed no difference in incidence across these racial/ethnic categories in adults.	('UPS', 'Gene', (30, 33))	('NH-black', 'Var', (74, 82))	('lower', 'NegReg', (38, 43))	('UPS', 'Gene', '3145', (30, 33))
83636	32928933	In all age groups, the incidence of (F -) and (F +) sarcomas in NH-black or Hispanic individuals compared to NH-white individuals were heterogeneous.	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('age', 'Gene', (7, 10))	('NH-black', 'Var', (64, 72))	('sarcomas', 'Disease', (52, 60))	('age', 'Gene', '5973', (7, 10))
83650	32928933	For example, it is hypothesized that individuals diagnosed with (F -) sarcomas more often harbor rare, pathogenic germline genetic variants than those with (F +) sarcomas, as evidenced by the increased frequency with which (F -) sarcoma cases are diagnosed in cancer predisposition syndromes and as secondary cancers.	('sarcoma', 'Disease', (70, 77))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('secondary cancers', 'Disease', 'MESH:D009369', (299, 316))	('variants', 'Var', (131, 139))	('sarcoma', 'Disease', (229, 236))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('cancers', 'Phenotype', 'HP:0002664', (309, 316))	('cancer', 'Disease', (309, 315))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('sarcomas', 'Disease', 'MESH:D012509', (162, 170))	('sarcoma', 'Disease', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('cancer', 'Disease', (260, 266))	('sarcomas', 'Disease', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('secondary cancers', 'Disease', (299, 316))
83708	31392182	From pathological point of view, high proliferative index, overexpression of p53, and SYT-SSX fusions are high risk for recurrences.	('high', 'Var', (33, 37))	('p53', 'Gene', '7157', (77, 80))	('p53', 'Gene', (77, 80))	('overexpression', 'PosReg', (59, 73))	('SYT', 'Gene', '6857', (86, 89))	('SYT', 'Gene', (86, 89))
83736	30580374	First, data on ES of bone was retrieved based on the International Classification of Diseases for Oncology, third edition (ICD-O-3; histologic type: 9260 and site code: C40.0-40.3, C40.8-41.4, C41.8-41.9), using the case-listing procedure.	('C40.8-41.4', 'Var', (181, 191))	('C41.8-41.9', 'CellLine', 'CVCL:2253', (193, 203))	('Oncology', 'Phenotype', 'HP:0002664', (98, 106))	('ES', 'Phenotype', 'HP:0012254', (15, 17))	('C40.0-40.3', 'Var', (169, 179))
83775	30580374	found that male sex was associated with decreased CSS at 10 years, but it was not an independent prognostic factor.	('CSS', 'Disease', (50, 53))	('decreased', 'NegReg', (40, 49))	('CSS', 'Chemical', '-', (50, 53))	('male sex', 'Var', (11, 19))
83824	29511155	Relevant ancillary test findings included lower hemoglobin of 10.3 g/dL, positive fecal occult blood, high erythrocyte sedimentation rate (ESR) of 80 mm/hour and C-reactive protein of 17.6 mg/dL; tests were negative for fever-filtering tests, thyroid function tests, and tumor markers (CA19-19, NSE, CEA, SCC, beta-HCG, AFP, CA72-4, c-PSA, CA125, CA153, CK19, CA242).	('SCC', 'Disease', (305, 308))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('CA19-19', 'Disease', (286, 293))	('CEA', 'Gene', (300, 303))	('NSE', 'Gene', (295, 298))	('CA242', 'Chemical', '-', (360, 365))	('CK19', 'Gene', (354, 358))	('CA125', 'Gene', '94025', (340, 345))	('lower', 'NegReg', (42, 47))	('CA153', 'Gene', '4582', (347, 352))	('CK19', 'Gene', '3880', (354, 358))	('CEA', 'Gene', '1084', (300, 303))	('fever', 'Disease', 'MESH:D005334', (220, 225))	('high erythrocyte sedimentation', 'Phenotype', 'HP:0003565', (102, 132))	('fever', 'Disease', (220, 225))	('CA242', 'Var', (360, 365))	('c-PSA', 'Disease', (333, 338))	('high erythrocyte', 'Phenotype', 'HP:0001901', (102, 118))	('tumor', 'Disease', (271, 276))	('fever', 'Phenotype', 'HP:0001945', (220, 225))	('CA19-19', 'Disease', 'MESH:C567026', (286, 293))	('hemoglobin', 'MPA', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('CA125', 'Gene', (340, 345))	('lower hemoglobin', 'Phenotype', 'HP:0001903', (42, 58))	('CA153', 'Gene', (347, 352))	('NSE', 'Gene', '2026', (295, 298))
83830	29511155	The proliferation index by Ki67 was 20%.	('Ki67', 'Var', (27, 31))	('proliferation', 'CPA', (4, 17))	('Ki67', 'Chemical', '-', (27, 31))
83959	22520978	Binding of IGF1 to the alpha subunit of IGF1R triggers a conformational change that causes activation of the catalytic domain in the intracellular beta subunit causing tyrosine autophosphorylation and transphosphorylation (Y1131, Y1135, and Y1136) that enhances its tyrosine kinase activity.	('tyrosine', 'Chemical', 'MESH:D014443', (168, 176))	('tyrosine autophosphorylation', 'MPA', (168, 196))	('enhances', 'PosReg', (253, 261))	('activation', 'PosReg', (91, 101))	('Y1135', 'Var', (230, 235))	('Y1131', 'Var', (223, 228))	('IGF1R', 'Gene', (40, 45))	('tyrosine kinase activity', 'MPA', (266, 290))	('catalytic domain in', 'MPA', (109, 128))	('tyrosine', 'Chemical', 'MESH:D014443', (266, 274))	('IGF1R', 'Gene', '3480', (40, 45))	('transphosphorylation', 'MPA', (201, 221))	('Y1136', 'Var', (241, 246))	('conformational', 'MPA', (57, 71))	('Binding', 'Interaction', (0, 7))
83962	22520978	Ultimately, activation of IGF1R results in increased cell proliferation and decreased apoptosis.	('IGF1R', 'Gene', (26, 31))	('decreased', 'NegReg', (76, 85))	('increased', 'PosReg', (43, 52))	('activation', 'Var', (12, 22))	('IGF1R', 'Gene', '3480', (26, 31))	('cell proliferation', 'CPA', (53, 71))	('apoptosis', 'CPA', (86, 95))
83970	22520978	Individuals with supra-physiologic levels of GH (acromegaly) appear to have an increased risk for cancer development, possibly via an IGF1-mediated mechanism.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('acromegaly', 'Disease', (49, 59))	('acromegaly', 'Phenotype', 'HP:0000845', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('supra-physiologic levels', 'Var', (17, 41))	('acromegaly', 'Disease', 'MESH:D000172', (49, 59))	('cancer', 'Disease', (98, 104))	('GH', 'Gene', '2688', (45, 47))
83977	22520978	In the case of Beckwith-Widemann syndrome, loss of imprinting results in marked IGF2 overexpression resulting in fetal and neonatal overgrowth.	('Beckwith-Widemann syndrome', 'Disease', (15, 41))	('overexpression', 'PosReg', (85, 99))	('IGF2', 'Gene', (80, 84))	('loss', 'Var', (43, 47))	('overgrowth', 'Phenotype', 'HP:0001548', (132, 142))	('Beckwith-Widemann syndrome', 'Disease', 'MESH:D001506', (15, 41))
83978	22520978	Many tumor types harbor bi-allelic expression of IGF2 via this mechanism, including Wilms tumor, esophageal carcinoma, Ewing's sarcoma, rhabdomyosarcoma, colorectal carcinoma, osteosarcoma, prostate adenocarcinoma, hepatocellular carcinoma and adrenocortical carcinoma.	('Wilms tumor', 'Phenotype', 'HP:0002667', (84, 95))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (244, 268))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('osteosarcoma', 'Phenotype', 'HP:0002669', (176, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('adrenocortical carcinoma', 'Disease', (244, 268))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (97, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('colorectal carcinoma', 'Disease', (154, 174))	('tumor', 'Disease', (90, 95))	('Wilms tumor', 'Disease', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('rhabdomyosarcoma', 'Disease', (136, 152))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (154, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('bi-allelic', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('IGF2', 'Gene', (49, 53))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (215, 239))	('osteosarcoma, prostate adenocarcinoma, hepatocellular carcinoma', 'Disease', 'MESH:D012516', (176, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (119, 134))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (136, 152))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (97, 117))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (136, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (244, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('Wilms tumor', 'Disease', 'MESH:D009396', (84, 95))	('esophageal carcinoma', 'Disease', (97, 117))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (5, 10))	("Ewing's sarcoma", 'Disease', (119, 134))
83989	22520978	Increased IGF1R copy number was found in small cell lung cancer.	('small cell lung cancer', 'Disease', 'MESH:D055752', (41, 63))	('copy number', 'Var', (16, 27))	('Increased IGF1R', 'Phenotype', 'HP:0030269', (0, 15))	('small cell lung cancer', 'Disease', (41, 63))	('Increased', 'PosReg', (0, 9))	('IGF1R', 'Gene', (10, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('IGF1R', 'Gene', '3480', (10, 15))
83999	22520978	Many preclinical studies have shown sensitization of cancer cell lines to chemotherapy agents by silencing or blocking IGF1R.	('silencing', 'Var', (97, 106))	('cancer', 'Disease', (53, 59))	('blocking', 'NegReg', (110, 118))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('IGF1R', 'Gene', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('IGF1R', 'Gene', '3480', (119, 124))
84001	22520978	In breast cancer cells, IGF1R blockade improved the response to taxol and doxorubicin.	('response to taxol', 'MPA', (52, 69))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('blockade', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('IGF1R', 'Gene', (24, 29))	('improved', 'PosReg', (39, 47))	('IGF1R', 'Gene', '3480', (24, 29))	('taxol', 'Chemical', 'MESH:D017239', (64, 69))
84007	22520978	Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents such as mitoxantrone, etoposide, and nitrogen mustard in prostate cancer cells.	('etoposide', 'Chemical', 'MESH:D005047', (94, 103))	('mitoxantrone', 'Chemical', 'MESH:D008942', (80, 92))	('sensitivity to DNA-damaging agents', 'MPA', (37, 71))	('enhances', 'PosReg', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('etoposide', 'MPA', (94, 103))	('mustard in prostate cancer', 'Disease', 'MESH:D011471', (118, 144))	('IGF1R', 'Gene', (17, 22))	('mustard in prostate cancer', 'Disease', (118, 144))	('mitoxantrone', 'MPA', (80, 92))	('Silencing', 'Var', (0, 9))	('prostate cancer', 'Phenotype', 'HP:0012125', (129, 144))	('IGF1R', 'Gene', '3480', (17, 22))
84009	22520978	Given its link to DNA repair pathway, it is not surprising that IGF1R inhibition can enhance the effect of radiation therapy.	('DNA repair pathway', 'Pathway', (18, 36))	('IGF1R', 'Gene', (64, 69))	('inhibition', 'Var', (70, 80))	('IGF1R', 'Gene', '3480', (64, 69))	('enhance', 'PosReg', (85, 92))
84010	22520978	IGF1R knockdown results in decreased ATM expression, while defective ATM kinase activity is associated with reduced expression of IGF1R.	('expression', 'MPA', (116, 126))	('ATM', 'Gene', '472', (69, 72))	('ATM', 'Gene', (37, 40))	('reduced', 'NegReg', (108, 115))	('decreased', 'NegReg', (27, 36))	('defective', 'NegReg', (59, 68))	('IGF1R', 'Gene', (130, 135))	('IGF1R', 'Gene', (0, 5))	('IGF1R', 'Gene', '3480', (130, 135))	('ATM', 'Gene', '472', (37, 40))	('ATM', 'Gene', (69, 72))	('knockdown', 'Var', (6, 15))	('IGF1R', 'Gene', '3480', (0, 5))
84011	22520978	These findings are consistent with clinical data in breast cancer, where a higher rate of tumor recurrence after surgery and radiation was seen in patients whose primary tumors showed high IGF1R expression.	('high IGF1', 'Phenotype', 'HP:0030269', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', (170, 175))	('primary tumors', 'Disease', 'MESH:D009369', (162, 176))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('high IGF1R', 'Phenotype', 'HP:0030269', (184, 194))	('tumor', 'Disease', (90, 95))	('patients', 'Species', '9606', (147, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('IGF1R', 'Gene', '3480', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('IGF1R', 'Gene', (189, 194))	('breast cancer', 'Disease', (52, 65))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('expression', 'MPA', (195, 205))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('primary tumors', 'Disease', (162, 176))	('high', 'Var', (184, 188))
84017	22520978	Moreover, IGF1R inhibitors have been able to inhibit growth of tamoxifen-resistant breast cancer cell lines in vitro.	('inhibitors', 'Var', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('tamoxifen', 'Chemical', 'MESH:D013629', (63, 72))	('IGF1R', 'Gene', (10, 15))	('growth', 'CPA', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('inhibit', 'NegReg', (45, 52))	('IGF1R', 'Gene', '3480', (10, 15))
84024	22520978	In addition, IGF1R silencing markedly increased apoptosis of gefitinib-treated cell lines.	('silencing', 'Var', (19, 28))	('IGF1R', 'Gene', (13, 18))	('IGF1R', 'Gene', '3480', (13, 18))	('apoptosis', 'CPA', (48, 57))	('gefitinib', 'Chemical', 'MESH:D000077156', (61, 70))	('increased', 'PosReg', (38, 47))
84034	22520978	There was a significant concern about hyperglycemia, since blockade of IGF1R causes a compensatory increase in the levels of GH, which can induce insulin resistance and stimulation of gluconeogenesis.	('insulin', 'Gene', '3630', (146, 153))	('IGF1R', 'Gene', (71, 76))	('GH', 'Gene', '2688', (125, 127))	('gluconeogenesis', 'MPA', (184, 199))	('insulin resistance', 'Phenotype', 'HP:0000855', (146, 164))	('hyperglycemia', 'Phenotype', 'HP:0003074', (38, 51))	('IGF1R', 'Gene', '3480', (71, 76))	('hyperglycemia', 'Disease', 'MESH:D006943', (38, 51))	('increase', 'PosReg', (99, 107))	('induce', 'Reg', (139, 145))	('stimulation', 'PosReg', (169, 180))	('blockade', 'Var', (59, 67))	('stimulation of gluconeogenesis', 'Phenotype', 'HP:0005959', (169, 199))	('hyperglycemia', 'Disease', (38, 51))	('insulin', 'Gene', (146, 153))
84052	22520978	In breast cancer models, there is evidence to support combination of IGF1R inhibitors and EGFR inhibitors given the cross-talk that these two relevant pathways have.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('inhibitors', 'Var', (75, 85))	('inhibitors', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('EGFR', 'Gene', '1956', (90, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('EGFR', 'Gene', (90, 94))	('IGF1R', 'Gene', (69, 74))	('IGF1R', 'Gene', '3480', (69, 74))
84094	29040904	The nasal cavity and the paranasal sinuses are mostly affected (54%), and consequently, MFHs can affect the maxillary alveolar bone and lead to laryngeal, maxillary, and mandibular sinus injuries.	('laryngeal', 'CPA', (144, 153))	('lead to', 'Reg', (136, 143))	('affect', 'Reg', (97, 103))	('maxillary', 'CPA', (155, 164))	('maxillary alveolar bone', 'Disease', (108, 131))	('maxillary alveolar bone', 'Disease', 'MESH:D016301', (108, 131))	('sinus injuries', 'Disease', 'MESH:D012852', (181, 195))	('MFHs', 'Var', (88, 92))	('sinus injuries', 'Disease', (181, 195))
84097	29040904	Necrosis can be observed in hyperintense areas as well as calcification and ossification (in 5-20% of these areas).	('Necrosis', 'Disease', 'MESH:D009336', (0, 8))	('calcification', 'Disease', (58, 71))	('Necrosis', 'Disease', (0, 8))	('hyperintense', 'Var', (28, 40))	('ossification', 'CPA', (76, 88))	('calcification', 'Disease', 'MESH:D002114', (58, 71))
84183	29932244	In contrast, tumor-targeting S. typhimurium A1-R demonstrated significant tumor growth suppression compared to the control group (G3: 2.03+-1.33, p=0.018) and DOX group on day14 (p= 0.047) (Fig.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('suppression', 'NegReg', (87, 98))	('DOX', 'Chemical', 'MESH:D004317', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('S. typhimurium', 'Species', '90371', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (74, 79))	('S. typhimurium', 'Var', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
84188	29932244	Mice treated with S. typhimurium A1-R had slight weight loss at the endpoint.	('weight loss', 'Disease', 'MESH:D015431', (49, 60))	('S. typhimurium', 'Species', '90371', (18, 32))	('S. typhimurium A1-R', 'Var', (18, 37))	('weight loss', 'Disease', (49, 60))	('weight loss', 'Phenotype', 'HP:0001824', (49, 60))	('Mice', 'Species', '10090', (0, 4))
84196	29932244	We have previously shown that tumor-targeting S. typhimurium A1-R has strong efficacy on a PDOX models of Ewing's sarcoma and follicular dendritic cell sarcoma.	('dendritic cell sarcoma', 'Disease', 'MESH:D054740', (137, 159))	('dendritic cell sarcoma', 'Disease', (137, 159))	("Ewing's sarcoma", 'Disease', (106, 121))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (106, 121))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (106, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('S. typhimurium', 'Species', '90371', (46, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('DOX', 'Chemical', 'MESH:D004317', (92, 95))	('S. typhimurium', 'Var', (46, 60))
84197	29932244	In a recent study, S. typhimurium A1-R was shown to be effective against USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) and was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy.	('sarcoma', 'Disease', (144, 151))	('pleomorphic sarcoma', 'Disease', (98, 117))	('USTS', 'Disease', (73, 77))	('DOX', 'Chemical', 'MESH:D004317', (277, 280))	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('sarcoma', 'Disease', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('STS', 'Phenotype', 'HP:0030448', (74, 77))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (98, 117))	('S. typhimurium', 'Species', '90371', (19, 33))	('sarcoma', 'Disease', 'MESH:D012509', (218, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('sarcoma', 'Disease', (218, 225))	('S. typhimurium A1-R', 'Var', (19, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))
84199	29932244	This is the first study that demonstrates efficacy of S. typhimurium A1-R on a PDOX model of doxorubicin-resistant pleomorphic liposarcoma and suggests that S. typhimurium A1-R can be effective in the clinic in the future in this recalcitrant tumor type.	('S. typhimurium', 'Var', (157, 171))	('doxorubicin', 'Chemical', 'MESH:D004317', (93, 104))	('pleomorphic liposarcoma', 'Disease', (115, 138))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('S. typhimurium', 'Species', '90371', (54, 68))	('DOX', 'Chemical', 'MESH:D004317', (80, 83))	('doxorubicin-resistant', 'MPA', (93, 114))	('liposarcoma', 'Phenotype', 'HP:0012034', (127, 138))	('S. typhimurium', 'Species', '90371', (157, 171))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (115, 138))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
84204	28188619	We have applied this approach to the genetic modelling of t(11;22)(q24;q12) and t(11;22)(p13;q12), translocation products of the EWSR1 gene and its 3' fusion partners FLI1 and WT1, present in Ewing's sarcoma and desmoplastic small round cell tumour, respectively.	("Ewing's sarcoma", 'Disease', (192, 207))	('desmoplastic small round cell tumour', 'Disease', 'MESH:D058405', (212, 248))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (192, 207))	('t(11;22)(q24', 'Var', (58, 70))	('desmoplastic small round cell tumour', 'Disease', (212, 248))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (80, 97))	('t(11;22)(p13;q12', 'Var', (80, 96))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (58, 75))	('tumour', 'Phenotype', 'HP:0002664', (242, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('WT1', 'Gene', '7490', (176, 179))	('EWSR1', 'Gene', (129, 134))	('WT1', 'Gene', (176, 179))	('FLI1', 'Gene', (167, 171))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (192, 207))	('FLI1', 'Gene', '2313', (167, 171))
84206	28188619	Recent advances in sequencing technologies have accelerated the identification of recurrent chromosomal rearrangements in several cancers.	('chromosomal rearrangements', 'Var', (92, 118))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))
84207	28188619	In solid and haematological malignancies, the chimeric protein products of these fusion genes have been shown not only to be pathognomonic, but also to constitute the disease's primary drivers.	('haematological malignancies', 'Disease', 'MESH:D019337', (13, 40))	('chimeric protein', 'Var', (46, 62))	('haematological malignancies', 'Disease', (13, 40))	('pathognomonic', 'Reg', (125, 138))
84210	28188619	With programmable zinc finger nucleases, transcription activator-like effector nucleases, and the recently described clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system, (CRISPR-Cas9) technology, it is possible to induce de novo translocations, deletions and inversions with synchronous introduction of two DSBs at two genomic loci.	('deletions', 'Var', (291, 300))	('translocations', 'Var', (275, 289))	('DSBs', 'Chemical', '-', (353, 357))	('inversions', 'Var', (305, 315))	('induce', 'Reg', (260, 266))
84238	28188619	A dual-colour/dual-fusion FISH assay was performed to verify EWSR1-FLI1 fusion, the t(11;22)(q24;q12) translocation, using a customized EWSR1-FLI1 fusion probe set from Agilent Technologies (Santa Clara, CA).	('FLI1', 'Gene', (142, 146))	('FLI1', 'Gene', '2313', (142, 146))	('fusion', 'Var', (72, 78))	('FLI1', 'Gene', '2313', (67, 71))	('FLI1', 'Gene', (67, 71))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (84, 101))
84242	28188619	Membranes were probed with the following antibodies: GAPDH (1:2000, Cell Signaling,14C10), Fli-1 (1:500, Santa Cruz Biotechnology, C-19, sc-356), WT1 (1:1000, Santa Cruz Biotechnology, C-19, sc-192).	('GAPDH', 'Gene', '2597', (53, 58))	('1:500', 'Var', (98, 103))	('WT1', 'Gene', '7490', (146, 149))	('Fli-1', 'Gene', '2313', (91, 96))	('GAPDH', 'Gene', (53, 58))	('WT1', 'Gene', (146, 149))	('Fli-1', 'Gene', (91, 96))
84246	28188619	The gRNAs were designed to induce DSBs within the first 500 bp downstream of the exon/intron boundary (Figure 1A).	('DSBs', 'Var', (34, 38))	('induce', 'Reg', (27, 33))	('DSBs', 'Chemical', '-', (34, 38))
84254	28188619	HEK293T cells were transfected with the E4:F3-gRNA combination of CRISPR-Cas9 plasmids, along with the linearized NG1 donor template (Figure 2A).	('donor', 'Species', '9606', (118, 123))	('NG1', 'Gene', '29949', (114, 117))	('NG1', 'Gene', (114, 117))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('E4:F3-gRNA', 'Var', (40, 50))
84258	28188619	This was confirmed by positive PCR amplicons from the insertion of the left and right arms of homology, and also a 3.4 kbp product generated from PCR primers residing outside of the homology arms in the targeted regions of EWSR1 and FLI1 (Figure 2B, Figure 2C and Figure 2D).	('FLI1', 'Gene', '2313', (233, 237))	('insertion', 'Var', (54, 63))	('FLI1', 'Gene', (233, 237))	('EWSR1', 'Gene', (223, 228))
84266	28188619	Moreover, RT-PCR (Figure 3B) and Western blot (Figure 3C) analyses of the NG1-EF-16.2 and NG1-EF-57.4 clones demonstrated that the chimeric EWSR1-FLI1 transcript and the EWSR1-FLI1 protein were expressed.	('chimeric', 'Var', (131, 139))	('NG1', 'Gene', '29949', (90, 93))	('FLI1', 'Gene', (146, 150))	('FLI1', 'Gene', '2313', (146, 150))	('FLI1', 'Gene', (176, 180))	('FLI1', 'Gene', '2313', (176, 180))	('NG1', 'Gene', '29949', (74, 77))	('NG1', 'Gene', (90, 93))	('EF-16.2', 'CellLine', 'CVCL:B377', (78, 85))	('NG1', 'Gene', (74, 77))
84272	28188619	In regards to EWSR1-FLI1, generation of the fusion by either CRISPR-Cas9/NHEJ or CRISPR-Cas9/HDR results in immediate expression of the genomic rearrangement (Figure 1B and Supplementary Figure S2).	('FLI1', 'Gene', (20, 24))	('FLI1', 'Gene', '2313', (20, 24))	('CRISPR-Cas9/HDR', 'Var', (81, 96))	('genomic rearrangement', 'MPA', (136, 157))
84275	28188619	Genome-wide gene-trap insertional mutagenesis is a powerful approach for loss-of-function studies.	('trap', 'Gene', '100187907', (17, 21))	('insertional mutagenesis', 'Var', (22, 45))	('trap', 'Gene', (17, 21))
84307	28188619	We have successfully applied this methodology to generate conditionally inducible EWSR1-FLI1 and EWSR1-WT1 translocations in a human cell line.	('translocations', 'Var', (107, 121))	('human', 'Species', '9606', (127, 132))	('WT1', 'Gene', '7490', (103, 106))	('FLI1', 'Gene', '2313', (88, 92))	('WT1', 'Gene', (103, 106))	('FLI1', 'Gene', (88, 92))
84319	28188619	In fact, several subsets of common cancers are driven by fusion genes.	('driven by', 'Reg', (47, 56))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('fusion genes', 'Var', (57, 69))	('cancers', 'Disease', (35, 42))
84320	28188619	For instance, non-small cell lung cancers harbouring fusion genes involving ALK, ROS1 or RET have no or few cell lines for functional studies, and the models currently available are not entirely representative of the spectrum of lesions harbouring these genomic events.	('ALK', 'Gene', '238', (76, 79))	('ROS1', 'Gene', (81, 85))	('RET', 'Gene', (89, 92))	('lung cancers', 'Phenotype', 'HP:0100526', (29, 41))	('ROS1', 'Gene', '6098', (81, 85))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (14, 41))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (14, 41))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('fusion genes', 'Var', (53, 65))	('ALK', 'Gene', (76, 79))	('RET', 'Gene', '5979', (89, 92))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (18, 41))	('non-small cell lung cancers', 'Disease', (14, 41))
84322	28188619	In generating a conditional chromosomal translocation, the insertion of the gene-trap into the 5' fusion partner to interrupt expression may not be functionally neutral.	('trap', 'Gene', '100187907', (81, 85))	('insertion', 'Var', (59, 68))	('trap', 'Gene', (81, 85))
84323	28188619	For EWSR1 in particular, heterozygous EWSR1 mice are viable and grossly normal, with no reported incidence of tumourigenesis.	('EWSR1', 'Var', (38, 43))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('EWSR1', 'Gene', (4, 9))	('mice', 'Species', '10090', (44, 48))	('tumour', 'Disease', (110, 116))
84334	20718708	The sequence of genetic and epigenetic events resulting in the malignant progression of carcinoma cells appears to be random in a stochastic point of view, but is most frequently accompanied by the loss of functional differentiation and the acquisition of a migratory phenotype.	('carcinoma cells', 'Disease', 'MESH:C538614', (88, 103))	('resulting in', 'Reg', (46, 58))	('loss', 'NegReg', (198, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('functional differentiation', 'CPA', (206, 232))	('malignant progression', 'CPA', (63, 84))	('epigenetic', 'Var', (28, 38))	('migratory phenotype', 'CPA', (258, 277))	('rat', 'Species', '10116', (261, 264))	('carcinoma cells', 'Disease', (88, 103))
84362	20718708	Importantly, loss of sensitivity to the effects of TGF-beta through bypassing the pathway via selective mutations of TGFBRs or Smad4 has a pivotal role in the progression of a variety of carcinomas.	('bypassing', 'NegReg', (68, 77))	('mutations', 'Var', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('pathway', 'Pathway', (82, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('carcinomas', 'Disease', 'MESH:D002277', (187, 197))	('loss', 'NegReg', (13, 17))	('carcinomas', 'Disease', (187, 197))	('TGFBR', 'Gene', (117, 122))	('TGFBR', 'Gene', '7046', (117, 122))	('Smad4', 'Gene', (127, 132))	('Smad4', 'Gene', '4089', (127, 132))
84363	20718708	In contrast to the tumor suppressor activities of TGF-beta, a multitude of studies demonstrated pro-oncogenic functions of TGF-beta signaling by dysregulation of CDKIs, altered production of extracellular matrix (ECM) constituents via mobilization of myofibroblasts, autocrine regulation of mitogens, induction of cell motility and EMT, suppression of immunosurveillance, stimulation of angiogenesis and priming of tumor cells towards metastasis.	('immunosurveillance', 'CPA', (352, 370))	('tumor', 'Disease', (415, 420))	('mobilization', 'MPA', (235, 247))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('suppression', 'NegReg', (337, 348))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('angiogenesis', 'CPA', (387, 399))	('altered', 'Var', (169, 176))	('stimulation', 'PosReg', (372, 383))	('CDKIs', 'Protein', (162, 167))	('tumor', 'Disease', (19, 24))	('cell motility', 'CPA', (314, 327))	('priming', 'CPA', (404, 411))	('tumor', 'Disease', 'MESH:D009369', (415, 420))	('EMT', 'CPA', (332, 335))	('tumor', 'Phenotype', 'HP:0002664', (415, 420))	('rat', 'Species', '10116', (90, 93))
84370	20718708	TGF-beta and RAS signaling also cooperates in the intestinal epithelium where overexpression of K-RAS in combination with deletion of TGFRII generated metastatic adenocarcinomas with activated epidermal growth factor (EGF) signaling independent of Wnt/beta-catenin.	('beta-catenin', 'Gene', '1499', (252, 264))	('EGF', 'Gene', (218, 221))	('K-RAS', 'Gene', '3845', (96, 101))	('TGFRII', 'Gene', (134, 140))	('rat', 'Species', '10116', (37, 40))	('K-RAS', 'Gene', (96, 101))	('adenocarcinomas', 'Disease', 'MESH:D000230', (162, 177))	('deletion', 'Var', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('EGF', 'Gene', '1950', (218, 221))	('epidermal growth factor', 'Gene', (193, 216))	('beta-catenin', 'Gene', (252, 264))	('adenocarcinomas', 'Disease', (162, 177))	('rat', 'Species', '10116', (145, 148))	('epidermal growth factor', 'Gene', '1950', (193, 216))
84371	20718708	Neither oncogenic K-RAS nor inactivation of TGFRII on its own was able to induce colorectal tumors.	('K-RAS', 'Gene', '3845', (18, 23))	('induce', 'Reg', (74, 80))	('TGFRII', 'Gene', (44, 50))	('K-RAS', 'Gene', (18, 23))	('inactivation', 'Var', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('colorectal tumors', 'Disease', 'MESH:D015179', (81, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal tumors', 'Disease', (81, 98))
84373	20718708	Activation of RAF caused endocytosis and ubiquitin-dependent lysosomal degradation of E-cadherin, and inhibited the ability of TGF-beta to induce apoptosis without affecting growth retardation.	('RAF', 'Gene', (14, 17))	('E-cadherin', 'Gene', (86, 96))	('RAF', 'Gene', '22882', (14, 17))	('inhibited', 'NegReg', (102, 111))	('growth retardation', 'Disease', 'MESH:D006130', (174, 192))	('growth retardation', 'Disease', (174, 192))	('ability', 'MPA', (116, 123))	('growth retardation', 'Phenotype', 'HP:0001510', (174, 192))	('Activation', 'Var', (0, 10))	('ubiquitin-dependent lysosomal degradation', 'MPA', (41, 82))	('endocytosis', 'MPA', (25, 36))	('apoptosis', 'CPA', (146, 155))	('E-cadherin', 'Gene', '999', (86, 96))
84381	20718708	This was shown by the pharmacological and genetic interference with the PI3K-AKT pathway which blocked Smad2 phosphorylation and transcriptional responses induced by TGF-beta.	('PI3', 'Gene', '5266', (72, 75))	('AKT', 'Gene', '207', (77, 80))	('PI3', 'Gene', (72, 75))	('blocked', 'NegReg', (95, 102))	('genetic', 'Var', (42, 49))	('transcriptional', 'MPA', (129, 144))	('Smad2', 'Gene', '4087', (103, 108))	('AKT', 'Gene', (77, 80))	('Smad2', 'Gene', (103, 108))	('phosphorylation', 'MPA', (109, 124))
84393	20718708	Mutations of the Smad3 linker region preventing JNK-dependent phosphorylation resulted in a preserved tumor-suppressive function of TGF-beta and inhibited tumor cell invasion.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (155, 160))	('TGF-beta', 'Protein', (132, 140))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('JNK-dependent phosphorylation', 'MPA', (48, 77))	('tumor', 'Disease', (102, 107))	('inhibited', 'NegReg', (145, 154))
84396	20718708	JNK inhibition reduced TGF-beta or HGF-mediated cell invasion.	('HGF', 'Gene', (35, 38))	('inhibition', 'Var', (4, 14))	('reduced', 'NegReg', (15, 22))	('JNK', 'Protein', (0, 3))	('HGF', 'Gene', '3082', (35, 38))	('TGF-beta', 'Protein', (23, 31))
84400	20718708	Dependent on CDK4, TGF-beta generated pSmad2C/L (C/L, phosphorylation at C-terminus and linker region) and pSmad3C/L, which enhanced cell growth by upregulation of c-MYC.	('Smad2', 'Gene', '4087', (39, 44))	('upregulation', 'PosReg', (148, 160))	('pSmad3C/L', 'Var', (107, 116))	('rat', 'Species', '10116', (32, 35))	('Smad2', 'Gene', (39, 44))	('c-MYC', 'Gene', '4609', (164, 169))	('enhanced', 'PosReg', (124, 132))	('cell growth', 'CPA', (133, 144))	('CDK4', 'Gene', (13, 17))	('CDK4', 'Gene', '1019', (13, 17))	('TGF-beta', 'Gene', (19, 27))	('c-MYC', 'Gene', (164, 169))
84427	20718708	Specific loss of activin signals in the course of tumor development has been connected to inactivating mutations of activin receptors in colon, pancreas, and prostate cancer as well as overexpression of antagonistic proteins such as follistatin and follistatin-related gene (FLRG) in breast cancer and HCC.	('breast cancer', 'Phenotype', 'HP:0003002', (284, 297))	('FLRG', 'Gene', (275, 279))	('activin', 'Gene', (116, 123))	('breast cancer', 'Disease', 'MESH:D001943', (284, 297))	('FLRG', 'Gene', '10272', (275, 279))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (284, 297))	('follistatin-related gene', 'Gene', '10272', (249, 273))	('HCC', 'Gene', '619501', (302, 305))	('HCC', 'Phenotype', 'HP:0001402', (302, 305))	('inactivating mutations', 'Var', (90, 112))	('overexpression', 'PosReg', (185, 199))	('follistatin', 'Gene', (233, 244))	('activin', 'Gene', (17, 24))	('HCC', 'Gene', (302, 305))	('activin', 'Gene', '83729', (116, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (158, 173))	('tumor', 'Disease', (50, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (158, 173))	('follistatin', 'Gene', (249, 260))	('loss', 'NegReg', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('prostate cancer', 'Disease', (158, 173))	('follistatin', 'Gene', '14313', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('activin', 'Gene', '83729', (17, 24))	('follistatin-related gene', 'Gene', (249, 273))	('follistatin', 'Gene', '14313', (249, 260))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))
84439	20718708	The synergistic cooperation of activin A with fibroblast growth factor (FGF)2, which mediates tube formation of bovine aortic endothelial cells, could be inhibited by follistatin, Smad7 or inhibition of ERK.	('activin', 'Gene', '83729', (31, 38))	('synergistic cooperation', 'MPA', (4, 27))	('inhibited', 'NegReg', (154, 163))	('follistatin', 'Gene', (167, 178))	('inhibition', 'Var', (189, 199))	('activin', 'Gene', (31, 38))	('rat', 'Species', '10116', (21, 24))	('follistatin', 'Gene', '14313', (167, 178))	('bovine', 'Species', '9913', (112, 118))	('ERK', 'Gene', (203, 206))
84447	20718708	Frequent inactivation of the BMP signaling pathway by mutation of BMP receptors or Smad proteins was found in colon cancer.	('mutation', 'Var', (54, 62))	('colon cancer', 'Disease', (110, 122))	('BMP', 'Gene', (66, 69))	('BMP', 'Gene', '649', (29, 32))	('inactivation', 'NegReg', (9, 21))	('Smad proteins', 'Protein', (83, 96))	('colon cancer', 'Disease', 'MESH:D015179', (110, 122))	('BMP', 'Gene', (29, 32))	('BMP', 'Gene', '649', (66, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
84448	20718708	In lung cancer, an association between RAS mutations and silencing of BMP expression has been demonstrated.	('RAS', 'Protein', (39, 42))	('rat', 'Species', '10116', (101, 104))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('BMP', 'Gene', (70, 73))	('silencing', 'Var', (57, 66))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('association', 'Interaction', (19, 30))	('BMP', 'Gene', '649', (70, 73))
84449	20718708	NSCLC patients with K-RAS codon 12 mutations were six times more likely to have epigenetically silenced BMP3b/GDF10 or BMP6 than those with wild type K-RAS.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('GDF10', 'Gene', '2662', (110, 115))	('K-RAS', 'Gene', (150, 155))	('K-RAS', 'Gene', (20, 25))	('NSCLC', 'Disease', (0, 5))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('codon 12 mutations', 'Var', (26, 44))	('GDF10', 'Gene', (110, 115))	('patients', 'Species', '9606', (6, 14))	('BMP3b', 'Gene', (104, 109))	('BMP6', 'Gene', '654', (119, 123))	('BMP6', 'Gene', (119, 123))	('epigenetically silenced', 'Var', (80, 103))	('K-RAS', 'Gene', '3845', (150, 155))	('BMP3b', 'Gene', '2662', (104, 109))	('K-RAS', 'Gene', '3845', (20, 25))
84461	20718708	For instance, the small molecule inhibitor LY2109761 targeting TGFBRI-ALK5 and TGFBRII induced a complete abrogation of Smad-dependent and - independent signaling in human colon carcinoma cells harboring activated K-RAS, resulting in reduced tumor cell invasion and liver metastasis.	('reduced', 'NegReg', (234, 241))	('LY2109761', 'Chemical', 'MESH:C530108', (43, 52))	('carcinoma cells', 'Disease', (178, 193))	('LY2109761', 'Var', (43, 52))	('tumor', 'Disease', (242, 247))	('liver metastasis', 'Disease', (266, 282))	('abrogation', 'NegReg', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('human', 'Species', '9606', (166, 171))	('TGFBR', 'Gene', (63, 68))	('TGFBR', 'Gene', (79, 84))	('K-RAS', 'Gene', (214, 219))	('TGFBRI-ALK5', 'Gene', (63, 74))	('colon carcinoma', 'Disease', (172, 187))	('carcinoma cells', 'Disease', 'MESH:C538614', (178, 193))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('K-RAS', 'Gene', '3845', (214, 219))	('liver metastasis', 'Disease', 'MESH:D009362', (266, 282))	('colon carcinoma', 'Disease', 'MESH:D015179', (172, 187))	('TGFBRI-ALK5', 'Gene', '7046', (63, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('TGFBR', 'Gene', '7046', (79, 84))	('TGFBR', 'Gene', '7046', (63, 68))
84462	20718708	Remarkably, TGF-beta antisense approaches showed reactivation of tumor-specific immune responses, rendering patients more susceptible to a number of different therapeutic measures.	('reactivation', 'PosReg', (49, 61))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('antisense approaches', 'Var', (21, 41))	('TGF-beta', 'Gene', (12, 20))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
84464	20718708	A TGF-beta2 antisense oligonucleotide (AP 12009) has begun phase II/III testing to treat high grade gliomas and phase I/II trials against pancreatic cancer.	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('pancreatic cancer', 'Disease', (138, 155))	('antisense', 'Var', (12, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('TGF-beta2', 'Gene', '7042', (2, 11))	('TGF-beta2', 'Gene', (2, 11))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('oligonucleotide', 'Chemical', 'MESH:D009841', (22, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('gliomas', 'Disease', (100, 107))
84471	20718708	Efforts to target hyperactive RAS (H-RAS, N-RAS or K-RAS) signaling emanating from mutations by employing GTP analogues or inhibitors of post-translational modifications such as farnesylation failed to prove successful so far.	('N-RAS', 'Gene', '4893', (42, 47))	('mutations', 'Var', (83, 92))	('H-RAS', 'Gene', (35, 40))	('GTP', 'Chemical', 'MESH:D006160', (106, 109))	('K-RAS', 'Gene', '3845', (51, 56))	('K-RAS', 'Gene', (51, 56))	('N-RAS', 'Gene', (42, 47))	('H-RAS', 'Gene', '3265', (35, 40))
84512	31030205	Myeloid sarcoma usually manifests concurrently or following the diagnosis of AML, chronic myeloid leukemia, myeloproliferative diseases, or myelodysplastic syndrome, and the presence of AML commonly and typically induces or predisposes a person to the development of myeloid sarcoma.	('myeloid sarcoma', 'Disease', (267, 282))	('AML', 'Disease', 'MESH:D015470', (186, 189))	('induces', 'Reg', (213, 220))	('AML', 'Phenotype', 'HP:0004808', (186, 189))	('AML', 'Disease', (186, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('presence', 'Var', (174, 182))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (140, 164))	('predisposes', 'Reg', (224, 235))	('chronic myeloid leukemia', 'Disease', (82, 106))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (140, 164))	('myeloproliferative diseases', 'Disease', (108, 135))	('person', 'Species', '9606', (238, 244))	('myeloproliferative diseases', 'Disease', 'MESH:D009196', (108, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('AML', 'Disease', 'MESH:D015470', (77, 80))	('AML', 'Disease', (77, 80))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (90, 106))	('AML', 'Phenotype', 'HP:0004808', (77, 80))	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('myelodysplastic syndrome', 'Disease', (140, 164))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (82, 106))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (82, 106))	('Myeloid sarcoma', 'Disease', 'MESH:D023981', (0, 15))	('Myeloid sarcoma', 'Disease', (0, 15))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (267, 282))
84562	29721194	In the present study, RNA sequencing of a LG-ESS showed a novel recombination of PHF1 with the Enhancer of Polycomb homolog 2 (EPC2).	('PHF1', 'Gene', (81, 85))	('Polycomb', 'Gene', '40358', (107, 115))	('Polycomb', 'Gene', (107, 115))	('recombination', 'Var', (64, 77))
84563	29721194	Recurrent chromosomal translocations leading to gene fusion formation have been described in uterine sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (101, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('gene fusion formation', 'MPA', (48, 69))	('sarcomas', 'Disease', (101, 109))	('chromosomal', 'Var', (10, 21))
84573	29721194	Subsequent cytogenetic and molecular studies detected additional partners for PHF1: MEAF6, recombined through a t(1;6)(p34;p21) and, recently, BRD8 from 5q31.	('MEAF6', 'Chemical', '-', (84, 89))	('MEAF6', 'Gene', (84, 89))	('PHF1: MEAF6', 'Gene', (78, 89))	('t(1;6)(p34;p21)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 127))	('t(1;6)(p34;p21', 'Var', (112, 126))
84576	29721194	Little is known about EPC2 though different genetic studies suggest that deletion of its yeast homolog Ep11 causes accumulation of cells in G2M, increases sensitivity to DNA damaging agents, leads to defective telomeric silencing, and may result in global loss of histone H2A as well as H4 acetylation.	('deletion', 'Var', (73, 81))	('cells in G2M', 'MPA', (131, 143))	('yeast', 'Species', '4932', (89, 94))	('sensitivity to DNA damaging agents', 'MPA', (155, 189))	('loss', 'NegReg', (256, 260))	('increases', 'PosReg', (145, 154))	('telomeric silencing', 'MPA', (210, 229))	('accumulation', 'PosReg', (115, 127))	('Ep11', 'Gene', (103, 107))	('histone H2A', 'Protein', (264, 275))	('leads', 'Reg', (191, 196))	('defective', 'NegReg', (200, 209))	('H4 acetylation', 'MPA', (287, 301))
84579	29721194	Mutation of EP400 complex components EPC1 and EPC2 has been identified as pathogenetic events in AML.	('pathogenetic', 'Reg', (74, 86))	('AML', 'Disease', (97, 100))	('Mutation', 'Var', (0, 8))	('AML', 'Disease', 'MESH:D015470', (97, 100))
84582	29721194	This suggests a common neoplastic mechanism, namely rearrangement of the same gene, in these tumors that show little or no morphologic or immunophenotypic overlap.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('rearrangement', 'Var', (52, 65))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))
84584	29721194	In this regard, PHF1 and the tumors characterized by its rearrangement do not differ principally from Soft Tissue Tumors in general where similar situations are known to be common.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('Soft Tissue Tumors', 'Phenotype', 'HP:0031459', (102, 120))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('Tumors', 'Phenotype', 'HP:0002664', (114, 120))	('Tumors', 'Disease', (114, 120))	('tumors', 'Disease', (29, 35))	('rearrangement', 'Var', (57, 70))	('Tumors', 'Disease', 'MESH:D009369', (114, 120))
84585	29721194	As seen in the LG-ESS, OFMT, and cardiac ossifying sarcomas analyzed so far, the rearrangements of PHF1 as the 3'- partner have breakpoints in exon 2 leading to retention of most of the gene sequence.	('rearrangements', 'Var', (81, 95))	('PHF1', 'Gene', (99, 103))	('cardiac ossifying sarcomas', 'Disease', 'MESH:D006331', (33, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('cardiac ossifying sarcomas', 'Disease', (33, 59))	('retention', 'MPA', (161, 170))	('ossifying sarcoma', 'Phenotype', 'HP:0002669', (41, 58))	('breakpoints', 'Var', (128, 139))
84587	29721194	It is finally worthy of note that the rearrangement of 6p21, the chromosomal band where PHF1 is located, was cryptic in the LG-ESS we report, hinting that it may be cytogenetically invisible also in other tumors.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('rearrangement', 'Var', (38, 51))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('PHF1', 'Gene', (88, 92))	('tumors', 'Disease', (205, 211))
84588	29721194	It seems certain that the use of FISH or molecular methods is necessary to detect this and related gene-level rearrangements in tumors with seemingly normal or complex karyotypes, perhaps especially when the lesions are histologically unusual.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('rearrangements', 'Var', (110, 124))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))
84600	29721194	The primer combinations were EPC2-2110F1 and PHF1-524R1 for the first PCR reaction and EPC2-2266F2 and PHF1-376R1 for Nested PCR.	('EPC2-2266F2', 'CellLine', 'CVCL:4361', (87, 98))	('PHF1-376R1', 'Var', (103, 113))	('EPC2-2266F2', 'Var', (87, 98))	('EPC2-2110F1', 'CellLine', 'CVCL:4W34', (29, 40))	('EPC2-2110F1', 'Var', (29, 40))	('PHF1-524R1', 'Var', (45, 55))
84615	25761175	Convex endobronchial ultrasound (C-EBUS)-guided transbronchial needle aspiration (TBNA) is an effective tool for the diagnosis of hilar, mediastinal, and central parenchymal lesions, but due to its thickness, C-EBUS scope cannot usually enter the subsegmental airways and reach pleural-based masses.	('pleural', 'Disease', 'MESH:D010995', (278, 285))	('pleural', 'Disease', (278, 285))	('C-EBUS', 'Chemical', '-', (33, 39))	('C-EBUS', 'Var', (209, 215))	('aspiration', 'Phenotype', 'HP:0002835', (70, 80))	('C-EBUS', 'Chemical', '-', (209, 215))
84759	22666562	In addition, the presence of HIV is linked to cytokine dysregulation and this may also play a role in increasing cancer risks.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cytokine dysregulation', 'MPA', (46, 68))	('HIV', 'Disease', (29, 32))	('linked to', 'Reg', (36, 45))	('cancer', 'Disease', (113, 119))	('increasing', 'PosReg', (102, 112))	('HIV', 'Disease', 'MESH:D015658', (29, 32))	('presence', 'Var', (17, 25))	('play', 'Reg', (87, 91))
84915	32601958	On CT imaging, they appear as midline expansile soft tissue lesions displacing the adjacent paraspinal musculature, resulting in a "mushroom" or "dumbbell" appearance.	('displacing', 'NegReg', (68, 78))	('mushroom', 'Species', '5341', (132, 140))	('lesions', 'Var', (60, 67))
85021	31337342	The inclusion criteria for this study are: (1) histopathologic diagnosis of primary malignant sarcoma of bone and soft tissue in extremity or trunk; (2) extremity or trunk bone sarcoma or STS presenting with advanced recurrence or metastatic disease diagnosed by biopsy as necessary; (3) previous received standard therapy for bone sarcoma or STS, or was unable to receive standard therapy; (4) age 10-70 years at the time of enrolment; (5) measurable lesion(s); (6) performance status (PS) ECOG 0 or 1; (7) primary tumour was in the limbs or trunk; and (8) laboratory data no more than14 days prior to enrolment meeting the following criteria: (i) neutrophil count > 1,500/mm3; (ii) haemoglobin > 8.0 g/dL (no blood transfusion within 14 days); (iii) platelet count > 100,000/mm3; (iv) total bilirubin < 1.5 mg/dL; (v) aspartate aminotransferase (glutamyl oxaloacetic transaminase) (AST [GOT]) < 100 IU/L; (vi) alanine aminotransferase (glutamyl pyruvic transaminase) (ALT [GPT]) < 100 IU/L; (vii) creatinine < 1.5 mg/dL; (viii) creatinine clearance (eGFR) > 60 mL/min; (ix) normal electrocardiogram no more than 28 days prior to enrolment; (x) no interstitial pneumonia, pulmonary fibrosis, or pulmonary emphysema; and (xi) written informed consent obtained after patients has been given a written explanation of the study protocol.	('alanine aminotransferase', 'Gene', (912, 936))	('eGFR', 'Gene', (1052, 1056))	('STS', 'Phenotype', 'HP:0030448', (188, 191))	('alanine aminotransferase', 'Gene', '2875', (912, 936))	('trunk bone sarcoma', 'Disease', (166, 184))	('AST', 'Gene', (884, 887))	('bone sarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('bone sarcoma', 'Disease', 'MESH:D001847', (327, 339))	('pneumonia', 'Phenotype', 'HP:0002090', (1162, 1171))	('GPT', 'Gene', (975, 978))	('creatinine clearance', 'MPA', (1030, 1050))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('primary malignant sarcoma of bone', 'Disease', 'MESH:D001859', (76, 109))	('patients', 'Species', '9606', (1266, 1274))	('interstitial pneumonia', 'Disease', 'MESH:D017563', (1149, 1171))	('pulmonary emphysema', 'Disease', (1196, 1215))	('bone sarcoma', 'Phenotype', 'HP:0002669', (327, 339))	('sarcoma', 'Phenotype', 'HP:0100242', (332, 339))	('GPT', 'Gene', '2875', (975, 978))	('bone sarcoma', 'Disease', 'MESH:D001847', (172, 184))	('STS', 'Phenotype', 'HP:0030448', (343, 346))	('pulmonary fibrosis', 'Disease', (1173, 1191))	('tumour', 'Phenotype', 'HP:0002664', (516, 522))	('primary malignant sarcoma of bone', 'Disease', (76, 109))	('tumour', 'Disease', 'MESH:D009369', (516, 522))	('pulmonary emphysema', 'Phenotype', 'HP:0002097', (1196, 1215))	('tumour', 'Disease', (516, 522))	('AST', 'Gene', '26503', (884, 887))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (1173, 1191))	('trunk bone sarcoma', 'Disease', 'MESH:D001847', (166, 184))	('eGFR', 'Gene', '1956', (1052, 1056))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (1173, 1191))	('< 100', 'Var', (981, 986))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('bone sarcoma', 'Disease', (327, 339))	('interstitial pneumonia', 'Disease', (1149, 1171))	('pulmonary emphysema', 'Disease', 'MESH:D011656', (1196, 1215))
85026	31337342	The drugs may be administered only after the participant has been confirmed to fulfil the following criteria within 3 days before Day 1 of each cycle: haemoglobin >=8.0 g/dL, neutrophil count >=1,000/mm3, platelet count >=50,000/mm3, AST (GOT) <= 90 IU/L, ALT (GPT) <= 125 IU/L for male and <= 69 IU/L for female participants, creatinine <=1.605 mg/dL for male and <= 1.185 mg/dL for female participants, grade 0-2 fatigue, grade 0-2 oedema limbs, grade 0-1 diarrhoea, grade 0-1 haematuria, grade 0-1 mucositis oral, grade 0-1 supraventricular tachycardia, grade 0-1 ventricular arrhythmia, grade 0-1 pneumonitis, and grade 0-1 infection.	('AST', 'Gene', (234, 237))	('diarrhoea', 'Disease', 'MESH:D003967', (458, 467))	('pneumonitis', 'Disease', 'MESH:D011014', (601, 612))	('participant', 'Species', '9606', (313, 324))	('arrhythmia', 'Phenotype', 'HP:0011675', (579, 589))	('GPT', 'Gene', (261, 264))	('mucositis oral', 'Disease', 'MESH:D013280', (501, 515))	('supraventricular tachycardia', 'Disease', (527, 555))	('participants', 'Species', '9606', (313, 325))	('pneumonitis', 'Disease', (601, 612))	('oedema', 'Disease', 'MESH:D004487', (434, 440))	('participant', 'Species', '9606', (391, 402))	('mucositis oral', 'Disease', (501, 515))	('haematuria', 'Disease', (479, 489))	('infection', 'Disease', (628, 637))	('ventricular arrhythmia', 'Phenotype', 'HP:0004308', (567, 589))	('infection', 'Disease', 'MESH:D007239', (628, 637))	('diarrhoea', 'Phenotype', 'HP:0002014', (458, 467))	('GPT', 'Gene', '2875', (261, 264))	('participants', 'Species', '9606', (391, 403))	('grade', 'Disease', (424, 429))	('oedema', 'Disease', (434, 440))	('AST', 'Gene', '26503', (234, 237))	('>=8.0', 'Var', (163, 168))	('ventricular arrhythmia', 'Disease', (567, 589))	('tachycardia', 'Phenotype', 'HP:0001649', (544, 555))	('grade', 'Disease', (469, 474))	('participant', 'Species', '9606', (45, 56))	('ventricular arrhythmia', 'Disease', 'MESH:D001145', (567, 589))	('supraventricular tachycardia', 'Disease', 'MESH:D013617', (527, 555))	('fatigue', 'Phenotype', 'HP:0012378', (415, 422))	('haematuria', 'Disease', 'MESH:D006417', (479, 489))	('diarrhoea', 'Disease', (458, 467))	('oedema', 'Phenotype', 'HP:0000969', (434, 440))	('supraventricular tachycardia', 'Phenotype', 'HP:0004755', (527, 555))
85027	31337342	The drugs may be administered only after the participant has been confirmed to fulfil the following criteria within 3 days before Day 8: haemoglobin >=8.0 g/dL, neutrophil count >=1,000/mm3, platelet count >=50,000/mm3, AST (GOT) <= 90 IU/L, ALT (GPT) <= 125 IU/L for male and <= 69 IU/L for female participants.	('AST', 'Gene', (220, 223))	('participant', 'Species', '9606', (299, 310))	('GPT', 'Gene', '2875', (247, 250))	('platelet', 'MPA', (191, 199))	('GPT', 'Gene', (247, 250))	('haemoglobin', 'MPA', (137, 148))	('neutrophil count', 'MPA', (161, 177))	('AST', 'Gene', '26503', (220, 223))	('ALT', 'MPA', (242, 245))	('participants', 'Species', '9606', (299, 311))	('>=8.0', 'Var', (149, 154))	('participant', 'Species', '9606', (45, 56))
85109	24723225	As vitamin D deficiency has been associated with the risk of developing colon, prostate, breast, and several other cancers, it is theoretically possible that abundant sunshine in Taiwan along with adequate intake of vitamin D in the elderly may contribute to the reduced risk of OS.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('vitamin D', 'Chemical', 'MESH:D014807', (3, 12))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('vitamin D', 'Gene', (3, 12))	('cancers', 'Disease', (115, 122))	('deficiency', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colon', 'Disease', (72, 77))	('prostate', 'Disease', (79, 87))	('vitamin D', 'Chemical', 'MESH:D014807', (216, 225))	('OS', 'Phenotype', 'HP:0002669', (279, 281))	('breast', 'Disease', (89, 95))	('developing colon', 'Disease', (61, 77))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (3, 23))
85147	22430386	Deletions or mutations of essential HSV-1 genes (e.g.	('mutations', 'Var', (13, 22))	('HSV-1', 'Species', '10298', (36, 41))	('essential HSV-1 genes', 'Gene', (26, 47))	('Deletions', 'Var', (0, 9))
85150	22430386	acyclovir, ganciclovir) are effective against mutant HSV in the unlikely event that the virus causes toxicity to normal cells.	('HSV', 'Gene', (53, 56))	('mutant', 'Var', (46, 52))	('HSV', 'Species', '10298', (53, 56))	('toxicity', 'Disease', 'MESH:D064420', (101, 109))	('ganciclovir', 'Chemical', 'MESH:D015774', (11, 22))	('toxicity', 'Disease', (101, 109))	('acyclovir', 'Chemical', 'MESH:D000212', (0, 9))
85152	22430386	Two mutant viruses, G207 and HSV1716, have been used safely without any dose limiting toxicities in adult patients with recurrent glioblastoma multiforme (GBM) (Table 2 summarizes viruses included in the text).	('glioblastoma multiforme', 'Disease', (130, 153))	('toxicities', 'Disease', (86, 96))	('G207', 'Var', (20, 24))	('HSV1716', 'Var', (29, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (130, 153))	('toxicities', 'Disease', 'MESH:D064420', (86, 96))	('patients', 'Species', '9606', (106, 114))	('HSV', 'Species', '10298', (29, 32))
85155	22430386	Insertion of the lacZ gene encoding beta-galactosidase effectively disables expression of ribonucleotide reductase while providing a useful marker.	('lacZ', 'Gene', (17, 21))	('beta-galactosidase', 'Gene', '2720', (36, 54))	('beta-galactosidase', 'Gene', (36, 54))	('disables', 'NegReg', (67, 75))	('expression', 'MPA', (76, 86))	('Insertion', 'Var', (0, 9))
85156	22430386	HSV1716 was produced by deleting both copies of gamma134.5 from wild type HSV strain 17.	('gamma134.5', 'Gene', (48, 58))	('HSV strain', 'Species', '10298', (74, 84))	('HSV', 'Species', '10298', (74, 77))	('deleting', 'Var', (24, 32))	('HSV', 'Species', '10298', (0, 3))
85158	22430386	Efficacy of mutant HSV has been demonstrated preclinically in pediatric gliomas, medulloblastomas, and neuroblastomas.	('pediatric gliomas', 'Disease', (62, 79))	('medulloblastoma', 'Phenotype', 'HP:0002885', (81, 96))	('neuroblastomas', 'Disease', (103, 117))	('neuroblastoma', 'Phenotype', 'HP:0003006', (103, 116))	('medulloblastomas', 'Disease', (81, 97))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('HSV', 'Gene', (19, 22))	('pediatric gliomas', 'Disease', 'MESH:D005910', (62, 79))	('neuroblastomas', 'Phenotype', 'HP:0003006', (103, 117))	('mutant', 'Var', (12, 18))	('neuroblastomas', 'Disease', 'MESH:D009447', (103, 117))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('medulloblastomas', 'Disease', 'MESH:D008527', (81, 97))	('HSV', 'Species', '10298', (19, 22))
85159	22430386	Recent research has examined the ability of mutant HSVs to kill CSC from pediatric neural tumors (Table 3 summarizes studies utilizing oncolytic viruses to target pediatric CSC).	('pediatric neural tumors', 'Disease', (73, 96))	('HSV', 'Species', '10298', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('pediatric neural tumors', 'Disease', 'MESH:D063766', (73, 96))	('mutant', 'Var', (44, 50))
85162	22430386	The pediatric GBM D456MG was more sensitive to killing than several adult GBM xenografts tested.	('D456MG', 'Var', (18, 24))	('D456MG', 'Chemical', '-', (18, 24))	('sensitive', 'MPA', (34, 43))
85168	22430386	Engineered HSV rQT3 has deletions of ICP6 and gamma134.5 and expresses human Tissue Inhibitor of Metallo-Proteinases 3 (TIMP3).	('Tissue Inhibitor of Metallo-Proteinases 3', 'Gene', '7078', (77, 118))	('Engineered HSV', 'Disease', 'MESH:C536395', (0, 14))	('TIMP3', 'Gene', '7078', (120, 125))	('deletions', 'Var', (24, 33))	('TIMP3', 'Gene', (120, 125))	('Engineered HSV', 'Disease', (0, 14))	('gamma134.5', 'Protein', (46, 56))	('Tissue Inhibitor of Metallo-Proteinases 3', 'Gene', (77, 118))	('ICP6', 'Gene', (37, 41))	('human', 'Species', '9606', (71, 76))
85178	22430386	Preclinical efficacy of G207 in pediatric rhabdomyosarcoma and osteosarcoma cell lines was demonstrated by Bharatan et al.	('G207', 'Var', (24, 28))	('osteosarcoma', 'Disease', (63, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (63, 75))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (42, 58))	('osteosarcoma', 'Disease', 'MESH:D012516', (63, 75))	('rhabdomyosarcoma', 'Disease', (42, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (42, 58))
85185	22430386	Deletions in immediate-early (E1A) or early (E1B) adenovirus genes result in attenuated mutants that cannot bind normal cellular proteins that drive gene expression initiating and maintaining cellular proliferation needed for productive virus infection.	('E1A', 'Gene', (30, 33))	('virus infection', 'Disease', 'MESH:D015658', (237, 252))	('adenovirus', 'Species', '28285', (50, 60))	('adenovirus genes', 'Gene', (50, 66))	('virus infection', 'Disease', (237, 252))	('Deletions', 'Var', (0, 9))
85186	22430386	These virus genome deletions do not effect its replication in cancer cells due to pathway defects such as p16/retinoblastoma (Rb) or p53.	('defects', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('p53', 'Gene', '7157', (133, 136))	('cancer', 'Disease', (62, 68))	('p16/retinoblastoma (Rb', 'Gene', (106, 128))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('retinoblastoma', 'Phenotype', 'HP:0009919', (110, 124))	('p53', 'Gene', (133, 136))	('p16/retinoblastoma (Rb)', 'Gene', '1029;5925', (106, 129))	('deletions', 'Var', (19, 28))
85189	22430386	Newer CRAds circumvent this limitation through modifications of the fiber knob of the viral capsid thereby altering the tropism of the virus and enabling infection of cancer cells through a CAR-independent mechanism.	('infection of cancer', 'Disease', (154, 173))	('infection of cancer', 'Disease', 'MESH:D009369', (154, 173))	('tropism', 'MPA', (120, 127))	('altering', 'Reg', (107, 115))	('enabling', 'PosReg', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('modifications', 'Var', (47, 60))	('CRAd', 'Gene', (6, 10))	('CRAd', 'Gene', '19683', (6, 10))
85197	22430386	The virus has a 24 base pair deletion in the Rb binding site of E1A and the native E1A promoter is replaced with the cyclooxygenase-2 (COX-2) promoter.	('deletion', 'Var', (29, 37))	('cyclooxygenase-2', 'Gene', '5743', (117, 133))	('cyclooxygenase-2', 'Gene', (117, 133))	('COX-2', 'Gene', (135, 140))	('COX-2', 'Gene', '5743', (135, 140))	('Rb', 'Chemical', '-', (45, 47))
85201	22430386	In a separate study, four children (2 to 5 years of age) with refractory metastatic neuroblastoma received several doses of Ad-DM-E2F-K-Delta24RGD (ICOVIR-5), a CRAd that contains a deletion in E1A, a substitution of the E1A promoter for E2F-responsive elements, and an RGD-4C peptide motif inserted into the adenoviral fiber to enhance adenoviral tropism.	('E1A', 'Gene', (194, 197))	('neuroblastoma', 'Disease', 'MESH:D009447', (84, 97))	('adenoviral tropism', 'Disease', (337, 355))	('neuroblastoma', 'Disease', (84, 97))	('deletion', 'Var', (182, 190))	('Delta', 'Chemical', '-', (136, 141))	('children', 'Species', '9606', (26, 34))	('CRAd', 'Gene', '19683', (161, 165))	('adenoviral tropism', 'Disease', 'None', (337, 355))	('CRAd', 'Gene', (161, 165))	('neuroblastoma', 'Phenotype', 'HP:0003006', (84, 97))	('enhance', 'PosReg', (329, 336))	('Ad-DM-E2F-K-Delta24RGD', 'Var', (124, 146))
85209	22430386	Delta-24-RGD is currently in a phase I trial in adults with recurrent malignant gliomas (NCT00805376).	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('malignant gliomas', 'Disease', (70, 87))	('malignant gliomas', 'Disease', 'MESH:D005910', (70, 87))	('Delta-24-RGD', 'Var', (0, 12))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('Delta', 'Chemical', '-', (0, 5))
85234	22430386	Breast CSC, marked by CD24-CD44+ expression and over-expression of aldehyde dehydrogenase, were as sensitive to killing by reovirus as the non-CSC.	('over-expression', 'PosReg', (48, 63))	('CD24-CD44+ expression', 'Var', (22, 43))	('aldehyde dehydrogenase', 'Gene', (67, 89))	('reovirus', 'Species', '10891', (123, 131))	('Breast CSC', 'Disease', (0, 10))
85261	22430386	Another promising approach to prevent infection in normal tissue involves deleting the B18R gene, which counteracts type I-interferons.	('B18R', 'SUBSTITUTION', 'None', (87, 91))	('deleting', 'Var', (74, 82))	('B18R', 'Var', (87, 91))
85262	22430386	The B18R-deleted mutant results in interferon-mediated enhanced virus inactivation in normal cells.	('virus inactivation', 'MPA', (64, 82))	('enhanced', 'PosReg', (55, 63))	('B18R', 'SUBSTITUTION', 'None', (4, 8))	('B18R', 'Var', (4, 8))
85273	22430386	Using a Western Reserve strain of VV with mutations in TK and viral growth genes that is delivered to tumor cells by an ex vivo expanded NK-T cell population (CIK-vvDD), Contag et al.	('VV', 'Species', '10245', (34, 36))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('mutations', 'Var', (42, 51))
85280	22430386	While there are no specific studies examining the effect of NDV on pediatric CSC, attenuated NDV has been used safely with demonstrated efficacy in children with high-grade gliomas.	('NDV', 'Species', '11176', (60, 63))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('gliomas', 'Disease', (173, 180))	('children', 'Species', '9606', (148, 156))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('attenuated', 'Var', (82, 92))	('NDV', 'Species', '11176', (93, 96))
85287	22430386	Furthermore, Akt inhibition has been shown to preferentially kill brain CSC relative to other brain tumor cells and reduce tumor invasiveness.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('brain tumor', 'Phenotype', 'HP:0030692', (94, 105))	('reduce', 'NegReg', (116, 122))	('tumor invasiveness', 'Disease', 'MESH:D009369', (123, 141))	('Akt', 'Gene', '207', (13, 16))	('inhibition', 'Var', (17, 27))	('preferentially', 'PosReg', (46, 60))	('brain CSC', 'CPA', (66, 75))	('brain tumor', 'Disease', 'MESH:D001932', (94, 105))	('brain tumor', 'Disease', (94, 105))	('Akt', 'Gene', (13, 16))	('tumor invasiveness', 'Disease', (123, 141))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
85297	22430386	Human osteosarcoma and Ewing's sarcoma were sensitive to infection with a different mutant VSV whereas a human synovial sarcoma line was very resistant.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('Human', 'Species', '9606', (0, 5))	('osteosarcoma', 'Disease', (6, 18))	('sensitive', 'Reg', (44, 53))	('osteosarcoma', 'Phenotype', 'HP:0002669', (6, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (111, 127))	('synovial sarcoma', 'Disease', 'MESH:D013584', (111, 127))	('osteosarcoma', 'Disease', 'MESH:D012516', (6, 18))	('VSV', 'Gene', (91, 94))	('VSV', 'Species', '11276', (91, 94))	('mutant', 'Var', (84, 90))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (23, 38))	('human', 'Species', '9606', (105, 110))	('synovial sarcoma', 'Disease', (111, 127))	("Ewing's sarcoma", 'Disease', (23, 38))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (23, 38))
85336	32551295	In a recent study, intimal sarcoma has been reported to be the most frequently occurring type of primary cardiac sarcoma (42%), with its characteristic pathological feature being MDM2 gene overexpression and amplification.	('sarcoma', 'Disease', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('amplification', 'Var', (208, 221))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('cardiac sarcoma', 'Disease', (105, 120))	('MDM2', 'Gene', (179, 183))	('sarcoma', 'Disease', (113, 120))	('overexpression', 'PosReg', (189, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('cardiac sarcoma', 'Phenotype', 'HP:0031350', (105, 120))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('cardiac sarcoma', 'Disease', 'MESH:D006331', (105, 120))
85384	32355640	For example, imatinib response in gastrointestinal stromal tumors depends on c-KIT gene mutations; although mutations in exon 11 usually respond to Imatinib, changes on exon 13 confer drug resistance.	('c-KIT', 'Gene', '3815', (77, 82))	('mutations', 'Var', (108, 117))	('drug resistance', 'MPA', (184, 199))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (34, 65))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (34, 65))	('drug resistance', 'Phenotype', 'HP:0020174', (184, 199))	('changes', 'Var', (158, 165))	('confer', 'Reg', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('respond to Imatinib', 'MPA', (137, 156))	('Imatinib', 'Chemical', 'MESH:D000068877', (148, 156))	('c-KIT', 'Gene', (77, 82))	('imatinib', 'Chemical', 'MESH:D000068877', (13, 21))	('gastrointestinal stromal tumors', 'Disease', (34, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
85392	32355640	A recent study in 5726 patients compared the radiation dose-response of non-retroperitoneal STS and detected higher OS in patients treated with 69 Gy compared to 66 Gy.	('patients', 'Species', '9606', (23, 31))	('STS', 'Phenotype', 'HP:0030448', (92, 95))	('higher', 'PosReg', (109, 115))	('patients', 'Species', '9606', (122, 130))	('69 Gy', 'Var', (144, 149))
85393	32355640	Another report showed lower local recurrence on patients treated with 64-68 Gy compared with 60 Gy.	('lower', 'NegReg', (22, 27))	('64-68 Gy', 'Var', (70, 78))	('local recurrence', 'CPA', (28, 44))	('patients', 'Species', '9606', (48, 56))
85422	32355640	Furthermore, NGS techniques detect specific tumor mutations and altered antigens, contributing to the development of targeted cancer therapies, such as monoclonal antibodies and cytotoxic lymphocytes modified to express antigen-specific receptors (T-cell receptor and chimeric antigen receptor).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
85435	31668005	Mechanistically, MS-275 inhibits YB-1 deacetylation, decreasing its binding to 5'-UTRs of NFE2L2 encoding the antioxidant factor NRF2, thereby reducing NFE2L2 translation and synthesis of NRF2 to increase cellular ROS.	('NFE2L2', 'Gene', (152, 158))	('MS-275', 'Var', (17, 23))	('decreasing', 'NegReg', (53, 63))	('reducing', 'NegReg', (143, 151))	('deacetylation', 'MPA', (38, 51))	('synthesis of NRF2', 'MPA', (175, 192))	('cellular ROS', 'MPA', (205, 217))	('YB-1', 'Gene', (33, 37))	('binding', 'Interaction', (68, 75))	('inhibits', 'NegReg', (24, 32))	('MS-275', 'Chemical', 'MESH:C118739', (17, 23))	('NFE2L2', 'Gene', '4780', (90, 96))	('increase cellular ROS', 'Phenotype', 'HP:0025464', (196, 217))	('NFE2L2', 'Gene', '4780', (152, 158))	('NFE2L2', 'Gene', (90, 96))	('translation', 'MPA', (159, 170))	('increase', 'PosReg', (196, 204))	('ROS', 'Chemical', 'MESH:D017382', (214, 217))
85436	31668005	By global acetylomics, MS-275 promotes rapid acetylation of the YB-1 RNA-binding protein at lysine-81, blocking binding and translational activation of NFE2L2, as well as known YB-1 mRNA targets, HIF1A, and the stress granule nucleator, G3BP1.	('NFE2L2', 'Gene', (152, 158))	('binding', 'Interaction', (112, 119))	('MS-275', 'Chemical', 'MESH:C118739', (23, 29))	('promotes', 'PosReg', (30, 38))	('YB-1', 'Gene', (64, 68))	('blocking', 'NegReg', (103, 111))	('RNA-binding protein', 'Gene', (69, 88))	('HIF1A', 'Gene', (196, 201))	('lysine', 'Chemical', 'MESH:D008239', (92, 98))	('translational activation', 'MPA', (124, 148))	('HIF1A', 'Gene', '3091', (196, 201))	('RNA-binding protein', 'Gene', '27303', (69, 88))	('acetylation', 'MPA', (45, 56))	('NFE2L2', 'Gene', '4780', (152, 158))	('MS-275', 'Var', (23, 29))
85437	31668005	MS-275 dramatically reduces sarcoma metastasis in vivo, but an MS-275-resistant YB-1K81-to-alanine mutant restores metastatic capacity and NRF2, HIF1alpha, and G3BP1 synthesis in MS-275-treated mice.	('G3BP1 synthesis', 'MPA', (160, 175))	('sarcoma metastasis', 'Disease', 'MESH:D009362', (28, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('NRF2', 'MPA', (139, 143))	('HIF1alpha', 'MPA', (145, 154))	('MS-275', 'Chemical', 'MESH:C118739', (0, 6))	('restores', 'PosReg', (106, 114))	('MS-275', 'Chemical', 'MESH:C118739', (179, 185))	('K81', 'Gene', (84, 87))	('MS-275', 'Chemical', 'MESH:C118739', (63, 69))	('alanine', 'Chemical', 'MESH:D000409', (91, 98))	('K81', 'Gene', '3887', (84, 87))	('mutant', 'Var', (99, 105))	('metastatic capacity', 'CPA', (115, 134))	('mice', 'Species', '10090', (194, 198))	('sarcoma metastasis', 'Disease', (28, 46))
85456	31668005	Moreover, pancreatic carcinoma cells with loss of NRF2 show defects in redox homeostasis and markedly diminished tumor initiation and maintenance, which is linked to translational inhibition due to oxidation of the different members of the translation machinery 17.	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (10, 30))	('loss', 'Var', (42, 46))	('redox homeostasis', 'MPA', (71, 88))	('diminished', 'NegReg', (102, 112))	('defects', 'NegReg', (60, 67))	('NRF2', 'Gene', (50, 54))	('tumor initiation', 'Disease', 'MESH:D009369', (113, 129))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('tumor initiation', 'Disease', (113, 129))	('pancreatic carcinoma', 'Disease', (10, 30))
85469	31668005	Mechanistically, MS-275 induces acetylation within the YB-1 CSD to block binding of target mRNAs, with widespread effects on YB-1 translational regulation of stress-adaptive mRNAs, including a new YB-1 target, NFE2L2, encoding NRF2.	('MS-275', 'Var', (17, 23))	('acetylation', 'MPA', (32, 43))	('MS-275', 'Chemical', 'MESH:C118739', (17, 23))	('effects', 'Reg', (114, 121))	('binding', 'Interaction', (73, 80))	('induces', 'Reg', (24, 31))	('NFE2L2', 'Gene', '4780', (210, 216))	('block', 'NegReg', (67, 72))	('NFE2L2', 'Gene', (210, 216))	('translational regulation', 'MPA', (130, 154))
85479	31668005	Of these compounds, only MS-275 had no toxicity alone at a 1 muM concentration (Fig 1B) and did not affect cell proliferation (Fig EV1A); however, MS-275-pre-treated cells were potently killed after a subsequent 1-h exposure to 100 muM NaAsO2, with a greater effect than NaAsO2 alone (Fig 1B), so we focused on MS-275 in subsequent studies.	('NaAsO2', 'Chemical', '-', (236, 242))	('muM', 'Gene', (61, 64))	('MS-275', 'Chemical', 'MESH:C118739', (311, 317))	('muM', 'Gene', '56925', (232, 235))	('MS-275', 'Chemical', 'MESH:C118739', (147, 153))	('MS-275', 'Chemical', 'MESH:C118739', (25, 31))	('NaAsO2', 'Chemical', '-', (271, 277))	('MS-275-pre-treated', 'Var', (147, 165))	('muM', 'Gene', (232, 235))	('toxicity', 'Disease', 'MESH:D064420', (39, 47))	('toxicity', 'Disease', (39, 47))	('muM', 'Gene', '56925', (61, 64))
85481	31668005	We first confirmed that MS-275 increases oxidative stress in NaAsO2-treated sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('MS-275', 'Var', (24, 30))	('NaAsO2', 'Chemical', '-', (61, 67))	('increases', 'PosReg', (31, 40))	('oxidative stress', 'Phenotype', 'HP:0025464', (41, 57))	('MS-275', 'Chemical', 'MESH:C118739', (24, 30))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('oxidative stress', 'MPA', (41, 57))
85482	31668005	Using chloromethyl derivative of 2',7'-dichlorofluorescin diacetate (CM-H2DCFDA) staining as a ROS readout, MS-275 alone failed to significantly increase ROS levels compared to vehicle in U2OS cells (Figs 1C and EV1B), and only moderately increased ROS in CHLA-10 cells (Fig EV1C).	('increase ROS levels', 'Phenotype', 'HP:0025464', (145, 164))	('CHLA-10', 'CellLine', 'CVCL:6583', (256, 263))	('CM-H2DCFDA', 'Chemical', '-', (69, 79))	('increase', 'PosReg', (145, 153))	('U2OS', 'CellLine', 'CVCL:0042', (188, 192))	('MS-275', 'Var', (108, 114))	('chloromethyl', 'Chemical', '-', (6, 18))	('ROS levels', 'MPA', (154, 164))	('ROS', 'Chemical', 'MESH:D017382', (95, 98))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('ROS', 'Chemical', 'MESH:D017382', (249, 252))	('MS-275', 'Chemical', 'MESH:C118739', (108, 114))	("2',7'-dichlorofluorescin diacetate", 'Chemical', 'MESH:C029569', (33, 67))
85483	31668005	However, MS-275 markedly increased ROS in combination with NaAsO2 co-treatment, in U2OS (Figs 1C and EV1B) and CHLA-10 EwS cells (Fig EV1C), which was confirmed using CellROX assays (Fig EV1D).	('CHLA-10 EwS', 'CellLine', 'CVCL:W742', (111, 122))	('MS-275', 'Chemical', 'MESH:C118739', (9, 15))	('increased', 'PosReg', (25, 34))	('ROS', 'Chemical', 'MESH:D017382', (35, 38))	('U2OS', 'CellLine', 'CVCL:0042', (83, 87))	('MS-275', 'Var', (9, 15))	('NaAsO2', 'Chemical', '-', (59, 65))	('ROS', 'MPA', (35, 38))
85484	31668005	Moreover, MS-275 significantly decreased the ratio of reduced to oxidized forms of glutathione (GSH/GSSG), a well-established readout of oxidative stress in cells and tissues, but only in combination with NaAsO2 (Fig 1D), and only increased apoptosis in NaAsO2-co-treated U2OS cells, which was reversed by the antioxidant, N-acetylcysteine (NAC; Fig 1E).	('NAC', 'Chemical', 'MESH:D000111', (341, 344))	('GSH', 'Chemical', '-', (96, 99))	('NaAsO2', 'Chemical', '-', (205, 211))	('oxidative stress', 'Phenotype', 'HP:0025464', (137, 153))	('GSSG', 'Chemical', 'MESH:D019803', (100, 104))	('MS-275', 'Var', (10, 16))	('U2OS', 'CellLine', 'CVCL:0042', (272, 276))	('decreased', 'NegReg', (31, 40))	('glutathione', 'Chemical', 'MESH:D005978', (83, 94))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (323, 339))	('ratio', 'MPA', (45, 50))	('NaAsO2', 'Chemical', '-', (254, 260))	('MS-275', 'Chemical', 'MESH:C118739', (10, 16))	('reduced', 'MPA', (54, 61))
85487	31668005	Treatment of sarcoma spheroids with MS-275 further increased ROS, which again could be reversed by antioxidants (Fig EV1F), and increased apoptosis, which was also blocked by antioxidants (Fig EV1G).	('sarcoma spheroids', 'Disease', (13, 30))	('MS-275', 'Chemical', 'MESH:C118739', (36, 42))	('increased', 'PosReg', (51, 60))	('increased', 'PosReg', (128, 137))	('sarcoma spheroids', 'Disease', 'MESH:D012509', (13, 30))	('ROS', 'MPA', (61, 64))	('apoptosis', 'CPA', (138, 147))	('MS-275', 'Var', (36, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
85493	31668005	Moreover, while NaAsO2 enhanced NRF2-linked antioxidant response element (ARE) reporter activity, this was again significantly reduced by MS-275 in U2OS and CHLA-10 cells (Fig 1G, left and right panels, respectively).	('enhanced', 'PosReg', (23, 31))	('NaAsO2', 'Chemical', '-', (16, 22))	('CHLA-10', 'CellLine', 'CVCL:6583', (157, 164))	('U2OS', 'CellLine', 'CVCL:0042', (148, 152))	('MS-275', 'Var', (138, 144))	('reduced', 'NegReg', (127, 134))	('MS-275', 'Chemical', 'MESH:C118739', (138, 144))
85494	31668005	Lastly, ectopic NRF2 expression blocked the ability of MS-275 to induce ROS accumulation in sarcoma cells under NaAsO2 co-treatment (Fig 1H).	('blocked', 'NegReg', (32, 39))	('NaAsO2', 'Chemical', '-', (112, 118))	('expression', 'Species', '29278', (21, 31))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('ROS accumulation', 'MPA', (72, 88))	('sarcoma', 'Disease', (92, 99))	('MS-275', 'Chemical', 'MESH:C118739', (55, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('NRF2', 'Gene', (16, 20))	('ectopic', 'Var', (8, 15))
85496	31668005	HDAC inhibitors such as MS-275 are thought to transcriptionally modify gene expression through hyperacetylation of histones such as H3 and H4, leading to chromatin remodeling which typically requires ~24 h or more to cause major transcriptional changes 41.	('gene expression', 'MPA', (71, 86))	('transcriptional changes', 'MPA', (229, 252))	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('MS-275', 'Var', (24, 30))	('modify', 'Reg', (64, 70))	('expression', 'Species', '29278', (76, 86))	('MS-275', 'Chemical', 'MESH:C118739', (24, 30))	('hyperacetylation', 'MPA', (95, 111))	('chromatin remodeling', 'MPA', (154, 174))
85499	31668005	This suggests that MS-275 specifically inhibits NFE2L2 translation rather than its transcription (see below).	('MS-275', 'Chemical', 'MESH:C118739', (19, 25))	('NFE2L2', 'Gene', '4780', (48, 54))	('NFE2L2', 'Gene', (48, 54))	('MS-275', 'Var', (19, 25))	('inhibits', 'NegReg', (39, 47))	('translation', 'MPA', (55, 66))
85501	31668005	We also tested whether MS-275 influences NRF2 protein stability by performing cycloheximide pulse-chase experiments in MS-275-treated U2OS and CHLA-10 cells.	('tested', 'Reg', (8, 14))	('MS-275-treated', 'Var', (119, 133))	('U2OS', 'CellLine', 'CVCL:0042', (134, 138))	('MS-275', 'Chemical', 'MESH:C118739', (23, 29))	('MS-275', 'Chemical', 'MESH:C118739', (119, 125))	('CHLA-10', 'CellLine', 'CVCL:6583', (143, 150))	('cycloheximide', 'Chemical', 'MESH:D003513', (78, 91))	('influences', 'Reg', (30, 40))	('NRF2 protein', 'Protein', (41, 53))
85503	31668005	Together, these results suggest that the major effect of MS-275 on NRF2 activity is by reducing its mRNA translation.	('MS-275', 'Chemical', 'MESH:C118739', (57, 63))	('activity', 'MPA', (72, 80))	('reducing', 'NegReg', (87, 95))	('MS-275', 'Var', (57, 63))	('NRF2', 'Gene', (67, 71))	('mRNA translation', 'MPA', (100, 116))
85504	31668005	The above findings indicate that MS-275 regulates NRF2 via mechanisms other than through histone modifications.	('MS-275', 'Var', (33, 39))	('regulates', 'Reg', (40, 49))	('MS-275', 'Chemical', 'MESH:C118739', (33, 39))	('NRF2', 'Gene', (50, 54))
85510	31668005	Indeed, apart from histones, and several ribosomal proteins, only DEK (DEK proto-oncogene), NAT10 (N-acetyltransferase 10), PARP1 (poly(ADP-ribose) polymerase 1), and TOP1 (DNA topoisomerase I), in addition to YBX1, showed consistently increased acetylation under MS275 treatment.	('DEK', 'Gene', (66, 69))	('acetylation', 'MPA', (246, 257))	('YBX1', 'Gene', (210, 214))	('poly(ADP-ribose) polymerase 1', 'Gene', (131, 160))	('DEK', 'Gene', '7913', (71, 74))	('PARP1', 'Gene', '142', (124, 129))	('poly(ADP-ribose) polymerase 1', 'Gene', '142', (131, 160))	('PARP1', 'Gene', (124, 129))	('N-acetyltransferase 10', 'Gene', (99, 121))	('MS275', 'Chemical', 'MESH:C118739', (264, 269))	('N-acetyltransferase 10', 'Gene', '55226', (99, 121))	('YBX1', 'Gene', '4904', (210, 214))	('MS275 treatment', 'Var', (264, 279))	('DEK', 'Gene', (71, 74))	('DEK', 'Gene', '7913', (66, 69))	('increased', 'PosReg', (236, 245))	('NAT10', 'Gene', '55226', (92, 97))	('NAT10', 'Gene', (92, 97))
85515	31668005	Histone H4, used as a positive control, was also acetylated in the presence of MS-275 but over a much longer time course; H4 acetylation was minimal at 3 h in these cells, but then increased markedly by 6-24 h of MS-275 treatment (Fig EV2C).	('acetylation', 'MPA', (125, 136))	('MS-275', 'Var', (213, 219))	('Histone H4', 'Gene', (0, 10))	('Histone H4', 'Gene', '8361', (0, 10))	('MS-275', 'Chemical', 'MESH:C118739', (213, 219))	('increased', 'PosReg', (181, 190))	('MS-275', 'Chemical', 'MESH:C118739', (79, 85))
85517	31668005	These data indicate that MS-275 enhances acetylation of YB-1 in sarcoma cells.	('enhances', 'PosReg', (32, 40))	('MS-275', 'Var', (25, 31))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('acetylation', 'MPA', (41, 52))	('MS-275', 'Chemical', 'MESH:C118739', (25, 31))	('sarcoma', 'Disease', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('YB-1', 'Gene', (56, 60))
85521	31668005	We therefore generated a K-to-alanine (A) substitution of K81 and expressed this mutant along with wild-type (wt) YB-1 as FLAG-tagged proteins in U2OS cells (Fig EV2E).	('K81', 'Gene', (58, 61))	('K81', 'Gene', '3887', (58, 61))	('K-to-alanine', 'Var', (25, 37))	('U2OS', 'CellLine', 'CVCL:0042', (146, 150))	('alanine', 'Chemical', 'MESH:D000409', (30, 37))
85526	31668005	We previously showed that YB-1 inactivation increases sensitivity to oxidative stress in sarcoma cells 32.	('inactivation', 'Var', (31, 43))	('YB-1', 'Gene', (26, 30))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('oxidative stress', 'Phenotype', 'HP:0025464', (69, 85))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('sensitivity to oxidative stress', 'MPA', (54, 85))	('increases', 'PosReg', (44, 53))
85528	31668005	Indeed, YB-1 knockdown under H2O2- or NaAsO2-induced oxidative stress markedly reduced NRF2 levels in vitro (Fig 3A).	('YB-1', 'Gene', (8, 12))	('oxidative stress', 'Phenotype', 'HP:0025464', (53, 69))	('reduced', 'NegReg', (79, 86))	('H2O2', 'Chemical', 'MESH:D006861', (29, 33))	('NaAsO2', 'Chemical', '-', (38, 44))	('NRF2 levels', 'MPA', (87, 98))	('knockdown', 'Var', (13, 22))
85531	31668005	Using this reporter in cell-free transcription/translation studies, recombinant YB-1 markedly enhanced Firefly LUC translation in a dose-dependent manner, but not of Renila LUC; therefore, YB-1 translationally activates the NFE2L2 5'-UTR but not a control HBB 5'-UTR (Fig 3B).	('activates', 'PosReg', (210, 219))	('YB-1', 'Gene', (80, 84))	('YB-1', 'Var', (189, 193))	('NFE2L2', 'Gene', '4780', (224, 230))	('HBB', 'Gene', '3043', (256, 259))	('enhanced', 'PosReg', (94, 102))	('HBB', 'Gene', (256, 259))	('NFE2L2', 'Gene', (224, 230))	('Firefly LUC translation', 'MPA', (103, 126))
85541	31668005	However, NRF2 synthesis was rescued in cells expressing YB-1-K81A (Fig 3E; compare lanes 4-7).	('YB-1-K81A', 'Var', (56, 65))	('K81A', 'Mutation', 'p.K81A', (61, 65))	('NRF2 synthesis', 'MPA', (9, 23))	('rescued', 'PosReg', (28, 35))
85543	31668005	Together, our findings strongly support a model whereby MS-275 increases acetylation of YB-1-K81 within the YB-1 CSD to inhibit NFE2L2 binding, in turn blocking its translational activation by YB-1.	('increases', 'PosReg', (63, 72))	('translational activation', 'MPA', (165, 189))	('acetylation', 'MPA', (73, 84))	('K81', 'Gene', (93, 96))	('K81', 'Gene', '3887', (93, 96))	('blocking', 'NegReg', (152, 160))	('MS-275', 'Var', (56, 62))	('inhibit', 'NegReg', (120, 127))	('NFE2L2', 'Gene', '4780', (128, 134))	('binding', 'Interaction', (135, 142))	('MS-275', 'Chemical', 'MESH:C118739', (56, 62))	('NFE2L2', 'Gene', (128, 134))
85545	31668005	In CHLA-10 cells, MS-275 markedly reduced both HIF1alpha under hypoxia (Fig 4A), and G3BP levels under NaAsO2 treatment (Fig 4B), without affecting YB-1 levels.	('reduced', 'NegReg', (34, 41))	('CHLA-10', 'CellLine', 'CVCL:6583', (3, 10))	('G3BP', 'Gene', '10146', (85, 89))	('hypoxia', 'Disease', 'MESH:D000860', (63, 70))	('MS-275', 'Var', (18, 24))	('NaAsO2', 'Chemical', '-', (103, 109))	('G3BP', 'Gene', (85, 89))	('hypoxia', 'Disease', (63, 70))	('HIF1alpha', 'MPA', (47, 56))	('MS-275', 'Chemical', 'MESH:C118739', (18, 24))
85546	31668005	Similar to NFE2L2, association of either HIF1A (encoding HIF1alpha) or G3BP1 transcripts (encoding G3BP) with polysomes was significantly reduced in MS-275-treated cells (Fig 4C and D), even though total mRNAs were increased.	('G3BP', 'Gene', '10146', (71, 75))	('reduced', 'NegReg', (138, 145))	('G3BP', 'Gene', '10146', (99, 103))	('NFE2L2', 'Gene', '4780', (11, 17))	('HIF1A', 'Gene', (41, 46))	('HIF1A', 'Gene', '3091', (41, 46))	('MS-275-treated', 'Var', (149, 163))	('NFE2L2', 'Gene', (11, 17))	('G3BP', 'Gene', (71, 75))	('G3BP', 'Gene', (99, 103))	('MS-275', 'Chemical', 'MESH:C118739', (149, 155))	('association', 'Interaction', (19, 30))
85547	31668005	Using RIP with anti-FLAG antibodies as described above for NFE2L2, YB-1-K81A bound significantly higher amounts of HIF1A and G3BP1 transcripts compared to wt YB-1, especially under MS-275 co-treatment with 1% O2 or NaAsO2, respectively (Fig 4E and F).	('K81A', 'Mutation', 'p.K81A', (72, 76))	('higher', 'PosReg', (97, 103))	('NaAsO2', 'Chemical', '-', (215, 221))	('YB-1-K81A', 'Var', (67, 76))	('NFE2L2', 'Gene', '4780', (59, 65))	('G3BP1', 'Gene', (125, 130))	('HIF1A', 'Gene', (115, 120))	('MS-275', 'Chemical', 'MESH:C118739', (181, 187))	('O2', 'Chemical', 'MESH:D010100', (209, 211))	('HIF1A', 'Gene', '3091', (115, 120))	('NFE2L2', 'Gene', (59, 65))	('O2', 'Chemical', 'MESH:D010100', (219, 221))	('bound', 'Interaction', (77, 82))
85548	31668005	Again, MS-275 completely blocked acute G3BP1 synthesis under NaAsO2, or HIF1alpha under 1% O2, both of which were rescued by YB-1-K81A but not wt YB-1 (Fig EV3A and B).	('O2', 'Chemical', 'MESH:D010100', (65, 67))	('NaAsO2', 'Chemical', '-', (61, 67))	('O2', 'Chemical', 'MESH:D010100', (91, 93))	('HIF1alpha', 'Gene', (72, 81))	('K81A', 'Mutation', 'p.K81A', (130, 134))	('MS-275', 'Chemical', 'MESH:C118739', (7, 13))	('blocked', 'NegReg', (25, 32))	('G3BP1', 'Gene', (39, 44))	('YB-1-K81A', 'Var', (125, 134))
85551	31668005	While wt YB-1 was unable to rescue SGs in the presence of MS-275, YB-1-K81A was almost as effective as G3BP1 overexpression in restoring NaAsO2-induced SG assembly in MS-275-treated cells (Fig EV3D).	('MS-275', 'Chemical', 'MESH:C118739', (167, 173))	('K81A', 'Mutation', 'p.K81A', (71, 75))	('NaAsO2', 'Chemical', '-', (137, 143))	('MS-275', 'Chemical', 'MESH:C118739', (58, 64))	('NaAsO2-induced SG assembly', 'MPA', (137, 163))	('YB-1-K81A', 'Var', (66, 75))	('expression', 'Species', '29278', (113, 123))	('restoring', 'PosReg', (127, 136))
85552	31668005	Therefore, MS-275-enhanced acetylation of YB-1 K81 is directly associated with its ability to block YB-1-mediated translational activation of target mRNAs and SG formation.	('MS-275-enhanced', 'PosReg', (11, 26))	('YB-1-mediated', 'Gene', (100, 113))	('SG formation', 'MPA', (159, 171))	('block', 'NegReg', (94, 99))	('acetylation', 'MPA', (27, 38))	('translational activation', 'MPA', (114, 138))	('MS-275', 'Chemical', 'MESH:C118739', (11, 17))	('YB-1', 'Gene', (42, 46))	('K81', 'Gene', (47, 50))	('MS-275-enhanced', 'Var', (11, 26))	('K81', 'Gene', '3887', (47, 50))
85563	31668005	We next validated MS-275 effects on in vivo YB-1 acetylation, which was readily detected in CHLA-10 tumors from MS-275-treated mice but not in corresponding tumors from vehicle control mice (Fig EV4D).	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CHLA-10', 'CellLine', 'CVCL:6583', (92, 99))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('MS-275', 'Chemical', 'MESH:C118739', (112, 118))	('YB-1', 'Gene', (44, 48))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('mice', 'Species', '10090', (185, 189))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('MS-275', 'Var', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('acetylation', 'MPA', (49, 60))	('MS-275', 'Chemical', 'MESH:C118739', (18, 24))
85564	31668005	We also confirmed that MS-275 alters ROS levels in vivo.	('alters', 'Reg', (30, 36))	('MS-275', 'Chemical', 'MESH:C118739', (23, 29))	('ROS levels', 'MPA', (37, 47))	('ROS', 'Chemical', 'MESH:D017382', (37, 40))	('MS-275', 'Var', (23, 29))
85566	31668005	Staining with a second oxidative stress marker, 4-hydroxynonenal (4-HNE), was also significantly higher in MS-275-treated CHLA-10 tumor xenografts compared to control tumors (Fig EV4E).	('Staining', 'MPA', (0, 8))	('tumor', 'Disease', (130, 135))	('higher', 'PosReg', (97, 103))	('oxidative stress', 'Phenotype', 'HP:0025464', (23, 39))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('MS-275-treated', 'Var', (107, 121))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('CHLA-10', 'CellLine', 'CVCL:6583', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('4-hydroxynonenal', 'Chemical', 'MESH:C027576', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('MS-275', 'Chemical', 'MESH:C118739', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('4-hydroxynonenal', 'MPA', (48, 64))	('tumors', 'Disease', (167, 173))	('4-HNE', 'Chemical', 'MESH:C027576', (66, 71))	('tumor', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
85567	31668005	Therefore, MS-275 also enhances sarcoma oxidative stress in vivo.	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('MS-275', 'Var', (11, 17))	('sarcoma', 'Disease', (32, 39))	('enhances', 'PosReg', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('MS-275', 'Chemical', 'MESH:C118739', (11, 17))	('oxidative stress', 'Phenotype', 'HP:0025464', (40, 56))
85571	31668005	Notably, as with CHLA-10 xenografts, MS-275 dramatically reduced local invasion (Fig 5B; see bar graph on the right) and lung metastasis (Fig 5C and D), as well as the size of metastatic nodules (Fig 5E).	('MS-275', 'Chemical', 'MESH:C118739', (37, 43))	('CHLA-10', 'CellLine', 'CVCL:6583', (17, 24))	('local invasion', 'CPA', (65, 79))	('MS-275', 'Var', (37, 43))	('lung metastasis', 'CPA', (121, 136))	('reduced', 'NegReg', (57, 64))
85573	31668005	Therefore, MS-275 markedly reduces EwS invasive and metastatic capacity, and this correlates with increased YB-1 acetylation, ROS accumulation, and oxidative stress in vivo.	('accumulation', 'PosReg', (130, 142))	('reduces', 'NegReg', (27, 34))	('MS-275', 'Var', (11, 17))	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('acetylation', 'MPA', (113, 124))	('ROS', 'Protein', (126, 129))	('oxidative', 'MPA', (148, 157))	('MS-275', 'Chemical', 'MESH:C118739', (11, 17))	('increased', 'PosReg', (98, 107))	('oxidative stress', 'Phenotype', 'HP:0025464', (148, 164))	('YB-1', 'Gene', (108, 112))
85575	31668005	By IHC, NRF2 expression in CHLA-10 xenografts was significantly reduced in MS-275-treated mice compared to controls (Fig EV5A).	('expression', 'Species', '29278', (13, 23))	('MS-275', 'Chemical', 'MESH:C118739', (75, 81))	('expression', 'MPA', (13, 23))	('CHLA-10', 'CellLine', 'CVCL:6583', (27, 34))	('mice', 'Species', '10090', (90, 94))	('NRF2', 'Gene', (8, 12))	('reduced', 'NegReg', (64, 71))	('MS-275-treated', 'Var', (75, 89))
85578	31668005	Therefore, MS-275 also blocks NRF2 expression in vivo in EwS tumors.	('NRF2', 'Gene', (30, 34))	('MS-275', 'Var', (11, 17))	('blocks', 'NegReg', (23, 29))	('expression', 'Species', '29278', (35, 45))	('expression', 'MPA', (35, 45))	('EwS tumors', 'Disease', 'MESH:C563168', (57, 67))	('MS-275', 'Chemical', 'MESH:C118739', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('EwS tumors', 'Disease', (57, 67))
85581	31668005	Again, together, these findings strongly support a model whereby MS-275 increases acetylation of YB-1-K81 within the YB-1 CSD to inhibit NFE2L2, G3BP1, and HIF1A binding, in turn blocking YB-1 translational activation of these key stress-adaptive targets.	('blocking', 'NegReg', (179, 187))	('NFE2L2', 'Gene', '4780', (137, 143))	('YB-1', 'Gene', (188, 192))	('increases', 'PosReg', (72, 81))	('inhibit', 'NegReg', (129, 136))	('G3BP1', 'Protein', (145, 150))	('MS-275', 'Var', (65, 71))	('acetylation', 'MPA', (82, 93))	('NFE2L2', 'Gene', (137, 143))	('MS-275', 'Chemical', 'MESH:C118739', (65, 71))	('translational activation', 'MPA', (193, 217))	('binding', 'Interaction', (162, 169))	('HIF1A', 'Gene', '3091', (156, 161))	('K81', 'Gene', (102, 105))	('K81', 'Gene', '3887', (102, 105))	('HIF1A', 'Gene', (156, 161))
85584	31668005	While wt YB-1 slightly increased primary tumor growth compared to vector alone cells, YB-1-K81A tumors were significantly larger than those from the other mouse cohorts (Fig 6A); MS-275 moderately but significantly reduced primary tumor sizes in all cohorts compared to vehicle treatment, albeit less in the YB-1-K81A cohort (Fig 6A).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MS-275', 'Var', (179, 185))	('tumors', 'Disease', (96, 102))	('tumor', 'Disease', (231, 236))	('reduced', 'NegReg', (215, 222))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('K81A', 'Mutation', 'p.K81A', (313, 317))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (96, 101))	('mouse', 'Species', '10090', (155, 160))	('MS-275', 'Chemical', 'MESH:C118739', (179, 185))	('K81A', 'Mutation', 'p.K81A', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('increased', 'PosReg', (23, 32))
85585	31668005	Strikingly, however, while MS-275 dramatically reduced metastatic growth of vector alone and wt YB-1-expressing tumors to lungs (Fig 6B and C), similar to the results of Figs EV4A and 5C-E, metastatic capacity was almost completely rescued in YB-1-K81A-expressing cells even with identical MS-275 treatment.	('metastatic capacity', 'CPA', (190, 209))	('MS-275', 'Var', (27, 33))	('MS-275', 'Chemical', 'MESH:C118739', (290, 296))	('metastatic growth', 'CPA', (55, 72))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('MS-275', 'Chemical', 'MESH:C118739', (27, 33))	('K81A', 'Mutation', 'p.K81A', (248, 252))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('reduced', 'NegReg', (47, 54))	('tumors', 'Disease', (112, 118))
85586	31668005	Moreover, while MS-275 increased acetylated YB-1 in primary tumors from the wt YB-1 overexpression cohorts (Fig 6D; compare lanes 2-4 to 5-7), we failed to detect YB-1 acetylation in the YB-1-K81A drug-treated primary tumors (Fig 6D; lanes 8-13).	('acetylated', 'MPA', (33, 43))	('MS-275', 'Chemical', 'MESH:C118739', (16, 22))	('YB-1', 'Gene', (44, 48))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('YB-1', 'Gene', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('acetylation', 'MPA', (168, 179))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increased', 'PosReg', (23, 32))	('K81A', 'Mutation', 'p.K81A', (192, 196))	('expression', 'Species', '29278', (88, 98))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('MS-275', 'Var', (16, 22))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', (60, 66))
85587	31668005	This correlated strongly with expression of YB-1 translationally controlled proteins, as G3BP1, HIF1alpha, and NRF2 were all reduced by MS-275 in wt YB-1 tumors (Fig 6E), but expression of each protein was retained in YB-1-K81A drug-treated primary tumors (Fig 6F).	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('G3BP1', 'Gene', (89, 94))	('expression', 'Species', '29278', (30, 40))	('MS-275', 'Var', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('YB-1 tumors', 'Disease', (149, 160))	('HIF1alpha', 'Gene', (96, 105))	('YB-1 tumors', 'Disease', 'MESH:D009369', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('expression', 'Species', '29278', (175, 185))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('expression', 'MPA', (30, 40))	('tumors', 'Disease', (154, 160))	('YB-1', 'Gene', (44, 48))	('MS-275', 'Chemical', 'MESH:C118739', (136, 142))	('reduced', 'NegReg', (125, 132))	('NRF2', 'Gene', (111, 115))	('K81A', 'Mutation', 'p.K81A', (223, 227))	('tumors', 'Disease', (249, 255))
85589	31668005	Finally, we analyzed publicly available EwS and OS gene expression datasets and found moderate correlations between HIF1A, G3BP1, and NFE2L2 transcripts in EwS and OS (Fig 7A and B); moreover, G3BP1 levels correlated significantly with poor outcome in both diseases (Fig 8A).	('NFE2L2', 'Gene', '4780', (134, 140))	('HIF1A', 'Gene', (116, 121))	('HIF1A', 'Gene', '3091', (116, 121))	('G3BP1', 'Gene', (123, 128))	('NFE2L2', 'Gene', (134, 140))	('expression', 'Species', '29278', (56, 66))	('poor', 'Disease', (236, 240))	('G3BP1', 'Var', (193, 198))
85597	31668005	However, we find that MS-275 enhances ROS indirectly in sarcoma cells by non-transcriptionally inhibiting YB-1-mediated translation of NFE2L2 encoding the antioxidant master regulator, NRF2.	('NFE2L2', 'Gene', (135, 141))	('inhibiting', 'NegReg', (95, 105))	('MS-275', 'Chemical', 'MESH:C118739', (22, 28))	('enhances', 'PosReg', (29, 37))	('sarcoma', 'Disease', (56, 63))	('ROS', 'Chemical', 'MESH:D017382', (38, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('translation', 'MPA', (120, 131))	('YB-1-mediated', 'Gene', (106, 119))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('NFE2L2', 'Gene', '4780', (135, 141))	('MS-275', 'Var', (22, 28))	('ROS', 'MPA', (38, 41))
85600	31668005	Moreover, YB-1-K81A rescued EwS metastasis to lungs, which correlated with re-expression of NRF2, G3BP1, and HIF1alpha in tumor tissues.	('G3BP1', 'Gene', (98, 103))	('K81A', 'Mutation', 'p.K81A', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('rescued', 'PosReg', (20, 27))	('YB-1-K81A', 'Var', (10, 19))	('metastasis to lungs', 'CPA', (32, 51))	('re-expression', 'PosReg', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('NRF2', 'Gene', (92, 96))	('tumor', 'Disease', (122, 127))	('expression', 'Species', '29278', (78, 88))
85603	31668005	HDAC inhibitors are known to enhance ROS levels, such as in melanoma cells 53 and other tumors 54, 55, 56, 57.	('HDAC', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('HDAC', 'Gene', '9734', (0, 4))	('inhibitors', 'Var', (5, 15))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('enhance ROS levels', 'Phenotype', 'HP:0025464', (29, 47))	('melanoma', 'Disease', (60, 68))	('ROS levels', 'MPA', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('enhance', 'PosReg', (29, 36))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('ROS', 'Chemical', 'MESH:D017382', (37, 40))
85606	31668005	We observed that MS-275 increases YB-1 acetylation as early ~30 min after initiation of treatment.	('MS-275', 'Var', (17, 23))	('increases', 'PosReg', (24, 33))	('MS-275', 'Chemical', 'MESH:C118739', (17, 23))	('acetylation', 'MPA', (39, 50))	('YB-1', 'Protein', (34, 38))
85609	31668005	Notably, mutation of YB-1-K81 (K81E) has been reported in human tumors (http://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=YBX1), although the functional significance of this finding remains to be established.	('mutation', 'Var', (9, 17))	('YBX1', 'Gene', '4904', (123, 127))	('K81', 'Gene', (31, 34))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('K81', 'Gene', '3887', (31, 34))	('human', 'Species', '9606', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('YBX1', 'Gene', (123, 127))	('reported', 'Reg', (46, 54))	('K81', 'Gene', (26, 29))	('K81', 'Gene', '3887', (26, 29))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('K81E', 'Mutation', 'rs200506377', (31, 35))
85615	31668005	Loss of NRF2 in pancreatic carcinoma cells oxidizes components of the translational machinery, leading to impaired mRNA translation and reduced proliferation 17.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('pancreatic carcinoma', 'Disease', (16, 36))	('proliferation 17', 'CPA', (144, 160))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (16, 36))	('impaired', 'NegReg', (106, 114))	('NRF2', 'Gene', (8, 12))	('reduced', 'NegReg', (136, 143))	('Loss', 'Var', (0, 4))	('mRNA translation', 'MPA', (115, 131))
85617	31668005	NRF2 could potentially reduce oxidative stress at one or more critical steps to facilitate tumor cell fitness within the metastatic cascade, consistent with oxidative stress preventing melanoma metastasis 4, 5.	('melanoma metastasis', 'Disease', (185, 204))	('NRF2', 'Gene', (0, 4))	('oxidative stress', 'Phenotype', 'HP:0025464', (157, 173))	('reduce', 'NegReg', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('melanoma metastasis', 'Disease', 'MESH:D009362', (185, 204))	('facilitate', 'PosReg', (80, 90))	('oxidative stress', 'Phenotype', 'HP:0025464', (30, 46))	('oxidative', 'Var', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('oxidative stress', 'MPA', (30, 46))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('tumor', 'Disease', (91, 96))
85618	31668005	Decreased NRF2 activity reduces trophoblast invasion in placenta 66, and KEAP1 overexpression suppresses migration of lung adenocarcinoma cells 67.	('trophoblast invasion in placenta 66', 'CPA', (32, 67))	('overexpression', 'Var', (79, 93))	('reduces', 'NegReg', (24, 31))	('NRF2', 'Gene', (10, 14))	('KEAP1', 'Gene', '9817', (73, 78))	('Decreased', 'NegReg', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung adenocarcinoma', 'Disease', (118, 137))	('activity', 'MPA', (15, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('expression', 'Species', '29278', (83, 93))	('KEAP1', 'Gene', (73, 78))	('suppresses', 'NegReg', (94, 104))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))
85644	31668005	Further IHC on tissue sections was conducted on a Ventana Discover XT system using antibodies against the G3BP1 at a dilution of 1:1,500, CD99 at 1:400, and anti-NRF2 at 1:150 with signal stain booster, and anti-4-HNE, a marker of oxidative stress 69, at 1:50.	('oxidative stress', 'Phenotype', 'HP:0025464', (231, 247))	('G3BP1', 'Gene', (106, 111))	('anti-NRF2', 'Var', (157, 166))	('4-HNE', 'Chemical', 'MESH:C027576', (212, 217))	('antibodies', 'Var', (83, 93))
85656	31668005	For "light" cultures (mock-treated, +- NaAsO2), the medium was supplemented with 100 mg/l of [14N2 12C6]-Lys and 100 mg/l of [14N4 12C6]-Arg.	('[14N2 12C6]-Lys', 'Chemical', '-', (93, 108))	('[14N4 12C6]-Arg', 'Chemical', '-', (125, 140))	('[14N2 12C6]-Lys', 'Var', (93, 108))	('[14N4 12C6]-Arg', 'Var', (125, 140))	('NaAsO2', 'Chemical', '-', (39, 45))
85657	31668005	For "heavy" cultures (+MS-275, +- NaAsO2), the medium was supplemented with 100 mg/l of [15N2, 13C6]-Lys and 100 mg/l of [15N4, 13C6]-Arg.	('[15N2', 'Var', (88, 93))	('[15N4', 'Var', (121, 126))	('MS-275', 'Chemical', 'MESH:C118739', (23, 29))	('13C6', 'Chemical', '-', (128, 132))	('NaAsO2', 'Chemical', '-', (34, 40))	('Lys', 'Chemical', 'MESH:D008239', (101, 104))	('15N2', 'Chemical', '-', (89, 93))	('Arg', 'Chemical', 'MESH:D001120', (134, 137))	('13C6', 'Chemical', '-', (95, 99))
85682	31668005	Briefly, tumor cells were seeded in 6-well plates and treated with selected compounds (+/MS-275, +/- NaAsO2).	('NaAsO2', 'Chemical', '-', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('+/MS-275', 'Var', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('+/- NaAsO2', 'Var', (97, 107))	('MS-275', 'Chemical', 'MESH:C118739', (89, 95))	('tumor', 'Disease', (9, 14))
85703	31668005	In brief, U2OS cells or CHLA10-expressing FLAG-tagged wtYB-1 or YB-1K-to-A mutants were further treated with MS-275 (1 muM, 2 h).	('muM', 'Gene', (119, 122))	('YB-1K-to-A', 'Gene', (64, 74))	('MS-275', 'Chemical', 'MESH:C118739', (109, 115))	('wtYB-1', 'Gene', (54, 60))	('U2OS', 'CellLine', 'CVCL:0042', (10, 14))	('mutants', 'Var', (75, 82))	('muM', 'Gene', '56925', (119, 122))
85712	31668005	To probe for direct and preferential binding of the YB-1-K81A mutant to HIF1A, G3BP1, and NFE2L2 mRNAs for translation activation, we expressed FLAG-tagged wtYB-1 or FLAG-tagged YB-1 K81A mutant, prepared at GenScript, in U2OS cells.	('U2OS', 'CellLine', 'CVCL:0042', (222, 226))	('K81A', 'Mutation', 'p.K81A', (183, 187))	('K81A', 'Var', (183, 187))	('K81A', 'Mutation', 'p.K81A', (57, 61))	('NFE2L2', 'Gene', '4780', (90, 96))	('HIF1A', 'Gene', (72, 77))	('HIF1A', 'Gene', '3091', (72, 77))	('YB-1', 'Gene', (178, 182))	('NFE2L2', 'Gene', (90, 96))
85718	31668005	Gene expression analysis correlation and survival was computed on publicly available datasets, downloaded from Gene Expression Omnibus (GEO) of Ewing sarcoma (GSE63157) (Data ref: 76) and osteosarcoma (GSE42352) (Data ref: 77).	('Expression', 'Species', '29278', (116, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (188, 200))	('GSE42352', 'Var', (202, 210))	('Ewing sarcoma', 'Disease', (144, 157))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (144, 157))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (144, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))	('expression', 'Species', '29278', (5, 15))	('osteosarcoma', 'Disease', (188, 200))
85758	30349420	Previously, it has been found that CD47 could regulate osteoclastogenesis by regulation of NO production, while its disruption was associated with a reduced level of metastasis in bone tumor.	('regulate', 'Reg', (46, 54))	('bone tumor', 'Disease', 'MESH:D001859', (180, 190))	('osteoclastogenesis', 'CPA', (55, 73))	('CD47', 'Gene', '961', (35, 39))	('disruption', 'Var', (116, 126))	('NO production', 'MPA', (91, 104))	('reduced', 'NegReg', (149, 156))	('CD47', 'Gene', (35, 39))	('regulation', 'MPA', (77, 87))	('bone tumor', 'Phenotype', 'HP:0010622', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('bone tumor', 'Disease', (180, 190))
85760	30349420	It has been reported that CD47 blockade was linked to tumor growth inhibition in the xenograft models of OS, resulting macrophage phagocytosis of tumorous cells with potential characteristic for therapeutic strategies of OS (immunotherapeutic),.	('CD47', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumorous', 'Disease', 'MESH:D009369', (146, 154))	('nti', 'Chemical', 'MESH:C055382', (170, 173))	('tumorous', 'Disease', (146, 154))	('blockade', 'Var', (31, 39))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('CD47', 'Gene', '961', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
85772	30349420	found that depletion of Sox2 in OS cells demonstrated a reduced level of osteosphere formation and Sca-1 expression, coupled with an escalation of differentiation into mature bone osteoblasts formation by activating Wnt signaling.	('Sca-1', 'Gene', '6310', (99, 104))	('Sox2', 'Gene', (24, 28))	('escalation', 'PosReg', (133, 143))	('reduced', 'NegReg', (56, 63))	('nti', 'Chemical', 'MESH:C055382', (154, 157))	('Sca-1', 'Gene', (99, 104))	('osteosphere formation', 'CPA', (73, 94))	('depletion', 'Var', (11, 20))	('expression', 'MPA', (105, 115))
85823	30349420	Epigenetic modulating intervention has also been evaluated for targeted therapy of cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('nti', 'Chemical', 'MESH:C055382', (29, 32))	('Epigenetic modulating intervention', 'Var', (0, 34))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
85844	30349420	Aberrant Wnt/beta-catenin signaling has been also recognized to be linked to overexpression of Sox-2, nestin Oct-4, CD133, and Nanog as stem cell proteins and tumorigenicity, supporting a role for Wnt/beta-catenin signaling and its downstream pathway in eliminating OS-CSCs.	('OS-CSCs', 'Disease', (266, 273))	('Sox-2', 'Gene', (95, 100))	('overexpression', 'PosReg', (77, 91))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Sox-2', 'Gene', '6657', (95, 100))	('nestin', 'Gene', '10763', (102, 108))	('nestin', 'Gene', (102, 108))	('Nanog', 'Gene', '79923', (127, 132))	('Oct-4', 'Gene', '5460', (109, 114))	('Nanog', 'Gene', (127, 132))	('Aberrant', 'Var', (0, 8))	('Oct-4', 'Gene', (109, 114))	('beta-catenin', 'Gene', (13, 25))	('beta-catenin', 'Gene', '1499', (13, 25))	('tumor', 'Disease', (159, 164))	('CD133', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('beta-catenin', 'Gene', (201, 213))	('linked', 'Reg', (67, 73))	('beta-catenin', 'Gene', '1499', (201, 213))
85846	30349420	JW74 (Tankyrases1, 2 inhibitors) exhibited an important role in inhibiting Wnt/beta-catenin signaling, where tankyrase play a role in cell cycle progression, reduction of differentiation and apoptosis in OS cell lines.	('apoptosis', 'CPA', (191, 200))	('JW74', 'Chemical', '-', (0, 4))	('inhibiting', 'NegReg', (64, 74))	('beta-catenin', 'Gene', '1499', (79, 91))	('JW74', 'Var', (0, 4))	('reduction', 'NegReg', (158, 167))	('nti', 'Chemical', 'MESH:C055382', (178, 181))	('cell cycle progression', 'CPA', (134, 156))	('differentiation', 'CPA', (171, 186))	('beta-catenin', 'Gene', (79, 91))
85854	30349420	The inhibition of this pathway is considered as an emerging therapeutic target for cancer by eradicating the CSCs.	('CSCs', 'Disease', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('inhibition', 'Var', (4, 14))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
85865	30349420	There is evidence of regulatory properties for Notch when have a strong impact on ALDH activity, and its up-regulation was linked to overexpression of ALDH.	('ALDH', 'Gene', '11670', (82, 86))	('activity', 'MPA', (87, 95))	('ALDH', 'Gene', '11670', (151, 155))	('ALDH', 'Gene', (82, 86))	('up-regulation', 'PosReg', (105, 118))	('ALDH', 'Gene', (151, 155))	('overexpression', 'PosReg', (133, 147))	('Notch', 'Var', (47, 52))	('impact', 'Reg', (72, 78))
85870	30349420	LY294002 has been exhibited inhibitory effect on phosphorylation of PKB/Akt through its preventive role in the PI3K phosphorylation, leading to cell cycle arrest, and apoptosis in OSCs, indicating key role of PI3K/Akt pathway.	('LY294002', 'Var', (0, 8))	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('PKB', 'Gene', (68, 71))	('Akt', 'Gene', '207', (72, 75))	('nti', 'Chemical', 'MESH:C055382', (93, 96))	('Akt', 'Gene', (72, 75))	('apoptosis', 'CPA', (167, 176))	('Akt', 'Gene', '207', (214, 217))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('arrest', 'Disease', (155, 161))	('leading to', 'Reg', (133, 143))	('Akt', 'Gene', (214, 217))	('phosphorylation', 'MPA', (49, 64))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('PKB', 'Gene', '207', (68, 71))	('OSCs', 'Disease', (180, 184))
85871	30349420	BYL719 was being shown to be a favorable drug, where exhibited its important role at inhibiting cell migration and inducing cell cycle arrest in OS cells.	('cell migration', 'CPA', (96, 110))	('inhibiting', 'NegReg', (85, 95))	('arrest', 'Disease', 'MESH:D006323', (135, 141))	('arrest', 'Disease', (135, 141))	('inducing', 'Reg', (115, 123))	('BYL719', 'Var', (0, 6))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (124, 141))
85872	30349420	VS5584as an inhibitor of mTORC1/2 was strongly exhibited inhibitory role in the growth and survival of CSCs, when comparing with non-stem-like cancer cells, meanwhile VS5584 was favorably targeted CSCs.	('inhibitory', 'NegReg', (57, 67))	('survival', 'CPA', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('VS5584as', 'Var', (0, 8))	('growth', 'CPA', (80, 86))	('mTORC1/2', 'Gene', (25, 33))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mTORC1/2', 'Gene', '74343;382056', (25, 33))	('CSCs', 'Disease', (103, 107))	('VS5584', 'Var', (167, 173))
85874	30349420	Furthermore, BRM270 has been demonstrate to decrease tumorigenic potential via suppression of NF-kappaB signaling in multidrug resistant OS stem-like cells, where targeting of NF-kappaB, and Cdk6 with IL-6 have provided support for programmed cell death and development of drug resistance therapy for CSCs.	('IL-6', 'Gene', (201, 205))	('suppression', 'NegReg', (79, 90))	('Cdk6', 'Gene', '1021', (191, 195))	('decrease', 'NegReg', (44, 52))	('IL-6', 'Gene', '3569', (201, 205))	('BRM270', 'Var', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (273, 288))	('nti', 'Chemical', 'MESH:C055382', (69, 72))	('NF-kappaB', 'Gene', '4790', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NF-kappaB', 'Gene', '4790', (94, 103))	('tumor', 'Disease', (53, 58))	('NF-kappaB', 'Gene', (176, 185))	('NF-kappaB', 'Gene', (94, 103))	('Cdk6', 'Gene', (191, 195))
85881	30349420	Targeting SDF-1 and neutralizing CXCR4 represented a therapeutic strategy for cancer, both of which depicted a elevated expression level in many kinds of tumor cells.	('SDF-1', 'Gene', '6387', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CXCR4', 'Gene', (33, 38))	('cancer', 'Disease', (78, 84))	('SDF-1', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('expression level', 'MPA', (120, 136))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Targeting', 'Var', (0, 9))	('CXCR4', 'Gene', '7852', (33, 38))	('tumor', 'Disease', (154, 159))
85883	30349420	OS has shown heterogeneity with various mutations in the genes that are generated by chromothripsis.	('chromothripsis', 'Disease', (85, 99))	('mutations', 'Var', (40, 49))	('chromothripsis', 'Disease', 'MESH:D000072837', (85, 99))
85916	30349420	Tumor-related genetic and epigenetic alterations are the basis for identification and tracking ctDNAs.	('nti', 'Chemical', 'MESH:C055382', (70, 73))	('epigenetic alterations', 'Var', (26, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ctDNAs', 'Disease', (95, 101))
85928	30349420	Moreover, translocation related vs. complex structural variants are currently being used in pediatric malignancies, which are improved study by providing the reliable detections of ctDNAs.	('ctDNAs', 'Disease', (181, 187))	('malignancies', 'Disease', (102, 114))	('translocation related', 'Var', (10, 31))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))
85937	30349420	Multitarget drugs have advantages of nti-angiogenesis therapy on OS (mostly with kinase activity); accordingly, many drugs such as Gefitinib, Everolimus Cixutumumab, R1507, Sunitinib, Pazopanib, Sorafenib, Bevacizumab have shown promise for OS based upon anti-angiogenesis therapy in clinical trial, while many clinical trials are evaluating therapeutic potential of angiogenesis inhibitors in many kinds of cancers (Table 3).	('cancer', 'Phenotype', 'HP:0002664', (408, 414))	('Sunitinib', 'Chemical', 'MESH:D000077210', (173, 182))	('Gefitinib', 'Chemical', 'MESH:D000077156', (131, 140))	('cancers', 'Phenotype', 'HP:0002664', (408, 415))	('nti', 'Chemical', 'MESH:C055382', (256, 259))	('nti', 'Chemical', 'MESH:C055382', (37, 40))	('R1507', 'Var', (166, 171))	('cancers', 'Disease', 'MESH:D009369', (408, 415))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (206, 217))	('cancers', 'Disease', (408, 415))	('Sorafenib', 'Chemical', 'MESH:D000077157', (195, 204))	('Everolimus Cixutumumab', 'Chemical', '-', (142, 164))	('nti', 'Chemical', 'MESH:C055382', (358, 361))	('Pazopanib', 'Chemical', 'MESH:C516667', (184, 193))
85938	30349420	Moreover, immune-based therapies such as Anti-GD2, GD2Bi-aATC, and mifamurtide, as well as stem cells and natural killer cells are potentially hampered cancer cells growth through harnessing of immune responses against tumors (Table 4),.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Anti-GD2', 'Var', (41, 49))	('cancer', 'Disease', (152, 158))	('GD2Bi-aATC', 'Var', (51, 61))	('hampered', 'NegReg', (143, 151))	('tumors', 'Disease', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('nti', 'Chemical', 'MESH:C055382', (135, 138))	('GD2Bi-aATC', 'Chemical', '-', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mifamurtide', 'Chemical', 'MESH:C037144', (67, 78))	('nti', 'Chemical', 'MESH:C055382', (42, 45))
85971	30349420	Epigenetic modulating intervention has attracted the most attention for targeted therapy of cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('nti', 'Chemical', 'MESH:C055382', (29, 32))	('cancers', 'Disease', (92, 99))	('Epigenetic modulating intervention', 'Var', (0, 34))	('nti', 'Chemical', 'MESH:C055382', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
85972	30349420	Present evidence supporting a role for imprinted gene TSSC3 pathway where reduced OSC phenotype, suggesting that targeting TSSC3 can be a new strategy for improving prognosis of OSC.	('TSSC3', 'Gene', (123, 128))	('targeting', 'Var', (113, 122))	('TSSC3', 'Gene', '7262', (54, 59))	('OSC', 'Disease', (82, 85))	('reduced', 'NegReg', (74, 81))	('OSC', 'Disease', (178, 181))	('TSSC3', 'Gene', '7262', (123, 128))	('TSSC3', 'Gene', (54, 59))
85974	30349420	A number of inhibitor has been entered in clinical trials as new therapeutic approaches for OS such as IGF1-R inhibitors, mTOR inhibitors, Multitarget inhibitors, and WNT/beta-catenin inhibitor.	('beta-catenin', 'Gene', '1499', (171, 183))	('IGF1-R', 'Gene', (103, 109))	('mTOR', 'Gene', '2475', (122, 126))	('IGF1-R', 'Gene', '3480', (103, 109))	('mTOR', 'Gene', (122, 126))	('beta-catenin', 'Gene', (171, 183))	('inhibitors', 'Var', (110, 120))
85976	30349420	Anti-GD2, GD2Bi-aATC, and Mifamurtide, as well as stem cells and natural killer cells are other suggested therapy in clinical trials that potentially hamper cancer cells growth through harnessing of immune responses against tumors.	('nti', 'Chemical', 'MESH:C055382', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('GD2Bi-aATC', 'Var', (10, 20))	('nti', 'Chemical', 'MESH:C055382', (1, 4))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('GD2Bi-aATC', 'Chemical', '-', (10, 20))	('Mifamurtide', 'Chemical', 'MESH:C037144', (26, 37))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (157, 163))	('hamper', 'NegReg', (150, 156))	('Anti-GD2', 'Var', (0, 8))
85987	30053614	We demonstrate the importance in early identification of a SMARCB1 deficiency.	('deficiency', 'Var', (67, 77))	('SMARCB1', 'Gene', (59, 66))	('SMARCB1', 'Gene', '6598', (59, 66))
85991	30053614	This case highlights the difficulty in making a definitive diagnosis, and the importance in identifying a SMARCB1 deficiency as it will affect treatment options and may allow for enrollment in ongoing clinical trials.	('SMARCB1', 'Gene', (106, 113))	('SMARCB1', 'Gene', '6598', (106, 113))	('affect', 'Reg', (136, 142))	('deficiency', 'Var', (114, 124))	('allow', 'Reg', (169, 174))
86016	30053614	Due to the lack of response to carcinoma chemotherapy regimen and deletion of SMARCB1, the possibility was raised that the patient could have proximal-type vulvar epithelioid sarcoma.	('patient', 'Species', '9606', (123, 130))	('vulvar epithelioid sarcoma', 'Disease', 'MESH:D012509', (156, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('carcinoma', 'Disease', (31, 40))	('SMARCB1', 'Gene', '6598', (78, 85))	('vulvar epithelioid sarcoma', 'Disease', (156, 182))	('SMARCB1', 'Gene', (78, 85))	('carcinoma', 'Disease', 'MESH:D002277', (31, 40))	('deletion', 'Var', (66, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
86036	30053614	Loss of SMARCB1 and INI-1 can be a characteristic of both epithelioid sarcomas and myoepithelial carcinomas of the vulva.	('SMARCB1', 'Gene', '6598', (8, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('INI-1', 'Gene', (20, 25))	('SMARCB1', 'Gene', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('epithelioid sarcomas and myoepithelial carcinomas of the vulva', 'Disease', 'MESH:D012509', (58, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('Loss', 'Var', (0, 4))	('INI-1', 'Gene', '6598', (20, 25))
86038	30053614	There is evidence that tumors with loss of SMARCB1 may be sensitive to targeted therapies such as inhibitors of EZH2.	('tumors', 'Disease', (23, 29))	('EZH2', 'Gene', (112, 116))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('sensitive', 'Reg', (58, 67))	('loss', 'Var', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SMARCB1', 'Gene', '6598', (43, 50))	('SMARCB1', 'Gene', (43, 50))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('EZH2', 'Gene', '2146', (112, 116))
86040	30053614	One study showed that specifically in SMARCB1-deficient tumors, inhibitors of EZH2 resulted in antiproliferative effects on tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('inhibitors', 'Var', (64, 74))	('tumor', 'Disease', (124, 129))	('antiproliferative effects', 'CPA', (95, 120))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (38, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('SMARCB1-deficient tumors', 'Disease', (38, 62))	('EZH2', 'Gene', (78, 82))	('EZH2', 'Gene', '2146', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
86043	30053614	Inhibitors of EZH2 may be the future treatment for SMARCB1-deficient tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('Inhibitors', 'Var', (0, 10))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (51, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('SMARCB1-deficient tumors', 'Disease', (51, 75))
86107	28900327	Despite higher dose of adriamycin, cyclophosphamide, IE, patients had early distant relapses soon after achieving excellent early remission of bone and marrow metastasis.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (35, 51))	('cyclophosphamide', 'Var', (35, 51))	('adriamycin', 'Chemical', 'MESH:D004317', (23, 33))	('patients', 'Species', '9606', (57, 65))	('IE', 'Chemical', '-', (53, 55))	('distant relapses', 'CPA', (76, 92))
86125	28900327	On the contrary, treatment-related toxicity was twice higher in allogenic arm along with threat for higher secondary malignancies.	('higher', 'PosReg', (54, 60))	('allogenic', 'Var', (64, 73))	('toxicity', 'Disease', 'MESH:D064420', (35, 43))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('toxicity', 'Disease', (35, 43))	('malignancies', 'Disease', (117, 129))
86153	28900327	Unfavorable intermediate-risk group comprising oligo-bone metastasis (<=3 bone metastases) has inferior outcomes as compared to unfavorable low-risk group.	('oligo-bone metastasis', 'Var', (47, 68))	('bone metastases', 'Disease', 'MESH:D009362', (74, 89))	('bone metastases', 'Disease', (74, 89))
86172	28007774	Most GISTs contain activating mutations of KIT or PDGFR-alpha, providing a role for tyrosine kinase inhibitors (TKI), such as imatinib, sunitinib, and regorafenib.	('GIST', 'Phenotype', 'HP:0100723', (5, 9))	('activating', 'PosReg', (19, 29))	('PDGFR-alpha', 'Gene', (50, 61))	('regorafenib', 'Chemical', 'MESH:C559147', (151, 162))	('KIT', 'Gene', (43, 46))	('mutations', 'Var', (30, 39))	('imatinib', 'Chemical', 'MESH:D000068877', (126, 134))	('PDGFR-alpha', 'Gene', '5156', (50, 61))	('sunitinib', 'Chemical', 'MESH:D000077210', (136, 145))
86178	28007774	TKIs such as sunitinib, imatinib, or dasatinib have been shown to have both suppressive and stimulating effects on multiple subpopulations of immune cells, such as CD4+ and CD8+ T cells, natural killer (NK) cells, and dendritic cells.	('suppressive', 'NegReg', (76, 87))	('CD4', 'Gene', '920', (164, 167))	('CD8', 'Gene', '925', (173, 176))	('sunitinib', 'Chemical', 'MESH:D000077210', (13, 22))	('dasatinib', 'Gene', (37, 46))	('CD8', 'Gene', (173, 176))	('stimulating', 'MPA', (92, 103))	('dasatinib', 'Chemical', 'MESH:D000069439', (37, 46))	('imatinib', 'Var', (24, 32))	('imatinib', 'Chemical', 'MESH:D000068877', (24, 32))	('CD4', 'Gene', (164, 167))
86187	28007774	In metastatic melanoma, blockade of CTLA-4 with ipilimumab has demonstrated an overall response rate of 10% to 15% and prolonged survival in up to 20% of patients beyond 3 years.	('melanoma', 'Disease', (14, 22))	('ipilimumab', 'Chemical', 'MESH:D000074324', (48, 58))	('prolonged', 'PosReg', (119, 128))	('patients', 'Species', '9606', (154, 162))	('survival', 'MPA', (129, 137))	('CTLA-4', 'Gene', (36, 42))	('blockade', 'Var', (24, 32))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
86191	28007774	The murine GIST model demonstrated that treatment with CTLA-4 blockade synergized with KIT inhibition to prevent regrowth of tumor.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('CTLA-4', 'Gene', (55, 61))	('tumor', 'Disease', (125, 130))	('blockade', 'Var', (62, 70))	('GIST', 'Phenotype', 'HP:0100723', (11, 15))	('murine', 'Species', '10090', (4, 10))
86216	28007774	All patients had tumor KIT mutational status identified using a CLIA-certified assay.	('tumor', 'Disease', (17, 22))	('mutational status', 'Var', (27, 44))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
86223	28007774	Antibodies were used against total and phosphorylated KIT (Tyr719) and GAPDH (Cell Signaling Technology).	('Tyr719', 'Chemical', '-', (59, 65))	('GAPDH', 'Gene', (71, 76))	('Tyr719', 'Var', (59, 65))
86227	28007774	There were 5 patients who had tumors with mutations in exon 11 or 9, 10 patients with tumors that harbored secondary mutations in exon 13, 14, or 17, 2 patients whose tumors had mutations in PDGFR exon 18 D842V, and 1 patient with an NF1 mutation and SDH deficiency, respectively.	('patient', 'Species', '9606', (218, 225))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('patient', 'Species', '9606', (72, 79))	('SDH deficiency', 'Disease', (251, 265))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('patient', 'Species', '9606', (152, 159))	('SDH deficiency', 'Disease', 'MESH:D007153', (251, 265))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('PDGFR', 'Gene', (191, 196))	('PDGFR', 'Gene', '5159', (191, 196))	('tumors', 'Disease', (86, 92))	('D842V', 'Mutation', 'rs121908585', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('D842V', 'Var', (205, 210))	('NF1', 'Gene', '4763', (234, 237))	('tumors', 'Disease', (167, 173))	('tumors', 'Disease', (30, 36))	('mutations', 'Var', (117, 126))	('patient', 'Species', '9606', (13, 20))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('NF1', 'Gene', (234, 237))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('patients', 'Species', '9606', (152, 160))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (178, 187))	('mutations', 'Var', (42, 51))	('patients', 'Species', '9606', (72, 80))
86271	28007774	Our hypothesis suggested that if a TKI is effective in altering the immune milieu and decreasing IDO expression, anti-CTLA-4 would enhance these antitumor effects by further enhancing T-cell activation.	('anti-CTLA-4', 'Var', (113, 124))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('enhancing', 'PosReg', (174, 183))	('T-cell activation', 'CPA', (184, 201))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('enhance', 'PosReg', (131, 138))	('IDO', 'Protein', (97, 100))	('decreasing', 'NegReg', (86, 96))
86293	28007774	In that study, no statistically significant differences in Choi responses by molecular status were seen, but a patient whose tumor harbored a PDGFR exon 18 D842V had a PFS of 9.67 months.	('PDGFR', 'Gene', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PDGFR', 'Gene', '5159', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('patient', 'Species', '9606', (111, 118))	('D842V', 'Mutation', 'rs121908585', (156, 161))	('D842V', 'Var', (156, 161))
86294	28007774	In our trial, there is one patient with a tumor that also had a PDGFR exon 18 D842V mutation that continues to remain on trial for greater than 13.9 months.	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('patient', 'Species', '9606', (27, 34))	('D842V', 'Mutation', 'rs121908585', (78, 83))	('PDGFR', 'Gene', (64, 69))	('PDGFR', 'Gene', '5159', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('D842V', 'Var', (78, 83))
86295	28007774	This highlights that dasatinib may potentially have some activity in tumors with PDGFR D842V mutations, but beyond this variant, there is no clear role for dasatinib in GIST.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('D842V', 'Mutation', 'rs121908585', (87, 92))	('D842V mutations', 'Var', (87, 102))	('dasatinib', 'Chemical', 'MESH:D000069439', (21, 30))	('PDGFR', 'Gene', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('PDGFR', 'Gene', '5159', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('activity', 'MPA', (57, 65))	('dasatinib', 'Chemical', 'MESH:D000069439', (156, 165))	('GIST', 'Phenotype', 'HP:0100723', (169, 173))
86310	28007774	Furthermore, we have recently found that intratumoral CD8+ T cells inhuman GISTs have high PD-1 expression, and in a murine model of GIST, anti-PD-1 and anti-PD-L1 increase the effects of imatinib.	('CD8', 'Gene', '925', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('GIST', 'Phenotype', 'HP:0100723', (133, 137))	('murine', 'Species', '10090', (117, 123))	('GIST', 'Phenotype', 'HP:0100723', (75, 79))	('tumor', 'Disease', (46, 51))	('expression', 'MPA', (96, 106))	('human', 'Species', '9606', (69, 74))	('PD-L1', 'Gene', '60533', (158, 163))	('anti-PD-1', 'Var', (139, 148))	('PD-L1', 'Gene', (158, 163))	('imatinib', 'Chemical', 'MESH:D000068877', (188, 196))	('effects', 'MPA', (177, 184))	('increase', 'PosReg', (164, 172))	('CD8', 'Gene', (54, 57))	('PD-1', 'Protein', (91, 95))
86371	23424592	In a recent study using comparative genomic hybridization (CGH), amplifications of the 12q13-14 region were identified in 6/8 tumours.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('amplifications', 'Var', (65, 79))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('tumours', 'Disease', (126, 133))	('12q13-14', 'Gene', (87, 95))
86372	23424592	Synovial sarcoma usually shows translocation of SYT-SSX t(X;18) (p11.2;q11.2) which is the characteristic and diagnostic feature.	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('SSX', 'Gene', '727837', (52, 55))	('SYT', 'Gene', '6760', (48, 51))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('translocation', 'Var', (31, 44))	('p11', 'Gene', (65, 68))	('sarcoma', 'Disease', (9, 16))	('SYT', 'Gene', (48, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('p11', 'Gene', '6281', (65, 68))	('SSX', 'Gene', (52, 55))
86395	20981341	germline p53 mutations/ Li-Fraumeni Syndrome(LFS)).	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (24, 44))	('mutations/', 'Var', (13, 23))	('Li-Fraumeni Syndrome', 'Disease', (24, 44))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))
86450	20981341	In particular, cyclophosphamide has been linked to monosomy 5 and monosomy 7 associated MDS with a latency of 5 years or more, and etoposide has been linked to 11q23 associated AML with a latency of 2 years or less.	('linked', 'Reg', (41, 47))	('monosomy 5', 'Var', (51, 61))	('etoposide', 'Chemical', 'MESH:D005047', (131, 140))	('cyclophosphamide', 'MPA', (15, 31))	('AML', 'Disease', (177, 180))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (15, 31))	('AML', 'Phenotype', 'HP:0004808', (177, 180))	('MDS', 'Phenotype', 'HP:0002863', (88, 91))	('MDS', 'Disease', (88, 91))	('MDS', 'Disease', 'MESH:D009190', (88, 91))	('monosomy 7', 'Gene', (66, 76))	('AML', 'Disease', 'MESH:D015470', (177, 180))
86536	20981341	Perhaps the underlying germline RB mutations found in patients with heritable RB combine with acquired EWS/FLI-1 translocations in mesenchymal or neuroectodermal tissues to create the necessary alterations to develop ES as SMN in RB patients.	('ES', 'Phenotype', 'HP:0012254', (217, 219))	('FLI-1', 'Gene', '2313', (107, 112))	('RB', 'Phenotype', 'HP:0009919', (32, 34))	('EWS', 'Gene', '2130', (103, 106))	('EWS', 'Gene', (103, 106))	('FLI-1', 'Gene', (107, 112))	('SMN', 'Chemical', '-', (223, 226))	('patients', 'Species', '9606', (54, 62))	('RB', 'Phenotype', 'HP:0009919', (78, 80))	('ES as SMN', 'Disease', (217, 226))	('RB', 'Phenotype', 'HP:0009919', (230, 232))	('translocations', 'Var', (113, 127))	('patients', 'Species', '9606', (233, 241))	('mutations', 'Var', (35, 44))
86544	20981341	Hematologic SMN have increased with intensified chemotherapy regimens containing high-dose alkylators and epipodophyllotoxins, which are known to cause secondary leukemias.	('leukemias', 'Phenotype', 'HP:0001909', (162, 171))	('leukemias', 'Disease', (162, 171))	('epipodophyllotoxins', 'Var', (106, 125))	('SMN', 'Chemical', '-', (12, 15))	('leukemias', 'Disease', 'MESH:D007938', (162, 171))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('epipodophyllotoxins', 'Chemical', 'MESH:D011034', (106, 125))	('Hematologic SMN', 'Disease', (0, 15))
86555	20981341	However, ES tumors have been shown to contain alterations in RB and p53, which are known to be mutated in hereditary RB and LFS, respectively.	('RB', 'Phenotype', 'HP:0009919', (61, 63))	('ES tumors', 'Disease', (9, 18))	('alterations', 'Var', (46, 57))	('LFS', 'Disease', (124, 127))	('RB', 'Phenotype', 'HP:0009919', (117, 119))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('ES', 'Phenotype', 'HP:0012254', (9, 11))	('p53', 'Gene', (68, 71))	('ES tumors', 'Disease', 'MESH:C563168', (9, 18))	('p53', 'Gene', '7157', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))
86569	33762319	Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI.	('differences', 'Reg', (113, 124))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('methylation', 'MPA', (101, 112))	('anti-PD-1', 'Var', (166, 175))	('tumor', 'Disease', (39, 44))
86574	33762319	The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)-receptor interaction.	('Phosphoinositide 3-kinase', 'Gene', (134, 159))	('Rap1', 'Gene', (84, 88))	('Phosphoinositide 3-kinase', 'Gene', '5295', (134, 159))	('Akt', 'Gene', '207', (167, 170))	('focal adhesion', 'CPA', (100, 114))	('interaction', 'Interaction', (221, 232))	('adherens', 'MPA', (116, 124))	('Rap1', 'Gene', '5906', (84, 88))	('methylation differences', 'Var', (23, 46))	('Akt', 'Gene', (167, 170))
86613	33762319	SVD analysis indicated that a significant variation of DNA methylation within the whole study cohort was associated with CD3+/CD8+ immune cell content, center of sample origin and sex (online supplemental figure S3A).	('CD8', 'Gene', (126, 129))	('DNA', 'Gene', (55, 58))	('SVD', 'Disease', 'MESH:C536677', (0, 3))	('CD8', 'Gene', '925', (126, 129))	('methylation', 'Var', (59, 70))	('associated', 'Reg', (105, 115))	('SVD', 'Disease', (0, 3))
86616	33762319	While methylation of 2043 DMPs was decreased, methylation of 410 DMPs was increased (figure 2B).	('methylation', 'MPA', (6, 17))	('2043 DMPs', 'Var', (21, 30))	('DMPs', 'Chemical', '-', (26, 30))	('decreased', 'NegReg', (35, 44))	('increased', 'PosReg', (74, 83))	('methylation', 'MPA', (46, 57))	('DMPs', 'Chemical', '-', (65, 69))
86619	33762319	The frequency of hypermethylated non-CpG island DMPs was only slightly lower (66.3%, figure 2B).	('non-CpG island', 'Protein', (33, 47))	('DMPs', 'Chemical', '-', (48, 52))	('hypermethylated', 'Var', (17, 32))
86620	33762319	In addition, the frequencies of hypomethylated and hypermethylated CpG island-associated DMPs were 7.2% and 7.3% for CGIs, 14.4% and 16.8% for shore regions (2 kb regions flanking CpG islands), and 6.9% and 9.5% for shelve regions (2 kb regions of flanking shore regions), respectively.	('hypomethylated', 'Var', (32, 46))	('CpG island-associated', 'Gene', (67, 88))	('DMPs', 'Chemical', '-', (89, 93))	('hypermethylated', 'Var', (51, 66))
86621	33762319	The locations of hypomethylated DMPs in the context of gene-associated regions were 49.9% in gene bodies, 23.7% in intergenic regions (IGR), 11.4% in transcriptional start sites, 10.9% in 5' UTRs, 2.4% in 3' UTRs, 1.4% in first exons and 0.4% in exon boundaries.	('DMPs', 'Gene', (32, 36))	('hypomethylated', 'Var', (17, 31))	('DMPs', 'Chemical', '-', (32, 36))
86622	33762319	Again, these values are very similar for hypermethylated DMPs with the exception of a higher IGR frequency and a lower gene body frequency.	('DMPs', 'Chemical', '-', (57, 61))	('lower', 'NegReg', (113, 118))	('gene body frequency', 'MPA', (119, 138))	('hypermethylated', 'Var', (41, 56))	('IGR frequency', 'MPA', (93, 106))
86623	33762319	Chromosomal distribution of hypomethylated and hypermethylated DMPs was relatively even, as shown in online supplemental figure S4.	('DMPs', 'Chemical', '-', (63, 67))	('hypomethylated', 'Var', (28, 42))	('hypermethylated', 'Var', (47, 62))	('DMPs', 'Gene', (63, 67))
86624	33762319	Clustering of sarcoma samples based on the 2453 DMPs revealed two main clusters, of which one consisted of 73% responders to anti-PD-1 ICI (MC1) and the other one contained only non-responders (MC2, figure 3A).	('sarcoma', 'Disease', (14, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('MC2', 'Gene', (194, 197))	('anti-PD-1', 'Var', (125, 134))	('DMPs', 'Chemical', '-', (48, 52))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))	('MC2', 'Gene', '4161', (194, 197))
86629	33762319	Among KEGG annotated pathways, the top five hits were focal adhesion (hsa04510, FDR=0.0009), adherens junction (hsa4520, FDR=0.005), Rap1 signaling pathway (hsa04015, FDR=0.005), pathways in cancer (hsa05200, FDR=0.008) and ECM-receptor interaction (hsa04512, 0.01) (figure 4A, online supplemental table S5).	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('hsa05200', 'Var', (199, 207))	('Rap1', 'Gene', (133, 137))	('pathways', 'Pathway', (179, 187))	('hsa04512', 'Var', (250, 258))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('focal adhesion', 'Pathway', (54, 68))	('Rap1', 'Gene', '5906', (133, 137))	('adherens junction', 'Pathway', (93, 110))	('hsa04015', 'Var', (157, 165))
86637	33762319	Anti-PD-1 ICI with pembrolizumab or nivolumab is a promising treatment that seems to benefit some patients with advanced sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (121, 129))	('nivolumab', 'Chemical', 'MESH:D000077594', (36, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('patients', 'Species', '9606', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('sarcomas', 'Disease', (121, 129))	('pembrolizumab', 'Chemical', 'MESH:C582435', (19, 32))	('Anti-PD-1', 'Var', (0, 9))	('benefit', 'PosReg', (85, 92))
86652	33762319	Pathway enrichment analyses showed that the genes most prominently affected by differential methylation are involved in Rap1 signaling, focal adhesion, adherens junction, pathways in cancer and ECM-receptor interaction.	('cancer', 'Disease', (183, 189))	('Rap1', 'Gene', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Rap1', 'Gene', '5906', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('differential methylation', 'Var', (79, 103))
86664	26856934	The integration of data from a variety sources including gene expression profiles, transcription factor (TF) binding data from ChIP-seq experiments, curated gene sets, and clinical information of patients indicated discrete regulatory programs (e.g., controlled by E2F1 and E2F4) with significantly different regulatory activity in one or multiple subtypes of liposarcoma with respect to normal adipose tissue.	('men', 'Species', '9606', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (364, 371))	('E2F4', 'Var', (274, 278))	('liposarcoma', 'Disease', (360, 371))	('patients', 'Species', '9606', (196, 204))	('regulatory activity', 'MPA', (309, 328))	('E2F1', 'Var', (265, 269))	('liposarcoma', 'Phenotype', 'HP:0012034', (360, 371))	('liposarcoma', 'Disease', 'MESH:D008080', (360, 371))
86673	26856934	Indeed, genomic alterations, including gene mutations, karyotype abnormalities, and copy number variations, have been identified in all liposarcoma subtypes.	('liposarcoma subtypes', 'Disease', 'MESH:D008080', (136, 156))	('liposarcoma subtypes', 'Disease', (136, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('copy number variations', 'Var', (84, 106))	('identified', 'Reg', (118, 128))	('liposarcoma', 'Phenotype', 'HP:0012034', (136, 147))
86674	26856934	For example, it has been shown that 18% of myxoid/round-cell liposarcomas have PIK3CA mutations and 17% of pleomorphic liposarcomas have TP53 mutations.	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('liposarcomas', 'Disease', 'MESH:D008080', (61, 73))	('liposarcomas', 'Disease', (119, 131))	('liposarcoma', 'Phenotype', 'HP:0012034', (61, 72))	('pleomorphic liposarcomas', 'Disease', (107, 131))	('liposarcomas', 'Phenotype', 'HP:0012034', (61, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('PIK3CA', 'Gene', '5290', (79, 85))	('TP53', 'Gene', (137, 141))	('mutations', 'Var', (86, 95))	('liposarcomas', 'Disease', 'MESH:D008080', (119, 131))	('liposarcomas', 'Disease', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('liposarcomas', 'Phenotype', 'HP:0012034', (119, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (107, 131))	('PIK3CA', 'Gene', (79, 85))	('TP53', 'Gene', '7157', (137, 141))	('liposarcoma', 'Phenotype', 'HP:0012034', (119, 130))	('myxoid/round-cell liposarcoma', 'Phenotype', 'HP:0012268', (43, 72))
86713	26856934	ChIP-seq data of E2F1 in HeLa S3 (two replicates from ENCODE data) and MCF7 cell lines, and E2F4 in HeLa 3, GM06900 and K562b cell lines, were used to define the core target genes sets for E2F1 and E2F4 (E2F1 and E2F4 signatures), respectively.	('K562', 'CellLine', 'CVCL:0004', (120, 124))	('E2F4', 'Gene', (198, 202))	('HeLa S3', 'CellLine', 'CVCL:0058', (25, 32))	('MCF7', 'CellLine', 'CVCL:0031', (71, 75))	('E2F1', 'Var', (189, 193))	('HeLa', 'CellLine', 'CVCL:0030', (100, 104))	('HeLa', 'CellLine', 'CVCL:0030', (25, 29))
86720	26856934	With these analyses, we characterized the TF regulatory programs that associate with liposarcoma oncogenesis and patient survival time, respectively, and identified two regulatory programs, E2F1 and E2F4, that are both associated with liposarcoma and patient survival.	('E2F1', 'Var', (190, 194))	('patient', 'Species', '9606', (113, 120))	('liposarcoma', 'Disease', (235, 246))	('liposarcoma', 'Disease', (85, 96))	('associated', 'Reg', (219, 229))	('liposarcoma oncogenesis', 'Disease', 'MESH:D063646', (85, 108))	('associate', 'Reg', (70, 79))	('patient', 'Species', '9606', (251, 258))	('liposarcoma', 'Phenotype', 'HP:0012034', (235, 246))	('liposarcoma', 'Disease', 'MESH:D008080', (235, 246))	('liposarcoma', 'Disease', 'MESH:D008080', (85, 96))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('E2F4', 'Var', (199, 203))	('liposarcoma oncogenesis', 'Disease', (85, 108))
86723	26856934	Finally, with the E2F1, E2F4 and 259 MSigDB survival-associated gene sets, we constructed a gene-set overlapping network to identify the overall structure of survival-associated pathways of liposarcoma.	('liposarcoma', 'Disease', (190, 201))	('liposarcoma', 'Disease', 'MESH:D008080', (190, 201))	('liposarcoma', 'Phenotype', 'HP:0012034', (190, 201))	('E2F1', 'Var', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('E2F4', 'Var', (24, 28))
86728	26856934	In contrast, the A549 NR3C1 program is associated with a negative RAS, suggesting lower activity of NR3C1 (assuming it is a transcriptional activator) in liposarcoma tumor samples.	('NR3C1', 'Gene', (22, 27))	('liposarcoma tumor', 'Disease', 'MESH:D008080', (154, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('A549', 'Var', (17, 21))	('liposarcoma tumor', 'Disease', (154, 171))	('NR3C1', 'Gene', '2908', (100, 105))	('activity', 'MPA', (88, 96))	('A549', 'CellLine', 'CVCL:0023', (17, 21))	('NR3C1', 'Gene', (100, 105))	('liposarcoma', 'Phenotype', 'HP:0012034', (154, 165))	('NR3C1', 'Gene', '2908', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('lower', 'NegReg', (82, 87))
86730	26856934	The MCF7 E2F1 (Figure 2A), HeLa S3 E2F4, and K562 E2F4 (Figure 2B) programs are seen to be significant in all three subtypes.	('K562 E2F4', 'CellLine', 'CVCL:4V85', (45, 54))	('HeLa S3 E2F4', 'CellLine', 'CVCL:0058', (27, 39))	('MCF7', 'Gene', (4, 8))	('MCF7 E2F1', 'CellLine', 'CVCL:M439', (4, 13))	('K562 E2F4', 'Var', (45, 54))
86731	26856934	However, the A549 NR3C1 program is significant in the dedifferentiated and the myxoid/RC subtypes, but not in the pleomorphic subtype (Figure 2C).	('A549', 'Var', (13, 17))	('myxoid/RC', 'Disease', (79, 88))	('dedifferentiated', 'Disease', (54, 70))	('NR3C1', 'Gene', (18, 23))	('NR3C1', 'Gene', '2908', (18, 23))	('A549', 'CellLine', 'CVCL:0023', (13, 17))
86734	26856934	The E2F4 programs are highly significant in all liposarcoma samples as well as in the three subtypes, suggesting that E2F4 is a key factor and plays a crucial role in the tumorigenesis and progression of liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (48, 59))	('liposarcoma', 'Disease', 'MESH:D008080', (48, 59))	('liposarcoma', 'Phenotype', 'HP:0012034', (204, 215))	('liposarcoma', 'Disease', 'MESH:D008080', (204, 215))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('E2F4', 'Var', (118, 122))	('liposarcoma', 'Disease', (48, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('liposarcoma', 'Disease', (204, 215))
86737	26856934	We compared the expression levels of E2F1, E2F4, and NR3C1 between liposarcoma tumor samples and normal fat samples (Figure 2).	('liposarcoma tumor', 'Disease', (67, 84))	('E2F1', 'Var', (37, 41))	('liposarcoma', 'Phenotype', 'HP:0012034', (67, 78))	('E2F4', 'Var', (43, 47))	('liposarcoma tumor', 'Disease', 'MESH:D008080', (67, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('NR3C1', 'Gene', (53, 58))	('NR3C1', 'Gene', '2908', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
86739	26856934	For E2F4, while we observed significantly enhanced activity in all subsets of liposarcoma samples (Figure 2B), E2F4 mRNA expression levels were found to be down-regulated in dedifferentiated and pleomorphic subtypes, but without significant expression change in the myxoid/RC subtype (Figure 2E).	('activity', 'MPA', (51, 59))	('mRNA expression levels', 'MPA', (116, 138))	('E2F4', 'Gene', (111, 115))	('liposarcoma', 'Disease', (78, 89))	('enhanced', 'PosReg', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('liposarcoma', 'Phenotype', 'HP:0012034', (78, 89))	('liposarcoma', 'Disease', 'MESH:D008080', (78, 89))	('E2F4', 'Var', (4, 8))	('down-regulated', 'NegReg', (156, 170))
86761	26856934	Table S1, E2F1 and E2F4 regulatory programs are found to be significantly associated with both liposarcoma development and liposarcoma survival outcome.	('liposarcoma', 'Disease', (95, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('liposarcoma', 'Disease', (123, 134))	('E2F4', 'Var', (19, 23))	('men', 'Species', '9606', (114, 117))	('liposarcoma', 'Disease', 'MESH:D008080', (95, 106))	('E2F1', 'Var', (10, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('liposarcoma', 'Phenotype', 'HP:0012034', (95, 106))	('liposarcoma', 'Disease', 'MESH:D008080', (123, 134))	('liposarcoma', 'Phenotype', 'HP:0012034', (123, 134))	('associated with', 'Reg', (74, 89))
86765	26856934	We then calculated the iRASs for E2F1 and E2F4 (denoted as E2F1 scores and E2F4 scores, respectively) in the 140 liposarcoma tumor samples by applying the BASE algorithm to the two signatures.	('E2F4', 'Var', (42, 46))	('liposarcoma tumor', 'Disease', (113, 130))	('E2F1', 'Var', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('iRAS', 'Gene', '11188', (23, 27))	('iRAS', 'Gene', (23, 27))	('liposarcoma', 'Phenotype', 'HP:0012034', (113, 124))	('liposarcoma tumor', 'Disease', 'MESH:D008080', (113, 130))
86766	26856934	Cox PH survival regression shows a significant hazardous effect of the E2F1 and E2F4 scores.	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('E2F4', 'Var', (80, 84))	('E2F1', 'Var', (71, 75))
86767	26856934	When patients are stratified based on E2F1 or E2F4 scores (setting 0 as the cut-off between strata), the resulting positive and negative groups show significantly different DRFS prognosis: the positive groups of both are associated with worse prognosis (Suppl.	('E2F1', 'Var', (38, 42))	('E2F4', 'Var', (46, 50))	('patients', 'Species', '9606', (5, 13))
86769	26856934	Figure S1D), but it seems that the E1F1 and E2F4 signatures are different in discriminating dedifferentiated liposarcoma samples.	('liposarcoma', 'Disease', (109, 120))	('E1F1', 'Var', (35, 39))	('liposarcoma', 'Phenotype', 'HP:0012034', (109, 120))	('liposarcoma', 'Disease', 'MESH:D008080', (109, 120))	('E2F4', 'Var', (44, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
86771	26856934	In GSE30929 data, we have identified 202 and 164 liposarcoma-specific target genes for E2F1 and E2F4, respectively.	('E2F1', 'Gene', (87, 91))	('liposarcoma', 'Phenotype', 'HP:0012034', (49, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('liposarcoma', 'Disease', (49, 60))	('E2F4', 'Var', (96, 100))	('liposarcoma', 'Disease', 'MESH:D008080', (49, 60))
86772	26856934	We then applied the BASE algorithm to obtain E2F1 scores and E2F4 scores liposarcoma samples based on these target gene sets.	('liposarcoma', 'Phenotype', 'HP:0012034', (73, 84))	('liposarcoma', 'Disease', 'MESH:D008080', (73, 84))	('E2F4 scores', 'Var', (61, 72))	('E2F1', 'Var', (45, 49))	('liposarcoma', 'Disease', (73, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
86804	26856934	As key factors in cell cycle regulation, E2F1 and E2F4 paly critical roles in different cancer types.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('E2F4', 'Var', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('E2F1', 'Gene', (41, 45))
86809	26856934	It has been shown that sustained knockdown of CDK4 significantly inhibits the proliferation of tumor cells.	('CDK4', 'Gene', (46, 50))	('inhibits', 'NegReg', (65, 73))	('knockdown', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
86812	26856934	Using the E2F1 and E2F4 signatures proposed in this study, it should be possible to predict the sensitivity of liposarcoma samples to this drug and other CDK4/CDK6 inhibitors.	('liposarcoma', 'Phenotype', 'HP:0012034', (111, 122))	('liposarcoma', 'Disease', 'MESH:D008080', (111, 122))	('E2F4', 'Var', (19, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('E2F1', 'Var', (10, 14))	('liposarcoma', 'Disease', (111, 122))
87278	27452744	3); immunohistochemical staining: PCK (-), LCA (-), Melanoma (-), Syn (+), desmin (-), S-100 (+), CD68 (+-), vimentin (+).	('CD68', 'Gene', (98, 102))	('desmin', 'Gene', '1674', (75, 81))	('LCA', 'Disease', (43, 46))	('vimentin', 'Gene', '7431', (109, 117))	('Melanoma', 'Disease', 'MESH:D008545', (52, 60))	('Melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('S-100', 'Var', (87, 92))	('vimentin', 'Gene', (109, 117))	('Syn', 'Gene', (66, 69))	('Melanoma', 'Disease', (52, 60))	('CD68', 'Gene', '968', (98, 102))	('Syn', 'Gene', '23336', (66, 69))	('desmin', 'Gene', (75, 81))
87332	27377912	Alterations of TP53; allelic imbalances of 1p, 80, and 20q; and loss of heterozygosity of 7p, 11p, 17p, and 22q have been reported in UESDL.	('UESDL', 'Disease', (134, 139))	('reported', 'Reg', (122, 130))	('Alterations', 'Var', (0, 11))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('imbalances', 'Phenotype', 'HP:0002172', (29, 39))
87334	27377912	A few cases of UESL arising in mesenchymal hamartomas have been reported in pediatric patients and they showed common cytogenetic alterations, t(11;19)(q13;q13.4), suggesting a common pathogenic pathway of the two lesions.	('mesenchymal hamartomas', 'Disease', (31, 53))	('t(11;19)(q13;q13.4)', 'STRUCTURAL_ABNORMALITY', 'None', (143, 162))	('UESL', 'Disease', (15, 19))	('t(11;19)(q13;q13.4', 'Var', (143, 161))	('hamartomas', 'Phenotype', 'HP:0010566', (43, 53))	('hamartoma', 'Phenotype', 'HP:0010566', (43, 52))	('mesenchymal hamartomas', 'Disease', 'MESH:D006222', (31, 53))	('patients', 'Species', '9606', (86, 94))
87337	27377912	Co-expression of desmin, myogenin, and myoglobin suggests rhabdomyosarcoma and loss of expression of INI1 suggests a malignant rhabdoid tumor.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (58, 74))	('loss', 'Var', (79, 83))	('desmin', 'Gene', (17, 23))	('myogenin', 'Gene', '4656', (25, 33))	('desmin', 'Gene', '1674', (17, 23))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (58, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (117, 141))	('INI1', 'Gene', '6598', (101, 105))	('myogenin', 'Gene', (25, 33))	('rhabdomyosarcoma', 'Disease', (58, 74))	('malignant rhabdoid tumor', 'Disease', (117, 141))	('INI1', 'Gene', (101, 105))
87416	26358059	The molecular signatures of mediastinal liposarcomas correspond to those of liposarcomas elsewhere, with presence of the t(12;16) FUS-DDIT-3 fusion in myxoid liposarcoma and amplification of mdm-2 in well-differentiated and dedifferentiated liposarcoma.	('mdm-2', 'Gene', (191, 196))	('liposarcoma', 'Disease', 'MESH:D008080', (40, 51))	('liposarcomas', 'Disease', (40, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('liposarcoma', 'Disease', (241, 252))	('FUS', 'Gene', (130, 133))	('liposarcoma', 'Disease', 'MESH:D008080', (158, 169))	('DDIT-3', 'Gene', (134, 140))	('liposarcomas', 'Disease', 'MESH:D008080', (76, 88))	('liposarcoma', 'Phenotype', 'HP:0012034', (76, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('FUS', 'Gene', '2521', (130, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('mediastinal liposarcomas', 'Phenotype', 'HP:0030785', (28, 52))	('liposarcomas', 'Phenotype', 'HP:0012034', (76, 88))	('liposarcoma', 'Phenotype', 'HP:0012034', (241, 252))	('liposarcoma', 'Disease', (40, 51))	('liposarcoma', 'Disease', 'MESH:D008080', (76, 87))	('liposarcoma', 'Disease', (158, 169))	('liposarcomas', 'Disease', 'MESH:D008080', (40, 52))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (151, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('liposarcoma', 'Disease', 'MESH:D008080', (241, 252))	('myxoid liposarcoma', 'Disease', (151, 169))	('mdm-2', 'Gene', '4193', (191, 196))	('liposarcomas', 'Disease', (76, 88))	('liposarcomas', 'Phenotype', 'HP:0012034', (40, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('fusion', 'Var', (141, 147))	('presence', 'Var', (105, 113))	('DDIT-3', 'Gene', '1649', (134, 140))	('liposarcoma', 'Phenotype', 'HP:0012034', (40, 51))	('amplification', 'Var', (174, 187))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (151, 169))	('liposarcoma', 'Disease', (76, 87))	('liposarcoma', 'Phenotype', 'HP:0012034', (158, 169))
87424	26358059	Dedifferentiated liposarcoma may mimic undifferentiated pleomorphic sarcoma, particularly in biopsy specimens; demonstration of amplification of mdm-2 confirms the diagnosis of liposarcoma.	('mdm-2', 'Gene', '4193', (145, 150))	('amplification', 'Var', (128, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('liposarcoma', 'Phenotype', 'HP:0012034', (177, 188))	('pleomorphic sarcoma', 'Disease', (56, 75))	('liposarcoma', 'Disease', 'MESH:D008080', (177, 188))	('liposarcoma', 'Disease', (17, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('liposarcoma', 'Disease', 'MESH:D008080', (17, 28))	('mdm-2', 'Gene', (145, 150))	('liposarcoma', 'Phenotype', 'HP:0012034', (17, 28))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (56, 75))	('liposarcoma', 'Disease', (177, 188))
87446	26358059	In addition, mdm-2 amplification remains a robust marker for liposarcoma and has not been reported in SFT (Fig.	('liposarcoma', 'Disease', (61, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('amplification', 'Var', (19, 32))	('liposarcoma', 'Disease', 'MESH:D008080', (61, 72))	('mdm-2', 'Gene', (13, 18))	('mdm-2', 'Gene', '4193', (13, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (61, 72))
87459	26358059	Cytoplasmic expression of ALK protein is detectable in about half of cases and correlates well with presence of ALK gene rearrangements.	('ALK', 'Gene', (26, 29))	('ALK', 'Gene', (112, 115))	('ALK', 'Gene', '238', (112, 115))	('ALK', 'Gene', '238', (26, 29))	('protein', 'Protein', (30, 37))	('presence', 'Var', (100, 108))
87486	26358059	Thus, identifying an i12p in the mesenchymal tissue could confirm the origin of a mediastinal sarcoma from a GCT.	('sarcoma', 'Disease', (94, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('GCT', 'Phenotype', 'HP:0100728', (109, 112))	('i12p', 'Var', (21, 25))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))
87534	32198341	On the other hand, right-sided tumors cause right-sided heart failure-like symptoms, increased right-sided pressures and pulmonary emboli.	('pulmonary emboli', 'Disease', 'MESH:D011655', (121, 137))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('heart failure', 'Phenotype', 'HP:0001635', (56, 69))	('heart failure', 'Disease', 'MESH:D006333', (56, 69))	('tumors', 'Disease', (31, 37))	('right-sided', 'Var', (19, 30))	('cause', 'Reg', (38, 43))	('pulmonary emboli', 'Disease', (121, 137))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('right-sided heart failure', 'Phenotype', 'HP:0001708', (44, 69))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('heart failure', 'Disease', (56, 69))	('increased', 'PosReg', (85, 94))	('right-sided pressures', 'CPA', (95, 116))	('pulmonary emboli', 'Phenotype', 'HP:0002204', (121, 137))
87581	32042142	The patients were excluded if any of the following conditions were present: a history of epilepsy, rapidly progressing visceral metastases, active infection, previous bleomycin chemotherapy up to the maximum cumulative dosage (400,000 IU), other local therapies within eight weeks; any systemic treatment four weeks before/after ECT.	('epilepsy', 'Disease', 'MESH:D004827', (89, 97))	('epilepsy', 'Phenotype', 'HP:0001250', (89, 97))	('visceral metastases', 'Disease', (119, 138))	('400,000', 'Var', (227, 234))	('infection', 'Disease', (147, 156))	('infection', 'Disease', 'MESH:D007239', (147, 156))	('epilepsy', 'Disease', (89, 97))	('patients', 'Species', '9606', (4, 12))	('bleomycin', 'Chemical', 'MESH:D001761', (167, 176))	('visceral metastases', 'Disease', 'MESH:D009362', (119, 138))
87819	27888797	In MLL1 fusion-driven leukemia, aberrant activation of HOXA genes is epigenetically mediated by the TrxG complex and HOXA gene expression and leukemogenesis are critically dependent on the protein-protein interaction between the TrxG proteins MLL1 and menin.	('leukemia', 'Disease', 'MESH:D007938', (22, 30))	('fusion-driven', 'Var', (8, 21))	('HOXA', 'Gene', '3197', (117, 121))	('leukemia', 'Phenotype', 'HP:0001909', (22, 30))	('TrxG', 'Chemical', '-', (229, 233))	('HOXA', 'Gene', '3197', (55, 59))	('protein-protein', 'Protein', (189, 204))	('menin', 'Gene', '4221', (252, 257))	('HOXA', 'Gene', (55, 59))	('HOXA', 'Gene', (117, 121))	('MLL1', 'Gene', (3, 7))	('activation', 'PosReg', (41, 51))	('menin', 'Gene', (252, 257))	('TrxG', 'Chemical', '-', (100, 104))	('leukemia', 'Disease', (22, 30))
87831	27888797	It is increasingly evident that epigenetic deregulation of HOX genes is a hallmark of several cancers, highlighting a critical role for these developmental programs in oncogenesis.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('epigenetic deregulation', 'Var', (32, 55))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('HOX genes', 'Gene', (59, 68))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
87832	27888797	Ewing sarcoma, an aggressive pediatric bone and soft tissue tumor, is characterized by the presence of EWS/ETS fusion oncogenes, most commonly EWS/FLI1, that arise as a consequence of recurrent chromosomal translocations.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWS', 'Gene', '2130', (143, 146))	('FLI1', 'Gene', '2313', (147, 151))	('EWS', 'Gene', '2130', (103, 106))	('EWS', 'Gene', (103, 106))	('chromosomal translocations', 'Var', (194, 220))	('Ewing sarcoma', 'Disease', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (48, 65))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('tumor', 'Disease', (60, 65))	('EWS', 'Gene', (143, 146))	('FLI1', 'Gene', (147, 151))
87837	27888797	Notably, posterior HOXD genes, particularly HOXD13, are markedly overexpressed by Ewing sarcoma cells and the promoters of these genes are enriched with the TrxG-dependent H3K4me3 histone modification, consistent with a transcriptionally active chromatin state.	('Ewing sarcoma', 'Disease', (82, 95))	('HOXD', 'Gene', (19, 23))	('overexpressed', 'PosReg', (65, 78))	('HOXD', 'Gene', (44, 48))	('H3K4me3', 'Var', (172, 179))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (82, 95))	('TrxG', 'Chemical', '-', (157, 161))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('HOXD', 'Gene', '3230', (44, 48))	('HOXD', 'Gene', '3230', (19, 23))	('H3', 'Chemical', 'MESH:C012616', (172, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
87838	27888797	Post-translational mono-, di-, and trimethylation of H3K4 are mediated by the KMT2 (MLL) family of histone methyltransferases in the context of COMPASS- (Complex of proteins associated with Set1)- and COMPASS-like multi-protein chromatin remodeling complexes.	('trimethylation', 'Var', (35, 49))	('mono-', 'Var', (19, 24))	('H3', 'Chemical', 'MESH:C012616', (53, 55))	('H3K4', 'Protein', (53, 57))	('Set1', 'Gene', '9739', (190, 194))	('di-', 'Var', (26, 29))	('Set1', 'Gene', (190, 194))	('MLL', 'Gene', (84, 87))	('MLL', 'Gene', '4297', (84, 87))
87840	27888797	In contrast, H3K4me3 modifications at the promoters of developmental transcription factors are dependent on TrxG COMPASS-like complexes that contain KMT2A (MLL1) and KMT2B (MLL4; Mll2 in mice).	('KMT2B', 'Var', (166, 171))	('developmental transcription factors', 'Gene', (55, 90))	('Mll2', 'Gene', '75410', (179, 183))	('KMT2A', 'Var', (149, 154))	('mice', 'Species', '10090', (187, 191))	('H3', 'Chemical', 'MESH:C012616', (13, 15))	('Mll2', 'Gene', (179, 183))	('TrxG', 'Chemical', '-', (108, 112))	('H3K4me3', 'Protein', (13, 20))
87842	27888797	In addition to their critical role in normal development, oncogenic roles for MLL are well-established, especially in leukemia where MLL1 gene rearrangements and fusion proteins cooperate with the wild-type MLL1 allele to induce malignant transformation of hematopoietic progenitors via deregulation of HOXA and other oncogenic genes.	('MLL', 'Gene', (133, 136))	('rearrangements', 'Var', (143, 157))	('MLL', 'Gene', (78, 81))	('MLL', 'Gene', '4297', (133, 136))	('MLL', 'Gene', '4297', (78, 81))	('HOXA', 'Gene', '3197', (303, 307))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('leukemia', 'Disease', 'MESH:D007938', (118, 126))	('HOXA', 'Gene', (303, 307))	('leukemia', 'Disease', (118, 126))	('malignant transformation', 'CPA', (229, 253))	('deregulation', 'Var', (287, 299))	('MLL', 'Gene', '4297', (207, 210))	('induce', 'PosReg', (222, 228))	('MLL', 'Gene', (207, 210))
87852	27888797	Both MLL1 (KMT2A) and SETD1B (KMT2G) are highly expressed by Ewing sarcoma cell lines, with expression levels comparable to those of several hematological malignancies known to be driven by MLL rearrangements and/or amplification (Figure 1A and Supplementary Figure S1).	('KMT2G', 'Gene', '23067', (30, 35))	('MLL', 'Gene', (5, 8))	('MLL', 'Gene', '4297', (5, 8))	('Ewing sarcoma', 'Disease', (61, 74))	('KMT2G', 'Gene', (30, 35))	('hematological malignancies', 'Phenotype', 'HP:0004377', (141, 167))	('SETD1B', 'Gene', '23067', (22, 28))	('SETD1B', 'Gene', (22, 28))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('hematological malignancies', 'Disease', (141, 167))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('amplification', 'Var', (216, 229))	('rearrangements', 'Var', (194, 208))	('hematological malignancies', 'Disease', 'MESH:D019337', (141, 167))	('MLL', 'Gene', (190, 193))	('MLL', 'Gene', '4297', (190, 193))
87862	27888797	Finally, we examined whether loss of MLL1 would reduce tumorigenicity in vivo.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MLL1', 'Protein', (37, 41))	('tumor', 'Disease', (55, 60))	('loss', 'Var', (29, 33))	('reduce', 'NegReg', (48, 54))
87864	27888797	The rate of engraftment, tumor frequency and growth rate of engrafted tumors were all substantially reduced in the context of MLL1 knockdown (Figure 2E).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('growth rate', 'CPA', (45, 56))	('reduced', 'NegReg', (100, 107))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('MLL1 knockdown', 'Var', (126, 140))
87868	27888797	To address this we measured expression of posterior HOXD genes 48 hours following shRNA-mediated knockdown of MLL1 (Figure 3A).	('MLL1', 'Gene', (110, 114))	('knockdown', 'Var', (97, 106))	('HOXD', 'Gene', '3230', (52, 56))	('expression', 'MPA', (28, 38))	('measured', 'Reg', (19, 27))	('HOXD', 'Gene', (52, 56))
87870	27888797	Although levels of HOXD10 and HOXD11 changed in some cells, HOXD13 was reproducibly downregulated following acute MLL1 knockdown (Figure 3B).	('downregulated', 'NegReg', (84, 97))	('levels', 'MPA', (9, 15))	('HOXD10', 'Gene', (19, 25))	('HOXD11', 'Gene', '3237', (30, 36))	('HOXD11', 'Gene', (30, 36))	('knockdown', 'Var', (119, 128))	('changed', 'Reg', (37, 44))	('HOXD10', 'Gene', '3236', (19, 25))
87872	27888797	In addition, knockdown of HOXD13 (Supplementary Figure S2B-2E), and also of HOXD10 and HOXD11, results in loss of tumorigenicity, verifying the identity of posterior HOXD genes as critical oncogenes in Ewing sarcoma.	('HOXD10', 'Gene', '3236', (76, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('knockdown', 'Var', (13, 22))	('HOXD', 'Gene', (76, 80))	('HOXD11', 'Gene', (87, 93))	('Ewing sarcoma', 'Disease', (202, 215))	('tumor', 'Disease', (114, 119))	('HOXD', 'Gene', '3230', (76, 80))	('HOXD11', 'Gene', '3237', (87, 93))	('loss', 'NegReg', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('HOXD', 'Gene', (26, 30))	('HOXD10', 'Gene', (76, 82))	('HOXD', 'Gene', (87, 91))	('HOXD', 'Gene', '3230', (26, 30))	('HOXD', 'Gene', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('HOXD', 'Gene', '3230', (87, 91))	('HOXD', 'Gene', '3230', (166, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (202, 215))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (202, 215))
87875	27888797	Nevertheless, given that MLL1 directly activates HOX genes in embryonic development, our data lend strong support for the hypothesis that MLL1 also contributes to epigenetic activation of HOXD13 in Ewing sarcoma.	('HOXD13', 'Gene', (188, 194))	('epigenetic', 'Var', (163, 173))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (198, 211))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (198, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('activation', 'PosReg', (174, 184))	('Ewing sarcoma', 'Disease', (198, 211))	('HOX genes', 'Gene', (49, 58))
87885	27888797	Colony formation in soft agar was similarly reduced with menin knockdown (Figure 4D), underscoring its importance in promoting tumorigenicity in vitro.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('promoting', 'PosReg', (117, 126))	('Colony formation in soft agar', 'CPA', (0, 29))	('agar', 'Chemical', 'MESH:D000362', (25, 29))	('tumor', 'Disease', (127, 132))	('menin', 'Gene', '4221', (57, 62))	('menin', 'Gene', (57, 62))	('reduced', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('knockdown', 'Var', (63, 72))
87887	27888797	In spite of this, even partial knockdown of menin was sufficient to yield a robust and reproducible phenotype, underscoring the exceptional dependence of Ewing sarcoma cells on menin for their proliferation, survival and tumorigenicity.	('Ewing sarcoma', 'Disease', (154, 167))	('menin', 'Gene', '4221', (177, 182))	('menin', 'Gene', '4221', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('yield', 'Reg', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (154, 167))	('menin', 'Gene', (177, 182))	('menin', 'Gene', (44, 49))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (154, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('knockdown', 'Var', (31, 40))
87890	27888797	Knockdown of menin caused a modest reduction in HOXD13 expression in 2 of 3 cell lines, as well as downregulation of HOXD10 (Figure 4F and 4G).	('HOXD13', 'Gene', (48, 54))	('Knockdown', 'Var', (0, 9))	('downregulation', 'NegReg', (99, 113))	('HOXD10', 'Gene', '3236', (117, 123))	('menin', 'Gene', '4221', (13, 18))	('HOXD10', 'Gene', (117, 123))	('menin', 'Gene', (13, 18))	('reduction', 'NegReg', (35, 44))
87901	27888797	To test the effect of MI-503 on Ewing sarcoma tumorigenicity in vitro, we pre-treated Ewing sarcoma cells with MI-503 for 6 days and then plated equal numbers of viable cells in soft agar for 2-4 weeks in the absence of compound.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('Ewing sarcoma', 'Disease', (32, 45))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 99))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MI-503', 'Chemical', '-', (22, 28))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (32, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('tumor', 'Disease', (46, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (32, 45))	('Ewing sarcoma', 'Disease', (86, 99))	('agar', 'Chemical', 'MESH:D000362', (183, 187))	('MI-503', 'Chemical', '-', (111, 117))	('MI-503', 'Var', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
87902	27888797	MI-503 pre-treatment led to a significant reduction in colony formation in soft agar, demonstrating that MI-503 reduces Ewing sarcoma cell tumorigenicity in vitro (Figure 5C).	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('colony formation', 'CPA', (55, 71))	('Ewing sarcoma', 'Disease', (120, 133))	('MI-503', 'Var', (105, 111))	('MI-503', 'Chemical', '-', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (120, 133))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (120, 133))	('agar', 'Chemical', 'MESH:D000362', (80, 84))	('MI-503', 'Chemical', '-', (0, 6))	('reduction', 'NegReg', (42, 51))	('reduces', 'NegReg', (112, 119))
87903	27888797	Next, we sought to determine whether MI-503 would block tumorigenicity in vivo.	('MI-503', 'Chemical', '-', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('MI-503', 'Var', (37, 43))	('tumor', 'Disease', (56, 61))	('block', 'NegReg', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
87906	27888797	In contrast, pre-treatment of cells with MI-503 delayed the median time to tumor engraftment to 28 days (Figure 5D).	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('delayed', 'NegReg', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('MI-503', 'Var', (41, 47))	('tumor', 'Disease', (75, 80))	('MI-503', 'Chemical', '-', (41, 47))
87908	27888797	We next assessed whether, like MLL-fusion driven leukemia, disruption of the MLL-menin interaction inhibits expression of oncogenic HOX programs in Ewing sarcoma cells.	('MLL', 'Gene', (77, 80))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (148, 161))	('inhibits', 'NegReg', (99, 107))	('leukemia', 'Disease', (49, 57))	('MLL', 'Gene', '4297', (31, 34))	('menin', 'Gene', '4221', (81, 86))	('leukemia', 'Disease', 'MESH:D007938', (49, 57))	('leukemia', 'Phenotype', 'HP:0001909', (49, 57))	('MLL', 'Gene', (31, 34))	('interaction', 'Interaction', (87, 98))	('Ewing sarcoma', 'Disease', (148, 161))	('disruption', 'Var', (59, 69))	('expression', 'MPA', (108, 118))	('menin', 'Gene', (81, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('MLL', 'Gene', '4297', (77, 80))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (148, 161))
87913	27888797	Notably, our studies also revealed the entirely unexpected finding that MI-503 induced a profound loss of both MLL1 and menin protein expression (Figure 6D).	('menin', 'Gene', '4221', (120, 125))	('loss', 'NegReg', (98, 102))	('MI-503', 'Chemical', '-', (72, 78))	('menin', 'Gene', (120, 125))	('MI-503', 'Var', (72, 78))	('MLL1', 'Protein', (111, 115))
87916	27888797	This finding of down-regulated MLL and menin protein expression in response to MI-503 appears to be unique to Ewing sarcoma since, in both leukemia and prostate cancer cells, MI-503 blocks the MLL-menin protein-protein interaction, without affecting their overall expression.	('MI-503', 'Var', (175, 181))	('down-regulated', 'NegReg', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MLL', 'Gene', '4297', (31, 34))	('MLL', 'Gene', (31, 34))	('leukemia and prostate cancer', 'Disease', 'MESH:D011471', (139, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (152, 167))	('MI-503', 'Chemical', '-', (79, 85))	('MI-503', 'Var', (79, 85))	('menin', 'Gene', '4221', (39, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (110, 123))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (110, 123))	('MI-503', 'Chemical', '-', (175, 181))	('menin', 'Gene', (39, 44))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('menin', 'Gene', '4221', (197, 202))	('blocks', 'NegReg', (182, 188))	('menin', 'Gene', (197, 202))	('MLL', 'Gene', (193, 196))	('MLL', 'Gene', '4297', (193, 196))	('Ewing sarcoma', 'Disease', (110, 123))
87929	27888797	Thus, our results suggest that, similar to MLL fusion-driven leukemias and glioblastoma, aberrant TrxG-mediated activation of developmental HOX programs plays a central role Ewing sarcoma pathogenesis.	('developmental HOX programs', 'Pathway', (126, 152))	('MLL', 'Gene', '4297', (43, 46))	('glioblastoma', 'Disease', (75, 87))	('MLL', 'Gene', (43, 46))	('activation', 'PosReg', (112, 122))	('aberrant', 'Var', (89, 97))	('Ewing sarcoma', 'Disease', (174, 187))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('leukemias', 'Phenotype', 'HP:0001909', (61, 70))	('leukemias', 'Disease', (61, 70))	('TrxG', 'Chemical', '-', (98, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (174, 187))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (174, 187))	('leukemias', 'Disease', 'MESH:D007938', (61, 70))	('leukemia', 'Phenotype', 'HP:0001909', (61, 69))
87931	27888797	The current work sheds further light on the molecular mechanisms that contribute to posterior HOXD gene deregulation in this disease.	('HOXD', 'Gene', (94, 98))	('HOXD', 'Gene', '3230', (94, 98))	('deregulation', 'Var', (104, 116))
87932	27888797	Specifically, our findings strongly implicate MLL1 and menin in mediating epigenetic activation of the HOXD locus.	('MLL1', 'Protein', (46, 50))	('implicate', 'Reg', (36, 45))	('menin', 'Gene', (55, 60))	('HOXD', 'Gene', '3230', (103, 107))	('HOXD', 'Gene', (103, 107))	('menin', 'Gene', '4221', (55, 60))	('epigenetic activation', 'Var', (74, 95))
87935	27888797	Thus, it is plausible that MLL1 and menin may each be necessary, but not sufficient, for full activation of the posterior HOXD locus and that disruption of the MLL1-menin interaction effectively abrogates TrxG complex-dependent epigenetic activation of posterior HOXD gene expression.	('disruption', 'Var', (142, 152))	('interaction', 'Interaction', (171, 182))	('HOXD', 'Gene', (263, 267))	('menin', 'Gene', '4221', (36, 41))	('TrxG', 'Chemical', '-', (205, 209))	('epigenetic activation', 'MPA', (228, 249))	('HOXD', 'Gene', (122, 126))	('menin', 'Gene', '4221', (165, 170))	('abrogates', 'NegReg', (195, 204))	('menin', 'Gene', (36, 41))	('HOXD', 'Gene', '3230', (263, 267))	('HOXD', 'Gene', '3230', (122, 126))	('menin', 'Gene', (165, 170))
87937	27888797	Moreover, MI-503 targets a binding site on menin that is critical not only for its interaction with MLL1 (KMT2A) but also its interactions with MLL4 (KMT2B) and with JUND.	('JUND', 'Gene', '3727', (166, 170))	('JUND', 'Gene', (166, 170))	('interactions', 'Interaction', (126, 138))	('menin', 'Gene', '4221', (43, 48))	('interaction', 'Interaction', (83, 94))	('MLL4', 'Protein', (144, 148))	('menin', 'Gene', (43, 48))	('MI-503', 'Var', (10, 16))	('MLL1', 'Protein', (100, 104))	('MI-503', 'Chemical', '-', (10, 16))
87938	27888797	Thus, it is possible that the impact of MI-503 on tumorigenicity is secondary to loss of menin interactions with other partner proteins and/or to loss of menin expression itself rather than to specific inhibition of the MLL1-menin interaction.	('interactions', 'Interaction', (95, 107))	('loss', 'NegReg', (146, 150))	('expression', 'MPA', (160, 170))	('menin', 'Gene', '4221', (225, 230))	('menin', 'Gene', (225, 230))	('MI-503', 'Chemical', '-', (40, 46))	('menin', 'Gene', '4221', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('MI-503', 'Var', (40, 46))	('menin', 'Gene', '4221', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('menin', 'Gene', (154, 159))	('loss', 'NegReg', (81, 85))	('menin', 'Gene', (89, 94))
87939	27888797	Our observation that Ewing cells rapidly select against menin knockdown supports this possibility, and we are now actively investigating the additional molecular targets of menin in Ewing sarcoma.	('menin', 'Gene', (56, 61))	('menin', 'Gene', '4221', (173, 178))	('Ewing sarcoma', 'Disease', (182, 195))	('menin', 'Gene', (173, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('menin', 'Gene', '4221', (56, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('knockdown', 'Var', (62, 71))
87942	27888797	We previously reported that expression of EWS/FLI1 in differentiating stem cells coordinately induces expression of HOXD10, HOXD11 and HOXD13 along with neighboring transcripts that are also under the control of the same enhancer elements.	('HOXD10', 'Gene', (116, 122))	('expression', 'MPA', (102, 112))	('HOXD11', 'Gene', (124, 130))	('induces', 'PosReg', (94, 101))	('FLI1', 'Gene', (46, 50))	('expression', 'Var', (28, 38))	('FLI1', 'Gene', '2313', (46, 50))	('HOXD11', 'Gene', '3237', (124, 130))	('HOXD10', 'Gene', '3236', (116, 122))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
87968	27888797	The following antibodies were used: Anti-menin (Bethyl A300-105A), 4 mug; anti-MLL (Millipore 05-765), 10mug, anti-H3K4me3 (Invitrogen 49-1005), 2 mug, anti-histone H3 (Cell Signaling Technology 2650), 15 mug.	('menin', 'Gene', (41, 46))	('H3', 'Chemical', 'MESH:C012616', (115, 117))	('anti-histone', 'Var', (152, 164))	('MLL', 'Gene', '4297', (79, 82))	('MLL', 'Gene', (79, 82))	('menin', 'Gene', '4221', (41, 46))	('anti-H3K4me3', 'Var', (110, 122))	('H3', 'Chemical', 'MESH:C012616', (165, 167))
87970	27888797	Western blot was performed according to established protocols with the following primary antibodies: Anti-menin 1:1000 (Bethyl A300-105A), Anti-MLLc 1:500 (Millipore 05-765), Anti-histone H3 1:1000 (Cell Signaling Technology 2650) and Anti-GAPDH 1:1000 (Cell Signaling 14C10).	('Anti-histone', 'Var', (175, 187))	('menin', 'Gene', '4221', (106, 111))	('MLL', 'Gene', (144, 147))	('MLL', 'Gene', '4297', (144, 147))	('H3', 'Chemical', 'MESH:C012616', (188, 190))	('menin', 'Gene', (106, 111))	('Anti-GAPDH 1:1000', 'Var', (235, 252))
88033	28276003	G-CSF is thought to cause paraneoplastic syndrome such as fever or increased CRP, and cytokines such as G-CSF have been suggested as markers for UPS.	('CRP', 'Gene', (77, 80))	('cause', 'Reg', (20, 25))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (26, 49))	('increased CRP', 'Phenotype', 'HP:0011227', (67, 80))	('G-CSF', 'Var', (0, 5))	('CRP', 'Gene', '1401', (77, 80))	('fever', 'Disease', 'MESH:D005334', (58, 63))	('increased', 'PosReg', (67, 76))	('fever', 'Disease', (58, 63))	('fever', 'Phenotype', 'HP:0001945', (58, 63))	('paraneoplastic syndrome', 'Disease', (26, 49))
88130	22963500	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/12/404/prepub This work was supported by the Food and Drug Administration (R01-FD003936), the Comprehensive Cancer Center of Wake Forest University (NCI-P30-CA012197) and the American Cancer Society (ACS-MRSG-07-152-01-CNE).	('Cancer', 'Phenotype', 'HP:0002664', (288, 294))	('R01-FD003936', 'Var', (179, 191))	('152-01-CNE', 'CellLine', 'CVCL:6888', (316, 326))	('Cancer', 'Phenotype', 'HP:0002664', (212, 218))	('ACS', 'Gene', (304, 307))	('ACS', 'Gene', '84680', (304, 307))
88131	22964827	Patterns of bone sarcomas as a second malignancy in relation to radiotherapy in adulthood and histologic type Radiotherapy decreases cancer mortality, but is associated with an increased incidence of second primary cancers, including osteosarcomas, especially after exposure in childhood.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('bone sarcomas', 'Disease', 'MESH:D001847', (12, 25))	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('osteosarcomas', 'Disease', (234, 247))	('decreases cancer', 'Disease', 'MESH:D009369', (123, 139))	('bone sarcomas', 'Disease', (12, 25))	('bone sarcomas', 'Phenotype', 'HP:0002669', (12, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('osteosarcomas', 'Phenotype', 'HP:0002669', (234, 247))	('malignancy', 'Disease', (38, 48))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('primary cancers', 'Disease', (207, 222))	('decreases cancer', 'Disease', (123, 139))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('Radiotherapy', 'Var', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))	('osteosarcoma', 'Phenotype', 'HP:0002669', (234, 246))	('osteosarcomas', 'Disease', 'MESH:D012516', (234, 247))	('sarcomas', 'Phenotype', 'HP:0100242', (239, 247))	('primary cancers', 'Disease', 'MESH:D009369', (207, 222))	('bone sarcoma', 'Phenotype', 'HP:0002669', (12, 24))
88142	22964827	Radiotherapy reduces cancer mortality and recurrence, but it has been associated with an increased risk of subsequent primary cancers.	('reduces', 'NegReg', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('Radiotherapy', 'Var', (0, 12))	('primary cancers', 'Disease', (118, 133))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('recurrence', 'CPA', (42, 52))	('primary cancers', 'Disease', 'MESH:D009369', (118, 133))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
88158	22964827	We used ICD-O3 morphology codes to further classify each bone sarcoma by histologic type: chondrosarcoma (ICD-O-3 codes 9220 - 9221, 9230 - 9231, 9240 - 9243), osteosarcoma (9180 - 9186, 9192 - 9194, 9200), fibrosarcoma/malignant fibrous histiocytoma (8810 - 8815, 8823 - 8825, 8830), Ewing sarcoma (9260), spindle cell sarcoma (8801), and giant cell sarcoma/malignant giant cell tumor of the bone (8802/9250).	('fibrosarcoma', 'Phenotype', 'HP:0100244', (207, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('8810 - 8815', 'Var', (252, 263))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (90, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('giant cell sarcoma/malignant giant cell tumor', 'Disease', 'MESH:D005870', (340, 385))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('fibrosarcoma', 'Disease', 'MESH:D005354', (207, 219))	('bone sarcoma', 'Disease', 'MESH:D001847', (57, 69))	('spindle cell sarcoma', 'Disease', 'MESH:D012509', (307, 327))	('fibrosarcoma', 'Disease', (207, 219))	('giant cell sarcoma/malignant giant cell tumor', 'Disease', (340, 385))	('spindle cell sarcoma', 'Disease', (307, 327))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (285, 298))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('histiocytoma', 'Phenotype', 'HP:0012315', (238, 250))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (285, 298))	('bone sarcoma', 'Phenotype', 'HP:0002669', (57, 69))	('9260', 'Var', (300, 304))	('8802/9250', 'Var', (399, 408))	('9180 - 9186', 'Var', (174, 185))	('osteosarcoma', 'Disease', (160, 172))	('osteosarcoma', 'Disease', 'MESH:D012516', (160, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('tumor of the bone', 'Phenotype', 'HP:0010622', (380, 397))	('chondrosarcoma', 'Disease', 'MESH:D002813', (90, 104))	('chondrosarcoma', 'Disease', (90, 104))	('8801', 'Var', (329, 333))	('Ewing sarcoma', 'Disease', (285, 298))	('bone sarcoma', 'Disease', (57, 69))	('giant cell tumor of the bone', 'Phenotype', 'HP:0011847', (369, 397))
88236	33006617	In this cohort study of 173 580 patients, the rate of secondary sarcoma among patients treated with radiotherapy was increased compared with patients who had surgery alone and with the general population.	('secondary sarcoma', 'Disease', (54, 71))	('patients', 'Species', '9606', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('patients', 'Species', '9606', (78, 86))	('secondary sarcoma', 'Disease', 'MESH:D060085', (54, 71))	('radiotherapy', 'Var', (100, 112))	('patients', 'Species', '9606', (141, 149))
88278	33006617	We used OHIP fee codes and Canadian Classification of Health Intervention (CCI) codes to identify patients who underwent abdominopelvic surgery, and fee codes X310, X311, X312, and X313 (planning codes for radiation) or X323, X324, X325, or X305 (intracavitary codes for radiation) and corresponding CCI codes to identify patients who underwent abdominopelvic radiation (eAppendix 2 in the Supplement).	('X311', 'Var', (165, 169))	('X305', 'Var', (241, 245))	('patients', 'Species', '9606', (322, 330))	('X310', 'Var', (159, 163))	('men', 'Species', '9606', (396, 399))	('X313', 'Var', (181, 185))	('patients', 'Species', '9606', (98, 106))	('X323', 'Var', (220, 224))	('X325', 'Var', (232, 236))	('X324', 'Var', (226, 230))	('X312', 'Var', (171, 175))
88383	27781381	The dataset was queried using tumor histology codes from the International Classification of Disease for Oncology 3rd Edition (ICD-O-3): code 8805 for undifferentiated sarcoma and code 8991 for embryonal sarcoma.	('Oncology', 'Phenotype', 'HP:0002664', (105, 113))	('undifferentiated sarcoma', 'Disease', (151, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('code 8991', 'Var', (180, 189))	('embryonal sarcoma', 'Disease', 'MESH:D012509', (194, 211))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (151, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('embryonal sarcoma', 'Disease', (194, 211))	('code 8805', 'Var', (137, 146))	('tumor', 'Disease', (30, 35))
88496	25431948	The sequences of 19 other KSHV strains consisted of 1 strain of subtype A1 XJ-27 (FJ853386); 1 strain of subtype A2: Ema-7 (AF130305); 1 strain of subtype A3: IT-268 (GU097421), 1 strain of subtype A4: BCBL-B (AF133039),US114 (GU097431) ; 1 strain of subtype A5: KE229 (GU097433); 3 strains of subtype B: UG-65 (FJ884618), UG-85 (FJ884620), MP10 (AF387367); 2 strains of subtype C2: XJ-6 (FJ853368), XJ30 (FJ853388); 1 strain of subtype C3: XJ-20 (FJ853379), AF17170531; 2 strains of subtype D: TKS10 (AF133043), ZKS3 (AF133044), 2 strains of subtype E: Sio1 (AY329025), Tupi1 (AF220292); and 2 strains of subtype F: AF178810, FJ884616.	('AF133043', 'Var', (502, 510))	('KSHV', 'Species', '37296', (26, 30))	('AY329025', 'Var', (560, 568))
88629	23781364	These include classic variant KS, endemic KS, transplant-associated KS, and AIDS-associated KS.	('endemic KS', 'Disease', (34, 44))	('variant', 'Var', (22, 29))	('transplant-associated KS', 'Disease', (46, 70))	('AIDS', 'Disease', (76, 80))	('AIDS', 'Disease', 'MESH:D000163', (76, 80))
88640	23781364	Although of Mediterranean descent, our patient had a rare type of KS known as lymphangioma-like KS, which can occur in each of the four KS variants and is less than 5% of all KS cases.	('patient', 'Species', '9606', (39, 46))	('lymphangioma', 'Phenotype', 'HP:0100764', (78, 90))	('lymphangioma', 'Disease', (78, 90))	('variants', 'Var', (139, 147))	('lymphangioma', 'Disease', 'MESH:D008202', (78, 90))
88669	31583145	Staging depending on chest X-ray, bone scintigraphy, and thoracoabdominal CT scan revealing no signs of metastatic disease suggested a T2N0M0 score and a stage IIA tumor.	('IIA tumor', 'Disease', 'MESH:C537988', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('IIA tumor', 'Disease', (160, 169))	('T2N0M0 score', 'Var', (135, 147))
88827	26909304	Recently, it was reported that a combination of MDM2 and CDK4 by immunohistochemical analysis shows 100% sensitivity and 97.5% specificity for the diagnosis of low-grade osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('CDK4', 'Gene', (57, 61))	('CDK4', 'Gene', '1019', (57, 61))	('osteosarcoma', 'Phenotype', 'HP:0002669', (170, 182))	('MDM2', 'Gene', '4193', (48, 52))	('osteosarcoma', 'Disease', (170, 182))	('MDM2', 'Gene', (48, 52))	('combination', 'Var', (33, 44))	('osteosarcoma', 'Disease', 'MESH:D012516', (170, 182))
88845	25500058	Synergistic Activity of PARP Inhibition by Talazoparib (BMN 673) with Temozolomide in Pediatric Cancer Models in the Pediatric Preclinical Testing Program Inhibitors of poly-ADP ribose polymerase (PARP), an enzyme involved in base excision repair (BER) have demonstrated single agent activity against tumors deficient in homologous repair processes.	('PARP', 'Gene', (197, 201))	('BMN', 'Chemical', '-', (56, 59))	('tumors deficient', 'Disease', (301, 317))	('Pediatric Cancer', 'Disease', 'MESH:D009369', (86, 102))	('Temozolomide', 'Chemical', 'MESH:D000077204', (70, 82))	('tumors deficient', 'Disease', 'MESH:D009369', (301, 317))	('PARP', 'Gene', (24, 28))	('PARP', 'Gene', '142', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('Pediatric Cancer', 'Disease', (86, 102))	('Inhibitors', 'Var', (155, 165))	('poly-ADP ribose polymerase', 'Gene', (169, 195))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('poly-ADP ribose polymerase', 'Gene', '142', (169, 195))	('Inhibition', 'NegReg', (29, 39))	('PARP', 'Gene', '142', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('Talazoparib', 'Chemical', 'MESH:C586365', (43, 54))
88855	25500058	Poly(ADP-ribose) polymerase1 (PARP1) plays a central role in the recognition of single-strand DNA damage and is involved in chromatin modification, transcription, and DNA repair.	('Poly(ADP-ribose) polymerase1', 'Gene', (0, 28))	('involved', 'Reg', (112, 120))	('Poly(ADP-ribose) polymerase1', 'Gene', '142', (0, 28))	('single-strand', 'Var', (80, 93))	('PARP1', 'Gene', '142', (30, 35))	('PARP1', 'Gene', (30, 35))
88862	25500058	The finding of synthetic lethality for PARP inhibition in the presence of defects in homologous DNA repair stimulated evaluations of PARP inhibitors as single agents against cancers arising in patients with BRCA mutations.	('PARP', 'Gene', (39, 43))	('patients', 'Species', '9606', (193, 201))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('BRCA', 'Gene', '672', (207, 211))	('cancers', 'Disease', (174, 181))	('inhibition', 'NegReg', (44, 54))	('defects', 'Var', (74, 81))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('BRCA', 'Gene', (207, 211))	('mutations', 'Var', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
88863	25500058	While these double-strand breaks can be repaired in patients with intact homologous recombination repair, they lead to lethal lesions in tumors with defective double-stand DNA repair such as those with homozygous BRCA1 or BRCA2 mutations.	('defective', 'NegReg', (149, 158))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('BRCA1', 'Gene', (213, 218))	('BRCA2', 'Gene', (222, 227))	('mutations', 'Var', (228, 237))	('double-stand', 'Phenotype', 'HP:0003698', (159, 171))	('BRCA1', 'Gene', '672', (213, 218))	('BRCA2', 'Gene', '675', (222, 227))	('lead to', 'Reg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('patients', 'Species', '9606', (52, 60))
88864	25500058	Multiple PARP inhibitors have shown single agent activity against cancers arising in patients with BRCA1 or BRCA2 mutations, and phase 3 clinical trials are ongoing for ovarian cancer and breast cancer.	('BRCA2', 'Gene', (108, 113))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('ovarian cancer', 'Disease', (169, 183))	('BRCA1', 'Gene', (99, 104))	('breast cancer', 'Disease', (188, 201))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('BRCA2', 'Gene', '675', (108, 113))	('patients', 'Species', '9606', (85, 93))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancers', 'Disease', (66, 73))	('ovarian cancer', 'Disease', 'MESH:D010051', (169, 183))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (169, 183))	('BRCA1', 'Gene', '672', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
88866	25500058	One report evaluating the activity of a range of anticancer agents across a large cell line panel found a highly significant association between cell lines with the EWS-FLI1 rearrangement and sensitivity to the PARP inhibitor olaparib (AZD2281).	('EWS', 'Gene', '2130', (165, 168))	('EWS', 'Gene', (165, 168))	('cancer', 'Disease', (53, 59))	('rearrangement', 'Var', (174, 187))	('sensitivity', 'MPA', (192, 203))	('olaparib', 'Chemical', 'MESH:C531550', (226, 234))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('FLI1', 'Gene', (169, 173))	('AZD2281', 'Chemical', 'MESH:C531550', (236, 243))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FLI1', 'Gene', '2313', (169, 173))
88868	25500058	PARP1 inhibitors have been thought to potentiate the activity of chemotherapy agents through their inhibition of the catalytic activity PARP1, leading to delays in repair and in subsequent accumulation of single strand DNA breaks.	('single strand DNA breaks', 'MPA', (205, 229))	('repair', 'MPA', (164, 170))	('potentiate', 'PosReg', (38, 48))	('accumulation', 'PosReg', (189, 201))	('inhibition', 'NegReg', (99, 109))	('activity', 'MPA', (53, 61))	('inhibitors', 'Var', (6, 16))	('PARP1', 'Gene', '142', (136, 141))	('PARP1', 'Gene', '142', (0, 5))	('PARP1', 'Gene', (136, 141))	('PARP1', 'Gene', (0, 5))	('delays', 'NegReg', (154, 160))
88875	25500058	A phase 3 clinical trial is evaluating talazoparib for patients with germline BRCA mutations and locally advanced and/or metastatic breast cancer (NCT01945775).	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BRCA', 'Gene', '672', (78, 82))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('patients', 'Species', '9606', (55, 63))	('BRCA', 'Gene', (78, 82))	('breast cancer', 'Disease', (132, 145))	('talazoparib', 'Chemical', 'MESH:C586365', (39, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
88882	25500058	Prioritization of this strategy was based in part on the emerging evidence that PARP1 inhibitors are cytotoxic by PARP trapping initiated by PARP1 binding to DNA with single-strand breaks.	('PARP trapping', 'MPA', (114, 127))	('binding', 'Interaction', (147, 154))	('PARP1', 'Gene', (141, 146))	('PARP1', 'Gene', '142', (141, 146))	('PARP1', 'Gene', '142', (80, 85))	('PARP1', 'Gene', (80, 85))	('inhibitors', 'Var', (86, 96))
89006	25500058	Temozolomide single agent cytotoxicity results from futile cycles of mismatch repair with removal and reinsertion of thymine opposite O6-methyl guanine (O6-meG) eventually resulting in an apoptosis-inducing double strand DNA break at the next cycle of DNA replication.	('O6-methyl guanine', 'Chemical', 'MESH:C008449', (134, 151))	('O6-meG', 'Chemical', 'MESH:C008449', (153, 159))	('cytotoxicity', 'Disease', (26, 38))	('mismatch', 'Var', (69, 77))	('resulting in', 'Reg', (172, 184))	('double strand DNA break', 'MPA', (207, 230))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('thymine', 'Chemical', 'MESH:D013941', (117, 124))	('apoptosis-inducing', 'CPA', (188, 206))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
89011	25500058	Rather, it should be considered as a new treatment strategy in which cytotoxicity can be initiated by non-O6-meG methyl adducts that promote PARP trapping.	('cytotoxicity', 'Disease', 'MESH:D064420', (69, 81))	('promote', 'PosReg', (133, 140))	('adducts', 'Var', (120, 127))	('O6-meG', 'Chemical', 'MESH:C008449', (106, 112))	('cytotoxicity', 'Disease', (69, 81))	('PARP trapping', 'MPA', (141, 154))
89017	25500058	While we cannot identify factors that predict response, we can identify several factors that do not appear to be related to sensitivity, including TP53 mutations (present in some sensitive and some resistant tumors) and MGMT expression (present in both sensitive and resistant tumors).	('MGMT', 'Gene', (220, 224))	('TP53', 'Gene', (147, 151))	('mutations', 'Var', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('TP53', 'Gene', '7157', (147, 151))	('MGMT', 'Gene', '4255', (220, 224))	('tumors', 'Disease', (277, 283))
89020	25500058	GBM2, for example, shows limited response to single agent temozolomide at concentrations below 300 muM, while the presence of talazoparib shifts the rIC50 by 85-fold with Relative I/O% values approaching -100% (indicative of a complete cytotoxic response at 96 hours).	('GBM2', 'Gene', (0, 4))	('muM', 'Gene', (99, 102))	('presence', 'Var', (114, 122))	('talazoparib', 'Chemical', 'MESH:C586365', (126, 137))	('temozolomide', 'Chemical', 'MESH:D000077204', (58, 70))	('response', 'MPA', (33, 41))	('rIC50', 'MPA', (149, 154))	('muM', 'Gene', '56925', (99, 102))
89021	25500058	In vivo, 4 of 5 xenograft lines with low MGMT expression showed complete responses to low-dose temozolomide plus talazoparib that were maintained for at least 6 weeks.	('temozolomide', 'Chemical', 'MESH:D000077204', (95, 107))	('low', 'Var', (37, 40))	('talazoparib', 'Chemical', 'MESH:C586365', (113, 124))	('MGMT', 'Gene', '4255', (41, 45))	('MGMT', 'Gene', (41, 45))
89022	25500058	This suggests that O6-meG adducts that are not rapidly removed by MGMT can initiate a robust cytotoxic response in the presence of talazoparib.	('cytotoxic response', 'CPA', (93, 111))	('MGMT', 'Gene', (66, 70))	('adducts', 'Var', (26, 33))	('O6-meG', 'Chemical', 'MESH:C008449', (19, 25))	('MGMT', 'Gene', '4255', (66, 70))	('talazoparib', 'Chemical', 'MESH:C586365', (131, 142))	('initiate', 'Reg', (75, 83))	('O6-meG adducts', 'Var', (19, 33))
89035	25500058	The loss of PARP transcripts is consistent with a model in which EWS-FLI1 regulation of PARP transcription is dependent upon the interaction with PARP binding at the PARP promoter, and that EWS-FLI1 gene fusions in ESFTs depend on the activity of PARP1, and is also consistent with reports that ETS transcription factors drive PARP1 expression in ESFTs.	('EWS', 'Gene', '2130', (190, 193))	('loss', 'NegReg', (4, 8))	('EWS', 'Gene', (65, 68))	('FLI1', 'Gene', (69, 73))	('fusions', 'Var', (204, 211))	('PARP1', 'Gene', (327, 332))	('dependent', 'Reg', (110, 119))	('PARP', 'Gene', (12, 16))	('PARP1', 'Gene', (247, 252))	('FLI1', 'Gene', '2313', (69, 73))	('EWS', 'Gene', (190, 193))	('FLI1', 'Gene', (194, 198))	('interaction', 'Interaction', (129, 140))	('PARP', 'Gene', (88, 92))	('EWS', 'Gene', '2130', (65, 68))	('PARP1', 'Gene', '142', (327, 332))	('FLI1', 'Gene', '2313', (194, 198))	('PARP', 'Protein', (146, 150))	('PARP1', 'Gene', '142', (247, 252))
89041	25500058	Experience to date with potentiating agents has highlighted this risk, as exemplified by experience with MGMT inhibitors (e.g., O6-benzylguanine and lomeguatrib).	('lomeguatrib', 'Disease', (149, 160))	('lomeguatrib', 'Chemical', 'MESH:C521206', (149, 160))	('O6-benzylguanine', 'Chemical', 'MESH:C064976', (128, 144))	('MGMT', 'Gene', '4255', (105, 109))	('MGMT', 'Gene', (105, 109))	('O6-benzylguanine', 'Var', (128, 144))
89042	25500058	For both O6-benzylguanine and lomeguatrib, their addition to alkylating agents (e.g., nitrosoureas and temozolomide) leads to increased toxicity requiring dose reductions, such that the combination is no more effective than the chemotherapy agent given alone at its single agent dose.	('O6-benzylguanine', 'Var', (9, 25))	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('toxicity', 'Disease', (136, 144))	('nitrosoureas', 'Chemical', 'MESH:D009607', (86, 98))	('O6-benzylguanine', 'Chemical', 'MESH:C064976', (9, 25))	('lomeguatrib', 'Chemical', 'MESH:C521206', (30, 41))	('temozolomide', 'Chemical', 'MESH:D000077204', (103, 115))
89167	20851743	Early sustained administration of anti-NGF, whose cognate receptor is TrkA, blocks the pathological sprouting of sensory and sympathetic nerve fibers, the formation of neuroma-like structures, and inhibits the development of cancer pain.	('neuroma', 'Disease', (168, 175))	('cancer pain', 'Disease', 'MESH:D000072716', (225, 236))	('inhibits', 'NegReg', (197, 205))	('cancer pain', 'Disease', (225, 236))	('blocks', 'NegReg', (76, 82))	('pain', 'Phenotype', 'HP:0012531', (232, 236))	('anti-NGF', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('neuroma', 'Disease', 'MESH:D009463', (168, 175))	('neuroma', 'Phenotype', 'HP:0030430', (168, 175))
89183	20851743	This pathological reorganization of nerve fibers would then set in place a neuroanatomical substrate that would not only be highly sensitive to movement of the tumor-bearing organ but also create an "ectopic generator" which could spontaneously discharge with accompanying pain.	('pathological', 'Var', (5, 17))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('pain', 'Phenotype', 'HP:0012531', (273, 277))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('pain', 'Disease', 'MESH:D010146', (273, 277))	('pain', 'Disease', (273, 277))	('tumor', 'Disease', (160, 165))
89223	20851743	The number of animals used for frozen section analysis was: n=8 for sham + vehicle, n=9 for sarcoma + vehicle, n=9 for sarcoma + early/sustained anti-NGF, and n=7 for sarcoma + late/acute anti-NGF.	('anti-NGF', 'Var', (145, 153))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Disease', (92, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('sarcoma', 'Disease', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
89255	20851743	Data from these studies demonstrated that early/sustained treatment with anti-NGF (given at 6, 12 and 18 days post tumor injection) significantly attenuated the sprouting of CGRP+ (Fig.	('anti-NGF', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('attenuated', 'NegReg', (146, 156))	('CGRP', 'Gene', '12310', (174, 178))	('CGRP', 'Gene', (174, 178))	('sprouting of', 'CPA', (161, 173))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
89258	20851743	Interestingly, significant attenuation of this sprouting was only observed with the early/sustained anti-NGF administration but not with late/acute administration (given once at day 18 post tumor injection) (Fig.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('attenuation', 'NegReg', (27, 38))	('anti-NGF', 'Var', (100, 108))
89259	20851743	Early/sustained administration of anti-NGF similarly resulted in a marked decrease in the formation of neuroma-like structures whereas in the late/acute administration group, as many as 50% of the animals examined had CGRP+, NF200+, and TH+ neuroma-like structures.	('neuroma', 'Phenotype', 'HP:0030430', (241, 248))	('neuroma', 'Disease', (241, 248))	('decrease', 'NegReg', (74, 82))	('TH', 'Chemical', '-', (237, 239))	('CGRP', 'Gene', '12310', (218, 222))	('CGRP', 'Gene', (218, 222))	('neuroma', 'Disease', (103, 110))	('neuroma', 'Phenotype', 'HP:0030430', (103, 110))	('NF200', 'Gene', (225, 230))	('anti-NGF', 'Var', (34, 42))	('NF200', 'Gene', '380684', (225, 230))	('neuroma', 'Disease', 'MESH:D009463', (241, 248))	('neuroma', 'Disease', 'MESH:D009463', (103, 110))
89260	20851743	Importantly, early/sustained administration of anti-NGF did not affect the organization or density of CGRP+, NF200+, or TH+ fibers in the contralateral, non-tumor bearing bones compared to sham mice (Table 1).	('tumor', 'Disease', (157, 162))	('NF200', 'Gene', (109, 114))	('density', 'CPA', (91, 98))	('NF200', 'Gene', '380684', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('organization', 'CPA', (75, 87))	('CGRP', 'Gene', '12310', (102, 106))	('CGRP', 'Gene', (102, 106))	('anti-NGF', 'Var', (47, 55))	('TH', 'Chemical', '-', (120, 122))	('mice', 'Species', '10090', (194, 198))
89261	20851743	Additionally, in agreement with previous in vivo studies, anti-NGF therapy had no effect on disease progression as measured by tumor growth within or outside the marrow space, tumor-induced bone destruction/remodeling, or tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('bone destruction', 'Phenotype', 'HP:0002797', (190, 206))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor metastasis', 'Disease', 'MESH:D009362', (222, 238))	('tumor metastasis', 'Disease', (222, 238))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (176, 181))	('tumor growth', 'Disease', 'MESH:D006130', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor growth', 'Disease', (127, 139))	('anti-NGF', 'Var', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
89262	20851743	To assess whether the observed aberrant nerve growth correlates with increasing cancer pain, and to determine whether anti-NGF therapy attenuates this pain, pain behaviors were analyzed in tumor-bearing mice treated with early/acute anti-NGF (anti-NGF administered once at day 6), early/sustained anti-NGF (anti-NGF administered at day 6, 12, and 18), and late/acute anti-NGF (anti-NGF administered once at day 18), and compared to sham animals treated with vehicle.	('pain', 'Disease', 'MESH:D010146', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('pain', 'Disease', (151, 155))	('cancer pain', 'Disease', (80, 91))	('pain', 'Disease', (87, 91))	('mice', 'Species', '10090', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('anti-NGF', 'Var', (297, 305))	('increasing', 'PosReg', (69, 79))	('anti-NGF', 'Var', (233, 241))	('pain', 'Phenotype', 'HP:0012531', (151, 155))	('cancer pain', 'Disease', 'MESH:D000072716', (80, 91))	('pain', 'Phenotype', 'HP:0012531', (87, 91))	('pain', 'Disease', (157, 161))	('pain', 'Phenotype', 'HP:0012531', (157, 161))	('pain', 'Disease', 'MESH:D010146', (151, 155))	('tumor', 'Disease', (189, 194))	('pain', 'Disease', 'MESH:D010146', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
89267	20851743	Behavioral analysis revealed that when anti-NGF was given at day 6 post tumor injection, pain behaviors are reduced by ~40% by day 8, whereas early/sustained administration of anti-NGF from days 6-18 reduced pain behaviors by ~60% at day 20.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('anti-NGF', 'Var', (176, 184))	('pain', 'Disease', (89, 93))	('reduced', 'NegReg', (108, 115))	('tumor', 'Disease', (72, 77))	('pain', 'Phenotype', 'HP:0012531', (208, 212))	('anti-NGF', 'Var', (39, 47))	('pain', 'Disease', 'MESH:D010146', (208, 212))	('pain', 'Phenotype', 'HP:0012531', (89, 93))	('pain', 'Disease', (208, 212))	('reduced pain', 'Phenotype', 'HP:0007328', (200, 212))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('pain', 'Disease', 'MESH:D010146', (89, 93))
89268	20851743	In contrast, when anti-NGF was administered late (on day 18), it did not produce a statistically significant reduction in cancer pain behaviors at day 20 (Fig.	('pain', 'Phenotype', 'HP:0012531', (129, 133))	('reduction', 'NegReg', (109, 118))	('cancer pain', 'Disease', 'MESH:D000072716', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer pain', 'Disease', (122, 133))	('anti-NGF', 'Var', (18, 26))
89270	20851743	In particular, we have shown that when GFP+ tumor cells growing within the bone marrow escape and invade the periosteum, a rapid and ectopic sprouting of CGRP+ and NF200+ sensory, and TH+ sympathetic nerve fibers occurs in the periosteum.	('NF200', 'Gene', (164, 169))	('GFP+', 'Var', (39, 43))	('NF200', 'Gene', '380684', (164, 169))	('TH', 'Chemical', '-', (184, 186))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('CGRP', 'Gene', '12310', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CGRP', 'Gene', (154, 158))	('tumor', 'Disease', (44, 49))
89286	20851743	Using a mouse monoclonal antibody against NGF (anti-NGF), we show that while early and sustained administration of anti-NGF results in a marked reduction of sprouting and neuroma-like formation by CGRP+, TH+, and NF200+ nerve fibers in the tumor-bearing bone, this treatment does not reduce the density of normal nerve fibers in the contralateral, non-tumor-bearing bone.	('anti-NGF', 'Var', (115, 123))	('NF200', 'Gene', (213, 218))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('CGRP', 'Gene', '12310', (197, 201))	('NF200', 'Gene', '380684', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('sprouting', 'CPA', (157, 166))	('CGRP', 'Gene', (197, 201))	('neuroma', 'Disease', (171, 178))	('TH', 'Chemical', '-', (204, 206))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', (352, 357))	('neuroma', 'Disease', 'MESH:D009463', (171, 178))	('mouse', 'Species', '10090', (8, 13))	('neuroma', 'Phenotype', 'HP:0030430', (171, 178))	('reduction', 'NegReg', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
89287	20851743	Whether NGF drives this sprouting through binding to the TrkA or p75 receptor is as yet unknown, but other studies suggest that TrkA is more involved in driving sprouting while p75 is more involved in apoptosis.	('p75', 'Gene', (177, 180))	('p75', 'Gene', '18053', (65, 68))	('driving sprouting', 'CPA', (153, 170))	('p75', 'Gene', (65, 68))	('TrkA', 'Var', (128, 132))	('p75', 'Gene', '18053', (177, 180))
89295	20851743	In contrast, when anti-NGF was administered late in disease progression at day 18 and pain behaviors assessed at day 20 (when ectopic spouting and neuroma formation had already occurred) there was no significant reduction in pain-related behaviors.	('pain', 'Phenotype', 'HP:0012531', (86, 90))	('pain', 'Disease', 'MESH:D010146', (86, 90))	('pain', 'Phenotype', 'HP:0012531', (225, 229))	('pain', 'Disease', (86, 90))	('pain', 'Disease', 'MESH:D010146', (225, 229))	('pain', 'Disease', (225, 229))	('reduction', 'NegReg', (212, 221))	('neuroma', 'Disease', 'MESH:D009463', (147, 154))	('neuroma', 'Phenotype', 'HP:0030430', (147, 154))	('neuroma', 'Disease', (147, 154))	('anti-NGF', 'Var', (18, 26))
89296	20851743	It should be noted that a mouse fracture pain model showed that when the anti-NGF therapy was administered at day 1 following fracture, when the pain was severe but nerve sprouting had yet to occur, anti-NGF achieved full analgesic efficacy (a 50% reduction in pain) one day following initial administration.	('pain', 'Disease', (41, 45))	('pain', 'Disease', 'MESH:D010146', (261, 265))	('pain', 'Disease', (145, 149))	('fracture', 'Disease', (32, 40))	('pain', 'Phenotype', 'HP:0012531', (41, 45))	('pain', 'Phenotype', 'HP:0012531', (145, 149))	('reduction', 'NegReg', (248, 257))	('pain', 'Disease', 'MESH:D010146', (41, 45))	('fracture', 'Disease', (126, 134))	('pain', 'Disease', (261, 265))	('analgesic efficacy', 'CPA', (222, 240))	('fracture', 'Disease', 'MESH:D050723', (32, 40))	('pain', 'Disease', 'MESH:D010146', (145, 149))	('anti-NGF', 'Var', (199, 207))	('pain', 'Phenotype', 'HP:0012531', (261, 265))	('fracture pain', 'Disease', 'MESH:D050723', (32, 45))	('fracture pain', 'Disease', (32, 45))	('mouse', 'Species', '10090', (26, 31))	('fracture', 'Disease', 'MESH:D050723', (126, 134))
89298	20851743	Interestingly, the present data fits well with previous data suggesting that whereas anti-NGF is highly efficacious at inhibiting the regeneration of sensory nerve fibers, anti-NGF showed little if any efficacy at "trimming back" or "pruning" nerve fibers once regeneration had occurred.	('inhibiting', 'NegReg', (119, 129))	('fits', 'Disease', 'MESH:D012640', (32, 36))	('anti-NGF', 'Var', (85, 93))	('anti-NGF', 'Var', (172, 180))	('regeneration of sensory nerve fibers', 'CPA', (134, 170))	('fits', 'Disease', (32, 36))
89299	20851743	It should be noted that previous studies in our lab have shown that anti-NGF therapy is effective at reducing the pain-related behaviors even before the appearance of nerve sprouting and neuroma-like structures.	('neuroma', 'Disease', 'MESH:D009463', (187, 194))	('neuroma', 'Phenotype', 'HP:0030430', (187, 194))	('neuroma', 'Disease', (187, 194))	('pain', 'Phenotype', 'HP:0012531', (114, 118))	('pain', 'Disease', 'MESH:D010146', (114, 118))	('anti-NGF', 'Var', (68, 76))	('pain', 'Disease', (114, 118))	('reducing', 'NegReg', (101, 109))
89300	20851743	Furthermore, it is important to note that in the present study, animals treated with anti-NGF still display some, albeit reduced, nociceptive behaviors.	('nociceptive behaviors', 'Disease', 'MESH:D059226', (130, 151))	('anti-NGF', 'Var', (85, 93))	('reduced', 'NegReg', (121, 128))	('nociceptive behaviors', 'Disease', (130, 151))
89304	20851743	The present data suggest that at least in bone cancer pain, anti-NGF produces optimal analgesic efficacy when administered early, before the development of a chronic pain state, a concept known as preventive analgesia.	('pain', 'Phenotype', 'HP:0012531', (166, 170))	('anti-NGF', 'Var', (60, 68))	('pain', 'Phenotype', 'HP:0012531', (54, 58))	('pain', 'Disease', 'MESH:D010146', (166, 170))	('pain', 'Disease', (166, 170))	('pain', 'Disease', 'MESH:D010146', (54, 58))	('chronic pain', 'Phenotype', 'HP:0012532', (158, 170))	('pain', 'Disease', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('bone cancer pain', 'Disease', 'MESH:D001859', (42, 58))	('bone cancer pain', 'Disease', (42, 58))	('bone cancer pain', 'Phenotype', 'HP:0002653', (42, 58))	('analgesic efficacy', 'MPA', (86, 104))
89307	20851743	Previous studies have shown that inappropriate remodeling of sensory and sympathetic nerve fibers, whether it be sprouting or neuroma-like formation, can give rise to hyperalgesia, allodynia, and spontaneous ectopic discharges that are perceived as highly painful in humans.	('humans', 'Species', '9606', (267, 273))	('hyperalgesia', 'Disease', 'MESH:D006930', (167, 179))	('hyperalgesia', 'Disease', (167, 179))	('give rise to', 'Reg', (154, 166))	('allodynia', 'Disease', (181, 190))	('allodynia', 'Phenotype', 'HP:0012533', (181, 190))	('hyperalgesia', 'Phenotype', 'HP:0031005', (167, 179))	('pain', 'Phenotype', 'HP:0012531', (256, 260))	('allodynia', 'Disease', 'MESH:D006930', (181, 190))	('pain', 'Disease', 'MESH:D010146', (256, 260))	('remodeling', 'Var', (47, 57))	('pain', 'Disease', (256, 260))	('neuroma', 'Disease', 'MESH:D009463', (126, 133))	('spontaneous ectopic discharges', 'MPA', (196, 226))	('neuroma', 'Phenotype', 'HP:0030430', (126, 133))	('neuroma', 'Disease', (126, 133))
89628	26291055	It appears to arise from primitive mesenchymal precursor cells, having a common pathogenic mechanism that is nearly always associated with translocations between EWSR1 and ETS family genes, most frequently involving EWSR1 and FLI1.	('EWS', 'Phenotype', 'HP:0012254', (216, 219))	('associated', 'Reg', (123, 133))	('EWS', 'Phenotype', 'HP:0012254', (162, 165))	('EWSR1', 'Gene', '2130', (216, 221))	('EWSR1', 'Gene', (162, 167))	('translocations', 'Var', (139, 153))	('EWSR1', 'Gene', '2130', (162, 167))	('FLI1', 'Gene', (226, 230))	('EWSR1', 'Gene', (216, 221))	('FLI1', 'Gene', '2313', (226, 230))
89630	26291055	A subsequent study showed that there is variable CASP8 expression in EWS cell lines, and re-expression of CASP8 via gene transfection or demethylation leads to increased sensitivity to TRAIL.	('CASP8', 'Gene', (106, 111))	('CASP8', 'Gene', '841', (106, 111))	('increased', 'PosReg', (160, 169))	('demethylation', 'Var', (137, 150))	('CASP8', 'Gene', '841', (49, 54))	('CASP8', 'Gene', (49, 54))	('sensitivity to TRAIL', 'MPA', (170, 190))	('EWS', 'Phenotype', 'HP:0012254', (69, 72))
89631	26291055	More recently, cationic lipid-mediated TRAIL gene transfer was shown to prevent EWS xenograft development and increases mouse survival.	('EWS', 'Phenotype', 'HP:0012254', (80, 83))	('EWS xenograft development', 'CPA', (80, 105))	('lipid', 'Chemical', 'MESH:D008055', (24, 29))	('increases', 'PosReg', (110, 119))	('prevent', 'NegReg', (72, 79))	('cationic', 'Var', (15, 23))	('mouse survival', 'CPA', (120, 134))	('mouse', 'Species', '10090', (120, 125))
89661	26291055	Only two cell lines (RD-ES and TC71) were sensitive to both DR4 and DR5 antibodies (Figure 1A and B, Table 1).	('TC71', 'CellLine', 'CVCL:2213', (31, 35))	('DR4', 'Gene', (60, 63))	('DR5', 'Var', (68, 71))	('DR4', 'Gene', '8797', (60, 63))
89684	26291055	For the gene transfer experiment, we used a wild-type CASP8-GFP (green fluorescence protein) and a protease-defective CASP8mt-GFP with a C360S mutation at the active-site cysteine of the caspase domain.	('CASP8', 'Gene', (54, 59))	('CASP8', 'Gene', '841', (54, 59))	('C360S', 'Var', (137, 142))	('C360S', 'Mutation', 'p.C360S', (137, 142))	('cysteine', 'Chemical', 'MESH:D003545', (171, 179))	('CASP8', 'Gene', (118, 123))	('caspase', 'Gene', '841;12370;843', (187, 194))	('CASP8', 'Gene', '841', (118, 123))	('caspase', 'Gene', (187, 194))
89686	26291055	Thus, our results indicate that the absence of caspase-8 expression is associated with resistance to conatumumab and that exogenous expression of CASP8 is sufficient to mediate conatumumab-induced apoptosis in resistant EWS cells, which is dependent on its catalytic activity.	('expression', 'MPA', (57, 67))	('apoptosis', 'CPA', (197, 206))	('resistance to conatumumab', 'MPA', (87, 112))	('absence', 'NegReg', (36, 43))	('caspase-8', 'Protein', (47, 56))	('conatumumab-induced', 'Var', (177, 196))	('CASP8', 'Gene', (146, 151))	('CASP8', 'Gene', '841', (146, 151))	('mediate', 'Reg', (169, 176))	('EWS', 'Phenotype', 'HP:0012254', (220, 223))	('conatumumab', 'Chemical', 'MESH:C554537', (101, 112))	('conatumumab', 'Chemical', 'MESH:C554537', (177, 188))	('associated', 'Reg', (71, 81))
89698	26291055	Immunoblot analysis of tumour fragments from these mice showed that while both xenografts expressed comparable levels of DR5, EWS4 had a higher level of caspase-8 (Figure 5C).	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('mice', 'Species', '10090', (51, 55))	('higher', 'PosReg', (137, 143))	('tumour', 'Disease', (23, 29))	('DR5', 'MPA', (121, 124))	('EWS', 'Phenotype', 'HP:0012254', (126, 129))	('EWS4', 'Var', (126, 130))	('caspase-8', 'MPA', (153, 162))
89710	26291055	Importantly, transient transfection experiments show that over expression of wild-type, but not mutant, caspase-8 restores the cellular sensitivity to conatumumab in a caspase-8-deficient cell line, further suggesting that caspase-8 is the key limiting factor.	('cellular sensitivity to conatumumab', 'MPA', (127, 162))	('mutant', 'Var', (96, 102))	('caspase-8', 'Gene', (104, 113))	('over expression', 'PosReg', (58, 73))	('conatumumab', 'Chemical', 'MESH:C554537', (151, 162))	('restores', 'PosReg', (114, 122))
89828	20854661	The volume of small bowel excluding the PTV (small bowel-PTV) that received 40 Gy and 30 Gy (V40Gy and V30Gy) in group A were 7.5 +- 4.4% [range 5.4-14.1%] and 18.5 +- 7.1% [range 10-30.4%], respectively.	('PTV', 'Chemical', '-', (57, 60))	('PTV', 'Chemical', '-', (40, 43))	('V40Gy', 'Var', (93, 98))	('V30Gy', 'Var', (103, 108))
89829	20854661	In group B, small bowel-PTV V40Gy and V30Gy were 4.7 +- 3.3% [range 3.3-8%] and 21.6 +- 7.5% [range 9.4-30%] respectively.	('V40Gy', 'Var', (28, 33))	('V30Gy', 'Var', (38, 43))	('PTV', 'Chemical', '-', (24, 27))
89875	20854661	Nevertheless, homogeneity (represented by D5%-D95%) inside the PTV could reach 12 and 18% for the two largest volumes (6198 and 4085 cc) of the preoperative group.	('6198', 'Var', (119, 123))	('homogeneity', 'MPA', (14, 25))	('PTV', 'Chemical', '-', (63, 66))
89891	20854661	Many authors reported for other tumor sites dosimetric plans at least similar for RapidArc when compared to IMRT with a static gantry position.	('tumor', 'Disease', (32, 37))	('RapidArc', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))
89896	20854661	Regarding the organs at risk, small bowel DVH showed that V30Gy and V40Gy results were better than initially required for both groups.	('small bowel DVH', 'Disease', (30, 45))	('small bowel DVH', 'Disease', 'MESH:D015212', (30, 45))	('V30Gy', 'Var', (58, 63))	('V40Gy', 'Var', (68, 73))
89900	20854661	Some authors showed that a V30Gy > 450 cc was correlated to a significant higher acute gastro-intestinal (GI) toxicity and that when small bowel - PTV V40Gy exceeded 200 cc, there was a 10% probability to develop G2-3 acute GI toxicity.	('GI toxicity', 'Disease', 'MESH:D005767', (224, 235))	('GI toxicity', 'Disease', (224, 235))	('PTV', 'Chemical', '-', (147, 150))	('higher', 'PosReg', (74, 80))	('gastro-intestinal (GI) toxicity', 'Disease', 'MESH:D007410', (87, 118))	('V40Gy', 'Var', (151, 156))	('acute', 'CPA', (81, 86))	('develop', 'PosReg', (205, 212))	('V30Gy > 450 cc', 'Var', (27, 41))
90010	24042734	In human T-PLL, both TCL1 and TCL1b are activated by chromosomal translocation.	('human', 'Species', '9606', (3, 8))	('TCL1', 'Gene', (21, 25))	('TCL1b', 'Gene', (30, 35))	('TCL1b', 'Gene', '9623', (30, 35))	('chromosomal translocation', 'Var', (53, 78))
90024	24042734	Genetic and functional alterations of the phosphatidylinositol-3 kinase-Akt signaling pathways underlie the pathogenesis of a wide variety of human diseases, such as neoplastic diseases, glucose intolerance, viral infection and autoimmune diseases.	('autoimmune diseases', 'Phenotype', 'HP:0002960', (228, 247))	('glucose intolerance', 'Disease', (187, 206))	('neoplastic disease', 'Phenotype', 'HP:0002664', (166, 184))	('glucose', 'Chemical', 'MESH:D005947', (187, 194))	('viral infection', 'Disease', 'MESH:D001102', (208, 223))	('underlie', 'Reg', (95, 103))	('human', 'Species', '9606', (142, 147))	('neoplastic diseases', 'Disease', 'MESH:D009386', (166, 185))	('autoimmune diseases', 'Disease', 'MESH:D001327', (228, 247))	('alterations', 'Var', (23, 34))	('glucose intolerance', 'Phenotype', 'HP:0001952', (187, 206))	('neoplastic diseases', 'Disease', (166, 185))	('autoimmune diseases', 'Disease', (228, 247))	('viral infection', 'Disease', (208, 223))
90025	24042734	The activation process of Akt is regulated by phosphorylation at two regulatory sites: threonine 308/309/305 and serine 473/474/472 (Akt1/2/3, respectively), with phosphorylation of both being required for maximum kinase activity.	('threonine', 'Chemical', 'MESH:D013912', (87, 96))	('Akt1/2/3', 'Gene', (133, 141))	('serine', 'Chemical', 'MESH:D012694', (113, 119))	('Akt', 'Protein', (26, 29))	('serine 473/474/472', 'Var', (113, 131))	('Akt1/2/3', 'Gene', '207;208;10000', (133, 141))
90033	24042734	In human T-PLL, both TCL1 and TCL1b genes are activated by juxtaposition onto the T-cell receptor alpha or beta loci, secondary to chromosomal translocations t(14:14) (q11: q32), t(7:14)(q35: q32) or inversion (14)(q11: q32).	('activated', 'PosReg', (46, 55))	('t(7:14)(q35: q32', 'Var', (179, 195))	('t(14:14) (q11: q32', 'Var', (158, 176))	('human', 'Species', '9606', (3, 8))	('TCL1', 'Gene', (21, 25))	('TCL1b', 'Gene', (30, 35))	('TCL1b', 'Gene', '9623', (30, 35))	('inversion (14)(q11: q32', 'Var', (200, 223))
90040	24042734	Consistently, human angiosarcoma samples and human cancer tissue array were positively stained with anti-TCL1b and anti-phospho-Akt antibodies.	('angiosarcoma', 'Phenotype', 'HP:0200058', (20, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('human', 'Species', '9606', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('human', 'Species', '9606', (45, 50))	('TCL1b', 'Gene', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('angiosarcoma', 'Disease', 'MESH:D006394', (20, 32))	('TCL1b', 'Gene', '9623', (105, 110))	('angiosarcoma', 'Disease', (20, 32))	('cancer', 'Disease', (51, 57))	('anti-phospho-Akt', 'Var', (115, 131))
90045	24042734	Co-immunoprecipitation assays were conducted using 293T cells with both Flag-TCL1b and HA-Akt transfected and demonstrated physical interaction of TCL1b with Akt (Figure 1b).	('TCL1b', 'Gene', (147, 152))	('HA-Akt', 'Gene', (87, 93))	('TCL1b', 'Gene', '9623', (147, 152))	('293T', 'CellLine', 'CVCL:0063', (51, 55))	('transfected', 'Var', (94, 105))	('interaction', 'Interaction', (132, 143))	('TCL1b', 'Gene', (77, 82))	('TCL1b', 'Gene', '9623', (77, 82))	('Akt', 'Pathway', (158, 161))
90050	24042734	Phospho-specific immunoblot demonstrated that the levels of Akt phosphorylation at Ser473 were potently augmented in TCL1b and TCL1 at similar extent as Myr-Akt-transfected cells (Figures 1f and g).	('Ser473', 'Chemical', '-', (83, 89))	('Akt phosphorylation', 'MPA', (60, 79))	('TCL1b', 'Gene', (117, 122))	('TCL1b', 'Gene', '9623', (117, 122))	('men', 'Species', '9606', (107, 110))	('augmented', 'PosReg', (104, 113))	('levels', 'MPA', (50, 56))	('Ser473', 'Var', (83, 89))
90085	24042734	In sarcoma tissues positively stained by both anti-VEGFR2 (vascular endothelial growth factor receptor 2) and TCL1b by confocal microscopy (Figure 4e).	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('TCL1b', 'Gene', (110, 115))	('anti-VEGFR2', 'Var', (46, 57))	('sarcoma', 'Disease', 'MESH:D012509', (3, 10))	('TCL1b', 'Gene', '9623', (110, 115))	('stained', 'Reg', (30, 37))	('vascular endothelial growth factor receptor 2', 'Gene', '3791', (59, 104))	('vascular endothelial growth factor receptor 2', 'Gene', (59, 104))	('sarcoma', 'Disease', (3, 10))
90087	24042734	Moreover, survival curve of the Kaplan-Meyer curve of the transgenic lines showed statistically significant early death compared to the wild type mice (Figure 4f).	('mice', 'Species', '10090', (146, 150))	('transgenic', 'Species', '10090', (58, 68))	('death', 'Disease', 'MESH:D003643', (114, 119))	('death', 'Disease', (114, 119))	('transgenic', 'Var', (58, 68))
90089	24042734	Having demonstrated that mouse-deregulated TCL1b expression resulted in angiosarcoma, we next examined human angiosarcoma tissues by immunostaining with anti-TCL1b or phospho-Akt antibodies.	('angiosarcoma', 'Disease', (72, 84))	('human', 'Species', '9606', (103, 108))	('expression', 'Species', '29278', (49, 59))	('angiosarcoma', 'Disease', 'MESH:D006394', (109, 121))	('resulted in', 'Reg', (60, 71))	('mouse', 'Species', '10090', (25, 30))	('angiosarcoma', 'Phenotype', 'HP:0200058', (72, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('TCL1b', 'Gene', '9623', (158, 163))	('TCL1b', 'Gene', (43, 48))	('angiosarcoma', 'Disease', (109, 121))	('TCL1b', 'Gene', '9623', (43, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('TCL1b', 'Gene', (158, 163))	('angiosarcoma', 'Phenotype', 'HP:0200058', (109, 121))	('expression', 'Var', (49, 59))	('angiosarcoma', 'Disease', 'MESH:D006394', (72, 84))
90112	24042734	Deregulation of TCL1 and MTCP1 in mouse immune cells resulted in lineage-specific leukemia of lymphoid cells.	('resulted in', 'Reg', (53, 64))	('leukemia of lymphoid', 'Disease', (82, 102))	('mouse', 'Species', '10090', (34, 39))	('Deregulation', 'Var', (0, 12))	('TCL1', 'Gene', (16, 20))	('leukemia of lymphoid', 'Disease', 'MESH:D007945', (82, 102))	('MTCP1', 'Gene', (25, 30))	('lineage-specific', 'CPA', (65, 81))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))
90137	24042734	Having demonstrated that the deregulation of TCL1b resulted in angiosarcoma and positive immunohistochemistry of TCL1b in human angiosarcoma and various human cancer types, we attempted to design the inhibitory peptides based on the amino-acid sequences and the three-dimensional predicted structure of TCL1b.	('human', 'Species', '9606', (122, 127))	('human', 'Species', '9606', (153, 158))	('TCL1b', 'Gene', '9623', (113, 118))	('cancer', 'Disease', (159, 165))	('angiosarcoma', 'Disease', 'MESH:D006394', (128, 140))	('TCL1b', 'Gene', (45, 50))	('TCL1b', 'Gene', '9623', (303, 308))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('angiosarcoma', 'Phenotype', 'HP:0200058', (128, 140))	('men', 'Species', '9606', (270, 273))	('deregulation', 'Var', (29, 41))	('angiosarcoma', 'Disease', 'MESH:D006394', (63, 75))	('resulted in', 'Reg', (51, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('angiosarcoma', 'Phenotype', 'HP:0200058', (63, 75))	('angiosarcoma', 'Disease', (128, 140))	('TCL1b', 'Gene', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('angiosarcoma', 'Disease', (63, 75))	('TCL1b', 'Gene', '9623', (45, 50))	('TCL1b', 'Gene', (303, 308))
90145	24042734	In this regard, we showed that 11 out of the 13 cases of human angiosarcoma showed positive result with anti-TCL1b and anti-phospho-Akt.	('angiosarcoma', 'Phenotype', 'HP:0200058', (63, 75))	('anti-phospho-Akt', 'Var', (119, 135))	('TCL1b', 'Gene', (109, 114))	('angiosarcoma', 'Disease', 'MESH:D006394', (63, 75))	('TCL1b', 'Gene', '9623', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('angiosarcoma', 'Disease', (63, 75))	('human', 'Species', '9606', (57, 62))
90177	24042734	Human cancer panel (SuperBioChips laboratories) and angiosarcoma samples were immunohistochemically stained using anti-TCL1b or anti-phospho-Ser473 Akt (Cell Signaling Technology, no.	('Human', 'Species', '9606', (0, 5))	('angiosarcoma', 'Disease', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('angiosarcoma', 'Phenotype', 'HP:0200058', (52, 64))	('anti-phospho-Ser473', 'Var', (128, 147))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('angiosarcoma', 'Disease', 'MESH:D006394', (52, 64))	('TCL1b', 'Gene', (119, 124))	('cancer', 'Disease', (6, 12))	('Ser473 Akt', 'Mutation', 'p.S473AKT', (141, 151))	('TCL1b', 'Gene', '9623', (119, 124))
90192	22173669	The cumulative sarcoma-related 5-year survival was 32% (95% confidence interval (CI): 22-42) for patients with RIS vs 51% (95% CI: 44-58) for controls (P<0.001).	('RIS', 'Var', (111, 114))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcoma', 'Disease', (15, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('RIS', 'Chemical', '-', (111, 114))	('patients', 'Species', '9606', (97, 105))
90298	22173669	In conclusion, this case-control study shows that the poor sarcoma-related survival in RIS patients compared with those with SPS is primarily related to a clustering of central tumour site and incomplete surgical remission.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('sarcoma', 'Disease', (59, 66))	('RIS', 'Var', (87, 90))	('tumour', 'Disease', (177, 183))	('patients', 'Species', '9606', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('poor', 'NegReg', (54, 58))	('SPS', 'Gene', (125, 128))	('RIS', 'Chemical', '-', (87, 90))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('SPS', 'Gene', '9496', (125, 128))
90330	33621727	This is not a distinct subtype of SS; rather it represents a form of tumor progression that can occur in either monophasic or biphasic Synovial Sarcoma.On cytogenetic analysis typically harbours a t(X;18) (p11.2;q11.2) translocation with fusion between SSX1 and SYT genes with a biphasic appearancein two-thirds of cases whilst the remainder show a fusionbetween SSX2 and SYT genes.	('biphasic Synovial Sarcoma', 'Disease', (126, 151))	('SS', 'Phenotype', 'HP:0100242', (253, 255))	('SS', 'Phenotype', 'HP:0100242', (363, 365))	('SSX1', 'Gene', (253, 257))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (135, 151))	('SSX2', 'Gene', (363, 367))	('SSX2', 'Gene', '6757', (363, 367))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('translocation', 'Var', (219, 232))	('Sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('SS', 'Phenotype', 'HP:0100242', (34, 36))	('biphasic Synovial Sarcoma', 'Disease', 'MESH:D013584', (126, 151))	('SYT', 'Gene', (262, 265))	('SYT', 'Gene', (372, 375))	('tumor', 'Disease', (69, 74))	('SYT', 'Gene', '6760', (262, 265))	('SYT', 'Gene', '6760', (372, 375))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('SSX1', 'Gene', '6756', (253, 257))
90338	33621727	Decreased survival rates are seen with large tumour size (greater than 5 cm), positive margin status, and high tumour grade (Grade 3).	('positive', 'Var', (78, 86))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('Decreased', 'NegReg', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('high tumour', 'Disease', (106, 117))	('high tumour', 'Disease', 'MESH:D009369', (106, 117))	('tumour', 'Disease', (111, 117))	('tumour', 'Disease', (45, 51))	('survival', 'MPA', (10, 18))
90382	30219191	In the evaluation of osseous metastases, a meta-analysis reported a greater sensitivity and specificity for detecting bone metastases with FDG PET-CT than with CT scan alone but with equal sensitivity and specificity to that of MR imaging.	('FDG PET-CT', 'Var', (139, 149))	('osseous metastases', 'Disease', (21, 39))	('metastases', 'Disease', (29, 39))	('FDG', 'Chemical', '-', (139, 142))	('metastases', 'Disease', 'MESH:D009362', (29, 39))	('metastases', 'Disease', (123, 133))	('metastases', 'Disease', 'MESH:D009362', (123, 133))	('osseous metastases', 'Disease', 'MESH:D009362', (21, 39))
90440	30219191	There are only a few case reports in literature regarding the usefulness of FDG PET-CT in the management of angiosarcoma, primarily due to its low incidence; however, FDG PET-CT has provided some reliability in the early detection of distant metastases, staging, and its prognostication of disease.	('angiosarcoma', 'Disease', (108, 120))	('metastases', 'Disease', (242, 252))	('FDG', 'Var', (167, 170))	('FDG', 'Chemical', '-', (76, 79))	('staging', 'CPA', (254, 261))	('angiosarcoma', 'Phenotype', 'HP:0200058', (108, 120))	('metastases', 'Disease', 'MESH:D009362', (242, 252))	('FDG', 'Chemical', '-', (167, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('angiosarcoma', 'Disease', 'MESH:D006394', (108, 120))
90483	29425228	As Plasmodium falciparum is an endemic pathogen in Uganda, our study shows that co-infection with other pathogens, such as KSHV, can severely impact the small RNA repertoire, complicating the use of exosome miRNAs as biomarkers of disease.	('small RNA repertoire', 'MPA', (153, 173))	('co-infection', 'Var', (80, 92))	('Plasmodium falciparum', 'Species', '5833', (3, 24))	('impact', 'NegReg', (142, 148))	('KSHV', 'Species', '37296', (123, 127))	('miR', 'Gene', '220972', (207, 210))	('miR', 'Gene', (207, 210))
90540	29425228	As seen in Table 1, the rate of KSHV detection in oral swabs was higher in the KSHV+/HIV+ group compared to KSHV+/HIV- group (average: 97% vs 17%) in agreement with previous observations.	('men', 'Species', '9606', (155, 158))	('KSHV', 'Species', '37296', (79, 83))	('KSHV', 'Species', '37296', (108, 112))	('KSHV', 'Species', '37296', (32, 36))	('KSHV+/HIV+', 'Var', (79, 89))	('higher', 'PosReg', (65, 71))	('KSHV', 'Gene', (32, 36))
90549	29425228	Three other miRNAs, miR-150-3p, miR-548z/h-5p, and miR-575, also showed decreased expression in both groups with detectable oral shedding (KSHV+/HIV-, KSHV+/HIV+)(Fig 1B), but the differences were not statistically significant due to greater variability in their expression levels.	('miR', 'Gene', (32, 35))	('KSHV', 'Species', '37296', (151, 155))	('expression', 'MPA', (82, 92))	('decreased', 'NegReg', (72, 81))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (20, 23))	('miR', 'Gene', (51, 54))	('miR', 'Gene', '220972', (32, 35))	('KSHV', 'Species', '37296', (139, 143))	('miR-150', 'Gene', (20, 27))	('miR-150', 'Gene', '406942', (20, 27))	('miR', 'Gene', '220972', (12, 15))	('KSHV+/HIV+', 'Var', (151, 161))	('miR', 'Gene', (12, 15))
90551	29425228	In contrast, two of the 26 miRNAs, miR-21-5p and miR-106a-5p, showed significantly increased expression in both groups with detectable oral shedding (KSHV+/HIV- and KSHV+/HIV+) compared to group without (KSHV-/HIV-) regardless of HIV status (Fig 2A).	('KSHV', 'Species', '37296', (150, 154))	('increased', 'PosReg', (83, 92))	('oral shedding', 'CPA', (135, 148))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('miR', 'Gene', '220972', (49, 52))	('expression', 'MPA', (93, 103))	('miR', 'Gene', (35, 38))	('miR', 'Gene', (49, 52))	('KSHV+/HIV-', 'Var', (150, 160))	('miR', 'Gene', '220972', (35, 38))	('KSHV', 'Species', '37296', (204, 208))	('KSHV', 'Species', '37296', (165, 169))	('KSHV+/HIV+', 'Var', (165, 175))
90553	29425228	In addition, the expression level of the oncogenic miR-21-5p was significantly higher in the KSHV+/HIV+ group compared to the KSHV+/HIV- group.	('KSHV', 'Species', '37296', (126, 130))	('KSHV+/HIV+', 'Var', (93, 103))	('KSHV', 'Species', '37296', (93, 97))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('expression level', 'MPA', (17, 33))	('higher', 'PosReg', (79, 85))
90558	29425228	The levels of two miRNAs, miR-221-3p, and miR-361-5p, were significantly increased in the KSHV+/HIV+ co-infected group compared to both of the HIV-negative groups (KSHV+/HIV- and KSHV-/HIV-) (Fig 3A).	('KSHV', 'Species', '37296', (164, 168))	('increased', 'PosReg', (73, 82))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('KSHV', 'Species', '37296', (90, 94))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (42, 45))	('miR', 'Gene', (18, 21))	('miR-361-5p', 'Gene', '100500847', (42, 52))	('miR', 'Gene', '220972', (42, 45))	('miR-361-5p', 'Gene', (42, 52))	('KSHV', 'Species', '37296', (179, 183))	('KSHV+/HIV+', 'Var', (90, 100))
90560	29425228	Six miRNAs, miR22-3p, miR-93-5p, miR-130a-3p, miR-146a-5p, miR-199a-5p and Let-7i-5p, were significantly increased in the KSHV+/HIV+ co-infected group compared to KSHV-/HIV- group (Fig 3B).	('miR', 'Gene', (46, 49))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', '220972', (4, 7))	('miR-146a', 'Gene', (46, 54))	('miR', 'Gene', (12, 15))	('miR-146a', 'Gene', '406938', (46, 54))	('miR', 'Gene', (4, 7))	('KSHV+/HIV+', 'Var', (122, 132))	('miR', 'Gene', (59, 62))	('miR-93', 'Gene', (22, 28))	('miR', 'Gene', '220972', (33, 36))	('KSHV', 'Species', '37296', (163, 167))	('miR-93', 'Gene', '407051', (22, 28))	('increased', 'PosReg', (105, 114))	('KSHV', 'Species', '37296', (122, 126))	('miR', 'Gene', '220972', (46, 49))	('miR', 'Gene', '220972', (22, 25))	('miR', 'Gene', (33, 36))	('Let-7i-5p', 'Var', (75, 84))	('miR', 'Gene', (22, 25))	('miR', 'Gene', '220972', (12, 15))
90562	29425228	The median level of all of these miRNAs, except miR-22-3p, was higher in KSHV+/HIV+ co-infected group than in the KSHV+/HIV- group, although this did not reach a level of significance due to variability between individuals.	('miR', 'Gene', '220972', (33, 36))	('KSHV+/HIV+ co-infected', 'Var', (73, 95))	('miR', 'Gene', (33, 36))	('KSHV', 'Species', '37296', (73, 77))	('KSHV', 'Species', '37296', (114, 118))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (48, 51))	('higher', 'PosReg', (63, 69))
90563	29425228	The levels of three miRNAs, miR-451a, miR-495-3p and miR-1972, were significantly decreased in the KSHV+/HIV+ group compared to the KSHV-/HIV- group (Fig 3C).	('miR', 'Gene', '220972', (53, 56))	('levels', 'MPA', (4, 10))	('miR', 'Gene', (53, 56))	('KSHV', 'Species', '37296', (132, 136))	('miR-451a', 'Gene', '574411', (28, 36))	('miR-451a', 'Gene', (28, 36))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('miR', 'Gene', '220972', (38, 41))	('KSHV+/HIV+', 'Var', (99, 109))	('miR', 'Gene', (38, 41))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('decreased', 'NegReg', (82, 91))	('KSHV', 'Species', '37296', (99, 103))
90565	29425228	The median level of all of these miRNAs was lower in the KSHV+/HIV+ co-infected group compare to the KSHV+/HIV- group, although this did not reach significance.	('miR', 'Gene', '220972', (33, 36))	('lower', 'NegReg', (44, 49))	('miR', 'Gene', (33, 36))	('KSHV', 'Species', '37296', (101, 105))	('KSHV+/HIV+ co-infected', 'Var', (57, 79))	('KSHV', 'Species', '37296', (57, 61))
90577	29425228	The median levels of the fifth miRNA, miR-223-3p was higher in the co-infected group compared to the HIV negative groups, but this increase was not statistically significant due to a greater variability between samples (median:13998 for the KSHV+/HIV- group vs 21073 for the KSHV+/HIV+ group).	('higher', 'PosReg', (53, 59))	('KSHV', 'Species', '37296', (241, 245))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('KSHV', 'Species', '37296', (275, 279))	('co-infected', 'Var', (67, 78))	('levels', 'MPA', (11, 17))
90588	29425228	As seen for the groups of individuals in the previous analysis, the average KSHV detection rate in oral swabs across the 15 day screening period was higher in the KSHV+/HIV+ group than in the KSHV+/HIV- group (average: 68% vs 30%).	('KSHV', 'Species', '37296', (192, 196))	('detection', 'MPA', (81, 90))	('KSHV+/HIV+', 'Var', (163, 173))	('KSHV', 'Species', '37296', (76, 80))	('KSHV', 'Species', '37296', (163, 167))	('higher', 'PosReg', (149, 155))	('KSHV', 'Gene', (76, 80))
90589	29425228	Similarly, the average KSHV detection rate in plasma was 60% in the KSHV+/HIV+ group compared to 26% in KSHV+/HIV- group.	('KSHV', 'Species', '37296', (104, 108))	('KSHV', 'Gene', (23, 27))	('KSHV+/HIV+', 'Var', (68, 78))	('KSHV', 'Species', '37296', (23, 27))	('KSHV', 'Species', '37296', (68, 72))
90592	29425228	In agreement with previously published data, the most abundant type of small RNAs in plasma was the miRNA, representing on average 41% of the total mapped reads (median = 41, range 31-54).	('small RNAs', 'Var', (71, 81))	('men', 'Species', '9606', (8, 11))	('miR', 'Gene', '220972', (100, 103))	('miR', 'Gene', (100, 103))
90627	29425228	Additional experiments are needed to confirm that the most abundant length variants are functional isomiRs and to identify their cellular mRNA targets.	('men', 'Species', '9606', (17, 20))	('variants', 'Var', (75, 83))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))
90666	29425228	The overall prevalence and total number of reads mapping to EBV miRNAs were higher among people in the KSHV+/HIV+ group.	('KSHV', 'Species', '37296', (103, 107))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('EBV', 'Species', '10376', (60, 63))	('higher', 'PosReg', (76, 82))	('people', 'Species', '9606', (89, 95))	('KSHV+/HIV+', 'Var', (103, 113))
90704	29425228	Nine cellular miRNAs (miR-26a-5p, Let-7a/b/c/d/e/f-5p and miR-10a/b-5p) were systematically present in all samples regardless of the patient viral status.	('miR', 'Gene', '220972', (22, 25))	('Let-7a/b/c/d/e/f-5p', 'Var', (34, 53))	('patient', 'Species', '9606', (133, 140))	('miR-10a', 'Gene', (58, 65))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('b-5p', 'Gene', '122876', (66, 70))	('miR-26a', 'Gene', '407015', (22, 29))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('miR-10a', 'Gene', '406902', (58, 65))	('b-5p', 'Gene', (66, 70))	('miR', 'Gene', (22, 25))	('miR-26a', 'Gene', (22, 29))
90706	29425228	Previous studies have shown that the levels of expression of the Let-7a/b/c/d/e/f-5p miRNAs are altered in KSHV infected cells.	('altered', 'Reg', (96, 103))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('KSHV infected', 'Disease', 'MESH:C537372', (107, 120))	('Let-7a/b/c/d/e/f-5p', 'Var', (65, 84))	('KSHV infected', 'Disease', (107, 120))	('levels of expression', 'MPA', (37, 57))
90708	29425228	Similarly, Let-7a/d/e-5p, and miR-10a have been shown to be preferentially associated with exosomes when released in an extracellular form in plasma, supporting the efficiency of our exosome enrichment procedure.	('Let-7a/d/e-5p', 'Var', (11, 24))	('associated', 'Interaction', (75, 85))	('miR-10a', 'Gene', (30, 37))	('men', 'Species', '9606', (197, 200))	('miR-10a', 'Gene', '406902', (30, 37))	('preferentially', 'PosReg', (60, 74))
90733	29425228	Malaria protein PF3D7_1239800, of unknown function, was significantly correlated with fifteen of the 419 cellular proteins detected in the 10 plasma exosome samples (Fig 12).	('correlated', 'Interaction', (70, 80))	('PF3D7_1239800', 'Var', (16, 29))	('Malaria', 'Disease', 'MESH:D008288', (0, 7))	('Malaria', 'Disease', (0, 7))	('3D7', 'Species', '36329', (18, 21))
90739	29425228	Significant correlations were observed between malaria protein PF3D7_1460800 and the relative abundance of nine cellular proteins (Fig 13).	('malaria', 'Disease', 'MESH:D008288', (47, 54))	('PF3D7_1460800', 'Var', (63, 76))	('malaria', 'Disease', (47, 54))	('relative abundance of nine cellular proteins', 'MPA', (85, 129))	('3D7', 'Species', '36329', (65, 68))
90741	29425228	Other cellular proteins correlating with PF3D7_1460800 included alpha-1-B glycoprotein (A1BG), complement factor B (CFB), and CD14, which were previously reported to be differentially expressed in malaria patients.	('PF3D7_1460800', 'Var', (41, 54))	('patients', 'Species', '9606', (205, 213))	('A1BG', 'Gene', '1', (88, 92))	('complement factor B', 'Gene', '629', (95, 114))	('CFB', 'Gene', (116, 119))	('CD14', 'Gene', (126, 130))	('3D7', 'Species', '36329', (43, 46))	('malaria', 'Disease', (197, 204))	('complement factor B', 'Gene', (95, 114))	('CD14', 'Gene', '929', (126, 130))	('alpha-1-B glycoprotein', 'Gene', (64, 86))	('A1BG', 'Gene', (88, 92))	('CFB', 'Gene', '629', (116, 119))	('malaria', 'Disease', 'MESH:D008288', (197, 204))	('alpha-1-B glycoprotein', 'Gene', '1', (64, 86))
90742	29425228	Finally, the plasmodium protein PH3D7_0802700 showed strong correlations with six cellular proteins, including apolipoprotein (APOB) and kallistatin (SERPINA4) (Fig 14).	('apolipoprotein', 'Protein', (111, 125))	('plasmodium', 'Species', '5855', (13, 23))	('APOB', 'Gene', '338', (127, 131))	('APOB', 'Gene', (127, 131))	('correlations', 'Interaction', (60, 72))	('PH3D7_0802700', 'Var', (32, 45))	('3D7', 'Species', '36329', (34, 37))
90744	29425228	The three Plasmodium falciparum proteins, PH3D7_1239800, PH3D7_1460800, and PH3D7_0802700 detected in the plasma exosomes of Ugandan individuals have been poorly studied, and their respective functions are still unknown.	('PH3D7_1460800', 'Var', (57, 70))	('Plasmodium falciparum', 'Species', '5833', (10, 31))	('3D7', 'Species', '36329', (44, 47))	('PH3D7_0802700', 'Var', (76, 89))	('3D7', 'Species', '36329', (78, 81))	('PH3D7_1239800', 'Var', (42, 55))	('3D7', 'Species', '36329', (59, 62))
90756	29425228	Among the 26 differently expressed mature miRNAs, Let-7i-5p, miR-21-5p, miR-93-5p, miR-106a:5p, miR-142-3p, miR-146a-5p, and miR-221-3p were previously reported to be altered in KSHV infected cell cultures in vitro.	('miR', 'Gene', '220972', (61, 64))	('miR-93', 'Gene', (72, 78))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (108, 111))	('miR', 'Gene', (125, 128))	('KSHV infected', 'Disease', 'MESH:C537372', (178, 191))	('miR-93', 'Gene', '407051', (72, 78))	('miR', 'Gene', (61, 64))	('miR', 'Gene', '220972', (96, 99))	('miR-146a', 'Gene', (108, 116))	('miR', 'Gene', (83, 86))	('miR', 'Gene', '220972', (42, 45))	('miR-146a', 'Gene', '406938', (108, 116))	('KSHV infected', 'Disease', (178, 191))	('miR', 'Gene', (96, 99))	('miR', 'Gene', (42, 45))	('miR', 'Gene', '220972', (72, 75))	('Let-7i-5p', 'Var', (50, 59))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (72, 75))
90764	29425228	These alterations would result in a more favorable environment for the development of KS or other KSHV-associated malignancies in immunosuppressed patients.	('alterations', 'Var', (6, 17))	('KSHV-associated', 'Gene', (98, 113))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('patients', 'Species', '9606', (147, 155))	('men', 'Species', '9606', (78, 81))	('malignancies', 'Disease', (114, 126))	('KSHV', 'Species', '37296', (98, 102))	('men', 'Species', '9606', (58, 61))
90809	29425228	In addition, miR-K12-10a and its associated variant also target cellular proteins from the TGF-b signaling pathway.	('TGF-b', 'Gene', (91, 96))	('target', 'Reg', (57, 63))	('miR', 'Gene', '220972', (13, 16))	('variant', 'Var', (44, 51))	('miR', 'Gene', (13, 16))	('cellular proteins', 'Protein', (64, 81))	('TGF-b', 'Gene', '7040', (91, 96))
90825	29425228	Inhibition of the sphingomyelinase SMPD3 promoted miRNA release in association with HDL instead of exosomes.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('promoted', 'PosReg', (41, 49))	('Inhibition', 'Var', (0, 10))	('SMPD3', 'Gene', '55512', (35, 40))	('SMPD3', 'Gene', (35, 40))
90832	29425228	In recent studies, patients infected with either plasmodium falciparum or plasmodium vivax showed elevated plasma levels of extracellular vesicles derived from platelets and erythrocytes.	('patients', 'Species', '9606', (19, 27))	('plasmodium falciparum', 'Var', (49, 70))	('elevated', 'PosReg', (98, 106))	('plasmodium falciparum', 'Species', '5833', (49, 70))	('plasmodium vivax', 'Species', '5855', (74, 90))
90853	29425228	With the exception of PF3D7_0831700, an HSP70-like plasmodium protein, none of these proteins have previously been detected in blood samples from patients diagnosed with malaria.	('malaria', 'Disease', (170, 177))	('PF3D7_0831700', 'Var', (22, 35))	('plasmodium', 'Species', '5855', (51, 61))	('patients', 'Species', '9606', (146, 154))	('3D7', 'Species', '36329', (24, 27))	('malaria', 'Disease', 'MESH:D008288', (170, 177))
90859	29425228	Interestingly, the relative abundance of the peptides associated with the malarial proteins PH3D7_1239800, PH3D7_1460800, and PH3D7_0802700 strongly correlated with the relative abundance of peptides derived from several cellular proteins involved in the complement cascade, coagulation and inflammation.	('PH3D7_0802700', 'Var', (126, 139))	('men', 'Species', '9606', (261, 264))	('correlated', 'Reg', (149, 159))	('peptides', 'MPA', (45, 53))	('malarial proteins', 'Disease', 'MESH:D011488', (74, 91))	('3D7', 'Species', '36329', (109, 112))	('relative abundance', 'MPA', (169, 187))	('relative abundance', 'MPA', (19, 37))	('inflammation', 'Disease', 'MESH:D007249', (291, 303))	('PH3D7_1239800', 'Var', (92, 105))	('malarial proteins', 'Disease', (74, 91))	('PH3D7_1460800', 'Var', (107, 120))	('inflammation', 'Disease', (291, 303))	('3D7', 'Species', '36329', (94, 97))	('3D7', 'Species', '36329', (128, 131))
90861	29425228	Since the Ugandan individuals both in the KSHV+/HIV- and KSHV+/HIV+ groups had no overt signs of ongoing malaria disease during the study enrollment, the presence of these peptides could be a critical biomarker for asymtomatic Plasmodium falciparum infection with submicroscopic parasitemia.	('men', 'Species', '9606', (144, 147))	('ongoing malaria disease', 'Disease', 'MESH:D008288', (97, 120))	('KSHV', 'Species', '37296', (42, 46))	('Plasmodium falciparum', 'Species', '5833', (227, 248))	('falciparum infection', 'Disease', (238, 258))	('parasitemia', 'Disease', (279, 290))	('parasitemia', 'Disease', 'MESH:D018512', (279, 290))	('KSHV', 'Species', '37296', (57, 61))	('presence', 'Var', (154, 162))	('falciparum infection', 'Disease', 'MESH:D016778', (238, 258))	('ongoing malaria disease', 'Disease', (97, 120))
90866	29425228	Our data showed that in plasma exosomes of individuals infected with Plasmodium falciparum, the relative abundance of peptides associated with cellular proteins involved in both the classical (C4BP, C1QA) and alternative pathway (Properdin) of complement activation strongly correlated with the relative abundance of a peptide associated with the malarial protein PH3D7_1239800.	('malaria', 'Disease', (347, 354))	('correlated', 'Reg', (275, 285))	('Plasmodium falciparum', 'Species', '5833', (69, 90))	('men', 'Species', '9606', (250, 253))	('C1QA', 'Gene', (199, 203))	('C1QA', 'Gene', '712', (199, 203))	('Plasmodium', 'Var', (69, 79))	('3D7', 'Species', '36329', (366, 369))	('malaria', 'Disease', 'MESH:D008288', (347, 354))
90868	29425228	Previous studies have shown that KSHV-infected endothelial cells are more resistant to complement mediated cell lysis and that complement activation promotes infected cell survival by inducing STAT3 phosphorylation.	('KSHV-infected', 'Disease', (33, 46))	('men', 'Species', '9606', (93, 96))	('STAT3', 'Gene', '6774', (193, 198))	('KSHV-infected', 'Disease', 'MESH:C537372', (33, 46))	('promotes', 'PosReg', (149, 157))	('STAT3', 'Gene', (193, 198))	('men', 'Species', '9606', (133, 136))	('inducing', 'Reg', (184, 192))	('complement', 'Var', (127, 137))
90938	28878254	Germline Mutations in Cancer Predisposition Genes are Frequent in Sporadic Sarcomas Associations of sarcoma with inherited cancer syndromes implicate genetic predisposition in sarcoma development.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Sarcomas', 'Phenotype', 'HP:0100242', (75, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))	('inherited cancer', 'Disease', 'MESH:D009386', (113, 129))	('sarcoma', 'Disease', (100, 107))	('Sporadic Sarcomas', 'Disease', (66, 83))	('Sporadic Sarcomas', 'Disease', 'MESH:D012509', (66, 83))	('inherited cancer', 'Disease', (113, 129))	('Associations', 'Interaction', (84, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('Germline Mutations', 'Var', (0, 18))	('cancer syndromes', 'Disease', (123, 139))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('sarcoma', 'Disease', (176, 183))	('Frequent', 'Reg', (54, 62))	('cancer syndromes', 'Disease', 'MESH:D009369', (123, 139))
90942	28878254	Our findings suggests that genetic predisposition plays a larger role than expected in our Asian cohort of sporadic sarcoma, therefore clinicians should be aware of the possibility that young sarcoma patients may be carriers of inherited mutations in cancer genes and should be considered for genetic testing, regardless of family history.	('patients', 'Species', '9606', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('mutations', 'Var', (238, 247))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('sporadic sarcoma', 'Disease', 'MESH:D012509', (107, 123))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('sporadic sarcoma', 'Disease', (107, 123))	('sarcoma', 'Disease', (116, 123))	('cancer', 'Disease', (251, 257))	('sarcoma', 'Disease', (192, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
90947	28878254	A primary example is Li-Fraumeni Syndrome (LFS), an autosomal-dominant cancer syndrome associated with germline TP53 mutations.	('mutations', 'Var', (117, 126))	('autosomal-dominant cancer syndrome', 'Disease', 'MESH:D009386', (52, 86))	('autosomal-dominant cancer syndrome', 'Disease', (52, 86))	('LFS', 'Disease', 'MESH:D016864', (43, 46))	('Li-Fraumeni Syndrome', 'Disease', (21, 41))	('associated', 'Reg', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', '7157', (112, 116))	('LFS', 'Disease', (43, 46))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (21, 41))	('TP53', 'Gene', (112, 116))
90949	28878254	In hereditary retinoblastoma, patients with germline RB1 mutations are at increased risk of second primary tumors comprising mostly sarcomas.	('RB1', 'Gene', '5925', (53, 56))	('hereditary retinoblastoma', 'Disease', (3, 28))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('sarcomas', 'Disease', 'MESH:D012509', (132, 140))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('retinoblastoma', 'Phenotype', 'HP:0009919', (14, 28))	('sarcomas', 'Disease', (132, 140))	('mutations', 'Var', (57, 66))	('RB1', 'Gene', (53, 56))	('patients', 'Species', '9606', (30, 38))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (3, 28))	('germline', 'Var', (44, 52))
90955	28878254	The largest study to-date was performed by the International Sarcoma Kindred Study (ISKS), in which a predominantly kindred-oriented cohort of 1192 sarcoma probands were interrogated for germline mutations in a panel of cancer-associated genes.	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('germline mutations', 'Var', (187, 205))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('sarcoma', 'Disease', (148, 155))	('Sarcoma', 'Disease', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('Sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('cancer', 'Disease', (220, 226))
90958	28878254	To address this, we interrogate an Asian cohort of sarcoma patients in this study for the prevalence of germline alterations in 52 cancer-associated genes using a combined approach of targeted genomic sequencing and digital multiplex ligation-dependent probe amplification (digitalMLPA).	('cancer', 'Disease', (131, 137))	('sarcoma', 'Disease', (51, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('digitalMLPA', 'Chemical', '-', (274, 285))	('patients', 'Species', '9606', (59, 67))	('alterations', 'Var', (113, 124))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
90963	28878254	These mutations affected 9 genes, two each in ATM, ERCC4 and FANCI, and one each in BRCA2, FANCC, FANCE, MSH6, POLE, and SDHA.	('FANCE', 'Gene', (98, 103))	('ATM', 'Gene', '472', (46, 49))	('SDHA', 'Gene', (121, 125))	('FANCE', 'Gene', '2178', (98, 103))	('SDHA', 'Gene', '6389', (121, 125))	('FA', 'Phenotype', 'HP:0001994', (98, 100))	('affected', 'Reg', (16, 24))	('mutations', 'Var', (6, 15))	('ATM', 'Gene', (46, 49))	('FANCC', 'Gene', '2176', (91, 96))	('BRCA2', 'Gene', (84, 89))	('MSH6', 'Gene', (105, 109))	('ERCC4', 'Gene', (51, 56))	('FANCI', 'Gene', (61, 66))	('ERCC4', 'Gene', '2072', (51, 56))	('FA', 'Phenotype', 'HP:0001994', (61, 63))	('MSH6', 'Gene', '2956', (105, 109))	('FANCI', 'Gene', '55215', (61, 66))	('FANCC', 'Gene', (91, 96))	('BRCA2', 'Gene', '675', (84, 89))	('FA', 'Phenotype', 'HP:0001994', (91, 93))
90965	28878254	Of these mutations, 11 (84.6%) occurred in genes associated with DNA damage repair (DDR) and the remaining two (15.4%) in known cancer predisposition genes (Fig.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('occurred', 'Reg', (31, 39))	('cancer', 'Disease', (128, 134))
90966	28878254	The predicted pathogenic mutations were found in 9 patients (13.6%, 95% CI: 6.8-24.8%) across 10 genes (Table 2).	('pathogenic', 'Reg', (14, 24))	('mutations', 'Var', (25, 34))	('patients', 'Species', '9606', (51, 59))
90968	28878254	Using their 1000 G data, we repeated the comparison against our cohort on the subset of our genes that overlapped with their 60 AD genes and observed a prevalence of predicted pathogenic mutation carriers at 6.1%, which is significantly higher than 1.1% in the 1000 G population (Fisher's exact test, P = 0.01) (Supplementary Table S1).	('pathogenic', 'Reg', (176, 186))	('mutation', 'Var', (187, 195))	('AD', 'Disease', (128, 130))	('AD', 'Disease', 'MESH:D000544', (128, 130))
90969	28878254	These include the two frameshift mutations in BRCA2 and FANCC, two ERCC4 nonsense mutations and one TP53 copy number alteration.	('TP53', 'Gene', '7157', (100, 104))	('ERCC4', 'Gene', '2072', (67, 72))	('ERCC4', 'Gene', (67, 72))	('BRCA2', 'Gene', (46, 51))	('FA', 'Phenotype', 'HP:0001994', (56, 58))	('TP53', 'Gene', (100, 104))	('frameshift mutations', 'Var', (22, 42))	('BRCA2', 'Gene', '675', (46, 51))	('FANCC', 'Gene', '2176', (56, 61))	('FANCC', 'Gene', (56, 61))
90970	28878254	Additionally, three predicted pathogenic mutations are recommended by ACMG for return as incidental findings to patients: one missense mutation in MSH6, one BRCA2 frameshift deletion and one TP53 copy number alteration.	('missense mutation', 'Var', (126, 143))	('frameshift deletion', 'Var', (163, 182))	('MSH6', 'Gene', '2956', (147, 151))	('TP53', 'Gene', '7157', (191, 195))	('TP53', 'Gene', (191, 195))	('patients', 'Species', '9606', (112, 120))	('BRCA2', 'Gene', (157, 162))	('MSH6', 'Gene', (147, 151))	('BRCA2', 'Gene', '675', (157, 162))
90974	28878254	Truncating mutations, including frameshift deletions and nonsense mutations, occurred in BRCA2, FANCC and ERCC4.	('BRCA2', 'Gene', '675', (89, 94))	('ERCC4', 'Gene', (106, 111))	('ERCC4', 'Gene', '2072', (106, 111))	('FA', 'Phenotype', 'HP:0001994', (96, 98))	('frameshift deletions', 'Var', (32, 52))	('occurred', 'Reg', (77, 85))	('nonsense mutations', 'Var', (57, 75))	('BRCA2', 'Gene', (89, 94))	('FANCC', 'Gene', '2176', (96, 101))	('FANCC', 'Gene', (96, 101))
90975	28878254	The ERCC4 nonsense mutation (p.Cys723*) was found in two patients, who were diagnosed with giant cell tumor of bone and alveolar rhabdomyosarcoma at 16- and 24-years-old respectively (Table 2).	('ERCC4', 'Gene', (4, 9))	('patients', 'Species', '9606', (57, 65))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (120, 145))	('ERCC4', 'Gene', '2072', (4, 9))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (91, 115))	('giant cell tumor', 'Disease', (91, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('p.Cys723*', 'Mutation', 'p.C723*', (29, 38))	('tumor of bone', 'Phenotype', 'HP:0010622', (102, 115))	('giant cell tumor', 'Disease', 'MESH:D005870', (91, 107))	('p.Cys723*', 'Var', (29, 38))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (129, 145))	('alveolar rhabdomyosarcoma', 'Disease', (120, 145))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (120, 145))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
90979	28878254	Seven patients harbored the 11predicted pathogenic mutations, marking a germline DDR mutation carrier frequency of 10.6% (95% CI: 4.7-21.2%) within our cohort.	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (51, 60))	('DDR', 'Gene', (81, 84))	('mutation', 'Var', (85, 93))
90980	28878254	The mutations were not observed to be associated with any particular sarcoma histology.	('mutations', 'Var', (4, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('particular sarcoma', 'Disease', (58, 76))	('particular sarcoma', 'Disease', 'MESH:D012509', (58, 76))
90981	28878254	However, two patients were found to harbour multiple germline mutations in DDR genes; both were female, one with alveolar rhabdomyosarcoma at 24-years-old and the other had undifferentiated pleomorphic sarcoma at age 48 years (Supplementary Table S3).	('DDR genes', 'Gene', (75, 84))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (122, 138))	('germline mutations', 'Var', (53, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (113, 138))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (173, 209))	('patients', 'Species', '9606', (13, 21))	('undifferentiated pleomorphic sarcoma', 'Disease', (173, 209))	('alveolar rhabdomyosarcoma', 'Disease', (113, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (113, 138))
90982	28878254	Interestingly, the former carried four germline mutations, all affecting DDR genes: ATM, ERCC4, FANCI and MSH6.	('ATM', 'Gene', (84, 87))	('FANCI', 'Gene', (96, 101))	('MSH6', 'Gene', '2956', (106, 110))	('ERCC4', 'Gene', '2072', (89, 94))	('FA', 'Phenotype', 'HP:0001994', (96, 98))	('ERCC4', 'Gene', (89, 94))	('affecting', 'Reg', (63, 72))	('DDR genes', 'Gene', (73, 82))	('ATM', 'Gene', '472', (84, 87))	('FANCI', 'Gene', '55215', (96, 101))	('MSH6', 'Gene', (106, 110))	('mutations', 'Var', (48, 57))
90985	28878254	In the latter patient with UPS, sequencing of her tumor showed loss of heterozygosity of the BRCA2 variant, supporting the pathogenic prediction of this variant (Supplementary Figure S4).	('BRCA2', 'Gene', '675', (93, 98))	('variant', 'Var', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('patient', 'Species', '9606', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('heterozygosity', 'MPA', (71, 85))	('loss', 'NegReg', (63, 67))	('tumor', 'Disease', (50, 55))	('BRCA2', 'Gene', (93, 98))
90986	28878254	Through targeted sequencing, one predicted pathogenic missense mutation was identified in SDHA, a known cancer predisposition gene, in a patient diagnosed with epitheloid sarcoma at 24-years-old (Table 2, Fig.	('epitheloid sarcoma', 'Disease', 'MESH:D012509', (160, 178))	('epitheloid sarcoma', 'Disease', (160, 178))	('SDHA', 'Gene', '6389', (90, 94))	('patient', 'Species', '9606', (137, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('pathogenic', 'Reg', (43, 53))	('SDHA', 'Gene', (90, 94))	('missense mutation', 'Var', (54, 71))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
90988	28878254	2), a catalytic domain in which germline mutations have been reported to be deleterious in patients presenting paragangliomas and pheochromocytomas as well as Leigh syndrome.	('pheochromocytomas', 'Disease', 'MESH:D010673', (130, 147))	('patients', 'Species', '9606', (91, 99))	('Leigh syndrome', 'Disease', (159, 173))	('germline mutations', 'Var', (32, 50))	('paragangliomas', 'Disease', (111, 125))	('paragangliomas', 'Disease', 'MESH:D010235', (111, 125))	('paragangliomas', 'Phenotype', 'HP:0002668', (111, 125))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (130, 147))	('Leigh syndrome', 'Disease', 'MESH:D007888', (159, 173))	('pheochromocytomas', 'Disease', (130, 147))
90991	28878254	The nine patients carrying predicted pathogenic mutations had varying sarcoma histological diagnoses (Table 2).	('patients', 'Species', '9606', (9, 17))	('sarcoma', 'Disease', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('mutations', 'Var', (48, 57))
90992	28878254	To explore potential associations between affected genes and tumor spectrum, the varying histological subtypes were categorized into three arbitrarily-assigned genetics-driven classifications based on literature: chromosomal translocation, complex genetics and loss of INI1/SMARCB1 (Supplementary Table S5); however, we did not find any clear associations between mutated genes and histological subtypes (Fig.	('INI1', 'Gene', (269, 273))	('loss', 'Var', (261, 265))	('SMARCB1', 'Gene', '6598', (274, 281))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('SMARCB1', 'Gene', (274, 281))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('INI1', 'Gene', '6598', (269, 273))	('tumor', 'Disease', (61, 66))
90999	28878254	To our knowledge, our study is the first to screen for germline cancer gene mutations in Southeast Asian sporadic sarcoma patients.	('sporadic sarcoma', 'Disease', (105, 121))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('patients', 'Species', '9606', (122, 130))	('sporadic sarcoma', 'Disease', 'MESH:D012509', (105, 121))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
91002	28878254	In our cohort of 66 sarcoma patients, 13.6% (95% CI: 6.8-24.8%) had at least one predicted pathogenic germline mutation in the 52 cancer-associated gene panel.	('sarcoma', 'Disease', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('germline mutation', 'Var', (102, 119))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('patients', 'Species', '9606', (28, 36))
91006	28878254	Interestingly, a truncating mutation in ERCC4 (p.Cys723*) was found in two patients with sarcoma diagnosed under age 25 years (Table 2).	('p.Cys723*', 'Var', (47, 56))	('ERCC4', 'Gene', '2072', (40, 45))	('ERCC4', 'Gene', (40, 45))	('patients', 'Species', '9606', (75, 83))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('p.Cys723*', 'Mutation', 'p.C723*', (47, 56))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('found', 'Reg', (62, 67))
91009	28878254	Incidentally, the ISKS reported an excess of pathogenic variants in ERCC2.	('variants', 'Var', (56, 64))	('ERCC2', 'Gene', (68, 73))	('ERCC2', 'Gene', '2068', (68, 73))
91010	28878254	The observation of ERCC2 and ERCC4 predicted pathogenic mutations in our study and the ISKS, coupled with the early age-of-onset in our two patients, suggests a potential role for the nucleotide excision repair (NER) pathway in sarcoma predisposition.	('ERCC4', 'Gene', (29, 34))	('pathogenic', 'Reg', (45, 55))	('mutations', 'Var', (56, 65))	('sarcoma', 'Disease', 'MESH:D012509', (228, 235))	('ERCC2', 'Gene', '2068', (19, 24))	('sarcoma', 'Disease', (228, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('patients', 'Species', '9606', (140, 148))	('ERCC2', 'Gene', (19, 24))	('ERCC4', 'Gene', '2072', (29, 34))
91011	28878254	The prevalence of predicted pathogenic DDR gene mutation carriers in our cohort (10.6%) suggests that constitutional defects in this pathway may be associated with sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('DDR gene', 'Gene', (39, 47))	('mutation', 'Var', (48, 56))	('associated', 'Reg', (148, 158))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
91013	28878254	From our analysis of TCGA sarcoma data for pathogenic somatic mutations in these eight DDR genes, we observed a 3.4% prevalence, suggesting that these genes may indeed have a role in sarcomagenesis.	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('sarcoma', 'Disease', (183, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('sarcoma', 'Disease', 'MESH:D012509', (26, 33))	('sarcoma', 'Disease', (26, 33))	('DDR', 'Gene', (87, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('role', 'Reg', (175, 179))	('mutations', 'Var', (62, 71))
91014	28878254	It is also noteworthy that only one patient in our cohort harboured a germline TP53 deletion, consistent with the relatively lower prevalence of germline versus somatic TP53 mutations in sarcomas.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('deletion', 'Var', (84, 92))	('sarcomas', 'Disease', 'MESH:D012509', (187, 195))	('TP53', 'Gene', '7157', (169, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('TP53', 'Gene', (169, 173))	('sarcomas', 'Disease', (187, 195))	('patient', 'Species', '9606', (36, 43))
91015	28878254	The presence of multiple predicted pathogenic DDR gene germline mutations (ERCC4, ATM, FANCI, MSH6) in an early-onset sarcoma in our study suggests that multiple pathogenic mutations may have an additive effect towards sarcoma predisposition, a hypothesis supported by the ISKS in which an earlier age-at-diagnosis was correlated with the cumulative burden of multiple pathogenic mutations.	('sarcoma', 'Disease', (219, 226))	('ERCC4', 'Gene', '2072', (75, 80))	('FANCI', 'Gene', (87, 92))	('pathogenic', 'Reg', (35, 45))	('ERCC4', 'Gene', (75, 80))	('MSH6', 'Gene', (94, 98))	('DDR gene', 'Gene', (46, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('sarcoma', 'Disease', (118, 125))	('ATM', 'Gene', (82, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('mutations', 'Var', (173, 182))	('FA', 'Phenotype', 'HP:0001994', (87, 89))	('sarcoma', 'Disease', 'MESH:D012509', (219, 226))	('FANCI', 'Gene', '55215', (87, 92))	('MSH6', 'Gene', '2956', (94, 98))	('ATM', 'Gene', '472', (82, 85))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
91016	28878254	Notably, all the variants found in our two patients with multiple predicted pathogenic germline mutations occurred in DDR genes (Table 2).	('patients', 'Species', '9606', (43, 51))	('occurred', 'Reg', (106, 114))	('variants', 'Var', (17, 25))	('DDR genes', 'Gene', (118, 127))
91017	28878254	Both patients have one protein-truncating variant co-occuring with predicted pathogenic single nucleotide variants.	('single nucleotide', 'Var', (88, 105))	('protein-truncating', 'MPA', (23, 41))	('patients', 'Species', '9606', (5, 13))
91018	28878254	It is conceivable that even if the deleterious effect of each mutation is non-significant independently, the collective impact of these co-occurring predicted pathogenic mutations may potentially lead to impaired DNA repair and genomic instability, therefore conferring susceptibility to tumorigenesis.	('tumor', 'Disease', (288, 293))	('impaired', 'NegReg', (204, 212))	('DNA repair', 'MPA', (213, 223))	('mutations', 'Var', (170, 179))	('lead to', 'Reg', (196, 203))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('genomic', 'MPA', (228, 235))	('susceptibility', 'Reg', (270, 284))
91019	28878254	Recent findings showing frequent germline mutations in DNA homologous recombination genes within a metastatic prostate cancer cohort suggests the potential application of targeted therapies, such as PARP1-inhibition and platinum-based chemotherapy.	('germline mutations', 'Var', (33, 51))	('DNA homologous recombination genes', 'Gene', (55, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('platinum', 'Chemical', 'MESH:D010984', (220, 228))	('PARP1', 'Gene', '142', (199, 204))	('prostate cancer', 'Disease', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('PARP1', 'Gene', (199, 204))
91020	28878254	The excess of predicted pathogenic DDR gene germline mutations in our sporadic sarcoma cohort suggests that a subset of sarcomas may be candidates for such targeted therapies.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('DDR gene', 'Gene', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Disease', (120, 128))	('germline mutations', 'Var', (44, 62))	('sporadic sarcoma', 'Disease', 'MESH:D012509', (70, 86))	('pathogenic', 'Reg', (24, 34))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('sporadic sarcoma', 'Disease', (70, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
91023	28878254	We sequenced tumors of the patients harbouring the missense variants as a means of assessing pathogenicity but tumor DNA was not available for most of the patients, hence the missense variants of these patients were interpreted with caution.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('patients', 'Species', '9606', (202, 210))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('missense variants', 'Var', (51, 68))
91024	28878254	The only two variants we successfully validated - FANCE (p.Glu448Lys) and FANCI (p.Asp728Gly) - did not show loss of heterozygosity, however structural data has shown that these positions of the two FANC genes are involved in the important protein-protein interaction with FANCD2.	('FANCI', 'Gene', '55215', (74, 79))	('protein-protein', 'Protein', (240, 255))	('FANCD2', 'Gene', (273, 279))	('FANC', 'Gene', (50, 54))	('FANC', 'Gene', '2176;675;2177;2178;55215;83990;2072;672', (50, 54))	('FA', 'Phenotype', 'HP:0001994', (50, 52))	('FANC', 'Gene', (74, 78))	('FANC', 'Gene', '2176;675;2177;2178;55215;83990;2072;672', (273, 277))	('FA', 'Phenotype', 'HP:0001994', (74, 76))	('FANC', 'Gene', (273, 277))	('FANC', 'Gene', '2176;675;2177;2178;55215;83990;2072;672', (74, 78))	('FA', 'Phenotype', 'HP:0001994', (199, 201))	('FANCD2', 'Gene', '2177', (273, 279))	('FANCE', 'Gene', (50, 55))	('FANCE', 'Gene', '2178', (50, 55))	('involved', 'Reg', (214, 222))	('FANC', 'Gene', (199, 203))	('FANC', 'Gene', '2176;675;2177;2178;55215;83990;2072;672', (199, 203))	('p.Asp728Gly', 'Mutation', 'rs752114490', (81, 92))	('interaction', 'Interaction', (256, 267))	('p.Glu448Lys', 'Var', (57, 68))	('FANCI', 'Gene', (74, 79))	('p.Glu448Lys', 'Mutation', 'p.E448K', (57, 68))	('FA', 'Phenotype', 'HP:0001994', (273, 275))
91027	28878254	As the Glu448 residue of FANCE is highly conserved across species and important for FANCD2 binding, mutation of Glu448Lys is likely to impact on the interaction between FANCE and FANCD2 due to the change in residue size and charge.	('FA', 'Phenotype', 'HP:0001994', (179, 181))	('interaction', 'Interaction', (149, 160))	('FANCD2', 'Gene', '2177', (84, 90))	('FA', 'Phenotype', 'HP:0001994', (169, 171))	('binding', 'Interaction', (91, 98))	('Glu448', 'Chemical', '-', (112, 118))	('change', 'Reg', (197, 203))	('FANCD2', 'Gene', (179, 185))	('FA', 'Phenotype', 'HP:0001994', (25, 27))	('FANCE', 'Gene', (169, 174))	('FANCE', 'Gene', '2178', (169, 174))	('impact', 'Reg', (135, 141))	('FANCD2', 'Gene', '2177', (179, 185))	('FANCE', 'Gene', (25, 30))	('Glu448', 'Chemical', '-', (7, 13))	('charge', 'MPA', (224, 230))	('FANCE', 'Gene', '2178', (25, 30))	('Glu448Lys', 'Chemical', '-', (112, 121))	('FA', 'Phenotype', 'HP:0001994', (84, 86))	('Glu448Lys', 'Var', (112, 121))	('residue size', 'MPA', (207, 219))	('FANCD2', 'Gene', (84, 90))	('mutation', 'Var', (100, 108))
91028	28878254	The two FANCI variants seen in our cohort - Asp728Gly and Asn580Ser - corresponded to residues in the FANCI helical domain 2 that are highly conserved across species.	('FA', 'Phenotype', 'HP:0001994', (102, 104))	('FANCI', 'Gene', '55215', (8, 13))	('FANCI', 'Gene', '55215', (102, 107))	('Asn580Ser', 'Var', (58, 67))	('FANCI', 'Gene', (8, 13))	('FA', 'Phenotype', 'HP:0001994', (8, 10))	('Asp728Gly', 'Var', (44, 53))	('Asp728Gly', 'SUBSTITUTION', 'None', (44, 53))	('FANCI', 'Gene', (102, 107))	('Asn580Ser', 'SUBSTITUTION', 'None', (58, 67))
91029	28878254	In particular, Asn580 is located in a region concentrated with polar residues shown to interface with FANCD2.	('FA', 'Phenotype', 'HP:0001994', (102, 104))	('Asn580', 'Chemical', '-', (15, 21))	('polar residues', 'MPA', (63, 77))	('FANCD2', 'Gene', '2177', (102, 108))	('FANCD2', 'Gene', (102, 108))	('Asn580', 'Var', (15, 21))
91030	28878254	While the specific effect of these mutations remains to be functionally confirmed, the potential deleterious consequence on the activity of FANCD2 in addition to the functional studies reported in literature demonstrating the loss of protein function in the FANC-family genes collectively provide some evidence favouring the assignment of pathogenicity to the missense mutations we observed in this study.	('FA', 'Phenotype', 'HP:0001994', (140, 142))	('FANC', 'Gene', '2176;675;2177;2178;55215;83990;2072;672', (140, 144))	('activity', 'MPA', (128, 136))	('FANC', 'Gene', (140, 144))	('FANC', 'Gene', (258, 262))	('FA', 'Phenotype', 'HP:0001994', (258, 260))	('missense mutations', 'Var', (360, 378))	('FANC', 'Gene', '2176;675;2177;2178;55215;83990;2072;672', (258, 262))	('FANCD2', 'Gene', '2177', (140, 146))	('FANCD2', 'Gene', (140, 146))	('mutations', 'Var', (35, 44))
91032	28878254	In summary, our study is the first to investigate and identify an excess of potentially pathogenic germline mutations in a Southeast Asian cohort of young sarcoma.	('sarcoma', 'Disease', (155, 162))	('mutations', 'Var', (108, 117))	('pathogenic', 'Reg', (88, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('germline', 'Gene', (99, 107))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))
91034	28878254	Additionally, frequent observation of potentially pathogenic germline mutations in the DDR pathway suggest that inherited defects in this pathway may contribute to sarcoma predisposition.	('germline mutations', 'Var', (61, 79))	('contribute', 'Reg', (150, 160))	('pathogenic', 'Reg', (50, 60))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('defects', 'NegReg', (122, 129))	('DDR pathway', 'Pathway', (87, 98))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
91035	28878254	Sarcoma patients encountered in the clinic, especially young ones, should therefore be treated as potential carriers of germline pathogenic mutations in cancer predisposition genes regardless of family history and considered for genetic testing.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('cancer', 'Disease', (153, 159))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (140, 149))	('patients', 'Species', '9606', (8, 16))
91046	28878254	Missense variants were classified as potentially pathogenic, variant of uncertain significance (VUS) or benign using in silico prediction algorithms SIFT, PolyPhen2 HDIV, Mutation Assessor, FATHMM and CADD.	('pathogenic', 'Reg', (49, 59))	('VUS', 'Chemical', '-', (96, 99))	('algorithms SIFT', 'Disease', 'None', (138, 153))	('FA', 'Phenotype', 'HP:0001994', (190, 192))	('algorithms SIFT', 'Disease', (138, 153))	('AD', 'Disease', 'MESH:D000544', (202, 204))	('AD', 'Disease', (202, 204))	('Missense', 'Var', (0, 8))
91051	28878254	Copy number variants detected through digitalMLPA were validated by quantitative PCR (qPCR).	('Copy number variants', 'Var', (0, 20))	('digitalMLPA', 'Gene', (38, 49))	('digitalMLPA', 'Chemical', '-', (38, 49))
91053	28878254	For validation of the somatic status of candidate variants, Sanger sequencing was performed on tumor DNA extracted from fresh frozen or formalin-fixed paraffin embedded tumors using QIAamp DNA mini (Qiagen, 51304) or QIAamp FFPE tissue (Qiagen, 56404) kits.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('paraffin', 'Chemical', 'MESH:D010232', (151, 159))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('formalin', 'Chemical', 'MESH:D005557', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (169, 174))	('variants', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (169, 175))	('tumor', 'Disease', (95, 100))
91075	25328803	Cells with high ALDH levels have demonstrated enhanced tumorigenicity in multiple cancer cell types.	('ALDH', 'Gene', '11670', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ALDH', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('enhanced', 'PosReg', (46, 54))	('high', 'Var', (11, 15))
91076	25328803	In clinical studies, high ALDH activity predicted poor survival in breast and ovarian cancer #x02013;.	('activity', 'MPA', (31, 39))	('ALDH', 'Gene', '11670', (26, 30))	('poor', 'NegReg', (50, 54))	('ALDH', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('high', 'Var', (21, 25))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (67, 92))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
91080	25328803	Finally, we treated OS cells with the ALDH inhibitor, disulfiram, and observed that disulfiram effectively reduced ALDH activity and altered metastatic OS cell morphology, resulting in fewer filopodia and greater uniformity of shape.	('uniformity of shape', 'CPA', (213, 232))	('disulfiram', 'Chemical', 'MESH:D004221', (84, 94))	('disulfiram', 'Chemical', 'MESH:D004221', (54, 64))	('OS', 'Phenotype', 'HP:0002669', (152, 154))	('disulfiram', 'Var', (84, 94))	('reduced', 'NegReg', (107, 114))	('ALDH', 'Gene', '11670', (38, 42))	('filopodia', 'CPA', (191, 200))	('ALDH', 'Gene', (38, 42))	('greater', 'PosReg', (205, 212))	('OS', 'Phenotype', 'HP:0002669', (20, 22))	('ALDH', 'Gene', '11670', (115, 119))	('activity', 'MPA', (120, 128))	('metastatic OS cell morphology', 'CPA', (141, 170))	('fewer', 'NegReg', (185, 190))	('ALDH', 'Gene', (115, 119))	('altered', 'Reg', (133, 140))
91174	22135505	Deregulation of signaling as a result of the aberrant expression of the EGFR has been implicated in oncogenesis.	('signaling', 'MPA', (16, 25))	('EGFR', 'Gene', '1956', (72, 76))	('aberrant', 'Var', (45, 53))	('Deregulation', 'MPA', (0, 12))	('EGFR', 'Gene', (72, 76))	('implicated', 'Reg', (86, 96))
91238	22135505	However, FasL became transcriptionally and translationally active in SW1353 cultures, as it does in other cell types, when the cultures were deprived of serum for extended periods of time.	('SW1353', 'Var', (69, 75))	('transcriptionally', 'MPA', (21, 38))	('SW1353', 'CellLine', 'CVCL:0543', (69, 75))	('FasL', 'Gene', '356', (9, 13))	('FasL', 'Gene', (9, 13))
91291	22135505	Inclusion of CTGF was based on evidence published previously by this lab that showed a very strong correlation between CTGF and Fas mRNA content in sarcomas with low-EGF content, which lacked correlation in sarcomas with higher-EGF content.	('sarcomas', 'Disease', (207, 215))	('sarcomas', 'Disease', 'MESH:D012509', (148, 156))	('sarcomas', 'Disease', 'MESH:D012509', (207, 215))	('low-EGF content', 'Var', (162, 177))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (207, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('CTGF', 'Gene', '1490', (119, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('sarcomas', 'Disease', (148, 156))	('Fas mRNA content', 'MPA', (128, 144))	('CTGF', 'Gene', (13, 17))	('CTGF', 'Gene', (119, 123))	('correlation', 'Interaction', (99, 110))	('Fas', 'Chemical', 'MESH:C038178', (128, 131))	('CTGF', 'Gene', '1490', (13, 17))
91343	22135505	Activation of the EGFR in quiescent HSC involves phosphorylation of the EGFR tyrosine residues 845, 1173, and 1045.	('tyrosine residues 845', 'Var', (77, 98))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', (72, 76))	('quiescent', 'Disease', (26, 35))	('phosphorylation', 'MPA', (49, 64))	('tyrosine', 'Chemical', 'MESH:D014443', (77, 85))
91344	22135505	Phosphorylation of tyrosine 1045 mediates EGFR internalization.	('internalization', 'MPA', (47, 62))	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))	('Phosphorylation', 'MPA', (0, 15))	('mediates', 'Reg', (33, 41))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))	('tyrosine 1045', 'Var', (19, 32))
91346	22135505	The proposed pathway in hepatocytes involves FasL activation of p47phlox, a regulatory subunit of NADPH oxidase.	('p47phlox', 'Var', (64, 72))	('FasL', 'Gene', (45, 49))	('FasL', 'Gene', '356', (45, 49))
91347	22135505	The resulting oxidative stress induces the Src family kinase Yes, which in turn induces EGFR phosphorylation at Tyr845 and Tyr1173.	('phosphorylation', 'MPA', (93, 108))	('induces', 'Reg', (31, 38))	('oxidative stress', 'Phenotype', 'HP:0025464', (14, 30))	('Tyr845', 'Chemical', '-', (112, 118))	('Src family kinase Yes', 'Enzyme', (43, 64))	('EGFR', 'Gene', '1956', (88, 92))	('Tyr1173', 'Chemical', '-', (123, 130))	('Tyr1173', 'Var', (123, 130))	('EGFR', 'Gene', (88, 92))	('induces', 'Reg', (80, 87))
91348	22135505	Tyr1045 is not phosphorylated, hence no EGFR internalization.	('Tyr1045', 'Chemical', '-', (0, 7))	('internalization', 'MPA', (45, 60))	('Tyr1045', 'Var', (0, 7))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))
91372	22135505	Our mRNA model predicts that FasL is functional in high-EGF tumors, but may also show limited activity in the mid-EGF range.	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('FasL', 'Gene', '356', (29, 33))	('FasL', 'Gene', (29, 33))	('high-EGF', 'Var', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
91388	22135505	We found (1) the presence of TGFbeta1 protein within a tumor sample lacked any discernable association with that tumor TGFbeta1 transcript concentration and (2) TGFbeta1-bearing tumors did not cluster along the EGF-derived tumor continuum.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('lacked', 'NegReg', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('TGFbeta1', 'Gene', (29, 37))	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('transcript concentration', 'MPA', (128, 152))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (223, 228))	('protein', 'Protein', (38, 45))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('rat', 'Species', '10116', (146, 149))	('tumors', 'Disease', (178, 184))	('TGFbeta1', 'Gene', (119, 127))	('tumor', 'Disease', (55, 60))	('presence', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
91407	22135505	CTGF subsequently activates MAPK/ERK, and activated MAPK/ERK blocks Fas-induced apoptosis.	('CTGF', 'Gene', (0, 4))	('blocks', 'NegReg', (61, 67))	('activated', 'Var', (42, 51))	('ERK', 'Gene', '5594', (33, 36))	('ERK', 'Gene', '5594', (57, 60))	('Fas', 'Chemical', 'MESH:C038178', (68, 71))	('ERK', 'Gene', (33, 36))	('Fas-induced apoptosis', 'CPA', (68, 89))	('ERK', 'Gene', (57, 60))	('CTGF', 'Gene', '1490', (0, 4))	('activates', 'PosReg', (18, 27))
91502	28430664	However a delay of tumor growth was observed especially with SARC-A2DR1 as compared to SARC-L1 cell line (Figure 6B).	('SARC-A2DR1', 'Var', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('delay', 'NegReg', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))
91545	28430664	For gene expression profile of specific sarcoma genes (ARSG, MYLK, NBEA), real time quantitative polymerase chain reaction (qRT-PCR) (Thermofisher, France) was performed using primer sets listed as follows : NBEA (Mm01281997_g1), ARSG (Mm00546931_m1), MYLK (Mm00546931_m1) (Assay On Demand, Applied Biosystems).	('Mm01281997_g1', 'Var', (214, 227))	('Mm00546931_m1', 'Var', (258, 271))	('NBEA', 'Gene', '26422', (67, 71))	('ARSG', 'Gene', '74008', (230, 234))	('ARSG', 'Gene', (230, 234))	('ARSG', 'Gene', (55, 59))	('MYLK', 'Gene', (252, 256))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('NBEA', 'Gene', '26422', (208, 212))	('MYLK', 'Gene', (61, 65))	('ARSG', 'Gene', '74008', (55, 59))	('MYLK', 'Gene', '107589', (252, 256))	('sarcoma', 'Disease', (40, 47))	('MYLK', 'Gene', '107589', (61, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Mm00546931_m1', 'Var', (236, 249))	('NBEA', 'Gene', (208, 212))	('NBEA', 'Gene', (67, 71))
91549	28430664	For the analysis of MHC molecules expression by SARC-L1, cells were stained with the following fluorescent conjugated monoclonal antibodies: Anti-2Kb, (clone AF6-88.5.5.3,); anti-H-2Kdand anti-IA/IE (Ebiosciences, France); anti-HLA-A2 (BD Biosciences, France); anti-HLA-DR (Diaclone, France) or with their respectively isotype control.	('HLA', 'Gene', '3123', (228, 231))	('MHC', 'Gene', '3107', (20, 23))	('HLA', 'Gene', '3123', (266, 269))	('HLA-A', 'Gene', (228, 233))	('HLA', 'Gene', (228, 231))	('HLA', 'Gene', (266, 269))	('H-2Kd', 'Gene', (179, 184))	('H-2Kd', 'Gene', '14972', (179, 184))	('HLA-A', 'Gene', '3105', (228, 233))	('MHC', 'Gene', (20, 23))	('anti-IA/IE', 'Var', (188, 198))
91566	28430664	Finally, cells expressing A2.1 and DR1 were purified using anti-A2 antibody (BD Pharmingen, San Diego, CA, USA), anti-DR antibody (Caltag Laboratories, Burlingame, CA) and anti-mouse IgG-coated magnetic beads (Dynabeads, Dynal, Oslo, Norway), following the manufacturers' instructions.	('A2.1', 'Gene', (26, 30))	('mouse', 'Species', '10090', (177, 182))	('anti-A2', 'Var', (59, 66))	('A2.1', 'Gene', '28922', (26, 30))	('rat', 'Species', '10116', (142, 145))
91594	28353666	Dysregulation of lncRNAs can influence metastasis, chemosensitivity, and tumor cell growth and proliferation.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('chemosensitivity', 'CPA', (51, 67))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('metastasis', 'CPA', (39, 49))	('tumor', 'Disease', (73, 78))	('lncRNAs', 'Protein', (17, 24))	('influence', 'Reg', (29, 38))
91601	28353666	Increasing evidence demonstrates that lncRNAs regulate cell growth and proliferation in osteseosarcoma, and dysregulation of lncRNAs is related to patient outcome including prognosis, metastasis, and recurrence.	('osteseosarcoma', 'Disease', 'None', (88, 102))	('related', 'Reg', (136, 143))	('patient', 'Species', '9606', (147, 154))	('osteseosarcoma', 'Disease', (88, 102))	('proliferation', 'CPA', (71, 84))	('dysregulation', 'Var', (108, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('cell growth', 'CPA', (55, 66))
91605	28353666	Decreased human osteosarcoma cell viability and downregulated H19 occurs after the inhibition of the hedgehog signaling pathway or knockdown of the Yap1 gene.	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('inhibition', 'NegReg', (83, 93))	('H19', 'Protein', (62, 65))	('knockdown', 'Var', (131, 140))	('human', 'Species', '9606', (10, 15))	('Decreased', 'NegReg', (0, 9))	('downregulated', 'NegReg', (48, 61))	('hedgehog signaling pathway', 'Pathway', (101, 127))	('osteosarcoma', 'Phenotype', 'HP:0002669', (16, 28))	('Yap1', 'Gene', '10413', (148, 152))	('osteosarcoma cell viability', 'Disease', 'MESH:D012516', (16, 43))	('Yap1', 'Gene', (148, 152))	('osteosarcoma cell viability', 'Disease', (16, 43))
91624	28353666	MALAT1 knockdown remarkably reduced the formation of tubular network structures and caused the breakage of stress fibers in human osteosarcoma cell lines.	('formation', 'MPA', (40, 49))	('reduced', 'NegReg', (28, 35))	('MALAT1', 'Gene', '378938', (0, 6))	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (130, 142))	('MALAT1', 'Gene', (0, 6))	('human', 'Species', '9606', (124, 129))	('stress fibers', 'CPA', (107, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('breakage', 'CPA', (95, 103))	('knockdown', 'Var', (7, 16))	('osteosarcoma', 'Disease', (130, 142))
91629	28353666	Osteosarcoma is driven by transcriptional deregulation, abnormal kinase signaling, epigenetic reprogramming and more.	('epigenetic', 'Var', (83, 93))	('abnormal', 'Var', (56, 64))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))
91634	28353666	The C allele of single nucleotide polymorphism (SNP) rs7958904 from HOTAIR was associated with a decreased risk for osteosarcoma development when compared with the G allele.	('single nucleotide polymorphism', 'Var', (16, 46))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('rs7958904', 'Mutation', 'rs7958904', (53, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('decreased', 'NegReg', (97, 106))	('HOTAIR', 'Gene', (68, 74))	('rs7958904', 'Var', (53, 62))	('HOTAIR', 'Gene', '100124700', (68, 74))	('osteosarcoma', 'Disease', (116, 128))
91635	28353666	Functional analyses on HOTAIR expression showed that the SNP rs7958904 CC genotype had significantly lower HOTAIR RNA levels than those of other genotypes.	('HOTAIR', 'Gene', '100124700', (107, 113))	('rs7958904 CC', 'Var', (61, 73))	('rs7958904', 'Mutation', 'rs7958904', (61, 70))	('lower', 'NegReg', (101, 106))	('HOTAIR', 'Gene', (23, 29))	('HOTAIR', 'Gene', '100124700', (23, 29))	('HOTAIR', 'Gene', (107, 113))
91647	28353666	In human osteosarcoma cell lines, the knockdown of MALAT1 by siRNA affected the PI3K/AT signaling pathway and inhibited invasion and metastasis in vitro and in vivo.	('affected', 'Reg', (67, 75))	('MALAT1', 'Gene', '378938', (51, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('PI3K/AT signaling pathway', 'Pathway', (80, 105))	('human', 'Species', '9606', (3, 8))	('MALAT1', 'Gene', (51, 57))	('inhibited', 'NegReg', (110, 119))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('osteosarcoma', 'Disease', (9, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('knockdown', 'Var', (38, 47))
91648	28353666	Further research also indicated that the knockdown of MALAT1 by siRNA significantly inhibited the migration of human osteosarcoma cell lines.	('osteosarcoma', 'Phenotype', 'HP:0002669', (117, 129))	('human', 'Species', '9606', (111, 116))	('osteosarcoma', 'Disease', (117, 129))	('osteosarcoma', 'Disease', 'MESH:D012516', (117, 129))	('MALAT1', 'Gene', '378938', (54, 60))	('MALAT1', 'Gene', (54, 60))	('knockdown', 'Var', (41, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('inhibited', 'NegReg', (84, 93))
91651	28353666	Downregulating HNF1A-AS1 prevented metastasis and influenced the Wnt/beta-catenin pathway activity, indicating that HNF1A-AS1 promotes metastasis in osteosarcoma via the Wnt/beta-catenin pathway.	('metastasis', 'CPA', (135, 145))	('metastasis', 'CPA', (35, 45))	('beta-catenin', 'Gene', (69, 81))	('influenced', 'Reg', (50, 60))	('osteosarcoma', 'Disease', 'MESH:D012516', (149, 161))	('promotes', 'PosReg', (126, 134))	('HNF1A-AS1', 'Gene', (15, 24))	('beta-catenin', 'Gene', '1499', (69, 81))	('Downregulating', 'Var', (0, 14))	('HNF1A-AS1', 'Gene', (116, 125))	('HNF1A-AS1', 'Gene', '283460', (15, 24))	('osteosarcoma', 'Phenotype', 'HP:0002669', (149, 161))	('osteosarcoma', 'Disease', (149, 161))	('beta-catenin', 'Gene', (174, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('HNF1A-AS1', 'Gene', '283460', (116, 125))	('beta-catenin', 'Gene', '1499', (174, 186))
91657	28353666	Inhibiting PVT1 reduced miR-195 activity and subsequently depressed osteosarcoma cell ability for migration and invasion.	('Inhibiting', 'Var', (0, 10))	('miR-195', 'Gene', (24, 31))	('miR-195', 'Gene', '406971', (24, 31))	('depressed osteosarcoma', 'Disease', 'MESH:D012516', (58, 80))	('reduced', 'NegReg', (16, 23))	('activity', 'MPA', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('depressed osteosarcoma', 'Disease', (58, 80))	('PVT1', 'Gene', (11, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (68, 80))	('PVT1', 'Gene', '5820', (11, 15))
91658	28353666	The inhibition of PVT1 had a cascading effect, in that it impeded miR-195 activity that then blocked fatty acid synthase (FASN), and, overall, the invasiveness of human osteosarcoma cell lines consequently decreased.	('blocked', 'NegReg', (93, 100))	('FASN', 'Gene', (122, 126))	('fatty acid synthase', 'Gene', '2194', (101, 120))	('FASN', 'Gene', '2194', (122, 126))	('miR-195', 'Gene', (66, 73))	('miR-195', 'Gene', '406971', (66, 73))	('decreased', 'NegReg', (206, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('impeded', 'NegReg', (58, 65))	('activity', 'MPA', (74, 82))	('inhibition', 'Var', (4, 14))	('PVT1', 'Gene', (18, 22))	('human', 'Species', '9606', (163, 168))	('osteosarcoma', 'Phenotype', 'HP:0002669', (169, 181))	('osteosarcoma', 'Disease', (169, 181))	('osteosarcoma', 'Disease', 'MESH:D012516', (169, 181))	('fatty acid synthase', 'Gene', (101, 120))	('PVT1', 'Gene', '5820', (18, 22))
91661	28353666	By contrast, ZEB1-AS1 knockdown inhibited osteosarcoma cell migration.	('osteosarcoma', 'Disease', (42, 54))	('inhibited', 'NegReg', (32, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('knockdown', 'Var', (22, 31))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))	('ZEB1-AS1', 'Gene', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
91662	28353666	Silencing ZEB1 prevented ZEB1-AS1 from inducing osteosarcoma cell migration (Table 2).	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('osteosarcoma', 'Disease', (48, 60))	('osteosarcoma', 'Disease', 'MESH:D012516', (48, 60))	('inducing', 'PosReg', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('ZEB1', 'Gene', (25, 29))	('ZEB1', 'Gene', '6935', (10, 14))	('ZEB1', 'Gene', '6935', (25, 29))	('ZEB1', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('prevented', 'NegReg', (15, 24))
91668	28353666	Another study showed that antisense non-coding RNA in the INK4 locus (ANRIL) expression was upregulated in human osteosarcoma tissue when compared with the surrounding normal tissue.	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('expression', 'MPA', (77, 87))	('upregulated', 'PosReg', (92, 103))	('human', 'Species', '9606', (107, 112))	('INK4', 'Gene', (58, 62))	('ANRIL', 'Gene', '100048912', (70, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('INK4', 'Gene', '1029', (58, 62))	('antisense non-coding RNA', 'Var', (26, 50))	('osteosarcoma', 'Disease', (113, 125))	('ANRIL', 'Gene', (70, 75))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))
91676	28353666	The most dysregulated lncRNAs:namely ENST00000563280 (osteosarcoma doxorubicin-resistance related upregulated lncRNA, ODRUL) and NR-036444:were critical for doxorubicin resistance due to their interactions with important genes including: ATP-binding cassette, subfamily B, member 1 (ABCB1), HIF-1alpha and forkhead box protein C2 (FOXC2).	('ATP-binding cassette, subfamily B, member 1', 'Gene', '5243', (238, 281))	('interactions', 'Interaction', (193, 205))	('HIF-1alpha', 'Gene', (291, 301))	('FOXC2', 'Gene', (331, 336))	('forkhead box protein C2', 'Gene', (306, 329))	('FOXC2', 'Gene', '2303', (331, 336))	('forkhead box protein C2', 'Gene', '2303', (306, 329))	('osteosarcoma', 'Phenotype', 'HP:0002669', (54, 66))	('doxorubicin', 'Chemical', 'MESH:D004317', (157, 168))	('ODRUL', 'Gene', (118, 123))	('ABCB1', 'Gene', (283, 288))	('ENST00000563280', 'Var', (37, 52))	('ABCB1', 'Gene', '5243', (283, 288))	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('HIF-1alpha', 'Gene', '3091', (291, 301))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('ODRUL', 'Gene', '103752587', (118, 123))	('osteosarcoma', 'Disease', (54, 66))	('osteosarcoma', 'Disease', 'MESH:D012516', (54, 66))
91685	28353666	HOXA Distal Transcript Antisense RNA (HOTTIP) was detected at heightened concentrations in human osteosarcoma tissue.	('HOTTIP', 'Gene', (38, 44))	('HOXA', 'Gene', (0, 4))	('osteosarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('osteosarcoma', 'Disease', (97, 109))	('Antisense', 'Var', (23, 32))	('osteosarcoma', 'Disease', 'MESH:D012516', (97, 109))	('HOXA', 'Gene', '3197', (0, 4))	('HOTTIP', 'Gene', '100316868', (38, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('human', 'Species', '9606', (91, 96))
91708	28353666	Furthermore, 91H expression was shown to be an independent prognostic factor for overall survival in osteosarcoma patients after treatments.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('91H expression', 'Var', (13, 27))	('91H', 'Chemical', '-', (13, 16))	('osteosarcoma', 'Disease', (101, 113))	('osteosarcoma', 'Phenotype', 'HP:0002669', (101, 113))	('osteosarcoma', 'Disease', 'MESH:D012516', (101, 113))	('patients', 'Species', '9606', (114, 122))
91712	28353666	Multivariate analysis indicated the expression of MEG3 to be one independent predictor of overall survival in osteosarcoma patients (Table 3).	('MEG3', 'Gene', (50, 54))	('osteosarcoma', 'Disease', (110, 122))	('expression', 'Var', (36, 46))	('patients', 'Species', '9606', (123, 131))	('MEG3', 'Gene', '55384', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (110, 122))	('osteosarcoma', 'Disease', 'MESH:D012516', (110, 122))
91729	28353666	In addition to FLI1, fusions can be found between EWSR1 and other E-twenty six (ETS) family transcription factors.	('EWSR1', 'Gene', '2130', (50, 55))	('FLI1', 'Gene', (15, 19))	('FLI1', 'Gene', '2313', (15, 19))	('fusions', 'Var', (21, 28))	('EWSR1', 'Gene', (50, 55))
91736	28353666	The outcome of patients with GISTs has significantly improved due to two primary innovations, namely the discovery of a mutation in the receptor tyrosine kinase (RTK) KIT proto-oncogene receptor tyrosine kinase (KIT) and pharmacological treatment with Gleevec (Imatinib mesylate).	('Gleevec', 'Chemical', 'MESH:D000068877', (252, 259))	('patients', 'Species', '9606', (15, 23))	('receptor tyrosine kinase', 'Gene', '5979', (136, 160))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', (167, 210))	('RTK', 'Gene', (162, 165))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', '3815', (167, 210))	('mutation', 'Var', (120, 128))	('receptor tyrosine kinase', 'Gene', '5979', (186, 210))	('Imatinib mesylate', 'Chemical', 'MESH:D000068877', (261, 278))	('RTK', 'Gene', '5979', (162, 165))	('GISTs', 'Phenotype', 'HP:0100723', (29, 34))	('KIT', 'Gene', (212, 215))	('receptor tyrosine kinase', 'Gene', (136, 160))
91747	28353666	The knockdown of PILRLS significantly inhibited cell proliferation and colony formation of etroperitoneal liposarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('cell proliferation', 'CPA', (48, 66))	('inhibited', 'NegReg', (38, 47))	('etroperitoneal liposarcoma', 'Disease', (91, 117))	('etroperitoneal liposarcoma', 'Disease', 'MESH:D008080', (91, 117))	('knockdown', 'Var', (4, 13))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))	('PILRLS', 'Gene', (17, 23))
91756	28353666	Moreover, targeted deletion studies in primary cells and animal models will be necessary to assess the specific functions of lncRNAs in sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('deletion', 'Var', (19, 27))	('sarcoma', 'Disease', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))
91781	25182322	Our results show that naive and IgM memory B cells, and plasma cell-like populations, support infection with HHV-8 both in vitro and in the blood of subjects with KS.	('KS', 'Phenotype', 'HP:0100726', (163, 165))	('HHV-8', 'Gene', (109, 114))	('infection', 'Var', (94, 103))	('HHV-8', 'Species', '37296', (109, 114))
91812	25182322	Of the HHV-8-infected cells, 35 to 41% produced at least 3 cytokines and chemokines, compared to 1.0 to 9.1% of uninfected cells (P < 0.01).	('to 9', 'Species', '1214577', (101, 105))	('chemokines', 'MPA', (73, 83))	('HHV-8-infected', 'Var', (7, 21))	('HHV-8-infected', 'Gene', (7, 21))	('HHV-8', 'Species', '37296', (7, 12))
91819	25182322	Analysis of serum collected within 1 year prior to KS diagnosis showed that levels of TNF-alpha, MIP-1alpha, and IL-8 were nearly 2-fold higher in KS positives than KS negatives (P = 0.01, 0.03, and 0.02, respectively) (Fig.	('levels', 'MPA', (76, 82))	('MIP-1alpha', 'Gene', (97, 107))	('IL-8', 'Gene', (113, 117))	('MIP-1alpha', 'Gene', '6348', (97, 107))	('TNF-alpha', 'Gene', '7124', (86, 95))	('KS', 'Phenotype', 'HP:0100726', (147, 149))	('KS', 'Phenotype', 'HP:0100726', (165, 167))	('KS', 'Phenotype', 'HP:0100726', (51, 53))	('higher', 'PosReg', (137, 143))	('TNF-alpha', 'Gene', (86, 95))	('positives', 'Var', (150, 159))	('IL-8', 'Gene', '3576', (113, 117))
91820	25182322	There was a trend for increased MIP-1beta and decreased IL-6 levels in KS positives compared to KS negatives (P = not significant).	('IL-6', 'Gene', (56, 60))	('IL-6', 'Gene', '3569', (56, 60))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('increased', 'PosReg', (22, 31))	('positives', 'Var', (74, 83))	('decreased', 'NegReg', (46, 55))	('MIP-1beta', 'Gene', (32, 41))	('KS', 'Phenotype', 'HP:0100726', (71, 73))	('KS positives', 'Var', (71, 83))	('MIP-1beta', 'Gene', '6351', (32, 41))
91831	25182322	5A, red, yellow and orange pieces, respectively, in ORF59 PF-8-positive compared to ORF59 PF-8-negative B cells).	('PF-8', 'Chemical', '-', (90, 94))	('ORF59', 'Gene', (52, 57))	('PF-8-positive', 'Var', (58, 71))	('ORF59', 'Gene', '4961492', (52, 57))	('ORF59', 'Gene', (84, 89))	('ORF59', 'Gene', '4961492', (84, 89))	('PF-8', 'Chemical', '-', (58, 62))
91837	25182322	This was visually evident from the greater size of the orange (5 functions), yellow (4 functions), and red (3 functions) sections in the pie charts for ORF59 PF-8-positive versus ORF59 PF-8-negative subjects in Fig.	('ORF59', 'Gene', '4961492', (179, 184))	('PF-8-positive', 'Var', (158, 171))	('ORF59', 'Gene', (152, 157))	('ORF59', 'Gene', '4961492', (152, 157))	('PF-8', 'Chemical', '-', (158, 162))	('ORF59', 'Gene', (179, 184))	('PF-8', 'Chemical', '-', (185, 189))
91840	25182322	In sum, 61% to 88% of infected B cell subsets among KS positives were polyfunctional, compared to 46% to 75% of KS negatives (P < 0.01).	('polyfunctional', 'Var', (70, 84))	('to 7', 'Species', '1214577', (102, 106))	('KS positives', 'Var', (52, 64))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('positives', 'Var', (55, 64))	('KS', 'Phenotype', 'HP:0100726', (112, 114))
91851	25182322	Using new flow cytometry methods to delineate infected B cells based on expression of ORF59 PF-8 directly in archived MACS samples, we found that B cells of KS positives had a higher percentage of viral lytic protein expression than KS negatives, i.e., approximately 2.3% and 0.64%, respectively.	('ORF59', 'Gene', (86, 91))	('KS', 'Phenotype', 'HP:0100726', (157, 159))	('KS', 'Phenotype', 'HP:0100726', (233, 235))	('viral lytic protein', 'Protein', (197, 216))	('ORF59', 'Gene', '4961492', (86, 91))	('PF-8', 'Chemical', '-', (92, 96))	('positives', 'Var', (160, 169))	('higher', 'PosReg', (176, 182))	('KS positives', 'Var', (157, 169))
91856	25182322	As detection of HHV-8 DNA is dependent on the number of PBMC used for DNA extraction, infected B cells with lower HHV-8 copy numbers could generate a negative PCR signal, while transcription/translation of the genome results in sufficient copies of ORF59 PF-8 for detection by flow cytometry.	('HHV-8', 'Species', '37296', (114, 119))	('ORF59', 'Gene', (249, 254))	('HHV-8', 'Species', '37296', (16, 21))	('copy numbers', 'Var', (120, 132))	('negative PCR signal', 'MPA', (150, 169))	('lower', 'NegReg', (108, 113))	('ORF59', 'Gene', '4961492', (249, 254))	('PF-8', 'Chemical', '-', (255, 259))	('HHV-8', 'Gene', (114, 119))
91979	21990424	The antigens most frequently detected at 1:10 000 dilution were ORF73C (10/15; 66% positive) and ORF38 (10/15; 66% positive).	('ORF38', 'Var', (97, 102))	('ORF73', 'Gene', '4961527', (64, 69))	('ORF73', 'Gene', (64, 69))
91982	21990424	Two subtypes of EBV, type 1 and type 2 (also called A and B), were originally defined on the basis of differences in the EBNA2 gene.	('differences', 'Var', (102, 113))	('type 1 and type 2', 'Gene', 'None', (21, 38))	('EBNA2', 'Gene', (121, 126))	('EBV', 'Disease', (16, 19))
91984	21990424	Nine of the 20 HIV-positive lymphoma patients recognized ORF73C at the 1:10 000 dilution vs 13 of the 15 HIV-positive KS patients (Figure 4A).	('HIV-positive lymphoma', 'Disease', 'MESH:D016483', (15, 36))	('lymphoma', 'Phenotype', 'HP:0002665', (28, 36))	('ORF73C', 'Var', (57, 63))	('HIV-positive lymphoma', 'Disease', (15, 36))
92081	31624759	> 10000 copies/microL), while massive lesions are associated with low CD4 cell counts (i.e.	('> 10000 copies/microL', 'Var', (0, 21))	('low', 'NegReg', (66, 69))	('CD4', 'Gene', (70, 73))	('CD4', 'Gene', '920', (70, 73))
92162	30364375	There have also been studies that suggest similarity of EMC pathogenesis to Ewing's sarcoma, including a reciprocal translocation (11;22)(q24;q12) and trisomy 8.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (76, 91))	('trisomy 8', 'Var', (151, 160))	("Ewing's sarcoma", 'Disease', (76, 91))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (76, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('11;22)(q24;q12', 'Var', (131, 145))
92235	27622032	Incubation with interleukin-2 plus TKD (a 14 amino acid derivative of heat shock protein 70) ex vivo was able to reverse NK cell dysfunction and might increase the efficacy of immunotherapeutic regimens in STS patients.	('NK cell dysfunction', 'Disease', 'MESH:D054066', (121, 140))	('STS', 'Phenotype', 'HP:0030448', (206, 209))	('interleukin-2', 'Gene', '3558', (16, 29))	('heat shock protein 70', 'Gene', (70, 91))	('shock', 'Phenotype', 'HP:0031273', (75, 80))	('NK cell dysfunction', 'Disease', (121, 140))	('patients', 'Species', '9606', (210, 218))	('heat shock protein 70', 'Gene', '3308', (70, 91))	('increase', 'PosReg', (151, 159))	('TKD', 'Var', (35, 38))	('interleukin-2', 'Gene', (16, 29))
92255	27622032	TKD can further augment the stimulatory capacity of IL-2.	('IL-2', 'Gene', '3558', (52, 56))	('IL-2', 'Gene', (52, 56))	('TKD', 'Var', (0, 3))	('augment', 'PosReg', (16, 23))	('stimulatory capacity', 'MPA', (28, 48))
92298	27622032	NK cells and CD8+ T lymphocytes can act as major players in antitumor responses, and inhibition of their function has been associated with tumor immune escape.	('associated', 'Reg', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (64, 69))	('CD8', 'Gene', (13, 16))	('CD8', 'Gene', '925', (13, 16))	('inhibition', 'Var', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
92332	27622032	Finally, we tested a scenario that patients with low NK cell-specific cytotoxicity might have a higher probability of relapse after 1st-line therapy.	('tested', 'Reg', (12, 18))	('low NK cell', 'Phenotype', 'HP:0040218', (49, 60))	('cytotoxicity', 'Disease', 'MESH:D064420', (70, 82))	('patients', 'Species', '9606', (35, 43))	('low', 'Var', (49, 52))	('cytotoxicity', 'Disease', (70, 82))
92336	27622032	Interestingly, new small molecule agents used for targeted therapy, e.g., BRAF inhibitors or TKIs like imatinib have been shown to positively affect NK cell proliferation and to increase NK cell cytotoxicity.	('affect', 'Reg', (142, 148))	('cytotoxicity', 'Disease', 'MESH:D064420', (195, 207))	('imatinib', 'Chemical', 'MESH:D000068877', (103, 111))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('cytotoxicity', 'Disease', (195, 207))	('inhibitors', 'Var', (79, 89))	('increase', 'PosReg', (178, 186))	('NK cell proliferation', 'CPA', (149, 170))
92397	27622032	PHC0021) and TKD (14 amino acid derivative of Hsp70, 2 microg/mL, gift from G. Multhoff, Munich) for 96 h at 37 C and 5 % CO2.	('PHC0021', 'Var', (0, 7))	('Hsp70, 2', 'Gene', '3306;3308', (46, 54))	('CO2', 'Gene', (122, 125))	('CO2', 'Gene', '717', (122, 125))
92517	26540571	Onset of symptoms was collected according to the type of cancer : date of first clinical signs (pain, tumor hardening, dysuria, hematuria, cough, hemoptysis, rectal bleeding...), or date of the first abnormal radiological or biological result for cancer screening (abnormal mammography, colonoscopy, PSA increase).	('pain', 'Disease', (96, 100))	('dysuria', 'Disease', (119, 126))	('rectal bleeding', 'Phenotype', 'HP:0002573', (158, 173))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('hematuria', 'Disease', (128, 137))	('pain', 'Phenotype', 'HP:0012531', (96, 100))	('hemoptysis', 'Phenotype', 'HP:0002105', (146, 156))	('cough', 'Disease', 'MESH:D003371', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('hemoptysis', 'Disease', (146, 156))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('PSA', 'Gene', (300, 303))	('colonoscopy', 'Disease', (287, 298))	('cough', 'Disease', (139, 144))	('hematuria', 'Disease', 'MESH:D006417', (128, 137))	('pain', 'Disease', 'MESH:D010146', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('abnormal', 'Var', (265, 273))	('hematuria', 'Phenotype', 'HP:0000790', (128, 137))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', (102, 107))	('rectal bleeding', 'Disease', (158, 173))	('dysuria', 'Disease', 'MESH:D053159', (119, 126))	('dysuria', 'Phenotype', 'HP:0100518', (119, 126))	('cough', 'Phenotype', 'HP:0012735', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PSA', 'Gene', '354', (300, 303))	('rectal bleeding', 'Disease', 'MESH:D006470', (158, 173))	('hemoptysis', 'Disease', 'MESH:D006469', (146, 156))
92585	24084772	Five-year estimated survival rate for patients with low CRP levels were 92.8% compared with 73.4% of patients with high CRP levels (P<0.001).	('patients', 'Species', '9606', (101, 109))	('CRP', 'Gene', '1401', (56, 59))	('CRP', 'Gene', (56, 59))	('CRP', 'Gene', (120, 123))	('patients', 'Species', '9606', (38, 46))	('CRP', 'Gene', '1401', (120, 123))	('low', 'Var', (52, 55))
92667	23227212	For example, gastrointestinal stromal tumor (GIST) patients with high amplification of KIT benefit from c-KIT inhibitors like imatinib.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('KIT', 'Gene', (87, 90))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (13, 43))	('high amplification', 'Var', (65, 83))	('c-KIT', 'Gene', (104, 109))	('GIST', 'Phenotype', 'HP:0100723', (45, 49))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (13, 43))	('c-KIT', 'Gene', '3815', (104, 109))	('patients', 'Species', '9606', (51, 59))	('benefit', 'PosReg', (91, 98))	('gastrointestinal stromal tumor', 'Disease', (13, 43))	('imatinib', 'Chemical', 'MESH:D000068877', (126, 134))
92717	23227212	Broad-spectrum kinase inhibitors targeting VEGFRs, such as sunitinib, semaxanib (SU5416) and SU6668 and the VEGF-A antibody bevacizumab, have been shown to inhibit growth of Ewing's sarcoma in mouse xenograft models.	('sunitinib', 'Chemical', 'MESH:D000077210', (59, 68))	('bevacizumab', 'Chemical', 'MESH:D000068258', (124, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('VEGFRs', 'Gene', (43, 49))	('inhibit', 'NegReg', (156, 163))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (174, 189))	('SU5416', 'Chemical', 'MESH:C116890', (81, 87))	('semaxanib', 'Chemical', 'MESH:C116890', (70, 79))	('SU6668', 'Chemical', 'MESH:C412603', (93, 99))	('SU6668', 'Var', (93, 99))	('VEGF-A', 'Gene', '22339', (108, 114))	('growth', 'MPA', (164, 170))	('VEGFRs', 'Gene', '2324;14257;3791', (43, 49))	('VEGF-A', 'Gene', (108, 114))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (174, 189))	('mouse', 'Species', '10090', (193, 198))	("Ewing's sarcoma", 'Disease', (174, 189))
92723	23227212	Taken together, broad spectrum VEGFR inhibitors, currently in use or tested for adult cancer patients, may slow progression of pediatric sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('inhibitors', 'Var', (37, 47))	('adult cancer', 'Disease', (80, 92))	('pediatric sarcomas', 'Disease', (127, 145))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (127, 145))	('VEGFR', 'Gene', '3791', (31, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('adult cancer', 'Disease', 'MESH:C535836', (80, 92))	('patients', 'Species', '9606', (93, 101))	('slow', 'NegReg', (107, 111))	('VEGFR', 'Gene', (31, 36))
92881	24341522	Mice with mutations in the Dystrophin (DMD), Calpain-3 (LGMD2A) or Dysferlin (LGMD2B) genes are susceptible to malignant tumours originating from the skeletal muscles (reviewed in).	('DMD', 'Disease', (39, 42))	('malignant tumours', 'Disease', (111, 128))	('Mice', 'Species', '10090', (0, 4))	('malignant tumours originating from the skeletal muscles', 'Phenotype', 'HP:0010622', (111, 166))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('LGMD', 'Disease', 'None', (56, 60))	('susceptible', 'Reg', (96, 107))	('LGMD', 'Disease', 'None', (78, 82))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('Dysferlin', 'Gene', '26903', (67, 76))	('LGMD', 'Disease', (56, 60))	('LGMD', 'Disease', (78, 82))	('Calpain-3', 'Gene', '12335', (45, 54))	('Dysferlin', 'Gene', (67, 76))	('Dystrophin', 'Gene', (27, 37))	('mutations', 'Var', (10, 19))	('Calpain-3', 'Gene', (45, 54))	('malignant tumours', 'Disease', 'MESH:D009369', (111, 128))	('DMD', 'Disease', 'MESH:D020388', (39, 42))
92885	24341522	The majority of FSHD patients carry a deletion of the 3.3 kb-long D4Z4 macrosatellite repeats, accompanied by DNA demethylation and chromatin structure alterations within the subtelomeric region of chromosome 4 (4q35) (for review see).	('FSHD', 'Gene', '2489', (16, 20))	('D4Z4', 'Gene', (66, 70))	('alterations', 'Reg', (152, 163))	('patients', 'Species', '9606', (21, 29))	('FSHD', 'Gene', (16, 20))	('deletion', 'Var', (38, 46))	('DNA demethylation', 'MPA', (110, 127))	('chromatin', 'MPA', (132, 141))
92887	24341522	The rearrangement of the FSHD-associated region in 4q35 has been also found in various tumours, including undifferentiated soft tissue sarcoma, Ewing's sarcoma and rhabdomyosarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('rearrangement', 'Var', (4, 17))	('sarcoma', 'Disease', (173, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('sarcoma', 'Disease', (135, 142))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (164, 180))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (144, 159))	('FSHD', 'Gene', '2489', (25, 29))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (164, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('tumours', 'Disease', (87, 94))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('found', 'Reg', (70, 75))	('FSHD', 'Gene', (25, 29))	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('sarcoma', 'Disease', (152, 159))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (123, 142))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('rhabdomyosarcoma', 'Disease', (164, 180))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))
92888	24341522	Epigenetic alterations of the same region have been documented in cervical and ovarian cancers.	('Epigenetic alterations', 'Var', (0, 22))	('ovarian cancers', 'Disease', 'MESH:D010051', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cervical', 'Disease', (66, 74))	('ovarian cancers', 'Phenotype', 'HP:0100615', (79, 94))	('ovarian cancers', 'Disease', (79, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('documented', 'Reg', (52, 62))
92889	24341522	D4Z4 repeats encode a powerful transcription regulator, double homeobox protein 4 (DUX4), playing an important if not the key role in the aetiology of FSHD and a potent enhancer that is capable of regulating a variety of genes.	('double homeobox protein 4', 'Gene', '107987486', (56, 81))	('DUX4', 'Gene', (83, 87))	('FSHD', 'Gene', '2489', (151, 155))	('D4Z4 repeats', 'Var', (0, 12))	('double homeobox protein 4', 'Gene', (56, 81))	('DUX4', 'Gene', '107987486', (83, 87))	('FSHD', 'Gene', (151, 155))
92890	24341522	Interestingly, the expression level of DUX4 is altered in cervical cancer and in Ewing's sarcoma where this gene functions as a chimeric oncogene if fused to CIC gene as a result of the t(4;19)(q35;q13.1) translocation.	('t(4;19)(q35;q13.1)', 'STRUCTURAL_ABNORMALITY', 'None', (186, 204))	('t(4;19)(q35;q13.1', 'Var', (186, 203))	('DUX4', 'Gene', '107987486', (39, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('expression level', 'MPA', (19, 35))	('cervical cancer', 'Disease', 'MESH:D002583', (58, 73))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('CIC', 'Gene', '23152', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (81, 96))	('sarcoma', 'Disease', (89, 96))	('cervical cancer', 'Disease', (58, 73))	('altered', 'Reg', (47, 54))	('CIC', 'Gene', (158, 161))	('DUX4', 'Gene', (39, 43))
92962	24341522	Specifically, it was found that the mice with the mutation in Dystrophin, Dysferlin and Calpain-3 were susceptible to spontaneous formation of rhabdomyo-, fibro-and liposarcomas derived from skeletal muscle tissue (reviewed in).	('Calpain-3', 'Gene', (88, 97))	('Dysferlin', 'Gene', (74, 83))	('mutation', 'Var', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('Dystrophin', 'Gene', (62, 72))	('Calpain-3', 'Gene', '12335', (88, 97))	('liposarcomas', 'Disease', 'MESH:D008080', (165, 177))	('mice', 'Species', '10090', (36, 40))	('liposarcomas', 'Disease', (165, 177))	('Dysferlin', 'Gene', '26903', (74, 83))	('fibro-and', 'CPA', (155, 164))	('susceptible', 'Reg', (103, 114))	('rhabdomyo-', 'Disease', (143, 153))
92981	24341522	Myotonic dystrophy is caused by CTG and CCTG microsatellite repeat expansion affecting the function of splicing factors in the cells of the MD patients.	('affecting', 'Reg', (77, 86))	('CCTG', 'Gene', '7203', (40, 44))	('function of splicing factors', 'MPA', (91, 119))	('CCTG', 'Gene', (40, 44))	('CTG', 'Chemical', '-', (32, 35))	('microsatellite repeat expansion', 'Var', (45, 76))	('patients', 'Species', '9606', (143, 151))	('caused', 'Reg', (22, 28))	('CTG', 'Chemical', '-', (41, 44))	('Myotonic dystrophy', 'Disease', (0, 18))	('Myotonic dystrophy', 'Disease', 'MESH:D009223', (0, 18))
92982	24341522	Therefore, an altered pre-mRNA splicing could potentially initiate the process of tumour formation in MD; however, currently, this hypothesis is missing a solid experiment support.	('initiate', 'Reg', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('altered', 'Var', (14, 21))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))
93014	33886686	In addition, radiotherapy has the potential to cause secondary cancers in irradiated tissues.	('cause', 'Reg', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('radiotherapy', 'Var', (13, 25))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
93024	33886686	We confirmed the antitumor effect of monotherapy OBP-301 in epithelial and mesenchymal types of malignant tumor cells, including osteosarcoma and STS, as well as its use in combination with radiation or chemotherapy.	('STS', 'Phenotype', 'HP:0030448', (146, 149))	('OBP-301', 'Gene', (49, 56))	('tumor', 'Disease', (21, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('malignant tumor', 'Disease', 'MESH:D009369', (96, 111))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('malignant tumor', 'Disease', (96, 111))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('tumor', 'Disease', (106, 111))	('osteosarcoma', 'Disease', 'MESH:D012516', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('epithelial', 'CPA', (60, 70))	('OBP-301', 'Chemical', '-', (49, 56))	('osteosarcoma', 'Disease', (129, 141))	('monotherapy', 'Var', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
93026	33886686	In combination with chemotherapy, we have shown that OBP-301 adenoviral E1A suppresses the expression of anti-apoptotic MCL1 protein, resulting in the enhancement of apoptosis induced by cisplatin and doxorubicin or zoledronic acid.	('expression', 'MPA', (91, 101))	('OBP-301', 'Var', (53, 60))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (216, 231))	('MCL1', 'Gene', (120, 124))	('OBP-301', 'Chemical', '-', (53, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('suppresses', 'NegReg', (76, 86))	('apoptosis', 'CPA', (166, 175))	('doxorubicin', 'Chemical', 'MESH:D004317', (201, 212))	('enhancement', 'PosReg', (151, 162))
93027	33886686	Furthermore, in combination with radiotherapy, OBP-301 adenoviral E1B inhibits the repair machinery for DNA double strand breaks, enhancing radiation-induced apoptosis.	('enhancing', 'PosReg', (130, 139))	('E1B', 'Gene', (66, 69))	('repair machinery for DNA double strand breaks', 'MPA', (83, 128))	('inhibits', 'NegReg', (70, 78))	('OBP-301', 'Var', (47, 54))	('radiation-induced apoptosis', 'CPA', (140, 167))	('OBP-301', 'Chemical', '-', (47, 54))	('E1B', 'Gene', '6080', (66, 69))
93028	33886686	However, whether OBP-301 can enhance the sensitivity to radiotherapy in STS remains unclear.	('STS', 'Phenotype', 'HP:0030448', (72, 75))	('sensitivity to radiotherapy', 'MPA', (41, 68))	('OBP-301', 'Var', (17, 24))	('enhance', 'PosReg', (29, 36))	('OBP-301', 'Chemical', '-', (17, 24))
93052	33886686	The secondary antibodies used were: horseradish peroxidase-conjugated antibodies against rabbit IgG (NA934; GE Healthcare) or mouse IgG (NA931; GE Healthcare).	('mouse', 'Species', '10090', (126, 131))	('IgG', 'Gene', '16059', (96, 99))	('NA931', 'Var', (137, 142))	('horseradish', 'Species', '3704', (36, 47))	('IgG', 'Gene', (96, 99))	('IgG', 'Gene', '16059', (132, 135))	('IgG', 'Gene', (132, 135))
93086	33886686	The combination of OBP-301 and ionizing radiation induced apoptosis (PARP cleavage) in SK-ES-1 and HT1080 cells, which was associated with the upregulation of E2F1 and downregulation of MCL1 (Fig 2C).	('E2F1', 'Protein', (159, 163))	('OBP-301', 'Var', (19, 26))	('OBP-301', 'Chemical', '-', (19, 26))	('upregulation', 'PosReg', (143, 155))	('downregulation', 'NegReg', (168, 182))	('apoptosis', 'CPA', (58, 67))	('MCL1', 'Gene', (186, 190))	('SK-ES-1', 'CellLine', 'CVCL:0627', (87, 94))
93087	33886686	MCL1 siRNA suppressed MCL1 expression and resulted in the enhancement of ionizing radiation-induced apoptosis in SK-ES-1 and HT1080 cells compared to control siRNA (Fig 2D).	('MCL1', 'Var', (0, 4))	('MCL1', 'Gene', (22, 26))	('ionizing radiation-induced apoptosis', 'CPA', (73, 109))	('SK-ES-1', 'CellLine', 'CVCL:0627', (113, 120))	('suppressed', 'NegReg', (11, 21))	('expression', 'MPA', (27, 37))	('enhancement', 'PosReg', (58, 69))
93100	33886686	The number of TUNEL-positive cells was significantly increased in combination therapy-treated SK-ES-1 tumors compared with mock or monotherapy-treated tumors (Fig 4C).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (102, 108))	('combination', 'Var', (66, 77))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('TUNEL-positive', 'Gene', (14, 28))	('increased', 'PosReg', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('SK-ES-1', 'CellLine', 'CVCL:0627', (94, 101))	('SK-ES-1', 'Gene', (94, 101))
93120	33886686	Similarly, it has been shown that MCL1 suppression with siRNA or antisense oligonucleotides enhances chemotherapy-induced apoptosis in human STS cells.	('antisense oligonucleotides', 'Var', (65, 91))	('enhances', 'PosReg', (92, 100))	('oligonucleotides', 'Chemical', 'MESH:D009841', (75, 91))	('MCL1', 'Gene', (34, 38))	('human', 'Species', '9606', (135, 140))	('chemotherapy-induced apoptosis', 'CPA', (101, 131))	('suppression', 'NegReg', (39, 50))	('STS', 'Phenotype', 'HP:0030448', (141, 144))
93126	33886686	In the present study, OBP-301 significantly enhanced the level of gammaH2AX in irradiated tumor cells both in vitro and in vivo, suggesting that OBP-301 has the potential to enhance ionizing radiation-induced DNA damage and thus the sensitivity to ionizing radiation.	('OBP-301', 'Chemical', '-', (145, 152))	('gammaH2AX', 'Gene', (66, 75))	('OBP-301', 'Chemical', '-', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('enhanced', 'PosReg', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('enhance ionizing radiation', 'Phenotype', 'HP:0011133', (174, 200))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (233, 266))	('gammaH2AX', 'Gene', '15270', (66, 75))	('ionizing radiation-induced DNA damage', 'MPA', (182, 219))	('enhance', 'PosReg', (174, 181))	('OBP-301', 'Var', (145, 152))
93130	33886686	Mattoo and colleagues have shown that knockdown of MCL1 by siRNA in human cancer cells, including osteosarcoma, increases gammaH2AX levels after irradiation via impairment of the homologous recombination pathway.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('human', 'Species', '9606', (68, 73))	('gammaH2AX', 'Gene', '15270', (122, 131))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('osteosarcoma', 'Disease', (98, 110))	('MCL1', 'Gene', (51, 55))	('homologous recombination pathway', 'Pathway', (179, 211))	('increases', 'PosReg', (112, 121))	('knockdown', 'Var', (38, 47))	('gammaH2AX', 'Gene', (122, 131))
93287	31239476	Of note, in the minority of cases with peritumoral lymphoid follicles, some cells inside these follicles stained for PD1 (supposedly T cells) and PD-L1 (supposedly dendritic cells) (Supplemental Fig.	('PD1', 'Protein', (117, 120))	('PD-L1', 'Var', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('stained', 'Reg', (105, 112))	('tumor', 'Disease', (43, 48))
93379	30903020	Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy.	('LPS malignancy', 'Disease', (94, 108))	('LPS', 'Phenotype', 'HP:0012034', (94, 97))	('SNAI2', 'Gene', '6591', (65, 70))	('SNAI2', 'Gene', (65, 70))	('mitigates', 'NegReg', (71, 80))	('Genetic depletion', 'Var', (0, 17))	('BET genes', 'Gene', (21, 30))	('LPS malignancy', 'Disease', 'MESH:C536528', (94, 108))
93392	30903020	Amplification of chromosome 12q13-15 and overexpression of CDK4 and MDM2 are prevalent in WDLPS and DDLPS patients, which has guided clinical investigation of MDM2 and CDK4 inhibitors.	('WDLPS', 'Disease', 'None', (90, 95))	('MDM2', 'Gene', (68, 72))	('CDK4', 'Gene', (59, 63))	('LPS', 'Disease', (92, 95))	('LPS', 'Disease', 'MESH:C536528', (102, 105))	('MDM2', 'Gene', '4193', (68, 72))	('LPS', 'Phenotype', 'HP:0012034', (102, 105))	('CDK4', 'Gene', '1019', (59, 63))	('LPS', 'Disease', 'MESH:C536528', (92, 95))	('WDLPS', 'Disease', (90, 95))	('prevalent', 'Reg', (77, 86))	('patients', 'Species', '9606', (106, 114))	('LPS', 'Phenotype', 'HP:0012034', (92, 95))	('CDK4', 'Gene', (168, 172))	('overexpression', 'PosReg', (41, 55))	('MDM2', 'Gene', (159, 163))	('Amplification', 'Var', (0, 13))	('LPS', 'Disease', (102, 105))	('CDK4', 'Gene', '1019', (168, 172))	('MDM2', 'Gene', '4193', (159, 163))
93393	30903020	Genomic rearrangements involving FUS-DDIT3 and EWSR1-DDIT3 translocations define MLPS subtype, which shows the highest response rate and survival benefit from Trabectedin treatment.	('MLPS', 'Disease', 'None', (81, 85))	('EWSR1', 'Gene', '2130', (47, 52))	('DDIT3', 'Gene', (37, 42))	('MLPS', 'Disease', (81, 85))	('DDIT3', 'Gene', (53, 58))	('FUS', 'Gene', (33, 36))	('Trabectedin', 'Chemical', 'MESH:D000077606', (159, 170))	('LPS', 'Phenotype', 'HP:0012034', (82, 85))	('FUS', 'Gene', '2521', (33, 36))	('DDIT3', 'Gene', '1649', (53, 58))	('EWSR1', 'Gene', (47, 52))	('DDIT3', 'Gene', '1649', (37, 42))	('translocations', 'Var', (59, 73))
93395	30903020	Trabectedin induces maturation of lipoblasts via inactivation of FUS-DDIT3 in MLPS.	('DDIT3', 'Gene', (69, 74))	('FUS', 'Gene', '2521', (65, 68))	('MLPS', 'Disease', (78, 82))	('DDIT3', 'Gene', '1649', (69, 74))	('Trabectedin', 'Chemical', 'MESH:D000077606', (0, 11))	('MLPS', 'Disease', 'None', (78, 82))	('inactivation', 'Var', (49, 61))	('lipoblasts', 'CPA', (34, 44))	('maturation', 'CPA', (20, 30))	('induces', 'Reg', (12, 19))	('LPS', 'Phenotype', 'HP:0012034', (79, 82))	('FUS', 'Gene', (65, 68))
93396	30903020	Aberrant DNA methylation and histone modifications have also been implicated in liposarcomagenesis.	('Aberrant', 'Var', (0, 8))	('liposarcoma', 'Phenotype', 'HP:0012034', (80, 91))	('histone', 'Protein', (29, 36))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Disease', (84, 91))	('DNA', 'Protein', (9, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('implicated', 'Reg', (66, 76))
93397	30903020	Promoter hyper-methylation silences the expression of master pro-adipogenic TFs: CEBPA and KLF4.	('expression', 'MPA', (40, 50))	('silences', 'NegReg', (27, 35))	('KLF4', 'Gene', (91, 95))	('KLF4', 'Gene', '9314', (91, 95))	('CEBPA', 'Gene', (81, 86))	('Promoter hyper-methylation', 'Var', (0, 26))	('CEBPA', 'Gene', '1050', (81, 86))
93399	30903020	To date, tremendous efforts have been made to determine genomic and epigenetic defects that block terminal differentiation of high-grade LPS, whereas the feed-forward transcriptional regulatory mechanism that reinforces and stabilizes the malignant characteristics remains unexplored.	('LPS', 'Disease', 'MESH:C536528', (137, 140))	('epigenetic defects', 'Var', (68, 86))	('block', 'NegReg', (92, 97))	('terminal differentiation', 'CPA', (98, 122))	('LPS', 'Phenotype', 'HP:0012034', (137, 140))	('LPS', 'Disease', (137, 140))
93402	30903020	As little is known about enhancer dysregulation in liposarcomagenesis, uncovering the SE architectures will be important to improve the current understanding of epigenetic mechanism underlying LPS malignancy.	('SE', 'Chemical', '-', (86, 88))	('liposarcoma', 'Phenotype', 'HP:0012034', (51, 62))	('sarcoma', 'Disease', (55, 62))	('dysregulation', 'Var', (34, 47))	('LPS', 'Phenotype', 'HP:0012034', (193, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('LPS malignancy', 'Disease', (193, 207))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('LPS malignancy', 'Disease', 'MESH:C536528', (193, 207))
93418	30903020	Moreover, nearly 60% of FUS-DDIT3 peaks were mapped to putative enhancers, including 97% of H3K27ac-defined SEs and 62% of typical enhancers.	('SEs', 'Chemical', '-', (108, 111))	('DDIT3', 'Gene', '1649', (28, 33))	('H3K27ac-defined', 'Var', (92, 107))	('FUS', 'Gene', (24, 27))	('DDIT3', 'Gene', (28, 33))	('FUS', 'Gene', '2521', (24, 27))
93426	30903020	Silencing of BET genes resembled partially the regulatory effect of FUS-DDIT3 knockdown on downstream targets (Fig.	('DDIT3', 'Gene', (72, 77))	('DDIT3', 'Gene', '1649', (72, 77))	('knockdown', 'Var', (78, 87))	('FUS', 'Gene', (68, 71))	('BET genes', 'Gene', (13, 22))	('FUS', 'Gene', '2521', (68, 71))	('Silencing', 'Var', (0, 9))
93427	30903020	Altogether, our data reveal that FUS-DDIT3 and BET proteins cooperate to regulate expression of SE-associated genes in MLPS, and support the notion that fusion TFs hijack BET proteins for malignant transformation.	('BET proteins', 'Protein', (171, 183))	('SE', 'Chemical', '-', (96, 98))	('expression', 'MPA', (82, 92))	('DDIT3', 'Gene', (37, 42))	('TFs', 'Gene', (160, 163))	('MLPS', 'Disease', (119, 123))	('LPS', 'Phenotype', 'HP:0012034', (120, 123))	('FUS', 'Gene', (33, 36))	('FUS', 'Gene', '2521', (33, 36))	('regulate', 'Reg', (73, 81))	('SE-associated genes', 'Gene', (96, 115))	('fusion', 'Var', (153, 159))	('hijack', 'PosReg', (164, 170))	('DDIT3', 'Gene', '1649', (37, 42))	('malignant transformation', 'CPA', (188, 212))	('MLPS', 'Disease', 'None', (119, 123))
93432	30903020	Silencing of core TFs diminished expression of each other, which was also observed by depletion of CBFB, the heterodimeric subunit for RUNX proteins (Fig.	('diminished', 'NegReg', (22, 32))	('TFs', 'Gene', (18, 21))	('CBFB', 'Gene', '865', (99, 103))	('expression', 'MPA', (33, 43))	('depletion', 'NegReg', (86, 95))	('Silencing', 'Var', (0, 9))	('CBFB', 'Gene', (99, 103))
93433	30903020	Importantly, silencing of individual core TFs and CBFB attenuated cell viability, clonogenic growth and tumorigenicity of DDLPS cells (Fig.	('clonogenic growth', 'CPA', (82, 99))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('LPS', 'Phenotype', 'HP:0012034', (124, 127))	('TFs', 'Gene', (42, 45))	('LPS', 'Disease', (124, 127))	('cell viability', 'CPA', (66, 80))	('attenuated', 'NegReg', (55, 65))	('CBFB', 'Gene', '865', (50, 54))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('LPS', 'Disease', 'MESH:C536528', (124, 127))	('CBFB', 'Gene', (50, 54))	('silencing', 'Var', (13, 22))
93443	30903020	Inhibition of BET bromodomains has been shown to impair the expression and/or activity of key oncogenic TFs (e.g., MYC, and PAX3-FOXO1).	('expression', 'MPA', (60, 70))	('FOXO1', 'Gene', (129, 134))	('impair', 'NegReg', (49, 55))	('MYC', 'Gene', (115, 118))	('MYC', 'Gene', '4609', (115, 118))	('Inhibition', 'Var', (0, 10))	('PAX3', 'Gene', '5077', (124, 128))	('activity', 'MPA', (78, 86))	('PAX3', 'Gene', (124, 128))	('FOXO1', 'Gene', '2308', (129, 134))	('bromodomains', 'Protein', (18, 30))
93449	30903020	Silencing of BET genes also retarded subcutaneous tumor formation in a DDLPS model (Fig.	('retarded subcutaneous tumor', 'Disease', (28, 55))	('LPS', 'Phenotype', 'HP:0012034', (73, 76))	('LPS', 'Disease', (73, 76))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (37, 55))	('LPS', 'Disease', 'MESH:C536528', (73, 76))	('BET genes', 'Gene', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Silencing', 'Var', (0, 9))	('retarded subcutaneous tumor', 'Disease', 'MESH:D013352', (28, 55))
93450	30903020	Similarly, depletion of BET genes prolonged the tumor-free survival of recipient mice in a MLPS model, with BRD4 knockdown reducing both incidence and burden of tumor (Fig.	('depletion', 'MPA', (11, 20))	('reducing', 'NegReg', (123, 131))	('mice', 'Species', '10090', (81, 85))	('tumor', 'Disease', (48, 53))	('prolonged', 'PosReg', (34, 43))	('MLPS', 'Disease', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('knockdown', 'Var', (113, 122))	('BET genes', 'Gene', (24, 33))	('LPS', 'Phenotype', 'HP:0012034', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('BRD4', 'Gene', (108, 112))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('MLPS', 'Disease', 'None', (91, 95))
93452	30903020	BET proteins not only bound active promoters that are positive for RNA-Pol2, H3K4me3 and H3K27ac, but also marked actively transcribed genes, including all core TFs and SNAI2 (Fig.	('marked', 'Reg', (107, 113))	('actively transcribed', 'MPA', (114, 134))	('SNAI2', 'Gene', '6591', (169, 174))	('SNAI2', 'Gene', (169, 174))	('H3K27ac', 'Var', (89, 96))	('H3K4me3', 'Var', (77, 84))
93461	30903020	ARV-825 triggered more prominent inhibition of cell cycle progression, BrdU incorporation, and anchorage-independent growth of LPS cells, relative to equimolar BBI OTX015 (Fig.	('ARV-825', 'Chemical', 'MESH:C000606252', (0, 7))	('BrdU', 'Chemical', 'MESH:D001973', (71, 75))	('LPS', 'Disease', 'MESH:C536528', (127, 130))	('anchorage-independent growth', 'CPA', (95, 123))	('BrdU incorporation', 'CPA', (71, 89))	('inhibition', 'NegReg', (33, 43))	('ARV-825', 'Var', (0, 7))	('cell cycle progression', 'CPA', (47, 69))	('LPS', 'Phenotype', 'HP:0012034', (127, 130))	('LPS', 'Disease', (127, 130))
93464	30903020	Mechanistically, ARV-825 induced a selective and efficient depletion of BET proteins, in contrast to the competitive interference of BET chromatin loading by OTX015 (Fig.	('BET proteins', 'Protein', (72, 84))	('depletion', 'MPA', (59, 68))	('ARV-825', 'Var', (17, 24))	('ARV-825', 'Chemical', 'MESH:C000606252', (17, 24))
93466	30903020	Genetic silencing of CRBN restored growth of LPS cells even in the presence of ARV-825, which was also phenocopied by disruption of the CRLCRBN complex via depletion of either RBX1 or DDB1 (Fig.	('CRBN', 'Gene', '51185', (21, 25))	('disruption', 'Var', (118, 128))	('restored', 'PosReg', (26, 34))	('ARV-825', 'Chemical', 'MESH:C000606252', (79, 86))	('Genetic silencing', 'Var', (0, 17))	('ARV-825', 'Gene', (79, 86))	('CRBN', 'Gene', (21, 25))	('LPS', 'Disease', 'MESH:C536528', (45, 48))	('RBX1', 'Gene', '9978', (176, 180))	('DDB1', 'Gene', '1642', (184, 188))	('LPS', 'Phenotype', 'HP:0012034', (45, 48))	('DDB1', 'Gene', (184, 188))	('CRBN', 'Gene', '51185', (139, 143))	('RBX1', 'Gene', (176, 180))	('CRBN', 'Gene', (139, 143))	('growth', 'MPA', (35, 41))	('depletion', 'NegReg', (156, 165))	('LPS', 'Disease', (45, 48))
93474	30903020	Meanwhile, ARV-825 suppressed preferentially the transcription of SE-associated genes, including FOSL2, MYC, and SNAI2, to a greater extent than OTX015 (Fig.	('SNAI2', 'Gene', '6591', (113, 118))	('SNAI2', 'Gene', (113, 118))	('suppressed', 'NegReg', (19, 29))	('MYC', 'Gene', (104, 107))	('FOSL2', 'Gene', '2355', (97, 102))	('transcription', 'MPA', (49, 62))	('SE-associated genes', 'Gene', (66, 85))	('MYC', 'Gene', '4609', (104, 107))	('ARV-825', 'Chemical', 'MESH:C000606252', (11, 18))	('ARV-825', 'Var', (11, 18))	('FOSL2', 'Gene', (97, 102))	('SE', 'Chemical', '-', (66, 68))
93478	30903020	Remarkably, both ARV-825 and OTX015 elicited a transcriptional signature of Trabectedin response, which has been attributed to the interruption of FUS-DDIT3 function in MLPS (Fig.	('OTX015', 'Var', (29, 35))	('MLPS', 'Disease', (169, 173))	('ARV-825', 'Chemical', 'MESH:C000606252', (17, 24))	('Trabectedin', 'Chemical', 'MESH:D000077606', (76, 87))	('DDIT3', 'Gene', '1649', (151, 156))	('MLPS', 'Disease', 'None', (169, 173))	('LPS', 'Phenotype', 'HP:0012034', (170, 173))	('FUS', 'Gene', (147, 150))	('elicited', 'Reg', (36, 44))	('ARV-825', 'Var', (17, 24))	('transcriptional', 'MPA', (47, 62))	('FUS', 'Gene', '2521', (147, 150))	('DDIT3', 'Gene', (151, 156))
93489	30903020	The de novo SEs in LPS are likely associated with transformation, such as MYC, JUN, and CDK6.	('associated', 'Reg', (34, 44))	('CDK6', 'Gene', (88, 92))	('MYC', 'Gene', '4609', (74, 77))	('CDK6', 'Gene', '1021', (88, 92))	('JUN', 'Disease', (79, 82))	('SEs', 'Var', (12, 15))	('SEs', 'Chemical', '-', (12, 15))	('LPS', 'Disease', (19, 22))	('LPS', 'Phenotype', 'HP:0012034', (19, 22))	('MYC', 'Gene', (74, 77))	('LPS', 'Disease', 'MESH:C536528', (19, 22))
93494	30903020	Either inhibition of BET protein activity or depletion of BET proteins consistently attenuated the fusion-dependent gene expression in the respective sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('BET proteins', 'Protein', (58, 70))	('BET protein', 'Protein', (21, 32))	('activity', 'MPA', (33, 41))	('attenuated', 'NegReg', (84, 94))	('sarcoma', 'Disease', (150, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('fusion-dependent gene', 'Gene', (99, 120))	('depletion', 'Var', (45, 54))	('inhibition', 'NegReg', (7, 17))
93496	30903020	As both FUS-DDIT3 and EWSR1-associated fusions involve the N-terminal domains of their respective FET proteins, exploration of whether these fusions show similar dependency on their N-terminus to recruit additional key co-factors such like FOXQ1 and BAF complex would be of interest.	('FUS', 'Gene', (8, 11))	('EWSR1', 'Gene', '2130', (22, 27))	('FUS', 'Gene', '2521', (8, 11))	('FOXQ1', 'Gene', '94234', (240, 245))	('DDIT3', 'Gene', (12, 17))	('fusions', 'Var', (39, 46))	('FOXQ1', 'Gene', (240, 245))	('involve', 'Reg', (47, 54))	('BAF', 'Gene', '8815', (250, 253))	('EWSR1', 'Gene', (22, 27))	('DDIT3', 'Gene', '1649', (12, 17))	('BAF', 'Gene', (250, 253))
93508	30903020	Despite different mechanisms, both ARV-825 and dBET6 attenuated the expression of RUNX1 protein.	('expression', 'MPA', (68, 78))	('dBET6', 'Var', (47, 52))	('RUNX1', 'Gene', (82, 87))	('attenuated', 'NegReg', (53, 63))	('RUNX1', 'Gene', '861', (82, 87))	('protein', 'Protein', (88, 95))	('ARV-825', 'Var', (35, 42))	('ARV-825', 'Chemical', 'MESH:C000606252', (35, 42))
93533	30903020	Plasmids expressing GFP-tagged BET proteins, and FUS-DDIT3 were gifts from Drs.	('DDIT3', 'Gene', (53, 58))	('GFP-tagged', 'Var', (20, 30))	('DDIT3', 'Gene', '1649', (53, 58))	('FUS', 'Gene', (49, 52))	('FUS', 'Gene', '2521', (49, 52))
93566	30903020	M2 Sepharose beads (Sigma-Aldrich), GFP-Trap  beads (ChromoTek), and Pierce  Anti-HA Agarose (Thermo Fisher Scientific) were used for IP of proteins with FLAG-Tag, GFP-Tag, or HA-Tag, respectively.	('Sepharose', 'Chemical', 'MESH:D012685', (3, 12))	('HA-Tag', 'Var', (176, 182))	('Agarose', 'Chemical', 'MESH:D012685', (85, 92))	('GFP-Tag', 'Var', (164, 171))	('FLAG-Tag', 'Var', (154, 162))
93574	30903020	Average signal was estimated and plotted in R. ChIP-seq data of adipocytes (GSE59703; sequence length = 50) and mesenchymal stem cells (GSE16256; sequence length = 36) have been published previously.	('GSE16256;', 'Var', (136, 145))	('SE', 'Chemical', '-', (137, 139))	('GSE59703;', 'Var', (76, 85))	('SE', 'Chemical', '-', (77, 79))
93587	30903020	; Investigation: Y.C., L.X., A.M., M.-L.H., D.K., T.Z.T., P.D., R.Y.-T.L., X.-Y.K., J.W.S., J.C., L.-W.D., Y.-Y.J.	('R.Y.-T.L.', 'Var', (64, 73))	('L.-W.D.', 'Var', (98, 105))	('X.-Y.K.', 'Var', (75, 82))	('Z.T', 'CellLine', 'CVCL:J056', (52, 55))	('P.D.', 'Var', (58, 62))
93588	30903020	; Writing-review and editing: Y.C., L.X., A.M., T.Z.T.	('Y.C.', 'Var', (30, 34))	('A.M.', 'Var', (42, 46))	('Z.T', 'CellLine', 'CVCL:J056', (50, 53))
93591	30903020	cDNA microarray data (GSE21122) of LPS and control normal fat specimens, and ChIP-seq data of adipocytes (GSE59703) and mesenchymal stem cells (GSE16256) are available from NCBI GEO.	('LPS', 'Disease', (35, 38))	('SE', 'Chemical', '-', (145, 147))	('GSE21122', 'Var', (22, 30))	('LPS', 'Disease', 'MESH:C536528', (35, 38))	('SE', 'Chemical', '-', (23, 25))	('SE', 'Chemical', '-', (107, 109))	('LPS', 'Phenotype', 'HP:0012034', (35, 38))
93594	27334220	We investigated how alterations in the cyclin D1-CDK4/6-Rb axis impact prognosis and studied effects of targeting this axis with the CDK4/6 inhibitor palbociclib.	('alterations', 'Var', (20, 31))	('impact', 'Reg', (64, 70))	('prognosis', 'CPA', (71, 80))	('palbociclib', 'Chemical', 'MESH:C500026', (150, 161))	('Rb', 'Gene', '5925', (56, 58))
93610	27334220	Deregulated expression via mutations, gene rearrangements, or amplification of CCND1 has been reported in various cancer types.	('mutations', 'Var', (27, 36))	('CCND1', 'Gene', '595', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('gene rearrangements', 'Var', (38, 57))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('CCND1', 'Gene', (79, 84))	('Deregulated expression', 'MPA', (0, 22))	('amplification', 'Var', (62, 75))	('reported', 'Reg', (94, 102))	('cancer', 'Disease', (114, 120))
93611	27334220	Also alterations of other proteins involved in the cyclin D1-CDK4/6-Rb axis (e.g., p16, retinoblastoma (Rb) protein, and p21) may lead to uncontrolled progression through the cell cycle.	('p21', 'Gene', '1026', (121, 124))	('lead to', 'Reg', (130, 137))	('protein', 'Protein', (108, 115))	('p21', 'Gene', (121, 124))	('p16, retinoblastoma (Rb', 'Gene', (83, 106))	('Rb', 'Gene', '5925', (68, 70))	('alterations', 'Var', (5, 16))	('uncontrolled progression through the cell cycle', 'CPA', (138, 185))	('retinoblastoma', 'Phenotype', 'HP:0009919', (88, 102))	('Rb', 'Gene', '5925', (104, 106))	('p16, retinoblastoma (Rb)', 'Gene', '1029;5925', (83, 107))
93615	27334220	Indeed, this "cellular dedifferentiation" pathway is constitutively active in a SYT-SSX2 transgenic mouse model, with corresponding cyclin D1 expression, and inhibition of Wnt signaling through functional knock-out of the beta-catenin gene reduced tumor formation.	('SSX2', 'Gene', '6757', (84, 88))	('reduced', 'NegReg', (240, 247))	('tumor', 'Disease', (248, 253))	('SYT', 'Gene', (80, 83))	('knock-out', 'Var', (205, 214))	('mouse', 'Species', '10090', (100, 105))	('inhibition', 'Var', (158, 168))	('SSX2', 'Gene', (84, 88))	('beta-catenin', 'Gene', (222, 234))	('SYT', 'Gene', '268996', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('expression', 'MPA', (142, 152))	('cyclin', 'MPA', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
93617	27334220	In vitro, PI3K inhibition resulted in decreased cell proliferation, which was linked to reduced cyclin D1 and increased levels of p27.	('decreased', 'NegReg', (38, 47))	('p27', 'Gene', '3429', (130, 133))	('p27', 'Gene', (130, 133))	('increased', 'PosReg', (110, 119))	('reduced', 'NegReg', (88, 95))	('cell proliferation', 'CPA', (48, 66))	('levels', 'MPA', (120, 126))	('PI3K', 'Gene', (10, 14))	('cyclin D1', 'MPA', (96, 105))	('inhibition', 'Var', (15, 25))
93620	27334220	Additionally, heterozygous loss of p16 has been reported in SyS tumors, and recently we reported the occurrence of a CCND1 mutation with additional nuclear overexpression of cyclin D1 in a patient sample.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('p16', 'Gene', '1029', (35, 38))	('mutation', 'Var', (123, 131))	('SyS', 'Phenotype', 'HP:0012570', (60, 63))	('heterozygous', 'Var', (14, 26))	('CCND1', 'Gene', '595', (117, 122))	('reported', 'Reg', (48, 56))	('p16', 'Gene', (35, 38))	('patient', 'Species', '9606', (189, 196))	('SyS tumors', 'Disease', 'MESH:D009369', (60, 70))	('SyS tumors', 'Disease', (60, 70))	('CCND1', 'Gene', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
93637	27334220	The 2 patient-derived SyS cell lines harboring the SSX1 translocation (Yamato-SS and Aska-SS) were generously provided by K. Itoh.	('SyS', 'Phenotype', 'HP:0012570', (22, 25))	('SSX1', 'Gene', '6756', (51, 55))	('patient', 'Species', '9606', (6, 13))	('translocation', 'Var', (56, 69))	('SSX1', 'Gene', (51, 55))
93653	27334220	The known CTNNB1 G34L mutation was verified in the SYO-1 cell line.	('G34L', 'Var', (17, 21))	('SYO-1', 'Gene', '55027', (51, 56))	('SYO-1', 'Gene', (51, 56))	('CTNNB1', 'Gene', (10, 16))	('G34L', 'Mutation', 'p.G34L', (17, 21))	('CTNNB1', 'Gene', '1499', (10, 16))
93663	27334220	FISH analysis showed sporadic breakage, in 10-20 % of the cells, of CCND1 in 15 % of the patient samples.	('CCND1', 'Gene', '595', (68, 73))	('patient', 'Species', '9606', (89, 96))	('breakage', 'Var', (30, 38))	('CCND1', 'Gene', (68, 73))
93665	27334220	The known CTNNB1 G34L mutation was confirmed in the SYO-1 cell line.	('SYO-1', 'Gene', '55027', (52, 57))	('G34L', 'Var', (17, 21))	('SYO-1', 'Gene', (52, 57))	('CTNNB1', 'Gene', (10, 16))	('G34L', 'Mutation', 'p.G34L', (17, 21))	('CTNNB1', 'Gene', '1499', (10, 16))
93666	27334220	The Yamato-SS cell line harbored a homozygous TP53 mutation in exon 8 (c.817C > T/p.R273C, rs121913343).	('rs121913343', 'Mutation', 'rs121913343', (91, 102))	('p.R273C', 'Mutation', 'rs121913343', (82, 89))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('rs121913343', 'Var', (91, 102))	('c.817C > T/p.R273C', 'Var', (71, 89))	('c.817C > T', 'Mutation', 'rs121913343', (71, 81))
93667	27334220	This deactivating TP53 mutation could explain the lack of downstream target p21 found by western blot.	('deactivating', 'Reg', (5, 17))	('TP53', 'Gene', '7157', (18, 22))	('mutation', 'Var', (23, 31))	('p21', 'Gene', '1026', (76, 79))	('p21', 'Gene', (76, 79))	('TP53', 'Gene', (18, 22))
93680	27334220	Here, we used patient tumor samples and 4 SyS cell lines to evaluate genetic alterations of CCND1 and the expression patterns of the proteins playing a possible role in deregulation of this axis (Fig.	('genetic alterations', 'Var', (69, 88))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('CCND1', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('patient', 'Species', '9606', (14, 21))	('tumor', 'Disease', (22, 27))	('SyS', 'Phenotype', 'HP:0012570', (42, 45))	('CCND1', 'Gene', '595', (92, 97))
93681	27334220	We showed CCND1 amplification in a SyS cell line and CCND1 rearrangement in a small percentage of cells in a subset of patient samples, although possible fusion partners and the significance of these rearrangements in a small subset of tumor cells remain elusive.	('CCND1', 'Gene', '595', (10, 15))	('patient', 'Species', '9606', (119, 126))	('CCND1', 'Gene', (53, 58))	('rearrangement', 'Var', (59, 72))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('CCND1', 'Gene', (10, 15))	('SyS', 'Phenotype', 'HP:0012570', (35, 38))	('tumor', 'Disease', (236, 241))	('CCND1', 'Gene', '595', (53, 58))
93685	27334220	Interestingly, previous studies showed that palbociclib was considerably less active in a number of non-synovial soft tissue sarcoma cell lines (IC50 values of 8.95-26.63 microM), suggesting that an aberrant cyclin D1-CDK4/6-Rb axis is a specific feature for the SyS subtype of soft tissue sarcomas.	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('SyS subtype', 'Disease', (263, 274))	('Rb', 'Gene', '5925', (225, 227))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (278, 298))	('soft tissue sarcomas', 'Disease', (278, 298))	('SyS', 'Phenotype', 'HP:0012570', (263, 266))	('sarcoma', 'Disease', 'MESH:D012509', (290, 297))	('aberrant', 'Var', (199, 207))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (113, 132))	('sarcoma', 'Disease', (125, 132))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (278, 297))	('sarcomas', 'Phenotype', 'HP:0100242', (290, 298))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('sarcoma', 'Disease', (290, 297))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (278, 298))	('palbociclib', 'Chemical', 'MESH:C500026', (44, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))
93688	27334220	SV40 large T antigen also affects Rb activity, which leads to a bypassing of the G1/S checkpoint with a resulting constitutive activation of the cell cycle.	('affects', 'Reg', (26, 33))	('G1/S checkpoint', 'Pathway', (81, 96))	('cell cycle', 'CPA', (145, 155))	('bypassing', 'MPA', (64, 73))	('Rb', 'Gene', '5925', (34, 36))	('activity', 'MPA', (37, 45))	('activation', 'PosReg', (127, 137))	('SV40', 'Var', (0, 4))
93714	25538264	The 1G4-alpha95:LY TCR that recognizes amino acids 157-165 of the NY-ESO-1 protein (NY-ESO-1:157-165) in the context of the HLA-A*0201 class I restriction element was cloned into the MSGV1 retroviral vector backbone as previously described.	('TCR', 'Gene', '6962', (19, 22))	('NY-ESO-1', 'Gene', (66, 74))	('amino acids 157-165', 'Var', (39, 58))	('NY-ESO-1', 'Gene', '246100', (66, 74))	('NY-ESO-1', 'Gene', (84, 92))	('TCR', 'Gene', (19, 22))	('NY-ESO-1', 'Gene', '246100', (84, 92))	('HLA-A', 'Gene', '3105', (124, 129))	('HLA-A', 'Gene', (124, 129))
93715	25538264	The 1G4-alpha95:LY TCR contained two amino acid substitutions in the third complementarity determining region of the native 1G4 TCR alpha chain that specifically enhanced the ability of transduced CD8+ and CD4+ T cells to recognize HLA-A*0201+ and NY-ESO-1+ target cells.	('TCR', 'Gene', (128, 131))	('substitutions', 'Var', (48, 61))	('TCR', 'Gene', '6962', (19, 22))	('NY-ESO-1', 'Gene', (248, 256))	('CD8', 'Gene', '925', (197, 200))	('CD4', 'Gene', (206, 209))	('NY-ESO-1', 'Gene', '246100', (248, 256))	('HLA-A', 'Gene', (232, 237))	('CD4', 'Gene', '920', (206, 209))	('ability', 'MPA', (175, 182))	('TCR', 'Gene', (19, 22))	('enhanced', 'PosReg', (162, 170))	('TCR', 'Gene', '6962', (128, 131))	('CD8', 'Gene', (197, 200))	('HLA-A', 'Gene', '3105', (232, 237))
93725	25538264	Responses to a first treatment with the 1G4-alphaLY TCR are shown with the exception of patient 2, who exhibited a partial response lasting 6 months to an initial infusion of TCR-transduced T cells, as well as a partial response lasting 9 months following a second infusion of a similar T cell product, for a total combined response of 18 months following the initial treatment (Table 2).	('patient', 'Species', '9606', (88, 95))	('1G4-alphaLY', 'Var', (40, 51))	('TCR', 'Gene', (52, 55))	('TCR', 'Gene', '6962', (175, 178))	('TCR', 'Gene', (175, 178))	('TCR', 'Gene', '6962', (52, 55))
93785	25538264	In a recent clinical trial, the adoptive transfer of autologous PBMC transduced with a MAGE-A3-reactive TCR resulted in the deaths of two patients due to severe neurological toxicity.	('TCR', 'Gene', (104, 107))	('neurological toxicity', 'Disease', 'MESH:D020258', (161, 182))	('MAGE-A3', 'Gene', (87, 94))	('neurological toxicity', 'Disease', (161, 182))	('TCR', 'Gene', '6962', (104, 107))	('transduced', 'Var', (69, 79))	('death', 'Disease', 'MESH:D003643', (124, 129))	('MAGE-A3', 'Gene', '4102', (87, 94))	('death', 'Disease', (124, 129))	('patients', 'Species', '9606', (138, 146))
93787	25538264	In addition, the adoptive transfer of autologous PBMC transduced with an HLA-A1 restricted, MAGE-A3-reactive TCR containing four alpha chain amino acid substitutions that were introduced to enhance antigen recognition resulted in cardiac arrest and the deaths of the first two patients treated on this protocol, which were attributed to cross-reactivity of TCR-transduced T cells with an epitope of titin, a protein that is highly expressed in cardiac tissue.	('cardiac arrest', 'Disease', (230, 244))	('TCR', 'Gene', '6962', (357, 360))	('patients', 'Species', '9606', (277, 285))	('enhance', 'PosReg', (190, 197))	('HLA-A', 'Gene', '3105', (73, 78))	('cardiac arrest', 'Phenotype', 'HP:0001695', (230, 244))	('death', 'Disease', (253, 258))	('TCR', 'Gene', '6962', (109, 112))	('TCR', 'Gene', (357, 360))	('titin', 'Gene', '7273', (399, 404))	('resulted in', 'Reg', (218, 229))	('MAGE-A3', 'Gene', '4102', (92, 99))	('TCR', 'Gene', (109, 112))	('titin', 'Gene', (399, 404))	('cardiac arrest', 'Disease', 'MESH:D006323', (230, 244))	('death', 'Disease', 'MESH:D003643', (253, 258))	('HLA-A', 'Gene', (73, 78))	('substitutions', 'Var', (152, 165))	('MAGE-A3', 'Gene', (92, 99))
93789	25538264	An overall clinical response rate of approximately 10% was observed in melanoma patients who received an antibody directed against the inhibitory receptor CTLA-4, and objective response rates of between 20 and 30% were seen in patients with melanoma, renal and non-small-cell lung cancer treated with BMS-936558, an antibody against the PD-1 checkpoint inhibitor.	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('melanoma', 'Disease', (241, 249))	('renal', 'Disease', (251, 256))	('patients', 'Species', '9606', (80, 88))	('CTLA-4', 'Gene', (155, 161))	('antibody', 'Var', (105, 113))	('lung cancer', 'Disease', 'MESH:D008175', (276, 287))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('lung cancer', 'Disease', (276, 287))	('lung cancer', 'Phenotype', 'HP:0100526', (276, 287))	('patients', 'Species', '9606', (227, 235))
93792	25538264	Combinations of checkpoint inhibitors with adoptive immunotherapies represents one strategy that may lead to enhanced anti-tumor responses, although a series of trials may be needed to determine the optimal dosage of checkpoint inhibitors and the appropriate sequencing of these treatments.	('tumor', 'Disease', (123, 128))	('Combinations', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('enhanced', 'PosReg', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
93801	25057021	Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma Ewing sarcoma is an aggressive pediatric bone cancer.	('aggressive pediatric bone cancer', 'Disease', 'MESH:D001859', (162, 194))	('cell adhesion', 'CPA', (111, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (142, 155))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (142, 155))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('actin cytoskeletal', 'MPA', (78, 96))	('EWS', 'Gene', '14030', (47, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('aggressive pediatric bone cancer', 'Disease', (162, 194))	('Ewing sarcoma', 'Disease', (142, 155))	('FLI', 'Gene', (51, 54))	('Ewing sarcoma', 'Disease', (128, 141))	('EWS', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('FLI', 'Gene', '2314', (51, 54))	('compromises', 'NegReg', (66, 77))	('expression', 'Var', (55, 65))
93806	25057021	Silencing of EWS/FLI in patient-derived tumor cells results in the altered expression of hundreds to thousands of genes and is accompanied by dramatic morphological changes in cytoarchitecture and adhesion.	('FLI', 'Gene', '2314', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('FLI', 'Gene', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('adhesion', 'CPA', (197, 205))	('patient', 'Species', '9606', (24, 31))	('changes', 'Reg', (165, 172))	('altered', 'Reg', (67, 74))	('cytoarchitecture', 'CPA', (176, 192))	('tumor', 'Disease', (40, 45))	('Silencing', 'Var', (0, 9))	('expression', 'MPA', (75, 85))
93817	25057021	In ~85% of cases, a t(11;22)(q24;q12) translocation results in the expression of a chimeric transcription factor in which a strong transcription regulatory domain found in EWS is fused to a portion of FLI that includes a DNA-binding domain.	('t(11;22)(q24;q12', 'Var', (20, 36))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (20, 37))	('FLI', 'Gene', '2314', (201, 204))	('expression', 'MPA', (67, 77))	('FLI', 'Gene', (201, 204))	('results in', 'Reg', (52, 62))
93827	25057021	In theory, the aberrant regulation of adhesion genes by EWS/FLI could affect multiple stages of Ewing sarcoma metastasis: initial tumor cell release and dissemination, extravasation, and second-site adhesion/colonization.	('affect', 'Reg', (70, 76))	('tumor', 'Disease', (130, 135))	('extravasation', 'CPA', (168, 181))	('adhesion genes', 'Gene', (38, 52))	('FLI', 'Gene', (60, 63))	('Ewing sarcoma metastasis', 'Disease', 'MESH:C563168', (96, 120))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('second-site adhesion/colonization', 'CPA', (187, 220))	('aberrant regulation', 'Var', (15, 34))	('Ewing sarcoma metastasis', 'Disease', (96, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('FLI', 'Gene', '2314', (60, 63))
93833	25057021	In addition, our findings suggest that misregulation of genes within tumors can alternately provide selective advantages or disadvantages, depending on the specific context.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('misregulation', 'Var', (39, 52))
93834	25057021	Our results illustrate that not all gene expression changes that are promoted by transforming oncogenes are advantageous for all aspects of a tumor's life history, but instead that the changes may be enabling for one aspect, such as supporting anchorage-independent cell growth, even as they may compromise the ability of the tumor cells to establish colonies at second sites.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('anchorage-independent cell growth', 'CPA', (244, 277))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('changes', 'Var', (185, 192))	('tumor', 'Disease', (326, 331))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
93837	25057021	To circumvent this challenge, we studied how the EWS/FLI oncoprotein influences cellular behavior by using an RNA interference (RNAi) approach to knock down EWS/FLI expression in patient-derived Ewing sarcoma cells (A673 and EWS502).	('FLI', 'Gene', '2314', (53, 56))	('FLI', 'Gene', (53, 56))	('FLI', 'Gene', '2314', (161, 164))	('Ewing sarcoma', 'Disease', (195, 208))	('patient', 'Species', '9606', (179, 186))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (195, 208))	('influences', 'Reg', (69, 79))	('FLI', 'Gene', (161, 164))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (195, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('knock', 'Var', (146, 151))	('cellular', 'MPA', (80, 88))
93838	25057021	We used retrovirally encoded short hairpin RNA directed against EWS/FLI transcripts to knock down the expression of EWS/FLI (EWS/FLI RNAi), with RNAi against luciferase serving as our control RNAi, and compared the resulting alterations in cellular behavior.	('FLI', 'Gene', '2314', (68, 71))	('FLI', 'Gene', (129, 132))	('FLI', 'Gene', (68, 71))	('expression', 'MPA', (102, 112))	('FLI', 'Gene', '2314', (120, 123))	('FLI', 'Gene', (120, 123))	('knock', 'Var', (87, 92))	('FLI', 'Gene', '2314', (129, 132))
93842	25057021	In contrast, when EWS/FLI expression was knocked down by RNAi, the Ewing sarcoma cells underwent a dramatic morphological transformation in which they exhibited pronounced adhesion and spreading to the fibronectin substratum and displayed robust actin stress fibers.	('underwent', 'Reg', (87, 96))	('FLI', 'Gene', (22, 25))	('adhesion', 'CPA', (172, 180))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('spreading', 'CPA', (185, 194))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('actin stress fibers', 'CPA', (246, 265))	('knocked down', 'Var', (41, 53))	('fibronectin', 'Gene', '14268', (202, 213))	('FLI', 'Gene', '2314', (22, 25))	('fibronectin', 'Gene', (202, 213))	('Ewing sarcoma', 'Disease', (67, 80))
93873	25057021	Consistent with the findings with A673 cells, expression of zyxin and alpha5 integrin, alone or in combination, was also sufficient to enhance cell area of EWS502 Ewing sarcoma cells, and enhanced actin cytoskeletons and focal adhesions were prominently induced by expression of zyxin (Supplemental Figure S1).	('enhanced', 'PosReg', (188, 196))	('expression', 'Var', (46, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (163, 176))	('zyxin and alpha5', 'Gene', '7791', (60, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (163, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('actin cytoskeletons', 'CPA', (197, 216))	('Ewing sarcoma', 'Disease', (163, 176))	('enhance', 'PosReg', (135, 142))	('cell area of', 'CPA', (143, 155))	('focal adhesions', 'CPA', (221, 236))
93875	25057021	Of interest, Ewing sarcoma cells programmed to knock down EWS/FLI displayed an average cell area (~2200 mum2) that was indistinguishable from the average area of cells expressing either zyxin alone or in combination with alpha5 integrin, illustrating that reexpression of zyxin is sufficient to fully rescue the cell spreading deficit observed in Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (347, 360))	('Ewing sarcoma', 'Disease', (13, 26))	('cell spreading deficit', 'CPA', (312, 334))	('FLI', 'Gene', '2314', (62, 65))	('FLI', 'Gene', (62, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (353, 360))	('Ewing sarcoma', 'Disease', (347, 360))	('knock down', 'Var', (47, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (347, 360))
93878	25057021	Although Ewing sarcoma cells reexpressing zyxin also displayed increased cell adhesion by this assay, the effect was not as dramatic as in the case of alpha5 integrin expression (Figure 2L).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (9, 22))	('increased', 'PosReg', (63, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (9, 22))	('cell adhesion', 'CPA', (73, 86))	('zyxin', 'Var', (42, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('Ewing sarcoma', 'Disease', (9, 22))
93909	25057021	Consistent with our quantitative analysis of viable tumor cells by in vivo luciferase monitoring in Figure 4C, coexpression of zyxin and alpha5 integrin synergistically retards cell growth in soft agar.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cell growth in soft agar', 'CPA', (177, 201))	('tumor', 'Disease', (52, 57))	('retards', 'Disease', 'MESH:D008607', (169, 176))	('zyxin and alpha5', 'Gene', '7791', (127, 143))	('retards', 'Disease', (169, 176))	('coexpression', 'Var', (111, 123))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('agar', 'Chemical', 'MESH:D000362', (197, 201))
93934	25057021	Consistent with our findings that knockdown of EWS/FLI expression in Ewing sarcoma cells results in a dramatic alteration in cell adhesion and cytoarchitecture, analysis of the gene expression signature of EWS/FLI using a previously published microarray revealed that the most prominent down-regulated targets of EWS/FLI were focal adhesion proteins, ECM-receptor proteins, and regulators of the actin cytoskeleton.	('alteration', 'Reg', (111, 121))	('ECM-receptor proteins', 'Protein', (351, 372))	('FLI', 'Gene', '2314', (210, 213))	('focal adhesion proteins', 'Protein', (326, 349))	('FLI', 'Gene', '2314', (51, 54))	('Ewing sarcoma', 'Disease', (69, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('FLI', 'Gene', (51, 54))	('FLI', 'Gene', (210, 213))	('FLI', 'Gene', '2314', (317, 320))	('FLI', 'Gene', (317, 320))	('knockdown', 'Var', (34, 43))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (69, 82))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (69, 82))	('down-regulated', 'NegReg', (287, 301))
93942	25057021	Expression of alpha5beta1 integrin has been shown to promote the acquisition of fibroblast-like cell morphology, consistent with our findings that the loss of integrin expression appears to play a key role in the loss of mesenchymal phenotype that accompanies EWS/FLI-dependent transformation.	('integrin', 'Protein', (159, 167))	('loss', 'NegReg', (213, 217))	('FLI', 'Gene', '2314', (264, 267))	('alpha5beta1 integrin', 'Protein', (14, 34))	('FLI', 'Gene', (264, 267))	('acquisition of fibroblast-like cell morphology', 'CPA', (65, 111))	('loss', 'Var', (151, 155))	('promote', 'PosReg', (53, 60))
93945	25057021	Analysis of fibroblasts derived from mice in which the zyxin gene was disrupted revealed that spontaneous, strain-induced actin stress fiber breakage occurred with increased frequency.	('actin stress fiber breakage', 'Phenotype', 'HP:0025200', (122, 149))	('disrupted', 'Var', (70, 79))	('actin stress', 'Protein', (122, 134))	('zyxin', 'Gene', (55, 60))	('mice', 'Species', '10090', (37, 41))
93963	25057021	In contrast with the growth and survival advantage achieved in Ewing sarcoma cells that is conferred by reduced expression of zyxin and alpha5 integrin, these changes in gene expression were associated with compromised ability of the tumors to metastasize to the lung.	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('tumors', 'Disease', (234, 240))	('Ewing sarcoma', 'Disease', (63, 76))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('zyxin and alpha5', 'Gene', '7791', (126, 142))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('changes', 'Var', (159, 166))
93966	25057021	Consistent with our findings, a recent study of breast, kidney, and bladder tumor cells revealed that alpha5 integrin expression facilitates cancer cell adhesion and invasion.	('invasion', 'CPA', (166, 174))	('expression', 'Var', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('bladder tumor', 'Disease', (68, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('alpha5 integrin', 'Protein', (102, 117))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('bladder tumor', 'Disease', 'MESH:D001749', (68, 81))	('bladder tumor', 'Phenotype', 'HP:0009725', (68, 81))	('cancer', 'Disease', (141, 147))	('facilitates', 'PosReg', (129, 140))
94213	21808463	As far as concerns SS, 99% present an identifiable translocation between chromosome 18 and X that results in the fusion of the SYT genes located on chromosome 18 and the SSX-1 or SSX-2 gene on chromosome X.	('SSX-1', 'Gene', '6756', (170, 175))	('SYT', 'Gene', '6760', (127, 130))	('SSX-2', 'Gene', '6757', (179, 184))	('fusion', 'Var', (113, 119))	('SSX-2', 'Gene', (179, 184))	('SYT', 'Gene', (127, 130))	('SSX-1', 'Gene', (170, 175))
94230	30709875	LFS is related to germline mutations of the tumor-suppressor gene TP53.	('germline mutations', 'Var', (18, 36))	('LFS', 'Disease', (0, 3))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('related', 'Reg', (7, 14))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
94234	30709875	Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 gene mutations, first described in 1969 by Li and Fraumeni.	('men', 'Species', '9606', (165, 168))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('autosomal dominant cancer', 'Disease', (37, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('caused', 'Reg', (87, 93))	('mutations', 'Var', (116, 125))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (37, 62))	('men', 'Species', '9606', (7, 10))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
94250	30709875	The patient met Chompret criteria for LFS and underwent TP53 genetic testing, which revealed a pathogenic deletion of exons 10-11.	('TP53', 'Gene', '7157', (56, 60))	('LFS', 'Disease', (38, 41))	('pathogenic', 'Reg', (95, 105))	('patient', 'Species', '9606', (4, 11))	('TP53', 'Gene', (56, 60))	('deletion', 'Var', (106, 114))
94254	30709875	At age 40 yr, she was diagnosed with therapy-related AML (t-AML) with adverse cytogenetics (monosomal karyotype with extensive chromosomal abnormalities) and IDH2 mutation (Tables 3 and 4).	('AML', 'Disease', 'MESH:D015470', (60, 63))	('chromosomal abnormalities', 'Disease', (127, 152))	('AML', 'Disease', 'MESH:D015470', (53, 56))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (127, 152))	('AML', 'Disease', (53, 56))	('IDH2', 'Gene', (158, 162))	('AML', 'Phenotype', 'HP:0004808', (60, 63))	('AML', 'Disease', (60, 63))	('AML', 'Phenotype', 'HP:0004808', (53, 56))	('mutation', 'Var', (163, 171))	('IDH2', 'Gene', '3418', (158, 162))
94261	30709875	She was identified to have the familial TP53 nonsense mutation, c.184G>T (p.E62*).	('c.184G>T', 'Mutation', 'rs786201592', (64, 72))	('p.E62*', 'Mutation', 'rs786201592', (74, 80))	('c.184G>T', 'Var', (64, 72))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))
94266	30709875	Two years later, she was noted to have pancytopenia and was diagnosed with therapy-related MDS (t-MDS) with complex cytogenetics and dual TP53 mutations c.764T>C (p.I255T) and c.184G>T (p.E62*).	('c.764T>C', 'Var', (153, 161))	('c.184G>T', 'Var', (176, 184))	('TP53', 'Gene', '7157', (138, 142))	('p.I255T', 'Mutation', 'rs876659675', (163, 170))	('c.764T>C', 'Mutation', 'rs876659675', (153, 161))	('pancytopenia', 'Disease', 'MESH:D010198', (39, 51))	('MDS', 'Disease', (91, 94))	('TP53', 'Gene', (138, 142))	('MDS', 'Disease', 'MESH:D009190', (91, 94))	('MDS', 'Phenotype', 'HP:0002863', (91, 94))	('therapy-related', 'Disease', (75, 90))	('MDS', 'Phenotype', 'HP:0002863', (98, 101))	('MDS', 'Disease', (98, 101))	('MDS', 'Disease', 'MESH:D009190', (98, 101))	('pancytopenia', 'Phenotype', 'HP:0001876', (39, 51))	('p.E62*', 'Mutation', 'rs786201592', (186, 192))	('pancytopenia', 'Disease', (39, 51))	('c.184G>T', 'Mutation', 'rs786201592', (176, 184))
94273	30709875	The patient met criteria for LFS evaluation, and TP53 germline analysis was performed on cultured skin fibroblasts, which revealed two alterations, c.800G>A (p.R267Q) and c.467G>A (p.R156H), both clinically classified as variants of uncertain significance (VUS) (Table 4).	('p.R267Q', 'Mutation', 'rs587780075', (158, 165))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('c.800G>A', 'Var', (148, 156))	('c.467G>A', 'Mutation', 'rs371524413', (171, 179))	('patient', 'Species', '9606', (4, 11))	('p.R156H', 'Mutation', 'rs371524413', (181, 188))	('c.800G>A', 'Mutation', 'rs587780075', (148, 156))	('c.467G>A', 'Var', (171, 179))
94274	30709875	His AML was characterized by adverse cytogenetics (including deletions in 5q, 7q, and 11q) with mutations in EGFR and TET2 in addition to the two germline TP53 mutations.	('AML', 'Disease', (4, 7))	('deletions', 'Var', (61, 70))	('TP53', 'Gene', '7157', (155, 159))	('TET2', 'Gene', '54790', (118, 122))	('TP53', 'Gene', (155, 159))	('TET2', 'Gene', (118, 122))	('AML', 'Disease', 'MESH:D015470', (4, 7))	('EGFR', 'Gene', '1956', (109, 113))	('EGFR', 'Gene', (109, 113))	('AML', 'Phenotype', 'HP:0004808', (4, 7))	('mutations', 'Var', (96, 105))
94278	30709875	A 28-yr-old woman with LFS presented with therapy-related AML with complex cytogenetics and BCORL1, TP53, and WT1 mutations.	('TP53', 'Gene', '7157', (100, 104))	('BCORL1', 'Gene', (92, 98))	('woman', 'Species', '9606', (12, 17))	('mutations', 'Var', (114, 123))	('TP53', 'Gene', (100, 104))	('AML', 'Disease', 'MESH:D015470', (58, 61))	('WT1', 'Gene', '7490', (110, 113))	('BCORL1', 'Gene', '63035', (92, 98))	('WT1', 'Gene', (110, 113))	('AML', 'Phenotype', 'HP:0004808', (58, 61))	('AML', 'Disease', (58, 61))
94279	30709875	She had a medical history of right breast pleomorphic spindle cell sarcoma and contralateral left breast ductal carcinoma in situ (DCIS), diagnosed at age 24 yr, after which genetic testing was performed and demonstrated a germline TP53 mutation c.586C>T (p.R196*) (Table 4).	('c.586C>T', 'Var', (246, 254))	('contralateral left breast ductal carcinoma in situ', 'Disease', 'MESH:D002285', (79, 129))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (105, 129))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (105, 121))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (98, 121))	('c.586C>T', 'Mutation', 'rs397516435', (246, 254))	('right breast pleomorphic spindle cell sarcoma', 'Disease', (29, 74))	('right breast pleomorphic spindle cell sarcoma', 'Disease', 'MESH:D012509', (29, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('p.R196*', 'Mutation', 'rs397516435', (256, 263))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('TP53', 'Gene', '7157', (232, 236))	('TP53', 'Gene', (232, 236))	('contralateral left breast ductal carcinoma in situ', 'Disease', (79, 129))
94286	30709875	TP53 germline analysis was performed and revealed a c.734G>A (p.R248Q) pathogenic mutation (Table 4), confirming LFS.	('c.734G>A', 'Var', (52, 60))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('p.R248Q', 'Mutation', 'rs11540652', (62, 69))	('c.734G>A', 'Mutation', 'rs121912656', (52, 60))
94287	30709875	At the age of 49, she was diagnosed with t-AML with complex karyotype and mutations in BCOR, DNMT3A, and her known TP53 mutation.	('TP53', 'Gene', '7157', (115, 119))	('AML', 'Disease', 'MESH:D015470', (43, 46))	('mutations', 'Var', (74, 83))	('BCOR', 'Gene', '54880', (87, 91))	('AML', 'Phenotype', 'HP:0004808', (43, 46))	('TP53', 'Gene', (115, 119))	('AML', 'Disease', (43, 46))	('DNMT3A', 'Gene', (93, 99))	('BCOR', 'Gene', (87, 91))	('DNMT3A', 'Gene', '1788', (93, 99))
94291	30709875	A 34-yr-old woman with de novo hypodiploid ALL, a TP53 mutation at ~50% variant allelic frequency, and a strong family history of cancers was referred to the HHMC for LFS evaluation.	('hypodiploid ALL', 'Disease', 'MESH:D054198', (31, 46))	('ALL', 'Phenotype', 'HP:0006721', (43, 46))	('woman', 'Species', '9606', (12, 17))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('TP53', 'Gene', '7157', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('TP53', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))	('variant', 'Var', (72, 79))	('hypodiploid ALL', 'Disease', (31, 46))
94293	30709875	Germline TP53 testing on cultured skin fibroblasts identified a TP53 c.325T>G (p.F109V) mutation, initially classified as a VUS (Table 4).	('c.325T>G', 'Mutation', 'rs1057523496', (69, 77))	('c.325T>G', 'Var', (69, 77))	('TP53', 'Gene', '7157', (9, 13))	('p.F109V', 'Mutation', 'rs1057523496', (79, 86))	('TP53', 'Gene', (9, 13))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))
94301	30709875	His T-ALL characteristics at the time of diagnosis included hypodiploid complex cytogenetics, and sequencing of the bone marrow demonstrated NOTCH1 and TP53 mutations.	('hypodiploid', 'Disease', (60, 71))	('TP53', 'Gene', '7157', (152, 156))	('ALL', 'Phenotype', 'HP:0006721', (6, 9))	('mutations', 'Var', (157, 166))	('NOTCH1', 'Gene', '4851', (141, 147))	('TP53', 'Gene', (152, 156))	('hypodiploid', 'Disease', 'None', (60, 71))	('NOTCH1', 'Gene', (141, 147))
94302	30709875	Based on the high clinical suspicion, evaluation for the germline versus somatic nature of this TP53 mutation was recommended, and he was referred to the HHMC.	('men', 'Species', '9606', (119, 122))	('mutation', 'Var', (101, 109))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', (96, 100))
94303	30709875	TP53 germline analysis confirmed the presence of a c.524G>A (p.R175H) mutation (Table 4) in cultured skin fibroblasts, consistent with LFS.	('TP53', 'Gene', '7157', (0, 4))	('c.524G>A', 'Var', (51, 59))	('TP53', 'Gene', (0, 4))	('c.524G>A', 'Mutation', 'rs28934578', (51, 59))	('p.R175H', 'Mutation', 'rs28934578', (61, 68))
94329	30709875	TP53 mutations are frequently inherited, and family history remains a key criterion for the consideration of LFS.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
94330	30709875	Additionally, the phenotypic variability of cancers even within families that have the same mutation is described, and genetic anticipation, often observed in families with LFS, has been hypothesized to be due to telomere shortening.	('telomere shortening', 'Var', (213, 232))	('mutation', 'Var', (92, 100))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('telomere shortening', 'Phenotype', 'HP:0031413', (213, 232))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
94331	30709875	Although ALL is a common pediatric cancer, attention should be paid to patients with presumed somatic TP53 mutations identified on NGS panels and/or hypodiploid cytogenetics (defined as fewer than 45 chromosomes), or the phenomenon of masked hypodiploidy, where hypodiploid genome undergoes reduplication resulting in hyperdiploid karyotype.	('TP53', 'Gene', (102, 106))	('hypodiploidy', 'Disease', (242, 254))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('pediatric cancer', 'Disease', (25, 41))	('hypodiploid', 'Disease', (242, 253))	('ALL', 'Phenotype', 'HP:0006721', (9, 12))	('hyperdiploid', 'Disease', 'MESH:D054198', (318, 330))	('hyperdiploid', 'Disease', (318, 330))	('TP53', 'Gene', '7157', (102, 106))	('hypodiploid genome undergoes', 'Disease', (262, 290))	('hypodiploidy', 'Disease', 'None', (242, 254))	('hypodiploid', 'Disease', 'None', (262, 273))	('hypodiploid', 'Disease', 'None', (149, 160))	('hypodiploid genome undergoes', 'Disease', 'MESH:D042822', (262, 290))	('mutations', 'Var', (107, 116))	('hypodiploid', 'Disease', 'None', (242, 253))	('hypodiploid', 'Disease', (149, 160))	('hypodiploid', 'Disease', (262, 273))	('pediatric cancer', 'Disease', 'MESH:D009369', (25, 41))	('men', 'Species', '9606', (226, 229))
94332	30709875	In the setting of hypodiploid cytogenetics, >90% of patients will have a TP53 mutation, and prior work suggests about half of these patients may have germline TP53 mutations.	('TP53', 'Gene', '7157', (73, 77))	('mutation', 'Var', (78, 86))	('TP53', 'Gene', (73, 77))	('hypodiploid', 'Disease', 'None', (18, 29))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (159, 163))	('hypodiploid', 'Disease', (18, 29))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (52, 60))
94335	30709875	Somatic TP53 mutations, often associated with complex cytogenetic abnormalities, are well described in hematologic malignancies including MDS, AML, and ALL and are known to confer poor outcomes and treatment resistance.	('hematologic malignancies', 'Disease', 'MESH:D019337', (103, 127))	('men', 'Species', '9606', (203, 206))	('MDS', 'Disease', (138, 141))	('MDS', 'Disease', 'MESH:D009190', (138, 141))	('hematologic malignancies', 'Disease', (103, 127))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('ALL', 'Disease', (152, 155))	('ALL', 'Phenotype', 'HP:0006721', (152, 155))	('mutations', 'Var', (13, 22))	('AML', 'Disease', (143, 146))	('AML', 'Phenotype', 'HP:0004808', (143, 146))	('MDS', 'Phenotype', 'HP:0002863', (138, 141))
94342	30709875	The National Comprehensive Cancer Network (NCCN) has guidelines for screening TP53 mutation carriers, and whole-body MRI has been shown to be an effective screening tool for early detection of solid tumors (Table 6).	('solid tumors', 'Disease', 'MESH:D009369', (193, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('Cancer', 'Disease', (27, 33))	('mutation', 'Var', (83, 91))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('TP53', 'Gene', '7157', (78, 82))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TP53', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('solid tumors', 'Disease', (193, 205))
94348	30709875	At MD Anderson, the LEAD program enrolls patients with germline TP53 mutations.	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))
94351	30709875	For example, Case 2 was referred to LEAD for genetic testing after the patient's sister was found to have a TP53 mutation.	('TP53', 'Gene', (108, 112))	('mutation', 'Var', (113, 121))	('patient', 'Species', '9606', (71, 78))	('TP53', 'Gene', '7157', (108, 112))
94354	30709875	LFS increases the lifetime risk of cancer in many organ sites, and it is important to consider hypodiploid ALL as a possible presenting malignancy for individuals with LFS.	('malignancy', 'Disease', (136, 146))	('hypodiploid ALL', 'Disease', (95, 110))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('hypodiploid ALL', 'Disease', 'MESH:D054198', (95, 110))	('LFS', 'Var', (0, 3))	('man', 'Species', '9606', (45, 48))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('ALL', 'Phenotype', 'HP:0006721', (107, 110))	('cancer', 'Disease', (35, 41))
94452	29061942	Consistent with this potential connection to bone growth, OS in dogs disproportionately affects large and giant breeds, and has been connected to dysregulation of the Insulin-like Growth Factor-1-Growth Hormone (IGF-I-GH) axis.	('dogs', 'Species', '9615', (64, 68))	('Growth Hormone', 'Gene', (196, 210))	('IGF-I', 'Gene', '610255', (212, 217))	('IGF-I', 'Gene', (212, 217))	('connected to', 'Reg', (133, 145))	('dysregulation', 'Var', (146, 159))	('OS', 'Phenotype', 'HP:0002669', (58, 60))	('Growth Hormone', 'Gene', '403795', (196, 210))
94511	29061942	Unlike naturally-occurring OS in people and dogs, whereby the majority of OS lesions arise from the metaphyseal regions of appendicular weight-bearing bones, plutonium-induced OS preferentially affected the axial skeleton within regions of high bone turnover and vascularity; accounting for 50%-69% of all OS lesions identified radiographically.	('OS', 'Phenotype', 'HP:0002669', (306, 308))	('OS lesions', 'Disease', (74, 84))	('affected', 'Reg', (194, 202))	('plutonium-induced', 'Var', (158, 175))	('appendicular', 'Disease', (123, 135))	('appendicular', 'Disease', 'MESH:D001259', (123, 135))	('plutonium', 'Chemical', 'MESH:D011005', (158, 167))	('people', 'Species', '9606', (33, 39))	('OS lesions', 'Disease', 'MESH:C567932', (306, 316))	('OS lesions', 'Disease', (306, 316))	('axial skeleton', 'CPA', (207, 221))	('OS', 'Phenotype', 'HP:0002669', (74, 76))	('OS', 'Phenotype', 'HP:0002669', (27, 29))	('OS', 'Phenotype', 'HP:0002669', (176, 178))	('OS lesions', 'Disease', 'MESH:C567932', (74, 84))	('dogs', 'Species', '9615', (44, 48))
94518	29061942	Unlike plutonium, which preferentially induces OS formation within the axial skeleton (69%), beagle dogs fed strontium-90 developed OS predominantly in appendicular sites (74%), more similar to the skeletal distribution of naturally-occurring canine OS.	('beagle dogs', 'Species', '9615', (93, 104))	('OS', 'Phenotype', 'HP:0002669', (132, 134))	('OS', 'Phenotype', 'HP:0002669', (250, 252))	('plutonium', 'Chemical', 'MESH:D011005', (7, 16))	('strontium-90', 'Chemical', 'MESH:C000615490', (109, 121))	('OS', 'Phenotype', 'HP:0002669', (47, 49))	('appendicular', 'Disease', 'MESH:D001259', (152, 164))	('canine', 'Species', '9615', (243, 249))	('strontium-90', 'Var', (109, 121))	('appendicular', 'Disease', (152, 164))
94528	29061942	Physiologic and pathologic perturbations in homeostatic bone turnover appear to participate in the etiopathogenesis of OS.	('participate', 'Reg', (80, 91))	('homeostatic bone turnover', 'Disease', 'MESH:D001851', (44, 69))	('OS', 'Phenotype', 'HP:0002669', (119, 121))	('homeostatic bone turnover', 'Disease', (44, 69))	('perturbations', 'Var', (27, 40))
94531	29061942	In addition to accelerated homeostatic bone turnover, dysregulated skeletal remodeling also participates in OS etiopathogenesis.	('homeostatic bone turnover', 'Disease', 'MESH:D001851', (27, 52))	('skeletal remodeling', 'CPA', (67, 86))	('homeostatic bone turnover', 'Disease', (27, 52))	('accelerated', 'PosReg', (15, 26))	('participates', 'Reg', (92, 104))	('dysregulated', 'Var', (54, 66))	('OS', 'Phenotype', 'HP:0002669', (108, 110))
94543	29061942	The evidence implicating genetic factors in OS development is supported by familial cancer predisposition syndromes, whereby germline or somatic defects in genes encoding either tumor suppressor proteins or RECQ helicase enzymes have been associated with increased incidences of OS.	('associated', 'Reg', (239, 249))	('defects', 'Var', (145, 152))	('RECQ helicase', 'Protein', (207, 220))	('tumor', 'Disease', (178, 183))	('familial cancer', 'Disease', 'MESH:D009369', (75, 90))	('OS', 'Phenotype', 'HP:0002669', (44, 46))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('OS', 'Phenotype', 'HP:0002669', (279, 281))	('familial cancer', 'Disease', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
94546	29061942	As such, mutations in P53 predispose to the development of cancer via global genomic instability and dysregulated cell cycling.	('predispose to', 'Reg', (26, 39))	('global genomic instability', 'CPA', (70, 96))	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('dysregulated cell cycling', 'CPA', (101, 126))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('P53', 'Gene', (22, 25))
94547	29061942	Li-Fraumeni syndrome is a rare autosomal dominant hereditary disorder linked to germline mutations of the P53 tumor suppressor gene.	('autosomal dominant hereditary disorder', 'Disease', (31, 69))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('linked', 'Reg', (70, 76))	('autosomal dominant hereditary disorder', 'Disease', 'MESH:D030342', (31, 69))	('P53', 'Gene', (106, 109))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mutations', 'Var', (89, 98))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
94549	29061942	OS is reported to be the second most common cancer developing in patients diagnosed with Li-Fraumeni syndrome, and germline mutations in P53 are responsible for 3% of all OS diagnosed in children.	('Li-Fraumeni syndrome', 'Disease', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('children', 'Species', '9606', (187, 195))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('P53', 'Gene', (137, 140))	('OS', 'Phenotype', 'HP:0002669', (171, 173))	('OS', 'Phenotype', 'HP:0002669', (0, 2))	('patients', 'Species', '9606', (65, 73))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (89, 109))	('responsible', 'Reg', (145, 156))	('germline mutations', 'Var', (115, 133))
94550	29061942	Although the incidence of OS development secondary to germline P53 mutations is relatively low, in sporadic OS arising in older patients, the frequency of P53 mutations range from 40 to 60% in high-grade tumors; suggesting that P53 is not only involved in OS formation, but also participates in OS progression.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('OS', 'Phenotype', 'HP:0002669', (26, 28))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('OS development', 'CPA', (26, 40))	('OS', 'Phenotype', 'HP:0002669', (295, 297))	('mutations', 'Var', (67, 76))	('OS', 'Phenotype', 'HP:0002669', (256, 258))	('tumors', 'Disease', (204, 210))	('P53', 'Gene', (155, 158))	('P53', 'Gene', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('patients', 'Species', '9606', (128, 136))	('OS', 'Phenotype', 'HP:0002669', (108, 110))
94552	29061942	The retinoblastoma protein (RB) belongs to a family of pocket proteins including p107 and p130, which regulates cellular progression through G1 phase of the cell cycle by virtue of their phosphorylation status.	('retinoblastoma protein', 'Gene', (4, 26))	('regulates', 'Reg', (102, 111))	('cellular progression', 'CPA', (112, 132))	('retinoblastoma protein', 'Gene', '476915', (4, 26))	('p130', 'Var', (90, 94))	('retinoblastoma', 'Phenotype', 'HP:0009919', (4, 18))	('RB', 'Phenotype', 'HP:0009919', (28, 30))	('p107', 'Var', (81, 85))
94553	29061942	As such, mutations in the RB gene result in dysregulated cell cycling and differentiation, with consequent predispositions for cancer development.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('RB', 'Phenotype', 'HP:0009919', (26, 28))	('mutations', 'Var', (9, 18))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('result in', 'Reg', (34, 43))	('dysregulated', 'MPA', (44, 56))
94554	29061942	Patients with hereditary retinoblastoma (RB) have a germline mutation in a parental RB allele, which predisposes to development of multifocal and bilateral retinoblastomas at a young age.	('RB', 'Phenotype', 'HP:0009919', (84, 86))	('hereditary retinoblastoma', 'Disease', (14, 39))	('retinoblastoma (RB)', 'Gene', '5925', (25, 44))	('retinoblastoma (RB', 'Gene', (25, 43))	('RB', 'Phenotype', 'HP:0009919', (41, 43))	('Patients', 'Species', '9606', (0, 8))	('retinoblastoma', 'Phenotype', 'HP:0009919', (25, 39))	('retinoblastomas', 'Phenotype', 'HP:0009919', (156, 171))	('predisposes to', 'Reg', (101, 115))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (14, 39))	('bilateral retinoblastomas', 'Disease', 'MESH:D012175', (146, 171))	('bilateral retinoblastomas', 'Disease', (146, 171))	('germline mutation', 'Var', (52, 69))	('retinoblastoma', 'Phenotype', 'HP:0009919', (156, 170))
94559	29061942	Mutations in specific human RECQ genes are implicated in heritable diseases including Rhothmund-Thomson, Werner, and Bloom syndromes.	('Rhothmund-Thomson', 'Disease', (86, 103))	('implicated', 'Reg', (43, 53))	('RECQ genes', 'Gene', (28, 38))	('Werner', 'Disease', (105, 111))	('Bloom syndromes', 'Disease', (117, 132))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (22, 27))
94562	29061942	Based upon one cohort study which evaluated loss of function mutations in the RECQL4 gene in patients diagnosed with Rhothmund-Thomson syndrome, 13 out of 41 patients developed OS.	('developed', 'Reg', (167, 176))	('OS', 'Phenotype', 'HP:0002669', (177, 179))	('RECQL4', 'Gene', '9401', (78, 84))	('mutations', 'Var', (61, 70))	('Rhothmund-Thomson syndrome', 'Disease', (117, 143))	('Rhothmund-Thomson syndrome', 'Disease', 'MESH:D011038', (117, 143))	('patients', 'Species', '9606', (158, 166))	('RECQL4', 'Gene', (78, 84))	('patients', 'Species', '9606', (93, 101))	('loss of function', 'NegReg', (44, 60))
94568	29061942	In corroboration with initial cell line studies, mutations in P53 have also been demonstrated in dogs with spontaneously-arising OS.	('mutations', 'Var', (49, 58))	('P53', 'Gene', (62, 65))	('OS', 'Phenotype', 'HP:0002669', (129, 131))	('dogs', 'Species', '9615', (97, 101))	('demonstrated', 'Reg', (81, 93))
94570	29061942	In 24 OS tumors, P53 mutations were identified with most gene abnormalities located in exons 4 and 5; however, two mutations were located in a non-coding region of the P53 gene, and one mutation was identified in exon 9.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('P53', 'Gene', (17, 20))	('P53', 'Gene', (168, 171))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('OS tumors', 'Disease', (6, 15))	('OS', 'Phenotype', 'HP:0002669', (6, 8))	('OS tumors', 'Disease', 'MESH:C567932', (6, 15))	('mutations', 'Var', (21, 30))
94571	29061942	Finally, through the implementation of targeted microarray-based comparative genomic hybridization analysis of 38 canine OS cases, similar recurrent cytogenetic aberrations classically present in human OS samples were also identified in OS specimens collected from dogs, including LOH of the P53 gene in 18% of tumors.	('tumors', 'Disease', (311, 317))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('canine', 'Species', '9615', (114, 120))	('LOH', 'Var', (281, 284))	('human', 'Species', '9606', (196, 201))	('P53', 'Gene', (292, 295))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('dogs', 'Species', '9615', (265, 269))	('OS', 'Phenotype', 'HP:0002669', (237, 239))	('OS', 'Phenotype', 'HP:0002669', (202, 204))	('OS', 'Phenotype', 'HP:0002669', (121, 123))
94572	29061942	Substantiation for the presence of P53 mutations in sporadic canine OS has also been documented by immunohistochemical studies, as a hallmark of many P53 mutations is enhanced protein stability of this normally labile protein, enabling detection of protein with methodologies, such as immunohistochemistry.	('P53', 'Gene', (150, 153))	('enhanced', 'PosReg', (167, 175))	('canine', 'Species', '9615', (61, 67))	('protein stability', 'MPA', (176, 193))	('OS', 'Phenotype', 'HP:0002669', (68, 70))	('mutations', 'Var', (154, 163))
94576	29061942	Interestingly, P53 index of appendicular OS derived from Rottweilers was significantly higher than Great Danes or other commonly affected breeds, supporting the notion that P53 gene mutations may be associated with breed susceptibilities to OS development.	('associated', 'Reg', (199, 209))	('P53', 'MPA', (15, 18))	('mutations', 'Var', (182, 191))	('appendicular OS', 'Disease', 'MESH:C567932', (28, 43))	('OS', 'Phenotype', 'HP:0002669', (241, 243))	('OS', 'Phenotype', 'HP:0002669', (41, 43))	('P53', 'Gene', (173, 176))	('appendicular OS', 'Disease', (28, 43))	('higher', 'PosReg', (87, 93))
94578	29061942	Although germline RB gene mutations have not been documented in canines, sporadic somatic RB gene mutations are likely responsible for the development of unilateral retinoblastoma infrequently documented in dogs.	('mutations', 'Var', (98, 107))	('retinoblastoma', 'Phenotype', 'HP:0009919', (165, 179))	('RB', 'Phenotype', 'HP:0009919', (90, 92))	('dogs', 'Species', '9615', (207, 211))	('canines', 'Species', '9615', (64, 71))	('unilateral retinoblastoma', 'Disease', (154, 179))	('RB', 'Phenotype', 'HP:0009919', (18, 20))	('unilateral retinoblastoma', 'Disease', 'MESH:D012175', (154, 179))
94581	29061942	Substantiating the possibility that RB gene may be have allelic deletion in spontaneously-arising canine OS, analysis of 38 OS samples with comparative genomic hybridization techniques identified copy number loss in 11/38 cases (29%), resulting in a correlative reduction or absence of RB protein expression in 62% of OS samples tested.	('RB protein', 'Protein', (286, 296))	('RB', 'Phenotype', 'HP:0009919', (36, 38))	('OS', 'Phenotype', 'HP:0002669', (105, 107))	('protein', 'Protein', (289, 296))	('OS', 'Phenotype', 'HP:0002669', (318, 320))	('absence', 'NegReg', (275, 282))	('copy number loss', 'Var', (196, 212))	('canine', 'Species', '9615', (98, 104))	('RB', 'Phenotype', 'HP:0009919', (286, 288))	('RB gene', 'Gene', (36, 43))	('reduction', 'NegReg', (262, 271))	('OS', 'Phenotype', 'HP:0002669', (124, 126))
94582	29061942	Based upon these recent investigative findings, it is probable that aberrations in the RB gene indeed participate in sporadic OS formation and/or progression in dogs.	('dogs', 'Species', '9615', (161, 165))	('sporadic OS', 'Disease', (117, 128))	('OS', 'Phenotype', 'HP:0002669', (126, 128))	('participate', 'Reg', (102, 113))	('aberrations', 'Var', (68, 79))	('RB', 'Phenotype', 'HP:0009919', (87, 89))	('progression', 'CPA', (146, 157))
94583	29061942	Inherited, cancer-prone disorders have not been thoroughly characterized in dogs, therefore it is uncertain if defects in the RECQ helicase genes predisposes to OS formation in canines.	('predisposes', 'Reg', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('OS formation', 'Disease', (161, 173))	('defects', 'Var', (111, 118))	('OS', 'Phenotype', 'HP:0002669', (161, 163))	('canines', 'Species', '9615', (177, 184))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('dogs', 'Species', '9615', (76, 80))	('RECQ helicase', 'Protein', (126, 139))	('cancer', 'Disease', (11, 17))
94628	26266067	In a randomized, placebo-controlled phase III trial, a significantly greater proportion of patients with SBS receiving teduglutide were able to reduce weekly TPN volume requirements >20% and experienced gain in weight compared to patients treated with placebo; however, none of the patients was able to wean off TPN.	('gain', 'PosReg', (203, 207))	('teduglutide', 'Var', (119, 130))	('weight', 'MPA', (211, 217))	('patients', 'Species', '9606', (91, 99))	('weekly TPN volume requirements', 'MPA', (151, 181))	('reduce', 'NegReg', (144, 150))	('patients', 'Species', '9606', (230, 238))	('SBS', 'Disease', (105, 108))	('teduglutide', 'Chemical', 'MESH:C494910', (119, 130))	('patients', 'Species', '9606', (282, 290))	('SBS', 'Disease', 'MESH:C536611', (105, 108))
94640	26266067	Inhibition of signaling through the IGF-1 receptor has been associated with significant reduction in ARMS growth in vitro.	('RMS', 'Phenotype', 'HP:0002859', (102, 105))	('ARMS growth in vitro', 'CPA', (101, 121))	('signaling', 'MPA', (14, 23))	('reduction', 'NegReg', (88, 97))	('ARMS', 'Phenotype', 'HP:0006779', (101, 105))	('IGF-1', 'Gene', '3479', (36, 41))	('IGF-1', 'Gene', (36, 41))	('Inhibition', 'Var', (0, 10))
94642	26266067	Activation of these receptors causes local release of insulin-like growth factor- (IGF-) 1, nitric oxide, and keratinocyte growth factor (KGF) which promotes growth of intestinal epithelium.	('insulin-like growth factor- (IGF-) 1', 'Gene', '3479', (54, 90))	('keratinocyte growth factor', 'Gene', '2252', (110, 136))	('nitric oxide', 'MPA', (92, 104))	('release', 'MPA', (43, 50))	('KGF', 'Gene', (138, 141))	('nitric oxide', 'Chemical', 'MESH:D009569', (92, 104))	('Activation', 'Var', (0, 10))	('KGF', 'Gene', '2252', (138, 141))	('promotes', 'PosReg', (149, 157))	('keratinocyte growth factor', 'Gene', (110, 136))	('growth of intestinal epithelium', 'Phenotype', 'HP:0200008', (158, 189))	('growth', 'CPA', (158, 164))
94647	26266067	), teduglutide caused statistically significant increases in the incidences of adenomas in the bile duct and jejunum of male rats.	('teduglutide', 'Chemical', 'MESH:C494910', (3, 14))	('increases', 'PosReg', (48, 57))	('teduglutide', 'Var', (3, 14))	('rats', 'Species', '10116', (125, 129))	('adenomas', 'Disease', 'MESH:D000236', (79, 87))	('adenomas', 'Disease', (79, 87))
94664	25222071	Immunohistochemistry showed strong positivity for CD99 (mic2) and cytogenetic analysis demonstrated evidence of EWSR1 fusion gene in eight cases.	('mic2', 'Gene', '4267', (56, 60))	('fusion gene', 'Var', (118, 129))	('mic2', 'Gene', (56, 60))	('CD99', 'Gene', '4267', (50, 54))	('EWSR1', 'Gene', (112, 117))	('EWSR1', 'Gene', '2130', (112, 117))	('CD99', 'Gene', (50, 54))
94715	25222071	Molecularly, ESFT is characterized by translocations and fusions of the EWSR1 gene with a number of the ETS family of genes.	('EWSR1', 'Gene', (72, 77))	('fusions', 'Var', (57, 64))	('EWSR1', 'Gene', '2130', (72, 77))	('translocations', 'Var', (38, 52))	('ESFT', 'Disease', (13, 17))
94717	25222071	The most frequent translocation is t (11;22) (q24;12) which results from fusion of the 5' end of the EWSR1 to the 3' of FLI-1 and accounts for >85% of all translocations.	('FLI-1', 'Gene', (120, 125))	('EWSR1', 'Gene', (101, 106))	('t (11;22) (q24;12', 'Var', (35, 52))	('FLI-1', 'Gene', '2313', (120, 125))	('EWSR1', 'Gene', '2130', (101, 106))
94719	25222071	Although helpful for the diagnosis, the absence of EWSR1 gene rearrangement does not entirely exclude the diagnosis of ESFT, especially if the clinical and morphological features are highly suggestive of the diagnosis.	('EWSR1', 'Gene', '2130', (51, 56))	('EWSR1', 'Gene', (51, 56))	('absence', 'Var', (40, 47))	('ESFT', 'Disease', (119, 123))
94720	25222071	In our series, cytogenetic analysis was performed in 10 out of 13 cases and eight of them demonstrated the presence of EWSR1 fusion gene rearrangement.	('fusion gene rearrangement', 'Var', (125, 150))	('EWSR1', 'Gene', (119, 124))	('EWSR1', 'Gene', '2130', (119, 124))	('presence', 'Reg', (107, 115))
94776	25709361	The CD4+ count (cells/mm3) was <200, 200-500, and >500 in 32 cases (64%), 16 cases (32%) and 2 cases (4%) respectively, and the mean CD4+ count was 169.82 in males and 142.8 in females (Table 2).	('CD4', 'Gene', '920', (133, 136))	('CD4', 'Gene', (4, 7))	('CD4', 'Gene', '920', (4, 7))	('CD4', 'Gene', (133, 136))	('>500', 'Var', (50, 54))
94882	24278806	In a study on metastatic melanoma, of 15 patients receiving MBV, 3 had a complete remission (20%) lasting at least 15, 21, and 32 months.	('MBV', 'Chemical', '-', (60, 63))	('patients', 'Species', '9606', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('MBV', 'Var', (60, 63))	('melanoma', 'Disease', (25, 33))
94915	24278806	Obviously, MBVs stimulated a complex cascade, a "perfect storm" of cytokines: among these, interleukin (IL)-2, interferon-alpha, TNF-alpha, and IL-12 are seen as critical:and of toll-like receptors and other pattern recognition receptor agonists, each of which plays a unique and vital role in the orchestration of the immune response.	('MBVs', 'Var', (11, 15))	('TNF-alpha', 'Gene', '7124', (129, 138))	('MBV', 'Chemical', '-', (11, 14))	('interleukin (IL)-2', 'Gene', (91, 109))	('TNF-alpha', 'Gene', (129, 138))	('interleukin (IL)-2', 'Gene', '3558', (91, 109))
94973	23935247	Cytotoxicity against tumor cell lines of its extracts, epigenetic modifications of cancer oncogenes, and tumor suppressor genes were described.	('Cytotoxicity', 'Disease', (0, 12))	('tumor', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('epigenetic modifications', 'Var', (55, 79))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (105, 110))	('Cytotoxicity', 'Disease', 'MESH:D064420', (0, 12))	('cancer', 'Disease', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
95063	23935247	Novel sulindac derivatives that do not inhibit COX-1 and COX 2 suppressed colon tumor cell growth in vitro by inhibiting cGMP phosphodiesterase and beta-catenin transcriptional activity and inhibited in vivo malignant pleural adenocarcinoma dissemination in mice.	('COX-1', 'Gene', '17708', (47, 52))	('malignant pleural adenocarcinoma dissemination', 'Disease', (208, 254))	('COX 2', 'Gene', '17709', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('COX 2', 'Gene', (57, 62))	('derivatives', 'Var', (15, 26))	('mice', 'Species', '10090', (258, 262))	('suppressed', 'NegReg', (63, 73))	('COX-1', 'Gene', (47, 52))	('beta-catenin', 'Gene', '12387', (148, 160))	('cGMP', 'Protein', (121, 125))	('beta-catenin', 'Gene', (148, 160))	('sulindac', 'Chemical', 'MESH:D013467', (6, 14))	('pleural adenocarcinoma', 'Phenotype', 'HP:0030078', (218, 240))	('inhibited', 'NegReg', (190, 199))	('colon tumor', 'Disease', 'MESH:D015179', (74, 85))	('colon tumor', 'Phenotype', 'HP:0100273', (74, 85))	('inhibiting', 'NegReg', (110, 120))	('malignant pleural adenocarcinoma dissemination', 'Disease', 'MESH:D016066', (208, 254))	('colon tumor', 'Disease', (74, 85))
95094	22862905	We performed the molecular genetic examination by a reverse-transcriptase polymerase chain reaction assay (RT-PCR) that detects (the paraffin blocks, formalin-fixed tissue) the SYT-SSX chimeric RNA transcript resulting from t(X; 18), the characteristic phenotype of SS.	('t(X', 'Var', (224, 227))	('SS', 'Phenotype', 'HP:0012570', (266, 268))	('RNA', 'Gene', (194, 197))	('SYT', 'Gene', (177, 180))	('formalin', 'Chemical', 'MESH:D005557', (150, 158))	('SS', 'Phenotype', 'HP:0012570', (181, 183))	('SSX', 'Gene', (181, 184))	('SSX', 'Gene', '6757', (181, 184))	('paraffin', 'Chemical', 'MESH:D010232', (133, 141))	('SYT', 'Gene', '6857', (177, 180))
95120	22862905	The studies we performed demonstrated the presence of SYT-SSX (including SYT-SSX1 and/or SYT-SSX2) fusion transcript in all five cases.	('SSX', 'Gene', '6757', (93, 96))	('SSX', 'Gene', (77, 80))	('SYT', 'Gene', '6857', (54, 57))	('presence', 'Reg', (42, 50))	('SSX', 'Gene', '6757', (58, 61))	('SYT', 'Gene', (89, 92))	('SSX', 'Gene', (93, 96))	('SSX2', 'Gene', (93, 97))	('fusion transcript', 'Var', (99, 116))	('SYT', 'Gene', (73, 76))	('SYT-SSX1', 'Gene', (73, 81))	('SSX', 'Gene', (58, 61))	('SYT-SSX1', 'Gene', '6857;6756', (73, 81))	('SSX2', 'Gene', '6757', (93, 97))	('SS', 'Phenotype', 'HP:0012570', (77, 79))	('SYT', 'Gene', (54, 57))	('SYT', 'Gene', '6857', (89, 92))	('SYT', 'Gene', '6857', (73, 76))	('SS', 'Phenotype', 'HP:0012570', (93, 95))	('SSX', 'Gene', '6757', (77, 80))	('SS', 'Phenotype', 'HP:0012570', (58, 60))
95139	22862905	Our follow-up date showed the prognosis of three patients with tumor size <5 cm was better than the other two patients with tumor size >5 cm.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('<5 cm', 'Var', (74, 79))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('patients', 'Species', '9606', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
95142	22862905	We have shown that the prognosis of PPSS is better in those patients with tumor size less than 5 cm than in the patients with larger tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumors', 'Disease', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('patients', 'Species', '9606', (60, 68))	('SS', 'Phenotype', 'HP:0012570', (38, 40))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PPSS', 'Disease', (36, 40))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (133, 138))	('less than 5 cm', 'Var', (85, 99))	('PPS', 'Chemical', '-', (36, 39))
95145	28844694	Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer.	('Alterations', 'Var', (68, 79))	('BAF', 'Gene', '8815', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('BAF', 'Gene', (31, 34))	('orchestrate', 'Reg', (114, 125))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('Prion', 'Species', '36469', (50, 55))
95146	28844694	Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors.	('BRG1/BRM-associated factor', 'Gene', '8815', (23, 49))	('EWSR1', 'Gene', (147, 152))	('BAF', 'Gene', '8815', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('interacts', 'Interaction', (132, 141))	('BAF', 'Gene', (51, 54))	('EWSR1', 'Gene', '2130', (147, 152))	('prion', 'Species', '36469', (192, 197))	('mutated', 'Var', (95, 102))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('BRG1/BRM-associated factor', 'Gene', (23, 49))	('human', 'Species', '9606', (118, 123))
95149	28844694	Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities.	('FLI1', 'Gene', (51, 55))	('BAF', 'Gene', '8815', (86, 89))	('fusion', 'Var', (13, 19))	('FLI1', 'Gene', '2130', (51, 55))	('EWSR1', 'Gene', '2130', (42, 47))	('BAF', 'Gene', (86, 89))	('FLI1', 'Gene', (118, 122))	('EWS-FLI1', 'Gene', '2130', (114, 122))	('EWS-FLI1', 'Gene', (114, 122))	('FLI1', 'Gene', '2130', (118, 122))	('EWSR1', 'Gene', (42, 47))
95153	28844694	The striking number of genetic alterations in genes encoding transcription factors, chromatin modifiers, and histones that have been uncovered in recent whole-exome sequencing efforts have further highlighted the importance of gene regulation in cancer.	('cancer', 'Disease', (246, 252))	('genetic alterations', 'Var', (23, 42))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (246, 252))
95154	28844694	Whereas these alterations can have profound consequences on cancer-specific gene expression, their precise mechanisms of action, in most cases, remain poorly understood.	('alterations', 'Var', (14, 25))	('consequences', 'Reg', (44, 56))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
95156	28844694	One of the most well-characterized translocations results in the fusion of the EWSR1 gene and the FLI1 E-Twenty Six (ETS) transcription factor in Ewing sarcoma, the second most common pediatric bone cancer.	('EWSR1', 'Gene', (79, 84))	('FLI1', 'Gene', '2130', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('bone cancer', 'Disease', 'MESH:D001859', (194, 205))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (146, 159))	('EWSR1', 'Gene', '2130', (79, 84))	('bone cancer', 'Disease', (194, 205))	('results in', 'Reg', (50, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('fusion', 'Var', (65, 71))	('Ewing sarcoma', 'Disease', (146, 159))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (146, 159))	('FLI1', 'Gene', (98, 102))
95165	28844694	The high frequency of alterations in BAF complex subunits across a range of tumor types points to their critical role in controlling chromatin architecture and gene expression in cancer.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('BAF', 'Gene', '8815', (37, 40))	('alterations', 'Var', (22, 33))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('BAF', 'Gene', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
95167	28844694	The BAF complex is specifically recruited by EWS-FLI1 to tumor-specific GGAA repeat microsatellites and is necessary for the activation of target genes.	('BAF', 'Gene', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('EWS-FLI1', 'Gene', '2130', (45, 53))	('microsatellites', 'Var', (84, 99))	('EWS-FLI1', 'Gene', (45, 53))	('tumor', 'Disease', (57, 62))	('BAF', 'Gene', '8815', (4, 7))
95169	28844694	These observations expand the set of human cancers in which BAF complex mistargeting contributes to oncogenesis beyond settings in which BAF complex genes themselves are mutated and show that recruitment via a prion-like domain is a powerful means of retargeting critical chromatin regulatory complexes to tumor-specific loci.	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('mistargeting', 'Var', (72, 84))	('contributes', 'Reg', (85, 96))	('BAF', 'Gene', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('tumor', 'Disease', (306, 311))	('mutated', 'Var', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('oncogenesis', 'CPA', (100, 111))	('BAF', 'Gene', '8815', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('human', 'Species', '9606', (37, 42))	('BAF', 'Gene', '8815', (137, 140))	('prion', 'Species', '36469', (210, 215))	('BAF', 'Gene', (60, 63))
95185	28844694	We recently demonstrated that EWS-FLI1 operates as a pioneer factor to induce tumor-specific de novo enhancers at GGAA microsatellite repeats, a process that may involve significant redistribution of chromatin remodeling complexes that directly govern DNA accessibility, such as BAF.	('BAF', 'Gene', '8815', (279, 282))	('BAF', 'Gene', (279, 282))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('EWS-FLI1', 'Gene', '2130', (30, 38))	('EWS-FLI1', 'Gene', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('microsatellite repeats', 'Var', (119, 141))	('enhancers', 'PosReg', (101, 110))	('tumor', 'Disease', (78, 83))
95190	28844694	To test this hypothesis, we depleted EWS-FLI1 in SK-N-MC Ewing sarcoma cells using short hairpin RNAs (shRNAs) and found that suppression of EWS-FLI1 led to an almost complete disappearance of BAF complex occupancy at GGAA repeats (Figures 2A-2C and S2A), whereas other BAF155 peaks outside these GGAA enhancer regions remained unaffected (Figure 2D).	('EWS-FLI1', 'Gene', (141, 149))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (57, 70))	('Ewing sarcoma', 'Disease', (57, 70))	('SK-N-MC', 'CellLine', 'CVCL:0530', (49, 56))	('BAF', 'Gene', (193, 196))	('EWS-FLI1', 'Gene', '2130', (37, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('EWS-FLI1', 'Gene', (37, 45))	('BAF', 'Gene', '8815', (193, 196))	('BAF155', 'Gene', (270, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('BAF', 'Gene', '8815', (270, 273))	('depleted', 'NegReg', (28, 36))	('BAF155', 'Gene', '6599', (270, 276))	('suppression', 'Var', (126, 137))	('disappearance', 'NegReg', (176, 189))	('BAF', 'Gene', (270, 273))	('EWS-FLI1', 'Gene', '2130', (141, 149))
95200	28844694	shRNA-mediated depletion of the BRG1 ATPase prior to expression of EWS-FLI1 in MSCs caused a striking reduction in target gene activation (Figure 2I).	('depletion', 'Var', (15, 24))	('ATP', 'Chemical', 'MESH:D000255', (37, 40))	('EWS-FLI1', 'Gene', '2130', (67, 75))	('BRG1', 'Gene', (32, 36))	('EWS-FLI1', 'Gene', (67, 75))	('BRG1', 'Gene', '6597', (32, 36))	('reduction', 'NegReg', (102, 111))	('target gene activation', 'MPA', (115, 137))
95201	28844694	Furthermore, knockdown of the subunit BAF155 in SK-N-MC Ewing sarcoma cells, using two independent BAF155-specific shRNAs, resulted in decreased expression of EWS-FLI1 target genes (Figures 2J and S2H) and significantly impaired viability of Ewing sarcoma cells in culture (Figure S2I).	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('expression', 'MPA', (145, 155))	('BAF155', 'Gene', (38, 44))	('EWS-FLI1', 'Gene', '2130', (159, 167))	('viability', 'CPA', (229, 238))	('knockdown', 'Var', (13, 22))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (242, 255))	('Ewing sarcoma', 'Disease', (242, 255))	('BAF155', 'Gene', '6599', (38, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('SK-N-MC', 'CellLine', 'CVCL:0530', (48, 55))	('decreased', 'NegReg', (135, 144))	('S2H', 'Chemical', 'MESH:C042345', (197, 200))	('BAF155', 'Gene', (99, 105))	('Ewing sarcoma', 'Disease', (56, 69))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (56, 69))	('EWS-FLI1', 'Gene', (159, 167))	('BAF155', 'Gene', '6599', (99, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (242, 255))	('impaired', 'NegReg', (220, 228))
95220	28844694	In keeping with previous studies, immunoprecipitation of tagged EWS-FLI1 showed a strong interaction with endogenous EWSR1 (Figure 4A).	('interaction', 'Interaction', (89, 100))	('EWSR1', 'Gene', (117, 122))	('EWS-FLI1', 'Gene', '2130', (64, 72))	('EWS-FLI1', 'Gene', (64, 72))	('tagged', 'Var', (57, 63))	('EWSR1', 'Gene', '2130', (117, 122))
95236	28844694	Having demonstrated interactions between EWS-FLI1 and EWSR1 and similar phase transition properties conferred by their prion-like domain in vitro, we expected to find these proteins in the same complexes at GGAA repeats in Ewing sarcoma cells.	('EWSR1', 'Gene', '2130', (54, 59))	('interactions', 'Interaction', (20, 32))	('GGAA repeats', 'Var', (207, 219))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (223, 236))	('prion', 'Species', '36469', (119, 124))	('EWS-FLI1', 'Gene', '2130', (41, 49))	('Ewing sarcoma', 'Disease', (223, 236))	('EWSR1', 'Gene', (54, 59))	('EWS-FLI1', 'Gene', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (223, 236))
95241	28844694	We next determined whether phase transition mediated by the prion-like domain of EWS-FLI1 is necessary for DNA binding, BAF complex recruitment, and de novo enhancer activation at GGAA microsatellite repeats by generating a series of V5-tagged EWS-FLI1 mutant proteins lacking the ability to precipitate in vitro.	('BAF', 'Gene', (120, 123))	('prion', 'Species', '36469', (60, 65))	('EWS-FLI1', 'Gene', '2130', (81, 89))	('EWS-FLI1', 'Gene', (81, 89))	('proteins', 'Protein', (260, 268))	('EWS-FLI1', 'Gene', '2130', (244, 252))	('EWS-FLI1', 'Gene', (244, 252))	('mutant', 'Var', (253, 259))	('BAF', 'Gene', '8815', (120, 123))
95242	28844694	The EWSR1 prion-like domain is rich in [G/S]Y[G/S] motifs (Figure S6A), and the substitution of these tyrosine residues with serine has been shown to abrogate phase transitions to hydrogels observed for the FET protein FUS.	('substitution', 'Var', (80, 92))	('EWSR1', 'Gene', '2130', (4, 9))	('tyrosine', 'Chemical', 'None', (102, 110))	('phase transitions', 'MPA', (159, 176))	('abrogate', 'NegReg', (150, 158))	('serine', 'Chemical', 'MESH:C047902', (125, 131))	('prion', 'Species', '36469', (10, 15))	('FUS', 'Gene', (219, 222))	('EWSR1', 'Gene', (4, 9))	('FUS', 'Gene', '2521', (219, 222))
95243	28844694	Thus, we generated two EWS-FLI1 mutant proteins with point mutations altering either 12 or all 37 tyrosines in the prion-like domain (namely EWS(YS12)-FLI1 and EWS(YS37)-FLI1; Figures 5A and S6A).	('FLI1', 'Gene', (151, 155))	('EWS', 'Gene', (141, 144))	('EWS', 'Gene', '2130', (141, 144))	('EWS-FLI1', 'Gene', '2130', (23, 31))	('FLI1', 'Gene', '2130', (151, 155))	('EWS-FLI1', 'Gene', (23, 31))	('FLI1', 'Gene', '2130', (27, 31))	('FLI1', 'Gene', (170, 174))	('EWS', 'Gene', '2130', (160, 163))	('EWS', 'Gene', (160, 163))	('tyrosines', 'Chemical', 'None', (98, 107))	('EWS', 'Gene', '2130', (23, 26))	('EWS', 'Gene', (23, 26))	('prion', 'Species', '36469', (115, 120))	('FLI1', 'Gene', '2130', (170, 174))	('point mutations', 'Var', (53, 68))	('FLI1', 'Gene', (27, 31))
95245	28844694	The EWS(YS12)-FLI1 mutant protein maintained significant interactions with wild-type EWSR1 and BRG1, and although diminished, b-isox-induced precipitation remained significantly higher than wild-type FLI1 (Figures 4E, 5B, and 5C).	('FLI1', 'Gene', '2130', (14, 18))	('5C', 'Chemical', 'MESH:D002244', (226, 228))	('mutant', 'Var', (19, 25))	('EWS', 'Gene', '2130', (85, 88))	('diminished', 'NegReg', (114, 124))	('EWSR1', 'Gene', (85, 90))	('FLI1', 'Gene', (14, 18))	('b-isox-induced precipitation', 'MPA', (126, 154))	('EWS', 'Gene', '2130', (4, 7))	('interactions', 'Interaction', (57, 69))	('higher', 'PosReg', (178, 184))	('EWS', 'Gene', (85, 88))	('FLI1', 'Gene', '2130', (200, 204))	('BRG1', 'Gene', '6597', (95, 99))	('EWSR1', 'Gene', '2130', (85, 90))	('FLI1', 'Gene', (200, 204))	('BRG1', 'Gene', (95, 99))	('protein', 'Protein', (26, 33))	('EWS', 'Gene', (4, 7))
95247	28844694	EWS(YS37)-FLI1, however, maintained the ability to homodimerize, a hallmark of ETS family transcription factors, as assessed by reciprocal immunoprecipitation experiments using overexpressed HA- and V5-tagged variants in HEK293-T cells (Figure S6D).	('variants', 'Var', (209, 217))	('ability', 'MPA', (40, 47))	('FLI1', 'Gene', (10, 14))	('FLI1', 'Gene', '2130', (10, 14))	('homodimerize', 'Interaction', (51, 63))	('HEK293-T', 'CellLine', 'CVCL:0063', (221, 229))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
95249	28844694	Based on these findings, we further tested the ability of the EWS(YS37)-FLI1 mutant protein to bind GGAA microsatellite repeats and to create active enhancers once expressed in MSCs (Figure S6F).	('tested', 'Reg', (36, 42))	('microsatellite repeats', 'Protein', (105, 127))	('FLI1', 'Gene', (72, 76))	('mutant', 'Var', (77, 83))	('FLI1', 'Gene', '2130', (72, 76))	('protein', 'Protein', (84, 91))	('bind', 'Interaction', (95, 99))	('EWS', 'Gene', '2130', (62, 65))	('EWS', 'Gene', (62, 65))	('enhancers', 'PosReg', (149, 158))
95250	28844694	ChIP-seq experiments clearly demonstrated a dramatic reduction in binding of the EWS(YS37)-FLI1 mutant at these sites, as well as impaired BAF complex recruitment (Figures5E and S6G).	('mutant', 'Var', (96, 102))	('FLI1', 'Gene', '2130', (91, 95))	('binding', 'Interaction', (66, 73))	('reduction', 'NegReg', (53, 62))	('BAF', 'Gene', '8815', (139, 142))	('EWS', 'Gene', '2130', (81, 84))	('EWS', 'Gene', (81, 84))	('impaired', 'NegReg', (130, 138))	('BAF', 'Gene', (139, 142))	('recruitment', 'MPA', (151, 162))	('FLI1', 'Gene', (91, 95))
95253	28844694	Taken together, our results demonstrate that the tyrosine residues in the EWS-FLI1 prion-like domain are necessary to mediate phase transitions and are required for its pioneer activity by allowing stable DNA binding, BAF complex recruitment at GGAA repeat microsatellites, and target gene activation.	('allowing', 'PosReg', (189, 197))	('EWS-FLI1', 'Gene', '2130', (74, 82))	('EWS-FLI1', 'Gene', (74, 82))	('recruitment', 'PosReg', (230, 241))	('DNA binding', 'Interaction', (205, 216))	('activation', 'PosReg', (290, 300))	('prion', 'Species', '36469', (83, 88))	('BAF', 'Gene', '8815', (218, 221))	('tyrosine', 'Chemical', 'None', (49, 57))	('BAF', 'Gene', (218, 221))	('tyrosine residues', 'Var', (49, 66))
95255	28844694	To this end, we generated a series of EWS-FLI1 internal deletion mutants (Figure S7A).	('EWS-FLI1', 'Gene', '2130', (38, 46))	('internal deletion mutants', 'Var', (47, 72))	('EWS-FLI1', 'Gene', (38, 46))
95256	28844694	Whereas the tyrosine residues that we showed to be critical are mostly evenly distributed over the EWSR1 prion-like domain, there are two regions that contain exact [G/S]Y[G/S] motifs followed by a glutamine (SYGQ), which we have designated as SYGQ1 (also called FETBM1) and SYGQ2.	('EWSR1', 'Gene', '2130', (99, 104))	('prion', 'Species', '36469', (105, 110))	('glutamine', 'Chemical', 'MESH:C578860', (198, 207))	('exact [G/S]Y[G/S] motifs', 'Var', (159, 183))	('EWSR1', 'Gene', (99, 104))	('tyrosine', 'Chemical', 'None', (12, 20))
95257	28844694	All EWS-FLI1 deletion mutant proteins accumulated in the nucleus of MSCs and exhibited comparable binding to wild-type EWSR1 and BRG1 (Figures S7B-S7D).	('binding', 'Interaction', (98, 105))	('BRG1', 'Gene', (129, 133))	('EWSR1', 'Gene', '2130', (119, 124))	('proteins', 'Protein', (29, 37))	('EWS-FLI1', 'Gene', '2130', (4, 12))	('EWS-FLI1', 'Gene', (4, 12))	('deletion mutant', 'Var', (13, 28))	('mutant', 'Var', (22, 28))	('accumulated', 'PosReg', (38, 49))	('BRG1', 'Gene', '6597', (129, 133))	('EWSR1', 'Gene', (119, 124))
95258	28844694	Similarly, EWS-FLI1 deletion mutants maintained b-isox-induced precipitation properties that were diminished when compared to EWS-FLI1 but significantly higher than those of wild-type FLI1 (Figure S7E).	('higher', 'PosReg', (153, 159))	('FLI1', 'Gene', '2130', (130, 134))	('b-isox-induced precipitation properties', 'MPA', (48, 87))	('FLI1', 'Gene', (184, 188))	('FLI1', 'Gene', (15, 19))	('EWS-FLI1', 'Gene', '2130', (126, 134))	('EWS-FLI1', 'Gene', (126, 134))	('deletion mutants', 'Var', (20, 36))	('FLI1', 'Gene', '2130', (184, 188))	('FLI1', 'Gene', (130, 134))	('EWS-FLI1', 'Gene', '2130', (11, 19))	('EWS-FLI1', 'Gene', (11, 19))	('FLI1', 'Gene', '2130', (15, 19))
95259	28844694	We next assessed changes in target gene expression after introduction of the different EWS-FLI1 mutants in MSCs and observed that a large set of target genes activated by GGAA microsatellites was still strongly induced by all constructs (Figure S7F).	('microsatellites', 'Var', (176, 191))	('induced', 'PosReg', (211, 218))	('EWS-FLI1', 'Gene', '2130', (87, 95))	('EWS-FLI1', 'Gene', (87, 95))	('mutants', 'Var', (96, 103))
95264	28844694	Fusion of the SYGQ2 fragment (64 amino acids) to the FLI1 C-terminal region was also sufficient to recapitulate EWS-FLI1 function (Figures 6A-6C and S7G).	('FLI1', 'Gene', '2130', (53, 57))	('Fusion', 'Var', (0, 6))	('64 amino acids', 'Chemical', 'MESH:C033067', (30, 44))	('FLI1', 'Gene', '2130', (116, 120))	('EWS-FLI1', 'Gene', '2130', (112, 120))	('EWS-FLI1', 'Gene', (112, 120))	('recapitulate', 'NegReg', (99, 111))	('function', 'MPA', (121, 129))	('FLI1', 'Gene', (53, 57))	('FLI1', 'Gene', (116, 120))
95266	28844694	Finally, the distinct abilities of mutant EWS-FLI1 proteins to recapitulate EWS-FLI1-mediated gene expression programs were evident by comparing RNA-seq expression profiles.	('proteins', 'Protein', (51, 59))	('mutant', 'Var', (35, 41))	('EWS-FLI1', 'Gene', '2130', (42, 50))	('EWS-FLI1', 'Gene', (42, 50))	('EWS-FLI1', 'Gene', '2130', (76, 84))	('EWS-FLI1', 'Gene', (76, 84))
95268	28844694	In agreement with these results, cell growth arrest and phenotypic changes induced by EWS-FLI1 knockdown were rescued by the SYGQ2-FLI1 mutant protein, but not by EWS(YS37)-FLI1 (Figure S7I).	('EWS-FLI1', 'Gene', (86, 94))	('FLI1', 'Gene', '2130', (173, 177))	('protein', 'Protein', (143, 150))	('mutant', 'Var', (136, 142))	('EWS', 'Gene', '2130', (163, 166))	('FLI1', 'Gene', (173, 177))	('FLI1', 'Gene', '2130', (131, 135))	('growth arrest', 'Phenotype', 'HP:0001510', (38, 51))	('phenotypic changes', 'CPA', (56, 74))	('EWS', 'Gene', (86, 89))	('FLI1', 'Gene', (131, 135))	('growth arrest', 'Disease', 'MESH:D006323', (38, 51))	('FLI1', 'Gene', '2130', (90, 94))	('EWS-FLI1', 'Gene', '2130', (86, 94))	('EWS', 'Gene', (163, 166))	('FLI1', 'Gene', (90, 94))	('knockdown', 'Var', (95, 104))	('growth arrest', 'Disease', (38, 51))	('EWS', 'Gene', '2130', (86, 89))
95269	28844694	These results thus demonstrate that even small isolated fragments of the EWSR1 prion-like domain are sufficient to recapitulate the function of the full EWS-FLI1 fusion on chromatin and to induce gene expression programs associated with GGAA microsatellites in Ewing sarcoma tumors.	('EWS-FLI1', 'Gene', (153, 161))	('EWS-FLI1', 'Gene', '2130', (153, 161))	('Ewing sarcoma tumors', 'Disease', 'MESH:D012512', (261, 281))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('EWSR1', 'Gene', (73, 78))	('Ewing sarcoma tumors', 'Disease', (261, 281))	('induce', 'PosReg', (189, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (267, 274))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('prion', 'Species', '36469', (79, 84))	('gene expression programs', 'MPA', (196, 220))	('EWSR1', 'Gene', '2130', (73, 78))	('fusion', 'Var', (162, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (261, 274))
95272	28844694	This process can be altered by mutations in the prion-like domain or local protein accumulation, as observed in amyotrophic lateral sclerosis (ALS), where the pathological aggregation of low-complexity proteins may be the result of the conversion from liquid to solid states.	('mutations', 'Var', (31, 40))	('local', 'MPA', (69, 74))	('altered', 'Reg', (20, 27))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (112, 141))	('accumulation', 'PosReg', (83, 95))	('prion', 'Species', '36469', (48, 53))	('protein', 'Protein', (75, 82))	('ALS', 'Gene', '6647', (143, 146))	('prion-like domain', 'Protein', (48, 65))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (112, 141))	('amyotrophic lateral sclerosis', 'Disease', (112, 141))	('ALS', 'Phenotype', 'HP:0007354', (143, 146))	('ALS', 'Gene', (143, 146))
95275	28844694	Mutations in the genes encoding BAF complex subunits are observed in many tumor types, suggesting that tumor-specific changes in BAF complex composition and function play important roles in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (103, 108))	('observed', 'Reg', (57, 65))	('BAF', 'Gene', '8815', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('BAF', 'Gene', '8815', (129, 132))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (74, 79))	('cancer', 'Disease', (196, 202))	('human', 'Species', '9606', (190, 195))	('BAF', 'Gene', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('BAF', 'Gene', (129, 132))
95280	28844694	Alterations in BAF subunits may also be associated with changes in both subunit composition and configuration of the BAF complex.	('subunit composition', 'MPA', (72, 91))	('BAF', 'Gene', '8815', (117, 120))	('Alterations', 'Var', (0, 11))	('BAF', 'Gene', (117, 120))	('BAF', 'Gene', '8815', (15, 18))	('BAF', 'Gene', (15, 18))	('changes', 'Reg', (56, 63))
95326	28844694	To compare changes in expression of GGAA-repeat associated EWS-FLI1 target genes in MSC experiments, we selected genes based on downregulation upon EWS-FLI1 knockdown in both A673 and SKNMC Ewing sarcoma cells (greater than 2-fold) and a maximum distance of 1 megabase from a EWS-FLI1-bound GGAA repeat.	('EWS-FLI1', 'Gene', '2130', (276, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('EWS-FLI1', 'Gene', (276, 284))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (190, 203))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (190, 203))	('SKNMC', 'CellLine', 'CVCL:0530', (184, 189))	('knockdown', 'Var', (157, 166))	('EWS-FLI1', 'Gene', '2130', (59, 67))	('EWS-FLI1', 'Gene', (59, 67))	('Ewing sarcoma', 'Disease', (190, 203))	('EWS-FLI1', 'Gene', '2130', (148, 156))	('EWS-FLI1', 'Gene', (148, 156))	('downregulation', 'NegReg', (128, 142))
95328	28844694	Principal components were calculated separately for repeat-associated genes (as described above) and non-repeat-associated genes with reciprocal changes in EWS-FLI1 knockdowns (2-fold in A673 and SKNMC cells) and MSCs infected with EWS-FLI1 (2-fold and corrected p value <0.05).	('EWS-FLI1', 'Gene', '2130', (156, 164))	('EWS-FLI1', 'Gene', (156, 164))	('SKNMC', 'CellLine', 'CVCL:0530', (196, 201))	('EWS-FLI1', 'Gene', '2130', (232, 240))	('MSCs infected', 'Disease', 'MESH:D007239', (213, 226))	('EWS-FLI1', 'Gene', (232, 240))	('MSCs infected', 'Disease', (213, 226))	('knockdowns', 'Var', (165, 175))	('changes', 'Reg', (145, 152))
95338	28844694	Wild-type and mutant constructs were cloned in pGEX-6P1, and expressed in E. coli BL21 (DE3) pLysS (Fisher Scientific).	('pLysS', 'Disease', 'None', (93, 98))	('mutant', 'Var', (14, 20))	('E. coli', 'Species', '562', (74, 81))	('pLysS', 'Disease', (93, 98))	('BL21', 'CellLine', 'CVCL:M639', (82, 86))
95399	31528412	Genetic subsets of these tumors seem to be emerging in younger patients, including round-cell sarcoma with EWSR1 translocations and non-ETS fusion partners, CIC-DUX4 translocation, and BCOR-CCNB3 fusion.	('DUX4', 'Gene', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('BCOR', 'Gene', '54880', (185, 189))	('sarcoma', 'Disease', (94, 101))	('tumors', 'Disease', (25, 31))	('CCNB3', 'Gene', (190, 195))	('EWSR1', 'Gene', (107, 112))	('DUX4', 'Gene', '100288687', (161, 165))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('EWSR1', 'Gene', '2130', (107, 112))	('translocations', 'Var', (113, 127))	('patients', 'Species', '9606', (63, 71))	('BCOR', 'Gene', (185, 189))	('CCNB3', 'Gene', '85417', (190, 195))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))
95433	28714986	We applied GROC-SVs to characterize chromothripsis and subsequent evolution of structural variation in a liposarcoma and to analyze SVs in a breast cancer cell line.	('liposarcoma', 'Disease', (105, 116))	('liposarcoma', 'Disease', 'MESH:D008080', (105, 116))	('structural variation', 'Var', (79, 99))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('liposarcoma', 'Phenotype', 'HP:0012034', (105, 116))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))
95454	28714986	Thus, the sarcoma must have undergone an initial period of substantial structural instability, accumulating hundreds of rearrangements and copy number changes, before converging to a stable genomic configuration.	('rearrangements', 'Var', (120, 134))	('copy number changes', 'Var', (139, 158))	('sarcoma', 'Disease', (10, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('sarcoma', 'Disease', 'MESH:D012509', (10, 17))
95563	23792708	However, in the case of the US study, the cutoff point for anemia was <10 g/dL which was not categorized by the level of MCV.	('anemia', 'Phenotype', 'HP:0001903', (59, 65))	('<10 g/dL', 'Var', (70, 78))	('anemia', 'Disease', (59, 65))	('anemia', 'Disease', 'MESH:D000740', (59, 65))
95583	28459883	Depletion of NLRX1 in either iSLK.219 or BCBL-1 cells significantly suppressed global viral transcription levels compared to the control group.	('BCBL-1', 'CellLine', 'CVCL:0165', (41, 47))	('suppressed', 'NegReg', (68, 78))	('Depletion', 'Var', (0, 9))	('global viral transcription levels', 'MPA', (79, 112))	('NLRX1', 'Gene', (13, 18))
95585	28459883	Further analysis revealed that upon NLRX1 depletion, higher IFNbeta transcription levels were observed, which was also associated with a transcriptional upregulation of JAK/STAT pathway related genes in both cell lines.	('higher', 'PosReg', (53, 59))	('upregulation', 'PosReg', (153, 165))	('NLRX1', 'Gene', (36, 41))	('depletion', 'Var', (42, 51))	('IFNbeta', 'Gene', (60, 67))	('JAK/STAT pathway', 'Pathway', (169, 185))	('IFNbeta', 'Gene', '3456', (60, 67))
95587	28459883	Upon BX795 or TBK1 siRNA treatment, NLRX1 depletion exhibited less inhibitory effects on reactivation and infectious virion production, suggesting that NLRX1 facilitates KSHV lytic replication by negatively regulating IFNbeta responses.	('negatively', 'NegReg', (196, 206))	('facilitates', 'PosReg', (158, 169))	('infectious virion production', 'MPA', (106, 134))	('KSHV', 'Species', '37296', (170, 174))	('KS', 'Phenotype', 'HP:0100726', (170, 172))	('reactivation', 'MPA', (89, 101))	('NLRX1', 'Var', (152, 157))	('IFNbeta', 'Gene', (218, 225))	('IFNbeta', 'Gene', '3456', (218, 225))
95608	28459883	In a similar vein, NLRX1 deficient mice also exhibited stronger innate immune responses and thus reduced HSV1 replication.	('NLRX1', 'Gene', (19, 24))	('reduced', 'NegReg', (97, 104))	('HSV1 replication', 'CPA', (105, 121))	('deficient', 'Var', (25, 34))	('stronger', 'PosReg', (55, 63))	('mice', 'Species', '10090', (35, 39))	('HSV1', 'Species', '10298', (105, 109))	('innate immune responses', 'CPA', (64, 87))
95611	28459883	KSHV reactivation has been previously reported to activate MAVS-dependent cytosolic RNA sensing pathways.	('MAVS', 'Gene', (59, 63))	('KSHV', 'Species', '37296', (0, 4))	('MAVS', 'Gene', '57506', (59, 63))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('reactivation', 'Var', (5, 17))	('KSHV', 'Gene', (0, 4))	('activate', 'PosReg', (50, 58))
95618	28459883	Moreover, while we did not observe significant GFP variation, RFP intensity quantitation showed significant inhibition of RFP intensity in the NLRX1 siRNA transfected samples compared to the control NS siRNA transfected samples.	('RFP', 'Gene', (62, 65))	('RFP', 'Gene', '5987', (122, 125))	('inhibition', 'NegReg', (108, 118))	('RFP', 'Gene', (122, 125))	('transfected', 'Var', (155, 166))	('RFP', 'Gene', '5987', (62, 65))	('NLRX1', 'Gene', (143, 148))
95622	28459883	Consistent with RFP expression levels, we detected significantly fewer KSHV genomes in the NLRX1 siRNA transfected samples compared to control NS siRNA transfected samples as determined by KSHV genome copy number (Fig 1D and 1E).	('C', 'Chemical', 'MESH:D002244', (0, 1))	('KSHV', 'Species', '37296', (189, 193))	('KSHV genomes', 'Gene', (71, 83))	('NLRX1', 'Gene', (91, 96))	('KS', 'Phenotype', 'HP:0100726', (189, 191))	('transfected', 'Var', (103, 114))	('RFP', 'Gene', '5987', (16, 19))	('KSHV', 'Species', '37296', (71, 75))	('KS', 'Phenotype', 'HP:0100726', (71, 73))	('RFP', 'Gene', (16, 19))	('fewer', 'NegReg', (65, 70))
95623	28459883	NLRX1 knockdown efficiency was checked by qRT-PCR (Fig 2A).	('knockdown', 'Var', (6, 15))	('C', 'Chemical', 'MESH:D002244', (47, 48))	('NLRX1', 'Gene', (0, 5))
95626	28459883	NLRX1 deficient cells showed a reduced ability to induce lytic gene transcription (such as ORF57, vIRF1 and K8.1) than the control NS siRNA transfected cells (Fig 2B and 2C; S2C and S2D Fig).	('reduced', 'NegReg', (31, 38))	('ORF57', 'Gene', (91, 96))	('C', 'Chemical', 'MESH:D002244', (176, 177))	('K8.1', 'Gene', '3887', (108, 112))	('vIRF1', 'Gene', '4961464', (98, 103))	('deficient', 'Var', (6, 15))	('lytic gene', 'Gene', (57, 67))	('NLRX1', 'Gene', (0, 5))	('K8.1', 'Gene', (108, 112))	('vIRF1', 'Gene', (98, 103))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('ORF57', 'Gene', '4961525', (91, 96))	('induce', 'PosReg', (50, 56))
95629	28459883	As seen in Fig 2E, Dox treatment successfully induced KSHV gene expression, and depletion of NLRX1 led to a suppression and delay of viral genome transcription at each time point that we tested, which correlates well with our qRT-PCR data (Fig 2E).	('KSHV gene', 'Gene', (54, 63))	('expression', 'MPA', (64, 74))	('induced', 'Reg', (46, 53))	('KS', 'Phenotype', 'HP:0100726', (54, 56))	('viral genome transcription', 'MPA', (133, 159))	('suppression', 'NegReg', (108, 119))	('C', 'Chemical', 'MESH:D002244', (231, 232))	('Dox', 'Chemical', 'MESH:D004318', (19, 22))	('KSHV', 'Species', '37296', (54, 58))	('delay', 'NegReg', (124, 129))	('depletion', 'Var', (80, 89))	('NLRX1', 'Gene', (93, 98))
95631	28459883	We next probed for the mechanism by which NLRX1 depletion restricts KSHV lytic reactivation from latency.	('KSHV', 'Gene', (68, 72))	('restricts', 'NegReg', (58, 67))	('KSHV', 'Species', '37296', (68, 72))	('depletion', 'Var', (48, 57))	('NLRX1', 'Gene', (42, 47))	('KS', 'Phenotype', 'HP:0100726', (68, 70))
95635	28459883	As seen in Fig 3A, loss of NLRX1 did result in stronger ifnb transcriptional activity.	('ifnb', 'Gene', '3456', (56, 60))	('transcriptional activity', 'MPA', (61, 85))	('stronger', 'PosReg', (47, 55))	('ifnb', 'Gene', (56, 60))	('loss', 'Var', (19, 23))	('NLRX1', 'Gene', (27, 32))
95637	28459883	To investigate this further, we next tested whether the upregulated ifnb transcription level in NLRX1 deficient cells led to the activation of the JAK/STAT pathway.	('tested', 'Reg', (37, 43))	('ifnb', 'Gene', '3456', (68, 72))	('deficient', 'Var', (102, 111))	('upregulated', 'PosReg', (56, 67))	('activation', 'PosReg', (129, 139))	('JAK/STAT pathway', 'Pathway', (147, 163))	('NLRX1', 'Gene', (96, 101))	('transcription level', 'MPA', (73, 92))	('ifnb', 'Gene', (68, 72))
95641	28459883	In summary, NLRX1 deficient cells induce a much wider variety of JAK/STAT pathway related genes at each time point tested in KSHV reactivated cells compared to the control cells.	('induce', 'PosReg', (34, 40))	('NLRX1', 'Gene', (12, 17))	('JAK/STAT pathway related genes', 'Gene', (65, 95))	('KS', 'Phenotype', 'HP:0100726', (125, 127))	('KSHV', 'Species', '37296', (125, 129))	('deficient', 'Var', (18, 27))
95652	28459883	As shown in Fig 4A, we transfected poly I:C into KSHV infected iSLK.219 cells and successfully triggered MAVS dependent IFNbeta induction, which is indicative of a functional RLR pathway.	('triggered', 'Reg', (95, 104))	('RLR', 'Gene', '79132', (175, 178))	('IFNbeta', 'Gene', '3456', (120, 127))	('IFNbeta', 'Gene', (120, 127))	('KSHV', 'Species', '37296', (49, 53))	('poly I:C', 'Chemical', 'MESH:D011070', (35, 43))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('RLR', 'Gene', (175, 178))	('MAVS', 'Gene', (105, 109))	('MAVS', 'Gene', '57506', (105, 109))	('poly I:C', 'Var', (35, 43))
95653	28459883	Moreover, NLRX1 depletion in these cells resulted in higher induction of IFNbeta, suggesting NLRX1 blocks MAVS signaling in KSHV-infected iSLK.219 cells without reactivation.	('blocks', 'NegReg', (99, 105))	('higher', 'PosReg', (53, 59))	('depletion', 'Var', (16, 25))	('IFNbeta', 'Gene', (73, 80))	('induction', 'MPA', (60, 69))	('IFNbeta', 'Gene', '3456', (73, 80))	('KSHV-infected', 'Disease', 'MESH:C537372', (124, 137))	('KS', 'Phenotype', 'HP:0100726', (124, 126))	('MAVS', 'Gene', (106, 110))	('MAVS', 'Gene', '57506', (106, 110))	('KSHV-infected', 'Disease', (124, 137))
95654	28459883	NLRX1 knockdown efficiency was monitored by qRT-PCR (Fig 4B).	('knockdown', 'Var', (6, 15))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('NLRX1', 'Gene', (0, 5))
95655	28459883	We also tested if poly I:C, an activator of the MAVS pathway, could mimic the effect of NLRX1 knockdown to inhibit KSHV reactivation.	('inhibit', 'NegReg', (107, 114))	('KSHV reactivation', 'MPA', (115, 132))	('knockdown', 'Var', (94, 103))	('poly I:C', 'Chemical', 'MESH:D011070', (18, 26))	('MAVS', 'Gene', (48, 52))	('MAVS', 'Gene', '57506', (48, 52))	('NLRX1', 'Gene', (88, 93))	('KSHV', 'Species', '37296', (115, 119))	('KS', 'Phenotype', 'HP:0100726', (115, 117))
95656	28459883	As shown in S5A-S5F Fig, poly I:C induced IFNbeta during reactivation, and this correlated with inhibition of KSHV reactivation as determined by RFP fluorescence and viral lytic gene expression.	('KSHV reactivation', 'MPA', (110, 127))	('KSHV', 'Species', '37296', (110, 114))	('IFNbeta', 'Gene', (42, 49))	('RFP', 'Gene', '5987', (145, 148))	('RFP', 'Gene', (145, 148))	('IFNbeta', 'Gene', '3456', (42, 49))	('KS', 'Phenotype', 'HP:0100726', (110, 112))	('induced', 'Reg', (34, 41))	('poly I:C', 'Var', (25, 33))	('poly I:C', 'Chemical', 'MESH:D011070', (25, 33))	('inhibition', 'NegReg', (96, 106))
95658	28459883	As shown in Fig 4C, when we treated cells with NLRX1 siRNA and BX795, we observed significant inhibition of IFNbeta compared to the NLRX1 siRNA and vehicle only treated group at 24 and 48 hours post reactivation.	('C', 'Chemical', 'MESH:D002244', (17, 18))	('inhibition', 'NegReg', (94, 104))	('BX795', 'Var', (63, 68))	('IFNbeta', 'Gene', (108, 115))	('IFNbeta', 'Gene', '3456', (108, 115))	('NLRX1 siRNA', 'Var', (47, 58))
95659	28459883	IFNbeta levels in the NLRX1 siRNA and BX795 treated group were similar to that of the NS siRNA treated group.	('IFNbeta', 'Gene', '3456', (0, 7))	('IFNbeta', 'Gene', (0, 7))	('BX795', 'Var', (38, 43))
95660	28459883	NLRX1 knockdown efficiency was monitored by qRT-PCR (Fig 4D).	('knockdown', 'Var', (6, 15))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('NLRX1', 'Gene', (0, 5))
95662	28459883	As shown in S1D-S1F Fig, NLRX1 overexpression inhibited dRIG-I- or MAVS- dependent activation of the IFNbeta promoter, but the IRF3(SA) activated IFNbeta promoter activation was not affected.	('IRF3', 'Gene', '3661', (127, 131))	('NLRX1', 'Gene', (25, 30))	('RIG-I', 'Gene', '23586', (57, 62))	('overexpression', 'Var', (31, 45))	('IFNbeta', 'Gene', (146, 153))	('RIG-I', 'Gene', (57, 62))	('MAVS', 'Gene', (67, 71))	('IFNbeta', 'Gene', (101, 108))	('activation', 'MPA', (83, 93))	('IFNbeta', 'Gene', '3456', (146, 153))	('MAVS', 'Gene', '57506', (67, 71))	('IFNbeta', 'Gene', '3456', (101, 108))	('IRF3', 'Gene', (127, 131))	('inhibited', 'NegReg', (46, 55))
95665	28459883	As shown in Fig 5A, while NLRX1 depletion resulted in less RFP positive cells than the control NS siRNA group, BX795 treatment partially rescued the block of lytic replication.	('depletion', 'Var', (32, 41))	('less', 'NegReg', (54, 58))	('RFP', 'Gene', (59, 62))	('lytic replication', 'CPA', (158, 175))	('RFP', 'Gene', '5987', (59, 62))	('NLRX1', 'Gene', (26, 31))
95668	28459883	We detected significantly fewer KSHV virions in cells transfected with NLRX1 siRNA compared to control NS siRNA samples, and a partial rescue of KSHV viral genomes upon BX795 treatment (Fig 5D).	('KSHV virions', 'CPA', (32, 44))	('NLRX1', 'Var', (71, 76))	('KS', 'Phenotype', 'HP:0100726', (145, 147))	('KSHV', 'Species', '37296', (145, 149))	('KSHV', 'Species', '37296', (32, 36))	('fewer', 'NegReg', (26, 31))	('KS', 'Phenotype', 'HP:0100726', (32, 34))	('KSHV', 'Gene', (145, 149))
95670	28459883	NLRX1 depletion led to a significant inhibition of ORF57 gene transcription, but this was partially rescued by BX795 treatment (Fig 5E).	('inhibition', 'NegReg', (37, 47))	('transcription', 'MPA', (62, 75))	('ORF57', 'Gene', '4961525', (51, 56))	('depletion', 'Var', (6, 15))	('NLRX1', 'Gene', (0, 5))	('ORF57', 'Gene', (51, 56))
95674	28459883	As shown in Fig 6D-6G, NLRX1 depletion led to significant inhibition of ORF57, K8.1 and vIRF1 gene transcription, but they were all rescued when the cells were co-transfected with TBK1 siRNA.	('depletion', 'Var', (29, 38))	('K8.1', 'Gene', '3887', (79, 83))	('transcription', 'MPA', (99, 112))	('NLRX1', 'Gene', (23, 28))	('ORF57', 'Gene', '4961525', (72, 77))	('vIRF1', 'Gene', '4961464', (88, 93))	('K8.1', 'Gene', (79, 83))	('ORF57', 'Gene', (72, 77))	('vIRF1', 'Gene', (88, 93))	('inhibition', 'NegReg', (58, 68))
95675	28459883	NLRX1 knockdown efficiency was monitored by qRT-PCR as shown in Fig 6D.	('knockdown', 'Var', (6, 15))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('NLRX1', 'Gene', (0, 5))
95676	28459883	We have also tested if TBK1 knockdown alone promoted KSHV replication by examining viral lytic gene transcription by qRT-PCR.	('TBK1', 'Gene', (23, 27))	('promoted', 'PosReg', (44, 52))	('KSHV replication', 'MPA', (53, 69))	('KSHV', 'Species', '37296', (53, 57))	('knockdown', 'Var', (28, 37))	('C', 'Chemical', 'MESH:D002244', (122, 123))	('KS', 'Phenotype', 'HP:0100726', (53, 55))
95677	28459883	As shown in S6A-S6D Fig, TBK1 knockdown resulted in elevated transcription of viral genes, such as orf57, virf1 and k8.1.	('TBK1', 'Gene', (25, 29))	('virf1', 'Gene', (106, 111))	('virf1', 'Gene', '4961464', (106, 111))	('orf57', 'Gene', (99, 104))	('orf57', 'Gene', '4961525', (99, 104))	('k8.1', 'Gene', (116, 120))	('knockdown', 'Var', (30, 39))	('k8.1', 'Gene', '3887', (116, 120))	('transcription', 'MPA', (61, 74))	('elevated', 'PosReg', (52, 60))
95682	28459883	As shown in Fig 7A and 7B, NLRX1 depletion resulted in significant inhibition of KSHV viral replication both in the cells and in the supernatant, as determined by the genome copy number.	('KSHV viral', 'Gene', (81, 91))	('depletion', 'Var', (33, 42))	('inhibition', 'NegReg', (67, 77))	('NLRX1', 'Gene', (27, 32))	('KS', 'Phenotype', 'HP:0100726', (81, 83))	('KSHV', 'Species', '37296', (81, 85))
95684	28459883	NLRX1 depletion resulted in significant inhibition of lytic gene transcription such as ORF57 (Immediate early), ORF36 (early), and K8.1 (late) than NS siRNA transfected cells (Fig 7D-7F).	('ORF36', 'Gene', (112, 117))	('ORF57', 'Gene', '4961525', (87, 92))	('inhibition', 'NegReg', (40, 50))	('K8.1', 'Gene', '3887', (131, 135))	('depletion', 'Var', (6, 15))	('NLRX1', 'Gene', (0, 5))	('lytic gene', 'Gene', (54, 64))	('ORF57', 'Gene', (87, 92))	('K8.1', 'Gene', (131, 135))
95685	28459883	NLRX1 knockdown efficiency was monitored by qRT-PCR as shown in Fig 7C.	('knockdown', 'Var', (6, 15))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('NLRX1', 'Gene', (0, 5))	('C', 'Chemical', 'MESH:D002244', (69, 70))
95689	28459883	As seen in Fig 8A, NLRX1 depletion enhanced ifnb transcriptional activity compared to the NS siRNA group, confirming NLRX1's role in restricting IFNbeta.	('transcriptional activity', 'MPA', (49, 73))	('NLRX1', 'Gene', (19, 24))	('IFNbeta', 'Gene', (145, 152))	('ifnb', 'Gene', '3456', (44, 48))	('IFNbeta', 'Gene', '3456', (145, 152))	('enhanced', 'PosReg', (35, 43))	('depletion', 'Var', (25, 34))	('ifnb', 'Gene', (44, 48))
95691	28459883	At 0, 24 and 48 hours, a significant number of genes were induced at least 2 fold higher in NLRX1 siRNA transfected cells compared to NS siRNA transfected cells, indicating a higher potential of JAK/STAT pathway upregulation when NLRX1 is depleted in BCBL-1 cells (Fig 8B-8D).	('induced', 'PosReg', (58, 65))	('transfected', 'Var', (104, 115))	('BCBL-1', 'CellLine', 'CVCL:0165', (251, 257))	('siRNA transfected', 'Var', (98, 115))	('higher', 'PosReg', (82, 88))	('NLRX1', 'Gene', (92, 97))	('upregulation', 'PosReg', (212, 224))	('JAK/STAT pathway', 'Pathway', (195, 211))
95697	28459883	vIRF1 knockdown in the context of viral reactivation can result in enhanced IFNbeta production and insufficient reactivation.	('insufficient', 'Disease', (99, 111))	('reactivation', 'MPA', (112, 124))	('IFNbeta', 'Gene', (76, 83))	('vIRF1', 'Gene', '4961464', (0, 5))	('IFNbeta', 'Gene', '3456', (76, 83))	('knockdown', 'Var', (6, 15))	('vIRF1', 'Gene', (0, 5))	('insufficient', 'Disease', 'MESH:D000309', (99, 111))	('enhanced', 'PosReg', (67, 75))
95743	28459883	The relative amount of IFNbeta, ORF57, ORF36 and K8.1 mRNA was normalized to actin RNA level in each sample and the fold difference between the treated and mock samples was calculated.	('ORF57', 'Gene', (32, 37))	('K8.1', 'Gene', '3887', (49, 53))	('K8.1', 'Gene', (49, 53))	('actin RNA level', 'MPA', (77, 92))	('IFNbeta', 'Gene', (23, 30))	('ORF57', 'Gene', '4961525', (32, 37))	('ORF36', 'Var', (39, 44))	('IFNbeta', 'Gene', '3456', (23, 30))
95759	27258263	Extensive epidemiologic studies confirmed the presence of KSHV genome in all the KS variants, demonstrating a strong temporal association, which indicates KSHV as the necessary agent for KS development.	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('KSHV', 'Species', '37296', (58, 62))	('KS', 'Phenotype', 'HP:0100726', (155, 157))	('KSHV', 'Species', '37296', (155, 159))	('KSHV', 'Gene', (58, 62))	('KS', 'Phenotype', 'HP:0100726', (187, 189))	('variants', 'Var', (84, 92))	('KS', 'Phenotype', 'HP:0100726', (81, 83))
95765	27258263	Conversely, HR is an error-free process that requires the presence of long and undamaged 3'-single-strand (ss)DNA of homologous DNA template during the S/G2 phase, to repair the broken ends.	('S/G2', 'SUBSTITUTION', 'None', (152, 156))	('error-free', 'Disease', 'MESH:D000072662', (21, 31))	('error-free', 'Disease', (21, 31))	('S/G2', 'Var', (152, 156))
95767	27258263	In particular, ATM is activated by DSBs, while ATR is activated at regions exposing ssDNA.	('ATM', 'Gene', (15, 18))	('ATR', 'Gene', '545', (47, 50))	('activated', 'PosReg', (22, 31))	('ATM', 'Gene', '472', (15, 18))	('ATR', 'Gene', (47, 50))	('DSBs', 'Var', (35, 39))
95768	27258263	After initially "sensing" DNA damage, ATM kinase is converted into a partially active monomer by an autophosphorylation process on S1981 and its interaction with MRN at the DSB site.	('ATM', 'Gene', '472', (38, 41))	('interaction', 'Interaction', (145, 156))	('ATM', 'Gene', (38, 41))	('MRN', 'Protein', (162, 165))	('S1981', 'Var', (131, 136))
95782	27258263	In unstressed cells, p53 is a short-lived protein and its degradation is promoted by the mouse double minute (MDM2) gene.	('gene', 'Var', (116, 120))	('MDM2', 'Gene', (110, 114))	('promoted', 'PosReg', (73, 81))	('p53', 'Gene', (21, 24))	('mouse', 'Species', '10090', (89, 94))	('degradation', 'MPA', (58, 69))
95783	27258263	After DNA damage, ATM and CHK2 phosphorylate p53 (S15 and S20), thus reducing its ability to bind MDM2 and contributing to its stabilization.	('MDM2', 'Protein', (98, 102))	('bind', 'Interaction', (93, 97))	('S20', 'Var', (58, 61))	('S15', 'Var', (50, 53))	('ATM', 'Gene', '472', (18, 21))	('contributing', 'Reg', (107, 119))	('ability', 'MPA', (82, 89))	('reducing', 'NegReg', (69, 77))	('CHK2', 'Gene', (26, 30))	('CHK2', 'Gene', '11200', (26, 30))	('stabilization', 'MPA', (127, 140))	('ATM', 'Gene', (18, 21))
95806	27258263	These noncoding RNAs participate in establishing and maintaining KSHV latent infection in vivo and in oncogenesis by miRNA-mediated RNA interference of host cell mRNAs.	('RNA interference', 'MPA', (132, 148))	('KSHV latent infection', 'Disease', (65, 86))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('KSHV latent infection', 'Disease', 'MESH:D055985', (65, 86))	('oncogenesis', 'CPA', (102, 113))	('participate', 'Reg', (21, 32))	('miRNA-mediated', 'Var', (117, 131))
95827	27258263	The possibility to modulate the DDR genes may also represent a key feature in suppressing apoptosis signals induced by KSHV infection or regulating the cell cycle checkpoints thus promoting viral replication.	('viral replication', 'MPA', (190, 207))	('promoting', 'PosReg', (180, 189))	('suppressing', 'NegReg', (78, 89))	('modulate', 'Var', (19, 27))	('regulating', 'Reg', (137, 147))	('KSHV infection', 'Disease', 'MESH:C537372', (119, 133))	('KSHV infection', 'Disease', (119, 133))	('DDR', 'Chemical', '-', (32, 35))	('KS', 'Phenotype', 'HP:0100726', (119, 121))	('cell', 'MPA', (152, 156))	('apoptosis signals induced', 'MPA', (90, 115))	('DDR genes', 'Gene', (32, 41))
95846	27258263	The observation that both N and C terminus residues of LANA are able to bind gammaH2AX suggests that gammaH2AX contributes to the binding of LANA to the TRs.	('LANA', 'Gene', '4961527', (141, 145))	('LANA', 'Gene', '4961527', (55, 59))	('gammaH2AX', 'Chemical', '-', (77, 86))	('LANA', 'Gene', (141, 145))	('LANA', 'Gene', (55, 59))	('gammaH2AX', 'Chemical', '-', (101, 110))	('binding', 'Interaction', (130, 137))	('gammaH2AX', 'Var', (101, 110))
95850	27258263	Inhibition of ATM kinase activity and H2AX knockdown reduced the expression of the LANA gene.	('H2AX', 'Gene', (38, 42))	('ATM', 'Gene', '472', (14, 17))	('knockdown', 'Var', (43, 52))	('reduced', 'NegReg', (53, 60))	('LANA', 'Gene', (83, 87))	('expression', 'MPA', (65, 75))	('H2AX', 'Gene', '3014', (38, 42))	('ATM', 'Gene', (14, 17))	('LANA', 'Gene', '4961527', (83, 87))
95851	27258263	Moreover, knockdown of H2AX caused a reduction of more than 80% of the nuclear KSHV DNA copy numbers impairing the ability of the virus to establish latency.	('KSHV', 'Species', '37296', (79, 83))	('reduction', 'NegReg', (37, 46))	('impairing', 'NegReg', (101, 110))	('H2AX', 'Gene', '3014', (23, 27))	('KS', 'Phenotype', 'HP:0100726', (79, 81))	('KSHV DNA', 'Gene', (79, 87))	('H2AX', 'Gene', (23, 27))	('knockdown', 'Var', (10, 19))	('ability', 'MPA', (115, 122))
95857	27258263	Therefore, alterations of the cell cycle regulation pathways may promote tumorigenesis while the ATM/ATR regulated checkpoint acts as a guard against tumor progression.	('alterations', 'Var', (11, 22))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('ATR', 'Gene', '545', (101, 104))	('ATM', 'Gene', '472', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', (73, 78))	('promote', 'PosReg', (65, 72))	('cell cycle regulation pathways', 'Pathway', (30, 60))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('ATM', 'Gene', (97, 100))	('ATR', 'Gene', (101, 104))
95872	27258263	Depletion of CDK6 showed a significant reduction of ATM and CHK2 phosphorylation, suggesting that v-Cyclin-induced DNA damage checkpoint is dependent on CDK6 expression.	('CDK6', 'Gene', (153, 157))	('CDK6', 'Gene', '1021', (153, 157))	('v-Cyclin', 'Gene', (98, 106))	('CHK2', 'Gene', (60, 64))	('ATM', 'Gene', '472', (52, 55))	('CDK6', 'Gene', (13, 17))	('CHK2', 'Gene', '11200', (60, 64))	('reduction', 'NegReg', (39, 48))	('Depletion', 'Var', (0, 9))	('CDK6', 'Gene', '1021', (13, 17))	('ATM', 'Gene', (52, 55))	('v-Cyclin', 'Gene', '4961471', (98, 106))
95879	27258263	These restrictions were overcome by the loss of p53, pointing to the oncogenic potential of v-Cyclin.	('loss', 'Var', (40, 44))	('p53', 'Protein', (48, 51))	('v-Cyclin', 'Gene', '4961471', (92, 100))	('v-Cyclin', 'Gene', (92, 100))
95888	27258263	KSHV vFLIP activates the inhibitor of kappaB kinase (IKK) complex, triggering the direct activation of nuclear factor-kappaB (NF-kappaB) and the expression of anti-apoptotic genes and cytokine secretion.	('vFLIP', 'Gene', (5, 10))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('anti-apoptotic genes', 'Gene', (159, 179))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('nuclear factor-kappaB', 'Pathway', (103, 124))	('expression', 'MPA', (145, 155))	('activation', 'PosReg', (89, 99))	('cytokine secretion', 'MPA', (184, 202))	('vFLIP', 'Gene', '4961494', (5, 10))
95890	27258263	Indeed, v-FLIP directly antagonizes the autophagy pathway limiting oncogene-induced and DDR-mediated senescence caused by KSHV.	('antagonizes', 'NegReg', (24, 35))	('DDR-mediated senescence', 'CPA', (88, 111))	('autophagy pathway', 'CPA', (40, 57))	('KSHV', 'Gene', (122, 126))	('oncogene-induced', 'CPA', (67, 83))	('v-FLIP', 'Var', (8, 14))	('DDR', 'Chemical', '-', (88, 91))	('KSHV', 'Species', '37296', (122, 126))	('KS', 'Phenotype', 'HP:0100726', (122, 124))
95896	27258263	Aberrations in hTREX protein expression and function have been implicated in human cancer.	('hTREX protein', 'Protein', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Aberrations', 'Var', (0, 11))	('function', 'MPA', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('expression', 'MPA', (29, 39))	('implicated', 'Reg', (63, 73))	('cancer', 'Disease', (83, 89))	('human', 'Species', '9606', (77, 82))
95899	27258263	It was proposed that sequestration of hTREX by ORF57 could cause newly transcribed mRNA to form R-loops through annealing to the DNA template causing DSBs (Figure 3).	('R-loops', 'MPA', (96, 103))	('ORF57', 'Gene', (47, 52))	('cause', 'Reg', (59, 64))	('DSBs', 'Disease', (150, 154))	('annealing', 'Var', (112, 121))	('ORF57', 'Gene', '4961525', (47, 52))
95900	27258263	Similarly, the expression of ORF57 during KSHV infection causes the sequestration of the hTREX complex, triggering genome instability.	('KSHV infection', 'Disease', (42, 56))	('expression', 'Var', (15, 25))	('KS', 'Phenotype', 'HP:0100726', (42, 44))	('sequestration of the hTREX complex', 'MPA', (68, 102))	('genome instability', 'MPA', (115, 133))	('ORF57', 'Gene', (29, 34))	('ORF57', 'Gene', '4961525', (29, 34))	('triggering', 'Reg', (104, 114))	('KSHV infection', 'Disease', 'MESH:C537372', (42, 56))	('causes', 'Reg', (57, 63))
95907	27258263	Deregulation of IRF3 and IRF7 mediated by vIRF1 induces disruption of cellular antiviral activity.	('disruption', 'NegReg', (56, 66))	('vIRF1', 'Gene', (42, 47))	('Deregulation', 'Var', (0, 12))	('cellular antiviral activity', 'MPA', (70, 97))	('vIRF1', 'Gene', '4961464', (42, 47))	('IRF3', 'Gene', (16, 20))	('IRF3', 'Gene', '3661', (16, 20))	('IRF7', 'Gene', '3665', (25, 29))	('IRF7', 'Gene', (25, 29))
95914	27258263	A further analysis revealed that vIRF1 interacts with ATM through its C-terminal domain reducing its activation, as shown by phosphorylation of S1981.	('ATM', 'Gene', (54, 57))	('vIRF1', 'Gene', '4961464', (33, 38))	('S1981', 'Var', (144, 149))	('vIRF1', 'Gene', (33, 38))	('ATM', 'Gene', '472', (54, 57))	('activation', 'MPA', (101, 111))	('reducing', 'NegReg', (88, 96))
95923	27258263	Hence, KSHV PF-8, by disrupting the interaction between the KU complex and DNA-PKcs, impairs NHEJ repair.	('impairs', 'NegReg', (85, 92))	('KSHV', 'Species', '37296', (7, 11))	('KSHV', 'Var', (7, 11))	('KS', 'Phenotype', 'HP:0100726', (7, 9))	('disrupting', 'NegReg', (21, 31))	('DNA-PKcs', 'Gene', '5591', (75, 83))	('NHEJ repair', 'CPA', (93, 104))	('interaction', 'Interaction', (36, 47))	('DNA-PKcs', 'Gene', (75, 83))
95933	27258263	These include inhibitors of molecules involved in DNA synthesis, alkylation or covalent cross-linking of DNA strands that cause the cleavage of the sugar-phosphate backbone, as well as molecules that exert indirect roles in DNA replication.	('cleavage of the sugar-phosphate backbone', 'MPA', (132, 172))	('sugar-phosphate', 'Chemical', 'MESH:D013403', (148, 163))	('alkylation', 'Var', (65, 75))
95942	27258263	Particularly, glycyrrhizic acid, which inhibits the lytic replication of herpes viruses by reducing the expression of LANA, induces G1 cell cycle arrest and p53-mediated apoptosis.	('p53-mediated apoptosis', 'CPA', (157, 179))	('lytic replication', 'MPA', (52, 69))	('LANA', 'Gene', (118, 122))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('glycyrrhizic acid', 'Var', (14, 31))	('LANA', 'Gene', '4961527', (118, 122))	('induces', 'PosReg', (124, 131))	('expression', 'MPA', (104, 114))	('G1 cell cycle arrest', 'CPA', (132, 152))	('reducing', 'NegReg', (91, 99))	('inhibits', 'NegReg', (39, 47))	('glycyrrhizic acid', 'Chemical', 'MESH:D019695', (14, 31))
95961	26779435	The molecular event that initiates the Ewing's family of tumors is a typical chromosomal translocation that occurs in cells of mesenchymal origin and that fuses the EWS gene on chromosome 22q12 to a member of the erythroblast transformation sequence (ETS) transcription gene family, most commonly FLI-1, on 11q24 in 85% of cases.	('EWS', 'Gene', '2130', (165, 168))	('EWS', 'Gene', (165, 168))	('Ewing', 'Disease', (39, 44))	('FLI-1', 'Gene', '2313', (297, 302))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('FLI-1', 'Gene', (297, 302))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('fuses', 'Var', (155, 160))
95963	26779435	The presence of this fusion gene, which represents the Ewing sarcoma signature, is used as a specific diagnostic marker of the Ewing's family of tumors thanks to fluorescence in situ hybridization and RT-qPCR.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('Ewing sarcoma', 'Disease', (55, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('presence', 'Var', (4, 12))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (55, 68))
95964	26779435	Numerous biological pathways, such as those involving insulin-like growth factor receptor (IGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), Sonic HedgeHog (SHH) pathway activation, Wnt, and transforming growth factor (TGF)-beta receptor II pathway inhibition, are modulated by EWS-FLI1 activity, leading to proliferation, angiogenesis, immune system escape, metastatic potential, and treatment resistance that contribute to the Ewing sarcoma malignant phenotype.	('activity', 'Var', (346, 354))	('EWS', 'Gene', (337, 340))	('FLI1', 'Gene', (341, 345))	('immune system escape', 'CPA', (396, 416))	('Ewing sarcoma malignant', 'Disease', (488, 511))	('Sonic HedgeHog', 'Gene', '6469', (200, 214))	('angiogenesis', 'CPA', (382, 394))	('SHH', 'Gene', (216, 219))	('FLI1', 'Gene', '2313', (341, 345))	('Ewing sarcoma malignant', 'Disease', 'MESH:C563168', (488, 511))	('vascular endothelial growth factor receptor', 'Gene', (147, 190))	('inhibition', 'NegReg', (308, 318))	('Sonic HedgeHog', 'Gene', (200, 214))	('treatment resistance', 'CPA', (444, 464))	('EWS', 'Gene', '2130', (337, 340))	('vascular endothelial growth factor receptor', 'Gene', '3791', (147, 190))	('proliferation', 'CPA', (367, 380))	('platelet-derived growth factor receptor', 'Gene', '5159', (98, 137))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (488, 501))	('transforming growth factor (TGF)-beta receptor II', 'Gene', '7048', (250, 299))	('modulated', 'Reg', (324, 333))	('platelet-derived growth factor receptor', 'Gene', (98, 137))	('PDGFR', 'Gene', (139, 144))	('VEGFR', 'Gene', '3791', (192, 197))	('insulin-like growth factor receptor', 'Gene', (54, 89))	('PDGFR', 'Gene', '5159', (139, 144))	('IGFR', 'Gene', '3480', (91, 95))	('insulin-like growth factor receptor', 'Gene', '3480', (54, 89))	('VEGFR', 'Gene', (192, 197))	('metastatic potential', 'CPA', (418, 438))	('SHH', 'Gene', '6469', (216, 219))	('IGFR', 'Gene', (91, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (494, 501))
96008	26779435	Accordingly, inhibiting osteoclast activity is a promising approach for breaking the vicious cycle, and thus indirectly limiting local cancer growth.	('cancer', 'Disease', (135, 141))	('osteoclast activity', 'CPA', (24, 43))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('vicious', 'MPA', (85, 92))	('limiting', 'NegReg', (120, 128))	('inhibiting', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
96020	26779435	Moreover, BPs may also inhibit bone resorption by increasing the production of OPG by human osteoblasts.	('increasing', 'PosReg', (50, 60))	('bone resorption', 'CPA', (31, 46))	('OPG', 'Gene', '4982', (79, 82))	('BPs', 'Var', (10, 13))	('inhibit', 'NegReg', (23, 30))	('human', 'Species', '9606', (86, 91))	('OPG', 'Gene', (79, 82))	('BPs', 'Chemical', 'MESH:D004164', (10, 13))	('bone resorption', 'Phenotype', 'HP:0002797', (31, 46))
96035	26779435	Of these studies, our team has recently shown that ZOL significantly inhibits tumor cell viability by blocking the cell cycle in S-G2M phase transition and by promoting caspase-3 activation.	('caspase-3', 'Gene', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('ZOL', 'Var', (51, 54))	('promoting', 'PosReg', (159, 168))	('inhibits', 'NegReg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('caspase-3', 'Gene', '836', (169, 178))	('ZOL', 'Chemical', 'MESH:D000077211', (51, 54))	('activation', 'PosReg', (179, 189))	('tumor', 'Disease', (78, 83))	('blocking', 'NegReg', (102, 110))	('cell cycle in S-G2M phase transition', 'CPA', (115, 151))
96046	26779435	There are three phase II/III trials currently in progress, evaluating the efficacy of ZOL as a single agent or an adjuvant to chemotherapy in localized and metastatic osteosarcoma (NCT00691236 and NCT00470223) and in Ewing sarcoma (NCT00987636).	('osteosarcoma', 'Disease', (167, 179))	('osteosarcoma', 'Disease', 'MESH:D012516', (167, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('Ewing sarcoma', 'Disease', (217, 230))	('NCT00691236', 'Var', (181, 192))	('NCT00987636', 'Var', (232, 243))	('ZOL', 'Chemical', 'MESH:D000077211', (86, 89))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (217, 230))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (217, 230))	('osteosarcoma', 'Phenotype', 'HP:0002669', (167, 179))	('NCT00470223', 'Var', (197, 208))
96058	26779435	High expression of RANKL is associated with reduced survival in osteosarcoma, and it has been reported that osteosarcoma cell lines and biopsies show high expression of functional RANK, suggesting a potential autocrine stimulation of this pathway.	('RANKL', 'Gene', '8600', (19, 24))	('RANKL', 'Gene', (19, 24))	('High expression', 'Var', (0, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (64, 76))	('survival', 'MPA', (52, 60))	('osteosarcoma', 'Phenotype', 'HP:0002669', (108, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('osteosarcoma', 'Disease', (108, 120))	('osteosarcoma', 'Disease', 'MESH:D012516', (108, 120))	('reduced', 'NegReg', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('osteosarcoma', 'Disease', (64, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (64, 76))
96059	26779435	Inhibition of RANKL using the shRNA strategy reduced motility and anoikis resistance in osteosarcoma cell lines, whereas overexpression of RANK increased OS cell motility without affecting cell proliferation.	('osteosarcoma', 'Disease', 'MESH:D012516', (88, 100))	('reduced', 'NegReg', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('motility', 'CPA', (53, 61))	('anoikis resistance', 'CPA', (66, 84))	('Inhibition', 'Var', (0, 10))	('RANKL', 'Gene', (14, 19))	('RANKL', 'Gene', '8600', (14, 19))	('osteosarcoma', 'Phenotype', 'HP:0002669', (88, 100))	('osteosarcoma', 'Disease', (88, 100))
96066	26779435	A disruption in the RANKL/OPG ratio in favor of RANKL has been shown to be responsible for severe osteolysis in a tumoral context.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('osteolysis', 'Phenotype', 'HP:0002797', (98, 108))	('disruption', 'Var', (2, 12))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('osteolysis', 'Disease', (98, 108))	('tumor', 'Disease', (114, 119))	('RANKL', 'Gene', (20, 25))	('RANKL', 'Gene', '8600', (20, 25))	('OPG', 'Gene', '4982', (26, 29))	('osteolysis', 'Disease', 'MESH:D010014', (98, 108))	('RANKL', 'Gene', '8600', (48, 53))	('RANKL', 'Gene', (48, 53))	('OPG', 'Gene', (26, 29))
96104	26779435	With regard to angiogenesis, VEGF-165 expression in the tumor microenvironment has been shown to influence the differentiation of bone marrow-derived pericytes, which play a part in the vasculature of Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (201, 214))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (201, 214))	('tumor', 'Disease', (56, 61))	('VEGF', 'Gene', (29, 33))	('differentiation', 'CPA', (111, 126))	('expression', 'Var', (38, 48))	('Ewing sarcoma', 'Disease', (201, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('VEGF', 'Gene', '7422', (29, 33))	('influence', 'Reg', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
96203	26445554	The expression of miR-34a decreases frequently in some p53 mutant cancer cells, such as U251 and chronic lymphocytic leukemia cells.	('miR-34a', 'Gene', '407040', (18, 25))	('p53', 'Gene', (55, 58))	('miR-34a', 'Gene', (18, 25))	('p53', 'Gene', '7157', (55, 58))	('exp', 'Gene', (4, 7))	('mutant', 'Var', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('exp', 'Gene', '4154', (4, 7))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (97, 125))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('lymphocytic leukemia', 'Disease', (105, 125))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (105, 125))	('U251', 'CellLine', 'CVCL:0021', (88, 92))	('decreases', 'NegReg', (26, 35))	('cancer', 'Disease', (66, 72))
96204	26445554	In these cells, some miR-34a target genes, which are related to cell cycle, tumor invasion, and migration, are upregulated, and restoration of functional miR-34a enhances the chemotherapy susceptibility and inhibits tumor cell growth.	('miR-34a', 'Gene', (21, 28))	('tumor', 'Disease', (216, 221))	('restoration', 'Var', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('chemotherapy susceptibility', 'CPA', (175, 202))	('inhibits', 'NegReg', (207, 215))	('miR-34a', 'Gene', '407040', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('miR-34a', 'Gene', '407040', (21, 28))	('miR-34a', 'Gene', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('enhances', 'PosReg', (162, 170))
96399	33463447	The mutation of telomerase reverse transcriptase (TERT) is present in 76% of the skin UPS cases and appears to be associated with the UV damage.	('skin UPS', 'Disease', 'MESH:D017118', (81, 89))	('TERT', 'Gene', '7015', (50, 54))	('mutation', 'Var', (4, 12))	('skin UPS', 'Disease', (81, 89))	('telomerase reverse transcriptase', 'Gene', (16, 48))	('telomerase reverse transcriptase', 'Gene', '7015', (16, 48))	('associated', 'Reg', (114, 124))	('TERT', 'Gene', (50, 54))	('UV damage', 'Disease', (134, 143))
96415	30979745	High-throughput Chemical Screening Identifies Focal Adhesion Kinase and Aurora Kinase B Inhibition as a Synergistic Treatment Combination in Ewing Sarcoma Ewing sarcoma is an aggressive solid tumor malignancy of childhood.	('Aurora Kinase B', 'Gene', '9212', (72, 87))	('Focal Adhesion Kinase', 'Gene', (46, 67))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (155, 168))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (141, 154))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (141, 154))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('Aurora Kinase B', 'Gene', (72, 87))	('Focal Adhesion Kinase', 'Gene', '5747', (46, 67))	('Ewing sarcoma', 'Disease', (155, 168))	('aggressive solid tumor malignancy', 'Disease', (175, 208))	('Ewing Sarcoma', 'Disease', (141, 154))	('aggressive solid tumor malignancy', 'Disease', 'MESH:D009369', (175, 208))	('Sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('Inhibition', 'Var', (88, 98))
96421	30979745	We found that Aurora kinase B inhibitors were synergistic across a larger range of concentrations than Aurora kinase A inhibitors when combined with FAK inhibitors in multiple Ewing cell lines.	('Aurora kinase A', 'Gene', '6790', (103, 118))	('inhibitors', 'Var', (30, 40))	('Aurora kinase A', 'Gene', (103, 118))	('synergistic', 'MPA', (46, 57))
96422	30979745	The combination of AZD-1152, an Aurora kinase B-selective inhibitor, and PF-562271 or VS-4718, FAK-selective inhibitors, induced apoptosis in Ewing sarcoma cells at concentrations that had minimal effects on survival when cells were treated with either drug alone.	('apoptosis', 'CPA', (129, 138))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (142, 155))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (142, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('PF-562271', 'Chemical', '-', (73, 82))	('Ewing sarcoma', 'Disease', (142, 155))	('PF-562271', 'Var', (73, 82))	('AZD-1152', 'Chemical', 'MESH:C520647', (19, 27))	('VS-4718', 'Var', (86, 93))	('AZD-1152', 'Var', (19, 27))	('induced', 'Reg', (121, 128))
96452	30979745	The half-maximal inhibitory concentration (IC50) of the Ewing sarcoma cell lines treated with GSK-1070916 was compared to all other cell lines by a two-tailed Mann-Whitney test.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('GSK-1070916', 'Var', (94, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('Ewing sarcoma', 'Disease', (56, 69))
96471	30979745	A673 and TC32 cell lines were treated for 36 hours with FAK inhibitors (PF-562271 and VS-4718 at 2.5 muM) and Aurora kinas B inhibitors (AZD-1152 and GSK 1070916 at 20 nM).	('PF-562271', 'Chemical', '-', (72, 81))	('TC32', 'CellLine', 'CVCL:7151', (9, 13))	('AZD-1152', 'Chemical', 'MESH:C520647', (137, 145))	('PF-562271', 'Var', (72, 81))	('VS-4718', 'Var', (86, 93))
96481	30979745	For each study, mice were divided into 4 groups: vehicle control, AZD-1152 alone, FAK inhibitor alone (PF-562271 in the A673 xenograft study and VS-4718 in the PDX study), and AZD-1152 in combination with a FAK inhibitor.	('AZD-1152', 'Chemical', 'MESH:C520647', (66, 74))	('AZD-1152', 'Chemical', 'MESH:C520647', (176, 184))	('mice', 'Species', '10090', (16, 20))	('PF-562271', 'Chemical', '-', (103, 112))	('PF-562271', 'Var', (103, 112))	('VS-4718', 'Var', (145, 152))
96482	30979745	In both studies, treatment began when tumors reached at least 100 mm3, with AZD-1152 on days 1-4 and 8-11 and FAK inhibitor on days 1-14.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('AZD-1152', 'Chemical', 'MESH:C520647', (76, 84))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('AZD-1152', 'Var', (76, 84))
96486	30979745	A673 Ewing sarcoma cells were treated with PF-562271 at six concentrations in combination with each compound from the MIPE 4.0 library at six concentrations, resulting in a treatment matrix of all possible combinations for each compound pair (Figure 1A).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (5, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (5, 18))	('PF-562271', 'Var', (43, 52))	('PF-562271', 'Chemical', '-', (43, 52))	('Ewing sarcoma', 'Disease', (5, 18))
96488	30979745	Indeed, we found that multiple dose combinations of tozasertib and PF-562271 in this screen induced synergistic inhibition of A673 cell viability as determined by Combination Index (Figure 1D).	('tozasertib', 'Chemical', 'MESH:C484810', (52, 62))	('PF-562271', 'Chemical', '-', (67, 76))	('PF-562271', 'Var', (67, 76))	('inhibition', 'NegReg', (112, 122))	('combinations', 'Interaction', (36, 48))
96496	30979745	For these experiments, we utilized MLN-8237, an Aurora kinase A-specific inhibitor, and AZD-1152, an Aurora kinase B-specific inhibitor.	('Aurora kinase A', 'Gene', (48, 63))	('MLN-8237', 'Chemical', 'MESH:C550258', (35, 43))	('AZD-1152', 'Chemical', 'MESH:C520647', (88, 96))	('Aurora kinase A', 'Gene', '6790', (48, 63))	('MLN-8237', 'Var', (35, 43))
96497	30979745	We treated nine Ewing sarcoma cell lines with MLN-8237 and AZD-1152 across a broad range of concentrations for two days.	('AZD-1152', 'Chemical', 'MESH:C520647', (59, 67))	('AZD-1152', 'Var', (59, 67))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (16, 29))	('MLN-8237', 'Chemical', 'MESH:C550258', (46, 54))	('Ewing sarcoma', 'Disease', (16, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('MLN-8237', 'Var', (46, 54))
96501	30979745	Cells were treated with the drug combinations AZD-1152 and PF-562271, AZD-1152 and VS-4718, or MLN-8237 and PF-562271 across a range of concentrations that specifically inhibited the target of each drug (Supplemental Figure S2C-F).	('VS-4718', 'Var', (83, 90))	('MLN-8237', 'Var', (95, 103))	('PF-562271', 'Chemical', '-', (59, 68))	('AZD-1152', 'Chemical', 'MESH:C520647', (70, 78))	('AZD-1152', 'Chemical', 'MESH:C520647', (46, 54))	('PF-562271', 'Var', (59, 68))	('PF-562271', 'Chemical', '-', (108, 117))	('AZD-1152', 'Var', (70, 78))	('AZD-1152', 'Var', (46, 54))	('MLN-8237', 'Chemical', 'MESH:C550258', (95, 103))	('PF-562271', 'Var', (108, 117))	('inhibited', 'NegReg', (169, 178))
96502	30979745	In all Ewing sarcoma cell lines treated with AZD-1152 in combination with PF-562271 or VS-4718, we found that a larger range of drug concentrations had a combination index < 0.7 compared to cells treated with MLN-8237 in combination with PF-562271 (Figure 2A-C, Supplemental Figures S3-S4).	('MLN-8237', 'Chemical', 'MESH:C550258', (209, 217))	('AZD-1152', 'Chemical', 'MESH:C520647', (45, 53))	('combination index', 'MPA', (154, 171))	('AZD-1152', 'Var', (45, 53))	('Ewing sarcoma', 'Disease', (7, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('PF-562271', 'Chemical', '-', (238, 247))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (7, 20))	('PF-562271', 'Chemical', '-', (74, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (7, 20))
96507	30979745	Indeed, EWS/FLI was the top scoring feature predicting response to GSK1070916, an Aurora kinase B-selective inhibitor, in this dataset (Figure 3A).	('FLI', 'Gene', (12, 15))	('EWS', 'Gene', (8, 11))	('EWS', 'Gene', '2130', (8, 11))	('GSK1070916', 'Chemical', 'MESH:C544308', (67, 77))	('GSK1070916', 'Var', (67, 77))	('FLI', 'Gene', '2314', (12, 15))
96508	30979745	Moreover, GSK1070916 ranked 9th ranked among 265 compounds ranked by confidence (P-value) in the correlation between EWS/FLI expression and sensitivity to treatment (Figure 3B).	('EWS', 'Gene', '2130', (117, 120))	('EWS', 'Gene', (117, 120))	('GSK1070916', 'Chemical', 'MESH:C544308', (10, 20))	('GSK1070916', 'Var', (10, 20))	('FLI', 'Gene', '2314', (121, 124))	('FLI', 'Gene', (121, 124))
96509	30979745	Accordingly, the average IC50 of Ewing sarcoma cell lines treated with GSK1070916 was significantly lower than the average IC50 of all other cancer cell lines screened (Figure 3C).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (33, 46))	('lower', 'NegReg', (100, 105))	('GSK1070916', 'Var', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('GSK1070916', 'Chemical', 'MESH:C544308', (71, 81))	('cancer', 'Disease', (141, 147))	('Ewing sarcoma', 'Disease', (33, 46))	('IC50', 'MPA', (25, 29))
96518	30979745	We found that knockout of Aurora kinase B decreased phosphorylation of histone H3, a ligand of Aurora kinas B (Supplemental Figure S5A), and significantly impaired cell viability in the A673 and TC32 cell lines compared to cells treated with a non-targeting control guide (P < 0.0001 for all comparisons; Figure 4C).	('impaired', 'NegReg', (155, 163))	('histone H3', 'Protein', (71, 81))	('cell viability', 'CPA', (164, 178))	('decreased', 'NegReg', (42, 51))	('TC32', 'CellLine', 'CVCL:7151', (195, 199))	('phosphorylation', 'MPA', (52, 67))	('knockout', 'Var', (14, 22))	('Aurora', 'Gene', (26, 32))
96519	30979745	Previous studies have reported that Aurora kinase inhibition primarily induces apoptosis in TP53-wild-type cancer cell lines while inducing cell cycle arrest and a more delayed induction of apoptosis in TP53-mutated cancer cell lines.	('Aurora kinase', 'Enzyme', (36, 49))	('TP53', 'Gene', '7157', (203, 207))	('arrest', 'Disease', 'MESH:D006323', (151, 157))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (140, 157))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('inhibition', 'Var', (50, 60))	('arrest', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TP53', 'Gene', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('inducing', 'Reg', (131, 139))	('apoptosis', 'CPA', (79, 88))	('TP53', 'Gene', '7157', (92, 96))	('cancer', 'Disease', (216, 222))	('TP53', 'Gene', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('induces', 'Reg', (71, 78))	('cancer', 'Disease', (107, 113))
96526	30979745	One possible explanation for our results is that loss of EWS/FLI expression reduces cell growth which reduces the rate of cell cycling causing cells to be resistant to Aurora kinase B inhibition.	('reduces', 'NegReg', (102, 109))	('FLI', 'Gene', '2314', (61, 64))	('loss', 'Var', (49, 53))	('FLI', 'Gene', (61, 64))	('cell growth', 'CPA', (84, 95))	('reduces', 'NegReg', (76, 83))	('EWS', 'Gene', '2130', (57, 60))	('EWS', 'Gene', (57, 60))	('rate', 'MPA', (114, 118))
96527	30979745	However, Ewing sarcoma cell lines remained sensitive to AZD-1152 when cell growth was reduced by restricting fetal bovine serum (FBS) levels in the culture medium (Figure 4H-I).	('reduced', 'NegReg', (86, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (9, 22))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (9, 22))	('restricting', 'NegReg', (97, 108))	('AZD-1152', 'Chemical', 'MESH:C520647', (56, 64))	('sensitive', 'Reg', (43, 52))	('AZD-1152', 'Var', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('Ewing sarcoma', 'Disease', (9, 22))	('cell growth', 'CPA', (70, 81))
96529	30979745	These studies demonstrate that the rate of cell growth cannot be the primary reason that the expression of EWS/FLI in Ewing sarcoma sensitizes cells to inhibition of Aurora kinase B.	('expression', 'Var', (93, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (118, 131))	('EWS', 'Gene', '2130', (107, 110))	('EWS', 'Gene', (107, 110))	('sensitizes', 'Reg', (132, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('FLI', 'Gene', '2314', (111, 114))	('Ewing sarcoma', 'Disease', (118, 131))	('FLI', 'Gene', (111, 114))
96531	30979745	We next examined whether the combination of FAK inhibition enhances the effects of Aurora kinase B inhibition on cell cycle arrest and apoptosis.	('apoptosis', 'CPA', (135, 144))	('arrest', 'Disease', 'MESH:D006323', (124, 130))	('FAK', 'Gene', (44, 47))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (113, 130))	('inhibition', 'Var', (48, 58))	('arrest', 'Disease', (124, 130))	('inhibition', 'NegReg', (99, 109))	('Aurora kinase B', 'Enzyme', (83, 98))	('enhances', 'PosReg', (59, 67))
96533	30979745	We also found that the combination of these compounds induced a significant increase in G2 arrest using a concentration of PF-562271 (1.25 muM or half the IC50) where FAK inhibition alone had no effect on cell cycle (Figure 5A-B).	('increase', 'PosReg', (76, 84))	('PF-562271', 'Chemical', '-', (123, 132))	('PF-562271', 'Var', (123, 132))	('arrest', 'Disease', 'MESH:D006323', (91, 97))	('arrest', 'Disease', (91, 97))
96534	30979745	To confirm that loss of Aurora kinase B activity sensitizes cells to FAK inhibition, we examined the effect of genetic downregulation of Aurora kinase B on sensitivity of A673 and TC32 cells to treatment with PF-562271.	('PF-562271', 'Chemical', '-', (209, 218))	('downregulation', 'NegReg', (119, 133))	('TC32', 'CellLine', 'CVCL:7151', (180, 184))	('loss', 'Var', (16, 20))	('activity', 'MPA', (40, 48))	('sensitizes', 'Reg', (49, 59))
96535	30979745	For these experiments, we chose an inducible shRNA system because CRISPR-Cas9 knockout of Aurora kinase B led to such a profound loss of viability that there were insufficient numbers of cells to treat with PF-562271.	('viability', 'MPA', (137, 146))	('PF-562271', 'Chemical', '-', (207, 216))	('loss', 'NegReg', (129, 133))	('knockout', 'Var', (78, 86))
96536	30979745	We found that downregulation of Aurora kinase B in A673 and TC32 cells resulted in sensitivity to lower concentrations of PF-562271 compared to cells treated with non-targeting control shRNA (Figure 5E-F).	('Aurora kinase B', 'Enzyme', (32, 47))	('PF-562271', 'Var', (122, 131))	('TC32', 'CellLine', 'CVCL:7151', (60, 64))	('downregulation', 'NegReg', (14, 28))	('lower', 'NegReg', (98, 103))	('PF-562271', 'Chemical', '-', (122, 131))
96538	30979745	We found that loss of FAK expression sensitized A673 and TC32 cells to lower concentrations of AZD-1152 (Figure 5H).	('loss', 'Var', (14, 18))	('FAK', 'Gene', (22, 25))	('AZD-1152', 'Chemical', 'MESH:C520647', (95, 103))	('TC32', 'CellLine', 'CVCL:7151', (57, 61))	('sensitized', 'Reg', (37, 47))
96540	30979745	Ewing sarcoma cells were treated for 36 hours with two FAK inhibitors (PF-562271 and VS-4718) and two Aurora kinase B inhibitors (AZD-1152 and GSK-1070916) at the IC50 for each drug.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('PF-562271', 'Var', (71, 80))	('VS-4718', 'Var', (85, 92))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('AZD-1152', 'Chemical', 'MESH:C520647', (130, 138))	('PF-562271', 'Chemical', '-', (71, 80))
96544	30979745	To confirm the finding that FAK and Aurora kinase inhibitors suppress mTOR pathway activity more than FAK inhibitors alone, we then treated Ewing sarcoma cells for 24 hours with VS-4718 and AZD-1152, alone and in combination, at one quarter the IC50 (Figure 6B) and one half the IC50 (Figure 6C).	('activity', 'MPA', (83, 91))	('mTOR', 'Gene', (70, 74))	('Ewing sarcoma', 'Disease', (140, 153))	('mTOR', 'Gene', '2475', (70, 74))	('VS-4718', 'Var', (178, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('AZD-1152', 'Chemical', 'MESH:C520647', (190, 198))	('suppress', 'NegReg', (61, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (140, 153))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (140, 153))	('AZD-1152', 'Var', (190, 198))
96548	30979745	We determined that zebrafish tolerated the combination of 5 muM PF-562271 with 6 muM AZD-1152 and treatment with this combination significantly impaired tumor progression in an A673 zebrafish xenograft model of Ewing sarcoma compared to vehicle or single agent treatment.	('AZD-1152', 'Chemical', 'MESH:C520647', (85, 93))	('impaired tumor', 'Disease', 'MESH:D060825', (144, 158))	('PF-562271', 'Chemical', '-', (64, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (211, 224))	('zebrafish', 'Species', '7955', (182, 191))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (211, 224))	('combination', 'Interaction', (43, 54))	('PF-562271', 'Var', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Ewing sarcoma', 'Disease', (211, 224))	('zebrafish', 'Species', '7955', (19, 28))	('impaired tumor', 'Disease', (144, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))
96550	30979745	We then tested the effects of the combination of PF-562271 or VS-4718 and AZD-1152 on tumor progression and survival in two mouse xenograft models of Ewing sarcoma.	('tested', 'Reg', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Ewing sarcoma', 'Disease', (150, 163))	('tumor', 'Disease', (86, 91))	('mouse', 'Species', '10090', (124, 129))	('PF-562271', 'Chemical', '-', (49, 58))	('AZD-1152', 'Chemical', 'MESH:C520647', (74, 82))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (150, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('VS-4718', 'Var', (62, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (150, 163))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('PF-562271', 'Var', (49, 58))
96554	30979745	We then treated Ncr nude mice, after establishment of palpable A673 xenograft tumors, with PF-562271 for 14 days and AZD-1152 on days 1-4 and 8-11.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('AZD-1152', 'Chemical', 'MESH:C520647', (117, 125))	('PF-562271', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('nude mice', 'Species', '10090', (20, 29))	('PF-562271', 'Chemical', '-', (91, 100))
96558	30979745	Finally, mice with established palpable Ewing sarcoma patient-derived xenografts (PDX) were treated with VS-4718 for 14 days and AZD-1152 on days 1-4 and 8-11.	('patient', 'Species', '9606', (54, 61))	('Ewing sarcoma', 'Disease', (40, 53))	('VS-4718', 'Var', (105, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (40, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('mice', 'Species', '10090', (9, 13))	('AZD-1152', 'Chemical', 'MESH:C520647', (129, 137))
96569	30979745	Aurora kinase inhibitors are also tolerated in children, and two recent studies demonstrated efficacy for some children with aggressive solid tumors treated with an Aurora kinase A inhibitor, MLN-8237.	('MLN-8237', 'Chemical', 'MESH:C550258', (192, 200))	('Aurora kinase A', 'Gene', (165, 180))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('children', 'Species', '9606', (111, 119))	('aggressive solid tumors', 'Disease', 'MESH:D009369', (125, 148))	('MLN-8237', 'Var', (192, 200))	('Aurora kinase A', 'Gene', '6790', (165, 180))	('aggressive solid tumors', 'Disease', (125, 148))	('children', 'Species', '9606', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
96587	30979745	Furthermore, we found that this combination impairs tumor progression in multiple xenograft models of Ewing sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Ewing sarcoma', 'Disease', (102, 115))	('impairs tumor', 'Disease', (44, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('combination', 'Var', (32, 43))	('impairs tumor', 'Disease', 'MESH:D060825', (44, 57))
96591	30979745	Finally, we utilized an unbiased proteomic screening approach to explore potential mechanisms of synergistic activity of FAK and AURKB inhibitors in Ewing sarcoma.	('FAK', 'Protein', (121, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (149, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('Ewing sarcoma', 'Disease', (149, 162))	('AURKB', 'Gene', '9212', (129, 134))	('inhibitors', 'Var', (135, 145))	('AURKB', 'Gene', (129, 134))
96592	30979745	We found that inhibiting both targets suppressed mTOR activity more than inhibition of either FAK or AURKB alone.	('mTOR', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (49, 53))	('AURKB', 'Gene', '9212', (101, 106))	('inhibiting', 'Var', (14, 24))	('suppressed', 'NegReg', (38, 48))	('AURKB', 'Gene', (101, 106))
96596	30979745	AURKB and mTOR appear to cross regulate each other and loss of AURKB activity sensitizes cells to direct inhibition of mTOR activity by rapamycin.	('AURKB', 'Gene', '9212', (63, 68))	('mTOR', 'Gene', (10, 14))	('activity', 'MPA', (69, 77))	('loss', 'Var', (55, 59))	('AURKB', 'Gene', (0, 5))	('AURKB', 'Gene', (63, 68))	('rapamycin', 'Chemical', 'MESH:D020123', (136, 145))	('mTOR', 'Gene', (119, 123))	('mTOR', 'Gene', '2475', (119, 123))	('AURKB', 'Gene', '9212', (0, 5))	('mTOR', 'Gene', '2475', (10, 14))
96602	30979745	With numerous inhibitors of mTOR activity in clinical investigation, including FAK and IGF1R inhibitors, and Aurora kinase B, pan-Aurora kinase, and other cell cycle inhibitors in various stages of clinical development, these classes of compounds are exciting therapeutic agents warranting further investigation for patients with Ewing sarcoma.	('mTOR', 'Gene', '2475', (28, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (330, 343))	('IGF1R', 'Gene', '3480', (87, 92))	('mTOR', 'Gene', (28, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))	('Ewing sarcoma', 'Disease', (330, 343))	('IGF1R', 'Gene', (87, 92))	('inhibitors', 'Var', (14, 24))	('patients', 'Species', '9606', (316, 324))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (330, 343))
96626	28735378	Ewing sarcoma tumors have fusion oncogenic trascription factors generated by chromosomal translocations involving the EWS gene and one of the E26 transformation-specific (ETS) transcription factors.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma tumors', 'Disease', (0, 20))	('EWS gene', 'Gene', (118, 126))	('chromosomal translocations', 'Var', (77, 103))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('rat', 'Species', '10116', (68, 71))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (0, 20))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
96627	28735378	In 85% of cases of Ewing sarcoma, the EWS-FLI1 fusion transcription factor is generated by a t(11;22)(q24;q12) chromosomal translocation.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (19, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (19, 32))	('t(11;22)(q24;q12', 'Var', (93, 109))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (93, 110))	('rat', 'Species', '10116', (82, 85))	('EWS-FLI1', 'Gene', (38, 46))	('Ewing sarcoma', 'Disease', (19, 32))	('EWS-FLI1', 'Gene', '2130;2313', (38, 46))
96629	28735378	Additionally, knockdown of EWS-FLI1 with antisense DNA, siRNA, or dominant negative methods is incompatible with Ewing sarcoma cell survival.	('Ewing sarcoma', 'Disease', (113, 126))	('antisense DNA', 'Var', (41, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (113, 126))	('EWS-FLI1', 'Gene', (27, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (113, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('knockdown', 'Var', (14, 23))	('EWS-FLI1', 'Gene', '2130;2313', (27, 35))
96647	28735378	Patients >=12 months <=17 years of age with evaluable refractory or recurrent extracranial solid tumors (phase 1) or >18 years of age with refractory, histologically confirmed Ewing sarcoma with documented EWS-FLI1 translocation and measurable disease (phase 2) were eligible.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (176, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (176, 189))	('solid tumors', 'Disease', 'MESH:D009369', (91, 103))	('EWS-FLI1', 'Gene', '2130;2313', (206, 214))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Patients', 'Species', '9606', (0, 8))	('Ewing sarcoma', 'Disease', (176, 189))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('EWS-FLI1', 'Gene', (206, 214))	('translocation', 'Var', (215, 228))	('solid tumors', 'Disease', (91, 103))
96650	28735378	Adequate bone marrow function was required and defined as an absolute neutrophil count (ANC) >=1000/muL and hemoglobin >=8.0 g/dL and transfusion independent platelet count of >=75,000/muL.	('muL', 'Gene', '4591', (185, 188))	('muL', 'Gene', '4591', (100, 103))	('muL', 'Gene', (185, 188))	('muL', 'Gene', (100, 103))	('>=8.0', 'Var', (119, 124))
96702	28735378	We explored the correlation of mithramycin-induced hepatotoxicity with single nucleotide polymorphisms (SNP) in several genes encoding transporter proteins regulating bile flow (Figg and colleagues, manuscript in preparation).	('hepatotoxicity', 'Disease', (51, 65))	('hepatotoxicity', 'Disease', 'MESH:D056486', (51, 65))	('rat', 'Species', '10116', (218, 221))	('mithramycin', 'Chemical', 'MESH:D008926', (31, 42))	('single nucleotide polymorphisms', 'Var', (71, 102))
96718	28735378	Variation in the bile salt export pump (BSEP) may cause specific populations to be more susceptible to this drug toxicity.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('bile salt export pump', 'Gene', (17, 38))	('BSEP', 'Gene', '8647', (40, 44))	('BSEP', 'Gene', (40, 44))	('bile salt export pump', 'Gene', '8647', (17, 38))	('Variation', 'Var', (0, 9))
96732	29416878	In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of GPC5 (GPC5/CEP13 ratio >= 2.2) was identified in 11/97 (11.3%) cases (9/64 carcinosarcoma, 1/3 rhabdomyosarcoma, 1/21 leiomyosarcoma, 0/8 adenosarcoma, 0/1 undifferentiated endometrial sarcoma) and an additional 4 (2.8%) cases had low level gains (GPC5/CEP13 ratio >=1.5 but <2.2).	('carcinosarcoma', 'Disease', 'MESH:D002296', (174, 188))	('carcinosarcoma', 'Disease', 'MESH:D002296', (38, 52))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('GPC5', 'Gene', '2262', (347, 351))	('rhabdomyosarcoma', 'Disease', (194, 210))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('adenosarcoma', 'Disease', (237, 249))	('adenosarcoma', 'Disease', 'MESH:D018195', (237, 249))	('carcinosarcomas', 'Disease', 'MESH:D002296', (38, 53))	('sarcomas', 'Disease', (72, 80))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (217, 231))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (217, 231))	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (194, 210))	('sarcomas', 'Disease', (45, 53))	('amplification', 'Var', (82, 95))	('GPC5', 'Gene', '2262', (105, 109))	('carcinosarcomas', 'Disease', (38, 53))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (272, 291))	('GPC5', 'Gene', '2262', (99, 103))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (194, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('GPC5', 'Gene', (347, 351))	('leiomyosarcoma', 'Disease', (217, 231))	('endometrial sarcoma', 'Disease', (272, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('carcinosarcoma', 'Disease', (174, 188))	('carcinosarcoma', 'Disease', (38, 52))	('GPC5', 'Gene', (105, 109))	('GPC5', 'Gene', (99, 103))
96741	29416878	The more widely accepted 'combination' and 'conversion' models imply monoclonality; according to the former, malignant transformation of a bipotential progenitor cell results in a tumour with a 'combination' of phenotypes, while in the latter scenario, tumour progression in a pre-existing endometrial carcinoma causes 'conversion' to sarcomatous differentiation.	("'combination", 'MPA', (194, 206))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (290, 311))	('endometrial carcinoma', 'Disease', (290, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('tumour', 'Disease', (253, 259))	('results in', 'Reg', (167, 177))	('sarcomatous', 'Disease', 'MESH:D018316', (335, 346))	("'conversion", 'Disease', (319, 330))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (290, 311))	('malignant', 'Var', (109, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (335, 342))	('sarcomatous', 'Disease', (335, 346))	('tumour', 'Disease', (180, 186))
96744	29416878	In contrast, a similar approach used to study another mixed uterine tumour, namely, de-differentiated endometrial carcinoma, identified additional mutations in the undifferentiated component relative to the low-grade endometrioid carcinoma component 3.	('mutations', 'Var', (147, 156))	('endometrial carcinoma', 'Disease', (102, 123))	('endometrioid carcinoma component', 'Disease', 'MESH:D016889', (217, 249))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (217, 239))	('uterine tumour', 'Phenotype', 'HP:0010784', (60, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (102, 123))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('endometrioid carcinoma component', 'Disease', (217, 249))	('tumour', 'Disease', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (102, 123))
96745	29416878	Given that the majority of uterine carcinosarcomas contain a serous carcinoma component and that the genomic landscape of serous carcinoma is dominated by frequent copy number gains and losses 4, 5, we hypothesized that an unbiased approach interrogating genome-wide copy number alterations (CNAs) may yield further insight into the underlying molecular basis of sarcomatous differentiation.	('carcinosarcomas', 'Disease', 'MESH:D002296', (35, 50))	('carcinosarcomas', 'Disease', (35, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('serous carcinoma component', 'Disease', 'MESH:D018284', (61, 87))	('sarcomatous', 'Disease', 'MESH:D018316', (363, 374))	('serous carcinoma component', 'Disease', (61, 87))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (27, 49))	('serous carcinoma', 'Disease', (122, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('copy number alterations', 'Var', (267, 290))	('serous carcinoma', 'Disease', 'MESH:D018284', (61, 77))	('serous carcinoma', 'Disease', 'MESH:D018284', (122, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (363, 370))	('sarcomatous', 'Disease', (363, 374))
96746	29416878	In this study, using a molecular inversion probe microarray profiling strategy to assess genomic CNAs and allelic imbalances, we provide evidence supporting the conversion theory of histogenesis and identify candidate genetic alterations that may be responsible for sarcomatous transformation of endometrial carcinoma.	('responsible', 'Reg', (250, 261))	('sarcomatous transformation of endometrial carcinoma', 'Disease', 'MESH:D016889', (266, 317))	('genetic alterations', 'Var', (218, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (296, 317))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('imbalances', 'Phenotype', 'HP:0002172', (114, 124))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (266, 292))
96756	29416878	The GPC5 BAC was labeled with red (02N34-050; Abbott Molecular) dUTPs using a nick translation kit (07J00-001; Abbott Molecular) according to the manufacturer's instructions.	('02N34-050', 'Var', (35, 44))	('dUTPs', 'Chemical', 'MESH:C027078', (64, 69))	('GPC5', 'Gene', '2262', (4, 8))	('GPC5', 'Gene', (4, 8))
96766	29416878	The average score was taken from repeated scoring of whole tissue sections and from replicate cores on the tissue microarray and used to classify GPC5 copy number status.	('copy number', 'Var', (151, 162))	('GPC5', 'Gene', (146, 150))	('GPC5', 'Gene', '2262', (146, 150))
96767	29416878	The cut-off values for scoring HER2 FISH in breast carcinoma, as per the 2007 ASCO/CAP Guidelines 7, were used for classification: GPC5/CEP13 ratio >= 2.2 for high-copy gain, and >= 1.5 but < 2.2 for low-copy gain.	('breast carcinoma', 'Disease', 'MESH:D001943', (44, 60))	('breast carcinoma', 'Disease', (44, 60))	('high-copy', 'Var', (159, 168))	('>= 1.5', 'Var', (179, 185))	('breast carcinoma', 'Phenotype', 'HP:0003002', (44, 60))	('gain', 'PosReg', (169, 173))	('GPC5', 'Gene', '2262', (131, 135))	('GPC5', 'Gene', (131, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
96775	29416878	Copy number profiles of the epithelial component from each case were consistent with the subtype-associated profiles reported in The Cancer Genome Atlas endometrial carcinoma study: high frequency of CNAs in serous and low frequency in endometrioid 8 (Figure 1A,B).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (153, 174))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Cancer Genome Atlas endometrial carcinoma', 'Disease', (133, 174))	('CNAs', 'Var', (200, 204))	('Cancer Genome Atlas endometrial carcinoma', 'Disease', 'MESH:D016889', (133, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))
96781	29416878	To identify potential genetic drivers of sarcomatous transformation, matched pair analysis was used to identify recurrent CNAs remaining in the sarcoma component copy number profile after subtracting out the copy number profile of the corresponding carcinoma component.	('sarcomatous transformation', 'Disease', 'MESH:D018316', (41, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('carcinoma component', 'Disease', (249, 268))	('sarcomatous transformation', 'Disease', (41, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('sarcoma component copy number', 'Disease', (144, 173))	('sarcoma component copy number', 'Disease', 'MESH:D012509', (144, 173))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (41, 67))	('carcinoma component', 'Disease', 'MESH:C562869', (249, 268))	('CNAs remaining', 'Var', (122, 136))
96784	29416878	Adapting the conservative cut-off values established for scoring HER2 FISH in breast carcinoma, as per the 2007 ASCO/CAP Guidelines 7 (GPC5/CEP13 ratio >= 2.2 for high-copy gain, and >= 1.5 but < 2.2 for low-copy gain), amplification of GPC5 was detected exclusively in the sarcoma component in five cases (Cases #1,2, 3, 6, and 9; Table 2 and Figure 3D,F).	('breast carcinoma', 'Disease', 'MESH:D001943', (78, 94))	('breast carcinoma', 'Disease', (78, 94))	('sarcoma component', 'Disease', (274, 291))	('GPC5', 'Gene', '2262', (237, 241))	('GPC5', 'Gene', (237, 241))	('GPC5', 'Gene', '2262', (135, 139))	('breast carcinoma', 'Phenotype', 'HP:0003002', (78, 94))	('GPC5', 'Gene', (135, 139))	('detected', 'Reg', (246, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('sarcoma component', 'Disease', 'MESH:D012509', (274, 291))	('amplification', 'Var', (220, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))
96785	29416878	In addition, one case harboured high-copy amplification throughout the tumour (Case #5).	('high-copy amplification', 'Var', (32, 55))	('tumour', 'Disease', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
96788	29416878	In an independent cohort comprised of 97 uterine mixed/mesenchymal tumours represented on a tissue microarray, the frequency of GPC5 amplification was 15 [11 (11.3%) high-gain, 4 (2.8%) low-gain; Table 3].	('mesenchymal tumours', 'Disease', (55, 74))	('GPC5', 'Gene', '2262', (128, 132))	('mesenchymal tumours', 'Disease', 'MESH:D008637', (55, 74))	('amplification', 'Var', (133, 146))	('GPC5', 'Gene', (128, 132))	('high-gain', 'Var', (166, 175))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
96804	29416878	In the first in-depth interrogation of the mutational landscape of gynecologic carcinosarcomas by whole exomic sequencing, Jones et al confirmed the presence of carcinoma-associated mutations in TP53 and components of the PI3K pathway, and identified novel genetic modifications in chromatin remodelling genes 11.	('carcinosarcomas', 'Disease', (79, 94))	('TP53', 'Gene', (195, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('PI3K pathway', 'Pathway', (222, 234))	('mutations', 'Var', (182, 191))	('genetic modifications', 'Var', (257, 278))	('carcinosarcomas', 'Disease', 'MESH:D002296', (79, 94))	('carcinoma', 'Disease', 'MESH:D002277', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Disease', (161, 170))
96805	29416878	It should be noted that 4 of 22 cases were mismatch repair- and ARID1A-deficient, raising concern that they may in fact represent de-differentiated endometrial carcinomas 12, rather than carcinosarcoma sensu stricto.	('carcinosarcoma sensu', 'Disease', 'MESH:D002296', (187, 207))	('endometrial carcinomas', 'Disease', (148, 170))	('ARID1A-deficient', 'Disease', 'MESH:D007153', (64, 80))	('carcinosarcoma sensu', 'Disease', (187, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('mismatch repair-', 'Var', (43, 59))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (148, 170))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (148, 170))	('ARID1A-deficient', 'Disease', (64, 80))
96807	29416878	These conclusions were confirmed in a subsequent whole-exome analysis of uterine and ovarian carcinosarcomas, in which novel missense mutations in genes coding for histone proteins, H2A and H2B, were identified in 21% of cases 13.	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('ovarian carcinosarcomas', 'Disease', (85, 108))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (85, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('H2A', 'Gene', (182, 185))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (85, 108))	('missense mutations', 'Var', (125, 143))	('H2B', 'Gene', (190, 193))	('uterine', 'Disease', (73, 80))
96810	29416878	After divergence into separate cell lineages at a variable time-point during tumour progression, mutations continue to accumulate independently in these subclonal populations.	('mutations', 'Var', (97, 106))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (77, 83))
96824	29416878	gains in GPC5, and histone gene mutations) causing a permanent switch in lineage commitment does not fit with the transient EMT model.	('histone gene', 'Gene', (19, 31))	('transient EMT', 'Phenotype', 'HP:0002326', (114, 127))	('mutations', 'Var', (32, 41))	('GPC5', 'Gene', '2262', (9, 13))	('GPC5', 'Gene', (9, 13))	('lineage commitment', 'CPA', (73, 91))	('gains', 'PosReg', (0, 5))
96832	29348492	Using cells that exhibit high expression efficiencies of inducible v-Src, we show that v-Src expression causes cell-cycle arrest through p21 up-regulation despite ERK activation.	('ERK', 'Gene', (163, 166))	('expression', 'Var', (93, 103))	('up-regulation', 'PosReg', (141, 154))	('ERK', 'Gene', '26413', (163, 166))	('activation', 'PosReg', (167, 177))	('expression', 'Species', '29278', (93, 103))	('cell-cycle arrest', 'CPA', (111, 128))	('expression', 'Species', '29278', (30, 40))	('v-Src', 'Gene', (87, 92))	('p21', 'Gene', (137, 140))
96833	29348492	v-Src expression also induces chromosome abnormalities and unexpected suppression of v-Src expression, leading to p21 down-regulation and ERK inactivation.	('suppression', 'NegReg', (70, 81))	('down-regulation', 'NegReg', (118, 133))	('ERK', 'Gene', (138, 141))	('expression', 'Species', '29278', (6, 16))	('p21', 'Gene', (114, 117))	('ERK', 'Gene', '26413', (138, 141))	('v-Src', 'Protein', (85, 90))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (30, 54))	('inactivation', 'NegReg', (142, 154))	('chromosome abnormalities', 'Disease', (30, 54))	('v-Src', 'Var', (0, 5))	('expression', 'Species', '29278', (91, 101))	('induces', 'Reg', (22, 29))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (30, 54))
96839	29348492	Although the activity of c-Src is tightly regulated in normal cells, deregulation of its activity often causes tumorigenesis.	('c-Src', 'Gene', '6714', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('deregulation', 'Var', (69, 81))	('tumor', 'Disease', (111, 116))	('causes', 'Reg', (104, 110))	('c-Src', 'Gene', (25, 30))	('activity', 'MPA', (89, 97))
96840	29348492	In particular, v-Src is the first identified oncogene product isolated from Rous sarcoma virus, and the kinase activity of v-Src is drastically increased compared with that of c-Src due to the presence of several point mutations and the lack of the C-terminal negative regulatory region.	('kinase activity', 'MPA', (104, 119))	('c-Src', 'Gene', '6714', (176, 181))	('point mutations', 'Var', (213, 228))	('Rous sarcoma', 'Disease', (76, 88))	('v-Src', 'Gene', (123, 128))	('Rous sarcoma', 'Disease', 'MESH:D001357', (76, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('increased', 'PosReg', (144, 153))	('c-Src', 'Gene', (176, 181))
96841	29348492	Colony formation assays have shown that expression of v-Src causes anchorage-independent and infinite cell proliferation.	('causes', 'Reg', (60, 66))	('rat', 'Species', '10116', (114, 117))	('expression', 'Var', (40, 50))	('infinite cell proliferation', 'CPA', (93, 120))	('v-Src', 'Gene', (54, 59))	('expression', 'Species', '29278', (40, 50))
96852	29348492	Western blotting analysis confirmed Dox-dependent expression of v-Src-wt using anti-Src (N-16) antibody, which preferentially recognizes v-Src compared with c-Src (Supplementary Fig.	('preferentially', 'PosReg', (111, 125))	('c-Src', 'Gene', (157, 162))	('Dox', 'Chemical', 'MESH:D004318', (36, 39))	('c-Src', 'Gene', '6714', (157, 162))	('expression', 'Species', '29278', (50, 60))	('v-Src', 'Var', (137, 142))
96854	29348492	However, the level of protein tyrosine phosphorylation was dramatically increased by v-Src-wt expression due to the point mutations and the lack of the C-terminal negative regulatory region (Supplementary Fig.	('increased', 'PosReg', (72, 81))	('point mutations', 'Var', (116, 131))	('expression', 'Species', '29278', (94, 104))	('protein tyrosine phosphorylation', 'MPA', (22, 54))	('tyrosine', 'Chemical', 'MESH:D014443', (30, 38))
96862	29348492	Unlike v-Src-wt, expression of v-Src(K295M) did not affect cell cycle progression (Fig.	('K295M', 'Mutation', 'p.K295M', (37, 42))	('expression', 'Species', '29278', (17, 27))	('cell cycle progression', 'CPA', (59, 81))	('v-Src(K295M', 'Var', (31, 42))
96866	29348492	Intriguingly, phosphorylation of ERK at Thr-202 and Tyr-204 was greatly increased, indicative of activation of the ERK/MAPK pathway (Fig.	('Thr', 'Chemical', 'MESH:D013912', (40, 43))	('increased', 'PosReg', (72, 81))	('activation', 'PosReg', (97, 107))	('ERK', 'Gene', (115, 118))	('Tyr', 'Chemical', 'MESH:D014443', (52, 55))	('ERK', 'Gene', '26413', (115, 118))	('phosphorylation', 'MPA', (14, 29))	('Tyr-204', 'Var', (52, 59))	('ERK', 'Gene', (33, 36))	('ERK', 'Gene', '26413', (33, 36))
96867	29348492	Despite activation of the ERK/MAPK pathway through the Src-Ras-Raf-MEK-ERK signaling cascade, these results suggest that v-Src expression causes cell cycle arrest against activated ERK-driven cell proliferation.	('ERK', 'Gene', (181, 184))	('ERK', 'Gene', '26413', (181, 184))	('expression', 'Species', '29278', (127, 137))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (145, 162))	('rat', 'Species', '10116', (204, 207))	('v-Src expression', 'Var', (121, 137))	('ERK', 'Gene', (26, 29))	('ERK', 'Gene', (71, 74))	('cell cycle arrest', 'CPA', (145, 162))	('ERK', 'Gene', '26413', (71, 74))	('causes', 'Reg', (138, 144))	('ERK', 'Gene', '26413', (26, 29))	('expression', 'Var', (127, 137))
96871	29348492	We then specifically inhibited the kinase activity of v-Src-wt using SU6656, a potent Src kinase inhibitor (see Supplementary Fig.	('SU6656', 'Var', (69, 75))	('kinase activity', 'MPA', (35, 50))	('inhibited', 'NegReg', (21, 30))	('SU6656', 'Chemical', 'MESH:C416927', (69, 75))
96872	29348492	Treatment with SU6656 was found to inhibit v-Src-wt-induced up-regulation of p21 (Fig.	('SU6656', 'Chemical', 'MESH:C416927', (15, 21))	('inhibit', 'NegReg', (35, 42))	('up-regulation', 'PosReg', (60, 73))	('SU6656', 'Var', (15, 21))
96873	29348492	Moreover, expression of v-Src(K295M) did not increase the expression level of p21 (Fig.	('expression level', 'MPA', (58, 74))	('expression', 'Species', '29278', (58, 68))	('K295M', 'Mutation', 'p.K295M', (30, 35))	('expression', 'Species', '29278', (10, 20))	('K295M', 'Var', (30, 35))
96874	29348492	These results suggest that v-Src expression induces up-regulation of CDK inhibitor proteins in a manner dependent on v-Src kinase activity.	('v-Src expression', 'Var', (27, 43))	('up-regulation', 'PosReg', (52, 65))	('CDK inhibitor proteins', 'Protein', (69, 91))	('expression', 'Species', '29278', (33, 43))
96875	29348492	Recently, we generated NIH3T3 cells expressing inducible v-Src-wt (NIH3T3/TR/v-Src-wt) and showed that, like HeLa S3 and HCT116 cells, v-Src-wt expression forces NIH3T3 cells to inhibit cell proliferation in a manner dependent on the expression level of v-Src-wt.	('HeLa S3', 'CellLine', 'CVCL:0058', (109, 116))	('expression', 'Species', '29278', (144, 154))	('expression', 'Species', '29278', (234, 244))	('rat', 'Species', '10116', (17, 20))	('inhibit', 'NegReg', (178, 185))	('cell proliferation', 'CPA', (186, 204))	('rat', 'Species', '10116', (198, 201))	('NIH3T3', 'CellLine', 'CVCL:0594', (162, 168))	('HCT116', 'CellLine', 'CVCL:0291', (121, 127))	('NIH3T3', 'CellLine', 'CVCL:0594', (67, 73))	('v-Src-wt', 'Var', (135, 143))	('NIH3T3', 'CellLine', 'CVCL:0594', (23, 29))
96882	29348492	These results suggest that v-Src expression inhibits cell cycle progression not only in HeLa S3 cells but also in NIH3T3 cells.	('expression', 'Var', (33, 43))	('NIH3T3', 'CellLine', 'CVCL:0594', (114, 120))	('expression', 'Species', '29278', (33, 43))	('cell cycle progression', 'CPA', (53, 75))	('v-Src', 'Protein', (27, 32))	('inhibits', 'NegReg', (44, 52))	('HeLa S3', 'CellLine', 'CVCL:0058', (88, 95))
96883	29348492	Although a number of studies have shown that expression of v-Src causes oncogenic transformation of NIH3T3 cells, our results indicate that expression of v-Src inhibits cell cycle progression despite activation of the ERK/MAPK pathway.	('expression', 'Species', '29278', (140, 150))	('NIH3T3', 'CellLine', 'CVCL:0594', (100, 106))	('expression', 'Species', '29278', (45, 55))	('expression', 'Var', (140, 150))	('cell cycle progression', 'CPA', (169, 191))	('v-Src', 'Gene', (154, 159))	('oncogenic transformation', 'CPA', (72, 96))	('causes', 'Reg', (65, 71))	('inhibits', 'NegReg', (160, 168))	('ERK', 'Gene', (218, 221))	('v-Src', 'Gene', (59, 64))	('ERK', 'Gene', '26413', (218, 221))	('expression', 'Var', (45, 55))	('activation', 'PosReg', (200, 210))
96885	29348492	In the early short-term treatment with Dox (~12 h), the levels of v-Src expression and the concomitant induction of tyrosine phosphorylation were gradually increased in almost all of NIH3T3/TR/v-Src-wt cells (Fig.	('levels', 'MPA', (56, 62))	('tyrosine phosphorylation', 'MPA', (116, 140))	('expression', 'Species', '29278', (72, 82))	('increased', 'PosReg', (156, 165))	('v-Src expression', 'MPA', (66, 82))	('NIH3T3', 'CellLine', 'CVCL:0594', (183, 189))	('tyrosine', 'Chemical', 'MESH:D014443', (116, 124))	('Dox', 'Chemical', 'MESH:D004318', (39, 42))	('NIH3T3/TR/v-Src-wt', 'Var', (183, 201))
96889	29348492	2D-plot analysis revealed that the level of p21 expression was highly correlated with that of v-Src expression in NIH3T3/TR/v-Src-wt cells (Fig.	('expression', 'Species', '29278', (48, 58))	('expression', 'Species', '29278', (100, 110))	('p21', 'Var', (44, 47))	('NIH3T3', 'CellLine', 'CVCL:0594', (114, 120))	('v-Src expression', 'MPA', (94, 110))
96902	29348492	Like NIH3T3/TR/v-Src-wt cells, NIH3T3/TR/v-Src-GFP cells showed the high efficiency of v-Src-wt-GFP expression in a manner dependent on Dox treatment (Fig.	('v-Src-wt-GFP', 'Var', (87, 99))	('Dox', 'Chemical', 'MESH:D004318', (136, 139))	('expression', 'Species', '29278', (100, 110))	('NIH3T3', 'CellLine', 'CVCL:0594', (31, 37))	('expression', 'MPA', (100, 110))	('NIH3T3', 'CellLine', 'CVCL:0594', (5, 11))
96908	29348492	Note that before Dox treatment (0 h), the expression of endogenous c-Src was only seen in NIH3T3/TR/v-Src-wt cells, and the peak positions of G1 and G2/M phases were marked.	('expression', 'Species', '29278', (42, 52))	('c-Src', 'Gene', (67, 72))	('NIH3T3', 'CellLine', 'CVCL:0594', (90, 96))	('c-Src', 'Gene', '6714', (67, 72))	('NIH3T3/TR/v-Src-wt', 'Var', (90, 108))	('Dox', 'Chemical', 'MESH:D004318', (17, 20))
96911	29348492	7b (36 h)], which corresponds to the cells having chromosome abnormalities, i.e., a broad range of DNA contents from subG1 to polyploidy [Fig.	('chromosome abnormalities', 'Disease', 'MESH:D002869', (50, 74))	('chromosome abnormalities', 'Disease', (50, 74))	('polyploidy', 'Var', (126, 136))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (50, 74))
96915	29348492	In the present study, we utilize HeLa S3 and NIH3T3 cells exhibiting extremely high expression efficiencies of tetracycline-inducible v-Src, and show that v-Src expression induces not only ERK activation but also p21 up-regulation, resulting in cell cycle arrest.	('expression', 'Species', '29278', (161, 171))	('ERK', 'Gene', '26413', (189, 192))	('v-Src expression', 'Var', (155, 171))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (245, 262))	('activation', 'PosReg', (193, 203))	('tetracycline', 'Chemical', 'MESH:D013752', (111, 123))	('NIH3T3', 'CellLine', 'CVCL:0594', (45, 51))	('expression', 'Var', (161, 171))	('expression', 'Species', '29278', (84, 94))	('cell cycle arrest', 'CPA', (245, 262))	('p21', 'Gene', (213, 216))	('up-regulation', 'PosReg', (217, 230))	('HeLa S3', 'CellLine', 'CVCL:0058', (33, 40))	('ERK', 'Gene', (189, 192))
96920	29348492	Notably, v-Src expression induces chromosome abnormalities and the subsequent suppression of v-Src expression brings about a broad range of the DNA content per cell.	('chromosome abnormalities', 'Disease', (34, 58))	('induces', 'Reg', (26, 33))	('expression', 'Species', '29278', (15, 25))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (34, 58))	('v-Src expression', 'Var', (9, 25))	('v-Src expression', 'Gene', (93, 109))	('suppression', 'NegReg', (78, 89))	('expression', 'Species', '29278', (99, 109))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (34, 58))
96941	29348492	The paper also described that, after more prolonged culture of the Rous sarcoma cells at a time when many giants were present, over half of the cells were polyploid.	('Rous sarcoma', 'Disease', (67, 79))	('Rous sarcoma', 'Disease', 'MESH:D001357', (67, 79))	('polyploid', 'Var', (155, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))
96944	29348492	p21 inhibits the activities of CDK2 in G1 phase and CDK1 in G2/M phase, leading to cell cycle arrest at G1 and G2 phase.	('leading to', 'Reg', (72, 82))	('activities', 'MPA', (17, 27))	('inhibits', 'NegReg', (4, 12))	('CDK1', 'Gene', '983', (52, 56))	('G2 phase', 'CPA', (111, 119))	('cell cycle arrest', 'CPA', (83, 100))	('CDK2', 'Protein', (31, 35))	('p21', 'Var', (0, 3))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('CDK1', 'Gene', (52, 56))
96950	29348492	S7a,b) were compared with NIH3T3/TR/v-Src-wt cells, c-Src-HA(Y530F) expression modestly increased tyrosine phosphorylation of cellular proteins and slowly suppressed Src expression (Supplementary Fig.	('expression', 'Species', '29278', (68, 78))	('tyrosine phosphorylation of', 'MPA', (98, 125))	('Src expression', 'MPA', (166, 180))	('cellular', 'Protein', (126, 134))	('expression', 'Var', (68, 78))	('increased', 'PosReg', (88, 97))	('suppressed', 'NegReg', (155, 165))	('tyrosine', 'Chemical', 'MESH:D014443', (98, 106))	('Y530F', 'Mutation', 'p.Y530F', (61, 66))	('expression', 'Species', '29278', (170, 180))	('NIH3T3', 'CellLine', 'CVCL:0594', (26, 32))	('c-Src', 'Gene', (52, 57))	('c-Src', 'Gene', '6714', (52, 57))
96951	29348492	Even though the kinase activity of c-Src-HA(Y530F) is lower than that of v-Src (Supplementary Fig.	('c-Src', 'Gene', (35, 40))	('c-Src', 'Gene', '6714', (35, 40))	('kinase activity', 'MPA', (16, 31))	('Y530F', 'Mutation', 'p.Y530F', (44, 49))	('Y530F', 'Var', (44, 49))	('lower', 'NegReg', (54, 59))
96967	29348492	The following rabbit monoclonal antibodies were used: phospho-p44/42 MAPK (ERK1/2) (Thr202/Tyr204) (D13.14.4E, Cell Signaling Technology), and p21 Waf1/Cip1 (12D1, Cell Signaling Technology).	('rabbit', 'Species', '9986', (14, 20))	('Cip1', 'Gene', (152, 156))	('Cip1', 'Gene', '12575', (152, 156))	('ERK1/2', 'Gene', '26417;26413', (75, 81))	('p44', 'Gene', (62, 65))	('p21', 'Var', (143, 146))	('p44', 'Gene', '26417', (62, 65))	('ERK1/2', 'Gene', (75, 81))	('Thr202', 'Chemical', '-', (84, 90))	('Tyr204', 'Chemical', '-', (91, 97))
96968	29348492	The following rabbit polyclonal antibodies were used: c-Src (N-16, Santa Cruz Biotechnology), ERK2 (C-14, Santa Cruz Biotechnology), Src[pY416] (phospho-Src family, Cell Signaling Technology), p16 (C-20, Santa Cruz Biotechnology), p21 (C-19, Santa Cruz Biotechnology) and Cleaved Caspase-3 (Asp175, Cell Signaling Technology).	('rabbit', 'Species', '9986', (14, 20))	('ERK', 'Gene', (94, 97))	('p16', 'Gene', '1029', (193, 196))	('p21', 'Var', (231, 234))	('ERK', 'Gene', '26413', (94, 97))	('c-Src', 'Gene', (54, 59))	('Src[pY416]', 'Var', (133, 143))	('Cleaved', 'Var', (272, 279))	('c-Src', 'Gene', '6714', (54, 59))	('p16', 'Gene', (193, 196))	('Caspase-3', 'Protein', (280, 289))
96969	29348492	The following rat monoclonal antibody was used: alpha-tubulin (MCA78G, Serotec).	('MCA78G', 'Var', (63, 69))	('alpha-tubulin', 'Protein', (48, 61))	('rat', 'Species', '10116', (14, 17))
96985	24909161	For example, it transcriptionally regulates genes that drive normal hematopoiesis and vasculogenesis.	('hematopoiesis', 'Disease', (68, 81))	('transcriptionally', 'Var', (16, 33))	('genes', 'Gene', (44, 49))	('regulates', 'Reg', (34, 43))	('hematopoiesis', 'Disease', 'MESH:C536227', (68, 81))
96986	24909161	Aberrant expression of Fli-1 also underlies a number of virally induced leukemias, including Friend virus-induced erythroleukemia and various types of human cancers, and it is the target of chromosomal translocations in childhood Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (230, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('leukemia', 'Phenotype', 'HP:0001909', (72, 80))	('leukemias', 'Disease', (72, 81))	('Fli-1', 'Gene', (23, 28))	('erythroleukemia', 'Disease', 'MESH:D004915', (114, 129))	('Aberrant expression', 'Var', (0, 19))	('human', 'Species', '9606', (151, 156))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (230, 245))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('underlies', 'Reg', (34, 43))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (230, 245))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('erythroleukemia', 'Disease', (114, 129))	('leukemias', 'Disease', 'MESH:D007938', (72, 81))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('leukemias', 'Phenotype', 'HP:0001909', (72, 81))
96987	24909161	Abnormal expression of Fli-1 is important in the aetiology of auto-immune diseases such as Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc).	('SLE', 'Disease', 'MESH:D008180', (121, 124))	('SLE', 'Disease', (121, 124))	('Sclerosis', 'Disease', (139, 148))	('Sclerosis', 'Disease', 'MESH:D012598', (139, 148))	('SLE', 'Phenotype', 'HP:0002725', (121, 124))	('Fli-1', 'Gene', (23, 28))	('Abnormal', 'Var', (0, 8))	('Lupus Erythematosus', 'Disease', (100, 119))	('Systemic Lupus Erythematosus', 'Phenotype', 'HP:0002725', (91, 119))	('important', 'Reg', (32, 41))	('auto-immune disease', 'Phenotype', 'HP:0002960', (62, 81))	('Lupus Erythematosus', 'Disease', 'MESH:D008180', (100, 119))
96991	24909161	Induction of Fli-1 expression as a result of proviral integration in the vicinity of this gene was shown to be responsible for the development of erythroleukemia.	('Fli-1', 'Gene', (13, 18))	('responsible', 'Reg', (111, 122))	('erythroleukemia', 'Disease', (146, 161))	('erythroleukemia', 'Disease', 'MESH:D004915', (146, 161))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))	('proviral integration', 'Var', (45, 65))
96993	24909161	A year after its discovery, Fli-1 was found to be a target of translocation in a majority (85%) of Ewing Sarcoma, a paediatric cancer of bones.	('Sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Fli-1', 'Gene', (28, 33))	('translocation', 'Var', (62, 75))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (99, 112))	('Ewing Sarcoma', 'Disease', (99, 112))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (99, 112))	('cancer', 'Disease', (127, 133))	('cancer of bones', 'Phenotype', 'HP:0010622', (127, 142))
96996	24909161	Here we review the effect of Fli-1 on hematopoiesis, vasculogenesis and cancer as well as certain diseases associated with abnormal expression of this transcription factors (TF).	('hematopoiesis', 'Disease', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('vasculogenesis', 'Disease', (53, 67))	('hematopoiesis', 'Disease', 'MESH:C536227', (38, 51))	('Fli-1', 'Gene', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('abnormal', 'Var', (123, 131))	('cancer', 'Disease', (72, 78))
97003	24909161	Indeed, using single and double knock-out mice for Fli-1 and Erg, this study demonstrated that disruption of both ETS genes in the hematopoietic linage significantly reduces the number of HSC/progenitors and mature megakaryocytes.	('Erg', 'Gene', (61, 64))	('ETS', 'Gene', (114, 117))	('disruption', 'Var', (95, 105))	('mice', 'Species', '10090', (42, 46))	('reduces', 'NegReg', (166, 173))	('Erg', 'Gene', '13876', (61, 64))
97005	24909161	Indeed, exogenous Fli-1 expression in erythroid progenitors (through transfection or viral infection) blocks differentiation and promotes uncontrolled cell proliferation.	('promotes', 'PosReg', (129, 137))	('viral infection', 'Disease', (85, 100))	('Fli-1', 'Gene', (18, 23))	('blocks', 'NegReg', (102, 108))	('exogenous', 'Var', (8, 17))	('uncontrolled cell proliferation', 'CPA', (138, 169))	('differentiation', 'CPA', (109, 124))	('viral infection', 'Disease', 'MESH:D001102', (85, 100))
97010	24909161	This initial Fli-1 mutant mouse strain expressed a truncated Fli-1 protein owing to an internal translation-initiation site and alternative splicing around the neo cassette used for gene targeting.	('Fli-1', 'Gene', (13, 18))	('mutant', 'Var', (19, 25))	('protein', 'Protein', (67, 74))	('Fli-1', 'Gene', (61, 66))	('mouse', 'Species', '10090', (26, 31))
97014	24909161	Increased NOTCH1 expression was detected in these Fli-1 transgenic T cells and, accordingly, activating Notch1 mutations were later identified in all tumors.	('mutations', 'Var', (111, 120))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('transgenic', 'Species', '10090', (56, 66))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('Notch1', 'Gene', (104, 110))	('expression', 'MPA', (17, 27))	('Increased', 'PosReg', (0, 9))	('Notch1', 'Gene', '18128', (104, 110))	('NOTCH1', 'Gene', '18128', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('NOTCH1', 'Gene', (10, 16))
97017	24909161	A role of Fli-1 in B-cells was also observed in a recently generated Fli-1 knock-out mice engineered to lack the CTA domain (Fli-1DeltaCTA), resulting in expression of mutant mRNA and protein.	('mice', 'Species', '10090', (85, 89))	('mutant', 'Var', (168, 174))	('mRNA and', 'MPA', (175, 183))	('Fli-1', 'Gene', (69, 74))	('protein', 'Protein', (184, 191))	('expression', 'MPA', (154, 164))
97018	24909161	Fli-1DeltaCTA homozygous mice are viable but exhibit partial perinatal lethality with reduced platelet numbers.	('platelet numbers', 'CPA', (94, 110))	('reduced', 'NegReg', (86, 93))	('mice', 'Species', '10090', (25, 29))	('Fli-1DeltaCTA', 'Var', (0, 13))
97019	24909161	These mutant mice have significantly fewer splenic follicular B cells and more transitional and marginal zone B cells relative to wild-type mice.	('splenic follicular B cells', 'CPA', (43, 69))	('mice', 'Species', '10090', (13, 17))	('more', 'PosReg', (74, 78))	('mutant', 'Var', (6, 12))	('mice', 'Species', '10090', (140, 144))	('fewer', 'NegReg', (37, 42))
97021	24909161	In addition, naive B-cells from Fli-1DeltaCTA mice show reduced responsiveness to mitogens.	('mice', 'Species', '10090', (46, 50))	('reduced', 'NegReg', (56, 63))	('responsiveness to mitogens', 'MPA', (64, 90))	('Fli-1DeltaCTA', 'Var', (32, 45))
97022	24909161	A dominant phenotype of Fli-1DeltaCTA mice is a significant reduction in the number of mature megakaryocytes and thrombocytopenia.	('mice', 'Species', '10090', (38, 42))	('thrombocytopenia', 'Disease', 'MESH:D013921', (113, 129))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (113, 129))	('reduction', 'NegReg', (60, 69))	('Fli-1DeltaCTA', 'Var', (24, 37))	('thrombocytopenia', 'Disease', (113, 129))
97023	24909161	As noted, a complete knock-out of Fli-1 results in embryonic lethality.	('knock-out', 'Var', (21, 30))	('embryonic lethality', 'Disease', 'MESH:D020964', (51, 70))	('embryonic lethality', 'Disease', (51, 70))	('Fli-1', 'Gene', (34, 39))
97029	24909161	A clinical relevance of Fli-1 in megakaryopoiesis was uncovered by Stockley et al., who detected mutations in Fli-1 and Runx1 in 6 families with excessive bleeding and defects in platelet development.	('mutations', 'Var', (97, 106))	('Runx1', 'Gene', '12394', (120, 125))	('Runx1', 'Gene', (120, 125))	('excessive bleeding', 'Disease', (145, 163))	('Fli-1', 'Gene', (110, 115))	('detected', 'Reg', (88, 96))	('platelet development', 'CPA', (179, 199))	('defects', 'NegReg', (168, 175))	('excessive bleeding', 'Disease', 'MESH:D006470', (145, 163))
97030	24909161	The discovery of inactivating mutation in these TFs affecting megakaryocytopoeisis suggests a common genetic aetiology for defective platelet dense granule secretion and mild thrombocytopenia.	('defective platelet dense granule secretion', 'MPA', (123, 165))	('megakaryocytopoeisis', 'CPA', (62, 82))	('TFs', 'Gene', (48, 51))	('inactivating mutation', 'Var', (17, 38))	('thrombocytopenia', 'Disease', (175, 191))	('affecting', 'Reg', (52, 61))	('thrombocytopenia', 'Disease', 'MESH:D013921', (175, 191))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (175, 191))
97031	24909161	Fli-1DeltaCTA mice exhibit significant reduction in the number of mature monocytes, marcrophages and dendritic cells.	('mice', 'Species', '10090', (14, 18))	('Fli-1DeltaCTA', 'Var', (0, 13))	('reduction', 'NegReg', (39, 48))
97035	24909161	Analysis of fli-1 mutant Zebrafish also revealed defects in the circulating system, indicating early evolutionary role for this TF in development of blood and vascular systems.	('circulating system', 'MPA', (64, 82))	('mutant', 'Var', (18, 24))	('Zebrafish', 'Species', '7955', (25, 34))	('fli-1', 'Gene', (12, 17))	('defects', 'NegReg', (49, 56))
97039	24909161	Individual fli-1, erg, ets or etsrp knock-out mice showed partial inhibition of endothelial differentiation, whereas loss of all 4 genes blocked endothelial differentiation, hence revealing extensive redundancy among these ets genes in endothelial cells.	('fli-1', 'Gene', (11, 16))	('loss', 'Var', (117, 121))	('endothelial differentiation', 'CPA', (145, 172))	('blocked', 'NegReg', (137, 144))	('etsrp', 'Gene', '555766', (30, 35))	('mice', 'Species', '10090', (46, 50))	('endothelial differentiation', 'CPA', (80, 107))	('etsrp', 'Gene', (30, 35))	('inhibition', 'NegReg', (66, 76))
97055	24909161	Transient ETV2 expression in ACs generated immature rAC-VECs, whereas co-expression with FLI-1/ERG1 endowed rAC-VECs with a vascular repertoire and morphology that matched mature ECs.	('expression', 'Var', (15, 25))	('ERG1', 'Gene', (95, 99))	('ETV2', 'Gene', (10, 14))	('ETV2', 'Gene', '14008', (10, 14))	('ERG1', 'Gene', '16511', (95, 99))	('FLI-1', 'Gene', '14247', (89, 94))	('FLI-1', 'Gene', (89, 94))
97058	24909161	For example, expression of Fli-1 as well as ERG and ELF-1 in ECs activates Endoglin during angiogenesis.	('ELF-1', 'Gene', (52, 57))	('Fli-1', 'Gene', (27, 32))	('Endoglin', 'Gene', (75, 83))	('Endoglin', 'Gene', '13805', (75, 83))	('expression', 'Var', (13, 23))	('ERG', 'Gene', (44, 47))	('activates', 'PosReg', (65, 74))
97065	24909161	In accordance, breeding of heterozygous mice carrying a Fli-1 null mutation into lupus MRL/lpr mice led to significantly reduced autoimmune disease.	('autoimmune disease', 'Disease', 'MESH:D001327', (129, 147))	('mice', 'Species', '10090', (95, 99))	('mutation', 'Var', (67, 75))	('autoimmune disease', 'Disease', (129, 147))	('Fli-1', 'Gene', (56, 61))	('reduced', 'NegReg', (121, 128))	('MRL/lpr', 'Gene', '14102', (87, 94))	('autoimmune disease', 'Phenotype', 'HP:0002960', (129, 147))	('MRL/lpr', 'Gene', (87, 94))	('mice', 'Species', '10090', (40, 44))
97066	24909161	Likewise, breeding Fli-1+/- heterozygous mice with NZM2410 mice, another lupus murine model, also significantly increased survival, which was associated with reduced levels of auto-antibodies including anti-dsDNA and anti-glomerular basement antigen.	('mice', 'Species', '10090', (59, 63))	('survival', 'CPA', (122, 130))	('Fli-1+/-', 'Var', (19, 27))	('mice', 'Species', '10090', (41, 45))	('anti-glomerular basement antigen', 'Protein', (217, 249))	('anti-dsDNA', 'Var', (202, 212))	('increased', 'PosReg', (112, 121))	('reduced', 'NegReg', (158, 165))	('murine', 'Species', '10090', (79, 85))
97067	24909161	The Fli-1+/-:NZM2410 mice also exhibited a reduced development of kidney disease (glomerulonephritis) associated with decreased monocyte chemo-attractant protein-1 (MCP-1) expression in endothelial cells in the kidney.	('monocyte chemo-attractant protein-1', 'Gene', (128, 163))	('MCP-1', 'Gene', '20296', (165, 170))	('mice', 'Species', '10090', (21, 25))	('MCP-1', 'Gene', (165, 170))	('NZM2410', 'Var', (13, 20))	('kidney disease', 'Disease', 'MESH:D007674', (66, 80))	('nephritis', 'Phenotype', 'HP:0000123', (91, 100))	('kidney disease', 'Phenotype', 'HP:0000112', (66, 80))	('expression', 'MPA', (172, 182))	('Fli-1+/-:NZM2410', 'Var', (4, 20))	('glomerulonephritis', 'Disease', 'MESH:D005921', (82, 100))	('decreased monocyte', 'Phenotype', 'HP:0012312', (118, 136))	('decreased', 'NegReg', (118, 127))	('glomerulonephritis', 'Phenotype', 'HP:0000099', (82, 100))	('glomerulonephritis', 'Disease', (82, 100))	('reduced', 'NegReg', (43, 50))	('monocyte chemo-attractant protein-1', 'Gene', '20296', (128, 163))	('kidney disease', 'Disease', (66, 80))
97074	24909161	The specific polymorphic microsatellite in the human fli-1 promoter was significantly more prevalent in SLE patients without nephritis and tended to be more prevalent in SLE patients with serenities.	('human', 'Species', '9606', (47, 52))	('polymorphic microsatellite', 'Var', (13, 39))	('SLE', 'Disease', (104, 107))	('SLE', 'Disease', 'MESH:D008180', (104, 107))	('SLE', 'Phenotype', 'HP:0002725', (104, 107))	('fli-1', 'Gene', (53, 58))	('patients', 'Species', '9606', (174, 182))	('prevalent', 'Reg', (91, 100))	('SLE', 'Disease', (170, 173))	('SLE', 'Disease', 'MESH:D008180', (170, 173))	('SLE', 'Phenotype', 'HP:0002725', (170, 173))	('prevalent', 'Reg', (157, 166))	('nephritis', 'Disease', 'MESH:D009393', (125, 134))	('patients', 'Species', '9606', (108, 116))	('nephritis', 'Disease', (125, 134))	('nephritis', 'Phenotype', 'HP:0000123', (125, 134))
97076	24909161	This one GA repeat deletion results in a lower Fli-1 expression and may be a major contributor to cutaneous leishmaniasis.	('cutaneous leishmaniasis', 'Disease', (98, 121))	('Fli-1', 'Gene', (47, 52))	('deletion', 'Var', (19, 27))	('lower', 'NegReg', (41, 46))	('cutaneous leishmaniasis', 'Disease', 'MESH:D016773', (98, 121))	('expression', 'MPA', (53, 63))
97079	24909161	A recent study suggests that epigenetic downregulation of Fli-1 in fibroblasts of SSC patients plays a pivotal role in the pathogenesis of disease.	('patients', 'Species', '9606', (86, 94))	('SSC', 'Disease', (82, 85))	('Fli-1', 'Gene', (58, 63))	('epigenetic', 'Var', (29, 39))
97080	24909161	In accordance, targeted disruption of Fli-1 in fibroblasts or endothelial cells reproduced the histopathologic features of fibrosis and vasculopathy seen in SSc, respectively.	('Fli-1', 'Gene', (38, 43))	('fibrosis and vasculopathy', 'Disease', 'MESH:D005355', (123, 148))	('SSc', 'Disease', (157, 160))	('targeted disruption', 'Var', (15, 34))
97084	24909161	Fli-1 acetylation in human fibroblasts decreases its stability and DNA binding, leading to de-repression of the alpha2(I) collagen (COL1A2) promoter and higher collagen production.	('acetylation', 'Var', (6, 17))	('de-repression', 'NegReg', (91, 104))	('higher', 'PosReg', (153, 159))	('alpha2(I) collagen', 'Gene', '1278', (112, 130))	('COL1A2', 'Gene', (132, 138))	('collagen production', 'MPA', (160, 179))	('human', 'Species', '9606', (21, 26))	('COL1A2', 'Gene', '1278', (132, 138))	('alpha2(I) collagen', 'Gene', (112, 130))	('DNA binding', 'Interaction', (67, 78))	('decreases', 'NegReg', (39, 48))	('stability', 'MPA', (53, 62))	('Fli-1', 'Gene', (0, 5))
97087	24909161	Moreover, a causal relationship between MBG-induced PKCdelta modification results in phosphorylation and decreased nuclear Fli-1 levels, and increased collagen production.	('PKCdelta', 'Gene', (52, 60))	('phosphorylation', 'MPA', (85, 100))	('nuclear Fli-1 levels', 'MPA', (115, 135))	('modification', 'Var', (61, 73))	('increased', 'PosReg', (141, 150))	('PKCdelta', 'Gene', '18753', (52, 60))	('decreased', 'NegReg', (105, 114))	('collagen production', 'MPA', (151, 170))
97088	24909161	Interestingly, in contrast to TGF-beta-mediated Fli-1 modification in SSc (Figure 3), MBG mediated PKCdelta phosphorylation resulted in downregulation of Fli-1 in fibroblasts.	('downregulation', 'NegReg', (136, 150))	('TGF-beta', 'Gene', '21803', (30, 38))	('Fli-1', 'Enzyme', (154, 159))	('TGF-beta', 'Gene', (30, 38))	('PKCdelta', 'Gene', '18753', (99, 107))	('MBG', 'Var', (86, 89))	('PKCdelta', 'Gene', (99, 107))
97091	24909161	As noted, Fli-1 was first identified as a proto-oncogene activated by proviral integration in F-MuLV-induced erythroleukemias and later in Cas-Br-E-induced Non-T/B-cell and 10A1 stem cell like-induced leukemias.	('leukemias', 'Phenotype', 'HP:0001909', (201, 210))	('Fli-1', 'Gene', (10, 15))	('leukemias', 'Disease', (201, 210))	('erythroleukemias', 'Disease', 'MESH:D004915', (109, 125))	('F-MuLV', 'Species', '11795', (94, 100))	('activated', 'PosReg', (57, 66))	('erythroleukemias', 'Disease', (109, 125))	('Non-T', 'Disease', (156, 161))	('leukemias', 'Disease', 'MESH:D007938', (201, 210))	('leukemias', 'Phenotype', 'HP:0001909', (116, 125))	('leukemias', 'Disease', (116, 125))	('Non-T', 'Disease', 'MESH:C580335', (156, 161))	('leukemia', 'Phenotype', 'HP:0001909', (201, 209))	('F-MuLV-induced', 'Var', (94, 108))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))	('leukemias', 'Disease', 'MESH:D007938', (116, 125))
97100	24909161	Fli-1 overexpression in erythroblasts also increases tyrosine phosphorylation of the p85 subunit of PI3-Kinase and phosphorylation of Shc/Ras pathway, two critical regulators of cell survival and proliferation.	('phosphorylation', 'MPA', (115, 130))	('overexpression', 'Var', (6, 20))	('Shc/Ras pathway', 'Pathway', (134, 149))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('increases', 'PosReg', (43, 52))	('tyrosine phosphorylation', 'MPA', (53, 77))	('Fli-1', 'Gene', (0, 5))
97103	24909161	Moreover, Fli-1 negatively regulates phosphatidyl-inositol polyphosphate 5-phosphatase (ship1) gene expression, leading to a higher phosphorylation of AKT/PKB by PI3K and erythroid proliferation.	('ship1', 'Gene', (88, 93))	('Fli-1', 'Gene', (10, 15))	('AKT/PKB', 'Pathway', (151, 158))	('PI3K', 'Var', (162, 166))	('erythroid proliferation', 'CPA', (171, 194))	('ship1', 'Gene', '16331', (88, 93))	('higher', 'PosReg', (125, 131))	('phosphorylation', 'MPA', (132, 147))
97107	24909161	In addition, shRNA-mediated knock-down of Fli-1 in murine and human erythroleukemic cells suppresses cell proliferation, induces differentiation and accelerates apoptosis associated with decreased expression of its target genes including gata-1 and Bcl-2.	('suppresses', 'NegReg', (90, 100))	('leukemic', 'Disease', 'MESH:D007938', (75, 83))	('Fli-1', 'Gene', (42, 47))	('human', 'Species', '9606', (62, 67))	('leukemic', 'Disease', (75, 83))	('knock-down', 'Var', (28, 38))	('murine', 'Species', '10090', (51, 57))	('apoptosis', 'CPA', (161, 170))	('induces', 'Reg', (121, 128))	('gata-1', 'Gene', '2623', (238, 244))	('gata-1', 'Gene', (238, 244))	('accelerates', 'PosReg', (149, 160))	('decreased', 'NegReg', (187, 196))	('cell proliferation', 'CPA', (101, 119))	('expression', 'MPA', (197, 207))	('differentiation', 'CPA', (129, 144))
97108	24909161	In addition to erythroleukemia, deregulated Fli-1 can induce other hematological malignancies.	('hematological malignancies', 'Disease', (67, 93))	('deregulated', 'Var', (32, 43))	('hematological malignancies', 'Disease', 'MESH:D019337', (67, 93))	('erythroleukemia', 'Disease', 'MESH:D004915', (15, 30))	('hematological malignancies', 'Phenotype', 'HP:0004377', (67, 93))	('erythroleukemia', 'Disease', (15, 30))	('induce', 'Reg', (54, 60))	('Fli-1', 'Gene', (44, 49))	('leukemia', 'Phenotype', 'HP:0001909', (22, 30))
97109	24909161	For examples, retroviral transduction of Fli-1 into murine T-cell progenitors disrupts normal development and induces pre-T-cell lymphoblastic lymphoma.	('cell lymphoblastic lymphoma', 'Phenotype', 'HP:0012191', (124, 151))	('disrupts', 'NegReg', (78, 86))	('lymphoblastic lymphoma', 'Disease', (129, 151))	('Fli-1', 'Gene', (41, 46))	('lymphoma', 'Phenotype', 'HP:0002665', (143, 151))	('retroviral transduction', 'Var', (14, 37))	('induces', 'Reg', (110, 117))	('lymphoblastic lymphoma', 'Disease', 'MESH:D054198', (129, 151))	('normal development', 'CPA', (87, 105))	('murine', 'Species', '10090', (52, 58))
97111	24909161	Abnormal Fli-1 expression is also associated with progression of acute myeloid leukemia (AML).	('associated with', 'Reg', (34, 49))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (71, 87))	('AML', 'Disease', 'MESH:D015470', (89, 92))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (65, 87))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('Fli-1', 'Gene', (9, 14))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (65, 87))	('expression', 'MPA', (15, 25))	('Abnormal', 'Var', (0, 8))	('AML', 'Phenotype', 'HP:0004808', (89, 92))	('AML', 'Disease', (89, 92))	('acute myeloid leukemia', 'Disease', (65, 87))
97113	24909161	In support of these observations, a recent study identified fli-1 gene amplification within a 11q23-25 amplicon in several cases of AML and diffuse large B-cell lymphomas.	('lymphomas', 'Phenotype', 'HP:0002665', (161, 170))	('AML', 'Disease', (132, 135))	('AML', 'Phenotype', 'HP:0004808', (132, 135))	('amplification', 'Var', (71, 84))	('lymphoma', 'Phenotype', 'HP:0002665', (161, 169))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (154, 170))	('fli-1', 'Gene', (60, 65))	('lymphomas', 'Disease', 'MESH:D008223', (161, 170))	('lymphomas', 'Disease', (161, 170))	('AML', 'Disease', 'MESH:D015470', (132, 135))
97118	24909161	In addition to hematological malignancies, high Fli-1 expression promotes the development of divergent types of solid tumors.	('expression', 'MPA', (54, 64))	('solid tumors', 'Disease', (112, 124))	('Fli-1', 'Gene', (48, 53))	('high', 'Var', (43, 47))	('hematological malignancies', 'Phenotype', 'HP:0004377', (15, 41))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('solid tumors', 'Disease', 'MESH:D009369', (112, 124))	('promotes', 'PosReg', (65, 73))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('hematological malignancies', 'Disease', (15, 41))	('hematological malignancies', 'Disease', 'MESH:D019337', (15, 41))
97119	24909161	The best example is the above mentioned EWS-FLI-1 translocation (t[11;22]) in Ewing sarcoma and certain neuroectodermal neoplasms.	('neuroectodermal neoplasms', 'Disease', 'MESH:D017599', (104, 129))	('neuroectodermal neoplasms', 'Phenotype', 'HP:0030061', (104, 129))	('neuroectodermal neoplasms', 'Disease', (104, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('neoplasms', 'Phenotype', 'HP:0002664', (120, 129))	('FLI-1', 'Gene', '14247', (44, 49))	('translocation', 'Var', (50, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('FLI-1', 'Gene', (44, 49))	('Ewing sarcoma', 'Disease', (78, 91))
97127	24909161	Together, these studies demonstrate high expression as well as translocations involving Fli-1 in a wide range of hematopoietic and solid tumors.	('translocations', 'Var', (63, 77))	('solid tumors', 'Disease', 'MESH:D009369', (131, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('expression', 'MPA', (41, 51))	('Fli-1', 'Gene', (88, 93))	('solid tumors', 'Disease', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
97134	24909161	As described above, Fli-1 regulates genes and pathways associated with hallmarks of cancer initiation and progression including sustained proliferation, angiogenesis, genomic instability, inhibition of apoptosis and differentiation; its abnormal expression or translocation induces diverse tumor types (Figure 4).	('induces', 'Reg', (274, 281))	('regulates', 'Reg', (26, 35))	('genes', 'Gene', (36, 41))	('differentiation', 'CPA', (216, 231))	('genomic', 'MPA', (167, 174))	('angiogenesis', 'CPA', (153, 165))	('abnormal', 'Var', (237, 245))	('sustained proliferation', 'CPA', (128, 151))	('hallmarks of cancer initiation', 'Disease', (71, 101))	('hallmarks of cancer initiation', 'Disease', 'MESH:D009369', (71, 101))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('apoptosis', 'CPA', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', (290, 295))	('Fli-1', 'Gene', (20, 25))
97137	24909161	The effectiveness of these compounds for the treatment of Ewing's sarcoma and other malignancies with a EWS-Fli-1 translocation is yet to be determined in randomized clinical trials.	('malignancies', 'Disease', (84, 96))	("Ewing's sarcoma", 'Disease', (58, 73))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (58, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (58, 73))	('translocation', 'Var', (114, 127))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('EWS-Fli-1', 'Gene', (104, 113))
97140	24909161	Many of these Fli-1 inhibitors have known biological activities and are presently used to treat of cancers.	('biological activities', 'MPA', (42, 63))	('Fli-1', 'Gene', (14, 19))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('inhibitors', 'Var', (20, 30))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
97153	24909161	Thus, both agonists and antagonists of Fli-1 may provide therapeutic benefits for the treatment of immune-diseases and cancers, respectively.	('antagonists', 'Var', (24, 35))	('immune-diseases and cancers', 'Disease', 'MESH:D009369', (99, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('Fli-1', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
97155	24909161	Abnormal expression of Fli-1 was shown to drive various diseases, hematological malignancies and solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('Abnormal expression', 'Var', (0, 19))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('hematological malignancies', 'Disease', (66, 92))	('drive', 'PosReg', (42, 47))	('Fli-1', 'Gene', (23, 28))	('hematological malignancies', 'Disease', 'MESH:D019337', (66, 92))	('solid tumors', 'Disease', (97, 109))	('diseases', 'Disease', (56, 64))	('hematological malignancies', 'Phenotype', 'HP:0004377', (66, 92))
97185	22928481	We developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone.	('dedifferentiated chondrosarcoma', 'Disease', 'MESH:D002813', (112, 143))	('L2975', 'Var', (145, 150))	('II chondrosarcoma', 'Disease', (82, 99))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (129, 143))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (85, 99))	('L2975', 'CellLine', 'CVCL:D706', (145, 150))	('II chondrosarcoma', 'Disease', 'MESH:D002813', (82, 99))	('L3252', 'Var', (155, 160))	('dedifferentiated chondrosarcoma', 'Disease', (112, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
97188	22928481	We show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice.	('L2975', 'Var', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('migration rate', 'CPA', (92, 106))	('L2975', 'CellLine', 'CVCL:D706', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('mice', 'Species', '10090', (143, 147))
97190	22928481	L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type.	('R172W', 'Var', (47, 52))	('IDH', 'Gene', (42, 45))	('IDH1', 'Gene', (12, 16))	('IDH', 'Gene', '3417', (42, 45))	('L2975', 'Var', (33, 38))	('R132C', 'Mutation', 'rs121913499', (17, 22))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('IDH2', 'Gene', (42, 46))	('IDH1', 'Gene', '3417', (12, 16))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('L2975', 'CellLine', 'CVCL:D706', (33, 38))	('R172W', 'Mutation', 'rs1057519906', (47, 52))	('IDH2', 'Gene', '3418', (42, 46))	('L835', 'Var', (0, 4))
97198	22928481	Recently IDH1 and IDH2 mutations were found in conventional central and dedifferentiated chondrosarcomas.	('dedifferentiated chondrosarcoma', 'Disease', 'MESH:D002813', (72, 103))	('IDH2', 'Gene', '3418', (18, 22))	('chondrosarcomas', 'Disease', 'MESH:D002813', (89, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('dedifferentiated chondrosarcoma', 'Disease', (72, 103))	('IDH1', 'Gene', (9, 13))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (89, 103))	('chondrosarcomas', 'Disease', (89, 104))	('IDH1', 'Gene', '3417', (9, 13))	('mutations', 'Var', (23, 32))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (89, 104))	('IDH2', 'Gene', (18, 22))	('found', 'Reg', (38, 43))
97199	22928481	IDH1 and IDH2 mutations are well known in gliomas, but are notoriously difficult to grow in culture.	('IDH2', 'Gene', (9, 13))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('IDH2', 'Gene', '3418', (9, 13))	('IDH1', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('mutations', 'Var', (14, 23))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))	('IDH1', 'Gene', '3417', (0, 4))
97204	22928481	L835 is derived from a grade III conventional chondrosarcoma, while L2975 and L3252 originate from dedifferentiated chondrosarcomas of bone.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (46, 60))	('L3252', 'Var', (78, 83))	('chondrosarcomas', 'Disease', 'MESH:D002813', (116, 131))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (116, 130))	('dedifferentiated chondrosarcoma', 'Disease', 'MESH:D002813', (99, 130))	('chondrosarcomas', 'Disease', (116, 131))	('L2975', 'CellLine', 'CVCL:D706', (68, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('chondrosarcoma', 'Disease', (46, 60))	('L2975', 'Var', (68, 73))	('dedifferentiated chondrosarcoma', 'Disease', (99, 130))	('chondrosarcoma', 'Disease', 'MESH:D002813', (46, 60))	('chondrosarcoma', 'Disease', 'MESH:D002813', (116, 130))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (116, 131))	('chondrosarcoma', 'Disease', (116, 130))	('L835', 'Var', (0, 4))
97211	22928481	For each cell line several cell culture passages were studied (L835: passage 17 and 35, L2975: passage 20 and 30, L3252: passage 7, 8, and 20) and karyotypes were described for each cell line according to the International System of Human Cytogenetic Nomenclature (ISCN) 2009.	('L2975', 'Var', (88, 93))	('L2975', 'CellLine', 'CVCL:D706', (88, 93))	('Human', 'Species', '9606', (233, 238))	('L3252', 'Var', (114, 119))
97212	22928481	RNA was isolated from L835 (passage 40), L2975 (passage 58), and L3252 (passage 21).	('L3252', 'Var', (65, 70))	('L2975', 'Var', (41, 46))	('L2975', 'CellLine', 'CVCL:D706', (41, 46))
97215	22928481	For L835 passage 36 was compared to primary tumor tissue, for L2975 passage 37 was used, and for L3252 passage 20 was compared to primary tumor tissue.	('L2975', 'Var', (62, 67))	('tumor', 'Disease', (138, 143))	('L2975', 'CellLine', 'CVCL:D706', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('L835', 'Var', (4, 8))	('tumor', 'Disease', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
97217	22928481	Prior to starting experiments cell number curves were run to determine optimal growth curves and for doubling time experiments cell lines were plated at a density of 1,000 cells per well for L2975 and L3252 and 10,000 cells per well for L835 in growth medium (10% FCS in RPMI1640).	('RPMI1640', 'Chemical', '-', (271, 279))	('L2975', 'Var', (191, 196))	('L2975', 'CellLine', 'CVCL:D706', (191, 196))	('L3252', 'Var', (201, 206))	('L835', 'Var', (237, 241))
97222	22928481	Mutation analysis for PIK3CA, KRAS, BRAF, EGFR was performed using hydrolysis probes assay at L835 (passage 36), L2975 (passage 37), and L3252 (passage 20).	('L2975', 'CellLine', 'CVCL:D706', (113, 118))	('EGFR', 'Gene', '1956', (42, 46))	('BRAF', 'Gene', (36, 40))	('PIK3CA', 'Gene', '5290', (22, 28))	('L835', 'Var', (94, 98))	('L3252', 'Var', (137, 142))	('EGFR', 'Gene', (42, 46))	('L2975', 'Var', (113, 118))	('KRAS', 'Gene', (30, 34))	('PIK3CA', 'Gene', (22, 28))	('BRAF', 'Gene', '673', (36, 40))	('KRAS', 'Gene', '3845', (30, 34))
97223	22928481	Mutation analysis for TP53 was performed at those same passage numbers and IDH mutation analysis was performed at L835 passage 38 and 47, L2975 passage 31 and 46, and L3252 passage 20, as well as on DNA obtained from CH-3573.	('L3252', 'Var', (167, 172))	('L2975', 'CellLine', 'CVCL:D706', (138, 143))	('TP53', 'Gene', '7157', (22, 26))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('L2975', 'Var', (138, 143))	('TP53', 'Gene', (22, 26))
97224	22928481	To determine expression of the IDH mutated allele cDNA was generated using 1 mug total RNA as described for L835 (passage 38), L2975 (passage 31), and L3252 (passage 20).	('IDH', 'Gene', (31, 34))	('L835', 'Var', (108, 112))	('L2975', 'CellLine', 'CVCL:D706', (127, 132))	('IDH', 'Gene', '3417', (31, 34))	('L3252', 'Var', (151, 156))	('L2975', 'Var', (127, 132))
97227	22928481	DNA of L835 passage 36, L2975 passage 37, and L3252 passage 20 was used.	('L835', 'Var', (7, 11))	('L3252', 'Var', (46, 51))	('L2975', 'Var', (24, 29))	('L2975', 'CellLine', 'CVCL:D706', (24, 29))
97234	22928481	L835 (passage 35), L2975 (passage 55), and L3252 (passage 17) cells were fixed in formalin and prepared using the Shandon Cytoblock cell block preparation system (Thermo Scientific, Etten-Leur, the Netherlands).	('L3252', 'Var', (43, 48))	('formalin', 'Chemical', 'MESH:D005557', (82, 90))	('L2975', 'Var', (19, 24))	('L2975', 'CellLine', 'CVCL:D706', (19, 24))
97244	22928481	L3252 is derived from the local recurrence of a chondrosarcoma located at the chest wall (costa) (Figure 1C, D) that had already metastasized to the spine and the lung at the time of first presentation.	('chondrosarcoma', 'Disease', 'MESH:D002813', (48, 62))	('chondrosarcoma', 'Disease', (48, 62))	('L3252', 'Var', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (48, 62))
97247	22928481	L835 was passaged routinely in vitro for 50 generations, L2975 for 60 generations, and L3252 for 30 generations.	('L2975', 'Var', (57, 62))	('L3252', 'Var', (87, 92))	('L2975', 'CellLine', 'CVCL:D706', (57, 62))	('L835', 'Var', (0, 4))
97248	22928481	The cell lines derived from dedifferentiated chondrosarcoma (L2975 and L3252) were noticeably easier to culture than the L835 cells.	('L3252', 'Var', (71, 76))	('dedifferentiated chondrosarcoma', 'Disease', (28, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('L2975', 'Var', (61, 66))	('dedifferentiated chondrosarcoma', 'Disease', 'MESH:D002813', (28, 59))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (45, 59))	('L2975', 'CellLine', 'CVCL:D706', (61, 66))
97249	22928481	This was also reflected by Ki-67 staining on embedded cells, with proliferation rates of ~60% (L835) versus ~100% and ~80% for L2975 and L3252, respectively.	('L3252', 'Var', (137, 142))	('L2975', 'Var', (127, 132))	('Ki-67', 'Chemical', '-', (27, 32))	('L2975', 'CellLine', 'CVCL:D706', (127, 132))
97252	22928481	L835 passage 36, L2975 passage 37, and L3252 passage 20 showed identical STR loci when compared to their matching original tumors.	('L2975', 'CellLine', 'CVCL:D706', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('original tumors', 'Disease', 'MESH:D009369', (114, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('original tumors', 'Disease', (114, 129))	('L2975', 'Var', (17, 22))	('L3252', 'Var', (39, 44))	('L835', 'Var', (0, 4))
97256	22928481	For L2975, cell migration occurred much more rapidly than cell attachment (Figure 2C).	('cell migration', 'CPA', (11, 25))	('L2975', 'Var', (4, 9))	('L2975', 'CellLine', 'CVCL:D706', (4, 9))
97261	22928481	Xenografting of L835 and L3252 did not result in tumors in 8 months.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('L3252', 'Var', (25, 30))	('L835', 'Var', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
97263	22928481	L2975 also revealed a stable karyotype at passage 30 with many numerical changes and complex rearrangements (Figure 4B').	('L2975', 'Var', (0, 5))	('numerical changes', 'CPA', (63, 80))	('L2975', 'CellLine', 'CVCL:D706', (0, 5))
97264	22928481	The resulting karyotype was: 61-65 < 3n > der(X;4)(p10;p10),der(X;8)(q10;q10),-Y,+der(Y;9)(p10;p10)x2,+der(1;15)(q10;q10),der(1;1)(q10;q10)t(1;6)(q21;q24)t(1;8)(q31;p11),der(1;8)(p10;p10),del(2)(q22q32),-4,-5,+der(7;15)(q10;q10),t(9;16)(q10;q10)x2,der(10;18)(q10;q10),-13,der(13;13)(q10;q10),der(14;15)(q10;q10)t(8;15)(q11;q21),-15,-15,-16,-17,i(17)(q10),-18,der(18)t(1;18)(p31;q22),der(20)t(X;20)(q23,p12),-21,+mar3x.	('t(8;15)(q11;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (311, 327))	('p10', 'Gene', '6281', (91, 94))	('p12', 'Gene', '56655', (402, 405))	('der(18)t(1;18)(p31;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (359, 382))	('p10', 'Gene', (183, 186))	('p10', 'Gene', '6281', (179, 182))	('p10', 'Gene', '6281', (51, 54))	('der(18)t(1;18)(p31;q22', 'Var', (359, 381))	('der(13;13)(q10;q10', 'Var', (272, 290))	('p10', 'Gene', (95, 98))	('der(14;15)(q10;q10)t(8;15)(q11;q21', 'Var', (292, 326))	('der(10;18)(q10;q10', 'Var', (248, 266))	('t(1;6)(q21;q24)t(1;8)(q31;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (139, 169))	('p10', 'Gene', (55, 58))	('i(17)(q10', 'Var', (344, 353))	('p12', 'Gene', (402, 405))	('p10', 'Gene', '6281', (183, 186))	('p10', 'Gene', '6281', (95, 98))	('der(20)t(X;20)(q23', 'Var', (383, 401))	('t(9;16)(q10;q10)', 'STRUCTURAL_ABNORMALITY', 'None', (229, 245))	('p10', 'Gene', '6281', (55, 58))	('p10', 'Gene', (91, 94))	('p10', 'Gene', (179, 182))	('p10', 'Gene', (51, 54))
97265	22928481	L3252 was stable at passage 20 with many numerical changes and complex rearrangements (Figure 4C'): 51 < 2n+>,X,-X,+der(3;11)t(3;11)(p10;q10)t(11;17) (q14;q22), der(4;8)t(4;8)(q10;p10),der(4),+der(5),der(6;15)t(6;15)(p10;q10), der(7)t(7;18),der(7),+der(8)x2,der(8),der(9),der (10),+12,der(13;13)(q10;q10),-13,der(17),i(17)(p10;p10)der(18)t(7;18),+der(20), der(21),+mar.	('p10', 'Gene', (180, 183))	('p10', 'Gene', (217, 220))	('der', 'Var', (227, 230))	('p10', 'Gene', '6281', (217, 220))	('p10', 'Gene', (327, 330))	('p10', 'Gene', '6281', (323, 326))	('p10', 'Gene', '6281', (180, 183))	('der(13;13)(q10;q10', 'Var', (285, 303))	('t(4;8)(q10;p10)', 'STRUCTURAL_ABNORMALITY', 'None', (169, 184))	('der(17', 'Var', (309, 315))	('p10', 'Gene', (133, 136))	('t(3;11)(p10;q10)', 'STRUCTURAL_ABNORMALITY', 'None', (125, 141))	('p10', 'Gene', '6281', (327, 330))	('der(9', 'Var', (265, 270))	('p10', 'Gene', '6281', (133, 136))	('p10', 'Gene', (323, 326))	('der (10', 'Var', (272, 279))	('t(6;15)(p10;q10)', 'STRUCTURAL_ABNORMALITY', 'None', (209, 225))
97266	22928481	In L835 and L2975, all aberrations present in the tumor were retained in the cell lines.	('L2975', 'Var', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('L2975', 'CellLine', 'CVCL:D706', (12, 17))	('tumor', 'Disease', (50, 55))	('L835', 'Var', (3, 7))
97267	22928481	L835 showed a homozygous CDKN2A deletion in both the original tumor and the cell line (Figure 4A").	('original tumor', 'Disease', (53, 67))	('deletion', 'Var', (32, 40))	('original tumor', 'Disease', 'MESH:D009369', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CDKN2A', 'Gene', (25, 31))	('CDKN2A', 'Gene', '1029', (25, 31))
97268	22928481	L2975 and L3252 both showed a homozygous deletion in the cell line (Figure 4B" and 4C"), the deletion status of the primary tumor was difficult to assess due to low tumor content and consequently resulting suppressed ratio profiles.	('ratio profiles', 'MPA', (217, 231))	('tumor', 'Disease', (165, 170))	('L2975', 'CellLine', 'CVCL:D706', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('L3252', 'Var', (10, 15))	('suppressed', 'NegReg', (206, 216))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('low tumor', 'Disease', 'MESH:D009800', (161, 170))	('L2975', 'Var', (0, 5))	('low tumor', 'Disease', (161, 170))
97269	22928481	For both L835 and L2975 clear DNA copy number alterations could be observed in the original tumor samples that were enhanced in the cell lines.	('L2975', 'CellLine', 'CVCL:D706', (18, 23))	('original tumor', 'Disease', (83, 97))	('L835', 'Var', (9, 13))	('L2975 clear DNA', 'Var', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('original tumor', 'Disease', 'MESH:D009369', (83, 97))
97270	22928481	For L3252 tumor DNA this was less pronounced.	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('L3252', 'Var', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
97271	22928481	We previously demonstrated L835 (passage 38) to harbor an IDH1 R132C mutation and L2975 (passage 31) an IDH2 R172W mutation.	('IDH2', 'Gene', '3418', (104, 108))	('R172W', 'Var', (109, 114))	('IDH1', 'Gene', '3417', (58, 62))	('R132C', 'Var', (63, 68))	('R132C', 'Mutation', 'rs121913499', (63, 68))	('IDH2', 'Gene', (104, 108))	('L2975', 'CellLine', 'CVCL:D706', (82, 87))	('R172W', 'Mutation', 'rs1057519906', (109, 114))	('IDH1', 'Gene', (58, 62))
97272	22928481	We here show that L3252 (passage 20) is wild type and that also later passages of L835 (passage 47) and L2975 (passage 46) retain the IDH mutation.	('IDH', 'Gene', '3417', (134, 137))	('L2975', 'Var', (104, 109))	('L3252', 'Var', (18, 23))	('L2975', 'CellLine', 'CVCL:D706', (104, 109))	('L835', 'Var', (82, 86))	('IDH', 'Gene', (134, 137))
97273	22928481	Using cDNA we found the mutated IDH alleles to be expressed (results not shown).	('mutated', 'Var', (24, 31))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))
97284	22928481	Recently chondrosarcoma has been found to harbor IDH1 and IDH2 mutations (5;15) and we published that the mutation is retained in a subset of chondrosarcoma cell lines.	('mutations', 'Var', (63, 72))	('IDH1', 'Gene', '3417', (49, 53))	('IDH2', 'Gene', '3418', (58, 62))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (142, 156))	('chondrosarcoma', 'Disease', 'MESH:D002813', (142, 156))	('chondrosarcoma', 'Disease', 'MESH:D002813', (9, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('chondrosarcoma', 'Disease', (142, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('chondrosarcoma', 'Disease', (9, 23))	('IDH2', 'Gene', (58, 62))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (9, 23))	('IDH1', 'Gene', (49, 53))
97285	22928481	In glioma IDH mutations seem to be the earliest event in gliomagenesis even before TP53 mutations occur.	('TP53', 'Gene', '7157', (83, 87))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('TP53', 'Gene', (83, 87))	('glioma IDH', 'Disease', (3, 13))	('glioma', 'Disease', (57, 63))	('glioma', 'Disease', (3, 9))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('mutations', 'Var', (14, 23))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('glioma IDH', 'Disease', 'MESH:D005910', (3, 13))
97286	22928481	In conventional chondrosarcoma we observe a similar phenomenon, where IDH mutations are present already in a high percentage of low-grade tumors and TP53 mutations are observed to increase with grade (4;5;15).	('increase', 'PosReg', (180, 188))	('IDH', 'Gene', (70, 73))	('TP53', 'Gene', '7157', (149, 153))	('mutations', 'Var', (74, 83))	('chondrosarcoma', 'Disease', 'MESH:D002813', (16, 30))	('IDH', 'Gene', '3417', (70, 73))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('TP53', 'Gene', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('chondrosarcoma', 'Disease', (16, 30))	('mutations', 'Var', (154, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (16, 30))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
97287	22928481	Cell lines created from IDH mutant gliomas have been reported to eliminate their IDH mutation under standard culture conditions.	('eliminate', 'NegReg', (65, 74))	('gliomas', 'Phenotype', 'HP:0009733', (35, 42))	('mutant', 'Var', (28, 34))	('IDH', 'Gene', (24, 27))	('IDH', 'Gene', '3417', (24, 27))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('IDH', 'Gene', (81, 84))	('gliomas', 'Disease', (35, 42))	('IDH', 'Gene', '3417', (81, 84))	('gliomas', 'Disease', 'MESH:D005910', (35, 42))
97288	22928481	Recently, however, a glioma cell line carrying an endogenous IDH1 R132H mutation was published, but this cell line showed a slow growth rate in culture.	('R132H', 'Var', (66, 71))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('IDH1', 'Gene', '3417', (61, 65))	('R132H', 'Mutation', 'rs121913500', (66, 71))	('slow growth', 'Phenotype', 'HP:0001510', (124, 135))	('IDH1', 'Gene', (61, 65))	('glioma', 'Disease', (21, 27))
97289	22928481	We here present three chondrosarcoma cell lines, one carrying an IDH1 R132C mutation, one carrying an IDH2 R172W mutation, and one wild type for IDH mutations with stable karyotypes and steady growth patterns.	('IDH1', 'Gene', '3417', (65, 69))	('IDH', 'Gene', '3417', (102, 105))	('IDH', 'Gene', (65, 68))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (22, 36))	('R172W', 'Mutation', 'rs1057519906', (107, 112))	('IDH', 'Gene', (145, 148))	('IDH2', 'Gene', (102, 106))	('IDH', 'Gene', (102, 105))	('IDH', 'Gene', '3417', (65, 68))	('IDH', 'Gene', '3417', (145, 148))	('R132C', 'Mutation', 'rs121913499', (70, 75))	('R132C mutation', 'Var', (70, 84))	('IDH2', 'Gene', '3418', (102, 106))	('chondrosarcoma', 'Disease', (22, 36))	('chondrosarcoma', 'Disease', 'MESH:D002813', (22, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('IDH1', 'Gene', (65, 69))
97290	22928481	We speculate that in IDH mutant chondrosarcoma the acquisition of additional mutations as we have shown here have facilitated their growth in culture.	('IDH', 'Gene', (21, 24))	('facilitated', 'PosReg', (114, 125))	('IDH', 'Gene', '3417', (21, 24))	('chondrosarcoma', 'Disease', 'MESH:D002813', (32, 46))	('mutations', 'Var', (77, 86))	('chondrosarcoma', 'Disease', (32, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('growth', 'MPA', (132, 138))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (32, 46))
97291	22928481	The inactivation of tumor suppressor genes is a well-known phenomenon in cancer and p16 mutations have been reported in 20-41% of human chondrosarcomas.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (136, 150))	('chondrosarcomas', 'Disease', (136, 151))	('reported', 'Reg', (108, 116))	('mutations', 'Var', (88, 97))	('p16', 'Gene', '1029', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (136, 151))	('human', 'Species', '9606', (130, 135))	('chondrosarcomas', 'Disease', 'MESH:D002813', (136, 151))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('p16', 'Gene', (84, 87))	('inactivation', 'NegReg', (4, 16))
97293	22928481	Recently, we showed inactivation of p16 in 30/38 (79%) dedifferentiated chondrosarcoma cases.	('dedifferentiated chondrosarcoma', 'Disease', (55, 86))	('inactivation', 'Var', (20, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('p16', 'Gene', '1029', (36, 39))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (72, 86))	('dedifferentiated chondrosarcoma', 'Disease', 'MESH:D002813', (55, 86))	('p16', 'Gene', (36, 39))
97295	22928481	Introduction of p16 in the endogenously TP53 mutant HT-1080 fibrosarcoma cell line, which was recently reported to carry an IDH1 R132C mutation, also led to cell cycle arrest and growth inhibition.	('mutant', 'Var', (45, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('arrest', 'Disease', (168, 174))	('R132C mutation', 'Var', (129, 143))	('IDH1', 'Gene', '3417', (124, 128))	('p16', 'Gene', '1029', (16, 19))	('fibrosarcoma', 'Disease', 'MESH:D005354', (60, 72))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (60, 72))	('HT-1080', 'CellLine', 'CVCL:0317', (52, 59))	('TP53', 'Gene', '7157', (40, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (157, 174))	('TP53', 'Gene', (40, 44))	('growth inhibition', 'CPA', (179, 196))	('R132C', 'Mutation', 'rs121913499', (129, 134))	('arrest', 'Disease', 'MESH:D006323', (168, 174))	('IDH1', 'Gene', (124, 128))	('p16', 'Gene', (16, 19))	('fibrosarcoma', 'Disease', (60, 72))
97296	22928481	We report here three new chondrosarcoma cell lines lacking p16 expression based on a homozygous deletion of the CDKN2A locus as shown by aCGH analysis, and confirmed loss of p16 expression using immunohistochemistry.	('p16', 'Gene', '1029', (59, 62))	('chondrosarcoma', 'Disease', (25, 39))	('CDKN2A', 'Gene', (112, 118))	('chondrosarcoma', 'Disease', 'MESH:D002813', (25, 39))	('p16', 'Gene', (174, 177))	('loss', 'NegReg', (166, 170))	('lacking', 'NegReg', (51, 58))	('CDKN2A', 'Gene', '1029', (112, 118))	('expression', 'MPA', (63, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('p16', 'Gene', (59, 62))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (25, 39))	('deletion', 'Var', (96, 104))	('p16', 'Gene', '1029', (174, 177))
97297	22928481	Moreover, aCGH analysis showed a copy number loss around the 17p13.1 locus in L835, whereas a copy number gain was observed in L2975 and L3252.	('copy number', 'Var', (33, 44))	('p13', 'Gene', (63, 66))	('L2975', 'CellLine', 'CVCL:D706', (127, 132))	('L835', 'Gene', (78, 82))	('p13', 'Gene', '440926', (63, 66))	('loss', 'NegReg', (45, 49))
97298	22928481	However, mutation analysis for TP53 showed no activating mutations in exons 5-8, and immunohistochemistry showed no p53 overexpression.	('mutation', 'Var', (9, 17))	('p53', 'Gene', (116, 119))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('p53', 'Gene', '7157', (116, 119))
97299	22928481	Together, our data suggest that while IDH mutations are important as early events in a subset of chondrosarcomas, additional inactivation of p16 may be crucial for acquiring a more aggressive phenotype.	('p16', 'Gene', '1029', (141, 144))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (97, 112))	('IDH', 'Gene', (38, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('IDH', 'Gene', '3417', (38, 41))	('chondrosarcomas', 'Disease', 'MESH:D002813', (97, 112))	('inactivation', 'Var', (125, 137))	('p16', 'Gene', (141, 144))	('chondrosarcomas', 'Disease', (97, 112))	('mutations', 'Var', (42, 51))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (97, 111))
97303	22928481	Indeed, 3 out of 3 dedifferentiated chondrosarcomas with IDH1 mutations carried the mutation in both components.	('chondrosarcomas', 'Disease', (36, 51))	('carried', 'Reg', (72, 79))	('dedifferentiated chondrosarcoma', 'Disease', 'MESH:D002813', (19, 50))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (36, 50))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (36, 51))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', '3417', (57, 61))	('dedifferentiated chondrosarcoma', 'Disease', (19, 50))	('chondrosarcomas', 'Disease', 'MESH:D002813', (36, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('mutations', 'Var', (62, 71))
97307	22928481	We show here the use of L2975 dedifferentiated chondrosarcoma cells with an IDH2 R172W mutation in mouse models, which can be an important asset in the research for new treatment strategies.	('R172W', 'Var', (81, 86))	('mouse', 'Species', '10090', (99, 104))	('dedifferentiated chondrosarcoma', 'Disease', 'MESH:D002813', (30, 61))	('IDH2', 'Gene', '3418', (76, 80))	('L2975', 'CellLine', 'CVCL:D706', (24, 29))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (47, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('dedifferentiated chondrosarcoma', 'Disease', (30, 61))	('R172W', 'Mutation', 'rs1057519906', (81, 86))	('IDH2', 'Gene', (76, 80))	('L2975', 'Var', (24, 29))
97308	22928481	We report the establishment and molecular, genetic and functional characterization of one grade III (L835) and two dedifferentiated chondrosarcoma (L2975 and L3252) cell lines.	('L835', 'Var', (101, 105))	('dedifferentiated chondrosarcoma', 'Disease', (115, 146))	('L2975', 'CellLine', 'CVCL:D706', (148, 153))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (132, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('dedifferentiated chondrosarcoma', 'Disease', 'MESH:D002813', (115, 146))
97310	22928481	In addition to the existing cell lines these cell lines present the field with an extensive model system as heterogeneous in IDH1 and IDH2 and TP53 mutations as the tumors they are derived from.	('TP53', 'Gene', (143, 147))	('mutations', 'Var', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Disease', (165, 171))	('IDH1', 'Gene', '3417', (125, 129))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('IDH2', 'Gene', (134, 138))	('TP53', 'Gene', '7157', (143, 147))	('IDH2', 'Gene', '3418', (134, 138))	('IDH1', 'Gene', (125, 129))
97311	22928481	This panel can be implemented in studies ascertaining human chondrosarcoma tumorigenesis, should provide useful tools in the ongoing search for new targeted therapies, and aid in expanding our knowledge on the role of IDH1 and IDH2 mutations in chondrosarcoma formation.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (60, 74))	('chondrosarcoma', 'Disease', 'MESH:D002813', (245, 259))	('mutations', 'Var', (232, 241))	('chondrosarcoma', 'Disease', (245, 259))	('IDH1', 'Gene', '3417', (218, 222))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('aid', 'Gene', (172, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('IDH2', 'Gene', (227, 231))	('aid', 'Gene', '57379', (172, 175))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (245, 259))	('IDH2', 'Gene', '3418', (227, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('chondrosarcoma', 'Disease', (60, 74))	('chondrosarcoma', 'Disease', 'MESH:D002813', (60, 74))	('human', 'Species', '9606', (54, 59))	('IDH1', 'Gene', (218, 222))
97330	29541442	Identification of oncogene mutations in KIT, PDGRFalpha and BRAF have led to the development of selective kinase inhibitors to target them.	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('PDGRFalpha', 'Gene', (45, 55))	('KIT', 'Gene', (40, 43))
97337	29541442	Their role in oncogenesis of several forms of cancer was recently discovered and arises from genetic mutation that causes dysregulation of these pathways to stimulate a variety of biologic pathways, including angiogenesis and cell growth.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('dysregulation', 'Var', (122, 135))	('cancer', 'Disease', (46, 52))	('stimulate', 'PosReg', (157, 166))	('cell growth', 'CPA', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('angiogenesis', 'CPA', (209, 221))	('mutation', 'Var', (101, 109))	('biologic pathways', 'Pathway', (180, 197))
97355	29541442	All PDX tumour biopsies performed for exome sequencing were performed from zero passage mice to minimise the amount of model acquired mutations, which have been demonstrated to increase with each passage.	('tumour', 'Disease', (8, 14))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (134, 143))	('mice', 'Species', '10090', (88, 92))	('tumour', 'Disease', 'MESH:D009369', (8, 14))
97357	29541442	All analysis parameters were as per those outlined by Hintzsche et al.. Further functional analysis of the gene mutations identified as a potential kinase inhibitor target was performed to investigate whether targeting these kinases had known effects on tumour biology.	('mutations', 'Var', (112, 121))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('tumour', 'Disease', (254, 260))
97361	29541442	Figure 1 lists identified single nucleotides variants that were predicted to be deleterious by six algorithms (SIFT, Polyphen2, MutationTaster, FATHMM, CADD, GERP) or by two algorithms if the variant is listed in COSMIC.	('SIFT', 'Disease', (111, 115))	('variants', 'Var', (45, 53))	('SIFT', 'Disease', 'None', (111, 115))	('single nucleotides variants', 'Var', (26, 53))	('GERP', 'Gene', (158, 162))	('GERP', 'Gene', '81603', (158, 162))
97365	29541442	One sample of osteosarcoma demonstrated a mutation of the KIT gene.	('osteosarcoma', 'Disease', (14, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (14, 26))	('osteosarcoma', 'Disease', 'MESH:D012516', (14, 26))	('mutation', 'Var', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('KIT', 'Gene', (58, 61))
97367	29541442	The mutation identified (E142Q) lies in the extracellular domain and may alter the structure of the receptor.	('alter', 'Reg', (73, 78))	('structure', 'MPA', (83, 92))	('E142Q', 'Mutation', 'p.E142Q', (25, 30))	('E142Q', 'Var', (25, 30))
97368	29541442	The same mutation of the ALK gene (C928fs) was demonstrated in a sample of Ewing's sarcoma and leiomyosarcoma.	('C928fs', 'Var', (35, 41))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (95, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('leiomyosarcoma', 'Disease', (95, 109))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (75, 90))	('ALK', 'Gene', (25, 28))	("Ewing's sarcoma", 'Disease', (75, 90))	('C928fs', 'Mutation', 'p.C928fsX', (35, 41))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (95, 109))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (75, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('ALK', 'Gene', '238', (25, 28))
97369	29541442	The exact action of this ALK mutation on oncogenesis is still unclear, however it has been implicated in numerous malignancies including non-small cell lung cancer.	('mutation', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (141, 163))	('numerous malignancies', 'Disease', (105, 126))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (137, 163))	('implicated', 'Reg', (91, 101))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (137, 163))	('ALK', 'Gene', '238', (25, 28))	('ALK', 'Gene', (25, 28))	('non-small cell lung cancer', 'Disease', (137, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('numerous malignancies', 'Disease', 'MESH:D009369', (105, 126))
97370	29541442	A mutation of ABL2 was demonstrated in a patient with undifferentiated pleomorphic sarcoma.	('ABL2', 'Gene', (14, 18))	('mutation', 'Var', (2, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('patient', 'Species', '9606', (41, 48))	('demonstrated', 'Reg', (23, 35))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (54, 90))	('undifferentiated pleomorphic sarcoma', 'Disease', (54, 90))	('ABL2', 'Gene', '27', (14, 18))
97372	29541442	The identified frameshift (I471fs) lies within the protein kinase domain, and may alter receptor function.	('receptor', 'Protein', (88, 96))	('I471fs', 'Mutation', 'p.I471fsX', (27, 33))	('I471fs', 'Var', (27, 33))	('alter', 'Reg', (82, 87))
97373	29541442	A second patient with the same tumour demonstrated a JAK2 mutation, a kinase with important roles in cell growth and development.	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('JAK2', 'Gene', (53, 57))	('mutation', 'Var', (58, 66))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('patient', 'Species', '9606', (9, 16))	('tumour', 'Disease', (31, 37))	('JAK2', 'Gene', '3717', (53, 57))
97376	29541442	Gene fusions with this gene are potentially oncogenic via up regulation of the TRKA protein.	('TRKA', 'Gene', '4914', (79, 83))	('Gene fusions', 'Var', (0, 12))	('TRKA', 'Gene', (79, 83))	('up regulation', 'PosReg', (58, 71))
97388	29541442	Two separate studies have described the presence of ALK mutations in Ewing's sarcoma and have hypothesized that this mutation may be targetable with Crizotinib.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (69, 84))	('mutations', 'Var', (56, 65))	("Ewing's sarcoma", 'Disease', (69, 84))	('ALK', 'Gene', '238', (52, 55))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (69, 84))	('Crizotinib', 'Chemical', 'MESH:D000077547', (149, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('ALK', 'Gene', (52, 55))
97402	29541442	Four demonstrated mutations in GXYLT1 and four had mutations in CNN2.	('mutations', 'Var', (18, 27))	('CNN2', 'Gene', '1265', (64, 68))	('GXYLT1', 'Gene', (31, 37))	('CNN2', 'Gene', (64, 68))	('GXYLT1', 'Gene', '283464', (31, 37))	('mutations', 'Reg', (51, 60))
97405	29541442	A sample of alveolar rhabdomyosarcoma and a sample of undifferentiated pleomorphic sarcoma both demonstrated a mutation in NCF1, mutation of which can be associated with chronic granulomatous disease.	('chronic granulomatous disease', 'Disease', (170, 199))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (21, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('alveolar rhabdomyosarcoma', 'Disease', (12, 37))	('chronic granulomatous disease', 'Disease', 'MESH:D006105', (170, 199))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (12, 37))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (54, 90))	('granulomatous disease', 'Phenotype', 'HP:0002955', (178, 199))	('undifferentiated pleomorphic sarcoma', 'Disease', (54, 90))	('NCF1', 'Gene', '653361', (123, 127))	('mutation', 'Var', (111, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('NCF1', 'Gene', (123, 127))	('associated', 'Reg', (154, 164))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (12, 37))
97407	29541442	Of the seven PDX models, five had targetable mutations identified in fresh tumour samples with only three of these remaining present in the PDX analysis.	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (45, 54))	('tumour', 'Disease', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
97408	29541442	Analysis of all seven PDX samples demonstrated the presence of novel targetable gene mutations in comparison to fresh tumour.	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (85, 94))	('tumour', 'Disease', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))
97409	29541442	The most marked of this was the osteosarcoma sample from patient 4, which demonstrated no actionable kinase inhibitor targets in the tumour WES and 35 novel actionable kinase targets with 227 novel variants in the PDX WES.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('patient', 'Species', '9606', (57, 64))	('tumour WES', 'Disease', (133, 143))	('tumour WES', 'Disease', 'MESH:D009369', (133, 143))	('osteosarcoma', 'Disease', (32, 44))	('osteosarcoma', 'Phenotype', 'HP:0002669', (32, 44))	('variants', 'Var', (198, 206))	('osteosarcoma', 'Disease', 'MESH:D012516', (32, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
97415	29541442	The leiomyosarcoma samples had different drug profiles but both demonstrated a mutation in AQP7.	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (4, 18))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (4, 18))	('demonstrated', 'Reg', (64, 76))	('mutation', 'Var', (79, 87))	('leiomyosarcoma', 'Disease', (4, 18))	('AQP7', 'Gene', (91, 95))	('AQP7', 'Gene', '364', (91, 95))
97467	27821709	Consequently, although the voting choices were identical to those of the prior example, the participant voting results and preferred answer differed as follows: significant differences, NOEL = 0.01mg/kg/day (39%); significant differences, NOEL = 0.1mg/kg/day (28%); no significant differences between control and treated groups (19%); significant differences, NOEL = 1mg/kg/day (7%); significant differences, no NOEL (6%); and other outcome (0%).	('NOEL = 0.01mg/kg/day', 'Var', (186, 206))	('NOEL', 'Var', (239, 243))	('participant', 'Species', '9606', (92, 103))
97707	27821709	This first case focused on the liver of an E13.5 conditional knockout embryo for voting, but two additional abnormalities were observed in the embryo that included subcutaneous edema, and pulmonary hypoplasia.	('edema', 'Disease', 'MESH:D004487', (177, 182))	('pulmonary hypoplasia', 'Phenotype', 'HP:0002089', (188, 208))	('edema', 'Phenotype', 'HP:0000969', (177, 182))	('pulmonary hypoplasia', 'Disease', 'MESH:D008171', (188, 208))	('pulmonary hypoplasia', 'Disease', (188, 208))	('edema', 'Disease', (177, 182))	('E13.5', 'Var', (43, 48))
97708	27821709	As summarized in Table 15, by E11.5 the liver is the primary site for hematopoiesis and at E13.5, the two main cell populations of the liver are the hepatocytes and the erythroblasts.	('E13.5', 'Var', (91, 96))	('hematopoiesis', 'Disease', (70, 83))	('E11.5', 'Var', (30, 35))	('hematopoiesis', 'Disease', 'MESH:C536227', (70, 83))
97711	27821709	The immature hepatocytes in the knockout mice were significantly larger than in the WT animals at E13.5 and more resembled tightly packed hepatoblasts.	('mice', 'Species', '10090', (41, 45))	('knockout', 'Var', (32, 40))	('larger', 'PosReg', (65, 71))
97716	27821709	This second case focused on the spleen of an E16.5 conditional knockout embryo for voting, however, additional abnormalities included subcutaneous edema, renal hypoplasia, and adrenal hypoplasia.	('renal hypoplasia', 'Disease', (154, 170))	('edema', 'Disease', (147, 152))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (176, 194))	('E16.5', 'Var', (45, 50))	('renal hypoplasia', 'Phenotype', 'HP:0000089', (178, 194))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (176, 194))	('renal hypoplasia', 'Phenotype', 'HP:0000089', (154, 170))	('adrenal hypoplasia', 'Disease', (176, 194))	('edema', 'Disease', 'MESH:D004487', (147, 152))	('renal hypoplasia', 'Disease', 'MESH:D007674', (178, 194))	('renal hypoplasia', 'Disease', 'MESH:D007674', (154, 170))	('edema', 'Phenotype', 'HP:0000969', (147, 152))
97717	27821709	Mesenchymal cells represent the majority of the cell population in earlier embryonic spleens (12-15 gestational days); however, by E15, the site of hematopoiesis for erythroid and myelolymphoid precursors shifts from the liver to the spleen (Table 15).	('E15', 'Var', (131, 134))	('hematopoiesis', 'Disease', (148, 161))	('hematopoiesis', 'Disease', 'MESH:C536227', (148, 161))
97718	27821709	At E16.5, the spleen of the conditional knockout mouse had a markedly reduced population of hematopoietic precursors relative to the wild type controls.	('population of hematopoietic precursors', 'CPA', (78, 116))	('reduced', 'NegReg', (70, 77))	('E16.5', 'Var', (3, 8))	('mouse', 'Species', '10090', (49, 54))
97722	27821709	Consequences of alterations to the developing mouse will depend on the stage at which gene inactivation or injury occurred.	('injury', 'Disease', 'MESH:D058186', (107, 113))	('alterations', 'Var', (16, 27))	('mouse', 'Species', '10090', (46, 51))	('injury', 'Disease', (107, 113))	('rat', 'Species', '10116', (20, 23))
97726	27821709	After organogenesis is complete (at GD15.0), damage to the embryo will either result in a delay in development or cause functional abnormalities.	('delay in development', 'Phenotype', 'HP:0001263', (90, 110))	('functional abnormalities', 'Disease', 'MESH:D000014', (120, 144))	('development', 'CPA', (99, 110))	('damage', 'Var', (45, 51))	('delay', 'NegReg', (90, 95))	('cause', 'Reg', (114, 119))	('functional abnormalities', 'Disease', (120, 144))
97747	27821709	The majority of the tumor was immunopositive for GFAP, Olig2, and GS (Figures 9E-G, respectively); although, the focal regions described above were strongly positive for Olig2, weakly positive for GS and negative for GFAP.	('positive', 'Reg', (157, 165))	('GS', 'Gene', '24957', (66, 68))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('GS', 'Gene', '24957', (197, 199))	('Olig2', 'Var', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
97871	26166119	Recently, in order to explore the molecular structure of the tumor, the mutations of 45 tumor-related driver genes were detected by a second-generation sequencing test (Beijing San Valley Biotechnology Inc., China).	('mutations', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (61, 66))	('Val', 'Chemical', 'MESH:D014633', (181, 184))
97876	26166119	Since there was a missense mutation of MLH1 gene with the PNET in this patient, Avastin or Cetuximab could be used for the target therapy.	('MLH1', 'Gene', '4292', (39, 43))	('missense mutation', 'Var', (18, 35))	('MLH1', 'Gene', (39, 43))	('Avastin', 'Chemical', 'MESH:D000068258', (80, 87))	('Cetuximab', 'Chemical', 'MESH:D000068818', (91, 100))	('patient', 'Species', '9606', (71, 78))
97899	26166119	A study reported that 85% of patients with these aggressive malignant tumors had the identification t(11;22)(q24;q12) chromosome rearrangement and the detection of p30/32 cell surface antigen (also known as the MIC2 gene product, which can be detected by antibodies such as HBA71 and O13), and the remaining 15% of the patients had variants of this translocation, including 22q12, 21q12 (10% of cases) and 7p22, 17q12, 2q36 (<1% of cases).	('7p22', 'Var', (406, 410))	('21q12', 'Var', (381, 386))	('p30', 'Gene', (164, 167))	('malignant tumors', 'Disease', 'MESH:D018198', (60, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (100, 117))	('patients', 'Species', '9606', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('malignant tumors', 'Disease', (60, 76))	('HBA71', 'Gene', (274, 279))	('O13', 'Gene', (284, 287))	('HBA71', 'Gene', '4267', (274, 279))	('O13', 'Gene', '28917', (284, 287))	('p30', 'Gene', '201161', (164, 167))	('17q12', 'Var', (412, 417))	('MIC2', 'Gene', (211, 215))	('cell surface antigen', 'Gene', (171, 191))	('MIC2', 'Gene', '4267', (211, 215))	('cell surface antigen', 'Gene', '963', (171, 191))	('2q36', 'Var', (419, 423))	('patients', 'Species', '9606', (319, 327))	('22q12', 'Var', (374, 379))
97916	26166119	In our case, the missense mutation of the MLH1 gene indicated that Avastin or Cetuximab was a possible targeted therapy alternative.	('missense mutation', 'Var', (17, 34))	('Cetuximab', 'Chemical', 'MESH:D000068818', (78, 87))	('Avastin', 'Chemical', 'MESH:D000068258', (67, 74))	('MLH1', 'Gene', '4292', (42, 46))	('MLH1', 'Gene', (42, 46))
97932	24612486	ES is defined by a chromosomal translocation involving the EWS gene on chromosome 22 with a gene of the ETS family located on different chromosomes, leading in 85% of cases to the EWS-FLI1 translocation t(11;22)(q24;q12), whereas the EWS-ERG gene occurs in the majority of the remaining 15% of EFTs.	('EWS', 'Gene', (59, 62))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('FLI1', 'Gene', '14247', (184, 188))	('EWS', 'Gene', (180, 183))	('t(11;22)(q24;q12', 'Var', (203, 219))	('FLI1', 'Gene', (184, 188))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (203, 220))	('EWS', 'Gene', '14030', (234, 237))	('EWS', 'Gene', '14030', (59, 62))	('EWS', 'Gene', '14030', (180, 183))	('EWS', 'Gene', (234, 237))
97982	24612486	Endogeneous peroxydases were blocked by H2O2 3% 15 min at room temperature and nonspecific sites were blocked by Goat serum 5%, BSA1% diluted in TBS 1x pH = 7.6 Tween 0.05%.	('Goat', 'Species', '9925', (113, 117))	('Endogeneous peroxydases', 'Enzyme', (0, 23))	('H2O2', 'Chemical', 'MESH:D006861', (40, 44))	('H2O2', 'Var', (40, 44))	('TBS 1x', 'Chemical', '-', (145, 151))	('Tween 0', 'Chemical', '-', (161, 168))
98056	24612486	Ewing's sarcomas are characterized by a specific translocation between the EWS gene and a gene from the ETS family.	('EWS', 'Gene', '14030', (75, 78))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (0, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('translocation', 'Var', (49, 62))	('EWS', 'Gene', (75, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	("Ewing's sarcomas", 'Disease', (0, 16))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (0, 16))
98083	21292819	Although widespread genetic alterations, affecting many important physiologic pathways, have been identified in several studies, the intratumoral gene expression changes resulting from thermoradiotherapy and their relationship with tumor response are not well understood.	('alterations', 'Var', (28, 39))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('affecting', 'Reg', (41, 50))	('tumor', 'Disease', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
98085	21292819	In addition, we compared gene changes to changes in tumor volume and the apparent diffusion coefficient (ADC) of water, quantified using diffusion weighted MRI (DWI).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('changes', 'Var', (30, 37))	('water', 'Chemical', 'MESH:D014867', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('apparent diffusion coefficient', 'MPA', (73, 103))
98086	21292819	We applied this analysis to spontaneous soft tissue sarcomas since they are more similar than rodent tumors to human cancers in terms of intertumoral heterogeneity, multiple mutations in oncogenes and tumor suppressor genes and varying environmental conditions.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (40, 59))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('human', 'Species', '9606', (111, 116))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (40, 60))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (201, 206))	('mutations', 'Var', (174, 183))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('sarcomas', 'Disease', (52, 60))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumors', 'Disease', (101, 107))	('cancers', 'Disease', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
98163	21292819	We also identify a strong positive correlation between the changes in ADC with both Stat5 (encodes a mediator of inflammatory response) and ACCN3 (encodes an acid-sensing channel protein).	('Stat5', 'Gene', (84, 89))	('ACCN3', 'Gene', (140, 145))	('ADC', 'Gene', (70, 73))	('changes', 'Var', (59, 66))	('ACCN3', 'Gene', '482801', (140, 145))
98209	21292819	Spontaneous canine soft tissue sarcomas exhibit intertumoral heterogeneity due to multiple mutations in oncogenes and tumor suppressor genes, varying environmental conditions, and inherited germline variations.	('oncogenes', 'Gene', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (19, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('canine', 'Species', '9615', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('sarcomas', 'Disease', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (118, 123))	('mutations', 'Var', (91, 100))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (19, 39))	('tumor', 'Disease', (53, 58))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
98232	21292819	In addition, we have also used heterogeneity in response to develop predictive gene signatures and identify geldanamycin enhancing the cell killing by thermoradiotherapy.	('cell killing', 'CPA', (135, 147))	('geldanamycin', 'Var', (108, 120))	('geldanamycin', 'Chemical', 'MESH:C001277', (108, 120))	('enhancing', 'PosReg', (121, 130))
98241	33546657	Clustered regularly spaced short palindromic repeats, i.e.,The CRISPR sequence was initially identified in E. coli.	('E. coli', 'Species', '562', (107, 114))	('short palindromic repeats', 'Var', (27, 52))	('CRISPR', 'Gene', '70873', (63, 69))	('CRISPR', 'Gene', (63, 69))
98247	33546657	Due to its high fidelity, HDR can perform precise genetic repair, whereas NHEJ performs error-prone and inaccurate repairs by generating random deletions or insertions at the break site.	('HDR', 'Disease', 'MESH:C537907', (26, 29))	('HDR', 'Disease', (26, 29))	('insertions', 'Var', (157, 167))
98271	33546657	Many studies have demonstrated that mutations in these genes affect drug sensitivity in patients with osteosarcoma and are often associated with poor prognosis.	('associated', 'Reg', (129, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('osteosarcoma', 'Disease', 'MESH:D012516', (102, 114))	('patients', 'Species', '9606', (88, 96))	('drug sensitivity', 'Phenotype', 'HP:0020174', (68, 84))	('mutations', 'Var', (36, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('drug sensitivity', 'MPA', (68, 84))	('affect', 'Reg', (61, 67))	('osteosarcoma', 'Disease', (102, 114))
98277	33546657	CD44 knockout suppressed the mobility of 143B and MNNG/HOS cells, both of which are highly invasive human osteosarcoma cell lines, and their spheroid formation and growth were also significantly inhibited.	('growth', 'CPA', (164, 170))	('osteosarcoma', 'Disease', (106, 118))	('knockout', 'Var', (5, 13))	('spheroid formation', 'CPA', (141, 159))	('osteosarcoma', 'Disease', 'MESH:D012516', (106, 118))	('inhibited', 'NegReg', (195, 204))	('CD44', 'Gene', '960', (0, 4))	('human', 'Species', '9606', (100, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('mobility', 'CPA', (29, 37))	('MNNG/HOS', 'CellLine', 'CVCL:0439', (50, 58))	('CD44', 'Gene', (0, 4))	('suppressed', 'NegReg', (14, 24))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
98282	33546657	KHOSR2, a multidrug-resistant osteosarcoma strain, exhibited increased sentivity to Adriamycin by mutant TP53 knockout.	('osteosarcoma', 'Disease', (30, 42))	('osteosarcoma', 'Phenotype', 'HP:0002669', (30, 42))	('osteosarcoma', 'Disease', 'MESH:D012516', (30, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('increased', 'PosReg', (61, 70))	('TP53', 'Gene', (105, 109))	('Adriamycin', 'Chemical', 'MESH:D004317', (84, 94))	('mutant', 'Var', (98, 104))	('sentivity to Adriamycin', 'MPA', (71, 94))
98286	33546657	These experiments suggest that targeted oncogene knockout via CRISPR/CAS9 technology has the potential to inhibit osteosarcoma progression, and hopefully overcome the problem of chemoresistance.	('osteosarcoma', 'Phenotype', 'HP:0002669', (114, 126))	('osteosarcoma', 'Disease', (114, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (114, 126))	('inhibit', 'NegReg', (106, 113))	('CRISPR', 'Gene', '70873', (62, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('CAS', 'Gene', (69, 72))	('CAS', 'Gene', '9564', (69, 72))	('knockout', 'Var', (49, 57))	('CRISPR', 'Gene', (62, 68))
98287	33546657	In addition to knocking out oncogenes, CRISPR/CAS9 technology was also used to edit cancer suppressor genes to verify their biological roles.	('CAS', 'Gene', (46, 49))	('CAS', 'Gene', '9564', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('edit', 'Var', (79, 83))	('CRISPR', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('CRISPR', 'Gene', '70873', (39, 45))
98288	33546657	The CRISPR/CAS9-mediated knockout of CNE9, CNE10 or STAG2 gene could decrease U2OS cell apoptosis.	('CRISPR', 'Gene', (4, 10))	('U2OS cell apoptosis', 'CPA', (78, 97))	('STAG2', 'Gene', (52, 57))	('STAG2', 'Gene', '10735', (52, 57))	('CNE9', 'Gene', (37, 41))	('CAS', 'Gene', (11, 14))	('decrease', 'NegReg', (69, 77))	('CNE10', 'Gene', (43, 48))	('CRISPR', 'Gene', '70873', (4, 10))	('knockout', 'Var', (25, 33))	('CNE9', 'Gene', '108410392', (37, 41))	('CAS', 'Gene', '9564', (11, 14))	('CNE10', 'CellLine', 'CVCL:6888', (43, 48))	('U2OS', 'CellLine', 'CVCL:0042', (78, 82))
98290	33546657	Decitabine (DAC), a DNA methylation inhibitor can inhibit in vitro cell proliferation, mobility, anchoring independence, and spheroid formation, reduce in vivo xenograft tumor growth and metastasis and reduce the expression of tumor stem cell markers such as SOX2, OCT4, NANOG, and CRISPR/CAS9-mediated ESR1 gene knockout, effectively eliminating the abovementioned effects of DAC, and demonstrating that the inhibitory effect of DAC on osteosarcoma depends on the presence of the ESR1 gene.	('tumor', 'Disease', (227, 232))	('DAC', 'Gene', '6468', (377, 380))	('OCT4', 'Gene', (265, 269))	('mobility', 'CPA', (87, 95))	('tumor', 'Disease', (170, 175))	('osteosarcoma', 'Phenotype', 'HP:0002669', (437, 449))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('knockout', 'Var', (313, 321))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('ES', 'Phenotype', 'HP:0012254', (303, 305))	('DAC', 'Gene', '6468', (430, 433))	('ESR1', 'Gene', '2099', (481, 485))	('ESR1', 'Gene', (481, 485))	('ESR1', 'Gene', '2099', (303, 307))	('CAS', 'Gene', (289, 292))	('CAS', 'Gene', '9564', (289, 292))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('CRISPR', 'Gene', (282, 288))	('expression', 'MPA', (213, 223))	('ESR1', 'Gene', (303, 307))	('DAC', 'Gene', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Decitabine', 'Chemical', 'MESH:D000077209', (0, 10))	('reduce', 'NegReg', (202, 208))	('NANOG', 'Gene', '79923', (271, 276))	('CRISPR', 'Gene', '70873', (282, 288))	('osteosarcoma', 'Disease', (437, 449))	('NANOG', 'Gene', (271, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (442, 449))	('reduce', 'NegReg', (145, 151))	('osteosarcoma', 'Disease', 'MESH:D012516', (437, 449))	('DAC', 'Gene', (377, 380))	('spheroid formation', 'CPA', (125, 143))	('ES', 'Phenotype', 'HP:0012254', (481, 483))	('OCT4', 'Gene', '5460', (265, 269))	('inhibit', 'NegReg', (50, 57))	('SOX2', 'Gene', '6657', (259, 263))	('SOX2', 'Gene', (259, 263))	('anchoring independence', 'CPA', (97, 119))	('cell proliferation', 'CPA', (67, 85))	('DAC', 'Gene', '6468', (12, 15))	('DAC', 'Gene', (430, 433))
98297	33546657	performed targeted TP53 knockout of pig in vitro zygotes, and half of the live piglets produced after in vivo transplantation developed various tissue tumors, including osteosarcoma.	('osteosarcoma', 'Disease', (169, 181))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('developed', 'Reg', (126, 135))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('pig', 'Species', '9823', (79, 82))	('TP53', 'Gene', (19, 23))	('pig', 'Species', '9823', (36, 39))	('osteosarcoma', 'Phenotype', 'HP:0002669', (169, 181))	('knockout', 'Var', (24, 32))	('osteosarcoma', 'Disease', 'MESH:D012516', (169, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))
98298	33546657	The combination of CRISPR/Cas9 technology and in vitro fertilization technology can effectively reduce the research cost of generating gene-mutant pigs, and generate a pig osteosarcoma model that is similar to the physiological anatomy and genetics of humans, which will certainly provide great help for preclinical osteosarcoma research.	('CRISPR', 'Gene', '70873', (19, 25))	('pig', 'Species', '9823', (168, 171))	('humans', 'Species', '9606', (252, 258))	('pig', 'Species', '9823', (147, 150))	('osteosarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('gene-mutant', 'Var', (135, 146))	('osteosarcoma', 'Disease', (172, 184))	('osteosarcoma', 'Disease', 'MESH:D012516', (172, 184))	('osteosarcoma', 'Phenotype', 'HP:0002669', (316, 328))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('osteosarcoma', 'Disease', (316, 328))	('osteosarcoma', 'Disease', 'MESH:D012516', (316, 328))	('sarcoma', 'Phenotype', 'HP:0100242', (321, 328))	('CRISPR', 'Gene', (19, 25))	('pigs', 'Species', '9823', (147, 151))
98301	33546657	Specifically, PAWS1 or CD2AP knockout by CRISPR/CAS9 resulted in disorganized and tangled actin mesh, reduced migration ability, and failure to properly form focal adhesions.	('CRISPR', 'Gene', (41, 47))	('knockout', 'Var', (29, 37))	('migration ability', 'CPA', (110, 127))	('PAWS1', 'Gene', '644815', (14, 19))	('CRISPR', 'Gene', '70873', (41, 47))	('CD2AP', 'Gene', '23607', (23, 28))	('disorganized', 'CPA', (65, 77))	('PAWS1', 'Gene', (14, 19))	('failure', 'NegReg', (133, 140))	('CAS', 'Gene', '9564', (48, 51))	('CD2AP', 'Gene', (23, 28))	('CAS', 'Gene', (48, 51))	('reduced', 'NegReg', (102, 109))
98306	33546657	Then, they used CRISPR/Cas9 and doxycycline to knock out and overexpress SRGAP2 respectively in murine osteosarcoma cell lines, and found that SRGAP2 knockout increased cell migration, whereas SRGAP2 overexpression reduced cell migration, demonstrating that SRGAP2 may act as a migration inhibitor.	('CRISPR', 'Gene', '70873', (16, 22))	('cell migration', 'CPA', (223, 237))	('doxycycline', 'Chemical', 'MESH:D004318', (32, 43))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('increased', 'PosReg', (159, 168))	('cell migration', 'CPA', (169, 183))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('knockout', 'Var', (150, 158))	('CRISPR', 'Gene', (16, 22))	('SRGAP2', 'Gene', (143, 149))	('murine', 'Species', '10090', (96, 102))
98328	33546657	In 2014, CRISPR/Cas9 technology was first used to construct an ES cell model of EWSR1-FLI1 translocation mutations in HEK293 and human adult mesenchymal stem cells (hMSCs) - one of the origin cells of human ES, and EWSR1-FLI1 fusion protein expression was observed.	('ES', 'Phenotype', 'HP:0012254', (63, 65))	('EWSR1', 'Gene', (80, 85))	('CRISPR', 'Gene', (9, 15))	('FLI1', 'Gene', (86, 90))	('FLI1', 'Gene', '2313', (221, 225))	('FLI1', 'Gene', (221, 225))	('FLI1', 'Gene', '2313', (86, 90))	('ES', 'Phenotype', 'HP:0012254', (207, 209))	('mutations', 'Var', (105, 114))	('EWSR1', 'Gene', (215, 220))	('human', 'Species', '9606', (201, 206))	('human', 'Species', '9606', (129, 134))	('CRISPR', 'Gene', '70873', (9, 15))	('EWSR1', 'Gene', '2130', (80, 85))	('HEK293', 'CellLine', 'CVCL:0045', (118, 124))	('EWSR1', 'Gene', '2130', (215, 220))
98332	33546657	developed a novel method that combines CRISPR/Cas9 with HDR to engineer and modulate the expression of chromosomal translocation products, and allowed the expression of the EWSR1-FLI1 fusion gene to be controlled in a timely manner, which effectively solved the problem that the permanent generation of the EWSR1-FLI1 fusion gene caused the expression change of its intracellular target gene in a short time and made them difficult to precisely target, This strategy is undoubtedly more conducive to the study of the genetic and pathogenic mechanisms of ES.	('FLI1', 'Gene', (179, 183))	('intracellular', 'MPA', (366, 379))	('HDR', 'Disease', 'MESH:C537907', (56, 59))	('FLI1', 'Gene', '2313', (313, 317))	('ES', 'Phenotype', 'HP:0012254', (554, 556))	('FLI1', 'Gene', (313, 317))	('EWSR1', 'Gene', '2130', (173, 178))	('EWSR1', 'Gene', (173, 178))	('EWSR1', 'Gene', (307, 312))	('CRISPR', 'Gene', (39, 45))	('HDR', 'Disease', (56, 59))	('EWSR1', 'Gene', '2130', (307, 312))	('fusion', 'Var', (318, 324))	('expression change', 'MPA', (341, 358))	('CRISPR', 'Gene', '70873', (39, 45))	('FLI1', 'Gene', '2313', (179, 183))
98334	33546657	knocked out multiple genes including MDM2, MDM4, PPM1D and USP7 in mutated TP53 and wild-type TP53 ES cell lines, and they found that cell viability was significantly reduced only in wild-type TP53 cells, suggesting that the presence of wild-type TP53 may be a prerequisite for these oncogenes to play carcinogenic roles.	('PPM1D', 'Gene', '8493', (49, 54))	('ES', 'Phenotype', 'HP:0012254', (99, 101))	('MDM2', 'Gene', (37, 41))	('mutated', 'Var', (67, 74))	('USP7', 'Gene', (59, 63))	('PPM1D', 'Gene', (49, 54))	('carcinogenic', 'Disease', 'MESH:D063646', (302, 314))	('USP7', 'Gene', '7874', (59, 63))	('carcinogenic', 'Disease', (302, 314))	('reduced', 'NegReg', (167, 174))	('MDM4', 'Gene', (43, 47))	('cell viability', 'CPA', (134, 148))
98341	33546657	A recent study produced a defective DNA mismatch repair (dMMR) phenotype by knocking out the MSH2 gene in A673 cells, which increased the cell's gene mutation rate, and was used as a forward genetics system to uncover compound targets.	('increased', 'PosReg', (124, 133))	('knocking', 'Var', (76, 84))	('gene mutation', 'MPA', (145, 158))	('MSH2', 'Gene', (93, 97))	('MSH2', 'Gene', '4436', (93, 97))
98342	33546657	Specifically, compound-resistant mutant clones can be obtained after treatment with three cellular toxins, namely, PSMB5, CD437 and MLN4924.	('CD4', 'Gene', '920', (122, 125))	('MLN4924', 'Var', (132, 139))	('PSMB5', 'Gene', (115, 120))	('PSMB5', 'Gene', '5693', (115, 120))	('CD4', 'Gene', (122, 125))
98350	33546657	The precise gene modification function of CRISPR/CAS9 technology has enabled its application in RSM research.	('gene modification', 'Var', (12, 29))	('CRISPR', 'Gene', '70873', (42, 48))	('CAS', 'Gene', (49, 52))	('CAS', 'Gene', '9564', (49, 52))	('CRISPR', 'Gene', (42, 48))
98356	33546657	HDAC3 knockout in 381 T ERMS cells significantly inhibited cell proliferation in vitro and tumor growth in vivo, and resulted in extensive tumor differentiation in xenograft mice, suggesting the potential value of CRISPR/CAS9 technology in RSM differentiation-induction therapy.	('CAS', 'Gene', (221, 224))	('CAS', 'Gene', '9564', (221, 224))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mice', 'Species', '10090', (174, 178))	('HDAC3', 'Gene', '15183', (0, 5))	('cell proliferation in vitro', 'CPA', (59, 86))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CRISPR', 'Gene', '70873', (214, 220))	('CRISPR', 'Gene', (214, 220))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('resulted in', 'Reg', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('knockout', 'Var', (6, 14))	('tumor', 'Disease', (91, 96))	('inhibited', 'NegReg', (49, 58))	('HDAC3', 'Gene', (0, 5))
98359	33546657	When PAX3-FOXO1 in primary tumor-derived cell lines was knocked out by CRISPR/CAS9, cell oncogenicity disappeared and these cell lines were differentiated following doxycycline withdrawal.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CRISPR', 'Gene', '70873', (71, 77))	('knocked out', 'Var', (56, 67))	('tumor', 'Disease', (27, 32))	('cell oncogenicity', 'CPA', (84, 101))	('CAS', 'Gene', (78, 81))	('CAS', 'Gene', '9564', (78, 81))	('doxycycline', 'Chemical', 'MESH:D004318', (165, 176))	('disappeared', 'NegReg', (102, 113))	('CRISPR', 'Gene', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('PAX3-FOXO1', 'Gene', (5, 15))
98360	33546657	However, recurrent tumor-derived cell lines with PAX3-FOXO1 knockout did not differentiate under these conditions.	('knockout', 'Var', (60, 68))	('PAX3-FOXO1', 'Gene', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))
98363	33546657	It is worth noting that in this study, a novel CRISPR/CAS9 MYXV vector delivery system can effectively achieve targeted knockout of the oncogene RAS in tumors of ERMS transplanted mice.	('CRISPR', 'Gene', '70873', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('CAS', 'Gene', (54, 57))	('CAS', 'Gene', '9564', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('RAS', 'Gene', (145, 148))	('knockout', 'Var', (120, 128))	('mice', 'Species', '10090', (180, 184))	('CRISPR', 'Gene', (47, 53))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
98370	33546657	To optimize the precision and specificity of CRISPR/Cas9 genetic modification, scientists have made many efforts in recent years to continuously develop new methods.	('genetic modification', 'Var', (57, 77))	('CRISPR', 'Gene', '70873', (45, 51))	('CRISPR', 'Gene', (45, 51))
98382	33546657	If scientists can effectively use CRISPR/Cas9 technology to accurately edit these cancer-related genes, there is new hope for the treatment of malignant musculoskeletal tumors.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('edit', 'Var', (71, 75))	('CRISPR', 'Gene', '70873', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('malignant musculoskeletal tumors', 'Disease', (143, 175))	('skeletal tumors', 'Phenotype', 'HP:0010622', (160, 175))	('malignant musculoskeletal tumors', 'Disease', 'MESH:D009140', (143, 175))	('CRISPR', 'Gene', (34, 40))
98391	32623326	Skp2 Depletion Reduces Tumor-Initiating Properties and Promotes Apoptosis in Synovial Sarcoma Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis.	('cancer', 'Disease', (145, 151))	('Skp2', 'Gene', (0, 4))	('Synovial sarcoma', 'Disease', 'MESH:D013584', (94, 110))	('Promotes', 'PosReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Skp2', 'Gene', '6502', (0, 4))	('Sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('Reduces', 'NegReg', (15, 22))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (77, 93))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('Depletion', 'Var', (5, 14))	('Synovial Sarcoma', 'Disease', (77, 93))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (94, 110))	('Synovial sarcoma', 'Disease', (94, 110))	('Tumor-Initiating Properties', 'MPA', (23, 50))	('Synovial Sarcoma', 'Disease', 'MESH:D013584', (77, 93))	('Apoptosis', 'CPA', (64, 73))
98394	32623326	Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors.	('Skp2', 'Gene', (13, 17))	('growth', 'CPA', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('SS xenografts tumors', 'Disease', (62, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('depletion', 'Var', (18, 27))	('SS xenografts tumors', 'Disease', 'MESH:D009369', (62, 82))	('suppressed', 'NegReg', (37, 47))
98399	32623326	Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.	('associated', 'Reg', (44, 54))	('cancer stemness', 'Disease', 'MESH:D009369', (60, 75))	('cancer stemness', 'Disease', (60, 75))	('Skp2', 'Gene', (101, 105))	('inhibitors', 'Var', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
98402	32623326	More than 95% of SSs is characterized by the cytogenetic aberration t(X:18)(p11.2:q11.2), in which the oncogenic event is the fusion of the SS18 gene on chromosome 18 with SSX1, SSX2, or SSX4 on the X chromosome.	('SSX4', 'Gene', (187, 191))	('fusion', 'Var', (126, 132))	('t(X:18)(p11.2:q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (68, 88))	('SSX1', 'Gene', '6756', (172, 176))	('SSX2', 'Gene', '6757', (178, 182))	('SS18', 'Gene', (140, 144))	('SSX4', 'Gene', '6759', (187, 191))	('SSX1', 'Gene', (172, 176))	('SSX2', 'Gene', (178, 182))	('SSs', 'Disease', (17, 20))
98409	32623326	Using the GEO database and tissue microarrays, we recently reported that high levels of Skp2 predict a poor prognosis in osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('high levels', 'Var', (73, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (121, 133))	('osteosarcoma', 'Disease', (121, 133))	('osteosarcoma', 'Disease', 'MESH:D012516', (121, 133))	('Skp2', 'Gene', (88, 92))
98414	32623326	Twist1 knockdown reduces the migratory and sphere-forming capacity of SS, suggesting that Twist1 is essential for SS stemness properties.	('Twist1', 'Gene', (0, 6))	('reduces', 'NegReg', (17, 24))	('Twist1', 'Gene', (90, 96))	('SS stemness', 'Disease', (114, 125))	('SS stemness', 'Disease', 'MESH:D020295', (114, 125))	('Twist1', 'Gene', '7291', (0, 6))	('Twist1', 'Gene', '7291', (90, 96))	('knockdown', 'Var', (7, 16))
98415	32623326	In addition, the depletion of Twist1 suppresses the mesenchymal phenotype in SS and profoundly inhibits the growth of SS xenografts.	('suppresses', 'NegReg', (37, 47))	('Twist1', 'Gene', '7291', (30, 36))	('depletion', 'Var', (17, 26))	('inhibits', 'NegReg', (95, 103))	('Twist1', 'Gene', (30, 36))	('mesenchymal phenotype in', 'CPA', (52, 76))	('growth of SS xenografts', 'CPA', (108, 131))
98424	32623326	These cellular changes induced apoptosis and inhibited the proliferative capacity, cancer stemness, and the mesenchymal state of SS.	('changes', 'Var', (15, 22))	('inhibited', 'NegReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('induced', 'Reg', (23, 30))	('cancer stemness', 'Disease', 'MESH:D009369', (83, 98))	('apoptosis', 'CPA', (31, 40))	('mesenchymal state of SS', 'CPA', (108, 131))	('proliferative capacity', 'CPA', (59, 81))	('cancer stemness', 'Disease', (83, 98))
98444	32623326	Antibodies against Skp2 (#2652), PARP (#9542s), cleaved PARP (#5625), ZO-1 (#8193), p27 Kip1 (#3686), caspase-7 (#9492), cleaved caspase-7(#8438), caspase-3 (#9662S), p21 Waf1/Cip1(# 2947), and E-cadherin (#14472) were purchased from Cell Signaling Technology.	('#2652', 'Var', (25, 30))	('#5625', 'Var', (62, 67))	('#9662S', 'Var', (158, 164))	('E-cadherin', 'Gene', (194, 204))	('caspase-7', 'Gene', (102, 111))	('caspase-7', 'Gene', '840', (129, 138))	('E-cadherin', 'Gene', '999', (194, 204))	('PARP', 'Gene', '1302', (33, 37))	('p21 Waf1/Cip1', 'Gene', (167, 180))	('#8193', 'Var', (76, 81))	('ZO-1', 'Gene', '7082', (70, 74))	('PARP', 'Gene', '1302', (56, 60))	('#3686', 'Var', (94, 99))	('#9492', 'Var', (113, 118))	('PARP', 'Gene', (33, 37))	('ZO-1', 'Gene', (70, 74))	('caspase-7', 'Gene', (129, 138))	('caspase-7', 'Gene', '840', (102, 111))	('caspase-3', 'Gene', '836', (147, 156))	('p27 Kip1', 'Gene', '1027', (84, 92))	('p27 Kip1', 'Gene', (84, 92))	('PARP', 'Gene', (56, 60))	('p21 Waf1/Cip1', 'Gene', '1026', (167, 180))	('#9542s', 'Var', (39, 45))	('caspase-3', 'Gene', (147, 156))
98445	32623326	Antibodies against Twist1 (sc-81417), vimentin (sc-6260), N-cadherin (sc-8424), ETV4 (sc-113), ECT2 (sc-514750), and ALDH (sc-166362) were purchased from Santa Cruz (Santa Cruz, TX).	('ECT2', 'Gene', (95, 99))	('vimentin', 'Gene', (38, 46))	('sc-6260', 'Var', (48, 55))	('Twist1', 'Gene', '7291', (19, 25))	('N-cadherin', 'Gene', (58, 68))	('sc-514750', 'Var', (101, 110))	('N-cadherin', 'Gene', '1000', (58, 68))	('ECT2', 'Gene', '1894', (95, 99))	('Twist1', 'Gene', (19, 25))	('ETV4', 'Gene', (80, 84))	('sc-8424', 'Var', (70, 77))	('ETV4', 'Gene', '2118', (80, 84))	('vimentin', 'Gene', '7431', (38, 46))
98475	32623326	In MTT assays, the silencing of Skp2 significantly reduced the proliferative capacity of Hssy-II and Syo-1 cell lines (P < .001) (Figure 2A), along with a corresponding elevation of p21 and p27, known SCF-Skp2 substrates (Figure 2C).	('p21', 'Gene', (182, 185))	('elevation', 'PosReg', (169, 178))	('SCF', 'Gene', (201, 204))	('reduced', 'NegReg', (51, 58))	('SCF', 'Gene', '4254', (201, 204))	('silencing', 'Var', (19, 28))	('MTT', 'Chemical', 'MESH:C070243', (3, 6))	('Syo-1', 'Gene', '55027', (101, 106))	('Skp2', 'Gene', (32, 36))	('p27', 'Gene', '10671', (190, 193))	('proliferative capacity', 'CPA', (63, 85))	('Syo-1', 'Gene', (101, 106))	('p21', 'Gene', '1026', (182, 185))	('p27', 'Gene', (190, 193))
98476	32623326	After Skp2 knockdown, Matrigel invasion assays showed 59.9% (2128 +- 1716 vs 5312 +- 1313, P = .018) and 41.6% (4742 +- 1348 vs 8121 +- 1426, P = .021) reduction in the invasion of Hssy-II and Syo-1 cell lines, respectively (Figure 2B).	('Skp2', 'Gene', (6, 10))	('invasion of Hssy-II', 'CPA', (169, 188))	('Syo-1', 'Gene', (193, 198))	('Syo-1', 'Gene', '55027', (193, 198))	('Matrigel invasion assays', 'CPA', (22, 46))	('knockdown', 'Var', (11, 20))	('reduction', 'NegReg', (152, 161))
98477	32623326	In addition, levels of cleaved PARP were elevated following Skp2 knockdown (Figure 2C), suggesting that depletion of SCF-Skp2 activity promotes apoptosis.	('SCF', 'Gene', (117, 120))	('depletion', 'MPA', (104, 113))	('SCF', 'Gene', '4254', (117, 120))	('PARP', 'Gene', '1302', (31, 35))	('apoptosis', 'CPA', (144, 153))	('elevated', 'PosReg', (41, 49))	('promotes', 'PosReg', (135, 143))	('PARP', 'Gene', (31, 35))	('knockdown', 'Var', (65, 74))	('Skp2', 'Gene', (60, 64))
98480	32623326	First, we found that Skp2 knockdown led to a marked reduction in TIC markers such as EVT4 and ALDH by immunoblotting (Figure 2C), and CD44, CD133, and CD29 by qPCR (Supplementary Figure 5).	('Skp2', 'Gene', (21, 25))	('TIC markers', 'MPA', (65, 76))	('EVT4', 'MPA', (85, 89))	('CD29', 'Gene', '3688', (151, 155))	('TIC', 'Phenotype', 'HP:0100033', (65, 68))	('ALDH', 'MPA', (94, 98))	('CD44', 'Gene', '960', (134, 138))	('knockdown', 'Var', (26, 35))	('CD29', 'Gene', (151, 155))	('CD44', 'Gene', (134, 138))	('CD133', 'Gene', (140, 145))	('CD133', 'Gene', '8842', (140, 145))	('EVT4', 'CellLine', 'CVCL:7377', (85, 89))	('reduction', 'NegReg', (52, 61))
98481	32623326	Next, we assessed the effects of Skp2 knockdown on anchorage-independent sphere-forming capacity as a surrogate indicator of cancer stemness.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('anchorage-independent sphere-forming capacity', 'CPA', (51, 96))	('cancer stemness', 'Disease', 'MESH:D009369', (125, 140))	('Skp2', 'Gene', (33, 37))	('knockdown', 'Var', (38, 47))	('cancer stemness', 'Disease', (125, 140))
98488	32623326	As a result, knockdown of Skp2 significantly inhibited the growth of Hssy-II xenografts (Figure 3, C and D), and the relative final tumor volume of the Skp2 knockdown group (428.4 +- 157.9 mm3) was significantly lower than that of the control group (2525.6 +- 243.1 mm3) (P = .008, Figure 3E).	('growth of', 'CPA', (59, 68))	('lower', 'NegReg', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('knockdown', 'Var', (157, 166))	('Skp2 knockdown', 'Var', (152, 166))	('inhibited', 'NegReg', (45, 54))	('knockdown', 'Var', (13, 22))	('Skp2', 'Gene', (26, 30))
98504	32623326	When Syo-I cells were treated with FKA for 48 hours with or without Z-VAD-FMK (a pan-caspase inhibitor), caspase-3 cleavage was partly blocked by Z-VAD-FMK (Supplementary Figure 4A), indicating inhibition of apoptosis induced by FKA.	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (68, 77))	('inhibition', 'NegReg', (194, 204))	('FKA', 'Chemical', 'MESH:C500809', (35, 38))	('blocked', 'NegReg', (135, 142))	('Z-VAD-FMK', 'Var', (146, 155))	('caspase-3', 'Gene', (105, 114))	('FKA', 'Chemical', 'MESH:C500809', (229, 232))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (146, 155))	('cleavage', 'MPA', (115, 123))	('caspase-3', 'Gene', '836', (105, 114))
98526	32623326	Together, these results suggest that FKA and doxorubicin display a potent synergistic efficacy, and therefore, a strategy of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.	('synergistic efficacy', 'MPA', (74, 94))	('inhibitors', 'Var', (140, 150))	('doxorubicin', 'Chemical', 'MESH:D004317', (45, 56))	('Skp2', 'Gene', (135, 139))	('FKA', 'Chemical', 'MESH:C500809', (37, 40))
98527	32623326	Since our in vitro studies suggest that FKA promotes apoptosis and inhibits TIC properties, we proceeded to examine the effects of FKA in vivo using an SS xenograft model.	('apoptosis', 'CPA', (53, 62))	('FKA', 'Chemical', 'MESH:C500809', (131, 134))	('TIC properties', 'MPA', (76, 90))	('FKA', 'Chemical', 'MESH:C500809', (40, 43))	('TIC', 'Phenotype', 'HP:0100033', (76, 79))	('FKA', 'Var', (40, 43))	('inhibits', 'NegReg', (67, 75))
98539	32623326	has linked Twist1 to TIC characteristics in SS cell lines, and deficiency in Twist1 inhibits the growth of SS xenografts by promoting apoptosis and cell cycle arrest.	('Twist1', 'Gene', (11, 17))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (148, 165))	('TIC', 'Phenotype', 'HP:0100033', (21, 24))	('arrest', 'Disease', 'MESH:D006323', (159, 165))	('growth of SS xenografts', 'CPA', (97, 120))	('linked', 'Reg', (4, 10))	('promoting', 'PosReg', (124, 133))	('Twist1', 'Gene', '7291', (77, 83))	('apoptosis', 'CPA', (134, 143))	('arrest', 'Disease', (159, 165))	('deficiency', 'Var', (63, 73))	('Twist1', 'Gene', (77, 83))	('Twist1', 'Gene', '7291', (11, 17))	('inhibits', 'NegReg', (84, 92))
98541	32623326	Others have also linked Twist1 through its inactivation of p53 to tumorigenesis of other sarcomas such leiomyosarcoma and pediatric osteosarcoma.	('p53', 'Gene', (59, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('osteosarcoma', 'Disease', (132, 144))	('osteosarcoma', 'Disease', 'MESH:D012516', (132, 144))	('linked', 'Reg', (17, 23))	('Twist1', 'Gene', (24, 30))	('tumor', 'Disease', (66, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('Twist1', 'Gene', '7291', (24, 30))	('sarcomas such leiomyosarcoma', 'Disease', 'MESH:D007890', (89, 117))	('sarcomas such leiomyosarcoma', 'Disease', (89, 117))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inactivation', 'Var', (43, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('p53', 'Gene', '7157', (59, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
98542	32623326	In our study, Skp2 depletion is associated with a corresponding decrease in Twist1, suggesting that Skp2 is upstream and essential for Twist1 expression in SS cells.	('depletion', 'Var', (19, 28))	('Twist1', 'Gene', (76, 82))	('decrease', 'NegReg', (64, 72))	('Skp2', 'Gene', (14, 18))	('Twist1', 'Gene', (135, 141))	('Twist1', 'Gene', '7291', (76, 82))	('Twist1', 'Gene', '7291', (135, 141))
98549	32623326	In the central nervous system, Skp2-mediated degradation of p27 has been shown to activate glial stem cells via Notch signaling.	('Skp2-mediated degradation', 'Var', (31, 56))	('activate', 'PosReg', (82, 90))	('glial stem cells', 'CPA', (91, 107))	('degradation', 'Var', (45, 56))	('Notch signaling', 'MPA', (112, 127))	('p27', 'Gene', '10671', (60, 63))	('p27', 'Gene', (60, 63))
98551	32623326	In SS, a survival analysis suggested that the lack of p27 is an independent negative prognostic factor for overall patient survival.	('lack', 'Var', (46, 50))	('p27', 'Gene', '10671', (54, 57))	('negative', 'NegReg', (76, 84))	('patient', 'Species', '9606', (115, 122))	('p27', 'Gene', (54, 57))
98554	32623326	Therefore, loss of p27 leads to increased stemness and upregulation of Twist1.	('p27', 'Gene', (19, 22))	('Twist1', 'Gene', '7291', (71, 77))	('loss', 'Var', (11, 15))	('stemness', 'CPA', (42, 50))	('Twist1', 'Gene', (71, 77))	('increased', 'PosReg', (32, 41))	('p27', 'Gene', '10671', (19, 22))	('upregulation', 'PosReg', (55, 67))
98556	32623326	Together, these results suggest that inhibitors of the Skp2-p27 axis may have clinical utilities in SS by modulating stemness properties.	('inhibitors', 'Var', (37, 47))	('modulating', 'Reg', (106, 116))	('stemness properties', 'CPA', (117, 136))	('p27', 'Gene', '10671', (60, 63))	('p27', 'Gene', (60, 63))
98561	32623326	Inhibitors of ALDH activity can serve to sensitize TICs to chemotherapeutic drugs.	('sensitize', 'Reg', (41, 50))	('TIC', 'Phenotype', 'HP:0100033', (51, 54))	('TICs', 'Disease', (51, 55))	('Inhibitors', 'Var', (0, 10))	('TICs', 'Disease', 'MESH:D020323', (51, 55))	('TICs', 'Phenotype', 'HP:0100033', (51, 55))	('activity', 'MPA', (19, 27))	('ALDH', 'Gene', (14, 18))
98564	32623326	In addition, our in vitro data showed that FKA and doxorubicin exert a synergistic efficacy, thus implicating a role for Skp2 inhibitors in suppressing the TIC subpopulation in SS.	('suppressing', 'NegReg', (140, 151))	('TIC subpopulation', 'MPA', (156, 173))	('inhibitors', 'Var', (126, 136))	('TIC', 'Phenotype', 'HP:0100033', (156, 159))	('FKA', 'Chemical', 'MESH:C500809', (43, 46))	('doxorubicin', 'Chemical', 'MESH:D004317', (51, 62))
98572	32623326	Our findings revealed that advanced clinical stages of SS express higher levels of Skp2 and that genetic knockdown of Skp2 inhibits SS proliferation, invasion, and cancer stemness.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('levels', 'MPA', (73, 79))	('SS proliferation', 'CPA', (132, 148))	('cancer stemness', 'Disease', 'MESH:D009369', (164, 179))	('knockdown', 'Var', (105, 114))	('invasion', 'CPA', (150, 158))	('Skp2', 'Protein', (83, 87))	('higher', 'PosReg', (66, 72))	('cancer stemness', 'Disease', (164, 179))	('inhibits', 'NegReg', (123, 131))	('Skp2', 'Gene', (118, 122))
98595	29881881	In this feasibility study, consecutive 18F-FDG PET-CT scans per patient were used to investigate the use of four VOI delineation techniques because variations in VOI will directly affect the measured SUVmean, MATV, and TLG and could thus affect the performance of the PET assessments.	('CT', 'Gene', '244329', (51, 53))	('affect', 'Reg', (180, 186))	('patient', 'Species', '9606', (64, 71))	('SUVmean', 'MPA', (200, 207))	('MATV', 'Species', '908873', (209, 213))	('affect', 'Reg', (238, 244))	('TLG', 'MPA', (219, 222))	('MATV', 'MPA', (209, 213))	('VOI', 'Gene', (162, 165))	('variations', 'Var', (148, 158))	('TLG', 'Chemical', '-', (219, 222))	('PET', 'MPA', (268, 271))	('18F-FDG', 'Chemical', 'MESH:D019788', (39, 46))
98664	29881881	The decrease in metabolic tumor activity was significantly more pronounced after HILP than after preoperative radiotherapy.	('metabolic tumor', 'Disease', 'MESH:D008659', (16, 31))	('HILP', 'Var', (81, 85))	('decrease', 'NegReg', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('metabolic tumor', 'Disease', (16, 31))
98757	29137065	In this scenario, it is essential to design translational and clinical trials focused on specific variants of rare tumors that often lack specific treatments, in order to improve the knowledge of the disease biology and to identify more effective "histology-driven" therapeutic agents.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('variants', 'Var', (98, 106))
98977	25506617	The systemic transgene expression of hIL-12 induced endogenous canine IFN-gamma release and tumor growth control in 4 of 6 treated dogs (complete response for two mast cell tumors and stable disease for one pulmonary histiocytic sarcoma and one osteosarcoma).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('dog', 'Species', '9615', (54, 57))	('mast cell tumors', 'Disease', 'MESH:D008415', (163, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('transgene expression', 'Var', (13, 33))	('hIL-12', 'Gene', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('osteosarcoma', 'Phenotype', 'HP:0002669', (245, 257))	('hIL-12', 'Chemical', '-', (37, 43))	('endogenous canine IFN-gamma release', 'MPA', (52, 87))	('dog', 'Species', '9615', (131, 134))	('pulmonary histiocytic sarcoma', 'Disease', 'MESH:D054747', (207, 236))	('mast cell tumors', 'Disease', (163, 179))	('mast cell tumors', 'Phenotype', 'HP:0100495', (163, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('canine', 'Species', '9615', (63, 69))	('pulmonary histiocytic sarcoma', 'Disease', (207, 236))	('tumor', 'Disease', (173, 178))	('dogs', 'Species', '9615', (131, 135))	('tumor', 'Disease', (92, 97))	('osteosarcoma', 'Disease', (245, 257))	('osteosarcoma', 'Disease', 'MESH:D012516', (245, 257))
99021	25506617	In addition to the immune enhancing effects of complexes carrying noncoding plasmid in a vaccine proposed against hemangiosarcoma, the expression of therapeutic genes displayed specific antitumor activity as repeatedly evidenced in many papers listed in Tables 1, 2, and 3.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (114, 129))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('genes', 'Var', (161, 166))	('tumor', 'Disease', (190, 195))	('hemangiosarcoma', 'Disease', (114, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
99114	32099494	In addition to neuropathic pain, the loss of sensation, proprioception, and distal muscle weakness can increase fall risk and decrease mobility.	('neuropathic pain', 'Disease', 'MESH:D009437', (15, 31))	('muscle weakness', 'Phenotype', 'HP:0001324', (83, 98))	('increase', 'PosReg', (103, 111))	('fall', 'Phenotype', 'HP:0002527', (112, 116))	('muscle weakness', 'Disease', (83, 98))	('distal', 'Disease', (76, 82))	('distal muscle weakness', 'Phenotype', 'HP:0002460', (76, 98))	('decrease', 'NegReg', (126, 134))	('fall risk', 'CPA', (112, 121))	('mobility', 'CPA', (135, 143))	('loss', 'Var', (37, 41))	('neuropathic pain', 'Disease', (15, 31))	('pain', 'Phenotype', 'HP:0012531', (27, 31))	('muscle weakness', 'Disease', 'MESH:D018908', (83, 98))
99115	32099494	Anthracyclines are known for causing cardiac dysfunction, which can lead to decreased endurance and activity tolerance, especially if concomitant lung metastases are present.	('lung metastases', 'Disease', (146, 161))	('decreased', 'NegReg', (76, 85))	('cardiac dysfunction', 'Disease', (37, 56))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (37, 56))	('lung metastases', 'Disease', 'MESH:D009362', (146, 161))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('causing', 'Reg', (29, 36))	('decreased endurance and activity tolerance', 'Phenotype', 'HP:0003546', (76, 118))	('Anthracyclines', 'Var', (0, 14))
99201	29698584	We then review how the replications of numerous viruses are enhanced and restricted by m6A with emphasis on the oncogenic DNA virus, Kaposi sarcoma-associated herpesvirus (KSHV), whose m6A epitranscriptome was recently mapped.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (133, 147))	('m6A', 'Var', (87, 90))	('KSHV', 'Species', '37296', (172, 176))	('Kaposi sarcoma', 'Disease', (133, 147))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (133, 147))	('replications', 'MPA', (23, 35))	('herpesvirus', 'Species', '39059', (159, 170))	('enhanced', 'PosReg', (60, 68))
99206	29698584	m6A was subsequently detected in both adenovirus and influenza A virus (IAV) with an average of 3 m6A modifications per viral mRNA in IAV, a level that is similar to that of cellular m6A.	('modifications', 'Var', (102, 115))	('influenza A virus', 'Disease', (53, 70))	('adenovirus', 'Species', '10515', (38, 48))	('IAV', 'Species', '11320', (134, 137))	('influenza A virus', 'Species', '11320', (53, 70))	('adenovirus', 'Disease', (38, 48))	('m6A', 'Gene', (98, 101))	('IAV', 'Species', '11320', (72, 75))
99215	29698584	A few months later, a technique called m6A individual nucleotide resolution cross-linking and immuno-precipitation (miCLIP) was published, which enabled transcriptomewide mapping of m6A or m6Am at a single nucleotide resolution.33 This technique improved on previous techniques by UV cross-linking the anti-m6A antibody to RNA and then digesting all but a small part of the antibody in contact with the RNA using proteinase K. The remaining antibody fragment caused mutations during the preparation of a sequencing library, resulting in an antibody-dependent mutational signature or a truncation in sequencing reads close to m6A or m6Am sites.	('CLIP', 'Gene', '6249', (118, 122))	('CLIP', 'Gene', (118, 122))	('antibody-dependent mutational signature', 'MPA', (540, 579))	('mutations', 'Var', (466, 475))	('sequencing', 'MPA', (599, 609))	('truncation', 'MPA', (585, 595))
99226	29698584	Before its function as an "eraser" was known, a single nucleotide polymorphism (SNP) in the first intron of FTO was shown to be strongly correlated with obesity.	('correlated with', 'Reg', (137, 152))	('FTO', 'Gene', '79068', (108, 111))	('single nucleotide polymorphism', 'Var', (48, 78))	('obesity', 'Disease', 'MESH:D009765', (153, 160))	('obesity', 'Phenotype', 'HP:0001513', (153, 160))	('FTO', 'Gene', (108, 111))	('obesity', 'Disease', (153, 160))
99245	29698584	Two of these studies demonstrated a proviral role of m6A as knockdown of METTL3/METTL14 decreased viral replication while knockdown of ALKBH5 had the opposite effect.	('METTL14', 'Chemical', '-', (80, 87))	('ALKBH5', 'Gene', (135, 141))	('viral replication', 'MPA', (98, 115))	('METTL3', 'Gene', '56339', (73, 79))	('knockdown', 'Var', (60, 69))	('decreased', 'NegReg', (88, 97))	('METTL3', 'Gene', (73, 79))	('ALKBH5', 'Gene', '54890', (135, 141))
99249	29698584	Knockdown of FTO lowered the viral titers of both viruses, whereas knockdown of ALKBH5 had no effect on HCV viral production but lowered ZIKV viral titers in the supernatants.	('ALKBH5', 'Gene', '54890', (80, 86))	('ZIKV viral titers', 'MPA', (137, 154))	('lowered', 'NegReg', (129, 136))	('ALKBH5', 'Gene', (80, 86))	('lowered', 'NegReg', (17, 24))	('knockdown', 'Var', (67, 76))	('FTO', 'Gene', (13, 16))	('HCV', 'Species', '11103', (104, 107))	('viral titers', 'MPA', (29, 41))	('FTO', 'Gene', '79068', (13, 16))	('ZIKV', 'Species', '64320', (137, 141))
99254	29698584	In addition, host immune-related transcripts were dynamically modified during ZIKV infection, indicating that m6A is involved in promoting an antiviral response.	('modified', 'Reg', (62, 70))	('ZIKV infection', 'Disease', 'MESH:D007239', (78, 92))	('m6A', 'Var', (110, 113))	('ZIKV infection', 'Disease', (78, 92))	('promoting', 'PosReg', (129, 138))	('antiviral response', 'MPA', (142, 160))
99255	29698584	A work by Courtney et al showed that inhibition of methylation with 3-deazaadenosine (3DAA) and METTL3 knockout in A549 lung cancer cells decreased the replication of IAV by reducing both viral mRNA and protein levels.	('reducing', 'NegReg', (174, 182))	('decreased', 'NegReg', (138, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('methylation', 'MPA', (51, 62))	('METTL3', 'Gene', '56339', (96, 102))	('METTL3', 'Gene', (96, 102))	('IAV', 'Species', '11320', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('A549 lung cancer', 'Disease', 'MESH:D008175', (115, 131))	('IAV', 'Disease', (167, 170))	('3DAA', 'Chemical', 'MESH:C018258', (86, 90))	('3-deazaadenosine', 'Chemical', 'MESH:C018258', (68, 84))	('knockout', 'Var', (103, 111))	('A549 lung cancer', 'Disease', (115, 131))	('replication', 'MPA', (152, 163))
99262	29698584	The authors also investigated the possibility that methylation of viral RNAs might prevent the activation of innate immune sensors such as RIG-I or MDA5 but saw no additional activation of interferon-beta when cells were infected with their mutant virions that carried fewer m6A sites.	('activation', 'MPA', (95, 105))	('interferon-beta', 'Gene', '3456', (189, 204))	('interferon-beta', 'Gene', (189, 204))	('mutant', 'Var', (241, 247))	('RIG-I', 'Gene', (139, 144))	('RNAs', 'Gene', (72, 76))	('MDA5', 'Gene', '64135', (148, 152))	('MDA5', 'Gene', (148, 152))	('innate immune sensors', 'MPA', (109, 130))	('methylation', 'Var', (51, 62))	('prevent', 'NegReg', (83, 90))	('RIG-I', 'Gene', '23586', (139, 144))
99282	29698584	The KSHV lytic epitranscriptome had widespread m6A methylation of viral genes.	('methylation', 'Var', (51, 62))	('m6A methylation', 'Var', (47, 62))	('KSHV', 'Species', '37296', (4, 8))
99287	29698584	Using RNA-binding protein immunoprecipitation and quantitative reverse transcription PCR (RIP-RT-qPCR), they showed that four m6A peaks on the RTA transcript are bound by YTHDC1 and mutation of each of these peaks results in decreased RTA splicing.	('RIP', 'Gene', (90, 93))	('RNA-binding protein', 'Gene', (6, 25))	('RTA splicing', 'MPA', (235, 247))	('bound', 'Interaction', (162, 167))	('RIP', 'Gene', '3267', (90, 93))	('decreased', 'NegReg', (225, 234))	('mutation', 'Var', (182, 190))	('YTHDC1', 'Gene', (171, 177))	('YTHDC1', 'Gene', '91746', (171, 177))	('RNA-binding protein', 'Gene', '27303', (6, 25))
99288	29698584	This observation was made by overexpressing the mutant RTA transcripts in 293T cells.	('293T', 'CellLine', 'CVCL:0063', (74, 78))	('RTA', 'Gene', (55, 58))	('mutant', 'Var', (48, 54))
99291	29698584	It is possible that SOX activity is influenced by m6A, but further studies are needed to confirm this hypothesis.	('influenced', 'Reg', (36, 46))	('SOX', 'Gene', '4961512', (20, 23))	('m6A', 'Var', (50, 53))	('SOX', 'Gene', (20, 23))
99292	29698584	In both cell models, hypermethylated and hypomethylated pathways are important for KSHV lytic replication, such as adipogenesis, protein kinase A signaling, ILK signaling, ERK/MAPK signaling, PI3K/AKT signaling, and integrin signaling.	('ERK/MAPK', 'MPA', (172, 180))	('KSHV', 'Species', '37296', (83, 87))	('adipogenesis', 'MPA', (115, 127))	('PI3K/AKT signaling', 'Pathway', (192, 210))	('ILK', 'MPA', (157, 160))	('protein kinase A', 'Pathway', (129, 145))	('hypomethylated', 'Var', (41, 55))
99293	29698584	Since many of these pathways are known to mediate KSHV lytic replication, m6A might be an additional mechanism regulating KSHV lytic replication via modulating these pathways.	('KSHV', 'Species', '37296', (122, 126))	('KSHV', 'Species', '37296', (50, 54))	('m6A', 'Var', (74, 77))	('modulating', 'Reg', (149, 159))
99300	29698584	Therefore, ablating methylation at specific sites on important viral transcripts such as LANA and RTA, for example, might provide more specific mechanisms on how m6A might regulate KSHV life cycle in future studies.	('KSHV', 'Species', '37296', (181, 185))	('methylation', 'MPA', (20, 31))	('KSHV life cycle', 'CPA', (181, 196))	('LANA', 'Gene', (89, 93))	('ablating', 'Var', (11, 19))	('regulate', 'Reg', (172, 180))	('LANA', 'Gene', '4961527', (89, 93))
99303	29698584	MTA-binding sites on PAN RNA, vIL6, and ORF59 have stem-loop structures; the presence of m6A might destabilize stem-loop formation, affecting its accessibility to RNA-binding proteins.	('destabilize', 'NegReg', (99, 110))	('RNA-binding protein', 'Gene', '27303', (163, 182))	('stem-loop formation', 'CPA', (111, 130))	('RNA-binding protein', 'Gene', (163, 182))	('vIL', 'Gene', (30, 33))	('IL6', 'Gene', '3569', (31, 34))	('IL6', 'Gene', (31, 34))	('presence', 'Var', (77, 85))	('vIL', 'Gene', '7429', (30, 33))	('m6A', 'Var', (89, 92))	('ORF59', 'Gene', (40, 45))	('affecting', 'Reg', (132, 141))	('accessibility', 'MPA', (146, 159))	('PA', 'Chemical', 'MESH:D011478', (21, 23))	('ORF59', 'Gene', '4961492', (40, 45))
99304	29698584	Various studies have shown that 3DAA, an methyltransferase inhibitor, can reduce viral replication; however, 3DAA also inhibits histone and DNA methylation.	('3DAA', 'Var', (109, 113))	('reduce', 'NegReg', (74, 80))	('3DAA', 'Chemical', 'MESH:C018258', (109, 113))	('viral replication', 'MPA', (81, 98))	('3DAA', 'Chemical', 'MESH:C018258', (32, 36))	('inhibits', 'NegReg', (119, 127))
99305	29698584	Similarly, an inhibitor of the "erasers," meclofenamic acid, could be used to inhibit HCV replication since m6A antagonizes its replication.	('HCV', 'Gene', (86, 89))	('m6A', 'Var', (108, 111))	('HCV', 'Species', '11103', (86, 89))	('meclofenamic acid', 'Chemical', 'MESH:D008469', (42, 59))	('inhibit', 'NegReg', (78, 85))	('antagonizes', 'NegReg', (112, 123))	('replication', 'MPA', (128, 139))
99307	29698584	Hence, inhibition of the m6A machinery might have an antitumor effect.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('inhibition', 'Var', (7, 17))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('m6A', 'Protein', (25, 28))	('tumor', 'Disease', (57, 62))
99309	29698584	These changes can lead to alterations in the host m6A methylome during viral infection or latency as we have shown in the context of KSHV infection.	('changes', 'Var', (6, 13))	('viral infection', 'Disease', 'MESH:D001102', (71, 86))	('viral infection', 'Disease', (71, 86))	('lead to alterations', 'Reg', (18, 37))	('KSHV infection', 'Disease', 'MESH:C537372', (133, 147))	('KSHV infection', 'Disease', (133, 147))
99324	28324233	All variants of KS are caused by Kaposi sarcoma-associated herpesvirus (KSHV).	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (33, 47))	('variants', 'Var', (4, 12))	('KS', 'Phenotype', 'HP:0100726', (72, 74))	('KSHV', 'Species', '37296', (72, 76))	('herpesvirus', 'Species', '39059', (59, 70))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (33, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('KS', 'Phenotype', 'HP:0100726', (16, 18))	('caused', 'Reg', (23, 29))	('Kaposi sarcoma', 'Disease', (33, 47))
99369	28324233	The introduction of ART has significantly reduced the incidence of KS in HIV-infected patients, as eloquently illustrated by Bohlius et al., who found that the early introduction of ART decreased the risk to develop KS by 80% in a cohort of HIV-infected South African patients.	('reduced', 'NegReg', (42, 49))	('KS', 'Phenotype', 'HP:0100726', (216, 218))	('HIV-infected', 'Disease', (73, 85))	('HIV-infected', 'Disease', (241, 253))	('ART', 'Var', (182, 185))	('decreased', 'NegReg', (186, 195))	('HIV-infected', 'Disease', 'MESH:D015658', (73, 85))	('KS', 'Phenotype', 'HP:0100726', (67, 69))	('HIV-infected', 'Disease', 'MESH:D015658', (241, 253))	('patients', 'Species', '9606', (268, 276))	('patients', 'Species', '9606', (86, 94))
99419	28324233	Even established KS lesions respond to rapamycin directly and independently of immune reconstitution in AIDS KS and immunodeficient preclinical models, though rapamycin primarily stalls tumor growth leading to stable disease rather than inducing tumor regression outright.	('stalls', 'NegReg', (179, 185))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('rapamycin', 'Var', (159, 168))	('rapamycin', 'Chemical', 'MESH:D020123', (159, 168))	('KS', 'Phenotype', 'HP:0100726', (17, 19))	('KS lesion', 'Disease', 'MESH:D051437', (17, 26))	('immunodeficient', 'Disease', 'MESH:D007153', (116, 131))	('immunodeficient', 'Disease', (116, 131))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('rapamycin', 'Chemical', 'MESH:D020123', (39, 48))	('AIDS KS', 'Disease', (104, 111))	('KS lesion', 'Disease', (17, 26))	('tumor', 'Disease', (246, 251))	('stable disease', 'MPA', (210, 224))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('AIDS KS', 'Disease', 'MESH:D000163', (104, 111))	('KS', 'Phenotype', 'HP:0100726', (109, 111))
99425	28324233	VEGF is essential for endothelial proliferation and inhibition of VEGF constitutes a rational therapeutic approach for Kaposi Sarcoma.	('VEGF', 'Gene', (66, 70))	('Sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('VEGF', 'Gene', '7422', (0, 4))	('Kaposi Sarcoma', 'Phenotype', 'HP:0100726', (119, 133))	('VEGF', 'Gene', '7422', (66, 70))	('inhibition', 'Var', (52, 62))	('Kaposi Sarcoma', 'Disease', (119, 133))	('Kaposi Sarcoma', 'Disease', 'MESH:D012514', (119, 133))	('VEGF', 'Gene', (0, 4))
99426	28324233	Thus far, however, clinical trials of single agent trials of VEGF neutralizing antibodies or VEGF-receptor inhibitors (bevacizumab, imatinib) have been ambiguous.	('VEGF', 'Gene', '7422', (61, 65))	('VEGF', 'Gene', (93, 97))	('imatinib', 'Chemical', 'MESH:D000068877', (132, 140))	('bevacizumab', 'Chemical', 'MESH:D000068258', (119, 130))	('VEGF', 'Gene', '7422', (93, 97))	('VEGF', 'Gene', (61, 65))	('neutralizing', 'Var', (66, 78))
99433	28324233	It is noteworthy, however, in that the clinical success of pegylated IFN-alpha provided the first in human evidence for the extreme immune reactivity of KS.	('human', 'Species', '9606', (101, 106))	('pegylated', 'Var', (59, 68))	('KS', 'Phenotype', 'HP:0100726', (153, 155))	('IFN-alpha', 'Gene', '3439', (69, 78))	('IFN-alpha', 'Gene', (69, 78))
99444	28324233	Immune checkpoint inhibitors have gained notoriety because of their overwhelming efficacy in a select group of immunoreactive cancers, including melanoma and polyomavirus associated Merkel cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('polyomavirus', 'Species', '36362', (158, 170))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (182, 203))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('Merkel cell carcinoma', 'Disease', (182, 203))	('polyomavirus', 'Var', (158, 170))
99506	26266009	The patient also showed positivity for CD10 (10-15%).	('patient', 'Species', '9606', (4, 11))	('CD10', 'Gene', '4311', (39, 43))	('CD10', 'Gene', (39, 43))	('positivity', 'Var', (24, 34))
99552	20572040	Sixty-one patients underwent resection in RTOG 9514, and 3 patients did not.	('resection', 'Var', (29, 38))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (10, 18))	('RTOG 9514', 'Gene', (42, 51))
99849	31110948	Ewing sarcoma family tumors (ESFTs), previously called primitive neuroectodermal tumor, Askin tumor, or Ewing sarcoma, harbor the chromosomal translocation t(11; 22)(q24; q12), which causes the chimeric fusion protein EWS/FLI-1.	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (65, 86))	('FLI-1', 'Gene', '2313', (222, 227))	('EWS', 'Gene', (218, 221))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('Askin tumor', 'Disease', 'MESH:C563168', (88, 99))	('causes', 'Reg', (183, 189))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (104, 117))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('FLI-1', 'Gene', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (55, 86))	('EWS', 'Gene', '2130', (218, 221))	('Ewing sarcoma', 'Disease', (104, 117))	('Askin tumor', 'Disease', (88, 99))	('Ewing sarcoma family tumors', 'Disease', (0, 27))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (65, 86))	('t(11; 22)(q24; q12', 'Var', (156, 174))	('Ewing sarcoma family tumors', 'Disease', 'MESH:C563168', (0, 27))	('neuroectodermal tumor', 'Disease', (65, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('chimeric', 'MPA', (194, 202))
99932	29400019	Supplementary Table 1 summarizes both the subjective and objective analyses of T2WI SI in the main solid portion of ULCD, ESS, and LMS lesions.	('T2WI', 'Var', (79, 83))	('ULCD', 'Disease', (116, 120))	('LMS lesions', 'Disease', (131, 142))	('LMS lesions', 'Disease', 'MESH:C535903', (131, 142))	('SI', 'Disease', 'None', (84, 86))	('ESS', 'Disease', (122, 125))
99942	29400019	specifically reported that bands of low SI are observed within the areas of myometrial involvement on T2WI in ESS and that these bands correspond to the preserved bundles of myometrium on pathologic examination.	('T2WI', 'Var', (102, 106))	('low SI', 'Disease', (36, 42))	('low SI', 'Disease', 'MESH:D009800', (36, 42))
99987	27793021	Preclinical trials looking at the combination of sirolimus and cyclophosphamide have also revealed therapeutic enhancement in xenograft models of pediatric solid tumors suggesting that mTOR inhibitors have the potential to augment the activity of conventional chemotherapy drugs.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (63, 79))	('mTOR', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('sirolimus', 'Chemical', 'MESH:D020123', (49, 58))	('augment', 'PosReg', (223, 230))	('pediatric solid tumors', 'Disease', (146, 168))	('activity', 'MPA', (235, 243))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (146, 168))	('inhibitors', 'Var', (190, 200))	('mTOR', 'Gene', '2475', (185, 189))
99989	27793021	In addition to direct effects on tumor cells, sirolimus has also been shown to reduce tumor angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (86, 91))	('sirolimus', 'Var', (46, 55))	('sirolimus', 'Chemical', 'MESH:D020123', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('reduce', 'NegReg', (79, 85))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
100119	25594667	Several studies indicate that KS spindle cells are of endothelial lineage as they express the vascular endothelial cell markers CD31, CD34, CD36.	('CD34', 'Var', (134, 138))	('CD31', 'Var', (128, 132))	('CD36', 'Species', '42374', (140, 144))	('CD36', 'Var', (140, 144))
100137	25594667	Though large parts of the KSHV genome are conserved in these variants, several regions were shown to be highly variable, including the K1 and K15 gene regions.	('KSHV', 'Species', '37296', (26, 30))	('variants', 'Var', (61, 69))	('K15', 'Gene', (142, 145))	('K15', 'Gene', '4961473', (142, 145))
100157	25594667	Importantly, chromatin and epigenetic modulation of KSHV genome represents a novel antiviral target for blocking virus-mediated tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('KSHV genome', 'Gene', (52, 63))	('epigenetic modulation', 'Var', (27, 48))	('KSHV', 'Species', '37296', (52, 56))	('blocking', 'NegReg', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
100183	25594667	Additionally, LANA has also been shown to deregulate the expressions many oncogenes (by stabilizing) and tumor suppressors (by degrading) to induce tumor growth and these includes c-Myc, p53, hypoxia-inducible factor 1 (HIF-1), glycogen synthase kinase 3 (GSK3), von Hippel-Lindau protein (pVHL) and beta-catenin.	('oncogenes', 'Gene', (74, 83))	('hypoxia-inducible factor 1', 'Gene', '3091', (192, 218))	('degrading', 'NegReg', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('von Hippel-Lindau', 'Disease', (263, 280))	('hypoxia-inducible factor 1', 'Gene', (192, 218))	('GSK3', 'Gene', (256, 260))	('pVHL', 'Gene', '7428', (290, 294))	('pVHL', 'Gene', (290, 294))	('tumor', 'Disease', (105, 110))	('beta-catenin', 'Gene', (300, 312))	('induce', 'PosReg', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('p53', 'Gene', '7157', (187, 190))	('c-Myc', 'Gene', (180, 185))	('beta-catenin', 'Gene', '1499', (300, 312))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (263, 280))	('HIF-1', 'Gene', '3091', (220, 225))	('c-Myc', 'Gene', '4609', (180, 185))	('deregulate', 'Var', (42, 52))	('p53', 'Gene', (187, 190))	('HIF-1', 'Gene', (220, 225))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('LANA', 'Gene', (14, 18))	('LANA', 'Gene', '4961527', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
100194	25594667	Scanning of this region for identifying the exact residues in DNA binding by generating substitution mutants determined that amino acids between 1007 and 10021aa may be the DNA contact residues as the mutants of this region abolished DNA binding as well as replication and episome persistence abilities of LANA.	('DNA', 'Protein', (234, 237))	('amino', 'Var', (125, 130))	('LANA', 'Gene', '4961527', (306, 310))	('abolished', 'NegReg', (224, 233))	('mutants', 'Var', (201, 208))	('episome persistence abilities', 'CPA', (273, 302))	('LANA', 'Gene', (306, 310))
100207	25594667	Increased levels of Lef-Tcf enhance the transcription of S-phase entry genes such as MYC, JUN and CCND1 (Cyclin D1), which drive cell cycle progression.	('transcription', 'MPA', (40, 53))	('Lef-Tcf', 'Var', (20, 27))	('Cyclin D1', 'Gene', '595', (105, 114))	('MYC', 'Gene', '4609', (85, 88))	('enhance', 'PosReg', (28, 35))	('CCND1', 'Gene', (98, 103))	('Cyclin D1', 'Gene', (105, 114))	('MYC', 'Gene', (85, 88))	('CCND1', 'Gene', '595', (98, 103))	('S-phase entry genes', 'Gene', (57, 76))	('JUN', 'Gene', (90, 93))
100209	25594667	LANA also modulates the activity of another tumor suppressor, pRb, which was determined by the fact that expression of LANA overcame the flat-cell (growth arrested) phenotype in RB1 negative cells.	('activity', 'MPA', (24, 32))	('LANA', 'Gene', '4961527', (0, 4))	('LANA', 'Gene', (119, 123))	('RB1', 'Gene', '5925', (178, 181))	('modulates', 'Reg', (10, 19))	('expression', 'Var', (105, 115))	('LANA', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('LANA', 'Gene', '4961527', (119, 123))	('overcame', 'PosReg', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('pRb', 'Gene', '5925', (62, 65))	('pRb', 'Gene', (62, 65))	('RB1', 'Gene', (178, 181))	('growth arrested', 'Phenotype', 'HP:0001510', (148, 163))	('tumor', 'Disease', (44, 49))
100219	25594667	NF-kB pathway activation by v-FLIP has been linked to KSHV lytic replication as the KSHV mutant deficient in v-FLIP inhibits ORF50/RTA lytic gene expression.	('KSHV', 'Gene', (84, 88))	('ORF50', 'Gene', (125, 130))	('v-FLIP', 'Gene', (109, 115))	('NF-kB pathway', 'Pathway', (0, 13))	('KSHV', 'Disease', (54, 58))	('deficient', 'NegReg', (96, 105))	('KSHV', 'Species', '37296', (84, 88))	('KSHV', 'Species', '37296', (54, 58))	('ORF50', 'Gene', '4961526', (125, 130))	('mutant', 'Var', (89, 95))	('inhibits', 'NegReg', (116, 124))
100228	25594667	Among these miRNAs, miR-K1 represses the expression of IkappaBalpha-an inhibitor of the pro-survival NF-kappaB pathway and inhibits the activation of lytic viral promoters.	('miR-K1', 'Var', (20, 26))	('IkappaBalpha', 'Gene', (55, 67))	('represses', 'NegReg', (27, 36))	('expression', 'MPA', (41, 51))	('lytic viral promoters', 'MPA', (150, 171))	('IkappaBalpha', 'Gene', '4792', (55, 67))	('inhibits', 'NegReg', (123, 131))	('activation', 'MPA', (136, 146))
100237	25594667	LANA mutant with deleted RFC binding domain was found to have a negative impact on LANA-mediated DNA replication and episome persistence.	('RFC', 'Protein', (25, 28))	('deleted', 'Var', (17, 24))	('episome persistence', 'CPA', (117, 136))	('LANA', 'Gene', (0, 4))	('LANA', 'Gene', (83, 87))	('mutant', 'Var', (5, 11))	('LANA', 'Gene', '4961527', (0, 4))	('negative', 'NegReg', (64, 72))	('LANA', 'Gene', '4961527', (83, 87))
100245	25594667	Studies so far clearly show that latent KSHV genome is extensively chromatinized with both the activating (H3ac and H3K4me3) and repressive (H3K9me3 and H3K27me3) histone marks among them the Latency-associated genes possess activating histone marks as well as colocalize with transcriptionally active RNA polymerase II (RNAPII).	('H3K27me3', 'Var', (153, 161))	('H3K4me3', 'Var', (116, 123))	('activating histone marks', 'MPA', (225, 249))	('KSHV', 'Species', '37296', (40, 44))	('H3K9me3', 'Var', (141, 148))	('H3ac', 'Var', (107, 111))
100249	25594667	DNA methylation slowly builds up over the entire KSHV genome following the de novo infection and typically represses the viral gene expression (Figure 2).	('KSHV', 'Species', '37296', (49, 53))	('infection', 'Disease', (83, 92))	('viral gene expression', 'MPA', (121, 142))	('represses', 'NegReg', (107, 116))	('infection', 'Disease', 'MESH:D007239', (83, 92))	('methylation', 'Var', (4, 15))
100264	25594667	Depletion of cohesin subunits disrupts the DNA loop between the latency and lytic promoter regions and a robust reactivation of lytic cycle gene transcription, indicating an important role of chromatin organizing factors and chromosome conformation in maintenance of stable gene programs during KSHV latent infection.	('KSHV latent infection', 'Disease', 'MESH:D055985', (295, 316))	('disrupts', 'NegReg', (30, 38))	('Depletion', 'Var', (0, 9))	('reactivation', 'MPA', (112, 124))	('DNA loop', 'MPA', (43, 51))	('KSHV latent infection', 'Disease', (295, 316))	('lytic cycle gene', 'Gene', (128, 144))
100273	25594667	The expression of early genes (E) is controlled by the IE genes and include the polyadenylated nuclear RNA (PAN RNA), Kaposin, ORF57, k-bZIP (K8), K5, K9, K14, K15 ORF6, ORF21 and ORF74, followed by expression of the late genes including major capsid protein (MCP) encoded by ORF25 and the small viral capsid (sVCA).	('K15', 'Gene', '4961473', (160, 163))	('ORF21', 'Gene', (170, 175))	('k-bZIP', 'Var', (134, 140))	('K15', 'Gene', (160, 163))	('ORF57', 'Gene', '4961525', (127, 132))	('MCP', 'Gene', (260, 263))	('K14', 'Var', (155, 158))	('ORF57', 'Gene', (127, 132))	('ORF74', 'Gene', (180, 185))	('major capsid protein', 'Gene', '4179', (238, 258))	('MCP', 'Gene', '4179', (260, 263))	('ORF74', 'Gene', '4961460', (180, 185))	('ORF25', 'Gene', (276, 281))	('major capsid protein', 'Gene', (238, 258))
100283	25594667	In order to elucidate the role of PAN RNA in the KSHV life cycle, recent studies on a recombinant BACmid with a deleted PAN RNA locus showed decreased RTA expression in the induced cells at both the early and late induction time points.	('KSHV', 'Species', '37296', (49, 53))	('decreased', 'NegReg', (141, 150))	('PAN RNA', 'Gene', (120, 127))	('RTA expression', 'MPA', (151, 165))	('deleted', 'Var', (112, 119))
100284	25594667	H3K27me3 is deposited by one of the Polycomb-group proteins, namely Polycomb Repressive Complex 2 (PRC2) that consists of subunit: EZH2, SUZ12, EED and the histone binding proteins RbAp48/46.	('SUZ12', 'Gene', '23512', (137, 142))	('SUZ12', 'Gene', (137, 142))	('RbAp48', 'Gene', (181, 187))	('RbAp48', 'Gene', '5928', (181, 187))	('EED', 'Gene', '8726', (144, 147))	('EED', 'Gene', (144, 147))	('H3K27me3', 'Var', (0, 8))	('EZH2', 'Gene', (131, 135))	('EZH2', 'Gene', '2146', (131, 135))
100285	25594667	Upon reactivation, chromatin remodeling proteins, JMJD3 and UTX H3K27me3 histone demethylases and H3K4me3 histone methyltransferase are recruited to the RTA promoter via KSHV-encoded Polyadenylated nuclear non-coding PAN RNA that disrupts polycomb mediated chromatin repression.	('H3K27me3', 'Var', (64, 72))	('polycomb mediated chromatin repression', 'MPA', (239, 277))	('disrupts', 'NegReg', (230, 238))	('JMJD3', 'Gene', (50, 55))	('KSHV', 'Species', '37296', (170, 174))	('UTX', 'Gene', (60, 63))	('JMJD3', 'Gene', '23135', (50, 55))	('UTX', 'Gene', '7403', (60, 63))
100297	25594667	Latent genes, IE and E lytic genes are found to be rich in H3K4me3/H3K9 (acH3) during latency and reactivation whereas the genomic regions of KSHV that encode for many late lytic genes display high levels of H3K9me3 /H3K27me3 during latency and early lytic reactivation.	('H3K9me3', 'Var', (208, 215))	('KSHV', 'Species', '37296', (142, 146))	('H3K4me3/H3K9', 'Var', (59, 71))	('E lytic genes', 'Gene', (21, 34))
100299	25594667	During the onset of infection, the KSHV epigenome develops a transcriptionally active chromatin structure (euchromatin) with a high level of activating histone marks H3K4me3 and H3K27ac, accompanied by the temporary induction of a limited number of lytic genes, which further increase the activating histone marks on the viral genome.	('H3K27ac', 'Var', (178, 185))	('infection', 'Disease', (20, 29))	('infection', 'Disease', 'MESH:D007239', (20, 29))	('activating histone marks', 'MPA', (289, 313))	('lytic genes', 'Gene', (249, 260))	('KSHV', 'Species', '37296', (35, 39))	('activating', 'MPA', (141, 151))	('H3K4me3', 'Var', (166, 173))	('transcriptionally', 'MPA', (61, 78))
100300	25594667	Between 24 and 72 h post-infection, levels of activating histone marks decrease due to the Polycomb group protein (PcG protein)-mediated increase in the amount of repressive histone marks H3K27me3 and H2AK119ub, thereby inhibiting lytic gene expression.	('H2AK119ub', 'Var', (201, 210))	('decrease', 'NegReg', (71, 79))	('infection', 'Disease', (25, 34))	('infection', 'Disease', 'MESH:D007239', (25, 34))	('inhibiting', 'NegReg', (220, 230))	('H3K27me3', 'Var', (188, 196))	('levels', 'MPA', (36, 42))	('increase', 'PosReg', (137, 145))	('lytic', 'MPA', (231, 236))	('activating histone marks', 'MPA', (46, 70))
100304	25594667	Thus, the differential epigenetic modification of the KSHV genome in distinct cell types is a potential determining factor for latent infection versus lytic replication.	('infection', 'Disease', 'MESH:D007239', (134, 143))	('epigenetic modification', 'Var', (23, 46))	('KSHV genome', 'Gene', (54, 65))	('KSHV', 'Species', '37296', (54, 58))	('infection', 'Disease', (134, 143))
100310	25594667	Depletion of ND10s core components, Sp100, PML or Daxx did not interfere with latency establishment, though depletion of Sp100 accelerates the occupancy of the repressive histone mark H3K27me3 on viral episomes indicating that Sp100 acts as a negative regulator of PRC2 recruitment onto the KSHV genome.	('Sp100', 'Gene', (36, 41))	('Sp100', 'Gene', '6672', (36, 41))	('Sp100', 'Gene', (227, 232))	('accelerates', 'PosReg', (127, 138))	('PML', 'Gene', (43, 46))	('occupancy', 'MPA', (143, 152))	('Sp100', 'Gene', '6672', (227, 232))	('Daxx', 'Gene', (50, 54))	('Sp100', 'Gene', (121, 126))	('men', 'Species', '9606', (95, 98))	('Sp100', 'Gene', '6672', (121, 126))	('Daxx', 'Gene', '1616', (50, 54))	('H3K27me3', 'Protein', (184, 192))	('men', 'Species', '9606', (277, 280))	('depletion', 'Var', (108, 117))	('KSHV', 'Species', '37296', (291, 295))	('PML', 'Gene', '5371', (43, 46))
100313	25594667	Undoubtedly, the chromatin remodeling and epigenetic modifications of both viral and host genomes play crucial roles in determining the expression pattern of genes, that will lead to abortive or persistent infection.	('expression', 'MPA', (136, 146))	('abortive', 'MPA', (183, 191))	('lead to', 'Reg', (175, 182))	('persistent infection', 'Phenotype', 'HP:0031035', (195, 215))	('epigenetic modifications', 'Var', (42, 66))	('infection', 'Disease', (206, 215))	('infection', 'Disease', 'MESH:D007239', (206, 215))
100320	25802700	It might be more commonly found in patients with specific cytogenetic abnormalities, particularly with the t (8; 21) translocation and less frequently the inv (16) type.	('found', 'Reg', (26, 31))	('t (8; 21) translocation', 'Var', (107, 130))	('patients', 'Species', '9606', (35, 43))
100337	25802700	Chen J, Yanuck R et al in her study showed 30 cases CD117 reactivity in 87%, MPO, 97%; lysozyme, 93%; CD34, 47%; CD45, 84%; CD43, 97%; TdT, 37%; CD79a, 20%; CD20, 10%; CD3, 10%; and CD10, 1%.	('CD43', 'Gene', (124, 128))	('CD20', 'Gene', '54474', (157, 161))	('CD34', 'Gene', '947', (102, 106))	('CD45', 'Gene', (113, 117))	('CD45', 'Gene', '5788', (113, 117))	('TdT', 'Gene', (135, 138))	('CD43', 'Gene', '6693', (124, 128))	('CD3', 'Var', (168, 171))	('reactivity', 'MPA', (58, 68))	('CD117', 'Gene', '3815', (52, 57))	('CD34', 'Gene', (102, 106))	('CD79a', 'Gene', '973', (145, 150))	('MPO', 'Gene', '4353', (77, 80))	('CD10', 'Gene', '4311', (182, 186))	('CD20', 'Gene', (157, 161))	('CD117', 'Gene', (52, 57))	('MPO', 'Gene', (77, 80))	('TdT', 'Gene', '1791', (135, 138))	('lysozyme', 'MPA', (87, 95))	('CD10', 'Gene', (182, 186))	('CD79a', 'Gene', (145, 150))
100355	25802700	Immunohistochemistry (IHC) study revealed positivity for myeloperoxidase (MPO) (Figure 3).	('MPO', 'Gene', '4353', (74, 77))	('positivity', 'Var', (42, 52))	('myeloperoxidase', 'Gene', (57, 72))	('MPO', 'Gene', (74, 77))	('myeloperoxidase', 'Gene', '4353', (57, 72))
100397	32051269	Our findings reveal that saliva containing HIV-associated exosomes is a risk factor for the enhancement of KSHV infection and that the inhibition of EGFR serves as a novel strategy for preventing KSHV infection and transmission in the oral cavity.	('KS', 'Phenotype', 'HP:0100726', (196, 198))	('KSHV infection', 'Disease', (196, 210))	('KSHV infection', 'Disease', (107, 121))	('KS', 'Phenotype', 'HP:0100726', (107, 109))	('KSHV infection', 'Disease', 'MESH:D007239', (196, 210))	('EGFR', 'Gene', '1956', (149, 153))	('enhancement', 'PosReg', (92, 103))	('KSHV infection', 'Disease', 'MESH:D007239', (107, 121))	('rat', 'Species', '10116', (174, 177))	('EGFR', 'Gene', (149, 153))	('HIV', 'Species', '12721', (43, 46))	('inhibition', 'Var', (135, 145))	('men', 'Species', '9606', (99, 102))
100414	32051269	Exosomes from T cells latently infected with an HIV-1 isolate that contains a dysfunctional mutant HIV Tat and the deletion of the Nef gene can still stimulate KSHV infection.	('Nef', 'Gene', (131, 134))	('deletion', 'Var', (115, 123))	('HIV', 'Species', '12721', (48, 51))	('HIV-1', 'Species', '11676', (48, 53))	('infected', 'Disease', 'MESH:D007239', (31, 39))	('stimulate', 'PosReg', (150, 159))	('dysfunctional', 'Disease', 'MESH:D009461', (78, 91))	('infected', 'Disease', (31, 39))	('KSHV infection', 'Disease', (160, 174))	('HIV Tat', 'Gene', (99, 106))	('KS', 'Phenotype', 'HP:0100726', (160, 162))	('HIV', 'Species', '12721', (99, 102))	('dysfunctional', 'Disease', (78, 91))	('KSHV infection', 'Disease', 'MESH:D007239', (160, 174))
100417	32051269	TAR RNA-enhanced KSHV infection is reduced by an aptamer against the TAR RNA.	('KS', 'Phenotype', 'HP:0100726', (17, 19))	('KSHV infection', 'Disease', (17, 31))	('TAR', 'Gene', '9939', (69, 72))	('reduced', 'NegReg', (35, 42))	('KSHV infection', 'Disease', 'MESH:D007239', (17, 31))	('aptamer', 'Var', (49, 56))	('TAR', 'Gene', (0, 3))	('TAR', 'Gene', (69, 72))	('TAR', 'Gene', '9939', (0, 3))
100420	32051269	Our findings reveal that HIV-associated saliva exosomes are a risk factor for the enhancement of KSHV infection and that inhibition of EGFR serves as a novel strategy for controlling KSHV infection and transmission in the oral cavity.	('HIV', 'Species', '12721', (25, 28))	('rat', 'Species', '10116', (160, 163))	('KSHV infection', 'Disease', (183, 197))	('KSHV infection', 'Disease', (97, 111))	('EGFR', 'Gene', '1956', (135, 139))	('inhibition', 'Var', (121, 131))	('KS', 'Phenotype', 'HP:0100726', (183, 185))	('KS', 'Phenotype', 'HP:0100726', (97, 99))	('KSHV infection', 'Disease', 'MESH:D007239', (183, 197))	('enhancement', 'PosReg', (82, 93))	('EGFR', 'Gene', (135, 139))	('men', 'Species', '9606', (89, 92))	('KSHV infection', 'Disease', 'MESH:D007239', (97, 111))
100433	32051269	Quantitative RT-PCR on total RNA extracted from exosomes secreted from HIV+ 8E5/LAV, J1.1, and 2D10 T cells demonstrated that J1.1 and 2D10 cell exosomes contained significantly higher levels of TAR RNA than Tat and Nef RNA (Fig.	('J1.1', 'CellLine', 'CVCL:8279', (85, 89))	('rat', 'Species', '10116', (115, 118))	('J1.1', 'CellLine', 'CVCL:8279', (126, 130))	('higher', 'PosReg', (178, 184))	('J1.1', 'Var', (126, 130))	('HIV', 'Species', '12721', (71, 74))	('D10 T', 'CellLine', 'CVCL:H945', (96, 101))	('TAR', 'Gene', (195, 198))	('TAR', 'Gene', '9939', (195, 198))
100459	32051269	KSHV infection was considerably enhanced by HIV+ saliva exosomes compared to HIV- saliva exosomes in primary HOECs (Fig.	('KSHV infection', 'Disease', 'MESH:D007239', (0, 14))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('HIV+ saliva', 'Var', (44, 55))	('HIV', 'Species', '12721', (77, 80))	('HIV', 'Species', '12721', (44, 47))	('enhanced', 'PosReg', (32, 40))	('KSHV infection', 'Disease', (0, 14))
100474	32051269	Treatment with HIV+ J1.1 T-cell exosomes significantly increased the number of LANA-expressing cells compared to the number obtained by treatment with HIV- Jurkat T-cell exosomes (Fig.	('HIV+ J1.1', 'Var', (15, 24))	('men', 'Species', '9606', (141, 144))	('Jurkat T-cell', 'CellLine', 'CVCL:0065', (156, 169))	('J1.1', 'CellLine', 'CVCL:8279', (20, 24))	('increased', 'PosReg', (55, 64))	('HIV- Jurkat', 'CellLine', 'CVCL:0065', (151, 162))	('HIV', 'Species', '12721', (15, 18))	('men', 'Species', '9606', (5, 8))	('HIV', 'Species', '12721', (151, 154))
100481	32051269	To determine if HIV+ exosomes contained viral proteins, such as Tat and Nef, that are known to contribute to cellular function, we performed immunoblot assays on total exosome proteins isolated from latently HIV-infected J1.1 cells; cells of the HIV+ Jurkat-based C22G cell line, which contain a disruptive HIV tat mutant and nef deletion; and cells of the 2D10 cell line, which lack the viral nef gene.	('nef', 'Gene', (326, 329))	('disruptive HIV', 'Disease', (296, 310))	('C22G', 'SUBSTITUTION', 'None', (264, 268))	('HIV', 'Species', '12721', (307, 310))	('HIV', 'Species', '12721', (16, 19))	('latently HIV-infected', 'Disease', 'MESH:D015658', (199, 220))	('HIV', 'Species', '12721', (246, 249))	('HIV', 'Species', '12721', (208, 211))	('J1.1', 'CellLine', 'CVCL:8279', (221, 225))	('deletion', 'Var', (330, 338))	('disruptive HIV', 'Disease', 'MESH:D019958', (296, 310))	('latently HIV-infected', 'Disease', (199, 220))	('C22G', 'Var', (264, 268))	('Jurkat', 'CellLine', 'CVCL:0065', (251, 257))
100482	32051269	While the whole-protein lysates from TNF-alpha-activated J1.1 cells expressed the Tat and Nef proteins, exosomes from J1.1 and C22G cells did not contain these HIV proteins (Fig.	('C22G', 'Var', (127, 131))	('J1.1', 'CellLine', 'CVCL:8279', (57, 61))	('HIV', 'Species', '12721', (160, 163))	('TNF-alpha', 'Gene', '7124', (37, 46))	('Tat', 'Protein', (82, 85))	('TNF-alpha', 'Gene', (37, 46))	('C22G', 'SUBSTITUTION', 'None', (127, 131))	('J1.1', 'CellLine', 'CVCL:8279', (118, 122))
100485	32051269	We have reported that exosomes from both the J1.1 and C22G cell lines contain HIV trans-activation response element (TAR) RNA, which is required for the HIV+ exosome-enhanced proliferation of cancer cells and extracellular signal-regulated kinase (ERK) signaling.	('ERK', 'Gene', (248, 251))	('TAR', 'Gene', '9939', (117, 120))	('J1.1', 'CellLine', 'CVCL:8279', (45, 49))	('C22G', 'SUBSTITUTION', 'None', (54, 58))	('men', 'Species', '9606', (111, 114))	('C22G', 'Var', (54, 58))	('cancer', 'Disease', (192, 198))	('HIV', 'Species', '12721', (153, 156))	('rat', 'Species', '10116', (182, 185))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('ERK', 'Gene', '5594', (248, 251))	('HIV', 'Species', '12721', (78, 81))	('TAR', 'Gene', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
100488	32051269	To test this hypothesis, we treated OKF6/TERT2 cells with exosomes derived from C22G, 2D10, and J1.1 cells and J1.1 cells treated with TNF-alpha (5 ng/ml), followed by KSHV infection.	('KS', 'Phenotype', 'HP:0100726', (168, 170))	('KSHV infection', 'Disease', (168, 182))	('OKF6/TERT2', 'CellLine', 'CVCL:L225', (36, 46))	('J1.1', 'CellLine', 'CVCL:8279', (96, 100))	('KSHV infection', 'Disease', 'MESH:D007239', (168, 182))	('TNF-alpha', 'Gene', '7124', (135, 144))	('C22G', 'SUBSTITUTION', 'None', (80, 84))	('J1.1', 'CellLine', 'CVCL:8279', (111, 115))	('TNF-alpha', 'Gene', (135, 144))	('C22G', 'Var', (80, 84))
100489	32051269	HIV+ exosomes from both the J1.1 and C22G cell lines increased KSHV infectivity in OKF6/TERT2 cells, as shown by GFP flow cytometry (Fig.	('HIV', 'Species', '12721', (0, 3))	('KSHV', 'Species', '37296', (63, 67))	('C22G', 'Var', (37, 41))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('KSHV', 'MPA', (63, 67))	('J1.1', 'CellLine', 'CVCL:8279', (28, 32))	('increased', 'PosReg', (53, 62))	('OKF6/TERT2', 'CellLine', 'CVCL:L225', (83, 93))	('C22G', 'SUBSTITUTION', 'None', (37, 41))
100495	32051269	Our results indicate that while the wild-type TAR RNA increased KSHV infection in oral epithelial cells, the mutant TAR RNA failed to affect KSHV infection (Fig.	('TAR', 'Gene', (46, 49))	('KS', 'Phenotype', 'HP:0100726', (64, 66))	('KSHV infection', 'Disease', 'MESH:D007239', (64, 78))	('KSHV infection', 'Disease', (141, 155))	('TAR', 'Gene', '9939', (46, 49))	('infection in oral', 'Phenotype', 'HP:0100649', (69, 86))	('KS', 'Phenotype', 'HP:0100726', (141, 143))	('KSHV infection', 'Disease', 'MESH:D007239', (141, 155))	('TAR', 'Gene', (116, 119))	('increased', 'PosReg', (54, 63))	('TAR', 'Gene', '9939', (116, 119))	('mutant', 'Var', (109, 115))	('KSHV infection', 'Disease', (64, 78))
100511	32051269	However, J1.1 cell exosome-induced ORF K8 expression was only partially reduced by cetuximab or AG1478 in OKF6/TERT2 cells (Fig.	('reduced', 'NegReg', (72, 79))	('cetuximab', 'Chemical', 'MESH:D000068818', (83, 92))	('ORF K8', 'Gene', (35, 41))	('expression', 'MPA', (42, 52))	('AG1478', 'Chemical', 'MESH:C101044', (96, 102))	('OKF6/TERT2', 'CellLine', 'CVCL:L225', (106, 116))	('J1.1', 'CellLine', 'CVCL:8279', (9, 13))	('AG1478', 'Var', (96, 102))
100521	32051269	Therefore, blocking EGFR can potentially inhibit KSHV infection mediated by HIV+ exosomes in the oral cavity.	('KSHV infection', 'Disease', (49, 63))	('EGFR', 'Gene', (20, 24))	('HIV', 'Species', '12721', (76, 79))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('KSHV infection', 'Disease', 'MESH:D007239', (49, 63))	('blocking', 'Var', (11, 19))	('inhibit', 'NegReg', (41, 48))	('EGFR', 'Gene', '1956', (20, 24))
100526	32051269	EGF phosphorylated EGFR tyrosine residues at positions 1068 (Y1068) and 1173 (Y1173); however, HIV+ exosomes failed to induce EGFR phosphorylation at these canonical sites.	('tyrosine', 'Chemical', 'MESH:D014443', (24, 32))	('EGF', 'Gene', (19, 22))	('Y1068', 'Var', (61, 66))	('EGFR', 'Gene', (126, 130))	('EGF', 'Gene', (126, 129))	('EGFR', 'Gene', '1956', (19, 23))	('EGF', 'Gene', '1950', (19, 22))	('EGF', 'Gene', (0, 3))	('HIV', 'Species', '12721', (95, 98))	('EGFR', 'Gene', (19, 23))	('EGF', 'Gene', '1950', (0, 3))	('EGF', 'Gene', '1950', (126, 129))	('EGFR', 'Gene', '1956', (126, 130))
100527	32051269	In addition, neither HIV+ exosomes nor EGF induced the phosphorylation of STAT3 at Y705, although these cells displayed basal levels of phosphorylation of STAT3 (Fig.	('Y705', 'Var', (83, 87))	('EGF', 'Gene', (39, 42))	('STAT3', 'Gene', '6774', (74, 79))	('STAT3', 'Gene', (155, 160))	('STAT3', 'Gene', (74, 79))	('EGF', 'Gene', '1950', (39, 42))	('phosphorylation', 'MPA', (55, 70))	('STAT3', 'Gene', '6774', (155, 160))	('HIV', 'Species', '12721', (21, 24))
100552	32051269	Exosomes from the plasma of people living with HIV and the culture supernatants of HIV-infected T-cell lines contain HIV TAR RNA at amounts in vast excess over those of all viral mRNAs.	('people', 'Species', '9606', (28, 34))	('HIV', 'Species', '12721', (83, 86))	('TAR', 'Gene', '9939', (121, 124))	('HIV', 'Species', '12721', (117, 120))	('HIV', 'Var', (117, 120))	('HIV-infected', 'Disease', (83, 95))	('HIV-infected', 'Disease', 'MESH:D015658', (83, 95))	('HIV', 'Species', '12721', (47, 50))	('TAR', 'Gene', (121, 124))
100555	32051269	In addition, exosomes from the C22G HIV+ T-cell line, which contains a dysfunctional Tat mutant, which lacks the Nef gene, and which does not produce HIV virions, exhibit HIV TAR RNA and promote KSHV infection in oral epithelial cells.	('KS', 'Phenotype', 'HP:0100726', (195, 197))	('KSHV infection', 'Disease', 'MESH:D007239', (195, 209))	('dysfunctional', 'Disease', 'MESH:D009461', (71, 84))	('exhibit', 'PosReg', (163, 170))	('TAR', 'Gene', (175, 178))	('lacks', 'NegReg', (103, 108))	('HIV', 'Species', '12721', (150, 153))	('TAR', 'Gene', '9939', (175, 178))	('HIV virions', 'Disease', 'MESH:D015658', (150, 161))	('C22G', 'Var', (31, 35))	('mutant', 'Var', (89, 95))	('KSHV infection', 'Disease', (195, 209))	('HIV virions', 'Disease', (150, 161))	('C22G', 'SUBSTITUTION', 'None', (31, 35))	('HIV', 'Species', '12721', (36, 39))	('infection in oral', 'Phenotype', 'HP:0100649', (200, 217))	('dysfunctional', 'Disease', (71, 84))	('HIV', 'Species', '12721', (171, 174))	('promote', 'PosReg', (187, 194))
100560	32051269	Similarly, our results demonstrate that, while the wild-type synthetic TAR RNA stimulates KSHV infection, the TAR RNA mutant cannot enhance KSHV infection in oral epithelial cells.	('TAR', 'Gene', '9939', (110, 113))	('KS', 'Phenotype', 'HP:0100726', (140, 142))	('KSHV infection', 'Disease', 'MESH:D007239', (140, 154))	('TAR', 'Gene', (71, 74))	('KSHV infection', 'Disease', (90, 104))	('TAR', 'Gene', '9939', (71, 74))	('rat', 'Species', '10116', (30, 33))	('KS', 'Phenotype', 'HP:0100726', (90, 92))	('stimulates', 'PosReg', (79, 89))	('mutant', 'Var', (118, 124))	('KSHV infection', 'Disease', 'MESH:D007239', (90, 104))	('infection in oral', 'Phenotype', 'HP:0100649', (145, 162))	('TAR', 'Gene', (110, 113))	('KSHV infection', 'Disease', (140, 154))
100561	32051269	In addition, the R06 nucleotide aptamer, which creates an imperfect hairpin to complement the entire TAR loop and which blocks TAR RNA function, attenuates TAR RNA-induced KSHV infection.	('TAR', 'Gene', (156, 159))	('KS', 'Phenotype', 'HP:0100726', (172, 174))	('blocks', 'NegReg', (120, 126))	('KSHV infection', 'Disease', 'MESH:D007239', (172, 186))	('TAR', 'Gene', '9939', (156, 159))	('R06', 'Var', (17, 20))	('attenuates', 'NegReg', (145, 155))	('TAR', 'Gene', (127, 130))	('TAR', 'Gene', '9939', (101, 104))	('TAR', 'Gene', '9939', (127, 130))	('KSHV infection', 'Disease', (172, 186))	('men', 'Species', '9606', (85, 88))	('TAR', 'Gene', (101, 104))
100562	32051269	The R06 aptamer and its derivatives are able to reduce HIV-1 infection and inhibit viral transcription.	('viral transcription', 'MPA', (83, 102))	('inhibit', 'NegReg', (75, 82))	('R06', 'Var', (4, 7))	('reduce', 'NegReg', (48, 54))	('HIV-1 infection', 'Disease', (55, 70))	('HIV-1 infection', 'Disease', 'MESH:D015658', (55, 70))
100564	32051269	Our results suggest that the R06 RNA aptamer and its functional derivatives can potentially be developed as treatments for controlling coinfection with herpesviruses in the HIV-infected population.	('R06 RNA', 'Var', (29, 36))	('coinfection', 'Disease', 'MESH:D060085', (135, 146))	('men', 'Species', '9606', (113, 116))	('HIV-infected', 'Disease', (173, 185))	('coinfection', 'Disease', (135, 146))	('HIV-infected', 'Disease', 'MESH:D015658', (173, 185))
100566	32051269	Similarly, EGFR is critical for HIV+ exosome-enhanced KSHV infectivity; blocking the receptor with cetuximab or the receptor kinase inhibitor effectively inhibits KSHV infection.	('inhibits', 'NegReg', (154, 162))	('EGFR', 'Gene', '1956', (11, 15))	('KSHV infection', 'Disease', (163, 177))	('EGFR', 'Gene', (11, 15))	('HIV', 'Species', '12721', (32, 35))	('KSHV', 'Species', '37296', (163, 167))	('KSHV infection', 'Disease', 'MESH:D007239', (163, 177))	('KS', 'Phenotype', 'HP:0100726', (163, 165))	('KSHV', 'Species', '37296', (54, 58))	('blocking', 'Var', (72, 80))	('cetuximab', 'Chemical', 'MESH:D000068818', (99, 108))	('KS', 'Phenotype', 'HP:0100726', (54, 56))
100577	32051269	Inhibition of the catalytic activity of phosphorylated p38 blocks KSHV reactivation, possibly through a reduction in global H3 acetylation and phosphorylation.	('KSHV', 'Disease', (66, 70))	('reduction', 'NegReg', (104, 113))	('KS', 'Phenotype', 'HP:0100726', (66, 68))	('H3', 'Chemical', 'MESH:C012616', (124, 126))	('KSHV', 'Species', '37296', (66, 70))	('global H3 acetylation', 'MPA', (117, 138))	('phosphorylation', 'MPA', (143, 158))	('blocks', 'NegReg', (59, 65))	('p38', 'Gene', '5594', (55, 58))	('Inhibition', 'Var', (0, 10))	('catalytic activity', 'MPA', (18, 36))	('p38', 'Gene', (55, 58))
100684	30697290	Prominent nucleoli with HMB45 positivity differentiate melanoma from SS.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('positivity', 'Var', (30, 40))	('HMB45', 'Protein', (24, 29))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
100690	30697290	Immunoreactivity to calretinin and negativity to HMB45 and other epithelial markers ruled out the possibility of metastatic melanoma, carcinoma.	('carcinoma', 'Disease', (134, 143))	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('calretinin', 'Gene', (20, 30))	('calretinin', 'Gene', '794', (20, 30))	('carcinoma', 'Disease', 'MESH:D002277', (134, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('negativity', 'Var', (35, 45))	('HMB45', 'Gene', (49, 54))
100704	30697290	Positivity for CD34, bcl2 with Vimentin characterises the tumor as seen in the present study.	('Vimentin', 'Gene', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Vimentin', 'Gene', '7431', (31, 39))	('CD34', 'Gene', (15, 19))	('CD34', 'Gene', '947', (15, 19))	('bcl2', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Positivity', 'Var', (0, 10))	('bcl2', 'Gene', '596', (21, 25))
100723	30487384	Translocation-Related Sarcomas Chromosomal translocations are observed in approximately 20% of soft tissue sarcomas (STS).	('Sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (95, 115))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (95, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('STS', 'Phenotype', 'HP:0030448', (117, 120))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (95, 115))	('soft tissue sarcomas', 'Disease', (95, 115))	('Sarcomas', 'Disease', (22, 30))	('Chromosomal translocations', 'Var', (31, 57))	('Sarcomas', 'Disease', 'MESH:D012509', (22, 30))	('observed', 'Reg', (62, 70))
100724	30487384	With the advances in pathological examination technology, the identification of translocations has enabled precise diagnoses and classifications of STS, and it has been suggested that the presence of and differences in translocations could be prognostic factors in some translocation-related sarcomas.	('translocations', 'Var', (80, 94))	('sarcomas', 'Phenotype', 'HP:0100242', (292, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('sarcomas', 'Disease', (292, 300))	('translocations', 'Var', (219, 233))	('sarcomas', 'Disease', 'MESH:D012509', (292, 300))	('STS', 'Phenotype', 'HP:0030448', (148, 151))
100727	30487384	In this review, we discuss the clinical significance of translocation-related sarcomas, including their diagnoses and targeted therapies.	('sarcomas', 'Disease', (78, 86))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('translocation-related', 'Var', (56, 77))
100732	30487384	About 10 years after the emergence of BCR-ABL therapy targeting CML, a new driver mutation based on fusion genes derived from chromosomal translocations was identified in solid tumors, i.e., EML4-ALK from t(2;5)(p23;q35) translocation.	('solid tumors', 'Disease', (171, 183))	('CML', 'Disease', 'MESH:D015464', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('CML', 'Phenotype', 'HP:0005506', (64, 67))	('t(2;5)(p23;q35) translocation', 'Var', (205, 234))	('ALK', 'Gene', (196, 199))	('CML', 'Disease', (64, 67))	('solid tumors', 'Disease', 'MESH:D009369', (171, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('BCR-ABL', 'Gene', (38, 45))	('t(2;5)(p23;q35)', 'STRUCTURAL_ABNORMALITY', 'None', (205, 220))	('BCR-ABL', 'Gene', '25', (38, 45))	('EML4', 'Gene', (191, 195))	('ALK', 'Gene', '238', (196, 199))	('EML4', 'Gene', '27436', (191, 195))
100733	30487384	Anaplastic lymphoma kinase (ALK)-related translocations are observed in only 2%-5% of non-small cell lung cancers (NSCLCs), but molecular-targeted therapy to ALK showed highly significant responses that were the same as those observed when targeting BCR-ABL in CML, bringing about a new paradigm of medical research and precision medicine.	('lung cancers', 'Phenotype', 'HP:0100526', (101, 113))	('BCR-ABL', 'Gene', (250, 257))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (86, 112))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (86, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('NSCLCs', 'Disease', 'MESH:D002289', (115, 121))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (90, 112))	('ALK', 'Gene', '238', (28, 31))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (0, 19))	('CML', 'Disease', 'MESH:D015464', (261, 264))	('responses', 'MPA', (188, 197))	('ALK', 'Gene', (28, 31))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (90, 113))	('Anaplastic lymphoma kinase', 'Gene', '238', (0, 26))	('CML', 'Disease', (261, 264))	('BCR-ABL', 'Gene', '25', (250, 257))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (86, 113))	('NSCLCs', 'Phenotype', 'HP:0030358', (115, 121))	('ALK', 'Gene', '238', (158, 161))	('molecular-targeted', 'Var', (128, 146))	('NSCLCs', 'Disease', (115, 121))	('ALK', 'Gene', (158, 161))	('Anaplastic lymphoma kinase', 'Gene', (0, 26))	('CML', 'Phenotype', 'HP:0005506', (261, 264))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('non-small cell lung cancers', 'Disease', (86, 113))
100734	30487384	There are many chromosomal translocations related to and/or detected in specific malignant diseases.	('detected', 'Reg', (60, 68))	('malignant diseases', 'Disease', (81, 99))	('malignant diseases', 'Disease', 'MESH:D009369', (81, 99))	('chromosomal translocations', 'Var', (15, 41))
100741	30487384	Approximately 300 gene fusions are known in mesenchymal tumors, and ~20% of the STS subtypes have chromosomal translocations; these are called translocation-related sarcomas (TRSs).	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (44, 62))	('mesenchymal tumors', 'Disease', (44, 62))	('STS', 'Phenotype', 'HP:0030448', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('sarcomas', 'Disease', (165, 173))	('chromosomal translocations', 'Var', (98, 124))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('sarcomas', 'Disease', 'MESH:D012509', (165, 173))
100745	30487384	The results of other retrospective analyses suggest a relationship between the response to trabectedin and its DNA repair function:including mutations in BRCA (breast cancer susceptibility gene), which are well known as risk factors of hereditary cancers.	('BRCA', 'Gene', '672', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('mutations', 'Var', (141, 150))	('hereditary cancers', 'Disease', (236, 254))	('BRCA', 'Gene', (154, 158))	('trabectedin', 'Chemical', 'MESH:D000077606', (91, 102))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('hereditary cancers', 'Disease', 'MESH:D009369', (236, 254))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('DNA', 'MPA', (111, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
100752	30487384	Other subtypes of Ewing family sarcomas usually have fusion proteins derived from the translocations of EWSR1 (Ewing sarcoma breakpoint region 1, also known as EWS).	('EWS', 'Gene', '2130', (104, 107))	('fusion proteins', 'Protein', (53, 68))	('EWS', 'Gene', (104, 107))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (111, 144))	('translocations', 'Var', (86, 100))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('EWSR1', 'Gene', (104, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Ewing family sarcomas', 'Disease', 'MESH:C563168', (18, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('EWS', 'Gene', '2130', (160, 163))	('EWS', 'Gene', (160, 163))	('Ewing family sarcomas', 'Phenotype', 'HP:0012254', (18, 39))	('EWSR1', 'Gene', '2130', (104, 109))	('Ewing family sarcomas', 'Disease', (18, 39))	('Ewing sarcoma breakpoint region 1', 'Gene', (111, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
100768	30487384	The IGF1R pathway is deregulated by the EWSR1-FLI1 translocation, which makes this pathway a potential target for therapy.	('EWSR1', 'Gene', '2130', (40, 45))	('IGF1R', 'Gene', (4, 9))	('translocation', 'Var', (51, 64))	('FLI1', 'Gene', (46, 50))	('EWSR1', 'Gene', (40, 45))	('FLI1', 'Gene', '2313', (46, 50))	('IGF1R', 'Gene', '3480', (4, 9))	('deregulated', 'Reg', (21, 32))
100776	30487384	Translocations with CIC, present at chromosome 19, were identified in some of these tumors, and CIC-arranged sarcoma is defined as a genetic variant of Ewing-like sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('Translocations', 'Var', (0, 14))	('CIC-arranged sarcoma', 'Disease', (96, 116))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('CIC', 'Gene', '23152', (20, 23))	('Ewing-like sarcoma', 'Disease', (152, 170))	('CIC', 'Gene', '23152', (96, 99))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (152, 170))	('CIC-arranged sarcoma', 'Disease', 'MESH:D012509', (96, 116))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (152, 170))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('CIC', 'Gene', (20, 23))	('CIC', 'Gene', (96, 99))
100783	30487384	As DSRCTs harbor EWSR1-related translocations, they could be examined in clinical trials that target EWSR1 or its surrounding signaling molecules along with other Ewing-family tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('translocations', 'Var', (31, 45))	('EWSR1', 'Gene', (101, 106))	('Ewing-family tumors', 'Disease', (163, 182))	('Ewing-family tumors', 'Disease', 'MESH:C563168', (163, 182))	('EWSR1', 'Gene', '2130', (17, 22))	('DSRCTs', 'Disease', (3, 9))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('EWSR1', 'Gene', '2130', (101, 106))	('EWSR1', 'Gene', (17, 22))
100787	30487384	Chromosomal translocation is observed particularly in alveolar rhabdomyosarcoma, including two patterns of translocations: t(2;13)(q35;q14) with the PAX3-FOXO1 fusion gene, and t(1;13)(p36;q14) with the PAX7-FOXO1 fusion gene.	('FOXO1', 'Gene', (208, 213))	('FOXO1', 'Gene', '2308', (208, 213))	('PAX3', 'Gene', (149, 153))	('FOXO1', 'Gene', '2308', (154, 159))	('t(2;13)(q35;q14', 'Var', (123, 138))	('PAX3', 'Gene', '5077', (149, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('FOXO1', 'Gene', (154, 159))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (63, 79))	('alveolar rhabdomyosarcoma', 'Disease', (54, 79))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (54, 79))	('PAX7', 'Gene', (203, 207))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (123, 139))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (177, 193))	('t(1;13)(p36;q14', 'Var', (177, 192))	('PAX7', 'Gene', '5081', (203, 207))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (54, 79))
100794	30487384	It was suggested that the presence of detectable fusion genes involving FOXO1 could be the predictive factor of poor prognosis in lymph node-positive alveolar rhabdomyosarcoma.	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (150, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (150, 175))	('fusion genes', 'Var', (49, 61))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (159, 175))	('FOXO1', 'Gene', (72, 77))	('FOXO1', 'Gene', '2308', (72, 77))	('alveolar rhabdomyosarcoma', 'Disease', (150, 175))	('presence', 'Var', (26, 34))
100795	30487384	In terms of the differences in translocations, for both non-metastatic and metastatic alveolar rhabdomyosarcoma patients, the translocation of PAX3-FOXO1 was suggested to result in shorter survival than PAX7-FOXO1 translocation.	('survival', 'MPA', (189, 197))	('FOXO1', 'Gene', (208, 213))	('translocation', 'Var', (126, 139))	('FOXO1', 'Gene', '2308', (208, 213))	('alveolar rhabdomyosarcoma', 'Disease', (86, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('shorter', 'NegReg', (181, 188))	('PAX3', 'Gene', '5077', (143, 147))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (95, 111))	('PAX3', 'Gene', (143, 147))	('patients', 'Species', '9606', (112, 120))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (86, 111))	('PAX7', 'Gene', (203, 207))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (86, 111))	('FOXO1', 'Gene', (148, 153))	('FOXO1', 'Gene', '2308', (148, 153))	('PAX7', 'Gene', '5081', (203, 207))
100805	30487384	ALK-related mutations, which are well known in lung cancer as noted in the Introduction, are also seen in rhabdomyosarcoma, especially in the alveolar type; an ALK gene copy number gain is detected in the vast majority of alveolar rhabdomyosarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (222, 247))	('rhabdomyosarcoma', 'Disease', (106, 122))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (222, 248))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (231, 248))	('rhabdomyosarcoma', 'Disease', (231, 247))	('lung cancer', 'Disease', (47, 58))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (106, 122))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (106, 122))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (231, 247))	('ALK', 'Gene', '238', (160, 163))	('alveolar rhabdomyosarcomas', 'Disease', (222, 248))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (231, 247))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('gain', 'PosReg', (181, 185))	('ALK', 'Gene', '238', (0, 3))	('sarcomas', 'Phenotype', 'HP:0100242', (240, 248))	('ALK', 'Gene', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('mutations', 'Var', (12, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('ALK', 'Gene', (0, 3))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (222, 248))	('copy number', 'Var', (169, 180))
100806	30487384	However, these mutations are genetic aberrations at the mRNA level in the specific domain of the ALK gene, and they are different from the ALK-related translocations observed in NSCLCs and inflammatory myofibroblastic tumors as we will discuss below in Section 2.7.	('ALK', 'Gene', (139, 142))	('inflammatory myofibroblastic tumors', 'Disease', (189, 224))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (202, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('mutations', 'Var', (15, 24))	('NSCLCs', 'Disease', 'MESH:D002289', (178, 184))	('ALK', 'Gene', '238', (97, 100))	('NSCLCs', 'Phenotype', 'HP:0030358', (178, 184))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (202, 224))	('ALK', 'Gene', '238', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ALK', 'Gene', (97, 100))	('NSCLCs', 'Disease', (178, 184))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (189, 224))
100809	30487384	An unbalanced chromosomal translocation, t(X;17)(p11;q25), is characteristic of ASPS, and it is also found in pediatric papillary renal cell cancers.	('found', 'Reg', (101, 106))	('pediatric papillary renal cell cancers', 'Disease', 'MESH:C538614', (110, 148))	('ASPS', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (41, 57))	('pediatric papillary renal cell cancers', 'Disease', (110, 148))	('ASPS', 'Gene', '79058', (80, 84))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('t(X;17)(p11;q25', 'Var', (41, 56))	('ASPS', 'Phenotype', 'HP:0012218', (80, 84))
100810	30487384	The translocation t(X;17)(p11;q25) includes the fusion of ASPL-TFE3, which brings the TFE3 DNA-binding domain, implicating transcriptional deregulation in the pathogenesis of ASPS.	('TFE3', 'Gene', (86, 90))	('ASPS', 'Gene', '79058', (175, 179))	('TFE3', 'Gene', '7030', (63, 67))	('fusion', 'Var', (48, 54))	('TFE3', 'Gene', '7030', (86, 90))	('ASPL', 'Gene', '79058', (58, 62))	('t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (18, 34))	('ASPS', 'Phenotype', 'HP:0012218', (175, 179))	('TFE3', 'Gene', (63, 67))	('ASPS', 'Gene', (175, 179))	('ASPL', 'Gene', (58, 62))
100830	30487384	Clinical trials of EZH2 inhibitors have begun, along with investigations of these inhibitors for STS, including synovial sarcoma.	('synovial sarcoma', 'Disease', (112, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('inhibitors', 'Var', (24, 34))	('EZH2', 'Gene', '2146', (19, 23))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (112, 128))	('synovial sarcoma', 'Disease', 'MESH:D013584', (112, 128))	('EZH2', 'Gene', (19, 23))	('STS', 'Phenotype', 'HP:0030448', (97, 100))
100832	30487384	Despite the high expression of NY-ESO-1 and expected responses to immunotherapy, immune checkpoint inhibitors, including anti-PD-1 (programmed death-1) or -PD-L1 (programmed death-ligand 1) antibodies, did not produce meaningful clinical responses in patients with synovial sarcomas.	('NY-ESO-1', 'Gene', '246100', (31, 39))	('PD-L1', 'Gene', (156, 161))	('anti-PD-1', 'Var', (121, 130))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (265, 282))	('patients', 'Species', '9606', (251, 259))	('PD-L1', 'Gene', '29126', (156, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (274, 282))	('synovial sarcomas', 'Disease', (265, 282))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('NY-ESO-1', 'Gene', (31, 39))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (265, 281))	('synovial sarcomas', 'Disease', 'MESH:D013584', (265, 282))
100838	30487384	These fusion genes act as abnormal transcription factors, and they generate tumor progression.	('generate', 'Reg', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('fusion', 'Var', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
100846	30487384	The key distinctive factor of CCS and melanoma is the t(12;22)(q13;q12) translocation, which is almost observed in CCS, but not in malignant melanoma.	('CCS', 'Disease', (115, 118))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Disease', (141, 149))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (54, 71))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('CCS', 'Disease', (30, 33))	('malignant melanoma', 'Phenotype', 'HP:0002861', (131, 149))	('malignant melanoma', 'Disease', (131, 149))	('t(12;22)(q13', 'Var', (54, 66))	('malignant melanoma', 'Disease', 'MESH:D008545', (131, 149))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
100848	30487384	BRAF and NRAS mutations (which are important treatment targets in malignant melanoma) are not usually observed in CCS, although there is an exceptional CCS case that harbored BRAF mutation and responded to BRAF-targeted therapy.	('malignant melanoma', 'Phenotype', 'HP:0002861', (66, 84))	('NRAS', 'Gene', (9, 13))	('BRAF', 'Gene', (175, 179))	('malignant melanoma', 'Disease', 'MESH:D008545', (66, 84))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (175, 179))	('malignant melanoma', 'Disease', (66, 84))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', '673', (206, 210))	('BRAF', 'Gene', (206, 210))	('mutation', 'Var', (180, 188))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
100849	30487384	Immune checkpoint inhibitors, including anti-PD-1, anti-PD-L1, and anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibodies, have become the standard therapy for malignant melanoma.	('PD-L1', 'Gene', '29126', (56, 61))	('CTLA-4', 'Gene', (72, 78))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('malignant melanoma', 'Disease', 'MESH:D008545', (174, 192))	('malignant melanoma', 'Phenotype', 'HP:0002861', (174, 192))	('malignant melanoma', 'Disease', (174, 192))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (80, 123))	('CTLA-4', 'Gene', '1493', (72, 78))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (80, 123))	('anti-PD-1', 'Var', (40, 49))	('PD-L1', 'Gene', (56, 61))
100861	30487384	The translocation of t(12;15)(p13;q25), resulting in the fusion gene ETV6-NTRK3, is related to infantile fibrosarcoma, which occurs in infants.	('translocation', 'Var', (4, 17))	('related', 'Reg', (84, 91))	('ETV6', 'Gene', (69, 73))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (105, 117))	('NTRK3', 'Gene', '4916', (74, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('t(12;15)(p13;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (21, 38))	('infantile fibrosarcoma', 'Disease', (95, 117))	('ETV6', 'Gene', '2120', (69, 73))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (95, 117))	('NTRK3', 'Gene', (74, 79))	('infants', 'Species', '9606', (135, 142))
100866	30487384	NTRK inhibitors, such as larotrectinib (LOXO-101) and entrectinib, are under investigation, and in early-phase clinical trials, they have produced excellent responses in cancers with NTRK-related translocations.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('TRK', 'Gene', (184, 187))	('TRK', 'Gene', (1, 4))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('entrectinib', 'Chemical', 'MESH:C000607349', (54, 65))	('larotrectinib', 'Chemical', 'MESH:C000609083', (25, 38))	('TRK', 'Gene', '7170', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('TRK', 'Gene', '7170', (1, 4))	('translocations', 'Var', (196, 210))	('LOXO-101', 'Chemical', 'MESH:C000609083', (40, 48))
100870	30487384	Other than TRS described above, STS known to have their specific translocations includes myxoinflammatory fibroblastic sarcoma with t(1;10)(p22-31;q24-25), low-grade fibromyxoid sarcoma with t(7;16)(q33;p11), extraskeletal myxoid chondrosarcoma with t(9;22)(q22;q12), and, moreover, there are many benign tumors with specific translocations.	('fibromyxoid sarcoma', 'Disease', (166, 185))	('t(9;22)(q22;q12', 'Var', (250, 265))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (223, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('p22', 'Gene', (140, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('myxoid chondrosarcoma', 'Disease', (223, 244))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (230, 244))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (166, 185))	('sarcoma', 'Disease', (178, 185))	('p22', 'Gene', '11331', (140, 143))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	('t(7;16)(q33;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (191, 207))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumors', 'Disease', (305, 311))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('t(9;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (250, 266))	('STS', 'Phenotype', 'HP:0030448', (32, 35))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Disease', (237, 244))	('tumors', 'Disease', 'MESH:D009369', (305, 311))
100876	30487384	In another study, integrative genomic and transcriptome analyses unveiled some translocations in leiomyosarcoma, which was not previously regarded as a TRS.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (97, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (97, 111))	('translocations', 'Var', (79, 93))	('leiomyosarcoma', 'Disease', (97, 111))
100877	30487384	Investigators could thus use tumor tissues with rare mutations, including translocations, and lower the thresholds for developing new drugs to treat patients with such mutations.	('patients', 'Species', '9606', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('translocations', 'Var', (74, 88))
100910	29433465	The complex neoplasia group consists of tumours of uncertain differentiation according to the WHO classification 2002 (complex mixed and stromal neoplasia (ICD-O-3 Morphology (ICD-O-3 M) 8930-8991), synovial-like neoplasms (9040-9044)) and the malignant glomus tumour (8711).	('neoplasia', 'Disease', (145, 154))	('stromal neoplasia', 'Disease', (137, 154))	('neoplasia', 'Phenotype', 'HP:0002664', (12, 21))	('synovial-like neoplasms', 'Phenotype', 'HP:0012570', (199, 222))	('neoplasms', 'Disease', 'MESH:D009369', (213, 222))	('stromal neoplasia', 'Disease', 'MESH:D009369', (137, 154))	('tumours', 'Disease', (40, 47))	('neoplasia', 'Phenotype', 'HP:0002664', (145, 154))	('malignant glomus tumour', 'Disease', 'MESH:D009369', (244, 267))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('neoplasms', 'Disease', (213, 222))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('neoplasia', 'Disease', 'MESH:D009369', (12, 21))	('9040-9044', 'Var', (224, 233))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('neoplasia', 'Disease', (12, 21))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('malignant glomus tumour', 'Disease', (244, 267))	('neoplasia', 'Disease', 'MESH:D009369', (145, 154))	('neoplasms', 'Phenotype', 'HP:0002664', (213, 222))
100998	27607470	Gastrointestinal stromal tumour (GIST) was historically classified as gastrointestinal leiomyosarcoma before the identification of activating mutations in KIT by and the immunohistochemical association, with interstitial cells of Cajal by Kindblom and others in the late 1990s.	('Gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (0, 31))	('GIST', 'Phenotype', 'HP:0100723', (33, 37))	('mutations', 'Var', (142, 151))	('KIT by', 'Gene', (155, 161))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('gastrointestinal leiomyosarcoma', 'Disease', (70, 101))	('Gastrointestinal stromal tumour', 'Disease', (0, 31))	('Gastrointestinal stromal tumour', 'Disease', 'MESH:D046152', (0, 31))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (87, 101))	('gastrointestinal leiomyosarcoma', 'Disease', 'MESH:D007890', (70, 101))
101049	27607470	The high expression of PDGFRA is associated with group II tumours, and is associated with the sensitivity to tyrosine kinase inhibitors.	('II tumours', 'Disease', 'MESH:D009369', (55, 65))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('sensitivity to tyrosine kinase inhibitors', 'MPA', (94, 135))	('II tumours', 'Disease', (55, 65))	('associated', 'Reg', (33, 43))	('high', 'Var', (4, 8))	('PDGFRA', 'Gene', '5156', (23, 29))	('PDGFRA', 'Gene', (23, 29))	('associated', 'Reg', (74, 84))
101059	27607470	Also included in these 16 additional genes was the gene for D10S170 DNA fragment (clone 563392, now called CCDC6 coiled-coil domain containing 6), which was present immediately next to the 'leio-subclass' genes in the gene dendrogram from and also showed similar expression pattern to these genes.	('CCDC6', 'Gene', '8030', (107, 112))	('CCDC6', 'Gene', (107, 112))	('D10S170 DNA', 'Var', (60, 71))
101129	27512674	Interestingly, some of the common cellular pathway alterations found in neoplasms allow viruses to productively and selectively infect tumor cells (Figure 1).	('alterations', 'Var', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('infect tumor', 'Disease', 'MESH:D009369', (128, 140))	('neoplasms allow viruses', 'Disease', (72, 95))	('cellular pathway', 'Pathway', (34, 50))	('neoplasms allow viruses', 'Disease', 'MESH:D009369', (72, 95))	('neoplasm', 'Phenotype', 'HP:0002664', (72, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))	('infect tumor', 'Disease', (128, 140))
101130	27512674	Several tumor cells have mutations in key components of intracellular signaling pathways which block apoptosis and/or promote proliferation, making them susceptible to viral infection.	('intracellular signaling pathways', 'Pathway', (56, 88))	('proliferation', 'CPA', (126, 139))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('viral infection', 'Disease', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('apoptosis', 'CPA', (101, 110))	('promote', 'PosReg', (118, 125))	('block', 'NegReg', (95, 100))	('viral infection', 'Disease', 'MESH:D001102', (168, 183))	('susceptible', 'Reg', (153, 164))
101138	27512674	Aberrant cytokine patterns in the tumor microenvironment may severely limit an antitumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (34, 39))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (83, 88))	('limit', 'NegReg', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
101143	27512674	Indeed, oncolytic viruses that eliminate xenografts in murine cancer models have been shown to induce an antitumor immune memory that prevents re-engraftment of the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('prevents', 'NegReg', (134, 142))	('viruses', 'Var', (18, 25))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('murine', 'Species', '10090', (55, 61))	('induce', 'PosReg', (95, 101))	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', (165, 170))
101147	27512674	Additionally, genetically altered oncolytic viruses can be used to target chemotherapeutics to the tumor and minimize the systemic effects of the drugs.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('genetically', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))
101153	27512674	More importantly for oncolytic virus research, studies have been published that report the safety profiles of replicating MYXV, modified adenovirus, and attenuated vesicular stomatitis and Semliki Forest viruses in healthy dogs (Table 4).	('MYXV', 'Species', '10273', (122, 126))	('stomatitis', 'Phenotype', 'HP:0010280', (174, 184))	('dogs', 'Species', '9615', (223, 227))	('Semliki Forest virus', 'Species', '11033', (189, 209))	('modified', 'Var', (128, 136))	('attenuated vesicular stomatitis', 'Disease', (153, 184))	('attenuated vesicular stomatitis', 'Disease', 'MESH:D054243', (153, 184))
101158	27512674	For example, CAV1 is the cause of infectious canine hepatitis.	('hepatitis', 'Disease', (52, 61))	('hepatitis', 'Phenotype', 'HP:0012115', (52, 61))	('CAV1', 'Var', (13, 17))	('CAV', 'Species', '10537', (13, 16))	('hepatitis', 'Disease', 'MESH:D056486', (52, 61))	('cause', 'Reg', (25, 30))	('canine', 'Species', '9615', (45, 51))
101166	27512674	When functional components encoded by CAV2 were inserted genetically into CRAd5, virus replication in canine osteosarcoma cells was improved and increased expression of a reporter gene encoded by the virus was observed in a murine xenograft model of canine osteosarcoma.	('canine', 'Species', '9615', (250, 256))	('virus replication', 'MPA', (81, 98))	('osteosarcoma', 'Disease', (257, 269))	('expression', 'Species', '29278', (155, 165))	('osteosarcoma', 'Disease', 'MESH:D012516', (257, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (262, 269))	('Ad5', 'Gene', '8081', (76, 79))	('osteosarcoma', 'Phenotype', 'HP:0002669', (109, 121))	('increased', 'PosReg', (145, 154))	('improved', 'PosReg', (132, 140))	('CAV', 'Species', '10537', (38, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (257, 269))	('inserted', 'Var', (48, 56))	('Ad5', 'Gene', (76, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('expression', 'MPA', (155, 165))	('murine', 'Species', '10090', (224, 230))	('canine', 'Species', '9615', (102, 108))	('osteosarcoma', 'Disease', (109, 121))	('osteosarcoma', 'Disease', 'MESH:D012516', (109, 121))
101167	27512674	Similarly, a CRAd that expresses canine p53 inhibited the growth of canine cancer cells and tumors in two murine xenograft models of canine osteosarcoma.	('canine', 'Species', '9615', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('osteosarcoma', 'Disease', (140, 152))	('osteosarcoma', 'Disease', 'MESH:D012516', (140, 152))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('inhibited', 'NegReg', (44, 53))	('canine', 'Species', '9615', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('canine p53', 'Var', (33, 43))	('tumors', 'Disease', (92, 98))	('growth of canine', 'Phenotype', 'HP:0012738', (58, 74))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (140, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('cancer', 'Disease', (75, 81))	('canine', 'Species', '9615', (133, 139))	('murine', 'Species', '10090', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('growth', 'CPA', (58, 64))
101189	27512674	A recombinant CAV2 virus with disruption of E1a, modification of cell receptor tropism, and hyaluronidase expression was evaluated in canine osteosarcoma and melanoma cell lines, murine xenograft models of canine osteosarcoma and melanoma, and in cancer-bearing dogs.	('osteosarcoma', 'Disease', (213, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('osteosarcoma', 'Disease', 'MESH:D012516', (213, 225))	('cancer', 'Disease', (247, 253))	('osteosarcoma', 'Disease', (141, 153))	('osteosarcoma', 'Disease', 'MESH:D012516', (141, 153))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanoma', 'Disease', (230, 238))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('disruption', 'Var', (30, 40))	('dogs', 'Species', '9615', (262, 266))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('osteosarcoma', 'Phenotype', 'HP:0002669', (213, 225))	('E1a', 'Gene', (44, 47))	('osteosarcoma', 'Phenotype', 'HP:0002669', (141, 153))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('canine', 'Species', '9615', (134, 140))	('CAV', 'Species', '10537', (14, 17))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('murine', 'Species', '10090', (179, 185))	('canine', 'Species', '9615', (206, 212))	('expression', 'Species', '29278', (106, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))
101213	27512674	Genetic manipulation of VACV has produced attenuated viruses with improved targeting of malignant cells and antitumor effects.	('targeting', 'MPA', (75, 84))	('VACV', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('improved', 'PosReg', (66, 74))	('Genetic manipulation', 'Var', (0, 20))	('VACV', 'Species', '10245', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))
101216	27512674	Vaccinia viral recombinants with deletion of three viral genes have been shown to replicate in canine tumor cells and significantly decrease tumor volume in murine xenograft models of canine mammary tumors and soft tissue sarcoma.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumors', 'Disease', (199, 205))	('soft tissue sarcoma', 'Disease', (210, 229))	('deletion', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('decrease', 'NegReg', (132, 140))	('canine', 'Species', '9615', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('murine', 'Species', '10090', (157, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('tumor', 'Disease', (199, 204))	('canine', 'Species', '9615', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (141, 146))	('Vaccinia', 'Species', '10245', (0, 8))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (210, 229))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (210, 229))
101223	27512674	Variations of a recombinant VACV with deletion of genes encoding thymidine kinase and vaccinia growth factor (vvdd) have shown positive results in many murine xenograft models of human cancer.	('human', 'Species', '9606', (179, 184))	('murine', 'Species', '10090', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('vvdd', 'Gene', (110, 114))	('VACV', 'Species', '10245', (28, 32))	('Variations', 'Var', (0, 10))	('vaccinia', 'Species', '10245', (86, 94))	('deletion', 'Var', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
101232	27512674	A pilot study to assess the safety of MYXV deleted for serp2 (MYXVDeltaserp2) in dogs with soft tissue sarcomas is currently underway at the Colorado State University College of Veterinary Medicine and Biomedical Sciences (Fort Collins, CO, USA).	('dogs', 'Species', '9615', (81, 85))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (91, 110))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('MYXV', 'Var', (38, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (91, 110))	('sarcomas', 'Disease', (103, 111))	('MYXV', 'Species', '10273', (38, 42))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (91, 111))	('MYXV', 'Species', '10273', (62, 66))	('soft tissue sarcoma', 'Disease', (91, 110))
101266	27354810	Dimerization leads to autophosphorylation of intracellular tyrosines, initiating signal transduction.	('Dimerization', 'Var', (0, 12))	('tyrosines', 'Chemical', 'MESH:D014443', (59, 68))	('initiating', 'Reg', (70, 80))	('autophosphorylation of intracellular tyrosines', 'MPA', (22, 68))	('leads to', 'Reg', (13, 21))
101401	27354810	At the time of the primary analysis, the study achieved its primary objective: median PFS was 4.6 months among the group receiving pazopanib versus 1.6 months in those receiving placebo.	('pazopanib', 'Var', (131, 140))	('pazopanib', 'Chemical', 'MESH:C516667', (131, 140))	('PFS', 'MPA', (86, 89))
101408	27354810	In addition, normal hemoglobin at baseline was also associated with longer PFS and OS.	('PFS', 'Disease', (75, 78))	('normal', 'Var', (13, 19))	('OS', 'Chemical', '-', (83, 85))	('hemoglobin', 'MPA', (20, 30))
101421	27354810	Thromboembolic adverse events occurred in 13 (5%) pazopanib-treated patients versus three (2%) placebo-treated patients.	('Thromboembolic adverse', 'Disease', (0, 22))	('pazopanib-treated', 'Var', (50, 67))	('Thromboembolic adverse', 'Disease', 'MESH:D013923', (0, 22))	('patients', 'Species', '9606', (68, 76))	('pazopanib', 'Chemical', 'MESH:C516667', (50, 59))	('Thromboembolic adverse events', 'Phenotype', 'HP:0001907', (0, 29))	('patients', 'Species', '9606', (111, 119))
101437	27354810	Studies of HRQoL and cost-effectiveness highlight important facts regarding pazopanib in soft tissue sarcoma: pazopanib has some significant toxicity; it is an expensive drug; and, when administered without targeting to patients requiring salvage therapy, it is only modestly active.	('pazopanib', 'Var', (110, 119))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (89, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (89, 108))	('patients', 'Species', '9606', (220, 228))	('pazopanib', 'Chemical', 'MESH:C516667', (76, 85))	('pazopanib', 'Chemical', 'MESH:C516667', (110, 119))	('toxicity', 'Disease', (141, 149))	('toxicity', 'Disease', 'MESH:D064420', (141, 149))	('soft tissue sarcoma', 'Disease', (89, 108))
101455	27354810	The authors identified good performance status, low or intermediate tumor grade, and a normal hemoglobin level at baseline as being associated with improved long-term outcomes.	('tumor', 'Disease', (68, 73))	('improved', 'PosReg', (148, 156))	('normal hemoglobin level', 'MPA', (87, 110))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('low', 'Var', (48, 51))
101472	27354810	Analysis of TP53 in enrolled patients was undertaken to identify those with specific TP53 mutations to determine whether they were more or less susceptible to this combination.	('TP53', 'Gene', (85, 89))	('patients', 'Species', '9606', (29, 37))	('mutations', 'Var', (90, 99))	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', '7157', (85, 89))	('TP53', 'Gene', (12, 16))
101480	27354810	In multivariate Cox analysis to predict patients qualifying as having clinical benefit (partial response or stable disease in at least 6 months), only hypoalbuminemia and lack of a mutation in one of the "hotspots" of TP53 were associated with a lower rate of clinical benefit.	('patients', 'Species', '9606', (40, 48))	('hypoalbuminemia', 'Disease', (151, 166))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (151, 166))	('lack', 'Var', (171, 175))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (151, 166))	('TP53', 'Gene', '7157', (218, 222))	('mutation', 'Var', (181, 189))	('Cox', 'Gene', '1351', (16, 19))	('TP53', 'Gene', (218, 222))	('Cox', 'Gene', (16, 19))
101483	27354810	In an analysis aggregating the 23 sarcoma patients and 14 colorectal cancer patients in the study, improved PFS and OS were reported for the group possessing a "hotspot" TP53 mutation versus those lacking such a mutation.	('patients', 'Species', '9606', (76, 84))	('sarcoma', 'Disease', (34, 41))	('improved', 'PosReg', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('colorectal cancer', 'Phenotype', 'HP:0003003', (58, 75))	('mutation', 'Var', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PFS', 'MPA', (108, 111))	('TP53', 'Gene', '7157', (170, 174))	('colorectal cancer', 'Disease', (58, 75))	('TP53', 'Gene', (170, 174))	('OS', 'Chemical', '-', (116, 118))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (58, 75))	('patients', 'Species', '9606', (42, 50))
101511	27354810	The answer could be biological in nature, with pazopanib having some inhibitory property that other agents lack.	('inhibitory property', 'MPA', (69, 88))	('pazopanib', 'Var', (47, 56))	('pazopanib', 'Chemical', 'MESH:C516667', (47, 56))
101535	27354810	The data of Fu et al indicated that "hotspot" mutations in TP53 of patients with either sarcoma or colorectal cancer enrolled in their Phase I clinical trial correlated with a higher probability of benefit.	('mutations', 'Var', (46, 55))	('TP53', 'Gene', (59, 63))	('patients', 'Species', '9606', (67, 75))	('colorectal cancer', 'Disease', (99, 116))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('sarcoma', 'Disease', (88, 95))	('benefit', 'PosReg', (198, 205))	('TP53', 'Gene', '7157', (59, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
101542	27354810	Pazopanib is associated with significant toxicities, including fatigue, nausea, vomiting, hypertension, thromboembolic events, and reduced cardiac ejection fraction.	('vomiting', 'Disease', 'MESH:D014839', (80, 88))	('fatigue', 'Disease', (63, 70))	('fatigue', 'Phenotype', 'HP:0012378', (63, 70))	('reduced', 'NegReg', (131, 138))	('nausea', 'Phenotype', 'HP:0002018', (72, 78))	('Pazopanib', 'Var', (0, 9))	('vomiting', 'Disease', (80, 88))	('vomiting', 'Phenotype', 'HP:0002013', (80, 88))	('reduced cardiac ejection fraction', 'Phenotype', 'HP:0012664', (131, 164))	('nausea', 'Disease', (72, 78))	('thromboembolic events', 'Phenotype', 'HP:0001907', (104, 125))	('toxicities', 'Disease', 'MESH:D064420', (41, 51))	('hypertension', 'Disease', 'MESH:D006973', (90, 102))	('fatigue', 'Disease', 'MESH:D005221', (63, 70))	('toxicities', 'Disease', (41, 51))	('hypertension', 'Disease', (90, 102))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('thromboembolic', 'Disease', 'MESH:D013923', (104, 118))	('nausea', 'Disease', 'MESH:D009325', (72, 78))	('cardiac ejection fraction', 'MPA', (139, 164))	('hypertension', 'Phenotype', 'HP:0000822', (90, 102))	('thromboembolic', 'Disease', (104, 118))
101556	25341583	Patients who carry a germline p53 gene mutation (Li Fraumeni syndrome) have an increased risk of soft tissue sarcoma, including uterine LMS, as well as other cancers.	('mutation', 'Var', (39, 47))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (97, 116))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (97, 116))	('cancers', 'Disease', (158, 165))	('soft tissue sarcoma', 'Disease', (97, 116))	('p53', 'Gene', (30, 33))	('Patients', 'Species', '9606', (0, 8))	('p53', 'Gene', '7157', (30, 33))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (49, 69))	('Li Fraumeni syndrome', 'Disease', (49, 69))	('uterine LMS', 'Disease', (128, 139))
101557	25341583	Patients with Rb mutations who are survivors of childhood retinoblastoma, and survivors of childhood rhabdomyosarcoma, or other childhood cancers whose treatment involves radiation, have an increased risk secondary cancers, including uterine LMS.	('rhabdomyosarcoma', 'Disease', (101, 117))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (101, 117))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('retinoblastoma', 'Phenotype', 'HP:0009919', (58, 72))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('cancers', 'Disease', (215, 222))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('Patients', 'Species', '9606', (0, 8))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (101, 117))	('childhood retinoblastoma', 'Disease', (48, 72))	('mutations', 'Var', (17, 26))	('childhood retinoblastoma', 'Disease', 'MESH:D012175', (48, 72))	('uterine LMS', 'Disease', (234, 245))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
101558	25341583	The familial syndrome hereditary leiomyomatosis with renal cell carcinoma (HLRCC), in which there are germline mutations in fumarate hydratase, has also been associated with an increased risk of uterine LMS.	('mutations', 'Var', (111, 120))	('associated', 'Reg', (158, 168))	('familial syndrome hereditary leiomyomatosis', 'Disease', (4, 47))	('renal cell carcinoma', 'Disease', (53, 73))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('uterine LMS', 'Disease', (195, 206))	('familial syndrome hereditary leiomyomatosis', 'Disease', 'MESH:C535516', (4, 47))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (53, 73))	('fumarate hydratase', 'Gene', '2271', (124, 142))	('fumarate hydratase', 'Gene', (124, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
101734	21921781	Thus TNFAIP2 is a novel marker of normal and neoplastic dendritic cells and histiocytes and we propose that the aberrant expression of TNFAIP2 by the malignant cells of cHL and PMBL can serve as a useful marker for distinguishing these tumor types from their morphologic and immunophenotypic mimics in routine surgical pathology practice.	('aberrant', 'Var', (112, 120))	('BL', 'Phenotype', 'HP:0030080', (179, 181))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (236, 241))	('TNFAIP2', 'Gene', (135, 142))
101877	28634564	The sensitivity and specificity of the polyclonal PAX8 antibody in a large cohort of epithelial tumors as well as lymphomas have been previously determined, the latter because polyclonal PAX8 is known to be immunoreactive in nonneoplastic B-cell lymphocytes which are often used as the positive internal control for immunohistochemistry.	('polyclonal', 'Var', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lymphomas', 'Disease', (114, 123))	('tumors', 'Disease', (96, 102))	('epithelial tumors', 'Disease', (85, 102))	('tumor', 'Disease', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('lymphomas', 'Disease', 'MESH:D008223', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('epithelial tumors', 'Disease', 'MESH:D002277', (85, 102))	('lymphomas', 'Phenotype', 'HP:0002665', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))
101885	28634564	Accordingly, polyclonal PAX8 (but not monoclonal PAX8) has been shown to be a sensitive and relatively specific marker of B-cell lymphomas (versus non-B-cell lymphomas) due to cross reaction with PAX5/B-cell specific activation protein (BSAP).	('BSAP', 'Gene', (237, 241))	('lymphomas', 'Phenotype', 'HP:0002665', (158, 167))	('lymphoma', 'Phenotype', 'HP:0002665', (129, 137))	('B-cell specific activation protein', 'Gene', (201, 235))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (122, 138))	('B-cell lymphomas', 'Disease', (122, 138))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (122, 138))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (151, 167))	('lymphomas', 'Phenotype', 'HP:0002665', (129, 138))	('B-cell lymphomas', 'Disease', (151, 167))	('polyclonal PAX8', 'Var', (13, 28))	('BSAP', 'Gene', '5079', (237, 241))	('PAX5', 'Gene', (196, 200))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (151, 167))	('lymphoma', 'Phenotype', 'HP:0002665', (158, 166))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (122, 137))	('B-cell specific activation protein', 'Gene', '5079', (201, 235))	('PAX5', 'Gene', '5079', (196, 200))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (151, 166))
101896	28634564	A subsequent round of immunohistochemistry (see Table 1 for antibody information) demonstrated that the neoplastic cells were positive for LCA (Figure 2(d)), CD20, PAX5/BSAP (Figure 2(e)), BCL6, and BCL2 (focal) and negative for CD3 and CD5 (Figure 2(f)).	('CD5', 'Gene', (237, 240))	('BCL2', 'Gene', '596', (199, 203))	('BCL6', 'Gene', (189, 193))	('CD20', 'Gene', '54474', (158, 162))	('CD5', 'Gene', '921', (237, 240))	('positive', 'Reg', (126, 134))	('LCA', 'Gene', (139, 142))	('CD20', 'Gene', (158, 162))	('PAX5/BSAP', 'Var', (164, 173))	('BCL2', 'Gene', (199, 203))	('LCA', 'Gene', '5788', (139, 142))	('BCL6', 'Gene', '604', (189, 193))
101909	24667836	Ewing sarcoma is characterised by translocations encoding fusion transcription factors with an EWSR1 transactivation domain fused to an ETS family DNA binding domain.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('translocations', 'Var', (34, 48))	('EWSR1', 'Gene', '2130', (95, 100))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('EWSR1', 'Gene', (95, 100))
101910	24667836	microRNAs are post-transcriptional regulators of gene expression and aberrantly expressed microRNAs have been identified as tumor suppressors or oncogenes in most cancer types.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('microRNAs', 'Gene', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('aberrantly expressed', 'Var', (69, 89))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
101913	24667836	In comparisons between Ewing sarcoma samples with EWS-FLI or EWS-ERG translocations, with differing dissemination characteristics and of primary samples and metastases no significantly differential expressed microRNAs were detected using various stringency criteria.	('Ewing sarcoma', 'Disease', (23, 36))	('translocations', 'Var', (69, 83))	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('ERG', 'Gene', '2078', (65, 68))	('FLI', 'Gene', (54, 57))	('ERG', 'Gene', (65, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (23, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (23, 36))	('EWS', 'Gene', '2130', (50, 53))	('EWS', 'Gene', (50, 53))	('EWS', 'Gene', '2130', (61, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('metastases', 'Disease', (157, 167))	('EWS', 'Gene', (61, 64))	('FLI', 'Gene', '2314', (54, 57))
101921	24667836	The typical genomic aberration in ES is a translocation between the EWSR1 gene and an ETS-family member with FLI1 in 85% and ERG in 5-10% of cases.	('translocation', 'Var', (42, 55))	('EWSR1', 'Gene', '2130', (68, 73))	('ERG', 'Gene', '2078', (125, 128))	('ERG', 'Gene', (125, 128))	('ES', 'Phenotype', 'HP:0012254', (34, 36))	('FLI1', 'Gene', (109, 113))	('FLI1', 'Gene', '2313', (109, 113))	('EWSR1', 'Gene', (68, 73))
101923	24667836	In ES cell lines EWS-FLI1 knockdown results in a MSC-like gene expression pattern and expression of EWS-FLI1 in heterologous cell types has shown that only MSCs of either mesodermal or neural crest origin are permissive for EWS-FLI1.	('EWS', 'Gene', '2130', (224, 227))	('EWS', 'Gene', (224, 227))	('FLI1', 'Gene', (104, 108))	('FLI1', 'Gene', '2313', (21, 25))	('FLI1', 'Gene', '2313', (104, 108))	('EWS', 'Gene', '2130', (100, 103))	('results in', 'Reg', (36, 46))	('FLI1', 'Gene', (228, 232))	('knockdown', 'Var', (26, 35))	('MSC-like gene expression pattern', 'MPA', (49, 81))	('FLI1', 'Gene', '2313', (228, 232))	('EWS', 'Gene', '2130', (17, 20))	('EWS', 'Gene', (17, 20))	('ES', 'Phenotype', 'HP:0012254', (3, 5))	('FLI1', 'Gene', (21, 25))	('EWS', 'Gene', (100, 103))
101925	24667836	microRNAs (miRNAs) are 18-25 nucleotide long non-coding RNA that act as post-transcriptional regulators of gene expression by hybridizing to complementary target-mRNA regions causing inhibition of translation with or without degradation of the mRNA.	('hybridizing', 'Var', (126, 137))	('inhibition', 'NegReg', (183, 193))	('translation', 'MPA', (197, 208))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))
101950	24667836	ES cell lines were transiently transfected with mirVana miRNA mimics (30-100 nM) or Ambion Pre-miR precursors (30-100 nM) (Life Technologies) using the HiPerFect Transfection Reagent (Qiagen).	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (95, 98))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('30-100', 'Var', (111, 117))
101956	24667836	TaqMan Low Density Array raw data and GeneChip Human 1.0 ST array raw data are available at EBI ArrayExpress E-MTAB-1337 and E-MTAB-1334.	('Human', 'Species', '9606', (47, 52))	('EBI', 'Gene', (92, 95))	('E-MTAB-1337', 'Var', (109, 120))	('E-MTAB-1334', 'Var', (125, 136))	('EBI', 'Gene', '6907', (92, 95))
101963	24667836	Supervised cluster analyses were then performed to identify miRNAs with aberrant expression in ES by comparing the tumor biopsy samples and the cell lines separately to MSCs as the putative cells of origin of ES (Table S2).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('tumor', 'Disease', (115, 120))	('aberrant', 'Var', (72, 80))	('ES', 'Phenotype', 'HP:0012254', (95, 97))	('ES', 'Phenotype', 'HP:0012254', (209, 211))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
101986	24667836	For TC-71 both assays indicated a slightly but statistically significant increased fraction of apoptotic cells upon miR-31 transfection (annexinV+/PI- fractions in apoptosis assay: 8.15% miR-31, 5.18% miRNA control, p = 0.006; Sub G1 fraction in cell cycle analysis: 8.51% miR-31, 5.68% miRNA control, p = 0.013).	('miR-31', 'Gene', '407035', (187, 193))	('miR-31', 'Gene', '407035', (273, 279))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', '220972', (201, 204))	('miR', 'Gene', (187, 190))	('miR', 'Gene', '220972', (273, 276))	('miR', 'Gene', (116, 119))	('miR-31', 'Gene', (116, 122))	('miR', 'Gene', (201, 204))	('increased', 'PosReg', (73, 82))	('miR', 'Gene', (273, 276))	('miR', 'Gene', '220972', (287, 290))	('transfection', 'Var', (123, 135))	('miR-31', 'Gene', (187, 193))	('miR-31', 'Gene', (273, 279))	('miR', 'Gene', (287, 290))	('miR-31', 'Gene', '407035', (116, 122))	('TC-71', 'Chemical', '-', (4, 9))	('apoptotic cells', 'CPA', (95, 110))	('miR', 'Gene', '220972', (187, 190))
101994	24667836	For all 3 cell lines miR-31 transfected cells showed reduced migration (TC-71:40%; CADO-ES1:56%; RD-ES: 26%; cell numbers were corrected for differences in proliferation upon miR-31 transfection)(Figure S3) in two independent experiments and a statistically significant reduced invasion compared to the cells transfected with the negative control (TC-71:42%, p = 0.008; CADO-ES1:29%, p = 0.052; RD-ES: 44%, p = 0.001; cell numbers were corrected for differences in proliferation upon miR-31 transfection) in at least three independent experiments (Figure 4).	('miR-31', 'Gene', (484, 490))	('transfected', 'Var', (28, 39))	('ES', 'Phenotype', 'HP:0012254', (375, 377))	('ES', 'Phenotype', 'HP:0012254', (398, 400))	('miR-31', 'Gene', '407035', (175, 181))	('migration', 'CPA', (61, 70))	('miR-31', 'Gene', '407035', (484, 490))	('reduced', 'NegReg', (270, 277))	('ES', 'Phenotype', 'HP:0012254', (88, 90))	('TC-71', 'Chemical', '-', (72, 77))	('miR-31', 'Gene', (21, 27))	('CADO-ES', 'Chemical', '-', (370, 377))	('reduced', 'NegReg', (53, 60))	('CADO-ES', 'Chemical', '-', (83, 90))	('invasion', 'CPA', (278, 286))	('-ES1', 'Chemical', 'MESH:C053617', (374, 378))	('-ES1', 'Chemical', 'MESH:C053617', (87, 91))	('ES', 'Phenotype', 'HP:0012254', (100, 102))	('TC-71', 'Chemical', '-', (348, 353))	('miR-31', 'Gene', '407035', (21, 27))	('miR-31', 'Gene', (175, 181))
101997	24667836	To directly identify miR-31 targets in ES we generated genome-wide gene expression profiles of TC-71 cells transfected with miR-31 mimics or negative control.	('miR-31', 'Gene', (21, 27))	('ES', 'Phenotype', 'HP:0012254', (39, 41))	('miR-31', 'Gene', (124, 130))	('TC-71', 'Chemical', '-', (95, 100))	('mimics', 'Var', (131, 137))	('miR-31', 'Gene', '407035', (21, 27))	('miR-31', 'Gene', '407035', (124, 130))
102007	24667836	For most of the 16 lower but only a minor fraction of the 19 higher expressed miRNAs aberrant expression has been described in other malignancies.	('aberrant', 'Var', (85, 93))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('malignancies', 'Disease', (133, 145))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))
102019	24667836	One factor could be deletions encompassing the MIR31 gene, which have been detected in 4 of 11 ES cell lines (among them TC-71 and RD-ES) and in 3 of 26 primary ES and most likely contribute in a significant fraction of cases to the lack or reduced expression of miR-31 (Savola et al 2007; Cancer Cell Line Encyclopedia of the Broad Institute).	('reduced', 'NegReg', (241, 248))	('expression', 'MPA', (249, 259))	('TC-71', 'Chemical', '-', (121, 126))	('miR-31', 'Gene', '407035', (263, 269))	('Cancer', 'Disease', (290, 296))	('Cancer', 'Disease', 'MESH:D009369', (290, 296))	('Cancer', 'Phenotype', 'HP:0002664', (290, 296))	('deletions', 'Var', (20, 29))	('MIR31', 'Gene', '407035', (47, 52))	('MIR31', 'Gene', (47, 52))	('ES', 'Phenotype', 'HP:0012254', (95, 97))	('miR-31', 'Gene', (263, 269))	('ES', 'Phenotype', 'HP:0012254', (134, 136))	('ES', 'Phenotype', 'HP:0012254', (161, 163))
102068	22606622	Ductal adenocarcinoma showed expression for PSA and P504.	('P504', 'Var', (52, 56))	('Ductal adenocarcinoma', 'Disease', 'MESH:D044584', (0, 21))	('Ductal adenocarcinoma', 'Disease', (0, 21))	('PSA', 'Disease', (44, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))
102115	26112006	The surgeons were diligent in removing the tumour; they also resected some tricuspid valve and involved the right ventricle wall, after which coronary artery bypass grafting was performed.	('tumour', 'Disease', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('resected', 'Var', (61, 69))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
102129	26112006	Fluorescence in situ hybridization (FISH) showed the rearrangement of SS18 (Vysis SS18 Break Apart FISH Probe Kit, Abbott Molecular Inc., USA) in the tumour cells (Fig.	('SS18', 'Gene', '6760', (82, 86))	('Break Apart', 'Phenotype', 'HP:0001061', (87, 98))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('SS', 'Phenotype', 'HP:0012570', (82, 84))	('tumour', 'Disease', (150, 156))	('SS18', 'Gene', (82, 86))	('SS18', 'Gene', '6760', (70, 74))	('SS', 'Phenotype', 'HP:0012570', (70, 72))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('rearrangement', 'Var', (53, 66))	('SS18', 'Gene', (70, 74))
102138	26112006	We arrived at our diagnosis because of the histological characteristics, including immunohistochemical staining and rearrangement of the SS18 gene.	('rearrangement', 'Var', (116, 129))	('SS18', 'Gene', (137, 141))	('SS', 'Phenotype', 'HP:0012570', (137, 139))	('SS18', 'Gene', '6760', (137, 141))
102141	26112006	The patients with PCSS more readily exhibit gastrointestinal and systemic symptoms, and they frequently also have pericardial effusions compared to patients with benign cardiac tumours.	('patients', 'Species', '9606', (148, 156))	('pericardial effusion', 'Phenotype', 'HP:0001698', (114, 134))	('cardiac tumour', 'Phenotype', 'HP:0100544', (169, 183))	('benign cardiac tumours', 'Disease', 'MESH:D006338', (162, 184))	('pericardial effusions', 'Phenotype', 'HP:0001698', (114, 135))	('PCSS', 'Var', (18, 22))	('gastrointestinal', 'Disease', (44, 60))	('benign cardiac tumours', 'Disease', (162, 184))	('PCSS', 'Chemical', '-', (18, 22))	('SS', 'Phenotype', 'HP:0012570', (20, 22))	('pericardial effusions', 'Disease', (114, 135))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('patients', 'Species', '9606', (4, 12))	('gastrointestinal', 'Disease', 'MESH:D005767', (44, 60))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('pericardial effusions', 'Disease', 'MESH:D010490', (114, 135))
102150	26112006	However, the patients with metastatic carcinosarcoma tend to be older and often have a history of malignant tumour, and the tumour cells tend to display nuclear pleomorphism.	('tumour', 'Disease', (108, 114))	('carcinosarcoma', 'Disease', 'MESH:D002296', (38, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('patients', 'Species', '9606', (13, 21))	('carcinosarcoma', 'Disease', (38, 52))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('malignant tumour', 'Disease', 'MESH:D009369', (98, 114))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('metastatic carcinosarcoma', 'Phenotype', 'HP:0200059', (27, 52))	('tumour', 'Disease', (124, 130))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('nuclear pleomorphism', 'Var', (153, 173))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('malignant tumour', 'Disease', (98, 114))
102159	26112006	The SS18 rearrangement was also observed in this case, and MPNST and metastatic carcinosarcoma were completely ruled out.	('observed', 'Reg', (32, 40))	('SS18', 'Gene', '6760', (4, 8))	('metastatic carcinosarcoma', 'Phenotype', 'HP:0200059', (69, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('carcinosarcoma', 'Disease', 'MESH:D002296', (80, 94))	('SS', 'Phenotype', 'HP:0012570', (4, 6))	('rearrangement', 'Var', (9, 22))	('carcinosarcoma', 'Disease', (80, 94))	('SS18', 'Gene', (4, 8))
102239	33390364	Both CD204 and CD163 are antibodies that bind to class A scavenger receptors on macrophages.	('CD163', 'Gene', (15, 20))	('class A scavenger', 'Protein', (49, 66))	('CD163', 'Gene', '9332', (15, 20))	('CD204', 'Var', (5, 10))	('bind', 'Interaction', (41, 45))	('scavenger', 'Protein', (57, 66))
102242	33390364	In four-toed hedgehogs, macrophages in each organ were reactive to CD204, consistent with previous reports.	('reactive', 'MPA', (55, 63))	('-toed', 'Phenotype', 'HP:0040083', (7, 12))	('four-toed hedgehogs', 'Species', '9368', (3, 22))	('CD204', 'Var', (67, 72))
102271	30979736	In addition to its role in tumor angiogenesis, targeting VEGF may have beneficial immune effects.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('targeting', 'Var', (47, 56))	('immune effects', 'CPA', (82, 96))	('beneficial', 'PosReg', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('VEGF', 'Protein', (57, 61))
102272	30979736	Prior studies have shown that antibodies against VEGF, such as bevacizumab, may improve immunological surveillance and has recently been shown to increase intratumoral CD8+ T cells in combination with immunotherapy among patients with renal cell cancer.	('VEGF', 'Gene', (49, 53))	('increase', 'PosReg', (146, 154))	('antibodies', 'Var', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('renal cell cancer', 'Disease', 'MESH:C538614', (235, 252))	('immunological surveillance', 'MPA', (88, 114))	('renal cell cancer', 'Disease', (235, 252))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('improve', 'PosReg', (80, 87))	('bevacizumab', 'Chemical', 'MESH:D000068258', (63, 74))	('tumor', 'Disease', (160, 165))
102298	30979736	In patients with HIV-KS receiving targeted therapy, improvement may be seen after an initial period of progression; therefore, patients with PD could be treated with bevacizumab at investigator discretion for up to 6 cycles.	('HIV-KS', 'Disease', 'MESH:D015658', (17, 23))	('KS', 'Phenotype', 'HP:0100726', (21, 23))	('targeted', 'Var', (34, 42))	('bevacizumab', 'Chemical', 'MESH:D000068258', (166, 177))	('PD', 'Disease', 'MESH:D010300', (141, 143))	('HIV-KS', 'Disease', (17, 23))
102346	30979736	The aim of this study was to investigate whether the combination of liposomal doxorubicin and bevacizumab would lead to a higher overall response rate, rapid responses, and that the continued bevacizumab monotherapy might then allow continued control of KS while reducing the amount of cumulative anthracycline exposure.	('KS', 'Phenotype', 'HP:0100726', (254, 256))	('higher', 'PosReg', (122, 128))	('doxorubicin', 'Chemical', 'MESH:D004317', (78, 89))	('response', 'MPA', (137, 145))	('anthracycline', 'Chemical', 'MESH:D018943', (297, 310))	('liposomal', 'Var', (68, 77))	('bevacizumab', 'Chemical', 'MESH:D000068258', (192, 203))	('bevacizumab', 'Chemical', 'MESH:D000068258', (94, 105))
102402	30871494	A recently proposed classification of these tumors distinguishes two classes of sarcomas, one with simple karyotypes involving specific genetic alterations, and one with complex and unbalanced karyotypes, usually involving non-specific genetic abnormalities, including copy number alterations.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('genetic abnormalities', 'Disease', 'MESH:D030342', (236, 257))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('genetic abnormalities', 'Disease', (236, 257))	('sarcomas', 'Disease', 'MESH:D012509', (80, 88))	('copy number alterations', 'Var', (269, 292))	('genetic alterations', 'Var', (136, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('sarcomas', 'Disease', (80, 88))
102409	30871494	mutational status of ALT-associated genes); and 4) in vitro or animal studies.	('mutational', 'Var', (0, 10))	('ALT', 'Gene', (21, 24))	('ALT', 'Gene', '76282', (21, 24))
102436	30871494	Interestingly, in pediatric malignant brain tumors, the presence of ALT is associated with a better prognosis, above all in cases of concomitant TP53 mutation.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('presence', 'Var', (56, 64))	('ALT', 'Gene', (68, 71))	('mutation', 'Var', (150, 158))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('brain tumors', 'Disease', 'MESH:D001932', (38, 50))	('brain tumors', 'Phenotype', 'HP:0030692', (38, 50))	('ALT', 'Gene', '76282', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('brain tumors', 'Disease', (38, 50))
102444	30871494	DAXX/ATRX mutations may be studied not only with molecular analysis but also with immunohistochemistry, representing a widely-accepted surrogate of their mutational status, that shows loss of the encoded proteins associated with their mutations.	('ATRX', 'Gene', '546', (5, 9))	('DAXX', 'Gene', (0, 4))	('mutations', 'Var', (235, 244))	('loss', 'NegReg', (184, 188))	('proteins', 'Protein', (204, 212))	('DAXX', 'Gene', '1616', (0, 4))	('ATRX', 'Gene', (5, 9))
102445	30871494	In general, mutations affecting DAXX are more common in PanNET, whereas those affecting ATRX are markedly prominent in sarcomas.	('sarcomas', 'Disease', (119, 127))	('DAXX', 'Gene', '1616', (32, 36))	('mutations', 'Var', (12, 21))	('ATRX', 'Gene', '546', (88, 92))	('common', 'Reg', (46, 52))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('PanNET', 'Disease', (56, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('DAXX', 'Gene', (32, 36))	('ATRX', 'Gene', (88, 92))
102451	30871494	Recent evidence has indicated that the inhibition of the protein kinase ATR (ataxia telangiectasia and Rad3-related protein), a crucial regulator of DNA recombination, can disrupt ALT by triggering chromosome fragmentation and apoptosis in ALT cells.	('ataxia telangiectasia and Rad3-related protein', 'Gene', '245000', (77, 123))	('inhibition', 'Var', (39, 49))	('ALT', 'Gene', '76282', (240, 243))	('ALT', 'Gene', '76282', (180, 183))	('ataxia', 'Phenotype', 'HP:0001251', (77, 83))	('disrupt', 'NegReg', (172, 179))	('telangiectasia', 'Phenotype', 'HP:0001009', (84, 98))	('triggering', 'Reg', (187, 197))	('ALT', 'Gene', (240, 243))	('chromosome fragmentation', 'CPA', (198, 222))	('apoptosis', 'CPA', (227, 236))	('ALT', 'Gene', (180, 183))
102468	30018380	Current understanding of the key genomic aberrations in soft tissue sarcomas is limited to demonstration that some exhibit recurrent single genetic alterations, such as chromosomal translocations resulting in gene fusions (SS18-SSX in synovial sarcoma, FUS-DDIT3 in myxoid/round cell liposarcoma, or NAB2-STAT6 in solitary fibrous tumor), or point mutations (KIT in gastrointestinal stromal tumors).	('SSX', 'Gene', (228, 231))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (366, 397))	('chromosomal translocations', 'Var', (169, 195))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (235, 251))	('liposarcoma', 'Phenotype', 'HP:0012034', (284, 295))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('DDIT3', 'Gene', '1649', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('liposarcoma', 'Disease', 'MESH:D008080', (284, 295))	('gastrointestinal stromal tumors', 'Disease', (366, 397))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (56, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('DDIT3', 'Gene', (257, 262))	('fibrous tumor', 'Disease', 'MESH:D054364', (323, 336))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (56, 75))	('sarcomas', 'Disease', (68, 76))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (56, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('SSX', 'Gene', '727837', (228, 231))	('soft tissue sarcoma', 'Disease', (56, 75))	('FUS', 'Gene', (253, 256))	('STAT6', 'Gene', (305, 310))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('fibrous tumor', 'Disease', (323, 336))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('synovial sarcoma', 'Disease', (235, 251))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (266, 295))	('tumors', 'Phenotype', 'HP:0002664', (391, 397))	('point mutations', 'Var', (342, 357))	('NAB2', 'Gene', (300, 304))	('liposarcoma', 'Disease', (284, 295))	('FUS', 'Gene', '2521', (253, 256))	('NAB2', 'Gene', '4665', (300, 304))	('synovial sarcoma', 'Disease', 'MESH:D013584', (235, 251))	('STAT6', 'Gene', '6778', (305, 310))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (366, 397))
102473	30018380	Amplifications of chromosome 5p (rapamycin-insensitive binding partner of mTOR, CDH9, LIFR) and 1p/1q (PI4KB, ETV3, MCL1), and deletions of tumor-suppressor genes including CDKN2A/B and TP53, have been reported in MFS, as have loss-of-function mutations in NF1 (5/35) and PTEN (1/35).	('LIFR', 'Gene', '3977', (86, 90))	('LIFR', 'Gene', (86, 90))	('MCL1', 'Gene', (116, 120))	('CDKN2A/B', 'Gene', '1029;1030', (173, 181))	('mTOR', 'Gene', (74, 78))	('loss-of-function', 'NegReg', (227, 243))	('ETV3', 'Gene', (110, 114))	('MCL1', 'Gene', '4170', (116, 120))	('mTOR', 'Gene', '2475', (74, 78))	('TP53', 'Gene', (186, 190))	('NF1', 'Gene', '4763', (257, 260))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutations', 'Var', (244, 253))	('PI4KB', 'Gene', (103, 108))	('PTEN', 'Gene', (272, 276))	('CDH9', 'Gene', (80, 84))	('CDH9', 'Gene', '1007', (80, 84))	('tumor-suppressor', 'Gene', '7248', (140, 156))	('PI4KB', 'Gene', '5298', (103, 108))	('CDKN2A/B', 'Gene', (173, 181))	('NF1', 'Gene', (257, 260))	('PTEN', 'Gene', '5728', (272, 276))	('ETV3', 'Gene', '2117', (110, 114))	('TP53', 'Gene', '7157', (186, 190))	('deletions', 'Var', (127, 136))	('tumor-suppressor', 'Gene', (140, 156))
102484	30018380	These alterations affected potential therapeutic targets (NF1, NTRK1, ATRX, CCND1, CDK6, NKX2-1, and JAK1) with a total frequency of 39% (45/116).	('alterations', 'Var', (6, 17))	('ATRX', 'Gene', '546', (70, 74))	('CCND1', 'Gene', (76, 81))	('NTRK1', 'Gene', (63, 68))	('NKX2-1', 'Gene', '7080', (89, 95))	('JAK1', 'Gene', '3716', (101, 105))	('CCND1', 'Gene', '595', (76, 81))	('NTRK1', 'Gene', '4914', (63, 68))	('CDK6', 'Gene', (83, 87))	('ATRX', 'Gene', (70, 74))	('affected', 'Reg', (18, 26))	('NF1', 'Gene', (58, 61))	('CDK6', 'Gene', '1021', (83, 87))	('NKX2-1', 'Gene', (89, 95))	('NF1', 'Gene', '4763', (58, 61))	('JAK1', 'Gene', (101, 105))
102485	30018380	However, frequencies of GNAS (primary 0.0%, metastatic 0.0% vs. recurrent 17.6%; p < 0.001, chi2-test) and SETD2 (primary 1.0%, metastatic 0.0% vs. recurrent 11.8%; p = 0.036, chi2-test) mutations were significantly higher in recurrent specimens.	('GNAS', 'Gene', '2778', (24, 28))	('mutations', 'Var', (187, 196))	('GNAS', 'Gene', (24, 28))	('higher', 'PosReg', (216, 222))	('SETD2', 'Gene', '29072', (107, 112))	('SETD2', 'Gene', (107, 112))
102487	30018380	Of note, alterations in RB1, CDKN2A/CDKN2B, and CCND1 were almost mutually exclusively, as were those in TP53 and MDM2 (Fig.	('CDKN2A', 'Gene', (29, 35))	('MDM2', 'Gene', (114, 118))	('RB1', 'Gene', (24, 27))	('CCND1', 'Gene', '595', (48, 53))	('CDKN2B', 'Gene', (36, 42))	('CDKN2A', 'Gene', '1029', (29, 35))	('RB1', 'Gene', '5925', (24, 27))	('alterations', 'Var', (9, 20))	('CDKN2B', 'Gene', '1030', (36, 42))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('CCND1', 'Gene', (48, 53))	('MDM2', 'Gene', '4193', (114, 118))
102488	30018380	These findings indicate central roles for dysregulation of p53 signaling and G1/S cell cycle in the development of MFS.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('MFS', 'Disease', (115, 118))	('dysregulation', 'Var', (42, 55))	('G1/S cell cycle', 'CPA', (77, 92))
102491	30018380	We also identified recurrent mutations in regulators of the epigenome, represented by ATRX, TET2, SETD2, HIST1H3B, and WT1 (16%) (Fig.	('ATRX', 'Gene', '546', (86, 90))	('TET2', 'Gene', '54790', (92, 96))	('SETD2', 'Gene', '29072', (98, 103))	('WT1', 'Gene', (119, 122))	('mutations', 'Var', (29, 38))	('SETD2', 'Gene', (98, 103))	('TET2', 'Gene', (92, 96))	('ATRX', 'Gene', (86, 90))	('HIST1H3B', 'Gene', (105, 113))	('HIST1H3B', 'Gene', '8358', (105, 113))	('WT1', 'Gene', '7490', (119, 122))
102493	30018380	Of ATRX mutations, eight (four frameshifts, two nonsenses, and two splice sites) of ten resulted in protein truncation (Fig.	('frameshifts', 'Var', (31, 42))	('protein truncation', 'MPA', (100, 118))	('resulted in', 'Reg', (88, 99))	('mutations', 'Var', (8, 17))	('ATRX', 'Gene', (3, 7))	('ATRX', 'Gene', '546', (3, 7))
102494	30018380	ATRX cooperates functionally with DAXX, and DAXX mutations are also associated with ALT.	('DAXX', 'Gene', (44, 48))	('associated', 'Reg', (68, 78))	('mutations', 'Var', (49, 58))	('ATRX', 'Gene', (0, 4))	('DAXX', 'Gene', (34, 38))	('ALT', 'Disease', (84, 87))	('DAXX', 'Gene', '1616', (44, 48))	('ATRX', 'Gene', '546', (0, 4))	('DAXX', 'Gene', '1616', (34, 38))
102495	30018380	DAXX and ATRX mutations are mutually exclusive in PNET and uterine leiomyosarcoma; however, no DAXX mutations were identified in our cohort.	('DAXX', 'Gene', (95, 99))	('mutations', 'Var', (14, 23))	('ATRX', 'Gene', '546', (9, 13))	('leiomyosarcoma', 'Disease', (67, 81))	('DAXX', 'Gene', (0, 4))	('PNET', 'Disease', (50, 54))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (67, 81))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (67, 81))	('DAXX', 'Gene', '1616', (0, 4))	('DAXX', 'Gene', '1616', (95, 99))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('ATRX', 'Gene', (9, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
102496	30018380	In addition, all four TET2 mutations were nonsense mutations resulting in truncated proteins lacking the functional double-stranded beta-helix (DSBH) domain (Fig.	('mutations', 'Var', (27, 36))	('truncated', 'MPA', (74, 83))	('TET2', 'Gene', '54790', (22, 26))	('proteins', 'Protein', (84, 92))	('lacking', 'NegReg', (93, 100))	('TET2', 'Gene', (22, 26))
102501	30018380	In addition, high incidence of amplification of CDK4 (86.0%, p < 0.001, chi2-test) made DDLS a more distinct entity compared to others in which RB1 and CDK6 were more frequently affected.	('CDK6', 'Gene', '1021', (152, 156))	('CDK4', 'Gene', '1019', (48, 52))	('CDK6', 'Gene', (152, 156))	('RB1', 'Gene', '5925', (144, 147))	('DDLS', 'Disease', (88, 92))	('CDK4', 'Gene', (48, 52))	('amplification', 'Var', (31, 44))	('RB1', 'Gene', (144, 147))
102503	30018380	NKX2-1 alterations were exclusively found in MFS (p = 0.013, chi2-test).	('NKX2-1', 'Gene', '7080', (0, 6))	('MFS', 'Disease', (45, 48))	('alterations', 'Var', (7, 18))	('NKX2-1', 'Gene', (0, 6))
102506	30018380	Subcutaneous transplantation of NIH3T3 cells expressing SLC37A3-BRAF, as well as those expressing the BRAF V600E mutation (a positive control), generated tumors in nude mice (Fig.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('SLC37A3-BRAF', 'Var', (56, 68))	('generated', 'PosReg', (144, 153))	('nude mice', 'Species', '10090', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('NIH3T3', 'CellLine', 'CVCL:0594', (32, 38))	('V600E', 'Mutation', 'rs113488022', (107, 112))
102512	30018380	NF1 alterations were significantly predominant in Cluster C (36%) compared with Cluster A (9%) and B (0%) (p = 0.013, chi2-test).	('predominant', 'Reg', (35, 46))	('alterations', 'Var', (4, 15))	('NF1', 'Gene', '4763', (0, 3))	('NF1', 'Gene', (0, 3))
102513	30018380	All ATRX mutations were observed in Cluster B (21%) (p = 0.077, chi2-test), while Cluster A was characterized by alterations of genes associated with histone/chromatin modification (TET2, SETD2, and WT1) (46%) (p = 0.013, chi2-test).	('TET2', 'Gene', (182, 186))	('WT1', 'Gene', '7490', (199, 202))	('ATRX', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('SETD2', 'Gene', '29072', (188, 193))	('alterations', 'Reg', (113, 124))	('WT1', 'Gene', (199, 202))	('SETD2', 'Gene', (188, 193))	('genes', 'MPA', (128, 133))	('ATRX', 'Gene', '546', (4, 8))	('TET2', 'Gene', '54790', (182, 186))
102514	30018380	Especially, all MFS cases with TET2 mutations were included in Cluster A (p = 0.012, chi2-test).	('MFS', 'Disease', (16, 19))	('TET2', 'Gene', '54790', (31, 35))	('mutations', 'Var', (36, 45))	('TET2', 'Gene', (31, 35))
102521	30018380	Alterations of any of cell cycle regulators (RB1, CDKN2A, CDKN2B, CCND1, and CDK6) were associated with poorer overall survival (p = 0.001, log-rank test) (Supplementary Fig.	('RB1', 'Gene', (45, 48))	('CDKN2A', 'Gene', (50, 56))	('CDK6', 'Gene', (77, 81))	('CDK6', 'Gene', '1021', (77, 81))	('overall survival', 'MPA', (111, 127))	('Alterations', 'Var', (0, 11))	('CCND1', 'Gene', '595', (66, 71))	('poorer', 'NegReg', (104, 110))	('CDKN2A', 'Gene', '1029', (50, 56))	('RB1', 'Gene', '5925', (45, 48))	('CDKN2B', 'Gene', (58, 64))	('CDKN2B', 'Gene', '1030', (58, 64))	('CCND1', 'Gene', (66, 71))
102522	30018380	RB1 (p = 0.040, log-rank test), CDKN2A (p < 0.001, log-rank test), and CDKN2B (p < 0.001, log-rank test) alterations were associated with poorer overall survival, whereas they were not with local recurrence-free survival.	('CDKN2B', 'Gene', (71, 77))	('RB1', 'Gene', '5925', (0, 3))	('CDKN2A', 'Gene', (32, 38))	('overall survival', 'MPA', (145, 161))	('CDKN2A', 'Gene', '1029', (32, 38))	('CDKN2B', 'Gene', '1030', (71, 77))	('alterations', 'Var', (105, 116))	('poorer', 'NegReg', (138, 144))	('RB1', 'Gene', (0, 3))
102523	30018380	The presence of TP53 alteration and KRAS amplification was also significantly associated with poorer overall survival (p = 0.038 and 0.010, respectively, log-rank test) (Supplementary Figs.	('KRAS', 'Gene', (36, 40))	('poorer', 'NegReg', (94, 100))	('overall', 'MPA', (101, 108))	('KRAS', 'Gene', '3845', (36, 40))	('TP53', 'Gene', '7157', (16, 20))	('presence', 'Var', (4, 12))	('TP53', 'Gene', (16, 20))
102524	30018380	The presence of GNAS mutations was significantly associated with local recurrence-free survival (p = 0.004, log-rank test) (Supplementary Fig.	('local recurrence-free survival', 'CPA', (65, 95))	('GNAS', 'Gene', (16, 20))	('associated', 'Reg', (49, 59))	('GNAS', 'Gene', '2778', (16, 20))	('mutations', 'Var', (21, 30))
102526	30018380	Of note, none of the GNAS mutations in MFSs involved the R201 locus that characterizes intramuscular myxoma.	('intramuscular myxoma', 'Disease', 'MESH:D009232', (87, 107))	('MFSs', 'Gene', (39, 43))	('GNAS', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('intramuscular myxoma', 'Disease', (87, 107))	('intramuscular myxoma', 'Phenotype', 'HP:0031461', (87, 107))	('GNAS', 'Gene', '2778', (21, 25))
102529	30018380	Similar to previous reports of other soft tissue sarcomas, copy number alterations, as well as point mutations, appear to play important roles in MFS tumorigenesis.	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('point mutations', 'Var', (95, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (37, 56))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (37, 56))	('copy number alterations', 'Var', (59, 82))	('sarcomas', 'Disease', (49, 57))	('MFS tumor', 'Disease', (146, 155))	('MFS tumor', 'Disease', 'MESH:D008382', (146, 155))	('soft tissue sarcoma', 'Disease', (37, 56))	('roles', 'Reg', (137, 142))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (37, 57))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))
102531	30018380	Mutations in RB1, CDKN2A/CDKN2B, and CCND1 were almost completely mutually exclusive (Figs.	('CDKN2A', 'Gene', '1029', (18, 24))	('RB1', 'Gene', '5925', (13, 16))	('CCND1', 'Gene', (37, 42))	('Mutations', 'Var', (0, 9))	('CCND1', 'Gene', '595', (37, 42))	('RB1', 'Gene', (13, 16))	('CDKN2A', 'Gene', (18, 24))	('CDKN2B', 'Gene', (25, 31))	('CDKN2B', 'Gene', '1030', (25, 31))
102533	30018380	Our results also provide a rationale for the use of CDK4/6 inhibitors in MFS harboring genetic changes in the Rb pathway, including CCND1 or CDK6 amplification.	('CCND1', 'Gene', (132, 137))	('CDK4/6', 'Gene', '1019;1021', (52, 58))	('genetic changes', 'Var', (87, 102))	('Rb pathway', 'Pathway', (110, 120))	('CCND1', 'Gene', '595', (132, 137))	('CDK6', 'Gene', (141, 145))	('CDK4/6', 'Gene', (52, 58))	('CDK6', 'Gene', '1021', (141, 145))
102538	30018380	Further, none of these tumors harbored CDK4 co-amplification, unlike DDLS that is characterized by coexistence of MDM2 (100%) and CDK4 (92%) amplifications.	('MDM2', 'Gene', (114, 118))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('co-amplification', 'Var', (44, 60))	('CDK4', 'Gene', (130, 134))	('CDK4', 'Gene', '1019', (39, 43))	('CDK4', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CDK4', 'Gene', '1019', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('MDM2', 'Gene', '4193', (114, 118))
102541	30018380	NF1, a tumor-suppressor gene in which mutations cause the hereditary cancer predisposition disease, neurofibromatosis type 1, encodes a negative regulator of RAS proteins.	('neurofibromatosis', 'Phenotype', 'HP:0001067', (100, 117))	('hereditary cancer', 'Disease', (58, 75))	('neurofibromatosis type 1', 'Gene', '4763', (100, 124))	('neurofibromatosis type 1', 'Gene', (100, 124))	('tumor-suppressor', 'Gene', '7248', (7, 23))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cause', 'Reg', (48, 53))	('tumor-suppressor', 'Gene', (7, 23))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (38, 47))	('NF1', 'Gene', '4763', (0, 3))	('hereditary cancer', 'Disease', 'MESH:D009369', (58, 75))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
102544	30018380	We detected four homozygous deletions and nine somatic mutations of NF1 in 116 MFSs.	('NF1', 'Gene', '4763', (68, 71))	('deletions', 'Var', (28, 37))	('NF1', 'Gene', (68, 71))
102545	30018380	Seven of the nine somatic mutations of NF1 caused premature truncation of the protein (Supplementary Fig.	('NF1', 'Gene', (39, 42))	('premature truncation of the protein', 'MPA', (50, 85))	('NF1', 'Gene', '4763', (39, 42))	('caused', 'Reg', (43, 49))	('mutations', 'Var', (26, 35))
102547	30018380	These data suggest that a distinctive pattern of NF1 aberrations may have a role in MFS tumorigenesis, similarly reported in other cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('role', 'Reg', (76, 80))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('aberrations', 'Var', (53, 64))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('NF1', 'Gene', (49, 52))	('MFS tumor', 'Disease', (84, 93))	('MFS tumor', 'Disease', 'MESH:D008382', (84, 93))	('NF1', 'Gene', '4763', (49, 52))
102548	30018380	Moreover, the use of MEK inhibitors may be a potential therapeutic option in NF1-deficient MFSs, as recent studies revealed that tumors harboring NF1 inactivation (inactivating/deleterious NF1 mutations) exhibited activation of the MAPK/ERK pathway and hence are potential targets for MEK inhibitors.	('tumors', 'Disease', (129, 135))	('inactivation', 'Var', (150, 162))	('MEK', 'Gene', '5609', (21, 24))	('MEK', 'Gene', (285, 288))	('NF1', 'Gene', '4763', (77, 80))	('mutations', 'Var', (193, 202))	('NF1-deficient MFSs', 'Disease', 'MESH:C537392', (77, 95))	('NF1', 'Gene', '4763', (189, 192))	('NF1-deficient MFSs', 'Disease', (77, 95))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('MEK', 'Gene', (21, 24))	('NF1', 'Gene', (77, 80))	('NF1', 'Gene', (189, 192))	('MAPK', 'Gene', (232, 236))	('NF1', 'Gene', '4763', (146, 149))	('activation', 'PosReg', (214, 224))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NF1', 'Gene', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('MAPK', 'Gene', '5594;26413', (232, 236))	('MEK', 'Gene', '5609', (285, 288))
102549	30018380	Amplification of JAK1 could be a therapeutic target in MFS because aberrant activation of the JAK/STAT pathway has been shown to be a promising target in various cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('Amplification', 'Var', (0, 13))	('JAK/STAT pathway', 'Pathway', (94, 110))	('cancer', 'Disease', (162, 168))	('JAK1', 'Gene', (17, 21))	('JAK1', 'Gene', '3716', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('activation', 'PosReg', (76, 86))
102554	30018380	Although cell of origin of MFS remains to be unknown, this suggests that promoter swapping between BRAF and SLC37A3 by structural rearrangement may increase expression of SLC37A-BRAF fusion gene compared to that of wild-type BRAF.	('increase', 'PosReg', (148, 156))	('expression', 'MPA', (157, 167))	('promoter swapping', 'Var', (73, 90))	('BRAF', 'Gene', (99, 103))	('SLC37A-BRAF', 'Gene', (171, 182))	('SLC37A-BRAF', 'Gene', '673', (171, 182))	('SLC37A3', 'Gene', (108, 115))
102559	30018380	Although TRIO fusion genes were speculated to be associated with a transcriptomic program of immunity/inflammation, cell proliferation, and migration, their oncogenic roles have been still unclear.	('TRIO', 'Gene', (9, 13))	('associated', 'Reg', (49, 59))	('fusion genes', 'Var', (14, 26))	('inflammation', 'Disease', 'MESH:D007249', (102, 114))	('inflammation', 'Disease', (102, 114))	('cell proliferation', 'CPA', (116, 134))	('TRIO', 'Gene', '7204', (9, 13))
102566	30018380	DNA methylation patterns clustered into three subtypes closely associated with immune cell compositions, especially the fraction of CD8+ T cell, as well as unique combinations of driver mutations and prognosis.	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))	('associated', 'Reg', (63, 73))	('mutations', 'Var', (186, 195))
102616	26537303	In contrary to other uterine sarcomas, such as carcinosarcoma, leiomyosarcoma, and high-grade ESS, low-grade ESS generally involves a slowly growing malignancy with an indolent clinical course and late recurrence.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (63, 77))	('malignancy', 'Disease', 'MESH:D009369', (149, 159))	('carcinosarcoma', 'Disease', (47, 61))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (63, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (21, 36))	('malignancy', 'Disease', (149, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('carcinosarcoma', 'Disease', 'MESH:D002296', (47, 61))	('sarcomas', 'Disease', (29, 37))	('leiomyosarcoma', 'Disease', (63, 77))	('low-grade', 'Var', (99, 108))
102617	26537303	Low-grade ESS patients tend to be younger than typical patients with other uterine sarcomas, with a mean age of 52 years.	('Low-grade', 'Var', (0, 9))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (75, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcomas', 'Disease', (83, 91))	('ESS', 'Disease', (10, 13))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (14, 22))	('sarcomas', 'Disease', 'MESH:D012509', (83, 91))
102619	26537303	However, the preoperative diagnosis of low-grade ESS is important because the current standard treatment for early-stage (stage I or II) low-grade ESS is hysterectomy and bilateral salpingo-oophorectomy for hormonally sensitive tumors, which is different from the treatment of the more common condition of benign leiomyoma.	('benign leiomyoma', 'Disease', (306, 322))	('benign leiomyoma', 'Disease', 'MESH:D007889', (306, 322))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('low-grade', 'Var', (137, 146))	('tumors', 'Disease', 'MESH:D009369', (228, 234))
102637	26537303	The ten patients with low-grade ESS were presented with symptoms including menorrhagia (n=4), abdominal pain (n=2), and postmenopausal vaginal bleeding (n=1).	('menorrhagia', 'Disease', (75, 86))	('vaginal bleeding', 'Disease', (135, 151))	('vaginal bleeding', 'Disease', 'MESH:D014592', (135, 151))	('abdominal pain', 'Phenotype', 'HP:0002027', (94, 108))	('menorrhagia', 'Phenotype', 'HP:0000132', (75, 86))	('abdominal pain', 'Disease', (94, 108))	('menorrhagia', 'Disease', 'MESH:D008595', (75, 86))	('pain', 'Phenotype', 'HP:0012531', (104, 108))	('low-grade', 'Var', (22, 31))	('abdominal pain', 'Disease', 'MESH:D015746', (94, 108))	('patients', 'Species', '9606', (8, 16))
102674	26537303	Subsequently, a subset of ESS with a unique YWHAE-FAM22 gene rearrangement was discovered, and the high-grade ESS category was re-established as a subset of ESS with a prognosis intermediate between low-grade ESS and UUS.	('YWHAE', 'Gene', (44, 49))	('rearrangement', 'Var', (61, 74))	('YWHAE', 'Gene', '7531', (44, 49))	('UUS', 'Disease', (217, 220))	('UUS', 'Chemical', '-', (217, 220))
102882	23497542	X-rays commonly cause single-strand DNA break, and double-strand DNA break by two hits is essential for cancer cell death.	('X-rays', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('single-strand DNA break', 'MPA', (22, 45))	('rays', 'Species', '255564', (2, 6))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cause', 'Reg', (16, 21))
102931	23497542	The low-dose irradiated volume of lung tissues is lower in C-ion RT than in stereotactic body RT.	('lower', 'NegReg', (50, 55))	('stereotactic body', 'Phenotype', 'HP:0000733', (76, 93))	('C-ion RT', 'Var', (59, 67))	('C', 'Chemical', 'MESH:D002244', (59, 60))
102982	23497542	Based on the clinical trials conducted at NIRS and GSI, C-ion RT has the following characteristics: (1) By location, C-ion RT is effective in tumours of the head and neck, skull base, lung, liver, prostate, bone and soft tissue sarcoma, etc.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('skull base', 'Disease', (172, 182))	('prostate', 'Disease', (197, 205))	('soft tissue sarcoma', 'Disease', (216, 235))	('tumours', 'Disease', (142, 149))	('GSI', 'Chemical', '-', (51, 54))	('C', 'Chemical', 'MESH:D002244', (117, 118))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (216, 235))	('lung', 'Disease', (184, 188))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (216, 235))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('bone', 'Disease', (207, 211))	('C-ion RT', 'Var', (117, 125))	('liver', 'Disease', (190, 195))
103000	32747783	A combination of cell-based and biochemical approaches reveals how oncogenic fusion protein SS18-SSX directs BAF complexes to H2AK119Ub-modified nucleosomes to remodel chromatin at cancer-specific gene targets.	('SSX', 'Gene', (97, 100))	('remodel', 'Reg', (160, 167))	('SSX', 'Gene', '6757', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('H2AK119Ub-modified', 'Var', (126, 144))	('SS18', 'Gene', (92, 96))	('H2AK119Ub', 'Chemical', '-', (126, 135))	('chromatin', 'MPA', (168, 177))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('BAF', 'Gene', '8815', (109, 112))	('cancer', 'Disease', (181, 187))	('BAF', 'Gene', (109, 112))	('SS18', 'Gene', '6760', (92, 96))
103004	32747783	Importantly, the results of recent large-scale human genetic sequencing studies indicate that perturbations across each of the above classes of chromatin-bound factors represent frequent and recurrent events in human cancer, intellectual disability and other disorders, with mutations ranging from point mutations and deletions to fusion proteins that alter target engagement and the activity of chromatin regulatory complexes on the genome.	('mutations', 'Var', (275, 284))	('fusion proteins', 'Protein', (331, 346))	('point mutations', 'Var', (298, 313))	('alter', 'Reg', (352, 357))	('intellectual disability', 'Phenotype', 'HP:0001249', (225, 248))	('human', 'Species', '9606', (211, 216))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('disability', 'Disease', 'MESH:D002658', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('target engagement', 'MPA', (358, 375))	('human', 'Species', '9606', (47, 52))	('disability', 'Disease', (238, 248))	('activity', 'MPA', (384, 392))	('deletions', 'Var', (318, 327))
103006	32747783	Incorporation of SS18-SSX into BAF complexes causes biochemical changes, such as destabilization of the SMARCB1 (BAF47) subunit, and results in de novo BAF complex targeting to a highly cancer-specific set of sites, particularly broad, polycomb-repressed regions at which polycomb complex occupancy is reduced and gene expression is activated.	('biochemical', 'MPA', (52, 63))	('BAF47', 'Gene', (113, 118))	('SSX', 'Gene', (22, 25))	('BAF', 'Gene', (31, 34))	('changes', 'Reg', (64, 71))	('SS18', 'Gene', (17, 21))	('BAF', 'Gene', '8815', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('BAF', 'Gene', '8815', (152, 155))	('SMARCB1', 'Gene', '6598', (104, 111))	('BAF47', 'Gene', '6598', (113, 118))	('SMARCB1', 'Gene', (104, 111))	('Incorporation', 'Var', (0, 13))	('targeting', 'MPA', (164, 173))	('BAF', 'Gene', '8815', (31, 34))	('SS18', 'Gene', '6760', (17, 21))	('cancer', 'Disease', (186, 192))	('BAF', 'Gene', (113, 116))	('SSX', 'Gene', '6757', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('activated', 'PosReg', (333, 342))	('BAF', 'Gene', (152, 155))	('destabilization', 'NegReg', (81, 96))
103010	32747783	Furthermore, SSX-nucleosome binding is augmented by the presence of ubiquitylated histone H2A (H2AK119Ub) on nucleosomes, preferential recognition of which requires a second, conserved region of SSX.	('H2AK119Ub', 'Chemical', '-', (95, 104))	('H2AK119Ub', 'Var', (95, 104))	('SSX', 'Gene', (13, 16))	('SSX', 'Gene', '6757', (13, 16))	('SSX', 'Gene', (195, 198))	('SSX', 'Gene', '6757', (195, 198))	('augmented', 'PosReg', (39, 48))
103014	32747783	Strikingly, fusion oncoprotein SS18-SSX-bound BAF complexes preferentially eluted in the CHR material, in contrast to WT complexes, which eluted nearly completely in the soluble NE material, as expected from previous studies examining WT (and other loss-of-function mutant variants of) BAF complexes.	('SSX', 'Gene', '6757', (36, 39))	('CHR', 'Disease', 'MESH:D015211', (89, 92))	('SSX', 'Gene', (36, 39))	('BAF', 'Gene', '8815', (286, 289))	('CHR', 'Disease', (89, 92))	('BAF', 'Gene', '8815', (46, 49))	('mutant', 'Var', (266, 272))	('BAF', 'Gene', (286, 289))	('SS18', 'Gene', '6760', (31, 35))	('preferentially', 'PosReg', (60, 74))	('BAF', 'Gene', (46, 49))	('SS18', 'Gene', (31, 35))
103017	32747783	Notably, we captured peptides corresponding to the H2AK119Ub mark only in the purifications of SS18-SSX-bound complexes but not in SS18 WT complexes, in agreement with the visualization of this mark upon colloidal blue staining (Fig.	('SS18', 'Gene', (131, 135))	('SS18', 'Gene', '6760', (95, 99))	('peptides', 'Chemical', 'MESH:D010455', (21, 29))	('SS18-SSX-bound complexes', 'Gene', '6757', (95, 119))	('SS18', 'Gene', (95, 99))	('H2AK119Ub', 'Var', (51, 60))	('H2AK119Ub', 'Chemical', '-', (51, 60))	('SS18', 'Gene', '6760', (131, 135))	('SS18-SSX-bound complexes', 'Gene', (95, 119))
103028	32747783	In addition, we found that binding to mammalian nucleosomes (purified via MNase digestion of HEK293T cell chromatin and hence representing the diverse array of histone variants and modifications) was stronger than binding to recombinant, unmodified nucleosomes (Extended Data Fig.	('binding', 'Interaction', (27, 34))	('variants', 'Var', (168, 176))	('stronger', 'PosReg', (200, 208))	('mammalian', 'Species', '9606', (38, 47))	('HEK293T', 'CellLine', 'CVCL:0063', (93, 100))
103031	32747783	For example, we detected enrichment of nucleosomes decorated with repressive marks such as H3K27me3 and H3K9me3, and depletion of nucleosomes decorated with activating marks such as H4 lysine acetylation and H3K4me2/3 (while nucleosomes containing unmodified H4 and H3 were enriched) in these SSX-mammalian nucleosome binding experiments.	('H3K4me2/3', 'Var', (208, 217))	('depletion', 'MPA', (117, 126))	('lysine', 'Chemical', 'MESH:D008239', (185, 191))	('H3K27me3', 'Var', (91, 99))	('activating', 'PosReg', (157, 167))	('H4 lysine acetylation', 'Var', (182, 203))	('mammalian', 'Species', '9606', (297, 306))	('H3K9me3', 'Var', (104, 111))	('SSX', 'Gene', (293, 296))	('SSX', 'Gene', '6757', (293, 296))
103040	32747783	Finally, to identify residues important for nucleosome binding, we designed a library of 34-residue SSX peptides containing alanine substitutions in either single conserved residues or alanine substitutions across the full basic and acidic regions.	('alanine substitutions', 'Var', (185, 206))	('alanine', 'Chemical', 'MESH:D000409', (185, 192))	('alanine substitutions', 'Var', (124, 145))	('alanine', 'Chemical', 'MESH:D000409', (124, 131))	('peptides', 'Chemical', 'MESH:D010455', (104, 112))	('SSX', 'Gene', '6757', (100, 103))	('SSX', 'Gene', (100, 103))
103042	32747783	To determine whether these minimal regions were sufficient for the genome-wide targeting of fully-formed, endogenous SS18-SSX-containing BAF complexes in cells, we expressed either WT SS18, SS18-SSX or SS18 fused to a range of mutant SSX variants by lentiviral infection in CRL7250 human fibroblasts.	('SSX', 'Gene', '6757', (234, 237))	('SS18', 'Gene', '6760', (117, 121))	('SSX', 'Gene', '6757', (195, 198))	('BAF', 'Gene', '8815', (137, 140))	('CRL', 'Gene', (274, 277))	('SS18', 'Gene', (184, 188))	('SS18', 'Gene', '6760', (202, 206))	('variants', 'Var', (238, 246))	('SSX', 'Gene', '6757', (122, 125))	('SSX', 'Gene', (234, 237))	('SSX', 'Gene', (195, 198))	('SS18', 'Gene', (190, 194))	('CRL', 'Gene', '133396', (274, 277))	('infection', 'Disease', (261, 270))	('infection', 'Disease', 'MESH:D007239', (261, 270))	('SSX', 'Gene', (122, 125))	('SS18', 'Gene', '6760', (184, 188))	('SS18', 'Gene', (117, 121))	('BAF', 'Gene', (137, 140))	('mutant', 'Var', (227, 233))	('human', 'Species', '9606', (282, 287))	('SS18', 'Gene', (202, 206))	('SS18', 'Gene', '6760', (190, 194))
103044	32747783	Notably, deletion of either the basic or the acidic conserved regions of SSX resulted in complete loss of oncogenic fusion complex targeting, suggesting that both of these regions are required for SS18-SSX-specific properties.	('oncogenic fusion complex targeting', 'MPA', (106, 140))	('SS18', 'Gene', '6760', (197, 201))	('deletion', 'Var', (9, 17))	('SS18', 'Gene', (197, 201))	('loss', 'NegReg', (98, 102))	('SSX', 'Gene', '6757', (202, 205))	('SSX', 'Gene', (202, 205))	('SSX', 'Gene', (73, 76))	('SSX', 'Gene', '6757', (73, 76))
103046	32747783	Importantly, these changes in chromatin targeting resulted in corresponding changes in gene expression by RNA-seq, as evidenced by clustering of the transcriptional profiles of the 34-residue tail fusion with the full SS18-SSX fusion (78-aa fusion tail), while deletion of either basic or acidic conserved regions or 24-aa SSX tail variants clustered with SS18 WT gene expression profiles (Fig.	('SSX', 'Gene', (323, 326))	('changes', 'Var', (19, 26))	('SS18', 'Gene', '6760', (356, 360))	('SS18', 'Gene', (218, 222))	('SS18', 'Gene', (356, 360))	('SSX', 'Gene', '6757', (223, 226))	('deletion', 'Var', (261, 269))	('gene expression', 'MPA', (87, 102))	('SS18', 'Gene', '6760', (218, 222))	('SSX', 'Gene', (223, 226))	('SSX', 'Gene', '6757', (323, 326))	('changes', 'Reg', (76, 83))
103048	32747783	4c) as well as beta-galactosidase senescence assays in IMR90 fibroblasts performed across SS18-SSX and SSX (alone) variants (Extended Data Fig.	('SS18', 'Gene', (90, 94))	('SSX', 'Gene', '6757', (95, 98))	('SSX', 'Gene', (95, 98))	('variants', 'Var', (115, 123))	('SS18', 'Gene', '6760', (90, 94))	('IMR90', 'CellLine', 'CVCL:0347', (55, 60))	('SSX', 'Gene', (103, 106))	('beta-galactosidase senescence', 'MPA', (15, 44))	('SSX', 'Gene', '6757', (103, 106))
103049	32747783	Finally, both SS18-SSX 78-aa and 34-aa minimal fusions rescued proliferation in SS cell lines that are well-established to be dependent on the function of SS18-SSX and bearing shRNA-mediated knockdown (KD) of the endogenous SS18-SSX fusion.	('SS18', 'Gene', (155, 159))	('SSX', 'Gene', (229, 232))	('SSX', 'Gene', (160, 163))	('proliferation', 'CPA', (63, 76))	('SSX', 'Gene', '6757', (229, 232))	('SSX', 'Gene', '6757', (160, 163))	('SS18', 'Gene', '6760', (224, 228))	('SSX', 'Gene', '6757', (19, 22))	('SS18', 'Gene', '6760', (14, 18))	('KD', 'Disease', 'MESH:C537017', (202, 204))	('SSX', 'Gene', (19, 22))	('knockdown', 'Var', (191, 200))	('rescued', 'PosReg', (55, 62))	('SS18', 'Gene', '6760', (155, 159))	('SS18', 'Gene', (14, 18))	('SS18', 'Gene', (224, 228))
103051	32747783	Using systematic mutagenesis on the SSX 34-residue region, we found that single-residue perturbations to the basic region, which includes a Kaposi's sarcoma-associated herpesvirus (KSHV) LANA (latency-associated nuclear antigen)-like RLR motif, resulted in complete loss of nucleosome binding (Fig.	("Kaposi's sarcoma-associated herpesvirus", 'Species', '37296', (140, 179))	('KSHV', 'Species', '37296', (181, 185))	('SSX', 'Gene', '6757', (36, 39))	('perturbations', 'Var', (88, 101))	('nucleosome binding', 'MPA', (274, 292))	('SSX', 'Gene', (36, 39))	('loss', 'NegReg', (266, 270))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (140, 156))
103053	32747783	Histone-SSX crosslinks were identified at several positions across the extended acidic patch region, most prominently at positions H2A E56 and H2B E113, which, importantly, were substantially reduced when key RLR basic residues in SSX were mutated (Fig.	('SSX', 'Gene', (8, 11))	('SSX', 'Gene', '6757', (231, 234))	('SSX', 'Gene', (231, 234))	('E113', 'Var', (147, 151))	('E56', 'Var', (135, 138))	('SSX', 'Gene', '6757', (8, 11))	('E56', 'CellLine', 'CVCL:5768', (135, 138))	('H2A', 'Var', (131, 134))	('reduced', 'NegReg', (192, 199))
103054	32747783	To probe this further, we assembled nucleosomes containing H2A mutant variants D90N, E92K and E113K, which disrupt the integrity of the acidic patch for GST-SSX pull-down experiments.	('E92K', 'Var', (85, 89))	('D90N', 'Mutation', 'p.D90N', (79, 83))	('integrity', 'MPA', (119, 128))	('H2A', 'Gene', (59, 62))	('E113K', 'Var', (94, 99))	('disrupt', 'NegReg', (107, 114))	('SSX', 'Gene', (157, 160))	('D90N', 'Var', (79, 83))	('SSX', 'Gene', '6757', (157, 160))	('GST', 'Gene', (153, 156))	('E92K', 'Mutation', 'p.E92K', (85, 89))	('E113K', 'Mutation', 'p.E113K', (94, 99))	('GST', 'Gene', '373156', (153, 156))
103057	32747783	In cells, single-residue mutations within the nucleosome acidic patch binding region of SSX (SSX R169A as well as W164A) resulted in attenuation of SS18-SSX-specific BAF complex chromatin occupancy, recruitment to Barr bodies, gene expression activation and proliferative maintenance in SS cell lines (Fig.	('SSX', 'Gene', '6757', (93, 96))	('gene expression', 'CPA', (227, 242))	('attenuation', 'NegReg', (133, 144))	('activation', 'PosReg', (243, 253))	('BAF', 'Gene', (166, 169))	('SS18', 'Gene', '6760', (148, 152))	('SSX', 'Gene', (93, 96))	('proliferative maintenance', 'CPA', (258, 283))	('R169A', 'Mutation', 'p.R169A', (97, 102))	('SSX', 'Gene', '6757', (153, 156))	('single-residue mutations', 'Var', (10, 34))	('SSX', 'Gene', '6757', (88, 91))	('BAF', 'Gene', '8815', (166, 169))	('SS18', 'Gene', (148, 152))	('W164A', 'SUBSTITUTION', 'None', (114, 119))	('W164A', 'Var', (114, 119))	('SSX', 'Gene', (153, 156))	('SSX', 'Gene', (88, 91))	('recruitment', 'MPA', (199, 210))
103063	32747783	7c), recent BAF complex structural insights and assessment of SMARCB1 levels across SS18-SSX mutant conditions (Extended Data Fig.	('SSX', 'Gene', '6757', (89, 92))	('BAF', 'Gene', '8815', (12, 15))	('SS18', 'Gene', (84, 88))	('SSX', 'Gene', (89, 92))	('mutant', 'Var', (93, 99))	('BAF', 'Gene', (12, 15))	('SMARCB1', 'Gene', (62, 69))	('SMARCB1', 'Gene', '6598', (62, 69))	('SS18', 'Gene', '6760', (84, 88))
103076	32747783	Given that the key histone modification placed by PRC1 is the H2AK119Ub mark, we sought to determine whether SSX exhibited any preferential binding to nucleosomes decorated with this modification.	('binding', 'Interaction', (140, 147))	('SSX', 'Gene', (109, 112))	('SSX', 'Gene', '6757', (109, 112))	('PRC1', 'Gene', (50, 54))	('H2AK119Ub', 'Chemical', '-', (62, 71))	('H2AK119Ub mark', 'Var', (62, 76))
103077	32747783	Notably, we found that in SS cell lines, H2AK119Ub directly co-localized with sites of SS18-SSX BAF complex occupancy (Fig.	('SSX', 'Gene', '6757', (92, 95))	('BAF', 'Gene', (96, 99))	('SS18', 'Gene', '6760', (87, 91))	('SSX', 'Gene', (92, 95))	('H2AK119Ub', 'Var', (41, 50))	('H2AK119Ub', 'Chemical', '-', (41, 50))	('SS18', 'Gene', (87, 91))	('BAF', 'Gene', '8815', (96, 99))
103078	32747783	Indeed, pull-down experiments and AlphaLISA binding assays performed with GST-SSX 78 aa protein revealed higher affinity to H2AK119Ub-decorated nucleosomes relative to unmodified nucleosomes or H2BK120Ub nucleosomes (4.8-fold difference (Ub/unmod) by AlphaLISA) (Fig.	('higher', 'PosReg', (105, 111))	('affinity', 'MPA', (112, 120))	('SSX', 'Gene', '6757', (78, 81))	('AlphaLISA', 'Chemical', '-', (34, 43))	('SSX', 'Gene', (78, 81))	('GST', 'Gene', (74, 77))	('AlphaLISA', 'Chemical', '-', (251, 260))	('H2AK119Ub-decorated', 'Var', (124, 143))	('GST', 'Gene', '373156', (74, 77))	('H2AK119Ub', 'Chemical', '-', (124, 133))
103081	32747783	Importantly, endogenously purified SS18-SSX-bound BAF complexes enriched for binding of recombinant H2AK119Ub-modified nucleosomes over unmodified nucleosomes by 5.62-fold (P = 0.03) (Fig.	('SS18', 'Gene', (35, 39))	('SSX', 'Gene', '6757', (40, 43))	('SSX', 'Gene', (40, 43))	('H2AK119Ub', 'Chemical', '-', (100, 109))	('BAF', 'Gene', '8815', (50, 53))	('H2AK119Ub-modified', 'Var', (100, 118))	('SS18', 'Gene', '6760', (35, 39))	('binding', 'Interaction', (77, 84))	('BAF', 'Gene', (50, 53))
103084	32747783	Finally, we performed a screen for SSX binding to a range of differentially marked recombinant mononucleosomes as well as mammalian (pooled) nucleosomes and again identified that GST-SSX 78 aa preferentially bound to H2AK119Ub and mammalian nucleosomes over unmodified nucleosomes or nucleosomes with other histone marks (Extended Data Fig.	('GST', 'Gene', (179, 182))	('SSX', 'Gene', '6757', (183, 186))	('GST', 'Gene', '373156', (179, 182))	('mammalian', 'Species', '9606', (231, 240))	('preferentially', 'PosReg', (193, 207))	('H2AK119Ub', 'Var', (217, 226))	('H2AK119Ub', 'Chemical', '-', (217, 226))	('bound', 'Interaction', (208, 213))	('SSX', 'Gene', (35, 38))	('SSX', 'Gene', '6757', (35, 38))	('mammalian', 'Species', '9606', (122, 131))	('SSX', 'Gene', (183, 186))
103087	32747783	To address whether the catalytic activity of PRC1 rather than PRC1 complex formation is required for SS18-SSX Barr body recruitment, we performed structure-guided mutagenesis to selectively disrupt the ubiquitin ligase activity of PRC1 and hence block its placement of H2AK119Ub (Fig.	('SS18', 'Gene', (101, 105))	('activity', 'MPA', (219, 227))	('ubiquitin ligase', 'Enzyme', (202, 218))	('block', 'NegReg', (246, 251))	('SSX', 'Gene', '6757', (106, 109))	('SS18', 'Gene', '6760', (101, 105))	('disrupt', 'NegReg', (190, 197))	('SSX', 'Gene', (106, 109))	('PRC1', 'Gene', (231, 235))	('H2AK119Ub', 'Chemical', '-', (269, 278))	('H2AK119Ub', 'Var', (269, 278))
103088	32747783	We designed a series of point mutations in RING1B to disrupt acidic patch recognition (R98A), zinc binding (H69Y, R70C) and the E2 binding interface (R91A and I53A/D56K) (Fig.	('R91A', 'Mutation', 'p.R91A', (150, 154))	('H69Y', 'Var', (108, 112))	('I53A', 'SUBSTITUTION', 'None', (159, 163))	('RING1B', 'Gene', '6045', (43, 49))	('acidic patch recognition', 'MPA', (61, 85))	('R98A', 'Mutation', 'p.R98A', (87, 91))	('R70C', 'Mutation', 'p.R70C', (114, 118))	('point mutations', 'Var', (24, 39))	('zinc', 'MPA', (94, 98))	('RING1B', 'Gene', (43, 49))	('I53A', 'Var', (159, 163))	('R91A', 'Var', (150, 154))	('disrupt', 'NegReg', (53, 60))	('E2', 'Chemical', 'MESH:D004958', (128, 130))	('D56K', 'Mutation', 'p.D56K', (164, 168))	('H69Y', 'Mutation', 'p.H69Y', (108, 112))
103089	32747783	Rescue of WT RING1B in RING1A-RING1B-dKO cells was able to completely rescue SSX localization.	('rescue', 'PosReg', (70, 76))	('SSX', 'Gene', (77, 80))	('SSX', 'Gene', '6757', (77, 80))	('Rescue', 'Var', (0, 6))	('RING1A', 'Gene', '6015', (23, 29))	('RING1B', 'Gene', '6045', (30, 36))	('RING1A', 'Gene', (23, 29))	('RING1B', 'Gene', (30, 36))	('RING1B', 'Gene', '6045', (13, 19))	('RING1B', 'Gene', (13, 19))
103090	32747783	However, restoration of RING1B mutant variants affected SS18-SSX localization in a manner directly proportional to the degree to which these RING1B mutations impacted H2AK119Ub deposition.	('RING1B', 'Gene', (141, 147))	('mutant variants', 'Var', (31, 46))	('mutations', 'Var', (148, 157))	('H2AK119Ub', 'Chemical', '-', (167, 176))	('variants', 'Var', (38, 46))	('impacted', 'Reg', (158, 166))	('H2AK119Ub deposition', 'MPA', (167, 187))	('affected', 'Reg', (47, 55))	('SSX', 'Gene', (61, 64))	('SSX', 'Gene', '6757', (61, 64))	('SS18', 'Gene', '6760', (56, 60))	('RING1B', 'Gene', '6045', (24, 30))	('RING1B', 'Gene', (24, 30))	('RING1B', 'Gene', '6045', (141, 147))	('SS18', 'Gene', (56, 60))
103091	32747783	Significantly for this study, RING1A ligase-deficient R91E and I53A/D56K were able to form polycomb foci but were unable to recruit SS18-SSX, further highlighting the importance of the H2AK119Ub mark placement for SSX targeting.	('SS18', 'Gene', (132, 136))	('R91E', 'Mutation', 'p.R91E', (54, 58))	('SSX', 'Gene', '6757', (214, 217))	('unable', 'NegReg', (114, 120))	('SSX', 'Gene', (214, 217))	('I53A', 'Var', (63, 67))	('SSX', 'Gene', (137, 140))	('H2AK119Ub', 'Chemical', '-', (185, 194))	('RING1A', 'Gene', '6015', (30, 36))	('D56K', 'Mutation', 'p.D56K', (68, 72))	('SSX', 'Gene', '6757', (137, 140))	('SS18', 'Gene', '6760', (132, 136))	('R91E', 'Var', (54, 58))	('RING1A', 'Gene', (30, 36))	('I53A', 'SUBSTITUTION', 'None', (63, 67))
103092	32747783	As controls, R98A and combined H69Y and R70C mutants had similar loss-of-function effects on SS18-SSX localization (Fig.	('localization', 'MPA', (102, 114))	('SS18', 'Gene', (93, 97))	('R98A', 'Mutation', 'p.R98A', (13, 17))	('H69Y', 'Var', (31, 35))	('R98A', 'Var', (13, 17))	('R70C', 'Var', (40, 44))	('SSX', 'Gene', '6757', (98, 101))	('loss-of-function', 'NegReg', (65, 81))	('SSX', 'Gene', (98, 101))	('R70C', 'Mutation', 'p.R70C', (40, 44))	('SS18', 'Gene', '6760', (93, 97))	('H69Y', 'Mutation', 'p.H69Y', (31, 35))
103093	32747783	The widely used I53A mutant only partially attenuated H2A ubiquitination, and therefore had little effect on SSX targeting.	('I53A', 'Var', (16, 20))	('I53A', 'Mutation', 'p.I53A', (16, 20))	('H2A', 'Protein', (54, 57))	('SSX', 'Gene', (109, 112))	('SSX', 'Gene', '6757', (109, 112))	('attenuated', 'NegReg', (43, 53))
103094	32747783	As further support for a role for H2AK119Ub in SSX recruitment, we used a peptide hybridization assay performed on IMR90 cells pretreated with the deubiquitinating enzyme USP2.	('H2AK119Ub', 'Var', (34, 43))	('SSX', 'Gene', (47, 50))	('H2AK119Ub', 'Chemical', '-', (34, 43))	('SSX', 'Gene', '6757', (47, 50))	('USP2', 'Gene', (171, 175))	('IMR90', 'CellLine', 'CVCL:0347', (115, 120))	('USP2', 'Gene', '9099', (171, 175))
103095	32747783	USP2-mediated removal of H2AK119Ub disrupted SSX peptide hybridization to Barr bodies specifically and without affecting its overall nuclear staining pattern, consistent with the general ability of SSX to bind unmodified nucleosomes via its acidic patch binding region.	('USP2', 'Gene', '9099', (0, 4))	('bind', 'Interaction', (205, 209))	('SSX', 'Gene', (198, 201))	('SSX', 'Gene', '6757', (198, 201))	('H2AK119Ub', 'Var', (25, 34))	('H2AK119Ub', 'Chemical', '-', (25, 34))	('SSX', 'Gene', (45, 48))	('SSX', 'Gene', '6757', (45, 48))	('USP2', 'Gene', (0, 4))	('disrupted', 'NegReg', (35, 44))
103097	32747783	Somewhat surprisingly, given the clear role for H2AK119Ub in recruiting SSX to chromatin, we did not observe direct binding between SSX and free ubiquitin, as assessed by a Ub-agarose pull-down assay (Extended Data Fig.	('SSX', 'Gene', (72, 75))	('SSX', 'Gene', '6757', (132, 135))	('SSX', 'Gene', (132, 135))	('binding', 'Interaction', (116, 123))	('H2AK119Ub', 'Var', (48, 57))	('H2AK119Ub', 'Chemical', '-', (48, 57))	('SSX', 'Gene', '6757', (72, 75))
103099	32747783	Finally, given that disruption of the conserved C-terminal acidic region of SSX did not disrupt SSX-nucleosome binding (Fig.	('SSX', 'Gene', (76, 79))	('disruption', 'Var', (20, 30))	('SSX', 'Gene', '6757', (96, 99))	('SSX', 'Gene', (96, 99))	('SSX', 'Gene', '6757', (76, 79))
103101	32747783	2g-i) in a manner comparable to loss of the basic region (acidic patch binding region), we sought to determine whether this region mediates the preference of SSX for H2AK119Ub-decorated nucleosomes.	('H2AK119Ub-decorated', 'Var', (166, 185))	('SSX', 'Gene', (158, 161))	('H2AK119Ub', 'Chemical', '-', (166, 175))	('SSX', 'Gene', '6757', (158, 161))
103102	32747783	Excitingly, we found that mutation of the C-terminal acidic region of SSX to alanines (that is DPEEDDE   AAAAAAA) relieved the preference of SSX for H2AK119Ub nucleosomes, while not altering general SSX binding to nucleosomes (Fig.	('SSX', 'Gene', (70, 73))	('relieved', 'NegReg', (114, 122))	('mutation', 'Var', (26, 34))	('H2AK119Ub', 'Chemical', '-', (149, 158))	('SSX', 'Gene', '6757', (70, 73))	('SSX', 'Gene', '6757', (199, 202))	('SSX', 'Gene', (199, 202))	('SSX', 'Gene', (141, 144))	('alanines', 'Chemical', 'MESH:D000409', (77, 85))	('H2AK119Ub', 'Var', (149, 158))	('SSX', 'Gene', '6757', (141, 144))	('preference', 'MPA', (127, 137))
103103	32747783	These data collectively indicate that the conserved C-terminal acidic amino acids are required to drive the preference of SSX for H2AK119Ub nucleosomes and hence SS18-SSX-bound BAF complex targeting to repressive regions genome-wide, as observed in cells.	('H2AK119Ub', 'Var', (130, 139))	('H2AK119Ub', 'Chemical', '-', (130, 139))	('SSX', 'Gene', (167, 170))	('BAF', 'Gene', '8815', (177, 180))	('SSX', 'Gene', '6757', (122, 125))	('SSX', 'Gene', '6757', (167, 170))	('BAF', 'Gene', (177, 180))	('SSX', 'Gene', (122, 125))	('SS18', 'Gene', '6760', (162, 166))	('SS18', 'Gene', (162, 166))
103110	32747783	The expression of full-length SSX (188 aa) is normally restricted to testes, where it plays a role in sperm development, potentially involving polycomb-driven XY-body repression through engagement of H2AK119Ub-decorated sex chromosomes.	('plays', 'Reg', (86, 91))	('decorated sex', 'Phenotype', 'HP:0030214', (210, 223))	('SSX', 'Gene', '6757', (30, 33))	('SSX', 'Gene', (30, 33))	('H2AK119Ub-decorated', 'Var', (200, 219))	('H2AK119Ub', 'Chemical', '-', (200, 209))
103113	32747783	In the case of SS, the KRAB domain is replaced with essentially the whole ATPase module of the BAF chromatin remodeling complex via fusion to SS18.	('BAF', 'Gene', '8815', (95, 98))	('SS18', 'Gene', '6760', (142, 146))	('ATPase', 'Gene', '1769', (74, 80))	('ATPase', 'Gene', (74, 80))	('fusion', 'Var', (132, 138))	('BAF', 'Gene', (95, 98))	('SS18', 'Gene', (142, 146))
103117	32747783	Our data suggest two non-mutually exclusive explanations for this reading preference: (1) H2AK119Ub modification influences nucleosome structure by further exposing the acidic patch binding site or (2) SSX directly engages ubiquitin in the nucleosomal context.	('influences', 'Reg', (113, 123))	('exposing', 'PosReg', (156, 164))	('ubiquitin', 'Protein', (223, 232))	('acidic patch binding site', 'MPA', (169, 194))	('engages', 'Interaction', (215, 222))	('H2AK119Ub modification', 'Var', (90, 112))	('nucleosome structure', 'MPA', (124, 144))	('SSX', 'Gene', '6757', (202, 205))	('SSX', 'Gene', (202, 205))	('H2AK119Ub', 'Chemical', '-', (90, 99))
103133	32747783	Constitutive expression of SS18 WT (SS18), SS18-SSX1 (SS18-SSX1) and SS18-SSX1 mutations with HA or V5 N-terminus tag was obtained using an EF1alpha-driven expression vector (modified from Clonetech, dual Promoter EF-1a-MCS-PGK-Puro or EF-1a-MCS-PGK-Blast) expressed in cells by lentiviral infection and selected with puromycin (2 mug ml-1) or blasticidin (10 microg ml-1).	('infection', 'Disease', (290, 299))	('infection', 'Disease', 'MESH:D007239', (290, 299))	('SS18', 'Gene', (43, 47))	('SS18', 'Gene', '6760', (69, 73))	('SS18', 'Gene', '6760', (36, 40))	('mutations', 'Var', (79, 88))	('SSX1', 'Gene', '6756', (59, 63))	('SS18', 'Gene', '6760', (27, 31))	('puromycin', 'Chemical', 'MESH:D011691', (318, 327))	('SSX1', 'Gene', (59, 63))	('blasticidin', 'Chemical', 'MESH:C004500', (344, 355))	('SSX1', 'Gene', '6756', (74, 78))	('EF1alpha', 'Gene', (140, 148))	('EF-1a', 'Gene', '1917', (214, 219))	('SS18', 'Gene', '6760', (43, 47))	('EF-1a', 'Gene', (214, 219))	('SSX1', 'Gene', (74, 78))	('SS18', 'Gene', (54, 58))	('SS18', 'Gene', (69, 73))	('SS18', 'Gene', (36, 40))	('EF-1a', 'Gene', '1917', (236, 241))	('EF-1a', 'Gene', (236, 241))	('SSX1', 'Gene', '6756', (48, 52))	('EF1alpha', 'Gene', '1917', (140, 148))	('SS18', 'Gene', (27, 31))	('SS18', 'Gene', '6760', (54, 58))	('SSX1', 'Gene', (48, 52))
103212	32747783	The substrates used for this assay measuring nucleosome-bound ATPase activity were purified recombinant mononucleosome (EpiDyne nucleosome remodeling assay substrate ST601-GATC1, EpiCypher, cat.	('ATPase', 'Gene', (62, 68))	('ST601-GATC1', 'Var', (166, 177))	('ATPase', 'Gene', '1769', (62, 68))
103331	32256920	Based on tumor pathology, our patients demonstrated two different molecular tumor subtypes: case 1 had PD-L1+ tumor cells, and case 2 had MDM2+ amplification.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('PD-L1+ tumor', 'Disease', 'MESH:D010300', (103, 115))	('tumor', 'Disease', (9, 14))	('PD-L1+ tumor', 'Disease', (103, 115))	('patients', 'Species', '9606', (30, 38))	('MDM2+ amplification', 'Var', (138, 157))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
103347	29462961	A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas Epigenetic events and genetic alterations under the control of the tumor microenvironment potentially mediate tumor induced angiogenesis involved in soft tissue sarcoma (STS) metastasis.	('Sarcomas', 'Disease', (151, 159))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (48, 59))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (309, 328))	('tumor', 'Disease', (227, 232))	('soft tissue sarcoma', 'Disease', (309, 328))	('Valproic Acid', 'Chemical', 'MESH:D014635', (124, 137))	('Sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (309, 328))	('mediate', 'Reg', (262, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (321, 328))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('genetic alterations', 'Var', (182, 201))	('Sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('tumor', 'Disease', (270, 275))	('Epigenetic events', 'Var', (160, 177))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
103349	29462961	We hypothesized the existence of an epigenetically mediated "angiogenic switch", and the tumor microenvironment, prevents bevacizumab from truly blocking angiogenesis.	('prevents', 'NegReg', (113, 121))	('blocking', 'NegReg', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('epigenetically mediated', 'Var', (36, 59))	('bevacizumab', 'Chemical', 'MESH:D000068258', (122, 133))	('angiogenesis', 'CPA', (154, 166))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
103379	29462961	Epigenetic manipulation is a novel approach to cancer therapy that is increasingly being explored in solid tumors with limited success.	('Epigenetic manipulation', 'Var', (0, 23))	('solid tumors', 'Disease', 'MESH:D009369', (101, 113))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (47, 53))	('solid tumors', 'Disease', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
103380	29462961	Clinical evidence supports that epigenetic silencing of the tumor suppressor genes with angiogenesis inhibiting properties may contribute to chemoresistance, and that drugs targeting epigenetic mechanisms may enhance chemosensitivity.	('chemoresistance', 'CPA', (141, 156))	('enhance', 'PosReg', (209, 216))	('chemosensitivity', 'CPA', (217, 233))	('epigenetic', 'Var', (183, 193))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('contribute', 'Reg', (127, 137))	('epigenetic silencing', 'Var', (32, 52))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
103409	29462961	Gain of function (GOF) TP53 mutations were found in 3 and loss of function (LOF) TP53 in 5 of the 30 available tumor specimens.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('loss of function', 'NegReg', (58, 74))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('TP53', 'Gene', '7157', (81, 85))	('mutations', 'Var', (28, 37))	('Gain of function', 'PosReg', (0, 16))	('TP53', 'Gene', (81, 85))
103412	29462961	We attempted to show that epigenetically modifying the tumor microenvironment may turn off the "angiogenic switch", improve cytotoxic cell kill, overcome chemotherapy resistance, and thereby, improve response rates.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('epigenetically modifying', 'Var', (26, 50))	('improve', 'PosReg', (116, 123))	('cytotoxic cell kill', 'CPA', (124, 143))	('improve', 'PosReg', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('overcome', 'NegReg', (145, 153))	('response rates', 'CPA', (200, 214))	('turn', 'Reg', (82, 86))	('chemotherapy resistance', 'CPA', (154, 177))
103424	29462961	Like many tumors, TP53 mutations have been reported in STS.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('TP53', 'Gene', '7157', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('TP53', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('mutations', 'Var', (23, 32))	('reported', 'Reg', (43, 51))
103425	29462961	The functional impact of different types of p53 mutant proteins may have different implications for chemosensitivity.	('p53', 'Gene', (44, 47))	('proteins', 'Protein', (55, 63))	('mutant', 'Var', (48, 54))	('p53', 'Gene', '7157', (44, 47))
103426	29462961	Some variants are relatively inconsequential from the perspective of p53 function, and proteins of this type retain wild type activity.	('activity', 'MPA', (126, 134))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('variants', 'Var', (5, 13))
103427	29462961	Other mutations are LOF or p53-null, in which single amino acid changes completely inactivate or destabilize the protein.	('p53', 'Gene', '7157', (27, 30))	('single amino acid changes', 'Var', (46, 71))	('protein', 'Protein', (113, 120))	('destabilize', 'NegReg', (97, 108))	('p53', 'Gene', (27, 30))	('inactivate', 'NegReg', (83, 93))
103428	29462961	Preclinical studies have shown that LOF p53 mutant sarcomas produced significantly more VEGF, which contribute directly to angiogenesis, metastasis, and growth.	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('LOF', 'NegReg', (36, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Disease', (51, 59))	('VEGF', 'Gene', (88, 92))	('growth', 'CPA', (153, 159))	('p53', 'Gene', (40, 43))	('angiogenesis', 'CPA', (123, 135))	('p53', 'Gene', '7157', (40, 43))	('more', 'PosReg', (83, 87))	('VEGF', 'Gene', '7422', (88, 92))	('metastasis', 'CPA', (137, 147))	('mutant', 'Var', (44, 50))
103429	29462961	Recent retrospective data suggests that LOF TP53 mutant sarcomas may be more sensitive to VEGF inhibitors.	('VEGF', 'Gene', (90, 94))	('mutant', 'Var', (49, 55))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('VEGF', 'Gene', '7422', (90, 94))	('TP53', 'Gene', '7157', (44, 48))	('sarcomas', 'Disease', (56, 64))	('TP53', 'Gene', (44, 48))
103430	29462961	Finally, an interesting category of TP53 mutations is the GOF or "oncogenic" TP53 mutations, that convert p53 from a tumor suppressor to an oncogene, also termed as oncomorphic p53, as proposed by Brachova et al..	('mutations', 'Var', (41, 50))	('p53', 'Gene', '7157', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('p53', 'Gene', (177, 180))	('p53', 'Gene', '7157', (177, 180))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))	('TP53', 'Gene', '7157', (77, 81))	('p53', 'Gene', (106, 109))	('TP53', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
103431	29462961	Treatment with HDAC inhibitor of ovarian cancer TP53 GOF mutant cell lines lead to potential dissociation of GOF p53-Hsp 90 complex, thereby leading to mutant p53 degradation.	('ovarian cancer', 'Disease', 'MESH:D010051', (33, 47))	('dissociation', 'MPA', (93, 105))	('degradation', 'MPA', (163, 174))	('TP53', 'Gene', '7157', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('p53', 'Gene', (159, 162))	('ovarian cancer', 'Disease', (33, 47))	('p53', 'Gene', '7157', (159, 162))	('TP53', 'Gene', (48, 52))	('HDAC', 'Gene', (15, 19))	('mutant', 'Var', (57, 63))	('mutant', 'Var', (152, 158))	('p53', 'Gene', '7157', (113, 116))	('HDAC', 'Gene', '9734', (15, 19))	('GOF', 'PosReg', (53, 56))	('p53', 'Gene', (113, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))
103432	29462961	We evaluated the available archival tumor blocks for gain of function TP53 mutations, but insufficient numbers of variants were detected to meet statistical significance (Table 4).	('TP53', 'Gene', '7157', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('gain', 'PosReg', (53, 57))	('tumor', 'Disease', (36, 41))
103433	29462961	This perhaps reflects either the dynamic nature of these mutations, or the use of weak HDAC inhibitor in our study, and a failure to achieve the rheostat effect.	('HDAC', 'Gene', (87, 91))	('mutations', 'Var', (57, 66))	('HDAC', 'Gene', '9734', (87, 91))
103471	26777415	We generated a mouse model with inducible endothelial cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('mTORC1', 'Gene', '382056', (96, 102))	('lymphangiosarcoma', 'Disease', (116, 133))	('deletion', 'Var', (68, 76))	('angiosarcoma', 'Phenotype', 'HP:0200058', (121, 133))	('lymphangiosarcoma', 'Disease', 'MESH:C537491', (116, 133))	('mouse', 'Species', '10090', (15, 20))	('mTORC1', 'Gene', (96, 102))	('Tsc1', 'Gene', (80, 84))
103476	26777415	These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma, and validate the mice as a valuable model for further study.	('lymphangiosarcoma', 'Disease', (80, 97))	('mice', 'Species', '10090', (116, 120))	('angiosarcoma', 'Phenotype', 'HP:0200058', (85, 97))	('lymphangiosarcoma', 'Disease', 'MESH:C537491', (80, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('mTORC1', 'Gene', '382056', (59, 65))	('mTORC1', 'Gene', (59, 65))	('aberrant', 'Var', (50, 58))	('activation', 'PosReg', (66, 76))
103477	26777415	Disruption or aberrations of these pathways can lead to vascular tumors or malformations according to their clinical behavior and endothelial cell (EC) characteristics.	('vascular tumors', 'Phenotype', 'HP:0100742', (56, 71))	('aberrations', 'Var', (14, 25))	('vascular tumors', 'Disease', (56, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('vascular tumor', 'Phenotype', 'HP:0100742', (56, 70))	('lead to', 'Reg', (48, 55))	('vascular tumors', 'Disease', 'MESH:D019043', (56, 71))	('malformations', 'Disease', 'MESH:D000014', (75, 88))	('malformations', 'Disease', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Disruption', 'Var', (0, 10))
103489	26777415	Dysfunction of mTORC1 signaling has been implicated in diseases including vascular tumors and malformations.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('vascular tumors', 'Disease', 'MESH:D019043', (74, 89))	('Dysfunction', 'Var', (0, 11))	('mTORC1', 'Gene', (15, 21))	('vascular tumors', 'Phenotype', 'HP:0100742', (74, 89))	('vascular tumor', 'Phenotype', 'HP:0100742', (74, 88))	('malformations', 'Disease', 'MESH:D000014', (94, 107))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('malformations', 'Disease', (94, 107))	('vascular tumors', 'Disease', (74, 89))	('implicated', 'Reg', (41, 51))	('mTORC1', 'Gene', '382056', (15, 21))
103494	26777415	Studies link mTORC1 signaling and vascular anomalies, but it remains to be determined whether hyperactivation of mTORC1 in ECs is sufficient to induce angiosarcomas with aggressive and metastatic features responsible for lethality.	('mTORC1', 'Gene', '382056', (113, 119))	('hyperactivation', 'Var', (94, 109))	('mTORC1', 'Gene', '382056', (13, 19))	('vascular anomalies', 'Disease', 'MESH:D000783', (34, 52))	('angiosarcoma', 'Phenotype', 'HP:0200058', (151, 163))	('angiosarcomas', 'Disease', (151, 164))	('vascular anomalies', 'Disease', (34, 52))	('mTORC1', 'Gene', (113, 119))	('mTORC1', 'Gene', (13, 19))	('angiosarcomas', 'Disease', 'MESH:D006394', (151, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('angiosarcomas', 'Phenotype', 'HP:0200058', (151, 164))	('vascular anomalies', 'Phenotype', 'HP:0002597', (34, 52))	('induce', 'Reg', (144, 150))
103496	26777415	Mutations in TSC1 or TSC2 result in benign malformations or tumors in many different organs, including lymphangioleiomyomatosis in the lungs, and angiomyolipomas in the kidney.	('angiomyolipomas', 'Disease', (146, 161))	('angiomyolipomas in the kidney', 'Phenotype', 'HP:0006772', (146, 175))	('TSC2', 'Gene', (21, 25))	('TSC1', 'Gene', '64930', (13, 17))	('benign malformations or tumors', 'Disease', (36, 66))	('result in', 'Reg', (26, 35))	('benign malformations or tumors', 'Disease', 'MESH:D000014', (36, 66))	('lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (103, 127))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TSC1', 'Gene', (13, 17))	('TSC2', 'Gene', '22084', (21, 25))	('angiomyolipomas', 'Disease', 'MESH:D018207', (146, 161))	('lymphangioleiomyomatosis', 'Disease', 'MESH:D018192', (103, 127))	('lymphangioleiomyomatosis', 'Disease', (103, 127))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
103504	26777415	These data raised the possibility that deregulated mTORC1 signaling plays a role in the development of human angiosarcomas.	('human', 'Species', '9606', (103, 108))	('deregulated', 'Var', (39, 50))	('angiosarcomas', 'Disease', 'MESH:D006394', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('angiosarcomas', 'Phenotype', 'HP:0200058', (109, 122))	('mTORC1', 'Gene', '382056', (51, 57))	('mTORC1', 'Gene', (51, 57))	('angiosarcomas', 'Disease', (109, 122))	('angiosarcoma', 'Phenotype', 'HP:0200058', (109, 121))
103505	26777415	We generated a mouse model for mTORC1 activation in ECs by specific deletion of its upstream inhibitor Tsc1.	('mTORC1', 'Gene', '382056', (31, 37))	('deletion', 'Var', (68, 76))	('Tsc1', 'Gene', (103, 107))	('mouse', 'Species', '10090', (15, 20))	('activation', 'PosReg', (38, 48))	('mTORC1', 'Gene', (31, 37))	('ECs', 'Disease', (52, 55))
103507	26777415	Administration of tamoxifen to Tsc1f/f;Scl-Cre mice (designated as Tsc1iDeltaEC mice after induced Tsc1 deletion) from postnatal day 1 (P1) to P3 induced activation of Cre recombinase in the retinal endothelium (Figures 1C, D), resulting in an efficient reduction of Tsc1 expression in ECs, as measured by immunoblotting analyses of lysates of ECs from the lungs at P5 (Figures 1E, F).	('Tsc1', 'Gene', (267, 271))	('expression', 'MPA', (272, 282))	('activation', 'PosReg', (154, 164))	('reduction', 'NegReg', (254, 263))	('tamoxifen', 'Chemical', 'MESH:D013629', (18, 27))	('mice', 'Species', '10090', (80, 84))	('deletion', 'Var', (104, 112))	('mice', 'Species', '10090', (47, 51))
103508	26777415	Increased phosphorylation of S6 was found in Tsc1iDeltaEC ECs relative to controls, indicating activation of mTORC1 upon Tsc1 deletion in these cells as expected.	('mTORC1', 'Gene', (109, 115))	('phosphorylation', 'MPA', (10, 25))	('activation', 'PosReg', (95, 105))	('deletion', 'Var', (126, 134))	('Tsc1', 'Gene', (121, 125))	('mTORC1', 'Gene', '382056', (109, 115))	('Increased phosphorylation of S6', 'Phenotype', 'HP:0003240', (0, 31))
103509	26777415	We also observed decreased Akt phosphorylation in the mutant cells, consistent with previous reports of its feedback inhibition by activated mTORC1 (Figures 1E, F).	('decreased', 'NegReg', (17, 26))	('mTORC1', 'Gene', '382056', (141, 147))	('Akt', 'Gene', '11651', (27, 30))	('mutant', 'Var', (54, 60))	('Akt', 'Gene', (27, 30))	('mTORC1', 'Gene', (141, 147))
103512	26777415	At 3 months or more after tamoxifen treatment, Tsc1iDeltaEC mice developed cutaneous tumors in tails and paws (Figure 2A).	('Tsc1iDeltaEC', 'Var', (47, 59))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (75, 91))	('developed', 'PosReg', (65, 74))	('tamoxifen', 'Chemical', 'MESH:D013629', (26, 35))	('cutaneous tumors', 'Disease', 'MESH:D009369', (75, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mice', 'Species', '10090', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('cutaneous tumors', 'Disease', (75, 91))
103514	26777415	At 3-4 months after tamoxifen administration, nearly half of the Tsc1iDeltaEC mice had developed liver tumors and about 30% had cutaneous tumors (Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cutaneous tumors', 'Disease', 'MESH:D009369', (128, 144))	('developed', 'PosReg', (87, 96))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('Tsc1iDeltaEC', 'Var', (65, 77))	('liver tumor', 'Phenotype', 'HP:0002896', (97, 108))	('cutaneous tumors', 'Disease', (128, 144))	('tamoxifen', 'Chemical', 'MESH:D013629', (20, 29))	('liver tumors', 'Disease', 'MESH:D008113', (97, 109))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (128, 144))	('liver tumors', 'Disease', (97, 109))	('liver tumors', 'Phenotype', 'HP:0002896', (97, 109))	('mice', 'Species', '10090', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
103515	26777415	By 6-8 months after tamoxifen, almost all the Tsc1iDeltaEC mice developed liver tumors, and about 80% showed cutaneous tumors (Figure 2E).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (109, 125))	('liver tumors', 'Disease', (74, 86))	('mice', 'Species', '10090', (59, 63))	('liver tumors', 'Phenotype', 'HP:0002896', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tamoxifen', 'Chemical', 'MESH:D013629', (20, 29))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('liver tumor', 'Phenotype', 'HP:0002896', (74, 85))	('Tsc1iDeltaEC', 'Var', (46, 58))	('cutaneous tumors', 'Disease', 'MESH:D009369', (109, 125))	('cutaneous tumors', 'Disease', (109, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('liver tumors', 'Disease', 'MESH:D008113', (74, 86))	('developed', 'PosReg', (64, 73))
103517	26777415	Tsc1iDeltaEC mice had a significantly reduced lifespan (Figure 2F).	('Tsc1iDeltaEC', 'Var', (0, 12))	('mice', 'Species', '10090', (13, 17))	('lifespan', 'CPA', (46, 54))	('reduced', 'NegReg', (38, 45))
103519	26777415	Similar tail and liver tumors were observed in a small fraction of either Tsc1+/- or Tsc2+/- heterozygous mice.	('mice', 'Species', '10090', (106, 110))	('liver tumors', 'Disease', 'MESH:D008113', (17, 29))	('liver tumors', 'Disease', (17, 29))	('Tsc2', 'Gene', '22084', (85, 89))	('liver tumors', 'Phenotype', 'HP:0002896', (17, 29))	('Tsc1+/-', 'Var', (74, 81))	('Tsc2', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('liver tumor', 'Phenotype', 'HP:0002896', (17, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
103521	26777415	Histological examination of liver sections of Tsc1iDeltaEC mice showed increased numbers of portal vein profiles within the portal tracts expanding into the adjacent lobular hepatic parenchyma.	('lobular hepatic parenchyma', 'Disease', (166, 192))	('mice', 'Species', '10090', (59, 63))	('lobular hepatic parenchyma', 'Disease', 'MESH:D010195', (166, 192))	('portal vein profiles', 'CPA', (92, 112))	('Tsc1iDeltaEC', 'Var', (46, 58))	('increased', 'PosReg', (71, 80))
103523	26777415	In Tsc1iDeltaEC mice, however, multiple irregular vascular tributaries were observed in the neoplasm area.	('Tsc1iDeltaEC', 'Var', (3, 15))	('neoplasm', 'Disease', (92, 100))	('observed', 'Reg', (76, 84))	('mice', 'Species', '10090', (16, 20))	('neoplasm', 'Disease', 'MESH:D009369', (92, 100))	('neoplasm', 'Phenotype', 'HP:0002664', (92, 100))
103532	26777415	As early as one month after tamoxifen administration, some Tsc1iDeltaEC mice showed signs of edema with swelling in paws and tails (Figure 3A), which correlated with hyperplasia of PROX1 positive lymphatic channels within the dermis (Figure 3B, S3).	('edema', 'Phenotype', 'HP:0000969', (93, 98))	('Tsc1iDeltaEC', 'Var', (59, 71))	('hyperplasia', 'Disease', (166, 177))	('edema', 'Disease', (93, 98))	('swelling', 'Disease', 'MESH:D004487', (104, 112))	('swelling', 'Disease', (104, 112))	('tamoxifen', 'Chemical', 'MESH:D013629', (28, 37))	('mice', 'Species', '10090', (72, 76))	('hyperplasia', 'Disease', 'MESH:D006965', (166, 177))	('PROX1', 'Protein', (181, 186))	('edema', 'Disease', 'MESH:D004487', (93, 98))
103548	26777415	These results demonstrate that Tsc1 deletion in adult ECs leads to vascular malformations that may progress to malignant cutaneous lymphangiosarcoma.	('vascular malformations', 'Disease', (67, 89))	('deletion', 'Var', (36, 44))	('cutaneous lymphangiosarcoma', 'Disease', (121, 148))	('progress', 'PosReg', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('leads to', 'Reg', (58, 66))	('vascular malformations', 'Disease', 'MESH:D000014', (67, 89))	('Tsc1', 'Gene', (31, 35))	('cutaneous lymphangiosarcoma', 'Disease', 'MESH:C537491', (121, 148))	('angiosarcoma', 'Phenotype', 'HP:0200058', (136, 148))
103550	26777415	To investigate mechanisms, primary cells were isolated from cutaneous lymphangiosarcomas of Tsc1iDeltaEC mice and lungs of control Tsc1f/f mice.	('angiosarcoma', 'Phenotype', 'HP:0200058', (75, 87))	('cutaneous lymphangiosarcomas', 'Disease', (60, 88))	('angiosarcomas', 'Phenotype', 'HP:0200058', (75, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('cutaneous lymphangiosarcomas', 'Disease', 'MESH:C537491', (60, 88))	('mice', 'Species', '10090', (139, 143))	('Tsc1iDeltaEC', 'Var', (92, 104))	('mice', 'Species', '10090', (105, 109))
103551	26777415	Tsc1iDeltaEC ECs and control primary ECs were of high purity based on their morphology, staining with CD31, and DiI-Ac-LDL uptake assays (Figure S4).	('Tsc1iDeltaEC', 'Var', (0, 12))	('CD31', 'Gene', '18613', (102, 106))	('DiI-Ac-LDL', 'Chemical', '-', (112, 122))	('CD31', 'Gene', (102, 106))
103553	26777415	Recipient mice injected with Tsc1iDeltaEC ECs all developed subcutaneous tumors after one month (Figure 4D), while none of the recipient mice with control EC injections showed tumors (data not shown).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (60, 79))	('mice', 'Species', '10090', (10, 14))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (60, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('developed', 'PosReg', (50, 59))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (63, 79))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Tsc1iDeltaEC', 'Var', (29, 41))	('tumors', 'Disease', (73, 79))	('subcutaneous tumors', 'Disease', (60, 79))	('mice', 'Species', '10090', (137, 141))
103568	26777415	Rapamycin-treated Tsc1iDeltaEC mice also exhibited significantly increased survival, with all mice still alive after more than 6 months of Tsc1 deletion (i.e., 3 months after tamoxifen injection followed by 3 additional months with rapamycin treatment), when a significant fraction of vehicle treated mice had died (Figure 5I, 2F).	('survival', 'CPA', (75, 83))	('increased', 'PosReg', (65, 74))	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('tamoxifen', 'Chemical', 'MESH:D013629', (175, 184))	('rapamycin', 'Chemical', 'MESH:D020123', (232, 241))	('deletion', 'Var', (144, 152))	('mice', 'Species', '10090', (31, 35))	('mice', 'Species', '10090', (94, 98))	('mice', 'Species', '10090', (301, 305))	('Tsc1', 'Gene', (139, 143))
103575	26777415	We examined VEGFA expression in the vascular tumors in Tsc1iDeltaEC mice compared to cutaneous ECs of controls.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('vascular tumor', 'Phenotype', 'HP:0100742', (36, 50))	('Tsc1iDeltaEC', 'Var', (55, 67))	('vascular tumors', 'Phenotype', 'HP:0100742', (36, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('examined', 'Reg', (3, 11))	('VEGFA', 'Protein', (12, 17))	('vascular tumors', 'Disease', (36, 51))	('vascular tumors', 'Disease', 'MESH:D019043', (36, 51))
103577	26777415	Interestingly, a recent paper reported on another Tsc1 deletion model by Darpp-32-Cre (expressed in brain and multiple other tissues) also observed accelerated paw angiosarcomas formation and elevated VEGF mRNA.	('angiosarcoma', 'Phenotype', 'HP:0200058', (164, 176))	('angiosarcomas', 'Disease', (164, 177))	('Darpp-32', 'Gene', (73, 81))	('elevated', 'PosReg', (192, 200))	('Darpp-32', 'Gene', '19049', (73, 81))	('angiosarcomas', 'Disease', 'MESH:D006394', (164, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('angiosarcomas', 'Phenotype', 'HP:0200058', (164, 177))	('deletion', 'Var', (55, 63))	('VEGF', 'MPA', (201, 205))	('Tsc1', 'Gene', (50, 54))	('accelerated', 'PosReg', (148, 159))
103588	26777415	Consistent with these results, inhibition of mTORC1 by rapamycin significantly decreased HIF1alpha mRNA in Tsc1iDeltaEC ECs (Figure 6H).	('rapamycin', 'Chemical', 'MESH:D020123', (55, 64))	('decreased', 'NegReg', (79, 88))	('HIF1alpha', 'Protein', (89, 98))	('mTORC1', 'Gene', '382056', (45, 51))	('inhibition', 'Var', (31, 41))	('mTORC1', 'Gene', (45, 51))
103593	26777415	Increased MEK1/2 activation was found in vascular tumor tissues of Tsc1iDeltaEC mice compared to ECs in controls (Figure 7B).	('MEK1/2', 'Gene', '26395;26396', (10, 16))	('MEK1/2', 'Gene', (10, 16))	('vascular tumor', 'Disease', (41, 55))	('vascular tumor', 'Disease', 'MESH:D019043', (41, 55))	('vascular tumor', 'Phenotype', 'HP:0100742', (41, 55))	('activation', 'PosReg', (17, 27))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Tsc1iDeltaEC', 'Var', (67, 79))
103594	26777415	We also found moderate to intense pERK1/2 immunostaining in most vascular tumors from Tsc1iDeltaEC mice, but not ECs of controls (Figure 7C).	('immunostaining', 'MPA', (42, 56))	('mice', 'Species', '10090', (99, 103))	('ERK1/2', 'Gene', (35, 41))	('Tsc1iDeltaEC', 'Var', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('vascular tumor', 'Phenotype', 'HP:0100742', (65, 79))	('vascular tumors', 'Phenotype', 'HP:0100742', (65, 80))	('vascular tumors', 'Disease', 'MESH:D019043', (65, 80))	('ERK1/2', 'Gene', '26417;26413', (35, 41))	('vascular tumors', 'Disease', (65, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
103601	26777415	The number of apoptotic cells remained similar to lesions from untreated mice (Figures 7H, 7I), suggesting that axitinib exerts an antiproliferative rather than a pro-apoptotic effect.	('axitinib', 'Var', (112, 120))	('mice', 'Species', '10090', (73, 77))	('axitinib', 'Chemical', 'MESH:D000077784', (112, 120))	('antiproliferative', 'CPA', (131, 148))
103602	26777415	These results suggest that increased VEGF autocrine signaling plays an important role in the development and maintenance of vascular tumors in Tsc1iDeltaEC mice.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('Tsc1iDeltaEC', 'Var', (143, 155))	('increased', 'PosReg', (27, 36))	('vascular tumors', 'Disease', (124, 139))	('VEGF autocrine signaling', 'MPA', (37, 61))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('vascular tumor', 'Phenotype', 'HP:0100742', (124, 138))	('vascular tumors', 'Disease', 'MESH:D019043', (124, 139))	('mice', 'Species', '10090', (156, 160))	('vascular tumors', 'Phenotype', 'HP:0100742', (124, 139))
103607	26777415	We also examined the role of increased VEGFA in tumor growth, and found that knockdown of VEGFA significantly reduced the growth of vascular tumor cells (Figure 7K).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (48, 53))	('reduced', 'NegReg', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('VEGFA', 'Gene', (90, 95))	('tumor', 'Disease', (141, 146))	('knockdown', 'Var', (77, 86))	('vascular tumor', 'Disease', 'MESH:D019043', (132, 146))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('vascular tumor', 'Disease', (132, 146))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('vascular tumor', 'Phenotype', 'HP:0100742', (132, 146))
103608	26777415	We wondered if hyperactivation of mTORC1 also increased VEGFC and/or VEGFD expression and could promote vascular tumor growth by stimulating EC proliferation as well as VEGFA.	('mTORC1', 'Gene', '382056', (34, 40))	('VEGFD', 'Gene', '14205', (69, 74))	('increased', 'PosReg', (46, 55))	('VEGFC', 'Gene', '22341', (56, 61))	('hyperactivation', 'Var', (15, 30))	('stimulating', 'Reg', (129, 140))	('VEGFC', 'Gene', (56, 61))	('promote', 'PosReg', (96, 103))	('VEGFD', 'Gene', (69, 74))	('vascular tumor', 'Disease', (104, 118))	('mTORC1', 'Gene', (34, 40))	('vascular tumor', 'Disease', 'MESH:D019043', (104, 118))	('VEGFA', 'CPA', (169, 174))	('vascular tumor', 'Phenotype', 'HP:0100742', (104, 118))	('EC proliferation', 'CPA', (141, 157))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('expression', 'MPA', (75, 85))
103611	26777415	Our results demonstrate that VEGF autocrine signaling triggered by aberrant hyperactivation of mTORC1 contributes to the development of vascular tumors in Tsc1iDeltaEC mice, and that blockage of the VEGFR pathway could be a rational and effective therapy for human vascular tumors.	('hyperactivation', 'PosReg', (76, 91))	('VEGF autocrine signaling', 'MPA', (29, 53))	('vascular tumor', 'Phenotype', 'HP:0100742', (265, 279))	('vascular tumors', 'Phenotype', 'HP:0100742', (265, 280))	('vascular tumors', 'Disease', (136, 151))	('vascular tumor', 'Phenotype', 'HP:0100742', (136, 150))	('vascular tumors', 'Phenotype', 'HP:0100742', (136, 151))	('vascular tumors', 'Disease', 'MESH:D019043', (265, 280))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('vascular tumors', 'Disease', 'MESH:D019043', (136, 151))	('mTORC1', 'Gene', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('human', 'Species', '9606', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('mTORC1', 'Gene', '382056', (95, 101))	('VEGFR', 'Gene', '3791', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mice', 'Species', '10090', (168, 172))	('VEGFR', 'Gene', (199, 204))	('aberrant', 'Var', (67, 75))	('vascular tumors', 'Disease', (265, 280))
103617	26777415	These results provide strong support for an important role of the VEGF autocrine loop induced by aberrant hyperactivated mTORC1 signaling in human angiosarcoma, and further validate our Tsc1iDeltaEC mice as a valuable model for this neoplasm.	('mice', 'Species', '10090', (199, 203))	('neoplasm', 'Disease', 'MESH:D009369', (233, 241))	('neoplasm', 'Phenotype', 'HP:0002664', (233, 241))	('mTORC1', 'Gene', '382056', (121, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('angiosarcoma', 'Disease', 'MESH:D006394', (147, 159))	('human', 'Species', '9606', (141, 146))	('aberrant', 'Var', (97, 105))	('hyperactivated', 'PosReg', (106, 120))	('angiosarcoma', 'Disease', (147, 159))	('VEGF', 'MPA', (66, 70))	('mTORC1', 'Gene', (121, 127))	('neoplasm', 'Disease', (233, 241))	('angiosarcoma', 'Phenotype', 'HP:0200058', (147, 159))
103618	26777415	We created an inducible EC-specific Tsc1 deletion mouse model and found that hyperactivation of mTORC1 signaling in ECs is sufficient to induce and maintain growth of vascular tumors that recapitulate salient features of human lymphangiosarcomas, including local invasion and systemic metastasis through the lymphatics.	('growth', 'MPA', (157, 163))	('Tsc1', 'Gene', (36, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('induce', 'PosReg', (137, 143))	('vascular tumor', 'Phenotype', 'HP:0100742', (167, 181))	('angiosarcomas', 'Phenotype', 'HP:0200058', (232, 245))	('lymphangiosarcomas', 'Disease', 'MESH:C537491', (227, 245))	('human', 'Species', '9606', (221, 226))	('lymphangiosarcomas', 'Disease', (227, 245))	('vascular tumors', 'Disease', (167, 182))	('systemic metastasis through the', 'CPA', (276, 307))	('angiosarcoma', 'Phenotype', 'HP:0200058', (232, 244))	('mTORC1', 'Gene', (96, 102))	('vascular tumors', 'Phenotype', 'HP:0100742', (167, 182))	('mTORC1', 'Gene', '382056', (96, 102))	('local invasion', 'CPA', (257, 271))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('vascular tumors', 'Disease', 'MESH:D019043', (167, 182))	('deletion', 'Var', (41, 49))	('hyperactivation', 'PosReg', (77, 92))	('mouse', 'Species', '10090', (50, 55))
103621	26777415	Blockade of VEGF signaling decreased tumor cell proliferation, validating this model for discovery of compounds to target important signaling molecules and pathways for lymphangiosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('lymphangiosarcoma', 'Disease', 'MESH:C537491', (169, 186))	('lymphangiosarcoma', 'Disease', (169, 186))	('Blockade', 'Var', (0, 8))	('decreased', 'NegReg', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('VEGF', 'Protein', (12, 16))	('angiosarcoma', 'Phenotype', 'HP:0200058', (174, 186))
103622	26777415	Previous studies showed that some of either Tsc1+/- or Tsc2+/- mice developed vascular tumors, implying a role for mTORC1 signaling.	('developed', 'PosReg', (68, 77))	('mTORC1', 'Gene', (115, 121))	('vascular tumor', 'Phenotype', 'HP:0100742', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('vascular tumors', 'Disease', 'MESH:D019043', (78, 93))	('Tsc1+/-', 'Var', (44, 51))	('vascular tumors', 'Phenotype', 'HP:0100742', (78, 93))	('mice', 'Species', '10090', (63, 67))	('Tsc2', 'Gene', '22084', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('mTORC1', 'Gene', '382056', (115, 121))	('vascular tumors', 'Disease', (78, 93))	('Tsc2', 'Gene', (55, 59))
103626	26777415	Our data establish that hyperactivation of mTORC1 signaling in ECs is a driver for vascular tumor initiation.	('hyperactivation', 'Var', (24, 39))	('mTORC1', 'Gene', (43, 49))	('vascular tumor', 'Disease', 'MESH:D019043', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('vascular tumor', 'Disease', (83, 97))	('vascular tumor', 'Phenotype', 'HP:0100742', (83, 97))	('mTORC1', 'Gene', '382056', (43, 49))
103631	26777415	We showed that mTORC1 activation following Tsc1 deletion led to decreased Akt phosphorylation in ECs, consistent with previous studies indicating a feedback inhibitory mechanism.	('Akt', 'Gene', '11651', (74, 77))	('mTORC1', 'Gene', (15, 21))	('Tsc1', 'Gene', (43, 47))	('activation', 'PosReg', (22, 32))	('Akt', 'Gene', (74, 77))	('mTORC1', 'Gene', '382056', (15, 21))	('deletion', 'Var', (48, 56))	('decreased', 'NegReg', (64, 73))
103632	26777415	Activation of the mTORC1/VEGF axis upon Tsc1 deletion, independent of Akt, is sufficient to initiate the development and progression of vascular tumors.	('development', 'CPA', (105, 116))	('Tsc1', 'Gene', (40, 44))	('mTORC1', 'Gene', (18, 24))	('vascular tumor', 'Phenotype', 'HP:0100742', (136, 150))	('vascular tumors', 'Disease', 'MESH:D019043', (136, 151))	('Akt', 'Gene', (70, 73))	('initiate', 'PosReg', (92, 100))	('vascular tumors', 'Phenotype', 'HP:0100742', (136, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('Activation', 'PosReg', (0, 10))	('mTORC1', 'Gene', '382056', (18, 24))	('vascular tumors', 'Disease', (136, 151))	('deletion', 'Var', (45, 53))	('Akt', 'Gene', '11651', (70, 73))
103646	26777415	This explanation is supported by the fact that the earliest sign of vascular abnormality in Tsc1iDeltaEC mice was lymphedema in the extremities, caused by hyperplasia of lymphatic vessels in cutaneous tissues.	('lymphedema', 'Disease', (114, 124))	('vascular abnormality', 'Disease', (68, 88))	('caused by hyperplasia of lymphatic vessels', 'Phenotype', 'HP:0001004', (145, 187))	('lymphedema', 'Disease', 'MESH:D008209', (114, 124))	('hyperplasia', 'Disease', 'MESH:D006965', (155, 166))	('hyperplasia of lymphatic vessels', 'Phenotype', 'HP:0003759', (155, 187))	('vascular abnormality', 'Disease', 'MESH:D000783', (68, 88))	('lymphedema', 'Phenotype', 'HP:0001004', (114, 124))	('edema', 'Phenotype', 'HP:0000969', (119, 124))	('Tsc1iDeltaEC', 'Var', (92, 104))	('mice', 'Species', '10090', (105, 109))	('vascular abnormality', 'Phenotype', 'HP:0002597', (68, 88))	('hyperplasia', 'Disease', (155, 166))
103647	26777415	Lymphatic hyperplasia and benign malformations were prominent at early time points after Tsc1 deletion; malignant cutaneous lymphangiosarcomas were more frequent at later time points.	('deletion', 'Var', (94, 102))	('Lymphatic hyperplasia', 'Disease', 'MESH:D008206', (0, 21))	('cutaneous lymphangiosarcomas', 'Disease', 'MESH:C537491', (114, 142))	('Lymphatic hyperplasia', 'Disease', (0, 21))	('angiosarcomas', 'Phenotype', 'HP:0200058', (129, 142))	('Tsc1', 'Gene', (89, 93))	('malformations', 'Disease', 'MESH:D000014', (33, 46))	('malformations', 'Disease', (33, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('cutaneous lymphangiosarcomas', 'Disease', (114, 142))	('angiosarcoma', 'Phenotype', 'HP:0200058', (129, 141))
103701	26236533	Diagnosis was confirmed upon fluorescent in situ hybridisation (FISH) testing which revealed a rearrangement of the EWS gene (Figure 3(b)), most commonly occurring due to translocation of EWSR1, a fusion transcription factor found in 85% of Ewing's family tumours.	('tumours', 'Phenotype', 'HP:0002664', (256, 263))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('occurring due to', 'Reg', (154, 170))	('EWS', 'Gene', '2130', (116, 119))	("Ewing's family tumours", 'Disease', 'MESH:C563168', (241, 263))	('EWS', 'Gene', '2130', (188, 191))	('EWS', 'Gene', (188, 191))	("Ewing's family tumours", 'Disease', (241, 263))	('translocation', 'Var', (171, 184))	('EWS', 'Gene', (116, 119))	('rearrangement', 'Var', (95, 108))
103755	22759736	The same factors that have led to increasing numbers of HIV+ patients presenting with end stage liver disease are leading to increased occurrence of HCC, as co-infection with HCV and HBV puts these patients at risk for cirrhosis and in turn HCC.	('HCV', 'Species', '11103', (175, 178))	('liver disease', 'Phenotype', 'HP:0001392', (96, 109))	('cirrhosis', 'Disease', (219, 228))	('patients', 'Species', '9606', (198, 206))	('HCC', 'Gene', '619501', (149, 152))	('HCC', 'Gene', (241, 244))	('patients', 'Species', '9606', (61, 69))	('co-infection', 'Var', (157, 169))	('HCC', 'Gene', (149, 152))	('HBV', 'Gene', (183, 186))	('cirrhosis', 'Disease', 'MESH:D005355', (219, 228))	('cirrhosis', 'Phenotype', 'HP:0001394', (219, 228))	('HCC', 'Gene', '619501', (241, 244))	('end stage liver disease', 'Disease', 'MESH:D058625', (86, 109))	('end stage liver disease', 'Disease', (86, 109))
103822	22033270	Since cancer cells are under stress and highly dependent on aberrations of apoptosis signalling pathways to survive, selective killing of tumour cells might be achievable with apoptosis-promoting drugs.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('apoptosis signalling pathways', 'Pathway', (75, 104))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('aberrations', 'Var', (60, 71))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', (6, 12))	('tumour', 'Disease', (138, 144))
103927	22033270	In a Phase 1 trial of the XIAP antisense inhibitor AEG35156, 28 of 38 patients exhibited significantly elevated biomarker responses (M30/M65 CK18 plasma levels), which were temporally associated with drug infusion.	('patients', 'Species', '9606', (70, 78))	('M30', 'Gene', (133, 136))	('XIAP', 'Gene', (26, 30))	('AEG35156', 'Var', (51, 59))	('elevated', 'PosReg', (103, 111))	('XIAP', 'Gene', '331', (26, 30))	('AEG35156', 'Chemical', 'MESH:C498209', (51, 59))	('M30', 'Gene', '258498', (133, 136))
103983	20684773	Immunohistochemistry was performed and the tumor cells revealed the following immunophenotype: desmin (-), alpha SMA (+++), CK7 (+), CK20 (-), CD117/C-Kit (-), S100 (-), CD34 (-), C125 (-), EMA (-), CD10 (diffuse +++), calretinine (-), CK 5.6 (-), MDM 2 (-), ER (-), PR (-).	('desmin', 'Gene', (95, 101))	('CD34', 'Gene', (170, 174))	('CK7', 'Gene', '3855', (124, 127))	('calretinine', 'Chemical', '-', (219, 230))	('tumor', 'Disease', (43, 48))	('SMA', 'Gene', (113, 116))	('CD117', 'Gene', '3815', (143, 148))	('C-Kit', 'Gene', (149, 154))	('desmin', 'Gene', '1674', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('CK20', 'Gene', (133, 137))	('MDM 2', 'Gene', '4193', (248, 253))	('S100', 'Gene', (160, 164))	('S100', 'Gene', '6271', (160, 164))	('CD34', 'Gene', '947', (170, 174))	('CD10', 'Gene', '4311', (199, 203))	('CD117', 'Gene', (143, 148))	('C-Kit', 'Gene', '3815', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CK20', 'Gene', '54474', (133, 137))	('MDM 2', 'Gene', (248, 253))	('SMA', 'Gene', '6606', (113, 116))	('C125 (-', 'Var', (180, 187))	('CD10', 'Gene', (199, 203))	('CK7', 'Gene', (124, 127))
103986	20684773	For diagnostic purposes the karyotype was determined: 66-71<3N>,XXX,+X,-1,der(2)t(1;2)(p35;q37)),-7,+11,-13,-14,der(14;15)(q10;q10),-15,-16,+17,der(18)t(7;18)(q11;q23),+20,+21,+21 [cp17].	('der(14;15)(q10;q10', 'Var', (112, 130))	('der(18)t(7;18)(q11;q23', 'Var', (144, 166))	('der(18)t(7;18)(q11;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (144, 167))	('der(2)t(1;2)(p35;q37)', 'STRUCTURAL_ABNORMALITY', 'None', (74, 95))
104046	20426857	A core biopsy from the soft tissue swelling, which was performed at another hospital, was reviewed at our institute and showed a spindle cell tumour with focal nuclear pleomorphism, intercellular collagenous stroma, and occasional mitotic figures.	('tumour', 'Disease', (142, 148))	('mitotic figures', 'CPA', (231, 246))	('collagenous stroma', 'Disease', (196, 214))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('collagenous stroma', 'Disease', 'MESH:D003095', (196, 214))	('focal nuclear pleomorphism', 'Var', (154, 180))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
104236	28445124	For example, substitution by triazole moiety enhanced the cytotoxicity of naphthalimides.	('triazole', 'Chemical', 'MESH:D014230', (29, 37))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))	('enhanced', 'PosReg', (45, 53))	('substitution', 'Var', (13, 25))	('cytotoxicity', 'Disease', (58, 70))	('naphthalimides', 'Chemical', 'MESH:D053644', (74, 88))
104253	28445124	The fluorescent confocal microscopy results show that both Hoechst33258 (14 muM, blue) and LSS-11 (5 muM, green) entered living cells and accumulated in nucleus.	('accumulated', 'PosReg', (138, 149))	('muM', 'Gene', '56925', (101, 104))	('muM', 'Gene', '56925', (76, 79))	('Hoechst33258', 'Chemical', 'MESH:D006690', (59, 71))	('LSS', 'Gene', '4047', (91, 94))	('muM', 'Gene', (76, 79))	('LSS', 'Gene', (91, 94))	('muM', 'Gene', (101, 104))	('Hoechst33258', 'Var', (59, 71))
104254	28445124	When cells were co-treated with both LSS-11 and Hoechst33258, the nuclei were stained by both compounds in a mutual exclusive pattern, which means Hoechst33258 binding would exclude LSS-11 binding and vice versa (Figure 3A).	('LSS', 'Gene', (182, 185))	('Hoechst33258', 'Chemical', 'MESH:D006690', (147, 159))	('exclude', 'NegReg', (174, 181))	('binding', 'Interaction', (189, 196))	('LSS', 'Gene', '4047', (37, 40))	('Hoechst33258', 'Chemical', 'MESH:D006690', (48, 60))	('binding', 'Interaction', (160, 167))	('LSS', 'Gene', '4047', (182, 185))	('Hoechst33258', 'Var', (147, 159))	('LSS', 'Gene', (37, 40))
104281	28445124	As shown by Hoechst33258/TRITC-phalloidin staining, LSS-11 treatment resulted in a typical apoptotic morphology, characterized by disruption of cytoskeleton, cell shrinkage, nuclei fragmentation and chromatin condensation (Figure 5B).	('TRITC-phalloidin', 'Chemical', 'MESH:C041085', (25, 41))	('LSS', 'Gene', '4047', (52, 55))	('cytoskeleton', 'CPA', (144, 156))	('nuclei fragmentation', 'CPA', (174, 194))	('treatment', 'Var', (59, 68))	('chromatin condensation', 'CPA', (199, 221))	('disruption', 'NegReg', (130, 140))	('LSS', 'Gene', (52, 55))	('apoptotic morphology', 'CPA', (91, 111))	('Hoechst33258', 'Chemical', 'MESH:D006690', (12, 24))	('cell shrinkage', 'CPA', (158, 172))
104316	28445124	Actually, inhibition of topoisomerases or DNA replication is the most common cause of DNA damage response, and cancer cells that have loose cell cycle control and more genome instability are more susceptible to DNA damage responses.	('DNA replication', 'CPA', (42, 57))	('topoisomerases', 'Enzyme', (24, 38))	('inhibition', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
104410	27823979	High frequency of clonal IG and T-cell receptor gene rearrangements in histiocytic and dendritic cell neoplasms The 2008 World Health Organization (WHO) diagnostic criteria of histiocytic and dendritic cell neoplasms from hematopoietic and lymphoid tissues no longer required the absence of clonal B-cell/T-cell receptor gene rearrangements.	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (87, 111))	('neoplasms', 'Phenotype', 'HP:0002664', (207, 216))	('dendritic cell neoplasms', 'Disease', (87, 111))	('neoplasms', 'Phenotype', 'HP:0002664', (102, 111))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (192, 216))	('rearrangements', 'Var', (53, 67))	('dendritic cell neoplasms', 'Disease', (192, 216))
104425	27823979	This provided evidence that there was a high frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('rearrangements', 'Var', (94, 108))	('immunoglobulin receptor', 'Gene', '80739', (65, 88))	('dendritic cell sarcoma', 'Disease', (133, 155))	('immunoglobulin receptor', 'Gene', (65, 88))	('dendritic cell sarcoma', 'Disease', 'MESH:D054740', (133, 155))
104458	27823979	After that, several cases of histiocytic and dendritic cell neoplasms were also reported to have the same B or T cell receptor gene rearrangements and chromosomal aberrations as the associated lymphoid neoplasms.	('histiocytic', 'Disease', (29, 40))	('dendritic cell neoplasms', 'Disease', (45, 69))	('B or T cell receptor gene', 'Gene', (106, 131))	('lymphoid neoplasms', 'Phenotype', 'HP:0002665', (193, 211))	('neoplasms', 'Phenotype', 'HP:0002664', (60, 69))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (151, 174))	('neoplasms', 'Phenotype', 'HP:0002664', (202, 211))	('rearrangements', 'Var', (132, 146))	('lymphoid neoplasms', 'Disease', 'MESH:D008223', (193, 211))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (45, 69))	('lymphoid neoplasms', 'Disease', (193, 211))
104464	27823979	In order to further understand the genetic characteristics of such group of tumors, we detected not only clonal IGH/IGK but also TCRbeta/TCRgamma gene rearrangements in 33 cases of histiocytic or dendritic cell neoplasms.	('dendritic cell neoplasms', 'Disease', (196, 220))	('rearrangements', 'Var', (151, 165))	('detected', 'Reg', (87, 95))	('TCRbeta', 'Gene', '28571', (129, 136))	('IGH', 'Gene', '3492', (112, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (211, 220))	('IGK', 'Gene', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('IGH', 'Gene', (112, 115))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('TCRbeta', 'Gene', (129, 136))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (196, 220))	('IGK', 'Gene', '50802', (116, 119))
104467	27823979	In the sporadic cases, our results showed clonal IGH/IGK or TCRbeta/TCRgamma gene rearrangements in more than half of LCH, FDCS and HS, which was similar to the previous findings.	('rearrangements', 'Var', (82, 96))	('FDCS', 'Disease', (123, 127))	('IGK', 'Gene', (53, 56))	('LCH', 'Gene', (118, 121))	('IGK', 'Gene', '50802', (53, 56))	('TCRbeta', 'Gene', (60, 67))	('TCRbeta', 'Gene', '28571', (60, 67))	('IGH', 'Gene', '3492', (49, 52))	('LCH', 'Gene', '8118', (118, 121))	('IGH', 'Gene', (49, 52))
104468	27823979	But compared with that, we also detected TCRbeta/TCRgamma gene rearrangements, and found there was a high frequency of T-cell receptor gene rearrangements in histiocytic and dendritic cell neoplasms as well.	('TCRbeta', 'Gene', (41, 48))	('rearrangements', 'Var', (140, 154))	('TCRbeta', 'Gene', '28571', (41, 48))	('T-cell receptor', 'Gene', (119, 134))	('rearrangements', 'Var', (63, 77))	('neoplasms', 'Phenotype', 'HP:0002664', (189, 198))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (174, 198))	('dendritic cell neoplasms', 'Disease', (174, 198))
104470	27823979	In addition, 4 of 11 (36.4%) LCH cases and 2 of 9 (22.2%) FDCS cases in our study showed both B and T cell receptor gene rearrangements concurrently in all 28 sporadic cases.	('LCH', 'Gene', '8118', (29, 32))	('LCH', 'Gene', (29, 32))	('T cell', 'Protein', (100, 106))	('rearrangements', 'Var', (121, 135))
104478	27823979	In short, for unknown reason, there was a high frequency of clonal IG and T-cell receptor gene rearrangements in histiocytic and dendritic cell neoplasms.	('T-cell receptor gene', 'Gene', (74, 94))	('rearrangements', 'Var', (95, 109))	('neoplasms', 'Phenotype', 'HP:0002664', (144, 153))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (129, 153))	('dendritic cell neoplasms', 'Disease', (129, 153))
104515	26301204	These tumor antigens are generally products of mutated genes, abnormally expressed normal genes, or genes coding for viral proteins.	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('mutated genes', 'Var', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
104566	26301204	While there have been notable successes (for example, anti-CD20 for hematologic malignancies, anti-human epidermal growth factor receptor 2 (HER2) for breast cancer, and anti-GD2 for neuroblastoma), most mAbs have failed to improve outcomes despite their initial promise, especially in pediatric sarcomas.	('CD20', 'Gene', (59, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('neuroblastoma', 'Disease', (183, 196))	('CD20', 'Gene', '931', (59, 63))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('neuroblastoma', 'Phenotype', 'HP:0003006', (183, 196))	('breast cancer', 'Disease', (151, 164))	('anti-human epidermal growth factor receptor 2', 'Gene', (94, 139))	('hematologic malignancies', 'Disease', (68, 92))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('anti-human epidermal growth factor receptor 2', 'Gene', '2064', (94, 139))	('neuroblastoma', 'Disease', 'MESH:D009447', (183, 196))	('HER2', 'Gene', '2064', (141, 145))	('pediatric sarcomas', 'Disease', (286, 304))	('hematologic malignancies', 'Disease', 'MESH:D019337', (68, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (296, 303))	('sarcomas', 'Phenotype', 'HP:0100242', (296, 304))	('anti-GD2', 'Var', (170, 178))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (286, 304))	('HER2', 'Gene', (141, 145))
104607	26301204	In both cases, treatment efficacy was associated with a higher number of mutations in the tumors.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('mutations', 'Var', (73, 82))
104608	26301204	In melanoma patients treated with ipilimumab, the investigators carefully examined the tumors of those who responded versus those who did not, and found that the responders had tumors with higher mutation rates and tumor antigens and in particular, those whose tumor neoantigens shared tetrapeptide sequences with viral antigens were most likely to be responders to checkpoint inhibition.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumors', 'Disease', (177, 183))	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('higher', 'PosReg', (189, 195))	('tumors', 'Disease', (87, 93))	('tumor', 'Disease', (177, 182))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mutation', 'MPA', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (215, 220))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tetrapeptide', 'Var', (286, 298))	('tumor', 'Disease', (261, 266))	('responders', 'MPA', (352, 362))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('ipilimumab', 'Chemical', 'MESH:D000074324', (34, 44))
104618	26301204	The most notable are the gangliosides GD2 and GD3, polysialic acid, and translocation breakpoints.	('polysialic acid', 'Chemical', 'MESH:C021319', (51, 66))	('GD3', 'Gene', '117189', (46, 49))	('GD3', 'Gene', (46, 49))	('translocation breakpoints', 'CPA', (72, 97))	('gangliosides', 'Chemical', 'MESH:D005732', (25, 37))	('polysialic', 'Var', (51, 61))
104622	26301204	Several additional pediatric sarcoma studies remain ongoing (NCT01241162, NCT01803152, NCT01061840).	('NCT01803152', 'Var', (74, 85))	('NCT01241162', 'Var', (61, 72))	('NCT01061840', 'Var', (87, 98))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (19, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('pediatric sarcoma', 'Disease', (19, 36))
104644	26301204	As approximately 50% of the Caucasian population in the U.S. express HLA A*0201, many studies have focused on associated antigens, particularly the cancer testis antigens.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer testis', 'Phenotype', 'HP:0010788', (148, 161))	('HLA A*0201', 'Var', (69, 79))
104657	26301204	Two of the open trials target HER2 expressing sarcomas (NCT00902044, NCT00889954), while two more target GD2 expression (NCT01953900, NCT02107963); it remains to be seen whether similar successes seen in hematologic malignancies can be achieved in solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('solid tumors', 'Disease', 'MESH:D009369', (248, 260))	('hematologic malignancies', 'Disease', 'MESH:D019337', (204, 228))	('NCT01953900', 'Var', (121, 132))	('NCT00902044', 'Var', (56, 67))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('solid tumors', 'Disease', (248, 260))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('hematologic malignancies', 'Disease', (204, 228))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('HER2', 'Gene', (30, 34))	('NCT00889954', 'Var', (69, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('HER2', 'Gene', '2064', (30, 34))	('sarcomas', 'Disease', (46, 54))	('NCT02107963)', 'Var', (134, 146))
104661	26301204	In a recently completed phase I study of ipilimumab (NCT01445379) in pediatric patients with refractory solid tumors including sarcomas, no objective responses were seen but significant autoimmune toxicity was observed, with up to 50% of patients experiencing symptoms (Personal communication, Dr. L. Wexler, 2015); however, no pediatric safety data for these agents are yet published.	('ipilimumab', 'Chemical', 'MESH:D000074324', (41, 51))	('sarcomas', 'Disease', (127, 135))	('autoimmune toxicity', 'Disease', 'MESH:D001327', (186, 205))	('autoimmune toxicity', 'Phenotype', 'HP:0002960', (186, 205))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('autoimmune toxicity', 'Disease', (186, 205))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('NCT01445379', 'Var', (53, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('patients', 'Species', '9606', (79, 87))	('sarcomas', 'Disease', 'MESH:D012509', (127, 135))	('experiencing', 'Reg', (247, 259))	('patients', 'Species', '9606', (238, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
104676	26301204	However, to fully realize that potential we believe that the following four areas must be carefully considered: Given the narrow mutation landscape in sarcomas, and especially so among those with translocations, neoantigens derived from gene mutations are predicted to be rare.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcomas', 'Disease', (151, 159))	('translocations', 'Var', (196, 210))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))
104691	26301204	Anti-GD2 immunotherapy is associated with significant infusional toxicities including severe pain; this pain side effect was completely unexpected when these mAbs were first used.	('pain', 'Phenotype', 'HP:0012531', (93, 97))	('pain', 'Disease', 'MESH:D010146', (104, 108))	('toxicities', 'Disease', (65, 75))	('pain', 'Disease', (104, 108))	('pain', 'Disease', 'MESH:D010146', (93, 97))	('pain', 'Disease', (93, 97))	('toxicities', 'Disease', 'MESH:D064420', (65, 75))	('pain', 'Phenotype', 'HP:0012531', (104, 108))	('Anti-GD2', 'Var', (0, 8))
104692	26301204	Fortunately, rather than halting the development of these antibody treatments, ways to overcome the toxicities were developed and as a result, anti-GD2 immunotherapy is now proven effective in neuroblastoma and is in active trials in sarcoma patients.	('sarcoma', 'Disease', (234, 241))	('toxicities', 'Disease', (100, 110))	('patients', 'Species', '9606', (242, 250))	('neuroblastoma', 'Disease', 'MESH:D009447', (193, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('neuroblastoma', 'Disease', (193, 206))	('toxicities', 'Disease', 'MESH:D064420', (100, 110))	('neuroblastoma', 'Phenotype', 'HP:0003006', (193, 206))	('sarcoma', 'Disease', 'MESH:D012509', (234, 241))	('anti-GD2', 'Var', (143, 151))
104704	24279301	We report a case initially diagnosed as undifferentiated sarcoma that was reclassified as intraperitoneal dedifferentiated liposarcoma showing an amplification of the MDM2 gene.	('amplification', 'Var', (146, 159))	('MDM2', 'Gene', (167, 171))	('liposarcoma', 'Disease', (123, 134))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (40, 64))	('liposarcoma', 'Phenotype', 'HP:0012034', (123, 134))	('undifferentiated sarcoma', 'Disease', (40, 64))	('liposarcoma', 'Disease', 'MESH:D008080', (123, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
104720	24279301	We report herein a case initially diagnosed as undifferentiated sarcoma that was reclassified as intraperitoneal dedifferentiated liposarcoma showing an amplification of the murine double minute 2 (MDM2) gene, in order to emphasize that in most cases of undifferentiated sarcomas, a specific line of differentiation can be demonstrated.	('undifferentiated sarcoma', 'Disease', (47, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (271, 279))	('MDM2', 'Gene', (198, 202))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (254, 278))	('liposarcoma', 'Disease', (130, 141))	('murine double minute 2', 'Gene', '17246', (174, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('undifferentiated sarcomas', 'Disease', (254, 279))	('amplification', 'Var', (153, 166))	('liposarcoma', 'Disease', 'MESH:D008080', (130, 141))	('murine double minute 2', 'Gene', (174, 196))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (47, 71))	('liposarcoma', 'Phenotype', 'HP:0012034', (130, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (254, 279))
104746	24279301	Identifying MDM2 amplification by immunohistochemistry, FISH, quantitative PCR, or comparative genomic hybridization (CGH) may prove an adjunctive tool in the diagnosis of lipomatous neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (183, 192))	('MDM2', 'Gene', (12, 16))	('lipomatous neoplasms', 'Phenotype', 'HP:0012031', (172, 192))	('lipomatous neoplasms', 'Disease', (172, 192))	('lipomatous neoplasms', 'Disease', 'MESH:D008080', (172, 192))	('amplification', 'Var', (17, 30))
104768	31824199	Although rare, PSC has increased their interest among oncologist community for different reasons: a. identification of the epithelial-to-mesenchymal phenomenon as a major mechanism of secondary resistance to tyrosine kinase inhibitors; b. over-expression of PD-L1 and effective treatment with immunotherapy; c. identification of c-MET exon 14 skipping mutation representing an effective target to crizotinib and other specific inhibitors.	('c-MET', 'Gene', '4233', (329, 334))	('tyrosine', 'Chemical', 'None', (208, 216))	('skipping mutation', 'Var', (343, 360))	('PSC', 'Disease', (15, 18))	('c-MET', 'Gene', (329, 334))	('PD-L1', 'Gene', (258, 263))	('men', 'Species', '9606', (154, 157))	('men', 'Species', '9606', (283, 286))	('crizotinib', 'Chemical', 'MESH:C551994', (397, 407))	('PSC', 'Disease', 'MESH:D002292', (15, 18))	('PD-L1', 'Gene', '29126', (258, 263))
104777	31824199	Indeed, previous works have consistently evidenced the clonal origin of PSC demonstrating identical mutations of KRAS and p53 in either carcinoma and sarcoma/sarcomatous component, as also disclosed in sarcomatoid carcinoma arising in other sites.	('mutations', 'Var', (100, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('sarcomatoid carcinoma', 'Disease', 'MESH:D002292', (202, 223))	('carcinoma and sarcoma/sarcomatous component', 'Disease', 'MESH:D018316', (136, 179))	('PSC', 'Disease', (72, 75))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (202, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('p53', 'Gene', '7157', (122, 125))	('sarcomatoid carcinoma', 'Disease', (202, 223))	('KRAS', 'Gene', (113, 117))	('PSC', 'Disease', 'MESH:D002292', (72, 75))	('KRAS', 'Gene', '3845', (113, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('p53', 'Gene', (122, 125))
104778	31824199	Basically, the appearance of an additional sarcomatoid/sarcomatous component in an otherwise conventional NSCLC is due to up-regulation of the epithelial-to-mesenchymal transition (EMT) secondary to activation of genetic mechanisms generally associated with resistance to chemotherapy and tyrosine kinase inhibitors, such as KRAS mutations, c-MET gene alterations, overexpression of vimentin, ZEB1, Snail, MiR-34 coupled to down-regulation of E-cadherin and expression of epithelial markers, miR-200, mutations of EGFR (Figure 1).	('ZEB1', 'Gene', '6935', (393, 397))	('sarcomatoid/sarcomatous component', 'Disease', 'MESH:D018316', (43, 76))	('miR-200', 'Gene', (492, 499))	('EGFR', 'Gene', '1956', (514, 518))	('c-MET', 'Gene', '4233', (341, 346))	('tyrosine', 'Chemical', 'None', (289, 297))	('mutations', 'Var', (501, 510))	('c-MET', 'Gene', (341, 346))	('vimentin', 'Gene', '7431', (383, 391))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('MiR-34', 'Gene', '407040', (406, 412))	('vimentin', 'Gene', (383, 391))	('Snail', 'Gene', (399, 404))	('ZEB1', 'Gene', (393, 397))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('EGFR', 'Gene', (514, 518))	('epithelial-to-mesenchymal transition', 'CPA', (143, 179))	('expression', 'MPA', (458, 468))	('MiR-34', 'Gene', (406, 412))	('NSCLC', 'Disease', (106, 111))	('KRAS', 'Gene', '3845', (325, 329))	('overexpression', 'PosReg', (365, 379))	('E-cadherin', 'Gene', (443, 453))	('down-regulation', 'NegReg', (424, 439))	('sarcomatoid/sarcomatous component', 'Disease', (43, 76))	('up-regulation', 'PosReg', (122, 135))	('E-cadherin', 'Gene', '999', (443, 453))	('KRAS', 'Gene', (325, 329))	('Snail', 'Gene', '6615', (399, 404))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
104828	31824199	34betaE12 and 5/6) are found in squamous and adenosquamous carcinoma and low-weight cytokeratins (i.e.	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (45, 68))	('squamous', 'Disease', (32, 40))	('low-weight', 'Phenotype', 'HP:0004325', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('adenosquamous carcinoma', 'Disease', (45, 68))	('low-weight', 'Var', (73, 83))
104866	31824199	Of note, BAP-1 negativity at immunohistochemistry may be very helpful in ruling out PSC and favouring mesothelioma.	('mesothelioma', 'Disease', (102, 114))	('BAP-1', 'Gene', (9, 14))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('PSC', 'Disease', (84, 87))	('PSC', 'Disease', 'MESH:D002292', (84, 87))	('negativity', 'Var', (15, 25))	('BAP-1', 'Gene', '8314', (9, 14))
104873	31824199	They reported mutations in TP53 (22.6%) KRAS (27.2%), EGFR (22.2%) and STK1 (7.4%) as the most common genetic alterations in these lesions.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('STK1', 'Gene', (71, 75))	('KRAS', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (54, 58))	('STK1', 'Gene', '2322', (71, 75))	('KRAS', 'Gene', '3845', (40, 44))	('EGFR', 'Gene', (54, 58))	('mutations', 'Var', (14, 23))
104875	31824199	In 2016, Schrock et al used a deep sequencing approach to map whole-exome mutations in a cohort of 125 PSCs.	('PSC', 'Disease', (103, 106))	('mutations', 'Var', (74, 83))	('PSC', 'Disease', 'MESH:D002292', (103, 106))
104876	31824199	While confirming that mutations in KRAS (34.4%) and TP53 (73.6%) are the most common mutations in PSCs, the results of these study refined the frequency of mutations and called into questions other relevant oncogenes that were not present in the Sequenom panel.	('PSC', 'Disease', 'MESH:D002292', (98, 101))	('KRAS', 'Gene', (35, 39))	('TP53', 'Gene', '7157', (52, 56))	('PSC', 'Disease', (98, 101))	('TP53', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (35, 39))	('mutations', 'Var', (22, 31))
104877	31824199	In particular, these authors showed that PSCs are characterized by a quite high tumor mutational burden (TMB, average of 8.1 mutations/Mb) and that both TP53 mutated tumors and KRAS mutated tumors were characterized by a higher TMB than WT samples.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('TP53', 'Gene', '7157', (153, 157))	('tumors', 'Disease', (190, 196))	('PSC', 'Disease', (41, 44))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('higher', 'PosReg', (221, 227))	('KRAS', 'Gene', '3845', (177, 181))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (166, 172))	('TMB', 'MPA', (228, 231))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (80, 85))	('PSC', 'Disease', 'MESH:D002292', (41, 44))	('tumor', 'Disease', (190, 195))	('KRAS', 'Gene', (177, 181))	('TP53', 'Gene', (153, 157))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutated', 'Var', (158, 165))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
104878	31824199	TP53 mutations were found in a consistent part of PSCs analyzed in this study and were reported to be widely heterogeneous as subsequentially confirmed by other reports.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PSC', 'Disease', (50, 53))	('mutations', 'Var', (5, 14))	('found', 'Reg', (20, 25))	('PSC', 'Disease', 'MESH:D002292', (50, 53))
104879	31824199	Furthermore, the occurrence of TP53 mutations in PSCs seemed to underpin a specific genetic subtype.	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('PSC', 'Disease', 'MESH:D002292', (49, 52))	('mutations', 'Var', (36, 45))	('PSC', 'Disease', (49, 52))
104880	31824199	For instance, mutation in NF1 and RB1 were reported to preferentially occur in TP53 mutated vs wild-type samples while NF2 mutations were more frequent in TP53 wild-type samples, thus hypothesizing distinct evolution pathways for PSCs with different genetic assets.	('NF2', 'Gene', (119, 122))	('TP53', 'Gene', '7157', (79, 83))	('preferentially', 'PosReg', (55, 69))	('TP53', 'Gene', (79, 83))	('NF2', 'Gene', '4771', (119, 122))	('TP53', 'Gene', '7157', (155, 159))	('RB1', 'Gene', '5925', (34, 37))	('NF1', 'Gene', (26, 29))	('PSC', 'Disease', 'MESH:D002292', (230, 233))	('TP53', 'Gene', (155, 159))	('occur', 'Reg', (70, 75))	('mutated', 'Var', (84, 91))	('mutation', 'Var', (14, 22))	('NF1', 'Gene', '4763', (26, 29))	('PSC', 'Disease', (230, 233))	('RB1', 'Gene', (34, 37))
104881	31824199	Besides TP53 and KRAS mutations, additional frequent alterations were found, including those in CDKN2B (23.2%), CDKN2A (37.6%), MET (13.6%) and NF1 (17.6%).	('CDKN2B', 'Gene', '1030', (96, 102))	('CDKN2A', 'Gene', (112, 118))	('CDKN2A', 'Gene', '1029', (112, 118))	('MET', 'Gene', (128, 131))	('TP53', 'Gene', '7157', (8, 12))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (8, 12))	('NF1', 'Gene', '4763', (144, 147))	('KRAS', 'Gene', '3845', (17, 21))	('NF1', 'Gene', (144, 147))	('CDKN2B', 'Gene', (96, 102))
104882	31824199	Noticeably, mutations in EGFR (8.8%) were detected at a lower frequency than previously reported and BRAF alterations (7.3%) were limited to a reduced number of PSC samples.	('BRAF', 'Gene', (101, 105))	('EGFR', 'Gene', (25, 29))	('PSC', 'Disease', 'MESH:D002292', (161, 164))	('mutations', 'Var', (12, 21))	('PSC', 'Disease', (161, 164))	('BRAF', 'Gene', '673', (101, 105))	('EGFR', 'Gene', '1956', (25, 29))
104884	31824199	By means of whole-exome sequencing, the Authors identified mutations in the exon 14 of MET as preferentially associated with PSC.	('associated', 'Reg', (109, 119))	('PSC', 'Disease', (125, 128))	('mutations in the', 'Var', (59, 75))	('MET', 'Gene', (87, 90))	('PSC', 'Disease', 'MESH:D002292', (125, 128))
104885	31824199	MET exon 14 skipping mutations already described in other tumors including NSCLC affect either donor or acceptor splice site between exon 13 and exon 14, causing a 47 amino acid deletion in the juxta-membrane domain of the MET proteins.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('proteins', 'Protein', (227, 235))	('acceptor splice site', 'MPA', (104, 124))	('MET exon 14', 'Gene', (0, 11))	('donor', 'MPA', (95, 100))	('MET proteins', 'Protein', (223, 235))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('donor', 'Species', '9606', (95, 100))	('causing', 'Reg', (154, 161))	('deletion', 'Var', (178, 186))	('affect', 'Reg', (81, 87))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('mutations', 'Var', (21, 30))
104887	31824199	Loss of c-CBL binding either by point mutations in the accepting site or by exon 14 skipping, leads to MET stabilization and constitutive activation of MET-dependent signaling.	('c-CBL', 'Gene', (8, 13))	('MET stabilization', 'MPA', (103, 120))	('binding', 'Interaction', (14, 21))	('Loss', 'NegReg', (0, 4))	('constitutive', 'MPA', (125, 137))	('MET-dependent signaling', 'MPA', (152, 175))	('c-CBL', 'Gene', '867', (8, 13))	('activation', 'PosReg', (138, 148))	('point mutations', 'Var', (32, 47))
104888	31824199	As in NSCLC, in PSC MET exon 14 mutations were mutually exclusive with other oncogene mutations like KRAS, BRAF, EGFR or ALK rearrangement, but co-occurrence with PI3K mutations has been reported.	('BRAF', 'Gene', (107, 111))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('PSC', 'Disease', (16, 19))	('PI3', 'Gene', (163, 166))	('ALK', 'Gene', '238', (121, 124))	('KRAS', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (101, 105))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('PI3', 'Gene', '5266', (163, 166))	('BRAF', 'Gene', '673', (107, 111))	('ALK', 'Gene', (121, 124))	('NSCLC', 'Disease', (6, 11))	('PSC', 'Disease', 'MESH:D002292', (16, 19))	('men', 'Species', '9606', (134, 137))
104889	31824199	Furthermore, at least in the original report, MET exon 14 mutations were exclusively found in pure PSCs or PSCs with an ADK component.	('mutations', 'Var', (58, 67))	('PSC', 'Disease', (107, 110))	('PSC', 'Disease', 'MESH:D002292', (99, 102))	('MET', 'Var', (46, 49))	('ADK', 'Gene', '132', (120, 123))	('PSC', 'Disease', (99, 102))	('found', 'Reg', (85, 90))	('PSC', 'Disease', 'MESH:D002292', (107, 110))	('ADK', 'Gene', (120, 123))
104890	31824199	Noticeably, while MET exon 14 mutations occur in about 3% of NSCLCs (according to TCGA data), up to 32% of PSCs are reported to carry this alteration.	('PSC', 'Disease', (107, 110))	('MET exon 14', 'Gene', (18, 29))	('mutations', 'Var', (30, 39))	('NSCLC', 'Disease', (61, 66))	('PSC', 'Disease', 'MESH:D002292', (107, 110))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
104891	31824199	Indeed, according to a recent systematic meta-analysis, the incidence of MET exon 14 mutations in PSC is variable.	('PSC', 'Disease', 'MESH:D002292', (98, 101))	('MET exon 14', 'Var', (73, 84))	('PSC', 'Disease', (98, 101))
104893	31824199	Despite the different characteristics of analyzed case series, MET exon 14 mutations seem to occur particularly in PSC, ranging from 3% to 31.8%.	('PSC', 'Disease', (115, 118))	('occur', 'Reg', (93, 98))	('mutations', 'Var', (75, 84))	('PSC', 'Disease', 'MESH:D002292', (115, 118))	('MET exon', 'Var', (63, 71))
104894	31824199	The particular attention focused on MET exon 14 skipping mutations is then related to the relatively high frequency of this genetic alteration in PSC histology when compared with other conventional NSCLC, also predicting a good clinical response to MET inhibitors.	('predicting', 'Reg', (210, 220))	('PSC', 'Disease', (146, 149))	('MET inhibitors', 'MPA', (249, 263))	('skipping mutations', 'Var', (48, 66))	('NSCLC', 'Disease', (198, 203))	('MET', 'Gene', (36, 39))	('PSC', 'Disease', 'MESH:D002292', (146, 149))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))
104895	31824199	The rate of MET exon 14 mutations is significantly higher in case series including PSC without common targetable mutations in EGFR, KRAS, ALK, ROS1, and RET.	('RET', 'Gene', (153, 156))	('ROS1', 'Gene', (143, 147))	('KRAS', 'Gene', (132, 136))	('EGFR', 'Gene', (126, 130))	('ROS1', 'Gene', '6098', (143, 147))	('MET exon', 'Var', (12, 20))	('KRAS', 'Gene', '3845', (132, 136))	('ALK', 'Gene', '238', (138, 141))	('mutations', 'Var', (24, 33))	('RET', 'Gene', '5979', (153, 156))	('ALK', 'Gene', (138, 141))	('PSC', 'Disease', 'MESH:D002292', (83, 86))	('higher', 'PosReg', (51, 57))	('EGFR', 'Gene', '1956', (126, 130))	('PSC', 'Disease', (83, 86))
104910	31824199	The recent identification of MET exon 14 mutations shed new lights on the unique biology of PSCs and opened the first prospective on PSC-oriented therapy.	('mutations', 'Var', (41, 50))	('PSC', 'Disease', 'MESH:D002292', (133, 136))	('PSC', 'Disease', 'MESH:D002292', (92, 95))	('PSC', 'Disease', (92, 95))	('PSC', 'Disease', (133, 136))	('MET exon 14', 'Gene', (29, 40))
104913	31824199	For instance, EGFR actionable mutations are quite frequent in NSCLC and treatment with TKI is a first-line therapy for EGFR mutated patients.	('EGFR', 'Gene', '1956', (14, 18))	('NSCLC', 'Disease', (62, 67))	('EGFR', 'Gene', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('actionable', 'Reg', (19, 29))	('men', 'Species', '9606', (77, 80))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', '1956', (119, 123))	('patients', 'Species', '9606', (132, 140))	('EGFR', 'Gene', (119, 123))
104915	31824199	EGFR mutations in PSC is controversial (0-28% depending on series) but surely inferior to NSCLC.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (90, 95))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('PSC', 'Disease', 'MESH:D002292', (18, 21))	('EGFR', 'Gene', '1956', (0, 4))	('PSC', 'Disease', (18, 21))
104916	31824199	Furthermore, according to the available information, the number of actionable EGFR mutations (p.L858R) is even lower further reducing the rationale for the employment of these drugs in this setting.	('mutations', 'Var', (83, 92))	('men', 'Species', '9606', (162, 165))	('p.L858R', 'Mutation', 'rs121434568', (94, 101))	('reducing', 'NegReg', (125, 133))	('lower', 'NegReg', (111, 116))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))
104917	31824199	Besides, the absence of evident response to EGFR inhibitors even in EGFR mutated PSCs, seems to indicate that EGFR mutations in these tumors may not be an essential driver but rather a secondary event.	('tumors', 'Disease', (134, 140))	('mutations', 'Var', (115, 124))	('mutated', 'Var', (73, 80))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('PSC', 'Disease', (81, 84))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', '1956', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', (68, 72))	('PSC', 'Disease', 'MESH:D002292', (81, 84))
104918	31824199	KRAS mutations are among the most common alterations detected in non-squamous NSCLC.	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', (78, 83))	('KRAS', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('KRAS', 'Gene', '3845', (0, 4))
104920	31824199	KRAS mutations have been found significantly associated with pure sarcomatoid or with PSC with an adenocarcinoma component.	('pure sarcomatoid', 'Disease', (61, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('pure sarcomatoid', 'Disease', 'MESH:D002292', (61, 77))	('adenocarcinoma component', 'Disease', (98, 122))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (45, 55))	('PSC', 'Disease', 'MESH:D002292', (86, 89))	('adenocarcinoma component', 'Disease', 'MESH:D000230', (98, 122))	('PSC', 'Disease', (86, 89))	('KRAS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('KRAS', 'Gene', '3845', (0, 4))
104921	31824199	KRAS mutations are predominantly found in PSCs from smokers, and the majority of the alteration detected are transversions, the typical DNA alterations found in smokers' adenocarcinomas.	('transversions', 'Var', (109, 122))	('mutations', 'Var', (5, 14))	('PSC', 'Disease', 'MESH:D002292', (42, 45))	('adenocarcinomas', 'Disease', 'MESH:D000230', (170, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('adenocarcinomas', 'Disease', (170, 185))	('PSC', 'Disease', (42, 45))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
104922	31824199	Prognostic significance of KRAS mutations in PSC has been a matter of debate, in particular due to the limited number of cases in the analyzed series that precluded conclusive results.	('KRAS', 'Gene', '3845', (27, 31))	('PSC', 'Disease', 'MESH:D002292', (45, 48))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', (27, 31))	('PSC', 'Disease', (45, 48))
104923	31824199	However, we recently showed that KRAS mutations alone or in combination with TP53 mutations were associated with local metastases at recurrence and with a significantly decreased survival probability in a cohort of surgically resected PSCs.	('survival probability', 'CPA', (179, 199))	('KRAS', 'Gene', (33, 37))	('metastases', 'Disease', 'MESH:D009362', (119, 129))	('PSC', 'Disease', (235, 238))	('KRAS', 'Gene', '3845', (33, 37))	('metastases', 'Disease', (119, 129))	('decreased', 'NegReg', (169, 178))	('mutations', 'Var', (38, 47))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', '7157', (77, 81))	('PSC', 'Disease', 'MESH:D002292', (235, 238))
104924	31824199	Similarly, Mehrad and colleagues reported a significant correlation of KRAS mutations with worse patients' outcome.	('mutations', 'Var', (76, 85))	('KRAS', 'Gene', (71, 75))	('correlation', 'Interaction', (56, 67))	('KRAS', 'Gene', '3845', (71, 75))	('patients', 'Species', '9606', (97, 105))
104925	31824199	We also showed that the presence of KRAS mutations significantly correlates with increased PD-L1 expression suggesting a possible correlation, to be further investigated, between these mutations and response to immunotherapy.	('mutations', 'Var', (41, 50))	('increased PD', 'Phenotype', 'HP:0008151', (81, 93))	('PD-L1', 'Gene', (91, 96))	('KRAS', 'Gene', (36, 40))	('PD-L1', 'Gene', '29126', (91, 96))	('KRAS', 'Gene', '3845', (36, 40))	('increased', 'PosReg', (81, 90))	('expression', 'MPA', (97, 107))
104926	31824199	These results together with the recent emerging MEK inhibitors may imply a potential value of KRAS mutations as relevant predictive markers in orienting PSC tailored treatment.	('KRAS', 'Gene', (94, 98))	('PSC', 'Disease', (153, 156))	('MEK', 'Gene', (48, 51))	('KRAS', 'Gene', '3845', (94, 98))	('mutations', 'Var', (99, 108))	('MEK', 'Gene', '5609', (48, 51))	('men', 'Species', '9606', (171, 174))	('PSC', 'Disease', 'MESH:D002292', (153, 156))
104928	31824199	NSCLCs with activating alterations of MET (including MET locus amplification) have shown remarkable response to small molecules like crizotinib, cabozantinib or capmatinib that target MET activity.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('response', 'MPA', (100, 108))	('crizotinib', 'Chemical', 'MESH:C551994', (133, 143))	('capmatinib', 'Chemical', 'None', (161, 171))	('MET', 'MPA', (53, 56))	('cabozantinib', 'Chemical', 'MESH:C558660', (145, 157))	('MET', 'Gene', (38, 41))	('alterations', 'Var', (23, 34))	('activating', 'PosReg', (12, 22))	('NSCLC', 'Disease', (0, 5))
104929	31824199	For the same reason, the presence of MET activating mutations in PSCs would qualify a good portion of patients (about 30%) based on the reported mutations incidence for treatment with these drugs.	('patients', 'Species', '9606', (102, 110))	('PSC', 'Disease', 'MESH:D002292', (65, 68))	('men', 'Species', '9606', (174, 177))	('PSC', 'Disease', (65, 68))	('presence', 'Var', (25, 33))
104930	31824199	Preclinical evidence shows that tumor cells harboring MET ex14 mutations are responsive to MET inhibition, even if co-occurrence of PI3KCA concomitant gain of function alterations may partially reduce effectiveness of MET inhibition.	('MET ex14 mutations', 'Var', (54, 72))	('responsive to MET inhibition', 'MPA', (77, 105))	('MET inhibition', 'MPA', (218, 232))	('PI3', 'Gene', (132, 135))	('PI3', 'Gene', '5266', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('effectiveness', 'MPA', (201, 214))	('tumor', 'Disease', (32, 37))	('alterations', 'Var', (168, 179))	('reduce', 'NegReg', (194, 200))
104931	31824199	Preliminary clinical data on small series or single case confirmed that in vivo, PSC harboring MET exon 14 mutations show effective response to MET targeting drugs.	('MET targeting drugs', 'MPA', (144, 163))	('response', 'MPA', (132, 140))	('mutations', 'Var', (107, 116))	('PSC', 'Disease', (81, 84))	('PSC', 'Disease', 'MESH:D002292', (81, 84))	('MET exon 14', 'Gene', (95, 106))
104932	31824199	Even if revolutionary in the desolated PSC treatments landscape, the discovery of MET exon 14 mutations and the consequential possibility of directing patients to MET inhibitors is limited to a reduced number of patients.	('MET exon 14', 'Gene', (82, 93))	('PSC', 'Disease', 'MESH:D002292', (39, 42))	('men', 'Species', '9606', (48, 51))	('mutations', 'Var', (94, 103))	('PSC', 'Disease', (39, 42))	('patients', 'Species', '9606', (151, 159))	('patients', 'Species', '9606', (212, 220))
104942	31824199	Targetable mutations in PSC are less frequent than in NSCLC with adenocarcinoma histology.	('mutations', 'Var', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('PSC', 'Disease', 'MESH:D002292', (24, 27))	('adenocarcinoma', 'Disease', (65, 79))	('NSCLC', 'Disease', (54, 59))	('adenocarcinoma', 'Disease', 'MESH:D000230', (65, 79))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('PSC', 'Disease', (24, 27))
104943	31824199	However, Fallet et al reported uncommon/rare EGFR mutations in 22%, NRAS and PI3KCA in 5%.	('EGFR', 'Gene', (45, 49))	('PI3', 'Gene', '5266', (77, 80))	('mutations', 'Var', (50, 59))	('NRAS', 'Gene', (68, 72))	('PI3', 'Gene', (77, 80))	('NRAS', 'Gene', '4893', (68, 72))	('EGFR', 'Gene', '1956', (45, 49))
104944	31824199	Li et al performed an NGS study evidencing hot spot druggable gene alterations involving EGFR (exon 19 deletion) and EML4-ALK fusion in sporadic cases.	('EGFR', 'Gene', (89, 93))	('alterations', 'Var', (67, 78))	('ALK', 'Gene', (122, 125))	('EML4', 'Gene', (117, 121))	('EML4', 'Gene', '27436', (117, 121))	('EGFR', 'Gene', '1956', (89, 93))	('ALK', 'Gene', '238', (122, 125))
104945	31824199	Mehrad et al evidenced actionable genetic mutations in EGFR in 2 out of 23 PSCs (8.7%) and Schrock et al observed targetable genomic alteration in EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%).	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (147, 151))	('erb-b2 receptor tyrosine kinase 2', 'Gene', '2064', (173, 206))	('ret', 'Gene', (231, 234))	('ret', 'Gene', '5979', (231, 234))	('EGFR', 'Gene', (55, 59))	('erb-b2 receptor tyrosine kinase 2', 'Gene', (173, 206))	('PSC', 'Disease', (75, 78))	('PSC', 'Disease', 'MESH:D002292', (75, 78))	('RET', 'Gene', (251, 254))	('HER2', 'Gene', (213, 217))	('EGFR', 'Gene', '1956', (147, 151))	('RET', 'Gene', '5979', (251, 254))	('mutations', 'Var', (42, 51))	('HER2', 'Gene', '2064', (213, 217))
104947	31824199	Finally, Ali et al disclosed sporadic mutations in EGFR (1 case), MET (2 cases) and BRAF (1 case), KRAS (2 cases), PI3KCA (2 cases) and 1 ALK-rearranged case among 14 PSC using a combined approach with Sequenom Mass-Array and Sanger sequencing and NanoString technology.	('BRAF', 'Gene', '673', (84, 88))	('EGFR', 'Gene', (51, 55))	('PSC', 'Disease', 'MESH:D002292', (167, 170))	('ALK', 'Gene', '238', (138, 141))	('PI3', 'Gene', (115, 118))	('BRAF', 'Gene', (84, 88))	('PSC', 'Disease', (167, 170))	('ALK', 'Gene', (138, 141))	('KRAS', 'Gene', (99, 103))	('mutations', 'Var', (38, 47))	('PI3', 'Gene', '5266', (115, 118))	('KRAS', 'Gene', '3845', (99, 103))	('EGFR', 'Gene', '1956', (51, 55))
104948	31824199	By contrast, Nakagomi et al evidenced prevalent mutations in TP53 and KRAS coupled to Microsatellite instability/Mismatch repair system alteration in one case among four PSCs deeply investigated by NGS.	('PSC', 'Disease', (170, 173))	('KRAS', 'Gene', (70, 74))	('mutations', 'Var', (48, 57))	('KRAS', 'Gene', '3845', (70, 74))	('Microsatellite instability', 'Disease', 'MESH:D053842', (86, 112))	('PSC', 'Disease', 'MESH:D002292', (170, 173))	('alteration', 'Reg', (136, 146))	('Microsatellite instability', 'Disease', (86, 112))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
104949	31824199	Several reasons may explain the wide range of incidence of druggable gene alterations in PSC, as follows: a) a selection bias related to the accuracy in diagnosing this unusual histology (i.e., application of morphologic criteria in biopsy versus resections, lack of specific diagnostic primary antibodies at immunohistochemistry); b) various methodologies in detecting gene alterations, including techniques with a significantly large range of sensitivity; and c) different ethnicities of the reported case series.	('PSC', 'Disease', 'MESH:D002292', (89, 92))	('PSC', 'Disease', (89, 92))	('alterations', 'Var', (74, 85))
104951	31824199	Interestingly, among acquired resistance mechanisms during treatments with tyrosine kinase inhibitors (i.e., EGFR and ALK inhibitors) or chemotherapy, histologic "change" from adenocarcinoma to small cell or squamous cell carcinomas have been well demonstrated in EGFR mutated (about 10% of cases) and ALK rearranged adenocarcinomas.	('mutated', 'Var', (269, 276))	('EGFR', 'Gene', '1956', (109, 113))	('adenocarcinoma', 'Disease', 'MESH:D000230', (317, 331))	('squamous cell carcinomas', 'Disease', (208, 232))	('EGFR', 'Gene', (264, 268))	('tyrosine', 'Chemical', 'None', (75, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('men', 'Species', '9606', (64, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('carcinomas', 'Phenotype', 'HP:0030731', (322, 332))	('adenocarcinoma', 'Disease', (176, 190))	('EGFR', 'Gene', (109, 113))	('ALK', 'Gene', (302, 305))	('EGFR', 'Gene', '1956', (264, 268))	('ALK', 'Gene', '238', (302, 305))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (208, 232))	('adenocarcinoma', 'Disease', (317, 331))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('adenocarcinomas', 'Disease', 'MESH:D000230', (317, 332))	('ALK', 'Gene', '238', (118, 121))	('adenocarcinomas', 'Disease', (317, 332))	('adenocarcinoma', 'Disease', 'MESH:D000230', (176, 190))	('ALK', 'Gene', (118, 121))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (208, 232))
104956	31824199	Xu et al reported a case of lung adenocarcinoma resistant to EGFR TKI with concurrent acquired T790M secondary EGFR mutation and sarcomatoid spindle cell occurrence.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('lung adenocarcinoma', 'Disease', (28, 47))	('sarcomatoid', 'Disease', 'MESH:D002292', (129, 140))	('EGFR', 'Gene', '1956', (111, 115))	('T790M', 'Mutation', 'rs121434569', (95, 100))	('EGFR', 'Gene', (111, 115))	('T790M', 'Var', (95, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('sarcomatoid', 'Disease', (129, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (28, 47))
104957	31824199	Finally, a case of exon 21 L858R EGFR-mutated sarcomatoid carcinoma of the lung resistant to icotinib was recently reported.	('L858R', 'Var', (27, 32))	('sarcomatoid carcinoma of the lung', 'Disease', 'MESH:D002292', (46, 79))	('EGFR', 'Gene', '1956', (33, 37))	('sarcomatoid carcinoma of the lung', 'Disease', (46, 79))	('L858R', 'Mutation', 'rs121434568', (27, 32))	('icotinib', 'Chemical', 'MESH:C531470', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('EGFR', 'Gene', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (46, 67))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (58, 79))
104958	31824199	Coexistence of Nkx2-4 mutation was considered responsible of its intrinsic resistance to EGFR TKI.	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', (89, 93))	('Nkx2-4', 'Gene', (15, 21))	('EGFR', 'Gene', '1956', (89, 93))	('Nkx2-4', 'Gene', '644524;4824', (15, 21))
104972	31824199	Chan et al assessed the PD-L1 expression in 713 consecutive NSCLC by four commercially available PD-L1 immunohistochemical assays (22C3, 28-8, SP142 and SP263) evidencing a high PD-L1 expression >=50% significantly associated with PSC (p < 0.001) and mutant KRAS (p = 0.005) also reporting good agreement between 22C2, 28-8 and SP263 primary antibodies.	('PD-L1', 'Gene', (97, 102))	('mutant', 'Var', (251, 257))	('PSC', 'Disease', (231, 234))	('PD-L1', 'Gene', '29126', (97, 102))	('men', 'Species', '9606', (300, 303))	('KRAS', 'Gene', '3845', (258, 262))	('PD-L1', 'Gene', '29126', (24, 29))	('PD-L1', 'Gene', (24, 29))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))	('PD-L1', 'Gene', (178, 183))	('NSCLC', 'Disease', (60, 65))	('PD-L1', 'Gene', '29126', (178, 183))	('PSC', 'Disease', 'MESH:D002292', (231, 234))	('associated', 'Reg', (215, 225))	('KRAS', 'Gene', (258, 262))
104976	31824199	Vieira et al reported high PD-L1 (clone 5H1) immunoreactivity in 40 out of 75 (53%) PSC, also confirming a significant association with the presence of KRAS mutations.	('KRAS', 'Gene', (152, 156))	('PSC', 'Disease', (84, 87))	('KRAS', 'Gene', '3845', (152, 156))	('mutations', 'Var', (157, 166))	('PD-L1', 'Gene', (27, 32))	('PSC', 'Disease', 'MESH:D002292', (84, 87))	('PD-L1', 'Gene', '29126', (27, 32))
104988	31824199	PD-L1 over-expression and MET exon 14 skipping mutation are the most important predictive biomarkers for effective targeted therapies in PSC.	('over-expression', 'PosReg', (6, 21))	('PSC', 'Disease', 'MESH:D002292', (137, 140))	('PD-L1', 'Gene', (0, 5))	('PSC', 'Disease', (137, 140))	('MET exon 14 skipping mutation', 'Var', (26, 55))	('PD-L1', 'Gene', '29126', (0, 5))
105002	29732738	Classically, vascular-targeted therapeutic agents may act by neutralizing the angiogenic proteins, inhibiting their synthesis by cancer cells, directly inducing endothelial cell (EC) apoptosis, inhibiting endothelial receptors of angiogenic proteins 11, 12, or by disrupting tubulin network of the established tumor vasculature and therefore tumor blood flow interruption 13, 14, 15, 16, 17.	('angiogenic', 'Gene', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('cancer', 'Disease', (129, 135))	('endothelial', 'Protein', (205, 216))	('inducing', 'Reg', (152, 160))	('inhibiting', 'NegReg', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('inhibiting', 'NegReg', (99, 109))	('neutralizing', 'Var', (61, 73))	('tubulin', 'Protein', (275, 282))	('synthesis', 'MPA', (116, 125))	('tumor', 'Disease', (342, 347))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', (310, 315))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('disrupting', 'NegReg', (264, 274))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('endothelial', 'MPA', (161, 172))
105015	29732738	Trabectedin has also been shown to alter the DNA repair genes including BRCA1 (breast cancer type 1 susceptibility gene) and BRCA2 (breast cancer type 2 susceptibility gene), which launches new perspectives as a chemotherapy option for patients with mutated ovarian and breast cancer (BC) 48.	('breast cancer', 'Phenotype', 'HP:0003002', (270, 283))	('alter', 'Reg', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (277, 283))	('ovarian', 'Disease', (258, 265))	('patients', 'Species', '9606', (236, 244))	('ovarian', 'Disease', 'MESH:D010051', (258, 265))	('mutated', 'Var', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('cancer', 'Disease', (86, 92))	('BRCA2', 'Gene', (125, 130))	('BRCA1', 'Gene', '672', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('BRCA1', 'Gene', (72, 77))	('cancer', 'Disease', (139, 145))	('Trabectedin', 'Chemical', 'MESH:D000077606', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BRCA2', 'Gene', '675', (125, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))
105018	29732738	In this direction, sequential cohorts of patients with advanced solid tumors were enrolled and treated with doses ranging from 0.46 to 0.80 mg/m2 (1-h schedule) and 0.30 to 0.65 mg/m2 (3-h schedule) 49.	('solid tumors', 'Disease', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('0.30 to 0.65', 'Var', (165, 177))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
105065	29732738	A definitive answer to this question may be provided by the recently initiated phase III trial that will include patients with recurrent OC and BRCA-mutated and/or BRCAness phenotype (NCT02903004, MITO-23).	('MITO', 'Species', '262676', (197, 201))	('BRCAness', 'Disease', 'None', (164, 172))	('BRCA', 'Gene', (144, 148))	('BRCA', 'Gene', (164, 168))	('patients', 'Species', '9606', (113, 121))	('NCT02903004', 'Var', (184, 195))	('BRCA', 'Gene', '672', (144, 148))	('BRCA', 'Gene', '672', (164, 168))	('BRCAness', 'Disease', (164, 172))
105073	29732738	Remarkably, a further very recent subset analysis of a phase II trial found that trabectedin had a high antitumor activity in advanced BC patients with BRCA2 mutations 81.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('patients', 'Species', '9606', (138, 146))	('mutations 81', 'Var', (158, 170))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BRCA2', 'Gene', '675', (152, 157))	('tumor', 'Disease', (108, 113))	('trabectedin', 'Chemical', 'MESH:D000077606', (81, 92))	('advanced BC', 'Disease', (126, 137))	('BRCA2', 'Gene', (152, 157))
105116	29732738	Based on the fact that CBT decreases the vasculature of the surviving tumor clones and, therefore, significantly increases the anticancer activity, another phase I trial using CBT (at 45, 54, or 63 mg/m2 on days 1 and 8 and then every 14 days) in combination with bevacizumab (a potent antiangiogenic monoclonal antibody, given at 10 mg/kg on day 8 and at subsequent cycles 4 h after CBT) was conducted by Nathan et al.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('bevacizumab', 'Chemical', 'MESH:D000068258', (264, 275))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('decreases', 'NegReg', (27, 36))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CBT', 'Chemical', 'MESH:C040105', (176, 179))	('vasculature', 'MPA', (41, 52))	('CBT', 'Chemical', 'MESH:C040105', (23, 26))	('CBT', 'Var', (23, 26))	('increases', 'PosReg', (113, 122))	('CBT', 'Chemical', 'MESH:C040105', (384, 387))
105153	29732738	It seems that developing selective inhibitors of PKC by modifying the existing bryostatin-1 using structure-activity relationship studies may potentially enhance the biological activity of temsirolimus (for details, see reviews by Mochly-Rosen et al.	('temsirolimus', 'Chemical', 'MESH:C401859', (189, 201))	('bryostatin-1', 'Chemical', 'MESH:C046785', (79, 91))	('PKC', 'Gene', (49, 52))	('PKC', 'Gene', '112476', (49, 52))	('bryostatin-1', 'Gene', (79, 91))	('modifying', 'Var', (56, 65))	('biological activity', 'MPA', (166, 185))	('enhance', 'PosReg', (154, 161))
105158	29732738	Preclinical investigations have shown that NPI-2358 causes direct cytotoxicity to rapidly proliferating ECs and/or cancer cells by inducing apoptosis through cleavage of poly(ADP-ribose) polymerase (PARP), activation of caspase-3, caspase-8, and caspase-9, and triggering phosphorylation of the stress response protein JNK (c-Jun N-terminal kinase) 150.	('caspase-3', 'Protein', (220, 229))	('NPI-2358', 'Chemical', 'MESH:C514351', (43, 51))	('inducing', 'PosReg', (131, 139))	('caspase-9', 'Gene', (246, 255))	('triggering', 'Reg', (261, 271))	('c-Jun N-terminal kinase', 'Gene', (324, 347))	('c-Jun N-terminal kinase', 'Gene', '44801', (324, 347))	('cytotoxicity', 'Disease', (66, 78))	('poly(ADP-ribose) polymerase', 'Gene', '3355109', (170, 197))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('apoptosis', 'CPA', (140, 149))	('caspase-8', 'Gene', (231, 240))	('poly(ADP-ribose) polymerase', 'Gene', (170, 197))	('NPI-2358', 'Var', (43, 51))	('activation', 'PosReg', (206, 216))	('cancer', 'Disease', (115, 121))	('phosphorylation', 'MPA', (272, 287))	('caspase-9', 'Gene', '39173', (246, 255))	('cleavage', 'MPA', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('caspase-8', 'Gene', '841', (231, 240))
105172	29732738	Preclinical studies have shown that plitidepsin inhibits angiogenesis by blocking the secretion of VEGF, MMP-2, MMP-9, and FGF-2 161, 162, 163.	('blocking', 'NegReg', (73, 81))	('inhibits', 'NegReg', (48, 56))	('VEGF', 'Gene', '7422', (99, 103))	('angiogenesis', 'CPA', (57, 69))	('MMP-2', 'Gene', '4313', (105, 110))	('FGF-2', 'Gene', '2247', (123, 128))	('MMP-9', 'Gene', '4318', (112, 117))	('secretion', 'MPA', (86, 95))	('FGF-2', 'Gene', (123, 128))	('VEGF', 'Gene', (99, 103))	('MMP-9', 'Gene', (112, 117))	('MMP-2', 'Gene', (105, 110))	('plitidepsin', 'Var', (36, 47))
105188	29732738	Interestingly, adding plitidepsin was found to significantly reduce the risk of progression or death by 35% 183.	('reduce', 'NegReg', (61, 67))	('death', 'Disease', 'MESH:D003643', (95, 100))	('death', 'Disease', (95, 100))	('progression', 'CPA', (80, 91))	('plitidepsin', 'Var', (22, 33))
105197	29732738	In addition, acute mobilization of bone marrow-derived progenitors of endothelial cells after treatment by vascular-targeted agents mediated by chemotactic proteins such as VEGF, G-CSF, and SDF-1 (stromal cell-derived factor-1, also known as CXCL-12) was also noted as a driving mechanism of resistance 184, 190, 191, 192.	('resistance', 'Var', (292, 302))	('G-CSF', 'Gene', '1440', (179, 184))	('CXCL-12', 'Gene', '6387', (242, 249))	('G-CSF', 'Gene', (179, 184))	('stromal cell-derived factor-1', 'Gene', '6387', (197, 226))	('VEGF', 'Gene', (173, 177))	('CXCL-12', 'Gene', (242, 249))	('SDF-1', 'Gene', '6387', (190, 195))	('SDF-1', 'Gene', (190, 195))	('stromal cell-derived factor-1', 'Gene', (197, 226))	('VEGF', 'Gene', '7422', (173, 177))
105200	29732738	Cancer cell survival and resistance are also dependent on tumor hypoxia caused by vascular shutdown 184, 193.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor hypoxia', 'Disease', 'MESH:D000860', (58, 71))	('vascular shutdown 184', 'Var', (82, 103))	('tumor hypoxia', 'Disease', (58, 71))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
105208	29732738	204 used a prodrug approach to selectively target the tumor pericytes of the peripheral blood vessels via abrogation of their cytoskeleton and observed complete regression of tumors as a surrogate therapy to overcome resistance to these agents.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('cytoskeleton', 'MPA', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('abrogation', 'Var', (106, 116))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
105320	27453659	A variety of chromosomal abnormalities are also reported in patients with AML with EM involvement, including translocation (t) (8,21), trisomy 8, inversion 16 and 11q23.	('trisomy', 'Disease', (135, 142))	('chromosomal abnormalities', 'Disease', (13, 38))	('AML', 'Disease', 'MESH:D015470', (74, 77))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (13, 38))	('patients', 'Species', '9606', (60, 68))	('translocation (t) (', 'Var', (109, 128))	('AML', 'Phenotype', 'HP:0004808', (74, 77))	('AML', 'Disease', (74, 77))	('11q23', 'Disease', (163, 168))	('inversion 16', 'Var', (146, 158))
105322	27453659	In this review, two cases were reported to have cytogenetic abnormalities including inversion 16(p13;q22) and t (3,7) in one patient and duplication of the long arm of chromosome 11 in the other.	('inversion 16(p13;q22', 'Var', (84, 104))	('duplication', 'Var', (137, 148))	('patient', 'Species', '9606', (125, 132))
105384	27357857	Cytogenetic analyses for PAX3-FOXO1A fusion and for translocation t(11;22)(q24;q12) were negative.	('FOXO1A', 'Gene', (30, 36))	('PAX3', 'Gene', '5077', (25, 29))	('PAX3', 'Gene', (25, 29))	('FOXO1A', 'Gene', '2308', (30, 36))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (66, 83))	('fusion', 'Var', (37, 43))
105530	23687450	Data were retrieved from the DCR, including 2260 patients living in western Denmark at the time of diagnosis with a tumor located in soft tissue or bone, based on the following ICD-10 codes: C40, C41, C47, and C49.	('C49', 'Var', (210, 213))	('C40', 'Gene', '55571', (191, 194))	('C40', 'Gene', (191, 194))	('DCR', 'Gene', '1637', (29, 32))	('DCR', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('C41', 'Var', (196, 199))	('patients', 'Species', '9606', (49, 57))	('C47', 'CellLine', 'CVCL:L675', (201, 204))	('tumor', 'Disease', (116, 121))	('C47', 'Var', (201, 204))
105597	21598240	Frequent loss of Rb expression and high p53 mutation rates (~60%) were identified.	('mutation', 'Var', (44, 52))	('expression', 'MPA', (20, 30))	('Rb', 'Chemical', 'MESH:D012413', (17, 19))	('loss', 'NegReg', (9, 13))	('p53', 'Gene', (40, 43))	('p53', 'Gene', '7157', (40, 43))
105606	21598240	In contrast, WDLPS/DDLPS and MRC commonly exhibit distinctive genetic aberrations; i.e., 12q13-15 chromosomal amplification in WDLPS/DDLPS and a  translocation resulting in a FUS-DDIT3 fusion gene in MRC.	('LPS', 'Disease', 'MESH:C536528', (129, 132))	('LPS', 'Disease', 'MESH:C536528', (21, 24))	('MRC', 'CellLine', 'CVCL:0440', (200, 203))	('MRC', 'CellLine', 'CVCL:0440', (29, 32))	('LPS', 'Disease', (15, 18))	('LPS', 'Disease', (135, 138))	('translocation', 'Var', (146, 159))	('LPS', 'Disease', (129, 132))	('FUS', 'Gene', (175, 178))	('DDIT3', 'Gene', (179, 184))	('LPS', 'Disease', 'MESH:C536528', (135, 138))	('12q13-15', 'Gene', (89, 97))	('LPS', 'Disease', (21, 24))	('FUS', 'Gene', '2521', (175, 178))	('LPS', 'Disease', 'MESH:C536528', (15, 18))	('DDIT3', 'Gene', '1649', (179, 184))
105677	21598240	Recently, a high rate of p53 mutations was reported to occur in PLS.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('PLS', 'Disease', 'MESH:D010214', (64, 67))	('mutations', 'Var', (29, 38))	('occur', 'Reg', (55, 60))	('PLS', 'Disease', (64, 67))
105679	21598240	p53 mutations were identified in 19 (60%) of the samples and included: exon 5 - R158P, A159V, and R175H; exon 6 - H193R and R209T; exon 7 - S241Y, G245A, and R248Q; exon 8 - L265P and T304I; exon 9 - S313T.	('G245A', 'Mutation', 'rs1057519992', (147, 152))	('S313T', 'Mutation', 'p.S313T', (200, 205))	('p53', 'Gene', '7157', (0, 3))	('S241Y', 'Mutation', 'rs28934573', (140, 145))	('R175H', 'Mutation', 'rs28934578', (98, 103))	('R175H; exon 6 - H193R', 'Var', (98, 119))	('T304I; exon 9 - S313T', 'Var', (184, 205))	('T304I', 'Mutation', 'p.T304I', (184, 189))	('L265P', 'Mutation', 'rs879253942', (174, 179))	('p53', 'Gene', (0, 3))	('exon 5 - R158P', 'Var', (71, 85))	('G245A', 'Var', (147, 152))	('R209T', 'Mutation', 'p.R209T', (124, 129))	('R248Q', 'Mutation', 'rs11540652', (158, 163))	('R158P', 'Mutation', 'rs587782144', (80, 85))	('H193R', 'Mutation', 'rs786201838', (114, 119))	('R209T; exon 7 - S241Y', 'Var', (124, 145))	('A159V', 'Mutation', 'p.A159V', (87, 92))	('R248Q; exon 8 - L265P', 'Var', (158, 179))	('A159V', 'Var', (87, 92))
105680	21598240	Of these S313T, L265P, and R248Q were the most frequent (Fig 3).	('R248Q', 'Var', (27, 32))	('L265P', 'Var', (16, 21))	('L265P', 'Mutation', 'rs879253942', (16, 21))	('S313T', 'Mutation', 'p.S313T', (9, 14))	('R248Q', 'Mutation', 'rs11540652', (27, 32))	('S313T', 'Var', (9, 14))
105692	21598240	If validated, PLS genetic profiling might possibly augment traditional staging, thereby optimizing patient treatment decisions.	('patient', 'Species', '9606', (99, 106))	('PLS', 'Disease', (14, 17))	('augment', 'NegReg', (51, 58))	('traditional staging', 'CPA', (59, 78))	('PLS', 'Disease', 'MESH:D010214', (14, 17))	('genetic', 'Var', (18, 25))	('optimizing', 'Reg', (88, 98))
105697	21598240	Tumor suppressor pathway deregulations commonly occur in PLS, including Rb and p53.	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (79, 82))	('deregulations', 'Var', (25, 38))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PLS', 'Disease', 'MESH:D010214', (57, 60))	('Rb', 'Chemical', 'MESH:D012413', (72, 74))	('Tumor suppressor pathway', 'Pathway', (0, 24))	('PLS', 'Disease', (57, 60))
105703	21598240	Clinical trials evaluating the effects of MDM2 and CDK inhibitors (e.g., RO5045337 and PD0332991, respectively) on LPS are currently being initiated.	('PD0332991', 'Var', (87, 96))	('LPS', 'Disease', (115, 118))	('MDM2', 'Gene', '4193', (42, 46))	('LPS', 'Disease', 'MESH:C536528', (115, 118))	('MDM2', 'Gene', (42, 46))	('RO5045337', 'Chemical', '-', (73, 82))	('RO5045337', 'Var', (73, 82))	('PD0332991', 'Chemical', 'MESH:C500026', (87, 96))
105705	21598240	A recent study has identified p53 as more frequently mutated in PLS compared to most other STS subtypes.	('PLS', 'Disease', 'MESH:D010214', (64, 67))	('mutated', 'Var', (53, 60))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('PLS', 'Disease', (64, 67))
105708	21598240	Therefore, p53 immunohistochemistry cannot be used as a surrogate methodology to identify p53 mutations in PLS.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('p53', 'Gene', (90, 93))	('mutations', 'Var', (94, 103))	('PLS', 'Disease', (107, 110))	('p53', 'Gene', '7157', (90, 93))	('PLS', 'Disease', 'MESH:D010214', (107, 110))
105709	21598240	p53 mutations contribute to chemoresistance, possibly explaining PLS therapeutic resistance and suggesting that reconstituting p53 function in these tumors might be fruitful.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('PLS', 'Disease', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('PLS', 'Disease', 'MESH:D010214', (65, 68))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('mutations', 'Var', (4, 13))	('contribute', 'Reg', (14, 24))	('p53', 'Gene', '7157', (127, 130))	('chemoresistance', 'CPA', (28, 43))	('p53', 'Gene', (127, 130))
105890	21512587	In adults receiving large single doses of irinotecan every 1-3 weeks, metabolism is significantly affected by polymorphisms in UGT1A1, which controls inactivation of SN-38 through the process of glucuronidation.	('UGT1A1', 'Gene', '54658', (127, 133))	('metabolism', 'MPA', (70, 80))	('SN-38', 'Chemical', 'MESH:D000077146', (166, 171))	('affected', 'Reg', (98, 106))	('UGT1A1', 'Gene', (127, 133))	('irinotecan', 'Chemical', 'MESH:D000077146', (42, 52))	('inactivation', 'MPA', (150, 162))	('polymorphisms', 'Var', (110, 123))
105919	21512587	Houghton and colleagues have demonstrated a schedule-dependent synergy between temozolomide and irinotecan, in which methyl groups placed on DNA by temozolomide cause recruitment of topoisomerase I, thus potentiating the cytotoxic effects of irinotecan given at least one hour later.	('recruitment', 'PosReg', (167, 178))	('irinotecan', 'Chemical', 'MESH:D000077146', (242, 252))	('potentiating', 'PosReg', (204, 216))	('cytotoxic effects', 'CPA', (221, 238))	('temozolomide', 'Chemical', 'MESH:D000077204', (79, 91))	('irinotecan', 'Chemical', 'MESH:D000077146', (96, 106))	('temozolomide', 'Chemical', 'MESH:D000077204', (148, 160))	('topoisomerase', 'Protein', (182, 195))	('temozolomide', 'Var', (148, 160))	('methyl groups', 'Var', (117, 130))
105944	21512587	Although originally thought to have antitumor activity by "choking off" the blood supply to tumors, the primary effect of bevacizumab may actually be related to normalization of the tumor-associated vasculature by pruning off immature or poorly formed blood vessels, thereby improving distribution of chemotherapy.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('distribution of chemotherapy', 'MPA', (285, 313))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('blood supply', 'MPA', (76, 88))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('normalization', 'MPA', (161, 174))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('bevacizumab', 'Chemical', 'MESH:D000068258', (122, 133))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (40, 45))	('tumors', 'Disease', (92, 98))	('improving', 'PosReg', (275, 284))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('pruning', 'Var', (214, 221))
105951	21512587	Clinical trials of anti-IGF-1R antibodies have already demonstrated single-agent activity against relapsed Ewing sarcoma, with one of the largest showing 2 (13%) of 16 patients having objective responses, with another 8 (50%) having stable disease for at least 4 months.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (107, 120))	('patients', 'Species', '9606', (168, 176))	('Ewing sarcoma', 'Disease', (107, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('anti-IGF-1R antibodies', 'Var', (19, 41))	('antibodies', 'Var', (31, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (107, 120))
105963	21512587	Inhibitors of PARP can effectively enhance the in vitro and in vivo activity of topotecan, irinotecan, and temozolomide against colorectal and lung cancer cell lines and xenograft models.	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (128, 154))	('irinotecan', 'Chemical', 'MESH:D000077146', (91, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('enhance', 'PosReg', (35, 42))	('Inhibitors', 'Var', (0, 10))	('topotecan', 'Chemical', 'MESH:D019772', (80, 89))	('temozolomide', 'Chemical', 'MESH:D000077204', (107, 119))	('PARP', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('activity', 'MPA', (68, 76))
105984	22388761	Its aberrant expression has been observed in a variety of neoplasms, including esophageal carcinoma, hepatocellular carcinoma, melanoma, and synovial sarcoma.	('neoplasms', 'Disease', (58, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('observed', 'Reg', (33, 41))	('esophageal carcinoma', 'Disease', (79, 99))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (141, 157))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (101, 125))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (79, 99))	('neoplasms', 'Phenotype', 'HP:0002664', (58, 67))	('hepatocellular carcinoma', 'Disease', (101, 125))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('synovial sarcoma', 'Disease', (141, 157))	('neoplasms', 'Disease', 'MESH:D009369', (58, 67))	('synovial sarcoma', 'Disease', 'MESH:D013584', (141, 157))	('aberrant', 'Var', (4, 12))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (79, 99))
106025	22388761	More recently, the same group found that expression of NY-ESO-1 was associated with tumor progression despite Imatinib treatment.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('associated with', 'Reg', (68, 83))	('NY-ESO-1', 'Gene', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('NY-ESO-1', 'Gene', '1485', (55, 63))	('tumor', 'Disease', (84, 89))	('Imatinib', 'Chemical', 'MESH:D000068877', (110, 118))	('expression', 'Var', (41, 51))
106036	29582409	We established a correlation between ES cells aggressiveness and p-EphA2S897.	('aggressiveness', 'Disease', (46, 60))	('aggressiveness', 'Phenotype', 'HP:0000718', (46, 60))	('p-EphA2S897', 'Var', (65, 76))	('ES', 'Phenotype', 'HP:0012254', (37, 39))	('aggressiveness', 'Disease', 'MESH:D001523', (46, 60))
106038	29582409	Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('EphA2', 'Gene', (27, 32))	('silencing', 'Var', (14, 23))	('lung metastasis incidence', 'CPA', (94, 119))	('tumor', 'Disease', (41, 46))	('reduced', 'NegReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
106039	29582409	ADAM19 knockdown by siRNA technology strongly reproduced the negative effects on cell migration observed after EphA2 silencing.	('silencing', 'Var', (117, 126))	('EphA2', 'Protein', (111, 116))	('ADAM19', 'Gene', (0, 6))	('ADAM19', 'Gene', '8728', (0, 6))	('cell migration', 'CPA', (81, 95))
106040	29582409	Altogether, our results suggest that p-EphA2S897 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.	('ES', 'Phenotype', 'HP:0012254', (83, 85))	('aggressiveness', 'Disease', 'MESH:D001523', (65, 79))	('correlates', 'Reg', (49, 59))	('aggressiveness', 'Disease', (65, 79))	('aggressiveness', 'Phenotype', 'HP:0000718', (65, 79))	('p-EphA2S897', 'Var', (37, 48))
106051	29582409	CAV1 knockdown results in a significant loss of S897 phosphorylation, demonstrating a clear relationship between both proteins.	('S897 phosphorylation', 'MPA', (48, 68))	('knockdown', 'Var', (5, 14))	('CAV1', 'Gene', (0, 4))	('loss', 'NegReg', (40, 44))	('CAV1', 'Gene', '857', (0, 4))
106056	29582409	RH1 transfected cells stably expressing pCMV6-EphA2 Myc-DKK tagged vector (Origene #RC205725) were selected with 0.6 mg/mL of neomycin (Life Technologies).	('neomycin', 'Chemical', 'MESH:D009355', (126, 134))	('Myc', 'Gene', '4609', (52, 55))	('Myc', 'Gene', (52, 55))	('pCMV6-EphA2', 'Var', (40, 51))
106059	29582409	For testing the expression of EphA2 and p-EphA2S897 in Tissue Micro Arrays (TMAs), tumor samples from a recent published study were used .	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('TMAs', 'Chemical', '-', (76, 80))	('EphA2', 'Var', (30, 35))	('p-EphA2S897', 'Var', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
106061	29582409	Staining of EphA2 and p-EphA2S897 in the TMA was scored by a blinded trained pathologist on a positive-negative scale.	('TMA', 'Chemical', '-', (41, 44))	('EphA2', 'Var', (12, 17))	('p-EphA2S897', 'Var', (22, 33))
106063	29582409	For MEK and Akt inhibitors treatments, cells were seeded and incubated with the corresponding drug 24 h later.	('Akt', 'Gene', '207', (12, 15))	('Akt', 'Gene', (12, 15))	('MEK', 'Gene', (4, 7))	('MEK', 'Gene', '5609', (4, 7))	('treatments', 'Var', (27, 37))
106073	29582409	After 24 h for A673, 48 h for TC252, 72 h for RH1, and 48 h for the cellular panel comparison, cells on the upper chamber were removed with a cotton swab.	('TC252', 'Var', (30, 35))	('A673', 'Var', (15, 19))	('TC252', 'CellLine', 'CVCL:S866', (30, 35))
106086	29582409	Immunodetection of alpha-tubulin (#ab28439) or beta-actin (#ab49900) from Abcam was used as a loading control.	('beta-actin', 'Gene', '728378', (47, 57))	('beta-actin', 'Gene', (47, 57))	('alpha-tubulin', 'Protein', (19, 32))	('#ab49900', 'Var', (59, 67))	('#ab28439', 'Var', (34, 42))
106089	29582409	Quantitative reverse transcription-PCR (qRT-PCR) was performed under universal cycling conditions on LightCycler 480 II instrument (Roche) using TaqMan PCR Mastermix and TaqMan probes from Life Technologies (ACTB 4333762F, ADAM19 Hs00224960_m1, CCL2 Hs00234140_m1, LUM Hs00929860_m1, PCDH8 Hs04187285_g1, PI3KCG Hs00277090_m1, and PTPN21 Hs00234784_m1).	('Hs00277090_m1', 'Var', (312, 325))	('LUM', 'Gene', '4060', (265, 268))	('PCDH8', 'Gene', '5100', (284, 289))	('PTPN21', 'Gene', '11099', (331, 337))	('CCL2', 'Gene', '6347', (245, 249))	('ADAM19', 'Gene', (223, 229))	('PCDH8', 'Gene', (284, 289))	('PTPN21', 'Gene', (331, 337))	('CCL2', 'Gene', (245, 249))	('ADAM19', 'Gene', '8728', (223, 229))	('Hs00234784_m1', 'Var', (338, 351))	('Hs04187285_g1', 'Var', (290, 303))	('LUM', 'Gene', (265, 268))
106091	29582409	In vivo tumors were induced with subcutaneous injections of 5 x 106 A673 wild type or EphA2 silenced cells, resuspended in 100 muL of RPMI.	('EphA2', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('RPMI', 'Chemical', '-', (134, 138))	('A673', 'Var', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
106108	29582409	Interestingly, Kaplan-Meier method compared by Long-rank (Mantel-Cox test) analysis showed only lower overall survival in patients that were positive for p-EphA2S897, p=0.0272 (Figure S1B and Fig.	('p=0.0272', 'Var', (167, 175))	('lower', 'NegReg', (96, 101))	('patients', 'Species', '9606', (122, 130))	('overall survival', 'MPA', (102, 118))	('p-EphA2S897', 'Var', (154, 165))
106110	29582409	Of those patients, 71.4% died because of disease and 60% of them (10) were positive for p-EphA2S897.	('patients', 'Species', '9606', (9, 17))	('p-EphA2S897', 'Var', (88, 99))	('positive', 'Reg', (75, 83))
106112	29582409	To further demonstrate the relationship between p-EphA2S897 and a more aggressive phenotype, we stably transfected RH1 cells with a wild type (wt) EphA2 construct (REph WT) and a non-phosphorylatable S897A EphA2 mutant construct (REph S897A) (Figs.	('S897A', 'Mutation', 'p.S897A', (235, 240))	('p-EphA2S897', 'Var', (48, 59))	('S897A', 'Mutation', 'p.S897A', (200, 205))	('S897A', 'Var', (200, 205))
106114	29582409	EphA2 knockdown in both cell lines significantly reduced both cell proliferation, as measured by the WST1 tetrazolium-based assay, and clonogenic capacity (Fig.	('reduced', 'NegReg', (49, 56))	('cell proliferation', 'CPA', (62, 80))	('EphA2', 'Gene', (0, 5))	('tetrazolium', 'Chemical', 'MESH:D013778', (106, 117))	('knockdown', 'Var', (6, 15))	('clonogenic capacity', 'CPA', (135, 154))
106115	29582409	Furthermore, EphA2 silencing resulted in reduced tumor growth in nude mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('reduced', 'NegReg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('silencing', 'Var', (19, 28))	('tumor', 'Disease', (49, 54))	('nude mice', 'Species', '10090', (65, 74))	('EphA2', 'Protein', (13, 18))
106116	29582409	EphA2 knockdown in the resulting tumors was demonstrated by western blot (Fig.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('knockdown', 'Var', (6, 15))	('tumors', 'Disease', (33, 39))	('EphA2', 'Protein', (0, 5))
106117	29582409	As observed with CAV1 silencing , EphA2 knockdown resulted in a significant reduction of the migratory and invasive capacity of ES cells in vitro (Fig.	('reduction', 'NegReg', (76, 85))	('CAV1', 'Gene', (17, 21))	('knockdown', 'Var', (40, 49))	('ES', 'Phenotype', 'HP:0012254', (128, 130))	('EphA2', 'Gene', (34, 39))	('CAV1', 'Gene', '857', (17, 21))
106123	29582409	To test whether this was the case in our model, we screened for changes in either Akt or ERK kinase pathway after EphA2 knockdown.	('Akt', 'Gene', '207', (82, 85))	('EphA2', 'Gene', (114, 119))	('changes', 'Reg', (64, 71))	('ERK', 'Gene', '5594', (89, 92))	('knockdown', 'Var', (120, 129))	('ERK', 'Gene', (89, 92))	('Akt', 'Gene', (82, 85))
106125	29582409	However, in the case of ERK, only the phosphorylation was affected by the loss of EphA2 (Fig.	('EphA2', 'Protein', (82, 87))	('ERK', 'Gene', '5594', (24, 27))	('loss', 'Var', (74, 78))	('ERK', 'Gene', (24, 27))
106133	29582409	To test whether EphA2 silencing in silico reproduces the phenotypic effects on motility and invasion, we used gene set enrichment analysis (GSEA).	('motility', 'CPA', (79, 87))	('silencing', 'Var', (22, 31))	('GSEA', 'Chemical', '-', (140, 144))	('EphA2', 'Protein', (16, 21))
106138	29582409	ADAM19 knockdown by siRNA technology strongly reproduced the negative effects on cell migration observed after EphA2 silencing in A673 cells (Fig.	('EphA2', 'Gene', (111, 116))	('silencing', 'Var', (117, 126))	('ADAM19', 'Gene', (0, 6))	('ADAM19', 'Gene', '8728', (0, 6))	('cell migration', 'CPA', (81, 95))
106141	29582409	Furthermore, ADAM19 knockdown also reversed the aggressive phenotype induced by wild type EphA2 in the RH1 model (Fig.	('knockdown', 'Var', (20, 29))	('aggressive phenotype', 'CPA', (48, 68))	('ADAM19', 'Gene', '8728', (13, 19))	('ADAM19', 'Gene', (13, 19))
106152	29582409	In our models, EphA2 phosphorylation on S897 depends mostly on the MEK/ERK pathway as only MEK inhibitors were able to greatly block phosphorylation on this site.	('S897', 'Var', (40, 44))	('ERK', 'Gene', '5594', (71, 74))	('phosphorylation', 'MPA', (133, 148))	('ERK', 'Gene', (71, 74))	('MEK', 'Gene', (67, 70))	('MEK', 'Gene', '5609', (67, 70))	('MEK', 'Gene', (91, 94))	('MEK', 'Gene', '5609', (91, 94))
106154	29582409	Although widely affecting the behavior of ES cells, EphA2 silencing affected more prominently migration and invasion in vitro and tumor growth and metastasis spread in vivo.	('tumor', 'Disease', (130, 135))	('EphA2', 'Gene', (52, 57))	('affecting', 'Reg', (16, 25))	('ES', 'Phenotype', 'HP:0012254', (42, 44))	('affected', 'Reg', (68, 76))	('migration', 'CPA', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('invasion', 'CPA', (108, 116))	('silencing', 'Var', (58, 67))
106158	29582409	Here, p-EphA2S897 was significantly reduced in CAV1-silenced models underscoring the relationship between these proteins in the progression of ES.	('CAV1', 'Gene', (47, 51))	('p-EphA2S897', 'Var', (6, 17))	('CAV1', 'Gene', '857', (47, 51))	('reduced', 'NegReg', (36, 43))	('ES', 'Phenotype', 'HP:0012254', (143, 145))
106176	29582409	In fact, deregulation of many ADAM proteins has been observed in the regulation of growth factor activities and integrin functions, leading to the promotion of cell growth and invasion in human tumors .	('promotion', 'PosReg', (147, 156))	('human', 'Species', '9606', (188, 193))	('tumors', 'Disease', (194, 200))	('cell growth', 'CPA', (160, 171))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('deregulation', 'Var', (9, 21))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('ADAM proteins', 'Protein', (30, 43))
106204	27239297	The patients CD4 count was 12 count cells/mm3 and HIV Viral Load was 1420045 copies/ml.	('HIV Viral', 'Disease', 'MESH:D001102', (50, 59))	('HIV Viral', 'Disease', (50, 59))	('patients', 'Species', '9606', (4, 12))	('1420045', 'Var', (69, 76))	('CD4', 'Gene', (13, 16))	('CD4', 'Gene', '920', (13, 16))
106380	33562455	The pharmacological effect of MTX is exerted when the drug is polyglutamated.	('MTX', 'Gene', (30, 33))	('MTX', 'Gene', '4580', (30, 33))	('polyglutamated', 'Var', (62, 76))	('exerted', 'Reg', (37, 44))	('polyglutamate', 'Chemical', 'MESH:D011099', (62, 75))
106389	33562455	The factors involved in resistance include decreased accumulation due to impaired transport, decreased retention as a consequence of lack of polyglutamate formation, increased DHFR, altered DHFR that binds MTX less avidly, and an increased level of a lysosomal enzyme, gamma-glutamil hydrolase, that hydrolyses MTX polyglutamates.	('altered', 'Var', (182, 189))	('MTX', 'Gene', '4580', (311, 314))	('MTX', 'Gene', (206, 209))	('DHFR', 'Gene', (176, 180))	('MTX', 'Gene', '4580', (206, 209))	('polyglutamate', 'Protein', (141, 154))	('polyglutamate', 'Chemical', 'MESH:D011099', (141, 154))	('impaired', 'NegReg', (73, 81))	('accumulation', 'MPA', (53, 65))	('DHFR', 'Gene', (190, 194))	('DHFR', 'Gene', '1719', (176, 180))	('retention', 'MPA', (103, 112))	('polyglutamate', 'Chemical', 'MESH:D011099', (315, 328))	('decreased', 'NegReg', (93, 102))	('increased', 'PosReg', (230, 239))	('lack', 'NegReg', (133, 137))	('MTX', 'Gene', (311, 314))	('DHFR', 'Gene', '1719', (190, 194))	('increased', 'PosReg', (166, 175))	('transport', 'MPA', (82, 91))	('decreased', 'NegReg', (43, 52))
106397	33562455	Doxorubicin, like all antitumor antibiotics, is a natural product of Streptomyces species with some chemical substitutions that yield a great array of similar compounds.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (26, 31))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('substitutions', 'Var', (109, 122))	('yield', 'Reg', (128, 133))
106415	33562455	DNA replication can be inhibited by platinum adducts.	('DNA replication', 'CPA', (0, 15))	('adducts', 'Var', (45, 52))	('platinum', 'Chemical', 'MESH:D010984', (36, 44))	('inhibited', 'NegReg', (23, 32))
106418	33562455	Nephrotoxicity is dose-limiting for cisplatinum resulting in glomerular and tubular damage and magnesium and potassium wasting.	('Nephrotoxicity', 'Disease', 'MESH:D007674', (0, 14))	('potassium wasting', 'Phenotype', 'HP:0000128', (109, 126))	('magnesium and', 'MPA', (95, 108))	('potassium', 'Chemical', 'MESH:D011188', (109, 118))	('cisplatinum', 'Var', (36, 47))	('magnesium', 'Chemical', 'MESH:D008274', (95, 104))	('cisplatinum', 'Chemical', 'MESH:D002945', (36, 47))	('glomerular and tubular damage', 'Disease', 'MESH:D007674', (61, 90))	('Nephrotoxicity', 'Disease', (0, 14))
106473	33562455	As a matter of fact, OS displays a great number of genetic, epigenetic and cellular pathway abnormalities with a high degree of intratumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cellular pathway', 'Pathway', (75, 91))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('epigenetic', 'Var', (60, 70))	('abnormalities', 'Reg', (92, 105))	('tumor', 'Disease', (133, 138))	('OS', 'Phenotype', 'HP:0002669', (21, 23))
106474	33562455	The most common example of genetic alterations are changes in aploidy and in copy number of genes.	('aploidy', 'Disease', 'None', (62, 69))	('alterations', 'Var', (35, 46))	('copy number', 'Var', (77, 88))	('aploidy', 'Disease', (62, 69))	('changes', 'Reg', (51, 58))
106497	33562455	The pharmacological reasons for tumor resistance to TKI are well known: VEGFR and PDGFR gene mutation, overexpression of targets, impaired membrane transport by the drug into the cell, accelerated drug clearances.	('membrane transport by the drug into the cell', 'MPA', (139, 183))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('VEGFR', 'Gene', '3791', (72, 77))	('mutation', 'Var', (93, 101))	('PDGFR', 'Gene', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('PDGFR', 'Gene', '5159', (82, 87))	('overexpression', 'PosReg', (103, 117))	('impaired', 'NegReg', (130, 138))	('tumor', 'Disease', (32, 37))	('accelerated', 'PosReg', (185, 196))	('drug clearances', 'MPA', (197, 212))	('VEGFR', 'Gene', (72, 77))
106543	31126284	Many studies have verified that overexpression or abnormal activation of c-Met leads to increased cell proliferation, migration, and invasion, as well as inhibition of apoptosis.	('cell proliferation', 'CPA', (98, 116))	('overexpression', 'PosReg', (32, 46))	('abnormal activation of c', 'Phenotype', 'HP:0012175', (50, 74))	('invasion', 'CPA', (133, 141))	('c-Met', 'Gene', (73, 78))	('migration', 'CPA', (118, 127))	('increased', 'PosReg', (88, 97))	('c-Met', 'Gene', '4233', (73, 78))	('apoptosis', 'CPA', (168, 177))	('inhibition', 'NegReg', (154, 164))	('abnormal', 'Var', (50, 58))	('activation', 'PosReg', (59, 69))
106593	31126284	To determine whether c-Met inhibitors enhanced sensitivity to TRAIL in sarcoma cell lines, MFH-ino cells were treated with increasing doses of one of two c-Met inhibitors, PHA or PF, in combination with rhTRAIL.	('sensitivity', 'MPA', (47, 58))	('c-Met', 'Gene', (21, 26))	('c-Met', 'Gene', '4233', (21, 26))	('TRAIL', 'Gene', '8743', (62, 67))	('enhanced', 'PosReg', (38, 46))	('MFH-ino', 'Chemical', '-', (91, 98))	('sarcoma cell lines', 'Disease', (71, 89))	('TRAIL', 'Gene', (62, 67))	('PHA', 'Gene', (172, 175))	('inhibitors', 'Var', (27, 37))	('sarcoma cell lines', 'Disease', 'MESH:D012509', (71, 89))	('TRAIL', 'Gene', '8743', (205, 210))	('PHA', 'Gene', '3930', (172, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('PF', 'Chemical', 'MESH:C002997', (179, 181))	('c-Met', 'Gene', (154, 159))	('c-Met', 'Gene', '4233', (154, 159))	('TRAIL', 'Gene', (205, 210))
106595	31126284	Combined treatment with c-Met inhibitors and rhTRAIL resulted in diminishing viability in SW872 cells (80-90%) compared to treatment with rhTRAIL alone (Fig.	('TRAIL', 'Gene', (47, 52))	('c-Met', 'Gene', (24, 29))	('TRAIL', 'Gene', (140, 145))	('diminishing', 'NegReg', (65, 76))	('c-Met', 'Gene', '4233', (24, 29))	('viability', 'MPA', (77, 86))	('inhibitors', 'Var', (30, 40))	('SW872', 'CellLine', 'CVCL:1730', (90, 95))	('TRAIL', 'Gene', '8743', (47, 52))	('TRAIL', 'Gene', '8743', (140, 145))
106614	31126284	3g) cells were sensitive to rhTRAIL treatment, whereas LPS246 (Fig.	('LPS246', 'Chemical', '-', (55, 61))	('TRAIL', 'Gene', '8743', (30, 35))	('LPS246', 'Var', (55, 61))	('TRAIL', 'Gene', (30, 35))
106627	31126284	These results showed that inhibition of c-Met could potentially induce DR5 expression in not only transcription level but also in translational quantity, which in turn could enhance TRAIL-induced apoptosis in DDLPS cells (Additional file 8: Figure S6 and Additional file 9: Figure S7).	('induce', 'PosReg', (64, 70))	('TRAIL', 'Gene', '8743', (182, 187))	('translational', 'MPA', (130, 143))	('inhibition', 'Var', (26, 36))	('DR5', 'Gene', (71, 74))	('LPS', 'Disease', (211, 214))	('TRAIL', 'Gene', (182, 187))	('DR5', 'Gene', '8795', (71, 74))	('LPS', 'Disease', 'MESH:C536528', (211, 214))	('c-Met', 'Gene', (40, 45))	('expression', 'MPA', (75, 85))	('enhance', 'PosReg', (174, 181))	('c-Met', 'Gene', '4233', (40, 45))
106628	31126284	For the purpose of evaluating these results, we knocked down DR5 in liposarcoma cell lines and PDCs.	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcoma cell lines', 'Disease', (72, 90))	('sarcoma cell lines', 'Disease', 'MESH:D012509', (72, 90))	('liposarcoma', 'Disease', (68, 79))	('liposarcoma', 'Disease', 'MESH:D008080', (68, 79))	('DR5', 'Gene', (61, 64))	('liposarcoma', 'Phenotype', 'HP:0012034', (68, 79))	('knocked', 'Var', (48, 55))	('DR5', 'Gene', '8795', (61, 64))
106629	31126284	In the DR5 knocked-down groups, we could not detect TRAIL-induced apoptosis.	('DR5', 'Gene', '8795', (7, 10))	('TRAIL', 'Gene', '8743', (52, 57))	('TRAIL', 'Gene', (52, 57))	('knocked-down', 'Var', (11, 23))	('DR5', 'Gene', (7, 10))
106650	31126284	They found a direct correlation between the c-Met expression level and TRAIL resistance, and also showed that the knockdown of the c-Met protein or targeting the c-MET using small interference RNA, sensitized tumor cells to TRAIL-mediated apoptosis by interrupting the interaction between c-Met and TRAIL cognate death receptors.	('interaction', 'Interaction', (269, 280))	('c-Met', 'Gene', '4233', (289, 294))	('tumor', 'Disease', (209, 214))	('TRAIL', 'Gene', '8743', (224, 229))	('c-Met', 'Gene', (131, 136))	('TRAIL', 'Gene', '8743', (71, 76))	('c-Met', 'Gene', (44, 49))	('sensitized', 'Reg', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('TRAIL', 'Gene', '8743', (299, 304))	('interrupting', 'NegReg', (252, 264))	('knockdown', 'Var', (114, 123))	('c-Met', 'Gene', (289, 294))	('TRAIL', 'Gene', (224, 229))	('c-MET', 'Gene', '4233', (162, 167))	('targeting', 'Var', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('TRAIL', 'Gene', (71, 76))	('c-MET', 'Gene', (162, 167))	('c-Met', 'Gene', '4233', (131, 136))	('expression level', 'MPA', (50, 66))	('TRAIL', 'Gene', (299, 304))	('c-Met', 'Gene', '4233', (44, 49))
106653	31126284	This may be due to the following reasons: 1) the DR5 pathway is strongly related to the activity of c-Met; or 2) inhibition of a tyrosine kinase associated with c-Met becomes enhancing DR5 expression and inducing the pro-apoptotic effect.	('DR5', 'Gene', (185, 188))	('DR5', 'Gene', (49, 52))	('DR5', 'Gene', '8795', (185, 188))	('c-Met', 'Gene', (100, 105))	('pro-apoptotic effect', 'CPA', (217, 237))	('enhancing', 'PosReg', (175, 184))	('DR5', 'Gene', '8795', (49, 52))	('c-Met', 'Gene', '4233', (161, 166))	('inhibition', 'Var', (113, 123))	('c-Met', 'Gene', '4233', (100, 105))	('expression', 'MPA', (189, 199))	('c-Met', 'Gene', (161, 166))	('inducing', 'Reg', (204, 212))
106654	31126284	To investigate this connection, we knocked down DR5 and then treated cells with PF and TRAIL.	('DR5', 'Gene', (48, 51))	('TRAIL', 'Gene', '8743', (87, 92))	('DR5', 'Gene', '8795', (48, 51))	('PF', 'Chemical', 'MESH:C002997', (80, 82))	('TRAIL', 'Gene', (87, 92))	('knocked', 'Var', (35, 42))
106663	31126284	These are particularly useful tools for elucidating the mechanisms behind the enhancement of DRs caused by c-MET inhibitors and TRAIL-induced apoptosis.	('c-MET', 'Gene', (107, 112))	('inhibitors', 'Var', (113, 123))	('c-MET', 'Gene', '4233', (107, 112))	('DRs', 'Disease', (93, 96))	('enhancement', 'PosReg', (78, 89))	('TRAIL', 'Gene', '8743', (128, 133))	('TRAIL', 'Gene', (128, 133))
106712	30760697	An early-stage radiation-induced sarcoma is difficult to identify by physical examination due to radiation-induced changes, often leading to a misdiagnosis as recurrent breast carcinoma, thereby delaying an accurate diagnosis.	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('leading to', 'Reg', (130, 140))	('breast carcinoma', 'Disease', (169, 185))	('sarcoma', 'Disease', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('breast carcinoma', 'Disease', 'MESH:D001943', (169, 185))	('recurrent', 'Disease', (159, 168))	('changes', 'Var', (115, 122))	('breast carcinoma', 'Phenotype', 'HP:0003002', (169, 185))
106719	28135250	Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('expression', 'Species', '29278', (154, 164))	('Ewing sarcoma', 'Disease', (116, 129))	('EWSR1-FLI1', 'Gene', '14247', (30, 40))	('EWSR1-FLI1', 'Gene', '14247', (181, 191))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('EWSR1-FLI1', 'Gene', (30, 40))	('proliferation/migration', 'CPA', (61, 84))	('Ewing sarcoma', 'Disease', (96, 109))	('EWSR1-FLI1', 'Gene', (181, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('chimeric', 'Var', (172, 180))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
106728	28135250	Moreover, the invalidation of EWSR1-FLI1 expression by specific si/shRNAs induces an arrest of Ewing sarcoma cell line proliferation in vitro and in vivo (reviewed in Toomey et al.).	('arrest of Ewing sarcoma', 'Disease', (85, 108))	('expression', 'Species', '29278', (41, 51))	('EWSR1-FLI1', 'Gene', '14247', (30, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('EWSR1-FLI1', 'Gene', (30, 40))	('invalidation', 'Var', (14, 26))	('arrest of Ewing sarcoma', 'Disease', 'MESH:C563168', (85, 108))
106732	28135250	The authors show that EWSR1-FLI1 expression loosens cell adhesion, and they therefore propose that poorly attached Ewing cells passively disseminate in the circulation.	('EWSR1-FLI1', 'Gene', '14247', (22, 32))	('expression', 'Var', (33, 43))	('cell adhesion', 'CPA', (52, 65))	('EWSR1-FLI1', 'Gene', (22, 32))	('loosens', 'NegReg', (44, 51))	('expression', 'Species', '29278', (33, 43))
106735	28135250	While numerous reports have investigated the transcriptional consequences of the modulation of EWSR1-FLI1 in Ewing sarcoma cells, the Ewing cell proteome upon EWSR1-FLI1 modulation still remains mostly unexplored.	('EWSR1-FLI1', 'Gene', (159, 169))	('Ewing sarcoma', 'Disease', (109, 122))	('EWSR1-FLI1', 'Gene', '14247', (95, 105))	('EWSR1-FLI1', 'Gene', (95, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('modulation', 'Var', (81, 91))	('EWSR1-FLI1', 'Gene', '14247', (159, 169))
106739	28135250	In the presence of DOX, the expression level of the EWSR1-FLI1 protein was decreased by 54 and 36% in the shA673-1c and shSK-E17T clones, respectively (Figure 1a).	('expression', 'Species', '29278', (28, 38))	('EWSR1-FLI1', 'Gene', (52, 62))	('protein', 'Protein', (63, 70))	('E17T', 'Mutation', 'p.E17T', (125, 129))	('EWSR1-FLI1', 'Gene', '14247', (52, 62))	('shA673-1c', 'Var', (106, 115))	('expression level', 'MPA', (28, 44))	('DOX', 'Chemical', 'MESH:D004318', (19, 22))	('decreased', 'NegReg', (75, 84))
106742	28135250	Following lentivirus-mediated silencing of EWSR1-FLI1 in the A673 cell line, 2D-DIGE was performed comparing Cy3- and Cy5-labelled A673 infected with either a control shRNA (EWSR1-FLI1high cells) or an EWSR1-FLI1-specific shRNA (EWSR1-FLI1low cells), respectively.	('EWSR1-FLI1', 'Gene', '14247', (43, 53))	('Cy5', 'Chemical', 'MESH:C085321', (118, 121))	('EWSR1-FLI1', 'Gene', '14247', (229, 239))	('EWSR1-FLI1', 'Gene', (43, 53))	('Cy3', 'Chemical', '-', (109, 112))	('EWSR1-FLI1', 'Gene', (229, 239))	('EWSR1-FLI1', 'Gene', '14247', (174, 184))	('EWSR1-FLI1', 'Gene', '14247', (202, 212))	('EWSR1-FLI1', 'Gene', (174, 184))	('silencing', 'Var', (30, 39))	('EWSR1-FLI1', 'Gene', (202, 212))
106752	28135250	Indeed, we compared the organization of the actin stress fibres in shA673-1c and shSK-E17T clones after 10 days of DOX treatment.	('compared', 'Reg', (11, 19))	('shSK-E17T', 'Var', (81, 90))	('DOX', 'Chemical', 'MESH:D004318', (115, 118))	('shA673-1c', 'Var', (67, 76))	('E17T', 'Mutation', 'p.E17T', (86, 90))
106759	28135250	After 24 h, in DOX-treated conditions, the collagen-matrix was invaded by cells, through either individual (shA673-1c+DOX) or more collective cell movements (shSK-E17T+DOX).	('DOX', 'Chemical', 'MESH:D004318', (168, 171))	('E17T', 'Mutation', 'p.E17T', (163, 167))	('shSK-E17T+DOX', 'Var', (158, 171))	('DOX', 'Chemical', 'MESH:D004318', (118, 121))	('DOX', 'Chemical', 'MESH:D004318', (15, 18))	('shA673-1c+DOX', 'Var', (108, 121))
106767	28135250	Resultantly, a significant reduction of the tumour burden was observed in DOX-treated as compared to untreated cells/embryos (Figure 1f).	('DOX-treated', 'Var', (74, 85))	('reduction of the tumour burden', 'Disease', (27, 57))	('reduction of the tumour burden', 'Disease', 'MESH:D009369', (27, 57))	('DOX', 'Chemical', 'MESH:D004318', (74, 77))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
106769	28135250	Our results indicate that the experimental modification of EWSR1-FLI1 expression level is sufficient to control the proliferation and migration properties of Ewing cells.	('EWSR1-FLI1', 'Gene', (59, 69))	('modification', 'Var', (43, 55))	('expression', 'Species', '29278', (70, 80))	('migration properties', 'CPA', (134, 154))	('EWSR1-FLI1', 'Gene', '14247', (59, 69))	('proliferation', 'CPA', (116, 129))	('control', 'Reg', (104, 111))
106774	28135250	This showed that cells with an equivalent number of the housekeeping RPLP0 mRNA molecules may display important variations of EWSR1-FLI1 (Supplementary Figure S3B).	('EWSR1-FLI1', 'Gene', '14247', (126, 136))	('RPLP0', 'Gene', (69, 74))	('EWSR1-FLI1', 'Gene', (126, 136))	('variations', 'Var', (112, 122))	('RPLP0', 'Gene', '6175', (69, 74))
106794	28135250	A double staining of LOX and actin further showed that these LOX positive cells were characterized by the presence of strong and robust actin stress fibres and well-spread shape (Figures 1b and c), all features of EWSR1-FLI1low cells (Figure 3a).	('EWSR1-FLI1', 'Gene', '14247', (214, 224))	('EWSR1-FLI1', 'Gene', (214, 224))	('LOX', 'Var', (61, 64))	('actin stress', 'Protein', (136, 148))
106808	28135250	We took advantage of the reversibility of the knock-down of EWSR1-FLI1 in shA673-1c cells upon DOX withdrawal (Supplementary Figure S2).	('DOX', 'Chemical', 'MESH:D004318', (95, 98))	('EWSR1-FLI1', 'Gene', (60, 70))	('EWSR1-FLI1', 'Gene', '14247', (60, 70))	('knock-down', 'Var', (46, 56))
106820	28135250	Indeed, the knockdown of EWSR1-FLI1 is associated with the increase of actin-binding proteins implied in cell contractility (MYL6, MYL12A, MYLPF), cytoskeleton assembly and maintenance (ACTN4, CFL1, GSN, MSN, PFN2, RDX, VCL), but also the decrease of cell-cell adhesion proteins as tight junctions (CLD1, OCL) and desmosome (DSP, PKP1) family proteins.	('cytoskeleton', 'MPA', (147, 159))	('decrease', 'NegReg', (239, 247))	('cell-cell adhesion proteins', 'Protein', (251, 278))	('knockdown', 'Var', (12, 21))	('cell contractility', 'CPA', (105, 123))	('desmosome', 'Protein', (314, 323))	('actin-binding proteins', 'Protein', (71, 93))	('EWSR1-FLI1', 'Gene', '14247', (25, 35))	('EWSR1-FLI1', 'Gene', (25, 35))	('tight junctions', 'Protein', (282, 297))	('increase', 'PosReg', (59, 67))
106822	28135250	Indeed, the invalidation of EWSR1-FLI1 expression (EWSR1-FLI1low cells) induced increased three-dimensional migration and invasion properties, as demonstrated here by spheroids culture embedded in three-dimensional collagen-matrix and zebrafish xenotransplantation models.	('EWSR1-FLI1', 'Gene', (51, 61))	('increased', 'PosReg', (80, 89))	('EWSR1-FLI1', 'Gene', '14247', (28, 38))	('invasion properties', 'CPA', (122, 141))	('three-dimensional migration', 'CPA', (90, 117))	('EWSR1-FLI1', 'Gene', '14247', (51, 61))	('zebrafish', 'Species', '7955', (235, 244))	('expression', 'Species', '29278', (39, 49))	('EWSR1-FLI1', 'Gene', (28, 38))	('invalidation', 'Var', (12, 24))
106840	28135250	Recently, it was demonstrated in a subtype of breast tumours that LOX secretion by the cancer cells induces the formation of osteolytic lesions and may drive the formation of a pre-metastatic niche in bones facilitating the metastasis formation.	('formation', 'MPA', (112, 121))	('cancer', 'Disease', (87, 93))	('osteolytic lesions', 'Phenotype', 'HP:0002797', (125, 143))	('osteolytic lesions', 'Disease', 'MESH:D030981', (125, 143))	('osteolytic lesions', 'Disease', (125, 143))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('breast tumours', 'Disease', 'MESH:D001943', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('induces', 'Reg', (100, 107))	('metastasis formation', 'CPA', (224, 244))	('drive', 'Reg', (152, 157))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('pre-metastatic niche', 'CPA', (177, 197))	('LOX', 'Var', (66, 69))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('breast tumours', 'Disease', (46, 60))
106851	28135250	While the EWSR1-FLI1 variations spontaneously observed in cell lines, in the absence of any stromal cells, support a role for the two first mechanisms, the impact of the microenvironment may also be crucial in vivo.	('variations', 'Var', (21, 31))	('EWSR1-FLI1', 'Gene', (10, 20))	('EWSR1-FLI1', 'Gene', '14247', (10, 20))
106857	28135250	In many tumour types the metastatic spread is suggested to be driven or at least favoured by the accumulation of genetic alterations that progressively provide the cancer cells the functional ability to escape from the primary mass and seed in distant sites.	('tumour', 'Disease', (8, 14))	('alterations', 'Var', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('escape', 'CPA', (203, 209))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('provide', 'PosReg', (152, 159))	('genetic alterations', 'Var', (113, 132))	('metastatic spread', 'CPA', (25, 42))	('tumour', 'Disease', 'MESH:D009369', (8, 14))
106859	28135250	Though STAG2 and TP53 mutations are associated with a more aggressive disease, their low frequency cannot account for the much more frequent occurrence of metastases.	('aggressive disease', 'Disease', (59, 77))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('STAG2', 'Gene', (7, 12))	('mutations', 'Var', (22, 31))	('aggressive disease', 'Disease', 'MESH:D001523', (59, 77))	('associated with', 'Reg', (36, 51))	('TP53', 'Gene', (17, 21))	('metastases', 'Disease', (155, 165))
106900	27955735	showed that a pre-metastatic niche in the target organ is pre-populated by vascular endothelial growth factor receptor 1 (VEGFR1)-positive bone marrow precursors, which prepare nests for metastatic cells prior to their arrival at the distant site, and that VEGFR1 inhibition abrogates the formation of these nests, thereby preventing metastasis.	('VEGFR1', 'Gene', '2321', (257, 263))	('preventing', 'NegReg', (323, 333))	('metastasis', 'CPA', (334, 344))	('VEGFR1', 'Gene', (257, 263))	('vascular endothelial growth factor receptor 1', 'Gene', (75, 120))	('vascular endothelial growth factor receptor 1', 'Gene', '2321', (75, 120))	('inhibition', 'Var', (264, 274))	('VEGFR1', 'Gene', '2321', (122, 128))	('VEGFR1', 'Gene', (122, 128))	('abrogates', 'NegReg', (275, 284))
106951	27955735	The recently closed Children's Oncology Group (COG) trial AREN0533, also eliminated lung radiation for patients who achieved complete remission of lung disease after 6 weeks of 3-drug chemotherapy, and encouraged biopsy of lung nodules after initial chemotherapy to ensure that patients did not receive unnecessary lung radiation.	('lung disease', 'Phenotype', 'HP:0002088', (147, 159))	('COG', 'Chemical', '-', (47, 50))	('Children', 'Species', '9606', (20, 28))	('AREN0533', 'Var', (58, 66))	('lung radiation', 'MPA', (84, 98))	('Oncology', 'Phenotype', 'HP:0002664', (31, 39))	('lung disease', 'Disease', (147, 159))	('patients', 'Species', '9606', (278, 286))	('patients', 'Species', '9606', (103, 111))	('eliminated', 'NegReg', (73, 83))	('lung disease', 'Disease', 'MESH:D008171', (147, 159))
107019	27955735	Although there is no contraindication to minimally invasive resection, there are ample data from adults that these tumors are at high risk of rupture during dissection and removal, and that spillage can lead to implants and carcinomatosis.	('carcinomatosis', 'Disease', (224, 238))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('rupture', 'Disease', 'MESH:D012421', (142, 149))	('rupture', 'Disease', (142, 149))	('spillage', 'Var', (190, 198))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('implants', 'CPA', (211, 219))	('lead to', 'Reg', (203, 210))	('carcinomatosis', 'Disease', 'MESH:D002277', (224, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
107026	28099924	Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic phenotype.	('sarcoma', 'Disease', (51, 58))	('spherogenic phenotype', 'CPA', (75, 96))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (39, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('mouse', 'Species', '10090', (25, 30))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('depletion', 'Var', (3, 12))	('induced', 'Reg', (65, 72))
107028	28099924	Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression.	('mmu-miR-140', 'Gene', (49, 60))	('overexpression', 'PosReg', (132, 146))	('depletion', 'Var', (89, 98))	('upregulated', 'PosReg', (71, 82))	('downregulated', 'NegReg', (103, 116))	('mmu-miR-140', 'Gene', '387158', (49, 60))	('mmu-mir-140', 'Gene', '387158', (120, 131))	('mmu-mir-140', 'Gene', (120, 131))	('Il-6', 'Gene', (62, 66))
107043	28099924	In this study, we employed an in vitro model of cancer progression wherein Rb inactivation enhances stem cell-like activities.	('inactivation', 'Var', (78, 90))	('stem cell-like activities', 'CPA', (100, 125))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('enhances', 'PosReg', (91, 99))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
107045	28099924	This unveiled a relationship between RB and miR-140; depletion of RB downregulates miR-140.	('depletion', 'Var', (53, 62))	('miR-140', 'Gene', '406932', (44, 51))	('RB', 'Gene', '5925', (66, 68))	('miR-140', 'Gene', (83, 90))	('RB', 'Gene', '5925', (37, 39))	('downregulates', 'NegReg', (69, 82))	('miR-140', 'Gene', (44, 51))	('miR-140', 'Gene', '406932', (83, 90))
107048	28099924	Rb depletion indeed upregulated IL-6 expression, which was antagonized by overexpression of mir-140.	('IL-6', 'Gene', (32, 36))	('IL-6', 'Gene', '3569', (32, 36))	('upregulated', 'PosReg', (20, 31))	('depletion', 'Var', (3, 12))	('upregulated IL-6 expression', 'Phenotype', 'HP:0030783', (20, 47))	('mir-140', 'Gene', (92, 99))	('expression', 'MPA', (37, 47))	('mir-140', 'Gene', '406932', (92, 99))
107050	28099924	Previously, we demonstrated that a p53-null background facilitates cells to acquire undifferentiated phenotypes including increased self-renewal upon RB inactivation.	('facilitates', 'PosReg', (55, 66))	('self-renewal', 'CPA', (132, 144))	('cells', 'CPA', (67, 72))	('increased', 'PosReg', (122, 131))	('RB', 'Gene', '5925', (150, 152))	('inactivation', 'Var', (153, 165))
107060	28099924	Collectively, these findings indicate that Rb depletion induces upregulation of specific growth factors and cytokines, and dedifferentiation in p53-null soft tissue sarcoma cells.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (153, 172))	('depletion', 'Var', (46, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('upregulation', 'PosReg', (64, 76))	('dedifferentiation', 'CPA', (123, 140))	('sarcoma', 'Disease', 'MESH:D012509', (165, 172))	('sarcoma', 'Disease', (165, 172))
107063	28099924	Among these six miRNAs, mmu-miR-140 and -337 appeared to be downregulated by Rb deletion in both 2D-cultured and sphere-derived cells.	('mmu-miR-140', 'Gene', (24, 35))	('deletion', 'Var', (80, 88))	('mmu-miR-140', 'Gene', '387158', (24, 35))	('downregulated', 'NegReg', (60, 73))
107068	28099924	These results indicated that both forms of mmu-mir-140 are downregulated by Rb depletion in primary cells; this downregulation was more robust in Rb-depleted secondary cells (Figure 2D).	('mmu-mir-140', 'Gene', '387158', (43, 54))	('mmu-mir-140', 'Gene', (43, 54))	('depletion', 'Var', (79, 88))	('downregulated', 'NegReg', (59, 72))
107069	28099924	In addition, we demonstrated that mmu-miR-140 downregulation induced by Rb depletion was antagonized by RB overexpression (Figure 2E), suggesting that Rb upregulates mmu-miR-140 expression.	('downregulation', 'NegReg', (46, 60))	('mmu-miR-140', 'Gene', (166, 177))	('depletion', 'Var', (75, 84))	('expression', 'MPA', (178, 188))	('RB', 'Gene', '5925', (104, 106))	('upregulates', 'PosReg', (154, 165))	('mmu-miR-140', 'Gene', '387158', (34, 45))	('mmu-miR-140', 'Gene', (34, 45))	('mmu-miR-140', 'Gene', '387158', (166, 177))
107084	28099924	Il-6 upregulation induced by Rb depletion was significantly antagonized by RB reconstitution (Figure 5A).	('depletion', 'Var', (32, 41))	('upregulation', 'PosReg', (5, 17))	('RB', 'Gene', '5925', (75, 77))	('antagonized', 'NegReg', (60, 71))	('Il-6', 'Gene', (0, 4))
107092	28099924	To examine whether the hsa-mir-140-IL-6 axis are involved in malignant phenotype induced by RB inactivation in human cancers, we employed MCF-7, a luminal-type breast cancer cell line.	('IL-6', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('hsa-mir-140', 'Gene', '406932', (23, 34))	('IL-6', 'Gene', '3569', (35, 39))	('MCF-7', 'CellLine', 'CVCL:0031', (138, 143))	('human', 'Species', '9606', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('luminal-type breast cancer', 'Disease', 'MESH:D001943', (147, 173))	('hsa-mir-140', 'Gene', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('inactivation', 'Var', (95, 107))	('RB', 'Gene', '5925', (92, 94))	('luminal-type breast cancer', 'Disease', (147, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('cancers', 'Disease', (117, 124))
107096	28099924	In addition, hsa-mir-140 antagonized enhancement of sphere-forming activity induced by RB depletion (Figure 6E).	('hsa-mir-140', 'Gene', (13, 24))	('antagonized', 'NegReg', (25, 36))	('sphere-forming activity', 'CPA', (52, 75))	('hsa-mir-140', 'Gene', '406932', (13, 24))	('RB', 'Gene', '5925', (87, 89))	('enhancement', 'PosReg', (37, 48))	('depletion', 'Var', (90, 99))
107106	28099924	Previously, it was reported that p53, another well-known tumor suppressor, upregulates the transcription of tumor-suppressor miRNAs such as miR-34a/b/c/, miR-107, miR-145, miR-192, and miR-215, which regulate cell proliferation, apoptosis, and angiogenesis.	('cell proliferation', 'CPA', (209, 227))	('tumor', 'Disease', (108, 113))	('miR-215', 'Gene', (185, 192))	('miR-107', 'Var', (154, 161))	('miR-34a', 'Gene', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('miR-145', 'Gene', '406937', (163, 170))	('miR-192', 'Gene', '406967', (172, 179))	('p53', 'Gene', (33, 36))	('miR-34a', 'Gene', '407040', (140, 147))	('tumor', 'Disease', (57, 62))	('miR-145', 'Gene', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('angiogenesis', 'CPA', (244, 256))	('regulate', 'Reg', (200, 208))	('transcription', 'MPA', (91, 104))	('upregulates', 'PosReg', (75, 86))	('miR-192', 'Gene', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('miR-215', 'Gene', '406997', (185, 192))	('apoptosis', 'CPA', (229, 238))
107108	28099924	The inactivation of RB functions is known to enhance stem cell-like activities.	('enhance', 'PosReg', (45, 52))	('inactivation', 'Var', (4, 16))	('stem cell-like activities', 'CPA', (53, 78))	('RB', 'Gene', '5925', (20, 22))
107117	28099924	We are currently testing the possibility that RB depletion promotes demethylation in their promoter regions.	('demethylation in', 'MPA', (68, 84))	('depletion', 'Var', (49, 58))	('RB', 'Gene', '5925', (46, 48))
107118	28099924	In addition to Il-6, the genes induced by Rb depletion possibly in a mir-140-dependent manner included those encoding various secreted proteins such as proteases, growth factors, cytokines, and chemokines (Table 1).	('depletion', 'Var', (45, 54))	('mir-140', 'Gene', '406932', (69, 76))	('mir-140', 'Gene', (69, 76))
107119	28099924	Among secreted protein genes, the 3'UTR of VEGF gene can be targeted by hsa-miR-140, and reportedly VEGF gene is induced by RB inactivation.	('miR-140', 'Gene', '406932', (76, 83))	('inactivation', 'Var', (127, 139))	('VEGF', 'Gene', '7422', (100, 104))	('RB', 'Gene', '5925', (124, 126))	('VEGF', 'Gene', (43, 47))	('miR-140', 'Gene', (76, 83))	('VEGF', 'Gene', (100, 104))	('hsa', 'Chemical', 'MESH:D006585', (72, 75))	('VEGF', 'Gene', '7422', (43, 47))
107131	28099924	More than 10 spheres induced by Rb depletion were manually picked up by micropippette under the microscope, collected into a 15 ml centrifuge tube, resuspended in 2 ml of 10% FBS-containing alphaMEM, disaggregated with cell a 40-mum strainer, and plated onto a 2D culture dish.	('alphaMEM', 'Chemical', '-', (190, 198))	('depletion', 'Var', (35, 44))	('FBS', 'Disease', (175, 178))	('FBS', 'Disease', 'MESH:D005198', (175, 178))
107137	28099924	RB7LP lacking stop codon was amplified by PCR using primers attB1-7LP (GGGGACAAGTTTGTACAAAAAAGCAGGCTTCGCCACCATGAACACTATCCAACA) and attB2-7LP (GGGGACCACTTTGTACAAGAAAGCTGGGTTTTTCTCTTCCTTGTTTGAGGTATCCA).	('attB2-7LP', 'Var', (131, 140))	('RB7LP', 'Gene', (0, 5))	('RB7LP', 'Gene', '5925', (0, 5))
107139	28099924	The TaqMan probes used were mmu-miR-140, hsa-miR-140-3p, snoRNA202, RNU48, Il6, IL6, Rb1, RB1, Actb and ACTB (Applied Biosystems, assay ID 001187, 002234, 001232, 001006, Mm00446190_m1, Hs00985639_m1, Mm00485586_m1, Hs01078066_m1, Mm00607939_s1 and Hs99999903_m1).	('Rb1', 'Gene', '5925', (85, 88))	('hsa', 'Chemical', 'MESH:D006585', (41, 44))	('ACTB', 'Gene', (104, 108))	('ACTB', 'Gene', '60', (104, 108))	('Il6', 'Gene', (75, 78))	('Mm00607939_s1', 'Var', (231, 244))	('Il6', 'Gene', '3569', (75, 78))	('Rb1', 'Gene', (85, 88))	('miR-140', 'Gene', (32, 39))	('IL6', 'Gene', '3569', (80, 83))	('001232', 'Var', (155, 161))	('Actb', 'Gene', (95, 99))	('RB1', 'Gene', (90, 93))	('mmu-miR-140', 'Gene', (28, 39))	('miR-140', 'Gene', '406932', (32, 39))	('001006', 'Var', (163, 169))	('RNU48', 'Gene', (68, 73))	('RNU48', 'Gene', '26801', (68, 73))	('Hs01078066_m1', 'Var', (216, 229))	('IL6', 'Gene', (80, 83))	('miR-140', 'Gene', (45, 52))	('Hs99999903_m1', 'Var', (249, 262))	('Actb', 'Gene', '60', (95, 99))	('Mm00485586_m1', 'Var', (201, 214))	('RB1', 'Gene', '5925', (90, 93))	('Hs00985639_m1', 'Var', (186, 199))	('miR-140', 'Gene', '406932', (45, 52))	('Mm00446190_m1', 'Var', (171, 184))	('mmu-miR-140', 'Gene', '387158', (28, 39))
107141	28099924	IB was conducted as described previously using the following antibodies to: Phospho-Rb (#9308, Cell Signaling Technology), Total RB (#554136, BD Biosciences), Cyclin D1 (#2926, Cell Signaling Technology), alpha-Tubulin (#CP06, Calbiochem) and beta-Actin (#3700, Cell Signaling Technology).	('#CP06', 'Var', (220, 225))	('Cyclin D1', 'Gene', (159, 168))	('beta-Actin', 'Gene', '728378', (243, 253))	('alpha-Tubulin', 'Gene', (205, 218))	('beta-Actin', 'Gene', (243, 253))	('#554136', 'Var', (133, 140))	('alpha-Tubulin', 'Gene', '10376', (205, 218))	('RB', 'Gene', '5925', (129, 131))	('Cyclin D1', 'Gene', '595', (159, 168))
107148	28099924	Platinum-E cells were maintained in DMEM supplemented with 10% FBS, and transfected with pMXs or pMXs- human RB.	('FBS', 'Disease', (63, 66))	('human', 'Species', '9606', (103, 108))	('pMXs', 'Var', (89, 93))	('FBS', 'Disease', 'MESH:D005198', (63, 66))	('DMEM', 'Chemical', '-', (36, 40))	('RB', 'Gene', '5925', (109, 111))
107153	28099924	We also mutated complementary seed sequences in the miR-140-binding region (See Figure 4B and Supplementary Figure 4A), and generated the reporter construct Il-6-3'UTR Mut.	('miR-140', 'Gene', '406932', (52, 59))	('mutated', 'Var', (8, 15))	('miR-140', 'Gene', (52, 59))
107154	28099924	NIH3T3 cells were transfected with 0.5 mug reporter construct, either 3.0 mug mmu-miR-140 construct or 3.0 mug scramble control construct, and 0.25 mug beta-galactosidase using 100 mul Opti-MEM (Life Technologies) and 11.25 mul FuGENE6 (Promega Corporation, Cat.	('mmu-miR-140', 'Gene', '387158', (78, 89))	('Opti-MEM', 'Chemical', '-', (185, 193))	('NIH3T3', 'CellLine', 'CVCL:0594', (0, 6))	('mmu-miR-140', 'Gene', (78, 89))	('0.25', 'Var', (143, 147))
107320	22741534	In addition, for the local excision of a subcutaneous tumor, violation of the underlying fascia may facilitate tumor local invasion, as the fascia provides an excellent deep barrier to tumor spread.	('tumor', 'Disease', (185, 190))	('fascia', 'Disease', 'None', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('facilitate', 'PosReg', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('violation', 'Var', (61, 70))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('fascia', 'Disease', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('fascia', 'Disease', 'None', (140, 146))	('fascia', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (54, 59))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (41, 59))
107397	30326879	We retrospectively reviewed the records of patients with refractory metastatic osteosarcoma at Peking University People's Hospital who were treated with gemcitabine (1000 mg/m2) intravenously (IV) on Day 1 and Day 8, and docetaxel (75 mg/m2) IV on Day 8, repeated every 21 days.	('People', 'Species', '9606', (113, 119))	('osteosarcoma', 'Phenotype', 'HP:0002669', (79, 91))	('patients', 'Species', '9606', (43, 51))	('osteosarcoma', 'Disease', (79, 91))	('osteosarcoma', 'Disease', 'MESH:D012516', (79, 91))	('1000 mg/m2', 'Var', (166, 176))	('docetaxel', 'Chemical', 'MESH:D000077143', (221, 230))	('gemcitabine', 'Chemical', 'MESH:C056507', (153, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))
107554	22684281	In addition, many third-generation antibodies and related structures designed to trigger different mechanisms of action simultaneously, such as targeting growth factors, inhibiting angiogenesis and restoring apoptosis, and associated with enhanced or silenced effector functions, e.g., antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) are being investigated in clinical trials.	('apoptosis', 'CPA', (208, 217))	('tor', 'Gene', '6097', (265, 268))	('tor', 'Gene', (164, 167))	('cytotoxicity', 'Disease', (363, 375))	('man', 'Species', '9606', (13, 16))	('tor', 'Gene', '6097', (201, 204))	('tor', 'Gene', (265, 268))	('cytotoxicity', 'Disease', (319, 331))	('tor', 'Gene', (201, 204))	('antibodies', 'Var', (35, 45))	('angiogenesis', 'CPA', (181, 193))	('cytotoxicity', 'Disease', 'MESH:D064420', (363, 375))	('silenced', 'NegReg', (251, 259))	('growth', 'Protein', (154, 160))	('tor', 'Gene', '6097', (164, 167))	('inhibiting', 'NegReg', (170, 180))	('enhanced', 'PosReg', (239, 247))	('cytotoxicity', 'Disease', 'MESH:D064420', (319, 331))
107598	22684281	The constant domain (Fc) of an antibody is responsible for interactions with immune cells, and the associated properties of the Fc can also be modulated by engineering at several levels, such as altering the glycosylation status to modulate anti- and pro-inflammatory properties; modulation of ADCC by site-directed mutagenesis to modulate binding to Fc receptors; increasing the serum half-life by Fc engineering to increase binding to the neonatal Fc receptor (FcRn), which prevents IgG degradation; and increasing complement activation by isotype chimerism.	('binding', 'Interaction', (426, 433))	('binding', 'Interaction', (340, 347))	('modulate', 'Reg', (331, 339))	('FcRn', 'Gene', (463, 467))	('F', 'Chemical', 'MESH:D005461', (128, 129))	('tor', 'Gene', '6097', (359, 362))	('increase', 'PosReg', (417, 425))	('tor', 'Gene', '6097', (263, 266))	('modulation', 'Var', (280, 290))	('increasing', 'PosReg', (506, 516))	('tor', 'Gene', '6097', (458, 461))	('F', 'Chemical', 'MESH:D005461', (21, 22))	('F', 'Chemical', 'MESH:D005461', (450, 451))	('serum half-life', 'MPA', (380, 395))	('tor', 'Gene', (359, 362))	('tor', 'Gene', (263, 266))	('IgG degradation', 'MPA', (485, 500))	('F', 'Chemical', 'MESH:D005461', (463, 464))	('complement activation', 'MPA', (517, 538))	('F', 'Chemical', 'MESH:D005461', (351, 352))	('tor', 'Gene', (458, 461))	('increasing', 'PosReg', (365, 375))	('F', 'Chemical', 'MESH:D005461', (399, 400))	('FcRn', 'Gene', '2217', (463, 467))
107615	22684281	Such "Me better" antibodies with controlled and optimized glycosylation have been obtained in glyco-engineered CHO cells or yeast strains, e.g., copies of rituximab and trastuzumab amino acid sequences with afucosylated glycoforms that result in a 40- to 100-fold increase in ADCC, or with increased plasmatic half-life, e.g., copies of rituximab, trastuzumab, bevacizumab that have a mutation of two or three amino acids in the Fc domain resulting in extended pharmacokinetics.	('increase', 'PosReg', (264, 272))	('bevacizumab', 'Chemical', 'MESH:D000068258', (361, 372))	('F', 'Chemical', 'MESH:D005461', (429, 430))	('rituximab', 'Chemical', 'MESH:D000069283', (155, 164))	('trastuzumab', 'Chemical', 'MESH:D000068878', (169, 180))	('extended pharmacokinetics', 'MPA', (452, 477))	('trastuzumab', 'Chemical', 'MESH:D000068878', (348, 359))	('ADCC', 'MPA', (276, 280))	('mutation', 'Var', (385, 393))	('plasmatic half-life', 'MPA', (300, 319))	('rituximab', 'Chemical', 'MESH:D000069283', (337, 346))	('increased', 'PosReg', (290, 299))	('yeast', 'Species', '4932', (124, 129))
107640	22684281	However, this approach still did not overcome the issue of random light chain association and only recently Schaefer and colleagues proposed and described a novel and generic approach to enforce correct light chain association by domain exchange within the Fab domain of one half of the bispecific antibody in combination with the knob-into-holes technology.	('domain exchange', 'Var', (230, 245))	('correct light chain association', 'MPA', (195, 226))	('Fab', 'Gene', '2187', (257, 260))	('Fab', 'Gene', (257, 260))
107654	22684281	This was not really associated with clinical reaction or development of anti-rituximab antibodies in the setting of lymphoma where some immunodeficiency exists related to the lymphoma or the previous therapies, but the presence of non-human sequence may cause difficulties when rituximab is used as a treatment in autoimmune diseases.	('immunodeficiency', 'Disease', (136, 152))	('presence', 'Var', (219, 227))	('lymphoma', 'Disease', (116, 124))	('lymphoma', 'Disease', (175, 183))	('lymphoma', 'Disease', 'MESH:D008223', (116, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (116, 124))	('rituximab', 'Chemical', 'MESH:D000069283', (278, 287))	('lymphoma', 'Disease', 'MESH:D008223', (175, 183))	('autoimmune diseases', 'Disease', 'MESH:D001327', (314, 333))	('lymphoma', 'Phenotype', 'HP:0002665', (175, 183))	('autoimmune diseases', 'Disease', (314, 333))	('non-human sequence', 'Var', (231, 249))	('immunodeficiency', 'Phenotype', 'HP:0002721', (136, 152))	('human', 'Species', '9606', (235, 240))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (314, 333))	('immunodeficiency', 'Disease', 'MESH:D007153', (136, 152))	('rituximab', 'Chemical', 'MESH:D000069283', (77, 86))
107664	22684281	This activity can be modulated by patient-related parameters such as gender, polymorphism of FCGR3A, genetic heterogeneity of CD11b, or natural killer cell effectors (Fig.	('FCGR3A', 'Gene', '2214', (93, 99))	('tor', 'Gene', (161, 164))	('F', 'Chemical', 'MESH:D005461', (167, 168))	('F', 'Chemical', 'MESH:D005461', (93, 94))	('FCGR3A', 'Gene', (93, 99))	('activity', 'MPA', (5, 13))	('patient', 'Species', '9606', (34, 41))	('CD11b', 'Gene', '3684', (126, 131))	('modulated', 'Reg', (21, 30))	('polymorphism', 'Var', (77, 89))	('tor', 'Gene', '6097', (161, 164))	('CD11b', 'Gene', (126, 131))
107695	22684281	The two radionuclides, 131I-tositumomab (Bexxar ) and 90Y-ibritumomab tiuxetan (Zevalin ) have not really succeeded in finding their place in the treatment of B cell lymphomas.	('90Y-ibritumomab tiuxetan', 'Chemical', 'MESH:C422802', (54, 78))	('lymphomas', 'Disease', (166, 175))	('131I-tositumomab', 'Chemical', 'MESH:C119496', (23, 39))	('131I-tositumomab', 'Var', (23, 39))	('lymphomas', 'Disease', 'MESH:D008223', (166, 175))	('Zevalin', 'Chemical', 'MESH:C422802', (80, 87))	('90Y-ibritumomab', 'Var', (54, 69))	('radionuclides', 'Chemical', 'MESH:D011868', (8, 21))	('lymphomas', 'Phenotype', 'HP:0002665', (166, 175))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (159, 174))	('Bexxar', 'Chemical', 'MESH:C119496', (41, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (166, 174))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (159, 175))	('cell lymphoma', 'Phenotype', 'HP:0012191', (161, 174))
107733	29487419	This study tested FGFR4-activating mutations and overexpression for the ability to generate RMS in mice.	('mice', 'Species', '10090', (99, 103))	('FGFR4-activating', 'Gene', (18, 34))	('RMS', 'Phenotype', 'HP:0002859', (92, 95))	('mutations', 'Var', (35, 44))
107735	29487419	Specifically, we provide the first mechanistic evidence of differential potency in the most common human RMS mutations, V550E or N535K, compared to FGFR4wt overexpression as murine myoblasts expressing FGFR4V550E undergo higher rates of cellular transformation, engraftment into mice, and rapidly form sarcomas that highly resemble human RMS.	('sarcoma', 'Phenotype', 'HP:0100242', (302, 309))	('sarcomas', 'Disease', 'MESH:D012509', (302, 310))	('engraftment', 'CPA', (262, 273))	('N535K', 'Var', (129, 134))	('V550E', 'Mutation', 'rs1057519793', (207, 212))	('murine', 'Species', '10090', (174, 180))	('sarcomas', 'Disease', (302, 310))	('RMS', 'Phenotype', 'HP:0002859', (338, 341))	('sarcomas', 'Phenotype', 'HP:0100242', (302, 310))	('higher', 'PosReg', (221, 227))	('V550E', 'Var', (120, 125))	('N535K', 'Mutation', 'rs1057519792', (129, 134))	('RMS', 'Phenotype', 'HP:0002859', (105, 108))	('human', 'Species', '9606', (332, 337))	('mice', 'Species', '10090', (279, 283))	('form', 'Reg', (297, 301))	('RMS', 'Disease', (105, 108))	('V550E', 'Mutation', 'rs1057519793', (120, 125))	('FGFR4V550E', 'Var', (202, 212))	('cellular transformation', 'CPA', (237, 260))	('human', 'Species', '9606', (99, 104))
107736	29487419	Murine tumor cells overexpressing FGFR4V550E were tested in an in vitro dose-response drug screen along with human RMS cell lines.	('human', 'Species', '9606', (109, 114))	('tumor', 'Disease', (7, 12))	('FGFR4V550E', 'Var', (34, 44))	('Murine', 'Species', '10090', (0, 6))	('RMS', 'Phenotype', 'HP:0002859', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
107737	29487419	RMS cells were highly sensitive to PI3K/mTOR inhibitors, in particular, GSK2126458 (omipalisib) was a potent inhibitor of FGFR4V550E tumor-derived cell and human RMS cell viability.	('GSK2126458', 'Chemical', 'MESH:C561454', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('RMS', 'Phenotype', 'HP:0002859', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('FGFR4V550E', 'Gene', (122, 132))	('GSK2126458', 'Var', (72, 82))	('tumor', 'Disease', (133, 138))	('RMS', 'Phenotype', 'HP:0002859', (162, 165))	('human', 'Species', '9606', (156, 161))
107739	29487419	Mass cytometry using mouse and human RMS cell lines validated GSK2126458 specificity at single-cell resolution, decreasing the abundance of phosphorylated Akt as well as decreasing phosphorylation of the downstream mTOR effectors 4ebp1, Eif4e, and S6.	('Eif4e', 'Gene', (237, 242))	('GSK2126458', 'Chemical', 'MESH:C561454', (62, 72))	('RMS', 'Phenotype', 'HP:0002859', (37, 40))	('decreasing', 'NegReg', (170, 180))	('decreasing', 'NegReg', (112, 122))	('mouse', 'Species', '10090', (21, 26))	('human', 'Species', '9606', (31, 36))	('4ebp1', 'Gene', (230, 235))	('phosphorylation', 'MPA', (181, 196))	('GSK2126458', 'Var', (62, 72))	('4ebp1', 'Gene', '1978', (230, 235))	('Akt', 'Gene', '207', (155, 158))	('Eif4e', 'Gene', '1977', (237, 242))	('phosphorylated', 'MPA', (140, 154))	('abundance', 'MPA', (127, 136))	('Akt', 'Gene', (155, 158))
107740	29487419	Moreover, PI3K/mTOR inhibition also robustly decreased the growth of RMS tumors in vivo.	('RMS tumors', 'Disease', (69, 79))	('growth', 'CPA', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('decreased', 'NegReg', (45, 54))	('RMS', 'Phenotype', 'HP:0002859', (69, 72))	('RMS tumors', 'Disease', 'MESH:D009369', (69, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('PI3K/mTOR', 'Var', (10, 19))
107741	29487419	Thus, by developing a preclinical platform for testing novel therapies, we identified PI3K/mTOR inhibition as a promising new therapy for this devastating pediatric cancer.	('PI3K/mTOR inhibition', 'Var', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('inhibition', 'Var', (96, 106))
107744	29487419	Despite an absence of pathognomonic fusion genes, the majority of ERMS contain mutations that dysregulate receptor tyrosine kinase (RTK), phosphatidyl-inositol 3 kinase (PI3K), and RAS signaling pathways.	('receptor tyrosine kinase', 'Gene', (106, 130))	('phosphatidyl-inositol 3 kinase', 'Gene', '5293', (138, 168))	('receptor tyrosine kinase', 'Gene', '5979', (106, 130))	('phosphatidyl-inositol 3 kinase', 'Gene', (138, 168))	('RTK', 'Gene', (132, 135))	('ERMS', 'Gene', (66, 70))	('dysregulate', 'Reg', (94, 105))	('RAS signaling pathways', 'Pathway', (181, 203))	('RMS', 'Phenotype', 'HP:0002859', (67, 70))	('RTK', 'Gene', '5979', (132, 135))	('mutations', 'Var', (79, 88))
107745	29487419	Mutations within the p53 pathway are also common as at least 60% of ERMS tumors contain a "p53 OFF" genotype.	('p53 pathway', 'Pathway', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ERMS tumors', 'Disease', (68, 79))	('RMS', 'Phenotype', 'HP:0002859', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('ERMS tumors', 'Disease', 'MESH:D009369', (68, 79))	('Mutations', 'Var', (0, 9))
107749	29487419	Alterations in FGFR4 signaling commonly occur in ARMS patients by overexpression, as FGFR4 is a transcriptional target of the PAX3-FOXO1 fusion gene and in ERMS patients due to FGFR4-activating mutations or amplification.	('RMS', 'Phenotype', 'HP:0002859', (157, 160))	('FGFR4-activating', 'Gene', (177, 193))	('Alterations', 'Reg', (0, 11))	('patients', 'Species', '9606', (54, 62))	('PAX3', 'Gene', '5077', (126, 130))	('patients', 'Species', '9606', (161, 169))	('PAX3', 'Gene', (126, 130))	('FOXO1', 'Gene', '2308', (131, 136))	('fusion gene', 'Var', (137, 148))	('FOXO1', 'Gene', (131, 136))	('FGFR4', 'Gene', (85, 90))	('RMS', 'Phenotype', 'HP:0002859', (50, 53))	('amplification', 'Var', (207, 220))
107752	29487419	Activating FGFR4 mutations occur in approximately 10% of ERMS patients, most commonly in the tyrosine kinase domain at residues V550E or V550L or N535K.	('Activating', 'PosReg', (0, 10))	('N535K', 'Var', (146, 151))	('V550L', 'Var', (137, 142))	('ERMS', 'Disease', (57, 61))	('FGFR4', 'Gene', (11, 16))	('V550L', 'Mutation', 'p.V550L', (137, 142))	('V550E', 'Mutation', 'rs1057519793', (128, 133))	('N535K', 'Mutation', 'rs1057519792', (146, 151))	('RMS', 'Phenotype', 'HP:0002859', (58, 61))	('tyrosine kinase domain', 'MPA', (93, 115))	('patients', 'Species', '9606', (62, 70))	('mutations', 'Var', (17, 26))
107753	29487419	Furthermore, expression of FGFR4-activating V550E and N535K mutations in NIH 3T3 fibroblasts caused development of more aggressive tumors than expression of wild-type FGFR4.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aggressive tumors', 'Disease', 'MESH:D001523', (120, 137))	('FGFR4-activating', 'Gene', (27, 43))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('V550E', 'Mutation', 'rs1057519793', (44, 49))	('FGFR4-activating', 'PosReg', (27, 43))	('N535K', 'Var', (54, 59))	('aggressive tumors', 'Disease', (120, 137))	('V550E', 'Var', (44, 49))	('N535K', 'Mutation', 'rs1057519792', (54, 59))	('NIH 3T3', 'CellLine', 'CVCL:0594', (73, 80))
107754	29487419	However, no difference in tumor biology was noted between the V550E vs. N535K mutations.	('V550E', 'Var', (62, 67))	('N535K', 'Mutation', 'rs1057519792', (72, 77))	('N535K', 'Var', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('V550E', 'Mutation', 'rs1057519793', (62, 67))
107756	29487419	We have recently established a novel approach to model high-grade sarcomas by genetically modifying skeletal muscle precursor cells followed by orthotopic injection into syngeneic, immunocompetent hosts.	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('genetically modifying', 'Var', (78, 99))	('sarcomas', 'Disease', (66, 74))
107758	29487419	In this study, we examined whether expression of human ERMS-associated FGFR4-activating mutations would induce RMS from myoblasts injected into muscle.	('FGFR4-activating', 'Gene', (71, 87))	('human', 'Species', '9606', (49, 54))	('mutations', 'Var', (88, 97))	('induce', 'Reg', (104, 110))	('RMS', 'Phenotype', 'HP:0002859', (56, 59))	('RMS from myoblasts', 'CPA', (111, 129))	('RMS', 'Phenotype', 'HP:0002859', (111, 114))
107760	29487419	Myoblasts expressing FGFR4V550E exhibited mammalian target of rapamycin (mTOR) pathway activation, providing a preclinical platform for drug discovery and validation.	('FGFR4V550E', 'Var', (21, 31))	('mammalian target of rapamycin', 'Gene', '2475', (42, 71))	('mammalian target of rapamycin', 'Gene', (42, 71))	('activation', 'PosReg', (87, 97))
107762	29487419	Furthermore, mass cytometry confirmed inhibition of PI3K/mTOR signaling by GSK2126458 at the single-cell level in RMS cell lines.	('GSK2126458', 'Var', (75, 85))	('RMS', 'Phenotype', 'HP:0002859', (114, 117))	('GSK2126458', 'Chemical', 'MESH:C561454', (75, 85))	('PI3K/mTOR signaling', 'Pathway', (52, 71))	('inhibition', 'NegReg', (38, 48))
107763	29487419	Finally, inhibition of mTOR signaling impaired growth of FGFR4V550E-expressing tumors to a greater extent than standard chemotherapy.	('inhibition', 'Var', (9, 19))	('FGFR4V550E-expressing', 'Gene', (57, 78))	('growth', 'MPA', (47, 53))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mTOR signaling', 'Pathway', (23, 37))	('impaired', 'NegReg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
107765	29487419	FGFR4V550E, and M25.EV were generated after transduction of the p53-deficient murine myoblast Myo25 cell line with lentivirus particles encoding wild-type FGFR4 (FGFR4wt), activating mutations of FGFR4 (FGFR4N535K, FGFR4V550E), or an empty vector (EV) control, followed by antibiotic selection (Fig.	('FGFR4', 'Gene', (196, 201))	('activating', 'PosReg', (172, 182))	('FGFR4V550E', 'Var', (215, 225))	('murine', 'Species', '10090', (78, 84))	('FGFR4N535K', 'Var', (203, 213))
107766	29487419	Human FGFR4 proteins were overexpressed in M25.FGFR4wt, M25.FGFR4N535K, and M25.FGFR4V550E myoblasts but were not detected in the parental Myo25 and M25.EV myoblasts (Fig.	('Human', 'Species', '9606', (0, 5))	('M25.FGFR4V550E', 'Var', (76, 90))	('myoblasts', 'CPA', (91, 100))	('proteins', 'Protein', (12, 20))	('M25.FGFR4N535K', 'Var', (56, 70))	('V550E', 'Mutation', 'rs1057519793', (85, 90))	('overexpressed', 'PosReg', (26, 39))
107767	29487419	To determine whether FGFR4-activating mutations differentially impact tumorigenesis compared to wild-type overexpression, myoblast cell lines expressing FGFR4N535K (n = 11) or FGFR4V550E (n = 12) were orthotopically engrafted into skeletal muscle of the right hind limb of neonatal p53+/- syngeneic mice and M25.FGFR4wt-overexpressing myoblasts were injected into left limbs (Fig.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('mice', 'Species', '10090', (299, 303))	('impact', 'Reg', (63, 69))	('mutations', 'Var', (38, 47))	('V550E', 'Mutation', 'rs1057519793', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
107768	29487419	We observed rapid tumor formation in mice injected with M25.FGFR4V550E-expressing myoblasts compared to mice engrafted with either M25.FGFR4N535K (p < 0.001) or M25.FGFR4wt (p < 0.01).	('tumor', 'Disease', (18, 23))	('M25.FGFR4V550E-expressing', 'Var', (56, 81))	('mice', 'Species', '10090', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('mice', 'Species', '10090', (37, 41))
107769	29487419	Specifically, M25.FGFR4V550E-injected mice developed tumors with a median latency of 11 weeks (range 9-26 weeks), which was highly penetrant as 11/12 mice (92%) reached end point (Fig.	('mice', 'Species', '10090', (150, 154))	('mice', 'Species', '10090', (38, 42))	('M25.FGFR4V550E-injected', 'Var', (14, 37))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('developed', 'PosReg', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
107770	29487419	The majority of mice injected with M25.FGFR4wt formed tumors (5/7, 71%) but with a longer median latency of 37 weeks (range 19-51 weeks) than the M25.FGFR4V550E cohort (p <= 0.01).	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('mice', 'Species', '10090', (16, 20))	('M25.FGFR4wt', 'Var', (35, 46))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
107771	29487419	One of the 11 (9%) mice injected with M25.FGFR4N535K developed a tumor, whereas control mice M25.EV (n = 10) remained disease free.	('tumor', 'Disease', (65, 70))	('M25.FGFR4N535K', 'Var', (38, 52))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mice', 'Species', '10090', (88, 92))	('mice', 'Species', '10090', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
107772	29487419	Another tumor from this cohort formed in a left hind limb that had been injected with M25.FGFR4wt and tumor DNA sequencing confirmed that it encoded wild-type FGFR4 (Supplemental Fig.	('FGFR4', 'Gene', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('M25.FGFR4wt', 'Var', (86, 97))
107773	29487419	FGFR4 constructs were confirmed by sequencing, and FGFR4wt and FGFR4V550E tumors also expressed human FGFR4 proteins (Fig.	('FGFR4V550E', 'Var', (63, 73))	('human', 'Species', '9606', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expressed', 'Reg', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('V550E', 'Mutation', 'rs1057519793', (68, 73))	('FGFR4', 'Gene', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
107774	29487419	Collectively, these data suggest that FGFR4V550E is significantly more tumorigenic than FGFR4N535K and FGFR4wt, which has not been previously demonstrated.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('more', 'PosReg', (66, 70))	('tumor', 'Disease', (71, 76))	('FGFR4V550E', 'Var', (38, 48))
107779	29487419	Specifically, tumors (3/6) generated following M25.FGFR4wt injection were undifferentiated (i.e., undifferentiated pleomorphic sarcoma (UPS)), based on a null immunophenotype (Fig.	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('M25.FGFR4wt', 'Var', (47, 58))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (98, 134))	('undifferentiated pleomorphic sarcoma', 'Disease', (98, 134))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
107781	29487419	Also, the single M25.FGFR4N535K tumor highly expressed SMA (Fig.	('M25.FGFR4N535K', 'Var', (17, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('SMA', 'Disease', (55, 58))	('tumor', 'Disease', (32, 37))
107782	29487419	All M25.FGFR4V550E-expressing tumors (11/11) expressed at least one myoid marker (e.g., SMA, Desmin, Myod1, and/or Myogenin).	('M25.FGFR4V550E-expressing', 'Var', (4, 29))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('Desmin', 'Gene', '1674', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('Myod1', 'Gene', (101, 106))	('Myogenin', 'Gene', (115, 123))	('Desmin', 'Gene', (93, 99))	('Myod1', 'Gene', '4654', (101, 106))	('SMA', 'MPA', (88, 91))	('Myogenin', 'Gene', '4656', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('V550E', 'Mutation', 'rs1057519793', (13, 18))
107785	29487419	The remaining M25.FGFR4V550E tumors (6/11) expressed SMA (Fig.	('M25.FGFR4V550E', 'Var', (14, 28))	('SMA', 'Disease', (53, 56))	('V550E', 'Mutation', 'rs1057519793', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('expressed', 'Reg', (43, 52))	('tumors', 'Disease', (29, 35))
107788	29487419	To determine whether FGFR4V550E tumors faithfully model human RMS, we used the differential expression (AGDEX) algorithm to correlate ortholog expression profiles of five oncogene-driven syngeneic mouse sarcoma models, including tumors from previously published models (KRASLo, KRASHi) as well as FGFR4wt-, FGFR4N535K- and FGFR4V550E-expressing tumors, with human sarcomas (ERMS, ARMS, UPS, Ewing sarcoma (EWS) and synovial sarcoma (SS)).	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (397, 404))	('synovial sarcoma', 'Disease', (415, 431))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('sarcoma', 'Disease', 'MESH:D012509', (364, 371))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('sarcomas', 'Disease', 'MESH:D012509', (364, 372))	('sarcoma', 'Disease', (364, 371))	('sarcomas', 'Phenotype', 'HP:0100242', (364, 372))	('FGFR4wt-', 'Var', (297, 305))	('synovial sarcoma', 'Disease', 'MESH:D013584', (415, 431))	('Ewing sarcoma', 'Disease', (391, 404))	('RMS', 'Phenotype', 'HP:0002859', (375, 378))	('sarcomas', 'Disease', (364, 372))	('human', 'Species', '9606', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (345, 351))	('EWS', 'Gene', (406, 409))	('mouse', 'Species', '10090', (197, 202))	('human', 'Species', '9606', (358, 363))	('FGFR4N535K-', 'Var', (307, 318))	('sarcoma', 'Disease', 'MESH:D012509', (203, 210))	('tumors', 'Disease', (229, 235))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (415, 431))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('sarcoma', 'Disease', (203, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (364, 371))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('sarcoma', 'Disease', 'MESH:D012509', (424, 431))	('V550E', 'Mutation', 'rs1057519793', (328, 333))	('tumors', 'Disease', (345, 351))	('sarcoma', 'Disease', (424, 431))	('FGFR4V550E-expressing', 'Var', (323, 344))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('sarcoma', 'Disease', 'MESH:D012509', (397, 404))	('RMS', 'Phenotype', 'HP:0002859', (62, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('RMS', 'Phenotype', 'HP:0002859', (381, 384))	('sarcoma', 'Disease', (397, 404))	('V550E', 'Mutation', 'rs1057519793', (26, 31))	('EWS', 'Gene', '2130', (406, 409))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (391, 404))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (391, 404))	('tumors', 'Disease', 'MESH:D009369', (345, 351))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (424, 431))
107792	29487419	As some degree of muscle-specific differentiation was identified in most murine sarcomas, we next sought to characterize the differentiation capacity of myoblasts expressing wild-type or mutant FGFR4 in vitro (Fig.	('murine', 'Species', '10090', (73, 79))	('muscle-specific', 'Gene', '27335', (18, 33))	('sarcomas', 'Disease', 'MESH:D012509', (80, 88))	('mutant', 'Var', (187, 193))	('FGFR4', 'Gene', (194, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('muscle-specific', 'Gene', (18, 33))	('sarcomas', 'Disease', (80, 88))
107793	29487419	However M25.FGFR4N535K differentiation was approximately twofold lower when compared to Myo25 (p < 0.001), and M25.FGFR4N535K-overexpressing myoblasts had barely detectable levels of MyHC by immunoblotting (Fig.	('MyHC', 'Gene', (183, 187))	('lower', 'NegReg', (65, 70))	('MyHC', 'Gene', '4624', (183, 187))	('M25.FGFR4N535K-overexpressing', 'Var', (111, 140))	('M25.FGFR4N535K-overexpressing', 'PosReg', (111, 140))	('M25.FGFR4N535K', 'Var', (8, 22))
107794	29487419	Overall, no significant differences in the expression of Pax3 and Myf5, early markers of skeletal muscle differentiation, in Myo25, M25.EV, M25.FGFR4wt, or M25.FGFR4V550E myoblasts (Fig.	('M25.EV', 'Var', (132, 138))	('Pax3', 'Gene', '5077', (57, 61))	('Myf5', 'Gene', '4617', (66, 70))	('Pax3', 'Gene', (57, 61))	('M25.FGFR4V550E', 'Var', (156, 170))	('M25.FGFR4wt', 'Var', (140, 151))	('Myf5', 'Gene', (66, 70))
107795	29487419	Pax7 gene expression was higher in all transduced myoblasts at day 0 (p < 0.001), which continued to rise in myoblasts expressing mutated FGFR4 compared to Myo25 (p < 0.001).	('FGFR4', 'Gene', (138, 143))	('Pax7', 'Gene', '5081', (0, 4))	('rise', 'PosReg', (101, 105))	('expression', 'MPA', (10, 20))	('mutated', 'Var', (130, 137))	('higher', 'PosReg', (25, 31))	('Pax7', 'Gene', (0, 4))
107798	29487419	Since a hallmark of tumorigenesis is the ability of transformed cells to self-renew, we generated cell lines from two different FGFR4V550E tumors and determined that secondary tumors developed following engraftment of M25.FV24c or M25.FV28c cells into host mice (Supplemental Fig.	('tumor', 'Disease', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('M25.FV28c', 'Var', (231, 240))	('FGFR4V550E', 'Gene', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mice', 'Species', '10090', (257, 261))	('tumor', 'Disease', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Disease', (139, 145))	('secondary tumor', 'Disease', 'MESH:D060085', (166, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('secondary tumor', 'Disease', (166, 181))	('M25.FV24c', 'Var', (218, 227))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumor', 'Disease', (20, 25))
107806	29487419	Finally, we verified that M25.FGFR4V550E myoblasts had a statistically significant EC50 reduction compared to control (mean EC50 = 10 nM vs. mean EC50 = 36 nM, respectively; p < 0.05) (Fig.	('M25.FGFR4V550E', 'Var', (26, 40))	('EC50', 'MPA', (83, 87))	('reduction', 'NegReg', (88, 97))	('V550E', 'Mutation', 'rs1057519793', (35, 40))
107811	29487419	Phosphorylation of AKT at S473, an mTORC2 substrate, was detected but was minimally affected by GSK212 in mouse and human RMS cells (Fig.	('RMS', 'Phenotype', 'HP:0002859', (122, 125))	('GSK212', 'Var', (96, 102))	('at S473', 'Var', (23, 30))	('Phosphorylation', 'MPA', (0, 15))	('AKT', 'Protein', (19, 22))	('human', 'Species', '9606', (116, 121))	('mTORC2', 'Gene', (35, 41))	('GSK212', 'Chemical', 'MESH:C561454', (96, 102))	('mTORC2', 'Gene', '74343', (35, 41))	('mouse', 'Species', '10090', (106, 111))
107812	29487419	The amount of phosphorylated S6, an mTORC1 substrate, was low in murine RMS cells and was also minimally affected by GSK212 treatment, whereas pS6 was essentially undetectable in both human RMS cells lines (Fig.	('GSK212', 'Var', (117, 123))	('pS6', 'Gene', '338413', (143, 146))	('mTORC1', 'Gene', (36, 42))	('murine', 'Species', '10090', (65, 71))	('low', 'NegReg', (58, 61))	('human', 'Species', '9606', (184, 189))	('RMS', 'Phenotype', 'HP:0002859', (72, 75))	('RMS', 'Phenotype', 'HP:0002859', (190, 193))	('GSK212', 'Chemical', 'MESH:C561454', (117, 123))	('mTORC1', 'Gene', '382056', (36, 42))	('pS6', 'Gene', (143, 146))
107816	29487419	Collectively, these data demonstrate that RMS cells with two different activating FGFR4 mutations (V550E or V550L) as well as PAX3-FOXO1 gene fusions exhibit active mTOR signaling and suggest that GSK212 selectively targets the 4EBP1/EIF4E cap-dependent translation arm of mTORC1 signaling in these cells.	('EIF4E', 'Gene', '1977', (234, 239))	('mTORC1', 'Gene', (273, 279))	('GSK212', 'Chemical', 'MESH:C561454', (197, 203))	('EIF4E', 'Gene', (234, 239))	('4EBP1', 'Gene', (228, 233))	('PAX3', 'Gene', (126, 130))	('FGFR4', 'Gene', (82, 87))	('mTORC1', 'Gene', '382056', (273, 279))	('activating', 'PosReg', (71, 81))	('V550L', 'Var', (108, 113))	('PAX3', 'Gene', '5077', (126, 130))	('FOXO1', 'Gene', '2308', (131, 136))	('V550L', 'Mutation', 'p.V550L', (108, 113))	('4EBP1', 'Gene', '1978', (228, 233))	('RMS', 'Phenotype', 'HP:0002859', (42, 45))	('V550E', 'Var', (99, 104))	('V550E', 'Mutation', 'rs1057519793', (99, 104))	('FOXO1', 'Gene', (131, 136))	('active mTOR signaling', 'MPA', (158, 179))
107823	29487419	Furthermore, there was a statistically significant decrease in tumor size (p < 0.05) in mice treated with GSK212 compared to control mice (Fig.	('GSK212', 'Var', (106, 112))	('tumor', 'Disease', (63, 68))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('GSK212', 'Chemical', 'MESH:C561454', (106, 112))	('decrease', 'NegReg', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mice', 'Species', '10090', (88, 92))
107827	29487419	In this study, we report that FGFR4 dysregulation combined with p53 deficiency results in sarcoma with variable myogenic differentiation.	('dysregulation', 'Var', (36, 49))	('sarcoma', 'Disease', (90, 97))	('FGFR4', 'Gene', (30, 35))	('deficiency', 'Var', (68, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('results in', 'Reg', (79, 89))	('p53', 'Gene', (64, 67))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
107828	29487419	Furthermore, we discovered that different FGFR4-activating mutations (V550E vs. N535K) affected the expression of key myogenic differentiation factors, which likely accounted for the spectrum of myogenic tumors observed.	('V550E', 'Mutation', 'rs1057519793', (70, 75))	('V550E', 'Var', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('N535K', 'Var', (80, 85))	('myogenic tumors', 'Disease', 'MESH:D009369', (195, 210))	('N535K', 'Mutation', 'rs1057519792', (80, 85))	('expression', 'MPA', (100, 110))	('affected', 'Reg', (87, 95))	('FGFR4-activating', 'Gene', (42, 58))	('myogenic tumors', 'Disease', (195, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
107830	29487419	To date, comprehensive genome-wide analysis of RMS samples revealed frequent mutations within RTK/RAS/PI3K pathways and FGFR4 represents the most commonly mutated RTK in ERMS.	('RMS', 'Phenotype', 'HP:0002859', (47, 50))	('RTK', 'Gene', (163, 166))	('RMS', 'Phenotype', 'HP:0002859', (171, 174))	('RTK', 'Gene', (94, 97))	('RTK', 'Gene', '5979', (163, 166))	('mutations', 'Var', (77, 86))	('RTK', 'Gene', '5979', (94, 97))	('FGFR4', 'Gene', (120, 125))
107831	29487419	In silico analysis suggests that FGFR4 mutation occurs early in the clonal evolution of RMS and high FGFR4 expression correlates with decreased survival of RMS patients.	('decreased', 'NegReg', (134, 143))	('patients', 'Species', '9606', (160, 168))	('mutation', 'Var', (39, 47))	('FGFR4', 'Gene', (101, 106))	('RMS', 'Disease', (156, 159))	('expression', 'MPA', (107, 117))	('FGFR4', 'Gene', (33, 38))	('high', 'Var', (96, 100))	('RMS', 'Phenotype', 'HP:0002859', (156, 159))	('RMS', 'Disease', (88, 91))	('survival', 'MPA', (144, 152))	('RMS', 'Phenotype', 'HP:0002859', (88, 91))
107834	29487419	In our murine model system, transgenic overexpression of human wild-type (FGFR4wt) or mutant FGFR4 (i.e., FGFR4N535K, FGFR4V550E) had distinct effects on myoblasts in vitro and in vivo.	('overexpression', 'PosReg', (39, 53))	('FGFR4V550E', 'Var', (118, 128))	('FGFR4', 'Gene', (93, 98))	('myoblasts', 'CPA', (154, 163))	('FGFR4N535K', 'Var', (106, 116))	('murine', 'Species', '10090', (7, 13))	('effects', 'Reg', (143, 150))	('human', 'Species', '9606', (57, 62))
107835	29487419	Specifically, FGFR4-activating mutations transformed p53-/- mouse myoblasts in vitro and FGFR4wt-, FGFR4N535K- and FGFR4V550E-overexpressing p53-/- myoblasts generated tumors following engraftment into neonatal p53+/- host skeletal muscle.	('mutations', 'Var', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('generated', 'PosReg', (158, 167))	('FGFR4-activating', 'Gene', (14, 30))	('mouse', 'Species', '10090', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
107836	29487419	While FGFR4N535K mutant myoblasts generated a single high-grade myoid sarcoma (1/11, Fig.	('myoid sarcoma', 'Disease', (64, 77))	('FGFR4N535K', 'Var', (6, 16))	('myoid sarcoma', 'Disease', 'MESH:D012509', (64, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))
107837	29487419	3d), the most penetrant mutation was FGFR4V550E, generating 11 myogenic sarcomas including 5 tumors with classic rhabdomyoblastic differentiation (Fig.	('classic rhabdomyoblastic differentiation', 'Disease', (105, 145))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('FGFR4V550E', 'Var', (37, 47))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('sarcomas', 'Disease', (72, 80))	('tumors', 'Disease', (93, 99))	('classic rhabdomyoblastic differentiation', 'Disease', 'MESH:D012734', (105, 145))
107839	29487419	Thus aberrant FGFR4 signaling, either by activating mutation and/or receptor overexpression, is a driver of sarcoma formation.	('FGFR4', 'Gene', (14, 19))	('overexpression', 'PosReg', (77, 91))	('sarcoma', 'Disease', (108, 115))	('activating', 'PosReg', (41, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('driver', 'Reg', (98, 104))	('aberrant', 'Var', (5, 13))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))
107840	29487419	The FGF axis has a known regulatory role in skeletal muscle development, which may provide insight into how FGFR4 dysregulation drives the growth of skeletal muscle tumors.	('skeletal muscle tumors', 'Disease', 'MESH:D005207', (149, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('FGFR4', 'Gene', (108, 113))	('skeletal muscle tumors', 'Disease', (149, 171))	('drives', 'PosReg', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('dysregulation', 'Var', (114, 127))	('growth', 'MPA', (139, 145))
107841	29487419	Specifically, Fgfr4 is required for chick embryo myogenic cell differentiation and ablation of Fgfr4 impairs murine adult skeletal muscle regeneration.	('murine', 'Species', '10090', (109, 115))	('chick', 'Species', '9031', (36, 41))	('murine adult skeletal muscle regeneration', 'CPA', (109, 150))	('impairs', 'NegReg', (101, 108))	('ablation', 'Var', (83, 91))	('Fgfr4', 'Gene', (95, 100))
107844	29487419	Interestingly, FGFR4N535K expression decreased Myod1 mRNA levels during differentiation and the sole FGFR4N535K-expressing tumor did not show Myod1 immunopositivity.	('Myod1', 'Gene', (142, 147))	('tumor', 'Disease', (123, 128))	('Myod1', 'Gene', '4654', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('FGFR4N535K expression', 'Var', (15, 36))	('Myod1', 'Gene', '4654', (47, 52))	('Myod1', 'Gene', (47, 52))	('decreased', 'NegReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
107845	29487419	Increasing this cohort size is necessary to determine whether FGFR4N535K truly drives formation of undifferentiated sarcomas (i.e., UPS) perhaps due to impaired Myod1 activity.	('FGFR4N535K', 'Var', (62, 72))	('Myod1', 'Gene', (161, 166))	('Myod1', 'Gene', '4654', (161, 166))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (99, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('drives', 'Reg', (79, 85))	('undifferentiated sarcomas', 'Disease', (99, 124))
107846	29487419	Finally, FGFR4V550E-expressing myoblasts generated tumors containing rhabdomyoblasts and expressing RMS diagnostic markers Myod1 and Myog and had the strongest correlation with human RMS using AGDEX scoring (Fig.	('FGFR4V550E-expressing', 'Var', (9, 30))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('RMS', 'Phenotype', 'HP:0002859', (100, 103))	('Myog', 'Gene', '4656', (133, 137))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('RMS', 'Phenotype', 'HP:0002859', (183, 186))	('myoblasts', 'CPA', (31, 40))	('Myod1', 'Gene', '4654', (123, 128))	('V550E', 'Mutation', 'rs1057519793', (14, 19))	('Myog', 'Gene', (133, 137))	('human', 'Species', '9606', (177, 182))	('Myod1', 'Gene', (123, 128))
107847	29487419	Taken together, the ability of FGFR4 overexpressing or V550E myoblasts to differentiate in vitro correlated with tumor differentiation.	('tumor', 'Disease', (113, 118))	('V550E', 'Var', (55, 60))	('V550E', 'Mutation', 'rs1057519793', (55, 60))	('FGFR4', 'Gene', (31, 36))	('differentiate', 'CPA', (74, 87))	('overexpressing', 'PosReg', (37, 51))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
107850	29487419	Since FGF receptors are known to activate multiple effectors, including RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we performed a functional drug screen using a well-characterized oncology-based drug library on FGFR4V550E-overexpressing tumor cells as well as human ARMS and ERMS cell lines.	('RMS', 'Phenotype', 'HP:0002859', (277, 280))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('FGFR4V550E-overexpressing', 'Var', (212, 237))	('human', 'Species', '9606', (261, 266))	('RMS', 'Phenotype', 'HP:0002859', (268, 271))	('oncology', 'Phenotype', 'HP:0002664', (181, 189))	('tumor', 'Disease', (238, 243))	('V550E', 'Mutation', 'rs1057519793', (217, 222))	('MEK', 'Gene', (80, 83))	('MEK', 'Gene', '5609', (80, 83))	('activate', 'PosReg', (33, 41))	('PI3K/AKT/mTOR pathways', 'Pathway', (92, 114))
107851	29487419	PI3K/mTOR inhibitors caused the most potent viability reduction, and GSK2126458, a dual PI3K/mTOR inhibitor, robustly decreased cell numbers in RMS lines in vitro and in vivo.	('cell numbers in RMS lines', 'CPA', (128, 153))	('GSK2126458', 'Chemical', 'MESH:C561454', (69, 79))	('reduction', 'NegReg', (54, 63))	('RMS', 'Phenotype', 'HP:0002859', (144, 147))	('decreased', 'NegReg', (118, 127))	('GSK2126458', 'Var', (69, 79))
107852	29487419	Furthermore, in single-cell assays, GSK2126458 exhibited a highly selective reduction in signaling downstream of mTOR activity but not other major pathways.	('reduction', 'NegReg', (76, 85))	('GSK2126458', 'Var', (36, 46))	('signaling downstream of mTOR activity', 'MPA', (89, 126))	('GSK2126458', 'Chemical', 'MESH:C561454', (36, 46))
107854	29487419	Furthermore, GSK2126458 decreased p4EBP1 more potently than pS6 in RMS cells.	('4EBP1', 'Gene', '1978', (35, 40))	('decreased', 'NegReg', (24, 33))	('pS6', 'Gene', '338413', (60, 63))	('GSK2126458', 'Var', (13, 23))	('4EBP1', 'Gene', (35, 40))	('RMS', 'Phenotype', 'HP:0002859', (67, 70))	('pS6', 'Gene', (60, 63))	('GSK2126458', 'Chemical', 'MESH:C561454', (13, 23))
107857	29487419	In a previous study, the FGFR4-activating mutations, N535K and V550E, also drove tumor formation in xenograft models employing NIH 3T3 fibroblasts transgenically expressing FGFR4 and engrafted into immunodeficient host mice.	('immunodeficient', 'Disease', 'MESH:D007153', (198, 213))	('immunodeficient', 'Disease', (198, 213))	('mice', 'Species', '10090', (219, 223))	('drove', 'PosReg', (75, 80))	('N535K', 'Var', (53, 58))	('FGFR4-activating', 'Gene', (25, 41))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('N535K', 'Mutation', 'rs1057519792', (53, 58))	('NIH 3T3', 'CellLine', 'CVCL:0594', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('V550E', 'Mutation', 'rs1057519793', (63, 68))	('V550E', 'Var', (63, 68))	('tumor', 'Disease', (81, 86))
107861	29487419	In our study, the dual PI3K/mTOR inhibitor GSK2126458 impaired tumor growth and improved survival in FGFR4V550E-overexpressing murine RMS, providing preclinical evidence that inhibition of these key pathways may prove therapeutically useful for RMS with FGFR4 mutations.	('FGFR4', 'Gene', (254, 259))	('RMS', 'Phenotype', 'HP:0002859', (134, 137))	('impaired tumor growth', 'Disease', 'MESH:D006130', (54, 75))	('FGFR4V550E-overexpressing', 'Gene', (101, 126))	('survival', 'CPA', (89, 97))	('impaired tumor growth', 'Disease', (54, 75))	('GSK2126458', 'Chemical', 'MESH:C561454', (43, 53))	('murine', 'Species', '10090', (127, 133))	('improved', 'PosReg', (80, 88))	('RMS', 'Disease', (245, 248))	('RMS', 'Phenotype', 'HP:0002859', (245, 248))	('mutations', 'Var', (260, 269))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('GSK2126458', 'Var', (43, 53))
107862	29487419	Despite the apparent toxicity associated with the combination of vincristine and GSK2126458, additional animal studies and Phase I clinical trials will determine effective dosing.	('GSK2126458', 'Var', (81, 91))	('toxicity', 'Disease', 'MESH:D064420', (21, 29))	('toxicity', 'Disease', (21, 29))	('vincristine', 'Chemical', 'MESH:D014750', (65, 76))	('GSK2126458', 'Chemical', 'MESH:C561454', (81, 91))
107864	29487419	Wild-type and mutant human FGFR4 constructs in pDONR vectors were cloned into pLenti PGK Blasticidin (Addgene: 19,065) using Gateway Technology (Invitrogen).	('mutant', 'Var', (14, 20))	('Blasticidin', 'Chemical', 'MESH:C004500', (89, 100))	('human', 'Species', '9606', (21, 26))	('FGFR4', 'Gene', (27, 32))
107872	29487419	To evaluate global gene expression, RNA was harvested from FGFR4wt (n = 3), FGFR4N535K (n = 1), and FGFR4V550E (n = 2) tumors using the RNAeasy MINI Kit (Qiagen), in vitro transcribed, hybridized, and applied to Affymetrix Mouse 430A arrays.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('FGFR4V550E', 'Var', (100, 110))	('FGFR4N535K', 'Var', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Mouse', 'Species', '10090', (223, 228))
107874	29487419	Published microarray gene expression data sets included mouse normal tissue (GSE10246), human normal tissue (GSE3526), and human tumors (GSE8840 for ARMS and ERMS, GSE12102 for EWS, GSE20196 for SS, and GSE21050 for UPS).	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('GSE3526', 'Chemical', '-', (109, 116))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('GSE12102', 'Var', (164, 172))	('EWS', 'Gene', (177, 180))	('human', 'Species', '9606', (123, 128))	('EWS', 'Gene', '2130', (177, 180))	('mouse', 'Species', '10090', (56, 61))	('RMS', 'Phenotype', 'HP:0002859', (159, 162))	('GSE20196', 'Var', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('GSE10246', 'Var', (77, 85))	('human', 'Species', '9606', (88, 93))	('GSE8840', 'Var', (137, 144))	('GSE21050', 'Var', (203, 211))	('RMS', 'Phenotype', 'HP:0002859', (150, 153))
107882	29487419	Displays are shown pregated on 191/193Ir+ 195Cisplatinlo cleaved caspase3- events.	('191/193Ir+ 195Cisplatinlo', 'Var', (31, 56))	('195Cisplatinlo', 'Chemical', '-', (42, 56))	('caspase3', 'Gene', '836', (65, 73))	('caspase3', 'Gene', (65, 73))
107932	27274393	In recent years, studies have demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('growth', 'CPA', (141, 147))	('sarcomas', 'Disease', (151, 159))	('attenuate', 'NegReg', (127, 136))	('inhibition', 'Var', (48, 58))	('angiogenic pathways', 'Pathway', (62, 81))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))
107938	27274393	In animal models of human sarcomas, inhibitors of angiogenesis have shown promising antitumor activity.	('human', 'Species', '9606', (20, 25))	('sarcomas', 'Disease', (26, 34))	('inhibitors', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('angiogenesis', 'CPA', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('sarcomas', 'Disease', 'MESH:D012509', (26, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('tumor', 'Disease', (88, 93))
107948	27274393	Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('angiogenesis', 'CPA', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
107956	27274393	Blockade of VEGF signaling results in transient pruning and active remodeling of the immature and leaky blood vessels of tumors in animal models so that it more closely resembled the normal vasculature.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('remodeling', 'CPA', (67, 77))	('VEGF signaling', 'Gene', (12, 26))	('Blockade', 'Var', (0, 8))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('pruning', 'CPA', (48, 55))
107966	27274393	In vivo [(15)O]H2O positron emission tomography (PET) imaging in a mouse model of lung cancer showed that treatment with the VEGFR/platelet-derived growth factor receptor (PDGFR) inhibitor PTK787 created a 7-day window of improved tumor blood flow when tumor vessels are transiently normalized.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('VEGFR/platelet-derived growth factor receptor', 'Gene', (125, 170))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('PTK787', 'Var', (189, 195))	('lung cancer', 'Disease', (82, 93))	('mouse', 'Species', '10090', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (231, 236))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('tumor', 'Disease', (253, 258))	('improved', 'PosReg', (222, 230))	('H2O', 'Chemical', 'MESH:D014867', (15, 18))	('VEGFR/platelet-derived growth factor receptor', 'Gene', '18596', (125, 170))
107976	27274393	Antiangiogenic therapy with DC101 (VEGFR2 inhibitor), while blunting tumor volume growth, was found to increase local invasion in multiple primary tumor models, including a patient-derived xenograft.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('increase', 'PosReg', (103, 111))	('tumor', 'Disease', (69, 74))	('VEGFR2', 'Gene', '3791', (35, 41))	('blunting tumor', 'Disease', 'MESH:D014949', (60, 74))	('DC101', 'Chemical', 'MESH:C511761', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('VEGFR2', 'Gene', (35, 41))	('patient', 'Species', '9606', (173, 180))	('DC101', 'Var', (28, 33))	('blunting tumor', 'Disease', (60, 74))	('local invasion', 'CPA', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
107987	27274393	demonstrated the sequence-dependent interactions of ZD6474 (VEGR, EGFR, and RET inhibitor) with oxaliplatin in colon cancer cell lines in vitro using three combination schedules.	('colon cancer', 'Disease', 'MESH:D015179', (111, 123))	('oxaliplatin', 'MPA', (96, 107))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colon cancer', 'Phenotype', 'HP:0003003', (111, 123))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('RET', 'Gene', '5979', (76, 79))	('colon cancer', 'Disease', (111, 123))	('ZD6474', 'Chemical', 'MESH:C452423', (52, 58))	('interactions', 'Interaction', (36, 48))	('RET', 'Gene', (76, 79))	('ZD6474', 'Var', (52, 58))
107990	27274393	ZD6474 enhanced oxaliplatin-induced apoptosis, but only when added after oxaliplatin.	('ZD6474', 'Var', (0, 6))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (73, 84))	('oxaliplatin-induced', 'MPA', (16, 35))	('enhanced', 'PosReg', (7, 15))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (16, 27))	('ZD6474', 'Chemical', 'MESH:C452423', (0, 6))
107991	27274393	Alternatively, Naumova and colleagues demonstrated that paclitaxel and SU6668, a VEGFR2/PDGFR inhibitor, synergistically inhibited the proliferation and increased apoptosis of endothelial cells.	('apoptosis', 'CPA', (163, 172))	('VEGFR2', 'Gene', (81, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (56, 66))	('increased', 'PosReg', (153, 162))	('SU6668', 'Var', (71, 77))	('proliferation', 'CPA', (135, 148))	('SU6668', 'Chemical', 'MESH:C412603', (71, 77))	('VEGFR2', 'Gene', '3791', (81, 87))	('inhibited', 'NegReg', (121, 130))
107992	27274393	These findings, together with the in vivo inhibition of angiogenesis in Matrigel plugs and the reduction of MVD of paclitaxel-resistant ovarian carcinoma xenograft models, support the hypothesis that the enhanced effect exerted by the combination of paclitaxel and SU6668 on tumor growth is mediated by an effect on the vasculature.	('SU6668', 'Var', (265, 271))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('SU6668', 'Chemical', 'MESH:C412603', (265, 271))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (136, 153))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (136, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('paclitaxel', 'Chemical', 'MESH:D017239', (250, 260))	('enhanced', 'PosReg', (204, 212))	('ovarian carcinoma', 'Disease', (136, 153))
108005	27274393	Combined DC101 and continuous low-dose doxorubicin resulted in more effective growth inhibition of STS xenografts compared to either agent alone.	('DC101', 'Var', (9, 14))	('doxorubicin', 'Chemical', 'MESH:D004317', (39, 50))	('growth inhibition', 'CPA', (78, 95))	('STS', 'Phenotype', 'HP:0030448', (99, 102))	('DC101', 'Chemical', 'MESH:C511761', (9, 14))
108006	27274393	DC101 plus doxorubicin also enhanced the inhibition of tumor angiogenesis and endothelial cell activity, as demonstrated by significantly reduced MVD and inhibition of neovascularization.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('neovascularization', 'CPA', (168, 186))	('reduced', 'NegReg', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('endothelial cell activity', 'CPA', (78, 103))	('MVD', 'MPA', (146, 149))	('enhanced', 'PosReg', (28, 36))	('tumor', 'Disease', (55, 60))	('DC101', 'Chemical', 'MESH:C511761', (0, 5))	('inhibition', 'NegReg', (154, 164))	('doxorubicin', 'Chemical', 'MESH:D004317', (11, 22))	('DC101', 'Var', (0, 5))	('inhibition', 'NegReg', (41, 51))
108009	27274393	Combined therapy with DC101 and low-dose doxorubicin in vivo suppressed the growth of VEGF165-overexpressing xenografts, inhibited angiogenesis, increased the vessel maturation index, and suppressed tumor cell proliferation compared to monotherapy-treated mice.	('tumor', 'Disease', (199, 204))	('suppressed', 'NegReg', (61, 71))	('angiogenesis', 'CPA', (131, 143))	('mice', 'Species', '10090', (256, 260))	('DC101', 'Chemical', 'MESH:C511761', (22, 27))	('vessel maturation index', 'CPA', (159, 182))	('DC101', 'Var', (22, 27))	('suppressed', 'NegReg', (188, 198))	('increased', 'PosReg', (145, 154))	('VEGF165-overexpressing', 'Gene', (86, 108))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('doxorubicin', 'Chemical', 'MESH:D004317', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('growth', 'MPA', (76, 82))	('inhibited', 'NegReg', (121, 130))
108018	27274393	A retrospective study of patients with advanced solid malignancies treated on phase 1 protocols between 2004 and 2013 showed that chemotherapy concomitant with VEGF(R) inhibitors was associated with significantly higher odds ratio for clinical benefit compared with chemotherapy without VEGF(R) inhibitors.	('malignancies', 'Disease', (54, 66))	('VEGF(R', 'Gene', (160, 166))	('higher', 'PosReg', (213, 219))	('inhibitors', 'Var', (168, 178))	('patients', 'Species', '9606', (25, 33))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('clinical', 'MPA', (235, 243))
108046	27274393	The lack of benefit from bevacizumab may be due in part to key mutations in angiosarcoma that may activate the proangiogenic pathway independently of the classic ligand-receptor activation shown in recent studies.	('mutations', 'Var', (63, 72))	('angiosarcoma', 'Disease', 'MESH:D006394', (76, 88))	('proangiogenic pathway', 'Pathway', (111, 132))	('angiosarcoma', 'Disease', (76, 88))	('receptor', 'Gene', (169, 177))	('angiosarcoma', 'Phenotype', 'HP:0200058', (76, 88))	('bevacizumab', 'Chemical', 'MESH:D000068258', (25, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('receptor', 'Gene', '7422', (169, 177))	('activate', 'PosReg', (98, 106))
108057	27274393	These include bevacizumab, cyclophosphamide, and topotecan in patients with relapsed/refractory Ewing sarcoma (NCT01492673); and maintenance bevacizumab therapy in high-risk Ewing sarcoma and desmoplastic small round cell tumor (NCT01946529).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('relapsed/refractory', 'Disease', (76, 95))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (192, 227))	('cyclophosphamide', 'Var', (27, 43))	('Ewing sarcoma', 'Disease', (174, 187))	('desmoplastic small round cell tumor', 'Disease', (192, 227))	('topotecan', 'Chemical', 'MESH:D019772', (49, 58))	('patients', 'Species', '9606', (62, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (174, 187))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('Ewing sarcoma', 'Disease', (96, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (174, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (27, 43))	('bevacizumab', 'Chemical', 'MESH:D000068258', (141, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('bevacizumab', 'Chemical', 'MESH:D000068258', (14, 25))
108059	27274393	In adults, phase 2 studies are evaluating pazopanib and topotecan in patients with high-risk sarcomas (NCT02357810); pazopanib plus gemcitabine in advanced STS (NCT02203760, NCT01593748 and NCT01532687); pazopanib and paclitaxel in advanced angiosarcoma (NCT02212015); sorafenib, epirubicin, ifosfamide, and radiotherapy followed by surgery in high-risk STS (NCT02050919).	('NCT02203760', 'Var', (161, 172))	('sorafenib', 'Chemical', 'MESH:D000077157', (269, 278))	('NCT02212015', 'Var', (255, 266))	('NCT02357810', 'Var', (103, 114))	('paclitaxel', 'Chemical', 'MESH:D017239', (218, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('patients', 'Species', '9606', (69, 77))	('angiosarcoma', 'Disease', 'MESH:D006394', (241, 253))	('STS', 'Phenotype', 'HP:0030448', (354, 357))	('STS', 'Phenotype', 'HP:0030448', (156, 159))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('pazopanib', 'Chemical', 'MESH:C516667', (42, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('angiosarcoma', 'Phenotype', 'HP:0200058', (241, 253))	('sarcomas', 'Disease', (93, 101))	('angiosarcoma', 'Disease', (241, 253))	('ifosfamide', 'Chemical', 'MESH:D007069', (292, 302))	('NCT01532687', 'Var', (190, 201))	('topotecan', 'Chemical', 'MESH:D019772', (56, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('pazopanib', 'Chemical', 'MESH:C516667', (117, 126))	('pazopanib', 'Chemical', 'MESH:C516667', (204, 213))	('gemcitabine', 'Chemical', 'MESH:C056507', (132, 143))
108074	25704812	Epigenome Mapping Reveals Distinct Modes of Gene Regulation and Widespread Enhancer Reprogramming by the Oncogenic Fusion Protein EWS-FLI1 Transcription factor fusion proteins can transform cells by inducing global changes of the transcriptome, often creating a state of oncogene addiction.	('Enhancer', 'PosReg', (75, 83))	('changes', 'Reg', (215, 222))	('inducing', 'Reg', (199, 207))	('creating', 'Reg', (251, 259))	('fusion proteins', 'Var', (160, 175))	('EWS', 'Gene', '2130', (130, 133))	('EWS', 'Gene', (130, 133))	('transform', 'Reg', (180, 189))
108081	25704812	Based on these data, they identify clusters of epigenetically regulated genes and a unique enhancer signature that is associated with EWS-FLI1 oncogene addiction.	('EWS-FLI1', 'Gene', (134, 142))	('enhancer', 'PosReg', (91, 99))	('EWS-FLI1', 'Gene', '2130;2313', (134, 142))	('epigenetically regulated genes', 'Var', (47, 77))
108085	25704812	Here, we focus on epigenetic deregulation as a mechanism by which an oncogenic fusion protein may rewire cells for malignancy.	('malignancy', 'Disease', (115, 125))	('malignancy', 'Disease', 'MESH:D009369', (115, 125))	('epigenetic deregulation', 'Var', (18, 41))
108099	25704812	Each experiment was performed in two biological replicates each for both the EWS-FLI1-high state (cells in normal growth conditions) and the EWS-FLI1-low state (53 hr after adding doxycycline to induce knockdown of EWS-FLI1).	('EWS-FLI1', 'Gene', (141, 149))	('EWS-FLI1', 'Gene', (215, 223))	('EWS-FLI1', 'Gene', '2130;2313', (141, 149))	('EWS-FLI1', 'Gene', '2130;2313', (215, 223))	('doxycycline', 'Chemical', 'MESH:D004318', (180, 191))	('EWS-FLI1', 'Gene', (77, 85))	('EWS-FLI1', 'Gene', '2130;2313', (77, 85))	('knockdown', 'Var', (202, 211))
108104	25704812	Promoters of highly expressed genes and those bound by EWS-FLI1 had high levels of the open-chromatin-associated marks H3K4me3, H3K27ac, and H3K56ac.	('EWS-FLI1', 'Gene', '2130;2313', (55, 63))	('H3K27ac', 'Var', (128, 135))	('H3K4me3', 'Protein', (119, 126))	('H3K56ac', 'Var', (141, 148))	('EWS-FLI1', 'Gene', (55, 63))
108106	25704812	Promoters with distal EWS-FLI binding (5-40 kb from the TSS) were no more enriched for the open-chromatin marks H3K4me3, H3K27ac, and H3K56ac than those showing no EWS-FLI1 binding within 40 kb from the TSS, but they were more strongly depleted for the repressive-histone marks H3K27me3 and H3K9me3.	('EWS-FLI1', 'Gene', '2130;2313', (164, 172))	('FLI', 'Gene', '2314', (168, 171))	('H3K56ac', 'Var', (134, 141))	('FLI', 'Gene', (26, 29))	('H3K9me3', 'Var', (291, 298))	('H3K4me3', 'Var', (112, 119))	('EWS', 'Gene', '2130', (22, 25))	('EWS', 'Gene', (22, 25))	('FLI', 'Gene', (168, 171))	('H3K27ac', 'Var', (121, 128))	('EWS-FLI1', 'Gene', (164, 172))	('EWS', 'Gene', '2130', (164, 167))	('EWS', 'Gene', (164, 167))	('H3K27me3', 'Var', (278, 286))	('FLI', 'Gene', '2314', (26, 29))
108108	25704812	Proximal binding sites of EWS-FLI1 carried the characteristic histone patterns of promoter regions (Figure 2C), whereas distal EWS-FLI1 binding sites showed the chromatin signature of active enhancers with high levels of H3K27ac and H3K4me1, low levels of H3K4me3, and a dip in H3K27ac levels at the binding site (Figure 2D).	('histone', 'MPA', (62, 69))	('H3K4me3', 'MPA', (256, 263))	('EWS-FLI1', 'Gene', (127, 135))	('H3K27ac', 'Var', (221, 228))	('EWS-FLI1', 'Gene', (26, 34))	('EWS-FLI1', 'Gene', '2130;2313', (26, 34))	('EWS-FLI1', 'Gene', '2130;2313', (127, 135))	('enhancers', 'PosReg', (191, 200))	('H3K27ac levels', 'MPA', (278, 292))	('H3K4me1', 'Var', (233, 240))
108109	25704812	H3K27ac was consistently associated with EWS-FLI1 binding, both for promoter regions and for distal enhancer elements.	('H3K27ac', 'Var', (0, 7))	('associated', 'Reg', (25, 35))	('EWS-FLI1', 'Gene', '2130;2313', (41, 49))	('EWS-FLI1', 'Gene', (41, 49))	('binding', 'Interaction', (50, 57))
108114	25704812	First, we identified all genes that were significantly downregulated or upregulated upon EWS-FLI1 knockdown, according to our RNA-seq data (Figure 3A).	('knockdown', 'Var', (98, 107))	('EWS-FLI1', 'Gene', (89, 97))	('upregulated', 'PosReg', (72, 83))	('downregulated', 'NegReg', (55, 68))	('EWS-FLI1', 'Gene', '2130;2313', (89, 97))
108121	25704812	For example, EWS-FLI1 promoter binding was more common for EWS-FLI1-correlated transcripts (i.e., those that are downregulated after knockdown of EWS-FLI1) than for anticorrelated transcripts (Figures 3D, 3E, and 4A).	('EWS-FLI1', 'Gene', '2130;2313', (146, 154))	('binding', 'Interaction', (31, 38))	('EWS-FLI1', 'Gene', '2130;2313', (59, 67))	('downregulated', 'NegReg', (113, 126))	('EWS-FLI1', 'Gene', (13, 21))	('knockdown', 'Var', (133, 142))	('EWS-FLI1', 'Gene', '2130;2313', (13, 21))	('EWS-FLI1', 'Gene', (59, 67))	('common', 'Reg', (48, 54))	('EWS-FLI1', 'Gene', (146, 154))
108125	25704812	The chromatin-based gene clusters not only showed distinct patters of functional enrichment but also responded differently to EWS-FLI1 knockdown (Figure 4C).	('EWS-FLI1', 'Gene', (126, 134))	('knockdown', 'Var', (135, 144))	('EWS-FLI1', 'Gene', '2130;2313', (126, 134))	('responded', 'Reg', (101, 110))
108126	25704812	Among the EWS-FLI1-correlated transcripts, H3K27ac was most strongly reduced at cluster 1 promoters after EWS-FLI1 knockdown, whereas H3K4me3 and H3K4me1 signals were largely retained even in the EWS-FLI1-low state.	('reduced', 'NegReg', (69, 76))	('EWS-FLI1', 'Gene', (196, 204))	('EWS-FLI1', 'Gene', (106, 114))	('EWS-FLI1', 'Gene', (10, 18))	('EWS-FLI1', 'Gene', '2130;2313', (10, 18))	('EWS-FLI1', 'Gene', '2130;2313', (196, 204))	('EWS-FLI1', 'Gene', '2130;2313', (106, 114))	('H3K27ac', 'Var', (43, 50))	('knockdown', 'Var', (115, 124))
108127	25704812	In contrast, clusters 2 and 3 showed reduced levels for all three marks (H3K4me3, H3K4me1, and H3K27ac), and cluster 4 promoters underwent relatively minor changes upon EWS-FLI1 knockdown.	('EWS-FLI1', 'Gene', (169, 177))	('EWS-FLI1', 'Gene', '2130;2313', (169, 177))	('knockdown', 'Var', (178, 187))	('H3K4me1', 'Var', (82, 89))	('reduced', 'NegReg', (37, 44))	('H3K4me3', 'Var', (73, 80))	('H3K27ac', 'Var', (95, 102))
108129	25704812	Together, these observations indicate that EWS-FLI1 expression promotes transcription of its target genes in at least two distinct ways: first, by further increasing H3K27ac levels and transcription of genes that are already widely expressed in proliferating cells (correlated cluster 1); and second, by establishing or maintaining the chromatin signature of active promoters (H3K4me3, H3K4me1, and H3K27ac) at cell type specific genes that would otherwise be silent in these cells (correlated clusters 2 and 3).	('H3K27ac levels', 'MPA', (166, 180))	('chromatin', 'MPA', (336, 345))	('transcription', 'MPA', (185, 198))	('EWS-FLI1', 'Gene', (43, 51))	('promotes', 'PosReg', (63, 71))	('H3K27ac', 'Var', (399, 406))	('establishing', 'PosReg', (304, 316))	('H3K4me1', 'Var', (386, 393))	('H3K4me3', 'Var', (377, 384))	('transcription', 'MPA', (72, 85))	('EWS-FLI1', 'Gene', '2130;2313', (43, 51))	('genes', 'Gene', (202, 207))	('increasing', 'PosReg', (155, 165))	('expression', 'Var', (52, 62))	('maintaining', 'PosReg', (320, 331))
108131	25704812	Based on these promoter-centric analyses, H3K27ac and, to a lesser degree, H3K4me3 and H3K4me1 emerged as the histone marks that were most strongly affected by EWS-FLI1 knockdown.	('H3K4me3', 'Var', (75, 82))	('EWS-FLI1', 'Gene', (160, 168))	('H3K27ac', 'Var', (42, 49))	('knockdown', 'Var', (169, 178))	('H3K4me1', 'Var', (87, 94))	('EWS-FLI1', 'Gene', '2130;2313', (160, 168))	('affected', 'Reg', (148, 156))
108132	25704812	This result was corroborated by western blots for all seven histone marks in additional Ewing sarcoma cell lines (TC252, SK-N-MC, and ST-ET-7.2), where we observed a global reduction in H3K4me3 and H3K27ac levels upon knockdown of EWS-FLI1 (Figure 4E).	('EWS-FLI1', 'Gene', (231, 239))	('reduction', 'NegReg', (173, 182))	('H3K27ac', 'Protein', (198, 205))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('knockdown', 'Var', (218, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('EWS-FLI1', 'Gene', '2130;2313', (231, 239))	('H3K4me3', 'Protein', (186, 193))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('SK-N-MC', 'CellLine', 'CVCL:0530', (121, 128))	('TC252', 'CellLine', 'CVCL:S866', (114, 119))	('Ewing sarcoma', 'Disease', (88, 101))
108134	25704812	Given that H3K27ac was most variable between the chromatin-based gene clusters and also most dynamic upon EWS-FLI1 knockdown (Figures 3 and 4), we hypothesized that the clustered genes should respond differently to induced global changes of acetylation, which would support the clusters' usefulness for identifying distinct modes of gene regulation among EWS-FLI1 target genes.	('EWS-FLI1', 'Gene', '2130;2313', (355, 363))	('respond', 'Reg', (192, 199))	('H3K27ac', 'Var', (11, 18))	('knockdown', 'Var', (115, 124))	('EWS-FLI1', 'Gene', (106, 114))	('acetylation', 'MPA', (241, 252))	('EWS-FLI1', 'Gene', '2130;2313', (106, 114))	('EWS-FLI1', 'Gene', (355, 363))
108137	25704812	None of the three HAT inhibitors that we tested (C646, CPTH2, and anacardic acid) had an effect on cell survival or gene expression at the chosen concentrations (data not shown); hence, we focused our analysis primarily on the HDAC inhibitors (Figures 5 and S4).	('HDAC', 'Gene', (227, 231))	('gene expression', 'MPA', (116, 131))	('HDAC', 'Gene', '9734', (227, 231))	('C646', 'Var', (49, 53))	('C646', 'Chemical', '-', (49, 53))	('anacardic', 'Chemical', '-', (66, 75))	('cell survival', 'CPA', (99, 112))
108147	25704812	Our promoter-centric analysis (Figures 3 and 4) established H3K4me3 and H3K27ac as the two histone marks that were most strongly associated with EWS-FLI1 expression.	('associated', 'Reg', (129, 139))	('EWS-FLI1', 'Gene', (145, 153))	('H3K4me3', 'Var', (60, 67))	('H3K27ac', 'Var', (72, 79))	('EWS-FLI1', 'Gene', '2130;2313', (145, 153))	('expression', 'MPA', (154, 164))
108149	25704812	In total, 15,300 H3K27ac peaks showed significantly lower intensity in EWS-FLI1-low cells ("EWS-FLI1 correlated peaks"), and 18,727 H3K27ac peaks showed significantly higher intensity ("EWS-FLI1 anticorrelated peaks").	('EWS-FLI1', 'Gene', (186, 194))	('H3K27ac', 'Var', (17, 24))	('higher', 'PosReg', (167, 173))	('EWS-FLI1', 'Gene', '2130;2313', (186, 194))	('EWS-FLI1', 'Gene', (92, 100))	('intensity', 'MPA', (58, 67))	('EWS-FLI1', 'Gene', (71, 79))	('lower', 'NegReg', (52, 57))	('EWS-FLI1', 'Gene', '2130;2313', (71, 79))	('EWS-FLI1', 'Gene', '2130;2313', (92, 100))
108150	25704812	27% of correlated peaks and only 6% of anticorrelated peaks overlapped with promoter regions (Figures 6A and S5A), indicating that the majority of EWS-FLI1-associated H3K27ac peaks are located at enhancer elements outside of promoter regions.	('H3K27ac', 'Var', (167, 174))	('EWS-FLI1', 'Gene', '2130;2313', (147, 155))	('EWS-FLI1', 'Gene', (147, 155))
108160	25704812	We also observed widespread loss of H3K27ac upon knockdown of EWS-FLI1 for some super-enhancers (Figure 6E), while others displayed more localized changes affecting only those H3K27ac peaks that overlapped with EWS-FLI1 binding sites (Figure S5F).	('EWS-FLI1', 'Gene', (211, 219))	('knockdown', 'Var', (49, 58))	('EWS-FLI1', 'Gene', '2130;2313', (62, 70))	('H3K27ac', 'Protein', (36, 43))	('EWS-FLI1', 'Gene', '2130;2313', (211, 219))	('EWS-FLI1', 'Gene', (62, 70))	('H3K27ac', 'Protein', (176, 183))	('loss', 'NegReg', (28, 32))
108168	25704812	Based on both ChIP-seq and western blots, H3K27ac emerged as the mark that was most strongly affected by EWS-FLI1 knockdown.	('knockdown', 'Var', (114, 123))	('EWS-FLI1', 'Gene', '2130;2313', (105, 113))	('H3K27ac', 'Protein', (42, 49))	('EWS-FLI1', 'Gene', (105, 113))
108169	25704812	33,170 H3K27ac peaks were significantly altered throughout the genome (Figure 7A), and 80% of the most strongly EWS-FLI1-correlated H3K27ac peaks were bound by EWS-FLI1 (Figure 6C).	('EWS-FLI1', 'Gene', (160, 168))	('H3K27ac', 'Gene', (7, 14))	('EWS-FLI1', 'Gene', (112, 120))	('EWS-FLI1', 'Gene', '2130;2313', (160, 168))	('H3K27ac', 'Var', (132, 139))	('altered', 'Reg', (40, 47))	('EWS-FLI1', 'Gene', '2130;2313', (112, 120))
108171	25704812	Similar but weaker patterns of EWS-FLI1 association were also observed for H3K4me3 and H3K4me1 (Figure 7A), while the other studied histone marks did not show widespread changes upon EWS-FLI1 knockdown.	('H3K4me3', 'Var', (75, 82))	('EWS-FLI1', 'Gene', '2130;2313', (183, 191))	('H3K4me1', 'Var', (87, 94))	('EWS-FLI1', 'Gene', (31, 39))	('EWS-FLI1', 'Gene', (183, 191))	('association', 'Interaction', (40, 51))	('EWS-FLI1', 'Gene', '2130;2313', (31, 39))
108172	25704812	Differences in response to EWS-FLI1 knockdown were also notably absent for DNA methylation (Figure 7B).	('DNA methylation', 'MPA', (75, 90))	('response', 'MPA', (15, 23))	('EWS-FLI1', 'Gene', '2130;2313', (27, 35))	('knockdown', 'Var', (36, 45))	('EWS-FLI1', 'Gene', (27, 35))	('absent', 'NegReg', (64, 70))
108173	25704812	Although this mark was anticorrelated with EWS-FLI1 binding (Figure 2E), no changes in DNA methylation patterns were observed 53 hr after knockdown:at a time point that should be sufficient for de novo methylation to have at least started.	('knockdown', 'Var', (138, 147))	('EWS-FLI1', 'Gene', (43, 51))	('EWS-FLI1', 'Gene', '2130;2313', (43, 51))
108178	25704812	Second, the genes in EWS-FLI1-correlated clusters 2 and 3 (Figure 4A) were more tissue specific than genes in correlated cluster 1, and they lacked active promoter marks such as H3K27ac and/or H3K4me3 in the EWS-FLI1-low state.	('H3K27ac', 'Var', (178, 185))	('EWS-FLI1', 'Gene', (208, 216))	('EWS-FLI1', 'Gene', '2130;2313', (208, 216))	('EWS-FLI1', 'Gene', (21, 29))	('H3K4me3', 'Var', (193, 200))	('lacked', 'NegReg', (141, 147))	('EWS-FLI1', 'Gene', '2130;2313', (21, 29))	('active promoter marks', 'MPA', (148, 169))
108184	25704812	Strikingly, the most dynamic enhancers upon EWS-FLI1 knockdown were also the most cell-type specific (Figure 6), which is illustrated by the absence of any ENCODE signal for H3K27ac at the EWS-FLI1-bound enhancers upstream of the CCND1 promoter (Figure 7C).	('CCND1', 'Gene', '595', (230, 235))	('EWS-FLI1', 'Gene', '2130;2313', (189, 197))	('EWS-FLI1', 'Gene', (44, 52))	('knockdown', 'Var', (53, 62))	('EWS-FLI1', 'Gene', '2130;2313', (44, 52))	('CCND1', 'Gene', (230, 235))	('EWS-FLI1', 'Gene', (189, 197))	('enhancers', 'PosReg', (29, 38))	('H3K27ac', 'Var', (174, 181))
108227	25611047	P9851 is a legacy biology study that intended to increase the knowledge of osteosarcoma biology and accelerate the discovery of novel therapeutic targets, uncover prognostic indicators and biomarkers of outcome.	('osteosarcoma', 'Disease', (75, 87))	('increase', 'PosReg', (49, 57))	('P9851', 'Var', (0, 5))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))
108228	25611047	P9851 also served as a companion biology study to the contemporaneous treatment studies P9754 (Protocol for Patients with Newly Diagnosed, Non-metastatic Osteosarcoma: A Pilot Study) and AOST0121 (A Group-wide Phase II Study of Trastuzumab Herceptin in Metastatic Osteosarcoma Patients with Tumors that Overexpress HER2).	('Tumors', 'Disease', (291, 297))	('Tumors', 'Disease', 'MESH:D009369', (291, 297))	('P9851', 'Var', (0, 5))	('Tumors', 'Phenotype', 'HP:0002664', (291, 297))	('P9754', 'Var', (88, 93))	('Non-metastatic Osteosarcoma', 'Disease', 'MESH:D012516', (139, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('Patients', 'Species', '9606', (277, 285))	('Metastatic Osteosarcoma', 'Disease', (253, 276))	('Non-metastatic Osteosarcoma', 'Disease', (139, 166))	('HER2', 'Gene', (315, 319))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (154, 166))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (264, 276))	('HER2', 'Gene', '2064', (315, 319))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (228, 239))	('Patients', 'Species', '9606', (108, 116))	('Metastatic Osteosarcoma', 'Disease', 'MESH:D012516', (253, 276))
108229	25611047	Subsequently, P9851 served as a companion to AOST0331 (A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-Operative Chemotherapy) until the opening of the current and active banking study AOST06B1.	('Osteosarcoma', 'Disease', (103, 115))	('Osteosarcoma', 'Disease', (176, 188))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (176, 188))	('Osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('Osteosarcoma', 'Disease', 'MESH:D012516', (176, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('P9851', 'Var', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('AOST06B1', 'Gene', (309, 317))
108231	25611047	During the time span that P9851 was accruing tumor samples derived from patients for biologic banking purposes, there were periods of time when there was no actively open accompanying treatment study for patients with localized or metastatic disease.	('patients', 'Species', '9606', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('P9851', 'Var', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('patients', 'Species', '9606', (72, 80))
108233	25611047	Indeed, although 5,369 tissue and tumor samples were collected on 1,105 patients, 46.1% of the patients enrolled on P9851 were not enrolled on any accompanying treatment study.	('P9851', 'Var', (116, 121))	('tumor', 'Disease', (34, 39))	('patients', 'Species', '9606', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('patients', 'Species', '9606', (72, 80))
108240	25611047	Both AOST06B1 and AOST0331 studies required IRB approved informed consent by all participating institutions prior to enrolling patients.	('patients', 'Species', '9606', (127, 135))	('AOST06B1', 'Var', (5, 13))	('AOST0331', 'Gene', (18, 26))
108245	25611047	From the opening of P9851 on September 15, 1999 to September 30, 2013, 3,935 children were treated for osteosarcoma at U.S. COG institutions (302 children per year).	('P9851', 'Var', (20, 25))	('children', 'Species', '9606', (146, 154))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('children', 'Species', '9606', (77, 85))
108247	25611047	The Children's Oncology Group, the QuadW Foundation, American Association of Cancer Research, and CureSearch recognized that a substantial proportion of samples derived from P9851 and AOST06B1 in the biorepository lacked clinically linked data, and the overall value of the repository was diminished for conducting biology-driven studies.	('P9851', 'Var', (174, 179))	('Children', 'Species', '9606', (4, 12))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('AOST06B1', 'Var', (184, 192))	('lacked', 'NegReg', (214, 220))	('Oncology', 'Phenotype', 'HP:0002664', (15, 23))
108253	25611047	Data derived from the TARGET initiative will include genome-wide analysis of matched tumor and normal samples, which have been performed using gene expression (Affymetrix Human Exon 1.0 STR arrays), copy number and loss of heterozygosity (affymetrix SNP 6.0 arrays), DNA methylation (Illumina Infinuim 450K methylation assay), miRNA analysis (MegaPlex Taq Man platform), whole genome, whole exome, and transcriptome sequencing (mRNA-seq).	('tumor', 'Disease', (85, 90))	('Human', 'Species', '9606', (171, 176))	('loss of', 'NegReg', (215, 222))	('copy number', 'Var', (199, 210))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Man', 'Species', '9606', (356, 359))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
108255	25611047	As a result, two loci achieved genome wide significance, rs1906953 at p621.3, as well as and the glutamate receptor metabotropic 4 (GRM4), rs7591996, and rs10208273 in a gene desert on p2p25.2.	('rs7591996', 'Mutation', 'rs7591996', (139, 148))	('rs7591996', 'Var', (139, 148))	('GRM4', 'Gene', (132, 136))	('glutamate receptor metabotropic 4', 'Gene', '2914', (97, 130))	('GRM4', 'Gene', '2914', (132, 136))	('rs1906953', 'Var', (57, 66))	('rs1906953', 'Mutation', 'rs1906953', (57, 66))	('rs10208273', 'Var', (154, 164))	('glutamate receptor metabotropic 4', 'Gene', (97, 130))	('rs10208273', 'Mutation', 'rs10208273', (154, 164))
108272	25611047	As a result of the two osteosarcoma banking studies P9851 and AOST06B1 prospectively initiated and supported by the efforts of COG, CureSearch, QuadW Foundation and the CSBAO, one of the world's largest tumor banks of osteosarcoma samples has been established.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('P9851', 'Var', (52, 57))	('osteosarcoma', 'Phenotype', 'HP:0002669', (218, 230))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('osteosarcoma', 'Phenotype', 'HP:0002669', (23, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (23, 35))	('osteosarcoma', 'Disease', (23, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (218, 230))	('osteosarcoma', 'Disease', (218, 230))
108284	24019980	Multivariate analysis revealed the expression of SIRT1 as an independent prognostic indicator for overall survival and event-free survival of sarcoma patients.	('SIRT1', 'Gene', (49, 54))	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('sarcoma', 'Disease', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('patients', 'Species', '9606', (150, 158))	('expression', 'Var', (35, 45))
108289	24019980	Recent extensive studies have shown that changes in SIRT1-mediated signaling give survival benefits under the stress conditions, which is closely related with tumorigenesis.	('SIRT1-mediated signaling', 'MPA', (52, 76))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('changes', 'Var', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('survival benefits', 'CPA', (82, 99))
108290	24019980	The expression of SIRT1 increases resistance to anticancer agents and is associated with progression of cancers and poor prognosis of cancer patients.	('increases', 'PosReg', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('patients', 'Species', '9606', (141, 149))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (104, 110))	('associated with', 'Reg', (73, 88))	('expression', 'Var', (4, 14))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('SIRT1', 'Gene', (18, 23))	('cancers', 'Disease', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
108294	24019980	Deleted in breast cancer 1(DBC1) was first identified by its deletion in breast cancer and was suggested as a tumor suppressor because it acts as a suppressor of SIRT1.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('deletion', 'Var', (61, 69))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('tumor', 'Disease', (110, 115))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('breast cancer', 'Disease', (11, 24))	('breast cancer', 'Disease', (73, 86))	('Deleted in breast cancer 1(DBC1', 'Gene', '57805', (0, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
108297	24019980	In human cancers, the expression of DBC1 is associated with advanced cancer and predicted poor survival of various human malignant tumors.	('cancer', 'Disease', (9, 15))	('expression', 'Var', (22, 32))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('DBC1', 'Gene', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('malignant tumors', 'Disease', 'MESH:D018198', (121, 137))	('poor', 'NegReg', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('malignant tumors', 'Disease', (121, 137))	('cancer', 'Disease', (69, 75))	('associated', 'Reg', (44, 54))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('DBC1', 'Gene', '57805', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('human', 'Species', '9606', (115, 120))
108319	24019980	DBC1 expression was also significantly associated with shorter OS (P = 0.029, HR; 2.338, 95% CI; 1.090-5.013) and EFS (P = 0.005, HR; 2.761, 95% CI; 1.361-5.601) by univariate analysis (Figure 2 D).	('DBC1', 'Gene', (0, 4))	('expression', 'Var', (5, 15))	('EFS', 'CPA', (114, 117))	('shorter OS', 'CPA', (55, 65))	('DBC1', 'Gene', '57805', (0, 4))
108320	24019980	The expression of P53, beta-catenin, and cyclin D1 were significantly associated with shorter OS (P<0.001, P = 0.002, and P = 0.006, respectively) and EFS (P<0.001, P = 0.026, and P = 0.007, respectively) by univariate analysis (Figure 2 E F and G).	('cyclin D1', 'Gene', (41, 50))	('EFS', 'CPA', (151, 154))	('beta-catenin', 'Gene', (23, 35))	('beta-catenin', 'Gene', '1499', (23, 35))	('P53', 'Gene', (18, 21))	('expression', 'Var', (4, 14))	('P53', 'Gene', '7157', (18, 21))	('cyclin D1', 'Gene', '595', (41, 50))	('shorter OS', 'Disease', (86, 96))
108321	24019980	The Ki67 index also predicted shorter OS (P = 0.002) and EFS (P = 0.007) (Figure 2 H).	('Ki67', 'Var', (4, 8))	('EFS', 'CPA', (57, 60))	('Ki67', 'Chemical', '-', (4, 8))	('shorter', 'NegReg', (30, 37))
108338	24019980	In this study, nuclear expression of SIRT1 was an independent prognostic indicator for OS and EFS in soft-tissue sarcoma patients.	('SIRT1', 'Gene', (37, 42))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('EFS', 'Disease', (94, 97))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (101, 120))	('sarcoma', 'Disease', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('patients', 'Species', '9606', (121, 129))	('nuclear expression', 'Var', (15, 33))
108339	24019980	When separately analyzed the soft-tissue sarcomas according to the tumor stage (stage I and II versus stage III and IV) and histological grade (grade 1 versus grade 2 and 3), nuclear expression of SIRT1 predicted sorter OS and EFS regardless of the tumor stage or histological grade (Figure S1).	('soft-tissue sarcomas', 'Disease', (29, 49))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (29, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('nuclear expression', 'Var', (175, 193))	('sorter', 'Disease', (213, 219))	('SIRT1', 'Gene', (197, 202))	('predicted', 'Reg', (203, 212))	('EFS', 'Disease', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (29, 48))	('tumor', 'Disease', (249, 254))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (29, 49))	('tumor', 'Disease', (67, 72))
108347	24019980	Concerning to the role of SIRT1 in human malignant tumors most studies demonstrated that the expression of SIRT1 in human tissue related to the survival of cells and present benefits to the survival of cells despite some controversies.	('expression', 'Var', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('human', 'Species', '9606', (35, 40))	('malignant tumors', 'Disease', (41, 57))	('SIRT1', 'Gene', (107, 112))	('benefits', 'PosReg', (174, 182))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('related to', 'Reg', (129, 139))	('malignant tumors', 'Disease', 'MESH:D018198', (41, 57))	('survival of cells', 'CPA', (144, 161))	('survival', 'CPA', (190, 198))	('human', 'Species', '9606', (116, 121))
108355	24019980	However, ectopic expression of SIRT1 increases the proliferation of cancer cells and blocks stress-induced apoptosis.	('ectopic expression', 'Var', (9, 27))	('blocks', 'NegReg', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('increases', 'PosReg', (37, 46))	('cancer', 'Disease', (68, 74))	('stress-induced apoptosis', 'CPA', (92, 116))	('SIRT1', 'Gene', (31, 36))
108358	24019980	Furthermore, inhibition of SIRT1 inhibited the proliferation of cancer cells and triggered cancer cell death.	('triggered', 'Reg', (81, 90))	('cancer', 'Disease', (91, 97))	('inhibition', 'Var', (13, 23))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('death', 'Disease', 'MESH:D003643', (103, 108))	('death', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SIRT1', 'Gene', (27, 32))	('inhibited', 'NegReg', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
108360	24019980	Knock-down of SIRT1 enhanced apoptosis only in the cancer cells, but not in normal cells.	('apoptosis', 'CPA', (29, 38))	('enhanced', 'PosReg', (20, 28))	('Knock-down', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('SIRT1', 'Gene', (14, 19))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
108377	24019980	Our results have also indicated that the expression of beta-catenin and cyclin D1 are significantly associated with shorter OS and EFS by univariate analysis.	('beta-catenin', 'Gene', (55, 67))	('cyclin D1', 'Gene', (72, 81))	('associated', 'Reg', (100, 110))	('beta-catenin', 'Gene', '1499', (55, 67))	('shorter OS', 'Disease', (116, 126))	('EFS', 'Disease', (131, 134))	('expression', 'Var', (41, 51))	('cyclin D1', 'Gene', '595', (72, 81))
108383	24019980	The mean Ki67 index of SIRT1-expressing sarcomas was eight times higher than SIRT1-negative sarcomas (mean +- standard error: 434 +- 85 versus 59 +- 24, 2-tailed t-test; P = 0.006).	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('sarcomas', 'Disease', (92, 100))	('Ki67 index', 'MPA', (9, 19))	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('higher', 'PosReg', (65, 71))	('Ki67', 'Chemical', '-', (9, 13))	('SIRT1-expressing', 'Var', (23, 39))	('sarcomas', 'Disease', (40, 48))
108387	24019980	In agreement with our findings, Ki67 as a prognostic indicator of soft-tissue sarcomas has been reported in the soft-tissue sarcoma and malignant fibrous histiocytoma.	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcoma', 'Disease', (124, 131))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (66, 85))	('malignant fibrous histiocytoma', 'Disease', (136, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('histiocytoma', 'Phenotype', 'HP:0012315', (154, 166))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (66, 86))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('sarcoma', 'Disease', (78, 85))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (112, 131))	('Ki67', 'Chemical', '-', (32, 36))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (66, 86))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('Ki67', 'Var', (32, 36))	('soft-tissue sarcomas', 'Disease', (66, 86))
108446	28621321	BCOR immunohistochemical staining is a highly sensitive marker for YWHAE-NUTM2 high-grade endometrial stromal sarcoma with both classic and unusual morphology and identifies a subset of high-grade endometrial stromal sarcoma with BCOR alterations, including BCOR rearrangement and internal tandem duplication.	('endometrial stromal sarcoma', 'Disease', (197, 224))	('BCOR', 'Gene', (258, 262))	('internal tandem duplication', 'Var', (281, 308))	('BCOR', 'Gene', '54880', (0, 4))	('BCOR', 'Gene', '54880', (258, 262))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (197, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('endometrial stromal sarcoma', 'Disease', (90, 117))	('YWHAE', 'Gene', '7531', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (90, 117))	('BCOR', 'Gene', (230, 234))	('BCOR', 'Gene', (0, 4))	('YWHAE', 'Gene', (67, 72))	('BCOR', 'Gene', '54880', (230, 234))
108449	28621321	Endometrial stromal nodules and low-grade endometrial stromal sarcomas are both characterized by small, bland, ovoid cells resembling proliferative-phase endometrial stroma and harbor rearrangement of genes often involved in transcriptional regulation with JAZF1-SUZ12 fusion being most common.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('endometrial stroma', 'Disease', 'MESH:D014591', (154, 172))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (42, 70))	('endometrial stroma', 'Disease', (154, 172))	('common', 'Reg', (287, 293))	('rearrangement', 'Var', (184, 197))	('endometrial stroma', 'Disease', 'MESH:D014591', (42, 60))	('JAZF1-SUZ12', 'Gene', (257, 268))	('endometrial stromal sarcomas', 'Disease', (42, 70))
108451	28621321	High-grade endometrial stromal sarcoma in the current World Health Organization classification is limited to tumors characterized by high-grade round cell morphology sometimes associated with a low-grade fibromyxoid component and harboring t(q22;p13) resulting in YWHAE-NUTM2 fusion.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('YWHAE', 'Gene', (264, 269))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('endometrial stromal sarcoma', 'Disease', (11, 38))	('associated', 'Reg', (176, 186))	('t(q22;p13', 'Var', (240, 249))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (11, 38))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('YWHAE', 'Gene', '7531', (264, 269))	('tumors', 'Disease', (109, 115))
108452	28621321	However, another recently described endometrial stromal sarcoma sharing morphologic overlap with myxoid leiomyosarcoma was found to harbor t(X;22)(p11.4;q13.2) resulting in ZC3H7B-BCOR fusion and has been proposed as another morphologic variant of high-grade endometrial stromal sarcoma due to its aggressive clinical behavior.	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (36, 63))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (298, 326))	('BCOR', 'Gene', (180, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('BCOR', 'Gene', '54880', (180, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('myxoid leiomyosarcoma', 'Disease', (97, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('endometrial stromal sarcoma', 'Disease', (259, 286))	('myxoid leiomyosarcoma', 'Disease', 'MESH:D007890', (97, 118))	('t(X;22)(p11.4;q13.2)', 'STRUCTURAL_ABNORMALITY', 'None', (139, 159))	('t(X;22)(p11.4;q13.2', 'Var', (139, 158))	('endometrial stromal sarcoma', 'Disease', (36, 63))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (259, 286))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (104, 118))
108462	28621321	BCOR immunostaining has now emerged as a robust marker of EWSR1-negative small blue round cell tumors of the soft tissues harboring YWHAE-NUTM2, BCOR-CCNB3, and BCOR-MAML3 fusions, as well as BCOR internal tandem duplications (ITD).	('BCOR', 'Gene', '54880', (161, 165))	('BCOR', 'Gene', '54880', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('YWHAE', 'Gene', '7531', (132, 137))	('internal tandem duplications', 'Var', (197, 225))	('BCOR', 'Gene', (145, 149))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('BCOR', 'Gene', '54880', (145, 149))	('BCOR', 'Gene', (161, 165))	('BCOR', 'Gene', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('YWHAE', 'Gene', (132, 137))	('BCOR', 'Gene', '54880', (192, 196))	('tumors', 'Disease', (95, 101))	('BCOR', 'Gene', (0, 4))
108469	28621321	Six high-grade endometrial stromal sarcomas with BCOR rearrangement originated from Memorial Sloan Kettering Cancer Center, including 3 that were previously reported, and 2 from Vancouver General Hospital.	('BCOR', 'Gene', (49, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('BCOR', 'Gene', '54880', (49, 53))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (84, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('endometrial stromal sarcomas', 'Disease', (15, 43))	('Memorial Sloan Kettering Cancer', 'Disease', (84, 115))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (15, 43))	('rearrangement', 'Var', (54, 67))
108479	28621321	Gene rearrangement status by FISH was known and previously reported for 34 low-grade endometrial stromal sarcomas and 8 endometrial stromal nodules, including 24, 3, and 2 tumors with JAZF1-SUZ12, JAZF1-PHF1, and EPC-PHF1 fusions, respectively, and 9 and 4 tumors with JAZF1 and PHF1 rearrangement with no known fusion partner, respectively.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('endometrial stroma', 'Disease', (120, 138))	('endometrial stromal sarcomas', 'Disease', (85, 113))	('low-grade', 'Disease', (75, 84))	('endometrial stroma', 'Disease', 'MESH:D014591', (85, 103))	('endometrial stroma', 'Disease', 'MESH:D014591', (120, 138))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('fusions', 'Var', (222, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (85, 113))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('JAZF1-SUZ12', 'Var', (184, 195))
108508	28621321	BCOR internal tandem duplication was absent in the adjacent normal myometrium.	('BCOR', 'Gene', '54880', (0, 4))	('internal tandem duplication', 'Var', (5, 32))	('BCOR', 'Gene', (0, 4))
108515	28621321	Gene rearrangement status was known in 2 of the low-grade endometrial stromal sarcomas exhibiting focal, weak BCOR expression with JAZF1-SUZ12 fusion in one and JAZF1 rearrangement with no known partner in the other.	('BCOR', 'Gene', (110, 114))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (58, 86))	('BCOR', 'Gene', '54880', (110, 114))	('JAZF1', 'Gene', (161, 166))	('JAZF1-SUZ12', 'Gene', (131, 142))	('fusion', 'Var', (143, 149))	('endometrial stromal sarcomas', 'Disease', (58, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('rearrangement', 'Var', (167, 180))
108522	28621321	A similar staining pattern was seen in 3 high-grade endometrial stromal sarcomas of unusual morphology which prompted FISH confirmation of YWHAE rearrangement in 2 and identification of a novel somatic BCOR in-frame internal tandem duplication by genomic PCR and targeted DNA sequencing of BCOR exon 16 in the third tumor.	('endometrial stromal sarcomas', 'Disease', (52, 80))	('tumor', 'Disease', 'MESH:D009369', (316, 321))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (52, 80))	('YWHAE', 'Gene', '7531', (139, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('tumor', 'Disease', (316, 321))	('in-frame internal tandem duplication', 'Var', (207, 243))	('BCOR', 'Gene', (290, 294))	('BCOR', 'Gene', '54880', (290, 294))	('YWHAE', 'Gene', (139, 144))	('BCOR', 'Gene', (202, 206))	('BCOR', 'Gene', '54880', (202, 206))
108533	28621321	In addition to identifying the round cell component of YWHAE-NUTM2 high-grade endometrial stromal sarcomas, BCOR expression led to the discovery of a novel in-frame BCOR internal tandem duplication in one of our high-grade endometrial stromal sarcomas sharing both morphologic and immunophenotypic features with YWHAE-NUTM2 high-grade endometrial stromal sarcomas, but lacking YWHAE, BCOR, and BCORL1 rearrangement.	('BCOR', 'Gene', (394, 398))	('BCOR', 'Gene', '54880', (384, 388))	('endometrial stromal sarcomas', 'Disease', (335, 363))	('BCOR', 'Gene', (384, 388))	('internal tandem duplication', 'Var', (170, 197))	('BCORL1', 'Gene', '63035', (394, 400))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (223, 251))	('sarcomas', 'Phenotype', 'HP:0100242', (355, 363))	('YWHAE', 'Gene', (55, 60))	('BCORL1', 'Gene', (394, 400))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (78, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (243, 251))	('endometrial stromal sarcomas', 'Disease', (223, 251))	('YWHAE', 'Gene', '7531', (55, 60))	('BCOR', 'Gene', '54880', (165, 169))	('BCOR', 'Gene', '54880', (108, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (355, 362))	('endometrial stromal sarcomas', 'Disease', (78, 106))	('BCOR', 'Gene', (165, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('YWHAE', 'Gene', (312, 317))	('BCOR', 'Gene', (108, 112))	('BCOR', 'Gene', '54880', (394, 398))	('YWHAE', 'Gene', (377, 382))	('YWHAE', 'Gene', '7531', (312, 317))	('YWHAE', 'Gene', '7531', (377, 382))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (335, 363))
108534	28621321	Highly recurrent BCOR internal tandem duplications have recently been discovered in clear cell sarcoma of the kidney and small blue round cell tumors of the soft tissues in infants.	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (95, 116))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('internal tandem duplications', 'Var', (22, 50))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (95, 116))	('sarcoma of the kidney', 'Disease', (95, 116))	('infants', 'Species', '9606', (173, 180))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (84, 116))	('BCOR', 'Gene', (17, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('BCOR', 'Gene', '54880', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
108535	28621321	The discovery of BCOR internal tandem duplication in one of our high-grade endometrial stromal sarcomas now expands the spectrum of cancers in which BCOR internal tandem duplication appears to be a genetic driver of tumorigenesis.	('tumor', 'Disease', (216, 221))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('BCOR', 'Gene', (149, 153))	('endometrial stromal sarcomas', 'Disease', (75, 103))	('BCOR', 'Gene', '54880', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('internal tandem duplication', 'Var', (22, 49))	('BCOR', 'Gene', (17, 21))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (75, 103))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('BCOR', 'Gene', '54880', (17, 21))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('internal tandem duplication', 'Var', (154, 181))
108536	28621321	While BCOR internal tandem duplication is present in the vast majority of clear cell sarcomas of the kidney, its prevalence among uterine sarcomas is currently unknown.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('sarcomas of the kidney', 'Disease', (85, 107))	('BCOR', 'Gene', '54880', (6, 10))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('sarcomas', 'Disease', (85, 93))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (130, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('internal tandem duplication', 'Var', (11, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcomas', 'Disease', (138, 146))	('clear cell sarcomas of the kidney', 'Phenotype', 'HP:0006770', (74, 107))	('sarcomas of the kidney', 'Disease', 'MESH:D007674', (85, 107))	('sarcomas', 'Disease', 'MESH:D012509', (85, 93))	('BCOR', 'Gene', (6, 10))
108538	28621321	BCOR internal tandem duplication and YWHAE-NUTM2 fusion appear mutually exclusive in clear cell sarcoma of the kidney.	('BCOR', 'Gene', '54880', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('YWHAE', 'Gene', '7531', (37, 42))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (96, 117))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (96, 117))	('sarcoma of the kidney', 'Disease', (96, 117))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (85, 117))	('YWHAE', 'Gene', (37, 42))	('internal tandem duplication', 'Var', (5, 32))	('BCOR', 'Gene', (0, 4))
108548	28621321	Given the identification of ZC3H7B-BCOR and BCOR-ZC3H7B fusions among our cohort of high-grade endometrial stromal sarcomas and lack of correlation between BCOR expression pattern and either gene fusion, it remains uncertain whether ZC3H7B or BCOR constitutes the genetic driver of these tumors.	('fusions', 'Var', (56, 63))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('BCOR', 'Gene', (35, 39))	('BCOR', 'Gene', (156, 160))	('endometrial stromal sarcomas', 'Disease', (95, 123))	('BCOR', 'Gene', '54880', (35, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('BCOR', 'Gene', (44, 48))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('BCOR', 'Gene', '54880', (156, 160))	('BCOR', 'Gene', (243, 247))	('BCOR', 'Gene', '54880', (44, 48))	('BCOR', 'Gene', '54880', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (95, 123))	('tumors', 'Disease', (288, 294))
108549	28621321	Our results also suggest that BCOR expression is a reliable marker that can distinguish high-grade endometrial stromal sarcomas with YWHAE-NUTM2, ZC3H7B-BCOR, BCOR-ZC3H7B, and BCOR internal tandem duplication from other uterine mesenchymal tumors.	('BCOR', 'Gene', '54880', (176, 180))	('BCOR', 'Gene', '54880', (153, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('YWHAE', 'Gene', (133, 138))	('mesenchymal tumors', 'Disease', (228, 246))	('BCOR', 'Gene', (176, 180))	('BCOR', 'Gene', (153, 157))	('YWHAE', 'Gene', '7531', (133, 138))	('BCOR', 'Gene', '54880', (159, 163))	('BCOR', 'Gene', (159, 163))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (99, 127))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('BCOR', 'Gene', '54880', (30, 34))	('internal tandem duplication', 'Var', (181, 208))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('endometrial stromal sarcomas', 'Disease', (99, 127))	('BCOR', 'Gene', (30, 34))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (228, 246))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))
108551	28621321	The presence of focal BCOR staining in a subset of leiomyosarcomas may be a potential caveat since this tumor type is in the differential diagnosis of high-grade endometrial stromal sarcomas, particularly those harboring BCOR rearrangements.	('leiomyosarcomas', 'Disease', (51, 66))	('rearrangements', 'Var', (226, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('endometrial stromal sarcomas', 'Disease', (162, 190))	('BCOR', 'Gene', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('tumor', 'Disease', (104, 109))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (162, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('BCOR', 'Gene', (22, 26))	('BCOR', 'Gene', '54880', (221, 225))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (51, 66))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (51, 66))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (51, 65))	('BCOR', 'Gene', '54880', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
108556	28621321	In tumors with BCOR internal tandem duplication, the duplicated BCOR region resides within a PUFD domain that facilitates binding with PCGF1, another member of the variant PRC1, and may disrupt the structure and/or function of the PRC1 in epigenetic modification.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('internal tandem duplication', 'Var', (20, 47))	('binding', 'Interaction', (122, 129))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('BCOR', 'Gene', (15, 19))	('facilitates', 'PosReg', (110, 121))	('BCOR', 'Gene', (64, 68))	('BCOR', 'Gene', '54880', (15, 19))	('epigenetic modification', 'MPA', (239, 262))	('disrupt', 'NegReg', (186, 193))	('BCOR', 'Gene', '54880', (64, 68))	('PRC1', 'Gene', (231, 235))	('structure', 'MPA', (198, 207))	('function', 'MPA', (215, 223))	('PCGF1', 'Gene', (135, 140))
108557	28621321	Further studies are needed to investigate the impact of BCOR internal tandem duplication, BCOR and YWHAE rearrangements on PRC1 function and the mechanism of high-grade endometrial stromal sarcoma oncogenesis.	('YWHAE', 'Gene', (99, 104))	('BCOR', 'Gene', (56, 60))	('BCOR', 'Gene', (90, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('BCOR', 'Gene', '54880', (56, 60))	('BCOR', 'Gene', '54880', (90, 94))	('YWHAE', 'Gene', '7531', (99, 104))	('endometrial stromal sarcoma oncogenesis', 'Disease', (169, 208))	('internal tandem duplication', 'Var', (61, 88))	('endometrial stromal sarcoma oncogenesis', 'Disease', 'MESH:D018203', (169, 208))
108558	28621321	In summary, BCOR expression is highly sensitive in identifying high-grade endometrial stromal sarcomas harboring YWHAE-NUTM2 fusion and BCOR internal tandem duplication as well as a subset of BCOR-rearranged high-grade endometrial stromal sarcomas.	('YWHAE', 'Gene', (113, 118))	('BCOR', 'Gene', '54880', (136, 140))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (219, 247))	('BCOR', 'Gene', (12, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('endometrial stromal sarcomas', 'Disease', (74, 102))	('internal tandem duplication', 'Var', (141, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('YWHAE', 'Gene', '7531', (113, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (239, 247))	('BCOR', 'Gene', (136, 140))	('BCOR', 'Gene', (192, 196))	('BCOR', 'Gene', '54880', (12, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('endometrial stromal sarcomas', 'Disease', (219, 247))	('BCOR', 'Gene', '54880', (192, 196))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (74, 102))
108559	28621321	Diffuse and strong expression should prompt FISH, RT-PCR, or RNA sequencing confirmation of YWHAE and BCOR rearrangement or targeted DNA sequencing for BCOR internal tandem duplication if those rearrangements are not detected.	('BCOR', 'Gene', '54880', (102, 106))	('internal tandem duplication', 'Var', (157, 184))	('BCOR', 'Gene', (152, 156))	('YWHAE', 'Gene', '7531', (92, 97))	('rearrangement', 'Var', (107, 120))	('BCOR', 'Gene', '54880', (152, 156))	('BCOR', 'Gene', (102, 106))	('YWHAE', 'Gene', (92, 97))
108560	28621321	Identification of BCOR internal tandem duplication and similar BCOR immunophenotype in high-grade endometrial stromal sarcomas adds to the growing body of histologic, immunophenotypic, and genetic evidence uniting these tumors with clear cell sarcoma of the kidney and soft tissue round cell sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('BCOR', 'Gene', '54880', (18, 22))	('sarcoma of the kidney', 'Disease', (243, 264))	('endometrial stromal sarcomas', 'Disease', (98, 126))	('sarcomas', 'Disease', (118, 126))	('sarcomas', 'Disease', 'MESH:D012509', (292, 300))	('BCOR', 'Gene', (18, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (292, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('BCOR', 'Gene', '54880', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('sarcomas', 'Disease', (292, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (232, 264))	('BCOR', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (243, 264))	('tumors', 'Disease', (220, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('internal tandem duplication', 'Var', (23, 50))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (243, 264))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (98, 126))
108608	27734516	Although it was impossible to continue bendamustine treatment because of bendamustine-induced adverse effects and subsequent reduced physical strength of the patient, a rapid decrease of ALP and CRP was observed regardless of the many other chemotherapy regimens administered previously.	('ALP', 'Gene', (187, 190))	('bendamustine', 'Chemical', 'MESH:D000069461', (73, 85))	('physical strength', 'CPA', (133, 150))	('reduced physical strength', 'Phenotype', 'HP:0003484', (125, 150))	('bendamustine-induced', 'Var', (73, 93))	('patient', 'Species', '9606', (158, 165))	('decrease', 'NegReg', (175, 183))	('bendamustine', 'Chemical', 'MESH:D000069461', (39, 51))	('ALP', 'Gene', '250', (187, 190))	('decrease of ALP', 'Phenotype', 'HP:0003282', (175, 190))	('reduced', 'NegReg', (125, 132))	('CRP', 'Gene', (195, 198))	('CRP', 'Gene', '1401', (195, 198))
108621	27547487	Collectively, knockdown of EWS expression increased various anti-tumor mechanisms of TFL in human Ewing's sarcoma in cell culture and animal models.	('increased', 'PosReg', (42, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (98, 113))	('tumor', 'Disease', (65, 70))	('TFL', 'Chemical', 'MESH:C003377', (85, 88))	('TFL', 'Gene', (85, 88))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('human', 'Species', '9606', (92, 97))	("Ewing's sarcoma", 'Disease', (98, 113))	('EWS', 'Gene', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
108628	27547487	Chromosomal translocations between this gene and various genes encoding transcription factors result in the production of chimeric proteins that are involved in tumorigenesis.	('production of chimeric proteins', 'MPA', (108, 139))	('result in', 'Reg', (94, 103))	('Chromosomal translocations', 'Var', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('involved', 'Reg', (149, 157))	('tumor', 'Disease', (161, 166))
108629	27547487	In Ewing's sarcoma, the chomosomal translocation t(11; 22)(q24; q12) generates a fusion of the 5' transcriptional activation domain of EWS gene with the 3' DNA-binding domain of Friend leukemia integration 1 (FLI1) gene resulting in the fusion oncoprotein EWS-FLI1, which acts as an aberrant transcriptional activator with strong transforming capabilities.	('FLI1', 'Gene', (209, 213))	('FLI1', 'Gene', '2313', (260, 264))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (3, 18))	('fusion', 'Var', (81, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('Friend leukemia integration 1', 'Gene', (178, 207))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))	('fusion', 'Var', (237, 243))	('EWS-FLI1', 'Gene', (256, 264))	('EWS', 'Gene', (135, 138))	('Friend leukemia integration 1', 'Gene', '2313', (178, 207))	('EWS-FLI1', 'Gene', '2130;2313', (256, 264))	('oncoprotein', 'Protein', (244, 255))	('FLI1', 'Gene', (260, 264))	('FLI1', 'Gene', '2313', (209, 213))
108630	27547487	About 80% - 90% of Ewing's sarcomas contain the chromosomal translocation t(11; 22) (q24; q12).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (19, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	("Ewing's sarcomas", 'Disease', (19, 35))	('t(11; 22) (q24; q12', 'Var', (74, 93))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (19, 35))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (19, 35))
108631	27547487	Stable expression of anti-sense EWS-FLI1 cDNA and dominant-negative inhibition of EWS-FLI1 cDNA resulted in growth reduction and provided evidence of EWS/FLI-l involvement in proliferation of Ewing's sarcoma cells.	('anti-sense', 'Var', (21, 31))	('reduction', 'NegReg', (115, 124))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (192, 207))	('EWS-FLI1', 'Gene', '2130;2313', (32, 40))	('EWS-FLI1', 'Gene', (82, 90))	('EWS-FLI1', 'Gene', '2130;2313', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('inhibition', 'NegReg', (68, 78))	('FLI-l', 'Gene', '2314', (154, 159))	('proliferation', 'CPA', (175, 188))	('FLI-l', 'Gene', (154, 159))	('growth', 'MPA', (108, 114))	('EWS-FLI1', 'Gene', (32, 40))
108632	27547487	However, therapeutic strategies to eliminate or inactivate EWS-FLI1 have not yet been successfully translated to clinics.	('inactivate', 'Var', (48, 58))	('EWS-FLI1', 'Gene', '2130;2313', (59, 67))	('EWS-FLI1', 'Gene', (59, 67))
108634	27547487	However, anti-sense oligonucleotide directed against the EWS part of EWS-FLI1 is known to cause tumor inhibitory effect in vivo.	('EWS-FLI1', 'Gene', '2130;2313', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('oligonucleotide', 'Chemical', 'MESH:D009841', (20, 35))	('tumor', 'Disease', (96, 101))	('anti-sense oligonucleotide', 'Var', (9, 35))	('EWS-FLI1', 'Gene', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
108639	27547487	EWS shRNA plasmid transfection can thereby be an effective strategy for knockdown of EWS expression to induce differentiation, inhibit migration and proliferation, and promote apoptosis in human Ewing's sarcoma cells in culture as well as in animal models.	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('human', 'Species', '9606', (189, 194))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (195, 210))	('migration', 'CPA', (135, 144))	('differentiation', 'CPA', (110, 125))	('promote', 'PosReg', (168, 175))	('induce', 'PosReg', (103, 109))	('inhibit', 'NegReg', (127, 134))	('EWS', 'Gene', (85, 88))	('apoptosis', 'CPA', (176, 185))	('knockdown', 'Var', (72, 81))
108698	27547487	The bisulfite-treated DNA was used as template for MSP amplification of the human p53 promoter region using MSP primers specific for either methylated (M pair) or unmethylated (U pair) DNA.	('methylated', 'Var', (140, 150))	('human', 'Species', '9606', (76, 81))	('bisulfite', 'Chemical', 'MESH:C042345', (4, 13))	('p53', 'Gene', '7157', (82, 85))	('p53', 'Gene', (82, 85))
108743	27547487	EWS shRNA plasmid transfection and TFL treatment increased expression of E-cadherin (a tight junction protein), which served as the prominent biochemical marker of differentiation in the cells.	('TFL', 'Chemical', 'MESH:C003377', (35, 38))	('E-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', '999', (73, 83))	('increased', 'PosReg', (49, 58))	('expression', 'MPA', (59, 69))	('transfection', 'Var', (18, 30))
108746	27547487	We examined whether knockdown of EWS expression could potentiate TFL in inhibition of migration of human Ewing's sarcoma SK-N-MC and RD-ES cells through the polycarbonate membranes and we also examined the alterations in expression of molecular markers of survival, angiogenesis, and invasion in the cells Figure 5).	('TFL', 'Chemical', 'MESH:C003377', (65, 68))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (105, 120))	('migration', 'CPA', (86, 95))	('RD-ES', 'Chemical', '-', (133, 138))	('EWS', 'Gene', (33, 36))	('human', 'Species', '9606', (99, 104))	('SK-N-MC', 'CellLine', 'CVCL:0530', (121, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('knockdown', 'Var', (20, 29))	('inhibition', 'NegReg', (72, 82))
108747	27547487	Only knockdown of EWS expression or TFL treatment substantially inhibited cell migration.	('cell migration', 'CPA', (74, 88))	('EWS', 'Gene', (18, 21))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (64, 73))	('TFL', 'Chemical', 'MESH:C003377', (36, 39))
108749	27547487	We determined the amounts of cells migration through the transwell polycarbonate membranes and found that combination of knockdown of EWS expression and TFL treatment most significantly inhibited migration of Ewing's sarcoma cells (Figure 5B).	('knockdown', 'Var', (121, 130))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (209, 224))	('migration', 'CPA', (196, 205))	('TFL', 'Chemical', 'MESH:C003377', (153, 156))	('EWS', 'Gene', (134, 137))	('inhibited', 'NegReg', (186, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))
108751	27547487	Methylation of DNA at the p53 promoter region is an impediment for expression of this acclaimed tumor suppressor protein in different tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (96, 101))	('p53', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('p53', 'Gene', '7157', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (134, 139))
108752	27547487	Therefore, unmethylation of DNA at the p53 promoter region is an important goal in increasing its expression and tumor suppressor function in promoting expression of other prominent pro-apoptotic proteins such as Puma (p53 upregulated mediator of apoptosis) and Noxa.	('tumor', 'Disease', (113, 118))	('p53', 'Gene', '7157', (219, 222))	('promoting', 'PosReg', (142, 151))	('Noxa', 'Gene', '5366', (262, 266))	('p53', 'Gene', (39, 42))	('unmethylation', 'Var', (11, 24))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('p53', 'Gene', '7157', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('expression', 'MPA', (152, 162))	('Noxa', 'Gene', (262, 266))	('p53', 'Gene', (219, 222))	('increasing', 'PosReg', (83, 93))	('expression', 'MPA', (98, 108))
108754	27547487	We used the bisulfite-treated DNA as template for MSP amplification of the human p53 promoter region using MSP primers specific for either methylated (M pair) or unmethylated (U pair) DNA (Figure 6A).	('bisulfite', 'Chemical', 'MESH:C042345', (12, 21))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))	('human', 'Species', '9606', (75, 80))	('methylated', 'Var', (139, 149))
108759	27547487	Unmethylation of DNA at the p53 promoter region increased expression of p53 protein, as we demonstrated by Western blotting (Figure 6B).	('p53', 'Gene', (28, 31))	('increased', 'PosReg', (48, 57))	('p53', 'Gene', '7157', (28, 31))	('expression', 'MPA', (58, 68))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('Unmethylation', 'Var', (0, 13))
108762	27547487	Therefore, we examined whether EWS shRNA plasmid transfection and TFL treatment could induce morphological (Figure 6C) and biochemical (Figure 6D) features of apoptosis in both Ewing's sarcoma SK-N-MC and RD-ES cell lines.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('TFL', 'Chemical', 'MESH:C003377', (66, 69))	('transfection', 'Var', (49, 61))	('RD-ES', 'Chemical', '-', (205, 210))	('induce', 'PosReg', (86, 92))	('SK-N-MC', 'CellLine', 'CVCL:0530', (193, 200))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (177, 192))
108764	27547487	Quantification of apoptotic cells on the basis of in situ Wright staining showed that combination of EWS shRNA plasmid transfection and TFL treatment caused the highest amounts of apoptosis in both Ewing's sarcoma cell lines (Figure 6C).	('transfection', 'Var', (119, 131))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (198, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('apoptosis', 'CPA', (180, 189))	('TFL', 'Chemical', 'MESH:C003377', (136, 139))
108768	27547487	We determined percentages of apoptotic cells demonstrating clearly that combination of EWS shRNA plasmid transfection and TFL treatment caused the highest increases in induction of apoptotic death in both Ewing's sarcoma cell lines (Figure 6D).	('transfection', 'Var', (105, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('increases', 'PosReg', (155, 164))	('apoptotic death', 'CPA', (181, 196))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (205, 220))	('TFL', 'Chemical', 'MESH:C003377', (122, 125))
108771	27547487	EWS shRNA plasmid transfection or TFL treatment moderately induced extrinsic pathway of apoptosis as evidenced from activation of caspase-8 in both cell lines.	('caspase-8', 'Gene', '841', (130, 139))	('activation', 'PosReg', (116, 126))	('extrinsic pathway of apoptosis', 'Pathway', (67, 97))	('transfection', 'Var', (18, 30))	('induced', 'Reg', (59, 66))	('caspase-8', 'Gene', (130, 139))	('TFL', 'Chemical', 'MESH:C003377', (34, 37))
108775	27547487	Combination of EWS shRNA plasmid transfection and TFL treatment caused the highest increase in expression of pro-apoptotic Bax protein and decrease in expression of anti-apoptotic Bcl-2 protein, which could result in increase in the Bax: Bcl-2 ratio for increasing mitochondrial permeability in both Ewing's sarcoma cell lines.	('Bax', 'Gene', '581', (123, 126))	('transfection', 'Var', (33, 45))	('Bcl-2', 'Gene', (180, 185))	('Bax', 'Gene', '581', (233, 236))	('Bcl-2', 'Gene', '596', (238, 243))	('TFL', 'Chemical', 'MESH:C003377', (50, 53))	('Bcl-2', 'Gene', '596', (180, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (308, 315))	('expression', 'MPA', (95, 105))	('decrease', 'NegReg', (139, 147))	('increase', 'PosReg', (83, 91))	('expression', 'MPA', (151, 161))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (300, 315))	('mitochondrial permeability', 'MPA', (265, 291))	('increase', 'PosReg', (217, 225))	('increasing', 'PosReg', (254, 264))	('Bax', 'Gene', (123, 126))	('Bcl-2', 'Gene', (238, 243))	('Bax', 'Gene', (233, 236))
108777	27547487	Combination of EWS shRNA plasmid transfection and TFL treatment caused the highest increase in mitochondrial release of cytochrome c, Smac/Diablo, and AIF into the cytosol to trigger mitochondrial caspase-dependent and caspase-independent pathways of apoptosis.	('transfection', 'Var', (33, 45))	('Diablo', 'Gene', (139, 145))	('increase', 'PosReg', (83, 91))	('Smac', 'Gene', '56616', (134, 138))	('cytochrome c', 'Gene', '54205', (120, 132))	('trigger', 'Reg', (175, 182))	('TFL', 'Chemical', 'MESH:C003377', (50, 53))	('Smac', 'Gene', (134, 138))	('Diablo', 'Gene', '56616', (139, 145))	('AIF', 'Gene', '9131', (151, 154))	('cytochrome c', 'Gene', (120, 132))	('AIF', 'Gene', (151, 154))
108804	27547487	Phosphorylation of Akt (p-Akt) triggers Akt kinase activity, which has high potential to deregulate cell cycle, induce cell proliferation, avoid apoptosis, and stimulate cell survival through upregulation of NF-kappaB.	('Akt', 'Gene', '207', (19, 22))	('cell proliferation', 'CPA', (119, 137))	('Akt', 'Gene', '207', (26, 29))	('Akt', 'Gene', '207', (40, 43))	('Phosphorylation', 'Var', (0, 15))	('induce', 'PosReg', (112, 118))	('cell cycle', 'CPA', (100, 110))	('NF-kappaB', 'Protein', (208, 217))	('cell survival', 'CPA', (170, 183))	('avoid', 'PosReg', (139, 144))	('upregulation', 'PosReg', (192, 204))	('Akt', 'Gene', (26, 29))	('Akt', 'Gene', (40, 43))	('triggers', 'Reg', (31, 39))	('Akt', 'Gene', (19, 22))	('deregulate', 'MPA', (89, 99))	('stimulate', 'PosReg', (160, 169))	('apoptosis', 'CPA', (145, 154))
108806	27547487	Deregulation of NF-kappaB is linked to pathogenesis of cancer and many inflammatory and autoimmune diseases.	('autoimmune diseases', 'Disease', (88, 107))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (88, 107))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('linked', 'Reg', (29, 35))	('NF-kappaB', 'Protein', (16, 25))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('autoimmune diseases', 'Disease', 'MESH:D001327', (88, 107))	('cancer', 'Disease', (55, 61))
108814	27547487	Introduction of CpG methylation at the human p53 promoter region down regulated the transcriptional activity of p53, indicating the necessity of unmethylation at the human p53 promoter region for promotion of its transcription and tumor suppressor function.	('p53', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('p53', 'Gene', '7157', (45, 48))	('transcription', 'MPA', (213, 226))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('human', 'Species', '9606', (166, 171))	('down regulated', 'NegReg', (65, 79))	('p53', 'Gene', '7157', (172, 175))	('tumor', 'Disease', (231, 236))	('p53', 'Gene', '7157', (112, 115))	('methylation', 'Var', (20, 31))	('p53', 'Gene', (112, 115))	('transcriptional activity', 'MPA', (84, 108))	('p53', 'Gene', (172, 175))	('human', 'Species', '9606', (39, 44))	('promotion', 'PosReg', (196, 205))
108822	27547487	Our morpholical and biochemical staining assays demonstrated that EWS shRNA plasmid transfection and TFL treatment significantly increased the apoptotic features in SK-N-MC and RD-ES cell lines.	('SK-N-MC', 'CellLine', 'CVCL:0530', (165, 172))	('TFL', 'Chemical', 'MESH:C003377', (101, 104))	('increased', 'PosReg', (129, 138))	('RD-ES', 'Chemical', '-', (177, 182))	('transfection', 'Var', (84, 96))	('apoptotic features', 'CPA', (143, 161))
108826	27547487	Thus, translocation of tBid to mitochondria provides a link between death receptor-mediated (extrinsic) and mitochondria-mediated (intrinsic) pathways of apoptosis.	('translocation', 'Var', (6, 19))	('tBid', 'Gene', (23, 27))	('mitochondria-mediated', 'Pathway', (108, 129))	('tBid', 'Chemical', '-', (23, 27))	('link', 'Reg', (55, 59))
108833	27547487	We also revealed that tumor regression was due to molecular alterations to promote differentiation, inhibit angiogenesis and invasion, and induce apoptosis in Ewing's sarcoma xenografts in animal models.	('promote', 'PosReg', (75, 82))	('differentiation', 'CPA', (83, 98))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	("Ewing's sarcoma", 'Disease', (159, 174))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (159, 174))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('induce', 'Reg', (139, 145))	('tumor', 'Disease', (22, 27))	('alterations', 'Var', (60, 71))	('angiogenesis', 'CPA', (108, 120))	('apoptosis', 'CPA', (146, 155))	('invasion', 'CPA', (125, 133))	('inhibit', 'NegReg', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
108847	24073000	The cancer exhibited hypermethylation at the O6-methylguanine-DNA methyltransferase promoter region, was wild-type at the IDH 132 position, and the epidermal growth factor receptor was amplified.	('hypermethylation', 'Var', (21, 37))	('O6-methylguanine-DNA methyltransferase', 'Gene', (45, 83))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (45, 83))	('epidermal growth factor receptor', 'Gene', (148, 180))	('epidermal growth factor receptor', 'Gene', '1956', (148, 180))
108864	32450834	Genetically Ewing's sarcoma is determined by recurrent balanced translocations involving the EWSR1 gene on chromosome 22 and members of the E-twenty six (ETS) family of transcription factor genes.	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('EWSR1', 'Gene', (93, 98))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (12, 27))	('balanced translocations', 'Var', (55, 78))	("Ewing's sarcoma", 'Disease', (12, 27))	('EWSR1', 'Gene', '2130', (93, 98))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (12, 27))
108919	32450834	The main two reasons of unfortunate consequence in our case was acute pancreatitis caused by R1 resection at the uncinated process and a very aggressive underlying disease.	('pancreatitis', 'Phenotype', 'HP:0001733', (70, 82))	('R1 resection', 'Var', (93, 105))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (64, 82))	('pancreatitis', 'Disease', (70, 82))	('caused by', 'Reg', (83, 92))	('pancreatitis', 'Disease', 'MESH:D010195', (70, 82))
108941	28932893	The radiologist interpreting the MRI obtained 7.3 years after resection noted that a curvilinear, tail-like band of T2-hyperintense, enhancing tissue measuring a few millimeters thick was located along the muscular fascia in the subcutaneous tissues in and beyond the operative bed.	('muscular fascia', 'Disease', (206, 221))	('T2-hyperintense', 'Var', (116, 131))	('muscular fascia', 'Disease', 'MESH:D009135', (206, 221))	('enhancing', 'PosReg', (133, 142))
109022	30917542	The seven serum exosomal miRNAs (let-7a, miR-1229, miR-1246, miR-150, miR-21, miR-223, and miR-23a) were found to be significantly higher in patients with colorectal cancer than in healthy controls.	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (78, 81))	('miR-21', 'Gene', (70, 76))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (70, 73))	('miR-1246', 'Gene', (51, 59))	('patients', 'Species', '9606', (141, 149))	('miR', 'Gene', (91, 94))	('miR-1229', 'Gene', (41, 49))	('miR-150', 'Gene', (61, 68))	('miR', 'Gene', (61, 64))	('miR', 'Gene', '220972', (41, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('miR', 'Gene', '220972', (25, 28))	('miR-1229', 'Gene', '100302156', (41, 49))	('miR', 'Gene', (51, 54))	('miR-223', 'Gene', (78, 85))	('higher', 'PosReg', (131, 137))	('let-7a', 'Var', (33, 39))	('miR', 'Gene', (41, 44))	('miR', 'Gene', (25, 28))	('miR-1246', 'Gene', '100302142', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('miR-21', 'Gene', '406991', (70, 76))	('miR-23a', 'Gene', '407010', (91, 98))	('miR-23a', 'Gene', (91, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('miR', 'Gene', '220972', (78, 81))	('miR-150', 'Gene', '406942', (61, 68))	('miR-223', 'Gene', '407008', (78, 85))	('miR', 'Gene', '220972', (70, 73))	('colorectal cancer', 'Disease', (155, 172))	('miR', 'Gene', '220972', (91, 94))
109034	30917542	In particular, the amplification of the 6p12-21 and 17p11 regions is detected most frequently, representing approximately 30-60% of the OS samples.	('amplification', 'Var', (19, 32))	('p11', 'Gene', (54, 57))	('OS', 'Phenotype', 'HP:0002669', (136, 138))	('p11', 'Gene', '6281', (54, 57))
109068	30917542	Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by a germline mutation of the TP53 gene.	('TP53', 'Gene', '7157', (100, 104))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('cancer', 'Disease', (32, 38))	('TP53', 'Gene', (100, 104))	('germline mutation', 'Var', (75, 92))	('LFS', 'Disease', 'MESH:D016864', (22, 25))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('LFS', 'Disease', (22, 25))	('caused by', 'Reg', (63, 72))
109163	30917542	Suppressing EYA3 improves drug susceptibility.	('Suppressing', 'Var', (0, 11))	('EYA3', 'Gene', '2140', (12, 16))	('improves', 'PosReg', (17, 25))	('drug susceptibility', 'MPA', (26, 45))	('EYA3', 'Gene', (12, 16))
109175	30917542	ARMS develops in adolescents and young adults and has specific chromosomal translocations, namely, t(2;13)(q35;q14) and t(1;13)(p36;q14).	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (99, 115))	('t(1;13)(p36;q14', 'Var', (120, 135))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (120, 136))	('t(2;13)(q35;q14', 'Var', (99, 114))
109191	30917542	MLPS has a specific chromosomal translocation t(12; 16)(q13; p11), which results in FUS-CHOP gene fusion, presenting in >95% of cases.	('CHOP', 'Gene', '1649', (88, 92))	('results in', 'Reg', (73, 83))	('p11', 'Gene', (61, 64))	('MLPS', 'Disease', 'None', (0, 4))	('LPS', 'Phenotype', 'HP:0012034', (1, 4))	('CHOP', 'Gene', (88, 92))	('t(12; 16)(q13', 'Var', (46, 59))	('p11', 'Gene', '6281', (61, 64))	('MLPS', 'Disease', (0, 4))	('MLPS', 'Phenotype', 'HP:0012268', (0, 4))
109200	30917542	miR-155 knockdown inhibited DDLPS growth in vitro and in vivo.	('miR-155', 'Gene', '406947', (0, 7))	('knockdown', 'Var', (8, 17))	('miR-155', 'Gene', (0, 7))	('LPS', 'Disease', (30, 33))	('LPS', 'Phenotype', 'HP:0012034', (30, 33))	('inhibited', 'NegReg', (18, 27))	('LPS', 'Disease', 'MESH:C536528', (30, 33))
109217	30917542	Chromosomal aberrations play a key role in OS tumorigenesis and lead to subsequent amplification and deficiency of specific gene regions.	('Chromosomal aberrations', 'Var', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('deficiency', 'NegReg', (101, 111))	('OS', 'Phenotype', 'HP:0002669', (43, 45))	('amplification', 'MPA', (83, 96))	('tumor', 'Disease', (46, 51))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
109225	30917542	For instance, there are no miRNA studies of IDH1/2 mutation, which plays a key role in the diagnosis and pathogenesis of CS.	('miR', 'Gene', '220972', (27, 30))	('IDH1/2', 'Gene', (44, 50))	('miR', 'Gene', (27, 30))	('mutation', 'Var', (51, 59))	('CS', 'Phenotype', 'HP:0006765', (121, 123))	('IDH1/2', 'Gene', '3417;3418', (44, 50))
109489	28900468	Positivity for Epstein-Barr virus (EBV) in malignant cells is more common in childhood Hodgkin disease than in adults, in the MC subtype and in cases from developing countries.	('EBV', 'Species', '10376', (35, 38))	('Hodgkin disease', 'Phenotype', 'HP:0012189', (87, 102))	('childhood Hodgkin disease', 'Disease', (77, 102))	('common', 'Reg', (67, 73))	('childhood Hodgkin disease', 'Disease', 'MESH:D006689', (77, 102))	('Positivity', 'Var', (0, 10))
109523	28900468	MYC-driven tumours usually acquire additional genetic mutations or epigenetic modifications that promote cell survival and shift the balance between proliferation and apoptosis towards proliferation.	('MYC', 'Gene', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('shift', 'Reg', (123, 128))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('cell survival', 'CPA', (105, 118))	('MYC', 'Gene', '4609', (0, 3))	('epigenetic modifications', 'Var', (67, 91))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))	('promote', 'PosReg', (97, 104))
109526	28900468	It was demonstrated that alternative mechanisms may be responsible of MYC over-expression in the absence of a detectable translocation; among these, microRNAs (miRNAs) deregulation, epigenetic mechanisms and NMYC over-expression.	('NMYC', 'Gene', (208, 212))	('deregulation', 'Var', (168, 180))	('MYC', 'Gene', '4609', (209, 212))	('MYC', 'Gene', (70, 73))	('NMYC', 'Gene', '4613', (208, 212))	('over-expression', 'PosReg', (74, 89))	('microRNAs', 'MPA', (149, 158))	('MYC', 'Gene', (209, 212))	('MYC', 'Gene', '4609', (70, 73))	('over-expression', 'PosReg', (213, 228))	('epigenetic mechanisms', 'Var', (182, 203))
109532	28900468	Interestingly, EBV-positive BL are characterised by altered lipid metabolism.	('lipid', 'Chemical', 'MESH:D008055', (60, 65))	('EBV-positive', 'Var', (15, 27))	('lipid metabolism', 'MPA', (60, 76))	('EBV', 'Species', '10376', (15, 18))	('altered', 'Reg', (52, 59))
109534	28900468	These findings was supported by the data on the mutational landscape of eBL, characterized by a lower number of point mutations in genes previously found altered in sBL, including MYC, ID3, TCF3, DDX3X, CCND3, and TP53.	('MYC', 'Gene', '4609', (180, 183))	('DDX3X', 'Gene', '1654', (196, 201))	('point mutations', 'Var', (112, 127))	('ID3', 'Gene', '3399', (185, 188))	('TCF3', 'Gene', '6929', (190, 194))	('sBL', 'Chemical', '-', (165, 168))	('MYC', 'Gene', (180, 183))	('CCND3', 'Gene', '896', (203, 208))	('TP53', 'Gene', '7157', (214, 218))	('TCF3', 'Gene', (190, 194))	('TP53', 'Gene', (214, 218))	('CCND3', 'Gene', (203, 208))	('ID3', 'Gene', (185, 188))	('DDX3X', 'Gene', (196, 201))
109535	28900468	A near mutual exclusivity between TCF3/ID3 mutations and the presence of EBV was detected, indicating that TCF3 pathway is more significantly activated in EBV-negative cases.	('EBV', 'Species', '10376', (155, 158))	('ID3', 'Gene', '3399', (39, 42))	('EBV', 'Species', '10376', (73, 76))	('TCF3', 'Gene', (34, 38))	('TCF3', 'Gene', '6929', (107, 111))	('TCF3', 'Gene', (107, 111))	('mutations', 'Var', (43, 52))	('ID3', 'Gene', (39, 42))	('activated', 'PosReg', (142, 151))	('TCF3', 'Gene', '6929', (34, 38))
109570	28900468	Mutations in both alleles of the RB1 gene in a retinal progenitor cell through diverse mechanisms including genetic and epigenetic modifications, is the crucial event in initiation of tumorigenesis.	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', (33, 36))	('RB1', 'Gene', '5925', (33, 36))
109571	28900468	In most patients with sporadic unilateral retinoblastoma, both RB1 gene mutations occur in somatic cells and are not passed over to offspring (nonhereditary retinoblastoma).	('sporadic unilateral retinoblastoma', 'Disease', 'MESH:D012175', (22, 56))	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (8, 16))	('RB1', 'Gene', '5925', (63, 66))	('retinoblastoma', 'Phenotype', 'HP:0009919', (42, 56))	('nonhereditary retinoblastoma', 'Disease', (143, 171))	('retinoblastoma', 'Phenotype', 'HP:0009919', (157, 171))	('nonhereditary retinoblastoma', 'Disease', 'MESH:D012175', (143, 171))	('sporadic unilateral retinoblastoma', 'Disease', (22, 56))	('RB1', 'Gene', (63, 66))	('occur', 'Reg', (82, 87))
109572	28900468	Almost all patients with sporadic bilateral and virtually all patients with familial retinoblastoma are heterozygous for RB1 gene mutations that cause predisposition to the disease (hereditary retinoblastoma).	('retinoblastoma', 'Phenotype', 'HP:0009919', (193, 207))	('familial retinoblastoma', 'Disease', (76, 99))	('hereditary retinoblastoma', 'Disease', (182, 207))	('retinoblastoma', 'Phenotype', 'HP:0009919', (85, 99))	('RB1', 'Gene', (121, 124))	('familial retinoblastoma', 'Disease', 'MESH:D012175', (76, 99))	('RB1', 'Gene', '5925', (121, 124))	('mutations', 'Var', (130, 139))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (182, 207))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (62, 70))
109594	28900468	Increases in incidence have been reported from the USA, which is thought to be due to an increase in premature births; low birth weight has been shown increase the risk of hepatoblastoma.	('hepatoblastoma', 'Disease', (172, 186))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (172, 186))	('premature births', 'Phenotype', 'HP:0001622', (101, 117))	('low birth weight', 'Var', (119, 135))	('low birth weight', 'Phenotype', 'HP:0001518', (119, 135))	('increase', 'PosReg', (151, 159))	('hepatoblastoma', 'Disease', 'MESH:D018197', (172, 186))
109734	26412983	For detection of protein expression, tissue arrays were labeled with anti-Myc (Cat# ab32072; Abcam), anti-Oct4 (Cat# ab18976; Abcam), anti-Sox2 (Cat# ab97959; Abcam), anti-Klf4 (Cat# ab118961; Abcam), and anti-Nanog (Cat# ab80892; Abcam) antibodies.	('Myc', 'Gene', (74, 77))	('Klf4', 'Gene', (172, 176))	('Cat# ab18976;', 'Var', (112, 125))	('Cat# ab32072;', 'Var', (79, 92))	('Cat# ab97959;', 'Var', (145, 158))	('Klf4', 'Gene', '9314', (172, 176))	('Cat# ab118961;', 'Var', (178, 192))	('Myc', 'Gene', '4609', (74, 77))
109743	26412983	With the exception of Myc, each of these proteins was detectable at variable levels across non-diseased vascular tissues, ranging from 50 % of normal tissues displaying Nanog and Klf4 immunoreactivity to 90 % of normal tissues displaying Oct4 immunoreactivity (Table 2).	('Klf4', 'Gene', (179, 183))	('Nanog', 'Var', (169, 174))	('Klf4', 'Gene', '9314', (179, 183))	('Myc', 'Gene', '4609', (22, 25))	('Myc', 'Gene', (22, 25))
109768	26412983	For instance, osteosarcomas and Ewing's sarcomas express Oct4 and Nanog and rhabdomyosarcomas express Oct4, Nanog, and Sox2.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('Oct4', 'Var', (102, 106))	('Oct4', 'Protein', (57, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	("Ewing's sarcomas", 'Disease', (32, 48))	('osteosarcomas', 'Disease', (14, 27))	('osteosarcomas', 'Phenotype', 'HP:0002669', (14, 27))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (76, 93))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (32, 48))	('osteosarcomas', 'Disease', 'MESH:D012516', (14, 27))	('rhabdomyosarcomas', 'Disease', (76, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Nanog', 'Var', (66, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (32, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('Nanog', 'Var', (108, 113))
109791	20664817	Oxman and others showed that the cellular transformation and neoantigen (SV40 T antigen) formation induced by oncogenic viruses like SV40 could be blocked by pre-treatment of cell cultures with IFN.	('IFN', 'Gene', '3439', (194, 197))	('IFN', 'Gene', (194, 197))	('SV40', 'Var', (133, 137))	('cellular transformation', 'CPA', (33, 56))
109825	20664817	Stress-induced responses result in p38 MAPK-induced phosphorylation of Stat1 at S727, but this has not been shown to be the case for IFN-gamma.	('p38', 'Gene', '1398', (35, 38))	('Stat1', 'Gene', '6772', (71, 76))	('S727', 'Var', (80, 84))	('Stat1', 'Gene', (71, 76))	('IFN-gamma', 'Gene', '3458', (133, 142))	('IFN-gamma', 'Gene', (133, 142))	('p38', 'Gene', (35, 38))
109868	20664817	The presence of IFN may also result in the activation of moncytes and macrophages.	('presence', 'Var', (4, 12))	('activation', 'PosReg', (43, 53))	('IFN', 'Gene', '3439', (16, 19))	('IFN', 'Gene', (16, 19))
109906	20664817	Discontinuation of Gleevec has been shown to result in very high relapse rates which might be the result of a resistance to the drug by CML stem cells.	('CML', 'Disease', 'MESH:D015464', (136, 139))	('CML', 'Phenotype', 'HP:0005506', (136, 139))	('Gleevec', 'Gene', (19, 26))	('CML', 'Disease', (136, 139))	('relapse', 'CPA', (65, 72))	('Discontinuation', 'Var', (0, 15))
109914	20664817	Progression-free survival among the patients receiving combination therapy was significantly greater (2.9 vs. 1.5 years) compared to the patients who received IFN monotherapy.	('patients', 'Species', '9606', (36, 44))	('greater', 'PosReg', (93, 100))	('combination', 'Var', (55, 66))	('patients', 'Species', '9606', (137, 145))	('IFN', 'Gene', '3439', (159, 162))	('Progression-free survival', 'CPA', (0, 25))	('IFN', 'Gene', (159, 162))
109920	20664817	Both relapse-free and overall survival rates were increased in the patients receiving Intron-A .	('patients', 'Species', '9606', (67, 75))	('increased', 'PosReg', (50, 59))	('relapse-free', 'CPA', (5, 17))	('overall survival rates', 'CPA', (22, 44))	('Intron-A', 'Var', (86, 94))
109944	20664817	No change was seen in either distribution or elimination over a dosing period of 28 days regardless of whether the IFN was administered once daily (1-54 MIU), twice daily (0.5-36 MIU) or three times weekly (1-136 MIU).	('IFN', 'Gene', (115, 118))	('MIU', 'Chemical', '-', (153, 156))	('MIU', 'Chemical', '-', (213, 216))	('MIU', 'Chemical', '-', (179, 182))	('IFN', 'Gene', '3439', (115, 118))	('1-54 MIU', 'Var', (148, 156))	('1-136 MIU', 'Var', (207, 216))
110015	31488818	EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells.	('oncogene-induced senescence', 'MPA', (28, 55))	('mice', 'Species', '10090', (91, 95))	('expression', 'Var', (9, 19))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('sarcoma', 'Disease', (115, 122))	('induces', 'Reg', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('EWS/ATF1', 'Gene', (0, 8))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('sarcoma-iPSC', 'Disease', (78, 90))	('sarcoma', 'Disease', (78, 85))	('prevents', 'NegReg', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcoma-iPSC', 'Disease', 'MESH:D012509', (78, 90))
110018	31488818	The EWS-ATF1 fusion gene causes clear cell sarcoma (CCS).	('EWS-ATF1', 'Gene', '14030;11908', (4, 12))	('fusion', 'Var', (13, 19))	('clear cell sarcoma', 'Disease', (32, 50))	('causes', 'Reg', (25, 31))	('EWS-ATF1', 'Gene', (4, 12))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (32, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
110021	31488818	Here, specific genes are mutated in particular types of cancer, and patients harboring germline mutations at tumor suppressor genes, such as APC and BRCA1/BRCA2, exclusively develop cancers in specific organs.	('develop', 'Reg', (174, 181))	('BRCA2', 'Gene', '675', (155, 160))	('APC', 'Disease', 'MESH:D011125', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('APC', 'Disease', (141, 144))	('cancer', 'Disease', (56, 62))	('mutations', 'Var', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancer', 'Disease', (182, 188))	('cancers', 'Disease', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('BRCA2', 'Gene', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('BRCA1', 'Gene', '672', (149, 154))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('BRCA1', 'Gene', (149, 154))	('tumor', 'Disease', (109, 114))
110024	31488818	However, it is unclear how the cellular context-dependent epigenetic regulations affect cancer development and progression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('affect', 'Reg', (81, 87))	('epigenetic regulations', 'Var', (58, 80))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('progression', 'CPA', (111, 122))
110027	31488818	Despite their shared properties, CCS is distinguished from malignant melanoma by the presence of a specific fusion oncogene, EWS/ATF1, which results from a reciprocal translocation, t(12;22)(q13;q12).	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (182, 199))	('malignant melanoma', 'Phenotype', 'HP:0002861', (59, 77))	('CCS', 'Disease', (33, 36))	('malignant melanoma', 'Disease', 'MESH:D008545', (59, 77))	('t(12;22)(q13;q12', 'Var', (182, 198))	('malignant melanoma', 'Disease', (59, 77))	('EWS/ATF1', 'Gene', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('results from', 'Reg', (141, 153))
110029	31488818	demonstrated that EWS/ATF1 can transform mesenchymal progenitor cells, while our previous study suggested that the sarcomas arose from neural crest-derived cells.	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('sarcomas', 'Disease', (115, 123))	('EWS/ATF1', 'Var', (18, 26))	('transform', 'Reg', (31, 40))
110033	31488818	Utilizing the one-step and cell-type-specific sarcoma model, we identify Tppp3-expressing peripheral nerve cell as a cell type that gives rise to CCSs and demonstrate that cellular context-dependent epigenetic regulations, in conjunction with genetic abnormalities, play a fundamental role in the maintenance of the malignant phenotype and thus can be a therapeutic target in sarcoma cells.	('genetic abnormalities', 'Disease', 'MESH:D030342', (243, 264))	('sarcoma', 'Disease', 'MESH:D012509', (376, 383))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('sarcoma', 'Disease', (376, 383))	('genetic abnormalities', 'Disease', (243, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (376, 383))	('CCSs', 'Disease', (146, 150))	('sarcoma', 'Disease', (46, 53))	('epigenetic regulations', 'Var', (199, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('gives rise', 'Reg', (132, 142))
110038	31488818	The iPSC-like cell lines often harbored the chromosomal abnormalities detected in G1297 (Fig.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (44, 69))	('harbored', 'Reg', (31, 39))	('G1297', 'CellLine', 'CVCL:9F04', (82, 87))	('chromosomal abnormalities', 'Disease', (44, 69))	('G1297', 'Var', (82, 87))
110039	31488818	Additionally, exome analysis revealed that candidate mutation sites in G1297 are often mutated in iPSC-like cell line (Sarcoma-iPSC-G3) (Fig.	('Sarcoma', 'Disease', (119, 126))	('Sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('G1297', 'CellLine', 'CVCL:9F04', (71, 76))	('Sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('G1297', 'Var', (71, 76))
110058	31488818	It has been shown that oncogene expression in somatic cells results in oncogene-induced senescence (OIS), which prevents cancer development.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('oncogene-induced senescence', 'Disease', (71, 98))	('prevents', 'NegReg', (112, 120))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('oncogene expression', 'Var', (23, 42))	('cancer', 'Disease', (121, 127))
110062	31488818	We found that the sarcoma-iPSC MEFs harbor genetic aberrations, including a part of chromosomal abnormalities and mutations at Plekhg5 and Alk, which are identical to those in the secondary sarcomas (Supplementary Fig.	('Plekhg5', 'Gene', (127, 134))	('Alk', 'Gene', (139, 142))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (84, 109))	('mutations', 'Var', (114, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcomas', 'Disease', 'MESH:D012509', (190, 198))	('Plekhg5', 'Gene', '269608', (127, 134))	('sarcoma-iPSC MEFs harbor genetic aberrations', 'Disease', 'MESH:D030342', (18, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (190, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('Alk', 'Gene', '11682', (139, 142))	('chromosomal abnormalities', 'Disease', (84, 109))	('sarcomas', 'Disease', (190, 198))	('sarcoma-iPSC MEFs harbor genetic aberrations', 'Disease', (18, 62))
110063	31488818	Notably, in sharp contrast to the active proliferation of EWS/ATF1-expressing sarcoma cells, EWS/ATF1-expressing sarcoma-iPSC MEFs ceased growth and changed morphology into a large and flat shape (Fig.	('sarcoma-iPSC MEFs', 'Disease', (113, 130))	('changed', 'Reg', (149, 156))	('growth', 'CPA', (138, 144))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma-iPSC MEFs', 'Disease', 'MESH:D012509', (113, 130))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('sarcoma', 'Disease', (113, 120))	('sarcoma', 'Disease', (78, 85))	('EWS/ATF1-expressing', 'Var', (93, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('morphology', 'MPA', (157, 167))	('ceased', 'NegReg', (131, 137))
110064	31488818	The senescence-associated beta-galactosidase (SA beta-gal)-positive cell ratio was significantly higher in EWS/ATF1-expressing MEFs than in non-expressing MEFs (Fig.	('beta-gal', 'Chemical', '-', (26, 34))	('higher', 'PosReg', (97, 103))	('SA beta', 'Gene', (46, 53))	('beta-gal', 'Chemical', '-', (49, 57))	('MEFs', 'CellLine', 'CVCL:9115', (127, 131))	('beta-galactosidase', 'Gene', (26, 44))	('senescence-associated', 'CPA', (4, 25))	('beta-galactosidase', 'Gene', '12091', (26, 44))	('EWS/ATF1-expressing', 'Var', (107, 126))	('MEFs', 'CellLine', 'CVCL:9115', (155, 159))	('SA beta', 'Gene', '24056', (46, 53))
110067	31488818	Moreover, knockdown of Trp53 rescued the growth arrest phenotype (Fig.	('Trp53', 'Gene', '22059', (23, 28))	('growth arrest', 'Disease', (41, 54))	('growth arrest', 'Disease', 'MESH:D006323', (41, 54))	('Trp53', 'Gene', (23, 28))	('growth arrest', 'Phenotype', 'HP:0001510', (41, 54))	('knockdown', 'Var', (10, 19))	('rescued', 'PosReg', (29, 36))
110068	31488818	4e), which supports our conclusion that EWS/ATF1 induces OIS in sarcoma-iPSC MEFs.	('sarcoma-iPSC MEFs', 'Disease', (64, 81))	('EWS/ATF1', 'Var', (40, 48))	('sarcoma-iPSC MEFs', 'Disease', 'MESH:D012509', (64, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('OIS', 'Disease', (57, 60))
110069	31488818	Conversely, SA beta-gal-positive cells were increased by the withdrawal of EWS/ATF1 in sarcoma cells (Fig.	('withdrawal', 'Var', (61, 71))	('EWS/ATF1', 'Gene', (75, 83))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('beta-gal', 'Chemical', '-', (15, 23))	('increased', 'PosReg', (44, 53))	('SA beta', 'Gene', '24056', (12, 19))	('SA beta', 'Gene', (12, 19))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
110081	31488818	We also found that EWS/ATF1-induced sarcoma cell lines express several Schwann cell marker genes such as P75NTR, S100b, Mbp, Plp1, and Pmp22 in vitro (Fig.	('S100b', 'Gene', (113, 118))	('Plp1', 'Gene', (125, 129))	('S100b', 'Gene', '20203', (113, 118))	('Pmp22', 'Gene', '18858', (135, 140))	('Plp1', 'Gene', '18823', (125, 129))	('Mbp', 'Gene', '17196', (120, 123))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('P75NTR', 'Var', (105, 111))	('Schwann cell marker genes', 'Gene', (71, 96))	('sarcoma', 'Disease', (36, 43))	('Pmp22', 'Gene', (135, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('Mbp', 'Gene', (120, 123))
110088	31488818	EWS/ATF1 knockdown led to a significant upregulation of melanocyte-related genes, such as TYR, MITF, and DCT.	('knockdown', 'Var', (9, 18))	('DCT', 'Disease', (105, 108))	('upregulation', 'PosReg', (40, 52))	('EWS/ATF1', 'Gene', (0, 8))	('MITF', 'Gene', (95, 99))	('TYR', 'Disease', (90, 93))	('melanocyte-related genes', 'Gene', (56, 80))	('TYR', 'Chemical', 'MESH:D014443', (90, 93))	('MITF', 'Gene', '17342', (95, 99))
110089	31488818	However, we also found that a majority of Schwann cell-related genes were similarly upregulated by EWS/ATF1 knockdown in human CCS cells, suggesting that CCSs harbor transcriptional signatures of both melanocytes and Schwann cells.	('knockdown', 'Var', (108, 117))	('upregulated', 'PosReg', (84, 95))	('Schwann cell-related genes', 'Gene', (42, 68))	('CCSs', 'Disease', (154, 158))	('human', 'Species', '9606', (121, 126))	('EWS/ATF1', 'Gene', (99, 107))
110107	31488818	Among four candidate genes, we focused on Tppp3 since remarkable increment of TPPP3 expression was observed by knockdown of EWS/ATF1 in human CCS cell line (MP-CCS-SY) (Fig.	('human', 'Species', '9606', (136, 141))	('knockdown', 'Var', (111, 120))	('MP-CCS-SY', 'CellLine', 'CVCL:0J33', (157, 166))	('TPPP3', 'Gene', (78, 83))	('increment', 'PosReg', (65, 74))	('expression', 'MPA', (84, 94))	('EWS/ATF1', 'Gene', (124, 132))	('TPPP3', 'Gene', '51673', (78, 83))
110144	31488818	Although there exists common EWS/ATF1 binding sites in the two cell types (n = 5109), we observed unique binding sites in G1297 and sarcoma-iPSC MEFs (n = 2981 and 15601, respectively) (Fig.	('sarcoma-iPSC MEFs', 'Disease', 'MESH:D012509', (132, 149))	('G1297', 'Var', (122, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('G1297', 'CellLine', 'CVCL:9F04', (122, 127))	('sarcoma-iPSC MEFs', 'Disease', (132, 149))	('binding', 'Interaction', (105, 112))
110145	31488818	Notably, the increased binding of EWS/ATF1 was associated with increased expression in G1297 (Supplementary Fig.	('increased', 'PosReg', (63, 72))	('G1297', 'Var', (87, 92))	('expression', 'MPA', (73, 83))	('EWS/ATF1', 'Protein', (34, 42))	('binding', 'Interaction', (23, 30))	('increased', 'PosReg', (13, 22))	('G1297', 'CellLine', 'CVCL:9F04', (87, 92))
110147	31488818	Moreover, EWS/ATF1 was enriched at a super-enhancer in G1297 (Supplementary Fig.	('G1297', 'CellLine', 'CVCL:9F04', (55, 60))	('G1297', 'Var', (55, 60))	('super-enhancer', 'PosReg', (37, 51))
110148	31488818	We focused on H3K27ac, an active epigenetic mark, in sarcoma cells (G1297) and MEFs before EWS/ATF1 induction.	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('H3K27ac', 'Var', (14, 21))	('sarcoma', 'Disease', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('MEFs', 'CellLine', 'CVCL:9115', (79, 83))	('G1297', 'CellLine', 'CVCL:9F04', (68, 73))
110149	31488818	ChIP-Seq data for H3K27ac in both Dox OFF sarcoma cells (sarcoma cells without EWS/ATF1 expression) and wild-type MEFs revealed that EWS/ATF1 was recruited to H3K27-pre-marked regions in both sarcoma cells and sarcoma-iPSC MEFs (Fig.	('Dox', 'Chemical', 'MESH:D004318', (34, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('MEFs', 'CellLine', 'CVCL:9115', (223, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('recruited', 'PosReg', (146, 155))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('sarcoma-iPSC MEFs', 'Disease', (210, 227))	('sarcoma', 'Disease', (210, 217))	('sarcoma-iPSC MEFs', 'Disease', 'MESH:D012509', (210, 227))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('sarcoma', 'Disease', (192, 199))	('sarcoma', 'Disease', (42, 49))	('MEFs', 'CellLine', 'CVCL:9115', (114, 118))	('EWS/ATF1', 'Var', (133, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('sarcoma', 'Disease', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
110150	31488818	Furthermore, cell-type-specific binding sites were differentially pre-marked with H3K27ac in the two cell types: in Dox OFF sarcoma cells, sarcoma-specific binding sites were preferentially pre-marked with H3K27ac and less marked at MEF-specific binding sites (Fig.	('Dox', 'Chemical', 'MESH:D004318', (116, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('sarcoma', 'Disease', (124, 131))	('H3K27ac', 'Var', (206, 213))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('MEF', 'Gene', (233, 236))	('MEF', 'Gene', '56501', (233, 236))	('sarcoma', 'Disease', (139, 146))	('pre-marked', 'PosReg', (190, 200))	('preferentially', 'PosReg', (175, 189))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('H3K27ac', 'Var', (82, 89))
110153	31488818	HOMER (Hypergeometric Optimization of Motif EnRichment)-known motif analysis revealed a list of TF-binding motifs at sarcoma-specific and MEF-specific binding sites (Table 2).	('motifs', 'Var', (107, 113))	('sarcoma', 'Disease', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('MEF', 'Gene', (138, 141))	('MEF', 'Gene', '56501', (138, 141))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))
110160	31488818	Importantly, knockdown of Ebf1 did not affect sarcoma cell growth (Supplementary Fig.	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('Ebf1', 'Gene', (26, 30))	('Ebf1', 'Gene', '13591', (26, 30))	('sarcoma', 'Disease', (46, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('knockdown', 'Var', (13, 22))
110162	31488818	Consistent with this, human CCS cell line MP-CCS-SY exhibited growth inhibition upon the transduction of KRAB genes fused with SOX10 and BRN2, both of which are important TFs for neural crest cell differentiation (Supplementary Fig.	('human', 'Species', '9606', (22, 27))	('BRN2', 'Gene', (137, 141))	('MP-CCS-SY', 'Var', (42, 51))	('MP-CCS-SY', 'CellLine', 'CVCL:0J33', (42, 51))	('fused', 'Var', (116, 121))	('SOX10', 'Gene', (127, 132))	('growth inhibition', 'CPA', (62, 79))	('KRAB genes', 'Gene', (105, 115))
110166	31488818	Notably, both mouse and human CCS cells showed reduced cell growth by JQ1 treatment in vitro (Fig.	('JQ1', 'Var', (70, 73))	('human', 'Species', '9606', (24, 29))	('mouse', 'Species', '10090', (14, 19))	('reduced', 'NegReg', (47, 54))	('cell growth', 'CPA', (55, 66))
110170	31488818	The fact that invasive growth starts as early as 5 days in a cellular context-dependent manner indicates that somatic cells with particular epigenetic regulation immediately turn into cancer cells in this model.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('invasive growth', 'CPA', (14, 29))	('epigenetic regulation', 'Var', (140, 161))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
110172	31488818	Indeed, taking advantage of the model, we here propose that Tppp3-expressing neural crest-derived cells are a cell of origin for mouse CCS cells and epigenetic regulation at the cell of origin affects the binding patterns of a key driver oncogenic protein, which leads to the establishment of a sarcoma-specific super-enhancer.	('epigenetic regulation', 'Var', (149, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (295, 302))	('sarcoma', 'Disease', 'MESH:D012509', (295, 302))	('binding', 'Interaction', (205, 212))	('mouse', 'Species', '10090', (129, 134))	('sarcoma', 'Disease', (295, 302))	('leads to', 'Reg', (263, 271))	('affects', 'Reg', (193, 200))
110173	31488818	Our results suggest that the epigenetic regulation of cell of origin may primarily play a critical role in the development and maintenance of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('epigenetic regulation', 'Var', (29, 50))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('play', 'Reg', (83, 87))	('cancer', 'Disease', (142, 148))
110177	31488818	Consistent with this, we demonstrated that epigenetic silencing at cell-type-specific enhancers promotes premature senescence and induces a growth arrest phenotype in sarcoma cells.	('premature senescence', 'CPA', (105, 125))	('growth arrest', 'Phenotype', 'HP:0001510', (140, 153))	('promotes', 'PosReg', (96, 104))	('growth arrest', 'Disease', 'MESH:D006323', (140, 153))	('growth arrest', 'Disease', (140, 153))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('sarcoma', 'Disease', (167, 174))	('induces', 'Reg', (130, 137))	('epigenetic silencing', 'Var', (43, 63))
110178	31488818	We propose that epigenetic regulations of the cell of origin could be targets for modulating cancer cell fate.	('epigenetic regulations', 'Var', (16, 38))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
110184	31488818	However, it should be noted that CCSs frequently express well-characterized markers of both Schwann cells and melanocytes, including SOX10 and TYR.	('TYR', 'Disease', (143, 146))	('SOX10', 'Var', (133, 138))	('TYR', 'Chemical', 'MESH:D014443', (143, 146))
110205	31488818	The established iPSCs were maintained with ESC media supplemented with LIF, 1 muM PD0325901 (Stemgent), and 3 muM CHIR99021 (Stemgent).	('PD0325901', 'Var', (82, 91))	('PSCs', 'Gene', (17, 21))	('LIF', 'Gene', '16878', (71, 74))	('PD0325901', 'Chemical', 'MESH:C506614', (82, 91))	('PSCs', 'Gene', '107810', (17, 21))	('LIF', 'Gene', (71, 74))
110229	31488818	A list of the common mutations in G1297 and sarcoma-iPSC#3 is shown in Supplementary Table 1.	('G1297', 'Var', (34, 39))	('sarcoma-iPSC', 'Disease', 'MESH:D012509', (44, 56))	('sarcoma-iPSC', 'Disease', (44, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('G1297', 'CellLine', 'CVCL:9F04', (34, 39))
110272	29915281	Sarcoma cell lines grown as monolayers and spheroids were then sorted by FACS analysis for CD133 expression, and the proportion of CD133(+) cells was 7-14 times higher in spheroid cells as compared to monolayer cells (Fig.	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('Sarcoma', 'Disease', (0, 7))	('spheroids', 'Chemical', '-', (43, 52))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('higher', 'PosReg', (161, 167))	('CD133', 'Gene', (91, 96))	('CD133', 'Var', (131, 136))
110274	29915281	Immunofluorescence analysis for self-renewal proteins confirmed increased expression of Nanog, Oct4, and Sox2 in CD133(+) cells compared to CD133(-) cells (Supplemental Fig.	('expression', 'MPA', (74, 84))	('Sox2', 'Gene', '6657', (105, 109))	('Nanog', 'Gene', '79923', (88, 93))	('Nanog', 'Gene', (88, 93))	('Sox2', 'Gene', (105, 109))	('CD133(+', 'Var', (113, 120))	('Oct4', 'Gene', '5460', (95, 99))	('increased', 'PosReg', (64, 73))	('Oct4', 'Gene', (95, 99))
110305	29915281	Single isoform knockdown of PDGFR-alpha or -beta or imatinib had marginal to no additive effect over chemotherapy alone in monolayer cells (Fig.	('PDGFR-alpha', 'Gene', (28, 39))	('imatinib', 'Chemical', 'MESH:D000068877', (52, 60))	('knockdown', 'Var', (15, 24))
110310	29915281	HT1080 cells stably transduced with PDGFR-alpha shRNA and PDGFR-beta shRNA or scrambled control shRNA were injected.	('HT1080', 'Gene', (0, 6))	('PDGFR-beta shRNA', 'Var', (58, 74))	('PDGFR-alpha shRNA', 'Var', (36, 53))	('HT1080', 'Gene', '8872', (0, 6))
110313	29915281	Tumors in mice treated with doxorubicin grew to an average of 739 mm3, tumors in mice treated with imatinib grew to an average of 641 mm3, and tumors with knockdown of PDGFR-alpha and PDGFR-beta grew on average to 675 mm3.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('PDGFR-alpha', 'Gene', (168, 179))	('tumors', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('knockdown', 'Var', (155, 164))	('tumors', 'Disease', (143, 149))	('Tumors', 'Disease', (0, 6))	('PDGFR-beta', 'Gene', (184, 194))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('mice', 'Species', '10090', (10, 14))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('imatinib', 'Chemical', 'MESH:D000068877', (99, 107))	('mice', 'Species', '10090', (81, 85))	('doxorubicin', 'Chemical', 'MESH:D004317', (28, 39))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
110314	29915281	The combination of doxorubicin with either imatinib or PDGFR-alpha/beta knockdown had a more-than-additive effect.	('doxorubicin', 'Chemical', 'MESH:D004317', (19, 30))	('PDGFR-alpha/beta', 'Gene', (55, 71))	('imatinib', 'Chemical', 'MESH:D000068877', (43, 51))	('combination', 'Interaction', (4, 15))	('knockdown', 'Var', (72, 81))
110319	29915281	We have previously demonstrated that CD133(+) CSCs in HT1080 fibrosarcoma xenografts are found preferentially in hypoxic regions of tumors but also reside in non-hypoxic regions.	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('fibrosarcoma', 'Disease', (61, 73))	('hypoxic regions of tumors', 'Disease', (113, 138))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (61, 73))	('HT1080', 'Gene', (54, 60))	('CD133(+', 'Var', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('HT1080', 'Gene', '8872', (54, 60))	('fibrosarcoma', 'Disease', 'MESH:D005354', (61, 73))	('hypoxic regions of tumors', 'Disease', 'MESH:D009369', (113, 138))
110321	29915281	HIF-1alpha levels are significantly higher in CD133(+) cells compared to CD133(-) cells (Suppl.	('CD133(+', 'Var', (46, 53))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('higher', 'PosReg', (36, 42))	('HIF-1alpha', 'Gene', (0, 10))
110328	29915281	Sarcoma cells also demonstrated increased migration, invasion, and soft agar colony formation under hypoxia, and these phenotypes were similarly reduced with knockdown of PDGFR-alpha and -beta shRNA (Suppl.	('migration', 'CPA', (42, 51))	('reduced', 'NegReg', (145, 152))	('PDGFR-alpha and -beta', 'Gene', '5156;5159', (171, 192))	('invasion', 'CPA', (53, 61))	('Sarcoma', 'Disease', (0, 7))	('soft agar colony formation', 'CPA', (67, 93))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('agar', 'Chemical', 'MESH:D000362', (72, 76))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('knockdown', 'Var', (158, 167))	('increased', 'PosReg', (32, 41))	('hypoxia', 'Disease', (100, 107))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
110335	29915281	PDGFR-alpha and PDGFR-beta knockdown by shRNA or pharmacologic inhibition with imatinib diminished the expression of the self-renewal transcription factor Nanog and blocked spheroid colony formation in vitro.	('knockdown', 'Var', (27, 36))	('expression', 'MPA', (103, 113))	('Nanog', 'Gene', (155, 160))	('PDGFR-alpha', 'Gene', (0, 11))	('spheroid colony formation in vitro', 'CPA', (173, 207))	('blocked', 'NegReg', (165, 172))	('PDGFR-beta', 'Gene', (16, 26))	('imatinib', 'Chemical', 'MESH:D000068877', (79, 87))	('Nanog', 'Gene', '79923', (155, 160))	('diminished', 'NegReg', (88, 98))
110336	29915281	Inhibition of these receptors also blocked expression of the EMT transcription factor Slug and dramatically reduced migration and invasion.	('reduced', 'NegReg', (108, 115))	('Slug', 'Gene', '6591', (86, 90))	('Inhibition', 'Var', (0, 10))	('Slug', 'Gene', (86, 90))	('expression', 'MPA', (43, 53))	('blocked', 'NegReg', (35, 42))
110340	29915281	Studies examining CSCs in sarcomas are scarce, but there is evidence that supports mesenchymal stem cells as the origin of both pleomorphic and translocation-associated sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('sarcomas', 'Disease', (26, 34))	('sarcomas', 'Disease', 'MESH:D012509', (169, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('sarcomas', 'Disease', 'MESH:D012509', (26, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('sarcomas', 'Disease', (169, 177))	('translocation-associated', 'Var', (144, 168))
110347	29915281	Blockage of PDGFR-alpha and PDGFR-beta activity in sarcoma CSCs downregulates Slug and reduces migration and invasion.	('Slug', 'Gene', (78, 82))	('downregulates', 'NegReg', (64, 77))	('Blockage', 'Var', (0, 8))	('PDGFR-alpha', 'Gene', (12, 23))	('sarcoma CSCs', 'Disease', 'MESH:D012509', (51, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcoma CSCs', 'Disease', (51, 63))	('reduces', 'NegReg', (87, 94))	('PDGFR-beta', 'Gene', (28, 38))	('Slug', 'Gene', '6591', (78, 82))
110351	29915281	The study showed that pazopanib improved median progression-free survival by 3 months, but there was no significant improvement in overall survival.	('improved', 'PosReg', (32, 40))	('progression-free', 'CPA', (48, 64))	('pazopanib', 'Var', (22, 31))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))
110353	29915281	Interestingly, in our present study, single isoform shRNA knockdown failed to reverse chemoresistance in vitro or in the nude mouse xenograft model.	('mouse', 'Species', '10090', (126, 131))	('chemoresistance', 'CPA', (86, 101))	('knockdown', 'Var', (58, 67))
110361	29915281	Given PDGFR signaling is also important in tumor endothelial cells and pericytes, targeting PDGFR signaling may inhibit both sarcoma CSCs and the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('targeting', 'Var', (82, 91))	('inhibit', 'NegReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (146, 151))	('sarcoma CSCs', 'Disease', 'MESH:D012509', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('sarcoma CSCs', 'Disease', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('tumor', 'Disease', (43, 48))	('PDGFR signaling', 'Gene', (92, 107))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
110365	29915281	The DDLS8817 dedifferentiated liposarcoma cell line was established a tumor sample from a patient who signed informed consent and was confirmed to harbor 12q amplification by cytogenetic analysis and by DNA copy number array (Agilent 244K).	('DDLS8817', 'Gene', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('liposarcoma', 'Disease', (30, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('tumor', 'Disease', (70, 75))	('12q amplification', 'Var', (154, 171))	('patient', 'Species', '9606', (90, 97))	('liposarcoma', 'Disease', 'MESH:D008080', (30, 41))	('liposarcoma', 'Phenotype', 'HP:0012034', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
110379	29915281	Following cell fixation, cells were incubated with antibodies for CD133 (MBS462020; Miltenyi Biotec), Nanog (#8822; Cell Signaling), Oct4 (#83932; Cell Signaling), Sox2 (#3570; Cell signaling), c-Myc (sc-40; Santa Cruz), N-cadherin (BD610920; BD Biosciences), and/or Slug (#9585; Cell Signaling) in a solution of PBS with 1% BSA and 0.1% Triton X-100 at 4  C overnight.	('Sox2', 'Gene', (164, 168))	('N-cadherin', 'Gene', '1000', (221, 231))	('PBS', 'Chemical', '-', (313, 316))	('Sox2', 'Gene', '6657', (164, 168))	('Oct4', 'Gene', (133, 137))	('Oct4', 'Gene', '5460', (133, 137))	('c-Myc', 'Gene', '4609', (194, 199))	('Triton X-100', 'Chemical', 'MESH:D017830', (338, 350))	('Slug', 'Gene', '6591', (267, 271))	('c-Myc', 'Gene', (194, 199))	('Nanog', 'Gene', '79923', (102, 107))	('Biotec', 'Chemical', '-', (93, 99))	('Nanog', 'Gene', (102, 107))	('N-cadherin', 'Gene', (221, 231))	('#3570', 'Var', (170, 175))	('Slug', 'Gene', (267, 271))
110389	29915281	Silencing of PDGFR-alpha and PDGFR-beta was achieved via lentiviral transduction of human PDGFR-alpha shRNA (sc-29443-V; Santa Cruz) and human PDGFR-beta shRNA (sc-29442-V; Santa Cruz) per the manufacturer's protocol.	('human', 'Species', '9606', (137, 142))	('sc-29443-V;', 'Var', (109, 120))	('human', 'Species', '9606', (84, 89))	('sc-29442-V;', 'Var', (161, 172))	('PDGFR-alpha', 'Gene', (90, 101))
110398	29915281	Staining was visualized using Alexa Fluor 488 (A-21206; ThermoFisher), Alexa Fluor 568 (A-11011; ThermoFisher), and Alexa Fluor 647 (A-27034; ThermoFisher).	('Alexa Fluor 647', 'Chemical', 'MESH:C569686', (116, 131))	('Alexa Fluor 568', 'Chemical', '-', (71, 86))	('A-11011', 'Var', (88, 95))	('Alexa Fluor 488', 'Chemical', '-', (30, 45))	('A-21206', 'Var', (47, 54))
110415	28807769	Emerging data suggest that a new nontolerant and nonexhausted transplanted immune system has the ability to augment the activity of most anticancer agents, small molecule as well as immunologic.	('small molecule', 'Var', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('augment', 'PosReg', (108, 115))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('activity', 'MPA', (120, 128))	('cancer', 'Disease', (141, 147))
110432	28807769	Patients were required to have a performance status (Karnofsky/Lansky) of >=70% and to have adequate organ function, defined as follows: cardiac: left ventricular ejection fraction at rest >= 35% or shortening fraction > 25%; hepatic: bilirubin <= 3.0 mg/dL and alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase < 5 times upper limits of normal; renal: serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or glomerular filtration rate) >40 mL/min/1.73 m; and pulmonary: forced expiratory volume in 1 second, forced vital capacity, DLCO (diffusion capacity) > 50% predicted (corrected for hemoglobin), if unable to perform pulmonary function tests, then O2 saturation > 92% on room air.	('creatinine', 'Chemical', 'MESH:D003404', (388, 398))	('alanine aminotransferase', 'Gene', '2875', (262, 286))	('serum', 'Var', (382, 387))	('creatinine', 'Chemical', 'MESH:D003404', (440, 450))	('forced expiratory volume in 1 second', 'Phenotype', 'HP:0032342', (588, 624))	('O2 saturation', 'MPA', (771, 784))	('renal', 'MPA', (486, 491))	('Patients', 'Species', '9606', (0, 8))	('creatinine', 'Chemical', 'MESH:D003404', (502, 512))	('alanine aminotransferase', 'Gene', (262, 286))	('DLCO', 'MPA', (649, 653))
110585	27895527	Serious adverse events that were at least possibly related to Ang-(1-7) included deep vein thrombosis (400 mcg/kg dose level), stroke (700 mcg/kg dose level), and cranial neuropathy (700 mcg/kg dose level).	('deep vein thrombosis', 'Disease', (81, 101))	('stroke', 'Phenotype', 'HP:0001297', (127, 133))	('vein thrombosis', 'Phenotype', 'HP:0004936', (86, 101))	('cranial neuropathy', 'Phenotype', 'HP:0006824', (163, 181))	('cranial neuropathy', 'Disease', (163, 181))	('stroke', 'Disease', (127, 133))	('400', 'Var', (103, 106))	('deep vein thrombosis', 'Phenotype', 'HP:0002625', (81, 101))	('deep vein thrombosis', 'Disease', 'MESH:D020246', (81, 101))	('stroke', 'Disease', 'MESH:D020521', (127, 133))	('Ang-', 'Var', (62, 66))	('cranial neuropathy', 'Disease', 'MESH:D003389', (163, 181))	('neuropathy', 'Phenotype', 'HP:0009830', (171, 181))
110639	25520907	On preoperative endometrial cytology examination, abnormalities of class III or greater were considered positive for uterine sarcoma.	('abnormalities of class III', 'Phenotype', 'HP:0001976', (50, 76))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('abnormalities', 'Var', (50, 63))	('sarcoma', 'Disease', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (117, 132))
110686	25520907	In addition, hyperintense signal on T1-weighted images is thought to indicate intratumoral hemorrhage and coagulative necrosis.	('hemorrhage', 'Disease', 'MESH:D006470', (91, 101))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (106, 126))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('necrosis', 'Disease', (118, 126))	('necrosis', 'Disease', 'MESH:D009336', (118, 126))	('hyperintense signal', 'Var', (13, 32))	('hemorrhage', 'Disease', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
110834	24760049	Survival rates after cervical cancer were statistically significantly lower in patients with CD4+ T-cell count less than 200 cell/mm3 at cancer diagnosis, although in our cohort the proportion of patients with CD4 counts above 200 cell/mm3 at cervical cancer diagnosis was higher compared with patients with other AIDS-related malignancies (p = 0.005).	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('patients', 'Species', '9606', (196, 204))	('malignancies', 'Disease', 'MESH:D009369', (327, 339))	('CD4', 'Gene', '920', (93, 96))	('cancer', 'Disease', (137, 143))	('malignancies', 'Disease', (327, 339))	('AIDS', 'Disease', 'MESH:D000163', (314, 318))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CD4', 'Gene', '920', (210, 213))	('CD4', 'Gene', (93, 96))	('less than 200', 'Var', (111, 124))	('cervical cancer', 'Disease', (21, 36))	('cervical cancer', 'Disease', 'MESH:D002583', (21, 36))	('Survival rates', 'CPA', (0, 14))	('CD4', 'Gene', (210, 213))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', (30, 36))	('cervical cancer', 'Disease', (243, 258))	('cervical cancer', 'Disease', 'MESH:D002583', (243, 258))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('AIDS', 'Disease', (314, 318))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('patients', 'Species', '9606', (294, 302))	('lower', 'NegReg', (70, 75))	('patients', 'Species', '9606', (79, 87))
110860	23741276	These malignancies are characterized by a chromosome 22 rearrangement, arise from bone or soft tissue, predominantly affect children and young adults, and are grouped in the Ewing family of tumors.	('children', 'Species', '9606', (124, 132))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('arise', 'Reg', (71, 76))	('malignancies', 'Disease', 'MESH:D009369', (6, 18))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('rearrangement', 'Var', (56, 69))	('malignancies', 'Disease', (6, 18))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('affect', 'Reg', (117, 123))
110878	23741276	ES/PNETs are rare and aggressive soft tissue neoplasms, part to Ewing's family, characterized by the presence of the traslocation t(11;22) (q24;q12).	('aggressive soft tissue neoplasms', 'Disease', (22, 54))	('ES/PNETs', 'Disease', (0, 8))	('t(11;22) (q24;q12', 'Var', (130, 147))	('aggressive soft tissue neoplasms', 'Disease', 'MESH:D012983', (22, 54))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (33, 54))	('Ewing', 'Disease', (64, 69))	('neoplasms', 'Phenotype', 'HP:0002664', (45, 54))	("Ewing's", 'Disease', 'MESH:C563168', (64, 71))
110915	34009296	ERG family genes are implicated in oncogenic gene fusions due to translocations that typify several cancers.	('translocations', 'Var', (65, 79))	('ERG', 'Gene', '2078', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('ERG', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('implicated', 'Reg', (21, 31))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
110918	34009296	Indeed, these fusions acquire specific transcriptional properties that are not shared by wild-type (wt) ERG factors.	('transcriptional', 'MPA', (39, 54))	('fusions', 'Var', (14, 21))	('ERG', 'Gene', '2078', (104, 107))	('ERG', 'Gene', (104, 107))
110919	34009296	For instance, EWS-FLI1, the primary oncogenic fusion of Ewing sarcoma gains the ability to bind and epigenetically convert silenced GGAA microsatellites into active enhancers.	('ability', 'MPA', (80, 87))	('silenced', 'Var', (123, 131))	('EWS-FLI1', 'Gene', '2130;2313', (14, 22))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('epigenetically convert silenced', 'Var', (100, 131))	('Ewing sarcoma', 'Disease', (56, 69))	('bind', 'Interaction', (91, 95))	('EWS-FLI1', 'Gene', (14, 22))	('microsatellites', 'Var', (137, 152))	('gains', 'PosReg', (70, 75))
110928	34009296	Inserts were transferred from the pDONR223 into destination vectors (N-terminal tags): pDEST1899 (FLAG), pDEST1899-MS2-CP (FLAG-MS2-CP Nter tag), pDEST475 (HA) (kind gifts of James L. Hartley and Dominic Esposito, SAIC-Frederick Inc.), and Gateway modified pGEX-2TK (GST) (kind gift from Pascal Braun, CCSB, Dana-Farber Cancer Institute).	('P', 'Chemical', 'MESH:D010758', (288, 289))	('pDEST1899', 'Var', (87, 96))	('MS2', 'Species', '2710868', (128, 131))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('S', 'Chemical', 'MESH:D013455', (90, 91))	('P', 'Chemical', 'MESH:D010758', (120, 121))	('S', 'Chemical', 'MESH:D013455', (149, 150))	('S', 'Chemical', 'MESH:D013455', (108, 109))	('MS2', 'Species', '2710868', (115, 118))	('pDEST1899-MS2-CP', 'Var', (105, 121))	('S', 'Chemical', 'MESH:D013455', (214, 215))	('S', 'Chemical', 'MESH:D013455', (304, 305))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('Cancer', 'Disease', (320, 326))	('Cancer', 'Phenotype', 'HP:0002664', (320, 326))	('S', 'Chemical', 'MESH:D013455', (129, 130))	('Cancer', 'Disease', 'MESH:D009369', (320, 326))	('S', 'Chemical', 'MESH:D013455', (268, 269))
110929	34009296	pDEST1899-FLAG Erg ORFs were subcloned in the pN-MS2-CP (MS2 Nt) described in, following classical cloning procedures.	('pDEST1899-FLAG', 'Var', (0, 14))	('MS2', 'Species', '2710868', (49, 52))	('P', 'Chemical', 'MESH:D010758', (54, 55))	('S', 'Chemical', 'MESH:D013455', (58, 59))	('S', 'Chemical', 'MESH:D013455', (50, 51))	('Erg', 'Gene', (15, 18))	('Erg', 'Gene', '2078', (15, 18))	('MS2', 'Species', '2710868', (57, 60))	('S', 'Chemical', 'MESH:D013455', (3, 4))
110965	34009296	For co-immunoprecipitation of overexpressed proteins, HEK293 cells overexpressing ERG-FLAG or deletion variants of ERG and HA/MYC-tagged proteins were lysed in IPLS buffer.	('HEK293', 'CellLine', 'CVCL:0045', (54, 60))	('MYC', 'Gene', (126, 129))	('ERG', 'Gene', (82, 85))	('ERG', 'Gene', '2078', (115, 118))	('MYC', 'Gene', '4609', (126, 129))	('ERG', 'Gene', (115, 118))	('IPLS buffer', 'Chemical', '-', (160, 171))	('ERG', 'Gene', '2078', (82, 85))	('deletion variants', 'Var', (94, 111))
110980	34009296	Dynabeads Protein G (ThermoFisher Scientific) were incubated with anti-RBFOX2 antibody (A300-864A, Bethyl Laboratories), anti-ERG antibody (ab133264, Abcam) or normal rabbit IgG (Santa Cruz) at 4 C overnight with rotation.	('RBFOX2', 'Gene', (71, 77))	('S', 'Chemical', 'MESH:D013455', (179, 180))	('ERG', 'Gene', (126, 129))	('P', 'Chemical', 'MESH:D010758', (10, 11))	('S', 'Chemical', 'MESH:D013455', (34, 35))	('RBFOX2', 'Gene', '23543', (71, 77))	('ERG', 'Gene', '2078', (126, 129))	('A300-864A', 'Var', (88, 97))
111003	34009296	The purpose of rMAPS is to identify known RBP motifs that are significantly enriched in differentially regulated exons between two sample groups as compared to control (background) events.	('rMAPS', 'Chemical', '-', (15, 20))	('RBP', 'Gene', '27303', (42, 45))	('RBP', 'Gene', (42, 45))	('motifs', 'Var', (46, 52))	('differentially regulated exons', 'MPA', (88, 118))
111023	34009296	Transfection with siRNA led to a reduction of ERG protein levels to <10% of its normal levels (Supplementary Figure S1B).	('reduction', 'NegReg', (33, 42))	('ERG', 'Gene', '2078', (46, 49))	('Transfection', 'Var', (0, 12))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('ERG', 'Gene', (46, 49))	('S', 'Chemical', 'MESH:D013455', (95, 96))
111024	34009296	Differential analysis of mRNA expression levels between control and ERG-depleted cells identified 2106 genes whose expression level was significantly altered by at least 2-fold following ERG knockdown, including 945 (45%) up- and 1160 (55%) down-regulated (Supplementary Table S1).	('ERG', 'Gene', (68, 71))	('expression level', 'MPA', (115, 131))	('ERG', 'Gene', '2078', (187, 190))	('S', 'Chemical', 'MESH:D013455', (257, 258))	('down-regulated', 'NegReg', (241, 255))	('knockdown', 'Var', (191, 200))	('mRNA expression', 'MPA', (25, 40))	('ERG', 'Gene', (187, 190))	('S', 'Chemical', 'MESH:D013455', (277, 278))	('ERG', 'Gene', '2078', (68, 71))	('altered', 'Reg', (150, 157))	('up-', 'PosReg', (222, 225))
111052	34009296	Compared to MS2-CP alone, tethering of ERG, FLI1 or FEV onto the intronic MS2 site significantly increased inclusion of exon 7 (Figure 2F, black bars).	('ERG', 'Gene', (39, 42))	('inclusion', 'MPA', (107, 116))	('increased', 'PosReg', (97, 106))	('MS2', 'Species', '2710868', (12, 15))	('P', 'Chemical', 'MESH:D010758', (17, 18))	('tethering', 'Var', (26, 35))	('MS2', 'Species', '2710868', (74, 77))	('ERG', 'Gene', '2078', (39, 42))	('FLI1', 'Gene', '2313', (44, 48))	('FLI1', 'Gene', (44, 48))	('exon 7', 'Protein', (120, 126))
111055	34009296	Among these constructs, the variant lacking the CTAD (ERG-DeltaCTAD) was the only one showing a significantly reduced effect on exon inclusion (Figure 2H).	('ERG', 'Gene', (54, 57))	('exon inclusion', 'MPA', (128, 142))	('reduced', 'NegReg', (110, 117))	('CTAD', 'MPA', (48, 52))	('ERG', 'Gene', '2078', (54, 57))	('variant', 'Var', (28, 35))	('lacking', 'NegReg', (36, 43))
111057	34009296	Because the variant lacking the ETS domain is unable to bind DNA but still promotes inclusion of the reporter exon, these results are consistent with the idea that the function of ERG in pre-mRNA splicing is direct, requiring its recruitment to pre-mRNA and independent of its transcriptional activity.	('variant', 'Var', (12, 19))	('promotes', 'PosReg', (75, 83))	('inclusion', 'MPA', (84, 93))	('ERG', 'Gene', '2078', (180, 183))	('ERG', 'Gene', (180, 183))	('S', 'Chemical', 'MESH:D013455', (34, 35))	('recruitment', 'MPA', (230, 241))
111063	34009296	To explore this possibility, we examined the effects of knocking-down RBFOX2 on the mRNA splicing programs of HeLa cells.	('RBFOX2', 'Gene', '23543', (70, 76))	('knocking-down', 'Var', (56, 69))	('RBFOX2', 'Gene', (70, 76))	('HeLa', 'CellLine', 'CVCL:0030', (110, 114))
111066	34009296	In agreement with previous studies, knockdown of RBFOX2 mostly resulted in ASEs (55.5%, 399/719, Figure 3C).	('SE', 'Disease', 'None', (76, 78))	('RBFOX2', 'Gene', '23543', (49, 55))	('knockdown', 'Var', (36, 45))	('resulted in', 'Reg', (63, 74))	('RBFOX2', 'Gene', (49, 55))
111068	34009296	Comparison with our dataset of ERG-regulated ASEs revealed that a highly significant proportion (132/410; 32.2%, P < 10E-50) of ERG-regulated ASEs were also sensitive to RBFOX2 knockdown (Figure 3D).	('sensitive', 'Reg', (157, 166))	('ERG', 'Gene', '2078', (31, 34))	('P', 'Chemical', 'MESH:D010758', (113, 114))	('RBFOX2', 'Gene', (170, 176))	('ERG', 'Gene', '2078', (128, 131))	('SE', 'Disease', 'None', (46, 48))	('ERG', 'Gene', (128, 131))	('ERG', 'Gene', (31, 34))	('knockdown', 'Var', (177, 186))	('SE', 'Disease', 'None', (143, 145))	('RBFOX2', 'Gene', '23543', (170, 176))
111069	34009296	Strikingly, 96% of the ASEs regulated by both RBFOX2 and ERG were similarly regulated following knockdown of either of the two proteins (Figure 3E).	('knockdown', 'Var', (96, 105))	('regulated', 'Reg', (76, 85))	('ERG', 'Gene', (57, 60))	('RBFOX2', 'Gene', (46, 52))	('ERG', 'Gene', '2078', (57, 60))	('RBFOX2', 'Gene', '23543', (46, 52))	('S', 'Chemical', 'MESH:D013455', (24, 25))	('SE', 'Disease', 'None', (24, 26))	('S', 'Chemical', 'MESH:D013455', (0, 1))
111076	34009296	As excepted, knocking down ERG or FLI1 dramatically altered gene expression levels in HUVECs as we identified respectively 4212 (1607 up and 2605 down) and 3092 (1491 up and 1601 down) genes whose expression was significantly modified across three replicates (Supplementary Figure S4B, Supplementary Tables S5 and S6).	('ERG', 'Gene', '2078', (27, 30))	('FLI1', 'Gene', (34, 38))	('knocking down', 'Var', (13, 26))	('ERG', 'Gene', (27, 30))	('FLI1', 'Gene', '2313', (34, 38))	('S', 'Chemical', 'MESH:D013455', (314, 315))	('S', 'Chemical', 'MESH:D013455', (286, 287))	('altered', 'Reg', (52, 59))	('gene expression levels', 'MPA', (60, 82))	('S', 'Chemical', 'MESH:D013455', (307, 308))	('HUVEC', 'CellLine', 'CVCL:2959', (86, 91))	('down', 'NegReg', (146, 150))	('S', 'Chemical', 'MESH:D013455', (281, 282))	('modified', 'Reg', (226, 234))	('S', 'Chemical', 'MESH:D013455', (260, 261))	('expression', 'MPA', (197, 207))
111089	34009296	After knocking down RBFOX2 in HUVECs and profiling associated splicing changes, we identified 531 RBFOX2-dependent ASEs (Supplementary Table S9).	('RBFOX2', 'Gene', '23543', (20, 26))	('RBFOX2', 'Gene', '23543', (98, 104))	('S', 'Chemical', 'MESH:D013455', (121, 122))	('S', 'Chemical', 'MESH:D013455', (141, 142))	('RBFOX2', 'Gene', (20, 26))	('RBFOX2', 'Gene', (98, 104))	('SE', 'Disease', 'None', (116, 118))	('HUVEC', 'CellLine', 'CVCL:2959', (30, 35))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('knocking down', 'Var', (6, 19))
111092	34009296	knocking down ERG or FLI1 recapitulated RBFOX2-depletion in most cases (91.9% and 92.4% for ERG and FLI1, respectively).	('ERG', 'Gene', (92, 95))	('FLI1', 'Gene', '2313', (21, 25))	('FLI1', 'Gene', '2313', (100, 104))	('FLI1', 'Gene', (100, 104))	('RBFOX2', 'Gene', '23543', (40, 46))	('RBFOX2', 'Gene', (40, 46))	('ERG', 'Gene', '2078', (14, 17))	('ERG', 'Gene', (14, 17))	('ERG', 'Gene', '2078', (92, 95))	('FLI1', 'Gene', (21, 25))	('knocking', 'Var', (0, 8))
111099	34009296	Knocking-down ERG had no impact on RBFOX2 expression (Supplementary Figure S5A), ruling out the trivial explanation that ERG might indirectly participate in RBFOX2-dependent splicing regulation by controlling the expression level of RBFOX2.	('expression level', 'MPA', (213, 229))	('participate', 'Reg', (142, 153))	('controlling', 'Reg', (197, 208))	('RBFOX2', 'Gene', '23543', (157, 163))	('RBFOX2', 'Gene', '23543', (233, 239))	('ERG', 'Gene', '2078', (14, 17))	('ERG', 'Gene', '2078', (121, 124))	('ERG', 'Gene', (14, 17))	('RBFOX2', 'Gene', '23543', (35, 41))	('Knocking-down', 'Var', (0, 13))	('ERG', 'Gene', (121, 124))	('RBFOX2', 'Gene', (233, 239))	('S', 'Chemical', 'MESH:D013455', (54, 55))	('RBFOX2', 'Gene', (157, 163))	('S', 'Chemical', 'MESH:D013455', (75, 76))	('RBFOX2', 'Gene', (35, 41))
111104	34009296	Using FLAG-tagged ERG variants lacking individual domains to identify the RBFOX2-interacting region of ERG, we found that only the ERG variant lacking the CTAD region, shown above to be important for the splicing activity of ERG in the SMN2 reporter assay, had lost the ability to associate with RBFOX2 (Figures 2H and 5C).	('ERG', 'Gene', '2078', (103, 106))	('SMN2', 'Gene', '6607', (236, 240))	('ERG', 'Gene', (131, 134))	('lost', 'NegReg', (261, 265))	('ERG', 'Gene', (225, 228))	('RBFOX2', 'Gene', (296, 302))	('ability', 'MPA', (270, 277))	('variant', 'Var', (135, 142))	('associate', 'Interaction', (281, 290))	('RBFOX2', 'Gene', (74, 80))	('RBFOX2', 'Gene', '23543', (296, 302))	('ERG', 'Gene', '2078', (225, 228))	('SMN2', 'Gene', (236, 240))	('ERG', 'Gene', (18, 21))	('ERG', 'Gene', '2078', (131, 134))	('RBFOX2', 'Gene', '23543', (74, 80))	('ERG', 'Gene', '2078', (18, 21))	('lacking', 'NegReg', (143, 150))	('ERG', 'Gene', (103, 106))
111126	34009296	Alternative splicing analysis revealed that knockdown of EWS-FLI1 mostly resulted in ASEs (72.3%, 1360/1880, Figure 6C and Supplementary Table S10).	('S', 'Chemical', 'MESH:D013455', (143, 144))	('S', 'Chemical', 'MESH:D013455', (86, 87))	('EWS-FLI1', 'Gene', (57, 65))	('S10', 'Gene', (143, 146))	('S10', 'Gene', '6204', (143, 146))	('S', 'Chemical', 'MESH:D013455', (59, 60))	('EWS-FLI1', 'Gene', '2130;2313', (57, 65))	('knockdown', 'Var', (44, 53))	('S', 'Chemical', 'MESH:D013455', (123, 124))	('resulted in', 'Reg', (73, 84))	('SE', 'Disease', 'None', (86, 88))
111134	34009296	Knockdown of RBFOX2 was associated with 768 splicing events.	('RBFOX2', 'Gene', (13, 19))	('splicing events', 'MPA', (44, 59))	('Knockdown', 'Var', (0, 9))	('RBFOX2', 'Gene', '23543', (13, 19))
111135	34009296	As observed in HeLa and HUVEC cells, ASEs accounted for the majority of splicing events regulated in Ewing sarcoma cells following RBFOX2 knockdown (74,1%, 569/768) (Supplementary Figure S6E, Supplementary Table S11).	('knockdown', 'Var', (138, 147))	('S', 'Chemical', 'MESH:D013455', (38, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('HUVEC', 'CellLine', 'CVCL:2959', (24, 29))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('HeLa', 'CellLine', 'CVCL:0030', (15, 19))	('S', 'Chemical', 'MESH:D013455', (166, 167))	('S', 'Chemical', 'MESH:D013455', (187, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('RBFOX2', 'Gene', '23543', (131, 137))	('splicing events regulated', 'MPA', (72, 97))	('SE', 'Disease', 'None', (38, 40))	('S11', 'Gene', '6267', (212, 215))	('RBFOX2', 'Gene', (131, 137))	('Ewing sarcoma', 'Disease', (101, 114))	('S', 'Chemical', 'MESH:D013455', (192, 193))	('S', 'Chemical', 'MESH:D013455', (212, 213))	('S11', 'Gene', (212, 215))
111138	34009296	Instead, knocking down EWS-FLI1 had an opposite effect to that of knocking down RBFOX2 in 50.2%, (105/209) of cases (Figure 6G).	('knocking down', 'Var', (66, 79))	('EWS-FLI1', 'Gene', (23, 31))	('knocking down', 'Var', (9, 22))	('RBFOX2', 'Gene', '23543', (80, 86))	('EWS-FLI1', 'Gene', '2130;2313', (23, 31))	('RBFOX2', 'Gene', (80, 86))
111150	34009296	We further validated the regulation of ADD3 exon 14 splicing by EWS-FLI1 depletion using siRNA transfection in a second Ewing sarcoma cell line (MHH-ES1, Supplementary Figure S7A).	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('S', 'Chemical', 'MESH:D013455', (66, 67))	('Ewing sarcoma', 'Disease', (120, 133))	('EWS-FLI1', 'Gene', (64, 72))	('EWS-FLI1', 'Gene', '2130;2313', (64, 72))	('ADD3', 'Gene', '120', (39, 43))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (120, 133))	('ADD3', 'Gene', (39, 43))	('depletion', 'Var', (73, 82))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (120, 133))	('S', 'Chemical', 'MESH:D013455', (175, 176))	('S', 'Chemical', 'MESH:D013455', (150, 151))	('S', 'Chemical', 'MESH:D013455', (154, 155))
111157	34009296	Depletion of EWS-FLI1 induces a switch towards a mesenchymal phenotype, with cells displaying increased actin stress fibers, cell size, and invasion capacity.	('invasion capacity', 'CPA', (140, 157))	('increased', 'PosReg', (94, 103))	('actin stress fibers', 'MPA', (104, 123))	('EWS-FLI1', 'Gene', (13, 21))	('increased actin stress fibers', 'Phenotype', 'HP:0025200', (94, 123))	('Depletion', 'Var', (0, 9))	('EWS-FLI1', 'Gene', '2130;2313', (13, 21))	('cell size', 'CPA', (125, 134))	('switch', 'Reg', (32, 38))
111159	34009296	Further analysis of cells with CRISPR deletion of ADD3 exon 14 showed an increase in cell size and invasion capacity (Figure 7G and H).	('invasion capacity', 'CPA', (99, 116))	('increase', 'PosReg', (73, 81))	('cell size', 'CPA', (85, 94))	('ADD3', 'Gene', '120', (50, 54))	('ADD3', 'Gene', (50, 54))	('deletion', 'Var', (38, 46))
111160	34009296	Conversely, in DOX-treated A673/TR/shEF cells, which express low levels of EWS-FLI1 and therefore of ADD3-L (See Figure 7D), ectopic expression of the ADD3-L isoform reduced stress fibers formation (Figure 7I and Supplementary Figure S7I).	('ectopic expression', 'Var', (125, 143))	('stress fibers formation', 'CPA', (174, 197))	('S', 'Chemical', 'MESH:D013455', (213, 214))	('ADD3', 'Gene', '120', (101, 105))	('ADD3', 'Gene', (101, 105))	('ADD3', 'Gene', '120', (151, 155))	('reduced', 'NegReg', (166, 173))	('EWS-FLI1', 'Gene', (75, 83))	('TR', 'Gene', '2149', (32, 34))	('EWS-FLI1', 'Gene', '2130;2313', (75, 83))	('S', 'Chemical', 'MESH:D013455', (77, 78))	('S', 'Chemical', 'MESH:D013455', (109, 110))	('ADD3', 'Gene', (151, 155))	('DOX', 'Chemical', 'MESH:D004318', (15, 18))	('S', 'Chemical', 'MESH:D013455', (234, 235))
111177	34009296	Indeed, there was no significant overlap between differentially expressed and differentially spliced genes in ERG knockdown cells; there was no enrichment of ERG binding sites in DNA regions around ERG regulated exons and the TSS of corresponding genes; and a transcriptionally inactive ERG variant lacking the DNA-binding domain exhibited full splicing activity in our minigene assay.	('ERG', 'Gene', (287, 290))	('ERG', 'Gene', '2078', (110, 113))	('ERG', 'Gene', '2078', (287, 290))	('ERG', 'Gene', (110, 113))	('variant', 'Var', (291, 298))	('lacking', 'NegReg', (299, 306))	('ERG', 'Gene', '2078', (158, 161))	('ERG', 'Gene', '2078', (198, 201))	('ERG', 'Gene', (198, 201))	('full splicing activity', 'MPA', (340, 362))	('ERG', 'Gene', (158, 161))
111183	34009296	Because we found that ERG also associates with several components of the spliceosome, its presence within LASR might affect the activity and/or the composition of the splicing complex around regulated exons or alter the interaction of the RBFOX2/LASR complex with the splicing machinery.	('RBFOX2', 'Gene', '23543', (239, 245))	('associates', 'Interaction', (31, 41))	('presence', 'Var', (90, 98))	('activity', 'MPA', (128, 136))	('interaction', 'Interaction', (220, 231))	('alter', 'Reg', (210, 215))	('RBFOX2', 'Gene', (239, 245))	('ERG', 'Gene', '2078', (22, 25))	('LASR', 'Chemical', '-', (246, 250))	('LASR', 'Chemical', '-', (106, 110))	('composition of the splicing complex around', 'MPA', (148, 190))	('ERG', 'Gene', (22, 25))	('affect', 'Reg', (117, 123))
111190	34009296	Perturbation of alternative splicing programs is a feature of Ewing sarcoma, and has been attributed to the presence of oncogenic fusion proteins (e.g.	('P', 'Chemical', 'MESH:D010758', (0, 1))	('Ewing sarcoma', 'Disease', (62, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('alternative splicing programs', 'MPA', (16, 45))	('Perturbation', 'Var', (0, 12))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (62, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (62, 75))
111192	34009296	In sharp contrast to the convergent effects shared by RBFOX2 and wild-type ERG family proteins on their common set of ASEs, the EWS-FLI1 fusion antagonizes a large proportion of RBFOX2-dependent ASEs.	('EWS-FLI1', 'Gene', '2130;2313', (128, 136))	('SE', 'Disease', 'None', (196, 198))	('fusion', 'Var', (137, 143))	('RBFOX2', 'Gene', (54, 60))	('RBFOX2', 'Gene', '23543', (178, 184))	('RBFOX2', 'Gene', (178, 184))	('ERG', 'Gene', '2078', (75, 78))	('SE', 'Disease', 'None', (119, 121))	('ERG', 'Gene', (75, 78))	('EWS-FLI1', 'Gene', (128, 136))	('antagonizes', 'NegReg', (144, 155))	('RBFOX2', 'Gene', '23543', (54, 60))
111205	34009296	While the idea of EWS-FLI1 influencing alternative splicing was expressed almost two decades ago, the only functional relevance of such a function for the Ewing sarcoma oncogenic process was a splicing regulation of the ARID1A gene.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (155, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('ARID1A', 'Gene', '8289', (220, 226))	('ARID1A', 'Gene', (220, 226))	('Ewing sarcoma', 'Disease', (155, 168))	('EWS-FLI1', 'Gene', (18, 26))	('splicing regulation', 'Var', (193, 212))	('EWS-FLI1', 'Gene', '2130;2313', (18, 26))
111207	34009296	Our study indicates that the EWS-FLI1-induced reprogramming of these cells may not only rely on transcriptional effects, in particular via genome-wide activation of GGAA microsatellites but also on post-transcriptional effects, such as modulation of the pro-mesenchymal splicing program driven by RBFOX2.	('GGAA', 'Protein', (165, 169))	('RBFOX2', 'Gene', (297, 303))	('EWS-FLI1', 'Gene', (29, 37))	('EWS-FLI1', 'Gene', '2130;2313', (29, 37))	('reprogramming', 'CPA', (46, 59))	('microsatellites', 'Var', (170, 185))	('RBFOX2', 'Gene', '23543', (297, 303))	('activation', 'PosReg', (151, 161))
111250	30219192	SUV measurements have been found to parallel histopathologic findings, with high SUV values correlating with increased mitotic counts and lower values corresponding with areas of tumor necrosis.	('tumor necrosis', 'Disease', (179, 193))	('tumor necrosis', 'Disease', 'MESH:D009336', (179, 193))	('lower', 'NegReg', (138, 143))	('SUV', 'Gene', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('high', 'Var', (76, 80))	('increased', 'PosReg', (109, 118))	('mitotic counts', 'CPA', (119, 133))
111273	30219192	PET/CT scanning is also highly efficacious in detecting lymph node and bone metastases, with sensitivity values of 90% to 98% compared with 25% to 83% for conventional imaging methods, with good specificity as well (97% for PET/CT scanning vs 78% for conventional imaging).	('PET/CT scanning', 'Var', (224, 239))	('bone metastases', 'Disease', 'MESH:D009362', (71, 86))	('PET/CT scanning', 'Var', (0, 15))	('bone metastases', 'Disease', (71, 86))
111317	30219192	MRI in myeloma demonstrates T2 hyperintensity and T1 hypointensity in involved areas of bone, with variable contrast enhancement seen.	('myeloma', 'Disease', 'MESH:D009101', (7, 14))	('T2 hyperintensity', 'Var', (28, 45))	('T1 hypointensity', 'Var', (50, 66))	('myeloma', 'Disease', (7, 14))
111337	30219192	The hybrid modalities of FDG PET/CT and PET/MRI have improved oncologic imaging that combine the sensitivity of metabolic imaging with the specificity of anatomic imaging.	('FDG', 'Chemical', 'MESH:D019788', (25, 28))	('PET/MRI', 'Gene', '78996', (40, 47))	('oncologic imaging', 'MPA', (62, 79))	('FDG', 'Var', (25, 28))	('improved', 'PosReg', (53, 61))	('PET/MRI', 'Gene', (40, 47))
111347	31799487	He had a diagnosis of hereditary nonpolyposis colorectal carcinoma or LS, with a mutation in the MLH1 mismatch repair gene.	('hereditary nonpolyposis colorectal carcinoma', 'Phenotype', 'HP:0006716', (22, 66))	('mutation', 'Var', (81, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('hereditary nonpolyposis colorectal carcinoma', 'Disease', 'MESH:D003123', (22, 66))	('hereditary nonpolyposis colorectal carcinoma', 'Disease', (22, 66))	('MLH1', 'Gene', '4292', (97, 101))	('LS', 'Disease', 'MESH:D003123', (70, 72))	('MLH1', 'Gene', (97, 101))
111380	31799487	Angiosarcoma has not been associated with LS in humans, although it has been associated with MMR mutations in zebrafish.	('mutations', 'Var', (97, 106))	('MMR', 'Gene', (93, 96))	('Angiosarcoma', 'Disease', (0, 12))	('Angiosarcoma', 'Disease', 'MESH:D006394', (0, 12))	('zebrafish', 'Species', '7955', (110, 119))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('LS', 'Disease', 'MESH:D003123', (42, 44))	('humans', 'Species', '9606', (48, 54))
111585	29392229	The major reason why CIBP can have a remarkably negative impact on a cancer patient's functional status and daily activity is that loading and use of the skeleton is required for most physical and social activities.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('functional', 'MPA', (86, 96))	('negative', 'NegReg', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('patient', 'Species', '9606', (76, 83))	('CIBP', 'Var', (21, 25))	('cancer', 'Disease', (69, 75))	('CIBP', 'Chemical', '-', (21, 25))
111596	29392229	Currently, the most commonly used endpoint to measure CIBP in preclinical models is an increase in mechanical or thermal hypersensitivity of the skin of the hind paw as assessed by von Frey (mechanical testing) or the Hargreaves method (thermal).	('von Frey', 'Disease', (181, 189))	('increase', 'PosReg', (87, 95))	('von Frey', 'Disease', 'MESH:D013547', (181, 189))	('hypersensitivity of the', 'Disease', 'MESH:D004342', (121, 144))	('CIBP', 'Var', (54, 58))	('hypersensitivity of the', 'Disease', (121, 144))	('CIBP', 'Chemical', '-', (54, 58))
111600	29392229	By contrast, anti-NGF showed significant efficacy in attenuating both CIBP-induced skin hypersensitivity and CIBP-induced skeletal pain-related behaviors.	('skeletal pain', 'Phenotype', 'HP:0002653', (122, 135))	('attenuating', 'NegReg', (53, 64))	('CIBP', 'Chemical', '-', (70, 74))	('pain', 'Phenotype', 'HP:0012531', (131, 135))	('skeletal pain', 'Disease', (122, 135))	('CIBP-induced', 'Disease', (70, 82))	('skeletal pain', 'Disease', 'MESH:D010146', (122, 135))	('anti-NGF', 'Var', (13, 21))	('hypersensitivity', 'Disease', (88, 104))	('hypersensitivity', 'Disease', 'MESH:D004342', (88, 104))	('CIBP', 'Chemical', '-', (109, 113))
111616	29392229	The present results clearly show CIBP not only produces marked changes in day/night activity but also significant changes in skin hypersensitivity in the ipsilateral but not contralateral hind paw.	('changes in skin hypersensitivity', 'Phenotype', 'HP:0002972', (114, 146))	('hypersensitivity in', 'Disease', 'MESH:D004342', (130, 149))	('CIBP', 'Var', (33, 37))	('CIBP', 'Chemical', '-', (33, 37))	('day/night activity', 'MPA', (74, 92))	('hypersensitivity in', 'Disease', (130, 149))	('changes', 'Reg', (63, 70))	('changes', 'Reg', (114, 121))
111633	27387325	Pazopanib is associated with promising tolerability according to previous studies and may offer a significant clinical advantage in first-line treatment of STS compared with doxorubicin.	('STS', 'Phenotype', 'HP:0030448', (156, 159))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('doxorubicin', 'Chemical', 'MESH:D004317', (174, 185))	('STS', 'Disease', (156, 159))	('advantage', 'PosReg', (119, 128))	('Pazopanib', 'Var', (0, 9))
111651	27387325	Pazopanib achieved a significant improvement in median progression-free survival (PFS) from 1.6 to 4.6 months (p < 0.0001), which was the primary endpoint of the trial.	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('progression-free', 'CPA', (55, 71))	('Pazopanib', 'Var', (0, 9))	('improvement', 'PosReg', (33, 44))
111652	27387325	Overall, pazopanib offers a distinct mechanism of action and spectrum of adverse events, thereby offering some advantage over conventional chemotherapy.	('pazopanib', 'Var', (9, 18))	('pazopanib', 'Chemical', 'MESH:C516667', (9, 18))	('advantage', 'PosReg', (111, 120))
111785	24675777	Some of these aberrant chromosomal translocations yield functional recombinant genes, which have been implicated as the cause of a number of lymphomas, leukemias, sarcomas, and solid tumors.	('yield', 'Reg', (50, 55))	('leukemias', 'Disease', (152, 161))	('lymphomas', 'Disease', 'MESH:D008223', (141, 150))	('cause', 'Reg', (120, 125))	('solid tumors', 'Disease', 'MESH:D009369', (177, 189))	('lymphomas', 'Phenotype', 'HP:0002665', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('leukemia', 'Disease', 'MESH:D007938', (152, 160))	('leukemia', 'Disease', (152, 160))	('tumors', 'Disease', (183, 189))	('aberrant chromosomal translocations', 'Var', (14, 49))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('lymphomas', 'Disease', (141, 150))	('sarcomas', 'Disease', 'MESH:D012509', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (163, 171))	('leukemias', 'Disease', 'MESH:D007938', (152, 161))	('tumor', 'Disease', (183, 188))	('functional recombinant genes', 'MPA', (56, 84))	('sarcomas', 'Disease', (163, 171))	('leukemias', 'Phenotype', 'HP:0001909', (152, 161))	('solid tumors', 'Disease', (177, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
111786	24675777	We demonstrate this method by detecting the BCR-ABL fusion transcripts that occur in chronic myeloid leukemia cells, and by detecting the EWSR1-FLI1 fusion transcripts that occur in Ewing's sarcoma cells.	('ABL', 'Gene', '25', (48, 51))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (182, 197))	('EWSR1-FLI1', 'Gene', (138, 148))	('ABL', 'Gene', (48, 51))	('BCR-ABL', 'Gene', (44, 51))	('chronic myeloid leukemia', 'Disease', (85, 109))	('BCR-ABL', 'Gene', '25', (44, 51))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (85, 109))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (85, 109))	('fusion', 'Var', (52, 58))	('BCR', 'Gene', (44, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (93, 109))	('BCR', 'Gene', '613', (44, 47))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (182, 197))	("Ewing's sarcoma", 'Disease', (182, 197))
111787	24675777	This technology should pave the way for accurate in situ typing of many cancers that are associated with, or caused by, fusion transcripts.	('associated', 'Reg', (89, 99))	('fusion transcripts', 'Var', (120, 138))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('caused by', 'Reg', (109, 118))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Disease', (72, 78))
111789	24675777	More recently, gene fusions were found to be responsible for soft-tissue sarcomas, prostrate cancer, lung cancer, and certain solid tumors.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('solid tumors', 'Disease', (126, 138))	('soft-tissue sarcomas', 'Disease', (61, 81))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (61, 81))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('prostrate cancer', 'Disease', (83, 99))	('gene fusions', 'Var', (15, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('responsible', 'Reg', (45, 56))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
111807	24675777	Philadelphia chromosomes arise as a result of a translocation between the long arm of chromosome 9 and the long arm of chromosome 22, which is denoted t(9;22)(q34;q11).	('translocation', 'Var', (48, 61))	('Philadelphia chromosomes', 'Disease', (0, 24))	('t(9;22)(q34;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (151, 167))
111808	24675777	Well-characterized examples of such tumors arising from fused genes include sarcomas, such as myxoid liposarcoma and Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (117, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	("Ewing's sarcoma", 'Disease', (117, 132))	('liposarcoma', 'Phenotype', 'HP:0012034', (101, 112))	('myxoid liposarcoma', 'Disease', (94, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (76, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('fused genes', 'Var', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (94, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcomas', 'Disease', (76, 84))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (94, 112))
111809	24675777	About 90% of reported cases have a translocation between the EWSR1 gene of chromosome 22 and the FLI1 gene of chromosome 11, denoted as t(11;22)(q24;q12), which results in the synthesis of EWSR1-FLI1 chimeric mRNA.	('synthesis', 'MPA', (176, 185))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (136, 153))	('FLI1', 'Gene', (97, 101))	('translocation', 'Var', (35, 48))	('results in', 'Reg', (161, 171))	('EWSR1', 'Gene', (61, 66))
112105	27355001	Extrapolating from the literature on uterine leiomyosarcoma, high grade has been shown to a significant risk factor for recurrence and death and hysterectomy is considered the treatment of choice.	('high grade', 'Var', (61, 71))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (45, 59))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (37, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('death', 'Disease', 'MESH:D003643', (135, 140))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (45, 59))	('death', 'Disease', (135, 140))	('leiomyosarcoma', 'Disease', (45, 59))
112152	26413364	Desmoplastic small round cell tumors (DSRCTs) are aggressive malignancies with characteristic clinical presentations, pathological findings, and specific associated chromosomal translocations t(11;22) (p13;q12) involving EWSR1 and WT1 genes.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('aggressive malignancies', 'Disease', 'MESH:D009369', (50, 73))	('aggressive malignancies', 'Disease', (50, 73))	('Desmoplastic small round cell tumors', 'Disease', (0, 36))	('EWSR1', 'Gene', (221, 226))	('t(11;22) (p13;q12', 'Var', (192, 209))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('EWSR1', 'Gene', '2130', (221, 226))	('WT1', 'Gene', '7490', (231, 234))	('WT1', 'Gene', (231, 234))	('Desmoplastic small round cell tumors', 'Disease', 'MESH:D058405', (0, 36))
112156	26413364	The characteristic translocations [t(11;22)] with resultant EWSR1-WT1 fusions can be detected by fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) technology.	('EWSR1', 'Gene', '2130', (60, 65))	('WT1', 'Gene', '7490', (66, 69))	('WT1', 'Gene', (66, 69))	('EWSR1', 'Gene', (60, 65))	('fusions', 'Var', (70, 77))
112202	26413364	EWSR1 rearrangements have been documented in many soft tissue neoplasms, including Ewing's sarcoma/primitive neuroectodermal tumor (EW/PNET), DSRCT, low grade myoid tumor, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, sclerosing epithelioid fibrosarcoma, myoepithelial tumor, angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue, clear cell sarcoma-like tumor of gastrointestinal tract, and primary pulmonary myxoid sarcoma.	('myxoid liposarcoma', 'Disease', (172, 190))	('primary pulmonary myxoid sarcoma', 'Disease', (417, 449))	('histiocytoma', 'Phenotype', 'HP:0012315', (307, 319))	('epithelioid fibrosarcoma', 'Disease', 'MESH:D005354', (240, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (83, 98))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (287, 319))	('myoid tumor', 'Disease', 'MESH:D009369', (159, 170))	('sarcoma', 'Disease', 'MESH:D012509', (332, 339))	('sarcoma', 'Disease', 'MESH:D012509', (220, 227))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (109, 130))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (172, 190))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('sarcoma', 'Disease', (332, 339))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (83, 98))	('sarcoma', 'Disease', (220, 227))	('angiomatoid fibrous histiocytoma', 'Disease', (287, 319))	('neuroectodermal tumor', 'Disease', (109, 130))	('primary pulmonary myxoid sarcoma', 'Disease', 'MESH:D045888', (417, 449))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('EWSR1', 'Gene', '2130', (0, 5))	('neoplasms', 'Disease', 'MESH:D009369', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('sarcoma', 'Disease', 'MESH:D012509', (442, 449))	('epithelioid fibrosarcoma', 'Disease', (240, 264))	('sarcoma', 'Disease', (442, 449))	('sarcoma', 'Disease', (91, 98))	('myoid tumor', 'Disease', (159, 170))	('PNET', 'Phenotype', 'HP:0030065', (135, 139))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (50, 71))	('sarcoma', 'Disease', 'MESH:D012509', (257, 264))	('tumor of gastrointestinal tract', 'Disease', (380, 411))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (206, 227))	('tumor of gastrointestinal tract', 'Disease', 'MESH:D004067', (380, 411))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (109, 130))	('liposarcoma', 'Phenotype', 'HP:0012034', (179, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (332, 339))	('sarcoma', 'Disease', (257, 264))	('rearrangements', 'Var', (6, 20))	("Ewing's sarcoma", 'Disease', (83, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('neoplasms', 'Disease', (62, 71))	('sarcoma', 'Disease', 'MESH:D012509', (367, 374))	('myxoid chondrosarcoma', 'Disease', (206, 227))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (213, 227))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (252, 264))	('man', 'Species', '9606', (45, 48))	('DSRCT', 'Disease', (142, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('EWSR1', 'Gene', (0, 5))	('sarcoma', 'Disease', (367, 374))	('myoepithelial tumor', 'Disease', 'MESH:D009208', (266, 285))	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('sarcoma', 'Disease', (183, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (172, 190))	('myoepithelial tumor', 'Disease', (266, 285))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (99, 130))	('neoplasms', 'Phenotype', 'HP:0002664', (62, 71))	('tumor of gastrointestinal tract', 'Phenotype', 'HP:0007378', (380, 411))
112203	26413364	Each of these soft tissue tumors with EWSR1 rearrangements is associated with characteristic clinical presentations and histopathologic findings.	('soft tissue tumors', 'Phenotype', 'HP:0031459', (14, 32))	('tumors', 'Disease', (26, 32))	('EWSR1', 'Gene', '2130', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('EWSR1', 'Gene', (38, 43))	('rearrangements', 'Var', (44, 58))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (14, 31))
112204	26413364	The only EWSR1 rearranged tumor that is likely to show overlapping clinical presentation and immunohistochemical features with DSRCT is EW/PNET.	('rearranged', 'Var', (15, 25))	('DSRCT', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('EWSR1', 'Gene', (9, 14))	('EW/PNET', 'Disease', (136, 143))	('PNET', 'Phenotype', 'HP:0030065', (139, 143))	('EWSR1', 'Gene', '2130', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
112232	33808256	However, recent evidence indicates that oncolytic viruses can also lead to tumor regression through other mechanisms, such as altering the tumor microenvironment into a milieu that enhances anticancer activity by modulating the immune system and inhibiting angiogenesis.	('modulating', 'Reg', (213, 223))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('altering', 'Reg', (126, 134))	('cancer', 'Disease', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (139, 144))	('angiogenesis', 'CPA', (257, 269))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('enhances', 'PosReg', (181, 189))	('oncolytic viruses', 'Var', (40, 57))	('viruses', 'Var', (50, 57))	('tumor', 'Disease', (75, 80))	('inhibiting', 'NegReg', (246, 256))
112250	33808256	Interestingly, the volume of tumors infected with CDV was already significantly smaller at 37 dpt when compared to neoplasms injected with medium (p = 0.0058).	('neoplasms', 'Phenotype', 'HP:0002664', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('dpt', 'Chemical', '-', (94, 97))	('neoplasms', 'Disease', 'MESH:D009369', (115, 124))	('tumors infected', 'Disease', (29, 44))	('neoplasms', 'Disease', (115, 124))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('CDV', 'Var', (50, 53))	('neoplasm', 'Phenotype', 'HP:0002664', (115, 123))	('CDV', 'Species', '11232', (50, 53))	('smaller', 'NegReg', (80, 87))	('tumors infected', 'Disease', 'MESH:D007239', (29, 44))
112257	33808256	Tumors injected with UV-inactivated CDV were significantly larger (p = 0.0225) than neoplasms infected with CDV until 70 dpt at which animals treated with UV-inactivated virus were sacrificed.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('larger', 'PosReg', (59, 65))	('neoplasms', 'Phenotype', 'HP:0002664', (84, 93))	('neoplasms infected', 'Disease', (84, 102))	('dpt', 'Chemical', '-', (121, 124))	('CDV', 'Species', '11232', (108, 111))	('Tumors', 'Disease', (0, 6))	('CDV', 'Var', (36, 39))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('neoplasms infected', 'Disease', 'MESH:D007239', (84, 102))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CDV', 'Species', '11232', (36, 39))	('neoplasm', 'Phenotype', 'HP:0002664', (84, 92))
112258	33808256	Taken together, a tenfold intratumoral injection with CDV-Ond led to a significant reduction in tumor growth from day 35 to day 70 compared to controls.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('reduction', 'NegReg', (83, 92))	('CDV-Ond', 'Var', (54, 61))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('CDV', 'Species', '11232', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
112266	33808256	DH82-CDVai xenografts showed a higher median area of necrosis compared to non-infected controls at all time points (Supplementary Table S1).	('necrosis', 'Disease', 'MESH:D009336', (53, 61))	('DH82-CDVai', 'Var', (0, 10))	('infected', 'Disease', (78, 86))	('DH82-CDVai', 'Chemical', '-', (0, 10))	('necrosis', 'Disease', (53, 61))	('infected', 'Disease', 'MESH:D007239', (78, 86))
112267	33808256	Statistical analysis (Figure 2A) of the results revealed significantly larger necrosis areas in DH82-CDVai xenografts compared with all control groups at 44 dpt (p values between 0.0051 and 0.0306).	('necrosis', 'Disease', 'MESH:D009336', (78, 86))	('DH82-CDVai', 'Var', (96, 106))	('larger', 'PosReg', (71, 77))	('DH82-CDVai', 'Chemical', '-', (96, 106))	('necrosis', 'Disease', (78, 86))	('dpt', 'Chemical', '-', (157, 160))
112268	33808256	At 54 dpt DH82-CDVai xenografts displayed significantly larger areas of necrosis than non-treated DH82 neoplasms (p = 0.0075) or DH82-UV-CDVai tumors (p = 0.0225).	('DH82', 'Chemical', '-', (98, 102))	('dpt', 'Chemical', '-', (6, 9))	('larger', 'PosReg', (56, 62))	('neoplasms', 'Disease', 'MESH:D009369', (103, 112))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('neoplasms', 'Disease', (103, 112))	('DH82-CDVai', 'Var', (10, 20))	('DH82', 'Chemical', '-', (10, 14))	('neoplasm', 'Phenotype', 'HP:0002664', (103, 111))	('necrosis', 'Disease', (72, 80))	('UV-CDVai tumors', 'Disease', 'MESH:C563466', (134, 149))	('DH82-CDVai', 'Chemical', '-', (10, 20))	('necrosis', 'Disease', 'MESH:D009336', (72, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (103, 112))	('DH82', 'Chemical', '-', (129, 133))	('UV-CDVai tumors', 'Disease', (134, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('DH82-UV-CDVai', 'Chemical', '-', (129, 142))
112269	33808256	Areas of necrosis were significantly larger in DH82-CDVai xenografts than non-treated DH82 transplants (p = 0.0081) at 63 dpt.	('dpt', 'Chemical', '-', (122, 125))	('DH82-CDVai', 'Chemical', '-', (47, 57))	('larger', 'PosReg', (37, 43))	('necrosis', 'Disease', (9, 17))	('DH82', 'Chemical', '-', (86, 90))	('necrosis', 'Disease', 'MESH:D009336', (9, 17))	('DH82-CDVai', 'Var', (47, 57))	('DH82', 'Chemical', '-', (47, 51))
112271	33808256	At 63 dpt, DH82-medium xenografts displayed significantly larger necrosis areas than non-treated DH82 neoplasms (p = 0.0082), whereas no significant differences were observed between the other control groups.	('necrosis', 'Disease', (65, 73))	('dpt', 'Chemical', '-', (6, 9))	('DH82', 'Chemical', '-', (11, 15))	('neoplasms', 'Phenotype', 'HP:0002664', (102, 111))	('neoplasm', 'Phenotype', 'HP:0002664', (102, 110))	('DH82', 'Chemical', '-', (97, 101))	('necrosis', 'Disease', 'MESH:D009336', (65, 73))	('DH82-medium', 'Chemical', '-', (11, 22))	('DH82-medium', 'Var', (11, 22))	('larger', 'PosReg', (58, 64))	('neoplasms', 'Disease', 'MESH:D009369', (102, 111))	('neoplasms', 'Disease', (102, 111))
112274	33808256	Morphometric analysis of DH82-CDVai xenografts exhibited a median positive area of 0.126% at 44 dpt (after 5x intratumoral infection with CDV), 0.227% at 54 dpt (after 10x intratumoral infection with CDV), and 0.121% at 63 dpt (10 days after last treatment).	('infection', 'Disease', (123, 132))	('infection', 'Disease', (185, 194))	('infection', 'Disease', 'MESH:D007239', (123, 132))	('dpt', 'Chemical', '-', (223, 226))	('infection', 'Disease', 'MESH:D007239', (185, 194))	('tumor', 'Disease', (115, 120))	('CDV', 'Species', '11232', (138, 141))	('DH82-CDVai', 'Chemical', '-', (25, 35))	('dpt', 'Chemical', '-', (157, 160))	('DH82-CDVai', 'Gene', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('CDV', 'Species', '11232', (200, 203))	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('CDV', 'Species', '11232', (30, 33))	('dpt', 'Chemical', '-', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('0.227%', 'Var', (144, 150))
112275	33808256	DH82-UV-CDVai xenografts exhibited a median positive area of 0.014% at 44 dpt (after 5x intratumoral injection with UV-inactivated CDV), 0.003% at 54 dpt (after 10x times intratumoral injection with UV-inactivated CDV), and 0.002% at 63 dpt (10 days after last intratumoral injection with UV-inactivated CDV).	('0.003%', 'Var', (137, 143))	('dpt', 'Chemical', '-', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('DH82-UV-CDVai', 'Chemical', '-', (0, 13))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', (93, 98))	('CDV', 'Species', '11232', (8, 11))	('CDV', 'Species', '11232', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('dpt', 'Chemical', '-', (150, 153))	('CDV', 'Species', '11232', (304, 307))	('dpt', 'Chemical', '-', (74, 77))	('tumor', 'Disease', (266, 271))	('CDV', 'Species', '11232', (214, 217))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
112278	33808256	In general, only small areas expressed cleaved caspase-3 in all groups, with the largest area (1.27%) present in DH82-CDVai at 44 dpt.	('DH82-CDVai', 'Chemical', '-', (113, 123))	('cleaved', 'MPA', (39, 46))	('caspase-3', 'Protein', (47, 56))	('DH82-CDVai', 'Var', (113, 123))	('dpt', 'Chemical', '-', (130, 133))
112279	33808256	However, DH82-CDVai xenografts displayed significantly larger cleaved caspase-3 antigen-positive areas at 44 dpt and 54 dpt than control groups of non-infected DH82, DH82-UV-CDVai and DH82-medium xenografts (p values ranging from 0.0081 to 0.0358), whereas no significant differences were observed between the different control groups.	('larger', 'PosReg', (55, 61))	('dpt', 'Chemical', '-', (120, 123))	('DH82-medium', 'Chemical', '-', (184, 195))	('infected', 'Disease', 'MESH:D007239', (151, 159))	('DH82-CDVai', 'Var', (9, 19))	('infected', 'Disease', (151, 159))	('cleaved caspase-3 antigen-positive areas', 'MPA', (62, 102))	('DH82', 'Chemical', '-', (184, 188))	('DH82', 'Chemical', '-', (9, 13))	('DH82-UV-CDVai', 'Chemical', '-', (166, 179))	('DH82', 'Chemical', '-', (160, 164))	('DH82', 'Chemical', '-', (166, 170))	('dpt', 'Chemical', '-', (109, 112))	('DH82-CDVai', 'Chemical', '-', (9, 19))
112283	33808256	Furthermore, there was an increase in the cleaved caspase-3 immunopositive area at 63 dpt in DH82-UV-CDVai xenografts compared to tumors at 54 dpt in this group (p = 0.0453).	('tumors', 'Disease', (130, 136))	('cleaved caspase-3 immunopositive area', 'MPA', (42, 79))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('dpt', 'Chemical', '-', (86, 89))	('DH82-UV-CDVai', 'Var', (93, 106))	('DH82-UV-CDVai', 'Chemical', '-', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('increase', 'PosReg', (26, 34))	('dpt', 'Chemical', '-', (143, 146))
112285	33808256	Summarized, the results revealed that, despite changes between individual groups, apoptosis was only present in a small area, while the area of necrotic cells differed markedly between tumors infected with CDV and controls.	('tumors infected', 'Disease', (185, 200))	('CDV', 'Species', '11232', (206, 209))	('CDV', 'Var', (206, 209))	('necrotic', 'Disease', 'MESH:D009336', (144, 152))	('tumors infected', 'Disease', 'MESH:D007239', (185, 200))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('necrotic', 'Disease', (144, 152))
112287	33808256	A mild to moderate infiltration with Mac3 expressing murine macrophages was evident in central tumor areas and around necrotic foci in DH82-CDVai and all control groups.	('murine', 'Species', '10090', (53, 59))	('DH82-CDVai', 'Var', (135, 145))	('Mac3', 'Gene', (37, 41))	('Mac3', 'Gene', '16784', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('necrotic foci', 'Disease', (118, 131))	('DH82-CDVai', 'Chemical', '-', (135, 145))	('necrotic foci', 'Disease', 'MESH:D009336', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
112288	33808256	Interestingly, DH82-CDVai xenografts exhibited a significantly larger Mac3 immunoreactive area at 44 dpt and 54 dpt than all control groups (p values ranging from 0.0051 to 0.0453; Figure 2D).	('larger', 'PosReg', (63, 69))	('Mac3', 'Gene', (70, 74))	('DH82-CDVai', 'Var', (15, 25))	('Mac3', 'Gene', '16784', (70, 74))	('dpt', 'Chemical', '-', (101, 104))	('DH82-CDVai', 'Chemical', '-', (15, 25))	('dpt', 'Chemical', '-', (112, 115))
112289	33808256	In addition, significantly larger Mac3 exhibiting areas were present in DH82-UV-CDVai than in non-treated controls at 44 dpt and 54 dpt (p = 0.0306).	('larger', 'PosReg', (27, 33))	('Mac3', 'Gene', '16784', (34, 38))	('dpt', 'Chemical', '-', (121, 124))	('DH82-UV-CDVai', 'Var', (72, 85))	('DH82-UV-CDVai', 'Chemical', '-', (72, 85))	('dpt', 'Chemical', '-', (132, 135))	('Mac3', 'Gene', (34, 38))
112292	33808256	Furthermore, a significant increase between 44 dpt and 54 dpt (p = 0.0306) or 63 dpt (p = 0.0306), respectively, was found in DH82-medium transplants.	('dpt', 'Chemical', '-', (58, 61))	('dpt', 'Chemical', '-', (47, 50))	('DH82-medium transplants', 'Var', (126, 149))	('dpt', 'Chemical', '-', (81, 84))	('DH82-medium', 'Chemical', '-', (126, 137))	('increase', 'PosReg', (27, 35))
112293	33808256	All neoplasms expressed MMP-2, MMP-9, MMP-14 and TIMP-1 independent of the infection state but displayed a variable distribution and intensity as demonstrated by immunohistochemistry (Figure 5, Figure 6, Figure 7 and Figure 8).	('MMP-9', 'Var', (31, 36))	('infection', 'Disease', 'MESH:D007239', (75, 84))	('neoplasms', 'Disease', 'MESH:D009369', (4, 13))	('neoplasms', 'Disease', (4, 13))	('TIMP-1', 'Gene', (49, 55))	('neoplasm', 'Phenotype', 'HP:0002664', (4, 12))	('MMP-14', 'Gene', (38, 44))	('neoplasms', 'Phenotype', 'HP:0002664', (4, 13))	('MMP-2', 'Var', (24, 29))	('infection', 'Disease', (75, 84))
112294	33808256	The only exceptions were present at 63 dpt, where MMP-2 in DH82-CDVai and MMP-14 in DH82-CDVai, and DH82-UV-CDVai lacked significant differences between the different localizations.	('DH82-CDVai', 'Var', (59, 69))	('DH82-CDVai', 'Var', (84, 94))	('DH82-UV-CDVai', 'Chemical', '-', (100, 113))	('DH82-CDVai', 'Chemical', '-', (59, 69))	('DH82-CDVai', 'Chemical', '-', (84, 94))	('MMP-14', 'Var', (74, 80))	('dpt', 'Chemical', '-', (39, 42))
112296	33808256	The MMP-2-positive area within the tumor periphery was at 54 dpt significantly larger in DH82-CDVai xenografts compared to untreated controls (p < 0.0001) and DH82-UV-CDVai tumors (p = 0.0005).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('DH82-CDVai', 'Chemical', '-', (89, 99))	('larger', 'PosReg', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('DH82-UV-CDVai', 'Chemical', '-', (159, 172))	('DH82-CDVai', 'Var', (89, 99))	('dpt', 'Chemical', '-', (61, 64))
112297	33808256	In addition, a significantly larger peripheral area expressing MMP-2 was noted at 63 dpt in DH82-UV-CDVai neoplasms compared to untreated controls (p = 0.0017) and DH82-medium xenografts (p = 0.0038).	('larger', 'PosReg', (29, 35))	('neoplasm', 'Phenotype', 'HP:0002664', (106, 114))	('neoplasms', 'Phenotype', 'HP:0002664', (106, 115))	('DH82-medium', 'Chemical', '-', (164, 175))	('dpt', 'Chemical', '-', (85, 88))	('neoplasms', 'Disease', 'MESH:D009369', (106, 115))	('DH82-UV-CDVai', 'Var', (92, 105))	('neoplasms', 'Disease', (106, 115))	('DH82-UV-CDVai', 'Chemical', '-', (92, 105))
112299	33808256	Similarly, DH82-medium xenografts comprised a smaller-sized MMP-2-positive area at 54 dpt (p = 0.0036) and 63 dpt (p < 0.0001) within the tumor periphery compared to 44 dpt.	('dpt', 'Chemical', '-', (86, 89))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('dpt', 'Chemical', '-', (110, 113))	('dpt', 'Chemical', '-', (169, 172))	('MMP-2-positive', 'Gene', (60, 74))	('smaller-sized', 'NegReg', (46, 59))	('DH82-medium', 'Chemical', '-', (11, 22))	('DH82-medium', 'Var', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
112301	33808256	The peripheral MMP-9 immunopositive area was significantly larger in DH82-CDVai xenografts than in all other groups at 44 dpt (p < 0.0001).	('dpt', 'Chemical', '-', (122, 125))	('DH82-CDVai xenografts', 'Var', (69, 90))	('larger', 'PosReg', (59, 65))	('DH82-CDVai', 'Chemical', '-', (69, 79))
112303	33808256	At this time point DH82-CDVai neoplasms exhibited a larger peripheral MMP-9 immunopositive area than DH82-UV-CDVai tumors (p = 0.0033) or DH82-medium xenografts (p < 0.0001).	('neoplasms', 'Disease', (30, 39))	('DH82-medium', 'Chemical', '-', (138, 149))	('UV-CDVai tumors', 'Disease', (106, 121))	('DH82-CDVai', 'Chemical', '-', (19, 29))	('neoplasm', 'Phenotype', 'HP:0002664', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('neoplasms', 'Phenotype', 'HP:0002664', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('UV-CDVai tumors', 'Disease', 'MESH:C563466', (106, 121))	('DH82-CDVai', 'Var', (19, 29))	('DH82-UV-CDVai', 'Chemical', '-', (101, 114))	('neoplasms', 'Disease', 'MESH:D009369', (30, 39))
112304	33808256	Furthermore, a significantly larger peripheral MMP-9 area was observed in DH82-medium tumors at 63 dpt compared to untreated control neoplasms (p = 0.0002).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('larger', 'PosReg', (29, 35))	('neoplasms', 'Phenotype', 'HP:0002664', (133, 142))	('tumors', 'Disease', (86, 92))	('DH82-medium', 'Chemical', '-', (74, 85))	('DH82-medium', 'Var', (74, 85))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('neoplasms', 'Disease', 'MESH:D009369', (133, 142))	('dpt', 'Chemical', '-', (99, 102))	('neoplasms', 'Disease', (133, 142))	('neoplasm', 'Phenotype', 'HP:0002664', (133, 141))
112307	33808256	The peripheral MMP-14 immunopositive area was significantly smaller in DH82-CDVai xenografts compared to all control groups at 63 dpt (p < 0.0001).	('DH82-CDVai', 'Chemical', '-', (71, 81))	('DH82-CDVai xenografts', 'Var', (71, 92))	('smaller', 'NegReg', (60, 67))	('dpt', 'Chemical', '-', (130, 133))
112310	33808256	In contrast, DH82-UV-CDVai and DH82-medium tumors developed a reduction of the peripheral MMP-14 immunopositive area from 44 dpt to 54 dpt (p = 0.0004 and p < 0.0001).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('DH82-UV-CDVai', 'Chemical', '-', (13, 26))	('dpt', 'Chemical', '-', (125, 128))	('dpt', 'Chemical', '-', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('DH82-medium', 'Chemical', '-', (31, 42))	('DH82-medium', 'Var', (31, 42))	('reduction', 'NegReg', (62, 71))	('DH82-UV-CDVai', 'Var', (13, 26))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
112314	33808256	At this time point, DH82-UV-CDVai neoplasms exhibited significantly larger peripheral TIMP-1 immunopositive areas than xenografts of all other groups (p < 0.0001).	('neoplasms', 'Disease', 'MESH:D009369', (34, 43))	('DH82-UV-CDVai', 'Var', (20, 33))	('neoplasms', 'Disease', (34, 43))	('DH82-UV-CDVai', 'Chemical', '-', (20, 33))	('neoplasm', 'Phenotype', 'HP:0002664', (34, 42))	('neoplasms', 'Phenotype', 'HP:0002664', (34, 43))	('larger', 'PosReg', (68, 74))
112315	33808256	At the last time point investigated (63 dpt), DH82-CDVai tumors revealed a significantly smaller peripheral TIMP-1 immunopositive area than DH82-medium xenografts (p < 0.0001).	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('DH82-CDVai', 'Var', (46, 56))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('DH82-medium', 'Chemical', '-', (140, 151))	('dpt', 'Chemical', '-', (40, 43))	('tumors', 'Disease', (57, 63))	('DH82-CDVai', 'Chemical', '-', (46, 56))	('peripheral TIMP-1 immunopositive area', 'MPA', (97, 134))	('smaller', 'NegReg', (89, 96))
112316	33808256	Furthermore, DH82-medium neoplasms displayed a smaller peripheral TIMP-1 immunopositive area than DH82-UV-CDVai (p < 0.0001) xenografts or untreated controls (p < 0.0001).	('neoplasms', 'Phenotype', 'HP:0002664', (25, 34))	('neoplasm', 'Phenotype', 'HP:0002664', (25, 33))	('smaller', 'NegReg', (47, 54))	('neoplasms', 'Disease', 'MESH:D009369', (25, 34))	('neoplasms', 'Disease', (25, 34))	('DH82-medium', 'Var', (13, 24))	('DH82-medium', 'Chemical', '-', (13, 24))	('peripheral TIMP-1 immunopositive area', 'MPA', (55, 92))	('DH82-UV-CDVai', 'Chemical', '-', (98, 111))
112317	33808256	Interestingly, DH82-CDVai, DH82-medium tumors and untreated controls showed a significant smaller peripheral TIMP-1 immunopositive area at 54 dpt (p < 0.0001) and 63 dpt (p < 0.0001) compared to 44 dpt.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('dpt', 'Chemical', '-', (142, 145))	('peripheral TIMP-1 immunopositive area', 'MPA', (98, 135))	('smaller', 'NegReg', (90, 97))	('DH82-CDVai', 'Var', (15, 25))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('dpt', 'Chemical', '-', (198, 201))	('dpt', 'Chemical', '-', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('DH82-CDVai', 'Chemical', '-', (15, 25))	('tumors', 'Disease', (39, 45))	('DH82-medium', 'Chemical', '-', (27, 38))
112318	33808256	In DH82-UV-CDVai xenografts, an increase in the peripheral TIMP-1 immunopositive area was observed from 44 dpt to 54 dpt (p = 0.0124), followed by a decrease from 54 dpt to 63 dpt (p < 0.0001).	('DH82-UV-CDVai', 'Var', (3, 16))	('dpt', 'Chemical', '-', (117, 120))	('increase', 'PosReg', (32, 40))	('DH82-UV-CDVai', 'Chemical', '-', (3, 16))	('dpt', 'Chemical', '-', (107, 110))	('dpt', 'Chemical', '-', (176, 179))	('dpt', 'Chemical', '-', (166, 169))
112320	33808256	Summarized, DH82-CDVai xenotransplants possessed a higher number of tumor-associated macrophages.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('DH82-CDVai', 'Var', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('higher', 'PosReg', (51, 57))	('DH82-CDVai', 'Chemical', '-', (12, 22))
112323	33808256	At 44 dpt, DH82-CDVai neoplasms exhibited a significantly higher number of vessels per area compared to DH82-UV-CDVai (p = 0.0303) and untreated controls (p = 0.0453).	('dpt', 'Chemical', '-', (6, 9))	('DH82-CDVai', 'Var', (11, 21))	('neoplasms', 'Phenotype', 'HP:0002664', (22, 31))	('DH82-CDVai', 'Chemical', '-', (11, 21))	('DH82-UV-CDVai', 'Chemical', '-', (104, 117))	('higher', 'PosReg', (58, 64))	('neoplasms', 'Disease', 'MESH:D009369', (22, 31))	('neoplasms', 'Disease', (22, 31))	('neoplasm', 'Phenotype', 'HP:0002664', (22, 30))
112324	33808256	At 63 dpt, a significantly lower microvessel density was present in DH82-CDVai xenografts compared to DH82-UV-CDVai (p = 0.0137) and untreated controls (p = 0.0080).	('DH82-UV-CDVai', 'Chemical', '-', (102, 115))	('dpt', 'Chemical', '-', (6, 9))	('DH82-CDVai', 'Chemical', '-', (68, 78))	('lower', 'NegReg', (27, 32))	('DH82-CDVai', 'Var', (68, 78))	('microvessel density', 'CPA', (33, 52))
112348	33808256	Furthermore, several studies demonstrated modulation of MMPs and their inhibitors in vitro and in spontaneously occurring canine CDV infections.	('modulation', 'Var', (42, 52))	('infections', 'Disease', 'MESH:D007239', (133, 143))	('MMPs', 'Protein', (56, 60))	('canine', 'Species', '9615', (122, 128))	('infections', 'Disease', (133, 143))	('CDV', 'Species', '11232', (129, 132))
112407	32658189	These fusions are often the sole recurring genomic aberration in the cancers they cause, making them attractive therapeutic targets.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('fusions', 'Var', (6, 13))	('cancers', 'Disease', (69, 76))
112412	32658189	We then use RNA-sequencing to analyze the transcriptomes of cells expressing these constructs to characterize the functional deficits associated with mutations in the EWS domain.	('EWS', 'Gene', (167, 170))	('mutations', 'Var', (150, 159))	('EWS', 'Gene', '2130', (167, 170))
112415	32658189	A subset of cancers, including many malignancies of childhood and adolescence, are characterized by chromosomal translocations which generate novel fusion oncogenes.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('malignancies', 'Disease', (36, 48))	('cancers', 'Disease', (12, 19))	('fusion oncogenes', 'MPA', (148, 164))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('malignancies', 'Disease', 'MESH:D009369', (36, 48))	('chromosomal', 'Var', (100, 111))
112416	32658189	The resulting fusion proteins frequently function as oncogenic transcription factors, orchestrating widespread changes in transcriptional regulation to promote tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('transcriptional regulation', 'MPA', (122, 148))	('fusion', 'Var', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('promote', 'PosReg', (152, 159))	('tumor', 'Disease', (160, 165))	('changes', 'Reg', (111, 118))
112417	32658189	Cancers with these translocations commonly possess an otherwise quiet mutational landscape, with few recurring genomic aberrations aside from the pathognomonic fusion.	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('translocations', 'Var', (19, 33))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancers', 'Disease', (0, 7))
112429	32658189	In this system EWS/FLI is depleted using an shRNA targeting the 3'UTR of the FLI1 gene, and expression is rescued with varying EWS/FLI mutant cDNA constructs lacking the 3'UTR.	('FLI', 'Gene', '2314', (19, 22))	('FLI', 'Gene', (77, 80))	('FLI', 'Gene', (19, 22))	('mutant', 'Var', (135, 141))	('expression', 'MPA', (92, 102))	('EWS', 'Gene', (15, 18))	('EWS', 'Gene', '2130', (15, 18))	('FLI', 'Gene', '2314', (131, 134))	('FLI1', 'Gene', (77, 81))	('FLI', 'Gene', '2314', (77, 80))	('FLI1', 'Gene', '2313', (77, 81))	('EWS', 'Gene', '2130', (127, 130))	('EWS', 'Gene', (127, 130))	('FLI', 'Gene', (131, 134))
112430	32658189	These experiments focused on constructs with various deletions to map the structure-function relationship between the EWS IDD and important oncogenic phenotypes, including activation of a GGAA-microsatellite reporter construct, colony formation assays, and targeted validation of EWS/FLI-activated and -repressed genes.	('FLI', 'Gene', (284, 287))	('deletions', 'Var', (53, 62))	('EWS', 'Gene', '2130', (118, 121))	('EWS', 'Gene', (118, 121))	('IDD', 'Disease', 'MESH:C535531', (122, 125))	('EWS', 'Gene', '2130', (280, 283))	('EWS', 'Gene', (280, 283))	('FLI', 'Gene', '2314', (284, 287))	('IDD', 'Disease', (122, 125))
112436	32658189	Successful implementation of this approach depends on the following: 1) A cell-based system that captures the phenotypes of interest (in this case A673 cells with shRNA-mediated EWS/FLI depletion), and 2) a panel of mutant constructs in an expression vector appropriate for the cell-based system (in this case, pMSCV-hygro with various 3X-FLAG-tagged EWS/FLI mutants to be delivered by retroviral transduction).	('S', 'Chemical', 'MESH:D013455', (313, 314))	('FLI', 'Gene', '2314', (182, 185))	('EWS', 'Gene', '2130', (351, 354))	('EWS', 'Gene', (351, 354))	('mutant', 'Var', (216, 222))	('FLI', 'Gene', '2314', (355, 358))	('S', 'Chemical', 'MESH:D013455', (180, 181))	('FLI', 'Gene', (182, 185))	('mutants', 'Var', (359, 366))	('EWS', 'Gene', '2130', (178, 181))	('EWS', 'Gene', (178, 181))	('FLI', 'Gene', (355, 358))	('S', 'Chemical', 'MESH:D013455', (353, 354))	('S', 'Chemical', 'MESH:D013455', (0, 1))
112437	32658189	In this paper, we apply this approach to characterize the activity of the DAF mutant of EWS/FLI.	('FLI', 'Gene', '2314', (92, 95))	('DAF', 'Gene', '1604', (74, 77))	('DAF', 'Gene', (74, 77))	('FLI', 'Gene', (92, 95))	('EWS', 'Gene', '2130', (88, 91))	('EWS', 'Gene', (88, 91))	('mutant', 'Var', (78, 84))
112438	32658189	The DAF mutant has 17 tyrosine to alanine mutations in the repetitive regions of the EWS IDD of EWS/FLI.	('EWS', 'Gene', '2130', (96, 99))	('EWS', 'Gene', (96, 99))	('IDD', 'Disease', 'MESH:C535531', (89, 92))	('17 tyrosine to alanine', 'Mutation', 'p.Y17A', (19, 41))	('FLI', 'Gene', '2314', (100, 103))	('DAF', 'Gene', '1604', (4, 7))	('DAF', 'Gene', (4, 7))	('FLI', 'Gene', (100, 103))	('tyrosine to alanine mutations', 'Var', (22, 51))	('EWS', 'Gene', (85, 88))	('IDD', 'Disease', (89, 92))	('EWS', 'Gene', '2130', (85, 88))
112439	32658189	This particular EWS mutant had been previously reported and is unable to activate reporter gene expression when fused to the ATF1 DBD.	('EWS', 'Gene', '2130', (16, 19))	('EWS', 'Gene', (16, 19))	('ATF1', 'Gene', (125, 129))	('ATF1', 'Gene', '466', (125, 129))	('mutant', 'Var', (20, 26))
112441	32658189	The transcriptomic approach described here enabled successful detection of partial function of the DAF mutant.	('mutant', 'Var', (103, 109))	('DAF', 'Gene', '1604', (99, 102))	('DAF', 'Gene', (99, 102))
112442	32658189	By pairing these transcriptomic data with information about EWS/FLI binding and recognition motifs we further show that the DAF mutant retains function at GGAA-microsatellite repeats.	('FLI', 'Gene', '2314', (64, 67))	('function', 'MPA', (143, 151))	('FLI', 'Gene', (64, 67))	('EWS', 'Gene', '2130', (60, 63))	('EWS', 'Gene', (60, 63))	('mutant', 'Var', (128, 134))	('DAF', 'Gene', '1604', (124, 127))	('DAF', 'Gene', (124, 127))
112443	32658189	These results identify DAF as the first partially functional EWS/FLI mutant and highlight function at non-microsatellite genes as important for oncogenesis (as reported).	('DAF', 'Gene', '1604', (23, 26))	('mutant', 'Var', (69, 75))	('DAF', 'Gene', (23, 26))	('FLI', 'Gene', '2314', (65, 68))	('FLI', 'Gene', (65, 68))	('EWS', 'Gene', '2130', (61, 64))	('EWS', 'Gene', (61, 64))
112455	32658189	Remove HEK293-EBNA growth media from tissue culture dishes and add 3 mL DMEM supplemented with 10% FBS, P/S/Q, and 10 mM sodium pyruvate.	('sodium pyruvate', 'Chemical', '-', (121, 136))	('add 3', 'Gene', '120', (63, 68))	('HEK293-EBNA', 'Var', (7, 18))	('DMEM', 'Chemical', '-', (72, 76))	('S', 'Chemical', 'MESH:D013455', (101, 102))	('HEK293', 'CellLine', 'CVCL:0045', (7, 13))	('add 3', 'Gene', (63, 68))	('mL', 'Gene', '21832', (69, 71))	('P', 'Chemical', 'MESH:D010758', (104, 105))	('S', 'Chemical', 'MESH:D013455', (106, 107))	('Q', 'Chemical', 'MESH:D005973', (108, 109))
112497	32658189	Select for poly-adenylated RNAs and strand-specific sequencing.	('strand-specific sequencing', 'Var', (36, 62))	('poly-adenylated', 'Var', (11, 26))	('S', 'Chemical', 'MESH:D013455', (0, 1))
112564	32658189	Preliminary qRT-PCR data suggested that an EWS/FLI mutant called DAF, with specific tyrosine to alanine mutations in the repetitive and disordered region of EWS, maintained the ability to activate EWS/FLI target genes, but failed to repress critical target genes.	('FLI', 'Gene', '2314', (47, 50))	('activate', 'PosReg', (188, 196))	('alanine', 'Chemical', 'MESH:D000409', (96, 103))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('FLI', 'Gene', (47, 50))	('tyrosine to alanine mutations', 'Var', (84, 113))	('EWS', 'Gene', (197, 200))	('EWS', 'Gene', '2130', (197, 200))	('tyrosine', 'Chemical', 'MESH:D014443', (84, 92))	('DAF', 'Gene', '1604', (65, 68))	('EWS', 'Gene', (43, 46))	('DAF', 'Gene', (65, 68))	('FLI', 'Gene', '2314', (201, 204))	('FLI', 'Gene', (201, 204))	('EWS', 'Gene', '2130', (43, 46))	('EWS', 'Gene', '2130', (157, 160))	('EWS', 'Gene', (157, 160))	('P', 'Chemical', 'MESH:D010758', (16, 17))
112567	32658189	After four days of selection, EWS/FLI function was rescued with viral transduction of different 3XFLAG-tagged EWS/FLI mutant constructs, with empty vector as a control for no rescue.	('EWS', 'Gene', '2130', (110, 113))	('EWS', 'Gene', (110, 113))	('FLI', 'Gene', '2314', (34, 37))	('EWS', 'Gene', '2130', (30, 33))	('EWS', 'Gene', (30, 33))	('FLI', 'Gene', (34, 37))	('mutant', 'Var', (118, 124))	('FLI', 'Gene', '2314', (114, 117))	('FLI', 'Gene', (114, 117))
112570	32658189	Four replicates were collected and representative qRT-PCR and western blots showing effective knockdown and rescue are shown in Figure 2B-D.	('rescue', 'CPA', (108, 114))	('knockdown', 'Var', (94, 103))	('P', 'Chemical', 'MESH:D010758', (54, 55))
112577	32658189	Following batch normalization, DESeq2 was used to generate transcriptional profiles for the three constructs (wtEF, Delta22, and DAF) relative to the baseline.	('DAF', 'Gene', '1604', (129, 132))	('DAF', 'Gene', (129, 132))	('S', 'Chemical', 'MESH:D013455', (33, 34))	('Delta22', 'Mutation', 'c.del22', (116, 123))	('Delta22', 'Var', (116, 123))
112584	32658189	Interestingly, the function of activated genes rescued by wtEF, but not by DAF, appear to be related to transcriptional control and chromatin regulation.	('wtEF', 'Var', (58, 62))	('DAF', 'Gene', (75, 78))	('rescued', 'PosReg', (47, 54))	('function', 'MPA', (19, 27))	('DAF', 'Gene', '1604', (75, 78))
112594	32658189	These data also suggest that the specific tyrosines mutated in DAF play important, but poorly understood, roles in EWS/FLI-mediated gene regulation from HA sites, as well as in gene repression, highlighting an important area of further investigation.	('tyrosines mutated', 'Var', (42, 59))	('FLI', 'Gene', (119, 122))	('tyrosines', 'Chemical', 'MESH:D014443', (42, 51))	('EWS', 'Gene', '2130', (115, 118))	('EWS', 'Gene', (115, 118))	('DAF', 'Gene', '1604', (63, 66))	('DAF', 'Gene', (63, 66))	('FLI', 'Gene', '2314', (119, 122))
112596	32658189	This is especially true in malignancies characterized by chromosomal translocations resulting in fusion transcription factors.	('malignancies', 'Disease', (27, 39))	('fusion transcription factors', 'Protein', (97, 125))	('malignancies', 'Disease', 'MESH:D009369', (27, 39))	('chromosomal translocations', 'Var', (57, 83))
112601	32658189	In the specific case of the DAF mutant of EWS/FLI, DAF was reported to show little activity in reporter assays using isolated response elements, but to show activity in the context of the full gene promoter, either in a reporter assay or in native chromatin, suggesting an interesting phenotype.	('FLI', 'Gene', (46, 49))	('DAF', 'Gene', (28, 31))	('mutant', 'Var', (32, 38))	('DAF', 'Gene', '1604', (28, 31))	('DAF', 'Gene', '1604', (51, 54))	('DAF', 'Gene', (51, 54))	('FLI', 'Gene', '2314', (46, 49))	('activity', 'MPA', (157, 165))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
112602	32658189	Many cell lines derived from malignancies with pathognomonic transcription factors do not readily tolerate knockdown of that transcription factor, and in many instances, particularly for pediatric cancers, the true cell of origin remains controversial and the expression of the oncogene in other cell backgrounds is prohibitively toxic.	('knockdown', 'Var', (107, 116))	('malignancies', 'Disease', (29, 41))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Disease', (197, 204))	('malignancies', 'Disease', 'MESH:D009369', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
112682	29152166	Docetaxel + gemcitabine, followed by doxorubicin and pazopanib, were the top three regimens in LOT1, and docetaxel + gemcitabine was the first line regimen in 47% of patients who received pazopanib as LOT2 and 58% of patients who received doxorubicin as LOT2.	('pazopanib', 'Chemical', 'MESH:C516667', (188, 197))	('gemcitabine', 'Chemical', 'MESH:C056507', (117, 128))	('doxorubicin', 'Chemical', 'MESH:D004317', (239, 250))	('doxorubicin', 'Chemical', 'MESH:D004317', (37, 48))	('LOT1', 'Gene', '5325', (95, 99))	('pazopanib', 'Var', (188, 197))	('Docetaxel', 'Chemical', 'MESH:D000077143', (0, 9))	('gemcitabine', 'Chemical', 'MESH:C056507', (12, 23))	('patients', 'Species', '9606', (217, 225))	('LOT1', 'Gene', (95, 99))	('docetaxel', 'Chemical', 'MESH:D000077143', (105, 114))	('patients', 'Species', '9606', (166, 174))	('pazopanib', 'Chemical', 'MESH:C516667', (53, 62))
112692	29152166	Compared to other regimens used in mSTS, pazopanib may be preferred by patients due to its oral route of administration.	('STS', 'Phenotype', 'HP:0030448', (36, 39))	('mSTS', 'Gene', (35, 39))	('patients', 'Species', '9606', (71, 79))	('mSTS', 'Gene', '20905', (35, 39))	('pazopanib', 'Chemical', 'MESH:C516667', (41, 50))	('pazopanib', 'Var', (41, 50))
112990	23085431	Alternatively, new analogs of ET-743 such as Zalipsys  and PM001183 are currently entering the clinic and may provide more potent or less toxic inhibition of EWS-FLI1 due to differences in effects on DNA damage pathways.	('ET-743', 'Gene', (30, 36))	('PM001183', 'Var', (59, 67))	('PM001183', 'Chemical', '-', (59, 67))	('effects', 'Reg', (189, 196))	('DNA damage pathways', 'Pathway', (200, 219))	('ET-743', 'Chemical', 'MESH:D000077606', (30, 36))	('EWS-FLI1', 'Gene', (158, 166))	('inhibition', 'NegReg', (144, 154))	('Zalipsys', 'Chemical', '-', (45, 53))
112995	23085431	This relationship approximated the statistical significance of the known relationship between imatinib and nilotinib and BCR-ABL as well as PLX4720 and SB590885 and mutation of BRAF.	('BCR-ABL', 'Gene', (121, 128))	('BCR-ABL', 'Gene', '25', (121, 128))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('imatinib', 'Chemical', 'MESH:D000068877', (94, 102))	('mutation', 'Var', (165, 173))	('nilotinib', 'Chemical', 'MESH:C498826', (107, 116))
112999	23085431	In addition, EWS-FLI1 gene transfer experiments seemed to increase the sensitivity to olaparib, an effect that was recapitulated in the other manuscript.	('increase', 'PosReg', (58, 66))	('sensitivity to olaparib', 'MPA', (71, 94))	('EWS-FLI1', 'Gene', (13, 21))	('olaparib', 'Chemical', 'MESH:C531550', (86, 94))	('gene transfer', 'Var', (22, 35))
113003	23085431	This increased PARP activity led to the demonstration that inhibition of PARP with chemical tool compounds sensitized ES cells to ionizing radiation (IR).	('activity', 'MPA', (20, 28))	('ES', 'Phenotype', 'HP:0012254', (118, 120))	('PARP', 'Gene', '142', (15, 19))	('sensitized', 'Reg', (107, 117))	('ionizing radiation', 'MPA', (130, 148))	('PARP', 'Gene', (73, 77))	('increased', 'PosReg', (5, 14))	('inhibition', 'Var', (59, 69))	('PARP', 'Gene', '142', (73, 77))	('PARP', 'Gene', (15, 19))
113005	23085431	However, it was shown that in A4573 Ewing sarcoma cells, PARP expression was driven by the FLI1 family member ETS1 and EWS-FLI1 actually suppressed PARP promoter activity and caused a minimal decrease in PARP expression.	('EWS-FLI1', 'Var', (119, 127))	('PARP', 'Gene', '142', (148, 152))	('decrease', 'NegReg', (192, 200))	('PARP', 'Gene', (57, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('suppressed', 'NegReg', (137, 147))	('PARP', 'Gene', '142', (204, 208))	('ETS1', 'Gene', '2113', (110, 114))	('ETS1', 'Gene', (110, 114))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('PARP', 'Gene', '142', (57, 61))	('PARP', 'Gene', (148, 152))	('PARP', 'Gene', (204, 208))
113006	23085431	In addition, this report showed that silencing ETS1 with an antisense DNA, decreased PARP expression and was associated with resistance to the DNA damaging agent etoposide, while the suppression of EWS-FLI1 caused a minor increase in PARP that nonetheless sensitized cells to etoposide, presumably by interfering with other DNA damage pathways.	('resistance', 'MPA', (125, 135))	('associated', 'Reg', (109, 119))	('EWS-FLI1', 'Gene', (198, 206))	('ETS1', 'Gene', (47, 51))	('PARP', 'Gene', (85, 89))	('ETS1', 'Gene', '2113', (47, 51))	('etoposide', 'Chemical', 'MESH:D005047', (276, 285))	('etoposide', 'Chemical', 'MESH:D005047', (162, 171))	('suppression', 'NegReg', (183, 194))	('silencing', 'Var', (37, 46))	('PARP', 'Gene', (234, 238))	('PARP', 'Gene', '142', (234, 238))	('interfering', 'NegReg', (301, 312))	('increase', 'PosReg', (222, 230))	('PARP', 'Gene', '142', (85, 89))	('sensitized', 'Reg', (256, 266))	('decreased', 'NegReg', (75, 84))
113029	23085431	It is known that downstream blockade of mTOR leads to feedback activation of AKT via the IGF receptor originally described in myeloma and rhabdomyosarcoma.	('IGF receptor', 'Gene', (89, 101))	('AKT', 'Gene', '207', (77, 80))	('myeloma and rhabdomyosarcoma', 'Disease', 'MESH:D012208', (126, 154))	('mTOR', 'Gene', (40, 44))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (138, 154))	('mTOR', 'Gene', '2475', (40, 44))	('blockade', 'Var', (28, 36))	('AKT', 'Gene', (77, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('activation', 'PosReg', (63, 73))
113035	23085431	Other important investigations have shown a wide range of IGF receptor expression that predicts response in rhabdomyosarcoma perhaps detectable with imaging methods.	('IGF receptor', 'Protein', (58, 70))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (108, 124))	('expression', 'Var', (71, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (108, 124))	('response', 'Disease', (96, 104))	('rhabdomyosarcoma', 'Disease', (108, 124))
113047	23085431	Disruption of HDAC1 with the HDAC inhibitor trichostatin A (TSA) restored the competency of this pathway, potentially providing the basis for combination therapies involving cytotoxic agents and TSA.	('HDAC', 'Gene', (14, 18))	('TSA', 'Chemical', 'MESH:C012589', (60, 63))	('competency', 'MPA', (78, 88))	('HDAC', 'Gene', '9734', (14, 18))	('TSA', 'Chemical', 'MESH:C012589', (195, 198))	('restored', 'PosReg', (65, 73))	('HDAC', 'Gene', (29, 33))	('HDAC1', 'Gene', (14, 19))	('trichostatin A', 'Chemical', 'MESH:C012589', (44, 58))	('HDAC', 'Gene', '9734', (29, 33))	('HDAC1', 'Gene', '3065', (14, 19))	('Disruption', 'Var', (0, 10))
113049	23085431	These results mirrored an earlier finding that showed that expression of EWS-FLI1 in mesenchymal stem cells upregulates EZH2 and triggers a transcriptional program that is similar to Ewing tumors.	('Ewing tumors', 'Phenotype', 'HP:0012254', (183, 195))	('EZH2', 'Gene', (120, 124))	('Ewing tumors', 'Disease', (183, 195))	('transcriptional program', 'MPA', (140, 163))	('triggers', 'Reg', (129, 137))	('EZH2', 'Gene', '2146', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('Ewing tumors', 'Disease', 'MESH:C563168', (183, 195))	('expression', 'Var', (59, 69))	('upregulates', 'PosReg', (108, 119))	('EWS-FLI1', 'Gene', (73, 81))
113147	28692601	Recurrent BRAF Gene Rearrangements in Myxoinflammatory Fibroblastic Sarcomas, but Not Hemosiderotic Fibrolipomatous Tumors Myxoinflammatory fibroblastic sarcoma (MIFS) is a low grade soft tissue sarcoma with a predilection for acral sites, being associated with a high rate of local recurrence but very infrequent distant metastases.	('sarcoma', 'Disease', (195, 202))	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('Rearrangements', 'Var', (20, 34))	('Myxoinflammatory Fibroblastic Sarcomas', 'Disease', 'MESH:D012509', (38, 76))	('Tumors', 'Phenotype', 'HP:0002664', (116, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('sarcoma', 'Disease', (153, 160))	('Hemosiderotic Fibrolipomatous Tumors', 'Disease', (86, 122))	('Sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('metastases', 'Disease', (322, 332))	('Myxoinflammatory Fibroblastic Sarcomas', 'Disease', (38, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('Hemosiderotic Fibrolipomatous Tumors', 'Disease', 'MESH:C565226', (86, 122))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('metastases', 'Disease', 'MESH:D009362', (322, 332))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (183, 202))
113151	28692601	There were 6 (32%) additional MIFS with BRAF genetic abnormalities, including 5 gene rearrangements and one showing BRAF amplification.	('BRAF', 'Gene', '673', (40, 44))	('genetic abnormalities', 'Disease', 'MESH:D030342', (45, 66))	('BRAF', 'Gene', (40, 44))	('BRAF', 'Gene', '673', (116, 120))	('BRAF', 'Gene', (116, 120))	('genetic abnormalities', 'Disease', (45, 66))	('gene rearrangements', 'Var', (80, 99))
113154	28692601	The 7 BRAF-rearranged/amplified MIFS arose in the fingers (n=3), and 1 each in wrist, forearm, foot, and knee, of adult patients (36-74 years; M:F=4:3).	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', (6, 10))	('MIFS', 'Var', (32, 36))	('patients', 'Species', '9606', (120, 128))
113177	28692601	In addition, 7 cases of MIFS harboring TGFBR3 and/or MGEA5 gene rearrangements were collected for morphologic comparison as well as to confirm that MGEA5 and TGFBR3 rearrangements are mutually exclusive to BRAF-gene abnormalities.	('MGEA5', 'Gene', (148, 153))	('TGFBR3', 'Gene', (158, 164))	('TGFBR3', 'Gene', '7049', (39, 45))	('BRAF-gene abnormalities', 'Disease', 'MESH:D025063', (206, 229))	('rearrangements', 'Var', (165, 179))	('BRAF-gene abnormalities', 'Disease', (206, 229))	('MGEA5', 'Gene', '10724', (53, 58))	('MGEA5', 'Gene', (53, 58))	('TGFBR3', 'Gene', '7049', (158, 164))	('TGFBR3', 'Gene', (39, 45))	('MGEA5', 'Gene', '10724', (148, 153))	('rearrangements', 'Var', (64, 78))
113178	28692601	Six of MIFS showed TGFBR3-MGEA5 fusions, while the remaining case had only TGFBR3 rearrangement.	('fusions', 'Var', (32, 39))	('TGFBR3', 'Gene', '7049', (19, 25))	('TGFBR3', 'Gene', '7049', (75, 81))	('MGEA5', 'Gene', '10724', (26, 31))	('MGEA5', 'Gene', (26, 31))	('TGFBR3', 'Gene', (19, 25))	('TGFBR3', 'Gene', (75, 81))
113186	28692601	FISH for BRAF rearrangements were performed for validation in the index case and screening in the following screening and control cohorts.	('rearrangements', 'Var', (14, 28))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (9, 13))
113187	28692601	Cases positive for BRAF rearrangements, were subsequently tested for TOM1L2 rearrangements.	('rearrangements', 'Var', (24, 38))	('BRAF', 'Gene', '673', (19, 23))	('positive', 'Reg', (6, 14))	('BRAF', 'Gene', (19, 23))	('TOM1L2', 'Gene', '146691', (69, 75))	('TOM1L2', 'Gene', (69, 75))
113199	28692601	Targeted RNAseq identified a novel inter-chromosomal TOM1L2-BRAF fusion candidate in the index case, which was further confirmed by RT-PCR showing exon 11 of TOM1L2 (17p11.2) fused to exon 9 of BRAF (7q34) (Fig.	('TOM1L2', 'Gene', '146691', (53, 59))	('BRAF', 'Gene', '673', (194, 198))	('TOM1L2', 'Gene', (53, 59))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', (194, 198))	('TOM1L2', 'Gene', (158, 164))	('BRAF', 'Gene', '673', (60, 64))	('TOM1L2', 'Gene', '146691', (158, 164))	('fusion', 'Var', (65, 71))
113204	28692601	In the subsequent screening cohort, FISH identified 5 additional MIFS with BRAF rearrangements among 19 TGFBR3/MGEA5-negative MIFS, indicating that BRAF rearrangement is a recurrent event in MIFS.	('MGEA5', 'Gene', (111, 116))	('TGFBR3', 'Gene', (104, 110))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('rearrangements', 'Var', (80, 94))	('BRAF', 'Gene', '673', (148, 152))	('TGFBR3', 'Gene', '7049', (104, 110))	('MGEA5', 'Gene', '10724', (111, 116))	('BRAF', 'Gene', (148, 152))
113205	28692601	BRAF rearrangements often showed unbalanced patterns with telomeric (5') deletion or inversions.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('telomeric', 'Var', (58, 67))	('rearrangements', 'Var', (5, 19))
113211	28692601	VGLL3 amplifications were found in 4 of 6 BRAF-rearranged cases, including the index case (Table 1).	('BRAF', 'Gene', '673', (42, 46))	('amplifications', 'Var', (6, 20))	('VGLL3', 'Gene', '389136', (0, 5))	('found', 'Reg', (26, 31))	('BRAF', 'Gene', (42, 46))	('VGLL3', 'Gene', (0, 5))
113215	28692601	VGLL3 amplifications were also identified in 4 of 7 MIFS with t(1;10) and 6 of 13 MIFS lacking both BRAF and t(1;10) fusions.	('identified', 'Reg', (31, 41))	('amplifications', 'Var', (6, 20))	('VGLL3', 'Gene', '389136', (0, 5))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (100, 104))	('VGLL3', 'Gene', (0, 5))
113216	28692601	Overall, VGLL3 amplifications were present in 52% (14/27) of MIFS tested, with equal distribution among different MIFS subsets.	('amplifications', 'Var', (15, 29))	('VGLL3', 'Gene', (9, 14))	('present', 'Reg', (35, 42))	('VGLL3', 'Gene', '389136', (9, 14))	('MIFS', 'Disease', (61, 65))
113217	28692601	All cases with VGLL3 amplifications were located in acral regions, except one MIFS from the lower leg lacking both fusions.	('VGLL3', 'Gene', (15, 20))	('VGLL3', 'Gene', '389136', (15, 20))	('lower leg', 'Phenotype', 'HP:0006385', (92, 101))	('amplifications', 'Var', (21, 35))
113221	28692601	The clinicopathologic features of the 7 MIFS with BRAF rearrangements or amplifications are summarized in Table 1.	('rearrangements', 'Var', (55, 69))	('BRAF', 'Gene', (50, 54))	('BRAF', 'Gene', '673', (50, 54))
113242	28692601	In this study, we describe a group of 6 MIFS with recurrent BRAF gene rearrangements which occurred in 22% of pure MIFS.	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('rearrangements', 'Var', (70, 84))
113248	28692601	After a single case report of a hybrid MIFS-HFLT harboring t(1;10) by cytogenetics, our group identified MGEA5 and TGFBR3 rearrangements by FISH not only in 5 of 7 (71%) pure MIFS, but also in 12 of 14 (86%) HFLT and 3 cases with mixed MIFS/HFLT histology.	('MGEA5', 'Gene', '10724', (105, 110))	('TGFBR3', 'Gene', (115, 121))	('MGEA5', 'Gene', (105, 110))	('TGFBR3', 'Gene', '7049', (115, 121))	('rearrangements', 'Var', (122, 136))
113249	28692601	In the present study, among the total cohort of 27 pure MIFS using very strict morphologic criteria, 7 (26%) cases had TGFBR3 and/or MGEA5 rearrangements (6, both genes; 1, TGFBR3 only), 7 (26%) cases had BRAF alterations (6, rearrangements; 1, amplification), and 13 (48%) cases were negative for TGFBR3, MGEA5 and BRAF gene rearrangements.	('rearrangements', 'Var', (226, 240))	('BRAF', 'Gene', (316, 320))	('TGFBR3', 'Gene', (298, 304))	('BRAF', 'Gene', (205, 209))	('MGEA5', 'Gene', '10724', (306, 311))	('MGEA5', 'Gene', '10724', (133, 138))	('MGEA5', 'Gene', (306, 311))	('MGEA5', 'Gene', (133, 138))	('TGFBR3', 'Gene', '7049', (119, 125))	('rearrangements', 'Var', (139, 153))	('TGFBR3', 'Gene', '7049', (298, 304))	('TGFBR3', 'Gene', '7049', (173, 179))	('TGFBR3', 'Gene', (173, 179))	('BRAF', 'Gene', '673', (316, 320))	('BRAF', 'Gene', '673', (205, 209))	('alterations', 'Reg', (210, 221))	('TGFBR3', 'Gene', (119, 125))
113251	28692601	Our data also show that BRAF rearrangements/amplifications were restricted to pure MIFS, and were not found in TGFBR3-MGEA5 fusion negative HFLTs.	('MGEA5', 'Gene', '10724', (118, 123))	('MGEA5', 'Gene', (118, 123))	('TGFBR3', 'Gene', (111, 117))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('TGFBR3', 'Gene', '7049', (111, 117))	('rearrangements/amplifications', 'Var', (29, 58))
113252	28692601	Unlike TGFBR3 and MGEA5 rearrangements which do not form a fusion transcript, BRAF rearrangements resulted in an in-frame fusion transcript which was detected by RNAseq and RT-PCR in our index case.	('TGFBR3', 'Gene', (7, 13))	('rearrangements', 'Var', (83, 97))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', (78, 82))	('resulted in', 'Reg', (98, 109))	('TGFBR3', 'Gene', '7049', (7, 13))	('MGEA5', 'Gene', '10724', (18, 23))	('MGEA5', 'Gene', (18, 23))
113254	28692601	MIFS with BRAF alterations were more common in the upper than the lower extremities (5 upper, 2 lower), while MIFS with TGFBR3 and/or MGEA5 rearrangements involved lower extremities more often (2 upper, 5 lower).	('rearrangements', 'Var', (140, 154))	('TGFBR3', 'Gene', '7049', (120, 126))	('alterations', 'Var', (15, 26))	('common', 'Reg', (37, 43))	('MGEA5', 'Gene', '10724', (134, 139))	('BRAF', 'Gene', (10, 14))	('MGEA5', 'Gene', (134, 139))	('BRAF', 'Gene', '673', (10, 14))	('TGFBR3', 'Gene', (120, 126))
113255	28692601	MIFS with BRAF alterations often displayed tumor cells with vesicular chromatin, prominent nucleoli, and Reed-Sternberg-like cells in varying amount.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('alterations', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('displayed', 'Reg', (33, 42))	('tumor', 'Disease', (43, 48))
113256	28692601	In contrast, MIFS with TGFBR3 and/or MGEA5 rearrangements had more variable chromatin patterns ranging from vesicular, fine, to hyperchromatic and Reed-Sternberg-like cells were more difficult to find (identified only in 3/7 cases).	('MGEA5', 'Gene', '10724', (37, 42))	('hyperchromatic', 'Disease', (128, 142))	('vesicular', 'MPA', (108, 117))	('fine', 'MPA', (119, 123))	('MGEA5', 'Gene', (37, 42))	('TGFBR3', 'Gene', '7049', (23, 29))	('chromatin patterns', 'MPA', (76, 94))	('TGFBR3', 'Gene', (23, 29))	('hyperchromatic', 'Disease', 'None', (128, 142))	('rearrangements', 'Var', (43, 57))
113257	28692601	In addition to morphologically typical areas, 2 MIFS with TGFBR3/MEGA5 alterations also showed elongated spindle cells arranged in fascicles, which were not seen in cases with BRAF alterations.	('TGFBR3', 'Gene', (58, 64))	('alterations', 'Var', (71, 82))	('elongated spindle cells arranged', 'CPA', (95, 127))	('TGFBR3', 'Gene', '7049', (58, 64))	('BRAF', 'Gene', (176, 180))	('BRAF', 'Gene', '673', (176, 180))
113258	28692601	Also of note VGLL3 gene amplifications were identified with the same frequency (4 of 7) in both MIFS cohorts, regardless of the TGFBR3-MGEA5 and BRAF alterations.	('TGFBR3', 'Gene', '7049', (128, 134))	('MGEA5', 'Gene', (135, 140))	('BRAF', 'Gene', (145, 149))	('amplifications', 'Var', (24, 38))	('VGLL3', 'Gene', '389136', (13, 18))	('TGFBR3', 'Gene', (128, 134))	('VGLL3', 'Gene', (13, 18))	('BRAF', 'Gene', '673', (145, 149))	('MGEA5', 'Gene', '10724', (135, 140))
113260	28692601	BRAF gene fusions have been identified as the driver genetic events in several different tumor types, including the majority of pilocytic astrocytomas, a subset of pancreatic acinar cell carcinomas, and smaller proportions of papillary thyroid carcinomas, spitzoid melanocytic neoplasms, rare cases of Langerhans cell histiocytosis, prostate cancer, gastric cancer, lung cancer, etc.	('neoplasm', 'Phenotype', 'HP:0002664', (277, 285))	('Langerhans cell histiocytosis', 'Disease', (302, 331))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (265, 286))	('BRAF', 'Gene', '673', (0, 4))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (128, 150))	('gastric cancer', 'Disease', 'MESH:D013274', (350, 364))	('astrocytoma', 'Phenotype', 'HP:0009592', (138, 149))	('lung cancer', 'Disease', 'MESH:D008175', (366, 377))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('BRAF', 'Gene', (0, 4))	('papillary thyroid carcinomas', 'Disease', (226, 254))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (226, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (366, 377))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('prostate cancer', 'Disease', 'MESH:D011471', (333, 348))	('gastric cancer', 'Phenotype', 'HP:0012126', (350, 364))	('tumor', 'Disease', (89, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('prostate cancer', 'Phenotype', 'HP:0012125', (333, 348))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (236, 254))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (226, 254))	('prostate cancer', 'Disease', (333, 348))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('pancreatic acinar cell carcinomas', 'Disease', (164, 197))	('histiocytosis', 'Phenotype', 'HP:0100727', (318, 331))	('fusions', 'Var', (10, 17))	('spitzoid melanocytic neoplasms', 'Disease', 'MESH:D009508', (256, 286))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('spitzoid melanocytic neoplasms', 'Disease', (256, 286))	('lung cancer', 'Disease', (366, 377))	('neoplasms', 'Phenotype', 'HP:0002664', (277, 286))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('pilocytic astrocytomas', 'Disease', (128, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('Langerhans cell histiocytosis', 'Disease', 'MESH:C538636', (302, 331))	('gastric cancer', 'Disease', (350, 364))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('pancreatic acinar cell carcinomas', 'Disease', 'MESH:D010190', (164, 197))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
113263	28692601	Similar to BRAF fusions in other tumors, the chimeric protein in our index case is predicted to lose the N-terminal autoinhibitory domain (encoded by exons 1-8) of wild type BRAF, and retain the C-terminal kinase domain (exons 11-18).	('lose', 'NegReg', (96, 100))	('N-terminal autoinhibitory domain', 'MPA', (105, 137))	('C-terminal kinase domain', 'MPA', (195, 219))	('BRAF', 'Gene', '673', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('BRAF', 'Gene', (174, 178))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('chimeric', 'Var', (45, 53))	('tumors', 'Disease', (33, 39))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
113265	28692601	BRAF fusions involve a wide range of different 5' fusion partners, resulting from either inter- or intra-chromosomal fusions.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('fusions', 'Var', (5, 12))
113269	28692601	Tumors with BRAF fusions, including pilocytic astrocytomas and melanomas, have shown evidence of clinical sensitivity to RAF or MEK inhibitors, based on in vitro experiments and few clinical reports.	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('astrocytoma', 'Phenotype', 'HP:0009592', (46, 57))	('RAF', 'Gene', '22882', (121, 124))	('RAF', 'Gene', (121, 124))	('MEK', 'Gene', (128, 131))	('MEK', 'Gene', '5609', (128, 131))	('Tumors', 'Disease', (0, 6))	('pilocytic astrocytomas', 'Disease', (36, 58))	('melanomas', 'Disease', (63, 72))	('fusions', 'Var', (17, 24))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('RAF', 'Gene', '22882', (13, 16))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (36, 58))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('RAF', 'Gene', (13, 16))
113270	28692601	The identification of BRAF fusions in MIFS may also offer new potential therapeutic options for clinically protracted cases.	('fusions', 'Var', (27, 34))	('BRAF', 'Gene', (22, 26))	('BRAF', 'Gene', '673', (22, 26))	('MIFS', 'Gene', (38, 42))
113271	28692601	In pilocytic astrocytoma with BRAF fusions, the slow growing and low-grade nature of the tumor has been attributed to oncogene-induced senescence (OIS).	('astrocytoma', 'Phenotype', 'HP:0009592', (13, 24))	('pilocytic astrocytoma', 'Disease', (3, 24))	('slow growing', 'CPA', (48, 60))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (3, 24))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('fusions', 'Var', (35, 42))
113273	28692601	Unlike activating mutations and fusions, the role of BRAF amplification as an oncogenic event is less defined.	('BRAF', 'Gene', (53, 57))	('amplification', 'Var', (58, 71))	('BRAF', 'Gene', '673', (53, 57))
113274	28692601	BRAF gene amplifications have been described in rare spitzoid melanocytic neoplasms: one desmoplastic Spitz nevus and one atypical Spitz tumor.	('neoplasm', 'Phenotype', 'HP:0002664', (74, 82))	('tumor', 'Disease', (137, 142))	('desmoplastic Spitz nevus', 'Disease', 'MESH:D018332', (89, 113))	('described', 'Reg', (35, 44))	('desmoplastic Spitz nevus', 'Disease', (89, 113))	('neoplasms', 'Phenotype', 'HP:0002664', (74, 83))	('nevus', 'Phenotype', 'HP:0003764', (108, 113))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (62, 83))	('BRAF', 'Gene', '673', (0, 4))	('amplifications', 'Var', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('BRAF', 'Gene', (0, 4))	('spitzoid melanocytic neoplasms', 'Disease', (53, 83))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('spitzoid melanocytic neoplasms', 'Disease', 'MESH:D009508', (53, 83))
113275	28692601	In an early report of MIFS, 2 cases were found to have chromosome 7 gains by comparative genomic hybridization, but the involved different regions (7q31q32 in one case; 7p15p21 in the other) did not encompass the BRAF locus (7q34).	('p21', 'Gene', (173, 176))	('BRAF', 'Gene', (213, 217))	('BRAF', 'Gene', '673', (213, 217))	('p21', 'Gene', '644914', (173, 176))	('7q31q32', 'Var', (148, 155))	('gains', 'PosReg', (68, 73))	('chromosome', 'Gene', (55, 65))
113276	28692601	Further investigations are needed to elucidate if BRAF amplification is a recurrent event in MIFS and is associated with any clinicopathologic features.	('amplification', 'Var', (55, 68))	('BRAF', 'Gene', (50, 54))	('BRAF', 'Gene', '673', (50, 54))	('MIFS', 'Disease', (93, 97))
113277	28692601	In this study, MIFS with BRAF fusions showed pERK immunoreactivity, indicating activated downstream MAPK signaling pathway, as in other tumors with BRAF fusions or activating mutations.	('ERK', 'Gene', '5594', (46, 49))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('MAPK signaling pathway', 'Pathway', (100, 122))	('ERK', 'Gene', (46, 49))	('fusions', 'Var', (30, 37))	('BRAF', 'Gene', '673', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('activated', 'PosReg', (79, 88))	('BRAF', 'Gene', (25, 29))	('BRAF', 'Gene', '673', (148, 152))	('BRAF', 'Gene', (148, 152))
113278	28692601	Notably, pERK immunostain was also positive in tumors with TGFBR3-MGEA5 fusions, including MIFS, HFLT, and hybrid HFLT-MIFS.	('MGEA5', 'Gene', (66, 71))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('hybrid', 'Var', (107, 113))	('TGFBR3', 'Gene', (59, 65))	('positive', 'Reg', (35, 43))	('TGFBR3', 'Gene', '7049', (59, 65))	('ERK', 'Gene', '5594', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('HFLT', 'Disease', (97, 101))	('fusions', 'Var', (72, 79))	('MGEA5', 'Gene', '10724', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('MIFS', 'Disease', (91, 95))	('ERK', 'Gene', (10, 13))	('HFLT-MIFS', 'CellLine', 'CVCL:BT03', (114, 123))
113279	28692601	MAPK pathway activation may be a common event shared by MIFS with BRAF fusions and those with TGFBR3-MGEA5 fusions.	('MGEA5', 'Gene', (101, 106))	('fusions', 'Var', (71, 78))	('TGFBR3', 'Gene', (94, 100))	('activation', 'PosReg', (13, 23))	('BRAF', 'Gene', '673', (66, 70))	('MAPK pathway', 'Pathway', (0, 12))	('BRAF', 'Gene', (66, 70))	('TGFBR3', 'Gene', '7049', (94, 100))	('MGEA5', 'Gene', '10724', (101, 106))
113280	28692601	This is of particular interest given MAPK signaling pathway is also known to be activated by FGF8, which is usually up-regulated in tumors with TGFBR3-MGEA5 rearrangements.	('rearrangements', 'Var', (157, 171))	('MGEA5', 'Gene', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('FGF8', 'Gene', (93, 97))	('TGFBR3', 'Gene', '7049', (144, 150))	('MAPK signaling pathway', 'Pathway', (37, 59))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('FGF8', 'Gene', '2253', (93, 97))	('MGEA5', 'Gene', '10724', (151, 156))	('tumors', 'Disease', (132, 138))	('up-regulated', 'PosReg', (116, 128))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('activated', 'PosReg', (80, 89))	('TGFBR3', 'Gene', (144, 150))
113282	28692601	Another common feature between MIFS with BRAF rearrangements and TGFBR3-MGEA5 rearrangements is the amplification and subsequent up-regulation of VGLL3 gene.	('MGEA5', 'Gene', (72, 77))	('VGLL3', 'Gene', (146, 151))	('TGFBR3', 'Gene', (65, 71))	('BRAF', 'Gene', '673', (41, 45))	('up-regulation', 'PosReg', (129, 142))	('amplification', 'MPA', (100, 113))	('VGLL3', 'Gene', '389136', (146, 151))	('BRAF', 'Gene', (41, 45))	('TGFBR3', 'Gene', '7049', (65, 71))	('MGEA5', 'Gene', '10724', (72, 77))	('rearrangements', 'Var', (46, 60))
113284	28692601	In addition to MIFS and HFLT, VGLL3 amplifications have also been reported in dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma, presumed to be a genetic event occurring during tumor progression.	('liposarcoma', 'Disease', (95, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('VGLL3', 'Gene', '389136', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (111, 147))	('reported', 'Reg', (66, 74))	('liposarcoma', 'Disease', 'MESH:D008080', (95, 106))	('undifferentiated pleomorphic sarcoma', 'Disease', (111, 147))	('amplifications', 'Var', (36, 50))	('VGLL3', 'Gene', (30, 35))	('liposarcoma', 'Phenotype', 'HP:0012034', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
113285	28692601	However, MIFS with VGLL3 amplifications showed no significant prognostic difference.	('amplifications', 'Var', (25, 39))	('VGLL3', 'Gene', '389136', (19, 24))	('VGLL3', 'Gene', (19, 24))
113286	28692601	Of note the VGLL3 amplification detected in our index case with BRAF fusion was associated with VGLL3 mRNA overexpression.	('VGLL3', 'Gene', '389136', (12, 17))	('VGLL3', 'Gene', (96, 101))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (64, 68))	('VGLL3', 'Gene', (12, 17))	('associated', 'Reg', (80, 90))	('VGLL3', 'Gene', '389136', (96, 101))	('overexpression', 'PosReg', (107, 121))	('amplification', 'Var', (18, 31))
113288	28692601	The presence of BRAF fusions in MIFS but not in HFLT or hybrid HFLT-MIFS seems to support the hypothesis that at least some pure MIFS are unrelated to HFLT.	('BRAF', 'Gene', (16, 20))	('HFLT-MIFS', 'CellLine', 'CVCL:BT03', (63, 72))	('BRAF', 'Gene', '673', (16, 20))	('fusions', 'Var', (21, 28))
113290	28692601	In addition, both tumor types share the accompanying VGLL3 amplifications in a subset of cases.	('tumor', 'Disease', (18, 23))	('VGLL3', 'Gene', (53, 58))	('amplifications', 'Var', (59, 73))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('VGLL3', 'Gene', '389136', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
113291	28692601	Further studies are needed to clarify whether the functional role of BRAF fusions in MIFS is equivalent to that of TGFBR3-MGEA5 fusions.	('MIFS', 'Disease', (85, 89))	('MGEA5', 'Gene', '10724', (122, 127))	('TGFBR3', 'Gene', (115, 121))	('fusions', 'Var', (74, 81))	('MGEA5', 'Gene', (122, 127))	('BRAF', 'Gene', '673', (69, 73))	('TGFBR3', 'Gene', '7049', (115, 121))	('BRAF', 'Gene', (69, 73))
113292	28692601	In conclusion, we describe BRAF rearrangements as novel and recurrent gene abnormalities occurring in 22% of pure MIFS showing classic clinicopathologic features, but not in other related lesions, such as HFLT or mixed HFLT-MIFS.	('HFLT-MIFS', 'CellLine', 'CVCL:BT03', (219, 228))	('rearrangements', 'Var', (32, 46))	('BRAF', 'Gene', (27, 31))	('BRAF', 'Gene', '673', (27, 31))
113296	27941796	Mutations in the genes encoding BAF subunits contribute to over 20% of human malignancy, yet the underlying mechanisms remain unclear owing largely to a lack of assays to assess BAF function in vivo.	('malignancy', 'Disease', (77, 87))	('human', 'Disease', (71, 76))	('Mutations', 'Var', (0, 9))	('malignancy', 'Disease', 'MESH:D009369', (77, 87))	('BAF', 'Gene', (32, 35))	('contribute', 'Reg', (45, 55))	('human', 'Species', '9606', (71, 76))
113298	27941796	Further, we find that tumor suppressor and oncogenic BAF complex mutations result in differential effects on PRC eviction.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PRC eviction', 'Disease', (109, 121))	('tumor', 'Disease', (22, 27))	('BAF complex', 'Gene', (53, 64))	('effects', 'Reg', (98, 105))	('mutations', 'Var', (65, 74))
113303	27941796	Subunits of the mammalian mSWI/SNF or BAF (for Brg/Brm associated factor) complexes are mutated in over 20% of all human cancers and a large number of human neurologic diseases.	('cancers', 'Disease', (121, 128))	('Brg/Brm associated factor', 'Gene', '8815', (47, 72))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('neurologic diseases', 'Disease', 'MESH:D019636', (157, 176))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (151, 156))	('neurologic diseases', 'Disease', (157, 176))	('mammalian', 'Species', '9606', (16, 25))	('human', 'Species', '9606', (115, 120))	('mutated', 'Var', (88, 95))	('SNF', 'Gene', '31442', (31, 34))	('Brg/Brm associated factor', 'Gene', (47, 72))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('SNF', 'Gene', (31, 34))
113306	27941796	The BAF subunit mutations in human cancer have a striking pattern of tissue specificity.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutations', 'Var', (16, 25))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('BAF subunit', 'Gene', (4, 15))	('human', 'Species', '9606', (29, 34))	('cancer', 'Disease', (35, 41))
113308	27941796	Malignant rhabdoid tumors (MRTs) are uniformly produced by deletions or loss-of-function mutations in BAF47 (hSNF5), but this subunit is less frequently involved in other human cancers.	('BAF47', 'Gene', '6598', (102, 107))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('hSNF5', 'Gene', '6598', (109, 114))	('BAF47', 'Gene', (102, 107))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('deletions', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('hSNF5', 'Gene', (109, 114))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('loss-of-function', 'NegReg', (72, 88))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('human', 'Species', '9606', (171, 176))
113309	27941796	In human MRTs, loss of BAF47 leads to polycomb-mediated repression of genes that suppress proliferation, such as INK4A and reexpression of BAF47 leads to removal of polycomb and loss of DNA methylation by an unknown mechanism(s) .	('polycomb', 'Protein', (165, 173))	('removal', 'NegReg', (154, 161))	('polycomb-mediated', 'MPA', (38, 55))	('BAF47', 'Gene', (23, 28))	('human', 'Species', '9606', (3, 8))	('loss', 'Var', (15, 19))	('INK4A', 'Gene', '1029', (113, 118))	('BAF47', 'Gene', '6598', (139, 144))	('repression', 'NegReg', (56, 66))	('BAF47', 'Gene', '6598', (23, 28))	('INK4A', 'Gene', (113, 118))	('DNA methylation', 'MPA', (186, 201))	('BAF47', 'Gene', (139, 144))	('loss', 'NegReg', (178, 182))
113315	27941796	To analyze the resolution of heterochromatin by BAF we developed the CiAO mouse (Chromatin Assay at and Indicator at Oct4) by modifying one Oct4 allele with two different arrays of transcription factor bindings sites upstream of the transcription initiation site (Fig.	('modifying', 'Var', (126, 135))	('mouse', 'Species', '10090', (74, 79))	('Oct4', 'Gene', (140, 144))
113316	27941796	The Oct4 allele containing the insertions is active in pluripotent cells and germ cells derived from the CIAO mouse, but intensely repressed in fibroblasts by polycomb group marks such as H3K27me3 as well as H3K9me3 (Fig.	('H3K9me3', 'Var', (208, 215))	('Oct4', 'Gene', (4, 8))	('mouse', 'Species', '10090', (110, 115))	('H3K27me3', 'Var', (188, 196))	('insertions', 'Var', (31, 41))
113318	27941796	We used the CIP (Chemical Inducer of Proximity), rapamycin, to induce proximity of proteins at the modified Oct4 allele by virtue of its ability to bind one protein tag (Frb) on one side and another tag (FKBP) on the other side of the molecule (Fig.	('bind', 'Interaction', (148, 152))	('rapamycin', 'Chemical', 'MESH:D020123', (49, 58))	('proteins', 'Protein', (83, 91))	('modified', 'Var', (99, 107))	('Oct4', 'Gene', (108, 112))
113328	27941796	Mutations of the Drosophila BAP (dSWI/SNF) ATPase, Brm, entirely suppresses the effects of PRC1 mutations on body plan morphogenesis, attesting to their functional dedication.	('SNF', 'Gene', (38, 41))	('BAP', 'Gene', (28, 31))	('dSWI', 'Gene', (33, 37))	('body plan morphogenesis', 'CPA', (109, 132))	('Drosophila', 'Species', '7227', (17, 27))	('Mutations', 'Var', (0, 9))	('SNF', 'Gene', '31442', (38, 41))	('BAP', 'Gene', '11331', (28, 31))	('suppresses', 'NegReg', (65, 75))	('PRC1', 'Gene', (91, 95))	('mutations', 'Var', (96, 105))	('dSWI', 'Gene', '31120', (33, 37))
113332	27941796	In flies, PRC1 (the pc1 or CBX6 subunit) mutants are repressed effectively by mutations in the ATPase Brm.	('mutants', 'Var', (41, 48))	('pc1', 'Gene', (20, 23))	('PRC1', 'Gene', (10, 14))	('pc1', 'Gene', '5167', (20, 23))	('mutations', 'Var', (78, 87))	('CBX6', 'Gene', '23466', (27, 31))	('CBX6', 'Gene', (27, 31))	('ATPase Brm', 'Gene', (95, 105))
113344	27941796	This was achieved using FK1012, a dimeric competitive inhibitor of rapamycin which binds only to the FKBP side and rapidly competes away rapamycin (Fig.	('rapamycin', 'Chemical', 'MESH:D020123', (67, 76))	('rapamycin', 'Chemical', 'MESH:D020123', (137, 146))	('rapamycin', 'MPA', (137, 146))	('FK1012', 'Var', (24, 30))	('competes away', 'NegReg', (123, 136))	('FK1012', 'Chemical', 'MESH:C084260', (24, 30))
113345	27941796	In comparing the kinetics of rapamycin washout (via media change) versus addition of FK1012, we determined that FK1012 resulted in more rapid, robust decreases in BAF complex tethering to the Oct4 locus (Fig.	('rapamycin', 'Chemical', 'MESH:D020123', (29, 38))	('BAF complex tethering', 'CPA', (163, 184))	('FK1012', 'Var', (112, 118))	('FK1012', 'Chemical', 'MESH:C084260', (112, 118))	('decreases', 'NegReg', (150, 159))	('FK1012', 'Chemical', 'MESH:C084260', (85, 91))
113346	27941796	We found that addition of FK1012 lead to the removal of BAF complexes within t=15'<t<30' minutes (Fig.	('BAF', 'Protein', (56, 59))	('FK1012', 'Chemical', 'MESH:C084260', (26, 32))	('removal', 'NegReg', (45, 52))	('FK1012', 'Var', (26, 32))
113348	27941796	We found that PRC2 (Ezh2) and PRC1 (Ring1b) began to reappear within ~2 hours post-addition of FK1012 and that this was paralleled by the reappearance of H3K27me3 and H2Aub1.	('PRC2', 'Gene', (14, 18))	('H3K27me3', 'Protein', (154, 162))	('FK1012', 'Var', (95, 101))	('Ezh2', 'Gene', (20, 24))	('Ezh2', 'Gene', '2146', (20, 24))	('Ring1b', 'Gene', '6045', (36, 42))	('FK1012', 'Chemical', 'MESH:C084260', (95, 101))	('Ring1b', 'Gene', (36, 42))
113351	27941796	Thus, we directly recruited Brg1 by fusing the Frb tag on the C-terminus of the protein.	('Frb', 'Protein', (47, 50))	('Brg1', 'Gene', (28, 32))	('Brg1', 'Gene', '6597', (28, 32))	('fusing', 'Var', (36, 42))
113353	27941796	However, we did find that the Brg1 fusion gave about a 4- to 8-fold increase in occupancy of Baf155 at the recruitment site, as compared to SS18 fusion (40- to 60-fold).	('Baf155', 'Gene', '6599', (93, 99))	('Baf155', 'Gene', (93, 99))	('SS18', 'Gene', '6760', (140, 144))	('Brg1', 'Gene', (30, 34))	('SS18', 'Gene', (140, 144))	('increase', 'PosReg', (68, 76))	('fusion', 'Var', (35, 41))	('occupancy', 'MPA', (80, 89))	('Brg1', 'Gene', '6597', (30, 34))
113355	27941796	Recruitment of this mutant Brg1 protein to the Oct4 locus of MEF (Fig.	('Recruitment', 'Reg', (0, 11))	('MEF', 'Gene', (61, 64))	('MEF', 'Gene', '2000', (61, 64))	('protein', 'Protein', (32, 39))	('Brg1', 'Gene', (27, 31))	('Brg1', 'Gene', '6597', (27, 31))	('mutant', 'Var', (20, 26))
113360	27941796	To this end, we recruited BAF complexes with highly specific, driving subunit mutations, which define specific cancer subtypes to polycomb-repressed chromatin.	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (78, 87))
113364	27941796	Intriguingly however, BAF47-lacking complexes exhibited significantly decreased ability to displace Ezh2 (PRC2 complexes), Ring1b (PRC1 complexes) and the H3K27me3 mark at the Zinc-finger binding domain, as compared to wild-type complexes (Fig.	('Ring1b', 'Gene', (123, 129))	('displace', 'MPA', (91, 99))	('decreased', 'NegReg', (70, 79))	('Ezh2', 'Gene', (100, 104))	('BAF47', 'Gene', '6598', (22, 27))	('Ezh2', 'Gene', '2146', (100, 104))	('H3K27me3', 'Var', (155, 163))	('BAF47', 'Gene', (22, 27))	('Ring1b', 'Gene', '6045', (123, 129))
113368	27941796	To perform these studies, we developed Frb-V5-SS18-SSX fusions to be directly compared with our measurements using Frb-V5-SS18 (wild-type) (Fig.	('SSX', 'Gene', '727837', (51, 54))	('SS18', 'Gene', '6760', (122, 126))	('SS18', 'Gene', (46, 50))	('SS18', 'Gene', (122, 126))	('SS18', 'Gene', '6760', (46, 50))	('SSX', 'Gene', (51, 54))	('fusions', 'Var', (55, 62))
113370	27941796	Notably, as compared to WT SS18 containing BAF complexes, SS18-SSX BAF complexes displayed a dramatically extended domain of BAF occupancy, spreading 2620+-456bp (CI=95%) into the Oct4 gene body as compared to WT SS18 (920+-305bp (CI=95%)), likely reflecting gained multimerization or processivity of complexes (Fig.	('spreading', 'PosReg', (140, 149))	('SSX', 'Gene', '727837', (63, 66))	('SS18', 'Gene', '6760', (213, 217))	('SS18', 'Gene', '6760', (27, 31))	('2620+-456bp', 'Var', (150, 161))	('SS18', 'Gene', '6760', (58, 62))	('SS18', 'Gene', (27, 31))	('SSX', 'Gene', (63, 66))	('SS18', 'Gene', (213, 217))	('SS18', 'Gene', (58, 62))
113374	27941796	4d,h) at +1034 bp and +2287 bp sites from the ZFHD1 recruitment site, while WT SS18 complexes were unable to achieve these effects outside of the ZFHD1+-500bp region of the recruitment site.	('SS18', 'Gene', '6760', (79, 83))	('SS18', 'Gene', (79, 83))	('ZFHD1', 'Gene', (46, 51))	('+2287 bp', 'Var', (22, 30))
113375	27941796	These kinetic results explain the robust removal of PRC2 and H3K27me3 over the entire SOX2 gene in synovial sarcoma.	('synovial sarcoma', 'Disease', (99, 115))	('removal', 'NegReg', (41, 48))	('SOX2', 'Gene', '6657', (86, 90))	('SOX2', 'Gene', (86, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('H3K27me3', 'Var', (61, 69))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (99, 115))	('synovial sarcoma', 'Disease', 'MESH:D013584', (99, 115))
113376	27941796	The ATPase activity of Brg1 is required for eviction, suggesting the specificity of the process and pointing toward possible mechanisms for ATPase-dead mutations in human cancers.	('human', 'Species', '9606', (165, 170))	('mutations', 'Var', (152, 161))	('Brg1', 'Gene', (23, 27))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('Brg1', 'Gene', '6597', (23, 27))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
113379	27941796	For example, switching the subunit composition to the neural specific nBAF complex in human fibroblasts converts them to a basal neuronal state that can be biased with specific transcription factors to produce types of neurons that have never been produced in culture from either ES cells or fibroblasts.	('human', 'Species', '9606', (86, 91))	('converts', 'Reg', (104, 112))	('switching', 'Var', (13, 22))
113384	27941796	Our direct in vivo recruitment studies indicate that the role of the SS18-SSX fusion is to produce a complex that propagates along the chromosome to occupy a larger region than is normally occupied by BAF over the Sox2 gene in cells in which it is inactive.	('fusion', 'Var', (78, 84))	('Sox2', 'Gene', '6657', (214, 218))	('SSX', 'Gene', (74, 77))	('SSX', 'Gene', '727837', (74, 77))	('SS18', 'Gene', '6760', (69, 73))	('Sox2', 'Gene', (214, 218))	('SS18', 'Gene', (69, 73))
113387	27941796	Our studies also indicate that the loss of the BAF47 (hSNF5) tumor suppressor subunit, in malignant rhabdoid tumors, leads to substantially diminished eviction (Fig.	('BAF47', 'Gene', (47, 52))	('hSNF5', 'Gene', '6598', (54, 59))	('diminished', 'NegReg', (140, 150))	('loss', 'Var', (35, 39))	('malignant rhabdoid tumors', 'Disease', (90, 115))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('eviction', 'MPA', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('hSNF5', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('BAF47', 'Gene', '6598', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (109, 114))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (90, 115))
113389	27941796	Thus, our studies provide an explanation for both the tumor suppressor (BAF47 deletion in MRT) and oncogenic (SS18-SSX fusion in synovial sarcoma) functions of BAF complexes.	('SSX', 'Gene', (115, 118))	('synovial sarcoma', 'Disease', (129, 145))	('SSX', 'Gene', '727837', (115, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('deletion', 'Var', (78, 86))	('MRT', 'Gene', (90, 93))	('BAF47', 'Gene', (72, 77))	('BAF47', 'Gene', '6598', (72, 77))	('SS18', 'Gene', '6760', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (129, 145))	('synovial sarcoma', 'Disease', 'MESH:D013584', (129, 145))	('tumor', 'Disease', (54, 59))	('SS18', 'Gene', (110, 114))
113390	27941796	Recent exome sequencing studies have revealed striking frequencies of mutations in both BAF and polycomb subunits in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (70, 79))	('human', 'Species', '9606', (117, 122))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('BAF', 'Protein', (88, 91))	('cancers', 'Disease', (123, 130))	('polycomb subunits', 'Protein', (96, 113))
113391	27941796	Where studied, mutations in subunits of BAF complexes lead to altered polycomb domains over the genome that have essential functions in either oncogenesis or pluripotency.	('altered', 'Reg', (62, 69))	('oncogenesis or pluripotency', 'Disease', 'MESH:D063646', (143, 170))	('BAF complexes', 'Gene', (40, 53))	('mutations', 'Var', (15, 24))	('polycomb domains over the', 'MPA', (70, 95))	('oncogenesis or pluripotency', 'Disease', (143, 170))
113446	27927247	The third time period was designated as "late HAART" (2009-2013) when HAART access was expanded to include patients with CD4 cell count >200 cells/microl but <=350 cells/microl or had WHO stage III or IV disease regardless of CD4 cell count.	('CD4', 'Gene', (226, 229))	('CD4', 'Gene', (121, 124))	('CD4', 'Gene', '920', (226, 229))	('IV disease regardless', 'Disease', (201, 222))	('CD4', 'Gene', '920', (121, 124))	('IV disease regardless', 'Disease', 'MESH:D020432', (201, 222))	('>200 cells/microl', 'Var', (136, 153))	('patients', 'Species', '9606', (107, 115))	('stage III', 'Disease', (188, 197))
113530	27927247	Though geohelminths are not AIDS-defining opportunistic infections, previous studies show that co-infection with geohelminths was associated with dysregulation of the immune response causing inability of the HIV positive patient to mount an effective immune response.	('inability of the HIV', 'Disease', (191, 211))	('inability of the HIV', 'Disease', 'MESH:D016388', (191, 211))	('co-infection', 'Var', (95, 107))	('geohelminths', 'Gene', (113, 125))	('immune response', 'CPA', (167, 182))	('AIDS-defining opportunistic infections', 'Disease', (28, 66))	('AIDS-defining opportunistic infections', 'Disease', 'MESH:D017088', (28, 66))	('dysregulation', 'Gene', (146, 159))	('patient', 'Species', '9606', (221, 228))	('opportunistic infections', 'Phenotype', 'HP:0031690', (42, 66))	('opportunistic infection', 'Phenotype', 'HP:0031690', (42, 65))	('associated', 'Reg', (130, 140))
113532	27927247	Geohelminths have also been associated with diarrhea, nutritional impairment, abdominal pain and in children they can lead to impaired cognitive and physical development.	('lead to', 'Reg', (118, 125))	('children', 'Species', '9606', (100, 108))	('men', 'Species', '9606', (165, 168))	('Geohelminths', 'Var', (0, 12))	('impaired cognitive', 'Disease', 'MESH:D003072', (126, 144))	('nutritional impairment', 'Disease', 'MESH:D009748', (54, 76))	('abdominal pain', 'Disease', (78, 92))	('associated', 'Reg', (28, 38))	('abdominal pain', 'Phenotype', 'HP:0002027', (78, 92))	('men', 'Species', '9606', (72, 75))	('abdominal pain', 'Disease', 'MESH:D015746', (78, 92))	('pain', 'Phenotype', 'HP:0012531', (88, 92))	('diarrhea', 'Disease', (44, 52))	('nutritional impairment', 'Disease', (54, 76))	('diarrhea', 'Phenotype', 'HP:0002014', (44, 52))	('diarrhea', 'Disease', 'MESH:D003967', (44, 52))	('impaired cognitive', 'Disease', (126, 144))
113544	27927247	A related study in Ethiopia also found higher prevalence of S. stercoralis among HIV-positive patients with CD4 count <200 cells/microl.	('patients', 'Species', '9606', (94, 102))	('S. stercoralis', 'Disease', (60, 74))	('HIV-positive', 'Disease', (81, 93))	('CD4', 'Gene', (108, 111))	('CD4', 'Gene', '920', (108, 111))	('HIV-positive', 'Disease', 'MESH:D015658', (81, 93))	('<200', 'Var', (118, 122))	('S. stercoralis', 'Species', '6248', (60, 74))
113555	27927247	Additionally, improvements in OI diagnosis like introduction of the lateral flow cryptococcal Antigen (CrAg) rapid tests for Cryptococcal meningitis and Gene Xpert for TB over time may have had an impact on prevalence of these OIs.	('Gene Xpert', 'Var', (153, 163))	('men', 'Species', '9606', (138, 141))	('Cryptococcal meningitis', 'Disease', 'MESH:D016919', (125, 148))	('Cryptococcal meningitis', 'Disease', (125, 148))	('Cryptococcal meningitis', 'Phenotype', 'HP:0032160', (125, 148))	('OIs', 'Phenotype', 'HP:0031690', (227, 230))	('CrAg', 'Gene', (103, 107))	('meningitis', 'Phenotype', 'HP:0001287', (138, 148))	('men', 'Species', '9606', (21, 24))
113589	26831502	The pathogenesis of MCD remains poorly understood, however infection of immunoblasts with HHV-8 appears to trigger an intense immune response and marked production of host-derived IL-6.	('HHV-8', 'Gene', (90, 95))	('IL-6', 'Gene', (180, 184))	('HHV-8', 'Species', '37296', (90, 95))	('MCD', 'Disease', 'MESH:D012514', (20, 23))	('IL-6', 'Gene', '3569', (180, 184))	('MCD', 'Disease', (20, 23))	('infection', 'Var', (59, 68))	('immune response', 'MPA', (126, 141))	('production', 'MPA', (153, 163))
113592	26831502	Kaposi sarcoma herpesvirus-inflammatory cytokine syndrome (KICS) has recently been described which can occur in the setting of HHV-8 and elevated IL-6 in the absence of the histological finding of MCD.	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('IL-6', 'Gene', '3569', (146, 150))	('elevated IL-6', 'Phenotype', 'HP:0030783', (137, 150))	('HHV-8', 'Var', (127, 132))	('Kaposi sarcoma herpesvirus', 'Disease', (0, 26))	('Kaposi sarcoma herpesvirus', 'Disease', 'MESH:D012514', (0, 26))	('elevated', 'PosReg', (137, 145))	('cytokine syndrome', 'Phenotype', 'HP:0031407', (40, 57))	('MCD', 'Disease', 'MESH:D012514', (197, 200))	('HHV-8', 'Species', '37296', (127, 132))	('IL-6', 'Gene', (146, 150))	('MCD', 'Disease', (197, 200))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (0, 14))
113690	26831502	Blockade of IL-6 has also shown some promise in achieving clinical and laboratory normalisation.	('Blockade', 'Var', (0, 8))	('IL-6', 'Gene', '3569', (12, 16))	('IL-6', 'Gene', (12, 16))
113785	31534554	Results: ATF4 significantly inhibited OS tumorigenesis, whereas knockdown of ATF4 prevented the antitumor effects of BTZ.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ATF4', 'Gene', (9, 13))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (100, 105))	('ATF4', 'Gene', (77, 81))	('OS', 'Phenotype', 'HP:0002669', (38, 40))	('inhibited', 'NegReg', (28, 37))	('BTZ', 'Chemical', 'MESH:D000069286', (117, 120))	('knockdown', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
113788	31534554	Loss of RET upregulated ATF4 and potentiated the apoptotic response to BTZ.	('BTZ', 'Chemical', 'MESH:D000069286', (71, 74))	('RET', 'Gene', '5979', (8, 11))	('potentiated', 'PosReg', (33, 44))	('apoptotic response', 'CPA', (49, 67))	('RET', 'Gene', (8, 11))	('Loss', 'Var', (0, 4))	('ATF4', 'Protein', (24, 28))	('upregulated', 'PosReg', (12, 23))
113800	31534554	Abrogating BTZ-induced upregulation of GRP78 was showed to strengthen the effect of ATF4 in OS.	('Abrogating', 'Var', (0, 10))	('upregulation', 'PosReg', (23, 35))	('BTZ', 'Chemical', 'MESH:D000069286', (11, 14))	('GRP78', 'Gene', (39, 44))	('OS', 'Phenotype', 'HP:0002669', (92, 94))	('GRP78', 'Gene', '3309', (39, 44))
113802	31534554	Recent advancements point to a role for ATF4 mutations in mediating drug resistance in tumor cells featured by xCT overexpression.	('drug resistance', 'Phenotype', 'HP:0020174', (68, 83))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ATF4', 'Gene', (40, 44))	('tumor', 'Disease', (87, 92))	('drug resistance', 'MPA', (68, 83))	('xCT', 'Gene', (111, 114))	('mediating', 'Reg', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('expression', 'Species', '29278', (119, 129))	('xCT', 'Gene', '23657', (111, 114))
113807	31534554	Activation of RET occurs via oncogenic mutations in multiple sporadic carcinomas, most notably those of the thyroid and lungs.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('RET', 'Gene', '5979', (14, 17))	('carcinomas', 'Disease', (70, 80))	('carcinomas', 'Disease', 'MESH:D002277', (70, 80))	('mutations', 'Var', (39, 48))	('Activation', 'PosReg', (0, 10))	('RET', 'Gene', (14, 17))
113808	31534554	Therapeutic approaches targeting RET with small-molecule kinase inhibitors are being evaluated for cancers that are associated with RET mutations or increased RET expression, such as MTC, chronic myelomonocytic leukaemia (CMML), and breast and pancreatic cancers.	('RET', 'Gene', '5979', (159, 162))	('increased', 'PosReg', (149, 158))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('RET', 'Gene', '5979', (33, 36))	('mutations', 'Var', (136, 145))	('myelomonocytic leukaemia', 'Disease', (196, 220))	('cancers', 'Disease', (255, 262))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('expression', 'Species', '29278', (163, 173))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (244, 262))	('RET', 'Gene', (159, 162))	('MTC', 'Disease', (183, 186))	('RET', 'Gene', (33, 36))	('CMML', 'Phenotype', 'HP:0012325', (222, 226))	('RET', 'Gene', '5979', (132, 135))	('increased RET', 'Phenotype', 'HP:0008151', (149, 162))	('breast and pancreatic cancers', 'Disease', 'MESH:D010190', (233, 262))	('MM', 'Disease', 'MESH:D009101', (223, 225))	('cancers', 'Disease', 'MESH:D009369', (255, 262))	('chronic myelomonocytic leukaemia', 'Phenotype', 'HP:0012325', (188, 220))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('MTC', 'Phenotype', 'HP:0002865', (183, 186))	('cancers', 'Disease', (99, 106))	('expression', 'MPA', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('myelomonocytic leukaemia', 'Disease', 'MESH:D054429', (196, 220))	('RET', 'Gene', (132, 135))
113814	31534554	Genetic silencing of ATF4 was observed in the OS/BTZ cells and cases.	('BTZ', 'Chemical', 'MESH:D000069286', (49, 52))	('Genetic silencing', 'Var', (0, 17))	('OS', 'Phenotype', 'HP:0002669', (46, 48))	('ATF4', 'Gene', (21, 25))
113824	31534554	Stable ATF4-overexpressing or ATF4 knockdown cells, including ATF4-U-2 OS, ATF4-HOS, shATF4-U-2 OS, shATF4-HOS or their corresponding controls, were generated by the stable transfection of ATF4 EF1a-GFP/puro or shATF4 pGLV-h1-GFP/puro lentiviral vector (GenePharma, China), respectively.	('shATF4', 'Var', (211, 217))	('U-2 OS', 'CellLine', 'CVCL:0042', (67, 73))	('U-2 OS', 'CellLine', 'CVCL:0042', (92, 98))	('EF1a', 'Gene', '1917', (194, 198))	('OS', 'Phenotype', 'HP:0002669', (71, 73))	('OS', 'Phenotype', 'HP:0002669', (81, 83))	('EF1a', 'Gene', (194, 198))	('OS', 'Phenotype', 'HP:0002669', (96, 98))	('OS', 'Phenotype', 'HP:0002669', (108, 110))
113842	31534554	Antibodies against ATF4, RET and GRP78 for immunofluorescence and antibodies against BCRP, phospho-RET (Y1062) and Cbl-c were purchased from Abcam Inc. (Cambridge, MA).	('RET', 'Gene', '5979', (25, 28))	('RET', 'Gene', (99, 102))	('BCRP', 'Gene', (85, 89))	('GRP78', 'Gene', (33, 38))	('RET', 'Gene', (25, 28))	('Cbl-c', 'Gene', '23624', (115, 120))	('GRP78', 'Gene', '3309', (33, 38))	('Y1062', 'Var', (104, 109))	('BCRP', 'Gene', '644079', (85, 89))	('RET', 'Gene', '5979', (99, 102))	('Cbl-c', 'Gene', (115, 120))
113845	31534554	Expression constructs (Myc-tagged full-length RET, RET-G93S, C634W, K758M, M918T, DeltaTK, DeltaCLD1, FLAG-tagged full-length ATF4, ATF4-DeltaDBD, GST-ATF4, His-ATF4, HA-GRP78, and HA-Cbl-c) were cloned into the pMT/V5 vector according to standard cloning procedures.	('His', 'Chemical', 'MESH:D006639', (157, 160))	('M918T', 'Mutation', 'rs74799832', (75, 80))	('RET', 'Gene', (51, 54))	('Expression', 'Species', '29278', (0, 10))	('C634W', 'SUBSTITUTION', 'None', (61, 66))	('G93S', 'Mutation', 'rs1477699803', (55, 59))	('K758M', 'Mutation', 'p.K758M', (68, 73))	('Myc', 'Gene', (23, 26))	('GRP78', 'Gene', '3309', (170, 175))	('GRP78', 'Gene', (170, 175))	('RET', 'Gene', '5979', (46, 49))	('Cbl-c', 'Gene', '23624', (184, 189))	('M918T', 'Var', (75, 80))	('C634W', 'Var', (61, 66))	('Myc', 'Gene', '4609', (23, 26))	('RET', 'Gene', (46, 49))	('RET', 'Gene', '5979', (51, 54))	('K758M', 'Var', (68, 73))	('DeltaCLD1', 'Var', (91, 100))	('Cbl-c', 'Gene', (184, 189))
113848	31534554	After overnight culture, the cells were transfected with equal amounts of the indicated expression plasmids or shRNA duplexes and the corresponding controls for 24 h using Lipofectamine 3000 (Invitrogen, CA), followed by BTZ (100 nM) or vehicle treatment for 24 h. The cells were selected for 12 days in medium containing 10% FBS and 500 mug/mL G418.	('G418', 'Var', (345, 349))	('FBS', 'Disease', 'MESH:D005198', (326, 329))	('expression', 'Species', '29278', (88, 98))	('FBS', 'Disease', (326, 329))	('Lipofectamine', 'Chemical', 'MESH:C086724', (172, 185))	('BTZ', 'Chemical', 'MESH:D000069286', (221, 224))
113859	31534554	Parental or BTZ-resistant osteosarcoma cells were transfected using Lipofectamine 3000 (Invitrogen, CA) with either pGL3-basic or the mentioned wild-type and mutant GRP78 luciferase reporter plasmids together with ATF4 expression plasmids or shATF4 and the Renilla luciferase reporter pRL-TK vector (Promega, USA) as the reference control.	('GRP78', 'Gene', '3309', (165, 170))	('expression', 'Species', '29278', (219, 229))	('osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('osteosarcoma', 'Disease', (26, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (26, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Lipofectamine', 'Chemical', 'MESH:C086724', (68, 81))	('mutant', 'Var', (158, 164))	('BTZ', 'Chemical', 'MESH:D000069286', (12, 15))	('GRP78', 'Gene', (165, 170))
113867	31534554	After 18 days of treatment, the growth of ATF4-expressing xenografts in BTZ-treated animals remained nearly completely inhibited, whereas the growth of xenografts of vehicle-treated animals was significantly more pronounced (median tumor volume increase 5.3% +- 27.8% versus 549.3% +- 133.5%; P = 0.001; Figure 1A).	('increase', 'PosReg', (245, 253))	('BTZ-treated', 'Var', (72, 83))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('inhibited', 'NegReg', (119, 128))	('ATF4-expressing', 'Gene', (42, 57))	('BTZ', 'Chemical', 'MESH:D000069286', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('growth', 'CPA', (32, 38))	('tumor', 'Disease', (232, 237))
113874	31534554	The results showed that compared with the control, ATF4 expression significantly increased the number of apoptotic HOS cells in vivo (from 2.2 +- 1.3% to 18.7% +- 3.2%; P = 0.001; Figure S1A).	('OS', 'Phenotype', 'HP:0002669', (116, 118))	('expression', 'Species', '29278', (56, 66))	('ATF4', 'Gene', (51, 55))	('increased', 'PosReg', (81, 90))	('expression', 'Var', (56, 66))
113875	31534554	Consistent with in vivo models, OS cells showed increased survival in response to BTZ when endogenous ATF4 was silenced; however, ATF4 overexpression alone not only suppressed the proliferation of tumor cells but also sensitized the cells to BTZ-induced growth arrest.	('BTZ', 'Chemical', 'MESH:D000069286', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('proliferation', 'CPA', (180, 193))	('OS', 'Phenotype', 'HP:0002669', (32, 34))	('ATF4', 'Gene', (130, 134))	('growth arrest', 'Disease', (254, 267))	('suppressed', 'NegReg', (165, 175))	('overexpression', 'Var', (135, 149))	('BTZ', 'Chemical', 'MESH:D000069286', (242, 245))	('expression', 'Species', '29278', (139, 149))	('growth arrest', 'Disease', 'MESH:D006323', (254, 267))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('sensitized', 'Reg', (218, 228))	('growth arrest', 'Phenotype', 'HP:0001510', (254, 267))	('tumor', 'Disease', (197, 202))
113880	31534554	A set of 19 genes was enriched for the reference group and represented a combination of pathways in cancer (hsa05200), protein processing in the ER (hsa04141) and ubiquitin-mediated proteolysis (hsa04120) (Figure S2A).	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ubiquitin-mediated', 'MPA', (163, 181))	('hsa04120', 'Var', (195, 203))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('hsa04141', 'Var', (149, 157))
113918	31534554	Depletion of ATF4 rescued OS/BTZ sublines from the antiproliferative effects of BTZ (Figure 4A and S4B).	('OS', 'Phenotype', 'HP:0002669', (26, 28))	('ATF4', 'Gene', (13, 17))	('Depletion', 'Var', (0, 9))	('BTZ', 'Chemical', 'MESH:D000069286', (80, 83))	('BTZ', 'Chemical', 'MESH:D000069286', (29, 32))
113923	31534554	Considering the overexpression of MDR1 and BCRP in OS/BTZ cells, we confirmed that aberrant ATF4 expression in BTZ-resistant OS cells effectively decreased the protein levels of MDR1 and BCRP to those in the wild-type cells (Figure 4D).	('OS', 'Phenotype', 'HP:0002669', (51, 53))	('BCRP', 'Gene', (43, 47))	('BCRP', 'Gene', '644079', (187, 191))	('ATF4', 'Gene', (92, 96))	('BCRP', 'Gene', '644079', (43, 47))	('aberrant', 'Var', (83, 91))	('MDR1', 'Gene', (178, 182))	('decreased', 'NegReg', (146, 155))	('protein levels', 'MPA', (160, 174))	('MDR1', 'Gene', (34, 38))	('OS', 'Phenotype', 'HP:0002669', (125, 127))	('MDR1', 'Gene', '5243', (34, 38))	('expression', 'Species', '29278', (97, 107))	('BTZ', 'Chemical', 'MESH:D000069286', (111, 114))	('MDR1', 'Gene', '5243', (178, 182))	('BTZ', 'Chemical', 'MESH:D000069286', (54, 57))	('BCRP', 'Gene', (187, 191))	('expression', 'Species', '29278', (20, 30))
113928	31534554	As inhibition of RET by RNAi resensitized OSATF4 and OS/BTZATF4 cells to BTZ, we reasoned that RNAi-mediated RET knockdown should act synergistically with BTZ to inhibit proliferation in these cell lines.	('RET', 'Gene', (109, 112))	('inhibit', 'NegReg', (162, 169))	('OS', 'Phenotype', 'HP:0002669', (53, 55))	('proliferation', 'CPA', (170, 183))	('BTZATF4', 'Chemical', '-', (56, 63))	('RET', 'Gene', (17, 20))	('BTZ', 'Chemical', 'MESH:D000069286', (155, 158))	('BTZ', 'Chemical', 'MESH:D000069286', (56, 59))	('knockdown', 'Var', (113, 122))	('BTZ', 'Chemical', 'MESH:D000069286', (73, 76))	('RET', 'Gene', '5979', (109, 112))	('OS', 'Phenotype', 'HP:0002669', (42, 44))	('OSATF4', 'Chemical', '-', (42, 48))	('RET', 'Gene', '5979', (17, 20))
113941	31534554	Transient treatment of OS cells with the proteasome inhibitor MG132 did not result in detectable RET protein until the cells had been treated for 12 h. In contrast, ATF4 expression was promptly augmented in the presence of MG132 but attenuated markedly over time (Figure 5A).	('MG132', 'Var', (223, 228))	('MG132', 'Chemical', 'MESH:C072553', (223, 228))	('MG132', 'Chemical', 'MESH:C072553', (62, 67))	('RET', 'Gene', '5979', (97, 100))	('OS', 'Phenotype', 'HP:0002669', (23, 25))	('ATF4', 'Gene', (165, 169))	('augmented', 'PosReg', (194, 203))	('expression', 'Species', '29278', (170, 180))	('RET', 'Gene', (97, 100))	('expression', 'MPA', (170, 180))
113943	31534554	In addition, the half-life of RET in the BTZ-resistant U-2 OS cells transfected with FLAG-ATF4 plasmids was approximately 3 hours, whereas the half-life of RET in cells transfected with control vectors was as long as 9 hours (Figure 5B).	('RET', 'Gene', (30, 33))	('BTZ', 'Chemical', 'MESH:D000069286', (41, 44))	('RET', 'Gene', '5979', (156, 159))	('RET', 'Gene', '5979', (30, 33))	('FLAG-ATF4', 'Var', (85, 94))	('OS', 'Phenotype', 'HP:0002669', (59, 61))	('RET', 'Gene', (156, 159))	('U-2 OS', 'CellLine', 'CVCL:0042', (55, 61))
113948	31534554	In a coimmunoprecipitation assay with ectopically expressed ATF4 and RET, we found that Myc-tagged RET could precipitate FLAG-ATF4 from transfected OS cells (Figure 5F-G).	('Myc', 'Gene', (88, 91))	('OS', 'Phenotype', 'HP:0002669', (148, 150))	('FLAG-ATF4', 'Var', (121, 130))	('RET', 'Gene', (99, 102))	('RET', 'Gene', '5979', (69, 72))	('RET', 'Gene', (69, 72))	('RET', 'Gene', '5979', (99, 102))	('precipitate', 'MPA', (109, 120))	('Myc', 'Gene', '4609', (88, 91))
113950	31534554	Together, these results suggested that ATF4 likely inhibits RET by mediating its degradation.	('RET', 'Gene', (60, 63))	('inhibits', 'NegReg', (51, 59))	('RET', 'Gene', '5979', (60, 63))	('degradation', 'MPA', (81, 92))	('ATF4', 'Var', (39, 43))
113954	31534554	We observed that the amino acid residues (ASP974 and GLU971) of two RET structures were positioned in close proximity to the binding surface of ATF4 (LYS335 and ARG323, respectively), suggesting a relatively stable docking conformation regardless of the RET phosphorylation status.	('docking', 'Interaction', (215, 222))	('RET', 'Gene', '5979', (68, 71))	('LYS335', 'Var', (150, 156))	('RET', 'Gene', '5979', (254, 257))	('GLU971', 'Var', (53, 59))	('ARG323', 'Chemical', '-', (161, 167))	('RET', 'Gene', (68, 71))	('ASP974', 'Chemical', '-', (42, 48))	('ARG323', 'Var', (161, 167))	('RET', 'Gene', (254, 257))	('LYS335', 'Chemical', '-', (150, 156))	('GLU971', 'Chemical', '-', (53, 59))	('ASP974', 'Var', (42, 48))
113955	31534554	Given the computational docking results and the significance of clinical subtypes harbouring different RET oncogenic mutations, we continued to assess whether the TK domain of RET was necessary for ATF4 controlling its stability in vitro.	('mutations', 'Var', (117, 126))	('RET', 'Gene', '5979', (103, 106))	('RET', 'Gene', '5979', (176, 179))	('stability', 'MPA', (219, 228))	('clinical', 'Species', '191496', (64, 72))	('RET', 'Gene', (103, 106))	('RET', 'Gene', (176, 179))
113956	31534554	First, we generated several deletion or point mutants of the Myc-tagged RET long isoform (RET 51) for coimmunoprecipitation with ubiquitin upon ectopic ATF4 expression in OS cells (Figure 5K).	('ATF4', 'Gene', (152, 156))	('Myc', 'Gene', '4609', (61, 64))	('expression', 'Species', '29278', (157, 167))	('ubiquitin', 'MPA', (129, 138))	('Myc', 'Gene', (61, 64))	('RET', 'Gene', '5979', (90, 93))	('RET', 'Gene', '5979', (72, 75))	('OS', 'Phenotype', 'HP:0002669', (171, 173))	('RET', 'Gene', (90, 93))	('deletion', 'Var', (28, 36))	('RET', 'Gene', (72, 75))	('point mutants', 'Var', (40, 53))
113957	31534554	Interestingly, TK-truncated RET (RET-DeltaTK) and RET-K758M were not readily ubiquitinated; however, wild-type RET (WT), RET-C634W and RET-M918T were substantially ubiquitinated under the same conditions (Figure 6A and S5B).	('M918T', 'Mutation', 'rs74799832', (139, 144))	('C634W', 'SUBSTITUTION', 'None', (125, 130))	('RET-DeltaTK', 'Gene', (33, 44))	('RET', 'Gene', '5979', (121, 124))	('RET-DeltaTK', 'Gene', '5979', (33, 44))	('RET', 'Gene', '5979', (33, 36))	('RET', 'Gene', (28, 31))	('RET', 'Gene', (50, 53))	('ubiquitinated', 'MPA', (164, 177))	('S5B', 'Gene', '5711', (219, 222))	('RET', 'Gene', '5979', (111, 114))	('RET', 'Gene', '5979', (135, 138))	('RET', 'Gene', (121, 124))	('C634W', 'Var', (125, 130))	('RET', 'Gene', (33, 36))	('RET', 'Gene', (111, 114))	('RET', 'Gene', (135, 138))	('RET', 'Gene', '5979', (28, 31))	('S5B', 'Gene', (219, 222))	('RET', 'Gene', '5979', (50, 53))	('K758M', 'Mutation', 'p.K758M', (54, 59))
113958	31534554	These results were confirmed by performing a GST pull-down assay in which WT RET, RET-C634W and RET-M918T were found to interact with ATF4, while RET-DeltaTK and RET-K758M failed to interact with ATF4 (Figure 6B and S5C), suggesting that the ubiquitination sites on RET are located in the TK domain, and this interaction is dependent on the kinase activity but not constitutive autophosphorylation activity or conformational change in RET.	('RET', 'Gene', '5979', (96, 99))	('RET', 'Gene', (146, 149))	('RET', 'Gene', (162, 165))	('RET', 'Gene', (82, 85))	('RET', 'Gene', (96, 99))	('RET', 'Gene', '5979', (77, 80))	('RET', 'Gene', '5979', (435, 438))	('C634W', 'Var', (86, 91))	('K758M', 'Mutation', 'p.K758M', (166, 171))	('RET', 'Gene', '5979', (266, 269))	('RET-DeltaTK', 'Gene', (146, 157))	('RET', 'Gene', (77, 80))	('RET', 'Gene', (435, 438))	('RET-DeltaTK', 'Gene', '5979', (146, 157))	('RET', 'Gene', '5979', (146, 149))	('RET', 'Gene', '5979', (162, 165))	('RET', 'Gene', '5979', (82, 85))	('interact', 'Interaction', (120, 128))	('M918T', 'Mutation', 'rs74799832', (100, 105))	('C634W', 'SUBSTITUTION', 'None', (86, 91))	('RET', 'Gene', (266, 269))
113964	31534554	An increasing amount of RET was found to coimmunoprecipitate with HA-Cbl-c after FLAG-ATF4 expression compared with that before (Figure 6D), whereas ATF4 knockdown in the presence of MG132 almost abolished this pattern of interaction (Figure 6E), further supporting that the ectopic expression of ATF4 increases the interaction between RET and Cbl-c.	('RET', 'Gene', '5979', (24, 27))	('ATF4', 'Gene', (297, 301))	('interaction', 'Interaction', (316, 327))	('expression', 'Var', (91, 101))	('RET', 'Gene', (336, 339))	('increases', 'PosReg', (302, 311))	('Cbl-c', 'Gene', '23624', (69, 74))	('Cbl-c', 'Gene', '23624', (344, 349))	('RET', 'Gene', (24, 27))	('expression', 'Species', '29278', (283, 293))	('MG132', 'Chemical', 'MESH:C072553', (183, 188))	('Cbl-c', 'Gene', (69, 74))	('coimmunoprecipitate', 'Interaction', (41, 60))	('Cbl-c', 'Gene', (344, 349))	('expression', 'Species', '29278', (91, 101))	('RET', 'Gene', '5979', (336, 339))
113965	31534554	Consistently, the introduction of ATF4 markedly facilitated Cbl-c-mediated ubiquitination of RET (Figure 6F and S5F).	('introduction', 'Var', (18, 30))	('Cbl-c', 'Gene', (60, 65))	('RET', 'Gene', '5979', (93, 96))	('ATF4', 'Gene', (34, 38))	('RET', 'Gene', (93, 96))	('facilitated', 'PosReg', (48, 59))	('Cbl-c', 'Gene', '23624', (60, 65))
113966	31534554	ATF4 silencing dramatically reduced RET ubiquitination (Figure 6G).	('RET', 'Gene', (36, 39))	('reduced', 'NegReg', (28, 35))	('silencing', 'Var', (5, 14))	('RET', 'Gene', '5979', (36, 39))	('ATF4', 'Gene', (0, 4))
113974	31534554	At the transcriptional level, Cbl-c mRNA was increased after ATF4 overexpression (Figure 6I) and decreased after ATF4 knockdown (Figure S5J).	('knockdown', 'Var', (118, 127))	('increased', 'PosReg', (45, 54))	('Cbl-c', 'Gene', (30, 35))	('expression', 'Species', '29278', (70, 80))	('ATF4', 'Gene', (61, 65))	('decreased', 'NegReg', (97, 106))	('overexpression', 'PosReg', (66, 80))	('Cbl-c', 'Gene', '23624', (30, 35))
113981	31534554	In agreement with this, both CLD1 deletion or expression of the immature form of G93S promoted GRP78-RET interaction and subsequent RET ubiquitination.	('CLD1', 'Gene', (29, 33))	('RET', 'Gene', '5979', (132, 135))	('RET', 'Gene', '5979', (101, 104))	('G93S', 'Mutation', 'rs1477699803', (81, 85))	('deletion', 'Var', (34, 42))	('expression', 'Species', '29278', (46, 56))	('GRP78', 'Gene', '3309', (95, 100))	('interaction', 'Interaction', (105, 116))	('GRP78', 'Gene', (95, 100))	('promoted', 'PosReg', (86, 94))	('RET', 'Gene', (101, 104))	('RET', 'Gene', (132, 135))
113985	31534554	The results showed that GRP78 significantly reduced the association of ATF4 with RET; ATF4 overexpression also reduced GRP78 binding to RET in U-2 OS and HEK293T cells (Figure 7D and S6D).	('RET', 'Gene', '5979', (136, 139))	('RET', 'Gene', (81, 84))	('GRP78', 'Gene', '3309', (24, 29))	('HEK293T', 'CellLine', 'CVCL:0063', (154, 161))	('OS', 'Phenotype', 'HP:0002669', (147, 149))	('RET', 'Gene', (136, 139))	('reduced', 'NegReg', (111, 118))	('binding', 'Interaction', (125, 132))	('association', 'Interaction', (56, 67))	('U-2 OS', 'CellLine', 'CVCL:0042', (143, 149))	('reduced', 'NegReg', (44, 51))	('RET', 'Gene', '5979', (81, 84))	('expression', 'Species', '29278', (95, 105))	('GRP78', 'Gene', (119, 124))	('ATF4', 'Gene', (86, 90))	('GRP78', 'Gene', '3309', (119, 124))	('overexpression', 'Var', (91, 105))	('GRP78', 'Gene', (24, 29))
113986	31534554	Moreover, exogenous GRP78 prominently reversed the increase in the levels of ubiquitin conjugates induced by the ectopic expression of ATF4 in OS cells (Figure S6E).	('increase', 'PosReg', (51, 59))	('GRP78', 'Gene', '3309', (20, 25))	('expression', 'Species', '29278', (121, 131))	('levels of ubiquitin conjugates', 'MPA', (67, 97))	('ectopic expression', 'Var', (113, 131))	('OS', 'Phenotype', 'HP:0002669', (143, 145))	('GRP78', 'Gene', (20, 25))	('ATF4', 'Gene', (135, 139))
113989	31534554	We previously reported that GRP78 deficiency upregulated ATF4 expression in OS cells.	('GRP78', 'Gene', (28, 33))	('GRP78', 'Gene', '3309', (28, 33))	('deficiency', 'Var', (34, 44))	('expression', 'Species', '29278', (62, 72))	('expression', 'MPA', (62, 72))	('ATF4', 'Gene', (57, 61))	('upregulated', 'PosReg', (45, 56))	('OS', 'Phenotype', 'HP:0002669', (76, 78))
113992	31534554	Consistent with these findings, we found that the loss of either RET or GRP78 downregulated the expression of MDR1 and BCRP associated with BTZ tolerance, as evidenced by ATF4 activation.	('RET', 'Gene', '5979', (65, 68))	('BCRP', 'Gene', (119, 123))	('GRP78', 'Gene', (72, 77))	('expression', 'Species', '29278', (96, 106))	('BTZ', 'Chemical', 'MESH:D000069286', (140, 143))	('GRP78', 'Gene', '3309', (72, 77))	('expression', 'MPA', (96, 106))	('BCRP', 'Gene', '644079', (119, 123))	('loss', 'Var', (50, 54))	('RET', 'Gene', (65, 68))	('MDR1', 'Gene', (110, 114))	('BTZ tolerance', 'Disease', (140, 153))	('MDR1', 'Gene', '5243', (110, 114))	('downregulated', 'NegReg', (78, 91))
113996	31534554	However, ATF4 overexpression was sufficient to alleviate the pro-proliferative activities of RET and GRP78, thus ameliorating resistance to BTZ, which was much more conspicuous when coupled with GRP78 knockdown (Figure 7H, lane 2 versus lane 4, lane 3 versus lane 5, and lane 4 versus lane 7, respectively; Figure S7A) highlighting the importance of ATF4 in accelerating OS progression during BTZ resistance.	('knockdown', 'Var', (201, 210))	('pro-proliferative activities', 'MPA', (61, 89))	('BTZ', 'Chemical', 'MESH:D000069286', (140, 143))	('alleviate', 'NegReg', (47, 56))	('GRP78', 'Gene', (101, 106))	('RET', 'Gene', '5979', (93, 96))	('ameliorating', 'PosReg', (113, 125))	('expression', 'Species', '29278', (18, 28))	('resistance', 'MPA', (126, 136))	('GRP78', 'Gene', '3309', (101, 106))	('BTZ', 'Chemical', 'MESH:D000069286', (393, 396))	('OS', 'Phenotype', 'HP:0002669', (371, 373))	('RET', 'Gene', (93, 96))	('GRP78', 'Gene', (195, 200))	('GRP78', 'Gene', '3309', (195, 200))
114002	31534554	To identify the HSPA5 promoter elements responsible for ATF4-mediated transcriptional repression, we constructed a panel of luciferase plasmids containing promoter fragments with increasing 5'-deletions or ATF/CRE mutations and tested them after the transient cotransfection of ATF4 into U-2 OS/BTZ cells.	('ATF', 'Gene', (206, 209))	('tested', 'Reg', (228, 234))	('ATF', 'Gene', '2668', (278, 281))	('ATF', 'Gene', '2668', (56, 59))	('ATF', 'Gene', (278, 281))	('BTZ', 'Chemical', 'MESH:D000069286', (295, 298))	('ATF', 'Gene', (56, 59))	('U-2 OS', 'CellLine', 'CVCL:0042', (288, 294))	('OS', 'Phenotype', 'HP:0002669', (292, 294))	('mutations', 'Var', (214, 223))	('HSPA5', 'Gene', '3309', (16, 21))	('HSPA5', 'Gene', (16, 21))	('ATF', 'Gene', '2668', (206, 209))
114004	31534554	However, ATF4 failed to transactivate HSPA5 when the CRE element was mutated in U-2 OS cells (Figure S7E).	('HSPA5', 'Gene', '3309', (38, 43))	('OS', 'Phenotype', 'HP:0002669', (84, 86))	('mutated', 'Var', (69, 76))	('HSPA5', 'Gene', (38, 43))	('U-2 OS', 'CellLine', 'CVCL:0042', (80, 86))
114007	31534554	Colony formation assays using OS and OS/BTZ cells treated with piperine and ribociclib indicated marked inhibition of in vitro proliferation (Figure 8A and S8A).	('inhibition', 'NegReg', (104, 114))	('ribociclib', 'Var', (76, 86))	('OS', 'Phenotype', 'HP:0002669', (37, 39))	('OS', 'Phenotype', 'HP:0002669', (30, 32))	('piperine', 'Chemical', 'MESH:C008922', (63, 71))	('BTZ', 'Chemical', 'MESH:D000069286', (40, 43))	('in vitro proliferation', 'CPA', (118, 140))
114014	31534554	Here, we demonstrated that the presence of upregulated ATF4 is beneficial for the growth delay of HOS xenografts and amplifies the apoptotic effects of BTZ, whereas ATF4 knockdown has opposite results.	('upregulated', 'PosReg', (43, 54))	('growth delay', 'Phenotype', 'HP:0001510', (82, 94))	('OS', 'Phenotype', 'HP:0002669', (99, 101))	('amplifies', 'PosReg', (117, 126))	('growth delay', 'CPA', (82, 94))	('apoptotic effects', 'CPA', (131, 148))	('BTZ', 'Chemical', 'MESH:D000069286', (152, 155))	('ATF4', 'Gene', (55, 59))	('presence', 'Var', (31, 39))
114028	31534554	However, ATF4 has also been proposed to activate a negative-feedback loop, leading to the downregulation of RET expression while upregulating expression of pro-apoptotic genes in MTC.	('upregulating', 'PosReg', (129, 141))	('RET', 'Gene', '5979', (108, 111))	('MTC', 'Phenotype', 'HP:0002865', (179, 182))	('expression', 'Species', '29278', (142, 152))	('ATF4', 'Var', (9, 13))	('RET', 'Gene', (108, 111))	('expression', 'MPA', (142, 152))	('expression', 'Species', '29278', (112, 122))	('downregulation', 'NegReg', (90, 104))	('expression', 'MPA', (112, 122))
114035	31534554	Rather, ATF4 overexpression inhibited GRP78-RET binding, which induced the nuclear translocation of RET for degradation.	('RET', 'Gene', '5979', (100, 103))	('RET', 'Gene', (44, 47))	('GRP78', 'Gene', '3309', (38, 43))	('degradation', 'MPA', (108, 119))	('expression', 'Species', '29278', (17, 27))	('overexpression', 'Var', (13, 27))	('ATF4', 'Gene', (8, 12))	('binding', 'Interaction', (48, 55))	('inhibited', 'NegReg', (28, 37))	('RET', 'Gene', '5979', (44, 47))	('RET', 'Gene', (100, 103))	('nuclear translocation', 'MPA', (75, 96))	('induced', 'Reg', (63, 70))	('GRP78', 'Gene', (38, 43))
114041	31534554	Genetic or chemical inhibition of this feedback loop to enhance ATF4 expression may represent a novel approach to overcome chemoresistance.	('inhibition', 'Var', (20, 30))	('ATF4', 'Gene', (64, 68))	('expression', 'Species', '29278', (69, 79))	('expression', 'MPA', (69, 79))	('enhance', 'PosReg', (56, 63))
114045	30174980	As with all procedures which utilize radiation, there is an inherent risk of genetic mutation and the possible development of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('malignancy', 'Disease', (126, 136))	('genetic mutation', 'Var', (77, 93))
114052	30174980	In the case of our patient, the likely etiology of this phenomenon is associated with the unique chromosomal aberrations and genetic mutations associated with RIS, including duplication and fusion of MYC as well as the many factors which may delay a timely diagnosis.	('MYC', 'Gene', '4609', (200, 203))	('patient', 'Species', '9606', (19, 26))	('duplication', 'Var', (174, 185))	('RIS', 'Chemical', '-', (159, 162))	('MYC', 'Gene', (200, 203))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (97, 120))	('fusion', 'Var', (190, 196))
114220	29196718	In this multivariate survival analysis on patients with colorectal cancer, low COP-NLR was shown to be related to a statistically better cancer specific survival (OR: 0.464 95% CI 0.267-0.807 p = 0.007).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('better', 'PosReg', (130, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (67, 73))	('low', 'Var', (75, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('COP-NLR', 'Gene', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('cancer', 'Disease', (137, 143))	('patients', 'Species', '9606', (42, 50))
114225	29196718	The CNP was calculated based on data obtained on the day of admission, where patients with both elevated NLR (>3.45) and PLR (>166.5) were allocated a score of 2, and patients showing one or neither were allocated a score of 1 or 0, respectively.	('CNP', 'Gene', (4, 7))	('>166.5', 'Var', (126, 132))	('NLR', 'MPA', (105, 108))	('patients', 'Species', '9606', (167, 175))	('CNP', 'Gene', '1267', (4, 7))	('patients', 'Species', '9606', (77, 85))	('elevated', 'PosReg', (96, 104))
114227	29196718	In this multivariate survival analysis on patients with endometrial cancer, both high NLR and PLR was shown to be related to a statistically significant worse overall survival (HR: 2.54 95% CI 1.61-4.01 p < 0.001) and worse cancer specific survival (HR: 2.26 95% CI 1.24-4.13 p = 0.008).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PLR', 'Var', (94, 97))	('endometrial cancer', 'Disease', (56, 74))	('overall', 'MPA', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('NLR', 'Gene', (86, 89))	('high', 'Var', (81, 85))	('endometrial cancer', 'Phenotype', 'HP:0012114', (56, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('endometrial cancer', 'Disease', 'MESH:D016889', (56, 74))	('worse', 'NegReg', (153, 158))	('cancer', 'Disease', (68, 74))	('worse', 'NegReg', (218, 223))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('patients', 'Species', '9606', (42, 50))	('cancer', 'Disease', (224, 230))
114231	29196718	In this multivariate survival analysis on patients with oesophageal cancer, CRP/Albumin ratio >0.50 was shown to be related to a statistically significant worse overall survival (HR: 2.44 95% CI 1.82-3.26 p < 0.0001).	('Albumin', 'Gene', (80, 87))	('>0.50', 'Var', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('CRP', 'Gene', '1401', (76, 79))	('worse', 'NegReg', (155, 160))	('oesophageal cancer', 'Disease', (56, 74))	('oesophageal cancer', 'Disease', 'MESH:D009369', (56, 74))	('Albumin', 'Gene', '213', (80, 87))	('patients', 'Species', '9606', (42, 50))	('overall survival', 'MPA', (161, 177))	('CRP', 'Gene', (76, 79))
114238	29196718	In this multivariate survival analysis on patients with lung cancer, low NLR and low CRP (compared to both high) was shown to predict better overall survival (RR: 0.403 95% CI 0.240-0.689 p = 0.0012).	('better', 'PosReg', (134, 140))	('low', 'NegReg', (81, 84))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('overall survival', 'MPA', (141, 157))	('CRP', 'Gene', (85, 88))	('CRP', 'Gene', '1401', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('low', 'Var', (69, 72))	('patients', 'Species', '9606', (42, 50))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('NLR', 'MPA', (73, 76))
114239	29196718	In this multivariate survival analysis on patients with gastric cancer, HALP >=56.8 was shown to predict better overall survival (HR: 0.700 95% CI 0.496-0.987 p = 0.042).	('better', 'PosReg', (105, 111))	('gastric cancer', 'Disease', (56, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('HALP >=56.8', 'Var', (72, 83))	('overall survival', 'MPA', (112, 128))	('patients', 'Species', '9606', (42, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
114242	29196718	In this multivariate survival analysis on patients with colon cancer, WLR >=3.4 was shown to predict worse overall survival (HR: 4.10 95% CI 3.13-7.42 p = 0.03).	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('colon cancer', 'Disease', (56, 68))	('overall survival', 'MPA', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('worse', 'NegReg', (101, 106))	('patients', 'Species', '9606', (42, 50))	('WLR >=3.4', 'Var', (70, 79))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))
114243	29196718	In this multivariate survival analysis on patients with liver cancer, APRI >=0.62 was shown to predict worse overall survival (HR: 1.508 95% CI 1.127-2.016 p = 0.006).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('worse', 'NegReg', (103, 108))	('liver cancer', 'Phenotype', 'HP:0002896', (56, 68))	('liver cancer', 'Disease', 'MESH:D006528', (56, 68))	('overall survival', 'MPA', (109, 125))	('liver cancer', 'Disease', (56, 68))	('APRI >=0.62', 'Var', (70, 81))	('patients', 'Species', '9606', (42, 50))
114245	29196718	In this multivariate survival analysis on patients with gastric cancer, PI 2 was shown to predict worse overall survival (HR: 0.37 95% CI 0.16-0.82 p = 0.01).	('PI 2', 'Var', (72, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('gastric cancer', 'Disease', (56, 70))	('patients', 'Species', '9606', (42, 50))	('PI 2', 'Species', '1214577', (72, 76))	('worse', 'NegReg', (98, 103))	('overall survival', 'MPA', (104, 120))
114246	29196718	In this multivariate survival analysis on patients with gastric cancer, elevated Canton score was shown to predict worse overall survival (HR: 1.643 95% CI 1.142-2.364 p = 0.007).	('Canton score', 'MPA', (81, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('overall survival', 'MPA', (121, 137))	('elevated', 'Var', (72, 80))	('worse', 'NegReg', (115, 120))	('gastric cancer', 'Disease', (56, 70))	('patients', 'Species', '9606', (42, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
114252	29196718	In this multivariate survival analysis on patients with ovarian cancer, PIS 2 was shown to predict better overall survival (HR: 0.18 95% CI 0.09-0.38 p < 0.001).	('PIS 2', 'Var', (72, 77))	('better', 'PosReg', (99, 105))	('PIS', 'Chemical', '-', (72, 75))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('ovarian cancer', 'Disease', 'MESH:D010051', (56, 70))	('overall survival', 'MPA', (106, 122))	('patients', 'Species', '9606', (42, 50))	('ovarian cancer', 'Disease', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
114254	29196718	In this multivariate survival analysis on patients with oesophageal cancer, high CONUT score was shown to predict worse overall survival (HR: 2.303 95% CI 1.191-4.455 p = 0.013).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('oesophageal cancer', 'Disease', (56, 74))	('worse', 'NegReg', (114, 119))	('oesophageal cancer', 'Disease', 'MESH:D009369', (56, 74))	('overall survival', 'MPA', (120, 136))	('high', 'Var', (76, 80))	('patients', 'Species', '9606', (42, 50))
114381	25329644	An aliquot of the protein extract (75 microg) was mixed with 50 microL of 2X reaction buffer supplemented with 10 mM DTT and the substrates of DEVD-pNA (caspase-3), IETD-pNA (caspase-8), or LEHD-pNA (caspase-9).	('DTT', 'Chemical', 'MESH:D004229', (117, 120))	('caspase-9', 'Gene', (200, 209))	('caspase-3', 'Gene', (153, 162))	('LEHD-pNA', 'Var', (190, 198))	('IETD-pNA', 'Chemical', '-', (165, 173))	('caspase-9', 'Gene', '12371', (200, 209))	('caspase-3', 'Gene', '12367', (153, 162))	('caspase-8', 'Gene', '12370', (175, 184))	('caspase-8', 'Gene', (175, 184))	('DEVD-pNA', 'Chemical', 'MESH:C475509', (143, 151))	('LEHD-pNA', 'Chemical', '-', (190, 198))
114398	25329644	All the synthesized complexes are of orange color, and their elemental analyses data suggest the formation of [Ru(AA)(dppb)(bipy)]PF6 species for the amino acids glycine, L-alanine, L-methionine and L-leucine and [Ru(AA)(dppb)(bipy)](PF6)2 for the L-aspartic acid.	('bipy', 'Chemical', '-', (124, 128))	('PF6', 'Gene', (130, 133))	('glycine', 'MPA', (162, 169))	('PF6', 'Gene', (234, 237))	('bipy', 'Chemical', '-', (227, 231))	('amino acids glycine', 'Chemical', '-', (150, 169))	('L-aspartic acid', 'Chemical', 'MESH:D001224', (248, 263))	('L-leucine', 'Var', (199, 208))	('dppb', 'Chemical', '-', (221, 225))	('L-methionine', 'Chemical', 'MESH:D008715', (182, 194))	('dppb', 'Chemical', '-', (118, 122))	('L-alanine', 'Chemical', 'MESH:D000409', (171, 180))	('L-leucine', 'Chemical', 'MESH:D007930', (199, 208))	('PF6', 'Gene', '74362', (130, 133))	('PF6', 'Gene', '74362', (234, 237))
114402	25329644	The complexes containing methionine and glycine were more active against S180 cells, with IC50 values of 22.53 microM and 31.15 microM, respectively.	('methionine', 'Var', (25, 35))	('active', 'MPA', (58, 64))	('S180 cells', 'CPA', (73, 83))	('S180', 'CellLine', 'CVCL:2874', (73, 77))	('methionine', 'Chemical', 'MESH:D008715', (25, 35))	('glycine', 'Chemical', 'MESH:D005998', (40, 47))
114403	25329644	The complex containing glycine showed lower toxicity against the L929 cells (51.65 microM) compared with the complex containing methionine (27.39 microM).	('lower', 'NegReg', (38, 43))	('L929', 'CellLine', 'CVCL:0462', (65, 69))	('glycine', 'Chemical', 'MESH:D005998', (23, 30))	('glycine', 'Var', (23, 30))	('methionine', 'Chemical', 'MESH:D008715', (128, 138))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('toxicity', 'Disease', (44, 52))
114404	25329644	As shown in Table 3, under the same conditions, cisplatin showed cytoxicity at concentrations as low as 29.05 microM, while its IC50 against S180 cells was 64.83 microM.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('S180', 'CellLine', 'CVCL:2874', (141, 145))	('cisplatin', 'Var', (48, 57))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))	('toxicity', 'Disease', (67, 75))
114425	25329644	The complexes containing aspartic acid, alanine, glycine, and leucine were less cytotoxic toward the L929 murine fibroblast cells, with IC50 values ranging from 106.72 microM to 47.15 microM; these values were significantly higher than the IC50 for cisplatin (29.05 microM) (Table 2).	('glycine', 'Var', (49, 56))	('alanine', 'Var', (40, 47))	('glycine', 'Chemical', 'MESH:D005998', (49, 56))	('leucine', 'Chemical', 'MESH:D007930', (62, 69))	('cytotoxic', 'CPA', (80, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (249, 258))	('aspartic acid', 'Chemical', 'MESH:D001224', (25, 38))	('murine', 'Species', '10090', (106, 112))	('L929', 'CellLine', 'CVCL:0462', (101, 105))	('alanine', 'Chemical', 'MESH:D000409', (40, 47))	('leucine', 'Var', (62, 69))
114436	25329644	Consistent with our results, previous studies have demonstrated that the cis-[RuCl2(NH3)4]Cl ruthenium compound also increased the numbers of Annexin V-positive S180 cells.	('increased', 'PosReg', (117, 126))	('S180', 'CellLine', 'CVCL:2874', (161, 165))	('Annexin V', 'Gene', (142, 151))	('Annexin V', 'Gene', '11747', (142, 151))	('cis-[RuCl2(NH3)4]Cl ruthenium', 'Chemical', '-', (73, 102))	('cis-', 'Var', (73, 77))
114444	25329644	Loss of DeltaPsim is associated with the activation of caspases and the initiation of apoptotic cascades.	('caspases', 'Gene', '12370;842;12371', (55, 63))	('apoptotic cascades', 'CPA', (86, 104))	('DeltaPsim', 'Gene', (8, 17))	('caspases', 'Gene', (55, 63))	('activation', 'PosReg', (41, 51))	('Loss', 'Var', (0, 4))
114492	24605193	In tumor size, survival was 70% in patients with smaller than 50 mm at final follow-up, which was better than tumors sized more than 42.9%.	('smaller than 50 mm', 'Var', (49, 67))	('tumor', 'Disease', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
114540	22526632	Based on these observations, the inhibition of Src kinase activity has been identified as a novel anticancer treatment strategy and lead agents dasatinib, saracatinib and bosutinib, are currently in clinical development in a number of solid tumor settings.	('inhibition', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (241, 246))	('dasatinib', 'Chemical', 'MESH:D000069439', (144, 153))	('bosutinib', 'Chemical', 'MESH:C471992', (171, 180))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('Src kinase activity', 'Enzyme', (47, 66))	('saracatinib', 'Chemical', 'MESH:C515233', (155, 166))
114541	22526632	Target validation studies including Src transfection, antisense Src constructs, and Src mutation studies support the role of Src as a key molecule in the metastatic cascade of cancer cells.	('mutation', 'Var', (88, 96))	('Src', 'Gene', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
114543	22526632	Preclinical studies of bladder and head and neck tumor models showed that saracatinib treatment impaired lymph node metastasis as was also the case for prostate cancer xenografts treated with dasatinib.	('prostate cancer', 'Disease', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('neck tumor', 'Disease', 'MESH:D006258', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('saracatinib', 'Var', (74, 85))	('impaired lymph node metastasis', 'Disease', (96, 126))	('dasatinib', 'Chemical', 'MESH:D000069439', (192, 201))	('head and neck tumor', 'Phenotype', 'HP:0012288', (35, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (152, 167))	('saracatinib', 'Chemical', 'MESH:C515233', (74, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (152, 167))	('neck tumor', 'Disease', (44, 54))	('impaired lymph node metastasis', 'Disease', 'MESH:D009362', (96, 126))
114546	22526632	The goal of the present study was to investigate which phase of the blood borne dissemination of tumor cells is impacted by Src inhibition.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('inhibition', 'Var', (128, 138))	('impacted', 'Reg', (112, 120))
114588	22526632	Src has been shown to play a role in this process and consequently a component of the antitumor effects associated with Src inhibitors may be attributed to their anti-angiogenic action.	('anti-angiogenic', 'CPA', (162, 177))	('Src', 'Gene', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('inhibitors', 'Var', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
114599	22526632	Similarly, skin flaps from mice treated with saracatinib also showed significant reductions in the number of blood vessels induced by KHT sarcoma cells (Fig.	('KHT sarcoma cell', 'Disease', 'MESH:D012509', (134, 150))	('skin flaps', 'Disease', (11, 21))	('KHT sarcoma cell', 'Disease', (134, 150))	('mice', 'Species', '10090', (27, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('reductions', 'NegReg', (81, 91))	('saracatinib', 'Var', (45, 56))	('skin flaps', 'Disease', 'MESH:D000070600', (11, 21))	('saracatinib', 'Chemical', 'MESH:C515233', (45, 56))	('number of blood vessels', 'CPA', (99, 122))
114607	22526632	Furthermore, two recent clinical studies have shown that saracatinib inhibits bone resorption.	('saracatinib', 'Var', (57, 68))	('inhibits', 'NegReg', (69, 77))	('saracatinib', 'Chemical', 'MESH:C515233', (57, 68))	('bone resorption', 'Phenotype', 'HP:0002797', (78, 93))	('bone resorption', 'CPA', (78, 93))
114619	22526632	Furthermore, when comparing the results illustrated in Figs 2 and 3 it is readily apparent that saracatinib treatments administered during the first week after intravenous injection of tumor cells were responsible for the observed reduction in the number of pulmonary tumor nodules with treatments commencing on day 10 or 14 failing to have a significant effect.	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('reduction', 'NegReg', (231, 240))	('pulmonary tumor', 'Disease', 'MESH:D008175', (258, 273))	('pulmonary tumor', 'Phenotype', 'HP:0100526', (258, 273))	('tumor', 'Disease', (268, 273))	('pulmonary tumor', 'Disease', (258, 273))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('treatments', 'Var', (108, 118))	('saracatinib', 'Chemical', 'MESH:C515233', (96, 107))
114625	22526632	In the case of saracatinib, neither bladder cancer nor head and neck squamous cell carcinoma (HNSCC) xenograft growth was significantly inhibited when treated with saracatinib while only a subset of human pancreatic xenografts responded to this agent.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (64, 92))	('human', 'Species', '9606', (199, 204))	('pancreatic', 'Disease', 'MESH:D010195', (205, 215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (36, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (36, 50))	('saracatinib', 'Var', (164, 175))	('inhibited', 'NegReg', (136, 145))	('saracatinib', 'Chemical', 'MESH:C515233', (15, 26))	('pancreatic', 'Disease', (205, 215))	('bladder cancer', 'Disease', (36, 50))	('saracatinib', 'Chemical', 'MESH:C515233', (164, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('neck squamous cell carcinoma', 'Disease', (64, 92))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
114632	22526632	Because aberrant Src signaling has been linked to cancer cell functions associated with an enhanced metastatic phenotype, Src inhibitors are being actively pursued for their potential as anti-metastatic anticancer agents.	('metastatic', 'CPA', (100, 110))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Disease', (207, 213))	('aberrant', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('linked', 'Reg', (40, 46))	('enhanced', 'PosReg', (91, 99))	('Src signaling', 'MPA', (17, 30))
114633	22526632	As such Src signaling interventions could prove efficacious against secondary disease or impact the spread of neoplastic cells from a primary tumor; a therapeutic distinction often blurred in experimental investigations of such agents.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('secondary disease', 'Disease', (68, 85))	('tumor', 'Disease', (142, 147))	('impact', 'Reg', (89, 95))	('interventions', 'Var', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
114653	22588051	Individual and familial germline characteristics interact with the environment to modify the risk of subsequent somatic genetic changes within cells, the accumulation of which eventually results in cancer development.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('results in', 'Reg', (187, 197))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('modify', 'Reg', (82, 88))	('changes', 'Var', (128, 135))
114723	22588051	The ISKS cohort is being systematically screened for mutations in the TP53 gene (manuscript in preparation) and 3 of the 16 probands in the HL families (including one who had both a sarcoma and HL) were positive for germline mutations in TP53 (19%).	('HL', 'Phenotype', 'HP:0012189', (140, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('TP53', 'Gene', '7157', (70, 74))	('HL', 'CellLine', 'CVCL:2492', (194, 196))	('positive', 'Reg', (203, 211))	('HL', 'CellLine', 'CVCL:2492', (140, 142))	('TP53', 'Gene', (238, 242))	('mutations', 'Var', (53, 62))	('TP53', 'Gene', '7157', (238, 242))	('TP53', 'Gene', (70, 74))	('sarcoma', 'Disease', 'MESH:D012509', (182, 189))	('germline mutations', 'Var', (216, 234))	('HL', 'Phenotype', 'HP:0012189', (194, 196))	('sarcoma', 'Disease', (182, 189))
114748	22588051	However, the rate of TP53 mutations in HL probands (19%) was higher than that reported in the only previous study of TP53 mutations in sarcoma-affected populations.	('TP53', 'Gene', (21, 25))	('HL', 'CellLine', 'CVCL:2492', (39, 41))	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('mutations', 'Var', (26, 35))	('sarcoma', 'Disease', (135, 142))	('HL', 'Phenotype', 'HP:0012189', (39, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('TP53', 'Gene', '7157', (21, 25))
114785	32316685	Recent advances in the classification of cutaneous mesenchymal neoplasms include description of recurrent chromosomal and genetic alterations in a significant subset of soft tissue tumors.	('cutaneous mesenchymal neoplasms', 'Disease', (41, 72))	('soft tissue tumors', 'Disease', (169, 187))	('soft tissue tumors', 'Disease', 'MESH:D012983', (169, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (169, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('neoplasm', 'Phenotype', 'HP:0002664', (63, 71))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (169, 187))	('cutaneous mesenchymal neoplasms', 'Disease', 'MESH:C535700', (41, 72))	('neoplasms', 'Phenotype', 'HP:0002664', (63, 72))	('chromosomal', 'Var', (106, 117))	('genetic alterations', 'Var', (122, 141))
114787	32316685	Inactivating mutations in the SMARCB1 (INI1) and SMARCB4 genes were recently described in a subset of soft tissue tumors with epithelioid or rhabdoid cell features.	('INI1', 'Gene', '6598', (39, 43))	('SMARCB1', 'Gene', '6598', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('INI1', 'Gene', (39, 43))	('SMARCB4', 'Gene', (49, 56))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (102, 119))	('SMARCB1', 'Gene', (30, 37))	('Inactivating mutations', 'Var', (0, 22))	('soft tissue tumors', 'Disease', (102, 120))	('soft tissue tumors', 'Disease', 'MESH:D012983', (102, 120))	('described', 'Reg', (77, 86))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (102, 120))	('epithelioid', 'Disease', (126, 137))
114834	32316685	Malignant glomus tumors are extremely rare, and the diagnosis of malignant glomus tumors should be reserved only for tumors showing marked nuclear atypia and any level of mitotic activity, or atypical mitotic figures.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('malignant glomus tumors', 'Disease', (65, 88))	('malignant glomus tumors', 'Disease', 'MESH:D005918', (65, 88))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (117, 123))	('atypical', 'Var', (192, 200))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('Malignant glomus tumors', 'Disease', 'MESH:D005918', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Malignant glomus tumors', 'Disease', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
114847	32316685	FOS gene rearrangements are present in the majority of bone and soft tissue epithelioid hemangiomas but are rare in cutaneous epithelioid hemangiomas.	('hemangioma', 'Phenotype', 'HP:0001028', (138, 148))	('hemangioma', 'Phenotype', 'HP:0001028', (88, 98))	('hemangiomas', 'Disease', 'MESH:D006391', (138, 149))	('FOS', 'Gene', (0, 3))	('hemangiomas', 'Disease', (138, 149))	('hemangiomas', 'Phenotype', 'HP:0001028', (138, 149))	('men', 'Species', '9606', (18, 21))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (76, 98))	('cutaneous epithelioid hemangiomas', 'Disease', 'MESH:D006391', (116, 149))	('hemangiomas', 'Disease', 'MESH:D006391', (88, 99))	('epithelioid hemangiomas', 'Phenotype', 'HP:0032060', (76, 99))	('epithelioid hemangiomas', 'Phenotype', 'HP:0032060', (126, 149))	('FOS', 'Gene', '2353', (0, 3))	('hemangiomas', 'Disease', (88, 99))	('rearrangements', 'Var', (9, 23))	('hemangiomas', 'Phenotype', 'HP:0001028', (88, 99))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (126, 148))	('cutaneous epithelioid hemangiomas', 'Disease', (116, 149))
114897	32316685	Loss-of-function mutations in ATP6AP1 and ATP6AP2 are present in about 70% of cases.	('Loss-of-function', 'NegReg', (0, 16))	('ATP6AP2', 'Gene', '10159', (42, 49))	('ATP6AP1', 'Gene', '537', (30, 37))	('ATP6AP1', 'Gene', (30, 37))	('ATP6AP2', 'Gene', (42, 49))	('mutations', 'Var', (17, 26))
114925	32316685	Approximately 80% of EMPNSTs show recurrent SMARCB1 (INI1) inactivation.	('INI1', 'Gene', '6598', (53, 57))	('SMARCB1', 'Gene', '6598', (44, 51))	('inactivation', 'Var', (59, 71))	('INI1', 'Gene', (53, 57))	('SMARCB1', 'Gene', (44, 51))
114933	32316685	Clear cell sarcomas are positive for melanocytic markers and show EWSR1 gene rearrangement.	('rearrangement', 'Var', (77, 90))	('EWSR1', 'Gene', (66, 71))	('men', 'Species', '9606', (86, 89))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('positive', 'Reg', (24, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcomas', 'Disease', (11, 19))	('EWSR1', 'Gene', '2130', (66, 71))
115013	32316685	BRAF mutations are observed in about 52% of malignant melanoma cases, but EWSR1 rearrangement has not been identified in malignant melanoma.	('malignant melanoma', 'Disease', 'MESH:D008545', (44, 62))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('malignant melanoma', 'Disease', (44, 62))	('malignant melanoma', 'Phenotype', 'HP:0002861', (121, 139))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('mutations', 'Var', (5, 14))	('EWSR1', 'Gene', (74, 79))	('malignant melanoma', 'Disease', 'MESH:D008545', (121, 139))	('BRAF', 'Gene', '673', (0, 4))	('malignant melanoma', 'Disease', (121, 139))	('EWSR1', 'Gene', '2130', (74, 79))	('BRAF', 'Gene', (0, 4))	('men', 'Species', '9606', (89, 92))	('malignant melanoma', 'Phenotype', 'HP:0002861', (44, 62))
115024	32316685	In contrast to visceral PEComas, cutaneous PEComas do not harbor TFE gene fusions and consistently lack TFE3 expression.	('lack', 'NegReg', (99, 103))	('visceral PEComas', 'Disease', 'MESH:D054973', (15, 31))	('expression', 'MPA', (109, 119))	('cutaneous PEComas', 'Disease', 'MESH:D054973', (33, 50))	('TFE3', 'Gene', '7030', (104, 108))	('cutaneous PEComas', 'Disease', (33, 50))	('visceral PEComas', 'Disease', (15, 31))	('TFE', 'Gene', (65, 68))	('fusions', 'Var', (74, 81))	('TFE3', 'Gene', (104, 108))
115053	31709173	Certain combinations of anti-cancer treatment resulted in a similar pattern of inadequate DC parameters, namely, a combination of temozolomide with irinotecan was associated with DCs showing poor maturation and decreased immunostimulatory features, and a combination of pazopanib, topotecan, and MTD-based cyclophosphamide was associated with poor monocyte differentiation and decreased DC immunostimulatory parameters.	('DC parameters', 'MPA', (90, 103))	('poor', 'NegReg', (191, 195))	('irinotecan', 'Chemical', 'MESH:C051890', (148, 158))	('decreased', 'NegReg', (377, 386))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (306, 322))	('DCs', 'Disease', (179, 182))	('temozolomide', 'Chemical', 'MESH:C047246', (130, 142))	('DC immunostimulatory parameters', 'MPA', (387, 418))	('poor monocyte', 'Phenotype', 'HP:0012312', (343, 356))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('combinations', 'Var', (8, 20))	('decreased', 'NegReg', (211, 220))	('pazopanib', 'Chemical', 'MESH:C516667', (270, 279))	('immunostimulatory features', 'MPA', (221, 247))
115061	31709173	Based on our experience, patients with neuroblastomas with a high MIBG score after induction therapy have very poor 2-year survival.	('neuroblastomas', 'Phenotype', 'HP:0003006', (39, 53))	('neuroblastomas', 'Disease', 'MESH:D009447', (39, 53))	('MIBG', 'Chemical', 'MESH:D019797', (66, 70))	('high', 'Var', (61, 65))	('neuroblastomas', 'Disease', (39, 53))	('patients', 'Species', '9606', (25, 33))	('neuroblastoma', 'Phenotype', 'HP:0003006', (39, 52))	('MIBG', 'Gene', (66, 70))	('poor', 'NegReg', (111, 115))
115083	31709173	All patients had to have adequate bone marrow, kidney, liver, and heart function, defined as absolute neutrophil count (ANC) >= 0.75 x 109/L, thrombocytes >= 75 x 109/L, hemoglobin 80 g/L, estimated glomerular filtration rate (eGFR) >= 70 mL/min/1.73 m2, serum creatinine <= 1.5-fold the upper limit for the appropriate age, bilirubin <= 1.5-fold the upper limit for the appropriate age, AST and ALT <= 2.5-fold the upper limit for the appropriate age, ejection fraction >= 50%, and fractional shortening >= 27% as assessed by echocardiography.	('ejection', 'MPA', (453, 461))	('creatinine', 'Chemical', 'MESH:D003404', (261, 271))	('fractional', 'MPA', (483, 493))	('>= 75 x 109/L', 'Var', (155, 168))	('bilirubin', 'MPA', (325, 334))	('patients', 'Species', '9606', (4, 12))	('bilirubin', 'Chemical', 'MESH:D001663', (325, 334))	('serum creatinine', 'MPA', (255, 271))
115086	31709173	The exclusion criteria were as follows: seropositivity to HIV1,2, Treponema pallidum, hepatitis B or C, known hypersensitivity to the study medication, autoimmune disease that was not adequately treated, uncontrolled psychiatric disease, or uncontrolled hypertension defined as systolic and diastolic blood pressure over the 95th percentile for the appropriate age and height (patients <= 17 years old) or >= 160/90 mmHg or diastolic blood pressure >= 90 mmHg (patients >= 17 years old).	('autoimmune disease', 'Disease', (152, 170))	('HIV1', 'Species', '11676', (58, 62))	('autoimmune disease', 'Disease', 'MESH:D001327', (152, 170))	('hepatitis B', 'Disease', 'MESH:D006509', (86, 97))	('hypersensitivity', 'Disease', (110, 126))	('autoimmune disease', 'Phenotype', 'HP:0002960', (152, 170))	('patients', 'Species', '9606', (377, 385))	('hypersensitivity', 'Disease', 'MESH:D004342', (110, 126))	('seropositivity', 'Var', (40, 54))	('hepatitis', 'Phenotype', 'HP:0012115', (86, 95))	('hypertension', 'Disease', 'MESH:D006973', (254, 266))	('psychiatric disease', 'Disease', (217, 236))	('hypertension', 'Disease', (254, 266))	('hepatitis B', 'Disease', (86, 97))	('diastolic blood pressure', 'MPA', (424, 448))	('psychiatric disease', 'Disease', 'MESH:D001523', (217, 236))	('psychiatric disease', 'Phenotype', 'HP:0000708', (217, 236))	('Treponema pallidum', 'Species', '160', (66, 84))	('hypertension', 'Phenotype', 'HP:0000822', (254, 266))	('patients', 'Species', '9606', (461, 469))
115132	31709173	Between April and September 2018, we performed elutriation in cases KDO-0121, -0137, and -0139, and adherence to plastic in cases KDO-0133, -0142, and -0144 due to there being > 10% neutrophils in the leukapheresis product or technical issues with the Elutra device for KDO-0119 and -0131.	('KDO-0119', 'Chemical', 'MESH:C002532', (270, 278))	('KDO-0121', 'Chemical', 'MESH:C002532', (68, 76))	('KDO-0121', 'Var', (68, 76))	('KDO-0133', 'Var', (130, 138))	('and -0139', 'Var', (85, 94))	('KDO-0133', 'Chemical', 'MESH:C002532', (130, 138))
115145	31709173	Batches KDO-0103 and KDO-0122 similarly exhibited poor yield, poor monocyte differentiation, a rather low IL-12/IL-10 ratio, and very low immunostimulatory functions toward donor T-cells.	('KDO-0122', 'Chemical', 'MESH:C002532', (21, 29))	('donor', 'Species', '9606', (173, 178))	('monocyte differentiation', 'CPA', (67, 91))	('low', 'NegReg', (102, 105))	('KDO-0122', 'Var', (21, 29))	('IL-12/IL-10 ratio', 'MPA', (106, 123))	('poor monocyte', 'Phenotype', 'HP:0012312', (62, 75))	('poor', 'NegReg', (62, 66))	('KDO-0103', 'Chemical', 'MESH:C002532', (8, 16))
115150	31709173	Notably, monocytes affected by retinoic acid (KDO-0135) or anti-RANKL denosumab (KDO-0124) produced DCs of average quality.	('KDO-0135', 'Var', (46, 54))	('KDO-0135', 'Chemical', 'MESH:C002532', (46, 54))	('KDO-0124', 'Var', (81, 89))	('KDO-0124', 'Chemical', 'MESH:C002532', (81, 89))	('retinoic acid', 'Chemical', 'MESH:D014212', (31, 44))
115158	31709173	We have previously shown that TKI pazopanib in vitro impairs the immunostimulatory properties of monocytes, including up-regulation of the immunoinhibitory surface molecule ILT-3 and decreased capability to up-regulate MHC II in response to LPS.	('impairs', 'NegReg', (53, 60))	('immunostimulatory properties of monocytes', 'MPA', (65, 106))	('pazopanib', 'Chemical', 'MESH:C516667', (34, 43))	('TKI pazopanib', 'Var', (30, 43))	('LPS', 'Disease', 'MESH:C536528', (241, 244))	('up-regulation', 'PosReg', (118, 131))	('decreased', 'NegReg', (183, 192))	('up-regulate', 'PosReg', (207, 218))	('MHC II', 'Enzyme', (219, 225))	('LPS', 'Disease', (241, 244))
115165	31709173	In vitro studies of TMZ/iri cytotoxicity to neuroblastoma cells have revealed single- or double-stranded DNA damage to be mostly due to SN-38 (the active metabolite of irinotecan) and to be further enhanced through the addition of TMZ.	('TMZ', 'Chemical', 'MESH:C047246', (20, 23))	('SN-38', 'Var', (136, 141))	('due', 'Reg', (129, 132))	('iri', 'Chemical', 'MESH:C051890', (168, 171))	('neuroblastoma', 'Disease', 'MESH:D009447', (44, 57))	('SN-38', 'Chemical', 'MESH:C051890', (136, 141))	('irinotecan', 'Chemical', 'MESH:C051890', (168, 178))	('iri', 'Chemical', 'MESH:C051890', (24, 27))	('neuroblastoma', 'Disease', (44, 57))	('single- or', 'MPA', (78, 88))	('TMZ', 'Chemical', 'MESH:C047246', (231, 234))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('toxicity', 'Disease', (32, 40))	('neuroblastoma', 'Phenotype', 'HP:0003006', (44, 57))
115168	31709173	Methotrexate has reportedly inducedl apoptosis, reduced viability, induced differentiation, and reduced inflammatory properties of monocytes, and we may speculate, although based on anecdotal observation, that if combined with cisplatin, thereby shifting monocyte differentiation into an immunosuppressive phenotype, methotrexate may result in failure of monocyte-derived DC generation.	('cisplatin', 'Chemical', 'MESH:D002945', (227, 236))	('methotrexate', 'Chemical', 'MESH:D008727', (317, 329))	('apoptosis', 'CPA', (37, 46))	('reduced', 'NegReg', (48, 55))	('Methotrexate', 'Var', (0, 12))	('viability', 'CPA', (56, 65))	('monocyte-derived DC generation', 'CPA', (355, 385))	('differentiation', 'CPA', (75, 90))	('Methotrexate', 'Chemical', 'MESH:D008727', (0, 12))	('inflammatory properties of monocytes', 'CPA', (104, 140))	('reduced', 'NegReg', (96, 103))
115180	31709173	As our model of ex vivo-activated DC preparation generally parallels the in vivo differentiation pathways of monocytes to the antigen-presenting cells, we may imply that drug combinations at doses used clinically may result in an impairment of patient DCs and possibly immune competence in general.	('combinations', 'Interaction', (175, 187))	('drug', 'Var', (170, 174))	('immune competence', 'CPA', (269, 286))	('patient', 'Species', '9606', (244, 251))	('patient DCs', 'CPA', (244, 255))	('result in', 'Reg', (217, 226))	('impairment', 'NegReg', (230, 240))
115188	29190494	FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway1 Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors.	('FAK', 'Gene', '14083', (111, 114))	('Myxoid Liposarcoma', 'Disease', (30, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('SRC', 'Gene', '20779', (59, 62))	('SRC', 'Gene', '20779', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Deregulated', 'Var', (95, 106))	('tumors', 'Disease', (183, 189))	('migration', 'CPA', (143, 152))	('Myxoid Liposarcoma', 'Phenotype', 'HP:0012268', (30, 48))	('CHOP', 'Gene', '13198', (4, 8))	('FUS', 'Gene', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('Liposarcoma', 'Phenotype', 'HP:0012034', (37, 48))	('enhanced', 'PosReg', (134, 142))	('FAK', 'Gene', (63, 66))	('FAK', 'Gene', (111, 114))	('rat', 'Species', '10116', (146, 149))	('invasion', 'CPA', (157, 165))	('FUS', 'Gene', '233908', (0, 3))	('Myxoid Liposarcoma', 'Disease', 'MESH:D018208', (30, 48))	('FAK', 'Gene', '14083', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('SRC', 'Gene', (59, 62))	('CHOP', 'Gene', (4, 8))	('SRC', 'Gene', (107, 110))
115193	29190494	The involvement of SRC/FAK activation in FUS-CHOP-mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA.	('CHOP', 'Gene', '13198', (45, 49))	('PF-573228', 'Var', (152, 161))	('FUS', 'Gene', '233908', (41, 44))	('PF-573228', 'Chemical', 'MESH:C521108', (152, 161))	('CHOP', 'Gene', (45, 49))	('dasatinib', 'Chemical', 'MESH:D000069439', (114, 123))	('FUS', 'Gene', (41, 44))
115194	29190494	Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations.	('PF573228', 'Var', (23, 31))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('block', 'NegReg', (55, 60))	('PF573228', 'Chemical', 'MESH:C521108', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('dasatinib', 'Chemical', 'MESH:D000069439', (9, 18))
115195	29190494	Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228.	('CHOP', 'Gene', '13198', (51, 55))	('MLC2', 'Gene', '17907', (132, 136))	('MLC2', 'Gene', (132, 136))	('dasatinib', 'Chemical', 'MESH:D000069439', (189, 198))	('FUS', 'Gene', '233908', (47, 50))	('FUS', 'Gene', (47, 50))	('PF573228', 'Chemical', 'MESH:C521108', (202, 210))	('CHOP', 'Gene', (51, 55))	('increases', 'PosReg', (67, 76))	('expression', 'Var', (56, 66))
115203	29190494	Deregulated activity of SRC-FAK signaling in cancer cells may lead to abnormal activation of several members of the Rho-family of GTPases, including RHOA/C (RHO) and RAC1, which are well-known regulators of cell migration and have been implicated in tumor cell invasion and metastasis.	('RAC1', 'Gene', '19353', (166, 170))	('Deregulated', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('RAC1', 'Gene', (166, 170))	('rat', 'Species', '10116', (215, 218))	('activity', 'MPA', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('activation', 'PosReg', (79, 89))	('RHOA/C (RHO', 'Gene', (149, 160))	('cancer', 'Disease', (45, 51))	('tumor', 'Disease', (250, 255))	('RHOA/C (RHO)', 'Gene', '212541', (149, 161))
115230	29190494	A pool of FAK-specific siRNAs (On-Target plus PTK-2 siRNA, L-003164-00-0005) and a siGenome RiSC-Free control siRNA (siControl; D-001220-01) were from Dharmacon (Lafayette, CO).	('RiSC', 'Gene', (92, 96))	('PTK-2', 'Gene', (46, 51))	('PTK-2', 'Gene', '14083', (46, 51))	('RiSC', 'Gene', '74617', (92, 96))	('L-003164-00-0005', 'Var', (59, 75))
115243	29190494	We found that, compared to MSC-4H-GFP cells, FUS-CHOP expression in MSC-4H-FC cells increased the phosphorylation levels of activating residues in SRC (Y-419) and FAK (Y-397) as well as the total protein levels of FAK (Figure 1A and Supplementary Figure S1).	('phosphorylation levels', 'MPA', (98, 120))	('4H', 'Chemical', '-', (31, 33))	('activating residues', 'MPA', (124, 143))	('Y-419', 'Var', (152, 157))	('CHOP', 'Gene', '13198', (49, 53))	('increased', 'PosReg', (84, 93))	('4H', 'Chemical', '-', (72, 74))	('FUS', 'Gene', '233908', (45, 48))	('CHOP', 'Gene', (49, 53))	('protein levels', 'MPA', (196, 210))	('FUS', 'Gene', (45, 48))
115245	29190494	Confirming the ability of FUS-CHOP to activate this pathway, its depletion in MSC-4H-FC cells using an shRNA designed to target CHOP prevented SRC/FAK activation, thereby reducing the levels of phospho-SRC (Y-419), phospho-FAK (Y-397), and total FAK (Figure 1A and Supplementary Figure S1).	('CHOP', 'Gene', (128, 132))	('reducing', 'NegReg', (171, 179))	('CHOP', 'Gene', '13198', (30, 34))	('levels', 'MPA', (184, 190))	('FUS', 'Gene', '233908', (26, 29))	('FUS', 'Gene', (26, 29))	('phospho-FAK', 'MPA', (215, 226))	('4H', 'Chemical', '-', (82, 84))	('CHOP', 'Gene', '13198', (128, 132))	('SRC/FAK activation', 'MPA', (143, 161))	('depletion', 'Var', (65, 74))	('CHOP', 'Gene', (30, 34))	('FAK', 'MPA', (246, 249))	('prevented', 'NegReg', (133, 142))
115248	29190494	Using live cell time-lapse microscopy, we found that MSC-4H-FC spheroids showed highly increased invasive properties when compared with MSC-4H-GFP spheroids.	('increased', 'PosReg', (87, 96))	('4H', 'Chemical', '-', (57, 59))	('4H', 'Chemical', '-', (140, 142))	('invasive properties', 'CPA', (97, 116))	('MSC-4H-FC', 'Var', (53, 62))
115249	29190494	Importantly, these statistically significant differences were completely reverted by FUS-CHOP depletion in MSC-4H-FC-shCHOP spheroids (Figure 1, B-C and Videos S1-S3).	('CHOP', 'Gene', '13198', (119, 123))	('FUS', 'Gene', '233908', (85, 88))	('CHOP', 'Gene', '13198', (89, 93))	('FUS', 'Gene', (85, 88))	('depletion', 'Var', (94, 103))	('CHOP', 'Gene', (119, 123))	('CHOP', 'Gene', (89, 93))	('4H', 'Chemical', '-', (111, 113))
115252	29190494	We observed that both cell types were able to extravasate out of the CAM vasculature; however, in accordance with in vitro results, MSC-4H-FC cells showed a significant increase in the extravasation efficiency (Figure 1, D and E).	('CAM', 'Gene', '71817', (69, 72))	('4H', 'Chemical', '-', (136, 138))	('increase', 'PosReg', (169, 177))	('extravasation efficiency', 'MPA', (185, 209))	('MSC-4H-FC', 'Var', (132, 141))	('CAM', 'Gene', (69, 72))
115256	29190494	In any case, dasatinib efficiently inhibited SRC-dependent phosphorylation of FAK on Y861, which is a requisite for an effective activation of this kinase (Figure 2A and Supplementary Figure S2).	('Y861', 'Var', (85, 89))	('dasatinib', 'Chemical', 'MESH:D000069439', (13, 22))	('SRC-dependent phosphorylation', 'MPA', (45, 74))	('FAK', 'Protein', (78, 81))	('inhibited', 'NegReg', (35, 44))
115257	29190494	In addition, the phosphorylation/activation of AKT (S473) was also reduced upon dasatinib treatment as efficiently as phospho-SRC (Y419) or phospho-FAK (Y861) (Figure 2A and Supplementary Figure S2).	('AKT', 'Gene', (47, 50))	('phosphorylation/activation', 'PosReg', (17, 43))	('S473', 'Var', (52, 56))	('reduced', 'NegReg', (67, 74))	('AKT', 'Gene', '11651', (47, 50))	('phosphorylation/activation', 'MPA', (17, 43))	('dasatinib', 'Chemical', 'MESH:D000069439', (80, 89))
115263	29190494	A 24-hour treatment with PF-573228 caused an effective dose-dependent inhibition of FAK phosphorylation (Figure 3A and Supplementary Figure S3, A-B).	('inhibition', 'NegReg', (70, 80))	('PF-573228', 'Var', (25, 34))	('FAK phosphorylation', 'MPA', (84, 103))	('PF-573228', 'Chemical', 'MESH:C521108', (25, 34))
115265	29190494	Mimicking the inhibitory effect on FAK phosphorylation, PF-573228 induced a dose-dependent inhibition of the invasive capability of MSC-4H-FC spheroids (Figure 3, B-C and Videos S10-S14).	('PF-573228', 'Var', (56, 65))	('4H', 'Chemical', '-', (136, 138))	('invasive capability', 'CPA', (109, 128))	('inhibition', 'NegReg', (91, 101))	('PF-573228', 'Chemical', 'MESH:C521108', (56, 65))
115266	29190494	In vivo, 10 muM of PF-573228 also inhibited cell extravasation out of the CAM vasculature (Figure 3, D-E).	('cell', 'CPA', (44, 48))	('CAM', 'Gene', (74, 77))	('inhibited', 'NegReg', (34, 43))	('PF-573228', 'Var', (19, 28))	('CAM', 'Gene', '71817', (74, 77))	('PF-573228', 'Chemical', 'MESH:C521108', (19, 28))
115267	29190494	Interestingly, intravital imaging revealed the release of extracellular vesicles or microparticles by intravascular PF-573228-treated cells into the stroma (Figure 3D).	('PF-573228', 'Chemical', 'MESH:C521108', (116, 125))	('release of extracellular vesicles', 'MPA', (47, 80))	('PF-573228-treated', 'Var', (116, 133))	('microparticles', 'MPA', (84, 98))
115268	29190494	Similar to that observed for dasatinib, 24-hour treatment with PF-573228 only induced mild/moderate antiproliferative effects in MSC-4H-GFP and MSC-4H-FC cells, although cytotoxicity increased at 48-hour treatment (Figure 3F).	('cytotoxicity', 'Disease', (170, 182))	('rat', 'Species', '10116', (111, 114))	('antiproliferative effects', 'MPA', (100, 125))	('rat', 'Species', '10116', (95, 98))	('cytotoxicity', 'Disease', 'MESH:D064420', (170, 182))	('4H', 'Chemical', '-', (133, 135))	('PF-573228', 'Chemical', 'MESH:C521108', (63, 72))	('dasatinib', 'Chemical', 'MESH:D000069439', (29, 38))	('4H', 'Chemical', '-', (148, 150))	('PF-573228', 'Var', (63, 72))
115270	29190494	Similar to that observed by pharmacologic inhibition of FAK, phospho-AKT (S473) levels also decreased upon FAK depletion, while SRC (Y-419) phosphorylation, instead of being reduced, was increased (Figure 3G and Supplementary Figure S3C).	('AKT', 'Gene', (69, 72))	('FAK depletion', 'Var', (107, 120))	('increased', 'PosReg', (187, 196))	('decreased', 'NegReg', (92, 101))	('AKT', 'Gene', '11651', (69, 72))	('depletion', 'Var', (111, 120))
115272	29190494	As seen, phosphorylation/activation of AKT (S473) was efficiently downregulated by dasatinib (Figure 2A), PF-573228 (Figure 3A), or FAK-siRNA (Figure 3E).	('phosphorylation/activation', 'MPA', (9, 35))	('PF-573228', 'Chemical', 'MESH:C521108', (106, 115))	('AKT', 'Gene', '11651', (39, 42))	('dasatinib', 'Chemical', 'MESH:D000069439', (83, 92))	('downregulated', 'NegReg', (66, 79))	('phosphorylation/activation', 'PosReg', (9, 35))	('S473', 'Var', (44, 48))	('PF-573228', 'Var', (106, 115))	('AKT', 'Gene', (39, 42))
115275	29190494	Therefore, we treated the 1765-92 cell line with dasatinib or PF-573228 and checked phospho-SRC and phospho-FAK levels as well as the ability to invade.	('PF-573228', 'Chemical', 'MESH:C521108', (62, 71))	('invade', 'CPA', (145, 151))	('dasatinib', 'Chemical', 'MESH:D000069439', (49, 58))	('checked', 'Reg', (76, 83))	('PF-573228', 'Var', (62, 71))	('phospho-FAK levels', 'MPA', (100, 118))
115276	29190494	Consistent with our results in MSC-4H-FC cells, dasatinib inhibited the phosphorylation of SRC (Y419) and AKT (S473), while PF-573228 efficiently reduced the phosphorylation levels of FAK (Y397) and AKT (S473) but not SRC (Y419) (Figure 4A and Supplementary Figure S5).	('AKT', 'Gene', (106, 109))	('AKT', 'Gene', (199, 202))	('PF-573228', 'Var', (124, 133))	('reduced', 'NegReg', (146, 153))	('dasatinib', 'Chemical', 'MESH:D000069439', (48, 57))	('phosphorylation', 'MPA', (72, 87))	('phosphorylation levels', 'MPA', (158, 180))	('4H', 'Chemical', '-', (35, 37))	('inhibited', 'NegReg', (58, 67))	('AKT', 'Gene', '11651', (106, 109))	('AKT', 'Gene', '11651', (199, 202))	('PF-573228', 'Chemical', 'MESH:C521108', (124, 133))	('FAK', 'MPA', (184, 187))	('SRC', 'Protein', (91, 94))
115283	29190494	Interestingly, when FAK expression was compared between malignant and benign/low-malignant tumors, high FAK expression was strongly and significantly associated with malignant sarcomas (P = .009).	('tumors', 'Disease', (91, 97))	('associated', 'Reg', (150, 160))	('malignant sarcomas', 'Disease', 'MESH:D009369', (166, 184))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('high FAK', 'Var', (99, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('malignant sarcomas', 'Disease', (166, 184))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
115289	29190494	First, we found that tumorsphere cultures of MSC-4H-GFP cells showed higher levels of phospho-FAK (Y861 and Y397), phospho-SRC (Y418), and phospho-AKT (S473) than unselected adherent cultures, while the levels of these phospho-kinases remained consistently high in MSC-4H-FC adherent and tumorsphere cultures (Figure 6B and Supplementary Figure S6).	('Y861', 'Var', (99, 103))	('Y397', 'Var', (108, 112))	('tumors', 'Disease', (288, 294))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('Y418', 'Var', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('AKT', 'Gene', '11651', (147, 150))	('4H', 'Chemical', '-', (269, 271))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('4H', 'Chemical', '-', (49, 51))	('higher', 'PosReg', (69, 75))	('phospho-SRC', 'MPA', (115, 126))	('phospho-FAK', 'MPA', (86, 97))	('AKT', 'Gene', (147, 150))
115290	29190494	As expected, we found that spheroids formed from MSC-4H-FC tumorspheres were able to invade 3D collagen matrices more efficiently than spheroids derived from the fraction of cells unable to form tumorspheres (Figure 6, C-D and Videos S21-S24).	('efficiently', 'PosReg', (118, 129))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('4H', 'Chemical', '-', (53, 55))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('MSC-4H-FC', 'Var', (49, 58))	('invade 3D collagen matrices', 'CPA', (85, 112))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
115291	29190494	Notably, dasatinib and PF-573228 were able to reduce invasion in spheroids-derived from tumorspheres (Figure 6, C-D and Videos S21-S24) as efficiently as in those derived from the unselected bulk tumor population (Figure 2C and Supplementary Figure 3C).	('PF-573228', 'Chemical', 'MESH:C521108', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('reduce', 'NegReg', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('invasion', 'CPA', (53, 61))	('PF-573228', 'Var', (23, 32))	('dasatinib', 'Chemical', 'MESH:D000069439', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
115292	29190494	Altogether, these results indicate that FAK inhibition prevents self-renewal and invasive potential of FUS-CHOP-expressing CSCs.	('invasive potential', 'CPA', (81, 99))	('self-renewal', 'CPA', (64, 76))	('FUS', 'Gene', (103, 106))	('inhibition', 'Var', (44, 54))	('FAK', 'Gene', (40, 43))	('CHOP', 'Gene', '13198', (107, 111))	('prevents', 'NegReg', (55, 63))	('FUS', 'Gene', '233908', (103, 106))	('CHOP', 'Gene', (107, 111))
115296	29190494	The ratio between phosphorylated and total forms of MLC2 was 3 times higher in MSC-4H-FC than in MSC-4H-GFP (Figure S7B), indicating that FUS-CHOP expression may act by regulating both the phosphorylation levels and the total MLC2 protein expression.	('4H', 'Chemical', '-', (83, 85))	('CHOP', 'Gene', (142, 146))	('MLC2', 'Gene', (52, 56))	('4H', 'Chemical', '-', (101, 103))	('MSC-4H-FC', 'Var', (79, 88))	('MLC2', 'Gene', '17907', (52, 56))	('CHOP', 'Gene', '13198', (142, 146))	('FUS', 'Gene', (138, 141))	('phosphorylation levels', 'MPA', (189, 211))	('rat', 'Species', '10116', (4, 7))	('FUS', 'Gene', '233908', (138, 141))	('higher', 'PosReg', (69, 75))	('MLC2', 'Gene', '17907', (226, 230))	('MLC2', 'Gene', (226, 230))	('regulating', 'Reg', (169, 179))
115298	29190494	Importantly, concentrations of RKI-1447 as low as 0.5 muM were able to completely abolish the invasion of MSC-4H-FC 3D spheroids (Figure 7C-D and Videos S25-S29) and to significantly reduce cell extravasation out of the CAM vasculature (Figure 7E) without having any relevant effect on cell proliferation (Figure 7F).	('invasion', 'CPA', (94, 102))	('CAM', 'Gene', '71817', (220, 223))	('RKI-1447', 'Var', (31, 39))	('rat', 'Species', '10116', (298, 301))	('rat', 'Species', '10116', (20, 23))	('CAM', 'Gene', (220, 223))	('abolish', 'NegReg', (82, 89))	('4H', 'Chemical', '-', (110, 112))	('reduce', 'NegReg', (183, 189))
115300	29190494	In addition, both dasatinib and PF-573228 were able to prevent MLC2 phosphorylation (Figure 7B and Supplementary Figure S7, C-D), thus reflecting that SRC and FAK are upstream mediators of the activation of RHO/ROCK signaling.	('PF-573228', 'Chemical', 'MESH:C521108', (32, 41))	('MLC2', 'Gene', '17907', (63, 67))	('MLC2', 'Gene', (63, 67))	('dasatinib', 'Chemical', 'MESH:D000069439', (18, 27))	('PF-573228', 'Var', (32, 41))	('prevent', 'NegReg', (55, 62))
115302	29190494	Deregulated SRC/FAK signaling has been extensively related with enhanced migration and invasion in many types of tumors.	('migration', 'CPA', (73, 82))	('Deregulated', 'Var', (0, 11))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('rat', 'Species', '10116', (76, 79))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('invasion', 'CPA', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SRC/FAK', 'MPA', (12, 19))	('enhanced', 'PosReg', (64, 72))
115304	29190494	In addition, the expression of FUS-CHOP in sarcoma cell lines increases migration and invasion and enhances the metastatic potential in these cells.	('FUS-CHOP in sarcoma cell lines increases migration', 'Disease', (31, 81))	('enhances', 'PosReg', (99, 107))	('expression', 'Var', (17, 27))	('metastatic potential in these cells', 'CPA', (112, 147))	('invasion', 'CPA', (86, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('FUS-CHOP in sarcoma cell lines increases migration', 'Disease', 'MESH:D012509', (31, 81))
115309	29190494	We found that the expression of FUS-CHOP induced the activation of SRC and the upregulation/activation of FAK and enhanced invasive potential.	('FUS', 'Gene', '233908', (32, 35))	('FUS', 'Gene', (32, 35))	('invasive potential', 'CPA', (123, 141))	('CHOP', 'Gene', (36, 40))	('activation', 'PosReg', (53, 63))	('upregulation/activation', 'PosReg', (79, 102))	('enhanced', 'PosReg', (114, 122))	('CHOP', 'Gene', '13198', (36, 40))	('SRC', 'Protein', (67, 70))	('FAK', 'Protein', (106, 109))	('expression', 'Var', (18, 28))
115310	29190494	Moreover, using dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA, we confirmed the hypothesis that the activation of SRC/FAK pathway is mediating the invasive properties induced by FUS-CHOP.	('CHOP', 'Gene', '13198', (199, 203))	('PF-573228', 'Var', (54, 63))	('FUS', 'Gene', '233908', (195, 198))	('CHOP', 'Gene', (199, 203))	('PF-573228', 'Chemical', 'MESH:C521108', (54, 63))	('FUS', 'Gene', (195, 198))	('dasatinib', 'Chemical', 'MESH:D000069439', (16, 25))	('SRC/FAK pathway', 'Pathway', (131, 146))
115311	29190494	Treatment with dasatinib or PF-573228 also had a partial impact on cell proliferation/survival, although these antiproliferative effects become relevant at later time points and/or higher drug concentrations than those that efficiently blocked cell invasion, thus suggesting that these drugs behave as genuine anti-invasive agents in sarcoma cells.	('sarcoma', 'Disease', (334, 341))	('rat', 'Species', '10116', (200, 203))	('cell proliferation/survival', 'CPA', (67, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (334, 341))	('dasatinib', 'Chemical', 'MESH:D000069439', (15, 24))	('PF-573228', 'Chemical', 'MESH:C521108', (28, 37))	('rat', 'Species', '10116', (122, 125))	('rat', 'Species', '10116', (79, 82))	('PF-573228', 'Var', (28, 37))	('sarcoma', 'Disease', 'MESH:D012509', (334, 341))
115312	29190494	Given that the inhibition of both kinases efficiently inhibits invasion, these findings show that FAK is a downstream effector of SRC activation and its activation is critical for FUS-CHOP-induced invasive phenotype.	('FUS', 'Gene', '233908', (180, 183))	('CHOP', 'Gene', (184, 188))	('FUS', 'Gene', (180, 183))	('SRC', 'Protein', (130, 133))	('invasion', 'CPA', (63, 71))	('inhibits', 'NegReg', (54, 62))	('CHOP', 'Gene', '13198', (184, 188))	('inhibition', 'Var', (15, 25))
115325	29190494	Therefore, the inhibition of this signaling could represent a potential antimetastatic therapeutic strategy for this type of tumors.	('rat', 'Species', '10116', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('inhibition', 'Var', (15, 25))
115487	30595709	Genetic defects have found to be responsible for 15% of children's cancers in general, but they play a more important role in specific types of pediatric cancers such as adrenocortical carcinoma and a less important role in some other types such as acute lymphocytic leukemia (ALL).	('Genetic defects', 'Var', (0, 15))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (249, 275))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (170, 194))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (170, 194))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('leukemia', 'Phenotype', 'HP:0001909', (267, 275))	('adrenocortical carcinoma', 'Disease', (170, 194))	('children', 'Species', '9606', (56, 64))	('ALL', 'Phenotype', 'HP:0006721', (277, 280))	('pediatric cancers', 'Disease', (144, 161))	('acute lymphocytic leukemia', 'Disease', (249, 275))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('pediatric cancers', 'Disease', 'MESH:D009369', (144, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (249, 275))
115599	29239891	Smoking also increases peripheral immune activation, compounding the state of chronic inflammation produced by HIV infection and the risk of lung cancer.	('increases', 'PosReg', (13, 22))	('inflammation', 'Disease', (86, 98))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('Smoking', 'Var', (0, 7))	('HIV infection', 'Disease', (111, 124))	('lung cancer', 'Disease', (141, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('peripheral', 'MPA', (23, 33))	('HIV infection', 'Disease', 'MESH:D015658', (111, 124))	('inflammation', 'Disease', 'MESH:D007249', (86, 98))
115666	28900340	Adverse prognostic factors include tumor size >5 cm, high-grade histology, positive or close margin status, and presence of NF-1 disease.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('NF-1 disease', 'Disease', 'MESH:C537392', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('high-grade', 'Var', (53, 63))	('tumor', 'Disease', (35, 40))	('NF-1 disease', 'Disease', (124, 136))
115690	28168190	Her medical history revealed an AML diagnosed 2 years earlier and classified as M4/M5 according to the French-American-British classification with FLT3-ITD and NPM1 mutations.	('AML', 'Disease', 'MESH:D015470', (32, 35))	('NPM1', 'Gene', '4869', (160, 164))	('AML', 'Phenotype', 'HP:0004808', (32, 35))	('AML', 'Disease', (32, 35))	('NPM1', 'Gene', (160, 164))	('FLT3-ITD', 'Disease', 'None', (147, 155))	('mutations', 'Var', (165, 174))	('FLT3-ITD', 'Disease', (147, 155))
115751	26029016	Here, we describe a case of a young woman with a de novo mutation in TP53 and multiple malignancies, with her most recent cancers found at early, curable stages due to aggressive cancer screening.	('mutation', 'Var', (57, 65))	('aggressive cancer', 'Disease', (168, 185))	('TP53', 'Gene', '7157', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('TP53', 'Gene', (69, 73))	('multiple malignancies', 'Disease', 'MESH:D009369', (78, 99))	('woman', 'Species', '9606', (36, 41))	('multiple malignancies', 'Disease', (78, 99))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('aggressive cancer', 'Disease', 'MESH:D009369', (168, 185))
115757	26029016	When individuals harbor a defective copy of the TP53 gene, they become prone to cancer development if the cell can no longer utilize a functional p53 protein to repair DNA or initiate normal apoptosis.	('defective', 'Var', (26, 35))	('TP53', 'Gene', '7157', (48, 52))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('TP53', 'Gene', (48, 52))	('prone', 'Reg', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
115758	26029016	While mutations in TP53 are typically inherited in an autosomal dominant manner, some families with Li-Fraumeni cancer phenotypes do not harbor an identifiable mutation or, on other occasions, TP53 mutations can arise de novo in an individual without a remarkable family history.	('Li-Fraumeni cancer', 'Disease', 'MESH:D016864', (100, 118))	('Li-Fraumeni cancer', 'Disease', (100, 118))	('TP53', 'Gene', '7157', (193, 197))	('mutations', 'Var', (198, 207))	('TP53', 'Gene', (193, 197))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (6, 15))
115760	26029016	In 2009, DNA sequencing of 525 patients with clinical suspicion of Li-Fraumeni syndrome found mutations in 91 patients.	('mutations', 'Var', (94, 103))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (67, 87))	('Li-Fraumeni syndrome', 'Disease', (67, 87))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (110, 118))
115761	26029016	All families with a TP53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma, and these were identified as "core cancers" in this syndrome.	('sarcoma', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('TP53', 'Gene', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('cancers', 'Disease', (160, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('mutation', 'Var', (25, 33))	('adrenocortical carcinoma', 'Disease', (99, 123))	('brain', 'Disease', (89, 94))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (99, 123))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (99, 123))	('TP53', 'Gene', '7157', (20, 24))	('breast', 'Disease', (81, 87))
115764	26029016	For female carriers of a TP53 mutation, lifetime risk of cancer by age 60 approaches 90 percent, with average age of first cancer diagnosis reported to be 28.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('TP53', 'Gene', (25, 29))	('cancer', 'Disease', (57, 63))	('mutation', 'Var', (30, 38))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TP53', 'Gene', '7157', (25, 29))
115785	26029016	The patient has no children of her own at this time, but she was counseled that as a confirmed TP53 germline mutation carrier, she has a 50 percent chance of passing the mutation on to her future children.	('patient', 'Species', '9606', (4, 11))	('children', 'Species', '9606', (19, 27))	('children', 'Species', '9606', (196, 204))	('passing', 'Reg', (158, 165))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('mutation', 'Var', (170, 178))
115795	26029016	While the lack of a strong family history in this case is unusual for Li-Fraumeni syndrome, de novo TP53 mutations are felt to arise in 7 to 20 percent of all cases.	('TP53', 'Gene', '7157', (100, 104))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (70, 90))	('TP53', 'Gene', (100, 104))	('Li-Fraumeni syndrome', 'Disease', (70, 90))	('mutations', 'Var', (105, 114))
115799	26029016	Her specific germline TP53 mutation, namely IVS6-2A>G, might be predicted to yield a mild phenotype.	('IVS6-2A>G', 'Var', (44, 53))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))	('IVS6-2A>G', 'Mutation', 'c.IVS6-2A>G', (44, 53))
115807	26029016	The differential diagnosis of Li-Fraumeni syndrome includes other inherited cancer syndromes, including hereditary breast and ovarian cancer syndrome, typically characterized by mutations in BRCA 1 and 2, and hereditary non-polyposis colorectal carcinoma (Lynch) syndrome.	('hereditary non-polyposis colorectal carcinoma', 'Phenotype', 'HP:0006716', (209, 254))	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('hereditary non-polyposis colorectal carcinoma (Lynch) syndrome', 'Disease', 'MESH:D003123', (209, 271))	('polyposis colorectal carcinoma', 'Phenotype', 'HP:0200063', (224, 254))	('characterized by', 'Reg', (161, 177))	('BRCA 1 and 2', 'Gene', '672;675', (191, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (30, 50))	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (104, 149))	('cancer syndromes', 'Disease', 'MESH:D009369', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer syndromes', 'Disease', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (178, 187))	('Li-Fraumeni syndrome', 'Disease', (30, 50))
115811	26029016	If mutations in BRCA 1/2 and/or Lynch syndrome-associated genes have been considered and not found, screening for Li-Fraumeni syndrome may be appropriate.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (114, 134))	('BRCA 1/2', 'Gene', (16, 24))	('Li-Fraumeni syndrome', 'Disease', (114, 134))	('Lynch syndrome', 'Disease', (32, 46))	('Lynch syndrome', 'Disease', 'MESH:D003123', (32, 46))	('mutations', 'Var', (3, 12))	('BRCA 1/2', 'Gene', '672;675', (16, 24))
115813	26029016	In general, the Classic and Chompret criteria can help identify families at risk for germline p53 mutation, though it is important to remember that negative results do not rule out a diagnosis of Li-Fraumeni syndrome if the personal or family history is suggestive of the syndrome.	('Li-Fraumeni syndrome', 'Disease', (196, 216))	('p53', 'Gene', '7157', (94, 97))	('p53', 'Gene', (94, 97))	('mutation', 'Var', (98, 106))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (196, 216))
115814	26029016	While most guidelines generally suggest testing for TP53 mutations in families with classic tumor types (sarcoma, breast, adrenocortical carcinoma, and brain tumors) and with cancer onset < age 45, an important independent testing criteria for clinicians to recognize is that all women with early-onset breast cancer (age of diagnosis < 35), regardless of family history, should also be considered for TP53 mutation testing, particularly if the breast tumor is Her2-positive.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('Her2', 'Gene', '2064', (461, 465))	('breast tumor', 'Disease', 'MESH:D001943', (445, 457))	('cancer', 'Disease', (175, 181))	('women', 'Species', '9606', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (452, 457))	('mutations', 'Var', (57, 66))	('brain tumors', 'Phenotype', 'HP:0030692', (152, 164))	('Her2', 'Gene', (461, 465))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('breast tumor', 'Phenotype', 'HP:0100013', (445, 457))	('brain tumors', 'Disease', 'MESH:D001932', (152, 164))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (122, 146))	('cancer', 'Disease', (310, 316))	('TP53', 'Gene', (402, 406))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('TP53', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('breast tumor', 'Disease', (445, 457))	('mutation', 'Var', (407, 415))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (122, 146))	('brain tumors', 'Disease', (152, 164))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('sarcoma', 'Disease', (105, 112))	('adrenocortical carcinoma', 'Disease', (122, 146))	('classic tumor', 'Disease', 'MESH:D005693', (84, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('TP53', 'Gene', '7157', (402, 406))	('classic tumor', 'Disease', (84, 97))	('TP53', 'Gene', '7157', (52, 56))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))
115822	26029016	Knowing she carried a TP53 mutation, she then opted to pursue bilateral mastectomies, not only to avoid radiation treatment but primarily to prevent future breast cancers from developing.	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutation', 'Var', (27, 35))	('breast cancers', 'Phenotype', 'HP:0003002', (156, 170))	('TP53', 'Gene', '7157', (22, 26))	('breast cancers', 'Disease', 'MESH:D001943', (156, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('TP53', 'Gene', (22, 26))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('breast cancers', 'Disease', (156, 170))
115826	26029016	In 33 asymptomatic TP53 mutation carriers, Villani et al.	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('mutation', 'Var', (24, 32))
115832	26029016	At the time of the discovery of her deleterious TP53 mutation, this patient expressed a sense of "exhaustion" about her clinical course thus far and indicated her worry about how many times she would have to go through cancer diagnosis and treatment before "enough was enough."	('TP53', 'Gene', '7157', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('mutation', 'Var', (53, 61))	('patient', 'Species', '9606', (68, 75))	('TP53', 'Gene', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))
115834	26029016	Very little exists in the literature specifically addressing psychosocial distress in Li-Fraumeni syndrome, though one small study reported that 36 percent of TP53 carriers report unnecessary worry as a barrier to screening adherence.	('psychosocial distress', 'Disease', (61, 82))	('psychosocial distress', 'Disease', 'MESH:C535569', (61, 82))	('Li-Fraumeni syndrome', 'Disease', (86, 106))	('TP53', 'Gene', '7157', (159, 163))	('unnecessary worry', 'Phenotype', 'HP:0000739', (180, 197))	('TP53', 'Gene', (159, 163))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (86, 106))	('carriers', 'Var', (164, 172))
115892	23351285	In the presence of a partial epithelial differentiation, the basic requirement for the diagnosis of a primary sarcoma of the breast is the exclusion of epithelial origin (axillary lymph node dissection is necessary) but the wide sampling we performed and the immunohistochemical negativity for cytokeratins and EMA exclude this diagnosis.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('EMA', 'Gene', '4582', (311, 314))	('sarcoma', 'Disease', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('partial epithelial', 'Var', (21, 39))	('men', 'Species', '9606', (74, 77))	('EMA', 'Gene', (311, 314))
115898	23351285	In the stromal component, the immunohistochemical strainings show positivity for vimentin and, variably, for pan-cytocheratin and cytocheratin 7.	('vimentin', 'Gene', (81, 89))	('pan-cytocheratin', 'Protein', (109, 125))	('vimentin', 'Gene', '7431', (81, 89))	('positivity', 'Var', (66, 76))
115910	23351285	Immunochemistry usually points out the positivity of stromal cells for CD34 and bcl-2 in 25< of the cases.	('CD34', 'Gene', '947', (71, 75))	('CD34', 'Gene', (71, 75))	('bcl-2', 'Gene', (80, 85))	('positivity', 'Var', (39, 49))	('bcl-2', 'Gene', '596', (80, 85))
115913	23351285	Immunohistochemistry showed positivity of the spindle cells for vimentin and, variably, for muscle actin and smooth muscle actin.	('smooth muscle actin', 'Protein', (109, 128))	('positivity', 'Var', (28, 38))	('vimentin', 'Gene', '7431', (64, 72))	('vimentin', 'Gene', (64, 72))	('muscle actin', 'Protein', (92, 104))
115919	23351285	Immunohistochemical staining shows positivity for vimentin and variably for CD34, and negativity for cytokeratin, S-100 and actin.	('cytokeratin', 'Protein', (101, 112))	('actin', 'Protein', (124, 129))	('positivity', 'Var', (35, 45))	('vimentin', 'Gene', '7431', (50, 58))	('vimentin', 'Gene', (50, 58))	('CD34', 'Gene', '947', (76, 80))	('S-100', 'Gene', (114, 119))	('S-100', 'Gene', '6285', (114, 119))	('CD34', 'Gene', (76, 80))
115938	23351285	Immunohistochemical evaluation shows positivity for vimentin, actin and CD10.	('actin', 'Protein', (62, 67))	('vimentin', 'Gene', '7431', (52, 60))	('CD10', 'Gene', (72, 76))	('vimentin', 'Gene', (52, 60))	('CD10', 'Gene', '4311', (72, 76))	('positivity', 'Var', (37, 47))
115981	20582972	CB17SC-M scid-/- female mice (Taconic Farms, Germantown NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described.	('osteosarcoma', 'Disease', (150, 162))	('osteosarcoma', 'Disease', 'MESH:D012516', (150, 162))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('non-glioblastoma brain tumors', 'Disease', (202, 231))	('CB17SC-M', 'Var', (0, 8))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (164, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('mice', 'Species', '10090', (252, 256))	('sarcomas', 'Disease', (133, 141))	('neuroblastoma', 'Disease', (183, 196))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (164, 180))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('rhabdoid tumors', 'Disease', (116, 131))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (116, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('neuroblastoma', 'Phenotype', 'HP:0003006', (183, 196))	('glioma', 'Disease', (271, 277))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('neuroblastoma', 'Disease', 'MESH:D009447', (183, 196))	('osteosarcoma', 'Phenotype', 'HP:0002669', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('glioma', 'Disease', 'MESH:D005910', (271, 277))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('mice', 'Species', '10090', (24, 28))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('non-glioblastoma brain tumors', 'Disease', 'MESH:D005909', (202, 231))	('brain tumors', 'Phenotype', 'HP:0030692', (219, 231))	('rhabdomyosarcoma', 'Disease', (164, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))
116018	20582972	Of note is the similar sensitivity to NTX-010 in Rh30 xenografts (established at diagnosis) and Rh30R xenografts (established at patient relapse), suggesting NTX-010 has therapeutic utility in both chemosensitive and chemorefractory disease.	('NTX-010', 'Chemical', '-', (38, 45))	('Rh30', 'Gene', (96, 100))	('Rh30', 'Gene', (49, 53))	('NTX-010', 'Var', (158, 165))	('Rh30', 'Gene', '6007', (96, 100))	('Rh30', 'Gene', '6007', (49, 53))	('NTX-010', 'Chemical', '-', (158, 165))	('patient', 'Species', '9606', (129, 136))
116053	32923153	STS are classically divided into sarcoma with complex genomic profile (SCG) and sarcoma driven by a specific genomic abnormality (translocation, mutation, amplification).	('amplification', 'Var', (155, 168))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('sarcoma', 'Disease', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcoma', 'Disease', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('translocation', 'Var', (130, 143))	('mutation', 'Var', (145, 153))
116058	32923153	Biomarkers of response in other cancer types than sarcoma, such as mutational load, infiltrating immune cells, PD-L1 expression, and ploidy have however been identified in subsets of sarcomas.	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('sarcomas', 'Disease', 'MESH:D012509', (183, 191))	('sarcoma', 'Disease', (183, 190))	('PD-L1', 'Gene', '29126', (111, 116))	('cancer', 'Disease', (32, 38))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('sarcoma', 'Disease', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('sarcomas', 'Disease', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutational load', 'Var', (67, 82))	('PD-L1', 'Gene', (111, 116))
116059	32923153	Translocation-driven sarcomas harbor specific immunogenic potential: fusion breakpoint sequences associated with synovial sarcoma (SS), clear cell sarcoma, desmoplastic small round cell tumor and Ewing sarcoma may serve as tumor-specific neo-antigen.	('synovial sarcoma', 'Disease', (113, 129))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('Ewing sarcoma', 'Disease', (196, 209))	('tumor', 'Disease', (186, 191))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('synovial sarcoma', 'Disease', 'MESH:D013584', (113, 129))	('sarcomas', 'Disease', 'MESH:D012509', (21, 29))	('sarcoma', 'Disease', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('sarcomas', 'Disease', (21, 29))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (113, 129))	('sarcoma', 'Disease', 'MESH:D012509', (202, 209))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('sarcoma', 'Disease', (147, 154))	('sarcoma', 'Disease', (202, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (196, 209))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (196, 209))	('sarcoma', 'Disease', (122, 129))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (156, 191))	('desmoplastic small round cell tumor', 'Disease', (156, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('fusion breakpoint', 'Var', (69, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
116102	32923153	M0-macrophages were associated with poor prognosis in the three other sarcoma subgroups.	('sarcoma', 'Disease', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('M0-macrophages', 'Var', (0, 14))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))
116138	32923153	reported that IHC detection of CD20 + B cells positively impacts disease-specific survival in non-GIST STS  but when focusing specifically on SS, peritumoral B cell detection appears of poor prognosis value, a result consistent with our observations.	('non-GIST STS', 'Disease', (94, 106))	('disease-specific', 'MPA', (65, 81))	('CD20 + B cells', 'Var', (31, 45))	('impacts', 'Reg', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
116239	27588404	Monoclonal antibodies interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, and anti-PD-L1 can unleash anti-tumor immunity and mediate durable cancer regressions.	('tumor', 'Disease', (119, 124))	('unleash', 'NegReg', (106, 113))	('cancer', 'Disease', (154, 160))	('mediate', 'Reg', (138, 145))	('anti-PD-1', 'Var', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('CTLA-4', 'Gene', '1493', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('anti-PD-L1', 'Var', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('CTLA-4', 'Gene', (68, 74))
116240	27588404	While the presence of PD-L1 expression is considered the best available biomarker for PD-L1/PD-1 blockade, several other predictive biomarkers of response to checkpoint blockade are currently being explored.. Programmed-death (PD) pathway blockade has resulted in significant and durable clinical responses in patients with a broad spectrum of so-called "inflamed cancers":such as melanoma, renal cell carcinoma, lung cancer, mismatch repair-deficient colorectal cancer, and bladder cancer:characterized by a high prevalence of neo-antigens, elevated PD-L1 expression, and robust infiltration of cytotoxic T cells (see review of "inflamed cancer" by Zou et al.).	('renal cell carcinoma', 'Disease', 'MESH:C538614', (391, 411))	('cancer', 'Phenotype', 'HP:0002664', (463, 469))	('patients', 'Species', '9606', (310, 318))	('PD-L1/PD-1', 'Gene', '29126;5133', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (639, 645))	('cancer', 'Disease', 'MESH:D009369', (483, 489))	('cancer', 'Disease', 'MESH:D009369', (418, 424))	('PD', 'Chemical', '-', (86, 88))	('melanoma', 'Phenotype', 'HP:0002861', (381, 389))	('melanoma', 'Disease', (381, 389))	('cancers', 'Disease', 'MESH:D009369', (364, 371))	('PD', 'Chemical', '-', (22, 24))	('mismatch', 'Var', (426, 434))	('lung cancer', 'Disease', 'MESH:D008175', (413, 424))	('elevated', 'PosReg', (542, 550))	('deficient colorectal cancer', 'Disease', 'MESH:D015179', (442, 469))	('PD', 'Chemical', '-', (227, 229))	('cancer', 'Disease', 'MESH:D009369', (463, 469))	('deficient colorectal cancer', 'Disease', (442, 469))	('renal cell carcinoma', 'Disease', (391, 411))	('cancer', 'Disease', (364, 370))	('cancer', 'Disease', 'MESH:D009369', (639, 645))	('expression', 'MPA', (557, 567))	('bladder cancer', 'Disease', (475, 489))	('PD', 'Chemical', '-', (92, 94))	('bladder cancer', 'Disease', 'MESH:D001749', (475, 489))	('lung cancer', 'Phenotype', 'HP:0100526', (413, 424))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (391, 411))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('cancer', 'Disease', (483, 489))	('bladder cancer', 'Phenotype', 'HP:0009725', (475, 489))	('cancer', 'Disease', (418, 424))	('PD', 'Chemical', '-', (551, 553))	('melanoma', 'Disease', 'MESH:D008545', (381, 389))	('cancers', 'Phenotype', 'HP:0002664', (364, 371))	('cancer', 'Phenotype', 'HP:0002664', (483, 489))	('PD-L1', 'Gene', (551, 556))	('cancers', 'Disease', (364, 371))	('cancer', 'Phenotype', 'HP:0002664', (418, 424))	('PD-L1/PD-1', 'Gene', (86, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (402, 411))	('cancer', 'Disease', 'MESH:D009369', (364, 370))	('cancer', 'Disease', (463, 469))	('lung cancer', 'Disease', (413, 424))	('colorectal cancer', 'Phenotype', 'HP:0003003', (452, 469))	('cancer', 'Disease', (639, 645))
116329	24415532	Over-expression of EWS-FLI-1 in human mesenchymal stem cells and human neural progenitor cells increased REST expression.	('human', 'Species', '9606', (65, 70))	('EWS-FLI-1', 'Gene', (19, 28))	('EWS-FLI-1', 'Gene', '2130', (19, 28))	('expression', 'Species', '29278', (110, 120))	('expression', 'Species', '29278', (5, 15))	('human', 'Species', '9606', (32, 37))	('Over-expression', 'Var', (0, 15))	('increased', 'PosReg', (95, 104))	('REST expression', 'MPA', (105, 120))
116330	24415532	Inhibition of EWS-FLI-1 using small interfering (si) RNA decreased REST expression in human Ewing sarcoma cells.	('small interfering', 'Var', (30, 47))	('expression', 'Species', '29278', (72, 82))	('human', 'Species', '9606', (86, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('EWS-FLI-1', 'Gene', (14, 23))	('EWS-FLI-1', 'Gene', '2130', (14, 23))	('REST expression', 'MPA', (67, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('decreased', 'NegReg', (57, 66))	('Ewing sarcoma', 'Disease', (92, 105))
116343	24415532	Abnormal expression of REST and Myc in neural progenitor cells has been shown to induce cerebellar tumors by blocking neuronal differentiation .	('neuronal differentiation', 'CPA', (118, 142))	('cerebellar tumors', 'Disease', (88, 105))	('Abnormal expression', 'Var', (0, 19))	('induce', 'PosReg', (81, 87))	('expression', 'Species', '29278', (9, 19))	('blocking', 'NegReg', (109, 117))	('cerebellar tumors', 'Disease', 'MESH:D002528', (88, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Myc', 'Gene', (32, 35))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
116347	24415532	Inhibition of EWS-FLI-1 resulted in decreased REST expression.	('expression', 'Species', '29278', (51, 61))	('EWS-FLI-1', 'Gene', (14, 23))	('Inhibition', 'Var', (0, 10))	('EWS-FLI-1', 'Gene', '2130', (14, 23))	('REST expression', 'MPA', (46, 61))	('decreased', 'NegReg', (36, 45))
116350	24415532	Here we further showed that inhibition of REST reduced DLL4 and Hes1 expression.	('Hes1', 'Gene', (64, 68))	('expression', 'Species', '29278', (69, 79))	('Hes1', 'Gene', '3280', (64, 68))	('inhibition', 'Var', (28, 38))	('reduced', 'NegReg', (47, 54))	('DLL4', 'Protein', (55, 59))
116384	24415532	The average number of apoptotic cells in control and TC71-siREST tumors was calculated by counting the number of TUNEL-positive cells in five random microscopic fields from different samples.	('TC71-siREST', 'Var', (53, 64))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Disease', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
116396	24415532	2A, both EWS-FLI-1 and REST expression levels were elevated in the cells after transfection with pG5-EWS-FLI-1 but not after transfection with the control vector.	('EWS-FLI-1', 'Gene', '2130', (101, 110))	('EWS-FLI-1', 'Gene', (9, 18))	('expression', 'Species', '29278', (28, 38))	('EWS-FLI-1', 'Gene', '2130', (9, 18))	('pG5', 'Gene', (97, 100))	('transfection', 'Var', (79, 91))	('pG5', 'Gene', '5222', (97, 100))	('elevated', 'PosReg', (51, 59))	('EWS-FLI-1', 'Gene', (101, 110))	('REST expression levels', 'MPA', (23, 45))
116398	24415532	To determine whether inhibition of EWS-FLI-1 inhibits REST expression, we transfected two different human Ewing sarcoma cell lines TC71 cells and A4573 with the siEWS-FLI-1 vector or siControl vectors.	('Ewing sarcoma cell lines', 'Disease', 'MESH:C563168', (106, 130))	('EWS-FLI-1', 'Gene', '2130', (163, 172))	('REST expression', 'MPA', (54, 69))	('EWS-FLI-1', 'Gene', (163, 172))	('inhibits', 'NegReg', (45, 53))	('expression', 'Species', '29278', (59, 69))	('human', 'Species', '9606', (100, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('inhibition', 'Var', (21, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('EWS-FLI-1', 'Gene', '2130', (35, 44))	('Ewing sarcoma cell lines', 'Disease', (106, 130))	('EWS-FLI-1', 'Gene', (35, 44))
116406	24415532	Immunofluorescent staining confirmed that REST expression was inhibited in TC71-siREST clone #5 cells compared with that in TC71-siControl cells (Fig.	('inhibited', 'NegReg', (62, 71))	('expression', 'Species', '29278', (47, 57))	('REST expression', 'MPA', (42, 57))	('TC71-siREST', 'Var', (75, 86))
116413	24415532	VEGF expression in TC71-siREST tumors was also not different from that in control tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('TC71-siREST', 'Var', (19, 30))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('VEGF', 'Gene', (0, 4))	('expression', 'Species', '29278', (5, 15))
116425	24415532	These results suggest that inhibition of REST may decrease tumor growth by altering tumor vessel morphology, which leads to increased tumor hypoxia and apoptosis.	('altering', 'Reg', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('increased tumor hypoxia', 'Disease', (124, 147))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (84, 89))	('inhibition', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('increased tumor hypoxia', 'Disease', 'MESH:D000860', (124, 147))	('apoptosis', 'CPA', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (134, 139))	('decrease', 'NegReg', (50, 58))
116427	24415532	Inhibition of DLL4 resulted in decreased pericyte marker expression in Ewing tumors in vivo, changed tumor vessel morphology, and increased tumor hypoxia.	('changed', 'Reg', (93, 100))	('Ewing tumors', 'Disease', 'MESH:C563168', (71, 83))	('DLL4', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('pericyte marker expression', 'MPA', (41, 67))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('increased tumor hypoxia', 'Disease', (130, 153))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Ewing tumors', 'Disease', (71, 83))	('decreased', 'NegReg', (31, 40))	('Inhibition', 'Var', (0, 10))	('expression', 'Species', '29278', (57, 67))	('increased tumor hypoxia', 'Disease', 'MESH:D000860', (130, 153))	('tumor', 'Disease', (101, 106))	('Ewing tumor', 'Phenotype', 'HP:0012254', (71, 82))	('Ewing tumors', 'Phenotype', 'HP:0012254', (71, 83))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', (140, 145))
116430	24415532	6B) showed that DLL 4 expression was lower in TC71-siREST tumor tissues than that in siControl tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('expression', 'Species', '29278', (22, 32))	('TC71-siREST', 'Var', (46, 57))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('lower', 'NegReg', (37, 42))	('DLL 4', 'Protein', (16, 21))	('tumors', 'Disease', (95, 101))	('expression', 'MPA', (22, 32))	('tumor', 'Disease', (95, 100))
116440	24415532	The transfection of EWS-FLI-1 into hMSC, where REST is not expressed, induced REST mRNA and protein production.	('induced', 'PosReg', (70, 77))	('EWS-FLI-1', 'Gene', '2130', (20, 29))	('transfection', 'Var', (4, 16))	('EWS-FLI-1', 'Gene', (20, 29))
116543	23549869	Two studies have suggested that IGF-1R antibodies exert a strong effect on tumor angiogenesis.	('IGF-1R', 'Gene', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('antibodies', 'Var', (39, 49))
116544	23549869	Many childhood cancers secrete IGF-2, suggesting that tumor-derived IGF-2 can promote angiogenesis in the presence of IGF-1R-targeted antibodies through binding to the insulin receptor (IR) permitting continued tumor growth.	('insulin receptor', 'Gene', '16337', (168, 184))	('antibodies', 'Var', (134, 144))	('insulin receptor', 'Gene', (168, 184))	('promote', 'PosReg', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('IR', 'Gene', '16337', (186, 188))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('binding', 'Interaction', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('childhood cancers', 'Disease', 'MESH:C536928', (5, 22))	('tumor', 'Disease', (54, 59))	('IGF-1R-targeted', 'Gene', (118, 133))	('angiogenesis', 'CPA', (86, 98))	('IGF-2', 'Gene', (68, 73))	('childhood cancers', 'Disease', (5, 22))
116547	23549869	Five fully human (CP-751871, AMG 479, R1507, IMC-A12, SCH717454) or humanized antibodies (H7C10/MK0646) have been evaluated in adult phase-I to -III clinical trials.	('CP-751871', 'Var', (18, 27))	('R1507', 'Var', (38, 43))	('human', 'Species', '9606', (68, 73))	('human', 'Species', '9606', (11, 16))
116563	23549869	We used primary antibodies to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), AKT, phospho-AKT (Ser473), IGF-1R, and phospho-IGF-1R (Tyr1131), IR and phosphor-IR (Tyr1146) (Cell Signaling).	('AKT', 'Gene', '11651', (93, 96))	('GAPDH', 'Gene', '14433', (72, 77))	('IR', 'Gene', '16337', (145, 147))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '14433', (30, 70))	('AKT', 'Gene', (93, 96))	('AKT', 'Gene', '11651', (80, 83))	('GAPDH', 'Gene', (72, 77))	('AKT', 'Gene', (80, 83))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (30, 70))	('Ser473', 'Chemical', '-', (98, 104))	('Tyr1146', 'Chemical', '-', (165, 172))	('Tyr1131', 'Var', (135, 142))	('Tyr1131', 'Chemical', '-', (135, 142))	('IR', 'Gene', '16337', (161, 163))
116576	23549869	Alternatively plugs containing VEGF (100 ng/ml) and IGF-2 (50 ng/ml) were implanted and mice received MEDI-573 alone, CP1-B02 alone or the two antibodies in combination.	('100 ng/ml', 'Var', (37, 46))	('CP1-B', 'Gene', (118, 123))	('IGF-2', 'Gene', (52, 57))	('mice', 'Species', '10090', (88, 92))	('CP1-B', 'Gene', '13078', (118, 123))
116607	23549869	Stimulation of cells by VEGF in combination with IGF-1 was also completely abrogated by MAB391, whereas VEGF combined with IGF-2 circumvented the block on signaling, consistent with IGF-2 signaling through the IR, and continued phosphorylation of Akt, Figure 4B.	('MAB391', 'Var', (88, 94))	('IR', 'Gene', '16337', (210, 212))	('abrogated', 'NegReg', (75, 84))
116608	23549869	In contrast a small molecule inhibitor of IGF-1R and IN-R, BMS754807 equally inhibited IGF-1 and -2 induced phosphorylation of Akt in HUVECs (Figure 4C).	('BMS754807', 'Chemical', 'MESH:C545990', (59, 68))	('inhibited', 'NegReg', (77, 86))	('BMS754807', 'Var', (59, 68))	('phosphorylation', 'MPA', (108, 123))	('IGF-1 and -2', 'Gene', '16000;16002', (87, 99))	('Akt', 'Pathway', (127, 130))
116622	23549869	Consistent with the tumor growth inhibition results, only the combination of antibodies significantly (p=0.05) suppressed angiogenesis (CD34 positive cells) or proliferation (Ki67 staining), Figure 6B and Supplemental Figure 5.	('antibodies', 'Var', (77, 87))	('CD34', 'Gene', (136, 140))	('proliferation', 'CPA', (160, 173))	('Ki67', 'Gene', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('suppressed', 'NegReg', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('CD34', 'Gene', '12490', (136, 140))	('Ki67', 'Gene', '17345', (175, 179))	('tumor', 'Disease', (20, 25))
116623	23549869	Alterations in the insulin-like growth factor (IGF) signaling axis have been linked to the pathogenesis of various cancers including sarcomas.	('sarcomas', 'Disease', (133, 141))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('Alterations', 'Var', (0, 11))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('linked', 'Reg', (77, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
116625	23549869	While receptor-targeted antibodies have shown antitumor activity in mouse models of childhood sarcomas, in most cases they do not induce actual tumor regression.	('mouse', 'Species', '10090', (68, 73))	('tumor', 'Disease', (144, 149))	('actual tumor', 'Disease', 'MESH:D009369', (137, 149))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('actual tumor', 'Disease', (137, 149))	('antibodies', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('sarcomas', 'Disease', (94, 102))	('tumor', 'Disease', (50, 55))
116632	23549869	We also evaluated available receptor binding antibodies for in vitro (MAB391) and in vivo (CP1-B02), in combination with MEDI-573 to block angiogenesis.	('angiogenesis', 'CPA', (139, 151))	('CP1-B', 'Gene', (91, 96))	('CP1-B', 'Gene', '13078', (91, 96))	('MAB391', 'Var', (70, 76))
116659	23145994	We then expressed aa 251-280 ectopically in Ewing's sarcoma cell-line and its effect on cell proliferation, tumorigenicity and expression of EWS-FLI1 target genes were analysed.	('EWS-FLI1', 'Gene', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (44, 59))	('EWS-FLI1', 'Gene', '2130;2313', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('tumor', 'Disease', (108, 113))	('aa 251-280', 'Var', (18, 28))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (44, 59))	("Ewing's sarcoma", 'Disease', (44, 59))
116661	23145994	Ectopically expressing this region in Ewing's sarcoma cells inhibited tumorigenicity, and EWS-FLI1 target genes indicating a dominant negative biological effect.	("Ewing's sarcoma", 'Disease', (38, 53))	('EWS-FLI1', 'Gene', '2130;2313', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (38, 53))	('Ectopically expressing', 'Var', (0, 22))	('tumor', 'Disease', (70, 75))	('inhibited', 'NegReg', (60, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (38, 53))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('EWS-FLI1', 'Gene', (90, 98))
116664	23145994	More than 85% of the Ewing's sarcoma family of tumours (ESFT) patients present with a balanced t(11:22) (q24;q12) chromosomal translocation.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (21, 36))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	("Ewing's sarcoma family of tumours", 'Disease', (21, 54))	('patients', 'Species', '9606', (62, 70))	('t(11:22) (q24;q12', 'Var', (95, 112))	("Ewing's sarcoma family of tumours", 'Disease', 'MESH:C563168', (21, 54))
116673	23145994	Finally our analysis of the biological effects of ectopically expressing junction region on expression of EWS-FLI1 target genes, and proliferation of Ewing's sarcoma cells in-vitro indicates a dominant negative function for the junction region.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (150, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('negative', 'NegReg', (202, 210))	('EWS-FLI1', 'Gene', '2130;2313', (106, 114))	('EWS-FLI1', 'Gene', (106, 114))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (150, 165))	("Ewing's sarcoma", 'Disease', (150, 165))	('ectopically', 'Var', (50, 61))	('expression', 'MPA', (92, 102))
116724	23145994	The modelled structure of EWS-FLI1 indicated the presence of alpha helices (30-37, 88-94, 116-120, 124-127, 254-262, 264-268, 326-334, 401-412, 458-465), beta sheets (12-15, 54-57, 105-109, 147,148, 352,353, 377-380, 387-389,425,426) and loops (Figure 1A).	('12-15', 'Var', (167, 172))	('alpha helices', 'Protein', (61, 74))	('EWS-FLI1', 'Gene', (26, 34))	('EWS-FLI1', 'Gene', '2130;2313', (26, 34))	('beta sheets', 'Protein', (154, 165))	('loops', 'MPA', (238, 243))
116737	23145994	Real time quantitative RT-PCR analysis of EWS-FLI1 up-regulated target genes were found to be down-regulated in junction construct (a.a. 251-280) transfected cell line - GLI1 by 2.47 fold, NKX2.2 by 2.3 fold, NROB1 by 3.15 fold, Cyclin D1 by 2.4 fold, c-MYC 1.69 by fold, and EZH2 by 1.48 fold compared to pcDNA-EWS502 vector control cell line (Figure 6A).	('EWS-FLI1', 'Gene', '2130;2313', (42, 50))	('NROB1', 'Gene', '190', (209, 214))	('NROB1', 'Gene', (209, 214))	('transfected', 'Var', (146, 157))	('EWS', 'Gene', (312, 315))	('EWS', 'Gene', (42, 45))	('Cyclin D1', 'Gene', '595', (229, 238))	('GLI1', 'Gene', '2735', (170, 174))	('Cyclin D1', 'Gene', (229, 238))	('NKX2.2', 'Gene', (189, 195))	('down-regulated', 'NegReg', (94, 108))	('EZH2', 'Gene', (276, 280))	('EZH2', 'Gene', '2146', (276, 280))	('NKX2.2', 'Gene', '4821', (189, 195))	('up-regulated', 'PosReg', (51, 63))	('EWS-FLI1', 'Gene', (42, 50))	('EWS', 'Gene', '2130', (312, 315))	('EWS', 'Gene', '2130', (42, 45))	('c-MYC', 'Gene', '4609', (252, 257))	('GLI1', 'Gene', (170, 174))	('c-MYC', 'Gene', (252, 257))
116739	23145994	The suppression of tumorigenic potential by the junction construct (aa 251-280) transfected cells also led us to study the effect on expression of EMT markers.	('suppression', 'NegReg', (4, 15))	('aa 251-280', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))
116758	23145994	Previous study with EWS-FLI1 deletion mutants showed that both EWS and FLI1 domains are necessary for transformation and deletion of either the EWS domain or the FLI1 DNA-binding domain totally abrogates the transforming ability.	('transforming ability', 'CPA', (208, 228))	('EWS', 'Gene', (20, 23))	('EWS', 'Gene', '2130', (63, 66))	('EWS', 'Gene', (63, 66))	('FLI1', 'Gene', (24, 28))	('FLI1', 'Gene', '2313', (24, 28))	('FLI1', 'Gene', (162, 166))	('FLI1', 'Gene', '2313', (162, 166))	('abrogates', 'NegReg', (194, 203))	('EWS-FLI1', 'Gene', '2130;2313', (20, 28))	('EWS-FLI1', 'Gene', (20, 28))	('FLI1', 'Gene', (71, 75))	('FLI1', 'Gene', '2313', (71, 75))	('deletion', 'Var', (121, 129))	('EWS', 'Gene', '2130', (144, 147))	('EWS', 'Gene', (144, 147))	('EWS', 'Gene', '2130', (20, 23))
116766	23145994	Previous studies have shown that TGFbetaRII is a major down regulated target of EWS-FLI1 oncoprotein and introduction of normal TGFbetaRII into Ewing's sarcoma cell lines restores TGFbeta sensitivity and blocks tumorigenicity.	('TGFbetaRII', 'Gene', (128, 138))	('EWS-FLI1', 'Gene', (80, 88))	('TGFbeta sensitivity', 'MPA', (180, 199))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('EWS-FLI1', 'Gene', '2130;2313', (80, 88))	('introduction', 'Var', (105, 117))	('restores', 'PosReg', (171, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('blocks', 'NegReg', (204, 210))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (144, 159))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	("Ewing's sarcoma", 'Disease', (144, 159))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (144, 159))
116776	23145994	Our study also indicates a propensity for a short junction construct (aa 251 - 280 a 30 amino acid-peptide) to exhibit a dominant negative effect on the functions of wild type EWS-FLI1 protein by inhibiting target gene expression and tumorigenicity in vitro.	('tumor', 'Disease', (234, 239))	('negative', 'NegReg', (130, 138))	('target gene expression', 'MPA', (207, 229))	('EWS-FLI1', 'Gene', '2130;2313', (176, 184))	('inhibiting', 'NegReg', (196, 206))	('functions', 'MPA', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('EWS-FLI1', 'Gene', (176, 184))	('aa 251 - 280', 'Var', (70, 82))
116779	21067607	Previous studies have shown that interleukin-13 receptor alpha2 chain (IL-13Ralpha2), a tumor-associated antigen is a promising target for cancer immunotherapy as high levels of IL-13Ralpha2 are expressed on a variety of human tumors.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (227, 232))	('interleukin-13 receptor alpha2 chain', 'Gene', '3598', (33, 69))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', (227, 233))	('interleukin-13 receptor alpha2 chain', 'Gene', (33, 69))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('human', 'Species', '9606', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('IL-13Ralpha2', 'Gene', (71, 83))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (88, 93))	('IL-13Ralpha2', 'Var', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('cancer', 'Disease', (139, 145))
116784	21067607	Furthermore, ECDalpha2 booster vaccination increased IFN-gamma production and CTL activity against tumor expressing IL-13Ralpha2.	('tumor', 'Disease', (99, 104))	('IFN-gamma', 'Gene', '15978', (53, 62))	('CTL activity', 'CPA', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('IFN-gamma', 'Gene', (53, 62))	('increased', 'PosReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('IL-13Ralpha2', 'Var', (116, 128))
116806	21067607	Tumors from vaccinated mice were infiltrated with CD4+ and CD8+ T cells, resulting in the production of chemokines, which were consistent with the ability of effector cells and molecules to play a role in tumor regression mechanisms.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('production of chemokines', 'MPA', (90, 114))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('rat', 'Species', '10116', (39, 42))	('Tumors', 'Disease', (0, 6))	('CD4', 'Gene', (50, 53))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (205, 210))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('CD4', 'Gene', '12504', (50, 53))	('CD8+', 'Var', (59, 63))	('mice', 'Species', '10090', (23, 27))
116838	21067607	We investigated the prophylactic effect of the IL-13Ralpha2 DNA vaccine followed by boost vaccination with ECDalpha2 protein mixed with adjuvants on naturally expressing IL-13Ralpha2 MCA304 sarcoma and 4T1 breast carcinoma tumors in C57BL/6 and BALB/c mice, respectively.	('mice', 'Species', '10090', (252, 256))	('MCA304 sarcoma', 'Disease', (183, 197))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('IL-13Ralpha2', 'Var', (170, 182))	('breast carcinoma tumors', 'Disease', (206, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('breast carcinoma tumors', 'Disease', 'MESH:D001943', (206, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('breast carcinoma', 'Phenotype', 'HP:0003002', (206, 222))	('MCA304 sarcoma', 'Disease', 'MESH:D012509', (183, 197))
116853	21067607	These results indicate that IL-13Ralpha2 DNA prime and ECDalpha2 boost vaccination induces specific CTL activity and IFN-gamma release in both MCA304 and 4T1 tumor models.	('tumor', 'Disease', (158, 163))	('IL-13Ralpha2', 'Var', (28, 40))	('CTL activity', 'MPA', (100, 112))	('IFN-gamma', 'Gene', (117, 126))	('ECDalpha2', 'Gene', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('MCA304', 'Chemical', '-', (143, 149))	('IFN-gamma', 'Gene', '15978', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
116855	21067607	Having identified the efficacy of the IL-13Ralpha2 DNA and ECDalpha2 boost vaccination in the prevention of MCA304, 4T1, and D5alpha2 tumor growth, we tested efficacy of this vaccine in mice with established tumors to simulate a clinical situation.	('MCA304', 'Gene', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', (208, 213))	('tested', 'Reg', (151, 157))	('mice', 'Species', '10090', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('D5alpha2', 'Var', (125, 133))	('MCA304', 'Chemical', '-', (108, 114))	('tumor', 'Disease', (134, 139))
116858	21067607	On day 30, the tumor volume of MCA304 tumors in mice receiving the ECDalpha2 boost protein (252 mm3) was significantly smaller than that of mice receiving the IL-13Ralpha2 DNA vaccine alone (1334 mm3) (P < 0.01).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('MCA304 tumors', 'Disease', (31, 44))	('smaller', 'NegReg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('MCA304 tumors', 'Disease', 'MESH:D009369', (31, 44))	('252', 'Var', (92, 95))	('mice', 'Species', '10090', (140, 144))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('mice', 'Species', '10090', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
116861	21067607	This tumor growth pattern was the same as the IL-13Ralpha2 DNA vaccine alone, indicating that the boost with ECDalpha2 generated IL-13Ralpha2 specific immune response.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('rat', 'Species', '10116', (123, 126))	('tumor', 'Disease', (5, 10))	('IL-13Ralpha2', 'Var', (129, 141))
116869	21067607	To assess whether the antitumor effect of the IL-13Ralpha2 DNA and boost vaccination were associated with induction of CTL against two tumor MCA304 and 4T1 models, IFN-gamma production and CTL activity were examined.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('IL-13Ralpha2', 'Var', (46, 58))	('tumor', 'Disease', (135, 140))	('IFN-gamma', 'Gene', '15978', (164, 173))	('MCA304', 'Chemical', '-', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('IFN-gamma', 'Gene', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
116878	21067607	We have previously demonstrated that splenocytes from C57BL/6 mice challenged with mouse melanoma (D5alpha2) when vaccinated with IL-13Ralpha2 DNA, mediated a significant lysis of target cells (38% lysis at E/T 50:1).	('E/T 50', 'Var', (207, 213))	('mouse', 'Species', '10090', (83, 88))	('mice', 'Species', '10090', (62, 66))	('rat', 'Species', '10116', (26, 29))	('E/T 50', 'SUBSTITUTION', 'None', (207, 213))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('lysis', 'MPA', (171, 176))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
116879	21067607	However, in current study in sarcoma model (MCA304), a significantly lower lysis was observed (13% lysis at E/T 50:1) although this lysis was enhanced by boosting mice with ECDalpha2 protein (38% lysis at E/T 50:1).	('lysis', 'MPA', (99, 104))	('E/T 50', 'Var', (108, 114))	('E/T 50', 'Var', (205, 211))	('MCA304', 'Chemical', '-', (44, 50))	('E/T 50', 'SUBSTITUTION', 'None', (108, 114))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('lower', 'NegReg', (69, 74))	('sarcoma', 'Disease', (29, 36))	('mice', 'Species', '10090', (163, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('E/T 50', 'SUBSTITUTION', 'None', (205, 211))	('lysis', 'MPA', (75, 80))
116884	21067607	These observations suggest that mice with melanoma tumors with human IL-13Ralpha2 (D5alpha2) elicit more robust immune response compared to naturally expressing murine MCA304 and 4T1 tumors.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('human', 'Species', '9606', (63, 68))	('melanoma tumors', 'Disease', 'MESH:D008545', (42, 57))	('IL-13Ralpha2', 'Var', (69, 81))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('immune response', 'MPA', (112, 127))	('tumors', 'Disease', (51, 57))	('murine', 'Species', '10090', (161, 167))	('mice', 'Species', '10090', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('MCA304', 'Chemical', '-', (168, 174))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('melanoma tumors', 'Disease', (42, 57))	('tumors', 'Disease', (183, 189))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
116887	21067607	The antibody against IL-13Ralpha2 in mice receiving IL-13Ralpha2 DNA and ECDalpha2 boost vaccination was dramatically higher than IL-13Ralpha2 DNA and ovalbumin vaccinated mice.	('higher', 'PosReg', (118, 124))	('ECDalpha2', 'Gene', (73, 82))	('antibody', 'MPA', (4, 12))	('ovalbumin', 'Gene', (151, 160))	('mice', 'Species', '10090', (37, 41))	('ovalbumin', 'Gene', '282665', (151, 160))	('mice', 'Species', '10090', (172, 176))	('IL-13Ralpha2 DNA', 'Var', (52, 68))	('IL-13Ralpha2', 'Gene', (21, 33))
116906	21067607	Although the significance of expression of IL-13Ralpha2 in cancer is not completely clear, our previous studies indicate that IL-13Ralpha2 could be linked to oncogenesis and metastasis and may provide a potential target for immunotherapy.	('oncogenesis', 'CPA', (158, 169))	('linked', 'Reg', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('metastasis', 'CPA', (174, 184))	('IL-13Ralpha2', 'Var', (126, 138))
116953	31592798	Recurrent YAP1 and KMT2A Gene Rearrangements in a Subset of MUC4-Negative Sclerosing Epithelioid Fibrosarcoma Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma, characterized by a distinctive epithelioid phenotype in a densely sclerotic collagenous stroma, that shows frequent MUC4 immunoreactivity and recurrent gene fusions, often involving EWSR1 gene.	('Rearrangements', 'Var', (30, 44))	('KMT2A', 'Gene', (19, 24))	('YAP1', 'Gene', (10, 14))	('aggressive soft tissue sarcoma', 'Disease', 'MESH:D012509', (158, 188))	('MUC4', 'Gene', '4585', (60, 64))	('sclerotic collagenous stroma', 'Disease', (256, 284))	('MUC4', 'Gene', (60, 64))	('MUC4', 'Gene', '4585', (306, 310))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (133, 145))	('EWSR1', 'Gene', '2130', (372, 377))	('MUC4', 'Gene', (306, 310))	('Fibrosarcoma', 'Phenotype', 'HP:0100244', (97, 109))	('sclerotic collagenous stroma', 'Disease', 'MESH:D003095', (256, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('KMT2A', 'Gene', '4297', (19, 24))	('Fibrosarcoma', 'Disease', (97, 109))	('Fibrosarcoma', 'Disease', 'MESH:D005354', (97, 109))	('sclerotic collagen', 'Phenotype', 'HP:0008271', (256, 274))	('EWSR1', 'Gene', (372, 377))	('YAP1', 'Gene', '10413', (10, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Sclerosing epithelioid fibrosarcoma', 'Disease', (110, 145))	('aggressive soft tissue sarcoma', 'Disease', (158, 188))	('Sclerosing epithelioid fibrosarcoma', 'Disease', 'MESH:D005354', (110, 145))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (169, 188))
116956	31592798	Triggered by the identification of recurrent YAP1-KMT2A gene fusions by RNA sequencing in 3 index cases of MUC4-negative, EWSR1/FUS fusion-negative SEF, we further investigated a cohort of 14 similar SEF cases (MUC4-negative, EWSR1/FUS fusion-negative) by fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), and/or DNA-based massively parallel sequencing (MSK-IMPACT) for abnormalities in these genes.	('FUS', 'Gene', (128, 131))	('EWSR1', 'Gene', '2130', (226, 231))	('FUS', 'Gene', (232, 235))	('MUC4', 'Gene', '4585', (107, 111))	('YAP1', 'Gene', (45, 49))	('FUS', 'Gene', '2521', (232, 235))	('EWSR1', 'Gene', '2130', (122, 127))	('KMT2A', 'Gene', (50, 55))	('MUC4', 'Gene', '4585', (211, 215))	('YAP1', 'Gene', '10413', (45, 49))	('FUS', 'Gene', '2521', (128, 131))	('KMT2A', 'Gene', '4297', (50, 55))	('MUC4', 'Gene', (107, 111))	('fusions', 'Var', (61, 68))	('EWSR1', 'Gene', (122, 127))	('EWSR1', 'Gene', (226, 231))	('MUC4', 'Gene', (211, 215))
116969	31592798	At the genetic level, a molecular dichotomy between these two tumors has emerged, with pure SEF harboring mostly EWSR1-CREB3L1 fusions, while LGFMS and hybrid SEF/LGFMS displaying FUS-CREB3L2 fusions.	('CREB3L2', 'Gene', '64764', (184, 191))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EWSR1', 'Gene', '2130', (113, 118))	('FUS', 'Gene', (180, 183))	('tumors', 'Disease', (62, 68))	('FUS', 'Gene', '2521', (180, 183))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('CREB3L1', 'Gene', (119, 126))	('fusions', 'Var', (127, 134))	('CREB3L1', 'Gene', '90993', (119, 126))	('CREB3L2', 'Gene', (184, 191))	('EWSR1', 'Gene', (113, 118))
116975	31592798	The resultant screening cohorts of SEF (n=14) and LGFMS (n=24) were studied using break-apart FISH assays for YAP1 and KMT2A rearrangements.	('YAP1', 'Gene', (110, 114))	('YAP1', 'Gene', '10413', (110, 114))	('rearrangements', 'Var', (125, 139))	('KMT2A', 'Gene', (119, 124))	('KMT2A', 'Gene', '4297', (119, 124))
116984	31592798	The fusions joined YAP1 exon 5 (NM_001130145) to KMT2A exon 4 (NM_001197104) in cases #1 and #3, and YAP1 exon 4 to KMT2A exon 5 in case #2 (Fig.	('KMT2A', 'Gene', '4297', (49, 54))	('NM_001130145', 'Var', (32, 44))	('YAP1', 'Gene', (101, 105))	('KMT2A', 'Gene', (116, 121))	('YAP1', 'Gene', '10413', (101, 105))	('KMT2A', 'Gene', '4297', (116, 121))	('YAP1', 'Gene', '10413', (19, 23))	('YAP1', 'Gene', (19, 23))	('KMT2A', 'Gene', (49, 54))	('NM_001197104', 'Var', (63, 75))
116987	31592798	RT-PCR confirmed the YAP1-KMT2A and KMT2A-YAP1 fusions in case #3 (Fig.	('YAP1', 'Gene', (21, 25))	('YAP1', 'Gene', '10413', (21, 25))	('YAP1', 'Gene', (42, 46))	('KMT2A', 'Gene', (36, 41))	('KMT2A', 'Gene', (26, 31))	('YAP1', 'Gene', '10413', (42, 46))	('KMT2A', 'Gene', '4297', (36, 41))	('fusions', 'Var', (47, 54))	('KMT2A', 'Gene', '4297', (26, 31))
116990	31592798	The case (case #9) studied by MSK-IMPACT showed fusion of KMT2A intron 6-7 (100bp) to YAP1 intron 8-9 (339bp).	('339bp', 'Var', (103, 108))	('YAP1', 'Gene', '10413', (86, 90))	('YAP1', 'Gene', (86, 90))	('KMT2A', 'Gene', (58, 63))	('KMT2A', 'Gene', '4297', (58, 63))
116992	31592798	FISH for YAP1 and KMT2A abnormalities were performed on the above-mentioned 5 cases with known YAP1 and KMT2A fusion sequences (cases #1-3, 8, 9).	('YAP1', 'Gene', (95, 99))	('KMT2A', 'Gene', (104, 109))	('YAP1', 'Gene', '10413', (95, 99))	('KMT2A', 'Gene', '4297', (104, 109))	('YAP1', 'Gene', (9, 13))	('KMT2A', 'Gene', (18, 23))	('YAP1', 'Gene', '10413', (9, 13))	('KMT2A', 'Gene', '4297', (18, 23))	('fusion sequences', 'Var', (110, 126))
116995	31592798	FISH for KMT2A rearrangements were negative in all 5 cases.	('KMT2A', 'Gene', '4297', (9, 14))	('rearrangements', 'Var', (15, 29))	('KMT2A', 'Gene', (9, 14))
116997	31592798	These findings suggest that YAP1 and KMT2A gene rearrangements in these tumors are often cryptic and beyond the FISH resolution.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('KMT2A', 'Gene', (37, 42))	('rearrangements', 'Var', (48, 62))	('KMT2A', 'Gene', '4297', (37, 42))	('YAP1', 'Gene', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('YAP1', 'Gene', '10413', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
116999	31592798	Based on the results of case# 3, it is likely that only a small fragment of the YAP1 locus is retained in the fusion event, being associated with a large deletion of the nearby locus (as demonstrated by the loss of the red, centromeric probe).	('YAP1', 'Gene', (80, 84))	('deletion', 'Var', (154, 162))	('YAP1', 'Gene', '10413', (80, 84))	('associated', 'Reg', (130, 140))
117001	31592798	Four additional cases with either YAP1 or KMT2A gene abnormalities were identified by FISH in the remaining SEF screening cohort, 1 with YAP1 rearrangement and 3 with KMT2A rearrangements (Fig.	('YAP1', 'Gene', '10413', (137, 141))	('YAP1', 'Gene', (34, 38))	('YAP1', 'Gene', '10413', (34, 38))	('KMT2A', 'Gene', (167, 172))	('abnormalities', 'Var', (53, 66))	('KMT2A', 'Gene', '4297', (167, 172))	('rearrangement', 'Var', (142, 155))	('KMT2A', 'Gene', (42, 47))	('YAP1', 'Gene', (137, 141))	('KMT2A', 'Gene', '4297', (42, 47))
117005	31592798	To investigate other potential fusion gene partners, FISH for VIM and MAML2 gene rearrangements, two recently described fusion partners of YAP1 or KMT2A gene, were performed on cases #4-7.	('rearrangements', 'Var', (81, 95))	('VIM', 'Gene', '7431', (62, 65))	('MAML2', 'Gene', '84441', (70, 75))	('MAML2', 'Gene', (70, 75))	('KMT2A', 'Gene', '4297', (147, 152))	('YAP1', 'Gene', (139, 143))	('YAP1', 'Gene', '10413', (139, 143))	('KMT2A', 'Gene', (147, 152))	('VIM', 'Gene', (62, 65))
117009	31592798	In total, 9 cases, including the 3 index cases and 6 additional from the screening cohort, were identified as harboring rearrangements in YAP1 and/or KMT2A genes (Table 1).	('rearrangements', 'Var', (120, 134))	('YAP1', 'Gene', (138, 142))	('YAP1', 'Gene', '10413', (138, 142))	('KMT2A', 'Gene', (150, 155))	('KMT2A', 'Gene', '4297', (150, 155))
117047	31592798	At the genetic level, most pure SEF cases showed EWSR1-CREB3L1 fusions, while the overwhelming majority of hybrid SEF/LGFMS lesions are characterized by FUS-CREB3L2.	('CREB3L1', 'Gene', '90993', (55, 62))	('CREB3L1', 'Gene', (55, 62))	('FUS', 'Gene', (153, 156))	('EWSR1', 'Gene', (49, 54))	('FUS', 'Gene', '2521', (153, 156))	('CREB3L2', 'Gene', '64764', (157, 164))	('EWSR1', 'Gene', '2130', (49, 54))	('CREB3L2', 'Gene', (157, 164))	('fusions', 'Var', (63, 70))
117052	31592798	More recently, two sarcoma cases with KMT2A rearrangements, fused with YAP1 and VIM, respectively, were identified by RNA sequencing.	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('YAP1', 'Gene', '10413', (71, 75))	('VIM', 'Gene', (80, 83))	('sarcoma', 'Disease', (19, 26))	('KMT2A', 'Gene', (38, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('VIM', 'Gene', '7431', (80, 83))	('KMT2A', 'Gene', '4297', (38, 43))	('YAP1', 'Gene', (71, 75))	('rearrangements', 'Var', (44, 58))
117057	31592798	Although the reciprocal KMT2A-YAP1 fusion transcript was present in the majority of these tumors reported to date and the number of reciprocal fusion reads exceeded YAP1-KMT2A reads in some of our cases, the immunoreactivity to the N-terminal YAP1 but not C-terminal YAP1 is in keeping with a YAP1-KMT2A being the main functional transcript.	('YAP1', 'Gene', '10413', (293, 297))	('KMT2A', 'Gene', (298, 303))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('YAP1', 'Gene', '10413', (165, 169))	('YAP1', 'Gene', (293, 297))	('KMT2A', 'Gene', (24, 29))	('YAP1', 'Gene', '10413', (267, 271))	('YAP1', 'Gene', '10413', (243, 247))	('YAP1', 'Gene', (165, 169))	('KMT2A', 'Gene', '4297', (170, 175))	('YAP1', 'Gene', '10413', (30, 34))	('N-terminal', 'Var', (232, 242))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('KMT2A', 'Gene', '4297', (298, 303))	('YAP1', 'Gene', (267, 271))	('YAP1', 'Gene', (243, 247))	('YAP1', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('KMT2A', 'Gene', '4297', (24, 29))	('KMT2A', 'Gene', (170, 175))
117065	31592798	The present study expands the clinicopathologic spectrum of sarcomas harboring YAP1-KMT2A fusions.	('sarcomas', 'Disease', (60, 68))	('KMT2A', 'Gene', (84, 89))	('YAP1', 'Gene', (79, 83))	('YAP1', 'Gene', '10413', (79, 83))	('KMT2A', 'Gene', '4297', (84, 89))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('fusions', 'Var', (90, 97))
117071	31592798	These findings may explain the high false-negative rate of the FISH assays, as none of our 3 index cases with YAP1-KMT2A fusions by RNA sequencing revealed KMT2A rearrangements and only one case showed YAP1 split signals.	('KMT2A', 'Gene', (115, 120))	('fusions', 'Var', (121, 128))	('YAP1', 'Gene', (202, 206))	('YAP1', 'Gene', '10413', (202, 206))	('KMT2A', 'Gene', '4297', (115, 120))	('YAP1', 'Gene', (110, 114))	('YAP1', 'Gene', '10413', (110, 114))	('KMT2A', 'Gene', (156, 161))	('rearrangements', 'Var', (162, 176))	('KMT2A', 'Gene', '4297', (156, 161))
117082	31592798	Nevertheless, in the previously reported sarcoma with VIM-KMT2A fusion, up-regulation of KMT2A and HOXA genes were noted.	('sarcoma', 'Disease', (41, 48))	('fusion', 'Var', (64, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('up-regulation', 'PosReg', (72, 85))	('HOXA', 'Gene', (99, 103))	('VIM', 'Gene', (54, 57))	('KMT2A', 'Gene', (89, 94))	('HOXA', 'Gene', '3197', (99, 103))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('KMT2A', 'Gene', (58, 63))	('KMT2A', 'Gene', '4297', (89, 94))	('KMT2A', 'Gene', '4297', (58, 63))	('VIM', 'Gene', '7431', (54, 57))
117084	31592798	One of our cases (case #5) showed rearrangements of both KMT2A and MAML2 genes by FISH.	('rearrangements', 'Var', (34, 48))	('MAML2', 'Gene', '84441', (67, 72))	('KMT2A', 'Gene', (57, 62))	('KMT2A', 'Gene', '4297', (57, 62))	('MAML2', 'Gene', (67, 72))
117089	31592798	Interestingly, a dura-based spindle cell tumor with MN1-KMT2A fusion has been reported recently in a 22-year-old female.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('fusion', 'Var', (62, 68))	('MN1', 'Gene', (52, 55))	('MN1', 'Gene', '4330', (52, 55))	('KMT2A', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('KMT2A', 'Gene', '4297', (56, 61))
117092	31592798	YAP1, a downstream effector of the Hippo signaling pathway, is also known to be involved in recurrent gene fusions in a subset of epithelioid hemangioendothelioma (YAP1-TFE3) and ependymoma (YAP1- MAMLD1 and FAM118B).	('YAP1', 'Gene', '10413', (0, 4))	('FAM118B', 'Gene', (208, 215))	('YAP1', 'Gene', (191, 195))	('FAM118B', 'Gene', '79607', (208, 215))	('ependymoma', 'Disease', (179, 189))	('gene fusions', 'Var', (102, 114))	('TFE3', 'Gene', (169, 173))	('YAP1', 'Gene', (0, 4))	('TFE3', 'Gene', '7030', (169, 173))	('epithelioid hemangioendothelioma', 'Disease', (130, 162))	('ependymoma', 'Phenotype', 'HP:0002888', (179, 189))	('involved', 'Reg', (80, 88))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (130, 162))	('MAMLD1', 'Gene', (197, 203))	('YAP1', 'Gene', '10413', (164, 168))	('ependymoma', 'Disease', 'MESH:D004806', (179, 189))	('YAP1', 'Gene', (164, 168))	('YAP1', 'Gene', '10413', (191, 195))	('MAMLD1', 'Gene', '10046', (197, 203))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (130, 162))
117093	31592798	In YAP1-KMT2A fusions, the N-terminal TEAD binding domain of YAP1 is retained, while the C-terminal transcriptional activation domain is lost.	('KMT2A', 'Gene', (8, 13))	('lost', 'NegReg', (137, 141))	('YAP1', 'Gene', (3, 7))	('C-terminal transcriptional activation', 'MPA', (89, 126))	('YAP1', 'Gene', '10413', (3, 7))	('KMT2A', 'Gene', '4297', (8, 13))	('YAP1', 'Gene', '10413', (61, 65))	('TEAD binding', 'Interaction', (38, 50))	('fusions', 'Var', (14, 21))	('YAP1', 'Gene', (61, 65))
117094	31592798	Interestingly, YAP1-MAML2 fusions through chromosomal inversions have also been described in poroma (88.5%), porocarcinoma (63.6%), and rare cases of various carcinoma types.	('porocarcinoma', 'Disease', 'MESH:D057090', (109, 122))	('MAML2', 'Gene', (20, 25))	('carcinoma', 'Disease', (158, 167))	('MAML2', 'Gene', '84441', (20, 25))	('described', 'Reg', (80, 89))	('fusions', 'Var', (26, 33))	('carcinoma', 'Disease', 'MESH:D009369', (113, 122))	('porocarcinoma', 'Disease', (109, 122))	('carcinoma', 'Disease', 'MESH:D009369', (158, 167))	('poroma', 'Disease', 'MESH:D057091', (93, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinoma', 'Disease', (113, 122))	('YAP1', 'Gene', (15, 19))	('poroma', 'Disease', (93, 99))	('YAP1', 'Gene', '10413', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('poroma', 'Phenotype', 'HP:0031405', (93, 99))	('chromosomal inversions', 'Var', (42, 64))
117098	31885955	Immunotherapy- (Blinatumomab-) Related Lineage Switch of KMT2A/AFF1 Rearranged B-Lymphoblastic Leukemia into Acute Myeloid Leukemia/Myeloid Sarcoma and Subsequently into B/Myeloid Mixed Phenotype Acute Leukemia The presence of KMT2A/AFF1 rearrangement in B-lymphoblastic leukemia (B-ALL) is an independent poor prognostic factor and has been associated with higher rate of treatment failure and higher risk of linage switch under therapy.	('Leukemia', 'Disease', 'MESH:D007938', (123, 131))	('Leukemia', 'Disease', 'MESH:D007938', (202, 210))	('B-lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (255, 279))	('presence', 'Var', (215, 223))	('Acute Leukemia', 'Phenotype', 'HP:0002488', (196, 210))	('Leukemia', 'Phenotype', 'HP:0001909', (202, 210))	('B-Lymphoblastic Leukemia', 'Phenotype', 'HP:0004812', (79, 103))	('KMT2A', 'Gene', (57, 62))	('Leukemia', 'Disease', (123, 131))	('Leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('Leukemia', 'Disease', (202, 210))	('AFF1', 'Gene', (233, 237))	('Leukemia', 'Disease', 'MESH:D007938', (95, 103))	('KMT2A', 'Gene', '4297', (227, 232))	('AFF1', 'Gene', '4299', (233, 237))	('AFF1', 'Gene', (63, 67))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (257, 279))	('Sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Lymphoblastic Leukemia', 'Phenotype', 'HP:0005526', (81, 103))	('Leukemia', 'Disease', (95, 103))	('Acute Myeloid Leukemia/Myeloid Sarcoma', 'Disease', (109, 147))	('AFF1', 'Gene', '4299', (63, 67))	('leukemia', 'Phenotype', 'HP:0001909', (271, 279))	('B-Lymphoblastic Leukemia', 'Disease', 'MESH:D015448', (79, 103))	('KMT2A', 'Gene', '4297', (57, 62))	('Leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('Acute Myeloid Leukemia/Myeloid Sarcoma', 'Disease', 'MESH:D015470', (109, 147))	('KMT2A', 'Gene', (227, 232))	('B-lymphoblastic leukemia', 'Disease', (255, 279))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (109, 131))	('B-lymphoblastic leukemia', 'Disease', 'MESH:D015448', (255, 279))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (115, 131))	('B-Lymphoblastic Leukemia', 'Disease', (79, 103))
117099	31885955	Blinatumomab has shown promising therapeutic results in refractory or relapsed B-ALL; however, it has potential risk of inducing lineage switch, especially in KMT2A/AFF1 rearranged B-ALL into acute myeloid leukemia and/or myeloid sarcoma.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (198, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('inducing', 'Reg', (120, 128))	('AFF1', 'Gene', '4299', (165, 169))	('KMT2A', 'Gene', '4297', (159, 164))	('leukemia', 'Phenotype', 'HP:0001909', (206, 214))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (192, 214))	('myeloid sarcoma', 'Disease', (222, 237))	('rearranged', 'Var', (170, 180))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (192, 214))	('Blinatumomab', 'Chemical', 'MESH:C510808', (0, 12))	('lineage switch', 'CPA', (129, 143))	('acute myeloid leukemia', 'Disease', (192, 214))	('AFF1', 'Gene', (165, 169))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (222, 237))	('KMT2A', 'Gene', (159, 164))
117107	31885955	The presence of KMT2A rearrangement, especially in B-ALL, has long been associated with a higher risk of lineage switch under therapy and is an independent dismal prognostic factor.	('KMT2A', 'Gene', (16, 21))	('KMT2A', 'Gene', '4297', (16, 21))	('lineage switch', 'CPA', (105, 119))	('presence', 'Var', (4, 12))	('rearrangement', 'Var', (22, 35))
117116	31885955	Chromosomal analysis revealed a complex karyotype including t(4; 11)(q21; q23), while fluorescence in situ hybridization (FISH) confirmed KMT2A rearrangement (Table 1).	('KMT2A', 'Gene', '4297', (138, 143))	('KMT2A', 'Gene', (138, 143))	('t(4; 11)(q21; q23', 'Var', (60, 77))
117127	31885955	Conventional chromosome analysis from the bone marrow aspirate revealed t(4; 11)(q21; q23) and additional chromosomal abnormalities (Figure 1, E1; Table 1).	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (106, 131))	('chromosomal abnormalities', 'Disease', (106, 131))	('t(4; 11)(q21; q23', 'Var', (72, 89))
117133	31885955	We present a case of a 40-year-old female with an initial diagnosis of KMT2A/AFF1 rearranged B-ALL that subsequently switched to more aggressive types of leukemic events and with extramedullary involvement.	('KMT2A', 'Gene', (71, 76))	('switched', 'Reg', (117, 125))	('AFF1', 'Gene', (77, 81))	('KMT2A', 'Gene', '4297', (71, 76))	('leukemic', 'Disease', (154, 162))	('rearranged B-ALL', 'Var', (82, 98))	('AFF1', 'Gene', '4299', (77, 81))	('leukemic', 'Disease', 'MESH:D007938', (154, 162))
117136	31885955	This case provides evidence that two key factors appear to be involved in this lineage switching event: KMT2A rearrangement and blinatumomab therapy.	('KMT2A', 'Gene', (104, 109))	('blinatumomab', 'Chemical', 'MESH:C510808', (128, 140))	('rearrangement', 'Var', (110, 123))	('KMT2A', 'Gene', '4297', (104, 109))
117138	31885955	The presence of KMT2A rearrangement has long been associated with a higher risk of lineage switch under chemotherapy and subsequent failure to treatment even before the emergence of immunotherapies.	('KMT2A', 'Gene', (16, 21))	('rearrangement', 'Var', (22, 35))	('KMT2A', 'Gene', '4297', (16, 21))	('presence', 'Var', (4, 12))	('lineage switch', 'CPA', (83, 97))
117155	28691711	Subsequent GEMMs applied homologous recombination by targeting tumour suppressor genes in embryonic stem (ES) cells by introducing specific mutations into a defined genetic locus.	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (140, 149))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Disease', (63, 69))
117165	28691711	Some sarcomas harbour simple translocations such as the t(11;22)(q24;q12) translocation commonly found in Ewing sarcoma, whereas others have complex genetics such as in malignant peripheral nerve sheath tumour (MPNST) and undifferentiated pleomorphic sarcoma (UPS).	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('nerve sheath tumour', 'Disease', 'MESH:D010524', (190, 209))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('Ewing sarcoma', 'Disease', (106, 119))	('MPNST', 'Phenotype', 'HP:0100697', (211, 216))	('malignant peripheral nerve sheath tumour', 'Phenotype', 'HP:0100697', (169, 209))	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('nerve sheath tumour', 'Disease', (190, 209))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('t(11;22)(q24;q12', 'Var', (56, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (222, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (56, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('sarcomas', 'Disease', (5, 13))	('undifferentiated pleomorphic sarcoma', 'Disease', (222, 258))
117176	28691711	We have previously shown that intramuscular delivery of an adenovirus expressing Cre recombinase into mice with conditional mutations in Kras and Trp53 results in the formation of soft tissue sarcomas at the site of injection.	('mice', 'Species', '10090', (102, 106))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (180, 199))	('mutations', 'Var', (124, 133))	('results in', 'Reg', (152, 162))	('Kras', 'Gene', (137, 141))	('Trp53', 'Gene', (146, 151))	('Kras', 'Gene', '16653', (137, 141))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (180, 200))	('soft tissue sarcomas', 'Disease', (180, 200))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (180, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
117181	28691711	PCR analysis of genomic DNA from transfected K MEFs revealed activation of KrasG12D alone, from transfected C MEFs revealed activation of Cas9 alone and from transfected KC MEFs revealed activation of both KrasG12D and Cas9 (Fig.	('MEFs', 'CellLine', 'CVCL:9115', (173, 177))	('MEFs', 'CellLine', 'CVCL:9115', (47, 51))	('KrasG12D', 'Var', (206, 214))	('activation', 'PosReg', (187, 197))	('MEFs', 'CellLine', 'CVCL:9115', (110, 114))	('Cas9', 'Chemical', '-', (138, 142))	('Cas9', 'Chemical', '-', (219, 223))	('Cas9', 'Gene', (219, 223))
117182	28691711	In addition, insertions or deletions (indels) in Trp53 were detected in transfected C MEFs and KC MEFs by Surveyor nuclease assay, but not in K MEFs as expected (Fig.	('insertions', 'Var', (13, 23))	('MEFs', 'CellLine', 'CVCL:9115', (98, 102))	('Trp53', 'Gene', (49, 54))	('MEFs', 'CellLine', 'CVCL:9115', (144, 148))	('detected', 'Reg', (60, 68))	('deletions', 'Var', (27, 36))	('MEFs', 'CellLine', 'CVCL:9115', (86, 90))
117183	28691711	Activation of oncogenic Kras and deletion of Trp53 were both required for anchorage-independent growth (Fig.	('deletion', 'Var', (33, 41))	('Kras', 'Gene', '16653', (24, 28))	('Trp53', 'Gene', (45, 50))	('Kras', 'Gene', (24, 28))
117185	28691711	Thus, these results show that a combined Cre-loxP and CRISPR-Cas9 system, which activates KrasG12D and mutates Trp53 in vitro, is sufficient for transformation.	('mutates', 'Var', (103, 110))	('Trp53', 'Gene', (111, 116))	('activates', 'PosReg', (80, 89))	('Cas9', 'Chemical', '-', (61, 65))
117190	28691711	Of note, the time frame of Ad-P-Cre adenovirus-initiated tumour development (median 9.6 weeks) was similar to that of tumours generated in KrasLSL-G12D/+; Trp53Flox/Flox (KP) mice by intramuscular injection of Ad-Cre (median 11.3 weeks).	('mice', 'Species', '10090', (175, 179))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('G12D', 'Mutation', 'rs121913529', (147, 151))	('tumours', 'Disease', (118, 125))	('adenovirus-initiated tumour', 'Disease', 'MESH:D000257', (36, 63))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('Kras', 'Gene', '16653', (139, 143))	('adenovirus-initiated tumour', 'Disease', (36, 63))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('Ad-P-Cre', 'Var', (27, 35))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('Kras', 'Gene', (139, 143))
117192	28691711	PCR confirmed KrasG12D activation and Surveyor assay showed evidence of Trp53 indels in three cell lines derived from Ad-P-Cre-initiated tumours (Fig.	('P-Cre-initiated tumours', 'Disease', (121, 144))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('Trp53', 'Gene', (72, 77))	('P-Cre-initiated tumours', 'Disease', 'MESH:C000656865', (121, 144))	('indels', 'Var', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
117197	28691711	Non-homologous end joining repair following Cas9-induced double-strand breaks results in multiple indels in the targeted Trp53 exon 7 (ref.).	('Trp53', 'Gene', (121, 126))	('Cas9', 'Chemical', '-', (44, 48))	('double-strand breaks', 'Var', (57, 77))	('indels', 'MPA', (98, 104))
117198	28691711	We assessed the clonality of sarcomas generated by Ad-P-Cre injection into KC mice by quantifying the number of unique mutations in exon 7 of Trp53 in each tumour.	('tumour', 'Disease', (156, 162))	('Trp53', 'Gene', (142, 147))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('mutations in exon', 'Var', (119, 136))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('sarcomas', 'Disease', (29, 37))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('mice', 'Species', '10090', (78, 82))
117199	28691711	To define the indels in Trp53 in primary sarcomas, we performed Sanger sequencing of cell lines derived from each independent primary sarcoma (n=4).	('indels', 'Var', (14, 20))	('Trp53', 'Gene', (24, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('primary sarcomas', 'Disease', 'MESH:D012509', (33, 49))	('primary sarcomas', 'Disease', (33, 49))	('primary sarcoma', 'Disease', 'MESH:D012509', (33, 48))	('primary sarcoma', 'Disease', (126, 141))	('primary sarcoma', 'Disease', 'MESH:D012509', (126, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
117201	28691711	Interestingly, four distinct indels in the Trp53 site were detected in one cell line (2995), suggesting that this sarcoma cell line either contained at least two clones or arose because of tetraploidization before mutagenesis, which is a frequent event in tumorigenesis.	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('tetraploidization', 'Var', (189, 206))	('sarcoma', 'Disease', (114, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('mutagenesis', 'Var', (214, 225))
117202	28691711	This high frequency of biallelic modification could reflect high efficiency of on-target CRISPR-Cas9 gene modification, such that if one allele is modified it is highly likely for the other allele to be modified as well.	('modification', 'Var', (106, 118))	('Cas9', 'Chemical', '-', (96, 100))	('CRISPR-Cas9', 'Gene', (89, 100))
117205	28691711	Surveyor assay of the on-target chromosome 17 site showed evidence of indels in the Cas9 recognition site (Supplementary Fig.	('Cas9 recognition', 'Gene', (84, 100))	('indels', 'Var', (70, 76))	('Cas9', 'Chemical', '-', (84, 88))
117212	28691711	Although Cas9 precisely cleaved the targeted Trp53 region and on-target chromosome 17 site with perfect complementarity to the sgRNA to produce site-specific indels in each tumour, several studies have shown that Cas9 activity may also result in off-target mutations in other regions of the genome.	('tumour', 'Disease', (173, 179))	('mutations', 'Var', (257, 266))	('Cas9', 'Chemical', '-', (213, 217))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('activity', 'MPA', (218, 226))	('Cas9', 'Gene', (213, 217))	('Trp53', 'Protein', (45, 50))	('Cas9', 'Chemical', '-', (9, 13))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
117215	28691711	In addition, the Surveyor assay identified DNA mismatches in the tumour DNA that further Sanger sequencing determined to be SNPs rather than mutations (Supplementary Fig.	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('mismatches', 'Var', (47, 57))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Disease', (65, 71))
117216	28691711	DNA mismatches were only detected in one off-target site by Surveyor assay, which were also confirmed as SNPs in both the tumour and normal DNA by Sanger sequencing.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('mismatches', 'Var', (4, 14))	('tumour', 'Disease', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
117217	28691711	Taken together, these results indicate that Cas9 specifically cleaves the targeted region to produce site-specific indels in each tumour without causing detectable off-target mutations in other regions of the genome.	('produce', 'Reg', (93, 100))	('Cas9', 'Chemical', '-', (44, 48))	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Disease', (130, 136))	('indels', 'Var', (115, 121))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
117219	28691711	To further simplify this approach, we injected the pX333-P-Cre plasmid directly into muscle and observed tumours in 4 out of 15 KC mice with tumours forming as early as 13.1 weeks (Fig.	('tumours', 'Disease', (141, 148))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (105, 112))	('mice', 'Species', '10090', (131, 135))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('pX333-P-Cre', 'Var', (51, 62))
117221	28691711	However, electroporation of plasmid efficiently generated tumours (80% penetrance after median 10.8 weeks, Fig.	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('electroporation', 'Var', (9, 24))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumours', 'Disease', (58, 65))
117222	28691711	In vivo electroporation (IVE) of naked plasmid pcDNA3-EGFP was ~38 times more efficient for enhanced green fluorescent protein (EGFP) delivery to muscle fibres compared with adenovirus delivery of EGFP, but this increased efficiency did not affect the penetrance or the kinetics of sarcoma formation (Supplementary Fig.	('pcDNA3-EGFP', 'Gene', (47, 58))	('electroporation', 'Var', (8, 23))	('sarcoma', 'Disease', (282, 289))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('more', 'PosReg', (73, 77))	('sarcoma', 'Disease', 'MESH:D012509', (282, 289))	('enhanced', 'PosReg', (92, 100))
117224	28691711	After electroporation with pX333-P-Cre plasmid, the K-loxP-C mice developed sarcomas with 100% penetrance (Fig.	('mice', 'Species', '10090', (61, 65))	('sarcomas', 'Disease', 'MESH:D012509', (76, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (76, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcomas', 'Disease', (76, 84))	('pX333-P-Cre', 'Var', (27, 38))
117228	28691711	Loss-of-function mutations in the Ras regulatory gene neurofibromin 1 (Nf1) and the tumour suppressor Cdkn2a (also known as p16/p19 or Ink4a/Arf) are commonly found in MPNSTs.	('neurofibromin 1', 'Gene', '18015', (54, 69))	('Loss-of-function', 'NegReg', (0, 16))	('tumour', 'Disease', (84, 90))	('Nf1', 'Gene', '18015', (71, 74))	('p16', 'Gene', '12578', (124, 127))	('p19', 'Gene', (128, 131))	('p19', 'Gene', '12581', (128, 131))	('MPNST', 'Phenotype', 'HP:0100697', (168, 173))	('Cdkn2a', 'Gene', '12578', (102, 108))	('Cdkn2a', 'Gene', (102, 108))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('p16', 'Gene', (124, 127))	('Nf1', 'Gene', (71, 74))	('Ink4a/Arf', 'Gene', '12578', (135, 144))	('Ink4a/Arf', 'Gene', (135, 144))	('mutations', 'Var', (17, 26))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('neurofibromin 1', 'Gene', (54, 69))
117231	28691711	Mice with mutations in Nf1 and Trp53 in cis on chromosome 11 (Nf1+/-; p53+/-) also develop MPNSTs through spontaneous loss of heterozygosity of the wild-type Nf1 and Trp53 alleles.	('p53', 'Gene', '22059', (168, 171))	('MPNSTs', 'CPA', (91, 97))	('Nf1', 'Gene', (158, 161))	('p53', 'Gene', (70, 73))	('Nf1', 'Gene', (62, 65))	('p53', 'Gene', '22059', (70, 73))	('Nf1', 'Gene', '18015', (23, 26))	('MPNST', 'Phenotype', 'HP:0100697', (91, 96))	('Nf1', 'Gene', '18015', (158, 161))	('loss', 'NegReg', (118, 122))	('develop', 'PosReg', (83, 90))	('Nf1', 'Gene', '18015', (62, 65))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '22059', (33, 36))	('Mice', 'Species', '10090', (0, 4))	('mutations', 'Var', (10, 19))	('Nf1', 'Gene', (23, 26))	('p53', 'Gene', (168, 171))
117240	28691711	Nf1 and Trp53 indels were detected by Surveyor assay in three of three cell lines derived from these tumours (Fig.	('indels', 'Var', (14, 20))	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('Nf1', 'Gene', (0, 3))	('tumours', 'Disease', (101, 108))	('Trp53', 'Gene', (8, 13))	('Nf1', 'Gene', '18015', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))
117247	28691711	We compared the mutational load, which we defined as the number of non-synonymous somatic mutations per megabase (MB) of DNA, from tumours generated in KC mice following Ad-P-Cre injection (n=5) and tumours generated in KP mice following Ad-Cre injection (n=7).	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (90, 99))	('tumours', 'Disease', (131, 138))	('mice', 'Species', '10090', (223, 227))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('DNA', 'Gene', (121, 124))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('mice', 'Species', '10090', (155, 159))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumours', 'Disease', (199, 206))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))
117248	28691711	We also compared the amplifications and deletions to assess global CNV in these tumours.	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('deletions', 'Var', (40, 49))	('tumours', 'Disease', (80, 87))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))
117249	28691711	Overall, there were no significant differences in mutational load and CNV between sarcomas generated with or without CRISPR-Cas9 technology (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('mutational', 'Var', (50, 60))	('sarcomas', 'Disease', 'MESH:D012509', (82, 90))	('Cas9', 'Chemical', '-', (124, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('CNV', 'MPA', (70, 73))	('sarcomas', 'Disease', (82, 90))
117250	28691711	Therefore, these results demonstrate that a combined Cre-loxP and CRISPR-Cas9 system that activates KrasG12D and deletes Trp53 in KC mice is sufficient to result in primary soft tissue sarcomas with mutational load and CNV similar to an established Cre-loxP tumour model.	('result in', 'Reg', (155, 164))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (173, 193))	('mice', 'Species', '10090', (133, 137))	('activates', 'PosReg', (90, 99))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (173, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (185, 193))	('Trp53', 'Gene', (121, 126))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (173, 193))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('tumour', 'Disease', 'MESH:D009369', (258, 264))	('Cas9', 'Chemical', '-', (73, 77))	('soft tissue sarcomas', 'Disease', (173, 193))	('KrasG12D', 'Gene', (100, 108))	('tumour', 'Disease', (258, 264))	('deletes', 'Var', (113, 120))
117270	28691711	For indel classes that could be detected by deep sequencing, such as the insertion in mouse 2981 and deletion in mouse 2925, the deep sequencing was validated by Sanger sequencing.	('deletion', 'Var', (101, 109))	('mouse', 'Species', '10090', (86, 91))	('insertion', 'Var', (73, 82))	('2981', 'Gene', (92, 96))	('2925', 'Gene', (119, 123))	('mouse', 'Species', '10090', (113, 118))
117271	28691711	For example, we found deletions up to 281 bp in size via Sanger sequencing, but these large deletions were not detected by deep sequencing of the same tumour DNA (Fig.	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('deletions', 'Var', (22, 31))	('tumour', 'Disease', (151, 157))
117273	28691711	These data showed exon 2 of Celsr1 contained variants, but these were identified as SNPs outside of the Cas9 recognition site (Supplementary Fig.	('Cas9', 'Chemical', '-', (104, 108))	('Celsr1', 'Gene', '12614', (28, 34))	('variants', 'Var', (45, 53))	('Celsr1', 'Gene', (28, 34))
117280	28691711	Therefore, we delivered pX333-P-Cre plasmid via IVE and successfully generated tumours in 80% of KC mice (median 10.8 weeks).	('mice', 'Species', '10090', (100, 104))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('pX333-P-Cre', 'Var', (24, 35))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumours', 'Disease', (79, 86))
117281	28691711	In KC mice infected with Ad-P-Cre, sarcomas arose over a similar time frame ranging from 7.3-15.7 weeks (median 9.6).	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('mice', 'Species', '10090', (6, 10))	('sarcomas', 'Disease', (35, 43))	('Ad-P-Cre', 'Var', (25, 33))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))
117282	28691711	Remarkably, we noticed that delivery of pX333-P-Cre plasmid via IVE in mice that constitutively express Cas9 (K-loxP-C mice) resulted in 100% tumour penetrance (median 7.4 weeks) with a more restricted period for tumour formation.	('mice', 'Species', '10090', (71, 75))	('tumour', 'Disease', (142, 148))	('mice', 'Species', '10090', (119, 123))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('pX333-P-Cre', 'Var', (40, 51))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('Cas9', 'Chemical', '-', (104, 108))	('tumour', 'Disease', (213, 219))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
117283	28691711	For example, the endogenous Cas9 expressed in K-loxP-C mice may increase the target population of cells that undergo both Cre-mediated recombination and Cas9-mediated genome editing that are required for tumorigenesis.	('mice', 'Species', '10090', (55, 59))	('increase', 'PosReg', (64, 72))	('endogenous', 'Var', (17, 27))	('Cas9', 'Chemical', '-', (28, 32))	('Cas9', 'Gene', (28, 32))	('Cas9', 'Chemical', '-', (153, 157))
117287	28691711	We also successfully generated a sarcoma model of MPNST using CRISPR-Cas9 mutagenesis to knockout Nf1 and Trp53 in wild-type mice.	('Nf1', 'Gene', (98, 101))	('MPNST', 'Phenotype', 'HP:0100697', (50, 55))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('mice', 'Species', '10090', (125, 129))	('Nf1', 'Gene', '18015', (98, 101))	('Cas9', 'Chemical', '-', (69, 73))	('sarcoma', 'Disease', (33, 40))	('knockout', 'Var', (89, 97))	('mutagenesis', 'Var', (74, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Trp53', 'Gene', (106, 111))
117291	28691711	We performed whole exome sequencing to profile the mutational load and CNV in the KP primary sarcoma models initiated by Cre alone or Cre and CRISPR-Cas9.	('mutational load', 'Var', (51, 66))	('primary sarcoma', 'Disease', (85, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('primary sarcoma', 'Disease', 'MESH:D012509', (85, 100))	('Cas9', 'Chemical', '-', (149, 153))
117307	28691711	Virus was prepared by mixing 25 mul of Ad-sgTrp53-cre (6 x 107 pfu mul-1) or Ad-CMV-EGFP (4 x 107 pfu mul-1) with 600 mul minimal essential medium (Sigma-Aldrich, M4655) or mixing 125 mul of Ad-sgNf1-sgTrp53-Cas9 (4 x 106 pfu mul-1) with 500 mul minimal essential medium.	('Nf1', 'Gene', (196, 199))	('Ad-CMV-EGFP', 'Var', (77, 88))	('Nf1', 'Gene', '18015', (196, 199))	('Cas9', 'Chemical', '-', (208, 212))
117317	28691711	In the final step, pX333-sgTrp53-Cre vector was cloned into the Ad5 adenoviral shuttle vector, which was kindly provided by A. Ventura (Memorial Sloan Kettering Cancer Center) using XhoI and EcoRI sites.	('shuttle vector', 'Species', '45197', (79, 93))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (136, 167))	('Memorial Sloan Kettering Cancer', 'Disease', (136, 167))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pX333-sgTrp53-Cre', 'Var', (19, 36))
117319	28691711	Recombinant adenoviruses were generated by Viraquest Inc. Recombination of the mutant Kras allele and the Cas9 allele were assessed by PCR using AccuPrime Taq HiFi DNA polymerase (Thermo Fisher Scientific, 12346-086) and utilized primers in Supplementary Table 5.	('Cas9', 'Chemical', '-', (106, 110))	('Kras', 'Gene', '16653', (86, 90))	('mutant', 'Var', (79, 85))	('Kras', 'Gene', (86, 90))
117336	28691711	Next, membranes were incubated overnight at 4  C with primary antibodies diluted in TBS-T (0.1% Tween-20): p53, 1:250 dilution (1C12, Cell Signaling Technology); Nf1, 1:500 dilution (A300-A140M, Bethyl Laboratories).	('Nf1', 'Gene', '18015', (162, 165))	('A140M', 'Mutation', 'p.A140M', (188, 193))	('Tween-20', 'Chemical', 'MESH:D011136', (96, 104))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '22059', (107, 110))	('A300-A140M', 'Var', (183, 193))	('Nf1', 'Gene', (162, 165))
117337	28691711	Membranes were washed three times in TBS-T for 5 min before secondary antibody incubation with goat anti-rabbit IRDye800 (Li-Cor Biosciences, P/N 925-32211) and goat anti-mouse IRDye680 (Li-Cor Biosciences, P/N 925-68070) both at 1:10,000 dilutions in TBS-T for 1 h at room temperature.	('P/N 925', 'Var', (207, 214))	('goat', 'Species', '9925', (161, 165))	('goat', 'Species', '9925', (95, 99))	('rabbit', 'Species', '9986', (105, 111))	('P/N 925', 'SUBSTITUTION', 'None', (207, 214))	('P/N 925', 'SUBSTITUTION', 'None', (142, 149))	('P/N 925', 'Var', (142, 149))	('mouse', 'Species', '10090', (171, 176))
117370	27266712	Although consensus is emerging that treatment should be histology-driven, recent studies suggest tailored therapies against these common molecular targets identifying the effects of genetic aberrations on downstream signalling pathways with activation of key intracellular mediators that may represent targets for biological therapies.	('gain', 'Disease', (117, 121))	('downstream signalling pathways', 'Pathway', (205, 235))	('activation', 'PosReg', (241, 251))	('gain', 'Disease', 'MESH:D015430', (117, 121))	('genetic aberrations', 'Var', (182, 201))
117371	27266712	Few highly recurrent driver genes have been described in sarcomas with high genomic complexity, including defects in oncosuppressor genes RB1 and PTEN, mutations in TP53 and homozygous deletions of p16/CDKN2A, a cyclin-dependent kinase inhibitor.	('PTEN', 'Gene', (146, 150))	('RB1', 'Gene', (138, 141))	('p16', 'Gene', (198, 201))	('TP53', 'Gene', (165, 169))	('mutations', 'Var', (152, 161))	('PTEN', 'Gene', '5728', (146, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('homozygous deletions', 'Var', (174, 194))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('RB1', 'Gene', '5925', (138, 141))	('CDKN2A', 'Gene', (202, 208))	('p16', 'Gene', '1029', (198, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('CDKN2A', 'Gene', '1029', (202, 208))	('defects', 'Var', (106, 113))	('TP53', 'Gene', '7157', (165, 169))	('sarcomas', 'Disease', (57, 65))
117374	27266712	Aberration in TP53 and p16/CDKN2A oncosuppressor genes, growth factor signalling pathway activation and increased proteolitic and angiogenesis activity contribute to metastatic progression.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('p16', 'Gene', (23, 26))	('increased', 'PosReg', (104, 113))	('growth factor signalling pathway', 'Pathway', (56, 88))	('metastatic progression', 'CPA', (166, 188))	('angiogenesis activity', 'CPA', (130, 151))	('activation', 'PosReg', (89, 99))	('CDKN2A', 'Gene', (27, 33))	('p16', 'Gene', '1029', (23, 26))	('proteolitic', 'MPA', (114, 125))	('CDKN2A', 'Gene', '1029', (27, 33))	('Aberration', 'Var', (0, 10))
117382	27266712	During malignant progression from well-differentiated LPS and myxoid LPS to de-differentiated and round-cell histotypes respectively, the secondary genetic mutations lead to an increased genomic complexity, multiple numerical and structural chromosome aberrations and loss of specific targets.	('LPS', 'Phenotype', 'HP:0012034', (69, 72))	('LPS', 'Disease', (69, 72))	('mutations', 'Var', (156, 165))	('LPS', 'Disease', 'MESH:C536528', (69, 72))	('increased', 'PosReg', (177, 186))	('genomic complexity', 'CPA', (187, 205))	('LPS', 'Phenotype', 'HP:0012034', (54, 57))	('LPS', 'Disease', (54, 57))	('LPS', 'Disease', 'MESH:C536528', (54, 57))
117434	27266712	This happens because conventional ADC values are calculated on a vast range of b value (b 0-600 s/mm2) and the low b values are sensitive to perfusion determined by the tumour extracellular water component as opposed to the use of high b values (300,500, 600 s/mm2) that are perfusion insensitive so perfusion effects tend to be canceled.	('300,500', 'Var', (246, 253))	('tumour', 'Disease', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('water', 'Chemical', 'MESH:D014867', (190, 195))
117445	27266712	It is also possible to differentiate necrotic masses such as hematomas and abscesses from necrotic hemorrhagic in malignant soft tumours by ADC map values both in the central component and on the peripheral rim.	('necrotic', 'Disease', 'MESH:D009336', (37, 45))	('abscesses', 'Phenotype', 'HP:0025615', (75, 84))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('necrotic hemorrhagic', 'Disease', 'MESH:D006470', (90, 110))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('necrotic', 'Disease', (90, 98))	('malignant soft tumours', 'Disease', (114, 136))	('hematomas', 'Disease', (61, 70))	('malignant soft tumours', 'Disease', 'MESH:D009369', (114, 136))	('ADC', 'Var', (140, 143))	('necrotic hemorrhagic', 'Disease', (90, 110))	('necrotic', 'Disease', 'MESH:D009336', (90, 98))	('necrotic', 'Disease', (37, 45))	('hematomas', 'Disease', 'MESH:D006406', (61, 70))	('abscesses', 'Disease', (75, 84))
117466	27266712	By using intravital microscope we demonstrated that the capacity of fluorescently labelled LMS cells to invade lymphatic vessels in living mice is increased by ectopic expression of proteoglycan NG2 involved in tumour cell-environment interaction, found also overexpressed in advanced/metastatic STS patients.	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('NG2', 'Gene', (195, 198))	('increased', 'PosReg', (147, 156))	('tumour', 'Disease', (211, 217))	('ectopic expression', 'Var', (160, 178))	('LMS', 'Phenotype', 'HP:0100243', (91, 94))	('NG2', 'Gene', '121021', (195, 198))	('mice', 'Species', '10090', (139, 143))	('invade lymphatic vessels', 'CPA', (104, 128))	('STS', 'Phenotype', 'HP:0030448', (296, 299))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('patients', 'Species', '9606', (300, 308))
117553	24827933	Sleeping Beauty mutagenesis was targeted to myeloid lineage cells using the Lysozyme2 promoter.	('mutagenesis', 'Var', (16, 27))	('Lysozyme2', 'Gene', (76, 85))	('Lysozyme2', 'Gene', '17105', (76, 85))
117554	24827933	Mice with activated Sleeping Beauty mutagenesis had significantly shortened lifespan and the majority of these mice developed tumors resembling human histiocytic sarcoma.	('developed', 'Reg', (116, 125))	('lifespan', 'CPA', (76, 84))	('tumors', 'Disease', (126, 132))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('human', 'Species', '9606', (144, 149))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('sarcoma', 'Disease', (162, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('mice', 'Species', '10090', (111, 115))	('shortened', 'NegReg', (66, 75))	('mutagenesis', 'Var', (36, 47))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
117569	24827933	ArrayCGH performed on over 100 canine HS samples revealed an average of 30 copy number alterations per tumor, while a genome wide association study in Bernese Mountain Dogs identified a strong association between HS and the MTAP-CDKN2A locus.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CDKN2A', 'Gene', '100271861', (229, 235))	('CDKN2A', 'Gene', (229, 235))	('copy number alterations', 'Var', (75, 98))	('tumor', 'Disease', (103, 108))	('MTAP', 'Gene', '474729', (224, 228))	('MTAP', 'Gene', (224, 228))	('canine', 'Species', '9615', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('Dogs', 'Species', '9615', (168, 172))
117575	24827933	In this study we activated SB mutagenesis using the Lysozyme2 (Lyz2) promoter in a cohort of mice resulting in early mortality and a large percentage of mice developing HS.	('Lysozyme2', 'Gene', '17105', (52, 61))	('Lysozyme2', 'Gene', (52, 61))	('Lyz2', 'Gene', (63, 67))	('mice', 'Species', '10090', (93, 97))	('mice', 'Species', '10090', (153, 157))	('mutagenesis', 'Var', (30, 41))	('Lyz2', 'Gene', '17105', (63, 67))	('SB', 'Chemical', '-', (27, 29))
117605	24827933	Each tumor is then represented by a set of genes containing at least one insertion in that tumor, which forms a binary transaction matrix in which rows are tumors and columns are affected genes.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('insertion', 'Var', (73, 82))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumors', 'Disease', (156, 162))
117612	24827933	The list of mutations in AML were derived from supplemental tables in the TCGA report on AML combining the list of Tier 1 mutated genes with the list of fusion genes.	('AML', 'Disease', 'MESH:D015470', (89, 92))	('mutations', 'Var', (12, 21))	('AML', 'Disease', 'MESH:D015470', (25, 28))	('AML', 'Disease', (89, 92))	('AML', 'Disease', (25, 28))
117620	24827933	The transposon was designed to be capable of overexpressing or disrupting genes, and these transposon-induced mutations provide cells with a selective advantage when they occur in oncogenes or tumor suppressors, respectively (Fig S1-C).	('mutations', 'Var', (110, 119))	('transposon-induced', 'Gene', (91, 109))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('advantage', 'PosReg', (151, 160))	('tumor', 'Disease', (193, 198))	('occur', 'Reg', (171, 176))
117621	24827933	We have shown that the SB transposon system is capable of generating insertional mutations leading to overexpression of oncogenes, overexpression of truncated genes, and disruption of genes.	('overexpression', 'PosReg', (102, 116))	('insertional mutations', 'Var', (69, 90))	('oncogenes', 'Protein', (120, 129))	('mutations', 'Var', (81, 90))	('SB', 'Chemical', '-', (23, 25))	('disruption', 'MPA', (170, 180))	('overexpression', 'PosReg', (131, 145))	('genes', 'Gene', (184, 189))
117624	24827933	Triple transgenic mice became moribund at a faster rate than controls, beginning around one year of age (Fig 1).	('transgenic mice', 'Species', '10090', (7, 22))	('Triple transgenic', 'Var', (0, 17))	('moribund', 'Disease', (30, 38))
117650	24827933	In previous screens we noted that transposon insertions mapping to the donor chromosome, where the original transposon transgene was located, constituted up to half of all the mapped transposon insertions, a phenomenon referred to as "local hopping".	('donor', 'Species', '9606', (71, 76))	('insertions', 'Var', (194, 204))	('transposon', 'Gene', (183, 193))
117661	24827933	It was apparent that several tumors were clonal, based on the large percentage of shared insertions, although the majority of tumors did not share transposon insertions with tumors from the same animal (Table S7).	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('insertions', 'Var', (89, 99))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
117666	24827933	Over 25% of all tumors had a mutation in one of these three genes, and half of these tumors had mutations in at least two of the genes.	('mutation', 'Var', (29, 37))	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
117668	24827933	We selected four tumors from three mice and measured the expression level of four genes (Fli1, Nf1, Mitf, and Raf1) in the tumors that had insertions in these four genes.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (123, 129))	('Raf1', 'Gene', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('Raf1', 'Gene', '110157', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (17, 23))	('Nf1', 'Gene', '18015', (95, 98))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Mitf', 'Gene', '17342', (100, 104))	('expression level', 'MPA', (57, 73))	('mice', 'Species', '10090', (35, 39))	('Mitf', 'Gene', (100, 104))	('insertions', 'Var', (139, 149))	('Nf1', 'Gene', (95, 98))	('Fli1', 'Gene', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
117669	24827933	Based on the transposon insertion pattern we predicted that Fli1, Mitf, and Raf1 would have gain of function mutations, while Nf1 would have a loss of function.	('gain of function', 'PosReg', (92, 108))	('Nf1', 'Gene', (126, 129))	('Raf1', 'Gene', (76, 80))	('Raf1', 'Gene', '110157', (76, 80))	('Fli1', 'Gene', (60, 64))	('Nf1', 'Gene', '18015', (126, 129))	('mutations', 'Var', (109, 118))	('Mitf', 'Gene', '17342', (66, 70))	('Mitf', 'Gene', (66, 70))
117671	24827933	Because Raf1 was the site of transposon mutagenesis in over 20% of tumors analyzed, we checked for transposons inserted near other MAPK pathway genes in tumors without a Raf1 insertion.	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('Raf1', 'Gene', (170, 174))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('Raf1', 'Gene', (8, 12))	('MAPK pathway', 'Gene', (131, 143))	('mutagenesis', 'Var', (40, 51))	('Raf1', 'Gene', '110157', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Disease', (153, 159))	('Raf1', 'Gene', '110157', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
117672	24827933	We found that 44 of the 92 tumors (48%) generated in our screen had a transposon insertion within 10 kb of an annotated MAPK pathway gene based on the KEGG MAPK pathway gene list (Table S8).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('transposon insertion', 'Var', (70, 90))	('MAPK pathway gene', 'Gene', (120, 137))
117674	24827933	After correcting for multiple testing, we found significant associations between Fli1 and Bach2 and between Mitf and Raf1, suggesting these pairs of mutations may cooperate in HS tumorigenesis, although formal proof of cooperation would require further experiments.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mutations', 'Var', (149, 158))	('Raf1', 'Gene', (117, 121))	('Raf1', 'Gene', '110157', (117, 121))	('Bach2', 'Gene', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('associations', 'Interaction', (60, 72))	('Fli1', 'Gene', (81, 85))	('cooperate', 'Reg', (163, 172))	('Mitf', 'Gene', '17342', (108, 112))	('Mitf', 'Gene', (108, 112))	('tumor', 'Disease', (179, 184))
117682	24827933	The AML study analyzed mutations and gene-fusions in 200 patient samples and identified 2,022 genes with mutations or gene fusions predicted to alter protein sequence.	('AML', 'Disease', (4, 7))	('protein sequence', 'MPA', (150, 166))	('patient', 'Species', '9606', (57, 64))	('alter', 'Reg', (144, 149))	('AML', 'Disease', 'MESH:D015470', (4, 7))	('mutations', 'Var', (23, 32))	('mutations', 'Var', (105, 114))
117689	24827933	Finally, we used a method of identifying cooperating mutations in our tumors that does not rely on defined CISs.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations', 'Var', (53, 62))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))
117693	24827933	For example, three mice had tumors with transposon insertions in seven of these eight genes (See itemset #11 in Table S12).	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('transposon insertions', 'Var', (40, 61))	('mice', 'Species', '10090', (19, 23))
117704	24827933	Altered RAF1 is associated with the development of Noonan and LEOPARD syndrome, AML, and pilocytic astrocytoma.	('RAF1', 'Gene', (8, 12))	('pilocytic astrocytoma', 'Disease', (89, 110))	('Altered', 'Var', (0, 7))	('AML', 'Disease', (80, 83))	('AML', 'Disease', 'MESH:D015470', (80, 83))	('associated', 'Reg', (16, 26))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (89, 110))	('LEOPARD syndrome', 'Disease', 'MESH:D044542', (62, 78))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))	('LEOPARD syndrome', 'Disease', (62, 78))
117707	24827933	FLI1 fusions have also been found in prostate cancer and abnormal FLI1 expression in AML patients correlates with poor prognosis.	('FLI1', 'Gene', (0, 4))	('expression', 'MPA', (71, 81))	('FLI1', 'Gene', (66, 70))	('fusions', 'Var', (5, 12))	('prostate cancer', 'Disease', (37, 52))	('AML', 'Disease', 'MESH:D015470', (85, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (37, 52))	('patients', 'Species', '9606', (89, 97))	('AML', 'Disease', (85, 88))	('found', 'Reg', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('abnormal', 'Var', (57, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (37, 52))
117718	24827933	We found that over 50% of tumors in our screen had transposon insertions near MAPK pathway genes, suggesting that MAPK pathway inhibitors or HDAC inhibitors, like FK228, that significantly decrease RAF1 levels may be effective therapeutics for HS patients.	('FK228', 'Chemical', 'MESH:C087123', (163, 168))	('MAPK pathway genes', 'Gene', (78, 96))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('patients', 'Species', '9606', (247, 255))	('decrease', 'NegReg', (189, 197))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('transposon insertions', 'Var', (51, 72))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('RAF1 levels', 'MPA', (198, 209))	('tumors', 'Disease', (26, 32))
117720	24827933	Abnormal expression of FLI1 is associated with AML and T-cell lymphoma, while FLI1 fusion proteins are linked to Ewing sarcoma and prostate cancer.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (113, 126))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (113, 126))	('FLI1', 'Gene', (23, 27))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (55, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('linked', 'Reg', (103, 109))	('associated', 'Reg', (31, 41))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (55, 70))	('T-cell lymphoma', 'Disease', (55, 70))	('Ewing sarcoma', 'Disease', (113, 126))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('cell lymphoma', 'Phenotype', 'HP:0012191', (57, 70))	('AML', 'Disease', (47, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Abnormal expression', 'Var', (0, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('prostate cancer', 'Disease', (131, 146))
117823	27845897	The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis The Polycomb repressive complex 2 (PRC2), which contains three core proteins EZH2, EED and SUZ12, controls chromatin compaction and transcription repression through trimethylation of lysine 27 on histone 3.	('disrupts', 'NegReg', (31, 39))	('endometrial stromal tumorogenesis', 'Disease', 'MESH:D036821', (101, 134))	('JAZF1', 'Gene', (4, 9))	('endometrial stromal tumorogenesis', 'Disease', (101, 134))	('SUZ12', 'Gene', (226, 231))	('EED', 'Gene', (218, 221))	('chromatin repression', 'MPA', (67, 87))	('impairs', 'NegReg', (59, 66))	('lysine 27', 'Protein', (318, 327))	('SUZ12', 'Gene', '23512', (226, 231))	('transcription', 'MPA', (267, 280))	('human', 'Species', '9606', (95, 100))	('trimethylation', 'Var', (300, 314))	('SUZ12', 'Gene', (10, 15))	('lysine', 'Chemical', 'MESH:D008239', (318, 324))	('Polycomb', 'Gene', '12416', (139, 147))	('EED', 'Gene', '8726', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('SUZ12', 'Gene', '23512', (10, 15))	('Polycomb', 'Gene', (139, 147))	('PRC2 complexes', 'MPA', (40, 54))	('JAZF1', 'Gene', '221895', (4, 9))
117824	27845897	The (7;17)(p15;q21) chromosomal translocation present in most cases of endometrial stromal sarcomas (ESSs) results in the in-frame fusion of the JAZF1 and SUZ12 genes.	('endometrial stromal sarcomas', 'Disease', (71, 99))	('p15', 'Gene', (11, 14))	('p15', 'Gene', '1030', (11, 14))	('fusion', 'Var', (131, 137))	('SUZ12', 'Gene', (155, 160))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (71, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('results in', 'Reg', (107, 117))	('JAZF1', 'Gene', (145, 150))
117825	27845897	Co-transient transfection assay indicated JAZF1-SUZ12 destabilized PRC2 components EZH2 and EED, resulting in decreased histone methyl transferase (HMT) activity, which was confirmed by in vitro studies using reconstituted PRC2 and nucleosome array substrates.	('histone methyl transferase', 'Gene', '56979', (120, 146))	('histone methyl transferase', 'Gene', (120, 146))	('EED', 'Gene', '8726', (92, 95))	('destabilized', 'NegReg', (54, 66))	('EED', 'Gene', (92, 95))	('HMT', 'Gene', (148, 151))	('decreased', 'NegReg', (110, 119))	('HMT', 'Gene', '56979', (148, 151))	('activity', 'MPA', (153, 161))	('PRC2', 'Gene', (67, 71))	('JAZF1-SUZ12', 'Var', (42, 53))
117827	27845897	In summary, our studies reveal that JAZF1-SUZ12 fusion protein disrupts the PRC2 complex, abolishes HMT activity and subsequently activates chromatin/genes normally repressed by PRC2.	('HMT', 'Gene', '56979', (100, 103))	('PRC2 complex', 'Protein', (76, 88))	('chromatin/genes', 'MPA', (140, 155))	('JAZF1-SUZ12', 'Var', (36, 47))	('disrupts', 'NegReg', (63, 71))	('activates', 'PosReg', (130, 139))	('HMT', 'Gene', (100, 103))	('abolishes', 'NegReg', (90, 99))
117828	27845897	Such dyesfunction of PRC2 inhibits normal neural differentiation of ES cell and increases cell proliferation.	('PRC2', 'Gene', (21, 25))	('inhibits', 'NegReg', (26, 34))	('normal neural differentiation of ES cell', 'CPA', (35, 75))	('ES', 'Chemical', 'MESH:D004540', (68, 70))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('cell proliferation', 'CPA', (90, 108))	('dyesfunction', 'Var', (5, 17))	('increases', 'PosReg', (80, 89))	('S', 'Chemical', 'MESH:D013455', (0, 1))
117829	27845897	Methylation modification on these histones has been shown to either inhibit or activate gene expression depending on the type of amino acids and the site as well as the degree of methylations.	('gene expression', 'MPA', (88, 103))	('expression', 'Species', '29278', (93, 103))	('inhibit', 'NegReg', (68, 75))	('activate', 'PosReg', (79, 87))	('Methylation modification', 'Var', (0, 24))
117839	27845897	The canonical function of PRC1 complexes is bond to the site of H3K27Me3 of chromatin therefore form the polycomb repression domain and lead to stabilizing the compacted chromatin, but in vivo study also revealed that variant PRC1 complexes (PHC2, for example) are proficient at catalyzing H2AK119ub1 on chromatin, and surprisingly, this modification auto-polymerizes through its sterile-alpha motif (SAM), and PRC1 can recruit PRC2 to chromatin through recognition of H2AK119ub1 marker, leading to chromatin compaction and gene silencing.	('PHC2', 'Gene', '1912', (242, 246))	('variant', 'Var', (218, 225))	('PHC2', 'Gene', (242, 246))	('chromatin compaction', 'CPA', (499, 519))	('gene silencing', 'CPA', (524, 538))	('S', 'Chemical', 'MESH:D013455', (401, 402))	('H2AK119ub1', 'Var', (469, 479))
117854	27845897	Chromosome abnormalities involving polycomb proteins have been frequently detected in human endometrial stromal sarcoma (ESS) patients, In low grade ESS, the most frequent genetic rearrangement is the t(7;17)(p15;q21), which results in genetic fusion of JAZF1 and SUZ12, which was originally referred to as JJAZ1.	('genetic', 'Var', (236, 243))	('endometrial stromal sarcoma', 'Disease', (92, 119))	('t(7;17)(p15;q21', 'Var', (201, 216))	('t(7;17)(p15;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (201, 217))	('JJAZ1', 'Gene', '23512', (307, 312))	('SUZ12', 'Gene', (264, 269))	('human', 'Species', '9606', (86, 91))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (92, 119))	('Chromosome abnormalities', 'Phenotype', 'HP:0031411', (0, 24))	('JAZF1', 'Gene', (254, 259))	('JJAZ1', 'Gene', (307, 312))	('patients', 'Species', '9606', (126, 134))	('Chromosome abnormalities', 'Disease', (0, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('Chromosome abnormalities', 'Disease', 'MESH:D002869', (0, 24))
117855	27845897	That the chromosomal rearrangements are closely associated with women's ESSs indicate these genetic events may play critical role in carcinogenesis/ metastasis.	("women's ESSs", 'Disease', (64, 76))	('associated', 'Reg', (48, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (133, 147))	('chromosomal rearrangements', 'Var', (9, 35))	('women', 'Species', '9606', (64, 69))	('carcinogenesis', 'Disease', (133, 147))
117868	27845897	High level of fusion protein was confirmed from ESS tumor samples as shown in Figure 1D using anti-SUZ12 antibody (and anti-JAZF1 antibody, data not showed).	('anti-SUZ12', 'Var', (94, 104))	('ESS tumor', 'Disease', (48, 57))	('ESS tumor', 'Disease', 'MESH:D009369', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))
117870	27845897	In the presence of comparable amounts of SUZ12 and JAZF1-SUZ12, EZH2 and EED were much lower in abundance in cells expressing JAZF1-SUZ12, while levels of AEBP2 and RBAP48 were not significantly different (data is not shown) in cells bearing expression vectors for SUZ12 and JAZF1-SUZ12.	('abundance', 'MPA', (96, 105))	('expression vectors', 'Species', '29278', (242, 260))	('AEBP2', 'Gene', (155, 160))	('RBAP48', 'Gene', (165, 171))	('lower', 'NegReg', (87, 92))	('RBAP48', 'Gene', '5928', (165, 171))	('EED', 'Gene', '8726', (73, 76))	('JAZF1-SUZ12', 'Var', (126, 137))	('EED', 'Gene', (73, 76))	('AEBP2', 'Gene', '121536', (155, 160))
117871	27845897	These results are consistent with that of JAZF1-SUZ12 significantly decreasing EZH2 and EED protein levels, in the presence or absence of EED (Figure 2B).	('EED', 'Gene', (88, 91))	('EZH2', 'MPA', (79, 83))	('EED', 'Gene', '8726', (138, 141))	('decreasing', 'NegReg', (68, 78))	('EED', 'Gene', (138, 141))	('JAZF1-SUZ12', 'Var', (42, 53))	('EED', 'Gene', '8726', (88, 91))
117872	27845897	In contrast, two other Polycomb protein RBAP48 and AEBP2 levels were not affected by the replacement of SUZ12 with JAZF1-SUZ12.	('RBAP48', 'Gene', '5928', (40, 46))	('RBAP48', 'Gene', (40, 46))	('AEBP2', 'Gene', (51, 56))	('Polycomb', 'Gene', '12416', (23, 31))	('Polycomb', 'Gene', (23, 31))	('SUZ12', 'Gene', (104, 109))	('replacement', 'Var', (89, 100))	('AEBP2', 'Gene', '121536', (51, 56))
117873	27845897	To verify the subcellular interactions, we co-transiently transfected 293T cells with GPP-SUZ12 or GFP-JAZF1-SUZ12 expression vectors in combination with RFP-EZH2 or RFP-EED vectors.	('RFP', 'Gene', '5987', (154, 157))	('expression vectors', 'Species', '29278', (115, 133))	('EED', 'Gene', (170, 173))	('RFP', 'Gene', (166, 169))	('293T', 'CellLine', 'CVCL:0063', (70, 74))	('GPP-SUZ12', 'Var', (86, 95))	('RFP', 'Gene', '5987', (166, 169))	('EED', 'Gene', '8726', (170, 173))	('RFP', 'Gene', (154, 157))	('GFP-JAZF1-SUZ12', 'Var', (99, 114))
117874	27845897	Confocal imaging revealed punctuated patterns of fluorescent proteins of GFP-SUZ12, GFP-JAZF1-SUZ12, RFP-EED and RFP-EZH2 in peripheral sections of the nucleus (Figure 3A and 3B).	('RFP', 'Gene', '5987', (113, 116))	('EED', 'Gene', '8726', (105, 108))	('GFP-SUZ12', 'Var', (73, 82))	('RFP', 'Gene', '5987', (101, 104))	('RFP', 'Gene', (101, 104))	('GFP-JAZF1-SUZ12', 'Var', (84, 99))	('RFP', 'Gene', (113, 116))	('EED', 'Gene', (105, 108))
117875	27845897	The green fluorescence dots of SUZ12 and JAZF1-SUZ12 were distributed in perichromatin region together with red fluorescence dots of EZH2 or EED.	('JAZF1-SUZ12', 'Var', (41, 52))	('EED', 'Gene', (141, 144))	('EED', 'Gene', '8726', (141, 144))
117876	27845897	The analysis showed wild type SUZ12 around 86% co-localized with EZH2 and 80% with EED, but fusion protein JAZF1-SUZ12 around 56% with EZH2 and 50% with EED.	('EED', 'Gene', (153, 156))	('EZH2', 'Var', (135, 139))	('EED', 'Gene', '8726', (83, 86))	('EED', 'Gene', (83, 86))	('EED', 'Gene', '8726', (153, 156))
117877	27845897	These results showed that SUZ12 fusing with transcriptional factor JAZF1 reduces the binding of the fusion SUZ12 with EZH2 and EED in the nucleus.	('EZH2', 'Protein', (118, 122))	('EED', 'Gene', '8726', (127, 130))	('reduces', 'NegReg', (73, 80))	('EED', 'Gene', (127, 130))	('SUZ12', 'Gene', (107, 112))	('fusing', 'Var', (32, 38))	('binding', 'Interaction', (85, 92))
117878	27845897	Analysis of HMT activities showed that PRC2 (with or without EED) in the presence of JAZF1-SUZ12 is significantly decreased compared to that in the presence of SUZ12.	('PRC2', 'MPA', (39, 43))	('EED', 'Gene', '8726', (61, 64))	('EED', 'Gene', (61, 64))	('JAZF1-SUZ12', 'Var', (85, 96))	('HMT', 'Gene', (12, 15))	('decreased', 'NegReg', (114, 123))	('HMT', 'Gene', '56979', (12, 15))
117881	27845897	To confirm the observation that JAZF1-SUZ12 reduces HMT activity, we carried out an in vitro experiment using reconstituted nucleosome arrays as substrate.	('HMT', 'Gene', (52, 55))	('JAZF1-SUZ12', 'Var', (32, 43))	('reduces', 'NegReg', (44, 51))	('HMT', 'Gene', '56979', (52, 55))
117890	27845897	Since PRC2 is a critical chromatin repression complex, it is important to test if JAZF1-SUZ12 affects the binding of PRC2 complex with target chromatin.	('binding', 'Interaction', (106, 113))	('JAZF1-SUZ12', 'Var', (82, 93))	('S', 'Chemical', 'MESH:D013455', (88, 89))	('affects', 'Reg', (94, 101))	('S', 'Chemical', 'MESH:D013455', (0, 1))
117900	27845897	To determine if the fusion protein changes normal biological function with respect to cell proliferation and differentiation, we expressed SUZ12 or JAZF1-SUZ12 from plasmids in murine Suz12 (-/-) ES cells.	('murine', 'Species', '10090', (177, 183))	('ES', 'Chemical', 'MESH:D004540', (196, 198))	('cell proliferation', 'CPA', (86, 104))	('differentiation', 'CPA', (109, 124))	('JAZF1-SUZ12', 'Var', (148, 159))
117901	27845897	EB body cells that were either Suz12 (-/-), Suz12 (-/-) +SUZ12, or Suz12 (-/-) +JAZF1-SUZ12 derived from ES cell were induced with all trans-retinoic acid (ATRA), as described in the methods and materials.	('ES', 'Chemical', 'MESH:D004540', (105, 107))	('Suz12 (-/-) +JAZF1-SUZ12', 'Var', (67, 91))	('EB', 'Chemical', 'MESH:C004912', (0, 2))	('trans-retinoic acid', 'Chemical', 'MESH:D014212', (135, 154))	('Suz12', 'Var', (31, 36))	('ATRA', 'Chemical', 'MESH:D014212', (156, 160))
117903	27845897	The Suz12 (-/-) ES cells expressing SUZ12 had lower proliferation rates than Suz12 (-/-) ES cells expressing JAZF1-SUZ12.	('ES', 'Chemical', 'MESH:D004540', (16, 18))	('ES', 'Chemical', 'MESH:D004540', (89, 91))	('proliferation rates', 'CPA', (52, 71))	('lower', 'NegReg', (46, 51))	('SUZ12', 'Var', (36, 41))
117904	27845897	Both Suz12 (-/-) ES cells expressing either SUZ12 or JAZF1-SUZ12 proliferated slower compared to Suz12 (-/-) ES cells, and expression of the ES cell marker Nanog mRNA was reduced around 3 fold in the cells of expressing SUZ12 or the fusion protein.	('proliferated', 'CPA', (65, 77))	('slower', 'NegReg', (78, 84))	('expression', 'MPA', (123, 133))	('ES', 'Chemical', 'MESH:D004540', (109, 111))	('ES', 'Chemical', 'MESH:D004540', (17, 19))	('Nanog', 'Gene', '79923', (156, 161))	('Nanog', 'Gene', (156, 161))	('reduced', 'NegReg', (171, 178))	('ES', 'Chemical', 'MESH:D004540', (141, 143))	('SUZ12', 'Var', (44, 49))	('expression', 'Species', '29278', (123, 133))	('JAZF1-SUZ12', 'Var', (53, 64))
117910	27845897	Among these chromosomal abnormalities, t(7;17)(p15;q21), which results in an in frame fusion of the Jazf1 gene with Suz12 on chromosome 17 is the most common cytogenetic abnormalities.	('Jazf1', 'Gene', (100, 105))	('t(7;17)(p15;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (39, 55))	('t(7;17)(p15;q21', 'Var', (39, 54))	('Jazf1', 'Gene', '221895', (100, 105))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (12, 37))	('chromosomal abnormalities', 'Disease', (12, 37))
117911	27845897	Other translocations include the t(6;7)(p21;p15), which results in an in-frame fusion of Jazf1 to Phf1; the t(6;10)(p21;p11), which results in an Epc1 fused to Phf1; the t(1;6)(p34;p21), which results in an in-frame fusion of Meaf6 gene to Phf1; der(22)(X;22)(p11;q13) results in Zc3h7b in-frame joints to Bcor gene; t(X;17)(p11;q21) results in Mbtd1 gene fuses to Cxorf67.	('Jazf1', 'Gene', (89, 94))	('p11', 'Gene', (260, 263))	('t(6;10)(p21;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (108, 124))	('Mbtd1', 'Gene', '54799', (345, 350))	('Mbtd1', 'Gene', (345, 350))	('Phf1', 'Gene', '5252', (98, 102))	('t(1;6)(p34;p21)', 'STRUCTURAL_ABNORMALITY', 'None', (170, 185))	('Phf1', 'Gene', '5252', (240, 244))	('Epc1', 'Gene', '80314', (146, 150))	('Phf1', 'Gene', '5252', (160, 164))	('Bcor', 'Gene', (306, 310))	('Jazf1', 'Gene', '221895', (89, 94))	('Phf1', 'Gene', (98, 102))	('Bcor', 'Gene', '54880', (306, 310))	('Phf1', 'Gene', (240, 244))	('Phf1', 'Gene', (160, 164))	('Zc3h7b', 'Gene', (280, 286))	('Epc1', 'Gene', (146, 150))	('t(6;7)(p21;p15)', 'STRUCTURAL_ABNORMALITY', 'None', (33, 48))	('p11', 'Gene', '118460', (325, 328))	('Zc3h7b', 'Gene', '23264', (280, 286))	('Meaf6', 'Gene', '64769', (226, 231))	('p11', 'Gene', (325, 328))	('Cxorf67', 'Gene', '340602', (365, 372))	('p11', 'Gene', '118460', (120, 123))	('Meaf6', 'Gene', (226, 231))	('t(X', 'Var', (317, 320))	('p11', 'Gene', (120, 123))	('Cxorf67', 'Gene', (365, 372))	('p11', 'Gene', '118460', (260, 263))	('t(X;17)(p11;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (317, 333))
117912	27845897	If the fusion of in-frame remains unknown; t(10;17)(q22;p13) results in Ywhae gene in-frame joins to Fam22a or Fam22b; this translocation is also known as 14-3-3 epsilon-FAM22A (FAM22B).	('Fam22a', 'Gene', (101, 107))	('Fam22a', 'Gene', '728118', (101, 107))	('t(10', 'Var', (43, 47))	('Ywhae', 'Gene', '7531', (72, 77))	('joins', 'Reg', (92, 97))	('FAM22A', 'Gene', (170, 176))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (43, 60))	('in-frame', 'Var', (83, 91))	('Ywhae', 'Gene', (72, 77))	('FAM22B', 'Gene', (178, 184))	('Fam22b', 'Gene', (111, 117))	('Fam22b', 'Gene', '729262', (111, 117))	('FAM22A', 'Gene', '728118', (170, 176))	('FAM22B', 'Gene', '729262', (178, 184))
117913	27845897	Some unidentified chromosome translocation in ESS have been reported such as der (3) t(3;6)(q29;p21.1), t(X;17)(p11;q23).	('t(X;17)(p11;q23', 'Var', (104, 119))	('t(X;17)(p11;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (104, 120))	('der (3) t(', 'Var', (77, 87))	('t(3;6)(q29;p21.1)', 'STRUCTURAL_ABNORMALITY', 'None', (85, 102))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('S', 'Chemical', 'MESH:D013455', (48, 49))
117914	27845897	For example, JAZF1-SUZ12 fusion exists predominantly in endometrial nodule and low grade ESS, and the YWHAE-FAM22 fusion is associated within high grade and undifferentiated ESS.	('YWHAE', 'Gene', (102, 107))	('fusion', 'Var', (25, 31))	('associated', 'Reg', (124, 134))	('YWHAE', 'Gene', '7531', (102, 107))	('JAZF1-SUZ12', 'Gene', (13, 24))	('endometrial nodule', 'Disease', (56, 74))
117916	27845897	To date, evidence consistent with a gene fusion resulting in the oncogenic protein in ESS comes from research on the YWHAE-FAM22.	('YWHAE', 'Gene', (117, 122))	('oncogenic protein', 'MPA', (65, 82))	('ESS', 'Disease', (86, 89))	('YWHAE', 'Gene', '7531', (117, 122))	('gene fusion', 'Var', (36, 47))
117917	27845897	Silence of Ywhae-Fam22 expression reversed the malignant phenotype of ESS tumor cells harboring this fusion gene, as indicated by the reduction of the proliferation rate and cell migration.	('cell migration', 'CPA', (174, 188))	('proliferation rate', 'CPA', (151, 169))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('Ywhae', 'Gene', '7531', (11, 16))	('S', 'Chemical', 'MESH:D013455', (72, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('reduction', 'NegReg', (134, 143))	('ESS tumor', 'Disease', 'MESH:D009369', (70, 79))	('Ywhae', 'Gene', (11, 16))	('S', 'Chemical', 'MESH:D013455', (71, 72))	('ESS tumor', 'Disease', (70, 79))	('expression', 'Species', '29278', (23, 33))	('Silence', 'Var', (0, 7))
117927	27845897	In addition the proteasome inhibition assay demonstrated MG132 treatment can increase the levels of these two proteins (Figure 9C).	('levels of these two proteins', 'MPA', (90, 118))	('increase', 'PosReg', (77, 85))	('MG132', 'Var', (57, 62))	('MG132', 'Chemical', 'MESH:C072553', (57, 62))
117933	27845897	This result suggests that the PRC2 of JAZF1-SUZ12 specifically decreases H3K27Me3 but H3K9Me3, the H3K9 methylation maybe catalyzed by other PRC2-EZH2 independent enzymes such as ESET, SUV39h1/2 and Eu-HMTase1 when PRC2 activities are reduced by JAZF1-SUZ12 in ESS cells (Figure 8B).	('JAZF1-SUZ12', 'Var', (246, 257))	('H3K9Me3', 'MPA', (86, 93))	('decreases', 'NegReg', (63, 72))	('JAZF1-SUZ12', 'Var', (38, 49))	('ES', 'Chemical', 'MESH:D004540', (179, 181))	('H3K27Me3', 'Protein', (73, 81))	('ES', 'Chemical', 'MESH:D004540', (261, 263))	('SUV39h1/2', 'Gene', (185, 194))	('Eu-HMTase1', 'Gene', '79813', (199, 209))	('Eu-HMTase1', 'Gene', (199, 209))	('SUV39h1/2', 'Gene', '6839', (185, 194))
117934	27845897	Alterations or abnormalities in histone methylation appear to be important factors in inducing or maintaining the neoplastic phenotype of cancer cells.	('cancer', 'Disease', (138, 144))	('abnormalities', 'Var', (15, 28))	('Alterations', 'Var', (0, 11))	('inducing', 'Reg', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('histone methylation', 'Protein', (32, 51))	('neoplastic phenotype of', 'CPA', (114, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
117938	27845897	EZH2 is also activated in many cancers, UTX, an H3K27me3 demethylase, is inactivated in multiple myeloma, esophageal, renal and bladder and in other cancers, the demethylase JMJD3 is expressed at very low levels therefore leads high level of H3K27me3.	('H3K27me3', 'Var', (242, 250))	('esophageal', 'Disease', 'MESH:D004941', (106, 116))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('esophageal', 'Disease', (106, 116))	('UTX', 'Gene', '7403', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('UTX', 'Gene', (40, 43))	('multiple myeloma', 'Phenotype', 'HP:0006775', (88, 104))	('multiple myeloma', 'Disease', 'MESH:D009101', (88, 104))	('JMJD3', 'Gene', (174, 179))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('multiple myeloma', 'Disease', (88, 104))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('JMJD3', 'Gene', '23135', (174, 179))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
117939	27845897	On the other hand, low level of EZH2 or reduced methylation at histone sites catalyzed by PRC2 may be oncogenic, for example, the recurrent Tyr 641 mutations in catalytic EZH2 SET domain, thought to impair activity, occur in two types of lymphomas arising from germinal center B cells.	('S', 'Chemical', 'MESH:D013455', (176, 177))	('occur', 'Reg', (216, 221))	('EZH2', 'Gene', (171, 175))	('methylation', 'MPA', (48, 59))	('lymphomas', 'Disease', (238, 247))	('PRC2', 'Gene', (90, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (238, 246))	('lymphomas', 'Disease', 'MESH:D008223', (238, 247))	('lymphomas', 'Phenotype', 'HP:0002665', (238, 247))	('Tyr 641 mutations', 'Var', (140, 157))	('Tyr', 'Chemical', 'MESH:D014443', (140, 143))	('activity', 'MPA', (206, 214))
117940	27845897	Loss of EZH2 in HSCs (hematopoietic stem cells) is sufficient to cause aggressive T-acute lymphoblastic leukemia (T-ALL) in mice.	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (90, 112))	('mice', 'Species', '10090', (124, 128))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('cause', 'Reg', (65, 70))	('aggressive T-acute lymphoblastic leukemia (T-ALL)', 'Disease', 'MESH:D054218', (71, 120))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (84, 112))	('Loss', 'Var', (0, 4))	('EZH2', 'Gene', (8, 12))	('S', 'Chemical', 'MESH:D013455', (17, 18))
117942	27845897	That impaired of PRC2 activity by mutation of EZH2 results in a dramatically reduction of H3K27me3 and subsequently promotion of breast tumorigenesis.	('reduction', 'NegReg', (77, 86))	('mutation', 'Var', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('PRC2', 'Enzyme', (17, 21))	('H3K27me3', 'Protein', (90, 98))	('promotion', 'PosReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('activity', 'MPA', (22, 30))	('EZH2', 'Gene', (46, 50))	('tumor', 'Disease', (136, 141))
117945	27845897	Therefore our study supported PRC2-SUZ12 effectively inducing ES cell differentiation, that knockout of SUZ12 or mutation of SUZ12 (fusion of SUZ112 with JAZF1) results in blocking of ES differentiation.	('S', 'Chemical', 'MESH:D013455', (185, 186))	('mutation', 'Var', (113, 121))	('blocking', 'NegReg', (172, 180))	('S', 'Chemical', 'MESH:D013455', (63, 64))	('S', 'Chemical', 'MESH:D013455', (142, 143))	('ES differentiation', 'CPA', (184, 202))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('S', 'Chemical', 'MESH:D013455', (125, 126))	('ES', 'Chemical', 'MESH:D004540', (62, 64))	('S', 'Chemical', 'MESH:D013455', (104, 105))	('SUZ12', 'Gene', (125, 130))	('SUZ12', 'Gene', (104, 109))	('ES cell differentiation', 'CPA', (62, 85))	('ES', 'Chemical', 'MESH:D004540', (184, 186))	('SUZ112', 'Gene', (142, 148))	('inducing', 'Reg', (53, 61))
117946	27845897	Taken together, our experiments prove that PRC2/H3K27me3 possess a tumor suppressor function.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('PRC2/H3K27me3', 'Var', (43, 56))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
117947	27845897	The PRC2 with JAZF1-SUZ12 profoundly loses suppressor function and acts as an oncogenic-like protein involved in tumorigenesis of human endometrial sarcoma (Figure 9D).	('PRC2', 'Gene', (4, 8))	('tumor', 'Disease', (113, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (136, 155))	('loses', 'NegReg', (37, 42))	('JAZF1-SUZ12', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('endometrial sarcoma', 'Disease', (136, 155))	('suppressor function', 'CPA', (43, 62))	('human', 'Species', '9606', (130, 135))
117948	27845897	Our study highlights that dysfunction of PRC2 as a possible mechanism in human endometrial carcinogenesis and the potential value of PRC2 as a therapeutic target in ESS patients.	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (79, 105))	('endometrial carcinogenesis', 'Disease', (79, 105))	('PRC2', 'Gene', (41, 45))	('patients', 'Species', '9606', (169, 177))	('human', 'Species', '9606', (73, 78))	('dysfunction', 'Var', (26, 37))	('mechanism', 'Reg', (60, 69))
117949	27845897	Full-length cDNA of human JAZF1, SUZ12 and JAZF1-SUZ12 were cloned into pcDNA3.1/NT-GFP-TOPO to generate in-frame fused GFP-SUZ12 and GFP-JAZF1-SUZ12 vectors.	('GFP-SUZ12', 'Var', (120, 129))	('JAZF1-SUZ12', 'Gene', (43, 54))	('human', 'Species', '9606', (20, 25))
117965	27845897	In vitro reconstituted PRC2 complexes as following: purified proteins of EZH2, EED and SUZ12 or EZH2, EED and JAZF1-SUZ12 were mixed together in approximately the same amounts in the presence of 4 M urea, and dialyzed against reconstituted buffer RCB (see below).	('EED', 'Gene', '8726', (102, 105))	('RCB', 'Chemical', '-', (247, 250))	('EED', 'Gene', '8726', (79, 82))	('EED', 'Gene', (102, 105))	('EED', 'Gene', (79, 82))	('urea', 'Chemical', 'MESH:D014508', (199, 203))	('EZH2', 'Var', (96, 100))
117970	27845897	Rabbit antibodies against EZH2, histone 3, ubiquitin, H3K9me3 and H3K27me3 were purchased from Upstate Company.	('EZH2', 'Gene', (26, 30))	('H3K9me3', 'Protein', (54, 61))	('histone 3', 'Protein', (32, 41))	('Rabbit', 'Species', '9986', (0, 6))	('H3K27me3', 'Var', (66, 74))
117987	27845897	Suz12 (-/-) ES cells transiently transfected with the expression construct of SUZ12myc or fusion gene JAZF1-SUZ12myc were selected with G418 to establish stable ES cell line expressed SUZ12 or JAZF1-SUZ12.	('JAZF1-SUZ12', 'Var', (193, 204))	('ES', 'Chemical', 'MESH:D004540', (12, 14))	('SUZ12', 'Var', (184, 189))	('ES', 'Chemical', 'MESH:D004540', (161, 163))	('Suz12', 'Gene', (0, 5))	('expression', 'Species', '29278', (54, 64))
117997	27845897	ESS endometrial stromal sarcoma PRC2 polycomb repressive complex 2 HMT histone methyltransferase HESC human endometrial stromal cells EB embryonic body; fusion protein JAZF1/SUZ12 = JAZF1-SUZ12.	('JAZF1/SUZ12 =', 'Var', (168, 181))	('EB', 'Chemical', 'MESH:C004912', (134, 136))	('ES', 'Chemical', 'MESH:D004540', (98, 100))	('endometrial stromal sarcoma', 'Disease', (4, 31))	('HMT', 'Gene', (67, 70))	('ES', 'Chemical', 'MESH:D004540', (0, 2))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('HMT', 'Gene', '56979', (67, 70))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (4, 31))	('human', 'Species', '9606', (102, 107))
118002	24660036	The Kaplan-Meier analysis demonstrated that patients with tumors measuring >=5 cm size and >=2.0 SUVmax were associated with a worse survival rate.	('survival', 'CPA', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('patients', 'Species', '9606', (44, 52))	('worse', 'NegReg', (127, 132))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('>=2.0', 'Var', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (58, 64))
118126	24548660	The advancement of immunohistochemistry, molecular technology and the identification of KIT oncogene mutation in more than 80% of GISTs have accelerated our understanding of GISTs .	('mutation', 'Var', (101, 109))	('KIT oncogene', 'Gene', (88, 100))	('accelerated', 'PosReg', (141, 152))	('men', 'Species', '9606', (11, 14))
118138	24548660	Before 2002, the diagnosis of GISTs by CD117 or c-KIT staining was unavailable; therefore, for cases diagnosed from January 1, 1998 to December 31, 2001, the morphology (M) codes of the International Classification of Disease for Oncology, Field Trial Edition (ICD-O-FT) were used to identify GIST cases with the algorithm established by Tran et al., which included stromal sarcoma (8930), leiomyosarcoma (8890), epithelioid leiomyosarcoma (8891), cellular leiomyosarcoma (8892), bizarre leiomyosarcoma (8893), myxoid leiomyosarcoma (8896), smooth muscle cell tumor (8897), sarcoma not otherwise specified (8800), spindle cell sarcoma (8801), giant cell sarcoma (8802), small cell sarcoma (8803), epithelioid sarcoma (8804), mesenchymoma (8990), fibrosarcoma (8810), fibromyxosarcoma (8811), ganglioneuroma (9490), ganglioneuromatosis (9491), neurobalstoma (9500), neuroepithelioma (9503), ganglioglioma (9505), neurofibroma (9504), schwannoma (9650), paragangmaluganglioma (8680), glomus tumor (8711), angiosarcoma (9120), and hemangiopericytoma (9150).	('sarcoma', 'Disease', 'MESH:D012509', (1008, 1015))	('angiosarcoma', 'Phenotype', 'HP:0200058', (1003, 1015))	('sarcoma', 'Phenotype', 'HP:0100242', (397, 404))	('epithelioid leiomyosarcoma', 'Disease', (413, 439))	('sarcoma', 'Disease', (1008, 1015))	('sarcoma', 'Disease', (776, 783))	('giant cell sarcoma', 'Disease', (643, 661))	('glomus tumor', 'Disease', (982, 994))	('leiomyosarcoma', 'Disease', (488, 502))	('neurofibroma', 'Phenotype', 'HP:0001067', (912, 924))	('sarcoma', 'Disease', 'MESH:D012509', (464, 471))	('9491', 'Var', (836, 840))	('9490', 'Var', (808, 812))	('sarcoma', 'Disease', (432, 439))	('neurofibroma', 'Disease', 'MESH:D009455', (912, 924))	('fibrosarcoma', 'Disease', 'MESH:D005354', (746, 758))	('9504', 'Var', (926, 930))	('tumor', 'Phenotype', 'HP:0002664', (560, 565))	('spindle cell sarcoma', 'Disease', 'MESH:D012509', (614, 634))	('ganglioneuroma', 'Disease', (792, 806))	('mesenchymoma', 'Disease', (725, 737))	('sarcoma', 'Disease', 'MESH:D012509', (397, 404))	('ganglioneuromatosis', 'Disease', (815, 834))	('sarcoma', 'Disease', (397, 404))	('leiomyosarcoma', 'Disease', (518, 532))	('neuroepithelioma', 'Disease', 'MESH:C563168', (865, 881))	('c-KIT', 'Gene', '3815', (48, 53))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (425, 439))	('neurofibroma', 'Disease', (912, 924))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (457, 471))	('sarcoma', 'Disease', (681, 688))	('schwannoma', 'Phenotype', 'HP:0100008', (933, 943))	('sarcoma', 'Disease', 'MESH:D012509', (776, 783))	('ganglioglioma', 'Disease', 'MESH:D018303', (890, 903))	('neurobalstoma', 'Disease', (843, 856))	('ganglioneuroma', 'Phenotype', 'HP:0003005', (792, 806))	('myxoid leiomyosarcoma', 'Disease', 'MESH:D007890', (511, 532))	('angiosarcoma', 'Disease', (1003, 1015))	('sarcoma', 'Disease', 'MESH:D012509', (751, 758))	('sarcoma', 'Disease', 'MESH:D012509', (432, 439))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (518, 532))	('sarcoma', 'Disease', (751, 758))	('CD117', 'Gene', (39, 44))	('sarcoma', 'Disease', 'MESH:D012509', (709, 716))	('stromal sarcoma', 'Disease', (366, 381))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (390, 404))	('ganglioglioma', 'Disease', (890, 903))	('sarcoma', 'Disease', (709, 716))	('fibrosarcoma', 'Disease', (746, 758))	('myxoid leiomyosarcoma', 'Disease', (511, 532))	('sarcoma', 'Phenotype', 'HP:0100242', (495, 502))	('fibromyxosarcoma', 'Disease', 'None', (767, 783))	('ganglioneuroma', 'Disease', 'MESH:D005729', (815, 829))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (457, 471))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (488, 502))	('angiosarcoma', 'Disease', 'MESH:D006394', (1003, 1015))	('sarcoma', 'Disease', 'MESH:D012509', (681, 688))	('CD117', 'Gene', '3815', (39, 44))	('Oncology', 'Phenotype', 'HP:0002664', (230, 238))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (746, 758))	('stromal sarcoma', 'Disease', 'MESH:D046152', (366, 381))	('schwannoma', 'Disease', (933, 943))	('sarcoma', 'Phenotype', 'HP:0100242', (374, 381))	('leiomyosarcoma', 'Disease', (425, 439))	('8711', 'Var', (996, 1000))	('paragangmaluganglioma', 'Disease', (952, 973))	('sarcoma', 'Disease', (495, 502))	('muscle cell tumor', 'Disease', 'MESH:D009217', (548, 565))	('giant cell sarcoma', 'Disease', 'MESH:D005870', (643, 661))	('schwannoma', 'Disease', 'MESH:D009442', (933, 943))	('epithelioid leiomyosarcoma', 'Disease', 'MESH:D007890', (413, 439))	('spindle cell sarcoma', 'Disease', (614, 634))	('sarcoma', 'Phenotype', 'HP:0100242', (464, 471))	('c-KIT', 'Gene', (48, 53))	('paragangmaluganglioma', 'Disease', 'None', (952, 973))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (488, 502))	('sarcoma', 'Disease', 'MESH:D012509', (525, 532))	('ganglioneuromatosis', 'Disease', 'MESH:C563519', (815, 834))	('sarcoma', 'Disease', 'MESH:D012509', (374, 381))	('epithelioid sarcoma', 'Disease', (697, 716))	('hemangiopericytoma', 'Disease', (1028, 1046))	('small cell sarcoma', 'Disease', 'MESH:D018228', (670, 688))	('sarcoma', 'Disease', (525, 532))	('sarcoma', 'Disease', (374, 381))	('leiomyosarcoma', 'Disease', (390, 404))	('neuroepithelioma', 'Disease', (865, 881))	('ganglioneuromatosis', 'Phenotype', 'HP:0025151', (815, 834))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (518, 532))	('leiomyosarcoma', 'Disease', (457, 471))	('glomus tumor', 'Disease', 'MESH:D005918', (982, 994))	('tumor', 'Phenotype', 'HP:0002664', (989, 994))	('ganglioneuroma', 'Phenotype', 'HP:0003005', (815, 829))	('sarcoma', 'Disease', 'MESH:D012509', (495, 502))	('sarcoma', 'Disease', 'MESH:D012509', (574, 581))	('sarcoma', 'Disease', (464, 471))	('sarcoma', 'Disease', 'MESH:D012509', (654, 661))	('fibromyxosarcoma', 'Disease', (767, 783))	('sarcoma', 'Disease', (574, 581))	('neurobalstoma', 'Disease', 'None', (843, 856))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (390, 404))	('sarcoma', 'Disease', (654, 661))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (697, 716))	('ganglioneuroma', 'Disease', 'MESH:D005729', (792, 806))	('sarcoma', 'Disease', 'MESH:D012509', (627, 634))	('sarcoma', 'Phenotype', 'HP:0100242', (432, 439))	('small cell sarcoma', 'Disease', (670, 688))	('muscle cell tumor', 'Disease', (548, 565))	('sarcoma', 'Disease', (627, 634))	('mesenchymoma', 'Disease', 'MESH:D008637', (725, 737))	('ganglioneuroma', 'Disease', (815, 829))	('small cell sarcoma', 'Phenotype', 'HP:0030357', (670, 688))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (425, 439))
118156	24548660	Among men, the 5-yr observed OS rate was 66.6%, 62.1% and 60.7% for GIST in colon/rectum, stomach, and small intestine, respectively.	('colon/rectum', 'Disease', 'MESH:D012004', (76, 88))	('GIST', 'Var', (68, 72))	('OS', 'Chemical', '-', (29, 31))	('colon/rectum', 'Disease', (76, 88))	('men', 'Species', '9606', (6, 9))
118165	24548660	The exact diagnosis and tumor origin of GISTs were difficult to determine until the discovery of the gain-of-function mutation in the KIT oncogene.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('KIT', 'Gene', (134, 137))	('tumor', 'Disease', (24, 29))	('mutation', 'Var', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('gain-of-function', 'PosReg', (101, 117))
118218	21876033	Indeed, we found that tumors from RAG2-/- or IFNAR-/- mice displayed increased immunogenicity.	('immunogenicity', 'CPA', (79, 93))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('increased', 'PosReg', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('RAG2-/-', 'Var', (34, 41))	('mice', 'Species', '10090', (54, 58))	('tumors', 'Disease', (22, 28))
118222	21876033	We found that certain unedited tumor cell lines derived from immune deficient RAG2-/- or IFNAR-/- mice displayed a regressor growth phenotype while others displayed a progressor growth phenotype.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('immune deficient', 'Phenotype', 'HP:0002721', (61, 77))	('RAG2-/-', 'Var', (78, 85))	('tumor', 'Disease', (31, 36))	('regressor growth phenotype', 'CPA', (115, 141))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('mice', 'Species', '10090', (98, 102))
118230	21876033	In mice deficient in NKG2D, there is increased development of prostate tumors and lymphomas compared to control mice, but the development of MCA sarcomas was not changed.	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('development', 'CPA', (47, 58))	('mice', 'Species', '10090', (3, 7))	('MCA sarcomas', 'Disease', 'MESH:D020244', (141, 153))	('prostate tumors', 'Disease', (62, 77))	('lymphomas', 'Disease', (82, 91))	('lymphomas', 'Disease', 'MESH:D008223', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('increased', 'PosReg', (37, 46))	('prostate tumors', 'Disease', 'MESH:D011471', (62, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('lymphomas', 'Phenotype', 'HP:0002665', (82, 91))	('MCA sarcomas', 'Disease', (141, 153))	('NKG2D', 'Var', (21, 26))	('mice', 'Species', '10090', (112, 116))	('deficient', 'Var', (8, 17))
118250	21876033	The passaged cell lines which were now progressors were transduced with a retrovirus expressing either green fluorescent protein (GFP), or GFP and H60a, and sorted as a >95% GFP+ population using a FACS Aria cell sorter.	('H60a', 'Gene', '15101', (147, 151))	('FACS', 'Gene', (198, 202))	('FACS', 'Gene', '14081', (198, 202))	('H60a', 'Gene', (147, 151))	('GFP', 'Var', (139, 142))
118259	21876033	with either PBS, anti-ASGM1, or anti-NKG2D on days -2 and 0 and every four days thereafter until tumor harvest.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('anti-NKG2D', 'Var', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('PBS', 'Chemical', 'MESH:D007854', (12, 15))	('anti-ASGM1', 'Var', (17, 27))
118278	21876033	This difference in heterogeneity was significant when the variances of the populations were compared in the group of tumors (F test, p=0.0024; Levene statistic p=0.001) from RAG2-/- but not IFNAR-/- mice.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mice', 'Species', '10090', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('Levene', 'Chemical', '-', (143, 149))	('RAG2-/-', 'Var', (174, 181))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))
118283	21876033	Interestingly, RAE1 expression, while lower than H60a expression, also displayed heterogeneity (Fig.	('H60a', 'Gene', (49, 53))	('expression', 'MPA', (20, 30))	('heterogeneity', 'MPA', (81, 94))	('RAE1', 'Var', (15, 19))	('H60a', 'Gene', '15101', (49, 53))
118289	21876033	4A) to demonstrate that the pattern of H60a staining ranged from unimodal (d27m2, F510, h31m1), broad staining (F515, d30m4), to bimodal staining, with equal distribution (F535, d100) between the two cell populations or uneven, "shoulder"-type distribution (d38m2, d42m1), suggesting that within a cell line, there were populations of cells that expressed differing levels of H60a.	('H60a', 'Gene', '15101', (39, 43))	('d42m1', 'Var', (265, 270))	('d27m2', 'Var', (75, 80))	('F510', 'Var', (82, 86))	('h31m1', 'Var', (88, 93))	('d38m2', 'Var', (258, 263))	('H60a', 'Gene', (376, 380))	('F515', 'Var', (112, 116))	('H60a', 'Gene', '15101', (376, 380))	('H60a', 'Gene', (39, 43))	('d30m4', 'Var', (118, 123))	('F535', 'Var', (172, 176))
118291	21876033	Since d100 and F535 are both regressor cell lines that reject in WT mice, we transplanted them into immune deficient mice in order to test if partial immune function could eliminate H60a-hi cells in vivo.	('mice', 'Species', '10090', (68, 72))	('F535', 'Var', (15, 19))	('H60a', 'Gene', (182, 186))	('H60a', 'Gene', '15101', (182, 186))	('mice', 'Species', '10090', (117, 121))	('immune deficient', 'Phenotype', 'HP:0002721', (100, 116))
118312	21876033	injections of PBS, anti-ASGM1 (to deplete NK cells), or a blocking anti-NKG2D monoclonal antibody and monitored tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PBS', 'Chemical', 'MESH:D007854', (14, 17))	('anti-ASGM1', 'Var', (19, 29))	('tumor', 'Disease', (112, 117))
118313	21876033	Depletion of NK cells with anti-ASGM1 showed a slight increase in tumor growth in RAG2-/- mice compared to control PBS treatment, while there was no change in growth when NKG2D function was blocked with anti-NKG2D (Fig 8A top panel).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('anti-ASGM1', 'Var', (27, 37))	('tumor', 'Disease', (66, 71))	('increase', 'PosReg', (54, 62))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('PBS', 'Chemical', 'MESH:D007854', (115, 118))
118315	21876033	Moreover, daughter cell lines generated in mice treated with anti-ASGM1 or anti-NKG2D still maintained ~70% H60a-hi cells (Fig 8B, p = 0.006, 0.03, respectively, when compared to H60a expression in cell lines passaged through mice treated with PBS), suggesting that NK cell recognition of H60a-hi cells through NKG2D leads to their elimination during RAG2-/--passaging.	('mice', 'Species', '10090', (43, 47))	('H60a', 'Gene', (289, 293))	('mice', 'Species', '10090', (226, 230))	('anti-NKG2D', 'Var', (75, 85))	('H60a', 'Gene', (108, 112))	('H60a', 'Gene', '15101', (179, 183))	('H60a', 'Gene', (179, 183))	('H60a', 'Gene', '15101', (108, 112))	('H60a', 'Gene', '15101', (289, 293))	('PBS', 'Chemical', 'MESH:D007854', (244, 247))	('anti-ASGM1', 'Var', (61, 71))	('NKG2D', 'Gene', (311, 316))
118344	21876033	It is also possible that F535 has very strong tumor antigens that mediate rejection independent of NKG2D ligand expression or NK cell priming of adaptive responses.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('pen', 'Chemical', 'MESH:C058388', (88, 91))	('F535', 'Var', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
118350	21876033	It should be noted that regressor cell lines that are bimodal in H60a expression (d100, F535) are completely rejected in WT mice, rather than undergoing an equilibrium phase that promotes the escape of H60a-lo clones.	('F535', 'Var', (88, 92))	('H60a', 'Gene', (65, 69))	('d100', 'Var', (82, 86))	('H60a', 'Gene', '15101', (202, 206))	('mice', 'Species', '10090', (124, 128))	('H60a', 'Gene', '15101', (65, 69))	('H60a', 'Gene', (202, 206))
118384	33505228	However, there are only a few studies on the use of 18F-FDG PET/CT in RPLS due to its rarity and low incidence.	('18F-FDG', 'Chemical', 'MESH:D019788', (52, 59))	('18F-FDG', 'Var', (52, 59))	('RPLS', 'Disease', (70, 74))
118422	33505228	Only a few studies have been published on the role of 18F-FDG PET/CT in the diagnoses of RPS so far.	('18F-FDG', 'Var', (54, 61))	('RPS', 'Disease', (89, 92))	('18F-FDG', 'Chemical', 'MESH:D019788', (54, 61))
118451	33147457	GDF6 silencing causes hyperactivation of Src and p21-dependent growth arrest.	('GDF6', 'Gene', (0, 4))	('hyperactivation', 'PosReg', (22, 37))	('silencing', 'Var', (5, 14))	('growth arrest', 'Disease', (63, 76))	('Src', 'CPA', (41, 44))	('growth arrest', 'Disease', 'MESH:D006323', (63, 76))	('growth arrest', 'Phenotype', 'HP:0001510', (63, 76))
118452	33147457	We demonstrate that two GDF6 prodomain mutants linked to Klippel-Feil syndrome are hyperactive in CD99-Src signaling.	('Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (57, 78))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (57, 78))	('CD99-Src signaling', 'MPA', (98, 116))	('hyperactive', 'PosReg', (83, 94))	('GDF6', 'Gene', (24, 28))	('Klippel-Feil syndrome', 'Disease', (57, 78))	('mutants', 'Var', (39, 46))	('linked', 'Reg', (47, 53))
118453	33147457	These results reveal a cytokine signaling pathway that regulates the CSK-Src axis and cancer cell proliferation and suggest the gain-of-function activity for disease-causing GDF6 mutants.	('GDF6', 'Gene', (174, 178))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('activity', 'MPA', (145, 153))	('regulates', 'Reg', (55, 64))	('gain-of-function', 'PosReg', (128, 144))	('CSK-Src axis', 'Pathway', (69, 81))	('mutants', 'Var', (179, 186))	('cancer', 'Disease', (86, 92))
118462	33147457	The silencing of CD99 was shown to inhibit the growth and migration of Ewing sarcoma cells or to induce neural differentiation in Ewing sarcoma cells and reduce their tumorigenicity and bone metastasis capability.	('Ewing sarcoma', 'Disease', (71, 84))	('Ewing sarcoma', 'Disease', (130, 143))	('CD99', 'Gene', (17, 21))	('reduce', 'NegReg', (154, 160))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (130, 143))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (71, 84))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (130, 143))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (167, 172))	('induce', 'Reg', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('inhibit', 'NegReg', (35, 42))	('silencing', 'Var', (4, 13))	('neural differentiation', 'CPA', (104, 126))
118469	33147457	Mutations in the prodomain of GDF6 are associated with several developmental abnormalities of skeleton, eye, and other organs, including Klippel-Feil syndrome.	('GDF6', 'Gene', (30, 34))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (137, 158))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (39, 49))	('Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (137, 158))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (63, 90))	('Klippel-Feil syndrome', 'Disease', (137, 158))	('developmental abnormalities', 'Disease', (63, 90))	('developmental abnormalities', 'Disease', 'MESH:D006130', (63, 90))
118473	33147457	GDF6 prodomain mutants linked to Klippel-Feil syndrome are hyperactive in GDF6-CD99-Src signaling.	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (33, 54))	('hyperactive', 'PosReg', (59, 70))	('GDF6', 'Gene', (0, 4))	('Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (33, 54))	('GDF6-CD99-Src signaling', 'MPA', (74, 97))	('Klippel-Feil syndrome', 'Disease', (33, 54))	('mutants', 'Var', (15, 22))	('linked', 'Reg', (23, 29))
118477	33147457	Silencing of EWS-FLI1 by a short hairpin RNA (shRNA) resulted in reduced GDF6 RNA and protein levels in Ewing sarcoma cells (Figures 1A and B).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('reduced', 'NegReg', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('EWS-FLI1', 'Gene', (13, 21))	('Ewing sarcoma', 'Disease', (104, 117))	('Silencing', 'Var', (0, 9))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (104, 117))
118482	33147457	Small interfering RNA (siRNA)-mediated silencing of GDF6 strongly inhibited the proliferation of all 12 Ewing sarcoma cell lines tested (A673, TC71, EW8, ES1, ES2, ES4, SK-N-MC, SK-ES-1, CHLA-258, SK-NEP-1, SK-PNET-Li, and CHLA-352; Figures 2A and S1A).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('proliferation', 'CPA', (80, 93))	('SK-N-MC', 'CellLine', 'CVCL:0530', (169, 176))	('SK-ES-1', 'CellLine', 'CVCL:0627', (178, 185))	('GDF6', 'Gene', (52, 56))	('Ewing sarcoma', 'Disease', (104, 117))	('silencing', 'Var', (39, 48))	('inhibited', 'NegReg', (66, 75))	('TC71', 'CellLine', 'CVCL:2213', (143, 147))	('SK-NEP-', 'Chemical', '-', (197, 204))	('CHLA-258', 'CellLine', 'CVCL:A058', (187, 195))	('SK-PNET-Li', 'Chemical', '-', (207, 217))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (104, 117))
118484	33147457	Ewing sarcoma growth was also inhibited by anti-GDF6 antibody in a dose-dependent manner (Figure 2B).	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (0, 20))	('inhibited', 'NegReg', (30, 39))	('anti-GDF6', 'Var', (43, 52))	('anti-GDF6', 'Gene', (43, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma growth', 'Disease', (0, 20))
118489	33147457	The growth inhibition by GDF6 silencing was completely rescued by the addition of conditioned medium from GDF6-transfected 293T cells (Figures 2F and 2G), indicating that Ewing sarcoma depends on extracellular GDF6.	('Ewing sarcoma', 'Disease', (171, 184))	('GDF6', 'Gene', (25, 29))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (171, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (171, 184))	('growth', 'MPA', (4, 10))	('silencing', 'Var', (30, 39))	('293T', 'CellLine', 'CVCL:0063', (123, 127))
118490	33147457	Surprisingly, the GDF6 prodomain conditioned medium, but not the GDF6 BMP domain conditioned medium, was also able to rescue the growth inhibition by GDF6 silencing (Figures 2F and 2G), suggesting that Ewing sarcoma depends on the GDF6 prodomain.	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('silencing', 'Var', (155, 164))	('growth inhibition', 'MPA', (129, 146))	('GDF6', 'Gene', (150, 154))	('Ewing sarcoma', 'Disease', (202, 215))	('BMP', 'Gene', (70, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (202, 215))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (202, 215))	('BMP', 'Gene', '649', (70, 73))
118493	33147457	We found that unlike GDF6, GDF5, GDF7, BMP2, and BMP4 are unable to rescue the growth inhibition by GDF6 silencing (Figure 2I).	('GDF5', 'Gene', (27, 31))	('BMP4', 'Gene', '652', (49, 53))	('GDF7', 'Gene', '151449', (33, 37))	('GDF6', 'Gene', (100, 104))	('BMP2', 'Gene', (39, 43))	('GDF7', 'Gene', (33, 37))	('BMP4', 'Gene', (49, 53))	('growth inhibition', 'MPA', (79, 96))	('BMP2', 'Gene', '650', (39, 43))	('silencing', 'Var', (105, 114))	('GDF5', 'Gene', '8200', (27, 31))
118495	33147457	Although GDF5-6 and GDF6 were both able to simulate BMP signaling (Figure 2J, right), unlike GDF6, GDF5-6 was unable to rescue the growth inhibition by GDF6 silencing (Figure 2J, left), further supporting the critical role for the GDF6 prodomain in Ewing sarcoma.	('GDF5-6', 'Gene', (99, 105))	('BMP', 'Gene', '649', (52, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('GDF5-6', 'Gene', '8200;392255', (99, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (249, 262))	('BMP', 'Gene', (52, 55))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (249, 262))	('GDF5-6', 'Gene', (9, 15))	('GDF6', 'Gene', (152, 156))	('silencing', 'Var', (157, 166))	('GDF5-6', 'Gene', '8200;392255', (9, 15))	('Ewing sarcoma', 'Disease', (249, 262))	('growth inhibition', 'MPA', (131, 148))
118501	33147457	shRNA-mediated silencing of GDF6 severely impaired anchorage-independent growth (Figure 2L), migration (Transwell assays in Figure 2M and wound closure assays in Figure 2N), invasion (Figure 2O), sphere formation (Figure 2P), and xenograft tumorigenicity (Figure 2Q) of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (270, 283))	('tumor', 'Disease', (240, 245))	('migration', 'CPA', (93, 102))	('invasion', 'CPA', (174, 182))	('silencing', 'Var', (15, 24))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (270, 283))	('GDF6', 'Gene', (28, 32))	('sphere formation', 'CPA', (196, 212))	('anchorage-independent growth', 'CPA', (51, 79))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (270, 283))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('impaired', 'NegReg', (42, 50))
118504	33147457	In addition, although the molecular mechanism is not well understood, there is evidence that CD99 contributes to Ewing sarcoma growth: CD99 knockdown in Ewing sarcoma cells inhibited anchorage-dependent and anchorage-independent growth, and reduced tumorigenicity.	('reduced', 'NegReg', (241, 248))	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (113, 133))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('inhibited', 'NegReg', (173, 182))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (153, 166))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('Ewing sarcoma growth', 'Disease', (113, 133))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (113, 126))	('tumor', 'Disease', (249, 254))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (113, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('knockdown', 'Var', (140, 149))	('CD99', 'Gene', (135, 139))	('Ewing sarcoma', 'Disease', (153, 166))
118508	33147457	C-terminally FLAG-tagged GDF6 prodomain (GDF6 pro-FLAG) was produced from transfected 293T cells and incubated with A673 cells that were transfected with CD99 siRNA and/or CD99L2 siRNA or control siRNA.	('CD99L2 siRNA', 'Var', (172, 184))	('CD99 siRNA', 'Var', (154, 164))	('pro-FLAG', 'Chemical', '-', (46, 54))	('293T', 'CellLine', 'CVCL:0063', (86, 90))
118510	33147457	As shown in Figure 3C, GDF6 pro-FLAG bound to control siRNA-transfected A673 cells, and this binding was significantly reduced by silencing of CD99 and/or CD99L2, indicating that the GDF6 prodomain binds CD99/CD99L2 in Ewing sarcoma.	('CD99', 'Gene', (143, 147))	('Ewing sarcoma', 'Disease', (219, 232))	('pro-FLAG', 'Chemical', '-', (28, 36))	('binding', 'Interaction', (93, 100))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (219, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (219, 232))	('bound', 'Interaction', (37, 42))	('silencing', 'Var', (130, 139))	('reduced', 'NegReg', (119, 126))
118512	33147457	GDF6 pro-AP bound efficiently to A673 cells transfected with control siRNA, but the binding was diminished in A673 cells transfected with CD99 siRNA and/or CD99L2 siRNA (Figure 3D).	('pro-AP', 'Chemical', '-', (5, 11))	('diminished', 'NegReg', (96, 106))	('CD99L2', 'Var', (156, 162))	('CD99', 'Var', (138, 142))	('bound', 'Interaction', (12, 17))
118515	33147457	Silencing of GDF6 or CD99 in Ewing sarcoma cells resulted in increased levels of active Src (Figure 4A, active Src assessed by phosphorylation of tyrosine 419 in human Src).	('GDF6', 'Gene', (13, 17))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (29, 42))	('active Src', 'MPA', (81, 91))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (29, 42))	('CD99', 'Gene', (21, 25))	('tyrosine', 'Chemical', 'MESH:D014443', (146, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('levels', 'MPA', (71, 77))	('human', 'Species', '9606', (162, 167))	('increased', 'PosReg', (61, 70))	('Silencing', 'Var', (0, 9))	('Ewing sarcoma', 'Disease', (29, 42))
118516	33147457	Conversely, transfection of GDF6 in 293 cells reduced active Src levels (Figure 4C, lanes 1 and 2).	('293 cells', 'CellLine', 'CVCL:0045', (36, 45))	('reduced', 'NegReg', (46, 53))	('GDF6', 'Gene', (28, 32))	('transfection', 'Var', (12, 24))	('active Src levels', 'MPA', (54, 71))
118517	33147457	The activity of Src is restricted by CSK, which phosphorylates the C-terminal regulatory tyrosine in Src (tyrosine 530 in human Src) and inactivates its activity.	('human', 'Species', '9606', (122, 127))	('tyrosine 530', 'Var', (106, 118))	('activity', 'MPA', (153, 161))	('inactivates', 'NegReg', (137, 148))	('tyrosine', 'Chemical', 'MESH:D014443', (106, 114))	('tyrosine', 'Chemical', 'MESH:D014443', (89, 97))
118519	33147457	Furthermore, silencing of CSK also abolished CD99-mediated inhibition of Src in 293 cells (Figure 4D).	('Src', 'MPA', (73, 76))	('inhibition', 'MPA', (59, 69))	('abolished', 'NegReg', (35, 44))	('293 cells', 'CellLine', 'CVCL:0045', (80, 89))	('CSK', 'Gene', (26, 29))	('silencing', 'Var', (13, 22))
118523	33147457	C-terminally FLAG-tagged CD99 co-immunoprecipitated with GFP-tagged CSK in 293T cells; the deletion of the YQKKK motif in CD99 abolished CSK interaction (Figure 4I).	('abolished', 'NegReg', (127, 136))	('deletion', 'Var', (91, 99))	('interaction', 'Interaction', (141, 152))	('CD99', 'Gene', (122, 126))	('CSK', 'Protein', (137, 140))	('293T', 'CellLine', 'CVCL:0063', (75, 79))
118527	33147457	Lentiviral expression of dominant-negative Src reduced the tyrosine phosphorylation of Src substrates, cortactin, p130 Cas, and STAT3 (Figure 4L, right) and abrogated growth inhibition by the silencing of GDF6 (Figure 4L, left).	('silencing', 'Var', (192, 201))	('tyrosine', 'Chemical', 'MESH:D014443', (59, 67))	('Src', 'Gene', (43, 46))	('tyrosine phosphorylation', 'MPA', (59, 83))	('cortactin', 'Gene', '2017', (103, 112))	('growth inhibition', 'CPA', (167, 184))	('dominant-negative', 'Var', (25, 42))	('p130 Cas', 'Gene', '12927', (114, 122))	('abrogated', 'NegReg', (157, 166))	('p130 Cas', 'Gene', (114, 122))	('GDF6', 'Gene', (205, 209))	('Src substrates', 'MPA', (87, 101))	('cortactin', 'Gene', (103, 112))	('reduced', 'NegReg', (47, 54))
118528	33147457	Conversely, the expression of Src with a mutation in the CSK phosphorylation site (Y530F), which evades inactivation by CSK, inhibited Ewing sarcoma growth (Figure 4M).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (135, 148))	('Ewing sarcoma growth', 'Disease', (135, 155))	('Y530F', 'Var', (83, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('Y530F', 'SUBSTITUTION', 'None', (83, 88))	('inhibited', 'NegReg', (125, 134))	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (135, 155))	('CSK', 'Gene', (57, 60))	('mutation in', 'Var', (41, 52))
118529	33147457	Growth inhibition by GDF6 silencing was also abolished by exogenous expression of CSK (Figure 4N) and by a Src inhibitor, dasatinib (Figure 4O).	('Growth inhibition', 'CPA', (0, 17))	('dasatinib', 'Chemical', 'MESH:D000069439', (122, 131))	('GDF6', 'Gene', (21, 25))	('abolished', 'NegReg', (45, 54))	('CSK', 'Protein', (82, 85))	('silencing', 'Var', (26, 35))
118530	33147457	These results suggest that GDF6 silencing inhibits Ewing sarcoma growth by inducing hyperactivation of Src.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('inhibits', 'NegReg', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('GDF6', 'Gene', (27, 31))	('silencing', 'Var', (32, 41))	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (51, 71))	('hyperactivation', 'PosReg', (84, 99))	('Ewing sarcoma growth', 'Disease', (51, 71))	('inducing', 'Reg', (75, 83))	('Src', 'MPA', (103, 106))
118532	33147457	Inhibition of cell migration by GDF6 silencing was abolished by dominant-negative Src and by CSK (Figure S3), suggesting that GDF6 silencing inhibits Ewing sarcoma migration through hyperactivation of Src.	('Ewing sarcoma', 'Disease', (150, 163))	('silencing', 'Var', (131, 140))	('GDF6', 'Gene', (126, 130))	('inhibits', 'NegReg', (141, 149))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (150, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('Src', 'Gene', (201, 204))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (150, 163))	('hyperactivation', 'PosReg', (182, 197))
118535	33147457	GDF6 silencing in Ewing sarcoma resulted in induction of a CDK inhibitor, p21 (Figure S4A).	('induction', 'PosReg', (44, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('GDF6', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('Ewing sarcoma', 'Disease', (18, 31))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (18, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (18, 31))
118536	33147457	Growth arrest induced by GDF6 silencing in Ewing sarcoma was abolished by simultaneous silencing of p21 (Figure S4B), indicating that GDF6 silencing results in p21-dependent growth arrest.	('silencing', 'Var', (87, 96))	('p21', 'Gene', (100, 103))	('Ewing sarcoma', 'Disease', (43, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('GDF6', 'Gene', (134, 138))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('GDF6', 'Gene', (25, 29))	('silencing', 'Var', (139, 148))	('Growth arrest', 'Disease', (0, 13))	('growth arrest', 'Disease', 'MESH:D006323', (174, 187))	('growth arrest', 'Disease', (174, 187))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('abolished', 'NegReg', (61, 70))	('silencing', 'Var', (30, 39))	('growth arrest', 'Phenotype', 'HP:0001510', (174, 187))	('Growth arrest', 'Disease', 'MESH:D006323', (0, 13))	('Growth arrest', 'Phenotype', 'HP:0001510', (0, 13))
118537	33147457	Although mitogen-activated protein kinase (MAPK) was shown to be activated by CD99 silencing in Ewing sarcoma, GDF6 silencing still induced p21 when the MAPK pathway was suppressed by a MEK inhibitor, PD98059 (Figure S4C).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('PD98059', 'Chemical', 'MESH:C093973', (201, 208))	('CD99', 'Gene', (78, 82))	('p21', 'MPA', (140, 143))	('induced', 'Reg', (132, 139))	('Ewing sarcoma', 'Disease', (96, 109))	('activated', 'PosReg', (65, 74))	('GDF6', 'Gene', (111, 115))	('MEK', 'Gene', (186, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('MEK', 'Gene', '5609', (186, 189))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('silencing', 'Var', (116, 125))	('silencing', 'Var', (83, 92))
118538	33147457	Dominant-negative Src, which abolished growth arrest by GDF6 silencing (Figure 4L), also abolished p21 induction by GDF6 silencing (Figure S4D).	('p21 induction', 'MPA', (99, 112))	('growth arrest', 'Disease', 'MESH:D006323', (39, 52))	('growth arrest', 'Disease', (39, 52))	('silencing', 'Var', (61, 70))	('growth arrest', 'Phenotype', 'HP:0001510', (39, 52))	('abolished', 'NegReg', (89, 98))
118539	33147457	Similarly, exogenous expression of CSK, which abolished growth arrest by GDF6 silencing (Figure 4N), also abolished p21 induction by GDF6 silencing (Figure S4E).	('p21 induction', 'MPA', (116, 129))	('GDF6', 'Gene', (133, 137))	('growth arrest', 'Phenotype', 'HP:0001510', (56, 69))	('CSK', 'Gene', (35, 38))	('GDF6', 'Gene', (73, 77))	('silencing', 'Var', (78, 87))	('growth arrest', 'Disease', 'MESH:D006323', (56, 69))	('growth arrest', 'Disease', (56, 69))	('abolished', 'NegReg', (106, 115))
118540	33147457	Furthermore, dasatinib, which abolished growth arrest by GDF6 silencing (Figure 4O), also abolished p21 induction by GDF6 silencing (Figure S4F).	('GDF6', 'Gene', (57, 61))	('silencing', 'Var', (62, 71))	('growth arrest', 'Disease', (40, 53))	('p21 induction', 'MPA', (100, 113))	('dasatinib', 'Chemical', 'MESH:D000069439', (13, 22))	('abolished', 'NegReg', (90, 99))	('growth arrest', 'Disease', 'MESH:D006323', (40, 53))	('GDF6', 'Gene', (117, 121))	('growth arrest', 'Phenotype', 'HP:0001510', (40, 53))
118541	33147457	Conversely, Src Y530F mutant, which inhibited Ewing sarcoma growth (Figure 4M), induced p21 (Figure S4G).	('induced', 'Reg', (80, 87))	('inhibited', 'NegReg', (36, 45))	('Y530F', 'SUBSTITUTION', 'None', (16, 21))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('Ewing sarcoma growth', 'Disease', (46, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (46, 66))	('Y530F', 'Var', (16, 21))	('p21', 'MPA', (88, 91))
118542	33147457	Furthermore, CSK silencing in Ewing sarcoma resulted in activation of Src (Figure S4H), induction of p21 (Figure S4H), and growth arrest (Figure S4I).	('Ewing sarcoma', 'Disease', (30, 43))	('growth arrest', 'Phenotype', 'HP:0001510', (123, 136))	('growth arrest', 'Disease', (123, 136))	('Src', 'Protein', (70, 73))	('growth arrest', 'Disease', 'MESH:D006323', (123, 136))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (30, 43))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (30, 43))	('CSK', 'Protein', (13, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('silencing', 'Var', (17, 26))	('activation', 'PosReg', (56, 66))	('p21', 'MPA', (101, 104))
118543	33147457	Collectively, these results are consistent with the notion that GDF6 silencing causes p21-dependent growth arrest of Ewing sarcoma through Src hyperactivation.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (117, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('growth arrest of Ewing sarcoma', 'Disease', 'MESH:C563168', (100, 130))	('growth arrest', 'Phenotype', 'HP:0001510', (100, 113))	('silencing', 'Var', (69, 78))	('growth arrest of Ewing sarcoma', 'Disease', (100, 130))	('Src', 'MPA', (139, 142))	('hyperactivation', 'PosReg', (143, 158))	('GDF6', 'Gene', (64, 68))
118544	33147457	Mutations in the prodomain of GDF6 are associated with Klippel-Feil syndrome, a congenital malformation syndrome characterized by the fusion of cervical vertebrae and variable abnormalities in multiple organs.	('Klippel-Feil syndrome', 'Disease', (55, 76))	('congenital malformation syndrome', 'Disease', 'MESH:D000014', (80, 112))	('Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (55, 76))	('fusion of cervical vertebrae', 'Phenotype', 'HP:0002949', (134, 162))	('GDF6', 'Gene', (30, 34))	('congenital malformation syndrome', 'Disease', (80, 112))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (39, 49))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (55, 76))
118545	33147457	Two recurrent GDF6 prodomain mutations in Klippel-Feil syndrome patients are A249E and L289P.	('Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (42, 63))	('Klippel-Feil syndrome', 'Disease', (42, 63))	('patients', 'Species', '9606', (64, 72))	('L289P', 'SUBSTITUTION', 'None', (87, 92))	('GDF6', 'Gene', (14, 18))	('A249E', 'Var', (77, 82))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (42, 63))	('A249E', 'SUBSTITUTION', 'None', (77, 82))	('L289P', 'Var', (87, 92))
118546	33147457	GDF6 A249E mutation is also linked to microphthalmia/anophthalmia with and without skeletal abnormalities, hereditary retinal dystrophy, and Chiari type I malformation (displacement of the cerebellar tonsils below the base of the skull).	('Chiari type I malformation', 'Disease', (141, 167))	('linked', 'Reg', (28, 34))	('Chiari type I malformation', 'Phenotype', 'HP:0007099', (141, 167))	('Chiari type I malformation', 'Disease', 'MESH:D001139', (141, 167))	('A249E', 'Var', (5, 10))	('GDF6', 'Gene', (0, 4))	('hereditary retinal dystrophy', 'Disease', 'MESH:D058499', (107, 135))	('microphthalmia/anophthalmia', 'Disease', 'MESH:D000853', (38, 65))	('skeletal abnormalities', 'Disease', (83, 105))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (83, 105))	('retinal dystrophy', 'Phenotype', 'HP:0000556', (118, 135))	('A249E', 'SUBSTITUTION', 'None', (5, 10))	('microphthalmia', 'Phenotype', 'HP:0000568', (38, 52))	('anophthalmia', 'Phenotype', 'HP:0000528', (53, 65))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (83, 105))	('microphthalmia/anophthalmia', 'Disease', (38, 65))	('hereditary retinal dystrophy', 'Disease', (107, 135))
118547	33147457	In addition, several other GDF6 prodomain mutations were associated with congenital eye and skeletal abnormalities.	('congenital eye and skeletal abnormalities', 'Disease', 'MESH:D005124', (73, 114))	('GDF6', 'Gene', (27, 31))	('mutations', 'Var', (42, 51))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (92, 114))	('associated', 'Reg', (57, 67))
118548	33147457	GDF6 prodomain mutants were reported to display diminished BMP signaling activity, which is not consistent with the autosomal dominant inheritance of abnormalities associated with GDF6 prodomain mutations.	('BMP', 'Gene', (59, 62))	('GDF6', 'Gene', (0, 4))	('diminished', 'NegReg', (48, 58))	('mutants', 'Var', (15, 22))	('BMP', 'Gene', '649', (59, 62))
118549	33147457	We thus evaluated the effects of GDF6 A249E and L289P mutations on GDF6-CD99-Src signaling.	('A249E', 'SUBSTITUTION', 'None', (38, 43))	('L289P', 'SUBSTITUTION', 'None', (48, 53))	('A249E', 'Var', (38, 43))	('L289P', 'Var', (48, 53))	('GDF6', 'Gene', (33, 37))
118550	33147457	As demonstrated in Figure 3A, GDF6 prodomain co-immunoprecipitates with CD99 upon co-transfection in 293T cells; GDF6 A249E and L289P prodomains displayed enhanced co-immunoprecipitation with CD99 compared with wild-type prodomain (Figure 5A).	('L289P', 'Var', (128, 133))	('A249E', 'Var', (118, 123))	('293T', 'CellLine', 'CVCL:0063', (101, 105))	('co-immunoprecipitation', 'Interaction', (164, 186))	('enhanced', 'PosReg', (155, 163))	('L289P', 'SUBSTITUTION', 'None', (128, 133))	('A249E', 'SUBSTITUTION', 'None', (118, 123))
118551	33147457	GDF6 A249E and L289P prodomains also displayed enhanced interaction with CD99 by in vitro binding assays: after incubation in vitro, Fc-tagged CD99 extracellular domain (23-122) pulled down more GDF6 A249E and L289P prodomains than wild-type GDF6 prodomain (Figure 5B).	('A249E', 'Var', (200, 205))	('L289P', 'Var', (210, 215))	('L289P', 'Var', (15, 20))	('A249E', 'Var', (5, 10))	('interaction', 'Interaction', (56, 67))	('A249E', 'SUBSTITUTION', 'None', (200, 205))	('L289P', 'SUBSTITUTION', 'None', (210, 215))	('A249E', 'SUBSTITUTION', 'None', (5, 10))	('L289P', 'SUBSTITUTION', 'None', (15, 20))
118552	33147457	Ligand-binding assays revealed that GDF6 A249E and L289P prodomains display increased binding to A673 cells compared with wild-type GDF6 prodomain (Figure 5C).	('L289P', 'Var', (51, 56))	('increased', 'PosReg', (76, 85))	('binding', 'Interaction', (86, 93))	('A249E', 'SUBSTITUTION', 'None', (41, 46))	('L289P', 'SUBSTITUTION', 'None', (51, 56))	('GDF6', 'Gene', (36, 40))	('A249E', 'Var', (41, 46))
118553	33147457	Microscale thermophoresis analysis determined the KD of GDF6 A249E and L289P prodomain interaction with CD99 to be 3.34 and 2.26 nM, respectively, which are much lower than the KD for wild-type GDF6 prodomain (17.2 nM) (Figure 3H).	('L289P', 'SUBSTITUTION', 'None', (71, 76))	('A249E', 'SUBSTITUTION', 'None', (61, 66))	('interaction', 'Interaction', (87, 98))	('L289P', 'Var', (71, 76))	('A249E', 'Var', (61, 66))	('GDF6', 'Gene', (56, 60))
118554	33147457	Lentiviral expression of GDF6 A249E and L289P prodomains more efficiently inhibited Src than did wild-type GDF6 prodomain in 293 cells (Figure 5D).	('inhibited', 'NegReg', (74, 83))	('Src', 'MPA', (84, 87))	('L289P', 'Var', (40, 45))	('A249E', 'Var', (30, 35))	('293 cells', 'CellLine', 'CVCL:0045', (125, 134))	('A249E', 'SUBSTITUTION', 'None', (30, 35))	('L289P', 'SUBSTITUTION', 'None', (40, 45))
118555	33147457	Similarly, lentiviral expression of GDF6 A249E and L289P mutants more efficiently inhibited Src than wild-type GDF6 in A673 cells (Figure 5E).	('L289P', 'Var', (51, 56))	('inhibited', 'NegReg', (82, 91))	('Src', 'MPA', (92, 95))	('A249E', 'SUBSTITUTION', 'None', (41, 46))	('L289P', 'SUBSTITUTION', 'None', (51, 56))	('GDF6', 'Gene', (36, 40))	('A249E', 'Var', (41, 46))
118556	33147457	GDF6 and GDF6 prodomain conditioned media were able to increase the PLA signals between CD99 and CSK-HA in co-transfected HeLa cells (Figure 5F); GDF6 A249E and L289P prodomain conditioned media more strongly enhanced the PLA signals between CD99 and CSK-HA (Figure 5F).	('A249E', 'Var', (151, 156))	('L289P', 'SUBSTITUTION', 'None', (161, 166))	('A249E', 'SUBSTITUTION', 'None', (151, 156))	('enhanced', 'PosReg', (209, 217))	('HeLa', 'CellLine', 'CVCL:0030', (122, 126))	('PLA signals', 'MPA', (68, 79))	('L289P', 'Var', (161, 166))	('PLA signals', 'MPA', (222, 233))
118557	33147457	These results suggest that GDF6 prodomain mutants linked to Klippel-Feil syndrome are hyperactive in GDF6-CD99-Src signaling.	('mutants', 'Var', (42, 49))	('GDF6-CD99-Src signaling', 'MPA', (101, 124))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (60, 81))	('hyperactive', 'PosReg', (86, 97))	('GDF6', 'Gene', (27, 31))	('linked', 'Reg', (50, 56))	('Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (60, 81))	('Klippel-Feil syndrome', 'Disease', (60, 81))
118562	33147457	CD99 silencing inhibits in vitro and in vivo growth of Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (55, 68))	('growth', 'CPA', (45, 51))	('CD99', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('inhibits', 'NegReg', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('Ewing sarcoma', 'Disease', (55, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (55, 68))
118565	33147457	Whereas the silencing of endogenous CD99 revealed a tumor-promoting role in Ewing sarcoma, exogenous expression of CD99 uncovered a tumor-suppressing role in osteosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('osteosarcoma', 'Phenotype', 'HP:0002669', (158, 170))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('osteosarcoma', 'Disease', (158, 170))	('tumor', 'Disease', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('osteosarcoma', 'Disease', 'MESH:D012516', (158, 170))	('silencing', 'Var', (12, 21))	('tumor', 'Disease', (132, 137))	('Ewing sarcoma', 'Disease', (76, 89))	('CD99', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('CD99', 'Gene', (36, 40))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (76, 89))
118566	33147457	In osteosarcoma, exogenous CD99 was shown to inhibit osteosarcoma cell migration through inhibition of Src and Rock2.	('Rock2', 'Gene', '9475', (111, 116))	('exogenous CD99', 'Var', (17, 31))	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('Src', 'Protein', (103, 106))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('CD99', 'Var', (27, 31))	('inhibition', 'NegReg', (89, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('inhibit', 'NegReg', (45, 52))	('Rock2', 'Gene', (111, 116))	('osteosarcoma', 'Disease', (53, 65))	('osteosarcoma', 'Disease', 'MESH:D012516', (53, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('osteosarcoma', 'Phenotype', 'HP:0002669', (53, 65))
118568	33147457	A Src inhibitor, dasatinib, was previously shown to inhibit Ewing sarcoma growth, although these studies used higher doses of dasatinib than the dose used to detect the rescue of growth arrest by GDF6 silencing (Figure 4O, dasatinib used at 50 nM).	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (60, 80))	('inhibit', 'NegReg', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Ewing sarcoma growth', 'Disease', (60, 80))	('GDF6', 'Gene', (196, 200))	('silencing', 'Var', (201, 210))	('dasatinib', 'Chemical', 'MESH:D000069439', (126, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('dasatinib', 'Chemical', 'MESH:D000069439', (223, 232))	('dasatinib', 'Chemical', 'MESH:D000069439', (17, 26))	('growth arrest', 'Disease', (179, 192))	('growth arrest', 'Disease', 'MESH:D006323', (179, 192))	('growth arrest', 'Phenotype', 'HP:0001510', (179, 192))
118573	33147457	This was further supported by that abrogation of BMP signaling by Noggin had no effect on Ewing sarcoma growth (Figure S2).	('BMP', 'Gene', '649', (49, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Noggin', 'Gene', (66, 72))	('BMP', 'Gene', (49, 52))	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (90, 110))	('Ewing sarcoma growth', 'Disease', (90, 110))	('abrogation', 'Var', (35, 45))	('Noggin', 'Gene', '9241', (66, 72))
118576	33147457	Our data also suggest that the GDF6 prodomain mutants associated with Klippel-Feil syndrome, A249E and L289P, are hyperactive in GDF6 prodomain signaling (Figure 5).	('L289P', 'Var', (103, 108))	('A249E', 'Var', (93, 98))	('Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (70, 91))	('A249E', 'SUBSTITUTION', 'None', (93, 98))	('Klippel-Feil syndrome', 'Disease', (70, 91))	('hyperactive', 'PosReg', (114, 125))	('L289P', 'SUBSTITUTION', 'None', (103, 108))	('GDF6', 'Gene', (31, 35))	('GDF6 prodomain signaling', 'MPA', (129, 153))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (70, 91))
118577	33147457	These results suggest that the Klippel-Feil syndrome-linked GDF6 mutants display a gain-of-function activity, which is consistent with the autosomal dominant inheritance of GDF6-linked Klippel-Feil syndrome.	('GDF6-linked Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (173, 206))	('Klippel-Feil syndrome-linked GDF6', 'Disease', (31, 64))	('mutants', 'Var', (65, 72))	('GDF6-linked Klippel-Feil syndrome', 'Disease', (173, 206))	('Klippel-Feil syndrome-linked GDF6', 'Disease', 'MESH:D007714', (31, 64))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (185, 206))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (31, 52))	('gain-of-function', 'PosReg', (83, 99))	('activity', 'MPA', (100, 108))
118578	33147457	Interestingly, the GDF6 prodomain mutants associated with Klippel-Feil syndrome have not been reported in Ewing sarcoma, which may suggest that although the presence of GDF6 prodomain signaling is critical in Ewing sarcoma (Figure 2), the intensity of GDF6 prodomain signaling is not critical.	('Klippel-Feil syndrome', 'Disease', (58, 79))	('mutants', 'Var', (34, 41))	('Ewing sarcoma', 'Disease', (106, 119))	('associated', 'Reg', (42, 52))	('Ewing sarcoma', 'Disease', (209, 222))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (209, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (58, 79))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (209, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('Klippel-Feil syndrome', 'Disease', 'MESH:D007714', (58, 79))
118585	33147457	GDF6 emerged as such dependency created by EWS-FLI1: GDF6 is a direct transcriptional activation target of EWS-FLI1 and is highly expressed in Ewing sarcoma (Figure 1), and silencing of GDF6 profoundly impaired in vitro and in vivo growth of Ewing sarcoma (Figure 2).	('Ewing sarcoma', 'Disease', (143, 156))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (242, 255))	('silencing', 'Var', (173, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (242, 255))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (143, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (143, 156))	('impaired', 'NegReg', (202, 210))	('growth', 'CPA', (232, 238))	('GDF6', 'Gene', (186, 190))	('Ewing sarcoma', 'Disease', (242, 255))	('GDF6', 'Gene', (53, 57))
118586	33147457	Indeed, anti-GDF6 prodomain antibody efficiently inhibited Ewing sarcoma growth (Figure 2B), suggesting the potential utility of GDF6 neutralizing antibodies as a therapeutic agent.	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('anti-GDF6', 'Gene', (8, 17))	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (59, 79))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma growth', 'Disease', (59, 79))	('inhibited', 'NegReg', (49, 58))	('anti-GDF6', 'Var', (8, 17))
118599	33147457	pCMV5 mouse src K295R Y527F was a gift from Joan Brugge and Peter Howley (Addgene plasmid # 13657; http://www.addgene.org/13657/; RRID:Addgene_13657).	('src', 'Gene', (12, 15))	('K295R', 'SUBSTITUTION', 'None', (16, 21))	('src', 'Gene', '20779', (12, 15))	('Y527F', 'SUBSTITUTION', 'None', (22, 27))	('Y527F', 'Var', (22, 27))	('K295R', 'Var', (16, 21))	('mouse', 'Species', '10090', (6, 11))
118602	33147457	The following siRNAs were used: human GDF6 siRNA SMARTpool (Cat# M-0330055-01-005; Dharmacon), human CSK siRNA SMARTpool (Cat# M-003110-02-0005; Dharmacon), human p21 siRNA SMARTpool (Cat# D-003471-00-0005, Dharmacon), and Non-Targeting siRNA Pool #2 (D-001206-14-05; Dharmacon).	('Cat', 'Gene', (60, 63))	('human', 'Species', '9606', (95, 100))	('Cat', 'Gene', '847', (184, 187))	('Cat', 'Gene', '847', (60, 63))	('Cat', 'Gene', (122, 125))	('siRNAs', 'Disease', (14, 20))	('Cat', 'Gene', '847', (122, 125))	('D-001206-14-05', 'Var', (252, 266))	('human', 'Species', '9606', (32, 37))	('siRNAs', 'Disease', 'None', (14, 20))	('human', 'Species', '9606', (157, 162))	('Cat', 'Gene', (184, 187))
118632	33147457	The GDF6 prodomain (residue 1 - 335), GDF6 A249E prodomain, or GDF6 L289P prodomain was produced by transfection in 293T cells, serially diluted in Opti-MEM (31985-070, Life Technologies), and combined with labeled CD99-Fc fusion protein in PBS/0.005% Tween-20.	('Tween-20', 'Chemical', 'MESH:D011136', (252, 260))	('L289P', 'SUBSTITUTION', 'None', (68, 73))	('A249E', 'Var', (43, 48))	('PBS', 'Chemical', 'MESH:D007854', (241, 244))	('CD99-Fc fusion', 'Protein', (215, 229))	('Opti-MEM', 'Chemical', '-', (148, 156))	('L289P', 'Var', (68, 73))	('293T', 'CellLine', 'CVCL:0063', (116, 120))	('A249E', 'SUBSTITUTION', 'None', (43, 48))
118633	33147457	The autocrine signaling mediated by GDF6 maintains Ewing sarcoma growth The GDF6 prodomain is a ligand for CD99, a widely used marker for Ewing sarcoma GDF6 triggers CSK recruitment to CD99 intracellular domain, inhibiting Src activity Klippel-Feil syndrome-linked GDF6 mutants are hyperactive in CD99-Src signaling	('Ewing sarcoma', 'Disease', 'MESH:C563168', (138, 151))	('Klippel-Feil syndrome-linked GDF6', 'Disease', 'MESH:D007714', (236, 269))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('CD99-Src', 'MPA', (297, 305))	('Klippel-Feil syndrome', 'Phenotype', 'HP:0004602', (236, 257))	('hyperactive', 'PosReg', (282, 293))	('Ewing sarcoma', 'Disease', (138, 151))	('inhibiting', 'NegReg', (212, 222))	('Ewing sarcoma growth', 'Disease', 'MESH:C563168', (51, 71))	('mutants', 'Var', (270, 277))	('Ewing sarcoma growth', 'Disease', (51, 71))	('CSK', 'MPA', (166, 169))	('Klippel-Feil syndrome-linked GDF6', 'Disease', (236, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (138, 151))	('Src activity', 'MPA', (223, 235))
118681	33025168	report a single patient with chromosomal translocation involving EWSR1, similar to that seen with CCS.	('EWSR1', 'Gene', (65, 70))	('chromosomal translocation', 'Var', (29, 54))	('EWSR1', 'Gene', '2130', (65, 70))	('patient', 'Species', '9606', (16, 23))
118682	33025168	also report patients with CCSLTGT and EWSR gene fusion similar to that seen with CCS.	('CCSLTGT', 'Disease', (26, 33))	('patients', 'Species', '9606', (12, 20))	('EWSR', 'Gene', (38, 42))	('gene fusion', 'Var', (43, 54))
118711	32194552	At a preclinical level, we investigated the modulation of the KP upon PDL1 blockade in a syngeneic model of sarcoma through mRNA quantification of key KP enzymes within the tumor.	('investigated', 'Reg', (27, 39))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('sarcoma', 'Disease', (108, 115))	('blockade', 'Var', (75, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('PDL1', 'Gene', (70, 74))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))
118716	32194552	In the pre-clinical setting, blockade of PDL1 led to a strong anti-tumor effect and was associated with an intratumoral inflammatory cytokines signature driven by Ifng but also with a modulation of the KP enzymes including Ido1 and Ido2.	('blockade', 'Var', (29, 37))	('Ifng', 'Gene', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('PDL1', 'Gene', (41, 45))	('Ido2', 'Gene', '169355', (232, 236))	('Ifng', 'Gene', '3458', (163, 167))	('Ido2', 'Gene', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (112, 117))
118717	32194552	IDO1 inhibition using GDC-0919 resulted in (i) a significant decrease of plasmatic Kynurenine to Tryptophan ratio and in (ii) a decrease of tumoral Kynurenine.	('decrease of plasmatic Kynurenine to Tryptophan ratio', 'Phenotype', 'HP:0500135', (61, 113))	('IDO1', 'Gene', (0, 4))	('decrease', 'NegReg', (61, 69))	('plasmatic Kynurenine to Tryptophan ratio', 'MPA', (73, 113))	('tumoral Kynurenine', 'Disease', (140, 158))	('tumoral Kynurenine', 'Disease', 'MESH:D009369', (140, 158))	('Kynurenine', 'Chemical', 'MESH:D007737', (148, 158))	('inhibition', 'NegReg', (5, 15))	('GDC-0919', 'Var', (22, 30))	('Tryptophan', 'Chemical', 'MESH:D014364', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('decrease', 'NegReg', (128, 136))	('GDC-0919', 'Chemical', 'MESH:C000626065', (22, 30))	('Kynurenine', 'Chemical', 'MESH:D007737', (83, 93))
118718	32194552	However, GDC-0919 used alone or combined with anti-PDL1, did not show anti-tumoral activity and did not affect the tumor immune cell infiltrate.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('anti-PDL1', 'Gene', (46, 55))	('GDC-0919', 'Var', (9, 17))	('tumor', 'Disease', (115, 120))	('GDC-0919', 'Chemical', 'MESH:C000626065', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('not', 'NegReg', (61, 64))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
118720	32194552	Interestingly, we have found that GDC-0919 induced a downregulation of the expression of pvr and granzymes, and an upregulation of inhba and Dtx4 suggesting a potential role of the IDO pathway in the control of NK function.	('inhba', 'Gene', '3624', (131, 136))	('GDC-0919', 'Chemical', 'MESH:C000626065', (34, 42))	('Dtx4', 'Gene', '23220', (141, 145))	('downregulation', 'NegReg', (53, 67))	('upregulation', 'PosReg', (115, 127))	('pvr', 'Gene', (89, 92))	('IDO', 'Gene', '3620', (181, 184))	('pvr', 'Gene', '5817', (89, 92))	('inhba', 'Gene', (131, 136))	('IDO', 'Gene', (181, 184))	('Dtx4', 'Gene', (141, 145))	('GDC-0919', 'Var', (34, 42))	('expression', 'MPA', (75, 85))
118736	32194552	These enzymes induce biostatic tryptophan starvation, which limits lymphocyte expansion, and produce a series of catabolites, collectively known as kynurenines.	('produce', 'Reg', (93, 100))	('tryptophan', 'Chemical', 'MESH:D014364', (31, 41))	('lymphocyte expansion', 'CPA', (67, 87))	('series of catabolites', 'MPA', (103, 124))	('induce', 'Reg', (14, 20))	('kynurenines', 'Chemical', 'MESH:D007737', (148, 159))	('enzymes', 'Var', (6, 13))	('limits', 'NegReg', (60, 66))	('biostatic tryptophan starvation', 'MPA', (21, 52))
118739	32194552	Recent preclinical data have also evidenced that IDO1 deficient mice (Ido1-/-) were more sensitive to immune checkpoint inhibitors, including anti-CTLA4, anti-PD1, and anti-PDL1, thus highlighting the crucial role of IDO1 in resistance to those treatments.	('anti-PDL1', 'Var', (168, 177))	('IDO1', 'Gene', (49, 53))	('anti-PD1', 'Var', (154, 162))	('CTLA4', 'Gene', (147, 152))	('sensitive', 'MPA', (89, 98))	('deficient', 'NegReg', (54, 63))	('CTLA4', 'Gene', '12477', (147, 152))	('mice', 'Species', '10090', (64, 68))
118750	32194552	We observed a hIFNg dose-dependent increase of Kynurenine, which was more pronounced for IB115 than for IB136 cell lines (Figure 2A).	('increase', 'PosReg', (35, 43))	('hIFNg', 'Gene', (14, 19))	('Kynurenine', 'Chemical', 'MESH:D007737', (47, 57))	('IB115', 'Var', (89, 94))	('Kynurenine', 'MPA', (47, 57))	('hIFNg', 'Gene', '3458', (14, 19))
118753	32194552	As expected, treatment with GDC-0919 significantly inhibited the production of Kynurenine with IC50 values at 5.1 10-7M and 2.4 10-7M for IB115 and IB136 cell lines, respectively.	('GDC-0919', 'Var', (28, 36))	('GDC-0919', 'Chemical', 'MESH:C000626065', (28, 36))	('production of Kynurenine', 'MPA', (65, 89))	('Kynurenine', 'Chemical', 'MESH:D007737', (79, 89))	('inhibited', 'NegReg', (51, 60))
118758	32194552	Interestingly, we observed an increase in Tryptophan-degrading enzymes upon PDL1 blockade:Ido1 and Ido2:while no change was observed for Tdo2 (Figure 4).	('Tdo2', 'Gene', '6999', (137, 141))	('Tryptophan', 'Chemical', 'MESH:D014364', (42, 52))	('Tdo2', 'Gene', (137, 141))	('blockade', 'Var', (81, 89))	('Tryptophan-degrading enzymes', 'MPA', (42, 70))	('increase', 'PosReg', (30, 38))	('Ido2', 'Gene', '169355', (99, 103))	('PDL1', 'Gene', (76, 80))	('Ido2', 'Gene', (99, 103))
118762	32194552	As expected, anti-PDL1 favored the induction of an immune response within the tumor as highlighted by Tnfa, Il6, Ifng, Il2, and Tgfb induction:Ifng expression levels being significantly correlated with survival (Data not shown).	('Ifng', 'Gene', (113, 117))	('correlated', 'Reg', (186, 196))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Tnfa', 'Gene', (102, 106))	('Il6', 'Gene', (108, 111))	('Il2', 'Gene', '3558', (119, 122))	('expression levels', 'MPA', (148, 165))	('Ifng', 'Gene', (143, 147))	('Tnfa', 'Gene', '7124', (102, 106))	('Il6', 'Gene', '3569', (108, 111))	('Ifng', 'Gene', '3458', (113, 117))	('anti-PDL1', 'Var', (13, 22))	('Il2', 'Gene', (119, 122))	('tumor', 'Disease', (78, 83))	('Ifng', 'Gene', '3458', (143, 147))	('Tgfb', 'Gene', '7040', (128, 132))	('immune response', 'MPA', (51, 66))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Tgfb', 'Gene', (128, 132))
118765	32194552	Two doses of GDC-0919-100 and 200mg/kg, po, bid:were explored in a LPS model known to promote Kynurenine production.	('GDC-0919-100', 'Chemical', '-', (13, 25))	('LPS', 'Disease', (67, 70))	('promote', 'PosReg', (86, 93))	('Kynurenine production', 'MPA', (94, 115))	('LPS', 'Disease', 'MESH:C536528', (67, 70))	('GDC-0919-100', 'Var', (13, 25))	('Kynurenine', 'Chemical', 'MESH:D007737', (94, 104))
118767	32194552	Treatment of MCA205 tumor bearing mice with GDC-0919 either as a single agent (100mg/kg, po, bid) or in combination with an anti-PDL1 antibody yielded a significant decrease in plasmatic Kynurenine to Tryptophan ratio.	('MCA205 tumor', 'Disease', 'MESH:D009369', (13, 25))	('mice', 'Species', '10090', (34, 38))	('Kynurenine', 'Chemical', 'MESH:D007737', (187, 197))	('decrease in plasmatic Kynurenine to Tryptophan ratio', 'Phenotype', 'HP:0500135', (165, 217))	('GDC-0919', 'Var', (44, 52))	('decrease', 'NegReg', (165, 173))	('Tryptophan', 'Chemical', 'MESH:D014364', (201, 211))	('plasmatic Kynurenine to Tryptophan ratio', 'MPA', (177, 217))	('GDC-0919', 'Chemical', 'MESH:C000626065', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('MCA205 tumor', 'Disease', (13, 25))
118770	32194552	As expected, GDC-0919 induced a substantial decrease in Kynurenine, Kynurenine to Tryptophan ratio, and Kynurenic acid.	('Kynurenine to Tryptophan ratio', 'MPA', (68, 98))	('decrease', 'NegReg', (44, 52))	('Kynurenine', 'MPA', (56, 66))	('Kynurenic acid', 'Chemical', 'MESH:D007736', (104, 118))	('Kynurenic acid', 'MPA', (104, 118))	('GDC-0919', 'Var', (13, 21))	('Kynurenine', 'Chemical', 'MESH:D007737', (68, 78))	('GDC-0919', 'Chemical', 'MESH:C000626065', (13, 21))	('Kynurenine', 'Chemical', 'MESH:D007737', (56, 66))	('Tryptophan', 'Chemical', 'MESH:D014364', (82, 92))
118772	32194552	As depicted by tumor growth assessment, anti-PDL1 administration triggered a significant anti-tumor response resulting in 1 out of 15 tumor rejection.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('15 tumor', 'Disease', (131, 139))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (15, 20))	('anti-PDL1', 'Var', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('15 tumor', 'Disease', 'MESH:C567447', (131, 139))	('tumor', 'Disease', (134, 139))
118775	32194552	As expected, PDL1 blockade favored tumor infiltration by CD45+ leukocytes, mainly composed of a higher fraction of CD4+ and CD8+ T cells also harboring a more pronounced activated state as depicted by intracellular IFNgamma staining.	('CD45', 'Gene', '5788', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('CD4', 'Gene', '920', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IFNgamma', 'Gene', (215, 223))	('PDL1', 'Gene', (13, 17))	('IFNgamma', 'Gene', '3458', (215, 223))	('CD4', 'Gene', (115, 118))	('tumor', 'Disease', (35, 40))	('CD8', 'Gene', (124, 127))	('blockade', 'Var', (18, 26))	('CD45', 'Gene', (57, 61))	('CD8', 'Gene', '925', (124, 127))	('CD4', 'Gene', '920', (115, 118))	('CD4', 'Gene', (57, 60))	('favored', 'PosReg', (27, 34))
118776	32194552	Combination of anti-PDL1 with GDC-0919 did not change the observed features.	('GDC-0919', 'Chemical', 'MESH:C000626065', (30, 38))	('anti-PDL1', 'Gene', (15, 24))	('anti-PDL1', 'Var', (15, 24))
118780	32194552	Analysis of Myeloid Derived Suppressor Cells (MDSCs) by mean of CD11b and Gr1 staining revealed that anti-PDL1 limited their infiltration within the tumor - especially CD11b+/Gr1Low and CD11b+/Gr1Int populations.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('anti-PDL1', 'Var', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('limited', 'NegReg', (111, 118))	('tumor', 'Disease', (149, 154))	('infiltration', 'CPA', (125, 137))
118784	32194552	When combined with anti-PDL1, GDC-0919 triggered several gene expression changes, including the upregulation of the inhibitory molecule Tigit that could participate in the lack of synergistic effect of GDC-0919 and anti-PDL1.	('gene expression', 'MPA', (57, 72))	('GDC-0919', 'Chemical', 'MESH:C000626065', (30, 38))	('Tigit', 'Gene', '201633', (136, 141))	('GDC-0919', 'Chemical', 'MESH:C000626065', (202, 210))	('Tigit', 'Gene', (136, 141))	('GDC-0919', 'Var', (30, 38))	('upregulation', 'PosReg', (96, 108))
118800	32194552	Indeed, GDC-0919 significantly reduced plasma Kynurenine in comparison to pre-dose levels.	('reduced', 'NegReg', (31, 38))	('plasma Kynurenine', 'MPA', (39, 56))	('Kynurenine', 'Chemical', 'MESH:D007737', (46, 56))	('GDC-0919', 'Chemical', 'MESH:C000626065', (8, 16))	('GDC-0919', 'Var', (8, 16))
118801	32194552	However, we observed that GDC-0919 alone or combined with anti-PDL1, only yielded to a transient decrease in plasmatic Kynurenine level thus suggesting a delayed compensatory mechanism restoring in turn Kynurenine production.	('Kynurenine', 'Chemical', 'MESH:D007737', (119, 129))	('GDC-0919', 'Var', (26, 34))	('decrease', 'NegReg', (97, 105))	('Kynurenine', 'Chemical', 'MESH:D007737', (203, 213))	('anti-PDL1', 'Gene', (58, 67))	('GDC-0919', 'Chemical', 'MESH:C000626065', (26, 34))	('plasmatic Kynurenine level', 'MPA', (109, 135))
118804	32194552	Nevertheless, whether alone or combined with anti-PDL1, GDC-0919 did not show anti-tumoral activity and did not significantly affect the tumor immune cell infiltrate, thereby corroborating the data obtained in patients.	('GDC-0919', 'Var', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (83, 88))	('GDC-0919', 'Chemical', 'MESH:C000626065', (56, 64))	('patients', 'Species', '9606', (210, 218))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
118818	32194552	FFPE specimens were processed for immunohistochemistry with respective antibodies specific for IDO1 (clone UMAB126, Origen), CD8 (clone SP16, Spring Bioscience), and anti-PDL1 (clone SP263, Ventana) according to conventional protocols using a Ventana Benchmark Ultra automated platform Briefly, tissue sections were deparaffinized, and processed for epitope retrieval in CC1 buffer.	('anti-PDL1', 'Var', (166, 175))	('CD8', 'Gene', (125, 128))	('CD8', 'Gene', '925', (125, 128))	('IDO1', 'Gene', (95, 99))
118838	32194552	Tubes were stored at -80 C until metabolite dosage by LC/MS including L-Tryptophan, L-Kynurenine, Kynurenic acid, 3-Hydroxyanthranilic acid.	('3-Hydroxyanthranilic acid', 'Chemical', 'MESH:D015095', (114, 139))	('L-Tryptophan', 'Chemical', 'MESH:D014364', (70, 82))	('3-Hydroxyanthranilic acid', 'MPA', (114, 139))	('L-Tryptophan', 'Var', (70, 82))	('Kynurenic acid', 'Chemical', 'MESH:D007736', (98, 112))	('L-Kynurenine', 'Var', (84, 96))	('L-Kynurenine', 'Chemical', 'MESH:D007737', (84, 96))	('Kynurenic acid', 'MPA', (98, 112))
118912	23755370	It has been shown that the tumor suppressor p53 is commonly mutated in sporadic OS (Miller et al.,).	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('p53', 'Gene', (44, 47))	('mutated', 'Var', (60, 67))	('sporadic OS', 'Disease', (71, 82))	('OS', 'Phenotype', 'HP:0002669', (80, 82))
118913	23755370	Alterations in genes that regulate p53 including the murine double minute 2 (MDM2), cyclin dependant kinase 4 (CDK4) (Mejia-Guerrero et al.,), and the p14 product of the INK4A gene (Benassi et al.,) have also been identified in OS.	('CDK4', 'Gene', (111, 115))	('p53', 'Gene', (35, 38))	('p14', 'Gene', (151, 154))	('p14', 'Gene', '20202', (151, 154))	('CDK4', 'Gene', '12567', (111, 115))	('murine', 'Species', '10090', (53, 59))	('OS', 'Phenotype', 'HP:0002669', (228, 230))	('INK4A', 'Gene', (170, 175))	('Alterations', 'Var', (0, 11))	('cyclin dependant kinase 4', 'Gene', (84, 109))	('cyclin dependant kinase 4', 'Gene', '12567', (84, 109))	('INK4A', 'Gene', '12578', (170, 175))
118914	23755370	Several groups have demonstrated that mutations in the retinoblastoma (Rb1) gene located on chromosome 13 occurred in a high percentage of OS samples (Wong et al.,; Nielsen et al.,).	('OS', 'Phenotype', 'HP:0002669', (139, 141))	('Rb1', 'Gene', (71, 74))	('retinoblastoma', 'Gene', (55, 69))	('retinoblastoma', 'Gene', '5925', (55, 69))	('retinoblastoma', 'Phenotype', 'HP:0009919', (55, 69))	('mutations', 'Var', (38, 47))	('Rb1', 'Gene', '5925', (71, 74))	('occurred', 'Reg', (106, 114))
118915	23755370	High frequencies of allelic loss have been detected at 3q and 18q (Yamaguchi et al.,), suggesting that other tumor suppressor genes may be important in OS.	('OS', 'Phenotype', 'HP:0002669', (152, 154))	('allelic', 'Var', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
118916	23755370	overexpression of human epidermal growth factor receptor 2 (HER2/neu, ErbB2) was suggested to be associated with early pulmonary metastases and decreased survival in approximately 40% of cases.	('pulmonary metastases', 'Disease', 'MESH:D009362', (119, 139))	('pulmonary metastases', 'Disease', (119, 139))	('decreased', 'NegReg', (144, 153))	('neu', 'Gene', (65, 68))	('epidermal growth factor receptor 2', 'Gene', '2064', (24, 58))	('epidermal growth factor receptor 2', 'Gene', (24, 58))	('HER2', 'Gene', (60, 64))	('survival', 'CPA', (154, 162))	('human', 'Species', '9606', (18, 23))	('HER2', 'Gene', '2064', (60, 64))	('ErbB2', 'Gene', (70, 75))	('associated', 'Reg', (97, 107))	('overexpression', 'Var', (0, 14))	('neu', 'Gene', '2064', (65, 68))	('ErbB2', 'Gene', '2064', (70, 75))
118918	23755370	Patients with Rothmund-Thomson Syndrome, associated with a high incidence of OS, have mutations in the RecQ protein-like 4 (RECQL4) gene (Simon et al.,).	('mutations', 'Var', (86, 95))	('RecQ protein-like 4', 'Gene', (103, 122))	('RECQL4', 'Gene', (124, 130))	('OS', 'Phenotype', 'HP:0002669', (77, 79))	('RecQ protein-like 4', 'Gene', '9401', (103, 122))	('Rothmund-Thomson Syndrome', 'Disease', 'MESH:D011038', (14, 39))	('Patients', 'Species', '9606', (0, 8))	('RECQL4', 'Gene', '9401', (124, 130))	('Rothmund-Thomson Syndrome', 'Disease', (14, 39))
118939	23755370	In OS, inhibition of c-Src prevents cell invasion and induces apoptosis in vitro and reduces tumor growth in vivo (Akiyama et al.,).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('prevents', 'NegReg', (27, 35))	('inhibition', 'Var', (7, 17))	('apoptosis', 'CPA', (62, 71))	('c-Src', 'Gene', '6714', (21, 26))	('OS', 'Phenotype', 'HP:0002669', (3, 5))	('reduces', 'NegReg', (85, 92))	('induces', 'Reg', (54, 61))	('c-Src', 'Gene', (21, 26))	('cell invasion', 'CPA', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
118968	23755370	Sorafenib is also being clinically investigated in combination with bevacizumab (NCT00665990) and irinotecan (NCT01518413).	('NCT00665990', 'Var', (81, 92))	('irinotecan', 'Chemical', 'MESH:D000077146', (98, 108))	('bevacizumab', 'Chemical', 'MESH:D000068258', (68, 79))	('NCT01518413', 'Var', (110, 121))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))
118975	23755370	IGF-1R has been implicated in the development of sarcomas and inhibition of IGF-1R function has been demonstrated to reduce growth in OS, rhabdomyosarcoma, and Ewing sarcoma cell lines (Toretsky et al.,; Scotlandi,).	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (160, 173))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (160, 173))	('reduce', 'NegReg', (117, 123))	('growth', 'MPA', (124, 130))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (138, 154))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (138, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('IGF-1R', 'Gene', '3480', (0, 6))	('IGF-1R', 'Gene', (0, 6))	('Ewing sarcoma', 'Disease', (160, 173))	('implicated', 'Reg', (16, 26))	('inhibition', 'Var', (62, 72))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))	('IGF-1R', 'Gene', (76, 82))	('IGF-1R', 'Gene', '3480', (76, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('reduce growth', 'Phenotype', 'HP:0001510', (117, 130))	('sarcomas', 'Disease', (49, 57))	('OS', 'Phenotype', 'HP:0002669', (134, 136))	('function', 'MPA', (83, 91))	('rhabdomyosarcoma', 'Disease', (138, 154))
118979	23755370	also showed similar tumor regression by SCH 717454 in an OS model, with enhanced anti-tumor effects when used in combination with cyclophosphamide and cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SCH 717454', 'Chemical', 'MESH:C573312', (40, 50))	('tumor', 'Disease', (86, 91))	('OS', 'Phenotype', 'HP:0002669', (57, 59))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('enhanced', 'PosReg', (72, 80))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (130, 146))	('SCH 717454', 'Var', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (20, 25))
118983	23755370	Combination (stage 2) testing of cixutumumab with rapamycin resulted in superior responses compared to the single agents alone (Kolb et al.,).	('cixutumumab', 'Chemical', 'MESH:C557414', (33, 44))	('responses', 'MPA', (81, 90))	('cixutumumab', 'Var', (33, 44))	('rapamycin', 'Chemical', 'MESH:D020123', (50, 59))
118984	23755370	In a phase II COG trial cixutumumab was also well-tolerated as single-agent therapy in patients with solid tumors (Malempati et al.,).	('solid tumors', 'Disease', 'MESH:D009369', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cixutumumab', 'Var', (24, 35))	('solid tumors', 'Disease', (101, 113))	('patients', 'Species', '9606', (87, 95))	('cixutumumab', 'Chemical', 'MESH:C557414', (24, 35))
119002	23755370	More recently in a phase III sarcoma maintenance study (Blay et al.,), ridaforolimus met the study endpoint of a statistically significant improvement in PFS, compared with a placebo group (hazard ratio = 0.72, P = 0.0001, stratified log-rank) though specific results in OS are not yet available.	('ridaforolimus', 'Chemical', 'MESH:C515074', (71, 84))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('improvement', 'PosReg', (139, 150))	('sarcoma', 'Disease', (29, 36))	('PFS', 'Disease', (154, 157))	('OS', 'Phenotype', 'HP:0002669', (271, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('ridaforolimus', 'Var', (71, 84))
119004	23755370	A phase II trial of pazopanib and everolimus in patients with PI3K mutations and/or phosphatase and tensin homolog (PTEN) tumor suppressor loss is underway (NCT01430572).	('pazopanib', 'Chemical', 'MESH:C516667', (20, 29))	('loss', 'NegReg', (139, 143))	('everolimus', 'Chemical', 'MESH:D000068338', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mutations', 'Var', (67, 76))	('PI3K', 'Gene', (62, 66))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PTEN', 'Gene', (116, 120))	('PTEN', 'Gene', '5728', (116, 120))	('tumor', 'Disease', (122, 127))
119006	23755370	The dual mTOR1/mTOR2 inhibitor AZD8055 demonstrated low activity in vivo against the PPTP OS xenografts as PD1 was reported for five of six tumors (Houghton et al.,).	('PPTP OS', 'Chemical', '-', (85, 92))	('PD1', 'Gene', '5133', (107, 110))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('activity', 'MPA', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('PD1', 'Gene', (107, 110))	('AZD8055', 'Var', (31, 38))	('AZD8055', 'Chemical', 'MESH:C546624', (31, 38))	('mTOR', 'Gene', (9, 13))	('mTOR', 'Gene', (15, 19))	('mTOR', 'Gene', '2475', (9, 13))	('mTOR', 'Gene', '2475', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('OS', 'Phenotype', 'HP:0002669', (90, 92))
119007	23755370	AZD8055 is not currently in clinical development while other novel small-molecule inhibitors that are mTOR-selective or dual mTOR/PI3K inhibitors have entered clinical trials.	('mTOR', 'Gene', '2475', (125, 129))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('AZD8055', 'Var', (0, 7))	('mTOR', 'Gene', (125, 129))	('mTOR', 'Gene', (102, 106))	('mTOR', 'Gene', '2475', (102, 106))
119010	23755370	Antibodies targeting IGF-1R (R1507, figitumumab, cixutumumab) in combination with rapamycin and rapalogs showed enhanced activity compared to the single agents (Juergens et al.,; Quek et al.,; Kolb et al.,).	('enhanced', 'PosReg', (112, 120))	('activity', 'MPA', (121, 129))	('rapamycin', 'Chemical', 'MESH:D020123', (82, 91))	('R1507', 'Var', (29, 34))	('figitumumab', 'Chemical', 'MESH:C525021', (36, 47))	('IGF-1R', 'Gene', (21, 27))	('IGF-1R', 'Gene', '3480', (21, 27))	('cixutumumab', 'Chemical', 'MESH:C557414', (49, 60))
119012	23755370	The phase I study of everolimus and CP-751871, a fully human anti-IGF-1R mAb, achieved SD in patients with sarcoma and other solid tumors (Quek et al.,).	('IGF-1R', 'Gene', (66, 72))	('solid tumors', 'Disease', 'MESH:D009369', (125, 137))	('SD', 'Disease', 'MESH:D029461', (87, 89))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('sarcoma', 'Disease', (107, 114))	('human', 'Species', '9606', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('CP-751871', 'Chemical', 'MESH:C525021', (36, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('CP-751871', 'Var', (36, 45))	('solid tumors', 'Disease', (125, 137))	('everolimus', 'Chemical', 'MESH:D000068338', (21, 31))	('IGF-1R', 'Gene', '3480', (66, 72))	('patients', 'Species', '9606', (93, 101))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))
119013	23755370	Further use of mTOR inhibitors in the treatment of OS patients is under investigation as single-dose therapy [everolimus (NCT01216826), sirolimus (NCT01331135)] and multi-agent therapy [sirolimus and cyclophosphamide (NCT00743509)] with the major goals of determining effective dosing schedules and additive combinations.	('everolimus', 'Chemical', 'MESH:D000068338', (110, 120))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (200, 216))	('sirolimus', 'Chemical', 'MESH:D020123', (186, 195))	('patients', 'Species', '9606', (54, 62))	('mTOR', 'Gene', (15, 19))	('mTOR', 'Gene', '2475', (15, 19))	('NCT01331135)]', 'Var', (147, 160))	('sirolimus', 'Chemical', 'MESH:D020123', (136, 145))	('NCT01216826', 'Var', (122, 133))	('OS', 'Phenotype', 'HP:0002669', (51, 53))
119015	23755370	Three mammalian aurora kinase genes encode aurora A, B, and C proteins and inhibition of any of these potentially results in abnormal mitotic events and apoptosis.	('results in', 'Reg', (114, 124))	('inhibition', 'Var', (75, 85))	('aurora A', 'Gene', (43, 51))	('mammalian', 'Species', '9606', (6, 15))	('C proteins', 'Protein', (60, 70))	('aurora A', 'Gene', '6790', (43, 51))	('apoptosis', 'CPA', (153, 162))
119016	23755370	Overexpression of aurora kinases has been correlated with poor prognosis in canine OS, which his high similarities to the human disease (Mueller et al.,).	('human', 'Species', '9606', (122, 127))	('canine', 'Species', '9615', (76, 82))	('Overexpression', 'Var', (0, 14))	('canine OS', 'Disease', (76, 85))	('OS', 'Phenotype', 'HP:0002669', (83, 85))
119020	23755370	A current COG pediatric phase 1/II study investigating MLN8237 in children with relapsed/refractory solid tumors (NCT00739427) includes a cohort of patients with OS.	('patients', 'Species', '9606', (148, 156))	('OS', 'Phenotype', 'HP:0002669', (162, 164))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('children', 'Species', '9606', (66, 74))	('refractory solid tumors', 'Disease', (89, 112))	('refractory solid tumors', 'Disease', 'MESH:D009369', (89, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MLN8237', 'Var', (55, 62))
119024	23755370	PI3K and Akt activation may drive tumorigenesis in OS by regulating effectors that are different from mTORC1.	('PI3K', 'Var', (0, 4))	('tumor', 'Disease', (34, 39))	('mTORC1', 'Gene', '382056', (102, 108))	('Akt', 'Gene', (9, 12))	('mTORC1', 'Gene', (102, 108))	('activation', 'PosReg', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('OS', 'Phenotype', 'HP:0002669', (51, 53))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Akt', 'Gene', '207', (9, 12))
119025	23755370	Inhibition of Akt signaling is anticipated to reduce tumor survival and enhance the effectiveness of cytotoxic chemotherapy by increasing apoptosis (Diaz-Montero et al.,; Carol et al.,).	('Akt', 'Gene', (14, 17))	('reduce', 'NegReg', (46, 52))	('enhance', 'PosReg', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('increasing', 'PosReg', (127, 137))	('apoptosis', 'CPA', (138, 147))	('Inhibition', 'Var', (0, 10))	('effectiveness', 'CPA', (84, 97))	('tumor', 'Disease', (53, 58))	('Akt', 'Gene', '207', (14, 17))
119034	23755370	The Akt inhibitor, GSK690693 was reported to have modest anti-tumor activity in the PPTP testing as intermediate activity against two of six OS xenografts was demonstrated (Carol et al.,).	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PPTP', 'Chemical', '-', (84, 88))	('GSK690693', 'Chemical', 'MESH:C528328', (19, 28))	('GSK690693', 'Var', (19, 28))	('tumor', 'Disease', (62, 67))	('Akt', 'Gene', '207', (4, 7))	('OS', 'Phenotype', 'HP:0002669', (141, 143))	('Akt', 'Gene', (4, 7))
119035	23755370	One planned study to investigate GSK690693 in pediatric subjects with relapsed or refractory hematologic malignancies was withdrawn prior to patient enrollment and this agent has not been clinically studied for any pediatric malignancies.	('hematologic malignancies', 'Disease', (93, 117))	('GSK690693', 'Chemical', 'MESH:C528328', (33, 42))	('GSK690693', 'Var', (33, 42))	('patient', 'Species', '9606', (141, 148))	('pediatric malignancies', 'Disease', 'MESH:D063766', (215, 237))	('pediatric malignancies', 'Disease', (215, 237))	('hematologic malignancies', 'Disease', 'MESH:D019337', (93, 117))
119039	23755370	Ras/Raf is upstream of MEK and aberrant activation of the Ras/Raf/MEK/MAP kinase pathway (MAPK pathway) is associated with the pathogenesis of many cancers including OS lung metastasis (Yu et al.,).	('OS', 'Phenotype', 'HP:0002669', (166, 168))	('MEK', 'Gene', (23, 26))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('Raf', 'Gene', '22882', (4, 7))	('aberrant', 'Var', (31, 39))	('OS lung metastasis', 'Disease', 'MESH:C567932', (166, 184))	('MEK', 'Gene', '5609', (66, 69))	('MAPK', 'Gene', (90, 94))	('Raf', 'Gene', (62, 65))	('associated', 'Reg', (107, 117))	('MEK', 'Gene', (66, 69))	('activation', 'PosReg', (40, 50))	('Raf', 'Gene', '22882', (62, 65))	('MAPK', 'Gene', '5594;26413', (90, 94))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('OS lung metastasis', 'Disease', (166, 184))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Raf', 'Gene', (4, 7))	('MEK', 'Gene', '5609', (23, 26))
119041	23755370	AZD6244 is a potent and specific inhibitor for MEK 1/2 and demonstrated effective tumor growth inhibition in the PPTP OS panel.	('PPTP OS', 'Chemical', '-', (113, 120))	('OS', 'Phenotype', 'HP:0002669', (118, 120))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('MEK 1/2', 'Gene', (47, 54))	('AZD6244', 'Var', (0, 7))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))	('tumor', 'Disease', (82, 87))	('MEK 1/2', 'Gene', '5604;5605', (47, 54))
119047	23755370	CDKs are frequently upregulated in human cancers along with overexpression of cyclin partners or inactivation of CDK inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CDKs', 'Gene', '983;1017;1019;12567;1020;1025', (0, 4))	('cyclin', 'Gene', '5111', (78, 84))	('overexpression', 'PosReg', (60, 74))	('CDKs', 'Gene', (0, 4))	('cyclin', 'Gene', (78, 84))	('human', 'Species', '9606', (35, 40))	('upregulated', 'PosReg', (20, 31))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('inactivation', 'Var', (97, 109))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
119057	23755370	Mutations in p53 (Miller et al.,) and amplification of MDM2 have been reported in OS, though with relatively low incidence in comparison to adult malignancies (Mejia-Guerrero et al.,).	('adult malignancies', 'Disease', 'MESH:D009369', (140, 158))	('adult malignancies', 'Disease', (140, 158))	('reported', 'Reg', (70, 78))	('OS', 'Phenotype', 'HP:0002669', (82, 84))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('MDM2', 'Gene', (55, 59))	('amplification', 'Var', (38, 51))
119066	23755370	Inhibition of CENP-E in cultured human tumor cells leads to cell cycle arrest in mitosis with bipolar mitotic spindles and misaligned chromosomes and eventual cell death.	('arrest in mitosis', 'Disease', (71, 88))	('CENP-E', 'Gene', '1062', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CENP-E', 'Gene', (14, 20))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('arrest in mitosis', 'Disease', 'MESH:D006323', (71, 88))	('bipolar mitotic', 'Disease', 'MESH:D001714', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('human', 'Species', '9606', (33, 38))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (39, 44))	('bipolar mitotic', 'Disease', (94, 109))
119069	23755370	GSK923295A is currently in a phase I clinical trial for adults with solid tumors however this agent is not in clinical development for pediatric OS patients.	('patients', 'Species', '9606', (148, 156))	('GSK923295A', 'Chemical', 'MESH:C571460', (0, 10))	('solid tumors', 'Disease', (68, 80))	('OS', 'Phenotype', 'HP:0002669', (145, 147))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('GSK923295A', 'Var', (0, 10))	('solid tumors', 'Disease', 'MESH:D009369', (68, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
119071	23755370	HDAC inhibitors induce growth arrest and cell death by epigenetic changes in many preclinical and clinical cancer models.	('HDAC', 'Gene', (0, 4))	('growth arrest', 'Disease', (23, 36))	('growth arrest', 'Disease', 'MESH:D006323', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('inhibitors', 'Var', (5, 15))	('growth arrest', 'Phenotype', 'HP:0001510', (23, 36))	('cell death', 'CPA', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('epigenetic changes', 'Var', (55, 73))	('cancer', 'Disease', (107, 113))
119079	23755370	Current phase II studies enrolling pediatric OS patients include the testing of vorinostat in children (NCT01422499) and in combination with etoposide in pediatric patients younger than 21 years at diagnosis with refractory solid tumors (NCT01294670).	('NCT01294670', 'Var', (238, 249))	('refractory solid tumors', 'Disease', 'MESH:D009369', (213, 236))	('etoposide', 'Chemical', 'MESH:D005047', (141, 150))	('OS', 'Phenotype', 'HP:0002669', (45, 47))	('children', 'Species', '9606', (94, 102))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('vorinostat', 'Chemical', 'MESH:D000077337', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('refractory solid tumors', 'Disease', (213, 236))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (48, 56))
119085	23755370	Overexpression of Smac has been shown to sensitize OS cells in vitro to chemotherapeutic drug-induced apoptosis (Hotta et al.,).	('sensitize', 'Reg', (41, 50))	('Smac', 'Gene', (18, 22))	('Smac', 'Gene', '56616', (18, 22))	('Overexpression', 'Var', (0, 14))	('OS', 'Phenotype', 'HP:0002669', (51, 53))
119087	23755370	LCL161 is a small-molecule Smac mimetic which induces apoptosis in some cancer cell lines and potentiates the effects of tyrosine kinase inhibition (Houghton et al.,).	('apoptosis', 'CPA', (54, 63))	('cancer', 'Disease', (72, 78))	('LCL161', 'Var', (0, 6))	('Smac', 'Gene', '56616', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('induces', 'PosReg', (46, 53))	('Smac', 'Gene', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tyrosine kinase inhibition', 'MPA', (121, 147))	('potentiates', 'PosReg', (94, 105))
119195	22114043	For example, in one study, siblings of survivors with limb disfigurement reported more psychosocial distress compared to siblings of survivors without limb disfigurement.	('more', 'PosReg', (82, 86))	('psychosocial distress', 'Disease', (87, 108))	('limb disfigurement', 'Var', (54, 72))	('psychosocial distress', 'Disease', 'MESH:C535569', (87, 108))
119377	33154370	Variant_Lecun is the best at binary classification of canine sarcoma, but when the number of classes is expanded to 12, variant_VGG9 is slightly better.	('sarcoma', 'Disease', (61, 68))	('canine', 'Species', '9615', (54, 60))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('variant_VGG9', 'Var', (120, 132))	('Variant_Lecun', 'Var', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
119378	33154370	The only classification that could be described as accurate is for canine sarcoma versus healthy tissue (binary classification) by variant_Lecun with an average accuracy of 0.98.	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('canine', 'Species', '9615', (67, 73))	('sarcoma', 'Disease', (74, 81))	('rat', 'Species', '10116', (55, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('variant_Lecun', 'Var', (131, 144))
119382	33154370	As shown in Table 2, transfer learning clearly improves the classification accuracies of both small SpiderMass datasets compared to CNN models trained from scratch (without transfer learning).	('classification', 'MPA', (60, 74))	('transfer learning', 'Var', (21, 38))	('rat', 'Species', '10116', (158, 161))	('improves', 'PosReg', (47, 55))
119384	33154370	Variant_LeNet and variant_VGG9 predict the correct classes with almost equal success, but both fail to separate some classes, as shown in the confusion matrix in Supplementary Table 12.	('confusion', 'Phenotype', 'HP:0001289', (142, 151))	('variant_VGG9', 'Var', (18, 30))	('Variant_LeNet', 'Var', (0, 13))	('rat', 'Species', '10116', (107, 110))
119390	33154370	As shown in Table 3, Scenario A improves the classification accuracies considerably relative to learning from scratch and slightly relative to transfer learning, the best improvement is obtained for variant_LeNet.	('rat', 'Species', '10116', (112, 115))	('classification', 'MPA', (45, 59))	('improves', 'PosReg', (32, 40))	('variant_LeNet', 'Var', (199, 212))
119393	33154370	Similar improvements in accuracy are observed, except that the variant_VGG9 architecture outperforms other networks on the canine sarcoma dataset.	('variant_VGG9', 'Var', (63, 75))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('outperforms', 'PosReg', (89, 100))	('sarcoma', 'Disease', (130, 137))	('canine', 'Species', '9615', (123, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
119401	33154370	Transfer learning improves classification accuracy from 0.78 for training from scratch to 0.98 for the high-resolution dataset as shown in Table 4.	('improves', 'PosReg', (18, 26))	('classification', 'MPA', (27, 41))	('rat', 'Species', '10116', (81, 84))	('Transfer', 'Var', (0, 8))
119572	30416964	found muscle oedema in eight patients with metal-on-metal hips, but they did not analysis the reason for these conditions.	('patients', 'Species', '9606', (29, 37))	('muscle oedema', 'Disease', (6, 19))	('metal', 'Chemical', 'MESH:D008670', (52, 57))	('metal-on-metal', 'Var', (43, 57))	('oedema', 'Phenotype', 'HP:0000969', (13, 19))	('muscle oedema', 'Disease', 'MESH:D004487', (6, 19))	('metal', 'Chemical', 'MESH:D008670', (43, 48))
119629	30038741	Mutation analysis of GIST cases revealed mutation of KIT exon 11 in two patients, PDGFR exon 12 in one patient, PDGFR exon 18 in one patient, and one patient had no mutational analysis done.	('patient', 'Species', '9606', (150, 157))	('patient', 'Species', '9606', (133, 140))	('GIST', 'Phenotype', 'HP:0100723', (21, 25))	('PDGFR', 'Gene', (112, 117))	('PDGFR', 'Gene', (82, 87))	('mutation', 'Var', (41, 49))	('patient', 'Species', '9606', (72, 79))	('PDGFR', 'Gene', '5159', (82, 87))	('KIT exon 11', 'Gene', (53, 64))	('PDGFR', 'Gene', '5159', (112, 117))	('patient', 'Species', '9606', (103, 110))	('patients', 'Species', '9606', (72, 80))
119670	30038741	In the case of GIST, there is also evidence that CSF-1R mutation (D802V) results in alteration at the binding site leading to resistance to imatinib.	('CSF-1R', 'Gene', '1436', (49, 55))	('leading to', 'Reg', (115, 125))	('binding', 'Interaction', (102, 109))	('D802V', 'Var', (66, 71))	('alteration', 'Reg', (84, 94))	('D802V', 'Mutation', 'p.D802V', (66, 71))	('CSF-1R', 'Gene', (49, 55))	('resistance to imatinib', 'MPA', (126, 148))	('imatinib', 'Chemical', 'MESH:D000068877', (140, 148))	('GIST', 'Phenotype', 'HP:0100723', (15, 19))
119739	29533008	OS was 96.9 +- 3.1% versus 78.8 +- 9.5%, respectively, for patients with low GI and high GI (P = 0.06).	('OS', 'Chemical', '-', (0, 2))	('high GI', 'Var', (84, 91))	('patients', 'Species', '9606', (59, 67))	('low GI', 'Var', (73, 79))
119753	29533008	The hypothesis is that, in some tumors, the more rearranged a genome is, the higher the probability to obtain a gene expression profile permitting cells to disseminate and develop distant metastases.	('cells', 'CPA', (147, 152))	('tumors', 'Disease', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('metastases', 'Disease', (188, 198))	('rearranged', 'Var', (49, 59))	('metastases', 'Disease', 'MESH:D009362', (188, 198))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
119777	29100075	Genetic analysis of soft tissue sarcomas shows that they are characterized predominantly by copy number changes and offers insights into the immune microenviroment to inform clinical trials of checkpoint inhibitors.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (20, 40))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('copy number changes', 'Var', (92, 111))	('sarcomas', 'Disease', (32, 40))
119781	29100075	Sarcomas fall into two broad genetic groups: those with simple karyotypes harboring specific genetic alterations (translocations, activating mutations), and those with complex karyotypes.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('translocations', 'Var', (114, 128))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('fall', 'Phenotype', 'HP:0002527', (9, 13))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
119783	29100075	The sixth type was a simple-karyotype sarcoma, synovial sarcoma (SS), defined by the translocation t(X;18)(p11;q11).	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (99, 115))	('sarcoma', 'Disease', (38, 45))	('sarcoma', 'Disease', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('synovial sarcoma', 'Disease', (47, 63))	('t(X;18)(p11;q11', 'Var', (99, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (47, 63))	('synovial sarcoma', 'Disease', 'MESH:D013584', (47, 63))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))
119789	29100075	MDM2 amplification was present in all DDLPS by definition, and deep deletions (as defined in Methods) of TP53 were found in 9% of LMS, 16% of UPS, and 12% of MFS.	('found', 'Reg', (115, 120))	('deep deletions', 'Var', (63, 77))	('MDM2', 'Gene', '4193', (0, 4))	('TP53', 'Gene', '7157', (105, 109))	('MDM2', 'Gene', (0, 4))	('TP53', 'Gene', (105, 109))	('LMS', 'Disease', (130, 133))
119791	29100075	RB pathway alterations in DDLPS included CDK4 amplification in 86% and CDKN2A deep deletion in 2%.	('RB pathway', 'Pathway', (0, 10))	('CDKN2A', 'Gene', (71, 77))	('amplification', 'Var', (46, 59))	('deep deletion', 'Var', (78, 91))	('RB', 'Chemical', 'MESH:D012413', (0, 2))	('CDKN2A', 'Gene', '1029', (71, 77))	('CDK4', 'Gene', (41, 45))	('CDK4', 'Gene', '1019', (41, 45))	('alterations', 'Reg', (11, 22))
119794	29100075	Analyses for fusion transcripts identified either SS18-SSX1 or SS18-SSX2 fusions in all SS cases.	('fusions', 'Var', (73, 80))	('SSX2', 'Gene', '6757', (68, 72))	('SS18', 'Gene', (50, 54))	('SSX2', 'Gene', (68, 72))	('SS18', 'Gene', '6760', (63, 67))	('SSX1', 'Gene', '6756', (55, 59))	('SS18', 'Gene', '6760', (50, 54))	('SSX1', 'Gene', (55, 59))	('SS18', 'Gene', (63, 67))
119800	29100075	TP53 mutations were most prevalent in LMS (40 of 80).	('prevalent', 'Reg', (25, 34))	('LMS', 'Disease', (38, 41))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
119801	29100075	RB1 mutations were seen in LMS, UPS, and MFS.	('LMS', 'Disease', (27, 30))	('RB1', 'Gene', '5925', (0, 3))	('seen', 'Reg', (19, 23))	('UPS', 'Disease', (32, 35))	('mutations', 'Var', (4, 13))	('MFS', 'Disease', (41, 44))	('RB1', 'Gene', (0, 3))
119802	29100075	We surveyed known cancer genes for potential driver mutations and found that 138 sarcomas (67%) contained at least one variant in a gene known to be involved in cancer progression, though few of these were known cancer hotspots (Figure 2A).	('sarcomas', 'Disease', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('variant', 'Var', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('contained', 'Reg', (96, 105))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))	('cancer', 'Disease', (161, 167))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
119803	29100075	Potentially functional mutations included truncating mutations in NF1 (n=3), NF2 (1), and PRKDC (4), a gene involved in telomere stabilization and critical for double-strand break repair (Figure 2B).	('PRKDC', 'Gene', '5591', (90, 95))	('functional', 'Reg', (12, 22))	('PRKDC', 'Gene', (90, 95))	('truncating mutations', 'Var', (42, 62))	('NF1', 'Gene', (66, 69))	('NF2', 'Gene', (77, 80))	('NF1', 'Gene', '4763', (66, 69))	('NF2', 'Gene', '4771', (77, 80))
119804	29100075	As ATRX, TP53, and PRKDC mutations may disrupt telomere maintenance, we inferred telomere lengths from WES data using TelSeq.	('mutations', 'Var', (25, 34))	('telomere maintenance', 'CPA', (47, 67))	('PRKDC', 'Gene', '5591', (19, 24))	('ATRX', 'Gene', (3, 7))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('ATRX', 'Gene', '546', (3, 7))	('PRKDC', 'Gene', (19, 24))	('disrupt', 'NegReg', (39, 46))
119806	29100075	In UPS/MFS, long telomeres were associated with ATRX deletion or mutation (p=0.013), as recently reported.	('deletion', 'Var', (53, 61))	('ATRX', 'Gene', (48, 52))	('mutation', 'Var', (65, 73))	('associated', 'Reg', (32, 42))	('ATRX', 'Gene', '546', (48, 52))
119807	29100075	This process identified predominant signatures similar to COSMIC 1, 3, 5, and 13 (http://cancer.sanger.ac.uk/cosmic/signatures), with the exception of the two tumors with the highest mutational burden, in which the COSMIC6 mismatch repair signature predominated (Figure S2B), and which respectively showed frameshift mutation in MSH6 and low MSH2 expression (Figure S2C).	('MSH2', 'Gene', (342, 346))	('frameshift mutation', 'Var', (306, 325))	('MSH6', 'Gene', '2956', (329, 333))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('MSH2', 'Gene', '4436', (342, 346))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('expression', 'MPA', (347, 357))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (89, 95))	('MSH6', 'Gene', (329, 333))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('low', 'NegReg', (338, 341))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
119809	29100075	Thus, sarcomas have a low mutation burden, and the mutations present in some sarcomas predominately reflect age-related C>T mutations at CpG dinucleotides, and thus likely represent passenger mutations.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('mutations', 'Var', (51, 60))	('sarcomas', 'Disease', (77, 85))	('C>T mutations', 'Var', (120, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcomas', 'Disease', (6, 14))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('sarcomas', 'Disease', 'MESH:D012509', (6, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))
119823	29100075	Our 50 DDLPS were defined by 12q13~15 amplifications, including highly recurrent copy number gains or amplification of MDM2 (100% of our samples), CDK4 (92%), and HMGA2 (76%), as previously reported as well as FRS2 (96%) and NAV3 (60%).	('gains', 'PosReg', (93, 98))	('FRS2', 'Gene', (210, 214))	('HMGA2', 'Gene', (163, 168))	('NAV3', 'Gene', '89795', (225, 229))	('copy number', 'Var', (81, 92))	('amplification', 'MPA', (102, 115))	('MDM2', 'Gene', '4193', (119, 123))	('MDM2', 'Gene', (119, 123))	('FRS2', 'Gene', '10818', (210, 214))	('NAV3', 'Gene', (225, 229))	('CDK4', 'Gene', (147, 151))	('HMGA2', 'Gene', '8091', (163, 168))	('CDK4', 'Gene', '1019', (147, 151))
119825	29100075	PTPRQ amplification tended to be mutually exclusive with JUN amplification (p=0.026), with only 1 tumor (2%) having amplification of both genes (Figure 4B).	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('amplification', 'Var', (6, 19))	('PTPRQ', 'Gene', '374462', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('PTPRQ', 'Gene', (0, 5))
119826	29100075	Recurrent deletions (Figure 4A) included ATRX (10% deep; 20% shallow), NF1 (6% deep; 22% shallow), and CDKN2A (2% deep; 42% shallow).	('ATRX', 'Gene', (41, 45))	('NF1', 'Gene', (71, 74))	('NF1', 'Gene', '4763', (71, 74))	('deletions', 'Var', (10, 19))	('ATRX', 'Gene', '546', (41, 45))	('CDKN2A', 'Gene', (103, 109))	('CDKN2A', 'Gene', '1029', (103, 109))
119827	29100075	Given that ATRX may be required for response to CDK4 inhibitors and 30% of DDLPS have ATRX deletions, ATRX alterations may represent an important correlative biomarker in future clinical trials of CDK4 inhibitors in DDLPS.	('ATRX', 'Gene', '546', (86, 90))	('CDK4', 'Gene', '1019', (48, 52))	('ATRX', 'Gene', (102, 106))	('deletions', 'Var', (91, 100))	('ATRX', 'Gene', '546', (102, 106))	('CDK4', 'Gene', '1019', (197, 201))	('ATRX', 'Gene', (11, 15))	('CDK4', 'Gene', (197, 201))	('DDLPS', 'Disease', (75, 80))	('ATRX', 'Gene', (86, 90))	('ATRX', 'Gene', '546', (11, 15))	('CDK4', 'Gene', (48, 52))
119829	29100075	The JUN amplification in K1 could contribute to the group's poor prognosis, given that JUN overexpression in DDLPS increases migration and invasion and that JUN inhibits adipocyte differentiation via repression of CEBPbeta.	('repression', 'NegReg', (200, 210))	('invasion', 'CPA', (139, 147))	('overexpression', 'PosReg', (91, 105))	('adipocyte', 'MPA', (170, 179))	('CEBPbeta', 'Gene', (214, 222))	('JUN', 'Var', (157, 160))	('migration', 'CPA', (125, 134))	('increases', 'PosReg', (115, 124))	('CEBPbeta', 'Gene', '1051', (214, 222))	('JUN', 'MPA', (87, 90))	('inhibits', 'NegReg', (161, 169))
119830	29100075	Unsupervised consensus clustering of DNA methylation data defined two clusters: hypomethylated (Meth1) and hypermethylated (Meth2) (Figure 4C).	('hypomethylated', 'Var', (80, 94))	('Meth2', 'Gene', (124, 129))	('Meth1', 'Gene', '9510', (96, 101))	('Meth2', 'Gene', '11095', (124, 129))	('Meth1', 'Gene', (96, 101))	('hypermethylated', 'Var', (107, 122))
119837	29100075	We found deletions of the tumor suppressors TP53 (9% deep and 60% shallow deletions), RB1 (14% deep, 78% shallow), and PTEN (13% deep, 68% shallow) (Figure 5A) and mutations of TP53 in 50%, RB1 in 15%, and PTEN in 5% of samples (Figure 5B).	('RB1', 'Gene', (86, 89))	('TP53', 'Gene', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('RB1', 'Gene', '5925', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('RB1', 'Gene', (190, 193))	('PTEN', 'Gene', (119, 123))	('tumor', 'Disease', (26, 31))	('TP53', 'Gene', '7157', (44, 48))	('PTEN', 'Gene', '5728', (119, 123))	('PTEN', 'Gene', '5728', (206, 210))	('TP53', 'Gene', '7157', (177, 181))	('RB1', 'Gene', '5925', (190, 193))	('deletions', 'Var', (9, 18))	('PTEN', 'Gene', (206, 210))	('mutations', 'Var', (164, 173))	('TP53', 'Gene', (44, 48))
119843	29100075	Despite their overall similarity and lack of discriminatory SCNAs, ULMS and STLMS had significantly different methylation and mRNA expression signatures, with ULMS showing a higher DNA damage response score (p=0.005), and hypomethylation of ESR1 target genes, while STLMS had a more prominent HIF1alpha signaling signature (p=6e-05) (Figure S6A, C).	('HIF1alpha', 'Gene', '3091', (293, 302))	('hypomethylation', 'Var', (222, 237))	('DNA damage response score', 'MPA', (181, 206))	('methylation', 'MPA', (110, 121))	('ESR1', 'Gene', (241, 245))	('higher', 'PosReg', (174, 180))	('mRNA expression', 'MPA', (126, 141))	('HIF1alpha', 'Gene', (293, 302))	('ESR1', 'Gene', '2099', (241, 245))
119847	29100075	C1 also showed more frequent mutations of RB1 (p=0.04) and amplification of 17p11.2-p12 (q=0.022; Figure S6D), a known alteration in LMS that notably includes MYOCD, encoding myocardin, a transcription factor involved in smooth muscle differentiation.	('RB1', 'Gene', (42, 45))	('p11', 'Gene', (78, 81))	('mutations', 'Var', (29, 38))	('MYOCD', 'Gene', (159, 164))	('p12', 'Gene', '56655', (84, 87))	('RB1', 'Gene', '5925', (42, 45))	('myocardin', 'Gene', '93649', (175, 184))	('p11', 'Gene', '6281', (78, 81))	('MYOCD', 'Gene', '93649', (159, 164))	('amplification', 'Var', (59, 72))	('myocardin', 'Gene', (175, 184))	('p12', 'Gene', (84, 87))
119849	29100075	Both the STLMS C1 cluster and ULMS were enriched for PTEN deletion, mutation, or downregulation and for amplification or overexpression of AKT pathway members.	('overexpression', 'PosReg', (121, 135))	('AKT', 'Gene', '207', (139, 142))	('mutation', 'Var', (68, 76))	('downregulation', 'NegReg', (81, 95))	('AKT', 'Gene', (139, 142))	('PTEN', 'Gene', (53, 57))	('deletion', 'Var', (58, 66))	('PTEN', 'Gene', '5728', (53, 57))
119852	29100075	In LMS as a whole, aberrant PI3K-AKT-MTOR signaling may be crucial, given recurrent deletion/mutation of PTEN along with frequent amplification and upregulation of IGF1R, AKT, RICTOR, and MTOR (Figure 5E) and high AKT pathway scores by RPPA.	('deletion/mutation', 'Var', (84, 101))	('upregulation', 'PosReg', (148, 160))	('RICTOR', 'Gene', '253260', (176, 182))	('AKT', 'Gene', (33, 36))	('PTEN', 'Gene', (105, 109))	('AKT', 'Gene', '207', (214, 217))	('MTOR', 'Gene', (37, 41))	('MTOR', 'Gene', (188, 192))	('PTEN', 'Gene', '5728', (105, 109))	('AKT', 'Gene', '207', (33, 36))	('AKT', 'Gene', '207', (171, 174))	('MTOR', 'Gene', '2475', (37, 41))	('IGF1R', 'Gene', (164, 169))	('MTOR', 'Gene', '2475', (188, 192))	('IGF1R', 'Gene', '3480', (164, 169))	('AKT', 'Gene', (214, 217))	('RICTOR', 'Gene', (176, 182))	('AKT', 'Gene', (171, 174))
119860	29100075	Copy number gains of VGLL3 and YAP1 correlated with gene expression (not shown), and a YAP1/VGLL3 target gene signature was strongly expressed in UPS/MFS (p=1e-24; Figure 6D).	('YAP1', 'Gene', (87, 91))	('YAP1', 'Gene', '10413', (87, 91))	('gains', 'PosReg', (12, 17))	('YAP1', 'Gene', (31, 35))	('VGLL3', 'Gene', (92, 97))	('VGLL3', 'Gene', '389136', (21, 26))	('VGLL3', 'Gene', '389136', (92, 97))	('YAP1', 'Gene', '10413', (31, 35))	('Copy number', 'Var', (0, 11))	('gene expression', 'MPA', (52, 67))	('VGLL3', 'Gene', (21, 26))
119878	29100075	Salient differences include MDM2, CDK4, JUN, and TERT amplifications in DDLPS; MYOCD amplification, PTEN mutations/deletions, and AKT, IGF1R, and MTOR pathway activation in LMS; and VGLL3 amplification and Hippo pathway activation in UPS/MFS.	('PTEN', 'Gene', (100, 104))	('mutations/deletions', 'Var', (105, 124))	('MTOR', 'Gene', (146, 150))	('DDLPS', 'Disease', (72, 77))	('MTOR', 'Gene', '2475', (146, 150))	('VGLL3', 'Gene', '389136', (182, 187))	('AKT', 'Gene', '207', (130, 133))	('amplification', 'Var', (85, 98))	('MDM2', 'Gene', (28, 32))	('IGF1R', 'Gene', '3480', (135, 140))	('VGLL3', 'Gene', (182, 187))	('PTEN', 'Gene', '5728', (100, 104))	('MYOCD', 'Gene', '93649', (79, 84))	('MDM2', 'Gene', '4193', (28, 32))	('CDK4', 'Gene', (34, 38))	('IGF1R', 'Gene', (135, 140))	('amplifications', 'Var', (54, 68))	('MYOCD', 'Gene', (79, 84))	('activation', 'PosReg', (159, 169))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('CDK4', 'Gene', '1019', (34, 38))	('AKT', 'Gene', (130, 133))	('JUN', 'Gene', (40, 43))	('Hippo pathway', 'Pathway', (206, 219))	('activation', 'PosReg', (220, 230))
119879	29100075	Across the sarcoma types (though less so in DDLPS), deletions were more prominent than amplifications, and relevant mutations in tumor suppressors substantially more frequent than those in oncogenes.	('frequent', 'Reg', (166, 174))	('sarcoma type', 'Disease', (11, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutations', 'Var', (116, 125))	('deletions', 'Var', (52, 61))	('tumor', 'Disease', (129, 134))	('sarcoma type', 'Disease', 'MESH:D012509', (11, 23))
119927	29100075	Significant focal copy number alterations across all sarcomas and within each sarcoma type were identified from ISAR-corrected segmented data using GISTIC 2.0.22.	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcoma type', 'Disease', 'MESH:D012509', (78, 90))	('copy number alterations', 'Var', (18, 41))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcoma type', 'Disease', (78, 90))	('sarcomas', 'Disease', (53, 61))
119930	29100075	To validate these definitions, we compared GISTIC 2.0 calls of shallow or deep deletion or other copy number status for CDKN2A and NF1 with manually curated ABSOLUTE calls for homozygous or heterozygous deletion or other copy number status.	('NF1', 'Gene', (131, 134))	('NF1', 'Gene', '4763', (131, 134))	('deep deletion', 'Var', (74, 87))	('CDKN2A', 'Gene', (120, 126))	('CDKN2A', 'Gene', '1029', (120, 126))	('shallow', 'Var', (63, 70))
119932	29100075	The copy number alteration (more specifically deletion) of ATRX was assessed independently using two methods, SNP6.0 arrays (see SNP-based copy number analysis, above) and VarScan 2.	('ATRX', 'Gene', (59, 63))	('deletion', 'Var', (46, 54))	('ATRX', 'Gene', '546', (59, 63))
119934	29100075	A sample was considered to have copy number deletion in ATRX when the outputs from both methods gave <1.79 in the locus or part of the locus and when GISTIC2.0 indicated a deletion status.	('copy number deletion', 'Var', (32, 52))	('ATRX', 'Gene', (56, 60))	('ATRX', 'Gene', '546', (56, 60))
119951	29100075	They had no support in the normal data More reads were reported by Pindel than reported by Samtools at the indel position or if the number of supporting reads from Pindel was >= 8% of the total depth at the position reported by Samtools Samtools reported a depth less than 10 at the region and Pindel reported more indel supporting reads than reads mapped with gaps at the site of the call A Fisher's exact test p-value <= 0.15 was returned when comparing the normal to the tumor in number of reads with gapped alignments versus reads without.	('tumor', 'Disease', (474, 479))	('Samtools', 'Chemical', '-', (237, 245))	('Samtools', 'Chemical', '-', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (474, 479))	('Samtools', 'Chemical', '-', (228, 236))	('gapped', 'Var', (504, 510))	('tumor', 'Phenotype', 'HP:0002664', (474, 479))
119963	29100075	Due to the smaller sample sizes per cohort and the lower mutation frequency of somatic point mutations and indels in sarcoma, we expanded our analysis to identify additional mutations in putative cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('sarcoma', 'Disease', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('point mutations', 'Var', (87, 102))	('indels', 'Var', (107, 113))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))
119964	29100075	A collection of 624 cancer genes was used to identify possible driver mutations in individual cases.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))
119967	29100075	The association of ATRX and TP53 mutations/deletions with telomere length of different sarcoma subtypes was assessed with Student's T-tests.	('TP53', 'Gene', '7157', (28, 32))	('ATRX', 'Gene', '546', (19, 23))	('mutations/deletions', 'Var', (33, 52))	('sarcoma', 'Disease', (87, 94))	('TP53', 'Gene', (28, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('ATRX', 'Gene', (19, 23))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
119968	29100075	Variables included in the multiple regression analysis were: ATRX mutation/deletion status, TP53 mutation status, and expression levels of ATRX, TP53, HNRNPC, APEX1, NPM1, RPS17, and SEC11C.	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (92, 96))	('NPM1', 'Gene', (166, 170))	('SEC11C', 'Gene', (183, 189))	('ATRX', 'Gene', (61, 65))	('ATRX', 'Gene', '546', (61, 65))	('expression levels', 'MPA', (118, 135))	('HNRNPC', 'Gene', '3183', (151, 157))	('SEC11C', 'Gene', '90701', (183, 189))	('mutation', 'Var', (97, 105))	('ATRX', 'Gene', (139, 143))	('RPS17', 'Gene', '6218', (172, 177))	('mutation/deletion', 'Var', (66, 83))	('ATRX', 'Gene', '546', (139, 143))	('APEX1', 'Gene', (159, 164))	('TP53', 'Gene', (145, 149))	('TP53', 'Gene', '7157', (92, 96))	('NPM1', 'Gene', '4869', (166, 170))	('HNRNPC', 'Gene', (151, 157))	('APEX1', 'Gene', '328', (159, 164))	('RPS17', 'Gene', (172, 177))
119971	29100075	De-novo signature discovery in both WES and WGS samples identified four major mutational processes: COSMIC1, spontaneous cytosine deamination; COSMIC5, unknown etiology; COSMIC6, microsatellite instability (MSI); and COSMIC2/13, APOBEC.	('COSMIC1', 'Var', (100, 107))	('cytosine', 'Chemical', 'MESH:D003596', (121, 129))	('COSMIC5', 'Var', (143, 150))	('microsatellite instability', 'MPA', (179, 205))	('COSMIC6', 'Var', (170, 177))	('spontaneous cytosine deamination', 'MPA', (109, 141))
119982	29100075	Percent myxoid component (described above in Pathology Review) was used to group UPS and MFS samples into three classes: no myxoid stroma (class 0), 1-49% myxoid stroma (class 1), or 50-100% myxoid stroma (class 2).	('1-49%', 'Var', (149, 154))	('myxoid stroma', 'Disease', (124, 137))	('myxoid stroma', 'Disease', (155, 168))	('myxoid stroma', 'Disease', 'MESH:D045888', (124, 137))	('myxoid stroma', 'Disease', (191, 204))	('myxoid stroma', 'Disease', 'MESH:D045888', (155, 168))	('myxoid stroma', 'Disease', 'MESH:D045888', (191, 204))
119984	29100075	HIF1alpha a target gene expression signature in LMS was calculated as the negative mean expression of genes down-regulated by HIF1A knockdown minus the mean expression of genes up-regulated by HIF1A knockdown.	('HIF1A', 'Gene', (193, 198))	('HIF1A', 'Gene', '3091', (193, 198))	('HIF1A', 'Gene', (126, 131))	('expression', 'MPA', (157, 167))	('HIF1alpha', 'Gene', (0, 9))	('knockdown', 'Var', (132, 141))	('HIF1A', 'Gene', '3091', (126, 131))	('HIF1alpha', 'Gene', '3091', (0, 9))	('up-regulated', 'PosReg', (177, 189))	('down-regulated', 'NegReg', (108, 122))	('expression', 'MPA', (88, 98))
120005	29100075	After passing quality control, bisulfite-converted DNA samples were whole-genome amplified, fragmented enzymatically, hybridized overnight to BeadChips, then subjected to locus-specific base extension with labeled nucleotides (Cy3 and Cy5).	('Cy5', 'Var', (235, 238))	('Cy3', 'Var', (227, 230))	('bisulfite', 'Chemical', 'MESH:C042345', (31, 40))
120015	29100075	To illustrate the role of cell signaling networks in sarcoma, we calculated twelve pathway and process scores (apoptosis, cell cycle, DNA damage response, EMT, hormone receptor, hormone signaling (breast), P13K/AKT, RAS/MAPK, RTK, TSC/MTOR, breast reactive and core reactive) based on a previously described method (Figure S4D).	('RAS/MAPK', 'Gene', (216, 224))	('P13K', 'Var', (206, 210))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('MTOR', 'Gene', (235, 239))	('EMT', 'Gene', (155, 158))	('DNA', 'MPA', (134, 137))	('EMT', 'Gene', '3702', (155, 158))	('sarcoma', 'Disease', (53, 60))	('hormone receptor', 'Gene', (160, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('P13K', 'SUBSTITUTION', 'None', (206, 210))	('MTOR', 'Gene', '2475', (235, 239))	('hormone receptor', 'Gene', '3164', (160, 176))
120023	29100075	Primary analyses were automatically performed for every data type of every cohort, such as: significance assessment of mutations with MutSig and copy number alterations with GISTIC; functional analysis with Mutation Assessor; analysis of mutagenesis by APOBEC cytidine deaminases; miR, mRNA, and protein expression cluster assignments using both consensus hierarchical and consensus NMF methods; and pathway analyses with PARADIGM and GSEA.	('miR', 'Gene', (281, 284))	('mutations', 'Var', (119, 128))	('GSEA', 'Chemical', '-', (435, 439))	('miR', 'Gene', '220972', (281, 284))
120052	24599718	Comprehensive molecular characterization of hemangiosarcoma may identify novel therapeutic targets and advanced clinical management strategies, but there are no published reports of tumor-associated genome instability and disrupted gene dosage in this cancer.	('disrupted gene dosage', 'Var', (222, 243))	('angiosarcoma', 'Phenotype', 'HP:0200058', (47, 59))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('tumor', 'Disease', (182, 187))	('hemangiosarcoma', 'Disease', (44, 59))	('cancer', 'Disease', (252, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
120056	24599718	Copy number gains of dog chromosomes 13, 24 and 31, and loss of chromosome 16, were the most recurrent CNAs involving large chromosome regions, but their relative distribution within and between cases suggests they most likely represent passenger aberrations.	('dog', 'Species', '9615', (21, 24))	('Copy number gains', 'Var', (0, 17))	('loss', 'NegReg', (56, 60))
120069	24599718	Prior studies have described tumor-associated disruption of global transcriptional profiles in canine hemangiosarcoma, and gene-inactivating sequence mutations of key pathways associated with angiogenesis.	('gene-inactivating sequence mutations', 'Var', (123, 159))	('global transcriptional profiles', 'MPA', (60, 91))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('hemangiosarcoma', 'Disease', (102, 117))	('disruption', 'Reg', (46, 56))	('canine', 'Species', '9615', (95, 101))	('tumor', 'Disease', (29, 34))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (102, 117))	('angiosarcoma', 'Phenotype', 'HP:0200058', (105, 117))	('key pathways', 'Pathway', (163, 175))
120070	24599718	To date, however, there remains no published knowledge of global somatic genome instability in the form of gene dosage imbalance in this cancer as a potential mechanism for transcriptional dysregulation.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gene dosage imbalance', 'Var', (107, 128))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('imbalance', 'Phenotype', 'HP:0002172', (119, 128))
120083	24599718	Recurrent CNAs within each tumor were defined using the FASST2 segmentation algorithm in Nexus Copy Number, based on a minimum of three consecutive probes with log2 tumor:reference values >= 0.201 (copy number gain) or <= -0.234 (copy number loss), resulting in an effective resolution of ~26kb (two intervals of ~13kb).	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('copy number', 'Var', (198, 209))	('tumor', 'Disease', (27, 32))	('gain', 'PosReg', (210, 214))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('<= -0.234', 'Var', (219, 228))	('tumor', 'Disease', (165, 170))
120089	24599718	Cases exhibiting discrete high level amplifications of the vascular endothelial growth factor A gene (VEGFA) in oaCGH were evaluated further by targeted fluorescence in situ hybridization (FISH) analysis.	('oaCGH', 'Chemical', '-', (112, 117))	('oaCGH', 'Disease', (112, 117))	('VEGFA', 'Gene', (102, 107))	('amplifications', 'Var', (37, 51))
120090	24599718	FISH analysis was performed using bacterial artificial chromosome (BAC) clones from the CHORI-82 canine BAC library (http://bacpac.chori.org, BACPAC Resources, Children's Hospital Oakland Research Institute, Oakland, CA), containing the full coding sequence of the VEGFA gene (clone 152L05) and associated receptor (VEGFR2/KDR, clone 34E11).	('clone', 'Var', (277, 282))	('VEGFR2/KDR', 'Gene', (316, 326))	('canine', 'Species', '9615', (97, 103))	('VEGFA gene', 'Gene', (265, 275))	('Children', 'Species', '9606', (160, 168))
120099	24599718	The most physical extensive CNAs present in >= 20% of the cohort were copy number gain along the full length of dog chromosomes 13 (CFA13), 24 and 31, and loss of CFA16 (Figure 1a).	('CFA16', 'Gene', (163, 168))	('CFA', 'Chemical', '-', (132, 135))	('CFA', 'Chemical', '-', (163, 166))	('loss', 'Var', (155, 159))	('dog', 'Species', '9615', (112, 115))	('CFA13', 'Gene', (132, 137))	('copy number', 'Var', (70, 81))	('gain', 'PosReg', (82, 86))
120104	24599718	A distinct peak of recurrent gain was evident on CFA12q13, corresponding to increased copy number of the vascular endothelial growth factor gene VEGFA (CFA12q13:15.2Mb) in 29% of cases, of which four cases (5% of the cohort) were consistent with a high level amplification.	('CFA', 'Chemical', '-', (49, 52))	('increased', 'PosReg', (76, 85))	('CFA', 'Chemical', '-', (152, 155))	('copy', 'MPA', (86, 90))	('CFA12q13', 'Var', (49, 57))	('gain', 'PosReg', (29, 33))
120105	24599718	oaCGH detected deletion of the CDKN2A/B tumor suppressor gene region (CFA11q16:44.3Mb) in 28% of cases, while the CDKN2A interacting protein gene CDKN2AIP (CFA16q24:49.9) was deleted in 20% of cases.	('CDKN2AIP', 'Gene', '607991', (146, 154))	('CDKN2A/B', 'Gene', (31, 39))	('CDKN2A interacting protein', 'Gene', '607991', (114, 140))	('CFA', 'Chemical', '-', (70, 73))	('deletion', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CFA', 'Chemical', '-', (156, 159))	('CDKN2AIP', 'Gene', (146, 154))	('oaCGH', 'Chemical', '-', (0, 5))	('CDKN2A/B', 'Gene', '100271861;481563', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('CDKN2A interacting protein', 'Gene', (114, 140))
120106	24599718	CNAs of other well-described tumor associated genes including PDGFRB (CFA4q32), TP53 (CFA5q22), MYC (CFA13q13) and PTEN (CFA26q25) were not recurrent, occurring with < 20% penetrance within the cohort.	('PDGFRB', 'Gene', (62, 68))	('CFA5q22', 'Var', (86, 93))	('CFA13q13', 'Var', (101, 109))	('CFA', 'Chemical', '-', (70, 73))	('PTEN', 'Gene', (115, 119))	('PDGFRB', 'Gene', '442985', (62, 68))	('CFA', 'Chemical', '-', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('TP53', 'Gene', '403869', (80, 84))	('CFA', 'Chemical', '-', (101, 104))	('TP53', 'Gene', (80, 84))	('PTEN', 'Gene', '403832', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('MYC', 'Disease', (96, 99))	('CFA', 'Chemical', '-', (86, 89))
120107	24599718	These data were interrogated further using GISTIC analysis to distinguish CNAs containing candidate genes as potential drivers of tumor pathogenesis from the background of generalized 'passenger' aberrations occurring at random.	('CNAs', 'Var', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))
120110	24599718	The second most significant (G-score = 13.6, Q-bound score = 2.44x10-5) was deletion of a region on CFA11q16:44,3Mb that contains the MTAP, CDKN2A and CDKN2B loci, with the peak of significance localized at the CDKN2A locus.	('CDKN2A', 'Gene', '100271861', (211, 217))	('deletion', 'Var', (76, 84))	('CDKN2A', 'Gene', (211, 217))	('CDKN2A', 'Gene', '100271861', (140, 146))	('CDKN2A', 'Gene', (140, 146))	('MTAP', 'Gene', '474729', (134, 138))	('MTAP', 'Gene', (134, 138))	('CDKN2B', 'Gene', (151, 157))	('CDKN2B', 'Gene', '481563', (151, 157))	('CFA', 'Chemical', '-', (100, 103))
120111	24599718	Also of note was a significant peak of gain on CFA5q32:60Mb (G-score = 10.9, Q-bound score = 1.48x10-5), detected in 21% of cases, which coincides with the SKI gene (v-ski sarcoma viral oncogene homolog).	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('v-ski sarcoma viral oncogene homolog', 'Gene', (166, 202))	('v-ski sarcoma viral oncogene homolog', 'Gene', '489610', (166, 202))	('CFA5q32:60Mb', 'Var', (47, 59))	('CFA', 'Chemical', '-', (47, 50))	('gain', 'PosReg', (39, 43))
120112	24599718	The combination of their penetrance in the population, accompanied by their significantly non-random relative distribution and amplitude and their biological function, supports the intimate association of disrupted dosage of VEGFA, CDKN2A and SKI genes with the disease phenotype.	('CDKN2A', 'Gene', '100271861', (232, 238))	('CDKN2A', 'Gene', (232, 238))	('VEGFA', 'Gene', (225, 230))	('SKI', 'Gene', (243, 246))	('disrupted dosage', 'Var', (205, 221))
120114	24599718	The VEGFA probe frequently showed clusters of intense fluorescent signal suggestive of tandem duplication, while the VEGFR2/KDR probe showed only modest increase in copy number in cases showing gain of this region in oaCGH (Figure 2).	('intense fluorescent signal', 'MPA', (46, 72))	('gain', 'PosReg', (194, 198))	('oaCGH', 'Chemical', '-', (217, 222))	('tandem duplication', 'Var', (87, 105))
120117	24599718	The relative distribution of these CNAs showed subregional variation; for example, GRs exhibited recurrent deletion along the full length of CFA16, while in other breeds this was restricted primarily to the distal 75% of this chromosome.	('deletion', 'Var', (107, 115))	('CFA16', 'Gene', (141, 146))	('CFA', 'Chemical', '-', (141, 144))
120122	24599718	Figure 3a shows, however, that the incidence of CFA31 gain was significantly elevated in GRs within the region spanning CFA31q11-q15.1 (4.3-28.4Mb), reaching a maximum of 45% of GRs versus 20% of other breeds.	('CFA31', 'Chemical', '-', (48, 53))	('CFA31 gain', 'Gene', (48, 58))	('CFA31q11-q15.1', 'Var', (120, 134))	('elevated', 'PosReg', (77, 85))	('CFA31', 'Chemical', '-', (120, 125))
120123	24599718	An additional cluster of significant regions reflected the increased incidence of deletion on CFA16qprox in GRs versus other breeds.	('CFA16qprox', 'Gene', (94, 104))	('CFA16qprox', 'Chemical', '-', (94, 104))	('deletion', 'Var', (82, 90))
120127	24599718	Partial deletion of the distal half of CFA16 (including the CDKN2A-interacting protein CDKN2AIP), and gain of CFA31qdist (including the transcription factor gene RUNX1) and subregions of CFA13 (including KIT, KDR and PDGFRA), were also significantly elevated in this breed.	('RUNX1', 'Gene', '487746', (162, 167))	('CDKN2A', 'Gene', (60, 66))	('CDKN2A', 'Gene', '100271861', (87, 93))	('RUNX1', 'Gene', (162, 167))	('CFA16', 'Gene', (39, 44))	('elevated', 'PosReg', (250, 258))	('CDKN2AIP', 'Gene', (87, 95))	('PDGFRA', 'Gene', '442860', (217, 223))	('PDGFRA', 'Gene', (217, 223))	('CFA31qdist', 'Gene', (110, 120))	('Partial deletion', 'Var', (0, 16))	('CDKN2A', 'Gene', '100271861', (60, 66))	('CFA', 'Chemical', '-', (110, 113))	('CFA31', 'Chemical', '-', (110, 115))	('CFA', 'Chemical', '-', (39, 42))	('gain', 'PosReg', (102, 106))	('CDKN2A', 'Gene', (87, 93))	('CFA', 'Chemical', '-', (187, 190))	('CDKN2AIP', 'Gene', '607991', (87, 95))
120129	24599718	The incidence of PDGFA gain was also significantly elevated in the GSD, along with subregional gain along CFA6qprox and CFA20qdist, and partial deletions of CFA7 and 38.	('CFA', 'Chemical', '-', (106, 109))	('partial deletions', 'Var', (136, 153))	('CFA7 and', 'Gene', (157, 165))	('PDGFA', 'Gene', (17, 22))	('CFA20qdist', 'Var', (120, 130))	('elevated', 'PosReg', (51, 59))	('gain', 'PosReg', (23, 27))	('GSD', 'Disease', 'MESH:D016098', (67, 70))	('CFA', 'Chemical', '-', (120, 123))	('GSD', 'Disease', (67, 70))	('PDGFA', 'Gene', '491597', (17, 22))	('CFA', 'Chemical', '-', (157, 160))
120131	24599718	While BMD cases also showed significantly elevated CFA12qprox gain, this region was located ~4Mb proximal to the VEGFA locus; however these cases showed a significant association with deletion of CFA5qprox and gain of CFA36qdist.	('CFA', 'Chemical', '-', (51, 54))	('gain', 'PosReg', (62, 66))	('deletion', 'Var', (184, 192))	('gain', 'PosReg', (210, 214))	('CFA36qdist', 'Gene', (218, 228))	('CFA5qprox', 'Gene', (196, 205))	('CFA', 'Chemical', '-', (218, 221))	('CFA', 'Chemical', '-', (196, 199))	('CFA12qprox', 'MPA', (51, 61))
120138	24599718	Increased copy number of CFA13 is recurrent in a diverse range of canine cancers, including non-Hodgkin's lymphoma, appendicular osteosarcoma, leukemia, glioma and histiocytic sarcoma .	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('CFA13', 'Gene', (25, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('lymphoma', 'Phenotype', 'HP:0002665', (106, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('canine', 'Species', '9615', (66, 72))	('CFA', 'Chemical', '-', (25, 28))	('cancers', 'Disease', (73, 80))	('leukemia', 'Disease', 'MESH:D007938', (143, 151))	('glioma', 'Disease', (153, 159))	('leukemia', 'Disease', (143, 151))	('appendicular osteosarcoma', 'Disease', (116, 141))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (92, 114))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('appendicular osteosarcoma', 'Disease', 'MESH:D012516', (116, 141))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (92, 114))	('histiocytic sarcoma', 'Disease', (164, 183))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('Increased copy number', 'Var', (0, 21))	("non-Hodgkin's lymphoma", 'Disease', (92, 114))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (96, 114))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (164, 183))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))
120143	24599718	GISTIC analysis revealed a significant peak of deletion in hemangiosarcoma on CFA11q16 encompassing CDKN2A/B and MTAP, with maximum significance coinciding with the CDKN2A gene, highlighting this locus as a potential driver of tumor development.	('CDKN2A/B', 'Gene', (100, 108))	('tumor', 'Disease', (227, 232))	('MTAP', 'Gene', '474729', (113, 117))	('MTAP', 'Gene', (113, 117))	('angiosarcoma', 'Phenotype', 'HP:0200058', (62, 74))	('CDKN2A', 'Gene', '100271861', (165, 171))	('CDKN2A', 'Gene', (165, 171))	('deletion', 'Var', (47, 55))	('CDKN2A', 'Gene', '100271861', (100, 106))	('CDKN2A/B', 'Gene', '100271861;481563', (100, 108))	('CDKN2A', 'Gene', (100, 106))	('hemangiosarcoma', 'Disease', (59, 74))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('CFA', 'Chemical', '-', (78, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (59, 74))
120144	24599718	Several additional dog cancers with recurrent CFA11 deletion also show a focal peak in penetrance at CFA11q16, similarly indicative of a fundamental role for this locus in tumor pathogenesis (for example, T-cell non-Hodgkins lymphoma, appendicular osteosarcoma and histiocytic sarcoma.	('lymphoma', 'Phenotype', 'HP:0002665', (225, 233))	('CFA11', 'Gene', (46, 51))	('tumor', 'Disease', (172, 177))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('osteosarcoma', 'Phenotype', 'HP:0002669', (248, 260))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (265, 284))	('appendicular osteosarcoma', 'Disease', (235, 260))	('appendicular osteosarcoma', 'Disease', 'MESH:D012516', (235, 260))	('non-Hodgkins lymphoma', 'Phenotype', 'HP:0012539', (212, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('CFA', 'Chemical', '-', (46, 49))	('dog', 'Species', '9615', (19, 22))	('Hodgkins lymphoma', 'Disease', 'MESH:D006689', (216, 233))	('Hodgkins lymphoma', 'Phenotype', 'HP:0012189', (216, 233))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('deletion', 'Var', (52, 60))	('CFA11q16', 'Var', (101, 109))	('Hodgkins lymphoma', 'Disease', (216, 233))	('histiocytic sarcoma', 'Disease', (265, 284))	('CFA', 'Chemical', '-', (101, 104))
120146	24599718	Interestingly the MTAP and CDKN2A/B region at CFA11q16 lies within the major germline risk haplotype for histiocytic sarcoma in the BMD.	('CDKN2A/B', 'Gene', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (105, 124))	('CFA', 'Chemical', '-', (46, 49))	('CDKN2A/B', 'Gene', '100271861;481563', (27, 35))	('histiocytic sarcoma', 'Disease', (105, 124))	('MTAP', 'Gene', '474729', (18, 22))	('MTAP', 'Gene', (18, 22))	('CFA11q16', 'Var', (46, 54))
120149	24599718	Interestingly, however, despite recurrent deletion of the CFA11q16 locus in hemangiosarcoma (28% of all cases, and 30% of all GRs), a recent genome-wide association study of germline risk factors in the GR shows no significant overlap with somatic CNA.	('hemangiosarcoma', 'Disease', 'MESH:D006394', (76, 91))	('CFA11q16', 'Gene', (58, 66))	('angiosarcoma', 'Phenotype', 'HP:0200058', (79, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('hemangiosarcoma', 'Disease', (76, 91))	('deletion', 'Var', (42, 50))	('CFA', 'Chemical', '-', (58, 61))
120150	24599718	Although 21/75 hemangiosarcoma cases exhibited deletion of the CDKN2A/B region, only two cases were consistent with homozygous deletion.	('hemangiosarcoma', 'Disease', (15, 30))	('CDKN2A/B', 'Gene', (63, 71))	('angiosarcoma', 'Phenotype', 'HP:0200058', (18, 30))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (15, 30))	('exhibited', 'Reg', (37, 46))	('deletion', 'Var', (47, 55))	('CDKN2A/B', 'Gene', '100271861;481563', (63, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))
120160	24599718	Aberrant upregulation of VEGFA in hemangiosarcoma has also been associated with the presence of inactivating point mutations and deletions within the PTEN tumor suppressor gene on CFA26q25, resulting in unregulated endothelial cell growth and angiogenesis.	('deletions', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('upregulation', 'PosReg', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('CFA', 'Chemical', '-', (180, 183))	('hemangiosarcoma', 'Disease', (34, 49))	('angiogenesis', 'CPA', (243, 255))	('unregulated', 'MPA', (203, 214))	('tumor', 'Disease', (155, 160))	('inactivating point mutations', 'Var', (96, 124))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (34, 49))	('PTEN', 'Gene', (150, 154))	('angiosarcoma', 'Phenotype', 'HP:0200058', (37, 49))	('VEGFA', 'Protein', (25, 30))	('PTEN', 'Gene', '403832', (150, 154))
120161	24599718	While PTEN deletion is highly recurrent in other dog sarcomas, only 5% of hemangiosarcoma cases (4/75) showed copy number loss of this locus, suggesting that genomic deletion does not constitute an alternative mechanism for loss of PTEN function in this disease.	('PTEN', 'Gene', '403832', (6, 10))	('hemangiosarcoma', 'Disease', (74, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (74, 89))	('PTEN', 'Gene', (232, 236))	('PTEN', 'Gene', '403832', (232, 236))	('deletion', 'Var', (11, 19))	('dog', 'Species', '9615', (49, 52))	('PTEN', 'Gene', (6, 10))	('sarcomas', 'Disease', (53, 61))	('angiosarcoma', 'Phenotype', 'HP:0200058', (77, 89))
120168	24599718	Comparison of all GR cases against those of the four other selected breeds showed that CNA profiles are broadly conserved between these subcategories, but revealed that GRs exhibit significantly more frequent gain of CFA31 and subregional loss on CFA16qprox, as well as a contrasting profile of copy number increase on CFA24.	('CFA31', 'Chemical', '-', (217, 222))	('CFA', 'Chemical', '-', (217, 220))	('CFA16qprox', 'Chemical', '-', (247, 257))	('CFA31', 'Protein', (217, 222))	('loss', 'NegReg', (239, 243))	('CFA16qprox', 'Var', (247, 257))	('CFA', 'Chemical', '-', (319, 322))	('CFA', 'Chemical', '-', (247, 250))	('gain', 'PosReg', (209, 213))
120175	24599718	In recent years, critical advances in human medicine have yielded several monoclonal antibodies and tyrosine kinase inhibitors of the VEGF pathway, with others showing promise in clinical trials.	('human', 'Species', '9606', (38, 43))	('VEGF pathway', 'Pathway', (134, 146))	('tyrosine', 'Var', (100, 108))
120179	24599718	FCR cases showed the most compelling evidence for intimate association between VEGFA copy number gain and tumor pathogenesis, but were otherwise globally consistent with observations across the entire cohort.	('copy number', 'Var', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('gain', 'PosReg', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('VEGFA', 'Gene', (79, 84))
120182	24599718	The global recurrence of CFA16 deletions and gains of CFA24 shown in figure 1a are strongly driven by the ASD, which in turn exhibits significantly elevated incidence of several genes that are fundamental to tumor pathogenesis (Figure 4).	('elevated', 'PosReg', (148, 156))	('gains', 'PosReg', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('ASD', 'Disease', 'MESH:D001321', (106, 109))	('deletions', 'Var', (31, 40))	('incidence', 'MPA', (157, 166))	('tumor', 'Disease', (208, 213))	('CFA16', 'Gene', (25, 30))	('ASD', 'Disease', (106, 109))	('CFA', 'Chemical', '-', (54, 57))	('CFA24', 'Gene', (54, 59))	('CFA', 'Chemical', '-', (25, 28))
120184	24599718	Conversely, the ANGPT2 gene product (CFA16q25.2) generally acts as an antagonist, promoting endothelial cell death and regression of blood vessels.	('CFA16q25.2', 'Var', (37, 47))	('endothelial cell death', 'CPA', (92, 114))	('CFA', 'Chemical', '-', (37, 40))	('promoting', 'PosReg', (82, 91))	('ANGPT2', 'Gene', (16, 22))	('regression of blood vessels', 'CPA', (119, 146))
120196	24599718	This concept has been supported by several studies that demonstrate related tumor-associated transcriptional profiles and gene-inactivating sequence mutations of key pathways associated with angiogenesis in angiosarcoma and hemangiosarcoma, and commonalities in the potential involvement of specific micro-RNA elements.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (224, 239))	('angiosarcoma', 'Disease', 'MESH:D006394', (207, 219))	('angiosarcoma', 'Disease', (227, 239))	('gene-inactivating sequence mutations', 'Var', (122, 158))	('angiosarcoma', 'Disease', (207, 219))	('angiosarcoma', 'Phenotype', 'HP:0200058', (227, 239))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('angiosarcoma', 'Phenotype', 'HP:0200058', (207, 219))	('hemangiosarcoma', 'Disease', (224, 239))	('angiosarcoma', 'Disease', 'MESH:D006394', (227, 239))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
120200	24599718	In the present study, increased copy number of MYC occurred in only 17% of canine hemangiosarcoma cases, and exceeded 20% penetrance in only two breeds, the ASD (30%) and BMD (33%).	('copy number', 'Var', (32, 43))	('MYC', 'Protein', (47, 50))	('angiosarcoma', 'Phenotype', 'HP:0200058', (85, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('hemangiosarcoma', 'Disease', (82, 97))	('canine', 'Species', '9615', (75, 81))	('ASD', 'Disease', 'MESH:D001321', (157, 160))	('increased', 'PosReg', (22, 31))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (82, 97))	('ASD', 'Disease', (157, 160))
120203	24599718	A more recent, high-resolution oaCGH study has since demonstrated that MYC amplification is also recurrent in de novo human angiosarcoma, and revealed significant conservation of genomic profiles in primary and secondary cases, blurring their distinction at a molecular level.	('angiosarcoma', 'Disease', (124, 136))	('angiosarcoma', 'Phenotype', 'HP:0200058', (124, 136))	('amplification', 'Var', (75, 88))	('MYC', 'Gene', (71, 74))	('human', 'Species', '9606', (118, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('oaCGH', 'Chemical', '-', (31, 36))	('angiosarcoma', 'Disease', 'MESH:D006394', (124, 136))
120215	24599718	These data reveal recurrent gene dosage imbalances with direct biological relevance to tumor pathogenesis that offer potential for therapeutic modulation of discrete pathways involved in tumor development.	('imbalances', 'Phenotype', 'HP:0002172', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (87, 92))	('gene dosage imbalances', 'Var', (28, 50))	('tumor', 'Disease', (187, 192))	('imbalance', 'Phenotype', 'HP:0002172', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
120221	24599718	ASD Australian Shepherd Dog BAC bacterial artificial chromosome BMD Bernese Mountain Dog CFA                Canis familiaris              CNA copy number aberration CNV copy number variant FCR Flat-Coated Retriever FFPE formalin-fixed, paraffin-embedded FISH fluorescence in situ hybridization GR Golden Retriever GSD German Shepherd Dog H&E hematoxylin and eosin oaCGH oligonucleotide array comparative genomic hybridization SSC saline-sodium citrate	('Dog', 'Species', '9615', (24, 27))	('Dog', 'Species', '9615', (334, 337))	('hematoxylin', 'Chemical', 'MESH:D006416', (342, 353))	('Canis familiaris', 'Species', '9615', (108, 124))	('GSD', 'Disease', 'MESH:D016098', (314, 317))	('eosin', 'Chemical', 'MESH:D004801', (358, 363))	('ASD', 'Disease', 'MESH:D001321', (0, 3))	('saline-sodium citrate', 'Chemical', '-', (430, 451))	('oligonucleotide', 'Chemical', 'MESH:D009841', (370, 385))	('Dog', 'Species', '9615', (85, 88))	('oaCGH', 'Chemical', '-', (364, 369))	('variant', 'Var', (181, 188))	('H&E', 'Chemical', '-', (338, 341))	('formalin', 'Chemical', 'MESH:D005557', (220, 228))	('GSD', 'Disease', (314, 317))	('CFA', 'Chemical', '-', (89, 92))	('paraffin', 'Chemical', 'MESH:D010232', (236, 244))	('ASD', 'Disease', (0, 3))
120254	33633477	Following the overexpression of RRM2 by cDNA transfection and silencing of RRM2 by siRRM2 in these STS cell lines, the RRM2 expression levels were analyzed by Western blot.	('RRM2', 'Gene', '6241', (85, 89))	('silencing', 'Var', (62, 71))	('RRM2', 'Gene', (32, 36))	('RRM2', 'Gene', '6241', (119, 123))	('STS', 'Phenotype', 'HP:0030448', (99, 102))	('RRM2', 'Gene', '6241', (32, 36))	('RRM2', 'Gene', (85, 89))	('RRM2', 'Gene', '6241', (75, 79))	('RRM2', 'Gene', (119, 123))	('RRM2', 'Gene', (75, 79))
120257	33633477	Silencing the RRM2 gene led to significantly greater cell survival (80%) compared with the control group (P = .003), whereas overexpression of the RRM2 increased viral oncolysis by 33% (P < .001).	('RRM2', 'Gene', '6241', (147, 151))	('RRM2', 'Gene', '6241', (14, 18))	('RRM2', 'Gene', (14, 18))	('greater', 'PosReg', (45, 52))	('viral oncolysis', 'MPA', (162, 177))	('cell survival', 'CPA', (53, 66))	('Silencing', 'Var', (0, 9))	('RRM2', 'Gene', (147, 151))
120274	33633477	We hypothesize that MYXV relies on host cell RRM2 levels to kill infected cancer cells and the oncolytic efficacy is greater in STS with high RRM2 expression compared with lower RRM2 expressing STS and normal adipose tissue.	('RRM2', 'Gene', (45, 49))	('oncolytic efficacy', 'CPA', (95, 113))	('RRM2', 'Gene', '6241', (178, 182))	('RRM2', 'Gene', (178, 182))	('infected', 'Disease', 'MESH:D007239', (65, 73))	('RRM2', 'Gene', '6241', (45, 49))	('expression', 'MPA', (147, 157))	('RRM2', 'Gene', '6241', (142, 146))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('high', 'Var', (137, 141))	('RRM2', 'Gene', (142, 146))	('MYXV', 'Species', '10273', (20, 24))	('greater', 'PosReg', (117, 124))	('cancer', 'Disease', (74, 80))	('STS', 'Phenotype', 'HP:0030448', (194, 197))	('infected', 'Disease', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('STS', 'Phenotype', 'HP:0030448', (128, 131))
120281	33633477	vMyx-GFP, a replication-competent, genetically engineered virus derived from the Lausanne strain which has a gene insertion for enhanced green fluorescent protein (eGFP) between open reading frames M135R and M136R of its genome was used.	('M136R', 'Var', (208, 213))	('enhanced', 'PosReg', (128, 136))	('M135R', 'Var', (198, 203))	('M136R', 'Mutation', 'p.M136R', (208, 213))	('M135R', 'SUBSTITUTION', 'None', (198, 203))
120287	33633477	LS141, HSSYII, DDLS8817, and RDD2213 were plated in 12-well flat-bottom plates and infected with vMyx-GFP at MOIs of 0.1, 1, or 10 in triplicate.	('LS141', 'CellLine', 'CVCL:2105', (0, 5))	('infected', 'Disease', 'MESH:D007239', (83, 91))	('DDLS8817', 'Var', (15, 23))	('infected', 'Disease', (83, 91))	('RDD2213', 'Gene', (29, 36))
120334	33633477	On day 5 after viral infection, a significant difference in the cellular sensitivity to MYXV-induced oncolysis was observed with 62% live siRRM2 transfected cells versus 37% of live siNTC cells (P = .003; Figure 5B).	('RRM2', 'Gene', (140, 144))	('MYXV', 'Species', '10273', (88, 92))	('transfected', 'Var', (145, 156))	('viral infection', 'Disease', 'MESH:D001102', (15, 30))	('viral infection', 'Disease', (15, 30))	('RRM2', 'Gene', '6241', (140, 144))
120338	33633477	On day 7 following infection of these cells with MYXV, a significant increase in oncolysis (P = .002) was observed in pcDNA-RRM2 transfected cells compared with cells transfected with the control plasmid (Figure 6B).	('increase', 'PosReg', (69, 77))	('MYXV', 'Species', '10273', (49, 53))	('oncolysis', 'CPA', (81, 90))	('infection', 'Disease', (19, 28))	('pcDNA-RRM2', 'Gene', '6241', (118, 128))	('infection', 'Disease', 'MESH:D007239', (19, 28))	('pcDNA-RRM2', 'Gene', (118, 128))	('transfected', 'Var', (129, 140))
120347	33633477	Overexpression of RRM2 in cancer cells has been implicated in the progression of several solid tumors, including lung, breast, colorectal, neuroblastoma, and STS.	('breast', 'Disease', (119, 125))	('neuroblastoma', 'Disease', 'MESH:D009447', (139, 152))	('cancer', 'Disease', (26, 32))	('RRM2', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('colorectal', 'Disease', (127, 137))	('implicated', 'Reg', (48, 58))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('STS', 'Disease', (158, 161))	('RRM2', 'Gene', '6241', (18, 22))	('neuroblastoma', 'Disease', (139, 152))	('neuroblastoma', 'Phenotype', 'HP:0003006', (139, 152))	('STS', 'Phenotype', 'HP:0030448', (158, 161))	('lung', 'Disease', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
120352	33633477	In a canine model that spontaneously develops STS, animals treated with intratumoral injection of a genetically modified MYXV with a deletion of the serp2 gene (MYXVDeltaserp2), no detrimental effects were observed in any of these canine subjects.	('STS', 'Phenotype', 'HP:0030448', (46, 49))	('deletion', 'Var', (133, 141))	('MYXV', 'Species', '10273', (161, 165))	('canine', 'Species', '9615', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('canine', 'Species', '9615', (5, 11))	('serp2', 'Gene', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MYXV', 'Species', '10273', (121, 125))	('serp2', 'Gene', (149, 154))	('tumor', 'Disease', (77, 82))	('serp2', 'Gene', '387923', (170, 175))	('serp2', 'Gene', '387923', (149, 154))
120360	33633477	Importantly, our results suggest that therapeutic strategies manipulating cellular levels of RR in target cancer cells could render otherwise unresponsive tumor cells susceptible to oncolytic virotherapy with MYXV and broaden the scope of immunotherapy for STS.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('oncolytic virotherapy with', 'MPA', (182, 208))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('manipulating', 'Var', (61, 73))	('MYXV', 'Species', '10273', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', (155, 160))	('cancer', 'Disease', (106, 112))	('STS', 'Phenotype', 'HP:0030448', (257, 260))	('render', 'Reg', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
120466	33249363	While RB1 and TP53 alterations have been found to be higher in RIS than in sporadic sarcomas, germline p53-mutations appear to be overall rare in most sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('RB1', 'Gene', (6, 9))	('RIS', 'Disease', (63, 66))	('TP53', 'Gene', (14, 18))	('sarcomas', 'Disease', (151, 159))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('higher', 'Reg', (53, 59))	('RB1', 'Gene', '5925', (6, 9))	('TP53', 'Gene', '7157', (14, 18))	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('alterations', 'Var', (19, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('sarcomas', 'Disease', (84, 92))
120467	33249363	found that BRCA or p53 mutations ultimately did not increase the risk of RIS and concluded they should not be considered in risk stratification of breast cancer patients receiving radiation therapy.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('BRCA', 'Gene', '672', (11, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('breast cancer', 'Disease', (147, 160))	('BRCA', 'Gene', (11, 15))	('RIS', 'Disease', (73, 76))	('mutations', 'Var', (23, 32))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('patients', 'Species', '9606', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
120520	33324570	In the SEER database of patients with uterine sarcoma, registered from 2004 to 2015 according to the International Classification of Tumor Diseases Third Edition (ICD-O-3), the included site codes were c54.0-C54.3, C54.8, and C54.9; these were histologically coded as 8800/3-8950/3, 8963/3, and 8982/3-8991/3, respectively.	('C54.8', 'Var', (215, 220))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('Tumor', 'Phenotype', 'HP:0002664', (133, 138))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (38, 53))	('C54.9', 'Var', (226, 231))	('sarcoma', 'Disease', (46, 53))	('c54.0-C54.3', 'Var', (202, 213))	('8800/3-8950/3', 'Var', (268, 281))	('Tumor Diseases', 'Disease', 'MESH:D009369', (133, 147))	('patients', 'Species', '9606', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('Tumor Diseases', 'Disease', (133, 147))
120541	33324570	Multivariate analysis results showed that, in general, early death and cancer-specific mortality risk was higher among black patients; older patients (51-67 years old, at the age of 68 or higher); those with larger tumors (98-148 mm, 149 mm or higher), higher FIGO staging (II, III, IV), or higher histological grade (GIII-GIV); those with tumors like endometrial stromal sarcoma, mixed epithelial and mesenchymal tumors, or other types of uterine sarcomas(except for leiomyosarcoma, endometrial stromal sarcoma and mixed epithelial and mesenchymal tumors); those who did not undergo surgery, radiotherapy, or chemotherapy; and those with brain metastases.	('tumors', 'Disease', (549, 555))	('higher', 'Var', (253, 259))	('death', 'Disease', 'MESH:D003643', (61, 66))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (402, 420))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Disease', 'MESH:D009369', (414, 420))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (537, 555))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (440, 455))	('endometrial stromal sarcoma', 'Disease', (352, 379))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('leiomyosarcoma', 'Disease', (468, 482))	('metastases', 'Disease', (645, 655))	('tumors', 'Disease', (215, 221))	('patients', 'Species', '9606', (141, 149))	('patients', 'Species', '9606', (125, 133))	('tumors', 'Disease', 'MESH:D009369', (549, 555))	('sarcoma', 'Phenotype', 'HP:0100242', (475, 482))	('endometrial stromal sarcoma', 'Disease', (484, 511))	('cancer', 'Disease', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('mesenchymal tumors', 'Disease', (402, 420))	('sarcoma', 'Phenotype', 'HP:0100242', (372, 379))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mesenchymal tumors', 'Disease', (537, 555))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('death', 'Disease', (61, 66))	('tumors', 'Disease', (340, 346))	('sarcomas', 'Disease', 'MESH:D012509', (448, 456))	('tumors', 'Phenotype', 'HP:0002664', (414, 420))	('sarcomas', 'Phenotype', 'HP:0100242', (448, 456))	('sarcoma', 'Phenotype', 'HP:0100242', (504, 511))	('mortality', 'Disease', (87, 96))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (468, 482))	('sarcomas', 'Disease', (448, 456))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (468, 482))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (352, 379))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('tumors', 'Phenotype', 'HP:0002664', (549, 555))	('tumors', 'Disease', 'MESH:D009369', (340, 346))	('higher', 'PosReg', (106, 112))	('tumors', 'Disease', (414, 420))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (484, 511))	('tumor', 'Phenotype', 'HP:0002664', (549, 554))	('sarcoma', 'Phenotype', 'HP:0100242', (448, 455))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('metastases', 'Disease', 'MESH:D009362', (645, 655))
120573	33324570	constructed an effective diagnostic model for uterine leiomyosarcoma using seven serum miRNA (Mir-4430, Mir-6511b-5p, Mir-191-5p, Mir-451A, Mir-4485-5p, Mir-4635, and Mir-1246) with high diagnostic performance for preoperative screening of uterine sarcoma, and proved that serum miRNA could be used as a preoperative biomarker.	('Mir-191', 'Gene', '406966', (118, 125))	('Mir-4430', 'Gene', (94, 102))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (46, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('Mir-4485', 'Gene', (140, 148))	('Mir-4430', 'Gene', '100616136', (94, 102))	('leiomyosarcoma', 'Disease', (54, 68))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('Mir-451A', 'Gene', (130, 138))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (240, 255))	('Mir-1246', 'Gene', (167, 175))	('sarcoma', 'Disease', (61, 68))	('Mir-6511b-5p', 'Var', (104, 116))	('Mir-4635', 'Gene', (153, 161))	('Mir-1246', 'Gene', '100302142', (167, 175))	('sarcoma', 'Disease', 'MESH:D012509', (248, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('Mir-451A', 'Gene', '574411', (130, 138))	('sarcoma', 'Disease', (248, 255))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (54, 68))	('Mir-191', 'Gene', (118, 125))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (54, 68))	('Mir-4485', 'Gene', '100616263', (140, 148))	('Mir-4635', 'Gene', '100616479', (153, 161))
120605	32639877	Clinicians indicated telemedicine appointments were generally shorter than face to face, did not increase their workload, and lack of physical examination did not affect patient care.	('shorter than face', 'Phenotype', 'HP:0011219', (62, 79))	('shorter', 'NegReg', (62, 69))	('telemedicine', 'Var', (21, 33))	('patient', 'Species', '9606', (170, 177))
120731	30305666	The different absorbance values for the FTIR region corresponding to amide II and amide I groups in the normal bone samples compared to ES and osteomyelitis bone tissues samples reflect the qualitative and quantitative dissimilarity in protein content between them.	('osteomyelitis', 'Phenotype', 'HP:0002754', (143, 156))	('amide II', 'Chemical', '-', (69, 77))	('osteomyelitis bone tissues', 'Disease', 'MESH:D010019', (143, 169))	('absorbance', 'MPA', (14, 24))	('amide', 'Chemical', 'MESH:D000577', (82, 87))	('ES', 'Phenotype', 'HP:0012254', (136, 138))	('osteomyelitis bone tissues', 'Disease', (143, 169))	('amide', 'Chemical', 'MESH:D000577', (69, 74))	('amide', 'Var', (69, 74))
120759	27500006	Her consciousness level on arrival was E1V4M5 on Glasgow Coma Scale.	('Coma', 'Phenotype', 'HP:0001259', (57, 61))	('E1V4M5', 'Var', (39, 45))	('Coma', 'Disease', (57, 61))	('Coma', 'Disease', 'MESH:D003128', (57, 61))
120802	27057136	LMS was found to possess features typically observed in malignant solid tumors, such as extensive chromosomal abnormalities, overexpression of cell cycle-related genes, hypomethylation spreading through large genomic regions, and frequent hypermethylation at the polycomb group target genes and protocadherin genes.	('LMS', 'Phenotype', 'HP:0100243', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('chromosomal abnormalities', 'Disease', (98, 123))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (98, 123))	('malignant solid tumors', 'Disease', 'MESH:D009369', (56, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('malignant solid tumors', 'Disease', (56, 78))	('hypermethylation', 'Var', (239, 255))	('hypomethylation', 'Var', (169, 184))	('overexpression', 'PosReg', (125, 139))	('LMS', 'Disease', (0, 3))
120826	27057136	Detection of copy neutral loss of heterozygosity (CNLOH) and copy number alterations (gain and loss) was performed using CNVpartition V3.0.7.0 (Illumina) and R-GADA (R-genome alteration detection analysis), respectively, with default parameters.	('alterations', 'Var', (73, 84))	('loss of heterozygosity', 'NegReg', (26, 48))	('R-GADA', 'Chemical', '-', (158, 164))	('copy number alterations', 'Var', (61, 84))
120833	27057136	This array platform uses logR ratio (LRR) and B allele frequency (BAF) as metrics to detect copy number changes.	('BAF', 'Gene', '8815', (66, 69))	('logR', 'MPA', (25, 29))	('copy number changes', 'Var', (92, 111))	('BAF', 'Gene', (66, 69))
120838	27057136	We regarded the sum of the ratio of the copy number altering changes (gain and loss) detected by R-GADA and that of copy neutral changes (CN-LOH) detected by CNV partition as the approximate ratio of chromosomal abnormalities in this study.	('copy', 'Var', (40, 44))	('loss', 'NegReg', (79, 83))	('chromosomal abnormalities', 'Disease', (200, 225))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (200, 225))	('R-GADA', 'Chemical', '-', (97, 103))
120846	27057136	Somatic mutations in the FH gene (encoding fumarate hydratase) and in the MED12 gene (encoding mediator complex subunit 12) have been identified in 1.3% of sporadic and 70% of unselected uterine LMs, respectively.	('MED12', 'Gene', (74, 79))	('FH', 'Gene', '2271', (25, 27))	('fumarate hydratase', 'Gene', (43, 61))	('MED12', 'Gene', '9968', (74, 79))	('uterine LMs', 'Disease', (187, 198))	('mutations', 'Var', (8, 17))	('mediator complex subunit 12', 'Gene', '9968', (95, 122))	('mediator complex subunit 12', 'Gene', (95, 122))	('identified', 'Reg', (134, 144))	('fumarate hydratase', 'Gene', '2271', (43, 61))
120848	27057136	Therefore, not only mutations in specific genes but also chromosomal abnormalities are likely involved in genetic causes of LM and should be further explored.	('involved', 'Reg', (94, 102))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (57, 82))	('mutations', 'Var', (20, 29))	('chromosomal abnormalities', 'Disease', (57, 82))
120856	27057136	Scatter plots (Figure 4(d)) of the average beta values for the same probe set also showed that LMS was globally hypomethylated compared to LM and NM, which is consistent with the global hypomethylation known to occur in most malignant tumors.	('malignant tumors', 'Disease', (225, 241))	('malignant tumors', 'Disease', 'MESH:D018198', (225, 241))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('hypomethylated', 'Var', (112, 126))	('LMS', 'Phenotype', 'HP:0100243', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))
120857	27057136	We confirmed the hypomethylation of LINE1 elements in LMS by the combined bisulfite restriction analysis (Figure 4(e) and Supplementary Material, Figure S2).	('LMS', 'Disease', (54, 57))	('hypomethylation', 'Var', (17, 32))	('bisulfite', 'Chemical', 'MESH:C042345', (74, 83))	('LMS', 'Phenotype', 'HP:0100243', (54, 57))
120858	27057136	CpG sites within CpG islands (CGIs), the majority of which are unmethylated, were found to be more frequently hypermethylated (4.5%) than those outside of CGIs (2.5% in open sea) and to be much less frequently hypomethylated (4.6%) than those outside CGIs (16.7% in shores and shelves, and 28.1% in open sea) (Figures 4(l)-4(n) and Table 2).	('open sea', 'Disease', (299, 307))	('open sea', 'Disease', 'MESH:D009041', (169, 177))	('open sea', 'Disease', (169, 177))	('open sea', 'Disease', 'MESH:D009041', (299, 307))	('hypermethylated', 'Var', (110, 125))
120861	27057136	Hypermethylation of the subset of PcG genes encoding developmental regulators is considered to potentially contribute to the stem-like state of cancer.	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PcG genes', 'Gene', (34, 43))	('stem-like state', 'CPA', (125, 140))	('cancer', 'Disease', (144, 150))	('contribute', 'Reg', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
120866	27057136	Taken together, the annotations for differentially methylated regions in LMS compared to NM demonstrate that LMS exhibits epigenomic features such as hypermethylation at the PcG target gene and protocadherin gene loci and hypomethylation within large blocks that are known to be common among malignant solid tumors (Supplementary Material, Figure S4).	('hypomethylation', 'Var', (222, 237))	('LMS', 'Phenotype', 'HP:0100243', (73, 76))	('malignant solid tumors', 'Disease', 'MESH:D009369', (292, 314))	('malignant solid tumors', 'Disease', (292, 314))	('LMS', 'Disease', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('LMS', 'Phenotype', 'HP:0100243', (109, 112))	('hypermethylation', 'Var', (150, 166))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))
120942	23136636	Advanced age, tumor size of greater than 5 cm, deep location, nuclear polymorphism, high mitotic activity, and the presence of vascular invasion are acceptable poor prognostic factors of penile epithelioid sarcoma.	('tumor', 'Disease', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('nuclear polymorphism', 'Var', (62, 82))	('penile epithelioid sarcoma', 'Disease', (187, 213))	('penile epithelioid sarcoma', 'Disease', 'MESH:D004414', (187, 213))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
120971	33256182	Furthermore, transplants may also help to reduce typical radiation sequelae such as fibrosis and radiation ulcers.	('ulcers', 'Disease', 'MESH:D014456', (107, 113))	('ulcers', 'Disease', (107, 113))	('transplants', 'Var', (13, 24))	('reduce', 'NegReg', (42, 48))	('fibrosis', 'Disease', 'MESH:D005355', (84, 92))	('fibrosis', 'Disease', (84, 92))
121012	33256182	The differences in total complication rates between the variant reconstructions were statistically significant (split skin graft: 19%, local/region flaps: 36% and free flaps: 31%) compared to primary wound closure.	('flap', 'Gene', (148, 152))	('variant', 'Var', (56, 63))	('complication', 'CPA', (25, 37))	('flap', 'Gene', '241', (168, 172))	('flap', 'Gene', '241', (148, 152))	('flap', 'Gene', (168, 172))
121046	33256182	Surprisingly we found a higher local recurrence rate in the split skin graft group, which seems inconsistent to the statement, that positive margins are the main predictor of local recurrence.	('split skin graft', 'Var', (60, 76))	('men', 'Species', '9606', (121, 124))	('local recurrence', 'CPA', (31, 47))
121047	33256182	In this study, grading was significantly higher in the group of free flaps compared to primary wound closure.	('flap', 'Gene', '241', (69, 73))	('grading', 'MPA', (15, 22))	('higher', 'PosReg', (41, 47))	('free', 'Var', (64, 68))	('flap', 'Gene', (69, 73))
121133	31827596	But first case of solitary penile KS with HHV8 positivity in HIV seronegative patient was published by Morelli et al..	('KS', 'Phenotype', 'HP:0100726', (34, 36))	('patient', 'Species', '9606', (78, 85))	('HHV8', 'Species', '37296', (42, 46))	('positivity', 'Var', (47, 57))	('solitary penile KS', 'Disease', (18, 36))	('HHV8', 'Gene', (42, 46))
121178	31523591	Risk factors influencing the survival, metastatic, and local recurrence rates include histological grade as well as tumor size and depth; Weiss and Enzinger analyzed 200 cases of UPS and found that tumors less than 2.5 cm in size had a metastatic rate of 21% as compared with a rate of 57% in those greater than 10 cm in size.	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('less than 2.5 cm', 'Var', (205, 221))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('metastatic rate', 'CPA', (236, 251))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (116, 121))
121232	30215049	demonstrated a common cytogenetic alteration on chromosome 19 in a UESL arising from a mesenchymal hamartomas (MH), suggesting a connection between the two entities similar to UESL representing a malignant progression from MH.	('alteration', 'Var', (34, 44))	('UESL', 'Disease', (67, 71))	('mesenchymal hamartomas', 'Disease', 'MESH:D006222', (87, 109))	('hamartomas', 'Phenotype', 'HP:0010566', (99, 109))	('mesenchymal hamartomas', 'Disease', (87, 109))
121299	28927093	Of the 18 metaphase cells available for analysis, 14 were of normal (46,XY) karyotype, 2 cells had a karyotype of t(2;5)(q31;q31), 1 had a karyotype of 42,Y,-X,-10,-18,-19, add(19)(p13), and 1 had a karyotype of t(7;14)(q21;q24) (Fig.	('t(2;5)(q31;q31', 'Var', (114, 128))	('p13', 'Gene', (181, 184))	('t(2;5)(q31;q31)', 'STRUCTURAL_ABNORMALITY', 'None', (114, 129))	('p13', 'Gene', '440926', (181, 184))	('t(7;14)(q21;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (212, 228))
121319	28927093	Juvenile-onset soft tissue sarcomas are often characterized by disease-specific fusion genes resulting from translocations, such as t(X;18) in synovial sarcomas, t(12;22) or t(2;22) in clear cell sarcomas, t(2;13) in alveolar rhabdomyosarcoma, and t(X;17) in alveolar soft part sarcomas.	('t(12;22', 'Var', (162, 169))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (268, 285))	('sarcomas', 'Disease', 'MESH:D012509', (278, 286))	('t(X;17', 'Var', (248, 254))	('sarcomas', 'Phenotype', 'HP:0100242', (278, 286))	('sarcomas', 'Disease', (278, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('sarcomas', 'Disease', 'MESH:D012509', (196, 204))	('sarcomas', 'Phenotype', 'HP:0100242', (196, 204))	('alveolar rhabdomyosarcoma', 'Disease', (217, 242))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (143, 160))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (226, 242))	('sarcomas', 'Disease', (196, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (278, 285))	('synovial sarcomas', 'Disease', (143, 160))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (217, 242))	('soft part sarcomas', 'Phenotype', 'HP:0030448', (268, 286))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('alveolar soft part sarcomas', 'Disease', (259, 286))	('sarcomas', 'Disease', (27, 35))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (15, 34))	('t(X;18', 'Var', (132, 138))	('t(2;13', 'Var', (206, 212))	('synovial sarcomas', 'Disease', 'MESH:D013584', (143, 160))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (217, 242))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (15, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (143, 159))	('translocations', 'Var', (108, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcomas', 'Disease', 'MESH:D012509', (152, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('sarcomas', 'Disease', (152, 160))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (259, 285))	('alveolar soft part sarcomas', 'Disease', 'MESH:D018234', (259, 286))	('t(2;22', 'Var', (174, 180))	('alveolar soft part sarcomas', 'Phenotype', 'HP:0012218', (259, 286))
121321	28927093	In previous studies, 3 patients with translocation-associated soft tissue tumors involving 2q31, including 2 patients with synovial sarcoma and 1 with lipoblastoma, and 1 patient with translocation-associated embryonal rhabdomyosarcoma involving 5q31, were documented.	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (23, 31))	('embryonal rhabdomyosarcoma', 'Disease', (209, 235))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (123, 139))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (219, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (209, 235))	('lipoblastoma', 'Disease', 'MESH:D062689', (151, 163))	('patient', 'Species', '9606', (23, 30))	('lipoblastoma', 'Disease', (151, 163))	('patient', 'Species', '9606', (109, 116))	('translocation-associated', 'Var', (37, 61))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (62, 80))	('synovial sarcoma', 'Disease', (123, 139))	('patient', 'Species', '9606', (171, 178))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (209, 235))	('synovial sarcoma', 'Disease', 'MESH:D013584', (123, 139))	('tumors', 'Disease', (74, 80))
121327	28927093	It was identified that t(2;5)(q31;q31) may be a disease-specific chromosomal aberration in SCPFT.	('t(2;5)(q31;q31)', 'STRUCTURAL_ABNORMALITY', 'None', (23, 38))	('SCPFT', 'Disease', (91, 96))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (65, 87))	('t(2;5)(q31;q31', 'Var', (23, 37))
121377	28145579	A recent review of human literature suggests that the majority of myeloid sarcomas (in formalin-fixed, paraffin-embedded tissue specimens) can be diagnosed using an immunohistochemical panel including CD43, MPO, CD117, CD68 (or CD163), CD3 and CD20.	('CD68', 'Gene', (219, 223))	('CD163', 'Gene', (228, 233))	('CD117', 'Gene', (212, 217))	('CD68', 'Gene', '968', (219, 223))	('CD43', 'Gene', (201, 205))	('CD20', 'Var', (244, 248))	('myeloid sarcomas', 'Disease', (66, 82))	('MPO', 'Var', (207, 210))	('paraffin', 'Chemical', 'MESH:D010232', (103, 111))	('CD3', 'Var', (236, 239))	('human', 'Species', '9606', (19, 24))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('CD43', 'Gene', '6693', (201, 205))	('CD163', 'Gene', '9332', (228, 233))	('CD117', 'Gene', '3815', (212, 217))	('myeloid sarcomas', 'Disease', 'MESH:D023981', (66, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('formalin', 'Chemical', 'MESH:D005557', (87, 95))
121490	31546971	Further highlighting the vital role of LPA signaling as a driver of tumor progression, overexpression of LPAR1-3 alone increases mammary tumorigenesis, invasion and metastasis in a mouse mammary tumor virus (MMTV) model.	('tumor', 'Disease', (68, 73))	('metastasis', 'CPA', (165, 175))	('overexpression', 'Var', (87, 101))	('increases', 'PosReg', (119, 128))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (137, 142))	('LPAR1', 'Gene', '1902', (105, 110))	('mouse mammary tumor virus', 'Species', '11757', (181, 206))	('MMTV', 'Species', '11757', (208, 212))	('LPAR1', 'Gene', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('LPA', 'Chemical', 'MESH:C522988', (39, 42))	('LPA', 'Chemical', 'MESH:C522988', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
121497	31546971	Cellular characteristics associated with tumor aggressiveness, including cell proliferation, cell survival, cell motility, invasion, angiogenesis, resistance to treatment and metastasis, are all augmented by ATX, and depend on its capacity to produce LPA.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor aggressiveness', 'Disease', (41, 61))	('invasion', 'CPA', (123, 131))	('cell survival', 'CPA', (93, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (47, 61))	('angiogenesis', 'CPA', (133, 145))	('LPA', 'Chemical', 'MESH:C522988', (251, 254))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (41, 61))	('cell proliferation', 'CPA', (73, 91))	('cell motility', 'CPA', (108, 121))	('augmented', 'PosReg', (195, 204))	('ATX', 'Var', (208, 211))
121500	31546971	LPP1 knockout mice have an increase in the plasma level of LPA and a four-fold increase in the half-life of intravenously injected LPA, while extracellular LPA levels are significantly augmented in LPP3 knockout fibroblasts.	('increase', 'PosReg', (79, 87))	('augmented', 'PosReg', (185, 194))	('extracellular LPA levels', 'MPA', (142, 166))	('LPA', 'Chemical', 'MESH:C522988', (59, 62))	('knockout', 'Var', (5, 13))	('mice', 'Species', '10090', (14, 18))	('LPA', 'Chemical', 'MESH:C522988', (156, 159))	('plasma level of LPA', 'MPA', (43, 62))	('LPP1', 'Gene', (0, 4))	('LPA', 'Chemical', 'MESH:C522988', (131, 134))	('half-life', 'MPA', (95, 104))	('increase', 'PosReg', (27, 35))
121535	31546971	Results indicated that ATX knockdown by shRNA abolished invadopodia production induced by hypoxia, suggesting an important role for ATX in hypoxia-induced invadopodia production (Figure 3A).	('hypoxia', 'Disease', 'MESH:D000860', (139, 146))	('knockdown', 'Var', (27, 36))	('hypoxia', 'Disease', (139, 146))	('ATX', 'Gene', (23, 26))	('abolished', 'NegReg', (46, 55))	('hypoxia', 'Disease', (90, 97))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('shRNA', 'Gene', (40, 45))
121540	31546971	Results showed that LPP1 or LPP3 knockdown induced a significant increase in the percentage of cells forming invadopodia, comparable to the increase induced by hypoxia (Figure 3E).	('increase', 'PosReg', (65, 73))	('hypoxia', 'Disease', (160, 167))	('hypoxia', 'Disease', 'MESH:D000860', (160, 167))	('knockdown', 'Var', (33, 42))	('LPP3', 'Gene', (28, 32))	('LPP1', 'Gene', (20, 24))
121541	31546971	In contrast, knockdown of LPP2 had no effect on invadopodia production (Figure 3E), which is consistent with the lack of inhibition of LPP2 gene expression in hypoxia (Figure 1J).	('invadopodia production', 'MPA', (48, 70))	('LPP2', 'Gene', (135, 139))	('LPP2', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('hypoxia', 'Disease', 'MESH:D000860', (159, 166))	('hypoxia', 'Disease', (159, 166))
121542	31546971	These results indicate that LPP1 and LPP3 play a negative role in invadopodia production, most likely through their known ability to degrade LPA.	('invadopodia production', 'MPA', (66, 88))	('LPP3', 'Var', (37, 41))	('LPA', 'Chemical', 'MESH:C522988', (141, 144))	('degrade', 'NegReg', (133, 140))	('negative', 'NegReg', (49, 57))	('LPA', 'MPA', (141, 144))	('LPP1', 'Gene', (28, 32))
121576	31546971	These findings suggest that ATX regulation at the gene level is not a general way by which hypoxia regulates LPA levels in cancers, and reinforce the possibility that enhanced autocrine ATX production in cancer cells is mostly attributed to copy number amplifications or increased translation.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (204, 210))	('increased', 'PosReg', (271, 280))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('hypoxia', 'Disease', (91, 98))	('enhanced', 'PosReg', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('cancer', 'Disease', (123, 129))	('LPA', 'Chemical', 'MESH:C522988', (109, 112))	('autocrine ATX production', 'MPA', (176, 200))	('copy number amplifications', 'Var', (241, 267))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))	('LPA levels', 'MPA', (109, 119))
121582	31546971	Our results uncovered ATX as an essential mediator of hypoxia-induced invadopodia production and cell migration in a 3D matrix, as ATX knockdown completely blocked these events.	('hypoxia', 'Disease', 'MESH:D000860', (54, 61))	('hypoxia', 'Disease', (54, 61))	('knockdown', 'Var', (135, 144))	('cell migration in a', 'CPA', (97, 116))	('invadopodia production', 'MPA', (70, 92))
121583	31546971	Furthermore, LPA, but not the ATX substrate LPC, was able to rescue ATX shRNA-mediated knockdown of invadopodia in hypoxic conditions, indicating that the effects of ATX are most likely due to its production of LPA and downstream signaling through LPARs.	('LPA', 'Chemical', 'MESH:C522988', (248, 251))	('LPA', 'Chemical', 'MESH:C522988', (211, 214))	('hypoxic conditions', 'Disease', (115, 133))	('LPC', 'Chemical', 'MESH:C470482', (44, 47))	('LPAR', 'Gene', '1902;9170', (248, 252))	('hypoxic conditions', 'Disease', 'MESH:D009135', (115, 133))	('LPAR', 'Gene', (248, 252))	('LPA', 'Chemical', 'MESH:C522988', (13, 16))	('knockdown', 'Var', (87, 96))
121585	31546971	In contrast, knockdown of the LPA-degrading enzymes, LPP1 and LPP3, resulted in an increase in invadopodia production, an effect mimicking hypoxic stimulation.	('LPA-degrading', 'Gene', (30, 43))	('LPP1', 'Gene', (53, 57))	('increase', 'PosReg', (83, 91))	('hypoxic', 'Disease', 'MESH:D000860', (139, 146))	('LPP3', 'Gene', (62, 66))	('invadopodia production', 'MPA', (95, 117))	('LPA', 'Chemical', 'MESH:C522988', (30, 33))	('hypoxic', 'Disease', (139, 146))	('knockdown', 'Var', (13, 22))
121604	31546971	This suggests that inhibition of the ATX-integrin interaction could be a selective approach to prevent localized LPA signaling that drives cell invasion in hypoxic cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('inhibition', 'Var', (19, 29))	('hypoxic cancer', 'Disease', 'MESH:D009369', (156, 170))	('cell invasion', 'CPA', (139, 152))	('LPA', 'Chemical', 'MESH:C522988', (113, 116))	('hypoxic cancer', 'Disease', (156, 170))	('localized LPA signaling', 'MPA', (103, 126))
121617	31546971	For lentiviral transductions, with LPP1, LPP2, LPP3 or scramble shRNA, cells were seeded at a density of 3 x 105 cells per 10 cm2 Petri dish and infected with 1 mL of viral stock in 2 mL of optiMEM supplemented with 2 muL Polybrene (10 mg/mL; EMD Millipore, Etobicoke, ON, Canada).	('EMD', 'Disease', (243, 246))	('EMD', 'Disease', 'None', (243, 246))	('LPP1', 'Var', (35, 39))	('Polybrene', 'Chemical', 'MESH:D006583', (222, 231))
121628	31546971	For quantification of ATX/LPP or ATX/LPAR1 co-localization, cells were incubated with ATX and LPP1, LPP2, LPP3, or LPAR1 antibodies.	('LPP2', 'Var', (100, 104))	('LPAR1', 'Gene', '1902', (37, 42))	('LPAR1', 'Gene', (115, 120))	('LPP3', 'Var', (106, 110))	('LPAR1', 'Gene', (37, 42))	('LPP1', 'Var', (94, 98))	('LPAR1', 'Gene', '1902', (115, 120))
121706	23572212	There is a very small risk of nephrogenic systemic fibrosis for patients who receive MRI contrast in the setting of severe renal failure, but no other biologic hazards have been reported with the use of MRI.	('renal failure', 'Phenotype', 'HP:0000083', (123, 136))	('patients', 'Species', '9606', (64, 72))	('renal failure', 'Disease', 'MESH:D051437', (123, 136))	('nephrogenic systemic fibrosis', 'Disease', (30, 59))	('nephrogenic systemic fibrosis', 'Disease', 'MESH:D054989', (30, 59))	('renal failure', 'Disease', (123, 136))	('MRI', 'Var', (85, 88))
121727	23572212	Importantly, there is a lack of specificity of sub-centimeric pulmonary lesions on imaging studies.	('sub-centimeric', 'Var', (47, 61))	('pulmonary lesions', 'Disease', 'MESH:D008171', (62, 79))	('pulmonary lesions', 'Disease', (62, 79))
121754	23572212	In contrast, minimizing imaging may inadvertently increase patient stress levels if they feel less reassured of no recurrence.	('patient', 'Species', '9606', (59, 66))	('increase', 'PosReg', (50, 58))	('minimizing', 'Var', (13, 23))	('imaging', 'MPA', (24, 31))	('patient stress levels', 'MPA', (59, 80))
121825	33072757	Notably, in melanoma, the dysregulated expression and/or activity of these proteins has been associated with cancer cell migration and invasion.	('rat', 'Species', '10116', (124, 127))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('melanoma', 'Disease', (12, 20))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('cancer', 'Disease', (109, 115))	('associated', 'Reg', (93, 103))	('activity', 'MPA', (57, 65))	('expression', 'MPA', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('dysregulated', 'Var', (26, 38))	('invasion', 'CPA', (135, 143))
121840	33072757	Previous studies demonstrated that 27% of all human cancers contain missense gain of function mutations in RAS genes.	('missense', 'Var', (68, 76))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('human', 'Species', '9606', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('rat', 'Species', '10116', (24, 27))	('RAS genes', 'Gene', (107, 116))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
121841	33072757	Indeed, 28% of all melanoma cases have mutations in the NRAS gene, being after BRAF mutations the second most frequent oncogenic alteration in this type of cancer.	('NRAS', 'Gene', (56, 60))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('NRAS', 'Gene', '4893', (56, 60))	('melanoma', 'Disease', (19, 27))	('rat', 'Species', '10116', (133, 136))	('mutations', 'Var', (39, 48))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
121842	33072757	More than 80% of NRAS mutations occur in codon 61 and induce conformational changes in NRAS motifs, blocking GTP hydrolysis by GAPs and promoting the prevalence of GTP-bound NRAS.	('GTP', 'Chemical', 'MESH:D006160', (164, 167))	('GTP hydrolysis', 'MPA', (109, 123))	('blocking', 'NegReg', (100, 108))	('conformational changes', 'MPA', (61, 83))	('NRAS', 'Gene', '4893', (87, 91))	('NRAS', 'Gene', (87, 91))	('promoting', 'PosReg', (136, 145))	('NRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('NRAS', 'Gene', '4893', (17, 21))	('GAPs', 'NegReg', (127, 131))	('NRAS', 'Gene', (174, 178))	('GTP-bound', 'MPA', (164, 173))	('GTP', 'Chemical', 'MESH:D006160', (109, 112))	('NRAS', 'Gene', '4893', (174, 178))
121845	33072757	As expected, NRAS silencing in melanoma cell lines significantly reduces cell proliferation, migration, and invasion and promotes cell apoptosis (Table 1).	('silencing', 'Var', (18, 27))	('cell apoptosis', 'CPA', (130, 144))	('migration', 'CPA', (93, 102))	('reduces', 'NegReg', (65, 72))	('NRAS', 'Gene', '4893', (13, 17))	('rat', 'Species', '10116', (85, 88))	('promotes', 'PosReg', (121, 129))	('NRAS', 'Gene', (13, 17))	('cell proliferation', 'CPA', (73, 91))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('rat', 'Species', '10116', (96, 99))	('melanoma', 'Disease', (31, 39))	('invasion', 'CPA', (108, 116))
121846	33072757	Consistently, in vivo experiments showed a decrease in melanoma growth after NRAS depletion, associated with the suppression of Ras/RAF/MEK/ERK and PI3K/Akt pathways.	('decrease', 'NegReg', (43, 51))	('PI3', 'Gene', (148, 151))	('Akt', 'Gene', '207', (153, 156))	('depletion', 'Var', (82, 91))	('RAF', 'Gene', '22882', (132, 135))	('NRAS', 'Gene', (77, 81))	('Akt', 'Gene', (153, 156))	('RAF', 'Gene', (132, 135))	('melanoma growth', 'Disease', (55, 70))	('ERK', 'Gene', '5594', (140, 143))	('NRAS', 'Gene', '4893', (77, 81))	('melanoma growth', 'Disease', 'MESH:D008545', (55, 70))	('suppression', 'NegReg', (113, 124))	('PI3', 'Gene', '5266', (148, 151))	('ERK', 'Gene', (140, 143))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))
121848	33072757	NRAS mutations are frequently detected in elderly melanoma patients, and they are preferentially found in the most aggressive histological subtype of melanoma, i.e., nodular melanoma, compared to the other histological subtypes.	('found', 'Reg', (97, 102))	('nodular melanoma', 'Disease', 'MESH:D008545', (166, 182))	('nodular melanoma', 'Disease', (166, 182))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('mutations', 'Var', (5, 14))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('patients', 'Species', '9606', (59, 67))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Disease', (174, 182))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Disease', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('nodular melanoma', 'Phenotype', 'HP:0012058', (166, 182))	('NRAS', 'Gene', '4893', (0, 4))
121849	33072757	Some authors reported that NRAS mutations are not prognostic factors for metastatic melanoma patients.	('NRAS', 'Gene', '4893', (27, 31))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('mutations', 'Var', (32, 41))	('NRAS', 'Gene', (27, 31))	('patients', 'Species', '9606', (93, 101))
121851	33072757	Nevertheless, NRAS mutational status was described as a prognostic factor of shorter OS for stage IV non-uveal metastatic melanoma and primary invasive melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('melanoma', 'Disease', (152, 160))	('NRAS', 'Gene', '4893', (14, 18))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('uveal metastatic melanoma', 'Phenotype', 'HP:0007716', (105, 130))	('invasive melanoma', 'Disease', (143, 160))	('patients', 'Species', '9606', (161, 169))	('mutational status', 'Var', (19, 36))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('invasive melanoma', 'Disease', 'MESH:D008545', (143, 160))	('NRAS', 'Gene', (14, 18))
121854	33072757	Additionally, NRAS mutations were categorized as a type of mutation characteristic of intermediate skin lesions.	('NRAS', 'Gene', '4893', (14, 18))	('skin lesions', 'Disease', (99, 111))	('mutations', 'Var', (19, 28))	('skin lesions', 'Disease', 'MESH:D012871', (99, 111))	('NRAS', 'Gene', (14, 18))
121856	33072757	Presently, there is evidence that NRAS mutations are associated with thicker melanomas, elevated mitotic rates, and a higher propensity for lymph node metastasis, highlighting the importance of these alterations in the clinical setting.	('mitotic rates', 'CPA', (97, 110))	('melanomas', 'Disease', (77, 86))	('rat', 'Species', '10116', (105, 108))	('elevated', 'PosReg', (88, 96))	('rat', 'Species', '10116', (204, 207))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('mutations', 'Var', (39, 48))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('lymph node metastasis', 'CPA', (140, 161))	('NRAS', 'Gene', (34, 38))	('NRAS', 'Gene', '4893', (34, 38))
121857	33072757	Thus, NRAS mutational analysis should be included in melanoma routine diagnosis, given its relevance as a biomarker of melanoma aggressiveness and easy evaluation.	('aggressiveness', 'Phenotype', 'HP:0000718', (128, 142))	('melanoma aggressiveness', 'Disease', (119, 142))	('mutational analysis', 'Var', (11, 30))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('NRAS', 'Gene', (6, 10))	('melanoma aggressiveness', 'Disease', 'MESH:D008545', (119, 142))	('NRAS', 'Gene', '4893', (6, 10))
121858	33072757	Considering that NRAS mutations are present in almost one third of melanoma cases, a successful targeted therapy would be expected by now.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('NRAS', 'Gene', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('mutations', 'Var', (22, 31))	('NRAS', 'Gene', '4893', (17, 21))
121867	33072757	RAL was described as an inducer of proliferation in melanoma cell lines, even in the presence of NRAS and/or BRAF oncogenic mutations (Table 1).	('NRAS', 'Gene', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('mutations', 'Var', (124, 133))	('BRAF', 'Gene', (109, 113))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('NRAS', 'Gene', '4893', (97, 101))	('proliferation', 'MPA', (35, 48))	('RAL', 'Gene', (0, 3))	('rat', 'Species', '10116', (42, 45))	('RAL', 'Gene', '5898', (0, 3))
121869	33072757	Moreover, RAP1 inhibition reduces melanoma cell adhesion and migration by suppressing tumor cell extravasation and consequently lung colonization in in vivo models.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('suppressing', 'NegReg', (74, 85))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('rat', 'Species', '10116', (64, 67))	('RAP1', 'Gene', '27342', (10, 14))	('RAP1', 'Gene', (10, 14))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('reduces', 'NegReg', (26, 33))	('melanoma', 'Disease', (34, 42))	('lung colonization', 'CPA', (128, 145))	('inhibition', 'Var', (15, 25))
121871	33072757	Overall, the imminent role of NRAS mutations in melanoma aggressiveness and response to therapy has been well established, although much is still to discover about the impact of the remaining Ras family members in melanoma pathophysiology and as putative therapeutic targets.	('melanoma', 'Disease', (48, 56))	('melanoma aggressiveness', 'Disease', (48, 71))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', (214, 222))	('aggressiveness', 'Phenotype', 'HP:0000718', (57, 71))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('NRAS', 'Gene', (30, 34))	('NRAS', 'Gene', '4893', (30, 34))	('melanoma aggressiveness', 'Disease', 'MESH:D008545', (48, 71))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('mutations', 'Var', (35, 44))
121878	33072757	Furthermore, the expression of Cdc42 constitutively active mutants induces cells to adopt a rounded shape increasing melanoma cell invasion and consequently allowing a mesenchymal-amoeboid transition.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('mutants', 'Var', (59, 66))	('Cdc42', 'Gene', (31, 36))	('increasing', 'PosReg', (106, 116))	('allowing', 'Reg', (157, 165))	('Cdc42', 'Gene', '998', (31, 36))	('induces', 'Reg', (67, 74))	('melanoma', 'Disease', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('mesenchymal-amoeboid transition', 'CPA', (168, 199))
121887	33072757	Despite mutations in Rho GTPase-encoding genes representing uncommon events, it was described that RAC1-activating mutations are present in approximately 4-9% of melanomas.	('mutations', 'Var', (115, 124))	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('GTP', 'Chemical', 'MESH:D006160', (25, 28))	('RAC1', 'Gene', '5879', (99, 103))	('mutations', 'Var', (8, 17))	('melanomas', 'Disease', (162, 171))	('RAC1', 'Gene', (99, 103))	('Rho GTPase-encoding', 'Gene', (21, 40))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))
121888	33072757	Particularly, the P29S substitution is the most common RAC1 mutation found in malignant melanomas, inducing RAC1 spontaneous activation through the constitutive GDP/GTP nucleotide exchange.	('inducing', 'Reg', (99, 107))	('RAC1', 'Gene', (55, 59))	('activation', 'PosReg', (125, 135))	('RAC1', 'Gene', '5879', (108, 112))	('GDP', 'Chemical', 'MESH:D006153', (161, 164))	('RAC1', 'Gene', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('P29S', 'Var', (18, 22))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('spontaneous', 'MPA', (113, 124))	('GTP', 'Chemical', 'MESH:D006160', (165, 168))	('P29S', 'Mutation', 'rs1057519874', (18, 22))	('malignant melanomas', 'Phenotype', 'HP:0002861', (78, 97))	('malignant melanomas', 'Disease', 'MESH:D008545', (78, 97))	('RAC1', 'Gene', '5879', (55, 59))	('malignant melanomas', 'Disease', (78, 97))
121889	33072757	From a clinical point of view, RAC1P29S mutation is associated with increased melanoma thickness, high mitotic rate, ulceration, and the occurrence of the nodular melanoma subtype (Table 1).	('nodular melanoma', 'Disease', (155, 171))	('ulceration', 'CPA', (117, 127))	('rat', 'Species', '10116', (111, 114))	('nodular melanoma', 'Phenotype', 'HP:0012058', (155, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma thickness', 'Disease', 'MESH:D008545', (78, 96))	('melanoma thickness', 'Disease', (78, 96))	('nodular melanoma', 'Disease', 'MESH:D008545', (155, 171))	('high mitotic rate', 'CPA', (98, 115))	('increased', 'PosReg', (68, 77))	('RAC1P29S', 'Var', (31, 39))	('rat', 'Species', '10116', (121, 124))
121891	33072757	Consequently, NF2/Merlin inhibition by phosphorylation of the Rac effector PAK promotes melanoma cell resistance to MAPK inhibitors (Table 1).	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('NF2', 'Gene', (14, 17))	('phosphorylation', 'Var', (39, 54))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('Rac', 'Gene', '207', (62, 65))	('promotes', 'PosReg', (79, 87))	('NF2', 'Gene', '4771', (14, 17))	('inhibition', 'NegReg', (25, 35))	('Merlin', 'Gene', (18, 24))	('Merlin', 'Gene', '4771', (18, 24))	('Rac', 'Gene', (62, 65))
121892	33072757	Consistently, the ectopic expression of RAC1P29S in melanoma cell lines increases resistance to BRAF and MEK inhibitor therapies.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('increases', 'PosReg', (72, 81))	('resistance to BRAF', 'MPA', (82, 100))	('RAC1P29S', 'Var', (40, 48))	('ectopic expression', 'MPA', (18, 36))
121893	33072757	Indeed, using a mouse xenograft model, the authors observed that this mutation enhances melanoma growth and invasion and confers drug resistance against BRAF and MEK kinase inhibitors (Table 1).	('melanoma growth', 'Disease', (88, 103))	('drug resistance', 'Phenotype', 'HP:0020174', (129, 144))	('enhances', 'PosReg', (79, 87))	('melanoma growth', 'Disease', 'MESH:D008545', (88, 103))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('drug resistance', 'MPA', (129, 144))	('mouse', 'Species', '10090', (16, 21))	('mutation', 'Var', (70, 78))	('invasion', 'CPA', (108, 116))
121894	33072757	More recently, using transgenic mouse models, it was also demonstrated that Rac1P29S can cooperate with BRAFV600E to promote melanoma tumorigenesis.	('rat', 'Species', '10116', (94, 97))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('BRAFV600E', 'Mutation', 'rs113488022', (104, 113))	('Rac1P29S', 'Var', (76, 84))	('melanoma tumorigenesis', 'Disease', (125, 147))	('melanoma tumorigenesis', 'Disease', 'MESH:D063646', (125, 147))	('mouse', 'Species', '10090', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('promote', 'PosReg', (117, 124))	('rat', 'Species', '10116', (65, 68))
121895	33072757	Besides triggering molecular cascades that are pivotal for melanoma aggressiveness and response to therapy, RAC1P29S can also alter the immune background of these tumors.	('RAC1P29S', 'Var', (108, 116))	('melanoma aggressiveness', 'Disease', (59, 82))	('alter', 'Reg', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('aggressiveness', 'Phenotype', 'HP:0000718', (68, 82))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma aggressiveness', 'Disease', 'MESH:D008545', (59, 82))
121897	33072757	Hence, these studies suggest that the P29S mutation can modulate melanoma immunogenicity to suppress the immune response against the tumor.	('modulate', 'Reg', (56, 64))	('P29S', 'Var', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('P29S', 'Mutation', 'rs1057519874', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('suppress', 'NegReg', (92, 100))	('tumor', 'Disease', (133, 138))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
121898	33072757	Considering the impact of RAC1P29S mutation in melanoma, it would be interesting to assess its relevance as a predictive biomarker of response to anti-PD-1 therapies, since it could select the patients who would most benefit from this therapy.	('patients', 'Species', '9606', (193, 201))	('PD-1', 'Gene', (151, 155))	('PD-1', 'Gene', '5133', (151, 155))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('RAC1P29S', 'Var', (26, 34))
121904	33072757	RHOA silencing was found to induce an increase in melanoma sensitivity to UV, increasing the number of DNA damages caused and dramatically reducing melanoma cell motility and invasion.	('RHOA', 'Gene', (0, 4))	('increase', 'PosReg', (38, 46))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('increasing', 'PosReg', (78, 88))	('silencing', 'Var', (5, 14))	('melanoma cell motility', 'Disease', (148, 170))	('invasion', 'CPA', (175, 183))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('melanoma cell motility', 'Disease', 'MESH:D015835', (148, 170))	('RHOA', 'Gene', '387', (0, 4))	('reducing', 'NegReg', (139, 147))	('DNA damages caused', 'MPA', (103, 121))
121939	33072757	Therefore, low levels of RAB7 expression in primary tumors are associated with an increased risk of melanoma metastasis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('expression', 'MPA', (30, 40))	('melanoma metastasis', 'Disease', (100, 119))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('RAB7', 'Gene', '338382', (25, 29))	('low levels', 'Var', (11, 21))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('RAB7', 'Gene', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma metastasis', 'Disease', 'MESH:D009362', (100, 119))
121944	33072757	For example, RAB4A expression directly affects the production of pro-cathepsin L, a cysteine protease that contributes for the resistance to complement-mediated cell lysis in melanoma cells (Table 1).	('RAB4A', 'Gene', (13, 18))	('cathepsin L', 'Gene', '1514', (69, 80))	('resistance to', 'MPA', (127, 140))	('affects', 'Reg', (39, 46))	('expression', 'Var', (19, 29))	('production', 'MPA', (51, 61))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('melanoma', 'Disease', (175, 183))	('RAB4A', 'Gene', '5867', (13, 18))	('cathepsin L', 'Gene', (69, 80))
121969	33072757	Additionally, ARF6 ectopic expression reduces tumor growth and increases the invasive ability of melanoma cells in an immunocompromised mouse model.	('increases', 'PosReg', (63, 72))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('ectopic expression', 'Var', (19, 37))	('reduces', 'NegReg', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ARF6', 'Gene', '11845', (14, 18))	('tumor', 'Disease', (46, 51))	('ARF6', 'Gene', (14, 18))	('mouse', 'Species', '10090', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
121980	33072757	Previously, the presence of a specific ARL1 variant (C148R) was assessed in 351 familial and sporadic melanomas and associated with an increased risk for heterozygous carriers to develop melanoma.	('melanomas', 'Disease', (102, 111))	('develop', 'PosReg', (179, 186))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Disease', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('melanoma', 'Disease', (102, 110))	('ARL1', 'Gene', '400', (39, 43))	('C148R', 'Var', (53, 58))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('C148R', 'Mutation', 'p.C148R', (53, 58))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('ARL1', 'Gene', (39, 43))
121989	33072757	Hence, the targeting of Ras GTPases could have harmful effects on tissues not affected by the disease.	('effects', 'Reg', (55, 62))	('GTPases', 'Protein', (28, 35))	('Ras', 'Protein', (24, 27))	('GTP', 'Chemical', 'MESH:D006160', (28, 31))	('targeting', 'Var', (11, 20))
121993	33072757	This drug was indicated for phase II trials and seems to be a promising therapeutic strategy for patients with RAS mutations who have no specific therapeutic options.	('RAS', 'Gene', (111, 114))	('rat', 'Species', '10116', (86, 89))	('mutations', 'Var', (115, 124))	('patients', 'Species', '9606', (97, 105))
121994	33072757	EHT1864 is an inhibitor with high affinity for Rac GTPases, impairing their activity by inhibiting GTP binding.	('GTP', 'Chemical', 'MESH:D006160', (99, 102))	('activity', 'MPA', (76, 84))	('EHT1864', 'Chemical', 'MESH:C506907', (0, 7))	('GTP', 'Chemical', 'MESH:D006160', (51, 54))	('GTP', 'Protein', (99, 102))	('Rac', 'Gene', '207', (47, 50))	('EHT1864', 'Var', (0, 7))	('impairing', 'NegReg', (60, 69))	('inhibiting', 'NegReg', (88, 98))	('Rac', 'Gene', (47, 50))
121996	33072757	NSC23766 is another Rac1 inhibitor that blocks the interaction of Rac1 with its GEFs TRIO and TIAM1.	('blocks', 'NegReg', (40, 46))	('NSC23766', 'Var', (0, 8))	('TIAM1', 'Gene', '7074', (94, 99))	('TRIO', 'Gene', (85, 89))	('interaction', 'Interaction', (51, 62))	('NSC23766', 'Chemical', 'MESH:C487513', (0, 8))	('Rac1', 'Gene', '5879', (20, 24))	('TRIO', 'Gene', '7204', (85, 89))	('Rac1', 'Gene', '5879', (66, 70))	('Rac1', 'Gene', (20, 24))	('Rac1', 'Gene', (66, 70))	('TIAM1', 'Gene', (94, 99))
121997	33072757	Despite several in vitro assays having demonstrated a reduction in the invasion ability of distinct types of tumor cells after NSC23766 treatment, this inhibitor has been described as inefficient for clinical administration due to its low efficacy.	('rat', 'Species', '10116', (46, 49))	('reduction', 'NegReg', (54, 63))	('NSC23766', 'Chemical', 'MESH:C487513', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('NSC23766', 'Var', (127, 135))	('rat', 'Species', '10116', (217, 220))	('tumor', 'Disease', (109, 114))
121999	33072757	Rab7 was the first member of the Rab GTPase family to be the target of an inhibitor, namely, CID1067700.	('CID1067700', 'Var', (93, 103))	('Rab', 'Gene', (33, 36))	('Rab', 'Gene', '3267', (0, 3))	('CID1067700', 'Chemical', 'MESH:C000607523', (93, 103))	('Rab', 'Gene', (0, 3))	('Rab7', 'Gene', '338382', (0, 4))	('Rab7', 'Gene', (0, 4))	('Rab', 'Gene', '3267', (33, 36))	('GTP', 'Chemical', 'MESH:D006160', (37, 40))
122108	31114671	Most high-grade pleomorphic liposarcomas did not express UCP1 but in a minority of pleomorphic liposarcomas, scattered small and large vacuolated tumour cells expressed UCP1 (Fig.	('liposarcoma', 'Phenotype', 'HP:0012034', (28, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('pleomorphic liposarcomas', 'Disease', (16, 40))	('tumour', 'Disease', (146, 152))	('liposarcomas', 'Phenotype', 'HP:0012034', (95, 107))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (83, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (16, 40))	('UCP1', 'Var', (169, 173))	('liposarcomas', 'Phenotype', 'HP:0012034', (28, 40))	('liposarcoma', 'Phenotype', 'HP:0012034', (95, 106))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('pleomorphic liposarcomas', 'Disease', (83, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
122124	31114671	UCP1-mRNA expression in lipomas of multiple symmetric lipomatosis, bearing pathogenic mitochondrial mutations has been reported, but UCP1 expression in simple lipomas or lipoma subtypes has not been identified.	('lipomas', 'Phenotype', 'HP:0001012', (159, 166))	('lipoma', 'Phenotype', 'HP:0012032', (170, 176))	('lipomas or lipoma', 'Disease', 'MESH:D008067', (159, 176))	('lipoma', 'Phenotype', 'HP:0012032', (24, 30))	('lipomas or lipoma', 'Disease', (159, 176))	('lipomas', 'Phenotype', 'HP:0001012', (24, 31))	('lipoma', 'Phenotype', 'HP:0012032', (159, 165))	('lipomas', 'Phenotype', 'HP:0012032', (159, 166))	('lipomatosis', 'Disease', 'MESH:D008068', (54, 65))	('UCP1-mRNA', 'MPA', (0, 9))	('lipomatosis', 'Disease', (54, 65))	('lipomas', 'Disease', 'MESH:D008067', (159, 166))	('lipomas', 'Disease', (159, 166))	('simple lipomas', 'Phenotype', 'HP:0001012', (152, 166))	('lipomas', 'Phenotype', 'HP:0012032', (24, 31))	('lipoma', 'Phenotype', 'HP:0012032', (54, 60))	('lipomas', 'Disease', (24, 31))	('lipomas', 'Disease', 'MESH:D008067', (24, 31))	('mutations', 'Var', (100, 109))	('lipomatosis', 'Phenotype', 'HP:0001012', (54, 65))
122134	31114671	Polyclonal antibodies can cross-react with structurally-related molecules so it is possible that staining with the anti-UCP1 antibody of malignant tumour cells in some non-adipose sarcomas could represent a cross-reaction with a UCP1 homologue, such as UCP2 and/or UCP3 in rhabdomyosarcomas.	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (273, 290))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('cross-reaction', 'Disease', (207, 221))	('UCP2', 'Gene', (253, 257))	('sarcomas', 'Disease', (180, 188))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (273, 289))	('anti-UCP1', 'Var', (115, 124))	('non-adipose', 'Disease', (168, 179))	('UCP3', 'Gene', '7352', (265, 269))	('sarcomas', 'Disease', 'MESH:D012509', (282, 290))	('sarcomas', 'Phenotype', 'HP:0100242', (282, 290))	('malignant tumour', 'Disease', 'MESH:D009369', (137, 153))	('sarcomas', 'Disease', (282, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('cross-reaction', 'Disease', 'MESH:D004342', (207, 221))	('UCP3', 'Gene', (265, 269))	('UCP2', 'Gene', '7351', (253, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('malignant tumour', 'Disease', (137, 153))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (273, 290))	('rhabdomyosarcomas', 'Disease', (273, 290))
122156	31186694	Results of RT-qPCR showed that mRNA expression levels of p16 and nm23-H1 in tumor tissues of STS patients were significantly lower than those in para-carcinoma normal tissues (P<0.01).	('nm23-H1', 'Gene', '4830', (65, 72))	('STS', 'Phenotype', 'HP:0030448', (93, 96))	('para-carcinoma', 'Disease', (145, 159))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('lower', 'NegReg', (125, 130))	('para-carcinoma', 'Disease', 'MESH:D002277', (145, 159))	('p16', 'Var', (57, 60))	('mRNA expression levels', 'MPA', (31, 53))	('nm23-H1', 'Gene', (65, 72))	('patients', 'Species', '9606', (97, 105))
122159	31186694	There was a positive correlation between the expression levels of p16 and nm23-H1 in tumor tissues of STS patients.	('tumor', 'Disease', (85, 90))	('p16', 'Var', (66, 69))	('nm23-H1', 'Gene', '4830', (74, 81))	('STS', 'Phenotype', 'HP:0030448', (102, 105))	('expression', 'MPA', (45, 55))	('nm23-H1', 'Gene', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
122161	31186694	The overall 5-year survival rate of patients was 54.68%, and the prognosis of patients with positive expression levels of p16 and nm23-H1 was better.	('p16', 'Var', (122, 125))	('patients', 'Species', '9606', (36, 44))	('nm23-H1', 'Gene', (130, 137))	('patients', 'Species', '9606', (78, 86))	('nm23-H1', 'Gene', '4830', (130, 137))	('better', 'PosReg', (142, 148))	('expression', 'MPA', (101, 111))
122162	31186694	Univariate survival analyses revealed that p16 and nm23-H1 were influencing factors of the overall survival rate of STS patients.	('nm23-H1', 'Gene', '4830', (51, 58))	('patients', 'Species', '9606', (120, 128))	('STS', 'Phenotype', 'HP:0030448', (116, 119))	('p16', 'Var', (43, 46))	('nm23-H1', 'Gene', (51, 58))
122173	31186694	Therefore, we selected to study the expression of p16 and nm23-H1 and its relationship with the pathogenesis and prognosis of soft tissue sarcoma.	('soft tissue sarcoma', 'Disease', (126, 145))	('p16', 'Var', (50, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (126, 145))	('nm23-H1', 'Gene', (58, 65))	('nm23-H1', 'Gene', '4830', (58, 65))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (126, 145))
122196	31186694	Results of immunohistochemical detection showed that the positive immunohistochemical staining of p16 and nm23-H1 was dark brown, and p16 staining was mainly located in the nucleus and cytoplasm.	('nm23-H1', 'Gene', '4830', (106, 113))	('p16', 'Var', (134, 137))	('p16', 'Gene', (98, 101))	('nm23-H1', 'Gene', (106, 113))
122208	31186694	Patients with negative protein expression levels of p16 and nm23-H1 had poorer survival.	('protein expression levels', 'MPA', (23, 48))	('nm23-H1', 'Gene', (60, 67))	('nm23-H1', 'Gene', '4830', (60, 67))	('p16', 'Var', (52, 55))	('negative', 'NegReg', (14, 22))	('poorer', 'NegReg', (72, 78))	('Patients', 'Species', '9606', (0, 8))
122209	31186694	Univariate survival analyses showed that both p16 and nm23-H1 could significantly affect the overall survival rate of STS patients (P<0.05; Fig.	('STS', 'Phenotype', 'HP:0030448', (118, 121))	('nm23-H1', 'Gene', (54, 61))	('nm23-H1', 'Gene', '4830', (54, 61))	('patients', 'Species', '9606', (122, 130))	('p16', 'Var', (46, 49))	('affect', 'Reg', (82, 88))
122213	31186694	Studies have proven that there are gene deletion, mutation, methylation and other abnormalities in p16 in a variety of tumor cell lines and solid tumors, so it is speculated that p16 gene plays a key role in tumor formation and development processes.	('p16', 'Gene', (99, 102))	('tumor', 'Disease', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('solid tumors', 'Disease', (140, 152))	('deletion', 'Var', (40, 48))	('methylation', 'Var', (60, 71))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', (208, 213))	('solid tumors', 'Disease', 'MESH:D009369', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mutation', 'Var', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
122218	31186694	Moreover, tumor patients with high nm23-H1 expression have better prognosis.	('nm23-H1', 'Gene', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('patients', 'Species', '9606', (16, 24))	('expression', 'MPA', (43, 53))	('high', 'Var', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('nm23-H1', 'Gene', '4830', (35, 42))
122220	31186694	Detection results showed that the expression levels of p16 and nm23-H1 in tumor tissues of STS patients were significantly lower than those in para-carcinoma normal tissues (P<0.01).	('nm23-H1', 'Gene', (63, 70))	('nm23-H1', 'Gene', '4830', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('patients', 'Species', '9606', (95, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('p16', 'Var', (55, 58))	('lower', 'NegReg', (123, 128))	('STS', 'Phenotype', 'HP:0030448', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('para-carcinoma', 'Disease', 'MESH:D002277', (143, 157))	('para-carcinoma', 'Disease', (143, 157))	('expression levels', 'MPA', (34, 51))
122222	31186694	The results of Spearman's test showed that the expression of p16 and nm23-H1 mRNA was positively correlated with the expression of protein.	('nm23-H1', 'Gene', (69, 76))	('nm23-H1', 'Gene', '4830', (69, 76))	('expression', 'MPA', (117, 127))	('expression', 'MPA', (47, 57))	('correlated', 'Interaction', (97, 107))	('p16', 'Var', (61, 64))	('protein', 'MPA', (131, 138))
122227	31186694	The 64 STS patients were followed up for 5 years, and results showed that the overall 5-year survival rate of patients was 54.68%, and patients with positive expression levels of p16 and nm23-H1 had a better prognosis.	('patients', 'Species', '9606', (135, 143))	('nm23-H1', 'Gene', '4830', (187, 194))	('p16', 'Var', (179, 182))	('nm23-H1', 'Gene', (187, 194))	('STS', 'Phenotype', 'HP:0030448', (7, 10))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (110, 118))
122228	31186694	Moreover, univariate survival analyses showed that both p16 and nm23-H1 could affect the overall survival rate of STS patients.	('p16', 'Var', (56, 59))	('nm23-H1', 'Gene', '4830', (64, 71))	('affect', 'Reg', (78, 84))	('nm23-H1', 'Gene', (64, 71))	('patients', 'Species', '9606', (118, 126))	('STS', 'Phenotype', 'HP:0030448', (114, 117))
122229	31186694	In conclusion, the expression of p16 and nm23-H1 is low in STS, and their expression levels are closely related to the pathological parameters and prognosis of STS patients, so they can serve as reference indexes for prognosis estimation of STS.	('expression', 'MPA', (19, 29))	('STS', 'Phenotype', 'HP:0030448', (59, 62))	('STS', 'Phenotype', 'HP:0030448', (160, 163))	('patients', 'Species', '9606', (164, 172))	('expression levels', 'MPA', (74, 91))	('STS', 'Phenotype', 'HP:0030448', (241, 244))	('p16', 'Var', (33, 36))	('related', 'Reg', (104, 111))	('nm23-H1', 'Gene', (41, 48))	('low', 'NegReg', (52, 55))	('nm23-H1', 'Gene', '4830', (41, 48))
122281	26942051	Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood gammadeltaT, which express the Vgamma9Vdelta2 T cell receptor (TCR) (Vdelta2 T cells).	('T cell receptor', 'Gene', (154, 169))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (27, 42))	('Vgamma9Vdelta2', 'Var', (139, 153))	('TCR', 'Gene', '6962', (171, 174))	('Vdelta2 T', 'CellLine', 'CVCL:0042', (146, 155))	('TCR', 'Gene', (171, 174))	('Vdelta2 T', 'CellLine', 'CVCL:0042', (177, 186))	('T cell receptor', 'Gene', '6962', (154, 169))
122287	26942051	Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation.	('ch14.18/CHO', 'Var', (28, 39))	('IL-2', 'Gene', (61, 65))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (41, 56))	('ch14.18', 'Chemical', 'MESH:C112746', (28, 35))
122294	26942051	Vgamma9Vdelta2+ gammadeltaT cells have previously been shown to be potent killers of a range of hematological and solid tumor cell lines but in the majority of cases their cytotoxicity is significantly enhanced by target opsonization; and in diseases such as neuroblastoma is almost entirely antibody dependent, which is in part a reflection of that cancer's immunoinhibitory environment.	('neuroblastoma', 'Disease', 'MESH:D009447', (259, 272))	('cytotoxicity', 'Disease', 'MESH:D064420', (172, 184))	('enhanced', 'PosReg', (202, 210))	('neuroblastoma', 'Disease', (259, 272))	('cancer', 'Disease', 'MESH:D009369', (350, 356))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Disease', (350, 356))	('Vgamma9Vdelta2+', 'Var', (0, 15))	('neuroblastoma', 'Phenotype', 'HP:0003006', (259, 272))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cytotoxicity', 'Disease', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('tumor', 'Disease', (120, 125))
122306	26942051	Given the evidence that the cytotoxicity of Vgamma9Vdelta2+ gammadeltaT cells is significantly enhanced by target opsonization, there is a rationale for determining the efficacy of therapeutic combinations of lytic antibodies with agents to activate and expand gammadeltaT cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('rat', 'Species', '10116', (139, 142))	('Vgamma9Vdelta2+', 'Var', (44, 59))	('cytotoxicity', 'Disease', (28, 40))	('enhanced', 'PosReg', (95, 103))
122313	26942051	This is consistent with our previous findings against neuroblastoma which indicate that Vdelta1+ and Vdelta1-/Vdelta2- gammadeltaT cell cytotoxicity is antibody independent.	('neuroblastoma', 'Disease', 'MESH:D009447', (54, 67))	('Vdelta1+', 'Var', (88, 96))	('cytotoxicity', 'Disease', (136, 148))	('neuroblastoma', 'Disease', (54, 67))	('Vdelta1-/Vdelta2-', 'Var', (101, 118))	('neuroblastoma', 'Phenotype', 'HP:0003006', (54, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (136, 148))
122326	26942051	Augmentation of cytotoxicity by target opsonization with ch14.18 was only observed in the GD2bright cell line TC71 (p = 0.006, n = 6).	('ch14.18', 'Var', (57, 64))	('cytotoxicity', 'Disease', 'MESH:D064420', (16, 28))	('ch14.18', 'Chemical', 'MESH:C112746', (57, 64))	('cytotoxicity', 'Disease', (16, 28))
122329	26942051	Opsonization of GD2bright DC-ES6 significantly enhanced killing by Vdelta2+ gammadeltaT cells, which was minimal in the absence of ch14.18/CHO antibody (Fig.	('GD2bright', 'Var', (16, 25))	('killing', 'CPA', (56, 63))	('enhanced', 'PosReg', (47, 55))	('DC-ES6', 'Gene', (26, 32))	('ch14.18', 'Chemical', 'MESH:C112746', (131, 138))
122332	26942051	Published studies have demonstrated that binding of anti-GD2 antibodies to GD2+ neuroblastoma, melanoma and small cell lung cancer cell lines leads to increased levels of cell death via caspase-dependent and -independent pathways.	('increased', 'PosReg', (151, 160))	('neuroblastoma', 'Disease', (80, 93))	('antibodies', 'Var', (61, 71))	('small cell lung cancer', 'Disease', 'MESH:D055752', (108, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (108, 130))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('binding', 'Interaction', (41, 48))	('neuroblastoma', 'Phenotype', 'HP:0003006', (80, 93))	('melanoma', 'Disease', (95, 103))	('anti-GD2', 'Protein', (52, 60))	('rat', 'Species', '10116', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cell death', 'MPA', (171, 181))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('small cell lung cancer', 'Disease', (108, 130))	('neuroblastoma', 'Disease', 'MESH:D009447', (80, 93))
122338	26942051	This effect was not seen in Ewing's sarcoma; ch14.18/CHO had minimal cytotoxicity at the same concentration against Ewing's sarcoma irrespective of GD2 expression; the difference between the killing of Kelly or LAN1 and GD2bright DC-ES6, was highly significant (p =<0.0001).	("Ewing's sarcoma", 'Disease', (116, 131))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (28, 43))	('rat', 'Species', '10116', (101, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (69, 81))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (116, 131))	("Ewing's sarcoma", 'Disease', (28, 43))	('ch14.18', 'Chemical', 'MESH:C112746', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (28, 43))	('cytotoxicity', 'Disease', (69, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('ch14.18/CHO', 'Var', (45, 56))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (116, 131))
122346	26942051	Mice with small established tumors were randomly assigned to treatment groups, this design ensuring that therapeutic benefits of intravenous injections of Vgamma9Vdelta2+ gammadeltaT cells relies not only on the gammadeltaT cells being able to kill the tumor cells, but also on their ability to infiltrate the tumor from the bloodstream.	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumors', 'Disease', (28, 34))	('rat', 'Species', '10116', (301, 304))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (310, 315))	('tumor', 'Disease', (253, 258))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Vgamma9Vdelta2+', 'Var', (155, 170))
122351	26942051	Interestingly, there was a suggestion of some inhibition of growth from the combination of ch14.18/CHO and zoledronate alone in the absence of any human gammadeltaT cells though this was not significantly different from the tumor growth rate seen with gammadeltaT cells + zoledronate only (p = 0.19).	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('human', 'Species', '9606', (147, 152))	('growth', 'MPA', (60, 66))	('inhibition', 'NegReg', (46, 56))	('zoledronate', 'Chemical', 'MESH:D000077211', (272, 283))	('tumor', 'Disease', (224, 229))	('zoledronate', 'Chemical', 'MESH:D000077211', (107, 118))	('ch14.18/CHO', 'Var', (91, 102))	('rat', 'Species', '10116', (237, 240))	('ch14.18', 'Chemical', 'MESH:C112746', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
122353	26942051	In Vgamma9Vdelta2 + zoledronate treated mice, there was exponential tumor growth; however, when ch14.18/CHO was administered alongside the zoledronate and Vgamma9Vdelta2+ cells, there was a significant reduction in growth with tumor shrinkage in 2/4 mice.	('tumor', 'Disease', (68, 73))	('growth', 'MPA', (215, 221))	('tumor', 'Disease', (227, 232))	('zoledronate', 'Chemical', 'MESH:D000077211', (20, 31))	('ch14.18', 'Chemical', 'MESH:C112746', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mice', 'Species', '10090', (40, 44))	('zoledronate', 'Chemical', 'MESH:D000077211', (139, 150))	('mice', 'Species', '10090', (250, 254))	('ch14.18/CHO', 'Var', (96, 107))	('reduction', 'NegReg', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
122355	26942051	As was observed in the Ewing's model, the addition of ch14.18/CHO + zoledronate in the absence of Vgamma9Vdelta2+ gammadeltaT cells also led to a non-significant reduction in tumor growth compared with the Vdelta2 + zoledronate treatment.	('reduction', 'NegReg', (162, 171))	('tumor', 'Disease', (175, 180))	('zoledronate', 'Chemical', 'MESH:D000077211', (216, 227))	('ch14.18/CHO + zoledronate', 'Var', (54, 79))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('zoledronate', 'Chemical', 'MESH:D000077211', (68, 79))	('ch14.18', 'Chemical', 'MESH:C112746', (54, 61))
122371	26942051	The breadth of signaling that occurs following CD16 ligation in NK cells is quite different from the relatively small subset of molecules which are implicated in the conventional T cell "signal 2" via co-stimulatory receptors such as CD28.	('ligation', 'Var', (52, 60))	('CD16', 'Gene', '2214', (47, 51))	('CD28', 'Gene', (234, 238))	('CD16', 'Gene', (47, 51))	('CD28', 'Gene', '940', (234, 238))
122377	26942051	A number of clinical trials have already demonstrated that treating cancer patients with a combination of zoledronate and low dose IL-2 can lead to objective clinical responses in those patients where gammadeltaT cell expansion is achieved.	('zoledronate', 'Chemical', 'MESH:D000077211', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rat', 'Species', '10116', (48, 51))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('gammadeltaT cell expansion', 'Var', (201, 227))	('patients', 'Species', '9606', (186, 194))
122378	26942051	Target opsonization with appropriate antibody led to significant increases in Vgamma9Vdelta2+ cytotoxicity against tumor cells in a number of previous in vitro studies but there is a paucity of in vivo evidence supporting the combination of Vgamma9Vdelta2+ gammadeltaT cell activation and tumor-targeting antibody, and this approach has never been attempted in a clinical setting despite the availability of appropriate agents with known safety profiles in adults and children.	('children', 'Species', '9606', (468, 476))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Target opsonization', 'Var', (0, 19))	('increases', 'PosReg', (65, 74))	('opsonization', 'Var', (7, 19))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('cytotoxicity', 'Disease', 'MESH:D064420', (94, 106))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('cytotoxicity', 'Disease', (94, 106))
122382	26942051	Here, we have demonstrated that, in the context of neuroblastoma or Ewing's sarcoma expressing high levels of GD2, Vgamma9Vdelta2+ gammadeltaT cells can exert an antibody-dependent suppression of tumor growth, even at low doses.	('suppression', 'NegReg', (181, 192))	('neuroblastoma', 'Disease', 'MESH:D009447', (51, 64))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (68, 83))	('tumor', 'Disease', (196, 201))	('neuroblastoma', 'Disease', (51, 64))	('neuroblastoma', 'Phenotype', 'HP:0003006', (51, 64))	('rat', 'Species', '10116', (21, 24))	("Ewing's sarcoma", 'Disease', (68, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('Vgamma9Vdelta2+ gammadeltaT cells', 'Var', (115, 148))
122405	26942051	Adult female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were injected with 1.5 x 106 tumor cells (TC-71 or Kelly) subcutaneously, and tumor growth was monitored using electronic callipers.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (86, 91))	('TC-71', 'CellLine', 'CVCL:2213', (99, 104))	('tumor', 'Disease', (135, 140))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('Il2rgtm1Wjl/SzJ', 'Var', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
122413	26942051	Spleen samples were passed through a 70 muM cell strainer before being treated with ACK lysis buffer and being stained for FACS analysis to confirm Vdelta2+ gammadeltaT cell engraftment.	('ACK', 'Gene', (84, 87))	('ACK', 'Gene', '10188', (84, 87))	('Vdelta2+ gammadeltaT', 'Var', (148, 168))
122529	26068641	In this study, PET/CT resulted in a significant change in the prognosis and in therapeutic recommendations for the lymphoma patients and is expected to be particularly beneficial in these patients to exclude or to detect systemic disease.	('systemic disease', 'Disease', (221, 237))	('lymphoma', 'Phenotype', 'HP:0002665', (115, 123))	('change', 'Reg', (48, 54))	('prognosis', 'MPA', (62, 71))	('patients', 'Species', '9606', (188, 196))	('systemic disease', 'Disease', 'MESH:D034721', (221, 237))	('lymphoma', 'Disease', (115, 123))	('PET/CT', 'Var', (15, 21))	('patients', 'Species', '9606', (124, 132))	('lymphoma', 'Disease', 'MESH:D008223', (115, 123))
122732	25071272	Some vessels had CD31-positive [Figure 1e] and D2-40-positive cells [Figure 1f].	('CD31', 'Gene', '5175', (17, 21))	('CD31', 'Gene', (17, 21))	('D2-40-positive', 'Var', (47, 61))
122738	25071272	In our study, in addition to CD34 staining, immunohistochemical staining with CD31 and D2-40 demonstrated vessels with D2-40-positive and CD31-positive cells.	('D2-40-positive', 'Var', (119, 133))	('CD31', 'Gene', '5175', (138, 142))	('CD34', 'Gene', (29, 33))	('CD34', 'Gene', '947', (29, 33))	('CD31', 'Gene', (78, 82))	('CD31', 'Gene', '5175', (78, 82))	('CD31', 'Gene', (138, 142))
122760	24132922	Blockade of VEGF signaling may help normalize tumor vasculature and enable better drug delivery to the tumor and oxygenation to enhance the effectiveness of radiation.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (46, 51))	('VEGF', 'Protein', (12, 16))	('oxygenation', 'CPA', (113, 124))	('enhance', 'PosReg', (128, 135))	('normalize', 'MPA', (36, 45))	('drug delivery', 'MPA', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
122810	24132922	In a recent breast DCE-MRI study, we have shown that DeltaKtrans is a more sensitive and specific imaging biomarker for breast cancer diagnosis than either Ktrans (SSM) or Ktrans (SM).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Ktrans', 'Chemical', '-', (172, 178))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('Ktrans', 'Chemical', '-', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('DCE', 'Gene', '1718', (19, 22))	('DeltaKtrans', 'Var', (53, 64))	('DCE', 'Gene', (19, 22))	('Ktrans', 'Chemical', '-', (156, 162))
122889	24132922	Data from a VEGF-overexpressing sarcoma mouse model demonstrated that VEGF receptor blockade can enhance chemotherapy responsiveness and decrease the development of pulmonary metastases, suggesting that the benefit of these agents could potentially be greatest in the low disease-burden setting of earlier stage disease.	('chemotherapy responsiveness', 'MPA', (105, 132))	('pulmonary metastases', 'Disease', 'MESH:D009362', (165, 185))	('pulmonary metastases', 'Disease', (165, 185))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('decrease', 'NegReg', (137, 145))	('sarcoma', 'Disease', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('enhance', 'PosReg', (97, 104))	('VEGF receptor', 'Gene', (70, 83))	('mouse', 'Species', '10090', (40, 45))	('blockade', 'Var', (84, 92))
122912	32977646	Our results support the development of a "first in humans" study to evaluate the potential of our anti-VEGFR2 CAR-T cell therapy as a new treatment option for sarcoma patients.	('sarcoma', 'Disease', (159, 166))	('patients', 'Species', '9606', (167, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('anti-VEGFR2', 'Var', (98, 109))	('humans', 'Species', '9606', (51, 57))	('sarcoma', 'Disease', 'MESH:D012509', (159, 166))	('CAR-T', 'CellLine', 'CVCL:4140', (110, 115))
122930	32977646	Previously, we have developed adoptive immunotherapy using T cells expressing a chimeric antigen receptor (CAR) that targets VEGFR2 and reported that anti-VEGFR2 CAR-T cells could inhibit tumor growth based on tumor vascular injury in a variety of tumor-bearing mouse models.	('tumor', 'Disease', (188, 193))	('tumor vascular injury', 'Disease', 'MESH:D019043', (210, 231))	('tumor vascular injury', 'Disease', (210, 231))	('tumor', 'Disease', (248, 253))	('chimeric antigen receptor', 'Gene', (80, 105))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('inhibit', 'NegReg', (180, 187))	('mouse', 'Species', '10090', (262, 267))	('tumor', 'Disease', (210, 215))	('chimeric antigen receptor', 'Gene', '9970', (80, 105))	('VEGFR2', 'Gene', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('anti-VEGFR2', 'Var', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('CAR-T', 'CellLine', 'CVCL:4140', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
122942	32977646	In addition, removal of non-self-sequences in the CAR extracellular region as much as possible is expected to reduce the antigenicity of CAR-T cells and diminish their potential elimination by the host immune cells.	('removal', 'Var', (13, 20))	('non-self-sequences', 'Var', (24, 42))	('elimination', 'CPA', (178, 189))	('diminish', 'NegReg', (153, 161))	('CAR-T', 'CellLine', 'CVCL:4140', (137, 142))	('reduce', 'NegReg', (110, 116))	('antigenicity', 'MPA', (121, 133))
122957	32977646	Furthermore, the substitution of uridines by 5-methoxyuridines (CAR#5-coding mRNA) resulted in high CAR expression levels in the early post-EP period; however, the expression declined rapidly thereafter, with CAR expression levels at 48 h being as low as those of CAR#1-, #2-, and #3-coding mRNAs.	('uridines', 'Chemical', 'MESH:D014529', (54, 62))	('EP', 'Gene', '2069', (140, 142))	('substitution', 'Var', (17, 29))	('CAR expression levels', 'MPA', (100, 121))	('uridines', 'Chemical', 'MESH:D014529', (33, 41))	('CAR#1', 'Gene', (264, 269))	('5-methoxyuridines', 'Chemical', 'MESH:C016562', (45, 62))	('CAR#1', 'Gene', '9970', (264, 269))
122961	32977646	Remarkably, CAR#4- and CAR#5-T cells showed markedly higher cytotoxic activity than the other three CAR-T cells.	('CAR#4-', 'Var', (12, 18))	('higher', 'PosReg', (53, 59))	('cytotoxic activity', 'CPA', (60, 78))	('CAR-T', 'CellLine', 'CVCL:4140', (100, 105))	('CAR#', 'Var', (23, 27))
122982	32977646	In malignant peripheral nerve sheath tumor (MPNST) tissue from patient OU008, the staining with the 55B11 antibody was restricted to endothelial cells, whereas the staining with the V-85 antibody was found not only in endothelial cells but also in perivascular cells (Figure 4A,B).	('malignant peripheral nerve sheath tumor', 'Disease', (3, 42))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (3, 42))	('MPNST', 'Phenotype', 'HP:0100697', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('patient', 'Species', '9606', (63, 70))	('55B11', 'Var', (100, 105))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (3, 42))
122985	32977646	Although the VEGFR2 staining pattern between V-85 and 55B11 antibodies differed in some STS tissues, the VEGFR2 staining levels (DeltaMFI per field) given using the V-85 antibody positively correlated with those given using the 55B11 antibody, and additionally, with CD31 staining levels (Figure 4C).	('CD31', 'Gene', '5175', (267, 271))	('CD31', 'Gene', (267, 271))	('VEGFR2 staining levels', 'MPA', (105, 127))	('V-85', 'Var', (165, 169))
122987	32977646	Importantly, we also analyzed the expression of VEGFR2 in normal muscle, adipose, and skin tissues (surrounding STS tissues) to assess the safety of anti-VEGFR2 CAR-T cells therapy.	('anti-VEGFR2', 'Var', (149, 160))	('VEGFR2', 'Gene', (48, 54))	('CAR-T', 'CellLine', 'CVCL:4140', (161, 166))
122988	32977646	These results suggested that our anti-VEGFR2 CAR-T cells would not harm, at least, normal muscle, adipose, and skin tissues and could specifically injure tumor vascular endothelial cells in adjacent STS tissues.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('anti-VEGFR2', 'Var', (33, 44))	('injure', 'NegReg', (147, 153))	('CAR-T', 'CellLine', 'CVCL:4140', (45, 50))	('tumor', 'Disease', (154, 159))
123003	32977646	In addition, mRNAs synthesized using 5-methoxyuridine were reported to be less immunogenic and more efficient in translation.	('translation', 'MPA', (113, 124))	('more efficient', 'PosReg', (95, 109))	('5-methoxyuridine', 'Chemical', 'MESH:C016562', (37, 53))	('5-methoxyuridine', 'Var', (37, 53))
123004	32977646	These results suggested that the translation rate of CAR#5-coding mRNA is superior to that of CAR#4-coding mRNA containing wild-type uridines.	('superior', 'PosReg', (74, 82))	('uridines', 'Chemical', 'MESH:D014529', (133, 141))	('translation', 'MPA', (33, 44))	('CAR#5-coding', 'Var', (53, 65))
123052	32977646	CAR cDNA was detected using Custom TaqMan Gene Expression Assay (Thermo Fisher Scientific, Waltham, MA, USA) targeting the anti-VEGFR2 scFv.	('anti-VEGFR2', 'Var', (123, 134))	('scFv', 'Gene', '652070', (135, 139))	('scFv', 'Gene', (135, 139))
123075	32977646	In the competitive inhibition assay using these cell lines (VEGFR2+ NIH/3T3 cells and CAR+ Jurkat cells), NIH/3T3 cells were first incubated with two anti-VEGFR2 antibodies (V-85 or 7D4-6; 25 ng/mL) overnight at 4  C, and only then co-cultured with Jurkat cells.	('NIH/3T3', 'CellLine', 'CVCL:0594', (68, 75))	('V-85', 'Var', (174, 178))	('NIH/3T3', 'CellLine', 'CVCL:0594', (106, 113))	('CAR+ Jurkat', 'CellLine', 'CVCL:0065', (86, 97))	('anti-VEGFR2', 'Gene', (150, 161))	('Jurkat', 'CellLine', 'CVCL:0065', (91, 97))	('Jurkat', 'CellLine', 'CVCL:0065', (249, 255))
123088	32977646	In the present study, we demonstrated that anti-VEGFR2 CAR-T cells prepared using GMP-compatible EP, and a relevant mRNA sequence containing CleanCap as the 5' cap structure, were highly cytotoxic.	('CAR-T', 'CellLine', 'CVCL:4140', (55, 60))	('EP', 'Gene', '2069', (97, 99))	('GMP', 'Chemical', 'MESH:C066524', (82, 85))	('cytotoxic', 'CPA', (187, 196))	('anti-VEGFR2', 'Var', (43, 54))
123092	32977646	The following are available online at , Figure S1: CAR expression profile and VEGFR2-specific cytotoxic activity of human T cells transfected with different CAR variants via the EP method.	('variants', 'Var', (161, 169))	('cytotoxic activity', 'CPA', (94, 112))	('VEGFR2-specific', 'Gene', (78, 93))	('EP', 'Gene', '2069', (178, 180))	('human', 'Species', '9606', (116, 121))
123149	28969007	In contrast for Ewing's sarcoma, low ASS expression was associated with poorer overall survival (p=0.0013), and high SLC7A1 expression was associated with poorer overall survival (p=0.019).	('low', 'NegReg', (33, 36))	('SLC7A1', 'Gene', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('high', 'Var', (112, 116))	('poorer', 'NegReg', (155, 161))	('overall', 'MPA', (162, 169))	('poorer', 'NegReg', (72, 78))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (16, 31))	('expression', 'MPA', (124, 134))	("Ewing's sarcoma", 'Disease', (16, 31))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (16, 31))	('SLC7A1', 'Gene', '6541', (117, 123))	('ASS', 'Gene', (37, 40))	('ASS', 'Gene', '445', (37, 40))	('overall survival', 'MPA', (79, 95))
123176	28969007	Modulation of SLC7A1 expression in colorectal carcinoma and breast cancer cells decreases arginine uptake and reduces their proliferation and survival.	('Modulation', 'Var', (0, 10))	('SLC7A1', 'Gene', '6541', (14, 20))	('breast cancer', 'Disease', (60, 73))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (35, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('SLC7A1', 'Gene', (14, 20))	('proliferation', 'CPA', (124, 137))	('reduces', 'NegReg', (110, 117))	('decreases arginine', 'Phenotype', 'HP:0005961', (80, 98))	('decreases', 'NegReg', (80, 89))	('arginine uptake', 'MPA', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('survival', 'CPA', (142, 150))	('arginine', 'Chemical', 'MESH:D001120', (90, 98))	('colorectal carcinoma', 'Disease', (35, 55))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
123197	28969007	The function of ASL can be regulated by fumarate hydratase expression in renal cell carcinoma and by epigenetic modulation in glioblastoma.	('ASL', 'Gene', (16, 19))	('renal cell carcinoma', 'Disease', (73, 93))	('fumarate hydratase', 'Gene', '2271', (40, 58))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (73, 93))	('function', 'MPA', (4, 12))	('fumarate hydratase', 'Gene', (40, 58))	('epigenetic modulation', 'Var', (101, 122))	('glioblastoma', 'Disease', (126, 138))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (73, 93))	('glioblastoma', 'Disease', 'MESH:D005909', (126, 138))	('ASL', 'Gene', '435', (16, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('expression', 'MPA', (59, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (126, 138))	('regulated', 'Reg', (27, 36))
123201	28969007	A number of human genetic syndromes have emerged that are caused by germline mutations in components of the Ras/mitogen activated protein kinase (MAPK) pathway, and are associated with an increased risk of developing cancer.	('caused', 'Reg', (58, 64))	('associated', 'Reg', (169, 179))	('germline mutations', 'Var', (68, 86))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('human', 'Species', '9606', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
123202	28969007	Dysregulated KRAS signaling has also been implicated in rhabdomyosarcoma and Ewing's sarcoma pathogenesis.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (56, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	("Ewing's sarcoma", 'Disease', (77, 92))	('KRAS', 'Protein', (13, 17))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (56, 72))	('Dysregulated', 'Var', (0, 12))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (77, 92))	('implicated', 'Reg', (42, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (77, 92))	('rhabdomyosarcoma', 'Disease', (56, 72))
123206	28969007	Inhibitors of SLC7 transporters are likely to lead to toxicity from inhibiting uptake of other amino acids by non-malignant tissues as well as the tumour cells, and due to the structural homology between different SLC7 family members.	('toxicity', 'Disease', (54, 62))	('inhibiting', 'NegReg', (68, 78))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('Inhibitors', 'Var', (0, 10))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('uptake of other amino acids', 'MPA', (79, 106))	('SLC7 transporters', 'Gene', (14, 31))	('toxicity', 'Disease', 'MESH:D064420', (54, 62))	('tumour', 'Disease', (147, 153))
123213	28969007	Phase I and II clinical trials have been completed in adults with relapsed/refractory hepatocellular carcinoma, demonstrating that BCT-100 can lead to a sustained depletion of plasma arginine to undetectable levels (<8uM) for 5 days or more with weekly dosing.	('depletion of plasma arginine', 'MPA', (163, 191))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (86, 110))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (86, 110))	('depletion of plasma arginine', 'Phenotype', 'HP:0005961', (163, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('hepatocellular carcinoma', 'Disease', (86, 110))	('BCT-100', 'Var', (131, 138))	('arginine', 'Chemical', 'MESH:D001120', (183, 191))
123236	28969007	Oncogenic signatures were generated from microarray gene expression data from cancer gene perturbations.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (78, 84))	('perturbations', 'Var', (90, 103))	('cancer', 'Disease', 'MESH:D009369', (78, 84))
123237	28969007	ARG1 arginase 1 ARG2 arginase 2 ASL argininosuccinate lyase ASS argininosuccinate synthase DIPG diffuse intrinsic pontine gliomas MDSC myeloid-derived suppressor cells iNOS nitric oxide synthetase OTC ornithine transcarbamylase	('argininosuccinate synthase', 'Gene', (64, 90))	('ASL', 'Gene', '435', (32, 35))	('nitric oxide', 'Chemical', 'MESH:D009569', (173, 185))	('OTC', 'Gene', (197, 200))	('arginase 2', 'Gene', (21, 31))	('arginase 2', 'Gene', '384', (21, 31))	('argininosuccinate lyase', 'Gene', (36, 59))	('ARG2', 'Gene', (16, 20))	('ASL', 'Gene', (32, 35))	('DIPG', 'Chemical', '-', (91, 95))	('gliomas', 'Disease', (122, 129))	('ornithine transcarbamylase', 'Gene', (201, 227))	('argininosuccinate synthase', 'Gene', '445', (64, 90))	('ARG1', 'Gene', (0, 4))	('ASS', 'Gene', (60, 63))	('ornithine transcarbamylase', 'Gene', '5009', (201, 227))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('argininosuccinate lyase', 'Gene', '435', (36, 59))	('ASS', 'Gene', '445', (60, 63))	('ARG2', 'Gene', '384', (16, 20))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('OTC', 'Gene', '5009', (197, 200))	('ARG1', 'Gene', '383', (0, 4))	('DIPG', 'Var', (91, 95))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))
123345	27571786	Lastly, the PredART trial participants are not being randomized to M indicus pranii; this is relevant, as most of the cancers were diagnosed in participants receiving both prednisolone and M indicus pranii in the IMPI trial.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('M indicus pranii', 'Var', (189, 205))	('participants', 'Species', '9606', (26, 38))	('PredART', 'Chemical', '-', (12, 19))	('prednisolone', 'Chemical', 'MESH:D011239', (172, 184))	('M indicus pranii', 'Species', '35617', (189, 205))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('participants', 'Species', '9606', (144, 156))	('diagnosed', 'Reg', (131, 140))	('M indicus pranii', 'Species', '35617', (67, 83))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
123381	26095524	As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma.	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('XI-006', 'Chemical', 'MESH:C000607970', (110, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('MDM4', 'Gene', (20, 24))	('sarcomas', 'Disease', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('osteosarcoma', 'Phenotype', 'HP:0002669', (148, 160))	('Ewing and osteosarcoma', 'Disease', 'MESH:C563168', (138, 160))	('amplification', 'Var', (3, 16))
123386	26095524	Our findings suggest that XI-006 represents a novel therapeutic intervention for the treatment of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (98, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (98, 111))	('XI-006', 'Chemical', 'MESH:C000607970', (26, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (98, 111))	('XI-006', 'Var', (26, 32))
123392	26095524	Cancer is a multifaceted process that can arise due to the activation of proto-oncogenes and/or inactivation of tumour suppressor genes.	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('inactivation', 'Var', (96, 108))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('proto-oncogenes', 'Gene', (73, 88))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('activation', 'PosReg', (59, 69))
123395	26095524	In keeping with this hypothesis, amplification and/or overexpression of MDM4 has been documented across a wide spectrum of tumours including cutaneous melanoma (68.5%), retinoblastoma (65%), head and neck squamous carcinoma (50%) , breast (19%) and sarcoma (17%).	('squamous carcinoma', 'Phenotype', 'HP:0002860', (205, 223))	('overexpression', 'PosReg', (54, 68))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (200, 223))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('cutaneous melanoma', 'Disease', (141, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('retinoblastoma', 'Disease', 'MESH:D012175', (169, 183))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (141, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (141, 159))	('head and neck squamous carcinoma', 'Phenotype', 'HP:0012288', (191, 223))	('MDM4', 'Gene', (72, 76))	('amplification', 'Var', (33, 46))	('sarcoma', 'Disease', 'MESH:D012509', (249, 256))	('sarcoma', 'Disease', (249, 256))	('breast', 'Disease', (232, 238))	('retinoblastoma', 'Phenotype', 'HP:0009919', (169, 183))	('retinoblastoma', 'Disease', (169, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('tumours', 'Disease', (123, 130))	('neck squamous carcinoma', 'Disease', (200, 223))
123396	26095524	In particular, MDM4 copy number gain was documented in 54% of conventional, intramedullary, high-grade osteosarcomas and 33% of parosteal osteosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('conventional', 'Disease', (62, 74))	('osteosarcomas', 'Disease', (138, 151))	('parosteal osteosarcomas', 'Disease', 'MESH:D012516', (128, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('osteosarcomas', 'Phenotype', 'HP:0002669', (138, 151))	('intramedullary', 'Disease', (76, 90))	('gain', 'PosReg', (32, 36))	('osteosarcomas', 'Disease', 'MESH:D012516', (103, 116))	('MDM4', 'Gene', (15, 19))	('osteosarcomas', 'Disease', (103, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('osteosarcoma', 'Phenotype', 'HP:0002669', (138, 150))	('parosteal osteosarcomas', 'Disease', (128, 151))	('osteosarcomas', 'Phenotype', 'HP:0002669', (103, 116))	('copy number', 'Var', (20, 31))	('osteosarcomas', 'Disease', 'MESH:D012516', (138, 151))
123400	26095524	Owing to the prevalence of MDM4 genomic amplification/mRNA overexpression in human cancers, several strategies aimed at inhibiting the oncogenic activity of MDM4 have been explored.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('genomic amplification/mRNA', 'Var', (32, 58))	('MDM4', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('overexpression', 'PosReg', (59, 73))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
123409	26095524	To our knowledge, no studies have hitherto directly addressed whether repression of MDM4 activity can represent a novel therapeutic strategy for the treatment of sarcomas.	('repression', 'Var', (70, 80))	('sarcomas', 'Disease', 'MESH:D012509', (162, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('sarcomas', 'Disease', (162, 170))	('MDM4', 'Gene', (84, 88))
123410	26095524	In particular, as MDM4 amplification is a characteristic of both Ewing and osteosarcoma, this study has examined the biological effects of XI-006 both as a single agent and in combination with standard chemotherapeutic agents and olaparib (PARP inhibitor) in a comprehensive panel of Ewing and osteosarcoma cell lines in vitro.	('olaparib', 'Chemical', 'MESH:C531550', (230, 238))	('MDM4', 'Var', (18, 22))	('Ewing and osteosarcoma', 'Disease', 'MESH:C563168', (284, 306))	('XI-006', 'Chemical', 'MESH:C000607970', (139, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('PARP', 'Gene', (240, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('Ewing and osteosarcoma', 'Disease', 'MESH:C563168', (65, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (294, 306))	('PARP', 'Gene', '142', (240, 244))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))
123419	26095524	Recently, Wynendaele and colleagues reported that presence of a single nucleotide polymorphism (SNP34091, rs4245739) located 32 nucleotides downstream of the stop codon in the 3'UTR of MDM4 was associated with statistically significant increased MDM4 protein expression in high-grade ovarian carcinomas.	('protein', 'Protein', (251, 258))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (284, 302))	('carcinomas', 'Phenotype', 'HP:0030731', (292, 302))	('rs4245739', 'Var', (106, 115))	('MDM4', 'Gene', (185, 189))	('presence', 'Var', (50, 58))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (284, 302))	('rs4245739', 'Mutation', 'rs4245739', (106, 115))	('expression', 'MPA', (259, 269))	('increased', 'PosReg', (236, 245))	('ovarian carcinomas', 'Disease', (284, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('MDM4', 'Gene', (246, 250))
123421	26095524	To determine whether SNP34091 regulates MDM4 protein expression in sarcomas, the 3'UTR of MDM4 was sequenced.	('SNP34091', 'Var', (21, 29))	('regulates', 'Reg', (30, 39))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('MDM4', 'Gene', (40, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('sarcomas', 'Disease', (67, 75))
123434	26095524	In the Ewing sarcoma cell lines TC252 and RD-ES, XI-006 induced a dose-dependent decrease in the number of G1-phase cells, and accumulation of cells in SubG1.	('-ES', 'Chemical', 'MESH:D004540', (44, 47))	('accumulation', 'PosReg', (127, 139))	('decrease', 'NegReg', (81, 89))	('XI-006', 'Var', (49, 55))	('Ewing sarcoma', 'Disease', (7, 20))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (7, 20))	('cells in SubG1', 'CPA', (143, 157))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (7, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('XI-006', 'Chemical', 'MESH:C000607970', (49, 55))
123435	26095524	In contrast, XI-006 effectively arrested cell cycle progression in osteosarcoma cell lines (U20S, Saos-2), depleting the G1 compartment to 18.6-19.9% and increasing the G2 compartment to 45.7-61.5% (3 muM treatment).	('cell cycle progression', 'CPA', (41, 63))	('depleting', 'NegReg', (107, 116))	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('increasing', 'PosReg', (154, 164))	('XI-006', 'Chemical', 'MESH:C000607970', (13, 19))	('XI-006', 'Var', (13, 19))	('U20S', 'CellLine', 'CVCL:0042', (92, 96))	('muM', 'Gene', '56925', (201, 204))	('muM', 'Gene', (201, 204))	('G1 compartment', 'MPA', (121, 135))	('osteosarcoma', 'Disease', (67, 79))	('arrested', 'NegReg', (32, 40))	('G2 compartment', 'MPA', (169, 183))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
123436	26095524	As XI-006 was shown to decrease MDM4 expression in breast cancer cell lines, we investigated the effects of XI-006 on both MDM4 mRNA and protein levels in cell lines with varying MDM4 genomic, mRNA and protein expression levels (Table 2, Fig.	('decrease', 'NegReg', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('XI-006', 'Var', (3, 9))	('XI-006', 'Chemical', 'MESH:C000607970', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('XI-006', 'Chemical', 'MESH:C000607970', (3, 9))
123445	26095524	As X1-006 had no effect on MDM4 promoter activity or mRNA/protein levels at concentrations required to induce 50% apoptosis in the most sensitive Ewing sarcoma cell lines (<0.5 muM), this suggest that the ability of XI-006 to impart apoptosis occurs independently of MDM4.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (146, 159))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (146, 159))	('XI-006', 'Var', (216, 222))	('muM', 'Gene', '56925', (177, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('apoptosis', 'CPA', (233, 242))	('Ewing sarcoma', 'Disease', (146, 159))	('muM', 'Gene', (177, 180))	('XI-006', 'Chemical', 'MESH:C000607970', (216, 222))	('mRNA/protein levels', 'MPA', (53, 72))
123446	26095524	We next examined whether XI-006 can induce expression of TP53 target genes implicated in apoptosis (BAX, PUMA), cell cycle arrest (CDKN1A) and p53 regulation (MDM2).	('p53', 'Gene', '7157', (143, 146))	('XI-006', 'Var', (25, 31))	('XI-006', 'Chemical', 'MESH:C000607970', (25, 31))	('BAX', 'Gene', (100, 103))	('apoptosis', 'Disease', (89, 98))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (112, 129))	('p53', 'Gene', (143, 146))	('BAX', 'Gene', '581', (100, 103))	('CDKN1A', 'Gene', (131, 137))	('expression', 'MPA', (43, 53))	('cell cycle', 'CPA', (112, 122))	('induce', 'PosReg', (36, 42))	('CDKN1A', 'Gene', '1026', (131, 137))
123448	26095524	XI-006 dramatically increased mRNA expression levels of all TP53 target genes in Ewing sarcoma cell lines in a dose and time dependent manner.	('increased', 'PosReg', (20, 29))	('Ewing sarcoma', 'Disease', (81, 94))	('XI-006', 'Var', (0, 6))	('mRNA expression levels', 'MPA', (30, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('XI-006', 'Chemical', 'MESH:C000607970', (0, 6))
123458	26095524	Previous reports proposed that XI-006 activates the DNA damage response pathway leading to a delay in cell cycle progression.	('XI-006', 'Var', (31, 37))	('delay', 'NegReg', (93, 98))	('DNA damage response pathway', 'Pathway', (52, 79))	('cell cycle progression', 'CPA', (102, 124))	('activates', 'PosReg', (38, 47))	('XI-006', 'Chemical', 'MESH:C000607970', (31, 37))
123459	26095524	As XI-006 cytotoxicity occurs independently of MDM4, we sought to address whether XI-006 drives apoptosis through DNA damage.	('XI-006', 'Var', (82, 88))	('cytotoxicity', 'Disease', (10, 22))	('apoptosis', 'CPA', (96, 105))	('XI-006', 'Chemical', 'MESH:C000607970', (82, 88))	('XI-006', 'Chemical', 'MESH:C000607970', (3, 9))	('cytotoxicity', 'Disease', 'MESH:D064420', (10, 22))
123469	26095524	A significant reduction in both ATM and ATR mRNA expression (82.0% and 87.5% respectively) was observed following monotherapy KU-55933 treatment (5 muM) (Supplementary Fig.	('ATM', 'Gene', (32, 35))	('ATR', 'Gene', '545', (40, 43))	('ATR', 'Gene', (40, 43))	('KU-55933', 'Chemical', 'MESH:C495818', (126, 134))	('muM', 'Gene', '56925', (148, 151))	('ATM', 'Gene', '472', (32, 35))	('KU-55933', 'Var', (126, 134))	('muM', 'Gene', (148, 151))	('reduction', 'NegReg', (14, 23))
123471	26095524	Previous chemogenomic profiling studies suggested that XI-006 imparts its cytotoxic effect through the activation of the DNA-damage-response pathway.	('DNA-damage-response pathway', 'Pathway', (121, 148))	('XI-006', 'Var', (55, 61))	('activation', 'PosReg', (103, 113))	('cytotoxic effect', 'CPA', (74, 90))	('XI-006', 'Chemical', 'MESH:C000607970', (55, 61))
123478	26095524	Finally, alkaline comet assays were employed to investigate whether XI-006 induces single-strand break DNA damage.	('comet', 'Species', '302767', (18, 23))	('XI-006', 'Var', (68, 74))	('XI-006', 'Chemical', 'MESH:C000607970', (68, 74))	('single-strand break DNA damage', 'MPA', (83, 113))	('induces', 'Reg', (75, 82))
123481	26095524	As such, the ability of XI-006 to enhance the cytotoxic effects of four standard Ewing sarcoma chemotherapeutic agents (vincristine, actinomycin D, doxorubicin or etoposide) was assessed in five Ewing sarcoma cell lines (TC252, STA-ET-1, WE-68, RD-ES, and SK-N-MC).	('vincristine', 'Chemical', 'MESH:D014750', (120, 131))	('Ewing sarcoma', 'Disease', (195, 208))	('SK-N-MC', 'Chemical', '-', (256, 263))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('STA', 'Gene', (228, 231))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('actinomycin D', 'Chemical', 'MESH:D003609', (133, 146))	('XI-006', 'Chemical', 'MESH:C000607970', (24, 30))	('STA', 'Gene', '2656', (228, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', (81, 94))	('XI-006', 'Var', (24, 30))	('etoposide', 'Chemical', 'MESH:D005047', (163, 172))	('-ES', 'Chemical', 'MESH:D004540', (247, 250))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (195, 208))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (195, 208))	('doxorubicin', 'Chemical', 'MESH:D004317', (148, 159))	('enhance', 'PosReg', (34, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('WE', 'Chemical', 'MESH:D003348', (238, 240))
123485	26095524	The primary function of PARP is to sense and mediate repair of DNA single strand breaks (SSB).	('DNA single strand breaks', 'Var', (63, 87))	('PARP', 'Gene', '142', (24, 28))	('PARP', 'Gene', (24, 28))
123492	26095524	As XI-006 was previously shown to induce a significant delay in replication, Mre11 mRNA expression levels following XI-006 treatment was assessed.	('Mre11', 'Gene', '4361', (77, 82))	('XI-006', 'Var', (3, 9))	('replication', 'MPA', (64, 75))	('XI-006', 'Chemical', 'MESH:C000607970', (116, 122))	('delay', 'NegReg', (55, 60))	('Mre11', 'Gene', (77, 82))	('XI-006', 'Chemical', 'MESH:C000607970', (3, 9))
123511	26095524	It is known that DNA damage induces ATM/Chk2 dependent phosphorylation of several MDM4 C-terminal residues (S342, S367, S403), resulting in degradation of MDM4 and activation of p53.	('ATM', 'Gene', (36, 39))	('Chk2', 'Gene', '11200', (40, 44))	('Chk2', 'Gene', (40, 44))	('S403', 'Var', (120, 124))	('MDM4', 'MPA', (155, 159))	('S367', 'Var', (114, 118))	('ATM', 'Gene', '472', (36, 39))	('activation', 'PosReg', (164, 174))	('phosphorylation', 'MPA', (55, 70))	('degradation', 'MPA', (140, 151))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))	('MDM4', 'Gene', (82, 86))	('S342', 'Var', (108, 112))
123512	26095524	Indeed, ATM mediated phosphorylation of serine 15 in p53 was observed in Ewing sarcoma cell lines following treatment with double-strand break inducing concentrations of XI-006 (>0.5 muM).	('serine', 'Chemical', 'MESH:D012694', (40, 46))	('XI-006', 'Chemical', 'MESH:C000607970', (170, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('ATM', 'Gene', '472', (8, 11))	('muM', 'Gene', '56925', (183, 186))	('phosphorylation', 'MPA', (21, 36))	('p53', 'Gene', (53, 56))	('Ewing sarcoma', 'Disease', (73, 86))	('muM', 'Gene', (183, 186))	('p53', 'Gene', '7157', (53, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (73, 86))	('ATM', 'Gene', (8, 11))	('serine', 'Var', (40, 46))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (73, 86))
123518	26095524	Inhibition of PARP-1, results in the accumulation of persistent single-strand breaks which are converted to lethal double-strand breaks upon replication.	('single-strand breaks', 'MPA', (64, 84))	('PARP-1', 'Gene', (14, 20))	('PARP-1', 'Gene', '142', (14, 20))	('Inhibition', 'Var', (0, 10))	('accumulation', 'PosReg', (37, 49))
123523	26095524	Furthermore, DNA damage induced by expression of EWS-FLI1 was potentiated by PARP1 inhibition in vitro.	('EWS', 'Gene', '2130', (49, 52))	('EWS', 'Gene', (49, 52))	('inhibition', 'NegReg', (83, 93))	('DNA', 'CPA', (13, 16))	('FLI1', 'Gene', (53, 57))	('PARP1', 'Gene', '142', (77, 82))	('FLI1', 'Gene', '2313', (53, 57))	('potentiated', 'PosReg', (62, 73))	('PARP1', 'Gene', (77, 82))	('expression', 'Var', (35, 45))
123525	26095524	Previous chemogenomic profiling studies suggested that XI-006 (referred to as NSC-207895) activates the DNA-damage-response pathway through an indirect mechanism leading to a significant delay in replication and cell cycle progression.	('activates', 'PosReg', (90, 99))	('XI-006', 'Var', (55, 61))	('DNA-damage-response pathway', 'Pathway', (104, 131))	('delay', 'NegReg', (187, 192))	('XI-006', 'Chemical', 'MESH:C000607970', (55, 61))	('cell cycle progression', 'CPA', (212, 234))
123528	26095524	Inhibition or loss of PARP impairs Mre11 localisation to stalled forks, RPA and RAD51 foci formation, HR and replication restart.	('PARP', 'Gene', (22, 26))	('localisation', 'MPA', (41, 53))	('loss', 'Var', (14, 18))	('RPA', 'Protein', (72, 75))	('Mre11', 'Gene', (35, 40))	('RAD51', 'Gene', (80, 85))	('impairs', 'NegReg', (27, 34))	('RAD51', 'Gene', '5888', (80, 85))	('PARP', 'Gene', '142', (22, 26))	('Mre11', 'Gene', '4361', (35, 40))	('replication restart', 'CPA', (109, 128))
123529	26095524	Indeed numerous studies have shown that due to impaired HR DNA repair, loss of Mre11 expression sensitizes breast, colorectal, endometrial, and haematological cancers to PARP-inhibitors.	('Mre11', 'Gene', (79, 84))	('breast', 'Disease', (107, 113))	('impaired HR', 'Disease', 'MESH:D009422', (47, 58))	('PARP', 'Gene', '142', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('haematological cancers', 'Disease', 'MESH:D009369', (144, 166))	('Mre11', 'Gene', '4361', (79, 84))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('endometrial', 'Disease', (127, 138))	('loss', 'Var', (71, 75))	('impaired HR', 'Disease', (47, 58))	('sensitizes', 'Reg', (96, 106))	('haematological cancers', 'Disease', (144, 166))	('PARP', 'Gene', (170, 174))	('colorectal', 'Disease', (115, 125))
123538	26095524	Knockdown of FLOT1 has been shown to significantly impair cell proliferation and tumourigenicity of breast and esophageal squamous cell carcinoma cells in vitro and in vivo through the Akt/FOXO3a pathways.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('Knockdown', 'Var', (0, 9))	('FLOT1', 'Gene', (13, 18))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('cell proliferation', 'CPA', (58, 76))	('tumour', 'Disease', (81, 87))	('FOXO3a', 'Gene', '2309', (189, 195))	('FOXO3a', 'Gene', (189, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('impair', 'NegReg', (51, 57))	('breast and esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (100, 145))	('Akt', 'Gene', '207', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('Akt', 'Gene', (185, 188))	('FLOT1', 'Gene', '10211', (13, 18))
123539	26095524	Indeed, silencing of FLOT1 induced G1-S-phase arrest of breast cancer cells due to upregulated expression of the CDK inhibitors p21Cip1 and p27Kip1.	('p27Kip1', 'Gene', '1027', (140, 147))	('FLOT1', 'Gene', '10211', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('silencing', 'Var', (8, 17))	('p21Cip1', 'Gene', (128, 135))	('FLOT1', 'Gene', (21, 26))	('p27Kip1', 'Gene', (140, 147))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('upregulated', 'PosReg', (83, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('p21Cip1', 'Gene', '1026', (128, 135))	('G1-S-phase arrest', 'CPA', (35, 52))	('expression', 'MPA', (95, 105))
123541	26095524	This may be the basis of the finding that XI-006 induces apoptosis in Ewing sarcoma cell lines but cell cycle arrest in osteosarcoma cell lines (Supplementary Fig.	('cell cycle arrest', 'CPA', (99, 116))	('osteosarcoma', 'Disease', (120, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('apoptosis', 'CPA', (57, 66))	('osteosarcoma', 'Disease', 'MESH:D012516', (120, 132))	('XI-006', 'Var', (42, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (99, 116))	('Ewing sarcoma', 'Disease', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('XI-006', 'Chemical', 'MESH:C000607970', (42, 48))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (70, 83))	('osteosarcoma', 'Phenotype', 'HP:0002669', (120, 132))
123547	26095524	Microinjection of anti-KIF20A antibody was shown to induce multi-nucleation in Hela cells and knockdown of endogenous KIF20A expression markedly attenuated the growth of pancreatic and gastric cancer cells.	('gastric cancer', 'Phenotype', 'HP:0012126', (185, 199))	('knockdown', 'Var', (94, 103))	('induce', 'Reg', (52, 58))	('pancreatic', 'Disease', 'MESH:D010195', (170, 180))	('KIF20A', 'Gene', (118, 124))	('attenuated', 'NegReg', (145, 155))	('KIF20A', 'Gene', '10112', (118, 124))	('pancreatic', 'Disease', (170, 180))	('gastric cancer', 'Disease', (185, 199))	('KIF20A', 'Gene', (23, 29))	('Hela', 'CellLine', 'CVCL:0030', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('gastric cancer', 'Disease', 'MESH:D013274', (185, 199))	('KIF20A', 'Gene', '10112', (23, 29))	('multi-nucleation', 'CPA', (59, 75))
123550	26095524	In summary, our findings demonstrate that XI-006 is a promising new potential therapeutic for the treatment of Ewing sarcoma as it induced potent p53-independent apoptosis at non-DNA damaging concentrations specifically in Ewing sarcoma cell lines.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('XI-006', 'Var', (42, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (223, 236))	('Ewing sarcoma', 'Disease', (111, 124))	('Ewing sarcoma', 'Disease', (223, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('XI-006', 'Chemical', 'MESH:C000607970', (42, 48))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (223, 236))
123588	26095524	XI-006 induces potent p53-independent apoptosis in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('XI-006', 'Var', (0, 6))	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (22, 25))	('Ewing sarcoma', 'Disease', (51, 64))	('XI-006', 'Chemical', 'MESH:C000607970', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
123708	24904686	Dr. Bartlett receives salary support from US National Institutes of Health awards P30AI64518, U01AI067854, D43CA153722 and D43TW06732, and Health Resources and Services Administration grant T84HA21123.	('U01AI067854', 'Var', (94, 105))	('P30AI64518', 'Var', (82, 92))	('D43CA153722', 'Var', (107, 118))	('D43TW06732', 'Var', (123, 133))	('U01', 'CellLine', 'CVCL:2220', (94, 97))
123745	33600679	Contrary to previous data, the size of STS cannot determine the grade of STS, as in our study no significant differences in the volumes of higher- and low-grade STS were found, even if polycyclic/multilobulated G3 STS show a not significant larger volume, compared to G2/1 sarcoma.	('STS', 'Phenotype', 'HP:0030448', (73, 76))	('STS', 'Phenotype', 'HP:0030448', (214, 217))	('STS', 'Phenotype', 'HP:0030448', (39, 42))	('sarcoma', 'Disease', 'MESH:D012509', (273, 280))	('STS', 'Phenotype', 'HP:0030448', (161, 164))	('sarcoma', 'Disease', (273, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('polycyclic/multilobulated', 'Var', (185, 210))
123759	31208434	Currently, DNA sequencing of tumors for druggable mutations leaves approximately 60% of patients without an actionable result.	('tumors', 'Disease', (29, 35))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))
123804	31208434	Chemical concentrations of agents in all chemical screens were either [10 nM, 100 nM, 1 muM, 10 muM] or [100 nM, 1 muM, 10 muM, 100 muM] depending on compound activity range.	('muM', 'Gene', (88, 91))	('muM', 'Gene', '56925', (96, 99))	('muM', 'Gene', (123, 126))	('muM', 'Gene', (96, 99))	('muM', 'Gene', '56925', (115, 118))	('[100 nM', 'Var', (104, 111))	('muM', 'Gene', '56925', (132, 135))	('muM', 'Gene', '56925', (88, 91))	('muM', 'Gene', '56925', (123, 126))	('muM', 'Gene', (115, 118))	('muM', 'Gene', (132, 135))	('[10 nM', 'Var', (70, 76))
123824	31208434	For GDC-0941, the functional range is approximately [5 nM, 1 muM] (mouse pharmacokinetics: ~ 12 muM Cmax, 1.59 muM Css, human pharmacokinetics: ~ 1.481 muM Cmax, 720 nM Css).	('Cmax', 'Chemical', '-', (156, 160))	('human', 'Species', '9606', (120, 125))	('muM', 'Gene', '56925', (96, 99))	('muM', 'Gene', (61, 64))	('muM', 'Gene', (96, 99))	('Cmax', 'Chemical', '-', (100, 104))	('muM', 'Gene', '56925', (152, 155))	('muM', 'Gene', '56925', (111, 114))	('mouse', 'Species', '10090', (67, 72))	('GDC-0941', 'Var', (4, 12))	('muM', 'Gene', (152, 155))	('muM', 'Gene', (111, 114))	('GDC-0941', 'Chemical', 'MESH:C532162', (4, 12))	('muM', 'Gene', '56925', (61, 64))
123838	31208434	U23674 underwent functional single gene knockdown (siRNA interference screen, Additional file 24: Table S10), however siRNA results were inconsistent with drug screening data (Additional file 25: Table S11) and are thus relegated to the supplement.	('S11', 'Gene', (202, 205))	('S10', 'Gene', (104, 107))	('U23674', 'Chemical', '-', (0, 6))	('S10', 'Gene', '6204', (104, 107))	('S11', 'Gene', '6267', (202, 205))	('U23674', 'Var', (0, 6))
123843	31208434	U23674 underwent phosphoproteome quantification (Kinexus phosphoproteomics analysis, Additional file 26: Table S12), however phosphoproteomics results were inconsistent among sample replicates and are thus relegated to the supplement.	('S12', 'Gene', (111, 114))	('U23674', 'Chemical', '-', (0, 6))	('phosphoproteome quantification', 'MPA', (17, 47))	('U23674', 'Var', (0, 6))	('S12', 'Gene', '6268', (111, 114))
123844	31208434	To identify differentially phosphorylated protein targets, phosphoproteomics assays (Kinexus, Vancouver, British Columbia, Canada) were used to compare two duplicate cell lysates from U23674 against two duplicate cell lysates from regenerating muscle tissue acting as normal control.	('British Columbia', 'Disease', 'OMIM:176500', (105, 121))	('U23674', 'Var', (184, 190))	('U23674', 'Chemical', '-', (184, 190))	('British Columbia', 'Disease', (105, 121))
123874	31208434	Potential for resistance abrogation by targeting 2 blocks common to both human and canine PTIM models directed a six-arm proof-of-principle experiment to show that inhibition of multiple blocks inhibited could abrogate tumor cell resistance.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('inhibition', 'Var', (164, 174))	('human', 'Species', '9606', (73, 78))	('abrogate', 'NegReg', (210, 218))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('canine', 'Species', '9615', (83, 89))
123882	31208434	The GDC-0941 arm lost one mouse during oral gavage; the corresponding data point was censored.	('GDC-0941', 'Var', (4, 12))	('mouse', 'Species', '10090', (26, 31))	('lost', 'NegReg', (17, 21))	('GDC-0941', 'Chemical', 'MESH:C532162', (4, 12))
123888	31208434	Adult female stock mice (Envigo Foxn1nu Athymic nudes) were implanted bilaterally with approximately 5x5x5mm fragments subcutaneously in the left and right flanks with JAX PDX model of Human Epithelioid Sarcoma (J000078604 (PCB490) - JAX-001).	('Epithelioid Sarcoma', 'Disease', (191, 210))	('Human', 'Species', '9606', (185, 190))	('Sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('Foxn1', 'Gene', '15218', (32, 37))	('Epithelioid Sarcoma', 'Disease', 'MESH:D012509', (191, 210))	('Foxn1', 'Gene', (32, 37))	('J000078604', 'Var', (212, 222))	('PCB490', 'Chemical', '-', (224, 230))	('mice', 'Species', '10090', (19, 23))
123892	31208434	When the TV reached approximately 150-250 mm3 animals were matched by tumor size and assigned into control or treatment groups (3/group for J000078604 (PCB490) - JAX-001).	('J000078604', 'Var', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('PCB490', 'Chemical', '-', (152, 158))
123913	31208434	Additionally, U23674 primary tissue was sequenced to enhance therapy design (tumor whole exome sequencing, matched normal whole exome sequencing, and whole transcriptome sequencing, Additional files 22 and 23: Tables S8 and S9).	('U23674', 'Var', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('U23674', 'Chemical', '-', (14, 20))	('tumor', 'Disease', (77, 82))
123920	31208434	While overexpressed, the Epha7 inhibitor on the PPTI drug screen was ineffective against U23674.	('Epha7', 'Gene', (25, 30))	('Epha7', 'Gene', '2045', (25, 30))	('U23674', 'Var', (89, 95))	('U23674', 'Chemical', '-', (89, 95))
123929	31208434	Both full-dose and low-dose OSI-906 + SB-772077-B in vitro validation experiments (Additional file 9: Figure S9) demonstrated non-constant ratio Combination Index synergy (Additional file 28: Table S14), though overall cell viability of was OSI-906 + SB-772077-B than higher the RNA-seq-informed combination.	('SB', 'Chemical', 'MESH:D000965', (38, 40))	('SB', 'Chemical', 'MESH:D000965', (251, 253))	('S14', 'Gene', (198, 201))	('OSI-906', 'Chemical', 'MESH:C551528', (28, 35))	('S14', 'Gene', '6208', (198, 201))	('OSI-906 + SB-772077-B than', 'Var', (241, 267))	('OSI-906', 'Chemical', 'MESH:C551528', (241, 248))
123935	31208434	2g) showed improvement in mouse lifespan from combination treatment (under Bonferroni correction: Vehicle - Combo, p = 0.005, OSI-906 - Combo, p = 0.014, GDC-0941 - Combo, p = 0.079.	('OSI-906', 'Chemical', 'MESH:C551528', (126, 133))	('GDC-0941 - Combo', 'Var', (154, 170))	('GDC-0941', 'Chemical', 'MESH:C532162', (154, 162))	('mouse', 'Species', '10090', (26, 31))	('mouse lifespan', 'CPA', (26, 40))	('improvement', 'PosReg', (11, 22))
123948	31208434	Sequencing identified germline and tumor amplified, expressed, high-impact druggable variants in two genes (ABL1, NOTCH1) and expressed, medium impact variants in three additional genes (MDM4, PAK4, MAP4K5).	('ABL1', 'Gene', '25', (108, 112))	('PAK4', 'Gene', '10298', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('NOTCH1', 'Gene', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('variants', 'Var', (85, 93))	('ABL1', 'Gene', (108, 112))	('tumor', 'Disease', (35, 40))	('MDM4', 'Gene', '4194', (187, 191))	('MAP4K5', 'Gene', '11183', (199, 205))	('MDM4', 'Gene', (187, 191))	('high-impact', 'PosReg', (63, 74))	('MAP4K5', 'Gene', (199, 205))	('NOTCH1', 'Gene', '4851', (114, 120))	('PAK4', 'Gene', (193, 197))
123950	31208434	The ABL1 variant was previously identified in the 1000 Genomes Project.	('ABL1', 'Gene', (4, 8))	('variant', 'Var', (9, 16))	('ABL1', 'Gene', '25', (4, 8))
123951	31208434	The ABL1, NOTCH1, MDM4 and PAK4 variants were previously submitted to the dbSNP database.	('ABL1', 'Gene', (4, 8))	('MDM4', 'Gene', '4194', (18, 22))	('MDM4', 'Gene', (18, 22))	('PAK4', 'Gene', '10298', (27, 31))	('variants', 'Var', (32, 40))	('PAK4', 'Gene', (27, 31))	('NOTCH1', 'Gene', '4851', (10, 16))	('NOTCH1', 'Gene', (10, 16))	('ABL1', 'Gene', '25', (4, 8))
123954	31208434	To compare drug sensitivity of PCB490 with other EPS models, three cell lines (ESX, FU-EPS-1, and VA-ES-BJ), a second human-derived cell culture (PCB495), and the SkMc skeletal myoblast cell line were assayed with Drug Screen V3 (Fig.	('ESX', 'Gene', '1999', (79, 82))	('drug sensitivity', 'Phenotype', 'HP:0020174', (11, 27))	('PCB495', 'Chemical', '-', (146, 152))	('PCB490', 'Chemical', '-', (31, 37))	('human', 'Species', '9606', (118, 123))	('ESX', 'Gene', (79, 82))	('VA-ES-BJ', 'CellLine', 'CVCL:1785', (98, 106))	('PCB490', 'Var', (31, 37))
123958	31208434	Correlation within primary cell cultures (PCB490 sites and PCB495) was significantly higher than correlation between primary cultures and cell lines (mu = 0.6466 vs. mu = 0.4708, p < 0.01), suggesting EPS primary cultures may be biologically distinct from EPS cell lines.	('higher', 'PosReg', (85, 91))	('PCB495', 'Chemical', '-', (59, 65))	('PCB495', 'Var', (59, 65))	('Correlation', 'MPA', (0, 11))	('PCB490 sites', 'Var', (42, 54))	('PCB490', 'Chemical', '-', (42, 48))
123966	31208434	We focused on high-scoring PTIM blocks treatable by a two-drug combination, resulting in selection of BEZ235 (PI3K/mTOR inhibitor) and sunitinib (poly-kinase inhibitor, including KDR and AXL).	('KDR', 'Gene', (179, 182))	('BEZ235', 'Chemical', 'MESH:C531198', (102, 108))	('AXL', 'Gene', (187, 190))	('mTOR', 'Gene', '2475', (115, 119))	('mTOR', 'Gene', (115, 119))	('sunitinib', 'Chemical', 'MESH:D000077210', (135, 144))	('KDR', 'Gene', '3791', (179, 182))	('AXL', 'Gene', '558', (187, 190))	('BEZ235', 'Var', (102, 108))
123970	31208434	PDX testing of BEZ235 + sunitinib demonstrated significant slowing of tumor growth over vehicle control (92% slower tumor growth at Day 19, p = 0.01) (Fig.	('slowing of tumor', 'Disease', 'MESH:D009369', (59, 75))	('sunitinib', 'Chemical', 'MESH:D000077210', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('BEZ235 +', 'Var', (15, 23))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('slowing of tumor', 'Disease', (59, 75))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('BEZ235', 'Chemical', 'MESH:C531198', (15, 21))
123971	31208434	In statistical analysis restricted to treated animals at Day 19, BEZ235 + sunitinib significantly slowed PDX tumor growth compared to both BEZ235 (p = 0.01) and sunitinib (p = 0.01) alone (Fig.	('PDX', 'Disease', (105, 108))	('sunitinib', 'Chemical', 'MESH:D000077210', (161, 170))	('slowed', 'NegReg', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('BEZ235', 'Chemical', 'MESH:C531198', (65, 71))	('BEZ235', 'Chemical', 'MESH:C531198', (139, 145))	('sunitinib', 'Chemical', 'MESH:D000077210', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('BEZ235 +', 'Var', (65, 73))	('tumor', 'Disease', (109, 114))
123976	31208434	The combination of panobinostat + obatoclax was predicted to abrogate resistance mechanisms and prevent cancer cell rewiring and regrowth; furthermore, the cross-species nature of the experiment supports the resistance-abrogation effect not being model specific.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('obatoclax', 'Chemical', 'MESH:C520962', (34, 43))	('combination', 'Var', (4, 15))	('prevent', 'NegReg', (96, 103))	('abrogate', 'NegReg', (61, 69))	('panobinostat', 'Chemical', 'MESH:D000077767', (19, 31))	('resistance mechanisms', 'CPA', (70, 91))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
123988	31208434	While validated PTIM models are currently based on low-passage cell cultures (U23674, PCB490, S1-12, PCB197), future application of PTIM models will use direct-to-plate tumor screening to best recapitulate the patient's disease state and to remove the dependence on cell culture establishment.	('U23674', 'Chemical', '-', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('U23674', 'Var', (78, 84))	('PCB490', 'Chemical', '-', (86, 92))	('patient', 'Species', '9606', (210, 217))	('tumor', 'Disease', (169, 174))
124013	28246524	Ezrin has been shown to play a role in tumor growth and metastasis through several mechanisms including drug efflux, prevention of apoptosis, aberrant signal transduction, and phagocytosis in certain cancers.	('metastasis', 'CPA', (56, 66))	('tumor growth', 'CPA', (39, 51))	('drug efflux', 'MPA', (104, 115))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('phagocytosis', 'CPA', (176, 188))	('cancers', 'Disease', (200, 207))	('aberrant', 'Var', (142, 150))	('Ezrin', 'Protein', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('apoptosis', 'CPA', (131, 140))
124024	28246524	Patients were categorized for analysis as having tumors with positive or negative ezrin expression, high (3+) versus low/no (0-2+) ezrin positivity, high (3+) versus low/no (0-2+) ezrin intensity, and cytoplasmic versus noncytoplasmic (membranous or diffuse) ezrin expression pattern (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('ezrin', 'Protein', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('negative', 'NegReg', (73, 81))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('high (3+', 'Var', (149, 157))
124045	26055763	Significant tissue defects may result from sarcoma excisions, with exposure of tendons, bones, joints, vessels, and prosthetic material, making substantial coverage crucial.	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('excisions', 'Var', (51, 60))	('result', 'Reg', (31, 37))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
124092	26055763	The pedicled + free-flap group had significantly more hematomas and wound healing problems than the other groups.	('hematomas', 'Disease', (54, 63))	('wound healing problems', 'Phenotype', 'HP:0001058', (68, 90))	('pedicled', 'Var', (4, 12))	('hematomas', 'Disease', 'MESH:D006406', (54, 63))	('more', 'PosReg', (49, 53))	('wound healing problems', 'CPA', (68, 90))
124154	32736540	This HR subgroup includes patients with large, deep, high FNCLCC grade, and extremity STS.	('high FNCLCC grade', 'Var', (53, 70))	('extremity STS', 'Disease', (76, 89))	('patients', 'Species', '9606', (26, 34))
124239	31692830	The pooled adjusted odds ratio (OR) analysis indicated that there was a direct relationship with regards the reduced recurrence rate of DFSP in the MMS group compared to the WLE group (OR:0.31;95%; CI :0.17-0.56).	('DFSP', 'Disease', (136, 140))	('recurrence', 'MPA', (117, 127))	('MMS', 'Var', (148, 151))	('reduced', 'NegReg', (109, 116))	('DFSP', 'Disease', 'None', (136, 140))
124249	31692830	Cytogenetically, these tumors have been associated with chromosomal translocation at position 17:22 leading to an overexpression of tyrosine kinase PDGFB, which can be targeted with Imatinib, a tyrosine kinase inhibitor.	('overexpression', 'PosReg', (114, 128))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tyrosine', 'Chemical', 'None', (194, 202))	('PDGFB', 'Gene', (148, 153))	('Imatinib', 'Chemical', 'MESH:C097613', (182, 190))	('chromosomal translocation', 'Var', (56, 81))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('PDGFB', 'Gene', '5155', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tyrosine', 'Chemical', 'None', (132, 140))
124258	31692830	The COL1A1-PDGFB fusion gene, exhibit growth factor activity, this furthers on the proliferation on tumor cells.	('PDGFB', 'Gene', (11, 16))	('COL1A1', 'Gene', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('growth factor activity', 'MPA', (38, 60))	('tumor', 'Disease', (100, 105))	('fusion', 'Var', (17, 23))	('PDGFB', 'Gene', '5155', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('furthers', 'Reg', (67, 75))	('COL1A1', 'Gene', '1277', (4, 10))
124288	31692830	Fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RTPCR) are reserved as screening tools for the presence of COL1A1-PDGFB fusion gene prior to initiation of oral imatinib in molecular targeted therapy.	('imatinib', 'Chemical', 'MESH:C097613', (207, 215))	('PDGFB', 'Gene', '5155', (161, 166))	('COL1A1', 'Gene', (154, 160))	('COL1A1', 'Gene', '1277', (154, 160))	('PDGFB', 'Gene', (161, 166))	('fusion', 'Var', (167, 173))
124306	31692830	The meta-analyses were conducted with the software Review Manager 5.2 (The Cochrane Collaboration, 2011) to evaluate the superiority of MMS over WLE in the management of DFSP.The recurrence rate was also used to establish the high cure rate of MMS by associating it with reduced rate of reoccurrence in cases that underwent MMS as opposed to those that opted for WLE for whatever reason.	('DFSP', 'Disease', (170, 174))	('reoccurrence', 'MPA', (287, 299))	('MMS', 'Var', (324, 327))	('DFSP', 'Disease', 'None', (170, 174))
124311	31692830	In the meta-analysis, the pooled adjusted odds ratio (OR) analysis indicated that there was a direct relationship with regards the reduced recurrence rate of DFSP in the MMS group compared to the WLE group (OR: 0.31;95% CI: 0.17-0.56) as shown in Table 3 (the forest plot).	('DFSP', 'Disease', (158, 162))	('DFSP', 'Disease', 'None', (158, 162))	('recurrence', 'MPA', (139, 149))	('reduced', 'NegReg', (131, 138))	('MMS', 'Var', (170, 173))
124319	31692830	The pooled adjusted odds ratio (OR) analysis, indicated that there was a direct relationship with regards the reduced recurrence rate of DFSP in the MMS group compared to the WLE group (OR: 0.31;95% CI :0.17-0.56) as shown in Table 3.	('DFSP', 'Disease', 'None', (137, 141))	('reduced', 'NegReg', (110, 117))	('MMS', 'Var', (149, 152))	('recurrence', 'MPA', (118, 128))	('DFSP', 'Disease', (137, 141))
124361	30808861	We also show that glutamine supports sarcoma nucleotide biosynthesis and optimal mitochondrial bioenergetics.	('mitochondrial bioenergetics', 'MPA', (81, 108))	('glutamine', 'Var', (18, 27))	('sarcoma', 'Disease', 'MESH:D012509', (37, 44))	('supports', 'PosReg', (28, 36))	('sarcoma', 'Disease', (37, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('glutamine', 'Chemical', 'MESH:D005973', (18, 27))
124371	30808861	Rather, approximately one-third of all sarcomas are driven by chimeric transcription factors, which are the result of well-defined chromosomal translocations.	('driven by', 'Reg', (52, 61))	('sarcomas', 'Disease', 'MESH:D012509', (39, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('sarcomas', 'Disease', (39, 47))	('chimeric', 'Var', (62, 70))
124375	30808861	Furthermore, the acute and long-term toxicities associated with exposure to current therapeutic regimens at such a young age are considerable, and those who do survive RMS and ES face a lifetime of significant treatment-related effects, including profound functional and cosmetic deficits, organ toxicities, secondary malignancies, and shortened life expectancies.	('ES', 'Phenotype', 'HP:0012254', (176, 178))	('RMS', 'Phenotype', 'HP:0002859', (168, 171))	('toxicities', 'Disease', 'MESH:D064420', (37, 47))	('malignancies', 'Disease', (318, 330))	('RMS', 'Var', (168, 171))	('toxicities', 'Disease', (37, 47))	('toxicities', 'Disease', 'MESH:D064420', (296, 306))	('cosmetic deficits', 'Disease', (271, 288))	('cosmetic deficits', 'Disease', 'MESH:D009461', (271, 288))	('malignancies', 'Disease', 'MESH:D009369', (318, 330))	('toxicities', 'Disease', (296, 306))
124378	30808861	Many signaling pathways affected by genetic events in cancer, as well as the tumor microenvironment, can significantly alter cellular metabolism to meet the increased biosynthetic and energy demands necessary to support cancer cell survival and proliferation.	('genetic', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cellular metabolism', 'MPA', (125, 144))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('alter', 'Reg', (119, 124))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (220, 226))	('tumor', 'Disease', (77, 82))	('signaling pathways', 'Pathway', (5, 23))
124391	30808861	We show that expression of glutamine synthetase (GS), the enzyme responsible for de novo glutamine synthesis, increased during glutamine deprivation, and that pharmacological or shRNA-mediated inhibition of GS abolished the ability of glutamine-deprived cells to proliferate, while having no effect on cells grown under normal culture conditions.	('inhibition', 'Var', (193, 203))	('glutamine synthetase', 'Gene', (27, 47))	('glutamine', 'MPA', (127, 136))	('expression', 'MPA', (13, 23))	('increased', 'PosReg', (110, 119))	('GS', 'Gene', '2752', (207, 209))	('glutamine', 'Chemical', 'MESH:D005973', (235, 244))	('glutamine synthetase', 'Gene', '2752', (27, 47))	('abolished', 'NegReg', (210, 219))	('glutamine', 'Chemical', 'MESH:D005973', (127, 136))	('glutamine', 'Chemical', 'MESH:D005973', (89, 98))	('proliferate', 'CPA', (263, 274))	('GS', 'Gene', '2752', (49, 51))	('glutamine', 'Chemical', 'MESH:D005973', (27, 36))
124392	30808861	Furthermore, pharmacological and shRNA-mediated inhibition of GS significantly reduced orthotopic xenograft tumor growth.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('reduced', 'NegReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('inhibition', 'Var', (48, 58))	('tumor', 'Disease', (108, 113))	('GS', 'Gene', '2752', (62, 64))
124400	30808861	Following 2 weeks of continuous passaging, proliferation was assayed in media with or without glutamine, generating four groups (see schematic in Supplementary Figure S1a): Gln +/+ (passaged with glutamine, assayed with glutamine), Gln +/- (passaged with glutamine, assayed without glutamine), Gln -/+ (passaged without glutamine, assayed with glutamine), Gln -/- (passaged without glutamine, assayed without glutamine).	('glutamine', 'Chemical', 'MESH:D005973', (94, 103))	('glutamine', 'Chemical', 'MESH:D005973', (320, 329))	('Gln', 'Chemical', 'MESH:D005973', (356, 359))	('glutamine', 'Chemical', 'MESH:D005973', (382, 391))	('glutamine', 'Chemical', 'MESH:D005973', (220, 229))	('Gln', 'Chemical', 'MESH:D005973', (173, 176))	('Gln', 'Chemical', 'MESH:D005973', (232, 235))	('glutamine', 'Chemical', 'MESH:D005973', (344, 353))	('Gln -/+', 'Var', (294, 301))	('Gln', 'Chemical', 'MESH:D005973', (294, 297))	('glutamine', 'Chemical', 'MESH:D005973', (409, 418))	('Gln +/+', 'Var', (173, 180))	('glutamine', 'Chemical', 'MESH:D005973', (282, 291))	('glutamine', 'Chemical', 'MESH:D005973', (196, 205))	('glutamine', 'Chemical', 'MESH:D005973', (255, 264))
124403	30808861	Furthermore, TC71 and EW8 cells continuously passaged in glutamine-free media had an increased rate of proliferation compared to cells continuously passaged in Control media, when assayed in glutamine-free media (Gln -/- vs. Gln +/-).	('proliferation', 'CPA', (103, 116))	('glutamine', 'Chemical', 'MESH:D005973', (191, 200))	('Gln +/-', 'Var', (225, 232))	('Gln', 'Chemical', 'MESH:D005973', (225, 228))	('TC71', 'Gene', (13, 17))	('glutamine', 'Chemical', 'MESH:D005973', (57, 66))	('increased', 'PosReg', (85, 94))	('TC71', 'CellLine', 'CVCL:2213', (13, 17))	('Gln', 'Chemical', 'MESH:D005973', (213, 216))
124414	30808861	2c, the addition of glutamine to glutamine-deprived EW8 cells led to an almost complete reduction of GS protein level following overnight incubation, however, this effect was blocked by the simultaneous addition of either of the proteosome inhibitors MG132 or Bortezomib at previously published concentrations.	('Bortezomib', 'Chemical', 'MESH:D000069286', (260, 270))	('GS', 'Gene', '2752', (101, 103))	('MG132', 'Chemical', 'MESH:C072553', (251, 256))	('reduction', 'NegReg', (88, 97))	('glutamine', 'Chemical', 'MESH:D005973', (33, 42))	('glutamine', 'Var', (20, 29))	('glutamine', 'Chemical', 'MESH:D005973', (20, 29))
124422	30808861	GS knockdown by either targeting sequence in three different sarcoma cell lines had no effect on proliferation of cells grown in the presence of glutamine, however, GS knockdown severely inhibited proliferation of cells grown in glutamine-free media, compared to shControl counterparts (Fig.	('GS', 'Gene', '2752', (165, 167))	('GS', 'Gene', '2752', (0, 2))	('glutamine', 'Chemical', 'MESH:D005973', (145, 154))	('glutamine', 'Chemical', 'MESH:D005973', (229, 238))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('proliferation', 'CPA', (197, 210))	('knockdown', 'Var', (168, 177))	('sarcoma', 'Disease', (61, 68))	('inhibited', 'NegReg', (187, 196))
124434	30808861	5a, knockdown of GS with either of the two distinct GS-targeting shRNAs, sh28 or sh31, caused a statistically significant decrease (p < 0.05) in average tumor volume of 23% or 28%, respectively, compared to shControl tumors.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('decrease', 'NegReg', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('sh28', 'Var', (73, 77))	('GS', 'Gene', '2752', (17, 19))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('GS', 'Gene', '2752', (52, 54))	('sh31', 'Var', (81, 85))	('knockdown', 'Var', (4, 13))
124467	30808861	We show that GS knockdown in three different sarcoma cell lines had no effect on proliferation of cells grown in glutamine-containing media, however, GS knockdown severely inhibited proliferation of the same cells when grown in glutamine-free media.	('proliferation', 'CPA', (182, 195))	('sarcoma', 'Disease', (45, 52))	('knockdown', 'Var', (153, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('GS', 'Gene', '2752', (150, 152))	('glutamine', 'Chemical', 'MESH:D005973', (228, 237))	('glutamine', 'Chemical', 'MESH:D005973', (113, 122))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('inhibited', 'NegReg', (172, 181))	('GS', 'Gene', '2752', (13, 15))
124473	30808861	GS knockdown caused a statistically significant decrease in average tumor volume of 23 or 28% (p < 0.05).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('decrease', 'NegReg', (48, 56))	('knockdown', 'Var', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('GS', 'Gene', '2752', (0, 2))
124476	30808861	Clinically, we show that high GS expression is correlated with worse overall survival in Ewing sarcoma patients, further supporting the importance of GS for sarcoma tumor growth.	('overall survival', 'MPA', (69, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('worse', 'NegReg', (63, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('GS', 'Gene', '2752', (150, 152))	('Ewing sarcoma', 'Disease', (89, 102))	('GS', 'Gene', '2752', (30, 32))	('high', 'Var', (25, 29))	('sarcoma tumor', 'Disease', 'MESH:D012509', (157, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('expression', 'MPA', (33, 43))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('patients', 'Species', '9606', (103, 111))	('sarcoma tumor', 'Disease', (157, 170))
124480	30808861	In line with our current findings, several recent studies have demonstrated that inhibition of GS can significantly impair tumorigenic growth and metastasis in preclinical models, however, there are currently no clinically approved drugs that specifically target GS.	('GS', 'Gene', '2752', (263, 265))	('tumor', 'Disease', (123, 128))	('inhibition', 'Var', (81, 91))	('GS', 'Gene', '2752', (95, 97))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('impair', 'NegReg', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
124520	28191765	Only the combination of Rb knockdown and c-Myc overexpression successfully transformed hMSCs derived from four individual donors, with increasing cell proliferation, decreasing cell senescence rate, and increasing ability to form colonies and spheres in serum-free medium.	('knockdown', 'Var', (27, 36))	('c-Myc', 'Gene', '4609', (41, 46))	('decreasing', 'NegReg', (166, 176))	('cell senescence rate', 'CPA', (177, 197))	('c-Myc', 'Gene', (41, 46))	('increasing', 'PosReg', (203, 213))	('Rb', 'Gene', '5925', (24, 26))	('increasing', 'PosReg', (135, 145))	('cell proliferation', 'CPA', (146, 164))
124524	28191765	This study successfully transformed human MSCs to OS-like cells by Rb knockdown and c-Myc overexpression that may be a useful platform for further investigation of preventive and target therapy for human OS.	('knockdown', 'Var', (70, 79))	('Rb', 'Gene', '5925', (67, 69))	('c-Myc', 'Gene', '4609', (84, 89))	('c-Myc', 'Gene', (84, 89))	('human', 'Species', '9606', (198, 203))	('human', 'Species', '9606', (36, 41))	('overexpression', 'PosReg', (90, 104))
124525	28191765	Stem Cells Translational Medicine 2017;6:512-526  In the present study, transformation of human mesenchymal stem cells (MSCs) was achieved by the combination of retinoblastoma (Rb) knockdown and c-Myc overexpression.	('overexpression', 'PosReg', (201, 215))	('Rb', 'Gene', '5925', (177, 179))	('retinoblastoma', 'Gene', '5925', (161, 175))	('retinoblastoma', 'Gene', (161, 175))	('human', 'Species', '9606', (90, 95))	('retinoblastoma', 'Phenotype', 'HP:0009919', (161, 175))	('knockdown', 'Var', (181, 190))	('c-Myc', 'Gene', '4609', (195, 200))	('c-Myc', 'Gene', (195, 200))
124529	28191765	These data strongly suggest that transformed human MSCs by Rb knockdown and c-Myc overexpression are associated with clinical OS tissues and patient survival.	('c-Myc', 'Gene', '4609', (76, 81))	('patient', 'Species', '9606', (141, 148))	('c-Myc', 'Gene', (76, 81))	('human', 'Species', '9606', (45, 50))	('overexpression', 'PosReg', (82, 96))	('Rb', 'Gene', '5925', (59, 61))	('associated', 'Reg', (101, 111))	('knockdown', 'Var', (62, 71))
124537	28191765	The transformation of MSCs has been achieved under the controlled expression or deletion of certain genes, such as by the expression of the EWS-FLI-1 chimeric gene to induce Ewing sarcoma 10, the deletion of p53 to induce leiomyosarcoma 11, and the deletion of the retinoblastoma (Rb) gene to induce liposarcoma 12.	('leiomyosarcoma', 'Disease', (222, 236))	('retinoblastoma', 'Gene', (265, 279))	('FLI-1', 'Gene', (144, 149))	('induce', 'PosReg', (167, 173))	('liposarcoma', 'Disease', 'MESH:D008080', (300, 311))	('deletion', 'Var', (80, 88))	('deletion', 'Var', (196, 204))	('p53', 'Gene', (208, 211))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (174, 187))	('Rb', 'Gene', '5925', (281, 283))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (174, 187))	('EWS', 'Gene', '2130', (140, 143))	('induce', 'PosReg', (215, 221))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (222, 236))	('retinoblastoma', 'Gene', '5925', (265, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('liposarcoma', 'Disease', (300, 311))	('retinoblastoma', 'Phenotype', 'HP:0009919', (265, 279))	('induce', 'Reg', (293, 299))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (222, 236))	('deletion', 'Var', (249, 257))	('Ewing sarcoma', 'Disease', (174, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('EWS', 'Gene', (140, 143))	('FLI-1', 'Gene', '2313', (144, 149))	('liposarcoma', 'Phenotype', 'HP:0012034', (300, 311))
124545	28191765	This study transforms human MSCs via genetic modification of several genes, including the knockdown of p53 and Rb and the overexpression of c-Myc and Ras.	('Ras', 'Protein', (150, 153))	('c-Myc', 'Gene', (140, 145))	('p53', 'Gene', (103, 106))	('knockdown', 'Var', (90, 99))	('Rb', 'Gene', '5925', (111, 113))	('overexpression', 'PosReg', (122, 136))	('c-Myc', 'Gene', '4609', (140, 145))	('human', 'Species', '9606', (22, 27))	('genetic modification', 'Var', (37, 57))
124556	28191765	The expression plasmids and the bacteria clone and lentiviral vectors carrying p53 (TRCN0000003755 and TRCN0000003756), Rb (TRCN0000010417 and TRCN0000040167), and beta-catenin (TRCN0000003845) short hairpin RNAs were provided by the National Science Council RNAi core facility, Academia Sinica, Taiwan.	('TRCN0000003845', 'Var', (178, 192))	('beta-catenin', 'Gene', (164, 176))	('TRCN0000010417', 'Var', (124, 138))	('Rb', 'Gene', '5925', (120, 122))	('beta-catenin', 'Gene', '1499', (164, 176))	('Academia Sinica', 'Disease', 'None', (279, 294))	('TRCN0000003756', 'Var', (103, 117))	('TRCN0000040167', 'Var', (143, 157))	('TRCN0000003755', 'Var', (84, 98))	('Academia Sinica', 'Disease', (279, 294))
124589	28191765	The primary antibodies included anti-p53, anti-Rb, anti-Oct4, anti-SOX-2, anti-Nanog, anti-c-Myc, anti-beta-catenin, and anti-beta-actin (1:1,000; Cell Signaling Technology, Beverly, MA, http://www.cellsignal.com).	('SOX-2', 'Gene', (67, 72))	('anti-p53', 'Var', (32, 40))	('beta-catenin', 'Gene', (103, 115))	('Rb', 'Gene', '5925', (47, 49))	('beta-catenin', 'Gene', '1499', (103, 115))	('c-Myc', 'Gene', '4609', (91, 96))	('anti-beta-actin', 'Var', (121, 136))	('Oct4', 'Gene', (56, 60))	('SOX-2', 'Gene', '6657', (67, 72))	('Nanog', 'Gene', '79923', (79, 84))	('Nanog', 'Gene', (79, 84))	('c-Myc', 'Gene', (91, 96))	('Oct4', 'Gene', '5460', (56, 60))
124596	28191765	The antibodies for immunohistochemistry were anti-human c-Myc (rabbit polyclonal, clone D3N8F, 1:50; Cell Signaling) and anti-human Rb1 (mouse monoclonal, clone 4H1, 1:50; Cell Signaling).	('human', 'Species', '9606', (126, 131))	('rabbit', 'Species', '9986', (63, 69))	('Rb1', 'Gene', (132, 135))	('mouse', 'Species', '10090', (137, 142))	('c-Myc', 'Gene', (56, 61))	('anti-human', 'Var', (121, 131))	('Rb1', 'Gene', '5925', (132, 135))	('human', 'Species', '9606', (50, 55))	('c-Myc', 'Gene', '4609', (56, 61))
124601	28191765	A combination of p53 knockdown and c-Myc overexpression (Sip53-OeMyc) also induced cell senescence and a termination of cell growth (Fig.	('induced', 'Reg', (75, 82))	('cell senescence', 'CPA', (83, 98))	('c-Myc', 'Gene', '4609', (35, 40))	('Myc', 'Gene', (37, 40))	('Myc', 'Gene', '4609', (65, 68))	('p53', 'Gene', (17, 20))	('termination', 'CPA', (105, 116))	('c-Myc', 'Gene', (35, 40))	('Myc', 'Gene', (65, 68))	('overexpression', 'PosReg', (41, 55))	('knockdown', 'Var', (21, 30))	('Myc', 'Gene', '4609', (37, 40))
124602	28191765	Interestingly, Rb knockdown combined with c-Myc overexpression (SiRb-OeMyc), but not Ras overexpression (SiRb-OeRas; data not shown), resulted in a slim and short cell shape, a significant decrease in cell size (Fig.	('Myc', 'Gene', (71, 74))	('knockdown', 'Var', (18, 27))	('Myc', 'Gene', (44, 47))	('Rb', 'Gene', '5925', (107, 109))	('c-Myc', 'Gene', (42, 47))	('resulted in', 'Reg', (134, 145))	('Rb', 'Gene', '5925', (15, 17))	('Rb', 'Gene', '5925', (66, 68))	('decrease', 'NegReg', (189, 197))	('slim', 'CPA', (148, 152))	('overexpression', 'PosReg', (48, 62))	('Myc', 'Gene', '4609', (71, 74))	('cell size', 'CPA', (201, 210))	('Myc', 'Gene', '4609', (44, 47))	('c-Myc', 'Gene', '4609', (42, 47))
124604	28191765	To confirm the transformation ability of genetic modification with SiRb-OeMyc, MSCs from three other donors were also applied for this study.	('Myc', 'Gene', (74, 77))	('genetic', 'Var', (41, 48))	('Myc', 'Gene', '4609', (74, 77))	('Rb', 'Gene', '5925', (69, 71))
124658	28191765	We further demonstrated that the increase of beta-catenin level by combined Rb knockdown and c-Myc overexpression was because of increased phosphorylation of glycogen synthase kinase-3beta (GSK3beta), a kinase that negatively regulates beta-catenin 40 (supplemental online Fig.	('beta-catenin', 'Gene', '1499', (236, 248))	('c-Myc', 'Gene', '4609', (93, 98))	('glycogen synthase kinase-3beta', 'Gene', '2932', (158, 188))	('phosphorylation', 'MPA', (139, 154))	('GSK3beta', 'Gene', (190, 198))	('c-Myc', 'Gene', (93, 98))	('beta-catenin', 'Gene', '1499', (45, 57))	('increased', 'PosReg', (129, 138))	('increase', 'PosReg', (33, 41))	('GSK3beta', 'Gene', '2932', (190, 198))	('glycogen synthase kinase-3beta', 'Gene', (158, 188))	('knockdown', 'Var', (79, 88))	('beta-catenin', 'Gene', (236, 248))	('Rb', 'Gene', '5925', (76, 78))	('beta-catenin', 'Gene', (45, 57))
124659	28191765	More importantly, knockdown of beta-catenin (supplemental online Fig.	('knockdown', 'Var', (18, 27))	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))
124669	28191765	From the review of Mutsaers and Walkley 45, genetic modification of preosteoblasts, rather than human MSCs (hMSCs), more readily induced OS, suggesting that preosteoblasts, rather than hMSCs, represent the ontological origins.	('human', 'Species', '9606', (96, 101))	('induced', 'Reg', (129, 136))	('genetic modification', 'Var', (44, 64))
124673	28191765	These data suggest that human MSCs can be successfully transformed into tumor initiation cells by using a combination of Rb knockdown and c-Myc overexpression.	('knockdown', 'Var', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('human', 'Species', '9606', (24, 29))	('c-Myc', 'Gene', '4609', (138, 143))	('tumor', 'Disease', (72, 77))	('c-Myc', 'Gene', (138, 143))	('Rb', 'Gene', '5925', (121, 123))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
124674	28191765	Notably, in murine models, various studies have shown that genetic modifications on stem cells or osteoblastic cells 11, 12, 14 induced tumorigenic transformation.	('induced', 'Reg', (128, 135))	('murine', 'Species', '10090', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('genetic modifications', 'Var', (59, 80))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
124679	28191765	However, knockout of p53 or of both p53 and Rb in mouse adipose-derived or bone marrow-derived MSCs initiates the formation of leiomyosarcoma in vitro 49.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (127, 141))	('knockout', 'Var', (9, 17))	('initiates', 'Reg', (100, 109))	('p53', 'Gene', (36, 39))	('Rb', 'Gene', '5925', (44, 46))	('leiomyosarcoma', 'Disease', (127, 141))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (127, 141))	('mouse', 'Species', '10090', (50, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('p53', 'Gene', (21, 24))
124680	28191765	The type of sarcoma initiated by mouse bone marrow-derived MSCs, upon knockout of these genes, also depends on the differentiation lineage and the stage 49.	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('sarcoma', 'Disease', (12, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('mouse', 'Species', '10090', (33, 38))	('knockout', 'Var', (70, 78))
124681	28191765	In contrast, single or combined knockdown of these genes produces no transformation in human MSCs.	('human MSCs', 'Disease', (87, 97))	('human', 'Species', '9606', (87, 92))	('knockdown', 'Var', (32, 41))
124687	28191765	Notably, the protein levels of p53 were lower in parental cells compared with transformed OS-like cells, indicating that the absence or disruption of p53 does not play a role in c-Myc overexpression and Rb knockdown-induced tumorigenic transformation of human MSCs in the present study.	('c-Myc', 'Gene', (178, 183))	('knockdown-induced', 'Var', (206, 223))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('human', 'Species', '9606', (254, 259))	('tumor', 'Disease', (224, 229))	('Rb', 'Gene', '5925', (203, 205))	('c-Myc', 'Gene', '4609', (178, 183))	('protein levels', 'MPA', (13, 27))	('lower', 'NegReg', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
124688	28191765	In this study, we investigated whether overexpression of c-Myc/Ras and/or disruption of p53 and Rb induced tumorigenic transformation of normal MSCs.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('p53', 'Protein', (88, 91))	('disruption', 'Var', (74, 84))	('c-Myc', 'Gene', '4609', (57, 62))	('Rb', 'Gene', '5925', (96, 98))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('c-Myc', 'Gene', (57, 62))
124689	28191765	We defined that only overexpression of c-Myc and disruption of Rb consistently induced tumorigenic transformations of human MSCs from four individuals into OS-like cells.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('induced', 'Reg', (79, 86))	('c-Myc', 'Gene', '4609', (39, 44))	('tumor', 'Disease', (87, 92))	('human', 'Species', '9606', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('disruption', 'Var', (49, 59))	('c-Myc', 'Gene', (39, 44))	('Rb', 'Gene', '5925', (63, 65))
124690	28191765	Notably, our data shown in human MSCs are consistent with and supported by a previous study, which shows that mouse MSCs derived from mice with a homozygous deletion of the Ink4a/Arf locus (Ink4aKO mice) can be transformed into mouse OS through overexpression of c-Myc 47.	('overexpression', 'PosReg', (245, 259))	('mice', 'Species', '10090', (134, 138))	('mouse', 'Species', '10090', (228, 233))	('human', 'Species', '9606', (27, 32))	('deletion', 'Var', (157, 165))	('mouse', 'Species', '10090', (110, 115))	('c-Myc', 'Gene', '4609', (263, 268))	('c-Myc', 'Gene', (263, 268))	('mice', 'Species', '10090', (198, 202))	('Ink4a/Arf', 'Gene', '12578', (173, 182))	('Ink4a/Arf', 'Gene', (173, 182))
124705	28191765	In contrast to the results of these studies, Rb deletion in mouse MSC lineage increases the adipogenic potential and decreases the osteogenic potential, which results in the formation of a liposarcoma 12.	('liposarcoma', 'Phenotype', 'HP:0012034', (189, 200))	('liposarcoma', 'Disease', 'MESH:D008080', (189, 200))	('decreases', 'NegReg', (117, 126))	('mouse', 'Species', '10090', (60, 65))	('liposarcoma', 'Disease', (189, 200))	('osteogenic potential', 'MPA', (131, 151))	('adipogenic potential', 'MPA', (92, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('increases', 'PosReg', (78, 87))	('deletion', 'Var', (48, 56))	('Rb', 'Gene', '5925', (45, 47))	('results in', 'Reg', (159, 169))
124709	28191765	For example, the overexpression of c-Myc, combined with Rb knockdown, in the model proposed by this study has been reported to enhance the expression of osteogenic genes in human MSCs 54.	('c-Myc', 'Gene', '4609', (35, 40))	('enhance', 'PosReg', (127, 134))	('c-Myc', 'Gene', (35, 40))	('overexpression', 'PosReg', (17, 31))	('human', 'Species', '9606', (173, 178))	('expression', 'MPA', (139, 149))	('knockdown', 'Var', (59, 68))	('Rb', 'Gene', '5925', (56, 58))	('osteogenic genes', 'Gene', (153, 169))
124711	28191765	The GO analysis of the changes in gene expression shows that the genes that are associated with cell differentiation, development, or growth are upregulated or downregulated, after the transformation of MSCs by a combination of Rb knockdown and c-Myc overexpression, which indicates that the malignant transformation of MSCs is accompanied by a change in stem cell properties, including the proliferation capacity and the differentiation potential.	('cell differentiation', 'CPA', (96, 116))	('Rb', 'Gene', '5925', (228, 230))	('proliferation capacity', 'CPA', (391, 413))	('knockdown', 'Var', (231, 240))	('c-Myc', 'Gene', '4609', (245, 250))	('differentiation potential', 'CPA', (422, 447))	('c-Myc', 'Gene', (245, 250))	('change', 'Reg', (345, 351))	('overexpression', 'PosReg', (251, 265))	('upregulated', 'PosReg', (145, 156))	('downregulated', 'NegReg', (160, 173))
124714	28191765	Knockdown of Rb induces premature senescence in MSCs (supplemental online Fig.	('Knockdown', 'Var', (0, 9))	('MSCs', 'Disease', (48, 52))	('Rb', 'Gene', '5925', (13, 15))	('induces', 'Reg', (16, 23))	('premature senescence', 'MPA', (24, 44))
124722	28191765	Nevertheless, this is the first study to succeed in using genetic modification to achieve prompt transformation of human MSCs into osteosarcoma-like metastatic cells, which provides a cell platform for future studies of the mechanisms for OS transformation, progression and treatment.	('genetic modification', 'Var', (58, 78))	('human', 'Species', '9606', (115, 120))	('osteosarcoma', 'Phenotype', 'HP:0002669', (131, 143))	('osteosarcoma', 'Disease', (131, 143))	('osteosarcoma', 'Disease', 'MESH:D012516', (131, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))
124758	27795864	Prolonged gene transcription inhibition due to long term immunosuppression with drugs like steroids and Azathioprine is hypothesized to enhance the risk of mutation in the B- and/or T-cells (translational mutations) causing differentiation into histiocytes or macrophages and subsequent proliferation of the mutated monoclonal clone.	('causing', 'Reg', (216, 223))	('differentiation', 'CPA', (224, 239))	('gene transcription', 'MPA', (10, 28))	('Azathioprine', 'Chemical', 'MESH:D001379', (104, 116))	('proliferation', 'CPA', (287, 300))	('steroids', 'Chemical', 'MESH:D013256', (91, 99))	('enhance', 'PosReg', (136, 143))	('mutation', 'Var', (156, 164))
124773	23763916	Interestingly, despite peripheral blood neutrophilic leukocytosis, both peripheral blood and bone marrow (BM) were morphologically and phenotypically normal despite exhibiting the t(9;22) translocation.	('blood neutrophilic leukocytosis', 'Disease', 'MESH:D007964', (34, 65))	('blood neutrophilic leukocytosis', 'Disease', (34, 65))	('t(9;22) translocation', 'Var', (180, 201))	('leukocytosis', 'Phenotype', 'HP:0001974', (53, 65))	('neutrophilic leukocytosis', 'Phenotype', 'HP:0011897', (40, 65))	('blood neutrophilic leukocytosis', 'Phenotype', 'HP:0011897', (34, 65))	('exhibiting', 'Reg', (165, 175))
124815	23763916	The BM evaluation of this patient showed only mild myeloid and eosinophilic hyperplasia without increased blasts, but, similar to our patient, the t(9;22)(q34;q11) and BCR-ABL fusion were detected on karyotypic and FISH evaluation of the BM.	('patient', 'Species', '9606', (26, 33))	('eosinophilic hyperplasia', 'Disease', (63, 87))	('eosinophilic hyperplasia', 'Disease', 'MESH:D004802', (63, 87))	('t(9;22)(q34;q11', 'Var', (147, 162))	('t(9;22)(q34;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (147, 163))	('BCR-ABL', 'Gene', (168, 175))	('BCR-ABL', 'Gene', '25', (168, 175))	('eosinophilic hyperplasia', 'Phenotype', 'HP:0001880', (63, 87))	('patient', 'Species', '9606', (134, 141))
124830	23763916	Evaluation of aleukemic GS for t(9;22) translocation by fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) assays should be considered even in the absence of bone marrow (BM) involvement by cytogenetic or FISH analysis.	('aleukemic GS', 'Disease', (14, 26))	('translocation', 'Var', (39, 52))	('absence of bone marrow', 'Phenotype', 'HP:0005528', (172, 194))	('aleukemic GS', 'Disease', 'MESH:D011125', (14, 26))
125016	22684860	HIF-1alpha inhibition blocks this evasive resistance and augments destruction of the tumor vasculature.	('evasive resistance', 'MPA', (34, 52))	('tumor', 'Disease', (85, 90))	('augments', 'NegReg', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('inhibition', 'Var', (11, 21))	('HIF-1alpha', 'Protein', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('blocks', 'NegReg', (22, 28))
125036	22684860	Inhibition of VEGF-A or its receptors can effectively suppress tumor angiogenesis in mouse sarcoma models, and numerous anti-VEGF agents are in various phases of clinical trials or approved for patients with cancer.	('tumor', 'Disease', (63, 68))	('mouse', 'Species', '10090', (85, 90))	('cancer', 'Disease', (208, 214))	('patients', 'Species', '9606', (194, 202))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('suppress', 'NegReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('VEGF-A', 'Gene', (14, 20))	('sarcoma', 'Disease', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Inhibition', 'Var', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
125068	22684860	Maximal knockdown of HIF1alpha occurred 72- to 96-hr post-transduction.	('knockdown', 'Var', (8, 17))	('HIF1alpha', 'Gene', (21, 30))	('HIF1alpha', 'Gene', '3091', (21, 30))
125116	22684860	HT1080 xenografts treated with DC101 showed delayed tumor growth, with tumors taking about 5-7 days longer to reach 1,000 mm3 in size.	('DC101', 'Var', (31, 36))	('HT1080', 'CellLine', 'CVCL:0317', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
125121	22684860	Alternatively, DC101 may have effects on HIF-1alpha nuclear localization, which are independent of hypoxia levels.	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('DC101', 'Var', (15, 20))	('nuclear localization', 'MPA', (52, 72))	('hypoxia', 'Disease', (99, 106))	('effects', 'Reg', (30, 37))	('HIF-1alpha', 'Protein', (41, 51))
125123	22684860	shRNA knockdown in HT1080 cells inhibited proliferation under normoxic and hypoxic conditions (Fig.	('hypoxic conditions', 'Disease', (75, 93))	('proliferation', 'CPA', (42, 55))	('inhibited', 'NegReg', (32, 41))	('hypoxic conditions', 'Disease', 'MESH:D009135', (75, 93))	('HT1080', 'CellLine', 'CVCL:0317', (19, 25))	('knockdown', 'Var', (6, 15))	('shRNA', 'Gene', (0, 5))
125125	22684860	Following HIF-1alpha knockdown in MS5907 sarcoma cell lines, we found no effect on proliferation; however, we found decreased migration under hypoxic conditions (Supporting Information Figs.	('sarcoma', 'Disease', (41, 48))	('hypoxic conditions', 'Disease', 'MESH:D009135', (142, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('HIF-1alpha', 'Gene', (10, 20))	('hypoxic conditions', 'Disease', (142, 160))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('knockdown', 'Var', (21, 30))	('migration', 'CPA', (126, 135))	('decreased', 'NegReg', (116, 125))
125126	22684860	HT1080 cells with stable knockdown of HIF-1alpha and control HT1080 cells were then grown as flank xenografts with or without treatment with DC101.	('knockdown', 'Var', (25, 34))	('HT1080', 'CellLine', 'CVCL:0317', (0, 6))	('HT1080', 'CellLine', 'CVCL:0317', (61, 67))	('HIF-1alpha', 'Gene', (38, 48))
125127	22684860	The knockdown of HIF-1alpha or DC101 treatment inhibited tumor growth; however, the combination of HIF-1alpha knockdown and DC101 caused the greatest degree of growth inhibition (Fig.	('knockdown', 'Var', (110, 119))	('growth', 'MPA', (160, 166))	('DC101', 'Gene', (124, 129))	('inhibited', 'NegReg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('HIF-1alpha', 'Gene', (99, 109))	('tumor', 'Disease', (57, 62))	('combination', 'Var', (84, 95))
125128	22684860	We assessed the levels of one HIF-1alpha target gene, CA9, in treated HT1080 tumors by qRT-PCR and found that HIF-1alpha knockdown did indeed repress CA9 levels (Fig.	('knockdown', 'Var', (121, 130))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('HIF-1alpha', 'Gene', (110, 120))	('CA9 levels', 'MPA', (150, 160))	('HT1080 tumors', 'Disease', 'MESH:D009369', (70, 83))	('repress', 'NegReg', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('HT1080 tumors', 'Disease', (70, 83))
125138	22684860	DC101 or metronomic Dox inhibited tumor growth by 30-31%, and the combination of DC101 or metronomic Dox inhibited tumor growth by 67% (Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (34, 39))	('inhibited', 'NegReg', (105, 114))	('Dox', 'Chemical', 'MESH:D004317', (101, 104))	('tumor', 'Disease', (115, 120))	('inhibited', 'NegReg', (24, 33))	('DC101', 'Var', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('Dox', 'Chemical', 'MESH:D004317', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
125144	22684860	Second, we examined MVD and found that DC101 reduced MVD by 42%, HIF-1alpha shRNA or metronomic Dox by 25-27% and the combination of HIF-1alpha shRNA or Dox and DC101 by 71-72% (Fig.	('reduced', 'NegReg', (45, 52))	('DC101', 'Var', (39, 44))	('Dox', 'Chemical', 'MESH:D004317', (153, 156))	('DC101', 'Gene', (161, 166))	('MVD', 'MPA', (53, 56))	('Dox', 'Chemical', 'MESH:D004317', (96, 99))
125148	22684860	The removal of VEGF-A from the cell culture media combined with HIF-1alpha knockdown inhibited the proliferation of HUVECs under both normoxic and hypoxic conditions (Supporting Information Fig.	('hypoxic conditions', 'Disease', (147, 165))	('inhibited', 'NegReg', (85, 94))	('knockdown', 'Var', (75, 84))	('hypoxic conditions', 'Disease', 'MESH:D009135', (147, 165))	('HIF-1alpha', 'Gene', (64, 74))	('proliferation', 'CPA', (99, 112))
125156	22684860	Genetic deletion of HIF-1alpha using shRNA or the pharmacologic blockade of HIF-1alpha binding to target DNA using low-dose Dox act synergistically with VEGF inhibition to suppress the growth of sarcoma xenografts.	('sarcoma', 'Disease', (195, 202))	('Dox', 'Chemical', 'MESH:D004317', (124, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('binding', 'Interaction', (87, 94))	('Genetic deletion', 'Var', (0, 16))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('HIF-1alpha', 'Gene', (20, 30))	('suppress', 'NegReg', (172, 180))
125160	22684860	Now after several years of antiangiogenic therapies being used in patients with solid tumors, oncologists have found that antiangiogenic therapies generally result only in a transitory inhibition or delay in tumor growth with ultimate regrowth of tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('solid tumors', 'Disease', 'MESH:D009369', (80, 92))	('tumors', 'Disease', (86, 92))	('tumor', 'Disease', (208, 213))	('antiangiogenic', 'Var', (122, 136))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (247, 252))	('delay', 'NegReg', (199, 204))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('inhibition', 'NegReg', (185, 195))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('patients', 'Species', '9606', (66, 74))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('solid tumors', 'Disease', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
125169	22684860	In our study, we found that anti-VEGFR-2 therapy with DC101 did not significantly change intratumoral hypoxia when comparing similar-sized tumors; however, DC101 did appear to increase nuclear localization of HIF-1alpha in small tumors (200-300 mm3).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (139, 144))	('HIF-1alpha in small tumors', 'Disease', (209, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('DC101', 'Var', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('HIF-1alpha in small tumors', 'Disease', 'MESH:D058405', (209, 235))	('tumors', 'Disease', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (229, 234))	('hypoxia', 'Disease', (102, 109))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('nuclear localization', 'MPA', (185, 205))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('increase', 'PosReg', (176, 184))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('tumor', 'Disease', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (139, 145))
125181	22684860	Mechanistically, we confirmed the synergistic effects of HIF-1alpha and VEGF inhibition on tumor growth and on tumor endothelium by specifically knocking down HIF-1alpha using shRNA.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('HIF-1alpha', 'Gene', (159, 169))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (111, 116))	('knocking', 'Var', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
125185	22684860	In addition, HIF-1alpha inhibition to VEGF inhibition augments destruction of the tumor vasculature in sarcomas, and this strategy should be investigated in clinical trials.	('augments', 'PosReg', (54, 62))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('inhibition', 'NegReg', (43, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Disease', (103, 111))	('inhibition', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('HIF-1alpha', 'Protein', (13, 23))	('VEGF', 'Gene', (38, 42))	('tumor', 'Disease', (82, 87))
125198	31799177	Immunotherapeutic approaches including antigen-presenting cell-based vaccines have been employed as single agent or as part of combination strategies having been substantiated by a report on immunogenicity of Ewing's sarcoma with specific translocation resulting in EWS/FLI1 fusion.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (209, 224))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (209, 224))	('EWS', 'Gene', '2130', (266, 269))	('EWS', 'Gene', (266, 269))	('FLI1', 'Gene', '2313', (270, 274))	('FLI1', 'Gene', (270, 274))	('translocation', 'Var', (239, 252))	('fusion', 'Interaction', (275, 281))	("Ewing's sarcoma", 'Disease', (209, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))
125212	31799177	Patients eligible for the clinical trial were children, adolescents, and young adults (1-25 years old) with histologically confirmed refractory, relapsing, or primarily metastatic high-risk tumors; Karnofsky or Lansky score >=50; life expectancy longer than 10 weeks; and adequate function of bone marrow, kidney, liver, and heart defined as absolute neutrophil count (ANC) >=0.75 x 103/mul, thrombocytes >=75 x 103/mul, hemoglobin 80 g/l, estimated glomerular filtration rate (eGFR) >=70 ml/min/1.73 m2, serum creatinine <= 1.5-fold upper limit for the appropriate age, bilirubin <= 1.5-fold upper limit for the appropriate age, AST and ALT <= 2.5-fold upper limit for the appropriate age, ejection fraction >=50%, and fractional shortening >=27% assessed by echocardiography.	('bilirubin', 'MPA', (571, 580))	('ALT', 'MPA', (638, 641))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('>=0.75', 'Var', (374, 380))	('ejection', 'MPA', (691, 699))	('bilirubin', 'Chemical', 'MESH:D001663', (571, 580))	('fractional', 'MPA', (720, 730))	('children', 'Species', '9606', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('>=75', 'Var', (405, 409))	('AST', 'Gene', (630, 633))	('tumors', 'Disease', (190, 196))	('creatinine', 'Chemical', 'MESH:D003404', (511, 521))	('AST', 'Gene', '26503', (630, 633))	('serum creatinine', 'MPA', (505, 521))
125269	31799177	We observed the lowest post-DC increase in autologous T-cell stimulation by self-tumor antigens in cases KDO-0114, KDO-0124, and KDO-0133 who started DC treatment in disease progression.	('KDO-0124', 'Var', (115, 123))	('autologous T-cell stimulation', 'MPA', (43, 72))	('KDO-0133', 'Var', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('KDO-0133', 'Chemical', 'MESH:C002532', (129, 137))	('KDO-0114', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('KDO-0114, KDO-0124', 'Chemical', 'MESH:C002532', (105, 123))	('tumor', 'Disease', (81, 86))
125285	31799177	Production of cytokines (IFN-gamma, TNF-alpha, IL-17A) during auto-MLR mildly increased in post-DC compared to pre-DC evaluation (Figure 6B blue).	('IFN-gamma', 'Gene', '3458', (25, 34))	('IFN-gamma', 'Gene', (25, 34))	('post-DC', 'Var', (91, 98))	('IL-17A', 'Gene', '3605', (47, 53))	('kin', 'Gene', '22944', (18, 21))	('kin', 'Gene', (18, 21))	('IL-17A', 'Gene', (47, 53))	('increased', 'PosReg', (78, 87))	('TNF-alpha', 'Gene', '7124', (36, 45))	('TNF-alpha', 'Gene', (36, 45))
125288	31799177	In this patient, gammadelta T-cells were predominantly Vgamma9-Vdelta2- prior to DC ITx initiation (baseline 39%).	('Vgamma9-Vdelta2-', 'Var', (55, 71))	('DC ITx', 'Disease', (81, 87))	('patient', 'Species', '9606', (8, 15))
125289	31799177	Vgamma9+Vdelta2+ T-cells represented 33% of gammadelta T-cells, and their proportion decreased during DC Itx, and this gammadelta subset was almost depleted from circulation after third-line CTx (Figure 6D).	('CTx', 'Gene', '1593', (191, 194))	('decreased', 'NegReg', (85, 94))	('CTx', 'Gene', (191, 194))	('Vgamma9+Vdelta2+', 'Var', (0, 16))
125290	31799177	In contrast to the Vgamma9+Vdelta2+ subset, Vgamma9-Vdelta2- T-cells were predominantly CD314(NKG2D)+ (Supplementary Material 4).	('Vgamma9-Vdelta2- T-cells', 'CellLine', 'CVCL:M092', (44, 68))	('Vgamma9-Vdelta2-', 'Var', (44, 60))	('CD314', 'Var', (88, 93))
125305	31799177	In comparison to the rest of the study group, patient KDO-0101 exhibited a lymphocyte count within the reference range, a high proportion of effector T-cells, and low levels of all observed parameters associated with adverse disease outcome, namely, Treg count, M-MDSC count, and neutrophil-to-lymphocyte ratio.	('patient', 'Species', '9606', (46, 53))	('M-MDSC count', 'CPA', (262, 274))	('Treg count', 'CPA', (250, 260))	('lymphocyte count', 'CPA', (75, 91))	('KDO-0101', 'Var', (54, 62))	('neutrophil-to-lymphocyte', 'CPA', (280, 304))
125310	31799177	Interestingly, however, in this patient, we observed an increase in number of Vgamma9-Vdelta2- T cells and depletion of Vgamma9+Vdelta2+ T-cells.	('Vgamma9-Vdelta2- T', 'Var', (78, 96))	('depletion', 'MPA', (107, 116))	('increase', 'PosReg', (56, 64))	('patient', 'Species', '9606', (32, 39))
125311	31799177	It is of note that only in two out of nine pediatric sarcoma patients (KDO-0118 and KDO-0139), the Vgamma9+Vdelta2+ subset represented a majority of circulating gammadelta T-cells.	('KDO-0118', 'Chemical', 'MESH:C002532', (71, 79))	('patients', 'Species', '9606', (61, 69))	('KDO-0139', 'Var', (84, 92))	('KDO-0139', 'Chemical', 'MESH:C086421', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('Vgamma9+Vdelta2+', 'Var', (99, 115))	('pediatric sarcoma', 'Disease', (43, 60))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (43, 60))
125316	31799177	Performance status declined after 1 year of RTx, DCs ITx, and metronomic vinblastine and zoledronic acid.	('vinblastine', 'Chemical', 'MESH:D014747', (73, 84))	('DCs', 'Var', (49, 52))	('declined', 'NegReg', (19, 27))	('zoledronic acid', 'Chemical', 'MESH:C088658', (89, 104))	('Performance status', 'MPA', (0, 18))
125334	31266185	Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas Soft-tissue sarcomas (STS) are rare tumors whose oncogenesis remains unknown and for which no common therapeutic target has yet been identified.	('Sarcomas', 'Disease', (79, 87))	('Soft-Tissue Sarcomas', 'Phenotype', 'HP:0030448', (67, 87))	('Deletions', 'Var', (14, 23))	('Sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('sarcomas', 'Disease', (100, 108))	('Sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('DMD', 'Gene', '1756', (10, 13))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('Sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('DMD', 'Gene', (10, 13))	('STS', 'Phenotype', 'HP:0030448', (110, 113))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
125335	31266185	Analysis of 318 STS by CGH array evidenced a frequent deletion affecting the DMD gene (encoding dystrophin isoforms) in 16.5% of STS, including sarcomas with complex genomics, gastrointestinal tumors (GIST), and synovial sarcomas (SS).	('sarcomas', 'Phenotype', 'HP:0100242', (144, 152))	('sarcomas', 'Disease', (144, 152))	('sarcomas', 'Disease', 'MESH:D012509', (221, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (221, 229))	('gastrointestinal tumors', 'Disease', (176, 199))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (176, 199))	('sarcomas', 'Disease', (221, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('deletion', 'Var', (54, 62))	('STS', 'Disease', (129, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (212, 229))	('STS', 'Phenotype', 'HP:0030448', (129, 132))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (176, 199))	('GIST', 'Phenotype', 'HP:0007378', (201, 205))	('synovial sarcomas', 'Disease', (212, 229))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('SS', 'Phenotype', 'HP:0100242', (231, 233))	('STS', 'Phenotype', 'HP:0030448', (16, 19))	('DMD gene', 'Gene', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('synovial sarcomas', 'Disease', 'MESH:D013584', (212, 229))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (212, 228))	('sarcomas', 'Disease', 'MESH:D012509', (144, 152))
125336	31266185	We observed that targeted deletions of DMD were restricted to the 5' region of the gene, which is responsible for the transcription of Dp427.	('Dp427', 'Gene', (135, 140))	('Dp427', 'Gene', '13405', (135, 140))	('deletions', 'Var', (26, 35))
125338	31266185	Dp427 depletion had no effect on cell growth or migration.	('Dp427', 'Gene', (0, 5))	('depletion', 'Var', (6, 15))	('Dp427', 'Gene', '13405', (0, 5))
125343	31266185	The protein encoded by this transcript is called dystrophin since mutations lead to the Becker and Duchenne muscular dystrophies.	('mutations', 'Var', (66, 75))	('Becker', 'Disease', 'MESH:D009224', (88, 94))	('Becker', 'Disease', (88, 94))	('Duchenne muscular dystrophies', 'Disease', (99, 128))	('Duchenne muscular dystrophies', 'Disease', 'MESH:D020388', (99, 128))	('muscular dystrophies', 'Phenotype', 'HP:0003560', (108, 128))	('lead to', 'Reg', (76, 83))
125345	31266185	(2014) reported DMD deletions in 25 of 40 myogenic tumors (29 gastrointestinal tumors (GIST), 4 rhabdomyosarcomas, and 7 leiomyosarcomas (LMS)), and observed that forced re-expression of the miniDMD construct (lacking exons 17-48) inhibited cell migration, cell invasion, anchorage independence, and invadopodia formation.	('GIST', 'Phenotype', 'HP:0007378', (87, 91))	('deletions', 'Var', (20, 29))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (62, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('myogenic tumors', 'Disease', (42, 57))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (121, 135))	('myogenic tumors', 'Disease', 'MESH:D009369', (42, 57))	('cell migration', 'CPA', (241, 255))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (96, 113))	('rhabdomyosarcomas', 'Disease', (96, 113))	('cell invasion', 'CPA', (257, 270))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (96, 113))	('inhibited', 'NegReg', (231, 240))	('gastrointestinal tumors', 'Disease', (62, 85))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (62, 85))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (121, 136))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('leiomyosarcomas', 'Disease', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('anchorage independence', 'CPA', (272, 294))	('invadopodia formation', 'CPA', (300, 321))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (121, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
125347	31266185	(2011) noticed that the mdx mutation led in 39% of cases to the spontaneous formation of skeletal-muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas (LPS).	('liposarcomas', 'Disease', (183, 195))	('fibro-', 'Disease', (171, 177))	('mice', 'Species', '10090', (133, 137))	('mutation', 'Var', (28, 36))	('LPS', 'Disease', 'MESH:C536528', (197, 200))	('mixed rhabdomyo-', 'Disease', (153, 169))	('malignant tumors', 'Disease', 'MESH:D018198', (113, 129))	('LPS', 'Phenotype', 'HP:0012034', (197, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('liposarcomas', 'Disease', 'MESH:D008080', (183, 195))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('malignant tumors', 'Disease', (113, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('liposarcomas', 'Phenotype', 'HP:0012034', (183, 195))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mdx', 'Gene', (24, 27))	('liposarcoma', 'Phenotype', 'HP:0012034', (183, 194))	('LPS', 'Disease', (197, 200))	('mdx', 'Gene', '13405', (24, 27))
125348	31266185	In line with this observation, inactivation of other genes implicated in muscular dystrophy often accompanies age-related soft-tissue sarcomas (STS), thereby suggesting a common mechanism for their oncogenesis (Schmidt et al.	('sarcomas', 'Disease', (134, 142))	('inactivation', 'Var', (31, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (73, 91))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (122, 142))	('muscular dystrophy', 'Disease', 'MESH:D009136', (73, 91))	('STS', 'Phenotype', 'HP:0030448', (144, 147))	('accompanies', 'Reg', (98, 109))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('muscular dystrophy', 'Disease', (73, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))
125352	31266185	In addition, high DMD expression was associated with poorer overall survival in B-cell chronic lymphocytic leukemia.	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (87, 115))	('high DMD expression', 'Var', (13, 32))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (95, 115))	('lymphocytic leukemia', 'Disease', (95, 115))	('poorer', 'NegReg', (53, 59))	('overall', 'MPA', (60, 67))
125355	31266185	Whereas Dp427 is the one that is altered in muscular dystrophies, Dp71 is ubiquitously expressed, except in differentiated muscle cells, and is involved in cognition, cell adhesion, cell cycle, and in nuclear-envelope-related functions.	('muscular dystrophies', 'Phenotype', 'HP:0003560', (44, 64))	('involved', 'Reg', (144, 152))	('Dp71', 'Var', (66, 70))	('Dp71', 'Chemical', '-', (66, 70))	('muscular dystrophies', 'Disease', 'MESH:D009136', (44, 64))	('Dp427', 'Gene', '13405', (8, 13))	('Dp427', 'Gene', (8, 13))	('cycle', 'Gene', '25729', (187, 192))	('muscular dystrophies', 'Disease', (44, 64))	('cycle', 'Gene', (187, 192))
125357	31266185	(2014) observed that inhibition of Dp71 dramatically decreased the growth of RMS cell lines.	('growth of RMS cell lines', 'CPA', (67, 91))	('inhibition', 'Var', (21, 31))	('Dp71', 'Chemical', '-', (35, 39))	('decreased', 'NegReg', (53, 62))	('Dp71', 'Gene', (35, 39))
125358	31266185	They also showed that inhibition of DMD enhanced migration and invasion, whereas its re-expression reduced migration and induced senescence in melanoma cell lines.	('inhibition', 'Var', (22, 32))	('migration', 'CPA', (107, 116))	('DMD', 'Gene', (36, 39))	('migration', 'CPA', (49, 58))	('invasion', 'CPA', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('senescence', 'CPA', (129, 139))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('reduced', 'NegReg', (99, 106))	('enhanced', 'PosReg', (40, 48))	('induced', 'Reg', (121, 128))
125360	31266185	We also investigated isoform expression and performed functional analyses to decipher the role of Dp427 and Dp71, which are the two isoforms expressed in these sarcomas.	('Dp71', 'Var', (108, 112))	('Dp71', 'Chemical', '-', (108, 112))	('sarcomas', 'Disease', 'MESH:D012509', (160, 168))	('Dp427', 'Gene', '13405', (98, 103))	('Dp427', 'Gene', (98, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('sarcomas', 'Disease', (160, 168))
125362	31266185	Deletion was significantly associated with a decrease in DMD expression (Figure 1A) (p = 0.002), independently of gender (53.7% of men vs. 46.3% of women) (Table 2), but was significantly more frequent in metastatic tumors (Chi2 = 2.68 x 10-4; Table 2).	('men', 'Species', '9606', (131, 134))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Disease', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('decrease', 'NegReg', (45, 53))	('men', 'Species', '9606', (150, 153))	('DMD expression', 'MPA', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('women', 'Species', '9606', (148, 153))	('Deletion', 'Var', (0, 8))
125363	31266185	Indeed, metastasis occurred in 30/54 (55.6%) of deleted tumors against 76/264 (28.8%) in non-deleted tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('metastasis', 'CPA', (8, 18))	('occurred', 'Reg', (19, 27))	('deleted', 'Var', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
125364	31266185	Accordingly, the DMD genomic status split the tumors into two groups with significant distinct prognosis, showing that DMD deletion is associated with a worse prognosis (Figure 1B).	('DMD deletion', 'Var', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
125365	31266185	To verify that the prognostic value of DMD deletion is not related to large alterations affecting the X chromosome but has a significant relevance by itself, metastasis-free survival (MFS) analysis was compared between non-deleted patients and patients with a targeted deletion of DMD (referred to as "DMD status") or with a deletion of the p-arm or the entire X chromosome (referred to as "chr.	('deletion', 'Var', (325, 333))	('deletion', 'Var', (269, 277))	('patients', 'Species', '9606', (231, 239))	('patients', 'Species', '9606', (244, 252))
125372	31266185	Since Dp427 was the target of deletions and Dp71 was never altered and was the only one expressed, we studied the impact of each of these isoforms first on metastatic outcome and then on tumor phenotypes.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('deletions', 'Var', (30, 39))	('tumor', 'Disease', (187, 192))	('Dp427', 'Gene', '13405', (6, 11))	('Dp427', 'Gene', (6, 11))	('Dp71', 'Chemical', '-', (44, 48))
125373	31266185	According to RNA sequencing data, metastasis-free survival (MFS) analysis depending on Dp427 or Dp71 expression showed that the isoform expression level was not prognostic of metastatic progression for sarcoma patients (Supplementary Figure S1).	('Dp427', 'Gene', (87, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('Dp71', 'Var', (96, 100))	('men', 'Species', '9606', (226, 229))	('Dp71', 'Chemical', '-', (96, 100))	('sarcoma', 'Disease', 'MESH:D012509', (202, 209))	('patients', 'Species', '9606', (210, 218))	('Dp427', 'Gene', '13405', (87, 92))	('sarcoma', 'Disease', (202, 209))
125374	31266185	This suggests that the deletion of Dp427 is the critical mechanism related to metastatic development, rather than each isoform expression level taken apart.	('Dp427', 'Gene', '13405', (35, 40))	('men', 'Species', '9606', (96, 99))	('related', 'Reg', (67, 74))	('Dp427', 'Gene', (35, 40))	('deletion', 'Var', (23, 31))	('metastatic development', 'CPA', (78, 100))
125375	31266185	Consequently, Dp427 downregulation was induced by CRISPR/Cas9 editing in the IB133 cell line (derived from leiomyosarcoma), which was selected for its relatively high Dp427 expression at both transcriptomic (Figure 2C) and protein (Figure 2D) levels.	('Dp427', 'Gene', (14, 19))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (107, 121))	('downregulation', 'NegReg', (20, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('Dp427', 'Gene', '13405', (167, 172))	('editing', 'Var', (62, 69))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (107, 121))	('Dp427', 'Gene', (167, 172))	('leiomyosarcoma', 'Disease', (107, 121))	('Dp427', 'Gene', '13405', (14, 19))
125376	31266185	Sanger sequencing showed that this CRISPR assay produced the deletion of one or two nucleotides (Figure 3A) associated with Dp427 down-regulation, as evidenced by Western blotting (Figure 3B) in five replicates.	('down-regulation', 'NegReg', (130, 145))	('Dp427', 'Gene', (124, 129))	('deletion', 'Var', (61, 69))	('Dp427', 'Gene', '13405', (124, 129))
125377	31266185	Despite effective Dp427 downregulation, we did not observe any significant difference in cell proliferation (Figure 3C), clonogenic properties (Figure 3D), or migration (Figure 3E) between the mutated and control cell lines.	('Dp427', 'Gene', '13405', (18, 23))	('clonogenic properties', 'CPA', (121, 142))	('Dp427', 'Gene', (18, 23))	('cell proliferation', 'CPA', (89, 107))	('mutated', 'Var', (193, 200))	('downregulation', 'NegReg', (24, 38))
125378	31266185	These observations contrasted with the effect of Dp71 inhibition on one synovial sarcoma (SW982) and two other LMS (IB112 and IB136) cell lines that all expressed Dp71 but not Dp427.	('Dp427', 'Gene', '13405', (176, 181))	('Dp427', 'Gene', (176, 181))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (72, 88))	('synovial sarcoma', 'Disease', 'MESH:D013584', (72, 88))	('Dp71', 'Chemical', '-', (49, 53))	('Dp71', 'Var', (163, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('Dp71', 'Chemical', '-', (163, 167))	('SW982', 'CellLine', 'CVCL:1734', (90, 95))	('synovial sarcoma', 'Disease', (72, 88))
125379	31266185	Indeed, two shRNA (under the control of the Tet promoter) targeting Dp71 (sh1251 and sh1836) and a control shNT (non-targeting) were transduced.	('Dp71', 'Chemical', '-', (68, 72))	('Dp71', 'Gene', (68, 72))	('Tet', 'Chemical', 'MESH:C010349', (44, 47))	('sh1251', 'Var', (74, 80))	('sh1836', 'Var', (85, 91))
125381	31266185	Of note, Dp71 inhibition even abolished the capacity of cells to grow as isolated clones (Figure 4C).	('Dp71', 'Chemical', '-', (9, 13))	('inhibition', 'Var', (14, 24))	('abolished', 'NegReg', (30, 39))	('Dp71', 'Gene', (9, 13))
125382	31266185	Furthermore, incorporation of propidium iodide (Figure 4D) in SW982-sh1251 vs SW982-shNT, incubated or not during 72 h with doxycycline, showed that Dp71 inhibition reduced the proportion of cells in the G0/G1 phase while increasing the percentage of cells in the G2/M phase, thus suggesting a G2/M-phase arrest.	('Dp71', 'Gene', (149, 153))	('doxycycline', 'Chemical', 'MESH:D004318', (124, 135))	('increasing', 'PosReg', (222, 232))	('SW982', 'CellLine', 'CVCL:1734', (78, 83))	('G0/G1 phase', 'CPA', (204, 215))	('SW982-sh1251', 'Var', (62, 74))	('inhibition reduced', 'NegReg', (154, 172))	('SW982', 'CellLine', 'CVCL:1734', (62, 67))	('propidium iodide', 'Chemical', 'MESH:D011419', (30, 46))	('Dp71', 'Chemical', '-', (149, 153))	('G2/M phase', 'CPA', (264, 274))
125384	31266185	Pleomorphic sarcomas are characterized more by frequent chromosome losses or gains than by recurrent single nucleotide variations.	('chromosome losses', 'Var', (56, 73))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('gains', 'PosReg', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('sarcomas', 'Disease', (12, 20))
125388	31266185	In contrast, Wang and collaborators observed intragenic deletions in 25 of 40 (63%) high-grade myogenic tumors, which suggests that DMD deletion could be associated with aggressiveness.	('myogenic tumors', 'Disease', 'MESH:D009369', (95, 110))	('aggressiveness', 'Phenotype', 'HP:0000718', (170, 184))	('myogenic tumors', 'Disease', (95, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('aggressiveness', 'Disease', 'MESH:D001523', (170, 184))	('deletions', 'Var', (56, 65))	('aggressiveness', 'Disease', (170, 184))	('associated', 'Reg', (154, 164))
125390	31266185	However, we also noticed such a deletion in myxofibrosarcoma, UPS, pLPS, and SS.	('deletion', 'Var', (32, 40))	('LPS', 'Disease', 'MESH:C536528', (68, 71))	('UPS', 'Disease', (62, 65))	('SS', 'Phenotype', 'HP:0100242', (77, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('LPS', 'Phenotype', 'HP:0012034', (68, 71))	('myxofibrosarcoma', 'Disease', (44, 60))	('LPS', 'Disease', (68, 71))	('myxofibrosarcoma', 'Disease', 'None', (44, 60))
125393	31266185	Indeed, DMD-deleted sarcomas could arise from multipotent mesenchymal or muscle-derived stem cells.	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcomas', 'Disease', (20, 28))	('DMD-deleted', 'Var', (8, 19))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
125399	31266185	In the same study, they also showed that the frequency of CFS breaks correlates with its transcription level, thereby confirming that DMD deletion is particularly relevant in myogenic sarcomas or more widely in those derived from DMD-expressing cells.	('breaks', 'Var', (62, 68))	('transcription level', 'MPA', (89, 108))	('myogenic sarcomas', 'Disease', (175, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (184, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('myogenic sarcomas', 'Disease', 'MESH:D012509', (175, 192))
125406	31266185	On the other hand, Dp71 inhibition dramatically reduced cell proliferation and clonogenicity in three sarcoma cell lines.	('Dp71', 'Gene', (19, 23))	('clonogenicity', 'CPA', (79, 92))	('reduced', 'NegReg', (48, 55))	('inhibition', 'Var', (24, 34))	('cell proliferation', 'CPA', (56, 74))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Dp71', 'Chemical', '-', (19, 23))
125411	31266185	This may explain why it is widely expressed in tumors and why specific DMD deletions systematically preserve the Dp71 reading frame.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('deletions', 'Var', (75, 84))	('Dp71 reading frame', 'MPA', (113, 131))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('Dp71', 'Chemical', '-', (113, 117))
125412	31266185	The fact that Dp427 or Dp71 expression level are not prognostic for metastatic progression is not very surprising given that Dp427 and Dp71 are respectively barely and widely expressed among tumors and so, Dp71 or Dp427 expression levels taken apart may not be the determining parameter for metastatic progression.	('Dp427', 'Gene', (14, 19))	('Dp71', 'Chemical', '-', (23, 27))	('Dp427', 'Gene', '13405', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('Dp427', 'Gene', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('Dp71', 'Chemical', '-', (206, 210))	('Dp427', 'Gene', '13405', (214, 219))	('Dp427', 'Gene', (214, 219))	('Dp71', 'Var', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('Dp71', 'Chemical', '-', (135, 139))	('Dp427', 'Gene', '13405', (14, 19))
125413	31266185	On the other hand, this strengthens the idea that the impact of DMD on metastatic progression is rather determined by the overall expression pattern of the different isoforms:that is to say, Dp71 expression combined with Dp427 deletion:and possibly relies on their protein interactions and/or subcellular localizations.	('Dp427', 'Gene', (221, 226))	('Dp427', 'Gene', '13405', (221, 226))	('Dp71', 'Var', (191, 195))	('Dp71', 'Chemical', '-', (191, 195))
125415	31266185	in 2012, when they stated that deletions can expose cancer-specific therapeutic vulnerabilities when the deleted gene is a member of a functionally redundant family of genes carrying out an essential function.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('deletions', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (52, 58))
125430	31266185	Deletion and inhibition of Dp427 were verified by Sanger sequencing and Western blot, respectively.	('Dp427', 'Gene', '13405', (27, 32))	('Dp427', 'Gene', (27, 32))	('Deletion', 'Var', (0, 8))
125441	31266185	The assay IDs were as follows: Hs00758098_m1 for DMD, and Hs99999902_m1 for RPLP0.	('RPLP0', 'Gene', '6175', (76, 81))	('RPLP0', 'Gene', (76, 81))	('Hs00758098_m1', 'Var', (31, 44))	('Hs99999902_m1', 'Var', (58, 71))
125452	31266185	Although Dp427 is the main target of these deletions, our in vitro data suggest that Dp71 is essential for tumor maintenance, at least by promoting cell proliferation.	('deletions', 'Var', (43, 52))	('Dp71', 'Var', (85, 89))	('Dp427', 'Gene', '13405', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('Dp427', 'Gene', (9, 14))	('promoting', 'PosReg', (138, 147))	('Dp71', 'Chemical', '-', (85, 89))	('cell proliferation', 'CPA', (148, 166))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
125490	29040875	Analyzing human microarray datasets, we showed that RUNX2 expression is linked to poor survival in ES patients.	('RUNX2', 'Gene', '860', (52, 57))	('human', 'Species', '9606', (10, 15))	('linked', 'Reg', (72, 78))	('patients', 'Species', '9606', (102, 110))	('poor', 'NegReg', (82, 86))	('RUNX2', 'Gene', (52, 57))	('expression', 'Var', (58, 68))	('ES', 'Phenotype', 'HP:0012254', (99, 101))
125507	29040875	Therefore, blocking ERK1/2 leads to reduced cell proliferation and survival in many tumors.	('ERK1/2', 'Gene', '5595;5594', (20, 26))	('survival', 'CPA', (67, 75))	('cell proliferation', 'CPA', (44, 62))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('blocking', 'Var', (11, 19))	('reduced', 'NegReg', (36, 43))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('ERK1/2', 'Gene', (20, 26))
125559	29040875	The fluid equation comes from:   which in the pressure formulation translates to:   where  epsilonvol/ t is the rate of change in volumetric strain from the equations for solid displacements, rhof is the fluid density and alphaB is the Biot-Willis coefficient.	('rhof', 'Gene', (192, 196))	('epsilonvol/ t', 'Var', (91, 104))	('rhof', 'Gene', '54509', (192, 196))
125584	29040875	Strong evidence suggests that the inhibition of EWS-FLI1, Ewing sarcoma's main oncogene, allows ES cells to recover the phenotype of their mesenchymal stem cells progenitors.	('EWS', 'Gene', (48, 51))	('ES', 'Phenotype', 'HP:0012254', (96, 98))	('EWS', 'Gene', '2130', (48, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('inhibition', 'Var', (34, 44))	('FLI1', 'Gene', '2313', (52, 56))	('FLI1', 'Gene', (52, 56))	('Ewing sarcoma', 'Disease', (58, 71))	('phenotype', 'MPA', (120, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (58, 71))
125600	29040875	Exposing ES cells to 10 muM of U0126, inhibited ERK1/2 phosphorylation both in the stimulated and the unstimulated groups (Fig.	('ERK1/2', 'Gene', (48, 54))	('U0126', 'Chemical', 'MESH:C113580', (31, 36))	('ERK1/2', 'Gene', '5595;5594', (48, 54))	('muM', 'Gene', '56925', (24, 27))	('muM', 'Gene', (24, 27))	('inhibited', 'NegReg', (38, 47))	('phosphorylation', 'MPA', (55, 70))	('ES', 'Phenotype', 'HP:0012254', (9, 11))	('U0126', 'Var', (31, 36))
125601	29040875	ERK1/2 blockade led to a drop in RUNX2 mRNA levels to baseline levels (Fig.	('drop', 'NegReg', (25, 29))	('ERK1/2', 'Gene', (0, 6))	('ERK1/2', 'Gene', '5595;5594', (0, 6))	('RUNX2', 'Gene', '860', (33, 38))	('blockade', 'Var', (7, 15))	('RUNX2', 'Gene', (33, 38))
125636	29040875	In both datasets studied, patients with high RUNX2 levels were associated with poor five-year survival probability (20-40%), compared to patients with low RUNX2 levels (60-80%).	('high', 'Var', (40, 44))	('RUNX2', 'Gene', '860', (45, 50))	('RUNX2', 'Gene', '860', (155, 160))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (26, 34))	('RUNX2', 'Gene', (155, 160))	('RUNX2', 'Gene', (45, 50))	('poor', 'NegReg', (79, 83))
125653	29040875	In our bioengineered ES model, mechanical loads reactivated signaling pathways targeted by commonly used anticancer drugs and altered cancer cells drug sensitivity.	('altered', 'Reg', (126, 133))	('signaling pathways', 'Pathway', (60, 78))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('reactivated', 'Reg', (48, 59))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mechanical loads', 'Var', (31, 47))	('drug sensitivity', 'Phenotype', 'HP:0020174', (147, 163))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('ES', 'Phenotype', 'HP:0012254', (21, 23))
125673	29040875	In addition, our genomic data showed that ES patients with high RUNX2 levels had a poor overall survival probability.	('ES', 'Phenotype', 'HP:0012254', (42, 44))	('RUNX2', 'Gene', (64, 69))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (45, 53))	('RUNX2', 'Gene', '860', (64, 69))
125685	27779808	INC280, a selective c-MET inhibitor, inhibited growth of Yamato-SS cells both in vitro and in vivo but not that of SYO-1 or HS-SY-II cells.	('SYO-1', 'Gene', '55027', (115, 120))	('HS-SY-II', 'CellLine', 'CVCL:8719', (124, 132))	('Yamato-SS cells', 'CPA', (57, 72))	('inhibited', 'NegReg', (37, 46))	('SS', 'Phenotype', 'HP:0012570', (64, 66))	('INC280', 'Var', (0, 6))	('SYO-1', 'Gene', (115, 120))	('INC280', 'Chemical', 'MESH:C000613976', (0, 6))	('growth', 'CPA', (47, 53))
125686	27779808	INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c-MET and its downstream effectors in Yamato-SS cells.	('phosphorylation', 'MPA', (60, 75))	('blocked', 'NegReg', (52, 59))	('c-MET', 'Protein', (79, 84))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (15, 32))	('apoptosis', 'CPA', (37, 46))	('INC280', 'Var', (0, 6))	('arrest', 'Disease', 'MESH:D006323', (26, 32))	('INC280', 'Chemical', 'MESH:C000613976', (0, 6))	('SS', 'Phenotype', 'HP:0012570', (124, 126))	('arrest', 'Disease', (26, 32))
125688	27779808	Taken together, activation of HGF/c-MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c-MET-activated SS.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('SS', 'Phenotype', 'HP:0012570', (198, 200))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('SS', 'Phenotype', 'HP:0012570', (110, 112))	('targeting', 'Var', (117, 126))	('tumor', 'Disease', (165, 170))
125704	27779808	Antibodies against c-MET, p-MET (Tyr1234/1235), platelet-derived growth factor receptor alpha (PDGFRalpha), p-PDGFRalpha (Tyr849), AKT, p-AKT (Ser473), ERK, p-ERK (Thr202/Tyr204), cleaved caspase-3 and beta-actin were purchased from Cell Signaling Technology (Danvers, MA, USA).	('AKT', 'Gene', '207', (131, 134))	('PDGFRalpha', 'Gene', (110, 120))	('ERK', 'Gene', '5594', (159, 162))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (48, 93))	('ERK', 'Gene', '5594', (152, 155))	('Tyr204', 'Chemical', '-', (171, 177))	('Thr202', 'Chemical', '-', (164, 170))	('PDGFRalpha', 'Gene', '5156', (95, 105))	('p-ERK', 'Gene', '9451', (157, 162))	('beta-actin', 'Gene', (202, 212))	('p-ERK', 'Gene', (157, 162))	('ERK', 'Gene', (159, 162))	('caspase-3', 'Gene', '836', (188, 197))	('PDGFRalpha', 'Gene', '5156', (110, 120))	('ERK', 'Gene', (152, 155))	('AKT', 'Gene', (138, 141))	('AKT', 'Gene', (131, 134))	('platelet-derived growth factor receptor alpha', 'Gene', (48, 93))	('caspase-3', 'Gene', (188, 197))	('Tyr1234', 'Chemical', '-', (33, 40))	('Ser473', 'Chemical', '-', (143, 149))	('p-MET', 'Var', (26, 31))	('Tyr849', 'Chemical', '-', (122, 128))	('beta-actin', 'Gene', '728378', (202, 212))	('PDGFRalpha', 'Gene', (95, 105))	('AKT', 'Gene', '207', (138, 141))
125705	27779808	Antibodies against HGF and p-PDGFRalpha (Tyr762) were purchased from R&D Systems.	('HGF', 'Gene', (19, 22))	('Tyr762', 'Var', (41, 47))	('PDGFRalpha', 'Gene', '5156', (29, 39))	('PDGFRalpha', 'Gene', (29, 39))	('Tyr762', 'Chemical', '-', (41, 47))
125752	27779808	It has been reported that c-MET could serve as a marker for cancer stem cells of several malignancies and that c-MET activation was associated with tumor sphere formation and resistance to chemotherapies.30, 31, 32, 33, 34, 35 We investigated anchorage-independent growth abilities of three SS cell lines and their sensitivities to doxorubicin and trabectedin, which are used for treatment of soft tissue sarcomas.36, 37 c-MET-activated Yamato-SS cells showed higher colony-forming capacity than did c-MET-inactivated SYO-1 or HS-SY-II cells (Fig.	('higher', 'PosReg', (460, 466))	('SS', 'Phenotype', 'HP:0012570', (444, 446))	('sarcoma', 'Phenotype', 'HP:0100242', (405, 412))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('malignancies', 'Disease', (89, 101))	('colony-forming capacity', 'CPA', (467, 490))	('SS', 'Phenotype', 'HP:0012570', (291, 293))	('soft tissue sarcomas', 'Disease', (393, 413))	('doxorubicin', 'Chemical', 'MESH:D004317', (332, 343))	('SYO-1', 'Gene', '55027', (518, 523))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (393, 413))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (393, 412))	('SYO-1', 'Gene', (518, 523))	('HS-SY-II', 'CellLine', 'CVCL:8719', (527, 535))	('trabectedin', 'Chemical', 'MESH:D000077606', (348, 359))	('c-MET-activated', 'Var', (421, 436))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (393, 413))	('tumor', 'Disease', (148, 153))	('cancer', 'Disease', (60, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (405, 413))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
125756	27779808	INC280 inhibited the proliferation of Yamato-SS cells in a dose-dependent manner but not that of SYO-1 or HS-SY-II cells (Fig.	('proliferation', 'CPA', (21, 34))	('SYO-1', 'Gene', (97, 102))	('SYO-1', 'Gene', '55027', (97, 102))	('INC280', 'Var', (0, 6))	('INC280', 'Chemical', 'MESH:C000613976', (0, 6))	('SS', 'Phenotype', 'HP:0012570', (45, 47))	('Yamato-SS cells', 'CPA', (38, 53))	('inhibited', 'NegReg', (7, 16))	('HS-SY-II', 'CellLine', 'CVCL:8719', (106, 114))
125758	27779808	Flow cytometry analyses showed that INC280 induced a dose-dependent increase in the G0/G1-phase population and a decrease in the S-phase population in Yamato-SS cells (Fig.	('decrease', 'NegReg', (113, 121))	('INC280', 'Chemical', 'MESH:C000613976', (36, 42))	('S-phase population', 'CPA', (129, 147))	('SS', 'Phenotype', 'HP:0012570', (158, 160))	('increase', 'PosReg', (68, 76))	('G0/G1-phase population', 'CPA', (84, 106))	('INC280', 'Var', (36, 42))
125760	27779808	These results indicated that INC280 inhibited the growth of c-MET-activated SS cells by inducing G0/G1 cell cycle arrest and apoptosis in vitro.	('INC280', 'Chemical', 'MESH:C000613976', (29, 35))	('inhibited', 'NegReg', (36, 45))	('arrest', 'Disease', 'MESH:D006323', (114, 120))	('arrest', 'Disease', (114, 120))	('growth', 'CPA', (50, 56))	('INC280', 'Var', (29, 35))	('apoptosis', 'CPA', (125, 134))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('inducing', 'Reg', (88, 96))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (103, 120))
125765	27779808	An INC280 dose of 3 or 10 mg/kg given orally once a day was selected on the basis of the previous observation that this therapeutic dose resulted in inhibition of c-MET phosphorylation in vivo.20, 38 Administration of INC280 notably abrogated Yamato-SS xenograft tumor growth relative to that of the vehicle control (Fig.	('abrogated', 'NegReg', (233, 242))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('SS', 'Phenotype', 'HP:0012570', (250, 252))	('INC280', 'Chemical', 'MESH:C000613976', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('INC280', 'Chemical', 'MESH:C000613976', (3, 9))	('tumor', 'Disease', (263, 268))	('INC280', 'Var', (218, 224))
125767	27779808	c-MET phosphorylation was strongly suppressed in INC280-treated Yamato-SS xenograft tumors by immunohistochemical studies (Fig.	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('c-MET phosphorylation', 'MPA', (0, 21))	('INC280-treated', 'Var', (49, 63))	('suppressed', 'NegReg', (35, 45))	('Yamato-SS xenograft tumors', 'Disease', 'MESH:D009369', (64, 90))	('INC280', 'Chemical', 'MESH:C000613976', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('Yamato-SS xenograft tumors', 'Disease', (64, 90))
125769	27779808	These results suggested that INC280 also exerted significant antitumor effects on the growth and survival of c-MET-activated SS xenograft tumors by blocking c-MET signaling.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('growth', 'CPA', (86, 92))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (65, 70))	('blocking', 'NegReg', (148, 156))	('c-MET signaling', 'MPA', (157, 172))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('SS', 'Phenotype', 'HP:0012570', (125, 127))	('INC280', 'Var', (29, 35))	('survival', 'CPA', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('INC280', 'Chemical', 'MESH:C000613976', (29, 35))	('SS xenograft tumors', 'Disease', (125, 144))	('SS xenograft tumors', 'Disease', 'MESH:D009369', (125, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
125772	27779808	Next, we compared clinicopathological characteristics and survival rates of the patients whose tumors co-expressed HGF and c-MET with those of the other patients.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (153, 161))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('HGF', 'Protein', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('c-MET', 'Var', (123, 128))	('tumors', 'Disease', (95, 101))
125775	27779808	Large tumor size (>5 cm) (P = 0.0377), lung metastasis at initial diagnosis (P < 0.001), and co-expression of HGF and c-MET (P = 0.0091) were significantly unfavorable predictors for overall survival in all SS patients according to the univariate analyses (Table S3).	('SS', 'Phenotype', 'HP:0012570', (207, 209))	('overall', 'MPA', (183, 190))	('HGF', 'Protein', (110, 113))	('lung metastasis', 'CPA', (39, 54))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('co-expression', 'Var', (93, 106))	('c-MET', 'Protein', (118, 123))	('patients', 'Species', '9606', (210, 218))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
125776	27779808	Among 29 patients with localized disease at initial diagnosis, co-expression of HGF and c-MET tended to be correlated with shorter overall survival than the other types of expression (P = 0.0659) (Fig.	('patients', 'Species', '9606', (9, 17))	('shorter', 'NegReg', (123, 130))	('overall survival', 'MPA', (131, 147))	('co-expression', 'Var', (63, 76))	('HGF', 'Protein', (80, 83))	('c-MET', 'Protein', (88, 93))
125780	27779808	HGF/c-MET signaling reportedly has an important role in the development of several human cancers and in drug resistance in cancer cells.10, 11, 12, 13, 19, 20, 21, 22, 23, 30, 31, 32, 33, 34, 35 In the present study, we found that c-MET-activated Yamato-SS cells were highly addicted to autocrine HGF/c-MET signaling and exhibited higher anchorage-independent growth ability and lesser sensitivity to chemotherapies than did c-MET-inactivated SYO-1 or HS-SY-II cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SYO-1', 'Gene', (443, 448))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancer', 'Disease', (89, 95))	('cancers', 'Disease', (89, 96))	('HS-SY-II', 'CellLine', 'CVCL:8719', (452, 460))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('addicted', 'MPA', (275, 283))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('SS', 'Phenotype', 'HP:0012570', (254, 256))	('higher', 'PosReg', (331, 337))	('anchorage-independent growth ability', 'CPA', (338, 374))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('c-MET-activated', 'Var', (231, 246))	('human', 'Species', '9606', (83, 88))	('autocrine HGF/c-MET signaling', 'MPA', (287, 316))	('cancer', 'Disease', (123, 129))	('SYO-1', 'Gene', '55027', (443, 448))
125788	27779808	However, such an approach would be highly impractical because of the failure in retaining c-MET phosphorylation in clinical samples.40 In fact, several studies have evaluated HGF/c-MET expression in SS clinical specimens probably due to the difficulty of detecting c-MET phosphorylation.24, 25, 26, 27 On the basis of our results, we proposed that co-expression of HGF and c-MET should result in c-MET autocrine activation and be predictive of response to anti-HGF/c-MET therapies in SS.	('clinical', 'Species', '191496', (202, 210))	('clinical samples', 'Species', '191496', (115, 131))	('SS', 'Phenotype', 'HP:0012570', (199, 201))	('clinical', 'Species', '191496', (115, 123))	('c-MET autocrine', 'MPA', (396, 411))	('SS', 'Phenotype', 'HP:0012570', (484, 486))	('activation', 'PosReg', (412, 422))	('co-expression', 'Var', (348, 361))	('HGF', 'Gene', (365, 368))	('c-MET', 'Gene', (373, 378))
125792	27779808	It has been demonstrated that the expression of c-MET correlated significantly with PAX3-FOXO1 expression, indicating that c-MET was a downstream target of PAX3-FOXO1 in alveolar rhabdomyosarcoma.44 Furthermore, it has been shown that EWS-ATF1, the product of the pathognomonic translocation associated with clear cell sarcoma, also induced c-MET expression.22 In sharp contrast, silencing of SS18-SSX in our parallel study did not decrease HGF/c-MET expression or c-MET phosphorylation in Yamato-SS cells (Fig.	('alveolar rhabdomyosarcoma', 'Disease', (170, 195))	('SS', 'Phenotype', 'HP:0012570', (398, 400))	('clear cell sarcoma', 'Disease', (308, 326))	('FOXO1', 'Gene', (89, 94))	('silencing', 'Var', (380, 389))	('PAX3', 'Gene', (156, 160))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (179, 195))	('PAX3', 'Gene', (84, 88))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (170, 195))	('SSX', 'Gene', '6757', (398, 401))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (170, 195))	('PAX3', 'Gene', '5077', (156, 160))	('PAX3', 'Gene', '5077', (84, 88))	('EWS-ATF1', 'Gene', (235, 243))	('SS', 'Phenotype', 'HP:0012570', (497, 499))	('FOXO1', 'Gene', '2308', (161, 166))	('EWS-ATF1', 'Gene', '466;2130', (235, 243))	('SSX', 'Gene', (398, 401))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (308, 326))	('SS', 'Phenotype', 'HP:0012570', (393, 395))	('FOXO1', 'Gene', (161, 166))	('FOXO1', 'Gene', '2308', (89, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (319, 326))
125794	27779808	Similar to HGF/c-MET signaling in Yamato-SS cells, silencing of SS18-SSX attenuated neither PDGFB/PDGFRalpha expression nor PDGFRalpha phosphorylation in PDGFRalpha-activated HS-SY-II cells (Fig.	('silencing', 'Var', (51, 60))	('PDGFRalpha', 'Gene', (154, 164))	('expression', 'MPA', (109, 119))	('SS', 'Phenotype', 'HP:0012570', (64, 66))	('PDGFB', 'Gene', '5155', (92, 97))	('PDGFRalpha', 'Gene', '5156', (124, 134))	('attenuated', 'NegReg', (73, 83))	('PDGFRalpha', 'Gene', (124, 134))	('SS', 'Phenotype', 'HP:0012570', (41, 43))	('PDGFRalpha', 'Gene', '5156', (98, 108))	('PDGFB', 'Gene', (92, 97))	('SSX', 'Gene', '6757', (69, 72))	('phosphorylation', 'MPA', (135, 150))	('SS', 'Phenotype', 'HP:0012570', (69, 71))	('SSX', 'Gene', (69, 72))	('PDGFRalpha', 'Gene', '5156', (154, 164))	('HS-SY-II', 'CellLine', 'CVCL:8719', (175, 183))	('PDGFRalpha', 'Gene', (98, 108))
125796	27779808	It has been reported that tumors with features of human SS developed when expression of the SS18-SSX gene was induced in Myf5-expressing murine myoblasts but not in the embryonic stage or in Myf6-expressing myocytes.45 These findings suggested that the window of permissive cells was relatively narrow for SS18-SSX.46 Previously, we demonstrated that one of the cellular origins for SS was a multipotent mesenchymal stem cell with potential to differentiate into mesenchymal and hematopoietic lineages by silencing of SS18-SSX.28 Human mesenchymal stem cells express a large number of growth factors and growth factor receptors with different functions.47, 48 In mesenchymal stem cells, HGF/c-MET signaling is important in the maintenance of stemness, whereas PDGF/PDGFR signaling is a key regulator of cell differentiation and mesenchymal tissue formation.49, 50 We propose that cellular origins of c-MET-activated SS might be more immature multipotent mesenchymal stem cells expressing higher levels of HGF/c-MET, whereas those of PDGFR-activated SS might be less immature mesenchymal stem cells dependent on PDGF/PDGFR signaling.	('SSX', 'Gene', (523, 526))	('SS', 'Phenotype', 'HP:0012570', (311, 313))	('SS', 'Phenotype', 'HP:0012570', (56, 58))	('stemness', 'Disease', 'MESH:D020295', (742, 750))	('stemness', 'Disease', (742, 750))	('PDGFR', 'Gene', (1033, 1038))	('human', 'Species', '9606', (50, 55))	('PDGFR', 'Gene', '5159', (1033, 1038))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('SS', 'Phenotype', 'HP:0012570', (97, 99))	('SSX', 'Gene', '6757', (311, 314))	('Myf6', 'Gene', (191, 195))	('Human', 'Species', '9606', (530, 535))	('Myf6', 'Gene', '17878', (191, 195))	('c-MET-activated', 'Var', (900, 915))	('SSX', 'Gene', '6757', (97, 100))	('Myf5', 'Gene', (121, 125))	('SSX', 'Gene', (311, 314))	('higher', 'PosReg', (988, 994))	('SS', 'Phenotype', 'HP:0012570', (306, 308))	('SSX', 'Gene', '6757', (523, 526))	('PDGFR', 'Gene', (1116, 1121))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('SSX', 'Gene', (97, 100))	('PDGFR', 'Gene', '5159', (1116, 1121))	('SS', 'Phenotype', 'HP:0012570', (92, 94))	('murine', 'Species', '10090', (137, 143))	('Myf5', 'Gene', '4617', (121, 125))	('PDGFR', 'Gene', (765, 770))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PDGFR', 'Gene', '5159', (765, 770))	('tumors', 'Disease', (26, 32))
125895	31404285	The objective of this study was to determine the presence of K1 and K15 (predominant alleles) genes in Kaposi's sarcoma-associated herpes virus (KSHV) among immunosuppressed patients due to HIV-1.	('K15', 'Var', (68, 71))	("Kaposi's sarcoma", 'Disease', (103, 119))	('HIV-1', 'Species', '11676', (190, 195))	('KSHV', 'Species', '37296', (145, 149))	('KS', 'Phenotype', 'HP:0100726', (145, 147))	('patients', 'Species', '9606', (174, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (103, 119))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (103, 119))
125925	31404285	The set of primers used were; K1 product size 868 bpK1a-f ATGTTCCTGTATGTTGTCTGC; K1a-r AGTACCAATCCACTGGTTGCG K1 product size 840 bp K1b-f GTCTGCAGTCTGGCGGTTTGC; K1b-r CTGGTTGCGTATAGTCTTCCG, K15 (P) product size 365 bp K15P-OF TGCAGGCTTGGTCATGGGTTAC; K15P-OR GGGACCACGCTGCAATTAAATG; K15 (P) product size 285 bpK15-3C ACGCATACATGTACTGCCAC; K15-4C CTTTGATATTGCCAGTGGTG.	('K15-4C', 'Var', (338, 344))	('K1b', 'Gene', '374454', (161, 164))	('K1b', 'Gene', (161, 164))	('K1b', 'Gene', (132, 135))	('K15P', 'Mutation', 'p.K15P', (218, 222))	('K15P', 'Mutation', 'p.K15P', (250, 254))	('K1b', 'Gene', '374454', (132, 135))
125942	31404285	Genotyping analysis in this study revealed that the Kaposi's sarcoma-associated herpes virus (KSHV) genes, K1 and K15 (P) were detected among the selected tissue blocks.	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (52, 68))	("Kaposi's sarcoma", 'Disease', (52, 68))	('KS', 'Phenotype', 'HP:0100726', (94, 96))	('KSHV', 'Species', '37296', (94, 98))	('K15', 'Var', (114, 117))	('KSHV) genes', 'Gene', (94, 105))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (52, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
125943	31404285	These findings affirm the earlier hypothesis that K1 and K15 (P) genes of Kaposi's sarcoma-associated herpes virus (KSHV) were present in the tissue blocks retrieved from patients with HIV-1 and AIDS.	('K15', 'Var', (57, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (74, 90))	('patients', 'Species', '9606', (171, 179))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (74, 90))	("Kaposi's sarcoma", 'Disease', (74, 90))	('KSHV', 'Species', '37296', (116, 120))	('HIV-1 and AIDS', 'Disease', 'MESH:D000163', (185, 199))	('KS', 'Phenotype', 'HP:0100726', (116, 118))
125954	31404285	Other studies have also indicated that CD4 cell count <350 cells/ mm3 are linked to high risk of developing KS whether one is on HIV treatment or not.	('men', 'Species', '9606', (138, 141))	('KS', 'Phenotype', 'HP:0100726', (108, 110))	('HIV', 'Species', '12721', (129, 132))	('<350 cells/', 'Var', (54, 65))	('CD4', 'Gene', (39, 42))	('CD4', 'Gene', '920', (39, 42))
125966	31404285	In conclusion, Kaposi's sarcoma-associated herpes virus (KSHV) genes, K1 and K15 (P) were detected among tissue blocks collected from patients infected with HIV-1 and AIDs.	('KSHV) genes', 'Gene', (57, 68))	('HIV-1 and AIDs', 'Disease', 'MESH:D015658', (157, 171))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (15, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (15, 31))	("Kaposi's sarcoma", 'Disease', (15, 31))	('patients', 'Species', '9606', (134, 142))	('KS', 'Phenotype', 'HP:0100726', (57, 59))	('KSHV', 'Species', '37296', (57, 61))	('K15', 'Var', (77, 80))
126014	30222020	found that clonal cytogenetic abnormalities and rearrangement might be associated with the development of IDCS.	('IDCS', 'Disease', (106, 110))	('rearrangement', 'Var', (48, 61))	('men', 'Species', '9606', (98, 101))	('men', 'Species', '9606', (57, 60))	('associated', 'Reg', (71, 81))
126037	30222020	Other factors that have been associated with a poor prognosis include younger age, larger tumor diameter, higher expression of Ki-67, p53 positivity, extranodal disease, and abdominal tumor infiltration.	('expression', 'MPA', (113, 123))	('extranodal disease', 'Disease', (150, 168))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('extranodal disease', 'Disease', 'MESH:D000079822', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('abdominal tumor', 'Disease', (174, 189))	('higher', 'PosReg', (106, 112))	('tumor', 'Disease', (184, 189))	('positivity', 'Var', (138, 148))	('abdominal tumor', 'Disease', 'MESH:D015746', (174, 189))	('p53', 'Gene', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('Ki-67', 'Protein', (127, 132))
126040	30222020	The latter two findings differ from those reported by Saygin et al., but our finding that abdominal involvement, high Ki-67, extranodal disease, and advanced clinical stage were associated with a poor prognosis are in agreement with the study by Saygin et al.	('high', 'Var', (113, 117))	('men', 'Species', '9606', (223, 226))	('men', 'Species', '9606', (107, 110))	('abdominal involvement', 'Disease', (90, 111))	('extranodal disease', 'Disease', 'MESH:D000079822', (125, 143))	('extranodal disease', 'Disease', (125, 143))	('Ki-67', 'Gene', (118, 123))
126108	28851813	We bred hSS2 mice to Bcl2fl/fl mice to generate combined expression of SS18-SSX2 and loss of BCL2 (Fig.	('loss', 'Var', (85, 89))	('mice', 'Species', '10090', (13, 17))	('SSX', 'Gene', (76, 79))	('hSS2', 'Gene', (8, 12))	('SSX', 'Gene', '727837', (76, 79))	('hSS2', 'Gene', '56244', (8, 12))	('mice', 'Species', '10090', (31, 35))	('BCL2', 'Gene', (93, 97))
126140	28851813	Importantly, we and others have noted previously that knock-down of BCL2/Bcl2 in human and mouse SS cell lines had no apparent impact on their survival or proliferation alone.	('knock-down', 'Var', (54, 64))	('proliferation', 'CPA', (155, 168))	('BCL2/Bcl2', 'Gene', (68, 77))	('human', 'Species', '9606', (81, 86))	('mouse', 'Species', '10090', (91, 96))
126156	28035071	Overexpression of a subset of mitotic genes from a signature called CINSARC is of bad prognosis, but the significance of this signature remains elusive.	('CIN', 'Disease', (68, 71))	('CIN', 'Disease', 'MESH:D007674', (68, 71))	('Overexpression', 'Var', (0, 14))	('CIN', 'Phenotype', 'HP:0040012', (68, 71))	('mitotic genes', 'Gene', (30, 43))
126158	28035071	We also found that the CINSARC cell lines, we studied, are composed of a mixture of aneuploid, diploid, and tetraploid cells that are highly motile in vitro.	('aneuploid', 'Var', (84, 93))	('CIN', 'Disease', 'MESH:D007674', (23, 26))	('CIN', 'Disease', (23, 26))	('CIN', 'Phenotype', 'HP:0040012', (23, 26))
126159	28035071	Owing that mitotic proteins are almost systematically degraded at the end of mitosis, we propose that it is the abnormal activity of the mitotic proteins during interphase that boosts the sarcoma cells migratory properties by affecting their cytoskeleton.	('affecting', 'Reg', (226, 235))	('mitosis', 'Disease', (77, 84))	('sarcoma', 'Disease', 'MESH:D012509', (188, 195))	('mitosis', 'Disease', 'None', (77, 84))	('cytoskeleton', 'MPA', (242, 254))	('sarcoma', 'Disease', (188, 195))	('boosts', 'PosReg', (177, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('abnormal', 'Var', (112, 120))
126161	28035071	We found that inhibition of several mitotic kinases drastically impairs the CINSARC cell invasive and migratory properties.	('impairs', 'NegReg', (64, 71))	('mitotic', 'Enzyme', (36, 43))	('CIN', 'Phenotype', 'HP:0040012', (76, 79))	('CIN', 'Disease', (76, 79))	('inhibition', 'Var', (14, 24))	('CIN', 'Disease', 'MESH:D007674', (76, 79))
126177	28035071	Thus deregulation of mitotic genes observed in CINSARC positive tumors likely participates to the increasing complexity in chromosomes aberrations, rearrangements and instability observed in metastatic STS tumors.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('CIN', 'Disease', (47, 50))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('mitotic genes', 'Gene', (21, 34))	('STS tumors', 'Disease', 'MESH:D016114', (202, 212))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('CIN', 'Disease', 'MESH:D007674', (47, 50))	('rearrangements', 'Var', (148, 162))	('STS', 'Phenotype', 'HP:0030448', (202, 205))	('instability', 'MPA', (167, 178))	('deregulation', 'Var', (5, 17))	('STS tumors', 'Disease', (202, 212))	('CIN', 'Phenotype', 'HP:0040012', (47, 50))
126190	28035071	The average cell cycle length was almost twice as long for MFH137 and MFH152 cells (32 hours) compared to IMR90 fibroblast cells (Figure 2A).	('IMR90', 'CellLine', 'CVCL:0347', (106, 111))	('MFH137', 'Var', (59, 65))	('MFH152', 'Var', (70, 76))	('cell cycle length', 'CPA', (12, 29))
126200	28035071	Quantification of the flow cytometry profiles shows that the fraction of Ser10 Phospho-histone H3 positive cells is largely similar in tetraploid and diploid clones (Figure 3F).	('Ser10', 'Chemical', '-', (73, 78))	('Ser10', 'Gene', (73, 78))	('tetraploid', 'Var', (135, 145))
126205	28035071	The same assays performed on 2n and 4n MFH137 clones (Supplementary Figure 2E-2F) confirmed that motility is greatly enhanced in tetraploid compared to diploid sarcoma subclones.	('MFH137', 'Gene', (39, 45))	('motility', 'CPA', (97, 105))	('diploid sarcoma', 'Disease', (152, 167))	('tetraploid', 'Var', (129, 139))	('enhanced', 'PosReg', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('diploid sarcoma', 'Disease', 'MESH:C548012', (152, 167))
126217	28035071	Although stabilized, the mutant TP53 protein remains unable to promote CDKN1A expression, in these cells.	('CDKN1A', 'Gene', (71, 77))	('mutant', 'Var', (25, 31))	('expression', 'MPA', (78, 88))	('CDKN1A', 'Gene', '1026', (71, 77))	('TP53', 'Gene', '7157', (32, 36))	('unable', 'NegReg', (53, 59))	('TP53', 'Gene', (32, 36))	('promote', 'PosReg', (63, 70))	('protein', 'Protein', (37, 44))
126227	28035071	Most of the kinesins, mitotic kinases and phosphatase inhibitors that proved to be very toxic at high doses, were only used at low concentrations with no noticeable effects on cell migration capacity (GSK 923295, Dimethylenastron, ZM 447439, RO3306, CDKi, Roscovitin, CDC25).	('Dimethylenastron', 'Chemical', 'MESH:C518969', (213, 229))	('Roscovitin', 'Chemical', 'MESH:D000077546', (256, 266))	('cell migration capacity', 'CPA', (176, 199))	('CDC25', 'Gene', '995', (268, 273))	('CDC25', 'Gene', (268, 273))	('RO3306', 'Var', (242, 248))
126228	28035071	Finally only the two drugs, Reversine and SP600125, met the criteria of conjugating low toxicity with significant inhibition of diploid and tetraploid sarcoma cells migration.	('tetraploid sarcoma', 'Disease', 'MESH:D057891', (140, 158))	('tetraploid sarcoma', 'Disease', (140, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('inhibition', 'NegReg', (114, 124))	('Reversine', 'Chemical', 'MESH:C484369', (28, 37))	('SP600125', 'Chemical', 'MESH:C432165', (42, 50))	('toxicity', 'Disease', 'MESH:D064420', (88, 96))	('toxicity', 'Disease', (88, 96))	('SP600125', 'Var', (42, 50))
126229	28035071	Specificity of Reversine is best toward TTK (IC50 6 nM) and good toward AURKB (IC50 of 98.5 nM) while SP600125 inhibits AURKA and AURKB (IC50 60nM and 190nM) but also JNK (IC50 100-200nM) and TTK (IC50 1,9 muM).	('AURKA', 'Gene', (120, 125))	('TTK', 'Gene', '7272', (192, 195))	('muM', 'Gene', '56925', (206, 209))	('AURKB', 'Gene', (130, 135))	('AURKB', 'Gene', '9212', (72, 77))	('muM', 'Gene', (206, 209))	('inhibits', 'NegReg', (111, 119))	('SP600125', 'Chemical', 'MESH:C432165', (102, 110))	('JNK', 'Gene', (167, 170))	('TTK', 'Gene', (40, 43))	('SP600125', 'Var', (102, 110))	('AURKB', 'Gene', (72, 77))	('AURKA', 'Gene', '6790', (120, 125))	('TTK', 'Gene', '7272', (40, 43))	('Reversine', 'Chemical', 'MESH:C484369', (15, 24))	('AURKB', 'Gene', '9212', (130, 135))	('JNK', 'Gene', '5599', (167, 170))	('TTK', 'Gene', (192, 195))
126232	28035071	Both Reversine and SP600125 inhibited the migration of all sub-clones.	('SP600125', 'Chemical', 'MESH:C432165', (19, 27))	('SP600125', 'Var', (19, 27))	('inhibited', 'NegReg', (28, 37))	('migration of all sub-clones', 'CPA', (42, 69))	('Reversine', 'Chemical', 'MESH:C484369', (5, 14))
126233	28035071	These results show that tetraploid cells, that overexpress CINSARC mitotic gene products, were more sensitive to Reversine and SP600125 treatments (Figure 6B).	('Reversine', 'Chemical', 'MESH:C484369', (113, 122))	('CIN', 'Phenotype', 'HP:0040012', (59, 62))	('overexpress', 'PosReg', (47, 58))	('CIN', 'Disease', (59, 62))	('SP600125', 'Var', (127, 135))	('SP600125', 'Chemical', 'MESH:C432165', (127, 135))	('CIN', 'Disease', 'MESH:D007674', (59, 62))	('sensitive', 'MPA', (100, 109))
126237	28035071	In contrast, when spheroids were incubated in collagen-based medium containing either reversine or SP600125, a complete inhibition of invasion was observed (Figure 7A and Supplementary Video 7-8) and quantified (Figure 7B).	('invasion', 'CPA', (134, 142))	('reversine', 'Chemical', 'MESH:C484369', (86, 95))	('inhibition', 'NegReg', (120, 130))	('SP600125', 'Chemical', 'MESH:C432165', (99, 107))	('SP600125', 'Var', (99, 107))
126239	28035071	Reversine and SP600125 target several major kinases.	('target', 'Reg', (23, 29))	('Reversine', 'Chemical', 'MESH:C484369', (0, 9))	('SP600125', 'Var', (14, 22))	('SP600125', 'Chemical', 'MESH:C432165', (14, 22))
126241	28035071	We focused on AURKA, AURKB and TTK kinases that are targeted by reversine and SP600125 and also chose KIF11 that strongly stains the lamellipodia of interphase tetraploid cells (Figure 5D).	('reversine', 'Chemical', 'MESH:C484369', (64, 73))	('KIF11', 'Gene', (102, 107))	('TTK', 'Gene', (31, 34))	('AURKA', 'Gene', (14, 19))	('AURKB', 'Gene', '9212', (21, 26))	('TTK', 'Gene', '7272', (31, 34))	('KIF11', 'Gene', '3832', (102, 107))	('AURKB', 'Gene', (21, 26))	('SP600125', 'Var', (78, 86))	('SP600125', 'Chemical', 'MESH:C432165', (78, 86))	('AURKA', 'Gene', '6790', (14, 19))
126243	28035071	MLN8237 (Alisertib), a selective AURKA inhibitor (IC50 of 1.2nM in cell free assay, with >200 fold higher selectivity for AURKA than AURKB); AZD1152-HQPA (Baraserib) that is highly selective against AURKB (IC 0.37nM is cell free assay, with >3700 fold more selective for AURKB than AURKA); SB743921, a KIF11 inhibitor (Ki of 0.1 nM, with almost no affinity to other kinesins); Mps-BAY2a, a TTK inhibitor (IC50 of 1nM).	('AURKA', 'Gene', (282, 287))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', '6790', (122, 127))	('TTK', 'Gene', '7272', (390, 393))	('KIF11', 'Gene', '3832', (302, 307))	('HQPA', 'Chemical', '-', (149, 153))	('AURKA', 'Gene', (122, 127))	('AURKA', 'Gene', '6790', (33, 38))	('AURKB', 'Gene', (199, 204))	('KIF11', 'Gene', (302, 307))	('AURKB', 'Gene', (271, 276))	('AURKA', 'Gene', (33, 38))	('AURKB', 'Gene', (133, 138))	('SB743921', 'Var', (290, 298))	('TTK', 'Gene', (390, 393))	('AZD1152', 'Chemical', 'MESH:C520647', (141, 148))	('AURKB', 'Gene', '9212', (199, 204))	('AURKB', 'Gene', '9212', (271, 276))	('AZD1152-HQPA', 'Var', (141, 153))	('AURKB', 'Gene', '9212', (133, 138))	('AURKA', 'Gene', '6790', (282, 287))
126244	28035071	Deregulation of AURKA kinase induces centrosomal abnormalities, defective chromosome segregation followed by aneuploidy and/or cell death.	('induces', 'Reg', (29, 36))	('aneuploidy', 'Disease', 'MESH:D000782', (109, 119))	('defective chromosome segregation', 'Phenotype', 'HP:0002916', (64, 96))	('Deregulation', 'Var', (0, 12))	('defective', 'NegReg', (64, 73))	('AURKA', 'Gene', '6790', (16, 21))	('centrosomal abnormalities', 'CPA', (37, 62))	('cell death', 'CPA', (127, 137))	('aneuploidy', 'Disease', (109, 119))	('AURKA', 'Gene', (16, 21))
126245	28035071	MLN8237 (AURKAi) inhibits AURKA at low nanomolar range (10nM).	('inhibits', 'NegReg', (17, 25))	('AURKA', 'Gene', '6790', (9, 14))	('AURKA', 'Gene', (9, 14))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', '6790', (26, 31))	('AURKA', 'Gene', (26, 31))
126246	28035071	But, as reported, MLN8237 concentration above 100nM induced AURKB inhibition dependent cell polyploidization.	('inhibition', 'NegReg', (66, 76))	('AURKB', 'Gene', (60, 65))	('cell polyploidization', 'CPA', (87, 108))	('AURKB', 'Gene', '9212', (60, 65))	('MLN8237 concentration', 'Var', (18, 39))
126248	28035071	Cytokinesis defect and polyploidization resulting from AURKB dysregulation was induced by 20nM AZD1152-HQPA treatment.	('AZD1152', 'Chemical', 'MESH:C520647', (95, 102))	('dysregulation', 'Var', (61, 74))	('AURKB', 'Gene', '9212', (55, 60))	('HQPA', 'Chemical', '-', (103, 107))	('polyploidization', 'Var', (23, 39))	('Cytokinesis', 'CPA', (0, 11))	('defect', 'NegReg', (12, 18))	('AURKB', 'Gene', (55, 60))	('AZD1152-HQPA', 'Var', (95, 107))
126253	28035071	Inhibition of cell invasiveness and motility mediated by SP60025 and reversine that have broader effects on several mitotic gene products further support this hypothesis.	('SP60025', 'Var', (57, 64))	('reversine', 'Chemical', 'MESH:C484369', (69, 78))	('motility', 'CPA', (36, 44))	('cell invasiveness', 'CPA', (14, 31))	('SP60025', 'Chemical', '-', (57, 64))
126256	28035071	Indeed, tetraploidy associates with increased DNA damage, abnormal bipolar/multipolar mitoses, chromosome breaks and/or missegregration.	('abnormal bipolar', 'Disease', 'MESH:D001714', (58, 74))	('tetraploidy', 'Var', (8, 19))	('increased', 'PosReg', (36, 45))	('chromosome breaks', 'CPA', (95, 112))	('abnormal bipolar', 'Disease', (58, 74))	('abnormal bipolar', 'Phenotype', 'HP:0007302', (58, 74))	('missegregration', 'CPA', (120, 135))	('DNA damage', 'CPA', (46, 56))	('chromosome breaks', 'Phenotype', 'HP:0040012', (95, 112))
126257	28035071	But, in contrast to functions in tumorigenesis, few data exist concerning a potential involvement of tetraploidization in the promotion of cell migration and/or invasion.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('invasion', 'CPA', (161, 169))	('tetraploidization', 'Var', (101, 118))	('cell migration', 'CPA', (139, 153))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('promotion', 'PosReg', (126, 135))
126269	28035071	We identified that inhibitors targeting the major mitotic kinases AURKA/B and TTK inhibited cell migration of diploid and tetraploid sarcoma cell subclones and invasion from diploid spheroids.	('AURKA', 'Gene', '6790', (66, 71))	('TTK', 'Gene', '7272', (78, 81))	('inhibited', 'NegReg', (82, 91))	('AURKA', 'Gene', (66, 71))	('inhibitors', 'Var', (19, 29))	('invasion from diploid spheroids', 'CPA', (160, 191))	('TTK', 'Gene', (78, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('tetraploid sarcoma', 'Disease', 'MESH:D057891', (122, 140))	('tetraploid sarcoma', 'Disease', (122, 140))
126270	28035071	Thus, misexpression of these mitotic kinases regulates the motile behavior of sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('sarcoma', 'Disease', (78, 85))	('regulates', 'Reg', (45, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('misexpression', 'Var', (6, 19))
126271	28035071	Inhibition of cell invasiveness and motility mediated by SP60025 and reversine that affect several mitotic gene products further support this hypothesis.	('SP60025', 'Var', (57, 64))	('reversine', 'Chemical', 'MESH:C484369', (69, 78))	('motility', 'CPA', (36, 44))	('cell invasiveness', 'CPA', (14, 31))	('SP60025', 'Chemical', '-', (57, 64))
126283	28035071	MLN8237 (Alisertib), AZD1152-HQPA (Baraserib) and SB743921 were purchased from Selleckchem.	('AZD1152-HQPA', 'Var', (21, 33))	('AZD1152', 'Chemical', 'MESH:C520647', (21, 28))	('SB743921', 'Var', (50, 58))	('MLN8237', 'Var', (0, 7))	('HQPA', 'Chemical', '-', (29, 33))
126342	23348519	For the cohort studies that contributed data to E2C2 (other than the California Teachers Study (CTS)), a nested case-control study design was employed, with inclusion of up to four controls (women with an intact uterus and no uterine cancer diagnosis) randomly selected from the risk set and matched to the corresponding uterine cancer case on year of birth, date of entry (within 6 months), and any additional matching criteria as appropriate in the individual study.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('women', 'Species', '9606', (191, 196))	('cancer', 'Disease', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('uterine cancer', 'Phenotype', 'HP:0010784', (321, 335))	('E2C2', 'Var', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('uterine cancer', 'Phenotype', 'HP:0010784', (226, 240))	('cancer', 'Disease', (234, 240))
126352	23348519	Uterine sarcoma cases with the following International Classification of Diseases for Oncology (ICD)-O-3 morphology codes were included: sarcoma, not otherwise specified (NOS) 8800-8806, fibromatous neoplasms 8810-8815, myomatous neoplasms 8890-8896 (includes leiomyosarcoma), rhabdomyosarcoma 8900-8902, embryonal rhabdomyosarcoma 8910-8912, and endometrial stromal sarcoma 8930-8934.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (277, 293))	('sarcoma', 'Disease', 'MESH:D012509', (286, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('sarcoma', 'Disease', (324, 331))	('sarcoma', 'Disease', (286, 293))	('fibromatous neoplasms', 'Disease', (187, 208))	('myomatous neoplasms', 'Disease', 'MESH:D009369', (220, 239))	('embryonal rhabdomyosarcoma', 'Disease', (305, 331))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (347, 374))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (315, 331))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (315, 331))	('leiomyosarcoma', 'Disease', (260, 274))	('sarcoma', 'Phenotype', 'HP:0100242', (324, 331))	('sarcoma', 'Phenotype', 'HP:0100242', (286, 293))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (305, 331))	('sarcoma', 'Disease', 'MESH:D012509', (267, 274))	('sarcoma', 'Disease', (267, 274))	('Oncology', 'Phenotype', 'HP:0002664', (86, 94))	('fibromatous neoplasms', 'Disease', 'MESH:D009369', (187, 208))	('endometrial stromal sarcoma', 'Disease', (347, 374))	('rhabdomyosarcoma', 'Disease', (277, 293))	('sarcoma', 'Disease', 'MESH:D012509', (367, 374))	('neoplasms', 'Phenotype', 'HP:0002664', (230, 239))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('myomatous neoplasms', 'Disease', (220, 239))	('neoplasms', 'Phenotype', 'HP:0002664', (199, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (267, 274))	('sarcoma', 'Disease', (367, 374))	('sarcoma', 'Disease', (137, 144))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (305, 331))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (277, 293))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (260, 274))	('sarcoma', 'Disease', (8, 15))	('8890-8896', 'Var', (240, 249))	('rhabdomyosarcoma', 'Disease', (315, 331))	('Uterine sarcoma', 'Phenotype', 'HP:0002891', (0, 15))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (260, 274))	('sarcoma', 'Disease', 'MESH:D012509', (324, 331))
126381	23348519	As in our study, high BMI was associated with increased risks of endometrial stromal sarcoma (n=26), while the risk of leiomyosarcoma (n=56) was lower among cigarette smokers than never smokers.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('leiomyosarcoma', 'Disease', (119, 133))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (119, 133))	('endometrial stromal sarcoma', 'Disease', (65, 92))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (65, 92))	('high BMI', 'Var', (17, 25))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (119, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
126384	23348519	Parity was associated with decreased uterine sarcoma risk in a prior study; however, our results concur with two other reports that did not observe clear associations with any live births, the number of live births, and uterine sarcoma risk.	('sarcoma', 'Disease', 'MESH:D012509', (228, 235))	('sarcoma', 'Disease', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('decreased', 'NegReg', (27, 36))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (37, 52))	('decreased uterine', 'Phenotype', 'HP:0000013', (27, 44))	('sarcoma', 'Disease', (228, 235))	('Parity', 'Var', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (220, 235))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))
126387	23348519	In a recent Finnish cohort study, menopausal estradiol and progestin treatment was associated with increased risks of leiomyosarcoma and endometrial stromal sarcoma, especially among women with longer exposures.	('menopausal', 'Var', (34, 44))	('endometrial stromal sarcoma', 'Disease', (137, 164))	('leiomyosarcoma', 'Disease', (118, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (118, 132))	('women', 'Species', '9606', (183, 188))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (118, 132))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (137, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))
126665	30829727	PGR Gene Fusions Identify a Molecular Subset of Uterine Epithelioid Leiomyosarcoma with Rhabdoid Features Genetic aberrations among uterine epithelioid leiomyosarcomas are unknown.	('Leiomyosarcoma', 'Disease', (68, 82))	('epithelioid leiomyosarcomas', 'Disease', (140, 167))	('PGR', 'Gene', '5241', (0, 3))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('Uterine Epithelioid Leiomyosarcoma', 'Phenotype', 'HP:0002891', (48, 82))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (152, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('uterine epithelioid leiomyosarcomas', 'Phenotype', 'HP:0002891', (132, 167))	('Fusions', 'Var', (9, 16))	('uterine epithelioid leiomyosarcoma', 'Phenotype', 'HP:0002891', (132, 166))	('Leiomyosarcoma', 'Disease', 'MESH:D007890', (68, 82))	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (68, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('PGR', 'Gene', (0, 3))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (152, 167))	('epithelioid leiomyosarcomas', 'Disease', 'MESH:D007890', (140, 167))
126666	30829727	Following identification of an index case with NR4A3-PGR fusion demonstrating monomorphic morphologic features, we interrogated additional uterine tumors demonstrating similar histology and sought to describe the morphologic and immunohistochemical characteristics of PGR-rearranged sarcomas.	('sarcomas', 'Disease', (283, 291))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('PGR', 'Gene', (268, 271))	('uterine tumors', 'Phenotype', 'HP:0010784', (139, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('sarcomas', 'Disease', 'MESH:D012509', (283, 291))	('PGR', 'Gene', '5241', (268, 271))	('PGR', 'Gene', (53, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (283, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (283, 290))	('fusion', 'Var', (57, 63))	('NR4A3', 'Gene', '8013', (47, 52))	('PGR', 'Gene', '5241', (53, 56))	('NR4A3', 'Gene', (47, 52))
126669	30829727	NR4A3-PGR fusion (n=4) and PGR rearrangement (n=2) were detected in six (35%) epithelioid leiomyosarcomas.	('PGR', 'Gene', '5241', (27, 30))	('NR4A3', 'Gene', '8013', (0, 5))	('PGR', 'Gene', '5241', (6, 9))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (90, 104))	('NR4A3', 'Gene', (0, 5))	('detected', 'Reg', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('rearrangement', 'Var', (31, 44))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (90, 105))	('fusion', 'Var', (10, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('epithelioid leiomyosarcomas', 'Disease', (78, 105))	('PGR', 'Gene', (6, 9))	('epithelioid leiomyosarcomas', 'Disease', 'MESH:D007890', (78, 105))	('PGR', 'Gene', (27, 30))
126675	30829727	PGR rearrangements define a genetic subset of epithelioid leiomyosarcomas with often biphasic morphology consisting of epithelioid and rhabdoid as well as spindle cell components.	('rhabdoid', 'Disease', 'MESH:D018335', (135, 143))	('PGR', 'Gene', '5241', (0, 3))	('rhabdoid', 'Disease', (135, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('rearrangements', 'Var', (4, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (58, 73))	('epithelioid leiomyosarcomas', 'Disease', 'MESH:D007890', (46, 73))	('epithelioid leiomyosarcomas', 'Disease', (46, 73))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (58, 72))	('PGR', 'Gene', (0, 3))
126676	30829727	Recurrent chromosomal translocations resulting in gene fusions have been well documented among uterine sarcomas, particularly those of endometrial stromal derivation.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (95, 110))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('gene fusions', 'MPA', (50, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Disease', (103, 111))	('chromosomal', 'Var', (10, 21))
126677	30829727	JAZF1-SUZ12 fusion represents the most common genetic aberration described among low-grade endometrial stromal sarcomas, followed by less frequent JAZF1-PHF1, EPC1-PHF1 (1), MEAF6-PHF1, MBTD1-CXorf67, and EPC2-PHF1 fusions.	('EPC2', 'Gene', '26122', (205, 209))	('SUZ12', 'Gene', (6, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('PHF1', 'Gene', (180, 184))	('CXorf67', 'Gene', (192, 199))	('SUZ12', 'Gene', '23512', (6, 11))	('fusion', 'Var', (12, 18))	('JAZF1', 'Gene', '221895', (147, 152))	('PHF1', 'Gene', (164, 168))	('PHF1', 'Gene', (210, 214))	('CXorf67', 'Gene', '340602', (192, 199))	('JAZF1', 'Gene', (147, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('PHF1', 'Gene', '5252', (180, 184))	('EPC1', 'Gene', '80314', (159, 163))	('JAZF1', 'Gene', '221895', (0, 5))	('EPC1', 'Gene', (159, 163))	('MBTD1', 'Gene', '54799', (186, 191))	('EPC2', 'Gene', (205, 209))	('MBTD1', 'Gene', (186, 191))	('PHF1', 'Gene', '5252', (210, 214))	('JAZF1', 'Gene', (0, 5))	('PHF1', 'Gene', '5252', (164, 168))	('PHF1', 'Gene', (153, 157))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (91, 119))	('MEAF6', 'Gene', (174, 179))	('endometrial stromal sarcomas', 'Disease', (91, 119))	('MEAF6', 'Gene', '64769', (174, 179))	('PHF1', 'Gene', '5252', (153, 157))
126681	30829727	These include inflammatory myofibroblastic tumors which often harbor ALK1 rearrangements and fibrosarcoma-like uterine sarcomas underpinned by NTRK fusions.	('sarcomas', 'Disease', (119, 127))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (111, 126))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (27, 49))	('fibrosarcoma', 'Disease', 'MESH:D005354', (93, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (93, 105))	('rearrangements', 'Var', (74, 88))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (27, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('fibrosarcoma', 'Disease', (93, 105))	('ALK1', 'Gene', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('myofibroblastic tumors', 'Disease', (27, 49))	('ALK1', 'Gene', '94', (69, 73))
126684	30829727	TFE3 and RAD51B rearrangements have also been described in a subset of uterine perivascular epithelioid cell tumors (PEComas).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('RAD51B', 'Gene', '5890', (9, 15))	('TFE3', 'Gene', '7030', (0, 4))	('RAD51B', 'Gene', (9, 15))	('PEComas', 'Disease', (117, 124))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('uterine perivascular epithelioid', 'Phenotype', 'HP:0000131', (71, 103))	('described', 'Reg', (46, 55))	('PEComas', 'Disease', 'MESH:D054973', (117, 124))	('TFE3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('rearrangements', 'Var', (16, 30))	('tumors', 'Disease', (109, 115))
126686	30829727	We recently encountered a group of uterine epithelioid leiomyosarcoma that harbors novel PGR gene rearrangements.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (55, 69))	('uterine epithelioid leiomyosarcoma', 'Phenotype', 'HP:0002891', (35, 69))	('epithelioid leiomyosarcoma', 'Disease', (43, 69))	('PGR', 'Gene', (89, 92))	('epithelioid leiomyosarcoma', 'Disease', 'MESH:D007890', (43, 69))	('rearrangements', 'Var', (98, 112))	('PGR', 'Gene', '5241', (89, 92))
126687	30829727	In this study, we characterized the fusion partner gene by targeted next-generation RNA sequencing (RNAseq) and confirmed PGR rearrangement by fluorescence in situ hybridization (FISH).	('PGR', 'Gene', (122, 125))	('PGR', 'Gene', '5241', (122, 125))	('rearrangement', 'Var', (126, 139))
126754	30829727	The remaining study group was screened by FISH for abnormalities in both NR4A3 and PGR genes.	('PGR', 'Gene', (83, 86))	('abnormalities', 'Var', (51, 64))	('PGR', 'Gene', '5241', (83, 86))	('NR4A3', 'Gene', (73, 78))	('NR4A3', 'Gene', '8013', (73, 78))
126755	30829727	A NR4A3-PGR fusion was detected in three additional tumors previously diagnosed as epithelioid leiomyosarcoma (Figure 6).	('fusion', 'Var', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('PGR', 'Gene', (8, 11))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('epithelioid leiomyosarcoma', 'Disease', (83, 109))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (95, 109))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('PGR', 'Gene', '5241', (8, 11))	('detected', 'Reg', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('NR4A3', 'Gene', '8013', (2, 7))	('epithelioid leiomyosarcoma', 'Disease', 'MESH:D007890', (83, 109))	('NR4A3', 'Gene', (2, 7))
126756	30829727	PGR rearrangement with no identifiable fusion partner was observed in two tumors also previously diagnosed as epithelioid leiomyosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('PGR', 'Gene', '5241', (0, 3))	('rearrangement', 'Var', (4, 17))	('epithelioid leiomyosarcoma', 'Disease', 'MESH:D007890', (110, 136))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('epithelioid leiomyosarcoma', 'Disease', (110, 136))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (122, 136))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('PGR', 'Gene', (0, 3))	('observed', 'Reg', (58, 66))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
126758	30829727	In this study, we identified a molecular subset of uterine epithelioid leiomyosarcoma exhibiting distinctive isomorphic epithelioid and rhabdoid features and harboring PGR rearrangements, often in association with an NR4A3 fusion partner.	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('epithelioid leiomyosarcoma', 'Disease', (59, 85))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (71, 85))	('uterine epithelioid leiomyosarcoma', 'Phenotype', 'HP:0002891', (51, 85))	('NR4A3', 'Gene', '8013', (217, 222))	('rearrangements', 'Var', (172, 186))	('NR4A3', 'Gene', (217, 222))	('rhabdoid', 'Disease', 'MESH:D018335', (136, 144))	('rhabdoid', 'Disease', (136, 144))	('PGR', 'Gene', (168, 171))	('epithelioid leiomyosarcoma', 'Disease', 'MESH:D007890', (59, 85))	('PGR', 'Gene', '5241', (168, 171))
126766	30829727	Somatic PGR mutations are usually missense and occur in approximately 1% of all cancer types.	('missense', 'Var', (34, 42))	('PGR', 'Gene', (8, 11))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PGR', 'Gene', '5241', (8, 11))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('occur', 'Reg', (47, 52))	('cancer', 'Disease', (80, 86))
126767	30829727	According to The Cancer Genome Atlas, PGR mutations were found in only 2.4% of endometrial carcinomas and were enriched among endometrioid tumors; PGR mutations comprise only 0.2% of ovarian high-grade serous carcinomas.	('ovarian high', 'Phenotype', 'HP:0008209', (183, 195))	('PGR', 'Gene', '5241', (38, 41))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (79, 101))	('serous carcinomas', 'Disease', 'MESH:D018297', (202, 219))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (79, 101))	('PGR', 'Gene', '5241', (147, 150))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (151, 160))	('PGR', 'Gene', (38, 41))	('Cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('endometrial carcinomas', 'Disease', (79, 101))	('PGR', 'Gene', (147, 150))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('serous carcinomas', 'Disease', (202, 219))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))	('mutations', 'Var', (42, 51))
126769	30829727	Thus, our findings suggest that this small subset of leiomyosarcomas with distinctive rhabdoid and epithelioid morphology are characterized by novel PGR rearrangements, not previously identified in other tumors types.	('rhabdoid', 'Disease', (86, 94))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('PGR', 'Gene', (149, 152))	('leiomyosarcomas', 'Disease', (53, 68))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('PGR', 'Gene', '5241', (149, 152))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (53, 68))	('rearrangements', 'Var', (153, 167))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (53, 68))	('rhabdoid', 'Disease', 'MESH:D018335', (86, 94))
126770	30829727	Fusion of PGR with the nuclear receptor subfamily 4, group A, member 3 (NR4A3) was seen in two-thirds of our uterine leiomyosarcomas with epithelioid and rhabdoid morphology.	('Fusion', 'Var', (0, 6))	('seen', 'Reg', (83, 87))	('PGR', 'Gene', '5241', (10, 13))	('leiomyosarcomas', 'Disease', (117, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (117, 132))	('rhabdoid', 'Disease', 'MESH:D018335', (154, 162))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (117, 132))	('NR4A3', 'Gene', '8013', (72, 77))	('nuclear receptor subfamily 4, group A, member 3', 'Gene', '8013', (23, 70))	('NR4A3', 'Gene', (72, 77))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (117, 131))	('rhabdoid', 'Disease', (154, 162))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (109, 132))	('PGR', 'Gene', (10, 13))
126772	30829727	NR4A3 gene fusions, mostly commonly with EWSR1, have been detected in extraskeletal myxoid chondrosarcomas.	('EWSR1', 'Gene', (41, 46))	('detected', 'Reg', (58, 66))	('NR4A3', 'Gene', '8013', (0, 5))	('NR4A3', 'Gene', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('myxoid chondrosarcomas', 'Disease', (84, 106))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (91, 106))	('EWSR1', 'Gene', '2130', (41, 46))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (84, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('fusions', 'Var', (11, 18))
126774	30829727	While our uterine leiomyosarcomas harboring NR4A3-PGR fusions are morphologically distinct from extraskeletal myxoid chondrosarcomas, it is of interest to note that rhabdoid features are characteristic of extraskeletal myxoid chondrosarcomas with non-EWSR1 NR4A3 fusions.	('leiomyosarcomas', 'Disease', (18, 33))	('myxoid chondrosarcomas', 'Disease', (219, 241))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (219, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('fusions', 'Var', (54, 61))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (10, 33))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (18, 33))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (226, 241))	('EWSR1', 'Gene', (251, 256))	('NR4A3', 'Gene', '8013', (44, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('NR4A3', 'Gene', '8013', (257, 262))	('PGR', 'Gene', '5241', (50, 53))	('rhabdoid', 'Disease', (165, 173))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (18, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('rhabdoid', 'Disease', 'MESH:D018335', (165, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('NR4A3', 'Gene', (44, 49))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (117, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (233, 241))	('PGR', 'Gene', (50, 53))	('NR4A3', 'Gene', (257, 262))	('EWSR1', 'Gene', '2130', (251, 256))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (110, 132))	('myxoid chondrosarcomas', 'Disease', (110, 132))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (18, 33))
126781	30829727	While mild to moderate cytologic atypia was present among our tumors harboring PGR rearrangement, overt nuclear pleomorphism was lacking.	('PGR', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PGR', 'Gene', '5241', (79, 82))	('rearrangement', 'Var', (83, 96))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))
126783	30829727	The biphasic appearance of PGR fusion-positive uterine leiomyosarcomas may be confused with low-grade endometrial stromal sarcomas with epithelioid change and high-grade endometrial stromal sarcomas harboring YWHAE-NUTM2 fusion or BCOR internal tandem duplication.	('endometrial stromal sarcomas', 'Disease', (170, 198))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (55, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (190, 198))	('BCOR', 'Gene', '54880', (231, 235))	('leiomyosarcomas', 'Disease', (55, 70))	('PGR', 'Gene', '5241', (27, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('BCOR', 'Gene', (231, 235))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (55, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (102, 130))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (47, 70))	('endometrial stromal sarcomas', 'Disease', (102, 130))	('internal tandem duplication', 'Var', (236, 263))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('PGR', 'Gene', (27, 30))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (55, 69))	('YWHAE', 'Gene', (209, 214))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (170, 198))	('YWHAE', 'Gene', '7531', (209, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
126792	30829727	With the exception of identifying TSC1/TSC2 mutations and TFE3 or RAD51B rearrangements, there is no gold standard in the diagnosis of uterine PEComas at this time.	('RAD51B', 'Gene', '5890', (66, 72))	('TFE3', 'Gene', '7030', (58, 62))	('rearrangements', 'Var', (73, 87))	('PEComas', 'Disease', 'MESH:D054973', (143, 150))	('TSC1', 'Gene', '7248', (34, 38))	('TSC2', 'Gene', '7249', (39, 43))	('mutations', 'Var', (44, 53))	('RAD51B', 'Gene', (66, 72))	('TFE3', 'Gene', (58, 62))	('TSC2', 'Gene', (39, 43))	('TSC1', 'Gene', (34, 38))	('PEComas', 'Disease', (143, 150))
126793	30829727	No PGR rearrangements were detected by FISH in the three PEComas tested in our cohort, nor in the cases tested by whole transcriptome RNAseq in our prior study.	('PEComas', 'Disease', (57, 64))	('PGR', 'Gene', '5241', (3, 6))	('rearrangements', 'Var', (7, 21))	('PEComas', 'Disease', 'MESH:D054973', (57, 64))	('PGR', 'Gene', (3, 6))
126798	30829727	In summary, PGR gene rearrangements define a novel molecular subset of epithelioid leiomyosarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('PGR', 'Gene', (12, 15))	('rearrangements', 'Var', (21, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (83, 98))	('PGR', 'Gene', '5241', (12, 15))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (83, 97))	('epithelioid leiomyosarcomas', 'Disease', 'MESH:D007890', (71, 98))	('epithelioid leiomyosarcomas', 'Disease', (71, 98))
126805	28963501	Apart from its role in host physiology, 1, 25(OH)2 D3 has been implicated as a potential agent for the prevention and/or treatment of many a tumors.	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('1, 25(OH)2 D3', 'Var', (40, 53))
126806	28963501	Here we show that 1, 25(OH)2 D3 induces both death of Kaposi sarcoma associated herpesvirus infected PEL cells and KSHV replication.	('death of Kaposi sarcoma', 'Disease', 'MESH:D012514', (45, 68))	('PEL', 'Phenotype', 'HP:0030069', (101, 104))	('1, 25(OH)2 D3', 'Var', (18, 31))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (18, 31))	('KSHV replication', 'CPA', (115, 131))	('KSHV', 'Species', '37296', (115, 119))	('KS', 'Phenotype', 'HP:0100726', (115, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (54, 68))	('death of Kaposi sarcoma', 'Disease', (45, 68))	('herpesvirus', 'Species', '39059', (80, 91))
126810	28963501	Furthermore, silencing of VDR resulted in reduced ORF57 expression compared to the control cells, signifying the potential role of 1, 25(OH)2 D3 in KSHV reactivation.	('reduced', 'NegReg', (42, 49))	('ORF57', 'Gene', (50, 55))	('KSHV', 'Species', '37296', (148, 152))	('VDR', 'Gene', (26, 29))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (131, 144))	('KS', 'Phenotype', 'HP:0100726', (148, 150))	('VDR', 'Gene', '7421', (26, 29))	('ORF57', 'Gene', '4961525', (50, 55))	('silencing', 'Var', (13, 22))
126827	28963501	However, studies are lacking on the role of 1, 25(OH)2 D3 in viral pathogenesis, only very few studies have indicated that vitamin D3 deficiency may confer increased risk of influenza and respiratory tract infection.	('respiratory tract infection', 'Disease', (188, 215))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (44, 57))	('vitamin D3', 'Chemical', 'MESH:D002762', (123, 133))	('deficiency', 'Var', (134, 144))	('respiratory tract infection', 'Disease', 'MESH:D012141', (188, 215))	('vitamin D3 deficiency', 'Phenotype', 'HP:0100497', (123, 144))	('respiratory tract infection', 'Phenotype', 'HP:0011947', (188, 215))	('influenza', 'Disease', (174, 183))	('vitamin D3', 'Gene', (123, 133))
126830	28963501	In addition, it remains to be identified whether 1, 25(OH)2 D3 is protective or pathogenic in cases of viral infection.	('pathogenic', 'Reg', (80, 90))	('viral infection', 'Disease', 'MESH:D001102', (103, 118))	('1, 25(OH)2 D3', 'Var', (49, 62))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (49, 62))	('viral infection', 'Disease', (103, 118))
126832	28963501	Further, it has been shown that 1, 25(OH)2 D3 also has anti-proliferative effect on KSHV GPCR transformed endothelial cells.	('1, 25(OH)2 D3', 'Var', (32, 45))	('KS', 'Phenotype', 'HP:0100726', (84, 86))	('KSHV', 'Species', '37296', (84, 88))	('anti-proliferative effect', 'CPA', (55, 80))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (32, 45))
126834	28963501	In view of these facts, the current investigations were taken up to dissect the mechanism (s) of action of 1, 25(OH)2 D3 on PEL cells, in particular its effect on apoptosis and reactivation.	('PEL', 'Phenotype', 'HP:0030069', (124, 127))	('apoptosis', 'CPA', (163, 172))	('1, 25(OH)2 D3', 'Var', (107, 120))	('reactivation', 'MPA', (177, 189))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (107, 120))
126879	28963501	Thus suggesting that VDR contributes to the cellular apoptosis induced by 1, 25(OH)2 D3 in PEL cells.	('VDR', 'Gene', '7421', (21, 24))	('PEL', 'Phenotype', 'HP:0030069', (91, 94))	('cellular apoptosis', 'CPA', (44, 62))	('VDR', 'Gene', (21, 24))	('1, 25(OH)2 D3', 'Var', (74, 87))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (74, 87))
126888	28963501	However, KSHV reactivation was comparatively lower in 1, 25(OH)2 D3 treatment than in the positive control, TPA (Fig.	('KSHV reactivation', 'MPA', (9, 26))	('KSHV', 'Species', '37296', (9, 13))	('lower', 'NegReg', (45, 50))	('TPA', 'Chemical', 'MESH:D013755', (108, 111))	('1, 25(OH)2 D3 treatment', 'Var', (54, 77))	('KS', 'Phenotype', 'HP:0100726', (9, 11))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (54, 67))
126890	28963501	Immunobloting, for expression of ORF57 and K8alpha showed lytic replication at the 24 h and 36 h with peak activation at 24 h (Fig.	('K8alpha', 'Var', (43, 50))	('lytic replication', 'CPA', (58, 75))	('ORF57', 'Gene', '4961525', (33, 38))	('activation', 'PosReg', (107, 117))	('ORF57', 'Gene', (33, 38))
126891	28963501	These results indicate that 1, 25(OH)2 D3 induces expression of lytic genes and progeny virus production.	('1, 25(OH)2 D3', 'Var', (28, 41))	('induces', 'PosReg', (42, 49))	('progeny virus production', 'CPA', (80, 104))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (28, 41))	('expression', 'MPA', (50, 60))	('lytic genes', 'Gene', (64, 75))
126899	28963501	Both PD 98059 and SB 203580 inhibited RTA upregulation but not SP 600125 (Fig.	('SB 203580', 'Var', (18, 27))	('SP 600125', 'Chemical', 'MESH:C432165', (63, 72))	('PD', 'Disease', 'MESH:D010300', (5, 7))	('SB 203580', 'Chemical', 'MESH:C093642', (18, 27))	('inhibited', 'NegReg', (28, 37))	('RTA', 'MPA', (38, 41))	('upregulation', 'PosReg', (42, 54))
126908	28963501	In summary, VDR knock-down lowers 1, 25(OH)2 D3 induced viral reactivation.	('VDR', 'Gene', (12, 15))	('lowers', 'NegReg', (27, 33))	('viral reactivation', 'MPA', (56, 74))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (34, 47))	('VDR', 'Gene', '7421', (12, 15))	('knock-down', 'Var', (16, 26))
126918	28963501	It has been previously demonstrated that active form of 1, 25(OH)2 D3 promotes growth inhibition in lymphocytes and in a variety of human cancer cell lines.	('cancer', 'Disease', (138, 144))	('1, 25(OH)2 D3', 'Var', (56, 69))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('growth inhibition', 'CPA', (79, 96))	('human', 'Species', '9606', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
126924	28963501	Even though the extent of reactivation by 1, 25(OH)2 D3 is comparatively lower than those caused by strong inducers, such as TPA.	('1, 25(OH)2 D3', 'Var', (42, 55))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (42, 55))	('reactivation', 'MPA', (26, 38))	('lower', 'NegReg', (73, 78))	('TPA', 'Chemical', 'MESH:D013755', (125, 128))
126932	28963501	In this study, the p38 MAPK pathway however appears to be generally activated by 1, 25(OH)2 D3 in PEL cells as assessed by expression of p-p38 protein (Fig.	('p38', 'Gene', '1432', (139, 142))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (81, 94))	('p38', 'Gene', '1432', (19, 22))	('p38', 'Gene', (139, 142))	('activated', 'PosReg', (68, 77))	('PEL', 'Phenotype', 'HP:0030069', (98, 101))	('p38', 'Gene', (19, 22))	('1, 25(OH)2 D3', 'Var', (81, 94))
126934	28963501	Furthermore, the p38 kinase inhibitor SB203580 not only prevented p38 phosphorylation but also abrogated KSHV reactivation (Fig.	('KSHV reactivation', 'MPA', (105, 122))	('prevented', 'NegReg', (56, 65))	('SB203580', 'Var', (38, 46))	('p38', 'Gene', '1432', (17, 20))	('SB203580', 'Chemical', 'MESH:C093642', (38, 46))	('KSHV', 'Species', '37296', (105, 109))	('p38', 'Gene', '1432', (66, 69))	('abrogated', 'NegReg', (95, 104))	('p38', 'Gene', (17, 20))	('KS', 'Phenotype', 'HP:0100726', (105, 107))	('p38', 'Gene', (66, 69))
126935	28963501	On the other hand, ERK inhibitor, PD98059 only partially suppressed KSHV reactivation, while there was no change with JNK inhibitor (Fig.	('JNK', 'Gene', (118, 121))	('KSHV reactivation', 'MPA', (68, 85))	('ERK', 'Gene', '5594', (19, 22))	('PD98059', 'Var', (34, 41))	('JNK', 'Gene', '5599', (118, 121))	('ERK', 'Gene', (19, 22))	('PD98059', 'Chemical', 'MESH:C093973', (34, 41))	('KSHV', 'Species', '37296', (68, 72))	('KS', 'Phenotype', 'HP:0100726', (68, 70))	('suppressed', 'NegReg', (57, 67))
126939	28963501	Our finding mirrors this as RTA expression occurred following stimulation by 1, 25(OH)2 D3 (Fig.	('RTA', 'MPA', (28, 31))	('1, 25(OH)2 D3', 'Var', (77, 90))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (77, 90))
126941	28963501	Thus, increase in the RTA expression induced by 1, 25(OH)2 D3 may lead to a greater degree of KSHV reactivation, making RTA a sensitive regulator between latency and reactivation as also confirmed through infection of 293 cells (Fig.	('expression', 'MPA', (26, 36))	('RTA', 'Gene', (22, 25))	('KSHV reactivation', 'MPA', (94, 111))	('1, 25(OH)2 D3', 'Var', (48, 61))	('KS', 'Phenotype', 'HP:0100726', (94, 96))	('KSHV', 'Species', '37296', (94, 98))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (48, 61))	('increase', 'PosReg', (6, 14))
126942	28963501	Lastly, we determined the effects of VDR knockdown on PEL cell proliferation and KSHV reactivation.	('knockdown', 'Var', (41, 50))	('VDR', 'Gene', (37, 40))	('PEL cell proliferation', 'CPA', (54, 76))	('PEL', 'Phenotype', 'HP:0030069', (54, 57))	('VDR', 'Gene', '7421', (37, 40))	('KS', 'Phenotype', 'HP:0100726', (81, 83))	('KSHV', 'Species', '37296', (81, 85))
126943	28963501	VDR Knockdown rendered JSC-1 cells significantly less susceptible to 1, 25(OH)2 D3 mediated KSHV reactivation, while virus reactivation by phorbol esters remained intact (Fig.	('KS', 'Phenotype', 'HP:0100726', (92, 94))	('phorbol esters', 'Chemical', 'MESH:D010703', (139, 153))	('VDR', 'Gene', '7421', (0, 3))	('Knockdown', 'Var', (4, 13))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (69, 82))	('KSHV reactivation', 'MPA', (92, 109))	('KSHV', 'Species', '37296', (92, 96))	('VDR', 'Gene', (0, 3))	('less', 'NegReg', (49, 53))
126944	28963501	The findings further suggest that 1, 25(OH)2 D3 may activate latent KSHV in vivo.	('latent', 'MPA', (61, 67))	('1, 25(OH)2 D3', 'Chemical', 'MESH:D002117', (34, 47))	('activate', 'PosReg', (52, 60))	('KSHV', 'Species', '37296', (68, 72))	('KS', 'Phenotype', 'HP:0100726', (68, 70))	('1, 25(OH)2 D3', 'Var', (34, 47))
127027	28100249	LC was significantly affected by resection margin (5y-LC 92% R0 vs 75% R1) and disease situation (5y-LC 90% primary vs 74% recurrent) in univariate analysis, but only disease situation remained significant in multivariate analysis.	('5y-LC', 'Var', (98, 103))	('5y-LC', 'Chemical', '-', (98, 103))	('LC', 'Chemical', '-', (101, 103))	('affected', 'Reg', (21, 29))	('LC', 'Chemical', '-', (54, 56))	('5y-LC', 'Chemical', '-', (51, 56))	('LC', 'Chemical', '-', (0, 2))
127075	28100249	described 3% NCI-IORT grade 2/3 neuropathy with IORT doses <=12.5 Gy compared to 21% with >= 15 Gy in a series of patient with colorectal cancer.	('neuropathy', 'Phenotype', 'HP:0009830', (32, 42))	('neuropathy', 'Disease', (32, 42))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('Gy', 'Chemical', 'MESH:C022013', (96, 98))	('Gy', 'Chemical', 'MESH:C022013', (66, 68))	('neuropathy', 'Disease', 'MESH:D009422', (32, 42))	('patient', 'Species', '9606', (114, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('<=12.5', 'Var', (59, 65))
127116	28100249	They observed a clearly improved 5-year LC rate of 83% with IORT compared to 61% in patients without IORT.	('IORT', 'Var', (60, 64))	('LC', 'Chemical', '-', (40, 42))	('improved', 'PosReg', (24, 32))	('patients', 'Species', '9606', (84, 92))
127138	28100249	In the randomized NCI trial, severe chronic GI-toxicity (scored according to NCI-IORT criteria) was found in 13% in the IORT + limited EBRT arm versus 50% in the postoperative EBRT only arm.	('EBRT', 'Chemical', '-', (135, 139))	('GI-toxicity', 'Disease', (44, 55))	('GI-toxicity', 'Disease', 'MESH:D005767', (44, 55))	('IORT + limited EBRT', 'Var', (120, 139))	('EBRT', 'Chemical', '-', (176, 180))
127219	27011434	However, tumor tissue architecture is evaluated much more accurately in CNB samples, and adequate tissue for ancillary diagnostics is obtained more often by CNB than by FNA.	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('CNB', 'Var', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))
127385	33906629	Changes in the immunosuppressive treatment were performed at PEL diagnosis in 4/13 cases as follows: 1/4: tacrolimus was changed to sirolimus (rapamycin) resulting in undetectable HHV8 DNA blood level; 1/4: cyclosporine reduction; 1/4: cyclosporine reduction plus azathioprine stopping; 1/4: cyclosporine and azathioprine stopping plus introduction of rapamycin.	('rapamycin', 'Chemical', 'MESH:D020123', (352, 361))	('cyclosporine', 'Chemical', 'MESH:D016572', (292, 304))	('changed', 'Var', (121, 128))	('cyclosporine', 'Chemical', 'MESH:D016572', (207, 219))	('sirolimus', 'Chemical', 'MESH:D020123', (132, 141))	('reduction', 'NegReg', (220, 229))	('undetectable HHV8 DNA blood level', 'MPA', (167, 200))	('tacrolimus', 'Chemical', 'MESH:D016559', (106, 116))	('rapamycin', 'Chemical', 'MESH:D020123', (143, 152))	('azathioprine', 'Chemical', 'MESH:D001379', (264, 276))	('azathioprine', 'Chemical', 'MESH:D001379', (309, 321))	('cyclosporine', 'MPA', (207, 219))	('HHV8', 'Species', '37296', (180, 184))	('cyclosporine', 'Chemical', 'MESH:D016572', (236, 248))
127414	33906629	It is worth mentioning that in the case of PT-PEL positive for TCR gene rearrangement, a T-cell lymphoma was excluded due to HHV8 positivity.	('PT-PEL', 'Gene', (43, 49))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (89, 104))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (89, 104))	('rearrangement', 'Var', (72, 85))	('T-cell lymphoma', 'Disease', (89, 104))	('TCR', 'Gene', '6962', (63, 66))	('cell lymphoma', 'Phenotype', 'HP:0012191', (91, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('HHV8', 'Species', '37296', (125, 129))	('PT-PEL', 'Gene', 'None', (43, 49))	('TCR', 'Gene', (63, 66))
127452	33906629	In addition to frank neoplastic diseases, in transplanted patients HHV8 may be the etiologic agent of serious non-neoplastic disorders typically associated with high HHV8 viremia.	('HHV8 viremia', 'Disease', 'MESH:D014766', (166, 178))	('frank neoplastic diseases', 'Disease', (15, 40))	('HHV8', 'Species', '37296', (67, 71))	('neoplastic disorders', 'Disease', (114, 134))	('agent', 'Reg', (93, 98))	('viremia', 'Phenotype', 'HP:0020071', (171, 178))	('HHV8', 'Gene', (67, 71))	('etiologic', 'Reg', (83, 92))	('high', 'Var', (161, 165))	('HHV8 viremia', 'Disease', (166, 178))	('patients', 'Species', '9606', (58, 66))	('neoplastic disorders', 'Disease', 'MESH:D009369', (114, 134))	('HHV8', 'Species', '37296', (166, 170))	('frank neoplastic diseases', 'Disease', 'MESH:D001946', (15, 40))
127510	33402862	On the other hand, the deletion of Meis1 downregulates p21, p15, p16, and p19arf expression in cardiomyocytes and improves the cell cycle (Muralidhar and Sadek, 2016).	('p15', 'Gene', (60, 63))	('p16', 'Gene', '1029', (65, 68))	('cell cycle', 'CPA', (127, 137))	('p15', 'Gene', '1030', (60, 63))	('deletion', 'Var', (23, 31))	('p21', 'Gene', (55, 58))	('Meis1', 'Gene', (35, 40))	('downregulates', 'NegReg', (41, 54))	('p21', 'Gene', '644914', (55, 58))	('p19arf', 'Gene', (74, 80))	('p19arf', 'Gene', '1029', (74, 80))	('p16', 'Gene', (65, 68))	('improves', 'PosReg', (114, 122))	('expression', 'MPA', (81, 91))
127523	33402862	Meis1 is essential for normal hematopoiesis, as was indicated by Meis1 mutant mice having an internal hemorrhage, liver hypoplasia, and anemia (Azcoitia et al., 2005).	('Meis1', 'Gene', (65, 70))	('anemia', 'Phenotype', 'HP:0001903', (136, 142))	('liver hypoplasia', 'Disease', 'MESH:D017093', (114, 130))	('hemorrhage', 'Disease', 'MESH:D006470', (102, 112))	('liver hypoplasia', 'Disease', (114, 130))	('anemia', 'Disease', (136, 142))	('hematopoiesis', 'Disease', 'MESH:C536227', (30, 43))	('anemia', 'Disease', 'MESH:D000740', (136, 142))	('mutant', 'Var', (71, 77))	('Azcoitia', 'Disease', (144, 152))	('hemorrhage', 'Disease', (102, 112))	('hematopoiesis', 'Disease', (30, 43))	('mice', 'Species', '10090', (78, 82))	('Azcoitia', 'Disease', 'None', (144, 152))	('internal hemorrhage', 'Phenotype', 'HP:0011029', (93, 112))
127536	33402862	Under normal circumstances, 11 Hox paralogs in locus C are involved in healthy urogenital development; however, in the case of bladder cancer, these gene family variants are upregulated (Cantile et al., 2003).	('variants', 'Var', (161, 169))	('upregulated', 'PosReg', (174, 185))	('bladder cancer', 'Phenotype', 'HP:0009725', (127, 141))	('men', 'Species', '9606', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('bladder cancer', 'Disease', 'MESH:D001749', (127, 141))	('bladder cancer', 'Disease', (127, 141))
127537	33402862	Genetic and epigenetic modifications have an important function in carcinoma formation.	('carcinoma', 'Disease', 'MESH:D009369', (67, 76))	('Genetic', 'Var', (0, 7))	('epigenetic modifications', 'Var', (12, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinoma', 'Disease', (67, 76))
127538	33402862	DNA hypermethylation is among the most common and characterized epigenetic modification in human malignancies.	('human', 'Species', '9606', (91, 96))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('malignancies', 'Disease', (97, 109))	('hypermethylation', 'Var', (4, 20))
127545	33402862	Alternative splicing has a significant function in the posttranscriptional regulation of genes, as well as cancer development or progression.	('posttranscriptional regulation of genes', 'MPA', (55, 94))	('men', 'Species', '9606', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('progression', 'CPA', (129, 140))	('function', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Alternative splicing', 'Var', (0, 20))	('cancer', 'Disease', (107, 113))
127548	33402862	Moreover, Meis2 knockdown significantly inhibits the migration and invasion capacities of bladder cancer cells (Xie et al., 2019).	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('knockdown', 'Var', (16, 25))	('invasion capacities', 'CPA', (67, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('inhibits', 'NegReg', (40, 48))	('Meis2', 'Gene', (10, 15))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
127557	33402862	Mutations that affect HOX/PBX/MEIS interactions may also contribute to breast cancer (Dard et al., 2018).	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('interactions', 'Interaction', (35, 47))	('contribute', 'Reg', (57, 67))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
127561	33402862	Distant metastasis and associated mortality are closely related to Meis2 expression in colorectal cancer (Wan et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('expression', 'Var', (73, 83))	('Meis2', 'Gene', (67, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('mortality', 'Disease', 'MESH:D003643', (34, 43))	('colorectal cancer', 'Disease', (87, 104))	('Distant metastasis', 'CPA', (0, 18))	('mortality', 'Disease', (34, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))
127563	33402862	Moreover, high Meis2 expression may reduce the overall survival period of patients with colorectal cancer (Wan et al., 2019).	('colorectal cancer', 'Disease', (88, 105))	('reduce', 'NegReg', (36, 42))	('patients', 'Species', '9606', (74, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('expression', 'MPA', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('high', 'Var', (10, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('overall survival period', 'CPA', (47, 70))	('Meis2', 'Protein', (15, 20))
127569	33402862	In addition, the knockdown of Hoxa9 and Hoxa4 in HT29 cells leads to a significant decrease in cell proliferation, and their overexpression causes an increase in the self-renewal ability of colorectal CSCs (Bhatlekar et al., 2018).	('cell proliferation', 'CPA', (95, 113))	('Hoxa4', 'Gene', (40, 45))	('HT29 cells', 'CellLine', 'CVCL:0320', (49, 59))	('Hoxa4', 'Gene', '3201', (40, 45))	('colorectal CSCs', 'Disease', (190, 205))	('colorectal CSCs', 'Disease', 'MESH:D015179', (190, 205))	('decrease', 'NegReg', (83, 91))	('Hoxa9', 'Gene', (30, 35))	('knockdown', 'Var', (17, 26))	('increase', 'PosReg', (150, 158))	('overexpression', 'PosReg', (125, 139))
127578	33402862	(2016) showed that the expression of Meis1 has a reverse association with lymph node involvement, metastasis, and tumor staging in ESCC (Rad et al., 2016).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('lymph node involvement', 'CPA', (74, 96))	('metastasis', 'CPA', (98, 108))	('expression', 'Var', (23, 33))	('tumor', 'Disease', (114, 119))	('Meis1', 'Gene', (37, 42))	('Rad', 'Gene', '6236', (137, 140))	('men', 'Species', '9606', (92, 95))	('Rad', 'Gene', (137, 140))	('ESCC', 'Disease', (131, 135))
127600	33402862	Nuclear receptor SET domain-containing protein-1 (NSD1) silencing by epigenetic modification leads to Sotos syndrome, as well as nonhereditary neuroblastoma and glioma development (Berdasco et al., 2009).	('Nuclear receptor SET domain-containing protein-1', 'Gene', (0, 48))	('NSD1', 'Gene', '64324', (50, 54))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('Sotos syndrome', 'Disease', 'MESH:D058495', (102, 116))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('leads', 'Reg', (93, 98))	('Nuclear receptor SET domain-containing protein-1', 'Gene', '64324', (0, 48))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('Sotos syndrome', 'Disease', (102, 116))	('neuroblastoma', 'Disease', (143, 156))	('epigenetic modification', 'Var', (69, 92))	('NSD1', 'Gene', (50, 54))	('glioma', 'Disease', (161, 167))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('silencing', 'NegReg', (56, 65))	('men', 'Species', '9606', (175, 178))
127601	33402862	Hypermethylation of Nsd1 causes the upregulation of Meis1 transcript and protein due to the absence of NSD1 binding to the Meis1 promoter in neuroblastoma cells (Berdasco et al., 2009).	('neuroblastoma', 'Disease', 'MESH:D009447', (141, 154))	('absence', 'NegReg', (92, 99))	('Meis1', 'Gene', (52, 57))	('Nsd1', 'Gene', (20, 24))	('neuroblastoma', 'Disease', (141, 154))	('protein', 'Protein', (73, 80))	('upregulation', 'PosReg', (36, 48))	('binding', 'Interaction', (108, 115))	('Hypermethylation', 'Var', (0, 16))	('NSD1', 'Gene', (103, 107))	('neuroblastoma', 'Phenotype', 'HP:0003006', (141, 154))	('transcript', 'MPA', (58, 68))	('Nsd1', 'Gene', '64324', (20, 24))	('NSD1', 'Gene', '64324', (103, 107))
127623	33402862	Intriguingly, stable transfection of the dominant-negative variant of MEIS1 has generated clones with altered cell proliferation, increased differentiated phenotype, and elevated contact inhibition and cell death.	('elevated', 'PosReg', (170, 178))	('death', 'Disease', 'MESH:D003643', (207, 212))	('death', 'Disease', (207, 212))	('differentiated phenotype', 'CPA', (140, 164))	('contact inhibition', 'CPA', (179, 197))	('MEIS1', 'Gene', (70, 75))	('variant', 'Var', (59, 66))	('increased', 'PosReg', (130, 139))	('cell proliferation', 'CPA', (110, 128))	('altered', 'Reg', (102, 109))
127641	33402862	Mutations in the MEIS-HOX signaling pathway and its downstream proteins have been found to cause MLL (Zhou et al., 2014).	('cause', 'Reg', (91, 96))	('MEIS-HOX signaling pathway', 'Pathway', (17, 43))	('Mutations', 'Var', (0, 9))	('MLL', 'Gene', (97, 100))	('MLL', 'Gene', '4297', (97, 100))
127643	33402862	In vivo studies have shown that PU.1 mutation contributes to MLL development by modulating MEIS-HOX downstream genes (Zhou et al., 2014).	('MLL', 'Gene', '4297', (61, 64))	('mutation', 'Var', (37, 45))	('MLL', 'Gene', (61, 64))	('men', 'Species', '9606', (72, 75))	('modulating', 'Reg', (80, 90))	('MEIS-HOX downstream genes', 'Gene', (91, 116))	('PU.1', 'Gene', '6688', (32, 36))	('PU.1', 'Gene', (32, 36))	('contributes', 'Reg', (46, 57))
127648	33402862	In cases with an inactivation mutation of Meis1 in fetal liver cells, myeloid transformation loses its capability for the differentiation and self-renewal of leukemia stem cells (Wong et al., 2007).	('Meis1', 'Gene', (42, 47))	('loses', 'NegReg', (93, 98))	('leukemia', 'Disease', (158, 166))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('leukemia', 'Disease', 'MESH:D007938', (158, 166))	('myeloid transformation', 'CPA', (70, 92))	('inactivation mutation', 'Var', (17, 38))
127658	33402862	Moreover, pre-B-cell ALL patients were observed to have E2A-PBX1 chimeric oncoprotein resulting from chromosomal translocation t(1;19), and translocation results in mutant oncoprotein (Carroll et al., 1984).	('t(1;19', 'Var', (127, 133))	('PBX1', 'Gene', (60, 64))	('translocation', 'Var', (140, 153))	('mutant', 'Var', (165, 171))	('E2A', 'Gene', '6929', (56, 59))	('oncoprotein', 'Protein', (74, 85))	('E2A', 'Gene', (56, 59))	('results in', 'Reg', (154, 164))	('pre-B', 'Gene', (10, 15))	('patients', 'Species', '9606', (25, 33))	('oncoprotein', 'Protein', (172, 183))	('PBX1', 'Gene', '5087', (60, 64))	('chimeric', 'Var', (65, 73))	('pre-B', 'Gene', '10113', (10, 15))
127660	33402862	MEIS1 and MEIS2 interact with HOX and PBX variants in leukemia (Garcia-Cuellar et al., 2015).	('PBX', 'Gene', (38, 41))	('Garcia-Cuellar', 'Disease', (64, 78))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('variants', 'Var', (42, 50))	('Garcia-Cuellar', 'Disease', 'MESH:C536767', (64, 78))	('leukemia', 'Disease', (54, 62))	('leukemia', 'Disease', 'MESH:D007938', (54, 62))
127661	33402862	The presence of PBX3 and MEIS1 increases HOXA9-induced leukemia (Garcia-Cuellar et al., 2015).	('PBX3', 'Gene', '5090', (16, 20))	('Garcia-Cuellar', 'Disease', 'MESH:C536767', (65, 79))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('increases', 'PosReg', (31, 40))	('HOXA9', 'Gene', '3205', (41, 46))	('leukemia', 'Disease', 'MESH:D007938', (55, 63))	('Garcia-Cuellar', 'Disease', (65, 79))	('leukemia', 'Disease', (55, 63))	('MEIS1', 'Gene', (25, 30))	('HOXA9', 'Gene', (41, 46))	('presence', 'Var', (4, 12))	('PBX3', 'Gene', (16, 20))
127667	33402862	The deletion of Meis2 differentially modulates TAL1, and thereby impairs endothelial specification and endothelial to hematopoietic transition (Wang et al., 2018b).	('Meis2', 'Gene', (16, 21))	('TAL1', 'Gene', '6886', (47, 51))	('deletion', 'Var', (4, 12))	('endothelial specification', 'CPA', (73, 98))	('TAL1', 'Gene', (47, 51))	('impairs', 'NegReg', (65, 72))	('modulates', 'Reg', (37, 46))	('endothelial to hematopoietic transition', 'CPA', (103, 142))
127668	33402862	Aberrant expression of Tlx1/Hox11 also results in T-cell leukemogenesis via Meis1 and Meis2 (Milech et al., 2010).	('Aberrant expression', 'Var', (0, 19))	('results in', 'Reg', (39, 49))	('Hox11', 'Gene', (28, 33))	('T-cell leukemogenesis', 'Phenotype', 'HP:0005517', (50, 71))	('T-cell leukemogenesis', 'Disease', (50, 71))	('Hox11', 'Gene', '15404', (28, 33))
127669	33402862	It has been found that Meis1/Hoxa9 deregulation has an important function in the progression of leukemia (Collins and Hess, 2016).	('deregulation', 'Var', (35, 47))	('leukemia', 'Disease', (96, 104))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('leukemia', 'Disease', 'MESH:D007938', (96, 104))	('Meis1/Hoxa9', 'Gene', (23, 34))
127670	33402862	Meis1 mutations lead blood cells to develop the symptoms of leukemia, as well as gain the chemoresistance and proliferation of leukemia cells by triggering other MEIS-cofactors (summarized in Table 1).	('gain', 'PosReg', (81, 85))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('leukemia', 'Disease', (127, 135))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('leukemia', 'Disease', 'MESH:D007938', (60, 68))	('leukemia', 'Disease', 'MESH:D007938', (127, 135))	('proliferation', 'CPA', (110, 123))	('mutations', 'Var', (6, 15))	('develop', 'PosReg', (36, 43))	('Meis1', 'Gene', (0, 5))	('leukemia', 'Disease', (60, 68))	('chemoresistance', 'CPA', (90, 105))
127671	33402862	The ectopic expression of Meis1 has been shown to inhibit cell proliferation in nonsmall-cell lung cancer (NSCLC) (Li et al., 2014).	('nonsmall-cell lung cancer', 'Disease', 'MESH:D002289', (80, 105))	('NSCLC', 'Disease', (107, 112))	('inhibit', 'NegReg', (50, 57))	('cell proliferation', 'CPA', (58, 76))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('nonsmall-cell lung cancer', 'Disease', (80, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('Meis1', 'Gene', (26, 31))	('ectopic expression', 'Var', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
127679	33402862	Furthermore, the differentiation of methylated CpG of Hoxa7 and Hoxa9 genes when compared to healthy controls is a point that needs to be examined on a molecular level (Rauch et al., 2007).	('methylated', 'Var', (36, 46))	('Hoxa7', 'Gene', '3204', (54, 59))	('Hoxa7', 'Gene', (54, 59))	('Hoxa9 genes', 'Gene', (64, 75))
127684	33402862	Blocking of HIF-1alpha complexes has been shown to cause increased metastasis and angiogenesis and an increase in cancer cell proliferation (Lin et al., 2017; Yang et al., 2017).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Blocking', 'Var', (0, 8))	('angiogenesis', 'CPA', (82, 94))	('metastasis', 'CPA', (67, 77))	('HIF-1alpha', 'Gene', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('increase', 'PosReg', (102, 110))	('increased', 'PosReg', (57, 66))	('HIF-1alpha', 'Gene', '3091', (12, 22))	('cancer', 'Disease', (114, 120))
127686	33402862	Surprisingly, however, cells that have a high expression of HIF-2alpha are more aggressive against radiotherapy and FDG uptake (Sun et al., 2015; Higashi et al., 2016).	('more', 'PosReg', (75, 79))	('high expression', 'Var', (41, 56))	('HIF-2alpha', 'Gene', (60, 70))	('HIF-2alpha', 'Gene', '2034', (60, 70))	('FDG', 'Chemical', 'MESH:D019788', (116, 119))
127697	33402862	Moreover, it has been shown that miRNA-196a modulates the expression of target genes (cadherin-11, calponin-1, and osteopontin) by regulating Hoxc8 in melanocyte and melanoma cells (Mueller and Bosserhoff, 2011).	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('modulates', 'Reg', (44, 53))	('calponin-1', 'Gene', '1264', (99, 109))	('Hoxc8', 'Gene', (142, 147))	('miRNA-196a', 'Var', (33, 43))	('expression', 'MPA', (58, 68))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('osteopontin', 'Gene', '6696', (115, 126))	('cadherin-11', 'Gene', '1009', (86, 97))	('Hoxc8', 'Gene', '3224', (142, 147))	('osteopontin', 'Gene', (115, 126))	('cadherin-11', 'Gene', (86, 97))	('regulating', 'Reg', (131, 141))	('calponin-1', 'Gene', (99, 109))
127699	33402862	Furthermore, the knockdown of Pbx1 by short interfering RNAs (siRNA) leads to the suppression of cell growth (Shiraishi et al., 2007).	('Pbx1', 'Gene', (30, 34))	('cell growth', 'CPA', (97, 108))	('knockdown', 'Var', (17, 26))	('Pbx1', 'Gene', '5087', (30, 34))	('suppression', 'NegReg', (82, 93))
127704	33402862	Moreover, a detailed DNA methylation analysis of all stages of human melanoma revealed that Hoxa9 DNA hypermethylation had a function in tumor development when compared to benign samples (Wouters et al., 2017).	('men', 'Species', '9606', (150, 153))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('human', 'Species', '9606', (63, 68))	('tumor', 'Disease', (137, 142))	('Hoxa9', 'Var', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('hypermethylation', 'Var', (102, 118))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('melanoma', 'Disease', (69, 77))
127708	33402862	Following the disruption of HOX-PBX interaction with double active peptide, c-Fos expression increases and apoptosis takes place (Platais et al., 2018).	('expression', 'MPA', (82, 92))	('c-Fos', 'Gene', '2353', (76, 81))	('increases', 'PosReg', (93, 102))	('interaction', 'Interaction', (36, 47))	('disruption', 'Var', (14, 24))	('apoptosis', 'CPA', (107, 116))	('c-Fos', 'Gene', (76, 81))
127710	33402862	The misregulated expression of Hoxc6 and Hoxa10 cluster proteins are involved in the proliferation, survival and migration of oral cell carcinoma.	('oral cell carcinoma', 'Disease', (126, 145))	('Hoxc6', 'Gene', '3223', (31, 36))	('Hoxa10', 'Gene', (41, 47))	('misregulated', 'Var', (4, 16))	('expression', 'MPA', (17, 27))	('involved', 'Reg', (69, 77))	('Hoxa10', 'Gene', '3206', (41, 47))	('survival', 'CPA', (100, 108))	('Hoxc6', 'Gene', (31, 36))	('migration', 'CPA', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('oral cell carcinoma', 'Disease', 'MESH:C538614', (126, 145))
127711	33402862	Disruption of Hoxc6 and Hoxa10 gene expression could enhance tumor progression (Carrera et al., 2015; Tang et al., 2019).	('Hoxa10', 'Gene', (24, 30))	('Hoxa10', 'Gene', '3206', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Hoxc6', 'Gene', (14, 19))	('enhance', 'PosReg', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Hoxc6', 'Gene', '3223', (14, 19))	('tumor', 'Disease', (61, 66))	('Disruption', 'Var', (0, 10))
127715	33402862	The hypermethylation of Meis1 has been identified in adenoid cystic carcinoma samples using the methylated CpG island amplification and microarray methods, but further validation studies are needed (Bell et al., 2011).	('adenoid cystic carcinoma', 'Disease', (53, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (53, 77))	('Meis1', 'Gene', (24, 29))	('hypermethylation', 'Var', (4, 20))
127716	33402862	Hoxa9 hypermethylation was also reported in the promoter methylation analysis of OSCC patient tissues (Guerrero-Preston et al., 2011) and salivary rinses (Schussel et al., 2013), which leads to the growth advantage of the tumor, and an increase in metastasis (Uchida et al., 2014).	('hypermethylation', 'Var', (6, 22))	('metastasis', 'CPA', (248, 258))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('growth advantage', 'CPA', (198, 214))	('OS', 'Phenotype', 'HP:0002669', (81, 83))	('patient', 'Species', '9606', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('increase', 'PosReg', (236, 244))
127717	33402862	Moreover, miR-139-5p inhibits cell proliferation, invasion, and migration by directly targeting Hoxa9 expression (Wang et al., 2017b).	('invasion', 'CPA', (50, 58))	('inhibits', 'NegReg', (21, 29))	('cell proliferation', 'CPA', (30, 48))	('expression', 'MPA', (102, 112))	('Hoxa9', 'Protein', (96, 101))	('targeting', 'Reg', (86, 95))	('migration', 'CPA', (64, 73))	('miR-139-5p', 'Var', (10, 20))	('miR-139-5p', 'Chemical', '-', (10, 20))
127719	33402862	Pbx2 and hypermethylation of Meis1 and HoxA9, however, may be considered prognostic markers of oral cancer.	('Pbx2', 'Gene', '5089', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('HoxA9', 'Gene', (39, 44))	('Meis1', 'Gene', (29, 34))	('hypermethylation', 'Var', (9, 25))	('HoxA9', 'Gene', '3205', (39, 44))	('Pbx2', 'Gene', (0, 4))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
127729	33402862	Similarly, lncRNA HOTAIR transcribed from the Hoxc locus of DNA in uterine cancers leads to cellular proliferation, metastasis, and radiotherapy resistance via the MAPK signaling pathway (Li et al., 2018).	('Hoxc', 'Gene', (46, 50))	('HOTAIR', 'Gene', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cellular proliferation', 'CPA', (92, 114))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('radiotherapy resistance', 'CPA', (132, 155))	('HOTAIR', 'Gene', '100124700', (18, 24))	('cancers', 'Disease', (75, 82))	('leads to', 'Reg', (83, 91))	('Hoxc', 'Gene', '3220', (46, 50))	('uterine cancer', 'Phenotype', 'HP:0010784', (67, 81))	('uterine cancers', 'Phenotype', 'HP:0010784', (67, 82))	('metastasis', 'CPA', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('DNA', 'Gene', (60, 63))	('lncRNA', 'Var', (11, 17))
127741	33402862	In a case with retroperitoneal leiomyoma, it was reported that tumor cells had a t(9;22)(q33;q12) translocation, which resulted in a fusion of Ewsr1 and Pbx3 genes (Panagopoulos et al., 2015).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Pbx3', 'Gene', '5090', (153, 157))	('fusion', 'Var', (133, 139))	('Ewsr1', 'Gene', (143, 148))	('resulted in', 'Reg', (119, 130))	('t(9;22)(q33;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (81, 97))	('retroperitoneal leiomyoma', 'Disease', (15, 40))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Pbx3', 'Gene', (153, 157))	('Ewsr1', 'Gene', '2130', (143, 148))	('retroperitoneal leiomyoma', 'Disease', 'MESH:D007889', (15, 40))
127746	33402862	The aberrantly expressed Hoxa9 in patients with epithelial ovarian cancer has no significant predictive value during first-line platinum-taxane chemotherapy (Pontikakis et al., 2017).	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (48, 73))	('Hoxa9', 'Protein', (25, 30))	('ovarian cancer', 'Phenotype', 'HP:0100615', (59, 73))	('platinum-taxane', 'Chemical', '-', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (34, 42))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (48, 73))	('aberrantly expressed', 'Var', (4, 24))	('epithelial ovarian cancer', 'Disease', (48, 73))
127748	33402862	Although, the methylation analyses of Hoxa9 with large cohorts has shown that Hoxa9 is hypermethylated in both high-grade serous ovarian cancer (Montavon et al., 2012) and primary ovarian cancer patients, (Wu et al., 2007) the association of hypermethylation with the stage, histological types, grade, and ascites could not be established (Xing et al., 2015).	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (122, 143))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('primary ovarian cancer', 'Disease', 'MESH:D016649', (172, 194))	('primary ovarian cancer', 'Disease', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ascites', 'Phenotype', 'HP:0001541', (306, 313))	('ovarian cancer', 'Phenotype', 'HP:0100615', (180, 194))	('Hoxa9', 'Gene', (78, 83))	('patients', 'Species', '9606', (195, 203))	('ascites', 'Disease', (306, 313))	('serous ovarian cancer', 'Disease', (122, 143))	('hypermethylated', 'Var', (87, 102))	('ascites', 'Disease', 'MESH:D001201', (306, 313))
127749	33402862	Interestingly, a study on ovarian cancer cell line and normal tissue showed that DNA methylation of some of the analyzed genes, including Hoxa9, Hoxa10, MiR-34b, Prom1, Cables1, Sparc, and Rsk4, had an inverse correlation with their expression level (Niskakoski et al., 2014).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Sparc', 'Gene', (178, 183))	('Cables1', 'Gene', '91768', (169, 176))	('Rsk4', 'Gene', (189, 193))	('Rsk4', 'Gene', '27330', (189, 193))	('methylation', 'Var', (85, 96))	('Prom1', 'Gene', (162, 167))	('ovarian cancer', 'Disease', 'MESH:D010051', (26, 40))	('MiR-34b', 'Gene', (153, 160))	('MiR-34b', 'Gene', '407041', (153, 160))	('Hoxa10', 'Gene', (145, 151))	('ovarian cancer', 'Disease', (26, 40))	('Hoxa10', 'Gene', '3206', (145, 151))	('Sparc', 'Gene', '6678', (178, 183))	('ovarian cancer', 'Phenotype', 'HP:0100615', (26, 40))	('expression level', 'MPA', (233, 249))	('Prom1', 'Gene', '8842', (162, 167))	('Cables1', 'Gene', (169, 176))	('Hoxa9', 'Gene', (138, 143))
127763	33402862	T3M4, a cellosaurus cell line, is known to have stimulated cell proliferation through the formation of HOXB2-A10-PBX HD heterodimers and associated pancreatic carcinogenesis (Aulisa et al., 2009).	('T3M4', 'Var', (0, 4))	('cell proliferation', 'CPA', (59, 77))	('pancreatic carcinogenesis', 'Disease', (148, 173))	('HOXB2', 'Gene', '3212', (103, 108))	('HOXB2', 'Gene', (103, 108))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (148, 173))	('stimulated', 'PosReg', (48, 58))	('HD', 'Disease', 'MESH:D006816', (117, 119))
127766	33402862	Studies have shown that the expression of mitochondrial genes could be downregulated when Meis1 specific siRNA was transfected into PaC cells (Tomoeda et al., 2011).	('downregulated', 'NegReg', (71, 84))	('PaC', 'Phenotype', 'HP:0006699', (132, 135))	('PaC', 'CellLine', 'CVCL:E280', (132, 135))	('expression', 'MPA', (28, 38))	('PaC', 'Phenotype', 'HP:0002894', (132, 135))	('transfected', 'Var', (115, 126))	('mitochondrial genes', 'Gene', (42, 61))
127767	33402862	In addition, MEIS proteins could contribute to the Warburg effect to facilitate the abnormal growth of cells in the hypoxic tumor microenvironment via transactivation of HIFs and cooperation with HOX proteins.	('men', 'Species', '9606', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('facilitate', 'PosReg', (69, 79))	('transactivation', 'Var', (151, 166))	('hypoxic tumor', 'Disease', (116, 129))	('abnormal growth', 'Phenotype', 'HP:0001507', (84, 99))	('HIFs', 'Disease', (170, 174))	('hypoxic tumor', 'Disease', 'MESH:D009369', (116, 129))	('HIFs', 'Disease', 'None', (170, 174))
127777	33402862	Binding of the HOTTIP to WDR5 induces Hoxa9 expression, which is also a significant factor for PCSCs maintenance (Cheng et al., 2015; Fu et al., 2017).	('PC', 'Phenotype', 'HP:0012125', (95, 97))	('Hoxa9', 'Protein', (38, 43))	('WDR5', 'Gene', '11091', (25, 29))	('HOTTIP', 'Gene', '100316868', (15, 21))	('WDR5', 'Gene', (25, 29))	('Binding', 'Var', (0, 7))	('HOTTIP', 'Gene', (15, 21))	('induces', 'Reg', (30, 37))
127782	33402862	Mutations in Hoxb13 generate a critical risk of developing prostate cancer (PC) (Johng et al., 2019).	('risk', 'Reg', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('Hoxb13', 'Gene', (13, 19))	('Hoxb13', 'Gene', '10481', (13, 19))	('PC', 'Phenotype', 'HP:0012125', (76, 78))	('Mutations', 'Var', (0, 9))	('prostate cancer', 'Disease', (59, 74))
127785	33402862	Depletion of Meis1 and Meis2 in vivo may cause tumor growth and an increase in the expression of protumorigenic genes c-Myc and CD142 (Bhanvadia et al., 2018).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Meis2', 'Gene', (23, 28))	('tumor', 'Disease', (100, 105))	('CD142', 'Gene', '2152', (128, 133))	('c-Myc', 'Gene', '4609', (118, 123))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('increase', 'PosReg', (67, 75))	('c-Myc', 'Gene', (118, 123))	('cause', 'PosReg', (41, 46))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CD142', 'Gene', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (47, 52))	('Meis1', 'Gene', (13, 18))
127814	33402862	In addition, the expression of Meis1/2 is associated with antimetastasis in PC (Bhanvadia et al., 2018).	('associated', 'Reg', (42, 52))	('PC', 'Phenotype', 'HP:0012125', (76, 78))	('antimetastasis', 'Disease', (58, 72))	('Meis1/2', 'Gene', (31, 38))	('expression', 'Var', (17, 27))	('Meis1/2', 'Gene', '150365', (31, 38))
127819	33402862	Sarcoma is genetically complicated as well, such that an increase in mutational burden, complex karyotype, translocation, and amplification could be the genetic basis of the disease (Dancsok et al., 2017).	('amplification', 'MPA', (126, 139))	('translocation', 'Var', (107, 120))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('mutational burden', 'MPA', (69, 86))	('increase', 'PosReg', (57, 65))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
127822	33402862	In addition, in vivo silencing of Meis1 remarkably suppresses xenograft tumor growth (Lin et al., 2019).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Meis1', 'Gene', (34, 39))	('tumor', 'Disease', (72, 77))	('suppresses', 'NegReg', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('silencing', 'Var', (21, 30))
127827	33402862	The vascular invasion, cellular necrosis, and perinephric fat invasion seen in both cases indicated that the Meis1-Ncoa2 fusion gene could be malignant (Argani et al., 2018).	('Ncoa2', 'Gene', (115, 120))	('fusion', 'Var', (121, 127))	('necrosis', 'Disease', (32, 40))	('necrosis', 'Disease', 'MESH:D009336', (32, 40))	('vascular invasion', 'CPA', (4, 21))	('Ncoa2', 'Gene', '10499', (115, 120))
127833	33402862	On the other hand, Hoxa9 expression is upregulated in OS tissues, and the silencing of Hoxa9 recovers the miR-873 downregulation effects.	('miR-873', 'Gene', (106, 113))	('Hoxa9', 'Gene', (19, 24))	('expression', 'MPA', (25, 35))	('upregulated', 'PosReg', (39, 50))	('OS', 'Phenotype', 'HP:0002669', (54, 56))	('recovers', 'NegReg', (93, 101))	('silencing', 'Var', (74, 83))	('miR-873', 'Gene', '100126316', (106, 113))	('downregulation', 'NegReg', (114, 128))	('Hoxa9', 'Gene', (87, 92))
127836	33402862	The silencing of Meis1 in the xenograft model was found to suppress tumor size in sarcoma (Lin et al., 2019).	('tumor', 'Disease', (68, 73))	('Meis1', 'Gene', (17, 22))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sarcoma', 'Disease', (82, 89))	('suppress', 'NegReg', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('silencing', 'Var', (4, 13))
127893	33402862	MEIS1 could trigger cell proliferation in colorectal cancer, while MEIS2 determines the relationship between colorectal cancer growth and death (Wan et al., 2019).	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('cell proliferation', 'CPA', (20, 38))	('MEIS1', 'Var', (0, 5))	('colorectal cancer', 'Disease', (42, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('death', 'Disease', 'MESH:D003643', (138, 143))	('death', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('trigger', 'Reg', (12, 19))
127894	33402862	MEIS2 could increase colorectal dependent cell death (Wang et al., 2019b).	('colorectal dependent cell death', 'Disease', (21, 52))	('MEIS2', 'Var', (0, 5))	('colorectal dependent cell death', 'Disease', 'MESH:D015179', (21, 52))	('increase', 'PosReg', (12, 20))
127900	33402862	The expression of noncoding RNAs has often been found to impair cancer (Di Leva et al., 2014; Hayes et al., 2014; Sanchez Calle et al., 2018).	('noncoding', 'Var', (18, 27))	('RNAs', 'Protein', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (64, 70))	('impair', 'NegReg', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
127915	33402862	lncRNA CASC11, TUG1, PCAT6, LOC730100, and LINK-A have important functions in the proliferation and metastasis of the bladder cancer, laryngocarcinoma, cervical, glioblastoma, and ovarian carcinoma (Li et al., 2019c; Luo et al., 2019; Lv et al., 2019; Zhang et al., 2019; Zhuang et al., 2019).	('laryngocarcinoma', 'Disease', (134, 150))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (180, 197))	('CASC11', 'Gene', (7, 13))	('LOC730100', 'Var', (28, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('metastasis of the bladder cancer', 'Disease', (100, 132))	('TUG1', 'Gene', '55000', (15, 19))	('CASC11', 'Gene', '100270680', (7, 13))	('cervical', 'Disease', (152, 160))	('glioblastoma', 'Disease', (162, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('laryngocarcinoma', 'Disease', 'None', (134, 150))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))	('proliferation', 'CPA', (82, 95))	('metastasis of the bladder cancer', 'Disease', 'MESH:D001749', (100, 132))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (180, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('PCAT6', 'Gene', (21, 26))	('ovarian carcinoma', 'Disease', (180, 197))	('PC', 'Phenotype', 'HP:0012125', (21, 23))	('PCAT6', 'Gene', '100506696', (21, 26))	('TUG1', 'Gene', (15, 19))
127932	33402862	Two small peptides, HXR9 and CXR9, were shown to induce apoptosis in NSCLC cells, breast, ovarian, prostate, and meningioma cells by disrupting the interaction of HOX and PBX (Plowright et al., 2009; Morgan et al., 2010; Morgan et al., 2012; Ando et al., 2014).	('HXR9', 'Var', (20, 24))	('ovarian', 'Disease', 'MESH:D010049', (90, 97))	('meningioma', 'Disease', (113, 123))	('ovarian', 'Disease', (90, 97))	('disrupting', 'NegReg', (133, 143))	('NSCLC', 'Disease', (69, 74))	('HOX', 'Protein', (163, 166))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('interaction', 'Interaction', (148, 159))	('meningioma', 'Phenotype', 'HP:0002858', (113, 123))	('induce', 'PosReg', (49, 55))	('PBX', 'Gene', (171, 174))	('meningioma', 'Disease', 'MESH:D008577', (113, 123))	('apoptosis', 'CPA', (56, 65))	('CXR9', 'Var', (29, 33))
127934	33402862	PHOX2B expression was reported as reduced in neuroblastoma cells as a result of small molecule combination, which included curcumin, SAHA, and trichostatin (Di Zanni et al., 2015).	('reduced', 'NegReg', (34, 41))	('neuroblastoma', 'Phenotype', 'HP:0003006', (45, 58))	('PHOX2B', 'Gene', (0, 6))	('curcumin', 'Chemical', 'MESH:D003474', (123, 131))	('combination', 'Interaction', (95, 106))	('small', 'Var', (80, 85))	('expression', 'MPA', (7, 17))	('PHOX2B', 'Gene', '8929', (0, 6))	('neuroblastoma', 'Disease', 'MESH:D009447', (45, 58))	('trichostatin', 'Chemical', 'MESH:C012589', (143, 155))	('neuroblastoma', 'Disease', (45, 58))
127939	33402862	CCI-006 also impairs mitochondria in the case of CCI-007 and increases apoptosis.	('apoptosis', 'CPA', (71, 80))	('CCI-007', 'Chemical', '-', (49, 56))	('impairs', 'NegReg', (13, 20))	('mitochondria', 'MPA', (21, 33))	('CCI-006', 'Chemical', '-', (0, 7))	('increases', 'PosReg', (61, 70))	('CCI-006', 'Var', (0, 7))	('CCI-007', 'Var', (49, 56))
127958	33402862	Disruption of the MEIS-PBX interaction could also cause caspase-dependent apoptosis in a cell-dependent manner.	('cause', 'Reg', (50, 55))	('interaction', 'Interaction', (27, 38))	('caspase', 'Gene', '841', (56, 63))	('caspase', 'Gene', (56, 63))	('Disruption', 'Var', (0, 10))
127968	33402862	In a number of in vitro studies where MEIS and MEIS partner proteins were targeted indirectly by small molecules or noncoding RNAs, cancer proliferation, spread, metastasis, and invasion could have been suppressed.	('metastasis', 'CPA', (162, 172))	('spread', 'CPA', (154, 160))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('suppressed', 'NegReg', (203, 213))	('invasion', 'CPA', (178, 186))	('small molecules', 'Var', (97, 112))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
127978	32013920	The secondary cancer risk was reduced with FFF both in the treated region and in the periphery.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('FFF', 'Var', (43, 46))	('reduced', 'NegReg', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
127979	32013920	VMAT plans resulted in a higher secondary brain cancer risk than IMRT plans, but the risk for secondary peripheral cancer was reduced.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('brain cancer', 'Disease', 'MESH:D001932', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('VMAT plans', 'Var', (0, 10))	('brain cancer', 'Phenotype', 'HP:0030692', (42, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('brain cancer', 'Disease', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
128001	32013920	TV49.4 Gy is the volume within the PTV which receives at least 49.4 Gy, V49.4 Gy is the volume enclosed by the corresponding isodose within the complete patient contour, and VPTV is the volume of the PTV.	('V49.4 Gy', 'Var', (72, 80))	('TV49.4 Gy', 'Var', (0, 9))	('patient', 'Species', '9606', (153, 160))
128018	32013920	CI is lowest for 2Fd plans, shows all IMRT variants on one level and all VMAT variants again improved on a significantly higher level.	('2Fd', 'Chemical', 'MESH:C498057', (17, 20))	('IMRT', 'Gene', (38, 42))	('variants', 'Var', (43, 51))	('VMAT', 'Gene', (73, 77))	('variants', 'Var', (78, 86))
128023	32013920	The non-coplanar techniques IMRT10 and VMAT2 create a higher risk than the coplanar techniques.	('IMRT10', 'Var', (28, 34))	('VMAT2', 'Gene', '6571', (39, 44))	('VMAT2', 'Gene', (39, 44))
128061	31842516	These results emphasize that, in spite of the heterogeneous mutational burden among different cancers and even within the same tumor, some common hubs do exist.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutational', 'Var', (60, 70))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cancers', 'Disease', (94, 101))
128090	31842516	As expected, point mutations in RAS are not common in breast and prostate cancer.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (54, 80))	('point mutations', 'Var', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('RAS', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
128091	31842516	Interestingly, genetic alterations in HDAC4 are more frequent in uterine and stomach cancers, with a conspicuous incidence of truncations and point mutations of still unknown impact on the activities of this deacetylase (Figure 1).	('activities', 'MPA', (189, 199))	('frequent', 'Reg', (53, 61))	('stomach cancers', 'Disease', 'MESH:D013274', (77, 92))	('stomach cancers', 'Disease', (77, 92))	('truncations', 'MPA', (126, 137))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('genetic alterations', 'Var', (15, 34))	('point mutations', 'Var', (142, 157))	('HDAC4', 'Gene', '9759', (38, 43))	('uterine', 'Disease', (65, 72))	('HDAC4', 'Gene', (38, 43))	('stomach cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
128095	31842516	To prove the above enounced concept, we interrogated the gene expression profiles of BJ-hTERT/ST/LT/MYC, BJ-hTERT/ST/LT/HRASG12V, and BJ-hTERT/ST/LT/HDAC4-S246A, S467A, S632A, relatively to the isogenic pre-transformed control cells, expressing the SV40 LT and ST or the entire early region.	('S246A', 'Mutation', 'p.S246A', (155, 160))	('HDAC4', 'Gene', (149, 154))	('MYC', 'Gene', (100, 103))	('HDAC4', 'Gene', '9759', (149, 154))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (134, 142))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (85, 93))	('S632A', 'Var', (169, 174))	('S632A', 'SUBSTITUTION', 'None', (169, 174))	('MYC', 'Gene', '4609', (100, 103))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (105, 113))	('S467A', 'Var', (162, 167))	('S467A', 'SUBSTITUTION', 'None', (162, 167))
128127	31842516	Finally, SRPX (sushi repeat containing protein X-linked), known also as ETX1 or DRS, was initially isolated as deleted in patients with X-linked retinitis pigmentosa, as well as downregulated by v-src.	('X-linked retinitis pigmentosa', 'Disease', (136, 165))	('retinitis', 'Phenotype', 'HP:0032118', (145, 154))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (145, 165))	('ETX1', 'Gene', '8406', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', '8406', (15, 55))	('SRPX', 'Gene', (9, 13))	('downregulated', 'NegReg', (178, 191))	('DRS', 'Gene', '8406', (80, 83))	('deleted', 'Var', (111, 118))	('patients', 'Species', '9606', (122, 130))	('SRPX', 'Gene', '8406', (9, 13))	('sushi repeat containing protein X-linked', 'Gene', (15, 55))	('ETX1', 'Gene', (72, 76))	('DRS', 'Gene', (80, 83))	('X-linked retinitis pigmentosa', 'Disease', 'MESH:D012174', (136, 165))
128136	31842516	In fact in ACC, which is a rare, aggressive malignancy, G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal disease, amenable to targeted assessment using routine molecular diagnostics.	('ACC', 'Disease', 'MESH:D018268', (11, 14))	('hypermethylation', 'Var', (61, 77))	('ACC', 'Disease', (11, 14))	('G0S2', 'Gene', (56, 60))	('aggressive malignancy', 'Disease', (33, 54))	('aggressive malignancy', 'Disease', 'MESH:D001523', (33, 54))
128137	31842516	Very low levels of G0S2 mRNA expression characterize tumors with G0S2 hypermethylation.	('hypermethylation', 'Var', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('G0S2', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))	('G0S2', 'Protein', (19, 23))
128172	31842516	G0S2 is abundantly expressed in adipose tissue and G0S2 transgenic mice experience difficulties in shifting from carbohydrate to FA oxidation during fasting.	('transgenic mice', 'Species', '10090', (56, 71))	('shifting from carbohydrate to FA oxidation', 'MPA', (99, 141))	('G0S2', 'Gene', (51, 55))	('carbohydrate', 'Chemical', 'MESH:D002241', (113, 125))	('transgenic', 'Var', (56, 66))
128180	31842516	The recent discovery that the targeting of MYC through an epigenetic therapy provides an important advantage for an efficient immunotherapy could represent an important clinical perspective of all these studies.	('advantage', 'PosReg', (99, 108))	('MYC', 'Gene', '4609', (43, 46))	('epigenetic therapy', 'Var', (58, 76))	('MYC', 'Gene', (43, 46))
128191	31842516	In each dataset, the transformation model represented by pre-transformed BJ cells expressing RAS G12V (GSE17941) or MYC (GSE72530) or HDAC4 (GSE120040) was compared to the pre-transformation model which is represented by BJ fibroblasts expressing hTERT, LT, and ST SV40 genes.	('G12V', 'Mutation', 'rs104894230', (97, 101))	('BJ', 'CellLine', 'CVCL:6573', (73, 75))	('BJ', 'CellLine', 'CVCL:6573', (221, 223))	('hTERT', 'Gene', (247, 252))	('MYC', 'Gene', '4609', (116, 119))	('HDAC4', 'Gene', '9759', (134, 139))	('GSE120040', 'Var', (141, 150))	('HDAC4', 'Gene', (134, 139))	('hTERT', 'Gene', '7015', (247, 252))	('GSE17941', 'Var', (103, 111))	('GSE72530', 'Var', (121, 129))	('MYC', 'Gene', (116, 119))
128202	31842516	To evaluate the contribution/disturbance of the inflammatory infiltrate to the prediction of survival based on the transformation signatures, patients were divided into four groups accordingly to the expression levels of genes belonging to the MCPcounter signatures and to the transformation signatures: High-high (high levels of both), high-low (high MCP/low transformation), low-low (low levels of both), or low-high (low MCP-high transformation).	('MCP', 'Gene', (352, 355))	('MCP', 'Gene', (424, 427))	('MCP', 'Gene', '822', (244, 247))	('low-high', 'Var', (410, 418))	('MCP', 'Gene', '822', (352, 355))	('MCP', 'Gene', '822', (424, 427))	('patients', 'Species', '9606', (142, 150))	('MCP', 'Gene', (244, 247))	('low MCP', 'Phenotype', 'HP:0025066', (420, 427))
128204	30563935	Broad spectrum activity of the checkpoint kinase 1 inhibitor prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death.	('tumor cell death', 'Disease', 'MESH:D003643', (326, 342))	('CHK1', 'Gene', (185, 189))	('potentiate', 'PosReg', (202, 212))	('Checkpoint kinase 1', 'Gene', (164, 183))	('inhibitors', 'Var', (191, 201))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('DNA damaging', 'MPA', (217, 229))	('tumor cell death', 'Disease', (326, 342))	('prexasertib', 'Chemical', 'MESH:C000608121', (61, 72))	('tumor', 'Disease', (326, 331))	('checkpoint kinase 1', 'Gene', '1111', (31, 50))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('elevated levels of replication stress', 'MPA', (276, 313))	('promote', 'PosReg', (268, 275))	('checkpoint kinase 1', 'Gene', (31, 50))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('Checkpoint kinase 1', 'Gene', '1111', (164, 183))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
128205	30563935	Prexasertib (LY2606368) is a CHK1 small molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers.	('Prexasertib', 'Chemical', 'MESH:C000608121', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('LY2606368', 'Var', (13, 22))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
128223	30563935	Inhibitors of CHK1 have historically been used to potentiate the DNA damaging effects of chemotherapy or radiation; however, recent clinical and non-clinical studies have demonstrated single agent activity of newer CHK1 inhibitors in both adult and pediatric cancers.	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('DNA damaging', 'MPA', (65, 77))	('cancers', 'Disease', (259, 266))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('inhibitors', 'Var', (220, 230))	('CHK1', 'Gene', (215, 219))
128224	30563935	Prexasertib (LY2606368) is a small molecule inhibitor of CHK1 shown previously to reduce cell viability at nanomolar concentrations across a panel of well-characterized human cancer cell lines representing a wide range of adult and pediatric malignancies.	('CHK1', 'Gene', (57, 61))	('Prexasertib', 'Chemical', 'MESH:C000608121', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('reduce', 'NegReg', (82, 88))	('human', 'Species', '9606', (169, 174))	('malignancies', 'Disease', 'MESH:D009369', (242, 254))	('LY2606368', 'Var', (13, 22))	('cell viability', 'CPA', (89, 103))	('malignancies', 'Disease', (242, 254))
128241	30563935	The following antibodies were purchased from Cell Signaling: CHK1 (cat#2360), CHK1 S296 (cat#90178), CHK1 S345 (cat#234), WEE1 (cat#4936), WEE1 S642 (cat#4910), PARP (cat#9542), AKT (cat#9272), AKT S473 (cat#4060), ERK1/2 (cat#4695), ERK1/2 T202/Y204 (cat#4370), MEK1/2 (cat#4694), MEK1/2 S217/221 (cat#9154), and BCL-xL (cat#2764).	('AKT', 'Gene', '207', (194, 197))	('ERK1/2', 'Gene', (234, 240))	('ERK1/2', 'Gene', '5595;5594', (234, 240))	('cat#9542', 'Var', (167, 175))	('cat#4910', 'Var', (150, 158))	('MEK1/2', 'Gene', '5604;5605', (282, 288))	('MEK1/2', 'Gene', (282, 288))	('PARP', 'Gene', '1302', (161, 165))	('cat#4694', 'Var', (271, 279))	('ERK1/2', 'Gene', (215, 221))	('ERK1/2', 'Gene', '5595;5594', (215, 221))	('AKT', 'Gene', (178, 181))	('cat#4695', 'Var', (223, 231))	('PARP', 'Gene', (161, 165))	('cat#4370', 'Var', (252, 260))	('MEK1/2', 'Gene', '5604;5605', (263, 269))	('cat#4060', 'Var', (204, 212))	('AKT', 'Gene', (194, 197))	('MEK1/2', 'Gene', (263, 269))	('BCL-xL', 'Gene', '598', (314, 320))	('BCL-xL', 'Gene', (314, 320))	('AKT', 'Gene', '207', (178, 181))	('cat#9272', 'Var', (183, 191))
128258	30563935	Prexasertib was given at a reduced dose of 8 mg/kg (BIDx3D, restx4D) when co-administered with the following small molecule inhibitors: pan-RAF inhibitor (LY3074753; 25 mg/kg BIDx21, po), ERK inhibitor (LY3214996; 50 mg/kg BIDx21, po), or PI3K/mTOR inhibitor (LY3023414; 7.5 mg/kg BIDx21, po).	('RAF', 'Gene', (140, 143))	('mTOR', 'Gene', (244, 248))	('Prexasertib', 'Chemical', 'MESH:C000608121', (0, 11))	('LY3074753', 'Chemical', '-', (155, 164))	('LY3214996', 'Chemical', '-', (203, 212))	('LY3023414;', 'Var', (260, 270))	('ERK', 'Gene', '5594', (188, 191))	('LY3214996;', 'Var', (203, 213))	('LY3074753;', 'Var', (155, 165))	('LY3023414', 'Chemical', 'MESH:C000621566', (260, 269))	('ERK', 'Gene', (188, 191))	('RAF', 'Gene', '22882', (140, 143))	('mTOR', 'Gene', '2475', (244, 248))
128271	30563935	Prexasertib also led to the activation of DNA damage response machinery responsible for double-strand break repair as measured by phosphorylation of CHK1 at S345 and of DNA damage sensors ataxia telangiectasia mutated (ATM) and DNA protein kinase (DNA-PK) at serine 1981 (S1981) and serine 2056 (S2056), respectively (Fig.	('S2056', 'Var', (296, 301))	('ATM', 'Gene', '472', (219, 222))	('Prexasertib', 'Chemical', 'MESH:C000608121', (0, 11))	('ataxia', 'Phenotype', 'HP:0001251', (188, 194))	('DNA protein kinase', 'Gene', (228, 246))	('S1981', 'Var', (272, 277))	('DNA-PK', 'Gene', (248, 254))	('DNA protein kinase', 'Gene', '5591', (228, 246))	('S2056', 'CellLine', 'CVCL:K818', (296, 301))	('damage sensors ataxia telangiectasia', 'Disease', (173, 209))	('serine', 'Chemical', 'MESH:D012694', (259, 265))	('activation', 'PosReg', (28, 38))	('ATM', 'Gene', (219, 222))	('CHK1', 'Gene', (149, 153))	('DNA-PK', 'Gene', '5591', (248, 254))	('damage sensors ataxia telangiectasia', 'Disease', 'MESH:D001260', (173, 209))	('telangiectasia', 'Phenotype', 'HP:0001009', (195, 209))	('serine', 'Chemical', 'MESH:D012694', (283, 289))
128276	30563935	As observed previously, neuroblastoma PDX models were sensitive to prexasertib, with 50% of the models responding with stable disease (COG-N-421x, NB-1643x, and NB-SDx) and the other three models demonstrating partial regression (COG-N-453x, COG-N-Felix-x, and NB-EBc1-x) (Fig.	('NB-1643x', 'Var', (147, 155))	('neuroblastoma', 'Phenotype', 'HP:0003006', (24, 37))	('neuroblastoma PDX', 'Disease', 'MESH:D009447', (24, 41))	('stable disease', 'Disease', (119, 133))	('COG-N-453x', 'Var', (230, 240))	('prexasertib', 'Chemical', 'MESH:C000608121', (67, 78))	('COG-N-421x', 'Var', (135, 145))	('responding', 'Reg', (103, 113))	('neuroblastoma PDX', 'Disease', (24, 41))
128286	30563935	However, prexasertib co-treatment with an inhibitor of RAF (LY3074753), ERK (LY3214996), or PI3K/mTOR (LY3023414) did not prevent the emergence of resistance to prexasertib in the SJCRH30 model (Supplementary Fig.	('prexasertib', 'Chemical', 'MESH:C000608121', (161, 172))	('ERK', 'Gene', (72, 75))	('LY3074753', 'Var', (60, 69))	('RAF', 'Gene', '22882', (55, 58))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('RAF', 'Gene', (55, 58))	('prexasertib', 'Chemical', 'MESH:C000608121', (9, 20))	('ERK', 'Gene', '5594', (72, 75))	('LY3074753', 'Chemical', '-', (60, 69))	('LY3214996', 'Chemical', '-', (77, 86))	('resistance', 'MPA', (147, 157))	('LY3214996', 'Var', (77, 86))	('LY3023414', 'Chemical', 'MESH:C000621566', (103, 112))	('LY3023414', 'Var', (103, 112))
128321	30563935	In this study, we report that prexasertib (LY2606368), a second-generation CHK1 inhibitor, is active as a monotherapy or in combination with chemotherapy across a range of preclinical pediatric cancer models.	('cancer', 'Disease', (194, 200))	('LY2606368', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('prexasertib', 'Chemical', 'MESH:C000608121', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
128326	30563935	CHK1 inhibition exacerbates RS by allowing increased and/or unscheduled replication origin firing as well as a delay or loss of DNA repair.	('inhibition', 'Var', (5, 15))	('CHK1', 'Gene', (0, 4))	('exacerbates', 'PosReg', (16, 27))	('RS', 'Chemical', '-', (28, 30))	('DNA repair', 'CPA', (128, 138))	('loss', 'NegReg', (120, 124))
128327	30563935	Though most pediatric cancers have a lower mutational burden (and therefore fewer targets available for therapeutic intervention) than adult malignancies, known drivers of some childhood tumors, such as chimeric transcription factors, can trigger RS and may promote tumor cell sensitivity to CHK1 inhibition.	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('RS', 'Chemical', '-', (247, 249))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', (266, 271))	('chimeric', 'Var', (203, 211))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancers', 'Disease', (22, 29))	('malignancies', 'Disease', 'MESH:D009369', (141, 153))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('malignancies', 'Disease', (141, 153))	('trigger', 'Reg', (239, 246))	('promote', 'PosReg', (258, 265))	('tumors', 'Disease', 'MESH:D009369', (187, 193))
128335	30563935	MYCN amplification, observed in approximately 20% of neuroblastoma (and 50% of high-risk cases), is associated with poor patient prognosis; in addition, MYCN-amplified/high-risk primary tumors expressed higher levels of CHK1 mRNA than non-MYCN-amplified/low-risk tumors.	('neuroblastoma', 'Disease', 'MESH:D009447', (53, 66))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('CHK1', 'Protein', (220, 224))	('higher', 'PosReg', (203, 209))	('neuroblastoma', 'Disease', (53, 66))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('neuroblastoma', 'Phenotype', 'HP:0003006', (53, 66))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (263, 269))	('patient', 'Species', '9606', (121, 128))	('MYCN-amplified/high-risk', 'Var', (153, 177))
128336	30563935	siRNA-mediated CHK1 knockdown was cytotoxic in a panel of neuroblastoma cell lines and preclinical neuroblastoma mouse models were highly sensitive to single agent prexasertib; however, these results were not dependent on MYCN status.	('neuroblastoma', 'Phenotype', 'HP:0003006', (99, 112))	('mouse', 'Species', '10090', (113, 118))	('neuroblastoma', 'Phenotype', 'HP:0003006', (58, 71))	('neuroblastoma', 'Disease', 'MESH:D009447', (99, 112))	('neuroblastoma', 'Disease', (99, 112))	('neuroblastoma', 'Disease', 'MESH:D009447', (58, 71))	('knockdown', 'Var', (20, 29))	('CHK1', 'Gene', (15, 19))	('neuroblastoma', 'Disease', (58, 71))	('prexasertib', 'Chemical', 'MESH:C000608121', (164, 175))
128339	30563935	Acquired prexasertib resistance observed in two aRMS mouse models following the initial dosing period may have resulted from either a new mutation or other novel alterations which rendered tumor cells resistant to subsequent CHK1 inhibition, or the selection of a pre-existing resistant population.	('tumor', 'Disease', (189, 194))	('resulted from', 'Reg', (111, 124))	('alterations', 'Var', (162, 173))	('resistant', 'MPA', (201, 210))	('mutation', 'Var', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mouse', 'Species', '10090', (53, 58))	('prexasertib', 'Chemical', 'MESH:C000608121', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
128341	30563935	Increased ERK1/2 phosphorylation in response to CHK1 inhibition has been reported in several cancer cell lines; furthermore, concurrent administration of the CHK1 inhibitor AZD7762 and selumetinib (AZD6244, a MEK1/2 inhibitor) in vitro promoted apoptosis in multiple myeloma cells, but not normal bone marrow cells.	('selumetinib', 'Chemical', 'MESH:C517975', (185, 196))	('MEK1/2', 'Gene', (209, 215))	('ERK1/2', 'Gene', (10, 16))	('AZD7762', 'Var', (173, 180))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('AZD7762', 'Chemical', 'MESH:C532363', (173, 180))	('multiple myeloma', 'Phenotype', 'HP:0006775', (258, 274))	('promoted', 'PosReg', (236, 244))	('phosphorylation', 'MPA', (17, 32))	('CHK1', 'Gene', (158, 162))	('myeloma', 'Disease', (267, 274))	('ERK1/2', 'Gene', '5595;5594', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('AZD6244', 'Chemical', 'MESH:C517975', (198, 205))	('MEK1/2', 'Gene', '5604;5605', (209, 215))	('myeloma', 'Disease', 'MESH:D009101', (267, 274))	('apoptosis', 'CPA', (245, 254))
128345	30563935	Other studies have demonstrated that CHK1 inhibitors sensitize pediatric tumor cells and xenograft models (including Ewing's sarcoma and neuroblastoma) to gemcitabine, a ribonucleotide reductase inhibitor.	('CHK1', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (117, 132))	("Ewing's sarcoma", 'Disease', (117, 132))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('neuroblastoma', 'Disease', 'MESH:D009447', (137, 150))	('gemcitabine', 'Chemical', 'MESH:C056507', (155, 166))	('sensitize', 'Reg', (53, 62))	('tumor', 'Disease', (73, 78))	('neuroblastoma', 'Disease', (137, 150))	('inhibitors', 'Var', (42, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('neuroblastoma', 'Phenotype', 'HP:0003006', (137, 150))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (117, 132))
128348	30563935	In addition, co-targeting CHK1 and its downstream effector WEE1 in cell lines and xenografts from genetically engineered mouse models of neuroblastoma resulted in increased double-strand DNA breaks and cell death through mitotic catastrophe and significant tumor growth delay, respectively.	('CHK1', 'Gene', (26, 30))	('mitotic catastrophe', 'CPA', (221, 240))	('tumor growth delay', 'Disease', (257, 275))	('co-targeting', 'Var', (13, 25))	('increased', 'PosReg', (163, 172))	('neuroblastoma', 'Disease', 'MESH:D009447', (137, 150))	('mouse', 'Species', '10090', (121, 126))	('cell death', 'CPA', (202, 212))	('neuroblastoma', 'Disease', (137, 150))	('tumor growth delay', 'Disease', 'MESH:D006130', (257, 275))	('double-strand DNA breaks', 'MPA', (173, 197))	('neuroblastoma', 'Phenotype', 'HP:0003006', (137, 150))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('growth delay', 'Phenotype', 'HP:0001510', (263, 275))
128349	30563935	Additional studies have also reported synergism between inhibitors of CHK1 and WEE1, ATR, or PARP in preclinical models of different tumor types.	('ATR', 'Gene', '545', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('ATR', 'Gene', (85, 88))	('PARP', 'Gene', '1302', (93, 97))	('synergism', 'MPA', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CHK1', 'Gene', (70, 74))	('inhibitors', 'Var', (56, 66))	('tumor', 'Disease', (133, 138))	('PARP', 'Gene', (93, 97))	('WEE1', 'Gene', (79, 83))
128355	30563935	Similarly, gemcitabine given approximately 24h prior to administration of the first-generation CHK1 inhibitor LY2603618 promoted superior combination effects in several xenografts of adult carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('carcinomas', 'Disease', (189, 199))	('gemcitabine', 'Chemical', 'MESH:C056507', (11, 22))	('combination effects', 'MPA', (138, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('LY2603618', 'Chemical', 'MESH:C582547', (110, 119))	('LY2603618', 'Var', (110, 119))	('carcinomas', 'Disease', 'MESH:D009369', (189, 199))
128361	30563935	Moreover, two phase II clinical trials are focused on evaluating prexasertib monotherapy in adult tumors that exhibit increased levels of RS or deficiencies in DNA repair (NCT02873975, NCT02203513), demonstrating the potential clinical utility of identifying and validating drivers of RS for pediatric cancers.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NCT02873975', 'Var', (172, 183))	('deficiencies', 'Var', (144, 156))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('prexasertib', 'Chemical', 'MESH:C000608121', (65, 76))	('NCT02203513', 'Var', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('RS', 'Chemical', '-', (285, 287))	('RS', 'Chemical', '-', (138, 140))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('cancers', 'Disease', 'MESH:D009369', (302, 309))	('cancers', 'Disease', (302, 309))
128364	30563935	Prexasertib (LY2606368) is a small molecule inhibitor of checkpoint kinase 1 (CHK1) currently in Phase I and II clinical trials as a single agent and in combination with chemotherapy in adult patients with advanced cancers.	('Prexasertib', 'Chemical', 'MESH:C000608121', (0, 11))	('checkpoint kinase 1', 'Gene', (57, 76))	('checkpoint kinase 1', 'Gene', '1111', (57, 76))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('patients', 'Species', '9606', (192, 200))	('cancers', 'Disease', (215, 222))	('LY2606368', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('CHK1', 'Gene', (78, 82))
128367	30563935	These data further support the ongoing clinical investigation of prexasertib in pediatric patients with recurrent or refractory solid tumors (NCT02808650) and nominates future combinatorial therapeutic strategies.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('prexasertib', 'Chemical', 'MESH:C000608121', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('NCT02808650', 'Var', (142, 153))	('patients', 'Species', '9606', (90, 98))
128380	30766860	in their study of 62 patients showed T2 lesions, presence of lymph node metastasis, advanced stage and invasion to adjacent bone, nerves were associated with decreased survival.	('T2 lesions', 'Var', (37, 47))	('decreased', 'NegReg', (158, 167))	('lymph node metastasis', 'CPA', (61, 82))	('survival', 'MPA', (168, 176))	('patients', 'Species', '9606', (21, 29))	('invasion', 'CPA', (103, 111))
128453	30386721	The cytogenetic hallmark of synovial sarcoma is the t (X; 18)(p11; q11) chromosomal translocation, leading to the rearrangement of the SS18 and one of the SSX genes.	('synovial sarcoma', 'Disease', 'MESH:D013584', (28, 44))	('p11', 'Gene', (62, 65))	('SS18', 'Gene', (135, 139))	('SSX genes', 'Gene', (155, 164))	('synovial sarcoma', 'Disease', (28, 44))	('SS18', 'Gene', '6760', (135, 139))	('p11', 'Gene', '6281', (62, 65))	('rearrangement', 'Var', (114, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('t (X', 'Var', (52, 56))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (28, 44))
128455	30386721	Poor prognostic factors include a >5 cm tumor, higher grade, male sex, older age, neurovascular invasion, and the SYT-SSX1 variant on cytogenetic studies.	('neurovascular invasion', 'Disease', 'MESH:D013901', (82, 104))	('SYT-SSX1', 'Gene', (114, 122))	('SYT-SSX1', 'Gene', '6760;6756', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('neurovascular invasion', 'Disease', (82, 104))	('variant', 'Var', (123, 130))	('higher grade', 'CPA', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
128467	33640895	CIC-DUX4 sarcoma, the most common type of CIC-rearranged sarcoma (CRS), has been described as an aggressive soft-tissue tumor associated with CIC-DUX4 fusion that results in either a t(4;19)(q35;q13) or t(10;19)(q26;q13) translocation.	('results in', 'Reg', (163, 173))	('CIC', 'Gene', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('CIC', 'Gene', '23152', (42, 45))	('CIC-DUX4 sarcoma', 'Disease', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('associated', 'Reg', (126, 136))	('CIC-rearranged sarcoma', 'Disease', (42, 64))	('CIC', 'Gene', '23152', (0, 3))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (203, 220))	('CIC', 'Gene', '23152', (142, 145))	('tumor', 'Disease', (120, 125))	('DUX4', 'Gene', (4, 8))	('DUX4', 'Gene', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('t(4;19)(q35;q13', 'Var', (183, 198))	('CIC-rearranged sarcoma', 'Disease', 'MESH:D012509', (42, 64))	('CIC-DUX4 sarcoma', 'Disease', 'MESH:D012509', (0, 16))	('CIC', 'Gene', (42, 45))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (183, 199))	('CRS', 'Chemical', '-', (66, 69))	('fusion', 'Var', (151, 157))	('DUX4', 'Gene', '100288687', (4, 8))	('DUX4', 'Gene', '100288687', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('soft-tissue tumor', 'Phenotype', 'HP:0031459', (108, 125))	('CIC', 'Gene', (0, 3))
128662	32352245	Copy number profiling identified amplification of the 12q15 region involving the MDM2 locus in all five HGESS-BCOR.	('amplification', 'Var', (33, 46))	('MDM2', 'Gene', '4193', (81, 85))	('MDM2', 'Gene', (81, 85))	('HGESS-BCOR', 'Gene', '54880', (104, 114))	('HGESS-BCOR', 'Gene', (104, 114))
128663	32352245	Subsequent validation analyses of three tumors confirmed MDM2 amplification using MDM2 FISH.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('MDM2', 'Gene', '4193', (57, 61))	('MDM2', 'Gene', '4193', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('MDM2', 'Gene', (57, 61))	('MDM2', 'Gene', (82, 86))	('amplification', 'Var', (62, 75))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
128665	32352245	None of the other uterine neoplasms in our series, including tumors that are in the histopathological differential diagnoses of HGESS-BCOR, showed copy number gains of MDM2.	('neoplasm', 'Phenotype', 'HP:0002664', (26, 34))	('copy number gains', 'Var', (147, 164))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('uterine neoplasms', 'Phenotype', 'HP:0010784', (18, 35))	('neoplasms', 'Phenotype', 'HP:0002664', (26, 35))	('HGESS-BCOR', 'Gene', '54880', (128, 138))	('HGESS-BCOR', 'Gene', (128, 138))	('MDM2', 'Gene', '4193', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MDM2', 'Gene', (168, 172))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('neoplasms', 'Disease', 'MESH:D009369', (26, 35))	('neoplasms', 'Disease', (26, 35))
128666	32352245	Together, our results indicate that HGESS-BCOR carries MDM2 amplifications, which has diagnostic implications and could potentially be used for targeted therapies in these clinically aggressive tumors.	('aggressive tumors', 'Disease', 'MESH:D001523', (183, 200))	('amplifications', 'Var', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('aggressive tumors', 'Disease', (183, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('MDM2', 'Gene', '4193', (55, 59))	('MDM2', 'Gene', (55, 59))	('HGESS-BCOR', 'Gene', '54880', (36, 46))	('HGESS-BCOR', 'Gene', (36, 46))
128669	32352245	While ESN and LGESS histologically resemble stromal cells of the proliferating endometrium and harbor recurrent chromosomal translocations most frequently associated with a JAZF1-SUZ12 gene fusion, UUS comprises endometrial and myometrial sarcomas which lack specific mesenchymal differentiation and are molecularly heterogenous [3, 4].	('JAZF1', 'Gene', (173, 178))	('proliferating endometrium', 'Phenotype', 'HP:0040298', (65, 90))	('SUZ12', 'Gene', (179, 184))	('associated', 'Reg', (155, 165))	('JAZF1', 'Gene', '221895', (173, 178))	('myometrial sarcomas', 'Disease', (228, 247))	('myometrial sarcomas', 'Disease', 'MESH:D012509', (228, 247))	('sarcomas', 'Phenotype', 'HP:0100242', (239, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('fusion', 'Var', (190, 196))	('SUZ12', 'Gene', '23512', (179, 184))
128672	32352245	Recently, a rare subtype of ESS with high-grade features and BCOR alterations, caused by either a gene fusion between BCOR and ZC3H7B or a mutually exclusive somatic internal tandem duplication (ITD) of exon 15 of BCOR, has been described (HGESS-BCOR) [7, 8].	('alterations', 'Var', (66, 77))	('gene fusion', 'Var', (98, 109))	('ZC3H7B', 'Gene', (127, 133))	('HGESS-BCOR', 'Gene', '54880', (240, 250))	('BCOR', 'Gene', (118, 122))	('BCOR', 'Gene', (214, 218))	('BCOR', 'Gene', '54880', (118, 122))	('BCOR', 'Gene', (246, 250))	('internal tandem duplication', 'Var', (166, 193))	('HGESS-BCOR', 'Gene', (240, 250))	('BCOR', 'Gene', '54880', (214, 218))	('BCOR', 'Gene', (61, 65))	('BCOR', 'Gene', '54880', (246, 250))	('ZC3H7B', 'Gene', '23264', (127, 133))	('caused by', 'Reg', (79, 88))	('BCOR', 'Gene', '54880', (61, 65))	('ESS', 'Disease', (28, 31))
128673	32352245	Although such BCOR alterations may well be the molecular driver in these tumors, little is known about their biology, or about potential cooperative and co-occurring genetic events.	('BCOR', 'Gene', '54880', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('alterations', 'Var', (19, 30))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('BCOR', 'Gene', (14, 18))
128674	32352245	We recently identified a case of HGESS-BCOR that carried an amplification of the 12q15 region involving the MDM2 locus.	('amplification', 'Var', (60, 73))	('HGESS-BCOR', 'Gene', '54880', (33, 43))	('MDM2', 'Gene', '4193', (108, 112))	('HGESS-BCOR', 'Gene', (33, 43))	('MDM2', 'Gene', (108, 112))
128690	32352245	In case 3, the fusion detection algorithm identified a rearrangement between BCOR and the LPP gene, including RNA reads spanning parts of both genes.	('BCOR', 'Gene', '54880', (77, 81))	('LPP gene', 'Gene', (90, 98))	('BCOR', 'Gene', (77, 81))	('rearrangement', 'Var', (55, 68))
128692	32352245	Thus, while RNA-seq data support the presence of a BCOR alteration, the precise functional consequences of this aberration remain unclear.	('BCOR', 'Gene', (51, 55))	('BCOR', 'Gene', '54880', (51, 55))	('alteration', 'Var', (56, 66))
128696	32352245	FISH and IHC confirmed the amplification of MDM2 and overexpression (Figure 2B) of MDM2 in all three tumors.	('MDM2', 'Gene', '4193', (44, 48))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('MDM2', 'Gene', (44, 48))	('overexpression', 'PosReg', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('MDM2', 'Gene', '4193', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('MDM2', 'Gene', (83, 87))	('amplification', 'Var', (27, 40))	('tumors', 'Disease', (101, 107))
128698	32352245	In addition to an MDM2 amplification, copy number analyses also revealed amplification of CDK4 in three tumors (cases 1-3) and a deletion of CDKN2A in one tumor (case 5).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('CDKN2A', 'Gene', '1029', (141, 147))	('CDK4', 'Gene', '1019', (90, 94))	('CDK4', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('deletion', 'Var', (129, 137))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('MDM2', 'Gene', '4193', (18, 22))	('amplification', 'MPA', (73, 86))	('MDM2', 'Gene', (18, 22))	('CDKN2A', 'Gene', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
128700	32352245	None of these cases carried an amplification of the 12q15 region involving the MDM2 locus (Table 2).	('MDM2', 'Gene', '4193', (79, 83))	('amplification', 'Var', (31, 44))	('MDM2', 'Gene', (79, 83))
128701	32352245	HGESS-BCOR represents a new subtype in the spectrum of EST, defined by genetic alterations involving BCOR.	('alterations', 'Var', (79, 90))	('BCOR', 'Gene', '54880', (6, 10))	('BCOR', 'Gene', (101, 105))	('HGESS-BCOR', 'Gene', '54880', (0, 10))	('HGESS-BCOR', 'Gene', (0, 10))	('BCOR', 'Gene', '54880', (101, 105))	('BCOR', 'Gene', (6, 10))
128702	32352245	ESS with BCOR alteration show a greater degree of atypia when compared to LGESS, and available clinical data suggest an aggressive clinical course similar to that of classical HGESS [13].	('alteration', 'Var', (14, 24))	('BCOR', 'Gene', (9, 13))	('BCOR', 'Gene', '54880', (9, 13))
128705	32352245	In the current study, we show HGESS-BCOR to harbor MDM2 amplifications, while all HGESS with YWHAE-NUTM2 gene fusion in our series were MDM2-balanced.	('MDM2', 'Gene', '4193', (136, 140))	('MDM2', 'Gene', (136, 140))	('YWHAE', 'Gene', (93, 98))	('MDM2', 'Gene', '4193', (51, 55))	('MDM2', 'Gene', (51, 55))	('amplifications', 'Var', (56, 70))	('HGESS-BCOR', 'Gene', '54880', (30, 40))	('HGESS-BCOR', 'Gene', (30, 40))	('YWHAE', 'Gene', '7531', (93, 98))
128708	32352245	Mechanistically, MDM2 overexpression functions as a powerful oncogene by negatively regulating TP53 transcriptional activity and therefore has been suggested as a druggable target for small molecule inhibitors [15].	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))	('negatively regulating', 'NegReg', (73, 94))	('overexpression', 'Var', (22, 36))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
128710	32352245	In line with this staining pattern, additional DNA sequencing did not identify pathogenic TP53 mutations in any HGESS-BCOR of our series (n = 5; data not shown).	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('HGESS-BCOR', 'Gene', '54880', (112, 122))	('mutations', 'Var', (95, 104))	('HGESS-BCOR', 'Gene', (112, 122))
128711	32352245	Thus, detecting MDM2 amplification in HGESS-BCOR might have clinical implications in affected patients.	('MDM2', 'Gene', '4193', (16, 20))	('patients', 'Species', '9606', (94, 102))	('HGESS-BCOR', 'Gene', '54880', (38, 48))	('MDM2', 'Gene', (16, 20))	('HGESS-BCOR', 'Gene', (38, 48))	('amplification', 'Var', (21, 34))
128715	32352245	Schoolmeester et al reported MDM2 amplification in two of 43 (5%) tumors, both of which showed an adverse clinical course.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('MDM2', 'Gene', '4193', (29, 33))	('MDM2', 'Gene', (29, 33))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('amplification', 'Var', (34, 47))
128717	32352245	The second tumor harboring a MDM2 amplification had high-grade morphology, polysomy of JAZF1, PHF1, and YWHAE but no rearrangements were reported, leading to a diagnosis of UUS.	('MDM2', 'Gene', '4193', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('MDM2', 'Gene', (29, 33))	('YWHAE', 'Gene', '7531', (104, 109))	('JAZF1', 'Gene', '221895', (87, 92))	('PHF1', 'Gene', '5252', (94, 98))	('tumor', 'Disease', (11, 16))	('PHF1', 'Gene', (94, 98))	('YWHAE', 'Gene', (104, 109))	('JAZF1', 'Gene', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('amplification', 'Var', (34, 47))	('leading to', 'Reg', (147, 157))	('polysomy', 'Var', (75, 83))	('UUS', 'Disease', (173, 176))
128719	32352245	Interestingly, a recent study suggests that UUS often represents under-recognized HGESS including tumors with BCOR alteration [18].	('UUS', 'Disease', (44, 47))	('BCOR', 'Gene', (110, 114))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('BCOR', 'Gene', '54880', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('alteration', 'Var', (115, 125))
128722	32352245	While MDM2 amplification in such tumors usually supports a diagnosis of dedifferentiated liposarcoma, HGESS-BCOR should also be considered in the differential diagnoses in such cases [19].	('dedifferentiated liposarcoma', 'Disease', (72, 100))	('HGESS-BCOR', 'Gene', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('MDM2', 'Gene', '4193', (6, 10))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('MDM2', 'Gene', (6, 10))	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (72, 100))	('liposarcoma', 'Phenotype', 'HP:0012034', (89, 100))	('tumors', 'Disease', (33, 39))	('amplification', 'Var', (11, 24))	('HGESS-BCOR', 'Gene', '54880', (102, 112))
128723	32352245	Notably, MDM2 positivity by immunohistochemistry has been reported in cases of uterine leiomyosarcoma and primary liposarcoma of the uterus [20, 21].	('MDM2', 'Gene', '4193', (9, 13))	('MDM2', 'Gene', (9, 13))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (87, 101))	('MDM2 positivity', 'Phenotype', 'HP:0031907', (9, 24))	('liposarcoma', 'Phenotype', 'HP:0012034', (114, 125))	('reported', 'Reg', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('liposarcoma of the uterus', 'Disease', (114, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('positivity', 'Var', (14, 24))	('leiomyosarcoma', 'Disease', (87, 101))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (79, 101))	('liposarcoma of the uterus', 'Disease', 'MESH:D008080', (114, 139))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (87, 101))
128725	32352245	As a limitation of our study, it is important to mention that our study cohort did not include cases of Mullerian adenosarcoma, a lesion known to harbor MDM2 amplifications in up to 28% of cases [22].	('MDM2', 'Gene', (153, 157))	('amplifications', 'Var', (158, 172))	('adenosarcoma', 'Disease', (114, 126))	('adenosarcoma', 'Disease', 'MESH:D018195', (114, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('MDM2', 'Gene', '4193', (153, 157))
128798	25918607	With regard to molecular pathology, PNETs are characterized by the translocation t(11;22) (q24;q12) with the fusion transcript of the EWS gene (22q12) and the ETS-associated oncogene FLI 1 (11q24).	('PNETs', 'Disease', (36, 41))	('PNET', 'Phenotype', 'HP:0030065', (36, 40))	('22q12', 'Var', (144, 149))	('EWS', 'Gene', '2130', (134, 137))	('EWS', 'Gene', (134, 137))
128884	29333190	Gains of chromosome 13 are a commonly reported finding in embryonal type RMS.	('RMS', 'Phenotype', 'HP:0002859', (73, 76))	('embryonal type RMS', 'Disease', (58, 76))	('Gains', 'Var', (0, 5))	('embryonal type RMS', 'Disease', 'MESH:D009373', (58, 76))
128906	29333190	EWSR1-FLI1 or EWSR1-ERG fusions or EWSR1 rearrangements are characteristic of these tumors.	('FLI1', 'Gene', (6, 10))	('FLI1', 'Gene', '2313', (6, 10))	('EWSR1', 'Gene', '2130', (0, 5))	('EWSR1', 'Gene', (35, 40))	('rearrangements', 'Var', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('EWSR1', 'Gene', '2130', (14, 19))	('EWSR1', 'Gene', '2130', (35, 40))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('EWSR1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('EWSR1', 'Gene', (14, 19))
128911	29333190	It is the specific rearrangement of 13q14 FOXO1 as either t(2;13)(q35;q14) PAX3/FOXO1 or t(1;13)(p36;q14) PAX7/FOXO1 that is detected by FISH in embryonal RMS.	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (89, 105))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (58, 74))	('t(2;13)(q35;q14', 'Var', (58, 73))	('t(1;13)(p36;q14', 'Var', (89, 104))	('RMS', 'Phenotype', 'HP:0002859', (155, 158))	('FOXO1', 'Gene', (42, 47))	('FOXO1', 'Gene', '2308', (42, 47))	('FOXO1', 'Gene', '2308', (80, 85))	('FOXO1', 'Gene', '2308', (111, 116))	('FOXO1', 'Gene', (80, 85))	('FOXO1', 'Gene', (111, 116))
128934	27383540	Consider three time-to-event outcomes for patient i denoted by , where T1ij is the time from surgical resection of the tumor to the jth local recurrence for the ith patient, T2ij' is the time from surgical resection of the tumor to the j'th distant recurrence, and T3i is survival time, which is defined as the time from surgical resection of the tumor to death or last follow-up.	('tumor', 'Disease', (119, 124))	("T2ij'", 'Var', (174, 179))	('tumor', 'Disease', (223, 228))	('death', 'Disease', 'MESH:D003643', (356, 361))	('T1ij', 'Var', (71, 75))	('tumor', 'Disease', (347, 352))	('death', 'Disease', (356, 361))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('patient', 'Species', '9606', (165, 172))	('patient', 'Species', '9606', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))
128940	27383540	Based on Model (1), the likelihood function for individual i may be expressed as  where , and  are survival functions of local recurrence, distant recurrence and death respectively with deltai denoting whether t3i is an observed death time (deltai = 1) or last follow-up (deltai = 0).	('deltai', 'Var', (186, 192))	('death', 'Disease', 'MESH:D003643', (162, 167))	('death', 'Disease', (162, 167))	('death', 'Disease', 'MESH:D003643', (229, 234))	('death', 'Disease', (229, 234))
128956	27383540	The procedures of the simulation study are summarized as follows:  We simulated 1,000 data sets from the multivariate joint frailty model for local, distant recurrences and survival with two scenarios (1) sigma1 = sigma2 = 0.25, rho = 0.60, alpha1 = alpha2 = 0.5 and (2) sigma1 = sigma2 = 0.50, rho = 0.80, alpha1 = alpha2 = 2.0, respectively.	('alpha1', 'Gene', (241, 247))	('sigma1 = sigma2 = 0.50', 'Var', (271, 293))	('alpha1', 'Gene', (307, 313))	('alpha1', 'Gene', '146', (241, 247))	('alpha1', 'Gene', '146', (307, 313))	('sigma1 = sigma2', 'Var', (205, 220))
128976	27383540	The details of implementing the hybrid algorithm are presented in Appendix C. High posterior correlations could cause the Markov chain to get stuck at a state for several iterations and thus the MCMC algorithm will mix slowly.	('High', 'Var', (78, 82))	('cause', 'Reg', (112, 117))	('MCMC', 'Chemical', '-', (195, 199))
129016	25889422	Interestingly, pseudotumors associated with osteolysis and periprosthetic bone loss are now being increasingly reported in patients with polyethylene-on-metal (POM) hip replacement.	('osteolysis', 'Disease', 'MESH:D010014', (44, 54))	('polyethylene-on-metal', 'Chemical', '-', (137, 158))	('tumors', 'Disease', (21, 27))	('osteolysis', 'Disease', (44, 54))	('patients', 'Species', '9606', (123, 131))	('polyethylene-on-metal', 'Var', (137, 158))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('bone loss', 'Phenotype', 'HP:0002797', (74, 83))	('bone loss', 'Disease', (74, 83))	('bone loss', 'Disease', 'MESH:D016301', (74, 83))	('osteolysis', 'Phenotype', 'HP:0002797', (44, 54))
129097	25085344	Outside of tumor biology, extent of resection (R0 vs. R1/R2) is the most important predictor of survival, with incomplete resection conferring a 70% greater risk of death.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('R1/R2', 'Gene', '910;6241', (54, 59))	('incomplete', 'Var', (111, 121))	('R1/R2', 'Gene', (54, 59))	('death', 'Disease', 'MESH:D003643', (165, 170))	('death', 'Disease', (165, 170))
129101	25085344	Patients were identified as having undergoing resection of a retroperitoneal sarcoma first by querying all patients with International Classification of Diseases Ninth Revision (ICD-9) code 158.0 (primary malignancy of the retroperitoneum), and then filtering by Current Procedural Terminology (CPT) code: 49200/49201 (excision or destruction, open, intra-abdominal or retroperitoneal tumors or cysts or endometriomas), 49203/49204/49205 (excision or destruction, open, intra-abdominal tumors, cysts, or endometriomas, 1 or more peritoneal, mesenteric, or retroperitoneal primary or secondary tumors), 49000 (exploratory laparotomy, exploratory celiotomy with or without biopsy), 49010 (exploration, retroperitoneal area with or without biopsy).	('tumors', 'Phenotype', 'HP:0002664', (593, 599))	('endometriomas', 'Disease', (504, 517))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('tumors', 'Phenotype', 'HP:0002664', (385, 391))	('49203/49204/49205', 'Var', (420, 437))	('intra-abdominal or retroperitoneal tumors or cysts or endometriomas', 'Disease', 'MESH:D004715', (350, 417))	('tumor', 'Phenotype', 'HP:0002664', (486, 491))	('tumor', 'Phenotype', 'HP:0002664', (593, 598))	('endometriomas', 'Disease', (404, 417))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('endometriomas', 'Disease', 'MESH:D004715', (404, 417))	('intra-abdominal tumors', 'Disease', (470, 492))	('intra-abdominal tumors', 'Disease', 'None', (470, 492))	('endometriomas', 'Disease', 'MESH:D004715', (504, 517))	('tumors', 'Phenotype', 'HP:0002664', (486, 492))
129144	24282418	Use of more specific markers of myeloid disease, such as CD33, myeloperoxidase (MPO), CD34, and CD117, is necessary to establish the diagnosis.	('myeloid disease', 'Disease', 'MESH:D007951', (32, 47))	('CD117', 'Var', (96, 101))	('CD34', 'Var', (86, 90))	('myeloid disease', 'Disease', (32, 47))	('CD33', 'Var', (57, 61))
129174	23761812	The expression of D2-40 was observed in partial or focal tumor cells in all cases while CXCL-13 was absent (Fig.	('CXCL-13', 'Gene', (88, 95))	('D2-40', 'Var', (18, 23))	('CXCL-13', 'Gene', '10563', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('observed', 'Reg', (28, 36))
129246	23365693	For example, high-penetrance mutations in genes such as MLH1, MSH2, APC, and MYH account for only about 5% of all colorectal cancer cases.	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('APC', 'Disease', 'MESH:D011125', (68, 71))	('APC', 'Disease', (68, 71))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('MYH', 'Gene', (77, 80))	('MSH2', 'Gene', (62, 66))	('MSH2', 'Gene', '4436', (62, 66))	('MYH', 'Gene', '4595', (77, 80))	('colorectal cancer', 'Disease', (114, 131))	('MLH1', 'Gene', '4292', (56, 60))	('MLH1', 'Gene', (56, 60))
129248	23365693	As an example, the discovery of familial pituitary adenoma clusters in Northern Finland led to the identification of aryl hydrocarbon receptor interacting protein (AIP) defects in patients with pituitary adenoma predisposition.	('defects', 'Var', (169, 176))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (41, 58))	('pituitary adenoma', 'Disease', (194, 211))	('familial pituitary adenoma clusters', 'Disease', 'MESH:D010911', (32, 67))	('pituitary adenoma clusters', 'Phenotype', 'HP:0011761', (41, 67))	('pituitary adenoma', 'Disease', 'MESH:D010911', (194, 211))	('aryl hydrocarbon receptor interacting protein', 'Gene', '9049', (117, 162))	('AIP', 'Gene', '9049', (164, 167))	('familial pituitary adenoma clusters', 'Disease', (32, 67))	('AIP', 'Gene', (164, 167))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (194, 211))	('pituitary adenoma', 'Disease', 'MESH:D010911', (41, 58))	('patients', 'Species', '9606', (180, 188))	('aryl hydrocarbon receptor interacting protein', 'Gene', (117, 162))
129249	23365693	Mutations in AIP originally identified in Finland have subsequently been found from similar patients worldwide.	('Mutations', 'Var', (0, 9))	('AIP', 'Gene', '9049', (13, 16))	('patients', 'Species', '9606', (92, 100))	('AIP', 'Gene', (13, 16))
129335	22455759	Since little is known about the health economics of sarcoma, we undertook a cost-effectiveness analysis (within the CONnective TIssue CAncer NETwork, CONTICANET) comparing costs and outcomes when clinicians adhered to CPGs and when they did not.	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('CAncer', 'Phenotype', 'HP:0002664', (134, 140))	('sarcoma', 'Disease', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('CPGs', 'Var', (218, 222))	('CAncer', 'Disease', (134, 140))	('CAncer', 'Disease', 'MESH:D009369', (134, 140))	('CONnective TIssue CAncer', 'Phenotype', 'HP:0100242', (116, 140))
129376	22455759	Overall average cost per patient of managing sarcomas (all subtypes included) was somewhat less in the GPG + group than in the CPG- group, but the difference did not reach statistical significance (p = 0.07).	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('GPG +', 'Var', (103, 108))	('sarcomas', 'Disease', (45, 53))	('less', 'NegReg', (91, 95))	('patient', 'Species', '9606', (25, 32))
129377	22455759	Overall average cost was significantly lower in the GPG + group than in the CPG- group for GIST and dermatofibrosarcoma (p < 0.01).	('GIST', 'Disease', (91, 95))	('dermatofibrosarcoma', 'Disease', (100, 119))	('GPG +', 'Var', (52, 57))	('dermatofibrosarcoma', 'Disease', 'MESH:D018223', (100, 119))	('cost', 'MPA', (16, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('lower', 'NegReg', (39, 44))
129383	22455759	Any resulting bias, however, would have tended to cause an underestimation rather than an overestimation of the true effect of compliance, since in the CPG + group the costs of diagnosis were higher (Table 4) despite a lower grade of tumours (Table 3).	('costs', 'MPA', (168, 173))	('CPG +', 'Var', (152, 157))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('lower', 'NegReg', (219, 224))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('higher', 'PosReg', (192, 198))	('tumours', 'Disease', 'MESH:D009369', (234, 241))	('tumours', 'Disease', (234, 241))
129408	27914109	Here we report a case of PD-SS lacking the canonical SS18-SSX gene fusion, but showing strong BCOR immunoreactivity and BCOR gene abnormalities by FISH which were misinterpreted as a URCS with BCOR gene rearrangements.	('BCOR', 'Gene', (193, 197))	('BCOR', 'Gene', (94, 98))	('SS', 'Phenotype', 'HP:0100242', (58, 60))	('BCOR', 'Gene', '54880', (94, 98))	('BCOR', 'Gene', '54880', (193, 197))	('abnormalities', 'Var', (130, 143))	('SSX', 'Gene', (58, 61))	('SS', 'Phenotype', 'HP:0100242', (28, 30))	('BCOR', 'Gene', (120, 124))	('SSX', 'Gene', '727837', (58, 61))	('BCOR', 'Gene', '54880', (120, 124))	('SS', 'Phenotype', 'HP:0100242', (53, 55))
129412	27914109	Further FISH testing validated rearrangements in SSX1 and SS18L1 genes, in addition to complex structural abnormalities of the Xp11.22-4 region.	('SS', 'Phenotype', 'HP:0100242', (58, 60))	('SS18L1', 'Gene', (58, 64))	('rearrangements', 'Var', (31, 45))	('SS', 'Phenotype', 'HP:0100242', (49, 51))	('SSX', 'Gene', (49, 52))	('SSX', 'Gene', '727837', (49, 52))
129413	27914109	This is the second reported SS case harboring an SS18L1-SSX1 alternative fusion variant, similarly occurring in association with a large nerve.	('SSX', 'Gene', (56, 59))	('SSX', 'Gene', '727837', (56, 59))	('variant', 'Var', (80, 87))	('SS', 'Phenotype', 'HP:0100242', (28, 30))	('SS', 'Phenotype', 'HP:0100242', (56, 58))	('SS', 'Phenotype', 'HP:0100242', (49, 51))
129416	27914109	The genetic hallmark of synovial sarcomas (SS) is a recurrent t(X;18) translocation resulting in the fusion of SS18 (18q11.2) to one of the SSX genes, including SSX1 (Xp11.23), SSX2 (Xp11.22), or rarely SSX4 (Xp11.23).	('SS', 'Phenotype', 'HP:0100242', (140, 142))	('SSX', 'Gene', '727837', (177, 180))	('translocation', 'Var', (70, 83))	('SSX', 'Gene', '727837', (161, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('t(X;18', 'Gene', (62, 68))	('fusion', 'Var', (101, 107))	('SS', 'Phenotype', 'HP:0100242', (43, 45))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (24, 41))	('SSX', 'Gene', (140, 143))	('synovial sarcomas', 'Disease', (24, 41))	('SSX', 'Gene', (203, 206))	('SS', 'Phenotype', 'HP:0100242', (177, 179))	('SSX', 'Gene', (177, 180))	('SS', 'Phenotype', 'HP:0100242', (161, 163))	('SSX', 'Gene', (161, 164))	('synovial sarcomas', 'Disease', 'MESH:D013584', (24, 41))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (24, 40))	('SS', 'Phenotype', 'HP:0100242', (111, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('SSX', 'Gene', '727837', (140, 143))	('SSX', 'Gene', '727837', (203, 206))
129420	27914109	Here we report a challenging diagnostic case of a PD-SS lacking the typical SS18 gene abnormalities and showing strong and diffuse BCOR immunoreactivity suggesting an alternative diagnosis of URCS.	('abnormalities', 'Var', (86, 99))	('BCOR', 'Gene', (131, 135))	('URCS', 'Disease', (192, 196))	('BCOR', 'Gene', '54880', (131, 135))	('lacking', 'NegReg', (56, 63))	('SS18 gene', 'Gene', (76, 85))	('SS', 'Phenotype', 'HP:0100242', (76, 78))	('SS', 'Phenotype', 'HP:0100242', (53, 55))
129425	27914109	Interphase FISH for SS18 and BCOR gene abnormalities were performed on 4 mum-thick formalin-fixed paraffin-embedded (FFPE) tissue sections.	('SS', 'Phenotype', 'HP:0100242', (20, 22))	('BCOR', 'Gene', (29, 33))	('abnormalities', 'Var', (39, 52))	('BCOR', 'Gene', '54880', (29, 33))	('formalin', 'Chemical', 'MESH:D005557', (83, 91))	('paraffin', 'Chemical', 'MESH:D010232', (98, 106))
129429	27914109	For the BCOR assay, we employed a combined BCOR-CCNB3 inversion-fusion design that can detect both BCOR gene abnormalities, including break-apart and inversion/fusion with CCNB3.	('CCNB3', 'Gene', (172, 177))	('CCNB3', 'Gene', '85417', (48, 53))	('inversion/fusion', 'Var', (150, 166))	('BCOR', 'Gene', (8, 12))	('CCNB3', 'Gene', '85417', (172, 177))	('BCOR', 'Gene', (43, 47))	('BCOR', 'Gene', (99, 103))	('BCOR', 'Gene', '54880', (8, 12))	('break-apart', 'Var', (134, 145))	('BCOR', 'Gene', '54880', (43, 47))	('CCNB3', 'Gene', (48, 53))	('BCOR', 'Gene', '54880', (99, 103))
129434	27914109	Immunohistochemical stains were performed on 4 mum-thick FFPE tissue sections for TLE1 (Santa Cruz Biotech, clone Poly; sc-9121; 1:100 dilution), BCL2 (Ventana: Ready to Use, clone 124Mo/Mo), H3K27me3 stain (clone C36B11; Cell Signaling Technology, Danvers, MA; 1:200 dilution), BCOR (clone C10; sc-514576; Santa Cruz, Dallas, TX; 1:150 dilution) and SATB2 (clone EP281; CellMarque, California, USA; 1:200 dilution).	('BCOR', 'Gene', '54880', (279, 283))	('BCOR', 'Gene', (279, 283))	('clone C10;', 'Var', (285, 295))
129450	27914109	Subsequent confirmatory FISH assays demonstrated rearrangements of SS18L1 and SSX1 genes (Fig.	('SS', 'Phenotype', 'HP:0100242', (78, 80))	('rearrangements', 'Var', (49, 63))	('SSX', 'Gene', (78, 81))	('SSX', 'Gene', '727837', (78, 81))	('SS18L1', 'Gene', (67, 73))	('SS', 'Phenotype', 'HP:0100242', (67, 69))
129453	27914109	A SS with SS18-SSX2 fusion in the control group also showed moderately elevated expression of BCOR, but not for SS18L1 and SSX1.	('SS', 'Phenotype', 'HP:0100242', (15, 17))	('SSX', 'Gene', (15, 18))	('fusion', 'Var', (20, 26))	('SS', 'Phenotype', 'HP:0100242', (123, 125))	('BCOR', 'Gene', (94, 98))	('BCOR', 'Gene', '54880', (94, 98))	('SS', 'Phenotype', 'HP:0100242', (10, 12))	('SSX', 'Gene', (123, 126))	('SSX', 'Gene', '727837', (15, 18))	('elevated', 'PosReg', (71, 79))	('SSX', 'Gene', '727837', (123, 126))	('expression', 'MPA', (80, 90))	('SS', 'Phenotype', 'HP:0100242', (2, 4))	('SS', 'Phenotype', 'HP:0100242', (112, 114))
129456	27914109	Furthermore, the presence of the SS18-SSX fusion in the overwhelming majority of SS have provided pathologists with a reliable molecular assay in confirming the diagnosis, either by RT-PCR amplification of the fusion transcript or more often by demonstration of SS18 break-apart by FISH.	('SSX', 'Gene', '727837', (38, 41))	('SS', 'Phenotype', 'HP:0100242', (81, 83))	('SS', 'Phenotype', 'HP:0100242', (38, 40))	('SS', 'Phenotype', 'HP:0100242', (262, 264))	('SS', 'Phenotype', 'HP:0100242', (33, 35))	('presence', 'Var', (17, 25))	('SSX', 'Gene', (38, 41))
129458	27914109	One entity recently emerging as having morphologic overlap with SS is the URCS with BCOR genetic abnormalities, including both fusions and internal tandem duplications (ITD).	('genetic abnormalities', 'Disease', 'MESH:D030342', (89, 110))	('SS', 'Phenotype', 'HP:0100242', (64, 66))	('BCOR', 'Gene', (84, 88))	('internal tandem duplications', 'Var', (139, 167))	('genetic abnormalities', 'Disease', (89, 110))	('fusions', 'Var', (127, 134))	('BCOR', 'Gene', '54880', (84, 88))
129461	27914109	Although BCOR immunohistochemistry has been recently shown as a highly sensitive marker for URCS with various BCOR genetic alterations, showing strong and diffuse reactivity, it is also positive in about half of SS cases tested.	('BCOR', 'Gene', (110, 114))	('BCOR', 'Gene', '54880', (110, 114))	('URCS', 'Disease', (92, 96))	('BCOR', 'Gene', (9, 13))	('reactivity', 'MPA', (163, 173))	('genetic alterations', 'Var', (115, 134))	('SS', 'Phenotype', 'HP:0100242', (212, 214))	('BCOR', 'Gene', '54880', (9, 13))	('positive', 'Reg', (186, 194))
129463	27914109	Located telomeric to the SSX gene cluster on the short arm of X chromosome, BCOR (Xp11.4) is a sarcoma-associated gene, whose rearrangements are associated with round cell sarcomas (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR), ossifying fibromyxoid tumors (ZC3H7B-BCOR) or endometrial stromal sarcoma (ZC3H7B-BCOR).	('sarcoma', 'Disease', 'MESH:D012509', (286, 293))	('BCOR', 'Gene', (76, 80))	('sarcoma', 'Disease', (286, 293))	('fibromyxoid tumors', 'Disease', 'MESH:D009369', (230, 248))	('BCOR', 'Gene', (194, 198))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('CCNB3', 'Gene', '85417', (187, 192))	('SSX', 'Gene', '727837', (25, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('sarcoma', 'Disease', (172, 179))	('rearrangements', 'Var', (126, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (286, 293))	('BCOR', 'Gene', '54880', (302, 306))	('fibromyxoid tumors', 'Disease', (230, 248))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('sarcomas', 'Phenotype', 'HP:0100242', (172, 180))	('BCOR', 'Gene', '54880', (182, 186))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (266, 293))	('BCOR', 'Gene', (302, 306))	('BCOR', 'Gene', '54880', (213, 217))	('CCNB3', 'Gene', (187, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('SS', 'Phenotype', 'HP:0100242', (25, 27))	('SSX', 'Gene', (25, 28))	('BCOR', 'Gene', (213, 217))	('round cell sarcomas', 'Disease', (161, 180))	('BCOR', 'Gene', (182, 186))	('short arm', 'Phenotype', 'HP:0009824', (49, 58))	('BCOR', 'Gene', '54880', (257, 261))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('associated', 'Reg', (145, 155))	('BCOR', 'Gene', '54880', (76, 80))	('BCOR', 'Gene', '54880', (194, 198))	('round cell sarcomas', 'Disease', 'MESH:D018208', (161, 180))	('sarcoma', 'Disease', (95, 102))	('BCOR', 'Gene', (257, 261))	('endometrial stromal sarcoma', 'Disease', (266, 293))
129466	27914109	Although most intraneural SS have been described to harbor typical SS18-SSX1/2 fusions, it is quite remarkable that both cases so far reported with this unusual SS18L1-SSX fusion variant have occurred within the nerves, further simulating a malignant peripheral nerve sheath tumor in the setting of negative SS18 gene abnormalities.	('SSX', 'Gene', (72, 75))	('SS', 'Phenotype', 'HP:0100242', (26, 28))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (241, 280))	('SSX', 'Gene', '727837', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('SS', 'Phenotype', 'HP:0100242', (161, 163))	('sheath tumor', 'Disease', 'MESH:D010524', (268, 280))	('SS', 'Phenotype', 'HP:0100242', (168, 170))	('sheath tumor', 'Disease', (268, 280))	('SSX', 'Gene', (168, 171))	('SS', 'Phenotype', 'HP:0100242', (72, 74))	('occurred', 'Reg', (192, 200))	('variant', 'Var', (179, 186))	('fusions', 'Var', (79, 86))	('SSX', 'Gene', '727837', (168, 171))	('SS', 'Phenotype', 'HP:0100242', (67, 69))
129468	27914109	Mutations of SS18L1 has been identified as one of the genetic risk factors related to amyotrophic lateral sclerosis, a motor neuron disease.	('SS', 'Phenotype', 'HP:0100242', (13, 15))	('SS18L1', 'Gene', (13, 19))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (86, 115))	('Mutations', 'Var', (0, 9))	('amyotrophic lateral sclerosis', 'Disease', (86, 115))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (86, 115))
129477	27914109	This case further illustrates the emerging overlap between SS and URCS with BCOR genetic alterations, at histologic, immunohistochemical, and transcriptional levels, implicating BCOR oncogenic activation as a potential downstream common core between SS with various gene fusions and BCOR-related URCS.	('BCOR', 'Gene', (76, 80))	('BCOR', 'Gene', '54880', (178, 182))	('SS', 'Phenotype', 'HP:0100242', (59, 61))	('BCOR', 'Gene', (283, 287))	('SS', 'Phenotype', 'HP:0100242', (250, 252))	('genetic alterations', 'Var', (81, 100))	('BCOR', 'Gene', '54880', (76, 80))	('BCOR', 'Gene', '54880', (283, 287))	('BCOR', 'Gene', (178, 182))
129507	24082182	isotretinoin, minocycline, doxycycline, tetracycline, can cause pseudo-tumor cerebri.	('tetracycline', 'Var', (40, 52))	('doxycycline', 'Var', (27, 38))	('isotretinoin', 'Chemical', 'MESH:D015474', (0, 12))	('cause', 'Reg', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tetracycline', 'Chemical', 'MESH:D013752', (40, 52))	('minocycline', 'Var', (14, 25))	('isotretinoin', 'Var', (0, 12))	('tumor', 'Disease', (71, 76))	('doxycycline', 'Chemical', 'MESH:D004318', (27, 38))	('minocycline', 'Chemical', 'MESH:D008911', (14, 25))
129644	32003460	For each cancer group, we used Cox survival regression models to estimate hazard ratios during the 5 years after cancer diagnosis, by period of cancer diagnosis (2006-2015 vs. 1996-2005) unadjusted and adjusted for CD4 count (0-99, 100-199, 200-349, 350-499, >=500 cells/mm3), HIV-1 RNA (0-499, 500-9,999, >=10,000 copies/ml), and age (16-39, 40-49, 50-59, >=60 years), all taken as the measurement closest to and before the date of cancer diagnosis, combined sex/transmission risk group, and stratified by cohort (ensuring that all comparisons are among patients in the same cohort).	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('0-499', 'Var', (288, 293))	('patients', 'Species', '9606', (555, 563))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (433, 439))	('CD4', 'Gene', (215, 218))	('HIV-1', 'Species', '11676', (277, 282))	('cancer', 'Disease', (433, 439))	('CD4', 'Gene', '920', (215, 218))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
129658	32003460	Both median age and median CD4 count at cancer diagnosis were lower for individuals diagnosed with an ADM than with an NADM, and for viral NADM compared to nonviral NADM.	('NADM', 'Var', (139, 143))	('CD4', 'Gene', (27, 30))	('CD4', 'Gene', '920', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('lower', 'NegReg', (62, 67))	('NADM', 'Chemical', '-', (139, 143))	('NADM', 'Chemical', '-', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('NADM', 'Chemical', '-', (165, 169))	('ADM', 'Disease', (102, 105))
129812	31906221	Resistance to gemcitabine was artificially induced by genetic modifications (transfection) in gene coding deoxynucleoside kinase in MES-SA, although such modifications were not performed in the cell line we used.	('modifications', 'Var', (62, 75))	('Resistance', 'MPA', (0, 10))	('deoxynucleoside kinase', 'Gene', (106, 128))	('MES-SA', 'Chemical', '-', (132, 138))	('gemcitabine', 'Chemical', 'MESH:C056507', (14, 25))	('induced', 'Reg', (43, 50))	('deoxynucleoside kinase', 'Gene', '1633', (106, 128))
129961	30250915	In over 85% of patients, the translocation is between chromosomes 22 and 11, fusing the N-terminal transactivation domain of the EWS RNA binding protein 1 (EWSR1) gene to the C-terminal DNA binding domain of the weak transcription factor Fli-1 proto-oncogene, ETS transcription factor (FLI1) gene.	('patients', 'Species', '9606', (15, 23))	('EWSR1', 'Gene', '2130', (156, 161))	('EWS RNA binding protein 1', 'Gene', (129, 154))	('EWS RNA binding protein 1', 'Gene', '2130', (129, 154))	('FLI1', 'Gene', (286, 290))	('FLI1', 'Gene', '2313', (286, 290))	('EWSR1', 'Gene', (156, 161))	('fusing', 'Var', (77, 83))	('binding', 'Interaction', (190, 197))
129983	30250915	One paradoxical observation from our work is that R-loops are thought to promote mutagenesis, but genomic instability is largely absent in Ewing sarcoma, with an average of five mutations found per primary tumor beyond the translocation.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (139, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (139, 152))	('R-loops', 'Var', (50, 57))	('tumor', 'Disease', (206, 211))	('Ewing sarcoma', 'Disease', (139, 152))	('promote', 'PosReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('mutagenesis', 'MPA', (81, 92))
129986	30250915	Irrespective, these findings raise significant questions about the consequences of these defects, the associated genome instability and whether genomic instability in of itself is important for cancer development in all instances, or a secondary consequence in some cases.	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('genome', 'MPA', (113, 119))	('defects', 'Var', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
129993	25636474	Methods to Generate Genetically Engineered Mouse Models of Soft Tissue Sarcoma We discuss the generation of primary soft tissue sarcomas in mice using the Cre-loxP system to activate conditional mutations in oncogenic Kras and the tumor suppressor p53 (LSL-KrasG12D/+; p53flox/flox).	('Sarcoma', 'Disease', (71, 78))	('Kras', 'Gene', (218, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('mice', 'Species', '10090', (140, 144))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (116, 135))	('p53flox/flox', 'Var', (269, 281))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (116, 135))	('Mouse', 'Species', '10090', (43, 48))	('mutations', 'Var', (195, 204))	('soft tissue sarcoma', 'Disease', (116, 135))	('Sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('activate', 'PosReg', (174, 182))	('LSL-KrasG12D/+; p53flox/flox', 'Var', (253, 281))	('G12D', 'Mutation', 'rs121913529', (261, 265))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcomas', 'Disease', (128, 136))	('Soft Tissue Sarcoma', 'Phenotype', 'HP:0030448', (59, 78))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (116, 136))
129997	25636474	In humans, these tumors are often characterized by inactivating mutations in the p53 tumor-suppressor pathway and activating mutations in the oncogenic Kras pathway.	('mutations', 'Var', (125, 134))	('tumor', 'Disease', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('inactivating mutations', 'Var', (51, 73))	('humans', 'Species', '9606', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('oncogenic Kras pathway', 'Pathway', (142, 164))	('activating', 'PosReg', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
129999	25636474	Sarcomas are generated by activation of Cre in mice or cells with conditional mutations in both oncogenic Kras (LSL-KrasG12D/+) and mutant p53 (p53flox/flox).	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('mutant', 'Var', (132, 138))	('Kras', 'Gene', (106, 110))	('mutations', 'Var', (78, 87))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('p53', 'Gene', (139, 142))	('G12D', 'Mutation', 'rs121913529', (120, 124))	('mice', 'Species', '10090', (47, 51))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
130000	25636474	The resulting tumor expresses KrasG12D and is p53-null.	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('KrasG12D', 'Var', (30, 38))
130001	25636474	Following intramuscular injection of Ad-Cre into the compound mutant mice (LSL-KrasG12D/+; p53flox/flox), high-grade sarcomas develop at the site of injection within 2-4 months.	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('mice', 'Species', '10090', (69, 73))	('sarcomas', 'Disease', (117, 125))	('p53flox/flox', 'Var', (91, 103))	('G12D', 'Mutation', 'rs121913529', (83, 87))
130010	25636474	This method allows direct isolation of putative tumor-initiating cells, facilitating the study of tumorigenesis by specific gene mutations.	('tumor', 'Disease', (48, 53))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
130011	25636474	After isolating and transforming satellite cells in vitro by deleting p53 and expressing oncogenic Kras, we have generated rhabdomyosarcomas following transplantation into recipient mice (Blum JM, Li Z, and Kirsch DG, unpublished data).	('generated', 'Reg', (113, 122))	('p53', 'Gene', (70, 73))	('rhabdomyosarcomas', 'Disease', (123, 140))	('deleting', 'Var', (61, 69))	('mice', 'Species', '10090', (182, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (123, 140))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (123, 140))
130014	25636474	First, the mutant genes that initiate sarcoma growth are expressed from their endogenous promoters at physiological levels.	('initiate sarcoma', 'Disease', 'MESH:D012509', (29, 45))	('mutant', 'Var', (11, 17))	('initiate sarcoma', 'Disease', (29, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))
130031	25636474	Finally, the models described above can be extended to test novel gene mutations that may be relevant to distinct subtypes of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('mutations', 'Var', (71, 80))	('sarcoma', 'Disease', (126, 133))
130032	25636474	For example, genomic analyses of patient sarcomas revealed that mutations in the neurofibromin 1 (NF1) gene are common in a number of STS.	('patient', 'Species', '9606', (33, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('neurofibromin 1', 'Gene', '4763', (81, 96))	('common', 'Reg', (112, 118))	('NF1', 'Gene', (98, 101))	('STS', 'Phenotype', 'HP:0030448', (134, 137))	('mutations', 'Var', (64, 73))	('neurofibromin 1', 'Gene', (81, 96))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
130035	25636474	In addition to demonstrating the utility of the model for examining different genetic mutations, this study also highlights the possibility of examining alternative anatomic sites for sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('mutations', 'Var', (86, 95))	('sarcoma', 'Disease', 'MESH:D012509', (184, 191))	('sarcoma', 'Disease', (184, 191))
130092	25636474	Add the antibody cocktail outlined in the accompanying antibody table to isolate cells with the immunophenotype CD45-, Ter119-, Sca1-, Cd11b-, CXCR4+, and beta1-integrin+.	('Sca1', 'Gene', '110454', (128, 132))	('Cd11b', 'Gene', (135, 140))	('CXCR4', 'Gene', '12767', (143, 148))	('Sca1', 'Gene', (128, 132))	('CD45', 'Gene', (112, 116))	('CD45', 'Gene', '19264', (112, 116))	('Ter119-', 'Var', (119, 126))	('CXCR4', 'Gene', (143, 148))	('Cd11b', 'Gene', '16409', (135, 140))
130105	22911740	In in vivo studies in athymic nude mice bearing multidrug-resistant uterine sarcoma cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects.	('activities', 'MPA', (275, 285))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (68, 83))	('levels', 'MPA', (239, 245))	('suppression', 'NegReg', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('caspase-3/7', 'Enzyme', (263, 274))	('K252a', 'Var', (158, 163))	('tumor', 'Disease', (89, 94))	('cell proliferation', 'CPA', (206, 224))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('sarcoma cell tumors', 'Disease', (76, 95))	('nude mice', 'Species', '10090', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('sarcoma cell tumors', 'Disease', 'MESH:D012509', (76, 95))	('tumor', 'Disease', (127, 132))	('decreased', 'NegReg', (196, 205))	('increased', 'PosReg', (229, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
130106	22911740	Our findings indicated that endogenous signaling of the TrkB pathway contributed to uterine sarcoma cell growth, and inhibition of TrkB signaling in these tumors could provide a novel medical therapy for patients with uterine sarcomas.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (84, 99))	('patients', 'Species', '9606', (204, 212))	('contributed', 'Reg', (69, 80))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (218, 233))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('sarcoma', 'Disease', 'MESH:D012509', (226, 233))	('sarcoma', 'Disease', (92, 99))	('sarcomas', 'Disease', 'MESH:D012509', (226, 234))	('sarcoma', 'Disease', (226, 233))	('sarcomas', 'Phenotype', 'HP:0100242', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcomas', 'Disease', (226, 234))	('endogenous signaling', 'MPA', (28, 48))	('tumors', 'Disease', (155, 161))	('inhibition', 'Var', (117, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('tumors', 'Disease', 'MESH:D009369', (155, 161))
130167	22911740	To determine the roles of endogenous TrkB ligands in cell proliferation and apoptosis of sarcoma cells, MES-SA and MES-SA/Dx5 cells, were incubated with K252a or the TrkB ectodomain.	('MES-SA', 'Chemical', '-', (104, 110))	('K252a', 'Var', (153, 158))	('MES-SA', 'Chemical', '-', (115, 121))	('Dx5', 'Gene', (122, 125))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('Dx5', 'Gene', '16398', (122, 125))
130170	22911740	To determine whether the observed in vitro inhibition of sarcoma cell growth by Trk receptor inhibitors could be translated into in vivo antitumor activity, K252a was administered to athymic nude mice bearing tumor xenografts of MES-SA/Dx5 cells, which were chosen for these studies due to their high BDNF and TrkB expression levels and multidrug-resistant character that could be more severe model of uterine sarcoma for in vivo analyses.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('Dx5', 'Gene', (236, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('tumor', 'Disease', (209, 214))	('sarcoma', 'Disease', 'MESH:D012509', (410, 417))	('nude mice', 'Species', '10090', (191, 200))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('K252a', 'Var', (157, 162))	('Dx5', 'Gene', '16398', (236, 239))	('TrkB', 'Protein', (310, 314))	('sarcoma', 'Disease', (410, 417))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('expression levels', 'MPA', (315, 332))	('BDNF', 'MPA', (301, 305))	('MES-SA', 'Chemical', '-', (229, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (410, 417))	('inhibitors', 'Var', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('tumor', 'Disease', (141, 146))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (402, 417))	('sarcoma', 'Disease', (57, 64))
130171	22911740	When the tumor volume reached >80 mm3, animals were given vehicle alone, K252a, or K252b at 1 mg/kg every 3 days for 15 days.	('K252b', 'Var', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('K252a', 'Var', (73, 78))
130172	22911740	Tumors in animals treated with K252a were significantly smaller than those that received vehicle or K252b (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('smaller', 'NegReg', (56, 63))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('K252a', 'Var', (31, 36))
130174	22911740	Excised tumors were further examined to determine the in vivo effects of K252a.	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('K252a', 'Var', (73, 78))
130176	22911740	Ki-67 staining confirmed the effects of K252a treatment on the suppression of cell proliferation (Fig.	('Ki-67', 'Chemical', '-', (0, 5))	('K252a', 'Var', (40, 45))	('suppression', 'NegReg', (63, 74))	('cell proliferation', 'CPA', (78, 96))
130177	22911740	Moreover, we characterized K252a-induced apoptosis in tumors by quantifying caspase activities and observed a 2.2-fold increase in the activation of caspase-3/7 within tumors of K252a-treated mice (Fig.	('K252a-induced', 'Var', (27, 40))	('activation', 'PosReg', (135, 145))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mice', 'Species', '10090', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('K252a-treated', 'Var', (178, 191))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('increase', 'PosReg', (119, 127))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('caspase-3/7', 'Enzyme', (149, 160))	('tumors', 'Disease', (54, 60))
130189	22911740	Overexpression of BDNF and TrkB is also associated with poor outcomes for neuroblastoma patients.	('TrkB', 'Protein', (27, 31))	('BDNF', 'Protein', (18, 22))	('neuroblastoma', 'Disease', 'MESH:D009447', (74, 87))	('patients', 'Species', '9606', (88, 96))	('neuroblastoma', 'Disease', (74, 87))	('Overexpression', 'Var', (0, 14))	('neuroblastoma', 'Phenotype', 'HP:0003006', (74, 87))
130194	22911740	Interestingly, the leiomyosarcoma patients with high BDNF expression also showed significantly high levels of TrkB, but not NT4/5.	('NT4/5', 'Gene', (124, 129))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (19, 33))	('TrkB', 'Protein', (110, 114))	('BDNF', 'Gene', (53, 57))	('high', 'PosReg', (95, 99))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (19, 33))	('expression', 'Var', (58, 68))	('patients', 'Species', '9606', (34, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('high', 'Var', (48, 52))	('NT4/5', 'Gene', '4909', (124, 129))	('leiomyosarcoma', 'Disease', (19, 33))
130196	22911740	In our leiomyosarcoma cases, clinical stage of the group with high-BDNF/TrkB was stage I (n = 1) and stage IV (n = 2), whereas low-BDNF/TrkB group was stage I (n = 2) and stage IV (n = 2).	('leiomyosarcoma', 'Disease', 'MESH:D007890', (7, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('high-BDNF/TrkB', 'Var', (62, 76))	('leiomyosarcoma', 'Disease', (7, 21))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (7, 21))
130206	22911740	In our study, stimulation of cell proliferation by exogenous BDNF was observed in MES-SA/Dx5, but not MES-SA, cells.	('exogenous', 'Var', (51, 60))	('Dx5', 'Gene', (89, 92))	('stimulation', 'PosReg', (14, 25))	('BDNF', 'Gene', (61, 65))	('cell proliferation', 'CPA', (29, 47))	('MES-SA', 'Chemical', '-', (82, 88))	('MES-SA', 'Chemical', '-', (102, 108))	('Dx5', 'Gene', '16398', (89, 92))
130210	22911740	Because the inhibitory effect of K252a on cell proliferation was similar to that of the TrkB ectodomain in vitro, K252a is likely to be specific for TrkB, although other members of the Trk family, including TrkA and TrkC, were expressed in these sarcoma cells (Fig.	('TrkC', 'Gene', '4916', (216, 220))	('K252a', 'Var', (114, 119))	('TrkA', 'Gene', '4914', (207, 211))	('sarcoma', 'Disease', 'MESH:D012509', (246, 253))	('sarcoma', 'Disease', (246, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('TrkA', 'Gene', (207, 211))	('TrkC', 'Gene', (216, 220))
130213	22911740	The suppressive effect of K252a on MES-SA/Dx5 tumor growth in athymic nude mice indicated that BDNF/TrkB signaling also played a significant role in uterine sarcoma growth and protection against apoptosis in vivo.	('Dx5', 'Gene', '16398', (42, 45))	('MES-SA', 'Chemical', '-', (35, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcoma growth', 'Disease', 'MESH:D006130', (157, 171))	('K252a', 'Var', (26, 31))	('tumor', 'Disease', (46, 51))	('Dx5', 'Gene', (42, 45))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (149, 164))	('sarcoma growth', 'Disease', (157, 171))	('suppressive', 'NegReg', (4, 15))	('nude mice', 'Species', '10090', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
130214	22911740	K252a is a small molecule (MW = 467 Da), easily delivered to tumor xenografts via i.p.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (61, 66))	('K252a', 'Var', (0, 5))
130256	22761558	We demonstrate the general applicability of our computational methodology on a publicly available data set of single RNAi perturbations across four cell lines in Ewing's sarcoma (ES).	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (162, 177))	('perturbations', 'Var', (122, 135))	("Ewing's sarcoma", 'Disease', (162, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (162, 177))
130286	22761558	In particular, the roles of STK10 and TNK2 in inhibiting proliferation and inducing apoptosis upon knocking-down were confirmed by further RNAi using independent siRNAs, real-time kinetic analysis as well as image based analysis of annexin V staining.	('inhibiting', 'NegReg', (46, 56))	('TNK2', 'Gene', '10188', (38, 42))	('apoptosis', 'CPA', (84, 93))	('STK10', 'Gene', (28, 33))	('inducing', 'Reg', (75, 83))	('proliferation', 'CPA', (57, 70))	('knocking-down', 'Var', (99, 112))	('TNK2', 'Gene', (38, 42))	('STK10', 'Gene', '6793', (28, 33))
130311	22761558	As expected, the fitted mixture coefficients of the  and  components for the PPI group (30.4% and 30.9%) are significantly higher than the non-PPI group (18.2% and 17.9%).	('PPI', 'Var', (77, 80))	('PPI', 'Chemical', '-', (143, 146))	('higher', 'PosReg', (123, 129))	('mixture coefficients', 'MPA', (24, 44))	('PPI', 'Chemical', '-', (77, 80))
130312	22761558	The fitting results suggest that gene pairs in the PPI group are much more likely to be positively or negatively associated (Figure 6).	('PPI', 'Chemical', '-', (51, 54))	('associated', 'Interaction', (113, 123))	('negatively', 'NegReg', (102, 112))	('PPI', 'Var', (51, 54))
130315	22761558	Even when relaxing the cutoff on module density to 0, far fewer modules were found by PPI (10) (Figure S3(B)) than by PAN (22).	('PAN', 'Gene', (118, 121))	('PPI', 'Chemical', '-', (86, 89))	('PPI (10', 'Var', (86, 93))	('PAN', 'Gene', '51816', (118, 121))	('fewer', 'NegReg', (58, 63))
130317	22761558	Of all modules predicted using PAN, we focused on nine modules with positive effects upon perturbation indicating that they are associated with self-renewal of epidermal stem cells (Figure 7).	('perturbation', 'Var', (90, 102))	('self-renewal', 'CPA', (144, 156))	('associated', 'Reg', (128, 138))	('PAN', 'Gene', '51816', (31, 34))	('PAN', 'Gene', (31, 34))
130327	22761558	In further RT-qPCR experiments, significant changes in mRNA expression of ING5 were observed when perturbing BPTF, SMARCA5, EZH2 and UHRF1 (Figure 8(D)).	('UHRF1', 'Gene', (133, 138))	('UHRF1', 'Gene', '29128', (133, 138))	('changes', 'Reg', (44, 51))	('ING5', 'Gene', '84289', (74, 78))	('BPTF', 'Gene', (109, 113))	('BPTF', 'Gene', '2186', (109, 113))	('EZH2', 'Gene', '2146', (124, 128))	('SMARCA5', 'Gene', '8467', (115, 122))	('EZH2', 'Gene', (124, 128))	('mRNA expression', 'MPA', (55, 70))	('ING5', 'Gene', (74, 78))	('SMARCA5', 'Gene', (115, 122))	('perturbing', 'Var', (98, 108))
130460	20924476	Radiotherapy may be associated with growth disturbances, musculoskeletal abnormalities and development of second malignancy.	('malignancy', 'Disease', (113, 123))	('associated', 'Reg', (20, 30))	('musculoskeletal abnormalities', 'Disease', (57, 86))	('Radiotherapy', 'Var', (0, 12))	('growth disturbances', 'CPA', (36, 55))	('growth disturbances', 'Phenotype', 'HP:0001507', (36, 55))	('musculoskeletal abnormalities', 'Disease', 'MESH:D009139', (57, 86))	('malignancy', 'Disease', 'MESH:D009369', (113, 123))
130467	20924476	Anthracyclines, including doxorubicin are known to cause chronic cardiomyopathy in a dose related manner.	('cardiomyopathy', 'Disease', 'MESH:D009202', (65, 79))	('doxorubicin', 'Chemical', 'MESH:D004317', (26, 37))	('cardiomyopathy', 'Disease', (65, 79))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('cause', 'Reg', (51, 56))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (65, 79))	('Anthracyclines', 'Var', (0, 14))
130471	20924476	In addition, ifosfamide can cause a persistent renal tubular electrolyte loss and, less commonly, a decrease in glomerular function, again in a dose-dependent fashion.	('glomerular function', 'MPA', (112, 131))	('decrease in glomerular function', 'Phenotype', 'HP:0012213', (100, 131))	('decrease', 'NegReg', (100, 108))	('renal tubular electrolyte loss', 'MPA', (47, 77))	('ifosfamide', 'Chemical', 'MESH:D007069', (13, 23))	('ifosfamide', 'Var', (13, 23))
130476	20924476	However, efficient delivery of EWS-FLI antisense oligonucleotide to malignant cells remains a barrier to therapeutic application of these agents.	('EWS', 'Gene', (31, 34))	('FLI', 'Gene', '2314', (35, 38))	('oligonucleotide', 'Chemical', 'MESH:D009841', (49, 64))	('FLI', 'Gene', (35, 38))	('antisense oligonucleotide', 'Var', (39, 64))	('EWS', 'Gene', '2130', (31, 34))
130482	20924476	IGF-1R targeted therapy results in synergistic effects with doxorubicin and vincristine due to the induction of apoptosis which has additional clinical implication.	('apoptosis', 'CPA', (112, 121))	('doxorubicin', 'Chemical', 'MESH:D004317', (60, 71))	('synergistic effects', 'MPA', (35, 54))	('vincristine', 'Chemical', 'MESH:D014750', (76, 87))	('IGF-1R', 'Gene', '3480', (0, 6))	('IGF-1R', 'Gene', (0, 6))	('targeted therapy', 'Var', (7, 23))
130491	20924476	Inhibition of mTOR signaling potentially inhibits cell cycle regulators as well as transcription factors such as c-Myc.	('mTOR', 'Gene', '2475', (14, 18))	('inhibits', 'NegReg', (41, 49))	('Inhibition', 'Var', (0, 10))	('Myc', 'Gene', '4609', (115, 118))	('Myc', 'Gene', (115, 118))	('cell', 'MPA', (50, 54))	('mTOR', 'Gene', (14, 18))
130504	33048366	8  POU class 5 homeobox 1 (POU5F1) is the fusion partner of EWSR1 in approximately 28% of EWSR1 rearrangement-positive myoepithelial tumors arising from soft tissue, bone, and visceral locations, with a predilection toward a more malignant phenotype.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (119, 139))	('POU class 5 homeobox 1', 'Gene', '5460', (3, 25))	('EWSR1', 'Gene', '2130', (60, 65))	('myoepithelial tumors', 'Disease', (119, 139))	('EWSR1', 'Gene', (90, 95))	('rearrangement-positive', 'Var', (96, 118))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EWSR1', 'Gene', (60, 65))	('POU5F1', 'Gene', '5460', (27, 33))	('EWSR1', 'Gene', '2130', (90, 95))	('POU5F1', 'Gene', (27, 33))	('POU class 5 homeobox 1', 'Gene', (3, 25))
130505	33048366	7  EWSR1 rearrangement is a pathognomonic feature of Ewing sarcoma (albeit with different fusion partners: Fli-1 proto-oncogene, ETS transcription factor [FLI1] in approximately 90% of cases and ETS transcription factor ERG [ERG] in approximately 10% cases).	('ERG', 'Gene', '2078', (220, 223))	('pathognomonic', 'Reg', (28, 41))	('ERG', 'Gene', (220, 223))	('Fli-1', 'Gene', (107, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('FLI1', 'Gene', (155, 159))	('Fli-1', 'Gene', '2313', (107, 112))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (53, 66))	('ERG', 'Gene', '2078', (225, 228))	('FLI1', 'Gene', '2313', (155, 159))	('EWSR1', 'Gene', '2130', (3, 8))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('ERG', 'Gene', (225, 228))	('rearrangement', 'Var', (9, 22))	('EWSR1', 'Gene', (3, 8))	('Ewing sarcoma', 'Disease', (53, 66))
130515	33048366	The presence of an EWSR1-POU5F1 fusion and cytokeratin expression in the poorly differentiated malignancy best fit with a diagnosis of high-grade myoepithelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('EWSR1', 'Gene', '2130', (19, 24))	('malignancy', 'Disease', 'MESH:D009369', (95, 105))	('EWSR1', 'Gene', (19, 24))	('POU5F1', 'Gene', '5460', (25, 31))	('fusion', 'Var', (32, 38))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (146, 169))	('POU5F1', 'Gene', (25, 31))	('malignancy', 'Disease', (95, 105))	('myoepithelial carcinoma', 'Disease', (146, 169))
130516	33048366	There were 4 variants of unknown significance noted: MER proto-oncogene, tyrosine kinase (MERTK) (R421Q); polymerase delta 1 (POLD1) (D679E); ring finger protein 43 (RNF43) (V217M); and smoothened, frizzled class receptor (SMO) (E224D).	('E224D', 'Mutation', 'p.E224D', (229, 234))	('POLD1', 'Gene', '5424', (126, 131))	('V217M', 'Var', (174, 179))	('R421Q', 'Var', (98, 103))	('D679E', 'Mutation', 'rs1283059353', (134, 139))	('RNF43', 'Gene', (166, 171))	('D679E', 'Var', (134, 139))	('ring finger protein 43', 'Gene', (142, 164))	('E224D', 'Var', (229, 234))	('polymerase delta 1', 'Gene', '5424', (106, 124))	('MERTK', 'Gene', '10461', (90, 95))	('MERTK', 'Gene', (90, 95))	('ring finger protein 43', 'Gene', '54894', (142, 164))	('polymerase delta 1', 'Gene', (106, 124))	('POLD1', 'Gene', (126, 131))	('V217M', 'Mutation', 'rs745467586', (174, 179))	('R421Q', 'Mutation', 'rs138908058', (98, 103))	('MER proto-oncogene, tyrosine kinase', 'Gene', '10461', (53, 88))	('RNF43', 'Gene', '54894', (166, 171))
130520	33048366	The choice of VDC/IE was based primarily on the partly shared genetic pathology with Ewing sarcoma, involving EWSR1 rearrangement (albeit with a different partner in POU5F1 instead of FLI1 or ERG).	('Ewing sarcoma', 'Disease', (85, 98))	('rearrangement', 'Var', (116, 129))	('POU5F1', 'Gene', '5460', (166, 172))	('POU5F1', 'Gene', (166, 172))	('EWSR1', 'Gene', (110, 115))	('FLI1', 'Gene', (184, 188))	('FLI1', 'Gene', '2313', (184, 188))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('EWSR1', 'Gene', '2130', (110, 115))	('ERG', 'Gene', '2078', (192, 195))	('VDC/IE', 'Chemical', '-', (14, 20))	('ERG', 'Gene', (192, 195))
130521	33048366	The POU5F1 gene encodes a transcription factor that plays a key role in embryonic development and stem cell pluripotency, with aberrant expression resulting in malignancy (as with myoepithelial carcinoma EWSR1-POU5F1 fusion).	('malignancy', 'Disease', (160, 170))	('expression', 'MPA', (136, 146))	('resulting in', 'Reg', (147, 159))	('aberrant', 'Var', (127, 135))	('POU5F1', 'Gene', '5460', (4, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('EWSR1', 'Gene', (204, 209))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))	('EWSR1', 'Gene', '2130', (204, 209))	('POU5F1', 'Gene', (4, 10))	('myoepithelial carcinoma', 'Disease', (180, 203))	('POU5F1', 'Gene', '5460', (210, 216))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (180, 203))	('POU5F1', 'Gene', (210, 216))
130522	33048366	The FLI1 gene also encodes a transcription factor that orchestrates multiple oncogenic pathways when aberrantly expressed (as with EWSR1-FLI1 fusion in Ewing sarcoma).	('FLI1', 'Gene', '2313', (4, 8))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (152, 165))	('FLI1', 'Gene', (4, 8))	('oncogenic pathways', 'Pathway', (77, 95))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('orchestrates', 'Reg', (55, 67))	('EWSR1', 'Gene', (131, 136))	('EWSR1', 'Gene', '2130', (131, 136))	('Ewing sarcoma', 'Disease', (152, 165))	('fusion', 'Var', (142, 148))	('FLI1', 'Gene', '2313', (137, 141))	('FLI1', 'Gene', (137, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
130524	33048366	9 ,  10  Put together, the genetic similarity between myoepithelial carcinoma with EWSR1-POU5F1 fusion and Ewing sarcoma with EWSR1-FLI1 fusion was an important consideration in choosing the VDC/IE regimen for this patient.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (107, 120))	('EWSR1', 'Gene', '2130', (126, 131))	('EWSR1', 'Gene', (83, 88))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (54, 77))	('FLI1', 'Gene', (132, 136))	('myoepithelial carcinoma', 'Disease', (54, 77))	('fusion', 'Var', (96, 102))	('EWSR1', 'Gene', '2130', (83, 88))	('FLI1', 'Gene', '2313', (132, 136))	('POU5F1', 'Gene', '5460', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('Ewing sarcoma', 'Disease', (107, 120))	('POU5F1', 'Gene', (89, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('EWSR1', 'Gene', (126, 131))	('VDC/IE', 'Chemical', '-', (191, 197))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (107, 120))	('patient', 'Species', '9606', (215, 222))
130565	30678671	Tumors have genomic instability, and by the time they are clinically detectable have often developed mutations that contribute to chemoresistance in the absence of drug exposure.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (101, 110))	('chemoresistance', 'CPA', (130, 145))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
130570	30678671	first demonstrated the anti-tumor properties of salinomycin when screening thousands of drugs against breast cancer stem cells; salinomycin caused > 100 fold decrease in cell viability.	('breast cancer', 'Disease', (102, 115))	('tumor', 'Disease', (28, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('salinomycin', 'Var', (128, 139))	('decrease', 'NegReg', (158, 166))	('cell viability', 'CPA', (170, 184))	('salinomycin', 'Chemical', 'MESH:C010327', (128, 139))	('rat', 'Species', '10116', (13, 16))	('salinomycin', 'Chemical', 'MESH:C010327', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
130571	30678671	Research by separate groups found that cancer stem cells treated with salinomycin have Wnt/beta-Catenin pathway inactivation and that salinomycin can inhibit Wnt1-induced phosphorylation of LRP6 (lipoprotein receptor related protein 6) and downregulate expression of target genes like cyclin D1.	('salinomycin', 'Chemical', 'MESH:C010327', (134, 145))	('rat', 'Species', '10116', (16, 19))	('inhibit', 'NegReg', (150, 157))	('salinomycin', 'Chemical', 'MESH:C010327', (70, 81))	('LRP6', 'Gene', '101082246', (190, 194))	('lipoprotein receptor related protein 6', 'Gene', '101082246', (196, 234))	('salinomycin', 'Var', (134, 145))	('cancer', 'Disease', (39, 45))	('Wnt1', 'Gene', '101094190', (158, 162))	('Wnt1', 'Gene', (158, 162))	('LRP6', 'Gene', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('inactivation', 'NegReg', (112, 124))	('cyclin D1', 'Gene', (285, 294))	('Wnt/beta-Catenin pathway', 'Pathway', (87, 111))	('downregulate', 'NegReg', (240, 252))	('expression', 'MPA', (253, 263))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('lipoprotein receptor related protein 6', 'Gene', (196, 234))	('cyclin D1', 'Gene', '100037407', (285, 294))
130639	30678671	When combining doxorubicin with 2.5 muM of salinomycin, SCCF1 cell viability decreased compared to either agent alone at doxorubicin concentrations of 4.6 (p < 0.005) and 9.2 muM (p < 0.003).	('salinomycin', 'Chemical', 'MESH:C010327', (43, 54))	('doxorubicin', 'Chemical', 'MESH:D004317', (15, 26))	('rat', 'Species', '10116', (140, 143))	('SCCF1', 'CellLine', 'CVCL:L419', (56, 61))	('doxorubicin', 'Var', (15, 26))	('doxorubicin', 'Chemical', 'MESH:D004317', (121, 132))	('SCCF1', 'Gene', (56, 61))	('decreased', 'NegReg', (77, 86))
130653	30678671	Similar to data with cytotoxic chemotherapeutics in human cancer cells, we found that salinomycin can inhibit feline cancer cell viability.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('salinomycin', 'Var', (86, 97))	('salinomycin', 'Chemical', 'MESH:C010327', (86, 97))	('human', 'Species', '9606', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('inhibit', 'NegReg', (102, 109))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (117, 123))
130912	25236925	These works demonstrate that high levels of VEGF-A in tumours and blood samples from STS patients are associated with higher tumour grade, increased tendency to form metastasis, reduced response to treatment, lower overall survival and increased risk of recurrence.	('VEGF-A', 'Gene', (44, 50))	('response', 'MPA', (186, 194))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('higher', 'PosReg', (118, 124))	('form metastasis', 'CPA', (161, 176))	('lower', 'NegReg', (209, 214))	('increased', 'PosReg', (139, 148))	('VEGF-A', 'Gene', '7422', (44, 50))	('tumours', 'Disease', (54, 61))	('high levels', 'Var', (29, 40))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('overall survival', 'CPA', (215, 231))	('patients', 'Species', '9606', (89, 97))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('reduced', 'NegReg', (178, 185))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
130957	25236925	In a genetically engineered mouse model of soft tissue sarcoma, the use of TKI sunitinib inhibited STS growth by affecting both tumour vasculature and cancer cells.	('TKI', 'Var', (75, 78))	('tumour vasculature', 'Disease', 'MESH:C565633', (128, 146))	('sunitinib', 'Chemical', 'MESH:D000077210', (79, 88))	('STS growth', 'CPA', (99, 109))	('tumour vasculature', 'Disease', (128, 146))	('affecting', 'Reg', (113, 122))	('mouse', 'Species', '10090', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (43, 62))	('inhibited', 'NegReg', (89, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (43, 62))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('soft tissue sarcoma', 'Disease', (43, 62))
130990	32105068	Whereas many of the proton resonances associated with the unsaturated hydrocarbon chain produced a series of overlapping (deltaH 1.22-1.44) signals, the chemical shifts for several critical proton spins [deltaH 2.74 (t, J = 7.5 Hz, H-3'), 1.72 (p, J = 7.5 Hz, H-4'), 2.10 (m, H-13'), 2.09 (m, H-16'), and 0.88 (t, J = 6.9 Hz, H-19')] were discernable enabling us to determine the position of the embedded cis olefin group [deltaH 5.51 (dd, J = 11.1, 6.3 Hz, H-14') and 5.46 (dd, J = 11.1, 6.3 Hz, H-15')].	('H-14', 'Gene', (458, 462))	('unsaturated hydrocarbon', 'Chemical', 'MESH:D006838', (58, 81))	('H-15', 'Gene', '3009', (497, 501))	('deltaH', 'Var', (423, 429))	('H-14', 'Gene', '3008', (458, 462))	('H-15', 'Gene', (497, 501))	('H-13', 'Gene', '3007', (276, 280))	('H-16', 'Gene', '3010', (293, 297))	('H-19', 'Gene', (326, 330))	('H-16', 'Gene', (293, 297))	('H-19', 'Gene', '283120', (326, 330))	('H-13', 'Gene', (276, 280))
131046	32105068	Interestingly, the MCT1 inhibitor AZD3965 had no effects on cell growth of A673 cells at concentrations up to 10 muM, consistent with its lack of efficacy in cells that additionally express MCT4.	('A673', 'CellLine', 'CVCL:0080', (75, 79))	('AZD3965', 'Chemical', 'MESH:C000592351', (34, 41))	('cell growth', 'CPA', (60, 71))	('MCT4', 'Gene', '9123', (190, 194))	('MCT4', 'Gene', (190, 194))	('MCT1', 'Gene', (19, 23))	('rat', 'Species', '10116', (96, 99))	('AZD3965', 'Var', (34, 41))	('MCT1', 'Gene', '6566', (19, 23))
131048	32105068	Our results are consistent with previous reports that have identified miR-124-dependent suppression of SLC16A1/MCT1 as a novel therapeutic target for medulloblastoma.	('SLC16A1', 'Gene', '6566', (103, 110))	('medulloblastoma', 'Phenotype', 'HP:0002885', (150, 165))	('medulloblastoma', 'Disease', 'MESH:D008527', (150, 165))	('miR-124-dependent', 'Var', (70, 87))	('medulloblastoma', 'Disease', (150, 165))	('MCT1', 'Gene', (111, 115))	('suppression', 'NegReg', (88, 99))	('MCT1', 'Gene', '6566', (111, 115))	('SLC16A1', 'Gene', (103, 110))
131071	32105068	Colorless, amorphous solid; [alpha]22D +-0 (c 0.5, MeOH or CH2Cl2); 1H and 13C NMR data, Tables 1 and 2; HRESIMS m/z 389.3072 [M - H]- (calcd for C25H41O3 389.3061).	('m/z', 'Var', (113, 116))	('C25H41O3', 'Chemical', '-', (146, 154))	('C25H41O3 389.3061', 'Var', (146, 163))	('1H', 'Chemical', '-', (68, 70))	('CH2Cl2', 'Chemical', '-', (59, 65))	('C', 'Chemical', 'MESH:D002244', (62, 63))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('13C', 'Chemical', 'MESH:C000615229', (75, 78))	('2D', 'Chemical', '-', (36, 38))	('MeOH', 'Chemical', '-', (51, 55))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (59, 60))
131072	32105068	Colorless, amorphous solid; [alpha]22D +-0 (c 0.2, MeOH or CH2Cl2); 1H and 13C NMR data, Tables 1 and 2; HRESIMS m/z 361.2760 [M - H]- (calcd for C23H37O3, 361.2748).	('1H', 'Chemical', '-', (68, 70))	('C', 'Chemical', 'MESH:D002244', (62, 63))	('C23H37O3', 'Var', (146, 154))	('CH2Cl2', 'Chemical', '-', (59, 65))	('m/z 361.2760 [', 'Var', (113, 127))	('C23H37O3', 'Chemical', '-', (146, 154))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('13C', 'Chemical', 'MESH:C000615229', (75, 78))	('2D', 'Chemical', '-', (36, 38))	('MeOH', 'Chemical', '-', (51, 55))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (59, 60))
131082	32105068	1H NMR (500 MHz, pyridine-d5) delta 7.53 (1H, d, J = 2.8 Hz, H-6), 7.31 (1H, d, J = 8.7 Hz, H-3), 7.20 (1H, dd, J = 8.7, 2.8 Hz, H-2), 6.25 (1H, br s, OH-2'), 5.50 (1H, dd, J = 11.3, 6.0 Hz, H-14'), 5.46 (1H, dd, J = 11.3, 6.5 Hz, H-15'), 4.19 (1H, m, H-2'), 3.01 (1H, dd, J = 13.8, 7.3 Hz, H-1'a), 2.97 (1H, dd, J = 13.8, 5.8 Hz, H-1'b), 2.28 (3H, s, Ac), 2.18 (3H, s, Ac), 2.10 (1H, m, H-13'), 2.09 (1H, m, H-16'), 1.75 (2H, m, H2-3'), 1.72, 1.56 (each 1H, m, H2-4'), 1.20-1.42 (20H, m, H2-5', H2-6', H2-7', H2-8', H2-9', H2-10', H2-11', H2-12', H2-17', and H2-18'), 0.88 (3H, t, J = 6.9 Hz, H3-19'); ESIMS m/z 497 [M + Na]+, 473 [M - H]-, 519 [M + HCOOH - H]-.	('H2', 'Chemical', 'MESH:D003903', (462, 464))	('H2', 'Chemical', 'MESH:D003903', (430, 432))	('1H', 'Chemical', '-', (104, 106))	('H-16', 'Gene', '3010', (409, 413))	('pyridine', 'Chemical', 'MESH:C023666', (17, 25))	('1H', 'Chemical', '-', (73, 75))	('H2', 'Chemical', 'MESH:D003903', (540, 542))	('H-14', 'Gene', (191, 195))	('H2', 'Chemical', 'MESH:D003903', (510, 512))	('H2', 'Chemical', 'MESH:D003903', (524, 526))	('1H', 'Chemical', '-', (0, 2))	('HCOOH', 'Chemical', '-', (651, 656))	('H2', 'Chemical', 'MESH:D003903', (548, 550))	('H2', 'Chemical', 'MESH:D003903', (532, 534))	('1H', 'Chemical', '-', (381, 383))	('1H', 'Chemical', '-', (141, 143))	('H2-7', 'Gene', '6019;126961;5414;3166', (503, 507))	('1H', 'Chemical', '-', (205, 207))	('H2', 'Chemical', 'MESH:D003903', (489, 491))	('1H', 'Chemical', '-', (245, 247))	('H-15', 'Gene', '3009', (231, 235))	('1H', 'Chemical', '-', (165, 167))	('1H', 'Chemical', '-', (402, 404))	('H-14', 'Gene', '3008', (191, 195))	('H-13', 'Gene', '3007', (388, 392))	('H-13', 'Gene', (388, 392))	('m/z 497 [M + Na]+', 'Var', (609, 626))	('H2', 'Chemical', 'MESH:D003903', (560, 562))	('H2', 'Chemical', 'MESH:D003903', (496, 498))	('1H', 'Chemical', '-', (305, 307))	('H2', 'Chemical', 'MESH:D003903', (503, 505))	('H-15', 'Gene', (231, 235))	('1H', 'Chemical', '-', (42, 44))	('1H', 'Chemical', '-', (265, 267))	('H-16', 'Gene', (409, 413))	('H2-7', 'Gene', (503, 507))	('1H', 'Chemical', '-', (455, 457))	('H2', 'Chemical', 'MESH:D003903', (517, 519))
131103	32105068	For BrPA inhibition experiments, 1 and AZD3965 were applied one hour prior to the addition of BrPA with DMSO used as the vehicle control.	('BrPA', 'Chemical', '-', (4, 8))	('AZD3965', 'Var', (39, 46))	('BrPA', 'Chemical', '-', (94, 98))	('BrPA', 'Enzyme', (4, 8))	('DMSO', 'Chemical', 'MESH:D004121', (104, 108))	('AZD3965', 'Chemical', 'MESH:C000592351', (39, 46))
131176	31938642	showed strong TLE1 positivity in all cases of poorly differentiated SS, which is different from the findings of this study in which only 3.3% of poorly differentiated SS cases showed weak and moderate staining.	('TLE1', 'Gene', (14, 18))	('positivity', 'Var', (19, 29))	('SS', 'Disease', 'MESH:D013584', (68, 70))	('SS', 'Phenotype', 'HP:0012570', (68, 70))	('TLE1', 'Gene', '7088', (14, 18))	('SS', 'Disease', 'MESH:D013584', (167, 169))	('SS', 'Phenotype', 'HP:0012570', (167, 169))
131178	31938642	In another study by Foo et al., 82% of SS cases displayed positivity for TLE1, including 78% biphasic, 79% monophasic, and 91% poorly differentiated types.	('SS', 'Phenotype', 'HP:0012570', (39, 41))	('TLE1', 'Gene', (73, 77))	('positivity', 'Var', (58, 68))	('SS', 'Disease', 'MESH:D013584', (39, 41))	('TLE1', 'Gene', '7088', (73, 77))	('biphasic', 'MPA', (93, 101))	('monophasic', 'MPA', (107, 117))
131196	29757143	NKG2D has also been implicated as a co-stimulatory molecule for T cells, and in some cases NKG2D can mediate lymphocyte trafficking to sites of inflammation.	('lymphocyte trafficking to', 'CPA', (109, 134))	('NKG2D', 'Var', (91, 96))	('inflammation', 'Disease', 'MESH:D007249', (144, 156))	('mediate', 'Reg', (101, 108))	('inflammation', 'Disease', (144, 156))
131227	29757143	Importantly, RAE-1delta staining on TAMs was completely absent in RAE-1-KO mice, which contain frameshift mutations in the genes encoding RAE-1delta and RAE-1epsilon, confirming the specificity of the RAE-1delta staining (Figure 1:figure supplement 1B).	('RAE-1', 'Gene', '66679', (66, 71))	('RAE-1', 'Gene', (13, 18))	('RAE-1', 'Gene', (138, 143))	('RAE-1', 'Gene', '66679', (153, 158))	('RAE-1', 'Gene', '66679', (201, 206))	('RAE-1delta', 'Gene', (138, 148))	('RAE-1delta', 'Gene', (201, 211))	('TAMs', 'Chemical', 'MESH:D013629', (36, 40))	('RAE-1', 'Gene', (66, 71))	('RAE-1', 'Gene', (153, 158))	('RAE-1', 'Gene', (201, 206))	('RAE-1delta', 'Gene', '56554', (13, 23))	('mice', 'Species', '10090', (75, 79))	('RAE-1epsilon', 'Gene', '379043', (153, 165))	('RAE-1', 'Gene', '66679', (13, 18))	('RAE-1', 'Gene', '66679', (138, 143))	('absent', 'NegReg', (56, 62))	('RAE-1epsilon', 'Gene', (153, 165))	('RAE-1delta', 'Gene', '56554', (138, 148))	('RAE-1delta', 'Gene', '56554', (201, 211))	('frameshift mutations', 'Var', (95, 115))	('RAE-1delta', 'Gene', (13, 23))
131234	29757143	In the KP sarcoma model driven by lentiviral-Cre activation of oncogenic Kras and deletion of Trp53, TAMs in primary tumors expressed robust RAE-1delta (Figure 1C).	('TAMs', 'Chemical', 'MESH:D013629', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('RAE-1delta', 'Gene', '56554', (141, 151))	('deletion', 'Var', (82, 90))	('tumors', 'Disease', (117, 123))	('Trp53', 'Gene', (94, 99))	('KP sarcoma', 'Disease', 'MESH:D012509', (7, 17))	('KP sarcoma', 'Disease', (7, 17))	('Kras', 'Gene', (73, 77))	('Kras', 'Gene', '16653', (73, 77))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('Trp53', 'Gene', '22059', (94, 99))	('RAE-1delta', 'Gene', (141, 151))
131266	29757143	To formally test whether tumor-derived CSF-1 was responsible for inducing TAM RAE-1delta, we used CRISPR/Cas9 to target the Csf1 open reading frame for deletion in B16 cells.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('deletion', 'Var', (152, 160))	('Csf1', 'Gene', (124, 128))	('tumor', 'Disease', (25, 30))	('RAE-1delta', 'Gene', (78, 88))	('Csf1', 'Gene', '12977', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('RAE-1delta', 'Gene', '56554', (78, 88))
131281	29757143	Interestingly, specific inhibition of PI3K p110alpha with two different chemical inhibitors (PI3Ka2i and PI-103) prevented CSF-1-induced RAE-1delta expression at low inhibitor concentrations, whereas inhibitors of p110 isoforms beta, delta, and gamma only inhibited RAE-1delta induction at high inhibitor concentrations, likely due to nonspecific inhibition or off-target effects (Figure 6A and B).	('rat', 'Species', '10116', (183, 186))	('prevented', 'NegReg', (113, 122))	('CSF-1-induced', 'Gene', (123, 136))	('RAE-1delta', 'Gene', '56554', (137, 147))	('p110alpha', 'Gene', '18706', (43, 52))	('RAE-1delta', 'Gene', (266, 276))	('rat', 'Species', '10116', (312, 315))	('p110alpha', 'Gene', (43, 52))	('RAE-1delta', 'Gene', (137, 147))	('inhibition', 'NegReg', (24, 34))	('RAE-1delta', 'Gene', '56554', (266, 276))	('PI-103', 'Chemical', 'MESH:C522973', (105, 111))	('PI-103', 'Var', (105, 111))
131297	29757143	However, the frequency of TAMs among CD45+ cells in B16 tumors was similar in WT and RAE-1-KO mice (Figure 7:figure supplement 1A).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TAMs', 'Chemical', 'MESH:D013629', (26, 30))	('tumors', 'Disease', (56, 62))	('CD45+', 'Var', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mice', 'Species', '10090', (94, 98))	('RAE-1', 'Gene', '66679', (85, 90))	('RAE-1', 'Gene', (85, 90))
131310	29757143	CSF-1, but not other tested cytokines, induced RAE-1delta on macrophages.	('induced', 'Reg', (39, 46))	('CSF-1', 'Var', (0, 5))	('RAE-1delta', 'Gene', (47, 57))	('RAE-1delta', 'Gene', '56554', (47, 57))
131325	29757143	These findings are similar to a previous study showing that expression of RAE-1 molecules on mononuclear myeloid-derived suppressor cells in certain tumor-bearing mice has a stimulatory effect on NK cells in a co-culture setting.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('expression', 'Var', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('NK cells', 'CPA', (196, 204))	('RAE-1', 'Gene', '66679', (74, 79))	('mice', 'Species', '10090', (163, 167))	('tumor', 'Disease', (149, 154))	('RAE-1', 'Gene', (74, 79))	('stimulatory effect', 'MPA', (174, 192))
131338	29757143	KP mice contain an inducible activating mutation in the proto-oncogene Kras and an inducible deletion mutation in the tumor suppressor gene Trp53 and were bred from mice obtained from The Jackson Laboratory.	('activating', 'PosReg', (29, 39))	('mutation', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mice', 'Species', '10090', (165, 169))	('Kras', 'Gene', (71, 75))	('rat', 'Species', '10116', (200, 203))	('mice', 'Species', '10090', (3, 7))	('Kras', 'Gene', '16653', (71, 75))	('Trp53', 'Gene', '22059', (140, 145))	('deletion mutation', 'Var', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('Trp53', 'Gene', (140, 145))
131339	29757143	TRAMP mice contain a transgene expressing the SV40 large T and small T antigens under the rat probasin promoter.	('mice', 'Species', '10090', (6, 10))	('TRAMP', 'Gene', '85030', (0, 5))	('TRAMP', 'Gene', (0, 5))	('small T antigens', 'Protein', (63, 79))	('SV40 large T', 'Var', (46, 58))	('rat', 'Species', '10116', (90, 93))
131395	29757143	- Does the in vivo treatment with anti-CSF-1 or anti-CSF1-R antibody affect the number of tumor-infiltrating macrophages?	('affect', 'Reg', (69, 75))	('CSF1', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('CSF1', 'Gene', '12977', (53, 57))	('rat', 'Species', '10116', (102, 105))	('anti-CSF-1', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
131447	29757143	As shown in Figure 4:figure supplement 1A, intra-tumoral macrophage numbers are reduced upon anti-CSF-1R treatment as early as day 5 post-treatment, whereas macrophage RAE-1delta expression is reduced as early as day 2 post-treatment.	('RAE-1delta', 'Gene', '56554', (168, 178))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('intra-tumoral', 'Disease', 'MESH:D009369', (43, 56))	('reduced', 'NegReg', (80, 87))	('intra-tumoral', 'Disease', (43, 56))	('RAE-1delta', 'Gene', (168, 178))	('anti-CSF-1R', 'Var', (93, 104))
131480	28386111	Case 2 presented 4.0 x 2.5 x 1.0 cm smashed white-grayish lymph nodes and the section showed solid, white-grayish, focal black, rough and diffused necrosis (Fig.	('necrosis', 'Disease', 'MESH:D009336', (147, 155))	('white-grayish', 'Var', (100, 113))	('necrosis', 'Disease', (147, 155))
131492	28386111	Braf with V600E mutation was not detected.	('V600E', 'Mutation', 'rs113488022', (10, 15))	('V600E', 'Var', (10, 15))	('Braf', 'Gene', '673', (0, 4))	('Braf', 'Gene', (0, 4))
131503	28386111	In multivariate analysis, diffuse lesion presented a 2.92-fold risk of progression (HR = 2.92, 95% CI 1.01, 8.51) and an 8.79-fold risk of death (HR = 8.79, 95% CI 1.86, 41.64) (Table 2).	('diffuse lesion', 'Var', (26, 40))	('death', 'Disease', 'MESH:D003643', (139, 144))	('death', 'Disease', (139, 144))
131529	28386111	BRAF V600E mutation analysis was performed to detect a T > A transversion of nucleotide 1799 of the BRAF oncogene.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('T > A transversion of nucleotide 1799', 'Var', (55, 92))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (100, 104))	('BRAF', 'Gene', (0, 4))
131531	28386111	Real-time PCR using a single primer set was used to amplify the region of the BRAF gene, which contained the mutation site, and two different fluorogenically labeled probes were used to detect the wild-type and V600E mutant.	('V600E', 'Mutation', 'rs113488022', (211, 216))	('BRAF', 'Gene', (78, 82))	('BRAF', 'Gene', '673', (78, 82))	('V600E', 'Var', (211, 216))
131568	28408855	Even though RMS occurs less frequently in the 15- to 29-year-old age group, the survival of AYA patients with RMS is significantly worse than that of younger patients with similar features.	('survival', 'MPA', (80, 88))	('worse', 'NegReg', (131, 136))	('patients', 'Species', '9606', (96, 104))	('RMS', 'Var', (110, 113))	('patients', 'Species', '9606', (158, 166))
131576	28408855	This change reflects recent data suggesting that this molecular characteristic more accurately predicts disease biology and outcomes, with translocation-negative patients usually having less aggressive disease and better outcomes regardless of histopathologic classification.	('aggressive disease', 'Disease', 'MESH:D001523', (191, 209))	('patients', 'Species', '9606', (162, 170))	('aggressive disease', 'Disease', (191, 209))	('translocation-negative', 'Var', (139, 161))
131589	28408855	The overall treatment outcomes are worse in AYA patients than in the pediatric population, and the AYA group is underrepresented in clinical trials.	('treatment outcomes', 'CPA', (12, 30))	('worse', 'NegReg', (35, 40))	('AYA', 'Var', (44, 47))	('patients', 'Species', '9606', (48, 56))
131629	28408855	These enzymes can be overactive in cancers, often through mutational activation, genetic rearrangements, or amplification.	('amplification', 'Var', (108, 121))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutational', 'Var', (58, 68))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('genetic rearrangements', 'Var', (81, 103))	('overactive', 'PosReg', (21, 31))	('cancers', 'Disease', (35, 42))	('activation', 'PosReg', (69, 79))
131639	28408855	Even though SU415 (semaxinib) did not provide significant antitumor activity, pazopanib, a multikinase inhibitor with strong antiangiogenic effects, was found to have a more favorable profile.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('SU415', 'Chemical', '-', (12, 17))	('tumor', 'Disease', (62, 67))	('SU415', 'Var', (12, 17))	('pazopanib', 'Gene', (78, 87))	('semaxinib', 'Chemical', 'MESH:C116890', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('pazopanib', 'Chemical', 'MESH:C516667', (78, 87))
131640	28408855	The PALETTE study, a Phase III study evaluating 369 adult patients with nonadipocytic STS who failed standard chemotherapy, showed prolonged median PFS and OS with pazopanib compared to placebo.	('pazopanib', 'Chemical', 'MESH:C516667', (164, 173))	('OS', 'Chemical', 'MESH:D009992', (156, 158))	('pazopanib', 'Var', (164, 173))	('prolonged', 'PosReg', (131, 140))	('PFS', 'MPA', (148, 151))	('patients', 'Species', '9606', (58, 66))
131688	28408855	These trials are currently ongoing in solid tumors (NCT01072890 and NCT01184326).	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('solid tumors', 'Disease', (38, 50))	('NCT01072890', 'Var', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('solid tumors', 'Disease', 'MESH:D009369', (38, 50))
131691	28408855	While adult carcinomas often have a significant mutational burden, gene mutations in sarcomas appear to be less frequent, and therefore, epigenetic alterations might have a stronger influence on sarcomagenesis.	('sarcoma', 'Disease', (195, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('sarcomas', 'Disease', (85, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('adult carcinomas', 'Disease', (6, 22))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('influence', 'Reg', (182, 191))	('sarcomas', 'Disease', 'MESH:D012509', (85, 93))	('mutational burden', 'MPA', (48, 65))	('epigenetic alterations', 'Var', (137, 159))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('sarcoma', 'Disease', (85, 92))	('adult carcinomas', 'Disease', 'MESH:C538052', (6, 22))
131721	28408855	Since it had previously been seen that cixutumumab had better efficacy in combination with mTOR inhibitors, it was combined with temsirolimus in an adult Phase II study enrolling AYA patients with chemotherapy-refractory sarcomas.	('cixutumumab', 'Var', (39, 50))	('sarcomas', 'Disease', 'MESH:D012509', (221, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (221, 229))	('temsirolimus', 'Chemical', 'MESH:C401859', (129, 141))	('cixutumumab', 'Chemical', 'MESH:C557414', (39, 50))	('mTOR', 'Gene', (91, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('mTOR', 'Gene', '2475', (91, 95))	('sarcomas', 'Disease', (221, 229))	('efficacy', 'MPA', (62, 70))	('patients', 'Species', '9606', (183, 191))
131726	28408855	These agents include R1507, AVE1642, MK-0646, and ganitumab alone or in combination with conatumumab (death receptor 5 agonist).	('R1507', 'Var', (21, 26))	('death receptor 5', 'Gene', '8795', (102, 118))	('MK-0646', 'Chemical', 'MESH:C569480', (37, 44))	('conatumumab', 'Chemical', 'MESH:C554537', (89, 100))	('AVE1642', 'Chemical', 'MESH:C545477', (28, 35))	('ganitumab', 'Chemical', 'MESH:C545764', (50, 59))	('death receptor 5', 'Gene', (102, 118))
131776	28096721	The earliest and the most successful example was the discovery of kit mutations in gastrointestinal stromal tumor (GIST), and subsequent development of the selective tyrosine kinase inhibitor imatinib, which revolutionized the treatment of GIST.	('kit', 'Gene', (66, 69))	('mutations', 'Var', (70, 79))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (83, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('GIST', 'Phenotype', 'HP:0100723', (240, 244))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (83, 113))	('imatinib', 'Chemical', 'MESH:D000068877', (192, 200))	('gastrointestinal stromal tumor', 'Disease', (83, 113))	('GIST', 'Phenotype', 'HP:0100723', (115, 119))
131784	28096721	The other group includes sarcomas with complex karyotypes and multiple chromosomal abnormalities such as losses and gains, unbalanced translocations, and lack of fusion proteins.	('unbalanced translocations', 'Var', (123, 148))	('fusion proteins', 'Protein', (162, 177))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (71, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('lack', 'Var', (154, 158))	('losses', 'Var', (105, 111))	('gains', 'PosReg', (116, 121))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('multiple chromosomal abnormalities', 'Phenotype', 'HP:0040012', (62, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('chromosomal abnormalities', 'Disease', (71, 96))
131805	28096721	On pathology, in addition to the histological findings, the presence of MDM2 and CDK4 positivity due to 12q13-15 amplification is a useful marker, a finding also seen in dedifferentiated liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (187, 198))	('liposarcoma', 'Disease', 'MESH:D008080', (187, 198))	('12q13-15 amplification', 'Var', (104, 126))	('presence', 'Var', (60, 68))	('positivity', 'Var', (86, 96))	('CDK4', 'Gene', (81, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('CDK4', 'Gene', '1019', (81, 85))	('MDM2', 'Gene', '4193', (72, 76))	('MDM2', 'Gene', (72, 76))	('liposarcoma', 'Disease', (187, 198))
131821	28096721	Presence of peritumoral edema and heterogeneous T2 appearance of the tumor was also found to indicate a more aggressive myxoid tumor and was predictive of the development of pulmonary metastases.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('edema', 'Disease', (24, 29))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (69, 74))	('heterogeneous', 'Var', (34, 47))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('pulmonary metastases', 'Disease', 'MESH:D009362', (174, 194))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('more', 'PosReg', (104, 108))	('tumor', 'Disease', (16, 21))	('edema', 'Phenotype', 'HP:0000969', (24, 29))	('edema', 'Disease', 'MESH:D004487', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('aggressive myxoid tumor', 'Disease', 'MESH:D045888', (109, 132))	('aggressive myxoid tumor', 'Disease', (109, 132))	('pulmonary metastases', 'Disease', (174, 194))
131835	28096721	Given the MDM2 and CDK4 positivity of well-differentiated and dedifferentiated liposarcomas, early studies are currently underway to test MTTs against these receptors, with promising initial results.	('liposarcoma', 'Phenotype', 'HP:0012034', (79, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('well-differentiated', 'Disease', (38, 57))	('CDK4', 'Gene', (19, 23))	('positivity', 'Var', (24, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('CDK4', 'Gene', '1019', (19, 23))	('MDM2', 'Gene', '4193', (10, 14))	('MDM2', 'Gene', (10, 14))	('liposarcomas', 'Disease', 'MESH:D008080', (79, 91))	('liposarcomas', 'Phenotype', 'HP:0012034', (79, 91))	('liposarcomas', 'Disease', (79, 91))
131840	28096721	Studies have suggested that MRI features such as ill-defined margins, greater than 50% T2 hyperintense signal, T1 hyperintense foci (due to hemorrhage or coagulative necrosis), low apparent diffusion coefficient values, and early enhancement on the dynamic contrast-enhanced study should be considered suspicious for leiomyosarcomas.	('apparent diffusion coefficient values', 'MPA', (181, 218))	('leiomyosarcomas', 'Disease', (317, 332))	('hemorrhage', 'Disease', 'MESH:D006470', (140, 150))	('necrosis', 'Disease', 'MESH:D009336', (166, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (324, 331))	('T2 hyperintense signal', 'MPA', (87, 109))	('necrosis', 'Disease', (166, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (324, 332))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (317, 332))	('greater', 'Var', (70, 77))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (154, 174))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (317, 331))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (317, 332))	('hemorrhage', 'Disease', (140, 150))	('low', 'NegReg', (177, 180))	('enhancement', 'PosReg', (230, 241))
131857	28096721	Imatinib, a small molecule tyrosine kinase inhibitor approved for management of GIST, can inhibit several receptor tyrosine kinases (C-kit, PDGF, colony stimulating factor receptor) and therefore can be effective in other sarcomas which have activating mutations of these kinases.	('inhibit', 'NegReg', (90, 97))	('receptor tyrosine kinases', 'MPA', (106, 131))	('PDGF', 'Gene', (140, 144))	('sarcomas', 'Disease', (222, 230))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('C-kit', 'Gene', (133, 138))	('mutations', 'Var', (253, 262))	('C-kit', 'Gene', '3815', (133, 138))	('sarcomas', 'Disease', 'MESH:D012509', (222, 230))	('colony', 'MPA', (146, 152))	('sarcomas', 'Phenotype', 'HP:0100242', (222, 230))	('GIST', 'Phenotype', 'HP:0100723', (80, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
131861	28096721	Inhibitors of mTOR, a protein kinase that is integral to the phosphatidylinositol 3-kinase pathway, are FDA approved for second line treatment of metastatic renal cell carcinoma.	('mTOR', 'Gene', '2475', (14, 18))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('Inhibitors', 'Var', (0, 10))	('renal cell carcinoma', 'Disease', (157, 177))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))	('mTOR', 'Gene', (14, 18))
131879	27259270	Additionally, inclusion of the constitutively active promoter of the EWSR1 gene leads to high levels of expression.	('expression', 'MPA', (104, 114))	('EWSR1', 'Gene', (69, 74))	('EWSR1', 'Gene', '2130', (69, 74))	('inclusion', 'Var', (14, 23))
131880	27259270	As such, these chimeric transcription factors result in extensive transcriptional reprogramming in Ewing sarcoma cells.	('chimeric', 'Var', (15, 23))	('result in', 'Reg', (46, 55))	('Ewing sarcoma', 'Disease', (99, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (99, 112))	('transcriptional reprogramming', 'CPA', (66, 95))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (99, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))
131881	27259270	Mounting evidence suggests that EWS-ETS fusions not only drive tumor initiation, but are also critically implicated in disease progression, underscoring the significance of these proteins as therapeutic targets for this disease.	('tumor initiation', 'Disease', 'MESH:D009369', (63, 79))	('drive', 'PosReg', (57, 62))	('fusions', 'Var', (40, 47))	('implicated', 'Reg', (105, 115))	('tumor initiation', 'Disease', (63, 79))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('EWS-ETS', 'Gene', (32, 39))
131883	27259270	Acetylated histone marks, such as H3K27ac, have profound implications in EWS-FLI1-driven transactivation.	('implications', 'Reg', (57, 69))	('H3K27ac', 'Var', (34, 41))	('H3K27ac', 'Chemical', '-', (34, 41))
131889	27259270	Shortly after discovery of JQ1, several groups independently demonstrated that inhibition of BET proteins suppressed expression and activity of MYC, a prominent oncogenic transcription factor that has long been deemed as "undruggable".	('MYC', 'Gene', (144, 147))	('activity', 'MPA', (132, 140))	('expression', 'MPA', (117, 127))	('inhibition', 'Var', (79, 89))	('suppressed', 'NegReg', (106, 116))	('BET proteins', 'Protein', (93, 105))	('MYC', 'Gene', '4609', (144, 147))
131893	27259270	In this study, we demonstrate that Ewing sarcoma cells were highly sensitive to BET bromodomain inhibitors, JQ1 and i-BET762.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('i-BET762', 'Chemical', 'MESH:C554645', (116, 124))	('Ewing sarcoma', 'Disease', (35, 48))	('i-BET762', 'Var', (116, 124))
131897	27259270	RNA interference-mediated depletion of EWS-FLI1 in Ewing sarcoma cells disrupts this transcription program, leading to differentiation, growth inhibition and cell death.	('transcription program', 'MPA', (85, 106))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('disrupts', 'NegReg', (71, 79))	('depletion', 'Var', (26, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('EWS-FLI1', 'Gene', (39, 47))	('cell death', 'CPA', (158, 168))	('growth inhibition', 'CPA', (136, 153))	('Ewing sarcoma', 'Disease', (51, 64))	('differentiation', 'CPA', (119, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('leading to', 'Reg', (108, 118))
131898	27259270	On the contrary, introduction of EWS-FLI1 transforms mouse or human mesenchymal progenitor cells, which are putative cell of origin for Ewing sarcoma, and generates expression patterns that resemble Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (136, 149))	('transforms', 'Reg', (42, 52))	('mouse', 'CPA', (53, 58))	('Ewing sarcoma', 'Disease', (199, 212))	('EWS-FLI1', 'Gene', (33, 41))	('human', 'Species', '9606', (62, 67))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (199, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (136, 149))	('introduction', 'Var', (17, 29))	('mouse', 'Species', '10090', (53, 58))	('expression patterns', 'MPA', (165, 184))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (199, 212))
131908	27259270	Expression of these genes was decreased in a concentration-dependent manner following exposure to JQ1 in TC32 cells (Figure 1B).	('JQ1', 'Var', (98, 101))	('Expression', 'MPA', (0, 10))	('TC32', 'CellLine', 'CVCL:7151', (105, 109))	('decreased', 'NegReg', (30, 39))
131917	27259270	However, no significant downregulation of EWS-FLI1 mRNA levels were observed in both TC32 and TC71 cells following JQ1 treatment across a broad range of concentrations (Figure 2A).	('mRNA levels', 'MPA', (51, 62))	('JQ1', 'Var', (115, 118))	('TC71', 'CellLine', 'CVCL:2213', (94, 98))	('downregulation', 'NegReg', (24, 38))	('EWS-FLI1', 'Gene', (42, 50))	('TC32', 'CellLine', 'CVCL:7151', (85, 89))
131918	27259270	Although a minor decrease of EWS-FLI1 in TC71 cells treated with 10 mumol/L JQ1 could be detected, this change could be secondary to toxicity of JQ1 at high concentrations (Figure 2B).	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('toxicity', 'Disease', (133, 141))	('JQ1', 'Var', (76, 79))	('EWS-FLI1', 'Gene', (29, 37))	('decrease', 'NegReg', (17, 25))	('TC71', 'CellLine', 'CVCL:2213', (41, 45))
131920	27259270	Consistently, neither EWS-ERG nor EWS-FLI1 was significantly downregulated by JQ1 (Figure 2C).	('ERG', 'Gene', '2078', (26, 29))	('ERG', 'Gene', (26, 29))	('downregulated', 'NegReg', (61, 74))	('JQ1', 'Var', (78, 81))
131927	27259270	Although most previous studies attribute the activities of BET inhibitors to inhibition of BRD4, our results showed that knockdown of either BRD3 or BRD4 partially recapitulated the ability of BET inhibitors to downregulate EWS-FLI1 target genes (Figure 4A and Supplementary Figure 4B).	('knockdown', 'Var', (121, 130))	('downregulate', 'NegReg', (211, 223))	('EWS-FLI1 target genes', 'Gene', (224, 245))	('BRD4', 'Gene', (91, 95))	('BRD3', 'Gene', '8019', (141, 145))	('BRD4', 'Gene', '23476', (149, 153))	('BRD3', 'Gene', (141, 145))	('BRD4', 'Gene', (149, 153))	('BRD4', 'Gene', '23476', (91, 95))
131934	27259270	Because IGF1 is a direct target gene of EWS-FLI1, this autocrine loop is largely driven by EWS-FLI1 in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (103, 116))	('IGF1', 'Gene', (8, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('EWS-FLI1', 'Gene', (40, 48))	('Ewing sarcoma', 'Disease', (103, 116))	('IGF1', 'Gene', '3479', (8, 12))	('EWS-FLI1', 'Var', (91, 99))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (103, 116))
131937	27259270	In addition, JQ1 significantly decreased phosphorylation of IGF1R and AKT in multiple Ewing sarcoma cell lines, including 5838 that expresses EWS-ERG (Figure 5B).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('AKT', 'Gene', '207', (70, 73))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 99))	('ERG', 'Gene', '2078', (146, 149))	('IGF1R', 'Gene', (60, 65))	('decreased', 'NegReg', (31, 40))	('AKT', 'Gene', (70, 73))	('phosphorylation', 'MPA', (41, 56))	('Ewing sarcoma', 'Disease', (86, 99))	('JQ1', 'Var', (13, 16))	('ERG', 'Gene', (146, 149))	('IGF1R', 'Gene', '3480', (60, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
131941	27259270	We next examined how inhibition of BET proteins might affect proliferation and survival of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (91, 104))	('BET proteins', 'Protein', (35, 47))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('inhibition', 'Var', (21, 31))	('survival', 'CPA', (79, 87))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('affect', 'Reg', (54, 60))	('proliferation', 'CPA', (61, 74))
131942	27259270	In all tested Ewing sarcoma cell lines, we showed that JQ1 and i-BET762 decreased cell viability in a concentration-dependent manner (Figure 6A and Supplementary Figure 5A).	('cell viability', 'CPA', (82, 96))	('JQ1', 'Var', (55, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('decreased', 'NegReg', (72, 81))	('Ewing sarcoma', 'Disease', (14, 27))	('i-BET762', 'Chemical', 'MESH:C554645', (63, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (14, 27))	('i-BET762', 'Var', (63, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (14, 27))
131946	27259270	These experiments showed that transient exposure to 500 nmol/L JQ1 was sufficient to block the majority of colony formation capacity in Ewing sarcoma lines (Figure 6B), indicating that BET inhibition imposes prolonged damage to tumorigenicity of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (246, 259))	('Ewing sarcoma lines', 'Disease', (136, 155))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (246, 259))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (246, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('Ewing sarcoma lines', 'Disease', 'MESH:C563168', (136, 155))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('tumor', 'Disease', (228, 233))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (136, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('JQ1', 'Var', (63, 66))	('block', 'NegReg', (85, 90))	('inhibition', 'NegReg', (189, 199))	('colony formation capacity', 'CPA', (107, 132))
131953	27259270	In both TC32 and TC71 xenograft models, tumor growth was either halted or marginally increased following administration of JQ1, whereas tumors in the control arm rapidly grew (Figure 7A and 7B).	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('halted', 'NegReg', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('JQ1', 'Var', (123, 126))	('TC32', 'CellLine', 'CVCL:7151', (8, 12))	('TC71', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('increased', 'PosReg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('TC71', 'CellLine', 'CVCL:2213', (17, 21))	('tumor', 'Disease', (136, 141))
131956	27259270	However, cleaved caspase 3 staining was significantly enhanced in JQ1-treated tumors, suggesting that increased cell death may play a key role in mediating the in vivo activities of BET inhibitors against Ewing sarcoma.	('tumors', 'Disease', (78, 84))	('cleaved', 'MPA', (9, 16))	('caspase 3', 'Gene', '836', (17, 26))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (205, 218))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (205, 218))	('staining', 'MPA', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('Ewing sarcoma', 'Disease', (205, 218))	('enhanced', 'PosReg', (54, 62))	('caspase 3', 'Gene', (17, 26))	('JQ1-treated', 'Var', (66, 77))
131964	27259270	For example, the lysine demethylase LSD1 (also known as KDMA1) was recently identified as an important epigenetic partner of EWS-FLI1 and LSD1 inhibitors showed promising activities in preclinical Ewing sarcoma models.	('Ewing sarcoma', 'Disease', (197, 210))	('LSD1', 'Gene', (138, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('LSD1', 'Gene', '23028', (138, 142))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (197, 210))	('LSD1', 'Gene', (36, 40))	('inhibitors', 'Var', (143, 153))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (197, 210))	('LSD1', 'Gene', '23028', (36, 40))	('activities', 'MPA', (171, 181))	('lysine', 'Chemical', 'MESH:D008239', (17, 23))
131974	27259270	Many other tumors sensitive to BET inhibitors are also driven by aberrantly activated oncogenic transcription factors.	('aberrantly', 'Var', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('oncogenic', 'Protein', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('driven by', 'Reg', (55, 64))
131976	27259270	Hence, our findings and mounting evidence suggest a model that BET inhibitors have particularly important therapeutic indications in cancers driven by amplified or mutated transcription factors.	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('mutated', 'Var', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
131981	27259270	Our results showed that BET inhibition downregulated top-ranked EWS-FLI1-activated genes that are associated with high levels of H3K27ac in adjacent chromatin regions, but did not upregulate EWS-FLI1-repressed genes associated with low levels of H3K27ac.	('EWS-FLI1-activated genes', 'Gene', (64, 88))	('H3K27ac', 'Chemical', '-', (246, 253))	('H3K27ac', 'Chemical', '-', (129, 136))	('H3K27ac', 'Var', (129, 136))	('downregulated', 'NegReg', (39, 52))
131995	27259270	It is an appealing strategy using BET inhibitors to block the IGF1 autocrine mechanism in Ewing sarcoma patients with high IGF1R expression, which is expected to spare normal tissues from toxicity of anti-IGF1R therapy.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('IGF1', 'Gene', '3479', (205, 209))	('IGF1R', 'Gene', (123, 128))	('toxicity', 'Disease', 'MESH:D064420', (188, 196))	('IGF1', 'Gene', '3479', (62, 66))	('Ewing sarcoma', 'Disease', (90, 103))	('IGF1', 'Gene', '3479', (123, 127))	('IGF1', 'Gene', (205, 209))	('high', 'Var', (118, 122))	('toxicity', 'Disease', (188, 196))	('IGF1R', 'Gene', '3480', (205, 210))	('IGF1', 'Gene', (62, 66))	('patients', 'Species', '9606', (104, 112))	('IGF1', 'Gene', (123, 127))	('IGF1R', 'Gene', (205, 210))	('high IGF1R', 'Phenotype', 'HP:0030269', (118, 128))	('IGF1R', 'Gene', '3480', (123, 128))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 103))
131997	27259270	These findings suggest a novel epigenetic-based treatment for Ewing sarcoma, particularly those resistant to currently available chemotherapies.	('Ewing sarcoma', 'Disease', (62, 75))	('epigenetic-based', 'Var', (31, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (62, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (62, 75))
131998	27259270	Our results also suggest a therapeutic paradigm that tumors driven by aberrantly activated oncogenic transcription factors are preferential targets for BET inhibitors.	('oncogenic transcription factors', 'Gene', (91, 122))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('aberrantly activated', 'Var', (70, 90))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
132006	27259270	The pLKO.1 lentiviral vectors encoding the non-targeting shRNA or shRNA sequences specific to BRD2 (TRCN000006310), BRD3 (TRCN0000021376), and BRD4 (TRCN0000196576) have been described in our previous publications.	('TRCN000006310', 'Var', (100, 113))	('BRD4', 'Gene', '23476', (143, 147))	('BRD4', 'Gene', (143, 147))	('BRD3', 'Gene', '8019', (116, 120))	('BRD3', 'Gene', (116, 120))	('TRCN0000196576', 'Var', (149, 163))	('BRD2', 'Gene', '6046', (94, 98))	('BRD2', 'Gene', (94, 98))	('TRCN0000021376', 'Var', (122, 136))
132048	27369431	Immunotherapy in Ewing sarcoma has been shown to have a promising potential role in vitro and is being tested in two clinical trials by administrating donor NK-cells (NCT01287104, NCT02100891).	('Ewing sarcoma', 'Disease', (17, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (17, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('donor', 'Species', '9606', (151, 156))	('NCT01287104', 'Var', (167, 178))
132060	27369431	Ewing sarcoma diagnosis was established according to WHO criteria, including immunohistochemistry (IHC) and Ewing sarcoma breakpoint region 1 (EWSR1) translocation detection either by real-time quantitative reverse transcriptase PCR (RT-Q-PCR) or by interphase fluorescence in situ hybridization (FISH).	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', (143, 148))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('EWSR1', 'Gene', '2130', (143, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('EWS', 'Phenotype', 'HP:0012254', (143, 146))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('translocation', 'Var', (150, 163))
132070	27369431	In brief, FFPE tumor sections were stained for CD3 (Dako, Heverlee, Belgium), CD4 and CD8 (Novocastra, Newcastle upon Tyne, UK) and scanned with Zeiss LSM-510 confocal microscope (Carl Zeiss AG, Gottingen, Germany).	('CD4', 'Gene', '920', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CD8', 'Gene', (86, 89))	('CD8', 'Gene', '925', (86, 89))	('tumor', 'Disease', (15, 20))	('CD3', 'Var', (47, 50))	('CD4', 'Gene', (78, 81))
132137	23543617	Frequently dysregulated in cancer, miRs have shed new light on molecular mechanisms of oncogenesis, and have generated substantial interest as biomarkers, and novel therapeutic agents and targets.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('miRs', 'Var', (35, 39))	('cancer', 'Disease', (27, 33))	('dysregulated', 'Reg', (11, 23))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
132139	23543617	Findings indicate that alterations in miR expression in Ewing Sarcoma are widespread, involve both EWS/Ets oncogenic fusion-dependent and independent mechanisms, and contribute to malignant phenotypes.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('Sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('miR', 'Gene', (38, 41))	('involve', 'Reg', (86, 93))	('EWS', 'Gene', (99, 102))	('alterations', 'Var', (23, 34))	('Ewing Sarcoma', 'Disease', (56, 69))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('EWS', 'Gene', '2130', (99, 102))
132144	23543617	In cancer, miRs function as context-dependent tumor suppressors or oncogenes, capable, through their molecular function as regulators of gene expression, of modifying all aspects of tumorigenesis, including tumor cell proliferation/apoptosis, invasion/metastasis, stem-like properties, and angiogenesis (Sotiropoulou et al.,; Visone and Croce,).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (182, 187))	('miRs', 'Var', (11, 15))	('angiogenesis', 'CPA', (290, 302))	('stem-like properties', 'CPA', (264, 284))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('modifying', 'Reg', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (207, 212))	('invasion/metastasis', 'CPA', (243, 262))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
132146	23543617	Examples of successful preclinical therapeutic trials in pediatric cancers include miR-380-5p replacement in neuroblastoma (Swarbrick et al.,), and miR replacement/anti-miR combination therapy, involving miR-100 and miR-371 clusters, in hepatoblastoma (Cairo et al.,).	('miR-380-5p replacement', 'Var', (83, 105))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('miR-371', 'Gene', (216, 223))	('miR-100', 'Gene', '406892', (204, 211))	('pediatric cancers', 'Disease', 'MESH:D009369', (57, 74))	('pediatric cancers', 'Disease', (57, 74))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (237, 251))	('neuroblastoma', 'Disease', 'MESH:D009447', (109, 122))	('hepatoblastoma', 'Disease', (237, 251))	('miR-380-5p', 'Chemical', '-', (83, 93))	('miR-371', 'Gene', '442916', (216, 223))	('neuroblastoma', 'Disease', (109, 122))	('miR-100', 'Gene', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('neuroblastoma', 'Phenotype', 'HP:0003006', (109, 122))	('hepatoblastoma', 'Disease', 'MESH:D018197', (237, 251))	('miR', 'Var', (148, 151))
132158	23543617	MiR-145 was the miR most consistently changed, namely reduced upon EWS/Fli1 depletion, and underexpressed in Ewing Sarcoma relative to MSCs.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('Fli1', 'Gene', '2313', (71, 75))	('underexpressed', 'NegReg', (91, 105))	('EWS', 'Gene', (67, 70))	('MiR-145', 'Gene', (0, 7))	('Ewing Sarcoma', 'Disease', (109, 122))	('EWS', 'Gene', '2130', (67, 70))	('Sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('reduced', 'NegReg', (54, 61))	('Fli1', 'Gene', (71, 75))	('MiR-145', 'Gene', '406937', (0, 7))	('depletion', 'Var', (76, 85))
132159	23543617	In support of a tumor suppressive role, the authors showed that miR-145 replacement results in inhibition of anchorage-independent growth of Ewing Sarcoma cells.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (141, 154))	('anchorage-independent growth', 'CPA', (109, 137))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('replacement', 'Var', (72, 83))	('inhibition', 'NegReg', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('miR-145', 'Gene', (64, 71))	('miR-145', 'Gene', '406937', (64, 71))	('tumor', 'Disease', (16, 21))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (141, 154))	('Ewing Sarcoma', 'Disease', (141, 154))	('Sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
132164	23543617	Focusing on a group of miRs upregulated following EWS/Fli1 knock-down (miRs 22, 100, 125b, 221/222, 27a, and 29a), they showed that levels of these miRs vary specifically with EWS/Fli1 manipulation, including EWS/Fli1 depletion with different shRNAs and ectopic EWS/Fli1 expression in a heterologous fusion-negative cell line, and that these miRs are underexpressed in Ewing Sarcoma cell lines relative to MSCs.	('depletion', 'NegReg', (218, 227))	('Fli1', 'Gene', '2313', (54, 58))	('EWS', 'Gene', '2130', (262, 265))	('Fli1', 'Gene', '2313', (213, 217))	('EWS', 'Gene', (50, 53))	('Fli1', 'Gene', '2313', (180, 184))	('Fli1', 'Gene', '2313', (266, 270))	('EWS', 'Gene', (176, 179))	('Fli1', 'Gene', (54, 58))	('ectopic', 'Var', (254, 261))	('upregulated', 'PosReg', (28, 39))	('Fli1', 'Gene', (213, 217))	('EWS', 'Gene', '2130', (209, 212))	('Fli1', 'Gene', (180, 184))	('EWS', 'Gene', (262, 265))	('Fli1', 'Gene', (266, 270))	('knock-down', 'Var', (59, 69))	('EWS', 'Gene', '2130', (50, 53))	('Ewing Sarcoma', 'Disease', (369, 382))	('Sarcoma', 'Phenotype', 'HP:0100242', (375, 382))	('EWS', 'Gene', '2130', (176, 179))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (369, 382))	('manipulation', 'Var', (185, 197))	('EWS', 'Gene', (209, 212))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (369, 382))
132165	23543617	These studies suggest that repression of select miRs promotes EWS/Fli1-driven oncogenesis by augmenting IGF pathway activity.	('Fli1', 'Gene', (66, 70))	('promotes', 'PosReg', (53, 61))	('miRs', 'Gene', (48, 52))	('augmenting', 'NegReg', (93, 103))	('IGF pathway', 'Pathway', (104, 115))	('Fli1', 'Gene', '2313', (66, 70))	('oncogenesis', 'Disease', (78, 89))	('activity', 'MPA', (116, 124))	('repression', 'Var', (27, 37))	('EWS', 'Gene', '2130', (62, 65))	('EWS', 'Gene', (62, 65))
132166	23543617	also profiled miRs in A673 cells following EWS/Fli1 depletion, but used an inducible shRNA approach and Illumina BeadChip technology as the profiling platform.	('profiled', 'Reg', (5, 13))	('Fli1', 'Gene', '2313', (47, 51))	('Fli1', 'Gene', (47, 51))	('EWS', 'Gene', '2130', (43, 46))	('EWS', 'Gene', (43, 46))	('depletion', 'Var', (52, 61))
132168	23543617	Focusing on miRs targeting CD99, they showed that miR-30a-5p, a miR downregulated by EWS/Fli1, contributes to the control of CD99 expression by EWS/Fli1.	('expression', 'MPA', (130, 140))	('Fli1', 'Gene', (148, 152))	('miR-30a-5p', 'Var', (50, 60))	('CD99', 'Gene', '4267', (125, 129))	('CD99', 'Gene', (27, 31))	('EWS', 'Gene', '2130', (144, 147))	('Fli1', 'Gene', '2313', (89, 93))	('control', 'MPA', (114, 121))	('EWS', 'Gene', '2130', (85, 88))	('EWS', 'Gene', (85, 88))	('CD99', 'Gene', (125, 129))	('Fli1', 'Gene', '2313', (148, 152))	('Fli1', 'Gene', (89, 93))	('EWS', 'Gene', (144, 147))	('CD99', 'Gene', '4267', (27, 31))
132169	23543617	The authors further showed that overexpression of miR-30a-5p inhibits proliferation of and invasion by Ewing Sarcoma cells.	('overexpression', 'PosReg', (32, 46))	('miR-30a-5p', 'Var', (50, 60))	('invasion', 'CPA', (91, 99))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (103, 116))	('Sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (103, 116))	('Ewing Sarcoma', 'Disease', (103, 116))	('inhibits', 'NegReg', (61, 69))
132174	23543617	The authors showed that EWS/Fli1 directly represses let-7a expression, and that forced replacement of let-7a inhibits Ewing Sarcoma tumor xenograft growth, in part through regulation of HMGA2 levels.	('EWS', 'Gene', '2130', (24, 27))	('EWS', 'Gene', (24, 27))	('Ewing Sarcoma tumor', 'Disease', (118, 137))	('HMGA2', 'Gene', (186, 191))	('let-7a', 'Gene', (52, 58))	('represses', 'NegReg', (42, 51))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('Sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('regulation', 'Reg', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('replacement', 'Var', (87, 98))	('expression', 'MPA', (59, 69))	('inhibits', 'NegReg', (109, 117))	('Fli1', 'Gene', '2313', (28, 32))	('Ewing Sarcoma tumor', 'Disease', 'MESH:C563168', (118, 137))	('HMGA2', 'Gene', '8091', (186, 191))	('Fli1', 'Gene', (28, 32))	('let-7a', 'Gene', (102, 108))
132180	23543617	However, different controls, shRNAs, and culture conditions, as well as the precise depth of EWS/Fli1 knock-down, represent additional variables.	('Fli1', 'Gene', (97, 101))	('knock-down', 'Var', (102, 112))	('EWS', 'Gene', '2130', (93, 96))	('EWS', 'Gene', (93, 96))	('Fli1', 'Gene', '2313', (97, 101))
132184	23543617	The profile similarities between these studies suggest that, as observed with gene expression profiles (Tirode et al.,), depletion of EWS/Fli1 can give rise to a miR profile resembling MSCs.	('give rise to', 'Reg', (147, 159))	('MSCs', 'Disease', (185, 189))	('Fli1', 'Gene', '2313', (138, 142))	('EWS', 'Gene', '2130', (134, 137))	('EWS', 'Gene', (134, 137))	('depletion', 'Var', (121, 130))	('miR profile', 'MPA', (162, 173))	('Fli1', 'Gene', (138, 142))
132186	23543617	Other noteworthy trends discernible from a cross-study comparison of miR alterations include the fairly consistent upregulation of members of the paralogous 17 ~ 92a, 106b ~ 25, and 106a ~ 363 "oncomiR" clusters, and downregulation of miR-145.	('upregulation', 'PosReg', (115, 127))	('alterations', 'Var', (73, 84))	('miR-145', 'Gene', (235, 242))	('miR-145', 'Gene', '406937', (235, 242))	('downregulation', 'NegReg', (217, 231))	('miR', 'Gene', (69, 72))
132187	23543617	The biological consequences of most of the EWS/Fli1-related miR alterations identified in the above profiling studies await characterization.	('Fli1', 'Gene', '2313', (47, 51))	('miR', 'Gene', (60, 63))	('Fli1', 'Gene', (47, 51))	('alterations', 'Var', (64, 75))	('EWS', 'Gene', '2130', (43, 46))	('EWS', 'Gene', (43, 46))
132198	23543617	They further showed that TARBP2 depletion in Ewing Sarcoma cell lines results in downregulation of a group of miRs depleted in CD133+ cells and enhanced tumor xenograft growth, while augmentation of TARBP2 activity, via treatment with the fluoroquinolone-class antibiotic enoxacin, results in upregulation of these miRs and impaired tumor xenograft growth.	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('activity', 'MPA', (206, 214))	('upregulation', 'PosReg', (293, 305))	('impaired tumor', 'Disease', (324, 338))	('enhanced', 'PosReg', (144, 152))	('tumor', 'Disease', (153, 158))	('fluoroquinolone', 'Chemical', 'MESH:D024841', (239, 254))	('impaired tumor', 'Disease', 'MESH:D015417', (324, 338))	('CD133', 'Gene', (127, 132))	('CD133', 'Gene', '8842', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('augmentation', 'PosReg', (183, 195))	('Ewing Sarcoma', 'Disease', (45, 58))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('TARBP2', 'Gene', '6895', (199, 205))	('tumor', 'Disease', (333, 338))	('TARBP2', 'Gene', (199, 205))	('Sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('TARBP2', 'Gene', (25, 31))	('depletion', 'Var', (32, 41))	('TARBP2', 'Gene', '6895', (25, 31))	('enoxacin', 'Chemical', 'MESH:D015365', (272, 280))	('downregulation', 'NegReg', (81, 95))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (45, 58))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (333, 338))
132203	23543617	In further analyses, low levels of miR-34a emerged as a particularly robust predictor of early relapse.	('early relapse', 'CPA', (89, 102))	('miR-34a', 'Gene', '407040', (35, 42))	('low levels', 'Var', (21, 31))	('miR-34a', 'Gene', (35, 42))
132205	23543617	Consistent with the established role of p53 as a regulator of miR-34a expression, miR-34a levels were found to be low in Ewing Sarcoma cell lines with p53 inactivating mutations.	('inactivating mutations', 'Var', (155, 177))	('p53', 'Gene', '7157', (151, 154))	('p53', 'Gene', (40, 43))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (121, 134))	('miR-34a', 'Gene', '407040', (82, 89))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (121, 134))	('low', 'NegReg', (114, 117))	('p53', 'Gene', '7157', (40, 43))	('miR-34a', 'Gene', (82, 89))	('Ewing Sarcoma', 'Disease', (121, 134))	('p53', 'Gene', (151, 154))	('Sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('miR-34a', 'Gene', (62, 69))	('miR-34a', 'Gene', '407040', (62, 69))
132206	23543617	Moreover, one tumor with low miR-34a levels was found to have a p53 mutation.	('tumor', 'Disease', (14, 19))	('mutation', 'Var', (68, 76))	('miR-34a', 'Gene', '407040', (29, 36))	('miR-34a', 'Gene', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('p53', 'Gene', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('p53', 'Gene', '7157', (64, 67))
132208	23543617	A question of interest for future studies is the extent of overlap between inactivation of the p53 pathway and miR-34a downregulation in Ewing Sarcoma tumors.	('inactivation', 'Var', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('miR-34a', 'Gene', '407040', (111, 118))	('downregulation', 'NegReg', (119, 133))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('miR-34a', 'Gene', (111, 118))	('Ewing Sarcoma tumors', 'Disease', (137, 157))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('Ewing Sarcoma tumors', 'Disease', 'MESH:C563168', (137, 157))	('Sarcoma', 'Phenotype', 'HP:0100242', (143, 150))
132214	23543617	Further, three other studies of EWS/Fli1-repressed miRs [miRs 30a (Franzetti et al.,) and 145 (Riggi et al.,), and let-7a (De Vito et al.,)] showed EWS/Fli1-dependent downregulation of the activity of the putative miR promoters in reporter assays.	('downregulation', 'NegReg', (167, 181))	('let-7a', 'Var', (115, 121))	('Fli1', 'Gene', (152, 156))	('Fli1', 'Gene', (36, 40))	('EWS', 'Gene', '2130', (148, 151))	('EWS', 'Gene', (148, 151))	('EWS', 'Gene', '2130', (32, 35))	('EWS', 'Gene', (32, 35))	('Fli1', 'Gene', '2313', (152, 156))	('activity', 'MPA', (189, 197))	('Fli1', 'Gene', '2313', (36, 40))
132231	23543617	The functional consequences of this to miR regulation and disease phenotype in Ewing Sarcoma are currently unknown, but changes in Dicer levels can profoundly influence cancer phenotypes (Lambertz et al.,; Nittner et al.,).	('cancer', 'Disease', (169, 175))	('Dicer', 'Gene', '23405', (131, 136))	('Dicer', 'Gene', (131, 136))	('changes', 'Var', (120, 127))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Ewing Sarcoma', 'Disease', (79, 92))	('Sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('influence', 'Reg', (159, 168))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
132235	23543617	Preclinical animal studies have also suggested potential candidate strategies for miR-based therapeutics, including replacement of miR-145 (Riggi et al.,; De Vito et al.,), miR-143 (De Vito et al.,) and let-7a (De Vito et al.,), and augmentation of TARBP2 activity (De Vito et al.,).	('replacement', 'Var', (116, 127))	('let-7a', 'Gene', (203, 209))	('augmentation', 'NegReg', (233, 245))	('miR-145', 'Gene', (131, 138))	('miR-145', 'Gene', '406937', (131, 138))	('activity', 'MPA', (256, 264))	('TARBP2', 'Gene', (249, 255))	('miR-143', 'Gene', '406935', (173, 180))	('TARBP2', 'Gene', '6895', (249, 255))	('miR-143', 'Gene', (173, 180))
132237	23543617	Particularly intriguing is the role of miRs like miR-21 and miRs-221/222, identified as upregulated and pro-oncogenic in most malignancies (Sotiropoulou et al.,; Visone and Croce,), but observed to be downregulated in most profiling analyses of Ewing Sarcoma (see Table 1).	('Sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('Ewing Sarcoma', 'Disease', (245, 258))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (245, 258))	('upregulated', 'PosReg', (88, 99))	('malignancies', 'Disease', (126, 138))	('miR-21', 'Gene', (49, 55))	('miRs-221/222', 'Var', (60, 72))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (245, 258))	('miR-21', 'Gene', '406991', (49, 55))
132323	33489900	ABCB7 is a mitochondrial iron transporter, and the expression of ABCB7 is associated with the prognosis of glioma patients.	('iron', 'Chemical', 'MESH:D007501', (25, 29))	('ABCB7', 'Gene', (0, 5))	('ABCB7', 'Gene', '22', (0, 5))	('ABCB7', 'Gene', (65, 70))	('ABCB7', 'Gene', '22', (65, 70))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('patients', 'Species', '9606', (114, 122))	('expression', 'Var', (51, 61))	('associated with', 'Reg', (74, 89))	('glioma', 'Disease', (107, 113))
132324	33489900	The loss of ABCB7 not only reduces the invasiveness of tumor cells but also results in cell death through dysregulated intracellular iron circulation and mitochondrial ROS generation.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('reduces', 'NegReg', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('iron', 'Chemical', 'MESH:D007501', (133, 137))	('ABCB7', 'Gene', '22', (12, 17))	('ABCB7', 'Gene', (12, 17))	('mitochondrial ROS generation', 'MPA', (154, 182))	('cell death', 'CPA', (87, 97))	('dysregulated intracellular iron circulation', 'MPA', (106, 149))	('results in', 'Reg', (76, 86))	('loss', 'Var', (4, 8))
132341	33489900	In patients with pancreatic cancer, the high expression of SLC25A37 is associated with poor prognosis.	('high', 'Var', (40, 44))	('pancreatic cancer', 'Disease', (17, 34))	('SLC25A37', 'Gene', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('patients', 'Species', '9606', (3, 11))	('SLC25A37', 'Gene', '51312', (59, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))
132389	33198264	After proximal femoral replacement hemiarthroplasty, monopolar or bipolar, a median of seven (95% CI: 5-8) different sports were recommended by respondents; 12 (95% CI: 10-15) were allowed, if asked by the patient; and 20 (95% CI: 17-23) were not allowed (Figure 3).	('bipolar', 'Disease', (66, 73))	('patient', 'Species', '9606', (206, 213))	('bipolar', 'Disease', 'MESH:D001714', (66, 73))	('monopolar', 'Var', (53, 62))
132391	33198264	After proximal tibial replacement hinge TKR with soft tissue extensor reconstruction probable gastrocnemius rotation, a median of four (95% CI: 3-7) sports were recommended; 10 (95% CI: 9-13) were allowed, if asked; and 22 (95% CI: 19-26) were not allowed.	('proximal tibial replacement hinge', 'Phenotype', 'HP:0005892', (6, 39))	('tibial replacement', 'Phenotype', 'HP:0005929', (15, 33))	('gastrocnemius rotation', 'Disease', 'MESH:D009069', (94, 116))	('hinge', 'Var', (34, 39))	('gastrocnemius rotation', 'Disease', (94, 116))
132460	32374488	Emerging data has revealed key insights into the biology of the translocations that drive these tumors, suggesting that molecularly targeted approaches and epigenetic modifications could be promising treatment strategies.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('epigenetic', 'Var', (156, 166))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('translocations', 'Var', (64, 78))
132495	32374488	Many patients with SS had treatment other than systemic anticancer therapy during any line of therapy, including metastectomy (n = 114 [45.8%]), radiation (n = 52 [20.9%]), radiofrequency ablation (n = 7 [2.8%]), and cryoablation (n = 2 [0.8%]).	('patients', 'Species', '9606', (5, 13))	('SS', 'Phenotype', 'HP:0012570', (19, 21))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('metastectomy', 'Disease', (113, 125))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cryoablation', 'Var', (217, 229))
132525	32374488	For patients with MRCL in first-line systemic anticancer therapy, the median OS for doxorubicin plus ifosfamide (n = 33), single agent doxorubicin (n = 20), and single agent trabectedin (n = 8) was 27.8, 54.6, and 28.8 months, respectively.	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('MRCL', 'Phenotype', 'HP:0012268', (18, 22))	('MRCL', 'Var', (18, 22))	('trabectedin', 'Chemical', 'MESH:D000077606', (174, 185))	('patients', 'Species', '9606', (4, 12))	('ifosfamide', 'Chemical', 'MESH:D007069', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('doxorubicin', 'Chemical', 'MESH:D004317', (135, 146))
132617	31015077	CD99 positivity in MS can cause diagnostic confusion with small round blue cell tumors.	('CD99', 'Gene', '4267', (0, 4))	('positivity', 'Var', (5, 15))	('confusion', 'Phenotype', 'HP:0001289', (43, 52))	('blue cell tumors', 'Disease', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CD99', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('blue cell tumors', 'Disease', 'MESH:D005935', (70, 86))
132619	31015077	Fluorescent in situ hybridization and/or cytogenetic studies can detect chromosomal aberrations such as monosomy 7, trisomy 8, MLL rearrangement, inv (16), monosomy 16, 16q, 5q, 20q, and trisomy 11 in around 55% of the cases.	('inv (16', 'Var', (146, 153))	('MLL', 'Gene', (127, 130))	('trisomy', 'Disease', (116, 123))	('trisomy 11', 'Var', (187, 197))	('MLL', 'Gene', '4297', (127, 130))	('monosomy 16', 'Var', (156, 167))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (72, 95))	('monosomy 7', 'Var', (104, 114))	('rearrangement', 'Var', (131, 144))	('16q', 'Var', (169, 172))
132620	31015077	About 16% cases show evidence of (nucleophosmin) NPM1 mutation.	('mutation', 'Var', (54, 62))	('NPM1', 'Gene', '4869', (49, 53))	('NPM1', 'Gene', (49, 53))	('nucleophosmin', 'Gene', '4869', (34, 47))	('nucleophosmin', 'Gene', (34, 47))
132771	28786923	reported the risk ratio for radiotherapy vs. no radiotherapy was 3.34 for malignant brain tumors, and 4.06 for meningiomas.	('brain tumors', 'Phenotype', 'HP:0030692', (84, 96))	('malignant brain tumors', 'Disease', 'MESH:D001932', (74, 96))	('malignant brain tumors', 'Disease', (74, 96))	('meningiomas', 'Disease', (111, 122))	('meningiomas', 'Disease', 'MESH:D008577', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('brain tumor', 'Phenotype', 'HP:0030692', (84, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('meningiomas', 'Phenotype', 'HP:0002858', (111, 122))	('radiotherapy', 'Var', (28, 40))	('meningioma', 'Phenotype', 'HP:0002858', (111, 121))
132800	28786923	Genetic alterations similar to those described in spontaneous high-grade gliomas, with the exception of PTEN mutations, were also observed in radiation-induced gliomas.	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('gliomas', 'Disease', (160, 167))	('observed', 'Reg', (130, 138))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('mutations', 'Var', (109, 118))	('PTEN', 'Gene', '5728', (104, 108))	('PTEN', 'Gene', (104, 108))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('gliomas', 'Disease', (73, 80))
132827	23785504	Using CFSE as a probe, better migration of T cells was noted within TME from NLGP treated mice than PBS cohort.	('better', 'PosReg', (23, 29))	('rat', 'Species', '10116', (33, 36))	('NLGP', 'Var', (77, 81))	('mice', 'Species', '10090', (90, 94))	('PBS', 'Chemical', '-', (100, 103))	('migration', 'CPA', (30, 39))
132833	23785504	The remedial strategies are designed with a major aim to optimize the antitumor immunity in the tumor vicinity, as the alterations in the tumor microenvironment (TME) are dominantly manifested as an impaired immune response.	('rat', 'Species', '10116', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (96, 101))	('rat', 'Species', '10116', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (74, 79))	('alterations', 'Var', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
132845	23785504	NLGP activates T cells, NK cells, inhibits suppressor Tregs, promote type 1 cytokines and maintains type 1, anti-tumor chemokine milieu, thereby, induces antigen specific tumor killing, as documented in vitro  and in vivo .	('tumor', 'Disease', (113, 118))	('type 1', 'MPA', (100, 106))	('maintains', 'PosReg', (90, 99))	('inhibits', 'NegReg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('T cells', 'CPA', (15, 22))	('promote', 'PosReg', (61, 68))	('activates', 'PosReg', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('induces', 'PosReg', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('type 1 cytokines', 'MPA', (69, 85))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('NK cells', 'CPA', (24, 32))	('tumor', 'Disease', (171, 176))	('NLGP', 'Var', (0, 4))	('suppressor Tregs', 'CPA', (43, 59))
132847	23785504	As CD8+ T cells are impregnated within TME, it might obtain some unexplored stimulatory or suppressive signals from their environment, crucial for tumor induced dysregulation of T cell functions.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('dysregulation of T', 'Disease', (161, 179))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('CD8+', 'Var', (3, 7))	('dysregulation of T', 'Disease', 'MESH:D021081', (161, 179))
132880	23785504	It was observed from experimental results that due to exposure of T cells to NLGP-TME, higher proportion of CD69 marker was expressed on T cells, in comparison to those cells exposed to PBS-TME (Figure 5A).	('expressed', 'MPA', (124, 133))	('CD69', 'Gene', '12515', (108, 112))	('NLGP-TME', 'Chemical', '-', (77, 85))	('CD69', 'Gene', (108, 112))	('NLGP-TME', 'Var', (77, 85))	('PBS-TME', 'Chemical', '-', (186, 193))	('higher', 'PosReg', (87, 93))
132882	23785504	NLGP-TME significantly enhances proliferation of T cells in comparison to PBS-TME (Figure 5B).	('NLGP-TME', 'Chemical', '-', (0, 8))	('enhances', 'PosReg', (23, 31))	('rat', 'Species', '10116', (39, 42))	('proliferation', 'CPA', (32, 45))	('PBS-TME', 'Chemical', '-', (74, 81))	('NLGP-TME', 'Var', (0, 8))
132888	23785504	Poor cytotoxic ability of PBS-TME exposed CD8+ T cells was partially recovered following neutralization of TGFbeta, VEGF, IL-10 and IL-6 in the system.	('IL-10', 'Gene', '16153', (122, 127))	('cytotoxic ability', 'CPA', (5, 22))	('VEGF', 'Gene', '22339', (116, 120))	('TGFbeta', 'Gene', '21803', (107, 114))	('IL-6', 'Gene', '16193', (132, 136))	('IL-10', 'Gene', (122, 127))	('neutralization', 'Var', (89, 103))	('VEGF', 'Gene', (116, 120))	('PBS-TME', 'Chemical', '-', (26, 33))	('IL-6', 'Gene', (132, 136))	('TGFbeta', 'Gene', (107, 114))
132891	23785504	On the otherhand, neutralization of IL-12 showed a marked decrease in cytotoxic ability of PBS-TME exposed CD8+ T cells (Figure 5D).	('neutralization', 'Var', (18, 32))	('decrease', 'NegReg', (58, 66))	('PBS-TME', 'Chemical', '-', (91, 98))	('IL-12', 'Gene', (36, 41))	('cytotoxic ability', 'CPA', (70, 87))
132899	23785504	Western blotting data showed the presence of greater amount of pNFAT in NLGP-TME exposed CD8+ T cells, in comparison to PBS-TME and ionomycin exposed control cells (Figure 6C).	('NLGP-TME', 'Var', (72, 80))	('greater', 'PosReg', (45, 52))	('ionomycin', 'Chemical', 'MESH:D015759', (132, 141))	('NLGP-TME', 'Chemical', '-', (72, 80))	('PBS-TME', 'Chemical', '-', (120, 127))
132905	23785504	CD8+ T cells either received no treatment or exposed to NLGP-TME expressed lower content of FasR mRNA compared to those exposed to PBS-TME, whereas, the level of mRNA content of cFLIP remains same for all three groups (Figure 6D.1 and D.2).	('lower', 'NegReg', (75, 80))	('content', 'MPA', (81, 88))	('FasR mRNA', 'MPA', (92, 101))	('NLGP-TME', 'Var', (56, 64))	('cFLIP', 'Gene', '12633', (178, 183))	('cFLIP', 'Gene', (178, 183))	('PBS-TME', 'Chemical', '-', (131, 138))	('NLGP-TME', 'Chemical', '-', (56, 64))
132908	23785504	NLGP-TME is able to restrict activation of Caspase 3 as well as Caspase 8, which in turn gives an additional support in favour of our hypothesis (Figure 6F).	('restrict', 'NegReg', (20, 28))	('Caspase 8', 'Gene', '12370', (64, 73))	('Caspase 3', 'Gene', (43, 52))	('NLGP-TME', 'Chemical', '-', (0, 8))	('Caspase 8', 'Gene', (64, 73))	('activation', 'MPA', (29, 39))	('Caspase 3', 'Gene', '12367', (43, 52))	('NLGP-TME', 'Var', (0, 8))
132915	23785504	Flow cytometric data suggested that T cells exposed to NLGP-TME have greater migratory ability to tumor draining lymph nodes, thereby, to tumor compartment (Figure 7A).	('NLGP-TME', 'Var', (55, 63))	('tumor', 'Disease', (138, 143))	('rat', 'Species', '10116', (80, 83))	('migratory ability', 'CPA', (77, 94))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('NLGP-TME', 'Chemical', '-', (55, 63))	('greater', 'PosReg', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
132933	23785504	It merits mentioning that NLGP mediates its effect by fine tuning of both the angiogenic and immunological factors at tumor vicinity, a finding not surprising considering the recent expansion of literature demonstrating their interdependent nature.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('rat', 'Species', '10116', (213, 216))	('tumor', 'Disease', (118, 123))	('rat', 'Species', '10116', (199, 202))	('NLGP', 'Gene', (26, 30))	('fine', 'Var', (54, 58))
132955	23785504	Moreover, neutralization of various type 2 cytokines and growth factors (TGFbeta, VEGF, IL-10 and IL-6) in different combination in PBS-TME restored the lytic ability of T cells, which indicates that NLGP induces its therapeutic effect by reducing these angiogenic and immunosuppressive mediators and NLGP-TME containing low amount of these mediators maintain normal T cell homeostasis.	('reducing', 'NegReg', (239, 247))	('TGFbeta', 'Gene', '21803', (73, 80))	('IL-10', 'Gene', '16153', (88, 93))	('NLGP-TME', 'Chemical', '-', (301, 309))	('IL-10', 'Gene', (88, 93))	('VEGF', 'Gene', '22339', (82, 86))	('IL-6', 'Gene', (98, 102))	('IL-6', 'Gene', '16193', (98, 102))	('PBS-TME', 'Chemical', '-', (132, 139))	('VEGF', 'Gene', (82, 86))	('lytic ability', 'CPA', (153, 166))	('TGFbeta', 'Gene', (73, 80))	('neutralization', 'Var', (10, 24))
132967	23785504	Accumulated evidences strongly suggest that NLGP normalized TME promotes T cells to exhibit its anti-tumor effector functions.	('normalized', 'Var', (49, 59))	('promotes', 'PosReg', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('T cells', 'CPA', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
132981	23785504	Our earlier studies depict NLGP's ability to inhibit this crucial regulator and we infer that inhibition of STAT3 may underpin NLGP's far reaching immunomodulatory and the inter-reliant anti-angiogenic capacities.	('inhibition', 'Var', (94, 104))	('STAT3', 'Gene', (108, 113))	('STAT3', 'Gene', '20848', (108, 113))	('NLGP', 'Gene', (127, 131))
133108	23036235	For those diagnosed before age 40 the SIRs for bone sarcoma were 4.40 for the radiotherapy group compared to 1.31 in the non-radiotherapy group, and for soft tissue sarcoma they were 5.32 and 2.25, respectively.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (153, 172))	('bone sarcoma', 'Disease', (47, 59))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (153, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('soft tissue sarcoma', 'Disease', (153, 172))	('radiotherapy', 'Var', (78, 90))	('bone sarcoma', 'Disease', 'MESH:D001847', (47, 59))	('bone sarcoma', 'Phenotype', 'HP:0002669', (47, 59))
133109	23036235	In general for each of the first cancer sites that we examined the SIRs for subsequent sarcomas were higher in the patients who were treated with radiotherapy than in the patients who did not receive radiotherapy (Table 4).	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('patients', 'Species', '9606', (115, 123))	('radiotherapy', 'Var', (146, 158))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('higher', 'PosReg', (101, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('patients', 'Species', '9606', (171, 179))	('sarcomas', 'Disease', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
133130	23036235	As described in the paragraphs above, a few rare genetic variants associated with human cancer susceptibility syndromes appear to increase radiosensitivity in individuals with certain hereditary cancer syndromes.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (130, 155))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('radiosensitivity', 'MPA', (139, 155))	('increase', 'PosReg', (130, 138))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (184, 211))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('variants', 'Var', (57, 65))	('hereditary cancer syndromes', 'Disease', (184, 211))	('human', 'Species', '9606', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
133139	23036235	More recent studies using polymerase chain reaction followed by direct sequencing were able to examine mutations in specific genes: a high rate of TP53 mutation was observed in radiation-induced sarcomas compared to sporadic sarcomas (88% vs 20%, and 58% vs. 16.8% for two different series).	('sarcomas', 'Disease', 'MESH:D012509', (195, 203))	('TP53', 'Gene', (147, 151))	('sarcomas', 'Phenotype', 'HP:0100242', (195, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('sarcomas', 'Disease', (195, 203))	('sporadic sarcomas', 'Disease', 'MESH:D012509', (216, 233))	('sarcomas', 'Disease', 'MESH:D012509', (225, 233))	('sporadic sarcomas', 'Disease', (216, 233))	('sarcomas', 'Phenotype', 'HP:0100242', (225, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('TP53', 'Gene', '7157', (147, 151))	('sarcomas', 'Disease', (225, 233))	('mutation', 'Var', (152, 160))
133140	23036235	While both studies focused on sarcoma subsequent to a variety of primary tumours, 12/36 of cases in the Gonin-Laurent study were secondary to retinoblastoma, a syndrome caused by mutations in the RB1 gene.	('retinoblastoma', 'Phenotype', 'HP:0009919', (142, 156))	('a syndrome', 'Disease', (158, 168))	('retinoblastoma', 'Disease', 'MESH:D012175', (142, 156))	('retinoblastoma', 'Disease', (142, 156))	('caused by', 'Reg', (169, 178))	('RB1', 'Gene', '5925', (196, 199))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('primary tumours', 'Disease', (65, 80))	('primary tumours', 'Disease', 'MESH:D009369', (65, 80))	('sarcoma', 'Disease', (30, 37))	('secondary', 'Reg', (129, 138))	('mutations', 'Var', (179, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('a syndrome', 'Disease', 'MESH:D013577', (158, 168))	('RB1', 'Gene', (196, 199))
133152	32891793	NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry.	('TRK', 'Gene', (1, 4))	('rearrangements', 'Var', (10, 24))	('TRK', 'Gene', '7170', (117, 120))	('TRK', 'Gene', '7170', (1, 4))	('TRK', 'Gene', (117, 120))
133153	32891793	The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians.	('TRK', 'Gene', '7170', (41, 44))	('TRK', 'Gene', (41, 44))	('gene fusions', 'Var', (45, 57))
133154	32891793	To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions.	('sarcoma', 'Disease', (227, 234))	('Sarcoma', 'Disease', (39, 46))	('Sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('TRK', 'Gene', '7170', (246, 249))	('gene fusions', 'Var', (250, 262))	('Sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('patients', 'Species', '9606', (213, 221))	('sarcoma', 'Disease', 'MESH:D012509', (227, 234))	('TRK', 'Gene', (246, 249))
133162	32891793	A classic example of this is mutational profiling of KIT, PDGFRA, and other genes to predict sensitivity of gastrointestinal stromal tumors (GISTs) to imatinib and other KIT/PDGFRA tyrosine kinase inhibitors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('gastrointestinal stromal tumors', 'Disease', (108, 139))	('PDGFRA', 'Gene', (58, 64))	('KIT', 'Gene', '3815', (170, 173))	('PDGFRA', 'Gene', '5156', (58, 64))	('mutational', 'Var', (29, 39))	('KIT', 'Gene', '3815', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('GISTs', 'Phenotype', 'HP:0100723', (141, 146))	('KIT', 'Gene', (170, 173))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (108, 139))	('KIT', 'Gene', (53, 56))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (108, 139))	('PDGFRA', 'Gene', (174, 180))	('imatinib', 'Chemical', 'MESH:D000068877', (151, 159))	('PDGFRA', 'Gene', '5156', (174, 180))
133163	32891793	More recently, the discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as pan-tumor oncogenic drivers has provided new precision medicine-based treatment options for a subset of patients with sarcoma.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('patients', 'Species', '9606', (197, 205))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TRK', 'Gene', '7170', (72, 75))	('pan', 'Gene', (93, 96))	('sarcoma', 'Disease', (211, 218))	('tumor', 'Disease', (97, 102))	('fusions', 'Var', (82, 89))	('pan', 'Gene', '51816', (93, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('TRK', 'Gene', (72, 75))	('gene fusions', 'Var', (77, 89))
133171	32891793	Fusions involving NTRK gene 5' regions have also been reported, although the pathogenicity of these is unclear.	('TRK', 'Gene', '7170', (19, 22))	('Fusions', 'Var', (0, 7))	('TRK', 'Gene', (19, 22))
133172	32891793	In addition to fusions, NTRK gene point mutations and amplifications have been identified in a variety of different cancer types; however, roles for these aberrations in tumorigenesis have not been established.	('identified', 'Reg', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Disease', (116, 122))	('point mutations', 'Var', (34, 49))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('TRK', 'Gene', '7170', (25, 28))	('TRK', 'Gene', (25, 28))	('tumor', 'Disease', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('amplifications', 'Var', (54, 68))
133174	32891793	lung and colorectal cancers), NTRK gene fusions are reported to be recurrent in a subset of rare tumor types (e.g.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('gene fusions', 'Var', (35, 47))	('lung', 'Disease', (0, 4))	('TRK', 'Gene', '7170', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('colorectal cancers', 'Disease', 'MESH:D015179', (9, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('TRK', 'Gene', (31, 34))	('colorectal cancers', 'Disease', (9, 27))
133184	32891793	Larotrectinib is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in adult and pediatric patients with solid tumors harboring an NTRK gene fusion who have disease that is locally advanced or metastatic, or where surgery is likely to result in severe morbidity, and who have no satisfactory treatment options.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('TRK', 'Gene', '7170', (179, 182))	('solid tumors', 'Disease', 'MESH:D009369', (152, 164))	('metastatic', 'CPA', (240, 250))	('EMA', 'Chemical', '-', (102, 105))	('TRK', 'Gene', (179, 182))	('gene fusion', 'Var', (183, 194))	('solid tumors', 'Disease', (152, 164))	('Larotrectinib', 'Chemical', 'MESH:C000609083', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patients', 'Species', '9606', (138, 146))
133201	32891793	Entrectinib is FDA-approved for use in adult and pediatric patients >=12 years of age with solid tumors harboring an NTRK gene fusion who have disease that is metastatic or where surgery is likely to result in severe morbidity, and who have progressed following treatment or have no satisfactory alternative therapy.	('TRK', 'Gene', (118, 121))	('gene fusion', 'Var', (122, 133))	('solid tumors', 'Disease', 'MESH:D009369', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Entrectinib', 'Chemical', 'MESH:C000607349', (0, 11))	('TRK', 'Gene', '7170', (118, 121))	('patients', 'Species', '9606', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('solid tumors', 'Disease', (91, 103))
133210	32891793	NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques such as FISH, reverse transcription polymerase chain reaction (RT-PCR), and massive parallel sequencing (MPS), while TRK protein expression can be demonstrated by immunohistochemistry (IHC) (Table 3).	('MPS', 'Disease', 'MESH:D009084', (215, 218))	('TRK', 'Gene', (1, 4))	('rearrangements', 'Var', (10, 24))	('TRK', 'Gene', '7170', (227, 230))	('TRK', 'Gene', '7170', (1, 4))	('MPS', 'Disease', (215, 218))	('TRK', 'Gene', (227, 230))
133211	32891793	To detect a particular NTRK gene fusion, colocalization of FISH probes to each gene component of the fusion can be demonstrated.	('TRK', 'Gene', '7170', (24, 27))	('TRK', 'Gene', (24, 27))	('fusion', 'Var', (33, 39))
133215	32891793	This method relies on the fact that most normal cells express low levels of TRK while tumor cells harboring an NTRK gene fusion typically display elevated TRK protein levels.	('gene fusion', 'Var', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TRK', 'Gene', '7170', (155, 158))	('tumor', 'Disease', (86, 91))	('TRK', 'Gene', (112, 115))	('TRK', 'Gene', '7170', (76, 79))	('TRK', 'Gene', (155, 158))	('TRK', 'Gene', '7170', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('elevated', 'PosReg', (146, 154))	('TRK', 'Gene', (76, 79))
133221	32891793	Furthermore, the subcellular pattern of pan-TRK IHC staining may indicate the nature of the underlying gene fusion, with nuclear staining suggestive of NTRK3 fusions and moderate to strong, diffuse cytoplasmic staining suggestive of NTRK1/NTRK2 fusions.	('NTRK2', 'Gene', (239, 244))	('NTRK3', 'Gene', '4916', (152, 157))	('TRK', 'Gene', (153, 156))	('NTRK1', 'Gene', (233, 238))	('TRK', 'Gene', '7170', (240, 243))	('TRK', 'Gene', '7170', (44, 47))	('TRK', 'Gene', (44, 47))	('TRK', 'Gene', (234, 237))	('NTRK2', 'Gene', '4915', (239, 244))	('NTRK3', 'Gene', (152, 157))	('pan', 'Gene', (40, 43))	('fusions', 'Var', (158, 165))	('TRK', 'Gene', '7170', (153, 156))	('pan', 'Gene', '51816', (40, 43))	('TRK', 'Gene', (240, 243))	('NTRK1', 'Gene', '4914', (233, 238))	('TRK', 'Gene', '7170', (234, 237))
133226	32891793	In a study of seven patients with soft tissue spindle cell tumors and NTRK3 rearrangement detected by both IHC and FISH, rearrangements were only confirmed by RNA sequencing in three cases.	('NTRK3', 'Gene', (70, 75))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('rearrangement', 'Var', (76, 89))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('NTRK3', 'Gene', '4916', (70, 75))
133231	32891793	Strong TRK IHC staining can also be found in cases with NTRK gene amplification, supporting the requirement to confirm the presence of NTRK rearrangements with an orthogonal molecular method (Figure 1).	('amplification', 'Var', (66, 79))	('TRK', 'Gene', (57, 60))	('TRK', 'Gene', (136, 139))	('TRK', 'Gene', (7, 10))	('TRK', 'Gene', '7170', (57, 60))	('TRK', 'Gene', '7170', (7, 10))	('TRK', 'Gene', '7170', (136, 139))
133237	32891793	MPS allows for the simultaneous detection of fusions between NTRK1:3 and any number of fusion partner genes, depending upon the particular assay used.	('MPS', 'Disease', (0, 3))	('detection', 'Reg', (32, 41))	('NTRK1', 'Gene', '4914', (61, 66))	('MPS', 'Disease', 'MESH:D009084', (0, 3))	('NTRK1', 'Gene', (61, 66))	('fusions', 'Var', (45, 52))
133245	32891793	In addition to functional NTRK fusion transcripts, RNA-based MPS assays may identify non-oncogenic aberrant NTRK rearrangements (incidental genomic alterations) that do not yield constitutively active fusion proteins.	('TRK', 'Gene', (109, 112))	('MPS', 'Disease', 'MESH:D009084', (61, 64))	('TRK', 'Gene', '7170', (109, 112))	('TRK', 'Gene', (27, 30))	('MPS', 'Disease', (61, 64))	('rearrangements', 'Var', (113, 127))	('TRK', 'Gene', '7170', (27, 30))
133247	32891793	Similarly, NTRK point mutations occur more often than gene fusions and may also be identified by MPS assays; however, these mutations are not considered predictive of treatment response.	('MPS', 'Disease', 'MESH:D009084', (97, 100))	('point mutations', 'Var', (16, 31))	('MPS', 'Disease', (97, 100))	('TRK', 'Gene', '7170', (12, 15))	('TRK', 'Gene', (12, 15))
133250	32891793	However, the overall benefit of molecular testing in the diagnosis and clinical management of patients with sarcoma has been demonstrated in large multicenter studies, similar to what has been shown for lung cancer.	('patients', 'Species', '9606', (94, 102))	('sarcoma', 'Disease', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('lung cancer', 'Disease', (203, 214))	('molecular testing', 'Var', (32, 49))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('lung cancer', 'Disease', 'MESH:D008175', (203, 214))
133251	32891793	While sequence-based testing methods (RNA MPS or RT-PCR) are recommended for the detection of productive NTRK gene rearrangements, IHC with a validated antibody against TRK proteins (most easily with a pan-TRK antibody) may be used as a fast and less expensive pre-screening tool.	('pan', 'Gene', (202, 205))	('TRK', 'Gene', '7170', (106, 109))	('pan', 'Gene', '51816', (202, 205))	('MPS', 'Disease', (42, 45))	('TRK', 'Gene', '7170', (169, 172))	('rearrangements', 'Var', (115, 129))	('TRK', 'Gene', (206, 209))	('TRK', 'Gene', (106, 109))	('TRK', 'Gene', (169, 172))	('MPS', 'Disease', 'MESH:D009084', (42, 45))	('TRK', 'Gene', '7170', (206, 209))
133256	32891793	Nevertheless, for patients at high risk of relapse, NTRK gene fusion testing might provide clinically actionable information for later in the disease course.	('TRK', 'Gene', '7170', (53, 56))	('TRK', 'Gene', (53, 56))	('gene fusion testing', 'Var', (57, 76))	('patients', 'Species', '9606', (18, 26))
133257	32891793	Testing for NTRK gene fusions should be carried out in patients with locally advanced, unresectable tumors or in those with metastatic disease failing conventional therapies.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('fusions', 'Var', (22, 29))	('TRK', 'Gene', (13, 16))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (55, 63))	('TRK', 'Gene', '7170', (13, 16))
133259	32891793	The highest priority for NTRK fusion testing is given to the histologic subtypes that commonly or non-infrequently harbor NTRK gene fusions, such as infantile fibrosarcomas and ALK and ROS1 fusion-negative inflammatory myofibroblastic tumors.	('TRK', 'Gene', (123, 126))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (219, 241))	('TRK', 'Gene', '7170', (26, 29))	('fusions', 'Var', (132, 139))	('TRK', 'Gene', (26, 29))	('ALK', 'Gene', '238', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('ROS1', 'Gene', '6098', (185, 189))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (219, 240))	('infantile fibrosarcomas', 'Disease', 'MESH:D005354', (149, 172))	('ALK', 'Gene', (177, 180))	('myofibroblastic tumors', 'Disease', (219, 241))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('infantile fibrosarcomas', 'Disease', (149, 172))	('ROS1', 'Gene', (185, 189))	('TRK', 'Gene', '7170', (123, 126))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (159, 171))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (219, 241))
133268	32891793	In a study of patients with various tumor types, 31% of NTRK fusion-negative cases harbored activating MAPK pathway alterations compared with only 1.5% (n = 1) of NTRK fusion-positive cases.	('MAPK pathway', 'Pathway', (103, 115))	('activating', 'MPA', (92, 102))	('fusion-negative', 'Var', (61, 76))	('TRK', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('TRK', 'Gene', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('alterations', 'Reg', (116, 127))	('patients', 'Species', '9606', (14, 22))	('TRK', 'Gene', '7170', (57, 60))	('tumor', 'Disease', (36, 41))	('fusion-negative', 'NegReg', (61, 76))	('TRK', 'Gene', '7170', (164, 167))
133271	32891793	Sarcomas with recurrent gene fusions, GISTs with KIT, PDGFR, SDH, NF1, or BRAF alterations, and liposarcomas with MDM2 or CDK4 amplification may be excluded from routine NTRK fusion testing.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('gene fusions', 'Var', (24, 36))	('SDH', 'Gene', (61, 64))	('TRK', 'Gene', (171, 174))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('GISTs', 'Phenotype', 'HP:0100723', (38, 43))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('CDK4', 'Gene', (122, 126))	('liposarcomas', 'Disease', 'MESH:D008080', (96, 108))	('NF1', 'Gene', '4763', (66, 69))	('KIT', 'Gene', (49, 52))	('MDM2', 'Gene', (114, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('PDGFR', 'Gene', (54, 59))	('liposarcomas', 'Phenotype', 'HP:0012034', (96, 108))	('PDGFR', 'Gene', '5159', (54, 59))	('CDK4', 'Gene', '1019', (122, 126))	('NF1', 'Gene', (66, 69))	('Sarcomas', 'Disease', (0, 8))	('MDM2', 'Gene', '4193', (114, 118))	('alterations', 'Var', (79, 90))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('KIT', 'Gene', '3815', (49, 52))	('liposarcomas', 'Disease', (96, 108))	('TRK', 'Gene', '7170', (171, 174))	('SDH', 'Gene', '10993', (61, 64))
133291	32891793	NTRK gene fusions have been shown to persist in tumors over time, suggesting that they remain the dominant oncogenic driver over the course of different treatments.	('TRK', 'Gene', (1, 4))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('TRK', 'Gene', '7170', (1, 4))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('fusions', 'Var', (10, 17))
133296	32891793	TRK inhibitors provide new personalized treatment options with the potential to extend survival and improve quality of life in some patients with sarcoma harboring NTRK gene fusions.	('TRK', 'Gene', '7170', (165, 168))	('TRK', 'Gene', '7170', (0, 3))	('sarcoma', 'Disease', (146, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('TRK', 'Gene', (0, 3))	('extend', 'PosReg', (80, 86))	('TRK', 'Gene', (165, 168))	('gene fusions', 'Var', (169, 181))	('survival', 'CPA', (87, 95))	('improve', 'PosReg', (100, 107))	('patients', 'Species', '9606', (132, 140))	('quality of life', 'CPA', (108, 123))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
133300	32891793	However, IHC provides a valuable pre-screening tool and focused MPS panels, such as those that detect NTRK gene fusions and other key gene fusions in parallel, are particularly relevant for sarcomas.	('TRK', 'Gene', '7170', (103, 106))	('pan', 'Gene', '51816', (68, 71))	('fusions', 'Var', (112, 119))	('sarcomas', 'Disease', 'MESH:D012509', (190, 198))	('MPS', 'Disease', 'MESH:D009084', (64, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (190, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('pan', 'Gene', (68, 71))	('MPS', 'Disease', (64, 67))	('TRK', 'Gene', (103, 106))	('sarcomas', 'Disease', (190, 198))
133360	32456671	The 3-year survival rate among patients with high-grade sarcoma was 42.8% and that among patients with low-grade sarcoma was 100%.	('high-grade', 'Var', (45, 55))	('sarcoma', 'Disease', (56, 63))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcoma', 'Disease', (113, 120))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))
133493	31297355	The presentations of vascular injury are diverse, including active bleeding by transection or laceration of the vessels, dissection, false aneurysms with delayed rupture, arteriovenous fistulas, acute thrombosis, and contusion with late thrombosis.	('bleeding', 'Disease', 'MESH:D006470', (67, 75))	('laceration', 'Var', (94, 104))	('thrombosis', 'Disease', (201, 211))	('transection', 'Var', (79, 90))	('arteriovenous fistulas', 'Phenotype', 'HP:0004947', (171, 193))	('dissection', 'Disease', (121, 131))	('false aneurysms', 'Disease', (133, 148))	('rupture', 'Disease', (162, 169))	('thrombosis', 'Disease', 'MESH:D013927', (237, 247))	('bleeding', 'Disease', (67, 75))	('aneurysms', 'Phenotype', 'HP:0002617', (139, 148))	('thrombosis', 'Disease', (237, 247))	('contusion', 'Disease', (217, 226))	('arteriovenous fistulas', 'Disease', (171, 193))	('rupture', 'Disease', 'MESH:D012421', (162, 169))	('aneurysm', 'Phenotype', 'HP:0002617', (139, 147))	('arteriovenous fistulas', 'Disease', 'MESH:D001165', (171, 193))	('false aneurysms', 'Disease', 'MESH:D017541', (133, 148))	('vascular injury', 'Disease', 'MESH:D057772', (21, 36))	('thrombosis', 'Disease', 'MESH:D013927', (201, 211))	('vascular injury', 'Disease', (21, 36))
133506	31297355	They concluded that pancreaticoduodenectomy with vascular reconstruction is a reasonable approach for T3N0 and T3N1 pancreatic adenocarcinoma invading the PV or HA (1-year survival rate, 71.1%), and an aggressive surgical approach can improve survival in high-volume institution.	('T3N0', 'Var', (102, 106))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (116, 141))	('pancreatic', 'Disease', 'MESH:D010195', (116, 126))	('pancreatic', 'Disease', 'MESH:D010195', (20, 30))	('pancreatic', 'Disease', (116, 126))	('pancreatic', 'Disease', (20, 30))	('T3N1', 'Var', (111, 115))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (116, 141))	('pancreatic adenocarcinoma', 'Disease', (116, 141))
133554	27342745	It was demonstrated that exosomes from CD99-silenced Ewing sarcoma cells were capable of influencing the recipient Ewing sarcoma cells by mimicking CD99 silencing, and inducing neural differentiation in recipient Ewing sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('Ewing sarcoma', 'Disease', (115, 128))	('inducing', 'Reg', (168, 176))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (213, 226))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (213, 226))	('influencing', 'Reg', (89, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('CD99', 'Gene', (39, 43))	('neural differentiation', 'CPA', (177, 199))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (53, 66))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('CD99', 'Gene', '4267', (39, 43))	('CD99', 'Gene', (148, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (115, 128))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (115, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('Ewing sarcoma', 'Disease', (213, 226))	('CD99', 'Gene', '4267', (148, 152))	('silencing', 'Var', (153, 162))	('Ewing sarcoma', 'Disease', (53, 66))
133562	27342745	Exosomes from human glioblastoma cells (U251-MG and U251) were shown to be internalized by human fibrosarcoma cells HT-1080, other tumor cells, and normal astrocytes through confocal microscopy analysis and flow cytometric analysis.	('HT-1080', 'CellLine', 'CVCL:0317', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (97, 109))	('human', 'Species', '9606', (14, 19))	('fibrosarcoma', 'Disease', 'MESH:D005354', (97, 109))	('glioblastoma', 'Disease', (20, 32))	('human', 'Species', '9606', (91, 96))	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('U251-MG', 'CellLine', 'CVCL:0021', (40, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('U251-MG', 'Var', (40, 47))	('fibrosarcoma', 'Disease', (97, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('U251', 'Var', (52, 56))
133573	27342745	As the most common tumors in gastrointestinal tract, gastrointestinal stromal tumors (GISTs) arise from interstitial cells of Cajal (ICCs) and their precursors, and present KIT and PDGFRA mutations most commonly.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('PDGFRA', 'Gene', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('KIT', 'Gene', (173, 176))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (29, 51))	('gastrointestinal stromal tumors', 'Disease', (53, 84))	('PDGFRA', 'Gene', '5156', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (188, 197))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (53, 84))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (53, 84))	('gastrointestinal tract', 'Disease', (29, 51))
133600	27342745	For further confirmation, scientists knocked down and overexpressed the NEU1 or LAMP1 genes respectively in RH41 and RH30 cells, and indicated that lysosomal exocytosis and release of exosomes were both enhanced by silencing NEU1 or upregulating LAMP1.	('LAMP1', 'Gene', (80, 85))	('lysosomal exocytosis', 'MPA', (148, 168))	('NEU1', 'Gene', '4758', (72, 76))	('NEU1', 'Gene', (72, 76))	('LAMP1', 'Gene', (246, 251))	('enhanced', 'PosReg', (203, 211))	('NEU1', 'Gene', (225, 229))	('NEU1', 'Gene', '4758', (225, 229))	('upregulating', 'PosReg', (233, 245))	('LAMP1', 'Gene', '3916', (80, 85))	('release of exosomes', 'MPA', (173, 192))	('LAMP1', 'Gene', '3916', (246, 251))	('silencing', 'Var', (215, 224))	('RH30', 'Gene', (117, 121))	('RH30', 'Gene', '6007', (117, 121))
133708	26347853	Translocations t(8;22)(q22;q11) in distal-type ES and t(10;22) in proximal-type ES were found.	('t(8;22)(q22;q11', 'Var', (15, 30))	('t(8;22)(q22;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (15, 31))	('distal-type ES', 'Disease', (35, 49))	('t(10;22', 'Var', (54, 61))
133710	26347853	The observation that a substantial number of ES had either rearrangements or deletions of 22q led to the hypothesis that this region may contain a tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('deletions', 'Var', (77, 86))	('rearrangements', 'Var', (59, 73))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('22q', 'Gene', (90, 93))
133713	26347853	Components of the SWI/SNF complex are mutated in 20% of cancers, most notably rhabdoid tumor.	('cancers', 'Disease', (56, 63))	('mutated', 'Var', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('rhabdoid tumor', 'Disease', (78, 92))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
133714	26347853	Inactivation of SMARCB1 leads to neoplastic transformation by transcriptional deregulation of target genes implicated in regulating genomic stability, cell-cycle progression, and other signaling pathways in cooperation with transcriptional co-regulators (e.g., MyoD, Olig2).	('Olig2', 'Gene', '10215', (267, 272))	('deregulation', 'NegReg', (78, 90))	('MyoD', 'Gene', '4654', (261, 265))	('SMARCB1', 'Gene', (16, 23))	('SMARCB1', 'Gene', '6598', (16, 23))	('leads to', 'Reg', (24, 32))	('neoplastic transformation', 'CPA', (33, 58))	('Olig2', 'Gene', (267, 272))	('MyoD', 'Gene', (261, 265))	('Inactivation', 'Var', (0, 12))	('transcriptional', 'MPA', (62, 77))
133717	26347853	demonstrated that loss of SMARCB1 expression in the ES cell line VAESBJ was caused by homozygous deletion of SMARCB1 through mutations of exon 1.	('mutations', 'Var', (125, 134))	('loss', 'NegReg', (18, 22))	('expression', 'MPA', (34, 44))	('SMARCB1', 'Gene', '6598', (109, 116))	('SMARCB1', 'Gene', '6598', (26, 33))	('SMARCB1', 'Gene', (109, 116))	('SMARCB1', 'Gene', (26, 33))	('deletion', 'Var', (97, 105))
133718	26347853	They also identified equally prevalent homozygous deletion of CDKN2A and CDKN2B loci, responsible for encoding p16, p14, and p15 proteins.	('p14', 'Gene', (116, 119))	('CDKN2B', 'Gene', (73, 79))	('deletion', 'Var', (50, 58))	('CDKN2B', 'Gene', '1030', (73, 79))	('p14', 'Gene', '1029', (116, 119))	('p16', 'Gene', '1029', (111, 114))	('CDKN2A', 'Gene', (62, 68))	('p15', 'Gene', (125, 128))	('p15', 'Gene', '1030', (125, 128))	('CDKN2A', 'Gene', '1029', (62, 68))	('p16', 'Gene', (111, 114))
133719	26347853	Restoration of SMARCB1 led to a reduction of cell proliferation and cell migration and to an increase in sensitivity to genotoxic stress, thereby providing evidence to support SMARCB1 inactivation in the tumorigenesis of ES.	('cell migration', 'CPA', (68, 82))	('SMARCB1', 'Gene', '6598', (176, 183))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('increase', 'PosReg', (93, 101))	('SMARCB1', 'Gene', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SMARCB1', 'Gene', '6598', (15, 22))	('cell proliferation', 'CPA', (45, 63))	('SMARCB1', 'Gene', (15, 22))	('tumor', 'Disease', (204, 209))	('reduction', 'NegReg', (32, 41))	('inactivation', 'Var', (184, 196))	('sensitivity to genotoxic stress', 'MPA', (105, 136))
133720	26347853	For rhabdoid tumor, SWI/SNF disruption is sufficient to cause neoplastic transformation.	('neoplastic transformation', 'CPA', (62, 87))	('disruption', 'Var', (28, 38))	('cause', 'Reg', (56, 61))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (4, 18))	('rhabdoid tumor', 'Disease', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
133721	26347853	However, in the context of ES, loss of SMARCB1 by itself is not sufficient.	('SMARCB1', 'Gene', '6598', (39, 46))	('loss', 'Var', (31, 35))	('SMARCB1', 'Gene', (39, 46))
133722	26347853	Interestingly, knockout of SMARCB1 in primary fibroblast cells causes rapid growth arrest and p53-mediated programed cell death.	('SMARCB1', 'Gene', (27, 34))	('growth arrest', 'Disease', 'MESH:D006323', (76, 89))	('knockout', 'Var', (15, 23))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('growth arrest', 'Phenotype', 'HP:0001510', (76, 89))	('SMARCB1', 'Gene', '6598', (27, 34))	('growth arrest', 'Disease', (76, 89))
133723	26347853	However, when mutations of TP53 co-exist, tumor proliferation is dramatically increased.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('increased', 'PosReg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mutations', 'Var', (14, 23))
133724	26347853	demonstrated that the VAESBJ cell line retains wild-type TP53, but hypothesized that the homozygous loss of CDKN2A which leads to impaired p16/RB and p14/TP53 responses likely contributes to the genomic instability seen in this cell line.	('loss', 'Var', (100, 104))	('CDKN2A', 'Gene', '1029', (108, 114))	('p14', 'Gene', '1029', (150, 153))	('TP53', 'Gene', (154, 158))	('TP53', 'Gene', '7157', (154, 158))	('genomic instability', 'MPA', (195, 214))	('p16', 'Gene', '1029', (139, 142))	('responses', 'MPA', (159, 168))	('impaired', 'NegReg', (130, 138))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('p14', 'Gene', (150, 153))	('CDKN2A', 'Gene', (108, 114))	('p16', 'Gene', (139, 142))
133730	26347853	identified different mechanisms to explain the loss of expression of SMARCB1: 13% of cases had biallelic deletions, 33% showed single-allelic deletion, and 4% had point mutations.	('SMARCB1', 'Gene', (69, 76))	('SMARCB1', 'Gene', '6598', (69, 76))	('single-allelic deletion', 'Var', (127, 150))	('point mutations', 'Var', (163, 178))	('biallelic deletions', 'Var', (95, 114))
133733	26347853	The role of oncomiRs was also validated by another group where miR193a-5p could equally inhibit the mRNA expression of SMARCB1.	('SMARCB1', 'Gene', '6598', (119, 126))	('inhibit', 'NegReg', (88, 95))	('SMARCB1', 'Gene', (119, 126))	('miR193a-5p', 'Var', (63, 73))	('mRNA expression', 'MPA', (100, 115))
133734	26347853	In summary, loss of SMARCB1 has a crucial role in the pathogenesis of ES (along with other signaling pathways) and therefore is an interesting target to pursue for the development of new therapies.	('loss', 'Var', (12, 16))	('SMARCB1', 'Gene', (20, 27))	('SMARCB1', 'Gene', '6598', (20, 27))
133740	26347853	Results demonstrated that silencing mTOR by transfecting cell lines with anti-mTOR-specific siRNAs suppressed cell proliferation.	('suppressed', 'NegReg', (99, 109))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('mTOR', 'Gene', (78, 82))	('mTOR', 'Gene', '2475', (78, 82))	('silencing', 'Var', (26, 35))	('cell proliferation', 'CPA', (110, 128))
133741	26347853	However, inhibition of mTOR with everolimus caused tumor growth delay without shrinkage.	('tumor growth delay', 'Disease', (51, 69))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('growth delay', 'Phenotype', 'HP:0001510', (57, 69))	('everolimus', 'Chemical', 'MESH:D000068338', (33, 43))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))	('tumor growth delay', 'Disease', 'MESH:D006130', (51, 69))	('inhibition', 'Var', (9, 19))
133777	26347853	Subsequently, inhibiting AKT reduced dysadherin's ability to promote cell mobility and tumor cell invasion.	('AKT', 'Gene', (25, 28))	('ability', 'MPA', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('promote', 'PosReg', (61, 68))	('inhibiting', 'Var', (14, 24))	('tumor', 'Disease', (87, 92))	('cell mobility', 'CPA', (69, 82))	('reduced', 'NegReg', (29, 36))	('AKT', 'Gene', '207', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('dysadherin', 'Gene', '53827', (37, 47))	('dysadherin', 'Gene', (37, 47))
133779	26347853	Agonists of the CCL2 receptor, CCR2, such as PF-04634817, may be one area to begin investigation.	('CCR2', 'Gene', '729230', (31, 35))	('CCL2', 'Gene', '6347', (16, 20))	('PF-04634817', 'Var', (45, 56))	('CCL2', 'Gene', (16, 20))	('CCR2', 'Gene', (31, 35))
133781	26347853	APC deficiency or beta-catenin mutations preventing its degradation lead to constitutive activation of beta-catenin signaling, which in turn contribute to stem-cell renewal and proliferation.	('mutations', 'Var', (31, 40))	('APC deficiency', 'Disease', 'MESH:D011125', (0, 14))	('beta-catenin', 'Gene', (18, 30))	('degradation', 'MPA', (56, 67))	('beta-catenin', 'Gene', (103, 115))	('beta-catenin', 'Gene', '1499', (18, 30))	('beta-catenin', 'Gene', '1499', (103, 115))	('APC deficiency', 'Disease', (0, 14))	('activation', 'PosReg', (89, 99))	('proliferation', 'CPA', (177, 190))	('stem-cell renewal', 'CPA', (155, 172))	('contribute', 'Reg', (141, 151))
133801	26347853	Results showed that reversing MDR with cyclosporin A increased sensitivity to actinomycin D, vincristine, and adriamycin.	('vincristine', 'MPA', (93, 104))	('MDR', 'Gene', (30, 33))	('reversing', 'Var', (20, 29))	('sensitivity to actinomycin D', 'MPA', (63, 91))	('actinomycin D', 'Chemical', 'MESH:D003609', (78, 91))	('increased', 'PosReg', (53, 62))	('vincristine', 'Chemical', 'MESH:D014750', (93, 104))	('cyclosporin A', 'Chemical', 'MESH:D016572', (39, 52))	('adriamycin', 'Chemical', 'MESH:D004317', (110, 120))
133837	28713152	Fluorescence in situ hybridization (FISH) test confirmed ALK-1 gene rearrangement in tumor cells, but genomic DNA sequencing failed to reveal the fusion partner, likely due to intron interference.	('tumor', 'Disease', (85, 90))	('rearrangement', 'Var', (68, 81))	('ALK-1', 'Gene', '94', (57, 62))	('ALK-1', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
133859	28713152	ALK-1 gene rearrangements were initially identified in a subset of anaplastic large cell lymphomas.	('lymphomas', 'Phenotype', 'HP:0002665', (89, 98))	('identified', 'Reg', (41, 51))	('rearrangements', 'Var', (11, 25))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('anaplastic large cell lymphomas', 'Phenotype', 'HP:0012193', (67, 98))	('ALK-1', 'Gene', '94', (0, 5))	('lymphomas', 'Disease', (89, 98))	('ALK-1', 'Gene', (0, 5))	('lymphomas', 'Disease', 'MESH:D008223', (89, 98))
133862	28713152	The third-generation ALK inhibitor lorlatinib (PF-06463922, Pfizer) is currently under clinical trial for the treatment for ALK-rearranged NSCLC, including those refractory to first and second-generation ALK inhibitors.	('ALK', 'Gene', (204, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('lorlatinib', 'Chemical', 'MESH:C000590786', (35, 45))	('ALK', 'Gene', '238', (124, 127))	('PF-06463922', 'Chemical', 'MESH:C000590786', (47, 58))	('ALK', 'Gene', '238', (204, 207))	('NSCLC', 'Disease', (139, 144))	('PF-06463922', 'Var', (47, 58))	('ALK', 'Gene', (21, 24))	('ALK', 'Gene', (124, 127))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('ALK', 'Gene', '238', (21, 24))
133867	28713152	It was proposed that poor brain penetration of crizotinib is likely due to its high efflux by P-glycoprotein (PGP).	('efflux', 'MPA', (84, 90))	('brain penetration', 'CPA', (26, 43))	('crizotinib', 'Chemical', 'MESH:D000077547', (47, 57))	('PGP', 'Gene', '5243', (110, 113))	('P-glycoprotein', 'Gene', (94, 108))	('PGP', 'Gene', (110, 113))	('P-glycoprotein', 'Gene', '5243', (94, 108))	('crizotinib', 'Var', (47, 57))
133875	28713152	Mechanisms responsible for resistance to crizotinib may be due to acquired ALK gene mutations, and activation of other signaling bypass pathway.	('mutations', 'Var', (84, 93))	('ALK', 'Gene', '238', (75, 78))	('crizotinib', 'Chemical', 'MESH:D000077547', (41, 51))	('ALK', 'Gene', (75, 78))
133893	25202378	The results of this study indicated that methylation may be significant in the development of Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (94, 109))	('significant', 'Reg', (60, 71))	("Ewing's sarcoma", 'Disease', (94, 109))	('methylation', 'Var', (41, 52))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (94, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
133896	25202378	Epigenetic changes, which represent reversible modifications that affect gene expression without altering the DNA sequence itself, are also a hallmark of cancer.	('affect', 'Reg', (66, 72))	('hallmark of cancer', 'Disease', (142, 160))	('hallmark of cancer', 'Disease', 'MESH:D009369', (142, 160))	('gene expression', 'MPA', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('Epigenetic changes', 'Var', (0, 18))
133899	25202378	Promoter CpG island hypermethylation is found in virtually all human cancer tissue types and acts as an important mechanism for the inactivation of tumor suppressor and tumor-related genes.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('hypermethylation', 'Var', (20, 36))	('human', 'Species', '9606', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (148, 153))	('inactivation', 'NegReg', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', (69, 75))
133900	25202378	Aberrant DNA methylation has been recognized as an early event in tumorigenesis and therefore, variations in the methylation patterns identified between normal and tumor cells may aid in the detection of tumor cells in biopsy specimens or tumor-derived DNA in body fluids.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('DNA', 'Protein', (9, 12))	('aid', 'Reg', (180, 183))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('variations', 'Var', (95, 105))
133903	25202378	The assay has also been used to assess the epigenetic specificity of the loss of IGF2 imprinting in Wilms' tumors and to identify the unique epigenetic signature of human embryonic stem cells.	("Wilms' tumors", 'Disease', (100, 113))	('human', 'Species', '9606', (165, 170))	('loss', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	("Wilms' tumors", 'Disease', 'MESH:D009396', (100, 113))	('IGF2', 'Gene', '3481', (81, 85))	('IGF2', 'Gene', (81, 85))	("Wilms' tumors", 'Phenotype', 'HP:0002667', (100, 113))
133928	25202378	1 shows a heat map of the differentially-methylated CpGs in the Ewing's sarcoma samples.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (64, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('CpGs', 'Protein', (52, 56))	('differentially-methylated', 'Var', (26, 51))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (64, 79))	("Ewing's sarcoma", 'Disease', (64, 79))
133931	25202378	However, no significant correlation was identified between the overall methylation mean and the clinical parameters of age, gender and tumor location (Table I).	('methylation', 'Var', (71, 82))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
133933	25202378	The methylation of these top four genes was confirmed to be common, occurring in 82.5% (GDF), 65% (OSM), 87.5% (APC) and 45% (HOXA11) of the Ewing's sarcoma samples.	('APC', 'Disease', 'MESH:D011125', (112, 115))	('GDF', 'Chemical', '-', (88, 91))	('APC', 'Disease', (112, 115))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (141, 156))	('occurring', 'Reg', (68, 77))	("Ewing's sarcoma", 'Disease', (141, 156))	('methylation', 'Var', (4, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (141, 156))	('HOXA11', 'Gene', '3207', (126, 132))	('HOXA11', 'Gene', (126, 132))
133935	25202378	The (11;22)(q24;q12) translocation is the most frequently occurring, and results in the formation of the EWS-FLI1 fusion protein.	('results in', 'Reg', (73, 83))	('11;22)(q24;q12', 'Var', (5, 19))	('EWS', 'Gene', '2130', (105, 108))	('EWS', 'Gene', (105, 108))	('FLI1', 'Gene', (109, 113))	('FLI1', 'Gene', '2313', (109, 113))
133944	25202378	The simultaneous hypermethylation of multiple CpG island loci, particularly the CpG island methylator phenotype (CIMP), may be associated with survival rather than individual gene hypermethylation.	('CIMP', 'Chemical', '-', (113, 117))	('associated with', 'Reg', (127, 142))	('hypermethylation', 'Var', (17, 33))
133945	25202378	The widespread hypermethylation of multiple promoter CpG island loci characterizes a subset of malignancies, designated as CIMP.	('characterizes', 'Reg', (69, 82))	('malignancies', 'Disease', (95, 107))	('CIMP', 'Chemical', '-', (123, 127))	('hypermethylation', 'Var', (15, 31))	('malignancies', 'Disease', 'MESH:D009369', (95, 107))
133948	25202378	However, no significant correlation was identified between the overall methylation mean and the clinical parameters of age, gender and tumor location.	('methylation', 'Var', (71, 82))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
133950	25202378	The top four hypermethylated genes may function as differential epigenetic biomarkers between Ewing's sarcoma and control samples.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (94, 109))	('hypermethylated', 'Var', (13, 28))	("Ewing's sarcoma", 'Disease', (94, 109))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (94, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
133955	25202378	Fiegl et al revealed that HOXA11 gene DNA methylation frequently occurs in ovarian cancer and that consequently, HOXA11 methylation status is a prognostic marker.	('ovarian cancer', 'Disease', 'MESH:D010051', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('HOXA11', 'Gene', '3207', (26, 32))	('ovarian cancer', 'Disease', (75, 89))	('HOXA11', 'Gene', '3207', (113, 119))	('occurs', 'Reg', (65, 71))	('DNA methylation', 'Var', (38, 53))	('HOXA11', 'Gene', (113, 119))	('ovarian cancer', 'Phenotype', 'HP:0100615', (75, 89))	('HOXA11', 'Gene', (26, 32))
133957	25202378	The study stated that Ewing's sarcoma patients with methylated RASSF1A showed poorer prognoses than those without.	('methylated', 'Var', (52, 62))	('RASSF1A', 'Gene', (63, 70))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (22, 37))	("Ewing's sarcoma", 'Disease', (22, 37))	('RASSF1A', 'Gene', '11186', (63, 70))	('patients', 'Species', '9606', (38, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (22, 37))
133963	25202378	In conclusion, the current study identified the hypermethylation of 92 genes in Ewing's sarcoma and a trend toward more aggressive behaviors in samples with methylation.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (80, 95))	('hypermethylation', 'Var', (48, 64))	("Ewing's sarcoma", 'Disease', (80, 95))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (80, 95))	('aggressive behavior', 'Phenotype', 'HP:0000718', (120, 139))	('aggressive behaviors', 'Phenotype', 'HP:0000718', (120, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
134127	32025898	To our knowledge, this is the first report of a patient, without right heart failure, experiencing cardiac arrest after anesthesia induction because of an embolism caused by a change in the position of the tip of the PPAS.	('cardiac arrest', 'Disease', (99, 113))	('cardiac arrest', 'Phenotype', 'HP:0001695', (99, 113))	('PPAS', 'Disease', (217, 221))	('right heart failure', 'Disease', 'MESH:D006333', (65, 84))	('heart failure', 'Phenotype', 'HP:0001635', (71, 84))	('patient', 'Species', '9606', (48, 55))	('PPAS', 'Disease', 'MESH:D012509', (217, 221))	('embolism', 'Disease', (155, 163))	('cardiac arrest', 'Disease', 'MESH:D006323', (99, 113))	('embolism', 'Disease', 'MESH:D004617', (155, 163))	('right heart failure', 'Disease', (65, 84))	('right heart failure', 'Phenotype', 'HP:0001708', (65, 84))	('change in', 'Var', (176, 185))
134252	26472661	Tumors were scored according to mitotic index, cellularity, cytonuclear polymorphism, and necrosis.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mitotic index', 'CPA', (32, 45))	('necrosis', 'Disease', (90, 98))	('cytonuclear polymorphism', 'Var', (60, 84))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('necrosis', 'Disease', 'MESH:D009336', (90, 98))
134301	26472661	This has been clearly established in the case of myxoid round-cell liposarcoma, where the characteristic chromosomal translocations of t(12;16)(q13;q11) and t(12;22)(q13;q12) code for the fusion transcripts FUS-DDIT3 and EWS-DDIT3, which bind to specific DNA and act as transcription factors for oncoproteins.	('liposarcoma', 'Disease', (67, 78))	('t(12;16)(q13;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (135, 152))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (157, 174))	('EWS', 'Gene', '2130', (221, 224))	('DDIT3', 'Gene', '1649', (225, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('DDIT3', 'Gene', '1649', (211, 216))	('code for', 'Reg', (175, 183))	('FUS', 'Gene', (207, 210))	('DDIT3', 'Gene', (225, 230))	('DDIT3', 'Gene', (211, 216))	('t(12;22)(q13;q12', 'Var', (157, 173))	('liposarcoma', 'Phenotype', 'HP:0012034', (67, 78))	('FUS', 'Gene', '2521', (207, 210))	('liposarcoma', 'Disease', 'MESH:D008080', (67, 78))	('bind', 'Interaction', (238, 242))	('EWS', 'Gene', (221, 224))	('t(12;16)(q13;q11', 'Var', (135, 151))	('DNA', 'Protein', (255, 258))
134311	26472661	Lastly, recent data have highlighted NAB2-STAT6 fusion, which is a result of inversion within chromosome 12, as a distinct molecular feature of SFTs.	('NAB2', 'Gene', '4665', (37, 41))	('STAT6', 'Gene', '6778', (42, 47))	('fusion', 'Var', (48, 54))	('NAB2', 'Gene', (37, 41))	('STAT6', 'Gene', (42, 47))
134331	24302852	However, high-dose ifosfamide is associated with an increased risk of toxicity.	('toxicity', 'Disease', 'MESH:D064420', (70, 78))	('toxicity', 'Disease', (70, 78))	('high-dose', 'Var', (9, 18))
134387	23436835	However, its utility is limited in patients with widespread metastases because it is difficult to distinguish the primary site from metastatic foci, and PET/CT may result in false-positive lesions.	('result', 'Reg', (164, 170))	('metastases', 'Disease', (60, 70))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('patients', 'Species', '9606', (35, 43))	('PET/CT', 'Var', (153, 159))
134431	23436835	If CA19-9 is highly increased and CA125 is negative (or mildly increased), the results further support the diagnosis of pancreatic cancer rather than gynecologic cancer.	('cancer', 'Disease', (131, 137))	('increased', 'PosReg', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('cancer', 'Disease', (162, 168))	('CA125', 'Gene', '94025', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('CA19-9', 'Var', (3, 9))	('CA19-9', 'Chemical', 'MESH:C086528', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('CA125', 'Gene', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('pancreatic cancer', 'Disease', (120, 137))
134472	23552700	Methylation analysis reveals RASSF10 promoter hypermethylation in lung cancer, head and neck (HN) cancer, sarcoma and pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('pancreatic cancer', 'Disease', (118, 135))	('hypermethylation', 'Var', (46, 62))	('RASSF10', 'Gene', '644943', (29, 36))	('head and neck (HN) cancer', 'Disease', 'MESH:D006258', (79, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('sarcoma', 'Disease', (106, 113))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('RASSF10', 'Gene', (29, 36))
134478	23552700	In summary, we found RASSF10 to be epigenetically inactivated by hypermethylation of its CpG island promoter in lung, HN, sarcoma and pancreatic cancer.	('RASSF10', 'Gene', '644943', (21, 28))	('pancreatic cancer', 'Disease', 'MESH:D010190', (134, 151))	('hypermethylation', 'Var', (65, 81))	('RASSF10', 'Gene', (21, 28))	('lung', 'Disease', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('ted ', 'Gene', (58, 62))	('ted ', 'Gene', '27112', (58, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('sarcoma', 'Disease', (122, 129))	('pancreatic cancer', 'Disease', (134, 151))
134491	23552700	In secondary glioblastomas, RASSF10 methylation was said to be an independent prognostic factor associated with worst progression-free survival and overall survival and occurred at an early stage in their development.	('RASSF10', 'Gene', '644943', (28, 35))	('glioblastomas', 'Phenotype', 'HP:0012174', (13, 26))	('overall survival', 'CPA', (148, 164))	('ted ', 'Gene', (103, 107))	('ted ', 'Gene', '27112', (103, 107))	('RASSF10', 'Gene', (28, 35))	('be an', 'Gene', '146227', (60, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (13, 26))	('progression-free survival', 'CPA', (118, 143))	('worst', 'NegReg', (112, 117))	('glioblastomas', 'Disease', (13, 26))	('methylation', 'Var', (36, 47))	('be an', 'Gene', (60, 65))
134494	23552700	Demethylation of the RASSF10 promoter is accompanied by reexpression of RASSF10 in cancer cell lines.	('RASSF10', 'Gene', '644943', (21, 28))	('is a', 'Gene', '312', (38, 42))	('RASSF10', 'Gene', '644943', (72, 79))	('RASSF10', 'Gene', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('RASSF10', 'Gene', (72, 79))	('Demethylation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('is a', 'Gene', (38, 42))	('cancer', 'Disease', (83, 89))
134496	23552700	Furthermore, ectopic expression of RASSF10 suppresses colony formation.	('suppresses', 'NegReg', (43, 53))	('colony formation', 'CPA', (54, 70))	('RASSF10', 'Gene', '644943', (35, 42))	('RASSF10', 'Gene', (35, 42))	('ectopic expression', 'Var', (13, 31))
134503	23552700	For HN cancer cell lines methylation was 67%, sarcoma cell lines 63% and pancreatic cancer cell lines 80% (Table 1 and Supplementary Table S1).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('pancreatic cancer', 'Disease', (73, 90))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('HN cancer', 'Disease', 'MESH:D009369', (4, 13))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('HN cancer', 'Disease', (4, 13))	('sarcoma', 'Disease', (46, 53))	('methylation', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
134513	23552700	Interestingly, none of the eight stage I tumors showed a RASSF10 methylation, this number increased to 2 of 17 stage II and to 5 of 15 stage III tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('I tumors', 'Disease', 'MESH:D009369', (39, 47))	('I tumors', 'Disease', (143, 151))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('increased', 'PosReg', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('I tumors', 'Disease', 'MESH:D009369', (143, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('methylation', 'Var', (65, 76))	('RASSF10', 'Gene', '644943', (57, 64))	('I tumors', 'Disease', (39, 47))	('RASSF10', 'Gene', (57, 64))
134514	23552700	However, only 1 of 6 stage IV tumors possessed a RASSF10 methylation, but process of metastasis might be related to other molecular factors.	('tumors', 'Disease', (30, 36))	('methylation', 'Var', (57, 68))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('RASSF10', 'Gene', '644943', (49, 56))	('RASSF10', 'Gene', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('ted ', 'Gene', (109, 113))	('ted ', 'Gene', '27112', (109, 113))
134518	23552700	Accordingly, COBRA revealed that RASSF10 was unmethylated for HCC366 and H358 (Figure 1b and Supplementary Table S1).	('RASSF10', 'Gene', '644943', (33, 40))	('HCC366', 'Var', (62, 68))	('HCC366', 'CellLine', 'CVCL:2059', (62, 68))	('ted ', 'Gene', (54, 58))	('RASSF10', 'Gene', (33, 40))	('H358', 'Var', (73, 77))	('ted ', 'Gene', '27112', (54, 58))
134519	23552700	Lower expression of RASSF10 was observed for CRL5869 and CRL5898 and both were partially methylated for RASSF10 (Supplementary Table S1).	('RASSF10', 'Gene', '644943', (20, 27))	('RASSF10', 'Gene', '644943', (104, 111))	('RASSF10', 'Gene', (20, 27))	('expression', 'MPA', (6, 16))	('ted ', 'Gene', (96, 100))	('ted ', 'Gene', '27112', (96, 100))	('RASSF10', 'Gene', (104, 111))	('CRL5898', 'Var', (57, 64))	('Lower', 'NegReg', (0, 5))	('CRL5869', 'Var', (45, 52))
134522	23552700	5-aza-2'-deoxycytidine (Aza) inhibits de novo methylation and is known to reverse epigenetic silencing of tumor suppressor genes.	('de novo methylation', 'MPA', (38, 57))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('epigenetic', 'Var', (82, 92))	('inhibits', 'NegReg', (29, 37))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('Aza', 'Chemical', 'MESH:D000077209', (24, 27))
134529	23552700	To clarify what kind of stimuli could induce RASSF10 expression, we used a luciferase assay and cloned the RASSF10 promoter (-900 to +157 bp) into the pRLnull vector (Figure 3).	('RASSF10', 'Gene', '644943', (45, 52))	('RASSF10', 'Gene', (45, 52))	('RASSF10', 'Gene', '644943', (107, 114))	('RASSF10', 'Gene', (107, 114))	('-900 to +157 bp', 'Var', (125, 140))
134531	23552700	Upon in vitro methylation of the RASSF10 plasmid that signal is lost (Figure 3a).	('methylation', 'Var', (14, 25))	('RASSF10', 'Gene', (33, 40))	('lost', 'NegReg', (64, 68))	('RASSF10', 'Gene', '644943', (33, 40))
134534	23552700	Next, we tested a set of inhibitors (LY294002, SB203580, SP600125, PD98059, Staurosporine and H89) to block the signaling of forskolin/IBMX on RASSF10, and found that the PKA inhibitor H89 reduces RASSF10 promoter induction (Figure 3e and data not shown).	('PD98059', 'Chemical', 'MESH:C093973', (67, 74))	('SP600125', 'Chemical', 'MESH:C432165', (57, 65))	('promoter induction', 'MPA', (205, 223))	('IBMX', 'Chemical', 'MESH:D015056', (135, 139))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('H89', 'Chemical', 'MESH:C063509', (185, 188))	('forskolin', 'Chemical', 'MESH:D005576', (125, 134))	('RASSF10', 'Gene', '644943', (143, 150))	('RASSF10', 'Gene', (143, 150))	('SP600125', 'Var', (57, 65))	('H89', 'Chemical', 'MESH:C063509', (94, 97))	('RASSF10', 'Gene', '644943', (197, 204))	('Staurosporine', 'Chemical', 'MESH:D019311', (76, 89))	('RASSF10', 'Gene', (197, 204))	('ted ', 'Gene', '27112', (12, 16))	('SB203580', 'Chemical', 'MESH:C093642', (47, 55))	('reduces', 'NegReg', (189, 196))	('LY294002', 'Var', (37, 45))	('ted ', 'Gene', (12, 16))
134541	23552700	However, we observed that a deletion from -272 to -218 (Deltae), covering a JunD binding site, lead to a significant reduction in RASSF10 promoter activation by PKACalpha compared with deletions -900 to -776 (Deltaa) and -501 to -273 (Deltac), both containing potential JunD binding sites predicted by Matinspector Genomatix software (http://www.genomatix.de) (Figure 3h).	('JunD', 'Gene', (270, 274))	('reduction', 'NegReg', (117, 126))	('ted ', 'Gene', (295, 299))	('JunD', 'Gene', '3727', (76, 80))	('promoter', 'MPA', (138, 146))	('JunD', 'Gene', '3727', (270, 274))	('ted ', 'Gene', '27112', (295, 299))	('RASSF10', 'Gene', '644943', (130, 137))	('activation', 'PosReg', (147, 157))	('RASSF10', 'Gene', (130, 137))	('deletion from -272 to -218', 'Var', (28, 54))	('JunD', 'Gene', (76, 80))
134544	23552700	Serial deletion constructs of the RASSF10 promoter allowed us to determine the core promoter region, where luciferase activity is down to empty vector control level at first between -271 to +157 (Deltad) and later narrowed down to -217 up to -106 (Deltaf) (Figure 3i).	('down', 'NegReg', (130, 134))	('RASSF10', 'Gene', '644943', (34, 41))	('activity', 'MPA', (118, 126))	('RASSF10', 'Gene', (34, 41))	('luciferase', 'Enzyme', (107, 117))	('deletion', 'Var', (7, 15))
134562	23552700	The knockdown of Fra2 did not downregulate endogenous RASSF10 expression (Figure 4g).	('Fra2', 'Gene', (17, 21))	('expression', 'MPA', (62, 72))	('downregulate', 'NegReg', (30, 42))	('endogenous', 'MPA', (43, 53))	('RASSF10', 'Gene', '644943', (54, 61))	('knockdown', 'Var', (4, 13))	('RASSF10', 'Gene', (54, 61))
134571	23552700	We observed a slight and reproducible increase of cells entering the cell cycle in S/G2/M phase by a mean of 2.7% after RASSF10 knockdown (Supplementary Figure S1B).	('increase', 'PosReg', (38, 46))	('RASSF10', 'Gene', (120, 127))	('S/G2', 'SUBSTITUTION', 'None', (83, 87))	('knockdown', 'Var', (128, 137))	('S/G2', 'Var', (83, 87))	('RASSF10', 'Gene', '644943', (120, 127))
134587	23552700	Furthermore, knockdown of RASSF10 was performed to test its endogenous influence on senescence or contact inhibition (Figure 5d).	('contact inhibition', 'CPA', (98, 116))	('senescence', 'CPA', (84, 94))	('RASSF10', 'Gene', '644943', (26, 33))	('knockdown', 'Var', (13, 22))	('RASSF10', 'Gene', (26, 33))
134592	23552700	Contact inhibition-associated upregulation of p27 is also unaltered upon knockdown of RASSF10 (Figure 5e).	('RASSF10', 'Gene', '644943', (86, 93))	('ted ', 'Gene', '27112', (26, 30))	('RASSF10', 'Gene', (86, 93))	('is a', 'Gene', (50, 54))	('is a', 'Gene', '312', (50, 54))	('p27', 'Gene', '3429', (46, 49))	('p27', 'Gene', (46, 49))	('ted ', 'Gene', (26, 30))	('knockdown', 'Var', (73, 82))
134595	23552700	RASSF10 expression was reduced by 50% in contact-inhibited cells upon knockdown of JunD, but not after downregulation of Fra2 (Figure 5f).	('knockdown', 'Var', (70, 79))	('RASSF10', 'Gene', '644943', (0, 7))	('RASSF10', 'Gene', (0, 7))	('ted ', 'Gene', (55, 59))	('ted ', 'Gene', '27112', (55, 59))	('JunD', 'Gene', (83, 87))	('JunD', 'Gene', '3727', (83, 87))	('expression', 'MPA', (8, 18))	('reduced', 'NegReg', (23, 30))
134596	23552700	We further observed a correlation between the degree of JunD knockdown and decrease in RASSF10 expression (Supplementary Figure S3).	('JunD', 'Gene', '3727', (56, 60))	('decrease', 'NegReg', (75, 83))	('RASSF10', 'Gene', '644943', (87, 94))	('knockdown', 'Var', (61, 70))	('RASSF10', 'Gene', (87, 94))	('JunD', 'Gene', (56, 60))	('expression', 'MPA', (95, 105))
134604	23552700	Epigenetic inactivation of the RASSF members has been shown in a variety of tumor entities.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('RASSF', 'Gene', '8045;644943', (31, 36))	('RASSF', 'Gene', (31, 36))	('shown', 'Reg', (54, 59))	('Epigenetic inactivation', 'Var', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
134606	23552700	Its hypermethylation was shown in thyroid tumors, melanoma, childhood leukemia and glioma.	('glioma', 'Disease', (83, 89))	('thyroid tumors', 'Disease', (34, 48))	('thyroid tumors', 'Disease', 'MESH:D013959', (34, 48))	('shown', 'Reg', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('leukemia', 'Disease', (70, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('hypermethylation', 'Var', (4, 20))
134620	23552700	It is further known that AP-1 is activated by PKA, but not by phosphorylation and therefore an indirect activation was suggested.	('ted ', 'Gene', '27112', (39, 43))	('AP-1', 'Gene', (25, 29))	('PKA', 'Var', (46, 49))	('is a', 'Gene', (30, 34))	('is a', 'Gene', '312', (30, 34))	('ted ', 'Gene', (39, 43))
134627	23552700	Hence, JunD knockdown is not able to fully block RASSF10 activation.	('RASSF10', 'Gene', '644943', (49, 56))	('knockdown', 'Var', (12, 21))	('RASSF10', 'Gene', (49, 56))	(', JunD', 'Gene', '3727', (5, 11))
134636	23552700	In accordance with our observation, knockdown of RASSF10 increases mitosis but decreases G1 phase (undistinguishable from G0 using propidium iodide staining in fluorescence-activated cell sorting; Supplementary Figure S1).	('ted ', 'Gene', (179, 183))	('decreases', 'NegReg', (79, 88))	('mitosis', 'Disease', (67, 74))	('propidium iodide', 'Chemical', 'MESH:D011419', (131, 147))	('RASSF10', 'Gene', '644943', (49, 56))	('ted ', 'Gene', '27112', (179, 183))	('mitosis', 'Disease', 'None', (67, 74))	('G1 phase', 'CPA', (89, 97))	('RASSF10', 'Gene', (49, 56))	('knockdown', 'Var', (36, 45))	('increases', 'PosReg', (57, 66))
134637	23552700	When RASSF10, however, is inactivated in cancer cells by promoter hypermethylation this inhibition is missing and cells exhibit the tumor phenotype, thereby growing beyond contact inhibition (Figure 7).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ted ', 'Gene', (34, 38))	('ted ', 'Gene', '27112', (34, 38))	('RASSF10', 'Gene', '644943', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('promoter hypermethylation', 'Var', (57, 82))	('tumor', 'Disease', (132, 137))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('RASSF10', 'Gene', (5, 12))
134650	23552700	In addition, JunD knockdown interferes with RASSF10 upregulation.	('knockdown', 'Var', (18, 27))	('upregulation', 'PosReg', (52, 64))	('interferes', 'NegReg', (28, 38))	('RASSF10', 'Gene', '644943', (44, 51))	('RASSF10', 'Gene', (44, 51))	(', JunD', 'Gene', '3727', (11, 17))
134655	23552700	In agreement with the tumor suppressive function of RASSF10 we observed that knockdown of RASSF10 increases mitosis in A549 lung cancer cells and decreases G1 phase (Supplementary Figure S1).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('RASSF10', 'Gene', '644943', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('mitosis in A549 lung cancer', 'Disease', 'MESH:D008175', (108, 135))	('mitosis in A549 lung cancer', 'Disease', (108, 135))	('decreases', 'NegReg', (146, 155))	('knockdown', 'Var', (77, 86))	('G1 phase', 'CPA', (156, 164))	('RASSF10', 'Gene', '644943', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('RASSF10', 'Gene', (90, 97))	('RASSF10', 'Gene', (52, 59))	('tumor', 'Disease', (22, 27))	('increases', 'PosReg', (98, 107))
134661	23552700	It will be fascinating to analyze the functional relationship of RASSF10 inactivation in cancer cell lines and their inability to respond appropriately to cell-cell contact.	('RASSF10', 'Gene', '644943', (65, 72))	('RASSF10', 'Gene', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('inactivation', 'Var', (73, 85))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
134677	23552700	Constructs were generated from cDNA vectors (RZPD, Berlin, Germany) and cloned into: PKACalpha-pCMVTag1 (IRAKp961P0684Q), PKARalpha-pCMVTag1 (IRAKp961P0312Q) and PKACgamma-pCMVTag1 (IRAKp961C0782Q).	('ted ', 'Gene', (22, 26))	('ted ', 'Gene', '27112', (22, 26))	('IRAKp961P0684Q', 'Var', (105, 119))	('IRAKp961C0782Q', 'Var', (182, 196))	('IRAKp961P0312Q', 'Var', (142, 156))
134680	23552700	Deletion mutants of RASSF10-pRLnull promoter were generated with mutagenesis primers listed in Supplementary Table S2.	('RASSF10', 'Gene', '644943', (20, 27))	('RASSF10', 'Gene', (20, 27))	('ted ', 'Gene', (56, 60))	('Deletion mutants', 'Var', (0, 16))	('ted ', 'Gene', '27112', (56, 60))	('ted ', 'Gene', (88, 92))	('ted ', 'Gene', '27112', (88, 92))
134715	31828566	This regimen consisted of 6-week treatment cycles starting with a 7-day period of low dose (0.005 mg/m2/d) blinatumomab to reduce the risk of immunological toxicities and increasing it to a higher 0.015 mg/m2/d dose thereafter.	('blinatumomab', 'Disease', 'None', (107, 119))	('0.005 mg/m2/d', 'Var', (92, 105))	('blinatumomab', 'Disease', (107, 119))	('immunological toxicities', 'Disease', (142, 166))	('immunological toxicities', 'Disease', 'MESH:D007154', (142, 166))
134749	31828566	Engagement of PD-L1 or PD-L2 by PD-1 results in the attenuation of T cell activity through negative regulation of proximal signaling elements of the T cell receptor.	('PD-L2', 'Gene', (23, 28))	('PD-L2', 'Gene', '574057', (23, 28))	('proximal signaling elements', 'MPA', (114, 141))	('negative', 'NegReg', (91, 99))	('PD-1', 'Gene', (32, 36))	('PD-L1', 'Var', (14, 19))	('T cell activity', 'CPA', (67, 82))	('attenuation', 'NegReg', (52, 63))
134751	31828566	While the exact mechanism(s) of how pembrolizumab and similar checkpoint inhibitors achieve their antitumor activity remain to be fully elucidated, PD-1 blockade has been shown to "reinvigorate" and expand exhausted T cells in the tumor microenvironment, thereby helping promote tumor rejection.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('blockade', 'Var', (153, 161))	('expand exhausted T cells', 'Phenotype', 'HP:0031514', (199, 223))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (231, 236))	('pembrolizumab', 'Chemical', 'MESH:C582435', (36, 49))	('promote', 'PosReg', (271, 278))	('PD-1', 'Gene', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
134786	31828566	One of the hallmarks of most pediatric cancers, however, is their relative lack of mutations (a rare exception are cancers arising from constitutional mismatch repair deficiencies, which do respond to checkpoint inhibition therapy).	('mutations', 'Var', (83, 92))	('pediatric cancers', 'Disease', (29, 46))	('mismatch repair deficiencies', 'Disease', 'MESH:C536928', (151, 179))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (115, 122))	('mismatch repair deficiencies', 'Disease', (151, 179))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lack', 'NegReg', (75, 79))	('pediatric cancers', 'Disease', 'MESH:D009369', (29, 46))
134822	31828566	Clinical data from two phase I clinical trials of modified herpes simplex virus (NCT00931931) and vaccinia virus (NCT01169584) in extracranial solid tumors have established the safety of these OVs in childhood cancer.	('solid tumors', 'Disease', (143, 155))	('herpes simplex', 'Phenotype', 'HP:0012302', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('NCT01169584', 'Var', (114, 125))	('vaccinia virus', 'Species', '10245', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('solid tumors', 'Disease', 'MESH:D009369', (143, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))	('NCT00931931', 'Var', (81, 92))
134824	31828566	Apart from this, phase I trials for oncolytic adenovirus (NCT00634231 and NCT03178032) and poliovirus (NCT03043391) are currently being tested against pediatric brain tumors.	('pediatric brain tumors', 'Disease', 'MESH:D001932', (151, 173))	('NCT03178032', 'Var', (74, 85))	('pediatric brain tumors', 'Disease', (151, 173))	('NCT03043391', 'Var', (103, 114))	('brain tumors', 'Phenotype', 'HP:0030692', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('NCT00634231', 'Var', (58, 69))	('poliovirus', 'Species', '138950', (91, 101))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
134841	31828566	To achieve sufficient volumes of NK cells for clinical use, ex vivo expansion systems using K562 feeder cells are designed to engage and activate NK cells with membrane bound ligands such as mbIL21-41BBL or mbIL15-41BBL as well as a combination of multiple stimulatory cytokines such as IL-2, IL-12, IL-15, and IL-18.	('IL-15', 'Gene', '3600', (300, 305))	('mbIL21-41BBL', 'Var', (191, 203))	('IL-15', 'Gene', (300, 305))	('IL-18', 'Gene', '3606', (311, 316))	('mbIL15-41BBL', 'Var', (207, 219))	('IL-18', 'Gene', (311, 316))	('K562', 'CellLine', 'CVCL:0004', (92, 96))	('activate', 'PosReg', (137, 145))
134850	31828566	Using the CRISPR modification approach, there is evidence showing that gene-modified primary NK cells have enhanced antitumor effects, including SOCS3 and CISH knockout NK cells.	('CISH', 'Gene', (155, 159))	('enhanced', 'PosReg', (107, 115))	('SOCS3', 'Gene', '9021', (145, 150))	('gene-modified', 'Var', (71, 84))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CISH', 'Gene', '1154', (155, 159))	('SOCS3', 'Gene', (145, 150))	('tumor', 'Disease', (120, 125))
134870	31828566	Another phase I clinical trial at the University of Florida is currently recruiting pediatric patients with high-grade glioma to evaluate cancer vaccines comprised of dendritic cells "pre-loaded" with allogenic tumor RNA given in combination with GM-CSF (NCT03334305).	('NCT03334305', 'Var', (255, 266))	('cancer', 'Disease', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('patients', 'Species', '9606', (94, 102))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('GM-CSF', 'Gene', (247, 253))	('GM-CSF', 'Gene', '1437', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('glioma', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
134879	31828566	Studies at the University of California, San Francisco, are also underway with a phase I trial evaluating a peptide vaccine in children and young adults with DIPG and other gliomas (NCT02960230).	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('gliomas', 'Disease', (173, 180))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('children', 'Species', '9606', (127, 135))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('NCT02960230', 'Var', (182, 193))	('DIPG', 'Chemical', '-', (158, 162))	('DIPG', 'Disease', (158, 162))
134880	31828566	This vaccine is based on the histone H3.3K27M mutation found in approximately 60% of high-grade pediatric glioma cases, which is known to drive tumorigenesis by silencing tumor suppressor genes.	('tumor', 'Disease', (144, 149))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('pediatric glioma', 'Disease', (96, 112))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('drive', 'PosReg', (138, 143))	('silencing', 'NegReg', (161, 170))	('H3.3K27M', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('pediatric glioma', 'Disease', 'MESH:D005910', (96, 112))
134882	31828566	Two of the more clinically advanced trials are being conducted by the biotechnology company Gradalis, who is actively investigating the proprietary Vigil cancer vaccine for treatment of Ewing sarcoma (NCT02511132 and NCT03495921).	('Ewing sarcoma', 'Disease', 'MESH:D012512', (186, 199))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (186, 199))	('NCT03495921', 'Var', (217, 228))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('NCT02511132', 'Var', (201, 212))	('Ewing sarcoma', 'Disease', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
134899	31828566	Pediatric neuroblastoma can have two different molecular phenotypes: tumors with amplified MYCN oncogene, deemed to be of high-risk clinically, or tumors without MYCN amplification which have a relatively better prognosis.	('MYCN', 'Gene', '4613', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('neuroblastoma', 'Phenotype', 'HP:0003006', (10, 23))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('MYCN', 'Gene', (162, 166))	('MYCN', 'Gene', '4613', (162, 166))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('amplified', 'Var', (81, 90))	('Pediatric neuroblastoma', 'Disease', (0, 23))	('Pediatric neuroblastoma', 'Disease', 'MESH:D009447', (0, 23))	('MYCN', 'Gene', (91, 95))
134910	31828566	CSF-1R blockade has also been shown to synergize with PD-1/PD-L1 checkpoint inhibition and increase antitumor efficacy in a spontaneous model of high-risk neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (155, 168))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('neuroblastoma', 'Disease', (155, 168))	('neuroblastoma', 'Phenotype', 'HP:0003006', (155, 168))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('increase', 'PosReg', (91, 99))	('CSF-1R', 'Gene', (0, 6))	('blockade', 'Var', (7, 15))	('CSF-1R', 'Gene', '1436', (0, 6))
134942	31828566	There are two clinical trials in pediatric osteosarcoma that combine antiangiogenic agents with immune checkpoint blockade at present: a phase I/II trial combines tyrosine kinase inhibitor famitinib with camrelizumab (NCT04044378) and a phase II trial combining apatinib with camrelizumab (NCT03359018).	('NCT04044378', 'Var', (218, 229))	('apatinib', 'Chemical', 'MESH:C553458', (262, 270))	('osteosarcoma', 'Disease', 'MESH:D012516', (43, 55))	('camrelizumab', 'Chemical', '-', (276, 288))	('camrelizumab', 'Chemical', '-', (204, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (43, 55))	('famitinib', 'Chemical', 'MESH:C584390', (189, 198))	('osteosarcoma', 'Disease', (43, 55))
134949	31828566	The suppression of immune function by MDSCs is mediated by their production of arginase I and prostaglandin E2, reactive oxygen species (ROS), and release of immune suppressive cytokines.	('reactive oxygen species', 'MPA', (112, 135))	('ROS', 'Chemical', 'MESH:D017382', (137, 140))	('suppression', 'NegReg', (4, 15))	('MDSCs', 'Var', (38, 43))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (112, 135))	('release', 'MPA', (147, 154))	('prostaglandin E2', 'MPA', (94, 110))	('arginase I', 'MPA', (79, 89))	('production', 'MPA', (65, 75))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (94, 110))	('immune function', 'CPA', (19, 34))	('suppression of immune function', 'Phenotype', 'HP:0002721', (4, 34))
134973	31828566	Targeting CAF mediated production of PGE2 in neuroblastoma through inhibition of a key enzyme in its synthesis, microsomal prostaglandin E synthase-1, suppressed CAF migration and infiltration leading to reduced tumor growth and decreased angiogenesis.	('inhibition', 'Var', (67, 77))	('PGE2', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('microsomal prostaglandin E synthase-1', 'Gene', '9536', (112, 149))	('CAF', 'Gene', '8850', (162, 165))	('angiogenesis', 'CPA', (239, 251))	('suppressed', 'NegReg', (151, 161))	('decreased', 'NegReg', (229, 238))	('CAF', 'Gene', (162, 165))	('CAF', 'Gene', '8850', (10, 13))	('CAF', 'Gene', (10, 13))	('neuroblastoma', 'Disease', (45, 58))	('tumor', 'Disease', (212, 217))	('infiltration', 'CPA', (180, 192))	('neuroblastoma', 'Phenotype', 'HP:0003006', (45, 58))	('microsomal prostaglandin E synthase-1', 'Gene', (112, 149))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('reduced', 'NegReg', (204, 211))	('neuroblastoma', 'Disease', 'MESH:D009447', (45, 58))	('PGE2', 'Chemical', 'MESH:D015232', (37, 41))
134982	31828566	Most pediatric cancers arise from embryonal cells as opposed to epithelial cells, for example, and are likewise thought to result from transcriptional abnormalities, copy number variants, and chromosomal rearrangements rather than an accumulation of nonsynonymous genetic mutations.	('arise', 'Reg', (23, 28))	('pediatric cancers', 'Disease', 'MESH:D009369', (5, 22))	('pediatric cancers', 'Disease', (5, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('result from', 'Reg', (123, 134))	('copy number variants', 'Var', (166, 186))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('chromosomal rearrangements', 'Var', (192, 218))
134991	31828566	For example, checkpoint inhibitors like pembrolizumab and ipilimumab bolster T cell activity through distinct mechanisms:PD-1 inhibition increases cytotoxic T lymphocyte proliferation, whereas CTLA-4 inhibition helps these cells remain activated.	('ipilimumab', 'Chemical', 'MESH:D000074324', (58, 68))	('CTLA-4', 'Gene', '1493', (193, 199))	('T cell activity', 'CPA', (77, 92))	('inhibition', 'Var', (126, 136))	('CTLA-4', 'Gene', (193, 199))	('PD-1', 'Gene', (121, 125))	('pembrolizumab', 'Chemical', 'MESH:C582435', (40, 53))	('increases cytotoxic T', 'Disease', 'MESH:D064420', (137, 158))	('increases cytotoxic T', 'Disease', (137, 158))
135048	28680140	While Ewing sarcomas harbour specific gene fusions that connect EWSR1 to one of the ETS gene family members, CDS is defined by a gene fusion between the CIC and DUX4 genes.	('CDS', 'Disease', (109, 112))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (6, 20))	('EWSR1', 'Gene', '2130', (64, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('CIC', 'Gene', (153, 156))	('fusions', 'Var', (43, 50))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (6, 19))	('Ewing sarcomas', 'Disease', (6, 20))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (6, 20))	('EWSR1', 'Gene', (64, 69))
135063	28680140	Notably, five peptides mimetics of non-receptor tyrosine kinases of the Src family substrates were prominently and consistently phosphorylated in all samples examined as follows: EFS_246_258 (GGTDEGIYDVPLL), SRC8_CHICK_492_504 (YQAEENTYDEYEN), SRC8_CHICK_476_488 (EYEPETVYEVAGA), PLCG1_764_776 (IGTAEPDYGALYE), FRK_380_392 (KVDNEDIYESRHE), PAXI_111_123 (VGEEEHVYSFPNK), and PAXI_24_36 (FLSEETPYSYPTG) (indicated by bold characters in Fig.	('PAXI_24_36', 'Var', (374, 384))	('SRC8_CHICK_476_488', 'Var', (244, 262))	('FRK_380_392', 'Var', (311, 322))	('PAXI_111_123', 'Var', (340, 352))	('EFS', 'CellLine', 'CVCL:5I29', (179, 182))	('EFS_246_258', 'Var', (179, 190))
135101	28680140	The search parameters were as follows: tolerance of one missed trypsin cleavage; variable modifications on the methionine (oxidation, +16 Da), and serine, threonine, and tyrosine (phosphorylation, +80 Da); fixed modifications on cysteine (carbamidomethly, +57 Da); maximum precursor ion mass tolerance of +-10 ppm; and a fragment ion mass tolerance of +-0.8 Da.	('threonine', 'Chemical', 'MESH:D013912', (155, 164))	('carbamidomethly', 'Chemical', '-', (239, 254))	('fragment ion mass', 'MPA', (321, 338))	('precursor ion mass', 'MPA', (273, 291))	('modifications', 'Var', (90, 103))	('cysteine', 'Chemical', 'MESH:D003545', (229, 237))	('serine', 'Chemical', 'MESH:D012694', (147, 153))	('methionine', 'Chemical', 'MESH:D008715', (111, 121))	('modifications', 'Var', (212, 225))
135103	27642091	Potential pitfalls of mass spectrometry to uncover mutations in childhood soft tissue sarcoma: A report from the Children's Oncology Group Mass spectrometry-based methods have been widely applied - often as the sole method - to detect mutations in human cancer specimens.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('sarcoma', 'Disease', (86, 93))	('mutations', 'Var', (51, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('human', 'Species', '9606', (248, 253))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (74, 93))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('Oncology', 'Phenotype', 'HP:0002664', (124, 132))	('cancer', 'Disease', (254, 260))	('sarcoma', 'Disease', 'MESH:D012509', (86, 93))	('Children', 'Species', '9606', (113, 121))
135105	27642091	We confirmed only three mutations, which encoded NRASA18T, JAK3V722I and METR970C in three specimens.	('NRAS', 'Gene', '4893', (49, 53))	('JAK3V722I', 'Var', (59, 68))	('METR970C', 'CellLine', 'CVCL:7312', (73, 81))	('METR970C', 'Var', (73, 81))	('NRAS', 'Gene', (49, 53))
135106	27642091	Beyond highlighting those mutations, our findings demonstrate potential pitfalls of primarily utilizing a mass spectrometry-based approach to broadly screen for DNA sequence variants in archived, clinical-grade tumor specimens.	('variants', 'Var', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (211, 216))
135107	27642091	Here, we utilized MassARRAY in a different way: to broadly screen for sequence variants in DNA extracted from formalin-fixed, paraffin-embedded (FFPE) childhood tumor specimens, with plans for secondary validation of variant alleles by using next-generation sequencing.	('variants', 'Var', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('DNA', 'Gene', (91, 94))	('formalin', 'Chemical', 'MESH:D005557', (110, 118))	('tumor', 'Disease', (161, 166))	('paraffin', 'Chemical', 'MESH:D010232', (126, 134))
135109	27642091	The de-identified DNA specimens were processed according to the MassARRAY guidelines, and the OncoCarta v1.0 and v3.0 panels were employed to interrogate 365 actionable mutations in 33 cancer-related genes in all 52 specimens.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('mutations', 'Var', (169, 178))
135110	27642091	The high confidence calls included FLT3I836M (called in four cases) and two different mutant BRAF and STK11 alleles in three and two cases, respectively (Table S3).	('BRAF', 'Gene', (93, 97))	('STK11', 'Gene', (102, 107))	('mutant', 'Var', (86, 92))	('STK11', 'Gene', '6794', (102, 107))	('BRAF', 'Gene', '673', (93, 97))	('FLT3I836M', 'Var', (35, 44))
135111	27642091	We were only able to confirm 3 of the 14 mutations tested (NRASA18T, JAK3V722I and METR970C) (Table S3).	('JAK3V722I', 'Var', (69, 78))	('METR970C', 'CellLine', 'CVCL:7312', (83, 91))	('METR970C', 'Var', (83, 91))	('NRAS', 'Gene', (59, 63))	('NRAS', 'Gene', '4893', (59, 63))
135112	27642091	Second, we found that the three verified mutations (NRASA18T, JAK3V722I and METR970C) were not biased toward cases with lower or higher average coverage in sequencing data when compared to those with unverified mutations (t-test, P = 0.47).	('NRAS', 'Gene', (52, 56))	('NRAS', 'Gene', '4893', (52, 56))	('JAK3V722I', 'Var', (62, 71))	('METR970C', 'CellLine', 'CVCL:7312', (76, 84))	('METR970C', 'Var', (76, 84))
135115	27642091	We evaluated all four combinations (HC + GQ, LC + GQ, HC + PQ, and LC + PQ) in duplicate using the OncoCarta v1.0 and v3.0 panels, according to the manufacturer's guidelines.	('LC + PQ', 'Var', (67, 74))	('PQ', 'Chemical', 'MESH:D011319', (72, 74))	('PQ', 'Chemical', 'MESH:D011319', (59, 61))	('GQ', 'Chemical', 'MESH:C039788', (41, 43))	('HC + GQ', 'Var', (36, 43))	('LC + PQ', 'Chemical', '-', (67, 74))	('LC + GQ', 'Var', (45, 52))	('GQ', 'Chemical', 'MESH:C039788', (50, 52))
135118	27642091	Consistent with our observations from actual tumor specimens, mass spectrometric mutation calls were associated with a relatively high FDR: 37.5% and 80% for good and poor quality DNA, respectively, and 54% overall (Fig.	('actual tumor', 'Disease', 'MESH:D009369', (38, 50))	('actual tumor', 'Disease', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mass', 'Var', (62, 66))
135123	27642091	We applied the same NGS approach previously applied to the tumor specimens to try to detect the RD- and Rh30-associated variants in the mixed DNA samples (average read depth after removing PCR duplicates: 1271x).	('variants', 'Var', (120, 128))	('tumor', 'Disease', (59, 64))	('Rh30', 'Gene', (104, 108))	('Rh30', 'Gene', '6007', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
135124	27642091	In summary, we can draw a number of conclusions from our analysis of a relatively large panel of childhood soft tissue sarcoma specimens: First, we did find potentially actionable mutations in a small number of childhood soft tissue sarcoma specimens (3 of 52) using this commonly-employed mass spectrometry-based assay as a screen, and the putative variants were confirmed with a complementary NGS approach.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (221, 240))	('mutations', 'Var', (180, 189))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Disease', 'MESH:D012509', (233, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcoma', 'Disease', (233, 240))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (107, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))
135135	27642091	All 52 cases were assayed using the Sequenom MassARRAY OncoCarta v1.0 and v3.0 panels (Sequenom, San Diego, CA), according to manufacturer's specifications, to examine 365 unique mutations in 33 cancer-related genes.	('examine', 'Reg', (160, 167))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('mutations', 'Var', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
135143	27642091	Our computational pipeline compared variants against common polymorphisms present in the dbSNP 138 and 1000 Genomes databases, as well as COSMIC version 73, a database of cancer somatic mutations.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('variants', 'Var', (36, 44))	('cancer', 'Disease', (171, 177))
135145	27642091	Potential pitfalls of mass spectrometry to uncover mutations in childhood soft tissue sarcoma: A report from the Children's Oncology Group.	('sarcoma', 'Disease', (86, 93))	('mutations', 'Var', (51, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (74, 93))	('Oncology', 'Phenotype', 'HP:0002664', (124, 132))	('sarcoma', 'Disease', 'MESH:D012509', (86, 93))	('Children', 'Species', '9606', (113, 121))
135181	22319237	In       these cells, cytokeratin AE1/AE3 gave a characteristic dot-like positive result as a       juxtanuclear globe, and coexpression with vimentin was comfirmed by double immunostaining.	('AE3', 'Gene', (38, 41))	('vimentin', 'Gene', (142, 150))	('AE1', 'Gene', (34, 37))	('AE3', 'Gene', '24781', (38, 41))	('cytokeratin', 'Var', (22, 33))	('vimentin', 'Gene', '81818', (142, 150))	('AE1', 'Gene', '24779', (34, 37))	('rat', 'Species', '10116', (28, 31))
135218	20166202	As dysregulated IGF-I signaling is common to several adult malignancies, targeting IGF-IR has become a major focus for therapeutic development.	('dysregulated', 'Var', (3, 15))	('IGF-I', 'Gene', (16, 21))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))	('IGF-I', 'Gene', '3479', (83, 88))	('IGF-IR', 'Gene', (83, 89))	('malignancies', 'Disease', (59, 71))	('IGF-IR', 'Gene', '3480', (83, 89))	('IGF-I', 'Gene', (83, 88))	('IGF-I', 'Gene', '3479', (16, 21))
135219	20166202	Five fully human (CP-751,871, AMG 479, R1507, IMC-A12, SCH717454) or humanized antibodies (H7C10/MK0646) are in adult phase-I to -III clinical trials.	('SCH717454', 'Chemical', 'MESH:C573312', (55, 64))	('human', 'Species', '9606', (11, 16))	('human', 'Species', '9606', (69, 74))	('R1507', 'Var', (39, 44))	('CP-751,871', 'Var', (18, 28))
135222	20166202	Another IGF-1R-targeted antibody, SCH717454 was found to induce regressions in several sarcoma histotypes, notably osteosarcoma and Ewing sarcoma.	('sarcoma', 'Disease', (87, 94))	('SCH717454', 'Var', (34, 43))	('Ewing sarcoma', 'Disease', (132, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('IGF-1R', 'Gene', '3480', (8, 14))	('IGF-1R', 'Gene', (8, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('osteosarcoma', 'Disease', (115, 127))	('osteosarcoma', 'Disease', 'MESH:D012516', (115, 127))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('sarcoma', 'Disease', (138, 145))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (132, 145))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (132, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('osteosarcoma', 'Phenotype', 'HP:0002669', (115, 127))	('SCH717454', 'Chemical', 'MESH:C573312', (34, 43))	('sarcoma', 'Disease', (120, 127))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
115981	20166202	CB17SC-M scid-/- female mice (Taconic Farms, Germantown NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described.	('osteosarcoma', 'Disease', (150, 162))	('osteosarcoma', 'Disease', 'MESH:D012516', (150, 162))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('non-glioblastoma brain tumors', 'Disease', (202, 231))	('CB17SC-M', 'Var', (0, 8))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (164, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('mice', 'Species', '10090', (252, 256))	('sarcomas', 'Disease', (133, 141))	('neuroblastoma', 'Disease', (183, 196))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (164, 180))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('rhabdoid tumors', 'Disease', (116, 131))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (116, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('neuroblastoma', 'Phenotype', 'HP:0003006', (183, 196))	('glioma', 'Disease', (271, 277))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('neuroblastoma', 'Disease', 'MESH:D009447', (183, 196))	('osteosarcoma', 'Phenotype', 'HP:0002669', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('glioma', 'Disease', 'MESH:D005910', (271, 277))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('mice', 'Species', '10090', (24, 28))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('non-glioblastoma brain tumors', 'Disease', 'MESH:D005909', (202, 231))	('brain tumors', 'Phenotype', 'HP:0030692', (219, 231))	('rhabdomyosarcoma', 'Disease', (164, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))
135260	20166202	Results presented here, and previously indicate that the predominant effect of antibodies that block ligand binding to IGF-1R is to slow tumor progression, rather than induce a high frequency of tumor regressions.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('antibodies', 'Var', (79, 89))	('IGF-1R', 'Gene', '3480', (119, 125))	('ligand binding', 'Interaction', (101, 115))	('IGF-1R', 'Gene', (119, 125))	('slow', 'NegReg', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('block', 'NegReg', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
135280	27180128	Margin status was defined as positive (SM(+)) if there was microscopic involvement (R1) or <=1 mm margin and negative (SM(-)) if >1 mm margin was obtained.	('SM', 'Chemical', 'MESH:D012493', (119, 121))	('SM', 'Chemical', 'MESH:D012493', (39, 41))	('microscopic involvement', 'CPA', (59, 82))	('<=1', 'Var', (91, 94))
135322	27180128	Eighty-five percent of patients were treated with 3500 cGy in 10 fractions BID (n = 34), the remaining patients treated BID with 3200 cGy in eight fractions (n = 2), 3375 cGy in nine fractions (n = 2), or 10 fractions with 4000 cGy (n = 1) or 4500 cGy (n = 1).	('3200 cGy', 'Var', (129, 137))	('3375 cGy', 'Var', (166, 174))	('patients', 'Species', '9606', (23, 31))	('3500 cGy', 'Var', (50, 58))	('patients', 'Species', '9606', (103, 111))
135384	27180128	Poor blood flow and hypoxia are known to decrease tumor radiosensitivity, which can affect local control.	('tumor radiosensitivity', 'Phenotype', 'HP:0010997', (50, 72))	('decrease', 'NegReg', (41, 49))	('Poor', 'Var', (0, 4))	('affect', 'Reg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('hypoxia', 'Disease', (20, 27))	('hypoxia', 'Disease', 'MESH:D000860', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('local control', 'CPA', (91, 104))	('tumor', 'Disease', (50, 55))
135463	32295076	The evaluation of temperature data from three hyperthermia sessions for each evaluable patients showed significant correlations with pathologic remission of T10 (VTu), T50 (VTu) and T90 (Vtherm), but not for T90 (VTu), CEM43 (VTu) and CEM 43 (Vtherm), as shown in Figure 5.	('VTu', 'Chemical', '-', (173, 176))	('hyperthermia', 'Disease', 'MESH:D005334', (46, 58))	('T90', 'Var', (182, 185))	('VTu', 'Chemical', '-', (162, 165))	('CEM43', 'Chemical', '-', (219, 224))	('hyperthermia', 'Phenotype', 'HP:0001945', (46, 58))	('hyperthermia', 'Disease', (46, 58))	('CEM', 'Chemical', 'MESH:C064671', (235, 238))	('T50', 'Var', (168, 171))	('VTu', 'Chemical', '-', (213, 216))	('T10', 'Var', (157, 160))	('CEM', 'Chemical', 'MESH:C064671', (219, 222))	('VTu', 'Chemical', '-', (226, 229))	('patients', 'Species', '9606', (87, 95))
135523	31819276	Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts.	('Inhibition', 'NegReg', (0, 10))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (90, 105))	('AML', 'Disease', 'MESH:D015470', (82, 85))	('tumor', 'Disease', (146, 151))	('upregulates', 'PosReg', (113, 124))	('AML', 'Disease', (82, 85))	('apoptosis', 'CPA', (125, 134))	('AML', 'Phenotype', 'HP:0004808', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (90, 105))	('JTE-607', 'Var', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('expression', 'MPA', (38, 48))	('mouse', 'Species', '10090', (172, 177))	("Ewing's sarcoma", 'Disease', (90, 105))	('causes', 'Reg', (139, 145))	('alters', 'Reg', (31, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('CPSF3', 'Gene', (14, 19))
135527	31819276	Pre-clinically, JTE-607 has been shown to inhibit the production of proinflammatory cytokines in rodent and human models of acute injury, septic shock and endotoxemia.	('septic shock', 'Phenotype', 'HP:0100806', (138, 150))	('shock', 'Phenotype', 'HP:0031273', (145, 150))	('JTE-607', 'Var', (16, 23))	('acute injury', 'Disease', (124, 136))	('endotoxemia', 'Disease', (155, 166))	('endotoxemia', 'Disease', 'MESH:D019446', (155, 166))	('septic shock', 'Disease', 'MESH:D012772', (138, 150))	('human', 'Species', '9606', (108, 113))	('production of proinflammatory cytokines', 'MPA', (54, 93))	('inhibit', 'NegReg', (42, 49))	('acute injury', 'Disease', 'MESH:D000208', (124, 136))	('septic shock', 'Disease', (138, 150))
135528	31819276	JTE-607 was also shown to cause cell death in AML cell lines in vitro and to prolong survival in a U-937 xenograft mouse model.	('U-937', 'CellLine', 'CVCL:0007', (99, 104))	('cell death', 'CPA', (32, 42))	('AML', 'Phenotype', 'HP:0004808', (46, 49))	('survival', 'CPA', (85, 93))	('AML', 'Disease', (46, 49))	('mouse', 'Species', '10090', (115, 120))	('prolong', 'PosReg', (77, 84))	('JTE-607', 'Var', (0, 7))	('AML', 'Disease', 'MESH:D015470', (46, 49))
135533	31819276	The CPSF complex is composed of at least five proteins (CPSF1, CPSF2, CPSF3, CPSF4 and FIP1L1) that recognizes the canonical nucleotide sequence AAUAAA in a newly synthesized pre-messenger RNA (pre-mRNA).	('CPSF2', 'Gene', '53981', (63, 68))	('CPSF4', 'Gene', (77, 82))	('CPSF4', 'Gene', '10898', (77, 82))	('CPSF1', 'Gene', '29894', (56, 61))	('CPSF1', 'Gene', (56, 61))	('CPSF2', 'Gene', (63, 68))	('FIP1L1', 'Gene', '81608', (87, 93))	('FIP1L1', 'Gene', (87, 93))	('AAUAAA', 'Var', (145, 151))
135554	31819276	As CES1 protein is known to hydrolyze functional ester groups in small molecules, the strong difference in activity of CES1 knockdown between the DMSO and compound 1 treatments (visualization of the gene-level activity in individual screening conditions shown in Supplementary Fig.	('knockdown', 'Var', (124, 133))	('CES1', 'Gene', (119, 123))	('activity', 'MPA', (107, 115))	('CES1', 'Gene', (3, 7))	('CES1', 'Gene', '1066', (119, 123))	('ester', 'Chemical', 'MESH:D004952', (49, 54))	('CES1', 'Gene', '1066', (3, 7))	('DMSO', 'Chemical', 'MESH:D004121', (146, 150))
135560	31819276	6b), high CES1 levels were not a prerequisite for compound sensitivity as several lines with high CES1 showed little to no viability defect (Supplementary Table 1).	('CES1', 'Gene', (98, 102))	('CES1', 'Gene', '1066', (98, 102))	('CES1', 'Gene', (10, 14))	('high', 'Var', (93, 97))	('CES1', 'Gene', '1066', (10, 14))
135564	31819276	Ectopic CES1 expression rendered both CMK, a non-translocated AML line, as well as SEM, an MLL-AF4 translocated ALL line, more sensitive to compound 1 in a cell viability assay, shifting IC50 values by approximately a factor of ten in both cases.	('CES1', 'Gene', (8, 12))	('MLL', 'Gene', (91, 94))	('MLL', 'Gene', '4297', (91, 94))	('AF4', 'Gene', '4299', (95, 98))	('CMK', 'Gene', (38, 41))	('CES1', 'Gene', '1066', (8, 12))	('more', 'PosReg', (122, 126))	('AML', 'Disease', 'MESH:D015470', (62, 65))	('sensitive', 'MPA', (127, 136))	('expression', 'Var', (13, 23))	('IC50 values', 'MPA', (187, 198))	('Ectopic', 'Var', (0, 7))	('AF4', 'Gene', (95, 98))	('AML', 'Disease', (62, 65))	('CMK', 'Gene', '4283', (38, 41))	('AML', 'Phenotype', 'HP:0004808', (62, 65))
135581	31819276	Critical interactions between compound 2 and CPSF3 are contributed by the carboxylate and hydroxyl groups of 2, which form bifurcated hydrogen bonds to the backbone NH groups of Phe241, Gly330 and Met331, respectively (Fig.	('Gly330', 'Var', (186, 192))	('CPSF3', 'Gene', (45, 50))	('Met331', 'Var', (197, 203))	('Met331', 'Chemical', '-', (197, 203))	('carboxylate', 'Chemical', '-', (74, 85))	('Phe241', 'Chemical', '-', (178, 184))	('hydrogen', 'Chemical', 'MESH:D006859', (134, 142))	('interactions', 'Interaction', (9, 21))	('Gly330', 'Chemical', '-', (186, 192))	('Phe241', 'Var', (178, 184))
135594	31819276	13a) identified from siRNA, chemical proteomics and PAL experiments, followed by identification of mutations that confer resistance to compound treatment.	('mutations', 'Var', (99, 108))	('resistance', 'MPA', (121, 131))	('PAL', 'Chemical', '-', (52, 55))
135595	31819276	Candidate mutants were engineered and transduced into A-673 cells where a shift (by up to 10-fold) in IC50 with compound 1 treatment compared to wild type (WT) was observed in a cell viability assay, assessing either the variome pool or CPSF3 point mutants A395T or G330S, with G330S showing the strongest effect (Fig.	('G330S', 'Mutation', 'p.G330S', (266, 271))	('G330S', 'Var', (266, 271))	('A395T', 'Var', (257, 262))	('G330S', 'Mutation', 'p.G330S', (278, 283))	('G330S', 'Var', (278, 283))	('A395T', 'Mutation', 'c.395A>T', (257, 262))	('CPSF3', 'Gene', (237, 242))
135596	31819276	Accordingly, we found binding of compound 2 to human CPSF3 G330S mutant protein to be strongly reduced as measured by SEC-TID (Supplementary Fig.	('protein', 'Protein', (72, 79))	('G330S', 'Var', (59, 64))	('G330S', 'Mutation', 'p.G330S', (59, 64))	('CPSF3', 'Gene', (53, 58))	('reduced', 'NegReg', (95, 102))	('binding', 'Interaction', (22, 29))	('human', 'Species', '9606', (47, 52))
135597	31819276	Additionally, compound-induced differentiation in A-673 cells was significantly blunted by overexpression of G330S mutant CPSF3 (Supplementary Fig.	('blunted', 'NegReg', (80, 87))	('G330S mutant', 'Var', (109, 121))	('G330S', 'Mutation', 'p.G330S', (109, 114))	('overexpression', 'PosReg', (91, 105))	('CPSF3', 'Gene', (122, 127))
135602	31819276	In line with crystallography and SEC-TID binding data, A-673 CPSF3 G330S mutant cells showed fewer foci upon imaging of NKX2-2 mRNA (Supplementary Fig.	('fewer', 'NegReg', (93, 98))	('G330S mutant', 'Var', (67, 79))	('NKX2-2', 'Gene', '4821', (120, 126))	('foci', 'MPA', (99, 103))	('CPSF3', 'Gene', (61, 66))	('NKX2-2', 'Gene', (120, 126))	('G330S', 'Mutation', 'p.G330S', (67, 72))
135607	31819276	In A-673 CPSF3 G330S mutant cells however, compound 1 dependent read-through or changes in gene expression were strongly reduced (Supplementary Fig.	('gene expression', 'MPA', (91, 106))	('changes', 'Reg', (80, 87))	('mutant', 'Var', (21, 27))	('read-through', 'MPA', (64, 76))	('reduced', 'NegReg', (121, 128))	('G330S', 'Mutation', 'p.G330S', (15, 20))
135608	31819276	Accordingly, at the NKX2-2 locus, read-through was abrogated in CPSF3 G330S mutant cells but not at the RUNX3 locus used as a control, in line with smFISH results (Supplementary Fig.	('abrogated', 'NegReg', (51, 60))	('NKX2-2', 'Gene', '4821', (20, 26))	('mutant', 'Var', (76, 82))	('RUNX3', 'Gene', (104, 109))	('RUNX3', 'Gene', '864', (104, 109))	('G330S', 'Mutation', 'p.G330S', (70, 75))	('G330S mutant', 'Var', (70, 82))	('read-through', 'MPA', (34, 46))	('NKX2-2', 'Gene', (20, 26))	('CPSF3', 'Gene', (64, 69))
135623	31819276	Since we did not observe a pan-toxic phenotype in our cell panel, nor have any adverse effects been reported in in vivo studies of compound 1 in both rodents and humans, it suggests that selective LMW targeting of CPSF3 could offer a therapeutic window.	('CPSF3', 'Gene', (214, 219))	('LMW targeting', 'Var', (197, 210))	('humans', 'Species', '9606', (162, 168))
135626	31819276	Specifically, inhibition of CPSF3 represents a novel druggable node whose modulation tips the balance between aberrant transcription characterizing these cancers and the genomic instability resulting from it towards misregulated gene expression, DNA damage and downstream cellular viability defects.	('tips', 'PosReg', (85, 89))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('balance', 'MPA', (94, 101))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('modulation', 'Var', (74, 84))	('inhibition', 'Var', (14, 24))	('CPSF3', 'Gene', (28, 33))
135631	31819276	In addition to targeting CPSF3 as a new therapeutic paradigm in cancer as described here, CPSF3 has recently been suggested as an anti-malarial target and modulation of CPSF3 by JTE-607 most likely underlies its previously described effects on cytokine production and immune modulation.	('modulation', 'Var', (155, 165))	('CPSF3', 'Gene', (90, 95))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('CPSF3', 'Gene', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
135663	31819276	Cells were washed into FACS staining buffer (PBS, with 1% BSA) and stained with either PE-conjugated CD73 (BioLegend 344004), CD44 (BioLegend 338808), CD54 (BioLegend 353106), or CD11b (BioLegend 301306).	('CD54', 'Gene', '3383', (151, 155))	('CD54', 'Gene', (151, 155))	('CD73', 'Gene', '4907', (101, 105))	('PE', 'Chemical', '-', (87, 89))	('CD44', 'Gene', '960', (126, 130))	('PBS', 'Chemical', 'MESH:D007854', (45, 48))	('BioLegend', 'Var', (157, 166))	('CD73', 'Gene', (101, 105))	('CD44', 'Gene', (126, 130))	('CD11b', 'Var', (179, 184))
135675	31819276	qPCR was performed using the following TaqMan assays (Applied Biosystems) with TaqMan Fast Advanced Mastermix (Thermo Fisher Scientific): EWSR1-FLI1 (Hs03024497_ft), NKX2-2 (Hs00159616_m1), MLL-AF9 (Hs03296416_ft), MYB (Hs00920556_m1), MYC (Hs00905030_m1), CEBPa (Hs00269972_s1), EGR1 (Hs00152928_m1), GFI1 (Hs00382207_m1), IL-8 (Hs00174103_m1), MPO (Hs00924296_m1), and PPIA endogenous control (Hs99999904_m1).	('MYC', 'Gene', '4609', (236, 239))	('MPO', 'Gene', '4353', (346, 349))	('GFI1', 'Gene', '2672', (302, 306))	('CEBPa', 'Gene', (257, 262))	('GFI1', 'Gene', (302, 306))	('Hs03296416_ft', 'Var', (199, 212))	('Hs00382207_m1', 'Var', (308, 321))	('MPO', 'Gene', (346, 349))	('IL-8', 'Gene', '3576', (324, 328))	('EWSR1', 'Gene', (138, 143))	('FLI1', 'Gene', '2313', (144, 148))	('PPIA', 'Gene', '5478', (371, 375))	('MYB', 'Gene', '4602', (215, 218))	('MYB', 'Gene', (215, 218))	('Hs00924296_m1', 'Var', (351, 364))	('CEBPa', 'Gene', '1050', (257, 262))	('Hs99999904_m1', 'Var', (396, 409))	('MLL', 'Gene', (190, 193))	('MLL', 'Gene', '4297', (190, 193))	('Hs00269972_s1', 'Var', (264, 277))	('Hs00174103_m1', 'Var', (330, 343))	('EGR1', 'Gene', (280, 284))	('Hs00920556_m1', 'Var', (220, 233))	('MYC', 'Gene', (236, 239))	('EGR1', 'Gene', '1958', (280, 284))	('NKX2-2', 'Gene', '4821', (166, 172))	('Hs03024497_ft', 'Var', (150, 163))	('PPIA', 'Gene', (371, 375))	('AF9', 'Gene', (194, 197))	('IL-8', 'Gene', (324, 328))	('Hs00905030_m1', 'Var', (241, 254))	('EWSR1', 'Gene', '2130', (138, 143))	('NKX2-2', 'Gene', (166, 172))	('Hs00152928_m1', 'Var', (286, 299))	('AF9', 'Gene', '4300', (194, 197))	('Hs00159616_m1', 'Var', (174, 187))	('FLI1', 'Gene', (144, 148))
135690	31819276	DMSO-treated cells were then treated with 0, 0.01, 0.1, 1 or 10 microM 7, while 1-treated cells were treated with 1 microM 7 for 1 h at 37 C with 5% CO2.	('0.01', 'Var', (45, 49))	('DMSO', 'Chemical', 'MESH:D004121', (0, 4))	('CO2', 'Chemical', 'MESH:D002245', (149, 152))	('0.1', 'Var', (51, 54))
135714	31819276	The Variomics lentiviral expression vector pXP1510 was modified from pINDUCER21 by replacing the existing protein expression units with a synthesized expression cassette that uses the EF1a promoter to drive expression of a transcript encoding both the mutant protein and the Neomycin resistance marker separated by an IRES element.	('EF1a', 'Gene', '1917', (184, 188))	('Neomycin', 'Chemical', 'MESH:D009355', (275, 283))	('EF1a', 'Gene', (184, 188))	('mutant', 'Var', (252, 258))	('protein', 'Protein', (259, 266))
135715	31819276	Error-prone PCR using the primers XPO1920 (5'GAGCCTACCTAGACTCAGC3') and XPO2007 (5'CTGCTTCCTTCACGACATTC3') followed by cloning of NotI-AscI-digested PCR products into pXP1510 yielded a library of CPSF3 mutants with an average of 4 mutations per clone (confirmed using Sanger sequencing 48 clones with XPO1920 and XPO2007).	('mutants', 'Var', (202, 209))	('CPSF3', 'Gene', (196, 201))	('TC', 'Chemical', 'MESH:D013667', (101, 103))	('TC', 'Chemical', 'MESH:D013667', (92, 94))	('mutations', 'Var', (231, 240))	('TC', 'Chemical', 'MESH:D013667', (88, 90))	('TC', 'Chemical', 'MESH:D013667', (59, 61))
135737	31819276	Global transcript levels and RNA Pol II read-through in A-673 cells, A-673 CPSF3 G330S mutant cells, NOMO-1 cells or A549 cells were measured using RNA sequencing (RNA-seq) technology.	('G330S', 'Mutation', 'p.G330S', (81, 86))	('G330S mutant', 'Var', (81, 93))	('A549', 'CellLine', 'CVCL:0023', (117, 121))	('mutant', 'Var', (87, 93))	('NOMO-1', 'Gene', '23420', (101, 107))	('NOMO-1', 'Gene', (101, 107))	('CPSF3', 'Gene', (75, 80))
135795	29955231	Alterations of TP53, RB1, and CDKN2A have been suggested to participate in rising of UPS.	('RB1', 'Gene', '5925', (21, 24))	('CDKN2A', 'Gene', (30, 36))	('Alterations', 'Var', (0, 11))	('CDKN2A', 'Gene', '1029', (30, 36))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('RB1', 'Gene', (21, 24))
135928	28376906	BRAFV600E expression in histiocytic sarcoma associated with splenic marginal zone lymphoma: a case report Histiocytic sarcoma is a rare histiocytic neoplasm of unknown etiology that constitutes less than 1% of hematologic malignancies.	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('sarcoma', 'Disease', (118, 125))	('neoplasm', 'Phenotype', 'HP:0002664', (148, 156))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcoma', 'Disease', (36, 43))	('BRAFV600E', 'Var', (0, 9))	('hematologic malignancies', 'Disease', (210, 234))	('Histiocytic sarcoma', 'Disease', (106, 125))	('neoplasm', 'Disease', 'MESH:D009369', (148, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('hematologic malignancies', 'Disease', 'MESH:D019337', (210, 234))	('associated', 'Reg', (44, 54))	('Histiocytic sarcoma', 'Disease', 'MESH:D054747', (106, 125))	('neoplasm', 'Disease', (148, 156))	('splenic marginal zone lymphoma', 'Disease', (60, 90))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('splenic marginal zone lymphoma', 'Disease', 'MESH:D018442', (60, 90))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
135933	28376906	The malignant cells tested positive for the BRAFV600E protein using immunohistochemistry.	('positive', 'Reg', (27, 35))	('BRAFV600E', 'Var', (44, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (44, 53))
135942	28376906	However, a small number of recent case reports have demonstrated the presence of the BRAF V600E mutation in HS, and the presence of this mutation raises the possibility of using targeted therapies such as vemurafenib.	('V600E', 'Mutation', 'rs113488022', (90, 95))	('V600E', 'Var', (90, 95))	('BRAF', 'Gene', '673', (85, 89))	('BRAF', 'Gene', (85, 89))	('vemurafenib', 'Chemical', 'MESH:D000077484', (205, 216))
135943	28376906	We report the case of a patient with splenic marginal zone lymphoma (SMZL) who developed HS expressing the BRAFV600E protein.	('splenic marginal zone lymphoma', 'Disease', (37, 67))	('BRAFV600E', 'Var', (107, 116))	('BRAFV600E', 'Mutation', 'rs113488022', (107, 116))	('patient', 'Species', '9606', (24, 31))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('splenic marginal zone lymphoma', 'Disease', 'MESH:D018442', (37, 67))	('SMZL', 'Chemical', '-', (69, 73))
135955	28376906	The presence of an underlying BRAF V600E mutation was not confirmed with deoxyribonucleic acid (DNA) sequencing.	('V600E', 'Var', (35, 40))	('BRAF', 'Gene', (30, 34))	('V600E', 'Mutation', 'rs113488022', (35, 40))	('BRAF', 'Gene', '673', (30, 34))
135964	28376906	A study by Haroche and colleagues in 2012 found a high prevalence of the mutation in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses (0 out of three cases of HS possessed the mutation).	('mutation', 'Var', (73, 81))	('Erdheim-Chester disease', 'Disease', (85, 108))	('Erdheim-Chester disease', 'Disease', 'MESH:D031249', (85, 108))
135965	28376906	Another study by Bubolz and colleagues concluded that BRAF mutations in histiocytic neoplasms are restricted to the Langerhans-cell type, although HS was not included in the study.	('neoplasms', 'Phenotype', 'HP:0002664', (84, 93))	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', (54, 58))	('neoplasms', 'Disease', 'MESH:D009369', (84, 93))	('neoplasms', 'Disease', (84, 93))	('mutations', 'Var', (59, 68))	('neoplasm', 'Phenotype', 'HP:0002664', (84, 92))
135966	28376906	The presence of the mutation has also been documented in two other cases: one case of primary HS involving the central nervous system, and one case of HS arising from hairy cell leukemia.	('hairy cell leukemia', 'Disease', 'MESH:D007943', (167, 186))	('hairy cell leukemia', 'Disease', (167, 186))	('mutation', 'Var', (20, 28))	('leukemia', 'Phenotype', 'HP:0001909', (178, 186))
135967	28376906	Our case provides rare evidence that HS associated with indolent lymphomas may harbor the BRAF V600E mutation.	('BRAF', 'Gene', (90, 94))	('harbor', 'Reg', (79, 85))	('lymphomas', 'Disease', 'MESH:D008223', (65, 74))	('lymphomas', 'Phenotype', 'HP:0002665', (65, 74))	('V600E', 'Mutation', 'rs113488022', (95, 100))	('lymphoma', 'Phenotype', 'HP:0002665', (65, 73))	('BRAF', 'Gene', '673', (90, 94))	('lymphomas', 'Disease', (65, 74))	('V600E', 'Var', (95, 100))
136188	26579879	Subsequently, over the next decade and a half, the Pediatric Oncology Group (POG)/Children's Cancer Group (CCG) and the Children's Oncology Group (COG) conducted two randomized phase 3 clinical trials INT-0154 and AEWS0031 in ESFT to investigate the role of increasing the dose intensity of chemotherapy.	('Oncology', 'Phenotype', 'HP:0002664', (131, 139))	('ESFT', 'Chemical', '-', (226, 230))	('Oncology', 'Phenotype', 'HP:0002664', (61, 69))	('INT-0154', 'Var', (201, 209))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('AEWS0031', 'Var', (214, 222))	('Children', 'Species', '9606', (82, 90))	('Cancer', 'Disease', (93, 99))	('Children', 'Species', '9606', (120, 128))	('Cancer', 'Disease', 'MESH:D009369', (93, 99))
136248	26579879	However, toxicity on AEWS0031 was reported using a different toxicity assessment schedule (CTCAE Version 2.0) than that used for AEWS07P1 (CTCAE Version 4.0).	('AEWS0031', 'Var', (21, 29))	('toxicity', 'Disease', 'MESH:D064420', (61, 69))	('toxicity', 'Disease', (61, 69))	('toxicity', 'Disease', 'MESH:D064420', (9, 17))	('toxicity', 'Disease', (9, 17))
136437	26558647	A subset of uLMS shows a loss of PTEN, resulting in aberrant signaling and increased activation of the AKT-mTOR pathway, which leads to unregulated cell proliferation.	('AKT', 'Gene', '207', (103, 106))	('signaling', 'MPA', (61, 70))	('leads to', 'Reg', (127, 135))	('mTOR', 'Gene', (107, 111))	('mTOR', 'Gene', '2475', (107, 111))	('PTEN', 'Gene', (33, 37))	('AKT', 'Gene', (103, 106))	('PTEN', 'Gene', '5728', (33, 37))	('aberrant', 'Var', (52, 60))	('increased activation', 'PosReg', (75, 95))	('loss', 'NegReg', (25, 29))	('unregulated', 'MPA', (136, 147))	('uLMS', 'Phenotype', 'HP:0002891', (12, 16))
136452	26558647	The combination of rapamycin and MLN8237 (an Aurora-A kinase inhibitor) resulted in synergistic inhibition of cell growth in both in vitro and in vivo models.	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('MLN8237', 'Var', (33, 40))	('rapamycin', 'Chemical', 'MESH:D020123', (19, 28))	('inhibition', 'NegReg', (96, 106))	('cell growth', 'CPA', (110, 121))
136547	23587410	Recent studies have also demonstrated that random X chromosome inactivation could be detected in various involved lymph nodes, supporting the hypothesis of a multifocal disease rather than a metastatic tendency.	('multifocal disease', 'Disease', (158, 176))	('multifocal disease', 'Disease', 'None', (158, 176))	('random X chromosome inactivation', 'Var', (43, 75))
136551	23587410	Hypercellularity, high or atypical mitotic figures, and even regional lymph node involvement might not indicate the overt malignancy of this tumor.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('malignancy', 'Disease', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('men', 'Species', '9606', (88, 91))	('Hypercellularity', 'Var', (0, 16))	('malignancy', 'Disease', 'MESH:D009369', (122, 132))
136671	26471914	CTX binds directly to Annexin A2, and knockdown of Annexin A2 expression in cultured cells causes loss of CTX binding.	('CTX', 'Disease', (0, 3))	('CTX', 'Disease', (106, 109))	('Annexin A2', 'Gene', (22, 32))	('CTX', 'Disease', 'MESH:D019294', (0, 3))	('Annexin A2', 'Gene', '403435', (51, 61))	('CTX', 'Disease', 'MESH:D019294', (106, 109))	('binding', 'Interaction', (110, 117))	('Annexin A2', 'Gene', '403435', (22, 32))	('loss', 'NegReg', (98, 102))	('knockdown', 'Var', (38, 47))	('Annexin A2', 'Gene', (51, 61))	('binds', 'Interaction', (4, 9))
136797	23170261	In a Th1 environment, pro-inflammatory cytokines such as interleukin (IL)-1alpha, IL-1beta, IL-6 and tumor-necrosis factor alpha (TNFalpha) enhance anti-cancer immunity.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('enhance', 'PosReg', (140, 147))	('IL-1beta', 'Var', (82, 90))	('tumor-necrosis factor alpha', 'Gene', (101, 128))	('cancer', 'Disease', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('interleukin (IL)-1alpha', 'Gene', '16175', (57, 80))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor-necrosis factor alpha', 'Gene', '21926', (101, 128))	('interleukin (IL)-1alpha', 'Gene', (57, 80))
136798	23170261	Inducing Th1-type inflammation may significantly improve immunotherapeutic strategies against cancer.	('inflammation', 'Disease', (18, 30))	('immunotherapeutic strategies', 'CPA', (57, 85))	('Inducing', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('improve', 'PosReg', (49, 56))	('inflammation', 'Disease', 'MESH:D007249', (18, 30))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
136801	23170261	For instance, high IL-6 serum levels have been associated with shorter survival in patients affected by multiple myeloma, lymphoma and lung cancer.	('serum levels', 'MPA', (24, 36))	('high IL-6 serum levels', 'Phenotype', 'HP:0030783', (14, 36))	('multiple myeloma', 'Phenotype', 'HP:0006775', (104, 120))	('multiple myeloma, lymphoma', 'Disease', 'MESH:D009101', (104, 130))	('shorter', 'NegReg', (63, 70))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('high', 'Var', (14, 18))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('survival', 'MPA', (71, 79))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
136810	23170261	We used T-cell receptor (TCR) transgenic mice in which all CD4+ T cells recognize a tumor-specific, immunoglobulin-derived antigen that is secreted by the MOPC315 myeloma as well as by the F9 B-cell lymphoma.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CD4', 'Gene', (59, 62))	('MOPC315', 'Var', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CD4', 'Gene', '12504', (59, 62))	('myeloma', 'Disease', 'MESH:D009101', (163, 170))	('B-cell lymphoma', 'Disease', (192, 207))	('transgenic mice', 'Species', '10090', (30, 45))	('tumor', 'Disease', (84, 89))	('cell lymphoma', 'Phenotype', 'HP:0012191', (194, 207))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (192, 207))	('lymphoma', 'Phenotype', 'HP:0002665', (199, 207))	('myeloma', 'Disease', (163, 170))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (192, 207))
136836	23170261	Furthermore, IL-1alpha and IL-1beta increase the expression of adhesion molecules on vascular endothelium, which may promote extravasation, i.e., the migration of leukocytes from the bloodstream into the inflamed tissue.	('IL-1beta', 'Var', (27, 35))	('IL-1alpha', 'Gene', '16175', (13, 22))	('increase', 'PosReg', (36, 44))	('adhesion molecules', 'Protein', (63, 81))	('expression', 'MPA', (49, 59))	('extravasation', 'MPA', (125, 138))	('promote', 'PosReg', (117, 124))	('IL-1alpha', 'Gene', (13, 22))	('migration', 'CPA', (150, 159))
136849	23170261	In line with these experimental findings, a genetic analysis of multiple myeloma patients revealed that individuals with a polymorphism in the promoter region of the IL1B gene, leading to reduced IL-1beta production, had significantly shorter survival after chemotherapy.	('IL-1beta production', 'MPA', (196, 215))	('IL1B', 'Gene', (166, 170))	('polymorphism in', 'Var', (123, 138))	('survival', 'MPA', (243, 251))	('patients', 'Species', '9606', (81, 89))	('IL1B', 'Gene', '3553', (166, 170))	('multiple myeloma', 'Phenotype', 'HP:0006775', (64, 80))	('multiple myeloma', 'Disease', 'MESH:D009101', (64, 80))	('shorter', 'NegReg', (235, 242))	('reduced', 'NegReg', (188, 195))	('multiple myeloma', 'Disease', (64, 80))
136850	23170261	Thus, antitumor effects for both IL-1alpha and IL-1beta have been demonstrated in various mouse models, and several studies suggest that IL-1alpha and IL-1beta can significantly enhance T-cell mediated antitumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('enhance', 'PosReg', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (10, 15))	('IL-1beta', 'Var', (151, 159))	('tumor', 'Disease', (206, 211))	('mouse', 'Species', '10090', (90, 95))	('IL-1alpha', 'Gene', (33, 42))	('IL-1alpha', 'Gene', (137, 146))	('IL-1alpha', 'Gene', '16175', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('IL-1alpha', 'Gene', '16175', (137, 146))
136859	23170261	IL-1beta was successfully used as an adjuvant, together with sonicated cancer cells, to induce tumor-specific immunity against MOPC104E plasmacytoma and MethA sarcoma in mice.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('plasmacytoma', 'Disease', 'MESH:D010954', (136, 148))	('plasmacytoma', 'Phenotype', 'HP:0011857', (136, 148))	('cancer', 'Disease', (71, 77))	('sarcoma', 'Disease', (159, 166))	('plasmacytoma', 'Disease', (136, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('MOPC104E', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mice', 'Species', '10090', (170, 174))	('induce', 'PosReg', (88, 94))	('sarcoma', 'Disease', 'MESH:D012509', (159, 166))	('tumor', 'Disease', (95, 100))
136861	23170261	Altogether, these data suggest that IL-1alpha and IL-1beta, as whole proteins or biologically active fragments, may represent potent adjuvants for cancer vaccines.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('IL-1alpha', 'Gene', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('IL-1beta', 'Var', (50, 58))	('IL-1alpha', 'Gene', '16175', (36, 45))
136862	23170261	In several types of human cancer, such as multiple myeloma, B-cell lymphoma and lung cancer, high IL-6 serum levels have been associated with short patient survival, supporting cancer-promoting effects for IL-6.	('cancer', 'Disease', (177, 183))	('lymphoma', 'Phenotype', 'HP:0002665', (67, 75))	('serum levels', 'MPA', (103, 115))	('cancer', 'Disease', (26, 32))	('cell lymphoma', 'Phenotype', 'HP:0012191', (62, 75))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('multiple myeloma', 'Disease', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (60, 75))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('high', 'Var', (93, 97))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (60, 75))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('multiple myeloma', 'Phenotype', 'HP:0006775', (42, 58))	('IL-6', 'Gene', (98, 102))	('high IL-6 serum levels', 'Phenotype', 'HP:0030783', (93, 115))	('cancer', 'Disease', (85, 91))	('patient', 'Species', '9606', (148, 155))	('B-cell lymphoma', 'Disease', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('human', 'Species', '9606', (20, 25))	('multiple myeloma', 'Disease', 'MESH:D009101', (42, 58))	('lung cancer', 'Disease', (80, 91))
136865	23170261	In mice inoculated with acute myeloid leukemia cells, IL-6 injections inhibited tumor development and increased survival.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('survival', 'CPA', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('IL-6', 'Gene', (54, 58))	('mice', 'Species', '10090', (3, 7))	('leukemia', 'Phenotype', 'HP:0001909', (38, 46))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (24, 46))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (30, 46))	('tumor', 'Disease', (80, 85))	('injections', 'Var', (59, 69))	('acute myeloid leukemia', 'Disease', (24, 46))	('increased', 'PosReg', (102, 111))	('inhibited', 'NegReg', (70, 79))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (24, 46))
136869	23170261	Fibrosarcoma cells transduced with IL-6 exhibited reduced tumorigenicity, increased immunogenicity and decreased metastatic potential.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('IL-6', 'Gene', (35, 39))	('transduced', 'Var', (19, 29))	('Fibrosarcoma', 'Disease', (0, 12))	('Fibrosarcoma', 'Phenotype', 'HP:0100244', (0, 12))	('Fibrosarcoma', 'Disease', 'MESH:D005354', (0, 12))	('decreased', 'NegReg', (103, 112))	('increased', 'PosReg', (74, 83))	('metastatic potential', 'CPA', (113, 133))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('reduced', 'NegReg', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('immunogenicity', 'MPA', (84, 98))
136872	23170261	Endogenous IL-6 reportedly increases CD8+ T cell trafficking to the tumors in mice with B16 melanoma treated with systemic thermal therapy combined with adoptive T cell transfer.	('CD8', 'Gene', (37, 40))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('CD8', 'Gene', '925', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('increases', 'PosReg', (27, 36))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mice', 'Species', '10090', (78, 82))	('Endogenous', 'Var', (0, 10))
136874	23170261	Moreover, in vitro studies on human melanoma demonstrated that exposure to IL-6 inhibits the growth of early-stage but not advanced stage melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('human', 'Species', '9606', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('growth', 'CPA', (93, 99))	('inhibits', 'NegReg', (80, 88))	('IL-6', 'Gene', (75, 79))	('exposure', 'Var', (63, 71))
136880	23170261	For example, TNFalpha-deficient mice were less susceptible to carcinogen-induced papilloma, a benign epithelial tumor, suggesting that TNFalpha may promote skin cancer development.	('skin cancer', 'Disease', (156, 167))	('epithelial tumor', 'Disease', 'MESH:D002277', (101, 117))	('skin cancer', 'Disease', 'MESH:D012878', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('skin cancer', 'Phenotype', 'HP:0008069', (156, 167))	('TNFalpha-deficient', 'Disease', 'MESH:D007153', (13, 31))	('TNFalpha', 'Var', (135, 143))	('papilloma', 'Phenotype', 'HP:0012740', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mice', 'Species', '10090', (32, 36))	('epithelial tumor', 'Disease', (101, 117))	('promote', 'PosReg', (148, 155))	('papilloma', 'Disease', (81, 90))	('TNFalpha-deficient', 'Disease', (13, 31))	('epithelial tumor', 'Phenotype', 'HP:0031492', (101, 117))	('papilloma', 'Disease', 'MESH:D010212', (81, 90))
136881	23170261	In chronic lymphocytic leukemia, patients with high plasma levels of TNFalpha had a significantly shorter survival rate.	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (3, 31))	('TNFalpha', 'Gene', (69, 77))	('patients', 'Species', '9606', (33, 41))	('high', 'Var', (47, 51))	('chronic lymphocytic leukemia', 'Disease', (3, 31))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('survival rate', 'CPA', (106, 119))	('shorter', 'NegReg', (98, 105))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (3, 31))
136889	23170261	J558L myeloma cells transfected with TNFalpha were efficiently eliminated in mice, and it was proposed that TNFalpha would function by recruiting and activating macrophages.	('mice', 'Species', '10090', (77, 81))	('activating', 'PosReg', (150, 160))	('myeloma', 'Disease', 'MESH:D009101', (6, 13))	('J558L', 'Var', (0, 5))	('J558', 'CellLine', 'CVCL:3529', (0, 4))	('myeloma', 'Disease', (6, 13))	('TNFalpha', 'Gene', (37, 45))
136891	23170261	In a mouse model for T-cell lymphoma, an opposing effect of TNFalpha on tumor growth was reported: TNFalpha induced the rejection of solid tumors but promoted the formation of hepatic metastases.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (139, 144))	('TNFalpha', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (21, 36))	('solid tumors', 'Disease', 'MESH:D009369', (133, 145))	('promoted', 'PosReg', (150, 158))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('mouse', 'Species', '10090', (5, 10))	('hepatic metastases', 'Disease', 'MESH:D009362', (176, 194))	('tumor', 'Disease', (72, 77))	('induced', 'PosReg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (21, 36))	('T-cell lymphoma', 'Disease', (21, 36))	('hepatic metastases', 'Disease', (176, 194))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cell lymphoma', 'Phenotype', 'HP:0012191', (23, 36))	('rejection', 'CPA', (120, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (28, 36))	('solid tumors', 'Disease', (133, 145))
136926	23170261	In the absence of sufficient numbers of tumor-specific Th1 cells, pro-inflammatory cytokines (Il-1alpha, IL-1beta, IL-6, TNFalpha) may participate in cancer development, progression and metastasis, for instance by stimulating angiogenesis and cancer cell growth, and by increasing vascular permeability (Fig.	('progression', 'CPA', (170, 181))	('Il-1alpha', 'Gene', (94, 103))	('increasing', 'PosReg', (270, 280))	('TNFalpha', 'Gene', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('stimulating', 'PosReg', (214, 225))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('Il-1alpha', 'Gene', '16175', (94, 103))	('vascular', 'MPA', (281, 289))	('participate', 'Reg', (135, 146))	('metastasis', 'CPA', (186, 196))	('IL-1beta', 'Var', (105, 113))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (243, 249))	('angiogenesis', 'CPA', (226, 238))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
136929	23170261	Early studies in mice revealed that treatment with double-stranded RNA or lipopolysaccharide induced lymphocyte-mediated rejection of L5178Y lymphoma and FS6 fibrosarcoma.	('lymphocyte-mediated rejection', 'CPA', (101, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (141, 149))	('mice', 'Species', '10090', (17, 21))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (158, 170))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (74, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('L5178Y', 'Var', (134, 140))	('FS6 fibrosarcoma', 'Disease', (154, 170))	('FS6 fibrosarcoma', 'Disease', 'MESH:D005354', (154, 170))	('lymphoma', 'Disease', (141, 149))	('lymphoma', 'Disease', 'MESH:D008223', (141, 149))
136930	23170261	More recently, mice with C26 colon carcinoma and B16F0 melanoma have been successfully treated with a combination of anti-IL-10-receptor antibodies and the intratumoral injection with CpG, a TLR-9 ligand.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('C26 colon carcinoma', 'Disease', 'MESH:D015179', (25, 44))	('anti-IL-10-receptor', 'Var', (117, 136))	('TLR-9', 'Gene', '81897', (191, 196))	('TLR-9', 'Gene', (191, 196))	('C26 colon carcinoma', 'Disease', (25, 44))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', (161, 166))	('melanoma', 'Disease', (55, 63))
136934	23170261	Collectively, these data suggest that inducing Th1-type inflammation may represent an efficient strategy to achieve successful cancer immunotherapy.	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('inflammation', 'Disease', (56, 68))	('inducing', 'Var', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
136962	31344922	Anthracycline-containing chemotherapy and chest radiotherapy are known to be associated with long-term, dose-dependent cardiotoxicity, which can manifest as clinical or subclinical cardiac dysfunction.	('cardiac dysfunction', 'Disease', (181, 200))	('Anthracycline', 'Chemical', 'MESH:D018943', (0, 13))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (181, 200))	('cardiotoxicity', 'Disease', (119, 133))	('Anthracycline-containing', 'Var', (0, 24))	('cardiotoxicity', 'Disease', 'MESH:D066126', (119, 133))
137060	31344922	Within the main analyses considering first live births only, higher anthracycline doses and a younger age at diagnosis were found to be associated with cardiac dysfunction.	('associated', 'Reg', (136, 146))	('anthracycline', 'Var', (68, 81))	('cardiac dysfunction', 'Disease', (152, 171))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (152, 171))	('anthracycline', 'Chemical', 'MESH:D018943', (68, 81))
137073	31344922	The current COG Guidelines recommend cardiac surveillance following lower anthracycline doses only if the survivor also received some cardiac irradiation, suggesting that the additional impact of radiotherapy increases the risk of cardiac events to be equivalent to that caused by higher doses of anthracyclines alone.	('anthracyclines', 'Chemical', 'MESH:D018943', (297, 311))	('anthracycline', 'Chemical', 'MESH:D018943', (74, 87))	('anthracycline', 'Chemical', 'MESH:D018943', (297, 310))	('cardiac events', 'MPA', (231, 245))	('radiotherapy', 'Var', (196, 208))	('COG', 'Chemical', '-', (12, 15))
137074	31344922	However, whilst combination therapy is a risk factor for A-CHF, it may not contribute to the overall peripartum risk of cardiac events in this population.	('A-CHF', 'Disease', (57, 62))	('combination', 'Var', (16, 27))	('A-CHF', 'Disease', 'MESH:D006333', (57, 62))
137098	31205866	However, further analysis by fluorescence in situ hybridization (commonly known as FISH) showed a rearrangement of the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22q12 in both patients, confirming the diagnosis of clear cell sarcoma.	('clear cell sarcoma', 'Disease', 'MESH:D018227', (224, 242))	('EWSR1', 'Gene', (146, 151))	('EWS RNA binding protein 1', 'Gene', (119, 144))	('EWS RNA binding protein 1', 'Gene', '2130', (119, 144))	('EWSR1', 'Gene', '2130', (146, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('clear cell sarcoma', 'Disease', (224, 242))	('patients', 'Species', '9606', (186, 194))	('rearrangement', 'Var', (98, 111))
137106	31205866	Cases of malignant melanoma may contain BRAF mutations, whereas clear cell sarcoma lacks this mutation and characteristically exhibits the reciprocal translocation t(12;22)(q13;q12) resulting in a rearrangement of the EWS RNA binding protein 1 (EWSR1) gene.	('BRAF', 'Gene', '673', (40, 44))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (64, 82))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (40, 44))	('EWS RNA binding protein 1', 'Gene', (218, 243))	('EWS RNA binding protein 1', 'Gene', '2130', (218, 243))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('malignant melanoma', 'Phenotype', 'HP:0002861', (9, 27))	('EWSR1', 'Gene', (245, 250))	('rearrangement', 'MPA', (197, 210))	('clear cell sarcoma', 'Disease', (64, 82))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (164, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('malignant melanoma', 'Disease', (9, 27))	('malignant melanoma', 'Disease', 'MESH:D008545', (9, 27))	('EWSR1', 'Gene', '2130', (245, 250))
137122	31205866	These results supported the initial diagnosis of malignant melanoma and excluded the diagnosis of a clear cell carcinoma due to negativity for cytokeratin.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('clear cell carcinoma', 'Disease', (100, 120))	('malignant melanoma', 'Phenotype', 'HP:0002861', (49, 67))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (100, 120))	('malignant melanoma', 'Disease', (49, 67))	('malignant melanoma', 'Disease', 'MESH:D008545', (49, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('negativity', 'Var', (128, 138))
137138	31205866	An EWSR1 gene rearrangement on chromosome 22q12 was found (Figure 4).	('rearrangement', 'Var', (14, 27))	('EWSR1', 'Gene', '2130', (3, 8))	('EWSR1', 'Gene', (3, 8))
137146	31205866	A rearrangement of the EWSR1 gene on chromosome 22q12 was found, confirming the diagnosis of clear cell sarcoma.	('clear cell sarcoma', 'Disease', 'MESH:D018227', (93, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('EWSR1', 'Gene', (23, 28))	('clear cell sarcoma', 'Disease', (93, 111))	('rearrangement', 'Var', (2, 15))	('EWSR1', 'Gene', '2130', (23, 28))
137166	31205866	The initial misdiagnosis was due to the morphologic and immunohistochemical similarities between clear cell sarcoma and malignant melanoma and lack of awareness of the t(12;22)(q13;q12) translocation, which was only recently described.	('lack of awareness', 'Phenotype', 'HP:0000757', (143, 160))	('clear cell sarcoma', 'Disease', (97, 115))	('malignant melanoma', 'Disease', 'MESH:D008545', (120, 138))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (97, 115))	('malignant melanoma', 'Disease', (120, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (168, 185))	('t(12;22)(q13;q12', 'Var', (168, 184))	('malignant melanoma', 'Phenotype', 'HP:0002861', (120, 138))
137175	31205866	Based on our previous experience we performed FISH testing, which demonstrated the EWRS1 rearrangement and confirmed the diagnosis of clear cell sarcoma.	('rearrangement', 'Var', (89, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('clear cell sarcoma', 'Disease', (134, 152))	('EWRS1', 'Gene', (83, 88))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (134, 152))
137261	27434038	While its function in these stromal cells is yet to be clearly defined, knockout mouse models have shown the absence of endosialin expression results in reduced growth, invasion and metastasis of human tumour xenografts, with increase in small immature vessels and decrease in medium and large tumour vessels, suggesting a role in controlling the interaction between tumour cells, endothelia and the extracellular matrix.	('endosialin', 'Gene', (120, 130))	('reduced', 'NegReg', (153, 160))	('metastasis', 'CPA', (182, 192))	('growth', 'CPA', (161, 167))	('small immature vessels', 'CPA', (238, 260))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('decrease', 'NegReg', (265, 273))	('increase', 'PosReg', (226, 234))	('tumour', 'Disease', (202, 208))	('tumour', 'Phenotype', 'HP:0002664', (367, 373))	('invasion', 'CPA', (169, 177))	('tumour', 'Disease', 'MESH:D009369', (367, 373))	('absence', 'Var', (109, 116))	('tumour', 'Disease', (367, 373))	('tumour', 'Phenotype', 'HP:0002664', (294, 300))	('tumour', 'Disease', 'MESH:D009369', (294, 300))	('human', 'Species', '9606', (196, 201))	('tumour', 'Disease', (294, 300))	('mouse', 'Species', '10090', (81, 86))
137278	27434038	Patients with advanced soft tissue sarcoma were randomised to receive gemcitabine/ docetaxel with the antibody or with placebo.	('docetaxel', 'Chemical', 'MESH:D000077143', (83, 92))	('sarcoma', 'Disease', (35, 42))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (23, 42))	('gemcitabine', 'Chemical', 'MESH:C056507', (70, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('Patients', 'Species', '9606', (0, 8))	('antibody', 'Var', (102, 110))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))
137575	26336878	Interestingly, a report on mouse Tem1 showed that the size of malignant tumors transplanted into abdominal sites in Tem1-knockout mice was smaller than that in wild-type mice, and this difference in size was correlated with poor metastasis and a longer survival.	('longer', 'PosReg', (246, 252))	('mice', 'Species', '10090', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Tem1-knockout', 'Var', (116, 129))	('mouse', 'Species', '10090', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Tem1-knockout', 'Gene', (116, 129))	('mice', 'Species', '10090', (170, 174))	('malignant tumors', 'Disease', (62, 78))	('poor metastasis', 'CPA', (224, 239))	('malignant tumors', 'Disease', 'MESH:D018198', (62, 78))	('smaller', 'NegReg', (139, 146))
137658	26336878	Vessel-TEM1-intensity was more commonly observed in patients with a pathological depth of penetration (P < 0.0001), pathological nodal status (P = 0.002), lymphatic vessel infiltration (P < 0.001), venous vessel infiltration (P < 0.001), vessel infiltration (P < 0.0001), and pTNM stage (P = 0.011), as shown in Table S1.	('TNM', 'Gene', '10178', (277, 280))	('venous vessel infiltration', 'Disease', (198, 224))	('pathological', 'Var', (68, 80))	('TEM1', 'Gene', '57124', (7, 11))	('observed', 'Reg', (40, 48))	('TNM', 'Gene', (277, 280))	('pathological', 'Var', (116, 128))	('TEM1', 'Gene', (7, 11))	('lymphatic vessel infiltration', 'CPA', (155, 184))	('venous vessel infiltration', 'Disease', 'None', (198, 224))	('patients', 'Species', '9606', (52, 60))	('vessel infiltration', 'CPA', (238, 257))
137665	26336878	Multivariate analyses using the Cox hazard model to identify clinicopathological factors influencing the RFS, OS, and COS (Table S3) exhibited a significant association with a poor prognosis, RFS for CAF-TEM1-intensity, as had been shown by the Hazard Ratio values.	('RFS', 'Chemical', '-', (105, 108))	('OS', 'Chemical', '-', (110, 112))	('RFS', 'Chemical', '-', (192, 195))	('COS', 'Chemical', '-', (118, 121))	('RFS', 'Var', (192, 195))	('CAF-TEM1', 'Gene', (200, 208))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))	('OS', 'Chemical', '-', (119, 121))	('CAF-TEM1', 'Gene', '8850;57124', (200, 208))
137666	26336878	However, venous vessel infiltration, pathological depth of penetration, and pStage were significantly associated with a poor prognosis, as previously known (Table S3).	('venous vessel infiltration', 'Disease', (9, 35))	('pathological depth', 'Var', (37, 55))	('venous vessel infiltration', 'Disease', 'None', (9, 35))	('pStage', 'Disease', (76, 82))
137719	25888919	However, in genetic examinations, polymerase chain reaction testing has greatly aided the diagnosis of SSK by allowing detection of the SYT-SSX fusion gene that results from translocation of the SYT gene on chromosome 18 with the SSX gene on the X chromosome.	('translocation', 'Var', (174, 187))	('results from', 'Reg', (161, 173))	('SSX', 'Gene', (230, 233))	('SYT', 'Gene', '6857', (136, 139))	('SYT', 'Gene', '6857', (195, 198))	('SSX', 'Gene', '6757', (230, 233))	('SSX', 'Gene', '6757', (140, 143))	('SSX', 'Gene', (140, 143))	('SYT', 'Gene', (136, 139))	('SSK', 'Disease', (103, 106))	('SYT', 'Gene', (195, 198))
137720	25888919	No SYT-SSX fusion gene is present in CCSK, though the chromosomal translocation t(10;17)(q22;p13) is recognized in 12% of CCSK cases.	('CCSK', 'Chemical', '-', (122, 126))	('CCSK', 'Phenotype', 'HP:0006770', (122, 126))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (80, 97))	('SSX', 'Gene', (7, 10))	('SSX', 'Gene', '6757', (7, 10))	('SYT', 'Gene', '6857', (3, 6))	('t(10;17)(q22;p13', 'Var', (80, 96))	('SYT', 'Gene', (3, 6))	('CCSK', 'Chemical', '-', (37, 41))	('CCSK', 'Disease', (122, 126))	('CCSK', 'Phenotype', 'HP:0006770', (37, 41))
137748	25657562	Variant cancers account for 5-10% of all prostate cancers.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('prostate cancers', 'Disease', 'MESH:D011471', (41, 57))	('cancers', 'Disease', (8, 15))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('prostate cancers', 'Phenotype', 'HP:0012125', (41, 57))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('prostate cancers', 'Disease', (41, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Variant', 'Var', (0, 7))
137804	25657562	The overexpression of MED12 gene mutation in sarcomas can be an indicator of poor prognosis.	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('mutation', 'Var', (33, 41))	('MED12', 'Gene', (22, 27))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcomas', 'Disease', (45, 53))	('MED12', 'Gene', '9968', (22, 27))	('overexpression', 'PosReg', (4, 18))
137869	32759845	HERVs are the genetic remnants of ancient retroviral germline infection of human ancestors and are typically silenced in normal tissues due to inactivating mutations and sequence loss.	('HERVs', 'Species', '206037', (0, 5))	('sequence loss', 'Var', (170, 183))	('infection', 'Disease', (62, 71))	('infection', 'Disease', 'MESH:D007239', (62, 71))	('human', 'Species', '9606', (75, 80))	('inactivating mutations', 'Var', (143, 165))
137870	32759845	While some HERV elements have been appropriated and contribute to human physiological functions, others can be reactivated through epigenetic dysregulations to express retroviral elements and promote carcinogenesis.	('promote', 'PosReg', (192, 199))	('human', 'Species', '9606', (66, 71))	('epigenetic dysregulations', 'Var', (131, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (200, 214))	('retroviral elements', 'Protein', (168, 187))	('express', 'Reg', (160, 167))	('carcinogenesis', 'Disease', (200, 214))
137908	32759845	Overall, almost all cervical cancers arise from human papilloma virus (HPV) oncogenesis, and the concomitant presence of HIV may augment its incidence by affecting the host immune response and thus preventing the clearance of HPV infection.	('papilloma', 'Phenotype', 'HP:0012740', (54, 63))	('HIV', 'Species', '12721', (121, 124))	('HIV', 'Gene', (121, 124))	('arise from', 'Reg', (37, 47))	('HPV', 'Species', '10566', (226, 229))	('incidence', 'MPA', (141, 150))	('human papilloma', 'Disease', (48, 63))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('presence', 'Var', (109, 117))	('human papilloma virus', 'Species', '10566', (48, 69))	('affecting', 'Reg', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('HPV', 'Species', '10566', (71, 74))	('HPV infection', 'Disease', 'MESH:D030361', (226, 239))	('host immune response', 'CPA', (168, 188))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('HPV infection', 'Disease', (226, 239))	('preventing', 'NegReg', (198, 208))	('clearance', 'MPA', (213, 222))	('cancers', 'Disease', (29, 36))	('augment', 'PosReg', (129, 136))
137911	32759845	In the majority of cases, oncogenesis is mediated by the co-infection with an oncovirus, in which HIV-induced immune dysregulation facilitates its immune evasion and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('co-infection', 'Disease', 'MESH:D060085', (57, 69))	('co-infection', 'Disease', (57, 69))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('immune evasion', 'MPA', (147, 161))	('immune dysregulation', 'Var', (110, 130))	('tumor', 'Disease', (166, 171))	('oncogenesis', 'Disease', (26, 37))	('immune dysregulation', 'Phenotype', 'HP:0002958', (110, 130))	('facilitates', 'PosReg', (131, 142))	('HIV', 'Species', '12721', (98, 101))	('mediated by', 'Reg', (41, 52))
137922	32759845	In addition to the above HIV-associated tumors, the presence of the infection augments the risk of incidental cancers as well, including colon, breast, prostate, and squamous-cell skin cancers.	('HIV', 'Species', '12721', (25, 28))	('prostate', 'Disease', (152, 160))	('infection', 'Disease', (68, 77))	('augments', 'PosReg', (78, 86))	('infection', 'Disease', 'MESH:D007239', (68, 77))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cancers', 'Disease', (185, 192))	('tumors', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('skin cancers', 'Phenotype', 'HP:0008069', (180, 192))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('cancers', 'Disease', (110, 117))	('colon', 'Disease', (137, 142))	('squamous-cell skin cancers', 'Disease', 'MESH:D002294', (166, 192))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('breast', 'Disease', (144, 150))	('presence', 'Var', (52, 60))	('squamous-cell skin cancers', 'Disease', (166, 192))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
137932	32759845	Owing to their critical physiological roles in the placenta, this domestication and appropriation of the HERV Envs exerts a positive selection for gene fixation or retention along the primate evolution, observing high degree of conservation and very limited human polymorphisms.	('gene fixation', 'Var', (147, 160))	('human', 'Species', '9606', (258, 263))	('HERV', 'Gene', (105, 109))
137935	32759845	In most tissues, HERVs are transcriptionally silenced by CpG methylation catalyzed by DNA methylase-1.	('HERVs', 'Species', '206037', (17, 22))	('HERVs', 'Gene', (17, 22))	('methylation', 'Var', (61, 72))	('CpG methylation', 'Var', (57, 72))
137936	32759845	The aberrant expression of HERV has been found in a number of human diseases, such as cancers, autoimmune diseases, and neurological diseases, possibly suggesting their role in pathogenesis.	('found', 'Reg', (41, 46))	('autoimmune diseases', 'Disease', (95, 114))	('neurological diseases', 'Disease', (120, 141))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (95, 114))	('neurological diseases', 'Disease', 'MESH:D020271', (120, 141))	('human', 'Species', '9606', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('HERV', 'Protein', (27, 31))	('aberrant expression', 'Var', (4, 23))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('autoimmune diseases', 'Disease', 'MESH:D001327', (95, 114))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
137937	32759845	Current literature suggests that HERV can be activated by a plethora of microenvironmental stimuli such as hormones, cytokines, epigenetic modifications or exogenous microorganisms.	('HERV', 'Protein', (33, 37))	('env', 'Gene', (77, 80))	('plethora', 'Phenotype', 'HP:0001050', (60, 68))	('epigenetic modifications', 'Var', (128, 152))	('activated', 'PosReg', (45, 54))	('env', 'Gene', '30816', (77, 80))
137949	32759845	In addition, it remains controversial whether the presence of HERV has a direct causative role or if it is simply a bystander effect of epigenetic changes, such as the hypomethylation of DNA and chromatin remodeling in the cancer cells, which could expose previously silent HERV LTRs.	('hypomethylation', 'Var', (168, 183))	('silent HERV LTRs', 'Disease', (267, 283))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))	('silent HERV LTRs', 'Disease', 'MESH:C566065', (267, 283))
137959	32759845	Anti-HERV-K Env antibodies and Env-directed chimeric antigen receptor (CAR) T cells exhibited significant tumor-specific cytotoxicity and prevented metastasis in mouse xenograft models.	('CAR', 'Gene', (71, 74))	('CAR', 'Gene', '9970', (71, 74))	('Anti-HERV-K', 'Var', (0, 11))	('cytotoxicity', 'Disease', 'MESH:D064420', (121, 133))	('mouse', 'Species', '10090', (162, 167))	('prevented', 'NegReg', (138, 147))	('metastasis in mouse xenograft models', 'CPA', (148, 184))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('HERV-K', 'Species', '45617', (5, 11))	('cytotoxicity', 'Disease', (121, 133))	('tumor', 'Disease', (106, 111))
137962	32759845	Research in pancreatic cancer also demonstrated that HERV-K(HML2) Env regulates the Ras-ERK pathway, and knockdown of Env in vitro and in vivo reduced the growth of pancreatic cancer and metastasis.	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('pancreatic cancer', 'Disease', (165, 182))	('ERK', 'Gene', '5594', (88, 91))	('HERV-K', 'Species', '45617', (53, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (12, 29))	('reduced', 'NegReg', (143, 150))	('HML2', 'Gene', (60, 64))	('metastasis', 'CPA', (187, 197))	('knockdown', 'Var', (105, 114))	('ERK', 'Gene', (88, 91))	('pancreatic cancer', 'Disease', (12, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Env', 'Gene', (118, 121))	('growth', 'CPA', (155, 161))	('regulates', 'Reg', (70, 79))	('HML2', 'Gene', '10462', (60, 64))
137977	32759845	For instance, it has been shown that the ERV avian leukosis virus-derived antisense long ncRNA in the chicken embryonic fibroblasts can stimulate the TLR3 pathway to induce an antiviral innate immune state against infection by other exogenous retroviruses.	('antiviral innate immune state', 'MPA', (176, 205))	('chicken', 'Species', '9031', (102, 109))	('TLR3 pathway', 'Pathway', (150, 162))	('stimulate', 'PosReg', (136, 145))	('antisense', 'Var', (74, 83))	('infection', 'Disease', (214, 223))	('infection', 'Disease', 'MESH:D007239', (214, 223))	('induce', 'PosReg', (166, 172))
137999	32759845	A similar observation was also found in ovarian cancer cells, in which a combination of the histone methyltransferase G9Ai and the DNMTi 5-aza-2'-deoxycytidine produced a synergistic anti-tumor effect that was associated with enhanced viral mimicry from the upregulated HERV expression.	('tumor', 'Disease', (188, 193))	('ovarian cancer', 'Disease', 'MESH:D010051', (40, 54))	('enhanced', 'PosReg', (226, 234))	('G9Ai', 'Var', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (40, 54))	('viral', 'MPA', (235, 240))	('ovarian cancer', 'Disease', (40, 54))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('upregulated', 'PosReg', (258, 269))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('HERV', 'Protein', (270, 274))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (137, 159))
138000	32759845	Indeed, the use of DNMTi has been demonstrated to trigger TLR3 and MAVS-associated dsRNA sensing pathways that accompanied ERV upregulation in ovarian cancer cells, and this higher viral defense signature expression also correlates with tumor sensitivity to immune checkpoint therapy, particularly with the addition of DNMTi.	('MAVS-associated dsRNA sensing pathways', 'Pathway', (67, 105))	('tumor', 'Disease', (237, 242))	('DNMTi', 'Var', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('higher', 'PosReg', (174, 180))	('ovarian cancer', 'Disease', 'MESH:D010051', (143, 157))	('ERV', 'Gene', (123, 126))	('trigger', 'PosReg', (50, 57))	('upregulation', 'PosReg', (127, 139))	('ovarian cancer', 'Disease', (143, 157))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('TLR3', 'Pathway', (58, 62))	('expression', 'MPA', (205, 215))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
138023	32759845	The exceptional depth at which cancer genomes are examined indicates that HERVs may have completely lost their direct tumor-causing ability due to insertional mutagenesis at the time of novel integration.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('insertional mutagenesis', 'Var', (147, 170))	('HERVs', 'Species', '206037', (74, 79))	('HERVs', 'Gene', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('lost', 'NegReg', (100, 104))	('tumor', 'Disease', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
138029	32759845	As described above, recent investigations have pinpointed that ARVs, beside reducing the risk for HIV-associated cancers, can also affect HERV gene transcription and HERV-encoded protein function.	('affect', 'Reg', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('HIV-associated cancers', 'Disease', (98, 120))	('HIV-associated cancers', 'Disease', 'MESH:D009369', (98, 120))	('HERV', 'Protein', (138, 142))	('transcription', 'MPA', (148, 161))	('function', 'MPA', (187, 195))	('reducing', 'NegReg', (76, 84))	('HERV-encoded protein', 'Protein', (166, 186))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ARVs', 'Var', (63, 67))	('ARVs', 'Chemical', '-', (63, 67))
138044	32806524	Some case reports suggest that several familial syndromes could possibly predispose for angiosarcoma, such as a mutation in the BRCA1 or BRCA2 gene.	('BRCA2', 'Gene', '675', (137, 142))	('mutation', 'Var', (112, 120))	('angiosarcoma', 'Disease', 'MESH:D006394', (88, 100))	('predispose', 'Reg', (73, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('angiosarcoma', 'Disease', (88, 100))	('BRCA1', 'Gene', '672', (128, 133))	('BRCA2', 'Gene', (137, 142))	('BRCA1', 'Gene', (128, 133))	('angiosarcoma', 'Phenotype', 'HP:0200058', (88, 100))
138101	32806524	have previously shown that in the treatment of cardiac sarcomas R0 resection margins resulted in better OS, but this was not easily achieved.	('cardiac sarcomas', 'Disease', (47, 63))	('cardiac sarcoma', 'Phenotype', 'HP:0031350', (47, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('R0 resection', 'Var', (64, 76))	('cardiac sarcomas', 'Phenotype', 'HP:0031350', (47, 63))	('better', 'PosReg', (97, 103))	('cardiac sarcomas', 'Disease', 'MESH:D006331', (47, 63))
138247	31722230	Molecular analysis has revealed that osteosarcomas are genomically unstable with complex karyotypes characterised by chromosomal instability and high levels of structural variants and copy number changes.	('osteosarcomas', 'Disease', 'MESH:D012516', (37, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('copy number changes', 'Var', (184, 203))	('chromosomal instability', 'Phenotype', 'HP:0040012', (117, 140))	('osteosarcomas', 'Phenotype', 'HP:0002669', (37, 50))	('osteosarcomas', 'Disease', (37, 50))	('osteosarcoma', 'Phenotype', 'HP:0002669', (37, 49))
138248	31722230	Furthermore in paediatric osteosarcoma, single-nucleotide variants exhibited kataegis, a pattern of localized hypermutation, with recurrent mutations most frequently observed in the tumour protein p53 (TP53) gene, and also in retinoblastoma protein-1 (RB1), alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), and discs large MAGUK scaffold protein-2 (DLG2).	('mental retardation', 'Phenotype', 'HP:0001249', (276, 294))	('RB1', 'Gene', (252, 255))	('kataegis', 'Disease', (77, 85))	('exhibited', 'Reg', (67, 76))	('observed', 'Reg', (166, 174))	('TP53', 'Gene', (202, 206))	('DLG2', 'Gene', '1740', (383, 387))	('osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('thalassemia/mental retardation syndrome', 'Disease', 'MESH:C538258', (264, 303))	('retinoblastoma', 'Phenotype', 'HP:0009919', (226, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('variants', 'Var', (58, 66))	('p53', 'Gene', '7157', (197, 200))	('RB1', 'Gene', '5925', (252, 255))	('thalassemia/mental retardation syndrome', 'Disease', (264, 303))	('retinoblastoma protein-1', 'Gene', '5925', (226, 250))	('single-nucleotide', 'Var', (40, 57))	('ATRX', 'Gene', (334, 338))	('p53', 'Gene', (197, 200))	('discs large MAGUK scaffold protein-2', 'Gene', (345, 381))	('mutations', 'Var', (140, 149))	('ATRX', 'Gene', '546', (334, 338))	('retinoblastoma protein-1', 'Gene', (226, 250))	('TP53', 'Gene', '7157', (202, 206))	('osteosarcoma', 'Disease', (26, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (26, 38))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('discs large MAGUK scaffold protein-2', 'Gene', '1740', (345, 381))	('DLG2', 'Gene', (383, 387))	('tumour', 'Disease', (182, 188))
138275	31722230	The presence of such pulmonary metastases vastly worsens prognosis, and is the most common cause of death in osteosarcoma.	('worsens', 'Reg', (49, 56))	('pulmonary metastases', 'Disease', (21, 41))	('pulmonary metastases', 'Disease', 'MESH:D009362', (21, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('prognosis', 'MPA', (57, 66))	('presence', 'Var', (4, 12))	('osteosarcoma', 'Phenotype', 'HP:0002669', (109, 121))	('osteosarcoma', 'Disease', (109, 121))	('osteosarcoma', 'Disease', 'MESH:D012516', (109, 121))
138290	31722230	ES is a translocation driven sarcoma; t(q24;q12) results in the formation of the EWSR1-FLI1 proto-oncogene (FLI1) fusion gene in 85% of cases; t(,22)(q22;q12) in the EWSR1-ETS transcription factor ERG (ERG) fusion gene in 10%; and the remaining 5% of cases are characterised by other translocations all resulting in a fusion gene containing a portion of the EWSR1 gene.	('FLI1', 'Gene', (87, 91))	('resulting in', 'Reg', (303, 315))	('fusion gene', 'Var', (318, 329))	('ERG', 'Gene', '2078', (197, 200))	('EWSR1', 'Gene', '2130', (81, 86))	('FLI1', 'Gene', '2313', (87, 91))	('ERG', 'Gene', (202, 205))	('FLI1', 'Gene', (108, 112))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('sarcoma', 'Disease', (29, 36))	('EWSR1', 'Gene', '2130', (166, 171))	('t(q24;q12', 'Var', (38, 47))	('EWSR1', 'Gene', '2130', (358, 363))	('t(,22)(q22;q12) in', 'Var', (143, 161))	('ERG', 'Gene', '2078', (202, 205))	('results in', 'Reg', (49, 59))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('FLI1', 'Gene', '2313', (108, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('EWSR1', 'Gene', (81, 86))	('EWSR1', 'Gene', (166, 171))	('EWSR1', 'Gene', (358, 363))	('ERG', 'Gene', (197, 200))
138296	31722230	To identify such candidate proteins, comparative proteomic profiling of the ES cell line TC-71 and an EWS-FLI1 knockdown TC-71 cell line variant known as shEWS-FLI1 has been performed using 2D-DIGE.	('ES', 'Phenotype', 'HP:0012254', (76, 78))	('EWS', 'Gene', '2130', (156, 159))	('EWS', 'Gene', (156, 159))	('TC-71', 'CellLine', 'CVCL:2213', (89, 94))	('variant', 'Var', (137, 144))	('FLI1', 'Gene', (160, 164))	('FLI1', 'Gene', '2313', (160, 164))	('TC-71', 'CellLine', 'CVCL:2213', (121, 126))	('EWS', 'Gene', (102, 105))	('EWS', 'Gene', '2130', (102, 105))	('FLI1', 'Gene', (106, 110))	('FLI1', 'Gene', '2313', (106, 110))
138299	31722230	Interestingly, network analysis revealed TNF Receptor Associated Factor 6 (TRAF6), an ubiquitin ligase which activates NF-kappa-B and JUN, as a hub node upregulated upon EWS-FLI1 knockdown.	('FLI1', 'Gene', '2313', (174, 178))	('FLI1', 'Gene', (174, 178))	('TNF Receptor Associated Factor 6', 'Gene', '222344', (41, 73))	('EWS', 'Gene', '2130', (170, 173))	('JUN', 'MPA', (134, 137))	('EWS', 'Gene', (170, 173))	('TRAF6', 'Gene', '222344', (75, 80))	('TRAF6', 'Gene', (75, 80))	('knockdown', 'Var', (179, 188))	('upregulated', 'PosReg', (153, 164))	('activates', 'PosReg', (109, 118))	('NF-kappa-B', 'Gene', (119, 129))	('TNF Receptor Associated Factor 6', 'Gene', (41, 73))	('NF-kappa-B', 'Gene', '4790', (119, 129))
138316	31722230	KIT is a member of the type III receptor tyrosine kinase family, and the mutated gene leads to ligand-independent activation and subsequent stimulation of downstream intra-cellular signalling pathways.	('activation', 'PosReg', (114, 124))	('mutated', 'Var', (73, 80))	('stimulation', 'PosReg', (140, 151))	('receptor tyrosine kinase', 'Gene', (32, 56))	('receptor tyrosine kinase', 'Gene', '5979', (32, 56))	('intra-cellular signalling pathways', 'Pathway', (166, 200))	('KIT', 'Gene', (0, 3))
138317	31722230	Aside from KIT mutations, a further 10% of GISTs harbour mutations in the platelet derived growth factor receptor alpha (PDGFRA) gene.	('PDGFRA', 'Gene', (121, 127))	('PDGFRA', 'Gene', '5156', (121, 127))	('mutations', 'Var', (57, 66))	('platelet derived growth factor receptor alpha', 'Gene', '5156', (74, 119))	('platelet derived growth factor receptor alpha', 'Gene', (74, 119))
138318	31722230	PDGFRA is also a member of the type III receptor tyrosine kinase family, and again mutation leads to constitutive activation of the receptor triggering downstream intracellular signalling pathways.	('PDGFRA', 'Gene', (0, 6))	('PDGFRA', 'Gene', '5156', (0, 6))	('mutation', 'Var', (83, 91))	('receptor tyrosine kinase', 'Gene', (40, 64))	('constitutive activation', 'MPA', (101, 124))	('receptor tyrosine kinase', 'Gene', '5979', (40, 64))
138320	31722230	These tumours are a genomically heterogeneous group with a variety of genetic anomalies previously reported, including mutations in B-Raf proto-oncogene (BRAF), succinate dehydrogenase (SDH) and neurofibromin 1 (NF1), however they do demonstrate phosphorylated KIT although the mechanisms behind this are unclear.	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('SDH', 'Gene', (186, 189))	('NF1', 'Gene', '4763', (212, 215))	('genetic anomalies', 'Disease', 'MESH:D030342', (70, 87))	('succinate dehydrogenase', 'Gene', (161, 184))	('genetic anomalies', 'Disease', (70, 87))	('NF1', 'Gene', (212, 215))	('mutations', 'Var', (119, 128))	('neurofibromin 1', 'Gene', '4763', (195, 210))	('B-Raf proto-oncogene', 'Gene', '673', (132, 152))	('phosphorylated KIT', 'MPA', (246, 264))	('neurofibromin 1', 'Gene', (195, 210))	('tumours', 'Disease', (6, 13))	('B-Raf proto-oncogene', 'Gene', (132, 152))	('succinate dehydrogenase', 'Gene', '6390', (161, 184))	('BRAF', 'Gene', '673', (154, 158))	('SDH', 'Gene', '6390', (186, 189))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('BRAF', 'Gene', (154, 158))	('tumours', 'Disease', 'MESH:D009369', (6, 13))
138326	31722230	Comparative proteomic profiling by ESI-MS/MS was performed on 4 surgically resected stomach GISTs, of which 2 were KIT/PDGFRA wild type and 2 harboured KIT mutations, and 4 surgically resected small intestine GISTs, all possessing KIT mutations.	('mutations', 'Var', (156, 165))	('PDGFRA', 'Gene', '5156', (119, 125))	('PDGFRA', 'Gene', (119, 125))	('ES', 'Phenotype', 'HP:0012254', (35, 37))
138341	31722230	DDX39 strong cases showed consistently higher probability of shorter survival, when compared to DDX39 weak cases, suggesting that high DDX39 expression is a predictor for high metastatic potential and, by extension, poor clinical outcome.	('shorter', 'NegReg', (61, 68))	('DDX39', 'Gene', '10212', (135, 140))	('high', 'Var', (130, 134))	('DDX39', 'Gene', (0, 5))	('DDX39', 'Gene', (96, 101))	('expression', 'MPA', (141, 151))	('DDX39', 'Gene', '10212', (0, 5))	('DDX39', 'Gene', (135, 140))	('high metastatic potential', 'CPA', (171, 196))	('DDX39', 'Gene', '10212', (96, 101))
138342	31722230	Despite studies highlighting both DDX39 and pfetin expression as predictive of GIST recurrence, their utility in the clinic is yet to be realised.	('pfetin', 'Gene', '115207', (44, 50))	('pfetin', 'Gene', (44, 50))	('DDX39', 'Gene', (34, 39))	('GIST recurrence', 'Disease', (79, 94))	('DDX39', 'Gene', '10212', (34, 39))	('expression', 'Var', (51, 61))
138348	31722230	Integration with clinical data indicated that high PTPN1 was associated with increased disease-free survival.	('high', 'Var', (46, 50))	('PTPN1', 'Gene', '5770', (51, 56))	('disease-free survival', 'CPA', (87, 108))	('PTPN1', 'Gene', (51, 56))	('increased', 'PosReg', (77, 86))
138350	31722230	Comparisons were performed on 1 untreated GIST case (KIT mutation present), 7 treated cases responsive to IM (all possessing a KIT mutation) and 8 non-responsive cases (1 KIT wild-type, 5 harbouring a KIT mutation and 2 a PDGFRA mutation).	('PDGFRA', 'Gene', '5156', (222, 228))	('PDGFRA', 'Gene', (222, 228))	('mutation', 'Var', (131, 139))
138358	31722230	Upon genetic suppression of FAK and FYN expression by RNA interference (RNAi), GIST-T1 cells displayed increased drug sensitivity to IM.	('drug sensitivity to IM', 'MPA', (113, 135))	('genetic', 'Var', (5, 12))	('FYN', 'Gene', (36, 39))	('increased', 'PosReg', (103, 112))	('FAK', 'Gene', '5747', (28, 31))	('FYN', 'Gene', '2534', (36, 39))	('drug sensitivity', 'Phenotype', 'HP:0020174', (113, 129))	('FAK', 'Gene', (28, 31))	('GIST-T1', 'CellLine', 'CVCL:4976', (79, 86))	('suppression', 'NegReg', (13, 24))
138360	31722230	Inhibition of FAK phosphorylation using the selective inhibitor TAG372 in these GIST-T1 IM resistant cells triggered apoptotic cell death.	('TAG372', 'Chemical', '-', (64, 70))	('GIST-T1', 'CellLine', 'CVCL:4976', (80, 87))	('FAK', 'Gene', '5747', (14, 17))	('Inhibition', 'Var', (0, 10))	('apoptotic cell death', 'CPA', (117, 137))	('FAK', 'Gene', (14, 17))
138385	31722230	Given the relative scarcity of PLPS, molecular studies of this subtype are sparse; however, reports suggest a complex karyotype including unpredictable gains and deletions, although deletion of 13q14.2-q14.3, a region including the known tumour suppressor RB1, has been observed in 60% of PLPS.	('gains', 'PosReg', (152, 157))	('tumour', 'Disease', (238, 244))	('LPS', 'Phenotype', 'HP:0012034', (32, 35))	('LPS', 'Disease', (32, 35))	('LPS', 'Phenotype', 'HP:0012034', (290, 293))	('LPS', 'Disease', (290, 293))	('deletions', 'Var', (162, 171))	('deletion', 'Var', (182, 190))	('RB1', 'Gene', (256, 259))	('LPS', 'Disease', 'MESH:C536528', (32, 35))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Disease', 'MESH:D009369', (238, 244))	('RB1', 'Gene', '5925', (256, 259))	('LPS', 'Disease', 'MESH:C536528', (290, 293))
138405	31722230	Furthermore, whole-exome sequencing analysis of cohorts of LMS and uLMS have confirmed a heterogeneous genomic landscape, but with frequent copy number variation and common alterations in the tumour suppressor genes RB1, TP53, PTEN and cadherin-1 (CDH1).	('LMS', 'Phenotype', 'HP:0100243', (59, 62))	('PTEN', 'Gene', (227, 231))	('CDH1', 'Gene', (248, 252))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('PTEN', 'Gene', '5728', (227, 231))	('alterations', 'Reg', (173, 184))	('RB1', 'Gene', '5925', (216, 219))	('TP53', 'Gene', '7157', (221, 225))	('copy number variation', 'Var', (140, 161))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('CDH1', 'Gene', '999', (248, 252))	('cadherin-1', 'Gene', '999', (236, 246))	('TP53', 'Gene', (221, 225))	('tumour', 'Disease', (192, 198))	('cadherin-1', 'Gene', (236, 246))	('LMS', 'Phenotype', 'HP:0100243', (68, 71))	('RB1', 'Gene', (216, 219))
138407	31722230	They reported soft tissue LMS and uLMS to be more similar to each other compared to other STS subtypes, however they identified distinct methylation and mRNA expression profiles between the two LMS groups, with non-uterine LMS displaying a more prominent HIF1alpha signalling signature compared to uLMS which showed a higher DNA damage response signature.	('LMS', 'Phenotype', 'HP:0100243', (35, 38))	('LMS', 'Phenotype', 'HP:0100243', (223, 226))	('LMS', 'Phenotype', 'HP:0100243', (299, 302))	('mRNA expression', 'MPA', (153, 168))	('LMS', 'Phenotype', 'HP:0100243', (194, 197))	('HIF1alpha', 'Gene', (255, 264))	('non-uterine', 'Var', (211, 222))	('HIF1alpha', 'Gene', '3091', (255, 264))	('LMS', 'Phenotype', 'HP:0100243', (26, 29))	('methylation', 'MPA', (137, 148))
138421	31722230	These phenotypic alterations may result in the development of a more aggressive tumour and thus contribute to an unfavourable prognosis.	('alterations', 'Var', (17, 28))	('more', 'PosReg', (64, 68))	('aggressive tumour', 'Disease', (69, 86))	('result in', 'Reg', (33, 42))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('aggressive tumour', 'Disease', 'MESH:D009369', (69, 86))	('contribute to', 'Reg', (96, 109))
138425	31722230	As validation of the proteomic data, IHC analysis was performed on the initial cohort, and confirmed that E-cadherin expression correlated with improved OS.	('expression', 'Var', (117, 127))	('E-cadherin', 'Gene', (106, 116))	('improved', 'PosReg', (144, 152))	('E-cadherin', 'Gene', '999', (106, 116))
138426	31722230	To assess the functional role MET in LMS, genetic knockdown by RNAi of Slug in the LMS cell line, SK-LMS-1, showed a significant increase in E-Cadherin expression, and a reduction in mesenchymal marker expression (vimetin and N-cadherin).	('reduction', 'NegReg', (170, 179))	('E-Cadherin', 'Gene', '999', (141, 151))	('Slug', 'Gene', (71, 75))	('knockdown', 'Var', (50, 59))	('N-cadherin', 'Gene', (226, 236))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (98, 106))	('LMS', 'Phenotype', 'HP:0100243', (83, 86))	('LMS', 'Phenotype', 'HP:0100243', (101, 104))	('mesenchymal marker', 'CPA', (183, 201))	('increase', 'PosReg', (129, 137))	('N-cadherin', 'Gene', '1000', (226, 236))	('LMS', 'Phenotype', 'HP:0100243', (37, 40))	('E-Cadherin', 'Gene', (141, 151))	('Slug', 'Gene', '6591', (71, 75))	('expression', 'MPA', (152, 162))
138432	31722230	Cytogenetic and molecular analyses identified a deletion on the long arm of chromosome 22 (22q11.2), with subsequent studies demonstrating a loss-of-function exonic mutation in the SWI/SNF related, matrix associated, actin dependant regulator of chromatin, subfamily b, member 1 (SMARCB1) tumour suppressor gene.	('tumour', 'Disease', (289, 295))	('SMARCB1', 'Gene', '6598', (280, 287))	('SMARCB1', 'Gene', (280, 287))	('SWI/SNF related', 'Gene', (181, 196))	('tumour', 'Phenotype', 'HP:0002664', (289, 295))	('tumour', 'Disease', 'MESH:D009369', (289, 295))	('loss-of-function', 'NegReg', (141, 157))	('deletion', 'Var', (48, 56))	('exonic mutation', 'Var', (158, 173))
138435	31722230	Mutational inactivation of SMARCB1, a core subunit of the SWI/SNF ATP dependent chromatin-remodelling complex, has been identified as the molecular mechanism driving MRT and AT/RT development.	('SMARCB1', 'Gene', (27, 34))	('Mutational inactivation', 'Var', (0, 23))	('ATP', 'Chemical', 'MESH:D000255', (66, 69))	('AT', 'Disease', 'None', (174, 176))	('AT', 'Disease', 'None', (66, 68))	('MRT', 'CPA', (166, 169))	('SMARCB1', 'Gene', '6598', (27, 34))
138442	31722230	Further analysis highlighted EGFR phosphorylation at Y1197, an autophosphorylation site associated with receptor activation, and phosphorylation of several of its downstream effectors, ERK2 (T183), JUN (S63), and MYC (T58) upon loss of Smarcb1.	('MYC', 'Gene', (213, 216))	('phosphorylation', 'MPA', (34, 49))	('phosphorylation', 'MPA', (129, 144))	('Smarcb1', 'Gene', (236, 243))	('Smarcb1', 'Gene', '20587', (236, 243))	('MYC', 'Gene', '4609', (213, 216))	('ERK2', 'Gene', (185, 189))	('Y1197', 'Var', (53, 58))	('loss', 'Var', (228, 232))	('EGFR', 'MPA', (29, 33))	('ERK2', 'Gene', '5594', (185, 189))
138444	31722230	AKT phosphorylation was reduced upon treatment with either drug, implicating the EGFR signalling axis in the AKT activation observed in Smarcb1 deficient cells, highlighting the potential use of EGFR inhibitors in the treatment of MRT and AT/RT.	('EGFR signalling axis', 'Pathway', (81, 101))	('reduced', 'NegReg', (24, 31))	('AT', 'Disease', 'None', (239, 241))	('deficient', 'Var', (144, 153))	('AKT', 'Pathway', (109, 112))	('Smarcb1', 'Gene', (136, 143))	('activation', 'PosReg', (113, 123))	('AKT', 'Pathway', (0, 3))	('Smarcb1', 'Gene', '20587', (136, 143))
138456	31722230	More recent studies have demonstrated a non-random loss of chromosome 9, with deletion of the methylthioadenosine phosphorylase (MTAP) and CDKN2A/CDKN2B genes (9q21.3) associated with increased aggressiveness in myxofibrosarcoma.	('aggressiveness in myxofibrosarcoma', 'Disease', (194, 228))	('CDKN2B', 'Gene', (146, 152))	('CDKN2A', 'Gene', '1029', (139, 145))	('aggressiveness', 'Phenotype', 'HP:0000718', (194, 208))	('MTAP', 'Gene', (129, 133))	('associated with', 'Reg', (168, 183))	('deletion', 'Var', (78, 86))	('increased', 'PosReg', (184, 193))	('CDKN2B', 'Gene', '1030', (146, 152))	('MTAP', 'Gene', '4507', (129, 133))	('aggressiveness in myxofibrosarcoma', 'Disease', 'MESH:D001523', (194, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('methylthioadenosine phosphorylase', 'Gene', '4507', (94, 127))	('methylthioadenosine phosphorylase', 'Gene', (94, 127))	('CDKN2A', 'Gene', (139, 145))
138463	31722230	DCBLD2 has previously been associated with tumourigenic activity in several other cancer types, and accordingly the observed positive correlation between high DCBLD2 expression and increased MFS invasiveness was selected for further assessment.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('DCBLD2', 'Gene', (0, 6))	('tumour', 'Disease', (43, 49))	('high', 'Var', (154, 158))	('associated', 'Reg', (27, 37))	('DCBLD2', 'Gene', (159, 165))	('cancer', 'Disease', (82, 88))	('MFS invasiveness', 'Disease', 'MESH:D008382', (191, 207))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('DCBLD2', 'Gene', '131566', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('DCBLD2', 'Gene', '131566', (0, 6))	('increased', 'PosReg', (181, 190))	('expression', 'MPA', (166, 176))	('MFS invasiveness', 'Disease', (191, 207))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
138468	31722230	ASPS is characterised by the pathognomonic unbalanced, non-reciprocal translocation t(X;17)(p11:q25), fusing the alveolar soft part sarcoma chromosome region candidate 1 (ASPSCR1) gene on chromosome 17 to the transcription factor binding to IGHM enhancer 3 (TFE3) gene on the X chromosome.	('ASPSCR1', 'Gene', (171, 178))	('ASPS', 'Gene', '79058', (171, 175))	('TFE3', 'Gene', '7030', (258, 262))	('sarcoma', 'Disease', (132, 139))	('ASPS', 'Gene', '79058', (0, 4))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (113, 139))	('t(X;17)(p11:q25)', 'STRUCTURAL_ABNORMALITY', 'None', (84, 100))	('ASPS', 'Phenotype', 'HP:0012218', (171, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (122, 139))	('ASPS', 'Phenotype', 'HP:0012218', (0, 4))	('TFE3', 'Gene', (258, 262))	('ASPSCR1', 'Gene', '79058', (171, 178))	('ASPS', 'Gene', (171, 175))	('fusing', 'Var', (102, 108))	('ASPS', 'Gene', (0, 4))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
138473	31722230	Moreover the involvement of SET in tumourigenesis was investigated by genetic knockdown in the ASPS cell line ASPS-KY. Silencing of SET resulted in reduced cell proliferation, invasion and migration, implicating this protein as a driver of tumourigenesis in ASPS.	('ASPS', 'Gene', (110, 114))	('ASPS', 'Gene', (95, 99))	('SET', 'Gene', (132, 135))	('ASPS', 'Gene', '79058', (110, 114))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('ASPS', 'Phenotype', 'HP:0012218', (110, 114))	('tumour', 'Disease', (35, 41))	('Silencing', 'Var', (119, 128))	('ASPS', 'Gene', (258, 262))	('ASPS', 'Gene', '79058', (95, 99))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('ASPS', 'Phenotype', 'HP:0012218', (95, 99))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('tumour', 'Disease', (240, 246))	('reduced', 'NegReg', (148, 155))	('ASPS', 'Gene', '79058', (258, 262))	('ASPS', 'Phenotype', 'HP:0012218', (258, 262))	('cell proliferation', 'CPA', (156, 174))
138499	31722230	In addition, phosphoproteomics has particular utility in revealing the key phosphorylation-mediated signalling nodes within biological networks in sarcomas driven by aberrant kinase signalling.	('sarcomas', 'Disease', (147, 155))	('aberrant', 'Var', (166, 174))	('driven by', 'Reg', (156, 165))	('sarcomas', 'Disease', 'MESH:D012509', (147, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
138537	31748582	Cancers were first classified according to ICD-10 C codes including C00-C99, and then subdivided according to site of cancer.	('cancer', 'Disease', (118, 124))	('Cancers', 'Disease', (0, 7))	('C00-C99', 'Var', (68, 75))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('C99', 'Chemical', 'MESH:C504596', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
138556	31748582	The SIR of non-Hodgkin's lymphoma was the significantly higher with SIR of 15.33 (95% CI = 7.00-23.66) followed by leukemia and skin cancer (SIR: 14.08 and 7.21).	('SIR', 'Phenotype', 'HP:0008069', (141, 144))	('SIR of 15.33', 'Var', (68, 80))	('SIR', 'Phenotype', 'HP:0008069', (4, 7))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (11, 33))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (15, 33))	("non-Hodgkin's lymphoma", 'Disease', (11, 33))	('SIR', 'Phenotype', 'HP:0008069', (68, 71))	('lymphoma', 'Phenotype', 'HP:0002665', (25, 33))	('skin cancer', 'Phenotype', 'HP:0008069', (128, 139))	('leukemia', 'Disease', (115, 123))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('leukemia', 'Disease', 'MESH:D007938', (115, 123))	('higher', 'PosReg', (56, 62))	('skin cancer', 'Disease', (128, 139))	('skin cancer', 'Disease', 'MESH:D012878', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (11, 33))
138558	31748582	In females, the SIR of non-Hodgkin's lymphoma was significantly higher with SIR of 26.97 (95% CI = 10.26-43.69) followed by liver cancer (SIR = 11.28, 95% CI = 4.61-17.95).	("non-Hodgkin's lymphoma", 'Disease', (23, 45))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (27, 45))	('SIR', 'Phenotype', 'HP:0008069', (76, 79))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (23, 45))	('SIR', 'Phenotype', 'HP:0008069', (16, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (37, 45))	('higher', 'PosReg', (64, 70))	('liver cancer', 'Phenotype', 'HP:0002896', (124, 136))	('liver cancer', 'Disease', 'MESH:D006528', (124, 136))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (23, 45))	('SIR of 26.97', 'Var', (76, 88))	('liver cancer', 'Disease', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('SIR', 'Phenotype', 'HP:0008069', (138, 141))
138635	30987403	Different mutations in Isocitrate Dehydrogenase-1 (IDH1), Isocitrate Dehydrogenase-2 (IDH2), and Tumor Supressor P53 (TP53) and deletion of Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) were detected both in cell lines and tumor samples.	('IDH2', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('IDH2', 'Gene', '3418', (86, 90))	('Tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CDKN2A', 'Gene', (178, 184))	('Tumor Supressor P53', 'Gene', '7157', (97, 116))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('IDH1', 'Gene', (51, 55))	('Tumor Supressor P53', 'Gene', (97, 116))	('deletion', 'Var', (128, 136))
138636	30987403	In addition, other mutations in TP53 and the amplification of Mouse Double Minute 2 homolog (MDM2) arose during cell culture in CDS17 cells.	('CDS17', 'Chemical', '-', (128, 133))	('mutations', 'Var', (19, 28))	('TP53', 'Gene', (32, 36))	('Mouse', 'Species', '10090', (62, 67))	('MDM2', 'Gene', (93, 97))
138637	30987403	Whole exome sequencing analysis of CDS17, T-CDS17, and matched patient samples confirmed that cell lines kept the most relevant mutations of the tumor, uncovered new mutations and revealed structural variants that emerged during in vitro/in vivo growth.	('CDS17', 'Chemical', '-', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('mutations', 'Var', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CDS17', 'Gene', (35, 40))	('tumor', 'Disease', (145, 150))	('CDS17', 'Chemical', '-', (44, 49))	('patient', 'Species', '9606', (63, 70))	('T-CDS17', 'Chemical', '-', (42, 49))
138646	30987403	Thus, mutations in Isocitrate Dehydrogenase-1 (IDH1) and -2 (IDH2) are found in 87% of enchondromas, up to 70% of conventional central chondrosarcomas and 54% of dedifferentiated chondrosarcomas and may drive sarcomagenic processes.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('sarcoma', 'Disease', (142, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('enchondromas', 'Disease', 'MESH:D002812', (87, 99))	('enchondroma', 'Phenotype', 'HP:0030038', (87, 98))	('chondrosarcomas', 'Disease', (135, 150))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (179, 194))	('chondrosarcomas', 'Disease', 'MESH:D002813', (179, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('IDH2', 'Gene', (61, 65))	('sarcoma', 'Disease', 'MESH:D012509', (209, 216))	('sarcoma', 'Disease', (209, 216))	('IDH2', 'Gene', '3418', (61, 65))	('mutations', 'Var', (6, 15))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (135, 149))	('dedifferentiated', 'CPA', (162, 178))	('enchondromas', 'Disease', (87, 99))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('found', 'Reg', (71, 76))	('sarcoma', 'Disease', (186, 193))	('chondrosarcomas', 'Disease', (179, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (179, 193))	('enchondromas', 'Phenotype', 'HP:0030038', (87, 99))	('drive', 'Reg', (203, 208))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (135, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('chondrosarcomas', 'Disease', 'MESH:D002813', (135, 150))	('Isocitrate Dehydrogenase-1 (IDH1) and -2', 'Gene', '3417;3418', (19, 59))
138647	30987403	In addition, mutations in the major cartilage collagen (COL2A1) or Tumor Supressor P53 (TP53) genes have been found in approximately 35% and 20% of the chondrosarcomas respectively.	('cartilage collagen', 'Gene', (36, 54))	('COL2A1', 'Gene', '1280', (56, 62))	('found', 'Reg', (110, 115))	('Tumor Supressor P53', 'Gene', (67, 86))	('Tumor Supressor P53', 'Gene', '7157', (67, 86))	('cartilage collagen', 'Gene', '1280', (36, 54))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (152, 167))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('COL2A1', 'Gene', (56, 62))	('chondrosarcomas', 'Disease', 'MESH:D002813', (152, 167))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', (88, 92))	('Tumor', 'Phenotype', 'HP:0002664', (67, 72))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (152, 166))	('chondrosarcomas', 'Disease', (152, 167))
138648	30987403	Other frequent copy number variations, such as the amplification of the 12q13 region, containing Mouse Double Minute 2 homolog (MDM2) and the cyclin-dependent kinase 4 genes, and the deletion of the 9p21 region, which includes the Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) locus, contribute to the deregulation of the p53 and Retinoblastoma (RB) pathways.	('Mouse', 'Species', '10090', (97, 102))	('Retinoblastoma', 'Disease', 'MESH:D012175', (330, 344))	('Retinoblastoma', 'Disease', (330, 344))	('RB', 'Phenotype', 'HP:0009919', (346, 348))	('cyclin-dependent kinase 4', 'Gene', (142, 167))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (330, 344))	('deregulation', 'Reg', (302, 314))	('CDKN2A', 'Gene', (269, 275))	('deletion', 'Var', (183, 191))	('9p21', 'Gene', (199, 203))	('cyclin-dependent kinase 4', 'Gene', '12567', (142, 167))
138704	30987403	There were no inflammatory infiltrates in these tumors and its mitotic index was 17 and 25 mitoses per 10 HPF for CDS17 and T-CDS17 respectively (Figure 1A).	('PF', 'Chemical', 'MESH:C002997', (107, 109))	('CDS17', 'Chemical', '-', (114, 119))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('mitoses', 'CPA', (91, 98))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('CDS17', 'Chemical', '-', (126, 131))	('T-CDS17', 'Var', (124, 131))	('T-CDS17', 'Chemical', '-', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
138713	30987403	Sequencing analysis of common mutations in chondrosarcoma identified point mutations in IDH1 (p.R132L) in CDS01 cells and IDH2 (p.R172G) in CDS17 and T-CDS17 cells which were also detected in the corresponding patient tumor samples.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (43, 57))	('IDH1', 'Gene', (88, 92))	('T-CDS17', 'Chemical', '-', (150, 157))	('tumor', 'Disease', (218, 223))	('CDS17', 'Chemical', '-', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('IDH1', 'Gene', '3417', (88, 92))	('p.R172G', 'Var', (128, 135))	('IDH2', 'Gene', (122, 126))	('p.R172G', 'Mutation', 'rs1057519906', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('p.R132L', 'Var', (94, 101))	('chondrosarcoma', 'Disease', (43, 57))	('chondrosarcoma', 'Disease', 'MESH:D002813', (43, 57))	('IDH2', 'Gene', '3418', (122, 126))	('CDS01', 'CellLine', 'CVCL:9726', (106, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('p.R132L', 'Mutation', 'rs121913500', (94, 101))	('CDS17', 'Chemical', '-', (140, 145))	('patient', 'Species', '9606', (210, 217))
138714	30987403	Otherwise, CDS06 cells did not show any IDH1 or IDH2 mutations.	('IDH2', 'Gene', '3418', (48, 52))	('IDH1', 'Gene', (40, 44))	('CDS06', 'Chemical', '-', (11, 16))	('IDH1', 'Gene', '3417', (40, 44))	('mutations', 'Var', (53, 62))	('IDH2', 'Gene', (48, 52))
138715	30987403	The single nucleotide variants (SNV) p.P72R was found in all cell lines and also in CDS06 and CDS11 patient samples, meanwhile the mutation p.S215R was only found in CDS17 and T-CDS17 cell lines but not in the corresponding patient sample (Figure 2A,C).	('p.P72R', 'Var', (37, 43))	('p.S215R', 'Mutation', 'rs886039484', (140, 147))	('T-CDS17', 'Chemical', '-', (176, 183))	('CDS17', 'Chemical', '-', (166, 171))	('CDS11', 'Chemical', '-', (94, 99))	('patient', 'Species', '9606', (224, 231))	('patient', 'Species', '9606', (100, 107))	('CDS06', 'Chemical', '-', (84, 89))	('p.S215R', 'Var', (140, 147))	('CDS17', 'Chemical', '-', (178, 183))	('p.P72R', 'Mutation', 'rs1042522', (37, 43))
138716	30987403	Additional analysis of hot spot mutations in Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PI3KCA) showed no alterations in any of the cell lines.	('mutations', 'Var', (32, 41))	('Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha', 'Gene', '5290', (45, 115))	('PI3KCA', 'Gene', (117, 123))	('PI3KCA', 'Gene', '5290', (117, 123))
138717	30987403	Finally, copy number analysis showed a significant gain of MDM2 in CDS17 and T-CDS17 cells which was not detected in the tumor sample and a homozygous deletion of CDKN2A (exon 3) in CDS11 cells and matched patient sample (Figure 2B,C).	('T-CDS17', 'Chemical', '-', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('gain', 'PosReg', (51, 55))	('patient', 'Species', '9606', (206, 213))	('CDS17', 'Chemical', '-', (67, 72))	('tumor', 'Disease', (121, 126))	('MDM2', 'Gene', (59, 63))	('deletion', 'Var', (151, 159))	('CDKN2A', 'Gene', (163, 169))	('CDS17', 'Chemical', '-', (79, 84))	('CDS11', 'Chemical', '-', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
138721	30987403	Similar to other type of tumors, C > T and G > A transitions were the most common mutations found in all samples (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('C > T', 'Var', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('G > A transitions', 'Var', (43, 60))
138724	30987403	Among them, cluster 1 is the one including a higher number of SNVs and must be the founder clone since the set of mutations that contain is present in virtually all the tumors cells (cellular prevalence equal to 1) and the other clones seem to derive from it.	('mutations', 'Var', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))
138728	30987403	To select the most relevant somatic mutations included in each group of clusters presenting similar trends we compared tumor versus normal, CDS17 versus tumor and T-CDS17 versus CDS17 samples and filter the results to select variants with non-synonymous effect on coded proteins which presented variant allele frequencies >0.035 in tumor, CDS17 or T-CDS17 samples and maximum allele frequencies <0.01 in population databases (dbSNP, ExAC, ESP, and 1000 Genomes) (Figure 3E).	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('T-CDS17', 'Chemical', '-', (348, 355))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('variants', 'Var', (225, 233))	('CDS17', 'Chemical', '-', (140, 145))	('CDS17', 'Chemical', '-', (350, 355))	('CDS17', 'Chemical', '-', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CDS17', 'Chemical', '-', (165, 170))	('T-CDS17', 'Chemical', '-', (163, 170))	('CDS17', 'Chemical', '-', (339, 344))	('tumor', 'Disease', (332, 337))
138729	30987403	Among these mutations, only the c.514A > G transition (p.R172G) in IDH2, previously detected by Sanger sequencing (Figure 2A), was listed in the Catalogue of Somatic Mutations in Cancer (COSMIC).	('p.R172G', 'Mutation', 'rs1057519906', (55, 62))	('c.514A > G', 'Mutation', 'rs1057519906', (32, 42))	('IDH2', 'Gene', (67, 71))	('IDH2', 'Gene', '3418', (67, 71))	('c.514A > G', 'Var', (32, 42))	('Cancer', 'Disease', (179, 185))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Cancer', 'Disease', 'MESH:D009369', (179, 185))
138730	30987403	In addition, we also selected two different mutations in the COL2A1 gene previously found in chondrosarcoma.	('COL2A1', 'Gene', (61, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('found', 'Reg', (84, 89))	('chondrosarcoma', 'Disease', (93, 107))	('chondrosarcoma', 'Disease', 'MESH:D002813', (93, 107))	('mutations', 'Var', (44, 53))	('COL2A1', 'Gene', '1280', (61, 67))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (93, 107))
138731	30987403	Mutations in the rest of genes were not previously described in cancer.	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
138732	30987403	Notably, some of these unreported variants, including SNVs in Vanin2 (VNN2), Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D), Melanin Concentrating Hormone Receptor 2 (MCHR2), Unc-5 Netrin Receptor D (UNC5D), or Mastermind Like Transcriptional Coactivator 2 (MAML2), showed high values in the 0 to 5 scale assigned by DREAMgenics (DG) value (integrated score of several predictive algorithms, see supplemental methods for details) used to predict deleterious mutations and, therefore, they might constitute new driver events in chondrosarcoma (Figure 3E and Figure 4B).	('UNC5D', 'Gene', (210, 215))	('VNN2', 'Gene', '8875', (70, 74))	('UNC5D', 'Gene', '137970', (210, 215))	('MAML2', 'Gene', (268, 273))	('VNN2', 'Gene', (70, 74))	('Calcium Voltage-Gated Channel Subunit Alpha1 D', 'Gene', '776', (77, 123))	('Melanin Concentrating Hormone Receptor 2', 'Gene', (135, 175))	('variants', 'Var', (34, 42))	('Mastermind Like Transcriptional Coactivator 2', 'Gene', (221, 266))	('Unc-5 Netrin Receptor D', 'Gene', '137970', (185, 208))	('MAML2', 'Gene', '84441', (268, 273))	('Melanin Concentrating Hormone Receptor 2', 'Gene', '84539', (135, 175))	('MCHR2', 'Gene', '84539', (177, 182))	('CACNA1D', 'Gene', '776', (125, 132))	('CACNA1D', 'Gene', (125, 132))	('chondrosarcoma', 'Disease', (537, 551))	('chondrosarcoma', 'Disease', 'MESH:D002813', (537, 551))	('Calcium Voltage-Gated Channel Subunit Alpha1 D', 'Gene', (77, 123))	('MCHR2', 'Gene', (177, 182))	('Mastermind Like Transcriptional Coactivator 2', 'Gene', '84441', (221, 266))	('Vanin2', 'Gene', (62, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (544, 551))	('Unc-5 Netrin Receptor D', 'Gene', (185, 208))	('Vanin2', 'Gene', '8875', (62, 68))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (537, 551))
138734	30987403	The most notably alterations in this group was the mutations p.S215R and p.P72R in TP53, previously detected by Sanger sequencing (Figure 2A), which was present in both alleles due to a copy-neutral (CN) loss of heterozygosity (LOH) event in chromosome 17 as detailed below.	('TP53', 'Gene', (83, 87))	('p.P72R', 'Mutation', 'rs1042522', (73, 79))	('loss of heterozygosity', 'NegReg', (204, 226))	('p.S215R', 'Var', (61, 68))	('p.P72R', 'Var', (73, 79))	('alterations', 'Reg', (17, 28))	('p.S215R', 'Mutation', 'rs886039484', (61, 68))
138735	30987403	Most relevant variations emerging in T-CDS17 cells (Clusters 5 and 6) included mutations in 20 genes.	('T-CDS17', 'Chemical', '-', (37, 44))	('genes', 'Gene', (95, 100))	('mutations', 'Var', (79, 88))
138736	30987403	Among them, a SNV in F-Box and WD Repeat Domain Containing 5 (FBXW5) is the only variation previously reported in COSMIC in tumor types different to chondrosarcoma (Figure 3E).	('FBXW5', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('chondrosarcoma', 'Disease', (149, 163))	('chondrosarcoma', 'Disease', 'MESH:D002813', (149, 163))	('SNV', 'Var', (14, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('WD', 'Disease', 'MESH:D006527', (31, 33))	('FBXW5', 'Gene', '54461', (62, 67))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
138737	30987403	Also, the set of variants of the tumor sample that were lost in CDS17 and T-CDS17 cells (Clusters 10-14) included a mutation in Kinesin Family Member 21A (KIF21A) previously reported in COSMIC for other types of tumor and other 13 unreported mutations.	('variants', 'Var', (17, 25))	('KIF21A', 'Gene', (155, 161))	('CDS17', 'Chemical', '-', (76, 81))	('mutation', 'Var', (116, 124))	('T-CDS17', 'Chemical', '-', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('Kinesin Family Member 21A', 'Gene', '55605', (128, 153))	('KIF21A', 'Gene', '55605', (155, 161))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('CDS17', 'Chemical', '-', (64, 69))	('Kinesin Family Member 21A', 'Gene', (128, 153))	('tumor', 'Disease', (212, 217))
138739	30987403	Besides the above described changes in somatic mutations, a major consequence of in vitro and in vivo growth of tumor cells was the emergence of structural alterations and copy number variants (CNV) leading to numerous LOH events in many mutations of CDS17 and T-CDS17 cells (Figure 4A,B).	('CDS17', 'Gene', (251, 256))	('T-CDS17', 'Gene', (261, 268))	('CDS17', 'Chemical', '-', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('mutations', 'Var', (238, 247))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('LOH', 'NegReg', (219, 222))	('variants', 'Var', (184, 192))	('tumor', 'Disease', (112, 117))	('CDS17', 'Chemical', '-', (251, 256))	('T-CDS17', 'Chemical', '-', (261, 268))
138740	30987403	Most relevant structural alterations detected in CDS17 and T-CDS17 cells included a CN-LOH affecting chromosome 17, which would explain the homozygous mutations of the TP53 gene (p.S215R and p.P72R) commented above.	('p.P72R', 'Var', (191, 197))	('p.P72R', 'Mutation', 'rs1042522', (191, 197))	('CDS17', 'Chemical', '-', (49, 54))	('TP53', 'Gene', (168, 172))	('p.S215R', 'Mutation', 'rs886039484', (179, 186))	('CDS17', 'Chemical', '-', (61, 66))	('T-CDS17', 'Chemical', '-', (59, 66))	('p.S215R', 'Var', (179, 186))
138741	30987403	Analysis of variant frequencies in this chromosome showed that the CN-LOH affected the whole chromosome and is detected in virtually all cells, as indicated by the disappearance of almost all intermediate frequencies in CDS17 and T-CDS17 cells (Figure 4B,C).	('affected', 'Reg', (74, 82))	('CDS17', 'Var', (220, 225))	('CDS17', 'Chemical', '-', (232, 237))	('T-CDS17', 'Chemical', '-', (230, 237))	('disappearance', 'NegReg', (164, 177))	('CDS17', 'Chemical', '-', (220, 225))
138742	30987403	Similar CN-LOH events were detected in chromosome 16, although in this case the structural variation affects to only a subset of the cells, as seen by the shift in the intermediate frequencies of variants in CDS17 and T-CDS-17 cells as compared to normal and tumor samples.	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('CDS17', 'Chemical', '-', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('CDS17', 'Gene', (208, 213))	('tumor', 'Disease', (259, 264))	('T-CDS-17', 'Chemical', '-', (218, 226))	('variants', 'Var', (196, 204))
138743	30987403	Noteworthy, the intermediate frequencies shift also indicated that the subpopulation presenting the CN-LOH in chromosome 16 increased in T-CDS17 as compared to CDS-17 cells (Figure 4B,C).	('increased', 'PosReg', (124, 133))	('T-CDS17', 'Var', (137, 144))	('CDS-17', 'Chemical', '-', (160, 166))	('T-CDS17', 'Chemical', '-', (137, 144))	('CN-LOH', 'Var', (100, 106))
138745	30987403	After filtering LOH events using the criteria described above for somatic variants and including also other LOH variants with a recurrence in the COSMIC database higher than 10, we selected 24 mutations that underwent LOH in CDS17, 17 LOH events which emerged in T-CDS-17 and 5 mutations which were detected as LOH variations in CDS17 but not in T-CDS17 (Figure 4D).	('LOH', 'Var', (218, 221))	('variations', 'Var', (315, 325))	('CDS17', 'Chemical', '-', (225, 230))	('CDS17', 'Gene', (225, 230))	('CDS17', 'Chemical', '-', (348, 353))	('T-CDS17', 'Chemical', '-', (346, 353))	('mutations', 'Var', (193, 202))	('T-CDS-17', 'Chemical', '-', (263, 271))	('CDS17', 'Chemical', '-', (329, 334))	('CDS17', 'Gene', (329, 334))
138746	30987403	Altogether, these data indicate that these cell lines kept the most relevant driver mutations present in the founder clone of the tumor sample.	('mutations', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))
138747	30987403	In addition, the adaptation of tumor cells to in vitro cell culture and in vivo growth is accompanied by the gain/loss of additional point mutations and structural variants affecting different subclones of the cell lines.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('structural variants', 'Var', (153, 172))	('point mutations', 'Var', (133, 148))	('tumor', 'Disease', (31, 36))	('gain/loss', 'PosReg', (109, 118))	('gain/loss', 'NegReg', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
138759	30987403	In accordance with its enhanced aggressiveness, T-CDS17 also displayed a significantly increased invasive potential when compared to the parental CDS17 cell line.	('enhanced', 'PosReg', (23, 31))	('increased', 'PosReg', (87, 96))	('CDS17', 'Chemical', '-', (146, 151))	('aggressiveness', 'Phenotype', 'HP:0000718', (32, 46))	('CDS17', 'Chemical', '-', (50, 55))	('invasive potential', 'CPA', (97, 115))	('aggressiveness', 'Disease', 'MESH:D001523', (32, 46))	('T-CDS17', 'Var', (48, 55))	('T-CDS17', 'Chemical', '-', (48, 55))	('aggressiveness', 'Disease', (32, 46))
138760	30987403	Deregulated SRC/FAK (Steroid receptor coactivator/Focal adhesion kinase) signaling is related to enhanced migration and invasion in many types of tumors and we previously found that several sarcoma models may invade through a mechanism depending on SRC/FAK signaling.	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('SRC', 'Gene', (249, 252))	('FAK', 'Gene', '5747', (253, 256))	('sarcoma', 'Disease', (190, 197))	('enhanced', 'PosReg', (97, 105))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('Deregulated', 'Var', (0, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('SRC', 'Gene', '6714', (12, 15))	('FAK', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('invasion', 'CPA', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('migration', 'CPA', (106, 115))	('SRC', 'Gene', (12, 15))	('FAK', 'Gene', '5747', (16, 19))	('SRC', 'Gene', '6714', (249, 252))	('FAK', 'Gene', (253, 256))	('tumors', 'Disease', (146, 152))
138761	30987403	Here, we found that both the SRC inhibitor dasatinib or the FAK inhibitor PF-573228 were able to dose-dependently inhibit cell invasion, thus indicating that this mechanism is also mediating invasion in chondrosarcoma cell lines (Figure 6C-F).	('PF-573228', 'Chemical', 'MESH:C521108', (74, 83))	('inhibit', 'NegReg', (114, 121))	('chondrosarcoma', 'Disease', (203, 217))	('dasatinib', 'Chemical', 'MESH:D000069439', (43, 52))	('SRC', 'Gene', '6714', (29, 32))	('FAK', 'Gene', (60, 63))	('FAK', 'Gene', '5747', (60, 63))	('SRC', 'Gene', (29, 32))	('PF-573228', 'Var', (74, 83))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (203, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('cell invasion', 'CPA', (122, 135))	('chondrosarcoma', 'Disease', 'MESH:D002813', (203, 217))
138767	30987403	Despite limitations, such as the accumulation of new mutations after endless in vitro culture, international studies reported that large panels of cell lines recapitulated the most relevant alterations of original tumors and, when using a relevant number of well characterized cell lines of a given cancer subtype, they were useful models to predict anti-cancer drug sensitivity and clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('mutations', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('drug sensitivity', 'Phenotype', 'HP:0020174', (362, 378))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (355, 361))	('original tumors', 'Disease', 'MESH:D009369', (205, 220))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', (355, 361))	('original tumors', 'Disease', (205, 220))
138770	30987403	Here we present four new chondrosarcoma cell lines with related clinical information and genetic characterization of the most common alterations (mutations in IDH1, IDH2, TP53, and PI3KCA and copy number variants in MDM2 and CDKN2).	('copy number variants', 'Var', (192, 212))	('TP53', 'Gene', (171, 175))	('chondrosarcoma', 'Disease', (25, 39))	('mutations', 'Var', (146, 155))	('IDH1', 'Gene', (159, 163))	('chondrosarcoma', 'Disease', 'MESH:D002813', (25, 39))	('PI3KCA', 'Gene', (181, 187))	('MDM2', 'Gene', (216, 220))	('IDH1', 'Gene', '3417', (159, 163))	('IDH2', 'Gene', (165, 169))	('PI3KCA', 'Gene', '5290', (181, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (25, 39))	('IDH2', 'Gene', '3418', (165, 169))	('CDKN2', 'Gene', '1029', (225, 230))	('CDKN2', 'Gene', (225, 230))
138771	30987403	All the alterations detected were also found in the original tumors with the exception of the TP53 mutations and MDM2 amplification found in CDS17 and T-CDS17 cell lines but not in tumor samples.	('CDS17', 'Chemical', '-', (141, 146))	('tumor', 'Disease', (181, 186))	('MDM2', 'Gene', (113, 117))	('CDS17', 'Chemical', '-', (153, 158))	('TP53', 'Gene', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('original tumors', 'Disease', 'MESH:D009369', (52, 67))	('mutations', 'Var', (99, 108))	('T-CDS17', 'Chemical', '-', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('original tumors', 'Disease', (52, 67))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (61, 66))
138775	30987403	In addition we add new dedifferentiated cchondrosarcoma cell lines with IDH2 mutations to only one reported so far.	('IDH2', 'Gene', (72, 76))	('IDH2', 'Gene', '3418', (72, 76))	('cchondrosarcoma', 'Disease', 'None', (40, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (41, 55))	('mutations', 'Var', (77, 86))	('cchondrosarcoma', 'Disease', (40, 55))
138776	30987403	Interestingly, none of previously published dedifferentiated lines described mutations in IDH1 (Table S3).	('IDH1', 'Gene', (90, 94))	('mutations', 'Var', (77, 86))	('IDH1', 'Gene', '3417', (90, 94))
138787	30987403	We found that the putative founder clone, that including a higher number of mutations and is present in all tumor cells, remains unaltered after in vitro cell culture (CDS17 cells) and in vivo growth (T-CDS17 cells).	('T-CDS17', 'Chemical', '-', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('CDS17', 'Chemical', '-', (168, 173))	('CDS17', 'Chemical', '-', (203, 208))
138788	30987403	This clone includes previously known mutations, such as that previously found by Sanger sequencing in IDH2 (R172G) or mutations in COL2A1 (G939Wfs*5 and P668Lfs*120), as well as other unreported non-synonymous mutations presenting high scores in impact prediction algorithms, such as VNN2, CACNA1D, MCHR2, UNC5D, or MAML2, which possibly contribute to chondrosarcoma progression must be studied in detail.	('MAML2', 'Gene', (316, 321))	('IDH2', 'Gene', (102, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (359, 366))	('IDH2', 'Gene', '3418', (102, 106))	('MCHR2', 'Gene', (299, 304))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (352, 366))	('COL2A1', 'Gene', '1280', (131, 137))	('P668Lfs*120', 'Var', (153, 164))	('MAML2', 'Gene', '84441', (316, 321))	('P668Lfs*120', 'Mutation', 'p.P668LfsX120', (153, 164))	('G939Wfs*5', 'Var', (139, 148))	('CACNA1D', 'Gene', '776', (290, 297))	('CACNA1D', 'Gene', (290, 297))	('COL2A1', 'Gene', (131, 137))	('R172G', 'Var', (108, 113))	('UNC5D', 'Gene', (306, 311))	('chondrosarcoma', 'Disease', 'MESH:D002813', (352, 366))	('UNC5D', 'Gene', '137970', (306, 311))	('MCHR2', 'Gene', '84539', (299, 304))	('R172G', 'Mutation', 'rs1057519906', (108, 113))	('chondrosarcoma', 'Disease', (352, 366))	('VNN2', 'Gene', '8875', (284, 288))	('VNN2', 'Gene', (284, 288))
138791	30987403	Importantly, alterations in TP53 were associated with aggressive behavior of chondrosarcomas and similar LOH affecting chromosome 17 was detected in high grade chondrosarcomas.	('aggressive behavior', 'CPA', (54, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (167, 175))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (160, 174))	('associated with', 'Reg', (38, 53))	('chondrosarcomas', 'Disease', (160, 175))	('chondrosarcomas', 'Disease', (77, 92))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (77, 91))	('aggressive behavior', 'Phenotype', 'HP:0000718', (54, 73))	('TP53', 'Gene', (28, 32))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (160, 175))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (77, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('alterations', 'Var', (13, 24))	('chondrosarcomas', 'Disease', 'MESH:D002813', (160, 175))	('chondrosarcomas', 'Disease', 'MESH:D002813', (77, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
138792	30987403	Therefore, despite not being present in the original tumor, the CN-LOH in chromosome 17 detected in CDS17 and T-CDS17 resembles a naturally occurring mechanism for increasing aggressiveness in chondrosarcomas.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (193, 207))	('aggressiveness in chondrosarcomas', 'Disease', (175, 208))	('original tumor', 'Disease', (44, 58))	('CDS17', 'Gene', (100, 105))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (193, 208))	('original tumor', 'Disease', 'MESH:D009369', (44, 58))	('aggressiveness', 'Phenotype', 'HP:0000718', (175, 189))	('CDS17', 'Chemical', '-', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('increasing', 'PosReg', (164, 174))	('aggressiveness in chondrosarcomas', 'Disease', 'MESH:D002813', (175, 208))	('T-CDS17', 'Var', (110, 117))	('T-CDS17', 'Chemical', '-', (110, 117))	('CDS17', 'Chemical', '-', (100, 105))
138793	30987403	Other structural variants, such as those detected chromosomes like 16, 18, or 20, affected a sequentially increased cell population in CDS17 and T-CDS17 cells.	('CDS17', 'Chemical', '-', (135, 140))	('variants', 'Var', (17, 25))	('affected', 'Reg', (82, 90))	('T-CDS17', 'Chemical', '-', (145, 152))	('increased', 'PosReg', (106, 115))	('CDS17', 'Chemical', '-', (147, 152))	('cell population', 'CPA', (116, 131))
138798	30987403	Furthermore, a pioneering genomic analysis using a cell line (CDS17)/xenograft line (T-CDS-17) tandem model confirmed that these cell lines kept the most relevant mutations of the original tumor and described the genetic drift process that tumor cells underwent during the adaptation to in vitro and in vivo growth.	('CDS17', 'Chemical', '-', (62, 67))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', (240, 245))	('mutations', 'Var', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('original tumor', 'Disease', (180, 194))	('original tumor', 'Disease', 'MESH:D009369', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('T-CDS-17', 'Chemical', '-', (85, 93))
138802	27797382	Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution DNA replication stress promotes genome instability in cancer.	('impairs', 'NegReg', (67, 74))	('genome instability', 'MPA', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('inhibits', 'NegReg', (38, 46))	('lymphomagenesis', 'CPA', (47, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('Defective', 'Var', (0, 9))	('lymphocyte reconstitution DNA', 'CPA', (75, 104))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
138810	27797382	Our results also provide important insight into the immunodeficiency observed in individuals with mutations in SMARCAL1 by suggesting that it is an HSPC defect.	('immunodeficiency', 'Phenotype', 'HP:0002721', (52, 68))	('HSPC defect', 'Disease', 'MESH:D005128', (148, 159))	('immunodeficiency', 'Disease', 'MESH:D007153', (52, 68))	('immunodeficiency', 'Disease', (52, 68))	('HSPC defect', 'Disease', (148, 159))	('mutations', 'Var', (98, 107))	('SMARCAL1', 'Gene', (111, 119))
138812	27797382	DNA damage is accrued through the processing of stalled forks into double-stranded DNA breaks, and incomplete DNA replication can result in deletions and chromosomal abnormalities.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (154, 179))	('chromosomal abnormalities', 'Disease', (154, 179))	('result in', 'Reg', (130, 139))	('deletions', 'Var', (140, 149))
138819	27797382	Bi-allelic mutations in SMARCAL1 cause the pleiotropic disorder Schimke Immuno-osseous Dysplasia (SIOD), which is characterized by immunodeficiency, spondyloepiphyseal dysplasia, facial dysmorphism, and progressive nephropathy.	('cause', 'Reg', (33, 38))	('pleiotropic disorder Schimke Immuno-osseous Dysplasia', 'Disease', 'MESH:C536629', (43, 96))	('spondyloepiphyseal dysplasia', 'Phenotype', 'HP:0002655', (149, 177))	('immunodeficiency', 'Disease', (131, 147))	('nephropathy', 'Disease', (215, 226))	('spondyloepiphyseal dysplasia', 'Disease', 'MESH:D010009', (149, 177))	('nephropathy', 'Disease', 'MESH:D007674', (215, 226))	('immunodeficiency', 'Disease', 'MESH:D007153', (131, 147))	('progressive nephropathy', 'Phenotype', 'HP:0012622', (203, 226))	('facial dysmorphism', 'Disease', 'None', (179, 197))	('facial dysmorphism', 'Phenotype', 'HP:0001999', (179, 197))	('facial dysmorphism', 'Disease', (179, 197))	('SIOD', 'Disease', 'MESH:C536629', (98, 102))	('immunodeficiency', 'Phenotype', 'HP:0002721', (131, 147))	('nephropathy', 'Phenotype', 'HP:0000112', (215, 226))	('spondyloepiphyseal dysplasia', 'Disease', (149, 177))	('Bi-allelic mutations', 'Var', (0, 20))	('SIOD', 'Disease', (98, 102))	('SMARCAL1', 'Gene', (24, 32))
138821	27797382	In an irradiation (IR)/replication stress-induced model of T-cell lymphomagenesis, a deficiency in Smarcal1 resulted in elevated DNA damage and a significant delay in T-cell lymphoma development.	('deficiency', 'Var', (85, 95))	('cell lymphoma', 'Phenotype', 'HP:0012191', (169, 182))	('delay in T-cell lymphoma', 'Disease', (158, 182))	('Smarcal1', 'Gene', (99, 107))	('delay in T-cell lymphoma', 'Disease', 'MESH:D016399', (158, 182))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (167, 182))	('lymphoma', 'Phenotype', 'HP:0002665', (174, 182))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (167, 182))	('DNA damage', 'MPA', (129, 139))	('elevated', 'PosReg', (120, 128))	('T-cell lymphomagenesis', 'Phenotype', 'HP:0012190', (59, 81))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (59, 74))	('T-cell lymphoma', 'Disease', (59, 74))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (59, 74))	('cell lymphoma', 'Phenotype', 'HP:0012191', (61, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (66, 74))
138825	27797382	Western blotting using an N-terminal specific Smarcal1 antibody showed half the levels of the 110 kDa full-length protein in Smarcal1+/Delta MEFs and its expected loss in Smarcal1Delta/Delta MEFs (Fig.	('levels', 'MPA', (80, 86))	('loss', 'NegReg', (163, 167))	('MEFs', 'CellLine', 'CVCL:9115', (141, 145))	('MEFs', 'CellLine', 'CVCL:9115', (191, 195))	('Smarcal1+/Delta', 'Var', (125, 140))
138832	27797382	Repeated whole body, low-dose IR of young mice induces T-cell lymphoma development, reportedly through the accumulation of DNA mutations in a hematopoietic stem or progenitor cell (HSPC) or an early T-cell progenitor derived from an HSPC.	('induces', 'PosReg', (47, 54))	('DNA', 'Gene', (123, 126))	('SP', 'Chemical', '-', (234, 236))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (55, 70))	('mice', 'Species', '10090', (42, 46))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (55, 70))	('cell lymphoma', 'Phenotype', 'HP:0012191', (57, 70))	('mutations', 'Var', (127, 136))	('lymphoma', 'Phenotype', 'HP:0002665', (62, 70))	('T-cell lymphoma', 'Disease', (55, 70))	('SP', 'Chemical', '-', (182, 184))
138834	27797382	The presence of IR-associated DNA damage, coupled with the proliferative burst that occurs after IR exposure, is expected to generate significant levels of replication stress in both cycling HSPCs and the HSPC-derived thymic progenitors repopulating the depleted thymus following each radiation cycle.	('replication stress', 'MPA', (156, 174))	('SP', 'Chemical', '-', (206, 208))	('DNA', 'Var', (30, 33))	('SP', 'Chemical', '-', (192, 194))
138837	27797382	However, Smarcal1+/Delta and Smarcal1Delta/Delta mice had a delay in tumor onset and significantly increased overall survival (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Smarcal1Delta/Delta', 'Var', (29, 48))	('delay', 'NegReg', (60, 65))	('Smarcal1+/Delta', 'Var', (9, 24))	('tumor', 'Disease', (69, 74))	('mice', 'Species', '10090', (49, 53))	('overall survival', 'CPA', (109, 125))	('increased', 'PosReg', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
138839	27797382	Genes that influence tumorigenesis can alter the rate of tumor development and/or the types of tumors that develop; therefore we also evaluated the tumor spectrum in the Smarcal1-deficient mice.	('alter', 'Reg', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('Genes', 'Var', (0, 5))	('tumor', 'Disease', (21, 26))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (57, 62))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
138840	27797382	As expected, most (89%) of the Smarcal1+/+ mice developed T-cell lymphomas, while 11% developed benign adenomas (Fig.	('mice', 'Species', '10090', (43, 47))	('cell lymphoma', 'Phenotype', 'HP:0012191', (60, 73))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (58, 74))	('Smarcal1+/+', 'Var', (31, 42))	('benign adenomas', 'Disease', 'MESH:D000236', (96, 111))	('lymphomas', 'Phenotype', 'HP:0002665', (65, 74))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (58, 73))	('developed', 'Reg', (48, 57))	('lymphoma', 'Phenotype', 'HP:0002665', (65, 73))	('T-cell lymphomas', 'Disease', 'MESH:D016399', (58, 74))	('T-cell lymphomas', 'Disease', (58, 74))	('benign adenomas', 'Disease', (96, 111))
138841	27797382	Surprisingly, T-cell lymphomas emerged in only 65% of the Smarcal1+/Delta mice, whereas 12% developed sarcomas (Fig.	('sarcomas', 'Disease', (102, 110))	('lymphomas', 'Phenotype', 'HP:0002665', (21, 30))	('cell lymphoma', 'Phenotype', 'HP:0012191', (16, 29))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('T-cell lymphomas', 'Disease', 'MESH:D016399', (14, 30))	('T-cell lymphomas', 'Disease', (14, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcomas', 'Disease', 'MESH:D012509', (102, 110))	('Smarcal1+/Delta', 'Var', (58, 73))	('mice', 'Species', '10090', (74, 78))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (14, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (14, 30))
138844	27797382	Only 59% of Smarcal1Delta/Delta mice developed T-cell lymphomas and an additional 12% had undetermined pathology (e.g., hind limb paralysis and death from unknown cause) (Fig.	('Smarcal1Delta/Delta', 'Var', (12, 31))	('T-cell lymphomas', 'Disease', (47, 63))	('lymphoma', 'Phenotype', 'HP:0002665', (54, 62))	('paralysis', 'Disease', (130, 139))	('T-cell lymphomas', 'Disease', 'MESH:D016399', (47, 63))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (47, 62))	('paralysis', 'Phenotype', 'HP:0003470', (130, 139))	('cell lymphoma', 'Phenotype', 'HP:0012191', (49, 62))	('mice', 'Species', '10090', (32, 36))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (47, 63))	('paralysis', 'Disease', 'MESH:D010243', (130, 139))	('lymphomas', 'Phenotype', 'HP:0002665', (54, 63))
138845	27797382	The reduction in T-cell lymphoma frequency for both Smarcal1+/Delta (24% reduction) and Smarcal1Delta/Delta mice (30% reduction) was significant (p=0.0400 +/+ vs. +/Delta and p=0.0216 +/+ vs. Delta/Delta, t-tests).	('Smarcal1+/Delta', 'Var', (52, 67))	('Smarcal1Delta/Delta', 'Var', (88, 107))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (17, 32))	('mice', 'Species', '10090', (108, 112))	('T-cell lymphoma', 'Disease', (17, 32))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (17, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('reduction', 'NegReg', (4, 13))	('cell lymphoma', 'Phenotype', 'HP:0012191', (19, 32))	('reduction', 'NegReg', (73, 82))
138846	27797382	The T-cell lymphomas that arose in all genotypes were Thy1.2 positive and also typically CD8+ or CD8+/CD4+ positive (Supplemental Fig.	('CD4', 'Gene', '12504', (102, 105))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (4, 20))	('cell lymphoma', 'Phenotype', 'HP:0012191', (6, 19))	('Thy1.2', 'Gene', '21838', (54, 60))	('Thy1.2', 'Gene', (54, 60))	('T-cell lymphomas', 'Disease', 'MESH:D016399', (4, 20))	('T-cell lymphomas', 'Disease', (4, 20))	('lymphomas', 'Phenotype', 'HP:0002665', (11, 20))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (4, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('CD8+', 'Var', (89, 93))	('CD4', 'Gene', (102, 105))
138847	27797382	Remarkably, 23% of Smarcal1+/Delta and 29% of Smarcal1Delta/Delta mice never developed a tumor up to 500 days after the last dose of IR, whereas tumors were present in all Smarcal1+/+ mice.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Smarcal1Delta/Delta', 'Var', (46, 65))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mice', 'Species', '10090', (66, 70))	('tumors', 'Disease', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (145, 150))	('Smarcal1+/Delta', 'Var', (19, 34))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('mice', 'Species', '10090', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
138849	27797382	Taken together, these data demonstrate that loss of Smarcal1 increased overall survival by inhibiting IR-induced T-cell lymphomagenesis and preventing tumor development altogether in a significant fraction of the mice.	('inhibiting', 'NegReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mice', 'Species', '10090', (213, 217))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (113, 128))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (113, 128))	('tumor', 'Disease', (151, 156))	('T-cell lymphomagenesis', 'Phenotype', 'HP:0012190', (113, 135))	('T-cell lymphoma', 'Disease', (113, 128))	('cell lymphoma', 'Phenotype', 'HP:0012191', (115, 128))	('increased', 'PosReg', (61, 70))	('lymphoma', 'Phenotype', 'HP:0002665', (120, 128))	('preventing', 'NegReg', (140, 150))	('loss', 'Var', (44, 48))	('Smarcal1', 'Gene', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
138853	27797382	There were similar percentages of CD4/CD8 double-positive (DP) and CD4 and CD8 single-positive (SP) T cells in Smarcal1-deficient mice compared to wild-type littermates (Fig.	('CD4', 'Gene', (34, 37))	('single-positive', 'Var', (79, 94))	('mice', 'Species', '10090', (130, 134))	('SP', 'Chemical', '-', (96, 98))	('CD4', 'Gene', '12504', (34, 37))	('CD4', 'Gene', (67, 70))	('DP', 'Chemical', '-', (59, 61))	('CD4', 'Gene', '12504', (67, 70))	('CD8', 'Gene', (75, 78))
138854	27797382	There appeared to be reduced thymic cellularity in Smarcal1+/Delta and Smarcal1Delta/Delta mice; however, the reductions in total numbers of DP and SP thymocytes were not statistically significant (Fig.	('reduced', 'NegReg', (21, 28))	('mice', 'Species', '10090', (91, 95))	('Smarcal1+/Delta', 'Var', (51, 66))	('thymic cellularity', 'CPA', (29, 47))	('Smarcal1Delta/Delta', 'Var', (71, 90))	('SP', 'Chemical', '-', (148, 150))	('DP', 'Chemical', '-', (141, 143))
138861	27797382	To determine if a loss of Smarcal1 would impact the cell cycle arrest that occurs upon radiation exposure, BrdU incorporation was measured in DP thymocytes.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('loss', 'Var', (18, 22))	('Smarcal1', 'Gene', (26, 34))	('cell cycle arrest', 'CPA', (52, 69))	('impact', 'NegReg', (41, 47))	('DP', 'Chemical', '-', (142, 144))	('BrdU', 'Chemical', 'MESH:D001973', (107, 111))
138864	27797382	Therefore, the early response to IR-induced DNA damage that results in cell cycle arrest and apoptosis is not altered with loss of Smarcal1 and likely does not contribute to the observed delay in T-cell lymphoma development in the Smarcal1+/Delta and Smarcal1Delta/Delta mice.	('delay in T-cell lymphoma', 'Disease', 'MESH:D016399', (187, 211))	('mice', 'Species', '10090', (271, 275))	('Smarcal1', 'Gene', (131, 139))	('Smarcal1+/Delta', 'Var', (231, 246))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (196, 211))	('lymphoma', 'Phenotype', 'HP:0002665', (203, 211))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (71, 88))	('cell lymphoma', 'Phenotype', 'HP:0012191', (198, 211))	('cell cycle arrest', 'CPA', (71, 88))	('delay in T-cell lymphoma', 'Disease', (187, 211))	('apoptosis', 'CPA', (93, 102))
138866	27797382	Compared to wild-type littermates, there was a significant decrease in both the percentage and total number of DP T cells and a reduction in the number of SP thymocytes in Smarcal1+/Delta and Smarcal1Delta/Delta mice (Fig.	('mice', 'Species', '10090', (212, 216))	('SP', 'Chemical', '-', (155, 157))	('reduction', 'NegReg', (128, 137))	('decrease', 'NegReg', (59, 67))	('Smarcal1Delta/Delta', 'Var', (192, 211))	('Smarcal1+/Delta', 'Var', (172, 187))	('DP', 'Chemical', '-', (111, 113))
138875	27797382	We identified the HSPC-enriched LSK population (lineage-, cKit+, Sca1+), which we further refined into multi-potent progenitors (MPPs; lineage-, cKit+, Sca1+, CD48+, CD150-) and long-term hematopoietic stem cells (LT-HSCs; lineage-, cKit+, Sca1+, CD48-, CD150+) (Supplemental Fig.	('CD150+', 'Var', (254, 260))	('Sca1', 'Gene', '12367', (152, 156))	('CD48', 'Gene', (247, 251))	('CD48', 'Gene', '12506', (159, 163))	('Sca1', 'Gene', (240, 244))	('Sca1', 'Gene', (65, 69))	('LSK', 'Gene', '16818', (32, 35))	('LSK', 'Gene', (32, 35))	('CD48', 'Gene', '12506', (247, 251))	('SP', 'Chemical', '-', (19, 21))	('Sca1', 'Gene', (152, 156))	('Sca1', 'Gene', '12367', (240, 244))	('CD48', 'Gene', (159, 163))	('Sca1', 'Gene', '12367', (65, 69))
138879	27797382	To determine whether loss of Smarcal1 affected rapidly cycling HSPCs, we evaluated HSPC populations at intervals following IR when HSPCs are induced to proliferate.	('loss', 'Var', (21, 25))	('SP', 'Chemical', '-', (132, 134))	('SP', 'Chemical', '-', (84, 86))	('SP', 'Chemical', '-', (64, 66))	('Smarcal1', 'Gene', (29, 37))
138880	27797382	Compared to wild-type littermates, there was a significant decrease (~30%) in each of the LSK, MPP, and LT-HSC populations in Smarcal1+/Delta and Smarcal1Delta/Delta mice 24 hours after IR (Fig.	('Smarcal1Delta/Delta', 'Var', (146, 165))	('LSK', 'Gene', (90, 93))	('LSK', 'Gene', '16818', (90, 93))	('decrease', 'NegReg', (59, 67))	('mice', 'Species', '10090', (166, 170))	('Smarcal1+/Delta', 'Var', (126, 141))
138881	27797382	At 72 hours after IR, there was a ~40%, ~55%, and ~30% reduction in the LSK, MPP, and LT-HSC populations, respectively, in the Smarcal1+/Delta mice compared to wild-type littermates (Fig.	('reduction', 'NegReg', (55, 64))	('LSK', 'Gene', '16818', (72, 75))	('LSK', 'Gene', (72, 75))	('LT-HSC populations', 'CPA', (86, 104))	('Smarcal1+/Delta', 'Var', (127, 142))	('MPP', 'CPA', (77, 80))	('mice', 'Species', '10090', (143, 147))
138882	27797382	Similarly, the Smarcal1Delta/Delta mice showed a ~60%, ~65% and ~40% decrease, respectively, in these same populations compared to wild-type mice (Fig.	('decrease', 'NegReg', (69, 77))	('Smarcal1Delta/Delta', 'Var', (15, 34))	('mice', 'Species', '10090', (35, 39))	('mice', 'Species', '10090', (141, 145))
138886	27797382	Since Smarcal1+/Delta and Smarcal1Delta/Delta LSKs appeared to be proliferating at equal rates to wild-type Smarcal1 LSKs in response to IR, we measured DNA damage and apoptosis in bone marrow cells during this forced proliferative stress.	('DNA damage', 'MPA', (153, 163))	('LSK', 'Gene', '16818', (117, 120))	('LSK', 'Gene', (117, 120))	('Smarcal1Delta/Delta', 'Var', (26, 45))	('LSK', 'Gene', (46, 49))	('LSK', 'Gene', '16818', (46, 49))	('apoptosis', 'CPA', (168, 177))	('measured', 'Reg', (144, 152))	('Smarcal1+/Delta', 'Var', (6, 21))
138887	27797382	Both Smarcal1+/Delta and Smarcal1Delta/Delta bone marrow cells had significantly increased numbers of cells with gammaH2AX foci (Fig 6B) and elevated amounts of broken DNA (Fig.	('elevated', 'PosReg', (141, 149))	('broken', 'CPA', (161, 167))	('gammaH2AX', 'Gene', (113, 122))	('gammaH2AX', 'Gene', '15270', (113, 122))	('Smarcal1+/Delta', 'Var', (5, 20))	('increased', 'PosReg', (81, 90))	('Smarcal1Delta/Delta', 'Var', (25, 44))
138889	27797382	These data indicate Smarcal1 is required to respond to proliferative stress in HSPCs, and loss of one or both alleles of Smarcal1 increases HSPC susceptibility to DNA breakage caused by replication stress, which results in HSPC apoptosis.	('SP', 'Chemical', '-', (224, 226))	('SP', 'Chemical', '-', (141, 143))	('SP', 'Chemical', '-', (80, 82))	('HSPC', 'Protein', (140, 144))	('susceptibility', 'MPA', (145, 159))	('loss', 'Var', (90, 94))	('Smarcal1', 'Gene', (121, 129))	('increases', 'PosReg', (130, 139))
138891	27797382	We subjected a cohort of Smarcal1+/+, Smarcal1+/Delta and Smarcal1Delta/Delta littermates to repeated injections of 5-fluorouracil (5-FU), a pyrimidine analogue that kills cycling hematopoietic cells, and thereby drives a burst of HSPC proliferation.	('HSPC', 'Protein', (231, 235))	('Smarcal1+/Delta', 'Var', (38, 53))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (116, 130))	('SP', 'Chemical', '-', (232, 234))	('Smarcal1Delta/Delta', 'Var', (58, 77))	('5-FU', 'Chemical', 'MESH:D005472', (132, 136))	('pyrimidine', 'Chemical', 'MESH:C030986', (141, 151))	('Smarcal1+/+', 'Var', (25, 36))
138896	27797382	Four weeks post-transplant, and at each of the subsequent analyses, we detected a significant decrease in the percentage of CD45.2 peripheral leukocytes in recipient mice that received Smarcal1+/Delta or Smarcal1Delta/Delta bone marrow compared to mice that received wild-type bone marrow (Fig.	('CD45', 'Gene', (124, 128))	('Smarcal1Delta/Delta', 'Var', (204, 223))	('CD45', 'Gene', '19264', (124, 128))	('mice', 'Species', '10090', (248, 252))	('mice', 'Species', '10090', (166, 170))	('Smarcal1+/Delta', 'Var', (185, 200))	('decrease', 'NegReg', (94, 102))
138897	27797382	By week 16, mice that received wild-type bone marrow had ~43% of circulating CD45.2 expressing leukocytes, whereas only ~32% of circulating leukocytes expressed CD45.2 in mice that received Smarcal1+/Delta or Smarcal1Delta/Delta bone marrow (Fig.	('mice', 'Species', '10090', (171, 175))	('mice', 'Species', '10090', (12, 16))	('Smarcal1+/Delta', 'Var', (190, 205))	('Smarcal1Delta/Delta', 'Var', (209, 228))	('CD45', 'Gene', '19264', (77, 81))	('CD45', 'Gene', (77, 81))	('CD45', 'Gene', (161, 165))	('CD45', 'Gene', '19264', (161, 165))
138899	27797382	Compared to mice that received wild-type bone marrow, we observed a decrease in the percentage of CD45.2 positive cells in the DP and SP T-cell compartments within the thymus of mice that received Smarcal1+/Delta or Smarcal1Delta/Delta bone marrow (Fig.	('DP', 'Chemical', '-', (127, 129))	('decrease', 'NegReg', (68, 76))	('mice', 'Species', '10090', (12, 16))	('Smarcal1+/Delta', 'Var', (197, 212))	('mice', 'Species', '10090', (178, 182))	('CD45', 'Gene', (98, 102))	('CD45', 'Gene', '19264', (98, 102))	('SP', 'Chemical', '-', (134, 136))	('Smarcal1Delta/Delta', 'Var', (216, 235))
138903	27797382	However, the in vivo significance of these findings, particularly in relationship to the development of malignancies and SIOD, the disease associated with mutant Smarcal1, remained unresolved.	('SIOD', 'Disease', (121, 125))	('malignancies', 'Disease', 'MESH:D009369', (104, 116))	('mutant', 'Var', (155, 161))	('malignancies', 'Disease', (104, 116))	('SIOD', 'Disease', 'MESH:C536629', (121, 125))	('Smarcal1', 'Gene', (162, 170))
138905	27797382	Loss of one or both alleles of Smarcal1 significantly delayed DNA-damage induced T-cell lymphomagenesis and prevented lymphoma development altogether in a quarter of the mice.	('T-cell lymphoma', 'Disease', 'MESH:D016399', (81, 96))	('cell lymphoma', 'Phenotype', 'HP:0012191', (83, 96))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (81, 96))	('T-cell lymphomagenesis', 'Phenotype', 'HP:0012190', (81, 103))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('T-cell lymphoma', 'Disease', (81, 96))	('Smarcal1', 'Gene', (31, 39))	('lymphoma', 'Disease', (118, 126))	('lymphoma', 'Disease', (88, 96))	('DNA-damage', 'CPA', (62, 72))	('prevented', 'NegReg', (108, 117))	('mice', 'Species', '10090', (170, 174))	('lymphoma', 'Disease', 'MESH:D008223', (118, 126))	('Loss', 'Var', (0, 4))	('delayed', 'NegReg', (54, 61))	('lymphoma', 'Disease', 'MESH:D008223', (88, 96))
138906	27797382	Thus, a Smarcal1 deficiency protected mice from IR-induced lymphomagenesis, indicating that a disabled replication stress response could shield against DNA replication stress-induced tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('mice', 'Species', '10090', (38, 42))	('deficiency', 'Var', (17, 27))	('lymphoma', 'Disease', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('lymphoma', 'Disease', 'MESH:D008223', (59, 67))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('tumor', 'Disease', (183, 188))	('Smarcal1', 'Gene', (8, 16))
138907	27797382	IR-induced T-cell lymphomagenesis is reportedly due to the combined effects of acquired mutations in an HSPC, resulting in its cellular transformation, and the induced proliferation of this cell from signals that indicate lymphoid compartments need to be repopulated.	('cell lymphoma', 'Phenotype', 'HP:0012191', (13, 26))	('cellular', 'MPA', (127, 135))	('HSPC', 'Gene', (104, 108))	('mutations', 'Var', (88, 97))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (11, 26))	('SP', 'Chemical', '-', (105, 107))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (11, 26))	('T-cell lymphomagenesis', 'Phenotype', 'HP:0012190', (11, 33))	('T-cell lymphoma', 'Disease', (11, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (18, 26))
138909	27797382	These results are in contrast to data with other cell systems (shRNA and knockout chicken cell lines) that indicate a reduction or loss of Smarcal1 increases radiosensitivity.	('Smarcal1', 'Gene', (139, 147))	('radiosensitivity', 'CPA', (158, 174))	('chicken', 'Species', '9031', (82, 89))	('increases', 'PosReg', (148, 157))	('loss', 'Var', (131, 135))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (148, 174))
138921	27797382	If a mesenchymal stem or progenitor cell is the cell of origin of sarcomas, a reduced ability of these cells to respond to replication stress during a time of increased mesenchymal cell development (weeks 4-8 of mouse life) occurred preferentially in the heterozygous mice and resulted in the acquisition of mutations that allowed it to transform and not die.	('transform', 'CPA', (337, 346))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('mice', 'Species', '10090', (268, 272))	('mutations', 'Var', (308, 317))	('sarcomas', 'Disease', (66, 74))	('reduced', 'NegReg', (78, 85))	('mouse', 'Species', '10090', (212, 217))
138930	27797382	SIOD patients with homozygous mutations in SMARCAL1 are characterized by a severe, progressive immunodeficiency and increased rates of infection.	('patients', 'Species', '9606', (5, 13))	('SMARCAL1', 'Gene', (43, 51))	('SIOD', 'Disease', 'MESH:C536629', (0, 4))	('immunodeficiency', 'Phenotype', 'HP:0002721', (95, 111))	('infection', 'Disease', (135, 144))	('immunodeficiency', 'Disease', (95, 111))	('immunodeficiency', 'Disease', 'MESH:D007153', (95, 111))	('infection', 'Disease', 'MESH:D007239', (135, 144))	('SIOD', 'Disease', (0, 4))	('homozygous mutations', 'Var', (19, 39))
138936	27797382	Our results also indicate that inhibiting DNA replication can provide a protective function against tumorigenesis caused from replication stress.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('DNA replication', 'Protein', (42, 57))	('tumor', 'Disease', (100, 105))	('inhibiting', 'Var', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
139022	26531827	The impairment could be rescued by re-expression of WT but not the phospho-deficient MDM2 mutant, supporting the involvement of hMps1-dependent MDM2 phosphorylation in the oxidative stress response.	('hMps1', 'Gene', '7272', (128, 133))	('MDM2', 'Gene', '4193', (85, 89))	('hMps1', 'Gene', (128, 133))	('MDM2', 'Gene', (85, 89))	('mutant', 'Var', (90, 96))	('MDM2', 'Gene', '4193', (144, 148))	('MDM2', 'Gene', (144, 148))	('oxidative stress', 'Phenotype', 'HP:0025464', (172, 188))
139030	26531827	The tumor suppressor protein p53 is another hMps1 substrate in the tetraploid checkpoint where phosphorylation at Thr18 by hMps1 disrupts p53-MDM2 interaction and causes stabilization and activation of p53.	('tumor', 'Disease', (4, 9))	('p53', 'Gene', (138, 141))	('hMps1', 'Gene', '7272', (44, 49))	('hMps1', 'Gene', (44, 49))	('hMps1', 'Gene', '7272', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('hMps1', 'Gene', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('interaction', 'Interaction', (147, 158))	('phosphorylation', 'Var', (95, 110))	('causes', 'Reg', (163, 169))	('p53', 'Gene', '7157', (29, 32))	('MDM2', 'Gene', (142, 146))	('p53', 'Gene', '7157', (202, 205))	('stabilization', 'MPA', (170, 183))	('disrupts', 'NegReg', (129, 137))	('p53', 'Gene', '7157', (138, 141))	('p53', 'Gene', (29, 32))	('activation', 'PosReg', (188, 198))	('MDM2', 'Gene', '4193', (142, 146))	('Thr18', 'Chemical', '-', (114, 119))	('p53', 'Gene', (202, 205))
139035	26531827	Modification of MDM2 has been reported to regulate either its enzymatic activity or protein stability.	('enzymatic activity', 'MPA', (62, 80))	('MDM2', 'Gene', '4193', (16, 20))	('MDM2', 'Gene', (16, 20))	('Modification', 'Var', (0, 12))	('protein stability', 'MPA', (84, 101))	('regulate', 'Reg', (42, 50))
139036	26531827	Acetylation of the RING domain diminishes its ability to promote p53 ubiquitination.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('promote', 'PosReg', (57, 64))	('Acetylation', 'Var', (0, 11))	('diminishes', 'NegReg', (31, 41))
139037	26531827	Phosphorylation by AKT at the S166 and S188 stabilizes MDM2 protein and promotes its nuclear translocation.	('S166', 'Var', (30, 34))	('S188', 'Var', (39, 43))	('AKT', 'Gene', '207', (19, 22))	('Phosphorylation', 'MPA', (0, 15))	('promotes', 'PosReg', (72, 80))	('MDM2', 'Gene', '4193', (55, 59))	('protein', 'Protein', (60, 67))	('AKT', 'Gene', (19, 22))	('MDM2', 'Gene', (55, 59))	('nuclear translocation', 'MPA', (85, 106))	('stabilizes', 'MPA', (44, 54))
139040	26531827	Moreover, MDM2 has been reported to ubiquitinate histone H2B at Lys120 and Lys125 in human cells to repress transcription, and more recently, MDM2 has been implicated in H2B ubiquitination in response to oxidative DNA damage to control chromatin relaxation for repair, though no direct evidence was provided.	('ubiquitination', 'MPA', (174, 188))	('H2B', 'Gene', '8349', (170, 173))	('Lys125', 'Var', (75, 81))	('implicated', 'Reg', (156, 166))	('H2B', 'Gene', '8349', (57, 60))	('MDM2', 'Gene', '4193', (142, 146))	('Lys125', 'Chemical', '-', (75, 81))	('MDM2', 'Gene', '4193', (10, 14))	('histone H2B', 'Gene', '852284', (49, 60))	('MDM2', 'Gene', (10, 14))	('H2B', 'Gene', (170, 173))	('Lys120', 'Chemical', '-', (64, 70))	('MDM2', 'Gene', (142, 146))	('histone H2B', 'Gene', (49, 60))	('repress transcription', 'MPA', (100, 121))	('human', 'Species', '9606', (85, 90))	('H2B', 'Gene', (57, 60))
139043	26531827	Human E3 ubiquitin ligase, RNF20 and RNF40 are the orthologs of Bre1 that monoubiquitinates histone H2B at Lys123 in budding yeast.	('Lys123', 'Chemical', '-', (107, 113))	('Lys123', 'Var', (107, 113))	('Human', 'Species', '9606', (0, 5))	('histone H2B', 'Gene', '852284', (92, 103))	('Bre1', 'Gene', '56254', (64, 68))	('Bre1', 'Gene', (64, 68))	('histone H2B', 'Gene', (92, 103))	('RNF20', 'Gene', '56254', (27, 32))	('E3 ubiquitin ligase', 'Protein', (6, 25))	('RNF40', 'Gene', '9810', (37, 42))	('yeast', 'Species', '4932', (125, 130))	('RNF40', 'Gene', (37, 42))	('monoubiquitinates', 'MPA', (74, 91))	('RNF20', 'Gene', (27, 32))
139044	26531827	Like Bre1, RNF20/40 monoubiquitinates H2B at Lys120 in mammals.	('RNF20', 'Gene', (11, 16))	('Bre1', 'Gene', '56254', (5, 9))	('Bre1', 'Gene', (5, 9))	('H2B', 'Gene', (38, 41))	('H2B', 'Gene', '8349', (38, 41))	('RNF20', 'Gene', '56254', (11, 16))	('monoubiquitinates', 'Var', (20, 37))	('Lys120', 'Chemical', '-', (45, 51))
139047	26531827	We observed previously that coexpression with hMps1 increases a slower migrating form of MDM2, suggesting that hMps1 might have an impact on MDM2.	('hMps1', 'Gene', (46, 51))	('hMps1', 'Gene', (111, 116))	('increases', 'PosReg', (52, 61))	('hMps1', 'Gene', '7272', (111, 116))	('MDM2', 'Gene', '4193', (89, 93))	('coexpression', 'Var', (28, 40))	('MDM2', 'Gene', (89, 93))	('hMps1', 'Gene', '7272', (46, 51))	('impact', 'Reg', (131, 137))	('MDM2', 'Gene', '4193', (141, 145))	('MDM2', 'Gene', (141, 145))
139056	26531827	GST-hMps1-His was generated by insertion of the His-tag into the C-terminus of GST-hMps1.	('His-tag', 'Protein', (48, 55))	('hMps1', 'Gene', '7272', (4, 9))	('His', 'Chemical', 'MESH:D006639', (10, 13))	('His', 'Chemical', 'MESH:D006639', (48, 51))	('insertion', 'Var', (31, 40))	('hMps1', 'Gene', '7272', (83, 88))	('hMps1', 'Gene', (4, 9))	('hMps1', 'Gene', (83, 88))
139062	26531827	Antibodies used for western blotting were as follows: anti-Myc (sc-40), anti-hMps1 (sc-540), anti-MDM2 (sc-965), anti-GST (sc-138), anti-His (sc-803), anti-CHK1 (sc-7898), anti-ATRIP (sc-365383) and anti-RPA2 (sc-56770) antibodies from Santa Cruz; anti-H2B-Ub (05-1312) and anti-histone H3 (07-690) antibodies from Millipore; anti-CHK1 pS345 (#2348), anti-CHK2 pT68 (#2661) and anti-ATM pS1981 (#2355) antibodies from Cell Signaling; anti-Flag M2 (F3165) and anti-actin (A2066) from Sigma; anti-H2B from Epitomics (1847-1) and GeneTex (GTX115955); anti-gammaH2Ax (#27505) from Upstate; anti-RPA2 pS33 (NB100-544) from Novus; and anti-HA (MMS-101p) from Covance.	('CHK1', 'Gene', '1111', (331, 335))	('CHK1', 'Gene', '1111', (156, 160))	('RPA2', 'Gene', '6118', (204, 208))	('H2B', 'Gene', (495, 498))	('Myc', 'Gene', '4609', (59, 62))	('RPA2', 'Gene', '6118', (591, 595))	('H3', 'Chemical', 'MESH:C012616', (287, 289))	('ATM', 'Gene', (383, 386))	('MDM2', 'Gene', (98, 102))	('H2B', 'Gene', '8349', (253, 256))	('RPA2', 'Gene', (204, 208))	('His', 'Chemical', 'MESH:D006639', (137, 140))	('anti-gammaH2Ax (#27505', 'Var', (548, 570))	('MDM2', 'Gene', '4193', (98, 102))	('ATRIP', 'Gene', (177, 182))	('#27505', 'Var', (564, 570))	('CHK2', 'Gene', (356, 360))	('Myc', 'Gene', (59, 62))	('CHK1', 'Gene', (331, 335))	('H2B', 'Gene', '8349', (495, 498))	('CHK1', 'Gene', (156, 160))	('H2B', 'Gene', (253, 256))	('RPA2', 'Gene', (591, 595))	('hMps1', 'Gene', '7272', (77, 82))	('hMps1', 'Gene', (77, 82))	('ATRIP', 'Gene', '84126', (177, 182))	('CHK2', 'Gene', '11200', (356, 360))	('ATM', 'Gene', '472', (383, 386))
139064	26531827	Anti-XRCC1 (sc-56254, sc-11429), anti-CRM1 (A300-469A), anti-8-oxoG (MAB3560) and anti-PARP1 (11835238001) used for immunofluorescence were from Santa Cruz, Bethyl, Millipore and Roche, respectively.	('XRCC1', 'Gene', (5, 10))	('PARP1', 'Gene', (87, 92))	('11835238001', 'Var', (94, 105))	('XRCC1', 'Gene', '7515', (5, 10))	('CRM1', 'Gene', '7514', (38, 42))	('CRM1', 'Gene', (38, 42))	('PARP1', 'Gene', '142', (87, 92))
139067	26531827	293T cells transfected with His-tagged ubiquitin, HA-hMps1, Flag-H2B and pCMV-MDM2 WT or its mutants were collected and sonicated in buffer A (6 M guanidine-HCl, 0.1 M Na2HPO4/NaH2PO4, 10 mM imidazole, pH 8.0).	('hMps1', 'Gene', '7272', (53, 58))	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('imidazole', 'Chemical', 'MESH:C029899', (191, 200))	('MDM2', 'Gene', '4193', (78, 82))	('NaH2PO4', 'Chemical', 'MESH:C018279', (176, 183))	('MDM2', 'Gene', (78, 82))	('H2B', 'Gene', '8349', (65, 68))	('hMps1', 'Gene', (53, 58))	('H2B', 'Gene', (65, 68))	('mutants', 'Var', (93, 100))	('His', 'Chemical', 'MESH:D006639', (28, 31))	('guanidine-HCl', 'Chemical', 'MESH:D019791', (147, 160))	('Na2HPO4', 'Chemical', 'MESH:C018279', (168, 175))
139079	26531827	In brief, cells were first grown in HAT medium (DMEM with 100 muM hypoxanthine, 0.4 muM aminopterin and 16 muM thymidine) for 3 days to eliminate those with a pre-existing HPRT mutation.	('HPRT', 'Gene', (172, 176))	('muM', 'Gene', '56925', (62, 65))	('mutation', 'Var', (177, 185))	('thymidine', 'Chemical', 'MESH:D013936', (111, 120))	('DMEM', 'Chemical', '-', (48, 52))	('muM', 'Gene', '56925', (107, 110))	('muM', 'Gene', (62, 65))	('aminopterin', 'Chemical', 'MESH:D000630', (88, 99))	('hypoxanthine', 'Chemical', 'MESH:D019271', (66, 78))	('HPRT', 'Gene', '3251', (172, 176))	('muM', 'Gene', (107, 110))	('muM', 'Gene', '56925', (84, 87))	('muM', 'Gene', (84, 87))
139094	26531827	We coexpressed hMps1 wild-type (WT) or the kinase-dead mutant (KD) with MDM2 in 293T cells and immunoprecipitated hMps1 or MDM2.	('hMps1', 'Gene', (114, 119))	('hMps1', 'Gene', '7272', (114, 119))	('hMps1', 'Gene', (15, 20))	('MDM2', 'Gene', '4193', (123, 127))	('MDM2', 'Gene', (123, 127))	('mutant', 'Var', (55, 61))	('293T', 'CellLine', 'CVCL:0063', (80, 84))	('KD', 'Disease', 'MESH:C537017', (63, 65))	('MDM2', 'Gene', '4193', (72, 76))	('MDM2', 'Gene', (72, 76))	('hMps1', 'Gene', '7272', (15, 20))
139100	26531827	Indeed, when the lysates were treated with lambda phophatase, the slower migrating form of MDM2 was reduced, whereas the faster migrating form was increased (Figure 2A).	('increased', 'PosReg', (147, 156))	('slower migrating form', 'MPA', (66, 87))	('reduced', 'NegReg', (100, 107))	('MDM2', 'Gene', '4193', (91, 95))	('MDM2', 'Gene', (91, 95))	('faster migrating', 'MPA', (121, 137))	('lambda phophatase', 'Var', (43, 60))
139104	26531827	Interrogation of these sites by Thr/Ser to Ala substitution revealed that Thr4, Thr306 and Ser307 are the major hMps1 target sites (Supplementary Figure S1A and B), which are conserved among mammals (Supplementary Figure S1C).	('Thr', 'Chemical', 'MESH:D013912', (80, 83))	('hMps1', 'Gene', '7272', (112, 117))	('Thr', 'Chemical', 'MESH:D013912', (74, 77))	('Ser307', 'Var', (91, 97))	('Thr306', 'Chemical', '-', (80, 86))	('hMps1', 'Gene', (112, 117))	('Ser307', 'Chemical', '-', (91, 97))	('Ala', 'Chemical', 'MESH:D000409', (43, 46))	('Thr4', 'Chemical', '-', (74, 78))	('Ser', 'Chemical', 'MESH:D012694', (91, 94))	('Ser', 'Chemical', 'MESH:D012694', (36, 39))	('Thr4', 'Var', (74, 78))	('Thr306', 'Var', (80, 86))	('Thr', 'Chemical', 'MESH:D013912', (32, 35))
139105	26531827	Mutations of Thr4 to Ala (T4A) in the truncated MDM2 (amino acids 1-13) and Thr306/Ser307 to Ala (AA) in MDM2 (amino acids 285-334) compromised the phosphorylation by hMps1 (Figure 2D).	('Ser307 to Ala', 'Mutation', 'p.S307A', (83, 96))	('MDM2', 'Gene', '4193', (105, 109))	('MDM2', 'Gene', (105, 109))	('Thr306', 'Chemical', '-', (76, 82))	('hMps1', 'Gene', '7272', (167, 172))	('Thr4 to Ala', 'Mutation', 'p.T4A', (13, 24))	('Thr306/Ser307', 'Var', (76, 89))	('compromised', 'NegReg', (132, 143))	('Mutations', 'Var', (0, 9))	('hMps1', 'Gene', (167, 172))	('MDM2', 'Gene', '4193', (48, 52))	('MDM2', 'Gene', (48, 52))	('phosphorylation', 'MPA', (148, 163))	('T4A', 'Mutation', 'c.4T>A', (26, 29))
139106	26531827	In the context of the MDM2 full-length protein, mutation of Thr4/Thr306/Ser307 to Ala (3A) also resulted in reduced phosphorylation by hMps1 (Figure 2E).	('hMps1', 'Gene', (135, 140))	('MDM2', 'Gene', '4193', (22, 26))	('Thr306', 'Chemical', '-', (65, 71))	('MDM2', 'Gene', (22, 26))	('reduced', 'NegReg', (108, 115))	('phosphorylation', 'MPA', (116, 131))	('Ser307 to Ala', 'Mutation', 'p.S307A', (72, 85))	('mutation', 'Var', (48, 56))	('hMps1', 'Gene', '7272', (135, 140))	('Thr4', 'Chemical', '-', (60, 64))	('Thr4/Thr306/Ser307', 'Var', (60, 78))
139107	26531827	This was not because the mutation had disrupted the interaction, as the 3A mutant and WT MDM2 were comparable in interaction with hMps1 (Supplementary Figure S1D).	('hMps1', 'Gene', '7272', (130, 135))	('mutation', 'Var', (25, 33))	('interaction', 'Interaction', (52, 63))	('hMps1', 'Gene', (130, 135))	('MDM2', 'Gene', '4193', (89, 93))	('MDM2', 'Gene', (89, 93))	('interaction', 'Interaction', (113, 124))
139108	26531827	Taken together, these results demonstrate that MDM2 can be phosphorylated by hMps1 at Thr4, Thr306 and Ser307 in vitro.	('MDM2', 'Gene', '4193', (47, 51))	('hMps1', 'Gene', '7272', (77, 82))	('MDM2', 'Gene', (47, 51))	('Thr306', 'Var', (92, 98))	('Thr4', 'Chemical', '-', (86, 90))	('hMps1', 'Gene', (77, 82))	('Thr306', 'Chemical', '-', (92, 98))	('Ser307', 'Var', (103, 109))	('Ser307', 'Chemical', '-', (103, 109))
139118	26531827	We compared ubiquitination of WT H2B with the H2B mutants with Arg substitution at Lys120 (K120R) or at Lys120 and Lys125 (2KR).	('Lys120', 'Chemical', '-', (104, 110))	('Lys125', 'Chemical', '-', (115, 121))	('Lys120', 'Chemical', '-', (83, 89))	('H2B', 'Gene', '8349', (33, 36))	('K120R', 'Var', (91, 96))	('Lys120', 'Var', (83, 89))	('H2B', 'Gene', (46, 49))	('Lys120', 'Var', (104, 110))	('Arg substitution at Lys120', 'Mutation', 'p.R120K', (63, 89))	('ubiquitination', 'MPA', (12, 26))	('K120R', 'SUBSTITUTION', 'None', (91, 96))	('H2B', 'Gene', (33, 36))	('compared', 'Reg', (3, 11))	('H2B', 'Gene', '8349', (46, 49))
139119	26531827	As a result, while ubiquitination of K120R was similar to WT, ubiquitination of 2KR was markedly reduced, suggesting that ubiquitination was mainly at Lys125 (Figure 3B).	('ubiquitination', 'MPA', (62, 76))	('ubiquitination', 'MPA', (19, 33))	('K120R', 'SUBSTITUTION', 'None', (37, 42))	('reduced', 'NegReg', (97, 104))	('Lys125', 'Chemical', '-', (151, 157))	('Lys125', 'Var', (151, 157))	('K120R', 'Var', (37, 42))	('ubiquitination', 'MPA', (122, 136))
139121	26531827	The results show that Ala substitution at MDM2 Thr4, Thr306 and Ser307, singularly or in combination dampened the hMps1-promoted MDM2-mediated H2B ubiquitination (Figure 3C).	('MDM2', 'Gene', '4193', (129, 133))	('hMps1', 'Gene', (114, 119))	('MDM2', 'Gene', (129, 133))	('H2B', 'Gene', (143, 146))	('Thr306', 'Var', (53, 59))	('hMps1', 'Gene', '7272', (114, 119))	('Ser307', 'Var', (64, 70))	('Ala', 'Chemical', 'MESH:D000409', (22, 25))	('Thr306', 'Chemical', '-', (53, 59))	('H2B', 'Gene', '8349', (143, 146))	('MDM2', 'Gene', '4193', (42, 46))	('Ser307', 'Chemical', '-', (64, 70))	('MDM2', 'Gene', (42, 46))	('Thr4', 'Chemical', '-', (47, 51))	('dampened', 'NegReg', (101, 109))
139123	26531827	Collectively, these results indicate that MDM2 phosphorylation at Thr4, Thr306 and Ser307 by hMps1 plays a decisive role in MDM2-mediated H2B ubiquitination.	('hMps1', 'Gene', (93, 98))	('Thr306', 'Chemical', '-', (72, 78))	('Thr4', 'Chemical', '-', (66, 70))	('Ser307', 'Chemical', '-', (83, 89))	('H2B', 'Gene', (138, 141))	('MDM2', 'Gene', '4193', (42, 46))	('ubiquitination', 'MPA', (142, 156))	('MDM2', 'Gene', (42, 46))	('MDM2', 'Gene', '4193', (124, 128))	('hMps1', 'Gene', '7272', (93, 98))	('MDM2', 'Gene', (124, 128))	('H2B', 'Gene', '8349', (138, 141))	('Ser307', 'Var', (83, 89))	('Thr306', 'Var', (72, 78))
139125	26531827	The results showed that although MG132 generally increased the observed ubiquitination, hMps1 stills markedly enhanced WT MDM2-mediated H2B ubiquitination compared to the 3A mutant (Supplementary Figure S2D), suggesting that the impact of hMps1 on MDM2 are most likely to be direct, through MDM2 phosphorylation.	('hMps1', 'Gene', '7272', (239, 244))	('H2B', 'Gene', (136, 139))	('hMps1', 'Gene', '7272', (88, 93))	('MDM2', 'Gene', '4193', (291, 295))	('hMps1', 'Gene', (239, 244))	('increased', 'PosReg', (49, 58))	('MDM2', 'Gene', (291, 295))	('ubiquitination', 'MPA', (72, 86))	('MDM2', 'Gene', (122, 126))	('hMps1', 'Gene', (88, 93))	('enhanced', 'PosReg', (110, 118))	('H2B', 'Gene', '8349', (136, 139))	('MDM2', 'Gene', '4193', (122, 126))	('MDM2', 'Gene', '4193', (248, 252))	('MDM2', 'Gene', (248, 252))	('MG132', 'Chemical', 'MESH:C072553', (33, 38))	('MG132', 'Var', (33, 38))
139131	26531827	Moreover, knockdown of hMps1 or MDM2 by small interfering RNA (siRNA) markedly reduced both basal and induced H2B ubiquitination (Figure 4C and D).	('hMps1', 'Gene', '7272', (23, 28))	('small interfering', 'Var', (40, 57))	('reduced', 'NegReg', (79, 86))	('H2B', 'Gene', (110, 113))	('hMps1', 'Gene', (23, 28))	('H2B', 'Gene', '8349', (110, 113))	('MDM2', 'Gene', '4193', (32, 36))	('knockdown', 'Var', (10, 19))	('MDM2', 'Gene', (32, 36))
139140	26531827	To determine whether MDM2 Thr4, Thr306 and Ser307 can be phosphorylated upon oxidative stress in cells, we generated phospho-specific antibodies against MDM2 phospho-Thr4 (pT4) and Thr306 (pT306).	('MDM2', 'Gene', (153, 157))	('Thr306', 'Chemical', '-', (181, 187))	('pT306', 'Chemical', '-', (189, 194))	('oxidative stress', 'Phenotype', 'HP:0025464', (77, 93))	('Ser307', 'Chemical', '-', (43, 49))	('Thr4', 'Chemical', '-', (166, 170))	('MDM2', 'Gene', '4193', (21, 25))	('MDM2', 'Gene', (21, 25))	('Thr306', 'Chemical', '-', (32, 38))	('Thr4', 'Chemical', '-', (26, 30))	('Thr306', 'Var', (181, 187))	('MDM2', 'Gene', '4193', (153, 157))
139141	26531827	The antibodies preferentially recognized the T4 and T306 phosphorylated peptides compared with the unphosphorylated peptides (Supplementary Figure S5A and B), and reacted with the in vitro phosphorylated full-length (Supplementary Figure S5C and D) or truncated (Supplementary Figure S5E and F) WT MDM2, but not the corresponding Ala mutants.	('MDM2', 'Gene', '4193', (298, 302))	('T306', 'Chemical', '-', (52, 56))	('preferentially', 'PosReg', (15, 29))	('T306', 'Var', (52, 56))	('MDM2', 'Gene', (298, 302))	('reacted', 'Interaction', (163, 170))	('S5A and B', 'Gene', '5710;5711', (147, 156))	('Ala', 'Chemical', 'MESH:D000409', (330, 333))
139144	26531827	Furthermore, the pT4 and pT306 antibodies detected endogenous phosphorylated MDM2 in HeLa cells after H2O2 treatment, and the detection was reduced in cells depleted of hMps1 or MDM2 (Figure 5C and D).	('hMps1', 'Gene', (169, 174))	('MDM2', 'Gene', '4193', (77, 81))	('MDM2', 'Gene', (77, 81))	('pT306', 'Chemical', '-', (25, 30))	('MDM2', 'Gene', '4193', (178, 182))	('pT306', 'Gene', (25, 30))	('MDM2', 'Gene', (178, 182))	('HeLa', 'CellLine', 'CVCL:0030', (85, 89))	('H2O2', 'Chemical', 'MESH:D006861', (102, 106))	('H2O2', 'Var', (102, 106))	('hMps1', 'Gene', '7272', (169, 174))	('endogenous phosphorylated', 'MPA', (51, 76))	('detected', 'Reg', (42, 50))
139148	26531827	Next, Thr4, Thr306 and Ser307 were mutated to Asp to mimic constitutive phosphorylation, and their H2B E3 activity was examined in 293T cells.	('Thr4, Thr306 and Ser307 were mutated to Asp', 'Mutation', 'p.T,T,S4,306,307D', (6, 49))	('H2B E', 'Gene', '8342', (99, 104))	('Thr306', 'Var', (12, 18))	('Ser307', 'Var', (23, 29))	('293T', 'CellLine', 'CVCL:0063', (131, 135))	('H2B E', 'Gene', (99, 104))
139149	26531827	As shown in Supplementary Figure S5G and quantified in Supplementary Figure S5H, T4/T306D and T4/S307D double substitution mutants but not the T4/T306/S307D triple mutant exhibited modest increase in the activity to promote H2B ubiquitination.	('S307D', 'Mutation', 'p.S307D', (97, 102))	('H2B', 'Gene', (224, 227))	('activity', 'MPA', (204, 212))	('T306', 'Chemical', '-', (146, 150))	('promote', 'PosReg', (216, 223))	('H2B', 'Gene', '8349', (224, 227))	('S307D', 'Mutation', 'p.S307D', (151, 156))	('increase', 'PosReg', (188, 196))	('T306D', 'Mutation', 'p.T306D', (84, 89))	('T306', 'Chemical', '-', (84, 88))	('T4/T306D', 'Var', (81, 89))	('T4/S307D', 'Var', (94, 102))
139150	26531827	These results suggest that phosphorylation at at least two of the sites, T4 and T306 or T4 and S307, is involved in regulating the H2B E3 activity of MDM2.	('activity', 'MPA', (138, 146))	('H2B E', 'Gene', (131, 136))	('MDM2', 'Gene', '4193', (150, 154))	('MDM2', 'Gene', (150, 154))	('T306', 'Chemical', '-', (80, 84))	('involved', 'Reg', (104, 112))	('T306', 'Var', (80, 84))	('H2B E', 'Gene', '8342', (131, 136))	('S307', 'Var', (95, 99))
139152	26531827	Moreover, H2B ubiquitination by itself could lead to chromatin relaxation in vitro.	('chromatin relaxation', 'MPA', (53, 73))	('H2B', 'Gene', (10, 13))	('lead to', 'Reg', (45, 52))	('H2B', 'Gene', '8349', (10, 13))	('ubiquitination', 'Var', (14, 28))
139155	26531827	The results indicate that depletion of either hMps1 or MDM2 significantly hampered DNA repair, evidenced by sustained tail DNA (Figure 6C) and consequently reduced clonogenic cell survival (Figure 6D).	('hMps1', 'Gene', (46, 51))	('MDM2', 'Gene', '4193', (55, 59))	('depletion', 'Var', (26, 35))	('hampered', 'NegReg', (74, 82))	('reduced', 'NegReg', (156, 163))	('clonogenic cell survival', 'CPA', (164, 188))	('DNA repair', 'CPA', (83, 93))	('hMps1', 'Gene', '7272', (46, 51))	('tail DNA', 'CPA', (118, 126))	('MDM2', 'Gene', (55, 59))
139158	26531827	The 8-oxoG positive cells appeared minutes after the removal of H2O2 whereas the unrelated protein CRM1 stained uniformly before and after the treatment, thus validating the specificity of the assay (Supplementary Figure S6C).	('H2O2', 'Var', (64, 68))	('CRM1', 'Gene', '7514', (99, 103))	('removal', 'NegReg', (53, 60))	('H2O2', 'Chemical', 'MESH:D006861', (64, 68))	('8-oxoG positive', 'MPA', (4, 19))	('CRM1', 'Gene', (99, 103))
139162	26531827	Moreover, knockdown of MDM2 or hMps1 increased comet tails in WT but not in 2KR cells (Figure 6I and Supplementary Figure S6G), suggesting that H2B ubiquitination functions downstream of hMps1 and MDM2 in oxidative DNA damage repair.	('MDM2', 'Gene', '4193', (197, 201))	('hMps1', 'Gene', (187, 192))	('MDM2', 'Gene', (197, 201))	('H2B', 'Gene', (144, 147))	('MDM2', 'Gene', '4193', (23, 27))	('MDM2', 'Gene', (23, 27))	('hMps1', 'Gene', '7272', (187, 192))	('ubiquitination', 'MPA', (148, 162))	('increased', 'PosReg', (37, 46))	('comet tails', 'CPA', (47, 58))	('H2B', 'Gene', '8349', (144, 147))	('hMps1', 'Gene', '7272', (31, 36))	('comet', 'Species', '302767', (47, 52))	('knockdown', 'Var', (10, 19))	('hMps1', 'Gene', (31, 36))
139170	26531827	Following H2O2 treatment, MDM2 relocalized to form foci in the nuclei, partially overlapped with those formed by PARP-1 and XRCC1, two key effectors participating in repair of oxidative DNA lesions (Figure 7A and B).	('H2O2', 'Var', (10, 14))	('MDM2', 'Gene', '4193', (26, 30))	('XRCC1', 'Gene', '7515', (124, 129))	('MDM2', 'Gene', (26, 30))	('PARP-1', 'Gene', (113, 119))	('PARP-1', 'Gene', '142', (113, 119))	('XRCC1', 'Gene', (124, 129))	('H2O2', 'Chemical', 'MESH:D006861', (10, 14))
139172	26531827	Moreover, we observed partial colocalization of MDM2 foci with those of hMps1 phosphorylated at Thr288 (Figure 7D), which has been reported to colocalize with gammaH2AX after ionizing irradiation and might function as a damage response marker.	('gammaH2AX', 'Chemical', '-', (159, 168))	('gammaH2AX', 'Var', (159, 168))	('Thr288', 'Chemical', '-', (96, 102))	('colocalization', 'Interaction', (30, 44))	('hMps1', 'Gene', '7272', (72, 77))	('MDM2 foci', 'Disease', 'MESH:C565785', (48, 57))	('hMps1', 'Gene', (72, 77))	('MDM2 foci', 'Disease', (48, 57))
139174	26531827	As depletion of hMps1 and MDM2 impaired oxidative DNA damage repair (Figure 6C and G), we wondered whether the DNA damage signaling was also affected.	('oxidative DNA damage repair', 'MPA', (40, 67))	('hMps1', 'Gene', (16, 21))	('depletion', 'Var', (3, 12))	('MDM2 impaired', 'Disease', (26, 39))	('MDM2 impaired', 'Disease', 'MESH:D009422', (26, 39))	('hMps1', 'Gene', '7272', (16, 21))
139179	26531827	Whether the signaling defect is related to H2B ubiquitination was examined using cells stably expressing the H2B 2KR mutant.	('mutant', 'Var', (117, 123))	('H2B', 'Gene', '8349', (109, 112))	('H2B', 'Gene', '8349', (43, 46))	('H2B', 'Gene', (109, 112))	('H2B', 'Gene', (43, 46))
139187	26531827	Of the several human cancer types analyzed, soft tissue sarcoma stood out with the highest proportion of tumors showing hMps1 mRNA upregulation.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('upregulation', 'PosReg', (131, 143))	('human', 'Species', '9606', (15, 20))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (44, 63))	('hMps1', 'Gene', '7272', (120, 125))	('sarcoma', 'Disease', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('hMps1', 'Gene', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mRNA', 'Var', (126, 130))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))
139213	26531827	In addition, our data suggest that MDM2 may have a housekeeping surveillance function in unstressed cells as its depletion in cells reduced H2B ubiquitination under not only the stressed but also the basal condition (Figure 4C, Supplementary Figure S3) and its knockdown increased 8-oxoG staining in untreated cell (Figure 6G).	('increased', 'PosReg', (271, 280))	('knockdown', 'Var', (261, 270))	('H2B', 'Gene', (140, 143))	('reduced', 'NegReg', (132, 139))	('8-oxoG staining', 'MPA', (281, 296))	('depletion', 'MPA', (113, 122))	('H2B', 'Gene', '8349', (140, 143))	('MDM2', 'Gene', '4193', (35, 39))	('MDM2', 'Gene', (35, 39))
139223	26531827	As hMps1 is also required for the SAC, a relevant question is that whether the observations we made in hMps1 knockdown cells were somehow linked to an inefficient SAC.	('hMps1', 'Gene', '7272', (3, 8))	('knockdown', 'Var', (109, 118))	('hMps1', 'Gene', '7272', (103, 108))	('hMps1', 'Gene', (3, 8))	('hMps1', 'Gene', (103, 108))
139224	26531827	Our earlier studies indicated that hMps1 knockdown or expression of a kinase-deficient hMps1 mutant did not grossly alter cell cycle unless cells were treated with DNA damage agent or spindle poison.	('hMps1', 'Gene', (35, 40))	('mutant', 'Var', (93, 99))	('hMps1', 'Gene', '7272', (87, 92))	('hMps1', 'Gene', '7272', (35, 40))	('cell cycle', 'CPA', (122, 132))	('hMps1', 'Gene', (87, 92))
139226	26531827	Furthermore, knockdown of MDM2, which has not been linked to SAC, yielded similar results.	('MDM2', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('MDM2', 'Gene', '4193', (26, 30))
139291	21822457	Histopathological examination of tumor sections showed that control group maintained characteristic growth of tumors, 4-HPR alone inhibited proliferation of tumor cells, GST alone induced apoptosis to some extent, and combination of 4-HPR and GST significantly induced apoptosis in both Ewing's sarcoma xenografts.	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('apoptosis', 'CPA', (269, 278))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (287, 302))	('sarcoma', 'Phenotype', 'HP:0100242', (295, 302))	('inhibited', 'NegReg', (130, 139))	('HPR', 'Gene', '3250', (235, 238))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('apoptosis', 'CPA', (188, 197))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (287, 302))	('tumors', 'Disease', (110, 116))	('induced', 'Reg', (261, 268))	('tumor', 'Disease', (33, 38))	('combination', 'Var', (218, 229))	('HPR', 'Gene', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('GST', 'Gene', (243, 246))	("Ewing's sarcoma", 'Disease', (287, 302))	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('HPR', 'Gene', '3250', (120, 123))	('HPR', 'Gene', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
139300	21822457	Ewing's sarcoma is characterized by poor neural differentiation, chromosomal translocation at t(11;22)(q24;q12) with high expression of the oncogenic chimeric transcription factor EWS-FLI1 fusion protein.	("Ewing's sarcoma", 'Disease', (0, 15))	('expression', 'MPA', (122, 132))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('EWS', 'Gene', '2130', (180, 183))	('EWS', 'Gene', (180, 183))	('FLI1', 'Gene', (184, 188))	('FLI1', 'Gene', '2313', (184, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (94, 111))	('chromosomal', 'Var', (65, 76))
139347	21822457	Following treatments for 8 or 15 days, H&E staining of tumor sections showed that CTL tumors maintained characteristic growth, 4-HPR alone inhibited tumor cell proliferation, GST alone induced cell death to some extent, and 4-HPR plus GST increased cell death; and extent of cell death was more due to treatment with 4-HPR plus GST for 15 days than for 8 days (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('HPR', 'Gene', (226, 229))	('induced', 'CPA', (185, 192))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('alone', 'NegReg', (133, 138))	('HPR', 'Gene', (129, 132))	('HPR', 'Gene', (319, 322))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('increased cell', 'CPA', (239, 253))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (86, 92))	('and', 'Var', (220, 223))	('that', 'Gene', (77, 81))	('HPR', 'Gene', '3250', (226, 229))	('HPR', 'Gene', '3250', (129, 132))	('HPR', 'Gene', '3250', (319, 322))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('H&E', 'Chemical', '-', (39, 42))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
139380	21822457	Previous studies reported that 4-HPR monotherapy in ESFT induced apoptosis through p38 MAPK pathway whereas GST monotherapy also induced apoptosis in SK-N-MC cells.	('HPR', 'Gene', '3250', (33, 36))	('apoptosis', 'CPA', (65, 74))	('p38 MAPK pathway', 'Pathway', (83, 99))	('HPR', 'Gene', (33, 36))	('SK-N-MC', 'CellLine', 'CVCL:0530', (150, 157))	('monotherapy', 'Var', (37, 48))
139412	29490948	Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis.	('increases', 'PosReg', (233, 242))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('YAP1', 'Gene', (227, 231))	('deregulation', 'Var', (108, 120))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (17, 36))	('aberrant', 'Var', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('proliferation', 'CPA', (243, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('tumor', 'Disease', (60, 65))	('stabilization', 'MPA', (155, 168))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('pleomorphic sarcoma', 'Disease', (17, 36))
139413	29490948	Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT).	('sarcomas', 'Disease', (113, 121))	('angiomotin', 'Gene', (167, 177))	('angiomotin', 'Gene', '27494', (167, 177))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('YAP1', 'Gene', (74, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('epigenetic silencing', 'Var', (129, 149))	('mouse', 'Species', '10090', (20, 25))
139418	29490948	Whereas loss or mutation of tumor suppressors (i.e.	('mutation', 'Var', (16, 24))	('tumor', 'Disease', (28, 33))	('loss', 'NegReg', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
139420	29490948	We previously reported that deactivation of the Hippo pathway, a signaling cascade that negatively regulates cell proliferation, promotes sarcomagenesis in skeletal muscle-derived UPS.	('sarcoma', 'Disease', (138, 145))	('promotes', 'PosReg', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Hippo', 'Gene', (48, 53))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('deactivation', 'Var', (28, 40))
139421	29490948	Furthermore, genome-wide analysis of The Cancer Genome Atlas (TCGA) sarcoma dataset confirmed that deregulated Hippo signaling is a contributing factor in sarcomagenesis.	('sarcoma', 'Disease', (68, 75))	('sarcoma', 'Disease', (155, 162))	('deregulated', 'Var', (99, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('Cancer Genome Atlas', 'Disease', (41, 60))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (41, 60))	('Hippo signaling', 'MPA', (111, 126))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
139422	29490948	Inhibtion of YAP1 reduces proliferation in multiple sarcoma subtypes, including UPS, though no genetically engineered mouse model of Yap1-deficient UPS existed prior to this study.	('multiple sarcoma subtypes', 'Disease', 'MESH:D012509', (43, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('reduces', 'NegReg', (18, 25))	('Inhibtion', 'Var', (0, 9))	('mouse', 'Species', '10090', (118, 123))	('multiple sarcoma subtypes', 'Disease', (43, 68))	('Yap1-deficient UPS', 'Disease', (133, 151))	('proliferation', 'CPA', (26, 39))	('YAP1', 'Gene', (13, 17))	('Yap1-deficient UPS', 'Disease', 'MESH:D017118', (133, 151))
139426	29490948	In addition to Hippo pathway deregulation, several studies have recently shown that alterations in the epigenetic landscape can promote sarcomagenesis.	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('epigenetic landscape', 'MPA', (103, 123))	('sarcoma', 'Disease', (136, 143))	('alterations', 'Var', (84, 95))	('promote', 'PosReg', (128, 135))
139427	29490948	Specifically, certain pediatric sarcomas are linked to chromosomal translocations of transcription factor loci encoding chromatin remodeling factors.	('linked', 'Reg', (45, 51))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('chromosomal translocations', 'Var', (55, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('sarcomas', 'Disease', (32, 40))
139430	29490948	These findings support the hypothesis that epigenetic modulation can reduce tumorigenesis by returning key transcription factors to the expression and activity levels found in quiescent cells.	('expression', 'MPA', (136, 146))	('returning', 'PosReg', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('epigenetic modulation', 'Var', (43, 64))	('reduce', 'NegReg', (69, 75))	('activity', 'MPA', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
139435	29490948	We conclude that epigenetic therapy can reclaim control of YAP1-mediated NF-kappaB signaling and subsequently inhibit tumor cell proliferation, induce differentiation and decrease sarcomagenesis in vivo.	('induce', 'PosReg', (144, 150))	('NF-kappaB signaling', 'MPA', (73, 92))	('differentiation', 'CPA', (151, 166))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('sarcoma', 'Disease', 'MESH:D012509', (180, 187))	('decrease', 'NegReg', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('sarcoma', 'Disease', (180, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('tumor', 'Disease', (118, 123))	('epigenetic therapy', 'Var', (17, 35))	('inhibit', 'NegReg', (110, 117))	('YAP1-mediated', 'Gene', (59, 72))
139452	29490948	Human HT-1080 (Fibrosarcoma), RD (Rhabdomyosarcoma), LPS224 and LPS863 (Liposarcoma), SKLMS1 and SKUT1 (Leiomyosarcoma) and HEK-293T cell lines were purchased from ATCC (Manassas, VA, USA).	('Fibrosarcoma', 'Disease', 'MESH:D005354', (15, 27))	('Human', 'Species', '9606', (0, 5))	('LPS224', 'Chemical', '-', (53, 59))	('HT-1080', 'CellLine', 'CVCL:0317', (6, 13))	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (104, 118))	('Liposarcoma', 'Disease', 'MESH:D008080', (72, 83))	('HEK-293T', 'CellLine', 'CVCL:0063', (124, 132))	('Leiomyosarcoma', 'Disease', 'MESH:D007890', (104, 118))	('Rhabdomyosarcoma', 'Disease', (34, 50))	('Liposarcoma', 'Disease', (72, 83))	('Leiomyosarcoma', 'Disease', (104, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('LPS863', 'Chemical', '-', (64, 70))	('LPS863', 'Var', (64, 70))	('SKLMS1', 'CellLine', 'CVCL:0628', (86, 92))	('SKUT1', 'CellLine', 'CVCL:0533', (97, 102))	('Fibrosarcoma', 'Phenotype', 'HP:0100244', (15, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (34, 50))	('Liposarcoma', 'Phenotype', 'HP:0012034', (72, 83))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (34, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('Fibrosarcoma', 'Disease', (15, 27))
139461	29490948	The following antibody concentrations were used: rabbit anti-YAP1 (4912; 1:100) (Cell Signaling Technology), anti-phospho p65 (Abcam) (86299; 1:250) rabbit anti-Ki-67 (15580; 1:100) (Abcam), rabbit anti-MYOD (18943-1-AP; 1:100) (Proteintech).	('rabbit', 'Species', '9986', (149, 155))	('rabbit', 'Species', '9986', (49, 55))	('15580; 1:100', 'Var', (168, 180))	('rabbit', 'Species', '9986', (191, 197))	('p65', 'Gene', (122, 125))	('p65', 'Gene', '5970', (122, 125))
139465	29490948	Protein lysate was prepared in SDS/Tris (pH7.6) lysis buffer, separated by electrophoresis in 8-10% SDS/PAGE gels, transferred to nitrocellulose membrane, and probed with the following antibodies: rabbit anti-YAP1 (4912; 1:1000), rabbit anti-p-Yap (Ser397) (13619; 1:1000), rabbit anti-GAPDH (2118; 1:1000), mouse anti-AMOT (60156-1-lg 1:500), rabbit anti-V5-tag (13202; 1:1000), rabbit anti-p65 (8242; 1:500), rabbit anti-p-p65 (Ser536) (3033; 1:500), rabbit anti-Caspase-3 (9662; 1:1000), rabbit anti-HSP90 (4875; 1:1000) (Cell Signaling Technology), rabbit USP31(12076-1-AP; 1:1000), rabbit anti-MYOD1 (18943-1-AP; 1:500) (Proteintech), rabbit FOXM1 (sc-502; 1:500) (Santa Cruz Biotechnology), c-Myc (32072; 1:2000), p57 Kip2 (75974; 1:500) (Abcam), mouse anti-Lamin B2 (D18) (University of Iowa Developmental Studies Hybridoma Bank).	('rabbit', 'Species', '9986', (553, 559))	('rabbit', 'Species', '9986', (274, 280))	('p65', 'Gene', (425, 428))	('rabbit', 'Species', '9986', (640, 646))	('mouse', 'Species', '10090', (308, 313))	('Caspase-3', 'Gene', '100008840', (465, 474))	('Lamin B2', 'Gene', '103350872', (764, 772))	('p65', 'Gene', (392, 395))	('Yap', 'Gene', '10413', (244, 247))	('rabbit', 'Species', '9986', (344, 350))	('GAPDH', 'Gene', '100009074', (286, 291))	('Lamin B2', 'Gene', (764, 772))	('32072', 'Var', (704, 709))	('mouse', 'Species', '10090', (753, 758))	('p65', 'Gene', '5970', (425, 428))	('rabbit', 'Species', '9986', (453, 459))	('p65', 'Gene', '5970', (392, 395))	('c-Myc', 'Gene', (697, 702))	('GAPDH', 'Gene', (286, 291))	('Yap', 'Gene', (244, 247))	('Caspase-3', 'Gene', (465, 474))	('rabbit', 'Species', '9986', (380, 386))	('c-Myc', 'Gene', '100327265', (697, 702))	('rabbit', 'Species', '9986', (587, 593))	('rabbit', 'Species', '9986', (491, 497))	('Kip2', 'Gene', (724, 728))	('rabbit', 'Species', '9986', (230, 236))	('75974;', 'Var', (730, 736))	('rabbit', 'Species', '9986', (197, 203))	('Kip2', 'Gene', '1028', (724, 728))	('rabbit', 'Species', '9986', (411, 417))
139479	29490948	Deregulation of the Hippo pathway is associated with muscle-derived sarcoma subtypes but the downstream mechanisms are unclear.	('Deregulation', 'Var', (0, 12))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (68, 84))	('sarcoma subtypes', 'Disease', (68, 84))	('Hippo pathway', 'Pathway', (20, 33))	('associated', 'Reg', (37, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
139480	29490948	Though we have access to only a small number of TCGA patient samples, which prevents our analysis from reaching statistical significance, expression of YAP1 strikingly correlates with long-term survival in human UPS patients (Figure 1A).	('human', 'Species', '9606', (206, 211))	('correlates with', 'Reg', (168, 183))	('patient', 'Species', '9606', (216, 223))	('YAP1', 'Gene', (152, 156))	('patients', 'Species', '9606', (216, 224))	('expression', 'Var', (138, 148))	('patient', 'Species', '9606', (53, 60))
139484	29490948	The Cre recombinase activates expression of oncogenic Kras and deletes p53 expression in infected muscle progenitor cells.	('Kras', 'Gene', (54, 58))	('expression', 'MPA', (30, 40))	('Kras', 'Gene', '3845', (54, 58))	('deletes', 'Var', (63, 70))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('activates', 'PosReg', (20, 29))	('expression', 'MPA', (75, 85))
139485	29490948	Though Kras mutation is rare in sarcomas, Trp53 mutation and deletion are very common.	('Trp53', 'Gene', (42, 47))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('deletion', 'Var', (61, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('mutation', 'Var', (48, 56))	('Kras', 'Gene', (7, 11))	('sarcomas', 'Disease', (32, 40))	('Kras', 'Gene', '3845', (7, 11))
139486	29490948	Furthermore, hyperactivation of the MAPK pathway, downstream of KRAS activation, is common in UPS and is an excellent prognostic indicator for recurrence.	('KRAS', 'Gene', '3845', (64, 68))	('hyperactivation', 'Var', (13, 28))	('MAPK pathway', 'Pathway', (36, 48))	('KRAS', 'Gene', (64, 68))
139494	29490948	Deletion of Yap1 delayed tumor initiation (Median latency KP:57 days; KPY:59 days, P<0.0001) and growth (Figure 1E-H).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Yap1', 'Gene', (12, 16))	('delayed', 'NegReg', (17, 24))	('tumor initiation', 'Disease', (25, 41))	('tumor initiation', 'Disease', 'MESH:D009369', (25, 41))	('growth', 'MPA', (97, 103))	('Deletion', 'Var', (0, 8))
139510	29490948	Acetylation of lysine residues on histone tails is linked to active euchromatin transcription, especially at H3K27Ac, which is associated with active cis-regulatory elements.	('linked', 'Reg', (51, 57))	('H3K27Ac', 'Var', (109, 116))	('lysine', 'Chemical', 'MESH:D008239', (15, 21))	('Acetylation', 'MPA', (0, 11))	('active', 'MPA', (61, 67))
139534	29490948	Recent findings from our group and others suggest a strong epigenetic basis for soft tissue sarcoma development and efficacy of HDAC inhibitors in pre-clinical UPS models.	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (80, 99))	('HDAC', 'Gene', (128, 132))	('soft tissue sarcoma', 'Disease', (80, 99))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (80, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('epigenetic', 'Var', (59, 69))
139541	29490948	JQ1 dramatically reduced tumor progression (Figure 4A) with a 5-fold reduction in final tumor volume (Figure 4B) and a 6-fold reduction in final tumor weight (Figure 4C) compared to DMSO-treated controls.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (25, 30))	('DMSO', 'Chemical', 'MESH:D004121', (182, 186))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('JQ1', 'Var', (0, 3))	('reduction', 'NegReg', (126, 135))	('reduction', 'NegReg', (69, 78))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('reduced', 'NegReg', (17, 24))
139542	29490948	We used HT-1080 cells, which are sensitive to 250 nM JQ1, easily transduced, and proliferate under control conditions at a less rapid pace than the other sarcoma cell lines.	('JQ1', 'Var', (53, 56))	('HT-1080', 'CellLine', 'CVCL:0317', (8, 15))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))
139561	29490948	To confirm that expression of Amot suppresses proliferation in sarcoma we transduced human HT-1080 cells with GFP tagged WT-AMOT.	('expression', 'Var', (16, 26))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('proliferation', 'CPA', (46, 59))	('HT-1080', 'CellLine', 'CVCL:0317', (91, 98))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('suppresses', 'NegReg', (35, 45))	('human', 'Species', '9606', (85, 90))
139562	29490948	Our findings show that expression of AMOT is a strong YAP1 inhibitor in our cells and accordingly suppress sarcoma cell proliferation.	('AMOT', 'Gene', (37, 41))	('sarcoma', 'Disease', (107, 114))	('expression', 'Var', (23, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('suppress', 'NegReg', (98, 106))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))
139573	29490948	These observations, suggest that SAHA/JQ1 may induce oscillation but that treatment ultimately reduces NF-kappaB signaling Combination SAHA/JQ1 treatment inhibits Yap1 and dramatically reduces proliferation of sarcoma cells (Figure 4G-I).	('NF-kappaB signaling', 'MPA', (103, 122))	('inhibits', 'NegReg', (154, 162))	('sarcoma', 'Disease', (210, 217))	('reduces', 'NegReg', (185, 192))	('SAHA', 'Chemical', 'MESH:D000077337', (135, 139))	('SAHA', 'Chemical', 'MESH:D000077337', (33, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('Yap1', 'MPA', (163, 167))	('proliferation', 'CPA', (193, 206))	('SAHA/JQ1', 'Var', (135, 143))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('reduces', 'NegReg', (95, 102))
139574	29490948	Therefore, we tested the possibility that epigenetic therapy differentiates sarcoma cells into a less malignant muscle-like cell.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('epigenetic therapy', 'Var', (42, 60))	('tested', 'Reg', (14, 20))
139581	29490948	Our data suggest that epigenetic therapy of sarcoma cells restores the NF-kappaB oscillation observed in differentiating myoblasts.	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('epigenetic therapy', 'Var', (22, 40))	('sarcoma', 'Disease', (44, 51))	('restores', 'PosReg', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('NF-kappaB oscillation', 'MPA', (71, 92))
139601	29490948	To determine whether NF-kappaB inhibition alone is sufficient to induce Myod expression and differentiation we investigated Myod levels in sarcoma cells treated with the NF-kappaB inhibitor BAY117085 and found that NF-kappaB inhibition alone could not induce MYOD1 protein expression (Figure 6F).	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('BAY117085', 'Var', (190, 199))	('sarcoma', 'Disease', (139, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('BAY117085', 'Chemical', 'MESH:C416282', (190, 199))
139602	29490948	Additional epigenetic changes due SAHA/JQ1 are necessary to facilitate the muscle differentiation program.	('muscle differentiation program', 'CPA', (75, 105))	('SAHA/JQ1', 'Gene', (34, 42))	('epigenetic changes', 'Var', (11, 29))	('SAHA', 'Chemical', 'MESH:D000077337', (34, 38))	('facilitate', 'PosReg', (60, 70))
139607	29490948	Importantly, these findings support the conclusion that SAHA/JQ1 inhibits NF-kappaB activity in multiple cell lines and sarcoma subtypes.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('inhibits', 'NegReg', (65, 73))	('NF-kappaB', 'Protein', (74, 83))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (120, 136))	('SAHA/JQ1', 'Var', (56, 64))	('activity', 'MPA', (84, 92))	('sarcoma subtypes', 'Disease', (120, 136))	('SAHA', 'Chemical', 'MESH:D000077337', (56, 60))
139614	29490948	K63 linked ubiquitination of Traf2 is dependent upon USP31.	('K63 linked', 'Var', (0, 10))	('Traf2', 'Gene', '7186', (29, 34))	('ubiquitination', 'MPA', (11, 25))	('Traf2', 'Gene', (29, 34))
139616	29490948	These data suggest that Usp31-mediated K63-linked ubiquitination affects Traf2 protein stability.	('Traf2', 'Gene', (73, 78))	('stability', 'MPA', (87, 96))	('protein', 'Protein', (79, 86))	('Traf2', 'Gene', '7186', (73, 78))	('K63-linked', 'Var', (39, 49))	('affects', 'Reg', (65, 72))
139618	29490948	As we have previously reported, expression of Yap1 shRNA significantly reduced tumor growth and weight compared to Scr shRNA control.	('Yap1', 'Gene', (46, 50))	('tumor', 'Disease', (79, 84))	('expression', 'Var', (32, 42))	('reduced', 'NegReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
139619	29490948	Consistent with our in vitro proliferation findings (Figure 7A), Usp31-specific shRNA increased tumor growth (Figure 7E,F).	('increased', 'PosReg', (86, 95))	('Usp31-specific', 'Var', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('shRNA', 'Gene', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
139620	29490948	Most importantly, loss of Usp31 expression rescued the Yap1 shRNA-mediated reduction in tumor growth.	('loss', 'Var', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Usp31', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('reduction', 'NegReg', (75, 84))	('Yap1', 'Gene', (55, 59))	('tumor', 'Disease', (88, 93))
139631	29490948	Together, these findings show that epigenetic modulation of the Hippo pathway restores normal NF-kappaB activity, leads to decreased sarcomagenesis, and increased muscle differentiation in vivo via Usp31.	('muscle differentiation', 'CPA', (163, 185))	('epigenetic modulation', 'Var', (35, 56))	('decreased sarcomagenesis', 'Disease', (123, 147))	('NF-kappaB', 'Protein', (94, 103))	('Hippo pathway', 'Pathway', (64, 77))	('activity', 'MPA', (104, 112))	('restores', 'PosReg', (78, 86))	('increased', 'PosReg', (153, 162))	('increased muscle', 'Phenotype', 'HP:0003712', (153, 169))	('decreased sarcomagenesis', 'Disease', 'MESH:D012021', (123, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
139632	29490948	Targetable oncogenic driver mutations are rare in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('sarcomas', 'Disease', (50, 58))	('mutations', 'Var', (28, 37))
139651	29490948	Collectively, our data suggest that YAP1 stabilization, p65 phosphorylation and AMOT suppression could potentially serve as useful biomarkers for UPS and provide the mechanistic rationale for epigenetic therapy to restore Hippo pathway activity to normal levels in the treatment of this disease.	('restore', 'PosReg', (214, 221))	('p65', 'Gene', '5970', (56, 59))	('Hippo pathway', 'Pathway', (222, 235))	('phosphorylation', 'Var', (60, 75))	('AMOT suppression', 'CPA', (80, 96))	('YAP1', 'Gene', (36, 40))	('activity', 'MPA', (236, 244))	('p65', 'Gene', (56, 59))
139654	30046410	Bone marrow biopsy revealed 15% blasts, and cytogenetics with an inversion 16 rearrangement was diagnostic of acute myeloid leukemia (AML).	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (110, 132))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (116, 132))	('AML', 'Disease', 'MESH:D015470', (134, 137))	('leukemia', 'Phenotype', 'HP:0001909', (124, 132))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (110, 132))	('AML', 'Disease', (134, 137))	('AML', 'Phenotype', 'HP:0004808', (134, 137))	('inversion 16 rearrangement', 'Var', (65, 91))	('acute myeloid leukemia', 'Disease', (110, 132))
139697	30046410	However, abnormalities in chromosome 8, in particular t(8;21) in children and trisomy 8 are more common in myeloid sarcoma compare to leukemic AML.	('leukemic AML', 'Disease', (134, 146))	('children', 'Species', '9606', (65, 73))	('abnormalities', 'Var', (9, 22))	('common', 'Reg', (97, 103))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (107, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('AML', 'Phenotype', 'HP:0004808', (143, 146))	('myeloid sarcoma', 'Disease', (107, 122))	('trisomy 8', 'Gene', (78, 87))	('leukemic AML', 'Disease', 'MESH:D015470', (134, 146))
139712	29022407	Cancers arising in younger individuals cannot invoke wear and tear - progressive accumulation of mutations over the span of years - as a cause, and indeed cancers arising in children and young adults are characterized by very few mutations.	('mutations', 'Var', (97, 106))	('Cancers', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tear', 'Phenotype', 'HP:0009926', (62, 66))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('children', 'Species', '9606', (174, 182))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', (155, 162))
139713	29022407	Epigenetic mechanisms can provide different means to the same end as gene mutations, through altered expression of genes critical to cancer-driving phenotypes.	('altered', 'Reg', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('Epigenetic', 'Var', (0, 10))	('expression', 'MPA', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
139714	29022407	Epigenetic mechanisms have been shown to contribute in some form to virtually all cancer types, and seem to play a disproportionately large role in cancers of childhood.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('contribute', 'Reg', (41, 51))	('Epigenetic mechanisms', 'Var', (0, 21))
139720	29022407	JHDMs have both unique and overlapping specificities for histone lysine methyl marks, collectively covering multiple marks related to control of gene expression, including the activating H3K4 methyl mark, and the repressive H3K27 and H3K9 methyl marks.	('lysine', 'Chemical', 'MESH:D008239', (65, 71))	('H3K9 methyl marks', 'Var', (234, 251))	('methyl mark', 'Var', (192, 203))	('activating', 'PosReg', (176, 186))	('H3K27', 'Var', (224, 229))	('H3K4', 'Protein', (187, 191))
139722	29022407	Recently, a number of studies have implicated KDM3A (JMJD1A/JHDM2A), a member of the KDM3 subfamily with specificity for removal of mono and di-methyl marks from H3K9, in tumor/metastasis promotion, chemoresistance and other phenotypes, in cancers of epithelial origin (including the common cancers of breast, prostate and colon), liver, and the hematopoietic system.	('chemoresistance', 'CPA', (199, 214))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('JMJD1A', 'Gene', (53, 59))	('KDM3A', 'Var', (46, 51))	('JHDM2A', 'Gene', '55818', (60, 66))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('liver', 'Disease', (331, 336))	('cancers', 'Disease', (240, 247))	('implicated', 'Reg', (35, 45))	('prostate', 'Disease', (310, 318))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('JMJD1A', 'Gene', '55818', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('JHDM2A', 'Gene', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('breast', 'Disease', (302, 308))	('cancers', 'Disease', (291, 298))	('tumor', 'Disease', (171, 176))
139741	29022407	Selective compound delivery to tumor cells, methodologies for which are rapidly evolving, could be a means to improve drug therapeutic index.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Selective', 'Var', (0, 9))	('tumor', 'Disease', (31, 36))	('improve drug therapeutic index', 'Phenotype', 'HP:0020173', (110, 140))	('improve', 'PosReg', (110, 117))	('drug therapeutic index', 'MPA', (118, 140))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
139744	29022407	In summary, epigenetic mechanisms have emerged as potent inducers of oncogenic pathways and silencers of tumor suppressive pathways in cancer.	('cancer', 'Disease', (135, 141))	('oncogenic pathways', 'Pathway', (69, 87))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('epigenetic mechanisms', 'Var', (12, 33))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('inducers', 'PosReg', (57, 65))	('silencers of tumor', 'Disease', (92, 110))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('silencers of tumor', 'Disease', 'MESH:D009369', (92, 110))
139745	29022407	Epigenetic alterations in cancer are common, and provide a complementary, or in the case of hypomutated cancers such as those of childhood, alternative means to gene mutations in the initiation and progression of malignant phenotypes.	('Epigenetic alterations', 'Var', (0, 22))	('hypomutated cancers', 'Disease', (92, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('hypomutated cancers', 'Disease', 'MESH:D009369', (92, 111))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
139805	22520024	A 60-year-old male patient had previously undergone a radical resection of a T2bN0M0G3 Stage III retroperitoneal sarcoma, including right nephrectomy and cholecystectomy, in 2002.	('patient', 'Species', '9606', (19, 26))	('retroperitoneal sarcoma', 'Disease', (97, 120))	('retroperitoneal sarcoma', 'Disease', 'MESH:D012186', (97, 120))	('cholecystectomy', 'Disease', (154, 169))	('T2bN0M0G3', 'Var', (77, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('right nephrectomy', 'Disease', (132, 149))	('Stage III retroperitoneal sarcoma', 'Phenotype', 'HP:0030739', (87, 120))
139855	32291430	Immunohistochemistry showed CK-, EMA-, Vim+, CD31++, S-100-, AACT+, a few cells were CD68+, actin+, and desmin-.	('AACT', 'Gene', '12', (61, 65))	('S-100-', 'Var', (53, 59))	('CD31++', 'Var', (45, 51))	('desmin', 'Gene', (104, 110))	('AACT', 'Gene', (61, 65))	('Vim', 'Gene', (39, 42))	('desmin', 'Gene', '1674', (104, 110))	('CK', 'Gene', '51727', (28, 30))	('Vim', 'Gene', '7431', (39, 42))
139901	32373525	Downstream activation of EWSR1-WT1 gene fusion includes signaling pathways of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and insulin growth factor (IGF)-1.	('fusion', 'Var', (40, 46))	('insulin growth factor (IGF)-1', 'Gene', (164, 193))	('EWSR1', 'Gene', (25, 30))	('insulin growth factor (IGF)-1', 'Gene', '3479', (164, 193))	('VEGF', 'Gene', (153, 157))	('WT1', 'Gene', '7490', (31, 34))	('EWSR1', 'Gene', '2130', (25, 30))	('vascular endothelial growth factor', 'Gene', (117, 151))	('signaling', 'MPA', (56, 65))	('WT1', 'Gene', (31, 34))	('VEGF', 'Gene', '7422', (153, 157))	('vascular endothelial growth factor', 'Gene', '7422', (117, 151))	('activation', 'PosReg', (11, 21))
139905	32373525	DSRCT arises from serosal surfaces and is molecularly characterized by translocation between Ewing sarcoma RNA binding protein 1 gene (EWSR1) and Wilms tumor suppressor gene (WT1).	('Wilms tumor', 'Disease', (146, 157))	('Wilms tumor', 'Disease', 'MESH:D009396', (146, 157))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (93, 106))	('WT1', 'Gene', '7490', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('DSRCT', 'Disease', (0, 5))	('EWSR1', 'Gene', (135, 140))	('WT1', 'Gene', (175, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Ewing sarcoma', 'Disease', (93, 106))	('translocation', 'Var', (71, 84))	('EWSR1', 'Gene', '2130', (135, 140))	('Wilms tumor', 'Phenotype', 'HP:0002667', (146, 157))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (93, 106))
139912	32373525	DSRCT is characterized by the t(11;22)(p13;q12) chromosomal translocation involving a fusion between the transcriptional activating domain of EWSR1 and the WT1 gene, a tumor suppressor gene whose protein product is a transcriptional activator of genes involved in renal and gonadal differentiation and regulates the mesenchymal to epithelial transition seen in renal development.	('EWSR1', 'Gene', (142, 147))	('tumor', 'Disease', (168, 173))	('DSRCT', 'Disease', (0, 5))	('fusion', 'Var', (86, 92))	('t(11', 'Var', (30, 34))	('WT1', 'Gene', '7490', (156, 159))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 47))	('EWSR1', 'Gene', '2130', (142, 147))	('regulates', 'Reg', (302, 311))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mesenchymal to epithelial', 'CPA', (316, 341))	('WT1', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
139913	32373525	The EWSR1-WT1 gene fusion forms a chimeric protein acting as transcription factor with at least 35 known target genes, including PDGF, IGF-1 receptor, epidermal growth factor receptor (EGFR) and others such as c-MYC and fibroblast growth factor receptor (FGFR).	('fusion', 'Var', (19, 25))	('EWSR1', 'Gene', '2130', (4, 9))	('epidermal growth factor receptor', 'Gene', (151, 183))	('EGFR', 'Gene', (185, 189))	('c-MYC', 'Gene', (210, 215))	('WT1', 'Gene', '7490', (10, 13))	('WT1', 'Gene', (10, 13))	('IGF-1 receptor', 'Gene', (135, 149))	('epidermal growth factor receptor', 'Gene', '1956', (151, 183))	('c-MYC', 'Gene', '4609', (210, 215))	('PDGF', 'Gene', (129, 133))	('EWSR1', 'Gene', (4, 9))	('EGFR', 'Gene', '1956', (185, 189))
139915	32373525	Among existing reports, one patient showed variants of unknown clinical significance in ARID1A and RUNX1 genes Another study detected no mutations in a panel of 29 genes (including MET, ALK and KIT) evaluated in 24 cases of DSRCT and in a large study of sarcomas analyzed by next generation or Sanger sequencing which included 9 DSRCT samples, few mutations were seen.	('sarcomas', 'Disease', 'MESH:D012509', (254, 262))	('KIT', 'Gene', '3815', (194, 197))	('ALK', 'Gene', (186, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (254, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('sarcomas', 'Disease', (254, 262))	('KIT', 'Gene', (194, 197))	('patient', 'Species', '9606', (28, 35))	('RUNX1', 'Gene', (99, 104))	('ALK', 'Gene', '238', (186, 189))	('variants', 'Var', (43, 51))	('RUNX1', 'Gene', '861', (99, 104))	('ARID1A', 'Gene', (88, 94))	('ARID1A', 'Gene', '8289', (88, 94))
139916	32373525	interrogated tumors from 10 DSRCT patients, who had received pre-treatment with chemotherapy, for somatic genetic mutations against a panel of genes known to be of importance in childhood cancer (tumor suppressor and oncogenic drivers) using a single-gene polymerase chain reaction (PCR) approach.	('tumor', 'Disease', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', (196, 201))	('tumors', 'Disease', (13, 19))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Disease', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
139917	32373525	One case had a mutation in the MET gene coding for the c-Met tyrosine kinase, which has been classified as proto-oncogene acting on the hepatocyte growth factor/scatter factor (HGF/SF).	('mutation', 'Var', (15, 23))	('HGF/SF', 'Gene', '3082', (177, 183))	('MET', 'Gene', (31, 34))	('HGF/SF', 'Gene', (177, 183))
139919	32373525	PI3KCA acts on PI3K/AKT/mTOR pathway and is important for cell proliferation and tumor growth.	('AKT', 'Gene', (20, 23))	('acts', 'Reg', (7, 11))	('mTOR', 'Gene', '2475', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('AKT', 'Gene', '207', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mTOR', 'Gene', (24, 28))	('PI3KCA', 'Var', (0, 6))	('tumor', 'Disease', (81, 86))
139967	32373525	found androgen receptors in 10 out of 27 DSRCT patients and in vitro assay showed growth of tumor cells when stimulated with diihydrotestosterone, indicating that they are functional.	('diihydrotestosterone', 'Chemical', '-', (125, 145))	('androgen receptor', 'Gene', '367', (6, 23))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('androgen receptor', 'Gene', (6, 23))	('diihydrotestosterone', 'Var', (125, 145))	('growth', 'PosReg', (82, 88))
139980	30922345	Using a comprehensive genomic profiling, we were able to identify recurrent chromosomal aberrations associated with MS including a rare KMT2A-ELL fusion, losses of chromosomes 1p, 9, 10, 15, 18, and gain of chromosome 1q and mutations in FLT3 and PTPN11, and achived the final diagnosis of a de novo MS.	('PTPN11', 'Gene', '5781', (247, 253))	('recurrent chromosomal aberrations', 'Phenotype', 'HP:0040012', (66, 99))	('FLT3', 'Gene', '2322', (238, 242))	('mutations', 'Var', (225, 234))	('gain', 'PosReg', (199, 203))	('ELL', 'Gene', '8178', (142, 145))	('PTPN11', 'Gene', (247, 253))	('ELL', 'Gene', (142, 145))	('KMT2A', 'Gene', (136, 141))	('FLT3', 'Gene', (238, 242))	('losses', 'Var', (154, 160))	('KMT2A', 'Gene', '4297', (136, 141))
139991	30922345	Fluorescence in situ hybridization (FISH) analysis was performed using Vysis  LSI  (Abbott Park, IL) dual color, break apart probes for detection of rearrangements of KMT2A (MLL) and CBFB, and dual color, dual fusion probe set for detection of t(8;21)/RUNX1T1-RUNX1 fusion.	('break apart', 'Phenotype', 'HP:0001061', (113, 124))	('MLL', 'Gene', (174, 177))	('MLL', 'Gene', '4297', (174, 177))	('KMT2A', 'Gene', (167, 172))	('CBFB', 'Gene', (183, 187))	('rearrangements', 'Var', (149, 163))	('KMT2A', 'Gene', '4297', (167, 172))	('RUNX1', 'Gene', (260, 265))	('RUNX1', 'Gene', (252, 257))	('RUNX1', 'Gene', '861', (252, 257))	('RUNX1', 'Gene', '861', (260, 265))
140000	30922345	FISH analysis on 4 mum FFPE slides identified a KMT2A (MLL) gene rearrangement, a recurrent genetic abnormality in MS, in 89.5% of cells examined in this case (Fig.	('genetic abnormality', 'Disease', (92, 111))	('genetic abnormality', 'Disease', 'MESH:D030342', (92, 111))	('rearrangement', 'Var', (65, 78))	('MLL', 'Gene', '4297', (55, 58))	('KMT2A', 'Gene', (48, 53))	('MLL', 'Gene', (55, 58))	('KMT2A', 'Gene', '4297', (48, 53))
140001	30922345	FISH analysis was negative for CBFB rearrangement or RUNX1T1-RUNX1 fusion.	('RUNX1', 'Gene', (53, 58))	('RUNX1', 'Gene', (61, 66))	('CBFB', 'Gene', (31, 35))	('RUNX1', 'Gene', '861', (53, 58))	('RUNX1', 'Gene', '861', (61, 66))	('rearrangement', 'Var', (36, 49))
140002	30922345	Additional next generation sequencing (NGS) analysis performed by Foundation Medicine revealed multiple genomic alterations including FLT3 S451F, CHEK2 T367 fs*15, PTPN11 A72V, RAD21 N462 fs*1, and most importantly, an KMT2A-ELL fusion.	('PTPN11', 'Gene', '5781', (164, 170))	('S451F', 'Mutation', 'p.S451F', (139, 144))	('CHEK2', 'Gene', '11200', (146, 151))	('RAD21', 'Gene', (177, 182))	('PTPN11', 'Gene', (164, 170))	('ELL', 'Gene', '8178', (225, 228))	('CHEK2', 'Gene', (146, 151))	('FLT3', 'Gene', '2322', (134, 138))	('RAD21', 'Gene', '5885', (177, 182))	('KMT2A', 'Gene', (219, 224))	('A72V', 'Mutation', 'rs121918454', (171, 175))	('T367 fs', 'Mutation', 'rs555607708', (152, 159))	('S451F', 'Var', (139, 144))	('ELL', 'Gene', (225, 228))	('KMT2A', 'Gene', '4297', (219, 224))	('FLT3', 'Gene', (134, 138))
140012	30922345	The presence of myeloid precursor markers such as CD34, CD117, and MPO, if present, would support a diagnosis MS.	('CD34', 'Gene', (50, 54))	('CD34', 'Gene', '947', (50, 54))	('CD117', 'Gene', '3815', (56, 61))	('CD117', 'Gene', (56, 61))	('MPO', 'Gene', (67, 70))	('presence', 'Var', (4, 12))	('MPO', 'Gene', '4353', (67, 70))
140013	30922345	Aberrant expression of CD56 would also favor MS, but rare cases of HS can also express CD56.	('CD56', 'Gene', '4684', (87, 91))	('CD56', 'Gene', (23, 27))	('Aberrant', 'Var', (0, 8))	('favor', 'PosReg', (39, 44))	('CD56', 'Gene', (87, 91))	('CD56', 'Gene', '4684', (23, 27))
140015	30922345	Previous studies have suggested that MS is more likely to be associated with certain translocations such as CBF family genes or KMT2A (MLL) rearrangements.	('rearrangements', 'Var', (140, 154))	('KMT2A', 'Gene', (128, 133))	('CBF family genes', 'Gene', (108, 124))	('KMT2A', 'Gene', '4297', (128, 133))	('translocations', 'Var', (85, 99))	('MLL', 'Gene', (135, 138))	('associated', 'Reg', (61, 71))	('MLL', 'Gene', '4297', (135, 138))
140016	30922345	AML with KMT2A rearrangements involves a number of translocations of the KMT2A gene with different partners.	('KMT2A', 'Gene', '4297', (73, 78))	('KMT2A', 'Gene', '4297', (9, 14))	('KMT2A', 'Gene', (9, 14))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('rearrangements', 'Var', (15, 29))	('translocations', 'MPA', (51, 65))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('AML', 'Disease', (0, 3))	('KMT2A', 'Gene', (73, 78))
140018	30922345	The t(11;19)(q23.3;p13.1) translocation, involving the KMT2A and ELL genes, is a recurrent abnormality in AML, acute lymphoblastic leukemia and mixed phenotype acute leukemia.	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (111, 139))	('AML', 'Disease', 'MESH:D015470', (106, 109))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (111, 139))	('t(11;19)(q23.3;p13.1)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 25))	('AML', 'Phenotype', 'HP:0004808', (106, 109))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (117, 139))	('AML', 'Disease', (106, 109))	('KMT2A', 'Gene', '4297', (55, 60))	('leukemia', 'Disease', 'MESH:D007938', (166, 174))	('leukemia', 'Disease', (166, 174))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('KMT2A', 'Gene', (55, 60))	('ELL', 'Gene', '8178', (65, 68))	('ELL', 'Gene', (65, 68))	('acute leukemia', 'Phenotype', 'HP:0002488', (160, 174))	('leukemia', 'Disease', 'MESH:D007938', (131, 139))	('acute lymphoblastic leukemia', 'Disease', (111, 139))	('t(11', 'Var', (4, 8))	('leukemia', 'Disease', (131, 139))
140022	30922345	NPM1, NRAS, and DNMT3A are found to be most frequently mutated in AML.	('AML', 'Phenotype', 'HP:0004808', (66, 69))	('DNMT3A', 'Gene', '1788', (16, 22))	('AML', 'Disease', (66, 69))	('DNMT3A', 'Gene', (16, 22))	('mutated', 'Var', (55, 62))	('AML', 'Disease', 'MESH:D015470', (66, 69))	('NPM1', 'Gene', (0, 4))	('NRAS', 'Gene', (6, 10))	('NPM1', 'Gene', '4869', (0, 4))	('NRAS', 'Gene', '4893', (6, 10))
140024	30922345	In our case, in addition to the KMT2A-ELL fusion, mutations associated with myeloid neoplasms, such as FLT3 and PTPN11, were also detected, indicating cooperative roles of these genetic alterations in the development of this MS case.	('myeloid neoplasms', 'Disease', 'MESH:D007951', (76, 93))	('FLT3', 'Gene', (103, 107))	('PTPN11', 'Gene', (112, 118))	('myeloid neoplasm', 'Phenotype', 'HP:0012324', (76, 92))	('neoplasms', 'Phenotype', 'HP:0002664', (84, 93))	('KMT2A', 'Gene', (32, 37))	('mutations', 'Var', (50, 59))	('myeloid neoplasms', 'Disease', (76, 93))	('ELL', 'Gene', '8178', (38, 41))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (76, 93))	('ELL', 'Gene', (38, 41))	('KMT2A', 'Gene', '4297', (32, 37))	('FLT3', 'Gene', '2322', (103, 107))	('neoplasm', 'Phenotype', 'HP:0002664', (84, 92))	('PTPN11', 'Gene', '5781', (112, 118))	('associated', 'Reg', (60, 70))
140026	30922345	Mutations in PTPN11 result in activated MAPK signaling.	('PTPN11', 'Gene', '5781', (13, 19))	('PTPN11', 'Gene', (13, 19))	('MAPK', 'Gene', '5594', (40, 44))	('activated', 'PosReg', (30, 39))	('Mutations', 'Var', (0, 9))	('MAPK', 'Gene', (40, 44))
140027	30922345	Rare cases of HS with PTPN11 mutations have been reported and showed response to the MEK inhibitor trametinib that blocks the RAS/MAPK pathway.	('MAPK', 'Gene', (130, 134))	('PTPN11', 'Gene', (22, 28))	('MAPK', 'Gene', '5594', (130, 134))	('MEK', 'Gene', '5609', (85, 88))	('trametinib', 'Chemical', 'MESH:C560077', (99, 109))	('mutations', 'Var', (29, 38))	('blocks', 'NegReg', (115, 121))	('PTPN11', 'Gene', '5781', (22, 28))	('MEK', 'Gene', (85, 88))
140028	30922345	The OncoScan SNP microarray analysis also revealed muliptle chromosomal gains and losses along with the KMT2A/ELL fusion, inidicative of the presence of complex aberrations that are known to be associated with meyolid neoplasms, e.g.	('KMT2A', 'Gene', (104, 109))	('gains', 'PosReg', (72, 77))	('KMT2A', 'Gene', '4297', (104, 109))	('ELL', 'Gene', '8178', (110, 113))	('neoplasms', 'Phenotype', 'HP:0002664', (218, 227))	('ELL', 'Gene', (110, 113))	('neoplasms', 'Disease', 'MESH:D009369', (218, 227))	('neoplasms', 'Disease', (218, 227))	('losses', 'NegReg', (82, 88))	('neoplasm', 'Phenotype', 'HP:0002664', (218, 226))	('muliptle', 'Var', (51, 59))
140030	30922345	The t(14;18) and trisomy 8 have been reported in rare cases of HS arising in the setting of previously diagnosed follicular lymphoma or chronic myelomonocytic leukemia, probably from a common neoplastic precursor.	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('chronic myelomonocytic leukemia', 'Disease', (136, 167))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (136, 167))	('HS arising', 'Disease', (63, 73))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (136, 167))	('follicular lymphoma', 'Disease', 'MESH:D008224', (113, 132))	('follicular lymphoma', 'Disease', (113, 132))	('trisomy', 'Var', (17, 24))
140033	30922345	The presence of BRAF mutation would support the diagnosis of histiocytic neoplasm as BRAF mutations are generally considered not present in acute monocytic/monoblastic leukemia.	('monoblastic leukemia', 'Disease', 'MESH:D007948', (156, 176))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('neoplasm', 'Disease', (73, 81))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('neoplasm', 'Phenotype', 'HP:0002664', (73, 81))	('BRAF', 'Gene', (85, 89))	('mutation', 'Var', (21, 29))	('BRAF', 'Gene', '673', (85, 89))	('neoplasm', 'Disease', 'MESH:D009369', (73, 81))	('monoblastic leukemia', 'Disease', (156, 176))
140034	30922345	The present case showed negativity of BRAF mutation.	('mutation', 'Var', (43, 51))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', '673', (38, 42))
140035	30922345	In addition to BRAF, activating ARAF, RAS, and MAP2K1 mutations, as well as activating fusions in BRAF, ALK, and NTRK1 have been reported in histiocytic neoplasms.	('fusions', 'Var', (87, 94))	('MAP2K1', 'Gene', '5604', (47, 53))	('neoplasms', 'Disease', (153, 162))	('MAP2K1', 'Gene', (47, 53))	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (15, 19))	('mutations', 'Var', (54, 63))	('NTRK1', 'Gene', '4914', (113, 118))	('ARAF', 'Gene', '369', (32, 36))	('NTRK1', 'Gene', (113, 118))	('neoplasms', 'Phenotype', 'HP:0002664', (153, 162))	('activating', 'PosReg', (21, 31))	('ARAF', 'Gene', (32, 36))	('ALK', 'Gene', '238', (104, 107))	('activating', 'PosReg', (76, 86))	('ALK', 'Gene', (104, 107))	('neoplasm', 'Phenotype', 'HP:0002664', (153, 161))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('neoplasms', 'Disease', 'MESH:D009369', (153, 162))
140047	29681762	In the POST set, increased p53 N/C ratio was associated with a significantly decreased DFS and DDFS (HR 4.13, p=0.017; HR 4.16, p=0.016), while increased ERCC1 and XPF expression were associated with an improved DFS and DDFS.	('increased', 'PosReg', (17, 26))	('ERCC1', 'Gene', '2067', (154, 159))	('expression', 'MPA', (168, 178))	('DDFS', 'CPA', (95, 99))	('XPF', 'Gene', (164, 167))	('DFS', 'CPA', (87, 90))	('p53 N/C ratio', 'Var', (27, 40))	('ERCC1', 'Gene', (154, 159))	('decreased', 'NegReg', (77, 86))	('increased', 'PosReg', (144, 153))	('XPF', 'Gene', '2072', (164, 167))
140065	29681762	Bone and STS patients with glut-1 overexpression had a significantly worse OS as compared to those without overexpression.	('glut-1', 'Gene', '6513', (27, 33))	('glut-1', 'Gene', (27, 33))	('overexpression', 'Var', (34, 48))	('worse', 'NegReg', (69, 74))
140074	29681762	Heat-induced epitope retrieval (HIER) was performed using a Decloaking Chamber (Biocare Medical, Concord, CA) for all target biomarkers by heating slides to 121 C for either 3 or 6 minutes, in either a citrate-based (pH 6.0) target retrieval solution (S1699, DAKO, Mississauga, Canada), or a Tris/EDTA-based (pH 9.0) target retrieval solution (S2367, DAKO).	('S2367', 'Var', (344, 349))	('Tris', 'Chemical', '-', (292, 296))	('EDTA', 'Chemical', 'MESH:D004492', (297, 301))	('citrate', 'Chemical', 'MESH:D019343', (202, 209))	('S1699', 'Var', (252, 257))
140076	29681762	Slides were washed in Tris-buffered saline and Tween  20 (TBST) wash buffer (S3006, DAKO) and then treated for 60 minutes with either goat anti-rabbit EnVision + (K4011, DAKO) or goat anti-mouse EnVision + (K4007, DAKO) secondary antibody.	('Tween  20', 'Chemical', 'MESH:D011136', (47, 56))	('mouse', 'Species', '10090', (189, 194))	('K4007', 'Var', (207, 212))	('goat', 'Species', '9925', (134, 138))	('goat', 'Species', '9925', (179, 183))	('K4011', 'Var', (163, 168))	('Tris-buffered saline', 'Chemical', '-', (22, 42))	('TBST', 'Chemical', '-', (58, 62))
140097	27697767	A second-generation trabectedin analog lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression.	('trabectedin', 'Chemical', 'MESH:D000077606', (20, 31))	('loss', 'NegReg', (128, 132))	('lurbinectedin', 'Chemical', 'MESH:C568606', (39, 52))	('EWS-FLI1', 'Gene', (105, 113))	('EWS-FLI1', 'Gene', '2130;2313', (105, 113))	('nuclear redistribution', 'MPA', (79, 101))	('PM01183', 'Var', (54, 61))	('expression', 'MPA', (190, 200))	('activity', 'MPA', (136, 144))
140103	27697767	Silencing of EWS-FLI1 activity is incompatible with continued proliferation and places the cell in a dedifferentiated state, which resembles that of mesenchymal stem cells.	('activity', 'MPA', (22, 30))	('Silencing', 'Var', (0, 9))	('EWS-FLI1', 'Gene', '2130;2313', (13, 21))	('EWS-FLI1', 'Gene', (13, 21))
140142	27697767	Transformation and differential expression analyses were conducted using the limma package v 3.28.7 in R and are available (SRA accession: SRP080099).The EWS-FLI1 gene signature consists of all genes in common from two data sets: a meta-analysis and a list of differentially expressed genes obtained by expression profiling following silencing of EWS-FLI1 in 5 cell lines.	('EWS-FLI1', 'Gene', '2130;2313', (347, 355))	('silencing', 'Var', (334, 343))	('EWS-FLI1', 'Gene', (154, 162))	('EWS-FLI1', 'Gene', '2130;2313', (154, 162))	('EWS-FLI1', 'Gene', (347, 355))
140155	27697767	In order to show that the mislocalization of EWS-FLI1 induced by lurbinectedin leads to a loss in EWS-FLI1 activity, we demonstrated that 5 nmol/L lurbinectedin suppressed an EWS-FLI1-driven (NR0B1) luciferase reporter to 42% of control (Fig.	('mislocalization', 'MPA', (26, 41))	('loss', 'NegReg', (90, 94))	('activity', 'MPA', (107, 115))	('lurbinectedin', 'Chemical', 'MESH:C568606', (65, 78))	('EWS-FLI1', 'Gene', (98, 106))	('EWS-FLI1', 'Gene', (175, 183))	('suppressed', 'NegReg', (161, 171))	('EWS-FLI1', 'Gene', '2130;2313', (98, 106))	('EWS-FLI1', 'Gene', (45, 53))	('lurbinectedin', 'Var', (147, 160))	('EWS-FLI1', 'Gene', '2130;2313', (175, 183))	('EWS-FLI1', 'Gene', '2130;2313', (45, 53))	('lurbinectedin', 'Chemical', 'MESH:C568606', (147, 160))
140166	27697767	Further, the EWS-FLI1 induced gene signature was significantly enriched (p=0.006) within the differentially expressed genes (adjusted p < 0.05), suggesting that drug treatment disrupts aberrant EWS-FLI1 induction of gene expression.	('induction of gene expression', 'MPA', (203, 231))	('EWS-FLI1', 'Gene', (194, 202))	('aberrant', 'Var', (185, 193))	('EWS-FLI1', 'Gene', '2130;2313', (194, 202))	('EWS-FLI1', 'Gene', (13, 21))	('EWS-FLI1', 'Gene', '2130;2313', (13, 21))	('disrupts', 'NegReg', (176, 184))
140176	27697767	The treatment resulted in the marked suppression of proliferation and a sub-nanomolar IC50 that was similar to that of trabectedin (Supplementary Fig.	('proliferation', 'CPA', (52, 65))	('IC50', 'MPA', (86, 90))	('sub-nanomolar', 'Var', (72, 85))	('suppression', 'NegReg', (37, 48))	('trabectedin', 'Chemical', 'MESH:D000077606', (119, 130))
140179	27697767	SN38 enhances the transcriptional repression of EWS-FLI1 by trabectedin.	('EWS-FLI1', 'Gene', '2130;2313', (48, 56))	('SN38', 'Var', (0, 4))	('enhances', 'PosReg', (5, 13))	('transcriptional repression', 'MPA', (18, 44))	('trabectedin', 'Chemical', 'MESH:D000077606', (60, 71))	('EWS-FLI1', 'Gene', (48, 56))
140204	27697767	Indeed, 60 minutes of exposure to lurbinectedin led to the long term suppression of proliferation that was accompanied by the robust induction of the fat differentiation genes CEBPA and PPARG as well as evidence of accumulation of neutral lipid in the Ewing sarcoma cells as measured by two different neutral lipid stains, Oil RedO and BODIPY (Fig 6 B, C, D).	('lurbinectedin', 'Chemical', 'MESH:C568606', (34, 47))	('CEBPA', 'Gene', '1050', (176, 181))	('Ewing sarcoma', 'Disease', (252, 265))	('suppression', 'NegReg', (69, 80))	('lipid', 'Chemical', 'MESH:D008055', (309, 314))	('PPARG', 'Gene', (186, 191))	('PPARG', 'Gene', '5468', (186, 191))	('lurbinectedin', 'Var', (34, 47))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (252, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (252, 265))	('proliferation', 'CPA', (84, 97))	('neutral lipid', 'MPA', (231, 244))	('lipid', 'Chemical', 'MESH:D008055', (239, 244))	('accumulation', 'PosReg', (215, 227))	('CEBPA', 'Gene', (176, 181))	('induction', 'PosReg', (133, 142))	('Oil Red', 'Chemical', 'MESH:C009213', (323, 330))
140272	22523704	The most important finding of this study was that POG grade 3 tumors fared much worse (52% survival at 5 years) as compared with POG grade 1 or 2 sarcomas (92% 5-year survival) defining tumor grade as an important prognostic factor influencing outcome.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('tumor', 'Disease', (186, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('sarcomas', 'Disease', (146, 154))	('POG grade 3', 'Var', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
140292	22523704	Factors associated with local recurrence were microscopic residual disease, large tumor size, and intra-abdominal disease, whereas improved local control was associated with the use of radiation therapy.	('microscopic', 'Var', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('intra-abdominal disease', 'Disease', 'MESH:D018784', (98, 121))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('intra-abdominal disease', 'Disease', (98, 121))	('local', 'CPA', (24, 29))	('tumor', 'Disease', (82, 87))
140307	22523704	For example, in Spunt's retrospective analysis of prognostic factors in pediatric NRSTS, POG grade 1 and 2 tumors were combined into a low grade group and compared with POG grade 3 high-grade tumors.	('POG grade 1', 'Var', (89, 100))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
140349	22523704	An additional concern when considering the administration of radiation therapy may be the predilection of the patient to develop a second cancer as a result of carrying an underlying germline mutation where ionizing radiation may upregulate critical molecular pathways associated with tumorigenesis.	('cancer', 'Disease', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumor', 'Disease', (285, 290))	('critical molecular pathways', 'Pathway', (241, 268))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('patient', 'Species', '9606', (110, 117))	('germline', 'Var', (183, 191))	('upregulate', 'PosReg', (230, 240))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
140350	22523704	One of the more common non-rhabdomyosarcomas in the pediatric age group, MPNST, has been associated with underlying germline mutation in NF1 in about 50% of patients.	('associated', 'Reg', (89, 99))	('MPNST', 'Phenotype', 'HP:0100697', (73, 78))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (27, 43))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (27, 44))	('rhabdomyosarcomas', 'Disease', (27, 44))	('germline mutation', 'Var', (116, 133))	('patients', 'Species', '9606', (157, 165))	('NF1', 'Gene', (137, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('NF1', 'Gene', '4763', (137, 140))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (27, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('MPNST', 'Disease', (73, 78))
140379	31954538	Inactivating SMARCA4 mutations are thought to be the driving molecular events in the majority of these tumors.	('SMARCA4', 'Gene', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('SMARCA4', 'Gene', '6597', (13, 20))	('Inactivating', 'Var', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('mutations', 'Var', (21, 30))
140380	31954538	Here, we report the clinical course of a family with germline SMARCA4 mutation and compare large cohorts of these rare tumor types.	('tumor', 'Disease', (119, 124))	('SMARCA4', 'Gene', (62, 69))	('SMARCA4', 'Gene', '6597', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutation', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
140381	31954538	We extracted clinico-pathological medical record data for the family with germline SMARCA4 mutation.	('SMARCA4', 'Gene', '6597', (83, 90))	('mutation', 'Var', (91, 99))	('SMARCA4', 'Gene', (83, 90))
140383	31954538	We identified a single family with an inherited germline SMARCA4 mutation, in which two different family members developed either SCCOHT or SMARCA4-DUS, both of whom died within one year of diagnosis, despite aggressive surgical, chemotherapy and immunotherapy treatment.	('SMARCA4', 'Gene', '6597', (57, 64))	('SMARCA4', 'Gene', (140, 147))	('SMARCA4', 'Gene', '6597', (140, 147))	('died', 'Disease', (166, 170))	('died', 'Disease', 'MESH:D003643', (166, 170))	('mutation', 'Var', (65, 73))	('SMARCA4', 'Gene', (57, 64))
140384	31954538	Retrospective comparative analysis of large SCCOHT (n=48) and SMARCA4-DUS (n=17) cohorts revealed that SCCOHT patients were younger (median age: 28.5 vs. 49.0) and more likely to have germline SMARCA4 alterations (37.5% vs. 11.8%) than SMARCA4-DUS patients.	('SMARCA4', 'Gene', (62, 69))	('SMARCA4', 'Gene', '6597', (193, 200))	('SMARCA4', 'Gene', '6597', (236, 243))	('SMARCA4', 'Gene', '6597', (62, 69))	('SCCOHT', 'Var', (103, 109))	('SMARCA4', 'Gene', (193, 200))	('patients', 'Species', '9606', (248, 256))	('SMARCA4', 'Gene', (236, 243))	('patients', 'Species', '9606', (110, 118))
140386	31954538	Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer, recently described to be oncogenically driven exclusively by somatic and/or germline mutations in SMARCA4 .	('aggressive form of ovarian cancer', 'Disease', (77, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('aggressive form of ovarian cancer', 'Disease', 'MESH:D001523', (77, 110))	('SMARCA4', 'Gene', (210, 217))	('germline mutations', 'Var', (188, 206))	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (11, 33))	('SMARCA4', 'Gene', '6597', (210, 217))	('Small cell carcinoma', 'Phenotype', 'HP:0030357', (0, 20))	('carcinoma of the ovary', 'Disease', (11, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
140387	31954538	Inactivating mutations in SMARCA4 also have been observed in a rare and aggressive form of uterine sarcoma, termed SMARCA4-deficient undifferentiated uterine sarcoma (SMARCA4-DUS, also known as malignant rhabdoid tumor of the uterus) .	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (194, 218))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (91, 106))	('malignant rhabdoid tumor', 'Disease', (194, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('tumor of the uterus', 'Phenotype', 'HP:0010784', (213, 232))	('SMARCA4', 'Gene', (167, 174))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('Inactivating mutations', 'Var', (0, 22))	('sarcoma', 'Disease', (99, 106))	('SMARCA4', 'Gene', '6597', (115, 122))	('SMARCA4-deficient undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (115, 165))	('SMARCA4', 'Gene', '6597', (26, 33))	('SMARCA4-deficient undifferentiated uterine sarcoma', 'Disease', (115, 165))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (150, 165))	('sarcoma', 'Disease', (158, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('SMARCA4', 'Gene', '6597', (167, 174))	('sarcoma', 'Disease', 'MESH:D012509', (158, 165))	('SMARCA4', 'Gene', (115, 122))	('SMARCA4', 'Gene', (26, 33))	('observed', 'Reg', (49, 57))
140389	31954538	Thus, interest has grown in further characterizing these SMARCA4 mutations to guide development of targeted therapies and genetic counseling recommendations for patients and their family members.	('SMARCA4', 'Gene', '6597', (57, 64))	('patients', 'Species', '9606', (161, 169))	('mutations', 'Var', (65, 74))	('SMARCA4', 'Gene', (57, 64))
140392	31954538	BRG1 (encoded by the SMARCA4 gene), a protein subunit of the SWI/SNF complex, is the most commonly mutated chromatin remodeling ATPase in cancer , occurring in lung adenocarcinomas , lymphomas , and medulloblastomas , which are associated with a poor prognosis .	('cancer', 'Disease', (138, 144))	('medulloblastomas', 'Disease', 'MESH:D008527', (199, 215))	('SMARCA4', 'Gene', '6597', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (160, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('occurring', 'Reg', (147, 156))	('lymphomas', 'Disease', (183, 192))	('lung adenocarcinomas', 'Disease', (160, 180))	('mutated', 'Var', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('BRG1', 'Gene', '6597', (0, 4))	('AT', 'Disease', 'None', (128, 130))	('SMARCA4', 'Gene', (21, 28))	('medulloblastomas', 'Disease', (199, 215))	('BRG1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('lymphomas', 'Disease', 'MESH:D008223', (183, 192))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (160, 180))	('lymphomas', 'Phenotype', 'HP:0002665', (183, 192))
140393	31954538	Loss of function somatic SMARCA4 mutations have also been described as secondary oncogenic events in microsatellite unstable gynecological carcinomas leading to de-differentiated carcinomas .	('carcinomas', 'Disease', (179, 189))	('SMARCA4', 'Gene', (25, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('SMARCA4', 'Gene', '6597', (25, 32))	('carcinomas', 'Disease', 'MESH:D009369', (139, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('mutations', 'Var', (33, 42))	('microsatellite', 'Var', (101, 115))	('Loss of function', 'NegReg', (0, 16))	('carcinomas', 'Disease', 'MESH:D009369', (179, 189))	('carcinomas', 'Disease', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))
140394	31954538	Germline mutations in SMARCA4 are best described as an inherited variant in rhabdoid tumor predisposition syndrome (RTPS) type 2 (RTPS2; OMIM 613325) .	('Germline mutations', 'Var', (0, 18))	('rhabdoid tumor', 'Disease', (76, 90))	('RTPS2', 'Gene', '6597', (130, 135))	('RTPS2', 'Gene', (130, 135))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('SMARCA4', 'Gene', (22, 29))	('SMARCA4', 'Gene', '6597', (22, 29))
140396	31954538	Genetic profiling has demonstrated these mutations in SCCOHT and SMARCA4-DUS, as well as atypical teratoid rhabdoid tumors (AT/RTs), malignant rhabdoid tumors (MRTs), and aggressive SMARCA4-deficient thoracic sarcomas (SMARCA4-DTS) .	('AT', 'Disease', 'None', (124, 126))	('SMARCA4', 'Gene', '6597', (219, 226))	('SMARCA4', 'Gene', (65, 72))	('aggressive SMARCA4-deficient thoracic sarcomas', 'Disease', 'MESH:D012509', (171, 217))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('SCCOHT', 'Disease', (54, 60))	('mutations', 'Var', (41, 50))	('SMARCA4', 'Gene', (182, 189))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (133, 158))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('rhabdoid tumors', 'Disease', (107, 122))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (107, 122))	('SMARCA4', 'Gene', (219, 226))	('SMARCA4', 'Gene', '6597', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('aggressive SMARCA4-deficient thoracic sarcomas', 'Disease', (171, 217))	('malignant rhabdoid tumors', 'Disease', (133, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (209, 217))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('SMARCA4', 'Gene', '6597', (182, 189))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (143, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
140398	31954538	All of these tumors represent aggressive malignant rhabdoid tumors across varying tissue types associated with SMARCA4 inactivation, though the genetic, histological, and phenotypic relationships is still an active area of research.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('aggressive malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (30, 66))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('aggressive malignant rhabdoid tumors', 'Disease', (30, 66))	('SMARCA4', 'Gene', (111, 118))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('SMARCA4', 'Gene', '6597', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('associated', 'Reg', (95, 105))	('inactivation', 'Var', (119, 131))
140400	31954538	In addition, we expand upon knowledge regarding known SMARCA4 variants in SCCOHT and SMARCA4-DUS with analysis of variants within large cohorts of these tumors.	('SMARCA4', 'Gene', (85, 92))	('SMARCA4', 'Gene', '6597', (54, 61))	('SMARCA4', 'Gene', '6597', (85, 92))	('variants', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('SMARCA4', 'Gene', (54, 61))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
140402	31954538	Understanding inherited mutations associated with SMARCA4 is critical to providing appropriate genetic counseling and treatment recommendations for SCCOHT and SMARCA4-DUS.	('SMARCA4', 'Gene', (159, 166))	('SMARCA4', 'Gene', '6597', (159, 166))	('SMARCA4', 'Gene', (50, 57))	('mutations', 'Var', (24, 33))	('SMARCA4', 'Gene', '6597', (50, 57))
140403	31954538	We extracted clinical and pathologic data for a mother and daughter affected by an inherited germline SMARCA4 mutation leading to SMARCA4-DUS and SCCOHT, respectively.	('SMARCA4', 'Gene', (102, 109))	('SMARCA4', 'Gene', (130, 137))	('SMARCA4', 'Gene', '6597', (102, 109))	('leading to', 'Reg', (119, 129))	('mutation', 'Var', (110, 118))	('SCCOHT', 'Disease', (146, 152))	('SMARCA4', 'Gene', '6597', (130, 137))
140414	31954538	SCCOHT cases that did not have a SMARCA4 mutation were excluded.	('mutation', 'Var', (41, 49))	('SMARCA4', 'Gene', (33, 40))	('SMARCA4', 'Gene', '6597', (33, 40))
140418	31954538	To assess whether a SMARCA4 alteration was potentially germline, a validated somatic germline zygosity algorithm was applied to each genomic variant as previously described.	('SMARCA4', 'Gene', (20, 27))	('SMARCA4', 'Gene', '6597', (20, 27))	('alteration', 'Var', (28, 38))
140428	31954538	Single gene germline testing of SMARCA4 identified a deleterious mutation c.1831C>T (p.Gln611*).	('c.1831C>T (p.Gln611*', 'Var', (74, 94))	('c.1831C>T', 'Mutation', 'c.1831C>T', (74, 83))	('SMARCA4', 'Gene', (32, 39))	('p.Gln611*', 'Mutation', 'p.Q611*', (85, 94))	('SMARCA4', 'Gene', '6597', (32, 39))
140444	31954538	Germline genetic testing was performed for 23 genes associated with breast and gynecologic cancers including BRCA1/2, TP53, MMR genes, and SMARCA4 based on the patient's personal and family history and identified only the same SMARCA4 mutation previously identified in the patient's daughter (c.1831C>T (p.Gln611*)).	('patient', 'Species', '9606', (273, 280))	('c.1831C>T', 'Mutation', 'c.1831C>T', (293, 302))	('TP53', 'Gene', (118, 122))	('patient', 'Species', '9606', (160, 167))	('c.1831C>T (p.Gln611*', 'Var', (293, 313))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('SMARCA4', 'Gene', '6597', (227, 234))	('SMARCA4', 'Gene', '6597', (139, 146))	('breast', 'Disease', (68, 74))	('BRCA1/2', 'Gene', (109, 116))	('TP53', 'Gene', '7157', (118, 122))	('MMR genes', 'Gene', (124, 133))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('SMARCA4', 'Gene', (227, 234))	('p.Gln611*', 'Mutation', 'p.Q611*', (304, 313))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SMARCA4', 'Gene', (139, 146))	('BRCA1/2', 'Gene', '672;675', (109, 116))
140448	31954538	A germline SMARCA4 c.1831C>T (p.Gln611*) mutation was identified in both patients.	('c.1831C>T (p.Gln611*', 'Var', (19, 39))	('c.1831C>T', 'Mutation', 'c.1831C>T', (19, 28))	('SMARCA4', 'Gene', (11, 18))	('SMARCA4', 'Gene', '6597', (11, 18))	('p.Gln611*', 'Mutation', 'p.Q611*', (30, 39))	('patients', 'Species', '9606', (73, 81))
140451	31954538	An additional somatic frameshift variant of unknown significance in SMARCA4 (p.K1602fs*8) was identified in the mother's tumor tissue.	('SMARCA4', 'Gene', '6597', (68, 75))	('p.K1602fs*8', 'Mutation', 'p.K1602fsX8', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('p.K1602fs*8', 'Var', (77, 88))	('SMARCA4', 'Gene', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
140456	31954538	Though some of these missense variants occur in known cancer-related genes (e.g.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('missense variants', 'Var', (21, 38))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (54, 60))
140466	31954538	Fewer patients in the SMARCA4-DUS cohort were predicted to have germline SMARCA4 mutations, representing only 11.8% of the population (Table 3).	('SMARCA4', 'Gene', (73, 80))	('SMARCA4', 'Gene', '6597', (73, 80))	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (81, 90))	('SMARCA4', 'Gene', (22, 29))	('SMARCA4', 'Gene', '6597', (22, 29))
140469	31954538	All of these mutations are predicted to lead to loss of function of the SMARCA4 protein.	('SMARCA4', 'Gene', (72, 79))	('SMARCA4', 'Gene', '6597', (72, 79))	('protein', 'Protein', (80, 87))	('loss of function', 'NegReg', (48, 64))	('mutations', 'Var', (13, 22))
140470	31954538	This study details the clinical course of a mother-daughter pair with inherited SMARCA4 germline mutation leading to two aggressive and rare rhabdoid tumors - SCCOHT and SMARCA4-DUS.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (141, 156))	('SMARCA4', 'Gene', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SMARCA4', 'Gene', (170, 177))	('mutation', 'Var', (97, 105))	('SMARCA4', 'Gene', '6597', (170, 177))	('rhabdoid tumors', 'Disease', (141, 156))	('leading to', 'Reg', (106, 116))	('SMARCA4', 'Gene', '6597', (80, 87))
140476	31954538	There is a non-significant difference in age between SCCOHT and SMARCA4-DUS patients with germline versus somatic variants in SMARCA4, suggesting that germline mutations may affect patients at slightly younger ages, consistent with previous reports .	('patients', 'Species', '9606', (76, 84))	('SMARCA4', 'Gene', (126, 133))	('SMARCA4', 'Gene', '6597', (64, 71))	('SMARCA4', 'Gene', '6597', (126, 133))	('variants', 'Var', (114, 122))	('patients', 'Species', '9606', (181, 189))	('SMARCA4', 'Gene', (64, 71))
140477	31954538	Both patients harbored a nonsense mutation in SMARCA4, expected to lead to decreased production of functional BRG1 protein.	('SMARCA4', 'Gene', '6597', (46, 53))	('BRG1', 'Gene', '6597', (110, 114))	('patients', 'Species', '9606', (5, 13))	('production of functional', 'MPA', (85, 109))	('harbored', 'Reg', (14, 22))	('nonsense', 'Var', (25, 33))	('SMARCA4', 'Gene', (46, 53))	('BRG1', 'Gene', (110, 114))	('decreased', 'NegReg', (75, 84))
140478	31954538	Though this mutation has not been specifically described in the literature in other patients, the vast majority of mutations in the SMARCA4 gene associated with pathologically-confirmed SCCOHT are frameshift, splice-site, or nonsense mutations , which are expected to produce truncated, non-functional protein.	('splice-site', 'Var', (209, 220))	('mutations', 'Var', (115, 124))	('nonsense', 'Var', (225, 233))	('patients', 'Species', '9606', (84, 92))	('associated', 'Reg', (145, 155))	('SCCOHT', 'Disease', (186, 192))	('frameshift', 'Var', (197, 207))	('SMARCA4', 'Gene', (132, 139))	('SMARCA4', 'Gene', '6597', (132, 139))
140487	31954538	This result is especially interesting given the association between loss of PBRM1 - a member of the SWI/SNF protein family closely related to SMARCA4 - and sensitivity to anti-PD-1 immune checkpoint therapy in renal cell carcinoma, another generally low-mutational-burden cancer with a prominent immune infiltrate .	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (210, 230))	('SMARCA4', 'Gene', (142, 149))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (210, 230))	('PD-1', 'Gene', (176, 180))	('renal cell carcinoma', 'Disease', (210, 230))	('cancer', 'Disease', (272, 278))	('SMARCA4', 'Gene', '6597', (142, 149))	('loss', 'Var', (68, 72))	('PBRM1', 'Gene', (76, 81))	('PBRM1', 'Gene', '55193', (76, 81))	('PD-1', 'Gene', '9825', (176, 180))
140488	31954538	Reports of families affected by germline SMARCA4 mutations are rare in the literature .	('SMARCA4', 'Gene', '6597', (41, 48))	('mutations', 'Var', (49, 58))	('SMARCA4', 'Gene', (41, 48))
140490	31954538	Given the potential severity of the phenotype and autosomal dominant inheritance pattern, identifying germline SMARCA4 as a driver of a hereditary cancer syndrome has important implications on treatment and counseling of patients.	('hereditary cancer syndrome', 'Disease', (136, 162))	('patients', 'Species', '9606', (221, 229))	('germline', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('SMARCA4', 'Gene', (111, 118))	('SMARCA4', 'Gene', '6597', (111, 118))	('hereditary cancer syndrome', 'Disease', 'MESH:D061325', (136, 162))
140492	31954538	The reliability of the medical management recommendations is further limited by insufficient information regarding the penetrance and lifetime cancer risks of carriers of these mutations.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (177, 186))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('carriers', 'Reg', (159, 167))
140507	31954538	SCCOHT and SMARCA4-DUS are morphological and genetically related tumors driven by loss of function mutations in SMARCA4 These tumors affect young women and generally carry a poor prognosis Identification of germline mutations in SMARCA4 is critical to providing counseling and treatment to affected individuals	('SMARCA4', 'Gene', '6597', (229, 236))	('loss of function', 'NegReg', (82, 98))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('SMARCA4', 'Gene', '6597', (112, 119))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('SMARCA4', 'Gene', (11, 18))	('SMARCA4', 'Gene', '6597', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (65, 71))	('mutations', 'Var', (99, 108))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('SMARCA4', 'Gene', (229, 236))	('SMARCA4', 'Gene', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('women', 'Species', '9606', (146, 151))
140553	33322259	The patient was diagnosed with surgical stage IIIA1 according to the latest International Federation of Gynecology and Obstetrics (FIGO) classification, and pT2aN1bMx, according to the TNM classification.	('patient', 'Species', '9606', (4, 11))	('pT2aN1bMx', 'Var', (157, 166))	('TNM', 'Gene', '10178', (185, 188))	('TNM', 'Gene', (185, 188))
140566	33322259	Risk factors are the same as for ovarian carcinomas and sarcomas: obesity, nulliparity, exogenous oestrogen, radiotherapy and long-term Tamoxifen use.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('nulliparity', 'Disease', (75, 86))	('ovarian carcinomas and sarcomas', 'Disease', 'MESH:D010051', (33, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('obesity', 'Phenotype', 'HP:0001513', (66, 73))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (33, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('exogenous', 'Var', (88, 97))	('obesity', 'Disease', 'MESH:D009765', (66, 73))	('radiotherapy', 'Disease', (109, 121))	('Tamoxifen', 'Chemical', 'MESH:D013629', (136, 145))	('obesity', 'Disease', (66, 73))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (33, 51))
140587	33322259	Although the mutation of the p53 gene does not always cause p53 immunostaining, most of the immunostained for p53 tumours have a p53 gene mutation.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumours', 'Disease', (114, 121))	('p53', 'Gene', (110, 113))	('mutation', 'Var', (13, 21))	('p53', 'Gene', '7157', (110, 113))	('p53', 'Gene', (29, 32))	('p53', 'Gene', (60, 63))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('mutation', 'Var', (138, 146))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (29, 32))	('p53', 'Gene', '7157', (129, 132))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('p53', 'Gene', '7157', (60, 63))
140590	33322259	Other studies, which support carcinosarcoma theory, include clonality studies, genomic analysis, loss of heterozygosity, gene mutations, and expressions.	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('loss of heterozygosity', 'Var', (97, 119))	('carcinosarcoma', 'Disease', 'MESH:D002296', (29, 43))	('carcinosarcoma', 'Disease', (29, 43))
140617	33322259	The authors concluded that median progression free-survival (PFS) was longer in patients treated with carboplatin/paclitaxel, whereas overall survival (OS) was similar for all treatment groups.	('carboplatin', 'Chemical', 'MESH:D016190', (102, 113))	('patients', 'Species', '9606', (80, 88))	('progression', 'MPA', (34, 45))	('paclitaxel', 'Chemical', 'MESH:D017239', (114, 124))	('longer', 'PosReg', (70, 76))	('carboplatin/paclitaxel', 'Var', (102, 124))
140649	33322259	Although some reports showed that descending colon, ischemia or necrosis might occur after high ligation of the IMA (especially for patients with advanced rectal or sigmoid cancer, cerebrovascular disease, and hypertension), in patients without general disease they are less likely to occur.	('descending colon', 'Disease', (34, 50))	('ischemia', 'Disease', 'MESH:D007511', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('necrosis', 'Disease', 'MESH:D009336', (64, 72))	('descending colon', 'Phenotype', 'HP:0012851', (34, 50))	('cancer', 'Disease', (173, 179))	('cerebrovascular disease', 'Disease', 'MESH:D002561', (181, 204))	('patients', 'Species', '9606', (228, 236))	('hypertension', 'Disease', 'MESH:D006973', (210, 222))	('cerebrovascular disease', 'Disease', (181, 204))	('necrosis', 'Disease', (64, 72))	('high ligation', 'Var', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('hypertension', 'Disease', (210, 222))	('advanced rectal', 'Disease', (146, 161))	('hypertension', 'Phenotype', 'HP:0000822', (210, 222))	('patients', 'Species', '9606', (132, 140))	('ischemia', 'Disease', (52, 60))
140666	33322259	Adhesion between the small bowel and the abdominal aorta leading to obstructive ileus is a possible complication after para-aortic lymph node dissection.	('Adhesion', 'Var', (0, 8))	('para-aortic lymph', 'Disease', 'MESH:D001018', (119, 136))	('ileus', 'Phenotype', 'HP:0002595', (80, 85))	('obstructive ileus', 'Disease', (68, 85))	('para-aortic lymph', 'Disease', (119, 136))
140676	31921698	The recently recognized subtype, spindle cell and sclerosing RMS is a rare variant of RMS characterized by recurring fusions of VGLL2 or NOCA2 and has a favorable prognosis, so it is treated without the aggressive multimodal regimens used to treat ARMS and ERMS.	('fusions', 'Var', (117, 124))	('RMS', 'Disease', 'MESH:D012208', (258, 261))	('RMS', 'Disease', (258, 261))	('RMS', 'Disease', (86, 89))	('RMS', 'Disease', 'MESH:D012208', (249, 252))	('NOCA2', 'Gene', (137, 142))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('ERMS', 'CellLine', 'CVCL:M564', (257, 261))	('VGLL2', 'Gene', '245806', (128, 133))	('RMS', 'Disease', 'MESH:D012208', (61, 64))	('RMS', 'Disease', (249, 252))	('RMS', 'Disease', (61, 64))	('RMS', 'Disease', 'MESH:D012208', (86, 89))	('VGLL2', 'Gene', (128, 133))
140678	31921698	The majority of ARMS tumors harbor a recurrent chromosomal translocation, t(2;13)(q35;q14) or t(1;13)(p36;q14).	('t(2;13)(q35;q14', 'Var', (74, 89))	('RMS', 'Disease', (17, 20))	('tumors', 'Disease', (21, 27))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (94, 110))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (74, 90))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (37, 72))	('t(1;13)(p36;q14', 'Var', (94, 109))	('RMS', 'Disease', 'MESH:D012208', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
140686	31921698	The oncogenic capacity of the PAX-FOXO1 fusion proteins has been well characterized by multiple studies and has been shown to act as a dominant-acting oncogene in driving tumorigenesis in fusion-positive RMS (FP RMS).	('RMS', 'Disease', (212, 215))	('FOXO1', 'Gene', '2308', (34, 39))	('RMS', 'Disease', 'MESH:D012208', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('FOXO1', 'Gene', (34, 39))	('fusion-positive', 'Var', (188, 203))	('RMS', 'Disease', (204, 207))	('RMS', 'Disease', 'MESH:D012208', (212, 215))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
140687	31921698	On the other hand, fusion-negative RMS (FN RMS) is characterized by higher rates of aneuploidy and single-nucleotide variations, with the RAS pathway most commonly activated in the majority of FN tumors.	('RMS', 'Disease', 'MESH:D012208', (35, 38))	('FN tumors', 'Disease', (193, 202))	('RMS', 'Disease', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('fusion-negative', 'Var', (19, 34))	('aneuploidy', 'Disease', (84, 94))	('activated', 'PosReg', (164, 173))	('RMS', 'Disease', 'MESH:D012208', (43, 46))	('FN tumors', 'Disease', 'MESH:D009369', (193, 202))	('RMS', 'Disease', (43, 46))	('aneuploidy', 'Disease', 'MESH:D000782', (84, 94))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('single-nucleotide variations', 'Var', (99, 127))	('N', 'Chemical', 'MESH:D009584', (194, 195))	('RAS pathway', 'Pathway', (138, 149))
140707	31921698	After three decades of controversy regarding the inclusion of doxorubicin in the chemotherapy regimen, an open-label phase 3 trial (EpSSG RMS 2005) conclusively showed that addition of doxorubicin to the standard IVA backbone did not improve patient outcomes in high-risk rhabdomyosarcoma.	('doxorubicin', 'Var', (185, 196))	('RMS', 'Disease', (138, 141))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (272, 288))	('doxorubicin', 'Chemical', 'MESH:D004317', (62, 73))	('doxorubicin', 'Chemical', 'MESH:D004317', (185, 196))	('patient', 'Species', '9606', (242, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (272, 288))	('rhabdomyosarcoma', 'Disease', (272, 288))	('RMS', 'Disease', 'MESH:D012208', (138, 141))
140711	31921698	The alkylating agent, cyclophosphamide used in the VAC chemotherapy regimen is known to cause acute and late effects, including severe myelosuppression, infectious complications, and infertility.	('myelosuppression', 'Disease', 'MESH:D001855', (135, 151))	('myelosuppression', 'Disease', (135, 151))	('infertility', 'Disease', 'MESH:D007246', (183, 194))	('infertility', 'Phenotype', 'HP:0000789', (183, 194))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (22, 38))	('infertility', 'Disease', (183, 194))	('infectious complications', 'Disease', (153, 177))	('cyclophosphamide', 'Var', (22, 38))
140748	31921698	Disappointingly, phase II trials for children with relapsed RMS have not demonstrated meaningful, single-agent activity of targeted inhibitors, such as a monoclonal antibody against IGF-1R (R1507) and a multi-kinase inhibitor, sorafenib.	('IGF-1R', 'Gene', (182, 188))	('RMS', 'Disease', 'MESH:D012208', (60, 63))	('sorafenib', 'Chemical', 'MESH:C471405', (227, 236))	('children', 'Species', '9606', (37, 45))	('IGF-1R', 'Gene', '3480', (182, 188))	('R1507', 'Var', (190, 195))	('RMS', 'Disease', (60, 63))
140757	31921698	One experimental approach is the use of nanoparticle carriers to deliver naked siRNA or antisense oligonucleotides (ASO) into tumor cells to silence specific genes.	('N', 'Chemical', 'MESH:D009584', (82, 83))	('silence', 'NegReg', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('antisense oligonucleotides', 'Var', (88, 114))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
140762	31921698	These new approaches include modulation of the auto-inhibitory state of transcription factors, proteolysis targeting chimeras (PROTACs), use of cysteine reactive inhibitors, and targeting intrinsically disordered regions [reviewed in ].	('proteolysis', 'MPA', (95, 106))	('chimeras', 'Var', (117, 125))	('modulation', 'Var', (29, 39))	('auto-inhibitory', 'MPA', (47, 62))	('cysteine', 'Chemical', 'MESH:D003545', (144, 152))
140772	31921698	Another study reported that the antitumor activity of JQ1 is mediated by a decrease in angiogenic activity, which is consistent with the hypothesis that disruption of the super-enhancer ablates transcriptional output of gene targets, one of which is vascular endothelial growth factor (VEGF).	('disruption', 'Var', (153, 163))	('vascular endothelial growth factor', 'Gene', '7422', (250, 284))	('decrease', 'NegReg', (75, 83))	('VEGF', 'Gene', (286, 290))	('transcriptional output of gene', 'MPA', (194, 224))	('ablates', 'NegReg', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('VEGF', 'Gene', '7422', (286, 290))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('JQ1', 'Gene', (54, 57))	('vascular endothelial growth factor', 'Gene', (250, 284))	('tumor', 'Disease', (36, 41))	('angiogenic activity', 'CPA', (87, 106))
140779	31921698	Other studies have implicated that inhibition of another epigenetic regulator, histone deacetylase (HDAC) has antitumor effects in preclinical RMS models.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('HDAC', 'Gene', '9734', (100, 104))	('RMS', 'Disease', 'MESH:D012208', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('histone deacetylase', 'Gene', '9734', (79, 98))	('tumor', 'Disease', (114, 119))	('histone deacetylase', 'Gene', (79, 98))	('inhibition', 'Var', (35, 45))	('RMS', 'Disease', (143, 146))	('HDAC', 'Gene', (100, 104))
140783	31921698	Beyond disrupting transcriptional complexes to suppress the expression of key oncogenic genes, perturbation with HDAC inhibitors has also been shown to induce transcriptional chaos in cancer cells, driving cells into terminal differentiation or apoptotic cell death.	('terminal differentiation', 'CPA', (217, 241))	('expression', 'MPA', (60, 70))	('transcriptional chaos', 'MPA', (159, 180))	('cancer', 'Disease', (184, 190))	('apoptotic cell death', 'CPA', (245, 265))	('perturbation', 'Var', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('HDAC', 'Gene', (113, 117))	('suppress', 'NegReg', (47, 55))	('HDAC', 'Gene', '9734', (113, 117))	('driving', 'Reg', (198, 205))	('induce', 'Reg', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
140784	31921698	Taken together, these studies illustrate that FP RMS cells are differentially sensitive to the targeted disruption of super-enhancer complexes.	('RMS', 'Disease', 'MESH:D012208', (49, 52))	('RMS', 'Disease', (49, 52))	('disruption', 'Var', (104, 114))
140790	31921698	In one study, a two-armed screening approach of kinome siRNA and small molecules identified that the kinase PLK1 stabilizes the fusion protein by phosphorylating S503.	('PLK1', 'Gene', (108, 112))	('PLK1', 'Gene', '5347', (108, 112))	('S503', 'Var', (162, 166))	('phosphorylating', 'MPA', (146, 161))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('stabilizes', 'MPA', (113, 123))
140791	31921698	Inhibition of PLK1 directly led to ubiquitination of the fusion protein, followed by rapid proteasomal degradation.	('fusion protein', 'Protein', (57, 71))	('ubiquitination', 'MPA', (35, 49))	('Inhibition', 'Var', (0, 10))	('proteasomal degradation', 'MPA', (91, 114))	('PLK1', 'Gene', (14, 18))	('PLK1', 'Gene', '5347', (14, 18))
140795	31921698	Another upstream enzyme, acetyltransferase KAT2B (P/CAF) is known to modulate fusion protein stability by acetylating residues K426 and K429.	('K426', 'Var', (127, 131))	('acetylating', 'MPA', (106, 117))	('P/CAF', 'Gene', (50, 55))	('P/CAF', 'Gene', '8850', (50, 55))	('modulate', 'Reg', (69, 77))	('fusion protein', 'Protein', (78, 92))	('K429', 'Var', (136, 140))
140796	31921698	Other phosphorylation sites are known to control the transcriptional activity of PAX3-FOXO1, including the residues S201 (phosphorylated by the kinase GSK3beta), S205/S209 (by CK2), and S430 (by CDK4).	('GSK3beta', 'Gene', '2932', (151, 159))	('S430', 'Var', (186, 190))	('PAX3', 'Gene', (81, 85))	('PAX3', 'Gene', '5077', (81, 85))	('S430', 'Chemical', 'MESH:C023540', (186, 190))	('FOXO1', 'Gene', (86, 91))	('GSK3beta', 'Gene', (151, 159))	('S201', 'Var', (116, 120))	('S205/S209', 'Var', (162, 171))	('CDK4', 'Gene', (195, 199))	('control', 'Reg', (41, 48))	('FOXO1', 'Gene', '2308', (86, 91))	('CDK4', 'Gene', '1019', (195, 199))	('transcriptional activity', 'MPA', (53, 77))
140808	31921698	This treatment combination was based on preclinical evidence which reported that IGF-1R inhibition promotes a bypass resistance pathway through other kinases, such as the SRC family kinase YES and ALK, suggesting that targeting multiple RTKs in combination is likely necessary to overcome resistance.	('ALK', 'Gene', (197, 200))	('bypass resistance pathway', 'Pathway', (110, 135))	('IGF-1R', 'Gene', '3480', (81, 87))	('promotes', 'PosReg', (99, 107))	('IGF-1R', 'Gene', (81, 87))	('ALK', 'Gene', '238', (197, 200))	('SRC family kinase YES', 'Enzyme', (171, 192))	('inhibition', 'Var', (88, 98))
140815	31921698	However, a recent clinical trial evaluating a monoclonal antibody against IGF-1R, R1507 in advanced sarcoma patients failed to achieve meaningful clinical responses to the therapy.	('sarcoma', 'Disease', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))	('IGF-1R', 'Gene', '3480', (74, 80))	('IGF-1R', 'Gene', (74, 80))	('patients', 'Species', '9606', (108, 116))	('R1507', 'Var', (82, 87))
140826	31921698	The relationship between Hh signaling dysregulation and RMS has subsequently been supported by several studies.	('dysregulation', 'Var', (38, 51))	('RMS', 'Disease', 'MESH:D012208', (56, 59))	('RMS', 'Disease', (56, 59))
140827	31921698	Aberrant Hh signaling can be attributed to various germline mutations: loss of chromosomal region 9q22 containing PTCH in 33% of ERMS tumors, loss of SUFU in 18% ERMS tumors, and/or genomic amplification of 12q13-15 containing the GLI1 gene in a small subset of ARMS tumors.	('SUFU', 'Gene', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('genomic amplification', 'Var', (182, 203))	('Hh signaling', 'MPA', (9, 21))	('loss', 'Var', (142, 146))	('GLI1', 'Gene', (231, 235))	('RMS', 'Disease', (263, 266))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('ERMS', 'CellLine', 'CVCL:M564', (162, 166))	('PTCH', 'Gene', (114, 118))	('tumors', 'Disease', (134, 140))	('ERMS', 'CellLine', 'CVCL:M564', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('RMS', 'Disease', 'MESH:D012208', (130, 133))	('tumors', 'Disease', (267, 273))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('SUFU', 'Gene', '51684', (150, 154))	('RMS', 'Disease', (163, 166))	('RMS', 'Disease', 'MESH:D012208', (263, 266))	('GLI1', 'Gene', '2735', (231, 235))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('PTCH', 'Gene', '5727', (114, 118))	('loss', 'NegReg', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('RMS', 'Disease', (130, 133))	('RMS', 'Disease', 'MESH:D012208', (163, 166))
140841	31921698	Several selective CDK4/6 inhibitors have already been approved for treatment in advanced stage breast cancer, and have been investigated in the context of RMS, as CDK4 is overexpressed in a subset of FP RMS tumors through the amplification of chromosomal region 12q13-q14.	('RMS', 'Disease', 'MESH:D012208', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('RMS', 'Disease', (155, 158))	('CDK4', 'Gene', (163, 167))	('breast cancer', 'Disease', (95, 108))	('RMS', 'Disease', (203, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('CDK4', 'Gene', '1019', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('amplification', 'Var', (226, 239))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('overexpressed', 'PosReg', (171, 184))	('RMS', 'Disease', 'MESH:D012208', (203, 206))	('CDK4', 'Gene', '1019', (18, 22))	('CDK4', 'Gene', (18, 22))
140844	31921698	The DNA damage response (DDR) pathway plays a critical role in normal cellular homeostasis and its dysregulation is closely linked to increased mutation rates which drive oncogenesis.	('N', 'Chemical', 'MESH:D009584', (5, 6))	('mutation', 'Var', (144, 152))	('dysregulation', 'MPA', (99, 112))	('increased', 'PosReg', (134, 143))	('oncogenesis', 'Disease', (171, 182))
140849	31921698	A recent study showed that PARP inhibitors can sensitize RMS cell lines to ionizing radiation (IR), resulting in more potent cytotoxic effects compared to either modality alone.	('potent', 'PosReg', (118, 124))	('inhibitors', 'Var', (32, 42))	('cytotoxic effects', 'CPA', (125, 142))	('PARP', 'Gene', (27, 31))	('RMS', 'Disease', 'MESH:D012208', (57, 60))	('PARP', 'Gene', '142', (27, 31))	('RMS', 'Disease', (57, 60))
140857	31921698	Because cancer cells are more reliant on the G2/M checkpoint for DNA repair than normal cells due to G1/S DNA repair deficiencies, Wee1 inhibition can halt progression through the G2/M checkpoint and selectively induce apoptosis in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('G2/M', 'MPA', (180, 184))	('cancer', 'Disease', (8, 14))	('inhibition', 'Var', (136, 146))	('induce', 'Reg', (212, 218))	('cancer', 'Disease', (232, 238))	('halt', 'NegReg', (151, 155))	('Wee1', 'Gene', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Wee1', 'Gene', '7465', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('apoptosis', 'CPA', (219, 228))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
140861	31921698	The authors identified Wee1 kinase to be the most significant target for high-risk RMS, which led them to propose that patients with high-risk and recurrent RMS may benefit from combination therapy that includes AZD1775, irinotecan, and vincristine.	('RMS', 'Disease', 'MESH:D012208', (83, 86))	('AZD1775', 'Chemical', 'MESH:C549567', (212, 219))	('patients', 'Species', '9606', (119, 127))	('RMS', 'Disease', (83, 86))	('vincristine', 'Chemical', 'MESH:D014750', (237, 248))	('irinotecan', 'Chemical', 'MESH:C051890', (221, 231))	('Wee1', 'Gene', (23, 27))	('RMS', 'Disease', 'MESH:D012208', (157, 160))	('Wee1', 'Gene', '7465', (23, 27))	('RMS', 'Disease', (157, 160))	('AZD1775', 'Var', (212, 219))
140862	31921698	Based on comprehensive preclinical testing data, patients with high-risk pediatric RMS were included in a phase I/II clinical trial (NCT02095132) of AZD1775 in combination with the chemotherapy agent irinotecan.	('RMS', 'Disease', 'MESH:D012208', (83, 86))	('irinotecan', 'Chemical', 'MESH:C051890', (200, 210))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('RMS', 'Disease', (83, 86))	('AZD1775', 'Var', (149, 156))	('AZD1775', 'Chemical', 'MESH:C549567', (149, 156))	('patients', 'Species', '9606', (49, 57))
140876	31921698	The recurrent 2;13 and 1;13 translocations in FP RMS encode for the PAX3-FOXO1 and PAX7-FOXO1 chimeric transcription factors, which are uniquely expressed in malignant cells but not in normal cells.	('RMS', 'Disease', (49, 52))	('PAX7', 'Gene', '5081', (83, 87))	('FOXO1', 'Gene', (88, 93))	('PAX3', 'Gene', (68, 72))	('encode', 'Reg', (53, 59))	('PAX3', 'Gene', '5077', (68, 72))	('PAX7', 'Gene', (83, 87))	('FOXO1', 'Gene', '2308', (73, 78))	('translocations', 'Var', (28, 42))	('RMS', 'Disease', 'MESH:D012208', (49, 52))	('FOXO1', 'Gene', (73, 78))	('FOXO1', 'Gene', '2308', (88, 93))
140893	31921698	Following preclinical evaluation of a HER2-specific CAR containing a CD28.zeta signaling domain, Navai et al.	('HER2', 'Gene', (38, 42))	('CD28.zeta', 'Var', (69, 78))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('HER2', 'Gene', '2064', (38, 42))
140925	31921698	On the other hand, FN RMS (lacking the chimeric transcription factor) harbors recurrent genetic alterations (RAS, FGFR4, IGFR1, CDK4, PI3KCA, etc.	('CDK4', 'Gene', '1019', (128, 132))	('IGFR1', 'Gene', (121, 126))	('RMS', 'Disease', 'MESH:D012208', (22, 25))	('FGFR4', 'Gene', (114, 119))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('RMS', 'Disease', (22, 25))	('IGFR1', 'Gene', '2209', (121, 126))	('PI3KCA', 'Var', (134, 140))	('CDK4', 'Gene', (128, 132))
140936	31921698	Pediatric cancers are characterized by dynamic chromosomal instability, which can result in loss of chromosomal segments or copy-number alterations, contributing to the genetic heterogeneity of the tumor mass.	('chromosomal instability', 'Phenotype', 'HP:0040012', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('Pediatric cancers', 'Disease', 'MESH:D009369', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Pediatric cancers', 'Disease', (0, 17))	('loss', 'NegReg', (92, 96))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('copy-number alterations', 'Var', (124, 147))	('tumor', 'Disease', (198, 203))	('chromosomal segments', 'Protein', (100, 120))
140937	31921698	A small subpopulation of drug-resistant tumor cells (harboring a genetic alteration conferring a survival advantage) present at initial treatment may persist and expand, resulting in eventual failure to eliminate residual tumor mass.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('genetic alteration', 'Var', (65, 83))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
141084	22823907	A microRNA activity map of human mesenchymal tumors: connections to oncogenic pathways; an integrative transcriptomic study MicroRNAs (miRNAs) are nucleic acid regulators of many human mRNAs, and are associated with many tumorigenic processes.	('human', 'Species', '9606', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('human', 'Species', '9606', (27, 32))	('MicroRNAs', 'Var', (124, 133))	('associated', 'Reg', (200, 210))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (33, 51))	('mesenchymal tumors', 'Disease', (33, 51))
141120	22823907	We observed that in addition to reads mapping directly to reference miRNA sequences, there were also a substantial number of reads (distinct from the reference by one base) which mapped to no region of the human genome, suggesting either post-transcriptional modification, or copy number changes combined with mutation.	('copy number changes', 'Var', (276, 295))	('human', 'Species', '9606', (206, 211))	('post-transcriptional modification', 'Var', (238, 271))
141121	22823907	Based on recent observations, the intuitive question - which is also highlighted by the finding of potential miRNA sequence alterations above - of whether miRNA expression levels correlate well with miRNA activity in human tissue has been raised, and we have explored this for the first time in sarcoma.	('miRNA activity', 'MPA', (199, 213))	('human', 'Species', '9606', (217, 222))	('alterations', 'Var', (124, 135))	('miRNA expression levels', 'MPA', (155, 178))	('sarcoma', 'Disease', 'MESH:D012509', (295, 302))	('miRNA sequence', 'MPA', (109, 123))	('sarcoma', 'Disease', (295, 302))	('sarcoma', 'Phenotype', 'HP:0100242', (295, 302))
141125	22823907	Finally we limited our analysis to the top 50% most variant miRNAs (in terms of expression) and observed an improvement on the separation of the soft-tissue sarcoma samples.	('variant', 'Var', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (145, 164))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('sarcoma', 'Disease', (157, 164))
141168	22823907	We found only two synovial sarcoma-specific miRNAs, miR-126 and miR-129, that have both lower expression levels and decreased activity in both studies.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (18, 34))	('miR-129', 'Var', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('miR-126', 'Gene', (52, 59))	('synovial sarcoma', 'Disease', 'MESH:D013584', (18, 34))	('expression levels', 'MPA', (94, 111))	('miR-126', 'Gene', '406913', (52, 59))	('synovial sarcoma', 'Disease', (18, 34))	('lower', 'NegReg', (88, 93))	('activity', 'MPA', (126, 134))	('decreased', 'NegReg', (116, 125))
141236	31687230	In a retrospective study of hemophagocytic syndrome in patients living with HIV, bone marrow aspirate had 93% specificity for diagnosis, while ferritin levels greater than 5000 ng/mL correlated with increased likelihood of death.	('hemophagocytic syndrome', 'Disease', 'MESH:D051359', (28, 51))	('ferritin', 'MPA', (143, 151))	('HIV', 'Disease', (76, 79))	('hemophagocytic syndrome', 'Disease', (28, 51))	('HIV', 'Disease', 'MESH:D015658', (76, 79))	('hemophagocytic syndrome', 'Phenotype', 'HP:0012156', (28, 51))	('patients', 'Species', '9606', (55, 63))	('greater', 'Var', (159, 166))
141355	28735817	Importantly, alterations in these genetic disease-associated genes have also been identified in samples of human sporadic osteosarcoma, accounting for the vast majority of osteosarcoma cases in the general population.	('osteosarcoma', 'Disease', (122, 134))	('genetic disease', 'Disease', (34, 49))	('osteosarcoma', 'Phenotype', 'HP:0002669', (122, 134))	('genetic disease', 'Disease', 'MESH:D030342', (34, 49))	('osteosarcoma', 'Disease', 'MESH:D012516', (122, 134))	('human', 'Species', '9606', (107, 112))	('osteosarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('osteosarcoma', 'Disease', (172, 184))	('osteosarcoma', 'Disease', 'MESH:D012516', (172, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('alterations', 'Var', (13, 24))	('identified', 'Reg', (82, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
141358	28735817	Osteosarcoma frequently carries gross genomic mutations and rearrangements including chromosomal translocations.	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', (0, 12))	('chromosomal translocations', 'Var', (85, 111))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))
141360	28735817	Chromosomal translocations and mutations may juxtapose proto-oncogenes with constitutively active promoters, cause deletion of tumor suppressor genes, or produce chimeric oncogenes (e.g., PMP22-ELOVL5).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('ELOVL5', 'Gene', '60481', (194, 200))	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (127, 132))	('cause', 'Reg', (109, 114))	('deletion', 'MPA', (115, 123))	('Chromosomal translocations', 'Var', (0, 26))	('PMP22', 'Gene', '5376', (188, 193))	('produce', 'Reg', (154, 161))	('PMP22', 'Gene', (188, 193))	('proto-oncogenes', 'Gene', (55, 70))	('chimeric', 'MPA', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('ELOVL5', 'Gene', (194, 200))
141362	28735817	For instance, The St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project compared the results of whole genome sequencing (WGS) from osteosarcoma specimens with matched germline DNA from affected patients and identified high rates of structural variations (SVs) and copy number alterations (CNAs) but low rates of single nucleotide variations (SNVs) in osteosarcoma tumors, indicating that chromosomal lesions by SVs and CNAs, rather than SNVs, are the main mechanism of recurrent mutations in osteosarcoma.	('Children', 'Species', '9606', (27, 35))	('osteosarcoma', 'Phenotype', 'HP:0002669', (391, 403))	('tumor', 'Phenotype', 'HP:0002664', (404, 409))	('structural variations', 'Var', (272, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (404, 410))	('osteosarcoma', 'Disease', (171, 183))	('copy number alterations', 'Var', (304, 327))	('osteosarcoma', 'Phenotype', 'HP:0002669', (532, 544))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('Cancer', 'Disease', (90, 96))	('patients', 'Species', '9606', (234, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (396, 403))	('osteosarcoma', 'Disease', (391, 403))	('osteosarcoma', 'Disease', 'MESH:D012516', (391, 403))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (391, 410))	('sarcoma', 'Phenotype', 'HP:0100242', (537, 544))	('Cancer', 'Disease', 'MESH:D009369', (90, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('osteosarcoma', 'Disease', (532, 544))	('osteosarcoma', 'Disease', 'MESH:D012516', (532, 544))	('osteosarcoma tumors', 'Disease', (391, 410))
141365	28735817	Inactivation of the tumor suppressor p53 from translocation into the first intron of the TP53 gene has been detected in 9 out of 19 patient osteosarcoma tumors.	('osteosarcoma', 'Phenotype', 'HP:0002669', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('TP53', 'Gene', (89, 93))	('detected', 'Reg', (108, 116))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (140, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('osteosarcoma tumors', 'Disease', (140, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('translocation', 'Var', (46, 59))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('patient', 'Species', '9606', (132, 139))	('Inactivation', 'Var', (0, 12))	('tumor', 'Disease', (20, 25))
141369	28735817	Hundreds of genomic rearrangements have been identified in osteosarcomas using genomic and transcriptomic analysis, including recurrent rearrangements of TP53, RB1, MDM2 and CDKN2A as well as PMP22-ELOVL5 gene fusions.	('RB', 'Phenotype', 'HP:0009919', (160, 162))	('ELOVL5', 'Gene', '60481', (198, 204))	('osteosarcomas', 'Disease', (59, 72))	('TP53', 'Gene', (154, 158))	('osteosarcoma', 'Phenotype', 'HP:0002669', (59, 71))	('osteosarcomas', 'Phenotype', 'HP:0002669', (59, 72))	('CDKN2A', 'Gene', (174, 180))	('PMP22', 'Gene', '5376', (192, 197))	('MDM2', 'Gene', (165, 169))	('RB1', 'Gene', (160, 163))	('osteosarcomas', 'Disease', 'MESH:D012516', (59, 72))	('CDKN2A', 'Gene', '1029', (174, 180))	('PMP22', 'Gene', (192, 197))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('rearrangements', 'Var', (136, 150))	('ELOVL5', 'Gene', (198, 204))
141370	28735817	The most frequent TP53 rearrangements (e.g., TP53-VAV1, TP53-EMR1, TP53-PPRAD and TP53-KPNA3) resulted in the inactivation of p53 in osteosarcoma, explaining how TP53 gene function can be consistently disrupted in osteosarcoma despite the low observed prevalence of TP53 mutations in sporadic osteosarcomas, as shown in traditional mutation analyses.	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('osteosarcoma', 'Disease', 'MESH:D012516', (214, 226))	('rearrangements', 'Var', (23, 37))	('osteosarcomas', 'Phenotype', 'HP:0002669', (293, 306))	('TP53-PPRAD', 'Var', (67, 77))	('osteosarcoma', 'Phenotype', 'HP:0002669', (293, 305))	('sarcomas', 'Phenotype', 'HP:0100242', (298, 306))	('EMR1', 'Gene', '2015', (61, 65))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (214, 226))	('KPNA3', 'Gene', (87, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('inactivation', 'NegReg', (110, 122))	('osteosarcoma', 'Disease', (133, 145))	('TP53', 'Gene', (18, 22))	('EMR1', 'Gene', (61, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (298, 305))	('p53', 'Gene', (126, 129))	('osteosarcomas', 'Disease', 'MESH:D012516', (293, 306))	('KPNA3', 'Gene', '3839', (87, 92))	('VAV1', 'Gene', '7409', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('osteosarcoma', 'Disease', (293, 305))	('osteosarcoma', 'Disease', 'MESH:D012516', (293, 305))	('VAV1', 'Gene', (50, 54))	('osteosarcomas', 'Disease', (293, 306))	('osteosarcoma', 'Disease', (214, 226))
141375	28735817	The MSC hypothesis proposes that a mutation-carrying MSC will give rise to osteosarcoma.	('osteosarcoma', 'Disease', (75, 87))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('mutation-carrying', 'Var', (35, 52))	('give rise to', 'Reg', (62, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))
141376	28735817	A high frequency of pathogenic variants in the TP53 and RB1 tumor suppressor genes and the c-MYC and RAS oncogenes is found in genomic studies of human osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('c-MYC', 'Gene', '4609', (91, 96))	('variants', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('osteosarcoma', 'Phenotype', 'HP:0002669', (152, 164))	('human', 'Species', '9606', (146, 151))	('osteosarcoma', 'Disease', (152, 164))	('osteosarcoma', 'Disease', 'MESH:D012516', (152, 164))	('pathogenic', 'Reg', (20, 30))	('RB', 'Phenotype', 'HP:0009919', (56, 58))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('c-MYC', 'Gene', (91, 96))	('tumor', 'Disease', (60, 65))	('TP53', 'Gene', (47, 51))
141380	28735817	This hypothesis stems from studies of MSCs derived from Trp53-mutant mice showing that a Trp53 mutation might result in early osteogenesis but impedes final maturation from osteoblast precursors into mature osteoblasts, which is evaluated by the expression of early and intermediate osteogenic marker osteopontin, rather than the terminal osteogenic marker osteocalcin.	('osteocalcin', 'Gene', (357, 368))	('osteocalcin', 'Gene', '12096', (357, 368))	('Trp53', 'Gene', (56, 61))	('osteoblast precursors into mature osteoblasts', 'CPA', (173, 218))	('impedes', 'NegReg', (143, 150))	('early osteogenesis', 'CPA', (120, 138))	('Trp53', 'Gene', '22059', (89, 94))	('mice', 'Species', '10090', (69, 73))	('final maturation', 'CPA', (151, 167))	('Trp53', 'Gene', '22059', (56, 61))	('result', 'Reg', (110, 116))	('Trp53', 'Gene', (89, 94))	('mutation', 'Var', (95, 103))
141381	28735817	Moreover, during osteogenic differentiation, depletion of Trp53 or both Trp53 and Rb1 in murine bone marrow-derived MSCs (BM-MSCs) -- but not adipose-derived MSCs (ASCs) -- induced the formation of osteosarcoma-like tumors.	('Trp53', 'Gene', (58, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('osteosarcoma', 'Phenotype', 'HP:0002669', (198, 210))	('Trp53', 'Gene', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('osteogenic differentiation', 'CPA', (17, 43))	('osteosarcoma-like tumors', 'Disease', (198, 222))	('murine', 'Species', '10090', (89, 95))	('Rb1', 'Gene', (82, 85))	('Trp53', 'Gene', '22059', (72, 77))	('Trp53', 'Gene', '22059', (58, 63))	('osteosarcoma-like tumors', 'Disease', 'MESH:D012516', (198, 222))	('depletion', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('induced', 'Reg', (173, 180))
141388	28735817	These hypotheses might be at least partially reconciled if the mutation-carrying MSCs indirectly result in osteosarcoma by potentiating the generation of osteoblasts with defective differentiation.	('mutation-carrying', 'Var', (63, 80))	('result in', 'Reg', (97, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('osteosarcoma', 'Disease', (107, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('potentiating', 'PosReg', (123, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('MSCs', 'Gene', (81, 85))
141402	28735817	p53 has been shown to suppress tumor angiogenesis and proliferation in osteosarcoma by inhibiting the PI3K/AKT/mTOR pathway, further supporting that detrimental mutations in the TP53 gene can affect other pathways involved in cancer.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('AKT', 'Gene', '207', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('p53', 'Gene', (0, 3))	('AKT', 'Gene', (107, 110))	('TP53', 'Gene', (178, 182))	('mTOR', 'Gene', (111, 115))	('affect', 'Reg', (192, 198))	('mTOR', 'Gene', '2475', (111, 115))	('tumor', 'Disease', (31, 36))	('suppress', 'NegReg', (22, 30))	('cancer', 'Disease', (226, 232))	('mutations', 'Var', (161, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('inhibiting', 'NegReg', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('osteosarcoma', 'Disease', (71, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))
141405	28735817	Specifically, introduction of mutant p53(R172H) into mice could lead to formation of osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('lead to', 'Reg', (64, 71))	('p53', 'Gene', (37, 40))	('R172H', 'Mutation', 'p.R172H', (41, 46))	('mutant', 'Var', (30, 36))	('mice', 'Species', '10090', (53, 57))	('R172H', 'Var', (41, 46))
141407	28735817	In addition, a LFS iPSC disease model of osteosarcoma revealed that impaired H19-mediated osteoblastic differentiation and tumor suppression were involved in mutant p53-associated oncogenic ability.	('impaired H19-mediated osteoblastic', 'Disease', (68, 102))	('tumor', 'Disease', (123, 128))	('osteosarcoma', 'Disease', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('osteosarcoma', 'Phenotype', 'HP:0002669', (41, 53))	('impaired H19-mediated osteoblastic', 'Disease', 'MESH:D009422', (68, 102))	('osteosarcoma', 'Disease', 'MESH:D012516', (41, 53))	('p53-associated', 'Gene', (165, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('oncogenic ability', 'CPA', (180, 197))	('mutant', 'Var', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
141408	28735817	For instance, mutant p53 is capable of cooperating with the SWI/SNF chromatin remodeling complex to regulate tumor angiogenesis in 2D and 3D cultures of MDA-468 breast cancer cell lines.	('MDA-468', 'CellLine', 'CVCL:0419', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('mutant', 'Var', (14, 20))	('breast cancer', 'Disease', (161, 174))	('regulate', 'Reg', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('p53', 'Gene', (21, 24))	('tumor', 'Disease', (109, 114))
141410	28735817	In addition to regulating chromatin function, mutant p53 associates with SREBP to abnormally upregulate the mevalonate pathway, resulting in disruption of normal acinar structures in human breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('disruption', 'NegReg', (141, 151))	('breast cancers', 'Phenotype', 'HP:0003002', (189, 203))	('breast cancers', 'Disease', 'MESH:D001943', (189, 203))	('breast cancers', 'Disease', (189, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('mutant', 'Var', (46, 52))	('chromatin function', 'MPA', (26, 44))	('p53', 'Gene', (53, 56))	('mevalonate pathway', 'Pathway', (108, 126))	('human', 'Species', '9606', (183, 188))	('mevalonate', 'Chemical', 'MESH:D008798', (108, 118))	('regulating', 'Reg', (15, 25))	('upregulate', 'PosReg', (93, 103))
141411	28735817	Mutant p53 also upregulates PDGFRbeta by inhibiting the p73/NF-Y complex leading to further invasion and metastasis in a pancreatic cancer mouse model.	('PDGFRbeta', 'Gene', (28, 37))	('p73', 'Gene', '7161', (56, 59))	('pancreatic cancer', 'Disease', (121, 138))	('PDGFRbeta', 'Gene', '18596', (28, 37))	('invasion', 'CPA', (92, 100))	('upregulates', 'PosReg', (16, 27))	('p73', 'Gene', (56, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (121, 138))	('inhibiting', 'NegReg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('metastasis', 'CPA', (105, 115))	('mouse', 'Species', '10090', (139, 144))	('Mutant', 'Var', (0, 6))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))	('p53', 'Gene', (7, 10))
141412	28735817	The effects of these gain-of-function mutations have not yet been characterized in LFS-associated osteosarcomagenesis, and systematic studies of mutant p53 will be important in understanding LFS-associated osteosarcoma etiology.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('osteosarcomagenesis', 'Disease', 'None', (98, 117))	('osteosarcoma', 'Phenotype', 'HP:0002669', (206, 218))	('osteosarcoma', 'Disease', (206, 218))	('mutant', 'Var', (145, 151))	('p53', 'Gene', (152, 155))	('osteosarcoma', 'Disease', 'MESH:D012516', (206, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('gain-of-function', 'PosReg', (21, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('osteosarcomagenesis', 'Disease', (98, 117))	('mutations', 'Var', (38, 47))	('osteosarcoma', 'Disease', (98, 110))
141417	28735817	Although expression of genes downstream of E2Fs leads to tumors, the lack of E2Fs also stimulates tumorigenesis in various species.	('tumor', 'Disease', (98, 103))	('leads to', 'Reg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('lack', 'Var', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Disease', (57, 62))	('E2Fs', 'Gene', (77, 81))	('stimulates', 'PosReg', (87, 97))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
141423	28735817	RB1 expression induces osteogenic lineage differentiation of mouse MSCs, which can differentiate into adipocytes in its absence.	('induces', 'Reg', (15, 22))	('RB', 'Phenotype', 'HP:0009919', (0, 2))	('expression', 'Var', (4, 14))	('mouse', 'Species', '10090', (61, 66))	('RB1', 'Gene', (0, 3))	('osteogenic lineage differentiation', 'CPA', (23, 57))
141424	28735817	Taken together, the role of RB1 in regulating osteoblast differentiation may explain the high incidence of osteosarcoma development in RB patients due to loss of RB1.	('RB', 'Phenotype', 'HP:0009919', (162, 164))	('RB', 'Gene', '5925', (28, 30))	('RB', 'Gene', '5925', (135, 137))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('osteosarcoma', 'Disease', (107, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('RB', 'Gene', '5925', (162, 164))	('RB', 'Phenotype', 'HP:0009919', (28, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('RB', 'Phenotype', 'HP:0009919', (135, 137))	('patients', 'Species', '9606', (138, 146))	('loss', 'Var', (154, 158))
141428	28735817	Since replication stress causes chromosomal instability in human cells, mutations in RECQL4 could cause replication stress leading to genome instability.	('mutations', 'Var', (72, 81))	('genome instability', 'MPA', (134, 152))	('cause', 'Reg', (98, 103))	('human', 'Species', '9606', (59, 64))	('RECQL4', 'Gene', '9401', (85, 91))	('chromosomal instability', 'MPA', (32, 55))	('RECQL4', 'Gene', (85, 91))	('replication stress', 'MPA', (104, 122))	('chromosomal instability', 'Phenotype', 'HP:0040012', (32, 55))
141430	28735817	RECQL4 co-localizes and interacts with xeroderma pigmentosum group A (XPA) protein which is required for NER, and UV damage to H1299 and HeLa cells has resulted in increased co-immunoprecipitation intensity and co-localization between RECQL4 and XPA.	('RECQL4', 'Gene', '9401', (235, 241))	('RECQL4', 'Gene', (0, 6))	('XPA', 'Gene', '7507', (70, 73))	('xeroderma pigmentosum group A', 'Gene', (39, 68))	('XPA', 'Gene', (70, 73))	('damage', 'Var', (117, 123))	('XPA', 'Gene', (246, 249))	('xeroderma pigmentosum group A', 'Gene', '7507', (39, 68))	('XPA', 'Gene', '7507', (246, 249))	('RECQL4', 'Gene', '9401', (0, 6))	('HeLa', 'CellLine', 'CVCL:0030', (137, 141))	('interacts', 'Interaction', (24, 33))	('RECQL4', 'Gene', (235, 241))	('co-localization', 'MPA', (211, 226))	('co-immunoprecipitation intensity', 'MPA', (174, 206))	('H1299', 'CellLine', 'CVCL:0060', (127, 132))	('increased', 'PosReg', (164, 173))
141436	28735817	In mammalian cells, RECQL4 also associates with RAD51, a key protein involved in homologous recombination (HR); thus, the defect in RECQL4 function is expected to result in defective HR associated genomic instability.	('RAD51', 'Gene', (48, 53))	('defective', 'NegReg', (173, 182))	('RECQL4', 'Gene', '9401', (20, 26))	('RAD51', 'Gene', '5888', (48, 53))	('RECQL4', 'Gene', (132, 138))	('genomic instability', 'CPA', (197, 216))	('defect', 'Var', (122, 128))	('RECQL4', 'Gene', '9401', (132, 138))	('RECQL4', 'Gene', (20, 26))	('function', 'MPA', (139, 147))	('mammalian', 'Species', '9606', (3, 12))
141438	28735817	Therefore, it is possible that defective HR-induced genomic instability might contribute to initiating osteosarcoma development in RTS patients with RECQL4 mutations.	('patients', 'Species', '9606', (135, 143))	('mutations', 'Var', (156, 165))	('RECQL4', 'Gene', (149, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('contribute', 'Reg', (78, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('RTS', 'Gene', (131, 134))	('RECQL4', 'Gene', '9401', (149, 155))	('initiating', 'Reg', (92, 102))	('RTS', 'Gene', '4204', (131, 134))
141439	28735817	Indeed, although the molecular mechanism of osteosarcomagenesis in RTS remains unclear, genomic instability due to mutations in RECQL4 has been implicated in disease development.	('osteosarcomagenesis', 'Disease', 'None', (44, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('mutations', 'Var', (115, 124))	('osteosarcomagenesis', 'Disease', (44, 63))	('RECQL4', 'Gene', (128, 134))	('RTS', 'Gene', (67, 70))	('osteosarcoma', 'Phenotype', 'HP:0002669', (44, 56))	('implicated', 'Reg', (144, 154))	('RECQL4', 'Gene', '9401', (128, 134))	('genomic', 'MPA', (88, 95))	('RTS', 'Gene', '4204', (67, 70))
141440	28735817	For instance, RECQL4 is also mutated in RAPA, which also presents an increased risk of osteosarcomagenesis.	('osteosarcomagenesis', 'Disease', (87, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('RECQL4', 'Gene', (14, 20))	('mutated', 'Var', (29, 36))	('RECQL4', 'Gene', '9401', (14, 20))	('osteosarcomagenesis', 'Disease', 'None', (87, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
141441	28735817	While the mouse global knockout of Recql4 (targeting exon 5 to 8) causes embryonic lethality, inactivation of Recql4 in skeletal tissues has recapitulated some features of RTS, including skeletal abnormalities and small stature.	('Recql4', 'Gene', (110, 116))	('small stature', 'Disease', (214, 227))	('mouse', 'Species', '10090', (10, 15))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (187, 209))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (187, 209))	('RTS', 'Gene', (172, 175))	('small stature', 'Phenotype', 'HP:0004322', (214, 227))	('RTS', 'Gene', '4204', (172, 175))	('embryonic lethality', 'Disease', 'MESH:D020964', (73, 92))	('embryonic lethality', 'Disease', (73, 92))	('skeletal abnormalities', 'Disease', (187, 209))	('inactivation', 'Var', (94, 106))	('Recql4', 'Gene', (35, 41))
141442	28735817	Cells from such Recql4 conditional mutant mice display elevated p53 activity, and the skeletal phenotypes in these mice can be partially rescued by p53 inactivation.	('mice', 'Species', '10090', (115, 119))	('mice', 'Species', '10090', (42, 46))	('mutant', 'Var', (35, 41))	('inactivation', 'Var', (152, 164))	('p53', 'Protein', (64, 67))	('activity', 'MPA', (68, 76))	('elevated', 'PosReg', (55, 63))
141443	28735817	Furthermore, mice that lack Recql4 in osteoblast progenitor cells demonstrate a decrease in mineral apposition rate and bone formation rate but no increase in osteosarcoma.	('mice', 'Species', '10090', (13, 17))	('lack', 'Var', (23, 27))	('mineral apposition rate', 'CPA', (92, 115))	('osteosarcoma', 'Disease', (159, 171))	('osteosarcoma', 'Phenotype', 'HP:0002669', (159, 171))	('osteosarcoma', 'Disease', 'MESH:D012516', (159, 171))	('bone formation rate', 'CPA', (120, 139))	('Recql4', 'Gene', (28, 34))	('decrease', 'NegReg', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
141444	28735817	These results imply that osteosarcoma susceptibility is most likely triggered by mutant, not null, alleles of RECQL4 in RTS patients.	('triggered', 'Reg', (68, 77))	('osteosarcoma', 'Phenotype', 'HP:0002669', (25, 37))	('RTS', 'Gene', (120, 123))	('osteosarcoma', 'Disease', (25, 37))	('osteosarcoma', 'Disease', 'MESH:D012516', (25, 37))	('RECQL4', 'Gene', (110, 116))	('RTS', 'Gene', '4204', (120, 123))	('mutant', 'Var', (81, 87))	('RECQL4', 'Gene', '9401', (110, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('patients', 'Species', '9606', (124, 132))
141449	28735817	Although loss of WRN in WS may directly lead to cancer development through increased chromosome instability, its overall function in cancer is not clear.	('lead to', 'Reg', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('increased chromosome instability', 'Phenotype', 'HP:0040012', (75, 107))	('increased', 'PosReg', (75, 84))	('cancer', 'Disease', (133, 139))	('loss', 'Var', (9, 13))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('chromosome', 'CPA', (85, 95))	('WRN', 'Protein', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
141457	28735817	Numerous mutations in human BLM causing premature stop codons have been shown to lead to BS.	('lead', 'Reg', (81, 85))	('mutations', 'Var', (9, 18))	('BLM', 'Gene', '641', (28, 31))	('human', 'Species', '9606', (22, 27))	('BLM', 'Gene', (28, 31))
141464	28735817	p53 can help the localization of BLM to PML nuclear bodies in mammalian cells.	('mammalian', 'Species', '9606', (62, 71))	('BLM', 'Gene', '641', (33, 36))	('PML', 'Gene', (40, 43))	('BLM', 'Gene', (33, 36))	('p53', 'Var', (0, 3))	('localization', 'MPA', (17, 29))	('PML', 'Gene', '5371', (40, 43))
141467	28735817	FA comprises a collection of diseases characterized by mutations in FA genes leading to genomic instability and increased cancer risk.	('FA genes', 'Gene', (68, 76))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (122, 128))	('leading to', 'Reg', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('FA', 'Phenotype', 'HP:0001994', (68, 70))	('genomic', 'MPA', (88, 95))
141472	28735817	Some RPs (e.g., RPL5, RPL11, RPS7, and RPS26) can interact with MDM2 and inhibit E3 ubiquitination of p53, leading to p53 accumulation in both cell lines and mouse model systems.	('RPS7', 'Gene', '20115', (29, 33))	('RPS7', 'Gene', (29, 33))	('mouse', 'Species', '10090', (158, 163))	('accumulation', 'PosReg', (122, 134))	('RPS26', 'Gene', '27370', (39, 44))	('RPL5', 'Var', (16, 20))	('RPL11', 'Var', (22, 27))	('E3 ubiquitination', 'MPA', (81, 98))	('RPS26', 'Gene', (39, 44))	('p53', 'Protein', (102, 105))	('p53', 'MPA', (118, 121))	('interact', 'Interaction', (50, 58))	('inhibit', 'NegReg', (73, 80))
141473	28735817	Other RPs (e.g., RPS19) have no direct interactions with MDM2/p53, but their mutation nonetheless increases p53 levels in zebrafish.	('zebrafish', 'Species', '7955', (122, 131))	('increases', 'PosReg', (98, 107))	('mutation', 'Var', (77, 85))	('p53 levels', 'MPA', (108, 118))
141474	28735817	Furthermore, ribosomal insufficiency caused by RPS19 and RPS24 mutations can result in G0/G1 arrest and G2/M reduction, respectively, suggesting that cell proliferation defects might contribute to the decreased number of erythroid precursors observed in DBA.	('mutations', 'Var', (63, 72))	('G0/G1 arrest', 'CPA', (87, 99))	('defects', 'NegReg', (169, 176))	('cell proliferation', 'CPA', (150, 168))	('RPS24', 'Gene', (57, 62))	('decreased', 'NegReg', (201, 210))	('RPS19', 'Gene', (47, 52))	('DBA', 'Disease', (254, 257))	('decreased number of erythroid', 'Phenotype', 'HP:0012133', (201, 230))	('RPS24', 'Gene', '6229', (57, 62))	('G2/M reduction', 'CPA', (104, 118))	('ribosomal insufficiency', 'Disease', 'MESH:D000309', (13, 36))	('ribosomal insufficiency', 'Disease', (13, 36))
141476	28735817	For instance, RPL5 heterozygous mutations or deletions are found in 11% of glioblastomas, 28% of melanomas and 34% of breast cancer patients.	('glioblastomas', 'Phenotype', 'HP:0012174', (75, 88))	('melanomas', 'Disease', 'MESH:D008545', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('glioblastomas', 'Disease', 'MESH:D005909', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('glioblastomas', 'Disease', (75, 88))	('heterozygous mutations', 'Var', (19, 41))	('deletions', 'Var', (45, 54))	('melanomas', 'Disease', (97, 106))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('found', 'Reg', (59, 64))	('breast cancer', 'Disease', (118, 131))	('patients', 'Species', '9606', (132, 140))	('RPL5', 'Gene', (14, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
141477	28735817	Besides being the most common RP mutation in cancer, RPL5 mutations also lead to craniofacial anomalies.	('mutations', 'Var', (58, 67))	('craniofacial anomalies', 'Disease', 'MESH:D019465', (81, 103))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('RPL5', 'Gene', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('craniofacial anomalies', 'Disease', (81, 103))	('lead to', 'Reg', (73, 80))	('cancer', 'Disease', (45, 51))
141484	28735817	Phosphorylated p62 then causes NRF2 release from KEAP1 and NRF2 stabilization, after which NRF2 can translocate to the nucleus, turning on downstream anti-oxidative genes or forming autophagosome.	('Phosphorylated', 'Var', (0, 14))	('anti-oxidative genes', 'MPA', (150, 170))	('NRF2', 'Gene', (59, 63))	('autophagosome', 'CPA', (182, 195))	('KEAP1', 'Gene', '9817', (49, 54))	('NRF2', 'Gene', (31, 35))	('p62', 'Gene', (15, 18))	('turning', 'Reg', (128, 135))	('NRF2', 'Gene', '4780', (91, 95))	('KEAP1', 'Gene', (49, 54))	('p62', 'Gene', '8878', (15, 18))	('NRF2', 'Gene', '4780', (59, 63))	('NRF2', 'Gene', (91, 95))	('NRF2', 'Gene', '4780', (31, 35))
141486	28735817	Most p62 mutations found in PDB patients occur in the autophagy- and ubiquitin-associated domain.	('patients', 'Species', '9606', (32, 40))	('PDB', 'Gene', (28, 31))	('mutations', 'Var', (9, 18))	('occur', 'Reg', (41, 46))	('PDB', 'Gene', '5131', (28, 31))	('p62', 'Gene', '8878', (5, 8))	('p62', 'Gene', (5, 8))
141487	28735817	Studies have suggested that these mutations enhance the sensitivity of RANKL and accelerate PDB patient osteoclast formation through NF-kappaB activation.	('accelerate', 'PosReg', (81, 91))	('RANKL', 'Gene', '8600', (71, 76))	('RANKL', 'Gene', (71, 76))	('PDB', 'Gene', '5131', (92, 95))	('NF-kappaB', 'Gene', (133, 142))	('patient', 'Species', '9606', (96, 103))	('sensitivity', 'MPA', (56, 67))	('activation', 'PosReg', (143, 153))	('enhance', 'PosReg', (44, 51))	('PDB', 'Gene', (92, 95))	('mutations', 'Var', (34, 43))	('NF-kappaB', 'Gene', '4790', (133, 142))
141505	28735817	DBA iPSCs from affected patient fibroblasts harboring either heterozygous RPS19 (Q126X) or RPL5 (R23X) mutations have been established.	('RPS19', 'Gene', (74, 79))	('patient', 'Species', '9606', (24, 31))	('Q126X', 'Var', (81, 86))	('R23X', 'Mutation', 'rs121434405', (97, 101))	('RPL5', 'Gene', (91, 95))	('Q126X', 'Mutation', 'p.Q126X', (81, 86))
141507	28735817	The same conclusion was also made by another study using distinct DBA patient iPSCs harboring either RPS19 (R94X) or RPL5 (Y16X).	('patient', 'Species', '9606', (70, 77))	('Y16X', 'Mutation', 'rs148673599', (123, 127))	('R94X', 'Mutation', 'rs61762293', (108, 112))	('RPS19 (R94X', 'Var', (101, 112))	('RPL5 (Y16X', 'Var', (117, 127))
141509	28735817	It will be valuable to explore whether (1) osteoblasts and hematopoietic progenitors in DBA patients share a similar differentiation defect due to heterozygous null mutations in ribosome proteins; (2) defective autophagy in DBA iPSC-derived osteoblasts contributes to osteosarcomagenesis; (3) SMER28 can be applied to treat and/or prevent DBA-associated osteosarcoma; and (4) defective ribosome biosynthesis is a general mechanism leading to osteosarcomagenesis.	('osteosarcoma', 'Disease', (354, 366))	('osteosarcoma', 'Disease', (268, 280))	('osteosarcoma', 'Disease', 'MESH:D012516', (354, 366))	('osteosarcoma', 'Disease', 'MESH:D012516', (268, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (359, 366))	('osteosarcomagenesis', 'Disease', 'None', (268, 287))	('osteosarcoma', 'Disease', (442, 454))	('osteosarcoma', 'Disease', 'MESH:D012516', (442, 454))	('patients', 'Species', '9606', (92, 100))	('defective', 'Var', (201, 210))	('mutations', 'Var', (165, 174))	('osteosarcomagenesis', 'Disease', (442, 461))	('osteosarcoma', 'Phenotype', 'HP:0002669', (354, 366))	('osteosarcoma', 'Phenotype', 'HP:0002669', (268, 280))	('autophagy', 'CPA', (211, 220))	('osteosarcoma', 'Phenotype', 'HP:0002669', (442, 454))	('sarcoma', 'Phenotype', 'HP:0100242', (447, 454))	('osteosarcomagenesis', 'Disease', (268, 287))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('osteosarcomagenesis', 'Disease', 'None', (442, 461))
141510	28735817	Because dysregulation of ribosome protein function (e.g., RPL5 and RPL11) influences the p53/MDM2 axis, this disease model may also help clarify the complex signaling networks in osteosarcoma.	('dysregulation', 'Var', (8, 21))	('influences', 'Reg', (74, 84))	('ribosome protein', 'Protein', (25, 41))	('osteosarcoma', 'Disease', (179, 191))	('osteosarcoma', 'Phenotype', 'HP:0002669', (179, 191))	('osteosarcoma', 'Disease', 'MESH:D012516', (179, 191))	('RPL11', 'Var', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('RPL5', 'Var', (58, 62))	('p53/MDM2 axis', 'Pathway', (89, 102))
141513	28735817	Given the presence of RB1 alterations in 30-75% of sporadic osteosarcoma and lack of success thus far in recapitulating the osteosarcoma phenotype in RB mouse models, RB iPSC-derived osteoblasts have the potential to substantially improve our understanding of the role of RB1 in osteosarcomagenesis.	('improve', 'PosReg', (231, 238))	('osteosarcoma', 'Phenotype', 'HP:0002669', (279, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('osteosarcoma', 'Disease', (124, 136))	('RB', 'Phenotype', 'HP:0009919', (272, 274))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('RB', 'Gene', '5925', (22, 24))	('osteosarcoma', 'Disease', (60, 72))	('osteosarcomagenesis', 'Disease', (279, 298))	('osteosarcoma', 'Disease', 'MESH:D012516', (60, 72))	('RB', 'Phenotype', 'HP:0009919', (167, 169))	('alterations', 'Var', (26, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (284, 291))	('RB', 'Gene', '5925', (272, 274))	('RB', 'Phenotype', 'HP:0009919', (150, 152))	('osteosarcoma', 'Disease', (279, 291))	('osteosarcoma', 'Disease', 'MESH:D012516', (279, 291))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcomagenesis', 'Disease', 'None', (279, 298))	('RB', 'Gene', '5925', (167, 169))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('RB', 'Phenotype', 'HP:0009919', (22, 24))	('mouse', 'Species', '10090', (153, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('RB', 'Gene', '5925', (150, 152))
141520	28735817	Currently, LFS mice carrying R172H and R270H (R175H and R273H in human) as well as humanized p53 knock-in (HUPKI) mice harboring R175H, R248W, R248Q and R273H are capable of modeling much of the broad cancer spectrum found in humans and highlight the importance of gain-of-function activity in p53.	('human', 'Species', '9606', (65, 70))	('R172H', 'Mutation', 'p.R172H', (29, 34))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('R175H', 'Mutation', 'rs28934578', (129, 134))	('R175H', 'Var', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('R172H', 'Var', (29, 34))	('R273H', 'Mutation', 'rs28934576', (153, 158))	('R248Q', 'Mutation', 'rs11540652', (143, 148))	('humans', 'Species', '9606', (226, 232))	('R248W', 'Mutation', 'rs121912651', (136, 141))	('mice', 'Species', '10090', (114, 118))	('R270H', 'Var', (39, 44))	('human', 'Species', '9606', (226, 231))	('R175H', 'Mutation', 'rs28934578', (46, 51))	('R273H', 'Mutation', 'rs28934576', (56, 61))	('R248Q', 'Var', (143, 148))	('R273H', 'Var', (153, 158))	('human', 'Species', '9606', (83, 88))	('R270H', 'Mutation', 'rs55819519', (39, 44))	('mice', 'Species', '10090', (15, 19))	('R248W', 'Var', (136, 141))
141521	28735817	Unfortunately, another HUPKI mouse harboring G245S, one of the most commonly inherited familial p53 mutations, shows similar tumor onset and survival compared with the p53-null HUPK mice and fails to recapitulate its dominant-negative function in vivo.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('G245S', 'Var', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mice', 'Species', '10090', (182, 186))	('tumor', 'Disease', (125, 130))	('mouse', 'Species', '10090', (29, 34))	('G245S', 'Mutation', 'rs28934575', (45, 50))
141522	28735817	Moreover, although children with germline RB1 mutations are likely to experience bilateral multifocal RB and increased risk of osteosarcoma, mice with a similar disruption of Rb1 do not develop either retinoblastoma or osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('children', 'Species', '9606', (19, 27))	('mice', 'Species', '10090', (141, 145))	('Rb1', 'Gene', (175, 178))	('RB', 'Phenotype', 'HP:0009919', (42, 44))	('RB', 'Gene', '5925', (102, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (127, 139))	('mutations', 'Var', (46, 55))	('osteosarcoma', 'Disease', (219, 231))	('osteosarcoma', 'Disease', 'MESH:D012516', (219, 231))	('retinoblastoma or osteosarcoma', 'Disease', (201, 231))	('RB', 'Gene', '5925', (42, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('retinoblastoma or osteosarcoma', 'Disease', 'MESH:C566714', (201, 231))	('develop', 'Reg', (186, 193))	('osteosarcoma', 'Disease', (127, 139))	('retinoblastoma', 'Phenotype', 'HP:0009919', (201, 215))	('osteosarcoma', 'Disease', 'MESH:D012516', (127, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (219, 231))	('RB', 'Phenotype', 'HP:0009919', (102, 104))
141523	28735817	RTS patients carrying RECQL4 mutations commonly develop osteosarcoma, but deletion of Recql4 in mice only conveys some RTS clinical features, such as skeletal abnormalities, but not osteosarcoma.	('RTS', 'Gene', (0, 3))	('develop', 'Reg', (48, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (182, 194))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('patients', 'Species', '9606', (4, 12))	('RECQL4', 'Gene', '9401', (22, 28))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (150, 172))	('mice', 'Species', '10090', (96, 100))	('RTS', 'Gene', '4204', (119, 122))	('mutations', 'Var', (29, 38))	('RTS', 'Gene', '4204', (0, 3))	('RECQL4', 'Gene', (22, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('skeletal abnormalities', 'Disease', (150, 172))	('osteosarcoma', 'Disease', (182, 194))	('deletion', 'Var', (74, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (182, 194))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (150, 172))	('osteosarcoma', 'Disease', (56, 68))	('osteosarcoma', 'Disease', 'MESH:D012516', (56, 68))	('Recql4', 'Gene', (86, 92))	('RTS', 'Gene', (119, 122))
141556	28735817	In addition, some patients who do not meet the classic LFS criteria nevertheless harbor germline TP53 mutations, which led to the development of the less stringent Chompret criteria to identify families at risk for LFS and thus eligible for TP53 testing.. LFS-associated germline p53 mutations are relatively rare, occurring in 1 in 20,000 individuals.	('p53', 'Gene', (280, 283))	('patients', 'Species', '9606', (18, 26))	('LFS-associated', 'Disease', (256, 270))	('mutations', 'Var', (284, 293))
141557	28735817	Over 300 distinct p53 mutations causing LFS have been identified (http://p53.free.fr/Database/p53_cancer_db.html).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('p53', 'Gene', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('causing', 'Reg', (32, 39))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (22, 31))	('LFS', 'Disease', (40, 43))
141558	28735817	Approximately 70% of these mutations occur in the DNA binding domain encoded by exons 5-8; over 75% are missense mutations and usually generate a truncated p53 protein (http://p53.free.fr/Database/p53_cancer_db.html).	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('generate', 'Reg', (135, 143))	('cancer', 'Disease', (201, 207))	('truncated', 'MPA', (146, 155))	('missense mutations', 'Var', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('p53 protein', 'Protein', (156, 167))
141560	28735817	RB, caused by autosomal dominant mutations in the RB1 tumor suppressor gene, is a rare cancer of the retina typically found in children with approximately 300 cases in the US and 5-10,000 cases worldwide reported annually.	('cancer', 'Disease', (87, 93))	('RB', 'Gene', '5925', (0, 2))	('RB', 'Phenotype', 'HP:0009919', (50, 52))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('RB', 'Phenotype', 'HP:0009919', (0, 2))	('RB', 'Gene', '5925', (50, 52))	('children', 'Species', '9606', (127, 135))	('tumor', 'Disease', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
141561	28735817	The RB autosomal dominant inheritance pattern suggests that one copy of the RB mutation in each cell is sufficient to increase patient RB risk.	('RB', 'Gene', '5925', (4, 6))	('increase', 'PosReg', (118, 126))	('patient', 'Species', '9606', (127, 134))	('RB', 'Gene', '5925', (76, 78))	('RB', 'Gene', '5925', (135, 137))	('mutation', 'Var', (79, 87))	('RB', 'Phenotype', 'HP:0009919', (4, 6))	('RB', 'Phenotype', 'HP:0009919', (76, 78))	('RB', 'Phenotype', 'HP:0009919', (135, 137))
141572	28735817	This suggests that Rb1/RB1 might be able to control early osteoblast progression, and its dysregulation may increase the risk of osteosarcoma development; however, further studies will be required to validate this concept RTS is an autosomal recessive genetic disease characterized by a distinct skin rash called poikiloderma that develops between the age of three and six months.	('autosomal recessive genetic disease', 'Disease', (232, 267))	('increase', 'PosReg', (108, 116))	('poikiloderma', 'Phenotype', 'HP:0001029', (313, 325))	('RB', 'Phenotype', 'HP:0009919', (23, 25))	('skin rash', 'Disease', 'MESH:D005076', (296, 305))	('skin rash', 'Disease', (296, 305))	('poikiloderma', 'Disease', 'MESH:D011038', (313, 325))	('RTS', 'Gene', '4204', (222, 225))	('rash', 'Phenotype', 'HP:0000988', (301, 305))	('autosomal recessive genetic disease', 'Disease', 'MESH:D030342', (232, 267))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('osteosarcoma', 'Disease', 'MESH:D012516', (129, 141))	('dysregulation', 'Var', (90, 103))	('poikiloderma', 'Disease', (313, 325))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('skin rash', 'Phenotype', 'HP:0000988', (296, 305))	('osteosarcoma', 'Disease', (129, 141))	('RTS', 'Gene', (222, 225))
141574	28735817	Recently, RTS has been categorized into two types, Type I and Type II, based on the absence (Type I) or presence (Type II) of mutations in the RECQL4 gene.	('RECQL4', 'Gene', (143, 149))	('RTS', 'Gene', (10, 13))	('RTS', 'Gene', '4204', (10, 13))	('presence', 'Reg', (104, 112))	('RECQL4', 'Gene', '9401', (143, 149))	('mutations', 'Var', (126, 135))
141577	28735817	The majority of patients with Type II RTS are compound heterozygous for RECQL4 mutations, and most of these mutations are predicted to cause truncated protein.	('protein', 'Protein', (151, 158))	('RECQL4', 'Gene', (72, 78))	('mutations', 'Var', (108, 117))	('Type II RTS', 'Disease', (30, 41))	('Type II RTS', 'Disease', 'MESH:D015518', (30, 41))	('patients', 'Species', '9606', (16, 24))	('RECQL4', 'Gene', '9401', (72, 78))	('truncated', 'MPA', (141, 150))	('cause', 'Reg', (135, 140))	('mutations', 'Var', (79, 88))
141581	28735817	Although RAPA patients have mutations in the same gene, RECQL4, as RTS patients, they lack poikiloderma which is the hallmark feature of RTS.	('RTS', 'Gene', (137, 140))	('poikiloderma', 'Disease', (91, 103))	('RECQL4', 'Gene', (56, 62))	('patients', 'Species', '9606', (71, 79))	('poikiloderma', 'Phenotype', 'HP:0001029', (91, 103))	('RTS', 'Gene', '4204', (137, 140))	('lack', 'NegReg', (86, 90))	('poikiloderma', 'Disease', 'MESH:D011038', (91, 103))	('RTS', 'Gene', (67, 70))	('RECQL4', 'Gene', '9401', (56, 62))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (28, 37))	('RTS', 'Gene', '4204', (67, 70))
141584	28735817	To date, 83 different mutations spanning the WRN gene have been identified in WS patients.	('identified', 'Reg', (64, 74))	('patients', 'Species', '9606', (81, 89))	('mutations', 'Var', (22, 31))	('WRN', 'Gene', (45, 48))
141589	28735817	BS is characterized by growth retardation, short stature, malar hypoplasia, hypo- and hyperpigmentation, immune deficiency, infertility, and occasional mild mental retardation, butterfly rash, and is caused by mutations in the BLM gene.	('BLM', 'Gene', (227, 230))	('immune deficiency', 'Phenotype', 'HP:0002721', (105, 122))	('mutations', 'Var', (210, 219))	('infertility', 'Phenotype', 'HP:0000789', (124, 135))	('rash', 'Disease', 'MESH:D005076', (187, 191))	('BLM', 'Gene', '641', (227, 230))	('mental retardation', 'Phenotype', 'HP:0001249', (157, 175))	('mental retardation', 'Disease', 'MESH:D008607', (157, 175))	('malar hypoplasia', 'Disease', (58, 74))	('caused by', 'Reg', (200, 209))	('malar hypoplasia', 'Phenotype', 'HP:0000272', (58, 74))	('malar hypoplasia', 'Disease', 'MESH:C535916', (58, 74))	('growth retardation', 'Phenotype', 'HP:0001510', (23, 41))	('short stature', 'Phenotype', 'HP:0004322', (43, 56))	('hypo- and', 'Disease', (76, 85))	('hypo- and hyperpigmentation', 'Phenotype', 'HP:0007509', (76, 103))	('mental retardation', 'Disease', (157, 175))	('infertility', 'Disease', (124, 135))	('hyperpigmentation, immune deficiency', 'Disease', 'MESH:D017495', (86, 122))	('growth retardation', 'Disease', 'MESH:D006130', (23, 41))	('rash', 'Phenotype', 'HP:0000988', (187, 191))	('growth retardation', 'Disease', (23, 41))	('infertility', 'Disease', 'MESH:D007247', (124, 135))	('mild mental retardation', 'Phenotype', 'HP:0001256', (152, 175))	('short stature', 'Disease', 'MESH:D006130', (43, 56))	('butterfly rash', 'Phenotype', 'HP:0025300', (177, 191))	('short stature', 'Disease', (43, 56))	('rash', 'Disease', (187, 191))
141592	28735817	The Ashkenazi Jewish population exhibits a higher incidence of BS, with around 1% of Ashkenazi Jews being carriers who harbor a heterozygous frameshift mutation of BLM.	('BLM', 'Gene', (164, 167))	('BLM', 'Gene', '641', (164, 167))	('frameshift mutation', 'Var', (141, 160))
141600	28735817	About half (~52.9%) of DBA patients carry heterozygous ribosomal protein mutations, and up to 9 ribosomal protein genes are reported to be involved in DBA.	('DBA', 'Disease', (23, 26))	('ribosomal protein', 'Protein', (55, 72))	('to 9', 'Species', '1214577', (91, 95))	('patients', 'Species', '9606', (27, 35))	('involved', 'Reg', (139, 147))	('mutations', 'Var', (73, 82))
141602	28735817	The next most common cause (~7%) is a mutation of RPL5, which is associated with a relatively high incidence of developmental anomalies compared with other forms of DBA.	('developmental anomalies', 'Disease', (112, 135))	('RPL5', 'Gene', (50, 54))	('developmental anomalies', 'Disease', 'MESH:D000014', (112, 135))	('associated', 'Reg', (65, 75))	('high incidence of developmental anomalies', 'Phenotype', 'HP:0001263', (94, 135))	('mutation', 'Var', (38, 46))
141604	28735817	Due to the insufficiency of ribosomes for translation, some have proposed that ribosomal defects interfere predominantly with the development of highly proliferated cell populations, such as erythrocytes.	('insufficiency', 'Disease', 'MESH:D000309', (11, 24))	('defects', 'Var', (89, 96))	('interfere', 'NegReg', (97, 106))	('insufficiency', 'Disease', (11, 24))	('ribosomal', 'Protein', (79, 88))
141605	28735817	Others have suggested that disruption of the heme exporter FLVCR1 in RPS19-mutated DBA patients may lead to heme toxicity and apoptosis of erythroid progenitors.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('FLVCR1', 'Gene', '28982', (59, 65))	('toxicity', 'Disease', (113, 121))	('patients', 'Species', '9606', (87, 95))	('apoptosis', 'CPA', (126, 135))	('RPS19-mutated', 'Gene', (69, 82))	('disruption', 'Var', (27, 37))	('heme', 'Chemical', 'MESH:D006418', (45, 49))	('lead to', 'Reg', (100, 107))	('DBA', 'Disease', (83, 86))	('FLVCR1', 'Gene', (59, 65))	('heme', 'Chemical', 'MESH:D006418', (108, 112))
141607	28735817	Finally, a DBA zebrafish model reveals that defects in ribosome synthesis accelerate apoptotic death of hematopoietic progenitors due to p53 activation.	('apoptotic death', 'CPA', (85, 100))	('accelerate', 'PosReg', (74, 84))	('defects', 'Var', (44, 51))	('ribosome synthesis', 'MPA', (55, 73))	('zebrafish', 'Species', '7955', (15, 24))	('p53', 'Gene', (137, 140))	('activation', 'PosReg', (141, 151))
141631	28735817	Other than mutations, genomic rearrangements are also involved in osteosarcomagenesis, which cany be ignored by traditional mutation analysis.	('genomic rearrangements', 'Var', (22, 44))	('osteosarcomagenesis', 'Disease', 'None', (66, 85))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('osteosarcomagenesis', 'Disease', (66, 85))	('involved', 'Reg', (54, 62))
141632	28735817	Osteosarcoma-specific fusion genes can offers potential therapeutic targets for further osteosarcoma treatment.	('osteosarcoma', 'Disease', 'MESH:D012516', (88, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('Osteosarcoma', 'Disease', (0, 12))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('osteosarcoma', 'Phenotype', 'HP:0002669', (88, 100))	('fusion', 'Var', (22, 28))	('osteosarcoma', 'Disease', (88, 100))
141636	28735817	How do deficiencies in genes with ostensibly similar functions (e.g., RECQL4, BLM, and WRN) result in different patient phenotypes?	('BLM', 'Gene', '641', (78, 81))	('patient', 'Species', '9606', (112, 119))	('WRN', 'Gene', (87, 90))	('RECQL4', 'Gene', (70, 76))	('result in', 'Reg', (92, 101))	('deficiencies', 'Var', (7, 19))	('BLM', 'Gene', (78, 81))	('RECQL4', 'Gene', '9401', (70, 76))
141641	28735817	Can differentiation defects constitute a trigger to initiate osteosarcoma development?	('osteosarcoma', 'Disease', (61, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('defects', 'Var', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))
141642	28735817	What are the pathological mechanisms (e.g., epigenetic regulation and defect on autophagy) involved in osteogenesis defects?	('autophagy', 'CPA', (80, 89))	('osteogenesis defects', 'Disease', (103, 123))	('osteogenesis defects', 'Disease', 'MESH:D010013', (103, 123))	('epigenetic regulation', 'Var', (44, 65))
141649	23982330	We demonstrate that axillary lymph node involvement and high expression of Ki-67 are associated with poorer prognosis.	('Ki-67', 'Gene', (75, 80))	('Ki-67', 'Chemical', '-', (75, 80))	('axillary lymph node involvement', 'CPA', (20, 51))	('high', 'Var', (56, 60))
141725	23982330	Four out of 5 patients with high Ki-67 expression, two of whom suffered from local recurrence, developed distal metastasis, and had a life span of 6 to 26 months.	('distal metastasis', 'CPA', (105, 122))	('Ki-67', 'Gene', (33, 38))	('high', 'Var', (28, 32))	('developed', 'PosReg', (95, 104))	('patients', 'Species', '9606', (14, 22))	('Ki-67', 'Chemical', '-', (33, 38))
141727	23982330	This indicates that patients with high Ki-67 expression have a dramatically shorter life span than those with low Ki-67 expression, and suggests that elevated expression of Ki-67 is associated with local recurrence, distant metastasis, and poor prognosis in MFH of the breast.	('associated with', 'Reg', (182, 197))	('Ki-67', 'Chemical', '-', (114, 119))	('MFH of the breast', 'Disease', (258, 275))	('expression', 'MPA', (159, 169))	('high', 'Var', (34, 38))	('elevated', 'PosReg', (150, 158))	('Ki-67', 'Gene', (39, 44))	('Ki-67', 'Gene', (173, 178))	('Ki-67', 'Chemical', '-', (39, 44))	('patients', 'Species', '9606', (20, 28))	('shorter', 'NegReg', (76, 83))	('local recurrence', 'CPA', (198, 214))	('distant metastasis', 'CPA', (216, 234))	('Ki-67', 'Chemical', '-', (173, 178))
141730	23982330	In addition to surgery, we recommend that the patients with high Ki-67 expression should be adjuvantly treated with systemic therapy.	('high', 'Var', (60, 64))	('Ki-67', 'Gene', (65, 70))	('patients', 'Species', '9606', (46, 54))	('Ki-67', 'Chemical', '-', (65, 70))
141732	23982330	Patients with axillary lymph node involvement and high expression of Ki-67 can be expected to display early local recurrence, distant metastasis, and poorer prognosis.	('high expression', 'Var', (50, 65))	('axillary lymph node involvement', 'CPA', (14, 45))	('Ki-67', 'Gene', (69, 74))	('Patients', 'Species', '9606', (0, 8))	('local recurrence', 'CPA', (108, 124))	('distant metastasis', 'CPA', (126, 144))	('Ki-67', 'Chemical', '-', (69, 74))
141743	23982330	Endogenous peroxidase activity was blocked with 0.5% H2O2 for 30 min, followed by antigen retrieval by boiling for 20 min in sodium citrate buffer, Ph 6.0.	('boiling', 'Phenotype', 'HP:0020083', (103, 110))	('0.5', 'Var', (48, 51))	('H2O2', 'Chemical', 'MESH:D006861', (53, 57))	('H2O2', 'Var', (53, 57))	('sodium citrate', 'Chemical', 'MESH:D000077559', (125, 139))	('activity', 'MPA', (22, 30))	('blocked', 'NegReg', (35, 42))
141754	33090227	In this national cohort study of 323 patients in Denmark diagnosed with retinoblastoma, the incidence and mortality of second primary cancer were significantly higher in patients with heritable retinoblastoma vs patients with nonheritable retinoblastoma.	('retinoblastoma', 'Disease', (72, 86))	('retinoblastoma', 'Phenotype', 'HP:0009919', (239, 253))	('higher', 'PosReg', (160, 166))	('retinoblastoma', 'Disease', 'MESH:D012175', (194, 208))	('patients', 'Species', '9606', (212, 220))	('retinoblastoma', 'Disease', (239, 253))	('patients', 'Species', '9606', (37, 45))	('cancer', 'Disease', (134, 140))	('mortality', 'Disease', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('retinoblastoma', 'Phenotype', 'HP:0009919', (194, 208))	('retinoblastoma', 'Disease', 'MESH:D012175', (72, 86))	('patients', 'Species', '9606', (170, 178))	('retinoblastoma', 'Disease', (194, 208))	('retinoblastoma', 'Disease', 'MESH:D012175', (239, 253))	('heritable', 'Var', (184, 193))	('mortality', 'Disease', 'MESH:D003643', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('retinoblastoma', 'Phenotype', 'HP:0009919', (72, 86))
141762	33090227	Heritability and retinoblastoma treatment.	('retinoblastoma', 'Phenotype', 'HP:0009919', (17, 31))	('men', 'Species', '9606', (37, 40))	('retinoblastoma', 'Disease', 'MESH:D012175', (17, 31))	('retinoblastoma', 'Disease', (17, 31))	('Heritability', 'Var', (0, 12))
141770	33090227	The cumulative incidence of SPCs at age 60 years was significantly higher in patients with heritable retinoblastoma (51%) compared with those with nonheritable retinoblastoma (13%) (P < .001) (hazard ratio, 5.0; 95% CI, 2.5-10.3).	('retinoblastoma', 'Phenotype', 'HP:0009919', (101, 115))	('heritable', 'Var', (91, 100))	('retinoblastoma', 'Phenotype', 'HP:0009919', (160, 174))	('higher', 'PosReg', (67, 73))	('SPC', 'Gene', (28, 31))	('retinoblastoma', 'Disease', 'MESH:D012175', (101, 115))	('retinoblastoma', 'Disease', (101, 115))	('retinoblastoma', 'Disease', (160, 174))	('patients', 'Species', '9606', (77, 85))	('retinoblastoma', 'Disease', 'MESH:D012175', (160, 174))	('SPC', 'Gene', '114131', (28, 31))
141772	33090227	Mortality due to SPC was also higher in survivors of heritable retinoblastoma compared with those with nonheritable retinoblastoma (cumulative mortality, 34% vs 12% at age 60 years; P = .03).	('retinoblastoma', 'Phenotype', 'HP:0009919', (116, 130))	('SPC', 'Gene', (17, 20))	('retinoblastoma', 'Disease', (63, 77))	('retinoblastoma', 'Disease', 'MESH:D012175', (63, 77))	('higher', 'PosReg', (30, 36))	('Mortality', 'Disease', 'MESH:D003643', (0, 9))	('mortality', 'Disease', 'MESH:D003643', (143, 152))	('SPC', 'Gene', '114131', (17, 20))	('retinoblastoma', 'Disease', 'MESH:D012175', (116, 130))	('retinoblastoma', 'Disease', (116, 130))	('retinoblastoma', 'Phenotype', 'HP:0009919', (63, 77))	('Mortality', 'Disease', (0, 9))	('mortality', 'Disease', (143, 152))	('heritable', 'Var', (53, 62))
141777	33090227	Retinoblastoma is a rare intraocular childhood cancer caused by a pathogenic variant (formerly termed a mutation) in both RB1 (OMIM 614041) alleles.	('intraocular', 'Disease', (25, 36))	('RB1', 'Gene', '5925', (122, 125))	('caused by', 'Reg', (54, 63))	('variant', 'Var', (77, 84))	('Retinoblastoma', 'Gene', '5925', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('cancer', 'Disease', (47, 53))	('Retinoblastoma', 'Gene', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('RB1', 'Gene', (122, 125))	('intraocular', 'Disease', 'MESH:D009798', (25, 36))	('pathogenic', 'Reg', (66, 76))
141778	33090227	In patients with heritable retinoblastoma, the patient has a germ-line RB1 pathogenic variant, and a new sporadic pathogenic variant in the other RB1 gene initiates tumorigenesis.	('tumor', 'Disease', (165, 170))	('patient', 'Species', '9606', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('RB1', 'Gene', (146, 149))	('initiates', 'PosReg', (155, 164))	('pathogenic', 'Reg', (75, 85))	('patient', 'Species', '9606', (3, 10))	('retinoblastoma', 'Phenotype', 'HP:0009919', (27, 41))	('RB1', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('patients', 'Species', '9606', (3, 11))	('RB1', 'Gene', '5925', (146, 149))	('RB1', 'Gene', '5925', (71, 74))	('variant', 'Var', (86, 93))	('retinoblastoma', 'Disease', 'MESH:D012175', (27, 41))	('retinoblastoma', 'Disease', (27, 41))
141779	33090227	The RB1 germ-line variant can be inherited from an affected parent, but is most often a de novo variant.	('RB1', 'Gene', '5925', (4, 7))	('RB1', 'Gene', (4, 7))	('variant', 'Var', (18, 25))
141780	33090227	In RB1 mosaicism, the RB1 variant is present in only a fraction of cells and tissues.	('mosaicism', 'Var', (7, 16))	('RB1', 'Gene', '5925', (3, 6))	('RB1', 'Gene', (22, 25))	('RB1', 'Gene', '5925', (22, 25))	('RB1', 'Gene', (3, 6))
141791	33090227	Because the study cohort contains both genetically tested and untested patients, heritable retinoblastoma was defined by bilateral or multifocal disease, familial presentation, and/or identification of an RB1 variant.	('retinoblastoma', 'Phenotype', 'HP:0009919', (91, 105))	('patients', 'Species', '9606', (71, 79))	('RB1', 'Gene', (205, 208))	('variant', 'Var', (209, 216))	('retinoblastoma', 'Disease', 'MESH:D012175', (91, 105))	('retinoblastoma', 'Disease', (91, 105))	('RB1', 'Gene', '5925', (205, 208))
141796	33090227	Three additional individuals, either unaffected RB1 variant carriers and/or diagnosed with retinoma (retinocytoma) or retinal scars, were not included.	('variant', 'Var', (52, 59))	('RB1', 'Gene', (48, 51))	('retinoma (retinocytoma) or retinal', 'Disease', 'MESH:D012173', (91, 125))	('RB1', 'Gene', '5925', (48, 51))	('scars', 'Phenotype', 'HP:0100699', (126, 131))
141858	33090227	Furthermore, we found that the cumulative mortality rate from SPCs was significantly higher for patients with heritable retinoblastoma compared with patients with nonheritable retinoblastoma.	('retinoblastoma', 'Disease', 'MESH:D012175', (176, 190))	('retinoblastoma', 'Disease', (176, 190))	('patients', 'Species', '9606', (149, 157))	('retinoblastoma', 'Phenotype', 'HP:0009919', (120, 134))	('higher', 'PosReg', (85, 91))	('SPC', 'Gene', '114131', (62, 65))	('mortality', 'Disease', 'MESH:D003643', (42, 51))	('heritable', 'Var', (110, 119))	('retinoblastoma', 'Disease', 'MESH:D012175', (120, 134))	('retinoblastoma', 'Disease', (120, 134))	('patients', 'Species', '9606', (96, 104))	('retinoblastoma', 'Phenotype', 'HP:0009919', (176, 190))	('mortality', 'Disease', (42, 51))	('SPC', 'Gene', (62, 65))
141863	33090227	The risk is caused by constitutional RB1 pathogenic variant, compromising tumor suppressor function.	('variant', 'Var', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('compromising', 'NegReg', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('RB1', 'Gene', (37, 40))	('RB1', 'Gene', '5925', (37, 40))
141883	33090227	Up to 14% of unilateral sporadic affected patients may carry an RB1 pathogenic variant.	('RB1', 'Gene', '5925', (64, 67))	('RB1', 'Gene', (64, 67))	('pathogenic', 'Reg', (68, 78))	('patients', 'Species', '9606', (42, 50))	('variant', 'Var', (79, 86))
141887	33090227	In addition, the exclusion of 3 RB1 variant carriers with no diagnosis of retinoblastoma could have affected data.	('variant', 'Var', (36, 43))	('retinoblastoma', 'Phenotype', 'HP:0009919', (74, 88))	('RB1', 'Gene', (32, 35))	('RB1', 'Gene', '5925', (32, 35))	('retinoblastoma', 'Disease', 'MESH:D012175', (74, 88))	('retinoblastoma', 'Disease', (74, 88))
141972	31278606	Lumbar hernias occur through defects in the lumbar muscles or the posterior transversalis or lumbodorsal fascia.	('hernias', 'Phenotype', 'HP:0100790', (7, 14))	('hernias', 'Disease', (7, 14))	('hernias', 'Disease', 'MESH:D006547', (7, 14))	('hernia', 'Phenotype', 'HP:0100790', (7, 13))	('defects', 'Var', (29, 36))	('lumbodorsal fascia', 'Disease', 'None', (93, 111))	('lumbodorsal fascia', 'Disease', (93, 111))
142020	31278606	Marginal excision was performed and cytogenetic analysis confirmed MDM2 amplification in keeping with ALT (Fig.	('amplification', 'Var', (72, 85))	('MDM2', 'Gene', '4193', (67, 71))	('MDM2', 'Gene', (67, 71))	('ALT', 'Chemical', '-', (102, 105))	('ALT', 'Disease', (102, 105))
142045	31278606	If however there is oedema in the lesion, or nodularity or thicker septations are seen, the protocol can be extended with post contrast series.	('oedema in the lesion', 'Disease', 'MESH:D004487', (20, 40))	('oedema', 'Phenotype', 'HP:0000969', (20, 26))	('oedema in the lesion', 'Disease', (20, 40))	('nodularity', 'Var', (45, 55))
142053	31278606	In addition, when biopsies are erroneously performed through large muscles such as the quadriceps or gluteal muscles, this could be a harmful procedure as the muscles would have to be included in the resection resulting in loss of function for the patient.	('large muscles', 'Phenotype', 'HP:0003712', (61, 74))	('erroneously', 'Var', (31, 42))	('function', 'MPA', (231, 239))	('patient', 'Species', '9606', (248, 255))	('loss', 'NegReg', (223, 227))
142097	27079325	In STS, biochemical analysis of patient samples from a phase II study investigating pazopanib-induced effects on serum cytokines and angiogenic factors showed that pazopanib decreases soluble VEGF receptor-2 (sVEGFR2) levels and increases placental-derived growth factor levels; changes in both of these factors are associated with pazopanib-specific toxicity, such as hypertension and thyroid stimulating hormone elevations and with poorer PFS (12 weeks) and OS (both p < 0.05).	('pazopanib', 'Chemical', 'MESH:C516667', (164, 173))	('VEGF', 'Gene', '7422', (210, 214))	('toxicity', 'Disease', (351, 359))	('patient', 'Species', '9606', (32, 39))	('hypertension', 'Disease', 'MESH:D006973', (369, 381))	('VEGF', 'Gene', (210, 214))	('VEGF', 'Gene', '7422', (192, 196))	('hypertension', 'Disease', (369, 381))	('thyroid stimulating hormone', 'MPA', (386, 413))	('STS', 'Phenotype', 'HP:0030448', (3, 6))	('VEGF', 'Gene', (192, 196))	('elevations', 'PosReg', (414, 424))	('hypertension', 'Phenotype', 'HP:0000822', (369, 381))	('levels', 'MPA', (218, 224))	('pazopanib', 'Var', (164, 173))	('increases', 'PosReg', (229, 238))	('placental-derived growth factor levels', 'MPA', (239, 277))	('stimulating hormone elevations', 'Phenotype', 'HP:0002925', (394, 424))	('pazopanib', 'Chemical', 'MESH:C516667', (332, 341))	('toxicity', 'Disease', 'MESH:D064420', (351, 359))	('pazopanib', 'Chemical', 'MESH:C516667', (84, 93))	('decreases', 'NegReg', (174, 183))
142161	22937319	Incidence is increased in FAB M4/M5 types, CD56 (+) blasts, cytogenetic abnormalities: t (8 : 21), inversion 16, infant leukemia, 11q abnormalities, cellular immune dysfunction, and with new treatments like allogeneic stem cell transplantation.	('infant', 'Species', '9606', (113, 119))	('men', 'Species', '9606', (196, 199))	('immune dysfunction', 'Disease', (158, 176))	('CD56', 'Gene', (43, 47))	('leukemia', 'Disease', (120, 128))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('leukemia', 'Disease', 'MESH:D007938', (120, 128))	('inversion 16', 'Var', (99, 111))	('11q abnormalities', 'Var', (130, 147))	('immune dysfunction', 'Disease', 'MESH:D007154', (158, 176))	('FAB', 'Gene', '2187', (26, 29))	('t (8 : 21', 'Var', (87, 96))	('FAB', 'Gene', (26, 29))	('CD56', 'Gene', '4684', (43, 47))	('increased', 'PosReg', (13, 22))
142195	22937319	In our patient, chromosome analysis revealed complex clonal aberrations with deletion of 5q.	('deletion of', 'Var', (77, 88))	('revealed', 'Reg', (36, 44))	('patient', 'Species', '9606', (7, 14))
142196	22937319	Deletion of 5q occurs in MDS/AML.	('AML', 'Disease', 'MESH:D015470', (29, 32))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('AML', 'Disease', (29, 32))	('MDS', 'Disease', (25, 28))	('MDS', 'Disease', 'MESH:D009190', (25, 28))	('Deletion', 'Var', (0, 8))
142265	22078023	As the analysis of our results indicates, CKS in Morocco exhibits some special clinico-epidemiological characteristics including nodular lesions as first presentation, a more frequent association with lymphedema, disseminated skin lesions at diagnosis, unusual visceral or lymph node involvement and rare coexistence of second primary neoplasm.	('CKS', 'Var', (42, 45))	('lymphedema', 'Disease', (201, 211))	('CKS', 'Chemical', '-', (42, 45))	('neoplasm', 'Disease', 'MESH:D009369', (335, 343))	('neoplasm', 'Phenotype', 'HP:0002664', (335, 343))	('nodular lesions', 'Disease', 'MESH:D020518', (129, 144))	('lymphedema', 'Disease', 'MESH:D008209', (201, 211))	('nodular lesions', 'Disease', (129, 144))	('skin lesions', 'Disease', 'MESH:D012871', (226, 238))	('lymphedema', 'Phenotype', 'HP:0001004', (201, 211))	('skin lesions', 'Disease', (226, 238))	('KS', 'Phenotype', 'HP:0100726', (43, 45))	('association', 'Interaction', (184, 195))	('men', 'Species', '9606', (291, 294))	('neoplasm', 'Disease', (335, 343))
142299	22078023	The findings of a large number (n = 5) of CKS in the penis in the current study may relate to an aggressive form of the disease.	('CKS', 'Var', (42, 45))	('CKS', 'Chemical', '-', (42, 45))	('relate to', 'Reg', (84, 93))	('aggressive form of the disease', 'Disease', (97, 127))	('KS', 'Phenotype', 'HP:0100726', (43, 45))
142335	30416982	As such, every cell within a tumor has equivalent tumorigenic potential, and random mutations in individual tumor cells promote the selection of the fittest clone.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('promote', 'PosReg', (120, 127))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('selection of the fittest clone', 'CPA', (132, 162))	('tumor', 'Disease', (50, 55))
142345	30416982	It has been suggested that the same transformed MSC can give a particular subtype of STS depending on the vulnerability to subsequent mutations involving specific developmental pathways or, alternatively, in the genesis of an undifferentiated sarcoma.	('STS', 'Disease', (85, 88))	('sarcoma', 'Disease', 'MESH:D012509', (243, 250))	('mutations', 'Var', (134, 143))	('sarcoma', 'Disease', (243, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))
142352	30416982	According to the type of genomic alteration, STSs can be classified into two main categories: (i) recurrent translocation-driven STSs, where reciprocal chromosomal translocations result in oncogenic fusion transcripts such as PAX3-FOXO1 in alveolar RMS (ARMS), SS18-SSX in SS, FUS-CHOP in myxoid/round-cell LPS, and (ii) non-translocation driven STSs characterized by complex genetic changes such as amplifications/deletions in various chromosomal regions as observed in embryonal RMS (ERMS), FS, LMS, LPS and MPNSTs.	('STSs', 'Phenotype', 'HP:0030448', (45, 49))	('LPS', 'Disease', (307, 310))	('SSX', 'Gene', '6757', (266, 269))	('LPS', 'Phenotype', 'HP:0012034', (502, 505))	('RMS', 'Phenotype', 'HP:0002859', (481, 484))	('SS18', 'Gene', '6760', (261, 265))	('result in', 'Reg', (179, 188))	('LMS', 'Disease', (497, 500))	('LMS', 'Phenotype', 'HP:0100243', (497, 500))	('STSs', 'Phenotype', 'HP:0030448', (346, 350))	('SSX', 'Gene', (266, 269))	('PAX3', 'Gene', (226, 230))	('LPS', 'Disease', 'MESH:C536528', (307, 310))	('SS', 'Phenotype', 'HP:0012570', (261, 263))	('STSs', 'Phenotype', 'HP:0030448', (129, 133))	('FS', 'Phenotype', 'HP:0100244', (493, 495))	('RMS', 'Phenotype', 'HP:0002859', (249, 252))	('alveolar RMS', 'Disease', (240, 252))	('RMS', 'Phenotype', 'HP:0002859', (487, 490))	('LPS', 'Phenotype', 'HP:0012034', (307, 310))	('LPS', 'Disease', (502, 505))	('RMS', 'Phenotype', 'HP:0002859', (255, 258))	('PAX3', 'Gene', '5077', (226, 230))	('FUS', 'Gene', (277, 280))	('translocations', 'Var', (164, 178))	('FOXO1', 'Gene', '2308', (231, 236))	('SS18', 'Gene', (261, 265))	('alveolar RMS', 'Disease', 'MESH:D002282', (240, 252))	('SS', 'Phenotype', 'HP:0012570', (273, 275))	('SS', 'Phenotype', 'HP:0012570', (266, 268))	('LPS', 'Disease', 'MESH:C536528', (502, 505))	('FUS', 'Gene', '2521', (277, 280))	('FOXO1', 'Gene', (231, 236))
142353	30416982	Fusion-positive STSs are characterized by cells that are morphologically and molecularly similar with the fusion oncoprotein as the major driver of the malignancy.	('STSs', 'Phenotype', 'HP:0030448', (16, 20))	('malignancy', 'Disease', (152, 162))	('Fusion-positive', 'Var', (0, 15))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))
142356	30416982	Genetically, approximately 80% of the cases are characterized by a t or t chromosomal translocation, which generates the fusion oncoproteins PAX3-FOXO1 or PAX7-FOXO1 that work as mutant transcription factors.	('PAX7', 'Gene', '5081', (155, 159))	('t or t chromosomal translocation', 'Var', (67, 99))	('FOXO1', 'Gene', (160, 165))	('FOXO1', 'Gene', '2308', (160, 165))	('FOXO1', 'Gene', '2308', (146, 151))	('PAX7', 'Gene', (155, 159))	('PAX3', 'Gene', '5077', (141, 145))	('FOXO1', 'Gene', (146, 151))	('PAX3', 'Gene', (141, 145))
142371	30416982	Consistently, silencing of SYT-SSX induced terminal differentiation of SS cells into multiple mesenchymal lineages (osteogenic, chondrogenic and adipogenic types).	('silencing', 'Var', (14, 23))	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('SSX', 'Gene', (31, 34))	('terminal differentiation', 'CPA', (43, 67))	('induced', 'Reg', (35, 42))	('SS', 'Phenotype', 'HP:0012570', (31, 33))	('SSX', 'Gene', '6757', (31, 34))	('adipogenic types', 'CPA', (145, 161))	('chondrogenic', 'CPA', (128, 140))
142372	30416982	On the one hand, these data point to MSCs as a cell of origin of SS and suggest that deregulation of normal differentiation by SYT-SSX could constitute the basis for MSC transformation.	('SSX', 'Gene', (131, 134))	('deregulation', 'Var', (85, 97))	('SSX', 'Gene', '6757', (131, 134))	('SS', 'Phenotype', 'HP:0012570', (131, 133))	('MSC', 'Disease', (166, 169))	('SS', 'Phenotype', 'HP:0012570', (65, 67))
142373	30416982	showed that SS cell lines, similarly to SS clinical samples, contain a subpopulation of cells characterized by high levels of the pluripotency factors SOX2, OCT4, and NANOG and that exhibit in vitro self-renewal ability and in vivo tumorigenicity following xenografting.	('NANOG', 'Var', (167, 172))	('self-renewal ability', 'CPA', (199, 219))	('SS', 'Phenotype', 'HP:0012570', (40, 42))	('OCT4', 'MPA', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('pluripotency factors', 'Disease', (130, 150))	('pluripotency factors', 'Disease', 'MESH:D005171', (130, 150))	('levels', 'MPA', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('clinical samples', 'Species', '191496', (43, 59))	('tumor', 'Disease', (232, 237))	('SOX2', 'Gene', '6657', (151, 155))	('SS', 'Phenotype', 'HP:0012570', (12, 14))	('SOX2', 'Gene', (151, 155))
142375	30416982	These studies identified a subpopulation of cells characterized by increased levels of OCT3/4, NANOG, SOX2, and SOX10, possessing stem-like characteristics such as self-renewal ability, proliferation and increased chemoresistance partly conferred by the overexpression of the multidrug resistance transporter MDR1.	('NANOG', 'Var', (95, 100))	('self-renewal ability', 'CPA', (164, 184))	('drug resistance', 'Phenotype', 'HP:0020174', (281, 296))	('SOX10', 'Gene', (112, 117))	('chemoresistance', 'CPA', (214, 229))	('proliferation', 'CPA', (186, 199))	('SOX10', 'Gene', '6663', (112, 117))	('increased', 'PosReg', (204, 213))	('MDR1', 'Gene', (309, 313))	('OCT3/4', 'Gene', '5460', (87, 93))	('increased', 'PosReg', (67, 76))	('SOX2', 'Gene', '6657', (102, 106))	('MDR1', 'Gene', '5243', (309, 313))	('OCT3/4', 'Gene', (87, 93))	('SOX2', 'Gene', (102, 106))
142378	30416982	NF1 syndrome is characterized by mutation-induced inactivation or more rarely complete germline loss of one NF1 allele that often leads to either dermal or plexiform benign neurofibromas.	('NF1', 'Gene', '4763', (108, 111))	('mutation-induced', 'Reg', (33, 49))	('leads to', 'Reg', (130, 138))	('loss', 'Var', (96, 100))	('neurofibromas', 'Phenotype', 'HP:0001067', (173, 186))	('NF1', 'Gene', '4763', (0, 3))	('neurofibroma', 'Phenotype', 'HP:0001067', (173, 185))	('NF1 syndrome', 'Disease', (0, 12))	('benign neurofibromas', 'Disease', (166, 186))	('NF1', 'Gene', (0, 3))	('inactivation', 'Var', (50, 62))	('NF1', 'Gene', (108, 111))	('benign neurofibromas', 'Disease', 'MESH:D009455', (166, 186))	('NF1 syndrome', 'Disease', 'MESH:C537392', (0, 12))
142379	30416982	The latter neurofibroma subtype, arising in nerve plexuses or deep large nerves, occurs following de novo somatic mutations or inactivation of the other NF1 allele specifically in the Schwann cell lineage and can undergo malignant transformation in MPNSTs.	('inactivation', 'Var', (127, 139))	('neurofibroma', 'Phenotype', 'HP:0001067', (11, 23))	('NF1', 'Gene', (153, 156))	('NF1', 'Gene', '4763', (153, 156))	('neurofibroma subtype', 'Disease', 'MESH:D009455', (11, 31))	('neurofibroma subtype', 'Disease', (11, 31))
142381	30416982	In addition, inactivating mutations of NF1 have been reported in adult tumors including brain, lung and ovarian cancers and in melanomas.	('inactivating mutations', 'Var', (13, 35))	('brain', 'Disease', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('NF1', 'Gene', (39, 42))	('melanomas', 'Disease', (127, 136))	('adult tumors', 'Disease', 'MESH:C538052', (65, 77))	('lung and ovarian cancers', 'Disease', 'MESH:D010051', (95, 119))	('NF1', 'Gene', '4763', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('adult tumors', 'Disease', (65, 77))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('reported', 'Reg', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian cancers', 'Phenotype', 'HP:0100615', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('melanomas', 'Disease', 'MESH:D008545', (127, 136))
142386	30416982	CDKN2A encodes for both p19ARF and p16INK4A and thus its inactivation can affect both p19ARF-MDM2-p53 and p16INK4A-Cyclin D-RB pathways leading to uncontrolled proliferation.	('leading to', 'Reg', (136, 146))	('p16INK4A', 'Gene', (106, 114))	('p53', 'Gene', (98, 101))	('MDM2', 'Gene', '4193', (93, 97))	('p16INK4A', 'Gene', '1029', (106, 114))	('p19ARF', 'Gene', '1029', (24, 30))	('uncontrolled proliferation', 'CPA', (147, 173))	('p19ARF', 'Gene', (24, 30))	('Cyclin', 'Gene', (115, 121))	('affect', 'Reg', (74, 80))	('CDKN2A', 'Gene', (0, 6))	('inactivation', 'Var', (57, 69))	('p19ARF', 'Gene', '1029', (86, 92))	('p19ARF', 'Gene', (86, 92))	('p16INK4A', 'Gene', (35, 43))	('Cyclin', 'Gene', '5111', (115, 121))	('MDM2', 'Gene', (93, 97))	('p53', 'Gene', '7157', (98, 101))	('CDKN2A', 'Gene', '1029', (0, 6))	('p16INK4A', 'Gene', '1029', (35, 43))
142394	30416982	In addition, PTEN point mutations as well as constitutive hyperactivation of PI3K/AKT pathway, have been detected in LMS, suggesting that loss of PTEN might contribute to the initiation or progression of LMS.	('hyperactivation', 'PosReg', (58, 73))	('LMS', 'Disease', (117, 120))	('PTEN', 'Gene', (146, 150))	('loss', 'Var', (138, 142))	('PTEN', 'Gene', '5728', (146, 150))	('LMS', 'Phenotype', 'HP:0100243', (117, 120))	('LMS', 'Disease', (204, 207))	('detected', 'Reg', (105, 113))	('AKT', 'Gene', '207', (82, 85))	('point mutations', 'Var', (18, 33))	('contribute', 'Reg', (157, 167))	('LMS', 'Phenotype', 'HP:0100243', (204, 207))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('AKT', 'Gene', (82, 85))
142395	30416982	showed that methylation-dependent silencing of CDKN2A, which is associated with decreased expression of both p16INK4A and p14ARF and with higher activity of MDM2 and CDK4/CDK6, results in LMS progression.	('CDK4', 'Gene', '1019', (166, 170))	('activity', 'MPA', (145, 153))	('MDM2', 'Gene', '4193', (157, 161))	('expression', 'MPA', (90, 100))	('p14ARF', 'Gene', '1029', (122, 128))	('results in', 'Reg', (177, 187))	('decreased', 'NegReg', (80, 89))	('silencing', 'NegReg', (34, 43))	('p16INK4A', 'Gene', (109, 117))	('p14ARF', 'Gene', (122, 128))	('CDKN2A', 'Gene', (47, 53))	('CDK6', 'Gene', '1021', (171, 175))	('p16INK4A', 'Gene', '1029', (109, 117))	('higher', 'PosReg', (138, 144))	('CDK4', 'Gene', (166, 170))	('CDK6', 'Gene', (171, 175))	('MDM2', 'Gene', (157, 161))	('LMS', 'Disease', (188, 191))	('CDKN2A', 'Gene', '1029', (47, 53))	('methylation-dependent', 'Var', (12, 33))	('LMS', 'Phenotype', 'HP:0100243', (188, 191))
142397	30416982	By using Cre-Lox technology to generate murine MSC cultures knock-out for Trp53 and Rb1 alone or in combination, Rubio et al.	('murine', 'Species', '10090', (40, 46))	('Rb1', 'Gene', (84, 87))	('knock-out', 'Var', (60, 69))	('Lox', 'Gene', (13, 16))	('Rb1', 'Gene', '19645', (84, 87))	('Trp53', 'Gene', (74, 79))	('Lox', 'Gene', '16948', (13, 16))
142398	30416982	showed that Tp53-/- mouse adult MSCs underwent in vitro transformation and developed LMS-like tumors in vivo when injected as xenografts in immunodeficient mice.	('immunodeficient', 'Disease', 'MESH:D007153', (140, 155))	('immunodeficient', 'Disease', (140, 155))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('LMS', 'Phenotype', 'HP:0100243', (85, 88))	('underwent', 'Reg', (37, 46))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('Tp53-/-', 'Var', (12, 19))	('mice', 'Species', '10090', (156, 160))	('developed', 'PosReg', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('mouse', 'Species', '10090', (20, 25))
142412	30416982	In support of this, Rodriguez and colleagues showed that the expression of a FUS-CHOP transgene in Trp53-deficient mouse ASCs was able to shift the tumor phenotype toward LPS-like tumors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('LPS', 'Disease', 'MESH:C536528', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('expression', 'Var', (61, 71))	('tumor', 'Disease', (180, 185))	('FUS', 'Gene', (77, 80))	('shift', 'Reg', (138, 143))	('FUS', 'Gene', '2521', (77, 80))	('mouse', 'Species', '10090', (115, 120))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('LPS', 'Phenotype', 'HP:0012034', (171, 174))	('LPS', 'Disease', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('Trp53-deficient', 'Gene', (99, 114))
142413	30416982	Consistently, the expression of FUS-CHOP in murine MSCs resulted in the development of tumors resembling LPS with features such as intracellular lipid accumulation, presence of lipoblasts with round nuclei, and an adipocyte differentiation block.	('resulted in', 'Reg', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FUS', 'Gene', (32, 35))	('LPS', 'Disease', 'MESH:C536528', (105, 108))	('lipoblasts', 'CPA', (177, 187))	('FUS', 'Gene', '2521', (32, 35))	('murine', 'Species', '10090', (44, 50))	('LPS', 'Phenotype', 'HP:0012034', (105, 108))	('intracellular lipid accumulation', 'MPA', (131, 163))	('LPS', 'Disease', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('lipid', 'Chemical', 'MESH:D008055', (145, 150))	('tumors', 'Disease', (87, 93))	('expression', 'Var', (18, 28))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('adipocyte differentiation block', 'CPA', (214, 245))
142416	30416982	They propose that additional secondary mutations could lead to morphologically diverse tumors arising from the same stage of transformation.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutations', 'Var', (39, 48))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('lead to', 'Reg', (55, 62))
142431	30416982	The first idea for CSCs isolation based on the expression of certain surface markers came with the identification of a small subset of leukemic stem cells with a CD34+CD38- phenotype.	('leukemic', 'Disease', 'MESH:D007938', (135, 143))	('leukemic', 'Disease', (135, 143))	('CD34+CD38-', 'Var', (162, 172))
142441	30416982	Interestingly, CXCR4 was found highly expressed on the surface of ARMS cells, where it correlates with unfavorable primary sites, advanced stage, decreased overall survival and bone marrow involvement, and was also used as a prognostic marker for MPNSTs, LMS, LPS and FS.	('overall survival', 'CPA', (156, 172))	('decreased', 'NegReg', (146, 155))	('MPNSTs', 'Disease', (247, 253))	('LPS', 'Phenotype', 'HP:0012034', (260, 263))	('LPS', 'Disease', (260, 263))	('FS', 'Phenotype', 'HP:0100244', (268, 270))	('CXCR4', 'Var', (15, 20))	('bone marrow involvement', 'Disease', (177, 200))	('bone marrow involvement', 'Disease', 'MESH:D001855', (177, 200))	('LMS', 'Disease', (255, 258))	('RMS', 'Phenotype', 'HP:0002859', (67, 70))	('LPS', 'Disease', 'MESH:C536528', (260, 263))	('LMS', 'Phenotype', 'HP:0100243', (255, 258))
142448	30416982	It was found upregulated in tumor cell spheres derived from MPNSTs compared to their corresponding adherent cells and overexpressed in RMS.	('tumor', 'Disease', (28, 33))	('upregulated', 'PosReg', (13, 24))	('MPNSTs', 'Var', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('RMS', 'Phenotype', 'HP:0002859', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
142465	30416982	Alternative methods to reprogram cancer cells include: the transfection of cancer cells with the family of micro-RNA miR-302 that is highly expressed in ES cells, thus generating pluripotent stem-like cells with both self-renewal and multipotency properties; the use of small chemical molecules to enrich for cancer stem-like cells endowed with increased in vitro tumor-sphere formation and in vivo tumorigenic abilities; and the application of the iPSC technology to primary tumor cells to successfully convert several cancer types into induced-pluripotent cancer stem cells (iPCSCs).	('cancer', 'Disease', (558, 564))	('cancer', 'Disease', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (558, 564))	('tumor', 'Phenotype', 'HP:0002664', (476, 481))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (520, 526))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('pluripotent cancer', 'Disease', 'MESH:D009369', (546, 564))	('tumor', 'Disease', (399, 404))	('cancer', 'Disease', 'MESH:D009369', (558, 564))	('cancer', 'Disease', (309, 315))	('tumor', 'Disease', 'MESH:D009369', (399, 404))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('transfection', 'Var', (59, 71))	('tumor', 'Disease', (476, 481))	('pluripotent cancer', 'Disease', (546, 564))	('cancer', 'Disease', (520, 526))	('tumor', 'Disease', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (476, 481))	('cancer', 'Phenotype', 'HP:0002664', (520, 526))	('tumor', 'Phenotype', 'HP:0002664', (399, 404))	('cancer', 'Disease', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (364, 369))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (309, 315))
142467	30416982	In fact, aberrant stemness signaling has been related to tumorigenesis, as deregulation of these pathways in adult SCs can lead to unchecked cell proliferation and aberrant differentiation in a tissue-specific manner.	('unchecked cell proliferation', 'CPA', (131, 159))	('lead to', 'Reg', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('aberrant differentiation', 'CPA', (164, 188))	('tumor', 'Disease', (57, 62))	('deregulation', 'Var', (75, 87))
142476	30416982	Dysregulation of the Hippo pathway has been linked to cancer development, including STSs.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('STSs', 'Disease', (84, 88))	('Hippo pathway', 'Pathway', (21, 34))	('linked', 'Reg', (44, 50))	('STSs', 'Phenotype', 'HP:0030448', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
142486	30416982	In this study, inhibition of the Wnt pathway with small molecule CK1alpha activators induced SS growth arrest and, importantly, reversed the myogenesis block induced by the fusion oncoprotein by downregulating many of the Wnt/beta-catenin targets involved in the embryonic program, including pluripotency factors, differentiation blockades, embryonic lineage determinants, homeobox, and forkhead box factors, suggesting that targeting this pathway may a rational approach in patients with SS.	('pluripotency factors', 'Disease', 'MESH:D005171', (292, 312))	('growth arrest', 'Phenotype', 'HP:0001510', (96, 109))	('myogenesis', 'CPA', (141, 151))	('patients', 'Species', '9606', (475, 483))	('CK1', 'Species', '2498238', (65, 68))	('SS growth arrest', 'Disease', (93, 109))	('CK1alpha', 'Gene', (65, 73))	('SS', 'Phenotype', 'HP:0012570', (489, 491))	('pluripotency factors', 'Disease', (292, 312))	('SS growth arrest', 'Disease', 'MESH:D006323', (93, 109))	('downregulating', 'NegReg', (195, 209))	('SS', 'Phenotype', 'HP:0012570', (93, 95))	('inhibition', 'Var', (15, 25))
142488	30416982	Data were confirmed in murine models of MPNST and in primary samples from patients, and the translational relevance was verified from the evidence that the blockade of this pathway affected the tumorigenic properties of tumor cell lines in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (220, 225))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('murine', 'Species', '10090', (23, 29))	('affected', 'Reg', (181, 189))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('blockade', 'Var', (156, 164))
142492	30416982	Some cancer cells have bivalently marked genes that correspond to those in embryonic SCs, but a remarkable number of regions that are bivalently marked in SCs are frequently hypermethylated and thus completely silenced in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('embryonic SCs', 'Disease', (75, 88))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', (5, 11))	('hypermethylated', 'Var', (174, 189))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('silenced', 'NegReg', (210, 218))	('embryonic SCs', 'Disease', 'MESH:C535687', (75, 88))
142493	30416982	Local DNA hypermethylation at tumor suppressor genes or genes associated with differentiation has been shown to predispose precancerous cells to oncogenic transformation and CSC establishment.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('oncogenic transformation', 'CPA', (145, 169))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('predispose', 'Reg', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Local DNA', 'Var', (0, 9))	('CSC establishment', 'CPA', (174, 191))	('tumor', 'Disease', (30, 35))
142501	30416982	Thus, it is not surprising that epigenetic modifiers constitute the most altered genes in both solid cancers and hematological malignancies.	('hematological malignancies', 'Disease', (113, 139))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('epigenetic modifiers', 'Var', (32, 52))	('altered', 'Reg', (73, 80))	('hematological malignancies', 'Disease', 'MESH:D019337', (113, 139))	('hematological malignancies', 'Phenotype', 'HP:0004377', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
142506	30416982	Also, a direct involvement of PRC2 components in the progression from neurofibroma to MPNST has been demonstrated showing that, surprisingly, EZH2 works as a tumor suppressor, and the detection of the loss of H3K27 trimethylation has entered the clinical practice to help in the diagnosis of MPNST.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('neurofibroma', 'Disease', (70, 82))	('neurofibroma', 'Phenotype', 'HP:0001067', (70, 82))	('loss', 'Var', (201, 205))	('neurofibroma', 'Disease', 'MESH:D009455', (70, 82))	('EZH2', 'Gene', (142, 146))	('EZH2', 'Gene', '2146', (142, 146))	('clinical', 'Species', '191496', (246, 254))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('MPNST', 'Disease', (292, 297))	('H3K27', 'Protein', (209, 214))
142509	30416982	Together, these data indicate that alterations in chromatin status may represent a key step for CSC formation and maintenance, by inducing the activation of several stemness signals in differentiated cancer cells.	('CSC', 'Disease', (96, 99))	('inducing', 'Reg', (130, 138))	('alterations', 'Var', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('stemness', 'CPA', (165, 173))	('activation', 'PosReg', (143, 153))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
142511	30416982	In RMS, several lines of evidence suggested that alteration of SWI/SNF components might help to maintain tumor cells in a less-differentiated state.	('RMS', 'Phenotype', 'HP:0002859', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('alteration', 'Var', (49, 59))	('tumor', 'Disease', (105, 110))
142513	30416982	Likewise, silencing of the SWI/SNF complex subunit BAF53a, which has been found hyper-expressed in primary RMS tumors compared to normal muscle, increases the expression of myogenic markers contributing to the differentiation program.	('myogenic', 'Protein', (173, 181))	('BAF53a', 'Gene', '86', (51, 57))	('RMS tumors', 'Disease', 'MESH:D009369', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('expression', 'MPA', (159, 169))	('increases', 'PosReg', (145, 154))	('BAF53a', 'Gene', (51, 57))	('RMS', 'Phenotype', 'HP:0002859', (107, 110))	('silencing', 'Var', (10, 19))	('RMS tumors', 'Disease', (107, 117))
142519	30416982	Since many STSs have unique signature translocations that drive their tumorigenesis, can we compare and contrast the impact of the encoded oncogenic fusion proteins on CSC stemness and identify commonalities to target?	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('STSs', 'Phenotype', 'HP:0030448', (11, 15))	('tumor', 'Disease', (70, 75))	('drive', 'Reg', (58, 63))	('translocations', 'Var', (38, 52))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
142606	32382649	The most common genetic alteration identified in ESN is t(7;17)(p15;g21), resulting in the fusion of the JAZFI-SUZ12 genes, which is also present in about 48% of LG-ESS.	('LG-ESS', 'Chemical', '-', (162, 168))	('fusion', 'Var', (91, 97))	('p15', 'Gene', (64, 67))	('p15', 'Gene', '1030', (64, 67))	('ESN', 'Chemical', '-', (49, 52))	('SUZ12', 'Gene', '23512', (111, 116))	('SUZ12', 'Gene', (111, 116))
142613	32382649	The patient is a 37-year-old Caucasian female, G2P2-0-0-2, who presented with abdominal pain and bright red blood per rectum with no other symptoms or significant medical, surgical and gynecologic history.	('abdominal pain', 'Disease', (78, 92))	('abdominal pain', 'Disease', 'MESH:D015746', (78, 92))	('patient', 'Species', '9606', (4, 11))	('pain', 'Phenotype', 'HP:0012531', (88, 92))	('abdominal pain', 'Phenotype', 'HP:0002027', (78, 92))	('G2P2-0-0-2', 'Var', (47, 57))
142675	32231779	Immune infiltrate analysis median (range) density in cells/mm2 varied broadly: CD3 178 (15-802); CD8 117 (11-661); FoxP3 4.8 (0.2-82); CD163 791 (264-1861); and PD1 5 (1-65).	('CD8', 'Gene', '925', (97, 100))	('FoxP3', 'Gene', '50943', (115, 120))	('CD163 791', 'Var', (135, 144))	('CD8', 'Gene', (97, 100))	('FoxP3', 'Gene', (115, 120))	('PD1', 'Gene', '5133', (161, 164))	('CD3', 'Var', (79, 82))	('PD1', 'Gene', (161, 164))
142688	32231779	Immunotherapy, particularly with blockade of the PD-1/PD-L1 pathway (programmed death-1/programmed death ligand-1) has proven effective in numerous malignancies, such as malignant melanoma, non-small cell lung cancer, renal cell carcinoma, and Hodgkin's Lymphoma, though results are still limited for sarcomas.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (194, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('sarcomas', 'Disease', 'MESH:D012509', (301, 309))	('sarcoma', 'Phenotype', 'HP:0100242', (301, 308))	("Hodgkin's Lymphoma", 'Disease', 'MESH:D006689', (244, 262))	("Hodgkin's Lymphoma", 'Phenotype', 'HP:0012189', (244, 262))	('sarcomas', 'Phenotype', 'HP:0100242', (301, 309))	('numerous malignancies', 'Disease', 'MESH:D009369', (139, 160))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (190, 216))	('sarcomas', 'Disease', (301, 309))	("Hodgkin's Lymphoma", 'Disease', (244, 262))	('PD-1', 'Gene', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('PD-1', 'Gene', '5133', (49, 53))	('renal cell carcinoma', 'Disease', (218, 238))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (218, 238))	('malignant melanoma', 'Disease', (170, 188))	('Lymphoma', 'Phenotype', 'HP:0002665', (254, 262))	('numerous malignancies', 'Disease', (139, 160))	('blockade', 'Var', (33, 41))	('non-small cell lung cancer', 'Disease', (190, 216))	('PD-L1', 'Gene', (54, 59))	('PD-L1', 'Gene', '29126', (54, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('malignant melanoma', 'Phenotype', 'HP:0002861', (170, 188))	('malignant melanoma', 'Disease', 'MESH:D008545', (170, 188))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (190, 216))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 238))
142722	32231779	For example, the median and range for CD3 was 178 (15-802), CD8 was 117 (11-661), FoxP3 was 4.8 (0.2-82), CD163 was 791 (264-1861), and for PD1 was 5 (1-65) (Table 2).	('PD1', 'Gene', (140, 143))	('CD163', 'Var', (106, 111))	('CD8', 'Gene', '925', (60, 63))	('FoxP3', 'Gene', '50943', (82, 87))	('FoxP3', 'Gene', (82, 87))	('PD1', 'Gene', '5133', (140, 143))	('CD8', 'Gene', (60, 63))
142739	32231779	Similar findings have been seen in ovarian cancers where the presence of CD3 was found to be a strong prognostic factor of 10-year survival rates.	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('ovarian cancers', 'Disease', 'MESH:D010051', (35, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('CD3', 'Gene', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('presence', 'Var', (61, 69))	('ovarian cancers', 'Phenotype', 'HP:0100615', (35, 50))	('ovarian cancers', 'Disease', (35, 50))
142740	32231779	The presence of CD8 was associated with improved 5 and 10-year survival.	('presence', 'Var', (4, 12))	('CD8', 'Gene', (16, 19))	('CD8', 'Gene', '925', (16, 19))	('improved', 'PosReg', (40, 48))
142741	32231779	TILs have also been have associated with improved outcomes in some soft tissue sarcoma subtypes and the presence of TILs may be a predictor of more favorable outcomes in uterine adenosarcomas.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (67, 86))	('TIL', 'Gene', '7096', (116, 119))	('improved', 'PosReg', (41, 49))	('TIL', 'Gene', '7096', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (67, 86))	('sarcoma subtype', 'Disease', 'MESH:D012509', (79, 94))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('TIL', 'Gene', (116, 119))	('soft tissue sarcoma', 'Disease', (67, 86))	('TIL', 'Gene', (0, 3))	('adenosarcomas', 'Disease', (178, 191))	('adenosarcomas', 'Disease', 'MESH:D018195', (178, 191))	('sarcoma subtype', 'Disease', (79, 94))	('presence', 'Var', (104, 112))
142824	27075180	Multiplicity may affect assignment of severity score of mild as that was mentioned as a factor during the discussion of these cases.	('Multiplicity', 'Var', (0, 12))	('affect', 'Reg', (17, 23))	('men', 'Species', '9606', (73, 76))	('men', 'Species', '9606', (30, 33))
143000	27075180	The literature reports greater than 50 cationic amphophilic drugs can cause drug-induced phospholipidosis.	('rat', 'Species', '10116', (8, 11))	('cationic amphophilic drugs', 'Var', (39, 65))	('cause', 'Reg', (70, 75))	('greater', 'Species', '9217', (23, 30))	('phospholipidosis', 'Disease', (89, 105))	('phospholipidosis', 'Disease', 'None', (89, 105))
143204	22787122	PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3), which then recruits Akt to the membrane where it is activated by phosphorylation.	('PI3K', 'Var', (0, 4))	('phosphatidylinositol 3,4,5-triphosphate', 'Chemical', 'MESH:C060974', (62, 101))	('Akt', 'Gene', '207', (130, 133))	('PIP2', 'Chemical', 'MESH:D019269', (53, 57))	('phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (14, 51))	('PIP3', 'Chemical', '-', (103, 107))	('Akt', 'Gene', (130, 133))	('recruits', 'PosReg', (121, 129))
143209	22787122	The PI3K/Akt/mTOR pathway is activated in sarcomas via several mechanisms, including genetic mutations within the pathway (e.g.	('sarcomas', 'Disease', 'MESH:D012509', (42, 50))	('activated', 'PosReg', (29, 38))	('mutations', 'Var', (93, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Akt', 'Gene', (9, 12))	('sarcomas', 'Disease', (42, 50))	('genetic mutations', 'Var', (85, 102))	('Akt', 'Gene', '207', (9, 12))
143210	22787122	KIT and PDGFRA mutations in gastrointestinal stromal tumors (GIST); PIK3CA mutations in myxoid/round-cell liposarcomas) or other pathognomonic alterations that promote reliance upon the pathway (e.g.	('PIK3CA', 'Gene', (68, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (28, 59))	('mutations', 'Var', (15, 24))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (28, 59))	('liposarcomas', 'Phenotype', 'HP:0012034', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PDGFRA', 'Gene', (8, 14))	('PIK3CA', 'Gene', '5290', (68, 74))	('liposarcomas', 'Disease', 'MESH:D008080', (106, 118))	('mutations', 'Var', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('liposarcomas', 'Disease', (106, 118))	('KIT', 'Gene', (0, 3))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))	('gastrointestinal stromal tumors', 'Disease', (28, 59))
143218	22787122	The observation that combining rapalogues with IGF-1R inhibitors results in suppression of Akt activation and enhancement of drug-mediated anti-proliferative effects in preclinical models led to efforts to clinically develop this combination for sarcoma patients.	('enhancement', 'PosReg', (110, 121))	('clinical', 'Species', '191496', (172, 180))	('Akt', 'Gene', '207', (91, 94))	('sarcoma', 'Disease', 'MESH:D012509', (246, 253))	('inhibitors', 'Var', (54, 64))	('suppression', 'NegReg', (76, 87))	('IGF-1R', 'Gene', '3480', (47, 53))	('Akt', 'Gene', (91, 94))	('drug-mediated anti-proliferative effects', 'MPA', (125, 165))	('IGF-1R', 'Gene', (47, 53))	('activation', 'PosReg', (95, 105))	('sarcoma', 'Disease', (246, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('patients', 'Species', '9606', (254, 262))	('clinical', 'Species', '191496', (206, 214))
143221	22787122	R1507 (Roche) is a fully human monoclonal antibody (IgG1) that binds the extracellular domain of IGF-1R with high affinity, causing displacement of IGF-1 and IGF-2 from the receptor as well as downregulation of receptor levels.	('downregulation', 'NegReg', (193, 207))	('R1507', 'Var', (0, 5))	('IGF-1', 'Gene', '3479', (97, 102))	('IGF-1', 'Gene', (97, 102))	('IGF-1R', 'Gene', '3480', (97, 103))	('IGF-2', 'Gene', '3481', (158, 163))	('IGF-1R', 'Gene', (97, 103))	('receptor levels', 'MPA', (211, 226))	('human', 'Species', '9606', (25, 30))	('displacement', 'MPA', (132, 144))	('IGF-1', 'Gene', '3479', (148, 153))	('IGF-1', 'Gene', (148, 153))	('IGF-2', 'Gene', (158, 163))
143238	22787122	The SYT-SSX siRNA was previously published and validated; the sense and antisense sequences 5'-CCAGAUCAUGCCCAAGAAGdTdT-3' and 5'-CUUCUUGGGCAUGAUCUGGdTdT-3' target the breakpoint of both Type I and Type II fusions.	('SSX', 'Gene', (8, 11))	('SYT', 'Gene', '6760', (4, 7))	("5'-CCAGAUCAUGCCCAAGAAGdTdT-3'", 'Var', (92, 121))	('SYT', 'Gene', (4, 7))	('SSX', 'Gene', '6757', (8, 11))
143252	22787122	The impact of mTORC1 and IGF-1R inhibition with rapamycin and R1507, respectively, was evaluated in a panel of 12 non-GIST soft-tissue and bone sarcoma cell lines.	('mTORC1', 'Gene', (14, 20))	('bone sarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('soft-tissue and bone sarcoma', 'Phenotype', 'HP:0030448', (123, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('R1507', 'Var', (62, 67))	('bone sarcoma', 'Disease', 'MESH:D001847', (139, 151))	('IGF-1R', 'Gene', (25, 31))	('mTORC1', 'Gene', '382056', (14, 20))	('bone sarcoma', 'Disease', (139, 151))	('IGF-1R', 'Gene', '3480', (25, 31))	('rapamycin', 'Chemical', 'MESH:D020123', (48, 57))
143256	22787122	In all the cell lines with detectable IGF-1R protein, R1507 reduced IGF-1R protein levels, indicative of receptor internalization/degradation, a marker of antibody-mediated IGF-1R targeting.	('reduced IGF-1R', 'Phenotype', 'HP:0030269', (60, 74))	('IGF-1R', 'Gene', '3480', (173, 179))	('IGF-1R', 'Gene', (173, 179))	('internalization/degradation', 'MPA', (114, 141))	('reduced', 'NegReg', (60, 67))	('IGF-1R', 'Gene', '3480', (68, 74))	('IGF-1R', 'Gene', '3480', (38, 44))	('IGF-1R', 'Gene', (68, 74))	('IGF-1R', 'Gene', (38, 44))	('R1507', 'Var', (54, 59))
143257	22787122	The impact of R1507-mediated IGF-1R inhibition was grouped into two categories.	('IGF-1R', 'Gene', (29, 35))	('IGF-1R', 'Gene', '3480', (29, 35))	('R1507-mediated', 'Var', (14, 28))
143258	22787122	For 7 cell lines (designated "Class I"), R1507 partially or completely suppressed rapamycin-induced Akt phosphorylation (Figure 1).	('Akt', 'Gene', (100, 103))	('rapamycin', 'Chemical', 'MESH:D020123', (82, 91))	('R1507', 'Var', (41, 46))	('Akt', 'Gene', '207', (100, 103))	('rapamycin-induced', 'MPA', (82, 99))	('suppressed', 'NegReg', (71, 81))
143259	22787122	In almost all these cells, R1507 alone also suppressed Akt phosphorylation, suggesting a degree of generalized IGF-1R dependence in Class I cells.	('Akt', 'Gene', (55, 58))	('IGF-1R', 'Gene', (111, 117))	('suppressed', 'NegReg', (44, 54))	('R1507', 'Var', (27, 32))	('Akt', 'Gene', '207', (55, 58))	('IGF-1R', 'Gene', '3480', (111, 117))
143260	22787122	In the five remaining cell lines (designated "Class II"), R1507 failed to suppress Akt phosphorylation alone or in combination with rapamycin (Figure 1).	('rapamycin', 'Chemical', 'MESH:D020123', (132, 141))	('R1507', 'Var', (58, 63))	('Akt', 'Gene', (83, 86))	('suppress', 'NegReg', (74, 82))	('Akt', 'Gene', '207', (83, 86))
143261	22787122	The impact upon Akt phosphorylation correlated to tumor cell viability: the R1507 and rapamycin combination cooperatively suppressed sarcoma cell viability in only the Class I, but not Class II, cells (Supplementary Figure 1).	('suppressed', 'NegReg', (122, 132))	('Akt', 'Gene', (16, 19))	('R1507', 'Var', (76, 81))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('sarcoma', 'Disease', (133, 140))	('Akt', 'Gene', '207', (16, 19))	('tumor', 'Disease', (50, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('rapamycin', 'Chemical', 'MESH:D020123', (86, 95))
143264	22787122	In fact, IGF-1R expression in the R1507-resistant synovial sarcoma cell line SYO-1 was comparable to that in the Class I synovial sarcoma cell line HS-SY-II (Figure 1), demonstrating that alternate mechanism(s) of rapamycin-induced Akt phosphorylation may be relevant even in the context of intact IGF-1R expression.	('IGF-1R', 'Gene', (9, 15))	('synovial sarcoma', 'Disease', 'MESH:D013584', (50, 66))	('SYO-1', 'Gene', '55027', (77, 82))	('SYO-1', 'Gene', (77, 82))	('synovial sarcoma', 'Disease', (121, 137))	('synovial sarcoma', 'Disease', (50, 66))	('synovial sarcoma', 'Disease', 'MESH:D013584', (121, 137))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (50, 66))	('HS-SY-II', 'CellLine', 'CVCL:8719', (148, 156))	('rapamycin', 'Chemical', 'MESH:D020123', (214, 223))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (121, 137))	('Akt', 'Gene', (232, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('Akt', 'Gene', '207', (232, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('R1507-resistant', 'Var', (34, 49))	('IGF-1R', 'Gene', '3480', (298, 304))	('IGF-1R', 'Gene', (298, 304))	('IGF-1R', 'Gene', '3480', (9, 15))
143292	22787122	High PDGFRA expression conferred a new susceptibility to imatinib-mediated inhibition of rapamycin-induced Akt phosphorylation (Figure 4A), suggesting that the level of PDGFRA expression may be a critical determinant of RTK dependence.	('Akt', 'Gene', (107, 110))	('High', 'Var', (0, 4))	('susceptibility', 'MPA', (39, 53))	('imatinib', 'Chemical', 'MESH:D000068877', (57, 65))	('rapamycin', 'Chemical', 'MESH:D020123', (89, 98))	('PDGFRA', 'Gene', (5, 11))	('Akt', 'Gene', '207', (107, 110))	('rapamycin-induced', 'MPA', (89, 106))
143295	22787122	Variability in the Xp11 breakpoint produces a fusion of the SYT gene with either the SSX1 or SSX2 (and rarely SSX4) genes.	('SSX2', 'Gene', (93, 97))	('SSX1', 'Gene', '6756', (85, 89))	('fusion', 'Interaction', (46, 52))	('produces', 'Reg', (35, 43))	('Variability', 'Var', (0, 11))	('p11', 'Gene', (20, 23))	('SYT', 'Gene', (60, 63))	('SSX1', 'Gene', (85, 89))	('SSX4', 'Gene', '6759', (110, 114))	('SSX2', 'Gene', '6757', (93, 97))	('SSX4', 'Gene', (110, 114))	('SYT', 'Gene', '6760', (60, 63))	('p11', 'Gene', '6281', (20, 23))
143308	22787122	In 25 synovial tumor cases and the two cell lines, no PDGFRA kinase (exons 12-16) or transmembrane (exons 18-21) domain mutations were found.	('synovial tumor', 'Phenotype', 'HP:0012570', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('synovial tumor', 'Disease', 'MESH:D013581', (6, 20))	('domain mutations', 'Var', (113, 129))	('synovial tumor', 'Disease', (6, 20))	('PDGFRA', 'Gene', (54, 60))
143312	22787122	Pre-therapy (within 2 weeks of starting drugs) and on-therapy (between the second and third week of treatment) tumor biopsies were performed on a patient who experienced a reduction in the size of lung metastases with everolimus (5 mg oral daily) and imatinib (400 mg oral daily) (Figure 5C).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('everolimus', 'Chemical', 'MESH:D000068338', (218, 228))	('lung metastases', 'Disease', (197, 212))	('400 mg', 'Var', (261, 267))	('tumor', 'Disease', (111, 116))	('lung metastases', 'Disease', 'MESH:D009362', (197, 212))	('reduction', 'NegReg', (172, 181))	('patient', 'Species', '9606', (146, 153))	('imatinib', 'Chemical', 'MESH:D000068877', (251, 259))
143319	22787122	A recent phase I study reported that 10 of 17 sarcoma patients treated with mTORC1 and IGF-1R inhibitors in combination still experienced increased tumor growth.	('increased', 'PosReg', (138, 147))	('IGF-1R', 'Gene', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Disease', (148, 153))	('sarcoma', 'Disease', (46, 53))	('mTORC1', 'Gene', '382056', (76, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('mTORC1', 'Gene', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('IGF-1R', 'Gene', '3480', (87, 93))	('inhibitors', 'Var', (94, 104))
143321	22787122	The R1507 +/- rapamycin sarcoma cell line screen presented here confirms that IGF-1R inhibition will not be an universally effective approach for overcoming intrinsic rapalogue resistance.	('intrinsic rapalogue resistance', 'MPA', (157, 187))	('sarcoma', 'Disease', (24, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('IGF-1R', 'Gene', (78, 84))	('inhibition', 'NegReg', (85, 95))	('IGF-1R', 'Gene', '3480', (78, 84))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('R1507 +/-', 'Var', (4, 13))	('rapamycin', 'Chemical', 'MESH:D020123', (14, 23))
143324	22787122	One study argued that the IGF-1R kinase inhibitor NVP-AEW541 can inhibit the proliferation of several synovial sarcoma cell lines, while another observed that these anti-proliferative effects could only be achieved with micromolar NVP-AEW541 concentrations 10 to 50 fold higher than those required for IGF-1R inhibition, implicating off-target drug effects rather than IGF-1R-dependence.	('IGF-1R', 'Gene', '3480', (369, 375))	('NVP-AEW541', 'Var', (50, 60))	('proliferation', 'CPA', (77, 90))	('IGF-1R', 'Gene', (369, 375))	('synovial sarcoma', 'Disease', (102, 118))	('IGF-1R', 'Gene', (26, 32))	('IGF-1R', 'Gene', '3480', (26, 32))	('IGF-1R', 'Gene', '3480', (302, 308))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (102, 118))	('inhibit', 'NegReg', (65, 72))	('synovial sarcoma', 'Disease', 'MESH:D013584', (102, 118))	('IGF-1R', 'Gene', (302, 308))
143329	22787122	Instead, we found that high PDGFRA expression mediates Akt phosphorylation in response to rapamycin in SYO-1 cells.	('Akt', 'Gene', (55, 58))	('rapamycin', 'Chemical', 'MESH:D020123', (90, 99))	('SYO-1', 'Gene', (103, 108))	('response to rapamycin', 'MPA', (78, 99))	('PDGFRA', 'Gene', (28, 34))	('high', 'Var', (23, 27))	('SYO-1', 'Gene', '55027', (103, 108))	('mediates', 'Reg', (46, 54))	('Akt', 'Gene', '207', (55, 58))
143331	22787122	Notably, high expression of a PDGFR pathway component has been demonstrated to be sufficient to drive oncogenesis in other sarcoma subtypes.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('high expression', 'Var', (9, 24))	('oncogenesis', 'CPA', (102, 113))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (123, 139))	('sarcoma subtypes', 'Disease', (123, 139))	('PDGFR pathway', 'Gene', (30, 43))	('drive', 'PosReg', (96, 101))
143332	22787122	The COL1A1-PDGFB fusion gene in dermatofibrosarcoma protuberans (DFSP) results in PDGF BB ligand overexpression, hyperactivation of the PDGFR pathway, and susceptibility to imatinib.	('PDGFB', 'Gene', (11, 16))	('COL1A1', 'Gene', (4, 10))	('overexpression', 'PosReg', (97, 111))	('susceptibility', 'MPA', (155, 169))	('dermatofibrosarcoma protuberans', 'Disease', (32, 63))	('PDGFR pathway', 'Pathway', (136, 149))	('fusion', 'Var', (17, 23))	('DFSP', 'Disease', (65, 69))	('PDGF BB', 'Gene', (82, 89))	('imatinib', 'Chemical', 'MESH:D000068877', (173, 181))	('DFSP', 'Disease', 'MESH:D018223', (65, 69))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (32, 63))	('PDGFB', 'Gene', '5155', (11, 16))	('hyperactivation', 'PosReg', (113, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('COL1A1', 'Gene', '1277', (4, 10))
143341	22787122	PDGFRA knockdown alone in HS- SY-II did result in decreased S6 RP phosphorylation and increased Akt phosphorylation (Figure 3A), while PDGFRA overexpression resulted in the opposite changes (Figure 4A).	('PDGFRA', 'Gene', (0, 6))	('increased', 'PosReg', (86, 95))	('decreased', 'NegReg', (50, 59))	('HS- SY', 'CellLine', 'CVCL:8719', (26, 32))	('Akt', 'Gene', '207', (96, 99))	('knockdown', 'Var', (7, 16))	('Akt', 'Gene', (96, 99))	('S6 RP', 'Protein', (60, 65))
143342	22787122	These observations suggest that at baseline PDGFRA may regulate mTOR activity in these cells and manipulating receptor expression can trigger changes to feedback pathways leading to Akt.	('mTOR activity', 'MPA', (64, 77))	('Akt', 'Gene', '207', (182, 185))	('regulate', 'Reg', (55, 63))	('Akt', 'Gene', (182, 185))	('manipulating', 'Var', (97, 109))	('feedback pathways leading', 'Pathway', (153, 178))	('changes', 'Reg', (142, 149))
143346	22787122	The SYT-SSX gene fusions are generally thought to promote oncogenesis in synovial sarcomas by altering chromatin remodeling and dysregulating the expression of several target genes.	('SSX', 'Gene', (8, 11))	('SYT', 'Gene', (4, 7))	('SYT', 'Gene', '6760', (4, 7))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('promote', 'PosReg', (50, 57))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (73, 89))	('oncogenesis', 'CPA', (58, 69))	('chromatin remodeling', 'MPA', (103, 123))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (73, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('altering', 'Reg', (94, 102))	('fusions', 'Var', (17, 24))	('synovial sarcomas', 'Disease', 'MESH:D013584', (73, 90))	('expression', 'MPA', (146, 156))	('synovial sarcomas', 'Disease', (73, 90))	('SSX', 'Gene', '6757', (8, 11))
143350	22787122	As for the mechanism by which rapamycin activates PDGFRA, mTORC1 inhibition has been shown to increase PDGFR transcript levels in hepatocellular tumor cells and in mTOR activated TSC1-/- or TSC2-/- mouse cells.	('PDGFR', 'Gene', (103, 108))	('TSC2', 'Gene', '22084', (190, 194))	('mTORC1', 'Gene', '382056', (58, 64))	('increase', 'PosReg', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TSC1', 'Gene', '64930', (179, 183))	('transcript levels', 'MPA', (109, 126))	('mTORC1', 'Gene', (58, 64))	('hepatocellular tumor', 'Phenotype', 'HP:0001402', (130, 150))	('TSC2', 'Gene', (190, 194))	('rapamycin', 'Chemical', 'MESH:D020123', (30, 39))	('hepatocellular tumor', 'Disease', 'MESH:D006528', (130, 150))	('inhibition', 'Var', (65, 75))	('TSC1', 'Gene', (179, 183))	('mouse', 'Species', '10090', (198, 203))	('hepatocellular tumor', 'Disease', (130, 150))
143372	34011115	DNA methylation is an epigenetic modification that is closely connected with gene expression regulation, and its signatures have great potential to become routine clinical cancer biomarkers due to their sensitivity, specificity, and ease of analysis.	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('methylation', 'Var', (4, 15))
143374	34011115	Moreover, epigenetic alterations, such as aberrant DNA methylation have great utility for cancer diagnosis in the early stage due to several advantages over other molecular markers, including their appearance early in tumorigenesis; wide distribution in the tumor tissue; and consistency across a larger genomic region, so that multiple CpG dinucleotides can be used for detection.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', (258, 263))	('DNA', 'Gene', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('aberrant', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
143396	34011115	To explore the clinical role of DNA methylation biomarkers in sarcoma patient prognosis, we first identified 35,499 DNA methylation sites that were significantly (P < .05) associated with the OS of sarcoma patients to serve as candidate biomarkers using univariate Cox proportional hazard regression analysis.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('OS of sarcoma', 'Disease', (192, 205))	('sites', 'Var', (132, 137))	('DNA', 'Gene', (116, 119))	('sarcoma', 'Disease', 'MESH:D012509', (198, 205))	('patient', 'Species', '9606', (206, 213))	('patient', 'Species', '9606', (70, 77))	('methylation sites', 'Var', (120, 137))	('associated', 'Reg', (172, 182))	('patients', 'Species', '9606', (206, 214))	('sarcoma', 'Disease', (198, 205))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('OS of sarcoma', 'Disease', 'MESH:C567932', (192, 205))	('sarcoma', 'Disease', (62, 69))
143397	34011115	Next, we performed multivariate Cox stepwise regression analysis and 3 methylation sites (cg07814289, cg09494609, and cg14144025) were ultimately screened as the optimum prognostic model for predicting the OS of patients with sarcoma (Table 3).	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('cg14144025', 'Var', (118, 128))	('cg07814289', 'Var', (90, 100))	('cg14144025', 'Chemical', '-', (118, 128))	('cg09494609', 'Var', (102, 112))	('cg07814289', 'Chemical', '-', (90, 100))	('patients', 'Species', '9606', (212, 220))	('sarcoma', 'Disease', 'MESH:D012509', (226, 233))	('sarcoma', 'Disease', (226, 233))	('cg09494609', 'Chemical', '-', (102, 112))
143398	34011115	We were thus able to establish a risk scoring formula for predicting OS based on the DNA methylation levels and regression coefficients of 3 methylation site results, as follows: Risk score = 0.025 x beta value of cg07814289 + 0.021 x beta value of cg09494609 + 0.015 x beta value of cg14144025.	('cg09494609 + 0.015', 'Var', (249, 267))	('cg14144025', 'Chemical', '-', (284, 294))	('cg14144025', 'Var', (284, 294))	('cg09494609', 'Chemical', '-', (249, 259))	('cg07814289', 'Chemical', '-', (214, 224))	('cg07814289 + 0.021', 'Var', (214, 232))
143399	34011115	Importantly, the 3-DNA methylation signature (cg07814289: P = .64, cg09494609: P = .87, cg14144025: P = .34) showed agreement with the proportional hazards (PH) assumption (Fig.	('cg09494609', 'Var', (67, 77))	('cg07814289:', 'Var', (46, 57))	('men', 'Species', '9606', (121, 124))	('cg14144025', 'Var', (88, 98))	('cg14144025', 'Chemical', '-', (88, 98))	('cg09494609', 'Chemical', '-', (67, 77))	('cg07814289', 'Chemical', '-', (46, 56))
143403	34011115	According to the results of multivariate Cox regression analysis, the 3-DNA methylation signature was significantly associated with the OS of patients (Table 2).	('OS of patients', 'Disease', (136, 150))	('patients', 'Species', '9606', (142, 150))	('methylation', 'Var', (76, 87))	('associated', 'Reg', (116, 126))
143407	34011115	These results indicated that the 3-DNA methylation signature had high sensitivity and specificity as well as good discriminatory capacity for predicting OS of patients with sarcoma.	('methylation', 'Var', (39, 50))	('sarcoma', 'Disease', (173, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('patients', 'Species', '9606', (159, 167))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))
143418	34011115	All these results indicated that the 3-DNA methylation signature was an independent prognostic predictor for sarcoma patients.	('methylation', 'Var', (43, 54))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('sarcoma', 'Disease', (109, 116))	('patients', 'Species', '9606', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))
143425	34011115	Based on a TCGA dataset that included 261 sarcoma samples, the current study identified a prognostic signature which contained 3 methylation sites (cg07814289, cg09494609, and cg14144025) and corresponded to 3 genes (DNM1, RP11-983P16.4, and LINC01097) by combining differential methylation analysis, survival analysis, ROC analysis, and Cox regression analysis.	('cg14144025', 'Var', (176, 186))	('sarcoma', 'Disease', (42, 49))	('cg14144025', 'Chemical', '-', (176, 186))	('cg09494609', 'Var', (160, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('RP11', 'Gene', '26121', (223, 227))	('LINC01097', 'Gene', '285547', (242, 251))	('cg07814289', 'Var', (148, 158))	('cg09494609', 'Chemical', '-', (160, 170))	('DNM1', 'Gene', '1759', (217, 221))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('LINC01097', 'Gene', (242, 251))	('cg07814289', 'Chemical', '-', (148, 158))	('RP11', 'Gene', (223, 227))	('DNM1', 'Gene', (217, 221))
143443	34011115	In conclusion, using genome-wide analysis of DNA methylation data of 261 patients, this study shows that a 3-DNA methylation signature is prominently associated with the OS of patients with sarcoma.	('associated', 'Reg', (150, 160))	('patients', 'Species', '9606', (176, 184))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('methylation', 'Var', (113, 124))	('sarcoma', 'Disease', (190, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('patients', 'Species', '9606', (73, 81))
143444	34011115	The 3-DNA methylation signature is not only independent of clinical characteristics including age at diagnosis, sex, anatomic location, tumor residual classification, and histological subtypes, but also exhibits good ability in predicting OS of patients.	('patients', 'Species', '9606', (245, 253))	('predicting', 'Reg', (228, 238))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('methylation', 'Var', (10, 21))	('tumor', 'Disease', (136, 141))
143479	31659510	Degeneration of dopaminergic neurons in the substantia nigra pars compacta is an inherent neuropathological sign of PD.	('dopamine', 'Chemical', 'MESH:D004298', (16, 24))	('PD', 'Disease', 'MESH:D010300', (116, 118))	('dopaminergic', 'Protein', (16, 28))	('Degeneration', 'Var', (0, 12))
143492	31659510	Histopathologic characteristics of MSA are inclusions of misfolded alpha-synuclein in oligodendrocytes (Jellinger).	('misfolded', 'Var', (57, 66))	('alpha-synuclein', 'Gene', (67, 82))	('inclusions', 'Reg', (43, 53))	('alpha-synuclein', 'Gene', '6622', (67, 82))	('MSA', 'Disease', (35, 38))
143505	31659510	a CAG repeat expansion in exon 1 of the huntingtin gene (MacDonald et al.).	('CAG repeat expansion in', 'Var', (2, 25))	('huntingtin', 'Gene', (40, 50))	('huntingtin', 'Gene', '3064', (40, 50))
143507	31659510	The cerebral accumulation of hyperphosphorylated tau aggregates seems to be a further histopathological characteristic besides the accumulation of the mutated Huntingtin protein (Vuono et al.).	('Huntingtin', 'Gene', '3064', (159, 169))	('Huntingtin', 'Gene', (159, 169))	('mutated', 'Var', (151, 158))
143516	31659510	Due to its broad availability and sufficient diagnostic accuracy, [18F]FDG is currently the widely used radiotracer in imaging of neurodegenerative diseases in clinical routine.	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (130, 156))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (130, 155))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (130, 156))	('neurodegenerative diseases', 'Disease', (130, 156))	('[18F]FDG', 'Var', (66, 74))
143528	31659510	[11C]PBR-28, [18F]DPA-714, [18F] FEPPA, [11C]DAA1106, [18F]PBR06, [18F]PBR111) (Fig.	('[11C]DAA1106', 'Var', (40, 52))	('[18F] FEPPA', 'Var', (27, 38))	('DPA', 'Chemical', '-', (18, 21))	('[11C', 'Chemical', 'MESH:C000615233', (0, 4))	('[18F]PBR06', 'Var', (54, 64))	('[18F]', 'Var', (13, 18))	('[11C', 'Chemical', 'MESH:C000615233', (40, 44))
143537	31659510	Because the dopaminergic system is crucially involved in the pathophysiology of parkinsonism, imaging of the dopaminergic system is of particular interest in diseases such as Parkinson's disease or variants of atypical parkinsonism.	('parkinsonism', 'Disease', (80, 92))	('parkinsonism', 'Disease', 'MESH:D010302', (80, 92))	('parkinsonism', 'Disease', 'MESH:D010302', (219, 231))	('atypical parkinsonism', 'Disease', (210, 231))	('parkinsonism', 'Disease', (219, 231))	('dopamine', 'Chemical', 'MESH:D004298', (12, 20))	('parkinsonism', 'Phenotype', 'HP:0001300', (219, 231))	("Parkinson's disease", 'Disease', (175, 194))	('variants', 'Var', (198, 206))	('dopamine', 'Chemical', 'MESH:D004298', (109, 117))	('parkinsonism', 'Phenotype', 'HP:0001300', (80, 92))	("Parkinson's disease", 'Disease', 'MESH:D010300', (175, 194))	('atypical parkinsonism', 'Disease', 'MESH:C566823', (210, 231))
143542	31659510	[123I]beta-CIT, [123I]FP-CIT (DaTSCAN ), [123I]IPT) and PET tracers [11C]methylphenidate, [11C]Cocaine, or [18F]FE-PE2I (Seibyl) (Fig.	('[18F]FE-PE2I', 'Var', (107, 119))	('[11C', 'Chemical', 'MESH:C000615233', (68, 72))	('beta-CIT', 'Chemical', 'MESH:C069723', (6, 14))	('FE-PE2I', 'Chemical', '-', (112, 119))	('methylphenidate', 'Chemical', 'MESH:D008774', (73, 88))	('IPT', 'Gene', (47, 50))	('Cocaine', 'Chemical', 'MESH:D003042', (95, 102))	('[11C', 'Chemical', 'MESH:C000615233', (90, 94))	('IPT', 'Gene', '54802', (47, 50))	('[123I', 'Var', (16, 21))
143551	31659510	Autoradiographic data revealed a significant reduction of different compartments of cholinergic neurotransmission, like nicotinic acetylcholine receptors (nAChRs) in patients with AD, PD and DLB (Perry et al.	('AD', 'Disease', (180, 182))	('DLB', 'Var', (191, 194))	('nAChR', 'Gene', '1137', (155, 160))	('nicotinic acetylcholine receptors', 'MPA', (120, 153))	('PD', 'Disease', 'MESH:D010300', (184, 186))	('acetylcholine', 'Chemical', 'MESH:D000109', (130, 143))	('nAChR', 'Gene', (155, 160))	('reduction', 'NegReg', (45, 54))	('patients', 'Species', '9606', (166, 174))	('AD', 'Disease', 'MESH:D000544', (180, 182))
143556	31659510	Most important and widely used early-generation alpha4beta2 nAChR PET ligands are 3-pyridylether derivatives such as 2-[18F]A-85380, 6-[18F]A-85380 and 5-[123I]A-85380 (Fig.	('6-[18F]A-85380', 'Var', (133, 147))	('nAChR', 'Gene', '1137', (60, 65))	('nAChR', 'Gene', (60, 65))	('2-[18F]A-85380', 'Var', (117, 131))	('5-[123I]A-85380', 'Var', (152, 167))
143557	31659510	These next-generation alpha4beta2 nAChR radioligands are derivatives of homoepibatidine ((-)-[18F]Flubatine, (+)-[18F]Flubatine), epibatidine ([18F]AZAN, [18F]XTRA) or 3-pyridylether derivatives ([18F]Nifene, [18F]Nifrolene and [18F]NIDA522131, [18F]Nifzetidine and [18F]ZW-104) (Horti et al.	('nAChR', 'Gene', '1137', (34, 39))	('[18F]ZW-104', 'Var', (266, 277))	('[18F]Nifzetidine', 'Var', (245, 261))	('nAChR', 'Gene', (34, 39))	('(-)-[18F]Flubatine', 'Chemical', '-', (89, 107))
143558	31659510	Results of the first applications in humans of these next-generation alpha4beta2 nAChR-targeting PET radioligands such as (-)-[18F]Flubatine, [18F]AZAN and [18F]XTRA are promising (Sabri et al.	('nAChR', 'Gene', '1137', (81, 86))	('[18F]', 'Var', (142, 147))	('humans', 'Species', '9606', (37, 43))	('nAChR', 'Gene', (81, 86))	('-)-[18F]Flubatine', 'Var', (123, 140))	('[18F]', 'Var', (156, 161))	('(-)-[18F]Flubatine', 'Chemical', '-', (122, 140))
143573	31659510	5c) and radioligands targeting AChE are [11C]MP4A and [11C]PMP (Kuhl et al.	('[11C', 'Chemical', 'MESH:C000615233', (54, 58))	('AChE', 'Gene', '43', (31, 35))	('[11C]PMP', 'Var', (54, 62))	('[11C]MP4A', 'Var', (40, 49))	('[11C', 'Chemical', 'MESH:C000615233', (40, 44))	('AChE', 'Gene', (31, 35))
143584	31659510	The most widely used Abeta-targeting PET tracer is [11C]Pittsburgh Compound B (PiB) (Fig.	('[11C', 'Var', (51, 55))	('[11C', 'Chemical', 'MESH:C000615233', (51, 55))	('Abeta', 'Gene', (21, 26))	('Abeta', 'Gene', '351', (21, 26))
143588	31659510	Other Abeta PET tracers, such as [11C]AZD2184, [18F]FIBT, and [18F]NAV4694 (Fig.	('NAV4694', 'Chemical', '-', (67, 74))	('[18F]FIBT', 'Var', (47, 56))	('[11C]AZD2184', 'Var', (33, 45))	('[18F]NAV4694', 'Var', (62, 74))	('Abeta', 'Gene', (6, 11))	('AZD2184', 'Chemical', 'MESH:C539976', (38, 45))	('[11C', 'Chemical', 'MESH:C000615233', (33, 37))	('Abeta', 'Gene', '351', (6, 11))
143593	31659510	Compared to the three approved 18F-labeled radiotracers, [11C]AZD2184 and [18F]NAV4694 seem to show lower white matter binding (Ito et al.	('[11C', 'Chemical', 'MESH:C000615233', (57, 61))	('[11C]AZD2184', 'Var', (57, 69))	('AZD2184', 'Chemical', 'MESH:C539976', (62, 69))	('lower', 'NegReg', (100, 105))	('NAV4694', 'Chemical', '-', (79, 86))	('[18F]NAV4694', 'Var', (74, 86))	('white matter binding', 'CPA', (106, 126))
143596	31659510	), resulting in an implementation of biomarkers such as Abeta PET or [18F]FDG PET.	('[18F]FDG', 'Var', (69, 77))	('Abeta', 'Gene', (56, 61))	('Abeta', 'Gene', '351', (56, 61))
143599	31659510	Importantly, the same clinical tauopathy phenotype can be caused by different misfolded tau proteins and vice-versa (Villemagne et al.).	('misfolded', 'Var', (78, 87))	('tau proteins', 'Protein', (88, 100))	('tauopathy', 'Disease', 'MESH:D024801', (31, 40))	('caused by', 'Reg', (58, 67))	('tauopathy', 'Disease', (31, 40))
143603	31659510	Second-generation selective tau PET radiotracers, such as [18F]RO6958948, [18F]GTP1, [18F]PI-2620, [18F]MK-6240 (Fig.	('[18F]RO6958948', 'Var', (58, 72))	('[18F]PI-2620', 'Var', (85, 97))	('[18F]MK-6240', 'Var', (99, 111))	('GTP1', 'Chemical', '-', (79, 83))	('[18F]GTP1', 'Var', (74, 83))
143604	31659510	However, [18F]GTP1 showed off-target binding in the basal ganglia (Bohorquez et al.	('binding', 'Interaction', (37, 44))	('GTP1', 'Gene', (14, 18))	('[18F]', 'Var', (9, 14))	('GTP1', 'Chemical', '-', (14, 18))	('off-target', 'NegReg', (26, 36))
143627	29516254	SS is characterized by the presence of the pathognomonic t(X;18) (p11.2;q11.2) translocation, involving a fusion of the SS18 (formerly SYT) gene on chromosome 18 to one of the synovial sarcoma X (SSX) genes on chromosome X (usually SSX1 or SSX2), which is seen in more than 90% of SS and results in the formation of SS18-SSX fusion oncogenes.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('SSX', 'Gene', '6757', (321, 324))	('SS', 'Phenotype', 'HP:0012570', (120, 122))	('SS18', 'Gene', '6760', (316, 320))	('SS', 'Phenotype', 'HP:0012570', (240, 242))	('SSX', 'Gene', (196, 199))	('SSX', 'Gene', '6757', (232, 235))	('SSX', 'Gene', (321, 324))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SS18', 'Gene', (120, 124))	('SSX', 'Gene', '6757', (240, 243))	('SSX', 'Gene', (232, 235))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (176, 192))	('SYT', 'Gene', (135, 138))	('fusion', 'Var', (106, 112))	('SS', 'Phenotype', 'HP:0012570', (196, 198))	('synovial sarcoma X', 'Gene', '6757', (176, 194))	('SSX2', 'Gene', (240, 244))	('SSX', 'Gene', (240, 243))	('SS18', 'Gene', (316, 320))	('SSX1', 'Gene', '6756', (232, 236))	('SS18', 'Gene', '6760', (120, 124))	('SSX1', 'Gene', (232, 236))	('SSX2', 'Gene', '6757', (240, 244))	('SSX', 'Gene', '6757', (196, 199))	('synovial sarcoma X', 'Gene', (176, 194))	('SYT', 'Gene', '6760', (135, 138))	('SS', 'Phenotype', 'HP:0012570', (232, 234))
143711	29516254	A variety of other clinical studies employing NY-ESO-1 in SS are currently under way (e.g., NCT02457650, NCT01343043).	('NY-ESO-1', 'Gene', '246100', (46, 54))	('NCT01343043', 'Var', (105, 116))	('NY-ESO-1', 'Gene', (46, 54))	('SS', 'Phenotype', 'HP:0012570', (58, 60))
143735	29516254	Also, very recently, a synthetic lethal interaction was reported between the presence of the SS18-SSX fusion oncogene and sensitivity to inhibitors directed against the DNA damage response (DDR) kinase, ATR .	('SS18', 'Gene', (93, 97))	('sensitivity', 'MPA', (122, 133))	('SS', 'Phenotype', 'HP:0012570', (98, 100))	('SSX', 'Gene', '6757', (98, 101))	('SSX', 'Gene', (98, 101))	('presence', 'Var', (77, 85))	('ATR', 'Gene', (203, 206))	('SS18', 'Gene', '6760', (93, 97))	('ATR', 'Gene', '545', (203, 206))	('SS', 'Phenotype', 'HP:0012570', (93, 95))
143737	29516254	As it was suggested that the presence of SS18-SSX fusions might introduce a vulnerability of these tumors to DDR inhibitors in general by creating a replication fork stress phenotype, and various DDR inhibitors are currently in clinical testing for other malignancies with encouraging results in certain histologies, this represents an interesting line of investigation that warrants further preclinical and clinical examination for SS.	('SSX', 'Gene', '6757', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('SSX', 'Gene', (46, 49))	('malignancies', 'Disease', 'MESH:D009369', (255, 267))	('SS', 'Phenotype', 'HP:0012570', (46, 48))	('replication fork stress phenotype', 'MPA', (149, 182))	('SS18', 'Gene', '6760', (41, 45))	('presence', 'Var', (29, 37))	('malignancies', 'Disease', (255, 267))	('SS', 'Phenotype', 'HP:0012570', (41, 43))	('SS', 'Phenotype', 'HP:0012570', (433, 435))	('creating', 'Reg', (138, 146))	('SS18', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
143751	26705220	AUCs were higher for TLG than for MTV40%.	('TLG', 'Chemical', '-', (21, 24))	('MTV40', 'Chemical', '-', (34, 39))	('AUCs', 'MPA', (0, 4))	('TLG', 'Var', (21, 24))
143793	26705220	The following categorical variables were included: gender, tumor size, surgery, metastasis at diagnosis, MTV40%, and TLG.	('tumor', 'Disease', (59, 64))	('MTV40', 'Chemical', '-', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('TLG', 'Chemical', '-', (117, 120))	('MTV40%', 'Var', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
143798	26705220	The AUCs were consistently higher for TLG compared to MTV40% (all patients: 0.779 vs 0.693; BS: 0.773 vs 0.727; STS: 0.780 vs 0.694).	('TLG', 'Var', (38, 41))	('STS', 'Phenotype', 'HP:0030448', (112, 115))	('MTV40', 'Chemical', '-', (54, 59))	('AUCs', 'MPA', (4, 8))	('higher', 'PosReg', (27, 33))	('TLG', 'Chemical', '-', (38, 41))	('BS', 'Phenotype', 'HP:0002669', (92, 94))	('patients', 'Species', '9606', (66, 74))
143818	26705220	Costelloe et al were the first reporting data on the prognostic value of volume-based FDG imaging markers in osteosarcoma, where high TLG before chemotherapy was associated with poor survival.	('FDG', 'Chemical', 'MESH:D019788', (86, 89))	('high', 'Var', (129, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('TLG', 'Chemical', '-', (134, 137))	('osteosarcoma', 'Phenotype', 'HP:0002669', (109, 121))	('osteosarcoma', 'Disease', (109, 121))	('osteosarcoma', 'Disease', 'MESH:D012516', (109, 121))
143823	26705220	In our study, measurements of the accuracy of MTV40% as prognostic variable for overall survival were in general lower than for TLG, and importantly, MTV40% did not have independent predictive value for overall survival in multivariate regression analyses.	('MTV40', 'Chemical', '-', (46, 51))	('lower', 'NegReg', (113, 118))	('accuracy', 'MPA', (34, 42))	('MTV40', 'Chemical', '-', (150, 155))	('MTV40%', 'Var', (46, 52))	('TLG', 'Chemical', '-', (128, 131))	('men', 'Species', '9606', (21, 24))
143850	26469906	Soft tissue cancers were classified according to the International Classification of Diseases for Oncology, version 3 (ICD-O-3: C47, C49 cancer of connective, subcutaneous, and other soft tissues).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('C49 cancer', 'Disease', 'MESH:D009369', (133, 143))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('Soft tissue cancer', 'Phenotype', 'HP:0031459', (0, 18))	('Oncology', 'Phenotype', 'HP:0002664', (98, 106))	('C49 cancer', 'Disease', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('C47', 'Var', (128, 131))
143894	26469906	The association between the genetic changes and the susceptibility to angiosarcoma found in males deserves further investigation to elucidate.	('angiosarcoma', 'Disease', (70, 82))	('genetic changes', 'Var', (28, 43))	('angiosarcoma', 'Phenotype', 'HP:0200058', (70, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('angiosarcoma', 'Disease', 'MESH:D006394', (70, 82))
143923	24696229	The frequency and severity of AEs were clearly greater at 1.5 mg/m2 than at the lower doses.	('AEs', 'Chemical', '-', (30, 33))	('greater', 'PosReg', (47, 54))	('AEs', 'Disease', (30, 33))	('1.5 mg/m2', 'Var', (58, 67))
143925	24696229	A partial response was obtained in three patients with translocation-related sarcomas (1 each with myxoid liposarcoma, synovial sarcoma, and extraskeletal Ewing sarcoma).	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (99, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('myxoid liposarcoma', 'Disease', (99, 117))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (99, 117))	('synovial sarcoma', 'Disease', (119, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('synovial sarcoma', 'Disease', 'MESH:D013584', (119, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('extraskeletal Ewing sarcoma', 'Disease', (141, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('sarcomas', 'Disease', (77, 85))	('patients', 'Species', '9606', (41, 49))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (119, 135))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))	('translocation-related', 'Var', (55, 76))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('extraskeletal Ewing sarcoma', 'Disease', 'MESH:C563168', (141, 168))
143929	24696229	Chromosomal translocations are the most frequent molecular alterations in sarcomas, occurring in about 20 % of cases.	('sarcomas', 'Disease', (74, 82))	('Chromosomal translocations', 'Var', (0, 26))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
143930	24696229	Sarcoma translocations and the associated chimeric oncoproteins provide attractive targets for therapeutic intervention, given that these fusion proteins are critical for disease pathogenesis and tumor-cell survival, and no alternative pathways exist to avoid their blockade.	('tumor', 'Disease', (196, 201))	('translocations', 'Var', (8, 22))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
143985	24696229	Trabectedin 1.5 mg/m2 as 24-h infusion every 3 weeks is approved by the European Medicines Agency (EMA) for STS based on the results of a phase I study in patients with solid tumors and a phase II study in patients with liposarcoma or leiomyosarcoma, which showed that trabectedin 1.5 mg/m2 every 3 weeks was associated with a longer time to progression than 0.58 mg/m2 every week.	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('liposarcoma', 'Phenotype', 'HP:0012034', (220, 231))	('trabectedin', 'Chemical', 'MESH:D000077606', (269, 280))	('solid tumors', 'Disease', 'MESH:D009369', (169, 181))	('leiomyosarcoma', 'Disease', (235, 249))	('Trabectedin', 'Chemical', 'MESH:D000077606', (0, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (235, 249))	('trabectedin', 'Var', (269, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('patients', 'Species', '9606', (206, 214))	('liposarcoma', 'Disease', (220, 231))	('patients', 'Species', '9606', (155, 163))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (235, 249))	('liposarcoma', 'Disease', 'MESH:D008080', (220, 231))	('solid tumors', 'Disease', (169, 181))
144042	24658839	IDO expression has been observed in a variety of cancers, and high IDO expression is associated with dismal prognosis.	('expression', 'MPA', (71, 81))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('IDO', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('IDO', 'Gene', '3620', (0, 3))	('IDO', 'Gene', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('high', 'Var', (62, 66))	('IDO', 'Gene', '3620', (67, 70))	('cancers', 'Disease', (49, 56))
144051	24658839	The depletion of l-arginine subsequently causes a down-regulation of the zeta-chain of the T cell receptor, as well as cell cycle arrest of T cells.	('l-arginine', 'Chemical', 'MESH:D001120', (17, 27))	('cell cycle arrest', 'CPA', (119, 136))	('l-arginine', 'Var', (17, 27))	('T cell receptor', 'Protein', (91, 106))	('down-regulation', 'NegReg', (50, 65))	('zeta-chain', 'MPA', (73, 83))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (119, 136))	('depletion', 'MPA', (4, 13))	('depletion of l-arginine', 'Phenotype', 'HP:0005961', (4, 27))
144052	24658839	Furthermore, MDSC produce reactive oxygen species (ROS) and nitric oxide (NO) radicals, which also capable of suppressing T cell function.	('reactive oxygen species', 'MPA', (26, 49))	('nitric oxide', 'MPA', (60, 72))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (26, 49))	('nitric oxide', 'Chemical', 'MESH:D009569', (60, 72))	('suppressing', 'NegReg', (110, 121))	('suppressing T cell function', 'Phenotype', 'HP:0005435', (110, 137))	('MDSC', 'Var', (13, 17))	('T cell function', 'CPA', (122, 137))
144090	24658839	Analysis of arginase-1 expression was done by replacing CD45-FITC with Arginase-1-fluorescein (R&D Systems) in the above-mentioned MDSC cocktail.	('arginase-1', 'Gene', (12, 22))	('Arginase-1', 'Gene', '383', (71, 81))	('Arginase-1', 'Gene', (71, 81))	('arginase-1', 'Gene', '383', (12, 22))	('CD45-FITC', 'Var', (56, 65))	('1-fluorescein', 'Chemical', '-', (80, 93))
144216	22878618	In multivariate analysis, factors associated with worse disease-specific survival (DSS) were larger size (HR 1.08; 95% CI 1.04-1.13; P<0.001) and positive margin (HR 3.30; 95% CI 1.74-6.28; P<0.001).	('DSS', 'Chemical', '-', (83, 86))	('disease-specific', 'MPA', (56, 72))	('positive', 'Var', (146, 154))
144222	22878618	NF1-associated and sporadic MPNSTs may be associated with improved DSS compared to RT-induced tumors.	('improved', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('MPNSTs', 'Phenotype', 'HP:0100697', (28, 34))	('DSS', 'Chemical', '-', (67, 70))	('DSS', 'Disease', (67, 70))	('tumors', 'Disease', (94, 100))	('NF1', 'Gene', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('NF1', 'Gene', '4763', (0, 3))	('MPNSTs', 'Var', (28, 34))
144226	22878618	Neurofibromatosis type 1 results from a gain-of-function mutation in the NF gene and is inherited in an autosomal dominant fashion.	('mutation', 'Var', (57, 65))	('gain-of-function', 'PosReg', (40, 56))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('NF', 'Gene', '23114', (73, 75))	('Neurofibromatosis type 1', 'Gene', (0, 24))	('Neurofibromatosis type 1', 'Gene', '4763', (0, 24))
144253	22878618	This diagnosis was given either in the setting of a confirmed mutation in the NF1 gene or if the patient met 2 or more of the NIH consensus criteria.	('NF1', 'Gene', (78, 81))	('mutation', 'Var', (62, 70))	('NF1', 'Gene', '4763', (78, 81))	('patient', 'Species', '9606', (97, 104))
144321	22878618	MPNST represents an exception to this generalization; the median age (38 years in this study) is more like that of a translocation-associated sarcoma than a genomically complex sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('translocation-associated', 'Var', (117, 141))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('sarcoma', 'Disease', (142, 149))	('sarcoma', 'Disease', (177, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('age', 'Gene', (65, 68))	('age', 'Gene', '5973', (65, 68))
144335	22878618	Others have reported that S100-negative MPNSTs are associated with a significant reduction in 5-year actuarial disease-specific death rates.	('death', 'Disease', (128, 133))	('S100', 'Gene', (26, 30))	('MPNSTs', 'Phenotype', 'HP:0100697', (40, 46))	('actuarial', 'MPA', (101, 110))	('S100', 'Gene', '6271', (26, 30))	('MPNSTs', 'Var', (40, 46))	('reduction', 'NegReg', (81, 90))	('death', 'Disease', 'MESH:D003643', (128, 133))
144404	31994170	The observed event times of the ith subject are respectively ti11 <= ti12 <=   <= ti1mi1 and ti21 <= ti22 <=   <= ti2mi2 for the two types of recurrent events.	('ti21 <= ti22 <=   <=', 'Var', (93, 113))	('s', 'Chemical', 'MESH:D013455', (50, 51))	('s', 'Chemical', 'MESH:D013455', (36, 37))	('s', 'Chemical', 'MESH:D013455', (23, 24))	('s', 'Chemical', 'MESH:D013455', (137, 138))	('s', 'Chemical', 'MESH:D013455', (157, 158))	('ti11 <= ti12 <=   <=', 'Var', (61, 81))	('s', 'Chemical', 'MESH:D013455', (6, 7))
144419	31994170	The pseudo-partial likelihood is the product of all of the conditional probabilities of eii or eii' (i   i'), given the corresponding risk sets constructed from the observed event times.	('s', 'Chemical', 'MESH:D013455', (147, 148))	('s', 'Chemical', 'MESH:D013455', (142, 143))	('s', 'Chemical', 'MESH:D013455', (83, 84))	('s', 'Chemical', 'MESH:D013455', (31, 32))	('s', 'Chemical', 'MESH:D013455', (125, 126))	('eii', 'Var', (95, 98))	('s', 'Chemical', 'MESH:D013455', (139, 140))	('s', 'Chemical', 'MESH:D013455', (184, 185))	('eii', 'Var', (88, 91))	('s', 'Chemical', 'MESH:D013455', (5, 6))	('s', 'Chemical', 'MESH:D013455', (136, 137))	('s', 'Chemical', 'MESH:D013455', (167, 168))
144548	28652778	The insulin receptor (IR) is highly homologous to the IGF-1R, allowing for the formation of hybrid receptors that can activate the downstream pathway.	('insulin receptor', 'Gene', (4, 20))	('IGF-1R', 'Gene', '3480', (54, 60))	('insulin receptor', 'Gene', '3643', (4, 20))	('IGF-1R', 'Gene', (54, 60))	('hybrid', 'Var', (92, 98))	('activate', 'PosReg', (118, 126))	('downstream pathway', 'Pathway', (131, 149))	('IR', 'Gene', '3643', (22, 24))
144551	28652778	This somatic mutation results in aberrant products of the Ewing sarcoma breakpoint region 1 (EWSR1) and the Friend leukemia virus integration 1 (FLI1) genes.	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('EWSR1', 'Gene', (93, 98))	('results in', 'Reg', (22, 32))	('FLI1', 'Gene', (145, 149))	('EWSR1', 'Gene', '2130', (93, 98))	('FLI1', 'Gene', '2313', (145, 149))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('products', 'MPA', (42, 50))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('Ewing sarcoma breakpoint region 1', 'Gene', (58, 91))	('Friend leukemia virus integration 1', 'Gene', (108, 143))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (58, 91))	('aberrant', 'Var', (33, 41))	('Friend leukemia virus integration 1', 'Gene', '2313', (108, 143))
144614	28652778	It seems counterintuitive that high levels of IGF-1 predict better survival in Ewing sarcoma, as IGF-1 is involved in the development, progression and therapy resistance of several solid tumors.	('better', 'PosReg', (60, 66))	('IGF-1', 'Gene', (46, 51))	('IGF-1', 'Gene', '3479', (97, 102))	('IGF-1', 'Gene', (97, 102))	('high levels of IGF-1', 'Phenotype', 'HP:0030269', (31, 51))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('survival', 'MPA', (67, 75))	('Ewing sarcoma', 'Disease', (79, 92))	('solid tumors', 'Disease', (181, 193))	('solid tumors', 'Disease', 'MESH:D009369', (181, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('high', 'Var', (31, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (79, 92))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('IGF-1', 'Gene', '3479', (46, 51))
144616	28652778	Indeed, low levels of IGF-1 were reported to be associated with greater tumor burden and more aggressive systemic illness in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('low levels of IGF', 'Phenotype', 'HP:0002850', (8, 25))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('aggressive systemic illness in Ewing sarcoma', 'Disease', (94, 138))	('IGF-1', 'Gene', '3479', (22, 27))	('tumor', 'Disease', (72, 77))	('IGF-1', 'Gene', (22, 27))	('aggressive systemic illness in Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('low levels', 'Var', (8, 18))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('greater', 'PosReg', (64, 71))
144620	28652778	Interestingly, low levels of circulating IGF-1 predicted worse survival in other solid tumors and systemic diseases.	('low levels of circulating IGF', 'Phenotype', 'HP:0002850', (15, 44))	('low', 'Var', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('solid tumors', 'Disease', (81, 93))	('systemic diseases', 'Disease', (98, 115))	('systemic diseases', 'Disease', 'MESH:D034721', (98, 115))	('solid tumors', 'Disease', 'MESH:D009369', (81, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('IGF-1', 'Gene', '3479', (41, 46))	('IGF-1', 'Gene', (41, 46))	('worse', 'NegReg', (57, 62))
144644	26601204	Over the past 4 years, nearly 100 exome sequencing studies have revealed the high frequency of mutations in the genes encoding the subunits of ATP-dependent chromatin remodelers in human cancer.	('human', 'Species', '9606', (181, 186))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('ATP', 'Chemical', 'MESH:D000255', (143, 146))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('mutations', 'Var', (95, 104))
144645	26601204	Most of these mutations are within the genes encoding subunits of the BAF (Brg/Brahma-associated factors) or mSWI/SNF complex, which is one of two dozen predicted ATP-dependent chromatin remodeling complexes in mammals.	('BAF', 'Chemical', '-', (70, 73))	('SWI/SNF', 'Gene', (110, 117))	('ATP', 'Chemical', 'MESH:D000255', (163, 166))	('SWI/SNF', 'Gene', '31120', (110, 117))	('mutations', 'Var', (14, 23))
144648	26601204	Several important conclusions emerge from these genomic data: specific subunits appear to be mutated in specific cancers, highlighting tissue-specific protective roles; mutations can function as tumor suppressors or oncogenes; mutations can be homozygous or, more commonly, heterozygous, implying their dosage-sensitive roles in an unknown yet fundamental process used to suppress the genesis of cancer.	('cancer', 'Disease', 'MESH:D009369', (396, 402))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('cancer', 'Disease', (396, 402))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancer', 'Disease', (113, 119))	('cancers', 'Disease', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('mutations', 'Var', (227, 236))
144653	26601204	Previous studies over the years involving drugs such as histone deacetylase and histone methyl transferase inhibitors, hydroxamic acids, sirtuins, and others had suggested the important role of epigenetic modulation in cancer:indeed, nearly all cancers display epigenetic changes, and most cancer mutations, in either a direct or an indirect manner, affect the epigenome :yet the extent of involvement was not fully appreciated.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('affect', 'Reg', (350, 356))	('cancers', 'Disease', (245, 252))	('cancer', 'Disease', (245, 251))	('mutations', 'Var', (297, 306))	('cancer', 'Disease', (290, 296))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('epigenetic changes', 'MPA', (261, 279))	('epigenome ', 'MPA', (361, 371))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
144654	26601204	Strikingly, among the most frequent mutations uncovered in human cancer sequencing efforts were mutations in genes encoding the subunits of adenosine triphosphate (ATP)-dependent chromatin remodeling complexes, most notably the mammalian SWI/SNF or BAF (Brg/Brahma-associated factors) complexes.	('human', 'Species', '9606', (59, 64))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (140, 162))	('BAF', 'Chemical', '-', (249, 252))	('ATP', 'Chemical', 'MESH:D000255', (164, 167))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mammalian', 'Species', '9606', (228, 237))	('SWI/SNF', 'Gene', (238, 245))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('SWI/SNF', 'Gene', '31120', (238, 245))	('mutations', 'Var', (96, 105))
144655	26601204	With more than 20% of human cancers bearing a mutation to one subunit of a 15-subunit complex, mechanistic studies that translate the meaning of these genetic perturbations are critical for understanding oncogenic function.	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation', 'Var', (46, 54))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('human', 'Species', '9606', (22, 27))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
144661	26601204	Genetic reversion of these signaling phenotypes was achieved by second mutations in histone genes, showing that specific SWI and SNF genes in yeast actually regulated chromatin remodeling rather than acting as participants in a signaling mechanism.	('actin', 'Gene', (200, 205))	('SNF', 'Gene', '31442', (129, 132))	('actin', 'Gene', '31521', (200, 205))	('SWI', 'Gene', (121, 124))	('regulated', 'Reg', (157, 166))	('participants', 'Species', '9606', (210, 222))	('SWI', 'Gene', '31120', (121, 124))	('mutations', 'Var', (71, 80))	('SNF', 'Gene', (129, 132))	('yeast', 'Species', '4932', (142, 147))	('chromatin remodeling', 'MPA', (167, 187))
144665	26601204	Significantly, revertants to mutations in Brm have never been found in histone genes, as is the case in yeast.	('Brm', 'Gene', '6595', (42, 45))	('mutations', 'Var', (29, 38))	('Brm', 'Gene', (42, 45))	('yeast', 'Species', '4932', (104, 109))
144667	26601204	Evidence indicating that Polycomb complexes are an important primary target of mammalian SWI/SNF or BAF complexes has emerged in more recent years from the observation that mutation of the ATPase Brg1 (Smarca4) of BAF complexes leads to H3K27Me3 accumulation and repression of many genes in embryonic stem (ES) cells.	('mammalian', 'Species', '9606', (79, 88))	('ATPase', 'Gene', '1769', (189, 195))	('repression', 'NegReg', (263, 273))	('Smarca4', 'Gene', '6597', (202, 209))	('SWI/SNF', 'Gene', '31120', (89, 96))	('BAF', 'Chemical', '-', (214, 217))	('ATPase', 'Gene', (189, 195))	('H3K27Me3', 'Protein', (237, 245))	('Brg1', 'Gene', (196, 200))	('Brg1', 'Gene', '6597', (196, 200))	('genes', 'Gene', (282, 287))	('accumulation', 'PosReg', (246, 258))	('BAF', 'Chemical', '-', (100, 103))	('Polycomb', 'Gene', '40358', (25, 33))	('Smarca4', 'Gene', (202, 209))	('Polycomb', 'Gene', (25, 33))	('SWI/SNF', 'Gene', (89, 96))	('mutation', 'Var', (173, 181))
144672	26601204	Genetically, these ATPases are nearly all nonredundant, indicating that they play specific biologic roles and their mutations give rise to specific phenotypes and diverse human diseases, as will be discussed below.	('ATPase', 'Gene', (19, 25))	('give rise to', 'Reg', (126, 138))	('mutations', 'Var', (116, 125))	('ATPase', 'Gene', '1769', (19, 25))	('human', 'Species', '9606', (171, 176))
144687	26601204	Thus, in this respect, mammalian BAF complexes resemble yeast INO80 and SWR1, which play critical roles as guardians of the genome against the accumulation of mutations and are probably most analogous to the p53 function in vertebrates.	('SWR1', 'Gene', (72, 76))	('mutations', 'Var', (159, 168))	('BAF', 'Chemical', '-', (33, 36))	('mammalian', 'Species', '9606', (23, 32))	('yeast', 'Species', '4932', (56, 61))	('SWR1', 'Gene', '851934', (72, 76))
144690	26601204	However, this explanation now seems unlikely because mutations in the subunits involved had phenotypes nearly identical to rapid conditional deletion of the Brg and/or Brm ATPase, indicating that individual subunit function was central to the fundamental mechanism of the complexes.	('ATPase', 'Gene', (172, 178))	('Brg', 'Gene', (157, 160))	('mutations', 'Var', (53, 62))	('Brm', 'Gene', (168, 171))	('Brm', 'Gene', '6595', (168, 171))	('ATPase', 'Gene', '1769', (172, 178))
144698	26601204	For example, BAF53a deletion has a phenotype that is slightly more severe than that of the ATPase Brg, whereas BAF53b has an entirely different phenotype because it is a subunit of the neuron-specific nBAF complex.	('BAF53b', 'Gene', (111, 117))	('BAF', 'Chemical', '-', (111, 114))	('BAF53a', 'Gene', (13, 19))	('BAF53b', 'Gene', '51412', (111, 117))	('BAF', 'Chemical', '-', (13, 16))	('deletion', 'Var', (20, 28))	('ATPase', 'Gene', '1769', (91, 97))	('BAF', 'Chemical', '-', (202, 205))	('BAF53a', 'Gene', '86', (13, 19))	('ATPase', 'Gene', (91, 97))
144715	26601204	Forcing the assembly of this neuron-specific nBAF complex in human fibroblasts can convert them to neurons, and knocking out the neuron-specific nBAF subunits leads to profound defects in critical postmitotic neuronal function such as dendritic outgrowth and synaptogenesis.	('BAF', 'Chemical', '-', (46, 49))	('dendritic outgrowth', 'Disease', (235, 254))	('BAF', 'Chemical', '-', (146, 149))	('defects', 'NegReg', (177, 184))	('synaptogenesis', 'CPA', (259, 273))	('knocking out', 'Var', (112, 124))	('critical postmitotic neuronal function', 'MPA', (188, 226))	('dendritic outgrowth', 'Disease', 'MESH:D007635', (235, 254))	('human', 'Species', '9606', (61, 66))
144716	26601204	Following these reports, exome sequencing studies of human neurologic diseases revealed that individuals with language acquisition deficiencies with or without mental retardation (Coffin-Siris syndrome and Nicolaides-Baraitser syndrome) generally have mutations in one of several subunits of the BAF complex.	('neurologic disease', 'Phenotype', 'HP:0000707', (59, 77))	('language acquisition', 'Phenotype', 'HP:0000750', (110, 130))	('Nicolaides-Baraitser syndrome', 'Disease', 'MESH:C536116', (206, 235))	('mental retardation', 'Phenotype', 'HP:0001249', (160, 178))	('mental retardation', 'Disease', (160, 178))	('Nicolaides-Baraitser syndrome', 'Disease', (206, 235))	('neurologic diseases', 'Disease', 'MESH:D019636', (59, 78))	('mental retardation', 'Disease', 'MESH:D008607', (160, 178))	('mutations', 'Var', (252, 261))	('neurologic diseases', 'Disease', (59, 78))	('Coffin-Siris syndrome', 'Disease', (180, 201))	('language acquisition deficiencies', 'Disease', (110, 143))	('BAF', 'Chemical', '-', (296, 299))	('human', 'Species', '9606', (53, 58))	('language acquisition deficiencies', 'Disease', 'MESH:D007806', (110, 143))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (180, 201))
144717	26601204	These studies and the finding that minor changes in subunit composition could result in malignancy (see below) put forward the understanding that biologic specificity likely emerged from subunit composition as the means of diversification of function or dysfunction.	('result in', 'Reg', (78, 87))	('malignancy', 'Disease', (88, 98))	('changes', 'Var', (41, 48))	('malignancy', 'Disease', 'MESH:D009369', (88, 98))
144726	26601204	In these tumors, most often, germline loss of one allele is followed by loss of the second allele in the tumor tissue (rhabdoid predisposition syndrome), indicating that mutations in BAF47 behave as classic tumor suppressors with genetics similar to that of retinoblastoma.	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('BAF47', 'Gene', (183, 188))	('retinoblastoma', 'Phenotype', 'HP:0009919', (258, 272))	('rhabdoid predisposition syndrome', 'Disease', (119, 151))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (105, 110))	('retinoblastoma', 'Disease', (258, 272))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('rhabdoid predisposition syndrome', 'Disease', 'MESH:C563738', (119, 151))	('tumor', 'Disease', (207, 212))	('mutations', 'Var', (170, 179))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Disease', (9, 15))	('loss', 'NegReg', (38, 42))	('retinoblastoma', 'Disease', 'MESH:D012175', (258, 272))
144727	26601204	Additional early studies by Reisman and colleagues discovered cell lines with inactivation of both Brg and Brm, such as the SW13 line.	('inactivation', 'Var', (78, 90))	('Brg', 'Gene', (99, 102))	('SW13', 'CellLine', 'CVCL:0542', (124, 128))	('Brm', 'Gene', (107, 110))	('Brm', 'Gene', '6595', (107, 110))
144728	26601204	These studies were confirmed by Wong and colleagues, who found that several breast cancer cell lines had lost both Brg and Brm at the protein level but seemed to have mutations in only one of the two homologous subunits.	('Brm', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (167, 176))	('Brm', 'Gene', '6595', (123, 126))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('lost', 'NegReg', (105, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('Brg', 'MPA', (115, 118))
144732	26601204	Initial reports showed that about 57% and 46% of ovarian clear cell carcinomas and endometriosis-associated ovarian carcinomas, respectively, contained inactivating mutations, distributed along the length of the BAF250A (ARID1A) subunit.	('BAF250A', 'Gene', '8289', (212, 219))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('endometriosis-associated ovarian carcinomas', 'Disease', (83, 126))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (49, 78))	('BAF250A', 'Gene', (212, 219))	('endometriosis', 'Phenotype', 'HP:0030127', (83, 96))	('ovarian clear cell carcinomas', 'Disease', (49, 78))	('inactivating mutations', 'Var', (152, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('contained', 'Reg', (142, 151))	('ARID1A', 'Gene', '8289', (221, 227))	('endometriosis-associated ovarian carcinomas', 'Disease', 'MESH:D004715', (83, 126))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (108, 126))	('ARID1A', 'Gene', (221, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
144733	26601204	Nearly all of these cases had mutations in only a single allele, indicating that BAF250A might be a dominant tumor suppressor subunit within the complex.	('BAF250A', 'Gene', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('BAF250A', 'Gene', '8289', (81, 88))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
144735	26601204	About this same time, studies of an unusual intellectual disability condition (Coffin-Siris syndrome) characterized by difficulty with language acquisition and mental retardation found mutations in BAF250B (ARID1B), which were also heterozygous in most cases.	('language acquisition', 'Phenotype', 'HP:0000750', (135, 155))	('Coffin-Siris syndrome', 'Disease', (79, 100))	('mental retardation', 'Phenotype', 'HP:0001249', (160, 178))	('ARID1B', 'Gene', (207, 213))	('mental retardation', 'Disease', (160, 178))	('intellectual disability condition', 'Disease', (44, 77))	('mental retardation', 'Disease', 'MESH:D008607', (160, 178))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (79, 100))	('BAF250B', 'Gene', (198, 205))	('intellectual disability', 'Phenotype', 'HP:0001249', (44, 67))	('mutations', 'Var', (185, 194))	('BAF250B', 'Gene', '57492', (198, 205))	('ARID1B', 'Gene', '57492', (207, 213))
144736	26601204	Because the issue of tumor heterogeneity can often inaccurately skew the determination of whether one or both alleles are inactivated, the discovery of the heterozygous BAF250B mutations in patients with these neurologic conditions was conceptually informative, lending further grounds to consider heterozygous mutations as causative candidates and prompting studies to identify the mechanism of allelic dominance.	('tumor', 'Disease', (21, 26))	('patients', 'Species', '9606', (190, 198))	('mutations', 'Var', (177, 186))	('BAF250B', 'Gene', (169, 176))	('BAF250B', 'Gene', '57492', (169, 176))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
144739	26601204	Additional exome sequencing studies revealed that specific cancers have mutations in different subunits of BAF complexes (Fig.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('BAF', 'Chemical', '-', (107, 110))
144749	26601204	For example, the ATPase BRG is mutated in more than 90% of small cell ovarian cancers but in less than 5% of small cell lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('small cell lung cancers', 'Disease', 'MESH:D055752', (109, 132))	('small cell lung cancers', 'Disease', (109, 132))	('ATPase', 'Gene', (17, 23))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (109, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('lung cancers', 'Phenotype', 'HP:0100526', (120, 132))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('ATPase', 'Gene', '1769', (17, 23))	('ovarian cancers', 'Phenotype', 'HP:0100615', (70, 85))	('small cell ovarian cancers', 'Disease', (59, 85))	('small cell ovarian cancers', 'Disease', 'MESH:D055752', (59, 85))	('mutated', 'Var', (31, 38))
144750	26601204	Thus, heterozygous mutations in BRG (SMARCA4) cause small cell ovarian cancer, but likely just bear passenger mutations related to dysfunction of genome maintenance mechanisms in certain other tumors in which they are less prevalent.	('SMARCA4', 'Gene', '6597', (37, 44))	('small cell ovarian cancer', 'Disease', 'MESH:D055752', (52, 77))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cause', 'Reg', (46, 51))	('small cell ovarian cancer', 'Disease', (52, 77))	('heterozygous mutations', 'Var', (6, 28))	('SMARCA4', 'Gene', (37, 44))
144752	26601204	One of the most well-studied mechanisms by which ATP-dependent chromatin remodeling can assume tumor suppressor functions comes from the rare childhood cancer MRT caused by biallelic inactivation of BAF47 (hSNF5, INI1) in virtually 100% of the tumors.	('BAF47', 'Gene', (199, 204))	('caused by', 'Reg', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('hSNF5', 'Gene', '6598', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('hSNF5', 'Gene', (206, 211))	('biallelic', 'Var', (173, 182))	('cancer MRT', 'Disease', (152, 162))	('ATP', 'Chemical', 'MESH:D000255', (49, 52))	('tumors', 'Disease', (244, 250))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', (244, 249))	('cancer MRT', 'Disease', 'MESH:D009369', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('INI1', 'Gene', (213, 217))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('INI1', 'Gene', '6598', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
144755	26601204	The conditional deletion of BAF47 in mice leads to T cell lymphomas with a short latency that is unprecedented for the deletion of a single gene.	('leads to', 'Reg', (42, 50))	('BAF47', 'Gene', (28, 33))	('deletion', 'Var', (16, 24))	('T cell lymphomas', 'Disease', (51, 67))	('T cell lymphomas', 'Disease', 'MESH:D016399', (51, 67))	('lymphomas', 'Phenotype', 'HP:0002665', (58, 67))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (51, 67))	('lymphoma', 'Phenotype', 'HP:0002665', (58, 66))	('cell lymphoma', 'Phenotype', 'HP:0012191', (53, 66))	('mice', 'Species', '10090', (37, 41))
144757	26601204	BAF complexes in the mutant cells are unable to remove Polycomb complexes and their histone modification, H3K27Me3, from the Ink4a (Cdkn2a) locus, which normally suppresses proliferation.	('Polycomb', 'Gene', (55, 63))	('H3K27Me3', 'Var', (106, 114))	('Cdkn2a', 'Gene', (132, 138))	('mutant', 'Var', (21, 27))	('Cdkn2a', 'Gene', '1029', (132, 138))	('Ink4a', 'Gene', '1029', (125, 130))	('BAF', 'Chemical', '-', (0, 3))	('proliferation', 'CPA', (173, 186))	('suppresses', 'NegReg', (162, 172))	('Ink4a', 'Gene', (125, 130))	('Polycomb', 'Gene', '40358', (55, 63))
144759	26601204	Thus, the tumors seem to be induced exclusively by changes in epigenetic regulation (except for the initiating mutations in BAF47).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutations', 'Var', (111, 120))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('BAF47', 'Gene', (124, 129))	('changes', 'Reg', (51, 58))	('epigenetic regulation', 'MPA', (62, 83))	('induced', 'Reg', (28, 35))
144760	26601204	The mechanism by which loss of BAF47 leads to a failure to remove Polycomb is unclear and suggests that one of the important roles of BAF complexes is to oppose Polycomb as indicated from studies in flies and mammals.	('Polycomb', 'Gene', '40358', (66, 74))	('Polycomb', 'Gene', (66, 74))	('Polycomb', 'Gene', '40358', (161, 169))	('BAF47', 'Gene', (31, 36))	('Polycomb', 'Gene', (161, 169))	('BAF', 'Chemical', '-', (134, 137))	('loss', 'Var', (23, 27))	('BAF', 'Chemical', '-', (31, 34))
144763	26601204	Most cancers bearing BAF subunit mutations are found in older age groups, as is cancer in general, and do not occur selectively in young children.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (5, 11))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('BAF subunit', 'Gene', (21, 32))	('mutations', 'Var', (33, 42))	('BAF', 'Chemical', '-', (21, 24))	('children', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
144764	26601204	In addition, many, if not most, of the cancers have a mutation in only one allele of the affected subunit, making them dominant tumor suppressors, rather than recessive tumor suppressors as in the case of MRTs.	('mutation', 'Var', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('recessive tumor', 'Disease', 'MESH:D009369', (159, 174))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', (128, 133))	('recessive tumor', 'Disease', (159, 174))
144766	26601204	Mutations that produce neurologic disease are also genetically dominant, suggesting that a single fundamental process, albeit context-dependent, is at fault in both neurologic disease and cancer caused by heterozygous mutations in BAF subunits.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('BAF', 'Chemical', '-', (231, 234))	('neurologic disease', 'Disease', 'MESH:D019636', (165, 183))	('neurologic disease', 'Phenotype', 'HP:0000707', (23, 41))	('caused by', 'Reg', (195, 204))	('neurologic disease', 'Disease', (165, 183))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('neurologic disease', 'Phenotype', 'HP:0000707', (165, 183))	('BAF', 'Gene', (231, 234))	('neurologic disease', 'Disease', 'MESH:D019636', (23, 41))	('neurologic disease', 'Disease', (23, 41))
144767	26601204	The most commonly affected BAF subunit in cancer to date is ARID1A (BAF250A), which has now been found to be mutated in a wide variety of tumors including endometrial carcinoma, colon and rectal cancers, pancreatic cancer, transitional cell carcinoma of the bladder, gastric cancer, cholangiocarcinomas, and childhood neuroblastoma.	('carcinoma of the bladder', 'Disease', 'MESH:D001749', (241, 265))	('ARID1A', 'Gene', (60, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('BAF250A', 'Gene', (68, 75))	('neuroblastoma', 'Disease', (318, 331))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('endometrial carcinoma', 'Disease', (155, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('mutated', 'Var', (109, 116))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('neuroblastoma', 'Phenotype', 'HP:0003006', (318, 331))	('pancreatic cancer', 'Disease', 'MESH:D010190', (204, 221))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (283, 302))	('transitional cell carcinoma of the bladder', 'Phenotype', 'HP:0006740', (223, 265))	('ARID1A', 'Gene', '8289', (60, 66))	('carcinoma of the bladder', 'Disease', (241, 265))	('neuroblastoma', 'Disease', 'MESH:D009447', (318, 331))	('cancer', 'Disease', (215, 221))	('gastric cancer', 'Disease', (267, 281))	('cholangiocarcinomas', 'Disease', (283, 302))	('pancreatic cancer', 'Disease', (204, 221))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (155, 176))	('colon and rectal cancers', 'Disease', 'MESH:D012004', (178, 202))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (292, 302))	('cancer', 'Disease', (195, 201))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (155, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (267, 281))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (204, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('BAF', 'Chemical', '-', (68, 71))	('tumors', 'Disease', (138, 144))	('cancer', 'Disease', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('BAF250A', 'Gene', '8289', (68, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (267, 281))	('BAF', 'Chemical', '-', (27, 30))
144769	26601204	BAF250A mutations occur throughout the length of the gene, without clustering to any one domain, and most appear to be frameshift mutations predicted to lead to a loss of function or alternative splicing.	('BAF250A', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('loss of function', 'NegReg', (163, 179))	('frameshift', 'Var', (119, 129))	('BAF250A', 'Gene', '8289', (0, 7))
144771	26601204	Thus far, the Arid domain mutant mice do not have a higher incidence of cancer.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mice', 'Species', '10090', (33, 37))	('mutant', 'Var', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
144772	26601204	A murine mutation near the N terminus of BAF250a leads to alternative splicing and the production of a protein that induces hematopoietic proliferation in a non-cell-autonomous manner.	('mutation', 'Var', (9, 17))	('induces', 'PosReg', (116, 123))	('BAF250a', 'Gene', (41, 48))	('murine', 'Species', '10090', (2, 8))	('leads to', 'Reg', (49, 57))	('hematopoietic proliferation', 'CPA', (124, 151))	('alternative splicing', 'MPA', (58, 78))
144774	26601204	Most of the missense mutations are scattered within the highly conserved ATPase domain and group in interesting ways.	('missense mutations', 'Var', (12, 30))	('ATPase', 'Gene', '1769', (73, 79))	('ATPase', 'Gene', (73, 79))
144775	26601204	A highly penetrant ATPase domain mutation made many years ago, K785R, is present in several cancers and suggest that at least some of these could be functioning as dominant negative mutations.	('ATPase', 'Gene', (19, 25))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('K785R', 'Var', (63, 68))	('cancers', 'Disease', (92, 99))	('ATPase', 'Gene', '1769', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('K785R', 'Mutation', 'rs562397332', (63, 68))
144776	26601204	Similar mutations have been reported in the homologous Brm protein (SMARCA2); these mutations are less frequent in human cancer, yet far more common in neurologic disease.	('neurologic disease', 'Disease', (152, 170))	('neurologic disease', 'Phenotype', 'HP:0000707', (152, 170))	('common', 'Reg', (142, 148))	('SMARCA2', 'Gene', (68, 75))	('SMARCA2', 'Gene', '6595', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (8, 17))	('mutations', 'Var', (84, 93))	('human', 'Species', '9606', (115, 120))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('Brm', 'Gene', (55, 58))	('Brm', 'Gene', '6595', (55, 58))	('cancer', 'Disease', (121, 127))	('neurologic disease', 'Disease', 'MESH:D019636', (152, 170))
144777	26601204	These human genetic observations therefore indicate that in Brg mutant cancers, targeting the synthetic lethal protein Brm (identified in several studies; see "Paralogous subunit compensation as unique synthetic lethalities") might lead to neurologic defects.	('human', 'Species', '9606', (6, 11))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('neurologic defects', 'Disease', 'MESH:D009422', (240, 258))	('Brm', 'Gene', (119, 122))	('Brm', 'Gene', '6595', (119, 122))	('neurologic defects', 'Phenotype', 'HP:0000707', (240, 258))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutant', 'Var', (64, 70))	('neurologic defects', 'Disease', (240, 258))	('lead to', 'Reg', (232, 239))
144778	26601204	In addition, the combined loss of Brg and Brm has been reported in many cancer cell lines, indicating that resistance might quickly develop when Brm is targeted in a Brg mutant.	('Brm', 'Gene', '6595', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Brm', 'Gene', (42, 45))	('Brm', 'Gene', (145, 148))	('mutant', 'Var', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Brm', 'Gene', '6595', (145, 148))	('cancer', 'Disease', (72, 78))
144779	26601204	Tumors with mutations in BAF57 (SMARCE1) provide an illustrative example of both the remarkable tissue specificity and domain specificity of the tumorigenic actions of BAF complexes.	('BAF57', 'Gene', (25, 30))	('SMARCE1', 'Gene', '6605', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutations', 'Var', (12, 21))	('BAF', 'Chemical', '-', (168, 171))	('tumor', 'Disease', (145, 150))	('Tumors', 'Disease', (0, 6))	('BAF', 'Chemical', '-', (25, 28))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BAF57', 'Gene', '6605', (25, 30))	('SMARCE1', 'Gene', (32, 39))
144780	26601204	For most cancers, rates of mutation of BAF57 are extremely low (yet breast cancers have about a 10 to 14% incidence of amplification).	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('BAF57', 'Gene', '6605', (39, 44))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('breast cancers', 'Disease', 'MESH:D001943', (68, 82))	('cancers', 'Disease', (9, 16))	('breast cancers', 'Disease', (68, 82))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('BAF57', 'Gene', (39, 44))	('mutation', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))
144781	26601204	However, in non-NF2-driven multiple spinal meningiomas, nearly 100% of the tumors have mutations in this gene.	('NF2', 'Gene', '4771', (16, 19))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('meningioma', 'Phenotype', 'HP:0002858', (43, 53))	('meningiomas', 'Phenotype', 'HP:0002858', (43, 54))	('NF2', 'Gene', (16, 19))	('meningiomas', 'Disease', (43, 54))	('meningiomas', 'Disease', 'MESH:D008577', (43, 54))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('spinal meningiomas', 'Phenotype', 'HP:0100010', (36, 54))	('tumors', 'Disease', (75, 81))	('mutations', 'Var', (87, 96))
144784	26601204	The DNA binding domain is a nonspecific HMG domain, and introducing a point mutation into this domain gives rise to a mouse that suppresses the endogenous alleles and a phenotype very much like the loss of the Brg ATPase.	('suppresses', 'NegReg', (129, 139))	('ATPase', 'Gene', '1769', (214, 220))	('point mutation', 'Var', (70, 84))	('endogenous alleles', 'MPA', (144, 162))	('mouse', 'Species', '10090', (118, 123))	('ATPase', 'Gene', (214, 220))
144785	26601204	In addition, mutations in SMARCE1 detected in patients with Coffin-Siris syndrome are also exclusive to the HMG domain.	('Coffin-Siris syndrome', 'Disease', (60, 81))	('SMARCE1', 'Gene', (26, 33))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (60, 81))	('patients', 'Species', '9606', (46, 54))	('SMARCE1', 'Gene', '6605', (26, 33))	('mutations', 'Var', (13, 22))
144786	26601204	BAF170 (SMARCC2) and BAF155 (SMARCC1) are mutated infrequently in cancers.	('BAF170', 'Gene', (0, 6))	('SMARCC1', 'Gene', (29, 36))	('SMARCC2', 'Gene', '6601', (8, 15))	('cancers', 'Disease', (66, 73))	('BAF155', 'Var', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('SMARCC1', 'Gene', '6599', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('SMARCC2', 'Gene', (8, 15))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
144788	26601204	The homologous subunit BAF155 is mutated in about 10% of small cell lung cancers.	('small cell lung cancers', 'Disease', 'MESH:D055752', (57, 80))	('small cell lung cancers', 'Disease', (57, 80))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (57, 80))	('lung cancers', 'Phenotype', 'HP:0100526', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutated', 'Var', (33, 40))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))
144799	26601204	As with all genetic discoveries that have poured out of laboratories in recent years:from thousands of genes associated with rare Mendelian disorders and common disease to the hundreds that have been implicated in human cancer:driver, causative function is often challenging to assign, especially in the setting of tumors with numerous mutations.	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('tumors', 'Disease', (315, 321))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Mendelian disorders', 'Disease', (130, 149))	('mutations', 'Var', (336, 345))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('cancer', 'Disease', (220, 226))	('human', 'Species', '9606', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('Mendelian disorders', 'Disease', 'MESH:D030342', (130, 149))
144800	26601204	However, in certain tumors, specific genes are mutated in 100% of the cancers in 100% of the cells, which provides definitive evidence that these mutations cause the development and maintenance of the tumor.	('cause', 'Reg', (156, 161))	('development', 'CPA', (166, 177))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('mutations', 'Var', (146, 155))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (201, 206))	('cancers', 'Disease', (70, 77))	('tumor', 'Disease', (20, 25))
144803	26601204	Human synovial sarcoma is a soft-tissue tumor in which 100% of tumors have a precise translocation involving the SS18 subunit of BAF complexes.	('tumor', 'Disease', (63, 68))	('Human', 'Species', '9606', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('SS18', 'Gene', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('BAF', 'Chemical', '-', (129, 132))	('synovial sarcoma', 'Disease', (6, 22))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('SS18', 'Gene', '6760', (113, 117))	('translocation', 'Var', (85, 98))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (6, 22))	('synovial sarcoma', 'Disease', 'MESH:D013584', (6, 22))
144806	26601204	The SS18-SSX containing complexes are then retargeted to oncogenic loci such as SOX2 and PAX6, activating these genes by displacement of PRC2 complexes and their H3K27me3 repressive marks.	('SSX', 'Gene', (9, 12))	('H3K27me3', 'Var', (162, 170))	('SSX', 'Gene', '6757', (9, 12))	('displacement', 'NegReg', (121, 133))	('SS18', 'Gene', '6760', (4, 8))	('SOX2', 'Gene', (80, 84))	('PAX6', 'Gene', (89, 93))	('PRC2 complexes', 'Protein', (137, 151))	('SOX2', 'Gene', '6657', (80, 84))	('PAX6', 'Gene', '5080', (89, 93))	('SS18', 'Gene', (4, 8))	('activating', 'PosReg', (95, 105))
144811	26601204	The name pBAF came from the discovery that this complex contained polybromo (PBRM1 or BAF180) and BAF200 (Arid2), as well as Brg (but not Brm) and several other subunits of the BAF complex.	('BAF180', 'Gene', '55193', (86, 92))	('PBRM1', 'Gene', (77, 82))	('BAF', 'Chemical', '-', (10, 13))	('BAF', 'Chemical', '-', (177, 180))	('polybromo', 'Var', (66, 75))	('BAF200', 'Gene', '196528', (98, 104))	('PBRM1', 'Gene', '55193', (77, 82))	('Arid2', 'Gene', '196528', (106, 111))	('BAF', 'Chemical', '-', (98, 101))	('BAF200', 'Gene', (98, 104))	('Brm', 'Gene', (138, 141))	('Arid2', 'Gene', (106, 111))	('BAF', 'Chemical', '-', (86, 89))	('BAF180', 'Gene', (86, 92))	('Brm', 'Gene', '6595', (138, 141))
144813	26601204	BAF180 is mutated or deleted in more than 50% of clear cell renal cell carcinoma (ccRCC).	('deleted', 'Var', (21, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (49, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (60, 80))	('BAF180', 'Gene', (0, 6))	('BAF180', 'Gene', '55193', (0, 6))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (49, 80))	('clear cell renal cell carcinoma', 'Disease', (49, 80))
144815	26601204	It seems that the bromodomains are not redundant for the tumor suppressor function in that mutation of any single bromodomain in one allele is sufficient to contribute to cancer formation.	('mutation', 'Var', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('contribute', 'Reg', (157, 167))	('tumor', 'Disease', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
144816	26601204	ccRCC is most often associated with a mutation in the VHL (von Hippel-Lindau) gene, which encodes an E3 ubiquitin ligase, either as a point mutation or as part of a large deletion of chromosomal arm 3p.	('associated', 'Reg', (20, 30))	('von Hippel-Lindau', 'Gene', (59, 76))	('VHL', 'Gene', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('ccRCC', 'Disease', (0, 5))	('VHL', 'Gene', '7428', (54, 57))	('von Hippel-Lindau', 'Gene', '7428', (59, 76))	('mutation', 'Var', (38, 46))
144819	26601204	However, it appears that missense mutation of either VHL, BAP1, or BAF180 can contribute to ccRCC independently, suggesting an interesting interplay of these genes in the pathogenesis of this tumor.	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('tumor', 'Disease', (192, 197))	('missense mutation', 'Var', (25, 42))	('ccRCC', 'Disease', (92, 97))	('BAP1', 'Gene', (58, 62))	('contribute', 'Reg', (78, 88))	('VHL', 'Gene', (53, 56))	('BAF180', 'Gene', (67, 73))	('BAF180', 'Gene', '55193', (67, 73))	('VHL', 'Gene', '7428', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('BAP1', 'Gene', '8314', (58, 62))
144820	26601204	Mutations in PBRM1 correlate with mutations in VHL, the most commonly mutated gene in ccRCC, and have a tendency toward mutual exclusivity with BAP1 mutations.	('PBRM1', 'Gene', (13, 18))	('BAP1', 'Gene', (144, 148))	('Mutations', 'Var', (0, 9))	('VHL', 'Gene', (47, 50))	('PBRM1', 'Gene', '55193', (13, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('VHL', 'Gene', '7428', (47, 50))	('mutations', 'Var', (34, 43))	('BAP1', 'Gene', '8314', (144, 148))
144822	26601204	BAF180 (pBRM) and BAF200 (Arid2), which are present in the same pBAF complex, are both frequently mutated in liver cancers, and about 18% of hepatitis-associated hepatocellular carcinomas have mutations in BAF200.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (162, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('mutations', 'Var', (193, 202))	('BAF180', 'Gene', (0, 6))	('BAF', 'Chemical', '-', (65, 68))	('BAF', 'Chemical', '-', (18, 21))	('liver cancers', 'Disease', (109, 122))	('Arid2', 'Gene', '196528', (26, 31))	('BAF', 'Chemical', '-', (0, 3))	('BAF', 'Chemical', '-', (206, 209))	('BRM', 'Gene', (9, 12))	('hepatitis-associated hepatocellular carcinomas', 'Disease', (141, 187))	('hepatitis-associated hepatocellular carcinomas', 'Disease', 'MESH:D056486', (141, 187))	('hepatitis', 'Phenotype', 'HP:0012115', (141, 150))	('Arid2', 'Gene', (26, 31))	('BAF200', 'Gene', '196528', (18, 24))	('mutated', 'Var', (98, 105))	('liver cancers', 'Disease', 'MESH:D006528', (109, 122))	('BAF200', 'Gene', (18, 24))	('BRM', 'Gene', '6595', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('BAF200', 'Gene', '196528', (206, 212))	('liver cancer', 'Phenotype', 'HP:0002896', (109, 121))	('BAF200', 'Gene', (206, 212))	('BAF180', 'Gene', '55193', (0, 6))	('liver cancers', 'Phenotype', 'HP:0002896', (109, 122))
144825	26601204	The advent of exome sequencing made it possible to not only identify recessive tumor suppressors but also identify mutations in genes that tend to co-occur with them, pointing toward potential mechanisms and therapeutic approaches.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mutations', 'Var', (115, 124))	('recessive tumor', 'Disease', 'MESH:D009369', (69, 84))	('recessive tumor', 'Disease', (69, 84))
144826	26601204	When BAF250A (ARID1A) mutations were first identified in ovarian cancer, it was immediately clear that cooperating mutations in phosphatidylinositol 3-kinase (PI3K) were frequent.	('mutations', 'Var', (115, 124))	('ovarian cancer', 'Disease', 'MESH:D010051', (57, 71))	('BAF250A', 'Gene', (5, 12))	('ovarian cancer', 'Disease', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ARID1A', 'Gene', '8289', (14, 20))	('BAF250A', 'Gene', '8289', (5, 12))	('ARID1A', 'Gene', (14, 20))	('mutations', 'Var', (22, 31))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (128, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('phosphatidylinositol 3-kinase', 'Gene', (128, 157))
144830	26601204	As yet, the significance of this binding is unclear, but it may regulate the activity of BAF complexes and their association with chromatin, and hence, PI3K activation could further reduce the activity of the BAF complex.	('regulate', 'Reg', (64, 72))	('association', 'Interaction', (113, 124))	('BAF', 'CPA', (209, 212))	('BAF complexes', 'Protein', (89, 102))	('BAF', 'Chemical', '-', (89, 92))	('activity', 'MPA', (193, 201))	('reduce', 'NegReg', (182, 188))	('BAF', 'Chemical', '-', (209, 212))	('PI3K', 'Var', (152, 156))	('activity', 'MPA', (77, 85))	('chromatin', 'Protein', (130, 139))
144831	26601204	For example, if the activation of PI3K leads to increased cell division in a cell lacking a BAF subunit, one would expect the consequent defect due to failure of TopoII function (see below) to be sensitized.	('lacking', 'NegReg', (82, 89))	('increased', 'PosReg', (48, 57))	('PI3K', 'Var', (34, 38))	('BAF', 'Chemical', '-', (92, 95))	('cell division', 'CPA', (58, 71))
144832	26601204	Activated PI3K would drive more "at-risk" cell divisions, leading to more mutations and advancement along the pathway to cancer.	('advancement', 'PosReg', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (74, 83))	('drive', 'PosReg', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('more', 'PosReg', (69, 73))	('cancer', 'Disease', (121, 127))	('Activated PI3K', 'Var', (0, 14))
144833	26601204	Another possibility would be that loss of BAF function leads to more point mutations and a greater likelihood of activation of PI3K.	('BAF', 'Protein', (42, 45))	('PI3K', 'Pathway', (127, 131))	('BAF', 'Chemical', '-', (42, 45))	('point mutations', 'Var', (69, 84))
144835	26601204	Recently, Chandler and colleagues demonstrated that mice with one allele of BAF250a deleted do not get cancer, but when bred to a mouse with a mutation in PI3K, they develop ovarian clear cell cancer, establishing this as an excellent model for these cancers.	('cancer', 'Disease', (193, 199))	('clear cell cancer', 'Phenotype', 'HP:0006770', (182, 199))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('develop', 'PosReg', (166, 173))	('mice', 'Species', '10090', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('BAF250a', 'Gene', (76, 83))	('mutation', 'Var', (143, 151))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('cancers', 'Disease', (251, 258))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (251, 257))	('mouse', 'Species', '10090', (130, 135))	('ovarian clear cell cancer', 'Disease', 'MESH:D008649', (174, 199))	('ovarian clear cell cancer', 'Disease', (174, 199))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('PI3K', 'Gene', (155, 159))
144836	26601204	They found that PI3K leads to the dissociation of BAF complexes from the interleukin-6 (IL-6) promoter, relieving its repression and leading to high levels of IL-6 production in the murine cancers.	('IL-6 production', 'MPA', (159, 174))	('BAF', 'Chemical', '-', (50, 53))	('IL-6', 'Gene', (88, 92))	('interleukin-6', 'Gene', '16193', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('interleukin-6', 'Gene', (73, 86))	('relieving', 'NegReg', (104, 113))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('repression', 'MPA', (118, 128))	('leading to', 'Reg', (133, 143))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('murine', 'Species', '10090', (182, 188))	('PI3K', 'Var', (16, 20))	('dissociation', 'MPA', (34, 46))	('cancers', 'Disease', (189, 196))
144839	26601204	The mechanism by which PI3K inactivates BAF on the IL-6 promoter is unclear.	('inactivates', 'NegReg', (28, 39))	('BAF', 'Chemical', '-', (40, 43))	('PI3K', 'Var', (23, 27))
144847	26601204	It is mutated in about 40% of low-grade gliomas, 20% of pancreatic cancers, 10% of small cell lung cancers, and 9% of uterine endometrial cancers.	('lung cancers', 'Phenotype', 'HP:0100526', (94, 106))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancers', 'Disease', 'MESH:D010190', (56, 74))	('mutated', 'Var', (6, 13))	('small cell lung cancers', 'Disease', (83, 106))	('small cell lung cancers', 'Disease', 'MESH:D055752', (83, 106))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (83, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('gliomas', 'Disease', (40, 47))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('endometrial cancers', 'Disease', (126, 145))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (56, 74))	('endometrial cancers', 'Disease', 'MESH:D016889', (126, 145))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('pancreatic cancers', 'Disease', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
144849	26601204	Mutations in ATRX cause a syndrome characterized by anemia (actually alpha-thalassemia) and mental retardation, and are encoded on the X chromosome.	('thalassemia', 'Disease', (75, 86))	('ATRX', 'Gene', (13, 17))	('anemia', 'Phenotype', 'HP:0001903', (52, 58))	('thalassemia', 'Disease', 'MESH:D013789', (75, 86))	('mental retardation', 'Disease', (92, 110))	('ATRX', 'Gene', '546', (13, 17))	('mental retardation', 'Phenotype', 'HP:0001249', (92, 110))	('mental retardation', 'Disease', 'MESH:D008607', (92, 110))	('cause', 'Reg', (18, 23))	('Mutations', 'Var', (0, 9))	('anemia', 'Disease', (52, 58))	('anemia', 'Disease', 'MESH:D000740', (52, 58))	('syndrome', 'Disease', (26, 34))
144851	26601204	Remarkably, in several tumors, notably glioma, it is mutated along with DAXX and histone H3.3, identifying a genetic pathway contributing to these tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (23, 29))	('DAXX', 'Gene', '1616', (72, 76))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (147, 153))	('glioma', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('histone H3.3', 'Gene', '3021', (81, 93))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('mutated', 'Var', (53, 60))	('histone H3.3', 'Gene', (81, 93))	('DAXX', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
144852	26601204	Patients with somatic null mutations in ATRX do not have a predisposition to cancer, indicating that other genes must contribute to the pathogenesis of cancer in those cases.	('null mutations', 'Var', (22, 36))	('cancer', 'Disease', (152, 158))	('ATRX', 'Gene', '546', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Patients', 'Species', '9606', (0, 8))	('ATRX', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
144862	26601204	Furthermore, unlike SMARCA4 (BRG1 or BAF190), there are no recurrent missense mutations in the ATPase domain of CHD1 in cancer that would indicate that this particular function is critical.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('ATPase', 'Gene', (95, 101))	('CHD1', 'Gene', (112, 116))	('BRG1', 'Gene', (29, 33))	('CHD1', 'Gene', '1105', (112, 116))	('SMARCA4', 'Gene', (20, 27))	('SMARCA4', 'Gene', '6597', (20, 27))	('cancer', 'Disease', (120, 126))	('BAF190', 'Gene', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('BRG1', 'Gene', '6597', (29, 33))	('BAF190', 'Gene', '6597', (37, 43))	('missense mutations', 'Var', (69, 87))	('ATPase', 'Gene', '1769', (95, 101))
144863	26601204	A knockdown was reported to interfere with murine ES cell formation and to be required for pluripotency, but this has not been confirmed yet with a null mutation.	('knockdown', 'Var', (2, 11))	('murine', 'Species', '10090', (43, 49))	('interfere', 'NegReg', (28, 37))	('murine ES cell formation', 'CPA', (43, 67))
144864	26601204	The other chromatin regulator commonly mutated in cancer is CHD8, which ranks 90th among the genes contributing to tumor suppression in a recent analysis provided by Davoli and colleagues.	('CHD8', 'Gene', '57680', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', (115, 120))	('mutated', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('CHD8', 'Gene', (60, 64))
144865	26601204	CHD8 is mutated in about 10% of pancreatic, colorectal, and uterine cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('pancreatic', 'Disease', 'MESH:D010195', (32, 42))	('CHD8', 'Gene', (0, 4))	('mutated', 'Var', (8, 15))	('colorectal', 'Disease', 'MESH:D015179', (44, 54))	('CHD8', 'Gene', '57680', (0, 4))	('pancreatic', 'Disease', (32, 42))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('colorectal', 'Disease', (44, 54))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('uterine cancers', 'Phenotype', 'HP:0010784', (60, 75))
144866	26601204	In Drosophila, CHD8 is called Kismet, and its deletion leads to the accumulation of H3K27Me3 over the fly genome, much in the same way that deletion of BAP or BAF subunits leads to enhanced H3K27Me3 at many loci over the mammalian genome.	('deletion', 'Var', (46, 54))	('accumulation', 'PosReg', (68, 80))	('BAF', 'Chemical', '-', (159, 162))	('mammalian', 'Species', '9606', (221, 230))	('enhanced', 'PosReg', (181, 189))	('H3K27Me3', 'MPA', (190, 198))	('BAP', 'Gene', (152, 155))	('Drosophila', 'Species', '7227', (3, 13))	('deletion', 'Var', (140, 148))	('BAP', 'Gene', '11331', (152, 155))	('CHD8', 'Gene', (15, 19))	('CHD8', 'Gene', '57680', (15, 19))	('H3K27Me3', 'Protein', (84, 92))
144868	26601204	CHD8-like Brg and Brm show repeated missense mutations within the ATPase domain, which are likely to have an effect on the protein.	('ATPase', 'Gene', '1769', (66, 72))	('missense mutations', 'Var', (36, 54))	('CHD8', 'Gene', (0, 4))	('CHD8', 'Gene', '57680', (0, 4))	('ATPase', 'Gene', (66, 72))	('effect', 'Reg', (109, 115))	('Brm', 'Gene', (18, 21))	('Brm', 'Gene', '6595', (18, 21))
144870	26601204	In yeast, the ATP-dependent chromatin remodelers INO80 and SWR1 are major guardians of the genome and prevent the accumulation of mutations, much as p53 does in mammalian cells.	('prevent', 'NegReg', (102, 109))	('SWR1', 'Gene', '851934', (59, 63))	('ATP', 'Chemical', 'MESH:D000255', (14, 17))	('mutations', 'Var', (130, 139))	('yeast', 'Species', '4932', (3, 8))	('accumulation', 'MPA', (114, 126))	('SWR1', 'Gene', (59, 63))	('mammalian', 'Species', '9606', (161, 170))
144875	26601204	Genes that are frequently mutated in a disease are not necessarily more important, but rather they cause human disease and are found frequently in exome sequencing studies because of their genetic dominance and dosage sensitivity.	('human', 'Species', '9606', (105, 110))	('mutated', 'Var', (26, 33))	('cause', 'Reg', (99, 104))	('human disease', 'Disease', (105, 118))
144879	26601204	From studies in ES cells, we know that BAF complexes oppose PRC complexes at most sites, with the exception of genes such as the Hox loci at which they appear to act synergistically to enable the placement of the H3K27Me3 mark.	('Hox', 'Gene', (129, 132))	('Hox', 'Gene', '42536', (129, 132))	('H3K27Me3', 'Var', (213, 221))	('BAF', 'Chemical', '-', (39, 42))
144887	26601204	The unbalanced state produced by either loss-of-function BAF subunit mutations or gain-of-function PRC2 mutations might be an effective site for therapeutic intervention (Fig.	('mutations', 'Var', (69, 78))	('BAF subunit', 'Protein', (57, 68))	('mutations', 'Var', (104, 113))	('gain-of-function', 'PosReg', (82, 98))	('BAF', 'Chemical', '-', (57, 60))	('PRC2', 'Gene', (99, 103))	('loss-of-function', 'NegReg', (40, 56))
144888	26601204	Although one would anticipate substantial toxicity associated with removal of PRC2 function, mice appeared to tolerate the treatment, and their tumors underwent regression with EZH2 inhibition.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('toxicity', 'Disease', (42, 50))	('mice', 'Species', '10090', (93, 97))	('inhibition', 'NegReg', (182, 192))	('removal', 'Var', (67, 74))	('PRC2', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
144889	26601204	Also, a diffuse large cell lymphoma with activating mutations in Ezh2 (Y641F/N) appears to be sensitive to Ezh2 inhibition.	('cell lymphoma', 'Phenotype', 'HP:0012191', (22, 35))	('cell lymphoma', 'Disease', 'MESH:D016399', (22, 35))	('activating', 'PosReg', (41, 51))	('Y641F', 'SUBSTITUTION', 'None', (71, 76))	('cell lymphoma', 'Disease', (22, 35))	('Ezh2', 'Gene', (65, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (27, 35))	('Ezh2', 'Gene', '2146', (65, 69))	('Ezh2', 'Gene', (107, 111))	('Ezh2', 'Gene', '2146', (107, 111))	('Y641F', 'Var', (71, 76))
144895	26601204	Deletion or shRNA depletion of the oncogenic BAF subunits leads to the formation of anaphase bridges, indicating a failure to untangle DNA at anaphase, whereas deletion of non-oncogenic subunits did not have this effect.	('failure', 'NegReg', (115, 122))	('depletion', 'NegReg', (18, 27))	('shRNA', 'Gene', (12, 17))	('anaphase bridges', 'CPA', (84, 100))	('BAF', 'Chemical', '-', (45, 48))	('Deletion', 'Var', (0, 8))
144896	26601204	The deletion of oncogenic BAF subunits surprisingly leads to arrest at G2/M with high levels of histone H3 S-10 phosphorylation, an indicator of incomplete mitosis.	('mitosis', 'Disease', (156, 163))	('BAF', 'Chemical', '-', (26, 29))	('arrest', 'MPA', (61, 67))	('mitosis', 'Disease', 'None', (156, 163))	('leads to', 'Reg', (52, 60))	('deletion', 'Var', (4, 12))	('histone H3 S-10 phosphorylation', 'MPA', (96, 127))
144902	26601204	These studies suggest that mutations in BAF subunits lead to the inability to resolve tangles at anaphase, with subsequent strand breakage and attempted repair of these breaks in the cytoplasm of the separating cells.	('mutations', 'Var', (27, 36))	('strand breakage', 'CPA', (123, 138))	('BAF', 'Chemical', '-', (40, 43))	('inability', 'NegReg', (65, 74))	('BAF', 'Gene', (40, 43))
144903	26601204	This could generate potential oncogenic driving mutations that would contribute to the pathogenesis of the cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('contribute', 'Reg', (69, 79))	('cancer', 'Disease', (107, 113))	('mutations', 'Var', (48, 57))
144905	26601204	First, the effect of BAF deletion on TopoII must be shown to be genetically dominant.	('BAF', 'Chemical', '-', (21, 24))	('deletion', 'Var', (25, 33))	('BAF', 'Gene', (21, 24))
144906	26601204	Thus, we would expect that loss of a single allele of an oncogenic BAF subunit would lead to impairment of TopoII function.	('BAF', 'Chemical', '-', (67, 70))	('loss', 'Var', (27, 31))	('TopoII function', 'CPA', (107, 122))	('BAF', 'Gene', (67, 70))
144909	26601204	In yeast, TopoII function was shown to require nucleosome-free DNA, and the loss of the snf5 gene interfered with the binding of TopoIIa.	('snf5', 'Gene', '852592', (88, 92))	('loss', 'Var', (76, 80))	('yeast', 'Species', '4932', (3, 8))	('binding', 'Interaction', (118, 125))	('interfered', 'NegReg', (98, 108))	('snf5', 'Gene', (88, 92))
144910	26601204	Because BAF subunit mutations prevent TopoII from contacting DNA, these studies predict that cancers with BAF subunit mutations should be resistant to TopoII inhibitors.	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('BAF subunit', 'Gene', (106, 117))	('actin', 'Gene', (54, 59))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('actin', 'Gene', '31521', (54, 59))	('BAF', 'Gene', (8, 11))	('BAF', 'Chemical', '-', (106, 109))	('mutations', 'Var', (20, 29))	('BAF', 'Chemical', '-', (8, 11))
144911	26601204	In other studies, the presence of a Brg (Smarca4) mutation has been shown to predict sensitivity to a combination of EZH2 and TopoIIa inhibition in a group of small cell lung cancers.	('Smarca4', 'Gene', '6597', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lung cancers', 'Phenotype', 'HP:0100526', (170, 182))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (159, 182))	('mutation', 'Var', (50, 58))	('predict', 'Reg', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('presence', 'Var', (22, 30))	('small cell lung cancers', 'Disease', 'MESH:D055752', (159, 182))	('small cell lung cancers', 'Disease', (159, 182))	('Smarca4', 'Gene', (41, 48))	('sensitivity', 'MPA', (85, 96))
144912	26601204	The underlying mechanism is unclear, but it is possible that EZH2 inhibition blocks Polycomb placement, allowing the binding of TopoIIa to DNA and, hence, sensitivity to these inhibitors in the face of a BAF subunit mutation.	('EZH2', 'Gene', (61, 65))	('BAF', 'Chemical', '-', (204, 207))	('sensitivity', 'MPA', (155, 166))	('binding', 'Interaction', (117, 124))	('Polycomb', 'Gene', '40358', (84, 92))	('mutation', 'Var', (216, 224))	('Polycomb', 'Gene', (84, 92))
144915	26601204	For example, loss or mutation of the Brg ATPase appears to make tumors containing these mutations highly susceptible to loss of the alternative ATPase, Brm.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('ATPase', 'Gene', '1769', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('ATPase', 'Gene', (144, 150))	('Brg', 'Gene', (37, 40))	('Brm', 'Gene', '6595', (152, 155))	('ATPase', 'Gene', (41, 47))	('mutations', 'Var', (88, 97))	('mutation', 'Var', (21, 29))	('loss', 'NegReg', (13, 17))	('loss', 'NegReg', (120, 124))	('ATPase', 'Gene', '1769', (144, 150))	('Brm', 'Gene', (152, 155))
144917	26601204	Similarly, in an shRNA-based screen for genes that were synthetically lethal with a mutation in BAF250a, the loss of BAF250b was detected.	('BAF250a', 'Gene', (96, 103))	('mutation', 'Var', (84, 92))	('BAF250b', 'Gene', (117, 124))	('loss', 'NegReg', (109, 113))	('BAF250b', 'Gene', '57492', (117, 124))
144918	26601204	These studies indicate that when one subunit is mutated, the tumor becomes dependent on the other subunit that can occupy this position in the complex.	('tumor', 'Disease', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutated', 'Var', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
144920	26601204	For example, BAF250b is the most commonly mutated gene discovered in a recent exome sequencing study of human developmental diseases, and Brm is mutated in and causes a number of human neurodevelopmental diseases.	('developmental diseases', 'Disease', (110, 132))	('developmental diseases', 'Disease', 'MESH:D001848', (110, 132))	('human', 'Species', '9606', (179, 184))	('mutated', 'Var', (145, 152))	('developmental diseases', 'Disease', 'MESH:D001848', (190, 212))	('neurodevelopmental diseases', 'Disease', 'MESH:D009422', (185, 212))	('neurodevelopmental diseases', 'Disease', (185, 212))	('Brm', 'Gene', '6595', (138, 141))	('human', 'Species', '9606', (104, 109))	('BAF250b', 'Gene', '57492', (13, 20))	('Brm', 'Gene', (138, 141))	('causes', 'Reg', (160, 166))	('BAF250b', 'Gene', (13, 20))
144922	26601204	In addition, many tumors show genetic inactivation of one subunit and epigenetic inactivation of the homolog.	('genetic inactivation', 'Var', (30, 50))	('epigenetic inactivation', 'Var', (70, 93))	('subunit', 'Protein', (58, 65))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
144923	26601204	For example, SW13 and several other cell lines contain a mutation in Brg, but do not express Brm, presumably by epigenetic inactivation.	('mutation', 'Var', (57, 65))	('Brg', 'Gene', (69, 72))	('Brm', 'Gene', (93, 96))	('Brm', 'Gene', '6595', (93, 96))	('SW13', 'CellLine', 'CVCL:0542', (13, 17))
144933	26601204	Here, the driving, oncogenic mutation is always the same and always results in the addition of exactly 78 amino acids of SSX to the SS18 gene at precisely the same place.	('SS18', 'Gene', (132, 136))	('mutation', 'Var', (29, 37))	('results in', 'Reg', (68, 78))	('SS18', 'Gene', '6760', (132, 136))	('SSX', 'Gene', '6757', (121, 124))	('SSX', 'Gene', (121, 124))
144941	26601204	Because there is no specific fusion to target or gained interaction identified to date, a cancer-specific treatment seems less likely unless the loss of BAF47 produces specific allosteric effects over the complex that would render it uniquely susceptible to small molecules.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('loss', 'Var', (145, 149))	('allosteric effects over the complex', 'MPA', (177, 212))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('BAF47', 'Gene', (153, 158))
144969	25897676	In preclinical breast and prostate cancer murine models, inhibition of mTORC1, which is composed of regulatory-associated protein of mTOR (RAPTOR), mLST8 (also known as GbetaL), and AKT substrate of 40 kDa (PRAS40), with the mTORi rapamycin, led to MAPK pathway activation through a PI3K-dependent feedback loop.	('PRAS40', 'Gene', (207, 213))	('RAPTOR', 'Gene', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('PI3', 'Gene', (283, 286))	('MAPK pathway', 'Pathway', (249, 261))	('mTOR', 'Gene', (225, 229))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))	('inhibition', 'Var', (57, 67))	('PRAS40', 'Gene', '67605', (207, 213))	('rapamycin', 'Chemical', 'MESH:D020123', (231, 240))	('mTOR', 'Gene', '2475', (225, 229))	('GbetaL', 'Chemical', '-', (169, 175))	('activation', 'PosReg', (262, 272))	('regulatory-associated protein of mTOR', 'Gene', (100, 137))	('mTORC1', 'Gene', (71, 77))	('mTOR', 'Gene', (71, 75))	('murine', 'Species', '10090', (42, 48))	('mTOR', 'Gene', (133, 137))	('mTORC1', 'Gene', '382056', (71, 77))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (15, 41))	('mLST8', 'Gene', '56716', (148, 153))	('regulatory-associated protein of mTOR', 'Gene', '74370', (100, 137))	('PI3', 'Gene', '5266', (283, 286))	('RAPTOR', 'Gene', '74370', (139, 145))	('mLST8', 'Gene', (148, 153))	('mTOR', 'Gene', '2475', (71, 75))	('mTOR', 'Gene', '2475', (133, 137))
144970	25897676	However, when rapamycin was combined with the MEK1/2 inhibitor, PD0325901, MAPK feedback activation was abrogated and resulted in an enhanced antitumoral effect.	('MAPK', 'Gene', (75, 79))	('abrogated', 'NegReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PD0325901', 'Var', (64, 73))	('tumor', 'Disease', (146, 151))	('MEK1/2', 'Gene', '5604;5605', (46, 52))	('MEK1/2', 'Gene', (46, 52))	('activation', 'PosReg', (89, 99))	('PD0325901', 'Chemical', 'MESH:C506614', (64, 73))	('rapamycin', 'Chemical', 'MESH:D020123', (14, 23))	('enhanced', 'PosReg', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
144978	25897676	Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of two or less, absolute neutrophil count >=1000 mm-3, platelet count>100 000 mm-3, haemoglobin >8 g dl-1, serum creatinine<1.5 x upper limits of normal (ULN), or calculated creatinine clearance >= 45 ml min-1, total bilirubin<=1.5 x ULN, SGPT (ALT)<=5 x ULN for age, and serum albumin>=2 g dl-1.	('min-1', 'Gene', '966', (301, 306))	('serum albumin', 'MPA', (369, 382))	('creatinine clearance', 'MPA', (271, 291))	('total bilirubin', 'MPA', (308, 323))	('>100 000', 'Var', (166, 174))	('>=1000 mm-3', 'Var', (139, 150))	('Oncology', 'Phenotype', 'HP:0002664', (56, 64))	('min-1', 'Gene', (301, 306))
145002	25897676	The drug combinations of temsirolimus (1, 10, 100 nM) with selumetinib (10, 100, 1000 nM), respectively, led to inhibition of proliferation combination Index (CI) values at the lowest concentrations of 0.001 (SK-UT-1, leiomyosarcoma), 0.047 (HT1080, fibrosarcoma), and 0.152 (SW872, liposarcoma).	('fibrosarcoma', 'Disease', (250, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (218, 232))	('liposarcoma', 'Phenotype', 'HP:0012034', (283, 294))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (218, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	('selumetinib', 'Chemical', 'MESH:C517975', (59, 70))	('liposarcoma', 'Disease', 'MESH:D008080', (283, 294))	('0.152', 'Var', (269, 274))	('leiomyosarcoma', 'Disease', (218, 232))	('HT1080', 'CellLine', 'CVCL:0317', (242, 248))	('0.047', 'Var', (235, 240))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (250, 262))	('SW872', 'CellLine', 'CVCL:1730', (276, 281))	('combinations', 'Interaction', (9, 21))	('temsirolimus', 'Chemical', 'MESH:C401859', (25, 37))	('liposarcoma', 'Disease', (283, 294))	('inhibition', 'NegReg', (112, 122))	('fibrosarcoma', 'Disease', 'MESH:D005354', (250, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('proliferation combination Index', 'MPA', (126, 157))	('SK-UT-1', 'CellLine', 'CVCL:0533', (209, 216))
145034	25897676	Pre- and post-treatment skin biopsies were obtained simultaneously with the PBMCs to evaluate as a surrogate for tumor mTOR-Akt pathway pharmacodynamic markers including: phospho-p70, phospho-AKT, Ki67 (proliferation), p62 (autophagic flux), BCL-2 (anti-apoptosis), and cleaved caspase 3 (apoptosis).	('BCL-2', 'Gene', (242, 247))	('tumor', 'Disease', (113, 118))	('Akt', 'Gene', (124, 127))	('p62', 'Gene', '23636', (219, 222))	('cleaved', 'MPA', (270, 277))	('p62', 'Gene', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mTOR', 'Gene', (119, 123))	('BCL-2', 'Gene', '596', (242, 247))	('mTOR', 'Gene', '2475', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Akt', 'Gene', '207', (124, 127))	('phospho-p70', 'Var', (171, 182))	('Ki67', 'Var', (197, 201))
145056	25897676	The PTEN gene is located on chromosome 10q, and partial loss of 10q is also a frequent event in leiomyosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (96, 111))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (96, 111))	('partial loss of 10q', 'Var', (48, 67))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (96, 110))	('leiomyosarcomas', 'Disease', (96, 111))	('PTEN', 'Gene', (4, 8))
145057	25897676	Mice with smooth muscle lineage-specific knockout of PTEN also develop widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, significantly implicating PTEN downregulation in leiomyosarcomagenesis.	('leiomyosarcomagenesis', 'Disease', (193, 214))	('muscle cell hyperplasia', 'Disease', 'MESH:D006965', (89, 112))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (193, 207))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (127, 142))	('downregulation', 'NegReg', (175, 189))	('leiomyosarcomagenesis', 'Disease', 'None', (193, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('knockout', 'Var', (41, 49))	('abdominal leiomyosarcomas', 'Disease', (117, 142))	('PTEN', 'Gene', (53, 57))	('abdominal leiomyosarcomas', 'Disease', 'MESH:D007890', (117, 142))	('Mice', 'Species', '10090', (0, 4))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (127, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('muscle cell hyperplasia', 'Disease', (89, 112))
145058	25897676	KRAS mutations can also activate the Akt/mTOR pathway, and KRAS mutations have been reported in a subset (7-33%) of leiomyosarcoma patients; MEK inhibitors act downstream of RAS in the MAPK pathway.	('patients', 'Species', '9606', (131, 139))	('KRAS', 'Gene', '3845', (59, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('KRAS', 'Gene', (59, 63))	('Akt', 'Gene', '207', (37, 40))	('leiomyosarcoma', 'Disease', (116, 130))	('MEK', 'Gene', (141, 144))	('mutations', 'Var', (5, 14))	('activate', 'PosReg', (24, 32))	('Akt', 'Gene', (37, 40))	('MEK', 'Gene', '5609', (141, 144))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (116, 130))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (116, 130))	('KRAS', 'Gene', (0, 4))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))	('KRAS', 'Gene', '3845', (0, 4))
145071	23036318	In order to glean insight into the pathobiology of sarcomas, scientists are now using in vivo mouse models whose genomes have been specifically tailored to carry gene deletions, gene amplifications, and point mutations commonly observed in human sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('gene deletions', 'Var', (162, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('human', 'Species', '9606', (240, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Disease', (51, 59))	('point mutations', 'Var', (203, 218))	('mouse', 'Species', '10090', (94, 99))	('sarcomas', 'Disease', 'MESH:D012509', (246, 254))	('gene amplifications', 'Var', (178, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('sarcomas', 'Phenotype', 'HP:0100242', (246, 254))	('sarcomas', 'Disease', (246, 254))
145072	23036318	The use of these model organisms has been successful in increasing our knowledge and understanding of how alterations in relevant oncogenic, tumor suppressive, and signaling pathways directly impact sarcomagenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('impact sarcomagenesis', 'Disease', 'MESH:D004834', (192, 213))	('tumor', 'Disease', (141, 146))	('oncogenic', 'Gene', (130, 139))	('impact sarcomagenesis', 'Disease', (192, 213))	('alterations', 'Var', (106, 117))
145080	23036318	The first and most simple genetic profile is the observation of translocation events in sarcomas with an otherwise normal diploid karyotype.	('sarcomas', 'Disease', (88, 96))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('translocation', 'Var', (64, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
145098	23036318	In this review, we will highlight several models engineered to harbor known translocations thought to drive human sarcomagenesis as well as tumor prone models with an increased propensity for sarcoma formation.	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('translocations', 'Var', (76, 90))	('sarcoma', 'Disease', (114, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('human', 'Species', '9606', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('sarcoma', 'Disease', (192, 199))	('tumor', 'Disease', (140, 145))
145101	23036318	The specificity of individual translocations are likewise useful diagnostic indicators of specific sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('sarcomas', 'Disease', (99, 107))	('translocations', 'Var', (30, 44))	('sarcomas', 'Disease', 'MESH:D012509', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
145102	23036318	Ewing's sarcomas commonly carry a t(11;22)(q24:q12) reciprocal translocation resulting in a gene fusion product between the RNA binding protein Ews and the transcription factor Fli1.	('Fli1', 'Gene', '14247', (177, 181))	('gene fusion', 'MPA', (92, 103))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('RNA binding protein Ews', 'Gene', (124, 147))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (0, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('Fli1', 'Gene', (177, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('t(11;22)(q24:q12)', 'STRUCTURAL_ABNORMALITY', 'None', (34, 51))	('RNA binding protein Ews', 'Gene', '14030', (124, 147))	("Ewing's sarcomas", 'Disease', (0, 16))	('t(11;22', 'Var', (34, 41))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (0, 16))
145105	23036318	Alveolar rhabdomyosarcomas, like Ewing's sarcomas, are also often defined by the presence of translocation events, most commonly t(2;13)(q35;q14) and t(1;13)(p36;q14).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (33, 48))	('Alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (0, 26))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (33, 49))	('t(1;13)(p36;q14', 'Var', (150, 165))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('t(2;13)(q35;q14', 'Var', (129, 144))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (9, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	("Ewing's sarcomas", 'Disease', (33, 49))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (129, 145))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (33, 49))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (150, 166))	('Alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (0, 26))	('Alveolar rhabdomyosarcomas', 'Disease', (0, 26))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (9, 25))
145112	23036318	Cytogenetic and karyotypic analyses of undifferentiated pleomorphic sarcomas, pleomorphic rhabdomyosarcomas, embryonal rhabdomyosarcomas, and osteosarcomas have revealed their genomes to be unstable and disorganized as evidenced by multiple deletions, amplifications, and chromosomal fusions.	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('embryonal rhabdomyosarcomas', 'Disease', (109, 136))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (90, 107))	('pleomorphic rhabdomyosarcomas', 'Disease', (78, 107))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (90, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (142, 154))	('osteosarcomas', 'Disease', 'MESH:D012516', (142, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('pleomorphic rhabdomyosarcomas', 'Disease', 'MESH:D012208', (78, 107))	('amplifications', 'Var', (252, 266))	('osteosarcomas', 'Disease', (142, 155))	('embryonal rhabdomyosarcomas', 'Disease', 'MESH:D018233', (109, 136))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (39, 76))	('undifferentiated pleomorphic sarcomas', 'Disease', (39, 76))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (119, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (119, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('osteosarcomas', 'Phenotype', 'HP:0002669', (142, 155))	('embryonal rhabdomyosarcomas', 'Phenotype', 'HP:0006743', (109, 136))
145115	23036318	Together, disruption of these genes and pathways are thought to be a driving force in sarcomagenesis.	('disruption', 'Var', (10, 20))	('sarcoma', 'Disease', (86, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcoma', 'Disease', 'MESH:D012509', (86, 93))
145116	23036318	Unlike the direct correlation between a single chromosomal translocation event in diploid sarcomas, it is more challenging to identify which of the numerous mutations, deletions, or amplifications drive the development of sarcomas with complex cytogenetics.	('drive', 'Reg', (197, 202))	('diploid sarcomas', 'Disease', (82, 98))	('sarcomas', 'Disease', (222, 230))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('amplifications', 'Var', (182, 196))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('sarcomas', 'Disease', (90, 98))	('mutations', 'Var', (157, 166))	('sarcomas', 'Disease', 'MESH:D012509', (222, 230))	('deletions', 'Var', (168, 177))	('diploid sarcomas', 'Disease', 'MESH:C548012', (82, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (222, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
145121	23036318	In addition to loss of p53 functions via inherited germline mutations, the p53 pathway is commonly disrupted by point mutations in the p53 gene during sporadic sarcomagenesis.	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('point mutations', 'Var', (112, 127))	('disrupted', 'NegReg', (99, 108))	('p53', 'Gene', (135, 138))	('sarcoma', 'Disease', (160, 167))	('p53 pathway', 'Pathway', (75, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))
145122	23036318	However, even though p53 gene alterations are widely regarded as having a significant impact on sarcomagenesis, many sarcomas retain wild type p53, yet phenotypically display a loss of p53 function.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('sarcoma', 'Disease', (117, 124))	('function', 'MPA', (189, 197))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('loss', 'NegReg', (177, 181))	('sarcomas', 'Disease', (117, 125))	('alterations', 'Var', (30, 41))	('impact', 'Reg', (86, 92))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('p53', 'Gene', (21, 24))	('sarcoma', 'Disease', (96, 103))
145123	23036318	Furthermore, both mice and humans with elevated levels of Mdm2 due to a high frequency single nucleotide polymorphism in the Mdm2 promoter (Mdm2SNP309) are more susceptible to sarcoma formation.	('sarcoma', 'Disease', (176, 183))	('mice', 'Species', '10090', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('susceptible', 'Reg', (161, 172))	('single nucleotide polymorphism', 'Var', (87, 117))	('humans', 'Species', '9606', (27, 33))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))
145124	23036318	Additionally, deletion or silencing of p19Arf (p14Arf in human), an inhibitor of the Mdm2-p53 axis, often results in development of sarcomas.	('p19Arf', 'Var', (39, 45))	('sarcomas', 'Disease', 'MESH:D012509', (132, 140))	('p14Arf', 'Gene', (47, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcomas', 'Disease', (132, 140))	('p14Arf', 'Gene', '1029', (47, 53))	('silencing', 'Var', (26, 35))	('results in', 'Reg', (106, 116))	('deletion', 'Var', (14, 22))	('human', 'Species', '9606', (57, 62))
145127	23036318	Individuals inheriting a germline Rb mutation typically develop cancers of the eye early in life.	('mutation', 'Var', (37, 45))	('cancers of the eye', 'Phenotype', 'HP:0100012', (64, 82))	('Rb', 'Phenotype', 'HP:0009919', (34, 36))	('germline', 'Var', (25, 33))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('develop', 'Reg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
145129	23036318	While inheritance of a germline Rb alterations increases sarcoma risk, there are also numerous examples of sporadic sarcomas harboring spontaneous Rb mutations and deletions, particularly osteosarcomas and rhabdomyosarcomas.	('osteosarcomas', 'Phenotype', 'HP:0002669', (188, 201))	('deletions', 'Var', (164, 173))	('increases sarcoma', 'Disease', 'MESH:D012509', (47, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('alterations', 'Var', (35, 46))	('increases sarcoma', 'Disease', (47, 64))	('Rb', 'Phenotype', 'HP:0009919', (147, 149))	('mutations', 'Var', (150, 159))	('sarcomas', 'Disease', 'MESH:D012509', (116, 124))	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcomas', 'Disease', (116, 124))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (206, 223))	('osteosarcomas', 'Disease', 'MESH:D012516', (188, 201))	('sarcomas', 'Disease', 'MESH:D012509', (193, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('rhabdomyosarcomas', 'Disease', (206, 223))	('sarcomas', 'Disease', (193, 201))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (206, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('Rb', 'Phenotype', 'HP:0009919', (32, 34))	('osteosarcomas', 'Disease', (188, 201))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (206, 222))	('sarcomas', 'Disease', 'MESH:D012509', (215, 223))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('sarcomas', 'Disease', (215, 223))
145130	23036318	Furthermore, p16Ikn4a, a negative regulator of the CDK-cyclin complexes that phosphorylate and activate Rb, is often deleted in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomas', 'Disease', (128, 136))	('p16Ikn4a', 'Var', (13, 21))	('activate', 'PosReg', (95, 103))	('Rb', 'Phenotype', 'HP:0009919', (104, 106))
145140	23036318	Sarcomas with simple diploid karyotypes often have chromosomal translocations that directly impact sarcomagenesis.	('chromosomal translocations', 'Var', (51, 77))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('impact sarcomagenesis', 'Disease', 'MESH:D004834', (92, 113))	('impact sarcomagenesis', 'Disease', (92, 113))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Sarcomas', 'Disease', (0, 8))
145148	23036318	To address this, mice expressing the Ews-Fli1 transgene were then crossed to mice harboring Prx-Cre-directed deletion of p53.	('mice', 'Species', '10090', (77, 81))	('mice', 'Species', '10090', (17, 21))	('deletion', 'Var', (109, 117))	('p53', 'Gene', (121, 124))	('Prx', 'Gene', (92, 95))	('Prx', 'Gene', '19153', (92, 95))	('Fli1', 'Gene', '14247', (41, 45))	('Ews', 'Gene', '14030', (37, 40))	('Ews', 'Gene', (37, 40))	('Fli1', 'Gene', (41, 45))
145149	23036318	The Prx-Cre;Ews-Fli1;p53-/- mice rapidly developed poorly differentiated sarcomas (median age of 21 weeks); while Prx-Cre mediated deletion of p53 alone resulted in the development of osteosarcomas (median age of 50 weeks), demonstrating the cooperative interactions between Ews-Fli1 and p53 in sarcomas.	('Ews', 'Gene', (275, 278))	('sarcomas', 'Disease', (295, 303))	('Ews', 'Gene', (12, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('Prx', 'Gene', (4, 7))	('osteosarcoma', 'Phenotype', 'HP:0002669', (184, 196))	('Prx', 'Gene', '19153', (4, 7))	('osteosarcomas', 'Disease', 'MESH:D012516', (184, 197))	('Prx', 'Gene', '19153', (114, 117))	('Prx', 'Gene', (114, 117))	('sarcomas', 'Disease', 'MESH:D012509', (189, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (295, 302))	('Fli1', 'Gene', '14247', (16, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (189, 197))	('mice', 'Species', '10090', (28, 32))	('sarcomas', 'Disease', (189, 197))	('osteosarcomas', 'Disease', (184, 197))	('Fli1', 'Gene', (16, 20))	('p53', 'Gene', (143, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('osteosarcomas', 'Phenotype', 'HP:0002669', (184, 197))	('Ews', 'Gene', '14030', (275, 278))	('deletion', 'Var', (131, 139))	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('Ews', 'Gene', '14030', (12, 15))	('Fli1', 'Gene', '14247', (279, 283))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcomas', 'Disease', (73, 81))	('sarcomas', 'Disease', 'MESH:D012509', (295, 303))	('Fli1', 'Gene', (279, 283))	('sarcomas', 'Phenotype', 'HP:0100242', (295, 303))
145151	23036318	Knock-in mice harboring the t(2;13)(q35;q14) translocation have been generated by knocking the Fkhr gene into the Pax-3 locus, resulting in a Pax-3-Fkhr fusion gene under the control of the endogenous Pax-3 promoter.	('Fkhr', 'Gene', '56458', (148, 152))	('Pax-3', 'Gene', '18505', (142, 147))	('Fkhr', 'Gene', (95, 99))	('Pax-3', 'Gene', '18505', (114, 119))	('in a', 'Reg', (137, 141))	('Pax-3', 'Gene', '18505', (201, 206))	('Pax-3', 'Gene', (142, 147))	('Fkhr', 'Gene', '56458', (95, 99))	('knocking', 'Var', (82, 90))	('Pax-3', 'Gene', (114, 119))	('mice', 'Species', '10090', (9, 13))	('Fkhr', 'Gene', (148, 152))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (28, 44))	('Pax-3', 'Gene', (201, 206))
145152	23036318	Similar to the Prx-Cre;Ews-Fli1 studies, these mice did not develop sarcomas, but did display numerous congenital defects, suggesting the Pax3-Fkhr fusion gene is important in normal murine development but requires additional genetic hits for sarcoma development.	('numerous congenital defects', 'Disease', 'MESH:D005124', (94, 121))	('numerous congenital defects', 'Disease', (94, 121))	('murine', 'Species', '10090', (183, 189))	('fusion', 'Var', (148, 154))	('Pax3', 'Gene', '18505', (138, 142))	('Fkhr', 'Gene', (143, 147))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('Fkhr', 'Gene', '56458', (143, 147))	('sarcoma', 'Disease', 'MESH:D012509', (243, 250))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('sarcoma', 'Disease', (243, 250))	('sarcoma', 'Disease', (68, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcomas', 'Disease', (68, 76))	('Fli1', 'Gene', '14247', (27, 31))	('Ews', 'Gene', '14030', (23, 26))	('Fli1', 'Gene', (27, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('Prx', 'Gene', (15, 18))	('Prx', 'Gene', '19153', (15, 18))	('Pax3', 'Gene', (138, 142))	('Ews', 'Gene', (23, 26))	('mice', 'Species', '10090', (47, 51))	('numerous congenital defects', 'Phenotype', 'HP:0002804', (94, 121))
145155	23036318	However, concomitant deletion of p53, p19Arf, or p16Ink4a in the Myf6-Cre;Pax3-Fkhr mice resulted in a rhabdomyosarcoma phenotype.	('p53', 'Var', (33, 36))	('Myf6', 'Gene', (65, 69))	('Pax3', 'Gene', '18505', (74, 78))	('Myf6', 'Gene', '17878', (65, 69))	('resulted in', 'Reg', (89, 100))	('Fkhr', 'Gene', '56458', (79, 83))	('Pax3', 'Gene', (74, 78))	('deletion', 'Var', (21, 29))	('p19Arf', 'Var', (38, 44))	('p16Ink4a', 'Gene', '12578', (49, 57))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (103, 119))	('Fkhr', 'Gene', (79, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('p16Ink4a', 'Gene', (49, 57))	('rhabdomyosarcoma', 'Disease', (103, 119))	('mice', 'Species', '10090', (84, 88))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (103, 119))
145158	23036318	In addition to the translocations noted above, chromosomal rearrangements t(X;18) and t(12;16) (q12;p11) are commonly observed in synovial and liposarcomas, respectively (Table 2).	('p11', 'Gene', '20194', (100, 103))	('synovial', 'Disease', (130, 138))	('liposarcomas', 'Phenotype', 'HP:0012034', (143, 155))	('p11', 'Gene', (100, 103))	('liposarcomas', 'Disease', 'MESH:D008080', (143, 155))	('liposarcomas', 'Disease', (143, 155))	('liposarcoma', 'Phenotype', 'HP:0012034', (143, 154))	('t(X;18', 'Var', (74, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('observed', 'Reg', (118, 126))
145162	23036318	In contrast to the sarcomas driven primarily by specific translocations, the majority of sarcomas possess highly aneuploid genomes due to disruptions in tumor suppressor pathways and aberrant oncogenic activation.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('sarcomas', 'Disease', (19, 27))	('sarcomas', 'Disease', (89, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('oncogenic activation', 'CPA', (192, 212))	('sarcomas', 'Disease', 'MESH:D012509', (19, 27))	('aneuploid genomes', 'Var', (113, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('disruptions', 'NegReg', (138, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
145165	23036318	The role of p53 in osteosarcomas is further highlighted by tumor analysis of p53 knock-in mice containing a mutant copy of p53R172H (corresponding to the R175H hot-spot mutation in humans).	('osteosarcomas', 'Disease', 'MESH:D012516', (19, 32))	('tumor', 'Disease', (59, 64))	('p53R172H', 'Var', (123, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('mutant', 'Var', (108, 114))	('mice', 'Species', '10090', (90, 94))	('osteosarcomas', 'Disease', (19, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('R175H', 'Mutation', 'rs28934578', (154, 159))	('humans', 'Species', '9606', (181, 187))	('osteosarcomas', 'Phenotype', 'HP:0002669', (19, 32))
145166	23036318	An important differentiation between the p53 knock-out and p53R172H knock-in mice is that p53R172H sarcomas developed a metastatic gain of function phenotype, faithfully recapitulating the phenotype observed in the human disease.	('mice', 'Species', '10090', (77, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('sarcomas', 'Disease', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('p53R172H', 'Var', (90, 98))	('human', 'Species', '9606', (215, 220))	('sarcomas', 'Disease', 'MESH:D012509', (99, 107))	('metastatic gain', 'CPA', (120, 135))
145167	23036318	The generation of the mutant p53R172H mouse model provides researchers, for the first time, with the ability to investigate metastatic osteosarcoma disease progression in a truly in vivo setting.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('mouse', 'Species', '10090', (38, 43))	('osteosarcoma disease', 'Disease', 'MESH:D012516', (135, 155))	('osteosarcoma disease', 'Disease', (135, 155))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('p53R172H', 'Var', (29, 37))
145168	23036318	In addition to direct ablation of p53 function, transgenic mice overexpressing the p53 regulator, Mdm2, as well as mice harboring a single nucleotide polymorphism in the Mdm2 promoter, have an increased risk to develop sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('mice', 'Species', '10090', (59, 63))	('single nucleotide polymorphism in', 'Var', (132, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('Mdm2', 'Gene', (98, 102))	('sarcomas', 'Disease', (219, 227))	('develop', 'PosReg', (211, 218))	('mice', 'Species', '10090', (115, 119))	('sarcomas', 'Disease', 'MESH:D012509', (219, 227))	('transgenic mice', 'Species', '10090', (48, 63))
145169	23036318	Furthermore, transgenic mice expressing the viral oncogene Tax, coupled with deletion of p19Arf, developed highly penetrant osteosarcomas.	('p19Arf', 'Gene', (89, 95))	('osteosarcomas', 'Disease', (124, 137))	('osteosarcomas', 'Phenotype', 'HP:0002669', (124, 137))	('deletion', 'Var', (77, 85))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcomas', 'Disease', 'MESH:D012516', (124, 137))	('transgenic mice', 'Species', '10090', (13, 28))	('highly penetrant', 'CPA', (107, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
145170	23036318	Together, these results further demonstrate the importance of ablating the p53 pathway in osteosarcomagenesis.	('osteosarcomagenesis', 'Disease', (90, 109))	('ablating', 'Var', (62, 70))	('p53 pathway', 'Pathway', (75, 86))	('osteosarcomagenesis', 'Disease', 'None', (90, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))
145171	23036318	In humans, loss of the Rb pathway has also been implicated in the etiology of osteosarcomas.	('osteosarcomas', 'Disease', 'MESH:D012516', (78, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('Rb pathway', 'Pathway', (23, 33))	('loss', 'Var', (11, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('Rb', 'Phenotype', 'HP:0009919', (23, 25))	('humans', 'Species', '9606', (3, 9))	('osteosarcomas', 'Disease', (78, 91))	('implicated', 'Reg', (48, 58))	('osteosarcomas', 'Phenotype', 'HP:0002669', (78, 91))	('osteosarcoma', 'Phenotype', 'HP:0002669', (78, 90))
145172	23036318	However, in the mouse, homozygous deletion of Rb results in an embryo lethal phenotype due to placental defects.	('results in', 'Reg', (49, 59))	('Rb', 'Phenotype', 'HP:0009919', (46, 48))	('embryo lethal phenotype', 'CPA', (63, 86))	('deletion', 'Var', (34, 42))	('placental defects', 'Phenotype', 'HP:0100767', (94, 111))	('mouse', 'Species', '10090', (16, 21))	('placental defects', 'CPA', (94, 111))
145179	23036318	Taken together, these studies demonstrate the absolute requirement for ablation of the p53 pathway in osteosarcomagenesis and suggest that pRb plays a co-operative role in osteosarcomagenesis.	('pRb', 'Gene', '19645', (139, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('Rb', 'Phenotype', 'HP:0009919', (140, 142))	('ablation', 'Var', (71, 79))	('p53 pathway', 'Pathway', (87, 98))	('osteosarcomagenesis', 'Disease', 'None', (102, 121))	('pRb', 'Gene', (139, 142))	('osteosarcomagenesis', 'Disease', 'None', (172, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('osteosarcomagenesis', 'Disease', (102, 121))	('osteosarcomagenesis', 'Disease', (172, 191))
145183	23036318	Mice harboring a latent copy of oncogenic KrasLSLG12D (silenced by a floxed "loxP-stop-loxP" (LSL) cassette) and two floxed p53 alleles (p53FlDelta2-10) that were simultaneously activated to express mutant KrasG12D and delete p53 following injection of adenoviral-Cre into the muscle, rapidly developed sarcomas with significant metastatic potential.	('sarcomas', 'Disease', 'MESH:D012509', (303, 311))	('sarcomas', 'Phenotype', 'HP:0100242', (303, 311))	('sarcoma', 'Phenotype', 'HP:0100242', (303, 310))	('KrasG12D', 'Gene', (206, 214))	('developed', 'PosReg', (293, 302))	('sarcomas', 'Disease', (303, 311))	('Mice', 'Species', '10090', (0, 4))	('p53', 'Gene', (226, 229))	('delete', 'Var', (219, 225))	('mutant', 'Var', (199, 205))
145185	23036318	Together, these data support the idea that both ablation of tumor suppressor pathways and activation of oncogenes cooperate to drive sarcomagenesis.	('oncogenes', 'Gene', (104, 113))	('sarcoma', 'Disease', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('drive', 'PosReg', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ablation', 'Var', (48, 56))	('tumor', 'Disease', (60, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
145186	23036318	Using the Cre-LoxP strategy to simultaneously activate a latent oncogenic K-rasG12V allele and delete the p53FlDelta2-10 alleles in myocytes, it was demonstrated that mice rapidly develop sarcomas that are histopathologically similar to pleomorphic rhabdomyosarcomas observed in humans.	('humans', 'Species', '9606', (279, 285))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (249, 266))	('sarcomas', 'Disease', 'MESH:D012509', (188, 196))	('K-rasG12V', 'Gene', (74, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (188, 196))	('sarcomas', 'Disease', (188, 196))	('pleomorphic rhabdomyosarcomas', 'Disease', (237, 266))	('p53FlDelta2-10', 'Gene', (106, 120))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (249, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('sarcomas', 'Disease', 'MESH:D012509', (258, 266))	('sarcomas', 'Phenotype', 'HP:0100242', (258, 266))	('pleomorphic rhabdomyosarcomas', 'Disease', 'MESH:D012208', (237, 266))	('sarcomas', 'Disease', (258, 266))	('develop', 'PosReg', (180, 187))	('delete', 'Var', (95, 101))	('mice', 'Species', '10090', (167, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('activate', 'PosReg', (46, 54))
145187	23036318	Although the undifferentiated pleomorphic and rhabdomyosarcoma studies used similar mouse models to identify the role of mutant K-ras and p53-loss in sarcomagenesis, these experiments resulted in somewhat different malignancies.	('resulted in', 'Reg', (184, 195))	('rhabdomyosarcoma', 'Disease', (46, 62))	('mutant', 'Var', (121, 127))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (46, 62))	('sarcoma', 'Disease', (55, 62))	('malignancies', 'Disease', (215, 227))	('p53-loss', 'NegReg', (138, 146))	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('p53-loss', 'Gene', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('mouse', 'Species', '10090', (84, 89))	('K-ras', 'Protein', (128, 133))	('sarcoma', 'Disease', (150, 157))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (46, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('malignancies', 'Disease', 'MESH:D009369', (215, 227))
145190	23036318	A recent study examined the impact of p53 in sarcomagenesis more accurately by not only deleting p53 but also expressing the p53R172H mutant (corresponding to the human p53R175 hotspot mutation) in the muscle.	('sarcoma', 'Disease', (45, 52))	('p53', 'Gene', (97, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('deleting', 'NegReg', (88, 96))	('human', 'Species', '9606', (163, 168))	('p53R172H', 'Var', (125, 133))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))
145192	23036318	In addition, unlike the tumors from Ah-Cre;KrasG12V;p53-/- mice, the tumors from the Ah-Cre;KrasG12V;p53R172H/- mice also recapitulated the metastatic phenotype typically observed in human rhabdomyosarcomas.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (189, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (59, 63))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('human', 'Species', '9606', (183, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (189, 206))	('rhabdomyosarcomas', 'Disease', (189, 206))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (189, 206))	('tumors', 'Disease', (69, 75))	('mice', 'Species', '10090', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('Ah-Cre;KrasG12V;p53R172H/-', 'Var', (85, 111))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('metastatic', 'CPA', (140, 150))
145193	23036318	Given the extreme heterogeneity of sarcomas with regards to tissue of origin, it is obvious that alterations to numerous genes, pathways, and signaling complexes play an important role in the pathobiology of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('alterations', 'Var', (97, 108))	('sarcomas', 'Disease', (35, 43))	('sarcomas', 'Disease', 'MESH:D012509', (208, 216))	('sarcomas', 'Phenotype', 'HP:0100242', (208, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('sarcomas', 'Disease', (208, 216))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))
145194	23036318	While this review does not cover all genetic alterations responsible for sarcoma development, there are numerous additional genes that impact this disease (Table 2).	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('genes', 'Var', (124, 129))	('impact', 'Reg', (135, 141))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
145195	23036318	For example, alterations in expression of tumor suppressor genes, such as Neurofibromatosis type 1 (NF1), likewise impact the etiology of some sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('etiology', 'MPA', (126, 134))	('NF1', 'Gene', '18015', (100, 103))	('tumor', 'Disease', (42, 47))	('sarcomas', 'Disease', (143, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('sarcomas', 'Disease', 'MESH:D012509', (143, 151))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (74, 91))	('expression', 'MPA', (28, 38))	('Neurofibromatosis type 1', 'Gene', (74, 98))	('Neurofibromatosis type 1', 'Gene', '18015', (74, 98))	('NF1', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('alterations', 'Var', (13, 24))	('impact', 'Reg', (115, 121))
145196	23036318	Mouse models that carry genomic deletions and/or tissue-specific Cre-mediated deletion of NF1 result in neurofibromas.	('deletions', 'Var', (32, 41))	('result in', 'Reg', (94, 103))	('neurofibromas', 'Disease', 'MESH:D009455', (104, 117))	('deletion', 'Var', (78, 86))	('NF1', 'Gene', '18015', (90, 93))	('neurofibromas', 'Phenotype', 'HP:0001067', (104, 117))	('Mouse', 'Species', '10090', (0, 5))	('neurofibromas', 'Disease', (104, 117))	('NF1', 'Gene', (90, 93))
145197	23036318	These NF1-dependent phenotypes are further exacerbated when NF1 is concomitantly deleted with other tumor suppressors (e.g.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('NF1', 'Gene', '18015', (6, 9))	('tumor', 'Disease', (100, 105))	('NF1', 'Gene', (60, 63))	('NF1', 'Gene', (6, 9))	('exacerbated', 'PosReg', (43, 54))	('NF1', 'Gene', '18015', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('deleted', 'Var', (81, 88))
145198	23036318	; p53 and p19ARF) resulting in more aggressive phenotypes as evidenced by malignant peripheral nerve sheath tumor formation.	('p19ARF', 'Gene', (10, 16))	('p53', 'Var', (2, 5))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('sheath tumor', 'Disease', 'MESH:D010524', (101, 113))	('p19ARF', 'Gene', '12578', (10, 16))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (74, 113))	('sheath tumor', 'Disease', (101, 113))
145199	23036318	To further illustrate that loss of a single gene impacts sarcoma formation, mice harboring an LMP-2 deletion resulted in spontaneous uterine leiomyosarcomas.	('LMP-2', 'Gene', '16912', (94, 99))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('resulted in', 'Reg', (109, 120))	('sarcoma', 'Disease', (148, 155))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('LMP-2', 'Gene', (94, 99))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (141, 156))	('mice', 'Species', '10090', (76, 80))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (141, 156))	('sarcoma', 'Disease', (57, 64))	('deletion', 'Var', (100, 108))	('leiomyosarcomas', 'Disease', (141, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (133, 156))
145203	23036318	However, given the availability of numerous genetic knock-outs, knock-ins, and conditional alleles coupled with the bevy of tissue-specific Cre-recombinase expressing mouse lines, we now have the ability to systematically and prospectively interrogate how individual genes and mutations impact sarcomagenesis.	('impact sarcomagenesis', 'Disease', 'MESH:D004834', (287, 308))	('mutations', 'Var', (277, 286))	('impact sarcomagenesis', 'Disease', (287, 308))	('sarcoma', 'Phenotype', 'HP:0100242', (294, 301))	('mouse', 'Species', '10090', (167, 172))
145205	23036318	These mouse models have clearly demonstrated that while there are driver mutations/translocations, sarcomagenesis is, in fact, a multi-hit disease.	('mutations/translocations', 'Var', (73, 97))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('sarcoma', 'Disease', (99, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('mouse', 'Species', '10090', (6, 11))
145208	23036318	For treatment of patients with translocations, one can envision a targeted therapeutic approach, like that which has been observed in the treatment of chronic myeloid leukemia.	('translocations', 'Var', (31, 45))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (151, 175))	('chronic myeloid leukemia', 'Disease', (151, 175))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (151, 175))	('patients', 'Species', '9606', (17, 25))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (159, 175))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))
145214	23036318	Preclinical drugs like PRIMA1-Met and NCS319726 have been shown to restore mutant p53 activities.	('PRIMA1', 'Gene', '170952', (23, 29))	('PRIMA1', 'Gene', (23, 29))	('activities', 'MPA', (86, 96))	('mutant', 'Var', (75, 81))	('p53', 'Gene', (82, 85))	('clinical', 'Species', '191496', (3, 11))
145215	23036318	These drugs could be rapidly screened for efficacy in mutant p53 sarcoma models.	('sarcoma', 'Disease', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('mutant', 'Var', (54, 60))	('p53', 'Gene', (61, 64))
145221	23036318	While mouse models can not completely predict the outcome of each disease, they can provide valuable and critical information, particularly in exceedingly rare types of sarcomas or when low penetrant single nucleotide polymorphisms confound data analysis.	('single nucleotide polymorphisms', 'Var', (200, 231))	('sarcomas', 'Disease', 'MESH:D012509', (169, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('sarcomas', 'Disease', (169, 177))	('mouse', 'Species', '10090', (6, 11))
145223	33906647	NKX6-1 mediates cancer stem-like properties and regulates sonic hedgehog signaling in leiomyosarcoma Leiomyosarcoma (LMS), the most common soft tissue sarcoma, exhibits heterogeneous and complex genetic karyotypes with severe chromosomal instability and rearrangement and poor prognosis.	('LMS', 'Phenotype', 'HP:0100243', (117, 120))	('sonic hedgehog', 'Gene', (58, 72))	('leiomyosarcoma', 'Disease', (86, 100))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('NKX6-1', 'Gene', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcoma', 'Disease', (108, 115))	('sarcoma', 'Disease', (93, 100))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('rearrangement', 'Var', (254, 267))	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (101, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('NKX6-1', 'Gene', '4825', (0, 6))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (86, 100))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (139, 158))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('chromosomal instability', 'Phenotype', 'HP:0040012', (226, 249))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (86, 100))	('Leiomyosarcoma', 'Disease', 'MESH:D007890', (101, 115))	('Leiomyosarcoma', 'Disease', (101, 115))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('sonic hedgehog', 'Gene', '6469', (58, 72))	('sarcoma', 'Disease', (151, 158))
145229	33906647	Moreover, overexpression and knockdown of NKX6-1 were associated with upregulation and downregulation, respectively, of stem cell transcription factors, including KLF8, MYC, and CD49F, and affected sphere formation, chemoresistance, NOTCH signaling and Sonic hedgehog (SHH) pathways in human sarcoma cells.	('sarcoma', 'Disease', (292, 299))	('knockdown', 'Var', (29, 38))	('MYC', 'Gene', (169, 172))	('NOTCH signaling', 'Pathway', (233, 248))	('stem cell transcription factors', 'Gene', (120, 151))	('NKX6-1', 'Gene', '4825', (42, 48))	('Sonic hedgehog', 'Gene', '6469', (253, 267))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('KLF8', 'Gene', '11279', (163, 167))	('human', 'Species', '9606', (286, 291))	('affected', 'Reg', (189, 197))	('MYC', 'Gene', '4609', (169, 172))	('upregulation', 'PosReg', (70, 82))	('Sonic hedgehog', 'Gene', (253, 267))	('KLF8', 'Gene', (163, 167))	('CD49F', 'Gene', '3655', (178, 183))	('overexpression', 'PosReg', (10, 24))	('chemoresistance', 'CPA', (216, 231))	('NKX6-1', 'Gene', (42, 48))	('sphere formation', 'CPA', (198, 214))	('CD49F', 'Gene', (178, 183))	('downregulation', 'NegReg', (87, 101))	('sarcoma', 'Disease', 'MESH:D012509', (292, 299))
145231	33906647	Finally, using the TCGA dataset, we demonstrated that LMS patients with high expression of NKX6-1 and HHAT, an SHH pathway acyltransferase, had poorer survival outcomes compared to those without.	('poorer', 'NegReg', (144, 150))	('NKX6-1', 'Gene', '4825', (91, 97))	('HHAT', 'Gene', (102, 106))	('NKX6-1', 'Gene', (91, 97))	('high expression', 'Var', (72, 87))	('survival outcomes', 'CPA', (151, 168))	('LMS', 'Phenotype', 'HP:0100243', (54, 57))	('patients', 'Species', '9606', (58, 66))	('HHAT', 'Gene', '55733', (102, 106))
145239	33906647	More specifically, NKX6-3 depletion results in multiple genetic mutations that drive carcinogenesis of the stomach, while NKX2-5 regulates thyroid cell differentiation in thyroid cancer.	('thyroid cell differentiation', 'CPA', (139, 167))	('regulates', 'Reg', (129, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('depletion', 'Var', (26, 35))	('NKX2-5', 'Gene', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('drive', 'Reg', (79, 84))	('results in', 'Reg', (36, 46))	('carcinogenesis', 'Disease', (85, 99))	('NKX6-3', 'Gene', (19, 25))	('thyroid cancer', 'Disease', (171, 185))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('mutations', 'Var', (64, 73))	('NKX2-5', 'Gene', '1482;4824', (122, 128))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))	('NKX6-3', 'Gene', '157848', (19, 25))
145240	33906647	NKX2-1 mutations have been found in 16% of lung cancers and are associated with lung cancer metastasis.	('associated', 'Reg', (64, 74))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('mutations', 'Var', (7, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('lung cancers', 'Disease', 'MESH:D008175', (43, 55))	('lung cancers', 'Phenotype', 'HP:0100526', (43, 55))	('lung cancer', 'Disease', (80, 91))	('NKX2-1', 'Gene', '7080', (0, 6))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lung cancers', 'Disease', (43, 55))	('found', 'Reg', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('NKX2-1', 'Gene', (0, 6))
145241	33906647	NKX3-1 deletion and promoter hypomethylation have been identified in prostate cancer.	('NKX3-1', 'Gene', '4824', (0, 6))	('promoter', 'MPA', (20, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('identified', 'Reg', (55, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('NKX3-1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('deletion', 'Var', (7, 15))	('prostate cancer', 'Disease', (69, 84))
145243	33906647	Moreover, hypermethylation of the NKX6-1 promoter is frequently detected in leukemia, cervical cancer, ovarian cancer and colon cancer.	('hypermethylation', 'Var', (10, 26))	('cervical cancer', 'Disease', 'MESH:D002583', (86, 101))	('ovarian cancer', 'Disease', (103, 117))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('NKX6-1', 'Gene', '4825', (34, 40))	('detected', 'Reg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('leukemia', 'Disease', (76, 84))	('cervical cancer', 'Disease', (86, 101))	('colon cancer', 'Disease', (122, 134))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('NKX6-1', 'Gene', (34, 40))
145248	33906647	Importantly, inhibition of the SHH pathway significantly inhibits the growth of sarcoma cells with high NKX6-1 expression, indicating possible new treatment options for LMS patients.	('NKX6-1', 'Gene', (104, 110))	('LMS', 'Disease', (169, 172))	('growth', 'CPA', (70, 76))	('patients', 'Species', '9606', (173, 181))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('LMS', 'Phenotype', 'HP:0100243', (169, 172))	('sarcoma', 'Disease', (80, 87))	('high', 'Var', (99, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('SHH pathway', 'Pathway', (31, 42))	('inhibition', 'NegReg', (13, 23))	('inhibits', 'NegReg', (57, 65))	('NKX6-1', 'Gene', '4825', (104, 110))
145259	33906647	Short hairpin RNAs (shRNAs) against human NKX6-1 (TRCN0000017548 and TRCN0000072223) were obtained from the National RNAi Core Facility located at the Institute of Molecular Biology/Genomic Research Center, Academia Sinica, Taiwan.	('NKX6-1', 'Gene', (42, 48))	('TRCN0000072223', 'Var', (69, 83))	('TRCN0000017548', 'Var', (50, 64))	('NKX6-1', 'Gene', '4825', (42, 48))	('human', 'Species', '9606', (36, 41))
145260	33906647	The target sites for the NKX6-1 shRNAs were: 5'- CCG GGA AGA CTT TCG AAC AAA CAA ACT CGA GTT TGT TTG TTC GAA AGT CTT CTT TTT-3' (TRCN0000017548) and 5'- CCG GCC GCT GTA CCC TGC CGC GTA TCT CGA GAT ACG CGG CAG GGT ACA GCG GTT TTT-3' (TRCN0000017551).	('NKX6-1', 'Gene', (25, 31))	('TRCN0000017551', 'Var', (233, 247))	('NKX6-1', 'Gene', '4825', (25, 31))	('TRCN0000017548', 'Var', (129, 143))
145290	33906647	In the survival analysis, patients with FPKM > 66th percentile (1/3) were defined as having high expression, while patients with FPKM <= 66th percentile (2/3) were defined as having low expression.	('high expression', 'MPA', (92, 107))	('FPKM > 66th percentile', 'Var', (40, 62))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (26, 34))
145293	33906647	However, compared to NKX6-1low patients, LMS patients with high NKX6-1 mRNA expression had a worse prognosis, with a median 5 year OS of 39.2 months (NKX6-1high vs. NKX6-1low, 39.2 vs. > 60 months, HR = 2.9, 95%: 1.5-5.7) and a 5 year survival rate of 34% (NKX6-1high vs. NKX6-1low, 34% vs. 66%).	('NKX6-1', 'Gene', (165, 171))	('NKX6-1', 'Gene', (257, 263))	('NKX6-1', 'Gene', '4825', (21, 27))	('NKX6-1', 'Gene', '4825', (150, 156))	('NKX6-1', 'Gene', '4825', (64, 70))	('high', 'Var', (59, 63))	('NKX6-1', 'Gene', (64, 70))	('NKX6-1', 'Gene', '4825', (272, 278))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (45, 53))	('NKX6-1', 'Gene', '4825', (257, 263))	('NKX6-1', 'Gene', '4825', (165, 171))	('NKX6-1', 'Gene', (150, 156))	('LMS', 'Phenotype', 'HP:0100243', (41, 44))	('NKX6-1', 'Gene', (21, 27))	('NKX6-1', 'Gene', (272, 278))
145298	33906647	Interestingly, malignant phenotypes, including proliferation and resistance to cisplatin, lipodox, and gemcitabine, were significantly higher in MES-SA/DX5 cells than in MES-SA cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('MES-SA', 'Chemical', '-', (145, 151))	('resistance to cisplatin', 'MPA', (65, 88))	('MES-SA', 'Chemical', '-', (170, 176))	('malignant phenotypes', 'CPA', (15, 35))	('gemcitabine', 'Chemical', 'MESH:C056507', (103, 114))	('MES-SA/DX5', 'Var', (145, 155))	('proliferation', 'CPA', (47, 60))	('higher', 'PosReg', (135, 141))	('lipodox', 'Chemical', 'MESH:C506643', (90, 97))	('lipodox', 'MPA', (90, 97))
145299	33906647	Thereafter, we generated NKX6-1 gain-of-function cells by transfecting full-length NKX6-1 into the MES-SA cell line and loss-of-function cells by transfecting NKX6-1 shRNAs into the MES-SA/DX5 cell line (confirmed by western blotting in Additional file 2: Figure S1).	('NKX6-1', 'Gene', (25, 31))	('NKX6-1', 'Gene', '4825', (83, 89))	('gain-of-function', 'PosReg', (32, 48))	('NKX6-1', 'Gene', (83, 89))	('NKX6-1', 'Gene', (159, 165))	('transfecting', 'Var', (58, 70))	('MES-SA', 'Chemical', '-', (99, 105))	('NKX6-1', 'Gene', '4825', (25, 31))	('NKX6-1', 'Gene', '4825', (159, 165))	('MES-SA', 'Chemical', '-', (182, 188))
145301	33906647	Conversely, knockdown of NKX6-1 in MES-SA/DX5 cells suppressed proliferation, colony formation, and resistance to cisplatin, gemcitabine, phyxol, and lipodox (Fig.	('NKX6-1', 'Gene', (25, 31))	('phyxol', 'Chemical', '-', (138, 144))	('MES-SA', 'Chemical', '-', (35, 41))	('proliferation', 'CPA', (63, 76))	('resistance to cisplatin', 'MPA', (100, 123))	('colony formation', 'CPA', (78, 94))	('knockdown', 'Var', (12, 21))	('lipodox', 'Chemical', 'MESH:C506643', (150, 157))	('lipodox', 'MPA', (150, 157))	('phyxol', 'MPA', (138, 144))	('gemcitabine', 'MPA', (125, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('suppressed', 'NegReg', (52, 62))	('NKX6-1', 'Gene', '4825', (25, 31))	('gemcitabine', 'Chemical', 'MESH:C056507', (125, 136))
145312	33906647	Conversely, PTCH1, HHAT, MYC, SOX2, CCND1 and BCL2 expression levels were decreased after NKX6-1 knockdown in MES-SA/DX5 cells (Fig.	('HHAT', 'Gene', (19, 23))	('NKX6-1', 'Gene', (90, 96))	('MYC', 'Gene', (25, 28))	('BCL2', 'Gene', (46, 50))	('knockdown', 'Var', (97, 106))	('MES-SA', 'Chemical', '-', (110, 116))	('PTCH1', 'Gene', '5727', (12, 17))	('CCND1', 'Gene', (36, 41))	('MYC', 'Gene', '4609', (25, 28))	('BCL2', 'Gene', '596', (46, 50))	('CCND1', 'Gene', '595', (36, 41))	('PTCH1', 'Gene', (12, 17))	('decreased', 'NegReg', (74, 83))	('HHAT', 'Gene', '55733', (19, 23))	('SOX2', 'Gene', '6657', (30, 34))	('SOX2', 'Gene', (30, 34))	('NKX6-1', 'Gene', '4825', (90, 96))
145321	33906647	NKX6-1 knockdown MES-SA/DX5 clone 1 was more sensitive than control cells, and there was no sensitivity difference between clone 2 and control cells (Fig.	('NKX6-1', 'Gene', (0, 6))	('NKX6-1', 'Gene', '4825', (0, 6))	('MES-SA', 'Chemical', '-', (17, 23))	('knockdown', 'Var', (7, 16))	('sensitive', 'MPA', (45, 54))
145338	33906647	In the present study, we investigated how oncogenic NKX6-1 confers poor prognosis in LMS and how NKX6-1 regulates cancer stem cells through activation of the SHH and NOTCH pathways.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('NKX6-1', 'Gene', '4825', (97, 103))	('NKX6-1', 'Gene', (97, 103))	('activation', 'PosReg', (140, 150))	('oncogenic', 'Var', (42, 51))	('LMS', 'Disease', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('regulates', 'Reg', (104, 113))	('LMS', 'Phenotype', 'HP:0100243', (85, 88))	('NKX6-1', 'Gene', '4825', (52, 58))	('NKX6-1', 'Gene', (52, 58))	('cancer', 'Disease', (114, 120))
145343	33906647	The dysregulated activation of SHH signaling is implicated in several cancers and has been linked to the maintenance of cancer stem-like cells, which are associated with the development of therapeutic resistance.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (120, 126))	('SHH', 'Protein', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('activation', 'PosReg', (17, 27))	('linked', 'Reg', (91, 97))	('cancers', 'Disease', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('dysregulated', 'Var', (4, 16))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancer', 'Disease', (70, 76))	('implicated', 'Reg', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
145355	33906647	NKX6-1 methylation status is an indicator of survival outcome and could inform treatment selection in stage III colon cancer.	('NKX6-1', 'Gene', (0, 6))	('inform', 'Reg', (72, 78))	('stage III colon cancer', 'Disease', (102, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('methylation', 'Var', (7, 18))	('NKX6-1', 'Gene', '4825', (0, 6))	('stage III colon cancer', 'Disease', 'MESH:D015179', (102, 124))
145375	33906647	Moreover, the inconsistent effects of NKX6-1 overexpression and knockdown during cisplatin treatment in human sarcoma cells require further investigation.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('sarcoma', 'Disease', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('human', 'Species', '9606', (104, 109))	('NKX6-1', 'Gene', '4825', (38, 44))	('knockdown', 'Var', (64, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('NKX6-1', 'Gene', (38, 44))
145377	33906647	Additionally, manipulation of NKX6-1 exhibits inconsistent effects on the expression of NOTCH1 and NOTCH2.	('NOTCH1', 'Gene', '4851', (88, 94))	('NOTCH1', 'Gene', (88, 94))	('expression', 'MPA', (74, 84))	('NOTCH2', 'Gene', '4853', (99, 105))	('NKX6-1', 'Gene', '4825', (30, 36))	('manipulation', 'Var', (14, 26))	('NKX6-1', 'Gene', (30, 36))	('NOTCH2', 'Gene', (99, 105))
145378	33906647	Although inhibition of NOTCH signaling has modest effects on LMS prognosis with either partial response or stable disease in approximately 40% of patients, our unpublished results demonstrate that NOTCH inhibition displays NKX6-1-independent chemosensitizing effects in LMS.	('NKX6-1', 'Gene', (223, 229))	('NOTCH', 'Var', (197, 202))	('LMS', 'Disease', (270, 273))	('LMS', 'Phenotype', 'HP:0100243', (270, 273))	('LMS', 'Disease', (61, 64))	('NKX6-1', 'Gene', '4825', (223, 229))	('inhibition', 'NegReg', (203, 213))	('LMS', 'Phenotype', 'HP:0100243', (61, 64))	('patients', 'Species', '9606', (146, 154))
145420	32709828	Metastasis to orbit generally presents clinically with proptosis, diplopia, decreased vision, or palpable mass.	('diplopia', 'Disease', (66, 74))	('decreased vision', 'Phenotype', 'HP:0007663', (76, 92))	('diplopia', 'Phenotype', 'HP:0000651', (66, 74))	('decreased vision', 'Disease', (76, 92))	('Metastasis', 'Var', (0, 10))	('diplopia', 'Disease', 'MESH:D004172', (66, 74))	('proptosis', 'Disease', (55, 64))	('decreased vision', 'Disease', 'MESH:D015354', (76, 92))	('proptosis', 'Phenotype', 'HP:0000520', (55, 64))	('palpable', 'Disease', (97, 105))
145439	27777717	Recorded incidence may have changed over time due to more accurate diagnosis, with the recognition of a characteristic translocation involving chromosome 18 and X, resulting in the detection of one of several types of fusion genes (SYT-SSX1, 2 and 4) in 90 % of cases.	('SS', 'Phenotype', 'HP:0012570', (236, 238))	('translocation', 'Var', (119, 132))	('SYT', 'Gene', (232, 235))	('detection', 'Reg', (181, 190))	('SYT', 'Gene', '6760', (232, 235))
145453	27777717	Metastatic status was derived from the HES data If a patient had a diagnosis of ICD-10 codes C77 (Secondary and unspecified malignant neoplasm of lymph nodes), C78 (Secondary malignant neoplasm of respiratory and digestive organs) or C79 (Secondary malignant neoplasm of other sites) recorded during an admission within 4 months following sarcoma diagnosis.	('neoplasm', 'Phenotype', 'HP:0002664', (134, 142))	('sarcoma', 'Disease', 'MESH:D012509', (339, 346))	('malignant neoplasm', 'Disease', (175, 193))	('neoplasm of lymph', 'Phenotype', 'HP:0002665', (134, 151))	('neoplasm', 'Phenotype', 'HP:0002664', (259, 267))	('sarcoma', 'Disease', (339, 346))	('C79', 'Var', (234, 237))	('C77', 'Var', (93, 96))	('patient', 'Species', '9606', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (339, 346))	('neoplasm', 'Phenotype', 'HP:0002664', (185, 193))	('malignant neoplasm', 'Disease', 'MESH:D009369', (249, 267))	('neoplasm of lymph nodes', 'Disease', (134, 157))	('malignant neoplasm', 'Disease', 'MESH:D009369', (124, 142))	('neoplasm of respiratory', 'Disease', 'MESH:D012131', (185, 208))	('HES', 'Chemical', '-', (39, 42))	('unspecified', 'Species', '32644', (112, 123))	('neoplasm of respiratory', 'Disease', (185, 208))	('malignant neoplasm', 'Disease', (249, 267))	('malignant neoplasm', 'Disease', (124, 142))	('neoplasm of lymph nodes', 'Disease', 'MESH:D000072717', (134, 157))	('C78', 'Var', (160, 163))	('malignant neoplasm', 'Disease', 'MESH:D009369', (175, 193))
145545	22589717	Because of the apparent duplication of the PAN RNA locus in BAC36, we generated BAC36CR, a recombinant BACmid that removes the duplicated region.	('PAN', 'Gene', '51816', (43, 46))	('PAN', 'Gene', (43, 46))	('BAC36CR', 'Chemical', '-', (80, 87))	('BAC36', 'Gene', (60, 65))	('duplication', 'Var', (24, 35))
145564	22589717	KSHV is primarily latent in cell culture but can be induced to undergo lytic DNA replication by treatment of cells with a variety of chemical agents or by the expression of the lytic switch protein encoded by ORF50, K-Rta.	('ORF50', 'Gene', (209, 214))	('KSHV', 'Species', '37296', (0, 4))	('K-Rta', 'Var', (216, 221))	('ORF50', 'Gene', '4961526', (209, 214))
145570	22589717	Knockdown of PAN RNA in virus-infected cells using antisense oligonucleotides apparently results in a decrease in both virus late RNA accumulation and infectious virion production.	('antisense oligonucleotides', 'Var', (51, 77))	('decrease', 'NegReg', (102, 110))	('PAN', 'Gene', '51816', (13, 16))	('oligonucleotides', 'Chemical', 'MESH:D009841', (61, 77))	('infectious virion production', 'CPA', (151, 179))	('virus late RNA accumulation', 'MPA', (119, 146))	('PAN', 'Gene', (13, 16))
145575	22589717	This BAC36 duplication also includes the locus that encodes PAN RNA, which partially overlaps with the K7 ORF.	('BAC36', 'Gene', (5, 10))	('PAN', 'Gene', '51816', (60, 63))	('duplication', 'Var', (11, 22))	('PAN', 'Gene', (60, 63))
145576	22589717	Hence the mutation or deletion of these ORFs or the PAN RNA locus within the BAC36 genome is complicated by this duplication.	('PAN', 'Gene', (52, 55))	('ORFs', 'Gene', (40, 44))	('deletion', 'Var', (22, 30))	('mutation', 'Var', (10, 18))	('PAN', 'Gene', '51816', (52, 55))
145584	22589717	These data strongly suggest that PAN RNA activates KSHV gene expression by mediating the removal of the repressive H3K27me3 mark while simultaneously marking H3K4me3, a mark associated with gene activation.	('KSHV', 'Species', '37296', (51, 55))	('H3K4me3', 'Var', (158, 165))	('PAN', 'Gene', '51816', (33, 36))	('H3', 'Chemical', 'MESH:C012616', (115, 117))	('PAN', 'Gene', (33, 36))	('H3', 'Chemical', 'MESH:C012616', (158, 160))	('KSHV gene', 'Gene', (51, 60))	('H3K27me3', 'Protein', (115, 123))	('expression', 'MPA', (61, 71))	('activates', 'PosReg', (41, 50))
145610	22589717	The primers used removes a 634 nt internal region of PAN, spanning nt 29022-29656 (GenBank accession no.	('nt 29022-29656', 'Var', (67, 81))	('PAN', 'Gene', '51816', (53, 56))	('PAN', 'Gene', (53, 56))
145612	22589717	PAN deletion mutants were first selected on chloramphenicol/kanamycin agar plates; correct insertional mutants were confirmed with southern blot analysis and subsequent sequencing confirmation.	('PAN', 'Gene', '51816', (0, 3))	('kanamycin', 'Chemical', 'MESH:D007612', (60, 69))	('agar', 'Chemical', 'MESH:D000362', (70, 74))	('deletion', 'Var', (4, 12))	('PAN', 'Gene', (0, 3))	('chloramphenicol', 'Chemical', 'MESH:D002701', (44, 59))
145625	22589717	5x106 cells containing BAC36CR or BAC36CRDeltaPAN were treated with 0.3 mM sodium butyrate to induce lytic reactivation.	('BAC36CR', 'Var', (23, 30))	('BAC36CR', 'Chemical', '-', (34, 41))	('BAC36CRDeltaPAN', 'Chemical', '-', (34, 49))	('sodium butyrate', 'Chemical', 'MESH:D020148', (75, 90))	('lytic reactivation', 'CPA', (101, 119))	('BAC36CRDeltaPAN', 'Var', (34, 49))	('BAC36CR', 'Chemical', '-', (23, 30))
145682	22589717	However the recent discovery of the duplication of a large region of the KSHV genome within this BACmid has hampered efforts to introduce mutations or deletions in genes present within the duplicated region.	('duplication', 'Var', (36, 47))	('KSHV', 'Species', '37296', (73, 77))	('deletions', 'Var', (151, 160))	('KSHV', 'Gene', (73, 77))	('mutations', 'Var', (138, 147))
145684	22589717	In order to generate a BACmid template such that recombinants could be generated with mutations or deletions in ORFs 18-K5 including the PAN RNA locus, we decided to remove the duplicated region from the original BAC36 genome.	('mutations', 'Var', (86, 95))	('ORFs 18-K5', 'Gene', (112, 122))	('deletions', 'Var', (99, 108))	('PAN', 'Gene', '51816', (137, 140))	('PAN', 'Gene', (137, 140))
145695	22589717	Similar levels of virus DNA accumulated from cells containing BAC36 and BAC36CR (Fig.	('BAC36CR', 'Chemical', '-', (72, 79))	('BAC36CR', 'Var', (72, 79))	('BAC36', 'Var', (62, 67))
145697	22589717	The generation of BAC36CR now allowed for the production of recombinant BACmids with mutations or deletions in regions of the KSHV genome that encoded ORFs K18-K5.	('KSHV', 'Species', '37296', (126, 130))	('BAC36CR', 'Chemical', '-', (18, 25))	('KSHV', 'Gene', (126, 130))	('mutations', 'Var', (85, 94))	('K18-K5', 'Var', (156, 162))	('deletions in', 'Var', (98, 110))
145700	22589717	Hence, any plan involving the deletion of the PAN RNA locus would have to preserve the K7 ORF along with the putative polyadenlyation signal down stream of PAN RNA (Fig.	('PAN', 'Gene', (156, 159))	('PAN', 'Gene', (46, 49))	('deletion', 'Var', (30, 38))	('PAN', 'Gene', '51816', (156, 159))	('PAN', 'Gene', '51816', (46, 49))
145701	22589717	Again using the insertion of the GalK-KanR cassette we removed nucleotide sequences from 29022-29656 (Fig.	('GalK', 'Gene', (33, 37))	('29022-29656', 'Var', (89, 100))	('GalK', 'Gene', '2584', (33, 37))
145704	22589717	BAC36, BAC36CR and BAC36CRDeltaPAN DNA was cleaved with BamHI and separated by agarose gel electrophoresis and transferred to a nylon membrane.	('BAC36CRDeltaPAN', 'Chemical', '-', (19, 34))	('BAC36CR', 'Var', (7, 14))	('BAC36CRDeltaPAN', 'Var', (19, 34))	('BAC36CR', 'Chemical', '-', (19, 26))	('agarose', 'Chemical', 'MESH:D012685', (79, 86))	('BAC36CR', 'Chemical', '-', (7, 14))	('nylon', 'Chemical', 'MESH:D009757', (128, 133))
145709	22589717	The BAC36CRDeltaPAN BamHI cleaved DNA shows the presence of a smaller band confirming the deletion of 634 nts from the PAN RNA locus (Fig.	('deletion', 'Var', (90, 98))	('PAN', 'Gene', '51816', (119, 122))	('PAN', 'Gene', (16, 19))	('PAN', 'Gene', (119, 122))	('BAC36CRDeltaPAN', 'Chemical', '-', (4, 19))	('PAN', 'Gene', '51816', (16, 19))
145713	22589717	Colonies harboring BAC36CRDeltaPAN, BAC36CR and revertant BACmid BAC36CRDeltaPANrevt were expanded and treated with TPA/n-butyrate for 5 days.	('BAC36CRDeltaPANrevt', 'Var', (65, 84))	('BAC36CR', 'Chemical', '-', (65, 72))	('TPA', 'Gene', '5327', (116, 119))	('BAC36CRDeltaPAN', 'Chemical', '-', (19, 34))	('n-butyrate', 'Chemical', 'MESH:D002087', (120, 130))	('BAC36CRDeltaPAN', 'Var', (19, 34))	('BAC36CRDeltaPAN', 'Chemical', '-', (65, 80))	('BAC36CR', 'Chemical', '-', (19, 26))	('BAC36CR', 'Chemical', '-', (36, 43))	('BAC36CR', 'Var', (36, 43))	('TPA', 'Gene', (116, 119))
145714	22589717	We measured supernatant virus accumulation by qPCR compared to uninduced BAC36CR collected samples.	('BAC36CR', 'Chemical', '-', (73, 80))	('supernatant virus accumulation', 'MPA', (12, 42))	('qPCR', 'Var', (46, 50))
145716	22589717	Since this observation could be due to a significant difference in the number of latent viral genomes between the wt and mutant viruses, we also measured the number of viral genomes present in wt BAC36CR and BAC36CRDeltaPAN.	('BAC36CRDeltaPAN', 'Var', (208, 223))	('mutant', 'Var', (121, 127))	('BAC36CR', 'Chemical', '-', (208, 215))	('BAC36CRDeltaPAN', 'Chemical', '-', (208, 223))	('BAC36CR', 'Chemical', '-', (196, 203))
145717	22589717	The lack of production of supernatant virus for the PAN RNA deletion mutant suggests that expression of the transcript is essential for virus growth.	('PAN', 'Gene', (52, 55))	('deletion', 'Var', (60, 68))	('PAN', 'Gene', '51816', (52, 55))
145720	22589717	We measured mRNA accumulation for the viral encoded mRNAs: ORF50, PAN, K7, K-bZIP (K8), ORF25, ORF57 and LANA (ORF73).	('ORF25', 'Var', (88, 93))	('LANA', 'Gene', (105, 109))	('ORF57', 'Var', (95, 100))	('mRNA accumulation', 'MPA', (12, 29))	('LANA', 'Gene', '4961527', (105, 109))	('ORF50', 'Gene', '4961526', (59, 64))	('PAN', 'Gene', '51816', (66, 69))	('ORF50', 'Gene', (59, 64))	('PAN', 'Gene', (66, 69))
145725	22589717	The detection of K7 expression indicated that the deletion of the PAN RNA locus and the placement of the putative polyadenlyation signal just downstream of the K7 ORF allowed for efficient expression of the K7 transcript.	('expression', 'MPA', (189, 199))	('PAN', 'Gene', (66, 69))	('deletion', 'Var', (50, 58))	('PAN', 'Gene', '51816', (66, 69))
145726	22589717	As expected the expression level of the early gene K-bZIP (K8) was reduced in induced cells harboring BAC36CRDeltaPAN compared to BAC36CR or revertant virus (Fig.	('K-bZIP (K8', 'Gene', (51, 61))	('BAC36CRDeltaPAN', 'Chemical', '-', (102, 117))	('expression level', 'MPA', (16, 32))	('reduced', 'NegReg', (67, 74))	('BAC36CR', 'Chemical', '-', (130, 137))	('BAC36CRDeltaPAN', 'Var', (102, 117))	('BAC36CR', 'Chemical', '-', (102, 109))
145730	22589717	We also evaluated protein accumulation for K-Rta, K-bZIP and LANA in induced and uninduced cells harboring BAC36CRDeltaPAN or BAC36CR by Western blot.	('BAC36CR', 'Var', (126, 133))	('BAC36CRDeltaPAN', 'Var', (107, 122))	('BAC36CR', 'Chemical', '-', (107, 114))	('LANA', 'Gene', (61, 65))	('protein accumulation', 'MPA', (18, 38))	('LANA', 'Gene', '4961527', (61, 65))	('BAC36CRDeltaPAN', 'Chemical', '-', (107, 122))	('BAC36CR', 'Chemical', '-', (126, 133))
145731	22589717	Protein lysates were prepared from cells harboring BAC36CRDeltaPAN or BAC36CR either induced with TPA/Butyrate or uninduced.	('BAC36CRDeltaPAN', 'Var', (51, 66))	('BAC36CR', 'Chemical', '-', (70, 77))	('BAC36CR', 'Chemical', '-', (51, 58))	('TPA', 'Gene', '5327', (98, 101))	('Butyrate', 'Chemical', 'MESH:D002087', (102, 110))	('induced', 'Reg', (85, 92))	('BAC36CR', 'Var', (70, 77))	('BAC36CRDeltaPAN', 'Chemical', '-', (51, 66))	('TPA', 'Gene', (98, 101))
145733	22589717	Consistent with qPCR results the level of K-Rta protein was reduced upon induction in cells containing BAC36CRDeltaPAN compared to BAC36CR (Fig.	('BAC36CRDeltaPAN', 'Var', (103, 118))	('BAC36CR', 'Chemical', '-', (103, 110))	('BAC36CR', 'Chemical', '-', (131, 138))	('K-Rta', 'MPA', (42, 47))	('reduced', 'NegReg', (60, 67))	('level', 'MPA', (33, 38))	('BAC36CRDeltaPAN', 'Chemical', '-', (103, 118))
145742	22589717	In all cases, induced or uninduced, the expression of PAN RNA did result in an increase in K-Rta expression from BACmid DNA (Fig.	('increase', 'PosReg', (79, 87))	('K-Rta expression', 'MPA', (91, 107))	('PAN', 'Gene', '51816', (54, 57))	('expression', 'Var', (40, 50))	('PAN', 'Gene', (54, 57))
145755	22589717	The presence of both K-Rta and PAN RNA expression plasmids had an enhanced effect on gene expression (Fig.	('gene expression', 'MPA', (85, 100))	('enhanced', 'PosReg', (66, 74))	('PAN', 'Gene', '51816', (31, 34))	('K-Rta', 'Var', (21, 26))	('PAN', 'Gene', (31, 34))
145777	22589717	A specific PCR product was detected in the sample using PAN RNA specific oligonucleotides whereas no specific amplification product was observed in control pull downs or amplification of the K6 promoter region (Fig.	('PAN', 'Gene', (56, 59))	('oligonucleotides', 'Var', (73, 89))	('oligonucleotides', 'Chemical', 'MESH:D009841', (73, 89))	('PAN', 'Gene', '51816', (56, 59))
145783	22589717	Evidence suggests that the transfection of a plasmid expressing demethylases is sufficient to activate lytic replication and hence the removal of the specific repressive H3K27me3 mark is important for lytic reactivation of latent KSHV genomes.	('demethylases', 'Var', (64, 76))	('H3', 'Chemical', 'MESH:C012616', (170, 172))	('lytic replication', 'CPA', (103, 120))	('activate', 'PosReg', (94, 102))	('H3K27me3', 'Protein', (170, 178))	('KSHV', 'Species', '37296', (230, 234))
145792	22589717	9, BAC36CR, ORF50 promoter, Panel: BAC36CR).	('ORF50', 'Gene', '4961526', (12, 17))	('BAC36CR', 'Chemical', '-', (35, 42))	('BAC36CR', 'Var', (35, 42))	('ORF50', 'Gene', (12, 17))	('BAC36CR', 'Chemical', '-', (3, 10))
145816	22589717	Hence these results strongly suggest that one mechanism of gene activation is by the specific targeting of PAN RNA to KSHV promoters that are repressed with the H3K27Me3 mark by the PRC2.	('H3K27Me3', 'Var', (161, 169))	('KSHV', 'Species', '37296', (118, 122))	('PAN', 'Gene', '51816', (107, 110))	('H3', 'Chemical', 'MESH:C012616', (161, 163))	('PAN', 'Gene', (107, 110))
145818	22589717	Since we show that PAN RNA interacts with the demethylases UTX and JMJD3 we evaluated the amount of H3K27me3 at the ORF50 promoter in the context of the PAN RNA deletion mutant BAC36CRDeltaPAN.	('PAN', 'Gene', '51816', (153, 156))	('H3', 'Chemical', 'MESH:C012616', (100, 102))	('PAN', 'Gene', '51816', (19, 22))	('PAN', 'Gene', (153, 156))	('UTX', 'Gene', '7403', (59, 62))	('ORF50', 'Gene', '4961526', (116, 121))	('JMJD3', 'Gene', (67, 72))	('PAN', 'Gene', (19, 22))	('deletion', 'Var', (161, 169))	('PAN', 'Gene', '51816', (189, 192))	('JMJD3', 'Gene', '23135', (67, 72))	('ORF50', 'Gene', (116, 121))	('BAC36CRDeltaPAN', 'Chemical', '-', (177, 192))	('PAN', 'Gene', (189, 192))	('UTX', 'Gene', (59, 62))
145830	22589717	The role of PAN RNA in KSHV replication and growth has been elusive partly due to the lack of a recombinant virus with a deletion in the PAN locus.	('PAN', 'Gene', (12, 15))	('PAN', 'Gene', '51816', (137, 140))	('PAN', 'Gene', (137, 140))	('KSHV', 'Species', '37296', (23, 27))	('deletion', 'Var', (121, 129))	('PAN', 'Gene', '51816', (12, 15))
145831	22589717	Although our laboratory has generated several BACmid mutants, the generation of a PAN RNA gene deletion appeared to be difficult.	('PAN', 'Gene', (82, 85))	('PAN', 'Gene', '51816', (82, 85))	('deletion', 'Var', (95, 103))
145832	22589717	The reason for the difficulty, with respect to introducing mutations or deletions within this region of the BAC36 genome, was illuminated by the recent publication demonstrating that ORFs 18, 17, 16, K7, K6, and K5, including the PAN RNA locus was duplicated in BAC36.	('PAN', 'Gene', '51816', (230, 233))	('mutations', 'Var', (59, 68))	('deletions', 'Var', (72, 81))	('PAN', 'Gene', (230, 233))	('ORFs', 'Var', (183, 187))
145833	22589717	Hence it became clear that this duplication had to be removed from BAC36 such that deletions or mutations within the PAN RNA locus could be introduced.	('PAN', 'Gene', (117, 120))	('deletions', 'Var', (83, 92))	('BAC36', 'Gene', (67, 72))	('PAN', 'Gene', '51816', (117, 120))	('mutations', 'Var', (96, 105))
145839	22589717	Our qPCR data indicates that the K7 transcript is produced and hence the generation of BAC36CRDeltaPAN strongly suggests that deletion we engineered into the genome only affects the expression of PAN RNA.	('affects', 'Reg', (170, 177))	('PAN', 'Gene', '51816', (99, 102))	('expression', 'MPA', (182, 192))	('PAN', 'Gene', (99, 102))	('PAN', 'Gene', '51816', (196, 199))	('deletion', 'Var', (126, 134))	('BAC36CRDeltaPAN', 'Chemical', '-', (87, 102))	('PAN', 'Gene', (196, 199))
145843	22589717	However, antisense oligonucleotide treatment showed only a small decrease in the expression of immediate early and early genes, whereas our study shows that the absence of PAN RNA expression results in a dramatic repression of both immediate early (K-Rta and ORF57) as well as early and late gene expression.	('ORF57', 'Gene', (259, 264))	('repression', 'NegReg', (213, 223))	('PAN', 'Gene', '51816', (172, 175))	('PAN', 'Gene', (172, 175))	('absence', 'Var', (161, 168))	('early', 'MPA', (277, 282))	('oligonucleotide', 'Chemical', 'MESH:D009841', (19, 34))	('expression', 'MPA', (81, 91))
145844	22589717	These differences are most likely due to the fact that in our system PAN RNA is not expressed whereas treatment with antisense oligonucleotides is associated with incomplete knockdown and toxicity.	('antisense oligonucleotides', 'Var', (117, 143))	('toxicity', 'Disease', (188, 196))	('oligonucleotides', 'Chemical', 'MESH:D009841', (127, 143))	('PAN', 'Gene', '51816', (69, 72))	('PAN', 'Gene', (69, 72))	('toxicity', 'Disease', 'MESH:D064420', (188, 196))
145852	22589717	Interestingly, it was shown previously that both H3K4me3 and H3K27me3 marked the ORF50 locus during latency, with an increase in activation and decrease in repressive marks upon lytic reactivation.	('increase', 'PosReg', (117, 125))	('repressive marks', 'MPA', (156, 172))	('ORF50', 'Gene', '4961526', (81, 86))	('decrease', 'NegReg', (144, 152))	('H3K27me3', 'Var', (61, 69))	('H3', 'Chemical', 'MESH:C012616', (61, 63))	('activation', 'PosReg', (129, 139))	('ORF50', 'Gene', (81, 86))	('H3K4me3', 'Var', (49, 56))	('H3', 'Chemical', 'MESH:C012616', (49, 51))
145854	22589717	This model is consistent with the observations that a small amount of K-Rta expression was detected in the PAN RNA deletion mutant and we speculate that this interaction was insufficient to maintain K-Rta expression and fully reactivate latent genomes.	('deletion mutant', 'Var', (115, 130))	('insufficient', 'Disease', 'MESH:D000309', (174, 186))	('insufficient', 'Disease', (174, 186))	('PAN', 'Gene', '51816', (107, 110))	('PAN', 'Gene', (107, 110))
145896	34046343	The TNM staging was T2aN0M0 IB according to the 8th edition of the AJCC/UICC TNM staging system for lung cancer.	('T2aN0M0 IB', 'Var', (20, 30))	('TNM', 'Gene', '10178', (4, 7))	('TNM', 'Gene', (77, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('TNM', 'Gene', (4, 7))	('TNM', 'Gene', '10178', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
145897	34046343	Immunohistochemistry showed that the cells were stained positive for EMA(focal+), CK8/18(focal+), TTF-1(focal+), Ki-67(70%), CD34(focal+), CD31(+), and SMA(+), and negative for AE1/AE3(-), NapsinA(-), CK5/6(-), P40(-), P63(-), S-100(-), ERG(-), and Desmin(-) ( Figure 2 ).	('TTF-1', 'Gene', '7270', (98, 103))	('CD31', 'Gene', (139, 143))	('CK5/6', 'Gene', '3852', (201, 206))	('Desmin', 'Gene', '1674', (249, 255))	('CK8/18', 'Gene', (82, 88))	('CD34', 'Gene', '947', (125, 129))	('CK8/18', 'Gene', '3856;3875', (82, 88))	('CD31', 'Gene', '5175', (139, 143))	('SMA', 'Gene', (152, 155))	('Desmin', 'Gene', (249, 255))	('CK5/6', 'Gene', (201, 206))	('TTF-1', 'Gene', (98, 103))	('SMA', 'Gene', '6606', (152, 155))	('CD34', 'Gene', (125, 129))	('Ki-67', 'Var', (113, 118))
145927	34046343	Recently, several studies have focused on the genetic features of this disease and revealed a wide range of alterations, including TP53, EGFR, KRAS, PIK3CA, STK11, BRCA1/BRCA2, and IDH1 mutations; MET exon 14 mutations; and MET, ALK, EGFR, CDK4, and MDM2 amplifications, some of which are associated with targeted therapy through the MET receptor pathway or MAP-kinase pathway.	('ALK', 'Gene', (229, 232))	('EGFR', 'Gene', (234, 238))	('BRCA1', 'Gene', (164, 169))	('amplifications', 'Var', (255, 269))	('BRCA2', 'Gene', '675', (170, 175))	('MET', 'Gene', (224, 227))	('STK11', 'Gene', '6794', (157, 162))	('MET', 'Gene', (334, 337))	('EGFR', 'Gene', (137, 141))	('MDM2', 'Gene', (250, 254))	('TP53', 'Gene', (131, 135))	('IDH1', 'Gene', (181, 185))	('CDK4', 'Gene', (240, 244))	('KRAS', 'Gene', '3845', (143, 147))	('EGFR', 'Gene', '1956', (234, 238))	('PIK3CA', 'Gene', '5290', (149, 155))	('MET', 'Gene', (197, 200))	('MDM2', 'Gene', '4193', (250, 254))	('MET', 'Gene', '79811', (334, 337))	('MET', 'Gene', '79811', (224, 227))	('KRAS', 'Gene', (143, 147))	('EGFR', 'Gene', '1956', (137, 141))	('CDK4', 'Gene', '1019', (240, 244))	('IDH1', 'Gene', '3417', (181, 185))	('STK11', 'Gene', (157, 162))	('BRCA2', 'Gene', (170, 175))	('ALK', 'Gene', '238', (229, 232))	('TP53', 'Gene', '7157', (131, 135))	('PIK3CA', 'Gene', (149, 155))	('MET', 'Gene', '79811', (197, 200))	('BRCA1', 'Gene', '672', (164, 169))
145933	34046343	Considering that NGS for this patient revealed a few gene mutations, including of the FGFR gene, we combined chemotherapy with anlotinib, which selectively targets FGFR, and achieved prominent tumor regression and a long PFS without evident toxicity.	('mutations', 'Var', (58, 67))	('patient', 'Species', '9606', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('toxicity', 'Disease', 'MESH:D064420', (241, 249))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('FGFR', 'Gene', (86, 90))	('toxicity', 'Disease', (241, 249))	('anlotinib', 'Chemical', 'MESH:C000625192', (127, 136))	('tumor', 'Disease', (193, 198))
145966	33884917	Hematoxylin and eosin staining showed a mixture of uniform oval non-lipogenic cells and small signet ring lipoblasts in a prominent myxoid stroma, and immunohistochemistry revealed S100 (-) and Ki-67 (2%-5% +).	('S100', 'Gene', (181, 185))	('S100', 'Gene', '6271', (181, 185))	('Ki-67', 'Var', (194, 199))	('eosin', 'Chemical', 'MESH:D004801', (16, 21))	('Hematoxylin', 'Chemical', 'MESH:D006416', (0, 11))
145972	33884917	The clinical diagnosis was recurrence of the right calf LPS, rpT2bN0M0G3, stage IIA (UICC 8th edition), and the patient's Eastern Cooperative Oncology Group physical status score was 1.	('patient', 'Species', '9606', (112, 119))	('LPS', 'Phenotype', 'HP:0012034', (56, 59))	('LPS', 'Disease', (56, 59))	('calf', 'Species', '9913', (51, 55))	('LPS', 'Disease', 'MESH:C536528', (56, 59))	('Oncology', 'Phenotype', 'HP:0002664', (142, 150))	('rpT2bN0M0G3', 'Var', (61, 72))
146080	26823601	Transaminitis in 31% of patients (grade 2: 24%; grade 3: 7%), grade 4 fever (n = 1), and grade 4 anaphylaxis (n = 1) were attributed to CYT107 (Supplementary Table S1).	('anaphylaxis', 'Phenotype', 'HP:0100845', (97, 108))	('CYT107', 'Chemical', '-', (136, 142))	('fever', 'Phenotype', 'HP:0001945', (70, 75))	('fever', 'Disease', (70, 75))	('CYT107', 'Var', (136, 142))	('fever', 'Disease', 'MESH:D005334', (70, 75))	('Transaminitis', 'Disease', (0, 13))	('patients', 'Species', '9606', (24, 32))
146082	26823601	Transient lymphopenia was commonly observed during the first 48 hours following CYT107 as previously described due to alterations in lymphocyte trafficking and was not graded as toxicity.	('toxicity', 'Disease', 'MESH:D064420', (178, 186))	('toxicity', 'Disease', (178, 186))	('lymphopenia', 'Phenotype', 'HP:0001888', (10, 21))	('alterations', 'Reg', (118, 129))	('lymphopenia', 'Disease', 'MESH:D008231', (10, 21))	('CYT107', 'Chemical', '-', (80, 86))	('lymphocyte trafficking', 'CPA', (133, 155))	('lymphopenia', 'Disease', (10, 21))	('CYT107', 'Var', (80, 86))
146110	26823601	However, immune reconstitution was significantly greater in CYT107 recipients as measured by the number of circulating CD4+ T cells at 6 and 14 weeks following initiation of immunotherapy and CD8+ T cells at 6 weeks following initiation of immunotherapy.	('CD4', 'Gene', '920', (119, 122))	('greater', 'PosReg', (49, 56))	('CD8', 'Gene', (192, 195))	('CD8', 'Gene', '925', (192, 195))	('CYT107', 'Var', (60, 66))	('CD4', 'Gene', (119, 122))	('immune reconstitution', 'CPA', (9, 30))	('CYT107', 'Chemical', '-', (60, 66))
146111	26823601	CYT107 recipients also had higher levels of natural killer cells at weeks 6 and 14, and higher levels of B cells at week 6, although interpretation of this result is confounded by the fact that CYT107 recipients retained higher B-cell levels post-standard therapy (Fig.	('higher', 'PosReg', (88, 94))	('CYT107', 'Var', (194, 200))	('natural killer cells', 'MPA', (44, 64))	('levels of B cells', 'MPA', (95, 112))	('CYT107', 'Chemical', '-', (194, 200))	('CYT107', 'Chemical', '-', (0, 6))	('higher', 'PosReg', (27, 33))	('CYT107', 'Var', (0, 6))	('B-cell levels', 'MPA', (228, 241))	('higher', 'PosReg', (221, 227))
146115	26823601	Notably however, CYT107 administration decreased regulatory T-cell frequencies at weeks 6, 14, and 20 compared with that present postchemotherapy, whereas subjects treated with IL2 on the first-generation trial experienced increased levels of regulatory T-cell frequencies at those time points.	('IL2', 'Gene', (177, 180))	('CYT107', 'Chemical', '-', (17, 23))	('regulatory T-cell frequencies', 'CPA', (49, 78))	('IL2', 'Gene', '3558', (177, 180))	('CYT107', 'Var', (17, 23))	('decreased', 'NegReg', (39, 48))
146116	26823601	Despite CYT1070's favorable impact on immune reconstitution and regulatory expansion, we observed no difference in OS between subjects treated on this study +- CYT107 (5-year OS 80% without CYT107 versus 58.3% with CYT107, P = 0.16).	('CYT107', 'Var', (190, 196))	('CYT107', 'Chemical', '-', (160, 166))	('CYT107', 'Chemical', '-', (8, 14))	('CYT107', 'Chemical', '-', (190, 196))	('CYT1070', 'Var', (8, 15))	('CYT107', 'Chemical', '-', (215, 221))
146118	26823601	The corollary to this is that tumors developing in the setting of immune depletion are more immunogenic and more susceptible to immune-based therapies.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('more', 'PosReg', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('immune depletion', 'Var', (66, 82))
146128	26823601	Furthermore, the CYT107 cohort demonstrated rapid reconstitution and diminished regulatory T-cell frequencies at weeks 6, 14, and 20 compared with that present following completion of standard therapy.	('CYT107', 'Chemical', '-', (17, 23))	('diminished', 'NegReg', (69, 79))	('CYT107', 'Var', (17, 23))	('regulatory T-cell frequencies', 'CPA', (80, 109))
146137	26823601	Pediatric sarcomas are genetically quiet compared with carcinomas and melanomas, and emerging science suggests that the mutational load is a major driver of immunogenicity by providing neoantigens capable of inducing immune responses.	('sarcomas', 'Phenotype', 'HP:0100242', (10, 18))	('mutational load', 'Var', (120, 135))	('carcinomas', 'Disease', 'MESH:D009369', (55, 65))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('sarcomas', 'Disease', (10, 18))	('immune responses', 'MPA', (217, 233))	('carcinomas', 'Disease', (55, 65))	('inducing', 'PosReg', (208, 216))	('melanomas', 'Disease', (70, 79))	('neoantigens', 'MPA', (185, 196))	('sarcomas', 'Disease', 'MESH:D012509', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
146352	33153100	treated 23 patients with borderline resectable STS with neoadjuvant RT (50.4-69 Gy) and concurrent doxorubicin (50 mg/m2 d2 and d30) and ifosfamide (1.5 g/m2 d1-5 and d29-33).	('a', 'Gene', '351', (3, 4))	('ifosfamide', 'Chemical', 'MESH:D007069', (137, 147))	('a', 'Gene', '351', (64, 65))	('a', 'Gene', '351', (59, 60))	('a', 'Gene', '351', (142, 143))	('a', 'Gene', '351', (42, 43))	('doxorubicin', 'Chemical', 'MESH:D004317', (99, 110))	('a', 'Gene', '351', (124, 125))	('a', 'Gene', '351', (163, 164))	('STS', 'Phenotype', 'HP:0030448', (47, 50))	('a', 'Gene', '351', (84, 85))	('a', 'Gene', '351', (12, 13))	('d29-33', 'Var', (167, 173))	('patients', 'Species', '9606', (11, 19))	('d30', 'Var', (128, 131))	('1.5', 'Var', (149, 152))	('a', 'Gene', '351', (133, 134))
146503	33153100	Similar concepts are currently investigated by several groups using slightly different fractionation regimens (5-15 fractions) and single-doses (2.85-7 Gy), which are biologically equivalent to roughly 50 Gy in conventional fractionation (NCT NCT03819985, NCT02701153, NCT04425967, NCT02634710).	('a', 'Gene', '351', (89, 90))	('a', 'Gene', '351', (185, 186))	('a', 'Gene', '351', (127, 128))	('a', 'Gene', '351', (17, 18))	('a', 'Gene', '351', (52, 53))	('a', 'Gene', '351', (95, 96))	('a', 'Gene', '351', (226, 227))	('a', 'Gene', '351', (118, 119))	('a', 'Gene', '351', (221, 222))	('a', 'Gene', '351', (163, 164))	('a', 'Gene', '351', (39, 40))	('NCT02701153', 'Var', (256, 267))	('NCT04425967', 'Var', (269, 280))	('NCT02634710', 'Var', (282, 293))	('a', 'Gene', '351', (232, 233))	('NCT NCT03819985', 'Var', (239, 254))	('a', 'Gene', '351', (5, 6))	('a', 'Gene', '351', (175, 176))
146516	33153100	A US multicenter phase I/II trial also investigates neoadjuvant irradiation with integrated boost to the high-risk area in retroperitoneal sarcomas using either intensity-modulated photons or protons (NCT01659203).	('a', 'Gene', '351', (87, 88))	('a', 'Gene', '351', (47, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('a', 'Gene', '351', (31, 32))	('a', 'Gene', '351', (70, 71))	('retroperitoneal sarcomas', 'Disease', (123, 147))	('a', 'Gene', '351', (55, 56))	('a', 'Gene', '351', (118, 119))	('retroperitoneal sarcomas', 'Disease', 'MESH:D012186', (123, 147))	('a', 'Gene', '351', (140, 141))	('A', 'Gene', '351', (0, 1))	('NCT01659203', 'Var', (201, 212))	('a', 'Gene', '351', (115, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('a', 'Gene', '351', (19, 20))	('a', 'Gene', '351', (67, 68))	('a', 'Gene', '351', (60, 61))	('a', 'Gene', '351', (34, 35))	('a', 'Gene', '351', (145, 146))	('a', 'Gene', '351', (176, 177))	('retroperitoneal sarcomas', 'Phenotype', 'HP:0006729', (123, 147))	('a', 'Gene', '351', (136, 137))
146526	33153100	Those include (but are not limited to) tyrosinkinase or multikinase inhibitors like sunitinib (NCT01498835) or cabozantinib (NCT04220229), PARP-inhibitors like Olaparib (NCT02787642), MDM2-inhibitors (NCT03217266), or checkpoint-inhibitors like pembrolizumab (NCT03338959) or atezolizumab (NCT03474094) with mature results pending.	('Olaparib', 'Chemical', 'MESH:C531550', (160, 168))	('a', 'Gene', '351', (309, 310))	('NCT03474094', 'Var', (290, 301))	('NCT03217266', 'Var', (201, 212))	('a', 'Gene', '351', (49, 50))	('NCT04220229', 'Var', (125, 136))	('a', 'Gene', '351', (286, 287))	('PARP', 'Gene', '1302', (139, 143))	('NCT03338959', 'Var', (260, 271))	('a', 'Gene', '351', (64, 65))	('pembrolizumab', 'Chemical', 'MESH:C582435', (245, 258))	('a', 'Gene', '351', (276, 277))	('NCT01498835', 'Var', (95, 106))	('sunitinib', 'Chemical', 'MESH:D000077210', (84, 93))	('a', 'Gene', '351', (116, 117))	('atezolizumab', 'Chemical', 'MESH:C000594389', (276, 288))	('PARP', 'Gene', (139, 143))	('MDM2', 'Gene', (184, 188))	('a', 'Gene', '351', (164, 165))	('a', 'Gene', '351', (162, 163))	('a', 'Gene', '351', (19, 20))	('MDM2', 'Gene', '4193', (184, 188))	('cabozantinib', 'Chemical', 'MESH:C558660', (111, 123))	('NCT02787642', 'Var', (170, 181))	('a', 'Gene', '351', (256, 257))	('a', 'Gene', '351', (112, 113))
146528	33153100	While combinations of RT with intratumoral injections of oncolytic virus particles like T-VEC (NCT02453191) or autologeous dendritic cells (NCT01347034) are currently evaluated in phase I/II trials with pending results, encouraging evidence for intratumoral injection of nanoparticles like NBTX3 has been recently published.	('a', 'Gene', '351', (255, 256))	('NCT02453191', 'Var', (95, 106))	('a', 'Gene', '351', (111, 112))	('a', 'Gene', '351', (40, 41))	('a', 'Gene', '351', (182, 183))	('a', 'Gene', '351', (276, 277))	('a', 'Gene', '351', (226, 227))	('a', 'Gene', '351', (172, 173))	('NCT01347034', 'Var', (140, 151))	('a', 'Gene', '351', (194, 195))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('a', 'Gene', '351', (12, 13))	('a', 'Gene', '351', (249, 250))	('a', 'Gene', '351', (297, 298))	('a', 'Gene', '351', (74, 75))	('a', 'Gene', '351', (34, 35))	('a', 'Gene', '351', (272, 273))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('a', 'Gene', '351', (169, 170))	('a', 'Gene', '351', (153, 154))
146564	33153100	Although no randomized trials specifically addressing its role in STS patients have been conducted, SBRT seems to result in similar local control rates and overall outcomes in patients with limited pulmonary metastases compared to surgery.	('a', 'Gene', '351', (129, 130))	('a', 'Gene', '351', (223, 224))	('a', 'Gene', '351', (135, 136))	('a', 'Gene', '351', (80, 81))	('a', 'Gene', '351', (214, 215))	('a', 'Gene', '351', (71, 72))	('a', 'Gene', '351', (152, 153))	('a', 'Gene', '351', (160, 161))	('a', 'Gene', '351', (26, 27))	('patients', 'Species', '9606', (70, 78))	('a', 'Gene', '351', (38, 39))	('a', 'Gene', '351', (204, 205))	('STS', 'Phenotype', 'HP:0030448', (66, 69))	('SBRT', 'Var', (100, 104))	('pulmonary metastases', 'Disease', (198, 218))	('A', 'Gene', '351', (0, 1))	('a', 'Gene', '351', (13, 14))	('a', 'Gene', '351', (43, 44))	('a', 'Gene', '351', (211, 212))	('patients', 'Species', '9606', (176, 184))	('a', 'Gene', '351', (147, 148))	('a', 'Gene', '351', (177, 178))	('pulmonary metastases', 'Disease', 'MESH:D009362', (198, 218))
146587	32054730	Major wound complications occurred in 16 of 50 patients (32%); a signature defined by 19 germline single nucleotide polymorphisms in miRNA binding sites of immune and DNA damage response genes, in addition to lower extremity tumor location, demonstrated strong predictive performance for major wound complications.	('lower extremity', 'Phenotype', 'HP:0006385', (209, 224))	('single nucleotide polymorphisms', 'Var', (98, 129))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('patients', 'Species', '9606', (47, 55))	('extremity tumor', 'Disease', (215, 230))	('extremity tumor', 'Disease', 'MESH:D009369', (215, 230))
146661	32054730	In exploratory analysis, among lower extremity tumor site and a panel of 116 annotated SNPs in miRNA binding sites, tumor site and 19 SNPs were identified as the top 20 predictors for major wound complication rate (Supplementary Table S4).	('extremity tumor', 'Disease', 'MESH:D009369', (37, 52))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('lower extremity', 'Phenotype', 'HP:0006385', (31, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('major wound complication', 'Disease', (184, 208))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SNPs', 'Var', (87, 91))	('tumor', 'Disease', (116, 121))	('extremity tumor', 'Disease', (37, 52))	('tumor', 'Disease', (47, 52))
146741	32128181	They are absent in GNET.11  The presence of osteoclast-like multinucleated giant cells is the most helpful distinguishing feature of GNET.12  In GI CCS, EWSR1 gene alteration is usually fused with the ATF1 gene (61.5%).	('CCS', 'Disease', (148, 151))	('GNET', 'Disease', 'MESH:D017599', (133, 137))	('CCS', 'Disease', 'MESH:D018227', (148, 151))	('multinucleated giant cells', 'Phenotype', 'HP:0031324', (60, 86))	('EWSR1', 'Gene', (153, 158))	('GI', 'Disease', 'MESH:D005767', (145, 147))	('alteration', 'Var', (164, 174))	('ATF1', 'Gene', (201, 205))	('GNET', 'Disease', (19, 23))	('EWSR1', 'Gene', '2130', (153, 158))	('ATF1', 'Gene', '466', (201, 205))	('GNET', 'Disease', (133, 137))	('GNET', 'Disease', 'MESH:D017599', (19, 23))
146742	32128181	In GNET, EWSR1 gene alteration is fused with the ATF1 gene (32.8%) and with the CREB1 (17,2%).11 The relationship between CCS-GIT and GNET continues to be debated.	('CREB1', 'Gene', '1385', (80, 85))	('GNET', 'Disease', (3, 7))	('GNET', 'Disease', 'MESH:D017599', (134, 138))	('ATF1', 'Gene', (49, 53))	('alteration', 'Var', (20, 30))	('GNET', 'Disease', 'MESH:D017599', (3, 7))	('ATF1', 'Gene', '466', (49, 53))	('EWSR1', 'Gene', (9, 14))	('CREB1', 'Gene', (80, 85))	('CCS', 'Disease', (122, 125))	('EWSR1', 'Gene', '2130', (9, 14))	('CCS', 'Disease', 'MESH:D018227', (122, 125))	('GI', 'Disease', 'MESH:D005767', (126, 128))	('GNET', 'Disease', (134, 138))
146847	29152060	Inhibition of CHK1 sensitizes Ewing sarcoma cells to the ribonucleotide reductase inhibitor gemcitabine Ewing sarcoma is a bone and soft tissue sarcoma that occurs in children and young adults.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('Ewing sarcoma', 'Disease', (30, 43))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (132, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (132, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('CHK1', 'Gene', (14, 18))	('soft tissue sarcoma', 'Disease', (132, 151))	('sensitizes', 'Reg', (19, 29))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (30, 43))	('Ewing sarcoma', 'Disease', (104, 117))	('Inhibition', 'Var', (0, 10))	('CHK1', 'Gene', '1111', (14, 18))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (30, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('children', 'Species', '9606', (167, 175))	('gemcitabine', 'Chemical', 'MESH:C056507', (92, 103))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (104, 117))
146865	29152060	Inhibition of RNR is known to cause cell cycle arrest and senescence in multiple types of cancer.	('cause', 'Reg', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (36, 53))	('cancer', 'Disease', (90, 96))	('Inhibition', 'Var', (0, 10))	('senescence', 'CPA', (58, 68))	('RNR', 'Protein', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cell cycle arrest', 'CPA', (36, 53))
146866	29152060	However, in Ewing sarcoma cells, in direct contrast to the other cell types we tested, inhibition of RNR causes cell cycle arrest and subsequent cell death with up-regulation of markers of apoptosis.	('Ewing sarcoma', 'Disease', (12, 25))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (12, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (12, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (112, 129))	('up-regulation', 'PosReg', (161, 174))	('cell cycle arrest', 'CPA', (112, 129))	('cell death', 'CPA', (145, 155))	('RNR', 'Gene', (101, 104))	('inhibition', 'Var', (87, 97))
146873	29152060	Moreover, we also found that inhibition of checkpoint kinase 1 (CHK1), the major regulator of the response to impaired DNA replication, significantly increases the toxicity of gemcitabine in Ewing sarcoma cells both in vitro and in vivo.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (191, 204))	('toxicity', 'Disease', 'MESH:D064420', (164, 172))	('checkpoint kinase 1', 'Gene', '1111', (43, 62))	('inhibition', 'Var', (29, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (191, 204))	('toxicity', 'Disease', (164, 172))	('checkpoint kinase 1', 'Gene', (43, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('gemcitabine', 'Chemical', 'MESH:C056507', (176, 187))	('Ewing sarcoma', 'Disease', (191, 204))	('increases', 'PosReg', (150, 159))	('CHK1', 'Gene', (64, 68))
146876	29152060	Inhibition of RNR is known to deplete nucleosides and cause DNA replication stress.	('cause', 'Reg', (54, 59))	('DNA replication stress', 'MPA', (60, 82))	('nucleosides', 'Chemical', 'MESH:D009705', (38, 49))	('deplete nucleosides', 'MPA', (30, 49))	('RNR', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('deplete', 'Chemical', '-', (30, 37))
146881	29152060	Furthermore, as shown in Figure 1C and Supplementary Figure 1, aphidicolin also caused cleavage of PARP-1 and activation of caspase-3/7, which are markers of apoptosis, in the Ewing sarcoma cells, but not the control cells.	('caspase-3', 'Gene', (124, 133))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (176, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('activation', 'PosReg', (110, 120))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (176, 189))	('caspase-3', 'Gene', '836', (124, 133))	('Ewing sarcoma', 'Disease', (176, 189))	('PARP-1', 'Gene', (99, 105))	('cleavage', 'MPA', (87, 95))	('aphidicolin', 'Chemical', 'MESH:D016590', (63, 74))	('PARP-1', 'Gene', '142', (99, 105))	('aphidicolin', 'Var', (63, 74))
146886	29152060	Clofarabine also induced apoptosis in Ewing sarcoma cells, as assessed using annexin-V staining (Figure 1G and 1H), activation of caspsase-3/7 (Figure 1I), and cleavage of PARP-1 (Figure 1J).	('PARP-1', 'Gene', '142', (172, 178))	('Clofarabine', 'Chemical', 'MESH:D000077866', (0, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('annexin-V', 'Gene', '308', (77, 86))	('annexin-V', 'Gene', (77, 86))	('caspsase-3/7', 'Enzyme', (130, 142))	('Ewing sarcoma', 'Disease', (38, 51))	('activation', 'PosReg', (116, 126))	('apoptosis', 'CPA', (25, 34))	('Clofarabine', 'Var', (0, 11))	('1H', 'Chemical', '-', (111, 113))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))	('PARP-1', 'Gene', (172, 178))	('cleavage', 'MPA', (160, 168))
146891	29152060	Although the clofarabine treatment significantly decreased tumor size compared to vehicle this effect on tumor growth was modest and not sustained, which suggests that clofarabine has a cytostatic effect against Ewing sarcoma cells in vivo (Figure 2A).	('tumor', 'Disease', (59, 64))	('Ewing sarcoma', 'Disease', (212, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('clofarabine', 'Var', (168, 179))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (212, 225))	('decreased', 'NegReg', (49, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (212, 225))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cytostatic effect', 'MPA', (186, 203))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (105, 110))	('clofarabine', 'Chemical', 'MESH:D000077866', (168, 179))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('clofarabine', 'Chemical', 'MESH:D000077866', (13, 24))
146895	29152060	Although treatment of Ewing sarcoma cells with clofarabine resulted in a time-dependent decrease in BrdU incorporation (Figure 2B), the cells were able to resume DNA synthesis within one hour after clofarabine was removed from the assay (Figure 2C).	('DNA synthesis', 'MPA', (162, 175))	('decrease', 'NegReg', (88, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('clofarabine', 'Var', (47, 58))	('BrdU', 'Chemical', 'MESH:D001973', (100, 104))	('BrdU incorporation', 'MPA', (100, 118))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (22, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (22, 35))	('clofarabine', 'Chemical', 'MESH:D000077866', (198, 209))	('clofarabine', 'Chemical', 'MESH:D000077866', (47, 58))	('Ewing sarcoma', 'Disease', (22, 35))
146896	29152060	The ability to re-initiate DNA synthesis after treatment with clofarabine correlated with reversal of phosphorylation of CHK1 and H2AX, markers of DNA replication stress and DNA damage (Figure 2D).	('clofarabine', 'Chemical', 'MESH:D000077866', (62, 73))	('phosphorylation', 'MPA', (102, 117))	('clofarabine', 'Var', (62, 73))	('H2AX', 'Gene', '3014', (130, 134))	('DNA synthesis', 'MPA', (27, 40))	('CHK1', 'Protein', (121, 125))	('H2AX', 'Gene', (130, 134))
146898	29152060	In summary, these data suggest that induction of apoptosis in Ewing sarcoma cells by RNR inhibitors require an extended treatment duration and that the reversibility of clofarabine, in combination with its in vivo half-life of ~5-7 hours, may limit the effectiveness of this drug in a clinical setting.	('RNR', 'Gene', (85, 88))	('clofarabine', 'Chemical', 'MESH:D000077866', (169, 180))	('inhibitors', 'Var', (89, 99))	('Ewing sarcoma', 'Disease', (62, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (62, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (62, 75))
146915	29152060	In a dose-response assay, Ewing sarcoma were sensitive to treatment with LY2603618, a potent inhibitor of CHK1, for 6 hours (Figure 4A) and 72 hours (Supplementary Figure 6) with IC50 values of ~2 muM and ~500 nM, respectively.	('Ewing sarcoma', 'Disease', (26, 39))	('CHK1', 'Gene', (106, 110))	('LY2603618', 'Chemical', 'MESH:C582547', (73, 82))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('muM', 'Gene', '56925', (197, 200))	('LY2603618', 'Var', (73, 82))	('muM', 'Gene', (197, 200))
146917	29152060	Supplementary Figure 7 shows that LY2603618 caused dose-dependent inhibition of CHK1-296 auto-phosphorylation, with maximum effect at drug concentrations > 200 nM.	('LY2603618', 'Chemical', 'MESH:C582547', (34, 43))	('CHK1-296', 'Protein', (80, 88))	('inhibition', 'NegReg', (66, 76))	('LY2603618', 'Var', (34, 43))
146918	29152060	We then treated Ewing sarcoma and osteosarcoma cells for 6 hours with 250 nM LY2603618 in combination with 10 nM gemcitabine, which is a gemcitabine concentration that does not affect cell viability when used in a 6-hour drug treatment (Figure 3D).	('gemcitabine', 'Chemical', 'MESH:C056507', (113, 124))	('LY2603618', 'Chemical', 'MESH:C582547', (77, 86))	('LY2603618', 'Var', (77, 86))	('gemcitabine', 'Chemical', 'MESH:C056507', (137, 148))	('osteosarcoma', 'Phenotype', 'HP:0002669', (34, 46))	('osteosarcoma', 'Disease', (34, 46))	('osteosarcoma', 'Disease', 'MESH:D012516', (34, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (16, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('Ewing sarcoma', 'Disease', (16, 29))
146921	29152060	Figure 4C shows that the addition of LY2603618 increased the sensitivity of two Ewing sarcoma cell lines to gemcitabine, with a ~5-fold reduction in IC50 values.	('LY2603618', 'Var', (37, 46))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('gemcitabine', 'Chemical', 'MESH:C056507', (108, 119))	('IC50 values', 'MPA', (149, 160))	('increased', 'PosReg', (47, 56))	('reduction', 'NegReg', (136, 145))	('Ewing sarcoma', 'Disease', (80, 93))	('sensitivity', 'MPA', (61, 72))	('LY2603618', 'Chemical', 'MESH:C582547', (37, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
146923	29152060	The combination of gemcitabine and LY2603618 demonstrated synergism (CI<0.9) in two Ewing sarcoma cell lines (EW8 and TC71) with CI values ranging from 0.18 to 0.83 (Figure 4D).	('Ewing sarcoma', 'Disease', (84, 97))	('EW8', 'CellLine', 'CVCL:V618', (110, 113))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('LY2603618', 'Var', (35, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('LY2603618', 'Chemical', 'MESH:C582547', (35, 44))	('TC71', 'CellLine', 'CVCL:2213', (118, 122))	('synergism', 'MPA', (58, 67))	('gemcitabine', 'Chemical', 'MESH:C056507', (19, 30))
146925	29152060	In contrast to the Ewing sarcoma cell lines, none of the control cell lines demonstrated toxicity with the combination of gemcitabine and LY2603618 when the drugs were used in a single, 6-hour treatment (Figure 4E).	('gemcitabine', 'Chemical', 'MESH:C056507', (122, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (19, 32))	('toxicity', 'Disease', (89, 97))	('LY2603618', 'Chemical', 'MESH:C582547', (138, 147))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (19, 32))	('LY2603618', 'Var', (138, 147))	('Ewing sarcoma', 'Disease', (19, 32))
146926	29152060	Similarly, long-term clonogenic assays showed that a 6-hour treatment with 10 nM gemcitabine and 250 nM LY2603618 significantly inhibited the growth of Ewing sarcoma (EW8 and TC71), but not osteosarcoma, cells (Figure 4F).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (152, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('inhibited', 'NegReg', (128, 137))	('LY2603618', 'Chemical', 'MESH:C582547', (104, 113))	('osteosarcoma', 'Disease', 'MESH:D012516', (190, 202))	('osteosarcoma', 'Phenotype', 'HP:0002669', (190, 202))	('Ewing sarcoma', 'Disease', (152, 165))	('osteosarcoma', 'Disease', (190, 202))	('EW8', 'CellLine', 'CVCL:V618', (167, 170))	('TC71', 'CellLine', 'CVCL:2213', (175, 179))	('LY2603618', 'Var', (104, 113))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))	('growth', 'MPA', (142, 148))
146929	29152060	Next, we tested the effect of 10 nM gemcitabine in combination with AZ20, as well as KU-55993 and a DNA-PK inhibitor (NU7441), on cell viability.	('KU-55993', 'Var', (85, 93))	('DNA-PK', 'Gene', (100, 106))	('DNA-PK', 'Gene', '5591', (100, 106))	('AZ20', 'Chemical', '-', (68, 72))	('gemcitabine', 'Chemical', 'MESH:C056507', (36, 47))	('KU-55993', 'Chemical', '-', (85, 93))	('tested', 'Reg', (9, 15))
146933	29152060	Consistent with this cell viability data, the combination of LY2603618 (250 nM) with 10 nM gemcitabine, but not 1 nM gemcitabine, caused robust phosphorylation of H2AX, a marker of DNA damage and double strand breaks (Figure 5A).	('phosphorylation', 'MPA', (144, 159))	('LY2603618', 'Var', (61, 70))	('gemcitabine', 'Chemical', 'MESH:C056507', (117, 128))	('H2AX', 'Gene', '3014', (163, 167))	('H2AX', 'Gene', (163, 167))	('gemcitabine', 'Chemical', 'MESH:C056507', (91, 102))	('LY2603618', 'Chemical', 'MESH:C582547', (61, 70))
146935	29152060	Figure 5B shows that the combination of LY2603618 with gemcitabine increases the phosphorylation of H2AX relative to treatment with either drug as a single agent.	('H2AX', 'Gene', (100, 104))	('phosphorylation', 'MPA', (81, 96))	('LY2603618', 'Var', (40, 49))	('H2AX', 'Gene', '3014', (100, 104))	('gemcitabine', 'Chemical', 'MESH:C056507', (55, 66))	('increases', 'PosReg', (67, 76))	('LY2603618', 'Chemical', 'MESH:C582547', (40, 49))
146936	29152060	Next, to use an orthogonal approach to block CHK1 function, we used siRNA to knockdown CHK1 and then treated cells with 10 nM gemcitabine for 6 hours.	('gemcitabine', 'Chemical', 'MESH:C056507', (126, 137))	('CHK1', 'Gene', (87, 91))	('knockdown', 'Var', (77, 86))
146942	29152060	In Ewing sarcoma cells, however, LY2603618 in combination with gemcitabine did not lead to abrogation of the cell cycle checkpoint or aberrant entry into mitosis (Supplementary Figure 8).	('cell cycle checkpoint', 'CPA', (109, 130))	('Ewing sarcoma', 'Disease', (3, 16))	('mitosis', 'Disease', (154, 161))	('gemcitabine', 'Chemical', 'MESH:C056507', (63, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('mitosis', 'Disease', 'None', (154, 161))	('LY2603618', 'Chemical', 'MESH:C582547', (33, 42))	('LY2603618', 'Var', (33, 42))
146943	29152060	We next tested whether gemcitabine and LY2603618 could inhibit the growth of tumor cells in a mouse xenograft experiment.	('tested', 'Reg', (8, 14))	('LY2603618', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mouse', 'Species', '10090', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('LY2603618', 'Chemical', 'MESH:C582547', (39, 48))	('tumor', 'Disease', (77, 82))	('inhibit', 'NegReg', (55, 62))	('gemcitabine', 'Chemical', 'MESH:C056507', (23, 34))
146944	29152060	The mice were then divided into cohorts and treated with vehicle, gemcitabine (150 mg/kg, intraperitoneal, once on day 1), LY2603618 (200 mg/kg, oral, once daily on days 1 and 2) and the combination of gemcitabine (day 1) and LY2603618 (day 1 and 2).	('LY2603618', 'Chemical', 'MESH:C582547', (226, 235))	('mice', 'Species', '10090', (4, 8))	('200 mg/kg', 'Var', (134, 143))	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('gemcitabine', 'Chemical', 'MESH:C056507', (202, 213))	('LY2603618', 'Var', (226, 235))	('LY2603618', 'Chemical', 'MESH:C582547', (123, 132))
146946	29152060	Notably, there was also a significant difference in survival between the mice treated with the combination of gemcitabine and LY2603618 as compared to vehicle, or either drug alone (Figure 6B).	('LY2603618', 'Chemical', 'MESH:C582547', (126, 135))	('mice', 'Species', '10090', (73, 77))	('gemcitabine', 'Chemical', 'MESH:C056507', (110, 121))	('LY2603618', 'Var', (126, 135))	('survival', 'CPA', (52, 60))
146964	29152060	We identified that the combination of gemcitabine with a CHK1 inhibitor (LY2603618) was more effective at inhibiting Ewing sarcoma cell growth than the combination of gemcitabine with an ATR inhibitor (AZ20).	('gemcitabine', 'Chemical', 'MESH:C056507', (38, 49))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (117, 130))	('CHK1', 'Gene', (57, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (117, 130))	('gemcitabine', 'Chemical', 'MESH:C056507', (167, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('inhibiting', 'NegReg', (106, 116))	('LY2603618', 'Chemical', 'MESH:C582547', (73, 82))	('Ewing sarcoma', 'Disease', (117, 130))	('AZ20', 'Chemical', '-', (202, 206))	('LY2603618', 'Var', (73, 82))	('ATR', 'Gene', '545', (187, 190))	('ATR', 'Gene', (187, 190))
146966	29152060	identified that CHK1 inhibitors induces cell death at a lower threshold of replication stress than ATR inhibitors.	('ATR', 'Gene', '545', (99, 102))	('ATR', 'Gene', (99, 102))	('cell death', 'CPA', (40, 50))	('inhibitors', 'Var', (21, 31))	('induces', 'Reg', (32, 39))	('CHK1', 'Gene', (16, 20))
146977	29152060	Or, EWSR1 translocations could mediate a dominant negative effect on endogenous EWSR1.	('translocations', 'Var', (10, 24))	('EWSR1', 'Gene', '2130', (4, 9))	('EWSR1', 'Gene', (80, 85))	('EWSR1', 'Gene', '2130', (80, 85))	('EWSR1', 'Gene', (4, 9))	('negative', 'NegReg', (50, 58))
146978	29152060	Furthermore, recent germline sequencing of patients with Ewing sarcoma identified enrichment for mutations in genes involved with DNA damage repair.	('mutations', 'Var', (97, 106))	('Ewing sarcoma', 'Disease', (57, 70))	('patients', 'Species', '9606', (43, 51))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))
146979	29152060	From a mechanistic standpoint, the treatment of Ewing sarcoma cells with LY2603618 in combination with gemcitabine did not lead to abrogation of the cell cycle checkpoint or aberrant entry into mitosis, as has been reported in other cell types, and the mechanism of apoptosis induction is the focus of ongoing work.	('mitosis', 'Disease', (194, 201))	('LY2603618', 'Chemical', 'MESH:C582547', (73, 82))	('Ewing sarcoma', 'Disease', (48, 61))	('gemcitabine', 'Chemical', 'MESH:C056507', (103, 114))	('mitosis', 'Disease', 'None', (194, 201))	('LY2603618', 'Var', (73, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('cell cycle checkpoint', 'CPA', (149, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (48, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (48, 61))
146988	29152060	Notably, in the mouse xenograft experiment (Figure 6), a single treatment with gemcitabine and LY2603618 resulted in a significant survival advantage compared to the control mice.	('LY2603618', 'Chemical', 'MESH:C582547', (95, 104))	('mice', 'Species', '10090', (174, 178))	('LY2603618', 'Var', (95, 104))	('gemcitabine', 'Chemical', 'MESH:C056507', (79, 90))	('survival advantage', 'CPA', (131, 149))	('mouse', 'Species', '10090', (16, 21))
147017	29152060	In the gemcitabine xenograft experiment, mice cohorts were treated with vehicle, gemcitabine (150 mg/kg, intraperitoneal, day 1), LY2603618 (200 mg/kg, oral gavage, days 1 and 2), or the combination of gemcitabine (150 mg/kg, intraperitoneal, day 1) and LY2603618 (200 mg/kg, oral gavage, days 1 and 2).	('LY2603618', 'Chemical', 'MESH:C582547', (130, 139))	('LY2603618', 'Var', (130, 139))	('gemcitabine', 'Chemical', 'MESH:C056507', (7, 18))	('gemcitabine', 'Chemical', 'MESH:C056507', (202, 213))	('mice', 'Species', '10090', (41, 45))	('LY2603618', 'Chemical', 'MESH:C582547', (254, 263))	('LY2603618', 'Var', (254, 263))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))	('150', 'Var', (94, 97))
147027	29152060	Antibodies to the following proteins were used in the immunoblots: phospho-Histone H2A.X (Ser139, Cell Signaling, #9718, 1:1000), phospho-Chk1 (Ser345, Cell Signaling, #2348, 1:1000), phospho-Chk1 (Ser317, Cell Signaling, #12302, 1:1000), phospho-Chk1 (Ser296, Cell Signaling, #12302, 1:1000), Chk1 (Cell Signaling, #2360, 1:1000), PARP (Cell Signaling, #9532, 1:1000), and tubulin (Proteintech, 66031-1, 1:2000).	('Ser296', 'Chemical', '-', (253, 259))	('PARP', 'Gene', (332, 336))	('Chk1', 'Gene', (294, 298))	('Chk1', 'Gene', (247, 251))	('Chk1', 'Gene', (192, 196))	('#12302', 'Var', (277, 283))	('Chk1', 'Gene', '1111', (294, 298))	('Ser296', 'Var', (253, 259))	('Chk1', 'Gene', '1111', (192, 196))	('Chk1', 'Gene', '1111', (247, 251))	('PARP', 'Gene', '142', (332, 336))	('Chk1', 'Gene', (138, 142))	('Chk1', 'Gene', '1111', (138, 142))
147030	25263539	Initial Testing (Stage 1) of the PARP Inhibitor BMN 673 by the Pediatric Preclinical Testing Program: PALB2 Mutation Predicts Exceptional in Vivo Response to BMN 673 BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers.	('poly-ADP ribose polymerase', 'Gene', '142', (199, 225))	('BRCA', 'Gene', '672', (285, 289))	('PALB2', 'Gene', '79728', (102, 107))	('BMN 673', 'Chemical', 'MESH:C586365', (48, 55))	('PARP', 'Gene', '142', (33, 37))	('PALB2', 'Gene', (102, 107))	('BRCA', 'Gene', (285, 289))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('PARP', 'Gene', (227, 231))	('cancers', 'Disease', (298, 305))	('BMN 673', 'Chemical', 'MESH:C586365', (166, 173))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('BMN 673', 'Chemical', 'MESH:C586365', (158, 165))	('Mutation', 'Var', (108, 116))	('PARP', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('poly-ADP ribose polymerase', 'Gene', (199, 225))	('PARP', 'Gene', '142', (227, 231))
147037	25263539	KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair.	('mutations', 'Var', (66, 75))	('PALB2', 'Gene', '79728', (41, 46))	('PALB2', 'Gene', '79728', (60, 65))	('PALB2', 'Gene', (60, 65))	('associated', 'Reg', (76, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('abrogate', 'NegReg', (134, 142))	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (92, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PALB2', 'Gene', (41, 46))
147038	25263539	The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers.	('BMN 673', 'Chemical', 'MESH:C586365', (43, 50))	('BMN', 'Var', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PPTP', 'Chemical', '-', (4, 8))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
147040	25263539	The observation that cancer cells defective in homologous recombination as a consequence of BRCA1 or BRCA2 mutations are hypersensitive to inhibitors of poly-ADP ribose polymerase (PARP) has spurred the development of PARP inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('BRCA2', 'Gene', (101, 106))	('mutations', 'Var', (107, 116))	('hypersensitive', 'Disease', (121, 135))	('poly-ADP ribose polymerase', 'Gene', (153, 179))	('BRCA2', 'Gene', '675', (101, 106))	('BRCA1', 'Gene', '672', (92, 97))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('poly-ADP ribose polymerase', 'Gene', '142', (153, 179))	('BRCA1', 'Gene', (92, 97))	('hypersensitive', 'Disease', 'MESH:D004342', (121, 135))
147044	25263539	Inhibition of PARP-1 catalytic activity results in trapping of the enzyme on DNA, as catalytic inhibitors prevent dissociation of PARP from DNA that is required for completion of DNA repair.	('dissociation', 'MPA', (114, 126))	('PARP-1', 'Gene', (14, 20))	('PARP-1', 'Gene', '142', (14, 20))	('results in', 'Reg', (40, 50))	('Inhibition', 'Var', (0, 10))	('trapping', 'MPA', (51, 59))
147049	25263539	Like other PARP inhibitors such as rucaparib, veliparib, and olaparib, BMN 673 shows inhibition of PARP catalytic activity at nanomolar concentrations, but the cytotoxic potency of BMN 673 exceeds that of these other PARP inhibitors by a factor of 10-fold or greater.	('olaparib', 'Chemical', 'MESH:C531550', (61, 69))	('BMN 673', 'Var', (181, 188))	('BMN 673', 'Chemical', 'MESH:C586365', (181, 188))	('inhibition', 'NegReg', (85, 95))	('PARP', 'Enzyme', (99, 103))	('BMN 673', 'Chemical', 'MESH:C586365', (71, 78))	('veliparib', 'Chemical', 'MESH:C521013', (46, 55))	('rucaparib', 'Chemical', 'MESH:C531549', (35, 44))
147051	25263539	Impressive antitumor activity was observed in BRCA-mutated patients with ovarian cancer and breast cancer, and a phase 3 clinical trial is evaluating BMN 673 for patients with germline BRCA mutations and locally advanced and/or metastatic breast cancer (NCT01945775).	('breast cancer', 'Disease', (239, 252))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('BRCA', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('mutations', 'Var', (190, 199))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('ovarian cancer', 'Disease', 'MESH:D010051', (73, 87))	('BMN 673', 'Chemical', 'MESH:C586365', (150, 157))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('patients', 'Species', '9606', (162, 170))	('BRCA', 'Gene', '672', (185, 189))	('breast cancer', 'Disease', (92, 105))	('tumor', 'Disease', (15, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('ovarian cancer', 'Disease', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('BRCA', 'Gene', (185, 189))	('metastatic', 'CPA', (228, 238))	('BRCA', 'Gene', '672', (46, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
147055	25263539	Cells were incubated in the presence of BMN 673 for 96 hours at concentrations from 0.1 nM to 1 muM and analyzed as previously described.	('muM', 'Gene', '56925', (96, 99))	('BMN 673', 'Chemical', 'MESH:C586365', (40, 47))	('muM', 'Gene', (96, 99))	('BMN', 'Var', (40, 43))
147077	25263539	Cell lines with high expression of SLFN11 show near complete cytotoxicity (median Relative I/O% = -88%) while those with low expression show significantly higher Relative I/O% values consistent with cytostasis (median Relative I/O% = +4%) (p=0.006) (Figure 1B).	('high expression', 'Var', (16, 31))	('cytotoxicity', 'Disease', (61, 73))	('SLFN11', 'Gene', (35, 41))	('SLFN11', 'Gene', '91607', (35, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('higher', 'PosReg', (155, 161))
147083	25263539	Complete details of testing are provided in Supplemental Table I. BMN 673 induced statistically significant differences in EFS distribution compared to control in 17 of 35 (48.6%) of the solid tumor xenografts evaluable for this measure and in 0 of 8 (0%) of the evaluable ALL xenografts Table II.	('BMN 673', 'Var', (66, 73))	('solid tumor', 'Disease', 'MESH:D009369', (187, 198))	('BMN 673', 'Chemical', 'MESH:C586365', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('differences', 'Reg', (108, 119))	('EFS distribution', 'MPA', (123, 139))	('solid tumor', 'Disease', (187, 198))
147086	25263539	BMN 673 induced tumor growth inhibition meeting criteria for intermediate/high EFS T/C activity in 2 of 32 (6.3%) solid tumor xenografts evaluable for this measure.	('solid tumor', 'Disease', 'MESH:D009369', (114, 125))	('BMN 673', 'Chemical', 'MESH:C586365', (0, 7))	('activity', 'MPA', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BMN', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('solid tumor', 'Disease', (114, 125))	('tumor', 'Disease', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
147093	25263539	For BT-45, mutations expected for the WNT subtype of medulloblastoma are observed, including a CTNNB1 mutation (G34R) and a TP53 mutation (R248W).	('CTNNB1', 'Gene', (95, 101))	('medulloblastoma', 'Disease', (53, 68))	('TP53', 'Gene', '7157', (124, 128))	('BT-45', 'Gene', (4, 9))	('G34R', 'Mutation', 'rs121913399', (112, 116))	('medulloblastoma', 'Disease', 'MESH:D008527', (53, 68))	('TP53', 'Gene', (124, 128))	('R248W', 'Mutation', 'rs121912651', (139, 144))	('CTNNB1', 'Gene', '1499', (95, 101))	('R248W', 'Var', (139, 144))	('G34R', 'Var', (112, 116))	('medulloblastoma', 'Phenotype', 'HP:0002885', (53, 68))
147094	25263539	For KT-10, the key finding is a frameshift mutation in Partner And Localizer of BRCA2 (PALB2) (c.3323delA leading to p.Y1108fs and to subsequent creation of a p.Stop(*)1122).	('p.Y1108fs', 'Mutation', 'rs180177135', (117, 126))	('BRCA2', 'Gene', (80, 85))	('c.3323delA', 'Mutation', 'rs180177135', (95, 105))	('BRCA2', 'Gene', '675', (80, 85))	('p.Stop', 'Var', (159, 165))	('PALB2', 'Gene', '79728', (87, 92))	('p.Y1108fs', 'Var', (117, 126))	('c.3323delA', 'Var', (95, 105))	('PALB2', 'Gene', (87, 92))
147095	25263539	The nucleotide and amino acid sequence of the normal and mutated PALB2 are shown in Supplemental Table III.	('mutated', 'Var', (57, 64))	('PALB2', 'Gene', (65, 70))	('PALB2', 'Gene', '79728', (65, 70))
147096	25263539	The mutation occurs in exon 12 of PALB2 and is homozygous or hemizyous as virtually all PALB2 reads are for the mutated rather than the wild type allele.	('PALB2', 'Gene', '79728', (88, 93))	('PALB2', 'Gene', (88, 93))	('PALB2', 'Gene', (34, 39))	('PALB2', 'Gene', '79728', (34, 39))	('mutated', 'Var', (112, 119))
147097	25263539	Figure 4 shows the Y1108fs mutation identified for KT-10 xenografts as well as other cancer or Fanconi anemia associated PALB2 mutations reported in the literature, nonsense or frameshift mutations are commonly observed.	('PALB2', 'Gene', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('anemia', 'Phenotype', 'HP:0001903', (103, 109))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (95, 109))	('Y1108fs', 'Mutation', 'rs180177135', (19, 26))	('cancer', 'Disease', (85, 91))	('Fanconi anemia', 'Disease', (95, 109))	('nonsense', 'Var', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('PALB2', 'Gene', '79728', (121, 126))	('Fanconi anemia', 'Disease', 'MESH:D005199', (95, 109))	('Y1108fs', 'Var', (19, 26))
147098	25263539	Of specific relevance to the KT-10 mutation, those that lead to loss of the WD40 domains in the C-terminus of the protein block the ability of PALB2 to associate with BRCA2 and are associated with Fanconi anemia and non-BRCA1/BRCA2 hereditary breast cancer.	('BRCA2', 'Gene', '675', (226, 231))	('BRCA2', 'Gene', (167, 172))	('PALB2', 'Gene', (143, 148))	('mutation', 'Var', (35, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('Fanconi anemia', 'Disease', (197, 211))	('anemia', 'Phenotype', 'HP:0001903', (205, 211))	('PALB2', 'Gene', '79728', (143, 148))	('Fanconi anemia', 'Disease', 'MESH:D005199', (197, 211))	('BRCA2', 'Gene', '675', (167, 172))	('block', 'NegReg', (122, 127))	('KT-10', 'Gene', (29, 34))	('loss', 'NegReg', (64, 68))	('associate', 'Interaction', (152, 161))	('BRCA2', 'Gene', (226, 231))	('non-BRCA1/BRCA2 hereditary breast cancer', 'Disease', 'MESH:D001943', (216, 256))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (197, 211))	('associated with', 'Reg', (181, 196))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('non-BRCA1/BRCA2 hereditary breast cancer', 'Disease', (216, 256))	('ability', 'MPA', (132, 139))
147099	25263539	The c.3323delA (Y1108fs) mutation has been reported in a child with Fanconi anemia who developed Wilms tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('Wilms tumor', 'Disease', (97, 108))	('Wilms tumor', 'Disease', 'MESH:D009396', (97, 108))	('Y1108fs', 'Mutation', 'rs180177135', (16, 23))	('c.3323delA (Y1108fs', 'Var', (4, 23))	('child', 'Species', '9606', (57, 62))	('anemia', 'Phenotype', 'HP:0001903', (76, 82))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (68, 82))	('Fanconi anemia', 'Disease', (68, 82))	('c.3323delA', 'Mutation', 'rs180177135', (4, 14))	('Fanconi anemia', 'Disease', 'MESH:D005199', (68, 82))	('Wilms tumor', 'Phenotype', 'HP:0002667', (97, 108))
147101	25263539	Relative to other cancer cell lines Ewing sarcoma cells were also reported to be sensitive to PARP inhibition, with IC50 values comparable to those for BRCA1 mutant cell lines.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('BRCA1', 'Gene', '672', (152, 157))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('inhibition', 'NegReg', (99, 109))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('PARP', 'Protein', (94, 98))	('BRCA1', 'Gene', (152, 157))	('mutant', 'Var', (158, 164))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('Ewing sarcoma', 'Disease', (36, 49))
147110	25263539	Our results showing a primary effect on Relative I/O% rather than rIC50 suggest that the primary effect of SLFN11 expression is in promoting a cytotoxic rather than a cytostatic response to PARP inhibition.	('expression', 'Var', (114, 124))	('cytotoxic', 'CPA', (143, 152))	('SLFN11', 'Gene', '91607', (107, 113))	('promoting', 'PosReg', (131, 140))	('SLFN11', 'Gene', (107, 113))
147112	25263539	Loss of 53BP1 has been shown to confer resistance to the PARP inhibitor olaparib in a BRCA-deficient mouse model of breast cancer, however, there was no obvious relationship between in vitro or in vivo sensitivity with expression levels of 53BP1 or p53 genotype.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('resistance', 'MPA', (39, 49))	('53BP1', 'Gene', (240, 245))	('mouse', 'Species', '10090', (101, 106))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('53BP1', 'Gene', '27223', (240, 245))	('BRCA-deficient', 'Disease', (86, 100))	('olaparib', 'Chemical', 'MESH:C531550', (72, 80))	('BRCA-deficient', 'Disease', 'OMIM:604370', (86, 100))	('Loss', 'Var', (0, 4))	('53BP1', 'Gene', (8, 13))	('53BP1', 'Gene', '27223', (8, 13))
147115	25263539	There were three solid tumors that regressed to treatment with BMN 673, KT-10 (Wilms tumor) and BT-45 (medulloblastoma) and BT-41 (ependymoma).	('BT-45', 'Gene', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('medulloblastoma', 'Disease', 'MESH:D008527', (103, 118))	('BMN', 'Var', (63, 66))	('medulloblastoma', 'Phenotype', 'HP:0002885', (103, 118))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('medulloblastoma', 'Disease', (103, 118))	('ependymoma', 'Disease', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Wilms tumor', 'Disease', 'MESH:D009396', (79, 90))	('BT-41', 'Var', (124, 129))	('ependymoma', 'Phenotype', 'HP:0002888', (131, 141))	('solid tumors', 'Disease', (17, 29))	('BT-41', 'Chemical', '-', (124, 129))	('BMN 673', 'Chemical', 'MESH:C586365', (63, 70))	('Wilms tumor', 'Phenotype', 'HP:0002667', (79, 90))	('ependymoma', 'Disease', 'MESH:D004806', (131, 141))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('Wilms tumor', 'Disease', (79, 90))
147119	25263539	We did not observe mutations affecting HR repair in BT-45, although we did observe CTNNB1 and TP53 mutations suggesting that this xenograft represents the WNT subtype of medulloblastoma.	('medulloblastoma', 'Disease', (170, 185))	('CTNNB1', 'Gene', '1499', (83, 89))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('CTNNB1', 'Gene', (83, 89))	('medulloblastoma', 'Disease', 'MESH:D008527', (170, 185))	('medulloblastoma', 'Phenotype', 'HP:0002885', (170, 185))
147121	25263539	Hence, predictive factors for cisplatin sensitivity extend beyond HR repair gene mutations.	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('HR repair gene', 'Gene', (66, 80))	('mutations', 'Var', (81, 90))
147123	25263539	Consistent with the sensitivity of KT-10 to both BMN 673 and to cisplatin, we identified a frameshift mutation in KT-10 in the gene, PALB2.	('PALB2', 'Gene', '79728', (133, 138))	('PALB2', 'Gene', (133, 138))	('KT-10', 'Gene', (114, 119))	('BMN 673', 'Chemical', 'MESH:C586365', (49, 56))	('frameshift mutation', 'Var', (91, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
147125	25263539	Truncation in the C-terminal end of PALB2 results in loss of its BRCA2 binding ability, leading to defective HR repair and sensitivity to chromosomal breakage induced by DNA cross-linking agents such as mitomycin C. The presence of biallelic mutations in PALB2 leads to Fanconi anemia, and an alias for PALB2 is FANC-N.	('anemia', 'Phenotype', 'HP:0001903', (278, 284))	('PALB2', 'Gene', (303, 308))	('Fanconi anemia', 'Disease', (270, 284))	('chromosomal breakage', 'Phenotype', 'HP:0040012', (138, 158))	('loss', 'NegReg', (53, 57))	('PALB2', 'Gene', '79728', (255, 260))	('Fanconi anemia', 'Disease', 'MESH:D005199', (270, 284))	('alias', 'Disease', (293, 298))	('PALB2', 'Gene', '79728', (303, 308))	('FANC-N', 'Gene', '79728', (312, 318))	('BRCA2', 'Gene', '675', (65, 70))	('leads to', 'Reg', (261, 269))	('mitomycin C', 'Chemical', 'MESH:D016685', (203, 214))	('alias', 'Disease', 'None', (293, 298))	('presence', 'Var', (220, 228))	('biallelic mutations', 'Var', (232, 251))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (270, 284))	('PALB2', 'Gene', (36, 41))	('binding', 'Interaction', (71, 78))	('PALB2', 'Gene', '79728', (36, 41))	('BRCA2', 'Gene', (65, 70))	('FANC-N', 'Gene', (312, 318))	('PALB2', 'Gene', (255, 260))
147126	25263539	Likewise, mutations in PALB2 that disrupt binding with BRCA2 are associated with hereditary breast cancer, and germline truncating mutations in PALB2 are observed in pancreatic cancer and ovarian cancer.	('PALB2', 'Gene', (23, 28))	('pancreatic cancer', 'Disease', (166, 183))	('associated', 'Reg', (65, 75))	('ovarian cancer', 'Disease', (188, 202))	('PALB2', 'Gene', '79728', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('PALB2', 'Gene', '79728', (23, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))	('BRCA2', 'Gene', (55, 60))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (81, 105))	('binding', 'Interaction', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ovarian cancer', 'Disease', 'MESH:D010051', (188, 202))	('BRCA2', 'Gene', '675', (55, 60))	('observed', 'Reg', (154, 162))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('PALB2', 'Gene', (144, 149))	('hereditary breast cancer', 'Disease', (81, 105))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
147127	25263539	The frameshift mutation that we observed in KT-10 has previously been reported for a patient with Fanconi anemia, confirming the pathogenic nature of the mutation.	('patient', 'Species', '9606', (85, 92))	('frameshift mutation', 'Var', (4, 23))	('anemia', 'Phenotype', 'HP:0001903', (106, 112))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (98, 112))	('reported', 'Reg', (70, 78))	('Fanconi anemia', 'Disease', (98, 112))	('Fanconi anemia', 'Disease', 'MESH:D005199', (98, 112))	('KT-10', 'Gene', (44, 49))
147128	25263539	Our results suggest that PALB2 mutations will behave similarly to BRCA1 and BRCA2 mutations in inducing synthetic lethality with PARP inhibition.	('PARP inhibition', 'MPA', (129, 144))	('mutations', 'Var', (31, 40))	('BRCA2', 'Gene', (76, 81))	('BRCA1', 'Gene', '672', (66, 71))	('synthetic lethality', 'MPA', (104, 123))	('BRCA1', 'Gene', (66, 71))	('BRCA2', 'Gene', '675', (76, 81))	('inducing', 'Reg', (95, 103))	('PALB2', 'Gene', '79728', (25, 30))	('PALB2', 'Gene', (25, 30))
147129	25263539	This observation is consistent with several prior reports describing in vitro sensitivity of PALB2 mutations to PARP inhibition.	('mutations', 'Var', (99, 108))	('PALB2', 'Gene', '79728', (93, 98))	('PALB2', 'Gene', (93, 98))
147131	25263539	Additionally, a patient with pancreatic cancer and with biallelically inactivated PALB2 showed a favorable response to mitomycin C, consistent with an HR repair defect.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('mitomycin C', 'Chemical', 'MESH:D016685', (119, 130))	('PALB2', 'Gene', (82, 87))	('PALB2', 'Gene', '79728', (82, 87))	('biallelically inactivated', 'Var', (56, 81))	('pancreatic cancer', 'Disease', (29, 46))	('pancreatic cancer', 'Disease', 'MESH:D010190', (29, 46))	('response to mitomycin C', 'MPA', (107, 130))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('patient', 'Species', '9606', (16, 23))
147133	25263539	The observation of a PALB2 mutation in Wilms tumor is consistent with the cancer spectrum associated with Fanconi anemia.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Wilms tumor', 'Disease', 'MESH:D009396', (39, 50))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('Wilms tumor', 'Phenotype', 'HP:0002667', (39, 50))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (106, 120))	('cancer', 'Disease', (74, 80))	('Wilms tumor', 'Disease', (39, 50))	('mutation', 'Var', (27, 35))	('Fanconi anemia', 'Disease', (106, 120))	('PALB2', 'Gene', (21, 26))	('anemia', 'Phenotype', 'HP:0001903', (114, 120))	('PALB2', 'Gene', '79728', (21, 26))	('Fanconi anemia', 'Disease', 'MESH:D005199', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
147134	25263539	Wilms tumor and medulloblastoma are the cancers most commonly reported in patients with Fanconi anemia and biallelic PALB2 mutations.	('Fanconi anemia', 'Phenotype', 'HP:0001994', (88, 102))	('medulloblastoma', 'Phenotype', 'HP:0002885', (16, 31))	('Wilms tumor', 'Disease', 'MESH:D009396', (0, 11))	('anemia', 'Phenotype', 'HP:0001903', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('Fanconi anemia', 'Disease', (88, 102))	('patients', 'Species', '9606', (74, 82))	('medulloblastoma are the cancers', 'Disease', 'MESH:D008527', (16, 47))	('Wilms tumor', 'Disease', (0, 11))	('medulloblastoma are the cancers', 'Disease', (16, 47))	('Fanconi anemia', 'Disease', 'MESH:D005199', (88, 102))	('PALB2', 'Gene', (117, 122))	('Wilms tumor', 'Phenotype', 'HP:0002667', (0, 11))	('PALB2', 'Gene', '79728', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('biallelic', 'Var', (107, 116))	('mutations', 'Var', (123, 132))
147135	25263539	Children with Fanconi anemia and biallelic BRCA2 mutations who develop cancer also show a predominance of Wilms tumor and medulloblastoma.	('biallelic', 'Var', (33, 42))	('Wilms tumor', 'Disease', 'MESH:D009396', (106, 117))	('BRCA2', 'Gene', '675', (43, 48))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', (71, 77))	('Wilms tumor', 'Phenotype', 'HP:0002667', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('anemia', 'Phenotype', 'HP:0001903', (22, 28))	('Fanconi anemia', 'Disease', (14, 28))	('Children', 'Species', '9606', (0, 8))	('Fanconi anemia', 'Disease', 'MESH:D005199', (14, 28))	('Wilms tumor', 'Disease', (106, 117))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('medulloblastoma', 'Disease', 'MESH:D008527', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('medulloblastoma', 'Phenotype', 'HP:0002885', (122, 137))	('BRCA2', 'Gene', (43, 48))	('medulloblastoma', 'Disease', (122, 137))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (14, 28))
147138	25263539	This caveat would likely not apply to patients heterozygous for PALB2 mutations who develop cancer as part of a BRCA-like predisposition syndrome.	('BRCA', 'Gene', (112, 116))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('PALB2', 'Gene', '79728', (64, 69))	('PALB2', 'Gene', (64, 69))	('patients', 'Species', '9606', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA', 'Gene', '672', (112, 116))
147144	25263539	BMN 673 single agent activity is more likely for patients whose tumors have defects in HR repair such as the PALB2 mutation that we describe, with the activity profile likely overlapping that of single agent cisplatin.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('BMN 673', 'Chemical', 'MESH:C586365', (0, 7))	('defects', 'NegReg', (76, 83))	('PALB2', 'Gene', '79728', (109, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (208, 217))	('PALB2', 'Gene', (109, 114))	('patients', 'Species', '9606', (49, 57))	('mutation', 'Var', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
147145	25263539	PALB2 mutations represent a small proportion of hereditary breast, pancreatic, and ovarian cancer cases, and our results suggest the potential utility of BMN 673 for these patients.	('BMN 673', 'Chemical', 'MESH:C586365', (154, 161))	('hereditary breast, pancreatic, and ovarian cancer', 'Disease', 'MESH:D061325', (48, 97))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('PALB2', 'Gene', '79728', (0, 5))	('PALB2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (172, 180))	('mutations', 'Var', (6, 15))
147295	31900276	Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('anti-PD-1', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('sarcomas', 'Disease', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('enhance', 'PosReg', (84, 91))	('sarcomas', 'Disease', 'MESH:D012509', (158, 166))
147371	31900276	Such studies have, to date, been largely retrospective with some studies reporting worse patient outcomes associated with tumor PD-L1 expression, others reporting better patient outcomes associated tumor PD-L1 expression, and yet other studies reporting no association between patient survival and tumor PD-L1 expression.	('PD-L1', 'Gene', (128, 133))	('tumor', 'Disease', (298, 303))	('patient', 'Species', '9606', (89, 96))	('patient', 'Species', '9606', (277, 284))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('expression', 'Var', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (122, 127))	('patient', 'Species', '9606', (170, 177))
147463	28826404	PERSIST-5, a phase II single-arm study, investigated the value of extending post-operative treatment for gastrointestinal stromal tumours (GISTs) with imatinib for up to 5 years in 91 patients with high risk of recurrence and confirmed imatinib effectiveness in preventing recurrence in patients with sensitive mutations; among seven relapsing patients, only one progressed (D842V mutation).	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (105, 137))	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('gastrointestinal stromal tumours', 'Disease', (105, 137))	('D842V mutation', 'Var', (375, 389))	('patients', 'Species', '9606', (184, 192))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('patients', 'Species', '9606', (287, 295))	('imatinib', 'Chemical', 'MESH:D000068877', (236, 244))	('mutations', 'Var', (311, 320))	('D842V', 'Mutation', 'p.D842V', (375, 380))	('recurrence', 'Disease', (273, 283))	('imatinib', 'Chemical', 'MESH:D000068877', (151, 159))	('patients', 'Species', '9606', (344, 352))
147469	28826404	Aldoxorubicin was associated with minimal cardiotoxicity (up to 40 cycles) compared to doxorubicin and with a significantly lower incidence of alopecia.	('doxorubicin', 'Chemical', 'MESH:D004317', (2, 13))	('Aldoxorubicin', 'Var', (0, 13))	('cardiotoxicity', 'Disease', 'MESH:D066126', (42, 56))	('alopecia', 'Phenotype', 'HP:0001596', (143, 151))	('cardiotoxicity', 'Disease', (42, 56))	('alopecia', 'Disease', 'MESH:D000505', (143, 151))	('Aldoxorubicin', 'Chemical', 'MESH:C575867', (0, 13))	('lower', 'NegReg', (124, 129))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))	('alopecia', 'Disease', (143, 151))
147484	28826404	A major breakthrough in the field of advanced GIST was achieved by a phase I study assessing the safety and activity of BLU-285 in refractory or primary PDGFRalpha D842V-mutated GIST.	('BLU', 'Gene', '51364', (120, 123))	('D842V-mutated', 'Var', (164, 177))	('BLU', 'Gene', (120, 123))	('D842V', 'Mutation', 'p.D842V', (164, 169))
147485	28826404	BLU-285 is a selective oral inhibitor that targets KIT Exon 17 and PDGFRalpha D842 activation loop mutants, reported to be well tolerated and associated with a RR of 18% in refractory KIT patients.	('patients', 'Species', '9606', (188, 196))	('BLU', 'Gene', (0, 3))	('BLU', 'Gene', '51364', (0, 3))	('PDGFRalpha D842', 'Gene', (67, 82))	('mutants', 'Var', (99, 106))
147496	28826404	NY-ESO-1 positivity was found to correlate with favourable PFS on standard treatment.	('NY-ESO-1', 'Gene', (0, 8))	('NY-ESO-1', 'Gene', '1485', (0, 8))	('positivity', 'Var', (9, 19))	('favourable PFS', 'Disease', (48, 62))	('PFS', 'Disease', (59, 62))
147503	28826404	Similarly, in the French retrospective experience of 587 STS patients, 93% had at least one targetable mutation, copy number alteration and/or fusion gene.	('copy number alteration', 'Var', (113, 135))	('patients', 'Species', '9606', (61, 69))	('fusion gene', 'Var', (143, 154))
147504	28826404	The significant proportion of actionable alterations detected in these two series could lead to the implementation of NGS for clinical decision-making in patients with advanced STS.	('patients', 'Species', '9606', (154, 162))	('alterations', 'Var', (41, 52))	('lead to', 'Reg', (88, 95))
147506	28826404	reported on 117 prospectively tested patients; NGS was found to influence clinical decision-making in 79% of patients and actionable mutations were identified in 81%; thus, the development of a GIST-specific panel might be of interest.	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (37, 45))	('NGS', 'Var', (47, 50))	('clinical decision-making', 'CPA', (74, 98))	('influence', 'Reg', (64, 73))
147514	28103823	Sarcomatous change of carcinoma occurs in the case of sarcomatoid cancer, and phenotypic changes to sarcomatoid cancer are associated with the addition of mutation patterns and derived from poorly differentiation tumor.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Sarcomatous change of carcinoma', 'Disease', (0, 31))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutation patterns', 'Var', (155, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('Sarcomatous change', 'Phenotype', 'HP:0100242', (0, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('sarcomatoid cancer', 'Phenotype', 'HP:0100242', (54, 72))	('tumor', 'Disease', (213, 218))	('sarcomatoid cancer', 'Disease', (54, 72))	('associated', 'Reg', (123, 133))	('sarcomatoid cancer', 'Phenotype', 'HP:0100242', (100, 118))	('sarcomatoid cancer', 'Disease', (100, 118))	('sarcomatoid cancer', 'Disease', 'MESH:C538614', (54, 72))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('Sarcomatous change of carcinoma', 'Disease', 'MESH:D018316', (0, 31))	('sarcomatoid cancer', 'Disease', 'MESH:C538614', (100, 118))
147530	28103823	In total, there were 26 mutations found in the cancer (Fig.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
147531	28103823	Common missense mutations in TP53 and KRAS genes were detected in the portion A, B and C (Table 1, Fig.	('KRAS', 'Gene', '3845', (38, 42))	('detected', 'Reg', (54, 62))	('missense mutations', 'Var', (7, 25))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('KRAS', 'Gene', (38, 42))
147539	28103823	In our case, comparative genetic analysis of different histological areas revealed intratumoral homogeneity for some mutations.	('rat', 'Species', '10116', (18, 21))	('mutations', 'Var', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('rat', 'Species', '10116', (86, 89))
147543	28103823	From the phylogenetic analyses, it can be concluded that stepwise addition of genetic changes caused the sarcomatous change in this cancer.	('cancer', 'Disease', (132, 138))	('sarcomatous change', 'Disease', 'MESH:D018316', (105, 123))	('sarcomatous change', 'Disease', (105, 123))	('caused', 'Reg', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('sarcomatous change', 'Phenotype', 'HP:0100242', (105, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('genetic changes', 'Var', (78, 93))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
147546	28103823	The different histological components in lung cancer result from genetic divergence.	('genetic divergence', 'Var', (65, 83))	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))	('result from', 'Reg', (53, 64))
147571	31799501	We used BrafV600E/Pten-/- (BP) mice, which develop spatially restricted melanoma upon tamoxifen application, and KrasLSL-G12D/+;p53fl/fl (KP) mice, which develop spatially restricted soft tissue sarcoma upon intramuscular administration of adenovirus expressing Cre (AdCre).	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (183, 202))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('Kras', 'Gene', (113, 117))	('G12D', 'Mutation', 'rs121913529', (121, 125))	('melanoma', 'Disease', (72, 80))	('Kras', 'Gene', '16653', (113, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('BrafV600E', 'Mutation', 'rs113488022', (8, 17))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('soft tissue sarcoma', 'Disease', (183, 202))	('mice', 'Species', '10090', (142, 146))	('mice', 'Species', '10090', (31, 35))	('tamoxifen', 'Chemical', 'MESH:D013629', (86, 95))	('rat', 'Species', '10116', (230, 233))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (183, 202))	('BrafV600E/Pten-/-', 'Var', (8, 25))
147584	31799501	We also evaluated LTX-315 treatment in the genetically induced BrafV600E/Pten-/- (BP) melanoma mouse model (Fig.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('LTX', 'Gene', '16992', (18, 21))	('BrafV600E/Pten-/-', 'Var', (63, 80))	('BrafV600E', 'Mutation', 'rs113488022', (63, 72))	('LTX', 'Gene', (18, 21))	('mouse', 'Species', '10090', (95, 100))
147592	31799501	By contrast, tumors in mice that were either left untreated or that received anti-PD-1 and anti-CTLA-4 continuously grew.	('CTLA-4', 'Gene', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('CTLA-4', 'Gene', '12477', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('anti-PD-1', 'Var', (77, 86))	('mice', 'Species', '10090', (23, 27))
147606	31799501	Specifically, mice were implanted with B16F10 tumors expressing green fluorescent protein (GFP) and injected intravenously with the blood pool agent Dextran-VT680 around ten minutes before LTX-315 administration in B16F10-GFP tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('LTX', 'Gene', '16992', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('rat', 'Species', '10116', (205, 208))	('tumors', 'Disease', (226, 232))	('mice', 'Species', '10090', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('B16F10-GFP', 'Var', (215, 225))	('LTX', 'Gene', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
147654	31799501	In addition to B16F10, we used the BrafV600E/Pten-/- (BP) model because melanoma tumors in this model carry mutations that are often found in the human disease and arise directly from somatic cells that are transformed in their normal tissue microenvironment.	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('mutations', 'Var', (108, 117))	('melanoma tumors', 'Disease', 'MESH:D008545', (72, 87))	('human', 'Species', '9606', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('BrafV600E', 'Mutation', 'rs113488022', (35, 44))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('melanoma tumors', 'Disease', (72, 87))
147668	31799501	The particularly low mutational load of KP tumors might make them less immunogenic when compared to BP tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('BP tumors', 'Disease', (100, 109))	('KP tumors', 'Disease', 'MESH:D009369', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('KP tumors', 'Disease', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('mutational', 'Var', (21, 31))	('BP tumors', 'Disease', 'MESH:D009369', (100, 109))
147746	31799501	Sections were immunostained with anti-human CD3 and anti-human CD8, respectively (clones from HalioDx).	('anti-human', 'Var', (33, 43))	('human', 'Species', '9606', (38, 43))	('CD3', 'Gene', '12501', (44, 47))	('anti-human', 'Var', (52, 62))	('CD8', 'Gene', (63, 66))	('CD8', 'Gene', '925', (63, 66))	('CD3', 'Gene', (44, 47))	('human', 'Species', '9606', (57, 62))
147753	31799501	BP - BrafV600E/Pten-/-, GFP - green fluorescence protein, KP - KrasLSL-G12D/+;p53fl/fl, NK - natural killer.	('p53fl/fl', 'Var', (78, 86))	('BrafV600E', 'Mutation', 'rs113488022', (5, 14))	('G12D', 'Mutation', 'rs121913529', (71, 75))	('Kras', 'Gene', '16653', (63, 67))	('Kras', 'Gene', (63, 67))
147926	31407171	The mean MSTS for the amputation patients ranged from 41.1% to 71% versus 70% to 76.6% for the patients with limb-sparing procedures, which is lower than the result of the current review.	('STS', 'Disease', (10, 13))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (95, 103))	('amputation', 'Var', (22, 32))	('STS', 'Disease', 'MESH:D012509', (10, 13))	('STS', 'Phenotype', 'HP:0030448', (10, 13))
147936	25204415	The landscape of kinase fusions in cancer Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells.	('deregulation', 'MPA', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Human', 'Species', '9606', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('rat', 'Species', '10116', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('key pathways', 'Pathway', (127, 139))	('cancer', 'Disease', (48, 54))	('alterations', 'Var', (84, 95))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (143, 149))	('cancer', 'Disease', (35, 41))	('fusions', 'Var', (24, 31))
147940	25204415	Kinases activated by gene fusions represent potentially important targets for the development of cancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gene fusions', 'Var', (21, 33))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
147942	25204415	Kinases activated by gene fusions represent an important class of oncogenes associated with both hematopoietic malignancies and solid tumours.	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('hematopoietic malignancies and solid tumours', 'Disease', 'MESH:D019337', (97, 141))	('associated', 'Reg', (76, 86))	('gene fusions', 'Var', (21, 33))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
147943	25204415	They are produced by translocations or other chromosomal rearrangements, and their protein products often represent ideal targets for the development of cancer drugs.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('translocations', 'Var', (21, 35))	('cancer', 'Disease', (153, 159))
147944	25204415	For example, imatinib induces remission in leukaemia patients who are positive for BCR-ABL1 fusions.	('patients', 'Species', '9606', (53, 61))	('BCR-ABL1', 'Gene', '613;25', (83, 91))	('leukaemia', 'Disease', 'MESH:D007938', (43, 52))	('fusions', 'Var', (92, 99))	('remission', 'MPA', (30, 39))	('leukaemia', 'Disease', (43, 52))	('imatinib', 'Chemical', 'MESH:D000068877', (13, 21))	('BCR-ABL1', 'Gene', (83, 91))
147947	25204415	While such studies have helped to identify numerous point mutations and small insertion/deletions in genes driving tumorigenesis, our understanding of the landscape of gene fusions in solid tumours is incomplete.	('solid tumours', 'Disease', 'MESH:D009369', (184, 197))	('insertion/deletions', 'Var', (78, 97))	('solid tumours', 'Disease', (184, 197))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))
147950	25204415	We identify several novel and recurrent fusions involving kinases that very likely play a role in cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('role', 'Reg', (90, 94))	('fusions', 'Var', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('play', 'Reg', (83, 87))	('kinases', 'Enzyme', (58, 65))
147952	25204415	We then focused our detailed analysis exclusively on recurrent (n>=2 across all cancer types), putatively functional kinase fusions (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('kinase fusions', 'Var', (117, 131))	('fusions', 'Var', (124, 131))	('cancer', 'Disease', (80, 86))
147954	25204415	First, as has been observed for point mutations, the proportion of samples harbouring kinase fusions was markedly different between cancer types, reflecting differences in the aetiology of these tumours.	('kinase fusions', 'Var', (86, 100))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('different', 'Reg', (114, 123))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
147955	25204415	For instance, sarcoma samples showed the highest frequency of kinase fusions (0.57 fusions per sample), consistent with the current understanding that a large fraction of sarcomas harbour specific translocations, but only 12% of those were recurrent kinase fusions (Supplementary Fig.	('sarcoma', 'Disease', (14, 21))	('sarcomas', 'Disease', (171, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('translocations', 'Var', (197, 211))	('kinase', 'Var', (62, 68))	('sarcoma', 'Disease', 'MESH:D012509', (171, 178))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('sarcoma', 'Disease', (171, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))
147957	25204415	Conversely, some cancer types, for example, clear cell and chromophobe renal cell carcinoma, showed a very low frequency of kinase fusions with no instances of recurrence (Supplementary Fig.	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (59, 91))	('clear cell', 'Disease', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('cancer', 'Disease', (17, 23))	('chromophobe renal cell carcinoma', 'Disease', (59, 91))	('kinase fusions', 'Var', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
147958	25204415	Overall, we detected recurrent kinase fusions in 3.0% of the samples, and all cancers except clear cell and chromophobe renal cell carcinoma harboured recurrent kinase fusions (0-12.9% of samples per cancer type, median=2.1%).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (108, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('detected', 'Reg', (12, 20))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('clear cell', 'Disease', (93, 103))	('chromophobe renal cell carcinoma', 'Disease', (108, 140))	('kinase fusions', 'Var', (31, 45))	('cancer', 'Disease', (200, 206))
147960	25204415	Interestingly, we identified new tumour types harbouring such fusions and discovered several novel fusion partners for these kinases.	('tumour type', 'Disease', (33, 44))	('tumour type', 'Disease', 'MESH:D009369', (33, 44))	('fusion', 'Interaction', (99, 105))	('fusions', 'Var', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))
147962	25204415	Third, we identified several novel and recurrent kinase fusions that very likely play a role in cancer, such as those involving the MET proto-oncogene and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('role', 'Reg', (88, 92))	('play', 'Reg', (81, 85))	('PIK3CA', 'Gene', (155, 161))	('MET', 'Gene', (132, 135))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('PIK3CA', 'Gene', '5290', (155, 161))	('kinase fusions', 'Var', (49, 63))
147963	25204415	Our analysis also uncovered novel, recurrent fusions in kinases with no known tumorigenic genomic alterations (that is, feline Gardner-Rasheed sarcoma viral oncogene homologue, FGR and protein kinase N1, PKN1), potentially resulting in active and oncogenic fusion proteins.	('protein kinase N1', 'Gene', '5585', (185, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('PKN1', 'Gene', (204, 208))	('kinases', 'Enzyme', (56, 63))	('Gardner-Rasheed sarcoma viral', 'Disease', (127, 156))	('Gardner-Rasheed sarcoma viral', 'Disease', 'MESH:D005736', (127, 156))	('oncogenic', 'MPA', (247, 256))	('rat', 'Species', '10116', (102, 105))	('active', 'MPA', (236, 242))	('fusion', 'Interaction', (257, 263))	('FGR', 'Gene', (177, 180))	('FGR', 'Gene', '2268', (177, 180))	('fusions', 'Var', (45, 52))	('protein kinase N1', 'Gene', (185, 202))	('PKN1', 'Gene', '5585', (204, 208))
147964	25204415	Finally, we discovered a recurrent fusion in sarcoma encoding the non-catalytic portion of TRIO kinase, which resulted in the upregulation of the transcription of telomerase reverse transcriptase (TERT) in those tumours.	('TERT', 'Gene', (197, 201))	('sarcoma', 'Disease', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('TRIO', 'Gene', (91, 95))	('TRIO', 'Gene', '7204', (91, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('telomerase reverse transcriptase', 'Gene', (163, 195))	('TERT', 'Gene', '7015', (197, 201))	('telomerase reverse transcriptase', 'Gene', '7015', (163, 195))	('tumours', 'Phenotype', 'HP:0002664', (212, 219))	('transcription', 'MPA', (146, 159))	('fusion', 'Var', (35, 41))	('tumours', 'Disease', (212, 219))	('tumours', 'Disease', 'MESH:D009369', (212, 219))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('upregulation', 'PosReg', (126, 138))
147966	25204415	Consistent with previous studies, we detected EML4-ALK fusions in ~1% (5/513) of lung adenocarcinoma samples, multiple ALK fusions, including a single STRN-ALK fusion, in thyroid cancer (3/498) and one in papillary renal carcinoma.	('EML4', 'Gene', '27436', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('ALK', 'Gene', '238', (156, 159))	('papillary renal carcinoma', 'Disease', (205, 230))	('STRN', 'Gene', '6801', (151, 155))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))	('ALK', 'Gene', (156, 159))	('ALK', 'Gene', '238', (51, 54))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (205, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('lung adenocarcinoma', 'Disease', (81, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('ALK', 'Gene', (51, 54))	('fusions', 'Var', (123, 130))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('ALK', 'Gene', '238', (119, 122))	('STRN', 'Gene', (151, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (205, 230))	('ALK', 'Gene', (119, 122))	('renal carcinoma', 'Phenotype', 'HP:0005584', (215, 230))	('thyroid cancer', 'Disease', (171, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('EML4', 'Gene', (46, 50))
147967	25204415	We also found several novel ALK fusion events, including a TPM1-ALK fusion in bladder cancer, a SMEK2-ALK fusion in rectal adenocarcinoma and a GTF2IRD1-ALK fusion in thyroid cancer (Fig.	('ALK', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (116, 137))	('ALK', 'Gene', '238', (28, 31))	('fusion', 'Var', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('thyroid cancer', 'Disease', (167, 181))	('ALK', 'Gene', (28, 31))	('GTF2IRD1', 'Gene', '9569', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('GTF2IRD1', 'Gene', (144, 152))	('bladder cancer', 'Disease', (78, 92))	('SMEK2', 'Gene', '57223', (96, 101))	('ALK', 'Gene', '238', (153, 156))	('ALK', 'Gene', '238', (64, 67))	('thyroid cancer', 'Disease', 'MESH:D013964', (167, 181))	('SMEK2', 'Gene', (96, 101))	('rectal adenocarcinoma', 'Disease', (116, 137))	('ALK', 'Gene', (153, 156))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('ALK', 'Gene', (64, 67))	('thyroid cancer', 'Phenotype', 'HP:0002890', (167, 181))	('ALK', 'Gene', '238', (102, 105))
147969	25204415	We also identified multiple c-ros oncogene 1 (ROS1) fusions, including ROS1 fusions in 8/513 lung adenocarcinomas, all of which have been previously described.	('c-ros oncogene 1', 'Gene', '6098', (28, 44))	('ROS1', 'Gene', '6098', (71, 75))	('lung adenocarcinomas', 'Disease', (93, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('fusions', 'Var', (76, 83))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (93, 113))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (93, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('ROS1', 'Gene', (46, 50))	('c-ros oncogene 1', 'Gene', (28, 44))	('ROS1', 'Gene', '6098', (46, 50))	('ROS1', 'Gene', (71, 75))	('fusions', 'Var', (52, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
147972	25204415	RET proto-oncogene fusions have been identified previously in both lung adenocarcinoma and thyroid cancer.	('RET', 'Gene', '5979', (0, 3))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('fusions', 'Var', (19, 26))	('thyroid cancer', 'Phenotype', 'HP:0002890', (91, 105))	('thyroid cancer', 'Disease', (91, 105))	('RET', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('lung adenocarcinoma', 'Disease', (67, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('identified', 'Reg', (37, 47))	('thyroid cancer', 'Disease', 'MESH:D013964', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
147973	25204415	Consistent with these studies, we observed recurrent CCDC6-RET fusions in thyroid cancer but also identified several RET fusions with novel partners, including AKAP13, FKBP15, SPECC1L and TBL1XR1 (Fig.	('FKBP15', 'Gene', '23307', (168, 174))	('SPECC1L', 'Gene', (176, 183))	('RET', 'Gene', (59, 62))	('AKAP13', 'Gene', (160, 166))	('SPECC1L', 'Gene', '23384', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('thyroid cancer', 'Disease', (74, 88))	('TBL1XR1', 'Gene', '79718', (188, 195))	('RET', 'Gene', '5979', (117, 120))	('TBL1XR1', 'Gene', (188, 195))	('thyroid cancer', 'Disease', 'MESH:D013964', (74, 88))	('RET', 'Gene', '5979', (59, 62))	('CCDC6', 'Gene', (53, 58))	('FKBP15', 'Gene', (168, 174))	('AKAP13', 'Gene', '11214', (160, 166))	('CCDC6', 'Gene', '8030', (53, 58))	('thyroid cancer', 'Phenotype', 'HP:0002890', (74, 88))	('RET', 'Gene', (117, 120))	('fusions', 'Var', (63, 70))
147975	25204415	In addition, we detected previously identified RET fusions in new tumour indications, including a single CCDC6-RET fusion in colon adenocarcinoma and a single ERC1-RET fusion in breast cancer.	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (125, 145))	('fusion', 'Var', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('CCDC6', 'Gene', (105, 110))	('RET', 'Gene', '5979', (111, 114))	('CCDC6', 'Gene', '8030', (105, 110))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))	('RET', 'Gene', '5979', (164, 167))	('RET', 'Gene', '5979', (47, 50))	('colon adenocarcinoma', 'Disease', (125, 145))	('ERC1', 'Gene', '23085', (159, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('RET', 'Gene', (111, 114))	('ERC1', 'Gene', (159, 163))	('RET', 'Gene', (164, 167))	('RET', 'Gene', (47, 50))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Disease', (178, 191))
147977	25204415	BRAF (v-raf murine sarcoma viral oncogene homologue B) fusions have also been described previously in multiple cancer types, including prostate cancer, melanoma, radiation-induced thyroid cancer and pediatric low-grade gliomas.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (144, 150))	('thyroid cancer', 'Disease', 'MESH:D013964', (180, 194))	('sarcoma viral', 'Disease', 'MESH:D001102', (19, 32))	('BRAF', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('cancer', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('sarcoma viral', 'Disease', (19, 32))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('thyroid cancer', 'Phenotype', 'HP:0002890', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('v-raf', 'Gene', '110157', (6, 11))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('murine', 'Species', '10090', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('prostate cancer', 'Disease', 'MESH:D011471', (135, 150))	('cancer', 'Disease', (188, 194))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('thyroid cancer', 'Disease', (180, 194))	('prostate cancer', 'Disease', (135, 150))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('v-raf', 'Gene', (6, 11))	('described', 'Reg', (78, 87))	('gliomas', 'Disease', (219, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('fusions', 'Var', (55, 62))
147978	25204415	Consistent with these studies, we identified a broad range of cancer types harbouring BRAF fusions, including prostate, melanoma and thyroid.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fusions', 'Var', (91, 98))	('BRAF', 'Var', (86, 90))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('prostate', 'Disease', (110, 118))	('thyroid', 'Disease', (133, 140))
147980	25204415	Interestingly, the BRAF fusions in melanoma are exclusive of other known oncogenic events such as BRAF and NRAS mutations.	('fusions', 'Var', (24, 31))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('BRAF', 'Disease', (98, 102))	('BRAF', 'Gene', (19, 23))	('NRAS', 'Gene', '4893', (107, 111))	('mutations', 'Var', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('NRAS', 'Gene', (107, 111))
147984	25204415	However, these fusions all remove at least the first eight exons of BRAF, which has previously been shown to promote BRAF dimerization, independent of activated RAS (rat sarcoma viral oncogene homologues) or other mechanisms of BRAF dimerization.	('promote', 'PosReg', (109, 116))	('rat', 'Species', '10116', (166, 169))	('sarcoma viral', 'Disease', 'MESH:D001102', (170, 183))	('fusions', 'Var', (15, 22))	('BRAF dimerization', 'MPA', (117, 134))	('BRAF', 'Gene', (68, 72))	('remove', 'NegReg', (27, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma viral', 'Disease', (170, 183))
147985	25204415	Consistent with previous studies, we also found recurrent RAF1 (also known as CRAF) fusions in various tumour types (Fig.	('tumour type', 'Disease', 'MESH:D009369', (103, 114))	('fusions', 'Var', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('RAF1', 'Gene', '5894', (58, 62))	('CRAF', 'Gene', (78, 82))	('CRAF', 'Gene', '5894', (78, 82))	('RAF1', 'Gene', (58, 62))	('tumour type', 'Disease', (103, 114))
147986	25204415	In addition to known tumour occurrences (four fusions in melanoma, two fusions in prostate adenocarcinoma), we identified AGGF1-RAF1 fusions in seven papillary thyroid carcinoma samples (1.4%).	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('fusions', 'Var', (133, 140))	('tumour', 'Disease', (21, 27))	('AGGF1', 'Gene', (122, 127))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (150, 177))	('prostate adenocarcinoma', 'Disease', (82, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('papillary thyroid carcinoma', 'Disease', (150, 177))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (150, 177))	('RAF1', 'Gene', '5894', (128, 132))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (82, 105))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('RAF1', 'Gene', (128, 132))	('AGGF1', 'Gene', '55109', (122, 127))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (160, 177))
147989	25204415	AGGF1-RAF1 fusions appear not to be limited to thyroid cancers, as we also found a single AGGF1-RAF1 fusion in prostate cancer.	('fusion', 'Var', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('thyroid cancers', 'Disease', (47, 62))	('prostate cancer', 'Disease', (111, 126))	('AGGF1', 'Gene', '55109', (0, 5))	('thyroid cancers', 'Disease', 'MESH:D013964', (47, 62))	('AGGF1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('RAF1', 'Gene', '5894', (6, 10))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('RAF1', 'Gene', (96, 100))	('RAF1', 'Gene', '5894', (96, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (47, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('AGGF1', 'Gene', '55109', (90, 95))	('RAF1', 'Gene', (6, 10))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('AGGF1', 'Gene', (0, 5))
147990	25204415	We observed a broad distribution of the fibroblast growth factor receptors FGFR1, FGFR2 and FGFR3 fusions:in particular FGFR3-TACC3 fusions:across eight of the 20 tumour types analysed (Fig.	('tumour type', 'Disease', 'MESH:D009369', (163, 174))	('TACC3', 'Gene', (126, 131))	('fusions', 'Var', (132, 139))	('FGFR3', 'Gene', (120, 125))	('FGFR3', 'Gene', (92, 97))	('FGFR1', 'Gene', (75, 80))	('fusions', 'Var', (98, 105))	('FGFR3', 'Gene', '2261', (92, 97))	('FGFR1', 'Gene', '2260', (75, 80))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('FGFR2', 'Gene', (82, 87))	('FGFR2', 'Gene', '2263', (82, 87))	('tumour type', 'Disease', (163, 174))	('TACC3', 'Gene', '10460', (126, 131))	('FGFR3', 'Gene', '2261', (120, 125))
147992	25204415	We also detected a single FGFR3-TACC3 fusion in a novel indication, papillary renal carcinoma, and a novel FGFR3-ELAVL3 fusion in low-grade glioma (Supplementary Fig.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('ELAVL3', 'Gene', (113, 119))	('FGFR3', 'Gene', (26, 31))	('fusion', 'Var', (38, 44))	('FGFR3', 'Gene', '2261', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('ELAVL3', 'Gene', '1995', (113, 119))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (68, 93))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (68, 93))	('renal carcinoma', 'Phenotype', 'HP:0005584', (78, 93))	('FGFR3', 'Gene', (107, 112))	('glioma', 'Disease', (140, 146))	('TACC3', 'Gene', '10460', (32, 37))	('FGFR3', 'Gene', '2261', (26, 31))	('papillary renal carcinoma', 'Disease', (68, 93))	('TACC3', 'Gene', (32, 37))
147993	25204415	Similar to RET and NTRK1-3 (see below), fusions involving FGFR1-3 provide a therapeutic opportunity for current and future FGFR inhibitors in multiple patient subpopulations.	('RET', 'Gene', '5979', (11, 14))	('NTRK1', 'Gene', '4914', (19, 24))	('fusions', 'Var', (40, 47))	('patient', 'Species', '9606', (151, 158))	('RET', 'Gene', (11, 14))	('FGFR1', 'Gene', (58, 63))	('NTRK1', 'Gene', (19, 24))	('FGFR1', 'Gene', '2260', (58, 63))
147994	25204415	Recurrent fusions involving members of the NTRK family have been identified previously in congenital fibrosarcoma, human secretory breast carcinoma and papillary thyroid cancer, which represent clinical indications for which currently available non-kinase-targeted treatment options are usually adequate.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('fusions', 'Var', (10, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (152, 176))	('congenital fibrosarcoma', 'Disease', (90, 113))	('thyroid cancer', 'Phenotype', 'HP:0002890', (162, 176))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (101, 113))	('identified', 'Reg', (65, 75))	('breast carcinoma and papillary thyroid cancer', 'Disease', 'MESH:D000077273', (131, 176))	('NTRK family', 'Gene', (43, 54))	('breast carcinoma', 'Phenotype', 'HP:0003002', (131, 147))	('human', 'Species', '9606', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('congenital fibrosarcoma', 'Disease', 'MESH:D005354', (90, 113))
147995	25204415	However, recurrent NTRK1 and NTRK2 fusions have also been recently identified in diseases which represent significant unmet medical needs, including glioblastoma, cholangiocarcinoma and pediatric high-grade glioma.	('glioblastoma', 'Disease', (149, 161))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('NTRK2', 'Gene', (29, 34))	('NTRK1', 'Gene', '4914', (19, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('glioma', 'Disease', (207, 213))	('cholangiocarcinoma', 'Disease', (163, 181))	('NTRK2', 'Gene', '4915', (29, 34))	('NTRK1', 'Gene', (19, 24))	('identified', 'Reg', (67, 77))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (163, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))	('fusions', 'Var', (35, 42))
147996	25204415	Consistent with previous studies, we observed recurrent NTRK1 and NTRK3 fusions in papillary thyroid cancer and glioblastoma, but also identified a number of novel NTRK2 fusions in head and neck squamous cell carcinoma (PAN3-NTRK2), low-grade glioma (AFAP1-NTRK2) and lung adenocarcinoma (TRIM24-NTRK2) (Fig.	('lung adenocarcinoma', 'Disease', (268, 287))	('NTRK2', 'Gene', '4915', (225, 230))	('AFAP1', 'Gene', '60312', (251, 256))	('glioma', 'Disease', (243, 249))	('TRIM24', 'Gene', '8805', (289, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (83, 107))	('NTRK2', 'Gene', '4915', (296, 301))	('NTRK2', 'Gene', '4915', (257, 262))	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('NTRK2', 'Gene', (164, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (268, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('AFAP1', 'Gene', (251, 256))	('neck squamous cell carcinoma', 'Disease', (190, 218))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (83, 107))	('NTRK2', 'Gene', (225, 230))	('NTRK1', 'Gene', '4914', (56, 61))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (190, 218))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (268, 287))	('PAN3', 'Gene', (220, 224))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('thyroid cancer', 'Phenotype', 'HP:0002890', (93, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (112, 124))	('NTRK1', 'Gene', (56, 61))	('fusions', 'Var', (170, 177))	('NTRK2', 'Gene', (257, 262))	('NTRK2', 'Gene', (296, 301))	('fusions', 'Var', (72, 79))	('PAN3', 'Gene', '255967', (220, 224))	('NTRK3', 'Gene', '4916', (66, 71))	('TRIM24', 'Gene', (289, 295))	('glioblastoma', 'Disease', (112, 124))	('NTRK3', 'Gene', (66, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('papillary thyroid cancer', 'Disease', (83, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('NTRK2', 'Gene', '4915', (164, 169))
147998	25204415	Across all tumour types analysed, NTRK1-3 fusions were observed at low frequency in 9 of the 20 cancer types analysed, providing a therapeutic opportunity for the use of pan-NTRK inhibitors in multiple patient populations.	('NTRK1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('patient', 'Species', '9606', (202, 209))	('tumour type', 'Disease', (11, 22))	('NTRK1', 'Gene', '4914', (34, 39))	('tumour type', 'Disease', 'MESH:D009369', (11, 22))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('fusions', 'Var', (42, 49))	('cancer', 'Disease', (96, 102))
147999	25204415	Protein kinase C fusions have recently been described in papillary glioneuronal tumours and benign fibrous histiocytoma.	('Protein', 'Protein', (0, 7))	('benign fibrous histiocytoma', 'Disease', (92, 119))	('papillary glioneuronal tumours', 'Phenotype', 'HP:0025170', (57, 87))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('fusions', 'Var', (17, 24))	('papillary glioneuronal tumours', 'Disease', 'MESH:D000077273', (57, 87))	('papillary glioneuronal tumours', 'Disease', (57, 87))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('described', 'Reg', (44, 53))	('histiocytoma', 'Phenotype', 'HP:0012315', (107, 119))
148000	25204415	We found two new occurrences of PRKCA (protein kinase C, alpha) fusions in lung squamous cell carcinoma and three PRKCB (protein kinase C, beta) fusions in lung squamous cell carcinoma, lung adenocarcinoma and low-grade glioma (Fig.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('lung squamous cell carcinoma', 'Disease', (75, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('PRKCA', 'Gene', (32, 37))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('lung adenocarcinoma', 'Disease', (186, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('PRKCB', 'Gene', (114, 119))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (186, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (186, 205))	('protein kinase C, alpha', 'Gene', '5578', (39, 62))	('PRKCA', 'Gene', '5578', (32, 37))	('glioma', 'Disease', (220, 226))	('fusions', 'Var', (64, 71))	('PRKCB', 'Gene', '5579', (114, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 184))	('lung squamous cell carcinoma', 'Disease', (156, 184))
148004	25204415	In both cases, however, N-terminal truncation of PRKCA removes the autoinhibitory pseudosubstrate segment, possibly leading to a constitutively activated kinase in the absence of a functional fusion partner.	('PRKCA', 'Gene', (49, 54))	('autoinhibitory pseudosubstrate segment', 'MPA', (67, 105))	('N-terminal truncation', 'Var', (24, 45))	('leading to', 'Reg', (116, 126))	('removes', 'NegReg', (55, 62))	('PRKCA', 'Gene', '5578', (49, 54))	('constitutively activated kinase', 'MPA', (129, 160))	('rat', 'Species', '10116', (93, 96))
148006	25204415	These data suggest that PRKCA fusions are potential oncogenic events in lung squamous cell carcinoma, leading to overexpression as well as constitutive activation of PRKCA.	('PRKCA', 'Gene', '5578', (166, 171))	('activation', 'PosReg', (152, 162))	('PRKCA', 'Gene', (166, 171))	('overexpression', 'PosReg', (113, 127))	('fusions', 'Var', (30, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 100))	('PRKCA', 'Gene', '5578', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung squamous cell carcinoma', 'Disease', (72, 100))	('PRKCA', 'Gene', (24, 29))
148007	25204415	In the same fashion, PRKCB fusions truncate the N-terminal part of the protein containing the autoinhibitory domain and are predicted to activate this kinase (Supplementary Fig.	('PRKCB', 'Gene', (21, 26))	('PRKCB', 'Gene', '5579', (21, 26))	('truncate', 'NegReg', (35, 43))	('fusions', 'Var', (27, 34))	('activate', 'PosReg', (137, 145))
148010	25204415	Anecdotally, a transforming TPR-MET fusion was previously generated in vitro via carcinogen-induced chromosomal rearrangement fusing the dimerization domain of TPR to the kinase domain of the MET receptor tyrosine kinase.	('TPR', 'Gene', '7175', (160, 163))	('TPR', 'Gene', (28, 31))	('TPR', 'Gene', '7175', (28, 31))	('dimerization', 'MPA', (137, 149))	('TPR', 'Gene', (160, 163))	('rat', 'Species', '10116', (62, 65))	('fusing', 'Var', (126, 132))
148015	25204415	We also identified single MET fusions in four other cancers: low-grade glioma, hepatocellular carcinoma, lung adenocarcinoma and thyroid carcinoma.	('cancers', 'Disease', (52, 59))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (129, 146))	('hepatocellular carcinoma', 'Disease', (79, 103))	('lung adenocarcinoma', 'Disease', (105, 124))	('thyroid carcinoma', 'Disease', (129, 146))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('glioma', 'Disease', (71, 77))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (129, 146))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('single MET fusions', 'Var', (19, 37))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
148018	25204415	Mutations and, to a lesser extent, increased copy numbers in another prevalent oncogene, PIK3CA, have been characterized in diverse cancers.	('cancers', 'Disease', (132, 139))	('increased', 'PosReg', (35, 44))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Mutations', 'Var', (0, 9))	('copy numbers', 'Var', (45, 57))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
148019	25204415	While activating missense mutations in PIK3CA have been described as frequently as 50% in endometrial cancers, 30% in breast invasive carcinomas and 20% in colorectal as well as head and neck cancers, this gene has not been implicated in activating fusion events.	('missense mutations', 'Var', (17, 35))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('neck cancers', 'Disease', (187, 199))	('head and neck cancers', 'Phenotype', 'HP:0012288', (178, 199))	('neck cancers', 'Disease', 'MESH:D006258', (187, 199))	('endometrial cancers', 'Disease', 'MESH:D016889', (90, 109))	('endometrial cancers', 'Disease', (90, 109))	('colorectal', 'Disease', 'MESH:D015179', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('PIK3CA', 'Gene', '5290', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('breast invasive carcinomas', 'Disease', (118, 144))	('activating', 'PosReg', (6, 16))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('PIK3CA', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal', 'Disease', (156, 166))	('breast invasive carcinomas', 'Disease', 'MESH:D018270', (118, 144))
148020	25204415	We found two TBL1XR1-PIK3CA fusions in 1,072 breast cancer samples, and a single occurrence of the same gene fusion in prostate adenocarcinoma (1/335).	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (119, 142))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TBL1XR1', 'Gene', '79718', (13, 20))	('PIK3CA', 'Gene', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('TBL1XR1', 'Gene', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('PIK3CA', 'Gene', '5290', (21, 27))	('fusions', 'Var', (28, 35))	('prostate adenocarcinoma', 'Disease', (119, 142))
148023	25204415	Indeed, in all samples where we detected PIK3CA translocations, and where PIK3CA was not amplified, PIK3CA mRNA expression levels were the highest within the respective tumour types (Fig.	('translocations', 'Var', (48, 62))	('highest', 'Reg', (139, 146))	('tumour type', 'Disease', 'MESH:D009369', (169, 180))	('PIK3CA', 'Gene', '5290', (74, 80))	('PIK3CA', 'Gene', (41, 47))	('PIK3CA', 'Gene', (100, 106))	('mRNA expression levels', 'MPA', (107, 129))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('PIK3CA', 'Gene', '5290', (41, 47))	('PIK3CA', 'Gene', '5290', (100, 106))	('tumour type', 'Disease', (169, 180))	('PIK3CA', 'Gene', (74, 80))
148025	25204415	These results strongly suggest that PIK3CA overexpression is driven by its fusion partner, and that PIK3CA promoter fusions are an additional oncogenic mechanism to be considered for expanding the use of targeted therapies such as PI3K, AKT or mTOR inhibitors.	('AKT', 'Gene', (237, 240))	('mTOR', 'Gene', (244, 248))	('PIK3CA', 'Gene', '5290', (36, 42))	('overexpression', 'PosReg', (43, 57))	('PIK3CA', 'Gene', (100, 106))	('fusions', 'Var', (116, 123))	('AKT', 'Gene', '207', (237, 240))	('PIK3CA', 'Gene', '5290', (100, 106))	('PIK3CA', 'Gene', (36, 42))	('mTOR', 'Gene', '2475', (244, 248))
148026	25204415	In addition to fusions involving known oncogenes, we found several novel and recurrent fusions involving kinases that have not been previously directly linked to cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('fusions', 'Var', (87, 94))	('cancer', 'Disease', (162, 168))	('kinases', 'Enzyme', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
148028	25204415	Here, we show for the first time that genetic events can lead to FGR overexpression in primary tumour samples.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('overexpression', 'MPA', (69, 83))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('lead to', 'Reg', (57, 64))	('tumour', 'Disease', (95, 101))	('FGR', 'Gene', (65, 68))	('FGR', 'Gene', '2268', (65, 68))	('genetic events', 'Var', (38, 52))
148030	25204415	The WASF2 and FGR genes are located very proximally on the short arm of chromosome 1, and the fusion presumably results from a tandem repeat that puts their coding regions in close proximity (Supplementary Fig.	('results from', 'Reg', (112, 124))	('tandem repeat', 'Var', (127, 140))	('FGR', 'Gene', (14, 17))	('WASF2', 'Gene', '10163', (4, 9))	('FGR', 'Gene', '2268', (14, 17))	('short arm', 'Phenotype', 'HP:0009824', (59, 68))	('WASF2', 'Gene', (4, 9))
148032	25204415	In all three cases, FGR mRNA expression in the samples harbouring a fusion was among the highest compared with all other tumours of that tissue type (Supplementary Fig.	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', (121, 128))	('fusion', 'Var', (68, 74))	('highest', 'Reg', (89, 96))	('FGR', 'Gene', (20, 23))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('FGR', 'Gene', '2268', (20, 23))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))
148034	25204415	Collectively, these data highlight a previously undocumented mechanism of genetic deregulation of a Src family member.	('genetic deregulation', 'Var', (74, 94))	('Src', 'Gene', '6714', (100, 103))	('Src', 'Gene', (100, 103))
148036	25204415	We detected fusions of PKN1 in samples of squamous cell carcinoma of the lung and hepatocellular carcinoma (Fig.	('squamous cell carcinoma of the lung and hepatocellular carcinoma', 'Disease', 'MESH:D002294', (42, 106))	('PKN1', 'Gene', '5585', (23, 27))	('fusions', 'Var', (12, 19))	('PKN1', 'Gene', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('detected', 'Reg', (3, 11))
148043	25204415	Overall, 3.0% of tumour samples contained a likely oncogenic, recurrent kinase fusion (2.1% excluding thyroid cancer).	('thyroid cancer', 'Disease', 'MESH:D013964', (102, 116))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (102, 116))	('tumour', 'Disease', (17, 23))	('thyroid cancer', 'Disease', (102, 116))	('kinase fusion', 'Var', (72, 85))
148044	25204415	The observed striking differences in the frequencies of kinase fusions across solid tumours are consistent with previous data on the relative contributions of diverse types of genetic aberrations to tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Disease', (84, 90))	('solid tumours', 'Disease', 'MESH:D009369', (78, 91))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('solid tumours', 'Disease', (78, 91))	('tumour', 'Disease', (199, 205))	('rat', 'Species', '10116', (188, 191))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('kinase', 'Var', (56, 62))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
148046	25204415	Other tumour types such as melanoma carry predominantly somatic point mutations.	('somatic point mutations', 'Var', (56, 79))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour type', 'Disease', (6, 17))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumour type', 'Disease', 'MESH:D009369', (6, 17))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
148047	25204415	Consistent with these observations, our data suggest that certain cancers are heavily driven by kinase rearrangements.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('driven by', 'Reg', (86, 95))	('cancers', 'Disease', (66, 73))	('kinase rearrangements', 'Var', (96, 117))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
148050	25204415	In stark contrast, clear cell and chromophobe renal cell carcinoma have the lowest frequencies of kinase fusions, none of which were recurrent in our analysis of this data set (Supplementary Fig.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (46, 66))	('clear cell', 'Disease', (19, 29))	('chromophobe renal cell carcinoma', 'Disease', (34, 66))	('kinase', 'Var', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (34, 66))
148052	25204415	Our study also revealed new cancer types harbouring known fusions (for example, BRAF fusion in rectal adenocarcinoma, FGFR3 fusion in prostate adenocarcinoma, RET fusions in colon adenocarcinoma and invasive breast carcinoma, EGFR-SEPT14 in low-grade glioma, and so on).	('fusion', 'Var', (85, 91))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (95, 116))	('RET', 'Gene', '5979', (159, 162))	('SEPT14', 'Gene', '346288', (231, 237))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('colon adenocarcinoma', 'Disease', (174, 194))	('fusion', 'Var', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('FGFR3', 'Gene', (118, 123))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('FGFR3', 'Gene', '2261', (118, 123))	('RET', 'Gene', (159, 162))	('prostate adenocarcinoma', 'Disease', (134, 157))	('EGFR', 'Gene', '1956', (226, 230))	('rectal adenocarcinoma', 'Disease', (95, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (199, 224))	('breast carcinoma', 'Phenotype', 'HP:0003002', (208, 224))	('SEPT14', 'Gene', (231, 237))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (174, 194))	('cancer', 'Disease', (28, 34))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (134, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('invasive breast carcinoma', 'Disease', (199, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('glioma', 'Disease', (251, 257))	('EGFR', 'Gene', (226, 230))
148057	25204415	For example, we found six cancer types with a single fusion in a gene of the NTRK family, but altogether, we detected a total of 23 NTRK1, NTRK2 and NTRK3 fusions across nine tumour types.	('NTRK2', 'Gene', (139, 144))	('NTRK1', 'Gene', '4914', (132, 137))	('cancer', 'Disease', (26, 32))	('NTRK3', 'Gene', '4916', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('NTRK2', 'Gene', '4915', (139, 144))	('NTRK', 'Gene', (77, 81))	('tumour type', 'Disease', (175, 186))	('NTRK1', 'Gene', (132, 137))	('tumour type', 'Disease', 'MESH:D009369', (175, 186))	('NTRK3', 'Gene', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('fusions', 'Var', (155, 162))
148058	25204415	NTRK fusions therefore represent a low frequency, pan-cancer event that nevertheless may account for a significant fraction of patients who could benefit from a pan-NTRK inhibitor.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('fusions', 'Var', (5, 12))	('cancer', 'Disease', (54, 60))	('patients', 'Species', '9606', (127, 135))	('NTRK', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
148060	25204415	In particular, we found recurrent fusions of MET and PIK3CA that are both bona fide oncogenes commonly activated by gene amplification or point mutations.	('fusions', 'Var', (34, 41))	('PIK3CA', 'Gene', (53, 59))	('MET', 'Gene', (45, 48))	('PIK3CA', 'Gene', '5290', (53, 59))
148061	25204415	In contrast, TBL1XR1-PIK3CA fusions likely drive increased PIK3CA mRNA expression by juxtaposing the promoter region of the partner gene to the 5' end of the intact PIK3CA coding sequence.	('TBL1XR1', 'Gene', '79718', (13, 20))	('increased', 'PosReg', (49, 58))	('PIK3CA', 'Gene', (165, 171))	('PIK3CA', 'Gene', (21, 27))	('TBL1XR1', 'Gene', (13, 20))	('PIK3CA', 'Gene', (59, 65))	('mRNA expression', 'MPA', (66, 81))	('PIK3CA', 'Gene', '5290', (165, 171))	('PIK3CA', 'Gene', '5290', (21, 27))	('fusions', 'Var', (28, 35))	('PIK3CA', 'Gene', '5290', (59, 65))
148063	25204415	We also observed fusions in some Ser/Thr kinases (for example, PRKCA, PKN1), where deletion of their regulatory N-terminal domain putatively leads to constitutive activation by de-repression of the kinase activity.	('Ser/Thr kinases', 'Enzyme', (33, 48))	('de-repression', 'NegReg', (177, 190))	('activity', 'MPA', (205, 213))	('PRKCA', 'Gene', '5578', (63, 68))	('PKN1', 'Gene', '5585', (70, 74))	('deletion', 'Var', (83, 91))	('PRKCA', 'Gene', (63, 68))	('PKN1', 'Gene', (70, 74))	('constitutive activation', 'MPA', (150, 173))
148068	25204415	However, the majority of singleton gene fusions in this set are predicted to be passenger events, occurring as a consequence of chromothripsis or genomic instability.	('chromothripsis', 'Disease', (128, 142))	('chromothripsis', 'Disease', 'MESH:D000072837', (128, 142))	('singleton gene fusions', 'Var', (25, 47))
148070	25204415	Although not the focus of this study, we describe here such an example: a recurrent fusion in two dedifferentiated liposarcoma samples (2/38; 5%) encoding the non-kinase portion of TRIO, which results in upregulation of its fusion partner TERT (Fig.	('TERT', 'Gene', (239, 243))	('liposarcoma', 'Disease', (115, 126))	('TRIO', 'Gene', (181, 185))	('TRIO', 'Gene', '7204', (181, 185))	('TERT', 'Gene', '7015', (239, 243))	('liposarcoma', 'Disease', 'MESH:D008080', (115, 126))	('upregulation', 'PosReg', (204, 216))	('liposarcoma', 'Phenotype', 'HP:0012034', (115, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('fusion', 'Var', (84, 90))
148071	25204415	Telomerase activity is a hallmark of many cancers, and two other genetic mechanisms of TERT reactivation have been described recently; both somatic mutations in the promoter of the TERT gene and DNA copy number gains of TERT were shown to activate its transcription.	('mutations in', 'Var', (148, 160))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('TERT', 'Gene', (181, 185))	('hallmark of many cancers', 'Disease', (25, 49))	('TERT', 'Gene', (220, 224))	('TERT', 'Gene', (87, 91))	('TERT', 'Gene', '7015', (220, 224))	('TERT', 'Gene', '7015', (181, 185))	('hallmark of many cancers', 'Disease', 'MESH:D009369', (25, 49))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('TERT', 'Gene', '7015', (87, 91))	('transcription', 'MPA', (252, 265))	('activate', 'PosReg', (239, 247))
148083	25204415	This step relied on the analysis of a large number of samples to filter out highly recurrent fusions that were detected at improbable frequencies within a cancer type: for instance, fusions detected in >95% of samples, or fusions where both gene partners are themselves involved in >1 fusions in >25% of samples, were flagged as putative false positives.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('fusions', 'Var', (222, 229))	('fusions', 'Var', (182, 189))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
148138	24378063	The role of cytomegalovirus in tumorigenesis is accomplished by the integration of a portion of its DNA into the host genome and, possibly, by amplification or mutation of oncogenetic sequences, in keeping with traditional models of virally induced tumor production.	('mutation', 'Var', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('amplification', 'Var', (143, 156))	('tumor', 'Disease', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
148273	31817500	Design and Conceptualization: A.S., M.A., C.M., K.M., H.T.	('C.M.', 'Var', (42, 46))	('H.T', 'Disease', 'MESH:D000848', (54, 57))	('H.T', 'Disease', (54, 57))
148281	31702654	Molecular genetic testing found no established variants of clinical significance but variants of unknown significance in APC, KMT2D, and MSH6 were detected.	('MSH6', 'Gene', '2956', (137, 141))	('variants', 'Var', (85, 93))	('KMT2D', 'Gene', (126, 131))	('KMT2D', 'Gene', '8085', (126, 131))	('APC', 'Disease', 'MESH:D011125', (121, 124))	('MSH6', 'Gene', (137, 141))	('APC', 'Disease', (121, 124))
148287	31702654	APC and MSH6 variation might be related with the disease progression and predict a poorer prognosis.	('related', 'Reg', (32, 39))	('variation', 'Var', (13, 22))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('MSH6', 'Gene', (8, 12))	('APC', 'Disease', (0, 3))	('MSH6', 'Gene', '2956', (8, 12))
148306	31702654	While molecular genetic testing (OncoKids Cancer Panel) showed no established variants of clinical significance, it detected variants of unknown significance detected in APC, KMT2D, and MSH6 (Table 1).	('APC', 'Disease', (170, 173))	('MSH6', 'Gene', (186, 190))	('variants', 'Var', (125, 133))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('KMT2D', 'Gene', (175, 180))	('KMT2D', 'Gene', '8085', (175, 180))	('MSH6', 'Gene', '2956', (186, 190))	('APC', 'Disease', 'MESH:D011125', (170, 173))
148319	31702654	Histologically, it demonstrates a widely variable morphology and is characterized by t(12;15) (p13;q25) translocation with ETV6-NTRK3 gene fusion.	('t(12', 'Var', (85, 89))	('NTRK3', 'Gene', '4916', (128, 133))	('ETV6', 'Gene', '2120', (123, 127))	('NTRK3', 'Gene', (128, 133))	('ETV6', 'Gene', (123, 127))
148325	31702654	Variants of unknown significance were detected in APC (p.Arg259Trp), KMT2D (p.Lys2548GIu), and MSH6 (p.Pro1082Ser).	('p.Lys2548G', 'SUBSTITUTION', 'None', (76, 86))	('KMT2D', 'Gene', '8085', (69, 74))	('APC', 'Disease', (50, 53))	('MSH6', 'Gene', '2956', (95, 99))	('p.Lys2548G', 'Var', (76, 86))	('p.Arg259Trp', 'Var', (55, 66))	('p.Arg259Trp', 'Mutation', 'rs762117133', (55, 66))	('MSH6', 'Gene', (95, 99))	('p.Pro1082Ser', 'Mutation', 'rs186240214', (101, 113))	('KMT2D', 'Gene', (69, 74))	('APC', 'Disease', 'MESH:D011125', (50, 53))
148332	31702654	According to one report, recurrent BCOR exon 16 internal tandem duplication (ITD) and YWHAE-NUTM2B fusions occur in half of infantile soft tissue URCS.	('internal tandem duplication', 'Var', (48, 75))	('BCOR', 'Gene', (35, 39))	('occur', 'Reg', (107, 112))	('BCOR', 'Gene', '54880', (35, 39))	('infant', 'Species', '9606', (124, 130))	('YWHAE', 'Gene', (86, 91))	('fusions', 'Var', (99, 106))	('NUTM2B', 'Gene', (92, 98))	('infantile soft tissue URCS', 'Disease', (124, 150))	('YWHAE', 'Gene', '7531', (86, 91))	('NUTM2B', 'Gene', '729262', (92, 98))
148347	31702654	Alterations in the APC gene have been previously detected in some cases of synovial sarcoma and were thought to contribute to the accumulation of beta-catenin.	('detected', 'Reg', (49, 57))	('accumulation', 'PosReg', (130, 142))	('APC', 'Disease', (19, 22))	('APC', 'Disease', 'MESH:D011125', (19, 22))	('Alterations', 'Var', (0, 11))	('synovial sarcoma', 'Disease', (75, 91))	('beta-catenin', 'Gene', (146, 158))	('beta-catenin', 'Gene', '1499', (146, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (75, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (75, 91))
148349	31702654	These studies indicate a potential role for APC and MSH6 mutations in sarcomas, where they may correlate with poor prognosis.	('APC', 'Disease', 'MESH:D011125', (44, 47))	('APC', 'Disease', (44, 47))	('MSH6', 'Gene', (52, 56))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))	('MSH6', 'Gene', '2956', (52, 56))	('mutations', 'Var', (57, 66))
148352	31702654	APC and MSH6 variation might be related with the disease progression and its poor prognosis.	('related', 'Reg', (32, 39))	('variation', 'Var', (13, 22))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('MSH6', 'Gene', (8, 12))	('APC', 'Disease', (0, 3))	('MSH6', 'Gene', '2956', (8, 12))
148361	31645347	Molecularly, ES is characterized by the presence of the EWSR1 gene fusions with one of several genes from the E26 transformation-specific (ETS) family of transcription factors, such as FLI1, ERG, ETV1, ETV4, and FEV.	('ES', 'Disease', 'MESH:D012512', (13, 15))	('FLI1', 'Gene', (185, 189))	('ETV4', 'Gene', (202, 206))	('ETV1', 'Gene', (196, 200))	('fusions', 'Var', (67, 74))	('EWSR1', 'Gene', (56, 61))	('FLI1', 'Gene', '2313', (185, 189))	('ETV1', 'Gene', '2115', (196, 200))	('ERG', 'Gene', '2078', (191, 194))	('ETV4', 'Gene', '2118', (202, 206))	('EWSR1', 'Gene', '2130', (56, 61))	('ERG', 'Gene', (191, 194))	('ES', 'Phenotype', 'HP:0012254', (13, 15))
148363	31645347	Additionally, there is an emerging new molecular category:Ewing-like tumor:that is morphologically similar to ES but has EWSR1 fusions involving non-ETS genes as well as fusions with genes other than ETS or TET family members (e.g., CIC-DUX4, BCOR-CCNB3).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('fusions', 'Var', (170, 177))	('EWSR1', 'Gene', (121, 126))	('tumor', 'Disease', (69, 74))	('DUX4', 'Gene', (237, 241))	('ES', 'Phenotype', 'HP:0012254', (110, 112))	('CCNB3', 'Gene', '85417', (248, 253))	('ES', 'Disease', 'MESH:D012512', (110, 112))	('fusions', 'Var', (127, 134))	('BCOR', 'Gene', (243, 247))	('EWSR1', 'Gene', '2130', (121, 126))	('DUX4', 'Gene', '100288687', (237, 241))	('Ewing-like tumor', 'Phenotype', 'HP:0012254', (58, 74))	('BCOR', 'Gene', '54880', (243, 247))	('CCNB3', 'Gene', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
148368	31645347	A large case-control study that sequenced 1162 sarcoma probands, including 134 of the Ewing subtype, reported a significant association between germline mutations in FANC genes and sarcomas characterized by somatic translocations.	('sarcomas', 'Disease', 'MESH:D012509', (181, 189))	('sarcoma', 'Disease', (181, 188))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('sarcomas', 'Disease', (181, 189))	('germline mutations', 'Var', (144, 162))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('sarcoma', 'Disease', 'MESH:D012509', (181, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('sarcoma', 'Disease', (47, 54))	('FANC genes', 'Gene', (166, 176))
148369	31645347	Other reported associations of germline mutations with ES include mutations in DNA repair pathway genes such as TP53, PMS2, and others, as well as known hereditary cancer syndrome genes such as RET, PTCH2, ATM, and others.	('mutations', 'Var', (66, 75))	('RET', 'Gene', (194, 197))	('PMS2', 'Gene', '5395', (118, 122))	('ES', 'Phenotype', 'HP:0012254', (55, 57))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('PTCH2', 'Gene', (199, 204))	('ES', 'Disease', 'MESH:D012512', (55, 57))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (153, 179))	('RET', 'Gene', '5979', (194, 197))	('PTCH2', 'Gene', '8643', (199, 204))	('associations', 'Reg', (15, 27))	('hereditary cancer syndrome', 'Disease', (153, 179))	('TP53', 'Gene', '7157', (112, 116))	('ATM', 'Gene', (206, 209))	('PMS2', 'Gene', (118, 122))	('DNA repair pathway', 'Pathway', (79, 97))	('ATM', 'Gene', '472', (206, 209))	('TP53', 'Gene', (112, 116))
148372	31645347	Neurofibromatosis type 1 (NF-1) is an autosomal dominant hereditary cancer syndrome caused by germline loss-of-function mutations in the NF1 gene, which encodes a RAS-GTPase-activating protein that functions as a negative regulator of Ras proteins.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('NF-1', 'Gene', (26, 30))	('GTP', 'Chemical', 'MESH:D006160', (167, 170))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('NF1', 'Gene', (137, 140))	('loss-of-function', 'NegReg', (103, 119))	('autosomal dominant hereditary cancer syndrome', 'Disease', (38, 83))	('Neurofibromatosis type 1', 'Gene', (0, 24))	('autosomal dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (38, 83))	('mutations', 'Var', (120, 129))	('NF1', 'Gene', '4763', (137, 140))	('Neurofibromatosis type 1', 'Gene', '4763', (0, 24))	('NF-1', 'Gene', '4763', (26, 30))
148374	31645347	NF-1 patients develop a variety of tumors by inactivation of the remaining wild-type allele of NF1.	('NF-1', 'Gene', '4763', (0, 4))	('patients', 'Species', '9606', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NF-1', 'Gene', (0, 4))	('inactivation', 'Var', (45, 57))	('develop', 'PosReg', (14, 21))	('NF1', 'Gene', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('NF1', 'Gene', '4763', (95, 98))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
148385	31645347	Here we describe a 3-yr-old child with NF-1, who was diagnosed with EWSR1-ERG fusion-positive ES that also harbored a somatic mutation of NF1 in addition to a germline nonsense mutation of NF1.	('NF-1', 'Gene', (39, 43))	('ES', 'Phenotype', 'HP:0012254', (94, 96))	('ES', 'Disease', 'MESH:D012512', (94, 96))	('EWSR1', 'Gene', '2130', (68, 73))	('mutation', 'Var', (126, 134))	('ERG', 'Gene', '2078', (74, 77))	('NF-1', 'Gene', '4763', (39, 43))	('NF1', 'Gene', (189, 192))	('child', 'Species', '9606', (28, 33))	('NF1', 'Gene', (138, 141))	('NF1', 'Gene', '4763', (189, 192))	('EWSR1', 'Gene', (68, 73))	('ERG', 'Gene', (74, 77))	('NF1', 'Gene', '4763', (138, 141))
148386	31645347	The second hit on NF1 suggests that biallelic inactivation of NF1 provided a growth advantage to the tumor cells and highlights the potential role of Ras pathway mutations as secondary events in ES.	('NF1', 'Gene', '4763', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('growth advantage', 'CPA', (77, 93))	('NF1', 'Gene', (62, 65))	('biallelic inactivation', 'Var', (36, 58))	('NF1', 'Gene', '4763', (62, 65))	('NF1', 'Gene', (18, 21))	('ES', 'Phenotype', 'HP:0012254', (195, 197))	('ES', 'Disease', 'MESH:D012512', (195, 197))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
148400	31645347	Although the histology of the tumor was consistent with ES, FISH analysis of the tumor specimen showed no structural rearrangements associated with ES, although gains of 12q13.1 (FOXO1), 18q11.2 (SS18), and 22q12 (EWSR1) were observed (Supplemental Table 2).	('ES', 'Phenotype', 'HP:0012254', (56, 58))	('ES', 'Disease', 'MESH:D012512', (56, 58))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('ES', 'Phenotype', 'HP:0012254', (148, 150))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('EWSR1', 'Gene', (214, 219))	('ES', 'Disease', 'MESH:D012512', (148, 150))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('gains', 'PosReg', (161, 166))	('18q11.2', 'Var', (187, 194))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('12q13.1', 'Var', (170, 177))	('EWSR1', 'Gene', '2130', (214, 219))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (81, 86))
148403	31645347	Panel testing revealed a truncating mutation of NF1 (p.K2396*) in the tumor and an inactivating NF1 mutation that was also present in the blood sample (p.Y2285*) (Table 1; Supplemental Fig.	('NF1', 'Gene', '4763', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('p.K2396*', 'Var', (53, 61))	('p.Y2285*', 'Var', (152, 160))	('tumor', 'Disease', (70, 75))	('p.K2396*', 'Mutation', 'p.K2396*', (53, 61))	('p.Y2285*', 'Mutation', 'rs772295894', (152, 160))	('NF1', 'Gene', '4763', (96, 99))	('NF1', 'Gene', (96, 99))	('truncating', 'MPA', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('NF1', 'Gene', (48, 51))
148412	31645347	Ewing sarcoma in patients with NF-1 has been reported only once in the literature, although in that report there was no characterization of the type of ES fusion or NF1 mutations.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (0, 13))	('mutations', 'Var', (169, 178))	('NF-1', 'Gene', '4763', (31, 35))	('ES', 'Phenotype', 'HP:0012254', (152, 154))	('Ewing sarcoma', 'Disease', (0, 13))	('ES', 'Disease', 'MESH:D012512', (152, 154))	('patients', 'Species', '9606', (17, 25))	('NF-1', 'Gene', (31, 35))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('NF1', 'Gene', (165, 168))	('NF1', 'Gene', '4763', (165, 168))
148415	31645347	Mechanistically, EWSR1-ETS fusions exert their oncogenic affect by driving dramatic changes in the transcriptome of cells harboring the fusion.	('changes', 'Reg', (84, 91))	('transcriptome', 'MPA', (99, 112))	('EWSR1', 'Gene', '2130', (17, 22))	('fusions', 'Var', (27, 34))	('EWSR1', 'Gene', (17, 22))
148418	31645347	In support of this, inhibition of the Ras pathway through MEK1/2 inhibitors has been shown to suppress malignant phenotypes in ES cell lines.	('MEK1/2', 'Gene', (58, 64))	('ES', 'Disease', 'MESH:D012512', (127, 129))	('Ras pathway', 'Pathway', (38, 49))	('inhibition', 'Var', (20, 30))	('suppress', 'NegReg', (94, 102))	('ES', 'Phenotype', 'HP:0012254', (127, 129))
148420	31645347	It is interesting to speculate that as Ras is a main converging point for downstream signaling of activated RTKs up-regulated in ES, the acquisition of mutations or implementation of other molecular mechanisms that can result in Ras pathway activation may be advantageous to ES cells.	('ES', 'Phenotype', 'HP:0012254', (275, 277))	('mutations', 'Var', (152, 161))	('ES', 'Disease', 'MESH:D012512', (275, 277))	('RTKs', 'Gene', (108, 112))	('up-regulated', 'PosReg', (113, 125))	('ES', 'Phenotype', 'HP:0012254', (129, 131))	('activation', 'PosReg', (241, 251))	('ES', 'Disease', 'MESH:D012512', (129, 131))
148423	31645347	The germline NF1 p.Y2285* (c.6855C>A) found in the patient described here is a known pathogenic variant associated with NF-1 (Table 1; ClinVar ID 185082).	('c.6855C>A', 'Mutation', 'rs772295894', (27, 36))	('p.Y2285*', 'Mutation', 'rs772295894', (17, 25))	('NF-1', 'Gene', (120, 124))	('NF1', 'Gene', (13, 16))	('NF1', 'Gene', '4763', (13, 16))	('patient', 'Species', '9606', (51, 58))	('NF-1', 'Gene', '4763', (120, 124))	('p.Y2285* (c.6855C>A', 'Var', (17, 36))
148424	31645347	The somatic nonsense mutation p.K2396* seen in this patient has been reported in a single sample of a grade IV astrocytoma (COSM5766195).	('astrocytoma', 'Disease', 'MESH:D001254', (111, 122))	('astrocytoma', 'Disease', (111, 122))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('patient', 'Species', '9606', (52, 59))	('p.K2396*', 'Var', (30, 38))	('p.K2396*', 'Mutation', 'p.K2396*', (30, 38))
148426	31645347	One possible explanation for this observation is that the tumor is polyploid and duplicate copies of the wild-type NF1 gene were removed by two independent events:the tumor-specific p.K2396* mutation and loss of a chromosome.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('NF1', 'Gene', (115, 118))	('p.K2396*', 'Mutation', 'p.K2396*', (182, 190))	('NF1', 'Gene', '4763', (115, 118))	('loss', 'NegReg', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('p.K2396*', 'Var', (182, 190))	('tumor', 'Disease', (167, 172))
148430	31645347	Although not definitive, the two nonsense mutations in NF1 in conjunction with the Chromosome 17 deletion encompassing NF1 favor a model of biallelic inactivation and reduces the likelihood that NF1 inactivation is happening by chance in this tumor; biallelic inactivation of NF1 suggests that there was a selective advantage to losing the wild-type allele and that NF1 is contributing to sarcomagenesis.	('NF1', 'Gene', '4763', (55, 58))	('NF1', 'Gene', '4763', (276, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (389, 396))	('NF1', 'Gene', (119, 122))	('NF1', 'Gene', (366, 369))	('NF1', 'Gene', (55, 58))	('tumor', 'Disease', (243, 248))	('NF1', 'Gene', (276, 279))	('biallelic', 'MPA', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('NF1', 'Gene', '4763', (195, 198))	('contributing', 'Reg', (373, 385))	('NF1', 'Gene', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('sarcoma', 'Disease', 'MESH:D012509', (389, 396))	('sarcoma', 'Disease', (389, 396))	('biallelic', 'Var', (250, 259))	('NF1', 'Gene', '4763', (119, 122))	('NF1', 'Gene', '4763', (366, 369))	('mutations', 'Var', (42, 51))
148431	31645347	Mutations in Ras pathway genes have only infrequently been reported in ES.	('ES', 'Phenotype', 'HP:0012254', (71, 73))	('Mutations', 'Var', (0, 9))	('ES', 'Disease', 'MESH:D012512', (71, 73))	('Ras pathway', 'Pathway', (13, 24))
148432	31645347	Querying the GENIE cBioPortal database (v5.0) confirmed the paucity of Ras pathway mutations in ES, with only four cases of 143 ES patients in whose tumors mutated Ras pathway genes were detected.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (83, 92))	('ES', 'Phenotype', 'HP:0012254', (96, 98))	('ES', 'Disease', 'MESH:D012512', (96, 98))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('ES', 'Phenotype', 'HP:0012254', (128, 130))	('ES', 'Disease', 'MESH:D012512', (128, 130))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Ras pathway', 'Pathway', (71, 82))
148442	31645347	The analysis was based on the human reference sequence (NCBI build 37) using the following software packages: BWA 0.7.13, Samtools 1.1 (using htslib 1.1), Picard tools 1.97 (1504), GATK Appistry v2015.1.1-3.4.46-0-ga8e1d99, CNVkit 0.7.2, Pindel 0.2.5b8, SATK Appistry v2015.1.1-1-gea45d62, ANNOVAR v2016Feb01, FreeBayes 0.9.20, and Delly 0.7.2.13-20 Single-nucleotide variants, insertions/deletions, and structural variants were visualized and verified using the Integrated Genome Viewer.	('human', 'Species', '9606', (30, 35))	('Single-nucleotide', 'Var', (350, 367))	('insertions/deletions', 'Var', (378, 398))
148444	31645347	Probes for detecting the EWSR1 fusion were from Abbott Molecular.	('fusion', 'Var', (31, 37))	('EWSR1', 'Gene', (25, 30))	('EWSR1', 'Gene', '2130', (25, 30))
148448	31645347	The NF1 and EWSR1-ERG variants described in this study were submitted to ClinVar  and can be found under accession numbers SCV000993588-SCV000993590.	('ERG', 'Gene', '2078', (18, 21))	('ERG', 'Gene', (18, 21))	('NF1', 'Gene', (4, 7))	('EWSR1', 'Gene', (12, 17))	('NF1', 'Gene', '4763', (4, 7))	('variants', 'Var', (22, 30))	('EWSR1', 'Gene', '2130', (12, 17))
148462	30709383	Reverse transcription-polymerase chain reaction (RT-PCR) from the resected specimen and sequencing of RT-PCR products demonstrated a chimeric SYT-SSX1 transcript, confirming the diagnosis of synovial sarcoma.	('SYT', 'Gene', (142, 145))	('synovial sarcoma', 'Disease', (191, 207))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (191, 207))	('SYT', 'Gene', '6760', (142, 145))	('chimeric', 'Var', (133, 141))	('SSX1', 'Gene', '6756', (146, 150))	('men', 'Species', '9606', (80, 83))	('synovial sarcoma', 'Disease', 'MESH:D013584', (191, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('SSX1', 'Gene', (146, 150))
148495	30709383	Reverse transcription-polymerase chain reaction (RT-PCR) from the resected specimen and sequencing of RT-PCR products demonstrated a chimeric SYT-SSX1 transcript (Fig.	('SYT', 'Gene', (142, 145))	('SYT', 'Gene', '6760', (142, 145))	('SSX1', 'Gene', '6756', (146, 150))	('chimeric', 'Var', (133, 141))	('men', 'Species', '9606', (80, 83))	('SSX1', 'Gene', (146, 150))
148525	30709383	Although the lesion was heterogeneously enhanced using Gd.-DTPA on T1-WI MRI, the findings did not lead us to suspect a malignant tumor.	('malignant tumor', 'Disease', 'MESH:D018198', (120, 135))	('Gd.-DTPA', 'Var', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Gd.-DTPA', 'Chemical', 'MESH:D019786', (55, 63))	('enhanced', 'PosReg', (40, 48))	('malignant tumor', 'Disease', (120, 135))
148583	28904666	Epidemiological studies have indicated that HHV-8 seropositivity in various populations is strongly correlated with the population's risk of developing KS.	('seropositivity', 'Var', (50, 64))	('HHV-8', 'Gene', (44, 49))	('KS', 'Phenotype', 'HP:0100726', (152, 154))	('HHV-8', 'Species', '37296', (44, 49))	('correlated', 'Reg', (100, 110))
148674	28690908	The histopathology report revealed that the patient had a round cell tumor, which was positive for Ewing's sarcoma, EWS-FLI1 fusion gene, and membranous expression of CD99 and S-100 proteins.	("Ewing's sarcoma", 'Disease', (99, 114))	('round', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('patient', 'Species', '9606', (44, 51))	('CD99', 'Gene', (167, 171))	('fusion gene', 'Var', (125, 136))	('S-100 proteins', 'Protein', (176, 190))	('tumor', 'Disease', (69, 74))	('CD99', 'Gene', '4267', (167, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (99, 114))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (99, 114))	('FLI1', 'Gene', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('EWS', 'Gene', '2130', (116, 119))	('EWS', 'Gene', (116, 119))	('FLI1', 'Gene', '2313', (120, 124))
148742	27981088	Similarly, patients under Taxane therapies had lower SoWB values (chi2 = 29.134, P = 0.0001) [Table 2].	('lower', 'NegReg', (47, 52))	('Taxane therapies', 'Var', (26, 42))	('SoWB values', 'MPA', (53, 64))	('patients', 'Species', '9606', (11, 19))	('Taxane', 'Chemical', 'MESH:C080625', (26, 32))
148750	27981088	In men, 6th cure of chemotherapy worsened SoWB; urinary cancer, student, taxane cure and lymphoma worsened SoWB; and singleness worsened general well-being and, therefore, quality of life.	('urinary cancer', 'Disease', 'MESH:D001749', (48, 62))	('SoWB', 'MPA', (42, 46))	('SoWB', 'MPA', (107, 111))	('worsened', 'NegReg', (33, 41))	('lymphoma', 'Disease', (89, 97))	('taxane', 'Chemical', 'MESH:C080625', (73, 79))	('worsened', 'NegReg', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lymphoma', 'Disease', 'MESH:D008223', (89, 97))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('urinary cancer', 'Disease', (48, 62))	('urinary cancer', 'Phenotype', 'HP:0010786', (48, 62))	('quality of life', 'CPA', (172, 187))	('worsened', 'NegReg', (128, 136))	('singleness', 'Var', (117, 127))	('general well-being', 'CPA', (137, 155))	('men', 'Species', '9606', (3, 6))
148764	27981088	We found that patients with operation, radiotherapy and chemotherapy had worse SoWB than those with chemotherapy or operation + chemotherapy.	('radiotherapy', 'Var', (39, 51))	('worse', 'NegReg', (73, 78))	('chemotherapy', 'Var', (56, 68))	('patients', 'Species', '9606', (14, 22))	('SoWB', 'MPA', (79, 83))
148799	27981088	stated that patients positive for religion had better quality of life than those negative for the same.	('patients', 'Species', '9606', (12, 20))	('religion', 'Var', (34, 42))	('quality of life', 'CPA', (54, 69))	('better', 'PosReg', (47, 53))
148802	22649772	Progressive disease may arise via a combination of: (1) selection of chemotherapy-resistant clones in primary tumor, (2) signaling from bone or lung microenvironments that may attract tumor cells to distant locations, and/or (3) genetic changes within the ES cells themselves due to DNA-damaging chemotherapeutic agents or other "hits."	('Progressive disease', 'Disease', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('arise', 'Reg', (24, 29))	('tumor', 'Disease', (184, 189))	('ES', 'Phenotype', 'HP:0012254', (256, 258))	('genetic changes', 'Var', (229, 244))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
148805	22649772	Nearly every case of ES harbors a translocation of the EWSR1 gene, found on chromosome 22, with a member of the ETS family on chromosomes 11, 21, or others.	('translocation', 'Var', (34, 47))	('EWSR1', 'Gene', (55, 60))	('EWSR1', 'Gene', '2130', (55, 60))	('ES', 'Phenotype', 'HP:0012254', (21, 23))
148811	22649772	This research supports that the EWS-FLI1 translocation is an initiating event in sarcomagenesis, but that other biological processes are required for full tumorigenesis to occur (Lessnick et al.,; Castillero-Trejo et al.,).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('translocation', 'Var', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('tumor', 'Disease', (155, 160))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('EWS-FLI1', 'Gene', (32, 40))
148855	22649772	Phosphorylation at threonine 567 (T567) of ezrin is essential for ezrin-mediated transduction of growth signals; mutation at this site, leading to absence of phosphorylation at T567 (so called ezrinT567A mutants), causes down-regulation of growth via the AKT/mTOR (mammalian target of rapamycin) pathway.	('mutation', 'Var', (113, 121))	('AKT', 'Gene', (255, 258))	('phosphorylation', 'MPA', (158, 173))	('absence', 'NegReg', (147, 154))	('down-regulation', 'NegReg', (221, 236))	('mTOR', 'Gene', (259, 263))	('mTOR', 'Gene', '2475', (259, 263))	('threonine', 'Chemical', 'MESH:D013912', (19, 28))	('AKT', 'Gene', '207', (255, 258))	('growth', 'MPA', (240, 246))	('mammalian target of rapamycin', 'Gene', '2475', (265, 294))	('mammalian target of rapamycin', 'Gene', (265, 294))
148856	22649772	have shown that ES cell lines (both previously established cell lines and primary cell lines from patient tumor samples) have high levels of ezrin expression, and ezrinT567A mutants maintain a significantly slower growth rate than those with wild type ezrin expression due to increased apoptosis.	('growth rate', 'CPA', (214, 225))	('patient', 'Species', '9606', (98, 105))	('ezrinT567A mutants', 'Var', (163, 181))	('ezrin', 'MPA', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('ES', 'Phenotype', 'HP:0012254', (16, 18))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('slower', 'NegReg', (207, 213))	('apoptosis', 'CPA', (286, 295))	('tumor', 'Disease', (106, 111))
148857	22649772	In addition, injection of ezrinT567A mutant cells into mice produced fewer experimental metastases (2/30 mice developed metastasis) than mice injected with wild type ezrin (8/10 mice) showing that ezrin may also have a role in development and growth of metastasis in ES.	('metastases', 'Disease', (88, 98))	('fewer', 'NegReg', (69, 74))	('mice', 'Species', '10090', (178, 182))	('ezrinT567A', 'Var', (26, 36))	('mice', 'Species', '10090', (55, 59))	('mutant', 'Var', (37, 43))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('ES', 'Phenotype', 'HP:0012254', (267, 269))	('mice', 'Species', '10090', (105, 109))	('mice', 'Species', '10090', (137, 141))
148860	22649772	As cancer genomes become more unstable, the number of copy number aberrations (CNA) increases (Jahromi et al.,).	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('increases', 'PosReg', (84, 93))	('cancer', 'Disease', (3, 9))	('copy number aberrations', 'Var', (54, 77))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
148861	22649772	Copy number analysis of primary tumors may be a way to identify tumors that are at higher risk of metastasis or relapse than others.	('tumors', 'Disease', (64, 70))	('primary tumors', 'Disease', (24, 38))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Copy', 'Var', (0, 4))	('primary tumors', 'Disease', 'MESH:D009369', (24, 38))	('metastasis', 'CPA', (98, 108))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
148862	22649772	Several other tumor types have copy number changes that are being used to risk stratify therapy for patients (e.g., neuroblastoma; Attiyeh et al.,), but this is currently not possible for ES due to its rarity and challenge of obtaining a large enough cohort to study.	('tumor', 'Disease', (14, 19))	('neuroblastoma', 'Disease', 'MESH:D009447', (116, 129))	('neuroblastoma', 'Disease', (116, 129))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('ES', 'Phenotype', 'HP:0012254', (188, 190))	('copy number changes', 'Var', (31, 50))	('neuroblastoma', 'Phenotype', 'HP:0003006', (116, 129))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
148863	22649772	In the late 1990s to early 2000s, several researchers described chromosomal gain in ES tumor samples - most commonly trisomy 1q [due to derivative chromosome (1:16)], trisomy 8, and trisomy 12 in 25, 35, and 25% of samples respectively (Armengol et al.,; Tarkkanen et al.,).	('chromosomal', 'MPA', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ES tumor', 'Disease', 'MESH:C563168', (84, 92))	('ES tumor', 'Disease', (84, 92))	('trisomy 12', 'Var', (182, 192))	('gain', 'PosReg', (76, 80))	('ES', 'Phenotype', 'HP:0012254', (84, 86))	('trisomy 1q [', 'Var', (117, 129))	('trisomy 8', 'Var', (167, 176))
148874	22649772	Mean copy number changes per tumor in other sarcomas such as osteosarcoma, malignant fibrous histiocytoma, and chondrosarcoma have been reported around 11, 6, and 6 respectively (Tarkkanen et al.,; Larramendy et al.,).	('osteosarcoma', 'Disease', (61, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('chondrosarcoma', 'Disease', 'MESH:D002813', (111, 125))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('malignant fibrous histiocytoma', 'Disease', (75, 105))	('chondrosarcoma', 'Disease', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('copy number changes', 'Var', (5, 24))	('sarcomas', 'Disease', 'MESH:D012509', (44, 52))	('tumor', 'Disease', (29, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (111, 125))	('sarcomas', 'Disease', (44, 52))	('histiocytoma', 'Phenotype', 'HP:0012315', (93, 105))
148876	22649772	This supports studies on cultured human ES cells in which knockdown of EWS-FLI expression was shown to be sufficient to reverse transformation and tumorigenic properties (May et al.,).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('human', 'Species', '9606', (34, 39))	('tumor', 'Disease', (147, 152))	('FLI', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('ES', 'Phenotype', 'HP:0012254', (40, 42))	('FLI', 'Gene', '2314', (75, 78))	('knockdown', 'Var', (58, 67))	('reverse transformation', 'CPA', (120, 142))
148900	32575417	Further, 75% of lung adenocarcinomas are caused by genetic alterations promoting the RTK/RAS/RAF (receptor tyrosine kinase, rat sarcoma virus, and serine/threonine-protein kinase, respectively) signaling pathway, including Kirsten rat sarcoma (KRAS, 32%), epidermal growth factor receptor (EGFR, 11%), v-Raf murine sarcoma viral oncogene homolog B (BRAF, 7%), and mesenchymal-epithelial transition (MET) exon 14 skipping mutations (4.3%).	('rat', 'Species', '10116', (231, 234))	('serine/threonine-protein kinase', 'Pathway', (147, 178))	('sarcoma', 'Disease', 'MESH:D012509', (315, 322))	('RAF', 'Gene', 'None', (350, 353))	('BRAF', 'Gene', (349, 353))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (16, 36))	('sarcoma', 'Disease', (315, 322))	('rat', 'Species', '10116', (63, 66))	('receptor tyrosine kinase', 'Gene', '5979', (98, 122))	('alterations', 'Var', (59, 70))	('lung adenocarcinomas', 'Disease', (16, 36))	('serine', 'Chemical', 'MESH:D012694', (147, 153))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('sarcoma', 'Disease', (235, 242))	('receptor tyrosine kinase', 'Gene', (98, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (315, 322))	('epidermal growth factor receptor', 'Gene', '24329', (256, 288))	('RAF', 'Gene', 'None', (93, 96))	('rat', 'Species', '10116', (124, 127))	('RAF', 'Gene', (350, 353))	('rat sarcoma virus', 'Species', '11848', (124, 141))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (302, 347))	('mesenchymal-epithelial transition', 'CPA', (364, 397))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('skipping', 'NegReg', (412, 420))	('epidermal growth factor receptor', 'Gene', (256, 288))	('sarcoma', 'Disease', 'MESH:D012509', (128, 135))	('BRAF', 'Gene', '109880', (349, 353))	('sarcoma', 'Disease', (128, 135))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '114486', (302, 347))	('RAF', 'Gene', (93, 96))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (16, 36))	('promoting', 'PosReg', (71, 80))
148901	32575417	The common alterations in squamous cell carcinoma include alterations in the RTK (26%), RAS (24%), and phosphoinositide 3-kinase (PI3K) pathways (47%); however, MET exon 14 skipping mutation does not qualify as one of the most common molecular mechanisms for its occurrence.	('rat', 'Species', '10116', (15, 18))	('rat', 'Species', '10116', (62, 65))	('RTK', 'Pathway', (77, 80))	('RAS', 'Pathway', (88, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (26, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('squamous cell carcinoma', 'Disease', (26, 49))	('phosphoinositide 3-kinase', 'Gene', (103, 128))	('phosphoinositide 3-kinase', 'Gene', '5293', (103, 128))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 49))	('MET exon 14 skipping mutation', 'Var', (161, 190))	('alterations', 'Reg', (58, 69))
148904	32575417	MET mutation, amplification, and/or overexpression leads to dysregulation of cell proliferation, apoptosis, and migration, which are related to NSCLC occurrence.	('apoptosis', 'CPA', (97, 106))	('NSCLC', 'Disease', (144, 149))	('MET mutation', 'Var', (0, 12))	('rat', 'Species', '10116', (115, 118))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('mutation', 'Var', (4, 12))	('rat', 'Species', '10116', (89, 92))	('migration', 'CPA', (112, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('cell proliferation', 'CPA', (77, 95))	('amplification', 'Var', (14, 27))
148905	32575417	Exon 14 skipping mutations are important molecular drivers in NSCLC and can be evaluated by new generation sequencing.	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('skipping mutations', 'Var', (8, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('rat', 'Species', '10116', (100, 103))
148909	32575417	This manuscript has focused on MET mutations, their inhibitors, and their use in the treatment of advanced NSCLC.	('NSCLC', 'Disease', (107, 112))	('men', 'Species', '9606', (90, 93))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('mutations', 'Var', (35, 44))
148920	32575417	No statistically significant difference in the median PFS was observed in the intent-to-treat population (9.3 months for erlotinib plus emibetuzumab versus (vs.) 9.5 months for erlotinib; hazard ratio (HR) = 0.89; 95% confidence interval (CI): 0.64-1.23), but high MET expression (MET 3+ (positive) in >= 90% of tumor cells) was shown to be related to poor prognosis, with an improvement of 15.3 months observed in the median PFS in the erlotinib plus emibetuzumab group.	('erlotinib', 'Chemical', 'MESH:D000069347', (121, 130))	('emibetuzumab', 'Chemical', 'MESH:C000599789', (136, 148))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('erlotinib', 'Chemical', 'MESH:D000069347', (437, 446))	('erlotinib', 'Chemical', 'MESH:D000069347', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('high MET expression', 'Var', (260, 279))	('men', 'Species', '9606', (383, 386))	('rat', 'Species', '10116', (195, 198))	('tumor', 'Disease', (312, 317))	('emibetuzumab', 'Chemical', 'MESH:C000599789', (452, 464))
148939	32575417	Grade 3 to 5 adverse effects were more frequently observed in the onartuzumab arm than in the placebo arm by 5%: neutropenia (14.8% vs. 5.8%, respectively) and pulmonary embolism (5.6% vs. 0%, respectively).	('pulmonary embolism', 'Disease', 'MESH:D011655', (160, 178))	('neutropenia', 'Disease', 'MESH:D009503', (113, 124))	('neutropenia', 'Phenotype', 'HP:0001875', (113, 124))	('onartuzumab', 'Chemical', 'MESH:C584058', (66, 77))	('onartuzumab', 'Var', (66, 77))	('neutropenia', 'Disease', (113, 124))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (160, 178))	('pulmonary embolism', 'Disease', (160, 178))
148944	32575417	The PFS endpoint in the intent-to-treat group was numerically worse in the onartuzumab arm of the MET+ subgroup of cohort 1.	('worse', 'NegReg', (62, 67))	('onartuzumab', 'Var', (75, 86))	('PFS', 'MPA', (4, 7))	('onartuzumab', 'Chemical', 'MESH:C584058', (75, 86))
148955	32575417	The median OS was 6.8 in the onartuzumab arm vs. 9.1 months in the placebo arm (HR: 1.27; 95% CI: 0.98-1.65; p-value = 0.67), and the former had more deaths (52% vs. 46%) than the latter; the median PFS was 2.7 vs. 2.6 months, respectively (stratified HR: 0.99; 95% CI: 0.81-1.20; p-value = 0.92); the ORR was 8.4% (onartuzumab) vs. 9.6% (placebo), respectively.	('onartuzumab', 'Chemical', 'MESH:C584058', (29, 40))	('rat', 'Species', '10116', (243, 246))	('deaths', 'Disease', 'MESH:D003643', (150, 156))	('onartuzumab', 'Chemical', 'MESH:C584058', (316, 327))	('deaths', 'Disease', (150, 156))	('onartuzumab', 'Var', (316, 327))
148957	32575417	In total, grade 3 to 5 adverse effects were more frequent in the onartuzumab (56%) than in the placebo arm (51.2%); some examples were dyspnea (5.2% vs. 4.5%), hypoalbuminemia (4.0% vs. 0%), venous thrombotic events (3.6% vs. 0.8%), and arterial thrombotic events (2.4% vs. 0.8%); while grade 1 or 2 events, such as rash (39%), diarrhea (39%), dermatitis acneiform (32%), decreased appetite (32%), and fatigue (30%), were similar in both groups.	('rash', 'Disease', (316, 320))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (160, 175))	('dyspnea', 'Disease', (135, 142))	('arterial thrombotic events', 'Phenotype', 'HP:0004420', (237, 263))	('decreased appetite', 'Phenotype', 'HP:0004396', (372, 390))	('dyspnea', 'Disease', 'MESH:D004417', (135, 142))	('dermatitis', 'Phenotype', 'HP:0011123', (344, 354))	('rash', 'Disease', 'MESH:D005076', (316, 320))	('appetite', 'Disease', (382, 390))	('dermatitis acneiform', 'Disease', (344, 364))	('fatigue', 'Disease', (402, 409))	('diarrhea', 'Phenotype', 'HP:0002014', (328, 336))	('venous thrombotic events', 'Phenotype', 'HP:0004936', (191, 215))	('decreased', 'NegReg', (372, 381))	('fatigue', 'Phenotype', 'HP:0012378', (402, 409))	('onartuzumab', 'Chemical', 'MESH:C584058', (65, 76))	('dyspnea', 'Phenotype', 'HP:0002094', (135, 142))	('diarrhea', 'Disease', (328, 336))	('venous thrombotic', 'Disease', (191, 208))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (160, 175))	('onartuzumab', 'Var', (65, 76))	('fatigue', 'Disease', 'MESH:D005221', (402, 409))	('rash', 'Phenotype', 'HP:0000988', (316, 320))	('venous thrombotic', 'Disease', 'MESH:D020246', (191, 208))	('thrombotic', 'Disease', (198, 208))	('thrombotic', 'Disease', (246, 256))	('dermatitis acneiform', 'Disease', 'MESH:D003872', (344, 364))	('diarrhea', 'Disease', 'MESH:D003967', (328, 336))	('thrombotic events', 'Phenotype', 'HP:0001907', (198, 215))	('thrombotic events', 'Phenotype', 'HP:0001907', (246, 263))	('thrombotic', 'Disease', 'MESH:D013927', (198, 208))	('thrombotic', 'Disease', 'MESH:D013927', (246, 256))	('hypoalbuminemia', 'Disease', (160, 175))
148963	32575417	The median OS did not improve in the combined arm compared to the monotherapy arm (8.5 vs. 7.8 months, respectively; HR = 0.98; 95% CI: 0.62-0.89; p-value < 0.001), but exploratory analysis suggested improvement in OS in patients with high MET expression, defined as membranous staining intensity >= 2 in >= 50% of tumor cells upon IHC analysis (HR: 0.70; 95% CI: 0.49-1.01).	('patients', 'Species', '9606', (221, 229))	('improvement', 'PosReg', (200, 211))	('high MET', 'Var', (235, 243))	('men', 'Species', '9606', (207, 210))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('rat', 'Species', '10116', (174, 177))	('expression', 'MPA', (244, 254))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (315, 320))
148975	32575417	Enrollment had to stop earlier than imagined, with 307 rather than 460 patients, because there was a higher rate of interstitial lung disease in the tivantinib (14 patients, 3 deaths) than the placebo group (6 patients, 0 deaths).	('rat', 'Species', '10116', (108, 111))	('deaths', 'Disease', 'MESH:D003643', (176, 182))	('deaths', 'Disease', (176, 182))	('patients', 'Species', '9606', (71, 79))	('deaths', 'Disease', 'MESH:D003643', (222, 228))	('lung disease', 'Disease', (129, 141))	('deaths', 'Disease', (222, 228))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (116, 141))	('lung disease', 'Disease', 'MESH:D008171', (129, 141))	('lung disease', 'Phenotype', 'HP:0002088', (129, 141))	('patients', 'Species', '9606', (210, 218))	('tivantinib', 'Chemical', 'MESH:C551661', (149, 159))	('patients', 'Species', '9606', (164, 172))	('rat', 'Species', '10116', (55, 58))	('men', 'Species', '9606', (6, 9))	('tivantinib', 'Var', (149, 159))
148997	32575417	The cabozantinib group had an overall DCR of 38%, ORR at week 12 was 10% (six patients confirmed partial response), and 64% of these patients showed tumor regression, including those with KRAS and EGFR mutations.	('cabozantinib', 'Chemical', 'MESH:C558660', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('patients', 'Species', '9606', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('patients', 'Species', '9606', (78, 86))	('KRAS', 'Var', (188, 192))	('tumor', 'Disease', (149, 154))	('EGFR', 'Gene', (197, 201))	('mutations', 'Var', (202, 211))
149000	32575417	Crizotinib (PF-02341066) is a selective inhibitor of receptors, such as anaplastic lymphoma kinase (ALK), MET, and proto-oncogene tyrosine-protein kinase ROS (ROS1).	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('anaplastic lymphoma kinase', 'Gene', '238', (72, 98))	('ALK', 'Gene', (100, 103))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (72, 91))	('ROS1', 'Gene', (159, 163))	('PF-02341066', 'Chemical', 'MESH:D000077547', (12, 23))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	('ROS1', 'Gene', '6098', (159, 163))	('anaplastic lymphoma kinase', 'Gene', (72, 98))	('ALK', 'Gene', '238', (100, 103))	('PF-02341066', 'Var', (12, 23))
149002	32575417	A key part of the binding of crizotinib to MET is the establishment of a pi-pi interaction, with the Tyr-1230 residue of the protein, in a dose-dependent manner.	('men', 'Species', '9606', (63, 66))	('crizotinib', 'Chemical', 'MESH:D000077547', (29, 39))	('Tyr-1230', 'Var', (101, 109))	('binding', 'Interaction', (18, 25))	('Tyr', 'Chemical', 'MESH:D014443', (101, 104))	('pi-pi', 'CPA', (73, 78))
149020	32575417	Additionally, the study showed that the group of patients who received crizotinib presented more CNS metastasis.	('crizotinib', 'Chemical', 'MESH:D000077547', (71, 81))	('more', 'PosReg', (92, 96))	('CNS metastasis', 'CPA', (97, 111))	('crizotinib', 'Var', (71, 81))	('patients', 'Species', '9606', (49, 57))
149023	32575417	This drug binds to MET via an aromatic stacking interaction with the Y1230 residue of the protein, and this, like crizotinib, stabilizes the kinase loop of MET in its inactive state.	('crizotinib', 'Chemical', 'MESH:D000077547', (114, 124))	('MET', 'MPA', (156, 159))	('Y1230', 'Chemical', '-', (69, 74))	('protein', 'Protein', (90, 97))	('kinase loop', 'MPA', (141, 152))	('stabilizes', 'Reg', (126, 136))	('aromatic stacking interaction', 'MPA', (30, 59))	('Y1230', 'Var', (69, 74))	('binds', 'Interaction', (10, 15))
149024	32575417	Capmatinib is more potent than crizotinib and is especially potent in c-MET molecules that have specific mutations, such as exon 14 deletions.	('c-MET', 'Gene', (70, 75))	('exon 14 deletions', 'Var', (124, 141))	('Capmatinib', 'Chemical', 'MESH:C000613976', (0, 10))	('c-MET', 'Gene', '4233', (70, 75))	('crizotinib', 'Chemical', 'MESH:D000077547', (31, 41))
149026	32575417	The GEOMETRY mono-1 phase II clinical trial tested the efficacy of daily administration of 400 mg of capmatinib in patients with various MET alterations, and the principal subgroups were composed either of patients with MET exon 14-mutated NSCLC who received 2 prior lines of treatment (cohort 4) or treatment-naive patients (cohort 5b).	('patients', 'Species', '9606', (115, 123))	('NSCLC', 'Disease', (240, 245))	('NSCLC', 'Disease', 'MESH:D002289', (240, 245))	('rat', 'Species', '10116', (81, 84))	('tested', 'Reg', (44, 50))	('men', 'Species', '9606', (305, 308))	('MET exon 14-mutated', 'Var', (220, 239))	('patients', 'Species', '9606', (206, 214))	('capmatinib', 'Chemical', 'MESH:C000613976', (101, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (240, 245))	('patients', 'Species', '9606', (316, 324))	('rat', 'Species', '10116', (145, 148))	('men', 'Species', '9606', (281, 284))
149029	32575417	conducted a phase II clinical trial, investigating the effects of capmatinib (400 mg twice a day) associated with gefitinib (250 mg once a day) in patients with activating MET mutations who had a background of tumor progression despite being administered anti-EGFR treatment.	('mutations', 'Var', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('activating', 'PosReg', (161, 171))	('MET', 'Gene', (172, 175))	('capmatinib', 'Chemical', 'MESH:C000613976', (66, 76))	('tumor', 'Disease', (210, 215))	('men', 'Species', '9606', (270, 273))	('patients', 'Species', '9606', (147, 155))	('gefitinib', 'Chemical', 'MESH:D000077156', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
149057	32575417	The two analyzed trials showed promising results, especially in treatment-naive patients with MET exon 14-mutated NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('men', 'Species', '9606', (69, 72))	('patients', 'Species', '9606', (80, 88))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('MET exon 14-mutated', 'Var', (94, 113))
149058	32575417	The second study also presented a positive perspective for the use of capmatinib to treat NSCLC, with more significant results in patients with a higher number of gene copy number.	('capmatinib', 'Chemical', 'MESH:C000613976', (70, 80))	('NSCLC', 'Disease', (90, 95))	('gene copy number', 'Var', (163, 179))	('patients', 'Species', '9606', (130, 138))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
149060	32575417	When it comes to immunotherapy, patients with mutated MET have a low ORR to these drugs (17%).	('patients', 'Species', '9606', (32, 40))	('mutated', 'Var', (46, 53))	('ORR to', 'MPA', (69, 75))	('low', 'NegReg', (65, 68))	('MET', 'Gene', (54, 57))
149063	32575417	This opens up a promising perspective because studies show that around 60% of patients with MET exon 14 skipping alterations are positive for PD-L1.	('positive', 'Reg', (129, 137))	('rat', 'Species', '10116', (117, 120))	('PD-L1', 'Gene', '29126', (142, 147))	('skipping alterations', 'Var', (104, 124))	('patients', 'Species', '9606', (78, 86))	('MET exon 14', 'Gene', (92, 103))	('PD-L1', 'Gene', (142, 147))
149067	32575417	MET inhibitors are a group of drugs that could help NSCLC patients with MET alterations, especially exon 14 skipping mutation, present in 2-3% of lung cancers.	('alterations', 'Var', (76, 87))	('patients', 'Species', '9606', (58, 66))	('NSCLC', 'Disease', (52, 57))	('rat', 'Species', '10116', (80, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancers', 'Disease', (146, 158))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('exon 14 skipping mutation', 'Var', (100, 125))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('MET', 'Gene', (72, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('lung cancers', 'Disease', 'MESH:D008175', (146, 158))	('lung cancers', 'Phenotype', 'HP:0100526', (146, 158))
149072	32575417	These drugs could be alternatives for NSCLC treatment of patients with MET mutations and/or EGFR-TKI resistance, resulting in improvements in the way patients with NSCLC are treated, their survival, and their quality of life during and after treatment.	('NSCLC', 'Disease', (38, 43))	('NSCLC', 'Disease', (164, 169))	('men', 'Species', '9606', (49, 52))	('EGFR-TKI', 'Gene', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('men', 'Species', '9606', (247, 250))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('patients', 'Species', '9606', (57, 65))	('survival', 'CPA', (189, 197))	('resistance', 'Var', (101, 111))	('quality of life', 'CPA', (209, 224))	('patients', 'Species', '9606', (150, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('men', 'Species', '9606', (133, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('improvements', 'PosReg', (126, 138))	('MET', 'Gene', (71, 74))
149180	29118718	Based on our in vivo and in vitro data, we have demonstrated that p38-MAPK and p21 are activated in the tumors of less-active mice and that p38-MAPK is able to up-regulate p21 expression (Assi et al.,).	('p21', 'Gene', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mice', 'Species', '10090', (126, 130))	('p21', 'Gene', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('expression', 'MPA', (176, 186))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('p38-MAPK', 'Gene', (66, 74))	('up-regulate', 'PosReg', (160, 171))	('activated', 'PosReg', (87, 96))	('p38-MAPK', 'Var', (140, 148))
149245	26380223	By contrast, a dose level in mice giving systemic exposure on the high side of that achievable in humans (66 mg/kg, Figure 1) showed activity only against Rh28 RMS that is deficient in MGMT required for repair of O6G adducts.	('MGMT', 'Gene', '4255', (185, 189))	('MGMT', 'Gene', (185, 189))	('O6G', 'Var', (213, 216))	('Rh28 RMS', 'Gene', (155, 163))	('humans', 'Species', '9606', (98, 104))	('activity', 'MPA', (133, 141))	('mice', 'Species', '10090', (29, 33))
149248	26380223	By contrast, the tubulin-binding agent, BAL101553, showed no significant antitumor activity against sarcoma models.	('sarcoma', 'Disease', (100, 107))	('BAL101553', 'Var', (40, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))
149251	26380223	However, at dose levels in mice that approximate human drug exposure, PR-104 was not active against solid tumor xenograft models.	('mice', 'Species', '10090', (27, 31))	('human', 'Species', '9606', (49, 54))	('not', 'NegReg', (81, 84))	('solid tumor', 'Disease', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PR-104', 'Var', (70, 76))	('solid tumor', 'Disease', 'MESH:D009369', (100, 111))
149252	26380223	The non-camptothecin topoisomerase I inhibitor, GENZ644282, was active against SK-NEP-1 Ewing sarcoma, whereas topotecan was not.	('GENZ644282', 'Var', (48, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('topotecan', 'Chemical', 'MESH:D019772', (111, 120))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('camptothecin', 'Chemical', 'MESH:D002166', (8, 20))	('GENZ644282', 'Chemical', 'MESH:C560916', (48, 58))	('Ewing sarcoma', 'Disease', (88, 101))	('active', 'MPA', (64, 70))
149253	26380223	Other cytotoxic agents having novel mechanisms of action [aplidin, KPT-330 (selinexor, a CRM1/XPO1 inhibitor), CX-5461 (RNA pol I inhibitor)] and the PARP1 inhibitor, BMN-673, showed little or no antitumor activity against sarcoma models.	('sarcoma', 'Disease', (223, 230))	('KPT-330', 'Chemical', 'MESH:C585161', (67, 74))	('CX-5461', 'Chemical', 'MESH:C557717', (111, 118))	('PARP1', 'Gene', '142', (150, 155))	('CRM1', 'Gene', (89, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('tumor', 'Disease', (200, 205))	('selinexor', 'Chemical', 'MESH:C585161', (76, 85))	('XPO1', 'Gene', (94, 98))	('KPT-330', 'Gene', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('CX-5461', 'Var', (111, 118))	('aplidin', 'Chemical', 'MESH:C098980', (58, 65))	('CRM1', 'Gene', '7514', (89, 93))	('PARP1', 'Gene', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('XPO1', 'Gene', '7514', (94, 98))	('BMN-673', 'Chemical', 'MESH:C586365', (167, 174))	('sarcoma', 'Disease', 'MESH:D012509', (223, 230))
149254	26380223	These include classical inhibitors of the IGF-PI3K-TOR pathway including antibodies and drugs targeting IGF-1R (19D12, IMC-A12, BMS-754807), and small molecule drugs that selectively inhibit PI3K (XL-147), AKT (MK-2206), TOR (rapamycin, AZD8055, INK128), MEK (AZD6244) as well as multikinase inhibitors (sorafenib, SU11248, cabozantinib), and inhibitors of mitotic kinases (MLN8237, BI6727).	('AKT', 'Gene', (206, 209))	('TOR', 'Gene', '6097', (51, 54))	('inhibit', 'NegReg', (183, 190))	('PI3K', 'Enzyme', (191, 195))	('MLN8237', 'Var', (374, 381))	('IGF-1R', 'Gene', '3480', (104, 110))	('IGF-1R', 'Gene', (104, 110))	('TOR', 'Gene', (51, 54))	('multikinase', 'Enzyme', (280, 291))	('AKT', 'Gene', '207', (206, 209))	('BI6727', 'Chemical', 'MESH:C541363', (383, 389))	('AZD8055', 'Var', (237, 244))	('MEK', 'Gene', '5609', (255, 258))	('AZD6244', 'Var', (260, 267))	('TOR', 'Gene', '6097', (221, 224))	('BI6727', 'Var', (383, 389))	('sorafenib', 'Var', (304, 313))	('INK128', 'Var', (246, 252))	('MEK', 'Gene', (255, 258))	('rapamycin', 'Var', (226, 235))	('SU11248', 'Var', (315, 322))	('TOR', 'Gene', (221, 224))	('mitotic', 'Enzyme', (357, 364))	('MK-2206', 'Var', (211, 218))
149256	26380223	Of these, inhibitors of mitotic kinases [PLK1 (BI6727), Aurora kinase (MLN8237)], and the kinesin inhibitor (GSK923295A) showed the greatest activity, consistent with the activity of other "non-signaling" anti-mitotic drugs (vincristine, eribulin).	('MLN8237)]', 'Var', (71, 80))	('activity', 'MPA', (141, 149))	('mitotic kinases', 'Enzyme', (24, 39))	('PLK1', 'Gene', (41, 45))	('GSK923295A', 'Chemical', 'MESH:C571460', (109, 119))	('eribulin', 'Chemical', 'MESH:C490954', (238, 246))	('BI6727', 'Var', (47, 53))	('PLK1', 'Gene', '5347', (41, 45))	('vincristine', 'Chemical', 'MESH:D014750', (225, 236))	('BI6727', 'Chemical', 'MESH:C541363', (47, 53))
149260	26380223	For example, notable exceptions are the response to selumetinib (MEK inhibitor) in an astrocytoma with a BRAFV600E mutation, the complete response to dasatinib in the Ph+ ALL-4 xenograft , expected based on the preclinical and clinical activity for dasatinib against Bcr-Abl expressing leukemias and responses in Ewing sarcoma and other sarcomas to IGF-1 receptor targeting antibodies.	('leukemias', 'Phenotype', 'HP:0001909', (286, 295))	('astrocytoma', 'Disease', 'MESH:D001254', (86, 97))	('astrocytoma', 'Disease', (86, 97))	('Ewing sarcoma', 'Disease', (313, 326))	('leukemia', 'Phenotype', 'HP:0001909', (286, 294))	('mutation', 'Var', (115, 123))	('Bcr-Abl', 'Gene', (267, 274))	('BRAFV600E', 'Gene', (105, 114))	('dasatinib', 'Chemical', 'MESH:D000069439', (150, 159))	('leukemias', 'Disease', (286, 295))	('selumetinib', 'Chemical', 'MESH:C517975', (52, 63))	('sarcomas', 'Disease', 'MESH:D012509', (337, 345))	('sarcomas', 'Phenotype', 'HP:0100242', (337, 345))	('MEK', 'Gene', '5609', (65, 68))	('astrocytoma', 'Phenotype', 'HP:0009592', (86, 97))	('sarcomas', 'Disease', (337, 345))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (313, 326))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (313, 326))	('Bcr-Abl', 'Gene', '25', (267, 274))	('dasatinib', 'Chemical', 'MESH:D000069439', (249, 258))	('MEK', 'Gene', (65, 68))	('ALL', 'Phenotype', 'HP:0006721', (171, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (337, 344))	('leukemias', 'Disease', 'MESH:D007938', (286, 295))	('BRAFV600E', 'Mutation', 'rs113488022', (105, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (319, 326))
149281	26380223	The drugs, MLN8237 (alisertib) and BI6726 (volasertib), are both somewhat effective anti-mitotic targeted therapies evaluated by the PPTP that inhibit Aurora kinase A (AURKA) and Polo-like kinase 1, respectively.	('BI6726', 'Chemical', '-', (35, 41))	('Polo-like kinase 1', 'Gene', (179, 197))	('volasertib', 'Chemical', 'MESH:C541363', (43, 53))	('BI6726', 'Var', (35, 41))	('Aurora kinase A', 'Gene', '6790', (151, 166))	('PPTP', 'Chemical', '-', (133, 137))	('MLN8237', 'Var', (11, 18))	('inhibit', 'NegReg', (143, 150))	('Aurora kinase A', 'Gene', (151, 166))	('alisertib', 'Chemical', 'MESH:C550258', (20, 29))	('Polo-like kinase 1', 'Gene', '5347', (179, 197))
149289	26380223	Disruption of the microtubules prevents formation of the mitotic spindle required to segregate chromosomes and arrests mitosis in metaphase.	('arrests mitosis', 'Disease', 'MESH:D006323', (111, 126))	('prevents', 'NegReg', (31, 39))	('microtubules', 'Protein', (18, 30))	('arrests mitosis', 'Disease', (111, 126))	('Disruption', 'Var', (0, 10))
149292	26380223	As shown in Figure 1, vincristine was evaluated against five Ewing sarcomas (SK-NEP-1, EW5, EW8, TC-71, and CHLA258), six alveolar rhabdomyosarcomas (Rh10, Rh28, Rh30, Rh30R, Rh41, and Rh65), two embryonal rhabdomyosarcomas (Rh18 and Rh36), and six OSs (OS-1, OS-2, OS-9, OS-17, OS-31, and OS-33).	('embryonal rhabdomyosarcomas', 'Disease', (196, 223))	('embryonal rhabdomyosarcomas', 'Phenotype', 'HP:0006743', (196, 223))	('Ewing sarcomas', 'Disease', (61, 75))	('OS-9', 'CellLine', 'CVCL:9988', (266, 270))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (61, 75))	('OS', 'Phenotype', 'HP:0002669', (260, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('alveolar rhabdomyosarcomas', 'Disease', (122, 148))	('Rh30', 'Gene', '6007', (162, 166))	('vincristine', 'Chemical', 'MESH:D014750', (22, 33))	('OS', 'Phenotype', 'HP:0002669', (266, 268))	('Rh30', 'Gene', (168, 172))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (131, 147))	('OS', 'Phenotype', 'HP:0002669', (272, 274))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (122, 148))	('Rh65', 'Var', (185, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (122, 147))	('OS', 'Phenotype', 'HP:0002669', (249, 251))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('OSs', 'Chemical', '-', (249, 252))	('embryonal rhabdomyosarcomas', 'Disease', 'MESH:D018233', (196, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('Rh30', 'Gene', '6007', (168, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (206, 223))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (122, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Rh10', 'Var', (150, 154))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (206, 222))	('Rh30', 'Gene', (162, 166))	('Rh41', 'Var', (175, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (61, 75))	('OS', 'Phenotype', 'HP:0002669', (254, 256))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (131, 148))
149315	26380223	The mechanism of inhibition of microtubule dynamic instability by eribulin is distinctive from that of other tubulin-binding anti-mitotic agents in that eribulin suppresses the growth parameters at microtubule plus ends without affecting microtubule shortening parameters.	('eribulin', 'Chemical', 'MESH:C490954', (153, 161))	('growth parameters at microtubule plus ends', 'MPA', (177, 219))	('microtubule', 'MPA', (31, 42))	('suppresses', 'NegReg', (162, 172))	('eribulin', 'Chemical', 'MESH:C490954', (66, 74))	('eribulin', 'Var', (153, 161))
149326	26380223	These enzymes play key roles in mitosis and meiosis, defects in which can lead to abnormal mitotic events and induction of programed cell death (apoptosis).	('lead to', 'Reg', (74, 81))	('programed cell death', 'CPA', (123, 143))	('defects', 'Var', (53, 60))	('mitosis and meiosis', 'Disease', 'MESH:C536875', (32, 51))	('abnormal mitotic events', 'CPA', (82, 105))
149334	26380223	Increased copy number was present 14 of the solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('copy number', 'Var', (10, 21))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('solid tumors', 'Disease', (44, 56))
149335	26380223	Loss of copy number was detected in seven solid tumors and one leukemia model.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('leukemia', 'Disease', (63, 71))	('leukemia', 'Phenotype', 'HP:0001909', (63, 71))	('leukemia', 'Disease', 'MESH:D007938', (63, 71))	('solid tumors', 'Disease', (42, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('Loss', 'NegReg', (0, 4))	('solid tumors', 'Disease', 'MESH:D009369', (42, 54))	('copy number', 'Var', (8, 19))
149336	26380223	While there is no absolute relationship between CNV and tumor sensitivity, of the 14 solid tumors with increased copy number, there were only two that showed sensitivity to alisertib.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('copy number', 'Var', (113, 124))	('solid tumors', 'Disease', (85, 97))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('alisertib', 'Chemical', 'MESH:C550258', (173, 182))	('solid tumors', 'Disease', 'MESH:D009369', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
149344	26380223	Numerous lines of evidence suggest that Plk1 is oncogenic through driving cell cycle progression, and overexpression of the gene transforms NIH 3T3 cells.	('Plk1', 'Gene', (40, 44))	('cell cycle progression', 'CPA', (74, 96))	('driving', 'PosReg', (66, 73))	('NIH 3T3', 'CellLine', 'CVCL:0594', (140, 147))	('overexpression', 'Var', (102, 116))
149351	26380223	Specifically, KAT7, DNHD1, DDX39B, and RASGRF1 are known to have protein-protein interactions with PLK1 while mutant PLK1 (51-356 AA deletion) increases MAD2L1 protein localization to kinetochores from misguided chromosomes of metaphase cells and PLK1 protein increases inhibition of active PKMYT1 as well as increase phosphorylation of a PKMYT1 protein fragment.	('PKMYT1', 'Gene', (291, 297))	('MAD2L1', 'Gene', (153, 159))	('localization', 'MPA', (168, 180))	('KAT7', 'Gene', (14, 18))	('PLK1', 'Gene', '5347', (117, 121))	('PKMYT1', 'Gene', (339, 345))	('DNHD1', 'Gene', (20, 25))	('PLK1', 'Gene', (99, 103))	('PLK1', 'Gene', (247, 251))	('protein', 'Protein', (160, 167))	('active', 'MPA', (284, 290))	('inhibition', 'MPA', (270, 280))	('DDX39B', 'Gene', (27, 33))	('phosphorylation', 'MPA', (318, 333))	('DDX39B', 'Gene', '7919', (27, 33))	('RASGRF1', 'Gene', '5923', (39, 46))	('PLK1', 'Gene', '5347', (99, 103))	('PLK1', 'Gene', '5347', (247, 251))	('interactions', 'Interaction', (81, 93))	('mutant', 'Var', (110, 116))	('PKMYT1', 'Gene', '9088', (291, 297))	('PKMYT1', 'Gene', '9088', (339, 345))	('increases', 'PosReg', (143, 152))	('RASGRF1', 'Gene', (39, 46))	('PLK1', 'Gene', (117, 121))	('DNHD1', 'Gene', '144132', (20, 25))	('MAD2L1', 'Gene', '4085', (153, 159))	('KAT7', 'Gene', '11143', (14, 18))	('increases', 'PosReg', (260, 269))	('increase', 'PosReg', (309, 317))
149352	26380223	MAD2L1 and PKMYT1, both negatively correlated with rIC50, may point to PLK1 targets over-expressed when PLK1 is mutated.	('PKMYT1', 'Gene', '9088', (11, 17))	('PLK1', 'Gene', '5347', (104, 108))	('negatively', 'NegReg', (24, 34))	('MAD2L1', 'Gene', '4085', (0, 6))	('rIC50', 'MPA', (51, 56))	('PLK1', 'Gene', (71, 75))	('over-expressed', 'PosReg', (84, 98))	('PKMYT1', 'Gene', (11, 17))	('PLK1', 'Gene', '5347', (71, 75))	('MAD2L1', 'Gene', (0, 6))	('mutated', 'Var', (112, 119))	('PLK1', 'Gene', (104, 108))
149354	26380223	The elevated PKMYT1 mRNA in sensitive cells is possibly indicating a cellular compensation for over active mitotic phase of the cell cycle due to mutated PLK1, and hence, these cell populations are ideal targets for PLK1 inhibition by BI6727.	('PLK1', 'Gene', '5347', (154, 158))	('BI6727', 'Chemical', 'MESH:C541363', (235, 241))	('mutated', 'Var', (146, 153))	('over active', 'PosReg', (95, 106))	('PKMYT1', 'Gene', (13, 19))	('PLK1', 'Gene', (154, 158))	('PLK1', 'Gene', (216, 220))	('elevated', 'PosReg', (4, 12))	('mRNA', 'MPA', (20, 24))	('PLK1', 'Gene', '5347', (216, 220))	('PKMYT1', 'Gene', '9088', (13, 19))
149489	25820683	Amp Amputation AYA Adolescent and Young Adult LS Limb-Sparing QOL Quality of Life	('Amp', 'Var', (0, 3))	('Limb-Sparing', 'CPA', (49, 61))	('Amp', 'Chemical', 'MESH:D000249', (0, 3))	('Amp', 'Chemical', 'MESH:D000249', (4, 7))	('AYA', 'Chemical', '-', (15, 18))
149530	26082937	Another point of view implies that morcellation of a uterine leiomyoma in a laparoscopic myomectomy may rarely cause dissemination.	('morcellation', 'Var', (35, 47))	('leiomyoma', 'Disease', (61, 70))	('leiomyoma', 'Disease', 'MESH:D007889', (61, 70))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (53, 70))
149614	22748119	Piwi-like 4 mRNA levels were negatively associated with the expression of the splice variant Delta 3 of the survivin gene (rs = -0.18; p = 0.047; Additional file 2: Table S1).	('expression', 'MPA', (60, 70))	('mRNA levels', 'MPA', (12, 23))	('Piwi-like 4', 'Gene', (0, 11))	('negatively', 'NegReg', (29, 39))	('Piwi-like 4', 'Gene', '143689', (0, 11))	('splice variant', 'Var', (78, 92))	('survivin gene', 'Gene', (108, 121))
149642	22748119	Analogously, one may speculate that Piwi-like proteins, as the main effector component of the RNA-induced silencing complex (RISC), may regulate their own expression by post-transcriptional gene silencing via an unknown small RNA binding partner.	('Piwi', 'Gene', '34521', (36, 40))	('expression', 'MPA', (155, 165))	('regulate', 'Reg', (136, 144))	('Piwi', 'Gene', (36, 40))	('post-transcriptional gene silencing', 'Var', (169, 204))
149644	22748119	The predominant form, PL2L60, is mainly expressed in tumor cells and promotes cell survival and proliferation of a human breast cancer cell line (MDA-MB-231), possibly by the upregulation of Bcl2 and Stat3.	('Stat3', 'Gene', '6774', (200, 205))	('Stat3', 'Gene', (200, 205))	('proliferation', 'CPA', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('promotes', 'PosReg', (69, 77))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('human', 'Species', '9606', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Bcl2', 'Gene', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cell survival', 'CPA', (78, 91))	('breast cancer', 'Disease', (121, 134))	('upregulation', 'PosReg', (175, 187))	('tumor', 'Disease', (53, 58))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (146, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('PL2L60', 'Var', (22, 28))	('Bcl2', 'Gene', '596', (191, 195))
149646	22748119	Piwi-like proteins bind exclusively to Piwi-interacting RNA (piRNA), a class of small RNAs that differ structurally from the classic siRNA and miRNA in several ways, including length (24-30 nt instead of 18-23 nt), the carriage of a 2'O-methyl modification at the 3' end and their low conservation among even closely related species.	('Piwi', 'Gene', (0, 4))	('carriage', 'Reg', (219, 227))	('Piwi', 'Gene', '34521', (39, 43))	('Piwi', 'Gene', (39, 43))	('Piwi', 'Gene', '34521', (0, 4))	("2'O-methyl modification", 'Var', (233, 256))
149647	22748119	Uncontrolled transposon activation in Piwi gene mutants has been observed in Drosophila and in mice, which points to a role of Piwi-like genes in transposon control during spermatogenesis.	('Piwi', 'Gene', (38, 42))	('mice', 'Species', '10090', (95, 99))	('Drosophila', 'Species', '7227', (77, 87))	('mutants', 'Var', (48, 55))	('Piwi', 'Gene', '34521', (127, 131))	('Piwi', 'Gene', '34521', (38, 42))	('Piwi', 'Gene', (127, 131))	('activation', 'PosReg', (24, 34))	('transposon', 'Gene', (13, 23))
149805	20694075	Perhaps the phase III study, which will evaluate the safety and effectiveness of trabectedin versus doxorubicin-based chemotherapy in patients with translocation-related sarcomas, will provide sufficient evidence for the US Food and Drug Administration to approve this drug in soft-tissue sarcoma for those patients who have exhausted other therapeutic options.	('sarcoma', 'Disease', 'MESH:D012509', (170, 177))	('sarcomas', 'Disease', 'MESH:D012509', (170, 178))	('sarcoma', 'Disease', (289, 296))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (289, 296))	('patients', 'Species', '9606', (134, 142))	('sarcoma', 'Disease', (170, 177))	('trabectedin', 'Chemical', 'MESH:D000077606', (81, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('doxorubicin', 'Chemical', 'MESH:D004317', (100, 111))	('sarcomas', 'Disease', (170, 178))	('sarcoma', 'Disease', 'MESH:D012509', (289, 296))	('patients', 'Species', '9606', (307, 315))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (277, 296))	('translocation-related', 'Var', (148, 169))
149806	30459475	Diagnosis of known sarcoma fusions and novel fusion partners by targeted RNA sequencing with identification of a recurrent ACTB-FOSB fusion in pseudomyogenic hemangioendothelioma Integration of morphological, immunohistochemical and molecular methods is often necessary for the precise diagnosis and optimal clinical management of sarcomas.	('hemangioendothelioma', 'Disease', 'MESH:D006390', (158, 178))	('FOSB', 'Gene', (128, 132))	('hemangioendothelioma', 'Disease', (158, 178))	('sarcoma', 'Disease', 'MESH:D012509', (331, 338))	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('fusion', 'Var', (133, 139))	('sarcomas', 'Disease', 'MESH:D012509', (331, 339))	('ACTB', 'Gene', '60', (123, 127))	('sarcoma', 'Disease', (331, 338))	('ACTB', 'Gene', (123, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (331, 339))	('sarcoma', 'Phenotype', 'HP:0100242', (331, 338))	('sarcoma', 'Disease', (19, 26))	('sarcomas', 'Disease', (331, 339))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('FOSB', 'Gene', '2354', (128, 132))
149807	30459475	We have validated and implemented a clinical molecular diagnostic assay, MSK-Fusion Solid, for detection of gene fusions in solid tumors including sarcomas.	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('sarcomas', 'Disease', (147, 155))	('gene fusions', 'Var', (108, 120))	('solid tumors', 'Disease', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('sarcomas', 'Disease', 'MESH:D012509', (147, 155))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
149815	30459475	In the last several years, identification of chromosomal translocations and fusion genes has substantially contributed to diagnostic precision, enabling better understanding of the genetic mechanisms underlying sarcomagenesis, thus leading to better risk stratification and development of novel therapeutics.	('contributed', 'Reg', (107, 118))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('sarcoma', 'Disease', (211, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('chromosomal translocations', 'Var', (45, 71))
149830	30459475	Finally, the analytical sensitivity of the assay was determined using 3 cell lines harboring 3 different fusions: A673 (EWSR1-FLI1), SYO1 (SS18-SSX2) and H3122 (EML4-ALK).	('ALK', 'Gene', '238', (166, 169))	('A673', 'Var', (114, 118))	('H3122', 'CellLine', 'CVCL:5160', (154, 159))	('ALK', 'Gene', (166, 169))	('H3122', 'Var', (154, 159))
149834	30459475	The tests were requested for the following reasons: 1) as part of work-up for primary diagnosis or diagnosis confirmation, 2) confirmation of fusion genes or complex rearrangements detected by MSK-IMPACT  (a targeted Next-Generation Sequencing assay), 3) for possible discovery of potential targetable rearrangements in certain tumors, including driver-negative cases by MSK-IMPACT .	('tumors', 'Phenotype', 'HP:0002664', (328, 334))	('tumors', 'Disease', 'MESH:D009369', (328, 334))	('rearrangements', 'Var', (302, 316))	('tumors', 'Disease', (328, 334))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))
149840	30459475	The most common gene involved in fusions is EWSR1 with different partners including ATF1, ERG, FLI1, NR4A3, PATZ1, and WT1 in various tumor types.	('fusions', 'Var', (33, 40))	('involved', 'Reg', (21, 29))	('ERG', 'Gene', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('ATF1', 'Gene', (84, 88))	('NR4A3', 'Gene', (101, 106))	('EWSR1', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('FLI1', 'Gene', (95, 99))	('tumor', 'Disease', (134, 139))
149843	30459475	In the following sections, we summarize the recurrent and novel fusions found in undifferentiated round cell and other sarcomas and describe the clinicopathological features of selected cases with novel fusions and tumors with potentially targetable fusions.	('sarcomas', 'Disease', (119, 127))	('fusions', 'Var', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('tumors', 'Disease', (215, 221))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('undifferentiated round cell', 'Disease', (81, 108))
149850	30459475	A TRPS1-PLAG1 gene fusion was identified in a myoepithelial tumor of soft tissue with break points in TRPS1 exon1 and PLAG1 exon2 (Figure 5).	('TRPS1', 'Gene', (102, 107))	('myoepithelial tumor', 'Disease', (46, 65))	('break points', 'Var', (86, 98))	('TRPS1-PLAG1', 'Gene', (2, 13))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('myoepithelial tumor', 'Disease', 'MESH:D009208', (46, 65))
149864	30459475	FISH confirmed TFE3 gene rearrangement (not shown).	('rearrangement', 'Var', (25, 38))	('TFE3', 'Gene', (15, 19))	('TFE3', 'Gene', '7030', (15, 19))
149867	30459475	A novel ACTB-FOSB fusion was detected between ACTB exon3 and FOSB exon2 (Figure 5), supporting the diagnosis of pseudomyogenic hemangioendothelioma.	('pseudomyogenic hemangioendothelioma', 'Disease', (112, 147))	('ACTB', 'Gene', (46, 50))	('ACTB', 'Gene', (8, 12))	('ACTB', 'Gene', '60', (46, 50))	('ACTB', 'Gene', '60', (8, 12))	('FOSB', 'Gene', '2354', (13, 17))	('FOSB', 'Gene', '2354', (61, 65))	('FOSB', 'Gene', (13, 17))	('fusion', 'Var', (18, 24))	('FOSB', 'Gene', (61, 65))	('pseudomyogenic hemangioendothelioma', 'Disease', 'MESH:D006390', (112, 147))
149869	30459475	This could be due to a complex gene rearrangement not apparent by FISH or insertion of portion of the ACTB gene into the FOSB locus or other alternative mechanism.	('FOSB', 'Gene', '2354', (121, 125))	('insertion', 'Var', (74, 83))	('FOSB', 'Gene', (121, 125))	('ACTB', 'Gene', '60', (102, 106))	('ACTB', 'Gene', (102, 106))
149887	30459475	The tumor cells were strongly positive for CD10 and moderately positive for CyclinD1, while negative for both epithelial or mesenchymal markers (ER, PR, SMA, Myogenin, Desmin, Caldesmon, EMA, Myoglobin, AE1/AE3, CK5/6, CK7, CK20, PAX8, RCC, ERG, S100, HMB45, MelanA, WT1, beta HCG, CA125, CD21, CD31, CD34, CD45, CD99, CD117 , ALK, CDK4 and MDM2) by immunohistochemistry.	('tumor', 'Disease', (4, 9))	('RCC', 'Disease', (236, 239))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('ALK', 'Gene', '238', (327, 330))	('CD10', 'Var', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ALK', 'Gene', (327, 330))
149896	30459475	In our cohort, we were able to identify the following rare events: 1) Novel partner genes for known recurrent gene fusions, which include TRPS1-PLAG1 in one soft tissue myoepithelial tumor, VCP-TFE3 in a pancreatic perivascular epithelioid cell tumor (PEComa) and ACTB-FOSB in a pseudomyogenic hemangioendothelioma.	('epithelioid cell tumor', 'Phenotype', 'HP:0032060', (228, 250))	('PEComa', 'Disease', (252, 258))	('FOSB', 'Gene', '2354', (269, 273))	('TFE3', 'Gene', (194, 198))	('myoepithelial tumor', 'Disease', (169, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('TFE3', 'Gene', '7030', (194, 198))	('ACTB', 'Gene', (264, 268))	('ACTB', 'Gene', '60', (264, 268))	('pancreatic perivascular epithelioid cell tumor', 'Disease', 'MESH:D054973', (204, 250))	('TRPS1-PLAG1', 'Gene', (138, 149))	('FOSB', 'Gene', (269, 273))	('fusions', 'Var', (115, 122))	('pancreatic perivascular epithelioid cell tumor', 'Disease', (204, 250))	('pseudomyogenic hemangioendothelioma', 'Disease', 'MESH:D006390', (279, 314))	('PEComa', 'Disease', 'MESH:D054973', (252, 258))	('pseudomyogenic hemangioendothelioma', 'Disease', (279, 314))	('myoepithelial tumor', 'Disease', 'MESH:D009208', (169, 188))
149897	30459475	EWSR1 and PLAG1 are the most common gene partners involved in rearrangements found in myoepithelial tumors and mixed tumors arising in soft tissue and skin respectively.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('rearrangements', 'Var', (62, 76))	('PLAG1', 'Gene', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', (117, 123))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (86, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('myoepithelial tumors', 'Disease', (86, 106))	('EWSR1', 'Gene', (0, 5))
149901	30459475	The genetic alterations underlying perivascular epithelioid cell tumor (PEComa) include inactivation of TSC1/TSC2 genes or TFE3 gene fusion.	('epithelioid cell tumor', 'Disease', (48, 70))	('TFE3', 'Gene', '7030', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('PEComa', 'Disease', 'MESH:D054973', (72, 78))	('TFE3', 'Gene', (123, 127))	('epithelioid cell tumor', 'Phenotype', 'HP:0032060', (48, 70))	('epithelioid cell tumor', 'Disease', 'MESH:D054973', (48, 70))	('PEComa', 'Disease', (72, 78))	('inactivation', 'Var', (88, 100))	('TSC1/TSC2 genes', 'Gene', (104, 119))
149906	30459475	Another differential diagnosis with the morphological pattern and TFE3 rearrangement is alveolar soft part sarcoma (ASPS).	('soft part sarcoma', 'Phenotype', 'HP:0030448', (97, 114))	('TFE3', 'Gene', '7030', (66, 70))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (88, 114))	('ASPS', 'Disease', (116, 120))	('ASPS', 'Disease', 'MESH:D018234', (116, 120))	('alveolar soft part sarcoma', 'Disease', (88, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('TFE3', 'Gene', (66, 70))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (88, 114))	('rearrangement', 'Var', (71, 84))
149917	30459475	The two cases of lipomatosis-like neural tumor which showed TPM3-NTRK1 and LMNA-NTRK1 fusions have been published recently.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('NTRK1', 'Gene', (65, 70))	('lipomatosis-like neural tumor', 'Disease', (17, 46))	('lipomatosis', 'Phenotype', 'HP:0001012', (17, 28))	('lipomatosis-like neural tumor', 'Disease', 'MESH:D008068', (17, 46))	('LMNA', 'Gene', (75, 79))	('NTRK1', 'Gene', (80, 85))	('TPM3', 'Gene', (60, 64))	('LMNA', 'Gene', '4000', (75, 79))	('NTRK1', 'Gene', '4914', (65, 70))	('fusions', 'Var', (86, 93))	('TPM3', 'Gene', '7170', (60, 64))	('NTRK1', 'Gene', '4914', (80, 85))
149921	30459475	ETV6-NTRK3 fusion was detected in one infantile fibrosarcoma and two inflammatory myofibroblastic tumors.	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (69, 104))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (82, 103))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('inflammatory myofibroblastic tumors', 'Disease', (69, 104))	('NTRK3', 'Gene', '4916', (5, 10))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (82, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('fusion', 'Var', (11, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (38, 60))	('infantile fibrosarcoma', 'Disease', (38, 60))	('detected', 'Reg', (22, 30))	('NTRK3', 'Gene', (5, 10))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (48, 60))
149923	30459475	Genetic alterations in NTRK genes have been found to be oncogenic in a variety of cancer types.	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TRK', 'Gene', '7170', (24, 27))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TRK', 'Gene', (24, 27))
149928	30459475	Although the efficacy of BRAF inhibitors and other kinase inhibitors in cancers driven by BRAF fusions has not been investigated systematically, the discovery of these novel fusions expands the potentially targetable genetic alteration repertoire in sarcomas.	('BRAF', 'Gene', (90, 94))	('sarcomas', 'Disease', (250, 258))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('fusions', 'Var', (95, 102))	('BRAF', 'Gene', '673', (25, 29))	('sarcomas', 'Disease', 'MESH:D012509', (250, 258))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (250, 258))	('cancers', 'Disease', (72, 79))	('BRAF', 'Gene', '673', (90, 94))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('BRAF', 'Gene', (25, 29))
149963	30656006	Amplification of MDM2 is the primary feature of well-differentiated liposarcoma, dedifferentiated liposarcoma, and well-differentiated osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Amplification', 'Var', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('liposarcoma', 'Disease', (98, 109))	('liposarcoma', 'Disease', (68, 79))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))	('osteosarcoma', 'Disease', (135, 147))	('liposarcoma', 'Disease', 'MESH:D008080', (68, 79))	('liposarcoma', 'Phenotype', 'HP:0012034', (98, 109))	('liposarcoma', 'Disease', 'MESH:D008080', (98, 109))	('liposarcoma', 'Phenotype', 'HP:0012034', (68, 79))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('osteosarcoma', 'Disease', 'MESH:D012516', (135, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
149964	30656006	Amplification of MDM2 can be detected by fluorescence in situ hybridization (FISH) or by an immunohistochemical stain which highlights the nuclei of tumor cells.	('Amplification', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('MDM2', 'Gene', '4193', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('MDM2', 'Gene', (17, 21))	('tumor', 'Disease', (149, 154))
149971	28827658	Aberrant PD-L1 expression is reported in various human cancers and is considered an immune escape mechanism.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('expression', 'MPA', (15, 25))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('PD-L1', 'Gene', (9, 14))	('cancers', 'Disease', (55, 62))
149974	28827658	In this study, the immunomodulatory effects of c4G12, a canine-chimerised anti-PD-L1 monoclonal antibody, were evaluated in vitro, demonstrating significantly enhanced cytokine production and proliferation of dog peripheral blood mononuclear cells.	('cytokine production', 'MPA', (168, 187))	('rat', 'Species', '10116', (138, 141))	('canine', 'Species', '9615', (56, 62))	('proliferation', 'CPA', (192, 205))	('enhanced', 'PosReg', (159, 167))	('dog', 'Species', '9615', (209, 212))	('c4G12', 'Var', (47, 52))	('rat', 'Species', '10116', (199, 202))
149976	28827658	Objective antitumour responses were observed in one dog with OMM (14.3%, 1/7) and one with undifferentiated sarcoma (50.0%, 1/2) when c4G12 was given at 2 or 5 mg/kg, every 2 weeks.	('dog', 'Species', '9615', (52, 55))	('tumour', 'Disease', (14, 20))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (91, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('undifferentiated sarcoma', 'Disease', (91, 115))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('c4G12', 'Var', (134, 139))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('OMM', 'Chemical', '-', (61, 64))
149977	28827658	c4G12 could be a safe and effective treatment option for canine cancers.	('canine', 'Species', '9615', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Disease', (64, 71))	('c4G12', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
149983	28827658	Of particular note, anti-PD-1 antibody has shown promising anticancer activity with tolerable toxicity profiles in a number of clinical trials, altering the standard of treatment for melanoma, non-small cell lung cancer and other cancers.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (193, 219))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('anti-PD-1', 'Var', (20, 29))	('non-small cell lung cancer', 'Disease', (193, 219))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('cancers', 'Disease', (230, 237))	('cancer', 'Disease', (213, 219))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', (63, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (193, 219))	('toxicity', 'Disease', (94, 102))	('altering', 'Reg', (144, 152))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (197, 219))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
149985	28827658	In humans, the expression of PD-1 is upregulated in tumour antigen-specific T cells, and aberrant PD-L1 expression in tumour cells or other cells in the tumour microenvironment has been demonstrated in various cancer types.	('tumour', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Disease', (52, 58))	('upregulated', 'PosReg', (37, 48))	('aberrant', 'Var', (89, 97))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('expression', 'MPA', (15, 25))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('tumour', 'Disease', (153, 159))	('humans', 'Species', '9606', (3, 9))	('rat', 'Species', '10116', (193, 196))	('PD-L1', 'Gene', (98, 103))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', (210, 216))	('PD-1', 'Gene', (29, 33))
149998	28827658	Here we provide the first evidence of clinical benefit of anti-PD-L1 mAb in dogs, suggesting that it could be a novel option for canine cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('dogs', 'Species', '9615', (76, 80))	('canine', 'Species', '9615', (129, 135))	('anti-PD-L1', 'Var', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
150000	28827658	In the blocking assay of canine PD-1/PD-L1 binding, 6G7 (rat IgM) and 4G12 (rat IgG2a) showed efficient blocking ability, while 5A2 (rat IgG1) did not have an apparent blocking effect (Supplementary Fig.	('binding', 'Interaction', (43, 50))	('rat', 'Species', '10116', (76, 79))	('rat', 'Species', '10116', (133, 136))	('IgG2a', 'Gene', (80, 85))	('rat', 'Species', '10116', (57, 60))	('4G12', 'Var', (70, 74))	('IgG2a', 'Gene', '367586', (80, 85))	('canine', 'Species', '9615', (25, 31))	('blocking', 'Interaction', (104, 112))	('6G7', 'Var', (52, 55))
150002	28827658	To assess this possibility, canine chimeric mAb, c4G12 or c6G7, was prepared using the variable regions of 4G12 or 6G7 and the constant regions of dog IgGD and the lambda chain.	('canine', 'Species', '9615', (28, 34))	('dog', 'Species', '9615', (147, 150))	('6G7', 'Var', (115, 118))	('4G12', 'Var', (107, 111))
150005	28827658	In the blocking assay of PD-1/PD-L1 binding, the blocking ability of c6G7 was obviously weakened, whereas that of c4G12 remained sufficient throughout the conversion to the canine chimeric IgG form (Supplementary Fig.	('weakened', 'NegReg', (88, 96))	('canine', 'Species', '9615', (173, 179))	('blocking', 'Interaction', (49, 57))	('PD-1/PD-L1', 'Protein', (25, 35))	('binding', 'Interaction', (36, 43))	('c6G7', 'Var', (69, 73))
150010	28827658	In the surface plasmon resonance (SPR) analysis, c4G12 was bound to cPD-L1 with a similar binding property (KD = 2.30 +- 0.07 nM, Table 1) to its original rat mAb 4G12.	('rat', 'Species', '10116', (155, 158))	('c4G12', 'Var', (49, 54))	('bound', 'Interaction', (59, 64))
150011	28827658	The KD value of c4G12 was 10-fold smaller than that of cPD-1-Ig and cCD80-Ig, indicating that the binding avidity of c4G12 was practically higher than those of cPD-1-Ig and cCD80-Ig (Table 1).	('c4G12', 'Var', (117, 122))	('binding', 'Interaction', (98, 105))	('CD80', 'Gene', (174, 178))	('CD80', 'Gene', (69, 73))	('CD80', 'Gene', '403765', (174, 178))	('CD80', 'Gene', '403765', (69, 73))	('higher', 'PosReg', (139, 145))
150012	28827658	This result was consistent with the observation that c4G12 sufficiently blocked PD-1/PD-L1 and CD80/PD-L1 binding.	('CD80', 'Gene', (95, 99))	('PD-1/PD-L1', 'Protein', (80, 90))	('binding', 'Interaction', (106, 113))	('c4G12', 'Var', (53, 58))	('CD80', 'Gene', '403765', (95, 99))	('blocked', 'NegReg', (72, 79))
150015	28827658	Treatment with c4G12 significantly enhanced interleukin (IL)-2 and interferon (IFN)-gamma production from dog PBMCs while cPD-L1-Ig treatment suppressed the production of IL-2 (Fig.	('IL-2', 'Gene', (171, 175))	('IL-2', 'Gene', '403989', (171, 175))	('c4G12', 'Var', (15, 20))	('enhanced', 'PosReg', (35, 43))	('dog', 'Species', '9615', (106, 109))	('suppressed', 'NegReg', (142, 152))
150016	28827658	The proliferation of CD4+ and CD8+ lymphocytes, indicated by the incorporation of nucleotide analogue 5-ethynyl-2'-deoxyuridine (EdU), was also enhanced by c4G12 treatment (Fig.	('rat', 'Species', '10116', (72, 75))	('proliferation', 'CPA', (4, 17))	('EdU', 'Chemical', 'MESH:C031086', (129, 132))	('enhanced', 'PosReg', (144, 152))	('c4G12', 'Var', (156, 161))	('CD', 'Chemical', 'MESH:D002104', (30, 32))	('rat', 'Species', '10116', (11, 14))	('CD', 'Chemical', 'MESH:D002104', (21, 23))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (102, 127))
150017	28827658	Taken together, c4G12 appeared to restore the effector functions of dog lymphocytes which are suppressed by the PD-1/PD-L1 and/or CD80/PD-L1 axis.	('CD80', 'Gene', (130, 134))	('c4G12', 'Var', (16, 21))	('CD80', 'Gene', '403765', (130, 134))	('restore', 'PosReg', (34, 41))	('dog', 'Species', '9615', (68, 71))	('effector functions', 'CPA', (46, 64))
150039	28827658	Among dogs with OMM treated with c4G12, four dogs with pulmonary metastasis had progression of the disease (PD).	('dogs', 'Species', '9615', (45, 49))	('dogs', 'Species', '9615', (6, 10))	('OMM', 'Chemical', '-', (16, 19))	('pulmonary metastasis', 'Disease', (55, 75))	('c4G12', 'Var', (33, 38))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (55, 75))
150062	28827658	Chimerisation did not affect the binding and blocking property of mAb when rat IgG was converted into dog IgG, and the chimeric mAb was well tolerated in dogs in the pilot clinical study, with no evidence of allergic reactions.	('allergic reactions', 'Disease', 'MESH:D004342', (208, 226))	('dogs', 'Species', '9615', (154, 158))	('rat', 'Species', '10116', (75, 78))	('dog', 'Species', '9615', (154, 157))	('chimeric', 'Var', (119, 127))	('dog', 'Species', '9615', (102, 105))	('allergic reactions', 'Phenotype', 'HP:0012393', (208, 226))	('allergic reactions', 'Disease', (208, 226))	('rat', 'Species', '10116', (145, 148))
150065	28827658	Treatment with c4G12 induced an obvious antitumour response in a dog with OMM and in another with undifferentiated sarcoma.	('OMM', 'Disease', (74, 77))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('c4G12', 'Var', (15, 20))	('tumour', 'Disease', (44, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (98, 122))	('OMM', 'Chemical', '-', (74, 77))	('undifferentiated sarcoma', 'Disease', (98, 122))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('dog', 'Species', '9615', (65, 68))
150067	28827658	Because objective response rate of anti-PD-L1 mAb in melanoma patients was 17.3% (9/52) in a human clinical trial, our result seems consistent with human studies.	('anti-PD-L1', 'Var', (35, 45))	('human', 'Species', '9606', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('human', 'Species', '9606', (148, 153))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('rat', 'Species', '10116', (27, 30))	('patients', 'Species', '9606', (62, 70))
150068	28827658	In addition, the c4G12 treatment may have prolonged survival in dogs with OMM with pulmonary metastasis, although statistical significance was not reached (p = 0.10), possibly because the sample size was too small (treatment group n = 4).	('OMM', 'Disease', (74, 77))	('dogs', 'Species', '9615', (64, 68))	('pulmonary metastasis', 'Disease', (83, 103))	('prolonged', 'PosReg', (42, 51))	('survival', 'CPA', (52, 60))	('OMM', 'Chemical', '-', (74, 77))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (83, 103))	('c4G12', 'Var', (17, 22))
150069	28827658	Considering that dogs with OMM with pulmonary metastasis have quite a poor prognosis with standard therapies, c4G12 could be a novel treatment option for at least palliative purposes.	('dogs', 'Species', '9615', (17, 21))	('c4G12', 'Var', (110, 115))	('OMM', 'Disease', (27, 30))	('pulmonary metastasis', 'Disease', (36, 56))	('OMM', 'Chemical', '-', (27, 30))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (36, 56))
150072	28827658	Although discussion continues as to whether measuring PD-L1 expression in cancers is a clinically useful predictive biomarker for response to PD-1/PD-L1 inhibitors, other PD-L1-positive cancers in dogs including osteosarcoma, hemangiosarcoma, mast cell tumour, mammary adenocarcinoma, lymphoma and prostate adenocarcinoma, could also be targeted by c4G12.	('osteosarcoma', 'Disease', (212, 224))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('mast cell tumour', 'Phenotype', 'HP:0100495', (243, 259))	('osteosarcoma', 'Disease', 'MESH:D012516', (212, 224))	('cancers', 'Disease', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('mast cell tumour', 'Disease', (243, 259))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('hemangiosarcoma', 'Disease', (226, 241))	('lymphoma', 'Phenotype', 'HP:0002665', (285, 293))	('mast cell tumour', 'Disease', 'MESH:D034801', (243, 259))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (226, 241))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('osteosarcoma', 'Phenotype', 'HP:0002669', (212, 224))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('PD-L1-positive cancers', 'Disease', (171, 193))	('dogs', 'Species', '9615', (197, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('adenocarcinoma, lymphoma and prostate adenocarcinoma', 'Disease', 'MESH:D000230', (269, 321))	('PD-L1-positive cancers', 'Disease', 'MESH:D010300', (171, 193))	('c4G12', 'Var', (349, 354))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))
150074	28827658	Because no systemic toxicity or autoimmune disease was noted in the trial, c4G12 seems to be safe and well tolerated in dogs despite repeated administration.	('dogs', 'Species', '9615', (120, 124))	('rat', 'Species', '10116', (111, 114))	('toxicity', 'Disease', 'MESH:D064420', (20, 28))	('toxicity', 'Disease', (20, 28))	('autoimmune disease', 'Disease', 'MESH:D001327', (32, 50))	('rat', 'Species', '10116', (150, 153))	('autoimmune disease', 'Phenotype', 'HP:0002960', (32, 50))	('c4G12', 'Var', (75, 80))	('autoimmune disease', 'Disease', (32, 50))
150077	28827658	Because evidence of autoimmune disease was reported in PD-1 knockout mice and treatment-related deaths due to pneumonitis have been reported in a human clinical trial, a careful attention should be paid to these possibilities in future studies in dogs using c4G12.	('pneumonitis', 'Disease', (110, 121))	('dogs', 'Species', '9615', (247, 251))	('pneumonitis', 'Disease', 'MESH:D011014', (110, 121))	('autoimmune disease', 'Disease', (20, 38))	('PD-1', 'Gene', (55, 59))	('mice', 'Species', '10090', (69, 73))	('human', 'Species', '9606', (146, 151))	('autoimmune disease', 'Disease', 'MESH:D001327', (20, 38))	('autoimmune disease', 'Phenotype', 'HP:0002960', (20, 38))	('c4G12', 'Var', (258, 263))
150079	28827658	The pilot clinical study demonstrated the safety and antitumour activity of anti-PD-L1 mAb in dogs.	('tumour', 'Disease', (57, 63))	('rat', 'Species', '10116', (32, 35))	('anti-PD-L1', 'Var', (76, 86))	('dogs', 'Species', '9615', (94, 98))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
150113	28827658	cPD-L1-His was captured on the sensor chip to obtain approximately 35 response units (RU) to analyse 4G12 or c4G12 binding, or approximately 400 RU to analyse cPD-1-Ig or cCD80-Ig binding.	('CD80', 'Gene', (172, 176))	('c4G12', 'Var', (109, 114))	('binding', 'Interaction', (115, 122))	('4G12', 'Protein', (101, 105))	('binding', 'Interaction', (180, 187))	('CD80', 'Gene', '403765', (172, 176))
150114	28827658	The kinetic constants of 4G12 or c4G12 were determined by fitting with the 1:1 kinetic binding model, and that of cPD-1-Ig or cCD80-Ig was determined by fitting with the two state reaction model because a conformational change of PD-L1 upon binding with PD-1 and CD80 has been suggested.	('CD80', 'Gene', (263, 267))	('CD80', 'Gene', (127, 131))	('binding', 'Interaction', (241, 248))	('c4G12', 'Var', (33, 38))	('CD80', 'Gene', '403765', (263, 267))	('CD80', 'Gene', '403765', (127, 131))	('conformational', 'MPA', (205, 219))
150145	20202195	We analyzed the influence of vorinostat on expression of different HDACs, p21WAF1 and activation of apoptosis.	('vorinostat', 'Chemical', 'MESH:D000077337', (29, 39))	('p21WAF1', 'Var', (74, 81))	('HDAC', 'Gene', (67, 71))	('HDAC', 'Gene', '9734', (67, 71))
150180	20202195	For in vitro experiments a 10 mM vorinostat stock solution was prepared with DMSO and stored at -20 C. Since it is well known that DMSO can cause different inflammatory reactions when injected intraperitoneally for a longer period of time, we wanted to avoid this solvent for our in vivo experiments.	('DMSO', 'Chemical', 'MESH:D004121', (131, 135))	('DMSO', 'Chemical', 'MESH:D004121', (77, 81))	('cause', 'Reg', (140, 145))	('inflammatory reactions', 'CPA', (156, 178))	('vorinostat', 'Chemical', 'MESH:D000077337', (33, 43))	('DMSO', 'Var', (131, 135))
150226	20202195	The expression of a cyclin-dependent kinase inhibitor p21WAF1 in vorinostat treated MES-SA cells was significantly upregulated already 24 hours after starting the treatment and continuously increased during the following 48 hours.	('MES-SA', 'CellLine', 'CVCL:1404', (84, 90))	('vorinostat', 'Chemical', 'MESH:D000077337', (65, 75))	('p21WAF1', 'Var', (54, 61))	('expression', 'MPA', (4, 14))	('increased', 'PosReg', (190, 199))	('upregulated', 'PosReg', (115, 126))
150257	20202195	While in most experimental systems vorinostat caused apoptotic changes, there are also data showing that autophagic processes are activated by vorinostat.	('vorinostat', 'Var', (143, 153))	('vorinostat', 'Chemical', 'MESH:D000077337', (143, 153))	('autophagic processes', 'CPA', (105, 125))	('activated', 'PosReg', (130, 139))	('vorinostat', 'Chemical', 'MESH:D000077337', (35, 45))
150288	30598078	CKS samples were categorized into three groups based on copy number variations that were associated with CDK4 and RB1 signatures.	('associated', 'Reg', (89, 99))	('CDK4', 'Gene', (105, 109))	('RB1', 'Gene', (114, 117))	('CDK4', 'Gene', '1019', (105, 109))	('RB1', 'Gene', '5925', (114, 117))	('amp', 'Chemical', '-', (5, 8))	('copy number variations', 'Var', (56, 78))	('CKS', 'Chemical', '-', (0, 3))
150295	30598078	STSs, grouped broadly according to molecular complexity, are classified into two groups: simple karyotype sarcoma with balanced translocation and complex karyotype sarcoma (CKS) without aberrant dislocation.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('simple karyotype', 'Disease', (89, 105))	('dislocation', 'Disease', 'MESH:D004204', (195, 206))	('CKS', 'Chemical', '-', (173, 176))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('dislocation', 'Disease', (195, 206))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Disease', (106, 113))	('balanced translocation', 'Var', (119, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
150296	30598078	Translocation-associated sarcomas, most represented by LPS and SS, account for 20-30% of all sarcomas.	('LPS', 'Disease', (55, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('LPS', 'Disease', 'MESH:C536528', (55, 58))	('Translocation-associated', 'Var', (0, 24))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcomas', 'Disease', (93, 101))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))
150297	30598078	Although targeted therapies against fusion genes have not been successful, it has been postulated that translocation variants in sarcoma are predictive of patient outcome.	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('patient', 'Species', '9606', (155, 162))	('translocation variants', 'Var', (103, 125))	('sarcoma', 'Disease', (129, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
150300	30598078	For example, NF1 tumor suppressor is mutated or deleted in several sarcoma subtypes.	('amp', 'Chemical', '-', (6, 9))	('tumor', 'Disease', (17, 22))	('sarcoma subtype', 'Disease', (67, 82))	('deleted', 'Var', (48, 55))	('NF1', 'Gene', (13, 16))	('NF1', 'Gene', '4763', (13, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcoma subtype', 'Disease', 'MESH:D012509', (67, 82))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
150307	30598078	CDK4 amplification and RB1 deletion were seen in patterns of genomic damage and PDGFRA profiles could be used to clearly separate samples.	('PDGFRA', 'Gene', (80, 86))	('amp', 'Chemical', '-', (131, 134))	('PDGFRA', 'Gene', '5156', (80, 86))	('deletion', 'Var', (27, 35))	('CDK4', 'Gene', (0, 4))	('RB1', 'Gene', (23, 26))	('amp', 'Chemical', '-', (5, 8))	('CDK4', 'Gene', '1019', (0, 4))	('RB1', 'Gene', '5925', (23, 26))
150319	30598078	To investigate the mutational process, we selected single-nucleotide alterations and converted them into the six classes of base substitution (C > A, C > G, C > T, T > A, T > C, and T > G).	('C > T', 'Mutation', 'c.C>T', (157, 162))	('C > A', 'Var', (143, 148))	('T > C', 'Mutation', 'c.T>C', (171, 176))	('C > G', 'Var', (150, 155))	('T > G', 'Mutation', 'c.T>G', (182, 187))	('C > G', 'Mutation', 'c.C>G', (150, 155))	('T > A', 'Var', (164, 169))	('C > T', 'Var', (157, 162))	('T > A', 'Mutation', 'c.T>A', (164, 169))	('C > A', 'Mutation', 'c.C>A', (143, 148))	('T > G', 'Var', (182, 187))	('T > C', 'Var', (171, 176))
150331	30598078	We detected four cell lines (G402, A204, TE441T, and G401) that had no amplification of CDK4 (copy number score < 0.1) and displayed positive gene expression of PDGFRA, and seven cell lines (SKUT1, MESSA, GCT, SKLMS1, RH41, RH18, and RH30) that had CDK4 amplification (amp) (> 0.1) and positive expression of PDGFRA.	('PDGFRA', 'Gene', (161, 167))	('CDK4', 'Gene', (249, 253))	('amp', 'Chemical', '-', (269, 272))	('SKLMS1', 'CellLine', 'CVCL:0628', (210, 216))	('amp', 'Chemical', '-', (254, 257))	('PDGFRA', 'Gene', '5156', (161, 167))	('PDGFRA', 'Gene', '5156', (309, 315))	('PDGFRA', 'Gene', (309, 315))	('CDK4', 'Gene', '1019', (88, 92))	('RH30', 'Gene', (234, 238))	('CDK4', 'Gene', (88, 92))	('SKUT1', 'CellLine', 'CVCL:0533', (191, 196))	('amp', 'Chemical', '-', (71, 74))	('CDK4', 'Gene', '1019', (249, 253))	('RH30', 'Gene', '6007', (234, 238))	('TE441T', 'Var', (41, 47))	('amplification', 'Var', (254, 267))
150349	30598078	PTEN mutations were enriched in hypermutators (100%; P = 0.003, Fisher's exact test).	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('mutations', 'Var', (5, 14))
150352	30598078	We observed a high mutational burden of increased C > T and/or C > A mutations at NpCpG (Fig.	('C > T', 'Mutation', 'c.C>T', (50, 55))	('C > A mutations', 'Var', (63, 78))	('NpCpG', 'Gene', (82, 87))	('C > T', 'Var', (50, 55))	('C > A', 'Mutation', 'c.C>A', (63, 68))	('increased', 'PosReg', (40, 49))
150357	30598078	Additionally, the hypermutators contained somatic mutations in DNA mismatch repair genes such as MSH2, MSH3, and MSH6, and showed a slight association with the downregulation of these genes (Fig.	('downregulation', 'NegReg', (160, 174))	('mutations', 'Var', (50, 59))	('MSH3', 'Gene', '4437', (103, 107))	('MSH6', 'Gene', (113, 117))	('MSH2', 'Gene', (97, 101))	('MSH2', 'Gene', '4436', (97, 101))	('MSH3', 'Gene', (103, 107))	('MSH6', 'Gene', '2956', (113, 117))
150361	30598078	In this study, we found amplifications of 1q21.2, 7p22.3, and 12q14.1, which occur frequently in sarcomas, and represent a prognostic factor for adverse outcomes in a variety of cancer types.	('amp', 'Chemical', '-', (24, 27))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('amplifications', 'Var', (24, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('7p22.3', 'Gene', (50, 56))	('1q21.2', 'Var', (42, 48))	('cancer', 'Disease', (178, 184))	('12q14.1', 'Gene', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('sarcomas', 'Disease', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))
150362	30598078	Also, deletions were found in 11q24.2, 12p13.31, and 13q14.2, reported previously in sarcoma (Additional file 1: Figure S2).	('sarcoma', 'Disease', (85, 92))	('deletions', 'Var', (6, 15))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
150368	30598078	The first cluster was enriched with CDK4 amplification (75%; P = 0.032, Fisher's exact test), which has an oncogenic role in sarcomagenesis.	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('CDK4', 'Gene', '1019', (36, 40))	('CDK4', 'Gene', (36, 40))	('sarcoma', 'Disease', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('amplification', 'Var', (41, 54))	('amp', 'Chemical', '-', (41, 44))
150369	30598078	Additionally, patients who were diagnosed with a recurrence had tumors that were enriched with CDK4 amplification (66.7%; Fig.	('tumors', 'Disease', (64, 70))	('amplification', 'Var', (100, 113))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('amp', 'Chemical', '-', (100, 103))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('CDK4', 'Gene', (95, 99))	('CDK4', 'Gene', '1019', (95, 99))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
150370	30598078	According to the TCGA sarcoma data, CDK4 amplification and recurrence showed co-occurrence (P = 1.60e-05, Chi-square test).	('CDK4', 'Gene', '1019', (36, 40))	('CDK4', 'Gene', (36, 40))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('sarcoma', 'Disease', (22, 29))	('amplification', 'Var', (41, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('amp', 'Chemical', '-', (41, 44))
150371	30598078	The second cluster was enriched with the RB1 deletion (100%; P = 0.002, Fisher's exact test), which accelerates additional cancer gene mutations in sarcomagenesis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('RB1', 'Gene', '5925', (41, 44))	('sarcoma', 'Disease', (148, 155))	('mutations', 'Var', (135, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('accelerates', 'PosReg', (100, 111))	('cancer', 'Disease', (123, 129))	('deletion', 'Var', (45, 53))	('RB1', 'Gene', (41, 44))
150372	30598078	Patients with metastasis had tumors that were enriched in the RB1 deletion (66%; Fig.	('RB1', 'Gene', '5925', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('RB1', 'Gene', (62, 65))	('deletion', 'Var', (66, 74))
150373	30598078	Although RB1 loss and metastasis showed no correlation in the TCGA sarcoma data, a strong association of RB1 deletion with metastasis was reported previously in human and mice.	('human', 'Species', '9606', (161, 166))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('deletion', 'Var', (109, 117))	('mice', 'Species', '10090', (171, 175))	('association', 'Interaction', (90, 101))	('sarcoma', 'Disease', (67, 74))	('RB1', 'Gene', (9, 12))	('RB1', 'Gene', (105, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('RB1', 'Gene', '5925', (105, 108))	('metastasis', 'CPA', (123, 133))	('RB1', 'Gene', '5925', (9, 12))
150382	30598078	Six drugs showed IC50 sensitivity using the Cancer Therapeutics Response Portal v2.	('Cancer', 'Disease', 'MESH:D009369', (44, 50))	('Cancer', 'Disease', (44, 50))	('Cancer', 'Phenotype', 'HP:0002664', (44, 50))	('IC50 sensitivity', 'Var', (17, 33))
150383	30598078	Four cell lines with no CDK4 amplification and positive expression of PDGFRA had lower IC50 values than seven cell lines that had CDK4 amplification and positive expression of PDGFRA (P = 0.028, Wilcoxon rank-sum test; Fig.	('lower', 'NegReg', (81, 86))	('PDGFRA', 'Gene', '5156', (176, 182))	('PDGFRA', 'Gene', '5156', (70, 76))	('PDGFRA', 'Gene', (176, 182))	('PDGFRA', 'Gene', (70, 76))	('CDK4', 'Gene', (130, 134))	('positive expression', 'Var', (47, 66))	('amp', 'Chemical', '-', (135, 138))	('CDK4', 'Gene', '1019', (130, 134))	('IC50 values', 'MPA', (87, 98))	('amp', 'Chemical', '-', (29, 32))	('CDK4', 'Gene', '1019', (24, 28))	('CDK4', 'Gene', (24, 28))
150384	30598078	We found that the PDGFRA signaling pathway in sarcoma cells, which have CDK4 amplification and PDGFRA expression, was disarranged by CDK4 activation, with decreased effects of drugs targeting PDGFRA.	('CDK4', 'Gene', (72, 76))	('PDGFRA', 'Gene', '5156', (192, 198))	('PDGFRA', 'Gene', (192, 198))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('CDK4', 'Gene', '1019', (72, 76))	('disarranged', 'NegReg', (118, 129))	('PDGFRA', 'Gene', '5156', (95, 101))	('PDGFRA', 'Gene', '5156', (18, 24))	('CDK4', 'Gene', (133, 137))	('PDGFRA', 'Gene', (18, 24))	('amplification', 'Var', (77, 90))	('amp', 'Chemical', '-', (77, 80))	('sarcoma', 'Disease', (46, 53))	('CDK4', 'Gene', '1019', (133, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('PDGFRA', 'Gene', (95, 101))	('activation', 'PosReg', (138, 148))
150386	30598078	According to a study that analyzed TCGA sarcoma data involving 206 sarcomas of six types, the type-specific copy-number alterations and histologic nuclear pleomorphisms correlate with aneuploidy estimates.	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('aneuploidy', 'Disease', (184, 194))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('sarcoma', 'Disease', (67, 74))	('sarcoma', 'Disease', (40, 47))	('copy-number alterations', 'Var', (108, 131))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('aneuploidy', 'Disease', 'MESH:D000782', (184, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('sarcomas', 'Disease', (67, 75))
150389	30598078	Molecular subtyping of the CKS samples showed the clusters of CDK4 amp, RB1 del, and PDGFRA putative target groups.	('amp', 'Var', (67, 70))	('CDK4', 'Gene', '1019', (62, 66))	('RB1', 'Gene', (72, 75))	('amp', 'Chemical', '-', (67, 70))	('amp', 'Chemical', '-', (32, 35))	('RB1', 'Gene', '5925', (72, 75))	('PDGFRA', 'Gene', '5156', (85, 91))	('PDGFRA', 'Gene', (85, 91))	('CKS', 'Chemical', '-', (27, 30))	('CDK4', 'Gene', (62, 66))
150392	30598078	The RB1 deletion occurred in 21.4% of CKS patients and 9.7% of TCGA sarcoma patients (P = 0.76, t-test; Fig.	('CKS', 'Chemical', '-', (38, 41))	('patients', 'Species', '9606', (76, 84))	('RB1', 'Gene', '5925', (4, 7))	('CKS', 'Disease', (38, 41))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('occurred', 'Reg', (17, 25))	('sarcoma', 'Disease', (68, 75))	('patients', 'Species', '9606', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('RB1', 'Gene', (4, 7))	('deletion', 'Var', (8, 16))
150395	30598078	We found that the well-established somatic drivers of gene mutation - FRG1B, CDC27, TP53, ATRX, and PTEN - were altered in 57, 43, 21, 21, and 21% of CKSs.	('PTEN', 'Gene', (100, 104))	('PTEN', 'Gene', '5728', (100, 104))	('CKS', 'Chemical', '-', (150, 153))	('CKSs', 'Disease', (150, 154))	('FRG1B', 'Gene', (70, 75))	('CDC27', 'Gene', '996', (77, 82))	('TP53', 'Gene', '7157', (84, 88))	('mutation', 'Var', (59, 67))	('FRG1B', 'Gene', '284802', (70, 75))	('ATRX', 'Gene', (90, 94))	('CDC27', 'Gene', (77, 82))	('TP53', 'Gene', (84, 88))	('altered', 'Reg', (112, 119))	('ATRX', 'Gene', '546', (90, 94))
150401	30598078	Missense mutations in TP53 may influence cancer phenotype and survival.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('survival', 'CPA', (62, 70))	('cancer', 'Disease', (41, 47))	('TP53', 'Gene', '7157', (22, 26))	('influence', 'Reg', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('TP53', 'Gene', (22, 26))	('Missense mutations', 'Var', (0, 18))
150403	30598078	Additionally, long telomeres are associated with ATRX deletion or mutations in UPS and MFS.	('mutations', 'Var', (66, 75))	('MFS', 'Gene', (87, 90))	('UPS', 'Disease', (79, 82))	('deletion', 'Var', (54, 62))	('ATRX', 'Gene', (49, 53))	('associated', 'Reg', (33, 43))	('ATRX', 'Gene', '546', (49, 53))	('UPS', 'Disease', 'MESH:D017118', (79, 82))
150405	30598078	A previous study suggested that the PTEN mutation might be a useful biomarker of cell proliferation in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('PTEN', 'Gene', (36, 40))	('sarcomas', 'Disease', (103, 111))	('mutation', 'Var', (41, 49))	('PTEN', 'Gene', '5728', (36, 40))
150408	30598078	We identified two patients with MSI-h that had chromosomal stability, PTEN mutation, and low PDGFRA expression; one of these patients was classified as US.	('PTEN', 'Gene', (70, 74))	('MSI-h', 'Gene', (32, 37))	('low', 'NegReg', (89, 92))	('mutation', 'Var', (75, 83))	('MSI-h', 'Gene', '5928', (32, 37))	('PDGFRA', 'Gene', (93, 99))	('PTEN', 'Gene', '5728', (70, 74))	('expression', 'MPA', (100, 110))	('PDGFRA', 'Gene', '5156', (93, 99))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (125, 133))
150416	30598078	The median overall survival (OS) was improved by 11.8 months in patients who received LARTRUVO-doxorubicin compared to those who received doxorubicin alone.	('overall survival', 'MPA', (11, 27))	('doxorubicin', 'Chemical', 'MESH:D004317', (95, 106))	('patients', 'Species', '9606', (64, 72))	('LARTRUVO-doxorubicin', 'Var', (86, 106))	('improved', 'PosReg', (37, 45))	('doxorubicin', 'Chemical', 'MESH:D004317', (138, 149))	('LARTRUVO-doxorubicin', 'Chemical', '-', (86, 106))
150423	30598078	High-level CDK4 amplification is associated with poor recurrence-free survival compared to low-level CDK4 amplification.	('amp', 'Chemical', '-', (106, 109))	('CDK4', 'Gene', '1019', (11, 15))	('CDK4', 'Gene', '1019', (101, 105))	('CDK4', 'Gene', (101, 105))	('recurrence-free survival', 'CPA', (54, 78))	('amplification', 'Var', (16, 29))	('amp', 'Chemical', '-', (16, 19))	('poor', 'NegReg', (49, 53))	('CDK4', 'Gene', (11, 15))
150439	30598078	Although this molecule awaits approval for marketing, it may be considered as a potential drug for patients with RB1 deletion.	('patients', 'Species', '9606', (99, 107))	('RB1', 'Gene', (113, 116))	('RB1', 'Gene', '5925', (113, 116))	('deletion', 'Var', (117, 125))
150462	29969193	In the clinical setting, MRI is the primary modality used in orthopedics for diagnosis of soft tissues injuries such as intervertebral disc injuries; tears in the menisci, ligaments and tendons; and occult bone injuries.	('tears', 'Var', (150, 155))	('occult bone injuries', 'Disease', 'MESH:D001848', (199, 219))	('tears', 'Phenotype', 'HP:0009926', (150, 155))	('intervertebral disc injuries', 'Disease', (120, 148))	('intervertebral disc injuries', 'Disease', 'MESH:D055959', (120, 148))	('soft tissues injuries', 'Disease', (90, 111))	('occult bone injuries', 'Disease', (199, 219))	('soft tissues injuries', 'Disease', 'MESH:D017695', (90, 111))
150467	29969193	New methods such zero echo time (ZTE) MRI and ultra-short echo time (uTE) have shown promise for visualization of cortical bone and for assessment of fracture risk.	('ultra-short', 'Var', (46, 57))	('fracture', 'Disease', (150, 158))	('cortical bone', 'CPA', (114, 127))	('fracture', 'Disease', 'MESH:D050723', (150, 158))
150484	29969193	Interestingly, a retrospective study examining the diagnostic accuracy of FDG PET/CT and conventional imaging (including MRI) of a heterogeneous cohort of 117 BS and STS showed slightly better T-staging by FDG PET/CT (overall accuracy 96%) compared to conventional imaging (94% accuracy).	('STS', 'Phenotype', 'HP:0030448', (166, 169))	('BS', 'Phenotype', 'HP:0002669', (159, 161))	('FDG', 'Chemical', '-', (74, 77))	('T-staging', 'CPA', (193, 202))	('better', 'PosReg', (186, 192))	('FDG PET/CT', 'Var', (206, 216))	('FDG', 'Chemical', '-', (206, 209))
150526	29969193	Positive response on conventional MRI sequences includes decrease in size and/or number of focal lesions, normalization of a diffuse pattern, and in focal lesions, the appearance of a peripheral halo of T1 hyperintense fatty marrow, or complete fatty replacement, also called fatty metamorphosis.	('decrease', 'NegReg', (57, 65))	('fatty metamorphosis', 'Disease', 'MESH:C536351', (276, 295))	('normalization', 'MPA', (106, 119))	('diffuse pattern', 'MPA', (125, 140))	('T1 hyperintense', 'Var', (203, 218))	('fatty metamorphosis', 'Disease', (276, 295))
150547	29969193	Both PET/CT and MRI have excellent accuracy for detecting osseous metastases, with one meta-analysis showing overall sensitivity of 98% with PET/CT and 95% with MRI.	('PET/CT', 'Var', (141, 147))	('osseous metastases', 'Disease', 'MESH:D009362', (58, 76))	('osseous metastases', 'Disease', (58, 76))
150563	29969193	A feasibility study in patients with knee pain or prior knee injury showed that the 18F-NaF PET uptake in subchondral bone marrow lesions (BML), osteophytes, and sclerosis identified on MRI was significantly higher than that of normal appearing bone on MRI (Fig.	('sclerosis', 'Disease', (162, 171))	('higher', 'PosReg', (208, 214))	('NaF', 'Gene', (88, 91))	('knee injury', 'Disease', 'MESH:D007718', (56, 67))	('pain', 'Disease', (42, 46))	('pain', 'Disease', 'MESH:D010146', (42, 46))	('patients', 'Species', '9606', (23, 31))	('subchondral bone marrow lesions', 'Disease', 'MESH:D001855', (106, 137))	('subchondral bone marrow lesions', 'Disease', (106, 137))	('18F', 'Chemical', 'MESH:C000615276', (84, 87))	('knee injury', 'Disease', (56, 67))	('sclerosis', 'Disease', 'MESH:D012598', (162, 171))	('knee pain', 'Phenotype', 'HP:0030839', (37, 46))	('MRI', 'Var', (186, 189))	('NaF', 'Gene', '3576', (88, 91))	('pain', 'Phenotype', 'HP:0012531', (42, 46))
150568	29969193	Further, in patients with unilateral, reconstructed anterior cruciate ligament (ACL) tears within the last 10 years, who have a known increased risk for developing accelerated OA, significantly increased 18F-NaF PET uptake was observed in the subchondral bone of ACL-Reconstructed knee joints, compared with their uninjured contralateral knees.	('patients', 'Species', '9606', (12, 20))	('NaF', 'Gene', (208, 211))	('OA', 'Phenotype', 'HP:0002758', (176, 178))	('tears', 'Var', (85, 90))	('18F', 'Chemical', 'MESH:C000615276', (204, 207))	('rat', 'Species', '10116', (170, 173))	('accelerated OA', 'Disease', (164, 178))	('increased', 'PosReg', (194, 203))	('NaF', 'Gene', '3576', (208, 211))	('tears', 'Phenotype', 'HP:0009926', (85, 90))
150619	29969193	An in-vivo animal study showed the increased uptake of 18F-FTC-146 at the site of nerve injury, demonstrating its feasibility as a neuropathic pain marker.	('18F', 'Chemical', 'MESH:C000615276', (55, 58))	('increased', 'PosReg', (35, 44))	('rat', 'Species', '10116', (103, 106))	('nerve injury', 'Disease', 'MESH:D000080902', (82, 94))	('nerve injury', 'Disease', (82, 94))	('neuropathic pain', 'Disease', (131, 147))	('pain', 'Phenotype', 'HP:0012531', (143, 147))	('uptake', 'MPA', (45, 51))	('neuropathic pain', 'Disease', 'MESH:D009437', (131, 147))	('18F-FTC-146', 'Var', (55, 66))
150647	29969193	In that prospective study of 30 patients, simultaneous 18F-FDG PET-MRI improved the sensitivity from 54% to 100% and the specificity from 71% to 88% compared to MRI alone.	('18F-FDG', 'Chemical', '-', (55, 62))	('patients', 'Species', '9606', (32, 40))	('18F-FDG', 'Var', (55, 62))	('PET-MRI', 'Gene', '78996', (63, 70))	('PET-MRI', 'Gene', (63, 70))	('improved', 'PosReg', (71, 79))
150840	29416168	Inappropriate excisions account for a frightening 18% to 53% of total referrals at a number of specialist sarcoma centers.	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Inappropriate excisions', 'Var', (0, 23))	('sarcoma', 'Disease', (106, 113))
150845	29416168	This shows that, despite the best efforts of sarcoma specialists to salvage a chance at good therapy, excision prior to diagnosis and referral can potentially have an irreversible downstream effect on a patient's life.	('sarcoma', 'Disease', (45, 52))	('excision', 'Var', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('patient', 'Species', '9606', (203, 210))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))
150847	29416168	Analysis revealed that the average size of a referred sarcoma was 10.2 cm, and that mortality increased with increasing size at presentation, showing a patient with a STS up to 15 cm had a 3.5 times greater risk of dying than a patient with a tumor <5 cm at diagnosis (P < 0.0001) [Figure 4].	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('up to 15 cm', 'Var', (171, 182))	('sarcoma', 'Disease', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('STS', 'Phenotype', 'HP:0030448', (167, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('patient', 'Species', '9606', (152, 159))	('patient', 'Species', '9606', (228, 235))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
150873	29416168	One of the largest scale trials conducted to compare preoperative to postoperative radiotherapy, known as the National Cancer Institute of Canada SR2 trial, revealed that STS patients treated with postoperative radiotherapy had more subcutaneous fibrosis (48% vs. 31.5%), joint stiffness (23% vs. 17.8%), and extremity edema (23% vs. 15.1%), when compared to the preoperative radiotherapy.	('more', 'PosReg', (228, 232))	('postoperative radiotherapy', 'Var', (197, 223))	('subcutaneous fibrosis', 'Phenotype', 'HP:0007618', (233, 254))	('edema', 'Disease', (319, 324))	('edema', 'Phenotype', 'HP:0000969', (319, 324))	('joint stiffness', 'Phenotype', 'HP:0001387', (272, 287))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (175, 183))	('edema', 'Disease', 'MESH:D004487', (319, 324))	('STS', 'Phenotype', 'HP:0030448', (171, 174))	('joint stiffness', 'Disease', 'MESH:C535724', (272, 287))	('joint stiffness', 'Disease', (272, 287))	('fibrosis', 'Disease', 'MESH:D005355', (246, 254))	('fibrosis', 'Disease', (246, 254))
150902	26327622	Recurrent deregulation of c-Myc (Myc) is a hallmark of many lymphoma such as Burkitt lymphoma (BL) and a fraction (~20%) of diffuse large B cell lymphomas (DLBCL), including post-germinal center (GC), non-Hodgkin's lymphoma.	('Myc', 'Gene', (33, 36))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (77, 93))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (205, 223))	('post-germinal center', 'Disease', (174, 194))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (138, 153))	('c-Myc', 'Gene', (26, 31))	("non-Hodgkin's lymphoma", 'Disease', (201, 223))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))	('lymphoma', 'Phenotype', 'HP:0002665', (215, 223))	('large B cell', 'Phenotype', 'HP:0005404', (132, 144))	('B cell lymphomas', 'Disease', 'MESH:D016393', (138, 154))	('Myc', 'Gene', '17869', (33, 36))	('hallmark of many lymphoma', 'Disease', (43, 68))	('c-Myc', 'Gene', '17869', (26, 31))	('BL', 'Phenotype', 'HP:0030080', (95, 97))	('hallmark of many lymphoma', 'Disease', 'MESH:D008223', (43, 68))	('Burkitt lymphoma', 'Disease', (77, 93))	('Myc', 'Gene', (28, 31))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (77, 93))	('lymphomas', 'Phenotype', 'HP:0002665', (145, 154))	('deregulation', 'Var', (10, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (60, 68))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (201, 223))	('lymphoma', 'Phenotype', 'HP:0002665', (85, 93))	('Myc', 'Gene', '17869', (28, 31))	('B cell lymphomas', 'Disease', (138, 154))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (138, 154))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (201, 223))
150905	26327622	This suggests that deregulated expression of the Myc protein by any means contributes to B cell lymphomagenesis.	('contributes', 'Reg', (74, 85))	('deregulated', 'Var', (19, 30))	('B cell lymphoma', 'Disease', 'MESH:D016393', (89, 104))	('B cell lymphoma', 'Disease', (89, 104))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (89, 104))	('Myc', 'Gene', (49, 52))	('expression', 'MPA', (31, 41))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('Myc', 'Gene', '17869', (49, 52))	('B cell lymphomagenesis', 'Phenotype', 'HP:0012191', (89, 111))
150907	26327622	The first and most aggressive transgenic model used the mouse Myc gene, driven by the IgH mu enhancer (EmuMyc mouse); here the transgene induced tumors, expansion of lymph nodes, and lymphoid malignancy within 6-15 weeks.	('expansion of lymph nodes', 'CPA', (153, 177))	('lymphoid malignancy', 'Disease', (183, 202))	('lymphoid malignancy', 'Phenotype', 'HP:0002665', (183, 202))	('Myc', 'Gene', (106, 109))	('Myc', 'Gene', (62, 65))	('transgene', 'Var', (127, 136))	('mouse', 'Species', '10090', (56, 61))	('mouse', 'Species', '10090', (110, 115))	('tumors', 'Disease', (145, 151))	('Myc', 'Gene', '17869', (62, 65))	('induced', 'Reg', (137, 144))	('transgenic', 'Species', '10090', (30, 40))	('lymphoid malignancy', 'Disease', 'MESH:D008223', (183, 202))	('Myc', 'Gene', '17869', (106, 109))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))
150976	26327622	The presence of the KSHV transgene increased the response to LPS.	('LPS', 'Gene', (61, 64))	('increased', 'PosReg', (35, 44))	('KSHV', 'Species', '37296', (20, 24))	('KSHV', 'Gene', (20, 24))	('LPS', 'Gene', '21898', (61, 64))	('presence', 'Var', (4, 12))
150977	26327622	The presence of the KSHV transgene dampened the response to BCR crosslinking by anti-IgM antibody.	('KSHV', 'Species', '37296', (20, 24))	('IgM', 'Gene', '16019', (85, 88))	('response to BCR crosslinking', 'MPA', (48, 76))	('KSHV', 'Gene', (20, 24))	('dampened', 'NegReg', (35, 43))	('anti-IgM antibody', 'Phenotype', 'HP:0003496', (80, 97))	('presence', 'Var', (4, 12))	('IgM', 'Gene', (85, 88))
151002	26327622	Chromosomal translocation of Myc has been identified as the defining cellular driver mutation in BL.	('Myc', 'Gene', '17869', (29, 32))	('BL', 'Phenotype', 'HP:0030080', (97, 99))	('Chromosomal translocation', 'Var', (0, 25))	('Myc', 'Gene', (29, 32))
151005	26327622	Based on the biology of B cell lymphoma and the broad transcriptional phenotype of activated Myc, we hypothesized that deregulated Myc signaling can cooperate with BCR/TLR activation and KSHV latent genes to drive lymphomagenesis.	('lymphoma', 'Disease', 'MESH:D008223', (214, 222))	('drive', 'PosReg', (208, 213))	('lymphoma', 'Phenotype', 'HP:0002665', (214, 222))	('lymphoma', 'Disease', (31, 39))	('deregulated', 'Var', (119, 130))	('KSHV', 'Species', '37296', (187, 191))	('lymphoma', 'Disease', 'MESH:D008223', (31, 39))	('B cell lymphoma', 'Disease', 'MESH:D016393', (24, 39))	('B cell lymphoma', 'Disease', (24, 39))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (24, 39))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('lymphoma', 'Disease', (214, 222))	('Myc', 'Gene', (93, 96))	('Myc', 'Gene', '17869', (93, 96))	('Myc', 'Gene', (131, 134))	('Myc', 'Gene', '17869', (131, 134))
151108	32351899	In addition, gain in 1q21-q23 was present in 5 MAS, involving NTRK1, CTSK, and HDGF; gain in 8q13-21 in 5 MAS, involving ARMC1, MYBL1, PRDM14, and TERF1; and gain in 5p15 in 3 MAS, involving TERT.	('TERF1', 'Gene', '7013', (147, 152))	('CTSK', 'Gene', '1513', (69, 73))	('1q21-q23', 'Var', (21, 29))	('HDGF', 'Gene', (79, 83))	('ARMC1', 'Gene', '55156', (121, 126))	('MYBL1', 'Gene', (128, 133))	('MYBL1', 'Gene', '4603', (128, 133))	('HDGF', 'Gene', '3068', (79, 83))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('NTRK1', 'Gene', '4914', (62, 67))	('gain', 'PosReg', (13, 17))	('gain', 'Var', (85, 89))	('ARMC1', 'Gene', (121, 126))	('NTRK1', 'Gene', (62, 67))	('PRDM14', 'Gene', (135, 141))	('PRDM14', 'Gene', '63978', (135, 141))	('TERF1', 'Gene', (147, 152))	('CTSK', 'Gene', (69, 73))
151117	32351899	The break-ends found in chr 7 were within 6 genes (CBX3, ORC5, PUS7, TRB, CNTNAP2, and KMT2C), and in-frame gene fusions or non-gene fusion in 12 chromosomes (Figure 4C, Supplementary Table 7).	('in-frame gene fusions', 'Var', (99, 120))	('non-gene', 'CPA', (124, 132))	('TRB', 'Gene', (69, 72))	('CNTNAP2', 'Gene', '26047', (74, 81))	('ORC5', 'Gene', '5001', (57, 61))	('CBX3', 'Gene', '11335', (51, 55))	('CNTNAP2', 'Gene', (74, 81))	('TRB', 'Gene', '6957', (69, 72))	('PUS7', 'Gene', '54517', (63, 67))	('CBX3', 'Gene', (51, 55))	('KMT2C', 'Gene', '58508', (87, 92))	('KMT2C', 'Gene', (87, 92))	('PUS7', 'Gene', (63, 67))	('ORC5', 'Gene', (57, 61))
151119	32351899	Three randomly selected SV breakpoints including 7q22-12q12 (ORC5-MUC19), 2q14-9q34 (DPP10-SET), and 12q14-15q15 (BAZ2A-FSIP1) were analyzed, and all were confirmed by sequencing analysis (Figure 4D).	('FSIP1', 'Gene', (120, 125))	('ORC5', 'Gene', (61, 65))	('FSIP1', 'Gene', '161835', (120, 125))	('MUC19', 'Gene', '283463', (66, 71))	('BAZ2A', 'Gene', (114, 119))	('12q14-15q15', 'Var', (101, 112))	('DPP10', 'Gene', '57628', (85, 90))	('ORC5', 'Gene', '5001', (61, 65))	('MUC19', 'Gene', (66, 71))	('2q14-9q34', 'Var', (74, 83))	('DPP10', 'Gene', (85, 90))	('7q22-12q12', 'Var', (49, 59))	('BAZ2A', 'Gene', '11176', (114, 119))
151120	32351899	Pathway analysis (KEGG pathway) of these mutant genes indicated dysfunction of many different pathways involving cellular and extracellular functions, AKT and AMPK signaling, and endometrial cancer-related gene function (Figure 5A).	('endometrial cancer', 'Phenotype', 'HP:0012114', (179, 197))	('AKT', 'Gene', (151, 154))	('AMPK', 'Gene', (159, 163))	('endometrial cancer', 'Disease', 'MESH:D016889', (179, 197))	('mutant', 'Var', (41, 47))	('endometrial cancer', 'Disease', (179, 197))	('AKT', 'Gene', '207', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('AMPK', 'Gene', '5562', (159, 163))
151121	32351899	To further detect gene mutations that are frequent in MAS and/or highly relevant to MAS tumorigenesis, we selected candidate genes (defined as hot gene mutations) that met the following criteria for further validation analysis: (1) mutations in at least 2 of 10 cases from WGS; (2) oncogenes or tumor suppressors reported to be closely related to any sarcoma or Mullerian malignancy; (3) altered expression found in MAS.	('sarcoma', 'Disease', 'MESH:D012509', (351, 358))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('hot', 'Gene', '137872', (143, 146))	('sarcoma', 'Disease', (351, 358))	('WGS', 'Disease', (273, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (351, 358))	('malignancy', 'Disease', 'MESH:D009369', (372, 382))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('mutations', 'Var', (23, 32))	('mutations', 'Var', (232, 241))	('malignancy', 'Disease', (372, 382))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('hot', 'Gene', (143, 146))	('expression', 'MPA', (396, 406))	('tumor', 'Disease', (88, 93))	('altered', 'Reg', (388, 395))	('tumor', 'Disease', (295, 300))
151123	32351899	Frequently mutated genes in MAS seemed to be centralized by BRCA1, by influencing cell cycle function and AKT signaling.	('BRCA1', 'Gene', (60, 65))	('cell cycle function', 'CPA', (82, 101))	('AKT', 'Gene', (106, 109))	('mutated genes', 'Var', (11, 24))	('influencing', 'Reg', (70, 81))	('AKT', 'Gene', '207', (106, 109))	('BRCA1', 'Gene', '672', (60, 65))
151124	32351899	We first compared the mutation patterns between WGS and NGS target validation in 10 cases and found that 98.2% of mutations were detected by both methods in the same tumors, indicative of a reliable assay for target validation.	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
151126	32351899	BCOR mutations, found 21% (6/29) of cases, were found in splicing sites and did not change amino acids (Figure 6A, Table 2B).	('BCOR', 'Gene', '54880', (0, 4))	('BCOR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
151128	32351899	Gain of chromosome 12q is a characteristic genomic alteration or landmark in most MAS, and HMGA2 gain/overexpression is significantly associated with MAS with SO and seems to be associated with tumor progression.	('HMGA2', 'Gene', '8091', (91, 96))	('associated', 'Reg', (134, 144))	('Gain', 'Var', (0, 4))	('associated', 'Reg', (178, 188))	('HMGA2', 'Gene', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('MAS', 'Disease', (150, 153))	('gain/overexpression', 'PosReg', (97, 116))	('MAS', 'Disease', (82, 85))
151130	32351899	Abnormalities in the PIK3-AKT-PTEN pathway, including CNVs and mutations, are also common (26-72% of cases).	('mutations', 'Var', (63, 72))	('CNVs', 'Disease', (54, 58))	('Abnormalities', 'Var', (0, 13))	('AKT', 'Gene', '207', (26, 29))	('PIK3', 'Gene', '5294', (21, 25))	('AKT', 'Gene', (26, 29))	('PTEN', 'Gene', (30, 34))	('PTEN', 'Gene', '5728', (30, 34))	('PIK3', 'Gene', (21, 25))
151133	32351899	reported two cases with fusion genes involving NCOA family members.	('NCOA', 'Gene', (47, 51))	('fusion genes', 'Var', (24, 36))	('NCOA', 'Gene', '10499', (47, 51))
151135	32351899	Using conventional cytogenetics, Howitt and colleagues found chromosomal abnormalities in 43% of cases; 71% of the 7 cases with noncomplex chromosomal aberrations demonstrated abnormalities in chr 8, which contains MYBL1.	('chromosomal abnormalities', 'Disease', (61, 86))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (61, 86))	('abnormalities', 'Var', (176, 189))	('MYBL1', 'Gene', (215, 220))	('MYBL1', 'Gene', '4603', (215, 220))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (139, 162))	('chr 8', 'Gene', (193, 198))
151140	32351899	Of note, ovarian MAS seemed to have higher number of mutated genes (Figure 6A) and higher expression of the selected gene products (Supplementary Table 6) than cervical and uterine MAS.	('ovarian MAS', 'Disease', (9, 20))	('higher', 'PosReg', (36, 42))	('mutated', 'Var', (53, 60))	('expression', 'MPA', (90, 100))	('ovarian MAS', 'Disease', 'MESH:D005357', (9, 20))	('uterine MAS', 'Phenotype', 'HP:0000130', (173, 184))	('higher', 'PosReg', (83, 89))
151142	32351899	Notably, TP53 mutations were uncommon, present in only two cases with SO.	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
151143	32351899	Three out of 18 cases (17%) had mutations in ATRX, all associated with SO.	('ATRX', 'Gene', (45, 49))	('mutations', 'Var', (32, 41))	('associated', 'Reg', (55, 65))	('ATRX', 'Gene', '546', (45, 49))
151147	32351899	Findings of increased alterations of BRCA1, MDM2, and TP53 in MAS may partially explain a high DNA instability and frequent CNVs in this tumor type, in particular in SO.	('MDM2', 'Gene', '4193', (44, 48))	('tumor', 'Disease', (137, 142))	('MDM2', 'Gene', (44, 48))	('increased', 'PosReg', (12, 21))	('TP53', 'Gene', '7157', (54, 58))	('alterations', 'Var', (22, 33))	('DNA instability', 'MPA', (95, 110))	('BRCA1', 'Gene', '672', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('TP53', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('BRCA1', 'Gene', (37, 42))
151148	32351899	This study also broadens our knowledge of the mutation spectrum in MAS and identified many new mutations, including in KMT2C (52%), MAGEC1 (34%), DCHS2 (31%), KDM6B and AHNAK (28%), FCGBP (24%), and BCOR (21%).	('FCGBP', 'Gene', '8857', (182, 187))	('AHNAK', 'Gene', (169, 174))	('BCOR', 'Gene', '54880', (199, 203))	('KDM6B', 'Gene', '23135', (159, 164))	('MAGEC1', 'Gene', '9947', (132, 138))	('AHNAK', 'Gene', '79026', (169, 174))	('DCHS2', 'Gene', (146, 151))	('DCHS2', 'Gene', '54798', (146, 151))	('KDM6B', 'Gene', (159, 164))	('KMT2C', 'Gene', (119, 124))	('mutations', 'Var', (95, 104))	('KMT2C', 'Gene', '58508', (119, 124))	('FCGBP', 'Gene', (182, 187))	('BCOR', 'Gene', (199, 203))	('MAGEC1', 'Gene', (132, 138))
151149	32351899	All these mutated genes showed a wide range of alteration in some cancers or sarcomas.	('mutated', 'Var', (10, 17))	('cancers', 'Disease', (66, 73))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('alteration', 'Reg', (47, 57))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))
151151	32351899	The prevalence of mutations of these genes in endometrial cancer and other cancer in cBioportal are 9.5% (1.5-19.6%) and 3.1% (0.5-8.4%), respectively.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('endometrial cancer', 'Disease', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('endometrial cancer', 'Disease', 'MESH:D016889', (46, 64))	('endometrial cancer', 'Phenotype', 'HP:0012114', (46, 64))	('mutations', 'Var', (18, 27))
151153	32351899	KMT2C mutation in MAS was reported in a previous study.	('KMT2C', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('KMT2C', 'Gene', '58508', (0, 5))
151154	32351899	KMT2C (lysine-specific methyltransferase 2C) is a putative tumor suppressor that is frequently mutated in many malignancies and associated with tumor aggressiveness.	('tumor', 'Disease', (144, 149))	('tumor aggressiveness', 'Disease', (144, 164))	('tumor', 'Disease', (59, 64))	('aggressiveness', 'Phenotype', 'HP:0000718', (150, 164))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('mutated', 'Var', (95, 102))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (144, 164))	('associated with', 'Reg', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('malignancies', 'Disease', (111, 123))
151156	32351899	Current studies indicate that KMT2C mutation may cause loss of function in MAS and other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('KMT2C', 'Gene', '58508', (30, 35))	('KMT2C', 'Gene', (30, 35))	('loss of function', 'NegReg', (55, 71))	('malignancies', 'Disease', (89, 101))	('MAS', 'Disease', (75, 78))	('mutation', 'Var', (36, 44))
151157	32351899	The high rate of KMT2C mutation and its high rate of SV in chr 7 suggests an important role in MAS.	('mutation', 'Var', (23, 31))	('KMT2C', 'Gene', '58508', (17, 22))	('KMT2C', 'Gene', (17, 22))
151158	32351899	This study also identified a relatively high rate of BCOR mutations in 21% MAS.	('BCOR', 'Gene', (53, 57))	('mutations', 'Var', (58, 67))	('BCOR', 'Gene', '54880', (53, 57))	('MAS', 'Disease', (75, 78))
151159	32351899	BCOR mutation was found in 4 MAS with SO and in 2 MAS without SO.	('found', 'Reg', (18, 23))	('BCOR', 'Gene', '54880', (0, 4))	('mutation', 'Var', (5, 13))	('BCOR', 'Gene', (0, 4))
151160	32351899	The role of BCOR mutation in MAS tumorigenesis merits further investigation.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('BCOR', 'Gene', (12, 16))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('BCOR', 'Gene', '54880', (12, 16))
151165	32351899	For example, while KMT2C mutations can be found in both types, mutations of KDM6B and MAGEC1 seem to be relatively specific for MAS with SO.	('mutations', 'Var', (63, 72))	('MAGEC1', 'Gene', '9947', (86, 92))	('KMT2C', 'Gene', '58508', (19, 24))	('KMT2C', 'Gene', (19, 24))	('MAS', 'Disease', (128, 131))	('KDM6B', 'Gene', '23135', (76, 81))	('KDM6B', 'Gene', (76, 81))	('MAGEC1', 'Gene', (86, 92))
151166	32351899	In particular, we identified CNV in chr 12q leading to HMGA2/CDK4 upregulation, a high rate of SV in chr 7q leading to several in-frame gene fusions, a high rate of KMT2C mutation, and gene mutation signatures specifically related to MAS tumor progression.	('upregulation', 'PosReg', (66, 78))	('CNV', 'Var', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('mutation', 'Var', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('CDK4', 'Gene', (61, 65))	('KMT2C', 'Gene', '58508', (165, 170))	('KMT2C', 'Gene', (165, 170))	('tumor', 'Disease', (238, 243))	('HMGA2', 'Gene', '8091', (55, 60))	('CDK4', 'Gene', '1019', (61, 65))	('HMGA2', 'Gene', (55, 60))
151210	31622129	Children who are diagnosed with hereditary retinoblastoma, a rare eye cancer caused by a germline mutation in the RB1 tumor suppressor gene, have excellent prognosis in high-income countries but have substantially increased risks for developing and dying of subsequent bone and soft-tissue sarcomas.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('eye cancer', 'Disease', 'MESH:D005134', (66, 76))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (278, 298))	('hereditary retinoblastoma', 'Disease', (32, 57))	('germline mutation', 'Var', (89, 106))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (278, 298))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('bone and', 'Disease', (269, 277))	('eye cancer', 'Disease', (66, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (290, 298))	('retinoblastoma', 'Phenotype', 'HP:0009919', (43, 57))	('Children', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('RB1', 'Gene', (114, 117))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (278, 297))	('soft-tissue sarcomas', 'Disease', (278, 298))	('eye cancer', 'Phenotype', 'HP:0100012', (66, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (32, 57))	('caused by', 'Reg', (77, 86))	('tumor', 'Disease', (118, 123))	('RB1', 'Gene', '5925', (114, 117))
151291	31622129	In addition, the importance of RB1 mutations in carcinogenesis is supported not only by the strikingly elevated sarcoma risks occurring outside the treatment field among irradiated survivors of hereditary retinoblastoma that we observed, but also by the importance of recurrent RB1 somatic mutations in sporadic sarcomas.	('RB1', 'Gene', (31, 34))	('RB1', 'Gene', (278, 281))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('retinoblastoma', 'Phenotype', 'HP:0009919', (205, 219))	('RB1', 'Gene', '5925', (278, 281))	('RB1', 'Gene', '5925', (31, 34))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (194, 219))	('sarcoma', 'Disease', 'MESH:D012509', (312, 319))	('sarcomas', 'Disease', 'MESH:D012509', (312, 320))	('sarcoma', 'Disease', (312, 319))	('sarcomas', 'Phenotype', 'HP:0100242', (312, 320))	('elevated', 'PosReg', (103, 111))	('carcinogenesis', 'Disease', (48, 62))	('sarcomas', 'Disease', (312, 320))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (48, 62))	('hereditary retinoblastoma', 'Disease', (194, 219))	('mutations', 'Var', (290, 299))	('sarcoma', 'Disease', (112, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (312, 319))	('mutations', 'Var', (35, 44))
151292	31622129	Understanding whether specific RB1 mutations or other genetic variants confer differential sarcoma risk, either in the presence or absence of radiation exposure, could provide insight into sarcoma etiology and identify individuals:even with low penetrance or mosaic RB1 mutations:who might benefit the most from increased surveillance.	('RB1', 'Gene', (31, 34))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('sarcoma', 'Disease', (189, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('mutations', 'Var', (270, 279))	('RB1', 'Gene', '5925', (31, 34))	('RB1', 'Gene', (266, 269))	('sarcoma', 'Disease', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))	('mosaic', 'Var', (259, 265))	('RB1', 'Gene', '5925', (266, 269))	('mutations', 'Var', (35, 44))
151343	30957058	Bone marrow aspirate and biopsy revealed myelodysplastic syndrome, 2% blasts, with complex cytogenetics and mutation in nucleophosmin 1 (NPM1) and DNA methyltransferase 3 alpha (DNMT3A).	('myelodysplastic syndrome', 'Disease', (41, 65))	('NPM1', 'Gene', (137, 141))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (41, 65))	('DNMT3A', 'Gene', (178, 184))	('DNA methyltransferase 3 alpha', 'Gene', '1788', (147, 176))	('DNA methyltransferase 3 alpha', 'Gene', (147, 176))	('nucleophosmin 1', 'Gene', '4869', (120, 135))	('nucleophosmin 1', 'Gene', (120, 135))	('DNMT3A', 'Gene', '1788', (178, 184))	('NPM1', 'Gene', '4869', (137, 141))	('mutation', 'Var', (108, 116))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (41, 65))
151351	30957058	Repeat bone marrow studies revealed a persistent morphologic remission with diploid cytogenetics and less than 1% NPM1 and DNMT3A mutations by polymerase chain reaction.	('NPM1', 'Gene', (114, 118))	('NPM1', 'Gene', '4869', (114, 118))	('DNMT3A', 'Gene', (123, 129))	('DNMT3A', 'Gene', '1788', (123, 129))	('mutations', 'Var', (130, 139))
151362	30957058	Activating programmed cell death protein 1 (PD-1) prevents CD28/B7 signaling that is crucial for CD8 T-cell activation.	('PD-1', 'Gene', (44, 48))	('prevents', 'NegReg', (50, 58))	('programmed cell death protein 1', 'Gene', '5133', (11, 42))	('CD28', 'Gene', (59, 63))	('Activating', 'Var', (0, 10))	('programmed cell death protein 1', 'Gene', (11, 42))	('CD8', 'Gene', (97, 100))	('CD28', 'Gene', '940', (59, 63))	('CD8', 'Gene', '925', (97, 100))
151364	30957058	Treatment with anti-PD-1 antibody improved survival in those models, indicating the importance of the PD-1/PD-L1 pathway in immune evasion by AML blasts as well as providing a rationale for clinical trials targeting this pathway in AML (eg, with nivolumab).	('improved', 'PosReg', (34, 42))	('AML', 'Disease', 'MESH:D015470', (232, 235))	('AML', 'Disease', (142, 145))	('nivolumab', 'Chemical', 'MESH:D000077594', (246, 255))	('AML', 'Phenotype', 'HP:0004808', (142, 145))	('AML', 'Phenotype', 'HP:0004808', (232, 235))	('AML', 'Disease', (232, 235))	('survival', 'MPA', (43, 51))	('immune evasion', 'MPA', (124, 138))	('anti-PD-1', 'Var', (15, 24))	('AML', 'Disease', 'MESH:D015470', (142, 145))
151366	30957058	All T-cell subpopulations (CD3+, CD4+, and CD8+ T cells) had significantly higher PD1 expression in relapsed AML (P < .006) and untreated AML (P < .05) compared with healthy controls.	('PD1', 'Gene', '5133', (82, 85))	('CD8', 'Gene', (43, 46))	('AML', 'Phenotype', 'HP:0004808', (138, 141))	('AML', 'Disease', (138, 141))	('AML', 'Disease', 'MESH:D015470', (109, 112))	('higher', 'PosReg', (75, 81))	('CD8', 'Gene', '925', (43, 46))	('expression', 'MPA', (86, 96))	('AML', 'Disease', (109, 112))	('CD3+', 'Var', (27, 31))	('AML', 'Phenotype', 'HP:0004808', (109, 112))	('AML', 'Disease', 'MESH:D015470', (138, 141))	('CD4', 'Gene', (33, 36))	('CD4', 'Gene', '920', (33, 36))	('PD1', 'Gene', (82, 85))
151380	30957058	AML with mutant NPM1 is considered to be of favorable risk, and, interestingly, one suggested explanation relates to immune responses developed against epitopes derived from the mutated region of NPM1.	('NPM1', 'Gene', (16, 20))	('mutant', 'Var', (9, 15))	('NPM1', 'Gene', (196, 200))	('NPM1', 'Gene', '4869', (16, 20))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('NPM1', 'Gene', '4869', (196, 200))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('AML', 'Disease', (0, 3))
151381	30957058	Higher PD-L1 expression in NPM1 mutated patients, particularly in leukemic stem/progenitor cells, has been noted, potentially making this particular subgroup of AML more likely to benefit from ICPI treatment.	('leukemic', 'Disease', 'MESH:D007938', (66, 74))	('expression', 'MPA', (13, 23))	('patients', 'Species', '9606', (40, 48))	('AML', 'Phenotype', 'HP:0004808', (161, 164))	('AML', 'Disease', 'MESH:D015470', (161, 164))	('mutated', 'Var', (32, 39))	('ICPI', 'Chemical', '-', (193, 197))	('NPM1', 'Gene', (27, 31))	('Higher', 'PosReg', (0, 6))	('leukemic', 'Disease', (66, 74))	('PD-L1', 'Gene', (7, 12))	('AML', 'Disease', (161, 164))	('NPM1', 'Gene', '4869', (27, 31))
151546	28814294	Canine neoplasms with transmission electron microscopy characteristics resembling type B-like synoviocytes should be considered similar to the human sarcomas that carry the specific translocations between chromosomes X and 18.	('neoplasms', 'Disease', 'MESH:D009369', (7, 16))	('human', 'Species', '9606', (143, 148))	('neoplasms', 'Disease', (7, 16))	('Canine', 'Species', '9615', (0, 6))	('neoplasm', 'Phenotype', 'HP:0002664', (7, 15))	('sarcomas', 'Disease', 'MESH:D012509', (149, 157))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('neoplasms', 'Phenotype', 'HP:0002664', (7, 16))	('sarcomas', 'Disease', (149, 157))	('translocations', 'Var', (182, 196))
151581	28814294	In people, sarcomas, designated synovial sarcoma, are associated with a specific translocation between chromosomes X and 18 leading to a fusion of the SYT gene on chromosome 18 to the SSX1, SSX2 or SSX4 genes on chromosome X.	('SSX1', 'Gene', (184, 188))	('synovial sarcoma', 'Disease', (32, 48))	('SYT', 'Gene', '6760', (151, 154))	('SSX4', 'Gene', '6759', (198, 202))	('fusion', 'Var', (137, 143))	('SSX2', 'Gene', (190, 194))	('SSX4', 'Gene', (198, 202))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (32, 48))	('synovial sarcoma', 'Disease', 'MESH:D013584', (32, 48))	('sarcomas', 'Disease', (11, 19))	('SSX2', 'Gene', '6757', (190, 194))	('SSX1', 'Gene', '6756', (184, 188))	('SYT', 'Gene', (151, 154))	('people', 'Species', '9606', (3, 9))
151586	28814294	The neoplasm had cytological, histological and ultrastructural characteristics that are similar to the human sarcomas that carry the specific translocations between chromosomes X and 18.	('neoplasm', 'Disease', 'MESH:D009369', (4, 12))	('human', 'Species', '9606', (103, 108))	('neoplasm', 'Phenotype', 'HP:0002664', (4, 12))	('translocations', 'Var', (142, 156))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('neoplasm', 'Disease', (4, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcomas', 'Disease', (109, 117))
151722	30105111	The negativity of calretinin in this case can help us to rule it out.	('negativity', 'Var', (4, 14))	('calretinin', 'Gene', (18, 28))	('calretinin', 'Gene', '794', (18, 28))
151736	30105111	Another study showed that polysomic chromosomes appeared more characteristically in UPS; however, in their study sarcoma-specific chromosomal breaks and oncogene amplifications were rarely identified.	('chromosomal breaks', 'Phenotype', 'HP:0040012', (130, 148))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('polysomic chromosomes', 'Var', (26, 47))	('sarcoma', 'Disease', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('UPS', 'Disease', (84, 87))
151737	30105111	There was also an investigation that indicated loss of 4q31 (encompassing the SMAD1 gene) and loss of 18q22 as independent predictors of metastasis.	('SMAD1', 'Gene', (78, 83))	('4q31', 'Protein', (55, 59))	('loss', 'Var', (94, 98))	('18q22', 'Protein', (102, 107))	('loss', 'Var', (47, 51))	('SMAD1', 'Gene', '4086', (78, 83))	('metastasis', 'CPA', (137, 147))
151826	29225247	It has been reported that high-dose MPA can cause adrenal insufficiency.	('high-dose', 'Var', (26, 35))	('cause', 'Reg', (44, 49))	('MPA', 'Chemical', 'MESH:D017258', (36, 39))	('adrenal insufficiency', 'Disease', (50, 71))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (50, 71))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (50, 71))
151888	28536380	T-Vec is attenuated by deletions of the genes encoding ICP34.5, a neurovirulence factor, and was designed to promote anti-tumor immunity by expressing human Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF).	('deletions', 'Var', (23, 32))	('promote', 'PosReg', (109, 116))	('human', 'Species', '9606', (151, 156))	('attenuated', 'NegReg', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('ICP34.5', 'Gene', (55, 62))	('Granulocyte-Macrophage Colony Stimulating Factor', 'Gene', (157, 205))	('Granulocyte-Macrophage Colony Stimulating Factor', 'Gene', '1437', (157, 205))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('GM-CSF', 'Gene', '1437', (207, 213))	('GM-CSF', 'Gene', (207, 213))	('tumor', 'Disease', (122, 127))
151930	28536380	In a preclinical model, an M-CSF blockade with the small inhibitor molecule BLZ945 decreased immunosuppressive macrophage (CD14/CD206) activation and increased inflammatory macrophage (HLA-DR/CD86) activation as well as DC and T cell infiltration, resulting in inhibition of tumor progression.	('decreased immunosuppressive macrophage', 'Phenotype', 'HP:0012648', (83, 121))	('CD86', 'Gene', '942', (192, 196))	('tumor', 'Disease', (275, 280))	('CD86', 'Gene', (192, 196))	('inflammatory macrophage', 'CPA', (160, 183))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('inhibition', 'NegReg', (261, 271))	('CD14', 'Gene', (123, 127))	('M-CSF', 'Gene', (27, 32))	('CD14', 'Gene', '929', (123, 127))	('immunosuppressive macrophage', 'MPA', (93, 121))	('blockade', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('activation', 'PosReg', (198, 208))	('M-CSF', 'Gene', '1435', (27, 32))	('CD206', 'Gene', '4360', (128, 133))	('CD206', 'Gene', (128, 133))	('decreased', 'NegReg', (83, 92))	('T cell infiltration', 'CPA', (227, 246))	('activation', 'MPA', (135, 145))	('increased', 'PosReg', (150, 159))
151934	28536380	Another oncolytic vaccinia virus, GLV-1h68, was associated with increased NK and macrophage infiltration and increased levels of many pro-inflammatory cytokines and chemokines involved in both antiviral and anti-tumor immune response (GCP-2, KC/GROalpha, IFNgamma, CXCL10, IL-3, IL-6, Lymphotactin, M-CSF1, MIP-1beta, MCP-1, MCP-3, MCP-5, RANTES).	('MCP-1', 'Gene', (318, 323))	('CSF1', 'Gene', '1435', (301, 305))	('M-CSF', 'Gene', (299, 304))	('CSF1', 'Gene', (301, 305))	('vaccinia virus, GLV-1h68', 'Species', '502057', (18, 42))	('MCP-1', 'Gene', '6347', (318, 323))	('IL-6', 'Gene', (279, 283))	('M-CSF', 'Gene', '1435', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('CXCL10', 'Gene', '3627', (265, 271))	('levels', 'MPA', (119, 125))	('IL-6', 'Gene', '3569', (279, 283))	('increased', 'PosReg', (64, 73))	('increased', 'PosReg', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('GLV-1h68', 'Var', (34, 42))	('tumor', 'Disease', (212, 217))	('CXCL10', 'Gene', (265, 271))
151942	28536380	Antibody neutralization of CCN1 improved the glioma response to oncolytic virus therapy most dramatically in glioblastoma models with high macrophage infiltration.	('glioblastoma', 'Disease', (109, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('neutralization', 'Var', (9, 23))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('CCN1', 'Gene', (27, 31))	('improved', 'PosReg', (32, 40))	('CCN1', 'Gene', '3491', (27, 31))	('glioma', 'Disease', (45, 51))
151951	28536380	Similar to neuroblastoma, the CSF1R blockade in pancreatic cancers inhibited macrophage infiltration and activated the remaining macrophages into inflammatory antigen-presenting subtype (decreased CD206, PD1, PDL2), resulting in T cell activation and synergistic tumor progression inhibition with immune checkpoint inhibition.	('neuroblastoma', 'Phenotype', 'HP:0003006', (11, 24))	('CSF1R', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('blockade', 'Var', (36, 44))	('neuroblastoma', 'Disease', 'MESH:D009447', (11, 24))	('macrophage infiltration', 'CPA', (77, 100))	('pancreatic cancers', 'Disease', 'MESH:D010190', (48, 66))	('inhibited', 'NegReg', (67, 76))	('tumor', 'Disease', (263, 268))	('PD1', 'Gene', '100622689', (204, 207))	('PD1', 'Gene', (204, 207))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (48, 65))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('activated', 'PosReg', (105, 114))	('PDL2', 'Gene', (209, 213))	('PDL2', 'Gene', '574057', (209, 213))	('T cell', 'CPA', (229, 235))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('activation', 'PosReg', (236, 246))	('pancreatic cancers', 'Disease', (48, 66))	('CD206', 'Gene', '4360', (197, 202))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('CD206', 'Gene', (197, 202))	('CSF1R', 'Gene', '100517086', (30, 35))	('neuroblastoma', 'Disease', (11, 24))
151968	27110595	To define the in vivo contribution of TMERs to MHV68 biology, we generated a panel of individual TMER mutant viruses.	('TMER', 'Gene', (97, 101))	('rat', 'Species', '10116', (69, 72))	('MHV68', 'Species', '1440122', (47, 52))	('mutant', 'Var', (102, 108))
151970	27110595	The TMER4 mutant virus replicated normally in lungs and spread with normal kinetics and distribution to lung-draining lymph nodes, but it was significantly attenuated for infection of circulating blood cells and for latency establishment at peripheral sites.	('attenuated', 'NegReg', (156, 166))	('TMER4', 'Chemical', '-', (4, 9))	('mutant', 'Var', (10, 16))	('TMER4', 'Gene', (4, 9))
151981	27110595	In addition, we previously reported that viruses with all 8 TMERs mutated have a slight attenuation in latency and are highly attenuated for lethal pneumonia.	('attenuated', 'NegReg', (126, 136))	('mutated', 'Var', (66, 73))	('pneumonia', 'Disease', (148, 157))	('pneumonia', 'Disease', 'MESH:D011014', (148, 157))	('attenuation', 'NegReg', (88, 99))	('latency', 'MPA', (103, 110))	('pneumonia', 'Phenotype', 'HP:0002090', (148, 157))	('lethal', 'CPA', (141, 147))
151986	27110595	To assess the effects of individual TMER mutations on latency, we infected wild-type C57BL6/J (B6) mice and determined the frequency of latently infected splenocytes.	('mutations', 'Var', (41, 50))	('mice', 'Species', '10090', (99, 103))	('TMER', 'Gene', (36, 40))
151988	27110595	with wild-type MHV68 (MHV68.betala marker virus), control MHV68 mutated in all 8 TMERs (MHV68.Zt6), or viruses with mutations in TMER2, TMER4, TMER5, or TMER8.	('TMER5', 'Gene', (143, 148))	('MHV68', 'Species', '1440122', (15, 20))	('MHV68', 'Species', '1440122', (88, 93))	('TMER4', 'Chemical', '-', (136, 141))	('MHV68', 'Species', '1440122', (22, 27))	('TMER8', 'Gene', (153, 158))	('mutated', 'Var', (64, 71))	('MHV68', 'Species', '1440122', (58, 63))	('mutations', 'Var', (116, 125))	('TMER2', 'Gene', (129, 134))	('TMER4', 'Gene', (136, 141))	('MHV68', 'Gene', (58, 63))
151989	27110595	Consistent with our previous findings, wild-type virus established latency in 1 in 250 splenocytes, while combinatorial TMER mutant MHV68.Zt6 displayed a subtle 2.8-fold attenuation (1 in 690).	('attenuation', 'NegReg', (170, 181))	('MHV68', 'Species', '1440122', (132, 137))	('MHV68.Zt6', 'Gene', (132, 141))	('mutant', 'Var', (125, 131))	('latency', 'MPA', (67, 74))
151990	27110595	In concordance with these results, MHV68 with mutations of individual transcripts TMER2, TMER5, or TMER8 demonstrated frequencies that ranged between that of wild-type virus and the combinatorial mutant virus (Fig.	('mutations', 'Var', (46, 55))	('rat', 'Species', '10116', (112, 115))	('TMER8', 'Gene', (99, 104))	('MHV68', 'Species', '1440122', (35, 40))	('TMER2', 'Gene', (82, 87))	('TMER5', 'Gene', (89, 94))
151991	27110595	Unexpectedly though, the TMER4 mutant MHV68.DeltamiR5.6 demonstrated a severe 26-fold attenuation in latency establishment (1 in 6,500), despite carrying a lesion identical to the MHV68.Zt6 TMER4 mutation.	('mutant', 'Var', (31, 37))	('latency establishment', 'CPA', (101, 122))	('TMER4', 'Chemical', '-', (25, 30))	('MHV68', 'Species', '1440122', (38, 43))	('TMER4', 'Chemical', '-', (190, 195))	('MHV68', 'Species', '1440122', (180, 185))	('attenuation', 'NegReg', (86, 97))	('rat', 'Species', '10116', (63, 66))
151993	27110595	To experimentally validate these results, we generated a second virus carrying an identical TMER4 mutation and a revertant virus in which the wild-type TMER4 sequence was recombined back into MHV68.DeltamiR5.6.	('mutation', 'Var', (98, 106))	('TMER4', 'Chemical', '-', (152, 157))	('MHV68', 'Species', '1440122', (192, 197))	('TMER4', 'Gene', (92, 97))	('TMER4', 'Chemical', '-', (92, 97))	('rat', 'Species', '10116', (49, 52))
151994	27110595	Importantly, the independently generated TMER4 mutant displayed a similar defect in latency (1 in 4,000), while the revertant virus established latency nearly equivalent (1 in 300) to wild-type virus (Fig.	('defect', 'NegReg', (74, 80))	('TMER4', 'Gene', (41, 46))	('TMER4', 'Chemical', '-', (41, 46))	('latency', 'MPA', (84, 91))	('rat', 'Species', '10116', (35, 38))	('mutant', 'Var', (47, 53))
151998	27110595	To determine whether TMER4 mutation disproportionately infected any specific B cell subsets, we employed flow cytometric analysis using a combination of staining for B cell markers and a fluorescent beta-lactamase substrate.	('TMER4', 'Chemical', '-', (21, 26))	('infected', 'Reg', (55, 63))	('mutation', 'Var', (27, 35))	('rat', 'Species', '10116', (219, 222))	('TMER4', 'Gene', (21, 26))
151999	27110595	beta-Lactamase is expressed by the parental virus and by all mutant viruses as a C-terminal fusion to episomal maintenance protein mLANA, facilitating facile identification of latently infected cells.	('mLANA', 'Gene', (131, 136))	('beta-Lactamase', 'Protein', (0, 14))	('mLANA', 'Gene', '77836', (131, 136))	('mutant', 'Var', (61, 67))
152007	27110595	To determine whether the critical TMER4 function was conveyed by the TMER4-encoded miRNAs mghv-M1-miR-5-5p or -6-3p, we constructed a panel of additional TMER4 single stem-loop and miRNA seed sequence mutants (Fig.	('TMER4', 'Chemical', '-', (154, 159))	('TMER4', 'Chemical', '-', (34, 39))	('TMER4', 'Chemical', '-', (69, 74))	('mutants', 'Var', (201, 208))	('TMER4', 'Gene', (154, 159))
152010	27110595	Further mutation of miRNA seed sequences within either remaining stem-loop did not compromise TMER4 function, unequivocally demonstrating that TMER4 miRNAs are dispensable for latency.	('rat', 'Species', '10116', (131, 134))	('TMER4', 'Chemical', '-', (143, 148))	('TMER4 function', 'MPA', (94, 108))	('TMER4', 'Chemical', '-', (94, 99))	('mutation', 'Var', (8, 16))
152014	27110595	Interestingly, while the TMER4 mutant MHV68.DeltamiR5.6 exhibited a 26-fold latency defect following i.n.	('mutant', 'Var', (31, 37))	('TMER4', 'Chemical', '-', (25, 30))	('MHV68', 'Species', '1440122', (38, 43))	('defect', 'NegReg', (84, 90))	('latency', 'MPA', (76, 83))
152018	27110595	inoculation of B6 mice, the TMER4 mutant displayed no defect in acute replication in the lungs (Fig.	('TMER4', 'Gene', (28, 33))	('TMER4', 'Chemical', '-', (28, 33))	('mice', 'Species', '10090', (18, 22))	('acute replication in the lungs', 'CPA', (64, 94))	('mutant', 'Var', (34, 40))
152025	27110595	In contrast to peripheral sites, the TMER4 mutant virus established latency in the MLN at a frequency (1 in 500) nearly equivalent to that of the wild-type virus (1 in 300) (Fig.	('TMER4 mutant', 'Var', (37, 49))	('latency', 'MPA', (68, 75))	('TMER4', 'Chemical', '-', (37, 42))
152026	27110595	Consistent with this, the number of virus-infected CD19+, CD19-CD11b+CD11c-, and CD19-CD11b-CD11c+ cells did not differ significantly between MHV68.DeltamiR5.6 and wild-type MHV68 (Fig.	('CD11b', 'Gene', (63, 68))	('CD11c', 'Gene', (92, 97))	('CD11b', 'Gene', '3684', (63, 68))	('CD19', 'Gene', '930', (51, 55))	('CD11b', 'Gene', (86, 91))	('CD11b', 'Gene', '3684', (86, 91))	('MHV68.DeltamiR5.6', 'Var', (142, 159))	('MHV68', 'Species', '1440122', (174, 179))	('CD11c', 'Gene', '3687', (69, 74))	('CD19', 'Gene', (81, 85))	('CD19', 'Gene', (51, 55))	('CD11c', 'Gene', (69, 74))	('CD19', 'Gene', (58, 62))	('CD19', 'Gene', '930', (81, 85))	('MHV68', 'Species', '1440122', (142, 147))	('CD19', 'Gene', '930', (58, 62))	('CD11c', 'Gene', '3687', (92, 97))
152030	27110595	In stark contrast to the equivalent replication and latency observed in the local MLN, TMER4 mutant virus genome was detected in only 1 in 40,000 circulating leukocytes, compared to 1 in 2,600 for wild-type virus (Fig.	('mutant', 'Var', (93, 99))	('TMER4', 'Gene', (87, 92))	('TMER4', 'Chemical', '-', (87, 92))
152034	27110595	Through the use of viral mutagenesis and comprehensive in vivo testing, we have now identified one of these ncRNAs, TMER4, as an essential determinant of hematogenous dissemination and peripheral latency establishment of wild-type MHV68.	('mutagenesis', 'Var', (25, 36))	('TMER4', 'Gene', (116, 121))	('TMER4', 'Chemical', '-', (116, 121))	('MHV68', 'Species', '1440122', (231, 236))
152042	27110595	A surprising finding was revealed by direct comparison of the TMER4 mutant MHV68.DeltamiR5.6 to the combinatorial mutant MHV68.Zt6, which carries an identical TMER4 mutation in addition to mutations in the seven remaining TMERs.	('MHV68', 'Species', '1440122', (75, 80))	('TMER4', 'Gene', (159, 164))	('TMER4', 'Chemical', '-', (159, 164))	('mutation', 'Var', (165, 173))	('TMER4', 'Chemical', '-', (62, 67))	('MHV68', 'Species', '1440122', (121, 126))	('mutant', 'Var', (68, 74))
152043	27110595	While the TMER4 mutant exhibited highly attenuated latency establishment in vivo, the combinatorial TMER mutant displayed only a subtle latency defect.	('TMER4', 'Chemical', '-', (10, 15))	('mutant', 'Var', (105, 111))	('mutant', 'Var', (16, 22))	('attenuated', 'NegReg', (40, 50))	('latency establishment', 'CPA', (51, 72))	('TMER4', 'Gene', (10, 15))
152045	27110595	For instance, it is possible that TMER4 turns off virus-repressive pathways that are activated by other TMERs or TMER-encoded miRNAs.	('TMER4', 'Chemical', '-', (34, 39))	('virus-repressive pathways', 'Pathway', (50, 75))	('TMER4', 'Var', (34, 39))
152047	27110595	As a direct effector, TMER4 may (i) provide a vital prosurvival signal or block apoptosis of MHV68-infected cells, (ii) suppress a key antiviral immune response that blocks systemic infection, or (iii) initiate an immune response necessary for egress of MHV68-infected cells into the peripheral circulation.	('TMER4', 'Var', (22, 27))	('key antiviral immune response', 'MPA', (131, 160))	('block', 'NegReg', (74, 79))	('MHV68', 'Species', '1440122', (254, 259))	('blocks systemic infection', 'Disease', (166, 191))	('MHV68', 'Species', '1440122', (93, 98))	('blocks systemic infection', 'Disease', 'MESH:D006327', (166, 191))	('TMER4', 'Chemical', '-', (22, 27))	('suppress', 'NegReg', (120, 128))	('apoptosis', 'CPA', (80, 89))	('initiate', 'Reg', (202, 210))
152054	27110595	For example, TMER4 may compete for binding of other TMERs to a sensor molecule that activates downstream pathways which prevent virus dissemination.	('TMER4', 'Chemical', '-', (13, 18))	('binding', 'Interaction', (35, 42))	('activates', 'PosReg', (84, 93))	('TMER4', 'Var', (13, 18))	('downstream pathways', 'Pathway', (94, 113))
152055	27110595	Although it is also conceivable that TMER4 directly suppresses expression of other TMERs, we have not noted any reduction in expression or processing of other TMERs in the absence of TMER4.	('TMER4', 'Var', (37, 42))	('expression', 'MPA', (63, 73))	('TMER4', 'Chemical', '-', (37, 42))	('TMER4', 'Chemical', '-', (183, 188))	('suppresses', 'NegReg', (52, 62))
152056	27110595	Owing to the complexity of pneumonia pathogenesis, the specific contribution of TMER4 to induction of this disease is unclear; however, it is likely that the role of TMER4 in pneumonia pathogenesis is distinct from its function in dissemination.	('pneumonia', 'Disease', (27, 36))	('pneumonia', 'Disease', 'MESH:D011014', (27, 36))	('pneumonia', 'Phenotype', 'HP:0002090', (175, 184))	('TMER4', 'Chemical', '-', (166, 171))	('TMER4', 'Chemical', '-', (80, 85))	('pneumonia', 'Phenotype', 'HP:0002090', (27, 36))	('pneumonia', 'Disease', (175, 184))	('pneumonia', 'Disease', 'MESH:D011014', (175, 184))	('TMER4', 'Var', (166, 171))
152057	27110595	We previously demonstrated that mutants deficient in a combination of TMERs are highly attenuated for pneumonia lethality, arguing that TMER4 does not counteract the effect of other TMERs in this model.	('pneumonia lethality', 'Disease', (102, 121))	('pneumonia lethality', 'Disease', 'MESH:D011014', (102, 121))	('pneumonia', 'Phenotype', 'HP:0002090', (102, 111))	('attenuated', 'NegReg', (87, 97))	('mutants', 'Var', (32, 39))	('rat', 'Species', '10116', (21, 24))	('TMER4', 'Chemical', '-', (136, 141))
152058	27110595	Confounding such an interpretation, viruses which express TMER1 or vtRNA1 but do not express other TMERs display partial restoration of disease, strongly suggesting that vtRNA1 is a key contributor to pathogenesis.	('vtRNA1', 'Gene', (67, 73))	('disease', 'MPA', (136, 143))	('rat', 'Species', '10116', (126, 129))	('TMER1', 'Var', (58, 63))
152063	27110595	Surprisingly though, restoration of either stem-loop resulted in normal latency establishment, and further mutation of miRNA seed sequences revealed no obvious constraint to the stem-loop nucleotide sequence.	('latency establishment', 'CPA', (72, 93))	('mutation', 'Var', (107, 115))	('rat', 'Species', '10116', (26, 29))
152158	29595344	HHV-8 genotypes C and A variants were detected at frequencies of 80% and 20%, respectively, among IDUs; and genotypes C, D, E, and A were detected at frequencies of 55.6%, 11.1%, 11.1%, and 5.6%, respectively, among MSM.	('HHV-8', 'Gene', (0, 5))	('HHV-8', 'Species', '37296', (0, 5))	('variants', 'Var', (24, 32))
152160	29595344	Evolution of the K1 gene occurred in HHV-8 variants of IDUs and MSM.	('MSM', 'Disease', (64, 67))	('HHV-8', 'Gene', (37, 42))	('HHV-8', 'Species', '37296', (37, 42))	('IDUs', 'Disease', (55, 59))	('variants', 'Var', (43, 51))
152165	29595344	Genotype D infects aboriginal people of the Pacific Rim.	('Genotype', 'Var', (0, 8))	('infects', 'Reg', (11, 18))	('people', 'Species', '9606', (30, 36))
152166	29595344	Genotypes A, B, C, and F are detected in patients infected with human immunodeficiency virus-1 (HIV-1), and genotype B correlates with the prognosis of Kaposi's sarcoma.	('human', 'Species', '9606', (64, 69))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (152, 168))	('immunodeficiency', 'Phenotype', 'HP:0002721', (70, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (152, 168))	("Kaposi's sarcoma", 'Disease', (152, 168))	('correlates with', 'Reg', (119, 134))	('immunodeficiency virus-1 (HIV-1)', 'Disease', 'MESH:D015658', (70, 102))	('patients', 'Species', '9606', (41, 49))	('infected', 'Disease', 'MESH:D007239', (50, 58))	('genotype', 'Var', (108, 116))	('infected', 'Disease', (50, 58))
152170	29595344	Further, the high HHV-8 seroprevalence in Greek IDUs is significantly associated with poor personal hygiene related to drug injection.	('seroprevalence', 'Var', (24, 38))	('HHV-8', 'Gene', (18, 23))	('HHV-8', 'Species', '37296', (18, 23))	('associated', 'Reg', (70, 80))
152190	29595344	Alignments of K1 gene sequences of HHV-8 variants were examined using the DNASTAR MegaAlign clustal method (DNASTAR, Madison, WI, USA).	('variants', 'Var', (41, 49))	('HHV-8', 'Gene', (35, 40))	('HHV-8', 'Species', '37296', (35, 40))	('men', 'Species', '9606', (5, 8))
152206	29595344	However, the HHV-8 viral loads were not significantly different between HHV-8 seropositive and seronegative patients (Table 3).	('HHV-8', 'Species', '37296', (72, 77))	('seropositive', 'Var', (78, 90))	('HHV-8', 'Gene', (13, 18))	('patients', 'Species', '9606', (108, 116))	('HHV-8', 'Species', '37296', (13, 18))	('HHV-8', 'Gene', (72, 77))
152208	29595344	Of the 5 IDU sequences, 1 was genotype A (TYKS 1), and the other 4 (TYKS 5, 17-19) were genotype C. Further, 10 (55.6%) sequences of the 18 HHV-8 variants of MSM were genotype C (TYKS 3, 4, 6-16), 2 (11.1%) were genotype D (TYKS 20, 21), 2 (11.1%) were genotype E (TYKS 22, 23), and 1 (5.6%) was genotype A (TYKS 2).	('HHV-8', 'Species', '37296', (140, 145))	('variants', 'Var', (146, 154))	('HHV-8', 'Gene', (140, 145))	('MSM', 'Gene', (158, 161))
152209	29595344	The deduced amino acid sequences of the K1 gene were based on the HHV-8 variants (18 MSM and 5 IDUs) (Figure 2).	('HHV-8', 'Species', '37296', (66, 71))	('HHV-8', 'Gene', (66, 71))	('variants', 'Var', (72, 80))
152211	29595344	TYKS 2 patients from MSM had nine notable amino acid residue changes in strains of BCBL-R (T37N, F58L, P60L, E62K, T63K, F66L, P67G, and T69N) in 85% of the clade's genes (Figure 2).	('F58L', 'Var', (97, 101))	('F66L', 'Mutation', 'p.F66L', (121, 125))	('F66L', 'Var', (121, 125))	('T63K', 'Mutation', 'p.T63K', (115, 119))	('P60L', 'Mutation', 'p.P60L', (103, 107))	('BCBL-R', 'Gene', (83, 89))	('E62K', 'Var', (109, 113))	('T37N', 'Mutation', 'p.T37N', (91, 95))	('T63K', 'Var', (115, 119))	('E62K', 'Mutation', 'p.E62K', (109, 113))	('T37N', 'Var', (91, 95))	('P67G', 'Mutation', 'p.P67G', (127, 131))	('F58L', 'Mutation', 'p.F58L', (97, 101))	('T69N', 'Var', (137, 141))	('P60L', 'Var', (103, 107))	('patients', 'Species', '9606', (7, 15))	('P67G', 'Var', (127, 131))	('T69N', 'Mutation', 'p.T69N', (137, 141))
152215	29595344	However, the HHV-8 viral load was not significantly different between HHV-8 seropositive and seronegative patients.	('seropositive', 'Var', (76, 88))	('HHV-8', 'Species', '37296', (70, 75))	('HHV-8', 'Gene', (13, 18))	('patients', 'Species', '9606', (106, 114))	('HHV-8', 'Gene', (70, 75))	('HHV-8', 'Species', '37296', (13, 18))
152220	29595344	Similarly, HIV-positive IDUs have a higher incidence of Kaposi's sarcoma compared with that of the general population.	('HIV-positive', 'Var', (11, 23))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (56, 72))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (56, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	("Kaposi's sarcoma", 'Disease', (56, 72))
152225	29595344	Phylogenetic analysis of the K1 sequence indicates that the frequencies of HHV-8 genotype-C variants were 80% in IDUs and 55.6% in MSM (Figure 1).	('HHV-8', 'Gene', (75, 80))	('HHV-8', 'Species', '37296', (75, 80))	('MSM', 'Disease', (131, 134))	('variants', 'Var', (92, 100))	('IDUs', 'Disease', (113, 117))
152407	29923984	We found that the high PD-L1 expression was associated with poorer overall survival (HR 1.27, 95% CI: 0.70-1.84 P = .000) and poorer events-free survival (HR 2.05, 95% CI: 1.55-2.70, P = .000) in bone and soft-tissue sarcoma patients.	('poorer', 'NegReg', (60, 66))	('PD-L1', 'Gene', (23, 28))	('events-free', 'MPA', (133, 144))	('patients', 'Species', '9606', (225, 233))	('sarcoma', 'Disease', 'MESH:D012509', (217, 224))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (205, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('high', 'Var', (18, 22))	('overall', 'MPA', (67, 74))	('expression', 'MPA', (29, 39))	('sarcoma', 'Disease', (217, 224))	('poorer', 'NegReg', (126, 132))
152427	29923984	The subgroup analysis stratified by the histological subtype indicates that the PD-L1 was a negative prognostic factor for soft tissue sarcoma and osteosarcoma, the pooled HR estimate for overall survival in soft tissue sarcoma group was 1.41 (95% CI: 0.92-1.90, P = .000) with no significant heterogeneity (I2 = 42.8%, P = .120), and the pooled HR estimate for overall survival in osteosarcoma group was 1.93 (95% CI: 1.18-2.68, P = .000) with no heterogeneity (I2 = 0.0%, P = .486).	('osteosarcoma', 'Disease', (147, 159))	('soft tissue sarcoma', 'Disease', (123, 142))	('negative', 'NegReg', (92, 100))	('PD-L1', 'Var', (80, 85))	('osteosarcoma', 'Phenotype', 'HP:0002669', (147, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (208, 227))	('osteosarcoma', 'Disease', 'MESH:D012516', (147, 159))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (123, 142))	('osteosarcoma', 'Disease', (382, 394))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('soft tissue sarcoma', 'Disease', (208, 227))	('osteosarcoma', 'Phenotype', 'HP:0002669', (382, 394))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (123, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (382, 394))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (208, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (387, 394))
152434	29923984	Overall, the meta-analysis showed a significant difference between positive and negative PD-L1 expression, revealed PD-L1 was a poor prognostic factor for events-free survival in sarcoma patients.	('patients', 'Species', '9606', (187, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('PD-L1', 'Gene', (89, 94))	('sarcoma', 'Disease', 'MESH:D012509', (179, 186))	('negative', 'NegReg', (80, 88))	('sarcoma', 'Disease', (179, 186))	('positive', 'Var', (67, 75))
152442	29923984	Recently, the association between PD-L1 expressions and various solid tumors has been studied by numerous researches and the results have shown that expression of PD-L1 significantly correlates with poor prognosis.	('solid tumors', 'Disease', (64, 76))	('PD-L1', 'Gene', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('poor prognosis', 'CPA', (199, 213))	('expression', 'Var', (149, 159))
152448	29923984	Interestingly, for tumor histological subtype, the analysis results have shown a significant association between PD-L1 expression and the poor overall survival of patient with osteosarcoma, soft tissue sarcoma, with no significant heterogeneity (I2 = 0.0%, P = .486; I2 = 42.8%, P = .120), respectively.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (190, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (190, 209))	('PD-L1', 'Gene', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('osteosarcoma', 'Disease', (176, 188))	('expression', 'Var', (119, 129))	('osteosarcoma', 'Phenotype', 'HP:0002669', (176, 188))	('soft tissue sarcoma', 'Disease', (190, 209))	('patient', 'Species', '9606', (163, 170))	('tumor', 'Disease', (19, 24))	('osteosarcoma', 'Disease', 'MESH:D012516', (176, 188))	('poor', 'NegReg', (138, 142))
152455	29923984	In conclusion, this meta-analysis demonstrates that PD-L1 expression is significantly correlated with poor OS and EFS for patients with sarcoma, and PD-L1 expression may be a useful predicative factor of prognosis for bone and soft tissue sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('poor OS', 'Disease', (102, 109))	('soft tissue sarcoma', 'Disease', (227, 246))	('correlated', 'Reg', (86, 96))	('sarcoma', 'Disease', 'MESH:D012509', (239, 246))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('EFS', 'Disease', (114, 117))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (227, 246))	('expression', 'Var', (58, 68))	('patients', 'Species', '9606', (122, 130))	('sarcoma', 'Disease', (136, 143))	('sarcoma', 'Disease', (239, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (227, 246))	('PD-L1', 'Gene', (52, 57))
152486	28346326	The CIC-DUX4 fusion results from either a t(4;19)(q35;q13) or a t(10;19)(q26;q13) translocation.	('t(4;19)(q35;q13', 'Var', (42, 57))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (64, 81))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (42, 58))	('results from', 'Reg', (20, 32))	('CIC', 'Gene', '23152', (4, 7))	('DUX4', 'Gene', (8, 12))	('DUX4', 'Gene', '100288687', (8, 12))	('CIC', 'Gene', (4, 7))
152504	28346326	Cases that were negative for DUX4 gene abnormalities were also investigated for the FOXO4 gene rearrangements, as previously described Supplementary Table 1).	('rearrangements', 'Var', (95, 109))	('FOXO4', 'Gene', (84, 89))	('FOXO4', 'Gene', '4303', (84, 89))	('DUX4', 'Gene', (29, 33))	('DUX4', 'Gene', '100288687', (29, 33))
152532	28346326	Cases with other CIC gene abnormalities, such as small, constant gaps suspicious for inversion, were not considered as a positive result and were not included in the study cohort.	('CIC gene abnormalities', 'Disease', 'MESH:D025063', (17, 39))	('CIC gene abnormalities', 'Disease', (17, 39))	('constant gaps', 'Var', (56, 69))
152535	28346326	The results showed that 40 (35%) cases were positive for fusion to DUX4 gene on 4q35 (Fig.	('fusion', 'Var', (57, 63))	('DUX4', 'Gene', (67, 71))	('DUX4', 'Gene', '100288687', (67, 71))	('positive', 'Reg', (44, 52))
152584	28346326	CIC is the human homologue of Drosophila capicua, a gene identified in a screen for mutations affecting the anterior-posterior pattern of Drosophila embryos.	('capicua', 'Gene', (41, 48))	('human', 'Species', '9606', (11, 16))	('Drosophila', 'Species', '7227', (30, 40))	('mutations', 'Var', (84, 93))	('CIC', 'Gene', '23152', (0, 3))	('capicua', 'Gene', '53560', (41, 48))	('Drosophila', 'Species', '7227', (138, 148))	('CIC', 'Gene', (0, 3))
152585	28346326	CIC gene abnormalities have been implicated in various neoplastic conditions, such as CIC loss of function mutations being identified in 83% of oligodendrogliomas.	('CIC gene abnormalities', 'Disease', 'MESH:D025063', (0, 22))	('implicated', 'Reg', (33, 43))	('CIC gene abnormalities', 'Disease', (0, 22))	('mutations', 'Var', (107, 116))	('CIC loss', 'Disease', (86, 94))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (144, 162))	('oligodendrogliomas', 'Disease', (144, 162))	('CIC loss', 'Disease', 'MESH:D015431', (86, 94))
152588	28346326	Their results further revealed that fusion of DUX4 to CIC sequence provides strong transcriptional activity, resulting in mostly upregulated gene expression, with minimal down-regulated genes.	('CIC', 'Gene', '23152', (54, 57))	('upregulated', 'PosReg', (129, 140))	('transcriptional activity', 'MPA', (83, 107))	('CIC', 'Gene', (54, 57))	('DUX4', 'Gene', (46, 50))	('gene expression', 'MPA', (141, 156))	('DUX4', 'Gene', '100288687', (46, 50))	('fusion', 'Var', (36, 42))
152590	28346326	In contrast, DUX4 gene is normally expressed in germ cells and is epigenetically silenced in somatic differentiated tissues through CpG methylation.	('DUX4', 'Gene', (13, 17))	('DUX4', 'Gene', '100288687', (13, 17))	('CpG methylation', 'Var', (132, 147))	('methylation', 'Var', (136, 147))
152591	28346326	Aberrant expression of DUX4 has been implicated in the development of facioscapulohumeral muscular dystrophy.	('DUX4', 'Gene', '100288687', (23, 27))	('Aberrant expression', 'Var', (0, 19))	('implicated', 'Reg', (37, 47))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (90, 108))	('muscular dystrophy', 'Disease', 'MESH:D009136', (90, 108))	('muscular dystrophy', 'Disease', (90, 108))	('DUX4', 'Gene', (23, 27))	('facioscapulohumeral muscular dystrophy', 'Phenotype', 'HP:0008970', (70, 108))
152592	28346326	The exact role in tumorigenesis of DUX4 dysregulation in the setting of CIC-DUX4 fusion remains poorly defined.	('tumor', 'Disease', (18, 23))	('CIC', 'Gene', (72, 75))	('dysregulation', 'Var', (40, 53))	('DUX4', 'Gene', (76, 80))	('DUX4', 'Gene', '100288687', (76, 80))	('DUX4', 'Gene', (35, 39))	('DUX4', 'Gene', '100288687', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('CIC', 'Gene', '23152', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
152598	28346326	No FOXO4 gene abnormalities were detected in any of the 39 cases tested lacking DUX4 abnormalities in the present series, including head and neck lesions, suggesting that CIC-FOXO4 fusion is a rare genetic event in the pathogenesis of SBRCTs.	('FOXO4', 'Gene', '4303', (3, 8))	('fusion', 'Var', (181, 187))	('CIC', 'Gene', '23152', (171, 174))	('DUX4', 'Gene', (80, 84))	('FOXO4', 'Gene', (3, 8))	('FOXO4', 'Gene', (175, 180))	('CIC', 'Gene', (171, 174))	('DUX4', 'Gene', '100288687', (80, 84))	('FOXO4', 'Gene', '4303', (175, 180))	('SBRCTs', 'Disease', (235, 241))
152599	28346326	Also of interest, a small subset of high grade angiosarcomas occurring in the soft tissue of young adults have been recently shown to harbor CIC-related fusions, including one case fused to the LEUTX gene, which, similar to DUX4, belongs to the paired (PRD) homeobox genes.	('fusions', 'Var', (153, 160))	('angiosarcoma', 'Phenotype', 'HP:0200058', (47, 59))	('angiosarcomas', 'Disease', (47, 60))	('DUX4', 'Gene', (224, 228))	('CIC', 'Gene', (141, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('angiosarcomas', 'Disease', 'MESH:D006394', (47, 60))	('DUX4', 'Gene', '100288687', (224, 228))	('LEUTX', 'Gene', (194, 199))	('LEUTX', 'Gene', '342900', (194, 199))	('angiosarcomas', 'Phenotype', 'HP:0200058', (47, 60))	('CIC', 'Gene', '23152', (141, 144))
152607	28346326	Immunohistochemically, the variable CD99 reactivity and strong WT1 are helpful ancillary techniques, diagnosis can be further confirmed by FISH for CIC gene rearrangements.	('rearrangements', 'Var', (157, 171))	('WT1', 'Gene', '7490', (63, 66))	('CIC', 'Gene', (148, 151))	('CD99', 'Gene', '4267', (36, 40))	('WT1', 'Gene', (63, 66))	('CD99', 'Gene', (36, 40))	('CIC', 'Gene', '23152', (148, 151))
152621	28144858	Immunohistochemical analyses showed the tumor stained with vimentin, alpha-smooth muscle actin, desmin, alpha1-antitrypsin, and alpha1-antichymotripsin.	('alpha1-antitrypsin', 'Gene', '5265', (104, 122))	('vimentin', 'Gene', (59, 67))	('desmin', 'Gene', (96, 102))	('alpha1-antitrypsin', 'Gene', (104, 122))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('alpha1-antichymotripsin', 'Var', (128, 151))	('alpha-smooth muscle actin', 'Protein', (69, 94))	('stained', 'Reg', (46, 53))	('desmin', 'Gene', '1674', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('vimentin', 'Gene', '7431', (59, 67))
152749	21791103	It is assumed here an alpha/beta = 3 Gy for all tissues, since analysis of breast cancer data has shown that the dose-response model is robust with variations in alpha/beta .	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('variations', 'Var', (148, 158))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
152847	29962886	In TI 600, regions with contrast uptake appear as high signal intensity (SI), whereas thrombi appear as homogeneously dark SI, and there is improved thrombus delineation.	('thrombi', 'Disease', 'MESH:D013927', (86, 93))	('improved', 'PosReg', (140, 148))	('SI', 'Disease', 'None', (123, 125))	('high signal intensity', 'MPA', (50, 71))	('thrombus delineation', 'Disease', (149, 169))	('thrombus delineation', 'Disease', 'MESH:D013927', (149, 169))	('SI', 'Disease', 'None', (73, 75))	('TI 600', 'Var', (3, 9))	('thrombi', 'Disease', (86, 93))
152898	29962886	Previously, a few studies have reported CT imaging findings in PAIS such as WES, lesions occupying the entire lumen at the level of the proximal PAs, expansion of PAs, and extraluminal extensions.	('PAs', 'Chemical', 'MESH:D011478', (145, 148))	('lesions', 'Var', (81, 88))	('PAs', 'Chemical', 'MESH:D011478', (163, 166))	('WES', 'Disease', (76, 79))	('expansion of', 'Disease', (150, 162))	('PAIS', 'Disease', (63, 67))
152932	27248664	BO-1055 induced more DNA double strand breaks and gammaH2AX expression in cancer cells compared to benign cells.	('expression', 'MPA', (60, 70))	('gammaH2AX', 'Chemical', '-', (50, 59))	('BO-1055', 'Chemical', 'MESH:C582286', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('DNA', 'MPA', (21, 24))	('cancer', 'Disease', (74, 80))	('BO-1055', 'Var', (0, 7))	('gammaH2AX', 'Protein', (50, 59))
152946	27248664	Like melphalan, BO-1055 induces N-alkyl adducts that are repairable by NER and HR pathways.	('melphalan', 'Chemical', 'MESH:D008558', (5, 14))	('N-alkyl adducts', 'MPA', (32, 47))	('induces', 'Reg', (24, 31))	('BO-1055', 'Chemical', 'MESH:C582286', (16, 23))	('BO-1055', 'Var', (16, 23))
152947	27248664	In addition, BO-1055 produces O-alkyl adducts (like BCNU/carmustine), which are repairable by MGMT.	('O-alkyl adducts', 'MPA', (30, 45))	('BO-1055', 'Chemical', 'MESH:C582286', (13, 20))	('MGMT', 'Gene', '4255', (94, 98))	('MGMT', 'Gene', (94, 98))	('BO-1055', 'Var', (13, 20))	('BCNU', 'Chemical', 'MESH:D002330', (52, 56))	('carmustine', 'Chemical', 'MESH:D002330', (57, 67))
152958	27248664	As shown in Figure 1D, BO-1055 was able to inhibit A673 spheroids at a 10 fold lower concentration when compared to 4-HC.	('BO-1055', 'Var', (23, 30))	('4-HC', 'Chemical', 'MESH:C011272', (116, 120))	('inhibit', 'NegReg', (43, 50))	('A673 spheroids', 'CPA', (51, 65))	('BO-1055', 'Chemical', 'MESH:C582286', (23, 30))
152959	27248664	Complete inhibition of spheroids was noted at 0.5muM of BO-1055 and 5muM of 4-HC.	('inhibition', 'NegReg', (9, 19))	('muM', 'Gene', '56925', (49, 52))	('muM', 'Gene', '56925', (69, 72))	('BO-1055', 'Chemical', 'MESH:C582286', (56, 63))	('muM', 'Gene', (49, 52))	('muM', 'Gene', (69, 72))	('spheroids', 'CPA', (23, 32))	('BO-1055', 'Var', (56, 63))	('4-HC', 'Chemical', 'MESH:C011272', (76, 80))
152960	27248664	We also examined the effect of BO-1055 in inhibiting the cell growth of different types of benign cells including human mesenchymal stromal cells, fetal lung fibroblasts and myofibroblasts, hematopoietic progenitor cells, bone marrow derived endothelial cells and human umbilical vein endothelial cells and murine mesenchymal stromal cells, MS-5 (murine).	('murine', 'Species', '10090', (307, 313))	('human', 'Species', '9606', (264, 269))	('BO-1055', 'Chemical', 'MESH:C582286', (31, 38))	('inhibiting', 'NegReg', (42, 52))	('cell growth', 'CPA', (57, 68))	('BO-1055', 'Var', (31, 38))	('human', 'Species', '9606', (114, 119))	('murine', 'Species', '10090', (347, 353))
152979	27248664	Human MSC and cord blood CD34+ cells treated with BO-1055 have relatively less olive moment compared to XRT (Figure 4B) suggesting less toxicity of BO-1055 to the benign cells.	('Human', 'Species', '9606', (0, 5))	('olive moment', 'MPA', (79, 91))	('BO-1055', 'Var', (50, 57))	('olive', 'Species', '4146', (79, 84))	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('less', 'NegReg', (74, 78))	('toxicity', 'Disease', (136, 144))	('CD34', 'Gene', '947', (25, 29))	('BO-1055', 'Chemical', 'MESH:C582286', (148, 155))	('CD34', 'Gene', (25, 29))	('BO-1055', 'Chemical', 'MESH:C582286', (50, 57))
152983	27248664	At 6h and 24h after treatment with BO-1055, we noted activation of pATM in both sensitive cell lines: A673 (Ewing sarcoma), H526 (small cell lung cancer) and resistant cell line: U20S.	('small cell lung cancer', 'Disease', (130, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('activation', 'PosReg', (53, 63))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('BO-1055', 'Chemical', 'MESH:C582286', (35, 42))	('pATM', 'Gene', (67, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('U20S', 'CellLine', 'CVCL:0042', (179, 183))	('small cell lung cancer', 'Disease', 'MESH:D055752', (130, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('BO-1055', 'Var', (35, 42))	('Ewing sarcoma', 'Disease', (108, 121))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))
152985	27248664	BO-1055 caused inhibition of tumor growth in A673 xenografts (n = 20) and prolonged survival when mice were treated with BO-1055 at 10mg/kg, 20mg/kg and 30mg/kg/dose q2d x 5; also mice showed no significant decrease in body weight (Figure 5A, 5B).	('inhibition', 'NegReg', (15, 25))	('decrease in body weight', 'Phenotype', 'HP:0004325', (207, 230))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('BO-1055', 'Chemical', 'MESH:C582286', (0, 7))	('body weight', 'CPA', (219, 230))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BO-1055', 'Chemical', 'MESH:C582286', (121, 128))	('BO-1055', 'Gene', (0, 7))	('tumor', 'Disease', (29, 34))	('mice', 'Species', '10090', (180, 184))	('BO-1055', 'Var', (121, 128))	('prolonged', 'PosReg', (74, 83))	('survival', 'CPA', (84, 92))	('mice', 'Species', '10090', (98, 102))
153004	27248664	In fact, polymorphisms in DNA repair and glutathione-S-transferase genes were shown to influence treatment outcome in osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('osteosarcoma', 'Disease', 'MESH:D012516', (118, 130))	('osteosarcoma', 'Phenotype', 'HP:0002669', (118, 130))	('osteosarcoma', 'Disease', (118, 130))	('influence', 'Reg', (87, 96))	('polymorphisms', 'Var', (9, 22))	('glutathione-S-transferase', 'Gene', (41, 66))	('DNA repair', 'Gene', (26, 36))
153018	27248664	In A204 (rhabdoid) tumor bearing mice, BO-1055 caused complete regression of tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('BO-1055', 'Var', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mice', 'Species', '10090', (33, 37))	('BO-1055', 'Chemical', 'MESH:C582286', (39, 46))	('rhabdoid) tumor', 'Disease', 'MESH:D018335', (9, 24))
153020	27248664	BO-1055 was shown to retain cytotoxicity against CCRF-CEM/Taxol cells, which are 330-fold resistant to taxol.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('CEM', 'Chemical', 'MESH:C064671', (54, 57))	('taxol', 'Chemical', 'MESH:D017239', (103, 108))	('BO-1055', 'Chemical', 'MESH:C582286', (0, 7))	('Taxol', 'Chemical', 'MESH:D017239', (58, 63))	('BO-1055', 'Var', (0, 7))	('cytotoxicity', 'Disease', (28, 40))
153023	27248664	We therefore tested four combinations including topotecan, SN38, doxorubicin and PU-H71.	('SN38', 'Var', (59, 63))	('topotecan', 'Chemical', 'MESH:D019772', (48, 57))	('tested', 'Reg', (13, 19))	('SN38', 'Chemical', 'MESH:D000077146', (59, 63))	('PU-H71', 'Chemical', 'MESH:C526550', (81, 87))	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))
153076	27248664	Tumors were induced using 106 A673 cells or A204 cells in 0.2ml 1:1 cellular medium, Matrigel matrix (BD Bioscience, Bedford, MA) and injected subcutaneously (s.q) into the right flank.	('A204 cells', 'Var', (44, 54))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
153174	27688605	More recently, the development of SST-analogs radiolabeled with 68Ga for PET imaging such as [68Ga-DOTA 0-Tyr 3] octreotide (68Ga-DOTATOC, 68Ga-edotreotide), [68Ga-DOTA 0-1NaI 3] octreotide (68Ga-DOTANOC), and [68Ga-DOTA 0-Tyr 3] octreotate (68Ga-DOTATATE) has brought clear advantages as compared to radiolabeled SST-analogs scintigraphy offering a higher spatial resolution and improving pharmacokinetics.	('68Ga', 'Chemical', 'MESH:C000615430', (211, 215))	('68Ga', 'Chemical', 'MESH:C000615430', (64, 68))	('[68Ga-DOTA', 'Var', (158, 168))	('68Ga', 'Chemical', 'MESH:C000615430', (94, 98))	('octreotide', 'Chemical', 'MESH:D015282', (113, 123))	('[68Ga-DOTA 0-Tyr 3] octreotate', 'Var', (210, 240))	('octreotide', 'Chemical', 'MESH:D015282', (179, 189))	('pharmacokinetics', 'MPA', (390, 406))	('men', 'Species', '9606', (26, 29))	('improving', 'PosReg', (380, 389))	('[68Ga-DOTA', 'Var', (93, 103))	('68Ga', 'Chemical', 'MESH:C000615430', (125, 129))	('68Ga', 'Chemical', 'MESH:C000615430', (159, 163))	('68Ga', 'Chemical', 'MESH:C000615430', (191, 195))	('68Ga', 'Chemical', 'MESH:C000615430', (242, 246))	('68Ga', 'Chemical', 'MESH:C000615430', (139, 143))
153176	27688605	In particular, 68Ga-DOTANOC also shows a good affinity for SSTR subtypes 3 and 5; 68Ga-DOTATOC also binds to SSTR5 (although with lower affinity than DOTANOC) while 68Ga-DOTATATE has a predominant affinity for SSTR2.	('68Ga', 'Chemical', 'MESH:C000615430', (82, 86))	('binds', 'Interaction', (100, 105))	('68Ga-DOTATOC', 'Var', (82, 94))	('68Ga', 'Chemical', 'MESH:C000615430', (165, 169))	('SSTR2', 'Gene', (210, 215))	('SSTR5', 'Gene', '6755', (109, 114))	('SSTR5', 'Gene', (109, 114))	('SSTR2', 'Gene', '6752', (210, 215))	('68Ga', 'Chemical', 'MESH:C000615430', (15, 19))
153217	27688605	Amino acid radiotracers generally have a higher specificity compared with other radiotracers for distinguishing radionecrosis from tumor recurrence with reported specificity of 100% for 11C-methionine, 93.5% for 18F-FET, and 86% for 18F-FDOPA.	('18F-FET', 'Var', (212, 219))	('11C-methionine', 'Chemical', '-', (186, 200))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (233, 242))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('necrosis', 'Disease', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('necrosis', 'Disease', 'MESH:D009336', (117, 125))	('11C-methionine', 'Var', (186, 200))	('FET', 'Chemical', '-', (216, 219))
153218	27688605	Methionine PET is generally false negative in cases of intermediate oligodendroglioma, metastatic tumor, chordoma, and cystic ganglion.	('oligodendroglioma', 'Disease', 'MESH:D009837', (68, 85))	('chordoma', 'Disease', (105, 113))	('chordoma', 'Phenotype', 'HP:0010762', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('oligodendroglioma', 'Disease', (68, 85))	('chordoma', 'Disease', 'MESH:D002817', (105, 113))	('Methionine PET', 'Var', (0, 14))	('tumor', 'Disease', (98, 103))	('cystic ganglion', 'Disease', (119, 134))
153312	25922651	RNA was analyzed for t (11; 22) by reverse transcription followed by RT-PCR method, result was negative for t (11; 22) (q24; q12), EWS-FLI1 fusion transcript.	('EWS', 'Gene', '2130', (131, 134))	('EWS', 'Gene', (131, 134))	('FLI1', 'Gene', (135, 139))	('t (11; 22) (q24; q12', 'Var', (108, 128))	('FLI1', 'Gene', '2313', (135, 139))
153351	25874175	The multivariate analysis showed that mitotic count was a significant prognostic factor for OS, but other factors, such as age, stage, histology, tumor size, WPRT and chemotherapy, did not affect OS (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('OS', 'Chemical', '-', (196, 198))	('mitotic', 'Var', (38, 45))	('tumor', 'Disease', (146, 151))	('OS', 'Chemical', '-', (92, 94))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
153363	25874175	The OS was significantly worse after adjuvant WPRT (45.5% vs. 90.0%; p = 0.001), but in the multivariate analysis, WPRT did not significantly influence OS.	('WPRT', 'Var', (46, 50))	('OS', 'Chemical', '-', (152, 154))	('OS', 'Chemical', '-', (4, 6))	('adjuvant', 'Var', (37, 45))
153397	25874175	The disease-free survival (DFS) was significantly better in the chemotherapy arm than in the RT alone arm (3-yr DFS: 55% vs. 41%, p = 0.048), but the OS was not different (3-yr OS: 81% vs. 69%, p = 0.41).	('OS', 'Chemical', '-', (177, 179))	('disease-free survival', 'CPA', (4, 25))	('OS', 'Chemical', '-', (150, 152))	('better', 'PosReg', (50, 56))	('chemotherapy', 'Var', (64, 76))
153636	27086914	Furthermore, HVS substantially impaired the c-Met-mediated growth across a broad spectrum of breast cancer cells, while similar treatment doses had no effect on the non-tumorigenic mammary epithelial cell growth.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('S', 'Chemical', 'MESH:D013455', (15, 16))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('breast cancer', 'Disease', (93, 106))	('tumor', 'Disease', (169, 174))	('c-Met-mediated growth', 'MPA', (44, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('impaired', 'NegReg', (31, 39))	('HVS', 'Var', (13, 16))
153644	27086914	There is a mounting evidence for the involvement of dysregulated activation of c-Met signaling in the development and progression of multiple types of cancers, inducing cell proliferation, angiogenesis, and survival.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('c-Met', 'Protein', (79, 84))	('dysregulated', 'Var', (52, 64))	('activation', 'PosReg', (65, 75))	('inducing', 'PosReg', (160, 168))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cell proliferation', 'CPA', (169, 187))	('survival', 'CPA', (207, 215))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('angiogenesis', 'CPA', (189, 201))
153645	27086914	Aberrant activation of the HGF/c-Met axis is known to promote cytoskeletal changes of many cancer cells, inducing migration, invasion, and eventual metastasis.	('promote', 'PosReg', (54, 61))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('migration', 'CPA', (114, 123))	('metastasis', 'CPA', (148, 158))	('inducing', 'PosReg', (105, 113))	('HGF/c-Met', 'Protein', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('invasion', 'CPA', (125, 133))	('cytoskeletal', 'MPA', (62, 74))
153646	27086914	In addition, phosphorylated c-Met has been considered as an important predictor of tumor aggressiveness, metastatic potential and poor survival.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('metastatic potential', 'CPA', (105, 125))	('tumor aggressiveness', 'Disease', (83, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('phosphorylated c-Met', 'Var', (13, 33))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (83, 103))
153648	27086914	Therefore, inhibition of the HGF/c-Met signaling axis has a great potential for therapeutic intervention in cancer.	('HGF/c-Met signaling axis', 'Pathway', (29, 53))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('inhibition', 'Var', (11, 21))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
153649	27086914	To date, the main strategies employed to interrupt c-Met signaling involve blocking the interaction between c-Met and HGF via neutralizing antibodies directed against either HGF or c-Met, or truncated forms of HGF with antagonistic activity on c-Met such as NK4, or c-Met biologics such as ribozymes, dominant-negative receptors, decoy receptors, and peptides.	('NK4', 'Gene', '9235', (258, 261))	('HGF', 'Gene', (174, 177))	('truncated', 'Var', (191, 200))	('HGF', 'Gene', (210, 213))	('NK4', 'Gene', (258, 261))	('c-Met', 'Protein', (108, 113))	('HGF', 'Protein', (118, 121))	('blocking', 'NegReg', (75, 83))	('interaction', 'Interaction', (88, 99))	('c-Met', 'Gene', (181, 186))
153672	27086914	Several c-Met-activating mutations have been identified in numerous human cancers.	('mutations', 'Var', (25, 34))	('numerous human cancers', 'Disease', 'MESH:D009369', (59, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('numerous human cancers', 'Disease', (59, 81))	('c-Met-activating', 'Gene', (8, 24))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('S', 'Chemical', 'MESH:D013455', (0, 1))
153673	27086914	Early identification of new hit abilities to inhibit wild-type and mutant kinases is essential for subsequent drug development process to design drugs useful for patients harboring c-Met mutations.	('mutations', 'Var', (187, 196))	('patients', 'Species', '9606', (162, 170))	('mutant', 'Var', (67, 73))
153674	27086914	HVS was evaluated for its ability to inhibit c-Met phosphorylation across three c-Met mutant variants, including two activation loop mutants Y1230C and Y1235D, as well as the P+1 loop mutant M1250T, which is near the ATP binding site.	('c-Met phosphorylation', 'MPA', (45, 66))	('Y1235D', 'Mutation', 'rs1057519824', (152, 158))	('Y1235D', 'Var', (152, 158))	('Y1230C', 'Var', (141, 147))	('M1250T', 'Var', (191, 197))	('Y1230C', 'Mutation', 'rs121913246', (141, 147))	('c-Met', 'Gene', (80, 85))	('inhibit', 'NegReg', (37, 44))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('ATP', 'Gene', (217, 220))	('ATP', 'Gene', '51761', (217, 220))	('M1250T', 'Mutation', 'rs121913245', (191, 197))
153675	27086914	Selection of these well-characterized mutations was based on the ability of M1250T mutant to display the strongest kinase activity and the highest neoplastic transforming potential among all c-Met mutants.	('kinase activity', 'MPA', (115, 130))	('neoplastic transforming potential', 'CPA', (147, 180))	('M1250T', 'Mutation', 'rs121913245', (76, 82))	('M1250T', 'Var', (76, 82))	('S', 'Chemical', 'MESH:D013455', (0, 1))
153676	27086914	In presence of 200 muM ATP, HVS exhibited slightly improved activity against M1250T oncogenic human c-Met mutant, with IC50 value of 0.9 muM, compared with the wild-type c-Met (Figure 2B, Table 1).	('muM', 'Gene', '56925', (137, 140))	('muM', 'Gene', (19, 22))	('ATP', 'Gene', '51761', (23, 26))	('muM', 'Gene', (137, 140))	('M1250T', 'Mutation', 'rs121913245', (77, 83))	('improved', 'PosReg', (51, 59))	('M1250T', 'Var', (77, 83))	('human', 'Species', '9606', (94, 99))	('activity', 'MPA', (60, 68))	('S', 'Chemical', 'MESH:D013455', (30, 31))	('muM', 'Gene', '56925', (19, 22))	('ATP', 'Gene', (23, 26))
153677	27086914	In contrast, a marked shift in HVS potency was observed against c-Met activation loop mutant variants Y1230C and Y1235D (IC50 > 10 muM, Table 1) compared with wild-type receptor.	('Y1230C', 'Var', (102, 108))	('Y1235D', 'Mutation', 'rs1057519824', (113, 119))	('muM', 'Gene', (131, 134))	('Y1235D', 'Var', (113, 119))	('S', 'Chemical', 'MESH:D013455', (33, 34))	('muM', 'Gene', '56925', (131, 134))	('Y1230C', 'Mutation', 'rs121913246', (102, 108))	('HVS potency', 'MPA', (31, 42))
153678	27086914	The differential activity of HVS against c-Met oncogenic variants in cell-free assays encouraged the in silico docking study using the highly resolved co-crystal structure of SU11274 with c-Met kinase (PDB code: 2RFS) as a docking model, in an attempt to elucidate HVS's binding mode within mutant-type c-Met and compare it with its pose in the ATP binding site of the wild-type (PDB code: 4XYF, Figure 3).	('PDB', 'Gene', (202, 205))	('PDB', 'Gene', '5131', (380, 383))	('S', 'Chemical', 'MESH:D013455', (31, 32))	('variants', 'Var', (57, 65))	('binding', 'Interaction', (271, 278))	('SU11274', 'Chemical', 'MESH:C478479', (175, 182))	('S', 'Chemical', 'MESH:D013455', (267, 268))	('PDB', 'Gene', '5131', (202, 205))	('S', 'Chemical', 'MESH:D013455', (215, 216))	('ATP', 'Gene', (345, 348))	('S', 'Chemical', 'MESH:D013455', (175, 176))	('ATP', 'Gene', '51761', (345, 348))	('PDB', 'Gene', (380, 383))	('silico', 'Chemical', '-', (104, 110))
153679	27086914	Selection of 2RFS crystal structure was based upon a previous study reporting this crystal structure for c-Met protein as the one containing the nine known activating point mutations in the c-Met proto-oncogene, including M1250T.	('M1250T', 'Var', (222, 228))	('c-Met', 'Gene', (190, 195))	('S', 'Chemical', 'MESH:D013455', (16, 17))	('activating', 'PosReg', (156, 166))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('M1250T', 'Mutation', 'rs121913245', (222, 228))
153680	27086914	HVS showed good fitting within the ATP binding pocket of mutant-type c-Met (Figure 3B).	('ATP', 'Gene', '51761', (35, 38))	('mutant-type', 'Var', (57, 68))	('ATP', 'Gene', (35, 38))	('S', 'Chemical', 'MESH:D013455', (2, 3))
153682	27086914	Surprisingly, HVS binds 10 A away from the C-helix pocket with a dramatic difference in its binding mode in the mutant-type compared to the wild-type c-Met (Figure 3A).	('binding', 'Interaction', (92, 99))	('S', 'Chemical', 'MESH:D013455', (16, 17))	('mutant-type', 'Var', (112, 123))	('difference', 'Reg', (74, 84))	('S', 'Chemical', 'MESH:D013455', (0, 1))
153683	27086914	Perhaps the most interesting and unexpected feature of the structure of HVS bound to the mutant-type c-Met is the absence of any binding role for the sinapic acid moiety at the ATP binding pocket (Figure 3C).	('S', 'Chemical', 'MESH:D013455', (74, 75))	('sinapic acid', 'Chemical', 'MESH:C073734', (150, 162))	('ATP', 'Gene', (177, 180))	('ATP', 'Gene', '51761', (177, 180))	('mutant-type', 'Var', (89, 100))	('binding', 'Interaction', (129, 136))
153685	27086914	The ester carbonyl group of HVS is participating in a critical hydrogen bonding (HB) interaction with the backbone NH of the Met1160 at the hinge region of the mutant c-Met kinase, unlike the wild-type where the ester moiety appeared not to contribute any binding role at the ATP binding pocket (Figure 3A and 3C).	('ester', 'Chemical', 'MESH:D004952', (212, 217))	('ester', 'Chemical', 'MESH:D004952', (4, 9))	('Met', 'Gene', (169, 172))	('Met', 'Gene', (125, 128))	('Met', 'Gene', '4233', (169, 172))	('Met', 'Gene', '4233', (125, 128))	('hydrogen', 'Chemical', 'MESH:D006859', (63, 71))	('mutant', 'Var', (160, 166))	('ATP', 'Gene', '51761', (276, 279))	('hydrogen bonding', 'MPA', (63, 79))	('S', 'Chemical', 'MESH:D013455', (30, 31))	('ATP', 'Gene', (276, 279))	('interaction', 'Interaction', (85, 96))
153686	27086914	This unique HB interaction appeared to stabilize the C-shaped conformation of HVS within the pocket of the mutant-type which in turn, allowed an exceptional fitting of the terminal ring A along with its 2-ethyl side chain in a deep hydrophobic pocket composed of Ala1226, Leu1157, Ala1108, Leu1140 and Val1092, making predominantly hydrophobic interactions with the protein and mimicking the indolin-2-one core group of SU11274 (Figure 3D).	('hydrophobic interactions', 'MPA', (332, 356))	('SU11274', 'Chemical', 'MESH:C478479', (420, 427))	('Ala1108', 'Chemical', '-', (281, 288))	('Leu1157', 'Chemical', '-', (272, 279))	('Ala1108', 'Var', (281, 288))	('Leu1157', 'Var', (272, 279))	('Val1092', 'Var', (302, 309))	('S', 'Chemical', 'MESH:D013455', (80, 81))	('stabilize', 'Reg', (39, 48))	('Ala1226', 'Chemical', '-', (263, 270))	('S', 'Chemical', 'MESH:D013455', (420, 421))	('Leu1140', 'Chemical', '-', (290, 297))	('indolin', 'Chemical', 'MESH:C057812', (392, 399))	('Val1092', 'Chemical', '-', (302, 309))	('Ala1226', 'Var', (263, 270))	('protein', 'Protein', (366, 373))	('Leu1140', 'Var', (290, 297))
153689	27086914	In particular, Asp1222 is rotated away from the active site where it is unable to coordinate Mg2+ and assist in catalysis.	('Mg2+', 'Chemical', '-', (93, 97))	('Mg2+', 'Protein', (93, 97))	('catalysis', 'MPA', (112, 121))	('unable', 'NegReg', (72, 78))	('coordinate', 'Interaction', (82, 92))	('Asp1222', 'Var', (15, 22))	('Asp1222', 'Chemical', '-', (15, 22))	('assist', 'Reg', (102, 108))
153692	27086914	The activating mutations Y1230C and Y1235D, which have been shown to confer resistance to HVS, are both located in the activation loop, which is disordered in this crystal structure and that is why it is difficult to rationalize why HVS was not able to inhibit these mutations equally well as wild-type c-Met.	('Y1235D', 'Mutation', 'rs1057519824', (36, 42))	('Y1235D', 'Var', (36, 42))	('Y1230C', 'Mutation', 'rs121913246', (25, 31))	('Y1230C', 'Var', (25, 31))	('disordered', 'Disease', (145, 155))	('S', 'Chemical', 'MESH:D013455', (92, 93))	('S', 'Chemical', 'MESH:D013455', (235, 236))	('disordered', 'Disease', 'MESH:D030342', (145, 155))
153693	27086914	A possible explanation for the lack of c-Met inhibitory potential against Y1230C mutant could be that HVS was not able to form HB interactions with the backbone of Tyr1230, rather than simply making an aromatic ring stacking interaction, via ring B in HVS, with its side chain in the wild-type c-Met (Figure 3A).	('interactions', 'Interaction', (130, 142))	('aromatic ring stacking interaction', 'MPA', (202, 236))	('S', 'Chemical', 'MESH:D013455', (104, 105))	('Tyr1230', 'Chemical', '-', (164, 171))	('Y1230C', 'Mutation', 'rs121913246', (74, 80))	('Y1230C', 'Var', (74, 80))	('making', 'Reg', (192, 198))	('S', 'Chemical', 'MESH:D013455', (254, 255))
153699	27086914	ERalpha, one of the most important targets in human breast cancer therapy, is expressed in MCF-7, BT-474 and T-47D cells, whereas MDA-MB-231 and MDA-MB-468 cells lack the expression of ERalpha due to epigenetic silencing.	('expression', 'MPA', (171, 181))	('ERalpha', 'Gene', (0, 7))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('lack', 'NegReg', (162, 166))	('ERalpha', 'Gene', (185, 192))	('ERalpha', 'Gene', '2099', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('ERalpha', 'Gene', '2099', (185, 192))	('human', 'Species', '9606', (46, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('epigenetic silencing', 'Var', (200, 220))	('T-47D', 'CellLine', 'CVCL:0553', (109, 114))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (145, 155))	('MCF-7', 'CellLine', 'CVCL:0031', (91, 96))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (130, 140))
153716	27086914	To overcome these problems, the MTT assay was multiplexed with the LDH-based cytotoxicity assay to allow further quantification by determining the percentage of dead cells after HVS treatment and distinguish whether HVS causes cancer cell death or growth arrest without the need of specialized equipment.	('growth arrest', 'Phenotype', 'HP:0001510', (248, 261))	('HVS', 'Var', (216, 219))	('cytotoxicity', 'Disease', 'MESH:D064420', (77, 89))	('S', 'Chemical', 'MESH:D013455', (180, 181))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cytotoxicity', 'Disease', (77, 89))	('causes', 'Reg', (220, 226))	('growth arrest', 'Disease', (248, 261))	('S', 'Chemical', 'MESH:D013455', (218, 219))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('growth arrest', 'Disease', 'MESH:D006323', (248, 261))	('MTT', 'Chemical', 'MESH:C070243', (32, 35))
153759	27086914	Surprisingly, (-)-oleocanthal did not show a significant inhibitory effect on c-Met activation in this prostate cancer model, corroborating the results of the scattering assay and suggesting that (-)-oleocanthal would interrupt c-Met signaling in a cell type-specific manner (Figure 7B).	('S', 'Chemical', 'MESH:D013455', (0, 1))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('-)-oleocanthal', 'Var', (197, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('(-)-oleocanthal', 'Chemical', 'MESH:C503534', (196, 211))	('c-Met signaling', 'MPA', (228, 243))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('(-)-oleocanthal', 'Chemical', 'MESH:C503534', (14, 29))	('interrupt', 'NegReg', (218, 227))	('prostate cancer', 'Disease', (103, 118))
153769	27086914	S-Oleocanthal was nearly without any significant effect on Akt phosphorylation while it appeared to have a little effect on activated ERK levels only at relatively high treatment dose (20 muM) in this prostate cancer model, compared to vehicle-treated cells (Figure 7B).	('Akt', 'Gene', (59, 62))	('S-Oleocanthal', 'Var', (0, 13))	('muM', 'Gene', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('S-Oleocanthal', 'Chemical', 'MESH:C503534', (0, 13))	('prostate cancer', 'Disease', 'MESH:D011471', (201, 216))	('activated', 'MPA', (124, 133))	('prostate cancer', 'Phenotype', 'HP:0012125', (201, 216))	('ERK', 'Gene', '5594', (134, 137))	('Akt', 'Gene', '207', (59, 62))	('ERK', 'Gene', (134, 137))	('muM', 'Gene', '56925', (188, 191))	('prostate cancer', 'Disease', (201, 216))
153778	27086914	Significant inhibition (> 50%) at 10 muM of HVS was observed only for abelson murine leukemia viral oncogene homolog 1 (ABL1) and c-Met, with greatest relative inhibition for ABL1 (Table 2).	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('c-Met', 'Var', (130, 135))	('S', 'Chemical', 'MESH:D013455', (46, 47))	('abelson murine leukemia viral', 'Disease', (70, 99))	('muM', 'Gene', '56925', (37, 40))	('ABL1', 'Gene', (120, 124))	('abelson murine leukemia viral', 'Disease', 'MESH:D016183', (70, 99))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('muM', 'Gene', (37, 40))
153780	27086914	HVS was determined to be more than 60-fold selective for c-Met versus insulin-like growth factor receptor 1 (IGF1R) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), whereas all other kinases evaluated in the panel, except ABL1, were found to be 3-16 fold less sensitive to HVS compared with c-Met.	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcoma viral', 'Disease', 'MESH:D001102', (151, 164))	('S', 'Chemical', 'MESH:D013455', (299, 300))	('IGF1R', 'Gene', (109, 114))	('c-Met', 'Var', (57, 62))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('sarcoma viral', 'Disease', (151, 164))	('IGF1R', 'Gene', '3480', (109, 114))
153795	27086914	Additionally, the ester carbonyl contributed a critical HB interaction with the backbone of Met318 at the hinge region while the aromatic C-7 phenolic hydroxyl group formed a HB with the side chain carboxylate of Glu286.	('carboxylate', 'Chemical', '-', (198, 209))	('hydroxyl', 'Chemical', 'MESH:D017665', (151, 159))	('Glu286', 'Chemical', '-', (213, 219))	('interaction', 'Interaction', (59, 70))	('phenol', 'Chemical', 'MESH:D019800', (142, 148))	('ester', 'Chemical', 'MESH:D004952', (18, 23))	('Met318', 'Var', (92, 98))	('Met318', 'Chemical', '-', (92, 98))
153800	27086914	The larger and deeper pocket of ABL1 allowed an exceptional fitting of the HVS, facilitating several favorable interactions with Val256, Ala269, Leu370, Ala380, Phe317, Val299, and Phe382 which in turn, stabilized the bioactive U-shaped conformation and conferred a substantial binding affinity towards ABL1 (Figure 9A).	('Val256', 'Chemical', '-', (129, 135))	('Val299', 'Var', (169, 175))	('ABL1', 'Gene', (32, 36))	('Ala380', 'Var', (153, 159))	('S', 'Chemical', 'MESH:D013455', (77, 78))	('Leu370', 'Var', (145, 151))	('Ala269', 'Chemical', '-', (137, 143))	('bioactive', 'MPA', (218, 227))	('Val256', 'Var', (129, 135))	('Phe317', 'Var', (161, 167))	('Phe382', 'Var', (181, 187))	('Phe317', 'Chemical', '-', (161, 167))	('Phe382', 'Chemical', '-', (181, 187))	('interactions', 'Interaction', (111, 123))	('Leu370', 'Chemical', '-', (145, 151))	('Ala269', 'Var', (137, 143))	('Val299', 'Chemical', '-', (169, 175))	('Ala380', 'Chemical', '-', (153, 159))	('ABL1', 'Protein', (303, 307))	('binding affinity', 'Interaction', (278, 294))	('stabilized', 'PosReg', (203, 213))
153805	27086914	Interestingly, the HVS C-5' methoxyl group was solvent exposed, upon binding to ABL1 (Figure 9A), and therefore should not have a significant impact on ABL1 inhibition unlike c-Met, where the same methoxyl group nicely fits into a hydrophobic sub-pocket created by Ile1084, Phe1089, and Val1092 (Figure 3A) and thus, caused remarkable c-Met inhibition improvement, compared to compounds lacking this functionality, in c-Met biochemical assays.	('Val1092', 'Var', (287, 294))	('inhibition', 'NegReg', (341, 351))	('fits', 'Disease', 'MESH:D012640', (219, 223))	('Phe1089', 'Chemical', '-', (274, 281))	('S', 'Chemical', 'MESH:D013455', (21, 22))	('Ile1084', 'Var', (265, 272))	('Val1092', 'Chemical', '-', (287, 294))	('improvement', 'PosReg', (352, 363))	('methoxyl', 'Chemical', '-', (28, 36))	('Phe1089', 'Var', (274, 281))	('c-Met', 'MPA', (335, 340))	('fits', 'Disease', (219, 223))	('Ile1084', 'Chemical', '-', (265, 272))	('methoxyl', 'Chemical', '-', (197, 205))
153807	27086914	Such modifications could presumably affect binding affinity to the clinically relevant c-Met mutant V1092I as well, in which the size of the hydrophobic sub-pocket is likely to be reduced.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('V1092I', 'Var', (100, 106))	('binding', 'Interaction', (43, 50))	('size of the hydrophobic sub-pocket', 'MPA', (129, 163))	('reduced', 'NegReg', (180, 187))	('affect', 'Reg', (36, 42))	('V1092I', 'Mutation', 'rs786202724', (100, 106))
153823	27086914	HVS stood out as a potent c-Met inhibitor resulting in a marked inhibition of the phosphorylation of a peptide substrate recognized by recombinant human wild-type c-Met kinase and its oncogenic variant M1250T, with IC50 values of 1 and 0.9 muM, respectively (Figure 2).	('human', 'Species', '9606', (147, 152))	('muM', 'Gene', '56925', (240, 243))	('M1250T', 'Mutation', 'rs121913245', (202, 208))	('phosphorylation of a peptide substrate recognized', 'MPA', (82, 131))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('inhibition', 'NegReg', (64, 74))	('muM', 'Gene', (240, 243))	('M1250T', 'Var', (202, 208))
153825	27086914	One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations which is often correlated with poor clinical outcomes.	('mutations', 'Var', (86, 95))	('leads to', 'Reg', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('deregulation', 'Var', (29, 41))	('gain-of-function', 'PosReg', (69, 85))	('cancer', 'Disease', (51, 57))	('c-Met', 'Protein', (23, 28))
153827	27086914	The presence of striking homologies between Met proto-oncogene mutations and mutations in other RTKs has already been documented.	('mutations', 'Var', (63, 72))	('Met', 'Gene', (44, 47))	('Met', 'Gene', '4233', (44, 47))
153828	27086914	Three of these mutations (D1228N, D1228H, and M1250T) are located in codons homologous to those mutated in the tyrosine kinase receptors Kit and Ret, suggesting that these amino acids are structurally conserved hotspots for mutations.	('M1250T', 'Var', (46, 52))	('Ret', 'Gene', (145, 148))	('Ret', 'Gene', '5979', (145, 148))	('D1228N', 'Var', (26, 32))	('D1228H', 'Var', (34, 40))	('D1228H', 'Mutation', 'p.D1228H', (34, 40))	('M1250T', 'Mutation', 'rs121913245', (46, 52))	('D1228N', 'Mutation', 'p.D1228N', (26, 32))
153829	27086914	Several more recent literature examples proved that c-Met inhibitors show differential ability to modulate the activities of wild and mutant-type kinases, which can either induce primary drug resistance in case of pre-existing mutations or acquired resistance due to chronic treatment.	('induce', 'Reg', (172, 178))	('activities', 'MPA', (111, 121))	('primary drug resistance', 'MPA', (179, 202))	('modulate', 'Reg', (98, 106))	('mutant-type', 'Var', (134, 145))	('drug resistance', 'Phenotype', 'HP:0020174', (187, 202))	('S', 'Chemical', 'MESH:D013455', (0, 1))
153831	27086914	The ability of HVS to inhibit the oncogenic human c-Met mutant M1250T with almost equal potency compared with the wild-type receptor in cell-free assays, supported by in silico docking studies (Figures 2B and 3, respectively), provides a stepping stone to: broaden the oleocanthal-based esters therapeutic scope as anticancer agent; cover clinical populations with higher expression levels of this mutant variant; and offer efficacy insights for use to control aggressive tumor phenotypes expressing mutant c-Met constructs.	('human', 'Species', '9606', (44, 49))	('silico', 'Chemical', '-', (170, 176))	('mutant M1250T', 'Var', (56, 69))	('inhibit', 'NegReg', (22, 29))	('aggressive tumor', 'Disease', 'MESH:D001523', (461, 477))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('cancer', 'Disease', (319, 325))	('M1250T', 'Mutation', 'rs121913245', (63, 69))	('oleocanthal-based esters', 'Chemical', '-', (269, 293))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('c-Met', 'Gene', (50, 55))	('c-Met', 'Gene', (507, 512))	('aggressive tumor', 'Disease', (461, 477))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('M1250T', 'Var', (63, 69))	('S', 'Chemical', 'MESH:D013455', (17, 18))
153832	27086914	However, additional studies will be needed to determine whether this mutant inhibition in cell-free system can be recapitulated in cells engineered to overexpress mutant c-Met constructs such as those found in hereditary papillary renal cell carcinoma patients.	('patients', 'Species', '9606', (252, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('c-Met', 'Gene', (170, 175))	('mutant', 'Var', (163, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (231, 251))	('hereditary papillary renal cell carcinoma', 'Disease', (210, 251))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (221, 251))	('hereditary papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (210, 251))
153833	27086914	c-Met inhibitors represented by SU11274 exhibit uncompromised inhibitory activity against this c-Met mutant but they have been limited to in vitro or brief in vivo studies and were not viable clinical candidates due to poor pharmaceutical properties and oral bioavailability.	('c-Met', 'Gene', (95, 100))	('inhibitory activity', 'MPA', (62, 81))	('SU11274', 'Var', (32, 39))	('SU11274', 'Chemical', 'MESH:C478479', (32, 39))
153835	27086914	Together, HVS is a promising c-Met inhibitory hit appropriate for further molecular level validation to determine whether its activity against mutant c-Met in cell-free assays could be recapitulated in vitro and in vivo.	('S', 'Chemical', 'MESH:D013455', (12, 13))	('mutant', 'Var', (143, 149))	('c-Met', 'Gene', (150, 155))
153846	27086914	These concentrations represent several-fold above HVS's antiproliferative IC50, suggesting lack of mitochondrial mechanism of cytotoxicity and hence HVS induces cell growth arrest rather than cellular death in mammary cancer cells at achievable anticancer doses.	('lack', 'NegReg', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('S', 'Chemical', 'MESH:D013455', (52, 53))	('cancer', 'Disease', (218, 224))	('HVS', 'Var', (149, 152))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('growth arrest', 'Phenotype', 'HP:0001510', (166, 179))	('cytotoxicity', 'Disease', (126, 138))	('cancer', 'Disease', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cellular', 'CPA', (192, 200))	('induces', 'Reg', (153, 160))	('cytotoxicity', 'Disease', 'MESH:D064420', (126, 138))	('growth arrest', 'Disease', 'MESH:D006323', (166, 179))	('growth arrest', 'Disease', (166, 179))	('S', 'Chemical', 'MESH:D013455', (151, 152))
153864	27086914	This function is mediated in part by its phosphorylation of paxillin, which leads to the activation of Rac1 via the adaptor protein, creatine kinase (CrkII).	('CrkII', 'Gene', (150, 155))	('paxillin', 'Gene', '5829', (60, 68))	('paxillin', 'Gene', (60, 68))	('Rac1', 'Gene', '5879', (103, 107))	('activation', 'PosReg', (89, 99))	('phosphorylation', 'Var', (41, 56))	('Rac1', 'Gene', (103, 107))	('CrkII', 'Gene', '1398', (150, 155))
153872	27086914	In addition, HVS substantially impaired c-Met-mediated scattering phenotype of DU145 prostate cancer cells in a dose-responsive fashion, while similar treatment doses did not affect EGF-mediated cell scattering, confirming a direct inhibition of the HGF/c-Met signaling pathway (Figure 5C).	('S', 'Chemical', 'MESH:D013455', (15, 16))	('EGF', 'Gene', (182, 185))	('prostate cancer', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('c-Met-mediated scattering phenotype', 'MPA', (40, 75))	('EGF', 'Gene', '1950', (182, 185))	('DU145', 'CellLine', 'CVCL:0105', (79, 84))	('impaired', 'NegReg', (31, 39))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('HVS', 'Var', (13, 16))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))
153876	27086914	Thus, engineering a TK inhibitor with selectivity for a small group of known, disease-critical kinases may offer the advantages of broad action without the development cost of singularly targeted agents or the potential toxicity of broad-acting agents with poorly defined selectivity.	('toxicity', 'Disease', 'MESH:D064420', (220, 228))	('toxicity', 'Disease', (220, 228))	('broad', 'MPA', (131, 136))	('engineering', 'Var', (6, 17))
153879	27086914	ABL1 was first identified as an oncogene required for the development of human leukemia initiated by retroviruses or chromosome translocations.	('ABL1', 'Gene', (0, 4))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('leukemia', 'Disease', 'MESH:D007938', (79, 87))	('chromosome translocations', 'Var', (117, 142))	('human', 'Species', '9606', (73, 78))	('leukemia', 'Disease', (79, 87))
153887	27086914	Additionally, inhibition of ABL1 and c-Met sensitizes solid tumor cells to conventional agents and overcomes drug resistance developed to anticancer therapies already in clinical use, including EGFR and BRAF kinase inhibitors.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('solid tumor', 'Disease', (54, 65))	('ABL1', 'Gene', (28, 32))	('drug resistance', 'MPA', (109, 124))	('sensitizes', 'Reg', (43, 53))	('solid tumor', 'Disease', 'MESH:D009369', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('c-Met', 'Protein', (37, 42))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('inhibition', 'Var', (14, 24))	('cancer', 'Disease', (142, 148))
153927	27086914	The Z'-LYTE  Kinase Assay-Tyr6 Peptide kit (Life Sciences) was used to assess the ability of HVS to inhibit the catalytic activity of wild-type c-Met (Product# PV3143) and its oncogenic variant M1250T (Product# PV3968).	('M1250T', 'Var', (194, 200))	('c-Met', 'Protein', (144, 149))	('catalytic activity', 'MPA', (112, 130))	('Tyr6', 'Chemical', '-', (26, 30))	('Product# PV3143', 'Var', (151, 166))	('S', 'Chemical', 'MESH:D013455', (49, 50))	('M1250T', 'Mutation', 'rs121913245', (194, 200))	('S', 'Chemical', 'MESH:D013455', (95, 96))	('inhibit', 'NegReg', (100, 107))
154031	27086914	HGF hepatocyte growth factor c-Met mesenchymal-epithelial transition factor EGF epidermal growth factor 3D three-dimensional ABL1 abelson murine leukemia viral oncogene homolog 1 TNBC triple negative breast cancer RTK receptor tyrosine kinase EGFR epidermal growth factor receptor BRAF v-RAF murine sarcoma viral oncogene homolog B1 NSCLC non-small cell lung cancer ROS1 v-ros avian UR2 sarcoma virus oncogene homolog 1 ALK anaplastic lymphoma kinase VEGFR2 vascular endothelial growth factor receptor 2 EVOO extra-virgin olive oil IC50 50% inhibitory concentration ATP adenosine triphosphate PDB protein data bank A angstrom HB hydrogen bond MTT 3-[45-dimethylthiazol-2-yl]-25-diphenyl-tetrazolium bromide ERalpha estrogen receptor alpha LDH lactate dehydrogenase BME basement membrane extract DMSO dimethyl sulfoxide 2D two-dimensional Rac1 Ras-related C3 botulinum toxin substrate 1 Cdc42 cell division control protein 42 homolog PI3K phosphoinositide 3-kinase Akt protein kinase B Brk breast tumor kinase Erk extracellular signal regulated kinase MAPK mitogen-activated protein kinase FAK focal adhesion kinase TK tyrosine kinase RON recepteur d'origine nantais TYRO3 tyrosine protein kinase IGF1R insulin-like growth factor receptor 1 Kit v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog XP extra-precision PD pharmacodynamics TGI tumor growth inhibition GFP green fluorescent protein i.p.	('ALK', 'Gene', (420, 423))	('NSCLC', 'Disease', 'MESH:D002289', (333, 338))	('EVOO', 'Chemical', '-', (504, 508))	('tumor', 'Phenotype', 'HP:0002664', (1349, 1354))	('NSCLC', 'Disease', (333, 338))	('Brk', 'Gene', (985, 988))	('PDB', 'Gene', (593, 596))	('Brk', 'Gene', '5753', (985, 988))	('hepatocyte growth factor', 'Gene', (4, 28))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (424, 443))	('abelson murine leukemia viral', 'Disease', (130, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (333, 338))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (800, 818))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('Akt', 'Gene', (964, 967))	('TNBC', 'Disease', (179, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (387, 394))	('ATP', 'Gene', '51761', (566, 569))	('ROS1', 'Gene', '6098', (366, 370))	('anaplastic lymphoma', 'Disease', (424, 443))	('FAK', 'Gene', '5747', (1089, 1092))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('EGF', 'Gene', (76, 79))	('breast tumor kinase', 'Gene', '5753', (989, 1008))	('VEGFR2', 'Gene', (451, 457))	('TYRO3', 'Gene', (1166, 1171))	('VEGFR2', 'Gene', '3791', (451, 457))	('breast cancer', 'Disease', (200, 213))	('hydrogen', 'Chemical', 'MESH:D006859', (753, 761))	('Cdc42', 'Gene', (886, 891))	('tumor', 'Disease', (996, 1001))	('hepatocyte growth factor', 'Gene', '3082', (4, 28))	('TNBC', 'Disease', 'None', (179, 183))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (424, 443))	('RON', 'Gene', (1134, 1137))	('tumor', 'Disease', 'MESH:D009369', (996, 1001))	('EGF', 'Gene', '1950', (76, 79))	('RON', 'Gene', '4486', (1134, 1137))	('olive', 'Species', '4146', (522, 527))	('epidermal growth factor', 'Gene', (248, 271))	('extracellular signal regulated kinase', 'Gene', (1013, 1050))	('Rac1', 'Gene', (838, 842))	('ERalpha', 'Gene', '2099', (707, 714))	('epidermal growth factor', 'Gene', '1950', (248, 271))	('3-[45-dimethylthiazol-2-yl]-25-diphenyl-tetrazolium bromide', 'Chemical', '-', (647, 706))	('Akt', 'Gene', '207', (964, 967))	('EGF', 'Gene', (243, 246))	('tumor', 'Disease', (1349, 1354))	('breast tumor kinase', 'Gene', (989, 1008))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (570, 592))	('PI3', 'Gene', '5266', (933, 936))	('tumor', 'Disease', 'MESH:D009369', (1349, 1354))	('lymphoma', 'Phenotype', 'HP:0002665', (435, 443))	('breast tumor', 'Phenotype', 'HP:0100013', (989, 1001))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('leukemia', 'Phenotype', 'HP:0001909', (145, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (354, 365))	('sarcoma viral', 'Disease', (1275, 1288))	('v-ros avian UR2 sarcoma virus oncogene homolog 1', 'Gene', '6098', (371, 419))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('EGF', 'Gene', '1950', (243, 246))	('v-ros avian UR2 sarcoma virus oncogene homolog 1', 'Gene', (371, 419))	('MTT', 'Chemical', 'MESH:C070243', (643, 646))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (339, 365))	('PDB', 'Gene', '5131', (593, 596))	('EGF', 'Gene', (452, 455))	('FAK', 'Gene', (1089, 1092))	('PD', 'Disease', 'MESH:D010300', (1325, 1327))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (343, 365))	('Cdc42', 'Gene', '998', (886, 891))	('IGF1R', 'Gene', '3480', (1196, 1201))	('PD', 'Disease', 'MESH:D010300', (593, 595))	('focal adhesion kinase', 'Gene', '5747', (1093, 1114))	('hydrogen', 'Chemical', 'MESH:D006859', (629, 637))	('v-RAF murine sarcoma viral oncogene homolog B1', 'Gene', '673', (286, 332))	('sarcoma', 'Phenotype', 'HP:0100242', (1275, 1282))	('IGF1R', 'Gene', (1196, 1201))	('cell lung cancer', 'Disease', (349, 365))	('sarcoma viral', 'Disease', 'MESH:D001102', (1275, 1288))	('ALK', 'Gene', '238', (420, 423))	('EGF', 'Gene', '1950', (452, 455))	('focal adhesion kinase', 'Gene', (1093, 1114))	('DMSO', 'Chemical', 'MESH:D004121', (795, 799))	('ROS1', 'Gene', (366, 370))	('TYRO3', 'Gene', '7301', (1166, 1171))	('ATP', 'Gene', (566, 569))	('abelson murine leukemia viral', 'Disease', 'MESH:D016183', (130, 159))	('ERalpha', 'Gene', (707, 714))	('PI3', 'Gene', (933, 936))	('epidermal growth factor', 'Gene', (80, 103))	('epidermal growth factor', 'Gene', '1950', (80, 103))	('tumor', 'Phenotype', 'HP:0002664', (996, 1001))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('cell lung cancer', 'Disease', 'MESH:D008175', (349, 365))	('TGI', 'Var', (1345, 1348))	('sarcoma viral', 'Disease', 'MESH:D001102', (299, 312))	('extracellular signal regulated kinase', 'Gene', '5594', (1013, 1050))	('Rac1', 'Gene', '5879', (838, 842))	('v-RAF murine sarcoma viral oncogene homolog B1', 'Gene', (286, 332))
154045	26879382	At the chromosome breakpoints sites 7p15 and 17q21, fusion of two zinc-finger proteins was described; the so-called JAZF1/JJAZ1 gene fusion.	('p15', 'Gene', '1030', (37, 40))	('JAZF1', 'Gene', (116, 121))	('fusion', 'Var', (52, 58))	('JAZF1', 'Gene', '221895', (116, 121))	('JJAZ1', 'Gene', '23512', (122, 127))	('p15', 'Gene', (37, 40))	('JJAZ1', 'Gene', (122, 127))
154061	26879382	In addition to RT-PCR, the interphase fluorescence in situ hybridisation (FISH) seems to be the method of choice for detection of the JAZF1/SUZ12 fusion.	('fusion', 'Var', (146, 152))	('JAZF1', 'Gene', (134, 139))	('JAZF1', 'Gene', '221895', (134, 139))
154062	26879382	The optimisation of the interphase FISH-based detection of JAZF1/SUZ12 gene fusion in archival FFPE material was described by Oliva et al..	('gene fusion', 'Var', (71, 82))	('JAZF1', 'Gene', (59, 64))	('JAZF1', 'Gene', '221895', (59, 64))
154064	26879382	Based on histological appearance, the accurate comparison of different variants of all described ESS cases is challenging because; (i) criteria for histological classification based on morphology varied in different studies and institutions, and/or they were not precisely specified, (ii) the number of cases in different categories was usually too small to make a precise conclusion on the frequency of JAZF1/SUZ12 fusion in ESSs of different histologic subtypes.	('JAZF1', 'Gene', (404, 409))	('JAZF1', 'Gene', '221895', (404, 409))	('ESSs', 'Disease', (426, 430))	('fusion', 'Var', (416, 422))
154066	26879382	described the presence of the JAZF1/SUZ12 fusion in one case of endometrial stromal nodule (ESN) with smooth muscle (SM) differentiation.	('endometrial stroma', 'Disease', (64, 82))	('JAZF1', 'Gene', (30, 35))	('fusion', 'Var', (42, 48))	('endometrial stroma', 'Disease', 'MESH:D014591', (64, 82))	('JAZF1', 'Gene', '221895', (30, 35))	('ESN', 'Chemical', '-', (92, 95))
154072	26879382	In the second study the JAZF1 rearrangement was reported in 70 % of LG-ESSs, however the presence/absence of the JAZF1/SUZ12 gene fusion was not clearly specified.	('JAZF1', 'Gene', '221895', (113, 118))	('JAZF1', 'Gene', '221895', (24, 29))	('rearrangement', 'Var', (30, 43))	('JAZF1', 'Gene', (113, 118))	('reported', 'Reg', (48, 56))	('JAZF1', 'Gene', (24, 29))	('LG-ESSs', 'Disease', (68, 75))
154079	26879382	Huang and co-workers categorized 15 ESSs based on their histological appearance and showed that the prevalence of JAZF1/SUZ12 fusion was mainly limited to the subset of ESSs with classic histology.	('JAZF1', 'Gene', '221895', (114, 119))	('fusion', 'Var', (126, 132))	('JAZF1', 'Gene', (114, 119))
154080	26879382	Beside these cases with classic histology, they detected the JAZF1/SUZ12 fusion in one ESN of mixed SM variant.	('JAZF1', 'Gene', (61, 66))	('ESN', 'Chemical', '-', (87, 90))	('mixed SM', 'Disease', (94, 102))	('JAZF1', 'Gene', '221895', (61, 66))	('fusion', 'Var', (73, 79))
154088	26879382	found the JAZF1/SUZ12 fusion transcript in one of two ESNs with sex SC differentiation.	('JAZF1', 'Gene', (10, 15))	('JAZF1', 'Gene', '221895', (10, 15))	('ESN', 'Chemical', '-', (54, 57))	('fusion', 'Var', (22, 28))
154094	26879382	confirmed the JAZF1/SUZ12 gene fusion by RT-PCR and FISH analysis in one primary extrauterine ESS arising from the extraperitoneal portion of the round ligament in the inguinal canal.	('fusion', 'Var', (31, 37))	('JAZF1', 'Gene', (14, 19))	('JAZF1', 'Gene', '221895', (14, 19))
154101	26879382	Altogether, these data suggest that JAZF1/SUZ12 fusion is frequently but not consistently present in ESNs and in ESTs of classic histology and less often in other histological subtypes.	('JAZF1', 'Gene', (36, 41))	('fusion', 'Var', (48, 54))	('EST', 'Gene', (113, 116))	('ESN', 'Chemical', '-', (101, 104))	('ESNs', 'Disease', (101, 105))	('EST', 'Gene', '6783', (113, 116))	('JAZF1', 'Gene', '221895', (36, 41))
154103	26879382	The ESTs exhibit different patterns of genetic aberrations, but rearrangements of the chromosomes 6, 7 and 17 seem to be the most common.	('genetic aberrations', 'Disease', (39, 58))	('common', 'Reg', (130, 136))	('EST', 'Gene', (4, 7))	('EST', 'Gene', '6783', (4, 7))	('genetic aberrations', 'Disease', 'MESH:D030342', (39, 58))	('rearrangements', 'Var', (64, 78))
154105	26879382	It has been shown that they are associated with the t(7;17)(p15;q21) alteration in ESSs.	('ESSs', 'Disease', (83, 87))	('t(7;17)(p15;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (52, 68))	('t(7;17)(p15;q21) alteration', 'Var', (52, 79))	('associated', 'Reg', (32, 42))
154107	26879382	In this break-point G-435 from the JAZF1 sequence was followed by A-468 from the SUZ12 sequence and was, therefore, identical with the break-point described by other authors in a limited number of cases.	('G-435', 'Var', (20, 25))	('JAZF1', 'Gene', (35, 40))	('JAZF1', 'Gene', '221895', (35, 40))
154121	26879382	Interestingly, TAK1 receptor deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance.	('insulin resistance', 'Phenotype', 'HP:0000855', (118, 136))	('mice', 'Species', '10090', (39, 43))	('obesity', 'Phenotype', 'HP:0001513', (66, 73))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (95, 112))	('insulin resistance', 'Disease', (118, 136))	('TAK1 receptor', 'Protein', (15, 28))	('obesity-linked inflammation', 'Disease', (66, 93))	('hepatic steatosis', 'Disease', (95, 112))	('obesity-linked inflammation', 'Disease', 'MESH:D009765', (66, 93))	('deficient', 'Var', (29, 38))	('hepatic steatosis', 'Disease', 'MESH:D005234', (95, 112))
154126	26879382	Single nuclear polymorphisms in the JAZF1 introns have been reported to be associated with an increases risk of type 2 diabetes and with increased susceptibility to prostate cancer.	('JAZF1', 'Gene', (36, 41))	('Single nuclear polymorphisms', 'Var', (0, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('prostate cancer', 'Disease', (165, 180))	('JAZF1', 'Gene', '221895', (36, 41))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (112, 127))	('diabetes', 'Disease', (119, 127))	('associated', 'Reg', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('diabetes', 'Disease', 'MESH:D003920', (119, 127))
154132	26879382	Furthermore, the expression of the JAZF1/SUZ12 protected HEK-293 cells from serum deprivation and from hypoxia-induced apoptosis.	('JAZF1', 'Gene', '221895', (35, 40))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))	('expression', 'Var', (17, 27))	('HEK-293', 'CellLine', 'CVCL:0045', (57, 64))	('hypoxia', 'Disease', (103, 110))	('JAZF1', 'Gene', (35, 40))	('protected', 'PosReg', (47, 56))
154139	26879382	D'Angelo and colleagues described a correlation between the occurrence of PHF1 rearrangement and ESSs with sex cord differentiation.	('ESSs', 'Disease', (97, 101))	('sex cord differentiation', 'CPA', (107, 131))	('rearrangement', 'Var', (79, 92))	('PHF1', 'Gene', (74, 78))	('PHF1', 'Gene', '5252', (74, 78))
154140	26879382	In their study all 7 cases with sex cord differentiation were positive for PHF1 rearrangement, whereas only one was positive for JAZF1 rearrangement.	('PHF1', 'Gene', (75, 79))	('JAZF1', 'Gene', (129, 134))	('PHF1', 'Gene', '5252', (75, 79))	('sex cord differentiation', 'CPA', (32, 56))	('positive', 'Reg', (62, 70))	('JAZF1', 'Gene', '221895', (129, 134))	('rearrangement', 'Var', (80, 93))
154141	26879382	One recent study, with a total of 40 cases, showed that 36 % of LG-ESSs (8 of 22) and none of 17 UESs (10 with nuclear uniformity and 7 with nuclear pleomorphism) were positive for the JAZF1/PHF1 rearrangement.	('rearrangement', 'Var', (196, 209))	('JAZF1', 'Gene', (185, 190))	('positive', 'Reg', (168, 176))	('PHF1', 'Gene', (191, 195))	('PHF1', 'Gene', '5252', (191, 195))	('JAZF1', 'Gene', '221895', (185, 190))	('LG-ESSs', 'Disease', (64, 71))
154150	26879382	Whereas all other gene fusions from ESTs were detected exclusively in these tumors, the JAZF1/PHF1 fusion was recently described in the sarcoma of the heart, thus being the only one detected outside of the EST spectrum.	('fusion', 'Var', (99, 105))	('JAZF1', 'Gene', (88, 93))	('EST', 'Gene', (36, 39))	('PHF1', 'Gene', '5252', (94, 98))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('EST', 'Gene', '6783', (36, 39))	('tumors', 'Disease', (76, 82))	('PHF1', 'Gene', (94, 98))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('sarcoma', 'Disease', (136, 143))	('JAZF1', 'Gene', '221895', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('EST', 'Gene', (206, 209))	('EST', 'Gene', '6783', (206, 209))	('described', 'Reg', (119, 128))
154152	26879382	Based on present studies, tumors with YWHAE/NUTM2 rearrangements are associated with high-grade morphology and aggressive clinical behaviour.	('high-grade morphology', 'CPA', (85, 106))	('YWHAE', 'Gene', (38, 43))	('associated', 'Reg', (69, 79))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('aggressive clinical behaviour', 'Phenotype', 'HP:0000718', (111, 140))	('aggressive clinical behaviour', 'CPA', (111, 140))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('rearrangements', 'Var', (50, 64))	('YWHAE', 'Gene', '7531', (38, 43))	('tumors', 'Disease', (26, 32))
154158	26879382	Two novel gene fusions, MEAF6/PHF1 and ZC3H7B/BCOR, were detected in a subset of ESSs with t(1;6)(p34;p21) and der(22)t(X;22)(p11;q13) genetic alterations, respectively.	('ZC3H7B', 'Gene', '23264', (39, 45))	('PHF1', 'Gene', (30, 34))	('BCOR', 'Gene', (46, 50))	('PHF1', 'Gene', '5252', (30, 34))	('der(22)t(X;22)(p11;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (111, 134))	('t(1;6)(p34;p21)', 'STRUCTURAL_ABNORMALITY', 'None', (91, 106))	('BCOR', 'Gene', '54880', (46, 50))	('detected', 'Reg', (57, 65))	('MEAF6', 'Gene', (24, 29))	('MEAF6', 'Gene', '64769', (24, 29))	('der(22)t(X;22)(p11;q13', 'Var', (111, 133))	('ZC3H7B', 'Gene', (39, 45))	('t(1;6)(p34;p21', 'Var', (91, 105))
154160	26879382	ESSs are genetically heterogeneous malignancies, with following chromosomal translocations identified: t(7;17)(p15;q21), t(6;7)(p21;p15), t(6;10;10)(p21;q22;p11), t(1;6)(p34;p21) and t(10;17)(q22;p13).	('p21', 'Gene', (174, 177))	('t(7;17)(p15;q21', 'Var', (103, 118))	('t(7;17)(p15;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (103, 119))	('t(6;7)(p21;p15)', 'STRUCTURAL_ABNORMALITY', 'None', (121, 136))	('p21', 'Gene', '644914', (174, 177))	('p21', 'Gene', (149, 152))	('p11', 'Gene', (157, 160))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (183, 200))	('p21', 'Gene', (128, 131))	('t(1;6)(p34;p21)', 'STRUCTURAL_ABNORMALITY', 'None', (163, 178))	('malignancies', 'Disease', 'MESH:D009369', (35, 47))	('p21', 'Gene', '644914', (128, 131))	('p21', 'Gene', '644914', (149, 152))	('p11', 'Gene', '6281', (157, 160))	('t(10;17)(q22;p13', 'Var', (183, 199))	('malignancies', 'Disease', (35, 47))	('ESSs', 'Disease', (0, 4))
154162	26879382	Data published so far show that the JAZF1/SUZ12 fusion is a genetic hallmark of ESNs and of LG-ESSs.	('JAZF1', 'Gene', (36, 41))	('fusion', 'Var', (48, 54))	('ESNs', 'Disease', (80, 84))	('ESN', 'Chemical', '-', (80, 83))	('JAZF1', 'Gene', '221895', (36, 41))
154194	25013420	Mouse MSCs (mMSCs) were isolated from C57BL/6 mice, and rat MSCs (rMSCs) were isolated from Sprague-Dawley rats, as described previously.	('MSC', 'Gene', '9242', (67, 70))	('rat', 'Species', '10116', (56, 59))	('MSC', 'Gene', '9242', (60, 63))	('C57BL/6', 'Var', (38, 45))	('MSC', 'Gene', (67, 70))	('MSC', 'Gene', '9242', (13, 16))	('MSC', 'Gene', (60, 63))	('mice', 'Species', '10090', (46, 50))	('MSC', 'Gene', (13, 16))	('Mouse', 'Species', '10090', (0, 5))	('MSC', 'Gene', '9242', (6, 9))	('MSC', 'Gene', (6, 9))	('Sprague-Dawley rats', 'Species', '10116', (92, 111))	('rat', 'Species', '10116', (107, 110))
154211	25013420	In brief, serially diluted cells (5, 10, 50, 100, 400, and 1,000 cells) for HT1080, WEHI164, and RR1022 were plated in a 24-well culture plate (Falcon, BD Bioscience).	('HT1080', 'Gene', (76, 82))	('HT1080', 'Gene', '8872', (76, 82))	('and 1', 'Gene', '218973', (55, 60))	('WEHI164', 'Chemical', '-', (84, 91))	('and 1', 'Gene', (55, 60))	('WEHI164', 'Var', (84, 91))	('RR1022', 'Var', (97, 103))
154216	25013420	2D-F): WEHI164 alone (group 1) and WEHI164 combined with mMSCs (group 2) in 100 microL PBS were inoculated into the subcutaneous tissue of the backs of 6- to 8-week-old Sprague-Dawley rats, 4x104 cells for WEHI164 and 1x105 cells for mMSCs.	('WEHI164', 'Chemical', '-', (35, 42))	('WEHI164', 'Var', (206, 213))	('MSC', 'Gene', '9242', (235, 238))	('WEHI164', 'Var', (35, 42))	('MSC', 'Gene', (235, 238))	('MSC', 'Gene', '9242', (58, 61))	('Sprague-Dawley rats', 'Species', '10116', (169, 188))	('and 1', 'Gene', '218973', (214, 219))	('MSC', 'Gene', (58, 61))	('WEHI164', 'Chemical', '-', (7, 14))	('and 1', 'Gene', (214, 219))	('WEHI164', 'Chemical', '-', (206, 213))	('PBS', 'Chemical', '-', (87, 90))
154218	25013420	2G-I): RR1022 alone (group 1) and RR1022 combined with rMSCs (group 2) in 100 microL PBS were inoculated into the subcutaneous tissue of the abdomens of 6- to 8-week-old C57BL/6 mice, 1.5x104 cells for RR1022 and 1x105 cells for rMSCs.	('MSC', 'Gene', (56, 59))	('and 1', 'Gene', (209, 214))	('mice', 'Species', '10090', (178, 182))	('RR1022', 'Var', (202, 208))	('PBS', 'Chemical', '-', (85, 88))	('MSC', 'Gene', '9242', (230, 233))	('and 1', 'Gene', '218973', (209, 214))	('MSC', 'Gene', (230, 233))	('MSC', 'Gene', '9242', (56, 59))
154232	25013420	The CFC frequencies were calculated as 1/5 (20%), 1/4 (25%), and 1/1.5 (66.6%) for HT1080, WEHI164, and RR1022, respectively.	('HT1080', 'Gene', '8872', (83, 89))	('WEHI164', 'Chemical', '-', (91, 98))	('and 1/1.5', 'Gene', '218973', (61, 70))	('WEHI164', 'Var', (91, 98))	('and 1/1.5', 'Gene', (61, 70))	('RR1022', 'Var', (104, 110))	('HT1080', 'Gene', (83, 89))
154242	25013420	WEHI164 alone and WEHI164 combined with mMSCs were inoculated into the subcutaneous tissue of Sprague-Dawley rats (n=6).	('WEHI164', 'Var', (0, 7))	('WEHI164', 'Chemical', '-', (18, 25))	('WEHI164', 'Var', (18, 25))	('Sprague-Dawley rats', 'Species', '10116', (94, 113))	('MSC', 'Gene', '9242', (41, 44))	('MSC', 'Gene', (41, 44))	('WEHI164', 'Chemical', '-', (0, 7))
154247	25013420	RR1022 alone and RR1022 combined with rMSCs were inoculated into the subcutaneous tissue of C57BL/6 mice (n=6).	('MSC', 'Gene', (39, 42))	('mice', 'Species', '10090', (100, 104))	('RR1022', 'Var', (17, 23))	('MSC', 'Gene', '9242', (39, 42))
154310	24277454	Indeed, the relation between risk for de novo cancers and estimates of average constitutional telomere length suggest that shortened telomeres may be a marker for cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('shortened', 'Var', (123, 132))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancer', 'Disease', (46, 52))	('cancers', 'Disease', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('shortened telomeres', 'Phenotype', 'HP:0031413', (123, 142))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
154350	24277454	Therefore, individuals with constitutionally short telomeres or telomere damage after chemotherapy or radiation exposure may be at increased risk for developing SMN.	('SMN', 'Chemical', '-', (161, 164))	('short telomeres', 'Phenotype', 'HP:0031413', (45, 60))	('telomere damage', 'Var', (64, 79))	('SMN', 'Disease', (161, 164))
154359	24277454	These findings support the existence of abnormalities in telomere maintenance specific to thyroid cancer with hereditary predisposition, which may be a contributing factor to the significant association between secondary thyroid cancer and shortened telomeres observed in our study population.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('secondary thyroid cancer', 'Disease', 'MESH:D013964', (211, 235))	('shortened telomeres', 'Phenotype', 'HP:0031413', (240, 259))	('thyroid cancer', 'Phenotype', 'HP:0002890', (90, 104))	('thyroid cancer', 'Disease', (90, 104))	('thyroid cancer', 'Phenotype', 'HP:0002890', (221, 235))	('telomere', 'MPA', (57, 65))	('thyroid cancer', 'Disease', 'MESH:D013964', (90, 104))	('abnormalities', 'Var', (40, 53))	('secondary thyroid cancer', 'Disease', (211, 235))	('thyroid cancer', 'Disease', 'MESH:D013964', (221, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
154366	24277454	In contrast, another case-control study examining constitutional telomere length and risk for de novo osteosarcoma demonstrated a statistically significant association with shortened telomeres among females.	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('shortened telomeres', 'Phenotype', 'HP:0031413', (173, 192))	('osteosarcoma', 'Disease', 'MESH:D012516', (102, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('shortened', 'Var', (173, 182))	('osteosarcoma', 'Disease', (102, 114))
154384	24277454	Shortened constitutional telomeres are a well-established risk factor for development of primary malignancies.	('Shortened constitutional telomeres', 'Phenotype', 'HP:0031413', (0, 34))	('Shortened', 'Var', (0, 9))	('primary malignancies', 'Disease', (89, 109))	('primary malignancies', 'Disease', 'MESH:D009369', (89, 109))
154387	24277454	Our results suggest an association between shortened telomeres and SMN that is primarily driven by thyroid SMN.	('SMN', 'Disease', (67, 70))	('SMN', 'Chemical', '-', (107, 110))	('SMN', 'Chemical', '-', (67, 70))	('thyroid SMN', 'Chemical', '-', (99, 110))	('shortened telomeres', 'Phenotype', 'HP:0031413', (43, 62))	('shortened', 'Var', (43, 52))
154393	22396649	Moreover, reintroduction of Aurora A dramatically enhances the binding affinity of p53 with LANA and LANASOCS-mediated ubiquitylation of p53 which requires phosphorylation on Ser215 and Ser315.	('binding affinity', 'Interaction', (63, 79))	('LANA', 'Gene', '4961527', (101, 105))	('enhances', 'PosReg', (50, 58))	('p53', 'Gene', (83, 86))	('ubiquitylation', 'MPA', (119, 133))	('LANA', 'Gene', (101, 105))	('LANA', 'Gene', (92, 96))	('LANA', 'Gene', '4961527', (92, 96))	('Ser315', 'Var', (186, 192))	('Ser315', 'Chemical', '-', (186, 192))	('Ser215', 'Chemical', '-', (175, 181))	('phosphorylation', 'MPA', (156, 171))
154394	22396649	Small hairpin RNA or a dominant negative mutant of Aurora A kinase efficiently disrupts LANA-induced p53 ubiquitylation and degradation, and leads to induction of p53 transcriptional and apoptotic activities.	('degradation', 'MPA', (124, 135))	('LANA', 'Gene', (88, 92))	('induction', 'PosReg', (150, 159))	('ubiquitylation', 'MPA', (105, 119))	('apoptotic activities', 'CPA', (187, 207))	('p53', 'Protein', (101, 104))	('p53', 'Gene', (163, 166))	('mutant', 'Var', (41, 47))	('LANA', 'Gene', '4961527', (88, 92))	('disrupts', 'NegReg', (79, 87))	('transcriptional', 'MPA', (167, 182))
154398	22396649	Aurora-kinase inhibition has been shown to effectively block cell growth and induce death of cancer cells.	('death of cancer', 'Disease', 'MESH:D003643', (84, 99))	('Aurora-kinase', 'Protein', (0, 13))	('block', 'NegReg', (55, 60))	('cell growth', 'CPA', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('inhibition', 'Var', (14, 24))	('death of cancer', 'Disease', (84, 99))	('induce', 'Reg', (77, 83))
154412	22396649	The promoter of Aurora A contains three putative binding sites for transcription factors: E2F, Sp1 and Ets.	('F, Sp1', 'Species', '289092', (92, 98))	('binding', 'Interaction', (49, 56))	('E2F', 'Var', (90, 93))	('Aurora A', 'Gene', (16, 24))
154414	22396649	Aberrant expression of Aurora A has been reported in a wide variety of tumor types and in most human cancer cell lines.	('reported', 'Reg', (41, 49))	('human', 'Species', '9606', (95, 100))	('Aurora A', 'Gene', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('expression', 'MPA', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (71, 76))
154416	22396649	Like the aberrant expression of Aurora A, loss of p53 function also induces similar phenotypes of centrosome amplification and aneuploidy in cells.	('induces', 'Reg', (68, 75))	('loss', 'Var', (42, 46))	('aneuploidy', 'Disease', 'MESH:D000782', (127, 137))	('centrosome amplification', 'CPA', (98, 122))	('p53', 'Gene', (50, 53))	('aneuploidy', 'Disease', (127, 137))
154417	22396649	It is well known that wild type p53 is able to induce growth arrest or apoptosis when cells are exposed to stress, and p53 is frequently mutated or deleted in human cancers.	('growth arrest', 'Disease', 'MESH:D006323', (54, 67))	('growth arrest', 'Disease', (54, 67))	('apoptosis', 'CPA', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('growth arrest', 'Phenotype', 'HP:0001510', (54, 67))	('deleted', 'Var', (148, 155))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('p53', 'Gene', (119, 122))	('induce', 'Reg', (47, 53))	('cancers', 'Disease', (165, 172))
154418	22396649	As a substrate of Aurora A kinase, p53 can be phosphorylated on both Ser215 and Ser315 and this leads to destabilization and inhibition of p53 via the Mdm2-mediated ubiquitylation and proteasomal degradation pathway.	('Ser215', 'Var', (69, 75))	('destabilization', 'MPA', (105, 120))	('Ser215', 'Chemical', '-', (69, 75))	('Mdm2', 'Gene', (151, 155))	('p53', 'Gene', (139, 142))	('Ser315', 'Var', (80, 86))	('Ser315', 'Chemical', '-', (80, 86))	('Mdm2', 'Gene', '4193', (151, 155))	('inhibition', 'NegReg', (125, 135))
154420	22396649	In this study, we further show that the protein levels of Aurora A kinase is upregulated by LANA, and that elevated Aurora A induces phosphorylation of p53 which enhances the interaction of LANA with p53, and promotes LANA-mediated p53 ubiquitylation and degradation, and hence inhibition of p53 transcriptional and apoptotic activities.	('interaction', 'Interaction', (175, 186))	('p53', 'Protein', (152, 155))	('p53', 'Protein', (200, 203))	('upregulated', 'PosReg', (77, 88))	('LANA', 'Gene', (92, 96))	('LANA', 'Gene', '4961527', (92, 96))	('LANA', 'Gene', (218, 222))	('LANA', 'Gene', '4961527', (218, 222))	('Aurora', 'Var', (116, 122))	('induces', 'Reg', (125, 132))	('p53', 'Gene', (292, 295))	('phosphorylation', 'MPA', (133, 148))	('promotes', 'PosReg', (209, 217))	('LANA', 'Gene', (190, 194))	('degradation', 'MPA', (255, 266))	('ubiquitylation', 'MPA', (236, 250))	('LANA', 'Gene', '4961527', (190, 194))	('inhibition', 'NegReg', (278, 288))	('apoptotic activities', 'CPA', (316, 336))	('enhances', 'PosReg', (162, 170))
154426	22396649	To elucidate the role of LANA on Aurora A expression, LANA in KSHV-positive BC3 cell line was transiently knocked down by introduction of small interference RNA specifically against LANA without interrupting other latent transcripts (supplementary Figure S1).	('small interference', 'Var', (138, 156))	('LANA', 'Gene', (54, 58))	('LANA', 'Gene', '4961527', (54, 58))	('KSHV', 'Species', '37296', (62, 66))	('LANA', 'Gene', (25, 29))	('knocked down', 'NegReg', (106, 118))	('LANA', 'Gene', (182, 186))	('LANA', 'Gene', '4961527', (25, 29))	('LANA', 'Gene', '4961527', (182, 186))
154435	22396649	A transcription factor analysis and previous studies identified three cis elements E2F, Sp1 and Ets within the Aurora A promoter.	('Sp1', 'Gene', (88, 91))	('Ets', 'Gene', (96, 99))	('F, Sp1', 'Species', '289092', (85, 91))	('E2F', 'Var', (83, 86))
154436	22396649	To define which cis element is critical for LANA to activate Aurora A transcription, a series of mutants of the Aurora A promoter driving the luciferase reporter gene were generated and subjected to reporter assays in HEK 293 cells in the presence or absence of the LANA.	('LANA', 'Gene', (44, 48))	('LANA', 'Gene', '4961527', (266, 270))	('LANA', 'Gene', '4961527', (44, 48))	('mutants', 'Var', (97, 104))	('HEK 293', 'CellLine', 'CVCL:0045', (218, 225))	('LANA', 'Gene', (266, 270))
154437	22396649	As shown in Figure 3A, in the presence of LANA, the Aurora A promoter with specific deletions of E2F or Ets transcription factor-related locus (DeltaE2F or DeltaEts) resulted in a mild difference in stimulation of Aurora A promoter activity when compared to the wild type Aurora A promoter (E2F+Sp1+Ets).	('Aurora A promoter activity', 'MPA', (214, 240))	('F+Sp1', 'Species', '289092', (293, 298))	('E2F', 'Gene', (97, 100))	('stimulation', 'PosReg', (199, 210))	('LANA', 'Gene', (42, 46))	('LANA', 'Gene', '4961527', (42, 46))	('deletions', 'Var', (84, 93))
154440	22396649	Inhibition of LANA expression dramatically reduced the association of Sp1 to its cis-acting element (Figure 3B).	('Sp1', 'Gene', (70, 73))	('association', 'Interaction', (55, 66))	('LANA', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (43, 50))	('LANA', 'Gene', '4961527', (14, 18))
154443	22396649	The results from reporter assays showed that both LANA and Aurora A individually reduced the transcriptional activity of p53 (Figure 4A, lane 3 and 4), and co-expression of Aurora A dramatically enhanced LANA-mediated inhibitory function of p53 expression (Figure 4A, lane 5).	('LANA', 'Gene', (50, 54))	('LANA', 'Gene', (204, 208))	('p53', 'Protein', (121, 124))	('LANA', 'Gene', '4961527', (50, 54))	('LANA', 'Gene', '4961527', (204, 208))	('enhanced', 'PosReg', (195, 203))	('reduced', 'NegReg', (81, 88))	('Aurora', 'Var', (173, 179))	('transcriptional activity', 'MPA', (93, 117))	('expression', 'MPA', (245, 255))	('p53', 'Gene', (241, 244))
154455	22396649	Substantially more LANA protein was pulled down by p53 in the presence of wild type Aurora A than in the presence of the mutant control in both Saos-2 and MEF cell lines (Figure 5A).	('LANA', 'Gene', (19, 23))	('LANA', 'Gene', '4961527', (19, 23))	('pulled down', 'MPA', (36, 47))	('more', 'PosReg', (14, 18))	('MEF', 'Gene', '2000', (155, 158))	('p53', 'Var', (51, 54))	('MEF', 'Gene', (155, 158))	('Saos-2', 'CellLine', 'CVCL:0548', (144, 150))
154457	22396649	The results showed that there is substantially higher amount of ubiquitylated p53 in cells expressing wild type LANA and Aurora A than in cells expressing only wild type LANA or Aurora A (Figure 5B, compare lane 4 with 2 and 3).	('LANA', 'Gene', (170, 174))	('ubiquitylated', 'MPA', (64, 77))	('LANA', 'Gene', '4961527', (170, 174))	('LANA', 'Gene', (112, 116))	('higher', 'PosReg', (47, 53))	('p53', 'Protein', (78, 81))	('LANA', 'Gene', '4961527', (112, 116))	('Aurora A', 'Var', (121, 129))
154458	22396649	Consistently, mutation of the SOCS motif of LANA, the inactive form of Aurora A or both led to a dramatic reduction of ubiquitylated p53 (Figure 5B, compare lane 4 with 5, 6, and 7).	('LANA', 'Gene', (44, 48))	('SOCS', 'Gene', '1154', (30, 34))	('LANA', 'Gene', '4961527', (44, 48))	('reduction', 'NegReg', (106, 115))	('SOCS', 'Gene', (30, 34))	('mutation', 'Var', (14, 22))	('ubiquitylated p53', 'MPA', (119, 136))
154460	22396649	Previous studies reported that Aurora A is able to phosphorylate p53 at Ser215 and Ser315.	('Ser215', 'Chemical', '-', (72, 78))	('Ser315', 'Chemical', '-', (83, 89))	('Ser315', 'Var', (83, 89))	('phosphorylate', 'MPA', (51, 64))	('Ser215', 'Var', (72, 78))	('p53', 'Protein', (65, 68))
154461	22396649	To determine if LANA-mediated p53 ubiquitylation is dependent on Aurora A-induced phosphorylation of p53 on Ser215 or Ser315, we performed similar ubiquitylation assays by using wild-type, S215A or S315A variants of p53 with wild-type Aurora A and LANA in MEF cells.	('LANA', 'Gene', '4961527', (248, 252))	('MEF', 'Gene', '2000', (256, 259))	('MEF', 'Gene', (256, 259))	('LANA', 'Gene', (16, 20))	('S215A', 'Mutation', 'p.S215A', (189, 194))	('Ser215', 'Chemical', '-', (108, 114))	('LANA', 'Gene', '4961527', (16, 20))	('S215A', 'Var', (189, 194))	('LANA', 'Gene', (248, 252))	('S315A', 'Var', (198, 203))	('Ser315', 'Chemical', '-', (118, 124))	('p53', 'Gene', (216, 219))	('S315A', 'Mutation', 'p.S315A', (198, 203))
154462	22396649	The results showed that compared with wild type p53, less ubiquitylated p53 appeared in cells expressing S215A, S315A or the S215A/S315A mutant of p53, and S315A had a greater impact than S215A (Figure 6A, lane 2 with 3, 4, and 5), suggesting that both Ser215 and Ser315 are phosphorylated by Aurora A and in turn facilitates LANA-induced ubiquitylation of p53.	('S215A', 'Mutation', 'p.S215A', (105, 110))	('p53', 'Protein', (357, 360))	('Ser215', 'Chemical', '-', (253, 259))	('S315A', 'Mutation', 'p.S315A', (112, 117))	('S215A/S315A', 'Var', (125, 136))	('Ser215', 'Var', (253, 259))	('S215A', 'Mutation', 'p.S215A', (125, 130))	('S315A', 'Var', (156, 161))	('facilitates', 'PosReg', (314, 325))	('S215A', 'Mutation', 'p.S215A', (188, 193))	('LANA', 'Gene', (326, 330))	('LANA', 'Gene', '4961527', (326, 330))	('S315A', 'Var', (112, 117))	('S215A', 'Var', (105, 110))	('ubiquitylation', 'MPA', (339, 353))	('S315A', 'Mutation', 'p.S315A', (131, 136))	('Ser315', 'Chemical', '-', (264, 270))	('Ser315', 'Var', (264, 270))	('S315A', 'Mutation', 'p.S315A', (156, 161))
154469	22396649	However, the combination of LANA with Aurora A mutant KR or LANA DeltaSOCS with wild type Aurora A, resulted in a dramatic reversal of the levels of p53 mediated apoptosis (Figure 7A, compare lane 2 with 6 and 7, supplementary Figure S4).	('reversal', 'NegReg', (123, 131))	('LANA', 'Gene', (60, 64))	('levels', 'MPA', (139, 145))	('LANA', 'Gene', '4961527', (60, 64))	('p53 mediated', 'MPA', (149, 161))	('SOCS', 'Gene', '1154', (70, 74))	('LANA', 'Gene', (28, 32))	('apoptosis', 'CPA', (162, 171))	('LANA', 'Gene', '4961527', (28, 32))	('mutant', 'Var', (47, 53))	('SOCS', 'Gene', (70, 74))
154476	22396649	The proportion of multinucleated cells or apoptotic cells was progressively increased once Aurora A was knocked down (Figure 8D and E), indicating that inhibition of Aurora A in KSHV-infected cells was sufficient to induce cell apoptosis.	('Aurora A', 'Gene', (166, 174))	('induce', 'Reg', (216, 222))	('cell apoptosis', 'CPA', (223, 237))	('knocked', 'Var', (104, 111))	('KSHV-infected', 'Disease', 'MESH:C537372', (178, 191))	('KSHV-infected', 'Disease', (178, 191))	('inhibition', 'Var', (152, 162))
154477	22396649	In addition, the result of Aurora A knockdown led to dramatic increase of p53 accumulation and subG1 population in 293 cells with KSHV infection but not mock 293 cells (Figure 8F), further supporting the notion that Aurora A is targeted by KSHV for inhibition of p53-mediated apoptotic function.	('KSHV', 'Species', '37296', (240, 244))	('p53', 'Protein', (74, 77))	('KSHV', 'Species', '37296', (130, 134))	('knockdown', 'Var', (36, 45))	('subG1 population', 'CPA', (95, 111))	('Aurora A', 'Gene', (27, 35))	('increase', 'PosReg', (62, 70))	('accumulation', 'PosReg', (78, 90))
154482	22396649	The elevated levels of Aurora A subsequently resulted in phosphorylation of p53 at Ser215 and Ser315 thus facilitating LANA-mediated ubiquitylation and destabilization of p53 (Figure 9).	('Ser215', 'Var', (83, 89))	('p53', 'Protein', (76, 79))	('LANA', 'Gene', (119, 123))	('destabilization', 'MPA', (152, 167))	('ubiquitylation', 'MPA', (133, 147))	('Ser215', 'Chemical', '-', (83, 89))	('LANA', 'Gene', '4961527', (119, 123))	('facilitating', 'PosReg', (106, 118))	('p53', 'Protein', (171, 174))	('Ser315', 'Chemical', '-', (94, 100))	('phosphorylation', 'MPA', (57, 72))	('Ser315', 'Var', (94, 100))
154484	22396649	A previous report showed that increased expression of Aurora A as a result of genetic mutations increased the growth and survival of HTLV-1-infected T cells.	('expression', 'MPA', (40, 50))	('HTLV-1-infected T', 'Disease', (133, 150))	('increased', 'PosReg', (96, 105))	('HTLV-1-infected T', 'Disease', 'MESH:D006800', (133, 150))	('Aurora A', 'Gene', (54, 62))	('growth', 'CPA', (110, 116))	('genetic mutations', 'Var', (78, 95))	('survival', 'CPA', (121, 129))	('increased', 'PosReg', (30, 39))
154491	22396649	In agreement with the critical role of LANA on Aurora A expression, the evidence have showed that increased transient expression of LANA can upregulate Aurora A expression in a dose-dependent manner, and that knock-down of LANA in KSHV-positive cell lines decreased both the transcript and protein levels of Aurora A.	('Aurora A', 'Gene', (152, 160))	('LANA', 'Gene', '4961527', (132, 136))	('knock-down', 'Var', (209, 219))	('LANA', 'Gene', (39, 43))	('expression', 'MPA', (161, 171))	('LANA', 'Gene', '4961527', (39, 43))	('KSHV', 'Species', '37296', (231, 235))	('LANA', 'Gene', (223, 227))	('LANA', 'Gene', (132, 136))	('upregulate', 'PosReg', (141, 151))	('LANA', 'Gene', '4961527', (223, 227))	('decreased', 'NegReg', (256, 265))
154495	22396649	For example, phosphorylation of Ser362/366 by NF-kappaB induces p53 degradation.	('NF-kappaB', 'Gene', (46, 55))	('Ser362', 'Chemical', '-', (32, 38))	('phosphorylation', 'Var', (13, 28))	('induces', 'Reg', (56, 63))	('p53 degradation', 'MPA', (64, 79))	('Ser362/366', 'Var', (32, 42))
154496	22396649	In regards to the effect of Aurora A-induced phosphorylation of p53, Aurora A is able to induce Mdm2-mediated p53 degradation by phosphorylating Ser315, and abrogate the DNA binding and transactivation activity of p53 by phosphorylating Ser215 not Ser315.	('Mdm2', 'Gene', '4193', (96, 100))	('induce', 'PosReg', (89, 95))	('Ser215', 'Chemical', '-', (237, 243))	('degradation', 'MPA', (114, 125))	('Ser315', 'Chemical', '-', (145, 151))	('DNA binding', 'Interaction', (170, 181))	('abrogate', 'NegReg', (157, 165))	('Mdm2', 'Gene', (96, 100))	('transactivation activity', 'MPA', (186, 210))	('Aurora A', 'Var', (69, 77))	('Ser215', 'Var', (237, 243))	('p53', 'Gene', (214, 217))	('Ser315', 'Chemical', '-', (248, 254))
154497	22396649	Although this is somehow controversial, these reports implicate that p53 is a physiological substrate of Aurora A and that Aurora A may exert its regulatory functions on p53 through phosphorylation of Ser215 and Ser315 in different cell types.	('regulatory', 'MPA', (146, 156))	('Ser215', 'Var', (201, 207))	('Ser315', 'Chemical', '-', (212, 218))	('phosphorylation', 'MPA', (182, 197))	('p53', 'Gene', (170, 173))	('Ser315', 'Var', (212, 218))	('Ser215', 'Chemical', '-', (201, 207))
154498	22396649	Our data showed that mutation of p53 at Ser315 dramatically reduced LANA-mediated ubiquitylation of p53 in the presence of Aurora A.	('LANA', 'Gene', (68, 72))	('mutation', 'Var', (21, 29))	('LANA', 'Gene', '4961527', (68, 72))	('p53', 'Gene', (33, 36))	('reduced', 'NegReg', (60, 67))	('p53', 'Protein', (100, 103))	('Ser315', 'Chemical', '-', (40, 46))
154499	22396649	However, mutation at Ser215 also reversed the inhibition of p53 ubiquitylation induced by LANA.	('mutation', 'Var', (9, 17))	('LANA', 'Gene', '4961527', (90, 94))	('Ser215', 'Chemical', '-', (21, 27))	('inhibition', 'NegReg', (46, 56))	('p53', 'Protein', (60, 63))	('Ser215', 'Var', (21, 27))	('LANA', 'Gene', (90, 94))
154501	22396649	To determine the role of LANA in destabilization of p53 phosphorylated by Aurora A kinase, we compared the effect of wild-type LANA and mutant LANA (DeltaSOCS) lacking the ability to ubiquitinate p53 and showed that the ubiquitination activity of LANA is critical for destabilization of p53 after induction of Aurora A expression.	('LANA', 'Gene', '4961527', (25, 29))	('LANA', 'Gene', (143, 147))	('LANA', 'Gene', (247, 251))	('ubiquitination', 'MPA', (220, 234))	('LANA', 'Gene', (25, 29))	('LANA', 'Gene', (127, 131))	('ubiquitinate', 'MPA', (183, 195))	('SOCS', 'Gene', (154, 158))	('ability', 'MPA', (172, 179))	('LANA', 'Gene', '4961527', (247, 251))	('LANA', 'Gene', '4961527', (127, 131))	('SOCS', 'Gene', '1154', (154, 158))	('LANA', 'Gene', '4961527', (143, 147))	('lacking', 'NegReg', (160, 167))	('mutant', 'Var', (136, 142))
154508	22396649	However, whether Aurora A is directly involved in a complex which contains p53 and LANA to increase their ability to interact remains to be further investigated.	('p53', 'Var', (75, 78))	('interact', 'Interaction', (117, 125))	('ability', 'MPA', (106, 113))	('increase', 'PosReg', (91, 99))	('LANA', 'Gene', (83, 87))	('LANA', 'Gene', '4961527', (83, 87))
154509	22396649	The observation of growth arrest of cells at the G2-M phase after silencing of Aurora A kinase in KSHV positive PEL cells, suggests that degradation of p53 phosphorylated at Ser215 and Ser315, has physiological relevance in allowing progression of normal cell proliferation cycle.	('Ser215', 'Chemical', '-', (174, 180))	('growth arrest', 'Disease', 'MESH:D006323', (19, 32))	('silencing', 'Var', (66, 75))	('growth arrest', 'Disease', (19, 32))	('Ser315', 'Chemical', '-', (185, 191))	('Aurora', 'Gene', (79, 85))	('Ser315', 'Var', (185, 191))	('growth arrest', 'Phenotype', 'HP:0001510', (19, 32))	('KSHV', 'Species', '37296', (98, 102))
154518	22396649	DNA constructs expressing LANA full length and SOCS-box mutant in the pA3M vector were described previously.	('SOCS', 'Gene', '1154', (47, 51))	('SOCS', 'Gene', (47, 51))	('LANA', 'Gene', (26, 30))	('mutant', 'Var', (56, 62))	('LANA', 'Gene', '4961527', (26, 30))
154519	22396649	HA-p53 WT, S215A, S315A and S215A/S315A mutant were a kind gift from Jin Q. Cheng (University of South Florida, Tampa, Florida).	('S315A', 'Var', (18, 23))	('S215A', 'Mutation', 'p.S215A', (11, 16))	('S215A', 'Mutation', 'p.S215A', (28, 33))	('S315A', 'Mutation', 'p.S315A', (34, 39))	('S315A', 'Mutation', 'p.S315A', (18, 23))	('HA-p53', 'Var', (0, 6))	('S215A', 'Var', (11, 16))	('S215A/S315A', 'Var', (28, 39))
154521	22396649	The deleted (DeltaE2F, DeltaEts, DeltaSp1 or DeltaSp1+Ets) mutants of Aurora A promoter are derived from pGL3-pAurora A.	('DeltaSp1', 'Var', (33, 41))	('Aurora', 'Gene', (70, 76))	('DeltaE2F', 'Var', (13, 21))	('pGL3', 'Gene', (105, 109))	('DeltaSp1+Ets', 'Var', (45, 57))	('pGL3', 'Gene', '6391', (105, 109))	('DeltaEts', 'Var', (23, 31))
154540	22396649	Fifteen million BC3 cells were transfected by electroporation (220v, 975 microF, 0.4-cm-gap cuvette) with 20 microg of shLANA (or shLuc).	('220v', 'Var', (63, 67))	('LANA', 'Gene', '4961527', (121, 125))	('LANA', 'Gene', (121, 125))
154553	22396649	MEF cells (15x106) were transfected by electroporation with appropriate combination of plasmids expressing HA-Ub (5 microg), p53-FLAG (or HA-p53) (8 microg), Aurora A-myc (8 microg) and LANA-myc (8 microg).	('LANA', 'Gene', (186, 190))	('LANA', 'Gene', '4961527', (186, 190))	('MEF', 'Gene', '2000', (0, 3))	('MEF', 'Gene', (0, 3))	('p53-FLAG', 'Var', (125, 133))	('HA-p53', 'Var', (138, 144))	('HA-Ub', 'Var', (107, 112))
154562	21255400	We present a rare case of GS of the small bowel, greater omentum and peritoneum, which caused obstruction, in a patient with AML associated with a CBFbeta/MYH11 fusion gene and an inv(16) (p13q22).	('AML', 'Disease', 'MESH:D015470', (125, 128))	('MYH11', 'Gene', '4629', (155, 160))	('GS of the small bowel', 'Disease', 'MESH:D011125', (26, 47))	('patient', 'Species', '9606', (112, 119))	('CBFbeta', 'Gene', (147, 154))	('AML', 'Disease', (125, 128))	('AML', 'Phenotype', 'HP:0004808', (125, 128))	('MYH11', 'Gene', (155, 160))	('GS of the small bowel', 'Disease', (26, 47))	('fusion gene', 'Var', (161, 172))	('CBFbeta', 'Gene', '865', (147, 154))
154563	21255400	In this patient there was only mild myeloid hyperplasia in bone marrow aspiration but molecular analysis identified a CBFbeta-MYH11 fusion and inv(16) (p13;q22).	('myeloid hyperplasia', 'Disease', (36, 55))	('myeloid hyperplasia', 'Disease', 'MESH:D006965', (36, 55))	('inv(16) (p13;q22', 'Var', (143, 159))	('MYH11', 'Gene', (126, 131))	('aspiration', 'Phenotype', 'HP:0002835', (71, 81))	('CBFbeta', 'Gene', '865', (118, 125))	('MYH11', 'Gene', '4629', (126, 131))	('patient', 'Species', '9606', (8, 15))	('CBFbeta', 'Gene', (118, 125))	('fusion', 'Var', (132, 138))
154579	21255400	In cases previously reported to involve the small bowel or its mesentery there has been an association with inv(16) or the CBFbeta/MYH11 fusion gene or both.	('CBFbeta', 'Gene', (123, 130))	('MYH11', 'Gene', '4629', (131, 136))	('inv(16', 'Gene', (108, 114))	('small bowel', 'Disease', 'MESH:D015212', (44, 55))	('MYH11', 'Gene', (131, 136))	('fusion gene', 'Var', (137, 148))	('CBFbeta', 'Gene', '865', (123, 130))	('association', 'Interaction', (91, 102))	('small bowel', 'Disease', (44, 55))
154589	21255400	Immunohistochemistry study revealed positivity for myeloperoxidase (MPO) and CD68.	('myeloperoxidase', 'Gene', (51, 66))	('myeloperoxidase', 'Gene', '4353', (51, 66))	('MPO', 'Gene', '4353', (68, 71))	('CD68', 'Gene', (77, 81))	('CD68', 'Gene', '968', (77, 81))	('positivity', 'Var', (36, 46))	('MPO', 'Gene', (68, 71))
154618	21255400	The patient reported here is one of the rare cases in which abdominal GS coincided with the onset of AML type FAB-M2 associated with a CBFbeta/MYH11 fusion and inv(16) (p13;q22).	('abdominal GS', 'Disease', (60, 72))	('abdominal GS', 'Disease', 'MESH:D011125', (60, 72))	('AML', 'Disease', 'MESH:D015470', (101, 104))	('associated', 'Reg', (117, 127))	('MYH11', 'Gene', (143, 148))	('AML', 'Phenotype', 'HP:0004808', (101, 104))	('AML', 'Disease', (101, 104))	('patient', 'Species', '9606', (4, 11))	('CBFbeta', 'Gene', '865', (135, 142))	('MYH11', 'Gene', '4629', (143, 148))	('inv(16) (p13;q22', 'Var', (160, 176))	('CBFbeta', 'Gene', (135, 142))
154630	21255400	Specific cytogenetic abnormalities most frequently associated with GS include t(8;21) and inv(16) (p13;q22).	('associated', 'Reg', (51, 61))	('t(8;21', 'Var', (78, 84))	('GS', 'Disease', 'MESH:D011125', (67, 69))	('inv(16) (p13;q22', 'Var', (90, 106))
154633	21255400	This fact was demonstrated in the current case report, where the patient showed only mild myeloid hyperplasia in bone marrow aspiration but molecular analysis identified a CBFbeta-MYH11 fusion and inv(16) (p13;q22).	('MYH11', 'Gene', '4629', (180, 185))	('aspiration', 'Phenotype', 'HP:0002835', (125, 135))	('CBFbeta', 'Gene', (172, 179))	('MYH11', 'Gene', (180, 185))	('patient', 'Species', '9606', (65, 72))	('myeloid hyperplasia', 'Disease', (90, 109))	('fusion', 'Var', (186, 192))	('myeloid hyperplasia', 'Disease', 'MESH:D006965', (90, 109))	('inv(16) (p13;q22', 'Var', (197, 213))	('CBFbeta', 'Gene', '865', (172, 179))
154645	21255400	Activating FLT3 mutations occur in approximately 40% of cytogenetically normal AML patients and the most frequent activating mutations is FLT3-ITD, whose presence is associated with resistence to chemotherapy and inferior outcome.	('AML', 'Disease', (79, 82))	('mutations', 'Var', (125, 134))	('Activating', 'PosReg', (0, 10))	('AML', 'Phenotype', 'HP:0004808', (79, 82))	('FLT3', 'Gene', (138, 142))	('FLT3', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('patients', 'Species', '9606', (83, 91))	('FLT3', 'Gene', '2322', (138, 142))	('FLT3', 'Gene', '2322', (11, 15))
154647	21255400	We describe a rare case of abdominal GS in a patient with AML associated with a CBFbeta/MYH11 fusion and inv(16) (p13q22).	('associated', 'Reg', (62, 72))	('AML', 'Disease', 'MESH:D015470', (58, 61))	('MYH11', 'Gene', '4629', (88, 93))	('abdominal GS', 'Disease', (27, 39))	('abdominal GS', 'Disease', 'MESH:D011125', (27, 39))	('CBFbeta', 'Gene', '865', (80, 87))	('patient', 'Species', '9606', (45, 52))	('fusion', 'Var', (94, 100))	('CBFbeta', 'Gene', (80, 87))	('AML', 'Phenotype', 'HP:0004808', (58, 61))	('AML', 'Disease', (58, 61))	('MYH11', 'Gene', (88, 93))
154714	32850366	In the largest phase III trial conducted for adult sarcomas, pazopanib reduced the risk of progression or death compared to placebo; main reported toxicities were fatigue, hypertension, anorexia, and diarrhea.	('anorexia', 'Disease', 'MESH:D000855', (186, 194))	('toxicities', 'Disease', 'MESH:D064420', (147, 157))	('hypertension', 'Disease', 'MESH:D006973', (172, 184))	('hypertension', 'Disease', (172, 184))	('toxicities', 'Disease', (147, 157))	('death', 'Disease', 'MESH:D003643', (106, 111))	('fatigue', 'Disease', (163, 170))	('anorexia', 'Phenotype', 'HP:0002039', (186, 194))	('fatigue', 'Phenotype', 'HP:0012378', (163, 170))	('reduced', 'NegReg', (71, 78))	('diarrhea', 'Phenotype', 'HP:0002014', (200, 208))	('hypertension', 'Phenotype', 'HP:0000822', (172, 184))	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcomas', 'Disease', (51, 59))	('pazopanib', 'Var', (61, 70))	('anorexia', 'Disease', (186, 194))	('diarrhea', 'Disease', (200, 208))	('fatigue', 'Disease', 'MESH:D005221', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('death', 'Disease', (106, 111))	('diarrhea', 'Disease', 'MESH:D003967', (200, 208))	('pazopanib', 'Chemical', 'MESH:C516667', (61, 70))
154715	32850366	Sporadically, thromboembolic events and left ventricular ejection fraction drop were reported in the pazopanib arm.	('pazopanib', 'Var', (101, 110))	('thromboembolic events', 'Phenotype', 'HP:0001907', (14, 35))	('left ventricular ejection fraction drop', 'Phenotype', 'HP:0005162', (40, 79))	('thromboembolic', 'Disease', 'MESH:D013923', (14, 28))	('drop', 'NegReg', (75, 79))	('pazopanib', 'Chemical', 'MESH:C516667', (101, 110))	('left ventricular ejection fraction', 'MPA', (40, 74))	('thromboembolic', 'Disease', (14, 28))
154780	32850366	Indeed, there are few clinical trials investigating pazopanib in children: one phase II single-agent trial in relapsed/refractory solid tumors, conducted by COG (NCT01956669), results not yet available; one phase I, open-label, multicenter trial testing pazopanib in combination with irinotecan and temozolomide in children and young adults with relapsed or refractory sarcoma (NCT03139331) and still recruiting.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('children', 'Species', '9606', (65, 73))	('irinotecan', 'Chemical', 'MESH:D000077146', (284, 294))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('sarcoma', 'Disease', 'MESH:D012509', (369, 376))	('pazopanib', 'Chemical', 'MESH:C516667', (254, 263))	('temozolomide', 'Chemical', 'MESH:D000077204', (299, 311))	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('sarcoma', 'Disease', (369, 376))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (369, 376))	('children', 'Species', '9606', (315, 323))	('NCT03139331', 'Var', (378, 389))
154800	32180983	Herein, we report a case of ASPS in a 20-year-old female, presenting with vaginal bleeding and profound anemia secondary to a lower uterine segment polyp that was later histologically proven to be ASPS.	('polyp', 'Var', (148, 153))	('ASPS', 'Disease', 'MESH:D018234', (28, 32))	('anemia', 'Disease', 'MESH:D000740', (104, 110))	('vaginal bleeding', 'Disease', (74, 90))	('ASPS', 'Disease', (197, 201))	('ASPS', 'Disease', 'MESH:D018234', (197, 201))	('anemia', 'Phenotype', 'HP:0001903', (104, 110))	('ASPS', 'Phenotype', 'HP:0012218', (197, 201))	('vaginal bleeding', 'Disease', 'MESH:D014592', (74, 90))	('ASPS', 'Disease', (28, 32))	('ASPS', 'Phenotype', 'HP:0012218', (28, 32))	('anemia', 'Disease', (104, 110))
154807	32180983	Fluorescence in-situ hybridization (FISH) studies showed evidence of TFE-3 and ASPSCR1 gene rearrangements.	('TFE-3', 'Gene', '7030', (69, 74))	('TFE-3', 'Gene', (69, 74))	('ASPS', 'Disease', 'MESH:D018234', (79, 83))	('ASPS', 'Phenotype', 'HP:0012218', (79, 83))	('rearrangements', 'Var', (92, 106))	('ASPS', 'Disease', (79, 83))
154840	28465589	We previously described peptide antagonists of the uPAR-FPR1 interaction that inhibited cell migration and angiogenesis.	('inhibited', 'NegReg', (78, 87))	('uPAR-FPR1', 'Gene', (51, 60))	('peptide', 'Var', (24, 31))	('cell migration', 'CPA', (88, 102))	('rat', 'Species', '10116', (96, 99))	('interaction', 'Interaction', (61, 72))	('peptide', 'Chemical', 'MESH:D010455', (24, 31))	('angiogenesis', 'CPA', (107, 119))
154849	28465589	When cell migration is deregulated, it contributes to numerous disorders including tumor metastasis, chronic inflammation, and vascular disease.	('vascular disease', 'Disease', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('deregulated', 'Var', (23, 34))	('numerous disorders', 'Disease', 'MESH:D030342', (54, 72))	('numerous disorders', 'Disease', (54, 72))	('inflammation', 'Disease', 'MESH:D007249', (109, 121))	('contributes to', 'Reg', (39, 53))	('vascular disease', 'Disease', 'MESH:D000783', (127, 143))	('tumor metastasis', 'Disease', 'MESH:D009362', (83, 99))	('tumor metastasis', 'Disease', (83, 99))	('rat', 'Species', '10116', (13, 16))	('inflammation', 'Disease', (109, 121))	('cell migration', 'CPA', (5, 19))
154855	28465589	The clinical relevance of uPAR as a prognostic marker in human cancers is well documented, and high levels of soluble uPAR in serum are associated with poor prognosis and increased risk of metastasis.	('human', 'Species', '9606', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('poor prognosis', 'CPA', (152, 166))	('cancers', 'Disease', 'MESH:D009369', (63, 70))	('high levels', 'Var', (95, 106))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('metastasis', 'CPA', (189, 199))	('uPAR', 'Gene', (118, 122))
154862	28465589	In the form of a synthetic peptide, the minimal 88-92 sequence (Ser88-Arg-Ser-Arg-Tyr92, SRSRY) retains chemotactic activity and triggers directional cell migration and angiogenesis in vitro and in vivo .	('triggers', 'PosReg', (129, 137))	('Ser88-Arg-Ser-Arg-Tyr92', 'Var', (64, 87))	('Tyr92', 'Chemical', '-', (82, 87))	('angiogenesis', 'CPA', (169, 181))	('Arg', 'Chemical', 'MESH:D001120', (70, 73))	('chemotactic activity', 'MPA', (104, 124))	('directional cell migration', 'CPA', (138, 164))	('Arg', 'Chemical', 'MESH:D001120', (78, 81))	('Ser88-Arg', 'Mutation', 'rs1206748975', (64, 73))	('rat', 'Species', '10116', (158, 161))	('peptide', 'Chemical', 'MESH:D010455', (27, 34))	('Ser', 'Chemical', 'MESH:D012694', (74, 77))	('Ser', 'Chemical', 'MESH:D012694', (64, 67))
154864	28465589	Recently, we found that cyclized SRSRY had an opposite effect on cell migration, as compared to its linear form, and inhibited fMLF-induced monocyte locomotion with an IC50 value of 10 pM as well as neovascularization and intravasation of osteosarcoma cells.	('intravasation', 'CPA', (222, 235))	('osteosarcoma', 'Disease', 'MESH:D012516', (239, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('cell migration', 'CPA', (65, 79))	('cyclized', 'Var', (24, 32))	('fMLF-induced', 'Gene', (127, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (239, 251))	('inhibited', 'NegReg', (117, 126))	('osteosarcoma', 'Disease', (239, 251))	('neovascularization', 'CPA', (199, 217))	('rat', 'Species', '10116', (73, 76))
154869	28465589	We previously showed that the substitution of Ser90 with Glu in the chemotactic sequence uPAR84-95 prevents agonist-triggered FPR1 activation and internalization.	('agonist-triggered', 'MPA', (108, 125))	('prevents', 'NegReg', (99, 107))	('substitution', 'Var', (30, 42))	('Ser90 with Glu', 'Mutation', 'p.S90E', (46, 60))	('internalization', 'MPA', (146, 161))	('activation', 'MPA', (131, 141))	('FPR1', 'Protein', (126, 130))
154875	28465589	When the interaction of the parent peptide with its receptor is dominated by side-chain interactions, the biological activity of the RI analog can be maintained, while the all-D amino acid composition ensures stability to proteases.	('biological activity', 'MPA', (106, 125))	('RI', 'Chemical', '-', (133, 135))	('D', 'Chemical', 'MESH:D003903', (176, 177))	('side-chain', 'Var', (77, 87))	('interaction', 'Interaction', (9, 20))	('peptide', 'Chemical', 'MESH:D010455', (35, 42))	('stability', 'MPA', (209, 218))
154876	28465589	However, inversion of the amide backbone may result in loss of key main chain hydrogen bonds, and the conformational preferences of the parent and RI peptides may be different.	('loss', 'NegReg', (55, 59))	('hydrogen', 'Chemical', 'MESH:D006859', (78, 86))	('RI', 'Chemical', '-', (147, 149))	('peptide', 'Chemical', 'MESH:D010455', (150, 157))	('amide', 'Chemical', 'MESH:D000577', (26, 31))	('key main chain hydrogen bonds', 'MPA', (63, 92))	('inversion', 'Var', (9, 18))
154883	28465589	In a total RI modification, all the amide bonds are reversed, while in a partially modified RI analog only some of the amide bonds are inverted.	('RI', 'Chemical', '-', (92, 94))	('reversed', 'Reg', (52, 60))	('RI', 'Chemical', '-', (11, 13))	('amide', 'Chemical', 'MESH:D000577', (36, 41))	('amide', 'Chemical', 'MESH:D000577', (119, 124))	('modification', 'Var', (14, 26))	('amide bonds', 'MPA', (36, 47))
154884	28465589	When the interaction of the parent peptide with its receptor occurs mainly through side-chain interactions, the biological activity of the RI analog should be maintained, while the all-D-amino acid composition ensures stability to proteases.	('D', 'Chemical', 'MESH:D003903', (185, 186))	('side-chain interactions', 'Var', (83, 106))	('biological activity', 'MPA', (112, 131))	('interaction', 'Interaction', (9, 20))	('RI', 'Chemical', '-', (139, 141))	('stability', 'MPA', (218, 227))	('peptide', 'Chemical', 'MESH:D010455', (35, 42))
154886	28465589	We designed RI tetrapeptide antagonists of the uPAR/FPR1 interaction (Table 1) using the structure-activity relationship derived from previously described tetrapeptides, in particular Ac-Arg-X1-Arg-X2-NH2 (X1 = Glu, Ser, X2 = Tyr, Phe, Trp), and Ac-Arg-Aib-Arg-Phe-NH2 .	('Ac-Arg-X1-Arg-X2-NH2', 'Var', (184, 204))	('Ac-Arg', 'Chemical', '-', (246, 252))	('Arg', 'Chemical', 'MESH:D001120', (249, 252))	('Arg', 'Chemical', 'MESH:D001120', (194, 197))	('Phe', 'Chemical', 'MESH:D010649', (231, 234))	('Aib', 'Gene', '116833', (253, 256))	('peptide', 'Chemical', 'MESH:D010455', (20, 27))	('Tyr', 'Chemical', 'MESH:D014443', (226, 229))	('Phe', 'Chemical', 'MESH:D010649', (261, 264))	('Trp', 'Chemical', 'MESH:D014364', (236, 239))	('Ser', 'Chemical', 'MESH:D012694', (216, 219))	('peptide', 'Chemical', 'MESH:D010455', (160, 167))	('Glu', 'Chemical', 'MESH:D018698', (211, 214))	('RI', 'Chemical', '-', (12, 14))	('Ac-Arg', 'Chemical', '-', (184, 190))	('NH2', 'Chemical', '-', (265, 268))	('Arg', 'Chemical', 'MESH:D001120', (187, 190))	('NH2', 'Chemical', '-', (201, 204))	('Aib', 'Gene', (253, 256))	('X2', 'Chemical', '-', (221, 223))	('Arg', 'Chemical', 'MESH:D001120', (257, 260))	('X2', 'Chemical', '-', (198, 200))
154896	28465589	The peptides RI-1, RI-2, RI-3, RI-4 and RI-5 reduced cell migration by 33%, 29%, 57%, 37% and 28%, respectively.	('RI-3', 'Chemical', '-', (25, 29))	('reduced', 'NegReg', (45, 52))	('RI-4', 'Var', (31, 35))	('RI-1', 'Var', (13, 17))	('RI', 'Chemical', '-', (13, 15))	('RI-3', 'Var', (25, 29))	('RI-5', 'Var', (40, 44))	('RI', 'Chemical', '-', (25, 27))	('RI', 'Chemical', '-', (31, 33))	('rat', 'Species', '10116', (61, 64))	('cell migration', 'CPA', (53, 67))	('RI-2', 'Var', (19, 23))	('RI', 'Chemical', '-', (40, 42))	('peptide', 'Chemical', 'MESH:D010455', (4, 11))	('RI', 'Chemical', '-', (19, 21))
154900	28465589	2c, RI-1, RI-2, RI-3, RI-4 and RI-5 reduced the extent of cell invasion by 27%, 23%, 51%, 23% and 9%, respectively.	('RI-5', 'Var', (31, 35))	('RI-3', 'Var', (16, 20))	('RI-2', 'Var', (10, 14))	('RI', 'Chemical', '-', (31, 33))	('RI-1', 'Var', (4, 8))	('RI', 'Chemical', '-', (4, 6))	('RI', 'Chemical', '-', (10, 12))	('reduced', 'NegReg', (36, 43))	('RI-4', 'Var', (22, 26))	('RI-3', 'Chemical', '-', (16, 20))	('RI', 'Chemical', '-', (16, 18))	('RI', 'Chemical', '-', (22, 24))
154910	28465589	The latter shows a stable turn structure, with the typical beta-turn H-bond between the CO of the first residue (D-Tyr1) and the NH of the fourth residue (D-Arg4).	('CO', 'Chemical', 'MESH:D002248', (88, 90))	('D-Tyr1', 'Chemical', '-', (113, 119))	('D-Tyr1', 'Var', (113, 119))	('beta-turn H-bond', 'MPA', (59, 75))	('D-Arg4', 'Chemical', '-', (155, 161))
154932	28465589	The addition of 10 nM RI-3 for 10 min caused a reduction in p38alpha(T180/Y182), ERK1/2(T202/Y204/T185/Y187), Akt(S473), CREB(S133), Fgr(Y412) and FAK(Y397) (21%, 25%, 22%, 42%, 43% and 30%, respectively, Supplementary Fig.	('RI-3', 'Chemical', '-', (22, 26))	('Fgr', 'Gene', (133, 136))	('ERK1/2', 'Gene', '5595;5594', (81, 87))	('p38alpha', 'Gene', '1432', (60, 68))	('reduction', 'NegReg', (47, 56))	('S473', 'Var', (114, 118))	('FAK', 'Gene', (147, 150))	('FAK', 'Gene', '5747', (147, 150))	('CREB', 'Gene', (121, 125))	('Fgr', 'Gene', '2268', (133, 136))	('p38alpha', 'Gene', (60, 68))	('ERK1/2', 'Gene', (81, 87))	('CREB', 'Gene', '1385', (121, 125))
154934	28465589	They also suggest that p38 MAPK and PI3K/AKT signaling cascades, which are documented to mediated fMLF-triggered signal transduction pathways, are affected by RI-3.	('p38', 'Gene', '5594', (23, 26))	('MAPK', 'Gene', (27, 31))	('affected', 'Reg', (147, 155))	('MAPK', 'Gene', '5595;5594;5595', (27, 31))	('AKT', 'Gene', '207', (41, 44))	('RI-3', 'Chemical', '-', (159, 163))	('p38', 'Gene', (23, 26))	('RI-3', 'Var', (159, 163))	('AKT', 'Gene', (41, 44))
154949	28465589	Interestingly, RI-3 reduced Saos-2 matrigel invasion by 24% only (Fig.	('RI-3', 'Var', (15, 19))	('Saos-2 matrigel invasion', 'CPA', (28, 52))	('reduced', 'NegReg', (20, 27))	('RI-3', 'Chemical', '-', (15, 19))
154951	28465589	We have previously shown that, upon exposure to uPAR84-95, endothelial cells form cord-like structures on matrigel and that peptide inhibitors of the uPAR/FPR1 interaction inhibit angiogenesis in vitro and in vivo .	('angiogenesis', 'CPA', (180, 192))	('uPAR/FPR1', 'Gene', (150, 159))	('cord-like structures on', 'CPA', (82, 105))	('uPAR84-95', 'Var', (48, 57))	('inhibit', 'NegReg', (172, 179))	('interaction', 'Interaction', (160, 171))	('peptide', 'Chemical', 'MESH:D010455', (124, 131))
154956	28465589	In agreement with previous data, both FBS or VEGF165 elicited morphological differentiation of endothelial cells into an extensive network of capillary-like structures, consisting of highly organized three-dimensional cords reaching 352% and 620%, respectively, above basal.	('VEGF', 'Gene', '7422', (45, 49))	('morphological differentiation', 'CPA', (62, 91))	('FBS', 'Var', (38, 41))	('elicited', 'Reg', (53, 61))	('VEGF', 'Gene', (45, 49))
154963	28465589	These data indicate that RI-3 prevents the attachment of tumor cells, and suggest that RI-3 may also reduce trans-endothelial migration of tumor cells.	('RI-3', 'Chemical', '-', (25, 29))	('reduce', 'NegReg', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('RI-3', 'Chemical', '-', (87, 91))	('rat', 'Species', '10116', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('prevents', 'NegReg', (30, 38))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('RI-3', 'Var', (87, 91))	('attachment', 'CPA', (43, 53))	('tumor', 'Disease', (57, 62))
154988	28465589	Although we cannot exclude that the RI-3-dependent decrease in CTC number may also depend on reduction of intra-tumoral vascularization, these findings indicate that RI-3 prevents three key events occurring during the metastatic process of sarcoma cells: extracellular matrix invasion, formation of a capillary network and entry into blood and lymph vessels.	('sarcoma', 'Disease', (240, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('extracellular matrix invasion', 'CPA', (255, 284))	('prevents', 'NegReg', (171, 179))	('intra-tumoral', 'Disease', 'MESH:D009369', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('RI-3', 'Chemical', '-', (166, 170))	('RI-3', 'Chemical', '-', (36, 40))	('sarcoma', 'Disease', 'MESH:D012509', (240, 247))	('intra-tumoral', 'Disease', (106, 119))	('RI-3', 'Var', (166, 170))
154992	28465589	The kinetics of tumor formation in vehicle-treated mice was faster than in mice treated with RI-3- or RERF (Fig.	('mice', 'Species', '10090', (75, 79))	('mice', 'Species', '10090', (51, 55))	('RI-3-', 'Var', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('RI-3', 'Chemical', '-', (93, 97))	('tumor', 'Disease', (16, 21))
154995	28465589	In keeping with its better stability in vitro, RI-3 reduced tumor growth more efficiently than RERF, although the differences between the two treated groups were not significant.	('RI-3', 'Var', (47, 51))	('reduced', 'NegReg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('RI-3', 'Chemical', '-', (47, 51))	('tumor', 'Disease', (60, 65))
155011	28465589	We found that the substitution of Ser90 with Glu prevented agonist-triggered FPR1 activation and internalization, and potently inhibited uPAR activity.	('uPAR activity', 'MPA', (137, 150))	('activation', 'MPA', (82, 92))	('Glu', 'Protein', (45, 48))	('inhibited', 'NegReg', (127, 136))	('FPR1', 'Gene', (77, 81))	('agonist-triggered', 'MPA', (59, 76))	('Ser90', 'Var', (34, 39))	('internalization', 'MPA', (97, 112))	('prevented', 'NegReg', (49, 58))	('Ser90 with Glu', 'Mutation', 'p.S90E', (34, 48))	('substitution', 'Var', (18, 30))
155012	28465589	Moreover, short synthetic peptides corresponding to the hinge region could recapitulate the activity of the whole receptor: (i) Ser88-Arg-Ser-Arg-Tyr92, SRSRY, within the sequence of uPAR84-95, showed chemotactic and angiogenic cell activity in vitro and in vivo , and (ii) introduction of the Ser90Glu mutation in the synthetic peptides mimicked the uPARS90E mutants, yielding antagonists of the FPR1 activation that prevented cell migration and angiogenesis.	('FPR1', 'Gene', (397, 401))	('peptide', 'Chemical', 'MESH:D010455', (329, 336))	('chemotactic', 'CPA', (201, 212))	('angiogenesis', 'CPA', (447, 459))	('rat', 'Species', '10116', (436, 439))	('peptide', 'Chemical', 'MESH:D010455', (26, 33))	('Ser', 'Chemical', 'MESH:D012694', (138, 141))	('prevented', 'NegReg', (418, 427))	('Ser88-Arg', 'Mutation', 'rs1206748975', (128, 137))	('Arg', 'Chemical', 'MESH:D001120', (142, 145))	('Ser90Glu', 'SUBSTITUTION', 'None', (294, 302))	('Ser', 'Chemical', 'MESH:D012694', (128, 131))	('cell migration', 'CPA', (428, 442))	('Ser88-Arg-Ser-Arg-Tyr92', 'Var', (128, 151))	('Tyr92', 'Chemical', '-', (146, 151))	('Arg', 'Chemical', 'MESH:D001120', (134, 137))	('Ser', 'Chemical', 'MESH:D012694', (294, 297))	('uPARS90E', 'Var', (351, 359))	('Ser90Glu', 'Var', (294, 302))
155020	28465589	RI-3 prevents three key steps of the metastatic process: (i) invasion of the extracellular matrix, (ii) entry of tumor cells into blood, and (iii) formation of a capillary network.	('RI-3', 'Chemical', '-', (0, 4))	('tumor', 'Disease', (113, 118))	('RI-3', 'Var', (0, 4))	('invasion of the extracellular matrix', 'CPA', (61, 97))	('metastatic process', 'CPA', (37, 55))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('entry', 'CPA', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
155027	28465589	Accordingly, RI-3 does not elicit any cell response by itself, but prevents in vitro the activation of p38 MAPK and PI3K/AKT signaling cascades, which are known to mediate fMLF-triggered signal transduction pathways.	('RI-3', 'Var', (13, 17))	('prevents', 'NegReg', (67, 75))	('p38', 'Gene', (103, 106))	('AKT', 'Gene', (121, 124))	('MAPK', 'Gene', (107, 111))	('p38', 'Gene', '5594', (103, 106))	('MAPK', 'Gene', '5595;5594;5595', (107, 111))	('AKT', 'Gene', '207', (121, 124))	('RI-3', 'Chemical', '-', (13, 17))
155064	28465589	Western blot analysis of AKT phosphorylation was performed as previously described using anti-phospho-Akt (Ser473) (pAKT) Ab (Cell Signaling) and anti-Akt mAb (R&D System).	('AKT', 'Gene', (25, 28))	('AKT', 'Gene', '207', (117, 120))	('D', 'Chemical', 'MESH:D003903', (162, 163))	('AKT', 'Gene', (117, 120))	('anti-phospho-Akt', 'Var', (89, 105))	('AKT', 'Gene', '207', (25, 28))	('anti-Akt', 'Var', (146, 154))	('Ser473', 'Chemical', '-', (107, 113))
155094	28465589	K.B., V.I., S.C., G.B., C.R., M.M., M.L.M., D.R., and G.S.	('D', 'Chemical', 'MESH:D003903', (44, 45))	('M.L.M.', 'Var', (36, 42))	('M.M.', 'Var', (30, 34))
155134	27852056	found that inhibition of TLE1 altered cancer cell proliferation and apoptosis through suppression of Bcl-2 expression.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('suppression', 'NegReg', (86, 97))	('Bcl-2', 'Gene', (101, 106))	('Bcl-2', 'Gene', '596', (101, 106))	('apoptosis', 'CPA', (68, 77))	('expression', 'MPA', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('inhibition', 'Var', (11, 21))	('cancer', 'Disease', (38, 44))	('TLE1', 'Gene', (25, 29))
155135	27852056	Moreover, knockdown of TLE1 in fibroblasts and synovial cells did not enhance the cytotoxicity of doxorubicin.	('cytotoxicity', 'Disease', (82, 94))	('doxorubicin', 'Chemical', 'MESH:D004317', (98, 109))	('TLE1', 'Gene', (23, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('knockdown', 'Var', (10, 19))
155139	27852056	Additionally, TLE1 deficiency resulted in enhanced tumor growth.	('TLE1', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('deficiency', 'Var', (19, 29))	('enhanced', 'PosReg', (42, 50))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
155150	27852056	Interestingly, in hematologic malignancies such as diffuse large B-cell lymphoma and acute myeloid leukemia, reintroduction of TLE1 into hypermethylated leukemia or lymphoma cells resulted in growth inhibition in vitro and in vivo.	('leukemia', 'Disease', 'MESH:D007938', (99, 107))	('lymphoma', 'Disease', (165, 173))	('leukemia', 'Disease', (99, 107))	('lymphoma', 'Disease', 'MESH:D008223', (165, 173))	('TLE1', 'Gene', (127, 131))	('leukemia', 'Disease', (153, 161))	('leukemia', 'Disease', 'MESH:D007938', (153, 161))	('acute myeloid leukemia', 'Disease', (85, 107))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (91, 107))	('growth', 'MPA', (192, 198))	('reintroduction', 'Var', (109, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (165, 173))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (85, 107))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (85, 107))	('hematologic malignancies', 'Disease', (18, 42))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (65, 80))	('lymphoma', 'Disease', (72, 80))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))	('lymphoma', 'Disease', 'MESH:D008223', (72, 80))	('hematologic malignancies', 'Disease', 'MESH:D019337', (18, 42))
155151	27852056	Conversely, depletion of TLE1 in unmethylated cells by shRNA enhanced tumor growth, indicating epigenetic inactivation of TLE1 promoted the development of hematologic malignancies by disrupting cell differentiation and growth-suppressive pathways.	('hematologic malignancies', 'Disease', (155, 179))	('epigenetic inactivation', 'Var', (95, 118))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('enhanced', 'PosReg', (61, 69))	('development', 'CPA', (140, 151))	('depletion', 'MPA', (12, 21))	('growth-suppressive', 'CPA', (219, 237))	('tumor', 'Disease', (70, 75))	('promoted', 'PosReg', (127, 135))	('cell differentiation', 'CPA', (194, 214))	('hematologic malignancies', 'Disease', 'MESH:D019337', (155, 179))	('TLE1', 'Gene', (122, 126))	('disrupting', 'NegReg', (183, 193))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
155157	27852056	Inhibition of TLE1 function may prevent cancer cell self-renewal resulting in decreased tumor burden.	('TLE1', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('decreased', 'NegReg', (78, 87))	('cancer', 'Disease', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Inhibition', 'Var', (0, 10))	('prevent', 'NegReg', (32, 39))	('tumor', 'Disease', (88, 93))
155161	27852056	Intriguingly, inhibition of FOXG1 and TLE1 reduced the growth of brain tumor-initiating cells (BTICs), indicating that both proteins regulate glioblastoma development and progression.	('brain tumor', 'Disease', 'MESH:D001932', (65, 76))	('FOXG1', 'Gene', '2290', (28, 33))	('regulate', 'Reg', (133, 141))	('growth of brain', 'Phenotype', 'HP:0001355', (55, 70))	('growth', 'CPA', (55, 61))	('progression', 'CPA', (171, 182))	('brain tumor', 'Phenotype', 'HP:0030692', (65, 76))	('FOXG1', 'Gene', (28, 33))	('brain tumor', 'Disease', (65, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('glioblastoma', 'Disease', (142, 154))	('glioblastoma', 'Disease', 'MESH:D005909', (142, 154))	('reduced', 'NegReg', (43, 50))	('inhibition', 'Var', (14, 24))	('TLE1', 'Gene', (38, 42))
155169	27852056	found that MicroRNA-657 promotes tumorigenesis in hepatocellular carcinoma by targeting TLE1 through NFkB pathways, which confirms the functions of TLE1 in hepatocellular carcinoma and provides new insight into the potential molecular mechanisms of hepatic carcinogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('targeting', 'Reg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('NFkB pathways', 'Pathway', (101, 114))	('hepatic carcinogenesis', 'Disease', (249, 271))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (156, 180))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (156, 180))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (50, 74))	('TLE1', 'Gene', (88, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('hepatocellular carcinoma', 'Disease', (50, 74))	('hepatocellular carcinoma', 'Disease', (156, 180))	('tumor', 'Disease', (33, 38))	('MicroRNA-657', 'Var', (11, 23))	('promotes', 'PosReg', (24, 32))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (50, 74))	('hepatic carcinogenesis', 'Disease', 'MESH:D063646', (249, 271))
155184	27852056	More recently, they demonstrated that Grg3/TLE3 and Grg1/TLE1 induced monohormonal pancreatic beta-cells while it repressed alpha-cell functions.	('induced', 'PosReg', (62, 69))	('TLE3', 'Gene', (43, 47))	('alpha-cell', 'MPA', (124, 134))	('pancreatic', 'Disease', (83, 93))	('Grg1/TLE1', 'Var', (52, 61))	('TLE3', 'Gene', '7090', (43, 47))	('pancreatic', 'Disease', 'MESH:D010195', (83, 93))
155188	27852056	For example, knockout of TLE3/4 inhibited embryonic stem cell differentiation.	('TLE3', 'Gene', '7090', (25, 29))	('inhibited', 'NegReg', (32, 41))	('knockout', 'Var', (13, 21))	('TLE3', 'Gene', (25, 29))	('embryonic stem cell differentiation', 'CPA', (42, 77))
155213	22567163	Abnormal expression, regulation, or function of TNF receptors have been strongly implicated in autoimmune disease, osteoporosis, and cancer.	('autoimmune disease', 'Disease', (95, 113))	('osteoporosis', 'Phenotype', 'HP:0000939', (115, 127))	('TNF', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('implicated', 'Reg', (81, 91))	('osteoporosis', 'Disease', 'MESH:D010024', (115, 127))	('autoimmune disease', 'Disease', 'MESH:D001327', (95, 113))	('cancer', 'Disease', (133, 139))	('osteoporosis', 'Disease', (115, 127))	('autoimmune disease', 'Phenotype', 'HP:0002960', (95, 113))	('Abnormal', 'Var', (0, 8))	('function', 'MPA', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('regulation', 'MPA', (21, 31))
155310	22567163	Consistent with this, it was recently shown that soluble DR6 is the result of matrix metalloproteinase 14 (MMP-14) cleavage of membrane bound DR6.	('matrix metalloproteinase 14', 'Gene', (78, 105))	('DR6', 'Gene', (142, 145))	('matrix metalloproteinase 14', 'Gene', '4323', (78, 105))	('DR6', 'Gene', '27242', (57, 60))	('MMP-14', 'Gene', (107, 113))	('cleavage', 'Var', (115, 123))	('DR6', 'Gene', (57, 60))	('DR6', 'Gene', '27242', (142, 145))	('MMP-14', 'Gene', '4323', (107, 113))
155316	29099504	Atypical fibroxanthoma and pleomorphic dermal sarcoma harbor frequent NOTCH1/2 and FAT1 mutations and similar DNA copy number alteration profiles Atypical fibroxanthomas and pleomorphic dermal sarcomas are tumors arising in sun-damaged skin of elderly patients.	('NOTCH1/2', 'Gene', (70, 78))	('Atypical fibroxanthoma', 'Disease', 'MESH:D009437', (146, 168))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('mutations', 'Var', (88, 97))	('Atypical fibroxanthoma', 'Disease', 'MESH:D009437', (0, 22))	('FAT1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (9, 53))	('patients', 'Species', '9606', (252, 260))	('tumors', 'Disease', (206, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('Atypical fibroxanthoma', 'Disease', (146, 168))	('Atypical fibroxanthoma', 'Disease', (0, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('fibroxanthomas and pleomorphic dermal sarcomas', 'Disease', 'MESH:D012509', (155, 201))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('FAT1', 'Gene', '2195', (83, 87))	('NOTCH1/2', 'Gene', '4851;4853', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('sun-damaged', 'Phenotype', 'HP:0000992', (224, 235))
155319	29099504	In an analysis of the entire coding region of 341 oncogenes and tumor suppressor genes in 13 atypical fibroxanthomas using an established hybridization-based next-generation sequencing approach, we found that these tumors harbor a large number of mutations.	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Disease', (64, 69))	('fibroxanthomas', 'Disease', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('fibroxanthomas', 'Disease', 'None', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (215, 220))	('mutations', 'Var', (247, 256))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (215, 221))
155320	29099504	Gene alterations were identified in more than half of the analyzed samples in FAT1, NOTCH1/2, CDKN2A, TP53, and the TERT promoter.	('TP53', 'Gene', (102, 106))	('CDKN2A', 'Gene', '1029', (94, 100))	('TERT', 'Gene', (116, 120))	('NOTCH1/2', 'Gene', (84, 92))	('TERT', 'Gene', '7015', (116, 120))	('FAT1', 'Gene', '2195', (78, 82))	('FAT1', 'Gene', (78, 82))	('alterations', 'Var', (5, 16))	('TP53', 'Gene', '7157', (102, 106))	('CDKN2A', 'Gene', (94, 100))	('NOTCH1/2', 'Gene', '4851;4853', (84, 92))
155321	29099504	The presence of these alterations was verified in 26 atypical fibroxanthoma and 35 pleomorphic dermal sarcoma samples by targeted amplicon-based next-generation sequencing.	('fibroxanthoma', 'Disease', 'None', (62, 75))	('alterations', 'Var', (22, 33))	('fibroxanthoma', 'Disease', (62, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (83, 109))	('pleomorphic dermal sarcoma', 'Disease', (83, 109))
155323	29099504	Activating RAS mutations (G12 and G13) identified in 3 pleomorphic dermal sarcoma were not found in atypical fibroxanthoma.	('fibroxanthoma', 'Disease', 'None', (109, 122))	('G13', 'Var', (34, 37))	('Activating', 'PosReg', (0, 10))	('pleomorphic dermal sarcoma', 'Disease', (55, 81))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (55, 81))	('G12', 'Var', (26, 29))	('fibroxanthoma', 'Disease', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
155324	29099504	Comprehensive DNA copy number analysis demonstrated a wide array of different copy number gains and losses, with similar profiles in atypical fibroxanthoma and pleomorphic dermal sarcoma.	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (142, 186))	('losses', 'NegReg', (100, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('gains', 'PosReg', (90, 95))	('copy number', 'Var', (78, 89))
155325	29099504	In summary, atypical fibroxanthoma and pleomorphic dermal sarcoma are highly mutated tumors with recurrent mutations in FAT1, NOTCH1/2, CDKN2A, TP53, and the TERT promoter, and a range of DNA copy number alterations.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('NOTCH1/2', 'Gene', '4851;4853', (126, 134))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (21, 65))	('TERT', 'Gene', (158, 162))	('TERT', 'Gene', '7015', (158, 162))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('FAT1', 'Gene', '2195', (120, 124))	('NOTCH1/2', 'Gene', (126, 134))	('FAT1', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('tumors', 'Disease', (85, 91))
155346	29099504	Previous smaller studies identified UV-signature mutations in TP53 in atypical fibroxanthoma (7/10 (ref.)	('TP53', 'Gene', '7157', (62, 66))	('mutations', 'Var', (49, 58))	('fibroxanthoma', 'Disease', 'None', (79, 92))	('TP53', 'Gene', (62, 66))	('fibroxanthoma', 'Disease', (79, 92))
155349	29099504	We have reported high frequencies of TERT promoter mutations in atypical fibroxanthoma and pleomorphic dermal sarcoma.	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (73, 117))	('mutations', 'Var', (51, 60))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))
155350	29099504	A recent study of 5 atypical fibroxanthoma and 5 pleomorphic dermal sarcoma demonstrated frequent TP53 mutations, as well as individual CDKN2A, HRAS, KNSTRN, and PIK3CA gene mutations.	('PIK3CA', 'Gene', '5290', (162, 168))	('mutations', 'Var', (103, 112))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (49, 75))	('HRAS', 'Gene', (144, 148))	('fibroxanthoma', 'Disease', (29, 42))	('KNSTRN', 'Gene', (150, 156))	('PIK3CA', 'Gene', (162, 168))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('KNSTRN', 'Gene', '90417', (150, 156))	('fibroxanthoma', 'Disease', 'None', (29, 42))	('TP53', 'Gene', '7157', (98, 102))	('HRAS', 'Gene', '3265', (144, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('pleomorphic dermal sarcoma', 'Disease', (49, 75))	('TP53', 'Gene', (98, 102))
155362	29099504	Significant copy number gains and losses were detected by requiring a greater-than twofold change in normalized coverage between tumor and a comparator reference fresh-frozen paraffin-embedded normal.	('copy number', 'Var', (12, 23))	('normalized coverage', 'MPA', (101, 120))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('losses', 'NegReg', (34, 40))	('paraffin', 'Chemical', 'MESH:D010232', (175, 183))	('tumor', 'Disease', (129, 134))	('gains', 'PosReg', (24, 29))
155375	29099504	A considerable number of mutations were identified in the 13 atypical fibroxanthoma tumor samples analyzed with an overall mean sequencing depth of 492-fold.	('fibroxanthoma tumor', 'Disease', (70, 89))	('mutations', 'Var', (25, 34))	('fibroxanthoma tumor', 'Disease', 'MESH:D009369', (70, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
155377	29099504	Particularly frequent were TP53 mutations, identified in all samples, with 10/13 (77%) samples harboring inactivating mutations.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('frequent', 'Reg', (13, 21))
155378	29099504	TERT promoter mutations were identified in 12/13 (92%) samples.	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))	('TERT', 'Gene', (0, 4))
155379	29099504	In FAT1, 8 of 13 (62%) samples harbored mutations, 7 (87.5%) were inactivating.	('FAT1', 'Gene', '2195', (3, 7))	('mutations', 'Var', (40, 49))	('harbored', 'Reg', (31, 39))	('FAT1', 'Gene', (3, 7))
155380	29099504	Other apparent alterations affected CDKN2A with 6 of 13 (46%) mutations, 5 (83%) inactivating.	('CDKN2A', 'Gene', (36, 42))	('CDKN2A', 'Gene', '1029', (36, 42))	('alterations', 'Var', (15, 26))	('affected', 'Reg', (27, 35))	('mutations', 'Var', (62, 71))
155381	29099504	NOTCH1 was mutated in 11 of 13 (85%) samples, also with 5 (45%) inactivating mutations (5).	('mutated', 'Var', (11, 18))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))
155382	29099504	Although the panel covers most known activating mutations in human cancer, no recurrent known functionally activating protein-coding mutations were identified in these tumors.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (67, 73))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (61, 66))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
155386	29099504	High numbers of TP53 mutations in 22/26 (85%) atypical fibroxanthoma and 31/35 (89%) pleomorphic dermal sarcoma, NOTCH1 mutations in 14/26 (54%) atypical fibroxanthoma and 22/35 (63%) pleomorphic dermal sarcoma, NOTCH2 mutations in 11/26 (42%) atypical fibroxanthoma, and 17/35 (49%) pleomorphic dermal sarcoma, as well as FAT1 mutations in 15/26 (58%) atypical fibroxanthoma and 24/35 (69%) pleomorphic dermal sarcoma were identified.	('fibroxanthoma', 'Disease', 'None', (154, 167))	('FAT1', 'Gene', (323, 327))	('fibroxanthoma', 'Disease', (55, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (303, 310))	('NOTCH1', 'Gene', '4851', (113, 119))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (284, 310))	('atypical', 'Disease', (46, 54))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (85, 111))	('mutations', 'Var', (120, 129))	('NOTCH2', 'Gene', (212, 218))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (392, 418))	('pleomorphic dermal sarcoma', 'Disease', (284, 310))	('fibroxanthoma', 'Disease', (362, 375))	('pleomorphic dermal sarcoma', 'Disease', (85, 111))	('TP53', 'Gene', '7157', (16, 20))	('fibroxanthoma', 'Disease', (154, 167))	('fibroxanthoma', 'Disease', 'None', (253, 266))	('pleomorphic dermal sarcoma', 'Disease', (392, 418))	('FAT1', 'Gene', '2195', (323, 327))	('sarcoma', 'Phenotype', 'HP:0100242', (411, 418))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (184, 210))	('fibroxanthoma', 'Disease', 'None', (55, 68))	('mutations', 'Var', (219, 228))	('mutations', 'Var', (21, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('pleomorphic dermal sarcoma', 'Disease', (184, 210))	('fibroxanthoma', 'Disease', (253, 266))	('NOTCH1', 'Gene', (113, 119))	('NOTCH2', 'Gene', '4853', (212, 218))	('fibroxanthoma', 'Disease', 'None', (362, 375))	('TP53', 'Gene', (16, 20))
155390	29099504	In 61 tumors, 93 mutations in TP53 were identified, 37 in 25 atypical fibroxanthoma and 56 in 36 pleomorphic dermal sarcoma.	('fibroxanthoma', 'Disease', (70, 83))	('TP53', 'Gene', (30, 34))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (97, 123))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('fibroxanthoma', 'Disease', 'None', (70, 83))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('TP53', 'Gene', '7157', (30, 34))	('mutations', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('pleomorphic dermal sarcoma', 'Disease', (97, 123))
155391	29099504	The frequency of mutations with a UV signature was high in both tumors, with C>T (G>A) and CC>TT (GG>AA) mutations being detected in 43% (16/37) and 14% (5/37) of mutations in atypical fibroxanthoma and 57% (32/56) and 7% (4/56) of mutations in pleomorphic dermal sarcoma, respectively.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (163, 172))	('pleomorphic dermal sarcoma', 'Disease', (245, 271))	('detected', 'Reg', (121, 129))	('fibroxanthoma', 'Disease', 'None', (185, 198))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (245, 271))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('CC>', 'Var', (91, 94))	('fibroxanthoma', 'Disease', (185, 198))	('mutations', 'Var', (105, 114))	('mutations', 'Var', (17, 26))
155405	29099504	In addition to known TERT promoter and TP53 mutations, alterations in CDKN2A, FAT1, NOTCH1, and NOTCH2 were identified particularly frequently.	('alterations', 'Var', (55, 66))	('NOTCH1', 'Gene', (84, 90))	('NOTCH2', 'Gene', (96, 102))	('FAT1', 'Gene', '2195', (78, 82))	('TERT', 'Gene', (21, 25))	('TERT', 'Gene', '7015', (21, 25))	('FAT1', 'Gene', (78, 82))	('NOTCH2', 'Gene', '4853', (96, 102))	('TP53', 'Gene', '7157', (39, 43))	('CDKN2A', 'Gene', (70, 76))	('NOTCH1', 'Gene', '4851', (84, 90))	('TP53', 'Gene', (39, 43))	('CDKN2A', 'Gene', '1029', (70, 76))
155406	29099504	The comprehensive screen for known cancer mutations in 341 known cancer genes demonstrated a very high frequency of mutations overall.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (35, 41))
155409	29099504	TERT promoter mutations, originally identified in cutaneous melanoma were subsequently identified in a wide array of cancers and previously shown by our group to occur in the majority (>70%) of atypical fibroxanthoma and pleomorphic dermal sarcoma samples.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('identified', 'Reg', (87, 97))	('TERT', 'Gene', (0, 4))	('occur', 'Reg', (162, 167))	('cutaneous melanoma', 'Disease', (50, 68))	('TERT', 'Gene', '7015', (0, 4))	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (203, 247))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))	('mutations', 'Var', (14, 23))	('cancers', 'Disease', (117, 124))
155411	29099504	Our study validates this finding, demonstrating TP53 mutations in the majority of all tumor samples (atypical fibroxanthoma MSK-IMPACT next-generation sequencing = 100%, atypical fibroxanthoma amplicon next-generation sequencing = 89%, and pleomorphic dermal sarcoma amplicon next-generation sequencing = 86%) with a considerable number of samples harboring inactivation mutations (atypical fibroxanthoma MSK-IMPACT next-generation sequencing = 77%, atypical fibroxanthoma amplicon next-generation sequencing = 36%, and pleomorphic dermal sarcoma amplicon next-generation sequencing = 31%).	('fibroxanthoma', 'Disease', 'None', (391, 404))	('fibroxanthoma', 'Disease', (110, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (539, 546))	('fibroxanthoma', 'Disease', (179, 192))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TP53', 'Gene', '7157', (48, 52))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (520, 546))	('fibroxanthoma', 'Disease', 'None', (459, 472))	('fibroxanthoma', 'Disease', (391, 404))	('mutations', 'Var', (371, 380))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (240, 266))	('pleomorphic dermal sarcoma', 'Disease', (520, 546))	('mutations', 'Var', (53, 62))	('fibroxanthoma', 'Disease', 'None', (110, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('pleomorphic dermal sarcoma', 'Disease', (240, 266))	('fibroxanthoma', 'Disease', 'None', (179, 192))	('tumor', 'Disease', (86, 91))	('fibroxanthoma', 'Disease', (459, 472))	('TP53', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
155414	29099504	FAT1 mutations were previously identified in various cancers, including glioblastoma, colorectal and head and neck cancer.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('identified', 'Reg', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('colorectal and head and neck cancer', 'Disease', 'MESH:D015179', (86, 121))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('FAT1', 'Gene', '2195', (0, 4))	('head and neck cancer', 'Phenotype', 'HP:0012288', (101, 121))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('glioblastoma', 'Disease', (72, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('FAT1', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
155416	29099504	In all screens performed, the mutation frequency was ~60% of tumors (atypical fibroxanthoma MSK-IMPACT next-generation sequencing = 62%, atypical fibroxanthoma amplicon next-generation sequencing = 58%, and pleomorphic dermal sarcoma amplicon next-generation sequencing = 67%), the percentage of inactivating FAT1 mutations >40% (atypical fibroxanthoma impact next-generation sequencing = 64%, atypical fibroxanthoma amplicon next-generation sequencing = 42%, and pleomorphic dermal sarcoma amplicon next-generation sequencing = 44%).	('fibroxanthoma', 'Disease', (403, 416))	('mutation', 'Var', (30, 38))	('pleomorphic dermal sarcoma', 'Disease', (207, 233))	('fibroxanthoma', 'Disease', (339, 352))	('FAT1', 'Gene', '2195', (309, 313))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (464, 490))	('fibroxanthoma', 'Disease', (146, 159))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('pleomorphic dermal sarcoma', 'Disease', (464, 490))	('fibroxanthoma', 'Disease', 'None', (78, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (483, 490))	('inactivating', 'Reg', (296, 308))	('tumors', 'Disease', (61, 67))	('fibroxanthoma', 'Disease', 'None', (403, 416))	('FAT1', 'Gene', (309, 313))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('fibroxanthoma', 'Disease', 'None', (339, 352))	('mutations', 'Var', (314, 323))	('fibroxanthoma', 'Disease', (78, 91))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (207, 233))	('fibroxanthoma', 'Disease', 'None', (146, 159))
155417	29099504	FAT1 inactivation has been associated with increased beta-catenin and Wnt signaling, suggesting Wnt signaling may play an important role in atypical fibroxanthoma and pleomorphic dermal sarcoma pathogenesis.	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (149, 193))	('Wnt signaling', 'MPA', (70, 83))	('beta-catenin', 'Gene', (53, 65))	('FAT1', 'Gene', '2195', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('increased', 'PosReg', (43, 52))	('inactivation', 'Var', (5, 17))	('beta-catenin', 'Gene', '1499', (53, 65))	('FAT1', 'Gene', (0, 4))
155419	29099504	Originally associated with activating genetic alterations in hematological malignancies, recurrent loss-of-function alterations have also been identified in a wide range of malignancies, including head and neck and cutaneous squamous cell carcinoma.	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('malignancies', 'Disease', (173, 185))	('hematological malignancies', 'Disease', 'MESH:D019337', (61, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('malignancies', 'Disease', (75, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (225, 248))	('hematological malignancies', 'Phenotype', 'HP:0004377', (61, 87))	('cutaneous squamous cell carcinoma', 'Disease', (215, 248))	('alterations', 'Var', (116, 127))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (215, 248))	('malignancies', 'Disease', 'MESH:D009369', (173, 185))	('loss-of-function', 'NegReg', (99, 115))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (215, 248))	('hematological malignancies', 'Disease', (61, 87))
155420	29099504	Very similar to cutaneous squamous cell carcinoma, we identified the highest frequency of mutations in NOTCH1 (atypical fibroxanthoma MSK-IMPACT next-generation sequencing = 85%, atypical fibroxanthoma amplicon next-generation sequencing = 54%, and pleomorphic dermal sarcoma amplicon next-generation sequencing = 66%) followed by NOTCH2 (atypical fibroxanthoma MSK-IMPACT next-generation sequencing = 62%, atypical fibroxanthoma amplicon next-generation sequencing = 42%, and pleomorphic dermal sarcoma amplicon next-generation sequencing = 49%).	('pleomorphic dermal sarcoma', 'Disease', (477, 503))	('NOTCH2', 'Gene', '4853', (331, 337))	('mutations', 'Var', (90, 99))	('fibroxanthoma', 'Disease', (348, 361))	('fibroxanthoma', 'Disease', 'None', (416, 429))	('NOTCH1', 'Gene', '4851', (103, 109))	('fibroxanthoma', 'Disease', 'None', (120, 133))	('cutaneous squamous cell carcinoma', 'Disease', (16, 49))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (249, 275))	('NOTCH2', 'Gene', (331, 337))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 49))	('fibroxanthoma', 'Disease', 'None', (188, 201))	('fibroxanthoma', 'Disease', (416, 429))	('pleomorphic dermal sarcoma', 'Disease', (249, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('fibroxanthoma', 'Disease', 'None', (348, 361))	('fibroxanthoma', 'Disease', (120, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (496, 503))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (477, 503))	('fibroxanthoma', 'Disease', (188, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (26, 49))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (16, 49))	('NOTCH1', 'Gene', (103, 109))
155425	29099504	The analysis of C>T (G>A) and CC>TT (GG>AA) mutations associated with UV exposure in the TP53 gene showed these were frequent both in atypical fibroxanthoma and pleomorphic dermal sarcoma, representing more than half of the identified alterations in both tumor entities (57% in atypical fibroxanthoma and 64% in pleomorphic dermal sarcoma).	('fibroxanthoma', 'Disease', 'None', (143, 156))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('fibroxanthoma', 'Disease', (287, 300))	('pleomorphic dermal sarcoma', 'Disease', (312, 338))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('pleomorphic dermal sarcoma', 'Disease', (161, 187))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (312, 338))	('mutations', 'Var', (44, 53))	('fibroxanthoma', 'Disease', (143, 156))	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (143, 187))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (161, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (331, 338))	('fibroxanthoma', 'Disease', 'None', (287, 300))	('frequent', 'Reg', (117, 125))
155426	29099504	Interestingly, C>T (G>A) alterations were detected more frequently in pleomorphic dermal sarcoma than atypical fibroxanthoma (57% and 43% of mutations, respectively), however CC>TT (GG>AA) were more frequent in atypical fibroxanthoma than pleomorphic dermal sarcoma (14% and 7% of mutations, respectively).	('alterations', 'Var', (25, 36))	('fibroxanthoma than pleomorphic dermal sarcoma', 'Disease', (220, 265))	('CC>TT', 'Var', (175, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('C>T', 'Var', (15, 18))	('pleomorphic dermal sarcoma than atypical fibroxanthoma', 'Disease', 'MESH:D012509', (70, 124))	('fibroxanthoma than pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (220, 265))
155427	29099504	The overall high frequency of these mutations (both C>T and CC>TT) in both atypical fibroxanthoma and pleomorphic dermal sarcoma clearly supports UV exposure being a relevant pathogenic event in both of these tumor entities.	('CC>TT', 'Var', (60, 65))	('tumor', 'Disease', (209, 214))	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (84, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('C>T', 'Var', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
155429	29099504	The rare associations identified in our study with individual clinicopathological parameters: age with NOTCH2 mutation status (P = 0.05); tumor depth and TP53 (P = 0.05) mutation status; and necrosis and TERT promoter mutation status (P = 0.002; Supplementary Table 4) will need to be validated in larger independent cohorts.	('NOTCH2', 'Gene', (103, 109))	('TP53', 'Gene', (154, 158))	('TERT', 'Gene', '7015', (204, 208))	('TP53', 'Gene', '7157', (154, 158))	('tumor depth', 'Disease', 'MESH:D007222', (138, 149))	('tumor depth', 'Disease', (138, 149))	('necrosis', 'Disease', (191, 199))	('mutation', 'Var', (110, 118))	('NOTCH2', 'Gene', '4853', (103, 109))	('necrosis', 'Disease', 'MESH:D009336', (191, 199))	('TERT', 'Gene', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
155430	29099504	Alterations in many genes including those recurrently detected in atypical fibroxanthoma and pleomorphic dermal sarcoma (TP53, CDKN2A, FAT1, NOTCH1/2, and the TERT promoter) have been reported by various groups in cutaneous squamous cell carcinoma.	('TERT', 'Gene', (159, 163))	('NOTCH1/2', 'Gene', (141, 149))	('Alterations', 'Var', (0, 11))	('TP53', 'Gene', '7157', (121, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (214, 247))	('FAT1', 'Gene', '2195', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('reported', 'Reg', (184, 192))	('TP53', 'Gene', (121, 125))	('cutaneous squamous cell carcinoma', 'Disease', (214, 247))	('CDKN2A', 'Gene', (127, 133))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (214, 247))	('FAT1', 'Gene', (135, 139))	('atypical', 'Disease', (66, 74))	('fibroxanthoma and pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (75, 119))	('NOTCH1/2', 'Gene', '4851;4853', (141, 149))	('CDKN2A', 'Gene', '1029', (127, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (224, 247))	('TERT', 'Gene', '7015', (159, 163))
155437	29099504	What is interesting is that activating RAS mutations, previously identified as being present in pleomorphic dermal sarcoma (diagnosed then as MFH) but not atypical fibroxanthoma, were also found to be distributed in a similar manner in our cohort.	('MFH', 'Gene', '27086', (142, 145))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (96, 122))	('fibroxanthoma', 'Disease', 'None', (164, 177))	('activating', 'PosReg', (28, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('MFH', 'Gene', (142, 145))	('mutations', 'Var', (43, 52))	('RAS', 'Gene', (39, 42))	('fibroxanthoma', 'Disease', (164, 177))	('pleomorphic dermal sarcoma', 'Disease', (96, 122))
155438	29099504	However, these activating mutations (2 HRAS G12S, G13V and 1 KRAS G12D) were rare, present only in 3 of 35 (9%) of pleomorphic dermal sarcoma.	('pleomorphic dermal sarcoma', 'Disease', (115, 141))	('G12D', 'Mutation', 'rs121913529', (66, 70))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (115, 141))	('G13V', 'Var', (50, 54))	('G12S', 'Mutation', 'rs104894229', (44, 48))	('KRAS', 'Gene', (61, 65))	('HRAS', 'Gene', '3265', (39, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('G13V', 'Mutation', 'rs112445441', (50, 54))	('HRAS', 'Gene', (39, 43))	('KRAS', 'Gene', '3845', (61, 65))
155442	29099504	As most mutations identified in our screen are assumed to be loss-of-function mutations, it may prove difficult identifying effective treatment strategies targeting cell intrinsic signaling pathways in atypical fibroxanthoma or pleomorphic dermal sarcoma.	('fibroxanthoma or pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (211, 254))	('mutations', 'Var', (8, 17))	('fibroxanthoma or pleomorphic dermal sarcoma', 'Disease', (211, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (247, 254))	('loss-of-function', 'NegReg', (61, 77))
155443	29099504	On the other hand, given that high mutational load is associated with better responses to immunotherapy with anti-CTLA4 and anti-PD1 immune checkpoint blockade therapies in many different cancer entities, our findings may suggest immunotherapy as a promising therapeutic approach for recurrent or metastatic pleomorphic dermal sarcoma.	('recurrent', 'Disease', (284, 293))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('high mutational load', 'Var', (30, 50))	('pleomorphic dermal sarcoma', 'Disease', (308, 334))	('CTLA4', 'Gene', '1493', (114, 119))	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (308, 334))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (327, 334))	('PD1', 'Gene', (129, 132))	('cancer', 'Disease', (188, 194))	('PD1', 'Gene', '5133', (129, 132))	('CTLA4', 'Gene', (114, 119))
155446	29099504	Despite certain shortcomings, our study is the most comprehensive to date identifying both a number of previously unrecognized recurrent gene mutations (ie, NOTCH1, NOTCH2, and FAT1) and a fairly comprehensive picture of copy number alterations in these tumors.	('mutations', 'Var', (142, 151))	('tumors', 'Disease', (254, 260))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('FAT1', 'Gene', '2195', (177, 181))	('FAT1', 'Gene', (177, 181))	('NOTCH1', 'Gene', '4851', (157, 163))	('NOTCH1', 'Gene', (157, 163))	('NOTCH2', 'Gene', '4853', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('NOTCH2', 'Gene', (165, 171))
155451	29099504	Rare activating RAS mutations were only present in pleomorphic dermal sarcoma (9% of tumors).	('pleomorphic dermal sarcoma', 'Disease', 'MESH:D012509', (51, 77))	('pleomorphic dermal sarcoma', 'Disease', (51, 77))	('activating', 'PosReg', (5, 15))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('RAS', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (20, 29))	('tumors', 'Disease', (85, 91))
155465	25330750	More recently, it has been elucidated that insulin-like growth factor (IGF) and its receptor IGF-R1 play a role in VEGF stimulation of angiogenesis and that inhibition of IGF-R1 can inhibit angiogenesis.	('IGF-R1', 'Gene', '2209', (93, 99))	('angiogenesis', 'CPA', (190, 202))	('IGF-R1', 'Gene', (93, 99))	('insulin', 'Gene', (43, 50))	('IGF-R1', 'Gene', '2209', (171, 177))	('VEGF', 'Gene', (115, 119))	('insulin', 'Gene', '3630', (43, 50))	('inhibition', 'Var', (157, 167))	('inhibit', 'NegReg', (182, 189))	('IGF-R1', 'Gene', (171, 177))	('VEGF', 'Gene', '7422', (115, 119))	('angiogenesis', 'CPA', (135, 147))
155468	25330750	This process is complex and not fully understood, but the interplay between numerous factors, including oncogenic mutations, mechanical stress, and tumoral and microenvironmental hypoxia are thought to shift tumors into a pro-angiogenic state.	('shift tumors', 'Disease', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutations', 'Var', (114, 123))	('tumoral', 'Disease', 'MESH:D009369', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('hypoxia', 'Disease', 'MESH:D000860', (179, 186))	('hypoxia', 'Disease', (179, 186))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumoral', 'Disease', (148, 155))	('shift tumors', 'Disease', 'MESH:D020178', (202, 214))
155534	25330750	Mutational changes involving the PDGF family can lead to overactive autocrine and paracrine signaling ultimately associated with tumorigenesis and the development of progressive disease and metastasis.	('associated with', 'Reg', (113, 128))	('PDGF family', 'Gene', (33, 44))	('progressive disease', 'Disease', 'MESH:D018450', (166, 185))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('overactive', 'PosReg', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('progressive disease', 'Disease', (166, 185))	('lead to', 'Reg', (49, 56))	('tumor', 'Disease', (129, 134))	('Mutational changes', 'Var', (0, 18))
155535	25330750	Evidence from in vitro and clinical correlative studies demonstrate an association between aberrant PDGF family signaling and numerous STS subtypes, including dermatofibrosarcoma protuberans (DFSP), AS, endometrial stromal sarcoma (ESS), LMS, rhabdomyosarcoma (RMS), LS, and SS.	('DFSP', 'Disease', (192, 196))	('STS', 'Phenotype', 'HP:0030448', (135, 138))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (243, 259))	('LS', 'Phenotype', 'HP:0012034', (267, 269))	('PDGF', 'Protein', (100, 104))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (243, 259))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (166, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (203, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('FS', 'Phenotype', 'HP:0100244', (193, 195))	('dermatofibrosarcoma protuberans', 'Disease', (159, 190))	('LMS', 'Disease', (238, 241))	('SS', 'Phenotype', 'HP:0012570', (275, 277))	('AS', 'Phenotype', 'HP:0200058', (199, 201))	('aberrant', 'Var', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('endometrial stromal sarcoma', 'Disease', (203, 230))	('DFSP', 'Disease', 'MESH:D018223', (192, 196))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (159, 190))	('SS', 'Phenotype', 'HP:0012570', (233, 235))	('rhabdomyosarcoma', 'Disease', (243, 259))	('RMS', 'Phenotype', 'HP:0002859', (261, 264))
155538	25330750	An association between aberrant PDGF activity and imatinib responsiveness has been described in a subset of DFSP patients.	('FS', 'Phenotype', 'HP:0100244', (109, 111))	('patients', 'Species', '9606', (113, 121))	('imatinib', 'Chemical', 'MESH:D000068877', (50, 58))	('PDGF', 'Protein', (32, 36))	('DFSP', 'Disease', (108, 112))	('imatinib responsiveness', 'MPA', (50, 73))	('activity', 'MPA', (37, 45))	('DFSP', 'Disease', 'MESH:D018223', (108, 112))	('aberrant', 'Var', (23, 31))
155550	25330750	Phase 2 studies investigating single-agent cixutumumab have shown modest clinical benefit in LPS, with an associated PFS of 12.1 weeks, double that of patients with other non-GIST STS subtypes.	('STS', 'Phenotype', 'HP:0030448', (180, 183))	('LPS', 'Disease', (93, 96))	('cixutumumab', 'Var', (43, 54))	('GIST', 'Phenotype', 'HP:0100723', (175, 179))	('patients', 'Species', '9606', (151, 159))	('LPS', 'Disease', 'MESH:C536528', (93, 96))	('cixutumumab', 'Chemical', 'MESH:C557414', (43, 54))	('FS', 'Phenotype', 'HP:0100244', (118, 120))
155551	25330750	Another monoclonal antibody, R1507, was associated with similar modest clinical benefit, such that in a phase 2 clinical trial investigating 163 eligible patients with osteosarcoma (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66), the overall ORR was 2.5%, including 4 partial responses.	('sarcomas', 'Disease', (228, 236))	('osteosarcoma', 'Phenotype', 'HP:0002669', (168, 180))	('osteosarcoma', 'Disease', (168, 180))	('osteosarcoma', 'Disease', 'MESH:D012516', (168, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('patients', 'Species', '9606', (154, 162))	('RMS', 'Disease', (191, 194))	('sarcomas', 'Disease', 'MESH:D012509', (228, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('R1507', 'Var', (29, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (228, 236))	('RMS', 'Phenotype', 'HP:0002859', (191, 194))	('SS', 'Phenotype', 'HP:0012570', (205, 207))
155555	25330750	Utilizing next generation sequencing, Jour et al, 2014 showed that in 25 patients with STS, that 40% of patients had tumors associated with a FGFR copy number gain and amplification, specifically in LMS and clear cell sarcomas.	('STS', 'Phenotype', 'HP:0030448', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('clear cell sarcomas', 'Disease', (207, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (73, 81))	('tumors', 'Disease', (117, 123))	('copy number', 'Var', (147, 158))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('gain', 'PosReg', (159, 163))	('FGF', 'Gene', (142, 145))	('amplification', 'Var', (168, 181))	('sarcomas', 'Phenotype', 'HP:0100242', (218, 226))	('FGF', 'Gene', '2247', (142, 145))	('patients', 'Species', '9606', (104, 112))	('clear cell sarcomas', 'Disease', 'MESH:D018227', (207, 226))	('LMS', 'Disease', (199, 202))
155557	25330750	Aberrant FGF signaling has also been implicated in other non-GIST STS subtypes including, but not limited to, AS, CS, OS, SS, and RMS.	('AS', 'Phenotype', 'HP:0200058', (110, 112))	('SS', 'Phenotype', 'HP:0012570', (122, 124))	('Aberrant', 'Var', (0, 8))	('FGF', 'Gene', '2247', (9, 12))	('implicated', 'Reg', (37, 47))	('GIST', 'Phenotype', 'HP:0100723', (61, 65))	('RMS', 'Phenotype', 'HP:0002859', (130, 133))	('STS', 'Phenotype', 'HP:0030448', (66, 69))	('RMS', 'Disease', (130, 133))	('FGF', 'Gene', (9, 12))
155558	25330750	Based on this preclinical data, aberrant FGF signaling likely has a tumorigenic role in STS.	('tumor', 'Disease', (68, 73))	('STS', 'Phenotype', 'HP:0030448', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('FGF', 'Gene', '2247', (41, 44))	('FGF', 'Gene', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('STS', 'Disease', (88, 91))	('aberrant', 'Var', (32, 40))
155563	25330750	Patients with immunohistochemical evidence of FGF2 expression were shown to have a significantly increased 3-month PFS (2.8 months versus 1.4 months), and the study was not able to exclude the benefit of this agent even in FGF2-negative patients.	('increased', 'PosReg', (97, 106))	('FGF2', 'Gene', '2247', (223, 227))	('FGF2', 'Gene', '2247', (46, 50))	('FGF2', 'Gene', (223, 227))	('Patients', 'Species', '9606', (0, 8))	('PFS', 'MPA', (115, 118))	('FGF2', 'Gene', (46, 50))	('patients', 'Species', '9606', (237, 245))	('expression', 'Var', (51, 61))	('FS', 'Phenotype', 'HP:0100244', (116, 118))
155565	25330750	(2014) conducted a phase 1 trial investigating JNJ042756493, a pan-fibroblast growth factor receptor (1 - 4) inhibitor in 37 patients with advanced solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (148, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('solid tumors', 'Disease', (148, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('JNJ042756493', 'Var', (47, 59))	('patients', 'Species', '9606', (125, 133))
155568	25330750	Considering the importance of FGF signaling in the pathogenesis of numerous malignancies, there are a number of ongoing early phase trials investigating the role of novel agents in patients with advanced STS, including BGJ398 (NCT01004224) and TEN-010 (NCT01987362).	('numerous malignancies', 'Disease', 'MESH:D009369', (67, 88))	('NCT01987362', 'Var', (253, 264))	('NCT01004224', 'Var', (227, 238))	('STS', 'Phenotype', 'HP:0030448', (204, 207))	('numerous malignancies', 'Disease', (67, 88))	('FGF', 'Gene', (30, 33))	('FGF', 'Gene', '2247', (30, 33))	('patients', 'Species', '9606', (181, 189))
155588	25330750	Clinical benefit at four months was achieved more often with ridaforolimus than placebo (40.6% vs 28.6%; p<0.001).	('Clinical', 'MPA', (0, 8))	('ridaforolimus', 'Chemical', 'MESH:C515074', (61, 74))	('ridaforolimus', 'Var', (61, 74))
155589	25330750	The ridaforolimus group had a 28% reduction in the risk of progression or death (p<0.001), but the median PFS benefit was small (17.7 weeks for ridaforolimus versus 14.6 weeks for placebo).	('ridaforolimus', 'Var', (144, 157))	('ridaforolimus', 'Chemical', 'MESH:C515074', (4, 17))	('ridaforolimus', 'Chemical', 'MESH:C515074', (144, 157))	('FS', 'Phenotype', 'HP:0100244', (107, 109))	('reduction', 'NegReg', (34, 43))	('death', 'Disease', 'MESH:D003643', (74, 79))	('death', 'Disease', (74, 79))
155593	25330750	Furthermore, inhibition of IGF-1R may abrograte some AKT activation in a TORC1 independent manner.	('TORC1', 'Gene', '23373', (73, 78))	('activation', 'PosReg', (57, 67))	('inhibition', 'Var', (13, 23))	('abrograte', 'NegReg', (38, 47))	('AKT', 'Gene', '207', (53, 56))	('TORC1', 'Gene', (73, 78))	('IGF-1R', 'Gene', (27, 33))	('AKT', 'Gene', (53, 56))	('IGF-1R', 'Gene', '3480', (27, 33))
155602	25330750	Nevertheless, whether any of these mTOR-cytotoxic combinations outperform single agent mTOR inhibition is still in question.	('mTOR', 'Gene', '2475', (87, 91))	('mTOR', 'Gene', (35, 39))	('mTOR', 'Gene', '2475', (35, 39))	('outperform', 'NegReg', (63, 73))	('combinations', 'Var', (50, 62))	('mTOR', 'Gene', (87, 91))
155604	25330750	Perhaps most interesting are the combinations that address feedback activation of PI3K/AKT pathways after mTORC1 inhibition with RAS/MEK pathway inhibitors.	('mTORC1', 'Gene', '382056', (106, 112))	('AKT', 'Gene', (87, 90))	('AS', 'Phenotype', 'HP:0200058', (130, 132))	('inhibition', 'Var', (113, 123))	('activation', 'PosReg', (68, 78))	('mTORC1', 'Gene', (106, 112))	('AKT', 'Gene', '207', (87, 90))
155610	25330750	(2013) conducted a small phase 1 study evaluating the oral MEK inhibitor RO5126766 in 12 patients with advanced solid tumors.	('solid tumors', 'Disease', (112, 124))	('RO5126766', 'Var', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('RO5126766', 'Chemical', 'MESH:C577924', (73, 82))	('solid tumors', 'Disease', 'MESH:D009369', (112, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (89, 97))
155618	25330750	In addition, recent preclinical work suggests that NF1 deletion may predispose STS to MEKi sensitivity.	('MEKi sensitivity', 'Disease', (86, 102))	('deletion', 'Var', (55, 63))	('NF1', 'Gene', (51, 54))	('predispose', 'Reg', (68, 78))	('NF1', 'Gene', '4763', (51, 54))	('STS', 'Phenotype', 'HP:0030448', (79, 82))
155628	25330750	Based on the finding that up to 90% of WDLS and DDLS are associated with CDK4 amplification, Schwartz et al.	('DDLS', 'Disease', (48, 52))	('CDK4', 'Gene', '1019', (73, 77))	('CDK4', 'Gene', (73, 77))	('LS', 'Phenotype', 'HP:0012034', (41, 43))	('amplification', 'Var', (78, 91))	('LS', 'Phenotype', 'HP:0012034', (50, 52))	('WDLS', 'Disease', (39, 43))	('associated', 'Reg', (57, 67))
155631	25330750	A follow-up phase 2 trial in 29 patients with CDK4 amplified advanced STS revealed that treatment was well tolerated and associated with a single PR and a median PFS of 18 months.	('patients', 'Species', '9606', (32, 40))	('amplified', 'Var', (51, 60))	('CDK4', 'Gene', (46, 50))	('CDK4', 'Gene', '1019', (46, 50))	('FS', 'Phenotype', 'HP:0100244', (163, 165))	('STS', 'Phenotype', 'HP:0030448', (70, 73))
155632	25330750	More recently, a phase 2 trial investigated the CDK4 inhibitor PD0332991 in 29 patients with locally advanced or metastatic WDLS and DDLS.	('PD0332991', 'Var', (63, 72))	('CDK4', 'Gene', '1019', (48, 52))	('LS', 'Phenotype', 'HP:0012034', (135, 137))	('patients', 'Species', '9606', (79, 87))	('DDLS', 'Disease', (133, 137))	('PD0332991', 'Chemical', 'MESH:C500026', (63, 72))	('CDK4', 'Gene', (48, 52))	('LS', 'Phenotype', 'HP:0012034', (126, 128))
155634	25330750	A phase 1 PK study of continuous oral administration of P1446A-05, a novel oral inhibitor of CDK4-D1, CDK1-B, and CDK9-T enrolled 39 patients with advanced malignancies.	('malignancies', 'Disease', (156, 168))	('P1446A', 'Mutation', 'p.P1446A', (56, 62))	('CDK4', 'Gene', '1019', (93, 97))	('P1446A-05', 'Var', (56, 65))	('CDK9-T', 'Disease', 'MESH:D001260', (114, 120))	('patients', 'Species', '9606', (133, 141))	('malignancies', 'Disease', 'MESH:D009369', (156, 168))	('CDK9-T', 'Disease', (114, 120))	('CDK4', 'Gene', (93, 97))
155638	25330750	In preclinical models, inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes.	('blocks', 'NegReg', (85, 91))	('AURKA', 'Gene', '6790', (69, 74))	('inhibition', 'Var', (23, 33))	('AURKA', 'Gene', '6790', (37, 42))	('AURKA', 'Gene', (69, 74))	('multiple sarcoma subtypes', 'Disease', (118, 143))	('AURKA', 'Gene', (37, 42))	('multiple sarcoma subtypes', 'Disease', 'MESH:D012509', (118, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
155647	25330750	Augmentation of this signaling pathway occurs in over 50% of malignancies and is caused either by suppression of p53 activity via MDM2 +/- MDM4 amplification in p53 wild-type alleles or by p53 mutational events that result in loss of p53 tumor suppression.	('malignancies', 'Disease', 'MESH:D009369', (61, 73))	('activity', 'MPA', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('malignancies', 'Disease', (61, 73))	('MDM4', 'Gene', '4194', (139, 143))	('mutational', 'Var', (193, 203))	('p53', 'Protein', (113, 116))	('tumor', 'Disease', (238, 243))	('MDM4', 'Gene', (139, 143))	('loss', 'NegReg', (226, 230))	('suppression', 'NegReg', (98, 109))	('p53', 'Gene', (189, 192))
155648	25330750	Numerous therapeutic strategies targeting aberrant p53 signaling are being developed, including MDM2 inhibitors in wild type p53 tumors, dual HDM2/HDMX antagonists, p53-binding antagonists, and agents that restore the activity of mutant p53.	('tumors', 'Disease', (129, 135))	('HDMX', 'Gene', (147, 151))	('mutant', 'Var', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('HDM2', 'Gene', '4193', (142, 146))	('MDM2', 'Gene', (96, 100))	('HDM2', 'Gene', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('activity', 'MPA', (218, 226))	('p53', 'Gene', (237, 240))	('HDMX', 'Gene', '4194', (147, 151))
155650	25330750	In STS, well-differentiated (WDLPS) and dedifferentiated liposarcomas (DDLPS) are closely associated with amplification of the chromosomal region 12q13-15; mutations that ultimately result in suppression of p53 activity and tumorigenesis.	('suppression', 'NegReg', (192, 203))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('WDLPS', 'Disease', (29, 34))	('p53', 'Protein', (207, 210))	('LPS', 'Disease', 'MESH:C536528', (31, 34))	('liposarcomas', 'Disease', (57, 69))	('STS', 'Phenotype', 'HP:0030448', (3, 6))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('LPS', 'Disease', (73, 76))	('WDLPS', 'Disease', 'None', (29, 34))	('mutations', 'Var', (156, 165))	('liposarcoma', 'Phenotype', 'HP:0012034', (57, 68))	('tumor', 'Disease', (224, 229))	('liposarcomas', 'Disease', 'MESH:D008080', (57, 69))	('activity', 'MPA', (211, 219))	('LPS', 'Disease', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('liposarcomas', 'Phenotype', 'HP:0012034', (57, 69))	('LPS', 'Disease', 'MESH:C536528', (73, 76))
155652	25330750	Treatment resulted in one confirmed PR and SD in 14 patients, results that suggest that inhibition of MDM2 is associated with p53 pathway activation and decreased cell proliferation in MDM2-amplified liposarcomas.	('p53 pathway', 'Pathway', (126, 137))	('liposarcomas', 'Disease', 'MESH:D008080', (200, 212))	('liposarcoma', 'Phenotype', 'HP:0012034', (200, 211))	('liposarcomas', 'Disease', (200, 212))	('MDM2', 'Gene', (102, 106))	('decreased', 'NegReg', (153, 162))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('patients', 'Species', '9606', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('cell proliferation', 'CPA', (163, 181))	('activation', 'PosReg', (138, 148))	('inhibition', 'Var', (88, 98))	('liposarcomas', 'Phenotype', 'HP:0012034', (200, 212))
155656	25330750	RG7388, a second generation MDM2 inhibitor, also recently reported stable disease in sarcoma patients in their phase I trial.	('RG7388', 'Var', (0, 6))	('stable disease', 'Disease', (67, 81))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('sarcoma', 'Disease', (85, 92))	('patients', 'Species', '9606', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
155657	25330750	Other MDM2 inhibitors, including MI-773 (SAR205838) and DS-3032b are undergoing clinical development.	('MI-773', 'Var', (33, 39))	('MI-773', 'Chemical', 'MESH:C000593797', (33, 39))	('DS-3032b', 'Var', (56, 64))	('MDM2', 'Gene', (6, 10))	('DS-3032b', 'Chemical', '-', (56, 64))
155658	25330750	Aberrant histone acetylase (HAT) and/or histone deacetylase modification of gene expression has been implicated in the pathogenesis of various malignancies.	('malignancies', 'Disease', 'MESH:D009369', (143, 155))	('Aberrant', 'Var', (0, 8))	('implicated', 'Reg', (101, 111))	('malignancies', 'Disease', (143, 155))	('histone acetylase (HAT) and/', 'Gene', '9407', (9, 37))
155664	25330750	This trial enrolled 48 patients, including 14 patients with translocation-related sarcoma (myxoid LS, SS, ESS, and alveolar soft part sarcoma), and non-translocation related sarcoma (WDLS, DDLS, pleomorphic LS, LMS, MPNST, and sarcoma NOS).	('patients', 'Species', '9606', (46, 54))	('sarcoma NOS', 'Disease', 'MESH:D012509', (227, 238))	('patients', 'Species', '9606', (23, 31))	('LMS', 'Disease', (211, 214))	('translocation-related', 'Var', (60, 81))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (115, 141))	('pleomorphic LS', 'Disease', (195, 209))	('sarcoma NOS', 'Disease', (227, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('DDLS', 'Disease', (189, 193))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (115, 141))	('sarcoma', 'Disease', 'MESH:D012509', (227, 234))	('sarcoma', 'Disease', (227, 234))	('alveolar soft part sarcoma', 'Disease', (115, 141))	('SS', 'Phenotype', 'HP:0012570', (102, 104))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('SS', 'Phenotype', 'HP:0012570', (107, 109))	('sarcoma', 'Disease', (82, 89))	('LS', 'Phenotype', 'HP:0012034', (98, 100))	('LS', 'Phenotype', 'HP:0012034', (185, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('MPNST', 'Phenotype', 'HP:0100697', (216, 221))	('ESS', 'Disease', (106, 109))	('LS', 'Phenotype', 'HP:0012034', (207, 209))	('LS', 'Phenotype', 'HP:0012034', (191, 193))	('sarcoma', 'Disease', (134, 141))	('sarcoma', 'Disease', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (124, 141))
155675	25203324	Expression of the NICD in immature osteoblasts was sufficient to drive the formation of bone tumors, including OS, with complete penetrance.	('bone tumors', 'Phenotype', 'HP:0010622', (88, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('OS', 'Phenotype', 'HP:0002669', (111, 113))	('bone tumors', 'Disease', (88, 99))	('drive', 'PosReg', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('NICD', 'Var', (18, 22))	('bone tumors', 'Disease', 'MESH:D001859', (88, 99))
155677	25203324	We show that Notch activation combined with loss of p53 synergistically accelerates OS development in mice although p53-driven OS is not Rbpj-dependent, which demonstrates a dual dominance of the Notch oncogene and p53 mutation in the development of OS.	('mice', 'Species', '10090', (102, 106))	('OS development', 'CPA', (84, 98))	('Rbpj', 'Gene', '19664', (137, 141))	('Notch', 'Gene', (13, 18))	('OS', 'Phenotype', 'HP:0002669', (84, 86))	('p53', 'Gene', (52, 55))	('Rbpj', 'Gene', (137, 141))	('activation', 'PosReg', (19, 29))	('Notch', 'Gene', (196, 201))	('Notch', 'Gene', '31293', (13, 18))	('OS', 'Phenotype', 'HP:0002669', (250, 252))	('OS', 'Phenotype', 'HP:0002669', (127, 129))	('accelerates', 'PosReg', (72, 83))	('loss', 'Var', (44, 48))	('Notch', 'Gene', '31293', (196, 201))
155682	25203324	Recently, Orkin and colleagues showed that bone-specific disruption of Trp53 and Rb leads to the formation of OS and mimics the human form of the disease, supporting the hypothesis that OS may arise from mesenchymal-stem-cell-derived osteoblasts, the predominant bone-forming cells.	('disruption', 'Var', (57, 67))	('human', 'Species', '9606', (128, 133))	('Trp53', 'Gene', (71, 76))	('leads to', 'Reg', (84, 92))	('OS', 'Phenotype', 'HP:0002669', (110, 112))	('OS', 'Phenotype', 'HP:0002669', (186, 188))
155687	25203324	Notch receptor mutations have been associated with several types of cancer, and current data suggest that Notch can serve as either a tumor promoter or a tumor suppressor in a context-dependent manner.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Notch', 'Gene', (0, 5))	('Notch', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mutations', 'Var', (15, 24))	('associated', 'Reg', (35, 45))	('Notch', 'Gene', '31293', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Notch', 'Gene', '31293', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (154, 159))
155691	25203324	A human Notch gain-of-function mutation was discovered in cells derived from a patient with T-cell acute lymphoblastic leukemia (T-ALL).	('Notch', 'Gene', '31293', (8, 13))	('T-ALL', 'Phenotype', 'HP:0006727', (129, 134))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (92, 127))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (92, 127))	('mutation', 'Var', (31, 39))	('T-cell acute lymphoblastic leukemia', 'Disease', (92, 127))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (105, 127))	('patient', 'Species', '9606', (79, 86))	('gain-of-function', 'PosReg', (14, 30))	('human', 'Species', '9606', (2, 7))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (99, 127))	('Notch', 'Gene', (8, 13))	('leukemia', 'Phenotype', 'HP:0001909', (119, 127))
155692	25203324	The mutation, a chromosomal 7-chromosome 9 translocation, results in the expression of a truncated NICD-like protein from NOTCH1, which encodes one of four closely related members (Notch1-4) in mammals.	('Notch1', 'Gene', (181, 187))	('chromosome 9 translocation', 'Phenotype', 'HP:0031581', (30, 56))	('NOTCH1', 'Gene', (122, 128))	('Notch1', 'Gene', '18128', (181, 187))	('mutation', 'Var', (4, 12))	('expression', 'MPA', (73, 83))	('results in', 'Reg', (58, 68))
155694	25203324	A subsequent study found that more than 50% of human T-ALLs have NOTCH1 gain-of-function mutations involving the extracellular hetero-dimerization domain and/or the C-terminal PEST domain, which regulates NICD degradation.	('gain-of-function', 'PosReg', (72, 88))	('extracellular', 'MPA', (113, 126))	('T-ALL', 'Phenotype', 'HP:0006727', (53, 58))	('mutations', 'Var', (89, 98))	('NOTCH1', 'Gene', (65, 71))	('human', 'Species', '9606', (47, 52))	('NICD degradation', 'MPA', (205, 221))
155695	25203324	These missense mutations and/or frame-shifting insertions or deletions result in ligand-independent cleavage and accumulation of NICD in the nucleus and/or NICD stabilization, inducing constitutively active Notch signaling.	('NICD stabilization', 'MPA', (156, 174))	('inducing', 'PosReg', (176, 184))	('Notch', 'Gene', '31293', (207, 212))	('missense mutations', 'Var', (6, 24))	('NICD in the nucleus', 'MPA', (129, 148))	('Notch', 'Gene', (207, 212))	('ligand-independent cleavage', 'MPA', (81, 108))	('accumulation', 'PosReg', (113, 125))	('insertions', 'Var', (47, 57))	('constitutively', 'MPA', (185, 199))
155696	25203324	Notch gain-of-function mutations have also been found in several types of solid tumors, including lung cancer.	('Notch', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('solid tumors', 'Disease', 'MESH:D009369', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (23, 32))	('Notch', 'Gene', '31293', (0, 5))	('gain-of-function', 'PosReg', (6, 22))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('solid tumors', 'Disease', (74, 86))
155730	25203324	To examine whether the Notch-induced tumors develop genomic instability, we first performed spectral karyotyping (SKY) on early passage cultures derived from six independent primary tumors (T3, T6, T8, T12, T14, and T29).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('primary tumors', 'Disease', (174, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('T14', 'Gene', (207, 210))	('Notch', 'Gene', '31293', (23, 28))	('T29', 'Var', (216, 219))	('primary tumors', 'Disease', 'MESH:D009369', (174, 188))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('T12', 'Gene', '923', (202, 205))	('tumors', 'Disease', (37, 43))	('Notch', 'Gene', (23, 28))	('T12', 'Gene', (202, 205))	('T14', 'Gene', '939', (207, 210))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
155750	25203324	Reduction of WIF1/Wif1 expression has been associated with epigenetic silencing in human OS and accelerated progression of OS in mice.	('epigenetic silencing', 'Var', (59, 79))	('human', 'Species', '9606', (83, 88))	('OS', 'Phenotype', 'HP:0002669', (89, 91))	('Reduction', 'NegReg', (0, 9))	('OS', 'Phenotype', 'HP:0002669', (123, 125))	('mice', 'Species', '10090', (129, 133))	('WIF1', 'Gene', (13, 17))	('accelerated', 'PosReg', (96, 107))	('WIF1', 'Gene', '11197', (13, 17))	('expression', 'MPA', (23, 33))
155753	25203324	To assess the functional link between Notch and other molecules associated with human OS such as p53, and the role of Notch signaling in an established spontaneous model of OS, we employed genetically engineered mice harboring the p53 mutation.	('mutation', 'Var', (235, 243))	('mice', 'Species', '10090', (212, 216))	('Notch', 'Gene', '31293', (118, 123))	('Notch', 'Gene', (38, 43))	('OS', 'Phenotype', 'HP:0002669', (173, 175))	('p53', 'Gene', (231, 234))	('human', 'Species', '9606', (80, 85))	('Notch', 'Gene', '31293', (38, 43))	('OS', 'Phenotype', 'HP:0002669', (86, 88))	('Notch', 'Gene', (118, 123))
155754	25203324	In human OS, deficiency of p53 may serve as an OS driver given that a small percentage of patients with Li-Fraumeni syndrome carrying TP53 germline mutations develop OS.	('mutations', 'Var', (148, 157))	('OS', 'Phenotype', 'HP:0002669', (166, 168))	('develop', 'Reg', (158, 165))	('Li-Fraumeni syndrome', 'Disease', (104, 124))	('TP53', 'Gene', (134, 138))	('human', 'Species', '9606', (3, 8))	('OS', 'Phenotype', 'HP:0002669', (9, 11))	('OS', 'Phenotype', 'HP:0002669', (47, 49))	('patients', 'Species', '9606', (90, 98))	('TP53', 'Gene', '7157', (134, 138))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (104, 124))
155759	25203324	To examine whether Notch gain of function modulates the tumorigenic process driven by p53 inactivation, we bred mice with the conditional NICD allele into an osteoblast-specific p53 null background.	('Notch', 'Gene', '31293', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('modulates', 'Reg', (42, 51))	('gain of function', 'PosReg', (25, 41))	('inactivation', 'Var', (90, 102))	('Notch', 'Gene', (19, 24))	('mice', 'Species', '10090', (112, 116))	('p53', 'Gene', (86, 89))
155765	25203324	These data suggest that the p53 deletion in the cNICD mice significantly influences not only tumor initiation and progression but also a preference for tumor location.	('p53', 'Gene', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('deletion', 'Var', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor initiation', 'Disease', 'MESH:D009369', (93, 109))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (152, 157))	('influences', 'Reg', (73, 83))	('tumor initiation', 'Disease', (93, 109))	('mice', 'Species', '10090', (54, 58))	('progression', 'CPA', (114, 125))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
155771	25203324	Our data show that Notch activation can independently initiate OS and also act synergistically with loss of p53 in tumor progression, suggesting that the genetic interaction between Notch and p53 promotes OS initiation and progression, although Rbpj or canonical Notch function is dispensable for p53-induced tumorigenesis in the context examined.	('OS', 'Phenotype', 'HP:0002669', (205, 207))	('promotes', 'PosReg', (196, 204))	('Notch', 'Gene', '31293', (263, 268))	('tumor', 'Disease', (115, 120))	('progression', 'CPA', (223, 234))	('p53', 'Gene', (192, 195))	('Notch', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('Notch', 'Gene', '31293', (182, 187))	('Notch', 'Gene', (263, 268))	('genetic', 'Var', (154, 161))	('Rbpj', 'Gene', (245, 249))	('tumor', 'Disease', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('interaction', 'Interaction', (162, 173))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('Rbpj', 'Gene', '19664', (245, 249))	('Notch', 'Gene', '31293', (19, 24))	('OS initiation', 'Disease', (205, 218))	('Notch', 'Gene', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('OS initiation', 'Disease', 'MESH:C567932', (205, 218))	('OS', 'Phenotype', 'HP:0002669', (63, 65))
155774	25203324	Since murine OS induced by inactivation of p53 exhibits transcriptional profiles comparable to human OS, we compared the expression profiles of tumors from both models.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('human', 'Species', '9606', (95, 100))	('OS', 'Phenotype', 'HP:0002669', (101, 103))	('inactivation', 'Var', (27, 39))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('OS', 'Phenotype', 'HP:0002669', (13, 15))	('p53', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('murine', 'Species', '10090', (6, 12))	('transcriptional profiles', 'MPA', (56, 80))
155775	25203324	Clustering analysis demonstrated a highly similar expression signature among osteosarcomas induced by either Notch or loss of p53.	('osteosarcomas', 'Disease', (77, 90))	('induced by', 'Reg', (91, 101))	('osteosarcomas', 'Phenotype', 'HP:0002669', (77, 90))	('Notch', 'Gene', (109, 114))	('osteosarcomas', 'Disease', 'MESH:D012516', (77, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('Notch', 'Gene', '31293', (109, 114))	('loss', 'Var', (118, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('p53', 'Gene', (126, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
155778	25203324	In addition, RNA-seq analysis of NOS tumors also revealed dysregulation of many components in Notch and p53 signaling pathways, including Notch1, Notch3, Il6, Cdkn2a, and Mdm2 (Figure S5A).	('Cdkn2a', 'Gene', (159, 165))	('Il6', 'Gene', '16193', (154, 157))	('Notch1', 'Gene', (138, 144))	('Mdm2', 'Gene', (171, 175))	('Notch', 'Gene', (146, 151))	('Notch', 'Gene', (138, 143))	('Notch3', 'Gene', '18131', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('Il6', 'Gene', (154, 157))	('NOS tumors', 'Disease', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('dysregulation', 'Var', (58, 71))	('OS', 'Phenotype', 'HP:0002669', (34, 36))	('Notch', 'Gene', '31293', (94, 99))	('p53 signaling pathways', 'Pathway', (104, 126))	('Mdm2', 'Gene', '17246', (171, 175))	('Notch1', 'Gene', '18128', (138, 144))	('Notch', 'Gene', '31293', (138, 143))	('Cdkn2a', 'Gene', '12578', (159, 165))	('Notch3', 'Gene', (146, 152))	('Notch', 'Gene', '31293', (146, 151))	('Notch', 'Gene', (94, 99))	('NOS tumors', 'Disease', 'MESH:D009369', (33, 43))
155797	25203324	Surprisingly, no Prx1-Cre;Rosa26NICD, or Osx-Cre;Rosa26NICD pups were generated; all compound mutant embryos were abnormal and significantly smaller compared to their littermates between E15.5 and E18.5, indicating that embryonic lethality (Figure 6C and data not shown).	('Rosa26', 'Gene', '14910', (26, 32))	('Rosa26', 'Gene', (49, 55))	('embryonic lethality', 'Disease', 'MESH:D020964', (220, 239))	('embryonic lethality', 'Disease', (220, 239))	('smaller', 'NegReg', (141, 148))	('Rosa26', 'Gene', (26, 32))	('Rosa26', 'Gene', '14910', (49, 55))	('compound mutant', 'Var', (85, 100))
155800	25203324	We also show a robust synergy between Notch and p53 in tumorigenesis, indicating that Notch gain of function greatly promotes progression of OS initiated by loss of p53.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('p53', 'Gene', (165, 168))	('gain of function', 'PosReg', (92, 108))	('Notch', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('progression', 'CPA', (126, 137))	('tumor', 'Disease', (55, 60))	('Notch', 'Gene', (86, 91))	('Notch', 'Gene', '31293', (38, 43))	('promotes', 'PosReg', (117, 125))	('Notch', 'Gene', '31293', (86, 91))	('OS', 'Phenotype', 'HP:0002669', (141, 143))	('loss', 'Var', (157, 161))
155803	25203324	We applied the same targeted strategy and generated a Notch OS mouse model by expressing the truncated protein NICD.	('Notch', 'Gene', (54, 59))	('mouse', 'Species', '10090', (63, 68))	('truncated', 'Var', (93, 102))	('Notch', 'Gene', '31293', (54, 59))	('OS', 'Phenotype', 'HP:0002669', (60, 62))
155808	25203324	Gain-of-function mutations in NOTCH1 have been found in approximately 10% of cases of non-small-cell lung cancer, the leading cause of cancer-related deaths.	('cancer', 'Disease', (135, 141))	('death', 'Disease', 'MESH:D003643', (150, 155))	('death', 'Disease', (150, 155))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('NOTCH1', 'Gene', (30, 36))	('Gain-of-function', 'PosReg', (0, 16))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (86, 112))	('cancer', 'Disease', (106, 112))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (90, 112))	('mutations', 'Var', (17, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
155816	25203324	It is currently unknown why the same oncogene leads to two types of tumors, but the transforming ability of Notch mutations may be dependent on the cell types in which the gene is expressed.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Disease', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (114, 123))	('Notch', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Notch', 'Gene', '31293', (108, 113))
155818	25203324	Alternatively, we speculate that a different hit induced by micro-environmental cues may promote different downstream events, as seen in the TAg-induced model, in which additional loss of Prkar1a defines a subclass of high-grade-type OS.	('high-grade-type OS', 'Disease', (218, 236))	('loss', 'Var', (180, 184))	('Prkar1a', 'Gene', (188, 195))	('Prkar1a', 'Gene', '19084', (188, 195))	('OS', 'Phenotype', 'HP:0002669', (234, 236))
155819	25203324	It is not unexpected that in our p53-loss-driven OS model, adding a "second hit" Notch activation mutation significantly shortens tumor latency and aggressiveness, suggesting a critical role for Notch signaling in OS progression.	('aggressiveness', 'Phenotype', 'HP:0000718', (148, 162))	('activation', 'PosReg', (87, 97))	('Notch', 'Gene', (195, 200))	('shortens', 'NegReg', (121, 129))	('mutation', 'Var', (98, 106))	('OS', 'Phenotype', 'HP:0002669', (214, 216))	('OS', 'Phenotype', 'HP:0002669', (49, 51))	('Notch', 'Gene', '31293', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Notch', 'Gene', '31293', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('aggressiveness', 'Disease', 'MESH:D001523', (148, 162))	('aggressiveness', 'Disease', (148, 162))	('tumor', 'Disease', (130, 135))	('Notch', 'Gene', (81, 86))
155821	25203324	Transgenic mice expressing NICD specifically in T cells developed T-cell leukemia at a frequency of about 20% by five months of age, but once a second mutation was added penetrance of leukemia increased to 100% and tumor latency decreased to 2 months.	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('T-cell leukemia', 'Disease', 'MESH:D015458', (66, 81))	('NICD', 'Var', (27, 31))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('leukemia', 'Disease', 'MESH:D007938', (73, 81))	('developed', 'Reg', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('leukemia', 'Disease', (73, 81))	('leukemia', 'Disease', 'MESH:D007938', (184, 192))	('tumor', 'Disease', (215, 220))	('Transgenic mice', 'Species', '10090', (0, 15))	('leukemia', 'Disease', (184, 192))	('T-cell leukemia', 'Disease', (66, 81))
155823	25203324	Additionally, in our cNICD model, p53 deletion can dramatically accelerate tumor progression, suggesting that p53 certainly constitutes a "second hit".	('p53', 'Gene', (34, 37))	('accelerate', 'PosReg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('deletion', 'Var', (38, 46))	('tumor', 'Disease', (75, 80))
155827	25203324	Moreover, Wif1 is often epigenetically silenced in human OS, and its targeted disruption accelerates OS development in mice.	('mice', 'Species', '10090', (119, 123))	('OS', 'Phenotype', 'HP:0002669', (101, 103))	('OS development', 'CPA', (101, 115))	('OS', 'Phenotype', 'HP:0002669', (57, 59))	('disruption', 'Var', (78, 88))	('accelerates', 'PosReg', (89, 100))	('human', 'Species', '9606', (51, 56))	('Wif1', 'Gene', (10, 14))
155828	25203324	It is currently unknown whether the epigenetic mechanism is accountable for Wif1 silencing in NOS tumors and whether ectopic Wif1 expression inhibits NOS cell growth.	('Wif1', 'Gene', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('ectopic', 'Var', (117, 124))	('OS', 'Phenotype', 'HP:0002669', (95, 97))	('silencing', 'NegReg', (81, 90))	('inhibits', 'NegReg', (141, 149))	('NOS tumors', 'Disease', (94, 104))	('NOS tumors', 'Disease', 'MESH:D009369', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('OS', 'Phenotype', 'HP:0002669', (151, 153))	('NOS cell growth', 'CPA', (150, 165))	('Wif1', 'Gene', (125, 129))
155829	25203324	On the one hand, aberrant activation of the WNT pathway is associated with numerous cancers including OS.	('aberrant', 'Var', (17, 25))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('numerous cancers', 'Disease', 'MESH:D009369', (75, 91))	('associated', 'Reg', (59, 69))	('activation', 'PosReg', (26, 36))	('OS', 'Phenotype', 'HP:0002669', (102, 104))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('numerous cancers', 'Disease', (75, 91))	('WNT pathway', 'Pathway', (44, 55))
155830	25203324	Elevated levels of nuclear localized beta-catenin, a critical mediator of the canonical Wnt pathway, have been detected in the majority of OS tumors, as well as sporadic mutations of beta-catenin.	('beta-catenin', 'Gene', '12387', (37, 49))	('OS', 'Phenotype', 'HP:0002669', (139, 141))	('nuclear localized', 'MPA', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('detected', 'Reg', (111, 119))	('beta-catenin', 'Gene', (183, 195))	('mutations', 'Var', (170, 179))	('OS tumors', 'Disease', 'MESH:C567932', (139, 148))	('beta-catenin', 'Gene', (37, 49))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('beta-catenin', 'Gene', '12387', (183, 195))	('OS tumors', 'Disease', (139, 148))
155841	25203324	We and others have shown that inhibition of Notch signaling impedes human OS growth.	('Notch', 'Gene', (44, 49))	('human', 'Species', '9606', (68, 73))	('impedes', 'NegReg', (60, 67))	('inhibition', 'Var', (30, 40))	('human OS growth', 'CPA', (68, 83))	('Notch', 'Gene', '31293', (44, 49))	('OS', 'Phenotype', 'HP:0002669', (74, 76))
155849	25203324	Much of our understanding of cells of origin has derived from the study of OS mouse models generated by cell-type-specific loss of p53.	('mouse', 'Species', '10090', (78, 83))	('p53', 'Gene', (131, 134))	('OS', 'Phenotype', 'HP:0002669', (75, 77))	('loss', 'Var', (123, 127))
155856	25203324	In summary, we have revealed the critical role of Notch gain-of-function mutations as a cause of OS in mice and advanced our understanding of the genetic factors and signaling pathways in pathogenesis of OS.	('OS', 'Phenotype', 'HP:0002669', (204, 206))	('Notch', 'Gene', (50, 55))	('OS', 'Phenotype', 'HP:0002669', (97, 99))	('mice', 'Species', '10090', (103, 107))	('Notch', 'Gene', '31293', (50, 55))	('gain-of-function', 'PosReg', (56, 72))	('mutations', 'Var', (73, 82))
155857	25203324	Our study also warrants future screening and identification of patients with mesenchyme-derived tumors affected by mutations in Notch receptors, and in other components of the pathway, for developing targeted treatment strategies.	('mutations', 'Var', (115, 124))	('Notch', 'Gene', '31293', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('affected by', 'Reg', (103, 114))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Notch', 'Gene', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('patients', 'Species', '9606', (63, 71))
155860	25203324	Conditional knockout mice (RbpjFlox/Flox, Trp53Flox/Flox) and transgenic mice (Col1a1 2.3kb-Cre, Rosa26NICD) have been previously described.	('Flox', 'Chemical', '-', (36, 40))	('transgenic mice', 'Species', '10090', (62, 77))	('mice', 'Species', '10090', (21, 25))	('Rosa26', 'Gene', (97, 103))	('mice', 'Species', '10090', (73, 77))	('Flox', 'Chemical', '-', (47, 51))	('Col1a1', 'Gene', (79, 85))	('Flox', 'Chemical', '-', (52, 56))	('Col1a1', 'Gene', '12842', (79, 85))	('Flox', 'Chemical', '-', (31, 35))	('Rosa26', 'Gene', '14910', (97, 103))	('Trp53Flox/Flox', 'Var', (42, 56))
155873	25203324	Our study also supports the hypothesis that Notch-activating mutations can act as an OS-initiating mechanism in cells of mesenchymal lineage such as committed osteoblasts.	('Notch', 'Gene', (44, 49))	('Notch', 'Gene', '31293', (44, 49))	('OS', 'Phenotype', 'HP:0002669', (85, 87))	('mutations', 'Var', (61, 70))	('committed osteoblasts', 'CPA', (149, 170))
155877	23818101	We postulated that DNA variants in the human homologs of viral genes that potentially alter the expression or the binding of the encoded factors controlling the antiviral response may facilitate viral interference.	('expression', 'MPA', (96, 106))	('facilitate', 'PosReg', (184, 194))	('binding', 'Interaction', (114, 121))	('viral interference', 'MPA', (195, 213))	('alter', 'Reg', (86, 91))	('variants', 'Var', (23, 31))	('human', 'Species', '9606', (39, 44))
155878	23818101	To test whether cellular homologs are candidate susceptibility genes, we evaluated the association of DNA variants in 92 immune-related genes including 7 cellular homologs with the risk for HIV-KS in a matched case and control study nested in the Multicenter AIDS Cohort Study.	('AIDS', 'Disease', 'MESH:D000163', (259, 263))	('variants', 'Var', (106, 114))	('HIV-KS', 'Disease', (190, 196))	('association', 'Interaction', (87, 98))	('AIDS', 'Disease', (259, 263))
155896	23818101	We postulated that in susceptible hosts (HIV-1 and KSHV seropositive individuals), DNA polymorphisms in immune or cell cycle/apoptosis genes that alter the expression or the binding of the encoded factors involved in the antiviral response may provide favorable conditions for viral homologs to interfere with that response.	('binding', 'Interaction', (174, 181))	('cell cycle/apoptosis genes', 'Gene', (114, 140))	('polymorphisms', 'Var', (87, 100))	('HIV-1 and KSHV seropositive', 'Disease', 'MESH:D006679', (41, 68))	('expression', 'MPA', (156, 166))	('alter', 'Reg', (146, 151))	('immune', 'Gene', (104, 110))
155903	23818101	Positivity at either sample defined a KSHV-infected individual and KSHV negativity at both visits defined an uninfected individual.	('KSHV', 'Species', '37296', (38, 42))	('KSHV', 'Species', '37296', (67, 71))	('Positivity', 'Var', (0, 10))	('KSHV-infected', 'Disease', 'MESH:C537372', (38, 51))	('KSHV-infected', 'Disease', (38, 51))
155930	23818101	In several instances the associated gene interactions implicate non-synonymous and functional non-coding SNPs (highlighted in bold, by parentheses or underlined in Table 1) with known variants at risk; for example the IL-6 high-producing gene promoter variant G-174C (rs1800795) and the G870A splice variant (rs603965, merged to rs9344) of CCND1 influencing the relative production of Cyclin D1b.	('influencing', 'Reg', (346, 357))	('G870A', 'Var', (287, 292))	('rs1800795', 'Var', (268, 277))	('interactions', 'Interaction', (41, 53))	('rs9344', 'Var', (329, 335))	('rs9344', 'Mutation', 'rs9344', (329, 335))	('rs603965', 'Var', (309, 317))	('CCND1', 'Gene', (340, 345))	('G-174C', 'Mutation', 'rs1800795', (260, 266))	('rs603965', 'Mutation', 'rs603965', (309, 317))	('G870A', 'Mutation', 'rs9344', (287, 292))	('implicate', 'Reg', (54, 63))	('rs1800795', 'Mutation', 'rs1800795', (268, 277))	('CCND1', 'Gene', '595', (340, 345))
155931	23818101	Consistent with the above findings is the observation that IL-6R, the cognate receptor of IL-6, also emerged in the interaction model 11 implicating the same CCND1 variant.	('CCND1', 'Gene', '595', (158, 163))	('IL-6R', 'Gene', (59, 64))	('variant', 'Var', (164, 171))	('IL-6R', 'Gene', '3570', (59, 64))	('CCND1', 'Gene', (158, 163))
155940	23818101	Under the proposed model, the affected cases carry risk variants in different combinations of homologue and non-homologue genes but acting in the same cellular pathways antagonized by KSHV or relevant to KS such as in angiogenesis.	('angiogenesis', 'Disease', (218, 230))	('acting', 'Reg', (132, 138))	('variants', 'Var', (56, 64))	('KSHV', 'Species', '37296', (184, 188))
155945	23818101	Human IRF-8 (hIRF-8) is the closest homolog (22% amino-acid identity) of vIRF-1 encoded by ORFK9; it is considered as a tumor suppressor and mutations in hIRF8 cause immunodeficiency and chronic myelogenous leukemia-like syndrome in mice.	('Human', 'Species', '9606', (0, 5))	('IRF-8', 'Gene', '3394', (6, 11))	('immunodeficiency', 'Phenotype', 'HP:0002721', (166, 182))	('IRF-8', 'Gene', '3394', (14, 19))	('hIRF8', 'Gene', '3394', (154, 159))	('cause', 'Reg', (160, 165))	('IRF-1', 'Gene', '3659', (74, 79))	('chronic myelogenous leukemia-like syndrome', 'Disease', (187, 229))	('tumor', 'Disease', (120, 125))	('hIRF8', 'Gene', (154, 159))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (195, 215))	('mutations', 'Var', (141, 150))	('mice', 'Species', '10090', (233, 237))	('IRF-8', 'Gene', (6, 11))	('IRF-1', 'Gene', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('IRF-8', 'Gene', (14, 19))	('immunodeficiency', 'Disease', (166, 182))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (187, 215))	('hIRF-8', 'Gene', '3394', (13, 19))	('hIRF-8', 'Gene', (13, 19))	('immunodeficiency', 'Disease', 'MESH:D007153', (166, 182))	('leukemia', 'Phenotype', 'HP:0001909', (207, 215))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('chronic myelogenous leukemia-like syndrome', 'Disease', 'MESH:D015464', (187, 229))
155946	23818101	The classification in latent and lytic replication patterns is relevant to our study because latency is generally assumed to be the state leading to cell proliferation, whereas lytic replication results in cell death and is therefore by definition antitumorigenic.	('death', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('results in', 'Reg', (195, 205))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Disease', (252, 257))	('lytic replication', 'Var', (177, 194))	('death', 'Disease', 'MESH:D003643', (211, 216))
155960	23818101	Our study revealed the -174 G>C promoter polymorphism of IL-6 (rs1800795) and the IL-6R SNP rs4129267, which is associated with a high level of serum level of sIL-6R (p=10-57), as gene interaction variants conferring excess risk for HIV-KS.	('rs1800795', 'Var', (63, 72))	('IL-6R', 'Gene', (160, 165))	('IL-6', 'Gene', (57, 61))	('-174 G>C', 'Mutation', 'rs1800795', (23, 31))	('rs4129267', 'Mutation', 'rs4129267', (92, 101))	('sIL-6R', 'Chemical', '-', (159, 165))	('IL-6R', 'Gene', '3570', (82, 87))	('IL-6R', 'Gene', '3570', (160, 165))	('rs4129267', 'Var', (92, 101))	('HIV-KS', 'Disease', (233, 239))	('IL-6R', 'Gene', (82, 87))	('rs1800795', 'Mutation', 'rs1800795', (63, 72))
155964	23818101	Second, polymorphism rs603965 (SNP 28) is the splice donor site G870A (Pro241Pro) that produces cyclin D1b, an alternate splice variant overexpressed in several cancer and associated with poor disease outcome.	('cyclin D1', 'Gene', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('G870A', 'Mutation', 'rs9344', (64, 69))	('G870A', 'Var', (64, 69))	('donor', 'Species', '9606', (53, 58))	('rs603965', 'Mutation', 'rs603965', (21, 29))	('rs603965', 'Var', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('polymorphism rs603965', 'Var', (8, 29))	('Pro241Pro', 'Mutation', 'rs9344', (71, 80))	('cancer', 'Disease', (161, 167))	('cyclin D1', 'Gene', '595', (96, 105))
155965	23818101	Third, regulation by cyclin D1 is a late event in the mitogenic signal transduction cascade; this suggests that dysregulation of cyclin D1 activity is a determinant and necessary event prior to engagement of the cell in the neoplastic process.	('dysregulation', 'Var', (112, 125))	('neoplastic process', 'Phenotype', 'HP:0002664', (224, 242))	('cyclin D1', 'Gene', '595', (129, 138))	('cyclin D1', 'Gene', (129, 138))	('men', 'Species', '9606', (200, 203))	('activity', 'MPA', (139, 147))	('cyclin D1', 'Gene', '595', (21, 30))	('cyclin D1', 'Gene', (21, 30))
155976	31811703	E/F expression leads to dysregulation of focal adhesions (FAs) enhancing the migratory capacity of EwS cells.	('FAs', 'Chemical', 'MESH:D053222', (58, 61))	('E/F expression', 'Var', (0, 14))	('enhancing', 'PosReg', (63, 72))	('focal adhesions', 'Protein', (41, 56))	('dysregulation', 'MPA', (24, 37))	('EwS', 'Gene', '2130', (99, 102))	('EwS', 'Gene', (99, 102))
155978	31811703	Employing different EwS cell lines as in vitro models, we found that key malignant properties of E/F are mediated via substrate-independent autophosphorylation of FAK on Y397.	('EwS', 'Gene', '2130', (20, 23))	('malignant properties', 'CPA', (73, 93))	('FAK', 'Protein', (163, 166))	('EwS', 'Gene', (20, 23))	('Y397', 'Var', (170, 174))	('autophosphorylation', 'MPA', (140, 159))	('mediated via', 'Reg', (105, 117))
155984	31811703	Since Y397 autophosphorylation can effectively be targeted by FAK inhibitor 15 (1,2,4,5-benzenetetraamine tetrahydrochloride (Y15), FAK might represent a valuable target for antimetastatic pharmacotherapy in EwS.	('EwS', 'Gene', '2130', (208, 211))	('Y397', 'Var', (6, 10))	('1,2,4,5-benzenetetraamine tetrahydrochloride', 'Chemical', 'MESH:C539551', (80, 124))	('EwS', 'Gene', (208, 211))
155995	31811703	Ectopic expression of constitutively active FAK rescues cancer cells from induced anoikis (Frisch et al., 1996).	('FAK', 'Gene', (44, 47))	('Ectopic expression', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('rescues', 'PosReg', (48, 55))	('induced anoikis', 'CPA', (74, 89))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
155998	31811703	The same group just recently showed that synergistic inhibition of FAK and Aurora B kinase effectively impairs EwS growth in multiple xenograft models, while another study revealed that dual inhibition of FAK and insulin-like growth factor-I receptor acts synergistically with conventional chemotherapy to induce apoptosis and impair invasion of EwS in vitro and in vivo (Moritake et al., 2019; Wang et al., 2019).	('EwS', 'Gene', (346, 349))	('inhibition', 'NegReg', (191, 201))	('EwS', 'Gene', '2130', (111, 114))	('induce', 'PosReg', (306, 312))	('synergistic', 'Var', (41, 52))	('apoptosis', 'CPA', (313, 322))	('impair', 'NegReg', (327, 333))	('invasion', 'CPA', (334, 342))	('EwS', 'Gene', (111, 114))	('impairs', 'NegReg', (103, 110))	('EwS', 'Gene', '2130', (346, 349))
155999	31811703	In line, another report showed that miR-138, via targeting FAK, inhibits proliferation and mobility and induces anoikis of EwS cells (Tanaka et al., 2016).	('miR-138', 'Var', (36, 43))	('EwS', 'Gene', (123, 126))	('proliferation', 'CPA', (73, 86))	('FAK', 'Gene', (59, 62))	('EwS', 'Gene', '2130', (123, 126))	('induces', 'Reg', (104, 111))	('inhibits', 'NegReg', (64, 72))	('anoikis', 'CPA', (112, 119))
156001	31811703	In this manuscript, we show that E/F-dependent autophosphorylation of FAK is a crucial mechanism underlying EwS aggressivity as it promotes a migratory phenotype and inhibits caspase-mediated apoptosis.	('migratory phenotype', 'CPA', (142, 161))	('EwS aggressivity', 'Disease', (108, 124))	('EwS aggressivity', 'Disease', 'MESH:D012512', (108, 124))	('inhibits', 'NegReg', (166, 174))	('caspase-mediated apoptosis', 'CPA', (175, 201))	('autophosphorylation', 'Var', (47, 66))	('promotes', 'PosReg', (131, 139))	('FAK', 'Gene', (70, 73))
156023	31811703	A set of prevalidated short interfering RNAs (Silencer Select siRNA; Life Technologies) was used to knock down EZR (Entrez Gene ID 7430, siRNA IDs s14796 and s14797) and FAK (Entrez Gene ID 5747, siRNA IDs s11485 and s707).	('Silencer', 'Disease', (46, 54))	('s707', 'Var', (217, 221))	('knock down', 'NegReg', (100, 110))	('EZR', 'Gene', (111, 114))	('EZR', 'Gene', '7430', (111, 114))	('s14797', 'Var', (158, 164))	('Silencer', 'Disease', 'None', (46, 54))
156042	31811703	In order to investigate E/F-dependent changes in FA gene expression levels, a DOX-inducible E/F knockdown in A673 EwS cells was performed, revealing decreased levels of Ezrin mRNA upon E/F knockdown (Fig.	('EwS', 'Gene', '2130', (114, 117))	('levels', 'MPA', (159, 165))	('DOX', 'Chemical', 'MESH:D004317', (78, 81))	('EwS', 'Gene', (114, 117))	('E/F knockdown', 'Var', (185, 198))	('decreased', 'NegReg', (149, 158))	('knockdown', 'Var', (189, 198))	('Ezrin mRNA', 'MPA', (169, 179))
156043	31811703	Correspondingly, IHC analyses of xenograft tumors derived from A673 cells in immunocompromised NSG (NOD/scid/gamma) mice showed significantly decreased Ezrin protein expression and Y397 phosphorylation of FAK upon loss of E/F while total FAK protein expression was unaffected (Fig.	('mice', 'Species', '10090', (116, 120))	('Ezrin protein', 'Protein', (152, 165))	('decreased', 'NegReg', (142, 151))	('FAK', 'Protein', (205, 208))	('loss', 'NegReg', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Y397', 'Var', (181, 185))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('Co', 'Chemical', 'MESH:C065987', (0, 2))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
156046	31811703	siRNA-based knockdown of Ezrin significantly impaired Y397 phosphorylation of FAK in A673, TC-32, and CADO-ES1 cells (Figs 1C and S1B).	('Y397 phosphorylation', 'MPA', (54, 74))	('CADO', 'Chemical', 'MESH:C034482', (102, 106))	('knockdown', 'Var', (12, 21))	('FAK', 'Protein', (78, 81))	('impaired', 'NegReg', (45, 53))	('TC-32', 'CellLine', 'CVCL:7151', (91, 96))
156050	31811703	A673, TC-32, and CADO-ES1 remained viable and showed persistent (TC-32, CADO-ES1) or enhanced (A673) Y397 phosphorylation of FAK when grown under nonadherent conditions on adhesion-free hydrogel plates (Fig.	('CADO', 'Chemical', 'MESH:C034482', (72, 76))	('Y397', 'Var', (101, 105))	('FAK', 'Protein', (125, 128))	('TC-32', 'CellLine', 'CVCL:7151', (6, 11))	('enhanced', 'PosReg', (85, 93))	('TC-32', 'CellLine', 'CVCL:7151', (65, 70))	('CADO', 'Chemical', 'MESH:C034482', (17, 21))	('TC-32', 'Var', (65, 70))
156054	31811703	The decrease in FAK phosphorylation upon Y15 treatment occurred in parallel with an increase in caspase-3 cleavage and apoptosis as shown by immunoblotting and ApoTox-Glo triplex assays.	('caspase-3', 'Gene', (96, 105))	('Y15', 'Var', (41, 44))	('caspase-3', 'Gene', '836', (96, 105))	('FAK', 'Protein', (16, 19))	('apoptosis', 'CPA', (119, 128))	('decrease', 'NegReg', (4, 12))	('increase', 'PosReg', (84, 92))
156056	31811703	Application of 10 microm Y15 significantly impaired cell migration of A673, TC-32, and CADO-ES1 in real-time cell migration assays using the xCeLLigence system (Fig.	('cell migration', 'CPA', (52, 66))	('Y15', 'Var', (25, 28))	('impaired', 'NegReg', (43, 51))	('CADO', 'Chemical', 'MESH:C034482', (87, 91))	('TC-32', 'CellLine', 'CVCL:7151', (76, 81))
156057	31811703	The impairment of EwS cell migration upon Y15 application paralleled the effect of FAK siRNA knockdown, underlining the specificity of the employed FAK inhibitor (Fig.	('knockdown', 'Var', (93, 102))	('EwS', 'Gene', (18, 21))	('EwS', 'Gene', '2130', (18, 21))	('impairment', 'NegReg', (4, 14))
156061	31811703	However, treatment of A673 cells with 10 microm Y15 prior to cell seeding significantly impaired tumor formation (P = 0.0122) and led to a significant decrease in the size of invasive experimental EwS (P = 0.0095) along with widespread tumor regression, necrosis, and microcalcification with only few residual tumor cell clusters (Fig.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('necrosis', 'Disease', (254, 262))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('impaired tumor', 'Disease', (88, 102))	('decrease', 'NegReg', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (97, 102))	('EwS', 'Gene', '2130', (197, 200))	('necrosis', 'Disease', 'MESH:D009336', (254, 262))	('tumor', 'Disease', (310, 315))	('Y15', 'Var', (48, 51))	('impaired tumor', 'Disease', 'MESH:D009369', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('EwS', 'Gene', (197, 200))	('tumor', 'Disease', (236, 241))
156065	31811703	Upon E/F knockdown, Ezrin mRNA levels were significantly decreased in A673 EwS cells.	('knockdown', 'Var', (9, 18))	('EwS', 'Gene', '2130', (75, 78))	('EwS', 'Gene', (75, 78))	('decreased', 'NegReg', (57, 66))	('Ezrin mRNA levels', 'MPA', (20, 37))
156067	31811703	Correspondingly, xenograft tumors derived from A673 cells after knockdown of E/F with significantly decreased Ezrin mRNA and protein expression showed diminished Y397 phosphorylation of FAK, although overall FAK mRNA and protein expression was unaffected.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Y397', 'Var', (162, 166))	('FAK', 'Protein', (186, 189))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('decreased', 'NegReg', (100, 109))	('E/F', 'Gene', (77, 80))	('diminished', 'NegReg', (151, 161))	('Co', 'Chemical', 'MESH:C065987', (0, 2))	('Ezrin', 'Protein', (110, 115))
156068	31811703	siRNA-based knockdown of Ezrin in the EwS cell lines A673, TC-32 (EWSR1-FLI1 fusion type 1), and CADO-ES1 (EWSR1-ERG fusion gene) (Matsui et al., 2003; Smith et al., 2006) significantly impaired Y397 phosphorylation of FAK in all investigated cell lines.	('impaired', 'NegReg', (186, 194))	('EwS', 'Gene', '2130', (38, 41))	('CADO', 'Chemical', 'MESH:C034482', (97, 101))	('TC-32', 'CellLine', 'CVCL:7151', (59, 64))	('EwS', 'Gene', (38, 41))	('EWSR1-FLI1', 'Gene', '2130;2313', (66, 76))	('knockdown', 'Var', (12, 21))	('Y397 phosphorylation', 'MPA', (195, 215))	('ERG', 'Gene', '2078', (113, 116))	('ERG', 'Gene', (113, 116))	('FAK', 'Protein', (219, 222))	('EWSR1-FLI1', 'Gene', (66, 76))
156073	31811703	Further in vitro analyses revealed that A673, TC-32, and CADO-ES1 remained viable and showed persistent or even enhanced FAK phosphorylation when grown under nonadherent conditions, which is of special interest since it had previously been shown that Y397 phosphorylation and activation of FAK inhibit anoikis (detachment-dependent apoptosis) (Frisch et al., 1996).	('enhanced', 'PosReg', (112, 120))	('FAK', 'Protein', (121, 124))	('anoikis', 'CPA', (302, 309))	('FAK', 'Gene', (290, 293))	('activation', 'PosReg', (276, 286))	('CADO', 'Chemical', 'MESH:C034482', (57, 61))	('A673', 'Var', (40, 44))	('inhibit', 'NegReg', (294, 301))	('Y397', 'Var', (251, 255))	('TC-32', 'CellLine', 'CVCL:7151', (46, 51))
156074	31811703	There was no detectable baseline FA phosphorylation on Y576/577 in all investigated EwS cell lines, and baseline Y925 phosphorylation of FAK could only be detected in CADO-ES1 (Fig.	('CADO', 'Chemical', 'MESH:C034482', (167, 171))	('Y576/577', 'Var', (55, 63))	('EwS', 'Gene', '2130', (84, 87))	('Y925', 'Var', (113, 117))	('EwS', 'Gene', (84, 87))
156075	31811703	S1F), indicating that Y397 might represent the most relevant FAK tyrosine phosphorylation site in EwS.	('EwS', 'Gene', (98, 101))	('EwS', 'Gene', '2130', (98, 101))	('Y397', 'Var', (22, 26))	('tyrosine', 'Chemical', 'None', (65, 73))
156076	31811703	This is in line with previous reports indicating that the Y397 autophosphorylation site is the primary site responsible for the pro-migratory, pro-invasive, and antiapoptotic role of FAK in tumor cells (Megison et al., 2014).	('Y397', 'Var', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('pro-migratory', 'CPA', (128, 141))	('tumor', 'Disease', (190, 195))
156077	31811703	The compounds PF-573228 (PF-228) and Y15 are potent and specific inhibitors of FAK autophosphorylation activity (Golubovskaya et al., 2015; Slack-Davis et al., 2007).	('Y15', 'Var', (37, 40))	('FAK autophosphorylation activity', 'MPA', (79, 111))	('inhibitors', 'NegReg', (65, 75))	('PF-573228', 'Chemical', 'MESH:C521108', (14, 23))	('PF-573228', 'Var', (14, 23))	('PF-228', 'Chemical', 'MESH:C521108', (25, 31))
156078	31811703	Y15 has previously been shown to decrease cell viability and clonogenicity of various carcinomas and to increase detachment, cause apoptosis, and inhibit invasion of glioblastoma cells through the inhibition of FAK phosphorylation (Golubovskaya et al., 2013; Zhang et al., 2016).	('inhibit', 'NegReg', (146, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('decrease', 'NegReg', (33, 41))	('cell viability', 'CPA', (42, 56))	('carcinomas', 'Disease', (86, 96))	('carcinomas', 'Disease', 'MESH:D002277', (86, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('inhibition', 'NegReg', (197, 207))	('Y15', 'Var', (0, 3))	('FAK', 'Protein', (211, 214))	('increase detachment', 'Disease', (104, 123))	('invasion', 'CPA', (154, 162))	('increase detachment', 'Disease', 'MESH:D012163', (104, 123))	('cause', 'Reg', (125, 130))	('apoptosis', 'CPA', (131, 140))	('glioblastoma', 'Disease', (166, 178))	('glioblastoma', 'Disease', 'MESH:D005909', (166, 178))	('clonogenicity', 'CPA', (61, 74))
156079	31811703	We could confirm that both Y15 and PF-228 (data not shown) abrogate Y397 phosphorylation of FAK in EwS; we selected Y15 for further experiments since the in vivo activity of the compound had already been documented (Hochwald et al., 2009).	('PF-228', 'Var', (35, 41))	('PF-228', 'Chemical', 'MESH:C521108', (35, 41))	('Y397 phosphorylation', 'MPA', (68, 88))	('FAK', 'Protein', (92, 95))	('EwS', 'Gene', '2130', (99, 102))	('EwS', 'Gene', (99, 102))	('abrogate', 'NegReg', (59, 67))
156081	31811703	The decrease in FAK phosphorylation upon Y15 treatment occurred in parallel with an increase in caspase-3 cleavage and apoptosis (as shown by ApoTox and FACS assay) and a decrease in the number and size of FAs together as well as dorsal actin stress fibers.	('caspase-3', 'Gene', (96, 105))	('FAs', 'Chemical', 'MESH:D053222', (206, 209))	('dorsal actin stress fibers', 'CPA', (230, 256))	('decrease', 'NegReg', (171, 179))	('Y15', 'Var', (41, 44))	('caspase-3', 'Gene', '836', (96, 105))	('FAK', 'Protein', (16, 19))	('apoptosis', 'CPA', (119, 128))	('decrease', 'NegReg', (4, 12))
156083	31811703	Moreover, the application of Y15 significantly impaired cell migration of all investigated EwS cell lines in real-time cell migration assays together with a decrease in active Rho levels as shown by Rho activity pull-down assays.	('Y15', 'Var', (29, 32))	('decrease', 'NegReg', (157, 165))	('cell migration', 'CPA', (56, 70))	('EwS', 'Gene', '2130', (91, 94))	('impaired', 'NegReg', (47, 55))	('active Rho levels', 'MPA', (169, 186))	('EwS', 'Gene', (91, 94))
156084	31811703	Since FAK has been identified as a potential therapeutic target in EwS in tyrosine kinase screening assay, and since migration and invasion of EwS depend on the activity of small Rho-GTPases (Crompton et al., 2013; Krook et al., 2014), these findings support a potential therapeutic role of FAK inhibition in prevention or slowing down metastatic dissemination of EwS.	('metastatic dissemination', 'CPA', (336, 360))	('invasion', 'CPA', (131, 139))	('EwS', 'Gene', (143, 146))	('EwS', 'Gene', '2130', (364, 367))	('migration', 'CPA', (117, 126))	('inhibition', 'Var', (295, 305))	('tyrosine', 'Chemical', 'None', (74, 82))	('EwS', 'Gene', (364, 367))	('EwS', 'Gene', '2130', (67, 70))	('FAK', 'Gene', (291, 294))	('EwS', 'Gene', (67, 70))	('GTP', 'Chemical', 'MESH:D006160', (183, 186))	('activity', 'MPA', (161, 169))	('EwS', 'Gene', '2130', (143, 146))	('slowing down', 'NegReg', (323, 335))
156086	31811703	Treatment of A673 cells with 10 microm Y15 prior to cell seeding significantly impaired tumor xenograft formation (P = 0.0122) and led to a significant decrease in the size of invasive experimental EwS (P = 0.0095) along with loss of FAK phosphorylation, widespread tumor regression, and necrosis.	('EwS', 'Gene', (198, 201))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('impaired tumor', 'Disease', 'MESH:D009369', (79, 93))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('Y15', 'Var', (39, 42))	('necrosis', 'Disease', 'MESH:D009336', (288, 296))	('EwS', 'Gene', '2130', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('necrosis', 'Disease', (288, 296))	('tumor', 'Disease', (266, 271))	('loss', 'NegReg', (226, 230))	('FAK', 'Protein', (234, 237))	('tumor', 'Disease', (88, 93))	('decrease', 'NegReg', (152, 160))	('impaired tumor', 'Disease', (79, 93))
156087	31811703	In summary, the findings presented here lead to a model where EWSR1-ETS-dependent expression of Ezrin, which can be demonstrated in the vast majority of EwS patient tumor samples, leads to SRC-independent autophosphorylation of FAK on tyrosine 397 that impairs apoptosis/anoikis and enhances focal adhesion formation as well as Rho-dependent cell migration of EwS cells.	('tyrosine', 'Chemical', 'None', (235, 243))	('impairs', 'NegReg', (253, 260))	('EwS', 'Gene', (360, 363))	('apoptosis/anoikis', 'CPA', (261, 278))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('EwS', 'Gene', (153, 156))	('FAK', 'Protein', (228, 231))	('SRC', 'Gene', '6714', (189, 192))	('EwS', 'Gene', '2130', (360, 363))	('patient', 'Species', '9606', (157, 164))	('tyrosine 397', 'Var', (235, 247))	('EwS', 'Gene', '2130', (153, 156))	('SRC', 'Gene', (189, 192))	('tumor', 'Disease', (165, 170))	('autophosphorylation', 'MPA', (205, 224))	('enhances', 'PosReg', (283, 291))	('focal adhesion formation', 'CPA', (292, 316))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Rho-dependent cell migration', 'CPA', (328, 356))
156088	31811703	Our results show that key tumorigenic properties of EwS cells depend on Y397 autophosphorylation of FAK, further underlining the crucial role of FA homeostasis in cancer cells (Sulzmaier et al., 2014), and a possible role of FAK inhibitors in the treatment of EwS.	('Y397', 'Var', (72, 76))	('EwS', 'Gene', '2130', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('EwS', 'Gene', (52, 55))	('EwS', 'Gene', '2130', (260, 263))	('FAK', 'Gene', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('EwS', 'Gene', (260, 263))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (163, 169))
156112	29357824	Overall survival (OS) was also significantly increased with pazopanib despite cross-over from placebo treatment to pazopanib treatment.	('pazopanib', 'Chemical', 'MESH:C516667', (60, 69))	('increased', 'PosReg', (45, 54))	('OS', 'Chemical', '-', (18, 20))	('pazopanib', 'Var', (60, 69))	('pazopanib', 'Chemical', 'MESH:C516667', (115, 124))	('Overall survival', 'CPA', (0, 16))
156123	29357824	Fifty to 60 % of the ESS harbour translocations involving JAZF1.	('JAZF1', 'Gene', '221895', (58, 63))	('JAZF1', 'Gene', (58, 63))	('translocations', 'Var', (33, 47))	('ESS', 'Disease', (21, 24))
156124	29357824	Recently, it was found that high grade ESS (negative for CD10, positive for Cyclin D1) are characterised by a t(10;17)(q22;p13) translocation resulting in a YWHAE-FAM22 (also known as YWHAE-NUTM2A/B) gene fusion.	('YWHAE', 'Gene', (157, 162))	('Cyclin D1', 'Gene', '595', (76, 85))	('YWHAE', 'Gene', '7531', (184, 189))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (110, 127))	('Cyclin D1', 'Gene', (76, 85))	('NUTM2A/B', 'Gene', '728118;729262', (190, 198))	('t(10;17)(q22;p13', 'Var', (110, 126))	('CD10', 'Gene', (57, 61))	('YWHAE', 'Gene', '7531', (157, 162))	('CD10', 'Gene', '4311', (57, 61))	('YWHAE', 'Gene', (184, 189))	('NUTM2A/B', 'Gene', (190, 198))
156166	29357824	Two SNP variants in CYP1A2 (rs762551 and rs2470890) and one in SLCO1B1 (rs4149057) were detected, but no evidence exists that these polymorphisms cause elevated levels of pazopanib.	('CYP1A2', 'Gene', (20, 26))	('SLCO1B1', 'Gene', (63, 70))	('pazopanib', 'Chemical', 'MESH:C516667', (171, 180))	('elevated', 'PosReg', (152, 160))	('rs762551', 'Var', (28, 36))	('rs2470890', 'Mutation', 'rs2470890', (41, 50))	('rs2470890', 'Var', (41, 50))	('SLCO1B1', 'Gene', '10599', (63, 70))	('CYP1A2', 'Gene', '1544', (20, 26))	('cause', 'Reg', (146, 151))	('rs4149057', 'Mutation', 'rs4149057', (72, 81))	('levels', 'MPA', (161, 167))	('rs762551', 'Mutation', 'rs762551', (28, 36))
156188	29357824	No specific data on the use of pazopanib in ESS is available, but this case report shows that pazopanib induced a partial response and prolonged PFS of 9 months which is more than the median PFS in the PALETTE study.	('PFS', 'MPA', (145, 148))	('pazopanib', 'Chemical', 'MESH:C516667', (31, 40))	('prolonged', 'PosReg', (135, 144))	('pazopanib', 'Chemical', 'MESH:C516667', (94, 103))	('pazopanib', 'Var', (94, 103))
156195	29357824	Second, pazopanib was found to result in a good response in this patient with a YWHAE-FAM22A/B translocated ESS which may be related to the KIT overexpression in these tumours.	('YWHAE', 'Gene', '7531', (80, 85))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('pazopanib', 'Chemical', 'MESH:C516667', (8, 17))	('FAM22A', 'Gene', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('patient', 'Species', '9606', (65, 72))	('YWHAE', 'Gene', (80, 85))	('FAM22A', 'Gene', '728118', (86, 92))	('tumours', 'Disease', (168, 175))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('translocated', 'Var', (95, 107))
156196	29357824	In conclusion this case illustrates two important new points: ALAT Alanine aminotransferase ASAT Aspartate aminotransferase CTCAE Common Terminology Criteria for Adverse Events ESS Endometrial stromal sarcoma NCI National Cancer Institute OS Overall survival PDGFR Platelet derived growth factor receptors PFS Progression free survival RCC  Renal-cell carcinoma SmPC Summary of product characteristics SNP Single nucleotide polymorphism TKI Tyrosine kinase inhibitor VEGFR Vascular endothelial growth factor receptors AV and HG did the conception and design of the case report, did a review of the literature and wrote the case report.	('VEGFR', 'Gene', '3791', (467, 472))	('Vascular endothelial growth factor', 'Gene', '7422', (473, 507))	('ALAT', 'Gene', '2875', (62, 66))	('Cancer', 'Disease', 'MESH:D009369', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('VEGFR', 'Gene', (467, 472))	('ASAT', 'Disease', 'MESH:C536358', (92, 96))	('ALAT', 'Gene', (62, 66))	('OS', 'Chemical', '-', (239, 241))	('RCC', 'Disease', (336, 339))	('AV', 'Disease', 'MESH:D054537', (518, 520))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('sarcoma', 'Disease', 'MESH:D012509', (201, 208))	('PDGFR', 'Gene', (259, 264))	('PDGFR', 'Gene', '5159', (259, 264))	('Tyrosine kinase', 'Gene', '7294', (441, 456))	('sarcoma', 'Disease', (201, 208))	('ASAT', 'Disease', (92, 96))	('Renal-cell carcinoma', 'Disease', 'MESH:C538614', (341, 361))	('Single nucleotide polymorphism', 'Var', (406, 436))	('RCC', 'Disease', 'MESH:C538614', (336, 339))	('Tyrosine kinase', 'Gene', (441, 456))	('Renal-cell carcinoma', 'Disease', (341, 361))	('Cancer', 'Disease', (222, 228))	('Vascular endothelial growth factor', 'Gene', (473, 507))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))
156205	24989082	According to PicTar and Miranda algorithms, which predicted CDKN1A (p21) as a putative target of miR-17, a luciferase assay was performed and revealed that miR-17 directly targets the 3'-UTR of p21 mRNA.	('miR-17', 'Var', (156, 162))	('CDKN1A', 'Gene', (60, 66))	('Miranda algorithms', 'Disease', (24, 42))	('CDKN1A', 'Gene', '1026', (60, 66))	('p21', 'Protein', (194, 197))	('Miranda algorithms', 'Disease', 'MESH:C537402', (24, 42))
156207	24989082	Meanwhile, introduction of anti-miR-17 in Fuji and HS-SYII cells significantly decreased cell growth, consistent with rescued expression of p21.	('expression', 'MPA', (126, 136))	('decreased', 'NegReg', (79, 88))	('p21', 'Var', (140, 143))	('anti-miR-17', 'Var', (27, 38))	('cell growth', 'CPA', (89, 100))	('rescued', 'PosReg', (118, 125))	('HS-SYII', 'CellLine', 'CVCL:W404', (51, 58))
156214	24989082	MicroRNA (miRNA) are small, non-coding RNA ranging from 18 to 24 nucleotides in length that negatively regulate gene expression at the post-transcriptional level, primarily through base pairing to the 3'-UTR of target mRNA.	('gene expression', 'MPA', (112, 127))	('base pairing', 'Var', (181, 193))	('negatively', 'NegReg', (92, 102))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('regulate', 'Reg', (103, 111))
156264	24989082	The number of Ki-67-positive proliferating cells within the tumor was significantly increased by miR-17-overexpresion (Fig.3d).	('miR-17-overexpresion', 'Var', (97, 117))	('Ki-67-positive', 'Gene', (14, 28))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increased', 'PosReg', (84, 93))	('tumor', 'Disease', (60, 65))
156265	24989082	Contrary of this, p21 positive cells were significantly reduced in the tumors formed in miR-17 overexpressing Fuji cells (Fig.3d,e).	('p21', 'Var', (18, 21))	('miR-17', 'Gene', (88, 94))	('reduced', 'NegReg', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('overexpressing', 'PosReg', (95, 109))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
156306	24989082	Upregulation of p21 protein by miR-17 depletion might exert potent effects in the therapy of human synovial sarcoma.	('Upregulation', 'PosReg', (0, 12))	('miR-17', 'Gene', (31, 37))	('synovial sarcoma', 'Disease', (99, 115))	('protein', 'Protein', (20, 27))	('human', 'Species', '9606', (93, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (99, 115))	('depletion', 'Var', (38, 47))	('synovial sarcoma', 'Disease', 'MESH:D013584', (99, 115))	('p21 protein', 'Protein', (16, 27))
156558	29156702	The majority of primary GCTB cell lines (n=15) exposed for 48h to LS were positive to MSC markers such as CD105 and CD44, with a median of 42% and 29%, respectively, across a variety of GCTBs.	('CD44', 'Gene', '960', (116, 120))	('LS', 'Chemical', '-', (66, 68))	('CD44', 'Gene', (116, 120))	('CD105', 'Var', (106, 111))	('GCTBs', 'Chemical', '-', (186, 191))	('positive', 'Reg', (74, 82))
156637	29156702	Primary MAb antibody incubation was performed for 1h at room temperature, and antibodies used were: CD31 (ab28364; Abcam), CD34 (EP373Y; ab81289; Abcam) or Alexa Fluor 647 Phalloidin (A22287; Life Technologies).	('1h', 'Chemical', '-', (50, 52))	('CD34', 'Gene', (123, 127))	('CD34', 'Gene', '947', (123, 127))	('Alexa Fluor 647 Phalloidin', 'Chemical', '-', (156, 182))	('CD31', 'Gene', (100, 104))	('CD31', 'Gene', '5175', (100, 104))	('EP373Y;', 'Var', (129, 136))
156644	29156702	Membranes were incubated with the following antibodies: Vimentin (V9; Abcam), Phospho-AKT (Ser473, D9E; Cell Signaling Technology), VE-Cadherin (ab33168 abcam), m-TOR (sc-293089) and N-cadherin (H63) (all from Santa Cruz Biotechnology), and beta-actin (Cell Signaling Technology).	('VE-Cadherin', 'Gene', '1003', (132, 143))	('Vimentin', 'Gene', (56, 64))	('TOR', 'Gene', (163, 166))	('TOR', 'Gene', '6097', (163, 166))	('sc-293089', 'Var', (168, 177))	('Vimentin', 'Gene', '7431', (56, 64))	('Ser473', 'Chemical', '-', (91, 97))	('N-cadherin', 'Gene', (183, 193))	('beta-actin', 'Gene', '728378', (241, 251))	('VE-Cadherin', 'Gene', (132, 143))	('beta-actin', 'Gene', (241, 251))	('N-cadherin', 'Gene', '1000', (183, 193))
156782	32717815	It is important to understand the impact of infection on the mutation of the immunoglobulin (Ig) gene and the selective processes that the infected cell undergoes to gain access to long-lived memory B cells.	('infection', 'Disease', (44, 53))	('infected', 'Disease', (139, 147))	('infection', 'Disease', 'MESH:D007239', (44, 53))	('mutation', 'Var', (61, 69))	('immunoglobulin', 'Gene', (77, 91))	('Ig', 'Gene', (93, 95))	('immunoglobulin', 'Gene', 'None', (77, 91))	('infected', 'Disease', 'MESH:D007239', (139, 147))
156852	32717815	In addition, MHV68 can immortalize fetal liver B cells ex vivo, and the latency-associated proteins LANA and v-cyclin, which are conserved with KSHV, are required.	('MHV68', 'Species', '1440122', (13, 18))	('LANA', 'Gene', '77836', (100, 104))	('KSHV', 'Species', '37296', (144, 148))	('LANA', 'Gene', (100, 104))	('cyclin', 'Gene', '5111', (111, 117))	('MHV68', 'Var', (13, 18))	('KS', 'Phenotype', 'HP:0100726', (144, 146))	('cyclin', 'Gene', (111, 117))
156869	32717815	Mutations can increase BCR affinity and give cells an advantage for antigen interaction and uptake.	('advantage', 'PosReg', (54, 63))	('antigen', 'CPA', (68, 75))	('Mutations', 'Var', (0, 9))	('R', 'Chemical', 'MESH:D001120', (25, 26))	('BCR affinity', 'CPA', (23, 35))	('uptake', 'CPA', (92, 98))	('increase', 'PosReg', (14, 22))
156872	32717815	Subsequent mutagenic repair results in either a mutation during SHM or DNA double-strand break (DSB) during CSR.	('S', 'Chemical', 'MESH:D013455', (97, 98))	('mutagenic', 'Var', (11, 20))	('SHM', 'Gene', (64, 67))	('mutation', 'Var', (48, 56))	('results in', 'Reg', (28, 38))	('S', 'Chemical', 'MESH:D013455', (64, 65))	('S', 'Chemical', 'MESH:D013455', (109, 110))	('S', 'Chemical', 'MESH:D013455', (0, 1))
156876	32717815	Most mature B lymphomas carry translocations with the Igh locus being a common partner (MYC, BCL6, etc.).	('Igh', 'Gene', '3492', (54, 57))	('lymphomas', 'Disease', 'MESH:D008223', (14, 23))	('MYC', 'Gene', '4609', (88, 91))	('lymphomas', 'Phenotype', 'HP:0002665', (14, 23))	('BCL6', 'Gene', (93, 97))	('B lymphomas', 'Phenotype', 'HP:0012191', (12, 23))	('translocations', 'Var', (30, 44))	('Igh', 'Gene', (54, 57))	('MYC', 'Gene', (88, 91))	('lymphoma', 'Phenotype', 'HP:0002665', (14, 22))	('lymphomas', 'Disease', (14, 23))	('BCL6', 'Gene', '604', (93, 97))
156879	32717815	These translocations bare hallmarks of either aberrant RAG1/2 mediated V(D)J or AID mediated CSR events as translocations junctions occur at J exons or IGH switch regions.	('IGH', 'Gene', '3492', (152, 155))	('IGH', 'Gene', (152, 155))	('RAG1/2', 'Gene', (55, 61))	('RAG1/2', 'Gene', '5896;5897', (55, 61))	('AID', 'Gene', '57379', (80, 83))	('AID', 'Gene', (80, 83))	('aberrant', 'Var', (46, 54))	('translocations', 'MPA', (107, 121))
156882	32717815	Break analysis performed on a genome wide scale found AID-dependent DSBs on a variety of transcribed genes including those associated with recurrent translocations in lymphomas.	('DSBs', 'Var', (68, 72))	('transcribed genes', 'Gene', (89, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (167, 175))	('AID', 'Gene', '57379', (54, 57))	('AID', 'Gene', (54, 57))	('lymphomas', 'Disease', (167, 176))	('lymphomas', 'Disease', 'MESH:D008223', (167, 176))	('DSBs', 'Chemical', 'MESH:C007563', (68, 72))	('lymphomas', 'Phenotype', 'HP:0002665', (167, 176))
156885	32717815	AID mis-expression induces genome instability and cancer.	('induces', 'Reg', (19, 26))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mis-expression', 'Var', (4, 18))	('genome instability', 'CPA', (27, 45))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('AID', 'Gene', '57379', (0, 3))	('AID', 'Gene', (0, 3))
156886	32717815	Within B cells, deregulation of AID protein levels or post-translational modifications that control activity result in genome instability and chromosome translocations.	('post-translational modifications', 'Var', (54, 86))	('AID', 'Gene', '57379', (32, 35))	('AID', 'Gene', (32, 35))	('result in', 'Reg', (109, 118))	('genome instability', 'CPA', (119, 137))	('deregulation', 'Var', (16, 28))	('chromosome translocations', 'CPA', (142, 167))
156890	32717815	BCR signaling functions to regulate the tolerance process which can alter specificity by receptor editing or eliminate the cell via anergy or cell death.	('R', 'Chemical', 'MESH:D001120', (2, 3))	('death', 'Disease', 'MESH:D003643', (147, 152))	('alter', 'Reg', (68, 73))	('eliminate', 'NegReg', (109, 118))	('receptor editing', 'Var', (89, 105))	('death', 'Disease', (147, 152))	('specificity', 'MPA', (74, 85))
156911	32717815	In a transgenic mouse model that limits LMP1 and LMP2A expression to the germinal center, the depletion of NK and T cells leads to plasmablast expansion, and upregulation of inflammatory cytokines, and mortality.	('mortality', 'Disease', (202, 211))	('LMP1', 'Gene', '9260', (40, 44))	('LMP1', 'Gene', (40, 44))	('depletion', 'Var', (94, 103))	('limits', 'NegReg', (33, 39))	('mortality', 'Disease', 'MESH:D003643', (202, 211))	('LMP2A', 'Gene', (49, 54))	('transgenic', 'Species', '10090', (5, 15))	('mouse', 'Species', '10090', (16, 21))	('LMP2A', 'Gene', '17494231', (49, 54))	('plasmablast expansion', 'CPA', (131, 152))	('inflammatory cytokines', 'MPA', (174, 196))	('upregulation', 'PosReg', (158, 170))
156936	32717815	Thus, receptor editing might reflect a much larger reprogramming event in response to KSHV infection.	('KSHV infection', 'Disease', 'MESH:D007239', (86, 100))	('receptor editing', 'Var', (6, 22))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('KSHV infection', 'Disease', (86, 100))
156940	32717815	MCD retains IgM and variable expression of CD30 and CD27 while PEL lacks many typical B cell surface receptors including CD19, CD29, CD22 and surface Ig, but express CD30 and CD138.	('CD19', 'Gene', '930', (121, 125))	('CD29', 'Gene', '3688', (127, 131))	('MCD', 'Disease', 'MESH:D012514', (0, 3))	('CD22', 'Gene', '933', (133, 137))	('CD22', 'Gene', (133, 137))	('CD30', 'Gene', '943', (166, 170))	('CD30', 'Gene', (166, 170))	('MCD', 'Disease', (0, 3))	('CD30', 'Gene', (43, 47))	('CD29', 'Gene', (127, 131))	('CD27', 'Gene', '939', (52, 56))	('CD30', 'Gene', '943', (43, 47))	('IgM', 'Gene', '16019', (12, 15))	('CD19', 'Gene', (121, 125))	('IgM', 'Gene', (12, 15))	('CD138', 'Var', (175, 180))	('CD27', 'Gene', (52, 56))	('PEL', 'Phenotype', 'HP:0030069', (63, 66))
156947	32717815	KSHV was also associated with an increase in EBV lytic gene expression.	('expression', 'MPA', (60, 70))	('KSHV', 'Var', (0, 4))	('KSHV', 'Species', '37296', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('EBV lytic gene', 'Gene', (45, 59))	('increase', 'PosReg', (33, 41))	('EBV', 'Species', '10376', (45, 48))
156962	32717815	Thus, KSHV directly alters the biology of the B cell it infects, while also shaping the microenvironment.	('microenvironment', 'MPA', (88, 104))	('KSHV', 'Species', '37296', (6, 10))	('KSHV', 'Var', (6, 10))	('men', 'Species', '9606', (100, 103))	('KS', 'Phenotype', 'HP:0100726', (6, 8))	('alters', 'Reg', (20, 26))	('shaping', 'Reg', (76, 83))
156963	32717815	With regard to direct effects on the Ig locus, expression of the potent NF-kappaB activator vFLIP upregulates AID while KSHV miRNAs, K12-11 and K12-5 contribute to post-transcriptional suppression of AID, perhaps to counter AID-mediated suppression of KSHV reactivation.	('AID', 'Gene', (224, 227))	('vFLIP', 'Gene', '4961494', (92, 97))	('KSHV', 'Species', '37296', (252, 256))	('AID', 'Gene', '57379', (224, 227))	('AID', 'Gene', (110, 113))	('vFLIP', 'Gene', (92, 97))	('AID', 'Gene', '57379', (110, 113))	('AID', 'Gene', '57379', (200, 203))	('AID', 'Gene', (200, 203))	('R', 'Chemical', 'MESH:D001120', (127, 128))	('NF-kappaB', 'Gene', '4790', (72, 81))	('upregulates', 'PosReg', (98, 109))	('K12-5', 'Var', (144, 149))	('NF-kappaB', 'Gene', (72, 81))	('KS', 'Phenotype', 'HP:0100726', (252, 254))	('KS', 'Phenotype', 'HP:0100726', (120, 122))	('KSHV', 'Species', '37296', (120, 124))
156984	32717815	Approaches to test how factors encoded by the human GHV influence the infected B cells include gain of function experiments that introduce human GHV genes into MHV68 or genetically complement MHV68 mutants.	('GHV', 'Chemical', '-', (145, 148))	('gain of function', 'PosReg', (95, 111))	('GHV genes', 'Gene', (145, 154))	('MHV68', 'Species', '1440122', (160, 165))	('GHV', 'Chemical', '-', (52, 55))	('men', 'Species', '9606', (187, 190))	('men', 'Species', '9606', (118, 121))	('MHV68', 'Gene', (160, 165))	('human', 'Species', '9606', (46, 51))	('MHV68', 'Species', '1440122', (192, 197))	('infected', 'Disease', 'MESH:D007239', (70, 78))	('human', 'Species', '9606', (139, 144))	('mutants', 'Var', (198, 205))	('MHV68', 'Gene', (192, 197))	('infected', 'Disease', (70, 78))
157001	32717815	As with KSHV and EBV, stimuli that drive B cell activation such as cross-linking of surface Ig cue MHV68 reactivation from latency.	('cross-linking', 'Var', (67, 80))	('reactivation', 'MPA', (105, 117))	('MHV68', 'Species', '1440122', (99, 104))	('KS', 'Phenotype', 'HP:0100726', (8, 10))	('KSHV', 'Species', '37296', (8, 12))	('EBV', 'Species', '10376', (17, 20))	('MHV68', 'Gene', (99, 104))
157008	32717815	B cell-specific loss of the host factor IRF-1 reduces MHV68 latency and GC expansion and reduces the activation of the tyrosine phosphatase SHP-1, another host determinant of latency.	('reduces', 'NegReg', (89, 96))	('IRF-1', 'Gene', '3659', (40, 45))	('SHP-1', 'Gene', (140, 145))	('MHV68', 'Species', '1440122', (54, 59))	('latency', 'MPA', (60, 67))	('MHV68', 'Gene', (54, 59))	('IRF-1', 'Gene', (40, 45))	('loss', 'Var', (16, 20))	('SHP-1', 'Gene', '8431', (140, 145))	('reduces', 'NegReg', (46, 53))	('GC expansion', 'CPA', (72, 84))	('activation', 'MPA', (101, 111))
157021	32717815	The viral bcl-2 functions to block apoptosis and autophagy and loss of bcl-2 impairs latency in both immature and transitional B cells and reactivation from latency in the spleen.	('reactivation', 'CPA', (139, 151))	('impairs', 'NegReg', (77, 84))	('loss', 'Var', (63, 67))	('bcl-2', 'Gene', '596', (71, 76))	('autophagy', 'CPA', (49, 58))	('latency', 'CPA', (85, 92))	('bcl-2', 'Gene', (10, 15))	('bcl-2', 'Gene', '596', (10, 15))	('apoptosis', 'CPA', (35, 44))	('bcl-2', 'Gene', (71, 76))
157023	32717815	Genetic complementation by the EBER1 non-coding RNA of EBV is a striking example of functional conservation.	('EBV', 'Species', '10376', (55, 58))	('Genetic complementation', 'Var', (0, 23))	('men', 'Species', '9606', (14, 17))	('R', 'Chemical', 'MESH:D001120', (34, 35))	('EBER1 non-coding RNA', 'Var', (31, 51))	('EBV', 'Gene', (55, 58))	('R', 'Chemical', 'MESH:D001120', (48, 49))
157028	32717815	MHV68 latent cell lines derived from fetal liver immortalization have a preplasmablast profile, B220+ CD19+ IgG2a+ IgD-/IgM- Igkappa+ CD5- c-kit- CD43- and cause tumors when transferred into immune deficient mice.	('CD5', 'Gene', (134, 137))	('Igkappa', 'Gene', '692182', (125, 132))	('IgM', 'Gene', '16019', (120, 123))	('B220+', 'Var', (96, 101))	('c-kit', 'Gene', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('CD43', 'Gene', (146, 150))	('CD5', 'Gene', '921', (134, 137))	('MHV68', 'Gene', (0, 5))	('Igkappa', 'Gene', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('IgM', 'Gene', (120, 123))	('MHV68', 'Species', '1440122', (0, 5))	('CD19', 'Gene', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('c-kit', 'Gene', '3815', (139, 144))	('CD43', 'Gene', '6693', (146, 150))	('mice', 'Species', '10090', (208, 212))	('cause', 'Reg', (156, 161))	('CD19', 'Gene', '930', (102, 106))	('tumors', 'Disease', (162, 168))	('immune deficient', 'Phenotype', 'HP:0002721', (191, 207))
157030	32717815	Taken together, as seen with the human GHV, viral-dependent gene expression drives lymphoproliferation in the context of immune deficiency and these lymphoproliferations have markers indicative of aberrant B cell differentiation.	('viral-dependent gene expression', 'Var', (44, 75))	('immune deficiency', 'Disease', 'MESH:D007153', (121, 138))	('aberrant B cell differentiation', 'Phenotype', 'HP:0005357', (197, 228))	('lymphoproliferation', 'Disease', (83, 102))	('drives', 'PosReg', (76, 82))	('human', 'Species', '9606', (33, 38))	('aberrant B cell', 'Phenotype', 'HP:0002846', (197, 212))	('GHV', 'Chemical', '-', (39, 42))	('immune deficiency', 'Phenotype', 'HP:0002721', (121, 138))	('immune deficiency', 'Disease', (121, 138))
157034	32717815	When PBMCs are sorted into naive (IgD+ CD27-), switched memory (IgD- CD27+) and non-switched memory (IgD+ CD27+) B cells and subsequently infected with EBV to generate LCL, mutations accumulate in Ig variable regions of naive cells (Table 1).	('CD27', 'Gene', '939', (39, 43))	('EBV', 'Species', '10376', (152, 155))	('CD27', 'Gene', (39, 43))	('infected', 'Disease', 'MESH:D007239', (138, 146))	('CD27', 'Gene', '939', (106, 110))	('accumulate', 'PosReg', (183, 193))	('CD27', 'Gene', (106, 110))	('mutations', 'Var', (173, 182))	('CD27', 'Gene', (69, 73))	('infected', 'Disease', (138, 146))	('CD27', 'Gene', '939', (69, 73))
157041	32717815	One feature of the antigen selection process is the accumulation of replacement mutations in antigen-interacting CDR regions of Igs and a higher R/S (replacement to silent) ratio in CDRs than the structural framework regions of V gene segments.	('R', 'Chemical', 'MESH:D001120', (184, 185))	('R', 'Chemical', 'MESH:D001120', (145, 146))	('S', 'Chemical', 'MESH:D013455', (147, 148))	('men', 'Species', '9606', (238, 241))	('replacement mutations', 'Var', (68, 89))	('CDR', 'Gene', (113, 116))	('men', 'Species', '9606', (75, 78))	('R/S', 'MPA', (145, 148))	('men', 'Species', '9606', (157, 160))	('higher', 'PosReg', (138, 144))	('R', 'Chemical', 'MESH:D001120', (115, 116))
157042	32717815	EBV-infected memory B cells accumulate mutations in Ig genes in a similar rate to non-infected cells, with R/S ratios higher in CDRs.	('higher', 'Reg', (118, 124))	('Ig genes', 'Gene', (52, 60))	('EBV-infected memory B', 'Disease', 'MESH:D020031', (0, 21))	('infected', 'Disease', 'MESH:D007239', (4, 12))	('R', 'Chemical', 'MESH:D001120', (130, 131))	('infected', 'Disease', (4, 12))	('mutations', 'Var', (39, 48))	('infected', 'Disease', 'MESH:D007239', (86, 94))	('R', 'Chemical', 'MESH:D001120', (107, 108))	('infected', 'Disease', (86, 94))	('S', 'Chemical', 'MESH:D013455', (109, 110))	('EBV-infected memory B', 'Disease', (0, 21))
157056	32717815	Apparent bias in IGHV gene utilization is detected in EBV+ endemic BL (eBL), where IGHV4-34, IGHV3-23 and IGHV1-69 is overrepresented when compared to the repertoire of normal B cells.	('IGHV1-69', 'Gene', '28461', (106, 114))	('IGHV3-23', 'Gene', (93, 101))	('utilization', 'MPA', (27, 38))	('IGHV4-34', 'Gene', '28395', (83, 91))	('BL', 'Phenotype', 'HP:0030080', (72, 74))	('IGHV1-69', 'Gene', (106, 114))	('EBV+', 'Var', (54, 58))	('EBV', 'Species', '10376', (54, 57))	('IGHV4-34', 'Gene', (83, 91))	('overrepresented', 'PosReg', (118, 133))	('IGHV gene', 'Gene', (17, 26))	('BL', 'Phenotype', 'HP:0030080', (67, 69))	('IGHV3-23', 'Gene', '28442;102723407;28474;28473;28472', (93, 101))
157116	32717815	Furthermore, the CDR3 length and charge characteristics as well as isotype switching were all similar between the MHV68+ and MHV68- populations.	('CDR3', 'Gene', (17, 21))	('MHV68+', 'Var', (114, 120))	('MHV68', 'Species', '1440122', (125, 130))	('CDR3', 'Gene', '8163', (17, 21))	('MHV68', 'Species', '1440122', (114, 119))
157119	32717815	In general, Ig bearing Ighv10 gene segments are overrepresented in the anti-nucleic acid antibody pool and are capable to bind its antigen regardless of CDR-H3 sequence.	('men', 'Species', '9606', (38, 41))	('overrepresented', 'PosReg', (48, 63))	('segments', 'Var', (35, 43))	('bind', 'Interaction', (122, 126))	('Ighv10', 'Gene', (23, 29))	('H3', 'Chemical', 'MESH:C012616', (157, 159))	('Ighv10', 'Gene', '16050', (23, 29))	('R', 'Chemical', 'MESH:D001120', (155, 156))
157123	32717815	Analysis of antibodies coded from MHV68+ cells revealed a lower incidence of self-reactivity and anti-viral specificity compared to the MHV68- population.	('MHV68+', 'Var', (34, 40))	('lower', 'NegReg', (58, 63))	('MHV68', 'Species', '1440122', (136, 141))	('self-reactivity', 'MPA', (77, 92))	('MHV68', 'Species', '1440122', (34, 39))	('anti-viral specificity', 'MPA', (97, 119))
157142	32717815	MHV68+ B cells undergo isotype class switching in the GC.	('MHV68+ B', 'Var', (0, 8))	('MHV68', 'Species', '1440122', (0, 5))	('undergo', 'Reg', (15, 22))
157164	32717815	The virus certainly partakes in the GC, but the origin of plasmablasts that drive MHV68 reactivation at d16 could be extrafollicular or GC experienced.	('MHV68', 'Species', '1440122', (82, 87))	('d16', 'Var', (104, 107))	('reactivation', 'MPA', (88, 100))	('MHV68', 'Gene', (82, 87))
157176	32717815	One interpretation of the data is that the loss of the host or viral factor leads to a specific defect in the GC compartment that does not preclude long-term latency.	('defect', 'NegReg', (96, 102))	('loss', 'Var', (43, 47))	('men', 'Species', '9606', (120, 123))
157178	32717815	To test for this GC-independent route, the Ig repertoire should be analyzed in the infected B cells of the mutant condition at early and late times after infection.	('mutant', 'Var', (107, 113))	('infection', 'Disease', (154, 163))	('infected', 'Disease', 'MESH:D007239', (83, 91))	('infection', 'Disease', 'MESH:D007239', (154, 163))	('infected', 'Disease', (83, 91))
157181	32717815	Immature and transitional B cells are infected by MHV68 and ablation of transitional B cells influences latency in the GC at late times after infection.	('MHV68', 'Species', '1440122', (50, 55))	('ablation', 'Var', (60, 68))	('infected', 'Disease', 'MESH:D007239', (38, 46))	('latency', 'MPA', (104, 111))	('infection', 'Disease', (142, 151))	('MHV68', 'Gene', (50, 55))	('influences', 'Reg', (93, 103))	('infection', 'Disease', 'MESH:D007239', (142, 151))	('infected', 'Disease', (38, 46))
157191	32717815	Simultaneously, MHV68 worsens the symptoms of autoimmune encephalomyelitis (EAE) and triggers relapses of autoimmune arthritis.	('worsens', 'NegReg', (22, 29))	('MHV68', 'Species', '1440122', (16, 21))	('autoimmune encephalomyelitis', 'Disease', (46, 74))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (46, 74))	('autoimmune arthritis', 'Disease', (106, 126))	('arthritis', 'Phenotype', 'HP:0001369', (117, 126))	('triggers', 'Reg', (85, 93))	('autoimmune arthritis', 'Disease', 'MESH:D001168', (106, 126))	('MHV68', 'Var', (16, 21))	('S', 'Chemical', 'MESH:D013455', (0, 1))
157192	32717815	demonstrated that MHV68 subverts the selection process giving rise to a biased BCR repertoire.	('biased', 'Reg', (72, 78))	('R', 'Chemical', 'MESH:D001120', (81, 82))	('BCR repertoire', 'CPA', (79, 93))	('MHV68', 'Species', '1440122', (18, 23))	('MHV68', 'Var', (18, 23))
157195	32717815	This brings up the intriguing possibility that MHV68 subversion of selection in the GC may disrupt tolerance and lead to the survival of B cells with autoreactive BCRs.	('MHV68', 'Species', '1440122', (47, 52))	('lead to', 'Reg', (113, 120))	('tolerance', 'CPA', (99, 108))	('subversion', 'Var', (53, 63))	('R', 'Chemical', 'MESH:D001120', (165, 166))	('survival', 'CPA', (125, 133))	('disrupt', 'NegReg', (91, 98))
157200	32717815	However, tracking MHV68 infection in autoimmune mice models and correlating self-reactive repertoire bias by the virus could give mechanistic insight into how viral subversion of B cell selection impacts tolerance and autoimmunity.	('infection', 'Disease', (24, 33))	('autoimmunity', 'Phenotype', 'HP:0002960', (218, 230))	('mice', 'Species', '10090', (48, 52))	('viral subversion', 'Var', (159, 175))	('infection', 'Disease', 'MESH:D007239', (24, 33))	('impacts', 'Reg', (196, 203))	('MHV68', 'Species', '1440122', (18, 23))	('MHV68', 'Gene', (18, 23))	('tolerance', 'CPA', (204, 213))
157207	32717815	Other genetic alterations include mutations in cell cycle and tumor suppressor proteins.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cell cycle', 'CPA', (47, 57))	('mutations', 'Var', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
157226	32717815	), in addition to NIH extramural funds AI125397 and AI111129 and CPRIT RP190507 (M.A.Z.	('R', 'Chemical', 'MESH:D001120', (71, 72))	('AI111129', 'Var', (52, 60))	('AI125397', 'Var', (39, 47))	('R', 'Chemical', 'MESH:D001120', (67, 68))
157253	31881074	In a KSHV tumorigenesis model in nude mice generated by transfecting KSHVBac36 to mouse endothelial lineage cells, we found that malignancy was only manifested in vivo and occurred with concomitant upregulation of oncogenic KSHV lytic genes, angiogenesis growth factors and their tyrosine kinase receptors that are characteristic of human KS lesions.	('malignancy', 'Disease', (129, 139))	('nude mice', 'Species', '10090', (33, 42))	('KS lesions', 'Disease', 'MESH:D051437', (339, 349))	('tyrosine', 'Chemical', 'None', (280, 288))	('KSHV', 'Species', '37296', (69, 73))	('tumor', 'Disease', (10, 15))	('transfecting', 'Var', (56, 68))	('rat', 'Species', '10116', (47, 50))	('upregulation', 'PosReg', (198, 210))	('KS lesions', 'Disease', (339, 349))	('KSHV', 'Species', '37296', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('human', 'Species', '9606', (333, 338))	('KSHVBac36', 'Gene', (69, 78))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('mouse', 'Species', '10090', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('KSHV', 'Species', '37296', (224, 228))	('oncogenic KSHV lytic genes', 'Gene', (214, 240))	('angiogenesis growth factors', 'Gene', (242, 269))
157268	31881074	We monitored KSHV infection by examining the expression of a GFP cassette in the viral genome, and KSHV lytic infection through expression of RFP under the lytic viral PAN promoter.	('RFP', 'Var', (142, 145))	('KSHV lytic infection', 'Disease', 'MESH:C537372', (99, 119))	('KSHV infection', 'Disease', 'MESH:C537372', (13, 27))	('KSHV lytic infection', 'Disease', (99, 119))	('KSHV infection', 'Disease', (13, 27))
157270	31881074	Using this method, we successfully generated mouse bone marrow-derived MSC latently infected with KSHV (K-Palpha(-)S and K-Palpha (+)S) (Fig 1B).	('K-Palpha(-)S', 'Chemical', 'MESH:D011188', (104, 116))	('KSHV', 'Gene', (98, 102))	('mouse', 'Species', '10090', (45, 50))	('rat', 'Species', '10116', (39, 42))	('K-Palpha (+)S', 'Chemical', 'MESH:D011188', (121, 134))	('K-Palpha (+)S', 'Var', (121, 134))	('KSHV', 'Species', '37296', (98, 102))
157305	31881074	Many of these KSHV genes are well-characterized viral oncogenes such as vGPCR (ORF74), K12, vIRF1 (ORFK9), vFLIP (ORF71), K15.	('KSHV', 'Species', '37296', (14, 18))	('K12', 'Var', (87, 90))	('ORF71', 'Gene', '4961494', (114, 119))	('vGPCR', 'Gene', (72, 77))	('vIRF1', 'Gene', '4961464', (92, 97))	('ORF74', 'Gene', (79, 84))	('vFLIP', 'Gene', '4961494', (107, 112))	('K15', 'Chemical', 'MESH:D011188', (122, 125))	('ORF74', 'Gene', '4961460', (79, 84))	('KSHV genes', 'Gene', (14, 24))	('vIRF1', 'Gene', (92, 97))	('vFLIP', 'Gene', (107, 112))	('K12', 'Chemical', 'MESH:D011188', (87, 90))	('ORF71', 'Gene', (114, 119))
157308	31881074	Activating histone modifications like H3K4me3 are enriched in some activated loci while repressive histone modifications like H3K27me3 are widespread across the KSHV viral genome.	('KSHV', 'Species', '37296', (161, 165))	('H3K4me3', 'Var', (38, 45))	('H3K27me3', 'Var', (126, 134))	('H3K4me3', 'Chemical', 'MESH:C024755', (38, 45))
157309	31881074	We determined if the differences in KSHV viral gene expression between non-tumorigenic K-Palpha(+)S MSC and tumorigenic K-Palpha(+)S KS cells could be attributed to differential epigenetic regulation at the viral promoters.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('KSHV viral gene', 'Gene', (36, 51))	('differences', 'Reg', (21, 32))	('tumor', 'Disease', (108, 113))	('expression', 'MPA', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('KSHV', 'Species', '37296', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('epigenetic', 'Var', (178, 188))	('tumor', 'Disease', (75, 80))
157310	31881074	We performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) in three biological replicates to map the distribution of two histone modifications, H3K4me3, and H3K27me3, that are enriched at actively transcribed and repressed genes, respectively.	('rat', 'Species', '10116', (64, 67))	('H3K4me3', 'Chemical', 'MESH:C024755', (178, 185))	('H3K27me3', 'Var', (191, 199))	('H3K4me3', 'Var', (178, 185))
157311	31881074	We found that KSHV chromatin contained both H3K4me3 and H3K27me3 marks; however, with distinct patterns of association at KSHV genomic regions between K-Palpha(+)S KS versus K-Palpha(+)S MSC cells (Fig 3A).	('KSHV', 'Species', '37296', (14, 18))	('H3K4me3', 'Chemical', 'MESH:C024755', (44, 51))	('association', 'Interaction', (107, 118))	('K-Palpha(+)S KS', 'Var', (151, 166))	('KSHV', 'Species', '37296', (122, 126))
157312	31881074	As previously reported, the latency-associated locus where KSHV genes that are constitutively expressed during latency are located, was enriched with H3K4me3 in both K-Palpha(+)S KS and K-Palpha(+)S MSC cells (Fig 3A).	('KSHV', 'Species', '37296', (59, 63))	('H3K4me3', 'Chemical', 'MESH:C024755', (150, 157))	('KSHV genes', 'Gene', (59, 69))	('H3K4me3', 'Var', (150, 157))
157313	31881074	Interestingly, H3K27me3 was widely distributed throughout the KSHV genome in both cells populations, but this repressive mark was more enriched in the KSHV genome in non-tumorigenic K-Palpha(+)S MSC cells.	('KSHV', 'Species', '37296', (151, 155))	('H3K27me3', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('KSHV', 'Species', '37296', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))
157318	31881074	These results point to epigenetic regulation as a contributory mechanism for the unique KSHV transcriptional program shown by K-Palpha(+)S KS tumorigenic cells in vitro and support our MSC mouse model for studying the connection between epigenetic regulation of KSHV gene expression and oncogenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mouse', 'Species', '10090', (189, 194))	('KSHV', 'Species', '37296', (262, 266))	('K-Palpha', 'Var', (126, 134))	('KS tumor', 'Disease', (139, 147))	('KS tumor', 'Disease', 'MESH:D009369', (139, 147))	('KSHV', 'Species', '37296', (88, 92))	('KSHV transcriptional program', 'Gene', (88, 116))
157324	31881074	Interestingly, Chip-seq analysis for the distribution of the two histone modifications, H3K4me3 and H3K27me3, over the host genome revealed that K-Palpha(+)S MSC cells displayed more global enrichment of H3K27me3 at host genes compared with K-Palpha(+)S KS cells, suggesting that the host genome of K-Palpha(+)S MSC cells is more transcriptionally repressed genome-wide (Fig 4E).	('men', 'Species', '9606', (196, 199))	('H3K27me3', 'Var', (204, 212))	('H3K4me3', 'Chemical', 'MESH:C024755', (88, 95))	('K-Palpha', 'Var', (145, 153))
157326	31881074	We found that while the number of genes decorated with H3K27me3 in the two K-Palpha(+)S cells were comparable (9,696 in KSHV KS cells versus 9,371 in K-Palpha(+)S MSC cells) with a large number of genes common between the two (8,158 genes decorated with H3K27me3 in both), 1,538 genes were exclusive to K-Palpha(+)S KS cells while 1,213 were exclusive to K-Palpha(+)S MSC cells (Fig 4F).	('rat', 'Species', '10116', (243, 246))	('rat', 'Species', '10116', (44, 47))	('H3K27me3', 'Var', (254, 262))	('H3K27me3', 'Var', (55, 63))	('KSHV', 'Species', '37296', (120, 124))
157327	31881074	KEGG and REACTOME pathway enrichment analysis was performed for these repressed H3K27me3 gene targets that are specific to K-Palpha(+)S KS or K-Palpha(+)S MSC.	('K-Palpha', 'Var', (142, 150))	('men', 'Species', '9606', (32, 35))	('H3K27me3', 'Gene', (80, 88))	('K-Palpha(+)S KS', 'Var', (123, 138))
157328	31881074	In K-Palpha(+)S MSC cells the most repressed genes involved NOTCH1 regulation, signaling by NOTCH1 in Cancer, VEGFA-VEGFR2 pathway, TGFBR1/2 KD mutants in cancer, VEGFR2-mediated cell proliferation, signaling by VEGF and p53 signaling pathways (Fig 4G).	('VEGF', 'Gene', '7422', (116, 120))	('Cancer', 'Disease', (102, 108))	('VEGFR2', 'Gene', '3791', (163, 169))	('rat', 'Species', '10116', (191, 194))	('VEGF', 'Gene', (116, 120))	('VEGF', 'Gene', '7422', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('NOTCH1', 'Gene', (92, 98))	('VEGF', 'Gene', (163, 167))	('Cancer', 'Disease', 'MESH:D009369', (102, 108))	('p53 signaling pathways', 'Pathway', (221, 243))	('TGFBR1', 'Gene', '7046', (132, 138))	('NOTCH1', 'Gene', '4851', (92, 98))	('TGFBR1', 'Gene', (132, 138))	('VEGF', 'Gene', '7422', (110, 114))	('VEGFA', 'Gene', (110, 115))	('NOTCH1', 'Gene', (60, 66))	('cancer', 'Disease', (155, 161))	('VEGF', 'Gene', (110, 114))	('mutants', 'Var', (144, 151))	('VEGFR2', 'Gene', (116, 122))	('VEGF', 'Gene', '7422', (212, 216))	('NOTCH1', 'Gene', '4851', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('VEGFR2', 'Gene', (163, 169))	('VEGF', 'Gene', (212, 216))	('VEGFR2', 'Gene', '3791', (116, 122))	('VEGFA', 'Gene', '7422', (110, 115))
157336	31881074	Fig 2A shows that K-Palpha(+)S KS tumorigenicity occurs along with a steep increase in KSHV lytic gene expression (KSHV in vivo lytic switch).	('KSHV lytic gene', 'Gene', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('KSHV', 'Species', '37296', (87, 91))	('KSHV', 'Species', '37296', (115, 119))	('increase', 'PosReg', (75, 83))	('KS tumor', 'Disease', 'MESH:D009369', (31, 39))	('KS tumor', 'Disease', (31, 39))	('K-Palpha', 'Var', (18, 26))
157342	31881074	We found that the RFP positive populations of both K-Palpha(+)S MSC and K-Palpha(+)S KS cells (Fig 5C, left panel) showed massive upregulation of KSHV lytic and latent genes, when compared to un-induced cells, characteristic of lytic induction.	('KSHV', 'Species', '37296', (146, 150))	('K-Palpha(+)S', 'Var', (72, 84))	('upregulation', 'PosReg', (130, 142))
157351	31881074	Moreover, K-Palpha(+)S KS cells showed more proliferation markers (such as Ki67) than K-Palpha(+)S MSC cells (Fig 5E) after 72hs of KSHV lytic reactivation.	('more', 'PosReg', (39, 43))	('KSHV', 'Species', '37296', (132, 136))	('Ki67', 'Gene', (75, 79))	('Ki67', 'Gene', '17345', (75, 79))	('proliferation markers', 'CPA', (44, 65))	('K-Palpha', 'Var', (10, 18))	('rat', 'Species', '10116', (51, 54))
157365	31881074	On the other hand, the growth inhibition shown by K-Palpha(+)S MSC cells directly occurred together with the upregulation of KSHV gene expression in vivo (Fig 5K).	('upregulation', 'PosReg', (109, 121))	('K-Palpha', 'Var', (50, 58))	('KSHV', 'Species', '37296', (125, 129))	('expression', 'MPA', (135, 145))	('growth', 'CPA', (23, 29))	('KSHV gene', 'Gene', (125, 134))
157415	31881074	Initial immunohistochemistry studies showed that KS SCs are poorly differentiated cells showing phenotypic markers such as VEGFRs that suggest an endothelial origin, however, KSHV-infected primary endothelial cells in culture do not outgrow their uninfected counterparts, lose their KSHV genomes after extended passage in tissue culture, do not grow in soft agar and do not form tumors in nude mice.	('KSHV', 'Species', '37296', (175, 179))	('nude mice', 'Species', '10090', (389, 398))	('KSHV-infected', 'Var', (175, 188))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('VEGFRs', 'Gene', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (379, 385))	('VEGFRs', 'Gene', '2321;2324;3791', (123, 129))	('tumors', 'Disease', (379, 385))	('tumors', 'Disease', 'MESH:D009369', (379, 385))	('KSHV', 'Species', '37296', (283, 287))	('lose', 'NegReg', (272, 276))	('KSHV', 'MPA', (283, 287))
157425	31881074	We previously found that KSHVBac36 is angiogenic and tumorigenic in an endothelial cell lineage of adherent bone marrow cell preparations, which prompted us to 'target' putative progenitors among this transfected heterogeneous cell population.	('KSHV', 'Species', '37296', (25, 29))	('KSHVBac36', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('rat', 'Species', '10116', (130, 133))	('angiogenic', 'CPA', (38, 48))	('tumor', 'Disease', (53, 58))
157433	31881074	Tumors that arise from K-Palpha(+)S KS cells have an increased expression of KSHV oncogenes (KSHV in vivo lytic switch), paralleling our previous findings in the mouse KS-like mECK36 model, and also displayed PDGFRA signaling activation that co-distributed with KSHV LANA, thus supporting the described link between KSHV and PDGFRA activation in the tumors.	('tumors', 'Disease', (350, 356))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('LANA', 'Gene', (267, 271))	('KSHV', 'Species', '37296', (262, 266))	('LANA', 'Gene', '4961527', (267, 271))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('increased', 'PosReg', (53, 62))	('activation', 'PosReg', (226, 236))	('tumors', 'Disease', 'MESH:D009369', (350, 356))	('PDGFRA', 'MPA', (209, 215))	('KSHV', 'Species', '37296', (316, 320))	('KSHV', 'Species', '37296', (93, 97))	('Tumors', 'Disease', (0, 6))	('KSHV', 'Species', '37296', (77, 81))	('mouse', 'Species', '10090', (162, 167))	('expression', 'MPA', (63, 73))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (350, 356))	('KSHV oncogenes', 'Gene', (77, 91))	('K-Palpha(+)S KS', 'Var', (23, 38))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))
157446	31881074	Here, we confirm that there were less repressive histone marks and more activating histone marks (H3K27me3-H3K4me3) on different portions of the KSHV genome in K-Palpha(+)S KS than in K-Palpha(+)S MSC cells, that correlated with increase KSHV gene expression by these tumorigenic cells (Fig 8).	('KSHV gene', 'Gene', (238, 247))	('less', 'NegReg', (33, 37))	('more', 'PosReg', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('activating', 'MPA', (72, 82))	('increase', 'PosReg', (229, 237))	('tumor', 'Disease', (268, 273))	('repressive', 'MPA', (38, 48))	('KSHV', 'Species', '37296', (145, 149))	('KSHV', 'Species', '37296', (238, 242))	('expression', 'MPA', (248, 258))	('H3K27me3-H3K4me3', 'Chemical', 'MESH:C024755', (98, 114))	('H3K27me3-H3K4me3', 'Var', (98, 114))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
157447	31881074	Pathway analysis of host genes enriched with H3K27me3 in non-tumorigenic K-Palpha(+)S MSC showed that the most repressed genes were all related to KS and KSHV oncogenic signaling, further indicating that distinct environments where KSHV infection occurs can lead to different host epigenetic landscape, thus prompting oncogenesis.	('oncogenesis', 'CPA', (318, 329))	('KSHV', 'Species', '37296', (154, 158))	('KSHV infection', 'Disease', 'MESH:C537372', (232, 246))	('KSHV infection', 'Disease', (232, 246))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('men', 'Species', '9606', (220, 223))	('lead', 'Reg', (258, 262))	('H3K27me3', 'Var', (45, 53))	('KSHV', 'Species', '37296', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('prompting', 'PosReg', (308, 317))	('tumor', 'Disease', (61, 66))	('host epigenetic landscape', 'MPA', (276, 301))
157457	31881074	Early steps of KSHV tumorigenesis involve activation of the DNA damage checkpoints that lead to selective pressure for mutations which abrogate checkpoints, thus providing an advantage for cells with defective DNA damage response components to propagate.	('KSHV', 'Disease', (15, 19))	('KSHV', 'Species', '37296', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('activation', 'PosReg', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (119, 128))	('tumor', 'Disease', (20, 25))
157560	31881074	Bedtools v2.26.0 intersect was used to determine peak overlaps with RefSeq genes +2.5kb upstream of TSS regions to identify H3K27me3 and H3K4me3 enriched genes.	('H3K4me3', 'Var', (137, 144))	('H3K27me3', 'Var', (124, 132))	('H3K4me3', 'Chemical', 'MESH:C024755', (137, 144))
157622	29719630	We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing sarcomas through searching PubMed, The Cochrane Library, Scopus and Web of Science databases.	('DNA', 'Gene', (94, 97))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('sarcomas', 'Disease', (131, 139))	('variation', 'Var', (98, 107))
157624	29719630	The estimated joint population attributable risk for three independent SNPs (rs11599754 of ZNF365/EGR2, rs231775 of CTLA4, and rs454006 of PRKCG) was 37.2%.	('CTLA4', 'Gene', '1493', (116, 121))	('ZNF365', 'Gene', '22891', (91, 97))	('CTLA4', 'Gene', (116, 121))	('PRKCG', 'Gene', (139, 144))	('rs454006', 'Mutation', 'rs454006', (127, 135))	('ZNF365', 'Gene', (91, 97))	('rs231775', 'Mutation', 'rs231775', (104, 112))	('rs454006', 'Var', (127, 135))	('rs11599754', 'Var', (77, 87))	('PRKCG', 'Gene', '5582', (139, 144))	('rs11599754', 'Mutation', 'rs11599754', (77, 87))	('rs231775', 'Var', (104, 112))	('EGR2', 'Gene', '1959', (98, 102))	('EGR2', 'Gene', (98, 102))
157625	29719630	We also identified 53 SNPs significantly associated with sarcoma risk based on single studies.	('SNPs', 'Var', (22, 26))	('associated with', 'Reg', (41, 56))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('sarcoma', 'Disease', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
157626	29719630	Pathway analysis enabled us to propose that sarcoma predisposition might be linked especially to germline variation of genes whose products are involved in the function of the DNA repair machinery.	('linked', 'Reg', (76, 82))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('sarcoma', 'Disease', (44, 51))	('germline variation', 'Var', (97, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))
157627	29719630	We built the first knowledgebase on the evidence linking DNA variation to sarcomas susceptibility, which can be used to generate mechanistic hypotheses and inform future studies in this field of oncology.	('sarcomas', 'Disease', (74, 82))	('oncology', 'Phenotype', 'HP:0002664', (195, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('variation', 'Var', (61, 70))	('DNA', 'Gene', (57, 60))
157631	29719630	It has been recognized that three types of somatic DNA alterations, translocations, mutations, and copy number variations, play a key role in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutations', 'Var', (84, 93))	('copy number variations', 'Var', (99, 121))	('translocations', 'Var', (68, 82))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Disease', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
157632	29719630	As a consequence, sarcomas are grouped into two categories: balanced translocation associated sarcomas (BATS) and complex genotype/karyotype sarcomas (CGKS), which are characterized by a stable genome and genomic instability, respectively.	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcomas', 'Disease', 'MESH:D012509', (141, 149))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcomas', 'Disease', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('sarcomas', 'Disease', (141, 149))	('sarcomas', 'Disease', (94, 102))	('balanced translocation', 'Var', (60, 82))
157636	29719630	Looking at the already existing international literature, some investigators have meta-analyzed the evidence regarding a handful of SNPs such as XRCC3 rs861539, MDM2 rs2279744, and CTLA4 rs231775: however, to the best of our knowledge no comprehensive collection of the available data in this field of oncology has been published thus far.	('rs231775', 'Var', (187, 195))	('CTLA4', 'Gene', '1493', (181, 186))	('XRCC3', 'Gene', '7517', (145, 150))	('rs861539', 'Mutation', 'rs861539', (151, 159))	('rs2279744', 'Mutation', 'rs2279744', (166, 175))	('CTLA4', 'Gene', (181, 186))	('MDM2', 'Gene', '4193', (161, 165))	('rs2279744', 'Var', (166, 175))	('MDM2', 'Gene', (161, 165))	('rs231775', 'Mutation', 'rs231775', (187, 195))	('rs861539', 'Var', (151, 159))	('XRCC3', 'Gene', (145, 150))	('oncology', 'Phenotype', 'HP:0002664', (302, 310))
157641	29719630	At least two independent datasets were available for 51 genetic variations allowing us to perform 118 meta-analyses, 16 of them were histology-based meta-analysis on osteosarcoma and Ewing's sarcoma.	('variations', 'Var', (64, 74))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (183, 198))	("Ewing's sarcoma", 'Disease', (183, 198))	('osteosarcoma', 'Phenotype', 'HP:0002669', (166, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('osteosarcoma', 'Disease', (166, 178))	('osteosarcoma', 'Disease', 'MESH:D012516', (166, 178))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (183, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))
157642	29719630	The eight most studied genetic variants were the following: TP53 rs1042522 (6 datasets), VEGF rs3025039 and GSTM1 deletion (5 datasets each), CTLA4 rs231775, CTLA4 rs5742909, MDM2 rs2279744, rs10434 VEGF and GSTT1 deletion (4 datasets each).	('rs231775', 'Var', (148, 156))	('rs3025039', 'Mutation', 'rs3025039', (94, 103))	('CTLA4', 'Gene', (142, 147))	('TP53', 'Gene', (60, 64))	('GSTT1', 'Gene', '2952', (208, 213))	('deletion', 'Var', (214, 222))	('GSTM1', 'Gene', (108, 113))	('rs2279744', 'Mutation', 'rs2279744', (180, 189))	('rs1042522', 'Var', (65, 74))	('CTLA4', 'Gene', (158, 163))	('rs231775', 'Mutation', 'rs231775', (148, 156))	('rs1042522', 'Mutation', 'rs1042522', (65, 74))	('GSTT1', 'Gene', (208, 213))	('VEGF', 'Gene', '7422', (89, 93))	('VEGF', 'Gene', '7422', (199, 203))	('MDM2', 'Gene', (175, 179))	('rs5742909', 'Var', (164, 173))	('rs3025039', 'Var', (94, 103))	('rs5742909', 'Mutation', 'rs5742909', (164, 173))	('TP53', 'Gene', '7157', (60, 64))	('VEGF', 'Gene', (89, 93))	('VEGF', 'Gene', (199, 203))	('deletion', 'Var', (114, 122))	('GSTM1', 'Gene', '2944', (108, 113))	('MDM2', 'Gene', '4193', (175, 179))	('rs2279744', 'Var', (180, 189))	('CTLA4', 'Gene', '1493', (142, 147))	('rs10434', 'Mutation', 'rs10434', (191, 198))	('CTLA4', 'Gene', '1493', (158, 163))
157643	29719630	Based on the number of subjects, the 10 most studied genetic variants, all with 5,347 subjects, were the following: EGR2 rs224292 and rs224278, ADO rs1848797 and rs1509966, MDM2 rs1690916, LOC107984012 rs9633562, rs944684 and rs6479860, ZNF365 rs11599754 and rs10761660.	('rs944684', 'Var', (213, 221))	('rs6479860', 'Mutation', 'rs6479860', (226, 235))	('rs11599754', 'Var', (244, 254))	('rs10761660', 'Var', (259, 269))	('MDM2', 'Gene', (173, 177))	('ADO', 'Gene', (144, 147))	('rs11599754', 'Mutation', 'rs11599754', (244, 254))	('rs1848797', 'Mutation', 'rs1848797', (148, 157))	('rs10761660', 'Mutation', 'rs10761660', (259, 269))	('rs1690916', 'Var', (178, 187))	('rs224292', 'Mutation', 'rs224292', (121, 129))	('MDM2', 'Gene', '4193', (173, 177))	('ZNF365', 'Gene', '22891', (237, 243))	('rs224278', 'Var', (134, 142))	('rs1690916', 'Mutation', 'rs1690916', (178, 187))	('LOC107984012 rs9633562', 'Var', (189, 211))	('rs1509966', 'Var', (162, 171))	('EGR2', 'Gene', '1959', (116, 120))	('rs224292', 'Var', (121, 129))	('rs224278', 'Mutation', 'rs224278', (134, 142))	('rs1848797', 'Var', (148, 157))	('ZNF365', 'Gene', (237, 243))	('EGR2', 'Gene', (116, 120))	('rs1509966', 'Mutation', 'rs1509966', (162, 171))	('rs9633562', 'Mutation', 'rs9633562', (202, 211))	('ADO', 'Gene', '84890', (144, 147))	('rs6479860', 'Var', (226, 235))	('rs944684', 'Mutation', 'rs944684', (213, 221))
157644	29719630	In order to provide an estimate of the impact of germline variants on sarcoma risk, the PAR (population attributable risk) was calculated.	('germline', 'Var', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcoma', 'Disease', (70, 77))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))
157645	29719630	As an example, we considered the following three independent SNPs with high quality evidence on their relationship with sarcoma risk: rs11599754 of ZNF365/EGR2 (chromosome 10, risk allele: C, risk allele frequency in European ancestry population: 0.39, meta-analysis OR: 1.48); rs231775 of CTLA4 (chromosome 2, risk allele: A, risk allele frequency in European ancestry population: 0.65, meta-analysis OR: 1.36); and rs454006 of PRKCG (chromosome 19, risk allele: C, risk allele frequency in European ancestry population: 0.25, meta-analysis OR: 1.35).	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('CTLA4', 'Gene', (290, 295))	('ZNF365', 'Gene', (148, 154))	('PRKCG', 'Gene', '5582', (429, 434))	('rs454006', 'Var', (417, 425))	('rs231775', 'Mutation', 'rs231775', (278, 286))	('EGR2', 'Gene', (155, 159))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('EGR2', 'Gene', '1959', (155, 159))	('PRKCG', 'Gene', (429, 434))	('ZNF365', 'Gene', '22891', (148, 154))	('rs231775', 'Var', (278, 286))	('rs11599754', 'Var', (134, 144))	('CTLA4', 'Gene', '1493', (290, 295))	('sarcoma', 'Disease', (120, 127))	('rs454006', 'Mutation', 'rs454006', (417, 425))	('rs11599754', 'Mutation', 'rs11599754', (134, 144))
157646	29719630	Beside the variations resulted to be statistically significantly associated with sarcoma risk in this meta-analysis, we retrieved from the included articles 906 SNPs statistically significantly associated with sarcoma risk (P-value <0.05) based on single-study analysis.	('sarcoma', 'Disease', (210, 217))	('variations', 'Var', (11, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('associated', 'Reg', (65, 75))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('associated with', 'Reg', (194, 209))
157649	29719630	Ewing's sarcoma associations in European and US European-descendant population mainly involved the candidate risk loci at 1p36.22, 10q21 reported by Postel-Vinay et al GWAS and in the following related study of Grunewald et al.	("Ewing's sarcoma", 'Disease', (0, 15))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('10q21', 'Var', (131, 136))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))
157652	29719630	The 10q21 variants strongly associated with Ewing's sarcoma are located in a block containing four genes: ADO (encoding cysteamine dioxygenase), ZNF365 (encoding zinc-finger protein 365), EGR2 (encoding early growth response protein 2) and LOC107984012 (unknown function).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (44, 59))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (44, 59))	('ZNF365', 'Gene', (145, 151))	('EGR2', 'Gene', '1959', (188, 192))	('variants', 'Var', (10, 18))	('LOC107984012', 'Var', (240, 252))	('early growth response protein 2', 'Gene', '1959', (203, 234))	("Ewing's sarcoma", 'Disease', (44, 59))	('EGR2', 'Gene', (188, 192))	('associated', 'Reg', (28, 38))	('zinc-finger protein 365', 'Gene', (162, 185))	('early growth response protein 2', 'Gene', (203, 234))	('ADO', 'Gene', '84890', (106, 109))	('zinc-finger protein 365', 'Gene', '22891', (162, 185))	('ADO', 'Gene', (106, 109))	('cysteamine dioxygenase', 'Gene', (120, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('ZNF365', 'Gene', '22891', (145, 151))	('cysteamine dioxygenase', 'Gene', '84890', (120, 142))
157655	29719630	Using the 36 genes whose SNPs were significantly associated with sarcoma risk (including data from both meta-analysis and single studies) and were also characterized by a significant eQTL effect, we found that the corresponding protein products interact with each other beyond chance (observed edges: 120; expected edges: 12; PPI enrichment P-value <10E-20), with an average node degree equal to 6.7 (see Figure 2).	('interact', 'Reg', (245, 253))	('sarcoma', 'Disease', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('associated', 'Reg', (49, 59))	('SNPs', 'Var', (25, 29))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))
157659	29719630	Overall, our findings support the hypothesis that genetic polymorphism does contribute to sarcoma susceptibility.	('sarcoma', 'Disease', (90, 97))	('genetic polymorphism', 'Var', (50, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('contribute', 'Reg', (76, 86))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
157660	29719630	This is exemplified by the population attributable risk (PAR=37.2%) calculated for three SNPs associated with the risk of sarcoma at a high level of evidence (rs11599754 of ZNF365/EGR2, rs231775 of CTLA4, and rs454006 of PRKCG), which indicates that more than one third of sarcoma cases would not occur in a hypothetical population where these three risk variants were absent.	('rs454006', 'Mutation', 'rs454006', (209, 217))	('CTLA4', 'Gene', (198, 203))	('rs231775', 'Var', (186, 194))	('associated', 'Reg', (94, 104))	('EGR2', 'Gene', '1959', (180, 184))	('ZNF365', 'Gene', '22891', (173, 179))	('PRKCG', 'Gene', (221, 226))	('rs11599754', 'Var', (159, 169))	('rs11599754', 'Mutation', 'rs11599754', (159, 169))	('sarcoma', 'Disease', 'MESH:D012509', (273, 280))	('rs231775', 'Mutation', 'rs231775', (186, 194))	('EGR2', 'Gene', (180, 184))	('sarcoma', 'Disease', (273, 280))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('sarcoma', 'Disease', (122, 129))	('rs454006', 'Var', (209, 217))	('ZNF365', 'Gene', (173, 179))	('PRKCG', 'Gene', '5582', (221, 226))	('CTLA4', 'Gene', '1493', (198, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
157661	29719630	This remarkable influence of just three SNPs is linked not only to the high frequency of the risk alleles but also to the interesting fact that the risk, defined as odds ratio, associated with single variants ranged between 1.35 and 1.48, which are values higher than those usually observed for other malignancies such as breast, colorectal, and gastric carcinomas, which generally include odds ratios between 1.10 and 1.30.	('colorectal', 'Disease', (330, 340))	('malignancies', 'Disease', 'MESH:D009369', (301, 313))	('malignancies', 'Disease', (301, 313))	('carcinomas', 'Phenotype', 'HP:0030731', (354, 364))	('gastric carcinomas', 'Disease', 'MESH:D013274', (346, 364))	('gastric carcinomas', 'Disease', (346, 364))	('variants', 'Var', (200, 208))	('breast', 'Disease', (322, 328))
157662	29719630	Considering that the mean risk among variants significantly associated with sarcoma predisposition was even higher (approximately 1.70, see Table 2), one might speculate that germline DNA variation is especially important in the determinism of the susceptibility to this family of tumors.	('tumors', 'Disease', (281, 287))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('sarcoma', 'Disease', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('variants', 'Var', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('associated', 'Reg', (60, 70))
157663	29719630	Conventional meta-analysis of single variants led us to identify 55 SNPs significantly associated with sarcoma risk (Table 2), and additional 53 SNPs were reported in single studies (Table 3): these variants are linked to a variety of genes whose protein products are involved in several cell activities.	('variants', 'Var', (199, 207))	('sarcoma', 'Disease', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('associated', 'Reg', (87, 97))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))	('linked', 'Reg', (212, 218))
157667	29719630	Finally, also somatic DNA alterations appear to confer a defective DNA repair capability to some sarcoma types such as Ewing's sarcoma, and thus the combinatory study of germline and somatic DNA variations characterizing sarcomas might lead to better understand the cascade of molecular events underlying sarcomagenesis, as recently proposed for the EWSR1-FLI1 fusion gene and the SNPs near EGR2 in Ewing's sarcoma patients.	('sarcoma', 'Disease', 'MESH:D012509', (221, 228))	('EGR2', 'Gene', (391, 395))	('sarcomas', 'Disease', 'MESH:D012509', (221, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (221, 229))	('sarcoma', 'Disease', (221, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (399, 414))	('sarcomas', 'Disease', (221, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('FLI1', 'Gene', (356, 360))	('sarcoma', 'Disease', 'MESH:D012509', (305, 312))	('EWSR1', 'Gene', '2130', (350, 355))	('defective', 'NegReg', (57, 66))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (399, 414))	('alterations', 'Var', (26, 37))	('sarcoma', 'Disease', (305, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (119, 134))	('FLI1', 'Gene', '2313', (356, 360))	('sarcoma', 'Disease', 'MESH:D012509', (407, 414))	('sarcoma', 'Disease', (407, 414))	("Ewing's sarcoma", 'Disease', (399, 414))	('patients', 'Species', '9606', (415, 423))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (119, 134))	('EWSR1', 'Gene', (350, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('EGR2', 'Gene', '1959', (391, 395))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (407, 414))	('sarcoma', 'Disease', (127, 134))	("Ewing's sarcoma", 'Disease', (119, 134))
157669	29719630	In our work we also confirmed the association between sarcoma risk and variants of single genes, such as ZNF365, ADO, EGR2, CTLA4, TP53, CD86, NUDT6, MDM2, ERCC5 and ADAMTS6 just to mention the top ten by statistical significance.	('ZNF365', 'Gene', '22891', (105, 111))	('CD86', 'Gene', '942', (137, 141))	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('CD86', 'Gene', (137, 141))	('NUDT6', 'Gene', '11162', (143, 148))	('MDM2', 'Gene', '4193', (150, 154))	('sarcoma', 'Disease', (54, 61))	('ADAMTS6', 'Gene', (166, 173))	('ZNF365', 'Gene', (105, 111))	('TP53', 'Gene', (131, 135))	('CTLA4', 'Gene', '1493', (124, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('ADAMTS6', 'Gene', '11174', (166, 173))	('EGR2', 'Gene', '1959', (118, 122))	('ADO', 'Gene', '84890', (113, 116))	('NUDT6', 'Gene', (143, 148))	('ERCC5', 'Gene', '2073', (156, 161))	('CTLA4', 'Gene', (124, 129))	('EGR2', 'Gene', (118, 122))	('variants', 'Var', (71, 79))	('ADO', 'Gene', (113, 116))	('ERCC5', 'Gene', (156, 161))	('MDM2', 'Gene', (150, 154))	('TP53', 'Gene', '7157', (131, 135))
157670	29719630	In this regard, our meta-analysis data can be utilized to inform future studies on candidate pathways whose genetic variation could affect sarcoma susceptibility.	('genetic variation', 'Var', (108, 125))	('affect', 'Reg', (132, 138))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('sarcoma', 'Disease', (139, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))
157678	29719630	Exclusion criteria were: virus-induced sarcomas (HHV8 - Kaposi sarcoma); sarcomas secondary to radiation therapy; sarcomas secondary to burns/scars/surgery; associations between mitochondrial DNA variations and sarcomas; gastrointestinal stromal tumors (GIST).	('HHV8 - Kaposi sarcoma', 'Disease', 'MESH:D012514', (49, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('sarcomas', 'Disease', 'MESH:D012509', (39, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('sarcomas', 'Disease', (39, 47))	('mitochondrial', 'Var', (178, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcomas', 'Disease', 'MESH:D012509', (211, 219))	('sarcomas', 'Phenotype', 'HP:0100242', (211, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('sarcomas', 'Disease', (211, 219))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (221, 252))	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('sarcomas; gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (211, 252))	('scars', 'Phenotype', 'HP:0100699', (142, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('HHV8 - Kaposi sarcoma', 'Disease', (49, 70))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (56, 70))	('sarcomas', 'Disease', (114, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('associations', 'Interaction', (157, 169))	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcomas', 'Disease', (73, 81))	('sarcomas; gastrointestinal stromal tumors', 'Disease', (211, 252))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))
157679	29719630	Database search of original articles analyzing the association between any genetic variant and susceptibility to sarcoma was conducted independently by two investigators though the following database: MEDLINE (via the PubMed gateway); The Cochrane Library; Scopus; Web of Science.	('variant', 'Var', (83, 90))	('sarcoma', 'Disease', (113, 120))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
157684	29719630	We calculated summary odds ratios (ORs) and their corresponding 95% confidence intervals (95%CI) starting from raw data to measure the strength of association between each polymorphism and sarcoma risk.	('sarcoma', 'Disease', (189, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))	('polymorphism', 'Var', (172, 184))
157687	29719630	In order to explore the mechanisms underlying the pathogenesis of sarcomas, we utilized network and pathway analysis to test the hypothesis that genes whose variations are associated with sarcoma risk interact with each other possibly within the frame of some specific molecular pathways.	('sarcoma', 'Disease', (66, 73))	('variations', 'Var', (157, 167))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('sarcoma', 'Disease', 'MESH:D012509', (188, 195))	('associated', 'Reg', (172, 182))	('sarcomas', 'Disease', (66, 74))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('sarcoma', 'Disease', (188, 195))	('interact', 'Reg', (201, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))
157688	29719630	To this aim, we first selected SNPs significantly associated with sarcoma risk.	('sarcoma', 'Disease', (66, 73))	('associated with', 'Reg', (50, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('SNPs', 'Var', (31, 35))
157790	29048650	Results from pathway analysis show that these involved genes associated with a wide range of pathways and functional annotation, like calcium signaling pathway, inflammatory mediator regulation of TRP channels, wnt signaling pathway, microRNAs and proteoglycans in cancer, transcriptional and misregulation in cancer, colorectal and pancreatic cancer.	('cancer', 'Disease', (310, 316))	('cancer', 'Disease', (344, 350))	('TRP', 'Gene', (197, 200))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('calcium', 'Chemical', 'MESH:D002118', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (333, 350))	('wnt signaling pathway', 'Pathway', (211, 232))	('associated', 'Reg', (61, 71))	('misregulation', 'Var', (293, 306))	('colorectal and pancreatic cancer', 'Disease', 'MESH:D010190', (318, 350))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('cancer', 'Disease', 'MESH:D009369', (344, 350))
157796	29048650	A meta-analysis suggests that NAT1 polymorphisms significantly associate with the risk of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('pancreatic cancer', 'Disease', (90, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('NAT1', 'Gene', '9', (30, 34))	('NAT1', 'Gene', (30, 34))	('polymorphisms', 'Var', (35, 48))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associate', 'Reg', (63, 72))
157828	28222219	Deaths were grouped into three mutually exclusive categories using ICD-9 and ICD-10 coding: 1) recurrence/progression of primary cancer; 2) external causes (accidents, suicides, poisonings, and other external causes; ICD 9: 800-999, ICD 10: V00-V99, Y00-Y89, X00-X99, W00-W99); and, 3) non-recurrence, non-external causes including SNs (ICD 9: 140-239, ICD 10: C00- C97, D10-D36), cardiac (ICD 9: 390-398, 402, 404, 410-429, ICD 10: I00- I02, I05-I09, I11, I13, I14, I20-I28, I30-I52), pulmonary (ICD 9: 460-519, ICD 10: J00-J99), and all other causes.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('I13', 'Var', (457, 460))	('I20-I28', 'Var', (467, 474))	('pulmonary', 'Disease', (486, 495))	('cancer', 'Disease', (129, 135))	('cardiac', 'Disease', (381, 388))	('I30-I52', 'Var', (476, 483))	('I14', 'Var', (462, 465))	('I11', 'Var', (452, 455))	('SNs', 'Disease', (332, 335))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('I05-I09', 'Var', (443, 450))
157916	25614846	reported that the lesions were iso- or hypointense compared to muscle on T1-weighted imaging, in 75.6% and 24.4% of the patients, respectively.	('hypointense', 'Var', (39, 50))	('patients', 'Species', '9606', (120, 128))	('iso-', 'Var', (31, 35))
158036	23820887	The DTP tumor microenvironment laboratory focuses on the discovery of targets and the development of therapeutic strategies targeting the tumor microenvironment and physiological abnormalities of tumors resulting from environmental factors or alterations in metabolic enzymes.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('abnormalities of tumors', 'Disease', 'MESH:D009369', (179, 202))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('DTP', 'Chemical', '-', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('abnormalities of tumors', 'Disease', (179, 202))	('alterations', 'Var', (243, 254))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
158074	23820887	SCLC has unique chromosomal changes; dysregulation of tumor suppressor genes, oncogenes, and signaling pathways; and active early development pathways.	('dysregulation', 'Var', (37, 50))	('SCLC', 'Disease', 'MESH:D018288', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('early development', 'CPA', (124, 141))	('signaling pathways', 'Pathway', (93, 111))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('SCLC', 'Disease', (0, 4))	('tumor', 'Disease', (54, 59))	('oncogenes', 'Pathway', (78, 87))
158085	23820887	Two general groups, sarcoma arising from chromosomal translocations and sarcoma with very complex genetics, can be defined.	('sarcoma', 'Disease', (72, 79))	('sarcoma', 'Disease', (20, 27))	('chromosomal translocations', 'Var', (41, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))
158089	23820887	While some alterations occur in specific subtypes of sarcoma, others cross several sarcoma types.	('alterations', 'Var', (11, 22))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('sarcoma', 'Disease', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma', 'Disease', (53, 60))	('cross', 'Reg', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('occur', 'Reg', (23, 28))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))
158102	23820887	This program will provide a public database on the cell line panels including: i) gene/exon expression; ii) microRNA expression; iii) mutations; iv) subpopulations; v) response to standard and investigational anticancer agents; vi) protein expression and activated pathways; and vii) cell surface and intracellular markers.	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (134, 143))	('cancer', 'Disease', (213, 219))
158117	23820887	The functional genomics laboratory is currently conducting a full genomic characterization (gene expression, exon expression, mutations, deletions, amplifications, microRNAs and other non-coding RNAs) for human sarcoma lines and SCLC lines with a goal of identifying potential drug targets in normal and mutant proteins.	('SCLC', 'Disease', (229, 233))	('deletions', 'Var', (137, 146))	('SCLC', 'Disease', 'MESH:D018288', (229, 233))	('sarcoma lines', 'Disease', 'MESH:D012509', (211, 224))	('sarcoma lines', 'Disease', (211, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('mutant', 'Var', (304, 310))	('mutations', 'Var', (126, 135))	('human', 'Species', '9606', (205, 210))
158118	23820887	The Developmental Therapeutics Program tumor microenvironment laboratory focuses on the discovery of targets and development of therapeutic strategies targeting the tumor microenvironment and physiological abnormalities of tumors resulting from environmental factors or alterations in metabolic enzymes.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('abnormalities of tumors', 'Disease', 'MESH:D009369', (206, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('alterations', 'Var', (270, 281))	('abnormalities of tumors', 'Disease', (206, 229))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (165, 170))
158130	22606441	Cytogenetics showed a translocation disrupting the EWSR 1 gene on 22 q 12 consistent with DSRCT.	('EWSR 1', 'Gene', (51, 57))	('translocation', 'Var', (22, 35))	('disrupting', 'NegReg', (36, 46))	('EWSR 1', 'Gene', '2130', (51, 57))
158170	22606441	Cytogenetic studies showed disruptions in the Ewing's sarcoma gene (*22p 11 q), Wilm's tumour gene by FISH probe, and RT-PCR studies were repeated at the Sullivan Nicolaides Pathology, Queensland and showed a positive result with the Ewing's sarcoma dual-colour break-apart probe.	("Ewing's sarcoma", 'Disease', (234, 249))	("Wilm's tumour", 'Disease', 'MESH:D009396', (80, 93))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (234, 249))	("Wilm's tumour", 'Disease', (80, 93))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (46, 61))	("Ewing's sarcoma", 'Disease', (46, 61))	('disruptions', 'Var', (27, 38))	("Wilm's tumour", 'Phenotype', 'HP:0002667', (80, 93))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (46, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (234, 249))
158182	22606441	Cytogenetics performed on fresh tissue with FISH showed a translocation disrupting the EWS gene on 22p 11q, with an EWS-WT1 gene fusion.	('translocation', 'Var', (58, 71))	('EWS', 'Gene', '2130', (87, 90))	('EWS', 'Gene', (87, 90))	('WT1', 'Gene', '7490', (120, 123))	('WT1', 'Gene', (120, 123))	('disrupting', 'NegReg', (72, 82))	('EWS', 'Gene', '2130', (116, 119))	('EWS', 'Gene', (116, 119))
158219	20197394	Inhibition of EWS/FLI-1 by either antisense oligonucleotides or siRNAs has shown antitumor effects in vitro.	('FLI-1', 'Gene', (18, 23))	('tumor', 'Disease', (85, 90))	('oligonucleotides', 'Chemical', 'MESH:D009841', (44, 60))	('Inhibition', 'NegReg', (0, 10))	('siRNAs', 'Gene', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('FLI-1', 'Gene', '14247', (18, 23))	('EWS', 'Phenotype', 'HP:0012254', (14, 17))	('antisense oligonucleotides', 'Var', (34, 60))
158220	20197394	Antisense oligonucleotides encapsulated in nanocapsules have inhibited growth of tumors in a mouse xenograft model.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('inhibited', 'NegReg', (61, 70))	('mouse', 'Species', '10090', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Antisense oligonucleotides', 'Var', (0, 26))	('oligonucleotides', 'Chemical', 'MESH:D009841', (10, 26))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
158228	20197394	In AML cell lines, ABT-869 was shown to inhibit phosphorylation of STAT5, ERK, KIT, and Pim-1.	('Pim-1', 'Gene', (88, 93))	('Pim-1', 'Gene', '18712', (88, 93))	('inhibit', 'NegReg', (40, 47))	('ABT-869', 'Chemical', 'MESH:C513486', (19, 26))	('STAT5', 'Gene', '20850', (67, 72))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('phosphorylation', 'MPA', (48, 63))	('ABT-869', 'Var', (19, 26))	('KIT', 'Protein', (79, 82))	('ERK', 'Protein', (74, 77))	('STAT5', 'Gene', (67, 72))	('AML', 'Disease', (3, 6))
158255	20197394	The antibodies used to characterize the phosphorylation status of PDGFRbeta and KIT were c-KIT (A4502, Dako, Carpinteria, CA), phospho-c-KIT (ab5631, Abcam, Cambridge, MA), PDGFRbeta (sc-432, SCBT, Santa Cruz, CA), and phospho-tyrosine (sc7020, SCBT, Santa Cruz, CA).	('tyrosine', 'Chemical', 'MESH:D014443', (227, 235))	('sc7020', 'Var', (237, 243))	('PDGFRbeta', 'Gene', (66, 75))
158257	20197394	TC71-GFP/LUC and A4573-GFP/LUC cells were grown in DMEM with 10% FBS, antibiotics (penicillin/streptomycin), and L-glutamine to a density of 75-90%.	('DMEM', 'Chemical', '-', (51, 55))	('L-glutamine', 'Chemical', 'MESH:D005973', (113, 124))	('FBS', 'Disease', (65, 68))	('streptomycin', 'Chemical', 'MESH:D013307', (94, 106))	('FBS', 'Disease', 'MESH:D005198', (65, 68))	('A4573-GFP/LUC', 'Var', (17, 30))	('penicillin', 'Chemical', 'MESH:D010406', (83, 93))
158261	20197394	Each mouse was injected with 5x106 TC71-GFP/LUC or A4573-GFP/LUC cells suspended in equal volume of DMEM (without FBS or antibiotics) and Matrigel, in 0.2 ml.	('A4573-GFP/LUC', 'Var', (51, 64))	('DMEM', 'Chemical', '-', (100, 104))	('FBS', 'Disease', (114, 117))	('FBS', 'Disease', 'MESH:D005198', (114, 117))	('mouse', 'Species', '10090', (5, 10))
158266	20197394	TC71-GFP/LUC and A4573-GFP/LUC cells were grown in DMEM with 10% FBS, antibiotics (penicillin/streptomycin), and L-glutamine.	('DMEM', 'Chemical', '-', (51, 55))	('L-glutamine', 'Chemical', 'MESH:D005973', (113, 124))	('FBS', 'Disease', (65, 68))	('streptomycin', 'Chemical', 'MESH:D013307', (94, 106))	('FBS', 'Disease', 'MESH:D005198', (65, 68))	('A4573-GFP/LUC', 'Var', (17, 30))	('penicillin', 'Chemical', 'MESH:D010406', (83, 93))
158269	20197394	Each mouse was injected with 5x106 TC71-GFP/LUC or A4573-GFP/LUC cells suspended in 0.1 ml DMEM (without FBS or antibiotics) through the tail vein using a 28 1/2-gauge needle.	('A4573-GFP/LUC', 'Var', (51, 64))	('thr', 'Chemical', 'MESH:D013912', (125, 128))	('FBS', 'Disease', (105, 108))	('mouse', 'Species', '10090', (5, 10))	('FBS', 'Disease', 'MESH:D005198', (105, 108))	('DMEM', 'Chemical', '-', (91, 95))
158282	20197394	Initial testing showed that the IC50 value for cellular proliferation for both A4573 and TC71 EWS cells were between 1 and 10 muM (Figure 1A).	('muM', 'Gene', '56925', (126, 129))	('EWS', 'Phenotype', 'HP:0012254', (94, 97))	('A4573', 'Var', (79, 84))	('muM', 'Gene', (126, 129))	('cellular proliferation', 'CPA', (47, 69))	('TC71 EWS', 'CellLine', 'CVCL:2213', (89, 97))
158304	20197394	By hematoxylin and eosin staining, the histology demonstrated that tumors from mice treated with ABT-869 had increased evidence of necrosis and inflammation compared to vehicle controls (Figures 5A and B).	('ABT-869', 'Chemical', 'MESH:C513486', (97, 104))	('hematoxylin', 'Chemical', 'MESH:D006416', (3, 14))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mice', 'Species', '10090', (79, 83))	('necrosis', 'Disease', (131, 139))	('ABT-869', 'Var', (97, 104))	('eosin', 'Chemical', 'MESH:D004801', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('inflammation', 'Disease', 'MESH:D007249', (144, 156))	('tumors', 'Disease', (67, 73))	('necrosis', 'Disease', 'MESH:D009336', (131, 139))	('inflammation', 'Disease', (144, 156))
158305	20197394	There were no differences in the cell cycle profile of cells treated with ABT-869 compared to vehicle control (data not shown).	('ABT-869', 'Var', (74, 81))	('cell cycle profile', 'CPA', (33, 51))	('ABT-869', 'Chemical', 'MESH:C513486', (74, 81))
158311	20197394	Furthermore, the tagged cells showed evidence of more aggressive disease in mice treated with ABT-869 compared to untreated mice (Figure 6C).	('aggressive disease', 'Disease', 'MESH:D001523', (54, 72))	('ABT-869', 'Var', (94, 101))	('mice', 'Species', '10090', (124, 128))	('aggressive disease', 'Disease', (54, 72))	('mice', 'Species', '10090', (76, 80))	('ABT-869', 'Chemical', 'MESH:C513486', (94, 101))
158312	20197394	As previously observed, the mice tolerated the ABT-869 well, maintained their normal activity levels and weight.	('activity levels', 'MPA', (85, 100))	('mice', 'Species', '10090', (28, 32))	('ABT-869', 'Chemical', 'MESH:C513486', (47, 54))	('ABT-869', 'Var', (47, 54))	('weight', 'CPA', (105, 111))
158330	20197394	The fact that ABT-869 is not a general antiproliferative drug, but rather inhibits both proliferation and induces cell death, is consistent with previous reports.	('ABT-869', 'Var', (14, 21))	('ABT-869', 'Chemical', 'MESH:C513486', (14, 21))	('inhibits', 'NegReg', (74, 82))	('proliferation', 'CPA', (88, 101))	('cell death', 'CPA', (114, 124))
158351	33666664	In an exploratory analysis, patients with increased antibiotic exposure were more likely to have lymphopenia (odds ratio, 1.96; 95% CI, 1.26-3.07 for total number of antimicrobial agents; odds ratio, 1.70; 95% CI, 1.10-2.57 for antimicrobial duration) than antimicrobial-naive patients.	('lymphopenia', 'Disease', (97, 108))	('lymphopenia', 'Phenotype', 'HP:0001888', (97, 108))	('patients', 'Species', '9606', (277, 285))	('lymphopenia', 'Disease', 'MESH:D008231', (97, 108))	('patients', 'Species', '9606', (28, 36))	('antibiotic', 'Var', (52, 62))
158421	33460400	For example, it was reported that phosphorylated SMC1A was overexpressed in hepatocellular carcinoma cells, and that this was significantly associated with poor prognosis.	('SMC1A', 'Gene', '8243', (49, 54))	('associated', 'Reg', (140, 150))	('overexpressed', 'PosReg', (59, 72))	('phosphorylated', 'Var', (34, 48))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 100))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('hepatocellular carcinoma', 'Disease', (76, 100))	('SMC1A', 'Gene', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))
158426	33460400	Previous reports showed that knocking down the SMC2 gene could inhibit tumor growth in colorectal cancer and increase apoptosis of neuroblastoma cells.	('SMC2', 'Gene', '10592', (47, 51))	('increase apoptosis of neuroblastoma', 'Disease', (109, 144))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('knocking down', 'Var', (29, 42))	('neuroblastoma', 'Phenotype', 'HP:0003006', (131, 144))	('SMC2', 'Gene', (47, 51))	('increase apoptosis of neuroblastoma', 'Disease', 'MESH:D009447', (109, 144))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('colorectal cancer', 'Disease', (87, 104))	('tumor', 'Disease', (71, 76))	('inhibit', 'NegReg', (63, 70))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))
158433	33460400	The risk of lung adenocarcinoma-related death in patients with high SMC4 expression was about 1.5-fold that of those with lower expression.	('expression', 'Var', (73, 83))	('SMC4', 'Gene', (68, 72))	('death', 'Disease', (40, 45))	('death', 'Disease', 'MESH:D003643', (40, 45))	('lung adenocarcinoma', 'Disease', (12, 31))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (12, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (12, 31))	('SMC4', 'Gene', '10051', (68, 72))
158462	33460400	Moreover, expression of SMC2 was significantly related to poor DFS (p<0.05) (Figure 5B).	('poor', 'Disease', (58, 62))	('SMC2', 'Gene', '10592', (24, 28))	('related', 'Reg', (47, 54))	('SMC2', 'Gene', (24, 28))	('expression', 'Var', (10, 20))
158464	33460400	Therefore, high expression SMC1A and SMC2 is potentially prognostic for sarcoma.	('sarcoma', 'Disease', (72, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('SMC2', 'Gene', (37, 41))	('prognostic', 'Reg', (57, 67))	('SMC1A', 'Gene', (27, 32))	('high expression', 'Var', (11, 26))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('SMC1A', 'Gene', '8243', (27, 32))	('SMC2', 'Gene', '10592', (37, 41))
158480	33460400	Previous studies indicated that Uterine Leiomyosarcoma was driven almost exclusively by the inactivation of tumor suppressor genes.	('inactivation', 'Var', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Uterine Leiomyosarcoma', 'Phenotype', 'HP:0002891', (32, 54))	('Leiomyosarcoma', 'Disease', 'MESH:D007890', (40, 54))	('tumor', 'Disease', (108, 113))	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (40, 54))	('Leiomyosarcoma', 'Disease', (40, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
158496	33460400	If one of the steps is abnormal, it will lead to the occurrence of cell mitosis and multipolarization, leading to severe aneuploidy and sarcoma formation.	('aneuploidy', 'Disease', (121, 131))	('multipolarization', 'CPA', (84, 101))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('cell mitosis', 'CPA', (67, 79))	('aneuploidy', 'Disease', 'MESH:D000782', (121, 131))	('sarcoma', 'Disease', (136, 143))	('lead to', 'Reg', (41, 48))	('abnormal', 'Var', (23, 31))	('leading to', 'Reg', (103, 113))	('occurrence', 'Reg', (53, 63))
158502	33460400	SMC2 gene knockdown prevents growth of colorectal cancer, and can also increase neuroblastoma cell apoptosis.	('neuroblastoma', 'Disease', 'MESH:D009447', (80, 93))	('neuroblastoma', 'Disease', (80, 93))	('SMC2', 'Gene', '10592', (0, 4))	('neuroblastoma', 'Phenotype', 'HP:0003006', (80, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('prevents', 'NegReg', (20, 28))	('increase', 'PosReg', (71, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('SMC2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('growth', 'MPA', (29, 35))	('knockdown', 'Var', (10, 19))	('colorectal cancer', 'Disease', (39, 56))
158506	33460400	Cells harboring SMC2 mutations indicated features with chromosomal destabilization as well, suggesting that impairment of condensin functions by somatic mutation of SMC2 might induce genome instability and contribute to the occurrence and progress of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('SMC2', 'Gene', '10592', (16, 20))	('impairment', 'NegReg', (108, 118))	('SMC2', 'Gene', '10592', (165, 169))	('condensin functions', 'MPA', (122, 141))	('SMC2', 'Gene', (16, 20))	('induce', 'Reg', (176, 182))	('sarcoma', 'Disease', 'MESH:D012509', (251, 258))	('SMC2', 'Gene', (165, 169))	('genome instability', 'MPA', (183, 201))	('contribute', 'Reg', (206, 216))	('sarcoma', 'Disease', (251, 258))	('mutation', 'Var', (153, 161))	('mutations', 'Var', (21, 30))
158507	33460400	Emerging evidence showed that SMC2 knockdown may suppress growth of sarcoma and increase apoptosis.	('knockdown', 'Var', (35, 44))	('growth of', 'CPA', (58, 67))	('SMC2', 'Gene', '10592', (30, 34))	('increase', 'PosReg', (80, 88))	('apoptosis', 'CPA', (89, 98))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('SMC2', 'Gene', (30, 34))	('sarcoma', 'Disease', (68, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('suppress', 'NegReg', (49, 57))
158514	33460400	Previous studies indicated that loss of the cohesin complex and its cofactors can cause the development of cancer.	('cause', 'Reg', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cohesin complex', 'Protein', (44, 59))	('loss', 'Var', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
158524	33460400	As reported by others, highly expressed SMC4 may upregulate the expression of PLK1, leading to cancer progression and poor prognosis in non-TNBC.	('expression', 'MPA', (64, 74))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('non-TNBC', 'Disease', (136, 144))	('leading to', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('PLK1', 'Gene', (78, 82))	('PLK1', 'Gene', '5347', (78, 82))	('SMC4', 'Gene', '10051', (40, 44))	('highly expressed', 'Var', (23, 39))	('upregulate', 'PosReg', (49, 59))	('SMC4', 'Gene', (40, 44))
158528	33460400	There is a view that the loss of the SMC5-SMC6 complex will cause abnormalities in the late stage of replication as it plays a role in the topological structure of DNA.	('SMC6', 'Gene', '79677', (42, 46))	('loss', 'Var', (25, 29))	('cause', 'Reg', (60, 65))	('SMC5', 'Gene', (37, 41))	('SMC6', 'Gene', (42, 46))	('abnormalities', 'MPA', (66, 79))	('role', 'Reg', (127, 131))	('SMC5', 'Gene', '23137', (37, 41))	('late stage', 'MPA', (87, 97))	('plays', 'Reg', (119, 124))
158550	32246378	Frequency of radiation-induced malignancies post-adjuvant radiotherapy for breast cancer in patients with Li-Fraumeni syndrome Women with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by germline mutations in TP53, have an over 50% risk of developing breast cancer by age 70.	('cancer', 'Disease', (280, 286))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('radiation-induced malignancies', 'Phenotype', 'HP:0010997', (13, 43))	('LFS', 'Disease', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('LFS', 'Disease', 'MESH:D016864', (160, 163))	('Women', 'Species', '9606', (127, 132))	('malignancies', 'Disease', 'MESH:D009369', (31, 43))	('patients', 'Species', '9606', (92, 100))	('malignancies', 'Disease', (31, 43))	('caused by', 'Reg', (199, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('Li-Fraumeni syndrome', 'Disease', (138, 158))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('germline mutations', 'Var', (209, 227))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TP53', 'Gene', (231, 235))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('breast cancer', 'Disease', (273, 286))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (138, 158))	('breast cancer', 'Disease', (75, 88))	('Li-Fraumeni syndrome', 'Disease', (106, 126))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (106, 126))
158553	32246378	A single-institution retrospective chart review was conducted for female breast cancer patients with confirmed germline TP53 mutation.	('mutation', 'Var', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('patients', 'Species', '9606', (87, 95))	('TP53', 'Gene', (120, 124))
158564	32246378	Li-Fraumeni syndrome (LFS) is an autosomal dominant inherited cancer predisposition syndrome, often due to germline mutations in TP53.	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('autosomal dominant inherited cancer', 'Disease', (33, 68))	('LFS', 'Disease', 'MESH:D016864', (22, 25))	('TP53', 'Gene', (129, 133))	('due to', 'Reg', (100, 106))	('germline mutations', 'Var', (107, 125))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('LFS', 'Disease', (22, 25))	('autosomal dominant inherited cancer', 'Disease', 'MESH:D009369', (33, 68))
158573	32246378	Previous studies have described increased chromosomal aberrations in in vitro mutant TP53 fibroblasts, as well as genotoxicity in mouse models with deficient germline TP53 due to radiation exposure.	('TP53', 'Gene', (85, 89))	('mouse', 'Species', '10090', (130, 135))	('increased', 'PosReg', (32, 41))	('chromosomal aberrations', 'CPA', (42, 65))	('mutant', 'Var', (78, 84))	('increased chromosomal aberrations', 'Phenotype', 'HP:0040012', (32, 65))
158577	32246378	Briefly, patients were identified via a query of the medical record for individuals with a germline mutation in TP53; and cases were cross-referenced with cancer predisposition registry records.	('patients', 'Species', '9606', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('germline mutation', 'Var', (91, 108))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('TP53', 'Gene', (112, 116))
158578	32246378	Eligibility criteria for the current analysis included: (i) confirmed germline mutation in TP53 and (ii) diagnosis of female breast cancer.	('TP53', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('germline mutation', 'Var', (70, 87))
158583	32246378	Data on the LFS cohort from the International Agency for Research on Cancer (IARC) database were downloaded for individuals with a pathogenic or likely pathogenic TP53 mutation.	('pathogenic', 'Reg', (131, 141))	('LFS', 'Disease', 'MESH:D016864', (12, 15))	('mutation', 'Var', (168, 176))	('LFS', 'Disease', (12, 15))	('Cancer', 'Disease', (69, 75))	('TP53', 'Gene', (163, 167))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer', 'Disease', 'MESH:D009369', (69, 75))
158624	32246378	However, it is theoretically possible that the non-LFS cohort includes TP53 mutation carriers that do not have a diagnosis of LFS documented in the electronic health record.	('LFS', 'Disease', (126, 129))	('mutation', 'Var', (76, 84))	('LFS', 'Disease', (51, 54))	('LFS', 'Disease', 'MESH:D016864', (51, 54))	('TP53', 'Gene', (71, 75))	('LFS', 'Disease', 'MESH:D016864', (126, 129))
158661	29434830	All these observations finally reached a conclusion that expression of CD133 is a confirmed indicator of lung metastasis in osteosarcoma patients.	('lung metastasis', 'Disease', (105, 120))	('expression', 'Var', (57, 67))	('osteosarcoma', 'Disease', (124, 136))	('lung metastasis', 'Disease', 'MESH:D009362', (105, 120))	('patients', 'Species', '9606', (137, 145))	('CD133', 'Chemical', '-', (71, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('CD133', 'Gene', (71, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
158666	29434830	Previously, two independent groups have reported that CD49f may serve in osteosarcoma as another marker that can distinguish CSCs from the cells with limited tumorigenic capacity.	('CSCs', 'Disease', (125, 129))	('tumor', 'Disease', (158, 163))	('osteosarcoma', 'Phenotype', 'HP:0002669', (73, 85))	('osteosarcoma', 'Disease', (73, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (73, 85))	('CD49f', 'Var', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
158683	29434830	In the diagnosis, these tumors showed the presence of specific fusion oncoproteins as result of chromosomal translocations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('chromosomal translocations', 'Var', (96, 122))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('oncoproteins', 'Protein', (70, 82))	('fusion oncoproteins', 'Protein', (63, 82))
158690	29434830	CD133+ cells displayed ability to start and maintain tumor growth via xenotransplantations, The CD133+ cells also expressed elevation in the levels of both OCT4 and NANOG, but not SOX2 or CD133- counterparts.	('NANOG', 'Gene', '79923', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NANOG', 'Gene', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CD133+', 'Var', (96, 102))	('CD133', 'Chemical', '-', (0, 5))	('levels of', 'MPA', (141, 150))	('OCT4', 'MPA', (156, 160))	('CD133', 'Chemical', '-', (188, 193))	('tumor', 'Disease', (53, 58))	('elevation', 'PosReg', (124, 133))	('CD133', 'Chemical', '-', (96, 101))
158696	29434830	Inhibition of miR-145 in dermal skin fibroblasts led to upregulation of pluripotency-associated genes including SOX2, KLF4, OCT4 and MYCC, and increased efficiency of reprogramming these fibroblasts to induced pluripotent stem cells.	('increased', 'PosReg', (143, 152))	('pluripotency', 'Disease', (72, 84))	('upregulation', 'PosReg', (56, 68))	('OCT4', 'Gene', (124, 128))	('pluripotency', 'Disease', 'None', (72, 84))	('miR-145', 'Chemical', '-', (14, 21))	('reprogramming', 'CPA', (167, 180))	('Inhibition', 'Var', (0, 10))	('SOX2', 'Gene', (112, 116))	('MYCC,', 'Gene', '4609', (133, 138))	('KLF4', 'Gene', (118, 122))	('miR-145', 'Gene', (14, 21))
158697	29434830	Moreover, the loss of the above miRNA might promote tumorigenesis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('loss', 'Var', (14, 18))	('promote', 'PosReg', (44, 51))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
158701	29434830	Consistent with this study, knockdown of EWS-FLI1 in Ewing's sarcoma cell lines dramatically increased the levels of miR-145, and forced miR-145 expression halted growth of the cells.	('growth of the cells', 'CPA', (163, 182))	('miR-145', 'Chemical', '-', (137, 144))	('levels of miR-145', 'MPA', (107, 124))	('increased', 'PosReg', (93, 102))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (53, 68))	('miR-145', 'Chemical', '-', (117, 124))	('FLI', 'Gene', '2314', (45, 48))	('FLI', 'Gene', (45, 48))	('miR-145', 'Var', (137, 144))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (53, 68))	('halted growth', 'Phenotype', 'HP:0001510', (156, 169))	("Ewing's sarcoma", 'Disease', (53, 68))	('knockdown', 'Var', (28, 37))	('halted', 'NegReg', (156, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
158706	29434830	CD57 high cells were more tumorigenic, formed spheres at higher frequency and had enhanced migratory potential than CD57 low cells.	('enhanced', 'PosReg', (82, 90))	('migratory potential', 'CPA', (91, 110))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('more', 'PosReg', (21, 25))	('spheres', 'CPA', (46, 53))	('CD57 high cells', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
158707	29434830	Interestingly, only partial overlap was observed among CD57 high and CD133+ populations of cells, suggesting that CD57 identify different population of Ewing's sarcoma cells with CSC phenotype.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (152, 167))	('CD57', 'Var', (114, 118))	("Ewing's sarcoma", 'Disease', (152, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (152, 167))	('CD133', 'Chemical', '-', (69, 74))
158711	29434830	Increased expression of LGR5 also corresponded with CD133 positivity and high ALDH activity in Ewing's sarcoma cell lines.	('positivity', 'Var', (58, 68))	('ALDH', 'Gene', (78, 82))	('CD133', 'Protein', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('expression', 'MPA', (10, 20))	('LGR5', 'Gene', (24, 28))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (95, 110))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (95, 110))	('Increased', 'PosReg', (0, 9))	("Ewing's sarcoma", 'Disease', (95, 110))	('high', 'Protein', (73, 77))	('ALDH', 'Gene', '11670', (78, 82))	('CD133', 'Chemical', '-', (52, 57))
158722	29434830	This subtype of rhabdomyosarcoma typically harbors one of two characteristic chromosomal translocations t(2;13) (q35;q14) or t(1;13) (p36;q14) that juxtapose PAX3 or PAX7 and FOXO1A genes, resulting in Pax3 and Pax7-FKHR fusion proteins.	('rhabdomyosarcoma', 'Disease', (16, 32))	('Pax7-FKHR fusion proteins', 'Protein', (211, 236))	('Pax3', 'Var', (202, 206))	('FOXO1A', 'Gene', (175, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (16, 32))	('PAX3', 'Gene', (158, 162))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (16, 32))	('PAX7', 'Gene', (166, 170))
158724	29434830	Ren et al showed that Pax3 and Pax7-FKHR induced skeletal myogenesis in murine MSCs, although additional secondary genetic event was needed for their transformation towards alveolar rhabdomyosarcoma and tumor formation in vivo.	('Pax3', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (173, 198))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (182, 198))	('alveolar rhabdomyosarcoma', 'Disease', (173, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('Pax7-FKHR', 'Var', (31, 40))	('induced', 'Reg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (173, 198))	('murine', 'Species', '10090', (72, 78))	('skeletal myogenesis', 'CPA', (49, 68))
158733	29434830	In contrast, no difference in tumorigenicity of CD133+ and CD133- cells was found in a previous study of three embryonal rhabdomyosarcoma cell lines.	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (111, 137))	('embryonal rhabdomyosarcoma', 'Disease', (111, 137))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (111, 137))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('CD133+', 'Var', (48, 54))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (121, 137))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CD133', 'Chemical', '-', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('CD133', 'Chemical', '-', (59, 64))	('tumor', 'Disease', (30, 35))
158741	29434830	These CD133+ CXCR4+ cells were shown to have migratory capacity in vitro and were demonstrated to be essential for metastatic phenotype of the PDAC in vivo.	('PDAC', 'Chemical', '-', (143, 147))	('CD133', 'Chemical', '-', (6, 11))	('migratory capacity', 'CPA', (45, 63))	('CD133+', 'Var', (6, 12))
158749	29434830	Co-expression of CD44 and CD133 was then proposed as more specific phenotype of CSCs and was shown to predict worse survival in PDAC patients.	('CSCs', 'Disease', (80, 84))	('CD133', 'Var', (26, 31))	('CD44', 'Var', (17, 21))	('PDAC', 'Chemical', '-', (128, 132))	('patients', 'Species', '9606', (133, 141))	('CD133', 'Chemical', '-', (26, 31))	('Co-expression', 'Var', (0, 13))	('predict', 'Reg', (102, 109))
158779	26293576	P53 gene mutations occur in approximately one-half of all tumors in a wide range of human malignancies and overexpression is associated with poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('malignancies', 'Disease', (90, 102))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (9, 18))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('P53', 'Gene', (0, 3))	('human', 'Species', '9606', (84, 89))	('P53', 'Gene', '7157', (0, 3))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('occur', 'Reg', (19, 24))
158789	26293576	AA98 inhibits human umbilical vein endothelial cell proliferation and migration as well as angiogenesis, validating CD146 as a novel target for antiangiogenic agents.	('AA98', 'Var', (0, 4))	('migration', 'CPA', (70, 79))	('angiogenesis', 'CPA', (91, 103))	('human', 'Species', '9606', (14, 19))	('inhibits', 'NegReg', (5, 13))	('CD146', 'Gene', '4162', (116, 121))	('CD146', 'Gene', (116, 121))
158844	26293576	On multivariate analyses, CD146 positivity varied statistically significantly with clinicopathological parameters, P53, and Ki-67 expression (P = 0.01).	('P53', 'Gene', '7157', (115, 118))	('CD146', 'Gene', (26, 31))	('CD146', 'Gene', '4162', (26, 31))	('positivity', 'Var', (32, 42))	('P53', 'Gene', (115, 118))	('varied', 'Reg', (43, 49))
158847	26293576	CD146 positivity also tended to be associated with poor prognosis in ESS, though the difference was not significant (P = 0.1).	('positivity', 'Var', (6, 16))	('ESS', 'Disease', (69, 72))	('CD146', 'Gene', '4162', (0, 5))	('CD146', 'Gene', (0, 5))
158872	26293576	CD146 positivity in the epithelial compartment showed a significant association with poor prognosis in ESS (P = 0.1).	('positivity', 'Var', (6, 16))	('CD146', 'Gene', '4162', (0, 5))	('ESS', 'Disease', (103, 106))	('CD146', 'Gene', (0, 5))
158877	26293576	WHO World Health Organization LMS leiomyosarcoma ESS endometrial stromal sarcoma UD undifferentiated sarcoma MMMT malignant mixed Mullerian tumor SYSUCC Sun Yat-Sen University Cancer Center FIGO International Federation of Obstetrics and Gynecology PE paraffin-embedded TAH total abdominal hysterectomy BSO bilateral salpingo-oophorectomy PL pelvic lymphadenectomy MI mitotic index HPF high-power field OS overall survival DFS disease-free survival LVSI lymphovascular space invasion	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (53, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('LMS', 'Phenotype', 'HP:0100243', (30, 33))	('leiomyosarcoma', 'Disease', (34, 48))	('OS', 'Chemical', '-', (403, 405))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (84, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (34, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('undifferentiated sarcoma', 'Disease', (84, 108))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('paraffin', 'Chemical', 'MESH:D010232', (252, 260))	('endometrial stromal sarcoma', 'Disease', (53, 80))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (34, 48))	('MI mitotic index HPF', 'Var', (365, 385))	('tumor', 'Disease', (140, 145))
158992	33937065	Furthermore, LMS in kidney sarcoma were associated with lower recurrence rate in comparison to rhabdomyosarcoma (RMS) (P = 0.043).	('LMS', 'Var', (13, 16))	('RMS', 'Phenotype', 'HP:0002859', (113, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('rhabdomyosarcoma', 'Disease', (95, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (95, 111))	('LMS', 'Phenotype', 'HP:0100243', (13, 16))	('lower', 'NegReg', (56, 61))	('kidney sarcoma', 'Disease', (20, 34))	('kidney sarcoma', 'Disease', 'MESH:D012509', (20, 34))	('kidney sarcoma', 'Phenotype', 'HP:0008663', (20, 34))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (95, 111))	('recurrence rate', 'MPA', (62, 77))
159047	33937065	Namely, patients with tumor size <=5 cm and those with obvious symptoms at presentation were associated with lower RFS.	('<=5', 'Var', (33, 36))	('lower', 'NegReg', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('RFS', 'Disease', (115, 118))	('patients', 'Species', '9606', (8, 16))
159161	28609402	During latency, few genes are expressed, including those encoded by ORFK12 (kaposin), ORF71 (vFLIP), ORF72 (v-cyclin), ORF73 (latency-associated nuclear antigen[LANA]), ORFK10.5 (vIRF3) and several viral microRNAs (miRNAs).	('ORFK10.5', 'Gene', (169, 177))	('LANA', 'Gene', (161, 165))	('ORF71', 'Gene', (86, 91))	('ORFK12', 'Gene', (68, 74))	('vFLIP', 'Gene', '4961494', (93, 98))	('LANA', 'Gene', '4961527', (161, 165))	('vFLIP', 'Gene', (93, 98))	('ORF72', 'Gene', (101, 106))	('ORF73', 'Var', (119, 124))
159166	28609402	While the evolutionary pressure for these genes is to promote KSHV survival, they can also lead to the development of KSHV-related tumors and proliferative diseases, which are unintended consequences.	('promote', 'PosReg', (54, 61))	('lead to', 'Reg', (91, 98))	('men', 'Species', '9606', (110, 113))	('KSHV', 'Species', '37296', (62, 66))	('KS', 'Phenotype', 'HP:0100726', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('KSHV', 'Species', '37296', (118, 122))	('KS', 'Phenotype', 'HP:0100726', (118, 120))	('genes', 'Var', (42, 47))	('proliferative diseases', 'CPA', (142, 164))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
159174	28609402	KSHV v-FLIP activates NF-kappaB which contributes to the pathogenesis of PEL, KS, and KSHV-MCD.	('KS', 'Phenotype', 'HP:0100726', (78, 80))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('KSHV-MCD', 'Disease', (86, 94))	('contributes', 'Reg', (38, 49))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('activates', 'PosReg', (12, 21))	('NF-kappaB', 'Gene', (22, 31))	('KSHV-MCD', 'Disease', 'MESH:D012514', (86, 94))	('KSHV', 'Species', '37296', (86, 90))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('PEL', 'Disease', (73, 76))	('PEL', 'Phenotype', 'HP:0030069', (73, 76))	('NF-kappaB', 'Gene', '4790', (22, 31))
159258	28609402	KSHV is the cause of a distinct subset of multicentric Castleman disease (KSHV-MCD) that usually develops in HIV-infected patients.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('KSHV', 'Species', '37296', (74, 78))	('multicentric Castleman disease', 'Disease', 'MESH:C537372', (42, 72))	('HIV-infected', 'Disease', (109, 121))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('KSHV-MCD', 'Disease', (74, 82))	('patients', 'Species', '9606', (122, 130))	('KSHV-MCD', 'Disease', 'MESH:D012514', (74, 82))	('multicentric Castleman disease', 'Disease', (42, 72))	('cause', 'Reg', (12, 17))	('KS', 'Phenotype', 'HP:0100726', (74, 76))	('HIV-infected', 'Disease', 'MESH:D015658', (109, 121))
159291	28609402	However, rituximab may have limitations in patients with low CD4+ T-cell counts, severe symptoms, organ dysfunction, and patients with coexisting KS, as rituximab can lead to worsening of KS.	('organ dysfunction', 'Disease', (98, 115))	('CD4', 'Gene', '920', (61, 64))	('KS', 'Phenotype', 'HP:0100726', (188, 190))	('low CD4+ T-', 'Phenotype', 'HP:0005407', (57, 68))	('patients', 'Species', '9606', (43, 51))	('rituximab', 'Var', (153, 162))	('KS', 'Phenotype', 'HP:0100726', (146, 148))	('organ dysfunction', 'Disease', 'MESH:D019965', (98, 115))	('rituximab', 'Chemical', 'MESH:D000069283', (153, 162))	('rituximab', 'Chemical', 'MESH:D000069283', (9, 18))	('patients', 'Species', '9606', (121, 129))	('CD4', 'Gene', (61, 64))
159312	28609402	There are several mechanisms by which KSHV can increase cytokine production, and we hypothesized that the symptoms in these patients resulted from direct or indirect cytokine activation by KSHV.	('KS', 'Phenotype', 'HP:0100726', (38, 40))	('KSHV', 'Species', '37296', (38, 42))	('KSHV', 'Var', (38, 42))	('KSHV', 'Species', '37296', (189, 193))	('increase cytokine', 'Phenotype', 'HP:0031407', (47, 64))	('KS', 'Phenotype', 'HP:0100726', (189, 191))	('cytokine production', 'MPA', (56, 75))	('increase', 'PosReg', (47, 55))	('patients', 'Species', '9606', (124, 132))
159325	28609402	It is now appreciated that KSHV can cause several diseases, several of which had not been previously recognized.	('cause', 'Reg', (36, 41))	('KSHV', 'Var', (27, 31))	('diseases', 'Disease', (50, 58))	('KS', 'Phenotype', 'HP:0100726', (27, 29))	('KSHV', 'Species', '37296', (27, 31))
159390	28921170	Furthermore, MTV (MO-PET) exhibited the most accurate trend line with GTV compared with those of other MTVs.	('MTV', 'Var', (13, 16))	('GTV', 'Chemical', '-', (70, 73))	('MTV', 'Chemical', '-', (103, 106))	('GTV', 'Disease', (70, 73))	('MTV', 'Chemical', '-', (13, 16))
159399	28921170	Furthermore, the Spearman and intra-class correlation coefficients of MTV (MO-PET) were higher than that of MTV (2.0).	('higher', 'PosReg', (88, 94))	('MTV', 'Chemical', '-', (108, 111))	('MTV', 'Chemical', '-', (70, 73))	('MTV', 'Var', (70, 73))
159555	21552147	The following cDNA samples were analyzed in duplicate: ASPS patient tumor, a xenograft of the same material and 5 passage stages of the ASPS-1 cell line (p5, p10, p15, p20, and p25).	('tumor', 'Disease', (68, 73))	('patient', 'Species', '9606', (60, 67))	('p20', 'Gene', '51673', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('p25', 'Gene', '8851', (177, 180))	('ASPS', 'Phenotype', 'HP:0012218', (136, 140))	('p10', 'Gene', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('p25', 'Gene', (177, 180))	('p15', 'Gene', (163, 166))	('p5', 'Var', (154, 156))	('p20', 'Gene', (168, 171))	('p15', 'Gene', '1030', (163, 166))	('p10', 'Gene', '6281', (158, 161))	('ASPS', 'Phenotype', 'HP:0012218', (55, 59))
159574	21552147	Analysis of metaphase chromosomes of ASPS-1 tumor cells (passage 14) revealed a near triploid modal chromosome number and the presence of numerous chromosomal rearrangements including the characteristic t(X;17)(q11;p25) translocation reported for this tumor.	('chromosomal rearrangements', 'CPA', (147, 173))	('t(X;17)(q11;p25) translocation', 'Var', (203, 233))	('t(X;17)(q11;p25)', 'STRUCTURAL_ABNORMALITY', 'None', (203, 219))	('ASPS', 'Phenotype', 'HP:0012218', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('ASPS-1 tumor', 'Disease', 'MESH:D018234', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ASPS-1 tumor', 'Disease', (37, 49))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', (44, 49))	('numerous chromosomal rearrangements', 'Phenotype', 'HP:0040012', (138, 173))
159600	21552147	The cells were expanded, over a period of 3 years, and characterized with respect to the ASPL-TFE3 fusion transcript, presence of the t(X;17)(p11;q25) translocation characteristic of ASPS, and expression of several signature genes and their respective proteins.	('t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (134, 150))	('expression', 'MPA', (193, 203))	('t(X;17)(p11;q25', 'Var', (134, 149))	('ASPS', 'Phenotype', 'HP:0012218', (183, 187))
159651	32183216	Lipoma was the most common diagnosis, followed by schwannoma and hemangioma in the benign-tumor group; atypical lipomatous tumor/well differentiated liposarcoma (ALT/WDL), followed by desmoid tumor in the intermediate-tumor group; and undifferentiated pleomorphic sarcoma (UPS) including malignant fibrous histiocytoma (MFH) and followed by leiomyosarcoma and myxofibrosarcoma in the malignant-tumor group (Table 1).	('tumor', 'Disease', (394, 399))	('lipomatous tumor', 'Disease', 'MESH:D008080', (112, 128))	('liposarcoma', 'Phenotype', 'HP:0012034', (149, 160))	('malignant-tumor', 'Disease', (384, 399))	('malignant fibrous histiocytoma', 'Disease', (288, 318))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('tumor', 'Disease', 'MESH:D009369', (394, 399))	('undifferentiated pleomorphic sarcoma', 'Disease', (235, 271))	('hemangioma', 'Phenotype', 'HP:0001028', (65, 75))	('tumor', 'Disease', (218, 223))	('lipomatous tumor', 'Disease', (112, 128))	('desmoid tumor', 'Disease', 'MESH:C535944', (184, 197))	('tumor', 'Disease', (123, 128))	('liposarcoma', 'Disease', 'MESH:D008080', (149, 160))	('Lipoma', 'Disease', (0, 6))	('schwannoma', 'Phenotype', 'HP:0100008', (50, 60))	('histiocytoma', 'Phenotype', 'HP:0012315', (306, 318))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', (90, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (348, 355))	('malignant fibrous histiocytoma', 'Disease', 'MESH:D051677', (288, 318))	('desmoid tumor', 'Phenotype', 'HP:0100245', (184, 197))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (341, 355))	('atypical', 'Var', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('tumor', 'Disease', (192, 197))	('leiomyosarcoma and myxofibrosarcoma', 'Disease', 'MESH:D007890', (341, 376))	('Lipoma', 'Phenotype', 'HP:0012032', (0, 6))	('malignant-tumor', 'Disease', 'MESH:D009369', (384, 399))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('schwannoma and hemangioma in the benign-tumor', 'Disease', 'MESH:D009442', (50, 95))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('liposarcoma', 'Disease', (149, 160))	('Lipoma', 'Disease', 'MESH:D008067', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('desmoid tumor', 'Disease', (184, 197))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (235, 271))	('sarcoma', 'Phenotype', 'HP:0100242', (369, 376))	('lipomatous tumor', 'Phenotype', 'HP:0012031', (112, 128))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
159655	32183216	Laboratory parameters were stratified as follows: WBC, >= 5700/microL versus < 5700/microL; Hb, > 12.4 g/dL versus <= 12.4 g/dL; CRP, >= 0.17 mg/dL versus < 0.17 mg/dL; and LDH, >= 240 IU/L versus < 240 IU/L.	('>= 240 IU/L', 'Var', (178, 189))	('CRP', 'Gene', (129, 132))	('CRP', 'Gene', '1401', (129, 132))	('> 12.4', 'Var', (96, 102))	('>= 5700/microL', 'Var', (55, 69))	('>= 0.17', 'Var', (134, 141))
159657	32183216	Older patients with large tumors, high WBC count, low Hb count, high serum CRP level, and high serum LDH level were likely to be diagnosed with soft tissue sarcoma (Table 4).	('low', 'NegReg', (50, 53))	('low Hb count', 'Phenotype', 'HP:0020062', (50, 62))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (144, 163))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (144, 163))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('soft tissue sarcoma', 'Disease', (144, 163))	('high', 'PosReg', (64, 68))	('CRP', 'Gene', (75, 78))	('high serum CRP', 'Phenotype', 'HP:0011227', (64, 78))	('diagnosed', 'Reg', (129, 138))	('high WBC count', 'Phenotype', 'HP:0020059', (34, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Hb count', 'MPA', (54, 62))	('CRP', 'Gene', '1401', (75, 78))	('high', 'Var', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('WBC count', 'MPA', (39, 48))	('tumors', 'Disease', (26, 32))
159669	32183216	Although reports on the relationship between the additional wide excision after unplanned excision and local recurrence of soft tissue sarcomas are controversial, unplanned excision is generally considered to be associated with an increased risk of local recurrence and the needed for additional and more extensive surgery.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (123, 143))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (123, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (123, 143))	('local recurrence', 'CPA', (249, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('unplanned excision', 'Var', (163, 181))	('soft tissue sarcomas', 'Disease', (123, 143))
159717	30633925	New fusion sarcomas: histopathology and clinical significance of selected entities Many sarcomas contain gene fusions that can be pathogenetic mechanisms and diagnostic markers.	('sarcomas', 'Disease', (88, 96))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcomas', 'Disease', (11, 19))	('gene fusions', 'Var', (105, 117))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('contain', 'Reg', (97, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
159727	30633925	Gene fusions created by chromosomal rearrangements are associated with cancers of various types, especially sarcomas, and are often used as diagnostic markers.	('chromosomal rearrangements', 'Var', (24, 50))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('men', 'Species', '9606', (45, 48))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('associated', 'Reg', (55, 65))	('sarcomas', 'Disease', (108, 116))
159729	30633925	Other well-known gene fusions used as diagnostic markers in sarcomas include fusion of Ewing sarcoma gene (EWSR1) with FLI1 or ERG in Ewing sarcoma and PAX3 or PAX7 fusions with FOXO1 in alveolar rhabdomyosarcoma.	('ERG', 'Gene', '2078', (127, 130))	('fusion', 'Var', (77, 83))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (196, 212))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (187, 212))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (187, 212))	('FLI1', 'Gene', '2313', (119, 123))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (87, 100))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (87, 100))	('EWSR1', 'Gene', (107, 112))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (134, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (134, 147))	('sarcomas', 'Disease', (60, 68))	('PAX7', 'Gene', '5081', (160, 164))	('FOXO1', 'Gene', '2308', (178, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('Ewing sarcoma', 'Disease', (87, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('PAX7', 'Gene', (160, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('PAX3', 'Gene', (152, 156))	('ERG', 'Gene', (127, 130))	('Ewing sarcoma', 'Disease', (134, 147))	('alveolar rhabdomyosarcoma', 'Disease', (187, 212))	('FOXO1', 'Gene', (178, 183))	('EWSR1', 'Gene', '2130', (107, 112))	('FLI1', 'Gene', (119, 123))	('PAX3', 'Gene', '5077', (152, 156))
159731	30633925	Traditionally, all chimeric RNAs were thought originate from gene fusions occurring due to chromosomal rearrangements, such as deletions, inversions, or translocations.	('inversions', 'Disease', (138, 148))	('men', 'Species', '9606', (112, 115))	('translocations', 'Var', (153, 167))	('deletions', 'Var', (127, 136))
159733	30633925	With the recent advances in next-generation sequencing, numerous new chimeric RNAs have been discovered in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('sarcomas', 'Disease', (107, 115))	('RNAs', 'Gene', (78, 82))	('chimeric', 'Var', (69, 77))	('discovered', 'Reg', (93, 103))
159734	30633925	In many cases, tumors harboring these fusions have emerged as new clinicopathologic entities with characteristic histological and immunophenotypic features.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('fusions', 'Var', (38, 45))	('tumors', 'Disease', (15, 21))
159740	30633925	The whole-genome NGS of tumor DNA has been successfully used to identify new fusion genes, such as the NAB2-STAT6 fusion in solitary fibrous tumor.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('NAB2', 'Gene', (103, 107))	('fibrous tumor', 'Disease', (133, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (24, 29))	('STAT6', 'Gene', (108, 113))	('fibrous tumor', 'Disease', 'MESH:D054364', (133, 146))	('tumor', 'Disease', (141, 146))	('NAB2', 'Gene', '4665', (103, 107))	('STAT6', 'Gene', '6778', (108, 113))	('fusion', 'Var', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
159750	30633925	Originally identified from cytogenetic studies on tumors histologically often considered Ewing sarcoma, subsequent larger series have been identified by screening of EWSR1 gene rearrangement-negative Ewing-like sarcomas.	('Ewing-like sarcomas', 'Disease', (200, 219))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('EWSR1', 'Gene', (166, 171))	('Ewing sarcoma', 'Disease', (89, 102))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (200, 219))	('men', 'Species', '9606', (186, 189))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (200, 219))	('EWSR1', 'Gene', '2130', (166, 171))	('sarcomas', 'Phenotype', 'HP:0100242', (211, 219))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('rearrangement-negative', 'Var', (177, 199))
159752	30633925	Most cases contain a t(4;19)(q35;q13) corresponding to a rearrangement between the CIC and DUX4 genes, and a smaller subset contains a t(10;19)(q26;q13), which corresponds to a fusion between CIC and the paralog gene DUX4L.	('DUX4', 'Gene', (91, 95))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (135, 152))	('men', 'Species', '9606', (66, 69))	('DUX4L', 'Gene', '100288687', (217, 222))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (21, 37))	('t(4;19)(q35;q13', 'Var', (21, 36))	('CIC', 'Gene', (83, 86))	('DUX4L', 'Gene', (217, 222))	('t(10;19)(q26;q13', 'Var', (135, 151))
159753	30633925	A small number of cases (currently 2) with CIC-FOXO4 fusions corresponding to t(X;19) (q13;q13;3) translocation have been reported (discussed in the end of this section).	('FOXO4', 'Gene', (47, 52))	('FOXO4', 'Gene', '4303', (47, 52))	('fusions', 'Var', (53, 60))
159755	30633925	CIC-DUX4 fusion up-regulates ETS transcription factors of PEA3 subfamily, especially ETV4.	('ETV4', 'Gene', (85, 89))	('PEA3', 'Gene', '2118', (58, 62))	('PEA3', 'Gene', (58, 62))	('up-regulates', 'PosReg', (16, 28))	('ETV4', 'Gene', '2118', (85, 89))	('ETS transcription factors', 'Gene', (29, 54))	('fusion', 'Var', (9, 15))
159776	30633925	In fact, these tumors have also genetic overlap as clear cell sarcoma of the kidney can have the same fusion, although it more often contains an internal tandem duplication of the BCOR gene.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('BCOR', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('sarcoma of the kidney', 'Disease', 'MESH:D012509', (62, 83))	('BCOR', 'Gene', '54880', (180, 184))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('internal tandem duplication', 'Var', (145, 172))	('contains', 'Reg', (133, 141))	('sarcoma of the kidney', 'Disease', (62, 83))	('tumors', 'Disease', (15, 21))
159800	30633925	There were 4 tumors with fusions involving the beta-actin gene: ACTB-GLI1 and 1 each of fusions involving patched 1 gene: PTCH1-GLI1, and a third fusion with the MALAT1 gene encoding metastasis associated lung adenocarcinoma transcript.	('GLI1', 'Gene', (128, 132))	('MALAT1', 'Gene', '378938', (162, 168))	('ACTB-GLI1 and 1', 'Gene', '60;2735', (64, 79))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (205, 224))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (205, 224))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('PTCH1', 'Gene', '5727', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('patched 1', 'Gene', (106, 115))	('GLI1', 'Gene', '2735', (128, 132))	('tumors', 'Disease', (13, 19))	('GLI1', 'Gene', (69, 73))	('patched 1', 'Gene', '5727', (106, 115))	('fusions', 'Var', (25, 32))	('PTCH1', 'Gene', (122, 127))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('lung adenocarcinoma', 'Disease', (205, 224))	('MALAT1', 'Gene', (162, 168))	('GLI1', 'Gene', '2735', (69, 73))
159813	30633925	Clinical follow-up of ACTB-GLI1 fusion tumors have shown only regional lymph node metastases with no evidence for distant metastases, but follow-up data is scant necessitating caution in prognostication.	('GLI1', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('ACTB', 'Gene', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('metastases', 'Disease', 'MESH:D009362', (82, 92))	('ACTB', 'Gene', '60', (22, 26))	('metastases', 'Disease', (122, 132))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (122, 132))	('fusion', 'Var', (32, 38))	('tumors', 'Disease', (39, 45))	('GLI1', 'Gene', '2735', (27, 31))
159816	30633925	ETV6-NTRK3 fusions were originally reported in infantile fibrosarcoma and cellular mesoblastic nephroma as recurrent genetic events.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('reported', 'Reg', (35, 43))	('infantile fibrosarcoma', 'Disease', (47, 69))	('mesoblastic nephroma', 'Disease', (83, 103))	('NTRK3', 'Gene', '4916', (5, 10))	('ETV6', 'Gene', '2120', (0, 4))	('mesoblastic nephroma', 'Disease', 'MESH:D018201', (83, 103))	('NTRK3', 'Gene', (5, 10))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (47, 69))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (57, 69))	('mesoblastic nephroma', 'Phenotype', 'HP:0100881', (83, 103))	('fusions', 'Var', (11, 18))	('ETV6', 'Gene', (0, 4))
159821	30633925	Tumors with fusions TPM3-NTRK1 may have similar histologic and clinicopathologic features.	('fusions', 'Var', (12, 19))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NTRK1', 'Gene', (25, 30))	('TPM3', 'Gene', '7170', (20, 24))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TPM3', 'Gene', (20, 24))	('NTRK1', 'Gene', '4914', (25, 30))
159830	30633925	A pan-NTRK antibody recognizing NTRKs 1-3 has been reported useful in screening NTRK gene-rearranged sarcomas.	('NTRK', 'Gene', (80, 84))	('NTRKs 1-3', 'Gene', (32, 41))	('NTRKs 1-3', 'Gene', '4914;4915;4916', (32, 41))	('sarcomas', 'Disease', 'MESH:D012509', (101, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('gene-rearranged', 'Var', (85, 100))	('sarcomas', 'Disease', (101, 109))
159834	30633925	ETV6-NTRK3 fusions have been recently in KIT/PDGRA and other known GIST driver mutation-negative (wild-type) gastrointestinal stromal tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('fusions', 'Var', (11, 18))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (109, 140))	('NTRK3', 'Gene', '4916', (5, 10))	('ETV6', 'Gene', '2120', (0, 4))	('KIT', 'Gene', '3815', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('stromal tumors', 'Disease', 'MESH:D036821', (126, 140))	('KIT', 'Gene', (41, 44))	('NTRK3', 'Gene', (5, 10))	('stromal tumors', 'Disease', (126, 140))	('ETV6', 'Gene', (0, 4))
159839	31528332	A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior.	('sarcoma', 'Disease', (42, 49))	('Sarcomas', 'Disease', (117, 125))	('CDKN2A', 'Gene', (67, 73))	('patients', 'Species', '9606', (50, 58))	('tumors', 'Disease', (161, 167))	('Sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('deletion', 'Var', (74, 82))	('Sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('CDKN2A', 'Gene', '1029', (67, 73))	('aggressive behavior', 'Phenotype', 'HP:0000718', (197, 216))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (30, 49))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('Sarcomas', 'Phenotype', 'HP:0100242', (117, 125))
159842	31528332	Genomic profiles of 7733 STS from the Foundation Medicine database were used to assess the frequency of CDKN2A alterations in histological subtypes of sarcoma.	('CDKN2A', 'Gene', '1029', (104, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('alterations', 'Var', (111, 122))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('CDKN2A', 'Gene', (104, 110))	('sarcoma', 'Disease', (151, 158))
159843	31528332	Compared to all other tumor types, sarcomas were found to carry the highest relative percentage of gene amplifications/deletions/fusions and the lowest average mutation count.	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('gene amplifications/deletions/fusions', 'Var', (99, 136))	('sarcomas', 'Disease', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))
159845	31528332	When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized STS, only CDKN2A alterations correlated significantly with prognosis, with a hazard ratio (HR) of 2.83 for overall survival (p = 0.017).	('CDKN2A', 'Gene', (124, 130))	('CDKN2A', 'Gene', '1029', (124, 130))	('alterations', 'Var', (131, 142))	('prognosis', 'MPA', (173, 182))	('correlated', 'Reg', (143, 153))
159847	31528332	Analysis of 7733 STS patients from Foundation One showed high prevalence of CDKN2A alterations in malignant peripheral nerve sheath tumors, myxofibrosarcomas, and undifferentiated pleomorphic sarcomas.	('malignant peripheral nerve sheath tumor', 'Disease', (98, 137))	('sheath tumors', 'Disease', (125, 138))	('patients', 'Species', '9606', (21, 29))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (98, 137))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (144, 156))	('sheath tumors', 'Disease', 'MESH:D010524', (125, 138))	('CDKN2A', 'Gene', '1029', (76, 82))	('alterations', 'Var', (83, 94))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('myxofibrosarcomas', 'Disease', (140, 157))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (98, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('myxofibrosarcomas', 'Disease', 'None', (140, 157))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (163, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('undifferentiated pleomorphic sarcomas', 'Disease', (163, 200))	('CDKN2A', 'Gene', (76, 82))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (98, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
159848	31528332	Our clinico-genomic profiling of STS shows that CDKN2A deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis.	('CDKN2A', 'Gene', '1029', (48, 54))	('prevalent', 'Reg', (77, 86))	('CDKN2A', 'Gene', (48, 54))	('deletion', 'Var', (55, 63))
159860	31528332	In addition, we explored the Foundation Medicine sequencing database to describe the landscape of CDKN2A alterations in STS.	('alterations', 'Var', (105, 116))	('CDKN2A', 'Gene', (98, 104))	('CDKN2A', 'Gene', '1029', (98, 104))
159877	31528332	When compared to other tumor types, the predominant genomic aberrations in soft tissue and bone sarcomas were DNA copy number and chromosomal translocations (Fig.	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('bone sarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('bone sarcomas', 'Disease', 'MESH:D001847', (91, 104))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('bone sarcomas', 'Disease', (91, 104))	('soft tissue', 'Disease', (75, 86))	('chromosomal translocations', 'Var', (130, 156))	('soft tissue and bone sarcomas', 'Phenotype', 'HP:0030448', (75, 104))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('bone sarcomas', 'Phenotype', 'HP:0002669', (91, 104))	('tumor', 'Disease', (23, 28))	('DNA copy number', 'Var', (110, 125))
159878	31528332	Based on the cohort of patients treated at Stanford Cancer Institute, sarcomas had the lowest average number of single nucleotide variants (SNVs), averaging 1.7 SNVs per tumor compared to 6.1 SNVs per tumor in melanoma, which had the highest mutation rate among the analyzed tumor types.	('tumor', 'Disease', (275, 280))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Disease', (170, 175))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('single nucleotide variants', 'Var', (112, 138))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))
159879	31528332	Conversely, sarcomas had relatively high percentage of copy number and fusion events, representing 57% of all gene alterations compared to 7% for renal neoplasms, which was the tumor type with the lowest frequency of copy number alterations.	('to 7', 'Species', '1214577', (136, 140))	('renal neoplasms', 'Phenotype', 'HP:0009726', (146, 161))	('renal neoplasms', 'Disease', 'MESH:D007680', (146, 161))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('neoplasms', 'Phenotype', 'HP:0002664', (152, 161))	('alterations', 'Var', (115, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('fusion', 'Var', (71, 77))	('copy number', 'Var', (55, 66))	('sarcomas', 'Disease', (12, 20))	('renal neoplasms', 'Disease', (146, 161))	('tumor', 'Disease', (177, 182))
159884	31528332	The majority of alterations in TP53, NF1, and ATRX were point mutations while the predominant alterations in CDKN2A and RB1 were copy number losses.	('ATRX', 'Gene', '546', (46, 50))	('RB1', 'Gene', '5925', (120, 123))	('TP53', 'Gene', '7157', (31, 35))	('alterations', 'Var', (16, 27))	('NF1', 'Gene', (37, 40))	('TP53', 'Gene', (31, 35))	('CDKN2A', 'Gene', (109, 115))	('NF1', 'Gene', '4763', (37, 40))	('copy number losses', 'Var', (129, 147))	('CDKN2A', 'Gene', '1029', (109, 115))	('ATRX', 'Gene', (46, 50))	('RB1', 'Gene', (120, 123))	('point mutations', 'Var', (56, 71))
159890	31528332	In a Cox proportional hazards model, adjusted for age, only CDKN2A alterations were associated with an effect on prognosis with a significantly worse overall survival (OS) (HR 2.83, mOS 3.3 vs. 7.7 years, p = 0.017, Fig.	('worse', 'NegReg', (144, 149))	('alterations', 'Var', (67, 78))	('CDKN2A', 'Gene', (60, 66))	('overall survival', 'MPA', (150, 166))	('OS', 'Chemical', '-', (183, 185))	('CDKN2A', 'Gene', '1029', (60, 66))	('OS', 'Chemical', '-', (168, 170))
159891	31528332	Twenty-two patients (23%) had CDKN2A alterations of which 18 (82%) were homozygous deletions, 3 (14%) were nonsense mutations, and 1 (5%) was a loss of function SNV.	('CDKN2A', 'Gene', (30, 36))	('deletions', 'Var', (83, 92))	('CDKN2A', 'Gene', '1029', (30, 36))	('alterations', 'Var', (37, 48))	('patients', 'Species', '9606', (11, 19))
159896	31528332	There was no difference in time to treatment failure (TTF) for first line chemotherapy, with a median time to progression of 3.9 vs. 5.2 months (p = 0.38) for CDKN2A altered vs. non-altered patients (Fig.	('patients', 'Species', '9606', (190, 198))	('CDKN2A', 'Gene', '1029', (159, 165))	('CDKN2A', 'Gene', (159, 165))	('altered', 'Var', (166, 173))
159897	31528332	These results suggest that suggests that there may be an inherently more aggressive biology in patients with alterations in the CDKN2A gene, with an earlier time to recurrence from initial surgery, but no substantial increase in resistance to chemotherapy once disease becomes metastatic.	('CDKN2A', 'Gene', '1029', (128, 134))	('patients', 'Species', '9606', (95, 103))	('more', 'PosReg', (68, 72))	('alterations', 'Var', (109, 120))	('aggressive biology', 'CPA', (73, 91))	('CDKN2A', 'Gene', (128, 134))
159901	31528332	There was only one patient who had a CDKN2A nonsense mutation and this patient also had concurrent CDKN2A copy number loss.	('patient', 'Species', '9606', (19, 26))	('CDKN2A', 'Gene', (37, 43))	('CDKN2A', 'Gene', (99, 105))	('CDKN2A', 'Gene', '1029', (37, 43))	('nonsense mutation', 'Var', (44, 61))	('CDKN2A', 'Gene', '1029', (99, 105))	('copy number loss', 'Var', (106, 122))	('patient', 'Species', '9606', (71, 78))
159903	31528332	In a multivariate Cox proportional hazards model adjusted for age, stage, and tumor size, CDKN2A alterations were significantly associated with a worse prognosis (HR 2.7, mOS 2.5 vs. 6.7 years, p = 0.002, Fig.	('CDKN2A', 'Gene', '1029', (90, 96))	('OS', 'Chemical', '-', (172, 174))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('alterations', 'Var', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('associated', 'Reg', (128, 138))	('tumor', 'Disease', (78, 83))	('CDKN2A', 'Gene', (90, 96))
159906	31528332	Exploratory analysis of CDKN2A-associated prognosis within each histology was performed, albeit at considerable loss of statistical power due to individually small sample size, and demonstrated pronounced survival differences in MFS, STLMS, UPS, and SS (Additional file 1: Figure S1).	('differences', 'Reg', (214, 225))	('SS', 'Phenotype', 'HP:0012570', (250, 252))	('LMS', 'Disease', (236, 239))	('CDKN2A', 'Gene', (24, 30))	('LMS', 'Phenotype', 'HP:0100243', (236, 239))	('LMS', 'Disease', 'MESH:C535903', (236, 239))	('CDKN2A', 'Gene', '1029', (24, 30))	('MFS', 'Var', (229, 232))
159909	31528332	We queried the Foundation Medicine database that has sequencing data on 7733 soft tissue sarcomas from numerous institutions for alterations in CDKN2A.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (77, 96))	('sarcomas', 'Disease', (89, 97))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (77, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('CDKN2A', 'Gene', (144, 150))	('alterations', 'Var', (129, 140))	('CDKN2A', 'Gene', '1029', (144, 150))	('soft tissue sarcoma', 'Disease', (77, 96))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (77, 97))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
159911	31528332	There is emerging data on germline CDKN2A mutations that predispose towards the development of sarcoma, however, we found that these cases were exceedingly rare (0.2%).	('CDKN2A', 'Gene', '1029', (35, 41))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('predispose', 'Reg', (57, 67))	('sarcoma', 'Disease', (95, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('CDKN2A', 'Gene', (35, 41))	('mutations', 'Var', (42, 51))
159915	31528332	In our single institution cohort, we show that CDKN2A deletions were the most prevalent DNA copy number aberrations in STS and these aberrations were associated with poor clinical outcome.	('deletions', 'Var', (54, 63))	('CDKN2A', 'Gene', (47, 53))	('CDKN2A', 'Gene', '1029', (47, 53))
159920	31528332	The DDLPS patients with poor clinical outcome were characterized by hypermethylation and certain chromosomal amplifications, while the LMS patients with adverse outcome were characterized by high expression levels of microRNA miR-181b-5p.	('expression levels', 'MPA', (196, 213))	('patients', 'Species', '9606', (139, 147))	('LPS', 'Disease', 'MESH:C536528', (6, 9))	('LMS', 'Disease', (135, 138))	('LMS', 'Phenotype', 'HP:0100243', (135, 138))	('LMS', 'Disease', 'MESH:C535903', (135, 138))	('patients', 'Species', '9606', (10, 18))	('hypermethylation', 'Var', (68, 84))	('microRNA miR-181b-5p', 'Var', (217, 237))	('LPS', 'Phenotype', 'HP:0012034', (6, 9))	('LPS', 'Disease', (6, 9))
159923	31528332	Other work has also found an association between CDKN2A deletion and poor prognosis in GIST.	('deletion', 'Var', (56, 64))	('CDKN2A', 'Gene', '1029', (49, 55))	('poor', 'Disease', (69, 73))	('GIST', 'Disease', (87, 91))	('CDKN2A', 'Gene', (49, 55))
159928	31528332	In our study, we found that loss of CDKN2A had a significant correlation with worse prognosis in localized STS at our institution and validated this in an independent cohort of patients from TCGA.	('loss', 'Var', (28, 32))	('CDKN2A', 'Gene', (36, 42))	('CDKN2A', 'Gene', '1029', (36, 42))	('patients', 'Species', '9606', (177, 185))	('localized STS', 'Disease', (97, 110))
159929	31528332	The histologic subtypes MPNST, MFS, and UPS had increased frequency of CDKN2A loss as compared to LMS and DDLPS.	('LPS', 'Phenotype', 'HP:0012034', (108, 111))	('LPS', 'Disease', (108, 111))	('LMS', 'Phenotype', 'HP:0100243', (98, 101))	('CDKN2A', 'Gene', (71, 77))	('CDKN2A', 'Gene', '1029', (71, 77))	('MPNST', 'Phenotype', 'HP:0100697', (24, 29))	('loss', 'NegReg', (78, 82))	('LPS', 'Disease', 'MESH:C536528', (108, 111))	('LMS', 'Disease', (98, 101))	('MPNST', 'Var', (24, 29))	('LMS', 'Disease', 'MESH:C535903', (98, 101))
159932	31528332	Detection of genomic aberrations in CDKN2A may also have therapeutic implications since a number of basket and umbrella clinical trials enroll patients with concordant loss of CDKN2A and amplifications of CDK4, CDK6, CCND1, CCND2 and/or CCND3.	('loss', 'NegReg', (168, 172))	('CDK6', 'Gene', '1021', (211, 215))	('CDKN2A', 'Gene', (36, 42))	('CCND1', 'Gene', '595', (217, 222))	('CDK4', 'Gene', '1019', (205, 209))	('CCND2', 'Gene', '894', (224, 229))	('CDKN2A', 'Gene', '1029', (36, 42))	('CCND3', 'Gene', (237, 242))	('patients', 'Species', '9606', (143, 151))	('CCND2', 'Gene', (224, 229))	('CCND3', 'Gene', '896', (237, 242))	('CDK6', 'Gene', (211, 215))	('CDKN2A', 'Gene', '1029', (176, 182))	('amplifications', 'Var', (187, 201))	('CDKN2A', 'Gene', (176, 182))	('CCND1', 'Gene', (217, 222))	('CDK4', 'Gene', (205, 209))
159933	31528332	We identified co-existing aberrations in these genes in a small subset (1.5%) of sarcoma patients analyzed in the TCGA study and Memorial Sloan Kettering genomic studies (summarized in Additional file 1: Tables S1, S2).	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('aberrations', 'Var', (26, 37))	('patients', 'Species', '9606', (89, 97))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
159942	31528332	We have recently shown the clinical utility of detection of SNVs, indels and copy number alterations in ctDNA of patients with LMS, and demonstrated that ctDNA analysis may capture the molecular intra-tumoral heterogeneity of LMS.	('LMS', 'Disease', 'MESH:C535903', (127, 130))	('LMS', 'Phenotype', 'HP:0100243', (226, 229))	('LMS', 'Disease', 'MESH:C535903', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('indels', 'Var', (66, 72))	('SNVs', 'Gene', (60, 64))	('LMS', 'Disease', (127, 130))	('copy number alterations', 'Var', (77, 100))	('LMS', 'Disease', (226, 229))	('LMS', 'Phenotype', 'HP:0100243', (127, 130))
159945	31528332	In summary, we demonstrate the association between genomic aberrations affecting the CDKN2A gene and worse prognosis in two independent data sets of STS.	('association', 'Interaction', (31, 42))	('genomic aberrations', 'Var', (51, 70))	('CDKN2A', 'Gene', (85, 91))	('CDKN2A', 'Gene', '1029', (85, 91))
159946	31528332	We also establish the frequency of CDKN2A alterations across histologies in a large STS genomic database, although limited by lack of central review of pathology.	('CDKN2A', 'Gene', '1029', (35, 41))	('CDKN2A', 'Gene', (35, 41))	('alterations', 'Var', (42, 53))
160006	30086293	In contrast, non-commercial insurance, greater comorbidity, treatment at a community cancer program, higher grade, more advanced size and larger tumor size were all associated with a lower likelihood of a minimally invasive procedure (P<0.05 for all).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('tumor', 'Disease', (145, 150))	('higher grade', 'Var', (101, 113))	('lower', 'NegReg', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
160123	27499897	However, as both tumours recurred, it suggests that intralesional excision is a significant risk factor for recurrence and highlights the need for detailed examination of the gross specimen by the pathologist.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('men', 'Species', '9606', (186, 189))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Disease', (17, 24))	('intralesional excision', 'Var', (52, 74))
160148	23922674	The hallmark of this disease is a EWS-WT1 translocation resulting from apposition of the Ewing's sarcoma (EWS) gene with the Wilms' tumor (WT1) gene.	('WT1', 'Gene', '7490', (38, 41))	('WT', 'Phenotype', 'HP:0002667', (38, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('EWS', 'Gene', (106, 109))	("Wilms' tumor", 'Disease', 'MESH:D009396', (125, 137))	("Wilms' tumor", 'Disease', (125, 137))	('EWS', 'Gene', (34, 37))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (89, 104))	('WT1', 'Gene', (139, 142))	('EWS-WT1', 'Gene', (34, 41))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (89, 104))	('EWS', 'Phenotype', 'HP:0012254', (34, 37))	('EWS', 'Phenotype', 'HP:0012254', (106, 109))	('WT1', 'Gene', '7490', (139, 142))	('WT', 'Phenotype', 'HP:0002667', (139, 141))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('EWS', 'Gene', '2130', (106, 109))	("Ewing's sarcoma", 'Disease', (89, 104))	('EWS', 'Gene', '2130', (34, 37))	('apposition', 'Var', (71, 81))	('EWS-WT1', 'Gene', '7490', (34, 41))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (125, 137))	('WT1', 'Gene', (38, 41))
160151	23922674	Morphoproteomics and immunohistochemical probes were applied to detect: p-mTOR (Ser2448); p-Akt (Ser473); p-ERK1/2 (Thr202/Tyr204); p-STAT3 (Tyr 705); and cell cycle-related analytes along with their negative controls.	('Ser2448', 'Var', (80, 87))	('Tyr', 'Chemical', 'MESH:D014443', (141, 144))	('Ser473', 'Var', (97, 103))	('Ser473', 'Chemical', '-', (97, 103))	('Ser2448', 'Chemical', '-', (80, 87))	('Tyr204', 'Chemical', '-', (123, 129))	('ERK1/2', 'Gene', (108, 114))	('Akt', 'Gene', '207', (92, 95))	('ERK1/2', 'Gene', '5595;5594', (108, 114))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('STAT3', 'Gene', '6774', (134, 139))	('Akt', 'Gene', (92, 95))	('Tyr', 'Chemical', 'MESH:D014443', (123, 126))	('p-ERK', 'Gene', '9451', (106, 111))	('STAT3', 'Gene', (134, 139))	('p-ERK', 'Gene', (106, 111))	('Thr202', 'Chemical', '-', (116, 122))
160156	23922674	There was constitutive activation of the Ras/Raf/ERK pathway p-ERK 1/2 (Thr202/Tyr204) expression in the Wilms tumor and metastatic Ewing's sarcoma, but not in the DSRCT.	('Raf', 'Gene', '22882', (45, 48))	('Wilms tumor', 'Disease', 'MESH:D009396', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (132, 147))	('Tyr204', 'Chemical', '-', (79, 85))	('ERK', 'Gene', '5594', (49, 52))	('Wilms tumor', 'Phenotype', 'HP:0002667', (105, 116))	("Ewing's sarcoma", 'Disease', (132, 147))	('ERK', 'Gene', '5594', (63, 66))	('ERK', 'Gene', (49, 52))	('Wilms tumor', 'Disease', (105, 116))	('p-ERK', 'Gene', '9451', (61, 66))	('expression', 'MPA', (87, 97))	('Raf', 'Gene', (45, 48))	('p-ERK', 'Gene', (61, 66))	('ERK 1/2', 'Gene', (63, 70))	('ERK', 'Gene', (63, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Thr202/Tyr204', 'Var', (72, 85))	('activation', 'PosReg', (23, 33))	('Thr202', 'Chemical', '-', (72, 78))	('ERK 1/2', 'Gene', '5595', (63, 70))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (132, 147))
160167	23922674	ES is caused by the translocation of the EWSR1 gene from chromosome 22 to chromosome 11 in most cases (EWSR1-FLI1) and chromosomes 21 and 7 in rare cases (EWSR1-ERG and EWSR1-ETV1).	('FLI1', 'Gene', (109, 113))	('EWSR1', 'Gene', '2130', (169, 174))	('translocation', 'Var', (20, 33))	('EWS', 'Phenotype', 'HP:0012254', (169, 172))	('EWSR1', 'Gene', (155, 160))	('EWSR1', 'Gene', '2130', (103, 108))	('EWSR1', 'Gene', '2130', (41, 46))	('EWS', 'Phenotype', 'HP:0012254', (41, 44))	('FLI1', 'Gene', '2313', (109, 113))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('ETV1', 'Gene', (175, 179))	('ERG', 'Gene', (161, 164))	('EWSR1', 'Gene', (169, 174))	('caused by', 'Reg', (6, 15))	('ERG', 'Gene', '2078', (161, 164))	('EWSR1', 'Gene', (41, 46))	('EWS', 'Phenotype', 'HP:0012254', (103, 106))	('EWSR1', 'Gene', (103, 108))	('ETV1', 'Gene', '2115', (175, 179))	('EWSR1', 'Gene', '2130', (155, 160))	('EWS', 'Phenotype', 'HP:0012254', (155, 158))
160168	23922674	Mutation of the WT1 gene on chromosome 11 is observed in 20% of WT cases.	('WT', 'Phenotype', 'HP:0002667', (16, 18))	('WT', 'Phenotype', 'HP:0002667', (64, 66))	('Mutation', 'Var', (0, 8))	('WT1', 'Gene', '7490', (16, 19))	('WT1', 'Gene', (16, 19))
160169	23922674	A CTNNB1 mutation is also seen in 14% of WT cases and the WT1 and CTNNB1 mutations are highly associated.	('CTNNB1', 'Gene', (2, 8))	('mutation', 'Var', (9, 17))	('CTNNB1', 'Gene', '1499', (66, 72))	('WT1', 'Gene', '7490', (58, 61))	('WT1', 'Gene', (58, 61))	('CTNNB1', 'Gene', '1499', (2, 8))	('CTNNB1', 'Gene', (66, 72))	('WT', 'Phenotype', 'HP:0002667', (41, 43))	('WT', 'Phenotype', 'HP:0002667', (58, 60))	('associated', 'Interaction', (94, 104))
160177	23922674	Morphoproteomics and immunohistochemical probes were used to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), p-STAT3 (Tyr 705), VEGF-A expression, cell cycle related analytes including Ki67, cyclin-D1 and Skp 2 along with negative and positive controls.	('Akt', 'Gene', '207', (88, 91))	('Ser473', 'Var', (93, 99))	('Tyr204', 'Chemical', '-', (119, 125))	('mTOR', 'Gene', '2475', (70, 74))	('VEGF-A', 'Gene', (147, 153))	('Ser473', 'Chemical', '-', (93, 99))	('cyclin-D1', 'Gene', '595', (210, 219))	('cyclin-D1', 'Gene', (210, 219))	('Skp 2', 'Gene', (224, 229))	('ERK1/2', 'Gene', (104, 110))	('ERK1/2', 'Gene', '5595;5594', (104, 110))	('Skp 2', 'Gene', '6502', (224, 229))	('p-ERK', 'Gene', '9451', (102, 107))	('Tyr', 'Chemical', 'MESH:D014443', (137, 140))	('p-ERK', 'Gene', (102, 107))	('VEGF-A', 'Gene', '7422', (147, 153))	('STAT3', 'Gene', (130, 135))	('Tyr', 'Chemical', 'MESH:D014443', (119, 122))	('Thr202', 'Chemical', '-', (112, 118))	('Ser2448', 'Chemical', '-', (76, 83))	('mTOR', 'Gene', (70, 74))	('STAT3', 'Gene', '6774', (130, 135))	('Akt', 'Gene', (88, 91))	('Ser2448', 'Var', (76, 83))
160205	23922674	There is minimal constitutive activation of the Ras/Raf kinase/ERK pathway as evidenced by the expression of phosphorylated (p-) extracellular signal-regulated kinase (ERK) 1/2 (Thr 202/Tyr204) with nuclear translocation in only a rare tumor cell.	('nuclear translocation', 'MPA', (199, 220))	('ERK', 'Gene', '5594', (63, 66))	('extracellular signal-regulated kinase (ERK) 1/2', 'Gene', '5595;5594', (129, 176))	('Raf', 'Gene', '22882', (52, 55))	('Thr', 'Chemical', 'MESH:D013912', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('Thr', 'Var', (178, 181))	('Tyr204', 'Chemical', '-', (186, 192))	('ERK', 'Gene', '5594', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('ERK', 'Gene', (168, 171))	('Raf', 'Gene', (52, 55))	('tumor', 'Disease', (236, 241))	('ERK', 'Gene', (63, 66))
160211	23922674	Notably, a minor but significant portion of the tumor nuclei express p-signal transducer and activator of the transcription (STAT) 3 (Tyr 705) in their nuclei in some regions (Figure 1).	('tumor', 'Disease', (48, 53))	('Tyr 705', 'Var', (134, 141))	('p-signal', 'MPA', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Tyr', 'Chemical', 'MESH:D014443', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
160235	23922674	Because mTORC2 phosphorylates S473 of AKT, an AKT inhibitor might be of benefit in the next line of treatment.	('AKT', 'Gene', (38, 41))	('AKT', 'Gene', '207', (46, 49))	('mTORC2', 'Gene', '74343', (8, 14))	('AKT', 'Gene', (46, 49))	('AKT', 'Gene', '207', (38, 41))	('S473', 'Var', (30, 34))	('mTORC2', 'Gene', (8, 14))
160237	23922674	Of interest morphoproteomic analysis of insulin-like growth factor(IGF) pathway reveals constitutive activation of IGF-1receptor as evidenced by the expression of phosphorylated (p)-IGF-1R (Tyr1165/1166) on the plasmalemmal aspect and in cytoplasmic compartments of the tumor cells in DSCRT (Patient#1) (Figure 3).	('activation', 'PosReg', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('IGF-1R', 'Gene', '3480', (182, 188))	('DSCRT', 'Disease', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('Tyr1165', 'Chemical', '-', (190, 197))	('IGF-1R', 'Gene', (182, 188))	('Tyr1165/1166', 'Var', (190, 202))	('Patient', 'Species', '9606', (292, 299))	('tumor', 'Disease', (270, 275))	('IGF-1receptor', 'Gene', (115, 128))
160239	23922674	In addition, the expression of both nuclear and cytoplastmic p-Akt (S473) also suggests mTORC2 pathway signaling.	('mTORC2', 'Gene', (88, 94))	('mTORC2', 'Gene', '74343', (88, 94))	('S473', 'Var', (68, 72))	('Akt', 'Gene', '207', (63, 66))	('Akt', 'Gene', (63, 66))
160268	27069481	The cytogenetically defined translocation t(X;18)(p11.2;q11.2) found in human synovial sarcoma results in the fusion of the SYT gene on chromosome 18 to SSX1, SSX2, or SSX4 on chromosome X at Xp11.2, leading to the formation of SYT-SSX fusion transcript.	('SYT-SSX fusion transcript', 'MPA', (228, 253))	('SYT', 'Gene', (124, 127))	('SSX2', 'Gene', (159, 163))	('SSX1', 'Gene', (153, 157))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (42, 62))	('human', 'Species', '9606', (72, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('SSX4', 'Gene', '6759', (168, 172))	('fusion', 'Var', (110, 116))	('SSX4', 'Gene', (168, 172))	('SSX1', 'Gene', '6756', (153, 157))	('SSX2', 'Gene', '6757', (159, 163))
160270	27069481	Also, SYT-SSX has been shown to affect polycomb-mediated gene repression and SWI/SNF chromatin remodeling as well as deregulating WNT-beta-catenin signaling in synovial sarcoma.	('synovial sarcoma', 'Disease', (160, 176))	('beta-catenin', 'Gene', '1499', (134, 146))	('deregulating', 'NegReg', (117, 129))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (160, 176))	('affect', 'Reg', (32, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('SWI/SNF', 'Gene', (77, 84))	('SYT-SSX', 'Var', (6, 13))	('beta-catenin', 'Gene', (134, 146))	('polycomb-mediated gene repression', 'Protein', (39, 72))
160290	27069481	Droplet digital PCR was carried out using the SS18-SSX1 + FAM (Hs 03024820_ft) and SS18-SSX2 + FAM (Hs03024398_ft) primers and the QX100 ddPCR system (Bio-Rad, Hercules, CA, USA) according to the manufacturer's protocol.	('Rad', 'Gene', (155, 158))	('Hs 03024820_ft', 'Var', (63, 77))	('Rad', 'Gene', '6236', (155, 158))	('Hs03024398_ft', 'Var', (100, 113))
160295	27069481	showed slightly higher sensitivity of ddPCR for the detection of the JAK2V617F mutation in Philadelphia-negative chronic myeloproliferative neoplasms compared to qPCR.	('higher', 'PosReg', (16, 22))	('sensitivity', 'MPA', (23, 34))	('myeloproliferative neoplasms', 'Disease', (121, 149))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (121, 149))	('neoplasms', 'Phenotype', 'HP:0002664', (140, 149))	('JAK2V617F', 'Var', (69, 78))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (121, 149))
160305	27069481	furthermore showed that tumor-derived microvesicles deliver genetic information and proteins to surrounding cells in the tumor periphery and induce proliferation of human glioma cells.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('proliferation', 'CPA', (148, 161))	('induce', 'PosReg', (141, 147))	('glioma', 'Disease', (171, 177))	('proteins', 'Protein', (84, 92))	('genetic information', 'Var', (60, 79))
160306	27069481	Thus, as tumor-specific mutant mRNA can be detected in serum microvesicles from glioblastoma patients, tumor-derived microvesicles may be a helpful tool in diagnosis as well as in therapeutic decisions for patients with malignant diseases.	('mutant', 'Var', (24, 30))	('mRNA', 'Protein', (31, 35))	('tumor-specific', 'Reg', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('malignant diseases', 'Disease', 'MESH:D009369', (220, 238))	('glioblastoma', 'Disease', (80, 92))	('malignant diseases', 'Disease', (220, 238))
160312	23590596	Apoptosis was determined by flow cytometric analysis of the propidium iodine stained nuclei of cells treated with PI3K inhibitor LY294002 in combination with either TNF-related apoptosis-inducing ligand (TRAIL) or doxorubicin.	('propidium iodine', 'Chemical', '-', (60, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (214, 225))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (165, 202))	('LY294002', 'Chemical', 'MESH:C085911', (129, 137))	('TRAIL', 'Gene', '8743', (204, 209))	('LY294002', 'Var', (129, 137))	('TNF-related apoptosis-inducing ligand', 'Gene', (165, 202))	('TRAIL', 'Gene', (204, 209))
160314	23590596	Targeting PI3K/Akt signaling by the inhibitor LY294002 (30 muM) significantly decreased the protein expression as well as DNA binding activity of HIF-1alpha and restored the apoptosis-inducing ability of cells in hypoxia Additionally, pretreatment with LY294002 sensitized A204 and A673 cells to TRAIL or doxorubicin induced apoptosis under hypoxia.	('restored', 'PosReg', (161, 169))	('protein expression', 'MPA', (92, 110))	('apoptosis-inducing ability', 'MPA', (174, 200))	('LY294002', 'Chemical', 'MESH:C085911', (253, 261))	('doxorubicin', 'Chemical', 'MESH:D004317', (305, 316))	('muM', 'Gene', '56925', (59, 62))	('hypoxia', 'Disease', 'MESH:D000860', (213, 220))	('TRAIL', 'Gene', '8743', (296, 301))	('hypoxia', 'Disease', 'MESH:D000860', (341, 348))	('TRAIL', 'Gene', (296, 301))	('LY294002', 'Var', (46, 54))	('hypoxia', 'Disease', (213, 220))	('muM', 'Gene', (59, 62))	('DNA binding activity', 'MPA', (122, 142))	('LY294002', 'Var', (253, 261))	('decreased', 'NegReg', (78, 87))	('hypoxia', 'Disease', (341, 348))	('LY294002', 'Chemical', 'MESH:C085911', (46, 54))
160324	23590596	Aberrant activation of PI3K/Akt plays important role in the resistance of tumor cells to anticancer therapy.	('resistance', 'CPA', (60, 70))	('activation', 'PosReg', (9, 19))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PI3K/Akt', 'Pathway', (23, 31))	('tumor', 'Disease', (74, 79))
160334	23590596	Next we used LY294002, the pharmacologic inhibitor of PI3K to interfere with phosphorylation of Akt, and here we show that upon treatment with LY294002 the level of p-Akt was decreased in a dose dependent manner in both A204 and A673 cells in normoxia (Figure 1A, B).	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('LY294002', 'Chemical', 'MESH:C085911', (143, 151))	('level', 'MPA', (156, 161))	('p-Akt', 'MPA', (165, 170))	('LY294002', 'Var', (143, 151))	('decreased', 'NegReg', (175, 184))
160335	23590596	To address whether PI3K/Akt signaling was sustained in hypoxia, phosphorylation of Akt was examined in the presence or absence of LY294002 in both normoxia and hypoxia.	('hypoxia', 'Disease', (160, 167))	('hypoxia', 'Disease', 'MESH:D000860', (160, 167))	('hypoxia', 'Disease', 'MESH:D000860', (55, 62))	('LY294002', 'Chemical', 'MESH:C085911', (130, 138))	('hypoxia', 'Disease', (55, 62))	('LY294002', 'Var', (130, 138))
160336	23590596	Accordingly, pretreatment of A204 and A673 cells by 30 muM LY294002 decreased phosphorylation of Akt in both conditions whereas protein levels of total Akt were not altered (Figure 1C, D).	('LY294002', 'Var', (59, 67))	('decreased', 'NegReg', (68, 77))	('phosphorylation', 'MPA', (78, 93))	('muM', 'Gene', '56925', (55, 58))	('Akt', 'Pathway', (97, 100))	('muM', 'Gene', (55, 58))	('LY294002', 'Chemical', 'MESH:C085911', (59, 67))
160337	23590596	As seen in Figure 1C and D, levels of p-Akt-Ser473 were similar in A204 and A673 cells either in normoxia or hypoxia and did not change by serum deprivation but suppressed by LY294002 addition.	('LY294002', 'Chemical', 'MESH:C085911', (175, 183))	('p-Akt-Ser473', 'Var', (38, 50))	('normoxia or hypoxia', 'Disease', (97, 116))	('Ser473', 'Chemical', '-', (44, 50))	('normoxia or hypoxia', 'Disease', 'MESH:D000860', (97, 116))
160338	23590596	Densitometry analysis also confirmed these data (Figure 1E and F) suggesting in A204 and A673 cells in normoxia p-Akt levels when normalized to Akt levels, is significantly decreased in the presence of LY294002 whether or not FCS is withdrawn.	('LY294002', 'Chemical', 'MESH:C085911', (202, 210))	('p-Akt levels', 'MPA', (112, 124))	('decreased', 'NegReg', (173, 182))	('LY294002', 'Var', (202, 210))
160341	23590596	Moreover, addition of LY294002 was able to suppress p-Akt levels significantly either in the presence or absence of FCS also in hypoxia in both cells.	('LY294002', 'Chemical', 'MESH:C085911', (22, 30))	('p-Akt levels', 'MPA', (52, 64))	('suppress', 'NegReg', (43, 51))	('hypoxia', 'Disease', 'MESH:D000860', (128, 135))	('LY294002', 'Var', (22, 30))	('hypoxia', 'Disease', (128, 135))
160342	23590596	Whereas pretreatment of A204 and A673 cells by 30 muM LY294002 did not alter the protein levels of total Akt.	('muM', 'Gene', '56925', (50, 53))	('LY294002', 'Chemical', 'MESH:C085911', (54, 62))	('muM', 'Gene', (50, 53))	('LY294002', 'Var', (54, 62))
160344	23590596	Thus, these data demonstrated that activation of PI3K/Akt signaling is constitutive in both cell lines in normoxia and hypoxia, as evidenced by high levels of phosphorylated p-Akt-Ser473, the downstream effector of PI3K (Figure 1C, D).	('hypoxia', 'Disease', 'MESH:D000860', (119, 126))	('p-Akt-Ser473', 'Var', (174, 186))	('hypoxia', 'Disease', (119, 126))	('PI3K/Akt signaling', 'Pathway', (49, 67))	('rat', 'Species', '10116', (24, 27))	('Ser473', 'Chemical', '-', (180, 186))
160345	23590596	In order to examine whether constitutive activation of PI3K/Akt signaling is involved in hypoxic induction of HIF-1alpha protein, either pretreated with 30 muM of LY294002, or left untreated (control) A204 and A673 cells were incubated under hypoxic conditions and subsequently subjected to Western blot analysis for stabilization of HIF-1alpha protein.	('hypoxic conditions', 'Disease', 'MESH:D009135', (242, 260))	('LY294002', 'Var', (163, 171))	('muM', 'Gene', '56925', (156, 159))	('muM', 'Gene', (156, 159))	('hypoxic conditions', 'Disease', (242, 260))	('LY294002', 'Chemical', 'MESH:C085911', (163, 171))
160347	23590596	Remarkably, pre-treatment with LY294002 decreased the expression of HIF-1alpha suggesting that induction of HIF-1alpha by hypoxia requires activation of PI3K pathway.	('expression', 'MPA', (54, 64))	('LY294002', 'Var', (31, 39))	('HIF-1alpha', 'Gene', (108, 118))	('hypoxia', 'Disease', (122, 129))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('PI3K pathway', 'Pathway', (153, 165))	('LY294002', 'Chemical', 'MESH:C085911', (31, 39))	('decreased', 'NegReg', (40, 49))	('HIF-1alpha', 'Gene', (68, 78))
160350	23590596	Pretreatment with LY294002 reduced hypoxia-induced DNA binding activity of HIF-1alpha in both cell lines, although this effect was more pronounced in A204 cells after 24 h compared to A673 cells.	('reduced', 'NegReg', (27, 34))	('LY294002', 'Var', (18, 26))	('HIF-1alpha', 'Protein', (75, 85))	('hypoxia', 'Disease', 'MESH:D000860', (35, 42))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))	('hypoxia', 'Disease', (35, 42))
160351	23590596	Next, we investigated whether or not decreased stabilization and DNA binding activity of HIF-1alpha by LY294002, can sensitize A204 and A673 cells to apoptosis under hypoxia.	('sensitize', 'Reg', (117, 126))	('apoptosis', 'CPA', (150, 159))	('stabilization', 'MPA', (47, 60))	('LY294002', 'Var', (103, 111))	('DNA', 'MPA', (65, 68))	('hypoxia', 'Disease', 'MESH:D000860', (166, 173))	('HIF-1alpha', 'Gene', (89, 99))	('LY294002', 'Chemical', 'MESH:C085911', (103, 111))	('hypoxia', 'Disease', (166, 173))
160352	23590596	In order to examine long lasting effects of LY294002, cells were cultured for up to 72 h under hypoxic conditions in the presence of 30 muM LY294002 and apoptosis was assessed every 24 hours.	('hypoxic conditions', 'Disease', (95, 113))	('LY294002', 'Var', (140, 148))	('LY294002', 'Chemical', 'MESH:C085911', (44, 52))	('hypoxic conditions', 'Disease', 'MESH:D009135', (95, 113))	('muM', 'Gene', (136, 139))	('LY294002', 'Chemical', 'MESH:C085911', (140, 148))	('muM', 'Gene', '56925', (136, 139))
160353	23590596	As seen in Figure 3A while hypoxia alone did not trigger apoptosis in both cell lines, pretreatment with LY294002 induced 15,5 (+-1,7)% and 16,0 (+-1,1)% apoptosis in A204 and A673 cells, respectively, in a time dependent manner (Figure 3A).	('LY294002', 'Chemical', 'MESH:C085911', (105, 113))	('apoptosis', 'CPA', (154, 163))	('LY294002', 'Var', (105, 113))	('hypoxia', 'Disease', (27, 34))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))
160354	23590596	These data suggest that decreased protein level and DNA binding activity of HIF-1alpha by LY294002 treatment restores apoptosis sensitivity in A204 RMS and A673 ES cells.	('decreased', 'NegReg', (24, 33))	('apoptosis sensitivity', 'CPA', (118, 139))	('restores', 'PosReg', (109, 117))	('HIF-1alpha', 'Gene', (76, 86))	('decreased protein level', 'Phenotype', 'HP:0003075', (24, 47))	('LY294002', 'Var', (90, 98))	('DNA', 'MPA', (52, 55))	('LY294002', 'Chemical', 'MESH:C085911', (90, 98))	('protein level', 'MPA', (34, 47))
160358	23590596	Therefore cells were pretreated with LY294002 and cultured for up to 72 h in the presence or absence of TRAIL in both normoxia and hypoxia.	('hypoxia', 'Disease', (131, 138))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('TRAIL', 'Gene', '8743', (104, 109))	('LY294002', 'Var', (37, 45))	('TRAIL', 'Gene', (104, 109))	('hypoxia', 'Disease', 'MESH:D000860', (131, 138))
160360	23590596	Interestingly, pretreatment with LY294002 significantly sensitized cells for TRAIL-induced apoptosis and rendered the protective effect of hypoxia (Figure 3A).	('hypoxia', 'Disease', 'MESH:D000860', (139, 146))	('TRAIL-', 'Gene', '8743', (77, 83))	('hypoxia', 'Disease', (139, 146))	('LY294002', 'Chemical', 'MESH:C085911', (33, 41))	('sensitized', 'Reg', (56, 66))	('TRAIL-', 'Gene', (77, 83))	('protective', 'MPA', (118, 128))	('rendered', 'PosReg', (105, 113))	('LY294002', 'Var', (33, 41))
160361	23590596	Next, the effect of HIF-1alpha inhibition by LY294002 treatment in combination with doxorubicin, typically triggering apoptosis via the mitochondrial pathway, was also tested.	('LY294002', 'Var', (45, 53))	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('triggering', 'Reg', (107, 117))	('LY294002', 'Chemical', 'MESH:C085911', (45, 53))	('mitochondrial pathway', 'Pathway', (136, 157))
160363	23590596	Pretreatment of cells with LY294002 greatly enhanced doxorubicin-induced apoptosis.	('doxorubicin', 'Chemical', 'MESH:D004317', (53, 64))	('enhanced', 'PosReg', (44, 52))	('LY294002', 'Chemical', 'MESH:C085911', (27, 35))	('doxorubicin-induced', 'MPA', (53, 72))	('LY294002', 'Var', (27, 35))
160364	23590596	When pretreated with LY294002 the rate of apoptosis was at least 20% higher in both A204 and A673 cells after 72 h exposure to hypoxia (Figure 3B).	('hypoxia', 'Disease', (127, 134))	('hypoxia', 'Disease', 'MESH:D000860', (127, 134))	('apoptosis', 'CPA', (42, 51))	('LY294002', 'Chemical', 'MESH:C085911', (21, 29))	('rat', 'Species', '10116', (34, 37))	('higher', 'PosReg', (69, 75))	('LY294002', 'Var', (21, 29))
160366	23590596	Apoptosis induced by combined treatments of LY294002 and TRAIL, or doxorubicin was significantly blocked in the presence of z-VAD-fmk under both normoxia and hypoxia in both cell lines in a time dependent manner (Figure 4A and B).	('z-VAD-fmk', 'Var', (124, 133))	('blocked', 'NegReg', (97, 104))	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('TRAIL', 'Gene', (57, 62))	('z-VAD-fmk', 'Chemical', 'MESH:C096713', (124, 133))	('LY294002', 'Chemical', 'MESH:C085911', (44, 52))	('hypoxia', 'Disease', (158, 165))	('hypoxia', 'Disease', 'MESH:D000860', (158, 165))	('LY294002', 'Var', (44, 52))	('TRAIL', 'Gene', '8743', (57, 62))	('Apoptosis', 'CPA', (0, 9))
160367	23590596	These results indicated that apoptosis induced by combined treatments with LY294002 and either TRAIL, or doxorubicin was mediated by caspases.	('apoptosis', 'CPA', (29, 38))	('caspases', 'Gene', (133, 141))	('doxorubicin', 'Chemical', 'MESH:D004317', (105, 116))	('TRAIL', 'Gene', (95, 100))	('caspases', 'Gene', '842', (133, 141))	('LY294002', 'Chemical', 'MESH:C085911', (75, 83))	('LY294002', 'Var', (75, 83))	('TRAIL', 'Gene', '8743', (95, 100))	('mediated', 'Reg', (121, 129))
160370	23590596	Here, it is presented for the first time that constitutively activated PI3K/Akt involved in hypoxic activation of HIF-1alpha and targeting PI3K/Akt via LY294002 prevented HIF-1alpha's stabilization and restored apoptosis sensitivity of RMS and ES cells under hypoxic conditions.	('apoptosis', 'MPA', (211, 220))	('restored', 'PosReg', (202, 210))	('activated', 'PosReg', (61, 70))	('PI3K/Akt', 'Enzyme', (71, 79))	('LY294002', 'Var', (152, 160))	('hypoxic conditions', 'Disease', (259, 277))	('hypoxic conditions', 'Disease', 'MESH:D009135', (259, 277))	('stabilization', 'MPA', (184, 197))	('LY294002', 'Chemical', 'MESH:C085911', (152, 160))
160373	23590596	Second, Akt phosphorylation was inhibited via PI3K inhibitor LY294002 that also decreased the protein expression and DNA binding activity of HIF-1alpha.	('inhibited', 'NegReg', (32, 41))	('Akt phosphorylation', 'CPA', (8, 27))	('LY294002', 'Chemical', 'MESH:C085911', (61, 69))	('decreased', 'NegReg', (80, 89))	('protein expression', 'MPA', (94, 112))	('DNA', 'MPA', (117, 120))	('LY294002', 'Var', (61, 69))
160374	23590596	More importantly inhibition of PI3K/Akt signaling or HIF-1alpha activity by LY294002 blocked protection against hypoxia-induced cell apoptosis.	('HIF-1alpha', 'Enzyme', (53, 63))	('hypoxia', 'Disease', (112, 119))	('hypoxia', 'Disease', 'MESH:D000860', (112, 119))	('blocked', 'NegReg', (85, 92))	('LY294002', 'Var', (76, 84))	('activity', 'MPA', (64, 72))	('PI3K/Akt signaling', 'Pathway', (31, 49))	('inhibition', 'NegReg', (17, 27))	('LY294002', 'Chemical', 'MESH:C085911', (76, 84))
160375	23590596	Third, inhibition of HIF-1alpha activation via LY294002 also sensitized RMS and ES cells for death receptor (TRAIL) - as well as drug (Doxorubicin) - induced apoptosis which could be blocked in the presence of z.VAD.	('VAD', 'Chemical', 'MESH:C041041', (212, 215))	('Doxorubicin', 'Chemical', 'MESH:D004317', (135, 146))	('TRAIL', 'Gene', (109, 114))	('activation', 'PosReg', (32, 42))	('LY294002', 'Chemical', 'MESH:C085911', (47, 55))	('sensitized', 'Reg', (61, 71))	('TRAIL', 'Gene', '8743', (109, 114))	('LY294002', 'Var', (47, 55))	('inhibition', 'NegReg', (7, 17))	('HIF-1alpha', 'Protein', (21, 31))
160383	23590596	Recent studies have shown that inhibition of PI3K/Akt might be a promising strategy to decrease the threshold for apoptosis induction via the death receptor triggering or cytotoxic drugs in neuroblastoma and glioblastoma.	('threshold for apoptosis induction', 'MPA', (100, 133))	('rat', 'Species', '10116', (77, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (208, 220))	('neuroblastoma', 'Phenotype', 'HP:0003006', (190, 203))	('neuroblastoma and glioblastoma', 'Disease', 'MESH:D005909', (190, 220))	('inhibition', 'Var', (31, 41))	('PI3K/Akt', 'Var', (45, 53))
160384	23590596	In line with that our data also provides evidence that PI3K/Akt inhibition cooperates with TRAIL or doxorubicin to trigger apoptosis under hypoxia in RMS or ES cells.	('hypoxia', 'Disease', 'MESH:D000860', (139, 146))	('hypoxia', 'Disease', (139, 146))	('PI3K/Akt inhibition', 'Var', (55, 74))	('rat', 'Species', '10116', (80, 83))	('inhibition', 'Var', (64, 74))	('apoptosis', 'CPA', (123, 132))	('doxorubicin', 'Chemical', 'MESH:D004317', (100, 111))	('TRAIL', 'Gene', '8743', (91, 96))	('TRAIL', 'Gene', (91, 96))
160387	23590596	Targeting PI3K/Akt via LY294002 prevented HIF-1alpha's stabilization and restored apoptosis sensitivity of RMS and ES cells under hypoxic conditions.	('HIF-1alpha', 'Gene', (42, 52))	('hypoxic conditions', 'Disease', 'MESH:D009135', (130, 148))	('prevented', 'NegReg', (32, 41))	('LY294002', 'Chemical', 'MESH:C085911', (23, 31))	('restored', 'PosReg', (73, 81))	('LY294002', 'Var', (23, 31))	('apoptosis sensitivity', 'MPA', (82, 103))	('stabilization', 'MPA', (55, 68))	('hypoxic conditions', 'Disease', (130, 148))
160432	21505457	In the current study, CHAID was used as a complementary method; this technique uses a systematic algorithm to detect the stronger association between potential PFs (named 'splitter') and the outcome variable (e.g., early death).	('CHAID', 'Disease', (22, 27))	('PFs', 'Var', (160, 163))	('death', 'Disease', 'MESH:D003643', (221, 226))	('CHAID', 'Disease', 'None', (22, 27))	('death', 'Disease', (221, 226))
160445	21505457	The following parameters were associated with the risk of early death in univariate analysis: age >=60 (OR=1.77, P=0.003), PS=1 (OR=3.04, P<0.0001), PS >=2 (OR=10.00, P<0.0001), time interval since the initial diagnosis of sarcoma >=540 days (OR=0.41, P<0.0001), presence of liver metastasis (OR=2.37, P=0.0041) and presence of other metastases (OR=2.00, P=0.0061; Table 2).	('metastases', 'Disease', (334, 344))	('sarcoma', 'Disease', (223, 230))	('PS >=2', 'Var', (149, 155))	('PS=1', 'Gene', (123, 127))	('liver metastasis', 'Disease', 'MESH:D009362', (275, 291))	('death', 'Disease', 'MESH:D003643', (64, 69))	('liver metastasis', 'Disease', (275, 291))	('PS', 'Chemical', 'MESH:D010758', (149, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('PS=1', 'Gene', '338399', (123, 127))	('metastases', 'Disease', 'MESH:D009362', (334, 344))	('death', 'Disease', (64, 69))	('PS', 'Chemical', 'MESH:D010758', (123, 125))	('sarcoma', 'Disease', 'MESH:D012509', (223, 230))
160446	21505457	The final logistic regression analysis retained the following PFs for early deaths: PS=1 (P<0.0001), PS >=2 (P<0.0001), presence of liver (P=0.0014) or other metastases (P=0.0055).	('PS=1', 'Gene', (84, 88))	('PS', 'Chemical', 'MESH:D010758', (101, 103))	('PS=1', 'Gene', '338399', (84, 88))	('PS', 'Chemical', 'MESH:D010758', (84, 86))	('PS >=2', 'Var', (101, 107))	('metastases', 'Disease', (158, 168))	('death', 'Disease', 'MESH:D003643', (76, 81))	('liver', 'Disease', (132, 137))	('death', 'Disease', (76, 81))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
160451	21505457	In the decision tree, the most powerful discriminator (splitter) was the PS; three subsets of patients were discriminated with increasing risk of early death: patients with PS=0 (early death rate: 3.3%), patients with PS=1 (early death rate: 9.4%) and patients with PS >=2 (early death rate: 25.5%).	('death', 'Disease', (280, 285))	('death', 'Disease', (230, 235))	('PS=1', 'Gene', '338399', (218, 222))	('PS', 'Chemical', 'MESH:D010758', (218, 220))	('PS', 'Chemical', 'MESH:D010758', (266, 268))	('patients', 'Species', '9606', (204, 212))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (252, 260))	('death', 'Disease', 'MESH:D003643', (185, 190))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', 'MESH:D003643', (280, 285))	('PS=1', 'Gene', (218, 222))	('PS', 'Chemical', 'MESH:D010758', (73, 75))	('death', 'Disease', 'MESH:D003643', (230, 235))	('patients', 'Species', '9606', (159, 167))	('death', 'Disease', (185, 190))	('PS', 'Chemical', 'MESH:D010758', (173, 175))	('PS=0', 'Var', (173, 177))	('death', 'Disease', (152, 157))
160492	21505457	The probability of early death for a patient with PS >=2 is ~11-24% compared with 0-3% for those with PS=0 (Figure 1).	('patient', 'Species', '9606', (37, 44))	('PS >=2', 'Var', (50, 56))	('PS', 'Chemical', 'MESH:D010758', (50, 52))	('death', 'Disease', 'MESH:D003643', (25, 30))	('death', 'Disease', (25, 30))	('PS', 'Chemical', 'MESH:D010758', (102, 104))	('early', 'Disease', (19, 24))
160581	32664595	In other malignancies, intra-tumoral PD-L1 positivity by immunohistochemical staining (IHC) has been shown to predict response rates with positive staining tumors having a doubled response rate compared to tumors showing no staining.	('malignancies', 'Disease', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Disease', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('positive', 'Var', (138, 146))	('tumors', 'Disease', (206, 212))	('intra-tumoral PD-L1', 'Disease', 'MESH:D010300', (23, 42))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('malignancies', 'Disease', 'MESH:D009369', (9, 21))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('positivity', 'Var', (43, 53))	('intra-tumoral PD-L1', 'Disease', (23, 42))
160632	30533200	Polymorphisms in KSHV-encoded microRNA sequences affect levels of mature viral microRNA in Kaposi Sarcoma lesions We previously reported Kaposi sarcoma-associated herpesvirus (KSHV) microRNA sequence variants in clinical samples correlated with increased risk of multicentric Castleman's disease (MCD).	('Kaposi Sarcoma lesions', 'Disease', 'MESH:D012514', (91, 113))	('MCD', 'Disease', 'MESH:D012514', (297, 300))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (137, 151))	('MCD', 'Disease', (297, 300))	('clinical samples', 'Species', '191496', (212, 228))	('KSHV', 'Gene', (176, 180))	('Kaposi Sarcoma', 'Phenotype', 'HP:0100726', (91, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('KS', 'Phenotype', 'HP:0100726', (176, 178))	('Polymorphisms', 'Var', (0, 13))	('Kaposi sarcoma', 'Disease', (137, 151))	('variants', 'Var', (200, 208))	('KS', 'Phenotype', 'HP:0100726', (17, 19))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (137, 151))	('Kaposi Sarcoma lesions', 'Disease', (91, 113))	("multicentric Castleman's disease", 'Disease', 'MESH:C537372', (263, 295))	('levels of mature viral microRNA', 'MPA', (56, 87))	('KSHV', 'Species', '37296', (17, 21))	('herpesvirus', 'Species', '39059', (163, 174))	('affect', 'Reg', (49, 55))	('KSHV', 'Species', '37296', (176, 180))	('correlated', 'Reg', (229, 239))	('KSHV-encoded', 'Gene', (17, 29))	("multicentric Castleman's disease", 'Disease', (263, 295))	('Sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
160637	30533200	Low levels of K12-9-5p were associated with single nucleotide polymorphisms (SNPs) in miR-K12-9-5p, 4-5p, 5-3p, 7-3p and pri-miR-K12-3.	('K12', 'Gene', (14, 17))	('K12', 'Gene', '3859', (14, 17))	('K12', 'Gene', (90, 93))	('K12', 'Gene', '3859', (90, 93))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('single nucleotide polymorphisms', 'Var', (44, 75))	('miR', 'Gene', (125, 128))	('miR', 'Gene', '220972', (125, 128))	('K12', 'Gene', (129, 132))	('K12', 'Gene', '3859', (129, 132))
160638	30533200	One SNP in pri-miR-K12-3 resulted in down regulation of miR-K12-6-3p, 8-3p, 10-3p, 12-5p and the upregulation of 5-5p, illustrating sequence variants outside pre-microRNAs were also associated with changes in mature microRNA levels.	('miR', 'Gene', (56, 59))	('changes', 'Reg', (198, 205))	('8-3p', 'MPA', (70, 74))	('5-5p', 'MPA', (113, 117))	('10-3p', 'MPA', (76, 81))	('upregulation', 'PosReg', (97, 109))	('miR', 'Gene', '220972', (15, 18))	('variants', 'Var', (141, 149))	('down regulation', 'NegReg', (37, 52))	('miR', 'Gene', '220972', (56, 59))	('K12', 'Gene', (60, 63))	('K12', 'Gene', '3859', (60, 63))	('K12', 'Gene', (19, 22))	('K12', 'Gene', '3859', (19, 22))	('mature microRNA levels', 'MPA', (209, 231))	('12-5p', 'MPA', (83, 88))	('miR', 'Gene', (15, 18))
160652	30533200	We have previously described sequence variation in the KSHV microRNA genes and shown how these can be functionally relevant.	('KSHV microRNA genes', 'Gene', (55, 74))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('sequence variation', 'Var', (29, 47))	('KSHV', 'Species', '37296', (55, 59))
160661	30533200	Previously reported KSHV microRNA polymorphisms were observed, particularly within samples from South African patients.	('KS', 'Phenotype', 'HP:0100726', (20, 22))	('KSHV', 'Species', '37296', (20, 24))	('polymorphisms', 'Var', (34, 47))	('KSHV', 'Gene', (20, 24))	('patients', 'Species', '9606', (110, 118))
160674	30533200	When we examined the global effects of sequence variation on mature microRNA levels, we observed that SNPs detected in pre-miR K12-9-5p, 4-5p, 5-3p, and 7-3p were all associated with downregulation of K12-9-5p, which was detected at lower levels in samples from UW patients compared to HAMB (Figure 5).	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('K12', 'Gene', (201, 204))	('K12', 'Gene', '3859', (201, 204))	('5-3p', 'Var', (143, 147))	('patients', 'Species', '9606', (265, 273))	('4-5p', 'Var', (137, 141))	('downregulation', 'NegReg', (183, 197))	('K12', 'Gene', (127, 130))	('K12', 'Gene', '3859', (127, 130))
160683	30533200	For example, in miR-K12-1, deletion of the C (nt 121685), involved in a G C base pair in BCBL-1, was compensated by formation of a G U wobble involving a previously unpaired U, thereby preserving the hairpin.	('K12', 'Gene', (20, 23))	('K12', 'Gene', '3859', (20, 23))	('hairpin', 'MPA', (200, 207))	('deletion', 'Var', (27, 35))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))
160691	30533200	In pre-miR-K12-9, a C A SNP was detected whereas in pre-miR-K12-6, we identified a G A SNP which modifies a G U base pair to A U base pair, preserving the secondary structure of the region.	('K12', 'Gene', (11, 14))	('K12', 'Gene', '3859', (11, 14))	('miR', 'Gene', (56, 59))	('secondary structure', 'MPA', (155, 174))	('miR', 'Gene', '220972', (7, 10))	('miR', 'Gene', (7, 10))	('G U base pair', 'MPA', (108, 121))	('miR', 'Gene', '220972', (56, 59))	('K12', 'Gene', (60, 63))	('K12', 'Gene', '3859', (60, 63))	('modifies', 'Var', (97, 105))
160692	30533200	We previously described KSHV microRNA sequence heterogeneity in PEL cell lines and clinical samples, and showed that certain SNPs in KSHV microRNAs were associated with MCD risk.	('clinical samples', 'Species', '191496', (83, 99))	('KSHV', 'Species', '37296', (24, 28))	('KSHV', 'Gene', (133, 137))	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('MCD', 'Disease', 'MESH:D012514', (169, 172))	('PEL', 'Phenotype', 'HP:0030069', (64, 67))	('associated with', 'Reg', (153, 168))	('MCD', 'Disease', (169, 172))	('KSHV', 'Species', '37296', (133, 137))	('SNPs', 'Var', (125, 129))	('KS', 'Phenotype', 'HP:0100726', (133, 135))
160705	30533200	It is unlikely that single polymorphisms are entirely responsible for RNA structure changes affecting the processing of adjacent microRNAs; instead, they may be associated with patterns of sequence variations, common to viral strains, that result in the changes observed as previously reported and shown in Supplementary Figures 1 and 2.	('changes', 'MPA', (254, 261))	('variations', 'Var', (198, 208))	('men', 'Species', '9606', (313, 316))
160707	30533200	We have previously observed linked SNPs that statistically significantly increased the probability of developing MCD.	('increased', 'PosReg', (73, 82))	('SNPs', 'Var', (35, 39))	('MCD', 'Disease', (113, 116))	('MCD', 'Disease', 'MESH:D012514', (113, 116))
160708	30533200	Of note, all the sequence variations reported in Table 2 down-regulate the expression of mir-K12-9-5p.	('mir', 'Gene', '220972', (89, 92))	('expression', 'MPA', (75, 85))	('K12', 'Gene', (93, 96))	('mir', 'Gene', (89, 92))	('K12', 'Gene', '3859', (93, 96))	('down-regulate', 'NegReg', (57, 70))	('variations', 'Var', (26, 36))
160711	30533200	We now observe sequence variations in miR-K12-3, 5, and 7 that also appear to specifically target miR-K12-9-5p.	('variations', 'Var', (24, 34))	('K12', 'Gene', (42, 45))	('K12', 'Gene', '3859', (42, 45))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('target', 'Reg', (91, 97))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('K12', 'Gene', (102, 105))	('K12', 'Gene', '3859', (102, 105))
160712	30533200	In this study, we report that the specific localization of SNPs within KSHV pri-microRNA cluster has a significant effect on levels of KSHV mature microRNAs.	('effect', 'Reg', (115, 121))	('KS', 'Phenotype', 'HP:0100726', (135, 137))	('SNPs', 'Var', (59, 63))	('KSHV', 'Species', '37296', (135, 139))	('levels of', 'MPA', (125, 134))	('KS', 'Phenotype', 'HP:0100726', (71, 73))	('KSHV', 'Species', '37296', (71, 75))
160716	30533200	The importance of sequences flanking the pre-microRNA in mature biogenesis has also been reported in both human and viral miRNA; SNPs located within pre-microRNAs have also been shown to affect the Drosha/DGCR8 processing step.	('Drosha', 'Gene', (198, 204))	('human', 'Species', '9606', (106, 111))	('DGCR8', 'Gene', (205, 210))	('affect', 'Reg', (187, 193))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (122, 125))	('DGCR8', 'Gene', '54487', (205, 210))	('SNPs located', 'Var', (129, 141))	('Drosha', 'Gene', '29102', (198, 204))
160717	30533200	In particular, this was demonstrated to occur with SNPs in KSHV miR-K12-5.	('KSHV', 'Species', '37296', (59, 63))	('KS', 'Phenotype', 'HP:0100726', (59, 61))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('SNPs', 'Var', (51, 55))	('K12', 'Gene', (68, 71))	('K12', 'Gene', '3859', (68, 71))
160718	30533200	In our data, the effect of sequence variations was mostly noted in the pri-microRNA regions of K12-5, -8, and -9, resulting in significantly different levels of mature microRNA.	('levels', 'MPA', (151, 157))	('different', 'Reg', (141, 150))	('K12', 'Gene', (95, 98))	('K12', 'Gene', '3859', (95, 98))	('variations', 'Var', (36, 46))	('mature microRNA', 'MPA', (161, 176))
160722	30533200	The specific action of the newly identified variations in this study on mature microRNA processing, whether the binding of Drosha or Dicer is directly affected, was not determined and requires further elucidation.	('variations', 'Var', (44, 54))	('Dicer', 'Gene', '23405', (133, 138))	('Dicer', 'Gene', (133, 138))	('Drosha', 'Gene', (123, 129))	('Drosha', 'Gene', '29102', (123, 129))
160723	30533200	However, we previously demonstrated changes in Drosha/DGCR8 and or Dicer processing associated with KSHV strain specific variations within pre-microRNA sequences miR-K2, 5, 6, 7, 9, and 10.	('changes', 'Reg', (36, 43))	('Drosha', 'Gene', (47, 53))	('KSHV', 'Species', '37296', (100, 104))	('DGCR8', 'Gene', (54, 59))	('variations', 'Var', (121, 131))	('KS', 'Phenotype', 'HP:0100726', (100, 102))	('Dicer', 'Gene', '23405', (67, 72))	('Dicer', 'Gene', (67, 72))	('DGCR8', 'Gene', '54487', (54, 59))	('Drosha', 'Gene', '29102', (47, 53))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
160724	30533200	In conclusion, although the structural characteristics and sequence elements required for microRNA processing are incompletely defined, our data, in the context of the current literature, suggest that microRNA processing can be profoundly altered by SNPs in the pri-, pre-, and mature microRNA sequences.	('SNPs', 'Var', (250, 254))	('altered', 'Reg', (239, 246))	('microRNA processing', 'MPA', (201, 220))	('men', 'Species', '9606', (71, 74))
160726	30533200	While further studies are needed, our results suggest that KSHV sequence variation that occurs within African A5/B/F subtypes influence the expression levels of mature microRNAs, potentially changing the specificity for mRNA targets, which can lead to altered regulation of viral gene products and key cellular pathways, modifying KS pathogenesis.	('KSHV', 'Species', '37296', (59, 63))	('viral gene products', 'Pathway', (274, 293))	('changing', 'Reg', (191, 199))	('KS', 'Phenotype', 'HP:0100726', (59, 61))	('variation', 'Var', (73, 82))	('regulation', 'MPA', (260, 270))	('KSHV', 'Gene', (59, 63))	('influence', 'Reg', (126, 135))	('KS', 'Phenotype', 'HP:0100726', (331, 333))	('modifying', 'Reg', (321, 330))	('specificity', 'MPA', (204, 215))	('altered', 'Reg', (252, 259))	('key cellular pathways', 'Pathway', (298, 319))	('expression levels', 'MPA', (140, 157))
160734	30533200	HAMB and UW patients were enrolled in one or more clinical studies evaluating KSHV associated diseases (NCT01495598; NCT00006518 and M090515 respectively).	('KS', 'Phenotype', 'HP:0100726', (78, 80))	('patients', 'Species', '9606', (12, 20))	('NCT00006518', 'Var', (117, 128))	('clinical', 'Species', '191496', (50, 58))	('M090515', 'Var', (133, 140))	('KSHV', 'Species', '37296', (78, 82))	('NCT01495598; NCT00006518', 'Var', (104, 128))
160748	30533200	KSHV Kaposi's sarcoma-associated herpesvirus MCD multicentric Castleman's disease KS Kaposi's sarcoma SNP single nucleotide polymorphism PEL primary effusion lymphoma KICS KSHV inflammatory cytokine syndrome wt wild type HAMB HIV and AIDS Malignancy Branch UW University of Witwatersrand nt nucleotide	('KSHV', 'Species', '37296', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (172, 174))	('MCD', 'Disease', 'MESH:D012514', (45, 48))	('AIDS Malignancy Branch', 'Disease', 'MESH:D000163', (234, 256))	('MCD', 'Disease', (45, 48))	('PEL', 'Phenotype', 'HP:0030069', (137, 140))	("Kaposi's sarcoma-associated herpesvirus", 'Species', '37296', (5, 44))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (5, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('cytokine syndrome', 'Phenotype', 'HP:0031407', (190, 207))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (85, 101))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (141, 166))	('KS', 'Phenotype', 'HP:0100726', (82, 84))	("multicentric Castleman's disease", 'Disease', 'MESH:C537372', (49, 81))	('KSHV', 'Species', '37296', (172, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (5, 21))	('PEL', 'Var', (137, 140))	("Kaposi's sarcoma", 'Disease', (5, 21))	('primary effusion lymphoma', 'Disease', (141, 166))	('AIDS Malignancy Branch', 'Disease', (234, 256))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (141, 166))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (85, 101))	('lymphoma', 'Phenotype', 'HP:0002665', (158, 166))	("Kaposi's sarcoma", 'Disease', (85, 101))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	("multicentric Castleman's disease", 'Disease', (49, 81))	('single nucleotide', 'Var', (106, 123))
160800	28717396	Microscopically residual tumours did better with IORT, gross residual disease however did not.	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('IORT', 'Var', (49, 53))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('tumours', 'Disease', (25, 32))
160814	28717396	To summarise the trials of single-dose IORT, both ELIOT trial (IOERT) and TARGIT trial (kV-IORT) demonstrated a higher recurrence rate compared to WBI, although within the equivalence margin.	('recurrence', 'MPA', (119, 129))	('WBI', 'Chemical', '-', (147, 150))	('single-dose', 'Var', (27, 38))
160832	28717396	There is increasing evidence (Table 3) to suggest that inclusion of IORT in the multi-modal treatment of locally advanced rectal cancer can lead to improved local control and survival especially in the setting of R+ resection.	('inclusion', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('rectal cancer', 'Disease', (122, 135))	('survival', 'CPA', (175, 183))	('rectal cancer', 'Phenotype', 'HP:0100743', (122, 135))	('improved', 'PosReg', (148, 156))	('local control', 'CPA', (157, 170))	('rectal cancer', 'Disease', 'MESH:D012004', (122, 135))
160863	28717396	A randomised trial at the NCI, at a median follow-up of 8 years, showed a significantly better local control with IOERT and low-dose post-operative EBRT compared to high-dose post-operative EBRT alone (60% vs. 20%, p < 0.05).	('low-dose', 'Var', (124, 132))	('local control', 'CPA', (95, 108))	('EBRT', 'Chemical', '-', (148, 152))	('better', 'PosReg', (88, 94))	('EBRT', 'Chemical', '-', (190, 194))
160952	27509178	The demonstration of specific genes mutations, fusion transcripts and chromosomal translocations has been of pivotal importance in the diagnosis of numerous cancers particularly sarcomas, some other solid tumors, lymphomas and leukemias.	('fusion transcripts', 'Var', (47, 65))	('lymphomas', 'Phenotype', 'HP:0002665', (213, 222))	('numerous cancers particularly sarcomas', 'Disease', 'MESH:D009369', (148, 186))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('leukemias', 'Disease', 'MESH:D007938', (227, 236))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))	('leukemias', 'Phenotype', 'HP:0001909', (227, 236))	('sarcomas', 'Phenotype', 'HP:0100242', (178, 186))	('lymphomas', 'Disease', (213, 222))	('leukemia', 'Phenotype', 'HP:0001909', (227, 235))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('lymphoma', 'Phenotype', 'HP:0002665', (213, 221))	('leukemias', 'Disease', (227, 236))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('numerous cancers particularly sarcomas', 'Disease', (148, 186))	('mutations', 'Var', (36, 45))	('lymphomas', 'Disease', 'MESH:D008223', (213, 222))
160954	27509178	The link between genetic aberrancies and activation of signaling pathways and the mapping of different growth factors and their receptors have been elucidated in many tumors.	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('genetic aberrancies', 'Var', (17, 36))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
160956	27509178	This tyrosine-inhibitory compound has been successful in targeting KIT mutations and related genetic aberrations in gastrointestinal stromal tumor (GIST), chronic myeloid leukemia and other c-kit expressing tumors.	('KIT', 'Gene', (67, 70))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('gastrointestinal stromal tumor', 'Disease', (116, 146))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('c-kit', 'Gene', '3815', (190, 195))	('GIST', 'Phenotype', 'HP:0100723', (148, 152))	('tumors', 'Disease', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tyrosine', 'Chemical', 'MESH:D014443', (5, 13))	('mutations', 'Var', (71, 80))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (155, 179))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (155, 179))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (163, 179))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('genetic aberrations', 'Disease', (93, 112))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('genetic aberrations', 'Disease', 'MESH:D030342', (93, 112))	('c-kit', 'Gene', (190, 195))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (116, 146))	('chronic myeloid leukemia', 'Disease', (155, 179))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (116, 146))
160957	27509178	In many instances, the presence of KIT mutations in a tumor is equivalent to responsiveness to imatinib mesylate.	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (95, 112))	('responsiveness to imatinib mesylate', 'MPA', (77, 112))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('KIT', 'Gene', (35, 38))
160986	27509178	The identification of EWS/FLI1 chromosomal translocation and KIT/PDGFR mutations are indispensable in confirming the diagnosis of Ewing's sarcoma and GIST respectively.	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('EWS', 'Gene', '2130', (22, 25))	('EWS', 'Gene', (22, 25))	('GIST', 'Phenotype', 'HP:0100723', (150, 154))	('mutations', 'Var', (71, 80))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (130, 145))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (130, 145))	('PDGFR', 'Gene', (65, 70))	('FLI1', 'Gene', '2313', (26, 30))	("Ewing's sarcoma", 'Disease', (130, 145))	('FLI1', 'Gene', (26, 30))	('PDGFR', 'Gene', '5159', (65, 70))
160989	27509178	The identification of FLT3 mutations in acute myeloid leukemia, exon 11 mutations in GIST tumors and alpha thalassemia x-linked protein (ATRX) and isocitrate dehydrogenase expression in brain gliomas is clinically useful to identify aggressive cancers of different prognosis and help guide appropriate chemotherapy.	('mutations', 'Var', (27, 36))	('brain gliomas', 'Disease', (186, 199))	('FLT3', 'Gene', (22, 26))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('myeloid leukemia', 'Disease', 'MESH:D007951', (46, 62))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (46, 62))	('brain gliomas', 'Disease', 'MESH:C564230', (186, 199))	('aggressive cancers', 'Disease', (233, 251))	('mutations', 'Var', (72, 81))	('FLT3', 'Gene', '2322', (22, 26))	('GIST', 'Phenotype', 'HP:0100723', (85, 89))	('GIST tumors', 'Disease', (85, 96))	('thalassemia', 'Disease', (107, 118))	('aggressive cancers', 'Disease', 'MESH:D009369', (233, 251))	('ATRX', 'Gene', (137, 141))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (40, 62))	('GIST tumors', 'Disease', 'MESH:D046152', (85, 96))	('ATRX', 'Gene', '546', (137, 141))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('thalassemia', 'Disease', 'MESH:D013789', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('myeloid leukemia', 'Disease', (46, 62))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))
160993	27509178	A good example is the identification of EWS gene rearrangements in Ewing's sarcoma, desmoplastic round cell sarcoma, extraskeletal myxoid chrondrosarcoma, myxoid liposarcoma, clear cell sarcoma and several other cancers Similarly, KIT mutations and KIT protein expression has been identified in numerous tumors including GIST and other tumors unrelated to GIST.	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('tumors', 'Disease', (304, 310))	('myxoid liposarcoma', 'Disease', (155, 173))	('rearrangements', 'Var', (49, 63))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (67, 82))	('sarcoma', 'Disease', (166, 173))	('tumors', 'Disease', (336, 342))	('GIST', 'Phenotype', 'HP:0100723', (356, 360))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (155, 173))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('sarcoma', 'Disease', (108, 115))	('numerous tumors', 'Disease', (295, 310))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('sarcoma', 'Disease', (75, 82))	('EWS', 'Gene', (40, 43))	('numerous tumors', 'Disease', 'MESH:D009369', (295, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	("Ewing's sarcoma", 'Disease', (67, 82))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))	('GIST', 'Disease', (321, 325))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('GIST', 'Phenotype', 'HP:0100723', (321, 325))	('clear', 'Disease', (175, 180))	('sarcoma', 'Disease', (146, 153))	('liposarcoma', 'Phenotype', 'HP:0012034', (162, 173))	('sarcoma', 'Disease', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('cancers', 'Disease', (212, 219))	('desmoplastic round cell sarcoma', 'Disease', (84, 115))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('myxoid chrondrosarcoma', 'Disease', 'MESH:D045888', (131, 153))	('desmoplastic round cell sarcoma', 'Disease', 'MESH:D058405', (84, 115))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('EWS', 'Gene', '2130', (40, 43))	('myxoid chrondrosarcoma', 'Disease', (131, 153))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (155, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (67, 82))
160995	27509178	SMAR CB1 (INI-1) deletions are increasingly being identified in multiple tumors.	('INI-1', 'Gene', '6598', (10, 15))	('INI-1', 'Gene', (10, 15))	('multiple tumors', 'Disease', 'MESH:D009369', (64, 79))	('deletions', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('CB1', 'Gene', '1268', (5, 8))	('CB1', 'Gene', (5, 8))	('multiple tumors', 'Disease', (64, 79))
160997	27509178	ALK-rearranged, KIT-mutated, EWS-rearranged, and INI-1 deleted.	('KIT-mutated', 'Var', (16, 27))	('INI-1', 'Gene', '6598', (49, 54))	('EWS', 'Gene', (29, 32))	('INI-1', 'Gene', (49, 54))	('ALK', 'Gene', (0, 3))	('EWS', 'Gene', '2130', (29, 32))	('ALK', 'Gene', '238', (0, 3))
161000	27509178	An interesting observation is that some genetic mutations are identified among tumors of various biologic behaviors including benign tumors, low grade and high grade malignancies.	('benign tumors', 'Disease', (126, 139))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('low grade', 'Disease', (141, 150))	('tumors', 'Disease', (133, 139))	('identified', 'Reg', (62, 72))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('malignancies', 'Disease', (166, 178))	('benign tumors', 'Disease', 'MESH:D009369', (126, 139))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('malignancies', 'Disease', 'MESH:D009369', (166, 178))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
161001	27509178	KIT mutations occur in benign entities such as mastocytosis as well as malignant tumors such as GIST.	('malignant tumors', 'Disease', (71, 87))	('GIST', 'Disease', (96, 100))	('occur', 'Reg', (14, 19))	('mastocytosis', 'Disease', 'MESH:D008415', (47, 59))	('malignant tumors', 'Disease', 'MESH:D018198', (71, 87))	('mastocytosis', 'Disease', (47, 59))	('GIST', 'Phenotype', 'HP:0100723', (96, 100))	('mastocytosis', 'Phenotype', 'HP:0100495', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
161006	27509178	Preclinical and clinical studies have focused on targeting these mutated genes, growth factor receptors and intracellular signal transduction pathways over-expressed by the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('over-expressed', 'PosReg', (151, 165))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('mutated', 'Var', (65, 72))
161007	27509178	Good examples include the use of mTor inhibitors in renal cell carcinomas, epidermal growth factor receptor (EGFR) and PDL1 inhibitors in non-small cell lung carcinoma and the experimental use of insulin growth factor-1 receptor (IGF1R) inhibitors in sarcomas.	('mTor', 'Gene', '2475', (33, 37))	('insulin growth factor-1 receptor', 'Gene', '3480', (196, 228))	('EGFR', 'Gene', '1956', (109, 113))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (52, 73))	('IGF1R', 'Gene', '3480', (230, 235))	('sarcomas', 'Disease', 'MESH:D012509', (251, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (251, 259))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (52, 72))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (138, 167))	('sarcomas', 'Disease', (251, 259))	('non-small cell lung carcinoma', 'Disease', (138, 167))	('renal cell carcinomas', 'Disease', (52, 73))	('IGF1R', 'Gene', (230, 235))	('mTor', 'Gene', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (142, 167))	('epidermal growth factor receptor', 'Gene', (75, 107))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (52, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('epidermal growth factor receptor', 'Gene', '1956', (75, 107))	('EGFR', 'Gene', (109, 113))	('inhibitors', 'Var', (124, 134))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (138, 167))	('PDL1', 'Gene', (119, 123))	('insulin growth factor-1 receptor', 'Gene', (196, 228))	('PDL1', 'Gene', '29126', (119, 123))
161016	27509178	Few notable successes in this field include the identification of trastuzumab-responsive breast cancers by testing for Her2-neu, BCR/ABl translocation in chronic myeloid leukemia, and KIT mutations in imatinib-responsive GIST.	('chronic myeloid leukemia', 'Disease', (154, 178))	('BCR/ABl', 'Gene', '25;613', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Her2-neu', 'Gene', '2064', (119, 127))	('translocation', 'Var', (137, 150))	('trastuzumab-responsive breast cancers', 'Disease', (66, 103))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (154, 178))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (154, 178))	('testing', 'Reg', (107, 114))	('imatinib', 'Chemical', 'MESH:D000068877', (201, 209))	('leukemia', 'Phenotype', 'HP:0001909', (170, 178))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (162, 178))	('KIT mutations', 'Var', (184, 197))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('Her2-neu', 'Gene', (119, 127))	('trastuzumab-responsive breast cancers', 'Disease', 'MESH:D001943', (66, 103))	('BCR/ABl', 'Gene', (129, 136))	('GIST', 'Phenotype', 'HP:0100723', (221, 225))
161017	27509178	Additional molecularly targetable biomarker discoveries include BRAF mutation testing for variable tumors like melanoma and craniopharyngioma and anaplastic lymphoma kinase (ALK) inhibitors and epidermal growth factor receptors in various subtypes of lung cancer.	('BRAF', 'Gene', '673', (64, 68))	('anaplastic lymphoma kinase', 'Gene', '238', (146, 172))	('BRAF', 'Gene', (64, 68))	('anaplastic lymphoma kinase', 'Gene', (146, 172))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (146, 165))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('craniopharyngioma', 'Disease', (124, 141))	('melanoma', 'Disease', (111, 119))	('lung cancer', 'Disease', (251, 262))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('craniopharyngioma', 'Phenotype', 'HP:0030062', (124, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (157, 165))	('lung cancer', 'Disease', 'MESH:D008175', (251, 262))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ALK', 'Gene', '238', (174, 177))	('epidermal growth factor receptor', 'Gene', (194, 226))	('tumors', 'Disease', (99, 105))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('epidermal growth factor receptor', 'Gene', '1956', (194, 226))	('ALK', 'Gene', (174, 177))	('mutation', 'Var', (69, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (251, 262))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
161029	27509178	The power of next-generation DNA sequencing methods in identifying targetable gene mutations has recently been appreciated in several studies that attempted to identify all the actionable mutations in well known cancers.	('mutations', 'Var', (83, 92))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
161065	27509178	Such genetic variation across individual tumors, intratumoralheterogeneity, has important implication for cancer progression and has been detected at the level of circulating tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumors', 'Disease', (41, 47))	('genetic variation', 'Var', (5, 22))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Disease', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
161076	27509178	This approach can also help in further classification of certain malignancies as recently highlighted in the new World Health Organization classification of hematopoietic malignancies which has categorized new entities with integrated nomenclature such as "myeloid neoplasm with PDGFRB rearrangement", B-cell lymphoma with IRF4 rearrangement and high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement.	('BCL6', 'Gene', (398, 402))	('B-cell lymphoma', 'Disease', (302, 317))	('MYC', 'Gene', (378, 381))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('"myeloid neoplasm', 'Disease', (256, 273))	('IRF4', 'Gene', (323, 327))	('malignancies', 'Disease', (65, 77))	('BCL2', 'Gene', (386, 390))	('"myeloid neoplasm', 'Disease', 'MESH:D007951', (256, 273))	('B-cell lymphoma', 'Disease', (357, 372))	('neoplasm', 'Phenotype', 'HP:0002664', (265, 273))	('BCL6', 'Gene', '604', (398, 402))	('MYC', 'Gene', '4609', (378, 381))	('hematopoietic malignancies', 'Disease', (157, 183))	('myeloid neoplasm', 'Phenotype', 'HP:0012324', (257, 273))	('lymphoma', 'Phenotype', 'HP:0002665', (309, 317))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (302, 317))	('rearrangement', 'Var', (286, 299))	('lymphoma', 'Phenotype', 'HP:0002665', (364, 372))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (357, 372))	('malignancies', 'Disease', 'MESH:D009369', (171, 183))	('PDGFRB', 'Gene', '5159', (279, 285))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (157, 183))	('IRF4', 'Gene', '3662', (323, 327))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (302, 317))	('BCL2', 'Gene', '596', (386, 390))	('PDGFRB', 'Gene', (279, 285))	('malignancies', 'Disease', (171, 183))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (357, 372))
161078	27509178	Comprehensive molecular profiling based on next generation sequencing methods is currently routinely not practical but may be helpful in certain clinical situations: To detect targetable mutations in otherwise difficult to treat, chemoresistant or metastatic tumors.	('metastatic', 'CPA', (248, 258))	('chemoresistant', 'Disease', (230, 244))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('mutations', 'Var', (187, 196))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('tumors', 'Disease', (259, 265))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))
161080	27509178	The practical use of mTOR inhibitors has been discussed in several clinical studies of metastatic renal cell carcinoma and ependymoma expressing the mutated gene or abnormal protein.	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (87, 118))	('abnormal', 'Var', (165, 173))	('metastatic renal cell carcinoma', 'Disease', (87, 118))	('ependymoma', 'Phenotype', 'HP:0002888', (123, 133))	('mutated gene', 'Var', (149, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('ependymoma', 'Disease', 'MESH:D004806', (123, 133))	('ependymoma', 'Disease', (123, 133))	('mTOR', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (21, 25))	('protein', 'Protein', (174, 181))
161087	27509178	In a recent transcriptome analysis of 19 undifferentiated sarcoma of the thorax, identifying SMARCA4 mutations has placed these tumors along with malignant rhabdoid tumors rather than lung carcinomas.	('malignant rhabdoid tumors', 'Disease', (146, 171))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('SMARCA4', 'Gene', '6597', (93, 100))	('tumors', 'Disease', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('lung carcinomas', 'Disease', 'MESH:D008175', (184, 199))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('lung carcinomas', 'Disease', (184, 199))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('sarcoma', 'Disease', (58, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('mutations', 'Var', (101, 110))	('tumors', 'Disease', (165, 171))	('SMARCA4', 'Gene', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (146, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
161140	27517001	The seroprevalence of HHV-8 is very variable and there is an association between HHV-8 antibodies and the incidence of KS.	('HHV-8', 'Gene', (81, 86))	('HHV-8', 'Species', '37296', (22, 27))	('HHV-8', 'Species', '37296', (81, 86))	('antibodies', 'Var', (87, 97))	('KS', 'Phenotype', 'HP:0100726', (119, 121))	('association', 'Interaction', (61, 72))
161192	26834480	In contrast to other DNA-damaging agents such as cisplatin, nucleotide excisional repair-deficient cells are two to ten times less sensitive to trabectedin.	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('less', 'NegReg', (126, 130))	('nucleotide', 'Var', (60, 70))	('trabectedin', 'Chemical', 'MESH:D000077606', (144, 155))	('sensitive', 'MPA', (131, 140))
161204	26834480	Recently, results from randomized, multicenter, prospective dose-selection Phase IIb trials to evaluate whether trabectedin as first-line chemotherapy for advanced/metastatic STS prolongs the PFS, compared to doxorubicin, were published.	('trabectedin', 'Var', (112, 123))	('PFS', 'MPA', (192, 195))	('doxorubicin', 'Chemical', 'MESH:D004317', (209, 220))	('prolongs', 'PosReg', (179, 187))	('trabectedin', 'Chemical', 'MESH:D000077606', (112, 123))
161207	26834480	No significant improvement in the PFS was observed in the trabectedin arms as compared to the doxorubicin arm (T24h vs doxorubicin: hazard ratio [HR] 1.13; 95% confidence interval [CI] 0.67-1.90, P=0.675; T3h vs doxorubicin: HR 1.50, 95% CI 0.91-2.48, P=0.944).	('T3h', 'Chemical', '-', (205, 208))	('PFS', 'MPA', (34, 37))	('doxorubicin', 'Chemical', 'MESH:D004317', (119, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (212, 223))	('doxorubicin', 'Chemical', 'MESH:D004317', (94, 105))	('T24h', 'Chemical', '-', (111, 115))	('T24h', 'Var', (111, 115))	('trabectedin', 'Chemical', 'MESH:D000077606', (58, 69))
161210	26834480	A weekly trabectedin schedule (0.58 mg/m2 3-hour IV infusion for 3 consecutive weeks in a 4-week cycle) was demonstrated to have substantial anticancer activity in pretreated ovarian cancer.	('cancer', 'Disease', (145, 151))	('0.58 mg/m2', 'Var', (31, 41))	('cancer', 'Disease', (183, 189))	('ovarian cancer', 'Phenotype', 'HP:0100615', (175, 189))	('ovarian cancer', 'Disease', 'MESH:D010051', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('trabectedin', 'Chemical', 'MESH:D000077606', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('ovarian cancer', 'Disease', (175, 189))	('pretreated ovarian cancer', 'Phenotype', 'HP:0008209', (164, 189))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
161236	26834480	This study was a randomized, Phase III study of first-line trabectedin vs doxorubicin-based chemotherapy in patients with translocation-related sarcoma subtypes.	('trabectedin', 'Chemical', 'MESH:D000077606', (59, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('translocation-related', 'Var', (122, 143))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (144, 160))	('patients', 'Species', '9606', (108, 116))	('sarcoma subtypes', 'Disease', (144, 160))
161293	23761810	Immunohistochemical analysis revealed positivity for cytokeratin (CK), EMA, vimentin and CD34, but was negative for S100, desmin, smooth muscle actin (SMA), melanin, CD68 and HMB45.	('EMA', 'Gene', '4582', (71, 74))	('vimentin', 'Gene', '7431', (76, 84))	('desmin', 'Gene', '1674', (122, 128))	('S100', 'Gene', (116, 120))	('CD68', 'Gene', (166, 170))	('positivity', 'Var', (38, 48))	('CD68', 'Gene', '968', (166, 170))	('vimentin', 'Gene', (76, 84))	('S100', 'Gene', '6271', (116, 120))	('EMA', 'Gene', (71, 74))	('CD34', 'Gene', (89, 93))	('CD34', 'Gene', '947', (89, 93))	('desmin', 'Gene', (122, 128))
161423	22893503	On the other hand, in screening experiments contractors have checked that enlarging the "window" in the egg shell increases the mortality of chick embryos, probably due to the higher water permeability making chick embryos dry out.	('water', 'Chemical', 'MESH:D014867', (183, 188))	('chick', 'Species', '9031', (141, 146))	('mortality', 'CPA', (128, 137))	('higher', 'PosReg', (176, 182))	('enlarging', 'Var', (74, 83))	('water permeability', 'MPA', (183, 201))	('chick', 'Species', '9031', (209, 214))
161481	32963243	From genetic point of view, sarcomas have been traditionally classified into two broad categories, those with near-diploid karyotypes and simple genetic alterations, including translocations or specific activating mutations, and those with a complex and unbalanced karyotype.	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('activating', 'PosReg', (203, 213))	('sarcomas', 'Disease', (28, 36))	('translocations', 'Var', (176, 190))
161487	32963243	Defects in cell cycle checkpoints and/or DNA repair genes, especially mutations or aberrant gene downregulation, are associated with a wide spectrum of human tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('mutations', 'Var', (70, 79))	('Defects', 'NegReg', (0, 7))	('associated', 'Reg', (117, 127))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('DNA repair genes', 'Gene', (41, 57))	('cell cycle checkpoints', 'Gene', (11, 33))	('human', 'Species', '9606', (152, 157))	('aberrant gene', 'Var', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('downregulation', 'NegReg', (97, 111))
161489	32963243	Generally, high DNA damage levels correlates with a higher grade and worse patient outcomes.	('patient', 'Species', '9606', (75, 82))	('DNA damage levels', 'MPA', (16, 33))	('high', 'Var', (11, 15))
161499	32963243	With low levels of DNA damage, PARP1 promotes cell survival by repairing single strand breaks (SSBs) of DNA and preventing its progression to toxic double strand breaks (DSBs).	('DSBs', 'Chemical', '-', (170, 174))	('PARP1', 'Gene', '142', (31, 36))	('SSBs', 'Chemical', '-', (95, 99))	('PARP1', 'Gene', (31, 36))	('progression', 'MPA', (127, 138))	('preventing', 'NegReg', (112, 122))	('DNA', 'Gene', (104, 107))	('cell survival', 'CPA', (46, 59))	('toxic double strand breaks', 'MPA', (142, 168))	('repairing', 'Var', (63, 72))	('single strand breaks', 'MPA', (73, 93))	('promotes', 'PosReg', (37, 45))
161505	32963243	Therefore, an increment in MAP17 levels can lead to increased DNA damage that can be detected using specific biomarkers, such as pH2AX.	('DNA damage', 'MPA', (62, 72))	('increased', 'PosReg', (52, 61))	('H2AX', 'Gene', '3014', (130, 134))	('men', 'Species', '9606', (19, 22))	('increment', 'Var', (14, 23))	('H2AX', 'Gene', (130, 134))	('MAP17', 'Gene', (27, 32))
161522	32963243	Furthermore, we measured the expression level of these genes in two sarcoma cell lines with modified MAP17 expression, previously described in our laboratory.	('MAP17', 'Gene', (101, 106))	('modified', 'Var', (92, 100))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('sarcoma', 'Disease', (68, 75))	('expression', 'MPA', (29, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
161537	32963243	Univariate Cox analysis showed that high pH2AX levels were associated with overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) (Table 1).	('H2AX', 'Gene', '3014', (42, 46))	('H2AX', 'Gene', (42, 46))	('associated', 'Reg', (59, 69))	('progression-free survival', 'CPA', (131, 156))	('overall survival', 'CPA', (75, 91))	('high', 'Var', (36, 40))	('disease-free survival', 'CPA', (98, 119))
161538	32963243	Thereby, high pH2AX levels were predictive of worse PFS (p = 0.001), DFS (p = 0.001), and OS (p = 0.01) (Fig.	('H2AX', 'Gene', '3014', (15, 19))	('DFS', 'MPA', (69, 72))	('H2AX', 'Gene', (15, 19))	('PFS', 'MPA', (52, 55))	('high', 'Var', (9, 13))
161539	32963243	Therefore, our data suggest that high levels of phosphorylated H2AX might be an independent marker of poorer prognosis in sarcoma patients.	('H2AX', 'Gene', (63, 67))	('phosphorylated', 'Var', (48, 62))	('patients', 'Species', '9606', (130, 138))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('high levels', 'Var', (33, 44))	('sarcoma', 'Disease', (122, 129))	('H2AX', 'Gene', '3014', (63, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
161544	32963243	High pH2AX levels were significantly associated with worse DFS (p = 0.002), PFS (p = 0.006), and OS (p = 0.019).	('High', 'Var', (0, 4))	('PFS', 'Disease', (76, 79))	('DFS', 'Disease', (59, 62))	('H2AX', 'Gene', '3014', (6, 10))	('H2AX', 'Gene', (6, 10))
161550	32963243	Relative pH2AX levels allowed us to separate cells into a group with high levels (CE, Saos-2, CP0024, HT-1080, SW872, A673, SK-UT-1, BG) and other with low levels (AA, BC, 93T449, AW, AX, BD) (Fig.	('AX', 'Chemical', 'MESH:D000658', (12, 14))	('H2AX', 'Gene', (10, 14))	('HT-1080', 'CellLine', 'CVCL:0317', (102, 109))	('A673', 'Var', (118, 122))	('CP0024', 'Var', (94, 100))	('SK-UT-1', 'CellLine', 'CVCL:0533', (124, 131))	('SW872', 'CellLine', 'CVCL:1730', (111, 116))	('AX', 'Chemical', 'MESH:D000658', (184, 186))	('93T449', 'CellLine', 'CVCL:M807', (172, 178))	('H2AX', 'Gene', '3014', (10, 14))
161586	32963243	However, CP0024 and Saos-2, with higher pH2AX levels, showed lower active caspase-3 and cleaved PARP levels.	('lower', 'NegReg', (61, 66))	('PARP', 'Gene', (96, 100))	('CP0024', 'Var', (9, 15))	('caspase-3', 'Gene', (74, 83))	('H2AX', 'Gene', '3014', (41, 45))	('caspase-3', 'Gene', '836', (74, 83))	('H2AX', 'Gene', (41, 45))	('PARP', 'Gene', '142', (96, 100))
161590	32963243	In the AA sarcoma cell line, we increased its expression by ectopic expression of MAP17 cDNA.	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('MAP17', 'Gene', (82, 87))	('AA sarcoma', 'Disease', (7, 17))	('ectopic expression', 'Var', (60, 78))	('increased', 'PosReg', (32, 41))	('expression', 'MPA', (46, 56))	('AA sarcoma', 'Disease', 'MESH:C566236', (7, 17))
161601	32963243	However, patients with low levels of both pH2AX and MAP17 showed a better prognosis, while high levels of only one of the biomarkers showed an intermediate prognosis.	('patients', 'Species', '9606', (9, 17))	('MAP17', 'Gene', (52, 57))	('low levels', 'Var', (23, 33))	('H2AX', 'Gene', '3014', (43, 47))	('H2AX', 'Gene', (43, 47))
161626	32963243	Furthermore, MAP17 ectopic expression induces increased sensitivity to the treatment with certain ROS-inducing drugs.	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('ectopic expression', 'Var', (19, 37))	('increased', 'PosReg', (46, 55))	('men', 'Species', '9606', (80, 83))	('MAP17', 'Gene', (13, 18))	('sensitivity to the treatment', 'MPA', (56, 84))
161629	32963243	Thereby, in colorectal cancer, patients with high levels of both MAP17 and pH2AX showed better OS and DFS after radiotherapy and olaparib treatment, suggesting that both biomarkers should be analyzed together for the design of a personalized treatment.	('colorectal cancer', 'Disease', (12, 29))	('H2AX', 'Gene', '3014', (76, 80))	('high levels', 'Var', (45, 56))	('men', 'Species', '9606', (247, 250))	('DFS', 'MPA', (102, 105))	('H2AX', 'Gene', (76, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('patients', 'Species', '9606', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('men', 'Species', '9606', (143, 146))	('better', 'PosReg', (88, 94))	('MAP17', 'Gene', (65, 70))	('olaparib', 'Chemical', 'MESH:C531550', (129, 137))
161630	32963243	Likewise, the data extracted from our cohort showed that sarcomas with high pH2AX levels have a poor prognosis, regardless of the tumor origin.	('high', 'Var', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('H2AX', 'Gene', '3014', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('H2AX', 'Gene', (77, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('tumor', 'Disease', (130, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcomas', 'Disease', (57, 65))
161671	32963243	The expression of MAP17 (Hs00906696_m1), CCNB1 (Hs01030099_m1), RAD51 (Hs00947967_m1), BTG2 (Hs00198887_m1), and CDKN1A (Hs00355782_m1) was determined using an ABI 7900HT PCR system (Applied Biosystems).	('RAD51', 'Gene', '5888', (64, 69))	('CCNB1', 'Gene', '891', (41, 46))	('Hs00906696_m1', 'Var', (25, 38))	('Hs00947967_m1', 'Var', (71, 84))	('MAP17', 'Gene', (18, 23))	('CDKN1A', 'Gene', (113, 119))	('Hs01030099_m1', 'Var', (48, 61))	('CDKN1A', 'Gene', '1026', (113, 119))	('BTG2', 'Gene', '7832', (87, 91))	('Hs00198887_m1', 'Var', (93, 106))	('BTG2', 'Gene', (87, 91))	('Hs00355782_m1', 'Var', (121, 134))	('RAD51', 'Gene', (64, 69))	('CCNB1', 'Gene', (41, 46))
161800	28616389	NF1 derives from an autosomal dominant event and increases the risk of developing malignant peripheral nerve sheath tumor (Evans et al., 2012); LFS results from germline mutations in the tumor suppressor gene TP53 and it is strongly related to the early development of a wide variety of tumors (eg., breast cancer, soft tissue sarcoma, brain tumor, adrenocortical carcinoma) (Gonzalez et al., 2009); Rb leads to a greater risk of developing secondary tumors, particularly osteosarcoma (Wong et al., 1997).	('tumor', 'Phenotype', 'HP:0002664', (451, 456))	('sarcoma', 'Phenotype', 'HP:0100242', (477, 484))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (327, 334))	('tumor', 'Disease', (187, 192))	('osteosarcoma', 'Disease', (472, 484))	('brain tumor', 'Phenotype', 'HP:0030692', (336, 347))	('NF1', 'Gene', (0, 3))	('osteosarcoma', 'Disease', 'MESH:D012516', (472, 484))	('breast cancer', 'Phenotype', 'HP:0003002', (300, 313))	('NF1', 'Gene', '480618', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('tumors', 'Phenotype', 'HP:0002664', (451, 457))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('brain tumor', 'Disease', (336, 347))	('malignant peripheral nerve sheath tumor', 'Disease', (82, 121))	('LFS', 'Disease', (144, 147))	('brain tumor', 'Disease', 'MESH:D001932', (336, 347))	('related', 'Reg', (233, 240))	('breast cancer', 'Disease', 'MESH:D001943', (300, 313))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('breast cancer', 'Disease', (300, 313))	('tumor', 'Disease', (287, 292))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (349, 373))	('tumors', 'Disease', (451, 457))	('tumor', 'Disease', (342, 347))	('LFS', 'Disease', 'MESH:D016864', (144, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (364, 373))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (82, 121))	('Rb', 'Phenotype', 'HP:0009919', (400, 402))	('TP53', 'Gene', (209, 213))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (315, 334))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (451, 456))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (315, 334))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('osteosarcoma', 'Phenotype', 'HP:0002669', (472, 484))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (349, 373))	('soft tissue sarcoma', 'Disease', (315, 334))	('results from', 'Reg', (148, 160))	('tumors', 'Disease', 'MESH:D009369', (451, 457))	('TP53', 'Gene', '403869', (209, 213))	('tumor', 'Disease', 'MESH:D009369', (451, 456))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (82, 121))	('mutations', 'Var', (170, 179))	('adrenocortical carcinoma', 'Disease', (349, 373))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (116, 121))	('tumors', 'Disease', (287, 293))
161988	20436945	However, in subsequent studies, mutagenesis of these residues in vIL-6 did not abolish gp80-independent signaling by vIL-6, nor did their introduction into hIL-6 confer gp80 independence.	('hIL-6', 'Gene', (156, 161))	('gp80', 'Gene', (87, 91))	('hIL-6', 'Gene', '3569', (156, 161))	('abolish', 'NegReg', (79, 86))	('vIL-6', 'Gene', (65, 70))	('vIL-6', 'Gene', (117, 122))	('gp80', 'Gene', (169, 173))	('vIL-6', 'Gene', '4961449', (65, 70))	('mutagenesis', 'Var', (32, 43))	('vIL-6', 'Gene', '4961449', (117, 122))	('gp80', 'Gene', '3570', (87, 91))	('gp80', 'Gene', '3570', (169, 173))
161989	20436945	Moreover, domain (e.g., helix B) and amino acid substitutions involving residues unconnected with the direct interaction with g130 rendered vIL-6 gp80 dependent, implicating the importance of overall cytokine conformation for vIL-6-induced tetrameric signaling.	('gp80', 'Gene', (146, 150))	('vIL-6', 'Gene', '4961449', (140, 145))	('vIL-6', 'Gene', '4961449', (226, 231))	('amino acid substitutions', 'Var', (37, 61))	('gp80', 'Gene', '3570', (146, 150))	('vIL-6', 'Gene', (226, 231))	('vIL-6', 'Gene', (140, 145))
161990	20436945	Recently published work has provided further support for this conclusion and determined that substitution of site III interface residues/regions of hIL-6 with those of vIL-6 can confer gp80-independence to the human cytokine.	('vIL-6', 'Gene', (168, 173))	('vIL-6', 'Gene', '4961449', (168, 173))	('hIL-6', 'Gene', (148, 153))	('gp80', 'Gene', '3570', (185, 189))	('human', 'Species', '9606', (210, 215))	('hIL-6', 'Gene', '3569', (148, 153))	('substitution', 'Var', (93, 105))	('gp80', 'Gene', (185, 189))
161994	20436945	Residues N78 and N89 are glycosylated and while glycosylation is not necessary for the association of vIL-6 with gp130 (glycosidase treatment of the secreted protein does not abrogate ligand-receptor association), N89 glycosylation is required for structural maturation of the protein in order to achieve native conformation.	('gp130', 'Gene', '3572', (113, 118))	('vIL-6', 'Gene', '4961449', (102, 107))	('N89', 'Var', (214, 217))	('association', 'Interaction', (200, 211))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('gp130', 'Gene', (113, 118))	('vIL-6', 'Gene', (102, 107))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('N', 'Chemical', 'MESH:D009584', (214, 215))
162054	20436945	CCR8 or vCCL-1/-2 depletion was found to lead to reduced viral titers in endothelial cell-based reactivation experiments.	('reduced', 'NegReg', (49, 56))	('CCR8', 'Gene', '1237', (0, 4))	('depletion', 'Var', (18, 27))	('viral titers', 'MPA', (57, 69))	('CCR8', 'Gene', (0, 4))
162069	20436945	The likely importance of cell-surface autocrine and paracrine signaling by the viral cytokines in promotion of lytic replication suggests that the development of strategies that extracellularly target and inactivate the viral cytokines may be particularly effective in blocking virus production and, thereby, inhibiting likely contributions of lytic replication to HHV-8-associated disease, in particular KS.	('virus production', 'MPA', (278, 294))	('KS', 'Phenotype', 'HP:0100726', (405, 407))	('lytic replication', 'MPA', (344, 361))	('inhibiting', 'NegReg', (309, 319))	('HHV-8', 'Species', '37296', (365, 370))	('blocking', 'NegReg', (269, 277))	('inactivate', 'Var', (205, 215))	('HHV-8-associated disease', 'Disease', (365, 389))
162096	33614360	BRAF p.V600E alteration and additional mutations of the RAS/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathways have been detected with variable frequency in recent years.	('phosphatidylinositol 3-kinase', 'Gene', (104, 133))	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('protein kinase B', 'Gene', (141, 157))	('AKT', 'Gene', (159, 162))	('p.V600E', 'Var', (5, 12))	('protein kinase B', 'Gene', '2185', (141, 157))	('BRAF', 'Gene', '673', (0, 4))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (104, 133))	('BRAF', 'Gene', (0, 4))	('RAS/mitogen-activated', 'Pathway', (56, 77))	('AKT', 'Gene', '207', (159, 162))
162111	33614360	The tumor cells expressed the following antigens: CD163, CD68/KP1, CD4, and focally CD31, MPO, and CD68R/PGM1 (Figure 2).	('tumor', 'Disease', (4, 9))	('CD68/KP1', 'Gene', (57, 65))	('CD163', 'Gene', (50, 55))	('MPO', 'Gene', (90, 93))	('CD4', 'Gene', (67, 70))	('PGM1', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CD4', 'Gene', '920', (67, 70))	('MPO', 'Gene', '4353', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CD163', 'Gene', '9332', (50, 55))	('PGM1', 'Gene', '5236', (105, 109))	('CD31', 'Var', (84, 88))
162114	33614360	Moreover, we tested histological material for BRAF (exon 15), NRAS (exons 2, 3, 4), and KRAS (exons 2, 3, 4) mutations by molecular biology, and no genetic alterations were detected.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('NRAS', 'Gene', '4893', (62, 66))	('tested', 'Reg', (13, 19))	('KRAS', 'Gene', (88, 92))	('mutations', 'Var', (109, 118))	('KRAS', 'Gene', '3845', (88, 92))	('NRAS', 'Gene', (62, 66))
162145	31719099	Penetrance estimates over time to first and second primary cancer diagnosis in families with Li-Fraumeni syndrome: a single institution perspective Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC).	('cancers', 'Phenotype', 'HP:0002664', (304, 311))	('cancer', 'Disease', (304, 310))	('cancers', 'Disease', (304, 311))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('associated', 'Reg', (213, 223))	('Li-Fraumeni syndrome', 'Disease', (93, 113))	('TP53', 'Gene', '7157', (229, 233))	('Li-Fraumeni syndrome', 'Disease', (148, 168))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (185, 212))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (148, 168))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (93, 113))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancers', 'Disease', 'MESH:D009369', (304, 311))	('MPC', 'Chemical', '-', (313, 316))	('autosomal dominant disorder', 'Disease', (185, 212))	('germline', 'Var', (234, 242))	('TP53', 'Gene', (229, 233))	('cancer', 'Disease', (59, 65))
162149	31719099	Additionally, TP53 mutation carriers had a hazard ratio of 1.65 (95%CI: 1.1, 2.5) for developing a second PC versus SPC.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('PC versus SPC', 'Disease', (106, 119))	('PC versus SPC', 'Disease', 'MESH:D015324', (106, 119))
162151	31719099	In summary, we provide the first set of penetrance estimates for SPC and MPC for TP53 germline mutation carriers, and demonstrate its accuracy for cancer risk assessment.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MPC', 'Chemical', '-', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('SPC', 'Disease', (65, 68))	('cancer', 'Disease', (147, 153))	('TP53', 'Gene', '7157', (81, 85))	('germline mutation', 'Var', (86, 103))	('TP53', 'Gene', (81, 85))	('MPC', 'Disease', (73, 76))
162152	31719099	Li-Fraumeni syndrome (LFS) is a familial cancer syndrome associated with germline TP53 mutations and predisposing to a high lifetime probability of developing a wide spectrum of cancers.	('TP53', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('familial cancer syndrome', 'Disease', 'MESH:D009369', (32, 56))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('familial cancer syndrome', 'Disease', (32, 56))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('TP53', 'Gene', '7157', (82, 86))	('mutations', 'Var', (87, 96))	('associated', 'Reg', (57, 67))
162153	31719099	Clinical management of families affected with TP53 mutations remains a significant challenge.	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))
162154	31719099	With the increasing success of treating cancer patients, many TP53 mutation carriers survive their first primary cancers only to develop additional primary cancers throughout their lives.	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('TP53', 'Gene', (62, 66))	('patients', 'Species', '9606', (47, 55))	('cancers', 'Disease', (113, 120))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('mutation', 'Var', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('TP53', 'Gene', '7157', (62, 66))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancer', 'Disease', (156, 162))	('cancers', 'Disease', (156, 163))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
162156	31719099	It has been estimated that the risk for a second primary diagnosis can be as high as 50% for germline TP53 mutation carriers and multiple malignancies have been previously observed in 43% of TP53 carriers.	('TP53', 'Gene', (102, 106))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('TP53', 'Gene', '7157', (191, 195))	('TP53', 'Gene', (191, 195))	('malignancies', 'Disease', (138, 150))	('TP53', 'Gene', '7157', (102, 106))	('mutation', 'Var', (107, 115))
162158	31719099	Use of age-specific penetrance estimates of TP53 mutation carriers may have implications for surveillance and clinical management.	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('mutation', 'Var', (49, 57))
162162	31719099	We defined the penetrance of primary cancer as the cumulative probability of developing the next primary cancer by a certain age given the mutation status of disease susceptibility variant and prior cancer history (e.g., previous primary cancer occurrence and diagnosis age).	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('variant', 'Var', (181, 188))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
162171	31719099	However, we decided to select the second best model in terms of the DIC, with {G,S,G x S,D(t),G x D(t)} as our final model since it has been reported that cancer status has different effects on cancer risk for mutation carriers and non-carriers.	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutation', 'Var', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
162184	31719099	For the MDA pediatric sarcoma cohort, which began collecting data in the 1980's, blood samples tested for a germline TP53 mutation were compared to the available literature for a suggestion of pathogenicity.	('TP53', 'Gene', '7157', (117, 121))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('TP53', 'Gene', (117, 121))	('mutation', 'Var', (122, 130))	('sarcoma', 'Disease', (22, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))
162185	31719099	If the mutation had not been reported then available family data was used to observe if direct transmission of the same TP53 mutation was present and if cancers segregated as established LFS phenotypes.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('mutation', 'Var', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
162187	31719099	Supplementary Table 1 lists all deleterious TP53 mutations that were observed in the MDACC cohorts.	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('mutations', 'Var', (49, 58))
162188	31719099	The final data was comprised 189 families and a total of 3,706 individuals, with a total of 964 (26.0%) individuals genotyped for TP53 mutations status (Table 1).	('mutations status', 'Var', (135, 151))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))
162197	31719099	The mutation prevalence for pathogenic TP53 mutations was specified as 0.0006 for LFSPRO, which was derived in our previous study.	('LFSPRO', 'Disease', (82, 88))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
162203	31719099	There are a total of 96 known TP53 mutation carriers, among which 48 were diagnosed with one primary cancer and 31 were diagnosed with more than one primary cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('diagnosed', 'Reg', (74, 83))	('TP53', 'Gene', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (157, 163))	('mutation', 'Var', (35, 43))	('TP53', 'Gene', '7157', (30, 34))
162204	31719099	There are 2,742 individuals who were not tested for TP53 mutations, among which 244 were diagnosed with one primary cancer and 15 were diagnosed with more than one primary cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('TP53', 'Gene', '7157', (52, 56))	('cancer', 'Disease', (116, 122))	('diagnosed', 'Reg', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (172, 178))
162206	31719099	As expected, the risk of the first and second primary cancers are strongly associated the TP53 mutation status with a hazard ratio (HR) of ebeta =27 (95% CI: 18, 40).	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('associated', 'Interaction', (75, 85))	('cancers', 'Disease', (54, 61))	('TP53', 'Gene', '7157', (90, 94))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('mutation status', 'Var', (95, 110))	('TP53', 'Gene', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
162207	31719099	Importantly, as illustrated in Figure 1, the TP53 mutation carriers with a primary cancer diagnosis present a sharper increase in risk of having another primary cancer diagnosis over age than carriers who are still disease-free (HR=1.65, 95%CI: 1.10, 2.48).	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('TP53', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutation', 'Var', (50, 58))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('TP53', 'Gene', '7157', (45, 49))	('cancer', 'Disease', (83, 89))
162226	31719099	This observation appears similar to a generic age effect wherein older people get more cancers and more often however, our observations remain significant because we have been able to quantify the risk of TP53 mutation carriers which is higher for getting a second cancer than the first cancer (HR=1.65, 95%CI: 1.1, 2.5), after adjusted for a baseline age effect.	('cancers', 'Disease', (87, 94))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('TP53', 'Gene', '7157', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutation', 'Var', (210, 218))	('TP53', 'Gene', (205, 209))	('people', 'Species', '9606', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('higher', 'Reg', (237, 243))
162227	31719099	Stringent surveillance recommendations for TP53 mutation carriers have been established that includes annual whole body MRI (WB-MRI) and brain MRI, among other screening exams, for early detection of tumors.	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('mutation', 'Var', (48, 56))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
162239	31719099	The different point mutations in TP53 are hypothesized to contribute to different effects of the syndrome.	('contribute', 'Reg', (58, 68))	('TP53', 'Gene', '7157', (33, 37))	('point mutations', 'Var', (14, 29))	('TP53', 'Gene', (33, 37))
162251	30420447	Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies.	('vasculogenic mimicry', 'CPA', (68, 88))	('lead to', 'Reg', (39, 46))	('neo-angiogenesis', 'CPA', (47, 63))	('aggressive malignancies', 'Disease', (92, 115))	('aggressive malignancies', 'Disease', 'MESH:D009369', (92, 115))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('ENG', 'Var', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
162253	30420447	High ENG expression has been associated with poor prognosis in Ewing sarcoma (ES), an aggressive bone cancer that primarily occurs in adolescents and young adults.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('aggressive bone cancer', 'Disease', 'MESH:D001859', (86, 108))	('High', 'Var', (0, 4))	('aggressive bone cancer', 'Disease', (86, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Ewing sarcoma', 'Disease', (63, 76))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('ENG', 'Gene', (5, 8))
162255	30420447	Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADCs), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of ES.	('OMTX503', 'Chemical', '-', (114, 121))	('cytolysin', 'Gene', '5551', (199, 208))	('clinical', 'Species', '191496', (259, 267))	('OMTX703', 'Chemical', '-', (126, 133))	('OMTX703', 'Var', (126, 133))	('cytolysin', 'Gene', (199, 208))	('antineoplastic potential', 'CPA', (18, 42))
162256	30420447	Moreover, the ADCs significantly delayed tumor growth in ES cell line-derived xenografts and patient-derived xenografts (PDXs) in a dose-dependent manner.	('delayed', 'NegReg', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('patient', 'Species', '9606', (93, 100))	('ADCs', 'Var', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
162274	30420447	Further, the sentinel trait of ES plasticity and epigenetic dysregulation appears to facilitate vasculogenic mimicry and promote tumor cell invasiveness.	('vasculogenic mimicry', 'CPA', (96, 116))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('epigenetic dysregulation', 'Var', (49, 73))	('tumor', 'Disease', (129, 134))	('facilitate', 'PosReg', (85, 95))	('promote', 'PosReg', (121, 128))
162276	30420447	Independently, we establish that human-specific anti-ENG ADCs are superior to unconjugated ENG-targeting therapies in their capacity to suppress cell proliferation and hinder tumor growth.	('tumor', 'Disease', (175, 180))	('hinder', 'NegReg', (168, 174))	('anti-ENG', 'Var', (48, 56))	('cell proliferation', 'CPA', (145, 163))	('human', 'Species', '9606', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('suppress', 'NegReg', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
162278	30420447	TRC105) are already being tested across a diverse window of tumor types, our data suggests that ADCs could significantly improve the likelihood of clinical benefit.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ADCs', 'Var', (96, 100))	('clinical benefit', 'MPA', (147, 163))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('improve', 'PosReg', (121, 128))	('tumor', 'Disease', (60, 65))	('clinical', 'Species', '191496', (147, 155))
162291	30420447	The ES panel comprises cell lines bearing various EWS-ETS fusion variants (Table 1S).	('EWS', 'Gene', '2130', (50, 53))	('EWS', 'Gene', (50, 53))	('variants', 'Var', (65, 73))
162292	30420447	When cleaved by MMP14, ENG is shed into the extracellular matrix in a soluble form (sENG), which can also be detected in the supernatants of ES cell lines (n = 7) by ELISA (Figure 1D).	('sENG', 'Chemical', '-', (84, 88))	('MMP14', 'Gene', (16, 21))	('cleaved', 'Var', (5, 12))
162315	30420447	As anticipated, OMTX503 demonstrated a compelling anti-proliferative effect in the assessed ES cells: RM82 (high ENG expression; IC50 = 1.18 10-10 M), TC71 (medium-low ENG expression; IC50 = 9.155 10-9 M) and CADO cell lines (no ENG expression; IC50   1.738 10-8 M-Figure 3C).	('OMTX503', 'Var', (16, 23))	('OMTX503', 'Chemical', '-', (16, 23))	('anti-proliferative', 'CPA', (50, 68))
162319	30420447	As a second pivotal control, the in vivo binding assay confirmed that OMTX003 binds specifically to human ENG, which was only present in tumor cells, but not in the murine-derived microvessels (Figure 4A).	('tumor', 'Disease', (137, 142))	('human', 'Species', '9606', (100, 105))	('OMTX003', 'Var', (70, 77))	('OMTX003', 'Chemical', '-', (70, 77))	('binds', 'Interaction', (78, 83))	('murine', 'Species', '10090', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ENG', 'Protein', (106, 109))
162321	30420447	OMTX003 (unconjugated MAb) and OMTX503 (nigrin-b A chain-ADC) were tested in vivo in dose-escalated manner and the animal weight loss (defined as a loss >20% of the initial animal weight) was assessed as an indirect metric of general drug toxicity (Figure 4B).	('OMTX503', 'Chemical', '-', (31, 38))	('toxicity', 'Disease', (239, 247))	('weight loss', 'Disease', (122, 133))	('weight loss', 'Phenotype', 'HP:0001824', (122, 133))	('OMTX003', 'Chemical', '-', (0, 7))	('toxicity', 'Disease', 'MESH:D064420', (239, 247))	('OMTX503', 'Var', (31, 38))	('weight loss', 'Disease', 'MESH:D015431', (122, 133))
162328	30420447	Notably, significant delays in tumor growth were observed in OMTX503-treated mice by day 13 (p = 0.0218-Figure 4C), and tumor growth inhibition (TGI) was higher than 50% after 15 days post-treatment (Figure 4D and Table 5S).	('OMTX503-treated', 'Var', (61, 76))	('mice', 'Species', '10090', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('delays', 'NegReg', (21, 27))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('OMTX503', 'Chemical', '-', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', (120, 125))
162330	30420447	H&E staining on the tumor samples revealed a loss of tumor viability in those groups treated with OMTX003 and OMTX503 after day 15 of treatment (Figure 4E).	('OMTX503', 'Chemical', '-', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('and', 'Var', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('H&E', 'Chemical', 'MESH:D006371', (0, 3))	('with', 'Var', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('OMTX003', 'Chemical', '-', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (20, 25))
162333	30420447	Collectively, these results suggest that the internalization of an immunotoxin by targeting ENG in ES xenografts impaired tumor growth.	('impaired tumor', 'Disease', 'MESH:D060825', (113, 127))	('targeting', 'Var', (82, 91))	('internalization', 'MPA', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('impaired tumor', 'Disease', (113, 127))	('ENG', 'Gene', (92, 95))
162336	30420447	Tumor growth was markedly impaired using the highest dose of OMTX703 (60 mg/kg, p = 0.019).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('OMTX703', 'Chemical', '-', (61, 68))	('OMTX703', 'Var', (61, 68))	('impaired', 'NegReg', (26, 34))	('Tumor growth', 'CPA', (0, 12))
162338	30420447	By principal component analysis (PCA), tumor specimens from mice treated with OMTX703 at 10 mg/kg clustered tightly with the placebo-treated group, suggesting that this dose had limited effect (Figure S6C).	('OMTX703', 'Chemical', '-', (78, 85))	('OMTX703', 'Var', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PCA', 'Disease', 'MESH:C562643', (33, 36))	('tumor', 'Disease', (39, 44))	('mice', 'Species', '10090', (60, 64))	('PCA', 'Disease', (33, 36))
162340	30420447	Cluster 1 was associated with proteins significantly downregulated by OMTX703 at 30 and 60mg/kg compared to a heterogeneously-treated group of tumors from mice that received placebo control, a naked anti-endoglin Ab (OMTX003), or a subtherapeutic (i.e.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('mice', 'Species', '10090', (155, 159))	('OMTX003', 'Chemical', '-', (217, 224))	('OMTX703', 'Chemical', '-', (70, 77))	('OMTX703', 'Var', (70, 77))	('proteins', 'Protein', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('downregulated', 'NegReg', (53, 66))
162343	30420447	In contrast, the most differentially upregulated proteins resulting from OMTX703 treatment (cluster 2, Figure S8) were linked to genes associated with nerve growth factor (NGF) and its cognate receptor (TRKA).	('proteins', 'Protein', (49, 57))	('upregulated', 'PosReg', (37, 48))	('TRKA', 'Gene', (203, 207))	('TRKA', 'Gene', '4914', (203, 207))	('OMTX703', 'Chemical', '-', (73, 80))	('OMTX703', 'Var', (73, 80))
162346	30420447	Notably, a protein regulator of altered metabolism (RPS6) was exclusively upregulated following OMTX703 (60 mg/kg), and a second metabolism biomarker (LDHA) was down-expressed in the 30 and 60 mg/kg-treated groups.	('LDHA', 'Gene', '3939', (151, 155))	('upregulated', 'PosReg', (74, 85))	('RPS6', 'Gene', (52, 56))	('down-expressed', 'NegReg', (161, 175))	('OMTX703', 'Chemical', '-', (96, 103))	('RPS6', 'Gene', '6194', (52, 56))	('OMTX703', 'Var', (96, 103))	('LDHA', 'Gene', (151, 155))
162351	30420447	Although animals did not experience weight loss during treatment (Figure 6A), OMTX703 at 60 mg/kg produced an acute toxic death rate of 50%, with 3 animals dying at days 21, 22 and 28 from treatment initiation.	('weight loss', 'Phenotype', 'HP:0001824', (36, 47))	('death', 'Disease', 'MESH:D003643', (122, 127))	('death', 'Disease', (122, 127))	('OMTX703', 'Chemical', '-', (78, 85))	('OMTX703', 'Var', (78, 85))	('weight loss', 'Disease', 'MESH:D015431', (36, 47))	('weight loss', 'Disease', (36, 47))
162353	30420447	Animals treated with OMTX003 experienced progressive tumor growth, as the control animals did.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('OMTX003', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('OMTX003', 'Chemical', '-', (21, 28))
162354	30420447	We found a dose-dependent antitumor response with OMTX703 at 30 mg/kg and 60 mg/kg.	('OMTX703', 'Chemical', '-', (50, 57))	('OMTX703', 'Var', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
162355	30420447	Interestingly, OMTX703 at 60 mg/kg induced a complete response (CR) rate of 60% at day 21 of treatment, in comparison to the reference treatment (irinotecan) which induced CR in 11% of tumors (Figure 6B and 6D).	('CR', 'Chemical', '-', (172, 174))	('OMTX703', 'Chemical', '-', (15, 22))	('OMTX703', 'Var', (15, 22))	('irinotecan', 'Chemical', '-', (146, 156))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('CR', 'Chemical', '-', (64, 66))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('complete', 'Disease', (45, 53))
162358	30420447	Median time to achieve endpoint is shown in Figures 6E-F, with significant longer median time in OMTX703 (60 mg/kg) and irinotecan-treated animals as compared to control-treated mice (60 days, p = 0.0065 for OMTX703 (60mg/kg); and 46 days, p = 0.0018 for irinotecan).	('OMTX703', 'Chemical', '-', (97, 104))	('OMTX703', 'Var', (97, 104))	('longer', 'PosReg', (75, 81))	('OMTX703', 'Chemical', '-', (208, 215))	('OMTX703', 'Var', (208, 215))	('mice', 'Species', '10090', (178, 182))	('irinotecan', 'Chemical', '-', (120, 130))	('irinotecan', 'Chemical', '-', (255, 265))
162359	30420447	Finally, IHC was performed to evaluate the possible changes on ENG and MMP14 expression amongst groups (Figure S10A-S10B, Tables 15S-16S) as well as proliferation rate by Ki67 staining (Figure S10C) and viability by H&E staining (Figure S9D).	('expression', 'MPA', (77, 87))	('S10A', 'SUBSTITUTION', 'None', (111, 115))	('Ki67', 'Chemical', '-', (171, 175))	('ENG', 'Gene', (63, 66))	('S10C', 'Mutation', 'p.S10C', (193, 197))	('MMP14', 'Gene', (71, 76))	('proliferation rate', 'CPA', (149, 167))	('S10A', 'Var', (111, 115))	('viability', 'CPA', (203, 212))	('S10B', 'Var', (116, 120))	('H&E', 'Chemical', 'MESH:D006371', (216, 219))	('changes', 'Reg', (52, 59))	('S10B', 'SUBSTITUTION', 'None', (116, 120))
162360	30420447	Compared to placebo-treated mice, we found a significant increase of ENG expression in mice treated with OMTX003 at 10 mg/kg (p = 0.0005-Figure S10A) and a significant increase of MMP14 expression in the groups treated with OMTX703 at 30 mg/kg (p = 0.0316), OMTX703 at 60 mg/kg (p = 0.0163) and irinotecan at 10 mg/kg (p = 0.0240) as reflected in Figure S10B.	('increase', 'PosReg', (168, 176))	('S10A', 'Var', (144, 148))	('OMTX703', 'Chemical', '-', (258, 265))	('ENG', 'Gene', (69, 72))	('mice', 'Species', '10090', (28, 32))	('S10B', 'SUBSTITUTION', 'None', (354, 358))	('irinotecan', 'Chemical', '-', (295, 305))	('mice', 'Species', '10090', (87, 91))	('OMTX003', 'Chemical', '-', (105, 112))	('S10B', 'Var', (354, 358))	('expression', 'MPA', (73, 83))	('increase', 'PosReg', (57, 65))	('S10A', 'SUBSTITUTION', 'None', (144, 148))	('expression', 'MPA', (186, 196))	('OMTX703', 'Chemical', '-', (224, 231))	('OMTX703', 'Var', (224, 231))	('OMTX703', 'Var', (258, 265))	('MMP14', 'Gene', (180, 185))
162362	30420447	However, regarding the cell proliferation evaluated by Ki67 staining, we found a significant decrease in the group treated with OMTX003 10 mg/kg (p = 0.0479) and a non-significant decrease in the groups treated with OMTX703 (30 mg/kg; 60 mg/kg) and irinotecan 10 mg/kg (Figure S10C).	('OMTX003', 'Chemical', '-', (128, 135))	('Ki67', 'Chemical', '-', (55, 59))	('S10C', 'Mutation', 'p.S10C', (277, 281))	('irinotecan', 'Chemical', '-', (249, 259))	('OMTX003', 'Var', (128, 135))	('OMTX703', 'Chemical', '-', (216, 223))	('decrease', 'NegReg', (93, 101))	('cell proliferation', 'CPA', (23, 41))
162377	30420447	Mutations in ENG are associated with hereditary hemorrhagic telangiectasia type 1 (HHT1).	('hereditary hemorrhagic telangiectasia type 1', 'Disease', (37, 81))	('hereditary hemorrhagic telangiectasia type 1', 'Disease', 'MESH:D013683', (37, 81))	('associated', 'Reg', (21, 31))	('telangiectasia', 'Phenotype', 'HP:0001009', (60, 74))	('Mutations', 'Var', (0, 9))	('ENG', 'Gene', (13, 16))
162387	30420447	The role of ENG on ES phenotype and malignancy has already been studied in in vitro and in vivo models, where ENG was associated with increased invasiveness and metastasis formation.	('ENG', 'Var', (110, 113))	('invasiveness', 'CPA', (144, 156))	('metastasis formation', 'CPA', (161, 181))	('malignancy', 'Disease', 'MESH:D009369', (36, 46))	('increased', 'PosReg', (134, 143))	('malignancy', 'Disease', (36, 46))
162388	30420447	Our finding of a possible epigenetic downregulation of ENG by methylation of its promoter region in the CADO cell line is consistent with other studies in solid tumors, where the hypermethylation of ENG promoter region results in gene silencing, and was reactivated after in vitro methylation reversal assays .	('downregulation', 'NegReg', (37, 51))	('ENG', 'Gene', (199, 202))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('ENG', 'Gene', (55, 58))	('solid tumors', 'Disease', (155, 167))	('silencing', 'NegReg', (235, 244))	('methylation', 'Var', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('gene', 'MPA', (230, 234))	('solid tumors', 'Disease', 'MESH:D009369', (155, 167))	('hypermethylation', 'Var', (179, 195))
162394	30420447	OMTX503 and OMTX703 share the same mechanism of action and both lead to cell-death after drug internalization.	('death', 'Disease', 'MESH:D003643', (77, 82))	('OMTX703', 'Chemical', '-', (12, 19))	('death', 'Disease', (77, 82))	('OMTX703', 'Var', (12, 19))	('lead to', 'Reg', (64, 71))	('OMTX503', 'Var', (0, 7))	('OMTX503', 'Chemical', '-', (0, 7))
162395	30420447	At this point, we found differences of response to treatment, depending on the drug administered, OMTX503 or OMTX703.	('OMTX503', 'Var', (98, 105))	('OMTX703', 'Chemical', '-', (109, 116))	('OMTX703', 'Var', (109, 116))	('OMTX503', 'Chemical', '-', (98, 105))
162403	30420447	In that regard, the capacity for OMTX703 to jointly target the tumor and stroma raises the tantalizing possibility that OMTX703 might delay tumor growth even when ENG expression is low or absent.	('tumor', 'Disease', (63, 68))	('delay', 'NegReg', (134, 139))	('OMTX703', 'Chemical', '-', (33, 40))	('OMTX703', 'Chemical', '-', (120, 127))	('OMTX703', 'Var', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (140, 145))
162417	30630271	Multivariate Cox proportional hazard analysis, with covariates including age, stage, resection margin, adjuvant chemotherapy, and adjuvant radiotherapy, revealed that adjuvant radiotherapy was associated with longer DFS (odds ratio = 0.369, p = 0.045).	('DFS', 'MPA', (216, 219))	('adjuvant radiotherapy', 'Var', (167, 188))	('Cox', 'Gene', '1351', (13, 16))	('Cox', 'Gene', (13, 16))
162453	30630271	Multivariate Cox proportional hazards analysis, with covariates including age, stage, resection margin, adjuvant chemotherapy, and adjuvant RT, revealed that adjuvant RT was associated with longer DFS (odds ratio = 0.369, p = 0.045).	('Cox', 'Gene', '1351', (13, 16))	('Cox', 'Gene', (13, 16))	('DFS', 'MPA', (197, 200))	('adjuvant', 'Var', (158, 166))
162476	30630271	RT on abdomen can acutely induce nausea, vomiting, anorexia, diarrhea and abdominal pain from gastritis or enteritis.	('diarrhea', 'Phenotype', 'HP:0002014', (61, 69))	('RT on', 'Var', (0, 5))	('nausea', 'Disease', (33, 39))	('induce', 'Reg', (26, 32))	('enteritis', 'Disease', 'MESH:D004751', (107, 116))	('diarrhea', 'Disease', (61, 69))	('anorexia', 'Phenotype', 'HP:0002039', (51, 59))	('nausea', 'Disease', 'MESH:D009325', (33, 39))	('abdominal pain', 'Phenotype', 'HP:0002027', (74, 88))	('enteritis', 'Disease', (107, 116))	('diarrhea', 'Disease', 'MESH:D003967', (61, 69))	('anorexia', 'Disease', (51, 59))	('vomiting', 'Disease', 'MESH:D014839', (41, 49))	('gastritis', 'Phenotype', 'HP:0005263', (94, 103))	('abdominal pain', 'Disease', (74, 88))	('abdominal pain', 'Disease', 'MESH:D015746', (74, 88))	('vomiting', 'Phenotype', 'HP:0002013', (41, 49))	('pain', 'Phenotype', 'HP:0012531', (84, 88))	('vomiting', 'Disease', (41, 49))	('gastritis', 'Disease', 'MESH:D005756', (94, 103))	('nausea', 'Phenotype', 'HP:0002018', (33, 39))	('anorexia', 'Disease', 'MESH:D000855', (51, 59))	('gastritis', 'Disease', (94, 103))
162478	30630271	RT on chest can typically induce lung injury.	('RT on', 'Var', (0, 5))	('lung injury', 'Disease', 'MESH:D055370', (33, 44))	('induce', 'Reg', (26, 32))	('lung injury', 'Disease', (33, 44))
162482	30630271	RT on chest can cause dysphagia and odynophagia from esophagitis as well.	('odynophagia', 'Phenotype', 'HP:0032043', (36, 47))	('dysphagia and odynophagia', 'Disease', 'MESH:D003680', (22, 47))	('RT on', 'Var', (0, 5))	('esophagitis', 'Phenotype', 'HP:0100633', (53, 64))	('esophagitis', 'Disease', (53, 64))	('esophagitis', 'Disease', 'MESH:D004941', (53, 64))	('dysphagia', 'Phenotype', 'HP:0002015', (22, 31))	('cause', 'Reg', (16, 21))
162498	29044540	On multivariate regression analysis, hospital LOS was significantly prolonged by underweight status, genitourinary cancer or sarcoma diagnosis, >=2 infections, anastomotic leak/fistula, requiring rehabilitation consult and admission, and >=2 consultations (p<0.05).	('anastomotic leak/fistula', 'Disease', 'MESH:D057868', (160, 184))	('underweight status', 'Var', (81, 99))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('genitourinary cancer', 'Phenotype', 'HP:0007379', (101, 121))	('genitourinary cancer', 'Disease', (101, 121))	('prolonged', 'PosReg', (68, 77))	('anastomotic leak/fistula', 'Disease', (160, 184))	('infections', 'Disease', (148, 158))	('sarcoma', 'Disease', (125, 132))	('hospital LOS', 'MPA', (37, 49))	('>=2', 'Var', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('genitourinary cancer', 'Disease', 'MESH:D014565', (101, 121))	('infections', 'Disease', 'MESH:D007239', (148, 158))
162499	29044540	In patients undergoing pelvic exenteration, prolonged hospital LOS is associated with underweight status, genitourinary cancer or sarcoma diagnosis, more than one infection, anastomotic leak/fistula, requiring rehabilitation consult and admission, and more than one consultation.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('genitourinary cancer', 'Disease', 'MESH:D014565', (106, 126))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('anastomotic leak/fistula', 'Disease', 'MESH:D057868', (174, 198))	('underweight status', 'Var', (86, 104))	('genitourinary cancer', 'Disease', (106, 126))	('anastomotic leak/fistula', 'Disease', (174, 198))	('sarcoma', 'Disease', (130, 137))	('infection', 'Disease', (163, 172))	('patients', 'Species', '9606', (3, 11))	('genitourinary cancer', 'Phenotype', 'HP:0007379', (106, 126))	('infection', 'Disease', 'MESH:D007239', (163, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
162537	29044540	In this study, we identified multiple risk factors that were associated with increased hospital LOS in patients undergoing pelvic exenteration: underweight status, sarcoma or genitourinary cancer diagnosis, >=2 infections, anastomotic leak/fistula, rehabilitation consult and inpatient rehabilitation admission, and >=2 consultation services used.	('anastomotic leak/fistula', 'Disease', (223, 247))	('hospital LOS', 'MPA', (87, 99))	('infections', 'Disease', 'MESH:D007239', (211, 221))	('genitourinary cancer', 'Disease', 'MESH:D014565', (175, 195))	('underweight', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('genitourinary cancer', 'Disease', (175, 195))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('infections', 'Disease', (211, 221))	('patient', 'Species', '9606', (103, 110))	('genitourinary cancer', 'Phenotype', 'HP:0007379', (175, 195))	('patients', 'Species', '9606', (103, 111))	('patient', 'Species', '9606', (278, 285))	('increased', 'PosReg', (77, 86))	('anastomotic leak/fistula', 'Disease', 'MESH:D057868', (223, 247))	('>=2', 'Var', (207, 210))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
162566	29044540	Underweight status and anastomotic leak/fistula were also associated with prolonged hospitalization.	('anastomotic leak/fistula', 'Disease', (23, 47))	('Underweight status', 'Var', (0, 18))	('anastomotic leak/fistula', 'Disease', 'MESH:D057868', (23, 47))
162732	33066095	In 85% of cases EWS is associated with, the t(11;22)(q24:q12) chromosomal translocation that generates the fusion of EWS gene-5' segment with the 3' segment of the ETS family gene FLI-1.	('FLI-1', 'Gene', '2313', (180, 185))	('EWS', 'Phenotype', 'HP:0012254', (117, 120))	('EWS', 'Gene', (117, 120))	('FLI-1', 'Gene', (180, 185))	('EWS', 'Phenotype', 'HP:0012254', (16, 19))	('t(11;22)(q24:q12)', 'STRUCTURAL_ABNORMALITY', 'None', (44, 61))	('fusion', 'Var', (107, 113))	('EWS', 'Disease', (16, 19))	('associated', 'Reg', (23, 33))
162753	33066095	They have reported that the treatment with the specific beta3-ARs antagonist SR59230A is effective in reducing melanoma angiogenesis and growth and in inducing apoptosis.	('apoptosis', 'CPA', (160, 169))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('SR59230A', 'Var', (77, 85))	('inducing', 'Reg', (151, 159))	('reducing', 'NegReg', (102, 110))	('beta3-AR', 'Gene', (56, 64))	('ARs', 'Gene', (62, 65))	('SR59230A', 'Chemical', 'MESH:C097869', (77, 85))	('ARs', 'Gene', '6012', (62, 65))	('beta3-AR', 'Gene', '140', (56, 64))	('growth', 'CPA', (137, 143))
162754	33066095	In addition, interesting results were observed about the effect of beta-adrenoreceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils).	('activity', 'MPA', (114, 122))	('beta-adrenoreceptor', 'Protein', (67, 86))	('macrophages', 'CPA', (176, 187))	('CD8', 'Gene', (165, 168))	('CD8', 'Gene', '925', (165, 168))	('MDSC', 'CPA', (170, 174))	('blockade', 'Var', (87, 95))
162755	33066095	The beta-adrenoreceptor blockade, both with antagonists (propranolol and SR59230A) and specific siRNAs, suggested the beta3-ARs involvement in immune-tolerance.	('ARs', 'Gene', '6012', (124, 127))	('SR59230A', 'Chemical', 'MESH:C097869', (73, 81))	('propranolol', 'Chemical', 'MESH:D011433', (57, 68))	('beta3-AR', 'Gene', (118, 126))	('beta3-AR', 'Gene', '140', (118, 126))	('SR59230A', 'Var', (73, 81))	('ARs', 'Gene', (124, 127))	('beta-adrenoreceptor blockade', 'Protein', (4, 32))
162760	33066095	However, additional studies on beta3-ARs blockers are necessary since currently the most widely used beta3-ARs antagonists are L-748,337 and SR59230A, but they have some limitations.	('ARs', 'Gene', (37, 40))	('beta3-AR', 'Gene', (31, 39))	('SR59230A', 'Chemical', 'MESH:C097869', (141, 149))	('ARs', 'Gene', '6012', (37, 40))	('beta3-AR', 'Gene', '140', (31, 39))	('L-748', 'Chemical', '-', (127, 132))	('beta3-AR', 'Gene', (101, 109))	('ARs', 'Gene', (107, 110))	('SR59230A', 'Var', (141, 149))	('beta3-AR', 'Gene', '140', (101, 109))	('ARs', 'Gene', '6012', (107, 110))
162761	33066095	SR59230A was previously considered as a selective beta3-adrenoceptor antagonist, but a similar affinity was demonstrated for all the three subtypes.	('beta3-adrenoceptor', 'Gene', '155', (50, 68))	('beta3-adrenoceptor', 'Gene', (50, 68))	('SR59230A', 'Chemical', 'MESH:C097869', (0, 8))	('SR59230A', 'Var', (0, 8))
162762	33066095	Another issue is that SR59230A can act as a partial agonist, and the degree of partial agonism depends on the model system.	('SR59230A', 'Var', (22, 30))	('partial agonist', 'MPA', (44, 59))	('SR59230A', 'Chemical', 'MESH:C097869', (22, 30))
162763	33066095	Moreover, in some systems, SR59230A acts as a full agonist.	('full agonist', 'MPA', (46, 58))	('SR59230A', 'Chemical', 'MESH:C097869', (27, 35))	('SR59230A', 'Var', (27, 35))
162780	33066095	The fraction of CD45- cells was centrifuged at 1200x rpm for 5 min, resuspended in MACSQuant Running Buffer, and labelled with the fluorescent antibodies beta3-PE, CD45-APC, and CD99-FITC following the same steps described above.	('FITC', 'Chemical', 'MESH:D016650', (183, 187))	('CD99-FITC', 'Var', (178, 187))	('APC', 'Gene', (169, 172))	('beta3', 'Gene', '28883', (154, 159))	('APC', 'Gene', '324', (169, 172))	('beta3', 'Gene', (154, 159))
162783	33066095	At the end of the protocol, samples were labelled with fluorescent antibodies, such as beta3-PE, CD45-APC, and CD99-FITC, and analysed by flow cytometry following the same steps described for blood samples and the same gating strategy shown in Figure 1.	('beta3', 'Gene', (87, 92))	('APC', 'Gene', (102, 105))	('APC', 'Gene', '324', (102, 105))	('CD99-FITC', 'Var', (111, 120))	('FITC', 'Chemical', 'MESH:D016650', (116, 120))	('beta3', 'Gene', '28883', (87, 92))
162787	33066095	For the analysis of CD99 expression, after 24 h of SR59230A treatment, cells were washed and labelled with CD99-FITC antibody as described above.	('FITC', 'Chemical', 'MESH:D016650', (112, 116))	('SR59230A', 'Var', (51, 59))	('CD99', 'Gene', (20, 24))	('SR59230A', 'Chemical', 'MESH:C097869', (51, 59))
162811	33066095	As expected, since beta3-ARs blockade had been reported to affect tumour cell proliferation, SR59230A treatment reduced the tumour cells viability (Figure 6A) in both cell lines.	('affect', 'Reg', (59, 65))	('beta3-AR', 'Gene', '140', (19, 27))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('SR59230A', 'Chemical', 'MESH:C097869', (93, 101))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumour', 'Disease', (66, 72))	('ARs', 'Gene', (25, 28))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('ARs', 'Gene', '6012', (25, 28))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('reduced', 'NegReg', (112, 119))	('SR59230A', 'Var', (93, 101))	('beta3-AR', 'Gene', (19, 27))	('tumour', 'Disease', (124, 130))
162812	33066095	Interestingly, the CD99 mean fluorescence intensity (MFI) decreased after SR59230A treatment with respect to control untreated cells (Figure 6B), showing a reduction of CD99 antigens expressed on cell surface, thus suggesting a role of beta3-AR in regulating the expression of CD99.	('beta3-AR', 'Gene', '140', (236, 244))	('SR59230A', 'Var', (74, 82))	('reduction', 'NegReg', (156, 165))	('CD99 antigen', 'Gene', (169, 181))	('decreased', 'NegReg', (58, 67))	('CD99 antigen', 'Gene', '4267', (169, 181))	('SR59230A', 'Chemical', 'MESH:C097869', (74, 82))	('beta3-AR', 'Gene', (236, 244))	('CD99', 'Gene', (19, 23))	('mean fluorescence intensity', 'MPA', (24, 51))
162833	33066095	On the other hand, some studies reported the detection of CTCs mostly in bone marrow samples of patients identified with metastatic disease and have been associated with poor prognosis.	('patients', 'Species', '9606', (96, 104))	('CTCs', 'Var', (58, 62))	('metastatic disease', 'Disease', (121, 139))	('detection', 'Reg', (45, 54))	('CTCs', 'Chemical', '-', (58, 62))
162835	33066095	This work showed the presence of high levels of CD45-CD99+ in EWS patients, confirming the presence of CTCs in this type of paediatric cancer.	('cancer', 'Disease', (135, 141))	('CD45-CD99+', 'Var', (48, 58))	('EWS', 'Disease', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('EWS', 'Phenotype', 'HP:0012254', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('patients', 'Species', '9606', (66, 74))	('CTCs', 'Chemical', '-', (103, 107))
162837	33066095	Thus, we suppose that a high level of CD45-CD99+ can correspond to a well-detectable amount of CTCs differently from other solid tumours.	('CD45-CD99+', 'Var', (38, 48))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('tumours', 'Disease', (129, 136))	('CTCs', 'Chemical', '-', (95, 99))
162858	32295254	The review summarizes recent advances concerning the molecular and genetic background of these three neoplasms and, of their most common variants, highlights the putative therapeutic targets and the clinical trials that are presently active, and notes the fundamental issues that remain unanswered.	('neoplasms', 'Phenotype', 'HP:0002664', (101, 110))	('neoplasms', 'Disease', 'MESH:D009369', (101, 110))	('neoplasms', 'Disease', (101, 110))	('neoplasm', 'Phenotype', 'HP:0002664', (101, 109))	('variants', 'Var', (137, 145))
162878	32295254	Different to HGOS, on which the following sections will focus, low-grade osteosarcoma varieties (parosteal and low-grade central) frequently harbor amplifications of the 12q13-15 amplicon, including the MDM2 and CDK4 genes, as supernumerary ring or giant chromosomes.	('12q13-15', 'Gene', (170, 178))	('osteosarcoma', 'Phenotype', 'HP:0002669', (73, 85))	('CDK4', 'Gene', (212, 216))	('osteosarcoma', 'Disease', (73, 85))	('MDM2', 'Gene', '4193', (203, 207))	('osteosarcoma', 'Disease', 'MESH:D012516', (73, 85))	('MDM2', 'Gene', (203, 207))	('CDK4', 'Gene', '1019', (212, 216))	('amplifications', 'Var', (148, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('giant chromosomes', 'CPA', (249, 266))
162881	32295254	Germline genetics have tried to identify common variants that may be associated with HGOS and to identify the genetic origin of osteosarcoma.	('variants', 'Var', (48, 56))	('associated', 'Reg', (69, 79))	('osteosarcoma', 'Disease', (128, 140))	('osteosarcoma', 'Phenotype', 'HP:0002669', (128, 140))	('osteosarcoma', 'Disease', 'MESH:D012516', (128, 140))	('HGOS', 'Disease', (85, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
162882	32295254	HGOS is associated with several rare and autosomal cancer predisposition syndromes, including the Li-Fraumeni syndrome (mutations of the TP53 gene), hereditary retinoblastoma (mutations of the RB1 gene), Bloom syndrome (mutations of the RECQL3 gene), Werner syndrome (mutations of the RECQL2 (WRN) gene), Rothmund-Thomson, Baller-Gerold and RAPADILINO syndromes (mutations of the RECQL4 gene).	('autosomal cancer', 'Disease', (41, 57))	('retinoblastoma', 'Phenotype', 'HP:0009919', (160, 174))	('RECQL2', 'Gene', (285, 291))	('WRN', 'Gene', (293, 296))	('WRN', 'Gene', '7486', (293, 296))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('associated', 'Reg', (8, 18))	('mutations', 'Var', (120, 129))	('Bloom syndrome', 'Disease', (204, 218))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (149, 174))	('RECQL4', 'Gene', '9401', (380, 386))	('Baller-Gerold', 'Disease', (323, 336))	('RECQL3', 'Gene', '7486', (237, 243))	('RECQL4', 'Gene', (380, 386))	('TP53', 'Gene', (137, 141))	('mutations', 'Var', (268, 277))	('autosomal cancer', 'Disease', 'MESH:D009369', (41, 57))	('RB1', 'Gene', (193, 196))	('hereditary retinoblastoma', 'Disease', (149, 174))	('RAPADILINO syndromes', 'Disease', (341, 361))	('Werner syndrome', 'Disease', (251, 266))	('RECQL2', 'Gene', '7486', (285, 291))	('HGOS', 'Disease', (0, 4))	('Li-Fraumeni syndrome', 'Disease', (98, 118))	('Werner syndrome', 'Disease', 'MESH:D014898', (251, 266))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (98, 118))	('RECQL3', 'Gene', (237, 243))	('Rothmund-Thomson', 'Disease', (305, 321))	('RB1', 'Gene', '5925', (193, 196))	('TP53', 'Gene', '7157', (137, 141))
162883	32295254	Additional rare variants were found in five cancer predisposition genes, APC, MSH2, PALB2, SQSTM1 and ERCC2, and in common variants in more than 20 genes belonging to bone homeostasis, growth, DNA repair-related, apoptosis, cell cycles, detox reactive oxidative species and tumor immunity pathways.	('PALB2', 'Gene', '79728', (84, 89))	('MSH2', 'Gene', (78, 82))	('PALB2', 'Gene', (84, 89))	('MSH2', 'Gene', '4436', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('SQSTM1', 'Gene', (91, 97))	('cancer', 'Disease', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('SQSTM1', 'Gene', '8878', (91, 97))	('ERCC2', 'Gene', '2068', (102, 107))	('APC', 'Disease', 'MESH:D011125', (73, 76))	('variants', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('APC', 'Disease', (73, 76))	('ERCC2', 'Gene', (102, 107))	('variants', 'Var', (123, 131))
162890	32295254	Recurrent somatic alterations were not found, except for structural variations (SVs) of TP53 in 9 out of 13 patients.	('patients', 'Species', '9606', (108, 116))	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('structural variations', 'Var', (57, 78))
162892	32295254	Copy number alterations showed higher conservation in metastases, whereas short variants were less conserved.	('metastases', 'Disease', (54, 64))	('metastases', 'Disease', 'MESH:D009362', (54, 64))	('Copy number alterations', 'Var', (0, 23))
162894	32295254	Single nucleotide polymorphisms (SNPs) in several candidate genes of possible relevance for the biology, treatment response and drugs activation or detoxification of HGOS have been evaluated in order to indicate markers predictive of tumor progression, therapy response or patients' susceptibility to develop treatment-related toxicities.	('tumor', 'Disease', (234, 239))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('patients', 'Species', '9606', (273, 281))	('toxicities', 'Disease', (327, 337))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('toxicities', 'Disease', 'MESH:D064420', (327, 337))
162897	32295254	Concerning DNA repair, the most consistent data have been reported for polymorphisms of the excision repair 1 (ERCC1) and excision repair 2 (ERCC2) genes, both involved in the nucleotide excision repair (NER) pathway.	('polymorphisms', 'Var', (71, 84))	('ERCC2', 'Gene', '2068', (141, 146))	('ERCC1', 'Gene', (111, 116))	('ERCC2', 'Gene', (141, 146))	('ERCC1', 'Gene', '2067', (111, 116))
162898	32295254	Although findings have sometimes been contradictory, two meta-analyses indicated that HGOS patients carrying the C allele of ERCC1 rs11615 or the A allele of ERCC2 rs1799793 have higher probabilities of responding to conventional chemotherapy among Chinese populations.	('ERCC2', 'Gene', (158, 163))	('patients', 'Species', '9606', (91, 99))	('rs11615', 'Mutation', 'rs11615', (131, 138))	('responding', 'MPA', (203, 213))	('rs1799793', 'Mutation', 'rs1799793', (164, 173))	('ERCC1', 'Gene', (125, 130))	('ERCC1', 'Gene', '2067', (125, 130))	('rs1799793', 'Var', (164, 173))	('ERCC2', 'Gene', '2068', (158, 163))	('higher', 'PosReg', (179, 185))	('rs11615', 'Var', (131, 138))
162900	32295254	The most remarkable information on the possible clinical impact about this gene consisted with the association of the variant allele (T) of MTHFR rs1801133 with higher degrees of liver and hematologic toxicities in a series of 59 Han Chinese HGOS patients.	('association', 'Interaction', (99, 110))	('rs1801133', 'Mutation', 'rs1801133', (146, 155))	('variant', 'Var', (118, 125))	('MTHFR', 'Gene', (140, 145))	('liver and hematologic toxicities', 'Disease', 'MESH:D006402', (179, 211))	('patients', 'Species', '9606', (247, 255))	('rs1801133', 'Var', (146, 155))	('MTHFR', 'Gene', '4524', (140, 145))
162901	32295254	The application of NGS and other genome-wide analyses to HGOS has further confirmed the presence of multiple genomic rearrangements, kataegis and a high degree of intratumor heterogeneity, but it has also indicated somatic gene mutations that appear to drive HGOS oncogenesis.	('tumor', 'Disease', (168, 173))	('mutations', 'Var', (228, 237))	('HGOS', 'Disease', (259, 263))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('oncogenesis', 'CPA', (264, 275))	('drive', 'PosReg', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
162903	32295254	Phase I/II trials have been thus launched for patients with advanced soft-tissue and bone sarcomas (including HGOS) to assess the clinical efficacy of different mTOR inhibitors: temsirolimus (CCI-779, Torisel , Wyeth Pharmaceuticals, Midrand, South Africa), everolimus (RAD-001; Novartis, Basel, Switzerland), deferolimus (AP23573, Ariad Pharmaceutical, Cambridge, MA, USA) and ridaforolimus (AP23573/MK-8669, Merck, Kenilworth, NJ).	('RAD-001; Novartis', 'Disease', (270, 287))	('RAD-001; Novartis', 'Disease', 'MESH:C535729', (270, 287))	('patients', 'Species', '9606', (46, 54))	('soft-tissue and bone sarcomas', 'Phenotype', 'HP:0030448', (69, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('temsirolimus', 'Disease', (178, 190))	('AP23573/MK-8669', 'Var', (393, 408))	('bone sarcomas', 'Disease', 'MESH:D012509', (85, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('bone sarcomas', 'Disease', (85, 98))	('temsirolimus', 'Disease', 'None', (178, 190))	('bone sarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('mTOR', 'Gene', '2475', (161, 165))	('bone sarcomas', 'Phenotype', 'HP:0002669', (85, 98))	('everolimus', 'Chemical', 'MESH:D000068338', (258, 268))	('mTOR', 'Gene', (161, 165))
162907	32295254	Another NGS finding with significant clinical relevance in HGOS, is the indication that this tumor frequently exhibits deficiencies in the BRCA1- and/or BRCA2-pathway (the so-called BRCAness phenotype).	('HGOS', 'Disease', (59, 63))	('BRCAness', 'Disease', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('BRCAness', 'Disease', 'None', (182, 190))	('BRCA2', 'Gene', (153, 158))	('BRCA1', 'Gene', '672', (139, 144))	('tumor', 'Disease', (93, 98))	('BRCA2', 'Gene', '675', (153, 158))	('deficiencies', 'Var', (119, 131))	('BRCA1', 'Gene', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
162911	32295254	Recently, another strategy, consisting of the integration of genomic copy number variations and chemotherapy response-related biomarkers, has provided insights that may be of help to tailor therapy in pediatric patients with bone and soft-tissue sarcomas on the basis of individual genomic data.	('copy number variations', 'Var', (69, 91))	('patients', 'Species', '9606', (211, 219))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (234, 254))	('sarcomas', 'Disease', 'MESH:D012509', (246, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('sarcomas', 'Phenotype', 'HP:0100242', (246, 254))	('sarcomas', 'Disease', (246, 254))
162912	32295254	Like for other human tumors, several evidence have reported the impact of epigenetic regulation on gene expression also in HGOS.	('gene expression', 'MPA', (99, 114))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('epigenetic regulation', 'Var', (74, 95))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (15, 20))	('HGOS', 'Disease', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
162918	32295254	The expression of the APC down-regulated 1 (APCDD1) gene, an inhibitor of the Wnt pathway that is frequently activated in HGOS, was also demonstrated to be down-regulated through hypermethylation of its promoter in HGOS, with a consequent enhancement of tumor invasion and metastatic properties.	('APCDD1', 'Gene', (44, 50))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('expression', 'MPA', (4, 14))	('APCDD1', 'Gene', '147495', (44, 50))	('APC down-regulated 1', 'Gene', '147495', (22, 42))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('metastatic properties', 'CPA', (273, 294))	('enhancement', 'PosReg', (239, 250))	('APC down-regulated 1', 'Gene', (22, 42))	('down-regulated', 'NegReg', (156, 170))	('hypermethylation', 'Var', (179, 195))
162920	32295254	Despite the loss of function of the TP53 and RB1 tumor-suppressor genes in HGOS that are mostly a consequence of genetic alterations, it has been reported that the expression of these genes can be dysregulated also through epigenetic mechanisms.	('RB1', 'Gene', (45, 48))	('tumor-suppressor', 'Gene', (49, 65))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('expression', 'MPA', (164, 174))	('TP53', 'Gene', '7157', (36, 40))	('RB1', 'Gene', '5925', (45, 48))	('tumor-suppressor', 'Gene', '7248', (49, 65))	('loss of function', 'NegReg', (12, 28))	('TP53', 'Gene', (36, 40))	('epigenetic', 'Var', (223, 233))	('HGOS', 'Disease', (75, 79))
162921	32295254	Moreover, recent findings have revealed promoter hypermethylation of the genes belonging to the TP53 pathway in HGOS experimental models and clinical samples, indicating that this epigenetic mechanism may induce the impairment of TP53-related activities.	('epigenetic', 'Var', (180, 190))	('TP53', 'Gene', (96, 100))	('TP53', 'Gene', (230, 234))	('promoter hypermethylation', 'Var', (40, 65))	('impairment', 'MPA', (216, 226))	('induce', 'PosReg', (205, 211))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', '7157', (230, 234))
162922	32295254	In another study, down-regulation of the p14ARF protein (which inhibits MDM2, thus influencing TP53 function), as a consequence of the p14ARF gene promoter hypermethylation, was detected in 15 out of 32 HGOS clinical samples and proved to be associated with a poor survival.	('p14ARF', 'Gene', '1029', (41, 47))	('TP53', 'Gene', '7157', (95, 99))	('p14ARF', 'Gene', '1029', (135, 141))	('protein', 'Protein', (48, 55))	('inhibits', 'NegReg', (63, 71))	('influencing', 'Reg', (83, 94))	('function', 'MPA', (100, 108))	('hypermethylation', 'Var', (156, 172))	('p14ARF', 'Gene', (41, 47))	('p14ARF', 'Gene', (135, 141))	('MDM2', 'Gene', '4193', (72, 76))	('MDM2', 'Gene', (72, 76))	('down-regulation', 'NegReg', (18, 33))	('TP53', 'Gene', (95, 99))
162923	32295254	Some authors suggested that the impact of TP53 mutations in the development of at least a subset of HGOS may be complemented by the reduced expression and loss of function of the HIC ZBTB transcriptional repressor 1 (HIC1) gene, consequent to the hypermethylation of its promoter, which was detected in the different series of the HGOS clinical samples.	('TP53', 'Gene', '7157', (42, 46))	('HGOS', 'Disease', (100, 104))	('HIC1', 'Gene', (217, 221))	('loss of function', 'NegReg', (155, 171))	('TP53', 'Gene', (42, 46))	('reduced', 'NegReg', (132, 139))	('mutations', 'Var', (47, 56))	('HIC1', 'Gene', '3090', (217, 221))	('HIC ZBTB transcriptional repressor 1', 'Gene', (179, 215))	('HIC ZBTB transcriptional repressor 1', 'Gene', '3090', (179, 215))
162924	32295254	The hypermethylation of the RB1 gene promoter has also been detected in HGOS, but its relevance for RB1's loss of function remains to be established.	('RB1', 'Gene', (100, 103))	('RB1', 'Gene', (28, 31))	('HGOS', 'Disease', (72, 76))	('RB1', 'Gene', '5925', (100, 103))	('RB1', 'Gene', '5925', (28, 31))	('detected', 'Reg', (60, 68))	('hypermethylation', 'Var', (4, 20))
162925	32295254	On the other hand, promoter hypermethylation of genes belonging to the RB1 pathway has been suggested to be involved in the decrease in RB1-related functions Indeed, two studies revealed hypermethylation of the p16INK4a gene promoter, which was associated with a negative or decreased p16INK4a expression, and may impair the RB1-mediated control of cell cycles and tumor cell growth in a minority of HGOS.	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('RB1', 'Gene', '5925', (71, 74))	('p16INK4a', 'Gene', '1029', (285, 293))	('RB1', 'Gene', '5925', (325, 328))	('p16INK4a', 'Gene', (211, 219))	('RB1', 'Gene', '5925', (136, 139))	('cell cycles', 'CPA', (349, 360))	('impair', 'NegReg', (314, 320))	('expression', 'MPA', (294, 304))	('hypermethylation', 'Var', (187, 203))	('p16INK4a', 'Gene', '1029', (211, 219))	('tumor', 'Disease', (365, 370))	('decreased p16INK4a expression', 'Phenotype', 'HP:0032429', (275, 304))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('decreased', 'NegReg', (275, 284))	('RB1', 'Gene', (71, 74))	('RB1', 'Gene', (325, 328))	('p16INK4a', 'Gene', (285, 293))	('RB1', 'Gene', (136, 139))
162926	32295254	Indeed, epigenetic regulators (first of all non-coding RNAs) were found to be involved in the reversion of tumor cells' malignancy and the induction of cell differentiation.	('involved', 'Reg', (78, 86))	('epigenetic regulators', 'Var', (8, 29))	('malignancy', 'Disease', (120, 130))	('tumor', 'Disease', (107, 112))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cell differentiation', 'CPA', (152, 172))	('reversion', 'CPA', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
162929	32295254	demonstrated that the novel nonnucleoside DNMT inhibitor MC3343 increased the stable doxorubicin bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death, thus indicating a potential therapeutic option for patients with HGOS who respond poorly to neoadjuvant chemotherapy.	('DNMT', 'Gene', (42, 46))	('doxorubicin', 'Chemical', 'MESH:D004317', (85, 96))	('HGOS', 'Disease', (258, 262))	('MC3343', 'Var', (57, 63))	('DNA damage', 'MPA', (156, 166))	('cell death', 'CPA', (181, 191))	('stable doxorubicin bonds to DNA', 'MPA', (78, 109))	('patients', 'Species', '9606', (244, 252))	('DNMT', 'Gene', '1786', (42, 46))	('increased', 'PosReg', (64, 73))	('MC3343', 'Chemical', '-', (57, 63))
162943	32295254	Although not mandatory for the diagnosis, genetic alterations characteristic of specific histotypes can be useful in the differential diagnosis with other neoplasms, in particular chondroblastic osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (195, 207))	('neoplasm', 'Phenotype', 'HP:0002664', (155, 163))	('neoplasms', 'Disease', 'MESH:D009369', (155, 164))	('neoplasms', 'Disease', (155, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('chondroblastic osteosarcoma', 'Disease', 'MESH:D012516', (180, 207))	('genetic alterations', 'Var', (42, 61))	('neoplasms', 'Phenotype', 'HP:0002664', (155, 164))	('chondroblastic osteosarcoma', 'Disease', (180, 207))
162945	32295254	Genetically, two main groups of chondrosarcomas exist: central chondrosarcomas, characterized by mutations in the isocitrate dehydrogenase genes IDH1 and IDH2, and secondary peripheral chondrosarcomas, characterized by alterations in the exostosin glycosyltransferase 1 (EXT1) and 2 (EXT2) genes.	('mutations', 'Var', (97, 106))	('IDH1', 'Gene', (145, 149))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (185, 199))	('chondrosarcomas', 'Disease', (63, 78))	('alterations', 'Reg', (219, 230))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('exostosin glycosyltransferase 1', 'Gene', (238, 269))	('EXT2', 'Gene', (284, 288))	('isocitrate dehydrogenase', 'Gene', '3417', (114, 138))	('EXT2', 'Gene', '2132', (284, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('IDH1', 'Gene', '3417', (145, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('EXT1', 'Gene', (271, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (32, 46))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (185, 200))	('chondrosarcomas', 'Disease', 'MESH:D002813', (185, 200))	('IDH2', 'Gene', (154, 158))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (32, 47))	('chondrosarcomas', 'Disease', 'MESH:D002813', (32, 47))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (63, 77))	('IDH2', 'Gene', '3418', (154, 158))	('isocitrate dehydrogenase', 'Gene', (114, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('exostosin glycosyltransferase 1', 'Gene', '2131', (238, 269))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (63, 78))	('chondrosarcomas', 'Disease', 'MESH:D002813', (63, 78))	('chondrosarcomas', 'Disease', (185, 200))	('EXT1', 'Gene', '2131', (271, 275))	('chondrosarcomas', 'Disease', (32, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
162947	32295254	Genetically, primary ACT/CS1 is characterized by somatic mutations in IDH1 and IDH2.	('IDH2', 'Gene', '3418', (79, 83))	('CS1', 'Gene', '6744', (25, 28))	('CS1', 'Gene', (25, 28))	('IDH1', 'Gene', '3417', (70, 74))	('mutations', 'Var', (57, 66))	('IDH2', 'Gene', (79, 83))	('IDH1', 'Gene', (70, 74))
162948	32295254	These mutations are present in about 50% of cases.. Hotspot mutations are present at the IDH1 p.Arg132 and the IDH2 p.Arg172 positions, the former being the most frequent.	('IDH2', 'Gene', '3418', (111, 115))	('p.Arg172', 'Var', (116, 124))	('Arg172', 'Chemical', '-', (118, 124))	('Arg132', 'Chemical', '-', (96, 102))	('p.Arg132', 'Var', (94, 102))	('IDH1', 'Gene', (89, 93))	('IDH2', 'Gene', (111, 115))	('IDH1', 'Gene', '3417', (89, 93))
162949	32295254	Mutations at the IDH1 p.Arg140 position have also been reported.	('p.Arg140', 'Var', (22, 30))	('Arg140', 'Chemical', '-', (24, 30))	('IDH1', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (17, 21))
162951	32295254	Similarly, to ACT/CS1, about 50% of cases show IDH1 or IDH2 mutations.	('IDH2', 'Gene', '3418', (55, 59))	('IDH2', 'Gene', (55, 59))	('CS1', 'Gene', (18, 21))	('IDH1', 'Gene', (47, 51))	('CS1', 'Gene', '6744', (18, 21))	('IDH1', 'Gene', '3417', (47, 51))	('mutations', 'Var', (60, 69))
162955	32295254	Recently, hotspot sequencing of the IDH1 and IDH2 genes in 89 central chondrosarcomas followed by targeted NGS in 54 of them indicated that IDH1/IDH2 mutations are not associated with the overall survival of patients.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (70, 85))	('IDH2', 'Gene', (145, 149))	('IDH1', 'Gene', '3417', (140, 144))	('associated', 'Reg', (168, 178))	('IDH1', 'Gene', (36, 40))	('patients', 'Species', '9606', (208, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('IDH2', 'Gene', '3418', (145, 149))	('chondrosarcomas', 'Disease', 'MESH:D002813', (70, 85))	('IDH1', 'Gene', '3417', (36, 40))	('IDH1', 'Gene', (140, 144))	('mutations', 'Var', (150, 159))	('IDH2', 'Gene', (45, 49))	('chondrosarcomas', 'Disease', (70, 85))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (70, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('IDH2', 'Gene', '3418', (45, 49))
162956	32295254	However, IDH1/IDH2 mutations were found to be associated with longer relapse-free survival and metastasis-free survival in high-grade chondrosarcomas.	('chondrosarcomas', 'Disease', 'MESH:D002813', (134, 149))	('IDH1', 'Gene', (9, 13))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (134, 148))	('chondrosarcomas', 'Disease', (134, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('longer', 'PosReg', (62, 68))	('IDH1', 'Gene', '3417', (9, 13))	('mutations', 'Var', (19, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (134, 149))	('IDH2', 'Gene', (14, 18))	('relapse-free survival', 'CPA', (69, 90))	('metastasis-free survival', 'CPA', (95, 119))	('IDH2', 'Gene', '3418', (14, 18))
162958	32295254	Other genetic alterations described in the literature are alterations of the RB1 pathway (86% of cases) with a loss of p16 and an overexpression and/or amplification of CDK4, a mutation of TP53 (in up to 59% of the cases) and mutations in COL2A1 (in 45% of cases), and also mutations in YEATS2 (12%), EGFR (19%), NRAS (12%), and IHH signaling (18%).	('IHH signaling', 'Gene', (329, 342))	('TP53', 'Gene', (189, 193))	('RB1', 'Gene', (77, 80))	('EGFR', 'Gene', '1956', (301, 305))	('COL2A1', 'Gene', (239, 245))	('overexpression', 'PosReg', (130, 144))	('alterations', 'Reg', (58, 69))	('RB1', 'Gene', '5925', (77, 80))	('TP53', 'Gene', '7157', (189, 193))	('mutation', 'Var', (177, 185))	('p16', 'Gene', (119, 122))	('NRAS', 'Gene', '4893', (313, 317))	('CDK4', 'Gene', (169, 173))	('p16', 'Gene', '1029', (119, 122))	('mutations', 'Var', (226, 235))	('EGFR', 'Gene', (301, 305))	('loss', 'NegReg', (111, 115))	('CDK4', 'Gene', '1019', (169, 173))	('YEATS2', 'Gene', '55689', (287, 293))	('mutations', 'Var', (274, 283))	('YEATS2', 'Gene', (287, 293))	('COL2A1', 'Gene', '1280', (239, 245))	('NRAS', 'Gene', (313, 317))
162959	32295254	In about 75% of cases, CDKN2A copy number variations are present.	('CDKN2A', 'Gene', '1029', (23, 29))	('CDKN2A', 'Gene', (23, 29))	('copy number variations', 'Var', (30, 52))
162962	32295254	Genetically, it is characterized by mutations in the IDH1 or IDH2 genes in 50-87% of cases.	('IDH1', 'Gene', (53, 57))	('IDH2', 'Gene', (61, 65))	('mutations', 'Var', (36, 45))	('IDH1', 'Gene', '3417', (53, 57))	('IDH2', 'Gene', '3418', (61, 65))
162964	32295254	IDH1 and IDH2 active site mutations result in the loss of the production of alpha-ketoglutarate (alpha-KG) and an accumulation of 2-hydroxyglutarate (2-HG) at supraphysiological levels within cells.	('alpha-KG', 'Chemical', 'MESH:D007656', (97, 105))	('IDH2', 'Gene', (9, 13))	('2-HG', 'Chemical', 'MESH:C019417', (150, 154))	('loss', 'NegReg', (50, 54))	('IDH2', 'Gene', '3418', (9, 13))	('mutations', 'Var', (26, 35))	('accumulation', 'PosReg', (114, 126))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (130, 148))	('IDH1', 'Gene', (0, 4))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (76, 95))	('IDH1', 'Gene', '3417', (0, 4))
162966	32295254	Thus, mutations in IDH1 and IDH2 may change the expression of potentially large numbers of genes, contributing to tumorigenesis through the alteration of the epigenetic control of gene expression in the cell of origin.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('IDH2', 'Gene', '3418', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('IDH1', 'Gene', (19, 23))	('expression', 'MPA', (48, 58))	('tumor', 'Disease', (114, 119))	('IDH1', 'Gene', '3417', (19, 23))	('alteration', 'Reg', (140, 150))	('IDH2', 'Gene', (28, 32))	('change', 'Reg', (37, 43))	('contributing', 'Reg', (98, 110))	('mutations', 'Var', (6, 15))	('epigenetic control of gene expression', 'MPA', (158, 195))
162967	32295254	Selective IDH inhibitors which suppress 2-HG production and induce antitumor responses in cells with IDH1 and IDH2 mutations were developed and validated in preclinical settings.	('induce', 'PosReg', (60, 66))	('IDH1', 'Gene', (101, 105))	('IDH', 'Gene', (10, 13))	('IDH2', 'Gene', '3418', (110, 114))	('mutations', 'Var', (115, 124))	('2-HG production', 'MPA', (40, 55))	('IDH', 'Gene', (110, 113))	('suppress', 'NegReg', (31, 39))	('IDH', 'Gene', '3417', (10, 13))	('IDH1', 'Gene', '3417', (101, 105))	('2-HG', 'Chemical', 'MESH:C019417', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('IDH', 'Gene', '3417', (110, 113))	('IDH', 'Gene', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('IDH2', 'Gene', (110, 114))	('IDH', 'Gene', '3417', (101, 104))	('tumor', 'Disease', (71, 76))
162968	32295254	Inhibitors of mutated IDH1/2 enzymes (Figure 2) entered clinical trials for targeted therapy of gliomas and may represent an interesting opportunity also for patients with chondrosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('mutated', 'Var', (14, 21))	('chondrosarcomas', 'Disease', 'MESH:D002813', (172, 187))	('Inhibitors', 'Var', (0, 10))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (172, 187))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('IDH1', 'Gene', (22, 26))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (172, 186))	('chondrosarcomas', 'Disease', (172, 187))	('IDH1', 'Gene', '3417', (22, 26))	('patients', 'Species', '9606', (158, 166))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
162979	32295254	Nevertheless, the loss of heterozygosity in the EXT1 and EXT2 genes has been implicated to cause hereditary multiple exostoses, one of the most common inherited musculoskeletal conditions, with an incidence of 1 in 50,000, whose most serious complication is chondrosarcoma transformation.	('EXT1', 'Gene', '2131', (48, 52))	('chondrosarcoma transformation', 'Disease', (258, 287))	('EXT2', 'Gene', (57, 61))	('cause', 'Reg', (91, 96))	('inherited musculoskeletal conditions', 'Disease', 'MESH:D009140', (151, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('EXT2', 'Gene', '2132', (57, 61))	('loss of heterozygosity', 'Var', (18, 40))	('multiple exostoses', 'Phenotype', 'HP:0002762', (108, 126))	('exostoses', 'Phenotype', 'HP:0100777', (117, 126))	('multiple exostoses', 'Disease', (108, 126))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (258, 272))	('chondrosarcoma transformation', 'Disease', 'MESH:D002813', (258, 287))	('inherited musculoskeletal conditions', 'Disease', (151, 187))	('EXT1', 'Gene', (48, 52))
162980	32295254	The presence of germline mutations in the EXT1 or EXT2 genes in patients with multiple osteochondromatosis leads to a 5% risk of developing a secondary peripheral ACT/CS1, compared with only 1% for patients with solitary osteochondromas.	('CS1', 'Gene', (167, 170))	('EXT2', 'Gene', (50, 54))	('EXT1', 'Gene', '2131', (42, 46))	('EXT2', 'Gene', '2132', (50, 54))	('patients', 'Species', '9606', (64, 72))	('germline mutations', 'Var', (16, 34))	('patients', 'Species', '9606', (198, 206))	('osteochondroma', 'Phenotype', 'HP:0030431', (221, 235))	('osteochondromas', 'Phenotype', 'HP:0030431', (221, 236))	('osteochondroma', 'Phenotype', 'HP:0030431', (87, 101))	('osteochondromas', 'Disease', (221, 236))	('multiple osteochondromatosis', 'Disease', 'MESH:D005097', (78, 106))	('multiple osteochondromatosis', 'Phenotype', 'HP:0005701', (78, 106))	('multiple osteochondromatosis', 'Disease', (78, 106))	('presence', 'Var', (4, 12))	('osteochondromas', 'Disease', 'MESH:D015831', (221, 236))	('EXT1', 'Gene', (42, 46))	('CS1', 'Gene', '6744', (167, 170))
162987	32295254	A subset of these tumors shows IDH1 and IDH2 mutations.	('mutations', 'Var', (45, 54))	('IDH2', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (31, 35))	('IDH2', 'Gene', '3418', (40, 44))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('IDH1', 'Gene', (31, 35))
162990	32295254	Clonal abnormalities with diploid or near-diploid complements, losses or structural aberrations of chromosome 9 and gains of chromosome 20, CDKN2A alterations and p53 overexpressions in the absence of detectable mutations have been described.	('Clonal abnormalities', 'Disease', 'MESH:C580365', (0, 20))	('overexpressions', 'PosReg', (167, 182))	('structural aberrations', 'CPA', (73, 95))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('CDKN2A', 'Gene', (140, 146))	('Clonal abnormalities', 'Disease', (0, 20))	('CDKN2A', 'Gene', '1029', (140, 146))	('gains', 'PosReg', (116, 121))	('losses', 'NegReg', (63, 69))	('alterations', 'Var', (147, 158))
162991	32295254	Interestingly, 1/15 clear cell chondrosarcomas investigated for the H3.3 mutations harbor the H3-3B (H3F3B) and p.Lys36Met mutations, suggesting a possible pathogenetic link with chondroblastoma.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (31, 46))	('chondroblastoma', 'Disease', (179, 194))	('p.Lys36Met', 'Var', (112, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('H3-3B', 'Gene', (94, 99))	('chondroblastoma', 'Phenotype', 'HP:0030432', (179, 194))	('chondroblastoma', 'Disease', 'MESH:D002804', (179, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('H3.3', 'Gene', (68, 72))	('chondrosarcomas', 'Disease', 'MESH:D002813', (31, 46))	('H3F3B', 'Gene', (101, 106))	('H3F3B', 'Gene', '3021', (101, 106))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (31, 45))	('chondrosarcomas', 'Disease', (31, 46))	('H3-3B', 'Gene', '3021', (94, 99))	('mutations', 'Var', (73, 82))	('p.Lys36Met', 'Mutation', 'p.K36M', (112, 122))
162999	32295254	Both these entities are characterized by FN1-ACVR2A and ACVR2A-FN1 fusions, which are present in at least 50% of synovial chondromatosis.	('fusions', 'Var', (67, 74))	('synovial chondromatosis', 'Disease', 'MESH:D015838', (113, 136))	('FN1', 'Gene', '2335', (63, 66))	('FN1', 'Gene', '2335', (41, 44))	('ACVR2A', 'Gene', '92', (45, 51))	('FN1', 'Gene', (41, 44))	('ACVR2A', 'Gene', '92', (56, 62))	('FN1', 'Gene', (63, 66))	('ACVR2A', 'Gene', (45, 51))	('synovial chondromatosis', 'Disease', (113, 136))	('ACVR2A', 'Gene', (56, 62))
163000	32295254	Overall, mutations in IDH1/IDH2 or EXT1/EXT2 have been shown to have a role in the pathogenesis of most common central or peripheral chondrosarcomas, respectively.	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('EXT2', 'Gene', '2132', (40, 44))	('EXT2', 'Gene', (40, 44))	('chondrosarcomas', 'Disease', (133, 148))	('mutations', 'Var', (9, 18))	('EXT1', 'Gene', '2131', (35, 39))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (133, 147))	('IDH1', 'Gene', (22, 26))	('IDH2', 'Gene', (27, 31))	('role', 'Reg', (71, 75))	('central', 'Disease', (111, 118))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (133, 148))	('IDH1', 'Gene', '3417', (22, 26))	('IDH2', 'Gene', '3418', (27, 31))	('chondrosarcomas', 'Disease', 'MESH:D002813', (133, 148))	('EXT1', 'Gene', (35, 39))
163001	32295254	In addition, inactivation of the Rb and/or p53 pathways are present in most of the tumors and are very likely to have a major role in chondrosarcoma development.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('inactivation', 'Var', (13, 25))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (134, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('chondrosarcoma', 'Disease', (134, 148))	('chondrosarcoma', 'Disease', 'MESH:D002813', (134, 148))
163009	32295254	In the 15-20% of Ewing sarcomas that are negative for EWSR1-FLI1, variant fusions between EWSR1 (or rarely FUS gene) and other members of the ETS family occur, most commonly ERG (encoding transcriptional regulator ERG) followed by ETV1, ETV4, FEV and E1AF.	('EWSR1', 'Gene', (54, 59))	('ERG', 'Gene', '2078', (214, 217))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (17, 30))	('EWSR1', 'Gene', '2130', (90, 95))	('E1AF', 'Gene', (251, 255))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('FUS', 'Gene', '2521', (107, 110))	('ETV4', 'Gene', (237, 241))	('ETV1', 'Gene', (231, 235))	('FLI1', 'Gene', (60, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('E1AF', 'Gene', '2118', (251, 255))	('FEV', 'Gene', '54738', (243, 246))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (17, 31))	('EWSR1', 'Gene', (90, 95))	('variant fusions', 'Var', (66, 81))	('Ewing sarcomas', 'Disease', (17, 31))	('ETV4', 'Gene', '2118', (237, 241))	('FLI1', 'Gene', '2313', (60, 64))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (17, 31))	('ETV1', 'Gene', '2115', (231, 235))	('FEV', 'Gene', (243, 246))	('ERG', 'Gene', (174, 177))	('EWSR1', 'Gene', '2130', (54, 59))	('ERG', 'Gene', '2078', (174, 177))	('FUS', 'Gene', (107, 110))	('ERG', 'Gene', (214, 217))
163011	32295254	Despite that 8-10% of pediatric cancers are due to germline or mosaic mutations in genes causing cancer predisposition syndromes, children at risk for Ewing sarcoma are not clearly defined.	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancer', 'Disease', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('due', 'Reg', (44, 47))	('cancer', 'Disease', (32, 38))	('cancers', 'Disease', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('Ewing sarcoma', 'Disease', (151, 164))	('germline', 'Var', (51, 59))	('mosaic mutations', 'Var', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('children', 'Species', '9606', (130, 138))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (151, 164))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (151, 164))
163013	32295254	Two recent genome-wide association studies suggest that the interactions between germline variation and somatically acquired EWSR1-FLI1 translocations are important etiologic contributors to EWS risk.	('etiologic', 'Reg', (165, 174))	('EWS', 'Gene', '2130', (125, 128))	('EWS', 'Gene', (125, 128))	('EWSR1', 'Gene', (125, 130))	('FLI1', 'Gene', (131, 135))	('EWS', 'Gene', '2130', (191, 194))	('EWS', 'Gene', (191, 194))	('FLI1', 'Gene', '2313', (131, 135))	('EWSR1', 'Gene', '2130', (125, 130))	('translocations', 'Var', (136, 150))	('interactions', 'Interaction', (60, 72))
163017	32295254	However, despite being a necessary condition, the hybrid product is not sufficient to generate a fully transformed phenotype and requires secondary alterations, which may include mutations of the STAG2 (Cohesin subunit SA2) and TP53 genes, which are detected at diagnosis in 15-21% and 5-7% of cases, as well as a deletion of CDKN2A, a cyclin-dependent kinase that regulates cell proliferation, in 10-22% of cases, respectively.	('deletion', 'Var', (314, 322))	('STAG2', 'Gene', '10735', (196, 201))	('Cohesin subunit SA2', 'Gene', '10735', (203, 222))	('CDKN2A', 'Gene', (326, 332))	('CDKN2A', 'Gene', '1029', (326, 332))	('TP53', 'Gene', '7157', (228, 232))	('Cohesin subunit SA2', 'Gene', (203, 222))	('TP53', 'Gene', (228, 232))	('mutations', 'Var', (179, 188))	('STAG2', 'Gene', (196, 201))
163020	32295254	Tumorigenesis in translocation-driven tumors is critically mediated via the IGF-1R signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('Tumorigenesis', 'CPA', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mediated', 'Reg', (59, 67))	('translocation-driven', 'Var', (17, 37))	('IGF-1R', 'Gene', (76, 82))	('IGF-1R', 'Gene', '3480', (76, 82))
163027	32295254	The combination of IGF-1R inhibitors and other targeted agents (for a review see) or non-specific drugs such as Trabectedin have been proposed.	('IGF-1R', 'Gene', '3480', (19, 25))	('inhibitors', 'Var', (26, 36))	('IGF-1R', 'Gene', (19, 25))
163032	32295254	Anti-CD99 antibodies exert additive/synergistic effects when combined with conventional agents, such as doxorubicin or vincristine, and are effective even against chemoresistant tumor cells.	('chemoresistant tumor', 'Disease', (163, 183))	('vincristine', 'Chemical', 'MESH:D014750', (119, 130))	('chemoresistant tumor', 'Disease', 'MESH:D009369', (163, 183))	('CD99', 'Gene', '4267', (5, 9))	('antibodies', 'Var', (10, 20))	('doxorubicin', 'Chemical', 'MESH:D004317', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('CD99', 'Gene', (5, 9))
163036	32295254	Ewing sarcoma is characterized by the paucity of other genetic mutations and due to the functions of their disease-defining oncogenes, epigenetic dysregulation plays an important role in the maintenance of their phenotype.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('epigenetic dysregulation', 'Var', (135, 159))
163040	32295254	Interestingly, the LSD1 inhibitor SP2509 was shown to display synergistic effects with the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) or romidepsin in vivo.	('romidepsin', 'Chemical', 'MESH:C087123', (149, 159))	('SP2509', 'Var', (34, 40))	('LSD1', 'Gene', (19, 23))	('LSD1', 'Gene', '23028', (19, 23))	('suberoylanilide hydroxamic acid', 'Chemical', 'MESH:D000077337', (107, 138))	('SP2509', 'Chemical', 'MESH:C000594309', (34, 40))
163044	32295254	have recently shown that sequential treatment with CDK4/6 inhibitors following DNA-damaging chemotherapy enhances therapeutic benefits in pancreatic cancer models, despite previous reports that concurrent treatment did not.	('pancreatic cancer', 'Disease', (138, 155))	('enhances', 'PosReg', (105, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('CDK4/6', 'Gene', '1019;1021', (51, 57))	('inhibitors', 'Var', (58, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('CDK4/6', 'Gene', (51, 57))	('therapeutic benefits', 'CPA', (114, 134))
163069	31416195	Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor that commonly loses its function via mutation, deletion, transcriptional silencing, or protein instability, and is frequently downregulated in distinct sarcoma subtypes.	('loses', 'NegReg', (85, 90))	('transcriptional', 'MPA', (128, 143))	('downregulated', 'NegReg', (197, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('PTEN', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('protein instability', 'MPA', (158, 177))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (223, 239))	('mutation', 'Var', (108, 116))	('function', 'MPA', (95, 103))	('tumor', 'Disease', (54, 59))	('deletion', 'Var', (118, 126))	('sarcoma subtypes', 'Disease', (223, 239))
163080	31416195	Sarcomas are widely believed to develop as a result of genetic alterations in mesenchymal progenitor/stem cells, but the precise cellular origin of most of these tumors remains unknown.	('genetic alterations', 'Var', (55, 74))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
163089	31416195	Activating mutations in growth factor receptors leads to activation of the phosphatidylinositol 3' kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) pathway.	('mutations', 'Var', (11, 20))	('mammalian', 'Species', '9606', (117, 126))	('Activating mutations', 'Var', (0, 20))	('activation', 'PosReg', (57, 67))	("phosphatidylinositol 3' kinase", 'Gene', (75, 105))	("phosphatidylinositol 3' kinase", 'Gene', '5290', (75, 105))	('rapamycin', 'Chemical', 'MESH:D020123', (141, 150))
163093	31416195	This pathway, due to its role in a wide range of key cellular processes, has been intensely studied for its involvement in tumor initiation and progression and is frequently dysregulated in cancer through the increased expression and/or activation of receptor tyrosine kinases, mutations in pathway components, or the loss of negative pathway regulators.	('mutations', 'Var', (278, 287))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor initiation', 'Disease', 'MESH:D009369', (123, 139))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('increased', 'PosReg', (209, 218))	('activation', 'PosReg', (237, 247))	('receptor tyrosine kinases', 'Enzyme', (251, 276))	('tumor initiation', 'Disease', (123, 139))
163096	31416195	Although PTEN functional loss is known to occur at a significant rate in the majority of human tumor subtypes, inactivating mutations of PTEN only occur in a fraction of PTEN-deficient tumors.	('tumor', 'Disease', (185, 190))	('human', 'Species', '9606', (89, 94))	('PTEN', 'Gene', (9, 13))	('inactivating mutations', 'Var', (111, 133))	('PTEN-deficient tumors', 'Disease', (170, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('PTEN-deficient tumors', 'Disease', 'MESH:D006223', (170, 191))	('PTEN', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('loss', 'NegReg', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (95, 100))
163098	31416195	A recent review profiled the data of the protein expression, amplification/translocation, and DNA sequencing of 2539 bone and STSs and concluded that the loss of PTEN expression is present in 38.6% of tumors, most commonly in leiomyosarcomas (LMSs), epithelioid sarcomas, alveolar rhabdomyosarcomas, osteosarcomas, and chordomas.	('chordomas', 'Disease', (319, 328))	('sarcomas', 'Phenotype', 'HP:0100242', (262, 270))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (281, 298))	('osteosarcomas', 'Phenotype', 'HP:0002669', (300, 313))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('alveolar rhabdomyosarcomas', 'Disease', (272, 298))	('expression', 'MPA', (167, 177))	('PTEN', 'Gene', (162, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (262, 269))	('sarcomas', 'Phenotype', 'HP:0100242', (290, 298))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (250, 270))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (272, 298))	('chordomas', 'Disease', 'MESH:D002817', (319, 328))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (226, 241))	('osteosarcomas', 'Disease', 'MESH:D012516', (300, 313))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))	('leiomyosarcomas', 'Disease', (226, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('sarcomas', 'Phenotype', 'HP:0100242', (305, 313))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('loss', 'Var', (154, 158))	('epithelioid sarcomas', 'Disease', (250, 270))	('sarcomas', 'Phenotype', 'HP:0100242', (233, 241))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (272, 298))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (226, 241))	('osteosarcomas', 'Disease', (300, 313))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (226, 240))	('tumors', 'Disease', (201, 207))
163100	31416195	Additionally, in a large panel of STSs, phosphorylated Akt (pAKT) expression by immunohistochemistry (IHC) has been shown to have some prognostic significance for both disease-free and overall survival.	('AKT', 'Gene', (61, 64))	('AKT', 'Gene', '207', (61, 64))	('phosphorylated', 'Var', (40, 54))
163107	31416195	The recent Cancer Genome Atlas (TCGA) study, which analyzed the deletion rate according to the Genomic Identification of Significant Targets in Cancer (GISTIC), reported that 13% of LMS samples had a deep deletion (possibly homozygous) and 68% had a shallow deletion (possibly heterozygous) of the PTEN gene, while PTEN mutations were detected in 5% of tumor samples (Figure 2C).	('tumor', 'Disease', (353, 358))	('deep deletion', 'Var', (200, 213))	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Cancer', 'Disease', (144, 150))	('Cancer Genome Atlas', 'Disease', (11, 30))	('Cancer', 'Disease', 'MESH:D009369', (144, 150))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Cancer', 'Disease', (11, 17))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (11, 30))	('PTEN', 'Gene', (298, 302))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('Cancer', 'Disease', 'MESH:D009369', (11, 17))	('LMS', 'Disease', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('shallow deletion', 'Var', (250, 266))
163110	31416195	reported, in their mice model with conditional smooth muscle-cell-specific PTEN knockout, widespread smooth muscle hyperplasia and hyperactivation of Akt signaling, which caused malignant progression to LMS in 80% of cases through the release and activation of mTOR via TSC2.	('knockout', 'Var', (80, 88))	('muscle hyperplasia', 'Disease', 'MESH:D006965', (108, 126))	('hyperactivation', 'PosReg', (131, 146))	('widespread smooth muscle hyperplasia', 'Phenotype', 'HP:0003720', (90, 126))	('TSC2', 'Gene', '22084', (270, 274))	('muscle hyperplasia', 'Disease', (108, 126))	('muscle hyperplasia', 'Phenotype', 'HP:0003712', (108, 126))	('TSC2', 'Gene', (270, 274))	('caused', 'Reg', (171, 177))	('activation', 'PosReg', (247, 257))	('LMS', 'Disease', (203, 206))	('mTOR', 'Protein', (261, 265))	('Akt signaling', 'Pathway', (150, 163))	('mice', 'Species', '10090', (19, 23))
163123	31416195	The reason for this can be found, as in other types of cancers, in their exclusive function of inhibition of mTORC1, which may lead to the feedback activation of Akt and sustained tumor growth signaling through mTORC2.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mTORC2', 'Gene', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('activation', 'PosReg', (148, 158))	('inhibition', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mTORC2', 'Gene', '74343', (211, 217))	('Akt', 'Pathway', (162, 165))	('mTORC1', 'Gene', (109, 115))	('tumor', 'Disease', (180, 185))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('mTORC1', 'Gene', '382056', (109, 115))	('cancers', 'Disease', (55, 62))
163126	31416195	In vitro studies with dual inhibition of PI3K and mTOR have established a strong anti-tumor activity in LMS, which was seen to be significantly higher than either agent alone.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('LMS', 'Disease', (104, 107))	('PI3K', 'Var', (41, 45))	('tumor', 'Disease', (86, 91))	('mTOR', 'Gene', (50, 54))	('higher', 'PosReg', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
163127	31416195	However, these combinations showed only limited benefits in time, due to the relatively rapid acquisition of drug resistance; indeed, although there is a thorough inhibition of mTORC1, mTORC2, and PI3K, an over-activation of the RAS/MEK/ERK pathway has been noted.	('inhibition', 'NegReg', (163, 173))	('mTORC1', 'Gene', (177, 183))	('MEK', 'Gene', (233, 236))	('MEK', 'Gene', '5609', (233, 236))	('over-activation', 'PosReg', (206, 221))	('mTORC2', 'Gene', (185, 191))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('mTORC1', 'Gene', '382056', (177, 183))	('PI3K', 'Var', (197, 201))	('mTORC2', 'Gene', '74343', (185, 191))
163140	31416195	MDM2 and P53 interact through an autoregulatory negative feedback loop as P53 stimulates the expression of MDM2 and, in turn, MDM2 inhibits p53 activity by stimulating its degradation in the nucleus and cytoplasm, blocks its transcriptional activity, and promotes its nuclear export.	('P53', 'Gene', (9, 12))	('stimulating', 'PosReg', (156, 167))	('P53', 'Gene', (74, 77))	('nuclear export', 'MPA', (268, 282))	('P53', 'Gene', '7157', (9, 12))	('stimulates', 'PosReg', (78, 88))	('MDM2', 'Var', (126, 130))	('promotes', 'PosReg', (255, 263))	('P53', 'Gene', '7157', (74, 77))	('activity', 'MPA', (144, 152))	('inhibits', 'NegReg', (131, 139))	('transcriptional activity', 'MPA', (225, 249))	('expression', 'MPA', (93, 103))	('p53', 'Protein', (140, 143))	('blocks', 'NegReg', (214, 220))	('degradation in the nucleus', 'MPA', (172, 198))	('MDM2', 'Gene', (107, 111))
163142	31416195	In LPS, MDM2 amplification and the consequent protein overexpression inactivate the function of p53, allowing cells to escape from the usual growth constraints and permitting the tumor to harbor more genomic alterations from one cell generation to the next.	('p53', 'Gene', (96, 99))	('MDM2', 'Gene', (8, 12))	('LPS', 'Disease', 'MESH:C536528', (3, 6))	('overexpression', 'PosReg', (54, 68))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('amplification', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('inactivate', 'NegReg', (69, 79))	('tumor', 'Disease', (179, 184))	('LPS', 'Disease', (3, 6))	('function', 'MPA', (84, 92))
163144	31416195	Akt can phosphorylate serine 166 and serine 186 in the domain of MDM2 that contains a nuclear localization motif.	('phosphorylate', 'MPA', (8, 21))	('serine 166', 'Var', (22, 32))	('serine 186', 'Var', (37, 47))	('MDM2', 'Gene', (65, 69))	('serine', 'Chemical', 'MESH:D012694', (22, 28))	('serine', 'Chemical', 'MESH:D012694', (37, 43))
163145	31416195	Furthermore, AKT-mediated phosphorylation of MDMX at Ser367 also stabilizes MDM2 E3-ligase activity.	('MDMX', 'Gene', '4194', (45, 49))	('MDM2 E3-ligase', 'Enzyme', (76, 90))	('MDMX', 'Gene', (45, 49))	('Ser367', 'Chemical', '-', (53, 59))	('activity', 'MPA', (91, 99))	('AKT', 'Gene', '207', (13, 16))	('Ser367', 'Var', (53, 59))	('stabilizes', 'PosReg', (65, 75))	('AKT', 'Gene', (13, 16))
163146	31416195	Additionally, MDM2 prevents the localization of the repressor element-1 silencing transcription factor (REST), a tumor suppressor that downregulates PI3-kinase activity and Akt phosphorylation on the p85 promoter.	('tumor', 'Disease', (113, 118))	('MDM2', 'Var', (14, 18))	('repressor element-1 silencing transcription factor', 'Gene', '5978', (52, 102))	('prevents', 'NegReg', (19, 27))	('Akt', 'Pathway', (173, 176))	('PI3-kinase activity', 'Pathway', (149, 168))	('repressor element-1 silencing transcription factor', 'Gene', (52, 102))	('localization', 'MPA', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('p85', 'Gene', '5296', (200, 203))	('p85', 'Gene', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('phosphorylation', 'MPA', (177, 192))	('downregulates', 'NegReg', (135, 148))
163148	31416195	Despite the upregulation of the Akt pathway in several LPS samples, the Cancer Genome Atlas (TCGA) study showed PTEN mutation/deletion in 5% of the DDLPS samples that were analyzed (Figure 2C).	('LPS', 'Disease', (55, 58))	('upregulation', 'PosReg', (12, 24))	('Akt pathway', 'Pathway', (32, 43))	('LPS', 'Disease', 'MESH:C536528', (55, 58))	('Cancer Genome Atlas', 'Disease', (72, 91))	('PTEN', 'Gene', (112, 116))	('LPS', 'Disease', (150, 153))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (72, 91))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutation/deletion', 'Var', (117, 134))	('LPS', 'Disease', 'MESH:C536528', (150, 153))
163155	31416195	These results are in agreement with studies on several epithelial tumors which indicate that inhibition of the PI3K pathway, including PI3K itself, Akt, or mTOR, can enhance the activity of MDM2 inhibition.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PI3K pathway', 'Pathway', (111, 123))	('Akt', 'Pathway', (148, 151))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('enhance', 'PosReg', (166, 173))	('activity', 'MPA', (178, 186))	('inhibition', 'Var', (93, 103))
163158	31416195	P53 homozygous mutant models showed a significant incidence of developing a tumor (29%) compared to p53 wild-type (8%) and p53 heterozygotes (6%), theorizing that both Akt pathway activation and p53 inactivation play an important role in the development of LPS.	('inactivation', 'NegReg', (199, 211))	('LPS', 'Disease', 'MESH:C536528', (257, 260))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('P53', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('Akt pathway', 'Pathway', (168, 179))	('P53', 'Gene', '7157', (0, 3))	('mutant', 'Var', (15, 21))	('activation', 'PosReg', (180, 190))	('LPS', 'Disease', (257, 260))
163161	31416195	BEZ235, a dual PI3K/mTOR inhibitor, was more effective and silenced the Akt pathway activation in LPS cell lines and induced G1 arrest and apoptosis compared to rapamycin.	('LPS', 'Disease', 'MESH:C536528', (98, 101))	('arrest', 'Disease', 'MESH:D006323', (128, 134))	('BEZ235', 'Var', (0, 6))	('activation', 'PosReg', (84, 94))	('induced', 'PosReg', (117, 124))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('rapamycin', 'Chemical', 'MESH:D020123', (161, 170))	('arrest', 'Disease', (128, 134))	('LPS', 'Disease', (98, 101))	('apoptosis', 'CPA', (139, 148))	('Akt pathway', 'Pathway', (72, 83))	('silenced', 'NegReg', (59, 67))
163173	31416195	Additionally, the amplifications and the mutations, mostly in exon 20 and exon 9, of PIK3Ca and PTEN loss, have been reported in 14-18% and 12% of cases, respectively.	('mutations', 'Var', (41, 50))	('loss', 'NegReg', (101, 105))	('PIK3Ca', 'Gene', '5290', (85, 91))	('reported', 'Reg', (117, 125))	('PIK3Ca', 'Gene', (85, 91))	('PTEN', 'Gene', (96, 100))
163175	31416195	There is a significant increase of p4EBP1 in round-cell LPS compared to the myxoid LPS, which is closely related to activating events, such as PTEN loss, IGF1R expression, or the mutation of PIK3CA.	('LPS', 'Disease', (83, 86))	('PIK3CA', 'Gene', '5290', (191, 197))	('loss', 'NegReg', (148, 152))	('IGF1R', 'Gene', (154, 159))	('LPS', 'Disease', (56, 59))	('mutation', 'Var', (179, 187))	('LPS', 'Disease', 'MESH:C536528', (83, 86))	('increase', 'PosReg', (23, 31))	('LPS', 'Disease', 'MESH:C536528', (56, 59))	('IGF1R', 'Gene', '3480', (154, 159))	('PTEN', 'Gene', (143, 147))	('PIK3CA', 'Gene', (191, 197))	('p4EBP1', 'Gene', (35, 41))
163178	31416195	Interestingly, the molecular analyses of one of these patients identified an inactivating mutation in PTEN.	('PTEN', 'Gene', (102, 106))	('patients', 'Species', '9606', (54, 62))	('inactivating mutation', 'Var', (77, 98))
163181	31416195	This autosomal dominant disease is caused by mutations of the NF1 gene located at chromosome 17q11.2, which encodes the neurofibromin, a protein involved in the regulation of several cellular signaling pathways and responsible for cell proliferation and differentiation.	('caused by', 'Reg', (35, 44))	('mutations', 'Var', (45, 54))	('neurofibromin', 'Gene', (120, 133))	('NF1', 'Gene', (62, 65))	('autosomal dominant disease', 'Disease', (5, 31))	('neurofibromin', 'Gene', '4763', (120, 133))
163185	31416195	Loss of neurofibromin is considered a tumor-promoting event that leads to RAS hyperactivity and the consequent activation of multiple downstream survival and proliferative pathways, including MAPK, mTOR, and Akt.	('activation', 'PosReg', (111, 121))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('RAS hyperactivity', 'Disease', (74, 91))	('RAS hyperactivity', 'Disease', 'MESH:D006948', (74, 91))	('hyperactivity', 'Phenotype', 'HP:0000752', (78, 91))	('neurofibromin', 'Gene', '4763', (8, 21))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('MAPK', 'Pathway', (192, 196))	('mTOR', 'Pathway', (198, 202))	('Akt', 'Pathway', (208, 211))	('Loss', 'Var', (0, 4))	('neurofibromin', 'Gene', (8, 21))
163193	31416195	The concomitant activation of the K-RAS oncogene along with the single allelic deletion of PTEN led to a 100% penetrable development of NF1 lesions and subsequent progression to MPNST in mice.	('activation', 'PosReg', (16, 26))	('K-RAS', 'Gene', '16653', (34, 39))	('K-RAS', 'Gene', (34, 39))	('lesions', 'Var', (140, 147))	('mice', 'Species', '10090', (187, 191))	('NF1', 'Gene', (136, 139))	('PTEN', 'Gene', (91, 95))	('deletion', 'Var', (79, 87))
163195	31416195	However, the effects of mTORC1 inhibitors were cytostatic rather than cytotoxic and were transient with tumor re-growth during and/or after discontinuation of the therapy.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mTORC1', 'Gene', '382056', (24, 30))	('tumor', 'Disease', (104, 109))	('mTORC1', 'Gene', (24, 30))	('inhibitors', 'Var', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
163196	31416195	The reason for this can be explained with the feedback loop by which mTORC1 inhibition promotes the activation of the pro-tumorigenic PI3K/Akt survival pathway.	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mTORC1', 'Gene', '382056', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('inhibition', 'Var', (76, 86))	('activation', 'PosReg', (100, 110))	('tumor', 'Disease', (122, 127))	('mTORC1', 'Gene', (69, 75))
163212	31416195	The high pAkt levels were associated with a poorer disease-specific survival (DSS) outcome, independent of other clinical variables (histological grade, site and depth of the tumor, positive/negative margins, gender and age of patients) and molecular factors (expression of phosphorylated FKHR, phosphorylated ERK1/2, Hepatocyte Growth Factor and C-Met).	('DSS', 'Chemical', '-', (78, 81))	('FKHR', 'Gene', (289, 293))	('C-Met', 'Gene', (347, 352))	('tumor', 'Disease', (175, 180))	('Hepatocyte Growth Factor', 'Gene', (318, 342))	('C-Met', 'Gene', '4233', (347, 352))	('FKHR', 'Gene', '2308', (289, 293))	('ERK1/2', 'Gene', (310, 316))	('pAkt', 'MPA', (9, 13))	('ERK1/2', 'Gene', '5595;5594', (310, 316))	('high', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('poorer', 'NegReg', (44, 50))	('patients', 'Species', '9606', (227, 235))	('Hepatocyte Growth Factor', 'Gene', '3082', (318, 342))	('disease-specific survival', 'MPA', (51, 76))
163213	31416195	In vitro studies have indicated that a combined inhibition of PI3K and mTOR has a strong antiproliferative effect at low nanomolar concentrations because of cell-cycle arrest in the G1 phase and the induction of apoptosis; however, an in vivo model compared with the non-treated tumors did not show any change in cell proliferation and apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('arrest', 'Disease', (168, 174))	('PI3K', 'Var', (62, 66))	('apoptosis', 'CPA', (212, 221))	('arrest', 'Disease', 'MESH:D006323', (168, 174))	('tumors', 'Disease', (279, 285))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('mTOR', 'Gene', (71, 75))	('antiproliferative effect', 'CPA', (89, 113))	('inhibition', 'NegReg', (48, 58))
163214	31416195	The potential role of the deregulation of PI3K/Akt/mTOR in UPS makes this pathway a potential therapeutic target, but each tumor, given their heterogeneity, has to be evaluated as a unique molecular entity.	('deregulation', 'Var', (26, 38))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('PI3K/Akt/mTOR', 'Pathway', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
163218	31416195	These findings encouraged the research to discover additional genetic or epigenetic changes necessary for tumor progression and metastasis.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('epigenetic', 'Var', (73, 83))
163219	31416195	It has been suggested that the biology of the SS18:SSX fusion protein can be altered according to associated genomic alterations, such as p53, H-RAS mutation, MDM2 amplification, and PTEN deregulation.	('H-RAS', 'Gene', (143, 148))	('MDM2', 'Gene', (159, 163))	('SSX', 'Gene', '727837', (51, 54))	('PTEN', 'Gene', (183, 187))	('deregulation', 'Var', (188, 200))	('altered', 'Reg', (77, 84))	('H-RAS', 'Gene', '3265', (143, 148))	('SSX', 'Gene', (51, 54))	('amplification', 'Var', (164, 177))	('mutation', 'Var', (149, 157))	('p53', 'Var', (138, 141))
163221	31416195	PTEN mutation occurs in 7-14% of tumors and PIK3CA is mutated in only a few cases, but immunohistochemical studies have detected a strong expression of pAkt and mTOR.	('PIK3CA', 'Gene', (44, 50))	('PIK3CA', 'Gene', '5290', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('PTEN', 'Gene', (0, 4))	('tumors', 'Disease', (33, 39))	('mutation', 'Var', (5, 13))
163222	31416195	Molecular studies have discovered mutations in catenin beta 1 (CTNNB1) and adenomatous polyposis coli (APC) in 8% and 13% of cases, respectively, providing some support for the oncogenic activation of the Akt-mTOR and WNT signaling pathways.	('CTNNB1', 'Gene', '1499', (63, 69))	('activation', 'PosReg', (187, 197))	('catenin beta 1', 'Gene', '1499', (47, 61))	('CTNNB1', 'Gene', (63, 69))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (75, 101))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (75, 101))	('APC', 'Disease', 'MESH:D011125', (103, 106))	('APC', 'Disease', (103, 106))	('catenin beta 1', 'Gene', (47, 61))	('mutations', 'Var', (34, 43))	('adenomatous polyposis coli', 'Disease', (75, 101))
163223	31416195	It has been observed that PTEN deletion promotes metastasis and angiogenesis in mice bearing conditional expression alleles of SS18-SSX1 or SS18-SSX2.	('SSX', 'Gene', '727837', (145, 148))	('metastasis', 'CPA', (49, 59))	('SSX', 'Gene', (132, 135))	('angiogenesis', 'CPA', (64, 76))	('SSX', 'Gene', '727837', (132, 135))	('deletion', 'Var', (31, 39))	('mice', 'Species', '10090', (80, 84))	('PTEN', 'Gene', (26, 30))	('SSX', 'Gene', (145, 148))	('promotes', 'PosReg', (40, 48))
163227	31416195	The modulation of EGR1 through the histone deacetylase (HDAC) inhibitor and its increase induce PTEN expression and consequent cell death.	('modulation', 'Var', (4, 14))	('EGR1', 'Gene', (18, 22))	('HDAC', 'Gene', (56, 60))	('increase', 'PosReg', (80, 88))	('HDAC', 'Gene', '9734', (56, 60))	('EGR1', 'Gene', '1958', (18, 22))	('histone deacetylase', 'Gene', '9734', (35, 54))	('cell death', 'CPA', (127, 137))	('histone deacetylase', 'Gene', (35, 54))	('PTEN', 'Protein', (96, 100))
163230	31416195	The tyrosine kinase inhibitors (TKIs) target almost 90% of the mutant form of both KIT and PDGFR.	('PDGFR', 'Gene', (91, 96))	('PDGFR', 'Gene', '5159', (91, 96))	('mutant', 'Var', (63, 69))	('KIT', 'Gene', (83, 86))
163236	31416195	Studies have confirmed that the combination of imatinib mesylate and PI3K inhibitors in the treatment of GIST xenograft models was more effective, with a more durable response compared to the use of a single-agent.	('GIST xenograft models', 'Disease', (105, 126))	('inhibitors', 'Var', (74, 84))	('imatinib', 'Chemical', 'MESH:D000068877', (47, 55))	('PI3K', 'Gene', (69, 73))
163238	31416195	From the molecular point of view, this tumor has been shown to have a homozygous SMARCB1 (INI1) deletion in >90% of both the proximal and conventional subtypes, resulting in the complete absence of INI1 protein expression.	('INI1', 'Gene', (198, 202))	('INI1', 'Gene', '6598', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('SMARCB1', 'Gene', '6598', (81, 88))	('absence', 'NegReg', (187, 194))	('SMARCB1', 'Gene', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('deletion', 'Var', (96, 104))	('tumor', 'Disease', (39, 44))	('INI1', 'Gene', '6598', (90, 94))	('INI1', 'Gene', (90, 94))
163251	31416195	The PTEN/PI3K/mTOR pathway is one of the main focuses in cancer discovery because of the frequent dysregulation through the increased expression and/or activation of receptor tyrosine kinases, mutations in pathway components, or loss of negative pathway regulators, such as PTEN.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('PTEN/PI3K/mTOR pathway', 'Pathway', (4, 26))	('activation', 'PosReg', (152, 162))	('cancer', 'Disease', (57, 63))	('increased', 'PosReg', (124, 133))	('dysregulation', 'MPA', (98, 111))	('receptor', 'Protein', (166, 174))	('loss', 'NegReg', (229, 233))	('PTEN', 'Gene', (274, 278))	('mutations', 'Var', (193, 202))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
163256	31416195	Inactivating mutations of PTEN take place in only a fraction of PTEN-deficient tumors.	('Inactivating mutations', 'Var', (0, 22))	('PTEN-deficient tumors', 'Disease', (64, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('PTEN', 'Gene', (26, 30))	('PTEN-deficient tumors', 'Disease', 'MESH:D006223', (64, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
163257	31416195	A recent study suggested that the copy number loss or mutation of PTEN analyzed by DNA sequencing instead of IHC has a better predictive value to establish the patients which can gain some potential benefit from treatment.	('gain', 'PosReg', (179, 183))	('mutation', 'Var', (54, 62))	('patients', 'Species', '9606', (160, 168))	('PTEN', 'Gene', (66, 70))	('copy number loss', 'Var', (34, 50))
163545	32123937	Experimental knock-down of the TET-2 gene improves CAR T cell function and persistence paving the way for a rational design of long-term persistent CAR T cells.	('knock-down', 'Var', (13, 23))	('TET-2', 'Gene', (31, 36))	('TET', 'Chemical', 'MESH:C010349', (31, 34))	('CAR T cell function', 'CPA', (51, 70))	('persistence', 'CPA', (75, 86))	('improves', 'PosReg', (42, 50))
163549	32123937	T cells artificially expressing truncated CD19 stimulated anti-CD19 CAR T cells and improved their persistence and functionality in vivo.	('stimulated', 'PosReg', (47, 57))	('persistence', 'CPA', (99, 110))	('functionality', 'CPA', (115, 128))	('CD19', 'Gene', (63, 67))	('improved', 'PosReg', (84, 92))	('CD19', 'Gene', (42, 46))	('truncated', 'Var', (32, 41))	('CD19', 'Gene', '930', (63, 67))	('CD19', 'Gene', '930', (42, 46))
163564	32123937	Carl H. June pointed out that T cells engineered with the 4-1BB CAR break the blood brain barrier less frequently than CD28 CAR T cells, which may be responsible for the different frequency and severity of neurotoxicity.	('4-1BB', 'Var', (58, 63))	('CD28', 'Gene', (119, 123))	('break', 'Reg', (68, 73))	('neurotoxicity', 'Disease', (206, 219))	('CD28', 'Gene', '940', (119, 123))	('neurotoxicity', 'Disease', 'MESH:D020258', (206, 219))
163573	32123937	In experimental models, inducible transgenic single-chain p40-p35 IL-12 locally deposited by CAR T cells upon CAR signaling attracted and activated innate cells eliminating antigen-negative cancer cells that are invisible to CAR T cells.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('IL-12', 'Gene', (66, 71))	('single-chain p40-p35', 'Var', (45, 65))	('p40-p35', 'Var', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('activated', 'PosReg', (138, 147))
163575	32123937	In experimental systems inducible release of transgenic IL-18 converted effector T cells to T-bethigh FoxO1low cells with improved cytolytic activities and prolonged persistence making the iIL-18 TRUCKs capable to eradicate advanced solid tumors that were not reduced by conventional CAR T cells.	('IL-18', 'Gene', '3606', (56, 61))	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('IL-18', 'Gene', (56, 61))	('IL-18', 'Gene', '3606', (190, 195))	('IL-18', 'Gene', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('FoxO1', 'Gene', (102, 107))	('FoxO1', 'Gene', '2308', (102, 107))	('transgenic', 'Var', (45, 55))	('improved', 'PosReg', (122, 130))
163594	32123937	In line with that Luca Gattinoni (Center for Cancer Research, NCI, NIH, Bethesda, MD, USA) discussed how manipulation of the microRNA-epigenetic regulatory circuitry could be an effective strategy to enhance T cell anti-tumor function.	('manipulation', 'Var', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', (45, 51))	('enhance T cell', 'Phenotype', 'HP:0100828', (200, 214))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('enhance', 'PosReg', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
163598	32123937	Moreover, inhibition of SHIP1 indirectly promotes PRC2 activity through the induction of the PRC2-associated factor PHF19 via AKT signaling, resulting in the epigenetic silencing of programs of senescence and exhaustion.	('AKT', 'Gene', (126, 129))	('PHF19', 'Gene', (116, 121))	('exhaustion', 'CPA', (209, 219))	('promotes', 'PosReg', (41, 49))	('SHIP1', 'Gene', (24, 29))	('programs of senescence', 'MPA', (182, 204))	('SHIP1', 'Gene', '3635', (24, 29))	('epigenetic silencing', 'MPA', (158, 178))	('AKT', 'Gene', '207', (126, 129))	('inhibition', 'Var', (10, 20))	('PRC2', 'CPA', (50, 54))	('PHF19', 'Gene', '26147', (116, 121))
163599	32123937	Finally, PHF19 could be directly harnessed to epigenetically reprogram CD8+ T cell fate and to potentiate T cell-based immunotherapy.	('CD8', 'Gene', '925', (71, 74))	('epigenetically', 'Var', (46, 60))	('T cell-based immunotherapy', 'CPA', (106, 132))	('potentiate', 'PosReg', (95, 105))	('PHF19', 'Gene', '26147', (9, 14))	('PHF19', 'Gene', (9, 14))	('CD8', 'Gene', (71, 74))
163613	32123937	In cancer patients Treg cell depletion may be beneficial; in addition to current Treg cell depletion strategies Dr Sakaguchi suggested depleting antibodies against CCR4 as an effective way to eliminate effector Treg cells.	('CCR4', 'Gene', (164, 168))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('depleting antibodies', 'Var', (135, 155))	('CCR4', 'Gene', '1233', (164, 168))	('patients', 'Species', '9606', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
163625	32123937	Research in this direction was presented by Megan K. Levings (BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada) reporting data on the modification of host-derived Treg cells with CARs directed against HLA class I mismatches for the induction of tolerance in HLA-mismatched solid organ transplantation.	('Children', 'Species', '9606', (65, 73))	('British Columbia', 'Disease', (119, 135))	('CARs', 'Gene', '833', (227, 231))	('modification', 'Var', (182, 194))	('British Columbia', 'Disease', 'OMIM:176500', (119, 135))	('CARs', 'Gene', (227, 231))
163647	32123937	The here described advances in T cell engineering, genetic editing, the selection of optimal lymphocyte subsets, and cell manufacturing have the potential to broaden immune cell-based therapies and foster new applications far beyond oncology, in particular for the treatment of infectious diseases, organ transplant rejection, and autoimmunity.	('autoimmunity', 'Phenotype', 'HP:0002960', (331, 343))	('genetic editing', 'Var', (51, 66))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('infectious diseases', 'Disease', 'MESH:D003141', (278, 297))	('immune cell-based therapies', 'CPA', (166, 193))	('oncology', 'Phenotype', 'HP:0002664', (233, 241))	('infectious diseases', 'Disease', (278, 297))	('broaden', 'PosReg', (158, 165))
163714	30116384	Fibroblast growth factor receptor (FGFR) 4 (c.1162G> A) and HRas proto-oncogene (HRAS; c.182A> G) mutations were also detected.	('c.182A> G', 'Mutation', 'rs121913233', (87, 96))	('HRAS', 'Gene', (81, 85))	('c.1162G> A', 'Mutation', 'rs1158457075', (44, 54))	('c.1162G> A', 'Var', (44, 54))	('HRAS', 'Gene', '3265', (81, 85))	('FGFR) 4', 'Gene', (35, 42))	('HRas', 'Gene', '3265', (60, 64))	('HRas', 'Gene', (60, 64))
163716	30116384	FGFR3 (c.1948A> G) and FGFR4 (c.1162G> A) mutations were found in the CTCs.	('FGFR3', 'Gene', (0, 5))	('c.1948A> G', 'Mutation', 'rs78311289', (7, 17))	('FGFR4', 'Gene', '2264', (23, 28))	('c.1162G> A', 'Var', (30, 40))	('FGFR4', 'Gene', (23, 28))	('c.1162G> A', 'Mutation', 'rs1158457075', (30, 40))	('c.1948A> G', 'Var', (7, 17))	('FGFR3', 'Gene', '2261', (0, 5))
163717	30116384	FGFR4 (c.1162G> A) and HRAS (c.182A> G) mutations were confirmed in cell-free circulating tumor DNA.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('c.182A> G', 'Mutation', 'rs121913233', (29, 38))	('HRAS', 'Gene', '3265', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('HRAS', 'Gene', (23, 27))	('FGFR4', 'Gene', '2264', (0, 5))	('FGFR4', 'Gene', (0, 5))	('c.182A> G', 'Var', (29, 38))	('c.1162G> A', 'Mutation', 'rs1158457075', (7, 17))	('c.1162G> A', 'Var', (7, 17))
163719	30116384	To the best of our knowledge, this is the first report of skeletal Ewing sarcoma being detected using multiple noninvasive diagnostic methods to observe genetic translocation and mutation in blood CTCs.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('mutation', 'Var', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('genetic translocation', 'Var', (153, 174))	('skeletal Ewing sarcoma', 'Disease', 'MESH:C563168', (58, 80))	('skeletal Ewing sarcoma', 'Disease', (58, 80))
163730	30116384	Molecular genetic testing has revealed that most Ewing sarcoma cases have chromosomes 11 and 22 dislocations involving fusion of EWS gene on chromosome 22 and FLI1 gene on 11.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('fusion', 'Var', (119, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('FLI1', 'Gene', (159, 163))	('FLI1', 'Gene', '2313', (159, 163))	('EWS', 'Gene', '2130', (129, 132))	('EWS', 'Gene', (129, 132))	('Ewing sarcoma', 'Disease', (49, 62))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))
163734	30116384	CTC and cfDNA carry mutations in tissues of primary carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('primary carcinomas', 'Disease', 'MESH:D002277', (44, 62))	('primary carcinomas', 'Disease', (44, 62))	('mutations', 'Var', (20, 29))
163750	30116384	Molecular genetic testing confirmed the fusion of EWS gene on chromosome 22 and FLI1 gene on chromosome 11, a EWS-FLI1 translocation (Fig.	('fusion', 'Var', (40, 46))	('EWS', 'Gene', '2130', (110, 113))	('EWS', 'Gene', (110, 113))	('FLI1', 'Gene', (80, 84))	('FLI1', 'Gene', '2313', (80, 84))	('FLI1', 'Gene', '2313', (114, 118))	('EWS', 'Gene', '2130', (50, 53))	('EWS', 'Gene', (50, 53))	('FLI1', 'Gene', (114, 118))
163775	30116384	Mutations of FGFR4 (c.1162G> a; p.G388A) and HRAS (c.182A> G; p.Q61R) were detected in DNA extracted from FFPE.	('HRAS', 'Gene', (45, 49))	('HRAS', 'Gene', '3265', (45, 49))	('p.G388A', 'Mutation', 'rs1158457075', (32, 39))	('c.182A> G', 'Mutation', 'rs121913233', (51, 60))	('c.1162G> a;', 'Var', (20, 31))	('p.Q61R', 'Mutation', 'rs121913233', (62, 68))	('c.1162G> a', 'Mutation', 'rs1158457075', (20, 30))	('FGFR4', 'Gene', '2264', (13, 18))	('c.182A> G;', 'Var', (51, 61))	('FGFR4', 'Gene', (13, 18))
163776	30116384	In DNA extracted from CTC, FGFR3 (c.1948A> G; p.K650E) and the same FGFR4 (c.1162G> A; p.G388A) mutation were detected in FFPE DNA.	('p.K650E', 'Var', (46, 53))	('p.K650E', 'Mutation', 'rs78311289', (46, 53))	('FGFR3', 'Gene', '2261', (27, 32))	('c.1948A> G', 'Mutation', 'rs78311289', (34, 44))	('FGFR3', 'Gene', (27, 32))	('c.1162G> A', 'Mutation', 'rs1158457075', (75, 85))	('c.1162G> A; p.G388A', 'Var', (75, 94))	('FGFR4', 'Gene', '2264', (68, 73))	('FGFR4', 'Gene', (68, 73))	('c.1948A> G; p.K650E', 'Var', (34, 53))	('p.G388A', 'Mutation', 'rs1158457075', (87, 94))
163777	30116384	Therefore, the FGFR4 genetic mutation was identified as a germ line mutation.	('mutation', 'Var', (29, 37))	('FGFR4', 'Gene', '2264', (15, 20))	('FGFR4', 'Gene', (15, 20))
163778	30116384	In addition, FGFR3 (c.1948A> G; p.K650E), FGFR4 (c.1162G> A; p.G388A) and HRAS (c.182A> G; p.Q61R) mutations in FFPE DNA and CTC DNA, were also detected in cfDNA (Table III).	('FGFR4', 'Gene', (42, 47))	('FFPE', 'Gene', (112, 116))	('c.1162G> A', 'Mutation', 'rs1158457075', (49, 59))	('c.1162G> A', 'Var', (49, 59))	('p.Q61R', 'Var', (91, 97))	('c.182A> G', 'Mutation', 'rs121913233', (80, 89))	('FGFR3', 'Gene', (13, 18))	('p.G388A', 'Mutation', 'rs1158457075', (61, 68))	('c.1948A> G', 'Mutation', 'rs78311289', (20, 30))	('HRAS', 'Gene', '3265', (74, 78))	('p.Q61R', 'Mutation', 'rs121913233', (91, 97))	('p.K650E', 'Mutation', 'rs78311289', (32, 39))	('HRAS', 'Gene', (74, 78))	('c.1948A> G', 'Var', (20, 30))	('FGFR3', 'Gene', '2261', (13, 18))	('detected', 'Reg', (144, 152))	('FGFR4', 'Gene', '2264', (42, 47))	('cfDNA', 'Disease', (156, 161))
163779	30116384	On the other hand, BRAF (c.1799T> A; p.V600E), CDKN2A (c.1_471del471), or TP53 (c.354_355insCA) mutations were not identified in Ewing sarcoma A673 cells.	('Ewing sarcoma', 'Disease', (129, 142))	('BRAF', 'Gene', '673', (19, 23))	('p.V600E', 'Mutation', 'rs113488022', (37, 44))	('c.1_471del471', 'Mutation', 'c.1_471del471', (55, 68))	('c.1_471del471', 'Var', (55, 68))	('BRAF', 'Gene', (19, 23))	('CDKN2A', 'Gene', (47, 53))	('c.1799T> A', 'Mutation', 'rs113488022', (25, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (129, 142))	('c.354_355insCA', 'Mutation', 'c.354_355insCA', (80, 94))	('p.V600E', 'Var', (37, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (129, 142))	('c.354_355insCA', 'Var', (80, 94))	('c.1799T> A; p.V600E', 'Var', (25, 44))	('TP53', 'Gene', '7157', (74, 78))	('CDKN2A', 'Gene', '1029', (47, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('TP53', 'Gene', (74, 78))
163780	30116384	The CTNNB1 (c.133_135delTCT; p.S45del) or NRAS (c.181C> A; p.Q61K) mutation identified in oncogene mutation profiling of Ewing sarcoma patients reported by Shukla et al, was not identified in Ewing sarcoma A673 cells either.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (121, 134))	('patients', 'Species', '9606', (135, 143))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (192, 205))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (192, 205))	('NRAS', 'Gene', (42, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('p.Q61K', 'Mutation', 'rs121913254', (59, 65))	('c.133_135delTCT', 'Mutation', 'rs587776850', (12, 27))	('CTNNB1', 'Gene', (4, 10))	('Ewing sarcoma', 'Disease', (121, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('p.S45del', 'Mutation', 'rs587776850', (29, 37))	('Ewing sarcoma', 'Disease', (192, 205))	('c.133_135delTCT', 'Var', (12, 27))	('NRAS', 'Gene', '4893', (42, 46))	('c.181C> A; p.Q61K', 'Var', (48, 65))	('c.181C> A', 'Mutation', 'rs121913254', (48, 57))	('CTNNB1', 'Gene', '1499', (4, 10))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (121, 134))
163789	30116384	Chromosomal translocation has been observed in about 90% of Ewing sarcoma cases.	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('Chromosomal translocation', 'Var', (0, 25))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (60, 73))	('observed', 'Reg', (35, 43))	('Ewing sarcoma', 'Disease', (60, 73))
163793	30116384	Fusion of EWS with chromosome 11q24 FLI1 gene, resulted in EWS gene translocation.	('EWS', 'Gene', (59, 62))	('Fusion', 'Var', (0, 6))	('resulted in', 'Reg', (47, 58))	('FLI1', 'Gene', '2313', (36, 40))	('FLI1', 'Gene', (36, 40))	('EWS', 'Gene', '2130', (10, 13))	('EWS', 'Gene', (10, 13))	('EWS', 'Gene', '2130', (59, 62))
163806	30116384	However, we identified a pathogenic somatic mutation in the patient's blood that closely resembled the genetic variation of CTC and cfDNA in primary cancers because CTCs occur in the pathway of tumor cells (originating from primary cancer tissues into the blood).	('patient', 'Species', '9606', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (149, 155))	('mutation', 'Var', (44, 52))	('primary cancers', 'Disease', (141, 156))	('cancer', 'Disease', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('primary cancers', 'Disease', 'MESH:D009369', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', (194, 199))	('pathogenic', 'Reg', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
163807	30116384	However, Ewing sarcoma-specific EWS-FLI1 translocation might be associated with a favorable prognosis following treatment.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (9, 22))	('translocation', 'Var', (41, 54))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (9, 22))	('men', 'Species', '9606', (117, 120))	('EWS', 'Gene', '2130', (32, 35))	('EWS', 'Gene', (32, 35))	('FLI1', 'Gene', '2313', (36, 40))	('FLI1', 'Gene', (36, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('Ewing sarcoma', 'Disease', (9, 22))
163839	29398899	The medical record numbers for these cases were identified through the Ottawa Hospital Data Warehouse, according to the International Classification of Diseases (ICD 10-CA) codes for Malignant Neoplasm of Cervix Uteri, Corpus Uteri, and Uterus Unspecified (C54*, C55*, and C53*) and Diagnosis type 4 (Morphology) codes for Sarcoma or Leiomyosarcoma (88903, 88913, and 88963), Mullerian Tumor/Carcinosarcoma (89503, 89803, and 89813), Endometrial Stromal Sarcoma (89303), Sarcoma Uterus Not Otherwise Specified (88003), and Adenosarcoma (89333).	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (334, 348))	('89303', 'Var', (463, 468))	('88913', 'Var', (357, 362))	('Sarcoma', 'Phenotype', 'HP:0100242', (454, 461))	('C55*', 'SUBSTITUTION', 'None', (263, 267))	('Mullerian Tumor/Carcinosarcoma', 'Disease', (376, 406))	('Malignant Neoplasm', 'Disease', (183, 201))	('Neoplasm', 'Phenotype', 'HP:0002664', (193, 201))	('89813', 'Var', (426, 431))	('Sarcoma Uterus', 'Disease', (471, 485))	('Sarcoma Uterus', 'Disease', 'MESH:D014594', (471, 485))	('C53*', 'Var', (273, 277))	('Adenosarcoma', 'Disease', 'MESH:D018195', (523, 535))	('Unspecified', 'Species', '32644', (244, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (341, 348))	('89503', 'Var', (408, 413))	('89803', 'Var', (415, 420))	('88963', 'Var', (368, 373))	('89333', 'Var', (537, 542))	('C53*', 'SUBSTITUTION', 'None', (273, 277))	('C54*', 'SUBSTITUTION', 'None', (257, 261))	('Adenosarcoma', 'Disease', (523, 535))	('Sarcoma', 'Phenotype', 'HP:0100242', (323, 330))	('ICD', 'Disease', (162, 165))	('C54*', 'Var', (257, 261))	('Malignant Neoplasm', 'Disease', 'MESH:D009369', (183, 201))	('C55*', 'Var', (263, 267))	('88003', 'Var', (511, 516))	('Endometrial Stromal Sarcoma', 'Disease', (434, 461))	('Endometrial Stromal Sarcoma', 'Disease', 'MESH:D018203', (434, 461))	('Tumor', 'Phenotype', 'HP:0002664', (386, 391))	('88903', 'Var', (350, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (528, 535))	('Sarcoma', 'Phenotype', 'HP:0100242', (471, 478))	('ICD', 'Disease', 'OMIM:252500', (162, 165))	('Sarcoma or Leiomyosarcoma', 'Disease', (323, 348))	('Mullerian Tumor/Carcinosarcoma', 'Disease', 'MESH:D002296', (376, 406))	('Sarcoma or Leiomyosarcoma', 'Disease', 'MESH:D007890', (323, 348))	('Cervix Uteri', 'Phenotype', 'HP:0000139', (205, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (399, 406))
163840	29398899	Fibroid cases were identified with ICD10-CA codes (D25*).	('ICD', 'Disease', (35, 38))	('D25*', 'SUBSTITUTION', 'None', (51, 55))	('Fibroid', 'Disease', (0, 7))	('ICD', 'Disease', 'OMIM:252500', (35, 38))	('D25*', 'Var', (51, 55))
163930	32780509	The four snoRNAs are: U3 (ENSG00000200693), SNORA73B (ENSG00000200087), SNORD46 (ENSG00000200913), and SNORA26 (ENSG00000212588).	('SNORA26', 'Gene', (103, 110))	('SNORA26', 'Gene', '677810', (103, 110))	('ENSG00000200913', 'Var', (81, 96))	('SNORD46', 'Gene', '94161', (72, 79))	('SNORA73B', 'Gene', '26768', (44, 52))	('ENSG00000212588', 'Var', (112, 127))	('ENSG00000200087', 'Var', (54, 69))	('SNORA73B', 'Gene', (44, 52))	('SNORD46', 'Gene', (72, 79))	('ENSG00000200693', 'Var', (26, 41))	('snoRNA', 'Gene', (9, 15))	('snoRNA', 'Gene', '85391', (9, 15))
163931	32780509	The calculation formula of risk score is as follows: risk score = ExpU3 x (-0.1803) + ExpSNORA73B x 0.1826 + ExpSNORD46 x 0.2846 + ExpSNORA26 x 0.1613.	('ExpU3 x', 'Var', (66, 73))	('SNORA73B', 'Gene', (89, 97))	('SNORA73B', 'Gene', '26768', (89, 97))	('SNORD46', 'Gene', (112, 119))	('SNORA26', 'Gene', (134, 141))	('SNORA26', 'Gene', '677810', (134, 141))	('SNORD46', 'Gene', '94161', (112, 119))
163950	32780509	Using the c2 reference gene set as a control gene set for GSEA analysis, we found that high risk score phenotype can be enriched in Myc, Wnt, SMAD2, SMAD3 nuclear, RB1, E2F, and TEL pathways, as well as transcriptional activity of SMAD2, SMAD3, SMAD4 heterotrimer, fibroblast growth factor receptor 2 (FGFR2) alternative splicing, cancer meta signature, hypoxia, BRCA1 targets, and hematopoiesis signal transducer and activator of transcription 3 (STAT3) targets (Figure 11A-L; Table S12).	('SMAD4', 'Gene', (245, 250))	('SMAD2', 'Gene', '4087', (231, 236))	('RB1', 'Gene', (164, 167))	('GSEA', 'Chemical', '-', (58, 62))	('signal transducer and activator of transcription 3', 'Gene', '6774', (396, 446))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('SMAD2', 'Gene', '4087', (142, 147))	('SMAD2', 'Gene', (231, 236))	('SMAD3', 'Gene', '4088', (238, 243))	('SMAD4', 'Gene', '4089', (245, 250))	('Myc', 'Gene', (132, 135))	('TEL', 'Gene', (178, 181))	('hematopoiesis', 'Disease', 'MESH:C536227', (382, 395))	('RB1', 'Gene', '5925', (164, 167))	('FGFR2', 'Gene', (302, 307))	('hematopoiesis', 'Disease', (382, 395))	('SMAD2', 'Gene', (142, 147))	('STAT3', 'Gene', (448, 453))	('SMAD3', 'Gene', '4088', (149, 154))	('BRCA1', 'Gene', '672', (363, 368))	('alternative splicing', 'Var', (309, 329))	('hypoxia', 'Disease', (354, 361))	('SMAD3', 'Gene', (238, 243))	('BRCA1', 'Gene', (363, 368))	('TEL', 'Gene', '2120', (178, 181))	('cancer', 'Disease', (331, 337))	('FGFR2', 'Gene', '2263', (302, 307))	('STAT3', 'Gene', '6774', (448, 453))	('Myc', 'Gene', '4609', (132, 135))	('fibroblast growth factor receptor 2', 'Gene', '2263', (265, 300))	('fibroblast growth factor receptor 2', 'Gene', (265, 300))	('hypoxia', 'Disease', 'MESH:D000860', (354, 361))	('SMAD3', 'Gene', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
163951	32780509	GSEA analysis using c5 reference gene set suggests that high risk score phenotype can be enriched in cell cycle-related biological processes, RNA splicing, protein SUMOylation, DNA replication, p53 binding, alternative mRNA splicing via spliceosome, protein k63 linked ubiquitination, regulation of DNA repair, and DNA methylation (Figure 12A-P; Table S13).	('alternative mRNA splicing', 'Var', (207, 232))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('cell cycle-related', 'CPA', (101, 119))	('protein', 'Protein', (250, 257))	('binding', 'Interaction', (198, 205))	('GSEA', 'Chemical', '-', (0, 4))
163971	32780509	31  Our previous study also reported that long noncoding RNA plasmacytoma variant translocation 1 can function in sarcoma through Wnt signaling pathway.	('plasmacytoma', 'Disease', (61, 73))	('Wnt signaling pathway', 'Pathway', (130, 151))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('plasmacytoma', 'Disease', 'MESH:D010954', (61, 73))	('sarcoma', 'Disease', (114, 121))	('plasmacytoma', 'Phenotype', 'HP:0011857', (61, 73))	('translocation 1', 'Gene', (82, 97))	('variant', 'Var', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('function', 'Reg', (102, 110))
163983	32780509	43  Cote et al through next-generation sequencing of sarcoma found that most common mutations of sarcomas were in the cell cycle, including RB1 mutations.	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('RB1', 'Gene', '5925', (140, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Disease', (53, 60))	('mutations', 'Var', (84, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Disease', (97, 105))	('mutations', 'Var', (144, 153))	('RB1', 'Gene', (140, 143))
163984	32780509	44  Liu et al study proved that Rb1 family mutation is sufficient for sarcoma initiation.	('sarcoma initiation', 'Disease', 'MESH:D012509', (70, 88))	('Rb1', 'Gene', (32, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('mutation', 'Var', (43, 51))	('Rb1', 'Gene', '5925', (32, 35))	('sarcoma initiation', 'Disease', (70, 88))
163985	32780509	45  Cheng et al reported that copy number variation signature of Myc can be used as chemotherapy-response biomarkers in pediatric sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('Myc', 'Gene', '4609', (65, 68))	('copy number variation', 'Var', (30, 51))	('Myc', 'Gene', (65, 68))	('sarcoma', 'Disease', (130, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
163987	32780509	47  At the same time, the phosphorylation of STAT3 is significantly associated with the prognosis of undifferentiated pleomorphic sarcoma.	('associated with', 'Reg', (68, 83))	('STAT3', 'Gene', (45, 50))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (101, 137))	('undifferentiated pleomorphic sarcoma', 'Disease', (101, 137))	('phosphorylation', 'Var', (26, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('STAT3', 'Gene', '6774', (45, 50))
163990	32780509	In previous studies, pizotifen has been reported to be closely associated with cancers, and can be used as an anticancer drug.	('pizotifen', 'Var', (21, 30))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', (79, 86))	('pizotifen', 'Chemical', 'MESH:D010918', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('associated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('cancer', 'Disease', (114, 120))
163991	32780509	Pizotifen can significantly inhibit colon and gastric cancer cell malignant phenotype via suppressing Wnt signaling pathway.	('colon', 'Disease', (36, 41))	('Wnt signaling pathway', 'Pathway', (102, 123))	('gastric cancer cell malignant', 'Disease', (46, 75))	('Pizotifen', 'Chemical', 'MESH:D010918', (0, 9))	('gastric cancer cell malignant', 'Disease', 'MESH:D013274', (46, 75))	('suppressing', 'NegReg', (90, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('Pizotifen', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('inhibit', 'NegReg', (28, 35))
163999	32780509	In this study, we identified 15 snoRNAs that were markedly related to the prognosis of sarcoma using the RNA-seq dataset of the TCGA sarcoma cohort, and constructed a prognostic signature based on four prognostic snoRNA expression values (U3, SNORA73B, SNORD46, and SNORA26).	('snoRNA', 'Gene', (32, 38))	('sarcoma', 'Disease', (87, 94))	('SNORD46', 'Gene', (253, 260))	('SNORA26', 'Gene', (266, 273))	('SNORD46', 'Gene', '94161', (253, 260))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('SNORA26', 'Gene', '677810', (266, 273))	('snoRNA', 'Gene', '85391', (213, 219))	('snoRNA', 'Gene', (213, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('U3', 'Var', (239, 241))	('SNORA73B', 'Gene', (243, 251))	('related', 'Reg', (59, 66))	('sarcoma', 'Disease', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('SNORA73B', 'Gene', '26768', (243, 251))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))	('snoRNA', 'Gene', '85391', (32, 38))
164033	31893311	Many studies have verified Ephs and Ephrins, aberrantly expressed in tumors which can drastically affect malignancy including progression, metastatic spread, and patient survival.	('aberrantly', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Ephrins', 'Protein', (36, 43))	('metastatic spread', 'CPA', (139, 156))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('progression', 'CPA', (126, 137))	('Ephs', 'Protein', (27, 31))	('malignancy', 'Disease', (105, 115))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('patient', 'Species', '9606', (162, 169))	('affect', 'Reg', (98, 104))
164038	31893311	Some mutations of Eph receptors are predicted to play a vital role in cancer progression.	('Eph receptors', 'Protein', (18, 31))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (5, 14))	('play', 'Reg', (49, 53))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
164039	31893311	For example, EphB2 mutations have been identified in human gastric, colorectal, and prostate tumors, some of which can impair kinase function.	('prostate tumors', 'Disease', (84, 99))	('impair', 'NegReg', (119, 125))	('kinase function', 'MPA', (126, 141))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('gastric', 'Disease', (59, 66))	('EphB2', 'Gene', '2048', (13, 18))	('colorectal', 'Disease', 'MESH:D015179', (68, 78))	('mutations', 'Var', (19, 28))	('EphB2', 'Gene', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('identified', 'Reg', (39, 49))	('colorectal', 'Disease', (68, 78))	('prostate tumors', 'Disease', 'MESH:D011471', (84, 99))	('human', 'Species', '9606', (53, 58))
164048	31893311	EBV infects B cells requiring interaction between its glycoproteins gp350 or splicing mutant gp220 and the cell surface receptor CD21, and interaction of viral glycoproteins gp42 with MHC II.	('gp220', 'Var', (93, 98))	('CD21', 'Gene', '1380', (129, 133))	('interaction', 'Interaction', (139, 150))	('CD21', 'Gene', (129, 133))	('interaction', 'Interaction', (30, 41))	('EBV', 'Species', '10376', (0, 3))	('infects', 'Reg', (4, 11))
164051	31893311	have shown that the interaction of glycoprotein gH/gL with three epithelial integrin receptors (alphavbeta5, alphavbeta6, alphavbeta8) is associated with EBV entry into epithelial cells.	('interaction', 'Interaction', (20, 31))	('alphavbeta8', 'Var', (122, 133))	('glycoprotein gH/gL with three epithelial integrin receptors (alphavbeta5, alphavbeta6', 'Gene', 'None', (35, 120))	('associated with', 'Reg', (138, 153))	('EBV', 'Species', '10376', (154, 157))	('EBV entry', 'Disease', (154, 163))
164057	31893311	Moreover, they show that the integrin receptors alphavbeta5, alphavbeta6, and alphavbeta8 have no effect on the entry of EBV into epithelial cells, which is distinct from the findings of Chesnokova et al..	('entry of EBV into epithelial cells', 'MPA', (112, 146))	('integrin receptors alphavbeta5, alphavbeta6', 'Gene', 'None', (29, 72))	('EBV', 'Species', '10376', (121, 124))	('alphavbeta8', 'Var', (78, 89))
164105	31893311	Therefore, inhibition of EphA2 may be a new strategy for preventing and counteracting HCV infection.	('HCV infection', 'Disease', (86, 99))	('EphA2', 'Gene', (25, 30))	('HCV infection', 'Disease', 'MESH:D006526', (86, 99))	('EphA2', 'Gene', '1969', (25, 30))	('inhibition', 'Var', (11, 21))
164298	29659611	To minimize adverse events, the following exclusion criteria were used: (1) age, 15-70 years, (2) white blood cell count, >3 x 106/mL, (3) platelet count, >7.5 x 107/mL, (4) hemoglobin, >70 g/L, (5) creatinine clearance, >60 mL/min, (6) normal hepatic function, and (7) ejection fraction, >60%.	('creatinine', 'Chemical', 'MESH:D003404', (199, 209))	('creatinine clearance', 'MPA', (199, 219))	('>70 g/L', 'Var', (186, 193))	('ejection fraction', 'MPA', (270, 287))	('hepatic function', 'MPA', (244, 260))
164373	29659611	Recently, it was shown that the expression of chemokines and HSP-1 increased the immunological responses after hyperthermia.	('HSP-1', 'Gene', (61, 66))	('expression', 'Var', (32, 42))	('hyperthermia', 'Phenotype', 'HP:0001945', (111, 123))	('hyperthermia', 'Disease', (111, 123))	('increased', 'PosReg', (67, 76))	('HSP-1', 'Gene', '6856', (61, 66))	('hyperthermia', 'Disease', 'MESH:D005334', (111, 123))	('immunological responses', 'CPA', (81, 104))
164380	28469328	Overall survival (OS), the primary end point, was significantly better in patients assigned to eribulin (n = 228) compared with those assigned to dacarbazine (n = 224) (median 13 5 months vs. 11 5 months; hazard ratio 0.77 [95% confidence interval (CI): 0.62-0.95]; P = 0.0169).	('eribulin', 'Chemical', 'MESH:C490954', (95, 103))	('better', 'PosReg', (64, 70))	('patients', 'Species', '9606', (74, 82))	('OS', 'Chemical', '-', (18, 20))	('Overall survival', 'MPA', (0, 16))	('dacarbazine', 'Chemical', 'MESH:D003606', (146, 157))	('eribulin', 'Var', (95, 103))
164392	22084170	MK1775, A Selective Wee1 Inhibitor, Shows Single-Agent Antitumor Activity Against Sarcoma Cells Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2.	('Wee1', 'Gene', (20, 24))	('Wee1', 'Gene', (96, 100))	('MK1775', 'Var', (0, 6))	('Wee1', 'Gene', '7465', (20, 24))	('Sarcoma', 'Disease', (82, 89))	('Wee1', 'Gene', '7465', (96, 100))	('Sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('phosphorylation', 'MPA', (216, 231))	('cell cycle', 'CPA', (180, 190))	('CDC2', 'Gene', '983', (235, 239))	('Sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (180, 197))	('CDC2', 'Gene', (235, 239))	('regulating', 'Reg', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('MK1775', 'Chemical', 'MESH:C549567', (0, 6))
164393	22084170	Inhibition of Wee1 by a selective small molecule inhibitor MK1775 can abrogate G2/M checkpoint resulting in premature mitotic entry and cell death.	('Wee1', 'Gene', (14, 18))	('MK1775', 'Chemical', 'MESH:C549567', (59, 65))	('abrogate', 'NegReg', (70, 78))	('cell death', 'CPA', (136, 146))	('G2/M checkpoint', 'Pathway', (79, 94))	('Inhibition', 'NegReg', (0, 10))	('premature mitotic entry', 'CPA', (108, 131))	('MK1775', 'Var', (59, 65))
164394	22084170	MK1775 has recently been tested in preclinical and clinical studies of human carcinoma to enhance the cytotoxic effect of DNA damaging agents.	('MK1775', 'Var', (0, 6))	('cytotoxic effect', 'CPA', (102, 118))	('enhance', 'PosReg', (90, 97))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinoma', 'Disease', (77, 86))	('human', 'Species', '9606', (71, 76))	('MK1775', 'Chemical', 'MESH:C549567', (0, 6))
164396	22084170	Here we studied the cytotoxic effect of MK1775 in various sarcoma cell lines and patient-derived tumor explants ex vivo.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('patient', 'Species', '9606', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('tumor', 'Disease', (97, 102))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('MK1775', 'Chemical', 'MESH:C549567', (40, 46))	('sarcoma', 'Disease', (58, 65))	('MK1775', 'Var', (40, 46))
164398	22084170	In MK1775 treated cells CDC2 activity was enhanced, as determined by decreased inhibitory phosphorylation of tyrosine-15 residue and increased expression of phosphorylated histone H3, a marker of mitotic entry.	('inhibitory phosphorylation of tyrosine-15 residue', 'MPA', (79, 128))	('MK1775', 'Var', (3, 9))	('CDC2', 'Gene', (24, 28))	('expression', 'MPA', (143, 153))	('CDC2', 'Gene', '983', (24, 28))	('decreased', 'NegReg', (69, 78))	('enhanced', 'PosReg', (42, 50))	('tyrosine', 'Chemical', 'MESH:D014443', (109, 117))	('activity', 'MPA', (29, 37))	('histone H3', 'Protein', (172, 182))	('increased', 'PosReg', (133, 142))	('MK1775', 'Chemical', 'MESH:C549567', (3, 9))
164399	22084170	The cytotoxic effect of Wee1 inhibition on sarcoma cells appears to be independent of p53 status as all sarcoma cell lines with different p53 mutation were highly sensitive to MK1775 treatment.	('p53', 'Gene', (138, 141))	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('p53', 'Gene', '7157', (86, 89))	('MK1775', 'Chemical', 'MESH:C549567', (176, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('p53', 'Gene', '7157', (138, 141))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('mutation', 'Var', (142, 150))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('p53', 'Gene', (86, 89))
164400	22084170	Finally, in patient-derived sarcoma samples we showed that MK1775 as a single agent causes significant apoptotic cell death suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas.	('MK1775', 'Chemical', 'MESH:C549567', (59, 65))	('sarcoma', 'Disease', (28, 35))	('sarcoma', 'Disease', 'MESH:D012509', (207, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('sarcomas', 'Disease', 'MESH:D012509', (207, 215))	('MK1775', 'Var', (59, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (207, 215))	('sarcoma', 'Disease', (207, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('sarcomas', 'Disease', (207, 215))	('patient', 'Species', '9606', (12, 19))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))	('apoptotic cell death', 'CPA', (103, 123))
164411	22084170	The inhibitory phosphorylation on Tyr15 maintains the CDC2-Cyclin B complex in an inactive state if there is incompletely replicated DNA or damaged DNA in the cell.	('CDC2', 'Gene', '983', (54, 58))	('Cyclin', 'Gene', (59, 65))	('Tyr15', 'Chemical', '-', (34, 39))	('Tyr15', 'Var', (34, 39))	('CDC2', 'Gene', (54, 58))	('Cyclin', 'Gene', '34924', (59, 65))
164414	22084170	In response to DNA damage, Wee1 causes inactivation of CDC2 and consequently leads to G2 arrest that gives tumor cells survival advantage by allowing time to repair their damaged DNA.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('Wee1', 'Var', (27, 31))	('CDC2', 'Gene', '983', (55, 59))	('CDC2', 'Gene', (55, 59))	('inactivation', 'NegReg', (39, 51))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('leads to', 'Reg', (77, 85))
164415	22084170	Inhibition of Wee1 has been shown to abrogate the G2/M checkpoint forcing cancer cells with DNA damage to enter into unscheduled mitosis to undergo cell death, often referred to as mitotic catastrophe.	('Wee1', 'Gene', (14, 18))	('cell death', 'CPA', (148, 158))	('abrogate', 'NegReg', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mitosis', 'Disease', (129, 136))	('cancer', 'Disease', (74, 80))	('mitosis', 'Disease', 'None', (129, 136))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('G2/M checkpoint', 'MPA', (50, 65))
164417	22084170	These studies showed that MK1775 is particularly effective in p53-defective cancer cells.	('MK1775', 'Chemical', 'MESH:C549567', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('MK1775', 'Var', (26, 32))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
164418	22084170	Here we demonstrate that Wee1 inhibition by MK1775 results in activation of CDC2, as assessed by decreased Tyr15 phosphorylation, unscheduled mitotic entry and significant cell death in sarcoma cell lines as well as in patient-derived sarcoma tumors.	('sarcoma tumors', 'Disease', (235, 249))	('decreased', 'NegReg', (97, 106))	('Wee1', 'Gene', (25, 29))	('Tyr15', 'Chemical', '-', (107, 112))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('inhibition', 'NegReg', (30, 40))	('sarcoma', 'Disease', (235, 242))	('CDC2', 'Gene', (76, 80))	('CDC2', 'Gene', '983', (76, 80))	('Tyr15 phosphorylation', 'MPA', (107, 128))	('MK1775', 'Var', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('patient', 'Species', '9606', (219, 226))	('sarcoma', 'Disease', (186, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('activation', 'PosReg', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('cell death', 'CPA', (172, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('MK1775', 'Chemical', 'MESH:C549567', (44, 50))	('sarcoma tumors', 'Disease', 'MESH:D012509', (235, 249))
164419	22084170	Our data demonstrate that MK1775 shows its cytotoxic effect in sarcoma cells as a single agent in a p53 independent manner and represents a promising therapeutic agent in treatment of sarcoma.	('cytotoxic effect', 'CPA', (43, 59))	('sarcoma', 'Disease', 'MESH:D012509', (184, 191))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('MK1775', 'Chemical', 'MESH:C549567', (26, 32))	('sarcoma', 'Disease', (184, 191))	('p53', 'Gene', '7157', (100, 103))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('MK1775', 'Var', (26, 32))	('p53', 'Gene', (100, 103))
164426	22084170	Rabbit gammaH2AX, total CDC2, CDC2 Y15P and total poly(ADP-ribose) polymerase (tPARP) antibodies were purchased from Cell Signaling Technology (Watertown, MA).	('poly(ADP-ribose) polymerase', 'Gene', (50, 77))	('CDC2', 'Gene', (30, 34))	('Y15P', 'SUBSTITUTION', 'None', (35, 39))	('CDC2', 'Gene', '983', (30, 34))	('CDC2', 'Gene', (24, 28))	('PARP', 'Gene', '142', (80, 84))	('CDC2', 'Gene', '983', (24, 28))	('Y15P', 'Var', (35, 39))	('poly(ADP-ribose) polymerase', 'Gene', '142', (50, 77))	('PARP', 'Gene', (80, 84))	('Rabbit', 'Species', '9986', (0, 6))
164452	22084170	Briefly, tumor explants were exposed to MK1775 at 500nM concentrations for 18h and vehicles as well as MK1775-treated tissue fragments were collected for western blot and morphological studies.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('MK1775', 'Chemical', 'MESH:C549567', (40, 46))	('MK1775', 'Var', (40, 46))	('MK1775', 'Chemical', 'MESH:C549567', (103, 109))
164455	22084170	Our data showed that this effect is independent of p53 mutational status as MK1775 showed effective cell death in both p53 wild type (U2OS and HT1080) and p53 mutant (MG63, SW872, A673, SKUT, MNNG and SKES) cell lines (Figure 1B).	('MK1775', 'Chemical', 'MESH:C549567', (76, 82))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('p53', 'Gene', (155, 158))	('U2OS', 'CellLine', 'CVCL:0042', (134, 138))	('p53', 'Gene', '7157', (155, 158))	('mutant', 'Var', (159, 165))	('MK1775', 'Var', (76, 82))	('p53', 'Gene', '7157', (119, 122))	('cell death', 'CPA', (100, 110))	('HT1080', 'CellLine', 'CVCL:0317', (143, 149))	('SW872', 'CellLine', 'CVCL:1730', (173, 178))	('p53', 'Gene', (119, 122))
164457	22084170	As illustrated in Figure 1C, all eight sarcoma cell lines showed a dramatic decrease in CDC2Tyr15 phosphorylation and a significant increase in cleaved PARP while total CDC2 levels remained the same, this demonstrates that MK1775 treatment induces apoptotic cell death in these cell lines at clinically relevant doses.	('MK1775', 'Chemical', 'MESH:C549567', (223, 229))	('MK1775', 'Var', (223, 229))	('PARP', 'Gene', '142', (152, 156))	('increase', 'PosReg', (132, 140))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('CDC2', 'Gene', (169, 173))	('PARP', 'Gene', (152, 156))	('sarcoma', 'Disease', (39, 46))	('CDC2', 'Gene', '983', (169, 173))	('apoptotic cell death', 'CPA', (248, 268))	('CDC2', 'Gene', (88, 92))	('decrease', 'NegReg', (76, 84))	('CDC2', 'Gene', '983', (88, 92))
164458	22084170	Additionally, MK1775 treatment led to increased Serine 139 phosphorylation of gamma-H2AX indicating that MK1775 may also cause DNA damage and lead to mitotic catastrophe by allowing cells with DNA damage to enter into mitosis.	('Serine 139 phosphorylation', 'MPA', (48, 74))	('mitotic catastrophe', 'CPA', (150, 169))	('MK1775', 'Chemical', 'MESH:C549567', (14, 20))	('increased Serine', 'Phenotype', 'HP:0500138', (38, 54))	('allowing', 'PosReg', (173, 181))	('mitosis', 'Disease', (218, 225))	('MK1775', 'Chemical', 'MESH:C549567', (105, 111))	('mitosis', 'Disease', 'None', (218, 225))	('Serine', 'Chemical', 'MESH:D012694', (48, 54))	('gamma-H2AX', 'Protein', (78, 88))	('increased', 'PosReg', (38, 47))	('cause', 'Reg', (121, 126))	('DNA damage', 'MPA', (127, 137))	('MK1775', 'Var', (105, 111))	('lead to', 'Reg', (142, 149))
164462	22084170	Our results demonstrate that all four cell lines underwent apoptotic cell death in response to MK1775 independent of their p53 status.	('underwent', 'Reg', (49, 58))	('apoptotic cell death', 'CPA', (59, 79))	('MK1775', 'Chemical', 'MESH:C549567', (95, 101))	('p53', 'Gene', (123, 126))	('MK1775', 'Var', (95, 101))	('p53', 'Gene', '7157', (123, 126))
164464	22084170	To further determine whether MK1775 treatment leads to unscheduled mitotic entry we first analyzed the microscopic features of sarcoma cells after treatment with MK1775.	('MK1775', 'Chemical', 'MESH:C549567', (29, 35))	('MK1775', 'Chemical', 'MESH:C549567', (162, 168))	('MK1775', 'Var', (162, 168))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('sarcoma', 'Disease', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
164466	22084170	As illustrated in Figure 2A, lower panel, MK1775 treatment caused marked nuclear abnormalities including multinucleation in all cell lines indicating abnormal mitosis with failed cytokinesis.	('MK1775', 'Chemical', 'MESH:C549567', (42, 48))	('MK1775', 'Var', (42, 48))	('abnormal mitosis', 'Disease', (150, 166))	('abnormal mitosis', 'Disease', 'MESH:D000014', (150, 166))	('nuclear abnormalities', 'CPA', (73, 94))	('multinucleation', 'CPA', (105, 120))
164467	22084170	Taken together, these results provide the first evidence that MK1775 monotherapy effectively induces cell death in sarcoma cells in a p53-independent manner.	('cell death', 'CPA', (101, 111))	('MK1775', 'Chemical', 'MESH:C549567', (62, 68))	('p53', 'Gene', '7157', (134, 137))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('sarcoma', 'Disease', (115, 122))	('MK1775 monotherapy', 'Var', (62, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('induces', 'Reg', (93, 100))	('p53', 'Gene', (134, 137))
164468	22084170	To provide further evidence that inhibition of Wee1 by MK1775 leads to mitotic cell death in sarcoma cells, we next performed immunofluorescence studies to co-localize mitosis and cell death.	('MK1775', 'Chemical', 'MESH:C549567', (55, 61))	('MK1775', 'Var', (55, 61))	('sarcoma', 'Disease', (93, 100))	('inhibition', 'NegReg', (33, 43))	('mitosis', 'Disease', 'None', (168, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('mitotic cell death', 'CPA', (71, 89))	('mitosis', 'Disease', (168, 175))	('Wee1', 'Gene', (47, 51))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
164469	22084170	As illustrated in Figure 3A, microscopic examination of MG63, U2OS, A673 and HT1080 cells treated with MK1775 produced micro- and multi-nucleation with significantly higher pH3 staining.	('higher', 'PosReg', (166, 172))	('HT1080', 'CellLine', 'CVCL:0317', (77, 83))	('U2OS', 'CellLine', 'CVCL:0042', (62, 66))	('MK1775', 'Var', (103, 109))	('pH3', 'Protein', (173, 176))	('MK1775', 'Chemical', 'MESH:C549567', (103, 109))
164470	22084170	Furthermore, MK1775 treated cells also often showed double staining with pH3 and cleaved caspase-3 compared to vehicle treated control cells.	('cleaved', 'MPA', (81, 88))	('pH3', 'Protein', (73, 76))	('showed', 'Reg', (45, 51))	('double staining', 'MPA', (52, 67))	('caspase-3', 'Protein', (89, 98))	('MK1775', 'Chemical', 'MESH:C549567', (13, 19))	('MK1775 treated', 'Var', (13, 27))
164472	22084170	In each of the cells lines we tested there was a significant increase in the total amount of pH3 staining upon MK1775 treatment.	('MK1775', 'Var', (111, 117))	('pH3', 'Protein', (93, 96))	('MK1775', 'Chemical', 'MESH:C549567', (111, 117))	('increase', 'PosReg', (61, 69))
164473	22084170	Taken together, these data show that MK1775 treatment causes cell death associated with abnormal mitosis and failed cytokinesis, which is suggestive of mitotic catastrophe, a type of cell death that occurs during mitosis.	('mitosis', 'Disease', (97, 104))	('cell death', 'CPA', (61, 71))	('treatment', 'Var', (44, 53))	('mitosis', 'Disease', 'None', (97, 104))	('failed cytokinesis', 'CPA', (109, 127))	('abnormal mitosis', 'Disease', (88, 104))	('MK1775', 'Chemical', 'MESH:C549567', (37, 43))	('mitotic catastrophe', 'Disease', (152, 171))	('abnormal mitosis', 'Disease', 'MESH:D000014', (88, 104))	('mitosis', 'Disease', (213, 220))	('mitosis', 'Disease', 'None', (213, 220))	('MK1775 treatment', 'Var', (37, 53))
164477	22084170	As illustrated in Figure 4A, lower panel, ex vivo treatment of cells with MK1775 (500 nM) caused increased cell death and activation of CDC2 in all samples, as analyzed by PARP cleavage and CDC2TYR 15 inhibition while total CDC2 levels remained the same.	('CDC2', 'Gene', (136, 140))	('PARP', 'Gene', '142', (172, 176))	('increased', 'PosReg', (97, 106))	('CDC2', 'Gene', (224, 228))	('CDC2', 'Gene', '983', (224, 228))	('PARP', 'Gene', (172, 176))	('activation', 'PosReg', (122, 132))	('CDC2', 'Gene', '983', (190, 194))	('cell death', 'CPA', (107, 117))	('MK1775', 'Chemical', 'MESH:C549567', (74, 80))	('CDC2', 'Gene', (190, 194))	('MK1775 (500 nM', 'Var', (74, 88))	('CDC2', 'Gene', '983', (136, 140))
164478	22084170	The histologic analysis of tumor explants confirmed that MK1775 treatment caused dramatic cell death, H&E stained paraffin section of vehicle and MK1775-treated UHGS, PMSS and MPNST explants are shown in Figure 4B.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('paraffin', 'Chemical', 'MESH:D010232', (114, 122))	('H&E', 'Chemical', 'MESH:D006371', (102, 105))	('MK1775', 'Chemical', 'MESH:C549567', (57, 63))	('MK1775', 'Chemical', 'MESH:C549567', (146, 152))	('MPNST', 'Phenotype', 'HP:0100697', (176, 181))	('and', 'Var', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('cell death', 'CPA', (90, 100))	('MK1775 treatment', 'Var', (57, 73))
164479	22084170	These results further support the findings presented above with sarcoma cell lines and strongly suggest that MK1775 could be used as a single agent in the treatment of sarcoma patients in future clinical studies.	('patients', 'Species', '9606', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('MK1775', 'Chemical', 'MESH:C549567', (109, 115))	('sarcoma', 'Disease', (64, 71))	('MK1775', 'Var', (109, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcoma', 'Disease', (168, 175))
164487	22084170	Here we showed that various soft tissue and bone sarcomas including osteosarcoma, Ewing sarcoma and MPNST are highly sensitive to the cytotoxic effect of MK1775 when used as a single agent at clinically achievable concentrations.	('MK1775', 'Var', (154, 160))	('Ewing sarcoma', 'Disease', (82, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('osteosarcoma', 'Disease', 'MESH:D012516', (68, 80))	('bone sarcomas', 'Disease', 'MESH:D001847', (44, 57))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (82, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('bone sarcomas', 'Disease', (44, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('MK1775', 'Chemical', 'MESH:C549567', (154, 160))	('MPNST', 'Phenotype', 'HP:0100697', (100, 105))	('soft tissue and bone sarcomas', 'Phenotype', 'HP:0030448', (28, 57))	('osteosarcoma', 'Phenotype', 'HP:0002669', (68, 80))	('bone sarcomas', 'Phenotype', 'HP:0002669', (44, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('osteosarcoma', 'Disease', (68, 80))
164490	22084170	There is compelling evidence that abrogation of this checkpoint through Wee1 inhibition may result in increased antitumor activity of agents that cause DNA damage such as radiation therapy or some cytotoxic agents.	('Wee1', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('inhibition', 'NegReg', (77, 87))	('abrogation', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('increased', 'PosReg', (102, 111))	('tumor', 'Disease', (116, 121))
164491	22084170	Our data presented here show that MK1775 treatment leads to unscheduled CDC2Y15 activation and consequently premature mitotic entry and cell death of sarcoma cells.	('MK1775', 'Var', (34, 40))	('CDC2', 'Gene', '983', (72, 76))	('CDC2', 'Gene', (72, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('death of sarcoma', 'Disease', 'MESH:D003643', (141, 157))	('MK1775', 'Chemical', 'MESH:C549567', (34, 40))	('death of sarcoma', 'Disease', (141, 157))	('activation', 'PosReg', (80, 90))
164492	22084170	MK1775 treatment led to increased Serine 139 phosphorylation of gamma-H2AX (Figure 1C) indicating that inhibition of Wee1 may also cause DNA damage and lead to mitotic catastrophe by allowing cells with DNA damage to enter into mitosis.	('allowing', 'Reg', (183, 191))	('mitotic catastrophe', 'CPA', (160, 179))	('mitosis', 'Disease', (228, 235))	('Wee1', 'Gene', (117, 121))	('mitosis', 'Disease', 'None', (228, 235))	('increased Serine', 'Phenotype', 'HP:0500138', (24, 40))	('Serine', 'Chemical', 'MESH:D012694', (34, 40))	('cause', 'Reg', (131, 136))	('inhibition', 'Var', (103, 113))	('gamma-H2AX', 'Protein', (64, 74))	('DNA damage', 'MPA', (137, 147))	('lead to', 'Reg', (152, 159))	('Serine 139 phosphorylation', 'MPA', (34, 60))	('increased', 'PosReg', (24, 33))	('MK1775', 'Chemical', 'MESH:C549567', (0, 6))
164493	22084170	Interestingly, in previous studies acute deletion of Wee1 has been demonstrated to cause profound growth defects and cell death in mouse models.	('growth defects', 'Disease', 'MESH:D006130', (98, 112))	('mouse', 'Species', '10090', (131, 136))	('growth defects', 'Disease', (98, 112))	('deletion', 'Var', (41, 49))	('cell death', 'CPA', (117, 127))	('Wee1', 'Gene', (53, 57))
164494	22084170	Wee1 deficient cells have been shown to display chromosome aneuploidy and DNA damage providing evidence that mammalian Wee1 also plays a critical role in maintaining genome integrity.	('aneuploidy', 'Disease', (59, 69))	('Wee1', 'Gene', (0, 4))	('aneuploidy', 'Disease', 'MESH:D000782', (59, 69))	('mammalian', 'Species', '9606', (109, 118))	('DNA damage', 'CPA', (74, 84))	('deficient', 'Var', (5, 14))
164496	22084170	These studies indicated that defective p53 pathway allows cells to pass G1/S checkpoint making them largely dependent on G2/M arrest to repair damage by cytotoxic agents.	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('defective', 'Var', (29, 38))
164497	22084170	Therefore, p53 mutation has been proposed as a predictor of tumor response to Wee1 inhibitors in clinical trials.	('p53', 'Gene', (11, 14))	('mutation', 'Var', (15, 23))	('p53', 'Gene', '7157', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
164499	22084170	We showed that MK1775 is effective as monotherapy in sarcoma cells independent of their p53 status, as we observed a similar degree of cell death in sarcoma cells with wild type p53, mutant p53 and null p53.	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('p53', 'Gene', '7157', (203, 206))	('sarcoma', 'Disease', (149, 156))	('p53', 'Gene', (190, 193))	('sarcoma', 'Disease', (53, 60))	('p53', 'Gene', (88, 91))	('MK1775', 'Chemical', 'MESH:C549567', (15, 21))	('p53', 'Gene', '7157', (190, 193))	('p53', 'Gene', '7157', (88, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('p53', 'Gene', (178, 181))	('MK1775', 'Var', (15, 21))	('p53', 'Gene', '7157', (178, 181))	('p53', 'Gene', (203, 206))
164500	22084170	However, the role of p53 in response of sarcoma cells to combination treatment with MK1775 and DNA damaging agents remains to be elucidated.	('p53', 'Gene', '7157', (21, 24))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('MK1775', 'Chemical', 'MESH:C549567', (84, 90))	('sarcoma', 'Disease', (40, 47))	('MK1775', 'Var', (84, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('p53', 'Gene', (21, 24))
164501	22084170	Recent studies showed that MK1775 is a well tolerated drug that has not demonstrated a clear dose limiting toxicity.	('MK1775', 'Var', (27, 33))	('toxicity', 'Disease', 'MESH:D064420', (107, 115))	('toxicity', 'Disease', (107, 115))	('MK1775', 'Chemical', 'MESH:C549567', (27, 33))
164502	22084170	The data presented here together with the high safety profile of this drug strongly suggest that MK1775 can be used as a potential therapeutic agent in the treatment of both adult as well as pediatric sarcoma patients.	('MK1775', 'Chemical', 'MESH:C549567', (97, 103))	('MK1775', 'Var', (97, 103))	('patients', 'Species', '9606', (209, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('pediatric sarcoma', 'Disease', (191, 208))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (191, 208))
164503	31433528	Genetic Diversity in Alveolar Soft Part Sarcoma: A Subset Contain Variant Fusion Genes, Highlighting Broader Molecular Kinship with Other MiT Family Tumors Alveolar soft part sarcoma (ASPS) is a rare malignancy that, since its initial description, remains a neoplasm of uncertain histogenesis.	('sarcoma', 'Disease', (175, 182))	('neoplasm', 'Disease', (258, 266))	('Alveolar Soft Part Sarcoma', 'Disease', (21, 47))	('Variant Fusion Genes', 'Var', (66, 86))	('Sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Tumors', 'Phenotype', 'HP:0002664', (149, 155))	('ASPS', 'Gene', '79058', (184, 188))	('ASPS', 'Phenotype', 'HP:0012218', (184, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('neoplasm', 'Phenotype', 'HP:0002664', (258, 266))	('Tumors', 'Disease', (149, 155))	('malignancy', 'Disease', 'MESH:D009369', (200, 210))	('Alveolar Soft Part Sarcoma', 'Phenotype', 'HP:0012218', (21, 47))	('Soft Part Sarcoma', 'Phenotype', 'HP:0030448', (30, 47))	('Tumors', 'Disease', 'MESH:D009369', (149, 155))	('Alveolar Soft Part Sarcoma', 'Disease', 'MESH:D018234', (21, 47))	('Alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (156, 182))	('ASPS', 'Gene', (184, 188))	('neoplasm', 'Disease', 'MESH:D009369', (258, 266))	('malignancy', 'Disease', (200, 210))	('sarcoma', 'Disease', 'MESH:D012509', (175, 182))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (165, 182))
164510	31433528	The latter two fusions have previously been identified in renal cell carcinoma; to our knowledge this is the first report of a HNRNPH3-TFE3 gene fusion.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('TFE3', 'Gene', (135, 139))	('HNRNPH3', 'Gene', '3189', (127, 134))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (58, 78))	('TFE3', 'Gene', '7030', (135, 139))	('fusion', 'Var', (145, 151))	('HNRNPH3', 'Gene', (127, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('renal cell carcinoma', 'Disease', (58, 78))
164518	31433528	ASPS has heretofore been reported to be genetically defined by der(17)t(X;17)(p11;q25), resulting in an ASPSCR1-TFE3 fusion gene.	('ASPS', 'Gene', (104, 108))	('der(17)t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (63, 86))	('ASPSCR1', 'Gene', '79058', (104, 111))	('ASPS', 'Gene', '79058', (0, 4))	('ASPS', 'Gene', '79058', (104, 108))	('TFE3', 'Gene', (112, 116))	('ASPSCR1', 'Gene', (104, 111))	('der(17)t', 'Var', (63, 71))	('ASPS', 'Phenotype', 'HP:0012218', (0, 4))	('ASPS', 'Phenotype', 'HP:0012218', (104, 108))	('TFE3', 'Gene', '7030', (112, 116))	('ASPS', 'Gene', (0, 4))
164519	31433528	Herein we report three cases of alveolar soft part sarcoma containing TFE3 gene fusion partners other than ASPSCR1.	('TFE3', 'Gene', (70, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('TFE3', 'Gene', '7030', (70, 74))	('ASPSCR1', 'Gene', '79058', (107, 114))	('fusion partners', 'Var', (80, 95))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (32, 58))	('alveolar soft part sarcoma', 'Disease', (32, 58))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (32, 58))	('ASPSCR1', 'Gene', (107, 114))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (41, 58))	('ASPS', 'Phenotype', 'HP:0012218', (107, 111))
164538	31433528	Routine diagnostic RNA-Seq revealed an HNRNPH3-TFE3 gene fusion in the tumor from the index patient; this was in-frame and occurred between HNRNPH3 (NCBI Reference Sequence: NM_012207) partial exon 10 and TFE3 (NM_006521) exon 3.	('patient', 'Species', '9606', (92, 99))	('HNRNPH3', 'Gene', '3189', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TFE3', 'Gene', (47, 51))	('TFE3', 'Gene', '7030', (205, 209))	('NM_006521', 'Var', (211, 220))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('HNRNPH3', 'Gene', (39, 46))	('occurred', 'Reg', (123, 131))	('TFE3', 'Gene', '7030', (47, 51))	('tumor', 'Disease', (71, 76))	('HNRNPH3', 'Gene', (140, 147))	('HNRNPH3', 'Gene', '3189', (39, 46))	('TFE3', 'Gene', (205, 209))
164539	31433528	Patient 2's tumor was found to have rearrangement of both the DVL2 and TFE3 genes by FISH, while lacking abnormalities in ASPSCR1, PRCC, CLTC and SFPQ genes; a bring-together FISH assay was subsequently used to confirm the juxtaposition of the two genes as a DVL2-TFE3 fusion.	('CLTC', 'Gene', '1213', (137, 141))	('ASPSCR1', 'Gene', (122, 129))	('ASPS', 'Phenotype', 'HP:0012218', (122, 126))	('TFE3', 'Gene', (264, 268))	('tumor', 'Disease', (12, 17))	('rearrangement', 'Var', (36, 49))	('DVL2', 'Gene', '1856', (62, 66))	('TFE3', 'Gene', '7030', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CLTC', 'Gene', (137, 141))	('DVL2', 'Gene', '1856', (259, 263))	('PRCC', 'Gene', (131, 135))	('DVL2', 'Gene', (62, 66))	('DVL2', 'Gene', (259, 263))	('TFE3', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('TFE3', 'Gene', '7030', (71, 75))	('ASPSCR1', 'Gene', '79058', (122, 129))	('SFPQ', 'Gene', '6421', (146, 150))	('SFPQ', 'Gene', (146, 150))	('PRCC', 'Gene', '5546', (131, 135))	('Patient', 'Species', '9606', (0, 7))
164544	31433528	The disease-defining molecular event underpinning the diagnosis of ASPS is the ASPSCR1-TFE3 gene fusion which, for almost two decades, was considered the sole driver for this neoplasm.	('ASPS', 'Gene', (79, 83))	('neoplasm', 'Disease', 'MESH:D009369', (175, 183))	('TFE3', 'Gene', '7030', (87, 91))	('neoplasm', 'Phenotype', 'HP:0002664', (175, 183))	('ASPSCR1', 'Gene', '79058', (79, 86))	('ASPS', 'Phenotype', 'HP:0012218', (67, 71))	('ASPS', 'Gene', '79058', (79, 83))	('ASPS', 'Gene', (67, 71))	('ASPSCR1', 'Gene', (79, 86))	('fusion', 'Var', (97, 103))	('ASPS', 'Phenotype', 'HP:0012218', (79, 83))	('neoplasm', 'Disease', (175, 183))	('TFE3', 'Gene', (87, 91))	('ASPS', 'Gene', '79058', (67, 71))
164554	31433528	that discovered that the translocation fuses ASPSCR1 (formerly ASPL) to TFE3, a finding consistently confirmed in many subsequent series.	('TFE3', 'Gene', (72, 76))	('translocation', 'Var', (25, 38))	('fuses', 'Var', (39, 44))	('ASPSCR1', 'Gene', (45, 52))	('TFE3', 'Gene', '7030', (72, 76))	('ASPL', 'Gene', '79058', (63, 67))	('ASPS', 'Phenotype', 'HP:0012218', (45, 49))	('ASPL', 'Gene', (63, 67))	('ASPSCR1', 'Gene', '79058', (45, 52))
164561	31433528	Assuming the potential for broader molecular overlap between ASPS and renal cell carcinoma - not to mention PEComa, a subset of which likewise harbor TFE3 rearrangement - it is presumed additional fusion genes may exist in ASPS.	('renal cell carcinoma', 'Disease', (70, 90))	('TFE3', 'Gene', '7030', (150, 154))	('ASPS', 'Gene', '79058', (61, 65))	('PEComa', 'Disease', 'MESH:D054973', (108, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('ASPS', 'Gene', '79058', (223, 227))	('ASPS', 'Phenotype', 'HP:0012218', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('TFE3', 'Gene', (150, 154))	('ASPS', 'Phenotype', 'HP:0012218', (223, 227))	('rearrangement -', 'Var', (155, 170))	('ASPS', 'Gene', (61, 65))	('PEComa', 'Disease', (108, 114))	('ASPS', 'Gene', (223, 227))
164564	31433528	One patient was identified following routine diagnostic testing using break-apart FISH probes for DVL2 and TFE3, which suggested rearrangement of both genes; a bring-together FISH assay was subsequently used to confirm the juxtaposition of the two genes in a DVL2-TFE3 fusion.	('TFE3', 'Gene', '7030', (264, 268))	('DVL2', 'Gene', (259, 263))	('TFE3', 'Gene', '7030', (107, 111))	('patient', 'Species', '9606', (4, 11))	('DVL2', 'Gene', (98, 102))	('DVL2', 'Gene', '1856', (259, 263))	('fusion', 'Var', (269, 275))	('TFE3', 'Gene', (264, 268))	('DVL2', 'Gene', '1856', (98, 102))	('TFE3', 'Gene', (107, 111))
164566	31433528	TFE3 fusions involving DVL2 and PRCC have previously been reported in renal cell carcinoma; in addition, the former has also been identified in a TFE3-rearranged PEComa.	('renal cell carcinoma', 'Disease', (70, 90))	('TFE3', 'Gene', '7030', (0, 4))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('reported', 'Reg', (58, 66))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('fusions', 'Var', (5, 12))	('TFE3', 'Gene', '7030', (146, 150))	('PEComa', 'Disease', 'MESH:D054973', (162, 168))	('PRCC', 'Gene', '5546', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('DVL2', 'Gene', (23, 27))	('TFE3', 'Gene', (0, 4))	('identified', 'Reg', (130, 140))	('PRCC', 'Gene', (32, 36))	('DVL2', 'Gene', '1856', (23, 27))	('TFE3', 'Gene', (146, 150))	('PEComa', 'Disease', (162, 168))
164567	31433528	However, to our knowledge, this represents the first report of the fusion of TFE3 to HNRNPH3, which appears to represent an altogether novel gene pairing.	('HNRNPH3', 'Gene', '3189', (85, 92))	('TFE3', 'Gene', (77, 81))	('HNRNPH3', 'Gene', (85, 92))	('TFE3', 'Gene', '7030', (77, 81))	('fusion', 'Var', (67, 73))
164572	31433528	Similar to ASPSCR1-TFE3, fusion of PRCC (proline rich mitotic checkpoint control factor) and TFE3 result in the formation of a more potent activator than TFE3, thereby leading to aberrant expression of TFE3 targets in renal cell carcinoma.	('TFE3', 'Gene', '7030', (202, 206))	('TFE3', 'Gene', (19, 23))	('proline rich mitotic checkpoint control factor', 'Gene', (41, 87))	('PRCC', 'Gene', '5546', (35, 39))	('TFE3', 'Gene', (154, 158))	('TFE3', 'Gene', '7030', (19, 23))	('leading to', 'Reg', (168, 178))	('ASPS', 'Phenotype', 'HP:0012218', (11, 15))	('TFE3', 'Gene', '7030', (154, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('renal cell carcinoma', 'Disease', (218, 238))	('activator', 'MPA', (139, 148))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (218, 238))	('proline rich mitotic checkpoint control factor', 'Gene', '5546', (41, 87))	('ASPSCR1', 'Gene', '79058', (11, 18))	('fusion', 'Var', (25, 31))	('PRCC', 'Gene', (35, 39))	('TFE3', 'Gene', (93, 97))	('expression', 'MPA', (188, 198))	('TFE3', 'Gene', '7030', (93, 97))	('ASPSCR1', 'Gene', (11, 18))	('TFE3', 'Gene', (202, 206))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 238))
164574	31433528	This, to our knowledge, represents the first report of a tumor harboring a HNRNPH3-TFE3 fusion gene.	('TFE3', 'Gene', '7030', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('HNRNPH3', 'Gene', (75, 82))	('fusion gene', 'Var', (88, 99))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('TFE3', 'Gene', (83, 87))	('tumor', 'Disease', (57, 62))	('HNRNPH3', 'Gene', '3189', (75, 82))
164581	31433528	These findings reveal a genetic diversity that has heretofore been underrecognized in ASPS; furthermore, this highlights an even greater degree of molecular kinship amongst ASPS and MiT family translocation renal cell carcinoma, as well as PEComa.	('ASPS', 'Phenotype', 'HP:0012218', (86, 90))	('PEComa', 'Disease', 'MESH:D054973', (240, 246))	('renal cell carcinoma', 'Disease', (207, 227))	('MiT', 'Var', (182, 185))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (207, 227))	('ASPS', 'Phenotype', 'HP:0012218', (173, 177))	('ASPS', 'Gene', (86, 90))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (207, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('ASPS', 'Gene', '79058', (86, 90))	('ASPS', 'Gene', (173, 177))	('PEComa', 'Disease', (240, 246))	('ASPS', 'Gene', '79058', (173, 177))
164607	32084238	We have designed and produced a large series of fusion proteins with NGR-peptides on the C-terminus of truncated tissue factor (tTF) with the objective of tumor vasculature occlusion by coagulation and resulting infarction.	('infarction', 'Disease', 'MESH:D007238', (212, 222))	('tissue factor', 'Gene', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('truncated', 'Var', (103, 112))	('tumor vasculature occlusion by coagulation', 'Disease', 'MESH:C565633', (155, 197))	('TF', 'Gene', '2152', (129, 131))	('tumor vasculature occlusion by coagulation', 'Disease', (155, 197))	('NGR', 'Gene', (69, 72))	('infarction', 'Disease', (212, 222))	('peptides', 'Chemical', 'MESH:D010455', (73, 81))	('tissue factor', 'Gene', '2152', (113, 126))	('NGR', 'Gene', '65078', (69, 72))	('vasculature occlusion', 'Phenotype', 'HP:0025324', (161, 182))
164650	32084238	As was shown by flow cytometry before and after irradiation, PS concentrations on the cell surface of HUVEC (Fig 1) could be significantly increased by irradiation as a sign for early apoptosis, whereas cells were not completely destroyed (PI-positive) so that they could be further used at identical cell numbers for FX assays.	('HUVEC', 'Gene', (102, 107))	('increased', 'PosReg', (139, 148))	('PS', 'Chemical', 'MESH:D010718', (61, 63))	('PS concentrations', 'MPA', (61, 78))	('irradiation', 'Var', (152, 163))
164677	32084238	dependence of pro-coagulant state by PS presence on outer cell surface and induction of this state by apoptotic stimuli, we and other groups could show increased pro-coagulant activity of endothelial cells by PS externalization induced by cytotoxics such as doxorubicin or by low-energy ultrasound.	('externalization', 'Var', (212, 227))	('increased', 'PosReg', (152, 161))	('doxorubicin', 'Chemical', 'MESH:D004317', (258, 269))	('PS', 'Chemical', 'MESH:D010718', (37, 39))	('pro-coagulant activity', 'MPA', (162, 184))	('PS', 'Chemical', 'MESH:D010718', (209, 211))
164826	28916654	DICER1 is an RNase III endoribonuclease central to microRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types.	('tumor', 'Disease', (188, 193))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('result in', 'Reg', (102, 111))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('DICER1', 'Gene', (85, 91))	('cancer', 'Disease', (114, 120))
164827	28916654	Here we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss.	('angiosarcoma', 'Disease', 'MESH:D006394', (90, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('angiosarcoma', 'Disease', (90, 102))	('Dicer1', 'Gene', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('aP2-Cre', 'Gene', (49, 56))	('metastatic angiosarcoma', 'Phenotype', 'HP:0200059', (79, 102))	('deletion', 'Var', (35, 43))	('angiosarcoma', 'Phenotype', 'HP:0200058', (90, 102))	('tumor', 'Disease', (160, 165))	('aP2-Cre', 'Gene', '226861', (49, 56))	('drives', 'PosReg', (57, 63))
164835	28916654	Recently, recurrent mutations in genes involved in angiogenesis, PTPRB and PLCG1, have been identified in secondary angiosarcomas while the drivers of spontaneous angiosarcoma are less clear, highlighting the need for genetic, in vivo animal models to further understand the molecular mechanisms of angiosarcoma development and assess novel therapeutics.	('angiosarcomas', 'Disease', (116, 129))	('angiosarcoma', 'Disease', (299, 311))	('angiosarcoma', 'Disease', (163, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('PLCG1', 'Gene', '18803', (75, 80))	('angiosarcoma', 'Disease', (116, 128))	('PLCG1', 'Gene', (75, 80))	('angiosarcomas', 'Disease', 'MESH:D006394', (116, 129))	('identified', 'Reg', (92, 102))	('angiosarcoma', 'Disease', 'MESH:D006394', (299, 311))	('angiosarcoma', 'Disease', 'MESH:D006394', (163, 175))	('mutations', 'Var', (20, 29))	('PTPRB', 'Gene', '19263', (65, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('angiosarcoma', 'Phenotype', 'HP:0200058', (299, 311))	('angiosarcomas', 'Phenotype', 'HP:0200058', (116, 129))	('angiosarcoma', 'Disease', 'MESH:D006394', (116, 128))	('PTPRB', 'Gene', (65, 70))	('angiosarcoma', 'Phenotype', 'HP:0200058', (163, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('angiosarcoma', 'Phenotype', 'HP:0200058', (116, 128))
164838	28916654	Numerous studies have described Dicer1 dysregulation in cancer.	('dysregulation', 'Var', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Dicer1', 'Gene', (32, 38))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
164839	28916654	In several mouse models, Dicer1 functions as a haploinsufficient tumor suppressor where loss of a single allele promotes tumorigenesis yet loss of both alleles abrogates tumor formation.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('promotes', 'PosReg', (112, 120))	('abrogates', 'NegReg', (160, 169))	('tumor', 'Disease', (65, 70))	('mouse', 'Species', '10090', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Dicer1', 'Gene', (25, 31))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (47, 70))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (121, 126))	('loss', 'Var', (139, 143))	('tumor', 'Disease', (170, 175))	('loss', 'Var', (88, 92))	('haploinsufficient tumor', 'Disease', (47, 70))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
164840	28916654	Heterozygous germline DICER1 loss-of-function mutations in humans is associated with a distinct cancer predisposition syndrome in which affected kindreds present with rare malignant and benign neoplasms including pleuropulmonary blastoma (PPB), pineoblastoma, embryonal rhabdomyosarcoma (ERMS), and others.	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('pineoblastoma', 'Phenotype', 'HP:0030408', (245, 258))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (260, 286))	('DICER1', 'Gene', (22, 28))	('pineoblastoma', 'Disease', 'MESH:D010871', (245, 258))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (213, 237))	('pleuropulmonary blastoma', 'Disease', (213, 237))	('neoplasms', 'Phenotype', 'HP:0002664', (193, 202))	('pineoblastoma', 'Disease', (245, 258))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (260, 286))	('benign neoplasms', 'Disease', (186, 202))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (270, 286))	('humans', 'Species', '9606', (59, 65))	('benign neoplasms', 'Disease', 'MESH:D009369', (186, 202))	('embryonal rhabdomyosarcoma', 'Disease', (260, 286))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (213, 237))	('loss-of-function', 'NegReg', (29, 45))
164841	28916654	Interestingly, some of these tumors have recently been shown to have secondary somatic missense mutations in the remaining DICER1 allele in exons 24 and 25 encoding the RNAse IIIb domain.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('missense mutations', 'Var', (87, 105))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('DICER1', 'Gene', (123, 129))
164846	28916654	Given the occurrence of DICER1 mutations in both sporadic ERMS and DICER1 syndrome associated ERMS, we sought to further interrogate the role of Dicer1 in ERMS oncogenesis utilizing mice with conditional deletion of Dicer1 with aP2-Cre.	('aP2-Cre', 'Gene', (228, 235))	('mutations', 'Var', (31, 40))	('Dicer1', 'Gene', (216, 222))	('aP2-Cre', 'Gene', '226861', (228, 235))	('mice', 'Species', '10090', (182, 186))	('DICER1', 'Gene', (67, 73))	('ERMS', 'Disease', (58, 62))	('DICER1', 'Gene', (24, 30))	('ERMS', 'Disease', (94, 98))
164847	28916654	Here we describe our findings illustrating Dicer1 deletion in aP2 expressing cells results in angiosarcoma.	('results in', 'Reg', (83, 93))	('angiosarcoma', 'Disease', 'MESH:D006394', (94, 106))	('deletion', 'Var', (50, 58))	('angiosarcoma', 'Disease', (94, 106))	('angiosarcoma', 'Phenotype', 'HP:0200058', (94, 106))	('Dicer1', 'Gene', (43, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
164872	28916654	and the Dicer1Flox mouse generated by Murchison et al.. We first bred compound mutant aP2-Cre;Dicer1Flox/+ (ADFlox/+) to Dicer1Flox/+ (DFlox/+) mice to determine the viability of aP2-Cre;Dicer1Flox/Flox (ADFlox/Flox) mice.	('mice', 'Species', '10090', (144, 148))	('mice', 'Species', '10090', (217, 221))	('mutant', 'Var', (79, 85))	('aP2-Cre', 'Gene', (179, 186))	('aP2-Cre', 'Gene', (86, 93))	('mouse', 'Species', '10090', (19, 24))	('aP2-Cre', 'Gene', '226861', (179, 186))	('aP2-Cre', 'Gene', '226861', (86, 93))
164875	28916654	In contrast, ADFlox/Flox mice in our studies using the aP2-Cre generated by Jonathan Graff and Dicer1Flox allele generated by Gregory Hannon with loxP sites flanking regions of the RNaseIII domain were born at normal Mendelian ratios and were phenotypically indistinguishable from AD+/+ and ADFlox/+ littermates.	('ADFlox/Flox', 'Var', (13, 24))	('aP2-Cre', 'Gene', (55, 62))	('aP2-Cre', 'Gene', '226861', (55, 62))	('mice', 'Species', '10090', (25, 29))
164877	28916654	Thus, no early postnatal death or lack of WAT was observed in our studies using the aP2-Cre generated by Tang et al.. Dicer1 expression decreased although was still detectable in both BAT and WAT from ADFlox/+ and ADFlox/Flox animals suggesting incomplete Cre-mediated recombination of the Dicer1Flox allele (Supplementary Fig.	('WAT', 'Disease', (42, 45))	('aP2-Cre', 'Gene', (84, 91))	('postnatal death', 'Disease', 'MESH:D003643', (15, 30))	('ADFlox/+', 'Var', (201, 209))	('WAT', 'Disease', 'None', (192, 195))	('aP2-Cre', 'Gene', '226861', (84, 91))	('expression', 'MPA', (125, 135))	('Dicer1', 'Gene', (118, 124))	('WAT', 'Disease', 'None', (42, 45))	('BAT', 'Disease', 'None', (184, 187))	('WAT', 'Disease', (192, 195))	('BAT', 'Disease', (184, 187))	('postnatal death', 'Disease', (15, 30))	('decreased', 'NegReg', (136, 145))
164880	28916654	Given that ADFlox/Flox animals were viable and exhibited incomplete Dicer1Flox Cre-mediated recombination in adipose tissue, we generated mice with global heterozygous Dicer1 deletion (Dicer1+/-) by breeding Dicer1Flox/Flox mice to mice with ubiquitous Cre expression under control of the cytomegalovirus immediate early enhancer and chicken beta-actin promoter (CAG-Cre).	('adipose', 'Gene', (109, 116))	('Dicer1', 'Gene', (168, 174))	('mice', 'Species', '10090', (224, 228))	('beta-actin', 'Gene', '396526', (342, 352))	('beta-actin', 'Gene', (342, 352))	('mice', 'Species', '10090', (138, 142))	('chicken', 'Species', '9031', (334, 341))	('deletion', 'Var', (175, 183))	('adipose', 'Gene', '230796', (109, 116))	('mice', 'Species', '10090', (232, 236))
164882	28916654	We then observed mice with AD+/+, ADFlox/+, AD+/-, and ADFlox/- genotypes to assess phenotypes with both global heterozygous and conditional loss of Dicer1.	('mice', 'Species', '10090', (17, 21))	('AD+/-', 'Var', (44, 49))	('loss', 'NegReg', (141, 145))	('Dicer1', 'Gene', (149, 155))	('ADFlox/-', 'Var', (55, 63))	('AD+/+', 'Var', (27, 32))
164883	28916654	Surprisingly, 100% of ADFlox/- mice developed large multifocal hemorrhagic blood-filled masses consistent with angiosarcomas with a median onset of 266 days (Fig.	('ADFlox/-', 'Var', (22, 30))	('angiosarcomas', 'Disease', (111, 124))	('mice', 'Species', '10090', (31, 35))	('angiosarcoma', 'Phenotype', 'HP:0200058', (111, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('angiosarcomas', 'Disease', 'MESH:D006394', (111, 124))	('angiosarcomas', 'Phenotype', 'HP:0200058', (111, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
164885	28916654	The hemorrhagic tumors in ADFlox/- mice occurred at various locations while primarily developing in the interscapular region of the back (75%) invading both the adjacent interscapular BAT and skeletal muscle.	('hemorrhagic tumors', 'Disease', (4, 22))	('ADFlox/-', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('hemorrhagic tumors', 'Disease', 'MESH:D006470', (4, 22))	('BAT', 'Disease', 'None', (184, 187))	('mice', 'Species', '10090', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('BAT', 'Disease', (184, 187))
164904	28916654	Genomic DNA from angiosarcomas of ADFlox/- mice only amplified the Cre-excised Dicer1- allele without detecting the presence of the non-recombined Dicer1Flox allele, indicating complete Cre-mediated recombination of Dicer1Flox and resulting Dicer1 deletion in angiosarcomas.	('mice', 'Species', '10090', (43, 47))	('angiosarcoma', 'Phenotype', 'HP:0200058', (17, 29))	('angiosarcoma', 'Phenotype', 'HP:0200058', (260, 272))	('angiosarcomas', 'Disease', (260, 273))	('Dicer1', 'Gene', (241, 247))	('sarcomas', 'Phenotype', 'HP:0100242', (265, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('angiosarcomas', 'Disease', (17, 30))	('angiosarcomas', 'Disease', 'MESH:D006394', (260, 273))	('Dicer1Flox', 'Var', (216, 226))	('angiosarcomas', 'Disease', 'MESH:D006394', (17, 30))	('angiosarcomas', 'Phenotype', 'HP:0200058', (260, 273))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('angiosarcomas', 'Phenotype', 'HP:0200058', (17, 30))	('deletion', 'Var', (248, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))
164908	28916654	To evaluate whether these were true angiosarcomas we sought to determine if gene sets related to endothelial cells and blood vessels were specifically altered in the tumors from the ADFlox/- mice.	('altered', 'Reg', (151, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('angiosarcomas', 'Disease', 'MESH:D006394', (36, 49))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('angiosarcomas', 'Phenotype', 'HP:0200058', (36, 49))	('gene sets', 'Gene', (76, 85))	('ADFlox/-', 'Var', (182, 190))	('mice', 'Species', '10090', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', (166, 172))	('angiosarcoma', 'Phenotype', 'HP:0200058', (36, 48))	('angiosarcomas', 'Disease', (36, 49))
164916	28916654	Immunoblots of angiosarcoma tumor lysates indicate hyperphosphorylation of p-ERK and p-S6 (Fig.	('p-S6', 'Var', (85, 89))	('angiosarcoma tumor', 'Disease', (15, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('hyperphosphorylation', 'MPA', (51, 71))	('angiosarcoma tumor', 'Disease', 'MESH:D006394', (15, 33))	('angiosarcoma', 'Phenotype', 'HP:0200058', (15, 27))	('p-ERK', 'Gene', (75, 80))	('p-ERK', 'Gene', '13666', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
164927	28916654	The deletion of Dicer1 with aP2-Cre is sufficient to drive angiosarcoma formation and results in decreased mature microRNA expression.	('angiosarcoma', 'Disease', (59, 71))	('angiosarcoma', 'Phenotype', 'HP:0200058', (59, 71))	('mature microRNA expression', 'MPA', (107, 133))	('decreased', 'NegReg', (97, 106))	('angiosarcoma', 'Disease', 'MESH:D006394', (59, 71))	('deletion', 'Var', (4, 12))	('aP2-Cre', 'Gene', (28, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('Dicer1', 'Gene', (16, 22))	('drive', 'PosReg', (53, 58))	('aP2-Cre', 'Gene', '226861', (28, 35))
164928	28916654	Therefore, we hypothesized that expression of target genes of the key microRNAs contributing to angiosarcoma development in the ADFlox/- mice would be enriched in tumors compared to normal blood vessels (Fig.	('angiosarcoma', 'Phenotype', 'HP:0200058', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('angiosarcoma', 'Disease', 'MESH:D006394', (96, 108))	('ADFlox/-', 'Var', (128, 136))	('angiosarcoma', 'Disease', (96, 108))	('mice', 'Species', '10090', (137, 141))
164942	28916654	DICER1 syndrome patients harbor germline nonsense or frameshift mutations resulting in DICER1 protein truncation and loss of enzymatic activity.	('DICER1 syndrome', 'Disease', (0, 15))	('enzymatic activity', 'MPA', (125, 143))	('loss', 'NegReg', (117, 121))	('truncation', 'MPA', (102, 112))	('DICER1', 'Gene', (87, 93))	('patients', 'Species', '9606', (16, 24))	('protein', 'Protein', (94, 101))	('germline nonsense or frameshift mutations', 'Var', (32, 73))
164943	28916654	The RNase IIIb domain is primarily responsible for generating 5p microRNAs, thus mutations in this domain affecting the metal-ion binding residues result in deficient pre-microRNA processing for mature 5p microRNAs while retaining expression of mature 3p microRNAs.	('deficient', 'NegReg', (157, 166))	('mutations', 'Var', (81, 90))	('pre-microRNA processing for mature 5p microRNAs', 'MPA', (167, 214))	('expression', 'MPA', (231, 241))	('metal', 'Chemical', 'MESH:D008670', (120, 125))
164945	28916654	An exception occurs in human pineoblastomas that display LOH of DICER1 and thus bialleic loss.	('LOH', 'Var', (57, 60))	('pineoblastoma', 'Phenotype', 'HP:0030408', (29, 42))	('bialleic loss', 'Disease', (80, 93))	('bialleic loss', 'Disease', 'MESH:D015431', (80, 93))	('human', 'Species', '9606', (23, 28))	('DICER1', 'Gene', (64, 70))	('pineoblastomas', 'Disease', (29, 43))	('pineoblastomas', 'Disease', 'MESH:D010871', (29, 43))
164946	28916654	In these studies, survival of Dicer1 null cells was contingent on cooperating oncogenes such as KrasG12D and/or loss of tumor suppressors such as p53.	('KrasG12D', 'Var', (96, 104))	('p53', 'Gene', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('loss', 'NegReg', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('p53', 'Gene', '22060', (146, 149))	('Dicer1', 'Gene', (30, 36))	('tumor', 'Disease', (120, 125))
164947	28916654	found that Dicer1 deletion in non-small cell lung cancer led to an angiogenic phenotype.	('angiogenic', 'CPA', (67, 77))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (30, 56))	('Dicer1', 'Gene', (11, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('non-small cell lung cancer', 'Disease', (30, 56))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (34, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('deletion', 'Var', (18, 26))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (30, 56))
164948	28916654	In this context, loss of Dicer1 relieved repression of the HIF inhibitor FIH1 leading to a non-cell autonomous reduction in tumor angiogenesis through down-regulation of Hif1a and Vegf.	('reduction', 'NegReg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Dicer1', 'Gene', (25, 31))	('Hif1a', 'Gene', (170, 175))	('FIH1', 'Gene', '319594', (73, 77))	('tumor', 'Disease', (124, 129))	('Vegf', 'Gene', '22339', (180, 184))	('FIH1', 'Gene', (73, 77))	('down-regulation', 'NegReg', (151, 166))	('Vegf', 'Gene', (180, 184))	('Hif1a', 'Gene', '15251', (170, 175))	('loss', 'Var', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
164949	28916654	In contrast, we found that Dicer1 deletion directly in endothelial cells leads to cell-autonomous tumorigenesis with no significant changes in Hif1a and Vegfa expression.	('Hif1a', 'Gene', (143, 148))	('Dicer1', 'Gene', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('leads to', 'Reg', (73, 81))	('Vegfa', 'Gene', '22339', (153, 158))	('Hif1a', 'Gene', '15251', (143, 148))	('deletion', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('Vegfa', 'Gene', (153, 158))
164950	28916654	Our aP2-Cre;Dicer1Flox/- angiosarcoma model represents the first in vivo evidence that biallelic Dicer1 loss functions as a cell-autonomous cancer driver.	('angiosarcoma', 'Disease', (25, 37))	('loss', 'NegReg', (104, 108))	('aP2-Cre', 'Gene', '226861', (4, 11))	('angiosarcoma', 'Phenotype', 'HP:0200058', (25, 37))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('aP2-Cre', 'Gene', (4, 11))	('angiosarcoma', 'Disease', 'MESH:D006394', (25, 37))	('Dicer1', 'Gene', (97, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('biallelic', 'Var', (87, 96))
164951	28916654	However, given the prolonged latency of angiosarcoma onset in ADFlox/- mice we cannot exclude the acquisitions of secondary "hits."	('mice', 'Species', '10090', (71, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('angiosarcoma', 'Disease', 'MESH:D006394', (40, 52))	('angiosarcoma', 'Disease', (40, 52))	('ADFlox/-', 'Var', (62, 70))	('angiosarcoma', 'Phenotype', 'HP:0200058', (40, 52))
164953	28916654	Dicer1 deletion drives angiosarcoma formation in our ADFlox/- model suggesting that abolishing microRNA regulation of target genes is central to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('angiosarcoma', 'Disease', 'MESH:D006394', (23, 35))	('Dicer1', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('angiosarcoma', 'Disease', (23, 35))	('tumor', 'Disease', (145, 150))	('microRNA regulation', 'MPA', (95, 114))	('angiosarcoma', 'Phenotype', 'HP:0200058', (23, 35))	('deletion', 'Var', (7, 15))
164958	28916654	Furthermore, deletion of Dicer1 and subsequent increased expression of miR-23 target genes likely participate in the pathogenesis of angiosarcoma through facilitating the G1/S transition with increased CCND1 and resulting CDK4/6 activity.	('CDK4/6', 'Gene', (222, 228))	('CDK4/6', 'Gene', '12567;12571', (222, 228))	('participate', 'Reg', (98, 109))	('CCND1', 'Gene', (202, 207))	('facilitating', 'Reg', (154, 166))	('expression', 'MPA', (57, 67))	('Dicer1', 'Gene', (25, 31))	('activity', 'MPA', (229, 237))	('deletion', 'Var', (13, 21))	('angiosarcoma', 'Disease', 'MESH:D006394', (133, 145))	('angiosarcoma', 'Phenotype', 'HP:0200058', (133, 145))	('CCND1', 'Gene', '12443', (202, 207))	('increased', 'PosReg', (192, 201))	('miR', 'Gene', (71, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('angiosarcoma', 'Disease', (133, 145))	('increased', 'PosReg', (47, 56))	('G1/S transition', 'CPA', (171, 186))	('miR', 'Gene', '735281', (71, 74))
165094	28004108	The evaluated markers were ER, PgR, p16, p53 and Ki67 for mitotic activity.	('p53', 'Gene', '7157', (41, 44))	('PgR', 'Gene', (31, 34))	('p16', 'Gene', '1029', (36, 39))	('Ki67', 'Var', (49, 53))	('mitotic activity', 'CPA', (58, 74))	('PgR', 'Gene', '5241', (31, 34))	('p16', 'Gene', (36, 39))	('p53', 'Gene', (41, 44))
165097	28004108	The STUMP showed a higher number of copy number alterations (CNAs) compared to the sarcoma (365 vs. 28); gains represent a totality of the sarcoma variations and the majority of STUMP (342/365).	('copy number', 'Var', (36, 47))	('sarcoma', 'Disease', (83, 90))	('sarcoma variations', 'Disease', 'MESH:D012509', (139, 157))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma variations', 'Disease', (139, 157))	('sarcoma', 'Disease', (139, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))
165107	28004108	FISH analysis performed on the relapsed cases 2 and 3 exhibited multiple copies of BCL2 (Fig.	('BCL2', 'Gene', (83, 87))	('BCL2', 'Gene', '596', (83, 87))	('multiple copies', 'Var', (64, 79))
165123	28004108	The role of BCL2 has been well characterized and amplification of this gene may result in blockage of apoptosis.	('amplification', 'Var', (49, 62))	('blockage', 'NegReg', (90, 98))	('apoptosis', 'CPA', (102, 111))	('BCL2', 'Gene', '596', (12, 16))	('BCL2', 'Gene', (12, 16))
165132	28004108	For this reason copy number gain of BCL2 appears notably also as a therapeutic target.	('BCL2', 'Gene', (36, 40))	('BCL2', 'Gene', '596', (36, 40))	('copy number gain', 'Var', (16, 32))
165244	26339191	This finding suggests that part of the positive benefit of OPG in CIBP may be a result of retarded tumor growth, in addition to inhibition of osteolysis.	('inhibition', 'NegReg', (128, 138))	('CIBP', 'Chemical', '-', (66, 70))	('osteolysis', 'Disease', (142, 152))	('retarded tumor', 'Disease', 'MESH:D009369', (90, 104))	('OPG', 'Var', (59, 62))	('osteolysis', 'Disease', 'MESH:D010014', (142, 152))	('CIBP', 'Disease', (66, 70))	('retarded tumor', 'Disease', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('osteolysis', 'Phenotype', 'HP:0002797', (142, 152))
165249	26339191	Modulating TGFbeta levels in the bone-tumor microenvironment, blocking TGFbeta signaling or disrupting PTHrP, IL-11, or VEGF production, and/or release may prove valuable strategies in the treatment of bone metastases.	('PTHrP', 'Gene', (103, 108))	('men', 'Species', '9606', (194, 197))	('bone-tumor', 'Phenotype', 'HP:0010622', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('rat', 'Species', '10116', (173, 176))	('disrupting', 'NegReg', (92, 102))	('IL-11', 'Gene', '16156', (110, 115))	('bone-tumor', 'Disease', 'MESH:D001859', (33, 43))	('men', 'Species', '9606', (56, 59))	('bone metastases', 'Disease', 'MESH:D009362', (202, 217))	('IL-11', 'Gene', (110, 115))	('VEGF', 'Gene', (120, 124))	('TGFbeta', 'Protein', (71, 78))	('Modulating', 'Var', (0, 10))	('VEGF', 'Gene', '22339', (120, 124))	('blocking', 'NegReg', (62, 70))	('bone metastases', 'Disease', (202, 217))	('release', 'MPA', (144, 151))	('bone-tumor', 'Disease', (33, 43))
165252	26339191	Additionally, blockade of TGFbeta signaling with the TFGbeta receptor I kinase inhibitor LY2109761 in this same model decreased intramedullary tumor burden as determined by histological staining.	('TGFbeta', 'Gene', (26, 33))	('tumor', 'Disease', (143, 148))	('LY2109761', 'Chemical', 'MESH:C530108', (89, 98))	('blockade', 'Var', (14, 22))	('decreased', 'NegReg', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
165257	26339191	Additionally, systemic administration of cancer-repressed miRNA inhibited osteoclasts in vivo and reduced breast cancer (MDA-MB-231) bone metastasis following intracardiac injection in nude mice.	('miRNA', 'Var', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('inhibited', 'NegReg', (64, 73))	('cancer', 'Disease', (113, 119))	('nude mice', 'Species', '10090', (185, 194))	('cancer', 'Disease', (41, 47))	('reduced', 'NegReg', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('osteoclasts', 'CPA', (74, 85))	('rat', 'Species', '10116', (31, 34))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
165270	26339191	A growing body of evidence suggests that NGF-induced aberrant nerve growth and reorganization contributes to CIBP.	('CIBP', 'Disease', (109, 113))	('reorganization', 'CPA', (79, 93))	('contributes', 'Reg', (94, 105))	('CIBP', 'Chemical', '-', (109, 113))	('aberrant', 'Var', (53, 61))
165288	26339191	Blockade of Trk receptors prevents downstream signaling not only from NGF but also from other neurotrophins.	('Trk', 'Gene', '18211', (12, 15))	('downstream signaling', 'MPA', (35, 55))	('Blockade', 'Var', (0, 8))	('prevents', 'NegReg', (26, 34))	('Trk', 'Gene', (12, 15))
165296	26339191	Taken together, these data suggest that neurotrophins may contribute to prostate, breast, and sarcoma CIBP through initiation of aberrant nerve sprouting, neuroma formation, and dysregulation of glutamatergic neurotransmission.	('neuroma', 'Phenotype', 'HP:0030430', (155, 162))	('neuroma', 'Disease', (155, 162))	('glutamate', 'Chemical', 'MESH:D018698', (195, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('dysregulation', 'Var', (178, 191))	('contribute', 'Reg', (58, 68))	('sarcoma CIBP', 'Disease', 'MESH:D012509', (94, 106))	('sarcoma CIBP', 'Disease', (94, 106))	('aberrant nerve sprouting', 'CPA', (129, 153))	('prostate', 'Disease', (72, 80))	('neuroma', 'Disease', 'MESH:D009463', (155, 162))	('breast', 'Disease', (82, 88))
165309	26339191	In addition to promoting glutamatergic neurotransmission, ROS/RNS may also drive tumor cell glutamate release.	('drive', 'Reg', (75, 80))	('RNS', 'Chemical', 'MESH:D011886', (62, 65))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('glutamate', 'Chemical', 'MESH:D018698', (25, 34))	('promoting', 'PosReg', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ROS/RNS', 'Var', (58, 65))	('glutamatergic neurotransmission', 'MPA', (25, 56))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('glutamate', 'Chemical', 'MESH:D018698', (92, 101))	('tumor', 'Disease', (81, 86))
165310	26339191	Several tumor cell lines, including C3L5 (mouse breast cancer), B16F1 (mouse melanoma), B16F10 (mouse melanoma), MAT-LyLu (rat prostate cancer), CNS-1 (rat astrocytoma), MDA-MB-231 (human breast cancer), and MCF-7 (human breast cancer), have been shown to release glutamate via the oxidative-stress inducible cystine-glutamate antiporter system xc-.	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('mouse', 'Species', '10090', (96, 101))	('rat', 'Species', '10116', (152, 155))	('cystine', 'Chemical', 'MESH:D003553', (309, 316))	('glutamate', 'Chemical', 'MESH:D018698', (317, 326))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('B16F10', 'CellLine', 'CVCL:0159', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('breast cancer', 'Disease', (48, 61))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('MAT-LyLu', 'Disease', (113, 121))	('breast cancer', 'Disease', (221, 234))	('mouse', 'Species', '10090', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Disease', (188, 201))	('B16F1', 'CellLine', 'CVCL:0158', (88, 93))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (170, 180))	('human', 'Species', '9606', (215, 220))	('prostate cancer', 'Disease', 'MESH:D011471', (127, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('human', 'Species', '9606', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('prostate cancer', 'Disease', (127, 142))	('melanoma', 'Disease', (77, 85))	('rat', 'Species', '10116', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', (8, 13))	('B16F1', 'CellLine', 'CVCL:0158', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('B16F10', 'Var', (88, 94))	('mouse', 'Species', '10090', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MAT-LyLu', 'Disease', 'MESH:C564683', (113, 121))	('glutamate', 'Chemical', 'MESH:D018698', (264, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('oxidative-stress', 'Phenotype', 'HP:0025464', (282, 298))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('MCF-7', 'CellLine', 'CVCL:0031', (208, 213))	('astrocytoma', 'Phenotype', 'HP:0009592', (156, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('release glutamate', 'MPA', (256, 273))
165334	26339191	Dysregulation of TNFalpha occurs in several inflammatory diseases, including rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, ulcerative colitis, and, recently, CIBP.	('TNFalpha', 'Gene', (17, 25))	('colitis', 'Phenotype', 'HP:0002583', (190, 197))	('occurs', 'Reg', (26, 32))	('Dysregulation', 'Var', (0, 13))	('psoriatic arthritis', 'Phenotype', 'HP:0003765', (140, 159))	('psoriasis', 'Phenotype', 'HP:0003765', (168, 177))	('rheumatoid arthritis', 'Disease', (77, 97))	('ulcerative colitis', 'Disease', 'MESH:D003093', (179, 197))	('ankylosing spondylitis', 'Disease', 'MESH:D013167', (116, 138))	('CIBP', 'Disease', (214, 218))	('psoriatic arthritis', 'Disease', (140, 159))	('psoriasis', 'Disease', 'MESH:D011565', (168, 177))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (77, 97))	('psoriasis', 'Disease', (168, 177))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (179, 197))	("Crohn's disease", 'Phenotype', 'HP:0100280', (99, 114))	('CIBP', 'Chemical', '-', (214, 218))	('psoriatic arthritis', 'Disease', 'MESH:D015535', (140, 159))	('TNFalpha', 'Gene', '21926', (17, 25))	('arthritis', 'Phenotype', 'HP:0001369', (88, 97))	("Crohn's disease", 'Disease', 'MESH:D003424', (99, 114))	("Crohn's disease", 'Disease', (99, 114))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (77, 97))	('ulcerative colitis', 'Disease', (179, 197))	('ankylosing spondylitis', 'Disease', (116, 138))	('arthritis', 'Phenotype', 'HP:0001369', (150, 159))
165342	26339191	Systemic antagonism of TNFalpha with the soluble receptor etanercept, marketed as Enbrel , reduced tactile hypersensitivity, spontaneous, and ambulatory pain in fibro-sarcoma tumor-bearing C57Bl/6J male mice.	('TNFalpha', 'Gene', (23, 31))	('hypersensitivity', 'Disease', 'MESH:D004342', (107, 123))	('TNFalpha', 'Gene', '21926', (23, 31))	('mice', 'Species', '10090', (203, 207))	('pain', 'Phenotype', 'HP:0012531', (153, 157))	('hypersensitivity', 'Disease', (107, 123))	('pain', 'Disease', 'MESH:D010146', (153, 157))	('fibro-sarcoma tumor', 'Disease', 'MESH:D009810', (161, 180))	('pain', 'Disease', (153, 157))	('reduced', 'NegReg', (91, 98))	('spontaneous', 'CPA', (125, 136))	('fibro-sarcoma tumor', 'Disease', (161, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('antagonism', 'Var', (9, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
165343	26339191	Likewise, in transgenic C57Bl/6J male mice deficient in both TNFR1 and TNFR2 (TNFR1-/-, TNFR2-/-), the development of tactile hypersensitivity following tumor cell injection was completely inhibited and spinal astrogliosis was markedly reduced, despite increased tumor growth.	('mice', 'Species', '10090', (38, 42))	('TNFR2', 'Gene', '21937', (71, 76))	('TNFR1', 'Gene', '21937', (61, 66))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', (263, 268))	('TNFR2', 'Gene', (88, 93))	('hypersensitivity', 'Disease', (126, 142))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('deficient', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('men', 'Species', '9606', (110, 113))	('reduced', 'NegReg', (236, 243))	('TNFR1', 'Gene', (78, 83))	('hypersensitivity', 'Disease', 'MESH:D004342', (126, 142))	('TNFR2', 'Gene', (71, 76))	('TNFR2', 'Gene', '21937', (88, 93))	('TNFR1', 'Gene', '21937', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('inhibited', 'NegReg', (189, 198))	('increased', 'PosReg', (253, 262))	('spinal astrogliosis', 'CPA', (203, 222))	('TNFR1', 'Gene', (61, 66))
165345	26339191	Deletion of TNFR2 (TNFR2-/-) but not TNFR1 (TNFR1-/-) attenuated heat hyperalgesia and prevented TRPV1 upregulation in tumor-bearing mice, suggesting a role for TNFR2 in TNFalpha TRPV1 regulation.	('mice', 'Species', '10090', (133, 137))	('TNFR1', 'Gene', '21937', (37, 42))	('prevented', 'NegReg', (87, 96))	('TNFR2', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('TNFR2', 'Gene', (19, 24))	('TNFR1', 'Gene', (44, 49))	('TNFR2', 'Gene', (161, 166))	('upregulation', 'PosReg', (103, 115))	('TNFR1', 'Gene', '21937', (44, 49))	('hyperalgesia', 'Disease', 'MESH:D006930', (70, 82))	('TRPV1', 'Protein', (97, 102))	('Deletion', 'Var', (0, 8))	('TNFalpha', 'Gene', '21926', (170, 178))	('TNFR2', 'Gene', '21937', (19, 24))	('TNFR2', 'Gene', '21937', (12, 17))	('TNFR2', 'Gene', '21937', (161, 166))	('hyperalgesia', 'Disease', (70, 82))	('attenuated', 'NegReg', (54, 64))	('hyperalgesia', 'Phenotype', 'HP:0031005', (70, 82))	('tumor', 'Disease', (119, 124))	('TNFalpha', 'Gene', (170, 178))	('TNFR1', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (119, 124))
165357	26339191	These findings suggest that CX3CR1 may promote pain in the spinal cord through a mechanism involving p38 MAPK and microglial activation.	('pain in the spinal cord', 'Phenotype', 'HP:0002176', (47, 70))	('microglial activation', 'CPA', (114, 135))	('promote', 'PosReg', (39, 46))	('p38 MAPK', 'Gene', (101, 109))	('CX3CR1', 'Var', (28, 34))	('pain', 'Phenotype', 'HP:0012531', (47, 51))	('pain', 'Disease', 'MESH:D010146', (47, 51))	('pain', 'Disease', (47, 51))	('p38 MAPK', 'Gene', '26416', (101, 109))
165373	26339191	In addition to these spinal alterations, CIBP is associated with a marked increase in sensory afferent expression of multiple acid-sensing ion channels, including TRPV1 and ASICs.	('CIBP', 'Chemical', '-', (41, 45))	('TRPV1', 'Gene', (163, 168))	('rat', 'Species', '10116', (32, 35))	('increase', 'PosReg', (74, 82))	('CIBP', 'Var', (41, 45))
165381	26339191	Additionally, blockade of TRPV1 with the selective antagonist JNJ-17203212 in 2472 osteolytic sarcoma-bearing C3H/HeJ mice attenuated both tumor-induced ongoing nocifensive behaviors and movement-evoked allodynia.	('allodynia', 'Disease', 'MESH:D006930', (203, 212))	('ongoing nocifensive behaviors', 'Disease', (153, 182))	('osteolytic sarcoma', 'Disease', (83, 101))	('JNJ-17203212', 'Chemical', 'MESH:C500065', (62, 74))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('osteolytic sarcoma', 'Phenotype', 'HP:0002669', (83, 101))	('allodynia', 'Disease', (203, 212))	('TRPV1', 'Gene', (26, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('allodynia', 'Phenotype', 'HP:0012533', (203, 212))	('men', 'Species', '9606', (191, 194))	('tumor', 'Disease', (139, 144))	('blockade', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('osteolytic sarcoma', 'Disease', 'MESH:D012509', (83, 101))	('mice', 'Species', '10090', (118, 122))	('ongoing nocifensive behaviors', 'Disease', 'MESH:D001523', (153, 182))	('attenuated', 'NegReg', (123, 133))
165382	26339191	JNJ-17203212's antihyperalgesic effect was evident in TRPV1 wild-type (+/+) and TRPV1 heterozygous mutant (+/-) mice but was occluded in TRPV1 homozygous mutant (-/-) mice, which displayed reduced ongoing and evoked pain-related behaviors as compared to wild-type mice, suggesting that a component of CIBP is TRPV1 mediated.	('TRPV1', 'Gene', (80, 85))	('mice', 'Species', '10090', (167, 171))	('antihyperalgesic', 'MPA', (15, 31))	('TRPV1', 'Gene', (54, 59))	('JNJ-17203212', 'Gene', (0, 12))	('mice', 'Species', '10090', (264, 268))	('JNJ-17203212', 'Chemical', 'MESH:C500065', (0, 12))	('pain', 'Phenotype', 'HP:0012531', (216, 220))	('CIBP', 'Chemical', '-', (301, 305))	('TRPV1', 'Gene', (137, 142))	('mice', 'Species', '10090', (112, 116))	('mutant', 'Var', (99, 105))	('pain', 'Disease', 'MESH:D010146', (216, 220))	('pain', 'Disease', (216, 220))	('mutant', 'Var', (154, 160))
165389	26339191	In the closely related MRMT-1 (mammary gland carcinoma) tibial injection Sprague-Dawley rat model, L4/5 DRG ASIC1a/1b expression was elevated.	('Sprague-Dawley rat', 'Species', '10116', (73, 91))	('ASIC1a', 'Gene', '11419', (108, 114))	('elevated', 'PosReg', (133, 141))	('carcinoma', 'Disease', (45, 54))	('mammary gland carcinoma', 'Phenotype', 'HP:0003002', (31, 54))	('L4/5 DRG', 'Var', (99, 107))	('expression', 'MPA', (118, 128))	('ASIC1a', 'Gene', (108, 114))	('carcinoma', 'Disease', 'MESH:D002277', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
165408	26339191	In sum, neurochemical reorganization in CIBP promotes nociceptive transmission and induces central sensitization.	('central sensitization', 'MPA', (91, 112))	('induces', 'Reg', (83, 90))	('promotes', 'PosReg', (45, 53))	('nociceptive transmission', 'MPA', (54, 78))	('CIBP', 'Chemical', '-', (40, 44))	('reorganization', 'Var', (22, 36))
165456	25153860	PM00104 (Zalypsis ): A Marine Derived Alkylating Agent PM00104 (Zalypsis ) is a synthethic tetrahydroisoquinolone alkaloid, which is structurally similar to many marine organisms.	('Zalypsis', 'Disease', 'None', (64, 72))	('Zalypsis', 'Disease', (64, 72))	('PM00104', 'Var', (55, 62))	('synthethic tetrahydroisoquinolone alkaloid', 'Chemical', '-', (80, 122))	('Zalypsis', 'Disease', 'None', (9, 17))	('Zalypsis', 'Disease', (9, 17))
165458	25153860	This manuscript provides a review of current trials and appraises the efficacy of PM00104 as a future cancer treatment.	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PM00104', 'Var', (82, 89))
165463	25153860	PM00104 (Zalypsis ) is a synthetic tetrahydroisoquinolone alkaloid, which mimics many natural marine compounds.	('PM00104', 'Var', (0, 7))	('synthetic tetrahydroisoquinolone alkaloid', 'Disease', (25, 66))	('synthetic tetrahydroisoquinolone alkaloid', 'Disease', 'OMIM:146820', (25, 66))	('Zalypsis', 'Disease', 'None', (9, 17))	('Zalypsis', 'Disease', (9, 17))
165465	25153860	PM00104 has shown strong initial in vitro models as a chemotherapeutic agent, and has had positive outcomes within in vivo experiments on a wide variety of human tumors.	('PM00104', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('human', 'Species', '9606', (156, 161))
165466	25153860	More recently, PM00104 has progressed into phase II clinical trials to treat Ewing sarcoma, urothelial carcinoma, multiple myeloma, endometrial and cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Ewing sarcoma', 'Disease', (77, 90))	('multiple myeloma', 'Phenotype', 'HP:0006775', (114, 130))	('multiple myeloma', 'Disease', 'MESH:D009101', (114, 130))	('endometrial and cervical cancer', 'Disease', 'MESH:D016889', (132, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('multiple myeloma', 'Disease', (114, 130))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('urothelial carcinoma', 'Disease', (92, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('PM00104', 'Var', (15, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (92, 112))
165469	25153860	The activation of tyrosine kinase receptors (RTKs) has been proposed to determine the susceptibility of tumors to PM00104.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('PM00104', 'Var', (114, 121))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('activation', 'PosReg', (4, 14))
165474	25153860	PM00104 has shown significant in vitro activity against both solid and non-solid human tumors.	('PM00104', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('human', 'Species', '9606', (81, 86))
165477	25153860	PM00104 has been able to treat breast, liver, prostate, bladder, gastric, and pancreatic tumors in xenografted mice.	('prostate', 'Disease', (46, 54))	('liver', 'Disease', (39, 44))	('PM00104', 'Var', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('bladder', 'Disease', (56, 63))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (78, 95))	('gastric', 'Disease', (65, 72))	('breast', 'Disease', (31, 37))	('mice', 'Species', '10090', (111, 115))	('pancreatic tumors', 'Disease', 'MESH:D010190', (78, 95))	('pancreatic tumors', 'Disease', (78, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
165478	25153860	Initial phase I clinical trials for PM00104 have primarily been set up as dose escalation studies to assess the toxicity of the drug.	('PM00104', 'Var', (36, 43))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))	('toxicity', 'Disease', (112, 120))
165482	25153860	Model based simulations comparing phase I clinical trials have found that PM00104-induced neutropenia is mainly dependent on the dosing frequency and concentration of the drug.	('PM00104-induced', 'Var', (74, 89))	('neutropenia', 'Disease', (90, 101))	('neutropenia', 'Disease', 'MESH:D009503', (90, 101))	('neutropenia', 'Phenotype', 'HP:0001875', (90, 101))
165486	25153860	The results of the study confirmed that combination therapy with PM00104 has the potential for overlapping toxicities, which hampers the dose escalation of either compound.	('toxicities', 'Disease', (107, 117))	('PM00104', 'Var', (65, 72))	('toxicities', 'Disease', 'MESH:D064420', (107, 117))
165489	25153860	The disease is characterized by rearrangements between the EWS gene and members of the ETS gene family.	('EWS', 'Gene', (59, 62))	('rearrangements', 'Var', (32, 46))	('EWS', 'Gene', '2130', (59, 62))
165490	25153860	The main goal of this study was to measure the objective response rates of patients with Ewing sarcoma to PM00104.	('PM00104', 'Var', (106, 113))	('patients', 'Species', '9606', (75, 83))	('Ewing sarcoma', 'Disease', (89, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))
165501	25153860	This clinical trial was an open-label, two-arm study designed to assess the antitumor activity and safety concerns with the use of PM00104 in advanced/metastatic endometrial or cervical cancer.	('cervical cancer', 'Disease', (177, 192))	('cervical cancer', 'Disease', 'MESH:D002583', (177, 192))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (80, 85))	('PM00104', 'Var', (131, 138))	('advanced/metastatic endometrial', 'Disease', (142, 173))
165506	25153860	Overall, PM00104 as a single-agent did not prove to be an effective therapy for patients with advanced/metastatic endometrial or cervical cancer.	('patients', 'Species', '9606', (80, 88))	('cervical cancer', 'Disease', (129, 144))	('cervical cancer', 'Disease', 'MESH:D002583', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('PM00104', 'Var', (9, 16))	('not', 'NegReg', (39, 42))
165510	25153860	This study was conducted to determine the recommended dose of PM00104 to be administered as a 1 h infusion on days 1, 8, and 15 every 4 weeks in relapsed or refractory multiple myeloma patients.	('PM00104', 'Var', (62, 69))	('multiple myeloma', 'Phenotype', 'HP:0006775', (168, 184))	('multiple myeloma', 'Disease', 'MESH:D009101', (168, 184))	('multiple myeloma', 'Disease', (168, 184))	('patients', 'Species', '9606', (185, 193))	('relapsed', 'Disease', (145, 153))
165511	25153860	The complete results from this trial have not been published, but preliminary data showed PM00104 to be safe to use in the treatment of multiple myeloma.	('PM00104', 'Var', (90, 97))	('multiple myeloma', 'Phenotype', 'HP:0006775', (136, 152))	('multiple myeloma', 'Disease', 'MESH:D009101', (136, 152))	('multiple myeloma', 'Disease', (136, 152))
165512	25153860	While PM00104 has shown promising single agent anti-tumor activity in laboratory studies, this has not translated into clinical benefit in a number of phase II trials.	('tumor', 'Disease', (52, 57))	('PM00104', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))
165529	30237940	Case series have identified UV-signature mutations in the TP53 gene as well as likely oncogenic HRAS, KRAS, NOTCH1/2, and FAT1 mutations by the sequencing of AFX tumor samples.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('KRAS', 'Gene', (102, 106))	('HRAS', 'Gene', (96, 100))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('NOTCH1/2', 'Gene', '4851;4853', (108, 116))	('AFX tumor', 'Disease', (158, 167))	('FAT1', 'Gene', '2195', (122, 126))	('NOTCH1/2', 'Gene', (108, 116))	('AFX tumor', 'Disease', 'MESH:D009369', (158, 167))	('FAT1', 'Gene', (122, 126))	('mutations', 'Var', (127, 136))	('KRAS', 'Gene', '3845', (102, 106))	('HRAS', 'Gene', '3265', (96, 100))
165530	30237940	Given the predilection of AFX for the sun-exposed skin of the head and neck in older patients and the presence of UV-signature p53 mutations, AFX emerges as a tumor with similar characteristics to non-melanoma skin cancers, such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (which are currently thought to be attributable to cumulative and chronic sun exposure).	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (263, 286))	('basal cell carcinoma', 'Disease', (232, 252))	('p53', 'Gene', '7157', (127, 130))	('SCC', 'Gene', '6317', (288, 291))	('AFX', 'Chemical', '-', (26, 29))	('skin cancer', 'Phenotype', 'HP:0008069', (210, 221))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (197, 222))	('patients', 'Species', '9606', (85, 93))	('squamous cell carcinoma', 'Disease', (263, 286))	('SCC', 'Gene', (288, 291))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('BCC', 'Phenotype', 'HP:0002671', (254, 257))	('p53', 'Gene', (127, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('skin cancers', 'Phenotype', 'HP:0008069', (210, 222))	('tumor', 'Disease', (159, 164))	('non-melanoma skin cancers', 'Disease', (197, 222))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (232, 252))	('AFX', 'Chemical', '-', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('mutations', 'Var', (131, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (263, 286))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (232, 252))	('SCC', 'Phenotype', 'HP:0002860', (288, 291))
165551	30237940	This decision is made difficult by the morphological similarities between AFX and PDS, such as spindle or round cell histology, the presence of pleomorphism and atypical mitotic figures, and CD10 marker positivity.	('CD10', 'Gene', (191, 195))	('AFX', 'Chemical', '-', (74, 77))	('PDS', 'Disease', 'MESH:C536648', (82, 85))	('CD10', 'Gene', '4311', (191, 195))	('pleomorphism', 'Var', (144, 156))	('PDS', 'Disease', (82, 85))
165647	26425101	Immunohistochemical staining of the tumor cells was positive for VIM, SMA, Ki-67, and CD99 (Figure 2B-E), but negative for DES (Figure 2F), S100, CK (pan), CD31, CD34, Actin, CD117, and CD68.	('S100', 'Var', (140, 144))	('VIM', 'Gene', (65, 68))	('CD117', 'Gene', (175, 180))	('CD31', 'Gene', (156, 160))	('CD68', 'Gene', (186, 190))	('CD34', 'Gene', '947', (162, 166))	('SMA', 'Gene', (70, 73))	('CD31', 'Gene', '5175', (156, 160))	('CD34', 'Gene', (162, 166))	('CD99', 'Gene', '4267', (86, 90))	('CD68', 'Gene', '968', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SMA', 'Gene', '6606', (70, 73))	('VIM', 'Gene', '7431', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CD99', 'Gene', (86, 90))	('tumor', 'Disease', (36, 41))	('CD117', 'Gene', '3815', (175, 180))
165686	26425101	An analysis of 20 cases by Wong et al suggested that patients who underwent PEA had significant alleviation of symptoms, even though surgery did not result in a statistically significant survival benefit.	('PEA', 'Var', (76, 79))	('patients', 'Species', '9606', (53, 61))	('PE', 'Phenotype', 'HP:0002204', (76, 78))	('symptoms', 'MPA', (111, 119))	('alleviation', 'NegReg', (96, 107))
165696	21646333	Differentially regulated splice variants and systems biology analysis of Kaposi's sarcoma-associated herpesvirus-infected lymphatic endothelial cells Alternative RNA splicing greatly increases proteome diversity, and the possibility of studying genome-wide alternative splicing (AS) events becomes available with the advent of high-throughput genomics tools devoted to this issue.	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (73, 89))	("Kaposi's sarcoma-associated herpesvirus", 'Species', '37296', (73, 112))	('increases', 'PosReg', (183, 192))	('Alternative', 'Var', (150, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('proteome diversity', 'MPA', (193, 211))
165717	21646333	For example, how KSHV-regulated AS events may produce profound changes in the predicted protein domain/motif composition that ought to affect protein function and interaction, such as changes in the genetic networking, and how exon inclusion/exclusion may modify the predicted microRNA binding site composition of transcripts, remains unelucidated.	('KS', 'Phenotype', 'HP:0100726', (17, 19))	('changes', 'Reg', (184, 191))	('interaction', 'MPA', (163, 174))	('affect', 'Reg', (135, 141))	('exon', 'Var', (227, 231))	('modify', 'Reg', (256, 262))	('KSHV', 'Species', '37296', (17, 21))	('microRNA binding site composition of transcripts', 'MPA', (277, 325))	('protein function', 'MPA', (142, 158))	('protein domain/motif composition', 'MPA', (88, 120))	('changes', 'Reg', (63, 70))	('KSHV-regulated', 'Var', (17, 31))
165753	21646333	For the lentivirus-expressed shRNA against RAPGEF5 (NM_012294), two 21-nt sequences corresponding coding sequences 1145-1165 (5'-gctaagaagtatcaaggcaaa-3') and 1376-1396 (5'-cgtcacactgtagatgaatat-3') inserted into pLKO.1 were obtained from the National RNAi Core Facility at Academia Sinica, Taiwan (http://rnai.genmed.sinica.edu.tw/en/).	('RAPGEF5', 'Gene', (43, 50))	('RAPGEF5', 'Gene', '9771', (43, 50))	('1145-1165', 'Var', (115, 124))
165771	21646333	Overexpressing GATA2 in matured endothelial cells induces dedifferentiation-like transcriptome drift.	('GATA2', 'Gene', '2624', (15, 20))	('GATA2', 'Gene', (15, 20))	('Overexpressing', 'Var', (0, 14))	('dedifferentiation-like transcriptome drift', 'MPA', (58, 100))	('induces', 'Reg', (50, 57))
165773	21646333	Various angiogenesis related genes, such as EPHB2, HIF3A and RUNX1T1, were also found to be altered by KSHV, which is consistent with the clinical observation that KS is a highly angiogenic neoplasm.	('neoplasm', 'Phenotype', 'HP:0002664', (190, 198))	('angiogenesis related genes', 'Gene', (8, 34))	('KSHV', 'Species', '37296', (103, 107))	('KSHV', 'Var', (103, 107))	('RUNX1T1', 'Gene', (61, 68))	('EPHB2', 'Gene', (44, 49))	('KS', 'Phenotype', 'HP:0100726', (103, 105))	('angiogenic neoplasm', 'Phenotype', 'HP:0100742', (179, 198))	('neoplasm', 'Disease', (190, 198))	('neoplasm', 'Disease', 'MESH:D009369', (190, 198))	('altered', 'Reg', (92, 99))	('HIF3A', 'Gene', (51, 56))	('KS', 'Phenotype', 'HP:0100726', (164, 166))
165781	21646333	We confirmed by Transwell assay that KSHV also stimulates the motility of primary LECs (Figure 2A, histogram).	('stimulates', 'PosReg', (47, 57))	('motility', 'CPA', (62, 70))	('KS', 'Phenotype', 'HP:0100726', (37, 39))	('KSHV', 'Species', '37296', (37, 41))	('KSHV', 'Var', (37, 41))
165782	21646333	The 'insulin receptor' and 'smoothened signaling' pathways were also both affected by KSHV (Figure 2A, Supplementary Figure S2A).	('affected', 'Reg', (74, 82))	("'smoothened signaling' pathways", 'Pathway', (27, 58))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('KSHV', 'Species', '37296', (86, 90))	('KSHV', 'Var', (86, 90))	('insulin receptor', 'Gene', (5, 21))	('men', 'Species', '9606', (109, 112))	('insulin receptor', 'Gene', '3643', (5, 21))
165799	21646333	Hub genes in a biological system very often play more important roles than spoke genes, and the dysregulation of a hub can eventually lead to disruption of the genetic network and the malfunction of the cell.	('lead to', 'Reg', (134, 141))	('genetic network', 'Pathway', (160, 175))	('hub', 'Gene', (115, 118))	('malfunction of the cell', 'CPA', (184, 207))	('disruption', 'MPA', (142, 152))	('dysregulation', 'Var', (96, 109))	('Hub', 'Gene', (0, 3))	('hub', 'Gene', '1993', (115, 118))	('Hub', 'Gene', '1993', (0, 3))
165805	21646333	From the present study, it can be clearly seen that KSHV is able to influence the splicing patterns of critical stemness genes and oncofetal proteins [such as GATA2 and NFATC4 ] in LECs.	('KSHV', 'Species', '37296', (52, 56))	('critical stemness genes', 'Gene', (103, 126))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('influence', 'Reg', (68, 77))	('KSHV', 'Var', (52, 56))	('splicing patterns', 'MPA', (82, 99))	('GATA2', 'Gene', (159, 164))	('NFATC4', 'Gene', (169, 175))	('NFATC4', 'Gene', '4776', (169, 175))	('GATA2', 'Gene', '2624', (159, 164))
165806	21646333	The splicing pattern of the CD34 precursor marker was also altered by KSHV (File S2 in Supplementary Data).	('altered', 'Reg', (59, 66))	('men', 'Species', '9606', (93, 96))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('KSHV', 'Species', '37296', (70, 74))	('KSHV', 'Var', (70, 74))	('CD34', 'Gene', '947', (28, 32))	('splicing pattern', 'MPA', (4, 20))	('CD34', 'Gene', (28, 32))
165807	21646333	Since re-expression of GATA2 stemness genes is able to induce reprogramming and dedifferentiation of matured endothelial cells, and it has been recognized that aggressive and poor prognostic tumors acquire characters reminiscent of embryonic stem cells (ESCs), we hypothesized that KSHV infection may induce dedifferentiation-like transcriptome reprogramming of mature LECs.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('KSHV infection', 'Disease', (282, 296))	('reprogramming', 'CPA', (62, 75))	('dedifferentiation-like', 'CPA', (308, 330))	('GATA2', 'Gene', '2624', (23, 28))	('KSHV infection', 'Disease', 'MESH:C537372', (282, 296))	('KS', 'Phenotype', 'HP:0100726', (282, 284))	('induce', 'Reg', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('re-expression', 'Var', (6, 19))	('GATA2', 'Gene', (23, 28))	('tumors', 'Disease', (191, 197))	('induce', 'Reg', (301, 307))	('dedifferentiation', 'CPA', (80, 97))
165815	21646333	The AS of EGFR and CASP9 could be validated by RT-qPCR using primer sets specific for exons 25 or 26 of EGFR, as well as primers for exons 4b or 5 of CASP9.	('EGFR', 'Gene', '1956', (10, 14))	('CASP9', 'Gene', '842', (150, 155))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', (10, 14))	('CASP9', 'Gene', (19, 24))	('exons', 'Var', (86, 91))	('CASP9', 'Gene', (150, 155))	('EGFR', 'Gene', '1956', (104, 108))	('CASP9', 'Gene', '842', (19, 24))
165834	21646333	So, when AS events with inclusive miRNA sites were checked, it was found that the levels were down in KSHV-LECs compared with those in parental LECs control.	('KS', 'Phenotype', 'HP:0100726', (102, 104))	('KSHV-LECs', 'Var', (102, 111))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('down', 'NegReg', (94, 98))	('KSHV', 'Species', '37296', (102, 106))	('levels', 'MPA', (82, 88))
165841	21646333	The role of RAPGEF5 in KSHV-induced pathogenicity was explored by examining its function in LEC motility: when the expression of endogenous RAPGEF5 was knocked down by shRNA, a reduced cellular motility was observed (Figure 6E), suggesting RAPGEF5 is crucial for LEC motility.	('knocked', 'Var', (152, 159))	('RAPGEF5', 'Gene', '9771', (12, 19))	('RAPGEF5', 'Gene', (240, 247))	('KS', 'Phenotype', 'HP:0100726', (23, 25))	('reduced', 'NegReg', (177, 184))	('cellular motility', 'CPA', (185, 202))	('RAPGEF5', 'Gene', (12, 19))	('expression', 'MPA', (115, 125))	('RAPGEF5', 'Gene', '9771', (140, 147))	('KSHV', 'Species', '37296', (23, 27))	('RAPGEF5', 'Gene', '9771', (240, 247))	('RAPGEF5', 'Gene', (140, 147))
165843	21646333	Understanding the added complexity of transcript-processing variations and the potential outcome of these differences will greatly enhance our knowledge of KS pathogenesis and KSHV life cycle.	('KS', 'Phenotype', 'HP:0100726', (176, 178))	('KSHV', 'Species', '37296', (176, 180))	('enhance', 'PosReg', (131, 138))	('KS', 'Phenotype', 'HP:0100726', (156, 158))	('variations', 'Var', (60, 70))
165851	21646333	In this analysis, 773 genes harbored alternative splicing upon early EBV infection, in which 49 AS events were also found in KSHV-infected LEC (Supplementary Figure S4 and Supplementary Table S2).	('KSHV-infected', 'Disease', (125, 138))	('KSHV-infected', 'Disease', 'MESH:C537372', (125, 138))	('alternative splicing', 'Var', (37, 57))	('EBV infection', 'Disease', (69, 82))	('EBV infection', 'Disease', 'MESH:D020031', (69, 82))	('KS', 'Phenotype', 'HP:0100726', (125, 127))	('men', 'Species', '9606', (150, 153))	('men', 'Species', '9606', (178, 181))
165873	21646333	On the other hand, the possibility that KSHV may induce dedifferentiation in infected cells has not been explored.	('induce', 'Reg', (49, 55))	('KSHV', 'Species', '37296', (40, 44))	('KSHV', 'Var', (40, 44))	('dedifferentiation', 'CPA', (56, 73))	('KS', 'Phenotype', 'HP:0100726', (40, 42))
165874	21646333	It has been recognized that during malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms that control cellular proliferation.	('mutations', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('override', 'PosReg', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
165879	21646333	In this study, it has been revealed by exon array that KSHV can also induce 'dedifferentiation' like exome drift, which is also readily disclosed by classical gene expression-based transcriptome analysis (Figure 4).	('exome drift', 'Disease', (101, 112))	('KSHV', 'Species', '37296', (55, 59))	("'dedifferentiation'", 'Disease', (76, 95))	('KSHV', 'Var', (55, 59))	('induce', 'Reg', (69, 75))	('KS', 'Phenotype', 'HP:0100726', (55, 57))
165888	32313375	The resected tumor showed a histopathology of pleomorphic sarcoma positive for the TP53 mutation.	('TP53', 'Gene', '7157', (83, 87))	('tumor', 'Disease', (13, 18))	('mutation', 'Var', (88, 96))	('pleomorphic sarcoma', 'Disease', 'MESH:D012509', (46, 65))	('TP53', 'Gene', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('pleomorphic sarcoma', 'Disease', (46, 65))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
165900	32313375	Herein, we report a case of a 13-yr-old girl with PMT-MCT that evolved to pleomorphic sarcoma harboring a TP53 mutation after a 4-yr-treatment course for TIO.	('TP53', 'Gene', '7157', (106, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('girl', 'Species', '9606', (40, 44))	('pleomorphic sarcoma', 'Disease', 'MESH:D012509', (74, 93))	('mutation', 'Var', (111, 119))	('pleomorphic sarcoma', 'Disease', (74, 93))	('TP53', 'Gene', (106, 110))
165907	32313375	Blood tests at Fukuoka Children's Hospital revealed high levels of alkaline phosphatase (4820 U/L, reference range [rr]: 400-1450), normal levels of calcium (9.8 mg/dl, rr: 8.8-10.1), and severe hypophosphatemia (1.7 mg/dl, rr: 3.7-5.8), along with increased levels of serum intact FGF23 (132 pg/ml, rr: 16-69).	('calcium', 'Chemical', 'MESH:D002118', (149, 156))	('increased levels of serum intact FGF23', 'Phenotype', 'HP:0030269', (249, 287))	('4820 U/L', 'Var', (89, 97))	('high levels of alkaline phosphatase', 'Phenotype', 'HP:0003155', (52, 87))	('hypophosphatemia', 'Disease', 'MESH:D017674', (195, 211))	('FGF23', 'Gene', '8074', (282, 287))	('alkaline phosphatase', 'MPA', (67, 87))	('increased', 'PosReg', (249, 258))	('hypophosphatemia', 'Phenotype', 'HP:0002148', (195, 211))	('Children', 'Species', '9606', (23, 31))	('hypophosphatemia', 'Disease', (195, 211))	('FGF23', 'Gene', (282, 287))
165921	32313375	All biopsied sample specimens showed a histopathology of PMT-MCT, identical to that of the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('PMT-MCT', 'Var', (57, 64))
165934	32313375	Direct sequencing of the tumor-derived DNA showed a mutation in TP53 gene; p.R249S (c747G>T).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('p.R249S', 'Mutation', 'rs28934571', (75, 82))	('p.R249S (c747G>T', 'Var', (75, 91))	('c747G>T', 'Mutation', 'rs28934571', (84, 91))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
165949	32313375	To the best of our knowledge, our case presented here is the first case of malignant PMT-MCT examined for mutations in the TP53 gene.	('TP53', 'Gene', '7157', (123, 127))	('mutations', 'Var', (106, 115))	('TP53', 'Gene', (123, 127))
165976	32313375	The diffuse positivity of p53 in immunohistochemical staining and the TP53 mutation identified in the patient suggested a contribution of the TP53 mutation to the transformation of PMT-MCT.	('patient', 'Species', '9606', (102, 109))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('mutation', 'Var', (147, 155))	('TP53', 'Gene', '7157', (70, 74))	('p53', 'Gene', (26, 29))	('contribution', 'Reg', (122, 134))	('TP53', 'Gene', (70, 74))	('p53', 'Gene', '7157', (26, 29))
165980	31664066	Cancer-prone Tp53+/C273X knockout rats received mediastinal irradiation with 3 x 5 or 3 x 8 Gy using volumetric-modulated arc therapy (VMAT, an advanced IMRT) or conventional anterior-posterior/posterior-anterior (AP/PA) beams using non-irradiated rats as controls (n = 15/group, ntotal = 90).	('rats', 'Species', '10116', (34, 38))	('rats', 'Species', '10116', (248, 252))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('C273X', 'Mutation', 'p.C273X', (19, 24))	('Tp53+/C273X', 'Var', (13, 24))
165984	31664066	LOH was strongly associated with sarcoma but not with treatment.	('LOH', 'Var', (0, 3))	('associated', 'Reg', (17, 27))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('sarcoma', 'Disease', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))
165985	31664066	The results do not support the hypothesis that IMRT increases the risk of second cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('IMRT', 'Var', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
165996	31664066	A nonsense mutation in codon 273 (C273) in exon 6 of the rat Tp53 gene (homologous to codon 275 in exon 8 of the human TP53 gene) produces no detectable truncated protein 53 (p53) in rats homozygous for this mutation, probably as a result of nonsense-mediated mRNA decay.	('rat', 'Species', '10116', (183, 186))	('C273', 'Var', (34, 38))	('human', 'Species', '9606', (113, 118))	('rats', 'Species', '10116', (183, 187))	('rat', 'Species', '10116', (57, 60))	('truncated', 'MPA', (153, 162))	('Tp53', 'Gene', (61, 65))
165997	31664066	Heterozygous Tp53+/C273X rats were chosen as a model because of the longer latency time for tumor development compared to homozygous animals.	('rats', 'Species', '10116', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('C273X', 'Mutation', 'p.C273X', (19, 24))	('Tp53+/C273X', 'Var', (13, 24))
165998	31664066	The model is similar but not identical to the classic Li-Fraumeni syndrome in humans, which is usually characterized by heterozygosity for an inactivating amino acid substitution in TP53.	('TP53', 'Gene', (182, 186))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (54, 74))	('humans', 'Species', '9606', (78, 84))	('inactivating amino acid substitution', 'Var', (142, 178))	('Li-Fraumeni syndrome', 'Disease', (54, 74))
166000	31664066	Experimental Tp53+/C273X rats were derived from 2 male and 3 female Tp53+/C273X ancestors for filial generation 1 (F1) rat litters 1 to 3 (L1-L3) and from six pairs of homozygous (Tp53C273X/C273X) male and wild type female F1 non-siblings generating F2 litters (L4-L14).	('C273X', 'Mutation', 'p.C273X', (19, 24))	('rats', 'Species', '10116', (25, 29))	('rat', 'Species', '10116', (105, 108))	('rat', 'Species', '10116', (243, 246))	('rat', 'Species', '10116', (119, 122))	('Tp53C273X/C273X', 'Var', (180, 195))	('C273X', 'Mutation', 'p.C273X', (190, 195))	('C273X', 'Mutation', 'p.C273X', (184, 189))	('C273X', 'Mutation', 'p.C273X', (74, 79))	('rat', 'Species', '10116', (25, 28))	('Tp53+/C273X', 'Var', (68, 79))
166042	31664066	Sequence analysis of 40 representative index tumors that could be examined for LOH of Tp53, revealed LOH in 55% of the tumors, which was strongly associated with sarcomas (bone and soft tissue) in contrast to non-sarcoma tumors (15/18 vs 7/24; p = 0.0015, Fisher's exact test; Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('tumors', 'Disease', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('non-sarcoma tumors', 'Disease', 'MESH:D012509', (209, 227))	('sarcomas', 'Disease', 'MESH:D012509', (162, 170))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (45, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('LOH', 'Var', (101, 104))	('sarcomas', 'Disease', (162, 170))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('associated', 'Reg', (146, 156))	('non-sarcoma tumors', 'Disease', (209, 227))
166043	31664066	All LOH showed the C273X mutation without sequence changes, consistent with complete loss of the wildtype allele or duplication of the mutated allele.	('C273X', 'Mutation', 'p.C273X', (19, 24))	('C273X', 'Var', (19, 24))	('loss', 'NegReg', (85, 89))	('duplication', 'Var', (116, 127))
166050	31664066	The hypothesis of increased induction of second cancers in the low-dose volume is based on models of radiation-induced carcinogenesis assuming a linear dose response that reaches a maximum, or saturation, at moderate doses owing to the combined effect of mutation, cell killing, and repopulation.	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('rat', 'Species', '10116', (197, 200))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('mutation', 'Var', (255, 263))	('rat', 'Species', '10116', (212, 215))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
166059	31664066	Lymphoma and soft tissue sarcoma were strongly associated with the irradiated volume but mesotheliomas and carcinomas were also found.	('mesotheliomas', 'Disease', 'MESH:D008654', (89, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('mesotheliomas', 'Disease', (89, 102))	('carcinomas', 'Disease', 'MESH:D002277', (107, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('carcinomas', 'Disease', (107, 117))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (13, 32))	('Lymphoma and soft tissue sarcoma', 'Disease', 'MESH:D012509', (0, 32))	('irradiated', 'Var', (67, 77))	('Lymphoma', 'Phenotype', 'HP:0002665', (0, 8))	('associated', 'Reg', (47, 57))
166070	31664066	The Tp53C273X rat model used here showed no detectable truncated p53 which makes it similar to other Tp53 knockout models in mice and rats.	('p53', 'Gene', (65, 68))	('rats', 'Species', '10116', (134, 138))	('mice', 'Species', '10090', (125, 129))	('truncated', 'MPA', (55, 64))	('rat', 'Species', '10116', (134, 137))	('C273X', 'Mutation', 'p.C273X', (8, 13))	('Tp53C273X', 'Var', (4, 13))	('rat', 'Species', '10116', (14, 17))
166073	31664066	By contrast, heterozygous Tp53+/C273X rats are expected to show haplo-insufficiency of the p53, which may compromise its role in maintaining genomic stability without producing a gain-of-function frequently associated with mutated TP53 in human tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('haplo-insufficiency', 'Var', (64, 83))	('rats', 'Species', '10116', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('genomic stability', 'CPA', (141, 158))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('p53', 'Gene', (91, 94))	('compromise', 'NegReg', (106, 116))	('Tp53+/C273X', 'Var', (26, 37))	('human', 'Species', '9606', (239, 244))	('tumors', 'Disease', (245, 251))	('C273X', 'Mutation', 'p.C273X', (32, 37))
166074	31664066	In the present study, Tp53+/C273X LOH was mainly associated with sarcomas but not with irradiation.	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('Tp53+/C273X LOH', 'Var', (22, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('C273X', 'Mutation', 'p.C273X', (28, 33))	('associated', 'Reg', (49, 59))	('sarcomas', 'Disease', (65, 73))
166075	31664066	This is consistent with the high rate of TP53 mutations and LOH in human radiation-induced sarcomas suggesting that p53 inactivation is an early event in many of these tumors.	('TP53', 'Gene', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (46, 55))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('rat', 'Species', '10116', (33, 36))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcomas', 'Disease', (91, 99))	('human', 'Species', '9606', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
166145	31034598	Treatment delays associated with an AE occurred in 42% of the patients receiving ontuxizumab plus G/D and in 45% of the patients receiving the placebo plus G/D.	('ontuxizumab', 'Var', (81, 92))	('ontuxizumab', 'Chemical', '-', (81, 92))	('patients', 'Species', '9606', (120, 128))	('Treatment', 'Disease', (0, 9))	('patients', 'Species', '9606', (62, 70))
166175	31034598	Longer PFS was associated with higher serum endosialin concentrations (HR, 0.61; 95% CI, 0.36-1.03), lower tissue endosialin expression in venous endothelial cells (HR, 1.01; 95% CI, 1.0-1.02), and lower tissue PDGFR-beta levels in capillary endothelial cells (HR, 0.74; 95% CI, 0.51-1.06).	('endosialin', 'Gene', '57124', (114, 124))	('PDGFR-beta', 'Gene', (211, 221))	('endosialin', 'Gene', (44, 54))	('PFS', 'Var', (7, 10))	('endosialin', 'Gene', '57124', (44, 54))	('lower', 'NegReg', (101, 106))	('endosialin', 'Gene', (114, 124))	('higher', 'PosReg', (31, 37))	('PDGFR-beta', 'Gene', '5159', (211, 221))	('lower', 'NegReg', (198, 203))
166242	32368290	Genetic alterations in ALT/WDL and DL include telomere fusion, ring chromosome, giant marker chromosome, and MDM2 and CDK4 amplification.	('MDM2', 'Gene', (109, 113))	('ring chromosome', 'CPA', (63, 78))	('CDK4', 'Gene', (118, 122))	('CDK4', 'Gene', '1019', (118, 122))	('telomere fusion', 'CPA', (46, 61))	('amplification', 'Var', (123, 136))	('giant marker chromosome', 'CPA', (80, 103))	('MDM2', 'Gene', '4193', (109, 113))
166243	32368290	In ML, the translocation of chromosome t (12; 16; q13; P11) leads to the fusion of DDIT3 and FUS, while t (12;22) causes the fusion of DDIT3 and EWSR1.	('DDIT3', 'Gene', (83, 88))	('FUS', 'Gene', '2521', (93, 96))	('DDIT3', 'Gene', (135, 140))	('DDIT3', 'Gene', '1649', (83, 88))	('t (12;22', 'Var', (104, 112))	('EWSR1', 'Gene', (145, 150))	('translocation', 'Var', (11, 24))	('DDIT3', 'Gene', '1649', (135, 140))	('EWSR1', 'Gene', '2130', (145, 150))	('leads to', 'Reg', (60, 68))	('FUS', 'Gene', (93, 96))
166244	32368290	Although the diagnosis of liposarcoma benefits from those variations, they do not have specificity in liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('liposarcoma benefits', 'Disease', (26, 46))	('liposarcoma', 'Disease', (26, 37))	('liposarcoma benefits', 'Disease', 'MESH:D008080', (26, 46))	('variations', 'Var', (58, 68))	('liposarcoma', 'Disease', (102, 113))	('liposarcoma', 'Phenotype', 'HP:0012034', (26, 37))	('liposarcoma', 'Disease', 'MESH:D008080', (26, 37))	('liposarcoma', 'Phenotype', 'HP:0012034', (102, 113))	('liposarcoma', 'Disease', 'MESH:D008080', (102, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
166252	32368290	The abnormal expression of perilipins is associated with the occurrence and development of various diseases, such as atherosclerotic disease, fatty liver, inflammation, sebaceous cancer, and gastrointestinal neoplasm.	('perilipin', 'Gene', (27, 36))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('atherosclerotic disease', 'Disease', 'MESH:D050197', (117, 140))	('inflammation', 'Disease', (155, 167))	('fatty liver', 'Disease', (142, 153))	('perilipin', 'Gene', '5346', (27, 36))	('atherosclerotic disease', 'Phenotype', 'HP:0002621', (117, 140))	('atherosclerotic disease', 'Disease', (117, 140))	('sebaceous cancer', 'Disease', (169, 185))	('abnormal', 'Var', (4, 12))	('gastrointestinal neoplasm', 'Disease', 'MESH:D004067', (191, 216))	('sebaceous cancer', 'Disease', 'MESH:D009369', (169, 185))	('neoplasm', 'Phenotype', 'HP:0002664', (208, 216))	('gastrointestinal neoplasm', 'Phenotype', 'HP:0007378', (191, 216))	('fatty liver', 'Phenotype', 'HP:0001397', (142, 153))	('expression', 'MPA', (13, 23))	('gastrointestinal neoplasm', 'Disease', (191, 216))	('sebaceous cancer', 'Phenotype', 'HP:0030410', (169, 185))	('fatty liver', 'Disease', 'MESH:D005234', (142, 153))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))
166316	32368290	High expression of PLIN5 leads to myocardial lipid accumulation and cardiomyopathy caused by type 1 diabetes.	('High expression', 'Var', (0, 15))	('diabetes', 'Disease', (100, 108))	('leads to', 'Reg', (25, 33))	('cardiomyopathy', 'Disease', (68, 82))	('myocardial lipid accumulation', 'MPA', (34, 63))	('PLIN5', 'Gene', '440503', (19, 24))	('diabetes', 'Disease', 'MESH:D003920', (100, 108))	('lipid', 'Chemical', 'MESH:D008055', (45, 50))	('PLIN5', 'Gene', (19, 24))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (93, 108))	('cardiomyopathy', 'Disease', 'MESH:D009202', (68, 82))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (68, 82))
166341	32368290	Studies have shown that the growth of cervical cancer cells with knocked-out PLIN3 was inhibited.	('growth', 'CPA', (28, 34))	('PLIN3', 'Gene', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('PLIN3', 'Gene', '10226', (77, 82))	('knocked-out', 'Var', (65, 76))	('inhibited', 'NegReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
166366	32115849	High IGF2 expression was also significantly associated with shorter overall survival in patients with ES.	('IGF2', 'Gene', '3481', (5, 9))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (88, 96))	('IGF2', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('overall survival', 'MPA', (68, 84))	('shorter', 'NegReg', (60, 67))	('High IGF2', 'Phenotype', 'HP:0030269', (0, 9))
166367	32115849	Finally, our results indicate that IGF inhibition may be successful as a first-line therapy in conjunction with conventional radiochemotherapy for a subset of patients.	('inhibition', 'Var', (39, 49))	('patients', 'Species', '9606', (159, 167))	('IGF', 'Protein', (35, 38))
166372	32115849	Recurrent secondary events include deletions of the CDK2NA gene and sporadic mutations in the TP53 and STAG2 genes, the two later having modest negative prognostic value (Brohl et al., 2014; Huang et al., 2005; Kovar et al., 1993, 1997).	('STAG2', 'Gene', (103, 108))	('STAG2', 'Gene', '10735', (103, 108))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('deletions', 'Var', (35, 44))	('CDK2NA', 'Gene', (52, 58))
166387	32115849	Comparative factors included fusion gene variant (EWS-Fli1 vs. EWS-ERG), tumor localization (central vs. extremity), patient gender, age (< 20 vs. >= 20 years old), and survival at follow-up.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('EWS-Fli1', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('. EWS', 'Gene', '2130', (61, 66))	('tumor', 'Disease', (73, 78))	('patient', 'Species', '9606', (117, 124))	('. EWS', 'Gene', (61, 66))
166405	32115849	STAG2 knockdown was confirmed by immunoblotting.	('knockdown', 'Var', (6, 15))	('STAG2', 'Gene', (0, 5))	('STAG2', 'Gene', '10735', (0, 5))
166419	32115849	A total of 25 mug of protein from each sample was separated on NuPAGE  SDS/PAGE (Thermo Fisher; Cat # NP0322BOX or Cat # NP0342BOX) and transferred to nitrocellulose membranes using electrophoresis.	('Cat # NP0342BOX', 'Var', (115, 130))	('Cat # NP0322BOX', 'Var', (96, 111))	('SDS', 'Chemical', 'MESH:D012967', (71, 74))
166421	32115849	The primary antibodies recognizing IGF-1R (#3027L; 1 : 800), pAKT (Thr308, #9275L; 1 : 800), pERK (Thr202/Tyr204, #9101L; 1 : 1000), total AKT(#9272S; 1 : 1000), total ERK (#4696S; 1 : 1000), PARP (#9542; 1 : 800), cleaved PARP (#5625; 1 : 800), Caspase 3 (#9665; 1 : 800), cleaved Caspase 3 (#9664; 1 : 800), Caspase 9 (#9508; 1 : 800), cleaved Caspase 9 (#52873; 1 : 800), Caspase 7 (#12827; 1 : 800), cleaved Caspase 7 (#8438; 1 : 800), p16 (#4824S; 1 : 800), produced by Cell Signaling Technology, and Histone 3 (#sc-10809; 1 : 1000), and GAPDH (#sc-25778, 1 : 2000) provided by Santa Cruz Biotechnology (Dallas, TX, USA) were used for immunoblots at the indicated concentrations.	('p16', 'Gene', '1029', (440, 443))	('AKT', 'Gene', (62, 65))	('ERK', 'Gene', (94, 97))	('AKT', 'Gene', '207', (139, 142))	('p16', 'Gene', (440, 443))	('#8438', 'Var', (423, 428))	('AKT', 'Gene', (139, 142))	('ERK', 'Gene', (168, 171))	('ERK', 'Gene', '5594', (168, 171))	('AKT', 'Gene', '207', (62, 65))	('ERK', 'Gene', '5594', (94, 97))
166454	32115849	Since IGF2 expression was associated with shorter patient survival and first-line therapy failure, we investigated the effects of IGF2 stimulation on ES cell radiosensitivity.	('shorter', 'NegReg', (42, 49))	('IGF2', 'Gene', '3481', (130, 134))	('cell radiosensitivity', 'Phenotype', 'HP:0010997', (153, 174))	('patient survival', 'CPA', (50, 66))	('IGF2', 'Gene', '3481', (6, 10))	('IGF2', 'Gene', (130, 134))	('expression', 'Var', (11, 21))	('IGF2', 'Gene', (6, 10))	('patient', 'Species', '9606', (50, 57))
166455	32115849	By 24 h after irradiation, exogenous IGF2 increased cell viability in RD-ES, SK-ES-1, SK-N-MC, and CADO cells (P < 0.01), but by 48 h the effects were significant only in RD-ES, CADO, and SK-N-MC cells (P < 0.05).	('increased', 'PosReg', (42, 51))	('exogenous', 'Var', (27, 36))	('CADO', 'Chemical', '-', (178, 182))	('SK-ES-1', 'CellLine', 'CVCL:0627', (77, 84))	('IGF2', 'Gene', '3481', (37, 41))	('cell viability', 'CPA', (52, 66))	('SK-N-MC', 'CellLine', 'CVCL:0530', (86, 93))	('IGF2', 'Gene', (37, 41))	('CADO', 'Chemical', '-', (99, 103))	('SK-N-MC', 'CellLine', 'CVCL:0530', (188, 195))
166484	32115849	It has previously been shown that loss of imprinting (LOI)-independent hypomethylation of P3 induces IGF2 expression in osteosarcoma, and ovarian and prostate cancer (Kuffer et al., 2018; Li et al., 2009; Murphy et al., 2006); however, several transcription factors have been known to regulate P3 methylation and activity, for example, Paxillin, STAT3, and PLAG1 (Akhtar et al., 2012; Huang et al., 2014; Lee et al., 2016; Marasek et al., 2015).	('osteosarcoma', 'Disease', (120, 132))	('loss', 'Var', (34, 38))	('IGF2', 'Gene', (101, 105))	('expression', 'MPA', (106, 116))	('osteosarcoma', 'Disease', 'MESH:D012516', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('induces', 'Reg', (93, 100))	('hypomethylation', 'Var', (71, 86))	('IGF2', 'Gene', '3481', (101, 105))	('ovarian and prostate cancer', 'Disease', 'MESH:D011472', (138, 165))	('prostate cancer', 'Phenotype', 'HP:0012125', (150, 165))	('osteosarcoma', 'Phenotype', 'HP:0002669', (120, 132))
166485	32115849	We investigated whether the IGF2/H19 expression could be triggered by either STAG2 mutations or CDKN2A deletion given the known role of these events in ES.	('mutations', 'Var', (83, 92))	('IGF2', 'Gene', (28, 32))	('IGF2', 'Gene', '3481', (28, 32))	('STAG2', 'Gene', (77, 82))	('H19', 'Gene', (33, 36))	('STAG2', 'Gene', '10735', (77, 82))	('H19', 'Gene', '283120', (33, 36))	('CDKN2A', 'Gene', (96, 102))	('triggered', 'Reg', (57, 66))	('deletion', 'Var', (103, 111))
166486	32115849	Experimentally, this was investigated in CADO cells by siRNA knockdown of STAG2 expression [CADO is STAG2 wild-type as described by Huang et al.	('STAG2', 'Gene', (100, 105))	('CADO', 'Chemical', '-', (41, 45))	('STAG2', 'Gene', '10735', (100, 105))	('STAG2', 'Gene', (74, 79))	('STAG2', 'Gene', '10735', (74, 79))	('knockdown', 'Var', (61, 70))	('CADO', 'Chemical', '-', (92, 96))
166487	32115849	Huang et al., 2011 (Tirode et al., 2014)] and by CDKN2A overexpression in CADO cells [which are known to harbor a homozygous CDKN2A deletion (Ottaviano et al., 2010)].	('deletion', 'Var', (132, 140))	('CADO', 'Chemical', '-', (74, 78))	('overexpression', 'PosReg', (56, 70))	('CDKN2A', 'Gene', (125, 131))	('CDKN2A', 'Gene', (49, 55))
166488	32115849	Opposite to our hypothesis, STAG2 knockdown resulted in decreased levels of IGF2 and H19 (Fig.	('STAG2', 'Gene', '10735', (28, 33))	('levels', 'MPA', (66, 72))	('IGF2', 'Gene', (76, 80))	('IGF2', 'Gene', '3481', (76, 80))	('decreased', 'NegReg', (56, 65))	('knockdown', 'Var', (34, 43))	('H19', 'Gene', (85, 88))	('H19', 'Gene', '283120', (85, 88))	('STAG2', 'Gene', (28, 33))
166500	32115849	Also, recurrent tumors and metastatic lesions had an increased number of genetic aberrations (Brohl et al., 2014).	('tumors', 'Disease', (16, 22))	('metastatic lesions', 'CPA', (27, 45))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('genetic aberrations', 'Var', (73, 92))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
166508	32115849	Another important observation is that IGF2 expression was accompanied by changes in other pathways (Fig.	('changes', 'Reg', (73, 80))	('IGF2', 'Gene', '3481', (38, 42))	('expression', 'Var', (43, 53))	('IGF2', 'Gene', (38, 42))
166620	30400799	From the tissue microarray, undifferentiated pleomorphic sarcoma showed >= 1% immunoreactivity in 20%, 17.6%, and 16.3% of the cases with PD-L1 22C3, SP263, and SP142 antibodies, respectively.	('PD-L1 22C3', 'Var', (138, 148))	('SP142 antibodies', 'Var', (161, 177))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (28, 64))	('undifferentiated pleomorphic sarcoma', 'Disease', (28, 64))	('immunoreactivity', 'MPA', (78, 94))	('SP142', 'Chemical', '-', (161, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('SP263', 'Var', (150, 155))
166673	30400799	In a comparison of the three PD-L1 antibodies, 22C3 and SP263 showed a strong correlation (Pearson's r = 0.882), but SP142 showed only moderate correlation with 22C3 (Pearson's r = 0.551) and SP263 (Pearson's r = 0.503) (Additional file 1: Table S4).	('correlation', 'Interaction', (78, 89))	('SP263', 'Var', (192, 197))	('SP142', 'Chemical', '-', (117, 122))	('SP263', 'Var', (56, 61))
166689	30400799	Sarcoma subtypes belonging to this group include translocation-associated tumors, such as synovial sarcoma and myxoid liposarcoma, and mutation-associated tumors such as a gastrointestinal stromal tumor.	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (172, 202))	('synovial sarcoma', 'Disease', 'MESH:D013584', (90, 106))	('liposarcoma', 'Phenotype', 'HP:0012034', (118, 129))	('Sarcoma', 'Disease', (0, 7))	('gastrointestinal stromal tumor', 'Disease', (172, 202))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (90, 106))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (111, 129))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('myxoid liposarcoma', 'Disease', (111, 129))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (155, 161))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (111, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (172, 202))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('synovial sarcoma', 'Disease', (90, 106))	('translocation-associated', 'Var', (49, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('tumors', 'Disease', (74, 80))
166735	29463311	A 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant.	('RAF', 'Gene', (96, 99))	('mutations', 'Var', (100, 109))	('cell myeloma', 'Disease', 'MESH:D009101', (43, 55))	('RAF', 'Gene', '22882', (96, 99))	('plasma cell myeloma', 'Phenotype', 'HP:0006775', (36, 55))	('cell myeloma', 'Disease', (43, 55))	('MAF', 'Gene', '4094', (65, 68))	('IGH', 'Gene', '3492', (61, 64))	('man', 'Species', '9606', (14, 17))	('IGH', 'Gene', (61, 64))	('MAF', 'Gene', (65, 68))	('melphalan', 'Chemical', 'MESH:D008558', (168, 177))
166737	29463311	Next generation sequencing (NGS) studies detected similar clonal aberrations in the diagnostic plasma cell population and post-therapy neoplastic cells, including IGH-MAF rearrangement, multiple genetic mutations in RAS signaling pathway proteins, and loss of tumor suppressor genes.	('rearrangement', 'Var', (171, 184))	('IGH', 'Gene', '3492', (163, 166))	('MAF', 'Gene', '4094', (167, 170))	('IGH', 'Gene', (163, 166))	('loss of tumor', 'Disease', 'MESH:D009369', (252, 265))	('MAF', 'Gene', (167, 170))	('RAS', 'Pathway', (216, 219))	('loss of tumor', 'Disease', (252, 265))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('mutations', 'Var', (203, 212))
166744	29463311	For example, KRAS, NRAS and BRAF mutations are detected in approximately 33% of newly diagnosed PCM patients.	('BRAF', 'Gene', '673', (28, 32))	('NRAS', 'Gene', (19, 23))	('mutations', 'Var', (33, 42))	('PCM', 'Disease', (96, 99))	('NRAS', 'Gene', '4893', (19, 23))	('patients', 'Species', '9606', (100, 108))	('BRAF', 'Gene', (28, 32))	('KRAS', 'Gene', (13, 17))	('PCM', 'Phenotype', 'HP:0006775', (96, 99))	('detected', 'Reg', (47, 55))	('KRAS', 'Gene', '3845', (13, 17))
166745	29463311	Disease progression in PCM can be associated with disease at extramedullary sites, high grade plasma cell morphology, acquisition of additional genetic mutations or possibly reactivation of Epstein Barr virus infection.	('Epstein Barr virus infection', 'Disease', (190, 218))	('associated', 'Reg', (34, 44))	('mutations', 'Var', (152, 161))	('PCM', 'Disease', (23, 26))	('PCM', 'Phenotype', 'HP:0006775', (23, 26))	('Epstein Barr virus infection', 'Disease', 'MESH:D020031', (190, 218))	('high grade plasma cell morphology', 'CPA', (83, 116))
166757	29463311	Cytogenetic analysis of the bone marrow aspirate cells revealed a complex karyotype: 43,XY,del(1)(p13p32),+ 3,der(3;6)(q10;p10),del(5)(q15q33),?	('p10', 'Gene', (123, 126))	('p10', 'Gene', '6281', (123, 126))	('del(1)(p13p32', 'Var', (91, 104))	('del(5)(q15q33', 'Var', (128, 141))
166758	29463311	t(9;15)(p24;q24),-10,add(13)(p11.2),del(14)(q24),-20,-22,inc[3]/46,XY[17].	('p11', 'Gene', (29, 32))	('t(9;15)(p24;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (0, 16))	('del(14)(q24', 'Var', (36, 47))	('p11', 'Gene', '6281', (29, 32))	('t(9;15)(p24;q24', 'Var', (0, 15))
166761	29463311	Foundation One  NGS studies revealed IGH-MAF gene rearrangement and several genomic alterations, including BRAF G469V and G466A, KRAS A146V, MAP3K6 Q943, CDKN2A/B loss, TRAF3 R505 and PTPRO E379K (Table 1).	('BRAF', 'Gene', (107, 111))	('G466A', 'Mutation', 'rs121913351', (122, 127))	('E379K', 'Mutation', 'p.E379K', (190, 195))	('MAF', 'Gene', '4094', (41, 44))	('IGH', 'Gene', '3492', (37, 40))	('G466A', 'Var', (122, 127))	('KRAS', 'Gene', (129, 133))	('MAF', 'Gene', (41, 44))	('IGH', 'Gene', (37, 40))	('CDKN2A/B', 'Gene', '1029;1030', (154, 162))	('KRAS', 'Gene', '3845', (129, 133))	('G469V', 'Mutation', 'rs121913355', (112, 117))	('BRAF', 'Gene', '673', (107, 111))	('MAP3K6 Q943', 'Var', (141, 152))	('CDKN2A/B', 'Gene', (154, 162))	('A146V', 'Mutation', 'rs1057519725', (134, 139))
166770	29463311	These cells expressed CD45 (bright), CD33, HLA-DR, CD14 (bright), CD11b (bright) and CD36 (variable) (Fig.	('CD45', 'Gene', '5788', (22, 26))	('CD36', 'Species', '42374', (85, 89))	('CD36', 'Var', (85, 89))	('CD11b', 'Gene', (66, 71))	('CD11b', 'Gene', '3684', (66, 71))	('CD14', 'Gene', (51, 55))	('CD45', 'Gene', (22, 26))	('CD14', 'Gene', '929', (51, 55))	('CD33', 'Gene', '945', (37, 41))	('CD33', 'Gene', (37, 41))
166775	29463311	FISH studies performed on the mediastinal lymph node and gingival biopsies revealed a translocation between chromosomes 14 and 16 [IGH and MAF genes; t(14;16)(q32;q23)] in approximately 76% and 73% of interphase nuclei examined (Fig.	('IGH', 'Gene', '3492', (131, 134))	('IGH', 'Gene', (131, 134))	('translocation', 'Var', (86, 99))	('t(14;16)(q32;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (150, 167))	('MAF', 'Gene', '4094', (139, 142))	('MAF', 'Gene', (139, 142))
166776	29463311	The gingival lesion showed a normal karyotype (46,XY[4]/45,Y,-X[1]) with a low mitotic index.	('low', 'NegReg', (75, 78))	('mitotic index', 'CPA', (79, 92))	('46', 'Var', (47, 49))	('gingival lesion', 'Disease', 'MESH:D005882', (4, 19))	('gingival lesion', 'Disease', (4, 19))	('45,Y,-X', 'STRUCTURAL_ABNORMALITY', 'None', (56, 63))
166777	29463311	NGS studies performed on the gingival lesion demonstrated IGH-MAF rearrangement, BRAF and KRAS mutations, CDKN2A/B loss, TNFAIP3 and NF1 mutations (Table 1).	('CDKN2A/B', 'Gene', (106, 114))	('BRAF', 'Gene', '673', (81, 85))	('gingival lesion', 'Disease', 'MESH:D005882', (29, 44))	('MAF', 'Gene', (62, 65))	('BRAF', 'Gene', (81, 85))	('NF1', 'Gene', '4763', (133, 136))	('TNFAIP3', 'Gene', '7128', (121, 128))	('MAF', 'Gene', '4094', (62, 65))	('loss', 'NegReg', (115, 119))	('TNFAIP3', 'Gene', (121, 128))	('NF1', 'Gene', (133, 136))	('rearrangement', 'Var', (66, 79))	('KRAS', 'Gene', '3845', (90, 94))	('CDKN2A/B', 'Gene', '1029;1030', (106, 114))	('IGH', 'Gene', (58, 61))	('mutations', 'Var', (95, 104))	('KRAS', 'Gene', (90, 94))	('gingival lesion', 'Disease', (29, 44))	('IGH', 'Gene', '3492', (58, 61))	('mutations', 'Var', (137, 146))
166793	29463311	showed overexpression of C/EBPalpha and C/EBPbeta converted mature murine B cells into macrophages by suppressing PAX-5 expression.	('C/EBPbeta', 'Var', (40, 49))	('expression', 'MPA', (120, 130))	('PAX-5', 'Gene', (114, 119))	('murine', 'Species', '10090', (67, 73))	('suppressing', 'NegReg', (102, 113))
166801	29463311	Similar to our case showing loss of CDKN2A/B, loss of CDKN2A has been reported in HS subsequent to B-lymphoblastic leukemia.	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (101, 123))	('CDKN2A', 'Gene', (36, 42))	('CDKN2A/B', 'Gene', '1029;1030', (36, 44))	('B-lymphoblastic leukemia', 'Disease', 'MESH:D015456', (99, 123))	('B-lymphoblastic leukemia', 'Disease', (99, 123))	('CDKN2A', 'Gene', '1029', (36, 42))	('loss', 'Var', (46, 50))	('CDKN2A', 'Gene', (54, 60))	('CDKN2A/B', 'Gene', (36, 44))	('CDKN2A', 'Gene', '1029', (54, 60))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))
166802	29463311	BRAF V600E mutation has been reported in de novo HS and HS following splenic marginal zone lymphoma and hairy cell leukemia.	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('splenic marginal zone lymphoma', 'Disease', 'MESH:D018442', (69, 99))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('splenic marginal zone lymphoma', 'Disease', (69, 99))	('hairy cell leukemia', 'Disease', (104, 123))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (104, 123))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('BRAF', 'Gene', (0, 4))
166803	29463311	NGS analysis of the myeloid sarcoma in this case showed a clonal, non V600E activating mutation in BRAF.	('non V600E activating', 'Var', (66, 86))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (20, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('myeloid sarcoma', 'Disease', (20, 35))	('V600E', 'Mutation', 'rs113488022', (70, 75))
166804	29463311	The BRAF mutation (G469A) is distinct from other variants identified in de novo HS, including BRAF F595 L, BRAF (G466R), BRAF (G464 V) and BRAF (N581S); however, as in this case, these BRAF variants are not mutually exclusive with activating RAS mutations.	('BRAF', 'Gene', (121, 125))	('N581S', 'Mutation', 'rs121913370', (145, 150))	('mutation (G469A', 'Var', (9, 24))	('BRAF', 'Gene', '673', (94, 98))	('BRAF', 'Gene', (94, 98))	('G466R', 'Mutation', 'rs121913353', (113, 118))	('F595 L', 'Var', (99, 105))	('G464 V', 'Mutation', 'rs121913348', (127, 133))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', '673', (107, 111))	('BRAF', 'Gene', '673', (139, 143))	('F595 L', 'Mutation', 'rs121913341', (99, 105))	('BRAF', 'Gene', (107, 111))	('BRAF', 'Gene', (139, 143))	('G469A', 'Mutation', 'rs121913355', (19, 24))	('BRAF', 'Gene', '673', (185, 189))	('BRAF', 'Gene', '673', (121, 125))	('BRAF', 'Gene', (185, 189))
166805	29463311	Like other cases of secondary HS, a clonal relationship between the primary PCM and secondary tumor in current case was confirmed by FISH and NGS analyses showing IGH-MAF gene rearrangement, and similar genomic alterations in KRAS, BRAF and MAK3K6.	('IGH', 'Gene', '3492', (163, 166))	('KRAS', 'Gene', '3845', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('MAF', 'Gene', '4094', (167, 170))	('gene rearrangement', 'Var', (171, 189))	('IGH', 'Gene', (163, 166))	('BRAF', 'Gene', '673', (232, 236))	('PCM', 'Phenotype', 'HP:0006775', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('MAF', 'Gene', (167, 170))	('BRAF', 'Gene', (232, 236))	('tumor', 'Disease', (94, 99))	('rearrangement', 'Var', (176, 189))	('MAK3K6', 'Gene', (241, 247))	('KRAS', 'Gene', (226, 230))
166808	29463311	In addition to shared clonal abnormalities, additional aberrancies were detected in the sarcoma tumor cells, including deletion of a subclone of BRAF (G466A), loss of TRAF3 R505 and new clonal mutations in NF1 and TNFAIP3 (Table 1).	('BRAF', 'Gene', (145, 149))	('sarcoma tumor', 'Disease', 'MESH:D012509', (88, 101))	('TNFAIP3', 'Gene', '7128', (214, 221))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TRAF3', 'Gene', (167, 172))	('deletion', 'Var', (119, 127))	('sarcoma tumor', 'Disease', (88, 101))	('NF1', 'Gene', '4763', (206, 209))	('loss', 'Var', (159, 163))	('clonal abnormalities', 'Disease', (22, 42))	('mutations', 'Var', (193, 202))	('TNFAIP3', 'Gene', (214, 221))	('G466A', 'Mutation', 'rs121913351', (151, 156))	('NF1', 'Gene', (206, 209))	('clonal abnormalities', 'Disease', 'MESH:C580365', (22, 42))	('R505', 'Var', (173, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('BRAF', 'Gene', '673', (145, 149))
166809	29463311	TRAF3 is a critical determinant of B cell survival and loss of function mutations in TRAF3 and TNFAIP3 are associated with B cell malignancies and PCM.	('mutations', 'Var', (72, 81))	('TNFAIP3', 'Gene', '7128', (95, 102))	('malignancies', 'Disease', (130, 142))	('PCM', 'Disease', (147, 150))	('TRAF3', 'Gene', (85, 90))	('loss of function', 'NegReg', (55, 71))	('TNFAIP3', 'Gene', (95, 102))	('PCM', 'Phenotype', 'HP:0006775', (147, 150))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))
166810	29463311	NF1 mutation, a negative regulator of RAS signaling, has been reported in rare cases of plasma cell myeloma and approximately 4% of acute myeloid leukemia, but not reported in HS.	('cell myeloma', 'Disease', (95, 107))	('cell myeloma', 'Disease', 'MESH:D009101', (95, 107))	('acute myeloid leukemia', 'Disease', (132, 154))	('plasma cell myeloma', 'Phenotype', 'HP:0006775', (88, 107))	('reported', 'Reg', (62, 70))	('mutation', 'Var', (4, 12))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (132, 154))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('NF1', 'Gene', (0, 3))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (138, 154))	('NF1', 'Gene', '4763', (0, 3))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (132, 154))
166816	29463311	The findings of an additional mutation in RAS-BRAF signaling (NF1 mutation) and NF-kB activation (TNFAIP3) suggests multiple mechanisms contribute to lineage transformation.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('NF-kB', 'Gene', (80, 85))	('mutation', 'Var', (30, 38))	('TNFAIP3', 'Gene', '7128', (98, 105))	('NF1', 'Gene', (62, 65))	('TNFAIP3', 'Gene', (98, 105))	('lineage transformation', 'CPA', (150, 172))	('NF1', 'Gene', '4763', (62, 65))	('activation', 'PosReg', (86, 96))
166824	25985210	We also found that Sgt1 heterozygous knockout resulted in suppressed Hras-mediated transformation in vitro and tumor formation in p53-/- mouse embryonic fibroblast cells and significantly increased survival of p53-/- mice.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('p53', 'Gene', (210, 213))	('p53', 'Gene', '22060', (130, 133))	('mouse', 'Species', '10090', (137, 142))	('Hras-mediated transformation', 'CPA', (69, 97))	('Sgt1', 'Gene', (19, 23))	('mice', 'Species', '10090', (217, 221))	('knockout', 'Var', (37, 45))	('p53', 'Gene', '22060', (210, 213))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('suppressed', 'NegReg', (58, 68))	('tumor', 'Disease', (111, 116))	('p53', 'Gene', (130, 133))	('increased', 'PosReg', (188, 197))
166825	25985210	Moreover, depletion of Sgt1 inhibited the growth of Ewing sarcoma and rhabdomyosarcoma cells and destabilized EWS-FLI1 and PAX3-FOXO1 oncogenic fusion proteins, respectively, which are required for cellular growth.	('growth', 'CPA', (42, 48))	('destabilized', 'NegReg', (97, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('Sgt1', 'Gene', (23, 27))	('Ewing sarcoma and rhabdomyosarcoma', 'Disease', 'MESH:C563168', (52, 86))	('depletion', 'Var', (10, 19))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (70, 86))	('inhibited', 'NegReg', (28, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
166827	25985210	Dysregulation of oncogenes and tumor suppressor genes is a common feature of different types of cancer.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('oncogenes', 'Protein', (17, 26))	('cancer', 'Disease', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
166828	25985210	Because aberrant oncoproteins are unstable, cancer cells utilize Hsp90 as a chaperone to promote folding and function of mutated or overexpressed oncoproteins.	('promote', 'PosReg', (89, 96))	('cancer', 'Disease', (44, 50))	('folding', 'MPA', (97, 104))	('mutated', 'Var', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('aberrant', 'Var', (8, 16))	('function', 'MPA', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
166835	25985210	Therefore, knockdown of Sgt1 expression induces misalignment of chromosomes, activation of a weakened spindle checkpoint and, possibly, the occurrence of aneuploidy.	('induces', 'Reg', (40, 47))	('aneuploidy', 'Disease', 'MESH:D000782', (154, 164))	('spindle checkpoint', 'CPA', (102, 120))	('activation', 'PosReg', (77, 87))	('aneuploidy', 'Disease', (154, 164))	('misalignment of chromosomes', 'CPA', (48, 75))	('Sgt1', 'Gene', (24, 28))	('knockdown', 'Var', (11, 20))
166857	25985210	These results indicate that the truncated Sgt1 protein is not functional and that Sgt1 homozygous knockout results in early embryonic lethality in mice.	('protein', 'Protein', (47, 54))	('mice', 'Species', '10090', (147, 151))	('knockout', 'Var', (98, 106))	('Sgt1', 'Gene', (82, 86))	('embryonic lethality', 'Disease', 'MESH:D020964', (124, 143))	('embryonic lethality', 'Disease', (124, 143))	('results in', 'Reg', (107, 117))	('Sgt1', 'Gene', (42, 46))
166858	25985210	To evaluate the effect of decreased Sgt1 protein, we established Sgt1+/+ p53-/- and Sgt1+/- p53-/- MEF cells by crossing Sgt1 knockout and p53 knockout mice.	('MEF', 'CellLine', 'CVCL:9115', (99, 102))	('p53', 'Gene', '22060', (139, 142))	('p53', 'Gene', '22060', (92, 95))	('Sgt1+/+', 'Var', (65, 72))	('p53', 'Gene', (73, 76))	('p53', 'Gene', (139, 142))	('p53', 'Gene', (92, 95))	('mice', 'Species', '10090', (152, 156))	('p53', 'Gene', '22060', (73, 76))	('Sgt1+/-', 'Var', (84, 91))	('Sgt1', 'Gene', (121, 125))
166864	25985210	To test the effect of Sgt1 heterozygous knockout in vivo, the survival of Sgt1+/+ and Sgt1+/- mice was monitored.	('Sgt1+/+', 'Var', (74, 81))	('mice', 'Species', '10090', (94, 98))	('Sgt1', 'Gene', (22, 26))
166867	25985210	To analyze the in vivo effect of the Sgt1 heterozygous knockout in mice that are deficient in a tumor suppressor gene, Sgt1+/+ p53-/- and Sgt1+/- p53-/- mice were produced, and the survival of these mice were monitored.	('deficient', 'Disease', (81, 90))	('p53', 'Gene', '22060', (127, 130))	('mice', 'Species', '10090', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('p53', 'Gene', (146, 149))	('Sgt1', 'Gene', (37, 41))	('tumor', 'Disease', (96, 101))	('deficient', 'Disease', 'MESH:D007153', (81, 90))	('mice', 'Species', '10090', (153, 157))	('p53', 'Gene', '22060', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Sgt1+/+', 'Var', (119, 126))	('mice', 'Species', '10090', (67, 71))	('p53', 'Gene', (127, 130))
166868	25985210	Sgt1 heterozygous knockout resulted in significantly longer survival of p53-/- mice than Sgt1 wild-type mice (Figure 2d).	('survival', 'CPA', (60, 68))	('p53', 'Gene', (72, 75))	('mice', 'Species', '10090', (79, 83))	('mice', 'Species', '10090', (104, 108))	('Sgt1', 'Gene', (0, 4))	('knockout', 'Var', (18, 26))	('p53', 'Gene', '22060', (72, 75))	('longer', 'PosReg', (53, 59))
166871	25985210	Sgt1 depletion by short interfering RNA (siRNA) in HeLa cells causes delocalization of kinetochore proteins and activation of the weakened spindle checkpoint, which may result in aneuploidy.	('depletion', 'Var', (5, 14))	('aneuploidy', 'Disease', 'MESH:D000782', (179, 189))	('result in', 'Reg', (169, 178))	('activation', 'PosReg', (112, 122))	('kinetochore proteins', 'Protein', (87, 107))	('spindle', 'CPA', (139, 146))	('delocalization', 'MPA', (69, 83))	('Sgt1', 'Gene', (0, 4))	('HeLa', 'CellLine', 'CVCL:0030', (51, 55))	('aneuploidy', 'Disease', (179, 189))
166873	25985210	Our phenotype analysis of MEF cells found that the level of Sgt1 protein in Sgt1+/- MEF cells was reduced to about 30% of the level in Sgt1+/+ MEF cells (Supplementary Figure S3A).	('MEF', 'CellLine', 'CVCL:9115', (143, 146))	('Sgt1', 'Gene', (60, 64))	('level', 'MPA', (51, 56))	('MEF', 'CellLine', 'CVCL:9115', (84, 87))	('reduced', 'NegReg', (98, 105))	('MEF', 'CellLine', 'CVCL:9115', (26, 29))	('Sgt1+/-', 'Var', (76, 83))
166874	25985210	Indirect immunofluorescence microscopy of kinetochore localization showed that CENP-H signals at kinetochores in Sgt1+/- MEF cells were indistinguishable from those in Sgt1+/+ MEF cells (Supplementary Figure S3B).	('CENP-H', 'Gene', (79, 85))	('MEF', 'CellLine', 'CVCL:9115', (176, 179))	('Sgt1+/- MEF', 'Var', (113, 124))	('MEF', 'CellLine', 'CVCL:9115', (121, 124))	('CENP-H', 'Gene', '26886', (79, 85))
166877	25985210	These results indicate that kinetochores are assembled properly and that the spindle checkpoint is normal in Sgt1+/- MEF cells and that there is no difference in ploidy between Sgt1+/+ MEF cells and Sgt1+/- MEF cells.	('MEF', 'CellLine', 'CVCL:9115', (185, 188))	('spindle checkpoint', 'CPA', (77, 95))	('Sgt1+/- MEF', 'Var', (109, 120))	('MEF', 'CellLine', 'CVCL:9115', (117, 120))	('Sgt1+/+', 'Var', (177, 184))	('MEF', 'CellLine', 'CVCL:9115', (207, 210))
166884	25985210	Because the reduced expression of Sgt1 protein that resulted from Sgt1 heterozygous knockout suppressed Hras-mediated transformation and tumorigenicity of p53-/- MEF cells and prolonged the survival of p53-/- mice (Figure 2), we hypothesized that Sgt1 is a potential target for cancer therapy.	('knockout', 'Var', (84, 92))	('p53', 'Gene', '22060', (202, 205))	('MEF', 'CellLine', 'CVCL:9115', (162, 165))	('Sgt1', 'Gene', (34, 38))	('cancer', 'Disease', (278, 284))	('Sgt1', 'Gene', (66, 70))	('survival', 'CPA', (190, 198))	('Hras-mediated transformation', 'CPA', (104, 132))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('protein', 'Protein', (39, 46))	('mice', 'Species', '10090', (209, 213))	('tumor', 'Disease', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('suppressed', 'NegReg', (93, 103))	('p53', 'Gene', (155, 158))	('expression', 'MPA', (20, 30))	('reduced', 'NegReg', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('p53', 'Gene', '22060', (155, 158))	('prolonged', 'PosReg', (176, 185))	('p53', 'Gene', (202, 205))
166886	25985210	To knock down Sgt1 expression, we incubated cancer cells transfected with two independent siRNAs against Sgt1 (Figure 4a and Supplementary Figure S4D) and recorded the extent of cell growth at 4-h intervals.	('Supplementary Figure S4D', 'Disease', (125, 149))	('Sgt1', 'Gene', (105, 109))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Supplementary Figure S4D', 'Disease', 'MESH:D017034', (125, 149))	('Sgt1', 'Gene', (14, 18))	('knock', 'Var', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
166890	25985210	Protein levels of EWS-FLI in EW8 cells and PAX3-FOXO1 in Rh41 cells were reduced by Sgt1 depletion or ganetespib (an Hsp90 inhibitor) treatment (Figures 4a and b).	('FLI', 'Gene', (22, 25))	('Sgt1', 'Gene', (84, 88))	('depletion', 'Var', (89, 98))	('reduced', 'NegReg', (73, 80))	('ganetespib', 'Chemical', 'MESH:C533237', (102, 112))	('PAX3-FOXO1', 'Gene', (43, 53))	('FLI', 'Gene', '2314', (22, 25))	('Protein levels', 'MPA', (0, 14))	('Rh41', 'CellLine', 'CVCL:2176', (57, 61))
166893	25985210	Sgt1 heterozygous knockout decreased Hras-mediated transformation and tumorigenicity of p53-/- MEF cells and extended the survival period of p53-/- mice.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('p53', 'Gene', (141, 144))	('extended', 'PosReg', (109, 117))	('decreased', 'NegReg', (27, 36))	('tumor', 'Disease', (70, 75))	('p53', 'Gene', (88, 91))	('mice', 'Species', '10090', (148, 152))	('p53', 'Gene', '22060', (141, 144))	('Sgt1', 'Gene', (0, 4))	('MEF', 'CellLine', 'CVCL:9115', (95, 98))	('Hras-mediated transformation', 'CPA', (37, 65))	('knockout', 'Var', (18, 26))	('survival period', 'CPA', (122, 137))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('p53', 'Gene', '22060', (88, 91))
166900	25985210	What is the molecular mechanism of tumor suppression caused by the Sgt1 heterozygous knockout?	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Sgt1', 'Gene', (67, 71))	('tumor suppression', 'Disease', (35, 52))	('heterozygous', 'Var', (72, 84))	('tumor suppression', 'Disease', 'OMIM:146850', (35, 52))
166904	25985210	In light of our finding that levels of the EWS-FLI1 protein in EW8 cells or PAX3-FOXO1 protein in Rh41 cells were decreased by the knockdown of Sgt1 expression, it is plausible that destabilization of the onco-proteins is a mechanism of tumor suppression that results from the Sgt1 heterozygous knockout.	('tumor suppression', 'Disease', (237, 254))	('knockdown', 'Var', (131, 140))	('levels', 'MPA', (29, 35))	('Sgt1', 'Gene', (277, 281))	('decreased', 'NegReg', (114, 123))	('Sgt1', 'Gene', (144, 148))	('tumor suppression', 'Disease', 'OMIM:146850', (237, 254))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('Rh41', 'CellLine', 'CVCL:2176', (98, 102))
166908	25985210	Given that Sgt1 is a cochaperone of Hsp90, that Sgt1 is overexpressed in tumor cells and that decreased Sgt1 protein suppresses cellular transformation and allograft growth, we believe that Sgt1 could be a potential target for cancer therapy.	('cellular transformation', 'CPA', (128, 151))	('Sgt1', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('tumor', 'Disease', (73, 78))	('decreased', 'Var', (94, 103))	('cancer', 'Disease', (227, 233))	('suppresses', 'NegReg', (117, 127))	('allograft growth', 'CPA', (156, 172))	('protein', 'Protein', (109, 116))
166909	25985210	Consistent with this possibility is the previous finding that knockdown of Sgt1 expression inhibits the growth of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', (114, 120))	('Sgt1', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('inhibits', 'NegReg', (91, 99))	('knockdown', 'Var', (62, 71))
166913	25985210	Levels of the EWS-FLI1 protein in EW8 cells or the PAX3-FOXO1 protein in Rh41 cells were decreased by knockdown of Sgt1 expression.	('protein', 'Protein', (62, 69))	('Sgt1', 'Gene', (115, 119))	('Rh41', 'CellLine', 'CVCL:2176', (73, 77))	('knockdown', 'Var', (102, 111))	('EWS-FLI1', 'Gene', (14, 22))	('decreased', 'NegReg', (89, 98))
166921	25985210	Primary MEF cells were derived from E13.5 or E14.5 embryos.	('E13.5', 'Var', (36, 41))	('E14.5', 'Var', (45, 50))	('MEF', 'CellLine', 'CVCL:9115', (8, 11))
167020	24618889	Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells The lack of knowledge about molecular pathology of uterine sarcomas with a representation of 3-7% of all malignant uterine tumors prevents the establishment of effective therapy protocols.	('Sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('pathology of uterine', 'Phenotype', 'HP:0000130', (187, 207))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (200, 215))	('TRAIL', 'Gene', (108, 113))	('Sarcoma', 'Disease', (135, 142))	('uterine tumors', 'Phenotype', 'HP:0010784', (264, 278))	('Sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('Uterine Sarcoma', 'Phenotype', 'HP:0002891', (127, 142))	('Epigenetic Silencing', 'Var', (0, 20))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('SAHA', 'Chemical', 'MESH:D000077337', (99, 103))	('Apoptosis-Inducing Gene', 'Gene', (24, 47))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('TRAIL', 'Gene', '8743', (108, 113))	('Expression', 'Species', '29278', (48, 58))	('sarcomas', 'Disease', 'MESH:D012509', (208, 216))	('sarcomas', 'Phenotype', 'HP:0100242', (208, 216))	('sarcomas', 'Disease', (208, 216))
167026	24618889	Apoptosis resistance was caused by reduced expression of caspase-8 and DR 4/TRAIL-R1 in ESS-1 and MES-SA cells, respectively, due to epigenetic silencing by DNA hypermethylation of gene promoter sequences.	('TRAIL-R1', 'Gene', '8797', (76, 84))	('reduced', 'NegReg', (35, 42))	('caspase-8', 'Gene', '841', (57, 66))	('ESS-1', 'Gene', '7046', (88, 93))	('caspase-8', 'Gene', (57, 66))	('TRAIL-R1', 'Gene', (76, 84))	('DR 4', 'Gene', (71, 75))	('DR 4', 'Gene', '8797', (71, 75))	('expression', 'Species', '29278', (43, 53))	('MES-SA', 'CellLine', 'CVCL:1404', (98, 104))	('ESS-1', 'Gene', (88, 93))	('epigenetic silencing', 'Var', (133, 153))	('expression', 'MPA', (43, 53))	('Apoptosis resistance', 'CPA', (0, 20))
167028	24618889	Our data provide evidence that deregulation of epigenetic silencing by histone acetylation and DNA hypermethylation might play a fundamental role in the origin of uterine sarcomas.	('epigenetic silencing', 'Var', (47, 67))	('histone', 'Protein', (71, 78))	('DNA', 'MPA', (95, 98))	('sarcomas', 'Disease', (171, 179))	('deregulation', 'Var', (31, 43))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (163, 178))
167039	24618889	A second way of epigenetic gene silencing, is provoked by the upregulation of HDAC expression which has a critical role in mediating a transcriptionally inactive chromatin structure.	('expression', 'Species', '29278', (83, 93))	('HDAC', 'Gene', (78, 82))	('expression', 'MPA', (83, 93))	('HDAC', 'Gene', '9734', (78, 82))	('epigenetic gene', 'Var', (16, 31))	('upregulation', 'PosReg', (62, 74))
167041	24618889	Some sarcomas are associated with chromosomal translocations for which antitumor activity by HDAC inhibitors has been demonstrated.	('HDAC', 'Gene', (93, 97))	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('HDAC', 'Gene', '9734', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('associated', 'Reg', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('chromosomal translocations', 'Var', (34, 60))	('sarcomas', 'Disease', (5, 13))	('tumor', 'Disease', (75, 80))
167043	24618889	Several translocation events and resultant gene fusions involving PcGs with the most common variant joining parts of the JAZF1 gene to the PcGJJAZ1/SUZ12 were also detected in ESS.	('JAZF1', 'Gene', '221895', (121, 126))	('SUZ12', 'Gene', '23512', (148, 153))	('variant', 'Var', (92, 99))	('SUZ12', 'Gene', (148, 153))	('JAZF1', 'Gene', (121, 126))
167045	24618889	Furthermore, the HDAC inhibitor SAHA (marketed as Vorinostat or Zolinza) significantly prevented tumor cell proliferation by increasing expression of the cell cycle kinase p21WAF1 and decreasing expression of HDAC2 and 7 in ESS-1 cells.	('prevented', 'NegReg', (87, 96))	('increasing', 'PosReg', (125, 135))	('HDAC', 'Gene', (209, 213))	('HDAC', 'Gene', (17, 21))	('expression', 'Species', '29278', (195, 205))	('expression', 'MPA', (136, 146))	('Vorinostat', 'Chemical', 'MESH:D000077337', (50, 60))	('tumor', 'Disease', (97, 102))	('p21WAF1', 'Var', (172, 179))	('decreasing', 'NegReg', (184, 194))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('expression', 'Species', '29278', (136, 146))	('Zolinza', 'Chemical', 'MESH:D000077337', (64, 71))	('expression', 'MPA', (195, 205))	('SAHA', 'Chemical', 'MESH:D000077337', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ESS-1', 'Gene', (224, 229))	('ESS-1', 'Gene', '7046', (224, 229))	('HDAC', 'Gene', '9734', (209, 213))	('HDAC', 'Gene', '9734', (17, 21))
167059	24618889	A second possibility of transmitting the apoptotic signal emanating from DISC-activated caspase-8 is via the intrinsic (mitochondrial) pathway.	('DISC-activated', 'Var', (73, 87))	('caspase-8', 'Gene', '841', (88, 97))	('caspase-8', 'Gene', (88, 97))	('apoptotic', 'MPA', (41, 50))
167067	24618889	Therefore, in recent years, HDAC inhibitors that reverse aberrant epigenetic changes have emerged as a potential strategy to sensitize cancer cells for TRAIL-induced apoptosis.	('HDAC', 'Gene', (28, 32))	('cancer', 'Disease', (135, 141))	('HDAC', 'Gene', '9734', (28, 32))	('TRAIL', 'Gene', '8743', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('epigenetic changes', 'Var', (66, 84))	('TRAIL', 'Gene', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
167106	24618889	Cells treated with 500 muM H2O2 presented the positive control while untreated cells were included as a negative control.	('H2O2', 'Chemical', 'MESH:D006861', (27, 31))	('H2O2', 'Var', (27, 31))	('muM', 'Gene', '56925', (23, 26))	('muM', 'Gene', (23, 26))
167125	24618889	Expression vectors containing human full-length cDNAs for caspase-8 (IMAGE ID 5217189; IRATp970F0250D) or TNFRSF10A (Image ID 3857315; IRATp970H0615D) were obtained from Source BioScience LifeSciences (Nottingham, UK).	('human', 'Species', '9606', (30, 35))	('TNFRSF10A', 'Gene', '8797', (106, 115))	('Expression vectors', 'Species', '29278', (0, 18))	('caspase-8', 'Gene', (58, 67))	('IMAGE ID 5217189; IRATp970F0250D', 'Var', (69, 101))	('caspase-8', 'Gene', '841', (58, 67))	('IRATp970F0250D', 'Var', (87, 101))	('TNFRSF10A', 'Gene', (106, 115))	('IRATp970H0615D', 'CellLine', 'CVCL:7312', (135, 149))	('Image ID 3857315; IRATp970H0615D', 'Var', (117, 149))
167127	24618889	The additive model predicts whether the combined effects of two or more drugs are synergistic when the ratio O/E < 0.8, additive when O/E  =  0.8-1.2, or subadditive when O/E > 1.2.	('E > 1.2', 'Gene', '26767', (173, 180))	('O/E < 0.8', 'Var', (109, 118))	('E > 1.2', 'Gene', (173, 180))
167183	24618889	We next analyzed, whether the expression of apoptosis inducing genes in the investigated uterine sarcoma cells was impaired by epigenetic silencing (Fig.	('epigenetic silencing', 'Var', (127, 147))	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('expression', 'MPA', (30, 40))	('impaired', 'NegReg', (115, 123))	('apoptosis inducing genes', 'Gene', (44, 68))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (89, 104))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('expression', 'Species', '29278', (30, 40))
167184	24618889	Previously, it has been shown that reduced caspase-8 expression in human cancer has been frequently caused by hypermethylation of the promoter region of the gene e.g.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('hypermethylation', 'Var', (110, 126))	('reduced', 'NegReg', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('expression', 'Species', '29278', (53, 63))	('expression', 'MPA', (53, 63))	('caspase-8', 'Gene', (43, 52))	('human', 'Species', '9606', (67, 72))	('caspase-8', 'Gene', '841', (43, 52))
167187	24618889	Regarding the MSP for caspase-8, only a band for the unmethylated form could be amplified from bisulfite modified genomic DNA in MES-SA cells while a dominant band for the methylated, together with a weaker band for the unmethylated form, was observed in ESS-1 cells.	('caspase-8', 'Gene', '841', (22, 31))	('bisulfite', 'Var', (95, 104))	('bisulfite', 'Chemical', 'MESH:C042345', (95, 104))	('ESS-1', 'Gene', (255, 260))	('MES-SA', 'CellLine', 'CVCL:1404', (129, 135))	('ESS-1', 'Gene', '7046', (255, 260))	('caspase-8', 'Gene', (22, 31))
167192	24618889	Bisulfite sequence analysis of the DR4 promoter region confirmed the presence of predominantly methylated CpG sites in MES-SA cells which were encountered in a clearly unmethylated status in ESS-1 cells.	('methylated', 'Var', (95, 105))	('ESS-1', 'Gene', '7046', (191, 196))	('MES-SA', 'CellLine', 'CVCL:1404', (119, 125))	('DR4', 'Gene', '8797', (35, 38))	('ESS-1', 'Gene', (191, 196))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('CpG', 'Gene', (106, 109))	('DR4', 'Gene', (35, 38))
167194	24618889	Next, we examined if the mRNA expression of caspase-8 and DR4 could be restored by demethylating the target genes.	('caspase-8', 'Gene', '841', (44, 53))	('mRNA expression', 'MPA', (25, 40))	('demethylating', 'Var', (83, 96))	('DR4', 'Gene', (58, 61))	('DR4', 'Gene', '8797', (58, 61))	('caspase-8', 'Gene', (44, 53))	('expression', 'Species', '29278', (30, 40))
167195	24618889	We treated ESS-1 and MES-SA cells for 5 days with 0.5 muM 5-Aza-dC and performed qRT-PCR.	('muM', 'Gene', (54, 57))	('ESS-1', 'Gene', (11, 16))	('muM', 'Gene', '56925', (54, 57))	('5-Aza-dC', 'Var', (58, 66))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (58, 66))	('ESS-1', 'Gene', '7046', (11, 16))	('MES-SA', 'CellLine', 'CVCL:1404', (21, 27))
167196	24618889	5D confirms that gene expression of caspase-8 in ESS-1 cells and DR4 in MES-SA cells can be restored with 5-Aza-dC treatment to a level comparable to the respective control cells.	('caspase-8', 'Gene', '841', (36, 45))	('MES-SA', 'CellLine', 'CVCL:1404', (72, 78))	('5-Aza-dC', 'Var', (106, 114))	('ESS-1', 'Gene', (49, 54))	('DR4', 'Gene', (65, 68))	('gene expression', 'MPA', (17, 32))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (106, 114))	('caspase-8', 'Gene', (36, 45))	('expression', 'Species', '29278', (22, 32))	('ESS-1', 'Gene', '7046', (49, 54))	('DR4', 'Gene', '8797', (65, 68))	('restored', 'PosReg', (92, 100))
167204	24618889	Surprisingly, the combination of TRAIL and 5-Aza-dC had a lesser apoptotic effect (~ 50%) indicating that no external signal is required upon reactivation of epigenetically silenced gene expression.	('5-Aza-dC', 'Var', (43, 51))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (43, 51))	('apoptotic', 'CPA', (65, 74))	('TRAIL', 'Gene', '8743', (33, 38))	('expression', 'Species', '29278', (187, 197))	('TRAIL', 'Gene', (33, 38))
167208	24618889	Therefore, we conclude that induction of apoptosis in the analyzed sarcoma cells is indeed hampered by transcriptional repression through DNA hypermethylation.	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('transcriptional', 'MPA', (103, 118))	('repression', 'NegReg', (119, 129))	('sarcoma', 'Disease', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('DNA hypermethylation', 'Var', (138, 158))
167229	24618889	Among those, mutations in death receptor and caspase-8 genes, overexpression of inhibitory molecules such as soluble death receptors, decoy receptors, and FLIP have been identified.	('decoy', 'MPA', (134, 139))	('expression', 'Species', '29278', (66, 76))	('caspase-8', 'Gene', (45, 54))	('soluble death receptors', 'Protein', (109, 132))	('caspase-8', 'Gene', '841', (45, 54))	('overexpression', 'PosReg', (62, 76))	('FLIP', 'MPA', (155, 159))	('mutations', 'Var', (13, 22))
167230	24618889	In cancer cells, methylation of CpG islands of tumor suppressor genes occurs more frequently and correlates with transcriptional repression.	('methylation', 'Var', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('transcriptional repression', 'MPA', (113, 139))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
167231	24618889	Especially, inactivation of the caspase-8, Fas and DR4/TRAIL-R1 genes either by DNA methylation or mutation as part of the malignant process have been detected in cancer cells, and are thought to contribute to carcinogenesis.	('caspase-8', 'Gene', '841', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('TRAIL-R1', 'Gene', (55, 63))	('DR4', 'Gene', '8797', (51, 54))	('TRAIL-R1', 'Gene', '8797', (55, 63))	('mutation', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('caspase-8', 'Gene', (32, 41))	('contribute', 'Reg', (196, 206))	('Fas', 'Gene', (43, 46))	('inactivation', 'Var', (12, 24))	('carcinogenesis', 'Disease', 'MESH:D063646', (210, 224))	('detected', 'Reg', (151, 159))	('DR4', 'Gene', (51, 54))	('carcinogenesis', 'Disease', (210, 224))	('cancer', 'Disease', (163, 169))
167233	24618889	The mechanisms responsible for this resistance were found to include silencing of caspase-8 in ESS-1 cells and TRAIL-R1 genes in MES-SA cells, by DNA hypermethylation of their promoter regions.	('ESS-1', 'Gene', (95, 100))	('TRAIL-R1', 'Gene', (111, 119))	('ESS-1', 'Gene', '7046', (95, 100))	('MES-SA', 'CellLine', 'CVCL:1404', (129, 135))	('hypermethylation', 'Var', (150, 166))	('TRAIL-R1', 'Gene', '8797', (111, 119))	('caspase-8', 'Gene', (82, 91))	('silencing', 'NegReg', (69, 78))	('caspase-8', 'Gene', '841', (82, 91))
167238	24618889	Silencing of tumor suppressor genes is often an early event in the development of human cancer.	('tumor', 'Disease', (13, 18))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('Silencing', 'Var', (0, 9))	('human', 'Species', '9606', (82, 87))
167242	24618889	Hypermethylation of the caspase-8 gene has been detected in childhood neuroblastomas, lung tumors and cell lines, pedriatric tumors and cell lines, breast cancer cells, and several others.	('pedriatric tumors', 'Disease', 'MESH:D009369', (114, 131))	('Hypermethylation', 'Var', (0, 16))	('caspase-8', 'Gene', '841', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('pedriatric tumors', 'Disease', (114, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('neuroblastomas', 'Phenotype', 'HP:0003006', (70, 84))	('neuroblastomas', 'Disease', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('lung tumors', 'Disease', 'MESH:D008175', (86, 97))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('lung tumors', 'Phenotype', 'HP:0100526', (86, 97))	('neuroblastomas', 'Disease', 'MESH:D009447', (70, 84))	('caspase-8', 'Gene', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('neuroblastoma', 'Phenotype', 'HP:0003006', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('lung tumors', 'Disease', (86, 97))	('detected', 'Reg', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))
167270	24618889	In summary, we provide here in vitro molecular evidence that epigenetic silencing of the uterine sarcoma cell lines, ESS-1 and MES-SA, is not only caused by upregulation of HDACs but also by hypermethylation of promoter regions of tumor suppressor genes.	('epigenetic silencing', 'Var', (61, 81))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('ESS-1', 'Gene', (117, 122))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (89, 104))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('sarcoma cell lines', 'Disease', (97, 115))	('hypermethylation', 'Var', (191, 207))	('tumor', 'Disease', (231, 236))	('sarcoma cell lines', 'Disease', 'MESH:D012509', (97, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('upregulation', 'PosReg', (157, 169))	('HDAC', 'Gene', (173, 177))	('HDAC', 'Gene', '9734', (173, 177))	('MES-SA', 'CellLine', 'CVCL:1404', (127, 133))	('ESS-1', 'Gene', '7046', (117, 122))
167295	33936870	IHC studies confirmed ES and it was found to be pan-CK (cytokeratin) positive, EMA (epithelial membrane antigen) positive, vimentin positive, and CD34 positive.	('pan-CK', 'Var', (48, 54))	('vimentin', 'Gene', '7431', (123, 131))	('EMA (epithelial membrane antigen', 'Gene', '4582', (79, 111))	('CD34', 'Gene', '947', (146, 150))	('vimentin', 'Gene', (123, 131))	('CD34', 'Gene', (146, 150))
167335	32748147	Severe toxicities (grade 3 and 4) emerged in 14 patients (70%) with mtRT and 7 patients (39%) with single-target RT.	('toxicities', 'Disease', (7, 17))	('mtRT', 'Var', (68, 72))	('toxicities', 'Disease', 'MESH:D064420', (7, 17))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (48, 56))	('mtRT', 'Chemical', '-', (68, 72))
167428	32748147	A low KPS was strongly associated with irradiation of tumors in the area of the head and neck (p = 0.053).	('irradiation', 'Disease', (39, 50))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('low KPS', 'Var', (2, 9))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('associated', 'Reg', (23, 33))	('tumors', 'Disease', (54, 60))
167445	32748147	Most patients with single-target RT (n = 8 [44%]) had stage IV disease at diagnosis, 2 patients (11%) were in stage III, and 5 patients (28%) in stage II.	('patients', 'Species', '9606', (5, 13))	('single-target', 'Var', (19, 32))	('stage IV disease', 'Disease', 'MESH:D058625', (54, 70))	('patients', 'Species', '9606', (127, 135))	('stage IV disease', 'Disease', (54, 70))	('patients', 'Species', '9606', (87, 95))
167490	32748147	Regarding localized disease, patients receiving single-target RT had a noteworthy 5-year OS rate of 75 +- 10.8% and mostly included Ewing sarcoma (n = 9) and nonrhabdomyosarcoma soft tissue sarcoma (n = 6).	('patients', 'Species', '9606', (29, 37))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (161, 177))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (132, 145))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (132, 145))	('nonrhabdomyosarcoma soft tissue sarcoma', 'Disease', 'MESH:D012509', (158, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (178, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('single-target', 'Var', (48, 61))	('nonrhabdomyosarcoma soft tissue sarcoma', 'Disease', (158, 197))	('Ewing sarcoma', 'Disease', (132, 145))
167509	32748147	When comparing both subgroups concerning hematological toxicity, the percentage of patients receiving mtRT (n = 18 [90%]) was higher than that of patients with single-target RT (n = 12 [67%]).	('toxicity', 'Disease', 'MESH:D064420', (55, 63))	('toxicity', 'Disease', (55, 63))	('mtRT', 'Var', (102, 106))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (146, 154))	('mtRT', 'Chemical', '-', (102, 106))
167515	32748147	Patients with single-target RT had no acute non-hematological grade 4 toxicity.	('toxicity', 'Disease', 'MESH:D064420', (70, 78))	('Patients', 'Species', '9606', (0, 8))	('toxicity', 'Disease', (70, 78))	('single-target', 'Var', (14, 27))
167518	32748147	Patients with single-target RT did not show any severe toxicity as a late effect.	('toxicity', 'Disease', (55, 63))	('Patients', 'Species', '9606', (0, 8))	('single-target', 'Var', (14, 27))	('toxicity', 'Disease', 'MESH:D064420', (55, 63))
167535	32748147	In particular, children with multifocal tumor stages treated with mtRT had no long-term side effects compared to patients receiving RT of just one tumor site.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mtRT', 'Var', (66, 70))	('children', 'Species', '9606', (15, 23))	('multifocal tumor', 'Disease', 'None', (29, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('patients', 'Species', '9606', (113, 121))	('mtRT', 'Chemical', '-', (66, 70))	('multifocal tumor', 'Disease', (29, 45))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
167561	30650963	The mean survival time of 8.7 months in the OGS group was significantly shorter than that of patients without OGS (28.6 months) (p<0.01) treated before 1990.	('shorter', 'NegReg', (72, 79))	('OGS', 'Var', (44, 47))	('OGS', 'Chemical', '-', (110, 113))	('survival time', 'CPA', (9, 22))	('patients', 'Species', '9606', (93, 101))	('OGS', 'Chemical', '-', (44, 47))
167677	25105036	However, morphologic bone marrow examination, IHC, karyotyping, and FISH (fluorescence in situ hybridization) using probes designed to detect rearrangements of the c-MYC (8q24), CDKN2A (9p21), and MLL (11q23) loci as well as t(9;22) and t(12;21) were normal.	('rearrangements', 'Var', (142, 156))	('MLL', 'Gene', (197, 200))	('MLL', 'Gene', '4297', (197, 200))
167692	25105036	However, in an Italian study of 92 MS cases, t(8:21) was rare (2.2%), while monosomy 7 (10.8%), trisomy 8 (10.4%), and mixed lineage leukemia (MLL) rearrangements (8.5%) were the commonest abnormalities.	('leukemia', 'Disease', 'MESH:D007938', (133, 141))	('trisomy', 'Var', (96, 103))	('MLL', 'Gene', '4297', (143, 146))	('MLL', 'Gene', (143, 146))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('monosomy', 'Var', (76, 84))	('leukemia', 'Disease', (133, 141))
167717	20842057	Depletion of CD8 T cells results in local recurrence in 100% of animals, indicating that these cells are involved in control of residual disease.	('CD8', 'Gene', '925', (13, 16))	('local recurrence', 'MPA', (36, 52))	('CD8', 'Gene', (13, 16))	('Depletion', 'Var', (0, 9))
167718	20842057	We further demonstrate that systemic adjuvant administration of alphaOX40 at surgery eliminates local recurrences.	('rat', 'Species', '10116', (18, 21))	('eliminates', 'NegReg', (85, 95))	('alphaOX40', 'Var', (64, 73))	('rat', 'Species', '10116', (54, 57))	('local recurrences', 'CPA', (96, 113))	('alphaOX40', 'Chemical', '-', (64, 73))
167719	20842057	In this model, alphaOX40 acts to directly enhance tumor antigen-specific CD8 T cell proliferation in the lymph node draining the surgical site, and results in increased tumor antigen-specific cytotoxicity in vivo.	('alphaOX40', 'Var', (15, 24))	('cytotoxicity', 'Disease', (192, 204))	('rat', 'Species', '10116', (91, 94))	('enhance', 'PosReg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('increased', 'PosReg', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (169, 174))	('alphaOX40', 'Chemical', '-', (15, 24))	('CD8', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (192, 204))	('CD8', 'Gene', '925', (73, 76))	('tumor', 'Disease', (50, 55))
167721	20842057	Administration of alphaOX40 in combination with radiation significantly extended survival compared to either agent alone, and resulted in a significant proportion of long-term tumor free survivors.	('rat', 'Species', '10116', (8, 11))	('survival', 'CPA', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('alphaOX40', 'Chemical', '-', (18, 27))	('tumor', 'Disease', (176, 181))	('alphaOX40', 'Var', (18, 27))	('extended', 'PosReg', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
167722	20842057	We conclude that alphaOX40 increases tumor antigen-specific CD8 T cell cytotoxic activity resulting in improved endogenous immune control of residual microscopic disease, and we propose that adjuvant alphaOX40 administration may be a valuable addition to surgical and radiation therapy for cancer.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('alphaOX40', 'Chemical', '-', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('increases', 'PosReg', (27, 36))	('CD8', 'Gene', '925', (60, 63))	('improved', 'PosReg', (103, 111))	('cancer', 'Disease', (290, 296))	('alphaOX40', 'Chemical', '-', (200, 209))	('tumor', 'Disease', (37, 42))	('alphaOX40', 'Var', (17, 26))	('rat', 'Species', '10116', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('CD8', 'Gene', (60, 63))
167740	20842057	Provision of alphaOX40 immediately following antigen priming enhances T cell expansion and effector function, and the number of long-term memory CD4 and CD8 T cells.	('CD8', 'Gene', (153, 156))	('alphaOX40', 'Chemical', '-', (13, 22))	('CD8', 'Gene', '925', (153, 156))	('CD4', 'Gene', (145, 148))	('effector function', 'CPA', (91, 108))	('enhances', 'PosReg', (61, 69))	('alphaOX40', 'Var', (13, 22))	('CD4', 'Gene', '12504', (145, 148))	('T cell expansion', 'CPA', (70, 86))
167741	20842057	Therapy with alphaOX40 closely following tumor challenge significantly enhances survival in a wide variety of animal tumor models.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('alphaOX40', 'Chemical', '-', (13, 22))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (117, 122))	('enhances', 'PosReg', (71, 79))	('alphaOX40', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('survival', 'CPA', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
167743	20842057	Treatment with alphaOX40 at this time provides tumor growth delay, enhanced infiltration of CD8 T cells and reduced suppression by tumor-infiltrating macrophages.	('alphaOX40', 'Var', (15, 24))	('infiltration', 'CPA', (76, 88))	('CD8', 'Gene', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('growth delay', 'Phenotype', 'HP:0001510', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('CD8', 'Gene', '925', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (131, 136))	('rat', 'Species', '10116', (143, 146))	('rat', 'Species', '10116', (82, 85))	('alphaOX40', 'Chemical', '-', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('enhanced', 'PosReg', (67, 75))
167744	20842057	Nevertheless, despite growth delay, alphaOX40 treatment at this stage results in only a few long-term tumor-free survivors due to the immune suppressive environment within the established tumor.	('tumor', 'Disease', (188, 193))	('growth delay', 'Phenotype', 'HP:0001510', (22, 34))	('alphaOX40', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('alphaOX40', 'Chemical', '-', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
167748	20842057	To address the mechanism by which alphaOX40 therapy controls residual disease, we identify a temporal window of tumor antigen-specific T cell priming following surgery, and establish that administration of alphaOX40 in this window enhances the tumor antigen-specific response following the surgical procedure, and enhances tumor-specific cytotoxicity in vivo.	('alphaOX40', 'Chemical', '-', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('enhances', 'PosReg', (314, 322))	('enhances', 'PosReg', (231, 239))	('cytotoxicity', 'Disease', 'MESH:D064420', (338, 350))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('rat', 'Species', '10116', (196, 199))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', (323, 328))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('alphaOX40', 'Chemical', '-', (206, 215))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cytotoxicity', 'Disease', (338, 350))	('tumor', 'Disease', (112, 117))	('alphaOX40', 'Var', (206, 215))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (323, 328))
167750	20842057	These data set the stage for the use of alphaOX40 as an adjuvant therapy with conventional treatment of primary tumors.	('alphaOX40', 'Var', (40, 49))	('primary tumors', 'Disease', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('primary tumors', 'Disease', 'MESH:D009369', (104, 118))	('alphaOX40', 'Chemical', '-', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
167762	20842057	To measure the effect of alphaOX40 therapy on endogenous T cell cytotoxicity towards the MCA205 tumor, we established MCA205 tumors and treated with 250mug alphaOX40 or control Ig on day 3 and day 7 following tumor challenge.	('alphaOX40', 'Var', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (209, 214))	('alphaOX40', 'Chemical', '-', (25, 34))	('cytotoxicity', 'Disease', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('alphaOX40', 'Chemical', '-', (156, 165))	('tumor', 'Disease', (96, 101))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('cytotoxicity', 'Disease', 'MESH:D064420', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
167763	20842057	At day 12 following tumor challenge the tumor-draining lymph nodes were harvested and cells activated in vitro with 5mug/ml anti-CD3 for 2 days, followed by 60 U/ml IL-2 for a further 3 days.	('IL-2', 'Gene', (165, 169))	('IL-2', 'Gene', '16183', (165, 169))	('anti-CD3', 'Var', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (20, 25))
167797	20842057	By contrast, anti-OX40 therapy completely eliminated local recurrence following surgery (Figure 1b), and these mice were protected from rechallenge with parental tumor (Table 1), demonstrating that long-term tumor-specific immune protection had been established.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('anti-OX40', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('rat', 'Species', '10116', (186, 189))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('eliminated', 'NegReg', (42, 52))	('mice', 'Species', '10090', (111, 115))	('parental tumor', 'Disease', (153, 167))	('parental tumor', 'Disease', 'MESH:D063129', (153, 167))	('local recurrence', 'MPA', (53, 69))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
167800	20842057	However, OX40 therapy generated a measureable cytotoxic T cell response that was tumor-specific (Figure 1c).	('rat', 'Species', '10116', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('OX40 therapy', 'Var', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
167801	20842057	These data demonstrate that boosting tumor antigen-specific immunity through adjuvant delivery of alphaOX40 reduces local recurrence.	('rat', 'Species', '10116', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('local recurrence', 'CPA', (116, 132))	('alphaOX40', 'Var', (98, 107))	('reduces', 'NegReg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('boosting', 'PosReg', (28, 36))	('alphaOX40', 'Chemical', '-', (98, 107))
167803	20842057	The majority of early studies focused on OX40 expression and function on CD4 T cells,: however, OX40 therapy also has powerful direct effects on the proliferation, effector function, and long-term survival of CD8 T cells.	('CD8', 'Gene', (209, 212))	('rat', 'Species', '10116', (156, 159))	('OX40 therapy', 'Var', (96, 108))	('CD8', 'Gene', '925', (209, 212))	('CD4', 'Gene', (73, 76))	('effector function', 'CPA', (164, 181))	('proliferation', 'CPA', (149, 162))	('CD4', 'Gene', '12504', (73, 76))	('effects', 'Reg', (134, 141))
167812	20842057	We hypothesized that adjuvant alphaOX40 therapy may reduce local recurrence by enhancing T cell activation and differentiation into tumor antigen-specific cytotoxic T cells.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('differentiation', 'CPA', (111, 126))	('enhancing', 'PosReg', (79, 88))	('reduce', 'NegReg', (52, 58))	('alphaOX40', 'Var', (30, 39))	('tumor', 'Disease', (132, 137))	('T cell activation', 'CPA', (89, 106))	('local recurrence', 'Disease', (59, 75))	('alphaOX40', 'Chemical', '-', (30, 39))
167813	20842057	To test whether treatment with the T cell adjuvant alphaOX40 enhanced the tumor antigen-specific CD8 T cell response, we established subcutaneous MCA205ova tumors and on surgical removal of the primary tumor, mice received adoptive transfer of CFSE-labeled naive OT1 cells along with alphaOX40 or control Ig.	('mice', 'Species', '10090', (209, 213))	('alphaOX40', 'Var', (284, 293))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MCA205ova tumors', 'Disease', 'MESH:D009369', (146, 162))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('alphaOX40', 'Chemical', '-', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('alphaOX40', 'Chemical', '-', (284, 293))	('CD8', 'Gene', (97, 100))	('tumor', 'Disease', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('MCA205ova tumors', 'Disease', (146, 162))	('CD8', 'Gene', '925', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
167815	20842057	alphaOX40 therapy increased the proportion of OT1 cells in the tumor-draining lymph node, but not the non-draining lymph node 5 days following surgery (Figure 3a).	('tumor', 'Disease', (63, 68))	('increased', 'PosReg', (18, 27))	('alphaOX40 therapy', 'Var', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('alphaOX40', 'Chemical', '-', (0, 9))
167817	20842057	In contrast, we saw proliferation in the tumor antigen-specific T cells in the draining lymph node of surgically removed MCA205ova, and this proliferation was increased with alphaOX40 treatment (Figure 3b).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('alphaOX40', 'Chemical', '-', (174, 183))	('rat', 'Species', '10116', (148, 151))	('tumor', 'Disease', (41, 46))	('increased', 'PosReg', (159, 168))	('alphaOX40', 'Var', (174, 183))	('rat', 'Species', '10116', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('MCA205ova', 'Gene', (121, 130))
167818	20842057	Interestingly, we also saw evidence of increased differentiation of the OT1 cells, with decreased expression of CD62L in the CFSElo population after alphaOX40 administration, a phenotype that is associated with effector differentiation and improved peripheral trafficking.	('peripheral trafficking', 'CPA', (249, 271))	('alphaOX40', 'Var', (149, 158))	('differentiation', 'CPA', (49, 64))	('alphaOX40', 'Chemical', '-', (149, 158))	('increased', 'PosReg', (39, 48))	('decreased', 'NegReg', (88, 97))	('rat', 'Species', '10116', (167, 170))	('CD62L', 'Gene', (112, 117))	('expression', 'MPA', (98, 108))
167819	20842057	These data support the hypothesis that administration of alphaOX40 enhances a tumor-antigen specific immune response mediated by CD8-T cells to control tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('CD8', 'Gene', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('CD8', 'Gene', '925', (129, 132))	('alphaOX40', 'Var', (57, 66))	('enhances', 'PosReg', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (152, 157))	('rat', 'Species', '10116', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('alphaOX40', 'Chemical', '-', (57, 66))	('tumor', 'Disease', (78, 83))
167820	20842057	To determine whether alphaOX40 therapy enhanced tumor antigen-specific cytotoxicity, we performed cytotoxicity assays in mice following surgical removal of the tumor (Figure 3ci).	('alphaOX40', 'Chemical', '-', (21, 30))	('tumor', 'Disease', (48, 53))	('cytotoxicity', 'Disease', (98, 110))	('cytotoxicity', 'Disease', (71, 83))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('removal of the tumor', 'Disease', 'MESH:D009369', (145, 165))	('alphaOX40 therapy', 'Var', (21, 38))	('removal of the tumor', 'Disease', (145, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mice', 'Species', '10090', (121, 125))	('cytotoxicity', 'Disease', 'MESH:D064420', (98, 110))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('enhanced', 'PosReg', (39, 47))
167821	20842057	MCA205ova tumors were surgically removed and mice received adoptive transfer of OT1 along with alphaOX40 or control Ig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mice', 'Species', '10090', (45, 49))	('MCA205ova tumors', 'Disease', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('alphaOX40', 'Var', (95, 104))	('alphaOX40', 'Chemical', '-', (95, 104))	('MCA205ova tumors', 'Disease', 'MESH:D009369', (0, 16))
167824	20842057	We saw tumor antigen-specific cytotoxicity following surgery (Figure 3cii), and this cytotoxicity was significantly increased in animals treated with alphaOX40 compared to those treated with control antibody (Figure 3ciii).	('tumor', 'Disease', (7, 12))	('cytotoxicity', 'Disease', (30, 42))	('alphaOX40', 'Var', (150, 159))	('cytotoxicity', 'Disease', (85, 97))	('increased', 'PosReg', (116, 125))	('cytotoxicity', 'Disease', 'MESH:D064420', (30, 42))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('alphaOX40', 'Chemical', '-', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
167825	20842057	These data support a model where alphaOX40 therapy delivered at the time of surgery enhances CD8 tumor antigen-specific cytotoxicity thereby enhancing the local control of tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('enhances', 'PosReg', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cytotoxicity', 'Disease', (120, 132))	('tumor', 'Disease', (97, 102))	('enhancing', 'PosReg', (141, 150))	('alphaOX40', 'Chemical', '-', (33, 42))	('CD8', 'Gene', (93, 96))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('CD8', 'Gene', '925', (93, 96))	('alphaOX40 therapy', 'Var', (33, 50))
167827	20842057	These data indicate that OX40 therapy directly targets the tumor antigen-specific T cells and enhances their expansion.	('enhances', 'PosReg', (94, 102))	('OX40 therapy', 'Var', (25, 37))	('tumor', 'Disease', (59, 64))	('expansion', 'CPA', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
167830	20842057	and 250mug control Ig or alphaOX40 i.p and were followed for local tumor recurrence.	('alphaOX40', 'Chemical', '-', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('alphaOX40', 'Var', (25, 34))
167831	20842057	The OT1 transfer with tumor expression of ovalbumin resulted in tumor recurrence in only one of 5 mice receiving control treatment (and no recurrences in mice receiving OX40 therapy).	('ovalbumin', 'Gene', (42, 51))	('tumor', 'Disease', (64, 69))	('mice', 'Species', '10090', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('OT1 transfer', 'Var', (4, 16))	('ovalbumin', 'Gene', '282665', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mice', 'Species', '10090', (98, 102))
167840	20842057	Our experiments suggest that the failure to control tumor recurrence in the absence of OX40 therapy is not due to tumor antigen loss variants or loss of antigen presenting capacity, but due to tumor-induced suppression of T cell function.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('loss', 'NegReg', (128, 132))	('tumor', 'Disease', (52, 57))	('antigen presenting capacity', 'MPA', (153, 180))	('suppression of T cell function', 'Phenotype', 'HP:0005435', (207, 237))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('loss', 'NegReg', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('suppression', 'NegReg', (207, 218))	('tumor', 'Disease', (114, 119))	('failure', 'Disease', 'MESH:D017093', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('T cell function', 'MPA', (222, 237))	('failure', 'Disease', (33, 40))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('variants', 'Var', (133, 141))
167848	20842057	CD8 depletion significantly decreased median survival caused by radiation (33 days p<0.001), though the survival benefit of radiation in the absence of CD8 T cells remained significantly better than no treatment (p<0.005).	('decreased', 'NegReg', (28, 37))	('median survival', 'MPA', (38, 53))	('depletion', 'Var', (4, 13))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('absence of CD8 T cells', 'Phenotype', 'HP:0005422', (141, 163))	('CD8', 'Gene', (152, 155))	('CD8', 'Gene', '925', (152, 155))
167852	20842057	Mice bearing 5-7 day 3LL tumors were treated with 3x20Gy focal radiation, and additionally treated with a single dose of alphaOX40 or control antibody one day following the first radiation dose (Figure 5ci).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('3x20Gy', 'Var', (50, 56))	('tumors', 'Disease', (25, 31))	('alphaOX40', 'Chemical', '-', (121, 130))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('Mice', 'Species', '10090', (0, 4))
167853	20842057	Treatment with alphaOX40 as a single agent also significantly enhanced median survival (31 days p<0.001), and the combination of radiation and alphaOX40 significantly increased survival compared to either agent alone (vs.alphaOX40 alone p<0.05, vs. radiation alone p<0.005).	('survival', 'CPA', (177, 185))	('alphaOX40', 'Chemical', '-', (143, 152))	('enhanced', 'PosReg', (62, 70))	('combination', 'Var', (114, 125))	('alphaOX40', 'Chemical', '-', (221, 230))	('increased', 'PosReg', (167, 176))	('alphaOX40', 'Var', (143, 152))	('median survival', 'CPA', (71, 86))	('alphaOX40', 'Chemical', '-', (15, 24))
167856	20842057	These data demonstrate that alphaOX40 therapy synergizes with radiation therapy to target residual disease and may represent a powerful strategy to augment existing primary therapies of cancer.	('rat', 'Species', '10116', (138, 141))	('rat', 'Species', '10116', (18, 21))	('alphaOX40', 'Chemical', '-', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('alphaOX40 therapy', 'Var', (28, 45))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
167858	20842057	Depletion of CD8 T cells substantially increased the local recurrence rate, indicating that the adaptive immune response played a role in the efficacy of the surgical therapy.	('local recurrence rate', 'CPA', (53, 74))	('rat', 'Species', '10116', (70, 73))	('CD8', 'Gene', (13, 16))	('CD8', 'Gene', '925', (13, 16))	('Depletion', 'Var', (0, 9))	('increased', 'PosReg', (39, 48))
167862	20842057	Moreover, we demonstrated increased tumor antigen-specific cytotoxicity in vivo with alphaOX40 therapy at surgery.	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('alphaOX40 therapy', 'Var', (85, 102))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cytotoxicity', 'Disease', (59, 71))	('increased', 'PosReg', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('rat', 'Species', '10116', (20, 23))	('alphaOX40', 'Chemical', '-', (85, 94))	('tumor', 'Disease', (36, 41))
167866	20842057	We demonstrated that this CD8 T cell response was necessary for the full efficacy of radiation therapy, and that boosting the T cell response with adjuvant alphaOX40 therapy significantly enhanced tumor-free survival.	('alphaOX40', 'Var', (156, 165))	('enhanced', 'PosReg', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('CD8', 'Gene', '925', (26, 29))	('alphaOX40', 'Chemical', '-', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('rat', 'Species', '10116', (10, 13))	('tumor', 'Disease', (197, 202))	('CD8', 'Gene', (26, 29))
167873	20842057	Nevertheless, we demonstrate here that adjuvant alphaOX40 therapy shows significant synergy with both surgery and radiation, and adjuvant alphaOX40 therapy has also been shown to synergize with chemotherapy in a murine melanoma model.	('alphaOX40', 'Chemical', '-', (48, 57))	('alphaOX40', 'Chemical', '-', (138, 147))	('alphaOX40 therapy', 'Var', (138, 155))	('murine', 'Species', '10090', (212, 218))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('rat', 'Species', '10116', (24, 27))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('melanoma', 'Disease', (219, 227))	('adjuvant', 'Var', (129, 137))
167874	20842057	Thus, preclinical data demonstrates that with careful timing, adjuvant alphaOX40 therapy may be an important addition to conventional therapies for cancer.	('cancer', 'Disease', (148, 154))	('alphaOX40 therapy', 'Var', (71, 88))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('rat', 'Species', '10116', (30, 33))	('alphaOX40', 'Chemical', '-', (71, 80))
167886	20842057	This effect may be transitory, since in vivo suppression of T regulatory cells has been described within 6 hours of alphaOX40 treatment, but not 48 hours following alphaOX40 treatment.	('alphaOX40', 'Var', (116, 125))	('T regulatory cells', 'CPA', (60, 78))	('alphaOX40', 'Chemical', '-', (116, 125))	('alphaOX40', 'Chemical', '-', (164, 173))
167887	20842057	In these experiments we have shown a dependence on direct OX40 ligation on CD8 T cells to increase tumor specific cytotoxicity in vivo.	('tumor', 'Disease', (99, 104))	('CD8', 'Gene', '925', (75, 78))	('increase', 'PosReg', (90, 98))	('cytotoxicity', 'Disease', 'MESH:D064420', (114, 126))	('CD8', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cytotoxicity', 'Disease', (114, 126))	('OX40 ligation', 'Var', (58, 71))
167888	20842057	This data is consistent with published data showing that CD8 T cells express OX40 and directly respond to OX40 ligation.	('respond', 'Reg', (95, 102))	('OX40', 'Var', (77, 81))	('CD8', 'Gene', (57, 60))	('OX40', 'Var', (106, 110))	('CD8', 'Gene', '925', (57, 60))
167893	20842057	While ligation of OX40 can transiently suppress T regulatory cells and reduce their accumulation in the tumor, it can also drive proliferation of regulatory T cells if the appropriate inflammatory milieu is present.	('reduce', 'NegReg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('accumulation in', 'MPA', (84, 99))	('T regulatory cells', 'CPA', (48, 66))	('tumor', 'Disease', (104, 109))	('regulatory T cells', 'CPA', (146, 164))	('drive', 'PosReg', (123, 128))	('OX40', 'Var', (18, 22))	('suppress', 'NegReg', (39, 47))	('proliferation', 'CPA', (129, 142))	('rat', 'Species', '10116', (136, 139))	('ligation', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
167895	20842057	We propose that there is a strong rationale for administration of OX40 therapy immediately post cytoreductive therapies to promote strong T helper and cytotoxic T cell differentiation while minimizing the suppressive differentiation pressures provided by the tumor.	('rat', 'Species', '10116', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('promote', 'PosReg', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('OX40', 'Var', (66, 70))	('tumor', 'Disease', (259, 264))	('rat', 'Species', '10116', (34, 37))
167896	20842057	The alphaOX40 reagent is one of a new class of immunotherapeutic adjuvant antibodies, which target receptors such as CD134 and CD137 to provide positive signals and CD152 (CTLA4) and CD279 (PD1) to block negative signals to activated T cells.	('alphaOX40', 'Chemical', '-', (4, 13))	('negative signals', 'MPA', (204, 220))	('CD134', 'Gene', '22163', (117, 122))	('CD134', 'Gene', (117, 122))	('CD279', 'Var', (183, 188))	('CTLA4', 'Gene', (172, 177))	('CD152', 'Gene', (165, 170))	('PD1', 'Gene', (190, 193))	('CD137', 'Gene', '21942', (127, 132))	('CD152', 'Gene', '12477', (165, 170))	('PD1', 'Gene', '18566', (190, 193))	('CTLA4', 'Gene', '12477', (172, 177))	('CD137', 'Gene', (127, 132))
167897	20842057	We show here for the first time that alphaOX40 therapy is an effective adjuvant to surgical therapy and in agreement with Yokouchi et al demonstrate that alphaOX40 therapy is an effective adjuvant to radiation therapy.	('alphaOX40 therapy', 'Var', (37, 54))	('alphaOX40', 'Chemical', '-', (154, 163))	('alphaOX40', 'Var', (154, 163))	('alphaOX40', 'Chemical', '-', (37, 46))	('rat', 'Species', '10116', (144, 147))
167901	20842057	In summary, antibodies to OX40 are known to specifically target T cells that have recently been triggered by antigen, may cause a transitory reduction in immune suppression, and recapitulate an element of an inflammatory state that is more akin to tissue autoimmunity than the standard suppressive tumor environment.	('antibodies', 'Var', (12, 22))	('immune suppression', 'MPA', (154, 172))	('OX40', 'Var', (26, 30))	('tumor', 'Disease', (298, 303))	('autoimmunity', 'Phenotype', 'HP:0002960', (255, 267))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('reduction', 'NegReg', (141, 150))
167902	20842057	The consequence is a synergy between alphaOX40 and primary therapy that can eliminate local tumor recurrence, with a potential to improve overall outcome.	('improve', 'PosReg', (130, 137))	('eliminate', 'NegReg', (76, 85))	('alphaOX40', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('alphaOX40', 'Chemical', '-', (37, 46))	('tumor', 'Disease', (92, 97))
167905	20842057	Agonistic antibodies to OX40 are in a Phase I Clinical Trial at our institution, and the preclinical experiments described in this manuscript suggest translation of alphaOX40 as an adjuvant therapy to reduce local recurrence rates.	('reduce', 'NegReg', (201, 207))	('alphaOX40', 'Chemical', '-', (165, 174))	('rat', 'Species', '10116', (225, 228))	('alphaOX40', 'Var', (165, 174))	('local recurrence rates', 'CPA', (208, 230))
167933	31608240	High NLR was found to be a reliable prognostic factor which was associated with worse survival for synovial sarcoma patients.	('synovial sarcoma', 'Disease', (99, 115))	('High NLR', 'Var', (0, 8))	('patients', 'Species', '9606', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (99, 115))	('synovial sarcoma', 'Disease', 'MESH:D013584', (99, 115))
167950	31608240	Patients with high NLR, PLR and lower LMR were likely to develop distant metastasis.	('Patients', 'Species', '9606', (0, 8))	('distant metastasis', 'CPA', (65, 83))	('high NLR', 'Var', (14, 22))	('develop', 'PosReg', (57, 64))
167957	31608240	Treatment strategies for SS remained unclear, however, our results suggested patients received resection surgery had better PFS (87.2 vs. 44.5 months, p = 0.056) and OS (89.6 vs. 58.7 months, p = 0.058) than those without resection surgery.	('resection surgery', 'Var', (95, 112))	('SS', 'Disease', 'MESH:D013584', (25, 27))	('better', 'PosReg', (117, 123))	('patients', 'Species', '9606', (77, 85))	('PFS', 'CPA', (124, 127))
167967	31608240	Previous studies have proved that high NLR, PLR and low LMR are associated poor prognosis in various malignancies.	('low LMR', 'Var', (52, 59))	('malignancies', 'Disease', (101, 113))	('PLR', 'MPA', (44, 47))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('high NLR', 'Var', (34, 42))
167981	31608240	In accordance with the critical role of lymphocytes in the suppression of tumor progression, high PLR suggests a rather poor prognosis for cancer patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('PLR', 'Gene', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('high', 'Var', (93, 97))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (139, 145))
167992	30134255	The discovery of recurrent genomic alterations in many benign and malignant mesenchymal neoplasms has added important biologic insights and expanded the spectrum of some diagnostic subgroups.	('genomic alterations', 'Var', (27, 46))	('neoplasms', 'Phenotype', 'HP:0002664', (88, 97))	('malignant mesenchymal neoplasms', 'Disease', 'MESH:C535700', (66, 97))	('malignant mesenchymal neoplasms', 'Disease', (66, 97))	('neoplasm', 'Phenotype', 'HP:0002664', (88, 96))
167993	30134255	Some tumors are defined by unique genomic alterations, whereas others share abnormalities that are not tumor-specific and can be observed in a sometimes broad range of biologically unrelated neoplasms.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('alterations', 'Var', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('neoplasms', 'Phenotype', 'HP:0002664', (191, 200))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('neoplasm', 'Phenotype', 'HP:0002664', (191, 199))	('tumor', 'Disease', (5, 10))	('neoplasms', 'Disease', 'MESH:D009369', (191, 200))	('neoplasms', 'Disease', (191, 200))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
168003	30134255	The discovery of highly recurrent mutations in histone 3.3 encoding genes in certain giant cell-rich bone tumors led to the introduction of mutation-specific antibodies with high specificity and sensitivity, which directly point to the underlying type of mutation.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('bone tumors', 'Disease', 'MESH:D001859', (101, 112))	('bone tumors', 'Disease', (101, 112))	('giant cell-rich bone tumors', 'Phenotype', 'HP:0011847', (85, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('bone tumors', 'Phenotype', 'HP:0010622', (101, 112))	('mutations', 'Var', (34, 43))
168009	30134255	Specifically, round cell sarcomas harboring rearrangements of CIC or BCOR will be discussed herein.	('BCOR', 'Gene', (69, 73))	('CIC', 'Gene', (62, 65))	('BCOR', 'Gene', '54880', (69, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('CIC', 'Gene', '23152', (62, 65))	('men', 'Species', '9606', (53, 56))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('rearrangements', 'Var', (44, 58))
168012	30134255	Approximately 90% of Ewing sarcomas harbor t(11;22)(q24;q12) leading to EWSR1-FLI1 fusion.	('t(11;22)(q24;q12', 'Var', (43, 59))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (21, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('EWSR1', 'Gene', (72, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (43, 60))	('FLI1', 'Gene', '2313', (78, 82))	('FLI1', 'Gene', (78, 82))	('EWSR1', 'Gene', '2130', (72, 77))	('Ewing sarcomas', 'Disease', (21, 35))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (21, 35))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))
168013	30134255	The remainder of cases show EWSR1 rearrangement with other fusion partners or unknown genes.	('EWSR1', 'Gene', '2130', (28, 33))	('men', 'Species', '9606', (43, 46))	('rearrangement', 'Var', (34, 47))	('EWSR1', 'Gene', (28, 33))
168019	30134255	In recent years, a novel subset of round cell sarcomas was identified that lacked EWSR1 rearrangement and instead harbored recurrent CIC-rearrangement, with CIC-DUX4 fusion resulting from t(4;19)(q35;q13) or t(10;19)(q26;q13) as the most common aberration, followed by rare alternate CIC-FOXO4 fusion.	('CIC-', 'Gene', '23152', (284, 288))	('lacked', 'NegReg', (75, 81))	('CIC-', 'Gene', '23152', (133, 137))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('CIC-', 'Gene', '23152', (157, 161))	('men', 'Species', '9606', (146, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('sarcomas', 'Disease', (46, 54))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (188, 204))	('men', 'Species', '9606', (97, 100))	('EWSR1', 'Gene', (82, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('t(10;19)(q26;q13', 'Var', (208, 224))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (208, 225))	('CIC-', 'Gene', (284, 288))	('CIC-', 'Gene', (133, 137))	('CIC-', 'Gene', (157, 161))	('EWSR1', 'Gene', '2130', (82, 87))	('t(4;19)(q35;q13', 'Var', (188, 203))
168029	30134255	Another subset of round cell sarcomas lacking EWSR1 and CIC rearrangements was recently identified to harbor recurrent BCOR rearrangement, including BCOR-CCNB3 fusion resulting from inv(X)(p11) in most cases, and rare alternate rearrangement with MAML3, ZC3H7B or KMT2D, as well as BCOR internal tandem duplication.	('CIC', 'Gene', (56, 59))	('p11', 'Gene', (189, 192))	('MAML3', 'Gene', '55534', (247, 252))	('BCOR', 'Gene', '54880', (119, 123))	('internal tandem duplication', 'Var', (287, 314))	('ZC3H7B', 'Gene', (254, 260))	('CCNB3', 'Gene', '85417', (154, 159))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('ZC3H7B', 'Gene', '23264', (254, 260))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('BCOR', 'Gene', (119, 123))	('EWSR1', 'Gene', '2130', (46, 51))	('KMT2D', 'Gene', '8085', (264, 269))	('sarcomas', 'Disease', (29, 37))	('CIC', 'Gene', '23152', (56, 59))	('men', 'Species', '9606', (237, 240))	('BCOR', 'Gene', '54880', (149, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('CCNB3', 'Gene', (154, 159))	('men', 'Species', '9606', (133, 136))	('fusion', 'Var', (160, 166))	('men', 'Species', '9606', (69, 72))	('BCOR', 'Gene', (149, 153))	('EWSR1', 'Gene', (46, 51))	('BCOR', 'Gene', '54880', (282, 286))	('p11', 'Gene', '6281', (189, 192))	('rearrangement', 'Var', (124, 137))	('MAML3', 'Gene', (247, 252))	('KMT2D', 'Gene', (264, 269))	('BCOR', 'Gene', (282, 286))
168054	30134255	A recently discovered recurrent t(7;19)(q22;q13), leading to SERPINE-FOSB fusion, is a defining feature of pseudomyogenic hemangioendothelioma and detected in the majority of cases.	('FOSB', 'Gene', (69, 73))	('hemangioendothelioma', 'Disease', 'MESH:D006390', (122, 142))	('hemangioendothelioma', 'Disease', (122, 142))	('t(7;19)(q22;q13', 'Var', (32, 47))	('t(7;19)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (32, 48))	('FOSB', 'Gene', '2354', (69, 73))
168063	30134255	Recurrent t(19;19)(q13.2;q13.2) or interstitial del19(q13.2-3) resulting in ZFP36-FOSB gene fusion as well as alternate t(3;19)(q25;q12) resulting in WWTR1-FOSB gene fusion have been identified in around 20% of cases.	('t(19;19)(q13.2;q13.2)', 'STRUCTURAL_ABNORMALITY', 'None', (10, 31))	('FOSB', 'Gene', '2354', (156, 160))	('FOSB', 'Gene', (156, 160))	('ZFP36', 'Gene', (76, 81))	('FOSB', 'Gene', '2354', (82, 86))	('t(3;19)(q25;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (120, 136))	('ZFP36', 'Gene', '7538', (76, 81))	('FOSB', 'Gene', (82, 86))	('del19', 'Var', (48, 53))	('WWTR1', 'Gene', (150, 155))	('WWTR1', 'Gene', '25937', (150, 155))
168064	30134255	Another subset of both conventional and cellular epithelioid hemangiomas (up to 20%) harbors FOS rearrangement, resulting from t(1;14)(q22;q24), t(10;14)(p13;q24) or t(3;14)(q25;q24).	('t(10;14)(p13;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (145, 162))	('t(3;14)(q25;q24', 'Var', (166, 181))	('t(1;14)(q22;q24', 'Var', (127, 142))	('hemangioma', 'Phenotype', 'HP:0001028', (61, 71))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (49, 71))	('FOS', 'Gene', (93, 96))	('t(1;14)(q22;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (127, 143))	('hemangiomas', 'Phenotype', 'HP:0001028', (61, 72))	('epithelioid hemangiomas', 'Phenotype', 'HP:0032060', (49, 72))	('t(3;14)(q25;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (166, 182))	('men', 'Species', '9606', (106, 109))	('FOS', 'Gene', '2353', (93, 96))	('epithelioid hemangiomas', 'Disease', 'MESH:D006391', (49, 72))	('epithelioid hemangiomas', 'Disease', (49, 72))	('t(10;14)(p13;q24', 'Var', (145, 161))
168070	30134255	Malignant rhabdoid tumor is the prototypical malignant neoplasm defined by genomic inactivation of SMARCB1 on 22q11.23, either by mutations and/or deletions, and associated loss of SMARCB1 expression in tumor cells.	('tumor', 'Disease', (203, 208))	('inactivation', 'NegReg', (83, 95))	('SMARCB1', 'Gene', '6598', (99, 106))	('SMARCB1', 'Gene', (99, 106))	('loss', 'NegReg', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', (19, 24))	('Malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('Malignant rhabdoid tumor', 'Disease', (0, 24))	('deletions', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('malignant neoplasm', 'Disease', 'MESH:D009369', (45, 63))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('malignant neoplasm', 'Disease', (45, 63))	('neoplasm', 'Phenotype', 'HP:0002664', (55, 63))	('expression', 'MPA', (189, 199))	('mutations', 'Var', (130, 139))	('SMARCB1', 'Gene', '6598', (181, 188))	('SMARCB1', 'Gene', (181, 188))
168072	30134255	In addition, SMARCB1 deficiency is found in 10-40% of myoepithelial tumors (mostly in pediatric patients) and in 17% of extraskeletal myxoid chondrosarcomas, classically harboring NR4A3 rearrangement, although the genomic mechanisms leading to SMARCB1 loss remain to be identified in this tumor type.	('myoepithelial tumors', 'Disease', (54, 74))	('found', 'Reg', (35, 40))	('tumor', 'Disease', (68, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('tumor', 'Disease', (289, 294))	('NR4A3', 'Gene', (180, 185))	('deficiency', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (54, 74))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('patients', 'Species', '9606', (96, 104))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (134, 156))	('myxoid chondrosarcomas', 'Disease', (134, 156))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('SMARCB1', 'Gene', (13, 20))	('NR4A3', 'Gene', '8013', (180, 185))	('SMARCB1', 'Gene', '6598', (13, 20))	('SMARCB1', 'Gene', '6598', (244, 251))	('men', 'Species', '9606', (195, 198))	('SMARCB1', 'Gene', (244, 251))
168073	30134255	In addition, nearly all renal medullary carcinomas, a highly aggressive renal neoplasm occurring in young patients with sickle cell trait or disease, show SMARCB1 loss resulting from a balanced translocation disrupting SMARCB1.	('renal neoplasm', 'Phenotype', 'HP:0009726', (72, 86))	('SMARCB1', 'Gene', '6598', (155, 162))	('neoplasm', 'Phenotype', 'HP:0002664', (78, 86))	('balanced translocation', 'Var', (185, 207))	('loss', 'NegReg', (163, 167))	('renal medullary carcinomas', 'Phenotype', 'HP:0008659', (24, 50))	('SMARCB1', 'Gene', '6598', (219, 226))	('patients', 'Species', '9606', (106, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('aggressive renal neoplasm', 'Disease', (61, 86))	('carcinomas', 'Disease', 'MESH:D002277', (40, 50))	('SMARCB1', 'Gene', (219, 226))	('aggressive renal neoplasm', 'Disease', 'MESH:D007680', (61, 86))	('disrupting', 'NegReg', (208, 218))	('carcinomas', 'Disease', (40, 50))	('SMARCB1', 'Gene', (155, 162))
168078	30134255	Nuclear pleomorphism, hyperchromasia, and an increased mitotic rate are usually absent.	('Nuclear pleomorphism', 'Var', (0, 20))	('mitotic rate', 'CPA', (55, 67))	('hyperchromasia', 'Disease', (22, 36))	('hyperchromasia', 'Disease', 'None', (22, 36))
168101	30134255	4C) in most cases, resulting from genomic inactivation of RB1 at 13q14, which is also a typical feature of cellular angiofibroma and (mammary-type) myofibroblastoma; many experts believe these tumor types are related.	('myofibroblastoma', 'Disease', 'MESH:D009217', (148, 164))	('angiofibroma', 'Disease', 'MESH:D018322', (116, 128))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('genomic inactivation', 'Var', (34, 54))	('angiofibroma', 'Disease', (116, 128))	('myofibroblastoma', 'Disease', (148, 164))	('cellular angiofibroma', 'Phenotype', 'HP:0010615', (107, 128))	('resulting from', 'Reg', (19, 33))	('RB1', 'Gene', (58, 61))
168118	30134255	The recent discovery of highly recurrent oncogenic mutations in the H3F3A and H3F3B genes in subsets of giant cell-rich bone tumors has provided important insights into the genetic underpinnings of these rare bone tumors and has led to the introduction of novel markers that aid in their diagnostic workup (Table 1).	('H3F3A', 'Gene', '3020', (68, 73))	('mutations', 'Var', (51, 60))	('bone tumors', 'Disease', 'MESH:D001859', (209, 220))	('bone tumors', 'Disease', 'MESH:D001859', (120, 131))	('bone tumors', 'Phenotype', 'HP:0010622', (120, 131))	('bone tumors', 'Phenotype', 'HP:0010622', (209, 220))	('giant cell-rich bone tumors', 'Phenotype', 'HP:0011847', (104, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('H3F3A', 'Gene', (68, 73))	('bone tumors', 'Disease', (209, 220))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('H3F3B', 'Gene', '3021', (78, 83))	('H3F3B', 'Gene', (78, 83))	('bone tumors', 'Disease', (120, 131))
168122	30134255	Approximately 92% of giant cell tumors of bone harbor H3F3A (and, rarely, H3F3B) mutations, which target codon 34 of H3.3.	('H3F3A', 'Gene', '3020', (54, 59))	('giant cell tumors', 'Disease', (21, 38))	('H3F3A', 'Gene', (54, 59))	('giant cell tumors', 'Disease', 'MESH:D005870', (21, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('giant cell tumors of bone', 'Phenotype', 'HP:0011847', (21, 46))	('H3F3B', 'Gene', '3021', (74, 79))	('mutations', 'Var', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('H3F3B', 'Gene', (74, 79))	('tumors of bone', 'Phenotype', 'HP:0010622', (32, 46))
168123	30134255	G34W is the most frequent type of mutation, found in around 85% of cases, followed by alternate G34V, G34R, G34M, or G34L mutations.	('G34M', 'Var', (108, 112))	('G34R', 'Var', (102, 106))	('G34V', 'Mutation', 'rs28931589', (96, 100))	('G34L', 'Mutation', 'p.G34L', (117, 121))	('G34W', 'Var', (0, 4))	('G34L', 'Var', (117, 121))	('G34V', 'Var', (96, 100))	('G34W', 'Mutation', 'p.G34W', (0, 4))	('G34R', 'Mutation', 'rs1057519902', (102, 106))	('G34M', 'Mutation', 'p.G34M', (108, 112))
168124	30134255	A mutation-specific antibody directed against mutant H3G34W demonstrates high specificity and sensitivity for the diagnosis of giant cell tumor of bone using immunohistochemistry (Fig.	('tumor of bone', 'Phenotype', 'HP:0010622', (138, 151))	('giant cell tumor', 'Disease', 'MESH:D005870', (127, 143))	('H3G34W', 'Gene', (53, 59))	('mutant', 'Var', (46, 52))	('giant cell tumor', 'Disease', (127, 143))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (127, 151))	('G34W', 'Mutation', 'p.G34W', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
168133	30134255	Instead, this tumor is characterized by oncogenic H3F3B (and, rarely, H3F3A) mutations that encode H3.3 K36M, which can be detected by sequencing in 70-100% of cases, depending on the method used.	('H3.3', 'Var', (99, 103))	('tumor', 'Disease', (14, 19))	('H3F3A', 'Gene', '3020', (70, 75))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('H3F3A', 'Gene', (70, 75))	('K36M', 'Mutation', 'p.K36M', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('H3F3B', 'Gene', (50, 55))	('H3F3B', 'Gene', '3021', (50, 55))
168135	30134255	The high specificity of H3G34W and H3K36M immunohistochemistry in the diagnosis of giant cell tumor of bone and chondroblastoma, respectively, highlights the value of these markers in the often challenging differential diagnosis of bone tumors, especially when only limited biopsy material is available.	('chondroblastoma', 'Phenotype', 'HP:0030432', (112, 127))	('chondroblastoma', 'Disease', 'MESH:D002804', (112, 127))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor of bone', 'Phenotype', 'HP:0010622', (94, 107))	('G34W', 'Mutation', 'p.G34W', (26, 30))	('giant cell tumor', 'Disease', 'MESH:D005870', (83, 99))	('K36M', 'Mutation', 'p.K36M', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('bone tumors', 'Phenotype', 'HP:0010622', (232, 243))	('bone tumors', 'Disease', (232, 243))	('giant cell tumor', 'Disease', (83, 99))	('bone tumors', 'Disease', 'MESH:D001859', (232, 243))	('H3K36M', 'Var', (35, 41))	('chondroblastoma', 'Disease', (112, 127))	('H3G34W', 'Var', (24, 30))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (83, 107))
168138	30134255	Biphenotypic sinonasal sarcoma is defined by characteristic co-expression of neural and myogenic markers, and, as discovered more recently, harbors recurrent PAX3 rearrangement, with PAX3-MAML3 fusion resulting from t(2;4)(q35;q31) being most frequent, followed by alternate PAX3-FOXO156 or PAX3-NCOA1 fusions.	('NCOA1', 'Gene', (296, 301))	('Biphenotypic', 'Disease', (0, 12))	('FOXO1', 'Gene', (280, 285))	('PAX3', 'Gene', (158, 162))	('PAX3', 'Gene', (275, 279))	('sinonasal sarcoma', 'Disease', (13, 30))	('NCOA1', 'Gene', '8648', (296, 301))	('t(2;4)(q35;q31)', 'STRUCTURAL_ABNORMALITY', 'None', (216, 231))	('MAML3', 'Gene', (188, 193))	('PAX3', 'Gene', (291, 295))	('PAX3', 'Gene', '5077', (158, 162))	('PAX3', 'Gene', '5077', (275, 279))	('sinonasal sarcoma', 'Disease', 'MESH:C535701', (13, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('MAML3', 'Gene', '55534', (188, 193))	('PAX3', 'Gene', '5077', (291, 295))	('men', 'Species', '9606', (172, 175))	('PAX3', 'Gene', (183, 187))	('t(2;4)(q35;q31', 'Var', (216, 230))	('FOXO1', 'Gene', '2308', (280, 285))	('PAX3', 'Gene', '5077', (183, 187))
168158	30134255	Rare cases show MAML3 rearrangement with an unknown fusion partner or lack a detectable structural rearrangement.	('men', 'Species', '9606', (31, 34))	('rearrangement', 'Var', (22, 35))	('men', 'Species', '9606', (108, 111))	('MAML3', 'Gene', '55534', (16, 21))	('MAML3', 'Gene', (16, 21))
168159	30134255	These findings suggest that absence of PAX3 rearrangement (and concurrent PAX3 expression) do not necessarily rule out a diagnosis of biphenotypic sinonasal sarcoma; correlation of clinical presentation with morphologic appearances and immunophenotype remains important in such cases.	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('rearrangement', 'Var', (44, 57))	('PAX3', 'Gene', '5077', (74, 78))	('biphenotypic sinonasal sarcoma', 'Disease', (134, 164))	('PAX3', 'Gene', '5077', (39, 43))	('PAX3', 'Gene', (74, 78))	('PAX3', 'Gene', (39, 43))	('men', 'Species', '9606', (53, 56))	('absence', 'Var', (28, 35))	('biphenotypic sinonasal sarcoma', 'Disease', 'MESH:C535701', (134, 164))
168167	30134255	The recent discovery of highly recurrent oncogenic H3F3A and H3F3B mutations that define giant cell tumor of bone and chondroblastoma, respectively, prompted the introduction of highly sensitive mutation-specific antibodies that provide additional insights into the oncogenic mechanisms that drive these rare benign bone tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor of bone', 'Phenotype', 'HP:0010622', (100, 113))	('giant cell tumor', 'Disease', 'MESH:D005870', (89, 105))	('bone tumors', 'Disease', (316, 327))	('chondroblastoma', 'Disease', (118, 133))	('H3F3A', 'Gene', '3020', (51, 56))	('chondroblastoma', 'Phenotype', 'HP:0030432', (118, 133))	('mutations', 'Var', (67, 76))	('bone tumors', 'Disease', 'MESH:D001859', (316, 327))	('chondroblastoma', 'Disease', 'MESH:D002804', (118, 133))	('bone tumors', 'Phenotype', 'HP:0010622', (316, 327))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('giant cell tumor', 'Disease', (89, 105))	('H3F3A', 'Gene', (51, 56))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (89, 113))	('H3F3B', 'Gene', (61, 66))	('H3F3B', 'Gene', '3021', (61, 66))
168168	30134255	Finally, biphenotypic sinonasal sarcoma sets an example of how the recognition of a unique immunophenotype, identification of PAX3 rearrangement and PAX3 expression helped delineate a novel diagnostic entity.	('men', 'Species', '9606', (140, 143))	('PAX3', 'Gene', (149, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('biphenotypic sinonasal sarcoma', 'Disease', 'MESH:C535701', (9, 39))	('PAX3', 'Gene', '5077', (126, 130))	('PAX3', 'Gene', (126, 130))	('rearrangement', 'Var', (131, 144))	('biphenotypic sinonasal sarcoma', 'Disease', (9, 39))	('PAX3', 'Gene', '5077', (149, 153))
168199	29385199	Of note, distributions of ctrl_A673 and particularly ctrl_HEK293 were broader in replicate 1 than in their replicate 2 counterparts, pinpointing the limitations of no more than two screen replicates.	('ctrl_A673', 'Var', (26, 35))	('HEK293', 'CellLine', 'CVCL:0045', (58, 64))	('ctrl_HEK293', 'Var', (53, 64))
168278	26906949	Lack of staining with the AE1:AE3 cocktail, MNF-116 and CK903 excluded a diagnosis of carcinoma and epithelioid sarcoma; lack of staining with S100 rendered a diagnosis of melanoma less likely; and CD20 negativity ruled out large B-cell lymphoma.	('large B-cell lymphoma', 'Disease', (224, 245))	('CD20', 'Gene', (198, 202))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (230, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('AE1', 'Gene', '6521', (26, 29))	('AE3', 'Gene', '6508', (30, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('less', 'NegReg', (181, 185))	('lymphoma', 'Phenotype', 'HP:0002665', (237, 245))	('MNF-116', 'CellLine', 'CVCL:G220', (44, 51))	('CD20', 'Gene', '54474', (198, 202))	('carcinoma and epithelioid sarcoma', 'Disease', 'MESH:D012509', (86, 119))	('lack', 'Var', (121, 125))	('AE3', 'Gene', (30, 33))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('AE1', 'Gene', (26, 29))	('melanoma', 'Disease', (172, 180))
168281	26906949	The location, clinical findings (no immunosuppression) and morphologic features argued against bacillary angiomatosis; specifically, the degree of pleomorphism and increased mitotic activity were beyond that seen in bacillary angiomatosis.	('angiomatosis', 'Disease', (226, 238))	('mitotic activity', 'CPA', (174, 190))	('angiomatosis', 'Disease', 'MESH:D000798', (226, 238))	('angiomatosis', 'Disease', 'MESH:D000798', (105, 117))	('pleomorphism', 'Var', (147, 159))	('angiomatosis', 'Disease', (105, 117))	('increased', 'PosReg', (164, 173))
168329	24428323	Accuracy of the cutoff values, including MHC class IIalpha, CD11b, CD11c, and CD86, was 87.9, 86.4, 86.4, and 84.8%, respectively.	('CD11b', 'Var', (60, 65))	('CD11c', 'Var', (67, 72))	('CD86', 'Gene', '403764', (78, 82))	('CD86', 'Gene', (78, 82))
168378	24428323	In addition, mRNA expression levels of MHC class IIalpha (median: 246, range: 106-398) in the 18 HS dogs that were MHC class II positive were higher than those (median: 112, range: 88-152) in the remaining 4 HS dogs that were negative.	('MHC', 'Gene', (115, 118))	('dogs', 'Species', '9615', (100, 104))	('mRNA expression levels', 'MPA', (13, 35))	('positive', 'Var', (128, 136))	('dogs', 'Species', '9615', (211, 215))	('higher', 'PosReg', (142, 148))
168379	24428323	mRNA expression levels of CD11b and CD11c were significantly higher in HS dogs than in dogs with lymphoma (P = .02 and P = .03, respectively), inflammatory diseases (P = .01 and P = .02, respectively), or other malignant neoplasms (P = .001 and P = .002, respectively) (Fig 1).	('neoplasms', 'Phenotype', 'HP:0002664', (221, 230))	('malignant neoplasms', 'Disease', (211, 230))	('CD11c', 'Var', (36, 41))	('CD11b', 'MPA', (26, 31))	('higher', 'PosReg', (61, 67))	('mRNA expression levels', 'MPA', (0, 22))	('dogs', 'Species', '9615', (87, 91))	('lymphoma', 'Disease', (97, 105))	('lymphoma', 'Disease', 'MESH:D008223', (97, 105))	('dogs', 'Species', '9615', (74, 78))	('lymphoma', 'Phenotype', 'HP:0002665', (97, 105))	('malignant neoplasms', 'Disease', 'MESH:D009369', (211, 230))
168397	24428323	Thus, a more accurate diagnosis of HS dogs was expected by additional combination of CD11b or CD11c analysis with MHC class IIalpha, with regard to the cell origin of HS.	('CD11b', 'Var', (85, 90))	('dogs', 'Species', '9615', (38, 42))	('CD11c', 'Gene', (94, 99))
168457	26175577	We adopted the following criteria for lymph node metastases: 1) > 1.5 cm in short diameter; 2) lymph nodes containing a necrotic portion; 3) high FDG avidity on PET/CT; and 4) histological confirmation by biopsy.	('metastases', 'Disease', 'MESH:D009362', (49, 59))	('necrotic', 'Disease', 'MESH:D009336', (120, 128))	('FDG', 'Chemical', '-', (146, 149))	('necrotic', 'Disease', (120, 128))	('high', 'Var', (141, 145))	('metastases', 'Disease', (49, 59))
168589	23762074	Finally, cytogenetic studies can look for the characteristic translocation t (11; 22) (q 24;12) that causes mutation of EWS gene resulting in EWS-FLI1 fusion protein identified in 85%-90% of peripheral PNET neuroepithelioma and Ewing's sarcoma.	('PNET', 'Phenotype', 'HP:0030065', (202, 206))	('neuroepithelioma', 'Disease', (207, 223))	('EWS', 'Gene', (142, 145))	('EWS', 'Gene', '2130', (142, 145))	('FLI1', 'Gene', (146, 150))	('FLI1', 'Gene', '2313', (146, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (228, 243))	('peripheral PNET neuroepithelioma', 'Phenotype', 'HP:0006717', (191, 223))	("Ewing's sarcoma", 'Disease', (228, 243))	('mutation', 'Var', (108, 116))	('EWS', 'Gene', '2130', (120, 123))	('EWS', 'Gene', (120, 123))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (228, 243))	('neuroepithelioma', 'Disease', 'MESH:C563168', (207, 223))
168697	28380040	Given that among the APE1-regulated transcription factors many are critical for KSHV replication and pathogenesis, we investigated whether inhibition of APE1 redox function blocks KSHV replication and Kaposi's sarcoma (KS) phenotypes.	('inhibition', 'Var', (139, 149))	('KS', 'Phenotype', 'HP:0100726', (219, 221))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (201, 217))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (201, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('KS', 'Phenotype', 'HP:0100726', (180, 182))	('KSHV', 'Species', '37296', (180, 184))	('APE1', 'Gene', (153, 157))	("Kaposi's sarcoma", 'Disease', (201, 217))	('KSHV', 'Species', '37296', (80, 84))	('KS', 'Phenotype', 'HP:0100726', (80, 82))	('blocks', 'NegReg', (173, 179))	('APE1', 'Gene', '328', (153, 157))	('APE1', 'Gene', (21, 25))	('KSHV', 'Gene', (180, 184))	('APE1', 'Gene', '328', (21, 25))
168700	28380040	C10 exhibits low cytotoxicity but efficiently inhibits KSHV lytic replication (EC50 of 0.16 muM and selective index of 165) and KSHV-mediated pathogenic phenotypes including cytokine production, angiogenesis and cell invasion, demonstrating its potential to become an effective drug for treatment of KS.	('cytokine production', 'MPA', (174, 193))	('muM', 'Gene', (92, 95))	('KSHV', 'Species', '37296', (55, 59))	('KSHV', 'Species', '37296', (128, 132))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('KS', 'Phenotype', 'HP:0100726', (300, 302))	('cytotoxicity', 'Disease', (17, 29))	('inhibits', 'NegReg', (46, 54))	('KS', 'Phenotype', 'HP:0100726', (128, 130))	('KSHV', 'Gene', (55, 59))	('C10', 'Var', (0, 3))	('angiogenesis', 'CPA', (195, 207))	('muM', 'Gene', '56925', (92, 95))	('cytotoxicity', 'Disease', 'MESH:D064420', (17, 29))	('cell invasion', 'CPA', (212, 225))
168705	28380040	Furthermore, we identified a novel small molecular compound, C10, which exhibited specific inhibitory activity on APE1 redox function and was demonstrated to efficiently inhibit KSHV replication and paracrine-mediated KS phenotypes such as angiogenesis and cell invasion.	('inhibit', 'NegReg', (170, 177))	('KSHV', 'Species', '37296', (178, 182))	('paracrine-mediated KS phenotypes', 'CPA', (199, 231))	('APE1', 'Gene', (114, 118))	('cell invasion', 'CPA', (257, 270))	('C10', 'Var', (61, 64))	('APE1', 'Gene', '328', (114, 118))	('inhibitory activity', 'MPA', (91, 110))	('KS', 'Phenotype', 'HP:0100726', (218, 220))	('angiogenesis', 'CPA', (240, 252))	('KSHV replication', 'CPA', (178, 194))	('KS', 'Phenotype', 'HP:0100726', (178, 180))
168706	28380040	As a potent inhibitor of APE1 redox, C10 not only has value in development of a novel therapeutics for KS, but also may be used in therapies for other human diseases such as leukemia, pancreatic cancer and macular degeneration.	('macular degeneration', 'Disease', (206, 226))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (184, 201))	('leukemia', 'Disease', (174, 182))	('leukemia', 'Phenotype', 'HP:0001909', (174, 182))	('leukemia', 'Disease', 'MESH:D007938', (174, 182))	('KS', 'Phenotype', 'HP:0100726', (103, 105))	('human', 'Species', '9606', (151, 156))	('C10', 'Var', (37, 40))	('macular degeneration', 'Phenotype', 'HP:0000608', (206, 226))	('pancreatic cancer', 'Disease', (184, 201))	('pancreatic cancer', 'Disease', 'MESH:D010190', (184, 201))	('APE1', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('APE1', 'Gene', '328', (25, 29))
168732	28380040	Indeed the inhibition of APE1 redox function decreases cell proliferation, prevents the angiogenesis progress, and blocks the differentiation of endothelial precursor cells.	('angiogenesis progress', 'CPA', (88, 109))	('differentiation of endothelial precursor cells', 'CPA', (126, 172))	('decreases', 'NegReg', (45, 54))	('prevents', 'NegReg', (75, 83))	('cell proliferation', 'CPA', (55, 73))	('inhibition', 'Var', (11, 21))	('blocks', 'NegReg', (115, 121))	('APE1', 'Gene', (25, 29))	('APE1', 'Gene', '328', (25, 29))
168739	28380040	To explore this hypothesis, we first determined the role of APE1 in KSHV lytic replication through shRNA-mediated knock down of APE1 expression in cells and examining the effects of APE1 silencing on KSHV lytic replication.	('APE1', 'Gene', '328', (182, 186))	('APE1', 'Gene', '328', (128, 132))	('knock down', 'Var', (114, 124))	('KS', 'Phenotype', 'HP:0100726', (200, 202))	('KSHV', 'Species', '37296', (200, 204))	('APE1', 'Gene', (60, 64))	('APE1', 'Gene', '328', (60, 64))	('KSHV', 'Species', '37296', (68, 72))	('APE1', 'Gene', (182, 186))	('KS', 'Phenotype', 'HP:0100726', (68, 70))	('APE1', 'Gene', (128, 132))
168744	28380040	The effect of APE1 knock down on progeny virion production was also determined.	('APE1', 'Gene', (14, 18))	('knock down', 'Var', (19, 29))	('APE1', 'Gene', '328', (14, 18))
168745	28380040	Results showed that with APE1 knock down, both KSHV lytic DNA replication and virion production were significantly reduced (Fig 1B and 1C).	('KSHV', 'Gene', (47, 51))	('reduced', 'NegReg', (115, 122))	('KS', 'Phenotype', 'HP:0100726', (47, 49))	('knock down', 'Var', (30, 40))	('virion production', 'CPA', (78, 95))	('APE1', 'Gene', (25, 29))	('KSHV', 'Species', '37296', (47, 51))	('APE1', 'Gene', '328', (25, 29))
168746	28380040	The expression of immediate-early gene RTA in shRNA-transduced BCBL-1 was determined by qRT-PCR and the result showed a significant reduction of RTA transcript with APE1 knock down (Fig 1D).	('BCBL-1', 'CellLine', 'CVCL:0165', (63, 69))	('reduction', 'NegReg', (132, 141))	('knock down', 'Var', (170, 180))	('RTA', 'Gene', (145, 148))	('APE1', 'Gene', '328', (165, 169))	('APE1', 'Gene', (165, 169))
168750	28380040	The half maximal inhibitory concentration of E3330 (IC50 for viral DNA replication) was calculated to be 17.7 muM (Fig 1E).	('muM', 'Gene', '56925', (110, 113))	('E3330', 'Chemical', 'MESH:C075569', (45, 50))	('muM', 'Gene', (110, 113))	('E3330', 'Var', (45, 50))
168754	28380040	Cytotoxicity of E3330 on BCBL-1 cells was assessed by Trypan blue exclusion that provided a homogeneous method for estimating both the numbers of viable and nonviable cells present in culture of each treatment.	('E3330', 'Chemical', 'MESH:C075569', (16, 21))	('Cytotoxicity', 'Disease', (0, 12))	('BCBL-1', 'CellLine', 'CVCL:0165', (25, 31))	('Cytotoxicity', 'Disease', 'MESH:D064420', (0, 12))	('Trypan blue', 'Chemical', 'MESH:D014343', (54, 65))	('E3330', 'Var', (16, 21))
168764	28380040	We found that the conditioned media of KSHV-infected PDLSC could increase the angiogenesis activity of PDLSCs, indicating that KSHV can induce angiogenesis of oral MSCs in a paracrine manner(Fig 2C).	('KSHV', 'Var', (127, 131))	('increase', 'PosReg', (65, 73))	('induce', 'PosReg', (136, 142))	('KS', 'Phenotype', 'HP:0100726', (127, 129))	('KSHV-infected', 'Disease', (39, 52))	('angiogenesis activity', 'CPA', (78, 99))	('KSHV-infected', 'Disease', 'MESH:C537372', (39, 52))	('angiogenesis', 'CPA', (143, 155))	('KS', 'Phenotype', 'HP:0100726', (39, 41))	('KSHV', 'Species', '37296', (39, 43))	('KSHV', 'Species', '37296', (127, 131))
168774	28380040	The results showed that along with reduced expression of APE1, the levels of VEGF-A, IL-6 and IL-8 mRNAs were significantly decreased in APE1 knock down cells (Fig 2F).	('IL-8', 'Gene', (94, 98))	('VEGF-A', 'Gene', (77, 83))	('IL-8', 'Gene', '3576', (94, 98))	('knock down', 'Var', (142, 152))	('IL-6', 'Gene', (85, 89))	('decreased', 'NegReg', (124, 133))	('APE1', 'Gene', (57, 61))	('APE1', 'Gene', (137, 141))	('APE1', 'Gene', '328', (57, 61))	('IL-6', 'Gene', '3569', (85, 89))	('VEGF-A', 'Gene', '7422', (77, 83))	('APE1', 'Gene', '328', (137, 141))
168784	28380040	Differential scanning fluorimetry (DSF) and circular dichroism (CD) were employed to test whether C10 is capable of interacting with APE1.	('circular dichroism', 'Disease', 'None', (44, 62))	('C10', 'Var', (98, 101))	('APE1', 'Gene', (133, 137))	('interacting', 'Interaction', (116, 127))	('APE1', 'Gene', '328', (133, 137))	('circular dichroism', 'Disease', (44, 62))
168786	28380040	Results showed that C10 shifted the Tm of APE1 by 1.3 C (Fig 3C), indicating the direct binding of C10 to APE1.	('APE1', 'Gene', (42, 46))	('APE1', 'Gene', '328', (42, 46))	('APE1', 'Gene', (106, 110))	('C10', 'Var', (20, 23))	('APE1', 'Gene', '328', (106, 110))	('binding', 'Interaction', (88, 95))
168787	28380040	As a reference, E3330 shifted the Tm of APE1 by 1.0 C. CD is an assay using polarized light to measure the melting temperature changes influenced by compound binding.	('E3330', 'Chemical', 'MESH:C075569', (16, 21))	('APE1', 'Gene', (40, 44))	('APE1', 'Gene', '328', (40, 44))	('binding', 'Interaction', (158, 165))	('E3330', 'Var', (16, 21))
168788	28380040	The result also confirmed that C10 destabilizes the structure of APE1 and so does E3330 (Fig 3D).	('APE1', 'Gene', '328', (65, 69))	('E3330', 'Var', (82, 87))	('E3330', 'Chemical', 'MESH:C075569', (82, 87))	('structure', 'MPA', (52, 61))	('APE1', 'Gene', (65, 69))	('destabilizes', 'NegReg', (35, 47))	('C10', 'Var', (31, 34))
168789	28380040	The binding affinities of C10 and E3330 to APE1 were determined by using surface plasmon resonance (SPR) and Kd's of interaction of C10 and E3330 with APE1 were measured to be 189 nM and 1.63 muM, respectively, indicating a higher binding affinity of C10 to APE1 than that of E3330 (Fig 3E).	('E3330', 'Chemical', 'MESH:C075569', (276, 281))	('APE1', 'Gene', '328', (151, 155))	('APE1', 'Gene', '328', (258, 262))	('C10', 'Var', (132, 135))	('binding affinity', 'Interaction', (231, 247))	('E3330', 'Var', (140, 145))	('muM', 'Gene', (192, 195))	('interaction', 'Interaction', (117, 128))	('APE1', 'Gene', (43, 47))	('E3330', 'Var', (34, 39))	('E3330', 'Chemical', 'MESH:C075569', (140, 145))	('E3330', 'Chemical', 'MESH:C075569', (34, 39))	('APE1', 'Gene', '328', (43, 47))	('higher', 'PosReg', (224, 230))	('APE1', 'Gene', (151, 155))	('APE1', 'Gene', (258, 262))	('muM', 'Gene', '56925', (192, 195))
168796	28380040	By comparison, a relatively weaker effect on APE1-dependent AP-1 binding was observed for E3330 (IC50 = 36.0 muM, Fig 4C).	('APE1', 'Gene', '328', (45, 49))	('E3330', 'Chemical', 'MESH:C075569', (90, 95))	('muM', 'Gene', (109, 112))	('AP-1', 'Gene', (60, 64))	('AP-1', 'Gene', '3725', (60, 64))	('binding', 'Interaction', (65, 72))	('E3330', 'Var', (90, 95))	('muM', 'Gene', '56925', (109, 112))	('APE1', 'Gene', (45, 49))
168797	28380040	To examine whether C10 also affects the C-terminal function of APE1, an in vitro assay for APE1 DNA excision activity was established.	('APE1', 'Gene', '328', (63, 67))	('C-terminal function', 'MPA', (40, 59))	('APE1', 'Gene', (91, 95))	('amine', 'Chemical', 'MESH:D000588', (5, 10))	('C10', 'Var', (19, 22))	('affects', 'Reg', (28, 35))	('APE1', 'Gene', '328', (91, 95))	('APE1', 'Gene', (63, 67))
168801	28380040	As shown in Fig 4E, the APE1 exonuclease activity was unaffected in the presence of up to 100 muM of C10.	('APE1', 'Gene', '328', (24, 28))	('C10', 'Var', (101, 104))	('muM', 'Gene', '56925', (94, 97))	('muM', 'Gene', (94, 97))	('APE1', 'Gene', (24, 28))
168803	28380040	Taken together, the results demonstrated that C10 is an inhibitor specific to the APE1 redox function.	('APE1', 'Gene', (82, 86))	('APE1', 'Gene', '328', (82, 86))	('C10', 'Var', (46, 49))
168811	28380040	Since RTA is known to be regulated by AP-1 signal transduction, inhibition of APE1 dependent AP-1 DNA binding would therefore disrupt this signaling.	('disrupt', 'NegReg', (126, 133))	('binding', 'Interaction', (102, 109))	('APE1', 'Gene', (78, 82))	('inhibition', 'Var', (64, 74))	('APE1', 'Gene', '328', (78, 82))	('AP-1', 'Gene', (38, 42))	('AP-1', 'Gene', '3725', (38, 42))	('AP-1', 'Gene', (93, 97))	('RTA', 'MPA', (6, 9))	('signaling', 'MPA', (139, 148))	('AP-1', 'Gene', '3725', (93, 97))
168812	28380040	Thus, functional inhibition of APE1 redox activity by C10 is speculated to result in the decreased expression of RTA expression.	('RTA', 'Protein', (113, 116))	('expression', 'MPA', (99, 109))	('APE1', 'Gene', (31, 35))	('APE1', 'Gene', '328', (31, 35))	('C10', 'Var', (54, 57))	('inhibition', 'NegReg', (17, 27))	('decreased', 'NegReg', (89, 98))
168817	28380040	C10 was able to block TPA-induced AP-1 promoter (Fig 5C) and RTA promoter activities in a dose-dependent manner (Fig 5D).	('RTA promoter activities', 'MPA', (61, 84))	('AP-1', 'Gene', '3725', (34, 38))	('AP-1', 'Gene', (34, 38))	('block', 'NegReg', (16, 21))	('C10', 'Var', (0, 3))	('TPA', 'Chemical', 'MESH:D013755', (22, 25))
168818	28380040	These results indicate that AP-1 redox inhibitor C10 blocks KSHV lytic replication through inhibiting TPA-induced AP-1 pathway and RTA expression.	('inhibiting', 'NegReg', (91, 101))	('AP-1', 'Gene', (114, 118))	('AP-1', 'Gene', '3725', (114, 118))	('TPA', 'Chemical', 'MESH:D013755', (102, 105))	('KSHV', 'Gene', (60, 64))	('RTA', 'Pathway', (131, 134))	('AP-1', 'Gene', '3725', (28, 32))	('AP-1', 'Gene', (28, 32))	('KSHV', 'Species', '37296', (60, 64))	('C10', 'Var', (49, 52))	('KS', 'Phenotype', 'HP:0100726', (60, 62))	('blocks', 'NegReg', (53, 59))
168822	28380040	In this system, C10 was found to be able to inhibit viral lytic DNA replication with an IC50 value of 5.8 muM and virion production with an EC50 value of 3.2 muM, respectively (Supporting Information, S1 Fig).	('virion production', 'MPA', (114, 131))	('muM', 'Gene', '56925', (106, 109))	('C10', 'Var', (16, 19))	('inhibit', 'NegReg', (44, 51))	('muM', 'Gene', (158, 161))	('muM', 'Gene', (106, 109))	('viral lytic DNA replication', 'MPA', (52, 79))	('muM', 'Gene', '56925', (158, 161))
168826	28380040	As shown in Fig 6A, the tubulogenesis of KSHV-PDLSC was inhibited by C10 in a dose dependent manner.	('KS', 'Phenotype', 'HP:0100726', (41, 43))	('tubulogenesis', 'CPA', (24, 37))	('inhibited', 'NegReg', (56, 65))	('C10', 'Var', (69, 72))	('KSHV', 'Species', '37296', (41, 45))
168827	28380040	E3330 was also included in the assay as a reference and showed inhibitory activity at higher doses (Fig 6A).	('E3330', 'Chemical', 'MESH:C075569', (0, 5))	('inhibitory activity', 'MPA', (63, 82))	('E3330', 'Var', (0, 5))
168828	28380040	In addition, C10 and E3330 were capable of inhibiting paracrine-mediated angiogenesis with conditioned media from KSHV-infected PDLSCs (Fig 6B).	('inhibiting', 'NegReg', (43, 53))	('paracrine-mediated angiogenesis', 'MPA', (54, 85))	('E3330', 'Var', (21, 26))	('KS', 'Phenotype', 'HP:0100726', (114, 116))	('C10', 'Var', (13, 16))	('KSHV-infected PDLSCs', 'Disease', (114, 134))	('E3330', 'Chemical', 'MESH:C075569', (21, 26))	('KSHV-infected PDLSCs', 'Disease', 'MESH:C537372', (114, 134))
168830	28380040	Next, we employed a murine Matrigel plug assay to examine the ability of C10 to inhibit angiogenesis ex vivo.	('inhibit', 'NegReg', (80, 87))	('angiogenesis', 'CPA', (88, 100))	('murine', 'Species', '10090', (20, 26))	('amine', 'Chemical', 'MESH:D000588', (52, 57))	('C10', 'Var', (73, 76))
168838	28380040	The finding that the paracrine-regulated angiogenesis requires the redox function of APE1 (Fig 2) prompted us to further investigate if blockade of APE1 redox function by C10 could reduce cytokine and angiogenic factor production.	('APE1', 'Gene', (148, 152))	('APE1', 'Gene', '328', (148, 152))	('blockade', 'Var', (136, 144))	('redox', 'MPA', (67, 72))	('reduce', 'NegReg', (181, 187))	('APE1', 'Gene', (85, 89))	('APE1', 'Gene', '328', (85, 89))
168840	28380040	KSHV-infected PDLSCs were treated with either C10 or E3330 for 24 hours.	('E3330', 'Var', (53, 58))	('C10', 'Var', (46, 49))	('E3330', 'Chemical', 'MESH:C075569', (53, 58))	('KSHV-infected PDLSCs', 'Disease', (0, 20))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('KSHV-infected PDLSCs', 'Disease', 'MESH:C537372', (0, 20))
168841	28380040	After changing media to remove C10 and E3330 from the media, cells were continued to culture for 24 hours.	('E3330', 'Var', (39, 44))	('C10', 'Var', (31, 34))	('E3330', 'Chemical', 'MESH:C075569', (39, 44))
168843	28380040	The results showed that both C10 (Fig 7A) and E3330 (Fig 7B) were able to reduce the levels of these angiogenic growth factors.	('levels of these angiogenic growth factors', 'MPA', (85, 126))	('reduce', 'NegReg', (74, 80))	('C10', 'Var', (29, 32))	('E3330', 'Var', (46, 51))	('E3330', 'Chemical', 'MESH:C075569', (46, 51))
168844	28380040	Similar results were also obtained with HUVECs where KSHV-induced productions of VEGF-A, IL-6 and IL-8 were inhibited by C10 (Supporting Information, S3 Fig).	('HUVEC', 'CellLine', 'CVCL:2959', (40, 45))	('IL-8', 'Gene', '3576', (98, 102))	('IL-6', 'Gene', '3569', (89, 93))	('VEGF-A', 'Gene', '7422', (81, 87))	('IL-8', 'Gene', (98, 102))	('IL-6', 'Gene', (89, 93))	('KSHV', 'Species', '37296', (53, 57))	('KS', 'Phenotype', 'HP:0100726', (53, 55))	('C10', 'Var', (121, 124))	('inhibited', 'NegReg', (108, 117))	('productions', 'MPA', (66, 77))	('VEGF-A', 'Gene', (81, 87))
168851	28380040	shRNA-mediated knock down of APE1 led to a significant decrease in cell invasion ability in both KSHV-infected PDLSCs and the use of the conditioned media (Fig 8C and 8D).	('APE1', 'Gene', (29, 33))	('knock down', 'Var', (15, 25))	('cell invasion ability', 'CPA', (67, 88))	('APE1', 'Gene', '328', (29, 33))	('decrease', 'NegReg', (55, 63))	('KS', 'Phenotype', 'HP:0100726', (97, 99))	('KSHV-infected PDLSCs', 'Disease', (97, 117))	('KSHV-infected PDLSCs', 'Disease', 'MESH:C537372', (97, 117))
168852	28380040	Consistently, C10 was also able to block cell migration and invasion of KSHV-PDLSC (Fig 8E).	('invasion', 'CPA', (60, 68))	('cell migration', 'CPA', (41, 55))	('block', 'NegReg', (35, 40))	('KSHV', 'Species', '37296', (72, 76))	('KS', 'Phenotype', 'HP:0100726', (72, 74))	('KSHV-PDLSC', 'Gene', (72, 82))	('C10', 'Var', (14, 17))
168854	28380040	C10 was identified through a ligand-based virtual screen using E3330 as a template molecule and proven to be a new inhibitor of APE1 redox function.	('C10', 'Gene', (0, 3))	('APE1', 'Gene', '328', (128, 132))	('E3330', 'Var', (63, 68))	('E3330', 'Chemical', 'MESH:C075569', (63, 68))	('APE1', 'Gene', (128, 132))
168855	28380040	C10 blocks the redox function of APE1 and shows no demonstrable effect on the base excision endonuclease activity (Fig 4).	('redox function', 'MPA', (15, 29))	('APE1', 'Gene', (33, 37))	('blocks', 'NegReg', (4, 10))	('APE1', 'Gene', '328', (33, 37))	('C10', 'Var', (0, 3))	('base excision', 'MPA', (78, 91))
168858	28380040	However, APE1 crystal structure showed that Cys65 is deeply buried inside the protein, raising a question how C10 interacts with APE1 and gains access to the redox active site.	('C10', 'Var', (110, 113))	('Cys65', 'Var', (44, 49))	('Cys65', 'Chemical', '-', (44, 49))	('APE1', 'Gene', (9, 13))	('APE1', 'Gene', '328', (9, 13))	('APE1', 'Gene', (129, 133))	('APE1', 'Gene', '328', (129, 133))
168859	28380040	In the early study on E3330, it was surprisingly found that E3330 binds at the C-terminal domain, distant from Cys65 in a NMR study.	('E3330', 'Var', (60, 65))	('E3330', 'Chemical', 'MESH:C075569', (22, 27))	('binds', 'Interaction', (66, 71))	('E3330', 'Chemical', 'MESH:C075569', (60, 65))	('Cys65', 'Chemical', '-', (111, 116))
168860	28380040	At high concentration, E3330 interacts with both regions of the N-terminus (amino acids 68-74) and C-terminus (amino acids 266-273) as mapped by hydrogen/deuterium exchange mass spectrometry.	('interacts', 'Reg', (29, 38))	('E3330', 'Chemical', 'MESH:C075569', (23, 28))	('deuterium', 'Chemical', 'MESH:D003903', (154, 163))	('hydrogen', 'Chemical', 'MESH:D006859', (145, 153))	('E3330', 'Var', (23, 28))
168863	28380040	These data suggest that C10 prefers to bind with the C-terminal rather than the N-terminal domain of APE1.	('APE1', 'Gene', (101, 105))	('C10', 'Var', (24, 27))	('APE1', 'Gene', '328', (101, 105))	('bind', 'Interaction', (39, 43))
168865	28380040	The binding mode derived from MD simulation results indicated that C10's aromatic groups prefer to form sigma-pi interactions with Trp280 and its carbonyl group trends to form hydrogen bonds with Arg177 side-chain (Fig 9C).	('hydrogen bonds', 'MPA', (176, 190))	('form', 'Reg', (171, 175))	('C10', 'Var', (67, 70))	('Trp280', 'Chemical', '-', (131, 137))	('hydrogen', 'Chemical', 'MESH:D006859', (176, 184))	('Arg177', 'Chemical', '-', (196, 202))	('sigma-pi interactions', 'MPA', (104, 125))	('Trp280', 'Gene', (131, 137))
168866	28380040	Now the question is how C10, through interacting with those amino acids in the C-terminal, affects APE-1 redox activity.	('affects', 'Reg', (91, 98))	('APE-1', 'Gene', '328', (99, 104))	('interacting', 'Interaction', (37, 48))	('APE-1', 'Gene', (99, 104))	('C10', 'Var', (24, 27))
168869	28380040	This result informs that C10 binds with the C-terminal pocket and results in conformation transitions of APE-1.	('APE-1', 'Gene', (105, 110))	('binds', 'Interaction', (29, 34))	('conformation transitions', 'MPA', (77, 101))	('C10', 'Var', (25, 28))	('results in', 'Reg', (66, 76))	('APE-1', 'Gene', '328', (105, 110))
168870	28380040	It is observed from the MD simulation that in the absence of C10, Cys65 is hidden behind an alpha-helix in APE1 (Fig 9E), while binding of C10 into the C-terminal pocket lifts up the alpha-helix domain, therefore resulting in Cys-65 exposed to the solvent (Fig 9F).	('APE1', 'Gene', (107, 111))	('binding', 'Var', (128, 135))	('APE1', 'Gene', '328', (107, 111))	('C10', 'Var', (139, 142))	('resulting in', 'Reg', (213, 225))	('Cys', 'Chemical', 'MESH:D003545', (66, 69))	('Cys65', 'Chemical', '-', (66, 71))	('lifts up', 'NegReg', (170, 178))	('Cys', 'Chemical', 'MESH:D003545', (226, 229))	('Cys-65 exposed to the solvent', 'MPA', (226, 255))	('alpha-helix domain', 'MPA', (183, 201))
168876	28380040	These two functions are completely independent in their actions as the mutation of Cys65 abolishes the redox function but does not affect the DNA repair function, whereas the mutation of His309, which is required for the DNA repair function, does not affect the redox function.	('mutation', 'Var', (71, 79))	('abolishes', 'NegReg', (89, 98))	('Cys65', 'Var', (83, 88))	('Cys65', 'Chemical', '-', (83, 88))	('His309', 'Chemical', '-', (187, 193))	('redox function', 'MPA', (103, 117))
168878	28380040	Selective inhibitors against APE1 base excision repair activity have been exploring to be used in combination with DNA-interactive anticancer drug to enhance the efficacy of chemotherapy.	('cancer', 'Disease', (135, 141))	('APE1', 'Gene', (29, 33))	('APE1', 'Gene', '328', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('inhibitors', 'Var', (10, 20))	('enhance', 'PosReg', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
168881	28380040	The specific APE1 redox inhibitor E3330 is reported to cause tumor growth inhibition in cell lines and pancreatic cancer xenograft model in mice, demonstrating the potential of APE1 inhibitors in pancreatic cancer treatment.	('pancreatic cancer', 'Disease', (196, 213))	('pancreatic cancer', 'Disease', 'MESH:D010190', (196, 213))	('mice', 'Species', '10090', (140, 144))	('pancreatic cancer', 'Disease', (103, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('E3330', 'Var', (34, 39))	('APE1', 'Gene', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (196, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('E3330', 'Chemical', 'MESH:C075569', (34, 39))	('APE1', 'Gene', '328', (177, 181))	('APE1', 'Gene', (13, 17))	('APE1', 'Gene', '328', (13, 17))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
168890	28380040	The critical roles of APE1 in KSHV-associated cytokine production through redox regulation of DNA binding activities of the transcription factors including HIF-1alpha, COX-2 and AP-1 in turn explain the pharmacological mechanism underlying inhibition of KSHV-mediated cytokine production, angiogenesis and cell invasive growth by APE1 inhibitor C10.	('inhibition', 'NegReg', (240, 250))	('KSHV', 'Species', '37296', (30, 34))	('C10', 'Var', (345, 348))	('APE1', 'Gene', '328', (330, 334))	('KSHV', 'Species', '37296', (254, 258))	('HIF-1alpha', 'Gene', '3091', (156, 166))	('APE1', 'Gene', '328', (22, 26))	('KS', 'Phenotype', 'HP:0100726', (254, 256))	('HIF-1alpha', 'Gene', (156, 166))	('APE1', 'Gene', (22, 26))	('COX-2', 'Gene', '4513', (168, 173))	('AP-1', 'Gene', '3725', (178, 182))	('AP-1', 'Gene', (178, 182))	('KS', 'Phenotype', 'HP:0100726', (30, 32))	('cell invasive growth', 'CPA', (306, 326))	('COX-2', 'Gene', (168, 173))	('angiogenesis', 'CPA', (289, 301))	('APE1', 'Gene', (330, 334))
168895	28380040	(ii) The EC50 of C10 for blocking virion particle release is 29-fold lower than IC50 for inhibiting intracellular viral DNA replication (Fig 5A), suggesting APE1 has an additional role in a certain step between viral DNA replication and virion assembly (e.g.	('is 29', 'Species', '1432549', (58, 63))	('intracellular viral DNA replication', 'MPA', (100, 135))	('inhibiting', 'NegReg', (89, 99))	('virion particle release', 'MPA', (34, 57))	('APE1', 'Gene', (157, 161))	('C10', 'Var', (17, 20))	('APE1', 'Gene', '328', (157, 161))	('blocking', 'NegReg', (25, 33))
168899	28380040	Although C10 is a specific inhibitor of APE1 and not an authentic multi-target compound in a narrow sense, it practically impacts multiple proteins and affects multiple biological processes.	('affects', 'Reg', (152, 159))	('C10', 'Var', (9, 12))	('APE1', 'Gene', (40, 44))	('APE1', 'Gene', '328', (40, 44))	('impacts', 'Reg', (122, 129))	('proteins', 'Protein', (139, 147))
168900	28380040	Therefore, C10 has a greater potential than a compound that affects a single biological reaction in becoming an effective drug to treat complex diseases such as KS and other cancers.	('KS', 'Phenotype', 'HP:0100726', (161, 163))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('C10', 'Var', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
168902	28380040	Therefore we have closely paid attention to the cytotoxicity issue with C10.	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('C10', 'Var', (72, 75))	('cytotoxicity', 'Disease', (48, 60))	('closely paid attention', 'Phenotype', 'HP:0000736', (18, 40))
168903	28380040	In cell-based assays, C10 showed relatively low cytotoxicity with an acceptable selectivity index (e.g., SI = 165 for inhibition of KSHV virion production in B cells).	('SI', 'Disease', 'None', (105, 107))	('KSHV virion production', 'MPA', (132, 154))	('inhibition', 'NegReg', (118, 128))	('C10', 'Var', (22, 25))	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('KSHV', 'Species', '37296', (132, 136))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('cytotoxicity', 'Disease', (48, 60))
168904	28380040	E3330 was also reported to exhibit low cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (39, 51))	('E3330', 'Chemical', 'MESH:C075569', (0, 5))	('cytotoxicity', 'Disease', (39, 51))	('E3330', 'Var', (0, 5))
168911	28380040	Dysregulation of APE1 has been reported to be associated with cancer where alteration of APE1 was found in both expression and subcellular localization levels.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Dysregulation', 'Var', (0, 13))	('APE1', 'Gene', '328', (17, 21))	('APE1', 'Gene', (17, 21))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('associated', 'Reg', (46, 56))	('APE1', 'Gene', (89, 93))	('APE1', 'Gene', '328', (89, 93))
168912	28380040	Inhibition of APE1 redox function decreases cell proliferation and migration of cancer cells, and blocks the differentiation of endothelial precursor cells and angiogenesis.	('decreases', 'NegReg', (34, 43))	('cell proliferation', 'CPA', (44, 62))	('blocks', 'NegReg', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('APE1', 'Gene', (14, 18))	('cancer', 'Disease', (80, 86))	('APE1', 'Gene', '328', (14, 18))
168913	28380040	As a novel and effective inhibitor of APE1 redox function, C10 has potential to become an anti-cancer agent to treat cancers and other angiogenesis-related human diseases.	('APE1', 'Gene', '328', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('C10', 'Var', (59, 62))	('cancer', 'Disease', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('human', 'Species', '9606', (156, 161))	('APE1', 'Gene', (38, 42))	('cancers', 'Disease', (117, 124))
168917	28380040	Inhibition of APE1 redox function appears to be a better strategy as APE1 inhibitors with multi-targeting property not only blocks VEGF production, but also reduces inflammatory reaction that also contributes to AMD development.	('inflammatory reaction', 'CPA', (165, 186))	('APE1', 'Gene', '328', (69, 73))	('APE1', 'Gene', (69, 73))	('VEGF', 'Gene', (131, 135))	('inhibitors', 'Var', (74, 84))	('AMD', 'Disease', 'MESH:D006009', (212, 215))	('blocks', 'NegReg', (124, 130))	('VEGF', 'Gene', '7422', (131, 135))	('AMD', 'Disease', (212, 215))	('APE1', 'Gene', (14, 18))	('reduces', 'NegReg', (157, 164))	('APE1', 'Gene', '328', (14, 18))
168918	28380040	It has been shown that inhibition of APE1 redox activity by E3330 blocks retinal angiogenesis in vitro and in an animal model.	('retinal angiogenesis', 'CPA', (73, 93))	('E3330', 'Var', (60, 65))	('E3330', 'Chemical', 'MESH:C075569', (60, 65))	('APE1', 'Gene', (37, 41))	('blocks', 'NegReg', (66, 72))	('APE1', 'Gene', '328', (37, 41))
168965	28380040	Purified APE1 protein (Supporting Information, S7 Fig) was diluted to 2 muM and incubated with C10 or E3330 in different concentrations at 37 C for 30 min.	('E3330', 'Var', (102, 107))	('APE1', 'Gene', (9, 13))	('C10', 'Var', (95, 98))	('muM', 'Gene', '56925', (72, 75))	('E3330', 'Chemical', 'MESH:C075569', (102, 107))	('APE1', 'Gene', '328', (9, 13))	('muM', 'Gene', (72, 75))
168971	28380040	Interactions of APE1 with C10 and E3330 were analyzed by using a ProteOn XPR36 SPR instrument (Bio-Rad, Hercules, CA).	('E3330', 'Var', (34, 39))	('Rad', 'Gene', '6236', (99, 102))	('APE1', 'Gene', (16, 20))	('Interactions', 'Interaction', (0, 12))	('Rad', 'Gene', (99, 102))	('E3330', 'Chemical', 'MESH:C075569', (34, 39))	('APE1', 'Gene', '328', (16, 20))
168987	28380040	Then APE1 was added with its buffer and incubated for another 30 min at 37 C. APE1 recognizes the abasic-site and cleave the DNA at the abasic site leading to release of the cy5.5- fluorophore labeled 18-nucleotide fragment, which can be resolved from the uncleaved 40-nucleotide fragment (intact substrate) on 20% denaturing polyacrylamide gels (TBE-Urea PAGE) and visualized with an Odyssey imager (LI-COR).	('APE1', 'Gene', (5, 9))	('APE1', 'Gene', (78, 82))	('40-nucleotide', 'Chemical', '-', (266, 279))	('cy5', 'Chemical', 'MESH:C085321', (174, 177))	('APE1', 'Gene', '328', (5, 9))	('APE1', 'Gene', '328', (78, 82))	('polyacrylamide', 'Chemical', 'MESH:C016679', (326, 340))	('18-nucleotide', 'Chemical', '-', (201, 214))	('cleave', 'Var', (114, 120))	('TBE', 'Chemical', '-', (347, 350))	('Urea', 'Chemical', 'MESH:D014508', (351, 355))	('release', 'MPA', (159, 166))
168990	28380040	Subconfluent 293T cells grown in 48-well plates were co-transfected with 50 ng of pAP-1-luc or pRTA-luc and 5ng of pRL-TK by using lipofectamine 2000 reagent (Life Technologies).	('lipofectamine 2000 reagent', 'Chemical', '-', (131, 157))	('pAP-1', 'Gene', (82, 87))	('pAP-1', 'Gene', '5068', (82, 87))	('pRTA-luc', 'Var', (95, 103))	('293T', 'CellLine', 'CVCL:0063', (13, 17))
169010	28380040	5 A near residues 68-74 and 266-273 on APE1 were defined as E3330 binding site over APE1.	('E3330', 'Var', (60, 65))	('E3330', 'Chemical', 'MESH:C075569', (60, 65))	('APE1', 'Gene', (84, 88))	('APE1', 'Gene', '328', (39, 43))	('APE1', 'Gene', (39, 43))	('APE1', 'Gene', '328', (84, 88))
169021	27893813	This showed that in addition to the previously described vFLIP protein, expression of vIRF3 also inhibited apoptosis delivered by these stimuli.	('vIRF3', 'Gene', '4961493', (86, 91))	('vFLIP', 'Gene', '4961494', (57, 62))	('vFLIP', 'Gene', (57, 62))	('vIRF3', 'Gene', (86, 91))	('apoptosis delivered', 'CPA', (107, 126))	('inhibited', 'NegReg', (97, 106))	('expression', 'Var', (72, 82))
169047	27893813	The finding that knock down of vFLIP induced sensitivity to Fas ligation indicates that this viral protein can interfere with this apoptotic pathway, however vFLIP is thought to be expressed at low levels within infected cells; whether other viral proteins contribute to this inhibition is unclear.	('Fas', 'Chemical', 'MESH:C038178', (60, 63))	('apoptotic pathway', 'Pathway', (131, 148))	('vFLIP', 'Gene', '4961494', (158, 163))	('vFLIP', 'Gene', (158, 163))	('vFLIP', 'Gene', '4961494', (31, 36))	('interfere', 'NegReg', (111, 120))	('knock down', 'Var', (17, 27))	('vFLIP', 'Gene', (31, 36))
169054	27893813	We also identified that in addition to vFLIP, expression of vIRF3 prevented apoptosis induced by extrinsic pathways and that AZT treatment inhibited this vIRF3 mediated protection.	('vFLIP', 'Gene', '4961494', (39, 44))	('vFLIP', 'Gene', (39, 44))	('expression', 'Var', (46, 56))	('extrinsic pathways', 'Pathway', (97, 115))	('prevented', 'NegReg', (66, 75))	('vIRF3', 'Gene', '4961493', (60, 65))	('vIRF3', 'Gene', (154, 159))	('vIRF3', 'Gene', (60, 65))	('vIRF3', 'Gene', '4961493', (154, 159))	('apoptosis', 'CPA', (76, 85))	('inhibited', 'NegReg', (139, 148))	('AZT', 'Chemical', 'MESH:D015215', (125, 128))
169074	27893813	However parallel assays using MHC-matched T cell clones showed that in the presence of 10 mug/ml AZT, PEL growth could be inhibited and in some cases completely controlled.	('AZT', 'Var', (97, 100))	('inhibited', 'NegReg', (122, 131))	('PEL', 'Phenotype', 'HP:0030069', (102, 105))	('PEL growth', 'CPA', (102, 112))	('AZT', 'Chemical', 'MESH:D015215', (97, 100))
169097	27893813	vCyclin and vFLIP were expressed at markedly higher levels in transduced BJAB cells compared to BCBL-1, while vIRF3 expression was increased compared to BCBL-1.	('expression', 'MPA', (116, 126))	('vFLIP', 'Gene', (12, 17))	('vCyclin', 'Gene', (0, 7))	('vIRF3', 'Gene', '4961493', (110, 115))	('increased', 'PosReg', (131, 140))	('vIRF3', 'Gene', (110, 115))	('vCyclin', 'Gene', '4961471', (0, 7))	('transduced', 'Var', (62, 72))	('BJAB', 'CellLine', 'CVCL:5711', (73, 77))	('higher', 'PosReg', (45, 51))	('vFLIP', 'Gene', '4961494', (12, 17))
169104	27893813	Anti-Fas antibody induced high levels of death in control transgene expressing BJAB cells, while those expressing vIL-6, LANA and vCyclin showed no significant difference in the percentage of dead cells compared to control cells when challenged with 0.15 mug/ml or 0.075 mug/ml of anti-Fas antibody (p>=0.2248 and p>=0.1642 respectively).	('vCyclin', 'Gene', '4961471', (130, 137))	('LANA', 'Gene', '4961527', (121, 125))	('Fas', 'Chemical', 'MESH:C038178', (5, 8))	('BJAB', 'CellLine', 'CVCL:5711', (79, 83))	('vIL-6', 'Gene', (114, 119))	('LANA', 'Gene', (121, 125))	('vCyclin', 'Gene', (130, 137))	('Anti-Fas', 'Var', (0, 8))	('vIL-6', 'Gene', '4961449', (114, 119))	('Fas', 'Chemical', 'MESH:C038178', (286, 289))
169110	27893813	Here control, vIRF3 and vFLIP BJAB cells were grown in media containing 10 mug/ml AZT for at least seven days, which did not obviously affect their growth (S3 Fig), and transgene expressing cells challenged with anti-Fas or TRAIL as before.	('TRAIL', 'Gene', '8743', (224, 229))	('AZT', 'Chemical', 'MESH:D015215', (82, 85))	('vFLIP', 'Gene', '4961494', (24, 29))	('BJAB', 'CellLine', 'CVCL:5711', (30, 34))	('TRAIL', 'Gene', (224, 229))	('vFLIP', 'Gene', (24, 29))	('Fas', 'Chemical', 'MESH:C038178', (217, 220))	('transgene', 'Var', (169, 178))	('vIRF3', 'Gene', '4961493', (14, 19))	('vIRF3', 'Gene', (14, 19))
169115	27893813	However parallel cultures of vIRF3-expressing BJABs treated with AZT had significantly more dead cells compared to non-treated vIRF3 expressing cells when challenged with both concentrations of anti-Fas (p = 0.0034 and p = 0.0014) or TRAIL (p<1x10-7 and p = 0.0027).	('BJABs', 'CellLine', 'CVCL:5711', (46, 51))	('vIRF3', 'Gene', '4961493', (29, 34))	('vIRF3', 'Gene', (29, 34))	('TRAIL', 'Gene', (234, 239))	('Fas', 'Chemical', 'MESH:C038178', (199, 202))	('AZT', 'Var', (65, 68))	('AZT', 'Chemical', 'MESH:D015215', (65, 68))	('vIRF3', 'Gene', '4961493', (127, 132))	('vIRF3', 'Gene', (127, 132))	('TRAIL', 'Gene', '8743', (234, 239))
169118	27893813	As before, vIRF3 expressing cells treated with 10 mug/ml AZT lost their protection from apoptosis induction as did those treated with 5 mug/ml AZT.	('apoptosis', 'CPA', (88, 97))	('lost', 'NegReg', (61, 65))	('vIRF3', 'Gene', (11, 16))	('AZT', 'Chemical', 'MESH:D015215', (143, 146))	('AZT', 'Var', (57, 60))	('AZT', 'Chemical', 'MESH:D015215', (57, 60))	('vIRF3', 'Gene', '4961493', (11, 16))	('protection', 'MPA', (72, 82))
169129	27893813	This work was prompted by our observations that although KSHV-specific CD4+ T cells could recognize PELs expressing MHC class II or PELs engineered to express surface class II, they were unable to control them despite killing other cell types.	('PEL', 'Phenotype', 'HP:0030069', (132, 135))	('MHC class II', 'Var', (116, 128))	('CD4', 'Gene', (71, 74))	('KSHV', 'Species', '37296', (57, 61))	('CD4', 'Gene', '920', (71, 74))	('KS', 'Phenotype', 'HP:0100726', (57, 59))	('PEL', 'Phenotype', 'HP:0030069', (100, 103))
169134	27893813	Consistent with these studies we found that expression of vFLIP in BJAB cells inhibited killing by anti-Fas antibody and TRAIL.	('inhibited', 'NegReg', (78, 87))	('TRAIL', 'Gene', '8743', (121, 126))	('killing', 'CPA', (88, 95))	('vFLIP', 'Gene', '4961494', (58, 63))	('expression', 'Var', (44, 54))	('TRAIL', 'Gene', (121, 126))	('vFLIP', 'Gene', (58, 63))	('Fas', 'Chemical', 'MESH:C038178', (104, 107))	('BJAB', 'CellLine', 'CVCL:5711', (67, 71))
169135	27893813	Unexpectedly we found that expression of vIRF3 also inhibited apoptosis induced by these two mechanisms.	('vIRF3', 'Gene', (41, 46))	('apoptosis', 'CPA', (62, 71))	('inhibited', 'NegReg', (52, 61))	('expression', 'Var', (27, 37))	('vIRF3', 'Gene', '4961493', (41, 46))
169137	27893813	Thus knockdown of vIRF3 in PELs induces growth arrest, caspase 3 activation and apoptosis.	('apoptosis', 'CPA', (80, 89))	('caspase 3', 'Gene', (55, 64))	('knockdown', 'Var', (5, 14))	('growth arrest', 'Disease', (40, 53))	('growth arrest', 'Disease', 'MESH:D006323', (40, 53))	('caspase 3', 'Gene', '836', (55, 64))	('PEL', 'Phenotype', 'HP:0030069', (27, 30))	('growth arrest', 'Phenotype', 'HP:0001510', (40, 53))	('vIRF3', 'Gene', (18, 23))	('activation', 'PosReg', (65, 75))	('vIRF3', 'Gene', '4961493', (18, 23))
169157	27893813	However knock down of either vFLIP or vIRF3 expression in PELs sensitizes or induces apoptosis in these cells, so establishing lines deficient in either of these may not be possible.	('vFLIP', 'Gene', (29, 34))	('knock down', 'Var', (8, 18))	('apoptosis', 'CPA', (85, 94))	('vFLIP', 'Gene', '4961494', (29, 34))	('PEL', 'Phenotype', 'HP:0030069', (58, 61))	('vIRF3', 'Gene', '4961493', (38, 43))	('vIRF3', 'Gene', (38, 43))	('induces', 'Reg', (77, 84))	('sensitizes', 'Reg', (63, 73))
169188	26036639	FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro Myxoid liposarcomas account for more than one third of liposarcomas and about 10% of all adult soft tissue sarcomas.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (203, 223))	('sarcomas', 'Disease', (119, 127))	('sarcomas', 'Disease', (167, 175))	('FGFR', 'Gene', (63, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('liposarcomas', 'Phenotype', 'HP:0012034', (163, 175))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (26, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('liposarcomas', 'Disease', 'MESH:D008080', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('liposarcoma', 'Phenotype', 'HP:0012034', (163, 174))	('Myxoid liposarcomas', 'Phenotype', 'HP:0012268', (108, 127))	('myxoid liposarcoma', 'Disease', (26, 44))	('impairs tumor', 'Disease', 'MESH:D015417', (78, 91))	('inhibition', 'Var', (49, 59))	('FGFR2', 'Gene', (0, 5))	('liposarcomas', 'Phenotype', 'HP:0012034', (115, 127))	('liposarcomas', 'Disease', (163, 175))	('Myxoid liposarcomas', 'Disease', (108, 127))	('impairs tumor', 'Disease', (78, 91))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (26, 44))	('liposarcoma', 'Phenotype', 'HP:0012034', (115, 126))	('Myxoid liposarcoma', 'Phenotype', 'HP:0012268', (108, 126))	('FGFR2', 'Gene', '2263', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('liposarcomas', 'Disease', (115, 127))	('sarcomas', 'Disease', 'MESH:D012509', (215, 223))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('liposarcoma', 'Phenotype', 'HP:0012034', (33, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcomas', 'Disease', (215, 223))	('sarcomas', 'Disease', 'MESH:D012509', (167, 175))	('liposarcomas', 'Disease', 'MESH:D008080', (163, 175))	('sarcomas', 'Phenotype', 'HP:0100242', (167, 175))	('Myxoid liposarcomas', 'Disease', 'MESH:D018208', (108, 127))
169193	26036639	Treatment of the myxoid liposarcoma cell lines MLS 402 and MLS 1765 with the FGFR inhibitors PD173074, TKI258 (dovitinib) and BGJ398 as well as specific siRNAs reduced cell proliferation, induced apoptosis and delayed cell migration.	('MLS', 'Disease', 'MESH:C537466', (59, 62))	('delayed', 'NegReg', (210, 217))	('FGF', 'Gene', '2247;2250;2256;8817', (77, 80))	('inhibitors', 'Var', (82, 92))	('MLS', 'Disease', (59, 62))	('TKI258', 'Chemical', 'MESH:C500007', (103, 109))	('PD173074', 'Chemical', 'MESH:C115711', (93, 101))	('cell migration', 'CPA', (218, 232))	('FGF', 'Gene', (77, 80))	('dovitinib', 'Chemical', 'MESH:C500007', (111, 120))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (17, 35))	('cell proliferation', 'CPA', (168, 186))	('reduced', 'NegReg', (160, 167))	('apoptosis', 'CPA', (196, 205))	('PD173074', 'Var', (93, 101))	('myxoid liposarcoma', 'Disease', (17, 35))	('induced', 'Reg', (188, 195))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (17, 35))	('MLS', 'Disease', 'MESH:C537466', (47, 50))	('BGJ398', 'Gene', (126, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('MLS', 'Disease', (47, 50))	('BGJ398', 'Chemical', 'MESH:C568950', (126, 132))	('liposarcoma', 'Phenotype', 'HP:0012034', (24, 35))
169194	26036639	Combination of FGFR inhibitors with trabectedin further increased the effect.	('FGF', 'Gene', (15, 18))	('increased', 'PosReg', (56, 65))	('trabectedin', 'Chemical', 'MESH:D000077606', (36, 47))	('FGF', 'Gene', '2247;2250;2256;8817', (15, 18))	('inhibitors', 'Var', (20, 30))	('Combination', 'Interaction', (0, 11))
169203	26036639	The translocations t(12;16)(q13;p11) and accordingly t(12;22)(q13;p12) are specific for this tumor entity and absent in other myxoid look-alikes such as myxofibrosarcoma.	('t(12;22)(q13;p12', 'Var', (53, 69))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (19, 36))	('tumor', 'Disease', (93, 98))	('t(12;16)(q13;p11', 'Var', (19, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('myxofibrosarcoma', 'Disease', (153, 169))	('t(12;22)(q13;p12)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 70))	('myxofibrosarcoma', 'Disease', 'None', (153, 169))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
169210	26036639	FGFR1 amplification has been described in osteosarcomas and rhabdomyosarcomas were identified to carry activating mutations in FGFR4.	('FGFR4', 'Gene', '2264', (127, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('FGFR4', 'Gene', (127, 132))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (60, 77))	('activating', 'PosReg', (103, 113))	('osteosarcomas', 'Phenotype', 'HP:0002669', (42, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))	('osteosarcomas and rhabdomyosarcomas', 'Disease', 'MESH:D012516', (42, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
169211	26036639	Furthermore, activation of FGFR signaling through amplification of the adaptor FRS2 has recently been described in high-grade liposarcomas.	('FRS2', 'Gene', (79, 83))	('amplification', 'Var', (50, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('FGF', 'Gene', (27, 30))	('liposarcomas', 'Phenotype', 'HP:0012034', (126, 138))	('activation', 'PosReg', (13, 23))	('liposarcomas', 'Disease', 'MESH:D008080', (126, 138))	('FRS2', 'Gene', '10818', (79, 83))	('liposarcomas', 'Disease', (126, 138))	('FGF', 'Gene', '2247;2250;2256;8817', (27, 30))	('liposarcoma', 'Phenotype', 'HP:0012034', (126, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
169245	26036639	Figure 3B shows apoptosis induction upon FGFR silencing, either of FGFR1, 2, 3 and 4 alone or by combined knock-down of several receptors.	('apoptosis', 'CPA', (16, 25))	('silencing', 'Var', (46, 55))	('FGF', 'Gene', '2247;2250;2256;8817', (67, 70))	('knock-down', 'Var', (106, 116))	('FGF', 'Gene', (41, 44))	('FGFR1, 2, 3 and 4', 'Gene', '2260;2263;2261;2264', (67, 84))	('FGF', 'Gene', '2247;2250;2256;8817', (41, 44))	('FGF', 'Gene', (67, 70))
169246	26036639	In MLS 402 single receptor silencing of FGFR2 induced apoptosis, whereas knock-down of the other receptors alone showed no effect (Figure 3B, left upper graph).	('apoptosis', 'CPA', (54, 63))	('silencing', 'Var', (27, 36))	('MLS', 'Disease', 'MESH:C537466', (3, 6))	('MLS', 'Disease', (3, 6))	('FGFR2', 'Gene', '2263', (40, 45))	('FGFR2', 'Gene', (40, 45))
169247	26036639	Accordingly, the combined knock-down of more than one FGF receptor induced apoptosis only when FGFR2 siRNA was included (Figure 3B, left bottom graph).	('FGFR2', 'Gene', '2263', (95, 100))	('induced', 'Reg', (67, 74))	('knock-down', 'Var', (26, 36))	('FGF', 'Gene', (95, 98))	('FGF', 'Gene', (54, 57))	('apoptosis', 'CPA', (75, 84))	('FGF', 'Gene', '2247;2250;2256;8817', (95, 98))	('FGF', 'Gene', '2247;2250;2256;8817', (54, 57))	('FGFR2', 'Gene', (95, 100))
169248	26036639	In MLS 1765 cells knock-down of FGFRs induced apoptosis as well, but to a lesser extent than in MLS 402.	('apoptosis', 'CPA', (46, 55))	('FGF', 'Gene', (32, 35))	('MLS', 'Disease', 'MESH:C537466', (3, 6))	('MLS', 'Disease', (3, 6))	('MLS', 'Disease', 'MESH:C537466', (96, 99))	('MLS', 'Disease', (96, 99))	('FGF', 'Gene', '2247;2250;2256;8817', (32, 35))	('induced', 'Reg', (38, 45))	('knock-down', 'Var', (18, 28))
169249	26036639	Silencing of FGFR2 alone did not cause apoptosis, but apoptosis induction was detected upon knock-down of either FGFR1 or FGFR3 (Figure 3B, right upper graph).	('apoptosis', 'CPA', (54, 63))	('FGFR3', 'Gene', (122, 127))	('FGFR1', 'Gene', (113, 118))	('FGFR1', 'Gene', '2260', (113, 118))	('FGFR2', 'Gene', '2263', (13, 18))	('knock-down', 'Var', (92, 102))	('FGFR2', 'Gene', (13, 18))	('FGFR3', 'Gene', '2261', (122, 127))
169250	26036639	In line with this all combinations of different siRNAs including those against FGFR1 and/or FGFR3 induced apoptosis in MLS 1765 cells (Figure 3B, right bottom graph).	('MLS', 'Disease', (119, 122))	('combinations', 'Var', (22, 34))	('FGFR3', 'Gene', (92, 97))	('induced', 'Reg', (98, 105))	('apoptosis', 'CPA', (106, 115))	('FGFR1', 'Gene', (79, 84))	('FGFR1', 'Gene', '2260', (79, 84))	('FGFR3', 'Gene', '2261', (92, 97))	('MLS', 'Disease', 'MESH:C537466', (119, 122))
169253	26036639	This result is in concordance with apoptosis induction in MLS 1765 cells after silencing of FGFR1 or FGFR3.	('FGFR1', 'Gene', (92, 97))	('MLS', 'Disease', 'MESH:C537466', (58, 61))	('MLS', 'Disease', (58, 61))	('FGFR1', 'Gene', '2260', (92, 97))	('FGFR3', 'Gene', '2261', (101, 106))	('FGFR3', 'Gene', (101, 106))	('silencing', 'Var', (79, 88))
169254	26036639	As silencing of FGF receptors with specific siRNAs induced apoptosis in the myxoid liposarcoma cell lines MLS 402 and MLS 1765, also the functional effects of small molecules directed against FGFRs were examined.	('silencing', 'Var', (3, 12))	('FGF', 'Gene', (16, 19))	('myxoid liposarcoma', 'Disease', (76, 94))	('liposarcoma', 'Phenotype', 'HP:0012034', (83, 94))	('MLS', 'Disease', 'MESH:C537466', (106, 109))	('MLS', 'Disease', (106, 109))	('FGF', 'Gene', (192, 195))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (76, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('MLS', 'Disease', (118, 121))	('FGF', 'Gene', '2247;2250;2256;8817', (16, 19))	('apoptosis', 'CPA', (59, 68))	('FGF', 'Gene', '2247;2250;2256;8817', (192, 195))	('MLS', 'Disease', 'MESH:C537466', (118, 121))	('induced', 'Reg', (51, 58))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (76, 94))
169255	26036639	Cells were treated with the in vitro compound PD173074 (purchased from Sigma Aldrich) as well as with the two clinically applicable FGFR inhibitors dovitinib (TKI258) and BGJ398 (both from Novartis).	('FGF', 'Gene', (132, 135))	('Novartis', 'Disease', (189, 197))	('FGF', 'Gene', '2247;2250;2256;8817', (132, 135))	('TKI258', 'Chemical', 'MESH:C500007', (159, 165))	('BGJ398', 'Chemical', 'MESH:C568950', (171, 177))	('PD173074', 'Var', (46, 54))	('Novartis', 'Disease', 'None', (189, 197))	('PD173074', 'Chemical', 'MESH:C115711', (46, 54))	('dovitinib', 'Chemical', 'MESH:C500007', (148, 157))
169263	26036639	FGFR inhibition in myxoid liposarcoma cell lines reduced kinase activity of the receptors, as detected by reduced receptor phosphorylation (Supplemental Figure S5A).	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (19, 37))	('inhibition', 'Var', (5, 15))	('reduced', 'NegReg', (49, 56))	('kinase activity', 'MPA', (57, 72))	('receptor phosphorylation', 'MPA', (114, 138))	('myxoid liposarcoma', 'Disease', (19, 37))	('liposarcoma', 'Phenotype', 'HP:0012034', (26, 37))	('FGF', 'Gene', (0, 3))	('FGF', 'Gene', '2247;2250;2256;8817', (0, 3))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (19, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('reduced', 'NegReg', (106, 113))
169265	26036639	All three FGFR inhibitors reduced the phosphorylation of ERK1/2, being one of the main downstream targets of FGFRs.	('FGF', 'Gene', '2247;2250;2256;8817', (10, 13))	('FGF', 'Gene', (109, 112))	('phosphorylation', 'MPA', (38, 53))	('ERK1/2', 'Gene', (57, 63))	('reduced', 'NegReg', (26, 33))	('FGF', 'Gene', (10, 13))	('ERK1/2', 'Gene', '5595;5594', (57, 63))	('FGF', 'Gene', '2247;2250;2256;8817', (109, 112))	('inhibitors', 'Var', (15, 25))
169267	26036639	The FGFR inhibitors PD173074, BGJ398 and TKI258 were applied in a final concentration of 0.1 muM, a concentration which does not affect cell viability in the regarded timeframe of 24 hours.	('FGF', 'Gene', '2247;2250;2256;8817', (4, 7))	('BGJ398', 'Gene', (30, 36))	('PD173074', 'Var', (20, 28))	('PD173074', 'Chemical', 'MESH:C115711', (20, 28))	('TKI258', 'Chemical', 'MESH:C500007', (41, 47))	('muM', 'Gene', '56925', (93, 96))	('muM', 'Gene', (93, 96))	('FGF', 'Gene', (4, 7))	('BGJ398', 'Chemical', 'MESH:C568950', (30, 36))
169270	26036639	All three FGFR inhibitors reduced the migratory activity of both myxoid liposarcoma cell lines (Figure 5B).	('liposarcoma', 'Phenotype', 'HP:0012034', (72, 83))	('FGF', 'Gene', '2247;2250;2256;8817', (10, 13))	('myxoid liposarcoma', 'Disease', (65, 83))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (65, 83))	('migratory activity', 'CPA', (38, 56))	('reduced', 'NegReg', (26, 33))	('FGF', 'Gene', (10, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (65, 83))	('inhibitors', 'Var', (15, 25))
169271	26036639	However, PD173074 and BGJ398 showed much stronger effects than TKI258, which had only little impact on the migration of MLS 402 cells.	('PD173074', 'Chemical', 'MESH:C115711', (9, 17))	('MLS', 'Disease', 'MESH:C537466', (120, 123))	('MLS', 'Disease', (120, 123))	('TKI258', 'Chemical', 'MESH:C500007', (63, 69))	('BGJ398', 'Chemical', 'MESH:C568950', (22, 28))	('BGJ398', 'Gene', (22, 28))	('PD173074', 'Var', (9, 17))
169274	26036639	As shown in Figure 6B for MLS 1765, the supplementary administration of FGFR inhibitors enhanced the effects of trabectedin in comparison to single agent treatment.	('MLS', 'Disease', 'MESH:C537466', (26, 29))	('inhibitors', 'Var', (77, 87))	('FGF', 'Gene', '2247;2250;2256;8817', (72, 75))	('effects', 'MPA', (101, 108))	('trabectedin', 'Chemical', 'MESH:D000077606', (112, 123))	('enhanced', 'PosReg', (88, 96))	('FGF', 'Gene', (72, 75))	('MLS', 'Disease', (26, 29))
169277	26036639	In MLS 402 as well as in MLS 1765 cells migration was delayed by the additional administration of FGFR inhibitors when compared to cells treated with trabectedin alone (Figure 6C).	('MLS', 'Disease', 'MESH:C537466', (25, 28))	('MLS', 'Disease', 'MESH:C537466', (3, 6))	('MLS', 'Disease', (25, 28))	('MLS', 'Disease', (3, 6))	('FGF', 'Gene', (98, 101))	('trabectedin', 'Chemical', 'MESH:D000077606', (150, 161))	('inhibitors', 'Var', (103, 113))	('FGF', 'Gene', '2247;2250;2256;8817', (98, 101))	('delayed', 'NegReg', (54, 61))
169278	26036639	As seen in the single agent migration assay, PD173074 and BGJ398 displayed a greater impact on the migration of myxoid liposarcoma cells than TKI258.	('BGJ398', 'Chemical', 'MESH:C568950', (58, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (112, 130))	('BGJ398', 'Gene', (58, 64))	('impact', 'Reg', (85, 91))	('PD173074', 'Var', (45, 53))	('PD173074', 'Chemical', 'MESH:C115711', (45, 53))	('migration', 'CPA', (99, 108))	('myxoid liposarcoma', 'Disease', (112, 130))	('TKI258', 'Chemical', 'MESH:C500007', (142, 148))	('liposarcoma', 'Phenotype', 'HP:0012034', (119, 130))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (112, 130))
169305	26036639	Furthermore, the FGFR specific inhibitors PD173074 and BGJ398 had a much greater impact on cell migration than the rather broad-spectrum tyrosine kinase inhibitor TKI258 also sustaining the hypothesis that in myxoid liposarcoma the role of FGFR signaling is especially prominent for cell migration.	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (209, 227))	('FGF', 'Gene', '2247;2250;2256;8817', (240, 243))	('liposarcoma', 'Phenotype', 'HP:0012034', (216, 227))	('impact', 'Reg', (81, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('myxoid liposarcoma', 'Disease', (209, 227))	('inhibitors', 'Var', (31, 41))	('BGJ398', 'Chemical', 'MESH:C568950', (55, 61))	('BGJ398', 'Gene', (55, 61))	('PD173074', 'Var', (42, 50))	('FGF', 'Gene', (17, 20))	('TKI258', 'Chemical', 'MESH:C500007', (163, 169))	('PD173074', 'Chemical', 'MESH:C115711', (42, 50))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (209, 227))	('FGF', 'Gene', (240, 243))	('cell migration', 'CPA', (91, 105))	('FGF', 'Gene', '2247;2250;2256;8817', (17, 20))
169306	26036639	The herein used FGFR inhibitors TKI258 and BGJ398 are already applied in clinical trials of other tumor entities, such as FGFR3 mutated bladder cancer or squamous cell lung cancer with FGFR1 amplification (e.g.	('squamous cell lung cancer', 'Disease', (154, 179))	('FGF', 'Gene', (16, 19))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('tumor', 'Disease', (98, 103))	('TKI258', 'Chemical', 'MESH:C500007', (32, 38))	('BGJ398', 'Gene', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (154, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('BGJ398', 'Chemical', 'MESH:C568950', (43, 49))	('FGFR1', 'Gene', '2260', (185, 190))	('FGFR3', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('FGF', 'Gene', '2247;2250;2256;8817', (122, 125))	('FGFR3', 'Gene', '2261', (122, 127))	('FGF', 'Gene', '2247;2250;2256;8817', (185, 188))	('amplification', 'Var', (191, 204))	('mutated', 'Var', (128, 135))	('FGF', 'Gene', '2247;2250;2256;8817', (16, 19))	('FGF', 'Gene', (122, 125))	('FGFR1', 'Gene', (185, 190))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (154, 179))	('FGF', 'Gene', (185, 188))
169308	26036639	This approach might involve the combination of FGFR inhibitors with chemotherapeutic agents like trabectedin.	('combination', 'Interaction', (32, 43))	('FGF', 'Gene', (47, 50))	('trabectedin', 'Chemical', 'MESH:D000077606', (97, 108))	('FGF', 'Gene', '2247;2250;2256;8817', (47, 50))	('inhibitors', 'Var', (52, 62))
169309	26036639	In this study we showed that the additional administration of FGFR inhibitors can improve the impact on myxoid liposarcoma cells in comparison to trabectedin alone.	('inhibitors', 'Var', (67, 77))	('myxoid liposarcoma', 'Disease', (104, 122))	('improve', 'PosReg', (82, 89))	('liposarcoma', 'Phenotype', 'HP:0012034', (111, 122))	('impact', 'MPA', (94, 100))	('trabectedin', 'Chemical', 'MESH:D000077606', (146, 157))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (104, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('FGF', 'Gene', (62, 65))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (104, 122))	('FGF', 'Gene', '2247;2250;2256;8817', (62, 65))
169310	26036639	In order to examine whether FGFR inhibitors alone or in combination with chemotherapy are efficient as a potent therapy in myxoid liposarcoma, further in vivo studies are needed.	('FGF', 'Gene', '2247;2250;2256;8817', (28, 31))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (123, 141))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (123, 141))	('liposarcoma', 'Phenotype', 'HP:0012034', (130, 141))	('FGF', 'Gene', (28, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('myxoid liposarcoma', 'Disease', (123, 141))	('inhibitors', 'Var', (33, 43))
169320	26036639	In order to detect FGFR knock-down after transfection of specific siRNAs the High-Capacity RNA-to-cDNA  Kit (Life Technologies, Carlsbad CA, U.S.A.) was used for cDNA synthesis.	('FGF', 'Gene', (19, 22))	('knock-down', 'Var', (24, 34))	('FGF', 'Gene', '2247;2250;2256;8817', (19, 22))
169330	26036639	Cell lines' entity was verified by proof of the specific FUS-DDIT3 translocation.	('DDIT3', 'Gene', (61, 66))	('FUS', 'Gene', (57, 60))	('FUS', 'Gene', '2521', (57, 60))	('translocation', 'Var', (67, 80))	('DDIT3', 'Gene', '1649', (61, 66))
169333	26036639	FGFR inhibitors PD173074 (purchased from Sigma Aldrich), BGJ398 and TKI258 (both provided by Novartis, Basel, Switzerland) as well as trabectedin (provided by PharmaMar, Madrid, Spain) were solved and prediluted in DMSO.	('PD173074', 'Var', (16, 24))	('Novartis', 'Disease', 'None', (93, 101))	('PD173074', 'Chemical', 'MESH:C115711', (16, 24))	('DMSO', 'Chemical', 'MESH:D004121', (215, 219))	('TKI258', 'Chemical', 'MESH:C500007', (68, 74))	('Novartis', 'Disease', (93, 101))	('FGF', 'Gene', (0, 3))	('BGJ398', 'Chemical', 'MESH:C568950', (57, 63))	('trabectedin', 'Chemical', 'MESH:D000077606', (134, 145))	('FGF', 'Gene', '2247;2250;2256;8817', (0, 3))
169346	25999740	We report an uncommon case of primary paraesophageal Ewing's sarcoma in a 25-year-old male harboring the infrequent EWSR1/ERG fusion transcript with multiple splice variants coexisting in the same tumor.	('ERG', 'Gene', '2078', (122, 125))	('ERG', 'Gene', (122, 125))	('fusion', 'Var', (126, 132))	('EWSR1', 'Gene', '2130', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	("paraesophageal Ewing's sarcoma", 'Disease', 'MESH:C563168', (38, 68))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('EWSR1', 'Gene', (116, 121))	("paraesophageal Ewing's sarcoma", 'Disease', (38, 68))	('tumor', 'Disease', (197, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
169361	25999740	The immunohistochemical study revealed intense expression of CD99/MIC2 +, c-kit +, FLI-1 + and Ki67 + in 60% of the neoplastic cells (Figure 3).	('MIC2', 'Gene', (66, 70))	('FLI-1', 'Gene', (83, 88))	('CD99', 'Gene', (61, 65))	('MIC2', 'Gene', '4267', (66, 70))	('c-kit', 'Gene', '3815', (74, 79))	('c-kit', 'Gene', (74, 79))	('Ki67 +', 'Var', (95, 101))	('CD99', 'Gene', '4267', (61, 65))	('FLI-1', 'Gene', '2313', (83, 88))
169382	25999740	Among recurrent cytogenetic alterations, the t(11;22)(q24;q12) translocation has been detected in approximately 90% of all cases, leading to fusion between the EWSR1 on chromosome 22 and the FLI1 on chromosome 11, but t(21;22)(q22,q12)(EWSR1/ERG) and others may also occur.	('EWSR1', 'Gene', '2130', (236, 241))	('alterations', 'Var', (28, 39))	('leading to', 'Reg', (130, 140))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (45, 62))	('fusion', 'Var', (141, 147))	('ERG', 'Gene', '2078', (242, 245))	('FLI1', 'Gene', '2313', (191, 195))	('FLI1', 'Gene', (191, 195))	('ERG', 'Gene', (242, 245))	('t(21;22)(q22', 'Var', (218, 230))	('EWSR1', 'Gene', (160, 165))	('EWSR1', 'Gene', (236, 241))	('EWSR1', 'Gene', '2130', (160, 165))
169386	25999740	The chimeric protein resulting from fusion interferes with different molecular pathways crucial for cell growth, differentiation and proliferation, and which are frequently involved in the pathogenesis of soft tissue tumors.	('cell growth', 'CPA', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('soft tissue tumors', 'Disease', (205, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('soft tissue tumors', 'Disease', 'MESH:D012983', (205, 223))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (205, 223))	('interferes', 'NegReg', (43, 53))	('proliferation', 'CPA', (133, 146))	('differentiation', 'CPA', (113, 128))	('chimeric', 'Var', (4, 12))	('molecular pathways', 'Pathway', (69, 87))	('fusion', 'Var', (36, 42))
169390	25999740	Approximately, 10% of all Ewing's sarcomas carry the t(21;22)(q22;q12) (EWSR1-ERG) translocation.	('ERG', 'Gene', (78, 81))	('EWSR1', 'Gene', (72, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('t(21', 'Var', (53, 57))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 70))	("Ewing's sarcomas", 'Disease', (26, 42))	('EWSR1', 'Gene', '2130', (72, 77))	('ERG', 'Gene', '2078', (78, 81))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (26, 42))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (26, 42))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (26, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (34, 42))
169399	25999740	Thus, we present the first case reported in the literature in which two fusion transcripts in the same patient arise from splicing out of exons from the ERG gene.	('splicing out of exons', 'Var', (122, 143))	('arise from', 'Reg', (111, 121))	('ERG', 'Gene', '2078', (153, 156))	('patient', 'Species', '9606', (103, 110))	('ERG', 'Gene', (153, 156))
169414	25999740	In the clinical setting, target cancer therapies under investigation in Ewing's sarcoma include inhibitors of the IGF-1 receptor plus an inhibitor of mTOR, which has resulted in tumor regression in approximately 25%-30% of patients with refractory metastatic disease.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (72, 87))	('IGF-1', 'Gene', (114, 119))	('tumor', 'Disease', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	("Ewing's sarcoma", 'Disease', (72, 87))	('cancer', 'Disease', (32, 38))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (72, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('inhibitors', 'Var', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mTOR', 'Gene', '2475', (150, 154))	('patients', 'Species', '9606', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mTOR', 'Gene', (150, 154))
169563	20949568	Consistent MYC and FLT4 Gene Amplification in Radiation-Induced Angiosarcoma but not in other Radiation-Associated Atypical Vascular Lesions Angiosarcoma (AS) is a distinct group of sarcomas characterized by up-regulation of vascular-specific receptor tyrosine kinases, including TIE1, KDR, TEK, and FLT1.	('TEK', 'Gene', (291, 294))	('MYC', 'Gene', (11, 14))	('up-regulation', 'PosReg', (208, 221))	('Angiosarcoma', 'Disease', (141, 153))	('Amplification', 'Var', (29, 42))	('TEK', 'Gene', '7010', (291, 294))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (141, 153))	('KDR', 'Gene', '3791', (286, 289))	('AS', 'Phenotype', 'HP:0200058', (155, 157))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('TIE1', 'Gene', (280, 284))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('sarcomas', 'Disease', (182, 190))	('TIE1', 'Gene', '7075', (280, 284))	('MYC', 'Gene', '4609', (11, 14))	('FLT1', 'Gene', (300, 304))	('Angiosarcoma', 'Disease', 'MESH:D006394', (64, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('FLT1', 'Gene', '2321', (300, 304))	('FLT4', 'Gene', (19, 23))	('Angiosarcoma', 'Disease', (64, 76))	('FLT4', 'Gene', '2324', (19, 23))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (64, 76))	('KDR', 'Gene', (286, 289))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Angiosarcoma', 'Disease', 'MESH:D006394', (141, 153))
169564	20949568	Furthermore, a high percentage of secondary AS, but not primary AS, show distinct 8q24 chromosomal gains, due to MYC amplification.	('gains', 'Disease', 'MESH:D015430', (99, 104))	('8q24', 'Gene', (82, 86))	('AS', 'Phenotype', 'HP:0200058', (44, 46))	('AS', 'Phenotype', 'HP:0200058', (64, 66))	('MYC', 'Var', (113, 116))	('gains', 'Disease', (99, 104))
169567	20949568	Co-amplification of FLT4 (encoding VEGFR3) was identified in 25% of secondary AS, but not in other types.	('VEGFR3', 'Gene', '2324', (35, 41))	('FLT4', 'Gene', (20, 24))	('VEGFR3', 'Gene', (35, 41))	('AS', 'Phenotype', 'HP:0200058', (78, 80))	('FLT4', 'Gene', '2324', (20, 24))	('secondary AS', 'Disease', (68, 80))	('Co-amplification', 'Var', (0, 16))
169568	20949568	Secondary genetic hits, such as FLT4 gene co-amplification or KDR mutations, may play a role in tumor progression, as well as potential therapeutic targeting.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('play', 'Reg', (81, 85))	('KDR', 'Gene', '3791', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('co-amplification', 'Var', (42, 58))	('FLT4', 'Gene', '2324', (32, 36))	('FLT4', 'Gene', (32, 36))	('KDR', 'Gene', (62, 65))
169571	20949568	By array-comparative genomic hybridization, recurrent genetic abnormalities were identified recently in secondary but not primary AS, with frequent high-level amplifications in chromosome bands 8q24.21 (50%), 10p12.33 (33%) and 5q35.3 (11%).	('AS', 'Phenotype', 'HP:0200058', (130, 132))	('genetic abnormalities', 'Disease', 'MESH:D030342', (54, 75))	('10p12.33', 'Var', (209, 217))	('genetic abnormalities', 'Disease', (54, 75))
169572	20949568	The hot spot in 8q24.21 was defined as being secondary to high-level MYC amplifications, found in more than half of AS associated with radiation and chronic lymphedema, but not in primary tumors.	('lymphedema', 'Disease', 'MESH:D008209', (157, 167))	('radiation', 'Disease', (135, 144))	('MYC', 'Gene', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('AS', 'Phenotype', 'HP:0200058', (116, 118))	('lymphedema', 'Phenotype', 'HP:0001004', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('primary tumors', 'Disease', (180, 194))	('amplifications', 'Var', (73, 87))	('lymphedema', 'Disease', (157, 167))	('primary tumors', 'Disease', 'MESH:D009369', (180, 194))	('associated', 'Reg', (119, 129))
169573	20949568	Amplification of MYC in these tumors did not predispose to higher-grade morphology or increased proliferation.	('higher-grade morphology', 'CPA', (59, 82))	('tumors', 'Disease', (30, 36))	('MYC', 'Gene', (17, 20))	('Amplification', 'Var', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('proliferation', 'CPA', (96, 109))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
169588	20949568	FISH on interphase nuclei from paraffin embedded 4-micron sections was performed applying custom probes using bacterial artificial chromosomes (BACs), covering MYC (RP11-440N18), TPD52 (RP11-668P13; RP11-880M10), and FLT4 (RP11-586L9).	('paraffin', 'Chemical', 'MESH:D010232', (31, 39))	('FLT4', 'Gene', (217, 221))	('FLT4', 'Gene', '2324', (217, 221))	('TPD52', 'Gene', '7163', (179, 184))	('RP11-586L9', 'Var', (223, 233))	('RP11-668P13; RP11-880M10', 'Var', (186, 210))	('TPD52', 'Gene', (179, 184))	('RP11-440N18', 'Var', (165, 176))
169626	20949568	FLT4 copy number alterations were always found to be co-amplified with MYC (Fig.	('FLT4', 'Gene', (0, 4))	('FLT4', 'Gene', '2324', (0, 4))	('MYC', 'Disease', (71, 74))	('copy number alterations', 'Var', (5, 28))
169631	20949568	However no FLT4 mutations were detected.	('FLT4', 'Gene', '2324', (11, 15))	('FLT4', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))
169635	20949568	The time period from radiation exposure to AS development ranged from 5.6-11 years (median 8.2) in the FLT4 and MYC co-amplified group, with no difference in morphologic appearance, as compared to MYC amplified alone tumors.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('co-amplified', 'Var', (116, 128))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('AS', 'Phenotype', 'HP:0200058', (43, 45))	('FLT4', 'Gene', '2324', (103, 107))	('FLT4', 'Gene', (103, 107))
169640	20949568	Full-sequencing of these five candidate genes identified 10% of patients harboring KDR mutations.	('KDR', 'Gene', '3791', (83, 86))	('mutations', 'Var', (87, 96))	('patients', 'Species', '9606', (64, 72))	('KDR', 'Gene', (83, 86))
169642	20949568	Transient transfection of KDR mutants into COS-7 cells demonstrated ligand-independent activation of the kinase, which was inhibited by sunitinib and sorafenib.	('activation', 'PosReg', (87, 97))	('KDR', 'Gene', '3791', (26, 29))	('mutants', 'Var', (30, 37))	('COS-7', 'CellLine', 'CVCL:0224', (43, 48))	('sorafenib', 'Chemical', 'MESH:D000077157', (150, 159))	('KDR', 'Gene', (26, 29))	('sunitinib', 'Chemical', 'MESH:D000077210', (136, 145))
169646	20949568	Thus MYC overexpression secondary to high level gene amplifications was identified preferentially in radiation-induced and lymphedema-associated AS, but not in other clinical settings.	('lymphedema', 'Phenotype', 'HP:0001004', (123, 133))	('overexpression', 'PosReg', (9, 23))	('lymphedema', 'Disease', (123, 133))	('gene amplifications', 'Var', (48, 67))	('radiation-induced', 'Disease', (101, 118))	('lymphedema', 'Disease', 'MESH:D008209', (123, 133))	('AS', 'Phenotype', 'HP:0200058', (145, 147))
169647	20949568	In contrast with the previous study where MYC amplification was found in only 55% of secondary AS, our results show that high level MYC amplification was identified in 100% of tumors that developed in the setting of radiation therapy after breast cancer, while it was absent in all primary AS, of any anatomic location.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('breast cancer', 'Disease', (240, 253))	('AS', 'Phenotype', 'HP:0200058', (95, 97))	('AS', 'Phenotype', 'HP:0200058', (290, 292))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('tumors', 'Disease', (176, 182))	('MYC', 'Gene', (132, 135))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('amplification', 'Var', (136, 149))
169648	20949568	The high predilection for MYC amplification present only in secondary AS tumors, particularly after radiation therapy for breast cancer, questions if this represents a true driver oncogenic event or a site-specific epi-phenomenon.	('secondary AS tumors', 'Disease', (60, 79))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('AS', 'Phenotype', 'HP:0200058', (70, 72))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('secondary AS tumors', 'Disease', 'MESH:D060085', (60, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('MYC', 'Var', (26, 29))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
169653	20949568	The two common mechanisms of MYC oncogenic activation include either gene amplification or gene rearrangement, as seen in a subset of breast carcinomas and most of Burkitt lymphomas, respectively .	('gene rearrangement', 'Var', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('breast carcinomas', 'Disease', 'MESH:D001943', (134, 151))	('breast carcinomas', 'Disease', (134, 151))	('Burkitt lymphomas', 'Disease', 'MESH:D002051', (164, 181))	('lymphomas', 'Phenotype', 'HP:0002665', (172, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('gene amplification', 'Var', (69, 87))	('breast carcinomas', 'Phenotype', 'HP:0003002', (134, 151))	('Burkitt lymphomas', 'Phenotype', 'HP:0030080', (164, 181))	('breast carcinoma', 'Phenotype', 'HP:0003002', (134, 150))	('lymphoma', 'Phenotype', 'HP:0002665', (172, 180))	('Burkitt lymphomas', 'Disease', (164, 181))
169660	20949568	Interestingly, the gene amplification of FLT4 was found in 25% of secondary AS and only in association with MYC amplification.	('AS', 'Phenotype', 'HP:0200058', (76, 78))	('secondary AS', 'Disease', (66, 78))	('FLT4', 'Gene', (41, 45))	('found', 'Reg', (50, 55))	('gene amplification', 'Var', (19, 37))	('FLT4', 'Gene', '2324', (41, 45))
169662	20949568	Notably, of the six patients with both MYC and FLT4 amplification, three patients were treated with sorafenib and showed either a Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 complete response in one patient or a partial response in the remaining two.	('FLT4', 'Gene', '2324', (47, 51))	('FLT4', 'Gene', (47, 51))	('amplification', 'Var', (52, 65))	('sorafenib', 'Chemical', 'MESH:D000077157', (100, 109))	('patients', 'Species', '9606', (73, 81))	('Tumors', 'Phenotype', 'HP:0002664', (168, 174))	('patient', 'Species', '9606', (20, 27))	('patient', 'Species', '9606', (73, 80))	('patients', 'Species', '9606', (20, 28))	('patient', 'Species', '9606', (221, 228))	('MYC', 'Gene', (39, 42))	('Solid Tumors', 'Disease', 'MESH:D009369', (162, 174))	('Solid Tumors', 'Disease', (162, 174))
169666	20949568	In contrast, 13% of tumors showing MYC gene amplification without a FLT4 abnormality revealed KDR mutations, as previously reported.	('FLT4', 'Gene', (68, 72))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('MYC gene', 'Gene', (35, 43))	('KDR', 'Gene', (94, 97))	('FLT4', 'Gene', '2324', (68, 72))	('revealed', 'Reg', (85, 93))	('mutations', 'Var', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('KDR', 'Gene', '3791', (94, 97))
169668	20949568	In an immunohistochemical study of 49 AS, more than half of the tumors were positive for all three markers: D2-40 (53%), VEGFR3 (57%) and Prox-1 (76%).	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Prox-1', 'Gene', '5629', (138, 144))	('D2-40', 'Var', (108, 113))	('VEGFR3', 'Gene', (121, 127))	('Prox-1', 'Gene', (138, 144))	('positive', 'Reg', (76, 84))	('AS', 'Phenotype', 'HP:0200058', (38, 40))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('VEGFR3', 'Gene', '2324', (121, 127))
169673	20949568	D2-40 is a sensitive marker for benign lymphangioma and Kaposi sarcoma, while it is typically not expressed in hemangioma.	('hemangioma', 'Disease', (111, 121))	('hemangioma', 'Disease', 'MESH:D006391', (111, 121))	('lymphangioma', 'Phenotype', 'HP:0100764', (39, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('benign lymphangioma', 'Disease', 'MESH:D008202', (32, 51))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (56, 70))	('hemangioma', 'Phenotype', 'HP:0001028', (111, 121))	('Kaposi sarcoma', 'Disease', (56, 70))	('benign lymphangioma', 'Disease', (32, 51))	('D2-40', 'Var', (0, 5))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (56, 70))
169748	30993699	In another study of 47 patients with sarcomas, a higher local recurrence rate was observed in patients with positive surgical margins, when compared to that in patients with close or negative surgical margins.	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (23, 31))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('positive', 'Var', (108, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('local recurrence', 'CPA', (56, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcomas', 'Disease', (37, 45))
169783	28121937	Other inclusion criteria were having more than 1 measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1); Eastern Cooperative Oncology Group performance score <=2; treated with one or more prior systemic chemotherapies; white cell count >4000/mm3; platelet count >100,000/mm3; and creatinine clearance >50 mL/min.	('creatinine', 'Chemical', 'MESH:D003404', (319, 329))	('Tumors', 'Phenotype', 'HP:0002664', (122, 128))	('creatinine clearance', 'MPA', (319, 339))	('Solid Tumors', 'Disease', 'MESH:D009369', (116, 128))	('Solid Tumors', 'Disease', (116, 128))	('Oncology', 'Phenotype', 'HP:0002664', (164, 172))	('>4000/mm3', 'Var', (275, 284))
169819	28121937	In a phase III trial, pazopanib significantly improved PFS compared with placebo (4.6 months vs 1.6 months; P < 0.001); however, OS was not different (12.5 months vs 10.7 months; P = 0.25).	('improved', 'PosReg', (46, 54))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))	('pazopanib', 'Var', (22, 31))	('PFS', 'MPA', (55, 58))
169847	25535732	Patients with <10% VT had a DSS of 94% at 5 years, compared with 61% for patients with >=10% VT (P=0.033); EFS was 75%, compared with 48% (P=0.030).	('VT', 'Disease', 'MESH:D017180', (93, 95))	('DSS', 'Chemical', '-', (28, 31))	('VT', 'Disease', 'MESH:D017180', (19, 21))	('Patients', 'Species', '9606', (0, 8))	('DSS', 'MPA', (28, 31))	('patients', 'Species', '9606', (73, 81))	('<10%', 'Var', (14, 18))
169892	25535732	Patients with <10% VT had a DSS of 94% at 5 years, compared to 61% for patients with >=10% VT (P=0.033), while EFS amounted to 75% compared to 48% (P=0.030).	('patients', 'Species', '9606', (71, 79))	('VT', 'Disease', 'MESH:D017180', (91, 93))	('DSS', 'Chemical', '-', (28, 31))	('VT', 'Disease', 'MESH:D017180', (19, 21))	('Patients', 'Species', '9606', (0, 8))	('DSS', 'MPA', (28, 31))	('<10%', 'Var', (14, 18))
170012	31972596	Although 1 of 30 osteosarcomas showed focal NKX3-1 positivity, all the remaining 155 cases tested, including 20 Ewing sarcomas, 20 myoepithelial tumors, 11 ossifying fibromyxoid tumors, and 1 FUS-NFATC2 sarcoma were negative for NKX3-1.	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('sarcoma', 'Disease', (118, 125))	('NFATC2', 'Gene', '4773', (196, 202))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (112, 125))	('FUS', 'Gene', (192, 195))	('sarcoma', 'Disease', (22, 29))	('NKX3-1', 'Gene', '4824', (44, 50))	('osteosarcomas', 'Disease', 'MESH:D012516', (17, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('FUS', 'Gene', '2521', (192, 195))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (112, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('sarcoma', 'Disease', 'MESH:D012509', (203, 210))	('myoepithelial tumors', 'Disease', (131, 151))	('sarcoma', 'Disease', (203, 210))	('osteosarcomas', 'Disease', (17, 30))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('NKX3-1', 'Gene', (229, 235))	('positivity', 'Var', (51, 61))	('Ewing sarcomas', 'Disease', (112, 126))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (112, 126))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))	('NFATC2', 'Gene', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('osteosarcomas', 'Phenotype', 'HP:0002669', (17, 30))	('NKX3-1', 'Gene', (44, 50))	('ossifying fibromyxoid tumors', 'Disease', 'MESH:D018214', (156, 184))	('NKX3-1', 'Gene', '4824', (229, 235))	('ossifying fibromyxoid tumors', 'Disease', (156, 184))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (131, 151))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
170021	31972596	The best-established subsets are sarcoma with CIC rearrangements and sarcoma with BCOR gene abnormalities, each of which is associated with distinct clinicopathological and molecular features.	('CIC rearrangements', 'Var', (46, 64))	('sarcoma', 'Disease', (69, 76))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('BCOR', 'Gene', (82, 86))	('sarcoma', 'Disease', (33, 40))	('men', 'Species', '9606', (59, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('BCOR', 'Gene', '54880', (82, 86))
170022	31972596	Less well studied is a group characterized by the gene fusion between EWSR1 and non-ETS genes, with the reported partners including NFATC2, PATZ1, SP3, and SMARCA5.	('SP3', 'Gene', (147, 150))	('PATZ1', 'Gene', (140, 145))	('EWSR1', 'Gene', (70, 75))	('NFATC2', 'Gene', (132, 138))	('PATZ1', 'Gene', '23598', (140, 145))	('EWSR1', 'Gene', '2130', (70, 75))	('SP3', 'Gene', '6670', (147, 150))	('died', 'Disease', (13, 17))	('SMARCA5', 'Gene', '8467', (156, 163))	('NFATC2', 'Gene', '4773', (132, 138))	('died', 'Disease', 'MESH:D003643', (13, 17))	('gene fusion', 'Var', (50, 61))	('SMARCA5', 'Gene', (156, 163))
170152	32588548	Furthermore, misdiagnosis and subsequent inappropriate treatment resulted in inferior outcomes in osteosarcoma14.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('inferior', 'NegReg', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('osteosarcoma14', 'Disease', (98, 112))	('misdiagnosis', 'Var', (13, 25))	('osteosarcoma14', 'Disease', 'None', (98, 112))
170254	27586237	Conclusions The net effects of changes in cancer treatments, and surveillance and management for late effects, over the period 1940 to 2006 was to reduce the excess number of deaths from both recurrence or progression and non-neoplastic causes among those treated more recently.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('death', 'Disease', 'MESH:D003643', (175, 180))	('death', 'Disease', (175, 180))	('reduce', 'NegReg', (147, 153))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('changes', 'Var', (31, 38))
170379	22190407	While no objective responses were observed, pazopanib induced statistically significant differences in event-free survival compared to controls in approximately one-half of the sarcoma xenograft models tested.	('differences', 'Reg', (88, 99))	('pazopanib', 'Chemical', 'MESH:C516667', (44, 53))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('sarcoma', 'Disease', (177, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('pazopanib', 'Var', (44, 53))	('event-free survival', 'CPA', (103, 122))
170384	22190407	Consequently, the blockage of VEGF, PDGFR, and KIT may prevent tumor growth and inhibit angiogenesis thereby slowing or stopping the growth and spread of malignancies.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('blockage', 'Var', (18, 26))	('inhibit', 'NegReg', (80, 87))	('malignancies', 'Disease', 'MESH:D009369', (154, 166))	('PDGFR', 'Gene', (36, 41))	('stopping', 'NegReg', (120, 128))	('angiogenesis', 'CPA', (88, 100))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('VEGF', 'Gene', (30, 34))	('malignancies', 'Disease', (154, 166))	('KIT', 'Gene', (47, 50))	('prevent', 'NegReg', (55, 62))	('slowing', 'NegReg', (109, 116))	('PDGFR', 'Gene', '5159', (36, 41))
170385	22190407	Previous in vivo studies in mice demonstrated that pazopanib inhibits VEGF-induced VEGR2 phosphorylation, tumor angiogenesis, and the growth of human tumor xenografts.	('phosphorylation', 'MPA', (89, 104))	('growth', 'CPA', (134, 140))	('VEGR2', 'Protein', (83, 88))	('human', 'Species', '9606', (144, 149))	('mice', 'Species', '10090', (28, 32))	('pazopanib', 'Chemical', 'MESH:C516667', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('VEGF-induced', 'Gene', (70, 82))	('pazopanib', 'Var', (51, 60))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (106, 111))	('inhibits', 'NegReg', (61, 69))
170393	22190407	The phase 3 trial for adults with previously treated metastatic soft tissue sarcoma observed that pazopanib significantly prolonged progression-free survival compared with placebo (4.6 vs. 1.5 months, respectively; hazard ratio [HR]: 0.31; p < 0.0001), with an interim analysis of overall survival showing a statistically non-significant improvement for pazopanib versus placebo (median: 11.9 versus 10.4 months, respectively).	('pazopanib', 'Chemical', 'MESH:C516667', (98, 107))	('prolonged', 'PosReg', (122, 131))	('pazopanib', 'Var', (98, 107))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (64, 83))	('progression-free survival', 'CPA', (132, 157))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (64, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('soft tissue sarcoma', 'Disease', (64, 83))	('pazopanib', 'Chemical', 'MESH:C516667', (354, 363))
170414	22190407	The activity observed for pazopanib by the PPTP is less than that described previously by Kumar et al against a variety of adult cancer xenografts using a dose of 100 mg/kg administered either daily or twice-daily.	('pazopanib', 'Chemical', 'MESH:C516667', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('adult cancer', 'Disease', 'MESH:C535836', (123, 135))	('activity', 'MPA', (4, 12))	('less', 'NegReg', (51, 55))	('PPTP', 'Chemical', 'MESH:C041869', (43, 47))	('adult cancer', 'Disease', (123, 135))	('PPTP', 'Var', (43, 47))
170463	24926183	Since then, various other factors have been implicated: immunological factors, cocarcinogens, and miscellaneous factors such as irritation, poor lymphatic regeneration, antibodies, DNA mutations and local toxins.	('irritation', 'Disease', 'MESH:D001523', (128, 138))	('poor lymphatic regeneration', 'CPA', (140, 167))	('DNA', 'Disease', (181, 184))	('mutations', 'Var', (185, 194))	('irritation', 'Disease', (128, 138))
170467	24926183	Hayashi et al and Harland et al independently reported on the abnormalities in the p53 gene in patients with burn scar carcinoma.	('abnormalities', 'Var', (62, 75))	('p53', 'Gene', '7157', (83, 86))	('p53', 'Gene', (83, 86))	('scar', 'Phenotype', 'HP:0100699', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('burn scar carcinoma', 'Disease', (109, 128))
170505	33499165	Genetic silencing of ASNS combined with depletion of systemic asparagine via asparaginase decreased sarcoma growth in vivo.	('asparagine', 'Chemical', 'MESH:D001216', (62, 72))	('asparaginase decreased', 'Phenotype', 'HP:0500157', (77, 99))	('decreased sarcoma growth', 'Disease', 'MESH:D006130', (90, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('depletion of systemic asparagine', 'Phenotype', 'HP:0500157', (40, 72))	('Genetic silencing', 'Var', (0, 17))	('depletion', 'MPA', (40, 49))	('ASNS', 'Gene', (21, 25))	('decreased sarcoma growth', 'Disease', (90, 114))
170511	33499165	Intracellular asparagine was depleted in KRAS-driven mouse sarcoma cells by abrogating asparagine synthesis via short hairpin RNA (shRNA)-mediated ASNS knockdown and culture in asparagine-free medium (A-N0).	('knockdown', 'Var', (152, 161))	('asparagine synthesis', 'MPA', (87, 107))	('sarcoma', 'Disease', (59, 66))	('KRAS', 'Gene', '16653', (41, 45))	('asparagine', 'Chemical', 'MESH:D001216', (14, 24))	('asparagine', 'Chemical', 'MESH:D001216', (87, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('asparagine', 'Chemical', 'MESH:D001216', (177, 187))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('mouse', 'Species', '10090', (53, 58))	('abrogating', 'NegReg', (76, 86))	('KRAS', 'Gene', (41, 45))
170530	33499165	The effects of asparagine deprivation by shASNS knockdown in asparagine-free conditions were investigated in medium containing different glutamine and glucose concentrations (Figure S2).	('glucose', 'Chemical', 'MESH:D005947', (151, 158))	('asparagine', 'Chemical', 'MESH:D001216', (15, 25))	('glutamine', 'Chemical', 'MESH:D005973', (137, 146))	('shASNS', 'Gene', (41, 47))	('asparagine', 'Chemical', 'MESH:D001216', (61, 71))	('knockdown', 'Var', (48, 57))
170531	33499165	Asparagine depletion reduced the proliferation of shASNS mouse sarcoma cells (A) cultured in medium containing low glucose (0.5 g/L)/physiological glutamine (73.1 mg/L) (Figure S2a, 4, p < 0.0001), high glucose (4.5 g/L)/physiological glutamine (73.1 mg/L) (Figure S2a, 3, p < 0.0001) and high glucose (4.5 g/L)/high glutamine (584.6 mg/L) (Figure S2a, 2, p < 0.0001) levels.	('reduced', 'NegReg', (21, 28))	('glutamine', 'Chemical', 'MESH:D005973', (317, 326))	('glutamine', 'Chemical', 'MESH:D005973', (147, 156))	('glucose', 'Chemical', 'MESH:D005947', (203, 210))	('high glutamine', 'Phenotype', 'HP:0003217', (312, 326))	('high glucose', 'Phenotype', 'HP:0003074', (289, 301))	('sarcoma', 'Disease', (63, 70))	('glutamine', 'Chemical', 'MESH:D005973', (235, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('glucose', 'Chemical', 'MESH:D005947', (115, 122))	('Asparagine', 'Chemical', 'MESH:D001216', (0, 10))	('proliferation', 'CPA', (33, 46))	('glucose', 'Chemical', 'MESH:D005947', (294, 301))	('high glucose', 'Phenotype', 'HP:0003074', (198, 210))	('depletion', 'Var', (11, 20))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('mouse', 'Species', '10090', (57, 62))
170566	33499165	Indeed, pyruvate supplementation resulted in a rise in NAD+/NADH ratios in A-N0 cells (p < 0.001) (Figure 4a), whereas exogenous pyruvate did not change the NAD+/NADH ratio in shASNS cells supplemented with excess amounts of asparagine (A-N100, ns), in control shLuc (C-N5, ns) or in wild-type cells (W-N5, ns) (Figure 4a).	('pyruvate', 'Var', (8, 16))	('pyruvate', 'Chemical', 'MESH:D019289', (129, 137))	('NADH', 'Chemical', '-', (162, 166))	('NAD+', 'Chemical', 'MESH:D009243', (157, 161))	('NAD+/NADH ratios', 'MPA', (55, 71))	('NADH', 'Chemical', '-', (60, 64))	('pyruvate', 'Chemical', 'MESH:D019289', (8, 16))	('asparagine', 'Chemical', 'MESH:D001216', (225, 235))	('NAD+', 'Chemical', 'MESH:D009243', (55, 59))	('supplementation', 'Var', (17, 32))	('excess amounts of asparagine', 'Phenotype', 'HP:0500156', (207, 235))	('rise', 'PosReg', (47, 51))
170571	33499165	Exogenous pyruvate did not change the metabolomic profile of control shLuc/wild-type cells (C-N5 and W-N5 versus C-N5-P and W-N5-P; marked in shades of blue) and shASNS cells supplemented with excess asparagine (A-N100 versus A-N100-P; marked in shades of green) (Figure 4e, Table S4).	('asparagine', 'Chemical', 'MESH:D001216', (200, 210))	('pyruvate', 'Chemical', 'MESH:D019289', (10, 18))	('metabolomic', 'MPA', (38, 49))	('excess asparagine', 'Phenotype', 'HP:0500156', (193, 210))	('A-N100', 'Var', (212, 218))	('A-N100-P', 'Var', (226, 234))
170579	33499165	previously demonstrated that 0.1 and 0.5 U/mL asparaginase had similar effects on the asparagine and glutamine content in medium after 48 h. Also, asparaginase was previously shown to reduce the growth of mouse and human sarcoma cells (Figure 5h-i).	('glutamine', 'Chemical', 'MESH:D005973', (101, 110))	('reduce', 'NegReg', (184, 190))	('sarcoma', 'Disease', 'MESH:D012509', (221, 228))	('asparaginase', 'Var', (147, 159))	('sarcoma', 'Disease', (221, 228))	('mouse', 'Species', '10090', (205, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('growth', 'CPA', (195, 201))	('human', 'Species', '9606', (215, 220))	('asparagine', 'Chemical', 'MESH:D001216', (86, 96))
170581	33499165	Asparaginase-treated sarcoma cells supplemented with exogenous asparagine (W-A-N100, marked in green) clustered with asparaginase-treated cells cultured in asparagine-free medium (W-A-N0, marked in red), but there were marked differences between asparaginase-treated (W-A-N0, W-A-N100) and control sarcoma cells (W-0-N0, W-0-N100, marked in shades of blue) (Figure 5c, Table S5).	('asparagine', 'Chemical', 'MESH:D001216', (63, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('asparagine', 'Chemical', 'MESH:D001216', (156, 166))	('sarcoma', 'Disease', 'MESH:D012509', (298, 305))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('sarcoma', 'Disease', (298, 305))	('W-A-N0', 'Var', (268, 274))	('sarcoma', 'Phenotype', 'HP:0100242', (298, 305))	('sarcoma', 'Disease', (21, 28))
170583	33499165	These differences were accompanied by lower aspartate, glutamate and glutamine content in asparaginase-treated cells (W-A-N0, W-A-N100) compared to control cells (W-0-N0) (Figure 5g) and reminiscent of the changes observed in shASNS sarcoma cells cultured in asparagine-free medium (Figure 3 and Figure 4).	('glutamine', 'Chemical', 'MESH:D005973', (69, 78))	('lower', 'NegReg', (38, 43))	('glutamine content', 'MPA', (69, 86))	('shASNS sarcoma', 'Disease', 'MESH:D012509', (226, 240))	('asparagine', 'Chemical', 'MESH:D001216', (259, 269))	('aspartate', 'Chemical', 'MESH:D001224', (44, 53))	('shASNS sarcoma', 'Disease', (226, 240))	('glutamate', 'Chemical', 'MESH:D018698', (55, 64))	('aspartate', 'MPA', (44, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('asparaginase-treated', 'Var', (90, 110))
170588	33499165	Yet, when mouse sarcoma cells were treated concomitantly with 10 microM phenformin and 0.3 U/mL asparaginase, phenformin significantly augmented the anti-proliferative effects of asparaginase alone (Figure 6b, p < 0.0001).	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('mouse', 'Species', '10090', (10, 15))	('anti-proliferative effects', 'CPA', (149, 175))	('sarcoma', 'Disease', (16, 23))	('phenformin', 'Chemical', 'MESH:D010629', (72, 82))	('phenformin', 'Var', (110, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('phenformin', 'Chemical', 'MESH:D010629', (110, 120))	('augmented', 'PosReg', (135, 144))
170591	33499165	We conclude that chemical disruption of the ETC augments the anti-proliferative effects of asparaginase exposure, likely by deepening the relative excess of NADH/reducing equivalents caused by asparagine deprivation.	('deepening', 'PosReg', (124, 133))	('excess', 'MPA', (147, 153))	('anti-proliferative effects', 'MPA', (61, 87))	('augments', 'NegReg', (48, 56))	('asparagine', 'Chemical', 'MESH:D001216', (193, 203))	('chemical disruption', 'Var', (17, 36))	('NADH/reducing equivalents', 'MPA', (157, 182))	('NADH', 'Chemical', '-', (157, 161))
170599	33499165	As complex 1 inhibitors significantly augmented the adverse effects of asparagine depletion of mouse sarcoma cells (Figure 6), human RD cells were exposed to combinatorial treatment with asparaginase and phenformin (Figure 7d-f).	('augmented', 'PosReg', (38, 47))	('human', 'Species', '9606', (127, 132))	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('inhibitors', 'Var', (13, 23))	('sarcoma', 'Disease', (101, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('asparagine', 'Chemical', 'MESH:D001216', (71, 81))	('asparagine depletion', 'MPA', (71, 91))	('phenformin', 'Chemical', 'MESH:D010629', (204, 214))	('mouse', 'Species', '10090', (95, 100))
170602	33499165	Analogous to our observations in mouse sarcoma cells treated with asparaginase and complex 1 inhibitors (Figure 6), supplementation with the electron acceptor pyruvate reversed the anti-proliferative effects of asparaginase and phenformin alone and in combination on human RD cells (Figure 7f, p < 0.01).	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('pyruvate', 'Chemical', 'MESH:D019289', (159, 167))	('supplementation', 'Var', (116, 131))	('anti-proliferative effects', 'MPA', (181, 207))	('sarcoma', 'Disease', (39, 46))	('mouse', 'Species', '10090', (33, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('human', 'Species', '9606', (267, 272))	('phenformin', 'Chemical', 'MESH:D010629', (228, 238))
170608	33499165	In fact, combinatorial treatment with asparaginase and phenformin caused a higher reduction in NAD+/NADH ratios than that induced by asparaginase alone (Figure 7g, p < 0.0001).	('NAD+', 'Chemical', 'MESH:D009243', (95, 99))	('reduction', 'NegReg', (82, 91))	('phenformin', 'Chemical', 'MESH:D010629', (55, 65))	('NADH', 'Chemical', '-', (100, 104))	('phenformin', 'Var', (55, 65))	('NAD+/NADH ratios', 'MPA', (95, 111))
170614	33499165	Reductive stress caused by deficiency of electron acceptors may be just as harmful as oxidative stress, as electron acceptors NAD+, NADP+ and GSH are essential for maintaining cellular homeostasis.	('Reductive stress', 'MPA', (0, 16))	('GSH', 'Chemical', '-', (142, 145))	('essential', 'Chemical', '-', (150, 159))	('NAD+', 'Chemical', 'MESH:D009243', (126, 130))	('oxidative stress', 'Phenotype', 'HP:0025464', (86, 102))	('deficiency', 'Var', (27, 37))	('NADP+', 'Chemical', 'MESH:D009249', (132, 137))
170616	33499165	We discovered that asparagine depletion of sarcoma cells causes reductive stress and that exogenous supplementation with the electron acceptor pyruvate restored the changes in NAD+/NADH ratios, proliferation and viability induced by asparagine deprivation.	('viability', 'CPA', (212, 221))	('asparagine', 'Var', (19, 29))	('pyruvate', 'Chemical', 'MESH:D019289', (143, 151))	('depletion', 'Var', (30, 39))	('reductive stress', 'MPA', (64, 80))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('NAD+/NADH ratios', 'MPA', (176, 192))	('proliferation', 'CPA', (194, 207))	('asparagine', 'Chemical', 'MESH:D001216', (19, 29))	('NADH', 'Chemical', '-', (181, 185))	('NAD+', 'Chemical', 'MESH:D009243', (176, 180))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('asparagine', 'Chemical', 'MESH:D001216', (233, 243))
170620	33499165	This was surprising at first as we had initially expected higher aspartate levels due to reduced aspartate consumption after ASNS knockdown or increased release of aspartate by asparaginase.	('aspartate levels', 'MPA', (65, 81))	('increased', 'PosReg', (143, 152))	('aspartate consumption', 'MPA', (97, 118))	('release of aspartate', 'MPA', (153, 173))	('knockdown', 'Var', (130, 139))	('aspartate', 'Chemical', 'MESH:D001224', (164, 173))	('increased release of aspartate', 'Phenotype', 'HP:0500159', (143, 173))	('aspartate', 'Chemical', 'MESH:D001224', (65, 74))	('higher aspartate levels', 'Phenotype', 'HP:0500159', (58, 81))	('ASNS', 'Protein', (125, 129))	('higher', 'PosReg', (58, 64))	('reduced', 'NegReg', (89, 96))	('aspartate', 'Chemical', 'MESH:D001224', (97, 106))
170622	33499165	Thus, we conclude that asparagine deprivation, through metabolic reprogramming, causes reductive stress, which, in turn, results in lower aspartate levels in asparagine-starved cells.	('asparagine', 'Var', (23, 33))	('asparagine', 'Chemical', 'MESH:D001216', (23, 33))	('asparagine', 'Chemical', 'MESH:D001216', (158, 168))	('lower', 'NegReg', (132, 137))	('aspartate', 'Chemical', 'MESH:D001224', (138, 147))	('reductive stress', 'MPA', (87, 103))	('aspartate levels in asparagine-starved', 'MPA', (138, 176))
170626	33499165	Findings from our experiments confirm that asparagine deprivation stalls proliferation, induces autophagy and increases apoptosis in sarcoma cells grown in physiological and supraphysiological glucose and glutamine conditions.	('autophagy', 'CPA', (96, 105))	('induces', 'Reg', (88, 95))	('stalls', 'NegReg', (66, 72))	('apoptosis', 'CPA', (120, 129))	('glucose', 'Chemical', 'MESH:D005947', (193, 200))	('glutamine', 'Chemical', 'MESH:D005973', (205, 214))	('increases', 'PosReg', (110, 119))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('asparagine', 'Chemical', 'MESH:D001216', (43, 53))	('sarcoma', 'Disease', (133, 140))	('asparagine deprivation', 'Var', (43, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
170650	33499165	This led us to examine if complex 1 inhibitors deepened the reductive stress and growth arrest caused by asparagine depletion.	('inhibitors', 'Var', (36, 46))	('growth arrest', 'Disease', (81, 94))	('deepened', 'PosReg', (47, 55))	('growth arrest', 'Disease', 'MESH:D006323', (81, 94))	('reductive stress', 'MPA', (60, 76))	('asparagine', 'Chemical', 'MESH:D001216', (105, 115))	('growth arrest', 'Phenotype', 'HP:0001510', (81, 94))	('asparagine depletion', 'MPA', (105, 125))
170651	33499165	Our experiments revealed a clear synergistic effect of asparaginase and complex 1 inhibitors on the growth of mouse and human sarcomas, including patient-derived rhabdomyosarcoma cultures.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('human', 'Species', '9606', (120, 125))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (162, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcomas', 'Disease', (126, 134))	('mouse', 'Species', '10090', (110, 115))	('inhibitors', 'Var', (82, 92))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (162, 178))	('asparaginase', 'Protein', (55, 67))	('growth', 'MPA', (100, 106))	('patient', 'Species', '9606', (146, 153))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))	('rhabdomyosarcoma', 'Disease', (162, 178))
170661	33499165	TRC clones TRCN0000324779, TRCN0000031703 and TRCN0000031702, delivered in PLKO vectors, were employed to knock down ASNS in mouse sarcoma cells as previously described.	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('mouse', 'Species', '10090', (125, 130))	('sarcoma', 'Disease', (131, 138))	('TRCN0000031702', 'Var', (46, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))
170663	33499165	After 24 h, cells were exposed to asparaginase (MBS142428, Biozol), phenformin (14997, Cayman Chemical, Ann Arbor, MI, USA), metformin (13118, Cayman Chemical) and imiquimod (14956, Cayman Chemical) at defined concentrations.	('imiquimod', 'Chemical', 'MESH:D000077271', (164, 173))	('phenformin', 'Chemical', 'MESH:D010629', (68, 78))	('MBS142428', 'Chemical', '-', (48, 57))	('Biozol', 'Chemical', '-', (59, 65))	('MBS142428', 'Var', (48, 57))	('metformin', 'Chemical', 'MESH:D008687', (125, 134))	('13118', 'Var', (136, 141))
170667	33499165	Annexin V staining was performed according to the manufacturer's instructions using Annexin V-APC (550474, BD Biosciences, San Jose, CA, USA) and 7AAD (559925, BD Biosciences) with a BD FACS Canto II flow cytometer.	('Annexin V', 'Gene', '11747', (84, 93))	('Annexin V', 'Gene', (0, 9))	('APC', 'Gene', '11789', (94, 97))	('Annexin V', 'Gene', '11747', (0, 9))	('559925', 'Var', (152, 158))	('550474', 'Var', (99, 105))	('APC', 'Gene', (94, 97))	('Annexin V', 'Gene', (84, 93))	('CA', 'Gene', '12310', (133, 135))
170669	33499165	Specific antibodies and concentrations were used to detect expression of asparagine synthetase (1:250, Sigma Aldrich, HPA029385), LC3I/II (1:500, Cell Signalling Technology, #1241) and actin (1:10,000, Sigma Aldrich, A5441).	('1:250', 'Var', (96, 101))	('asparagine synthetase', 'Gene', (73, 94))	('asparagine synthetase', 'Gene', '27053', (73, 94))	('LC3I/II', 'Gene', (130, 137))
170673	33499165	Metabolite extraction and quenching were performed on plate with 1.5 mL ice cold extraction medium (90% methanol, 10% water) containing 1 microg/mL ribitol (A5502, Sigma Aldrich), phenyl beta-d-glucopyranoside (292710, Sigma Aldrich), isoguanosine (sc-207768, Santa Cruz, Dallas, TX, USA), d4-succinate (293075, Sigma Aldrich) and methyl-tyrosine (M8131, Sigma Aldrich) as the internal standard.	('methanol', 'Chemical', 'MESH:D000432', (104, 112))	('succinate', 'Chemical', 'MESH:D019802', (293, 302))	('293075', 'Var', (304, 310))	('292710', 'Var', (211, 217))	('phenyl beta-d-glucopyranoside', 'Chemical', 'MESH:C033857', (180, 209))	('ribitol', 'Chemical', 'MESH:D012255', (148, 155))	('A5502', 'Var', (157, 162))	('water', 'Chemical', 'MESH:D014867', (118, 123))
170705	25165708	Although several diagnostic explorations in the past three decades, such as identification of chromosomal translocation, have greatly improved the diagnosis of soft tissue sarcomas, the unsolved issues, including the limited useful biomarkers, remain.	('improved', 'PosReg', (134, 142))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (160, 180))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (160, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (172, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (160, 180))	('soft tissue sarcomas', 'Disease', (160, 180))	('chromosomal translocation', 'Var', (94, 119))
170726	25165708	Over the past several years, it has become evident that dysregulation of many types of miRNAs has been associated with the initiation and progression of human cancers.	('cancers', 'Disease', (159, 166))	('associated', 'Reg', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('human', 'Species', '9606', (153, 158))	('dysregulation', 'Var', (56, 69))	('miR', 'Gene', '220972', (87, 90))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('miR', 'Gene', (87, 90))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
170738	25165708	Furthermore, reexpression of miR-143 in DDLS cell lines inhibited cell proliferation and induced apoptosis through downregulation of BCL2, topoisomerase 2A, protein regulator of cytokinesis 1 (PRC1), and polo-like kinase 1 (PLK1).	('PLK1', 'Gene', '5347', (224, 228))	('PLK1', 'Gene', (224, 228))	('BCL2', 'Gene', (133, 137))	('polo-like kinase 1', 'Gene', (204, 222))	('miR-143', 'Var', (29, 36))	('induced', 'Reg', (89, 96))	('cell proliferation', 'CPA', (66, 84))	('polo-like kinase 1', 'Gene', '5347', (204, 222))	('topoisomerase 2A, protein regulator of cytokinesis 1', 'Gene', '9055', (139, 191))	('PRC1', 'Gene', (193, 197))	('PRC1', 'Gene', '9055', (193, 197))	('BCL2', 'Gene', '596', (133, 137))	('inhibited', 'NegReg', (56, 65))	('downregulation', 'NegReg', (115, 129))	('apoptosis', 'CPA', (97, 106))
170740	25165708	They determined that miR-155 was upregulated in DDLS, and silencing of miR-155 in DDLS cells inhibited cell growth and colony formation, induced G1-S cell-cycle arrest in vitro, and blocked tumor growth in vivo.	('upregulated', 'PosReg', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('arrest', 'Disease', (161, 167))	('miR-155', 'Gene', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('induced', 'Reg', (137, 144))	('tumor', 'Disease', (190, 195))	('blocked', 'NegReg', (182, 189))	('miR-155', 'Gene', '406947', (71, 78))	('inhibited', 'NegReg', (93, 102))	('miR-155', 'Gene', (71, 78))	('arrest', 'Disease', 'MESH:D006323', (161, 167))	('miR-155', 'Gene', '406947', (21, 28))	('silencing', 'Var', (58, 67))
170742	25165708	identified miR-218-1* and HS_303_a as being upregulated miRNAs and miR-144 and -1238 as being downregulated miRNAs relative to that in normal adipose tissues.	('miR-144', 'Gene', '406936', (67, 74))	('miR', 'Gene', (56, 59))	('HS_303_a', 'Var', (26, 34))	('upregulated', 'PosReg', (44, 55))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('miR', 'Gene', '220972', (108, 111))	('miR-144', 'Gene', (67, 74))	('miR', 'Gene', (108, 111))	('miR-218-1', 'Gene', '407000', (11, 20))	('downregulated', 'NegReg', (94, 107))	('miR', 'Gene', '220972', (56, 59))	('miR-218-1', 'Gene', (11, 20))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))
170755	25165708	Importantly, high miR-26a-2 expression significantly correlated with poor patient survival in both types of liposarcoma, regardless of histological subtypes.	('poor', 'NegReg', (69, 73))	('patient', 'Species', '9606', (74, 81))	('miR-26a-2', 'Gene', (18, 27))	('liposarcoma', 'Disease', 'MESH:D008080', (108, 119))	('high', 'Var', (13, 17))	('liposarcoma', 'Phenotype', 'HP:0012034', (108, 119))	('expression', 'MPA', (28, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('patient survival', 'CPA', (74, 90))	('liposarcoma', 'Disease', (108, 119))	('miR-26a-2', 'Gene', '407016', (18, 27))
170773	25165708	Silencing of BAF53a in RMS cells inhibited cell proliferation and anchorage-independent growth in vitro, inhibited ERMS and ARMS tumor growth, and induced myogenic differentiation in vivo, therefore, leading to the conclusion that failure to downregulate the BAF53a subunit may contribute to RMS pathogenesis.	('BAF53a', 'Gene', (13, 19))	('RMS', 'Phenotype', 'HP:0002859', (125, 128))	('Silencing', 'Var', (0, 9))	('downregulate', 'NegReg', (242, 254))	('ARMS tumor', 'Disease', (124, 134))	('ARMS tumor', 'Disease', 'MESH:D009369', (124, 134))	('RMS', 'Disease', (292, 295))	('RMS', 'Phenotype', 'HP:0002859', (116, 119))	('BAF53a', 'Gene', '86', (259, 265))	('anchorage-independent growth', 'CPA', (66, 94))	('BAF53a', 'Gene', '86', (13, 19))	('inhibited', 'NegReg', (33, 42))	('inhibited', 'NegReg', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('myogenic differentiation', 'CPA', (155, 179))	('RMS', 'Phenotype', 'HP:0002859', (292, 295))	('induced', 'Reg', (147, 154))	('BAF53a', 'Gene', (259, 265))	('cell proliferation', 'CPA', (43, 61))	('RMS', 'Phenotype', 'HP:0002859', (23, 26))
170788	25165708	Silencing of miR-183 in RMS cells revealed deregulation of a miRNA network composed of miR-183-EGR1-PTEN.	('deregulation', 'PosReg', (43, 55))	('miR-183', 'Gene', (87, 94))	('PTEN', 'Gene', (100, 104))	('PTEN', 'Gene', '5728', (100, 104))	('miR', 'Gene', '220972', (13, 16))	('EGR1', 'Gene', '1958', (95, 99))	('miR', 'Gene', (13, 16))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('RMS', 'Phenotype', 'HP:0002859', (24, 27))	('miR-183', 'Gene', (13, 20))	('miR-183', 'Gene', '406959', (13, 20))	('miR', 'Gene', '220972', (87, 90))	('EGR1', 'Gene', (95, 99))	('miR', 'Gene', (87, 90))	('Silencing', 'Var', (0, 9))	('miR-183', 'Gene', '406959', (87, 94))
170835	25165708	They also performed miRNA profiling of these tumor sets and found a relative downregulation of miR-34a expression in most MPNSTs, concluding that p53 inactivation and the subsequent loss of miR-34a expression may significantly contribute to MPNST development.	('loss', 'NegReg', (182, 186))	('inactivation', 'Var', (150, 162))	('miR-34a', 'Gene', '407040', (190, 197))	('p53', 'Gene', (146, 149))	('tumor', 'Disease', (45, 50))	('miR', 'Gene', '220972', (20, 23))	('contribute', 'Reg', (227, 237))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('downregulation', 'NegReg', (77, 91))	('expression', 'MPA', (103, 113))	('miR', 'Gene', (20, 23))	('expression', 'MPA', (198, 208))	('miR', 'Gene', '220972', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MPNST development', 'CPA', (241, 258))	('miR-34a', 'Gene', (95, 102))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (95, 98))	('p53', 'Gene', '7157', (146, 149))	('MPNST', 'Phenotype', 'HP:0100697', (122, 127))	('miR-34a', 'Gene', '407040', (95, 102))	('miR-34a', 'Gene', (190, 197))	('MPNST', 'Phenotype', 'HP:0100697', (241, 246))	('miR', 'Gene', (190, 193))
170838	25165708	Functional analysis using an MPNST cell line indicated that silencing of miR-21 could induce apoptosis of MPNST cells.	('miR-21', 'Gene', '406991', (73, 79))	('MPNST', 'Phenotype', 'HP:0100697', (29, 34))	('MPNST', 'Phenotype', 'HP:0100697', (106, 111))	('induce', 'PosReg', (86, 92))	('miR-21', 'Gene', (73, 79))	('silencing', 'Var', (60, 69))	('apoptosis', 'CPA', (93, 102))
170840	25165708	The former included miR-29c, -30c, -139-5p, 195, -151-5p, 342-5p, 146a, -150, and -223, and the latter included miR-210 and -339-5p.	('miR-29c', 'Gene', '407026', (20, 27))	('342-5p', 'Var', (58, 64))	('miR-210 and -339-5p', 'Gene', '406992', (112, 131))	('miR-29c', 'Gene', (20, 27))
170880	25165708	RT-PCR using tumor samples identified the overexpression of miR-206, -381, -671-5p, and -765 in epithelioid sarcomas.	('tumor', 'Disease', (13, 18))	('miR-206', 'Gene', '406989', (60, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('and -765', 'Var', (84, 92))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (96, 116))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('overexpression', 'PosReg', (42, 56))	('epithelioid sarcomas', 'Disease', (96, 116))	('miR-206', 'Gene', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
170940	25165708	In these past three decades, genetic exploration has greatly improved the diagnosis for soft tissue sarcomas, including the identification of fusion genes in soft tissue sarcomas such as synovial sarcoma, MLS, or clear cell sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (187, 203))	('soft tissue sarcomas', 'Disease', (88, 108))	('soft tissue sarcomas', 'Disease', (158, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (88, 108))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (158, 178))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (88, 107))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (158, 177))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (88, 108))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (158, 178))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (213, 231))	('MLS', 'Phenotype', 'HP:0012268', (205, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('MLS', 'Disease', 'MESH:C537466', (205, 208))	('synovial sarcoma', 'Disease', (187, 203))	('MLS', 'Disease', (205, 208))	('synovial sarcoma', 'Disease', 'MESH:D013584', (187, 203))	('fusion genes', 'Var', (142, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('clear cell sarcoma', 'Disease', (213, 231))
170981	24472378	Exposure to hardwood dust, leather dust, flour milling, polycyclic aromatic hydrocarbons (PAH), and asbestos are known to be associated with adenocarcinoma.	('polycyclic aromatic', 'Var', (56, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('PAH', 'Chemical', 'MESH:D011084', (90, 93))	('associated', 'Reg', (125, 135))	('adenocarcinoma', 'Disease', (141, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (141, 155))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (56, 88))
171038	24472378	The maximum level of each hazardous compound detected was as follows: during the painting process at Workplace 1: 0.0013 mg/m3 hexavalent chromium, 0.0047 mg/m3 nickel (insoluble inorganic compounds), and 0.3244 ppm formaldehyde; during the painting process at Workplace 2: 0.0006 mg/m3 lead chromate, 0.0001 mg/m3 nickel (insoluble inorganic compounds), and 0.1069 ppm formaldehyde.	('nickel', 'Chemical', 'MESH:D009532', (161, 167))	('tin', 'Chemical', 'MESH:D014001', (245, 248))	('0.0047', 'Var', (148, 154))	('formaldehyde', 'Chemical', 'MESH:D005557', (370, 382))	('0.0006 mg/m3', 'Var', (274, 286))	('chromate', 'Chemical', 'MESH:D002840', (292, 300))	('formaldehyde', 'Chemical', 'MESH:D005557', (216, 228))	('tin', 'Chemical', 'MESH:D014001', (85, 88))	('hexavalent', 'MPA', (127, 137))	('0.0001 mg/m3', 'Var', (302, 314))	('0.1069 ppm', 'Var', (359, 369))	('0.3244 ppm', 'Var', (205, 215))	('chromium', 'Chemical', 'MESH:D002857', (138, 146))	('formaldehyde', 'MPA', (370, 382))	('nickel', 'Chemical', 'MESH:D009532', (315, 321))
171068	24472378	A low level of chromium is an essential mineral for the human body, but it has been reported that high-dose exposure to hexavalent chromium can lead to respiratory or paranasal sinus cancers.	('chromium', 'Chemical', 'MESH:D002857', (131, 139))	('chromium', 'Chemical', 'MESH:D002857', (15, 23))	('paranasal sinus cancer', 'Phenotype', 'HP:0030072', (167, 189))	('human', 'Species', '9606', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lead to', 'Reg', (144, 151))	('respiratory or paranasal sinus cancers', 'Disease', (152, 190))	('respiratory or paranasal sinus cancers', 'Disease', 'MESH:D010255', (152, 190))	('hexavalent chromium', 'Var', (120, 139))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
171071	24472378	One study reported that microsatellite instability due to DNA mismatch repair system alterations was higher in the chromium-exposed group than in the non-exposed group.	('chromium', 'Chemical', 'MESH:D002857', (115, 123))	('higher', 'PosReg', (101, 107))	('DNA mismatch repair system', 'Gene', (58, 84))	('alterations', 'Var', (85, 96))	('microsatellite instability', 'MPA', (24, 50))
171078	24472378	In mammalian nasal cavity tissue, formaldehyde exposure has been observed to cause an increase in DNA adducts, DNA-protein cross-links, DNA-DNA cross-links, and DNA single-strand breaks.	('increase', 'PosReg', (86, 94))	('DNA adducts', 'MPA', (98, 109))	('cross-links', 'MPA', (123, 134))	('formaldehyde', 'Chemical', 'MESH:D005557', (34, 46))	('single-strand breaks', 'Var', (165, 185))	('cross-links', 'Interaction', (144, 155))	('mammalian', 'Species', '9606', (3, 12))
171281	33050651	Also, the presence of thrombus in the renal vein and, or the IVC was associated with worse EFS (p = 0.053), but the association with OS did not reach statistical significance (p = 0.15) (Figure 3).	('presence', 'Var', (10, 18))	('thrombus in the renal vein', 'Disease', (22, 48))	('thrombus in the renal vein', 'Disease', 'MESH:D013927', (22, 48))	('EFS', 'MPA', (91, 94))
171290	33050651	The 2020 WHO classification of soft tissue and bone tumours defines Ewing sarcoma as a small round cell sarcoma showing gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors.	('gene fusions', 'Var', (120, 132))	('bone tumours defines Ewing sarcoma', 'Disease', 'MESH:C563168', (47, 81))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('EWS', 'Phenotype', 'HP:0012254', (190, 193))	('EWSR1', 'Gene', (190, 195))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('EWSR1', 'Gene', '2130', (190, 195))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('bone tumours defines Ewing sarcoma', 'Disease', (47, 81))	('sarcoma', 'Disease', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
171348	29152290	Acute promyelocytic leukemia (APL) is defined by the World Health Organization (WHO) as a subtype of acute myeloid leukemia (AML) with recurrent cytogenetic abnormalities, typically demonstrating t(15;17)(q22q21) involving the fusion of the promyelocytic leukemia gene (PML) and the retinoic acid receptor-alpha gene (RARA).	('retinoic acid receptor-alpha', 'Gene', '5914', (283, 311))	('fusion', 'Var', (227, 233))	('RARA', 'Gene', '5914', (318, 322))	('acute myeloid leukemia', 'Disease', (101, 123))	('promyelocytic leukemia gene (PML)', 'Gene', '5371', (241, 274))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (6, 28))	('Acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (0, 28))	('RARA', 'Gene', (318, 322))	('promyelocytic leukemia gene (PML', 'Gene', (241, 273))	('Acute promyelocytic leukemia', 'Disease', (0, 28))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (101, 123))	('leukemia', 'Phenotype', 'HP:0001909', (20, 28))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (101, 123))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (107, 123))	('AML', 'Disease', 'MESH:D015470', (125, 128))	('leukemia', 'Phenotype', 'HP:0001909', (255, 263))	('AML', 'Disease', (125, 128))	('AML', 'Phenotype', 'HP:0004808', (125, 128))	('APL', 'Phenotype', 'HP:0004836', (30, 33))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (241, 263))	('Acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (0, 28))	('retinoic acid receptor-alpha', 'Gene', (283, 311))
171358	29152290	Fluorescence In situ-Hybridization (FISH) was promptly performed on the aspirate, and identified a t(15;17) translocation with fusion of PML/RARA in 79% of interphase cells.	('PML', 'Gene', '5371', (137, 140))	('RARA', 'Gene', '5914', (141, 145))	('fusion', 'Var', (127, 133))	('t(15;17', 'Gene', (99, 106))	('RARA', 'Gene', (141, 145))	('PML', 'Gene', (137, 140))	('translocation', 'Var', (108, 121))
171398	26297069	Massively parallel sequencing (MPS) technologies allow for high throughput multiplex detection of a wide range of genetic aberrations, including single nucleotide changes (SNVs), copy number alterations (CNA), insertions and deletions (indels) and chromosomal rearrangements.	('MPS', 'Disease', (31, 34))	('single nucleotide changes', 'Var', (145, 170))	('copy number alterations', 'Var', (179, 202))	('genetic aberrations', 'Disease', 'MESH:D030342', (114, 133))	('insertions', 'Var', (210, 220))	('chromosomal', 'Disease', (248, 259))	('MPS', 'Disease', 'MESH:D009084', (31, 34))	('genetic aberrations', 'Disease', (114, 133))	('deletions', 'Var', (225, 234))
171410	26297069	A PDGFRA exon 12 mutation detected in a gastric epithelioid mesenchymal tumor biopsy, for example, would be an actionable mutation supporting a diagnosis of gastrointestinal stromal tumor, with a relatively good prognosis, predicting moderate sensitivity to imatinib.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('moderate sensitivity to imatinib', 'MPA', (234, 266))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (157, 187))	('mutation', 'Var', (17, 25))	('gastric epithelioid mesenchymal tumor', 'Disease', (40, 77))	('gastric epithelioid mesenchymal tumor', 'Disease', 'MESH:D013274', (40, 77))	('gastrointestinal stromal tumor', 'Disease', (157, 187))	('PDGFRA', 'Gene', (2, 8))	('predicting', 'Reg', (223, 233))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (157, 187))	('imatinib', 'Chemical', 'MESH:D000068877', (258, 266))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
171412	26297069	The difficulty in detecting chromosomal rearrangements by sequencing targeted cancer gene panels is particularly inconvenient for the field of soft tissue tumor pathology; the inclusion of intronic sequences, as well as specific computational approaches may improve the detection of select rearrangements,  but the sensitivity is still low.	('rearrangements', 'Var', (290, 304))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('detection', 'MPA', (270, 279))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Disease', (155, 160))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (143, 160))	('improve', 'PosReg', (258, 265))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
171421	26297069	In the research setting, exome sequencing has led to the identification of fusions such as NAB2-STAT6 in solitary fibrous tumor.	('fibrous tumor', 'Disease', (114, 127))	('NAB2-STAT6', 'Gene', (91, 101))	('fusions', 'Var', (75, 82))	('fibrous tumor', 'Disease', 'MESH:D054364', (114, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
171426	26297069	The various amplicons characteristic of well-differentiated / dedifferentiated liposarcoma are also readily detected as copy number gains of MDM2 and CDK4, while MYC amplification is present in radiation-associated angiosarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (79, 90))	('liposarcoma', 'Disease', 'MESH:D008080', (79, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('angiosarcoma', 'Disease', 'MESH:D006394', (215, 227))	('copy number', 'Var', (120, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('gains', 'PosReg', (132, 137))	('angiosarcoma', 'Disease', (215, 227))	('CDK4', 'Gene', (150, 154))	('angiosarcoma', 'Phenotype', 'HP:0200058', (215, 227))	('liposarcoma', 'Disease', (79, 90))	('MDM2', 'Gene', (141, 145))
171427	26297069	Mutations in TP53 are often identified in some sarcomas (osteosarcoma, leiomyosarcoma), as well as occasional PTEN loses, although with little value for diagnosis or patient management at this time.	('PTEN', 'Gene', '5728', (110, 114))	('TP53', 'Gene', (13, 17))	('leiomyosarcoma', 'Disease', (71, 85))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (57, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcomas', 'Disease', (47, 55))	('Mutations', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('TP53', 'Gene', '7157', (13, 17))	('patient', 'Species', '9606', (166, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (71, 85))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (71, 85))	('PTEN', 'Gene', (110, 114))	('osteosarcoma', 'Disease', (57, 69))	('identified', 'Reg', (28, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (57, 69))
171428	26297069	CDKN2A inactivating events are common (malignant peripheral nerve sheath tumors, fibrosarcomatous dermatofibrosarcoma protuberans, advanced gastrointestinal stromal tumors).	('malignant peripheral nerve sheath tumors', 'Disease', (39, 79))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (140, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('fibrosarcomatous dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (81, 129))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (140, 171))	('inactivating events', 'Var', (7, 26))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (39, 79))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (140, 170))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (39, 78))	('gastrointestinal stromal tumors', 'Disease', (140, 171))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (39, 79))	('CDKN2A', 'Gene', (0, 6))	('fibrosarcomatous dermatofibrosarcoma protuberans', 'Disease', (81, 129))
171430	26297069	The mean sequencing depth is approximately 30 to 60 reads, and the high number of sequence variants requires paired tumor and normal samples to filter out the germline variants from the tumor genome calls.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('variants', 'Var', (91, 99))	('tumor', 'Disease', (116, 121))
171432	26297069	As a discovery tool, WGS has led to the discovery of STAG2 mutations in Ewing sarcoma and H3.3 mutations in chondroblastoma and giant cell tumor of bone.	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (128, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('giant cell tumor', 'Disease', (128, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 85))	('H3.3', 'Gene', (90, 94))	('chondroblastoma', 'Phenotype', 'HP:0030432', (108, 123))	('chondroblastoma', 'Disease', (108, 123))	('tumor of bone', 'Phenotype', 'HP:0010622', (139, 152))	('STAG2', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Ewing sarcoma', 'Disease', (72, 85))	('giant cell tumor', 'Disease', 'MESH:D005870', (128, 144))	('giant cell tumor', 'Phenotype', 'HP:0011847', (128, 144))	('chondroblastoma', 'Disease', 'MESH:D002804', (108, 123))	('mutations', 'Var', (59, 68))	('mutations', 'Var', (95, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))
171439	26297069	The relevance of chromosomal rearrangements in soft tissue tumor pathogenesis and their diagnostic utility is well documented, and recurrent rearrangements have been used as a dichotomous classifier to define a whole category of translocation-associated soft tissue tumors.	('soft tissue tumors', 'Phenotype', 'HP:0031459', (254, 272))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('translocation-associated', 'Var', (229, 253))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (47, 64))	('soft tissue tumors', 'Disease', (254, 272))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (254, 271))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Disease', (266, 271))	('soft tissue tumors', 'Disease', 'MESH:D012983', (254, 272))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
171445	26297069	Notable examples of fusions genes detected by RNA-seq include YWHAE-NUTM2A/B in high-grade endometrial stromal sarcoma, WWTR1-CAMTA1 in epithelioid hemangioendothelioma,  and BCOR-CCNB3 in undifferentiated round cell sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (91, 118))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (136, 168))	('YWHAE-NUTM2A/B', 'Gene', (62, 76))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Disease', 'MESH:D012509', (217, 224))	('fusions', 'Var', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('epithelioid hemangioendothelioma', 'Disease', (136, 168))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (136, 168))	('BCOR-CCNB3', 'Gene', (175, 185))	('sarcoma', 'Disease', (217, 224))	('endometrial stromal sarcoma', 'Disease', (91, 118))
171452	26297069	Copy number changes are extremely common in cancer, and induce significant functional changes that drive oncogenesis in proportions comparable to sequence variations.	('drive', 'Reg', (99, 104))	('oncogenesis', 'CPA', (105, 116))	('Copy number changes', 'Var', (0, 19))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('functional changes', 'MPA', (75, 93))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
171453	26297069	In sarcoma, several oncogenic events are engaged by copy number changes, such as amplification of oncogenes (MDM2 and CDK4 in dedifferentiated liposarcoma and paraosteal osteosarcoma) and deletion of critical tumor suppressors (NF1 in malignant peripheral nerve sheath tumor, DMD in myogenic sarcomas).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('sarcoma', 'Disease', (292, 299))	('sarcoma', 'Disease', (175, 182))	('CDK4', 'Gene', (118, 122))	('myogenic sarcomas', 'Disease', 'MESH:D012509', (283, 300))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (235, 274))	('NF1', 'Gene', (228, 231))	('myogenic sarcomas', 'Disease', (283, 300))	('tumor', 'Disease', (209, 214))	('sarcomas', 'Phenotype', 'HP:0100242', (292, 300))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('sheath tumor', 'Disease', 'MESH:D010524', (262, 274))	('deletion', 'Var', (188, 196))	('sarcoma', 'Disease', 'MESH:D012509', (3, 10))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('sarcoma', 'Disease', (147, 154))	('sarcoma', 'Disease', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('MDM2', 'Gene', (109, 113))	('liposarcoma and paraosteal osteosarcoma', 'Disease', 'MESH:D012516', (143, 182))	('tumor', 'Disease', (269, 274))	('sheath tumor', 'Disease', (262, 274))	('osteosarcoma', 'Phenotype', 'HP:0002669', (170, 182))	('sarcoma', 'Disease', 'MESH:D012509', (292, 299))	('sarcoma', 'Disease', 'MESH:D012509', (175, 182))	('liposarcoma', 'Phenotype', 'HP:0012034', (143, 154))	('DMD', 'Disease', 'MESH:D020388', (276, 279))	('DMD', 'Disease', (276, 279))
171455	26297069	Such approaches have been successfully applied in soft tissue tumors for discovery purposes (leading to the identification of GRM1 fusions in chondromyxoid fibroma).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('fusions', 'Var', (131, 138))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (50, 67))	('soft tissue tumors', 'Disease', (50, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('soft tissue tumors', 'Disease', 'MESH:D012983', (50, 68))	('fibroma', 'Phenotype', 'HP:0010614', (156, 163))	('chondromyxoid fibroma', 'Disease', (142, 163))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (50, 68))	('chondromyxoid fibroma', 'Disease', 'MESH:D005350', (142, 163))	('GRM1', 'Gene', (126, 130))
171457	26297069	The main limitation is its relatively low sensitivity, with a detection threshold of approximately 30% allelic frequency (problematic in cases with low tumor content, or in the detection of subclonal/heterogeneous genetic changes).	('low tumor', 'Disease', 'MESH:D009800', (148, 157))	('allelic frequency', 'Var', (103, 120))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('low tumor', 'Disease', (148, 157))
171460	26297069	At present, about 30 recurrent chromosomal rearrangements are known to be involved in soft tissue tumors and can be used for diagnostic purposes (reviewed by Mertens et al, and Al-Zaid et al).	('soft tissue tumor', 'Phenotype', 'HP:0031459', (86, 103))	('involved', 'Reg', (74, 82))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (86, 104))	('chromosomal rearrangements', 'Var', (31, 57))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('soft tissue tumors', 'Disease', (86, 104))	('soft tissue tumors', 'Disease', 'MESH:D012983', (86, 104))
171466	26297069	Overexpression of STAT6, TFE3 or ALK as a result of chromosomal rearrangements in solitary fibrous tumor, alveolar soft part sarcoma and inflammatory myofibroblastic tumors, respectively, can also be detected by robust immunohistochemical techniques.	('STAT6', 'Gene', (18, 23))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (115, 132))	('chromosomal rearrangements', 'Var', (52, 78))	('ALK', 'Gene', (33, 36))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (106, 132))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (150, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('fibrous tumor', 'Disease', (91, 104))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (137, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('fibrous tumor', 'Disease', 'MESH:D054364', (91, 104))	('TFE3', 'Gene', (25, 29))	('alveolar soft part sarcoma', 'Disease', (106, 132))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (106, 132))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('inflammatory myofibroblastic tumors', 'Disease', (137, 172))
171485	26297069	Massively parallel sequencing technologies detect somatic mutations, indels and copy number changes in tumor samples generating clinically relevant information for cancer patient management.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('clinical', 'Species', '191496', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('patient', 'Species', '9606', (171, 178))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('copy number changes', 'Var', (80, 99))	('indels', 'Var', (69, 75))
171487	26297069	Genomic alterations detected in soft tissue tumors provide biological information complementary to clinicopathological variables, and substantiate therapeutic decisions or enrolment in clinical trials.	('clinical', 'Species', '191496', (185, 193))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('soft tissue tumors', 'Disease', (32, 50))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (32, 49))	('soft tissue tumors', 'Disease', 'MESH:D012983', (32, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Genomic alterations', 'Var', (0, 19))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (32, 50))
171610	25420707	The inactivation of TSC1/TSC2 in PEComa leads to increased mTOR complex 1 (TORC1) activation.	('TSC2', 'Gene', '7249', (25, 29))	('TSC2', 'Gene', (25, 29))	('inactivation', 'Var', (4, 16))	('activation', 'MPA', (82, 92))	('increased', 'PosReg', (49, 58))	('PEComa', 'Disease', 'MESH:D054973', (33, 39))	('TSC1', 'Gene', '7248', (20, 24))	('TSC1', 'Gene', (20, 24))	('TORC1', 'Gene', (75, 80))	('mTOR', 'Gene', '2475', (59, 63))	('TORC1', 'Gene', '382056', (75, 80))	('PEComa', 'Disease', (33, 39))	('mTOR', 'Gene', (59, 63))
171618	24129240	Variability in functional p53 reactivation by PRIMA-1Met/APR-246 in Ewing sarcoma Though p53 mutations are rare in ES, there is a strong indication that p53 mutant tumours form a particularly bad prognostic group.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('APR', 'Gene', (57, 60))	('p53', 'Gene', (26, 29))	('p53', 'Gene', (89, 92))	('p53', 'Gene', '7157', (153, 156))	('Ewing sarcoma', 'Disease', (68, 81))	('p53', 'Gene', (153, 156))	('ES', 'Chemical', 'MESH:D004540', (115, 117))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (68, 81))	('tumours', 'Disease', (164, 171))	('APR', 'Gene', '5366', (57, 60))	('mutant', 'Var', (157, 163))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('reactivation', 'MPA', (30, 42))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('p53', 'Gene', '7157', (26, 29))	('p53', 'Gene', '7157', (89, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
171619	24129240	As such, novel treatment strategies are warranted that would specifically target and eradicate tumour cells containing mutant p53 in this subset of ES patients.	('p53', 'Gene', '7157', (126, 129))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (151, 159))	('tumour', 'Disease', (95, 101))	('ES', 'Chemical', 'MESH:D004540', (148, 150))	('mutant', 'Var', (119, 125))	('p53', 'Gene', (126, 129))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
171620	24129240	PRIMA-1Met, also known as APR-246, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types.	('tumour', 'Disease', (94, 100))	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cell death', 'CPA', (164, 174))	('induce', 'PosReg', (157, 163))	('restore', 'PosReg', (86, 93))	('PRIMA-1', 'Gene', '145270', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('PRIMA-1', 'Gene', (0, 7))	('cancer', 'Disease', (186, 192))	('APR', 'Gene', '5366', (26, 29))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('mutant', 'Var', (134, 140))	('APR', 'Gene', (26, 29))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
171621	24129240	In this study, we interrogated the ability of APR-246 to induce apoptosis and inhibit tumour growth in ES cells with different p53 mutations.	('mutations', 'Var', (131, 140))	('apoptosis', 'CPA', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('inhibit', 'NegReg', (78, 85))	('ES', 'Chemical', 'MESH:D004540', (103, 105))	('APR', 'Gene', '5366', (46, 49))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('APR', 'Gene', (46, 49))	('induce', 'PosReg', (57, 63))	('tumour', 'Disease', (86, 92))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
171622	24129240	APR-246 variably induced apoptosis, associated with Noxa, Puma or p21WAF1 upregulation, in both mutant and wild-type p53 harbouring cells.	('p21', 'Gene', (66, 69))	('APR', 'Gene', '5366', (0, 3))	('mutant', 'Var', (96, 102))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('APR', 'Gene', (0, 3))	('Puma', 'Disease', (58, 62))	('upregulation', 'PosReg', (74, 86))	('induced', 'Reg', (17, 24))	('apoptosis', 'CPA', (25, 34))	('Noxa', 'Chemical', 'MESH:C008586', (52, 56))	('p21', 'Gene', '1026', (66, 69))
171624	24129240	Three ES cell lines established from the same patient at different stages of the disease and two cell lines of different patients with identical p53 mutations all exhibited different sensitivities to APR-246, indicating cellular context dependency.	('patient', 'Species', '9606', (46, 53))	('mutations', 'Var', (149, 158))	('p53', 'Gene', '7157', (145, 148))	('p53', 'Gene', (145, 148))	('exhibited', 'Reg', (163, 172))	('patient', 'Species', '9606', (121, 128))	('ES', 'Chemical', 'MESH:D004540', (6, 8))	('APR', 'Gene', '5366', (200, 203))	('APR', 'Gene', (200, 203))	('patients', 'Species', '9606', (121, 129))
171633	24129240	TP53 mutations may be associated with an aggressive phenotype and poor prognosis, and some p53 mutants counteract the effects of anticancer agents that attack tumours.	('TP53', 'Gene', '7157', (0, 4))	('tumours', 'Disease', (159, 166))	('TP53', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('mutations', 'Var', (5, 14))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('cancer', 'Disease', (133, 139))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('mutants', 'Var', (95, 102))	('associated', 'Reg', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
171634	24129240	Given the high frequency of p53 mutations in human tumours, reactivation of the p53 pathway has been widely proposed as beneficial for cancer therapy.	('p53', 'Gene', (28, 31))	('cancer', 'Disease', (135, 141))	('p53', 'Gene', '7157', (28, 31))	('p53', 'Gene', (80, 83))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('human', 'Species', '9606', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('mutations', 'Var', (32, 41))	('p53', 'Gene', '7157', (80, 83))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('tumours', 'Disease', (51, 58))
171635	24129240	In addition, several reported structural studies have shown that mutant p53 core domain unfolding is reversible and, as mutant p53 is expressed at high levels in many tumours, it therefore serves as a potential target for novel cancer therapy.	('cancer', 'Disease', (228, 234))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('mutant', 'Var', (65, 71))	('p53', 'Gene', (72, 75))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('p53', 'Gene', '7157', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumours', 'Disease', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('p53', 'Gene', '7157', (127, 130))	('mutant', 'Var', (120, 126))	('p53', 'Gene', (127, 130))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
171636	24129240	Its reactivation will restore p53-dependent apoptosis, among others, resulting in efficient eradication of tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('restore', 'PosReg', (22, 29))	('reactivation', 'Var', (4, 16))	('tumour', 'Disease', (107, 113))
171641	24129240	Although about half of all human malignancies harbour dysfunctional, mutated p53 proteins, approximately 90% of all ES retain wild-type p53, and the downstream DNA damage cell cycle checkpoints and p53 pathways remain functionally intact.	('ES', 'Chemical', 'MESH:D004540', (116, 118))	('p53', 'Gene', '7157', (136, 139))	('mutated', 'Var', (69, 76))	('human', 'Species', '9606', (27, 32))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('malignancies harbour dysfunctional', 'Disease', 'MESH:D009369', (33, 67))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('proteins', 'Protein', (81, 89))	('malignancies harbour dysfunctional', 'Disease', (33, 67))	('p53', 'Gene', (136, 139))
171644	24129240	Multivariate analysis identified alterations of TP53 as an adverse prognostic factor defining a subset of ES with highly aggressive behaviour and poor chemoresponse.	('aggressive behaviour', 'Phenotype', 'HP:0000718', (121, 141))	('TP53', 'Gene', '7157', (48, 52))	('ES', 'Chemical', 'MESH:D004540', (106, 108))	('TP53', 'Gene', (48, 52))	('alterations', 'Var', (33, 44))
171645	24129240	Therefore, novel treatment options specifically targeting mutant p53 are highly warranted.	('mutant', 'Var', (58, 64))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))
171646	24129240	There is a prospective COG (Children's Oncology Group, USA) study ongoing to validate a retrospective study which strongly suggested that mutant p53 ES constitutes a particularly bad prognostic group (ClinicalTrials.gov identifier: NCT00898053).	('p53', 'Gene', '7157', (145, 148))	('p53', 'Gene', (145, 148))	('Children', 'Species', '9606', (28, 36))	('Oncology', 'Phenotype', 'HP:0002664', (39, 47))	('mutant', 'Var', (138, 144))	('ES', 'Chemical', 'MESH:D004540', (149, 151))
171647	24129240	If data from the retrospective study is confirmed, this would strongly support the need for novel mutant p53 targeting therapeutic strategies in ES.	('p53', 'Gene', (105, 108))	('mutant', 'Var', (98, 104))	('p53', 'Gene', '7157', (105, 108))	('ES', 'Chemical', 'MESH:D004540', (145, 147))
171648	24129240	In this study, we investigated whether the small pharmacological molecule APR-246 is able to reactivate mutant p53 in Ewing sarcoma cells in order to drive tumour cells into apoptosis.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (118, 131))	('tumour', 'Disease', (156, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('drive', 'PosReg', (150, 155))	('mutant', 'Var', (104, 110))	('p53', 'Gene', (111, 114))	('apoptosis', 'CPA', (174, 183))	('p53', 'Gene', '7157', (111, 114))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('APR', 'Gene', '5366', (74, 77))	('Ewing sarcoma', 'Disease', (118, 131))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('APR', 'Gene', (74, 77))
171650	24129240	We observed that cell lines with similar p53 mutations as well as cell lines established from the same patient at different stages of the disease all exhibited variable responses to the drug.	('mutations', 'Var', (45, 54))	('responses', 'MPA', (169, 178))	('p53', 'Gene', (41, 44))	('patient', 'Species', '9606', (103, 110))	('p53', 'Gene', '7157', (41, 44))
171653	24129240	We propose, therefore, that APR-246 will not be a suitable candidate to consider for targeting p53 mutant Ewing sarcoma.	('Ewing sarcoma', 'Disease', (106, 119))	('APR', 'Gene', '5366', (28, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('APR', 'Gene', (28, 31))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('mutant', 'Var', (99, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
171681	24129240	As PRIMA-1 has been shown to inhibit growth of breast cancer cells, we chose as a positive control the non-ES cell line MDA-MB-468, which harbours a p53 mutation (R273H) similar to the ES cell line RM82.	('PRIMA-1', 'Gene', '145270', (3, 10))	('p53', 'Gene', (149, 152))	('breast cancer', 'Disease', (47, 60))	('R273H', 'Mutation', 'rs28934576', (163, 168))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (120, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('p53', 'Gene', '7157', (149, 152))	('R273H', 'Var', (163, 168))	('inhibit', 'NegReg', (29, 36))	('ES', 'Chemical', 'MESH:D004540', (185, 187))	('PRIMA-1', 'Gene', (3, 10))	('ES', 'Chemical', 'MESH:D004540', (107, 109))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
171683	24129240	As shown in Figure 1A, the expression level of mutant p53 in the ES cell lines varied.	('p53', 'Gene', (54, 57))	('ES', 'Chemical', 'MESH:D004540', (65, 67))	('p53', 'Gene', '7157', (54, 57))	('expression level', 'MPA', (27, 43))	('mutant', 'Var', (47, 53))
171690	24129240	PARP cleavage, an indicator of apoptosis induction, is shown in both the wild-type p53 cell line TC252 and the mutant p53 cell line RM82 in a dose-dependent manner on APR-246 treatment (Figure 1C).	('APR', 'Gene', (167, 170))	('APR', 'Gene', '5366', (167, 170))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('PARP', 'Gene', '1302', (0, 4))	('mutant', 'Var', (111, 117))	('p53', 'Gene', (118, 121))	('PARP', 'Gene', (0, 4))	('p53', 'Gene', '7157', (118, 121))	('TC252', 'CellLine', 'CVCL:S866', (97, 102))
171692	24129240	In the STA-ET-7.2 and IARC-EW2 cell lines, despite sharing an identical p53 mutation (R273C), response to APR-246 varied (Figure 1B).	('R273C', 'Var', (86, 91))	('IARC-EW2', 'CellLine', 'CVCL:3446', (22, 30))	('APR', 'Gene', '5366', (106, 109))	('STA', 'Gene', (7, 10))	('APR', 'Gene', (106, 109))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('R273C', 'Mutation', 'rs121913343', (86, 91))	('response to', 'MPA', (94, 105))	('STA', 'Gene', '2656', (7, 10))
171696	24129240	To ascertain whether these variable responses reflect differences in mutant p53 expression, we performed immunoblot analysis to determine p53 expression in these cell lines.	('p53', 'Gene', (138, 141))	('mutant', 'Var', (69, 75))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('p53', 'Gene', '7157', (138, 141))
171697	24129240	As shown in Figure 2A, mutant p53 expression varied only slightly among the three cell lines.	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('expression', 'MPA', (34, 44))	('mutant', 'Var', (23, 29))
171698	24129240	To investigate the role of mutant p53 in APR-246 mediated apoptosis, the effect of APR-246 was tested in the STA-ET-7.2 ES cell line in which mutant p53 was downregulated using siRNA.	('STA', 'Gene', (109, 112))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('p53', 'Gene', (149, 152))	('APR', 'Gene', (41, 44))	('downregulated', 'NegReg', (157, 170))	('APR', 'Gene', '5366', (41, 44))	('p53', 'Gene', '7157', (149, 152))	('mutant', 'Var', (142, 148))	('APR', 'Gene', '5366', (83, 86))	('7.2 ES', 'CellLine', 'CVCL:1203', (116, 122))	('APR', 'Gene', (83, 86))	('STA', 'Gene', '2656', (109, 112))
171705	24129240	This enhanced activation was abrogated upon siRNA-mediated mutant p53 knockdown (Figure 3C).	('mutant', 'Var', (59, 65))	('knockdown', 'Var', (70, 79))	('p53', 'Gene', (66, 69))	('p53', 'Gene', '7157', (66, 69))
171714	24129240	Its silencing in MCF7 cells has previously been linked to enhanced sensitivity to tamoxifen (; data not shown).	('tamoxifen', 'Chemical', 'MESH:D013629', (82, 91))	('enhanced', 'PosReg', (58, 66))	('MCF7', 'CellLine', 'CVCL:0031', (17, 21))	('sensitivity to tamoxifen', 'MPA', (67, 91))	('silencing', 'Var', (4, 13))
171715	24129240	ES is a very aggressive disease and though TP53 mutations are rare in ES, with the majority of tumours expressing wild-type p53, patients with point mutation of TP53 are associated with a dismal prognosis.	('p53', 'Gene', (124, 127))	('TP53', 'Gene', (161, 165))	('very aggressive disease', 'Disease', (8, 31))	('point mutation', 'Var', (143, 157))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('patients', 'Species', '9606', (129, 137))	('TP53', 'Gene', '7157', (161, 165))	('p53', 'Gene', '7157', (124, 127))	('ES', 'Chemical', 'MESH:D004540', (0, 2))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', (95, 102))	('ES', 'Chemical', 'MESH:D004540', (70, 72))	('very aggressive disease', 'Disease', 'MESH:D000326', (8, 31))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
171717	24129240	A study of 308 ES cases established that mutant p53 expression was more frequent in disseminated disease than in primary localised tumours, indicating a role in the progression and metastasis of ES.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('p53', 'Gene', (48, 51))	('ES', 'Chemical', 'MESH:D004540', (15, 17))	('ES', 'Chemical', 'MESH:D004540', (195, 197))	('mutant', 'Var', (41, 47))	('p53', 'Gene', '7157', (48, 51))	('tumours', 'Disease', (131, 138))	('disseminated disease', 'Disease', (84, 104))	('expression', 'MPA', (52, 62))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))
171719	24129240	In the current study, we addressed the possibility of using the small-molecule compound, APR-246/PRIMA-1Met, capable of reactivating mutant p53 and inducing apoptosis in several different cancer types, to induce cell death in ES cells harbouring different p53 mutants.	('APR', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('PRIMA-1', 'Gene', (97, 104))	('apoptosis', 'CPA', (157, 166))	('ES', 'Chemical', 'MESH:D004540', (226, 228))	('induce', 'PosReg', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('inducing', 'Reg', (148, 156))	('PRIMA-1', 'Gene', '145270', (97, 104))	('cell death', 'CPA', (212, 222))	('p53', 'Gene', (256, 259))	('p53', 'Gene', '7157', (256, 259))	('cancer', 'Disease', (188, 194))	('reactivating', 'PosReg', (120, 132))	('mutant', 'Var', (133, 139))	('p53', 'Gene', (140, 143))	('APR', 'Gene', '5366', (89, 92))	('p53', 'Gene', '7157', (140, 143))
171721	24129240	For instance, three ES cell lines established from the same patient at different stages of the disease (with identical p53 mutation) all reacted variably to APR-246 treatment (Figure 2A).	('patient', 'Species', '9606', (60, 67))	('APR', 'Gene', (157, 160))	('APR', 'Gene', '5366', (157, 160))	('mutation', 'Var', (123, 131))	('reacted', 'Reg', (137, 144))	('p53', 'Gene', '7157', (119, 122))	('ES', 'Chemical', 'MESH:D004540', (20, 22))	('p53', 'Gene', (119, 122))
171722	24129240	We also asked whether tumour cell lines with the same mutation will show similar cellular response to APR-246.	('mutation', 'Var', (54, 62))	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('APR', 'Gene', '5366', (102, 105))	('APR', 'Gene', (102, 105))	('tumour', 'Disease', (22, 28))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
171725	24129240	To investigate whether induction of apoptosis was mediated via p53 upon APR-246 exposure, we used RNAi to knockdown p53 in mt-p53 cell lines before treatment with APR-246.	('p53', 'Gene', '7157', (126, 129))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('APR', 'Gene', '5366', (163, 166))	('APR', 'Gene', '5366', (72, 75))	('knockdown', 'Var', (106, 115))	('APR', 'Gene', (163, 166))	('p53', 'Gene', '7157', (116, 119))	('APR', 'Gene', (72, 75))	('p53', 'Gene', (126, 129))	('p53', 'Gene', (116, 119))
171730	24129240	We also observed that APR-246 induced expression of variable sets of classical p53 target genes in ES cells harbouring mutant and wild-type p53 (Figures 3A and B).	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('induced', 'Reg', (30, 37))	('expression', 'MPA', (38, 48))	('ES', 'Chemical', 'MESH:D004540', (99, 101))	('p53', 'Gene', (140, 143))	('APR', 'Gene', '5366', (22, 25))	('mutant', 'Var', (119, 125))	('APR', 'Gene', (22, 25))	('p53', 'Gene', '7157', (140, 143))
171740	24129240	These results are consistent with the reported capability of APR-246 to restore transcriptional activity to mutant p53 and trigger mutant p53-dependent apoptosis.	('APR', 'Gene', (61, 64))	('p53', 'Gene', (138, 141))	('APR', 'Gene', '5366', (61, 64))	('mutant', 'Var', (131, 137))	('p53', 'Gene', '7157', (138, 141))	('trigger', 'Reg', (123, 130))	('restore', 'PosReg', (72, 79))	('mutant', 'Var', (108, 114))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('transcriptional activity', 'MPA', (80, 104))
171741	24129240	This is also in line with the suggestion by) that adducts of the APR-246 conversion product methylene quinuclidinone could create novel protein-DNA contacts, which could affect the choice of target genes.	('protein-DNA', 'Protein', (136, 147))	('create', 'Reg', (123, 129))	('adducts', 'Var', (50, 57))	('quinuclidinone', 'Chemical', '-', (102, 116))	('APR', 'Gene', (65, 68))	('affect', 'Reg', (170, 176))	('APR', 'Gene', '5366', (65, 68))
171743	24129240	This notion reflects our finding of the induction of different p53 target genes in different mutant p53 cell lines after APR-246 treatments, notwithstanding the cellular context dependency exhibited by ES cells in response to APR-246.	('p53', 'Gene', (63, 66))	('APR', 'Gene', '5366', (226, 229))	('p53', 'Gene', '7157', (63, 66))	('APR', 'Gene', (226, 229))	('APR', 'Gene', '5366', (121, 124))	('ES', 'Chemical', 'MESH:D004540', (202, 204))	('APR', 'Gene', (121, 124))	('mutant', 'Var', (93, 99))	('p53', 'Gene', '7157', (100, 103))	('induction', 'Reg', (40, 49))	('p53', 'Gene', (100, 103))
171745	24129240	This corroborates reported results by, where they found that Bax-dependent apoptosis induced by APR-246 is mutant p53 dependent but transcription independent.	('mutant', 'Var', (107, 113))	('p53', 'Gene', (114, 117))	('APR', 'Gene', '5366', (96, 99))	('p53', 'Gene', '7157', (114, 117))	('apoptosis', 'CPA', (75, 84))	('APR', 'Gene', (96, 99))	('Bax', 'Gene', (61, 64))	('Bax', 'Gene', '581', (61, 64))
171923	32664672	In these studies, we found that infection with C1-opt1 at a MOI of 0.5 exhibited the strongest expression of FP635 in both CT1258 (Figure 2A) and STSA-1 cells (Figure 2B).	('C1-opt1', 'Var', (47, 54))	('FP635', 'Gene', (109, 114))	('C1-opt1', 'Chemical', '-', (47, 54))	('infection', 'Disease', (32, 41))	('infection', 'Disease', 'MESH:D007239', (32, 41))	('expression', 'MPA', (95, 105))	('CT1258', 'CellLine', 'CVCL:W737', (123, 129))
171930	32664672	The maximum viral titers were determined for L3-opt1 at 48 hpvi (1.52 x 106 pfu/mL, five-fold increase compared to loaded virus at 0 hpi) and for C1-opt1 at 72 hpvi (1.51 x 106 pfu/mL, five-fold increase compared to loaded virus at 0 hpi) (Figure 5).	('increase', 'PosReg', (94, 102))	('C1-opt1', 'Chemical', '-', (146, 153))	('viral titers', 'MPA', (12, 24))	('L3-opt1', 'Var', (45, 52))
171951	32664672	Interestingly, we also found viral particles in lungs of most mice injected with cAdMSCs/C1-opt1 but not with C1-opt1 alone (Table 2).	('found', 'Reg', (23, 28))	('mice', 'Species', '10090', (62, 66))	('C1-opt1', 'Chemical', '-', (110, 117))	('cAdMSCs/C1-opt1', 'Var', (81, 96))	('C1-opt1', 'Chemical', '-', (89, 96))
171952	32664672	However, the detected C1-opt1 PFUs in tumors were about 103-105-fold higher when compared to PFUs in the lungs of corresponding animals at the same timepoint (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('C1-opt1 PFUs', 'Var', (22, 34))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('C1-opt1', 'Chemical', '-', (22, 29))	('higher', 'PosReg', (69, 75))
171954	32664672	For this purpose, tissue sections of primary tumors of STSA-1 tumor-bearing mice injected with C1-opt1, cAdMSCs/C1-opt1 at 24 dpvi and with cAdMSCs alone at 13 dpi were prepared as described in the Materials and Methods section.	('C1-opt1', 'Chemical', '-', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('C1-opt1', 'Var', (95, 102))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('mice', 'Species', '10090', (76, 80))	('C1-opt1', 'Chemical', '-', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
171969	32664672	The results demonstrated that both C1-opt1 alone and when loaded into the stem cells achieved a significant inhibition of tumor growth in the STSA-1 canine xenograft models.	('canine', 'Species', '9615', (149, 155))	('inhibition', 'NegReg', (108, 118))	('C1-opt1', 'Chemical', '-', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('C1-opt1', 'Var', (35, 42))	('tumor', 'Disease', (122, 127))
172032	30075493	The melanin containing tumors appear hyper-intense on T1WI and hypo-intense on T2WI, which is a classical presentation because of the paramagnetic properties of melanin causing the shortening of T1 and T2 relaxation time.	('T2 relaxation time', 'MPA', (202, 220))	('shortening', 'NegReg', (181, 191))	('T2WI', 'Var', (79, 83))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('T1WI', 'Var', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('melanin', 'Chemical', 'MESH:D008543', (161, 168))	('melanin', 'Chemical', 'MESH:D008543', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
172084	26646010	The KSHV protein expressed by ORF K2 is known as viral interleukin-6 (vIL-6) because of its sequence and structural similarity to the cytokine, human interleukin-6 (hIL-6).	('KSHV', 'Species', '37296', (4, 8))	('ORF', 'Var', (30, 33))	('human', 'Species', '9606', (144, 149))	('hIL-6', 'Gene', (165, 170))	('KS', 'Phenotype', 'HP:0100726', (4, 6))	('vIL-6', 'Gene', (70, 75))	('vIL-6', 'Gene', '4961449', (70, 75))	('hIL-6', 'Gene', '3569', (165, 170))
172099	26646010	In addition, CEACAM1 has consistently been shown to augment angiogenesis, increase the migration of endothelial cells, and to induce vascular remodeling.	('induce', 'Reg', (126, 132))	('men', 'Species', '9606', (55, 58))	('angiogenesis', 'CPA', (60, 72))	('vascular remodeling', 'CPA', (133, 152))	('increase', 'PosReg', (74, 82))	('migration of endothelial cells', 'CPA', (87, 117))	('augment', 'PosReg', (52, 59))	('CEACAM1', 'Var', (13, 20))
172103	26646010	Finally, we found that knockdown of CEACAM1 abrogated the vIL-6-mediated migration of endothelial cells, indicating that CEACAM1 may play a critical role in promoting invasion of KSHV-infected endothelial cells.	('vIL-6', 'Gene', (58, 63))	('KS', 'Phenotype', 'HP:0100726', (179, 181))	('CEACAM1', 'Gene', (36, 43))	('knockdown', 'Var', (23, 32))	('invasion', 'CPA', (167, 175))	('vIL-6', 'Gene', '4961449', (58, 63))	('KSHV-infected', 'Disease', (179, 192))	('KSHV-infected', 'Disease', 'MESH:C537372', (179, 192))	('abrogated', 'NegReg', (44, 53))	('promoting', 'PosReg', (157, 166))
172114	26646010	We confirmed that expression of FLAG-tagged vIL-6 in endothelial cells significantly upregulates the CEACAM1 mRNA message compared to that of the EV by real-time quantitative PCR (qPCR) (Fig.	('EV', 'Chemical', '-', (146, 148))	('vIL-6', 'Gene', '4961449', (44, 49))	('upregulates', 'PosReg', (85, 96))	('CEACAM1 mRNA message', 'MPA', (101, 121))	('vIL-6', 'Gene', (44, 49))	('expression', 'Var', (18, 28))
172115	26646010	vIL-6 expression also upregulated the CEACAM1 protein in endothelial cells (Fig.	('upregulated', 'PosReg', (22, 33))	('vIL-6', 'Gene', '4961449', (0, 5))	('CEACAM1 protein', 'Protein', (38, 53))	('expression', 'Var', (6, 16))	('vIL-6', 'Gene', (0, 5))
172119	26646010	S3I-201 is a small molecule that inhibits the ability of STAT3 to dimerize and become activated.	('STAT3', 'MPA', (57, 62))	('ability', 'MPA', (46, 53))	('S3I-201', 'Chemical', 'MESH:C520337', (0, 7))	('S3I-201', 'Var', (0, 7))	('activated', 'MPA', (86, 95))	('inhibits', 'NegReg', (33, 41))	('dimerize', 'MPA', (66, 74))
172120	26646010	reported that S3I-201 has a preference for STAT3 and that at concentrations that inhibit STAT3, S3I-201 has very little effect on STAT1 and STAT5.	('S3I-201', 'Var', (96, 103))	('S3I-201', 'Chemical', 'MESH:C520337', (96, 103))	('inhibit', 'NegReg', (81, 88))	('S3I-201', 'Chemical', 'MESH:C520337', (14, 21))	('STAT5', 'Gene', '6776', (140, 145))	('STAT3', 'Gene', (89, 94))	('STAT5', 'Gene', (140, 145))	('STAT1', 'Gene', (130, 135))	('STAT1', 'Gene', '6772', (130, 135))
172121	26646010	Hence, in our experiments, we used a concentration of S3I-201 (60 to 75 microM) that would inhibit STAT3 but not affect STAT1.	('STAT3', 'MPA', (99, 104))	('STAT1', 'Gene', '6772', (120, 125))	('inhibit', 'NegReg', (91, 98))	('S3I-201', 'Var', (54, 61))	('STAT1', 'Gene', (120, 125))	('S3I-201', 'Chemical', 'MESH:C520337', (54, 61))	('men', 'Species', '9606', (20, 23))
172123	26646010	In vehicle-treated cells, CEACAM1 levels were much higher in vIL-6-expressing cells than in EV-expressing cells; however, treatment with S3I-201 greatly reduced CEACAM1 transcript levels in vIL-6-expressing cells (Fig.	('S3I-201', 'Chemical', 'MESH:C520337', (137, 144))	('vIL-6', 'Gene', '4961449', (61, 66))	('CEACAM1', 'MPA', (26, 33))	('reduced', 'NegReg', (153, 160))	('CEACAM1 transcript levels', 'MPA', (161, 186))	('vIL-6', 'Gene', (190, 195))	('EV-', 'Chemical', '-', (92, 95))	('vIL-6', 'Gene', (61, 66))	('vIL-6', 'Gene', '4961449', (190, 195))	('S3I-201', 'Var', (137, 144))	('men', 'Species', '9606', (127, 130))
172124	26646010	Furthermore, treatment with S3I-201 produced significantly lower CEACAM1 protein levels in vIL-6-expressing cells than in vehicle control-treated cells (Fig.	('vIL-6', 'Gene', '4961449', (91, 96))	('S3I-201', 'Var', (28, 35))	('men', 'Species', '9606', (18, 21))	('lower', 'NegReg', (59, 64))	('S3I-201', 'Chemical', 'MESH:C520337', (28, 35))	('vIL-6', 'Gene', (91, 96))	('CEACAM1 protein levels', 'MPA', (65, 87))
172125	26646010	Western blot assays confirmed that Tyr705 phosphorylation of STAT3 was increased by expression of vIL-6 and that treatment with S3I-201 reduced STAT3 phosphorylation, as expected (Fig.	('expression', 'Var', (84, 94))	('STAT3 phosphorylation', 'MPA', (144, 165))	('vIL-6', 'Gene', '4961449', (98, 103))	('Tyr705', 'Chemical', '-', (35, 41))	('S3I-201', 'Var', (128, 135))	('men', 'Species', '9606', (118, 121))	('S3I-201', 'Chemical', 'MESH:C520337', (128, 135))	('reduced', 'NegReg', (136, 143))	('increased', 'PosReg', (71, 80))	('Tyr705 phosphorylation', 'MPA', (35, 57))	('vIL-6', 'Gene', (98, 103))
172136	26646010	vIL-6-expressing endothelial cells rapidly migrated and closed the scratch much more quickly than EV-expressing cells; however, knockdown of CEACAM1 reduced the ability of vIL-6-expressing cells to close the gap as quickly.	('CEACAM1', 'Gene', (141, 148))	('vIL-6', 'Gene', (172, 177))	('knockdown', 'Var', (128, 137))	('vIL-6', 'Gene', '4961449', (0, 5))	('reduced', 'NegReg', (149, 156))	('ability', 'MPA', (161, 168))	('vIL-6', 'Gene', '4961449', (172, 177))	('EV-', 'Chemical', '-', (98, 101))	('vIL-6', 'Gene', (0, 5))
172137	26646010	Following completion of the assay, lysates were harvested for SDS-PAGE and Western blotting to confirm CEACAM1 knockdown (Fig.	('SDS', 'Chemical', 'MESH:D012967', (62, 65))	('knockdown', 'Var', (111, 120))	('CEACAM1', 'Gene', (103, 110))
172143	26646010	At 30 h postinfection, almost 100% of the cells receiving KSHV were GFP positive, whereas the mock-infected control contained no detectable GFP-positive cells (Fig.	('GFP', 'Gene', (68, 71))	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('KSHV', 'Species', '37296', (58, 62))	('KSHV', 'Var', (58, 62))	('positive', 'Reg', (72, 80))
172174	26646010	One gene, CEACAM1, was highly upregulated by vIL-6 expression at both the message and protein levels.	('CEACAM1', 'Gene', (10, 17))	('upregulated', 'PosReg', (30, 41))	('vIL-6', 'Gene', (45, 50))	('vIL-6', 'Gene', '4961449', (45, 50))	('expression', 'Var', (51, 61))
172179	26646010	It has been previously shown that knockout of STAT3 can reduce CEACAM1 expression in APCmin mice, and vIL-6 is a known inducer of STAT3 signaling.	('expression', 'MPA', (71, 81))	('CEACAM1', 'Gene', (63, 70))	('vIL-6', 'Gene', '4961449', (102, 107))	('STAT3', 'Gene', (46, 51))	('reduce', 'NegReg', (56, 62))	('knockout', 'Var', (34, 42))	('vIL-6', 'Gene', (102, 107))	('mice', 'Species', '10090', (92, 96))
172180	26646010	Inhibition of STAT3 activity with S3I-201 reduced the CEACAM1 message and protein levels in vIL-6-expressing endothelial cells.	('reduced', 'NegReg', (42, 49))	('vIL-6', 'Gene', '4961449', (92, 97))	('S3I-201', 'Var', (34, 41))	('CEACAM1', 'Gene', (54, 61))	('S3I-201', 'Chemical', 'MESH:C520337', (34, 41))	('vIL-6', 'Gene', (92, 97))
172187	26646010	In the presence of CEACAM1, vIL-6-expressing endothelial cells migrated rapidly, but knockdown of CEACAM1 abrogated the ability of these cells to migrate.	('vIL-6', 'Gene', (28, 33))	('migrated', 'CPA', (63, 71))	('vIL-6', 'Gene', '4961449', (28, 33))	('CEACAM1', 'Var', (98, 105))	('knockdown', 'Var', (85, 94))	('abrogated', 'NegReg', (106, 115))
172192	26646010	In the present study, we found that both KSHV latent and de novo infection of endothelial cells upregulated CEACAM1 expression compared to that in uninfected cells, and reactivation of PEL also resulted in increased CEACAM1 expression.	('expression', 'MPA', (116, 126))	('CEACAM1', 'Gene', (108, 115))	('increased', 'PosReg', (206, 215))	('reactivation', 'Var', (169, 181))	('KS', 'Phenotype', 'HP:0100726', (41, 43))	('KSHV', 'Gene', (41, 45))	('upregulated', 'PosReg', (96, 107))	('expression', 'MPA', (224, 234))	('PEL', 'Gene', (185, 188))	('PEL', 'Phenotype', 'HP:0030069', (185, 188))	('CEACAM1', 'Gene', (216, 223))	('KSHV', 'Species', '37296', (41, 45))
172201	26646010	Based on CEACAM1's established roles in angiogenesis, vascular remodeling, cell migration, and cancer metastasis, vIL-6-induced CEACAM1 may be a very important player in promoting KSHV-associated pathogenesis, particularly for endothelial-cell-derived KS.	('cancer metastasis', 'Disease', 'MESH:D009362', (95, 112))	('CEACAM1', 'Var', (128, 135))	('KS', 'Phenotype', 'HP:0100726', (180, 182))	('KSHV', 'Species', '37296', (180, 184))	('promoting', 'PosReg', (170, 179))	('KSHV-associated', 'Disease', (180, 195))	('vIL-6', 'Gene', (114, 119))	('KS', 'Phenotype', 'HP:0100726', (252, 254))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer metastasis', 'Disease', (95, 112))	('vIL-6', 'Gene', '4961449', (114, 119))
172235	26015695	Nonrandom chromosomal abnormalities, most commonly translocations are present in the majority of white cell neoplasms.	('translocations', 'Var', (51, 65))	('white cell neoplasms', 'Disease', (97, 117))	('present', 'Reg', (70, 77))	('neoplasm', 'Phenotype', 'HP:0002664', (108, 116))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (10, 35))	('chromosomal abnormalities', 'Disease', (10, 35))	('neoplasms', 'Phenotype', 'HP:0002664', (108, 117))	('white cell neoplasms', 'Disease', 'MESH:D056784', (97, 117))
172240	26015695	In addition, both Down syndrome (trisomy 21) and neurofibromatosis type 1 are associated with an increased incidence of childhood leukemia.	('Down syndrome', 'Disease', (18, 31))	('leukemia', 'Disease', (130, 138))	('leukemia', 'Phenotype', 'HP:0001909', (130, 138))	('leukemia', 'Disease', 'MESH:D007938', (130, 138))	('neurofibromatosis type 1', 'Gene', '4763', (49, 73))	('trisomy 21', 'Var', (33, 43))	('neurofibromatosis type 1', 'Gene', (49, 73))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (49, 66))
172282	26015695	Unlike most other lymphoid malignancies, chromosomal translocations are rare in CLL.	('chromosomal translocations', 'Var', (41, 67))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (18, 39))	('CLL', 'Disease', (80, 83))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (18, 39))	('lymphoid malignancies', 'Disease', (18, 39))
172287	26015695	Some 10-15% of patients develop autoantibodies directed against RBC or platelets that produce autoimmune hemolytic anemia or thrombocytopenia.	('RBC', 'Gene', (64, 67))	('patients', 'Species', '9606', (15, 23))	('thrombocytopenia', 'Disease', 'MESH:D013921', (125, 141))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (105, 121))	('autoimmune hemolytic anemia', 'Disease', 'MESH:D000744', (94, 121))	('autoimmune hemolytic anemia', 'Disease', (94, 121))	('autoantibodies', 'Var', (32, 46))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (125, 141))	('anemia', 'Phenotype', 'HP:0001903', (115, 121))	('autoimmune hemolytic anemia', 'Phenotype', 'HP:0001890', (94, 121))	('thrombocytopenia', 'Disease', (125, 141))	('produce', 'Reg', (86, 93))
172292	26015695	In up to 90% of follicular lymphomas, translocation seen in (14;18) that juxtaposes the IgH locus on chromosome 14 and the BCL2 locus on chromosome 18, which leads to overexpression of BCL2 protein.	('BCL2', 'Gene', (123, 127))	('IgH', 'Gene', '3492', (88, 91))	('BCL2', 'Gene', '596', (185, 189))	('translocation', 'Var', (38, 51))	('overexpression', 'PosReg', (167, 181))	('follicular lymphomas', 'Disease', 'MESH:D008224', (16, 36))	('lymphomas', 'Phenotype', 'HP:0002665', (27, 36))	('BCL2', 'Gene', (185, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (27, 35))	('follicular lymphomas', 'Disease', (16, 36))	('BCL2', 'Gene', '596', (123, 127))	('IgH', 'Gene', (88, 91))
172305	26015695	Tumor, lacking 3q27 rearrangements often have acquired mutations in BCL6 promoter sequences.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BCL6', 'Gene', '604', (68, 72))	('rearrangements', 'Var', (20, 34))	('mutations', 'Var', (55, 64))	('BCL6', 'Gene', (68, 72))	('3q27', 'Protein', (15, 19))
172306	26015695	Point mutations and possible DNA breakage in BCL6 regulatory regions produced by somatic hypermutation provide possible mechanisms for BCL6 dysregulation and translocation.	('BCL6', 'Gene', (45, 49))	('BCL6', 'Gene', (135, 139))	('BCL6', 'Gene', '604', (45, 49))	('Point mutations', 'Var', (0, 15))	('BCL6', 'Gene', '604', (135, 139))
172307	26015695	Normally, BCL6 expression is downregulated when B-cells leave the germinal center, but both 3q27 rearrangements and BCL6 promoter mutations cause persistent and dysregulated expression of unknown target genes.	('BCL6', 'Gene', (10, 14))	('cause', 'Reg', (140, 145))	('BCL6', 'Gene', '604', (116, 120))	('BCL6', 'Gene', '604', (10, 14))	('mutations', 'Var', (130, 139))	('dysregulated expression', 'MPA', (161, 184))	('rearrangements', 'Var', (97, 111))	('3q27', 'Gene', (92, 96))	('BCL6', 'Gene', (116, 120))
172312	26015695	In all cases, the tumor cells are infected with 38 KSHV/HHV8, which may play a role in the development of this tumor.	('play', 'Reg', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('38 KSHV/HHV8', 'Var', (48, 60))	('KSHV', 'Species', '37296', (51, 55))	('infected', 'Disease', 'MESH:D007239', (34, 42))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('infected', 'Disease', (34, 42))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('HHV8', 'Species', '37296', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
172330	26015695	All forms of BL are associated with translocations of the c-myc gene on chromosome 8.	('associated', 'Reg', (20, 30))	('BL', 'Phenotype', 'HP:0030080', (13, 15))	('c-myc', 'Gene', '4609', (58, 63))	('c-myc', 'Gene', (58, 63))	('translocations', 'Var', (36, 50))
172337	26015695	Most importantly, the chromosomal translocations characteristic of BL always result in the juxtaposition of the DNA coding sequences for c-myc with sequences from Ig genes termed enhancers.	('c-myc', 'Gene', '4609', (137, 142))	('c-myc', 'Gene', (137, 142))	('juxtaposition', 'MPA', (91, 104))	('chromosomal', 'Var', (22, 33))	('result in', 'Reg', (77, 86))	('BL', 'Phenotype', 'HP:0030080', (67, 69))
172339	26015695	In addition, negative regulatory sequences residing within c-myc are often removed as a direct consequence of chromosomal 42 translocation or are mutated through other mechanisms, further contributing to increased c-myc activity.	('negative', 'NegReg', (13, 21))	('c-myc', 'Gene', '4609', (59, 64))	('c-myc', 'Gene', (59, 64))	('mutated', 'Var', (146, 153))	('increased', 'PosReg', (204, 213))	('chromosomal 42 translocation', 'Var', (110, 138))	('c-myc', 'Gene', '4609', (214, 219))	('c-myc', 'Gene', (214, 219))
172366	26015695	The most frequent karyotypic abnormalities are deletions of 13q and translocations involving the Ig heavy-chain locus on 14q32.	('inv', 'Gene', '27130', (83, 86))	('inv', 'Gene', (83, 86))	('deletions', 'Var', (47, 56))	('translocations', 'CPA', (68, 82))	('13q', 'Gene', (60, 63))
172390	26015695	MGUS cells often contain the same chromosomal translocations that are found in full-blown multiple myeloma.	('multiple myeloma', 'Phenotype', 'HP:0006775', (90, 106))	('multiple myeloma', 'Disease', 'MESH:D009101', (90, 106))	('contain', 'Reg', (17, 24))	('multiple myeloma', 'Disease', (90, 106))	('chromosomal translocations', 'Var', (34, 60))
172396	26015695	Acute myeloid leukemia (AML) with recurrent genetic abnormalities Acute myeloid leukemia with t (8;21)(q22;q22), (AML1/ETO) Acute myeloid leukemia with abnormal bone marrow eosinophils and inv (16)(p13q22) or t (16;16)(p13;q22), (CBFbeta/MYH11) Acute promyelocytic leukemia with t (15;17)(q22;q12), (PML/RARalpha) and variants Acute myeloid leukemia with 11q23 (MLL) abnormalities.	('AML', 'Disease', (114, 117))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (0, 22))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (333, 349))	('AML', 'Phenotype', 'HP:0004808', (114, 117))	('RARalpha', 'Gene', '5914', (304, 312))	('abnormal bone marrow eosinophils', 'Disease', 'MESH:D004802', (152, 184))	('abnormal bone marrow eosinophils', 'Disease', (152, 184))	('PML', 'Gene', '5371', (300, 303))	('leukemia', 'Phenotype', 'HP:0001909', (341, 349))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (72, 88))	('abnormal bone marrow', 'Phenotype', 'HP:0005561', (152, 172))	('ETO', 'Gene', '862', (119, 122))	('CBFbeta', 'Gene', '865', (230, 237))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (251, 273))	('MYH11', 'Gene', '4629', (238, 243))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (6, 22))	('leukemia', 'Phenotype', 'HP:0001909', (14, 22))	('AML1', 'Gene', '861', (114, 118))	('RARalpha', 'Gene', (304, 312))	('AML', 'Disease', 'MESH:D015470', (24, 27))	('inv', 'Gene', (189, 192))	('MYH11', 'Gene', (238, 243))	('AML', 'Phenotype', 'HP:0004808', (24, 27))	('AML', 'Disease', (24, 27))	('Acute myeloid leukemia', 'Disease', (124, 146))	('CBFbeta', 'Gene', (230, 237))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (124, 146))	('Acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (245, 273))	('leukemia', 'Phenotype', 'HP:0001909', (265, 273))	('RA', 'Phenotype', 'HP:0005505', (304, 306))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('ETO', 'Gene', (119, 122))	('MLL', 'Gene', (362, 365))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (124, 146))	('MLL', 'Gene', '4297', (362, 365))	('inv', 'Gene', '27130', (189, 192))	('PML', 'Gene', (300, 303))	('t (15;17)(q22;q12', 'Var', (279, 296))	('genetic abnormalities', 'Disease', 'MESH:D030342', (44, 65))	('Acute myeloid leukemia', 'Disease', (66, 88))	('AML1', 'Gene', (114, 118))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (66, 88))	('Acute myeloid leukemia', 'Disease', (327, 349))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (327, 349))	('promyelocytic leukemia', 'Disease', (251, 273))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (130, 146))	('genetic abnormalities', 'Disease', (44, 65))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (66, 88))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (327, 349))	('Acute myeloid leukemia', 'Disease', (0, 22))	('AML', 'Disease', 'MESH:D015470', (114, 117))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (0, 22))
172403	26015695	AML arising de novo in patients with no risk factors are often associated with balanced chromosomal translocations, particularly t (8;21) and t (15;17).	('patients', 'Species', '9606', (23, 31))	('associated', 'Reg', (63, 73))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('t (15;17', 'Var', (142, 150))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('AML', 'Disease', (0, 3))	('t (8;21', 'Var', (129, 136))
172404	26015695	In contrast, AMLs following myelodysplastic syndromes or exposure to DNA-damaging agents, such as chemotherapy or radiation therapy, are commonly associated with deletions or monosomies involving chromosomes 5 and 7 and usually lack 76 chromosomal translocations.	('inv', 'Gene', (186, 189))	('inv', 'Gene', '27130', (186, 189))	('monosomies', 'Var', (175, 185))	('AMLs following myelodysplastic syndromes', 'Disease', (13, 53))	('deletions', 'Var', (162, 171))	('associated', 'Reg', (146, 156))	('AML', 'Phenotype', 'HP:0004808', (13, 16))	('AMLs following myelodysplastic syndromes', 'Disease', 'MESH:D009190', (13, 53))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (28, 53))
172419	26015695	This results in translocation involving the BCR gene on chromosome 9and the ABL gene on chromosome 22.	('ABL', 'Gene', '25', (76, 79))	('ABL', 'Gene', (76, 79))	('inv', 'Gene', (30, 33))	('results in', 'Reg', (5, 15))	('BCR', 'Gene', (44, 47))	('inv', 'Gene', '27130', (30, 33))	('BCR', 'Gene', '613', (44, 47))	('translocation', 'Var', (16, 29))	('BL', 'Phenotype', 'HP:0030080', (77, 79))
172496	23525758	In addition, multiple clinical trials have started to evaluate the safety and efficacy of selected IGF-1R inhibitors, in combination with standard chemotherapeutic regimens or other targeted agents in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('patients', 'Species', '9606', (208, 216))	('cancer', 'Disease', (201, 207))	('IGF-1R', 'Gene', '3480', (99, 105))	('IGF-1R', 'Gene', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('inhibitors', 'Var', (106, 116))
172512	23525758	Phosphorylation of the IRS adapter molecules on one hand triggers activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, whereas, on the other hand, the Shc adapter activates signaling by the Ras/Raf/MEK/Erk signaling pathway (Figure 1).	('Shc', 'Gene', '6464', (172, 175))	('Erk', 'Gene', (223, 226))	('Raf', 'Gene', (215, 218))	('activates', 'PosReg', (184, 193))	('Akt', 'Gene', (117, 120))	('Phosphorylation', 'Var', (0, 15))	('MEK', 'Gene', (219, 222))	('MEK', 'Gene', '5609', (219, 222))	('Erk', 'Gene', '2048', (223, 226))	('Raf', 'Gene', '22882', (215, 218))	('phosphoinositide 3-kinase', 'Gene', '5290', (84, 109))	('Shc', 'Gene', (172, 175))	('IRS', 'Gene', '3376', (23, 26))	('Akt', 'Gene', '207', (117, 120))	('signaling', 'MPA', (194, 203))	('phosphoinositide 3-kinase', 'Gene', (84, 109))	('IRS', 'Gene', (23, 26))
172516	23525758	While no recurrent cancer-specific mutations of the IGF-1R or its ligands have been described to date, a plethora of studies have provided evidence for a link between this signaling pathway and the risk of developing cancer.	('plethora', 'Phenotype', 'HP:0001050', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', (217, 223))	('link', 'Reg', (154, 158))	('IGF-1R', 'Gene', '3480', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('IGF-1R', 'Gene', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('mutations', 'Var', (35, 44))
172517	23525758	The most common findings associated with deregulated IGF signaling are over-expression of the IGF-1R or the establishment of autocrine or paracrine signaling loops.	('IGF-1R', 'Gene', '3480', (94, 100))	('IGF-1R', 'Gene', (94, 100))	('IGF signaling', 'MPA', (53, 66))	('establishment', 'Reg', (108, 121))	('deregulated', 'Var', (41, 52))	('autocrine or paracrine signaling loops', 'MPA', (125, 163))	('over-expression', 'PosReg', (71, 86))
172523	23525758	The most significant correlation between increased levels of IGF-1 and the risk of cancer diagnosis was found for prostate cancer, pre-menopausal breast cancer, and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('increased levels of IGF-1', 'Phenotype', 'HP:0030269', (41, 66))	('cancer', 'Disease', (153, 159))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('levels', 'Var', (51, 57))	('IGF-1', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('prostate cancer', 'Disease', (114, 129))	('IGF-1', 'Gene', '3479', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (165, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('pre-menopausal breast cancer', 'Phenotype', 'HP:0008209', (131, 159))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('increased levels of IGF', 'Phenotype', 'HP:0003496', (41, 64))	('colorectal cancer', 'Disease', (165, 182))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('breast cancer', 'Disease', (146, 159))	('increased', 'PosReg', (41, 50))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', (83, 89))
172524	23525758	However, it should be noted that no significant overall associations were found between breast cancer and common germline variation in IGF1 and other genes involved in IGF-1 metabolism in a large, comprehensive study.	('variation', 'Var', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('IGF1', 'Gene', '3479', (135, 139))	('IGF-1', 'Gene', '3479', (168, 173))	('IGF-1', 'Gene', (168, 173))	('IGF1', 'Gene', (135, 139))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
172528	23525758	I will focus the discussion on the two approaches which are currently being evaluated in clinical trials: (A) neutralizing antibodies and (B) small molecule inhibitors of the IGF-1R tyrosine kinase activity.	('small molecule', 'Var', (142, 156))	('tyrosine', 'Chemical', 'MESH:D014443', (182, 190))	('IGF-1R', 'Gene', (175, 181))	('IGF-1R', 'Gene', '3480', (175, 181))
172530	23525758	A feature common to all anti-IGF-1R antibodies, probably more important than the blocking activity itself, is their ability to down-regulate of the IGF-1R overtime by promoting internalization of the receptor.	('IGF-1R', 'Gene', (148, 154))	('antibodies', 'Var', (36, 46))	('IGF-1R', 'Gene', (29, 35))	('IGF-1R', 'Gene', '3480', (148, 154))	('down-regulate', 'NegReg', (127, 140))	('internalization', 'MPA', (177, 192))	('promoting', 'PosReg', (167, 176))	('IGF-1R', 'Gene', '3480', (29, 35))
172533	23525758	Most IGF-1R antibodies which have been evaluated in clinical trials so far have proven to be well tolerated.	('antibodies', 'Var', (12, 22))	('IGF-1R', 'Gene', (5, 11))	('IGF-1R', 'Gene', '3480', (5, 11))
172565	23525758	Different studies reported on the enhanced efficacy of R-1507 in combination with chemotherapy or other targeted agents in several tumors.	('R-1507', 'Var', (55, 61))	('enhanced', 'PosReg', (34, 42))	('efficacy', 'MPA', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('R-1507', 'Chemical', 'MESH:C551399', (55, 61))
172567	23525758	In a phase II study in patients with recurrent or refractory Ewing's sarcoma, R-1507 induced partial/complete responses in only a subgroup of patients.	('patients', 'Species', '9606', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('R-1507', 'Chemical', 'MESH:C551399', (78, 84))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (61, 76))	('R-1507', 'Var', (78, 84))	("Ewing's sarcoma", 'Disease', (61, 76))	('patients', 'Species', '9606', (142, 150))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (61, 76))
172570	23525758	Several clinical trials evaluating R-1507, as single agent or in combination with other drugs, are ongoing in patients with various types of solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('R-1507', 'Var', (35, 41))	('solid tumors', 'Disease', 'MESH:D009369', (141, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('solid tumors', 'Disease', (141, 153))	('R-1507', 'Chemical', 'MESH:C551399', (35, 41))	('patients', 'Species', '9606', (110, 118))
172584	23525758	NVP-ADW742 and NVP-AEW541 (Novartis) are small molecular weight kinase inhibitors of the IGF-1R, which are specific for the IGF-1R at the cellular level.	('IGF-1R', 'Gene', '3480', (124, 130))	('IGF-1R', 'Gene', (124, 130))	('NVP-ADW742', 'Var', (0, 10))	('IGF-1R', 'Gene', '3480', (89, 95))	('IGF-1R', 'Gene', (89, 95))	('NVP-AEW541', 'Var', (15, 25))
172585	23525758	NVP-ADW742 and NVP-AEW541 have been extensively used in pre-clinical studies in a broad range of human cancer models.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('NVP-ADW742', 'Var', (0, 10))	('human', 'Species', '9606', (97, 102))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('NVP-AEW541', 'Var', (15, 25))
172588	23525758	In atypical teratoid/rhabdoid tumor cells of the central nervous system, NVP-AEW541 was shown to inhibit cell proliferation and survival by blocking IGF-1R and IR activation by autocrine loops involving IGFs and insulin.	('blocking', 'NegReg', (140, 148))	('IGF-1R', 'Gene', '3480', (149, 155))	('inhibit', 'NegReg', (97, 104))	('IR', 'Gene', '3643', (160, 162))	('IGF-1R', 'Gene', (149, 155))	('autocrine loops', 'MPA', (177, 192))	('insulin', 'Gene', (212, 219))	('IGFs', 'Protein', (203, 207))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (21, 35))	('rhabdoid tumor', 'Disease', (21, 35))	('insulin', 'Gene', '3630', (212, 219))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('survival', 'CPA', (128, 136))	('tumor cells of the central nervous system', 'Phenotype', 'HP:0100006', (30, 71))	('cell proliferation', 'CPA', (105, 123))	('NVP-AEW541', 'Var', (73, 83))
172595	23525758	In human tumor cells co-expressing IGF-1R and IR, it was reported that co-targeting IGF-1R and IR with OSI-906 provides superior anti-tumor efficacy compared with targeting IGF-1R alone using a neutralizing antibody.	('co-targeting', 'Var', (71, 83))	('IGF-1R', 'Gene', '3480', (173, 179))	('IGF-1R', 'Gene', '3480', (84, 90))	('IR', 'Gene', '3643', (46, 48))	('IR', 'Gene', '3643', (95, 97))	('human', 'Species', '9606', (3, 8))	('IGF-1R', 'Gene', (173, 179))	('IGF-1R', 'Gene', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('OSI-906', 'Chemical', 'MESH:C551528', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('IGF-1R', 'Gene', '3480', (35, 41))	('tumor', 'Disease', (134, 139))	('IGF-1R', 'Gene', (35, 41))
172597	23525758	Baseline gene expression data from cell lines and xenografts, in combination with IGF-1R detection by in situ hybridization and KRAS mutational status, was able to accurately predict OSI-906 sensitivity.	('predict', 'Reg', (175, 182))	('KRAS', 'Gene', (128, 132))	('IGF-1R', 'Gene', (82, 88))	('KRAS', 'Gene', '3845', (128, 132))	('IGF-1R', 'Gene', '3480', (82, 88))	('OSI-906', 'Chemical', 'MESH:C551528', (183, 190))	('mutational', 'Var', (133, 143))
172600	23525758	The IGF-1R antibodies appear to have a favorable safety profile and have been demonstrated to reduce IGF-1R signaling in patients.	('reduce IGF-1R', 'Phenotype', 'HP:0030269', (94, 107))	('IGF-1R', 'Gene', '3480', (101, 107))	('IGF-1R', 'Gene', (101, 107))	('antibodies', 'Var', (11, 21))	('reduce', 'NegReg', (94, 100))	('IGF-1R', 'Gene', '3480', (4, 10))	('patients', 'Species', '9606', (121, 129))	('IGF-1R', 'Gene', (4, 10))
172602	23525758	There have been several cases of responses in phase I and II trials with anti-IGF-1R antibodies, but these agents will most likely not be useful in unselected patient populations.	('antibodies', 'Var', (85, 95))	('IGF-1R', 'Gene', '3480', (78, 84))	('patient', 'Species', '9606', (159, 166))	('IGF-1R', 'Gene', (78, 84))
172615	33363930	Blood count revealed neutrophilia (30 000 elements/mm3).	('30 000', 'Var', (35, 41))	('neutrophilia', 'Phenotype', 'HP:0011897', (21, 33))	('neutrophilia', 'Disease', (21, 33))	('neutrophilia', 'Disease', 'MESH:C563010', (21, 33))
172697	30825757	Omitting "unplanned excision" as a complication, the odds of complications after the initial excision and in total (combined first excisions and re-excisions) were greater for patients with MRI and biopsy and MRI alone compared to patients with unplanned excision in the IPTW multivariate (p<0.05, Table 2) and unadjusted models.	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (231, 239))	('complications', 'Disease', (61, 74))	('IPTW', 'Chemical', '-', (271, 275))	('MRI', 'Var', (190, 193))
172706	30825757	When analyzing costs, actual and standardized total Medicare payments were greater for planned excisions compared to unplanned excisions in the unadjusted and multivariate IPTW analyses (p<0.05, Table A1, Supplement).	('planned excisions', 'Var', (87, 104))	('IPTW', 'Chemical', '-', (172, 176))	('greater', 'PosReg', (75, 82))
172711	30825757	Although our a priori hypothesis was that preoperative MRI and biopsy would improve DSS and OS by permitting optimal surgical planning leading to a reduction in positive margins, fewer operations, and better compliance with multimodality care, we did not observe such findings.	('reduction', 'NegReg', (148, 157))	('MRI', 'Var', (55, 58))	('DSS', 'Chemical', '-', (84, 87))	('DSS', 'Disease', (84, 87))	('positive margins', 'MPA', (161, 177))	('improve', 'PosReg', (76, 83))
172788	29334791	Furthermore, simultaneous injection of ABY-029, PpIX, and low-molecular-weight IRDye 680RD-CX (LI-COR Biosciences, Inc) showed that for EGFR-positive tumors, ABY-029 had higher tumor contrast than PpIX or perfusion dye (IRDye 680RD-CX) and that combining ABY-029 and PpIX information provided better discrimination between tumor and normal brain than either alone.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('COR', 'Gene', (98, 101))	('tumors', 'Disease', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('ABY-029', 'Var', (158, 165))	('tumor', 'Disease', (177, 182))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('PpIX', 'Chemical', 'MESH:C028025', (48, 52))	('EGFR-positive', 'Gene', (136, 149))	('tumor', 'Disease', (150, 155))	('COR', 'Gene', '108031', (98, 101))	('higher', 'PosReg', (170, 176))	('tumor', 'Disease', (323, 328))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('PpIX', 'Chemical', 'MESH:C028025', (197, 201))	('PpIX', 'Chemical', 'MESH:C028025', (267, 271))	('tumor', 'Disease', 'MESH:D009369', (323, 328))
172843	29334791	In the experimental mice, there were no differences observed between ABY-029 and IRDye 700DX carboxylate for each imaging system, time point, and tissue type, indicating that ABY-029 binding to native EGFR in these naive tissues was not contributing to the accumulation or retention of the targeted agent.	('ABY-029', 'Var', (175, 182))	('binding', 'Interaction', (183, 190))	('mice', 'Species', '10090', (20, 24))	('700DX carboxylate', 'Chemical', '-', (87, 104))
172900	27729091	The latency to RIOSM was significantly shorter for patients who received a radiation dose >68 Gy than for those who received <=68 Gy (median 13.6 vs. 8.0 years, P = 0.005).	('latency', 'MPA', (4, 11))	('>68', 'Var', (90, 93))	('shorter', 'NegReg', (39, 46))	('patients', 'Species', '9606', (51, 59))
172927	27729091	Moreover, many uncertainties can affect the calculation of radiation dose, such as scatter dose; a previous study pointed out that a high scatter dose would cause scattering low dose ratio, which induced malignancies.	('malignancies', 'Disease', (204, 216))	('scatter', 'MPA', (138, 145))	('high', 'Var', (133, 137))	('induced', 'Reg', (196, 203))	('low dose ratio', 'MPA', (174, 188))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))
172929	27729091	Some researchers have suggested that medium-to-low-dose radiation may induce carcinogenesis more effectively than high-dose radiation.	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('carcinogenesis', 'Disease', (77, 91))	('medium-to-low-dose radiation', 'Var', (37, 65))	('induce', 'Reg', (70, 76))
172931	27729091	We made two speculations: first, whether IMRT indeed increases the occurrence rate of secondary malignancies; and second, whether IMRT did not increase the risk of secondary cancer.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('malignancies', 'Disease', (96, 108))	('cancer', 'Disease', (174, 180))	('IMRT', 'Var', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('increases', 'PosReg', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
172941	27729091	RISOM results in worse outcomes compared with stage-matched osteogenic sarcomas of the jaw.	('osteogenic sarcomas', 'Phenotype', 'HP:0002669', (60, 79))	('osteogenic sarcomas of the jaw', 'Disease', 'MESH:D012516', (60, 90))	('RISOM', 'Var', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('osteogenic sarcomas of the jaw', 'Disease', (60, 90))
172943	27729091	This study clearly indicates that the prognosis of patients with RIOS in the maxilla and mandible is poorer than patients with primary osteosarcoma of the maxilla and mandible.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('RIOS', 'Var', (65, 69))	('patients', 'Species', '9606', (113, 121))	('osteosarcoma of the maxilla', 'Disease', (135, 162))	('osteosarcoma of the maxilla', 'Disease', 'MESH:D012516', (135, 162))	('patients', 'Species', '9606', (51, 59))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('mandible is poorer', 'Phenotype', 'HP:0000347', (89, 107))
173117	33026169	Lingual alveolar soft part sarcoma with absent TFE3 rearrangement Lingual ASPS is extremely rare and aggressive tumor.	('sarcoma', 'Disease', (27, 34))	('absent', 'Var', (40, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (8, 34))	('ASPS', 'Phenotype', 'HP:0012218', (74, 78))	('TFE3', 'Gene', (47, 51))	('ASPS', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('aggressive tumor', 'Disease', 'MESH:D001523', (101, 117))	('TFE3', 'Gene', '7030', (47, 51))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (17, 34))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('aggressive tumor', 'Disease', (101, 117))	('ASPS', 'Gene', '79058', (74, 78))
173118	33026169	rearrangement is typically detected in ASPS patients using FISH analysis.	('rearrangement', 'Var', (0, 13))	('patients', 'Species', '9606', (44, 52))	('ASPS', 'Phenotype', 'HP:0012218', (39, 43))	('ASPS', 'Gene', (39, 43))	('ASPS', 'Gene', '79058', (39, 43))
173166	33026169	6   Recently, it was proposed that the unbalanced translocation, del (17) t(X,17) (p11,p25), which results in the formation of ASPL-TFE3 transcript fusion detected on tumor cell, could specifically explain the tumorigenesis of ASPS.	('explain', 'Reg', (198, 205))	('p25', 'Gene', (87, 90))	('p25', 'Gene', '11076', (87, 90))	('p11', 'Gene', '6281', (83, 86))	('del (17) t(X,17', 'Var', (65, 80))	('tumor', 'Disease', (210, 215))	('ASPL', 'Gene', (127, 131))	('p11', 'Gene', (83, 86))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('ASPS', 'Gene', (227, 231))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('TFE3', 'Gene', (132, 136))	('ASPL', 'Gene', '79058', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('TFE3', 'Gene', '7030', (132, 136))	('ASPS', 'Gene', '79058', (227, 231))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ASPS', 'Phenotype', 'HP:0012218', (227, 231))
173171	33026169	Also, a discordance between molecular and immunohistochemistry findings was reported in certain neoplasm in term of TFE3 rearrangement.	('neoplasm', 'Disease', 'MESH:D009369', (96, 104))	('neoplasm', 'Phenotype', 'HP:0002664', (96, 104))	('TFE3', 'Gene', (116, 120))	('rearrangement', 'Var', (121, 134))	('TFE3', 'Gene', '7030', (116, 120))	('neoplasm', 'Disease', (96, 104))
173185	33026169	Although molecular methods provide a great support to the diagnosis of ASPS, the absence of TFE3 fusion gene does not always rule out ASPS.	('ASPS', 'Gene', '79058', (71, 75))	('ASPS', 'Gene', '79058', (134, 138))	('TFE3', 'Gene', (92, 96))	('absence', 'Var', (81, 88))	('ASPS', 'Phenotype', 'HP:0012218', (71, 75))	('ASPS', 'Phenotype', 'HP:0012218', (134, 138))	('ASPS', 'Gene', (71, 75))	('TFE3', 'Gene', '7030', (92, 96))	('ASPS', 'Gene', (134, 138))
173208	33435917	Recent study indicated that several autophagy-related genes (ARGs) affect the activation of autophagy and the mutation of ARGs play an important role in the pathogenesis of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('role', 'Reg', (145, 149))	('affect', 'Reg', (67, 73))	('ARGs', 'Gene', (122, 126))	('activation', 'PosReg', (78, 88))	('mutation', 'Var', (110, 118))	('autophagy', 'CPA', (92, 101))	('ARGs', 'Chemical', '-', (122, 126))	('ARGs', 'Chemical', '-', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))
173217	33435917	Meanwhile, for independent cohorts, including GSE2719, GSE21122, GSE30929, and TARGET-OS, were included as validation cohorts.	('GSE2719', 'Chemical', '-', (46, 53))	('GSE30929', 'Var', (65, 73))	('GSE21122', 'Var', (55, 63))	('ARG', 'Gene', '27', (80, 83))	('GSE2719', 'Var', (46, 53))	('ARG', 'Gene', (80, 83))
173218	33435917	The first two cohorts were used to validate the diagnostic value of ARGs for sarcoma, while the remaining cohorts were used to validate the prognostic value of ARGs for sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (169, 176))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('ARGs', 'Var', (68, 72))	('ARGs', 'Chemical', '-', (160, 164))	('sarcoma', 'Disease', (169, 176))	('ARGs', 'Chemical', '-', (68, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
173241	33435917	The risk score of patients in TARGET-OS were calculated by the OS signature, whereas the risk score of patients in GSE30929 were calculated by the DFS signature.	('ARG', 'Gene', '27', (31, 34))	('ARG', 'Gene', (31, 34))	('patients', 'Species', '9606', (18, 26))	('GSE30929', 'Var', (115, 123))	('patients', 'Species', '9606', (103, 111))
173252	33435917	Generally, both GO and KEGG analyses showed these 84 DEARGs were significantly associated with autophagy and malignance.	('malignance', 'CPA', (109, 119))	('ARGs', 'Chemical', '-', (55, 59))	('associated', 'Reg', (79, 89))	('DEARGs', 'Var', (53, 59))	('autophagy', 'CPA', (95, 104))
173258	33435917	Interestingly, seven genes were successfully validated in both GSE2719 and GSE21122 cohorts and BIRC5 has highest AUC values in in both cohorts.	('GSE2719', 'Chemical', '-', (63, 70))	('BIRC5', 'Gene', '332', (96, 101))	('BIRC5', 'Gene', (96, 101))	('GSE2719', 'Var', (63, 70))
173294	33435917	reported that survivin and its downstream target Bcl-2 were suppressed by Panobinostat in osteosarcoma cells, which provide new perspectives for the therapy of osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('Bcl-2', 'Gene', (49, 54))	('Bcl-2', 'Gene', '596', (49, 54))	('suppressed', 'NegReg', (60, 70))	('Panobinostat', 'Var', (74, 86))	('survivin', 'Gene', (14, 22))	('osteosarcoma', 'Disease', (90, 102))	('osteosarcoma', 'Disease', 'MESH:D012516', (160, 172))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (160, 172))	('osteosarcoma', 'Disease', (160, 172))	('survivin', 'Gene', '11799', (14, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))
173296	33435917	found that high expression of FOXO1 induces cell death in Ewing's sarcoma through WS-FLI1 inhibitory signals.	("Ewing's sarcoma", 'Disease', (58, 73))	('FLI1', 'Gene', '2313', (85, 89))	('cell death', 'CPA', (44, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (58, 73))	('FOXO1', 'Gene', (30, 35))	('FOXO1', 'Gene', '2308', (30, 35))	('high expression', 'Var', (11, 26))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (58, 73))	('FLI1', 'Gene', (85, 89))
173297	33435917	In addition to sarcomas, high expression of APOL1 can induce autophagy and autophagy-related cell death, which may be the key to maintaining cell homeostasis in the kidney.	('autophagy-related cell death', 'CPA', (75, 103))	('APOL1', 'Gene', '8542', (44, 49))	('high expression', 'Var', (25, 40))	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('APOL1', 'Gene', (44, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('sarcomas', 'Disease', (15, 23))	('autophagy', 'CPA', (61, 70))	('induce', 'PosReg', (54, 60))
173300	33435917	Silence of EIF4EBP1 can significantly inhibit the proliferation of breast cancer cells by promoting G1 cell cycle arrest.	('EIF4EBP1', 'Gene', '1978', (11, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('arrest', 'Disease', 'MESH:D006323', (114, 120))	('proliferation', 'CPA', (50, 63))	('promoting', 'PosReg', (90, 99))	('arrest', 'Disease', (114, 120))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('breast cancer', 'Disease', (67, 80))	('EIF4EBP1', 'Gene', (11, 19))	('inhibit', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Silence', 'Var', (0, 7))
173319	30655021	Abnormal BMI was associated with worse overall survival (OS) in Ewing sarcoma (hazard ratio (HR): 3.46, P = 0.022), osteosarcoma (HR: 1.6, P<0.005), and a trend towards poorer OS in rhabdomyosarcoma (HR: 1.70, P = 0.0596).	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (182, 198))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (64, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('overall survival', 'MPA', (39, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (182, 198))	('Abnormal', 'Var', (0, 8))	('worse', 'NegReg', (33, 38))	('rhabdomyosarcoma', 'Disease', (182, 198))	('BMI', 'Gene', (9, 12))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (64, 77))	('Abnormal BMI', 'Phenotype', 'HP:0045081', (0, 12))	('Ewing sarcoma', 'Disease', (64, 77))	('osteosarcoma', 'Disease', (116, 128))
173320	30655021	High BMI in osteosarcoma was associated with increased nephrotoxicity (odds ratio: 2.8, P = 0.01) and post-operative complications.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('nephrotoxicity', 'Disease', (55, 69))	('increased', 'PosReg', (45, 54))	('nephrotoxicity', 'Disease', 'MESH:D007674', (55, 69))	('osteosarcoma', 'Disease', (12, 24))	('osteosarcoma', 'Phenotype', 'HP:0002669', (12, 24))	('osteosarcoma', 'Disease', 'MESH:D012516', (12, 24))	('High BMI', 'Var', (0, 8))
173326	30655021	Nutritional status has been linked to diminished tolerance to chemotherapy, treatment delays, increased rates of infection, impaired prognosis, and poorer quality of life.	('infection', 'Disease', (113, 122))	('increased rates of infection', 'Phenotype', 'HP:0002719', (94, 122))	('infection', 'Disease', 'MESH:D007239', (113, 122))	('Nutritional', 'Var', (0, 11))	('increased', 'PosReg', (94, 103))	('diminished', 'NegReg', (38, 48))	('rates', 'MPA', (104, 109))	('tolerance to chemotherapy', 'CPA', (49, 74))
173328	30655021	In a meta-analysis exploring this association in pediatric leukemia, high BMI was associated with 56% increased risk of mortality.	('pediatric leukemia', 'Disease', 'MESH:D063766', (49, 67))	('high BMI', 'Var', (69, 77))	('pediatric leukemia', 'Disease', (49, 67))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))
173350	30655021	In a third study, also of fair quality (N = 50), abnormal BMI (high and low collapsed into one category) was significantly associated with poor histologic response (tumor necrosis <90%) (OR: 4.33, 95% CI: 1.12-19.14, P = 0.034), as well as worse OS (HR: 2.76, 95% CI: 1.19-9.99, P = 0.022).	('abnormal BMI', 'Phenotype', 'HP:0045081', (49, 61))	('poor', 'NegReg', (139, 143))	('abnormal', 'Var', (49, 57))	('histologic response', 'CPA', (144, 163))	('tumor necrosis', 'Disease', (165, 179))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('BMI', 'MPA', (58, 61))	('tumor necrosis', 'Disease', 'MESH:D009336', (165, 179))
173354	30655021	One study of good quality (N = 498) showed that in the post-operative period those with high BMI had significantly increased odds of developing arterial thrombosis (OR: 9.4, P = 0.03), while those with low BMI had a twofold increased risk of developing wound infection and slough (OR: 2.0, P = 0.07).	('infection', 'Disease', 'MESH:D007239', (259, 268))	('low BMI', 'Phenotype', 'HP:0045082', (202, 209))	('thrombosis', 'Disease', (153, 163))	('high BMI', 'Var', (88, 96))	('infection', 'Disease', (259, 268))	('thrombosis', 'Disease', 'MESH:D013927', (153, 163))	('slough', 'Disease', (273, 279))	('arterial thrombosis', 'Phenotype', 'HP:0004420', (144, 163))
173355	30655021	A fair quality study (N = 710) showed a significant association between high BMI and grade III-IV nephrotoxicity (OR: 2.8, P = 0.01).	('nephrotoxicity', 'Disease', 'MESH:D007674', (98, 112))	('high BMI', 'Var', (72, 80))	('nephrotoxicity', 'Disease', (98, 112))
173442	30050850	While this is especially true for cats treated with surgery alone, incomplete margins following multimodal treatment has also been associated with shorter DFI.	('cats', 'Species', '9685', (34, 38))	('DFI', 'Disease', (155, 158))	('incomplete margins', 'Var', (67, 85))
173515	29977483	Genetically, MIFS has been associated with a marker/ring chromosome 3 with 3p amplicons as well as with a characteristic translocation, t(1;10)(p22: q24) with rearrangements of TGFBR3 and MGEA5 on chromosomes 1p22 and 10q24.	('TGFBR3', 'Gene', '7049', (177, 183))	('t(1;10)(p22: q24', 'Var', (136, 152))	('associated', 'Reg', (27, 37))	('TGFBR3', 'Gene', (177, 183))	('MGEA5', 'Gene', '10724', (188, 193))	('rearrangements', 'Var', (159, 173))	('MGEA5', 'Gene', (188, 193))	('MIFS', 'Disease', (13, 17))
173517	29977483	documented consistent t(1;10) with TGFBR3 and MGEA5 gene rearrangements in both MIFS and HFLT, including all three hybrid MIFS/HFLT studied, suggesting that these might represent different clinical and morphologic spectra of the same biologic entity.	('MGEA5', 'Gene', (46, 51))	('TGFBR3', 'Gene', (35, 41))	('rearrangements', 'Var', (57, 71))	('TGFBR3', 'Gene', '7049', (35, 41))	('MGEA5', 'Gene', '10724', (46, 51))
173518	29977483	TGFBR3 and/or MGEA5 rearrangements have also been shown in 3/3 hybrid MIFS/HFLT by Carter et al.	('TGFBR3', 'Gene', (0, 6))	('rearrangements', 'Var', (20, 34))	('MGEA5', 'Gene', '10724', (14, 19))	('MIFS/HFLT', 'Disease', (70, 79))	('TGFBR3', 'Gene', '7049', (0, 6))	('shown', 'Reg', (50, 55))	('MGEA5', 'Gene', (14, 19))
173520	29977483	These authors therefore postulated that because TGFBR3 and MGEA5 rearrangements were more frequent in hybrid HFLT/MIFS than in classic MIFS, MIFS and HFLT may not be related, and that hybrid HFLT/MIFS could represent HFLTs showing progression to sarcomatous features rather than HFLT and MIFS indicating a single entity.	('hybrid HFLT/MIFS', 'Disease', (102, 118))	('sarcomatous', 'Disease', 'MESH:D018316', (246, 257))	('TGFBR3', 'Gene', (48, 54))	('rearrangements', 'Var', (65, 79))	('sarcomatous', 'Disease', (246, 257))	('TGFBR3', 'Gene', '7049', (48, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('MGEA5', 'Gene', '10724', (59, 64))	('MGEA5', 'Gene', (59, 64))	('frequent', 'Reg', (90, 98))
173558	29147349	A EWSR-1 gene rearrangement and BRAF V600E mutation were then sent to confirm ES/PNET and melanoma respectively.	('EWSR-1', 'Gene', (2, 8))	('melanoma', 'Disease', (90, 98))	('BRAF', 'Gene', '673', (32, 36))	('EWSR-1', 'Gene', '2130', (2, 8))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('ES', 'Chemical', 'MESH:D004540', (78, 80))	('BRAF', 'Gene', (32, 36))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('rearrangement', 'Var', (14, 27))	('confirm', 'Reg', (70, 77))	('ES/PNET', 'Disease', (78, 85))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
173583	29147349	Finally, the paper found that if multiple stains were used together, the overall specificity improved, namely S100 and nestin (specificity 100%, sensitivity 48%) for MPNST and CD99 and Fli-1 (specificity 96%, sensitivity 56%) for ES.	('Fli-1', 'Gene', (185, 190))	('S100', 'Var', (110, 114))	('Fli-1', 'Gene', '2313', (185, 190))	('CD99', 'Gene', '4267', (176, 180))	('improved', 'PosReg', (93, 101))	('ES', 'Chemical', 'MESH:D004540', (230, 232))	('MPNST', 'Phenotype', 'HP:0100697', (166, 171))	('nestin', 'Protein', (119, 125))	('CD99', 'Gene', (176, 180))	('MPNST', 'Disease', (166, 171))	('specificity', 'MPA', (81, 92))
173874	31356260	We acknowledge that there is a theoretical increase in the risk of scoliosis resulting from chest wall resection in younger patients who have greater growth potential and suggest that this issue requires further investigation.	('scoliosis', 'Disease', 'MESH:D012600', (67, 76))	('resection', 'Var', (103, 112))	('scoliosis', 'Phenotype', 'HP:0002650', (67, 76))	('scoliosis', 'Disease', (67, 76))	('patients', 'Species', '9606', (124, 132))
173877	31356260	In addition to number of ribs, another measure for further study may be the total area and dimensions of chest wall resected, as larger defects may have a greater impact on development of scoliosis than smaller defects even when the same number of ribs are resected.	('scoliosis', 'Disease', (188, 197))	('scoliosis', 'Disease', 'MESH:D012600', (188, 197))	('defects', 'Var', (136, 143))	('scoliosis', 'Phenotype', 'HP:0002650', (188, 197))	('impact', 'Reg', (163, 169))
173937	29723407	These antibodies can "release the brakes" on the immune system, which has the potential to unleash an anti-tumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('antibodies', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('unleash', 'Reg', (91, 98))
173948	29723407	Interestingly, the three sarcoma subtypes with high levels of copy number alterations (UPS, myxofibrosarcomas (MFS), and dedifferentiated liposarcomas) were found to have a similar immune microenvironment.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('sarcomas', 'Disease', 'MESH:D012509', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcoma', 'Disease', (142, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('sarcomas', 'Disease', (142, 150))	('liposarcomas', 'Disease', 'MESH:D008080', (138, 150))	('dedifferentiated liposarcoma', 'Disease', (121, 149))	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('sarcomas', 'Disease', 'MESH:D012509', (101, 109))	('sarcoma', 'Disease', (101, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('liposarcomas', 'Phenotype', 'HP:0012034', (138, 150))	('sarcomas', 'Disease', (101, 109))	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (121, 149))	('myxofibrosarcoma', 'Disease', 'None', (92, 108))	('liposarcoma', 'Phenotype', 'HP:0012034', (138, 149))	('copy number alterations', 'Var', (62, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('sarcoma', 'Disease', 'MESH:D012509', (25, 32))	('liposarcomas', 'Disease', (138, 150))	('sarcoma', 'Disease', (25, 32))	('UPS', 'Disease', 'MESH:D002277', (87, 90))	('UPS', 'Disease', (87, 90))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (96, 108))	('myxofibrosarcoma', 'Disease', (92, 108))
173950	29723407	Taken together, these studies suggest that STS, especially those with high frequency of copy number alterations such as UPS and MFS, may be capable of eliciting an immune response.	('MFS', 'Disease', (128, 131))	('copy number alterations', 'Var', (88, 111))	('eliciting', 'Reg', (151, 160))	('UPS', 'Disease', (120, 123))	('STS', 'Phenotype', 'HP:0030448', (43, 46))	('immune response', 'CPA', (164, 179))	('UPS', 'Disease', 'MESH:D002277', (120, 123))
173978	29723407	In this phase II multi-arm study, patients with previously treated soft tissue or bone sarcoma receive anti-PD-L1 (durvalumab) and anti-CTLA-4 (tremelimumab) therapy for four cycles, followed by durvalumab for 12 weeks.	('soft tissue', 'Disease', (67, 78))	('anti-PD-L1', 'Gene', (103, 113))	('bone sarcoma', 'Disease', 'MESH:D012509', (82, 94))	('bone sarcoma', 'Phenotype', 'HP:0002669', (82, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('patients', 'Species', '9606', (34, 42))	('bone sarcoma', 'Disease', (82, 94))	('anti-CTLA-4', 'Var', (131, 142))
174213	29736143	In multivariate analysis, Medicaid (hazard ratio (HR), 2.47; 95% confidence interval (CI), 1.62-3.77; p < 0.001) and Medicare (HR, 1.68; 95% CI, 1.10-2.57; p=0.017) were independently associated with worse OS.	('worse OS', 'Disease', (200, 208))	('OS', 'Chemical', '-', (206, 208))	('Medicare', 'Var', (117, 125))	('Medicaid', 'Var', (26, 34))
174229	29736143	We identified female patients 18 years and older who were diagnosed with histologically confirmed malignant breast sarcoma in 2004-2013 (International Classification of Diseases for Oncology-3 (ICD-O-3) site C50.0-50.9; ICD-O-3 histology 8800, 8801, 8802, 8810, 8830, 8831, 8850, 8851, 8852, 8854, 8890, 8894, 8930, 8940, 8990, 9120, 9130, 9180, 9220, and 9580).	('8854', 'Var', (292, 296))	('9130', 'Var', (334, 338))	('8930', 'Var', (310, 314))	('8940', 'Var', (316, 320))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('8890', 'Var', (298, 302))	('patients', 'Species', '9606', (21, 29))	('9120', 'Var', (328, 332))	('Oncology', 'Phenotype', 'HP:0002664', (182, 190))	('8852', 'Var', (286, 290))	('8894', 'Var', (304, 308))	('malignant breast sarcoma', 'Disease', (98, 122))	('malignant breast sarcoma', 'Disease', 'MESH:D001943', (98, 122))	('8990', 'Var', (322, 326))	('9180', 'Var', (340, 344))
174263	29736143	On univariate analysis, Medicaid and Medicare insurance were associated with increased hazard of death compared to private insurance (Table 4).	('death', 'Disease', 'MESH:D003643', (97, 102))	('death', 'Disease', (97, 102))	('Medicare insurance', 'Var', (37, 55))	('Medicaid', 'Var', (24, 32))
174291	29736143	Delays between diagnosis and treatment of breast cancer have been shown to be associated with inferior cancer outcomes.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('inferior cancer', 'Disease', 'MESH:D009369', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('Delays', 'Var', (0, 6))	('inferior cancer', 'Disease', (94, 109))
174309	29736143	This may suggest that the survival detriment associated with Medicare is related to the agedness and higher comorbidity of Medicare patients more than the healthcare access issues that might be worse with a rare cancer.	('survival', 'CPA', (26, 34))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('Medicare', 'Var', (61, 69))	('patients', 'Species', '9606', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
174344	26191531	As part of that study, we looked briefly at fibulin-2 binding partners using DMVEC cells, and found that both tropoelastin (25-fold) and fibronectin (5-fold) were decreased 10 days following addition of KSHV, relative to untreated controls.	('fibronectin', 'MPA', (137, 148))	('KSHV', 'Species', '37296', (203, 207))	('KSHV', 'Var', (203, 207))	('decreased', 'NegReg', (163, 172))	('fibulin-2', 'Gene', (44, 53))	('fibulin-2', 'Gene', '2199', (44, 53))	('tropoelastin', 'MPA', (110, 122))
174385	26191531	However at 5, 7 and 10 days post infection, there was a consistent decrease in tropoelastin mRNA expression in KSHV infected cells compared mock infected controls.	('decrease', 'NegReg', (67, 75))	('mRNA expression', 'MPA', (92, 107))	('KSHV', 'Species', '37296', (111, 115))	('KSHV', 'Var', (111, 115))	('infection', 'Disease', (33, 42))	('infection', 'Disease', 'MESH:D007239', (33, 42))	('tropoelastin', 'Gene', (79, 91))
174386	26191531	Over the same time frame, we observed a consistent increase in LANA transcription in KSHV infected cells compared to mock infected control cells (Figure 2b).	('increase', 'PosReg', (51, 59))	('KSHV', 'Species', '37296', (85, 89))	('infected', 'Var', (90, 98))	('LANA', 'Gene', (63, 67))	('KSHV infected', 'Var', (85, 98))	('LANA', 'Gene', '4961527', (63, 67))
174401	26191531	This study is a continuation of our previous studies that link dysregulation of yet another important ECM protein, namely tropoelastin, to viral replication and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('dysregulation', 'Var', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('viral replication', 'CPA', (139, 156))	('tumor', 'Disease', (161, 166))
174411	26191531	We observed consistent transcriptional downregulation of tropoelastin mRNA in 3 of 3 whole tumor biopsies all shown to express high levels of KSHV LANA compared biopsies of normal skin from uninfected animals (Figure 3).	('LANA', 'Gene', '4961527', (147, 151))	('KSHV', 'Species', '37296', (142, 146))	('LANA', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('KSHV', 'Var', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tropoelastin', 'Gene', (57, 69))	('tumor', 'Disease', (91, 96))	('downregulation', 'NegReg', (39, 53))	('mRNA', 'MPA', (70, 74))
174423	21753790	First are those sarcomas with near-diploid karyotypes and simple genetic alterations including translocations or specific activating mutations.	('sarcomas', 'Disease', (16, 24))	('activating', 'PosReg', (122, 132))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('translocations', 'Var', (95, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))
174429	21753790	Although well studied, the physiological roles of the individual genes in these fusions have seldom been directly linked to their respective sarcoma phenotypes, save perhaps for translocations of the myogenic transcription factor genes paired box 3 (PAX3) and PAX7 with forkhead box O1 (FOXO1) in alveolar rhabdomyosarcomas (ARMS; discussed below).	('FOXO1', 'Gene', (287, 292))	('ARMS', 'Phenotype', 'HP:0006779', (325, 329))	('sarcoma', 'Disease', (141, 148))	('sarcoma', 'Disease', 'MESH:D012509', (315, 322))	('alveolar rhabdomyosarcomas', 'Disease', (297, 323))	('sarcoma', 'Disease', (315, 322))	('PAX7', 'Gene', '5081', (260, 264))	('PAX7', 'Gene', (260, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (297, 323))	('paired box 3', 'Gene', (236, 248))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (306, 322))	('sarcoma', 'Phenotype', 'HP:0100242', (315, 322))	('forkhead box O1', 'Gene', '2308', (270, 285))	('sarcomas', 'Phenotype', 'HP:0100242', (315, 323))	('forkhead box O1', 'Gene', (270, 285))	('PAX3', 'Gene', (250, 254))	('AR', 'Gene', '367', (325, 327))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (297, 323))	('paired box 3', 'Gene', '5077', (236, 248))	('translocations', 'Var', (178, 192))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (306, 323))
174435	21753790	The mechanisms that drive human sarcomagenesis fall into three broad categories: transcriptional dysregulation owing to aberrant fusion proteins resulting from genomic rearrangements (FIG.	('aberrant', 'Var', (120, 128))	('transcriptional dysregulation', 'MPA', (81, 110))	('fall', 'Phenotype', 'HP:0002527', (47, 51))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('fusion proteins', 'Protein', (129, 144))	('sarcoma', 'Disease', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('human', 'Species', '9606', (26, 31))
174441	21753790	Finally, regarding external risk factors, sarcoma translocations, in particular the t(X;18) of synovial sarcoma, may be rarely related to radiotherapy-induced DNA damage.	('sarcoma', 'Disease', (42, 49))	('sarcoma', 'Disease', (104, 111))	('synovial sarcoma', 'Disease', (95, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('t(X;18', 'Var', (84, 90))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (95, 111))	('synovial sarcoma', 'Disease', 'MESH:D013584', (95, 111))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))
174450	21753790	As noted above, most recurrent tumor-type-specific translocations in sarcomas produce gene fusions that encode aberrant transcriptional proteins.	('translocations', 'Var', (51, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('gene fusions', 'Var', (86, 98))	('tumor', 'Disease', (31, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcomas', 'Disease', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('sarcomas', 'Disease', 'MESH:D012509', (69, 77))
174452	21753790	Likewise, general reviews of translocation-associated sarcomas, including comprehensive listings of recurrent gene fusions in sarcomas, have recently been published (FIG.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcomas', 'Disease', (126, 134))	('translocation-associated', 'Var', (29, 53))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))	('sarcomas', 'Disease', (54, 62))
174462	21753790	Intergenic germline variation or somatic mutations, while under-explored currently, could play an important role in sarcomagenesis.	('play', 'Reg', (90, 94))	('germline variation', 'Var', (11, 29))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('sarcoma', 'Disease', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
174463	21753790	This is typified by the MDM2SNP309 promoter polymorphism, which along with MDM2 amplification and TP53 deletion and mutation, represents another mechanism of aberrant p53 activity in a broad range of sarcomas.	('activity', 'MPA', (171, 179))	('mutation', 'Var', (116, 124))	('MDM2', 'Gene', '4193', (75, 79))	('sarcomas', 'Disease', 'MESH:D012509', (200, 208))	('MDM2', 'Gene', (75, 79))	('MDM2', 'Gene', '4193', (24, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('MDM2', 'Gene', (24, 28))	('p53', 'Gene', '7157', (167, 170))	('TP53', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (98, 102))	('p53', 'Gene', (167, 170))	('sarcomas', 'Disease', (200, 208))	('deletion', 'Var', (103, 111))
174472	21753790	Microsatellites containing 6 or more GGAA repeats (the core ETS domain binding sequence) are associated with EWS-FLI1 target gene upregulation.	('EWS-FLI1', 'Gene', (109, 117))	('EWS-FLI1', 'Gene', '2130;2313', (109, 117))	('upregulation', 'PosReg', (130, 142))	('GGAA', 'Protein', (37, 41))	('Microsatellites', 'Var', (0, 15))
174478	21753790	Genes found to be directly up-regulated by specific aberrant sarcoma fusion proteins can be subjected to focused RNA interference (RNAi)-based screens to identify the genes most essential to the sarcoma in question (see Target Discovery below).	('up-regulated', 'PosReg', (27, 39))	('sarcoma', 'Disease', (195, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('aberrant', 'Var', (52, 60))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('sarcoma', 'Disease', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
174483	21753790	Silencing EWS-FLI1 in Ewing sarcoma cell lines produces an expression profile most similar to mesenchymal stem cells (MSCs) or mesenchymal progenitor cells and these can subsequently be induced to differentiate along adipogenic or osteoblastic lineages.	('induced', 'Reg', (186, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('expression', 'Species', '29278', (59, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (22, 35))	('osteoblastic', 'Disease', 'None', (231, 243))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (22, 35))	('EWS-FLI1', 'Gene', (10, 18))	('osteoblastic', 'Disease', (231, 243))	('expression profile', 'MPA', (59, 77))	('Silencing', 'Var', (0, 9))	('Ewing sarcoma', 'Disease', (22, 35))	('EWS-FLI1', 'Gene', '2130;2313', (10, 18))
174485	21753790	In the converse experiment, EWS-FLI1 expression in human MSCs induces a Ewing sarcoma gene expression profile, especially clear in MSCs derived from younger individuals.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('expression', 'Var', (37, 47))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 85))	('EWS-FLI1', 'Gene', '2130;2313', (28, 36))	('induces', 'Reg', (62, 69))	('human', 'Species', '9606', (51, 56))	('Ewing sarcoma', 'Disease', (72, 85))	('expression', 'Species', '29278', (37, 47))	('EWS-FLI1', 'Gene', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('expression', 'Species', '29278', (91, 101))
174489	21753790	Synovial sarcomas contain fusions of the SS18 (also known as SYT) gene with either SSX1 or SSX2.	('SYT', 'Gene', '6760', (61, 64))	('fusions', 'Var', (26, 33))	('SSX2', 'Gene', '6757', (91, 95))	('SSX1', 'Gene', '6756', (83, 87))	('SS18', 'Gene', '6760', (41, 45))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('SYT', 'Gene', (61, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SSX2', 'Gene', (91, 95))	('sarcomas', 'Disease', (9, 17))	('SSX1', 'Gene', (83, 87))	('SS18', 'Gene', (41, 45))	('Synovial sarcomas', 'Phenotype', 'HP:0012570', (0, 17))
174490	21753790	In a striking analogy to the EWS-FLI1 data, synovial sarcoma cell lines also express POU5F1, SOX2 and NANOG, and silencing of SYT-SSX in these cell lines enhances their potential to differentiate along adipogenic, osteoblastic or chondrogenic lineages.	('SYT', 'Gene', '6760', (126, 129))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (44, 60))	('enhances', 'PosReg', (154, 162))	('chondrogenic lineages', 'CPA', (230, 251))	('EWS-FLI1', 'Gene', (29, 37))	('SSX', 'Gene', '6757', (130, 133))	('POU5F1', 'Gene', '5460', (85, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('osteoblastic', 'Disease', 'None', (214, 226))	('silencing', 'Var', (113, 122))	('EWS-FLI1', 'Gene', '2130;2313', (29, 37))	('SSX', 'Gene', (130, 133))	('SYT', 'Gene', (126, 129))	('osteoblastic', 'Disease', (214, 226))	('NANOG', 'Gene', '79923', (102, 107))	('synovial sarcoma', 'Disease', (44, 60))	('SOX2', 'Gene', (93, 97))	('SOX2', 'Gene', '6657', (93, 97))	('NANOG', 'Gene', (102, 107))	('POU5F1', 'Gene', (85, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (44, 60))
174495	21753790	GIST, one of the more common human sarcoma types, is characterized by oncogenic mutations in KIT, or less often in platelet-derived growth factor receptor-alpha (PDGFRA), or rarely in BRAF .	('platelet-derived growth factor receptor-alpha', 'Gene', (115, 160))	('KIT', 'Gene', (93, 96))	('BRAF', 'Gene', (184, 188))	('sarcoma', 'Disease', (35, 42))	('mutations', 'Var', (80, 89))	('PDGFRA', 'Gene', '5156', (162, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (115, 160))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('PDGFRA', 'Gene', (162, 168))	('human', 'Species', '9606', (29, 34))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('BRAF', 'Gene', '673', (184, 188))
174497	21753790	Nevertheless, oncogenic KIT mutations (in the activation domain; D816V in particular) are also found in tumors of diverse lineages including mastocytosis, acute myeloid leukemia, and germ cell tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('D816V', 'Var', (65, 70))	('cell tumors', 'Disease', 'MESH:D005935', (188, 199))	('D816V', 'Mutation', 'rs121913507', (65, 70))	('leukemia', 'Phenotype', 'HP:0001909', (169, 177))	('tumors', 'Disease', (104, 110))	('germ cell tumors', 'Phenotype', 'HP:0100728', (183, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('acute myeloid leukemia', 'Disease', (155, 177))	('mastocytosis', 'Phenotype', 'HP:0100495', (141, 153))	('found', 'Reg', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('mutations', 'Var', (28, 37))	('mastocytosis', 'Disease', (141, 153))	('KIT', 'Gene', (24, 27))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (155, 177))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (161, 177))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (155, 177))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('mastocytosis', 'Disease', 'MESH:D008415', (141, 153))	('cell tumors', 'Disease', (188, 199))
174498	21753790	Approximately 10% of adult GISTs lack a KIT or PDGFRA mutation, a small subset (<1% of total GIST cases) harbor BRAF-V600E mutations (Table 1).	('mutation', 'Var', (54, 62))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('GIST', 'Phenotype', 'HP:0100723', (27, 31))	('GIST', 'Phenotype', 'HP:0100723', (93, 97))	('KIT', 'Gene', (40, 43))	('PDGFRA', 'Gene', (47, 53))	('V600E', 'Mutation', 'rs113488022', (117, 122))	('PDGFRA', 'Gene', '5156', (47, 53))
174499	21753790	Most pediatric GISTs harbor no mutations in KIT, PDGFRA, or BRAF, although KIT pathway activity is high in pediatric cases and in adult cases lacking mutations.	('mutations', 'Var', (31, 40))	('activity', 'MPA', (87, 95))	('BRAF', 'Gene', (60, 64))	('PDGFRA', 'Gene', (49, 55))	('BRAF', 'Gene', '673', (60, 64))	('KIT pathway', 'Pathway', (75, 86))	('PDGFRA', 'Gene', '5156', (49, 55))	('KIT', 'Gene', (44, 47))	('GIST', 'Phenotype', 'HP:0100723', (15, 19))
174500	21753790	In total, approximately 10% of adult and most pediatric GISTs harbor no mutations in KIT, PDGFRA, or BRAF, although KIT pathway activity is high.	('BRAF', 'Gene', (101, 105))	('mutations', 'Var', (72, 81))	('PDGFRA', 'Gene', '5156', (90, 96))	('PDGFRA', 'Gene', (90, 96))	('KIT', 'Gene', (85, 88))	('BRAF', 'Gene', '673', (101, 105))	('GIST', 'Phenotype', 'HP:0100723', (56, 60))
174502	21753790	In fact, pediatric tumors have mostly diploid genomes with few if any DNA copy-number alterations.	('pediatric tumors', 'Disease', 'MESH:D063766', (9, 25))	('diploid genomes', 'Var', (38, 53))	('pediatric tumors', 'Disease', (9, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
174508	21753790	Sequencing of these five genes revealed KDR mutations in about 10% of cases of angiosarcoma.	('angiosarcoma', 'Disease', (79, 91))	('KDR', 'Gene', '3791', (40, 43))	('angiosarcoma', 'Phenotype', 'HP:0200058', (79, 91))	('revealed', 'Reg', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('mutations', 'Var', (44, 53))	('angiosarcoma', 'Disease', 'MESH:D006394', (79, 91))	('KDR', 'Gene', (40, 43))
174509	21753790	The VEGFR2 mutant proteins, when expressed in COS-7 cells, showed ligand-independent activation.	('VEGFR2', 'Gene', '3791', (4, 10))	('mutant', 'Var', (11, 17))	('proteins', 'Protein', (18, 26))	('VEGFR2', 'Gene', (4, 10))	('activation', 'PosReg', (85, 95))	('COS-7', 'CellLine', 'CVCL:0224', (46, 51))
174510	21753790	A recent large-scale analysis of the genomic landscape of sarcomas encompassing seven major subtypes (myxoid/round-cell, dedifferentiated, and pleomorphic liposarcomas; myxofibrosarcoma, leiomyosarcoma, GIST, and synovial sarcoma) identified frequent mutations in TP53 (which encodes p53), NF1, and PI3K catalytic subunit-alpha (PIK3CA).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (213, 229))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (187, 201))	('TP53', 'Gene', '7157', (264, 268))	('pleomorphic liposarcomas; myxofibrosarcoma', 'Disease', 'MESH:D008080', (143, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('liposarcomas', 'Phenotype', 'HP:0012034', (155, 167))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (187, 201))	('liposarcoma', 'Phenotype', 'HP:0012034', (155, 166))	('PIK3CA', 'Gene', (329, 335))	('NF1', 'Gene', '4763', (290, 293))	('p53', 'Gene', '7157', (284, 287))	('GIST', 'Phenotype', 'HP:0100723', (203, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('leiomyosarcoma', 'Disease', (187, 201))	('pleomorphic liposarcomas; myxofibrosarcoma', 'Disease', (143, 185))	('TP53', 'Gene', (264, 268))	('NF1', 'Gene', (290, 293))	('p53', 'Gene', (284, 287))	('synovial sarcoma', 'Disease', (213, 229))	('sarcomas', 'Disease', 'MESH:D012509', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcomas', 'Disease', 'MESH:D012509', (159, 167))	('synovial sarcoma', 'Disease', 'MESH:D013584', (213, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('mutations', 'Var', (251, 260))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('sarcomas', 'Disease', (58, 66))	('PIK3CA', 'Gene', '5290', (329, 335))	('sarcomas', 'Disease', (159, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))
174511	21753790	TP53 mutations were identified in 17% of pleomorphic liposarcomas, consistent with these mutations being frequent in sarcomas with complex karyotypes.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('liposarcomas', 'Phenotype', 'HP:0012034', (53, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('mutations', 'Var', (5, 14))	('sarcomas', 'Disease', (117, 125))	('pleomorphic liposarcomas', 'Disease', (41, 65))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('liposarcoma', 'Phenotype', 'HP:0012034', (53, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (41, 65))	('sarcomas', 'Disease', (57, 65))
174512	21753790	By contrast, in translocation-associated sarcomas secondary genetic alterations, such as TP53 mutations or homozygous deletions of cyclin-dependent kinase inhibitor 2A (CDKN2A), are less common but, when present, are associated with a highly aggressive clinical course.	('CDKN2A', 'Gene', (169, 175))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('associated with', 'Reg', (217, 232))	('mutations', 'Var', (94, 103))	('sarcomas', 'Disease', (41, 49))	('CDKN2A', 'Gene', '1029', (169, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('clinical', 'Species', '191496', (253, 261))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
174513	21753790	The discovery of PIK3CA mutations in 18% of myxoid/round-cell liposarcomas (Table 1) raises the possibility that secondary mutations may cooperate with the FUS-CHOP fusion protein in oncogenesis.	('FUS', 'Gene', (156, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('liposarcomas', 'Disease', (62, 74))	('FUS', 'Gene', '2521', (156, 159))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))	('PIK3CA', 'Gene', (17, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('PIK3CA', 'Gene', '5290', (17, 23))	('mutations', 'Var', (24, 33))	('liposarcomas', 'Disease', 'MESH:D008080', (62, 74))	('liposarcomas', 'Phenotype', 'HP:0012034', (62, 74))
174514	21753790	PIK3CA mutations clustered in the same two hot spots observed in epithelial tumors: the helical domain (E542K and E545K) and the kinase domain (H1047L and H1047R).	('H1047L', 'Var', (144, 150))	('E542K', 'Var', (104, 109))	('H1047R', 'Mutation', 'rs121913279', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('PIK3CA', 'Gene', (0, 6))	('epithelial tumors', 'Disease', (65, 82))	('E542K', 'Mutation', 'rs121913273', (104, 109))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('epithelial tumor', 'Phenotype', 'HP:0031492', (65, 81))	('E545K', 'Mutation', 'rs104886003', (114, 119))	('epithelial tumors', 'Disease', 'MESH:D002277', (65, 82))	('E545K', 'Var', (114, 119))	('H1047R', 'Var', (155, 161))	('H1047L', 'Mutation', 'rs121913279', (144, 150))
174515	21753790	Patients with helical domain mutations had a shorter disease-specific survival and increased AKT phosphorylation at both CREB-regulated transcription coactivator 2 (TORC2; also known as CRTC2) and pyruvate dehydrogenase kinase 1 (PDK1) phosphorylation sites than those with wild-type or kinase-domain-mutant tumors.	('CREB-regulated transcription coactivator 2', 'Gene', (121, 163))	('shorter', 'NegReg', (45, 52))	('pyruvate dehydrogenase kinase 1', 'Gene', '5163', (197, 228))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('helical domain mutations', 'Var', (14, 38))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('disease-specific survival', 'CPA', (53, 78))	('increased', 'PosReg', (83, 92))	('PDK1', 'Gene', '5163', (230, 234))	('AKT', 'Gene', (93, 96))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (308, 314))	('TORC2', 'Gene', (165, 170))	('CRTC2', 'Gene', '200186', (186, 191))	('AKT', 'Gene', '207', (93, 96))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('TORC2', 'Gene', '200186', (165, 170))	('CRTC2', 'Gene', (186, 191))	('PDK1', 'Gene', (230, 234))	('pyruvate dehydrogenase kinase 1', 'Gene', (197, 228))	('CREB-regulated transcription coactivator 2', 'Gene', '200186', (121, 163))
174516	21753790	Another novel finding is that of NF1 alterations (point mutations or deletions) in 10% of myxofibrosarcomas and 8% of pleomorphic liposarcomas (Table 1).	('pleomorphic liposarcomas', 'Disease', (118, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('NF1', 'Gene', (33, 36))	('myxofibrosarcomas', 'Disease', 'None', (90, 107))	('liposarcomas', 'Phenotype', 'HP:0012034', (130, 142))	('myxofibrosarcomas', 'Disease', (90, 107))	('NF1', 'Gene', '4763', (33, 36))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (118, 142))	('deletions', 'Var', (69, 78))	('liposarcoma', 'Phenotype', 'HP:0012034', (130, 141))	('alterations', 'Var', (37, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))
174517	21753790	NF1 germline and somatic mutations are typically associated with NF1 inactivation in sarcomas in individuals with neurofibromatosis type 1 syndrome, but NF1 mutations had not been previously described in sporadic sarcomas.	('NF1', 'Gene', (153, 156))	('associated', 'Reg', (49, 59))	('NF1', 'Gene', (0, 3))	('sarcomas', 'Disease', 'MESH:D012509', (213, 221))	('sporadic sarcomas', 'Disease', (204, 221))	('mutations', 'Var', (25, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (213, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('sarcomas', 'Disease', (213, 221))	('neurofibromatosis type 1 syndrome', 'Disease', 'MESH:C537392', (114, 147))	('sarcomas', 'Disease', 'MESH:D012509', (85, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('sarcomas', 'Disease', (85, 93))	('neurofibromatosis type 1 syndrome', 'Disease', (114, 147))	('sporadic sarcomas', 'Disease', 'MESH:D012509', (204, 221))	('NF1', 'Gene', '4763', (65, 68))	('neurofibroma', 'Phenotype', 'HP:0001067', (114, 126))	('inactivation', 'NegReg', (69, 81))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (114, 131))	('NF1', 'Gene', '4763', (153, 156))	('NF1', 'Gene', (65, 68))	('NF1', 'Gene', '4763', (0, 3))
174519	21753790	Sarcomas span a wide range of complexity among human malignancies in their copy-number alterations.	('copy-number alterations', 'Var', (75, 98))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('malignancies', 'Disease', (53, 65))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('human', 'Species', '9606', (47, 52))	('Sarcomas', 'Disease', (0, 8))
174523	21753790	These three groups are genomically simple sarcomas, driven by pathognomonic translocations or point mutations; non-translocation-associated sarcomas of intermediate genomic complexity; and highly genomically complex sarcomas, while some subtypes may not fit so neatly in these broad groups, such as PAX7-FOXO1-positive ARMS.	('PAX7', 'Gene', '5081', (299, 303))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('PAX7', 'Gene', (299, 303))	('non-translocation-associated', 'Disease', (111, 139))	('AR', 'Gene', '367', (319, 321))	('sarcomas', 'Disease', 'MESH:D012509', (140, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcomas', 'Disease', (140, 148))	('sarcomas', 'Disease', 'MESH:D012509', (216, 224))	('sarcomas', 'Disease', 'MESH:D012509', (42, 50))	('ARMS', 'Phenotype', 'HP:0006779', (319, 323))	('sarcomas', 'Phenotype', 'HP:0100242', (216, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcomas', 'Disease', (216, 224))	('translocations', 'Var', (76, 90))	('sarcomas', 'Disease', (42, 50))	('point mutations', 'Var', (94, 109))
174525	21753790	The first group, genomically simple sarcomas, harbor characteristic gene fusions or activating mutations thought to represent early events in their pathogenesis.	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('sarcomas', 'Disease', (36, 44))	('activating', 'PosReg', (84, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('gene fusions', 'Var', (68, 80))
174527	21753790	Intermediate complexity sarcomas are exemplified by well-differentiated and dedifferentiated liposarcomas, which are driven mainly by chromosome 12 alterations, often generating extra-chromosomal episomes, ring chromosomes and larger markers (FIG.	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('alterations', 'Var', (148, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('liposarcoma', 'Phenotype', 'HP:0012034', (93, 104))	('sarcomas', 'Disease', (24, 32))	('extra-chromosomal episomes', 'MPA', (178, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (97, 105))	('liposarcomas', 'Phenotype', 'HP:0012034', (93, 105))	('generating', 'Reg', (167, 177))	('liposarcomas', 'Disease', 'MESH:D008080', (93, 105))	('ring chromosomes', 'Var', (206, 222))	('liposarcomas', 'Disease', (93, 105))
174531	21753790	This genomic remodeling of chromosome 12 is likely the result of progressive rearrangement and amplification in an evolving amplicon rather than a single catastrophic event such as the recently proposed chromothripsis, seen in a subset of osteosarcomas and chordomas (Table 1).	('rearrangement', 'Var', (77, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (244, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('amplification', 'Var', (95, 108))	('osteosarcomas and chordomas', 'Disease', 'MESH:D002817', (239, 266))	('osteosarcoma', 'Phenotype', 'HP:0002669', (239, 251))	('osteosarcomas', 'Phenotype', 'HP:0002669', (239, 252))
174536	21753790	Some targets of genomic amplification appear to be shared among a subset of both intermediate and highly complex sarcomas, including Yes-associated protein 1 (YAP1) and vestigial like 3 (VGLL3) on 11q22 and 3p12, respectively.	('sarcomas', 'Disease', (113, 121))	('intermediate', 'Disease', (81, 93))	('vestigial like 3', 'Gene', (169, 185))	('Yes-associated protein 1', 'Gene', '10413', (133, 157))	('VGLL3', 'Gene', (187, 192))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('Yes-associated protein 1', 'Gene', (133, 157))	('YAP1', 'Gene', (159, 163))	('YAP1', 'Gene', '10413', (159, 163))	('vestigial like 3', 'Gene', '389136', (169, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('VGLL3', 'Gene', '389136', (187, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('genomic amplification', 'Var', (16, 37))
174538	21753790	Broad amplifications of several chromosome arms (such as 5p) often occur in combination with deletions affecting well-established tumor suppressors such as CDKN2A, CDKN2B, PTEN, retinoblastoma 1 (RB1), NF1 and TP53.	('PTEN', 'Gene', '5728', (172, 176))	('CDKN2A', 'Gene', (156, 162))	('TP53', 'Gene', (210, 214))	('retinoblastoma', 'Phenotype', 'HP:0009919', (178, 192))	('CDKN2A', 'Gene', '1029', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('retinoblastoma 1 (RB1', 'Gene', '5925', (178, 199))	('CDKN2B', 'Gene', '1030', (164, 170))	('NF1', 'Gene', (202, 205))	('CDKN2B', 'Gene', (164, 170))	('deletions', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('NF1', 'Gene', '4763', (202, 205))	('tumor', 'Disease', (130, 135))	('occur', 'Reg', (67, 72))	('TP53', 'Gene', '7157', (210, 214))	('PTEN', 'Gene', (172, 176))
174540	21753790	In other subtypes, such as leiomyosarcoma, genomic deletions are more common than amplifications.	('common', 'Reg', (70, 76))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (27, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('genomic deletions', 'Var', (43, 60))	('leiomyosarcoma', 'Disease', (27, 41))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (27, 41))
174541	21753790	Nevertheless, at least a subset of leiomyosarcomas depends on the specific amplification of myocardin (MYOCD), which encodes a smooth muscle-specific transcriptional coactivator of the serum response factor (SRF) (Table 1).	('serum response factor', 'Gene', '6722', (185, 206))	('MYOCD', 'Gene', (103, 108))	('serum response factor', 'Gene', (185, 206))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('SRF', 'Gene', (208, 211))	('myocardin', 'Gene', '93649', (92, 101))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (35, 49))	('MYOCD', 'Gene', '93649', (103, 108))	('amplification', 'Var', (75, 88))	('myocardin', 'Gene', (92, 101))	('SRF', 'Gene', '6722', (208, 211))	('leiomyosarcomas depends', 'Disease', (35, 58))	('leiomyosarcomas depends', 'Disease', 'MESH:D007890', (35, 58))
174543	21753790	Therefore, while systematic catalogues of copy numbers alterations point to pathways potentially activated in specific subtypes, to precisely delineate genes involved in these events that drive sarcomagenesis it will be essential to annotate genomic characterization with high-throughput functional genetics for target discovery.	('alterations', 'Var', (55, 66))	('activated', 'Reg', (97, 106))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('sarcoma', 'Disease', (194, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('copy numbers alterations', 'Var', (42, 66))
174558	21753790	Two such methods, Genomic Identification of Significant Targets in Cancer (GISTIC) and RAE, assign a statistical significance to candidate driver alterations emerging from a background of random, passenger abnormalities using their pattern of recurrence, amplitude, and extent, but also assign to individuals the set of CNAs they have undergone.	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('GIST', 'Phenotype', 'HP:0100723', (75, 79))	('alterations', 'Var', (146, 157))	('Cancer', 'Disease', (67, 73))
174563	21753790	Along these lines, we recently sought to functionally annotate the dedifferentiated liposarcoma genome by systematically knocking down genes altered by recurrent genomic amplification on 12q and elsewhere.	('liposarcoma', 'Disease', (84, 95))	('knocking', 'Var', (121, 129))	('liposarcoma', 'Disease', 'MESH:D008080', (84, 95))	('liposarcoma', 'Phenotype', 'HP:0012034', (84, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
174582	21753790	For example, in leiomyosarcoma, the most prominent genetic alteration is chromosome 10 deletions affecting PTEN, but this may be a secondary alteration.	('PTEN', 'Gene', (107, 111))	('leiomyosarcoma', 'Disease', (16, 30))	('PTEN', 'Gene', '5728', (107, 111))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (16, 30))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (16, 30))	('deletions', 'Var', (87, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))
174583	21753790	Nonetheless, this was modeled by genetically inactivating Pten in smooth muscle cells of mice, which led to leiomyosarcomagenesis.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (108, 122))	('mice', 'Species', '10090', (89, 93))	('genetically inactivating', 'Var', (33, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('led to', 'Reg', (101, 107))	('leiomyosarcomagenesis', 'Disease', 'None', (108, 129))	('leiomyosarcomagenesis', 'Disease', (108, 129))	('Pten', 'Gene', (58, 62))	('Pten', 'Gene', '19211', (58, 62))
174584	21753790	Another recent mouse model introduced oncogenic Kras and mutant Trp53 in the muscle of mice; these changes were sufficient to generate high-grade sarcomas with myofibroblastic differentiation, but KRAS is rarely mutated in human sarcomas.	('Trp53', 'Gene', '22059', (64, 69))	('sarcomas', 'Disease', 'MESH:D012509', (229, 237))	('mutant', 'Var', (57, 63))	('KRAS', 'Gene', (197, 201))	('mouse', 'Species', '10090', (15, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (229, 237))	('sarcomas', 'Disease', (229, 237))	('Trp53', 'Gene', (64, 69))	('human', 'Species', '9606', (223, 228))	('KRAS', 'Gene', '16653', (197, 201))	('Kras', 'Gene', (48, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('sarcomas', 'Disease', (146, 154))	('generate', 'Reg', (126, 134))	('Kras', 'Gene', '16653', (48, 52))	('mice', 'Species', '10090', (87, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))
174595	21753790	These responses to imatinib depend, however, on the specific site of mutation; tumors with activation loop mutations are generally insensitive.	('mutations', 'Var', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('imatinib', 'Chemical', 'MESH:D000068877', (19, 27))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
174598	21753790	For example, the recent success of Raf inhibitors in BRAF-V600E mutant melanoma suggests that responses may be elicited in other tumor types with a dependence on oncogenic Raf, a possible therapeutic option for the approximately 1% of adult GIST patients with BRAF-V600E mutation.	('Raf', 'Gene', '22882', (172, 175))	('patients', 'Species', '9606', (246, 254))	('tumor', 'Disease', (129, 134))	('Raf', 'Gene', '22882', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('V600E', 'Mutation', 'rs113488022', (58, 63))	('V600E', 'Mutation', 'rs113488022', (265, 270))	('mutant', 'Var', (64, 70))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (260, 264))	('Raf', 'Gene', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('BRAF', 'Gene', (260, 264))	('GIST', 'Phenotype', 'HP:0100723', (241, 245))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('Raf', 'Gene', (35, 38))
174601	21753790	Among these are responses to imatinib in dermatofibrosarcoma protuberans (DFSP) and giant-cell tumors of the tendon sheath with collagen Ialpha1 (COL1A1)-platelet- derived growth factor-beta (PDGFB) and collagen Ivalpha3 (COL6A3)-colony-stimulating factor 1 (CSF1) fusions, respectively, MET inhibitor responses in ASPS and clear-cell sarcomas with ASPL-TFE3 and EWS-activating transcription factor 1 (ATF1) fusions, respectively, ALK inhibitor responses in inflammatory myofibroblastic tumors with ALK fusions, and IGF1R antibody responses in Ewing sarcoma with EWS-FLI1 or EWS-ERG fusions.	('sarcomas', 'Phenotype', 'HP:0100242', (335, 343))	('EWS', 'Gene', (575, 578))	('sarcomas', 'Disease', (335, 343))	('EWS-FLI1', 'Gene', (563, 571))	('EWS', 'Gene', '2130', (363, 366))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('EWS-activating transcription factor 1', 'Gene', '466', (363, 400))	('Ewing sarcoma', 'Disease', (544, 557))	('giant-cell tumors of the tendon sheath', 'Disease', 'MESH:D000070779', (84, 122))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (471, 493))	('PDGFB', 'Gene', (192, 197))	('CSF1', 'Gene', (259, 263))	('IGF1R', 'Gene', '3480', (516, 521))	('imatinib', 'Chemical', 'MESH:D000068877', (29, 37))	('EWS-activating transcription factor 1', 'Gene', (363, 400))	('colony-stimulating factor 1', 'Gene', (230, 257))	('ASPL', 'Gene', (349, 353))	('ALK', 'Gene', '238', (431, 434))	('EWS', 'Gene', (563, 566))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (471, 493))	('dermatofibrosarcoma protuberans', 'Disease', (41, 72))	('giant-cell tumors of the tendon sheath', 'Disease', (84, 122))	('ASPS', 'Gene', (315, 319))	('IGF1R', 'Gene', (516, 521))	('EWS-FLI1', 'Gene', '2130;2313', (563, 571))	('ALK', 'Gene', (431, 434))	('CSF1', 'Gene', '1435', (259, 263))	('EWS', 'Gene', '2130', (575, 578))	('ATF1', 'Gene', (402, 406))	('COL1A1', 'Gene', '1277', (146, 152))	('fusions', 'Var', (503, 510))	('EWS', 'Gene', (363, 366))	('COL6A3', 'Gene', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (487, 492))	('COL6A3', 'Gene', '1293', (222, 228))	('TFE3', 'Gene', (354, 358))	('myofibroblastic tumors', 'Disease', (471, 493))	('DFSP', 'Disease', 'MESH:D018223', (74, 78))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (41, 72))	('ASPL', 'Gene', '79058', (349, 353))	('ALK', 'Gene', '238', (499, 502))	('tumors', 'Phenotype', 'HP:0002664', (487, 493))	('ASPS', 'Gene', '79058', (315, 319))	('COL1A1', 'Gene', (146, 152))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (544, 557))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (544, 557))	('sarcoma', 'Phenotype', 'HP:0100242', (550, 557))	('TFE3', 'Gene', '7030', (354, 358))	('ATF1', 'Gene', '466', (402, 406))	('sarcoma', 'Phenotype', 'HP:0100242', (335, 342))	('ASPS', 'Phenotype', 'HP:0012218', (315, 319))	('colony-stimulating factor 1', 'Gene', '1435', (230, 257))	('EWS', 'Gene', '2130', (563, 566))	('ALK', 'Gene', (499, 502))	('PDGFB', 'Gene', '5155', (192, 197))	('DFSP', 'Disease', (74, 78))	('sarcomas', 'Disease', 'MESH:D012509', (335, 343))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
174610	21753790	As NF1 inactivation leads to aberrant MAPK and mTOR pathway activity, the NF1 mutations and genomic deletions recently observed in pleomorphic liposarcomas and myxofibrosarcomas may identify a broader range of patients who might respond to either RAF/MEK inhibitors or rapamycin and its analogs (rapalogues).	('inactivation', 'Var', (7, 19))	('MEK', 'Gene', '5609', (251, 254))	('RAF', 'Gene', (247, 250))	('MEK', 'Gene', (251, 254))	('mutations', 'Var', (78, 87))	('pleomorphic liposarcomas and myxofibrosarcomas', 'Disease', 'MESH:D008080', (131, 177))	('NF1', 'Gene', '4763', (3, 6))	('patients', 'Species', '9606', (210, 218))	('MAPK', 'Pathway', (38, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('NF1', 'Gene', '4763', (74, 77))	('NF1', 'Gene', (3, 6))	('activity', 'MPA', (60, 68))	('mTOR', 'Gene', (47, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('rapamycin', 'Chemical', 'MESH:D020123', (269, 278))	('NF1', 'Gene', (74, 77))	('liposarcomas', 'Phenotype', 'HP:0012034', (143, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('mTOR', 'Gene', '2475', (47, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('liposarcoma', 'Phenotype', 'HP:0012034', (143, 154))	('RAF', 'Gene', '22882', (247, 250))
174611	21753790	In fact, deploying rapalogues in several complex subtypes could be justified on the basis of highly prevalent PTEN deletions, as in leiomyosarcoma.	('PTEN', 'Gene', '5728', (110, 114))	('leiomyosarcoma', 'Disease', (132, 146))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (132, 146))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (132, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('deletions', 'Var', (115, 124))	('PTEN', 'Gene', (110, 114))
174613	21753790	The finding of frequent PIK3CA mutations in myxoid/round-cell liposarcoma (Table 1) suggests that at least this molecular subset of patients might benefit from PI3K inhibitors; this is currently being tested in clinical trials.	('mutations', 'Var', (31, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))	('PIK3CA', 'Gene', (24, 30))	('clinical', 'Species', '191496', (211, 219))	('liposarcoma', 'Disease', (62, 73))	('PIK3CA', 'Gene', '5290', (24, 30))	('patients', 'Species', '9606', (132, 140))	('liposarcoma', 'Disease', 'MESH:D008080', (62, 73))
174619	21753790	For instance, GIST harboring the more common and imatinib-sensitive KIT exon 11 mutation tend to become resistant by acquiring a second-site KIT mutation in exon 11 rather than in exon 9.	('mutation', 'Var', (80, 88))	('GIST', 'Phenotype', 'HP:0100723', (14, 18))	('KIT exon 11', 'Gene', (68, 79))	('imatinib', 'Chemical', 'MESH:D000068877', (49, 57))	('mutation', 'Var', (145, 153))
174621	21753790	Another mechanism of resistance may involve alternative oncogenic pathways or rewiring of signaling networks, as experimental evidence suggests is the case for IGF1R inhibitors in rhabdomyosarcomas and Ewing sarcoma cell lines.	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('sarcomas', 'Phenotype', 'HP:0100242', (189, 197))	('IGF1R', 'Gene', (160, 165))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (180, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('Ewing sarcoma', 'Disease', (202, 215))	('IGF1R', 'Gene', '3480', (160, 165))	('rhabdomyosarcomas', 'Disease', (180, 197))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (180, 196))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (202, 215))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (202, 215))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (180, 197))	('inhibitors', 'Var', (166, 176))
174622	21753790	This adaptive resistance is consistent with the lack of IGF1R mutations observed in cancer types where these therapies are active.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('IGF1R', 'Gene', '3480', (56, 61))	('adaptive resistance', 'MPA', (5, 24))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('IGF1R', 'Gene', (56, 61))	('mutations', 'Var', (62, 71))
174628	21753790	Considering therapeutic strategies aimed at the aberrant transcriptional proteins driving translocation sarcomas, we note that transcription factors are considered poorly druggable because their protein-protein and protein-DNA interactions have historically been difficult to inhibit with small molecules.	('sarcomas', 'Disease', 'MESH:D012509', (104, 112))	('protein-protein', 'Protein', (195, 210))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('aberrant', 'Var', (48, 56))	('sarcomas', 'Disease', (104, 112))
174633	21753790	In clear-cell sarcoma, EWS-ATF1 transactivates microphthalmia-associated transcription factor (MITF), which in turn directly activates MET transcription.	('activates', 'PosReg', (125, 134))	('sarcoma', 'Disease', (14, 21))	('EWS-ATF1', 'Gene', (23, 31))	('transactivates', 'Var', (32, 46))	('microphthalmia-associated transcription factor', 'Gene', (47, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('EWS-ATF1', 'Gene', '466;2130', (23, 31))	('microphthalmia', 'Phenotype', 'HP:0000568', (47, 61))	('MET transcription', 'MPA', (135, 152))	('MITF', 'Gene', '4286', (95, 99))	('MITF', 'Gene', (95, 99))	('microphthalmia-associated transcription factor', 'Gene', '4286', (47, 93))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))
174638	21753790	These findings have in part provided the rationale for trials of IGF1R inhibitors in these sarcomas.	('inhibitors', 'Var', (71, 81))	('IGF1R', 'Gene', (65, 70))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcomas', 'Disease', (91, 99))	('IGF1R', 'Gene', '3480', (65, 70))
174644	21753790	Epigenetic approaches may lead to re-expression of pro-apoptotic molecules, rendering sarcomas sensitive to other agents, or itself induce apoptosis or senescence, although unknown at present.	('sarcomas', 'Disease', 'MESH:D012509', (86, 94))	('lead to', 'Reg', (26, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('senescence', 'CPA', (152, 162))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('re-expression', 'MPA', (34, 47))	('induce', 'Reg', (132, 138))	('Epigenetic approaches', 'Var', (0, 21))	('expression', 'Species', '29278', (37, 47))	('sarcomas', 'Disease', (86, 94))	('apoptosis', 'CPA', (139, 148))
174646	21753790	Targeting the p53-MDM2 pathway with nutlins is promising in tumors with MDM2 amplification (predominantly well- and dedifferentiated liposarcomas).	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('liposarcomas', 'Phenotype', 'HP:0012034', (133, 145))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('liposarcomas', 'Disease', 'MESH:D008080', (133, 145))	('amplification', 'Var', (77, 90))	('liposarcomas', 'Disease', (133, 145))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('liposarcoma', 'Phenotype', 'HP:0012034', (133, 144))	('MDM2', 'Gene', '4193', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('MDM2', 'Gene', '4193', (72, 76))	('MDM2', 'Gene', (18, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('MDM2', 'Gene', (72, 76))	('tumors', 'Disease', (60, 66))
174651	21753790	Over the next few years, the catalog of mutations that drive all but the least common diseases will become known, thanks to large-scale efforts such as TCGA and the International Cancer Genome Consortium, as well as others.	('Cancer', 'Disease', 'MESH:D009369', (179, 185))	('mutations', 'Var', (40, 49))	('Cancer', 'Disease', (179, 185))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))
174653	21753790	Translocation Structural rearrangement that juxtaposes distant genome sequences, resulting in aberrant gene expression or modified regulatory control of a gene (promoter substitution) or the formation of a fusion gene that encodes an aberrant, chimeric protein (gene fusion).	('resulting in', 'Reg', (81, 93))	('rearrangement', 'Var', (25, 38))	('expression', 'Species', '29278', (108, 118))	('aberrant gene expression', 'MPA', (94, 118))	('modified', 'Reg', (122, 130))	('regulatory control', 'MPA', (131, 149))
174658	21753790	Three core and context-dependent molecular mechanisms drive sarcomagenesis: dysregulation of gene expression by aberrant, chimeric transcription factors generated by specific gene fusions in translocation-associated sarcomas, somatic mutations affecting key signaling pathways, and DNA copy number abnormalities.	('dysregulation of gene expression', 'MPA', (76, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (216, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('sarcomas', 'Disease', (216, 224))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('key signaling pathways', 'Pathway', (254, 276))	('affecting', 'Reg', (244, 253))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Disease', 'MESH:D012509', (216, 223))	('sarcomas', 'Disease', 'MESH:D012509', (216, 224))	('chimeric', 'Var', (122, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('expression', 'Species', '29278', (98, 108))	('copy number abnormalities', 'Disease', 'MESH:D007674', (286, 311))	('copy number abnormalities', 'Disease', (286, 311))	('sarcoma', 'Disease', (216, 223))
174659	21753790	Novel genomic findings from diverse approaches in sarcoma are identifying point mutations that co-occur with translocations, lineage-specific oncogenes, chromosomal remodeling events, and both genomic alterations and mutations that alter canonical signaling and differentiation pathways.	('alter', 'Reg', (232, 237))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('differentiation pathways', 'Pathway', (262, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('mutations', 'Var', (217, 226))	('translocations', 'Disease', (109, 123))
174694	31456613	In a cancer database of 3,422 patients with large extremity or truncal sarcoma, radiotherapy was shown to decrease the hazard ratio of death by 34% and chemotherapy by 24% when compared with surgery alone.	('truncal sarcoma', 'Disease', (63, 78))	('radiotherapy', 'Var', (80, 92))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('decrease', 'NegReg', (106, 114))	('patients', 'Species', '9606', (30, 38))	('death', 'Disease', 'MESH:D003643', (135, 140))	('truncal sarcoma', 'Disease', 'MESH:D001259', (63, 78))	('death', 'Disease', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))
174743	31456613	This method involves detaching the long head of biceps femoris from the distal fibular insertion, anchoring it distally to the patella and tethering it longitudinally to the remains of the quadriceps.	('patella', 'Disease', (127, 134))	('long head', 'Phenotype', 'HP:0000256', (35, 44))	('patella', 'Disease', 'MESH:C535540', (127, 134))	('detaching', 'Var', (21, 30))
174921	27785074	The role of neoadjuvant radiotherapy in the context of new chemotherapy regimens has however been challenged and is being examined further in the ongoing PROSPECT trial, which is investigating the efficacy of neoadjuvant chemotherapy alone in patients with cT2N1 or cT3N0-1 tumors who are eligible for sphincter sparing TME.	('sphincter sparing', 'Phenotype', 'HP:0002839', (302, 319))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('patients', 'Species', '9606', (243, 251))	('TME', 'Chemical', '-', (320, 323))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('cT2N1', 'Var', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumors', 'Disease', (274, 280))
174966	27785074	R0 rate was not affected by the extent of sacral resection, although high sacrectomy did increase the rate of neurological deficit (P=0.04).	('high sacrectomy', 'Var', (69, 84))	('neurological deficit', 'Disease', (110, 130))	('neurological deficit', 'Phenotype', 'HP:0000707', (110, 130))	('neurological deficit', 'Disease', 'MESH:D009461', (110, 130))
175018	27453666	Family cancer syndromes are disorders caused by genetic mutations that a patient can be inherited with or spontaneously occur.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutations', 'Var', (56, 65))	('cancer syndromes', 'Disease', (7, 23))	('patient', 'Species', '9606', (73, 80))	('cancer syndromes', 'Disease', 'MESH:D009369', (7, 23))
175019	27453666	Some of these syndromes include neurofibromatosis (NF) (also known as von Recklinghausen disease) which is caused by a NF1 gene mutation; Gardner syndrome, caused by a mutation in adenomatous polyposis coli gene which is associated with familial adenomatous polyposis.	('caused by', 'Reg', (107, 116))	('NF', 'Phenotype', 'HP:0001067', (119, 121))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (32, 49))	('NF1', 'Gene', (119, 122))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (180, 206))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (180, 206))	('adenomatous polyposis coli', 'Disease', (180, 206))	('von Recklinghausen disease', 'Disease', 'MESH:C537392', (70, 96))	('mutation', 'Var', (128, 136))	('neurofibromatosis (NF', 'Gene', (32, 53))	('familial adenomatous polyposis', 'Disease', (237, 267))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (246, 267))	('mutation', 'Var', (168, 176))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (237, 267))	('NF', 'Phenotype', 'HP:0001067', (51, 53))	('von Recklinghausen disease', 'Disease', (70, 96))	('caused by', 'Reg', (156, 165))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (180, 201))	('Gardner syndrome', 'Disease', (138, 154))	('neurofibromatosis (NF)', 'Gene', '4763', (32, 54))	('NF1', 'Gene', '4763', (119, 122))	('Gardner syndrome', 'Disease', 'MESH:D005736', (138, 154))
175022	27453666	Werner syndrome, mutation within RECQL2 gene, children develop problems that the elderly are at increased risk for such as cataracts, skin changes, arteriolosclerosis, and increased risk of STSs.	('problems', 'Disease', (63, 71))	('skin changes', 'Phenotype', 'HP:0000951', (134, 146))	('RECQL2', 'Gene', '7486', (33, 39))	('RECQL2', 'Gene', (33, 39))	('arteriolosclerosis', 'Disease', 'MESH:D050379', (148, 166))	('cataracts', 'Phenotype', 'HP:0000518', (123, 132))	('children', 'Species', '9606', (46, 54))	('mutation', 'Var', (17, 25))	('STSs', 'Disease', (190, 194))	('skin changes', 'Disease', (134, 146))	('STSs', 'Phenotype', 'HP:0030448', (190, 194))	('Werner syndrome', 'Disease', 'MESH:D014898', (0, 15))	('Werner syndrome', 'Disease', (0, 15))	('arteriolosclerosis', 'Disease', (148, 166))	('cataracts', 'Disease', 'MESH:D002386', (123, 132))	('cataracts', 'Disease', (123, 132))
175028	27453666	One genetic marker that can help with the outcome of the patient is the over expression of MED12 gene mutation.	('MED12', 'Gene', (91, 96))	('patient', 'Species', '9606', (57, 64))	('mutation', 'Var', (102, 110))	('MED12', 'Gene', '9968', (91, 96))	('over expression', 'PosReg', (72, 87))
175029	27453666	This has been studied in a sample of patients, and this mutation within the sarcomas can be an indicator of poor prognosis.	('patients', 'Species', '9606', (37, 45))	('sarcomas', 'Disease', 'MESH:D012509', (76, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (76, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcomas', 'Disease', (76, 84))	('mutation', 'Var', (56, 64))
175096	26130233	On multivariate analysis, only high grade (P=0.04, HR 2.5; 95% CI 1.1-5.9) and positive or uncertain margins (P=0.02, HR 1.8; 95% CI 1.1-3.1) remained significantly associated with poorer DSS.	('poorer DSS', 'Disease', (181, 191))	('DSS', 'Chemical', '-', (188, 191))	('DSS', 'Disease', (188, 191))	('high grade', 'Var', (31, 41))
175142	25317334	To overcome this, we tested a strategy combining IL-21 modulation during in vitro stimulation with first-in-class use of tetramer-guided cell sorting to generate NY-ESO-1 specific cytotoxic T lymphocytes (CTL).	('NY-ESO-1', 'Gene', '246100', (162, 170))	('modulation', 'Var', (55, 65))	('NY-ESO-1', 'Gene', (162, 170))	('cytotoxic T lymphocytes', 'CPA', (180, 203))	('IL-21', 'Gene', (49, 54))	('L', 'Chemical', '-', (207, 208))	('tet', 'Chemical', 'MESH:C010349', (121, 124))	('L', 'Chemical', '-', (50, 51))	('IL-21', 'Gene', '59067', (49, 54))
175150	25317334	Recent trials using genetic modification of T cells to introduce chimeric antigen receptors (CAR's) or T cell receptors (TCR's) and redirect their target specificity to tumor cells can be remarkably effective in reducing tumor burden and providing durable remissions in B cell malignancies and some solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('solid tumors', 'Disease', (299, 311))	('tumor', 'Disease', (305, 310))	('TCR', 'Gene', (121, 124))	('CAR', 'Gene', '653108', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('tumor', 'Disease', (169, 174))	('chimeric', 'Var', (65, 73))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	('solid tumors', 'Disease', 'MESH:D009369', (299, 311))	('reducing', 'NegReg', (212, 220))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('TCR', 'Gene', '6962', (121, 124))	('CAR', 'Gene', (93, 96))	('B cell malignancies', 'CPA', (270, 289))
175157	25317334	To address this issue, we previously discovered that the addition of IL-21 during the initial priming period could increase the total number of antigen-specific CD8 T cells by >20-fold and, at the clonal level, enrich for a population of high-affinity CD8 T cells with sustained elevation of CD28 levels and a helper-independent phenotype.	('CD8', 'Gene', '925', (252, 255))	('CD8', 'Gene', (161, 164))	('increase', 'PosReg', (115, 123))	('IL-21', 'Gene', (69, 74))	('CD28', 'Gene', (292, 296))	('CD8', 'Gene', '925', (161, 164))	('addition', 'Var', (57, 65))	('IL-21', 'Gene', '59067', (69, 74))	('elevation', 'PosReg', (279, 288))	('CD28', 'Gene', '940', (292, 296))	('CD8', 'Gene', (252, 255))
175196	25317334	In order to confirm that NY-ESO-1 specific cells could be generated in patients without NY-ESO-1 expressing tumors, we also made cells through this process in two healthy donors which were also able to recognize peptide pulsed T2's and endogenously expressed peptide.	('peptide', 'Var', (212, 219))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (71, 79))	('NY-ESO-1', 'Gene', '246100', (88, 96))	('NY-ESO-1', 'Gene', (88, 96))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('NY-ESO-1', 'Gene', (25, 33))	('NY-ESO-1', 'Gene', '246100', (25, 33))
175214	25317334	Genetic modification has the advantage of using an off the shelf reagent to engineer each patient's T cells with an identical high affinity TCR.	('TCR', 'Gene', '6962', (140, 143))	('patient', 'Species', '9606', (90, 97))	('TCR', 'Gene', (140, 143))	('Genetic', 'Var', (0, 7))
175230	25317334	Patients that expressed HLA A*0201, had an ECOG performance status of 1 and tumor biopsies with positive staining for NY-ESO-1 in >25% of cells by immunohistochemistry underwent leukapheresis at either the PSBC or University of Washington General Clinical Research Center.	('NY-ESO-1', 'Gene', '246100', (118, 126))	('L', 'Chemical', '-', (25, 26))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('NY-ESO-1', 'Gene', (118, 126))	('Patients', 'Species', '9606', (0, 8))	('HLA A*0201', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
175308	24198985	Conventional cytogenetic analysis revealed trisomy 8, a common finding in myeloid sarcomas that may be associated with a poorer prognosis.	('myeloid sarcomas', 'Disease', 'MESH:D023981', (74, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('trisomy 8', 'Var', (43, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('myeloid sarcomas', 'Disease', (74, 90))
175446	22942649	Inhibition of the mammalian target of rapamycin (mTOR) has emerged as an exciting treatment approach and is being studied extensively in sarcoma patients.	('patients', 'Species', '9606', (145, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('mTOR', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (49, 53))	('mammalian target of rapamycin', 'Gene', '2475', (18, 47))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('Inhibition', 'Var', (0, 10))	('mammalian target of rapamycin', 'Gene', (18, 47))	('sarcoma', 'Disease', (137, 144))
175461	22942649	Ewing sarcoma is characterized by translocations involving the EWS gene; however, the search for targeted therapies directed to these driver mutations has been disappointing.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWS', 'Gene', '2130', (63, 66))	('EWS', 'Gene', (63, 66))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('translocations', 'Var', (34, 48))
175466	22942649	The target of rapamycin (TOR) was identified in yeast possessing mutations that rendered them resistant to rapamycin, and Sabers et al first identified the mammalian homolog (mTOR) in 1995.	('resistant to rapamycin', 'MPA', (94, 116))	('mammalian', 'Species', '9606', (156, 165))	('yeast', 'Species', '4932', (48, 53))	('mTOR', 'Gene', '2475', (175, 179))	('rapamycin', 'Chemical', 'MESH:D020123', (14, 23))	('rapamycin', 'Chemical', 'MESH:D020123', (107, 116))	('mTOR', 'Gene', (175, 179))	('mutations', 'Var', (65, 74))
175474	22942649	Upstream regulators of mTORC2 are less well defined, but it appears to be activated by growth factors and amino acids, including insulin, through PI3K.	('insulin', 'Gene', (129, 136))	('mTORC2', 'Gene', (23, 29))	('activated', 'PosReg', (74, 83))	('PI3K', 'Var', (146, 150))	('insulin', 'Gene', '3630', (129, 136))	('mTORC2', 'Gene', '74343', (23, 29))
175487	22942649	As mTOR appears to be a major regulator of translational control in response to environmental signals, it is not difficult to see how its dysregulation could lead to the development of several disease processes.	('mTOR', 'Gene', '2475', (3, 7))	('lead to', 'Reg', (158, 165))	('ase', 'Chemical', '-', (197, 200))	('disease', 'Disease', (193, 200))	('dysregulation', 'Var', (138, 151))	('mTOR', 'Gene', (3, 7))
175488	22942649	In vitro and in vivo models have shown that manipulation of the mTORC complexes can lead to impaired development and alterations in cellular function.	('alterations', 'Reg', (117, 128))	('manipulation', 'Var', (44, 56))	('mTOR', 'Gene', (64, 68))	('impaired', 'NegReg', (92, 100))	('mTOR', 'Gene', '2475', (64, 68))	('cellular function', 'MPA', (132, 149))	('development', 'CPA', (101, 112))
175489	22942649	Mutations in tsc1 and tsc2 lead to the tuberous sclerosis complex, which is characterized by the formation of benign tumors suggesting a link between the mTOR pathway and neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (171, 180))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tsc1', 'Gene', (13, 17))	('tsc1', 'Gene', '7248', (13, 17))	('neoplasia', 'Disease', (171, 180))	('tuberous sclerosis', 'Disease', (39, 57))	('benign tumors', 'Disease', 'MESH:D009369', (110, 123))	('Mutations', 'Var', (0, 9))	('neoplasia', 'Phenotype', 'HP:0002664', (171, 180))	('lead to', 'Reg', (27, 34))	('benign tumors', 'Disease', (110, 123))	('mTOR', 'Gene', (154, 158))	('tsc2', 'Gene', '7249', (22, 26))	('mTOR', 'Gene', '2475', (154, 158))	('tsc2', 'Gene', (22, 26))
175495	22942649	LKB1 germline mutations lead to Peutz-Jehgers syndrome characterized by mucocutaneous pigmentation and hamartomas of the gastrointestinal tract.	('hamartomas of the gastrointestinal tract', 'Phenotype', 'HP:0004390', (103, 143))	('hamartomas of the gastrointestinal tract', 'Disease', 'MESH:D004067', (103, 143))	('Peutz-Jehgers syndrome', 'Disease', 'MESH:D010580', (32, 54))	('LKB1', 'Gene', (0, 4))	('hamartomas', 'Phenotype', 'HP:0010566', (103, 113))	('pigmentation', 'Disease', 'MESH:D010859', (86, 98))	('pigmentation', 'Disease', (86, 98))	('LKB1', 'Gene', '6794', (0, 4))	('hamartomas of the gastrointestinal tract', 'Disease', (103, 143))	('lead to', 'Reg', (24, 31))	('mutations', 'Var', (14, 23))	('Peutz-Jehgers syndrome', 'Disease', (32, 54))
175496	22942649	Subsequently, mutations of the mTOR pathway and altered regulation have been found in many cancers.	('regulation', 'MPA', (56, 66))	('mTOR', 'Gene', (31, 35))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('mTOR', 'Gene', '2475', (31, 35))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('found', 'Reg', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (14, 23))
175498	22942649	Somatic PTEN mutations and inactivation have been identified in several cancers including hematologic malignancies, melanoma, glioblastoma, prostate, endometrial, breast, lung, pancreas, liver, and adrenal gland cancers.	('glioblastoma', 'Disease', (126, 138))	('pancreas', 'Disease', 'MESH:D010190', (177, 185))	('PTEN', 'Gene', '5728', (8, 12))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (126, 138))	('cancers', 'Disease', (72, 79))	('identified', 'Reg', (50, 60))	('inactivation', 'Var', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast', 'Disease', (163, 169))	('endometrial', 'Disease', (150, 161))	('adrenal gland cancers', 'Disease', 'MESH:D000310', (198, 219))	('liver', 'Disease', (187, 192))	('hematologic malignancies', 'Disease', (90, 114))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('melanoma', 'Disease', (116, 124))	('prostate', 'Disease', (140, 148))	('mutations', 'Var', (13, 22))	('cancers', 'Disease', (212, 219))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('hematologic malignancies', 'Disease', 'MESH:D019337', (90, 114))	('lung', 'Disease', (171, 175))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('pancreas', 'Disease', (177, 185))	('adrenal gland cancers', 'Disease', (198, 219))	('PTEN', 'Gene', (8, 12))	('glioblastoma', 'Disease', 'MESH:D005909', (126, 138))
175505	22942649	Similarly, as our understanding of the mTORC2 complex is less well defined, we are only now recognizing how inhibiting either complex or both will impact tumor growth.	('impact tumor', 'Disease', 'MESH:D004834', (147, 159))	('mTORC2', 'Gene', '74343', (39, 45))	('mTORC2', 'Gene', (39, 45))	('inhibiting', 'Var', (108, 118))	('impact tumor', 'Disease', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
175509	22942649	Several studies have demonstrated that inhibition of mTOR by rapamycin induces apoptosis or delays growth in several sarcoma models including rhabdomyosarcoma, Ewing sarcoma, and Kaposi sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (179, 193))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (160, 173))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (160, 173))	('sarcoma', 'Disease', (166, 173))	('mTOR', 'Gene', '2475', (53, 57))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcoma', 'Disease', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('Ewing sarcoma', 'Disease', (160, 173))	('rhabdomyosarcoma', 'Disease', (142, 158))	('inhibition', 'Var', (39, 49))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcoma', 'Disease', (186, 193))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (179, 193))	('delays growth', 'Phenotype', 'HP:0001510', (92, 105))	('delays', 'NegReg', (92, 98))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (142, 158))	('rapamycin', 'Chemical', 'MESH:D020123', (61, 70))	('Kaposi sarcoma', 'Disease', (179, 193))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (142, 158))	('mTOR', 'Gene', (53, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('apoptosis', 'CPA', (79, 88))	('growth', 'CPA', (99, 105))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('induces', 'Reg', (71, 78))	('sarcoma', 'Disease', (151, 158))
175510	22942649	Hu et al discovered loss of PTEN through 10q deletions in over half of human leiomyosarcomas, and it was subsequently discovered that PTEN deletion leads to smooth muscle cell hyperplasia and initiation of leiomyosarcoma.	('initiation of leiomyosarcoma', 'Disease', (192, 220))	('PTEN', 'Gene', '5728', (134, 138))	('muscle cell hyperplasia', 'Disease', (164, 187))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (77, 92))	('PTEN', 'Gene', (28, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('leiomyosarcomas', 'Disease', (77, 92))	('initiation of leiomyosarcoma', 'Disease', 'MESH:D007890', (192, 220))	('smooth', 'Disease', (157, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('human', 'Species', '9606', (71, 76))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (77, 92))	('PTEN', 'Gene', '5728', (28, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('leads to', 'Reg', (148, 156))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (206, 220))	('muscle cell hyperplasia', 'Disease', 'MESH:D006965', (164, 187))	('deletion', 'Var', (139, 147))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (77, 91))	('PTEN', 'Gene', (134, 138))
175511	22942649	The ewing family of tumors (EFT) includes Ewing sarcoma and primitive neuroectodermal tumors, and is characterized by fusion translocations involving the EWS gene and several genes encoding transcription factors.	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (70, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (70, 92))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('Ewing sarcoma', 'Disease', (42, 55))	('tumors', 'Disease', (86, 92))	('neuroectodermal tumors', 'Disease', (70, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('EWS', 'Gene', '2130', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('fusion translocations', 'Var', (118, 139))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('EWS', 'Gene', (154, 157))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (60, 92))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (42, 55))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (42, 55))
175512	22942649	Inhibition of mTOR by rapamycin in EFT cell lines leads to G1 cell cycle arrest and decreased levels of EWS translocated proteins.	('EWS', 'Gene', '2130', (104, 107))	('EWS', 'Gene', (104, 107))	('mTOR', 'Gene', '2475', (14, 18))	('rapamycin', 'Chemical', 'MESH:D020123', (22, 31))	('G1 cell cycle arrest', 'CPA', (59, 79))	('ase', 'Chemical', '-', (89, 92))	('Inhibition', 'Var', (0, 10))	('decreased', 'NegReg', (84, 93))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))	('mTOR', 'Gene', (14, 18))
175513	22942649	Alterations of the growth factor receptors and their signaling through PI3K are frequently found in many sarcoma subtypes.	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('Alterations', 'Var', (0, 11))	('found', 'Reg', (91, 96))	('growth factor receptors', 'Protein', (19, 42))	('sarcoma', 'Disease', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('PI3K', 'Var', (71, 75))	('signaling', 'MPA', (53, 62))
175527	22942649	Ridaforolimus (AP23573, M-8669, formerly deforolimus) is a non prodrug rapalogue which may have improved in vivo stability and is available in both intravenous and oral formulations.	('improved', 'PosReg', (96, 104))	('Ridaforolimus', 'Chemical', 'MESH:C515074', (0, 13))	('stability', 'MPA', (113, 122))	('AP23573', 'Var', (15, 22))
175539	22942649	Median PFS and 6-month PFS rates were 17.7 weeks and 34% in the ridaforolimus group and 14.6 weeks and 23% in the placebo group.	('ridaforolimus', 'Chemical', 'MESH:C515074', (64, 77))	('ridaforolimus', 'Var', (64, 77))	('PFS', 'CPA', (7, 10))
175553	22942649	A Phase I study of everolimus and CP-751871, a fully human IgG2 anti-IGF1R monoclonal antibody, in patients with sarcoma and other solid tumors demonstrated SD in most patients, with one patient with a solitary fibrous tumor having a PR.	('CP-751871', 'Var', (34, 43))	('patient', 'Species', '9606', (168, 175))	('SD', 'Disease', 'MESH:D029461', (157, 159))	('ase', 'Chemical', '-', (4, 7))	('everolimus', 'Chemical', 'MESH:D000068338', (19, 29))	('solid tumors', 'Disease', (131, 143))	('IGF1R', 'Gene', '3480', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('fibrous tumor', 'Disease', 'MESH:D054364', (211, 224))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('patients', 'Species', '9606', (99, 107))	('sarcoma', 'Disease', (113, 120))	('IGF1R', 'Gene', (69, 74))	('human', 'Species', '9606', (53, 58))	('CP-751871', 'Chemical', 'MESH:C525021', (34, 43))	('patient', 'Species', '9606', (187, 194))	('fibrous tumor', 'Disease', (211, 224))	('patient', 'Species', '9606', (99, 106))	('solid tumors', 'Disease', 'MESH:D009369', (131, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('patients', 'Species', '9606', (168, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
175571	33380808	Therefore, targeting BRD9 to study its biological roles will be an attractive tool for cancer diagnosis and treatment, but it remains a great challenge.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('targeting', 'Var', (11, 20))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('BRD9', 'Gene', (21, 25))
175577	33380808	For example, in malignant rhabdoid tumors (MRT), biallelic inactivation of SMARCB1 was first reported, and thereafter, in myoepithelial tumors and hepatoblastomas, repeated mutations were reported.	('hepatoblastomas', 'Disease', (147, 162))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (122, 142))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (16, 41))	('SMARCB1', 'Gene', '6598', (75, 82))	('biallelic inactivation', 'Var', (49, 71))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('hepatoblastomas', 'Disease', 'MESH:D018197', (147, 162))	('myoepithelial tumors', 'Disease', (122, 142))	('SMARCB1', 'Gene', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('malignant rhabdoid tumors', 'Disease', (16, 41))
175579	33380808	Several studies have revealed that SMARCA4 undergoes mutations at different frequencies in Burkitt's lymphoma, lung adenocarcinoma, esophageal adenocarcinoma, and medulloblastoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('adenocarcinoma', 'Disease', (143, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (111, 130))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (91, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (132, 157))	('adenocarcinoma', 'Disease', (116, 130))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (91, 109))	("Burkitt's lymphoma", 'Disease', (91, 109))	('SMARCA4', 'Gene', '6597', (35, 42))	('adenocarcinoma', 'Disease', 'MESH:D000230', (143, 157))	('medulloblastoma', 'Disease', 'MESH:D008527', (163, 178))	('medulloblastoma', 'Phenotype', 'HP:0002885', (163, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('medulloblastoma', 'Disease', (163, 178))	('adenocarcinoma', 'Disease', 'MESH:D000230', (116, 130))	('mutations', 'Var', (53, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (101, 109))	('lung adenocarcinoma', 'Disease', (111, 130))	('SMARCA4', 'Gene', (35, 42))
175580	33380808	Moreover, researchers have found that the mutation frequency of ARID1A, which encodes the BAF250a subunit, is high in hepatocellular carcinoma, gastric cancer, bladder cancer, colorectal cancer, pancreatic cancer, Burkitt's lymphoma, and cholangiocarcinoma.	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('BAF250a', 'Gene', '8289', (90, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (144, 158))	('colorectal cancer', 'Disease', (176, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (224, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('high', 'Reg', (110, 114))	('pancreatic cancer', 'Disease', 'MESH:D010190', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('bladder cancer', 'Disease', (160, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('hepatocellular carcinoma', 'Disease', (118, 142))	('mutation', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('pancreatic cancer', 'Disease', (195, 212))	('gastric cancer', 'Phenotype', 'HP:0012126', (144, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (238, 256))	('ARID1A', 'Gene', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('BAF250a', 'Gene', (90, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('cholangiocarcinoma', 'Disease', (238, 256))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (214, 232))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (214, 232))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (238, 256))	("Burkitt's lymphoma", 'Disease', (214, 232))	('ARID1A', 'Gene', '8289', (64, 70))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (118, 142))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (195, 212))	('gastric cancer', 'Disease', (144, 158))
175586	33380808	A study reported that prostate cancer cell line (PC3) proliferation and colony formation was dependent on GLTSCR1 expression, and knocking out GLTSCR1 could decreased PC3 cell proliferation and colony formation.	('rat', 'Species', '10116', (183, 186))	('colony formation', 'CPA', (72, 88))	('prostate cancer', 'Disease', (22, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colony formation', 'CPA', (194, 210))	('PC3', 'CellLine', 'CVCL:0035', (167, 170))	('rat', 'Species', '10116', (61, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (22, 37))	('GLTSCR1', 'Gene', (143, 150))	('knocking out', 'Var', (130, 142))	('PC3', 'CellLine', 'CVCL:0035', (49, 52))	('PC3 cell proliferation', 'CPA', (167, 189))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('GLTSCR1', 'Gene', (106, 113))	('decreased', 'NegReg', (157, 166))
175589	33380808	Kang et al confirmed the presence of BRD9 amplification on chromosome 5p in patients with non-small cell lung cancer (NSCLC) through high-resolution array comparative genomic hybridization analysis.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('patients', 'Species', '9606', (76, 84))	('non-small cell lung cancer', 'Disease', (90, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('rat', 'Species', '10116', (160, 163))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('BRD9', 'Gene', (37, 41))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('NSCLC', 'Disease', (118, 123))	('SCLC', 'Phenotype', 'HP:0030359', (119, 123))	('amplification', 'Var', (42, 55))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (90, 116))
175595	33380808	Wei et al confirmed that BRD9 inhibitors could restore beta-cell function and reduce inflammation to a certain extent.	('beta-cell function', 'CPA', (55, 73))	('reduce', 'NegReg', (78, 84))	('restore', 'PosReg', (47, 54))	('inhibitors', 'Var', (30, 40))	('inflammation', 'Disease', 'MESH:D007249', (85, 97))	('BRD9', 'Gene', (25, 29))	('inflammation', 'Disease', (85, 97))
175599	33380808	Inoue et al suggested that mutant SF3B1 recognized BRD9 introns and induced mis-splicing of BRD9, which ultimately led to the degradation of BRD9, and thus, promoted melanomagenesis.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('BRD9', 'Gene', (141, 145))	('led to', 'Reg', (115, 121))	('mutant', 'Var', (27, 33))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('SF3B1', 'Gene', (34, 39))	('promoted', 'PosReg', (157, 165))	('induced', 'Reg', (68, 75))	('mis-splicing', 'MPA', (76, 88))	('BRD9', 'Gene', (92, 96))	('SF3B1', 'Gene', '23451', (34, 39))	('degradation', 'MPA', (126, 137))	('BRD9', 'Gene', (51, 55))
175605	33380808	BRD9 contains a bromodomain and a DUF3512 domain.	('DUF3512', 'Chemical', '-', (34, 41))	('DUF3512 domain', 'Var', (34, 48))	('bromodomain', 'Gene', '679713', (16, 27))	('BRD9', 'Gene', (0, 4))	('bromodomain', 'Gene', (16, 27))
175613	33380808	The BRPF1 protein is a component of the MOZ/HAT complex, and its bromodomain recognizes H2AK5ac, H4K12ac, H3K14ac, H4K8ac, and H4K5ac.	('H4K12ac', 'Var', (97, 104))	('H4K5ac', 'Var', (127, 133))	('bromodomain', 'Gene', (65, 76))	('H2AK5ac', 'Chemical', '-', (88, 95))	('bromodomain', 'Gene', '679713', (65, 76))	('H2AK5ac', 'Var', (88, 95))	('H4K8ac', 'Var', (115, 121))	('BRPF1', 'Gene', (4, 9))	('H3K14ac', 'Var', (106, 113))
175616	33380808	ATAD2 is mainly located in reproductive tissues, and its bromodomain can recognize H4K5ac, H4K12ac, and H4K5acK12ac; ATAD2B is expressed in neural tissues, and its bromodomain and histone ligand have not been fully studied.	('bromodomain', 'Gene', '679713', (164, 175))	('bromodomain', 'Gene', (164, 175))	('H4K5acK12ac', 'Var', (104, 115))	('H4K5ac', 'Var', (83, 89))	('ATAD2B', 'Gene', (117, 123))	('bromodomain', 'Gene', '679713', (57, 68))	('bromodomain', 'Gene', (57, 68))	('H4K12ac', 'Var', (91, 98))
175617	33380808	BRD7 and BRD9 are the subunits of the PBAF and ncBAF complexes, respectively.	('BRD9', 'Var', (9, 13))	('BAF', 'Gene', '12016', (39, 42))	('cBAF', 'Chemical', '-', (48, 52))	('BAF', 'Gene', (49, 52))	('BAF', 'Gene', '12016', (49, 52))	('BAF', 'Gene', (39, 42))	('BRD7', 'Var', (0, 4))
175621	33380808	Although few biological ligands for the BRD9 bromodomain are known, BRD9 has been demonstrated to bind to diacetylated H4K5acK8ac and dipropionylated H4K5prK8pr.	('H4K5prK8pr', 'Var', (150, 160))	('H4K5acK8ac', 'Protein', (119, 129))	('bromodomain', 'Gene', '679713', (45, 56))	('bromodomain', 'Gene', (45, 56))	('rat', 'Species', '10116', (89, 92))	('H4K5acK8ac', 'Chemical', '-', (119, 129))	('bind', 'Interaction', (98, 102))	('BRD9', 'Gene', (68, 72))
175628	33380808	In leukemia, BRD9 is overexpressed, and induces the activation of the signal transducer and activator of transcription 5 (STAT5) pathway.	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('leukemia', 'Disease', 'MESH:D007938', (3, 11))	('BRD9', 'Var', (13, 17))	('leukemia', 'Disease', (3, 11))	('activation', 'PosReg', (52, 62))
175629	33380808	The activation of STAT5 is known to promote the proliferation and survival of AML cells and the occurrence of inflammation.	('STAT5', 'Gene', (18, 23))	('inflammation', 'Disease', (110, 122))	('promote', 'PosReg', (36, 43))	('AML', 'Disease', 'MESH:D015470', (78, 81))	('proliferation', 'CPA', (48, 61))	('activation', 'Var', (4, 14))	('survival', 'CPA', (66, 74))	('AML', 'Phenotype', 'HP:0004808', (78, 81))	('AML', 'Disease', (78, 81))	('rat', 'Species', '10116', (55, 58))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))
175631	33380808	Therefore, knocking down BRD9 to decrease the activation of STAT5 and induce apoptosis through the Caspase8 signaling cascade may be a possible therapeutic strategy.	('knocking down', 'Var', (11, 24))	('decrease', 'NegReg', (33, 41))	('STAT5', 'MPA', (60, 65))	('apoptosis', 'CPA', (77, 86))	('Caspase8', 'Gene', '841', (99, 107))	('Caspase8', 'Gene', (99, 107))	('induce', 'PosReg', (70, 76))	('rat', 'Species', '10116', (158, 161))	('BRD9', 'Gene', (25, 29))	('activation', 'MPA', (46, 56))
175638	33380808	For example, in lung cancer, miR-342-3p and miR-30d-5p are inhibited in lung cancer, whereas miR-29b, hsa-miR-3180, and miR-14,081 are highly expressed.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('miR-29b', 'Gene', '407024', (93, 100))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('inhibited', 'NegReg', (59, 68))	('miR-342-3p', 'Var', (29, 39))	('miR-30d', 'Gene', (44, 51))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miR-30d', 'Gene', '407033', (44, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('miR-29b', 'Gene', (93, 100))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('lung cancer', 'Disease', (16, 27))
175639	33380808	Huang et al demonstrated that miR-140-3p was downregulated in NSCLC cells and tissues, and regulated the process of NSCLC by directly targeting BRD9.	('BRD9', 'Gene', (144, 148))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('SCLC', 'Phenotype', 'HP:0030359', (117, 121))	('NSCLC', 'Disease', (62, 67))	('targeting', 'Reg', (134, 143))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('rat', 'Species', '10116', (19, 22))	('regulated', 'Reg', (91, 100))	('downregulated', 'NegReg', (45, 58))	('miR-140-3p', 'Var', (30, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('miR-140-3p', 'Chemical', '-', (30, 40))	('NSCLC', 'Disease', (116, 121))	('process', 'MPA', (105, 112))	('SCLC', 'Phenotype', 'HP:0030359', (63, 67))
175641	33380808	miR-140-3p directly targets BRD9 mRNA, inhibiting its protein translation and consequently downregulating the expression level of C-myc, and suppressing the proliferation of SCLC.	('expression level', 'MPA', (110, 126))	('miR-140-3p', 'Chemical', '-', (0, 10))	('BRD9', 'Gene', (28, 32))	('protein translation', 'MPA', (54, 73))	('C-myc', 'Gene', '4609', (130, 135))	('C-myc', 'Gene', (130, 135))	('downregulating', 'NegReg', (91, 105))	('suppressing', 'NegReg', (141, 152))	('SCLC', 'Disease', (174, 178))	('SCLC', 'Disease', 'MESH:D018288', (174, 178))	('rat', 'Species', '10116', (164, 167))	('SCLC', 'Phenotype', 'HP:0030359', (174, 178))	('miR-140-3p', 'Var', (0, 10))	('inhibiting', 'NegReg', (39, 49))
175652	33380808	For example, small-molecule inhibitors of the BRD9 bromodomain selectively suppress tumor cell proliferation and survival and induce apoptosis.	('survival', 'CPA', (113, 121))	('induce', 'Reg', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('apoptosis', 'CPA', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRD9', 'Gene', (46, 50))	('bromodomain', 'Gene', '679713', (51, 62))	('tumor', 'Disease', (84, 89))	('suppress', 'NegReg', (75, 83))	('bromodomain', 'Gene', (51, 62))	('inhibitors', 'Var', (28, 38))	('rat', 'Species', '10116', (102, 105))
175654	33380808	LP99 is the first reported selective BRD7/9 inhibitor that effectively inhibits the binding of BRD7/9 to acetylated histones in vivo and in vitro; Moreover, LP99 inhibits the secretion of proinflammatory cytokine IL-6.	('IL-6', 'Gene', '3569', (213, 217))	('acetylated', 'MPA', (105, 115))	('inhibits', 'NegReg', (162, 170))	('BRD7/9', 'Gene', '29117;65980', (37, 43))	('LP99', 'Var', (157, 161))	('LP99', 'Chemical', '-', (157, 161))	('BRD7/9', 'Gene', '29117;65980', (95, 101))	('IL-6', 'Gene', (213, 217))	('LP99', 'Chemical', '-', (0, 4))	('BRD7/9', 'Gene', (37, 43))	('binding', 'Interaction', (84, 91))	('inhibits', 'NegReg', (71, 79))	('BRD7/9', 'Gene', (95, 101))
175657	33380808	BRD9 inhibitors, BI-7273 and BI-9564, used to investigate the biological functions of BRD9 in vivo and in vitro were proven to be non-toxic by fragment-based screening.	('BI-7273', 'Chemical', '-', (17, 24))	('BRD9', 'Gene', (86, 90))	('BI-7273', 'Var', (17, 24))	('BI-9564', 'Var', (29, 36))	('BI-9564', 'Chemical', 'MESH:C000619421', (29, 36))
175659	33380808	Studies on the selection mechanism of I-BRD9 for the BRD9 bromodomain have demonstrated that several residues in the ZA and ZB loops of the bromodomain, such as Asp144, Ile53, Lys91, Thr104, Pro82, Asn140, Asn100, and Phe44, can be used as important references for designing BRD9 inhibitors.	('bromodomain', 'Gene', (140, 151))	('bromodomain', 'Gene', '679713', (140, 151))	('Asn100', 'Var', (206, 212))	('Ile53', 'Var', (169, 174))	('Asp144', 'Var', (161, 167))	('Phe44', 'Var', (218, 223))	('Asn100', 'Chemical', '-', (206, 212))	('bromodomain', 'Gene', '679713', (58, 69))	('bromodomain', 'Gene', (58, 69))	('Pro82', 'Var', (191, 196))	('Asp144', 'Chemical', '-', (161, 167))	('Asn140', 'Chemical', '-', (198, 204))	('Thr104', 'Chemical', '-', (183, 189))	('Lys91', 'Chemical', '-', (176, 181))	('Asn140', 'Var', (198, 204))	('Ile53', 'Chemical', '-', (169, 174))	('Thr104', 'Var', (183, 189))	('Phe44', 'Chemical', '-', (218, 223))	('rat', 'Species', '10116', (82, 85))	('Pro82', 'Chemical', '-', (191, 196))	('Lys91', 'Var', (176, 181))
175667	33380808	Repeated mutations in the subunits of the SWI/SNF complex in cancer make it a promising therapeutic target.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('SWI/SNF', 'Gene', (42, 49))	('mutations', 'Var', (9, 18))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
175675	33380808	It consists of a bromodomain and a DUF3512 domain.	('DUF3512', 'Chemical', '-', (35, 42))	('DUF3512', 'Var', (35, 42))	('bromodomain', 'Gene', (17, 28))	('bromodomain', 'Gene', '679713', (17, 28))
175676	33380808	The deletion of the DUF3512 domain affects the assembly of the ncBAF complex.	('DUF3512', 'Chemical', '-', (20, 27))	('assembly', 'MPA', (47, 55))	('DUF3512', 'Gene', (20, 27))	('affects', 'Reg', (35, 42))	('deletion', 'Var', (4, 12))	('cBAF', 'Chemical', '-', (64, 68))
175889	32511259	29 May 2020  PONE-D-19-28754R2  Hyperbaric oxygen therapy for radiation-induced tissue injury following sarcoma treatment: a retrospective analysis of a Dutch cohort.	('sarcoma', 'Disease', (104, 111))	('PONE-D-19-28754', 'Chemical', '-', (13, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('men', 'Species', '9606', (117, 120))	('tissue injury', 'Disease', (80, 93))	('oxygen', 'Chemical', 'MESH:D010100', (43, 49))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('tissue injury', 'Disease', 'MESH:D017695', (80, 93))	('PONE-D-19-28754R2', 'Var', (13, 30))
175943	30416636	The EWSR1 gene break apart rearrangement studies that were performed were positive, supporting and confirming the final diagnosis of ES of the cervical spine arising from the C-5 vertebral body.	('EWSR1', 'Gene', '2130', (4, 9))	('break', 'Var', (15, 20))	('ES', 'Phenotype', 'HP:0012254', (133, 135))	('EWSR1', 'Gene', (4, 9))	('break apart', 'Phenotype', 'HP:0001061', (15, 26))	('ES of the cervical spine', 'Disease', (133, 157))
175948	30416636	ES is characterized by Ewing's sarcoma family tumor containing 1 of 2 chromosomal translocations, with over 90% having a t(11;22) (q24;q12) translocation and the balance expressing a t(21;12)(22;12) translocation.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	("Ewing's sarcoma family tumor", 'Disease', (23, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	("Ewing's sarcoma family tumor", 'Disease', 'MESH:C563168', (23, 51))	('t(21', 'Var', (183, 187))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (23, 38))
175981	29497315	Overexpression or aberrant activation of this receptor has been demonstrated on both tumor cells and stroma.	('tumor', 'Disease', (85, 90))	('aberrant', 'Var', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('activation', 'PosReg', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
175983	29497315	PDGFR amplification and activating mutations have also been found in gastrointestinal stromal tumor (GIST).	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (69, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('activating', 'PosReg', (24, 34))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (69, 99))	('PDGFR', 'Gene', (0, 5))	('GIST', 'Phenotype', 'HP:0100723', (101, 105))	('amplification', 'Var', (6, 19))	('gastrointestinal stromal tumor', 'Disease', (69, 99))
175986	29497315	Pazopanib improved median PFS (4.6 vs 1.6 months, HR 0.31, 95% CI 0.24-0.40, p<0.001) compared with placebo, even if no differences in terms of OS were observed.	('improved', 'PosReg', (10, 18))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('OS', 'Chemical', '-', (144, 146))	('Pazopanib', 'Var', (0, 9))	('PFS', 'MPA', (26, 29))
175987	29497315	An in vitro study also showed that PDGFR overexpression represents a negative prognostic marker for survival in STS patients: the median OS in patients with a high vs low expression of PDGFRalpha was 27 vs 91 months, respectively.	('high', 'Var', (159, 163))	('PDGFRalpha', 'Gene', (185, 195))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (143, 151))	('OS', 'Chemical', '-', (137, 139))
176005	29497315	Later, it was also shown that olaratumab enhances the antitumor activity of doxorubicin against the same human soft-tissue sarcoma xenograft model.	('human', 'Species', '9606', (105, 110))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('olaratumab', 'Var', (30, 40))	('olaratumab', 'Chemical', 'MESH:C000589393', (30, 40))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('enhances', 'PosReg', (41, 49))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (111, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (76, 87))	('sarcoma', 'Disease', (123, 130))
176047	29497315	AEs were more frequent with combination therapy vs doxorubicin alone and included neutropenia (58% vs 35%, respectively), mucositis (53% vs 35%, respectively), nausea (73% vs 52%, respectively), vomiting (45% vs 18%, respectively), and diarrhea (34% vs 23%, respectively).	('diarrhea', 'Phenotype', 'HP:0002014', (236, 244))	('diarrhea', 'Disease', 'MESH:D003967', (236, 244))	('combination therapy', 'Var', (28, 47))	('neutropenia', 'Disease', 'MESH:D009503', (82, 93))	('diarrhea', 'Disease', (236, 244))	('neutropenia', 'Phenotype', 'HP:0001875', (82, 93))	('vomiting', 'Phenotype', 'HP:0002013', (195, 203))	('mucositis', 'Disease', (122, 131))	('vomiting', 'Disease', (195, 203))	('vomiting', 'Disease', 'MESH:D014839', (195, 203))	('neutropenia', 'Disease', (82, 93))	('doxorubicin', 'Chemical', 'MESH:D004317', (51, 62))	('nausea', 'Phenotype', 'HP:0002018', (160, 166))	('mucositis', 'Disease', 'MESH:D052016', (122, 131))	('nausea', 'Disease', (160, 166))	('nausea', 'Disease', 'MESH:D009325', (160, 166))
176064	29497315	The Phase II study of olaratumab in previously treated patients with metastatic GIST by Wagner et al showed a statistically different disease control rate in two different cohorts including patients with or without PDGFRalpha mutations.	('olaratumab', 'Chemical', 'MESH:C000589393', (22, 32))	('patients', 'Species', '9606', (190, 198))	('mutations', 'Var', (226, 235))	('patients', 'Species', '9606', (55, 63))	('GIST', 'Phenotype', 'HP:0100723', (80, 84))	('PDGFRalpha', 'Gene', (215, 225))	('metastatic GIST', 'Disease', (69, 84))
176095	29497315	Some differences between cohorts in the study arms were noticed; for example, the proportion of patients with undifferentiated pleomorphic sarcoma, an aggressive STS subtype, was higher in the doxorubicin monotherapy arm vs the combination arm (21% vs 15%, respectively).	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (110, 146))	('undifferentiated pleomorphic sarcoma', 'Disease', (110, 146))	('doxorubicin', 'Var', (193, 204))	('patients', 'Species', '9606', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('doxorubicin', 'Chemical', 'MESH:D004317', (193, 204))
176098	29497315	The effect of olaratumab on the PDGFR pathway also seems to be interesting, even if in the Phase Ib/II study, PDGFRalpha expression in tumor samples did not show any predictive value on efficacy and, indeed, the authors reported that negative expression of this marker was associated with a favorable outcome, which does not support PDGFRalpha inhibition in the tumor as the main mechanism of action.	('olaratumab', 'Chemical', 'MESH:C000589393', (14, 24))	('negative expression', 'Var', (234, 253))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('PDGFR', 'Pathway', (32, 37))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumor', 'Disease', (362, 367))	('favorable', 'Disease', (291, 300))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
176150	28905842	Both PEComas and smooth muscle neoplasms can show positivity to SMA, but the latter do not stain positive for melanocytic markers.	('SMA', 'Protein', (64, 67))	('PEComas', 'Disease', (5, 12))	('neoplasm', 'Phenotype', 'HP:0002664', (31, 39))	('PEComas', 'Disease', 'MESH:D054973', (5, 12))	('muscle neoplasms', 'Disease', 'MESH:D009217', (24, 40))	('SMA', 'Chemical', '-', (64, 67))	('muscle neoplasms', 'Disease', (24, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (31, 40))	('positivity', 'Var', (50, 60))
176151	28905842	Co-expression of melanocytic markers and SMA is thought to be the hallmark of PEComa and was seen in over 80% of cases in the review by Folpe et al.	('Co-expression', 'Var', (0, 13))	('PEComa', 'Disease', (78, 84))	('SMA', 'Chemical', '-', (41, 44))	('PEComa', 'Disease', 'MESH:D054973', (78, 84))
176177	28572589	Unfortunately, the limited availability of human sarcoma cell lines, as well as the complex genomic structures associated with the large number of STS subtypes, including chromosomal translocations and complex unstable karyotypes, has hampered sarcoma research.	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('sarcoma', 'Disease', (244, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('STS', 'Phenotype', 'HP:0030448', (147, 150))	('chromosomal translocations', 'Var', (171, 197))	('hampered', 'NegReg', (235, 243))	('sarcoma', 'Disease', 'MESH:D012509', (244, 251))	('human', 'Species', '9606', (43, 48))	('sarcoma', 'Disease', (49, 56))
176180	28572589	This is due to a number of factors, including introduction of new mutations in culture, difficulties in modeling interactions between tumor cells and host microenvironment, and the inability to study early tumor formation events.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('interactions', 'Interaction', (113, 125))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', (134, 139))
176182	28572589	These include transgenic murine models containing Pten  or Kras and Trp53  mutations that can develop a number of STS subtypes.	('Trp53', 'Gene', (68, 73))	('Pten', 'Gene', (50, 54))	('Pten', 'Gene', '19211', (50, 54))	('Trp53', 'Gene', '22059', (68, 73))	('Kras', 'Gene', (59, 63))	('Kras', 'Gene', '16653', (59, 63))	('mutations', 'Var', (75, 84))	('murine', 'Species', '10090', (25, 31))	('STS', 'Phenotype', 'HP:0030448', (114, 117))
176189	28572589	Although KRAS is rarely mutated in human STS, TP53 is among the most frequently mutated genes identified, and deregulation of both TP53 and KRAS signaling pathways is commonly utilized to produce sarcoma animal models.	('KRAS', 'Gene', '3845', (140, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('deregulation', 'Var', (110, 122))	('KRAS', 'Gene', (9, 13))	('human', 'Species', '9606', (35, 40))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('sarcoma', 'Disease', 'MESH:D012509', (196, 203))	('TP53', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (9, 13))	('STS', 'Phenotype', 'HP:0030448', (41, 44))	('KRAS', 'Gene', (140, 144))	('sarcoma', 'Disease', (196, 203))
176206	28572589	While exposure to adenoviral particle vectors encoding GFP (AdGFP) had no effect on total, wild type (WT), or mutant KRAS G12D and TP53 R167H expression in vitro (Fig.	('KRAS', 'Gene', (117, 121))	('mutant', 'Var', (110, 116))	('KRAS', 'Gene', '3845', (117, 121))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('R167H', 'Mutation', 'p.R167H', (136, 141))	('expression', 'MPA', (142, 152))	('G12D', 'Mutation', 'rs121913529', (122, 126))
176208	28572589	In addition, significantly higher mutant KRAS G12D and TP53 R167H expression (p = 0.013 and 0.011, respectively), and significantly lower WT KRAS and TP53 expression (p = 0.029 and 0.003, respectively) were observed in the STS cell lines compared to primary fibroblasts (Fig.	('G12D', 'Var', (46, 50))	('TP53', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (41, 45))	('KRAS', 'Gene', (141, 145))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('KRAS', 'Gene', '3845', (141, 145))	('G12D', 'Mutation', 'rs121913529', (46, 50))	('expression', 'MPA', (155, 165))	('expression', 'MPA', (66, 76))	('R167H', 'Mutation', 'p.R167H', (60, 65))	('higher', 'PosReg', (27, 33))	('lower', 'NegReg', (132, 137))	('KRAS', 'Gene', (41, 45))	('TP53', 'Gene', '7157', (150, 154))	('mutant', 'Var', (34, 40))	('STS', 'Phenotype', 'HP:0030448', (223, 226))
176211	28572589	However, significantly higher expression of mutant KRAS G12D was observed in the leiomyosarcomas (p = 0.026; Fig.	('KRAS', 'Gene', '3845', (51, 55))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (81, 96))	('expression', 'MPA', (30, 40))	('G12D', 'Mutation', 'rs121913529', (56, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('leiomyosarcomas', 'Disease', (81, 96))	('higher', 'PosReg', (23, 29))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (81, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('mutant', 'Var', (44, 50))	('KRAS', 'Gene', (51, 55))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (81, 96))
176212	28572589	Increased mutant TP53 R167H expression was also observed in the leiomyosarcomas, although the result was not significant due to the high level of variation in mutant TP53 R167H expression observed amongst the samples (p = 0.075; Fig.	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (64, 79))	('mutant', 'Var', (10, 16))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (64, 79))	('expression', 'MPA', (28, 38))	('TP53', 'Gene', '7157', (166, 170))	('R167H', 'Mutation', 'p.R167H', (22, 27))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (64, 78))	('leiomyosarcomas', 'Disease', (64, 79))	('Increased', 'PosReg', (0, 9))	('TP53', 'Gene', (166, 170))	('R167H', 'Mutation', 'p.R167H', (171, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('R167H', 'Var', (22, 27))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
176224	28572589	Disruptions in TP53 signaling result in uncontrolled proliferation and escape from cell death through altered regulation of the cell cycle and apoptosis, which represent crucial steps in tumor development and progression.	('Disruptions', 'Var', (0, 11))	('regulation', 'MPA', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('cell cycle', 'CPA', (128, 138))	('TP53', 'Gene', (15, 19))	('uncontrolled proliferation', 'CPA', (40, 66))	('apoptosis', 'CPA', (143, 152))	('TP53', 'Gene', '7157', (15, 19))	('escape from cell death', 'CPA', (71, 93))	('altered', 'Reg', (102, 109))
176237	28572589	Another important role of TP53 signaling is the induction of apoptosis, with evasion of apoptosis via altered TP53 signaling commonly observed in human STS.	('TP53', 'Gene', (26, 30))	('STS', 'Phenotype', 'HP:0030448', (152, 155))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('human', 'Species', '9606', (146, 151))	('TP53', 'Gene', '7157', (26, 30))	('altered', 'Var', (102, 109))
176268	28572589	Furthermore, knockdown of EZH2 induces cell death and inhibits tumor growth, suggesting that EZH2 may be an effective therapeutic target for STS.	('EZH2', 'Gene', '2146', (26, 30))	('tumor', 'Disease', (63, 68))	('EZH2', 'Gene', (26, 30))	('EZH2', 'Gene', '2146', (93, 97))	('EZH2', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('inhibits', 'NegReg', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('knockdown', 'Var', (13, 22))	('STS', 'Phenotype', 'HP:0030448', (141, 144))	('cell death', 'CPA', (39, 49))
176271	28572589	However, further epigenetic studies are required to confirm altered epigenetic regulator expression results in genome-wide epigenetic reprogramming in Oncopig STS, as well as their similarity to alterations observed in human STS subtypes.	('STS', 'Phenotype', 'HP:0030448', (225, 228))	('human', 'Species', '9606', (219, 224))	('epigenetic', 'MPA', (68, 78))	('pig', 'Species', '9823', (18, 21))	('pig', 'Species', '9823', (124, 127))	('pig', 'Species', '9823', (69, 72))	('pig', 'Species', '9823', (155, 158))	('altered', 'Var', (60, 67))	('Oncopig', 'Disease', (151, 158))	('STS', 'Phenotype', 'HP:0030448', (159, 162))
176275	28572589	FOSL1 is a key transcriptional regulator in human STS, with inhibitors of FOSL1 showing promise as osteosarcoma therapies.	('osteosarcoma', 'Disease', 'MESH:D012516', (99, 111))	('FOSL1', 'Gene', '8061', (0, 5))	('human', 'Species', '9606', (44, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('inhibitors', 'Var', (60, 70))	('STS', 'Phenotype', 'HP:0030448', (50, 53))	('FOSL1', 'Gene', (74, 79))	('FOSL1', 'Gene', '8061', (74, 79))	('FOSL1', 'Gene', (0, 5))	('osteosarcoma', 'Phenotype', 'HP:0002669', (99, 111))	('osteosarcoma', 'Disease', (99, 111))
176276	28572589	TP53 is also believed to regulate FOSL1 expression, providing an indirect link between mutant TP53 R167H expression and nearly half of the elevated gene expression identified in the Oncopig STS cell lines.	('TP53', 'Gene', '7157', (0, 4))	('FOSL1', 'Gene', (34, 39))	('TP53', 'Gene', (0, 4))	('STS', 'Phenotype', 'HP:0030448', (190, 193))	('FOSL1', 'Gene', '8061', (34, 39))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutant', 'Var', (87, 93))	('R167H', 'Mutation', 'p.R167H', (99, 104))	('pig', 'Species', '9823', (186, 189))
176285	28572589	In addition, increased ETV4 expression, as well as gene fusions between ETV4 and EWSR1 or EWS, are observed in human Ewing sarcomas, highlighting the importance of these transcription factors in human STS development.	('EWS', 'Gene', (90, 93))	('ETV4', 'Gene', (72, 76))	('EWS', 'Gene', (81, 84))	('ETV4', 'Gene', (23, 27))	('increased', 'PosReg', (13, 22))	('EWSR1', 'Gene', '2130', (81, 86))	('human', 'Species', '9606', (111, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('ETV4', 'Gene', '2118', (72, 76))	('STS', 'Phenotype', 'HP:0030448', (201, 204))	('EWS', 'Gene', '2130', (90, 93))	('gene fusions', 'Var', (51, 63))	('ETV4', 'Gene', '2118', (23, 27))	('EWS', 'Gene', '2130', (81, 84))	('EWSR1', 'Gene', (81, 86))	('human', 'Species', '9606', (195, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (117, 131))	('expression', 'MPA', (28, 38))	('Ewing sarcomas', 'Disease', (117, 131))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (117, 131))
176308	28572589	Samtools mpileup was used to determine WT:mutant TP53 and KRAS expression ratios based on the reads overlapping the mutation site.	('KRAS', 'Gene', (58, 62))	('mutant', 'Var', (42, 48))	('KRAS', 'Gene', '3845', (58, 62))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))
176445	21344536	mRNA and Protein Levels of FUS, EWSR1 and TAF15 are Upregulated in Liposarcoma Translocations or mutations of FUS, EWSR1 and TAF15 (FET) result in distinct genetic diseases.	('mutations', 'Var', (97, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('TAF15', 'Gene', (125, 130))	('FUS', 'Gene', '2521', (27, 30))	('EWSR1', 'Gene', (115, 120))	('TAF15', 'Gene', '8148', (125, 130))	('genetic diseases', 'Disease', 'MESH:D030342', (156, 172))	('result in', 'Reg', (137, 146))	('Liposarcoma', 'Phenotype', 'HP:0012034', (67, 78))	('EWSR1', 'Gene', '2130', (32, 37))	('FUS', 'Gene', (110, 113))	('genetic diseases', 'Disease', (156, 172))	('TAF15', 'Gene', (42, 47))	('Liposarcoma', 'Disease', 'MESH:D008080', (67, 78))	('TAF15', 'Gene', '8148', (42, 47))	('Upregulated', 'PosReg', (52, 63))	('FUS', 'Gene', '2521', (110, 113))	('Liposarcoma', 'Disease', (67, 78))	('EWSR1', 'Gene', (32, 37))	('EWSR1', 'Gene', '2130', (115, 120))	('FUS', 'Gene', (27, 30))
176446	21344536	N-terminal translocations of any FET protein to a series of transcription factors yields chimeric proteins that contribute to sarcomagenesis, whereas mutations in the conserved C-terminal domain of wild-type FUS were recently shown to cause familial amyotrophic lateral sclerosis.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('familial amyotrophic lateral sclerosis', 'Disease', 'MESH:C531617', (241, 279))	('contribute', 'Reg', (112, 122))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (250, 279))	('chimeric', 'MPA', (89, 97))	('sarcoma', 'Disease', (126, 133))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('mutations in', 'Var', (150, 162))	('proteins', 'Protein', (98, 106))	('familial amyotrophic lateral sclerosis', 'Disease', (241, 279))	('cause', 'Reg', (235, 240))
176447	21344536	We thus investigated whether the loss of one FUS allele by translocation in liposarcoma may be followed by mutations in either the remaining FUS allele or the paralogous EWSR1.	('liposarcoma', 'Phenotype', 'HP:0012034', (76, 87))	('liposarcoma', 'Disease', 'MESH:D008080', (76, 87))	('mutations', 'Var', (107, 116))	('translocation', 'Var', (59, 72))	('EWSR1', 'Gene', (170, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('EWSR1', 'Gene', '2130', (170, 175))	('liposarcoma', 'Disease', (76, 87))
176460	21344536	Recently, mutations in the very C-terminus of FUS have been described in familial amyotrophic lateral sclerosis (FALS) in about 5 - 10 % of all cases.	('familial amyotrophic lateral sclerosis', 'Disease', 'MESH:C531617', (73, 111))	('FUS', 'Gene', (46, 49))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (82, 111))	('mutations in', 'Var', (10, 22))	('described', 'Reg', (60, 69))	('familial amyotrophic lateral sclerosis', 'Disease', (73, 111))
176461	21344536	Prior to the discovery that FUS mutations cause FALS, recurrent translocations of both FUS and EWSR1 were recognized in sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('EWSR1', 'Gene', '2130', (95, 100))	('sarcomas', 'Disease', (120, 128))	('FALS', 'Disease', (48, 52))	('mutations', 'Var', (32, 41))	('translocations', 'Var', (64, 78))	('EWSR1', 'Gene', (95, 100))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('FUS', 'Gene', (87, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
176463	21344536	Myxoid-round cell liposarcoma (MRCLS) is the second most common biological group of liposarcoma and is characterized by the presence of a reciprocal chromosomal translocation, t(12;16)(q13;p11), involving FUS and DDIT3/CHOP, found in more than 90% of MRCLS cases.	('MRCLS', 'Chemical', '-', (31, 36))	('t(12;16)(q13;p11', 'Var', (176, 192))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (176, 193))	('liposarcoma', 'Disease', 'MESH:D008080', (18, 29))	('liposarcoma', 'Phenotype', 'HP:0012034', (18, 29))	('Myxoid-round cell liposarcoma', 'Disease', (0, 29))	('liposarcoma', 'Disease', (84, 95))	('CHOP', 'Gene', '1649', (219, 223))	('liposarcoma', 'Disease', 'MESH:D008080', (84, 95))	('Myxoid-round cell liposarcoma', 'Disease', 'MESH:D018208', (0, 29))	('liposarcoma', 'Phenotype', 'HP:0012034', (84, 95))	('liposarcoma', 'Disease', (18, 29))	('CHOP', 'Gene', (219, 223))	('MRCLS', 'Chemical', '-', (251, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
176468	21344536	As already mentioned, the characteristic FUS-DDIT3 translocation is found in 90% of all MRCLS whereas its EWSR1 counterpart in only 5%.	('EWSR1', 'Gene', '2130', (106, 111))	('EWSR1', 'Gene', (106, 111))	('MRCLS', 'Chemical', '-', (88, 93))	('translocation', 'Var', (51, 64))
176473	21344536	Drawing parallels to leukemia, chromosome translocations are necessary, but not sufficient to directly cause leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (21, 29))	('leukemia', 'Disease', 'MESH:D007938', (21, 29))	('leukemia', 'Disease', (21, 29))	('chromosome translocations', 'Var', (31, 56))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('leukemia', 'Disease', (109, 117))	('leukemia', 'Disease', 'MESH:D007938', (109, 117))
176475	21344536	The discovery of FALS-causing mutations in FUS, but also the reduction in FET protein levels due to the loss of one allele in the translocation, prompted us to investigate whether mutations in the FET proteins or unexpected changes in the FET protein or transcript abundance play an additional role in sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (302, 309))	('FET protein levels', 'MPA', (74, 92))	('FUS', 'Gene', (43, 46))	('reduction', 'NegReg', (61, 70))	('transcript abundance', 'MPA', (254, 274))	('changes', 'Reg', (224, 231))	('mutations', 'Var', (30, 39))	('sarcoma', 'Disease', 'MESH:D012509', (302, 309))	('FET', 'MPA', (239, 242))	('FALS-causing', 'Reg', (17, 29))	('sarcoma', 'Disease', (302, 309))
176503	21344536	TaqMan Gene Expression Assays (AB), which include gene-specific probe and primer sets, were used according to the manufacturer's protocol to detect EWSR1 (Hs01580532_g1), FUS (Hs01100216_g1), TAF15 (Hs00896635_m1) and 18s rRNA (Hs99999901_s1).	('Hs01100216_g1', 'Var', (176, 189))	('Hs01580532_g1', 'Var', (155, 168))	('Hs99999901_s1', 'Var', (228, 241))	('EWSR1', 'Gene', (148, 153))	('TAF15', 'Gene', (192, 197))	('Hs00896635_m1', 'Var', (199, 212))	('EWSR1', 'Gene', '2130', (148, 153))	('TAF15', 'Gene', '8148', (192, 197))
176516	21344536	We detected no mutations and also found no single nucleotide polymorphisms (SNPs) in the FUS segments of the 96 samples that we sequenced, despite several reported SNPs in the selected genomic region (NCBI database of single nucleotide polymorphisms: rs68121698, rs72550884, rs72550885, rs68121698, rs13331793).	('rs72550885', 'Var', (275, 285))	('rs72550884', 'Var', (263, 273))	('rs68121698', 'Mutation', 'rs68121698', (287, 297))	('rs13331793', 'Mutation', 'rs13331793', (299, 309))	('rs68121698', 'Var', (251, 261))	('rs72550885', 'Mutation', 'rs72550885', (275, 285))	('rs68121698', 'Mutation', 'rs68121698', (251, 261))	('rs72550884', 'Mutation', 'rs72550884', (263, 273))	('rs13331793', 'Var', (299, 309))	('rs68121698', 'Var', (287, 297))
176519	21344536	We also sequenced the paralogous region of the EWSR1 gene, but although we confirmed a previously reported SNP (rs2518683; average heterozygous frequency 19%) in three patient tissues (3.1%), we did not find any new mutations.	('EWSR1', 'Gene', '2130', (47, 52))	('patient', 'Species', '9606', (168, 175))	('rs2518683', 'Mutation', 'rs2518683', (112, 121))	('EWSR1', 'Gene', (47, 52))	('rs2518683;', 'Var', (112, 122))
176521	21344536	Additionally, we found two previously not reported, intronic sequence variations (hg19: chr22:28,025,421 and chr22:28,025,871) in two independent DDLS samples, the first was a homozygous base change from C to T, the second a heterozygous base change from C to T. Next, we examined how the loss of one FET family member allele affected FET family mRNA and protein levels in various liposarcoma cell lines compared to reference samples.	('liposarcoma', 'Phenotype', 'HP:0012034', (381, 392))	('affected', 'Reg', (326, 334))	('sarcoma', 'Phenotype', 'HP:0100242', (385, 392))	('variations', 'Var', (70, 80))	('liposarcoma', 'Disease', (381, 392))	('liposarcoma', 'Disease', 'MESH:D008080', (381, 392))
176528	21344536	Looking specifically at liposarcoma cell lines with FUS-DDIT3 translocations (MRCLS) and those characterized by 12q amplification without FUS-DDIT3 translocations (DDLS, WDLS), there was a 5.3% decrease in mRNA levels for FUS, and an 8.3% increase of TAF15 compared with ASCs.	('translocations', 'Var', (62, 76))	('liposarcoma', 'Disease', 'MESH:D008080', (24, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('FUS-DDIT3 translocations', 'Var', (52, 76))	('TAF15', 'Gene', '8148', (251, 256))	('TAF15', 'Gene', (251, 256))	('MRCLS', 'Chemical', '-', (78, 83))	('increase', 'PosReg', (239, 247))	('liposarcoma', 'Disease', (24, 35))	('decrease', 'NegReg', (194, 202))	('liposarcoma', 'Phenotype', 'HP:0012034', (24, 35))	('mRNA levels', 'MPA', (206, 217))
176530	21344536	The fact that the mRNA level for FUS in the MRCLS cell line harboring a FUS-DDIT3 translocation was only 9.3% reduced instead of the expected 50% down-regulation suggests that posttranscriptional regulation compensates for the loss of one allele upon translocation to a certain degree.	('MRCLS', 'Chemical', '-', (44, 49))	('mRNA level', 'MPA', (18, 28))	('translocation', 'Var', (82, 95))	('reduced', 'NegReg', (110, 117))
176541	21344536	Translocations involving the promoter and N-terminal domains of the FET family of RNA-binding proteins have long been recognized as important players in human sarcomagenesis, and are now widely used by pathologists to improve diagnostic accuracy and tumor classification.	('Translocations', 'Var', (0, 14))	('sarcoma', 'Disease', (159, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('human', 'Species', '9606', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (250, 255))	('sarcoma', 'Disease', 'MESH:D012509', (159, 166))
176543	21344536	Nevertheless, while the chimeric translocation proteins are considered to act as oncogenic transcription factors activating downstream targets important in sarcomagenesis, FET proteins may also function as tumor suppressors, and the concomitant loss of one of its alleles may be followed by mutations in its remaining allele.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('sarcoma', 'Disease', 'MESH:D012509', (156, 163))	('tumor', 'Disease', (206, 211))	('loss', 'NegReg', (245, 249))	('sarcoma', 'Disease', (156, 163))	('mutations', 'Var', (291, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
176544	21344536	The latter hypothesis has never been tested, but when C-terminal domain mutations in FUS were shown to cause familial amyotrophic sclerosis (FALS), we were interested in assessing the mutational status of FUS and its paralog EWSR1 in this region.	('EWSR1', 'Gene', (225, 230))	('FUS', 'Gene', (85, 88))	('amyotrophic sclerosis', 'Phenotype', 'HP:0007354', (118, 139))	('cause', 'Reg', (103, 108))	('familial amyotrophic sclerosis', 'Disease', (109, 139))	('familial amyotrophic sclerosis', 'Disease', 'MESH:C531617', (109, 139))	('EWSR1', 'Gene', '2130', (225, 230))	('C-terminal domain mutations', 'Var', (54, 81))
176546	21344536	Given the frequency at which FALS is caused by mutations in FUS, we might have expected at least a few patients to carry a mutation, especially if the mutations functioned as tumor suppressors, yet we detected none.	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('FUS', 'Gene', (60, 63))	('caused by', 'Reg', (37, 46))	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('patients', 'Species', '9606', (103, 111))	('FALS', 'Disease', (29, 33))
176547	21344536	It is probably safe to assume that mutations in FUS as found in FALS are not oncogenic and control pathways unrelated to tumorigenesis but rather contribute to the death of motor neurons.	('contribute', 'Reg', (146, 156))	('death', 'CPA', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('FUS', 'Gene', (48, 51))	('mutations', 'Var', (35, 44))
176549	21344536	Another interesting aspect of FET family genes is their involvement in translocations that contribute to sarcomagenesis and leukemogenesis.	('sarcomagenesis and leukemogenesis', 'Disease', 'None', (105, 138))	('involvement', 'Reg', (56, 67))	('contribute', 'Reg', (91, 101))	('translocations', 'Var', (71, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('FET family genes', 'Gene', (30, 46))
176556	21344536	Overall, EWSR1 translocations in sarcomas - with the exception of liposarcoma - are much more common than FUS translocation.	('common', 'Reg', (94, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('EWSR1', 'Gene', (9, 14))	('translocations', 'Var', (15, 29))	('liposarcoma', 'Disease', (66, 77))	('sarcomas', 'Disease', 'MESH:D012509', (33, 41))	('EWSR1', 'Gene', '2130', (9, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('liposarcoma', 'Disease', 'MESH:D008080', (66, 77))	('sarcomas', 'Disease', (33, 41))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))
176557	21344536	Our results indicate that this might be due to the fact that EWSR1 fusions with their very strong promoter have even more oncogenic potential than those of FUS.	('EWSR1', 'Gene', (61, 66))	('EWSR1', 'Gene', '2130', (61, 66))	('oncogenic potential', 'CPA', (122, 141))	('fusions', 'Var', (67, 74))
176569	29891538	These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('NY-ESO-1c259T', 'Var', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('NY-ESO-1c259T', 'Chemical', '-', (46, 59))
176600	29891538	We also observed direct evidence of tumor trafficking by NY-ESO-1c259T cells in patient 206, who received a dose of NY-ESO-1c259T cells below the protocol-specified minimum dose (Table 1), then developed signs and symptoms consistent with a delayed cytokine release syndrome (CRS) on day 56 following cell infusion.	('delayed cytokine release', 'Phenotype', 'HP:0031407', (241, 265))	('NY-ESO-1c259T', 'Chemical', '-', (57, 70))	('NY-ESO-1c259T', 'Chemical', '-', (116, 129))	('NY-ESO-1c259T cells', 'Var', (116, 135))	('CRS', 'Disease', (276, 279))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('CRS', 'Disease', 'MESH:D003398', (276, 279))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('developed', 'Reg', (194, 203))	('delayed cytokine release syndrome', 'Disease', (241, 274))	('tumor', 'Disease', (36, 41))	('patient', 'Species', '9606', (80, 87))
176602	29891538	2C) and drainage of pleural fluid was performed, which demonstrated NY-ESO-1c259T cells within both the tumor mass and the pleural fluid (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('NY-ESO-1c259T', 'Var', (68, 81))	('tumor', 'Disease', (104, 109))	('pleural fluid', 'Phenotype', 'HP:0002202', (20, 33))	('pleural fluid', 'Phenotype', 'HP:0002202', (123, 136))	('NY-ESO-1c259T', 'Chemical', '-', (68, 81))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
176633	29891538	Because the dextramer reagent used to identify NY-ESO-1c259T cells binds more reliably to CD8+ T cells compared with CD4+ T cells, this analysis was limited to the CD8+ subset.	('dextramer', 'Chemical', '-', (12, 21))	('CD8', 'Gene', '925', (90, 93))	('NY-ESO-1c259T', 'Chemical', '-', (47, 60))	('CD8', 'Gene', (164, 167))	('CD8', 'Gene', '925', (164, 167))	('CD4', 'Gene', (117, 120))	('CD4', 'Gene', '920', (117, 120))	('CD8', 'Gene', (90, 93))	('NY-ESO-1c259T', 'Var', (47, 60))
176646	29891538	Beyond small studies demonstrating activity of virus-specific TILs in cervical cancer or a TIL product enriched for mutations in hepatobiliary carcinoma, the efficacy of adoptive therapy using TILs has not been convincingly demonstrated beyond melanoma.	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('carcinoma', 'Disease', (143, 152))	('carcinoma', 'Disease', 'MESH:D009369', (143, 152))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('mutations', 'Var', (116, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('melanoma', 'Disease', (244, 252))
176649	29891538	We demonstrate expansion of NY-ESO-1c259T cells postinfusion in all patients and persistence of NY-ESO-1c259T cells for 6 months in all responders and in 1 of 6 nonresponders.	('NY-ESO-1c259T', 'Var', (96, 109))	('patients', 'Species', '9606', (68, 76))	('NY-ESO-1c259T', 'Chemical', '-', (28, 41))	('NY-ESO-1c259T', 'Gene', (28, 41))	('NY-ESO-1c259T', 'Chemical', '-', (96, 109))
176658	29891538	The impressive persistence of the NY-ESO-1c259T cells in these patients, associated with continued antitumor effects in vivo and polyfunctionality ex vivo, provided an opportunity to more deeply analyze biological features associated with persistently functional T-cell populations following adoptive transfer.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('NY-ESO-1c259T', 'Var', (34, 47))	('tumor', 'Disease', (103, 108))	('NY-ESO-1c259T', 'Chemical', '-', (34, 47))	('patients', 'Species', '9606', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
176671	29891538	Furthermore, the observation that persistent clonotypes distribute more uniformly across regenerative and effector subsets than random clonotypes, due to the efficient generation of effector pools, illustrates that NY-ESOc259T exhibits a balance of efficient effector T-cell generation and robust self-renewal.	('NY-ESOc259T', 'Chemical', '-', (215, 226))	('effector T-cell generation', 'CPA', (259, 285))	('NY-ESOc259T', 'Var', (215, 226))
176695	29891538	Vector was produced at the City of Hope (Duarte, CA) using transient transfection with four plasmids expressing the transfer vector, rev, VSV-G, and gag/pol, in 293T cells.	('293T', 'CellLine', 'CVCL:0063', (161, 165))	('VSV-G', 'Var', (138, 143))	('gag/pol', 'Gene', (149, 156))	('gag/pol', 'Gene', '100616496', (149, 156))
176703	29891538	The following antibodies were used for T-cell phenotyping: CD8-BV650 (BD), CD4-BV605 (BD Biosciences), CD3-Alexa Fluor700 (BD Biosciences), CD95-BV711 (BD Biosciences), CD45RO-PerCPCy5.5 (BD Biosciences), CD25-APC-Cy7 (BD Biosciences), CD127-BV421 (BioLegend), CCR7-PE-Cy7 (BioLegend), CD45RA-ECD (Beckman Coulter), PD-1-BV785 (BioLegend), LAG3-FITC (R&D Systems), and TIM3-APC (R&D Systems).	('CD4', 'Gene', (286, 289))	('CD25', 'Gene', '3559', (205, 209))	('LAG3', 'Gene', (340, 344))	('CD4', 'Gene', '920', (75, 78))	('CD95', 'Gene', '355', (140, 144))	('APC', 'Gene', (374, 377))	('PD-1-BV785', 'Var', (316, 326))	('TIM3', 'Gene', (369, 373))	('CCR7', 'Gene', (261, 265))	('TIM3', 'Gene', '84868', (369, 373))	('CD4', 'Gene', (75, 78))	('CD4', 'Gene', '920', (169, 172))	('APC', 'Gene', '324', (210, 213))	('CD45RO', 'Gene', (169, 175))	('CD45RA', 'Gene', (286, 292))	('CD8-BV650', 'Gene', '925', (59, 68))	('CD8-BV650', 'Gene', (59, 68))	('CD45RA', 'Gene', '5788', (286, 292))	('CD4', 'Gene', (169, 172))	('CCR7', 'Gene', '1236', (261, 265))	('CD45RO', 'Gene', '5788', (169, 175))	('CD95', 'Gene', (140, 144))	('CD25', 'Gene', (205, 209))	('PE', 'Chemical', '-', (266, 268))	('APC', 'Gene', (210, 213))	('CD4', 'Gene', '920', (286, 289))	('APC', 'Gene', '324', (374, 377))	('LAG3', 'Gene', '3902', (340, 344))
176707	29891538	The following antibodies were used for identification of transduced T cells for sorting and subsequent postsort phenotypic analysis: CD8-QDOT655 (Life Technologies), CD4-AF780 (eBioscience), CD3-AF700 (eBioscience), CCR7-PE-CF594 (BD Biosciences) and CD45RA-FITC (eBioscience), CD127-BV421 (BioLegend), CD95-BV711 (BD Biosciences).	('CD4', 'Gene', (251, 254))	('CD127-BV421', 'Var', (278, 289))	('CD95', 'Gene', '355', (303, 307))	('CCR7', 'Gene', (216, 220))	('CD8', 'Gene', (133, 136))	('CD4', 'Gene', '920', (251, 254))	('CD8', 'Gene', '925', (133, 136))	('CCR7', 'Gene', '1236', (216, 220))	('CD4', 'Gene', (166, 169))	('CD4', 'Gene', '920', (166, 169))	('PE', 'Chemical', '-', (221, 223))	('CD95', 'Gene', (303, 307))	('CD45RA', 'Gene', (251, 257))	('CD3-AF700', 'Var', (191, 200))	('CD45RA', 'Gene', '5788', (251, 257))
176749	33099834	It has been known for more than 30 years that gene fusions play an important role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('gene fusions', 'Var', (46, 58))
176754	33099834	8  The aberration leads at the molecular level to fusion of two zinc finger genes, JAZF1 (from 7p15) and SUZ12 (previously known as JJAZ1; from 17q21; Figure 1).	('JAZF1', 'Gene', '221895', (83, 88))	('JJAZ1', 'Gene', '23512', (132, 137))	('JJAZ1', 'Gene', (132, 137))	('JAZF1', 'Gene', (83, 88))	('SUZ12', 'Gene', '23512', (105, 110))	('SUZ12', 'Gene', (105, 110))	('fusion', 'Var', (50, 56))
176758	33099834	11  Other partners are EPC1 through a 6;10-rearrangement 11 ; MEAF6 through a t(1;6)(p34;p21) 12 ; BRD8 via t(5;6)(q31;p21) 13 ; EPC2 through a 2;6-rearrangement 14 ; and recently a MBTD1/PHF1 was also reported.	('MEAF6', 'Gene', '64769', (62, 67))	('MBTD1', 'Gene', (182, 187))	('PHF1', 'Gene', '5252', (188, 192))	('EPC1', 'Gene', '80314', (23, 27))	('EPC1', 'Gene', (23, 27))	('t(5;6)(q31;p21)', 'STRUCTURAL_ABNORMALITY', 'None', (108, 123))	('EPC2', 'Gene', '26122', (129, 133))	('EPC2', 'Gene', (129, 133))	('BRD8', 'Gene', '10902', (99, 103))	('BRD8', 'Gene', (99, 103))	('t(1;6)(p34;p21)', 'STRUCTURAL_ABNORMALITY', 'None', (78, 93))	('MBTD1', 'Gene', '54799', (182, 187))	('MEAF6', 'Gene', (62, 67))	('PHF1', 'Gene', (188, 192))	('t(5;6)(q31;p21) 13', 'Var', (108, 126))
176759	33099834	16  showed that tumors bearing PHF1 fusions, independently of which partner gene is involved, typically present sex cord-like differentiation, leading the authors to suggest that rearrangements of this gene preferentially induce such differentiation.	('rearrangements', 'Var', (179, 193))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('sex cord-like differentiation', 'CPA', (112, 141))	('fusions', 'Var', (36, 43))	('PHF1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('PHF1', 'Gene', '5252', (31, 35))	('induce', 'Reg', (222, 228))	('tumors', 'Disease', (16, 22))
176760	33099834	A less frequent chromosomal rearrangement is the t(X;17)(p11;q21) leading to the MBTD1/EZHIP (previously known as CXorf67) fusion.	('t(X;17)(p11;q21', 'Var', (49, 64))	('fusion', 'Var', (123, 129))	('CXorf67', 'Gene', (114, 121))	('MBTD1', 'Gene', '54799', (81, 86))	('MBTD1', 'Gene', (81, 86))	('CXorf67', 'Gene', '340602', (114, 121))	('t(X;17)(p11;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 65))
176778	33099834	41  reported a low frequency of YWHAE and NUTM2A/B rearrangements in epithelioid leiomyosarcoma; admittedly, the immunostaining data of that study were suggestive of an unusual ESS.	('NUTM2A/B', 'Gene', (42, 50))	('leiomyosarcoma', 'Disease', (81, 95))	('rearrangements', 'Var', (51, 65))	('YWHAE', 'Gene', '7531', (32, 37))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (81, 95))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (81, 95))	('NUTM2A/B', 'Gene', '728118;729262', (42, 50))	('YWHAE', 'Gene', (32, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
176780	33099834	42  Despite the fact that no fusion transcript involving the mentioned genes was discovered, the authors suggested that abnormalities of them may contribute to development of uterine angiosarcoma in much the same manner as they do in ESS.	('contribute', 'Reg', (146, 156))	('angiosarcoma', 'Disease', (183, 195))	('uterine angiosarcoma', 'Phenotype', 'HP:0000131', (175, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('angiosarcoma', 'Phenotype', 'HP:0200058', (183, 195))	('abnormalities', 'Var', (120, 133))	('angiosarcoma', 'Disease', 'MESH:D006394', (183, 195))
176795	33099834	52  reported the first HG-ESS with BCOR internal tandem duplication (ITD), the same aberration previously found in clear cell sarcoma of the kidney (CCSK) 58 ,  59  and primitive myxoid mesenchymal tumor of infancy.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (126, 147))	('BCOR', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('BCOR', 'Gene', '54880', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('clear cell sarcoma of the kidney', 'Disease', (115, 147))	('CCSK', 'Chemical', '-', (149, 153))	('tumor', 'Disease', (198, 203))	('clear cell sarcoma of the kidney', 'Disease', 'MESH:D018227', (115, 147))	('internal tandem duplication', 'Var', (40, 67))
176799	33099834	62 ,  63  Truncating mutations or gene deletions occurring in BCOR have also been identified in acute myeloid leukemia, retinoblastoma, diffuse glioma, and medulloblastoma.	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('identified', 'Reg', (82, 92))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (96, 118))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (102, 118))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (96, 118))	('glioma', 'Disease', (144, 150))	('retinoblastoma', 'Disease', 'MESH:D012175', (120, 134))	('medulloblastoma', 'Disease', 'MESH:D008527', (156, 171))	('medulloblastoma', 'Phenotype', 'HP:0002885', (156, 171))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('medulloblastoma', 'Disease', (156, 171))	('BCOR', 'Gene', '54880', (62, 66))	('BCOR', 'Gene', (62, 66))	('Truncating mutations', 'Var', (10, 30))	('retinoblastoma', 'Phenotype', 'HP:0009919', (120, 134))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('retinoblastoma', 'Disease', (120, 134))	('acute myeloid leukemia', 'Disease', (96, 118))	('gene deletions', 'Var', (34, 48))
176800	33099834	64 ,  65 ,  66  The detection of aberrations of this gene already plays a key role in the diagnosis of some malignancies, for example, high-grade neuroepithelial tumor of the central nervous system with BCOR gene alteration.	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (146, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (146, 167))	('BCOR', 'Gene', '54880', (203, 207))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('aberrations', 'Var', (33, 44))	('tumor of the central nervous system', 'Phenotype', 'HP:0100006', (162, 197))	('malignancies', 'Disease', (108, 120))	('neuroepithelial tumor', 'Disease', (146, 167))	('BCOR', 'Gene', (203, 207))
176810	33099834	48  BCOR immunohistochemistry can be used diagnostically to separate all the above-mentioned tumors (with BCOR genetic rearrangement) from their histological mimics.	('genetic rearrangement', 'Var', (111, 132))	('BCOR', 'Gene', '54880', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('BCOR', 'Gene', (106, 110))	('tumors', 'Disease', (93, 99))	('BCOR', 'Gene', (4, 8))	('BCOR', 'Gene', '54880', (106, 110))
176812	33099834	70  who detected rearrangements of YWHAE, BCOR, and PHF1 in a series of tumors previously classified as UUS based on morphologic and immunohistochemical features.	('YWHAE', 'Gene', '7531', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('rearrangements', 'Var', (17, 31))	('BCOR', 'Gene', '54880', (42, 46))	('PHF1', 'Gene', (52, 56))	('detected', 'Reg', (8, 16))	('YWHAE', 'Gene', (35, 40))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('PHF1', 'Gene', '5252', (52, 56))	('BCOR', 'Gene', (42, 46))
176813	33099834	71  identified a YWHAE deletion in a vagina wall metastasis from a monomorphic undifferentiated sarcoma, as the tumor was classified at that time.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('deletion', 'Var', (23, 31))	('undifferentiated sarcoma', 'Disease', (79, 103))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('YWHAE', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('YWHAE', 'Gene', '7531', (17, 22))	('tumor', 'Disease', (112, 117))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (79, 103))
176814	33099834	Also, two tumors with morphologic feature of LG-ESS have had YWHAE rearrangements: a YWHAE/NUTM2A fusion was identified in a tumor confined within the endometrium, 72  whereas deletion of a 3' probe for YWHAE was shown in an LG-ESS and in its recurrence in a case showing progression from LG- to HG-ESS.	('deletion', 'Var', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumors', 'Disease', (10, 16))	('LG-ESS', 'Disease', (225, 231))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('LG-ESS', 'Chemical', '-', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('YWHAE', 'Gene', (61, 66))	('NUTM2A', 'Gene', (91, 97))	('YWHAE', 'Gene', (85, 90))	('YWHAE', 'Gene', (203, 208))	('YWHAE', 'Gene', '7531', (61, 66))	('YWHAE', 'Gene', '7531', (85, 90))	('YWHAE', 'Gene', '7531', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('LG-ESS', 'Chemical', '-', (225, 231))	('NUTM2A', 'Gene', '728118', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', (125, 130))
176817	33099834	50 ,  74 ,  75 ,  76  These tumors harbor gene fusions that are typically associated with LG-ESS.	('LG-ESS', 'Disease', (90, 96))	('gene fusions', 'Var', (42, 54))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('LG-ESS', 'Chemical', '-', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('associated', 'Reg', (74, 84))
176823	33099834	In later years, much effort has gone into the identification of molecular mechanisms behind ESS-specific genetic rearrangements with the goal of unraveling how they contribute to tumorigenesis and, eventually, how this knowledge can lead to novel therapeutic approaches.	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('lead', 'Reg', (233, 237))	('contribute', 'Reg', (165, 175))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('rearrangements', 'Var', (113, 127))	('genetic rearrangements', 'Var', (105, 127))	('tumor', 'Disease', (179, 184))
176826	33099834	78 ,  79  The JAZF1/SUZ12 chimera was first demonstrated to inhibit apoptosis and induce proliferation rates above normal in both benign and malignant uterine tumors, although only in the malignant form was suppression of the wild type/unrearranged SUZ12 allele identified.	('proliferation rates', 'CPA', (89, 108))	('uterine tumors', 'Phenotype', 'HP:0010784', (151, 165))	('malignant uterine tumors', 'Disease', 'MESH:D009369', (141, 165))	('malignant uterine tumors', 'Disease', (141, 165))	('SUZ12', 'Gene', (20, 25))	('induce', 'PosReg', (82, 88))	('inhibit', 'NegReg', (60, 67))	('chimera', 'Var', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('apoptosis', 'CPA', (68, 77))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('SUZ12', 'Gene', '23512', (249, 254))	('uterine tumor', 'Phenotype', 'HP:0010784', (151, 164))	('JAZF1', 'Gene', (14, 19))	('SUZ12', 'Gene', (249, 254))	('SUZ12', 'Gene', '23512', (20, 25))	('JAZF1', 'Gene', '221895', (14, 19))
176828	33099834	80  A similar mechanism was seen for ESS bearing JAZF1/PHF1 fusion with simultaneous silencing of the normal PHF1 allele.	('fusion', 'Var', (60, 66))	('JAZF1', 'Gene', '221895', (49, 54))	('PHF1', 'Gene', (55, 59))	('silencing', 'NegReg', (85, 94))	('PHF1', 'Gene', '5252', (55, 59))	('JAZF1', 'Gene', (49, 54))	('PHF1', 'Gene', (109, 113))	('PHF1', 'Gene', '5252', (109, 113))
176830	33099834	JAZF1/SUZ12 destabilizes the PRC2 components leading to a decrease of methyltransferase activity, especially on H3K27, and therefore activates chromatin and/or genes normally repressed by PRC2.	('methyltransferase', 'Enzyme', (70, 87))	('SUZ12', 'Gene', (6, 11))	('destabilizes', 'NegReg', (12, 24))	('JAZF1', 'Gene', (0, 5))	('H3K27', 'Var', (112, 117))	('activity', 'MPA', (88, 96))	('chromatin', 'MPA', (143, 152))	('decrease', 'NegReg', (58, 66))	('activates', 'PosReg', (133, 142))	('PRC2', 'Gene', (29, 33))	('SUZ12', 'Gene', '23512', (6, 11))	('JAZF1', 'Gene', '221895', (0, 5))
176836	33099834	86  BCOR has a number of functions within normal tissue and its alteration can result in developmental disorders and a variety of hematologic and solid malignancies.	('developmental disorders', 'Disease', 'MESH:D002658', (89, 112))	('BCOR', 'Gene', '54880', (4, 8))	('alteration', 'Var', (64, 74))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('result in', 'Reg', (79, 88))	('BCOR', 'Gene', (4, 8))	('developmental disorders', 'Disease', (89, 112))	('malignancies', 'Disease', (152, 164))
176841	33099834	92  showed MDM2 amplification in an LG-ESS with JAZF1-rearrangement and in a UUS.	('LG-ESS', 'Chemical', '-', (36, 42))	('amplification', 'Var', (16, 29))	('JAZF1', 'Gene', (48, 53))	('MDM2', 'Gene', '4193', (11, 15))	('MDM2', 'Gene', (11, 15))	('JAZF1', 'Gene', '221895', (48, 53))
176843	33099834	The discovery of MDM2 amplification opens up for potential use of targeted therapy in a subset of HG-ESS.	('amplification', 'Var', (22, 35))	('HG-ESS', 'Disease', (98, 104))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))
176844	33099834	57  recently investigated the genomic profile of 40 uterine sarcomas harboring BCOR alterations.	('sarcomas', 'Disease', (60, 68))	('investigated', 'Reg', (13, 25))	('BCOR', 'Gene', '54880', (79, 83))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('alterations', 'Var', (84, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('BCOR', 'Gene', (79, 83))
176845	33099834	The analyzed tumors were found to be stable at the microsatellite level; however, some of them showed homozygous deletion of CDKN2A which codes for an inhibitor of CDK4 and CDKN2B.	('CDKN2B', 'Gene', (173, 179))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('deletion', 'Var', (113, 121))	('CDKN2B', 'Gene', '1030', (173, 179))	('CDK4', 'Gene', (164, 168))	('CDKN2A', 'Gene', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('CDK4', 'Gene', '1019', (164, 168))	('CDKN2A', 'Gene', '1029', (125, 131))
176847	33099834	It seems that alteration of CDK4 pathway members contributes to the pathogenesis of BCOR-rearranged tumors, something that may have therapeutic implications.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CDK4', 'Gene', '1019', (28, 32))	('BCOR', 'Gene', (84, 88))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('contributes', 'Reg', (49, 60))	('BCOR', 'Gene', '54880', (84, 88))	('alteration', 'Var', (14, 24))	('CDK4', 'Gene', (28, 32))
176851	33099834	Of all chimeric proteins associated with ESS, YWHAE/NUTM2A/B is the only one that does not undergo epigenetic modification.	('chimeric', 'Var', (7, 15))	('NUTM2A/B', 'Gene', (52, 60))	('YWHAE', 'Gene', (46, 51))	('ESS', 'Disease', (41, 44))	('NUTM2A/B', 'Gene', '728118;729262', (52, 60))	('YWHAE', 'Gene', '7531', (46, 51))
176868	31950476	Genetically, recurrent somatic PDGFRB mutations are reported in the majority of cases.	('mutations', 'Var', (38, 47))	('PDGFRB', 'Gene', (31, 37))	('PDGFRB', 'Gene', '5159', (31, 37))
176888	31950476	Nuclear expression of beta-catenin is a result of mutations in the corresponding CTNNB or ABC gene, leading to reduced degradation of the protein.	('beta-catenin', 'Gene', '1499', (22, 34))	('ABC', 'Gene', (90, 93))	('mutations', 'Var', (50, 59))	('reduced', 'NegReg', (111, 118))	('CTNNB', 'Gene', (81, 86))	('ABC', 'Gene', '10058', (90, 93))	('beta-catenin', 'Gene', (22, 34))	('Nuclear expression', 'MPA', (0, 18))	('CTNNB', 'Gene', '1499', (81, 86))	('degradation of the protein', 'MPA', (119, 145))
176895	31950476	The immunohistochemical key marker is beta-catenin, which shows nuclear expression due to an activating hot spot mutation in CTNNB1.	('beta-catenin', 'Gene', (38, 50))	('mutation', 'Var', (113, 121))	('nuclear expression', 'MPA', (64, 82))	('beta-catenin', 'Gene', '1499', (38, 50))	('CTNNB1', 'Gene', (125, 131))	('activating hot spot', 'PosReg', (93, 112))	('CTNNB1', 'Gene', '1499', (125, 131))
176898	31950476	Nuclear expression of STAT6 due to a NAB2-STAT6 fusion gene is a consistent finding of SFT.	('NAB2', 'Gene', '4665', (37, 41))	('STAT6', 'Gene', '6778', (42, 47))	('fusion', 'Var', (48, 54))	('STAT6', 'Gene', (22, 27))	('NAB2', 'Gene', (37, 41))	('Nuclear expression', 'MPA', (0, 18))	('STAT6', 'Gene', '6778', (22, 27))	('STAT6', 'Gene', (42, 47))
176916	31950476	In contrast, vascular malformations develop in utero as a result of mosaic mutations leading to erroneous development of (mostly heterogeneous) vessels with proportionate growth.	('mosaic mutations', 'Var', (68, 84))	('erroneous development', 'CPA', (96, 117))	('vascular malformations', 'Disease', 'MESH:D054079', (13, 35))	('vascular malformations', 'Disease', (13, 35))	('leading to', 'Reg', (85, 95))	('men', 'Species', '9606', (113, 116))
176947	31950476	Genetically, EH harbor FOS and FOSB rearrangements, although these findings are very rare in the superficially located head and neck cases and analyses are not very helpful in this respect.	('FOSB', 'Gene', (31, 35))	('men', 'Species', '9606', (45, 48))	('FOS', 'Gene', '2353', (23, 26))	('FOS', 'Gene', (31, 34))	('FOS', 'Gene', (23, 26))	('FOS', 'Gene', '2353', (31, 34))	('rearrangements', 'Var', (36, 50))	('FOSB', 'Gene', '2354', (31, 35))
176956	31950476	Negativity for FOSB suggest possibly a distinct pathogenesis from epithelioid hemangioma.	('FOSB', 'Gene', '2354', (15, 19))	('FOSB', 'Gene', (15, 19))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (66, 88))	('hemangioma', 'Phenotype', 'HP:0001028', (78, 88))	('Negativity', 'Var', (0, 10))	('epithelioid hemangioma', 'Disease', (66, 88))	('epithelioid hemangioma', 'Disease', 'MESH:D006391', (66, 88))
176972	31950476	GVMs are associated with mutations in the GLMN gene, which can be seen in both sporadic or hereditary cases.	('mutations', 'Var', (25, 34))	('VM', 'Disease', 'MESH:C563977', (1, 3))	('GLMN', 'Gene', (42, 46))	('associated', 'Reg', (9, 19))	('GLMN', 'Gene', '11146', (42, 46))
176991	31950476	Inhibitors of VEGF and VEGFR and broad-spectrum tyrosine kinase inhibitors have been reported to show clinical response with short-term outcomes.	('VEGFR', 'Gene', (23, 28))	('VEGF', 'Gene', '7422', (14, 18))	('Inhibitors', 'Var', (0, 10))	('VEGF', 'Gene', (23, 27))	('VEGFR', 'Gene', '3791', (23, 28))	('VEGF', 'Gene', (14, 18))	('VEGF', 'Gene', '7422', (23, 27))
177041	31950476	Reported genetic changes are scarce with GNA14 mutations described in one case each of KHE and TA.	('GNA14', 'Gene', (41, 46))	('mutations', 'Var', (47, 56))	('scar', 'Phenotype', 'HP:0100699', (29, 33))	('GNA14', 'Gene', '9630', (41, 46))	('KHE', 'Disease', (87, 90))
177042	31950476	However, GNA14 mutations are also reported in congenital hemangioma, hepatic small vessel neoplasm and anastomosing hemangioma which are potential differential diagnoses.	('reported', 'Reg', (34, 42))	('hemangioma', 'Phenotype', 'HP:0001028', (57, 67))	('vessel neoplasm', 'Phenotype', 'HP:0100742', (83, 98))	('hemangioma', 'Disease', (57, 67))	('mutations', 'Var', (15, 24))	('neoplasm', 'Phenotype', 'HP:0002664', (90, 98))	('hemangioma', 'Phenotype', 'HP:0001028', (116, 126))	('GNA14', 'Gene', (9, 14))	('hemangioma', 'Disease', (116, 126))	('hemangioma', 'Disease', 'MESH:D006391', (57, 67))	('hemangioma', 'Disease', 'MESH:D006391', (116, 126))	('GNA14', 'Gene', '9630', (9, 14))	('hepatic small vessel neoplasm', 'Disease', (69, 98))	('congenital hemangioma', 'Disease', 'MESH:D006391', (46, 67))	('congenital hemangioma', 'Disease', (46, 67))	('hepatic small vessel neoplasm', 'Disease', 'MESH:D059345', (69, 98))
177046	31950476	Furthermore SCH is typically located on the extremities and harbors and IDH1/2 mutation.	('IDH1/2', 'Gene', '3417;3418', (72, 78))	('SCH', 'Disease', 'MESH:D002277', (12, 15))	('mutation', 'Var', (79, 87))	('SCH', 'Disease', (12, 15))	('IDH1/2', 'Gene', (72, 78))
177066	27918490	The amplification of the 12q13-15 chromosome region is one of the most important genetic events of these LPS subtypes.	('amplification', 'Var', (4, 17))	('LPS', 'Phenotype', 'HP:0012034', (105, 108))	('LPS', 'Disease', (105, 108))	('LPS', 'Disease', 'MESH:C536528', (105, 108))
177187	30386739	The mechanisms involved in the cancerogenesis of RIS are represented by damage to double-stranded DNA, resulting in genomic instability.	('RIS', 'Disease', (49, 52))	('genomic', 'MPA', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('damage', 'Var', (72, 78))	('RIS', 'Chemical', '-', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
177190	30386739	In fact, RB1 activation induces the expression of a panel of proteins called senescence-associated secretory phenotypes (SASP), that is formed by cytokines (with interleukine-6 the most important) and complement proteins.	('activation', 'Var', (13, 23))	('SASP', 'Gene', (121, 125))	('SASP', 'Gene', '7295', (121, 125))	('RB1', 'Gene', (9, 12))	('senescence-associated', 'Disease', (77, 98))	('RB1', 'Gene', '5925', (9, 12))	('expression', 'MPA', (36, 46))
177197	30386739	Moreover, Mdm2-p53 interaction has gained interest in the last years, since a better response to chemotherapy was found in patients Mdm2+/p53- in well-differentiated/dedifferentiated liposarcomas.	('Mdm2+/p53-', 'Var', (132, 142))	('liposarcomas', 'Disease', (183, 195))	('liposarcoma', 'Phenotype', 'HP:0012034', (183, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('patients', 'Species', '9606', (123, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('liposarcomas', 'Phenotype', 'HP:0012034', (183, 195))	('liposarcomas', 'Disease', 'MESH:D008080', (183, 195))
177249	26987706	Upon review of the original resection specimen, we were able to show that the tumor demonstrated MDM2 amplification.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('amplification', 'Var', (102, 115))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MDM2', 'Gene', '4193', (97, 101))	('MDM2', 'Gene', (97, 101))
177250	26987706	MDM2 amplification was also present in some adjacent bland adipose tissue, and also in the tumor recurrence as a pleomorphic undifferentiated sarcoma.	('amplification', 'Var', (5, 18))	('pleomorphic undifferentiated sarcoma', 'Disease', (113, 149))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('MDM2', 'Gene', '4193', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('MDM2', 'Gene', (0, 4))	('tumor', 'Disease', (91, 96))	('pleomorphic undifferentiated sarcoma', 'Disease', 'MESH:D002277', (113, 149))
177276	26987706	The demonstration of amplification of MDM2 with FISH has proven to be a robust and reliable method of differentiating ALT/WDLPS from benign lipomatous tumors.	('lipomatous tumors', 'Phenotype', 'HP:0012031', (140, 157))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('benign lipomatous tumors', 'Disease', 'MESH:D008080', (133, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('benign lipomatous tumors', 'Disease', (133, 157))	('MDM2', 'Gene', '4193', (38, 42))	('MDM2', 'Gene', (38, 42))	('ALT/WDLPS', 'Disease', (118, 127))	('amplification', 'Var', (21, 34))	('lipomatous tumor', 'Phenotype', 'HP:0012031', (140, 156))
177277	26987706	found MDM2 amplification in 98 % (48 of 49) of ALT/WDLPS but in no benign adipose tumors.	('adipose tumors', 'Disease', (74, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('MDM2', 'Gene', '4193', (6, 10))	('MDM2', 'Gene', (6, 10))	('ALT/WDLPS', 'Disease', (47, 56))	('adipose tumors', 'Disease', 'MESH:D008067', (74, 88))	('amplification', 'Var', (11, 24))
177278	26987706	demonstrated MDM2 amplification in 100 % of ALT/WDLPS (13 out of 13) and dedifferentiated liposarcomas (14 out of 14).	('liposarcomas', 'Disease', 'MESH:D008080', (90, 102))	('ALT/WDLPS', 'Disease', (44, 53))	('liposarcoma', 'Phenotype', 'HP:0012034', (90, 101))	('liposarcomas', 'Disease', (90, 102))	('MDM2', 'Gene', '4193', (13, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('MDM2', 'Gene', (13, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('amplification', 'Var', (18, 31))	('liposarcomas', 'Phenotype', 'HP:0012034', (90, 102))
177279	26987706	Of note MDM2 amplification has been consistently demonstrated in areas of WDLPS with minimal cellular atypia, indicating that the presence of MDM2 amplification even in cytologically bland adipose tissue can be considered prima facie evidence of ALT/WDLPS.	('MDM2', 'Gene', '4193', (8, 12))	('MDM2', 'Gene', (8, 12))	('MDM2', 'Gene', '4193', (142, 146))	('MDM2', 'Gene', (142, 146))	('ALT/WDLPS', 'Disease', (246, 255))	('presence', 'Var', (130, 138))
177281	26987706	There is also emerging evidence that the presence of MDM2 amplification in an otherwise undifferentiated sarcoma is strong evidence that the tumor has arisen from dedifferentiation of a liposarcoma.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('MDM2', 'Gene', '4193', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('MDM2', 'Gene', (53, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('liposarcoma', 'Phenotype', 'HP:0012034', (186, 197))	('otherwise', 'Disease', (78, 87))	('tumor', 'Disease', (141, 146))	('liposarcoma', 'Disease', 'MESH:D008080', (186, 197))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (88, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('undifferentiated sarcoma', 'Disease', (88, 112))	('amplification', 'Var', (58, 71))	('liposarcoma', 'Disease', (186, 197))
177282	26987706	reported that tumors that would otherwise be classified as pleomorphic undifferentiated sarcoma, but that demonstrated MDM2 amplification, had similar clinical characteristics, morphology, genomic profile, and outcome to conventional dedifferentiated liposarcoma and were significantly less aggressive than pleomorphic undifferentiated sarcomas without MDM2 amplification.	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('aggressive', 'MPA', (291, 301))	('MDM2', 'Gene', (353, 357))	('pleomorphic undifferentiated sarcoma', 'Disease', (59, 95))	('liposarcoma', 'Phenotype', 'HP:0012034', (251, 262))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('MDM2', 'Gene', '4193', (353, 357))	('pleomorphic undifferentiated sarcoma', 'Disease', 'MESH:D002277', (307, 343))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('liposarcoma', 'Disease', 'MESH:D008080', (251, 262))	('less', 'NegReg', (286, 290))	('pleomorphic undifferentiated sarcoma', 'Disease', 'MESH:D002277', (59, 95))	('MDM2', 'Gene', (119, 123))	('tumors', 'Disease', (14, 20))	('sarcomas', 'Disease', 'MESH:D012509', (336, 344))	('sarcomas', 'Phenotype', 'HP:0100242', (336, 344))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))	('sarcomas', 'Disease', (336, 344))	('MDM2', 'Gene', '4193', (119, 123))	('liposarcoma', 'Disease', (251, 262))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('amplification', 'Var', (124, 137))	('pleomorphic undifferentiated sarcoma', 'Disease', (307, 343))
177337	25870707	Detection of EWS/FLI-1 fusion in non-Ewing soft tissue tumors Objectives: EWS/FLI-1 fusion mainly appears in Ewing's sarcoma or the primitive neuroectodermal tumors and represents a genomic marker for these tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (142, 164))	('non-Ewing soft tissue tumors', 'Disease', (33, 61))	('appears', 'Reg', (98, 105))	('neuroectodermal tumors', 'Disease', (142, 164))	('EWS', 'Gene', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('FLI-1', 'Gene', '2313', (78, 83))	('EWS', 'Gene', '2130', (13, 16))	('tumors', 'Disease', (207, 213))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (43, 61))	('Ewing soft tissue tumors', 'Phenotype', 'HP:0012254', (37, 61))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('tumors', 'Disease', (158, 164))	('FLI-1', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('sarcoma', 'Disease', (117, 124))	('tumors', 'Disease', (55, 61))	('FLI-1', 'Gene', (78, 83))	('non-Ewing soft tissue tumors', 'Disease', 'MESH:C563168', (33, 61))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('EWS', 'Gene', '2130', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('EWS', 'Gene', (13, 16))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (109, 124))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (132, 164))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (142, 164))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('fusion', 'Var', (84, 90))	('FLI-1', 'Gene', '2313', (17, 22))
177338	25870707	The paper investigates the presence of EWS/FLI-1 fusion in clinically diagnosed sarcoma belonging to different non-Ewing connective tissue tumors in order to search for a possible new biomarker valuable for investigators.	('connective tissue tumors', 'Phenotype', 'HP:0100242', (121, 145))	('Ewing connective tissue tumors', 'Phenotype', 'HP:0012254', (115, 145))	('sarcoma belonging', 'Disease', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	('FLI-1', 'Gene', (43, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('tumors', 'Disease', (139, 145))	('fusion', 'Var', (49, 55))	('FLI-1', 'Gene', '2313', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('sarcoma belonging', 'Disease', 'MESH:D012509', (80, 97))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
177342	25870707	The translocation results in the fusion of the N-terminal region of the EWS (Ewing's sarcoma) gene with the DNA binding domain of the proto-oncogene FLI-1 (Friend leukemia integration site 1) .	('Friend leukemia integration site 1', 'Gene', '2313', (156, 190))	('FLI-1', 'Gene', '2313', (149, 154))	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', (72, 75))	('FLI-1', 'Gene', (149, 154))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('Friend leukemia integration site 1', 'Gene', (156, 190))	('leukemia', 'Phenotype', 'HP:0001909', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcoma', 'Disease', (85, 92))	('fusion', 'Var', (33, 39))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (77, 92))	('results in', 'Reg', (18, 28))
177350	25870707	Detection of EWS/FLI-1 fusion  EWS/FLI-1 fusion was screened by quantitative real-time PCR (qPCR) with Rotor Gene 6000 thermocycler (Corbett Life Science, Qiagen Sciences, Maryland, USA) using the TaqMan RNA-to-Ct 1 Step Kit (Applied Biosystems - Life Technologies, Carlsbad, CA, USA), with Hs03024497_ft primer specific for fusion.	('EWS/FLI-1', 'Gene', (31, 40))	('Hs03024497_ft', 'Var', (291, 304))	('Ct 1', 'Gene', '1489', (211, 215))	('Ct 1', 'Gene', (211, 215))
177362	24765416	Immunohistochemistry with panel of markers was done which showed positivity for CD99, vimentin and negative for desmin and myogenin.	('vimentin', 'Gene', '7431', (86, 94))	('desmin', 'Gene', '1674', (112, 118))	('positivity', 'Var', (65, 75))	('vimentin', 'Gene', (86, 94))	('CD99', 'Gene', '4267', (80, 84))	('CD99', 'Gene', (80, 84))	('myogenin', 'Gene', (123, 131))	('desmin', 'Gene', (112, 118))	('myogenin', 'Gene', '4656', (123, 131))
177384	24765416	The main etiology of rhabdomyosarcomas lies in the genetic mutations.	('genetic mutations', 'Var', (51, 68))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (21, 38))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (21, 37))	('rhabdomyosarcomas', 'Disease', (21, 38))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (21, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))
177386	24765416	In contrast to the specific translocations found in alveolar rhabdomyosarcoma, most embryonal rhabdomyosarcoma cases have allelic loss at chromosome 11p15.	('alveolar rhabdomyosarcoma', 'Disease', (52, 77))	('embryonal rhabdomyosarcoma', 'Disease', (84, 110))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (52, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (84, 110))	('allelic loss', 'Var', (122, 134))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (84, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (52, 77))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (94, 110))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (61, 77))
177410	24765416	So a panel of markers like CD31, CD34, CD45, CD20, CD1A, CD3, CD45 and CD138 were used and negativity to this ruled out Ewing's sarcoma and lymphoma.	("Ewing's sarcoma", 'Disease', (120, 135))	('CD20', 'Gene', '54474', (45, 49))	('CD1A', 'Gene', '909', (51, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('CD138', 'Gene', '6382', (71, 76))	('lymphoma', 'Disease', (140, 148))	('CD34', 'Gene', (33, 37))	('lymphoma', 'Disease', 'MESH:D008223', (140, 148))	('CD31', 'Gene', '5175', (27, 31))	('CD138', 'Gene', (71, 76))	('CD1A', 'Gene', (51, 55))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (120, 135))	('CD45', 'Gene', (39, 43))	('CD3', 'Var', (57, 60))	('CD45', 'Gene', '5788', (39, 43))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (120, 135))	('CD45', 'Gene', (62, 66))	('CD34', 'Gene', '947', (33, 37))	('CD20', 'Gene', (45, 49))	('CD45', 'Gene', '5788', (62, 66))	('lymphoma', 'Phenotype', 'HP:0002665', (140, 148))	('CD31', 'Gene', (27, 31))
177411	24765416	CD68 negativity further ruled out langerhans cell histiocytosis.	('CD68', 'Gene', '968', (0, 4))	('histiocytosis', 'Phenotype', 'HP:0100727', (50, 63))	('negativity', 'Var', (5, 15))	('ruled out', 'Reg', (24, 33))	('langerhans', 'MPA', (34, 44))	('CD68', 'Gene', (0, 4))
177412	24765416	The presence of an alveolar pattern, pleomorphism, cohesive nature of the cells and the absence of lymphadenopathy further ruled out the diagnosis of lymphoma.	('pleomorphism', 'Var', (37, 49))	('lymphadenopathy', 'Disease', 'MESH:D008206', (99, 114))	('lymphoma', 'Disease', (150, 158))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (99, 114))	('lymphoma', 'Disease', 'MESH:D008223', (150, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (150, 158))	('cohesive nature', 'CPA', (51, 66))	('alveolar pattern', 'CPA', (19, 35))	('lymphadenopathy', 'Disease', (99, 114))
177513	32325418	All patients who required a dose reduction had clinical benefit with at least SD and received the treatment regimen with reduced doses for a median of 9 courses (range, 2-18).	('SD', 'Disease', 'MESH:D029461', (78, 80))	('patients', 'Species', '9606', (4, 12))	('dose reduction', 'Var', (28, 42))	('benefit', 'PosReg', (56, 63))
177536	32325418	Pediatric rhabdoid tumors are rare, aggressive malignancies, primarily driven by deletion or loss of function mutations in the SMARCB1 tumor suppressor gene.	('mutations', 'Var', (110, 119))	('aggressive malignancies', 'Disease', (36, 59))	('aggressive malignancies', 'Disease', 'MESH:D009369', (36, 59))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('deletion', 'Var', (81, 89))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('rhabdoid tumors', 'Disease', (10, 25))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (10, 25))	('loss of function', 'NegReg', (93, 109))	('tumor', 'Disease', (19, 24))	('SMARCB1', 'Gene', '6598', (127, 134))	('SMARCB1', 'Gene', (127, 134))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
177614	31490916	Significantly higher PIRs were found among males in the population with HIV/AIDS along with those diagnosed between 2007-2015, age of diagnosis under 60 years, African American, metro residence, Medicaid or uninsured, and had Kaposi sarcoma, NHL, other lymphomas, squamous cell neoplasm or another histology of the anus, squamous cell neoplasm of male genital organs, or adenocarcinoma of the liver.	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (226, 240))	('NHL', 'Phenotype', 'HP:0012539', (242, 245))	('under 60', 'Var', (144, 152))	('squamous cell neoplasm', 'Disease', (264, 286))	('adenocarcinoma of the liver', 'Disease', (371, 398))	('squamous cell neoplasm', 'Phenotype', 'HP:0002860', (321, 343))	('lymphomas', 'Disease', (253, 262))	('squamous cell neoplasm', 'Phenotype', 'HP:0002860', (264, 286))	('squamous cell neoplasm', 'Disease', 'MESH:D002294', (321, 343))	('higher', 'PosReg', (14, 20))	('squamous cell neoplasm', 'Disease', 'MESH:D002294', (264, 286))	('lymphoma', 'Phenotype', 'HP:0002665', (253, 261))	('HIV/AIDS', 'Disease', (72, 80))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (226, 240))	('HIV/AIDS', 'Disease', 'MESH:D000163', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('neoplasm', 'Phenotype', 'HP:0002664', (335, 343))	('neoplasm', 'Phenotype', 'HP:0002664', (278, 286))	('Kaposi sarcoma', 'Disease', (226, 240))	('adenocarcinoma of the liver', 'Disease', 'MESH:D000230', (371, 398))	('lymphomas', 'Disease', 'MESH:D008223', (253, 262))	('NHL', 'Disease', (242, 245))	('lymphomas', 'Phenotype', 'HP:0002665', (253, 262))	('squamous cell neoplasm', 'Disease', (321, 343))
177687	31387281	Although they do not primarily endanger patients  lives, ULM can markedly decrease the quality of life if they become symptomatic.	('quality of life', 'CPA', (87, 102))	('patients', 'Species', '9606', (40, 48))	('decrease', 'NegReg', (74, 82))	('ULM', 'Var', (57, 60))
177739	31387281	(1) Targeted approaches are based on identifying the following mutations/abnormalities in the ctDNA elements: (a) previously accepted abnormal patterns in ctDNAs (e.g., in different cancer type or based on in silico prediction) and (b) the same pattern in the primary tumor and the released ctDNA.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('mutations/abnormalities', 'Var', (63, 86))	('ctDNAs', 'Disease', (155, 161))	('tumor', 'Disease', (268, 273))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
177747	31387281	The origin of the cells was verified by the presence of fusions typical for this tumor.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('fusions', 'Var', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
177768	31387281	In addition, the let-7 family miRNA family has the HMGA2 gene as a target and HMGA2 abnormal expression, especially from translocations, is considered a typical ULM mark.	('HMGA2', 'Gene', (51, 56))	('translocations', 'Var', (121, 135))	('HMGA2', 'Gene', '8091', (78, 83))	('HMGA2', 'Gene', (78, 83))	('HMGA2', 'Gene', '8091', (51, 56))	('abnormal expression', 'Var', (84, 103))
177775	31387281	In addition, non-sporadic germline mutations of this gene occurred more often in women with both ULM and LMS.	('women', 'Species', '9606', (81, 86))	('germline mutations', 'Var', (26, 44))	('LMS', 'Disease', (105, 108))	('LMS', 'Phenotype', 'HP:0100243', (105, 108))	('ULM', 'Disease', (97, 100))
177776	31387281	Interestingly, malignant uterine LMS also have MED12 gene mutation in almost 70% of tumors, and this can be, therefore, considered a typical mark for these tumors.	('MED12', 'Gene', (47, 52))	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutation', 'Var', (58, 66))	('MED12', 'Gene', '9968', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('LMS', 'Phenotype', 'HP:0100243', (33, 36))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
177777	31387281	While this common mutation potentially distinguishes the two tumor groups from healthy tissue, unfortunately it cannot be used as a distinguishing factor of these tumors and is, therefore, unsuitable for LB diagnostics.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Disease', (163, 168))	('mutation', 'Var', (18, 26))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
177778	31387281	In contrast to ULM, LMS have quite often mutated TP53 gene.	('LMS', 'Phenotype', 'HP:0100243', (20, 23))	('mutated', 'Var', (41, 48))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('LMS', 'Disease', (20, 23))
177779	31387281	Although mutations in this gene are typical for many cancerous diseases, LB determination of TP53 mutation in women with previous image-diagnosed UMT should always provoke rapid tissue biopsy, subsequent histological examination, and close observation of the patient.	('mutation', 'Var', (98, 106))	('mutations', 'Var', (9, 18))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancerous diseases', 'Disease', (53, 71))	('UMT', 'Chemical', '-', (146, 149))	('cancerous diseases', 'Disease', 'MESH:D009369', (53, 71))	('patient', 'Species', '9606', (259, 266))	('women', 'Species', '9606', (110, 115))
177786	31387281	However, mutation changes in the TP53, ATRX, and RB1 genes have been detected and analyzed in LB samples in patients with different cancer diseases.	('ATRX', 'Gene', (39, 43))	('cancer diseases', 'Disease', 'MESH:D009369', (132, 147))	('RB1', 'Gene', (49, 52))	('ATRX', 'Gene', '546', (39, 43))	('RB1', 'Gene', '5925', (49, 52))	('TP53', 'Gene', '7157', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TP53', 'Gene', (33, 37))	('patients', 'Species', '9606', (108, 116))	('cancer diseases', 'Disease', (132, 147))	('mutation changes', 'Var', (9, 25))
177788	31387281	The methylation profiles of ULM and sarcoma promoter regions provide further possibilities for tumor differentiation based on LB, because changes in DNA methylation patterns can be identified in ctDNA and have been proposed as potential biomarkers for tumor staging, prognosis, and monitoring of the treatment response.	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('ctDNA', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('sarcoma', 'Disease', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('changes', 'Var', (138, 145))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', (95, 100))
177796	31387281	In addition, women of African origin have hypermethylated DLEC1, KRT1,9 and KLF11 genes in ULM as compared to MM.	('ULM', 'Disease', (91, 94))	('DLEC1', 'Gene', (58, 63))	('DLEC1', 'Gene', '9940', (58, 63))	('KLF11', 'Gene', (76, 81))	('KRT1,9', 'Gene', '3880;3848;3857', (65, 71))	('women', 'Species', '9606', (13, 18))	('KLF11', 'Gene', '8462', (76, 81))	('hypermethylated', 'Var', (42, 57))
177800	31387281	For LMS are typical aberrations altering the cell cycle, whereby promoter region hypermethylation is supposed to induces loss of function of the important cell cycle regulator CDKN2 and hypermethylation also most likely causes the BRCA1 gene s protein reduction in almost 30% of uterine LMS.	('LMS', 'Phenotype', 'HP:0100243', (4, 7))	('protein', 'Protein', (244, 251))	('BRCA1', 'Gene', '672', (231, 236))	('hypermethylation', 'Var', (186, 202))	('reduction', 'NegReg', (252, 261))	('causes', 'Reg', (220, 226))	('loss of function', 'NegReg', (121, 137))	('BRCA1', 'Gene', (231, 236))	('CDKN2', 'Gene', '1029', (176, 181))	('LMS', 'Phenotype', 'HP:0100243', (287, 290))	('CDKN2', 'Gene', (176, 181))	('hypermethylation', 'Var', (81, 97))
177801	31387281	The LMS also have often hypomethylated ESR1 target genes and the polycomb group target genes.	('hypomethylated', 'Var', (24, 38))	('LMS', 'Phenotype', 'HP:0100243', (4, 7))	('ESR1', 'Gene', (39, 43))	('ESR1', 'Gene', '2099', (39, 43))
177812	31387281	These were divided into the following four groups: those with the mutated MED12 gene, those with HMGA2 gene translocations, the group with FH gene biallelic inactivation, and COL4A5-COL4A6 deletions.	('mutated', 'Var', (66, 73))	('MED12', 'Gene', (74, 79))	('COL4A5', 'Gene', '1287', (175, 181))	('MED12', 'Gene', '9968', (74, 79))	('COL4A5', 'Gene', (175, 181))	('deletions', 'Var', (189, 198))	('COL4A6', 'Gene', '1288', (182, 188))	('HMGA2', 'Gene', '8091', (97, 102))	('COL4A6', 'Gene', (182, 188))	('biallelic', 'Var', (147, 156))	('HMGA2', 'Gene', (97, 102))
177817	31387281	However, while it is generally accepted that vitamin D deficiency is strongly associated with ULM occurrence, its abnormal metabolites were not confirmed in these tumors.	('associated', 'Reg', (78, 88))	('abnormal metabolites', 'Phenotype', 'HP:0032180', (114, 134))	('vitamin D', 'Chemical', 'MESH:D014807', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (45, 65))	('vitamin D', 'Gene', (45, 54))	('deficiency', 'Var', (55, 65))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('ULM', 'Disease', (94, 97))
177822	31387281	In addition, FTICR-MSI identified m/z 241.0118 as inositol cyclic phosphate and m/z 160.8417 as carnitine.	('inositol cyclic phosphate', 'Chemical', 'MESH:C010199', (50, 75))	('inositol cyclic phosphate', 'MPA', (50, 75))	('m/z 241.0118', 'Var', (34, 46))	('m/z 160.8417', 'Var', (80, 92))	('carnitine', 'Chemical', 'MESH:D002331', (96, 105))
177823	31387281	In this review, we based the differentiation of UMT on the LB approach because of the diverse action of non-coding RNAs, and mutational and methylation changes and differences in metabolic activity in ULM, other UMT, and MM.	('changes', 'Var', (152, 159))	('mutational', 'Var', (125, 135))	('differences', 'Reg', (164, 175))	('UMT', 'Chemical', '-', (212, 215))	('UMT', 'Chemical', '-', (48, 51))
177841	31387281	The first study of these discrepancies we are aware of was conducted by Osoborne et al.. Woman with metastatic neuroendocrine carcinoma gave birth to a healthy infant, and although both invasive testing during pregnancy and postnatal placental histology revealed no abnormalities, NIPT testing indicated trisomy in chromosomes 13 and 18.	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (111, 135))	('Woman', 'Species', '9606', (89, 94))	('neuroendocrine carcinoma', 'Disease', (111, 135))	('indicated', 'Reg', (294, 303))	('infant', 'Species', '9606', (160, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (111, 135))	('trisomy', 'Var', (304, 311))
177847	31387281	The authors found TP53 and HRAS mutations in both primary tumors and plasma samples.	('primary tumors', 'Disease', 'MESH:D009369', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TP53', 'Gene', '7157', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HRAS', 'Gene', (27, 31))	('found', 'Reg', (12, 17))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (32, 41))	('primary tumors', 'Disease', (50, 64))	('HRAS', 'Gene', '3265', (27, 31))
177848	31387281	However, it is necessary to remember that the percentage of these mutations differs in tissue and plasma samples and the authors do not mention if these leiomyosarcomas arise from uterine tissues or not.	('mutations', 'Var', (66, 75))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (153, 167))	('leiomyosarcomas', 'Disease', (153, 168))	('leiomyosarcomas arise', 'Phenotype', 'HP:0100243', (153, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (153, 168))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (153, 168))
177871	30253794	Particular success has been seen with immune checkpoint inhibitors, which are now approved as standard therapy in melanoma, lung, genitourinary, and cancers with microsatellite instability with an increasing number of indications as new data emerges.	('microsatellite instability', 'Var', (162, 188))	('cancers', 'Disease', (149, 156))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('genitourinary', 'Disease', (130, 143))	('lung', 'Disease', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('melanoma', 'Disease', (114, 122))
177887	30253794	NextGen sequencing (NGS) revealed a mutation in exon 4 of IDH2 and a variant of unknown significance in exon 11 of BRCA2.	('BRCA2', 'Gene', (115, 120))	('mutation in', 'Var', (36, 47))	('revealed', 'Reg', (25, 33))	('BRCA2', 'Gene', '675', (115, 120))	('IDH2', 'Gene', (58, 62))
177896	30253794	Efforts to identify druggable targets in chondrosarcoma have recently revealed recurrent mutations in IDH1 and IDH2, as was seen in the patient presented here.	('patient', 'Species', '9606', (136, 143))	('chondrosarcoma', 'Disease', 'MESH:D002813', (41, 55))	('chondrosarcoma', 'Disease', (41, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('IDH1', 'Gene', (102, 106))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (41, 55))	('mutations', 'Var', (89, 98))	('IDH1', 'Gene', '3417', (102, 106))	('IDH2', 'Gene', (111, 115))
177899	30253794	Mutated IDH is able to catalyze conversion of alpha-ketoglutarate into delta-2-hydroxyglutarate (2HG).	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (46, 65))	('IDH', 'Gene', (8, 11))	('conversion', 'MPA', (32, 42))	('IDH', 'Gene', '3417', (8, 11))	('delta-2-hydroxyglutarate', 'Chemical', '-', (71, 95))	('Mutated', 'Var', (0, 7))
177900	30253794	Mutant IDH2 leads to increased intracellular 2HG and hypermethylated DNA in mesenchymal cells, inhibiting their differentiation in a manner reversible by treatment with DNA-hypomethylating agents.	('increased', 'PosReg', (21, 30))	('inhibiting', 'NegReg', (95, 105))	('man', 'Species', '9606', (133, 136))	('intracellular 2HG', 'MPA', (31, 48))	('IDH2', 'Gene', (7, 11))	('Mutant', 'Var', (0, 6))	('differentiation', 'CPA', (112, 127))	('increased intracellular 2HG', 'Phenotype', 'HP:0003575', (21, 48))	('hypermethylated DNA', 'MPA', (53, 72))
177902	30253794	The clinical utility of this approach is being tested in trials for patients with IDH mutated cancers including chondrosarcoma (NCT02073994, NCT02746081).	('IDH', 'Gene', '3417', (82, 85))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (112, 126))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('chondrosarcoma', 'Disease', (112, 126))	('chondrosarcoma', 'Disease', 'MESH:D002813', (112, 126))	('NCT02746081', 'Var', (141, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('IDH', 'Gene', (82, 85))	('NCT02073994', 'Var', (128, 139))	('cancers', 'Disease', (94, 101))
177903	30253794	Interestingly, introduction of an activating IDH2 mutation in a syngeneic mouse model of glioma led to reduced levels of CXCL10 and suppression of cytotoxic T-cell recruitment to the tumor.	('activating', 'PosReg', (34, 44))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('reduced', 'NegReg', (103, 110))	('suppression', 'NegReg', (132, 143))	('cytotoxic', 'MPA', (147, 156))	('CXCL10', 'Gene', '15945', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('IDH2', 'Gene', (45, 49))	('glioma', 'Disease', (89, 95))	('mouse', 'Species', '10090', (74, 79))	('CXCL10', 'Gene', (121, 127))	('mutation', 'Var', (50, 58))
177904	30253794	IDH mutant gliomas also escape natural killer cell mediated lysis by epigenetic reprogramming that leads to downregulation of NKG2D ligand expression.	('NKG2D', 'Gene', (126, 131))	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (4, 10))	('natural killer cell mediated lysis', 'MPA', (31, 65))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('NKG2D', 'Gene', '22914', (126, 131))	('downregulation', 'NegReg', (108, 122))	('expression', 'MPA', (139, 149))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('escape', 'NegReg', (24, 30))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
177905	30253794	Given these findings in glioma, one might have expected this IDH2 mutant chondrosarcoma to evade the immune system.	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('mutant', 'Var', (66, 72))	('chondrosarcoma', 'Disease', (73, 87))	('IDH2', 'Gene', (61, 65))	('chondrosarcoma', 'Disease', 'MESH:D002813', (73, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('glioma', 'Disease', (24, 30))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (73, 87))
177906	30253794	However, this patient responded in spite of the presence of the IDH2 mutation.	('mutation', 'Var', (69, 77))	('patient', 'Species', '9606', (14, 21))	('responded', 'MPA', (22, 31))	('IDH2', 'Gene', (64, 68))
177908	30253794	A small retrospective series of chondrosarcoma patients suggested clinical benefit with VEGFR2 inhibitors.	('inhibitors', 'Var', (95, 105))	('patients', 'Species', '9606', (47, 55))	('chondrosarcoma', 'Disease', 'MESH:D002813', (32, 46))	('VEGFR2', 'Gene', '3791', (88, 94))	('benefit', 'PosReg', (75, 82))	('chondrosarcoma', 'Disease', (32, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('VEGFR2', 'Gene', (88, 94))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (32, 46))
177909	30253794	Additional efforts to identify targets by NGS have revealed recurrent alterations in TP53, ACVR2A, COL2A1, and YEATS2 in addition to the previously identified recurrent IDH mutations.	('COL2A1', 'Gene', (99, 105))	('alterations', 'Var', (70, 81))	('TP53', 'Gene', (85, 89))	('YEATS2', 'Gene', '55689', (111, 117))	('YEATS2', 'Gene', (111, 117))	('IDH', 'Gene', (169, 172))	('ACVR2A', 'Gene', (91, 97))	('rat', 'Species', '10116', (74, 77))	('IDH', 'Gene', '3417', (169, 172))	('TP53', 'Gene', '7157', (85, 89))	('COL2A1', 'Gene', '1280', (99, 105))	('ACVR2A', 'Gene', '92', (91, 97))
177951	29545923	It has also been shown that calcium electroporation is associated with acute and severe ATP depletion across tested cell lines (H69 - human small-cell lung cancer, SW780 - human bladder cancer, HT29, Human colon cancer, MDA-MB231 - human breast cancer, U937 - human leukemia, DC-3F - transformed Chinese hamster lung fibroblast cell line as well as HDF-n - primary normal human dermal fibroblasts).	('H69', 'CellLine', 'CVCL:8121', (128, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (140, 162))	('small-cell lung cancer', 'Disease', (140, 162))	('MDA-MB231', 'CellLine', 'CVCL:0062', (220, 229))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('human', 'Species', '9606', (232, 237))	('calcium', 'Chemical', 'MESH:D002118', (28, 35))	('U937', 'CellLine', 'CVCL:0007', (253, 257))	('breast cancer', 'Disease', (238, 251))	('HT29', 'CellLine', 'CVCL:0320', (194, 198))	('human', 'Species', '9606', (372, 377))	('colon cancer', 'Phenotype', 'HP:0003003', (206, 218))	('leukemia', 'Phenotype', 'HP:0001909', (266, 274))	('human', 'Species', '9606', (134, 139))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (140, 162))	('SW780', 'CellLine', 'CVCL:1728', (164, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('calcium electroporation', 'Var', (28, 51))	('colon cancer', 'Disease', 'MESH:D015179', (206, 218))	('leukemia', 'Disease', (266, 274))	('leukemia', 'Disease', 'MESH:D007938', (266, 274))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('human', 'Species', '9606', (260, 265))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('ATP', 'Chemical', 'MESH:D000255', (88, 91))	('ATP depletion', 'MPA', (88, 101))	('Chinese hamster', 'Species', '10029', (296, 311))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('human', 'Species', '9606', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Human', 'Species', '9606', (200, 205))	('bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('bladder cancer', 'Disease', (178, 192))	('colon cancer', 'Disease', (206, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))
177961	29545923	In this study, we have confirmed these results by showing higher toxicity of calcium electroporation on sarcoma cells (RD) compared to normal muscle cells (C2C12).	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('calcium', 'Chemical', 'MESH:D002118', (77, 84))	('toxicity', 'Disease', 'MESH:D064420', (65, 73))	('toxicity', 'Disease', (65, 73))	('C2C12', 'Chemical', '-', (156, 161))	('calcium electroporation', 'Var', (77, 100))
177965	29545923	As expected, calcium electroporation induces cell death, and the highest electric field combined with the highest calcium concentration tested caused the lowest cell survival for both cell lines (p < 0.01).	('cell survival', 'CPA', (161, 174))	('lowest', 'NegReg', (154, 160))	('calcium', 'Chemical', 'MESH:D002118', (114, 121))	('calcium electroporation', 'Var', (13, 36))	('cell death', 'CPA', (45, 55))	('calcium', 'Chemical', 'MESH:D002118', (13, 20))
177971	29545923	Interestingly, attached C2C12 and C2C12-D have 25% higher viability after 0.5 mM calcium electroporation (all EP parameters) compared to untreated cells (p < 0.001; Figure 1C and 1D).	('C2C12', 'Var', (24, 29))	('C2C12', 'Chemical', '-', (34, 39))	('viability', 'CPA', (58, 67))	('C2C12', 'Chemical', '-', (24, 29))	('C2C12-D', 'Var', (34, 41))	('calcium', 'Chemical', 'MESH:D002118', (81, 88))	('higher', 'PosReg', (51, 57))
177973	29545923	Since calcium electroporation was less effective in normal than malignant muscle cells, we investigated intracellular calcium level in both cell lines, undifferentiated (C2C12, RD) and differentiated (C2C12-D, RD-D), before and after calcium electroporation.	('calcium', 'Chemical', 'MESH:D002118', (118, 125))	('intracellular calcium level', 'MPA', (104, 131))	('C2C12', 'Chemical', '-', (170, 175))	('calcium', 'Chemical', 'MESH:D002118', (234, 241))	('investigated', 'Reg', (91, 103))	('C2C12', 'Chemical', '-', (201, 206))	('C2C12-D', 'Var', (201, 208))	('calcium', 'Chemical', 'MESH:D002118', (6, 13))
177975	29545923	Calcium content was approximately twice as high in untreated C2C12 as in RD cells (p < 0.0001) and in C2C12-D as in RD-D (p < 0.001).	('C2C12-D', 'Var', (102, 109))	('high', 'PosReg', (43, 47))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	('C2C12', 'Var', (61, 66))	('Calcium content', 'MPA', (0, 15))	('C2C12', 'Chemical', '-', (102, 107))	('C2C12', 'Chemical', '-', (61, 66))
177976	29545923	The differentiation process also increased calcium content in both cell lines, especially in C2C12-D where the calcium level was 43% higher than in C2C12 (p < 0.01) and 22% higher in RD-D than in RD (p < 0.05).	('calcium', 'Chemical', 'MESH:D002118', (111, 118))	('increased calcium content', 'Phenotype', 'HP:0003072', (33, 58))	('C2C12', 'Chemical', '-', (148, 153))	('C2C12', 'Chemical', '-', (93, 98))	('higher', 'PosReg', (133, 139))	('calcium level', 'MPA', (111, 124))	('calcium', 'Chemical', 'MESH:D002118', (43, 50))	('increased', 'PosReg', (33, 42))	('C2C12-D', 'Var', (93, 100))	('higher', 'PosReg', (173, 179))	('calcium content', 'MPA', (43, 58))
177979	29545923	In the normal C2C12 and C2C12-D cells, intracellular calcium concentration also increased after calcium electroporation, but less than in the RD and RD-D cells, and not significantly for all tested parameters compared with untreated controls (see Figure 2B).	('C2C12', 'Chemical', '-', (14, 19))	('calcium', 'Chemical', 'MESH:D002118', (53, 60))	('intracellular calcium concentration', 'MPA', (39, 74))	('C2C12', 'Chemical', '-', (24, 29))	('increased', 'PosReg', (80, 89))	('C2C12-D', 'Var', (24, 31))	('calcium electroporation', 'Var', (96, 119))	('calcium', 'Chemical', 'MESH:D002118', (96, 103))	('less', 'NegReg', (125, 129))
177980	29545923	In the differentiated C2C12-D cells only the highest calcium concentration (1 mM) with electroporation caused significantly higher intracellular calcium concentration compared with untreated control (p < 0.05).	('calcium', 'Chemical', 'MESH:D002118', (145, 152))	('electroporation', 'Var', (87, 102))	('calcium', 'Chemical', 'MESH:D002118', (53, 60))	('higher intracellular calcium concentration', 'Phenotype', 'HP:0003575', (124, 166))	('C2C12', 'Chemical', '-', (22, 27))	('higher', 'PosReg', (124, 130))	('intracellular calcium concentration', 'MPA', (131, 166))
177988	29545923	The total PMCA1-4 protein expression (Figure 3A) was significantly higher in untreated normal cells than in malignant cells: twice as high in C2C12 than RD (p < 0.05), and 48% higher in C2C12-D than RD-D (p < 0.01).	('expression', 'MPA', (26, 36))	('higher', 'PosReg', (67, 73))	('C2C12', 'Var', (142, 147))	('PMCA1-4', 'Gene', (10, 17))	('protein', 'Protein', (18, 25))	('PMCA1-4', 'Gene', '67972;11941;320707;381290', (10, 17))	('C2C12', 'Chemical', '-', (142, 147))	('high', 'PosReg', (134, 138))	('C2C12', 'Chemical', '-', (186, 191))	('higher', 'PosReg', (176, 182))	('C2C12-D', 'Var', (186, 193))
177989	29545923	Interestingly, the differentiation process increased PMCA1-4 expression by 44% for C2C12-D (p < 0.0001) and even doubled for RD-D (p < 0.0001).	('C2C12', 'Chemical', '-', (83, 88))	('C2C12-D', 'Var', (83, 90))	('PMCA1-4', 'Gene', (53, 60))	('increased', 'PosReg', (43, 52))	('PMCA1-4', 'Gene', '67972;11941;320707;381290', (53, 60))	('expression', 'MPA', (61, 71))
177991	29545923	PMCA3 expression was almost twice as high in C2C12 and C2C12-D compared with RD and RD-D (180-185%, p < 0.0001).	('C2C12', 'Var', (45, 50))	('high', 'PosReg', (37, 41))	('expression', 'MPA', (6, 16))	('C2C12', 'Chemical', '-', (45, 50))	('PMCA3', 'Gene', (0, 5))	('C2C12', 'Chemical', '-', (55, 60))	('C2C12-D', 'Var', (55, 62))	('PMCA3', 'Gene', '320707', (0, 5))
177992	29545923	The expression of PMCA4 (Figure 3D) was 3.6-fold higher in C2C12 compared with RD (p < 0.0001) and 40% higher in C2C12-D than RD-D (p < 0.0001).	('C2C12', 'Chemical', '-', (113, 118))	('C2C12-D', 'Var', (113, 120))	('C2C12', 'Chemical', '-', (59, 64))	('PMCA4', 'Gene', '381290', (18, 23))	('expression', 'MPA', (4, 14))	('higher', 'PosReg', (103, 109))	('PMCA4', 'Gene', (18, 23))	('higher', 'PosReg', (49, 55))	('C2C12', 'Var', (59, 64))
177996	29545923	In the expression of NCX1, no significant difference was seen between untreated C2C12 and RD, but a higher expression in C2C12-D than RD-D, p < 0.05 (Figure 4A-4D).	('NCX1', 'Gene', '21909', (21, 25))	('expression', 'MPA', (107, 117))	('C2C12', 'Chemical', '-', (121, 126))	('C2C12', 'Chemical', '-', (80, 85))	('higher', 'PosReg', (100, 106))	('NCX1', 'Gene', (21, 25))	('C2C12-D', 'Var', (121, 128))
178008	29545923	F-actin filaments in C2C12 and C2C12-D cells were well-organized in higher-order structure, forming a stable net.	('C2C12', 'Chemical', '-', (21, 26))	('C2C12', 'Chemical', '-', (31, 36))	('C2C12-D', 'Var', (31, 38))	('F-actin filaments', 'Protein', (0, 17))	('C2C12', 'Var', (21, 26))
178013	29545923	Electroporation with and without calcium disassembled actin cytoskeleton and inhibited zyxin expression.	('disassembled', 'Reg', (41, 53))	('inhibited', 'NegReg', (77, 86))	('calcium', 'Chemical', 'MESH:D002118', (33, 40))	('Electroporation', 'Var', (0, 15))	('zyxin', 'Gene', (87, 92))	('expression', 'MPA', (93, 103))	('zyxin', 'Gene', '22793', (87, 92))	('actin cytoskeleton', 'MPA', (54, 72))
178014	29545923	As seen in the graph, the intensity of the zyxin signal decreased (p < 0.05) after treatment with calcium electroporation, opposite the normal cells.	('intensity', 'MPA', (26, 35))	('zyxin', 'Gene', '22793', (43, 48))	('calcium electroporation', 'Var', (98, 121))	('zyxin', 'Gene', (43, 48))	('decreased', 'NegReg', (56, 65))	('calcium', 'Chemical', 'MESH:D002118', (98, 105))
178028	29545923	This study has confirmed our previous work about cytotoxic effect of calcium electroporation on malignant muscle cells, which increased with increasing calcium concentration and/or applied voltage, as well as less effect was shown in normal muscle cells.	('calcium', 'Chemical', 'MESH:D002118', (152, 159))	('cytotoxic effect', 'CPA', (49, 65))	('calcium electroporation', 'Var', (69, 92))	('increased', 'PosReg', (126, 135))	('calcium concentration', 'MPA', (152, 173))	('calcium', 'Chemical', 'MESH:D002118', (69, 76))
178032	29545923	We showed an increased intracellular calcium concentration in all cells after calcium electroporation.	('calcium electroporation', 'Var', (78, 101))	('increased intracellular calcium', 'Phenotype', 'HP:0003575', (13, 44))	('calcium', 'Chemical', 'MESH:D002118', (78, 85))	('calcium', 'Chemical', 'MESH:D002118', (37, 44))	('intracellular calcium concentration', 'MPA', (23, 58))	('increased', 'PosReg', (13, 22))
178053	29545923	It has previously been shown that calcium electroporation causes acute and severe ATP depletion.	('calcium electroporation', 'Var', (34, 57))	('calcium', 'Chemical', 'MESH:D002118', (34, 41))	('ATP depletion', 'MPA', (82, 95))	('ATP', 'Chemical', 'MESH:D000255', (82, 85))
178058	29545923	According to previous studies, the membrane components spatial rearrangement, caused by electroporation, may affect the focal adhesion junctions and disturb zyxin expression leading to F-actin bundles unbinding.	('disturb', 'Reg', (149, 156))	('zyxin', 'Gene', (157, 162))	('zyxin', 'Gene', '22793', (157, 162))	('membrane components', 'MPA', (35, 54))	('F-actin', 'MPA', (185, 192))	('affect', 'Reg', (109, 115))	('electroporation', 'Var', (88, 103))	('expression', 'MPA', (163, 173))	('focal adhesion junctions', 'Protein', (120, 144))
178073	29545923	Although, a slight decrease of the tumor volume was seen after CaEP compared with untreated control tumors, the differences were not statistically significant.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('decrease', 'NegReg', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (100, 105))	('CaEP', 'Var', (63, 67))	('tumors', 'Disease', (100, 106))	('tumor', 'Disease', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('CaEP', 'Chemical', '-', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
178079	29545923	Interestingly, in the same study, lower necrotic fraction was observed in normal muscle tissue directly treated with calcium electroporation compared with tumor tissue, which also confirms our in vitro data.	('calcium', 'Chemical', 'MESH:D002118', (117, 124))	('necrotic', 'Disease', 'MESH:D009336', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('lower', 'NegReg', (34, 39))	('calcium electroporation', 'Var', (117, 140))	('tumor', 'Disease', (155, 160))	('necrotic', 'Disease', (40, 48))
178175	28404587	Recipient mice transplanted with eMC expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small-round to short-spindle cells.	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (90, 114))	('mice', 'Species', '10090', (10, 14))	('undifferentiated sarcoma', 'Disease', (90, 114))	('developed', 'Reg', (65, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('CIC-DUX4', 'Var', (48, 56))
178178	28404587	Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro.	('CIC-DUX4', 'Gene', (18, 26))	('Ccnd2', 'Gene', (38, 43))	('inhibited', 'NegReg', (71, 80))	('Ret', 'Gene', (45, 48))	('CDS tumor', 'Disease', (81, 90))	('CDS tumor', 'Disease', 'MESH:C536560', (81, 90))	('Gene silencing', 'Var', (0, 14))	('Ret', 'Gene', '19713', (45, 48))	('Bcl2', 'Gene', '12043', (54, 58))	('Bcl2', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
178182	28404587	Although EWS-ETS-negative small round cell sarcomas were previously classified as Ewing-like sarcoma or Ewing sarcoma-like round cell sarcoma, increasing evidence suggests the distinct biology of CDS with CIC-DUX4 gene fusions, secondary to either a t(4;19)(q35;q13) or t(10;19)(q26.3;q13) translocation.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('sarcoma', 'Disease', (110, 117))	('CIC-DUX4', 'Gene', (205, 213))	('t(10;19)(q26.3;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (270, 289))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (104, 117))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('CDS', 'Gene', (196, 199))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Disease', (93, 100))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (250, 266))	('t(4', 'Var', (250, 253))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('Ewing sarcoma', 'Disease', (104, 117))	('sarcoma', 'Disease', (43, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcomas', 'Disease', (43, 51))	('Ewing-like sarcoma', 'Disease', (82, 100))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (82, 100))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcoma', 'Disease', (134, 141))	('CDS', 'Gene', '1040', (196, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
178192	28404587	Deregulation of CIC target genes such as ETV4 is one of the key events in the development and progression of CDS, and chimeric transcription factors act as an oncogene only in proper cellular context.	('Deregulation', 'Var', (0, 12))	('ETV4', 'Gene', (41, 45))	('CDS', 'Gene', '1040', (109, 112))	('ETV4', 'Gene', '18612', (41, 45))	('CDS', 'Gene', (109, 112))
178200	28404587	Modeling fusion gene-associated sarcomas thus provides important tools for further our understanding in the pathogenesis of these rare types of neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (144, 153))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('sarcomas', 'Disease', (32, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (144, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('fusion', 'Var', (9, 15))	('neoplasms', 'Disease', (144, 153))
178210	28404587	The following primary antibodies were used: anti-MUC5AC (Santa Cruz Biotechnology), anti-ETV4 (Abcam), anti-CCND2 (Santa Cruz Biotechnology).	('anti-MUC5AC', 'Var', (44, 55))	('ETV4', 'Gene', '18612', (89, 93))	('ETV4', 'Gene', (89, 93))	('anti-CCND2', 'Var', (103, 113))
178215	28404587	The murine HT MG-430 PM array (Affymetrix) was hybridized with aRNA probes generated from eMC 48 h after transduction with pMYs-CIC-DUX4 or empty vector, CDS and ES tumor tissues, or a mixture of mouse normal tissues according to methods described previously.	('ES tumor', 'Disease', (162, 170))	('mouse', 'Species', '10090', (196, 201))	('pMYs-CIC-DUX4', 'Var', (123, 136))	('ES', 'Phenotype', 'HP:0012254', (162, 164))	('CDS', 'Gene', '1040', (154, 157))	('murine', 'Species', '10090', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('CDS', 'Gene', (154, 157))	('ES tumor', 'Disease', 'MESH:C563168', (162, 170))
178219	28404587	CEL files from E-MEXP-1142, E-MEXP-353, GSE21122, GSE7529, mCDS and hCDS samples were summarized by MAS5 algorithm with Affymetrix Power Tool software version 1.12.0 (Affymetrix).	('E-MEXP-1142', 'Var', (15, 26))	('E-MEXP', 'Chemical', '-', (28, 34))	('E-MEXP-353', 'Var', (28, 38))	('GSE21122', 'Var', (40, 48))	('GSE7529', 'Var', (50, 57))	('mCDS', 'Chemical', '-', (59, 63))	('hCDS', 'Gene', '1040', (68, 72))	('GSE7529', 'Chemical', '-', (50, 57))	('E-MEXP', 'Chemical', '-', (15, 21))	('hCDS', 'Gene', (68, 72))
178242	28404587	Comparing the gene expression profiles of the eMC transduced with the CIC-DUX4 retrovirus versus the empty vector, and between murine CDS (mCDS) and eMC with an empty vector.	('CDS', 'Gene', (140, 143))	('CDS', 'Gene', (134, 137))	('CDS', 'Gene', '1040', (134, 137))	('CIC-DUX4', 'Var', (70, 78))	('murine', 'Species', '10090', (127, 133))	('CDS', 'Gene', '1040', (140, 143))	('mCDS', 'Chemical', '-', (139, 143))
178255	28404587	Our previous study also showed upregulation of ETV1 and ETV5 by CIC-DUX4 in the human osteosarcoma U2OS cell, and CIC-DUX4 expression induced anchorage-independent growth of NIH3T3 cells.	('NIH3T3', 'CellLine', 'CVCL:0594', (174, 180))	('ETV1', 'Gene', (47, 51))	('ETV5', 'Gene', (56, 60))	('ETV1', 'Gene', '2115', (47, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('osteosarcoma', 'Disease', (86, 98))	('CIC-DUX4', 'Gene', (64, 72))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('human', 'Species', '9606', (80, 85))	('ETV5', 'Gene', '2119', (56, 60))	('CIC-DUX4', 'Var', (114, 122))	('anchorage-independent growth', 'CPA', (142, 170))	('osteosarcoma', 'Disease', 'MESH:D012516', (86, 98))	('induced', 'PosReg', (134, 141))	('U2OS', 'CellLine', 'CVCL:0042', (99, 103))	('upregulation', 'PosReg', (31, 43))
178279	28404587	To this end specific inhibitors for cyclin dependent kinases 4 and 6 (palbociclib), Ret (vandetanib) and Bcl2 (ABT199) were tested for their tumor suppressive activities against mCDS cells, as knockdown of Ccnd2, Ret and Bcl2 genes was effective for growth inhibition.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('Ret', 'Gene', '19713', (84, 87))	('Ret', 'Gene', (213, 216))	('Ccnd2', 'Gene', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('ABT199', 'Chemical', 'MESH:C579720', (111, 117))	('palbociclib', 'Chemical', 'MESH:C500026', (70, 81))	('Ret', 'Gene', '19713', (213, 216))	('vandetanib', 'Chemical', 'MESH:C452423', (89, 99))	('knockdown', 'Var', (193, 202))	('tumor', 'Disease', (141, 146))	('Bcl2', 'Gene', '12043', (221, 225))	('Bcl2', 'Gene', (221, 225))	('mCDS', 'Chemical', '-', (178, 182))	('cyclin dependent kinases 4 and 6', 'Gene', '12567;12571', (36, 68))	('Bcl2', 'Gene', '12043', (105, 109))	('Bcl2', 'Gene', (105, 109))	('Ret', 'Gene', (84, 87))
178302	28404587	A previous report showed that transcription of Ccnd2 is directly regulated by ETV4, suggesting that Ccnd2 upregulation is achieved by multiple PEA3 family proteins induced by CIC-DUX4 in CDS.	('ETV4', 'Gene', (78, 82))	('PEA3', 'Gene', (143, 147))	('CIC-DUX4', 'Var', (175, 183))	('CDS', 'Gene', '1040', (187, 190))	('Ccnd2', 'Gene', (100, 105))	('ETV4', 'Gene', '18612', (78, 82))	('CDS', 'Gene', (187, 190))	('PEA3', 'Gene', '18612', (143, 147))	('upregulation', 'PosReg', (106, 118))
178306	28404587	Inhibition of CDK4/6 is therefore expected to suppress cell proliferation of mCDS.	('CDK4/6', 'Gene', (14, 20))	('mCDS', 'Chemical', '-', (77, 81))	('CDK4/6', 'Gene', '12567;12571', (14, 20))	('suppress', 'NegReg', (46, 54))	('cell proliferation of mCDS', 'CPA', (55, 81))	('Inhibition', 'Var', (0, 10))
178317	28404587	In this context, juxtaposition of DUX4 to the IgG enhancer in human B cell lymphoblastic leukemia where the transactivation domain of DUX4 is deleted is intriguing.	('DUX4', 'Gene', (134, 138))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('human', 'Species', '9606', (62, 67))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (75, 97))	('deleted', 'Var', (142, 149))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (75, 97))	('lymphoblastic leukemia', 'Disease', (75, 97))
178319	28404587	In oligodendroglioma, mutations result in loss-of-function of CIC.	('oligodendroglioma', 'Disease', (3, 20))	('oligodendroglioma', 'Disease', 'MESH:D009837', (3, 20))	('loss-of-function', 'NegReg', (42, 58))	('mutations', 'Var', (22, 31))	('CIC', 'Gene', (62, 65))
178320	28404587	Collectively these findings indicate aberrations of CIC function is one of key molecular events in multiple human cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (108, 113))	('aberrations', 'Var', (37, 48))	('cancer', 'Disease', (114, 120))
178322	28404587	The eMC exhibit sufficient plasticity to tolerate cancer-associated fusion genes, possibly by bypassing oncogene-induced senescence.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('fusion genes', 'Var', (68, 80))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
178360	25756523	Results showed that due to significant inhibition of three important stages of angiogenesis (endothelial cell proliferation, migration, and tube formation) induced by philinopside A, the formation and growth of new blood vessels were greatly decreased.	('rat', 'Species', '10116', (117, 120))	('migration', 'CPA', (125, 134))	('inhibition', 'NegReg', (39, 49))	('rat', 'Species', '10116', (128, 131))	('growth of new blood vessels', 'CPA', (201, 228))	('philinopside A', 'Chemical', 'MESH:C500379', (167, 181))	('decreased', 'NegReg', (242, 251))	('philinopside', 'Var', (167, 179))
178368	25756523	Studies of the action of philinopside A on the angiogenesis-related receptor tyrosine kinases (RTKs) revealed that philinopside A broadly inhibited all tested RTKs, including fibroblast growth factor receptor-1 (FGFR1), platelet-derived growth factor receptor-beta (PDGFbeta), vascular endothelial growth factor receptor (VEGFR), along with epithelial growth factor receptor (EGFR), at IC50 values ranging from 2.6 to 4.9 muM.	('PDGFbeta', 'Gene', (266, 274))	('philinopside A', 'Chemical', 'MESH:C500379', (25, 39))	('philinopside A', 'Chemical', 'MESH:C500379', (115, 129))	('muM', 'Gene', (422, 425))	('FGFR1', 'Gene', (212, 217))	('RTKs', 'Enzyme', (159, 163))	('philinopside', 'Var', (115, 127))	('inhibited', 'NegReg', (138, 147))	('muM', 'Gene', '56925', (422, 425))
178369	25756523	These results suggest that philinopside A, because of its inhibition of all the tested RTKs, might prove to be an effective inhibitor of RTK, while a lethal dose (LD50) in mice was only 625 mg/kg orally.	('philinopside A', 'Chemical', 'MESH:C500379', (27, 41))	('philinopside', 'Var', (27, 39))	('mice', 'Species', '10090', (172, 176))	('inhibition', 'NegReg', (58, 68))
178376	25756523	Philinopside E also suppressed the active (phosphorylated) forms of vascular endothelial growth factor receptors including: KDR/Flk-1 (which trigger downstream signaling pathways), VEGF2 ERK (which is required for the mitogenic activities of VEGF in endothelial cells), FAK (which regulates mitogenicity), paxillin (which associates with FAK and plays an important role in cell adhesion and migration and is involved in proliferation, adhesion, migration and survival of endothelial cells), and Akt (which regulates cell survival).	('Akt', 'Gene', (495, 498))	('Philinopside', 'Var', (0, 12))	('FAK', 'Gene', (270, 273))	('rat', 'Species', '10116', (427, 430))	('active', 'MPA', (35, 41))	('suppressed', 'NegReg', (20, 30))	('paxillin', 'Gene', (306, 314))	('rat', 'Species', '10116', (448, 451))	('rat', 'Species', '10116', (394, 397))	('Akt', 'Gene', '207', (495, 498))	('vascular', 'Protein', (68, 76))	('KDR/Flk-1', 'Gene', (124, 133))	('VEGF2 ERK', 'Gene', (181, 190))
178379	25756523	It was also shown that philinopside E significantly suppresses alphavbeta3 integrin-driven downstream signaling caused by a disturbance of the interaction between KDR and alphavbeta3 integrin in HMECs, followed by a disruption of the cytoskeleton organization of actin and decreased adhesion of cells to vitronectin.	('decreased adhesion of cells', 'Phenotype', 'HP:0008352', (273, 300))	('disruption', 'Reg', (216, 226))	('philinopside E', 'Chemical', 'MESH:C512676', (23, 37))	('KDR', 'Protein', (163, 166))	('disturbance', 'Var', (124, 135))	('adhesion', 'MPA', (283, 291))	('cytoskeleton organization', 'MPA', (234, 259))	('alphavbeta3 integrin', 'Protein', (171, 191))	('decreased', 'NegReg', (273, 282))	('alphavbeta3 integrin-driven downstream signaling', 'MPA', (63, 111))	('suppresses', 'NegReg', (52, 62))	('interaction', 'Interaction', (143, 154))
178395	25756523	Ds-echinoside A significantly decreased Nuclear factor NF-kappaB expression, but echinoside A was not involved in concerning the expression.	('expression', 'MPA', (65, 75))	('Ds-echinoside A', 'Chemical', '-', (0, 15))	('decreased', 'NegReg', (30, 39))	('echinoside A', 'Chemical', 'MESH:C043973', (81, 93))	('NF-kappaB', 'Gene', '4790', (55, 64))	('echinoside A', 'Chemical', 'MESH:C043973', (3, 15))	('NF-kappaB', 'Gene', (55, 64))	('Ds-echinoside', 'Var', (0, 13))
178396	25756523	Echinoside A and Ds-echinoside A (2.5 mg/kg) induced the reduction of H22 hepatocarcinoma tumor weight by 49.8% and 55.0%, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('reduction of H22 hepatocarcinoma tumor', 'Disease', (57, 95))	('reduction of H22 hepatocarcinoma tumor', 'Disease', 'MESH:D009369', (57, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Echinoside A', 'Chemical', 'MESH:C043973', (0, 12))	('Ds-echinoside', 'Var', (17, 30))	('Ds-echinoside A', 'Chemical', '-', (17, 32))
178437	25756523	Frondanol A5 revealed inhibition of the growth at S and G2/M phases along with a decrease in Cdc25c and an increase in p21WAF1/CIP along with significant apoptosis caused by H2AX phosphorylation and the cleavage of caspase-2 in HCT116 cells.	('H2AX', 'Gene', (174, 178))	('Cdc25c', 'Gene', '995', (93, 99))	('decrease', 'NegReg', (81, 89))	('increase', 'PosReg', (107, 115))	('Cdc25c', 'Gene', (93, 99))	('phosphorylation', 'Var', (179, 194))	('inhibition', 'NegReg', (22, 32))	('apoptosis', 'CPA', (154, 163))	('cleavage', 'MPA', (203, 211))	('CIP', 'Gene', '90523', (127, 130))	('HCT116', 'CellLine', 'CVCL:0291', (228, 234))	('H2AX', 'Gene', '3014', (174, 178))	('G2/M phases', 'CPA', (56, 67))	('caspase-2', 'Gene', '835', (215, 224))	('CIP', 'Gene', (127, 130))	('growth at S', 'CPA', (40, 51))	('caspase-2', 'Gene', (215, 224))
178440	25756523	Frondanol-A5P inhibited cell proliferation and induced cell cycle arrest at G2/M phase in both cell lines with decreased expression of cdc25c, cyclin A, and cyclin B. Frondanol-A5P also induced phosphorylation of Janus kinase (SAPK/JAK) and stress-activated protein kinase along with p38 mitogen-activated protein kinase (MAP) during 5 min and markedly increased expression of p21waf1 messenger RNA and protein at 3 h in both cell lines.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (55, 72))	('phosphorylation', 'MPA', (194, 209))	('p21waf1', 'Gene', (377, 384))	('cdc25c', 'Gene', '995', (135, 141))	('expression', 'MPA', (363, 373))	('rat', 'Species', '10116', (36, 39))	('cdc25c', 'Gene', (135, 141))	('Frondanol-A5P', 'Var', (167, 180))	('increased', 'PosReg', (353, 362))
178442	25756523	Frondanol-A5P also significantly increased annexin V binding and caspase-3 activation.	('Frondanol-A5P', 'Var', (0, 13))	('caspase', 'Gene', '835;842', (65, 72))	('activation', 'PosReg', (75, 85))	('increased', 'PosReg', (33, 42))	('caspase', 'Gene', (65, 72))	('annexin V', 'Protein', (43, 52))
178457	25756523	Frondoside A antagonizes the receptors EP2 and EP4 of prostaglandin E. Frondoside A inhibited 3H-PGE2 binding to recombinant EP2 or EP4-expressing cells at a high concentration (IC50 of 16.5 muM and 3.7 muM, respectively) that may be caused by cytotoxic effects.	('prostaglandin E', 'Chemical', 'MESH:D011458', (54, 69))	('binding', 'Interaction', (102, 109))	('muM', 'Gene', '56925', (203, 206))	('Frondoside A', 'Var', (71, 83))	('Frondoside A', 'Chemical', 'MESH:C534797', (71, 83))	('3H', 'Chemical', 'MESH:D014316', (94, 96))	('rat', 'Species', '10116', (170, 173))	('Frondoside A', 'Chemical', 'MESH:C534797', (0, 12))	('muM', 'Gene', (203, 206))	('muM', 'Gene', '56925', (191, 194))	('PGE2', 'Chemical', 'MESH:D015232', (97, 101))	('3H-PGE2', 'Protein', (94, 101))	('muM', 'Gene', (191, 194))	('inhibited', 'NegReg', (84, 93))
178458	25756523	Moreover, frondoside A also inhibited EP4 or EP2-linked activation of intracellular cAMP along with EP4-mediated ERK1/2 activation.	('cAMP', 'Chemical', '-', (84, 88))	('frondoside A', 'Chemical', 'MESH:C534797', (10, 22))	('EP4', 'Var', (38, 41))	('intracellular cAMP', 'MPA', (70, 88))	('inhibited', 'NegReg', (28, 37))	('activation', 'PosReg', (56, 66))	('EP2-linked', 'Var', (45, 55))
178493	25756523	Cucumariosides A2-2 (18) and A4-2 (19) from Cucumaria japonica (Chart 9) and stichoposides S (14) and D (15) from Thelenota anax, in cytotoxic doses, were shown to induce apoptosis in human leukemia cells HL-60, THP-1, NB-4 and K562 in vitro by a caspase-dependent mechanism.	('A4-2', 'Var', (29, 33))	('THP-1', 'Gene', '2736', (212, 217))	('THP-1', 'Gene', (212, 217))	('leukemia', 'Disease', 'MESH:D007938', (190, 198))	('caspase', 'Gene', '835;842', (247, 254))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('HL-60', 'CellLine', 'CVCL:0002', (205, 210))	('induce', 'PosReg', (164, 170))	('apoptosis', 'CPA', (171, 180))	('caspase', 'Gene', (247, 254))	('stichoposides', 'Chemical', 'MESH:C001883', (77, 90))	('Cucumaria japonica', 'Disease', 'MESH:D012554', (44, 62))	('human', 'Species', '9606', (184, 189))	('Thelenota anax', 'Species', '574476', (114, 128))	('leukemia', 'Disease', (190, 198))	('Cucumaria japonica', 'Disease', (44, 62))	('K562', 'CellLine', 'CVCL:0004', (228, 232))
178551	25756523	However, the general details of this mechanism may be reduced to the following points: (a) induction of tumor cell apoptosis was shown to be one of the primary causative factors through the activation of intracellular caspase cell death pathways (caspases 3/7 and 9); (b) arrest of the cell cycle at S or G2/M phases and increase of the sub-G0/G1 cell population which leads to the block of proliferation and apoptosis; (c) regulation (up or down) of nuclear factor NF-kappaB, a key player linking chronic inflammation and cancer; (d) regulation (up or down) of certain cellular receptors and enzymes participating in cancerogenesis, such as: EGFR (epithelial growth factor receptor, mutations affecting EGFR expression or activity could result in cancer); AKt (or protein kinase B, involved in cellular survival pathways by inhibiting apoptotic processes); ERK (extracellular signal-regulated kinase controlling many cellular processes such as survival, proliferation, differentiation and motility); FAK (focal adhesion kinase, a cell growth, cell proliferation, cell survival and cell migration mediator, often dysfunctional in cells of cancer); and MMP-9 (matrix metalloproteinase-9, implicated in tumor metastasis) and some others.	('caspase', 'Gene', '835;842', (247, 254))	('inflammation', 'Disease', 'MESH:D007249', (506, 518))	('rat', 'Species', '10116', (1056, 1059))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('caspases', 'Gene', '835;842', (247, 255))	('cancer', 'Disease', (748, 754))	('AKt', 'Gene', '207', (757, 760))	('cancer', 'Phenotype', 'HP:0002664', (748, 754))	('tumor', 'Disease', (1201, 1206))	('caspase', 'Gene', (218, 225))	('result', 'Reg', (738, 744))	('tumor metastasis', 'Disease', 'MESH:D009362', (1201, 1217))	('inflammation', 'Disease', (506, 518))	('cancer', 'Disease', 'MESH:D009369', (1139, 1145))	('caspase', 'Gene', (247, 254))	('tumor', 'Disease', 'MESH:D009369', (1201, 1206))	('cancer', 'Disease', (618, 624))	('ERK', 'Gene', (858, 861))	('cancer', 'Phenotype', 'HP:0002664', (618, 624))	('FAK', 'Gene', (1001, 1004))	('cancer', 'Disease', (523, 529))	('NF-kappaB', 'Gene', (466, 475))	('tumor metastasis', 'Disease', (1201, 1217))	('cancer', 'Disease', 'MESH:D009369', (748, 754))	('caspases', 'Gene', (247, 255))	('tumor', 'Disease', (104, 109))	('AKt', 'Gene', (757, 760))	('cancer', 'Phenotype', 'HP:0002664', (523, 529))	('MMP-9', 'Gene', '4318', (1152, 1157))	('tumor', 'Phenotype', 'HP:0002664', (1201, 1206))	('MMP-9', 'Gene', (1152, 1157))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('caspase', 'Gene', '835;842', (218, 225))	('rat', 'Species', '10116', (962, 965))	('NF-kappaB', 'Gene', '4790', (466, 475))	('rat', 'Species', '10116', (1090, 1093))	('cancer', 'Disease', (1139, 1145))	('cancer', 'Disease', 'MESH:D009369', (618, 624))	('rat', 'Species', '10116', (398, 401))	('cancer', 'Phenotype', 'HP:0002664', (1139, 1145))	('mutations', 'Var', (684, 693))	('cancer', 'Disease', 'MESH:D009369', (523, 529))
178671	28806949	Infection of HHV-8 is thought to precede the development of KS and be one of the factors leading to bone marrow failure after transplantation.	('KS', 'Phenotype', 'HP:0100726', (60, 62))	('bone marrow failure', 'Disease', (100, 119))	('bone marrow failure', 'Disease', 'MESH:D000080983', (100, 119))	('HHV-8', 'Gene', (13, 18))	('Infection', 'Var', (0, 9))	('HHV-8', 'Species', '37296', (13, 18))	('bone marrow failure', 'Phenotype', 'HP:0005528', (100, 119))
178700	28348507	POs were more likely than NPs to use CXR in addition to CT chest (p = 0.02) and were more likely to include bone marrow aspirate (p = 0.006) (presumed with reference to Ewing sarcoma patients with bone marrow involvement at diagnosis; data not collected).	('bone marrow', 'Disease', 'MESH:D001855', (197, 208))	('bone marrow', 'Disease', 'MESH:D001855', (108, 119))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (169, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (169, 182))	('CXR', 'MPA', (37, 40))	('bone marrow', 'Disease', (108, 119))	('bone marrow involvement', 'Disease', (197, 220))	('bone marrow involvement', 'Disease', 'MESH:D001855', (197, 220))	('POs', 'Var', (0, 3))	('Ewing sarcoma', 'Disease', (169, 182))
178702	28348507	In addition, cumulative radiation exposure factored into the decision process for the RS modality being utilized (n = 31, N = 42; 74%) (e.g., CXR replacing CTs; the presence of TP53 mutation; risk stratification with radiation minimization in low risk patients).	('presence', 'Var', (165, 173))	('TP53', 'Gene', '7157', (177, 181))	('mutation', 'Var', (182, 190))	('CXR', 'Disease', (142, 145))	('TP53', 'Gene', (177, 181))	('CTs', 'Disease', (156, 159))
178740	27544129	In the overall population as well as in the TNBCs, high SPARC expression was associated with a greater likelihood of pathological complete response to neoadjuvant chemotherapy with docetaxel, doxorubicin, and cyclophosphamide +/- capecitabine and vinorelbine suggesting a role as a predictive biomarker.	('capecitabine', 'Chemical', 'MESH:D000069287', (230, 242))	('SPARC', 'Gene', '6678', (56, 61))	('doxorubicin', 'Chemical', 'MESH:D004317', (192, 203))	('high', 'Var', (51, 55))	('SPARC', 'Gene', (56, 61))	('vinorelbine', 'Chemical', 'MESH:D000077235', (247, 258))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (209, 225))	('docetaxel', 'Chemical', 'MESH:D000077143', (181, 190))
178783	27544129	The 5 year relapse-free survival rates were 73 % (0.44-0.89) and 56 % (0.37-0.71) in the absence and presence of SPARC expression, respectively.	('SPARC', 'Gene', (113, 118))	('SPARC', 'Gene', '6678', (113, 118))	('presence', 'Var', (101, 109))	('relapse-free survival', 'CPA', (11, 32))
178786	27544129	The 5 year OS rates were 87 % (0.56-0.94, 95%CI) and 66 % (0.47-0.80) in the absence and presence of SPARC expression, respectively.	('SPARC', 'Gene', (101, 106))	('OS', 'Chemical', '-', (11, 13))	('presence', 'Var', (89, 97))	('SPARC', 'Gene', '6678', (101, 106))
178806	27544129	High SPARC expression was found in the majority of specimens, 51/55 (96.3 %) and correlated with a poorer event free-survival (p = 0.03) and relapse free survival (p = 0.07).	('relapse free survival', 'CPA', (141, 162))	('poorer', 'NegReg', (99, 105))	('SPARC', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('SPARC', 'Gene', '6678', (5, 10))	('event free-survival', 'CPA', (106, 125))
178811	27544129	This has led to studies in various malignancies evaluating the efficacy of nanoparticle albumin-bound (nab)-paclitaxel based upon SPARC expression with correlation in response rates in high SPARC expressers in head and neck cancer patients but inconsistent results in pancreatic cancer patients.	('SPARC', 'Gene', (130, 135))	('paclitaxel', 'Chemical', 'MESH:D017239', (108, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (268, 285))	('neck cancer', 'Disease', 'MESH:D006258', (219, 230))	('neck cancer', 'Disease', (219, 230))	('SPARC', 'Gene', '6678', (130, 135))	('head and neck cancer', 'Phenotype', 'HP:0012288', (210, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('pancreatic cancer', 'Disease', (268, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('SPARC', 'Gene', (190, 195))	('SPARC', 'Gene', '6678', (190, 195))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (268, 285))	('patients', 'Species', '9606', (231, 239))	('malignancies', 'Disease', 'MESH:D009369', (35, 47))	('high', 'Var', (185, 189))	('malignancies', 'Disease', (35, 47))	('nab', 'Chemical', '-', (103, 106))	('patients', 'Species', '9606', (286, 294))
178814	27544129	Preclinical work in xenograft models of osteosarcoma and Ewing's sarcoma has demonstrated inhibition of tumor growth by nab-paclitaxel.	('inhibition', 'NegReg', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('tumor', 'Disease', (104, 109))	('nab-paclitaxel', 'Var', (120, 134))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (57, 72))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (120, 134))	("Ewing's sarcoma", 'Disease', (57, 72))	('osteosarcoma', 'Disease', (40, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (40, 52))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (57, 72))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('osteosarcoma', 'Disease', 'MESH:D012516', (40, 52))
178829	26997645	We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation.	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('withdrawal', 'Var', (21, 31))	('mature bone formation', 'CPA', (124, 145))	('leading to', 'Reg', (113, 123))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcoma', 'Disease', (98, 105))	('osteogenic differentiation of sarcoma', 'Phenotype', 'HP:0002669', (68, 105))	('EWS-FLI1', 'Gene', (35, 43))	('enhances', 'PosReg', (55, 63))
178835	26997645	They showed that EWS-FLI1 expression inhibits the osteogenic differentiation of sarcoma cells in vitro and in vivo.	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('expression', 'Var', (26, 36))	('sarcoma', 'Disease', (80, 87))	('osteogenic differentiation of sarcoma', 'Phenotype', 'HP:0002669', (50, 87))	('EWS-FLI1', 'Gene', (17, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('inhibits', 'NegReg', (37, 45))
178840	26997645	Moreover, more aggressive phenotypes of osteosarcomas are correlated with features of early osteogenic progenitors, suggesting that defects in the osteogenic differentiation program may play a role in osteosarcoma development and progression.	('osteosarcomas', 'Disease', (40, 53))	('osteosarcomas', 'Phenotype', 'HP:0002669', (40, 53))	('osteosarcomas', 'Disease', 'MESH:D012516', (40, 53))	('osteosarcoma', 'Disease', 'MESH:D012516', (201, 213))	('role', 'Reg', (193, 197))	('play', 'Reg', (186, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('defects', 'Var', (132, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (201, 213))	('osteosarcoma', 'Disease', (201, 213))	('osteosarcoma', 'Disease', (40, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (40, 52))	('osteogenic differentiation program', 'CPA', (147, 181))	('osteosarcoma', 'Disease', 'MESH:D012516', (40, 52))
178844	26997645	Indeed, genetic variants near EGR2 and TARDBP are associated with susceptibility to Ewing sarcoma.	('Ewing sarcoma', 'Disease', (84, 97))	('TARDBP', 'Gene', '230908', (39, 45))	('EGR2', 'Gene', (30, 34))	('EGR2', 'Gene', '13654', (30, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('susceptibility', 'Reg', (66, 80))	('TARDBP', 'Gene', (39, 45))	('genetic variants', 'Var', (8, 24))	('associated', 'Reg', (50, 60))
178846	26997645	However, it remains unclear whether these mutations are additional driver mutations or passenger mutations and how they contribute to the sarcoma development.	('sarcoma', 'Disease', (138, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('contribute', 'Reg', (120, 130))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('mutations', 'Var', (42, 51))
178848	26997645	Considering that cancer is a genetic disease involving genetic mutations, single nucleotide variants, and structural abnormalities of the chromosome, iPSCs derived from cancer cells are expected to harbor shared genetic abnormalities with the parental cancer cells and therefore should be a powerful tool for dissecting the role of the cancer genome on the phenotype.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (169, 175))	('structural abnormalities', 'Var', (106, 130))	('parental cancer', 'Disease', 'MESH:D063129', (243, 258))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('genetic abnormalities', 'Disease', 'MESH:D030342', (212, 233))	('genetic abnormalities', 'Disease', (212, 233))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('single nucleotide variants', 'Var', (74, 100))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('parental cancer', 'Disease', (243, 258))	('genetic disease', 'Disease', 'MESH:D030342', (29, 44))	('genetic disease', 'Disease', (29, 44))
178850	26997645	We revealed that EWS-FLI1 expression inhibits the osteogenic differentiation of sarcoma cells in vitro and in vivo.	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('expression', 'Var', (26, 36))	('sarcoma', 'Disease', (80, 87))	('osteogenic differentiation of sarcoma', 'Phenotype', 'HP:0002669', (50, 87))	('EWS-FLI1', 'Gene', (17, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('inhibits', 'NegReg', (37, 45))
178853	26997645	We established two transgenic systems using embryonic stem cell (ESC) lines containing Dox-inducible EWS-FLI1 alleles that were integrated at different loci by utilizing the KH2 system and Rosa26 targeting vector (Figures 1A, S1A, and S1B).	('Rosa26', 'Gene', (189, 195))	('KH2', 'Chemical', '-', (174, 177))	('Dox', 'Chemical', 'MESH:D004318', (87, 90))	('alleles', 'Var', (110, 117))	('transgenic', 'Species', '10090', (19, 29))	('ES', 'Chemical', 'MESH:D004540', (65, 67))	('Rosa26', 'Gene', '14910', (189, 195))	('EWS-FLI1', 'Gene', (101, 109))
178862	26997645	Indeed, there is no report that shows the generation of EWS-FLI1-driven sarcomas by the targeted insertion of EWS-FLI1 except for one study that reported the development of myeloid/erythroid leukemia.	('myeloid/erythroid leukemia', 'Disease', 'MESH:D007951', (173, 199))	('leukemia', 'Phenotype', 'HP:0001909', (191, 199))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('myeloid/erythroid leukemia', 'Disease', (173, 199))	('sarcomas', 'Disease', (72, 80))	('insertion', 'Var', (97, 106))	('EWS-FLI1', 'Gene', (110, 118))	('myeloid/erythroid leukemia', 'Phenotype', 'HP:0005531', (173, 199))
178863	26997645	However, previous studies have succeeded in modeling Ewing-like sarcomas in mice when combined with Trp53 deletion or an integrating viral delivery system with the EWS-FLI1 fusion gene, which is consistent with the hypothesis that additional genetic mutations may be required for EWS-FLI1-induced sarcoma development.	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (53, 72))	('sarcoma', 'Disease', 'MESH:D012509', (297, 304))	('Ewing-like sarcomas', 'Disease', (53, 72))	('Trp53', 'Gene', (100, 105))	('sarcoma', 'Disease', (297, 304))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (297, 304))	('mice', 'Species', '10090', (76, 80))	('deletion', 'Var', (106, 114))	('Trp53', 'Gene', '22059', (100, 105))	('sarcoma', 'Disease', (64, 71))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (53, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
178879	26997645	At the same time, we found increased expressions of p53 and p21, but no increase in beta-gal (SAbetagal) activity, which is associated with senescence (Figure S2G).	('senescence', 'Disease', (140, 150))	('increased', 'PosReg', (27, 36))	('SAbetagal', 'Chemical', '-', (94, 103))	('beta-gal', 'Chemical', '-', (84, 92))	('p21', 'Gene', (60, 63))	('p21', 'Gene', '12575', (60, 63))	('p53', 'Var', (52, 55))	('expressions', 'MPA', (37, 48))
178881	26997645	The reversible phenotype suggested that EWS-FLI1 depletion results in cell-cycle arrest of the osteosarcoma cells.	('EWS-FLI1', 'Gene', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('arrest of the osteosarcoma', 'Disease', 'MESH:D012516', (81, 107))	('arrest of the osteosarcoma', 'Disease', (81, 107))	('osteosarcoma', 'Phenotype', 'HP:0002669', (95, 107))	('depletion', 'Var', (49, 58))
178888	26997645	Intriguingly, in both cell lines, extracellular matrix and space-related genes, which often include bone and cartilage development-related genes, were significantly enriched in Dox OFF sarcoma cells (for 72 hr) compared with Dox ON EWS-FLI1-expressing sarcoma cells by GO enrichment analysis (Figures 3A, 3B, and S3B).	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('sarcoma', 'Disease', 'MESH:D012509', (252, 259))	('Dox OFF', 'Var', (177, 184))	('S3B', 'Gene', '11778', (313, 316))	('enriched', 'PosReg', (165, 173))	('Dox', 'Chemical', 'MESH:D004318', (225, 228))	('Dox', 'Chemical', 'MESH:D004318', (177, 180))	('sarcoma', 'Disease', (252, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('cartilage', 'Disease', (109, 118))	('cartilage', 'Disease', 'MESH:D002357', (109, 118))	('S3B', 'Gene', (313, 316))	('sarcoma', 'Disease', 'MESH:D012509', (185, 192))	('sarcoma', 'Disease', (185, 192))
178890	26997645	Long-term knockdown of EWS-FLI1 with shRNA in Ewing sarcoma cells resulted in cellular differentiation to osteogenic, adipogenic, and chondrogenic lineage, consistent with an MSC origin of Ewing sarcoma.	('cellular differentiation', 'CPA', (78, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('osteogenic', 'MPA', (106, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (46, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('EWS-FLI1', 'Gene', (23, 31))	('Ewing sarcoma', 'Disease', (189, 202))	('resulted in', 'Reg', (66, 77))	('Ewing sarcoma', 'Disease', (46, 59))	('adipogenic', 'MPA', (118, 128))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (189, 202))	('knockdown', 'Var', (10, 19))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (189, 202))	('chondrogenic lineage', 'CPA', (134, 154))
178891	26997645	Notably, after long-term depletion of EWS-FLI1, a subset of sarcoma cells slowly proliferated and exhibited heterogeneous morphology (Figure 3D).	('heterogeneous morphology', 'MPA', (108, 132))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('exhibited', 'Reg', (98, 107))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('depletion', 'Var', (25, 34))	('EWS-FLI1', 'Gene', (38, 46))
178911	26997645	The sarcoma-derived iPSC-like cells exhibited demethylation of both Nanog promoter and Oct3/4 distal enhancer (Figure 4C), implying that these cells underwent epigenetic reorganization to acquire pluripotency.	('pluripotency', 'Disease', 'None', (196, 208))	('Oct3/4', 'Gene', '18999', (87, 93))	('sarcoma', 'Disease', (4, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Oct3/4', 'Gene', (87, 93))	('Nanog', 'Gene', '71950', (68, 73))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('pluripotency', 'Disease', (196, 208))	('Nanog', 'Gene', (68, 73))	('demethylation', 'Var', (46, 59))
178914	26997645	Furthermore, exome analysis revealed hundreds of identical missense mutations between SCOS#2 and sarcoma-derived iPSC-like cells (Figure S5E and Table S2), affirming that these iPSC-like clones were derived from the parental sarcoma cell.	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('parental sarcoma', 'Disease', (216, 232))	('sarcoma', 'Disease', 'MESH:D012509', (225, 232))	('sarcoma', 'Disease', (225, 232))	('sarcoma', 'Disease', (97, 104))	('parental sarcoma', 'Disease', 'MESH:D063129', (216, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('missense mutations', 'Var', (59, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('SCOS#2', 'Gene', (86, 92))
178919	26997645	The enhanced osteogenic differentiation of sarcoma cells upon the depletion of EWS-FLI1 raised the possibility that EWS-FLI1-dependent osteosarcomas arise from osteogenic cells.	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('enhanced', 'PosReg', (4, 12))	('osteogenic differentiation', 'CPA', (13, 39))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('osteogenic differentiation of sarcoma', 'Phenotype', 'HP:0002669', (13, 50))	('osteosarcomas', 'Disease', (135, 148))	('depletion', 'Var', (66, 75))	('osteosarcomas', 'Phenotype', 'HP:0002669', (135, 148))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('EWS-FLI1', 'Gene', (79, 87))	('osteosarcomas', 'Disease', 'MESH:D012516', (135, 148))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcoma', 'Disease', (140, 147))
178928	26997645	Collectively, sarcoma-derived iPSCs exhibit impaired osteogenic differentiation irrespective of EWS-FLI1 expression, suggesting that genetic and epigenetic alterations besides EWS-FLI1 fusion also inhibit osteogenic differentiation and maintain the proliferating progenitor state.	('sarcoma', 'Disease', (14, 21))	('epigenetic alterations', 'Var', (145, 167))	('maintain', 'PosReg', (236, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('osteogenic differentiation', 'CPA', (205, 231))	('inhibit', 'NegReg', (197, 204))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))	('proliferating progenitor state', 'CPA', (249, 279))	('osteogenic differentiation', 'CPA', (53, 79))	('EWS-FLI1', 'Gene', (176, 184))
178940	26997645	Together, these results suggest that the impaired differentiation potential associated with the sarcoma genome contributes to a rapid malignant transformation of osteogenic cells upon EWS-FLI1 expression.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('EWS-FLI1', 'Gene', (184, 192))	('expression', 'Var', (193, 203))	('impaired', 'NegReg', (41, 49))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('differentiation potential', 'CPA', (50, 75))	('sarcoma', 'Disease', (96, 103))
178947	26997645	Moreover, EWSR1 rearrangement, which includes EWS-FLI1, has been identified in a subset of small-cell osteosarcomas.	('osteosarcomas', 'Phenotype', 'HP:0002669', (102, 115))	('EWSR1', 'Gene', (10, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('osteosarcomas', 'Disease', 'MESH:D012516', (102, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('identified', 'Reg', (65, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('osteosarcomas', 'Disease', (102, 115))	('rearrangement', 'Var', (16, 29))	('EWS-FLI1', 'Gene', (46, 54))
178950	26997645	Previous studies demonstrated that the knockdown of EWS-FLI1 in Ewing sarcoma cell lines results in osteogenic, adipogenic and chondrogenic differentiation.	('chondrogenic differentiation', 'CPA', (127, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('knockdown', 'Var', (39, 48))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (64, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (64, 77))	('results in', 'Reg', (89, 99))	('adipogenic', 'MPA', (112, 122))	('osteogenic', 'CPA', (100, 110))	('EWS-FLI1', 'Gene', (52, 60))	('Ewing sarcoma', 'Disease', (64, 77))
178967	26997645	Recently, established iPSCs from patients with Li-Fraumeni syndrome and demonstrated that mutant p53 causes defective osteoblastic differentiation.	('Li-Fraumeni syndrome', 'Disease', (47, 67))	('p53', 'Gene', (97, 100))	('patients', 'Species', '9606', (33, 41))	('mutant', 'Var', (90, 96))	('osteoblastic differentiation', 'CPA', (118, 146))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (47, 67))	('defective', 'NegReg', (108, 117))
178970	26997645	It is likely that a summation of extensive genetic abnormalities and epigenetic alterations is associated with the impaired differentiation of sarcoma iPSCs into multiple lineages.	('epigenetic alterations', 'Var', (69, 91))	('genetic abnormalities', 'Disease', 'MESH:D030342', (43, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('genetic abnormalities', 'Disease', (43, 64))	('sarcoma iPSCs', 'Disease', (143, 156))	('sarcoma iPSCs', 'Disease', 'MESH:D012509', (143, 156))
179079	29534016	The CD99sh protein has a molecular weight of 28 kDa and displays a deletion in its intracytoplasmic fragment.	('deletion', 'Var', (67, 75))	('CD99', 'Gene', '4267', (4, 8))	('CD99', 'Gene', (4, 8))
179096	29534016	It has been postulated that truncation of the cytoplasmic domain of the CD99 short form alters the three-dimensional structure of the molecule, leading to different binding sites for its ligand.	('binding', 'Interaction', (165, 172))	('CD99', 'Gene', '4267', (72, 76))	('different', 'Reg', (155, 164))	('CD99', 'Gene', (72, 76))	('three-dimensional structure', 'MPA', (99, 126))	('truncation', 'Var', (28, 38))	('alters', 'Reg', (88, 94))
179107	29534016	The Ser168 of CD99 long form has been reported to be a site for PKCalpha phosphorylation, which induces focal adhesion kinase (FAK) phosphorylation and is thereby, in turn, involved in actin polymerization and cell adhesion and migration.	('CD99', 'Gene', '4267', (14, 18))	('phosphorylation', 'MPA', (132, 147))	('Ser168', 'Chemical', '-', (4, 10))	('focal adhesion kinase', 'Gene', '5747', (104, 125))	('cell adhesion', 'CPA', (210, 223))	('induces', 'Reg', (96, 103))	('FAK', 'Gene', (127, 130))	('Ser168', 'Var', (4, 10))	('FAK', 'Gene', '5747', (127, 130))	('migration', 'CPA', (228, 237))	('CD99', 'Gene', (14, 18))	('focal adhesion kinase', 'Gene', (104, 125))	('PKCalpha', 'Gene', (64, 72))	('PKCalpha', 'Gene', '5578', (64, 72))	('actin polymerization', 'CPA', (185, 205))	('involved', 'Reg', (173, 181))
179109	29534016	Up to now, data available in osteosarcoma, only pointed out the importance of the presence of the Ser168 residue of CD99: Ser168 is required for the CD99wt-mediated inhibition of migration and metastatization of osteosarcoma and prostate cancer cells.	('Ser168', 'Chemical', '-', (98, 104))	('osteosarcoma', 'Disease', (212, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (212, 224))	('osteosarcoma', 'Disease', (29, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('metastatization', 'CPA', (193, 208))	('inhibition', 'NegReg', (165, 175))	('migration', 'CPA', (179, 188))	('Ser168', 'Var', (122, 128))	('osteosarcoma and prostate cancer', 'Disease', 'MESH:D011471', (212, 244))	('osteosarcoma', 'Phenotype', 'HP:0002669', (212, 224))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('Ser168', 'Chemical', '-', (122, 128))	('CD99', 'Gene', (149, 153))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('CD99', 'Gene', (116, 120))	('CD99', 'Gene', '4267', (149, 153))	('CD99', 'Gene', '4267', (116, 120))
179110	29534016	Ser168 is not present in CD99sh, consistent with the positive contribution of CD99sh to tumor malignancy.	('CD99', 'Gene', '4267', (25, 29))	('CD99', 'Gene', (78, 82))	('Ser168', 'Chemical', '-', (0, 6))	('CD99', 'Gene', (25, 29))	('Ser168', 'Var', (0, 6))	('tumor malignancy', 'Disease', (88, 104))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CD99', 'Gene', '4267', (78, 82))	('tumor malignancy', 'Disease', 'MESH:D018198', (88, 104))
179112	29534016	In human breast cancer, expression of the splice variant of CD99 increased the activity and expression of MMP-9 and contributed to the invasive phenotype by upregulating AP1-mediated gene expression through the AKT-dependent, ERK, and JNK signaling pathways.	('human', 'Species', '9606', (3, 8))	('ERK', 'Gene', (226, 229))	('activity', 'MPA', (79, 87))	('AKT', 'Gene', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('MMP-9', 'Gene', '4318', (106, 111))	('contributed', 'Reg', (116, 127))	('MMP-9', 'Gene', (106, 111))	('splice variant', 'Var', (42, 56))	('increased', 'PosReg', (65, 74))	('JNK', 'Gene', (235, 238))	('AP1', 'Gene', '3725', (170, 173))	('JNK', 'Gene', '5599', (235, 238))	('AP1', 'Gene', (170, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('expression', 'MPA', (92, 102))	('CD99', 'Gene', (60, 64))	('AKT', 'Gene', '207', (211, 214))	('upregulating', 'PosReg', (157, 169))	('CD99', 'Gene', '4267', (60, 64))	('ERK', 'Gene', '5594', (226, 229))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('breast cancer', 'Disease', (9, 22))
179118	29534016	The consistent, high-level expression of CD99 and the presence of a EWS gene-rearrangement with FLI1, ERG or, in rare cases, other ETS genes are the hallmarks of Ewing sarcoma, and a functional relation exists between the two, although that relation remains unclear.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (162, 175))	('FLI1', 'Gene', (96, 100))	('ERG', 'Gene', (102, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (162, 175))	('gene-rearrangement', 'Var', (72, 90))	('FLI1', 'Gene', '2313', (96, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('CD99', 'Gene', (41, 45))	('presence', 'Var', (54, 62))	('expression', 'MPA', (27, 37))	('Ewing sarcoma', 'Disease', (162, 175))	('EWS', 'Gene', '2130', (68, 71))	('EWS', 'Gene', (68, 71))	('ERG', 'Gene', '2078', (102, 105))	('CD99', 'Gene', '4267', (41, 45))
179124	29534016	From a mechanistic point of view, the results obtained to date suggest that high CD99 expression levels may contribute to tumor cell growth and dissemination by interfering with the following: (1) the migration inhibitory activity of KCMF1, a potassium channel modulatory factor reported to affect the biological function of 14-3-3sigma protein and stabilize MAPK signaling, and (2) PI3K/AKT signaling, which is generally repressed, and MAPK signaling, which is stabilized in CD99-deprived cells or after CD99 ligation with specific antibodies.	('migration inhibitory activity', 'MPA', (201, 230))	('KCMF1', 'Gene', '56888', (234, 239))	('affect', 'Reg', (291, 297))	('biological function', 'MPA', (302, 321))	('tumor', 'Disease', (122, 127))	('CD99', 'Gene', (81, 85))	('KCMF1', 'Gene', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('AKT', 'Gene', '207', (388, 391))	('MAPK', 'Gene', (437, 441))	('MAPK', 'Gene', (359, 363))	('CD99', 'Gene', '4267', (81, 85))	('MAPK', 'Gene', '3354888', (437, 441))	('MAPK', 'Gene', '3354888', (359, 363))	('CD99', 'Gene', (476, 480))	('CD99', 'Gene', (505, 509))	('CD99', 'Gene', '4267', (476, 480))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('high', 'Var', (76, 80))	('CD99', 'Gene', '4267', (505, 509))	('interfering', 'NegReg', (161, 172))	('AKT', 'Gene', (388, 391))
179128	29534016	In addition to the induction of ERK1/2, the silencing of CD99 was shown to lead to increased expression of the oncosuppressor miR34a, which in turn could both reduce both Notch 1 and NF-kappaB signaling.	('miR34a', 'Gene', (126, 132))	('CD99', 'Gene', (57, 61))	('NF-kappaB', 'Gene', (183, 192))	('increased', 'PosReg', (83, 92))	('Notch 1', 'Gene', '4851', (171, 178))	('silencing', 'Var', (44, 53))	('miR34a', 'Gene', '407040', (126, 132))	('NF-kappaB', 'Gene', '4790', (183, 192))	('expression', 'MPA', (93, 103))	('ERK1/2', 'Gene', (32, 38))	('CD99', 'Gene', '4267', (57, 61))	('ERK1/2', 'Gene', '5595;5594', (32, 38))	('Notch 1', 'Gene', (171, 178))	('reduce', 'NegReg', (159, 165))
179129	29534016	Notably, the same outcome was obtained by exposing Ewing sarcoma cells to exosomes derived from cells deprived of CD99, confirming the sequential path of miR34a/Notch/NF-kappaB and MAPK upregulation that follows CD99 silencing.	('silencing', 'Var', (217, 226))	('miR34a', 'Gene', (154, 160))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('CD99', 'Gene', (212, 216))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('upregulation', 'PosReg', (186, 198))	('MAPK', 'Gene', (181, 185))	('NF-kappaB', 'Gene', (167, 176))	('CD99', 'Gene', '4267', (114, 118))	('miR34a', 'Gene', '407040', (154, 160))	('MAPK', 'Gene', '3354888', (181, 185))	('Ewing sarcoma', 'Disease', (51, 64))	('CD99', 'Gene', '4267', (212, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('CD99', 'Gene', (114, 118))	('NF-kappaB', 'Gene', '4790', (167, 176))
179138	29534016	Knocking down CD99 expression by siRNA in cell lines derived from these tumors significantly decreased cell migration, further suggesting that CD99 may contribute to the infiltrative ability of tumor cells.	('CD99', 'Gene', '4267', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('contribute', 'Reg', (152, 162))	('infiltrative ability', 'CPA', (170, 190))	('Knocking down', 'Var', (0, 13))	('CD99', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (72, 77))	('cell migration', 'CPA', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', (72, 78))	('decreased', 'NegReg', (93, 102))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('CD99', 'Gene', (14, 18))	('tumor', 'Disease', (194, 199))	('CD99', 'Gene', '4267', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
179147	29534016	Methylation of the CD99 promoter, CD99 loss of heterozygosity (LOH), and loss of SP1 expression, which is a potent positive regulator of CD99, can account for CD99 downregulation in most cases.	('loss', 'NegReg', (73, 77))	('expression', 'MPA', (85, 95))	('CD99', 'Gene', '4267', (34, 38))	('CD99', 'Gene', (137, 141))	('Methylation', 'Var', (0, 11))	('SP1', 'Gene', (81, 84))	('CD99', 'Gene', (34, 38))	('CD99', 'Gene', '4267', (159, 163))	('downregulation', 'NegReg', (164, 178))	('CD99', 'Gene', '4267', (19, 23))	('CD99', 'Gene', '4267', (137, 141))	('loss of heterozygosity', 'NegReg', (39, 61))	('CD99', 'Gene', (159, 163))	('CD99', 'Gene', (19, 23))
179148	29534016	The involvement of CD99 mutations, posttranslational modifications, such as regulation by miRNAs, and additional derangements of other transcription factors may also occur.	('regulation', 'MPA', (76, 86))	('CD99', 'Gene', '4267', (19, 23))	('mutations', 'Var', (24, 33))	('involvement', 'Reg', (4, 15))	('CD99', 'Gene', (19, 23))
179150	29534016	In osteosarcoma, transfection of CD99 inhibited tumor metastasis through the suppression of c-Src and Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) activities.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('osteosarcoma', 'Disease', (3, 15))	('transfection', 'Var', (17, 29))	('c-Src', 'Gene', (92, 97))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('c-Src', 'Gene', '6714', (92, 97))	('inhibited', 'NegReg', (38, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('activities', 'MPA', (166, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('CD99', 'Gene', '4267', (33, 37))	('Rho-associated, coiled-coil-containing protein kinase 2', 'Gene', '9475', (102, 157))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('suppression', 'NegReg', (77, 88))	('ROCK2', 'Gene', (159, 164))	('ROCK2', 'Gene', '9475', (159, 164))	('CD99', 'Gene', (33, 37))
179153	29534016	By favoring N-cadherin/beta-catenin cell membrane recruitment, adherens junction formation and stable cell-cell interactions, the re-expression of CD99wt increases contact strength and reactivates stop-migration signals that counteract the otherwise dominant promigratory action of ezrin in osteosarcoma cells.	('CD99', 'Gene', '4267', (147, 151))	('favoring', 'PosReg', (3, 11))	('re-expression', 'Var', (130, 143))	('stable cell-cell interactions', 'CPA', (95, 124))	('ezrin', 'Gene', '7430', (282, 287))	('N-cadherin', 'Gene', (12, 22))	('osteosarcoma', 'Disease', (291, 303))	('increases', 'PosReg', (154, 163))	('N-cadherin', 'Gene', '1000', (12, 22))	('osteosarcoma', 'Disease', 'MESH:D012516', (291, 303))	('beta-catenin', 'Gene', (23, 35))	('beta-catenin', 'Gene', '1499', (23, 35))	('contact', 'MPA', (164, 171))	('osteosarcoma', 'Phenotype', 'HP:0002669', (291, 303))	('adherens junction formation', 'CPA', (63, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (296, 303))	('reactivates stop-migration signals', 'MPA', (185, 219))	('CD99', 'Gene', (147, 151))	('ezrin', 'Gene', (282, 287))
179161	29534016	CD99 engagement reduces the malignant potential of these tumors through different mechanisms, including the induction of caspase-independent programmed cell death or methuosis, a process characterized by excessive accumulation of vacuoles in the cytoplasm, leading to compromised cell viability.	('CD99', 'Gene', '4267', (0, 4))	('CD99', 'Gene', (0, 4))	('methuosis', 'Disease', (166, 175))	('caspase-independent', 'CPA', (121, 140))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('reduces', 'NegReg', (16, 23))	('engagement', 'Var', (5, 15))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('accumulation', 'PosReg', (214, 226))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
179163	29534016	Accordingly, anti-CD99 antibodies exert additive/synergistic effects when combined with conventional agents, such as doxorubicin or vincristine, and are effective even against chemoresistant tumor cells.	('CD99', 'Gene', '4267', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('antibodies', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('CD99', 'Gene', (18, 22))	('doxorubicin', 'Chemical', 'MESH:D004317', (117, 128))	('vincristine', 'Chemical', 'MESH:D014750', (132, 143))
179170	29534016	CD99 ligation by antibodies can increase natural killer cell-mediated tumor lysis by inducing HSP70 expression.	('CD99', 'Gene', '4267', (0, 4))	('HSP70', 'Gene', '3308', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('inducing', 'Reg', (85, 93))	('increase', 'PosReg', (32, 40))	('ligation', 'Var', (5, 13))	('tumor', 'Disease', (70, 75))	('CD99', 'Gene', (0, 4))	('HSP70', 'Gene', (94, 99))	('expression', 'MPA', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
179171	29534016	In addition, peptides from CD99 have been described as promising candidates for immunotherapeutic glioblastoma treatment.	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('peptides', 'Var', (13, 21))	('CD99', 'Gene', (27, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('CD99', 'Gene', '4267', (27, 31))
179185	29534016	Considering the role that the loss of CD99 has in many common tumors, a true appreciation of the possible mechanisms involved (DNA methylation, LOH, transcriptional, and post-transcriptional mechanisms) is urgently required.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('CD99', 'Gene', (38, 42))	('loss', 'Var', (30, 34))	('CD99', 'Gene', '4267', (38, 42))
179193	29534016	A full appreciation of how the presence or absence of CD99 may affect tumor infiltration and the cross-talk between tumor and normal host cells may open new therapeutic avenues.	('CD99', 'Gene', (54, 58))	('affect', 'Reg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('absence', 'NegReg', (43, 50))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('CD99', 'Gene', '4267', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('presence', 'Var', (31, 39))
179249	26207772	Patients who underwent excision/biopsy tended to have a poorer prognosis in terms of both mortality and DFS than those who did not, likely because progressive disease was the indication for which they underwent the procedure.	('Patients', 'Species', '9606', (0, 8))	('excision/biopsy', 'Var', (23, 38))	('DFS', 'CPA', (104, 107))	('progressive', 'Disease', (147, 158))
179391	23045358	Low levels of these hormones may decrease premenopausal breast cancer and prostate cancer risk; however, the evidence is inconclusive.	('decrease', 'NegReg', (33, 41))	('men', 'Species', '9606', (45, 48))	('prostate cancer', 'Disease', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (42, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('breast cancer', 'Disease', (56, 69))	('Low levels', 'Var', (0, 10))
179454	33738167	In one study of 122 sarcomas of the head or neck, patients with high-grade lesions had significantly worse survival compared with those with low-grade lesions (HR for death: 5.52; 95% CI: 1.51-20.21).	('survival', 'MPA', (107, 115))	('patients', 'Species', '9606', (50, 58))	('death', 'Disease', 'MESH:D003643', (167, 172))	('death', 'Disease', (167, 172))	('sarcomas of the head', 'Disease', (20, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('worse', 'NegReg', (101, 106))	('sarcomas of the head', 'Disease', 'MESH:D012509', (20, 40))	('high-grade', 'Var', (64, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
179494	32703229	In a publication in 1995, they proved that DSRCT represents the third tumor type associated with EWSR1 translocation, and it is the only malignancy holding EWSR1 - WT1 rearrangement.	('EWSR1', 'Gene', '2130', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('malignancy', 'Disease', (137, 147))	('DSRCT', 'Disease', (43, 48))	('WT1', 'Gene', '7490', (164, 167))	('WT1', 'Gene', (164, 167))	('tumor', 'Disease', (70, 75))	('EWSR1', 'Gene', (97, 102))	('translocation', 'Var', (103, 116))	('WT', 'Phenotype', 'HP:0002667', (164, 166))	('EWSR1', 'Gene', (156, 161))	('EWSR1', 'Gene', '2130', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
179509	32703229	Extensive (> 75%) paranuclear dotlike desmin positivity in addition to negative PAX8 and bland nuclear features will suggest DSRCT.	('desmin', 'Gene', (38, 44))	('positivity', 'Var', (45, 55))	('PAX8', 'Gene', '7849', (80, 84))	('desmin', 'Gene', '1674', (38, 44))	('DSRCT', 'Disease', (125, 130))	('PAX8', 'Gene', (80, 84))	('desmin positivity', 'Phenotype', 'HP:0100300', (38, 55))
179516	32703229	These two different tumor types have similar age distribution, similar cytology and both harbor EWSR1 rearrangements.	('EWSR1', 'Gene', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('harbor', 'Reg', (89, 95))	('EWSR1', 'Gene', '2130', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('rearrangements', 'Var', (102, 116))	('tumor', 'Disease', (20, 25))
179617	30114371	Development of Mithramycin Analogues with Increased Selectivity toward ETS Transcription Factor Expressing Cancers Mithramycin A (1) was identified as the top potential inhibitor of the aberrant ETS transcription factor EWS-FLI1, which causes Ewing sarcoma.	('Ewing sarcoma', 'Disease', (243, 256))	('Mithramycin', 'Chemical', 'MESH:C066851', (115, 126))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (243, 256))	('Mithramycin A', 'Chemical', 'MESH:C066851', (115, 128))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (243, 256))	('Mithramycin', 'Chemical', 'MESH:C066851', (15, 26))	('Mithramycin A', 'Chemical', 'MESH:C066851', (15, 28))	('Cancers', 'Phenotype', 'HP:0002664', (107, 114))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('aberrant', 'Var', (186, 194))	('EWS-FLI1', 'Gene', '2130', (220, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('EWS-FLI1', 'Gene', (220, 228))	('Cancers', 'Disease', (107, 114))	('Cancers', 'Disease', 'MESH:D009369', (107, 114))	('causes', 'Reg', (236, 242))
179630	30114371	Aside from Ewing sarcoma, aberrant ETS transcription factors contribute significantly to the malignancy of prostate cancer, leukemia, and lymphoma.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('aberrant', 'Var', (26, 34))	('contribute', 'Reg', (61, 71))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (11, 24))	('ETS transcription factors', 'Gene', (35, 60))	('lymphoma', 'Disease', (138, 146))	('leukemia', 'Disease', (124, 132))	('Ewing sarcoma', 'Disease', (11, 24))	('leukemia', 'Disease', 'MESH:D007938', (124, 132))	('lymphoma', 'Disease', 'MESH:D008223', (138, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('leukemia', 'Phenotype', 'HP:0001909', (124, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (11, 24))	('lymphoma', 'Phenotype', 'HP:0002665', (138, 146))	('malignancy of prostate cancer', 'Disease', (93, 122))	('malignancy of prostate cancer', 'Disease', 'MESH:D011471', (93, 122))	('malignancy of prostate', 'Phenotype', 'HP:0100787', (93, 115))
179634	30114371	This was tested in a recent national cancer institute (NCI) conducted clinical study where Ewing sarcoma patients were enrolled to assess the utility of MTM (1) in a population of patients, all of whom express ETS fusions.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('Ewing sarcoma', 'Disease', (91, 104))	('patients', 'Species', '9606', (105, 113))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (91, 104))	('cancer', 'Disease', (37, 43))	('MTM', 'Chemical', 'MESH:C093781', (153, 156))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('ETS fusions', 'Var', (210, 221))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('patients', 'Species', '9606', (180, 188))
179639	30114371	We previously found that mithramycin SA (MTMSA; 2, Figure 1), which is a combinatorial biosynthetic analogue of MTM (1) produced by S. argillaceus, upon inactivation of the mtmW gene, has no cytotoxicity (Table 1, entry 19).	('MTM', 'Chemical', 'MESH:C093781', (41, 44))	('mithramycin SA', 'Chemical', 'MESH:C066851', (25, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (191, 203))	('S. argillaceus', 'Species', '41951', (132, 146))	('MTM', 'Chemical', 'MESH:C093781', (112, 115))	('inactivation', 'Var', (153, 165))	('mtmW', 'Gene', (173, 177))	('cytotoxicity', 'Disease', (191, 203))	('mithramycin', 'Disease', (25, 36))
179644	30114371	In this article, we describe our efforts to find more selective MTM (1) analogues for the treatment of cancers expressing aberrant ETS fusions or ETS factors.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aberrant', 'Var', (122, 130))	('MTM', 'Chemical', 'MESH:C093781', (64, 67))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
179646	30114371	Initial pharmacological studies showed that both MTMSA-Trp (3) and MTMSA-Phe (4) appeared to have the potential to overcome the limitation of MTM (1), with MTMSA-Trp (3) being the more cytotoxic of the two derivatives (Table 3, entry 10).	('MTM', 'Chemical', 'MESH:C093781', (49, 52))	('MTMSA-Trp (3', 'Var', (156, 168))	('MTM', 'Chemical', 'MESH:C093781', (156, 159))	('MTMSA-Trp', 'Var', (49, 58))	('MTM', 'Chemical', 'MESH:C093781', (142, 145))	('MTM', 'Chemical', 'MESH:C093781', (67, 70))	('MTMSA-Trp', 'Chemical', 'MESH:C509690', (49, 58))	('MTMSA-Trp', 'Chemical', 'MESH:C509690', (156, 165))	('MTMSA-Phe', 'Chemical', 'MESH:C026650', (67, 76))
179659	30114371	Trifluoromethylation of 15 using the Togni reagent produced a complex mixture, possibly because of the interference of the free indole-NH.	('produced', 'Reg', (51, 59))	('Trifluoromethylation', 'Var', (0, 20))	('indole-NH', 'Chemical', 'MESH:C030374', (128, 137))	('complex mixture', 'MPA', (62, 77))
179682	30114371	Thus, analogues with >3-fold selectivity toward TC-32 cell line were considered selective and were further investigated in a broader panel of cell lines to confirm and validate the selectivity in the context of multiple ETS fusion or aberrant ETS expression and across multiple cancer types that do not depend on the ETS fusions.	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('aberrant', 'Var', (234, 242))	('TC-32', 'CellLine', 'CVCL:7151', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('ETS', 'Gene', (243, 246))	('cancer', 'Disease', (278, 284))
179683	30114371	In this secondary screen, analogues were tested in panel of seven additional Ewing sarcoma cell lines that express the majority of the EWS-ETS fusions and on the only available prostate cancer cell line (VCaP) that expresses aberrant ERG.	('prostate cancer', 'Disease', (177, 192))	('Ewing sarcoma', 'Disease', (77, 90))	('ERG', 'Gene', '2078', (234, 237))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (77, 90))	('ERG', 'Gene', (234, 237))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('EWS', 'Gene', '2130', (135, 138))	('EWS', 'Gene', (135, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (177, 192))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (177, 192))	('fusions', 'Var', (143, 150))	('VCaP', 'CellLine', 'CVCL:2235', (204, 208))	('aberrant ERG', 'Phenotype', 'HP:0000512', (225, 237))
179687	30114371	N-methylation will cut off the potential hydrogen-bonding donation and will increase the hydrophobicity of the indole ring.	('hydrogen-bonding donation', 'MPA', (41, 66))	('increase', 'PosReg', (76, 84))	('hydrophobicity of the indole ring', 'MPA', (89, 122))	('cut off', 'NegReg', (19, 26))	('N-methylation', 'Var', (0, 13))	('hydrogen', 'Chemical', 'MESH:D006859', (41, 49))	('N-methyl', 'Chemical', 'MESH:C031105', (0, 8))	('indole', 'Chemical', 'MESH:C030374', (111, 117))
179710	30114371	Likewise, analogue MTMSA-Trp-Trp (61), which contains two consecutive tryptophan moieties, was found to have much better selectivity than MTMSA-Trp (3) (Table 2; entry 3).	('MTMSA-Trp-Trp', 'Var', (19, 32))	('selectivity', 'MPA', (121, 132))	('MTMSA-Trp', 'Chemical', 'MESH:C509690', (138, 147))	('MTMSA-Trp', 'Chemical', 'MESH:C509690', (19, 28))	('MTMSA-Trp-Trp', 'Chemical', 'MESH:C509690', (19, 32))	('tryptophan', 'Chemical', 'None', (70, 80))
179717	30114371	Overall, the above-described initial screen identified five novel MTMSA (2) analogues with cytotoxicity (GI50) in TC-32 cells of less than 250 nM and selectivity against TC-32 cells greater than 3 times of that of PC-3, determined by PC-3/TC-32 GI50 ratio (Tables 1 and 2, highlighted in red).	('analogues', 'Var', (76, 85))	('PC-3', 'Gene', '3853', (234, 238))	('MTM', 'Chemical', 'MESH:C093781', (66, 69))	('PC-3', 'Gene', (214, 218))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('PC-3', 'Gene', (234, 238))	('TC-32', 'CellLine', 'CVCL:7151', (114, 119))	('PC-3', 'Gene', '3853', (214, 218))	('TC-32', 'CellLine', 'CVCL:7151', (170, 175))	('TC-32', 'CellLine', 'CVCL:7151', (239, 244))	('MTMSA (2', 'Gene', (66, 74))	('cytotoxicity', 'Disease', (91, 103))
179718	30114371	To deepen these findings and to further investigate the most promising analogues, we expanded the array of cancer cell lines to include a panel of eight Ewing sarcoma cell lines (expressing aberrant ETS transcription factors) versus nine non-Ewing sarcoma cell lines (lacking aberrant ETS transcription factors) (Figure 2; see Supporting Information).	('Ewing sarcoma', 'Disease', (242, 255))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (242, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('aberrant', 'Var', (190, 198))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (153, 166))	('cancer', 'Disease', (107, 113))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (242, 255))	('Ewing sarcoma', 'Disease', (153, 166))
179729	30114371	Previous modification of MTM (1) leading to the identification of EC-8105 with improved suppression of EWS-FLI1 by almost 10-fold focused on the introduction of an allyl carbonate residue in the 3B position of the disaccharide residue of MTM (1) (Figure 1).	('allyl carbonate', 'Chemical', 'MESH:D002254', (164, 179))	('MTM', 'Chemical', 'MESH:C093781', (238, 241))	('disaccharide', 'Chemical', 'MESH:D004187', (214, 226))	('suppression', 'NegReg', (88, 99))	('EWS-FLI1', 'Gene', '2130', (103, 111))	('EC-8105', 'Var', (66, 73))	('EWS-FLI1', 'Gene', (103, 111))	('MTM', 'Chemical', 'MESH:C093781', (25, 28))
179731	30114371	Therefore, the identification of MTMSA-Phe-Trp (60) and MTMSA-Trp-Trp (61) with improved selectivity of 19.1 and 15.6, respectively, cemented our initial hypothesis that adding an additional tryptophan residue to MTMSA-Phe (4) and MTMSA-Trp (3) at the 3-side chain position would enhance their interaction with EWS-FLI1.	('MTMSA-Phe', 'Chemical', 'MESH:C026650', (213, 222))	('tryptophan', 'Chemical', 'None', (191, 201))	('MTMSA-Phe-Trp', 'Var', (33, 46))	('MTMSA-Trp-Trp', 'Chemical', 'MESH:C509690', (56, 69))	('EWS-FLI1', 'Gene', '2130', (311, 319))	('EWS-FLI1', 'Gene', (311, 319))	('MTMSA-Phe-Trp', 'Chemical', 'MESH:C028281', (33, 46))	('MTMSA-Trp', 'Chemical', 'MESH:C509690', (56, 65))	('MTMSA-Phe', 'Chemical', 'MESH:C026650', (33, 42))	('MTMSA-Trp-Trp', 'Var', (56, 69))	('enhance', 'PosReg', (280, 287))	('MTMSA-Trp', 'Chemical', 'MESH:C509690', (231, 240))	('interaction', 'Interaction', (294, 305))
179733	30114371	We initially expected that they would follow a similar selectivity trend to 5838 cells, which overexpress the more rare EWS-ERG gene alteration in Ewing sarcoma.	('Ewing sarcoma', 'Disease', (147, 160))	('ERG', 'Gene', '2078', (124, 127))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (147, 160))	('alteration', 'Var', (133, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('ERG', 'Gene', (124, 127))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (147, 160))	('EWS', 'Gene', '2130', (120, 123))	('EWS', 'Gene', (120, 123))
179736	30114371	Since it is recognized that MTM displaces Sp1 from DNA and likely affects the expression of Sp1 target genes (e.g., BCL-2), we performed qRT-PCR to determine the effect of MTM (1) and MTMSA analogue treatment on the expression of those genes as well as on EWS-FLI1 and its target gene NR0B1.	('expression', 'MPA', (78, 88))	('MTM', 'Chemical', 'MESH:C093781', (172, 175))	('BCL-2', 'Gene', (116, 121))	('MTM', 'Chemical', 'MESH:C093781', (28, 31))	('Sp1', 'Gene', (42, 45))	('NR0B1', 'Gene', (285, 290))	('EWS-FLI1', 'Gene', '2130', (256, 264))	('EWS-FLI1', 'Gene', (256, 264))	('NR0B1', 'Gene', '190', (285, 290))	('MTM', 'Chemical', 'MESH:C093781', (184, 187))	('MTM', 'Var', (28, 31))	('affects', 'Reg', (66, 73))	('N', 'Chemical', 'MESH:D009584', (285, 286))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('displaces', 'NegReg', (32, 41))	('BCL-2', 'Gene', '596', (116, 121))
179748	30114371	None of the analogues reduced CMV driven luciferase signal at the range of their GI50 concentrations.	('CMV driven', 'MPA', (30, 40))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('reduced', 'NegReg', (22, 29))	('analogues', 'Var', (12, 21))
179750	30114371	Lack of effect of analogues MTMSA-Phe-Trp (60) and MTMSA-Trp-Trp (61) on CMV promoter driven transcription while maintaining activities against EWS-FLI1 mediated transcription supports the observed selectivity in our cytotoxicity assays (cf.	('MTMSA-Trp-Trp (61', 'Var', (51, 68))	('activities', 'MPA', (125, 135))	('CMV', 'Gene', (73, 76))	('cytotoxicity', 'Disease', (217, 229))	('EWS-FLI1', 'Gene', '2130', (144, 152))	('EWS-FLI1', 'Gene', (144, 152))	('MTMSA-Trp-Trp', 'Chemical', 'MESH:C509690', (51, 64))	('MTMSA-Phe-Trp', 'Chemical', 'MESH:C028281', (28, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (217, 229))
179751	30114371	Furthermore, MTMSA-Trp-Phe (59), which reduces CMV promoter driven transcription, lacks selectivity in our cytotoxicity assays (cf.	('lacks', 'NegReg', (82, 87))	('cytotoxicity', 'Disease', 'MESH:D064420', (107, 119))	('MTMSA-Trp-Phe (59', 'Var', (13, 30))	('CMV promoter driven transcription', 'MPA', (47, 80))	('MTMSA-Trp-Phe', 'Chemical', 'MESH:C028281', (13, 26))	('cytotoxicity', 'Disease', (107, 119))	('reduces', 'NegReg', (39, 46))
179755	30114371	This study was aimed at refinement of two amino acid derivatives of MTMSA (2), namely, MTMSA-Trp (3) and MTMSA-Phe (4), both of which showed promising activity and increased selectivity in a preliminary cytotoxicity assay looking at effects on cell lines overexpressing aberrant ETS transcription factors.	('MTMSA-Trp', 'Var', (87, 96))	('MTM', 'Chemical', 'MESH:C093781', (87, 90))	('MTMSA-Trp', 'Chemical', 'MESH:C509690', (87, 96))	('MTMSA', 'Gene', (68, 73))	('cytotoxicity', 'Disease', (203, 215))	('MTMSA-Phe', 'Var', (105, 114))	('MTM', 'Chemical', 'MESH:C093781', (105, 108))	('MTMSA-Phe', 'Chemical', 'MESH:C026650', (105, 114))	('activity', 'MPA', (151, 159))	('MTM', 'Chemical', 'MESH:C093781', (68, 71))	('cytotoxicity', 'Disease', 'MESH:D064420', (203, 215))
179758	30114371	Initially, the focus was on refining the Trp residue, since MTMSA-Trp (3) showed better cytotoxicity than MTMSA-Phe (4) (Table 3).	('cytotoxicity', 'Disease', (88, 100))	('better', 'PosReg', (81, 87))	('MTMSA-Trp', 'Chemical', 'MESH:C509690', (60, 69))	('MTMSA-Trp (3', 'Var', (60, 72))	('Trp', 'Chemical', 'MESH:C509690', (66, 69))	('Trp', 'Chemical', 'MESH:C509690', (41, 44))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))	('MTMSA-Phe', 'Chemical', 'MESH:C026650', (106, 115))
179762	30114371	These studies started with phenyl-expanded Trp derivatives, in which the indole of Trp was expanded by an aromatic ring or through phenyl-Trp derivatives, and ended with dipeptide analogues of MTMSA (2), with all combinations of dipeptide side chains, namely, MTMSA-Trp-Phe (59), MTMSA-Phe-Trp (60), MTMSA-Phe-Phe (63), and MTMSA-Trp-Trp (61).	('MTMSA-Phe-Trp (60', 'Var', (280, 297))	('Trp', 'Chemical', 'MESH:C509690', (43, 46))	('MTM', 'Chemical', 'MESH:C093781', (324, 327))	('Trp', 'Chemical', 'MESH:C509690', (334, 337))	('MTM', 'Chemical', 'MESH:C093781', (260, 263))	('indole', 'Chemical', 'MESH:C030374', (73, 79))	('phenyl', 'Chemical', 'MESH:C064635', (131, 137))	('MTMSA-Trp-Phe (59', 'Var', (260, 277))	('MTMSA-Phe-Trp', 'Chemical', 'MESH:C028281', (280, 293))	('MTMSA-Phe-Phe (63', 'Var', (300, 317))	('MTM', 'Chemical', 'MESH:C093781', (300, 303))	('dipeptide', 'Chemical', 'MESH:D004151', (170, 179))	('MTMSA-Trp-Phe', 'Chemical', 'MESH:C028281', (260, 273))	('phenyl', 'Chemical', 'MESH:C064635', (27, 33))	('MTMSA-Trp-Trp (61', 'Var', (324, 341))	('MTM', 'Chemical', 'MESH:C093781', (193, 196))	('phenyl-Trp', 'Chemical', 'MESH:C509690', (131, 141))	('Trp', 'Chemical', 'MESH:C509690', (330, 333))	('MTM', 'Chemical', 'MESH:C093781', (280, 283))	('MTMSA-Phe-Phe', 'Chemical', 'MESH:C026650', (300, 313))	('Trp', 'Chemical', 'MESH:C509690', (266, 269))	('Trp', 'Chemical', 'MESH:C509690', (290, 293))	('Trp', 'Chemical', 'MESH:C509690', (138, 141))	('Trp', 'Chemical', 'MESH:C509690', (83, 86))	('dipeptide', 'Chemical', 'MESH:D004151', (229, 238))	('MTMSA-Trp-Trp', 'Chemical', 'MESH:C509690', (324, 337))
179770	30114371	We found that analogues 60 and 61 decreased EWS-FLI1 and NR0B1 mRNA expression, as well as NR0B1 promoter driven luciferase signal (Figure 3A, Figure 3B, Figure 4A).	('NR0B1', 'Gene', '190', (91, 96))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('EWS-FLI1', 'Gene', '2130', (44, 52))	('decreased', 'NegReg', (34, 43))	('EWS-FLI1', 'Gene', (44, 52))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('mRNA expression', 'MPA', (63, 78))	('NR0B1', 'Gene', (57, 62))	('NR0B1', 'Gene', (91, 96))	('analogues', 'Var', (14, 23))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('NR0B1', 'Gene', '190', (57, 62))
179777	30114371	1H and 13C chemical shifts are reported in ppm downfield of tetramethylsilane and referenced to residual solvent peaks (CHCl3; deltah = 7.26 and deltaC = 77.23, MeOH-d4; deltah= 3.31 and deltaC = 49.1).	('deltah', 'Var', (127, 133))	('13C', 'Chemical', 'MESH:C513342', (7, 10))	('HCl', 'Chemical', 'MESH:C014843', (121, 124))	('deltaC', 'Var', (145, 151))
179826	30114371	Compound 39 (58 g, 70%) was prepared following the general procedure A by HOBt-DCC coupling of BocNH-NMeTrp-OH (50 mg, 0.15 mmol) with NH2-NMeTrp-OMe (40 mg, 0.17 mmol) in the presence of HOBt (20 mg, 0.15 mmol) and DCC (35 mg, 0.17 mmol) in THF (5 mL) as a white solid.	('DCC', 'Gene', '1630', (216, 219))	('THF', 'Chemical', 'MESH:C006461', (242, 245))	('DCC', 'Gene', '1630', (79, 82))	('BocNH-NMeTrp-OH', 'Chemical', 'MESH:C071497', (95, 110))	('DCC', 'Gene', (216, 219))	('BocNH-NMeTrp-OH', 'Var', (95, 110))	('DCC', 'Gene', (79, 82))	('NH2-NMeTrp-OMe', 'Chemical', 'MESH:C481863', (135, 149))
179881	25794275	Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases.	('inhibition', 'Var', (52, 62))	('KSHV-associated diseases', 'Disease', (128, 152))	('KSHV', 'Species', '37296', (128, 132))
179886	25794275	Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology.	('prevented', 'NegReg', (25, 34))	('expression', 'Species', '29278', (93, 103))	('KSHV', 'Species', '37296', (173, 177))	('viral', 'Protein', (35, 40))	('inhibition', 'Var', (14, 24))
179887	25794275	Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt).	('MLN4924 treatment', 'Var', (30, 47))	('MLN4924', 'Chemical', 'MESH:C539933', (30, 37))	('recruitment', 'MPA', (62, 73))	('precluded', 'NegReg', (48, 57))
179889	25794275	Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('inhibition', 'Var', (32, 42))	('KSHV', 'Species', '37296', (107, 111))	('malignancies', 'Disease', (123, 135))	('NEDDylation', 'Protein', (46, 57))
179891	25794275	Previous research has shown that blockade of the ubiquitin proteasome system (UPS, a normal quality control pathway that degrades cellular proteins) is able to kill KSHV-infected lymphoma cells.	('KSHV-infected lymphoma', 'Disease', (165, 187))	('blockade', 'Var', (33, 41))	('lymphoma', 'Phenotype', 'HP:0002665', (179, 187))	('KSHV-infected lymphoma', 'Disease', 'MESH:C537372', (165, 187))	('degrades', 'NegReg', (121, 129))
179893	25794275	Recently, an inhibitor of NEDDylation (MLN4924) was developed and is currently in clinical trials as an anti-cancer drug.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('MLN4924', 'Chemical', 'MESH:C539933', (39, 46))	('cancer', 'Disease', (109, 115))	('MLN4924', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
179895	25794275	Firstly we show that NEDDylation is essential for the viability of KSHV-infected lymphoma cells, and MLN4924 treatment killed these cells by blocking NF-kappaB activity (required for KSHV latency gene expression and KSHV-associated cancer).	('KSHV-infected lymphoma', 'Disease', 'MESH:C537372', (67, 89))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('KSHV', 'Species', '37296', (183, 187))	('MLN4924', 'Chemical', 'MESH:C539933', (101, 108))	('cancer', 'Disease', (232, 238))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('KSHV-infected lymphoma', 'Disease', (67, 89))	('MLN4924 treatment', 'Var', (101, 118))	('activity', 'MPA', (160, 168))	('blocking', 'NegReg', (141, 149))	('expression', 'Species', '29278', (201, 211))	('NF-kappaB', 'Protein', (150, 159))	('KSHV', 'Species', '37296', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('KSHV', 'Species', '37296', (216, 220))
179902	25794275	Infection with KSHV is commonly associated with fatal malignancies, is the causative agent of primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS) and is frequently associated with multicentric Castleman's disease (MCD).	('MCD', 'Disease', 'MESH:D012514', (220, 223))	('MCD', 'Disease', (220, 223))	('KSHV', 'Species', '37296', (15, 19))	('Infection', 'Var', (0, 9))	('associated', 'Reg', (32, 42))	('agent', 'Reg', (85, 90))	("multicentric Castleman's disease", 'Disease', 'MESH:C537372', (186, 218))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (94, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('KSHV', 'Gene', (15, 19))	('malignancies', 'Disease', (54, 66))	("multicentric Castleman's disease", 'Disease', (186, 218))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (130, 146))	('primary effusion lymphoma', 'Disease', (94, 119))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (94, 119))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (130, 146))	("Kaposi's sarcoma", 'Disease', (130, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('associated', 'Reg', (170, 180))
179917	25794275	Recently, a specific NAE1 inhibitor has been developed (MLN4924) and is currently in clinical trials for various malignancies.	('MLN4924', 'Var', (56, 63))	('malignancies', 'Disease', (113, 125))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))	('NAE1', 'Gene', '8883', (21, 25))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))	('NAE1', 'Gene', (21, 25))
179918	25794275	MLN4924-mediated inhibition of NEDDylation blocks CRL activity resulting in the global stabilization of CRL targets.	('blocks', 'NegReg', (43, 49))	('NEDDylation', 'Protein', (31, 42))	('CRL', 'Gene', '133396', (50, 53))	('CRL', 'Gene', '133396', (104, 107))	('CRL', 'Gene', (104, 107))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('MLN4924-mediated', 'Var', (0, 16))	('stabilization', 'MPA', (87, 100))	('CRL', 'Gene', (50, 53))
179924	25794275	Treatment of cancer cells with MLN4924 leads to dramatic cytotoxicity, and some of the best characterized mechanisms include the induction of DNA re-replication by blocking the degradation of Cdt-1, or by inhibiting NF-kappaB signaling via stabilization of the inhibitor of NF-kappaB protein IkappaBalpha, both of which eventually lead to apoptosis.	('inhibiting', 'NegReg', (205, 215))	('MLN4924', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('blocking', 'NegReg', (164, 172))	('IkappaBalpha', 'Gene', (292, 304))	('NF-kappaB', 'MPA', (216, 225))	('cytotoxicity', 'Disease', (57, 69))	('degradation', 'MPA', (177, 188))	('apoptosis', 'CPA', (339, 348))	('cancer', 'Disease', (13, 19))	('MLN4924', 'Chemical', 'MESH:C539933', (31, 38))	('stabilization', 'MPA', (240, 253))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))	('Cdt-1', 'Gene', (192, 197))	('Cdt-1', 'Gene', '81620', (192, 197))	('lead to', 'Reg', (331, 338))	('IkappaBalpha', 'Gene', '4792', (292, 304))
179926	25794275	We found that, indeed, MLN4924 led to significant PEL cytotoxicity and this was mediated via inhibition of NF-kappaB signaling.	('inhibition', 'NegReg', (93, 103))	('cytotoxicity', 'Disease', (54, 66))	('MLN4924', 'Chemical', 'MESH:C539933', (23, 30))	('cytotoxicity', 'Disease', 'MESH:D064420', (54, 66))	('NF-kappaB', 'MPA', (107, 116))	('MLN4924', 'Var', (23, 30))
179927	25794275	Intriguingly, we also showed that NEDDylation was essential for amplification of the KSHV genome during reactivation of the lytic cycle and that treatment with MLN4924 prevented the recruitment of RTA to the origin of lytic replication (OriLyt).	('MLN4924', 'Chemical', 'MESH:C539933', (160, 167))	('KSHV', 'Gene', (85, 89))	('prevented', 'NegReg', (168, 177))	('MLN4924', 'Var', (160, 167))	('recruitment', 'MPA', (182, 193))	('RTA', 'Protein', (197, 200))	('KSHV', 'Species', '37296', (85, 89))
179931	25794275	As MLN4924 has demonstrated anti-proliferative activity in various cancer cell lines, we assessed its cytotoxic effects in PEL cells.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('MLN4924', 'Chemical', 'MESH:C539933', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('MLN4924', 'Var', (3, 10))	('anti-proliferative activity', 'CPA', (28, 55))
179933	25794275	These data demonstrated that MLN4924 was indeed cytotoxic to latently infected PEL cells with approximate EC50 values of 1.10 muM and 0.15 muM, for TREx-BCBL-1-RTA and BC-3 respectively (Fig.	('muM', 'Gene', '56925', (126, 129))	('muM', 'Gene', (126, 129))	('MLN4924', 'Chemical', 'MESH:C539933', (29, 36))	('muM', 'Gene', '56925', (139, 142))	('MLN4924', 'Var', (29, 36))	('muM', 'Gene', (139, 142))
179935	25794275	We also noted that MLN4924 led to apoptosis in BC-3 cells as shown by the cleavage of PARP (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('apoptosis', 'CPA', (34, 43))	('MLN4924', 'Var', (19, 26))	('PARP', 'Protein', (86, 90))	('cleavage', 'MPA', (74, 82))
179936	25794275	To investigate MLN4924-induced cytotoxicity, cell cycle analysis of TREx-BCBL-1-RTA cells was performed 24 h after treatment with 1 muM MLN4924.	('cytotoxicity', 'Disease', 'MESH:D064420', (31, 43))	('MLN4924', 'Chemical', 'MESH:C539933', (136, 143))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('muM', 'Gene', '56925', (132, 135))	('MLN4924-induced', 'Var', (15, 30))	('MLN4924', 'Var', (136, 143))	('cytotoxicity', 'Disease', (31, 43))	('muM', 'Gene', (132, 135))
179937	25794275	1D (i)), MLN4924 treatment led to a reduction in S-phase and an accumulation of cells in G2/M (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('reduction', 'NegReg', (36, 45))	('MLN4924', 'Var', (9, 16))	('cells in G2/M', 'CPA', (80, 93))	('S-phase', 'CPA', (49, 56))	('accumulation', 'PosReg', (64, 76))
179941	25794275	In agreement with this, we also showed that lytic reactivation did not activate Caspase 9; nevertheless, MLN4924 did, resulting in the activation of Caspase 3 (Fig.	('activation', 'PosReg', (135, 145))	('Caspase 3', 'Gene', '836', (149, 158))	('Caspase 9', 'Gene', (80, 89))	('MLN4924', 'Chemical', 'MESH:C539933', (105, 112))	('Caspase 9', 'Gene', '842', (80, 89))	('MLN4924', 'Var', (105, 112))	('Caspase 3', 'Gene', (149, 158))
179942	25794275	Importantly however, caspase inhibition (using the pan-caspase inhibitor, z-VAD-FMK) did not prevent PEL cell death after treatment with MLN4924 (Fig.	('z-VAD-FMK', 'Chemical', 'MESH:C096713', (74, 83))	('MLN4924', 'Chemical', 'MESH:C539933', (137, 144))	('MLN4924', 'Var', (137, 144))	('PEL cell death', 'CPA', (101, 115))
179950	25794275	This suggested that MLN4924 treatment modulated latency-associated viral gene expression, rather than inducing the full KSHV lytic cycle.	('MLN4924 treatment', 'Var', (20, 37))	('inducing', 'Reg', (102, 110))	('latency-associated viral gene', 'Gene', (48, 77))	('expression', 'MPA', (78, 88))	('MLN4924', 'Chemical', 'MESH:C539933', (20, 27))	('modulated', 'Reg', (38, 47))	('KSHV', 'Species', '37296', (120, 124))	('expression', 'Species', '29278', (78, 88))
179951	25794275	To further investigate the potential of MLN4924 to reactivate lytic cycle gene expression, rKSHV.219 cells were cultured for 36 h in the presence of 0.1 muM MLN4924, a concentration that was tolerated while in culture.	('expression', 'Species', '29278', (79, 89))	('muM', 'Gene', (153, 156))	('MLN4924', 'Chemical', 'MESH:C539933', (40, 47))	('muM', 'Gene', '56925', (153, 156))	('MLN4924', 'Chemical', 'MESH:C539933', (157, 164))	('KSHV', 'Species', '37296', (92, 96))	('MLN4924', 'Var', (40, 47))	('MLN4924', 'Var', (157, 164))
179953	25794275	2B, RFP expression was observed in numerous cells demonstrating that MLN4924 was indeed able to induce the expression of RTA.	('MLN4924', 'Var', (69, 76))	('expression', 'Species', '29278', (107, 117))	('induce', 'PosReg', (96, 102))	('expression', 'MPA', (107, 117))	('expression', 'Species', '29278', (8, 18))	('RTA', 'Gene', (121, 124))	('MLN4924', 'Chemical', 'MESH:C539933', (69, 76))
179954	25794275	MLN4924 was also capable of initiating expression of ORF57 (activated by RTA during reactivation) (Fig.	('ORF57', 'Gene', (53, 58))	('MLN4924', 'Var', (0, 7))	('initiating', 'Reg', (28, 38))	('ORF57', 'Gene', '4961525', (53, 58))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('expression', 'Species', '29278', (39, 49))
179957	25794275	We next investigated the potential mechanisms of MLN4924-mediated cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('MLN4924', 'Chemical', 'MESH:C539933', (49, 56))	('MLN4924-mediated', 'Var', (49, 65))	('cytotoxicity', 'Disease', (66, 78))
179958	25794275	The reported mechanisms of MLN4924-induced cytotoxicity is the induction of DNA re-replication (by blocking the CRL-mediated degradation of Cdt-1), or by inhibiting NF-kappaB signaling as CRL-mediated degradation of IkappaBalpha is prevented, thus precluding NF-kappaB's transcriptional activity.	('MLN4924-induced', 'Var', (27, 42))	('DNA re-replication', 'Disease', (76, 94))	('CRL', 'Gene', (188, 191))	('inhibiting', 'NegReg', (154, 164))	('cytotoxicity', 'Disease', (43, 55))	('CRL', 'Gene', '133396', (112, 115))	('CRL', 'Gene', '133396', (188, 191))	('Cdt-1', 'Gene', (140, 145))	('Cdt-1', 'Gene', '81620', (140, 145))	('NF-kappaB signaling', 'MPA', (165, 184))	('cytotoxicity', 'Disease', 'MESH:D064420', (43, 55))	('IkappaBalpha', 'Gene', '4792', (216, 228))	('blocking', 'NegReg', (99, 107))	('MLN4924', 'Chemical', 'MESH:C539933', (27, 34))	('IkappaBalpha', 'Gene', (216, 228))	('CRL', 'Gene', (112, 115))
179961	25794275	2A) are consistent with an inhibition of NF-kappaB, we tested whether it was inhibited after MLN4924 treatment.	('MLN4924', 'Chemical', 'MESH:C539933', (93, 100))	('MLN4924', 'Var', (93, 100))	('NF-kappaB', 'Protein', (41, 50))
179964	25794275	Therefore, MLN4924 inhibition of CRL1 function should stabilize phosphorylated IkappaBalpha (pIkappaBalpha) leading to an inhibition in NF-kappaB function.	('IkappaBalpha', 'Gene', (79, 91))	('IkappaBalpha', 'Gene', '4792', (94, 106))	('CRL1', 'Gene', '57050', (33, 37))	('inhibition', 'NegReg', (122, 132))	('IkappaBalpha', 'Gene', (94, 106))	('MLN4924 inhibition', 'Var', (11, 29))	('MLN4924', 'Chemical', 'MESH:C539933', (11, 18))	('CRL1', 'Gene', (33, 37))	('NF-kappaB function', 'MPA', (136, 154))	('IkappaBalpha', 'Gene', '4792', (79, 91))
179965	25794275	To investigate the most likely mechanism of MLN4924-induced cytotoxicity we performed a timecourse experiment (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))	('MLN4924', 'Chemical', 'MESH:C539933', (44, 51))	('cytotoxicity', 'Disease', (60, 72))	('MLN4924-induced', 'Var', (44, 59))
179966	25794275	Here we show that as little as 1 h treatment of TREX-BCBL-1-RTA cells with MLN4924 led to an inhibition of NEDDylation (as shown by the lack of NEDDylated Cul2 compared to DMSO-treated cells).	('inhibition', 'NegReg', (93, 103))	('Cul2', 'Gene', '8453', (155, 159))	('Cul2', 'Gene', (155, 159))	('MLN4924', 'Chemical', 'MESH:C539933', (75, 82))	('MLN4924', 'Var', (75, 82))	('DMSO', 'Chemical', 'MESH:D004121', (172, 176))	('NEDDylated', 'MPA', (144, 154))	('NEDDylation', 'MPA', (107, 118))
179970	25794275	Likewise, we did not observe significant alterations in the levels of phosphorylated H2Ax (gammaH2Ax):a marker of DNA strand breaks:although gammaH2Ax is known to be present in latently infected cells due to its association with LANA expression.	('LANA', 'Gene', (229, 233))	('expression', 'Species', '29278', (234, 244))	('association', 'Interaction', (212, 223))	('LANA', 'Gene', '4961527', (229, 233))	('gammaH2Ax', 'Var', (141, 150))
179971	25794275	Importantly, the MLN4924-associated reduction of ORF73 mRNA expression occurs prior to any indication of DNA damage (Fig.	('ORF73', 'Gene', (49, 54))	('reduction', 'NegReg', (36, 45))	('MLN4924', 'Chemical', 'MESH:C539933', (17, 24))	('expression', 'Species', '29278', (60, 70))	('MLN4924-associated', 'Var', (17, 35))
179973	25794275	Additionally, pIkappaBalpha levels increased in an MLN4924-dose-dependent manner in latently-infected TREx-BCBL-1-RTA (Fig.	('increased', 'PosReg', (35, 44))	('IkappaBalpha', 'Gene', '4792', (15, 27))	('IkappaBalpha', 'Gene', (15, 27))	('MLN4924', 'Chemical', 'MESH:C539933', (51, 58))	('MLN4924-dose-dependent', 'Var', (51, 73))
179977	25794275	Previous reports have shown that upon lytic reactivation, IkappaBalpha is posttranscriptionally downregulated and consistent with this, cytoplasmic p65/RelA decreased in Dox-treated (reactivated) cells further highlighting the involvement of IkappaBalpha for MLN4924-induced inhibition of NF-kappaB.	('IkappaBalpha', 'Gene', (58, 70))	('IkappaBalpha', 'Gene', '4792', (242, 254))	('p65', 'Gene', '5970', (148, 151))	('MLN4924', 'Chemical', 'MESH:C539933', (259, 266))	('IkappaBalpha', 'Gene', (242, 254))	('Dox', 'Chemical', '-', (170, 173))	('MLN4924-induced', 'Var', (259, 274))	('downregulated', 'NegReg', (96, 109))	('IkappaBalpha', 'Gene', '4792', (58, 70))	('decreased', 'NegReg', (157, 166))	('p65', 'Gene', (148, 151))
179978	25794275	Additionally, we did not observe pIkappaBalpha expression in reactivated cells (those with RTA expression) regardless of MLN4924 treatment (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (121, 128))	('IkappaBalpha', 'Gene', (34, 46))	('MLN4924', 'Var', (121, 128))	('expression', 'Species', '29278', (47, 57))	('expression', 'Species', '29278', (95, 105))	('IkappaBalpha', 'Gene', '4792', (34, 46))
179979	25794275	This was also highlighted in our confocal analysis of p65/RelA localization showing it had translocated to the nucleus in reactivated cells even when treated with MLN4924 (S2 Fig).	('p65', 'Gene', '5970', (54, 57))	('MLN4924', 'Chemical', 'MESH:C539933', (163, 170))	('MLN4924', 'Var', (163, 170))	('p65', 'Gene', (54, 57))
179980	25794275	We therefore surmised that inhibition of NF-kappaB, via stabilization of IkappaBalpha was responsible for cytotoxicity and demonstrated that inhibition of NEDDylation may provide a therapeutic option for the treatment of NF-kappaB-dependent PEL.	('IkappaBalpha', 'Gene', (73, 85))	('NEDDylation', 'Protein', (155, 166))	('inhibition', 'Var', (141, 151))	('cytotoxicity', 'Disease', (106, 118))	('inhibition', 'Var', (27, 37))	('stabilization', 'MPA', (56, 69))	('cytotoxicity', 'Disease', 'MESH:D064420', (106, 118))	('IkappaBalpha', 'Gene', '4792', (73, 85))
179981	25794275	Treatment of cells with MLN4924 blocks total NEDDylation, which undoubtedly has far-reaching implications on cellular function.	('total NEDDylation', 'MPA', (39, 56))	('blocks', 'NegReg', (32, 38))	('MLN4924', 'Chemical', 'MESH:C539933', (24, 31))	('MLN4924', 'Var', (24, 31))
179985	25794275	That CRL1 inhibition reactivated lytic expression is not surprising as it is known to regulate NF-kappaB signaling, corroborating our earlier analyses (Fig.	('lytic expression', 'MPA', (33, 49))	('NF-kappaB', 'MPA', (95, 104))	('reactivated', 'Reg', (21, 32))	('inhibition', 'Var', (10, 20))	('CRL1', 'Gene', '57050', (5, 9))	('expression', 'Species', '29278', (39, 49))	('CRL1', 'Gene', (5, 9))
179997	25794275	Here, we also investigated the expression of K12, which in contrast to the reduced expression we observed in the presence of MLN4924, was increased by Cul4B knockdown (Fig.	('Cul4B', 'Gene', (151, 156))	('increased', 'PosReg', (138, 147))	('MLN4924', 'Chemical', 'MESH:C539933', (125, 132))	('K12', 'Gene', (45, 48))	('expression', 'Species', '29278', (31, 41))	('K12', 'Gene', '4961446', (45, 48))	('expression', 'Species', '29278', (83, 93))	('expression', 'MPA', (31, 41))	('knockdown', 'Var', (157, 166))	('Cul4B', 'Gene', '8450', (151, 156))
179998	25794275	Although a thorough investigation of individual CRLs is required (for example, using RNAi experiments to inhibit the various CRL components), this data suggests that MLN4924's effect on KSHV latency is through its inhibition of CRL activity.	('CRL', 'Gene', '133396', (228, 231))	('CRL', 'Gene', '133396', (125, 128))	('MLN4924', 'Chemical', 'MESH:C539933', (166, 173))	('KSHV latency', 'MPA', (186, 198))	('inhibition', 'NegReg', (214, 224))	('MLN4924', 'Var', (166, 173))	('CRL', 'Gene', (48, 51))	('KSHV', 'Species', '37296', (186, 190))	('activity', 'MPA', (232, 240))	('CRL', 'Gene', (228, 231))	('CRL', 'Gene', (125, 128))	('CRL', 'Gene', '133396', (48, 51))
180002	25794275	However, in the presence of low concentration MLN4924 (1 muM), the degree of replication compartment ubiquitylation was reduced.	('MLN4924', 'Chemical', 'MESH:C539933', (46, 53))	('muM', 'Gene', (57, 60))	('MLN4924', 'Var', (46, 53))	('replication compartment ubiquitylation', 'MPA', (77, 115))	('muM', 'Gene', '56925', (57, 60))	('reduced', 'NegReg', (120, 127))
180008	25794275	Cells were treated with varying concentrations of MLN4924, the lytic cycle was induced and 24 h later cells were harvested and viral protein expression was assessed by immunoblotting.	('MLN4924', 'Chemical', 'MESH:C539933', (50, 57))	('MLN4924', 'Var', (50, 57))	('lytic cycle', 'CPA', (63, 74))	('expression', 'Species', '29278', (141, 151))
180009	25794275	5B, MLN4924 was able to inhibit the expression of RTA-Myc and its downstream target ORF57 in a dose-responsive manner, corresponding to the levels of Cul2 NEDDylation.	('MLN4924', 'Var', (4, 11))	('Myc', 'Gene', (54, 57))	('Cul2', 'Gene', '8453', (150, 154))	('ORF57', 'Gene', '4961525', (84, 89))	('expression', 'Species', '29278', (36, 46))	('Myc', 'Gene', '4609', (54, 57))	('ORF57', 'Gene', (84, 89))	('inhibit', 'NegReg', (24, 31))	('MLN4924', 'Chemical', 'MESH:C539933', (4, 11))	('expression', 'MPA', (36, 46))	('Cul2', 'Gene', (150, 154))
180011	25794275	not from the KSHV genome) in TREx-BCBL-1-RTA cells, these results showed that MLN4924 inhibited all transcription in these cells.	('KSHV', 'Species', '37296', (13, 17))	('MLN4924', 'Chemical', 'MESH:C539933', (78, 85))	('MLN4924', 'Var', (78, 85))	('inhibited', 'NegReg', (86, 95))
180012	25794275	Using qPCR analysis of viral genomes, we also confirmed that MLN4924 was able to inhibit KSHV DNA replication (Fig.	('KSHV', 'Species', '37296', (89, 93))	('inhibit', 'NegReg', (81, 88))	('KSHV DNA', 'Gene', (89, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (61, 68))	('MLN4924', 'Var', (61, 68))
180015	25794275	3B) which may account for the ability of MLN4924 to prevent KSHV genome replication.	('KSHV', 'Gene', (60, 64))	('MLN4924', 'Var', (41, 48))	('prevent', 'NegReg', (52, 59))	('KSHV', 'Species', '37296', (60, 64))	('MLN4924', 'Chemical', 'MESH:C539933', (41, 48))
180020	25794275	ORF57) in reactivated cells; caspase inhibition also led to an increase in viral protein expression as noted by the increased levels of full length ORF57 (FL ORF57) and RTA expression in reactivated cells (lane 4, Fig.	('caspase', 'Protein', (29, 36))	('increase', 'PosReg', (63, 71))	('inhibition', 'Var', (37, 47))	('ORF57', 'Gene', '4961525', (0, 5))	('ORF57', 'Gene', '4961525', (158, 163))	('ORF57', 'Gene', (0, 5))	('RTA expression', 'MPA', (169, 183))	('ORF57', 'Gene', (158, 163))	('ORF57', 'Gene', '4961525', (148, 153))	('viral', 'MPA', (75, 80))	('expression', 'Species', '29278', (173, 183))	('ORF57', 'Gene', (148, 153))	('increased', 'PosReg', (116, 125))	('expression', 'Species', '29278', (89, 99))
180021	25794275	Importantly, inhibition of caspase activity restored ORF57 and RTA-Myc expression, clearly demonstrating that MLN4924-induced apoptosis was responsible for inhibiting viral protein expression (lane 6, Fig.	('ORF57', 'Gene', (53, 58))	('MLN4924', 'Chemical', 'MESH:C539933', (110, 117))	('expression', 'Species', '29278', (181, 191))	('MLN4924-induced', 'Var', (110, 125))	('ORF57', 'Gene', '4961525', (53, 58))	('Myc', 'Gene', '4609', (67, 70))	('viral', 'MPA', (167, 172))	('expression', 'Species', '29278', (71, 81))	('Myc', 'Gene', (67, 70))	('inhibiting', 'NegReg', (156, 166))
180022	25794275	To our surprise however, when we treated cells with z-VAD-FMK and MLN4924 and investigated viral genome copy number by qPCR, viral DNA replication was still inhibited (Fig.	('inhibited', 'NegReg', (157, 166))	('z-VAD-FMK', 'Chemical', 'MESH:C096713', (52, 61))	('viral DNA replication', 'MPA', (125, 146))	('MLN4924', 'Chemical', 'MESH:C539933', (66, 73))	('MLN4924', 'Var', (66, 73))
180024	25794275	However, even in cells clearly expressing RTA, MLN4924 treatment prevented virus replication, as shown by the lack of EdU-positive replication compartments.	('EdU', 'Chemical', '-', (118, 121))	('prevented', 'NegReg', (65, 74))	('MLN4924', 'Chemical', 'MESH:C539933', (47, 54))	('virus replication', 'MPA', (75, 92))	('MLN4924 treatment', 'Var', (47, 64))
180025	25794275	Inhibition of caspases restored viral protein expression in MLN4924-treated cells; however, viral DNA replication was still inhibited (Fig.	('caspases', 'Gene', '841;842', (14, 22))	('MLN4924', 'Chemical', 'MESH:C539933', (60, 67))	('viral protein expression', 'MPA', (32, 56))	('MLN4924-treated', 'Var', (60, 75))	('caspases', 'Gene', (14, 22))	('expression', 'Species', '29278', (46, 56))	('viral DNA replication', 'MPA', (92, 113))	('inhibited', 'NegReg', (124, 133))
180029	25794275	These data confirm that MLN4924-mediated activation of caspases was not responsible for the inhibition of KSHV genome replication upon MLN4924 treatment.	('caspases', 'Gene', '841;842', (55, 63))	('MLN4924', 'Chemical', 'MESH:C539933', (135, 142))	('KSHV', 'Gene', (106, 110))	('MLN4924', 'Var', (135, 142))	('caspases', 'Gene', (55, 63))	('MLN4924', 'Chemical', 'MESH:C539933', (24, 31))	('KSHV', 'Species', '37296', (106, 110))
180030	25794275	Throughout our studies, we noticed that reactivated cells treated with MLN4924 displayed an unusual RTA expression pattern; as shown in Figs.	('MLN4924', 'Var', (71, 78))	('RTA expression', 'MPA', (100, 114))	('expression', 'Species', '29278', (104, 114))	('MLN4924', 'Chemical', 'MESH:C539933', (71, 78))
180032	25794275	We therefore hypothesized that this would have implications for RTA's ability to mediate KSHV genome replication, and therefore provide a rationale for the MLN4924-induced block in replication.	('KSHV', 'Species', '37296', (89, 93))	('MLN4924', 'Chemical', 'MESH:C539933', (156, 163))	('implications', 'Reg', (47, 59))	('MLN4924-induced', 'Var', (156, 171))
180034	25794275	Therefore, as MLN4924 inhibited viral genome replication and prevented the correct localization of RTA, we asked whether treatment precluded the loading of the replication complex.	('RTA', 'Protein', (99, 102))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))	('inhibited', 'NegReg', (22, 31))	('MLN4924', 'Var', (14, 21))	('correct localization', 'MPA', (75, 95))	('viral genome replication', 'CPA', (32, 56))	('prevented', 'NegReg', (61, 70))
180036	25794275	These results confirm that MLN4924 was able to induce transcription in latently infected cells; however, they show that only low levels of RTA are required.	('transcription', 'MPA', (54, 67))	('induce', 'PosReg', (47, 53))	('MLN4924', 'Chemical', 'MESH:C539933', (27, 34))	('MLN4924', 'Var', (27, 34))
180037	25794275	However, after MLN4924 treatment, RNA Pol II occupancy reduced ca.	('reduced', 'NegReg', (55, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('MLN4924 treatment', 'Var', (15, 32))	('occupancy', 'MPA', (45, 54))	('RNA Pol II', 'Enzyme', (34, 44))
180039	25794275	Consequently, by using MLN4924 to investigate the role of NEDDylation in KSHV biology, we have uncovered a novel mechanism that regulates lytic reactivation.	('regulates', 'Reg', (128, 137))	('KSHV', 'Species', '37296', (73, 77))	('MLN4924', 'Chemical', 'MESH:C539933', (23, 30))	('MLN4924', 'Var', (23, 30))	('lytic reactivation', 'MPA', (138, 156))
180045	25794275	An example of this is MLN4924, a small molecule inhibitor that blocks the function of NAE1, the first enzyme (E1) in the NEDDylation cascade.	('NAE1', 'Gene', '8883', (86, 90))	('NAE1', 'Gene', (86, 90))	('MLN4924', 'Chemical', 'MESH:C539933', (22, 29))	('MLN4924', 'Var', (22, 29))	('blocks', 'NegReg', (63, 69))	('function', 'MPA', (74, 82))
180046	25794275	Inhibition of NEDDylation leads to a global stabilization of CRL targets, and this drug has proved to be potently cytotoxic in many cancer models.	('cancer', 'Disease', (132, 138))	('CRL', 'Gene', (61, 64))	('NEDDylation', 'Protein', (14, 25))	('stabilization', 'MPA', (44, 57))	('CRL', 'Gene', '133396', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Inhibition', 'Var', (0, 10))	('cytotoxic in', 'Disease', (114, 126))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cytotoxic in', 'Disease', 'MESH:D064420', (114, 126))
180047	25794275	The principal mechanisms of MLN4924 cytotoxicity in cancer cells appear to involve blocking NF-kappaB signaling (via stabilization of IkappaBalpha, and the retention of the NF-kappaB transcription factor in the cytoplasm) or leading to unlicensed DNA replication (via stabilization Cdt-1), ultimately leading to apoptotic cells death.	('Cdt-1', 'Gene', '81620', (282, 287))	('blocking', 'NegReg', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('MLN4924', 'Var', (28, 35))	('IkappaBalpha', 'Gene', (134, 146))	('leading to', 'Reg', (225, 235))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('leading to', 'Reg', (301, 311))	('unlicensed', 'MPA', (236, 246))	('apoptotic cells death', 'CPA', (312, 333))	('NF-kappaB signaling', 'MPA', (92, 111))	('IkappaBalpha', 'Gene', '4792', (134, 146))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('Cdt-1', 'Gene', (282, 287))	('MLN4924', 'Chemical', 'MESH:C539933', (28, 35))	('cytotoxicity', 'Disease', (36, 48))
180048	25794275	Given that PEL cells absolutely require NF-kappaB signaling for their survival, we asked whether MLN4924 was able to kill these cells.	('NF-kappaB signaling', 'MPA', (40, 59))	('MLN4924', 'Chemical', 'MESH:C539933', (97, 104))	('MLN4924', 'Var', (97, 104))
180050	25794275	For example, we showed that MLN4924 led to: i) accumulation of pIkappaBalpha, ii) a KSHV gene expression profile consistent with inhibition of NF-kappaB and iii) the induction of apoptosis (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (28, 35))	('KSHV gene', 'Gene', (84, 93))	('MLN4924', 'Var', (28, 35))	('apoptosis', 'CPA', (179, 188))	('IkappaBalpha', 'Gene', '4792', (64, 76))	('expression', 'Species', '29278', (94, 104))	('induction', 'Reg', (166, 175))	('KSHV', 'Species', '37296', (84, 88))	('IkappaBalpha', 'Gene', (64, 76))	('accumulation', 'PosReg', (47, 59))
180051	25794275	This corroborates recent work demonstrating that MLN4924 killed NF-kappaB-dependent ABC-DLBCL cells in a comparable fashion.	('MLN4924', 'Chemical', 'MESH:C539933', (49, 56))	('MLN4924', 'Var', (49, 56))	('NF-kappaB-dependent', 'Protein', (64, 83))
180053	25794275	NF-kappaB is also required for transcription of the latency control locus which expresses an alternatively spliced transcript that produces ORF71 (vFLIP), ORF72 (vCyclin) and ORF73 (LANA).	('ORF71', 'Var', (140, 145))	('ORF72', 'Var', (155, 160))	('LANA', 'Gene', (182, 186))	('LANA', 'Gene', '4961527', (182, 186))	('ORF73', 'Var', (175, 180))
180055	25794275	Interestingly, MLN4924 did not appear to overtly affect LANA expression (despite reducing its mRNA level) which is in line with previous reports showing that its half-life exceeds the time course of our experiments and signifying that cytotoxicity was not a result of KSHV genome loss.	('expression', 'Species', '29278', (61, 71))	('reducing', 'NegReg', (81, 89))	('cytotoxicity', 'Disease', (235, 247))	('LANA', 'Gene', '4961527', (56, 60))	('KSHV', 'Species', '37296', (268, 272))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('cytotoxicity', 'Disease', 'MESH:D064420', (235, 247))	('MLN4924', 'Var', (15, 22))	('LANA', 'Gene', (56, 60))
180057	25794275	Importantly, this phenotypic alteration has been shown to be NF-kappaB-dependent; therefore, it will be of particular interest to investigate if MLN4924 can inhibit this characteristic feature of KS.	('MLN4924', 'Var', (145, 152))	('inhibit', 'NegReg', (157, 164))	('MLN4924', 'Chemical', 'MESH:C539933', (145, 152))
180061	25794275	Hence, the induction of lytic cycle-associated gene expression in PEL and rKSHV.219 cells is very likely due to MLN4924-induced inhibition of NF-kappaB.	('NF-kappaB', 'Protein', (142, 151))	('inhibition', 'NegReg', (128, 138))	('expression', 'Species', '29278', (52, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (112, 119))	('MLN4924-induced', 'Var', (112, 127))	('KSHV', 'Species', '37296', (75, 79))	('lytic cycle-associated gene expression', 'Gene', (24, 62))
180063	25794275	In agreement the above hypothesis, we found that individual expression of dominant-negative versions of Cul1 (DNCul) was able to activate lytic cycle gene expression.	('activate', 'PosReg', (129, 137))	('Cul1', 'Gene', (104, 108))	('Cul', 'Gene', (112, 115))	('Cul1', 'Gene', '8454', (104, 108))	('expression', 'Species', '29278', (155, 165))	('Cul', 'Gene', '8454;8453;8452;8451;8450;8065;9820', (112, 115))	('Cul', 'Gene', (104, 107))	('lytic cycle gene', 'Gene', (138, 154))	('expression', 'Species', '29278', (60, 70))	('dominant-negative', 'Var', (74, 91))	('Cul', 'Gene', '8454;8453;8452;8451;8450;8065;9820', (104, 107))
180064	25794275	Importantly, these data also suggest that MLN4924's effect on viral gene expression was due to its inhibition of the CRL activity as opposed to a direct role of NEDDylation in KSHV gene expression or the over-arching effects a global block in NEDDylation would have on cellular function.	('global block', 'Phenotype', 'HP:0001709', (227, 239))	('MLN4924', 'Var', (42, 49))	('expression', 'Species', '29278', (73, 83))	('inhibition', 'NegReg', (99, 109))	('CRL', 'Gene', (117, 120))	('expression', 'Species', '29278', (186, 196))	('KSHV', 'Species', '37296', (176, 180))	('CRL', 'Gene', '133396', (117, 120))	('MLN4924', 'Chemical', 'MESH:C539933', (42, 49))	('viral', 'MPA', (62, 67))
180066	25794275	In addition to the ability of DNCul1 to reactivate lytic cycle associated gene expression, DNCul4B and shRNA knockdown of Cul4B were both able to induce lytic cycle gene expression.	('expression', 'Species', '29278', (79, 89))	('Cul4B', 'Gene', (93, 98))	('expression', 'Species', '29278', (170, 180))	('Cul4B', 'Gene', '8450', (122, 127))	('Cul1', 'Gene', '8454', (32, 36))	('Cul4B', 'Gene', '8450', (93, 98))	('Cul1', 'Gene', (32, 36))	('knockdown', 'Var', (109, 118))	('lytic', 'CPA', (153, 158))	('Cul4B', 'Gene', (122, 127))	('induce', 'PosReg', (146, 152))	('reactivate', 'MPA', (40, 50))
180067	25794275	Using K12 expression as an indicator of latency versus lytic cycle-associated gene expression, the complete blockade of NEDDylation led to a reduction in its expression, whereas knockdown of Cul4B led to its increase, pointing to differing mechanisms.	('K12', 'Gene', (6, 9))	('expression', 'Species', '29278', (158, 168))	('K12', 'Gene', '4961446', (6, 9))	('blockade', 'NegReg', (108, 116))	('expression', 'MPA', (158, 168))	('NEDDylation', 'Protein', (120, 131))	('expression', 'Species', '29278', (10, 20))	('Cul4B', 'Gene', (191, 196))	('expression', 'Species', '29278', (83, 93))	('knockdown', 'Var', (178, 187))	('Cul4B', 'Gene', '8450', (191, 196))	('reduction', 'NegReg', (141, 150))
180068	25794275	These data are in line with the hypothesis that complete blockade (via MLN4924) effects NF-kappaB expression by inhibiting CRL1 and that inhibition of Cul1 NEDDylation is more sensitive than its inhibition of Cul4B modification.	('CRL1', 'Gene', (123, 127))	('Cul4B', 'Gene', '8450', (209, 214))	('MLN4924', 'Chemical', 'MESH:C539933', (71, 78))	('expression', 'Species', '29278', (98, 108))	('NF-kappaB', 'Protein', (88, 97))	('MLN4924', 'Var', (71, 78))	('Cul1', 'Gene', '8454', (151, 155))	('effects', 'Reg', (80, 87))	('CRL1', 'Gene', '57050', (123, 127))	('Cul4B', 'Gene', (209, 214))	('Cul1', 'Gene', (151, 155))	('inhibiting', 'NegReg', (112, 122))	('expression', 'MPA', (98, 108))
180069	25794275	It is not currently known whether differences exist in the sensitivity of individual CRLs following MLN4924 treatment.	('CRL', 'Gene', (85, 88))	('CRL', 'Gene', '133396', (85, 88))	('MLN4924', 'Chemical', 'MESH:C539933', (100, 107))	('MLN4924', 'Var', (100, 107))
180078	25794275	A striking observation however, was that MLN4924 treatment blocked viral genome replication despite appreciable levels of viral gene expression.	('MLN4924', 'Var', (41, 48))	('viral', 'MPA', (67, 72))	('MLN4924', 'Chemical', 'MESH:C539933', (41, 48))	('blocked', 'NegReg', (59, 66))	('expression', 'Species', '29278', (133, 143))
180079	25794275	At 1 muM MLN4924, ORF57 expression was not significantly reduced, but genome replication was reduced by ca.	('expression', 'Species', '29278', (24, 34))	('muM', 'Gene', (5, 8))	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('ORF57', 'Gene', '4961525', (18, 23))	('genome replication', 'CPA', (70, 88))	('reduced', 'NegReg', (93, 100))	('MLN4924', 'Var', (9, 16))	('ORF57', 'Gene', (18, 23))	('muM', 'Gene', '56925', (5, 8))
180081	25794275	Even though this led to a recovery in KSHV protein expression even when up to 10 muM MLN4924 was used, genome replication was still not observed.	('KSHV', 'Species', '37296', (38, 42))	('expression', 'Species', '29278', (51, 61))	('MLN4924', 'Chemical', 'MESH:C539933', (85, 92))	('KSHV', 'Gene', (38, 42))	('muM', 'Gene', '56925', (81, 84))	('MLN4924', 'Var', (85, 92))	('recovery', 'PosReg', (26, 34))	('muM', 'Gene', (81, 84))
180082	25794275	Over the course of our studies, we did notice aberrant RTA localization in BCBL-1 cells treated with MLN4924, followed by reactivation (e.g.	('MLN4924', 'Var', (101, 108))	('MLN4924', 'Chemical', 'MESH:C539933', (101, 108))	('RTA localization', 'MPA', (55, 71))	('reactivation', 'MPA', (122, 134))
180086	25794275	Firstly, we showed that reactivation of KSHV is associated with ubiquitylation within replication compartments, and that MLN4924 treatment inhibited this.	('MLN4924', 'Chemical', 'MESH:C539933', (121, 128))	('MLN4924 treatment', 'Var', (121, 138))	('KSHV', 'Species', '37296', (40, 44))	('ubiquitylation within replication compartments', 'MPA', (64, 110))	('inhibited', 'NegReg', (139, 148))	('reactivation', 'MPA', (24, 36))	('KSHV', 'Gene', (40, 44))
180089	25794275	Here we showed that 1 muM MLN4924 (a concentration that still permits viral gene expression) blocked RTA recruitment to OriLyt.	('blocked', 'NegReg', (93, 100))	('RTA recruitment to OriLyt', 'MPA', (101, 126))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('muM', 'Gene', '56925', (22, 25))	('MLN4924', 'Var', (26, 33))	('expression', 'Species', '29278', (81, 91))	('muM', 'Gene', (22, 25))
180090	25794275	It might be possible that proteins within the pre-replication complex are themselves targets for NEDD8 modification.	('NEDD8', 'Gene', '4738', (97, 102))	('NEDD8', 'Gene', (97, 102))	('modification', 'Var', (103, 115))
180092	25794275	This may include CRL-mediated ubiquitylation (via K48) that targets a latency-associated protein for degradation thus allowing access to OriLyt by the pre-replication complex.	('degradation', 'MPA', (101, 112))	('K48', 'Var', (50, 53))	('CRL', 'Gene', (17, 20))	('CRL', 'Gene', '133396', (17, 20))
180094	25794275	Inhibition of NEDDylation using MLN4924 proved cytotoxic to PEL cells due to their dependence on NF-kappaB.	('MLN4924', 'Var', (32, 39))	('NEDDylation', 'Protein', (14, 25))	('MLN4924', 'Chemical', 'MESH:C539933', (32, 39))
180097	25794275	Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies, including KS that is dependent on both lytic replication and the latency-associated activation of NF-kappaB.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('inhibition', 'Var', (32, 42))	('KSHV', 'Species', '37296', (107, 111))	('malignancies', 'Disease', (123, 135))	('KSHV-associated', 'Gene', (107, 122))	('NEDDylation', 'Protein', (46, 57))
180109	25794275	Inhibition of caspase enzymes was achieved by the addition of 50 muM z-VAD-FMK or FMK-negative control (MBL International) 30 min prior to MLN4924 and/or reactivation treatment.	('FMK', 'Chemical', '-', (75, 78))	('Inhibition', 'NegReg', (0, 10))	('z-VAD-FMK', 'Chemical', 'MESH:C096713', (69, 78))	('FMK', 'Chemical', '-', (82, 85))	('MLN4924', 'Chemical', 'MESH:C539933', (139, 146))	('MBL', 'Gene', '50639', (104, 107))	('muM', 'Gene', '56925', (65, 68))	('caspase enzymes', 'Enzyme', (14, 29))	('muM', 'Gene', (65, 68))	('MLN4924', 'Var', (139, 146))	('MBL', 'Gene', (104, 107))
180111	25794275	For the ATPlite assay, 10,000 cells were seeded into white 96-well plates and allowed to settle for 16 h at 37 C. Varying concentrations of MLN4924 were added to the cells followed by 96 h incubation at 37 C. Cellular proliferation was determined according to the manufacturer's instructions.	('MLN4924', 'Chemical', 'MESH:C539933', (140, 147))	('ATPlite', 'Chemical', '-', (8, 15))	('MLN4924', 'Var', (140, 147))	('Cellular proliferation', 'CPA', (209, 231))
180112	25794275	Cells (106) were treated with 1 muM MLN4924 (or left untreated) for 24 h, washed in cold PBS and fixed for 24 h in cold 70% ethanol at -20 C. Prior to analysis, cells were washed in PBS and treated with 1 ml PBS, 10 mug/ml propidium iodide (Sigma), 0.5 mg RNase A for 3 h at 37 C. Cells were then pelleted, resuspended in 1 ml PBS and analysed using a Becton Dickinson BD-LSRFortessa flow cytometer.	('ethanol', 'Chemical', 'MESH:D000431', (124, 131))	('RNase A', 'Gene', '6035', (256, 263))	('PBS', 'Disease', 'MESH:D011535', (327, 330))	('MLN4924', 'Chemical', 'MESH:C539933', (36, 43))	('PBS', 'Disease', (327, 330))	('PBS', 'Disease', (208, 211))	('RNase A', 'Gene', (256, 263))	('muM', 'Gene', '56925', (32, 35))	('PBS', 'Disease', 'MESH:D011535', (208, 211))	('MLN4924', 'Var', (36, 43))	('propidium iodide', 'Chemical', 'MESH:D011419', (223, 239))	('PBS', 'Disease', 'MESH:D011535', (89, 92))	('PBS', 'Disease', (89, 92))	('PBS', 'Disease', 'MESH:D011535', (182, 185))	('PBS', 'Disease', (182, 185))	('muM', 'Gene', (32, 35))
180205	25519700	MLN0128, an ATP-Competitive mTOR Kinase Inhibitor, with Potent In vitro and In vivo Antitumor Activity as Potential Therapy for Bone and Soft-Tissue Sarcoma The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism.	('MLN0128', 'Var', (0, 7))	('mTOR', 'Gene', (28, 32))	('Sarcoma', 'Disease', (149, 156))	('mTOR', 'Gene', (192, 196))	('Soft-Tissue Sarcoma', 'Phenotype', 'HP:0030448', (137, 156))	('mTOR', 'Gene', '2475', (28, 32))	('mTORC1', 'Gene', (265, 271))	('Sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('mTOR', 'Gene', (265, 269))	('mTORC1', 'Gene', '382056', (265, 271))	('mTOR', 'Gene', '2475', (192, 196))	('mTORC2', 'Gene', (276, 282))	('mTOR', 'Gene', '2475', (265, 269))	('mTOR', 'Gene', (276, 280))	('mammalian target of rapamycin', 'Gene', '2475', (161, 190))	('mTORC2', 'Gene', '74343', (276, 282))	('mammalian target of rapamycin', 'Gene', (161, 190))	('mTOR', 'Gene', '2475', (276, 280))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Sarcoma', 'Disease', 'MESH:D012509', (149, 156))
180208	25519700	Here we report that MLN0128, a second-generation, ATP-competitive, pan-mTOR kinase inhibitor, acts on both mTORC1 and mTORC2, and has potent in vitro and in vivo anti-tumor activity in multiple sarcoma subtypes.	('mTOR', 'Gene', (107, 111))	('mTORC1', 'Gene', '382056', (107, 113))	('mTOR', 'Gene', '2475', (118, 122))	('multiple sarcoma subtypes', 'Disease', (185, 210))	('mTOR', 'Gene', '2475', (107, 111))	('mTORC2', 'Gene', (118, 124))	('tumor', 'Disease', (167, 172))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))	('MLN0128', 'Var', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mTOR', 'Gene', (71, 75))	('mTORC2', 'Gene', '74343', (118, 124))	('MLN0128', 'Chemical', 'MESH:C572449', (20, 27))	('mTOR', 'Gene', (118, 122))	('acts', 'Reg', (94, 98))	('mTOR', 'Gene', '2475', (71, 75))	('multiple sarcoma subtypes', 'Disease', 'MESH:D012509', (185, 210))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('mTORC1', 'Gene', (107, 113))
180209	25519700	In vitro, MLN0128 inhibits mTORC1/2 targets in a concentration dependent fashion, and shows striking anti-proliferative effect in rhabdomyosarcoma (RMS), Ewing sarcoma (ES), malignant peripheral nerve sheath tumor, synovial sarcoma, osteosarcoma, and liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (174, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('osteosarcoma', 'Phenotype', 'HP:0002669', (233, 245))	('ES', 'Phenotype', 'HP:0012254', (169, 171))	('rhabdomyosarcoma', 'Disease', (130, 146))	('MLN0128', 'Chemical', 'MESH:C572449', (10, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('mTORC1', 'Gene', (27, 33))	('RMS', 'Phenotype', 'HP:0002859', (148, 151))	('liposarcoma', 'Phenotype', 'HP:0012034', (251, 262))	('synovial sarcoma', 'Disease', (215, 231))	('Ewing sarcoma', 'Disease', (154, 167))	('mTORC1', 'Gene', '382056', (27, 33))	('synovial sarcoma', 'Disease', 'MESH:D013584', (215, 231))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (130, 146))	('liposarcoma', 'Disease', 'MESH:D008080', (251, 262))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (130, 146))	('malignant peripheral nerve sheath tumor', 'Disease', (174, 213))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (215, 231))	('osteosarcoma', 'Disease', (233, 245))	('osteosarcoma', 'Disease', 'MESH:D012516', (233, 245))	('anti-proliferative', 'NegReg', (101, 119))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (174, 213))	('MLN0128', 'Var', (10, 17))	('inhibits', 'NegReg', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('liposarcoma', 'Disease', (251, 262))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (154, 167))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (154, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))
180210	25519700	Unlike rapamycin, MLN0128 inhibits phosphorylation of 4EBP1 and NDRG1 as well as prevents the reactivation of pAKT that occurs via negative feedback release with mTORC1 inhibition alone.	('AKT', 'Gene', '207', (111, 114))	('inhibits', 'NegReg', (26, 34))	('NDRG1', 'Gene', '10397', (64, 69))	('mTORC1', 'Gene', (162, 168))	('MLN0128', 'Var', (18, 25))	('prevents', 'NegReg', (81, 89))	('negative feedback release', 'MPA', (131, 156))	('mTORC1', 'Gene', '382056', (162, 168))	('AKT', 'Gene', (111, 114))	('phosphorylation', 'MPA', (35, 50))	('MLN0128', 'Chemical', 'MESH:C572449', (18, 25))	('4EBP1', 'Gene', (54, 59))	('rapamycin', 'Chemical', 'MESH:D020123', (7, 16))	('4EBP1', 'Gene', '1978', (54, 59))	('NDRG1', 'Gene', (64, 69))
180211	25519700	In xenograft models, MLN0128 treatment results in suppression of tumor growth with two dosing schedules (1 mg/kg daily and 3 mg/kg BID TIW).	('BID', 'Gene', '637', (131, 134))	('tumor', 'Disease', (65, 70))	('MLN0128', 'Chemical', 'MESH:C572449', (21, 28))	('MLN0128 treatment', 'Var', (21, 38))	('BID', 'Gene', (131, 134))	('suppression', 'NegReg', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
180212	25519700	At the 3 mg/kg dosing schedule, MLN0128 treatment results in significantly better tumor growth suppression than rapamycin in RMS and ES models.	('MLN0128 treatment', 'Var', (32, 49))	('better', 'PosReg', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('rapamycin', 'Chemical', 'MESH:D020123', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('RMS', 'Phenotype', 'HP:0002859', (125, 128))	('ES', 'Phenotype', 'HP:0012254', (133, 135))	('tumor', 'Disease', (82, 87))	('MLN0128', 'Chemical', 'MESH:C572449', (32, 39))
180213	25519700	Additionally, MLN0128 induces apoptosis in models of RMS both in vitro and in vivo.	('MLN0128', 'Var', (14, 21))	('apoptosis', 'CPA', (30, 39))	('MLN0128', 'Chemical', 'MESH:C572449', (14, 21))	('RMS', 'Disease', (53, 56))	('RMS', 'Phenotype', 'HP:0002859', (53, 56))	('induces', 'Reg', (22, 29))
180214	25519700	Results from our study strongly suggest that MLN0128 treatment should be explored further as potential therapy for sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('sarcoma', 'Disease', (115, 122))	('MLN0128 treatment', 'Var', (45, 62))	('MLN0128', 'Chemical', 'MESH:C572449', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))
180220	25519700	Most recently, large-scale genomic sequencing projects have revealed distinct mutations clustered in and around the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR axis, which further verify mTOR as a valid anti-tumor target in the treatment of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (243, 251))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('AKT', 'Gene', '207', (153, 156))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (116, 145))	('tumor', 'Disease', (210, 215))	('mutations', 'Var', (78, 87))	('AKT', 'Gene', (153, 156))	('phosphatidylinositol 3-kinase', 'Gene', (116, 145))	('sarcomas', 'Disease', 'MESH:D012509', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('mTOR', 'Gene', (157, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('mTOR', 'Gene', '2475', (157, 161))	('mTOR', 'Gene', (189, 193))	('sarcomas', 'Disease', (243, 251))	('mTOR', 'Gene', '2475', (189, 193))
180225	25519700	MLN0128 (Millennium/Takeda Pharmaceuticals) is a selective, highly potent, and orally bioavailable adenosine triphosphate (ATP) competitor of both mTORC1 and mTORC2, which is currently in phase I and II clinical trials as a single agent in patients with advanced solid malignancies (NCT01899053, NCT01058707, NCT01351350, NCT0133183, NCT02091531), in combination with bevacizumab in patients with glioblastoma multiforme or advanced solid tumors (NCT02142803), in combination with MLN1117 (PI3K inhibitor) in patients with advanced non-hematologic malignancies (NCT01899053), in combination with ziv-afilbercept in recurrent solid tumors (NCT02159989), and breast cancer (NCT02049957).	('solid tumors', 'Disease', (625, 637))	('NCT01058707', 'Var', (296, 307))	('NCT01899053', 'Var', (283, 294))	('mTORC1', 'Gene', (147, 153))	('glioblastoma multiforme or advanced solid tumors', 'Disease', 'MESH:D005909', (397, 445))	('tumors', 'Phenotype', 'HP:0002664', (631, 637))	('NCT01899053', 'Var', (562, 573))	('non-hematologic malignancies', 'Disease', 'MESH:D019337', (532, 560))	('ATP', 'Chemical', 'MESH:D000255', (123, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (657, 670))	('mTORC1', 'Gene', '382056', (147, 153))	('mTORC2', 'Gene', (158, 164))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (631, 636))	('solid tumors', 'Disease', 'MESH:D009369', (625, 637))	('breast cancer', 'Disease', 'MESH:D001943', (657, 670))	('NCT0133183', 'Var', (322, 332))	('breast cancer', 'Disease', (657, 670))	('non-hematologic malignancies', 'Disease', (532, 560))	('tumors', 'Phenotype', 'HP:0002664', (439, 445))	('cancer', 'Phenotype', 'HP:0002664', (664, 670))	('mTORC2', 'Gene', '74343', (158, 164))	('patients', 'Species', '9606', (240, 248))	('patients', 'Species', '9606', (509, 517))	('NCT02091531', 'Var', (334, 345))	('tumor', 'Phenotype', 'HP:0002664', (439, 444))	('glioblastoma', 'Phenotype', 'HP:0012174', (397, 409))	('solid tumors', 'Disease', 'MESH:D009369', (433, 445))	('patients', 'Species', '9606', (383, 391))	('NCT01351350', 'Var', (309, 320))	('solid malignancies', 'Disease', 'MESH:D009369', (263, 281))	('solid malignancies', 'Disease', (263, 281))	('glioblastoma multiforme or advanced solid tumors', 'Disease', (397, 445))
180227	25519700	Pre-clinically, MLN0128 has been shown to have antitumor activity in prostate cancer, B-cell leukemia, breast cancer, and renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (122, 142))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('B-cell leukemia', 'Disease', (86, 101))	('breast cancer', 'Disease', (103, 116))	('MLN0128', 'Chemical', 'MESH:C572449', (16, 23))	('B-cell leukemia', 'Disease', 'MESH:D015448', (86, 101))	('tumor', 'Disease', (51, 56))	('leukemia', 'Phenotype', 'HP:0001909', (93, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('renal cell carcinoma', 'Disease', (122, 142))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (122, 142))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('MLN0128', 'Var', (16, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('prostate cancer', 'Disease', (69, 84))
180228	25519700	In the current study we describe the preclinical characterization of MLN0128 in bone and soft tissue sarcomas, evaluate its in vitro and in vivo effects, and demonstrate its anti-tumor properties superior to those of its first-generation rapalogue predecessors.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (89, 109))	('MLN0128', 'Var', (69, 76))	('sarcomas', 'Disease', 'MESH:D012509', (101, 109))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (89, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('MLN0128', 'Chemical', 'MESH:C572449', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('bone and', 'Disease', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('sarcomas', 'Disease', (101, 109))	('tumor', 'Disease', (179, 184))
180247	25519700	Approximately eight-week old athymic female mice were injected with 10-15 million cells in MatriGelTM of the cell line of interest and allowed to grow until tumors reached 100 mm3 in volume prior to treatment with either vehicle, rapamycin, or MLN0128.	('MLN0128', 'Var', (244, 251))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('MLN0128', 'Chemical', 'MESH:C572449', (244, 251))	('rapamycin', 'Chemical', 'MESH:D020123', (230, 239))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mice', 'Species', '10090', (44, 48))
180252	25519700	MLN0128 (Figure 1A) was tested against a broad panel of bone and soft tissue sarcoma cell lines following three days of exposure to increasing concentrations of the drug to determine its anti-proliferative activity.	('MLN0128', 'Var', (0, 7))	('anti-proliferative', 'MPA', (187, 205))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('sarcoma', 'Disease', (77, 84))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (65, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
180253	25519700	MLN0128 was found to inhibit proliferation of all sarcoma subtypes tested in a dose-dependent fashion at low nanomolar concentrations (Figure 1B) with IC50 values ranging from 2 to 130 nM (Table 1).	('MLN0128', 'Var', (0, 7))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (50, 66))	('sarcoma subtypes', 'Disease', (50, 66))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('proliferation', 'CPA', (29, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('inhibit', 'NegReg', (21, 28))
180254	25519700	At concentrations ranging from 6.25nM to 1muM, the target inhibition profile of MLN0128 was examined using western immunoblotting (Figure 1C).	('muM', 'Gene', (42, 45))	('MLN0128', 'Var', (80, 87))	('MLN0128', 'Chemical', 'MESH:C572449', (80, 87))	('muM', 'Gene', '56925', (42, 45))
180258	25519700	In all sarcoma subtypes tested, MLN0128 potently inhibited each of these anticipated targets in a dose-dependent fashion (Figure 1C).	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('MLN0128', 'Var', (32, 39))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (7, 23))	('sarcoma subtypes', 'Disease', (7, 23))	('MLN0128', 'Chemical', 'MESH:C572449', (32, 39))	('inhibited', 'NegReg', (49, 58))
180261	25519700	AKT phosphorylation at Thr308 was, however, limited due to weak signal and detection of non-specific proteins in many of the sarcoma cell lines studied, but when detectable, MLN0128 inhibited this PDK1 phosphorylation site (Supplemental Figure 1A).	('AKT', 'Gene', (0, 3))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('Thr308', 'Chemical', '-', (23, 29))	('PDK1', 'Gene', '5163', (197, 201))	('PDK1', 'Gene', (197, 201))	('MLN0128', 'Chemical', 'MESH:C572449', (174, 181))	('sarcoma', 'Disease', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('inhibited', 'NegReg', (182, 191))	('AKT', 'Gene', '207', (0, 3))	('MLN0128', 'Var', (174, 181))
180262	25519700	Rapamycin allosterically inhibits mTORC1 kinase activity via binding of the FKBP12-rapamycin (FR) complex to the FR binding domain of mTORC1, while MLN0128 provides direct, ATP-competitive kinase inhibition of both mTORC1 and mTORC2.	('mTORC1', 'Gene', '382056', (34, 40))	('inhibits', 'NegReg', (25, 33))	('mTORC1', 'Gene', (215, 221))	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('mTORC1', 'Gene', (134, 140))	('MLN0128', 'Var', (148, 155))	('mTORC2', 'Gene', '74343', (226, 232))	('mTORC2', 'Gene', (226, 232))	('mTORC1', 'Gene', (34, 40))	('ATP', 'Chemical', 'MESH:D000255', (173, 176))	('rapamycin', 'Chemical', 'MESH:D020123', (83, 92))	('MLN0128', 'Chemical', 'MESH:C572449', (148, 155))	('mTORC1', 'Gene', '382056', (134, 140))	('mTORC1', 'Gene', '382056', (215, 221))	('binding', 'Interaction', (61, 68))
180267	25519700	Similar to rapamycin treatment, MLN0128 treatment resulted in concentration-dependent inhibition of phosphorylation of S6K1 and S6.	('S6K1', 'Gene', '6198', (119, 123))	('phosphorylation', 'MPA', (100, 115))	('MLN0128', 'Var', (32, 39))	('rapamycin', 'Chemical', 'MESH:D020123', (11, 20))	('MLN0128', 'Chemical', 'MESH:C572449', (32, 39))	('inhibition', 'NegReg', (86, 96))	('S6K1', 'Gene', (119, 123))
180268	25519700	MLN0128, however, also inhibited phosphorylation of 4EBP1 in all sarcoma subtypes suggesting more comprehensive mTORC1 targeting when compared with rapamycin (Figure 2A).	('MLN0128', 'Var', (0, 7))	('rapamycin', 'Chemical', 'MESH:D020123', (148, 157))	('phosphorylation', 'MPA', (33, 48))	('4EBP1', 'Gene', '1978', (52, 57))	('4EBP1', 'Gene', (52, 57))	('mTORC1', 'Gene', (112, 118))	('inhibited', 'NegReg', (23, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('mTORC1', 'Gene', '382056', (112, 118))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (65, 81))	('sarcoma subtypes', 'Disease', (65, 81))
180269	25519700	In addition to complete blockade of the mTORC1 targets pS6K1, pS6 and p4EBP1, MLN0128 treatment also inhibited phosphorylation of NDRG1 at Thr346 indicating distinct mTORC2 inhibition.	('NDRG1', 'Gene', '10397', (130, 135))	('Thr346', 'Chemical', '-', (139, 145))	('pS6', 'Gene', (55, 58))	('MLN0128', 'Var', (78, 85))	('pS6', 'Gene', '338413', (62, 65))	('4EBP1', 'Gene', '1978', (71, 76))	('NDRG1', 'Gene', (130, 135))	('pS6', 'Gene', '338413', (55, 58))	('phosphorylation', 'MPA', (111, 126))	('mTORC2', 'Gene', (166, 172))	('MLN0128', 'Chemical', 'MESH:C572449', (78, 85))	('mTORC1', 'Gene', (40, 46))	('4EBP1', 'Gene', (71, 76))	('S6K1', 'Gene', (56, 60))	('Thr346', 'Var', (139, 145))	('mTORC1', 'Gene', '382056', (40, 46))	('mTORC2', 'Gene', '74343', (166, 172))	('S6K1', 'Gene', '6198', (56, 60))	('inhibited', 'NegReg', (101, 110))	('pS6', 'Gene', (62, 65))
180271	25519700	Importantly, simultaneous inhibition of both mTOR complexes by MLN0128 prevented feedback reactivation of pAKT, whereas rapamycin led to an increase in pAKTS473 (Figure 2A) as has been previously reported.	('MLN0128', 'Var', (63, 70))	('AKT', 'Gene', '207', (153, 156))	('AKT', 'Gene', (107, 110))	('rapamycin', 'Chemical', 'MESH:D020123', (120, 129))	('inhibition', 'NegReg', (26, 36))	('MLN0128', 'Chemical', 'MESH:C572449', (63, 70))	('AKT', 'Gene', (153, 156))	('increase', 'PosReg', (140, 148))	('mTOR', 'Gene', '2475', (45, 49))	('prevented', 'NegReg', (71, 80))	('AKT', 'Gene', '207', (107, 110))	('mTOR', 'Gene', (45, 49))
180272	25519700	Taken together, these data indicate that MLN0128 provides more comprehensive inhibition of the mTOR axis, including superior mTORC1 inhibition when compared with that of rapamycin as evidenced by down-regulation of p4EBP1 in addition to pS6K1 and pS6, effective targeting of the mTORC2 complex as illustrated by inhibition of pNDRG1, as well as attenuation of the release of negative feedback observed with rapamycin treatment.	('rapamycin', 'Chemical', 'MESH:D020123', (170, 179))	('pS6', 'Gene', (237, 240))	('mTOR', 'Gene', '2475', (125, 129))	('pS6', 'Gene', '338413', (247, 250))	('MLN0128', 'Chemical', 'MESH:C572449', (41, 48))	('NDRG1', 'Gene', '10397', (327, 332))	('mTORC2', 'Gene', (279, 285))	('mTOR', 'Gene', (279, 283))	('rapamycin', 'Chemical', 'MESH:D020123', (407, 416))	('pS6', 'Gene', '338413', (237, 240))	('down-regulation', 'NegReg', (196, 211))	('4EBP1', 'Gene', (216, 221))	('mTOR', 'Gene', '2475', (279, 283))	('mTORC2', 'Gene', '74343', (279, 285))	('NDRG1', 'Gene', (327, 332))	('attenuation', 'NegReg', (345, 356))	('mTOR', 'Gene', (95, 99))	('mTORC1', 'Gene', (125, 131))	('S6K1', 'Gene', (238, 242))	('pS6', 'Gene', (247, 250))	('MLN0128', 'Var', (41, 48))	('release of negative feedback', 'MPA', (364, 392))	('mTOR', 'Gene', (125, 129))	('mTORC1', 'Gene', '382056', (125, 131))	('inhibition', 'NegReg', (312, 322))	('4EBP1', 'Gene', '1978', (216, 221))	('S6K1', 'Gene', '6198', (238, 242))	('mTOR', 'Gene', '2475', (95, 99))
180273	25519700	In order to determine if the broader molecular profile of MLN0128 also translated into superior anti-proliferative effect in vitro when compared with rapamycin, concentrations based upon complete blockade of downstream targets were chosen for testing.	('superior', 'PosReg', (87, 95))	('MLN0128', 'Chemical', 'MESH:C572449', (58, 65))	('anti-proliferative effect', 'CPA', (96, 121))	('rapamycin', 'Chemical', 'MESH:D020123', (150, 159))	('MLN0128', 'Var', (58, 65))
180274	25519700	Figure 2B illustrates that MLN0128 treatment resulted in superior anti-proliferative effect compared with that of rapamycin (p<0.04 and p<0.000006 when comparing rapamycin at 20nM and 200nM MLN0128 respectively) across the broad spectrum of cell lines tested.	('MLN0128', 'Chemical', 'MESH:C572449', (190, 197))	('MLN0128', 'Var', (27, 34))	('rapamycin', 'Chemical', 'MESH:D020123', (114, 123))	('superior', 'PosReg', (57, 65))	('MLN0128', 'Var', (190, 197))	('MLN0128', 'Chemical', 'MESH:C572449', (27, 34))	('anti-proliferative effect', 'CPA', (66, 91))	('rapamycin', 'Chemical', 'MESH:D020123', (162, 171))
180275	25519700	MLN0128 was next compared with rapamycin in its ability to induce cleavage of poly-ADP ribose polymerase (PARP).	('MLN0128', 'Var', (0, 7))	('PARP', 'Gene', (106, 110))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('poly-ADP ribose polymerase', 'Gene', (78, 104))	('PARP', 'Gene', '142', (106, 110))	('cleavage', 'MPA', (66, 74))	('rapamycin', 'Chemical', 'MESH:D020123', (31, 40))	('poly-ADP ribose polymerase', 'Gene', '142', (78, 104))
180276	25519700	In models of alveolar (ARMS, Rh30) and embryonal (ERMS, SMS-CTR) rhabdomyosarcoma, MLN0128 treatment at 200nM induced cleavage of poly-ADP ribose polymerase (PARP) at time points as early as 6 hours (Figure 2C).	('poly-ADP ribose polymerase', 'Gene', '142', (130, 156))	('Rh30', 'Gene', '6007', (29, 33))	('MLN0128', 'Var', (83, 90))	('RMS', 'Phenotype', 'HP:0002859', (51, 54))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (65, 81))	('PARP', 'Gene', (158, 162))	('RMS', 'Phenotype', 'HP:0002859', (24, 27))	('MLN0128', 'Chemical', 'MESH:C572449', (83, 90))	('CTR', 'Gene', '799', (60, 63))	('Rh30', 'Gene', (29, 33))	('cleavage', 'MPA', (118, 126))	('poly-ADP ribose polymerase', 'Gene', (130, 156))	('induced', 'Reg', (110, 117))	('rhabdomyosarcoma', 'Disease', (65, 81))	('CTR', 'Gene', (60, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('PARP', 'Gene', '142', (158, 162))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (65, 81))
180277	25519700	Induction of PARP cleavage was also seen in two other rhabdomyosarcoma cell lines RMS-559 as well as SK-RMS -3 only when treated with MLN0128 but not with rapamycin (Supplemental Figure 1B).	('RMS', 'Phenotype', 'HP:0002859', (82, 85))	('Supplemental Figure 1B', 'Disease', (166, 188))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (54, 70))	('PARP', 'Gene', (13, 17))	('rhabdomyosarcoma', 'Disease', (54, 70))	('SK-RMS -3', 'Chemical', '-', (101, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('RMS', 'Phenotype', 'HP:0002859', (104, 107))	('MLN0128', 'Chemical', 'MESH:C572449', (134, 141))	('PARP', 'Gene', '142', (13, 17))	('MLN0128', 'Var', (134, 141))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (54, 70))	('rapamycin', 'Chemical', 'MESH:D020123', (155, 164))	('Supplemental Figure 1B', 'Disease', 'MESH:C565748', (166, 188))
180278	25519700	MLN0128, however, was unable to induce cleavage of PARP in an MPNST and Ewing sarcoma model (MPNST, CHP100, Figure 2C) as well as in liposarcoma, leiomyosarcoma, or synovial sarcoma (data not shown).	('MLN0128', 'Var', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('liposarcoma', 'Phenotype', 'HP:0012034', (133, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('PARP', 'Gene', '142', (51, 55))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 85))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (146, 160))	('PARP', 'Gene', (51, 55))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (146, 160))	('liposarcoma', 'Disease', 'MESH:D008080', (133, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('synovial sarcoma', 'Disease', (165, 181))	('Ewing sarcoma', 'Disease', (72, 85))	('synovial sarcoma', 'Disease', 'MESH:D013584', (165, 181))	('cleavage', 'MPA', (39, 47))	('leiomyosarcoma', 'Disease', (146, 160))	('liposarcoma', 'Disease', (133, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (165, 181))
180280	25519700	Both MLN0128 and rapamycin were able to inhibit phosphorylation of Rictor, a component of mTORC2, at Thr1135 (Figure 2C) as has been shown in previously published studies.	('Rictor', 'Gene', '253260', (67, 73))	('inhibit', 'NegReg', (40, 47))	('Rictor', 'Gene', (67, 73))	('phosphorylation', 'MPA', (48, 63))	('MLN0128', 'Var', (5, 12))	('Thr1135', 'Chemical', '-', (101, 108))	('rapamycin', 'Chemical', 'MESH:D020123', (17, 26))	('mTORC2', 'Gene', '74343', (90, 96))	('mTORC2', 'Gene', (90, 96))	('MLN0128', 'Chemical', 'MESH:C572449', (5, 12))
180281	25519700	To confirm superior in vitro effects of MLN0128 treatment when compared with those of rapamycin, and that increased concentrations of rapamycin would not improve the anti-proliferative potency or induce apoptotic effects in the cell lines tested, we next tested equivalent concentrations of both rapamycin and MLN0128 up to 1muM.	('MLN0128', 'Chemical', 'MESH:C572449', (40, 47))	('muM', 'Gene', (325, 328))	('rapamycin', 'Chemical', 'MESH:D020123', (134, 143))	('MLN0128', 'Var', (40, 47))	('muM', 'Gene', '56925', (325, 328))	('MLN0128', 'Chemical', 'MESH:C572449', (310, 317))	('rapamycin', 'Chemical', 'MESH:D020123', (296, 305))	('rapamycin', 'Chemical', 'MESH:D020123', (86, 95))
180283	25519700	As observed previously, MLN0128 exhibited superior anti-tumor effect when compared with rapamycin in all cell lines tested.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('MLN0128', 'Var', (24, 31))	('rapamycin', 'Chemical', 'MESH:D020123', (88, 97))	('tumor', 'Disease', (56, 61))	('MLN0128', 'Chemical', 'MESH:C572449', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
180284	25519700	To further compare the molecular signaling profiles of rapamycin and MLN0128 at higher and equivalent doses, two cell lines, MPNST and Rh30, were chosen for additional analysis.	('Rh30', 'Gene', '6007', (135, 139))	('rapamycin', 'Chemical', 'MESH:D020123', (55, 64))	('MLN0128', 'Var', (69, 76))	('MLN0128', 'Chemical', 'MESH:C572449', (69, 76))	('Rh30', 'Gene', (135, 139))
180286	25519700	Similar to earlier results (Figure 2C), neither rapamycin nor MLN0128 treatment resulted in induction of cleaved PARP in MPNST, however, treatment of Rh30 cells with MLN0128 but not with rapamycin resulted in dose dependent induction of cleaved PARP as well as cleaved caspase-3 (Figure 3B) strongly indicating induction of apoptosis.	('Rh30', 'Gene', (150, 154))	('rapamycin', 'Chemical', 'MESH:D020123', (187, 196))	('PARP', 'Gene', '142', (245, 249))	('induction', 'PosReg', (224, 233))	('cleaved caspase-3', 'MPA', (261, 278))	('MLN0128', 'Var', (166, 173))	('PARP', 'Gene', '142', (113, 117))	('MLN0128', 'Chemical', 'MESH:C572449', (62, 69))	('Rh30', 'Gene', '6007', (150, 154))	('MLN0128', 'Chemical', 'MESH:C572449', (166, 173))	('rapamycin', 'Chemical', 'MESH:D020123', (48, 57))	('PARP', 'Gene', (245, 249))	('PARP', 'Gene', (113, 117))
180287	25519700	To further confirm apoptosis in rhabdomyosarcoma models, an in vitro assay (Caspase Glo) was carried out to determine induction of cleaved caspase 3/7 after 6 hours of treatment with rapamycin or MLN0128 (Figure 3C).	('rhabdomyosarcoma', 'Disease', (32, 48))	('cleaved', 'MPA', (131, 138))	('rapamycin', 'Chemical', 'MESH:D020123', (183, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (32, 48))	('MLN0128', 'Chemical', 'MESH:C572449', (196, 203))	('caspase 3', 'Gene', (139, 148))	('caspase 3', 'Gene', '836', (139, 148))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (32, 48))	('MLN0128', 'Var', (196, 203))
180291	25519700	While the exact mechanism warrants further investigation, these data are highly suggestive of MLN0128's ability to induce apoptosis in rhabdomyosarcoma models.	('rhabdomyosarcoma', 'Disease', (135, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('MLN0128', 'Var', (94, 101))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (135, 151))	('apoptosis', 'CPA', (122, 131))	('MLN0128', 'Chemical', 'MESH:C572449', (94, 101))	('induce', 'PosReg', (115, 121))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (135, 151))
180292	25519700	The efficacy of MLN0128 was next tested in multiple tumor xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('MLN0128', 'Var', (16, 23))	('MLN0128', 'Chemical', 'MESH:C572449', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
180294	25519700	Treatment of MPNST and CHP100 xenografts with MLN0128 resulted in suppression of tumor volume (Figure 4A-B) compared to vehicle control.	('MLN0128', 'Var', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('suppression', 'NegReg', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('MLN0128', 'Chemical', 'MESH:C572449', (46, 53))	('tumor', 'Disease', (81, 86))
180296	25519700	While MLN0128 activity in these models was confirmed at a dosing schedule of 1 mg/kg orally daily, only tumor growth suppression but not tumor stability or regression was noted.	('MLN0128', 'Var', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (137, 142))	('MLN0128', 'Chemical', 'MESH:C572449', (6, 13))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
180300	25519700	Treatment of CHP100 (ES) tumor xenografts with MLN0128 resulted in significantly enhanced tumor suppression when compared with rapamycin (Figure 5A) at the end of 5 weeks of treatment (p<0.01).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('MLN0128', 'Chemical', 'MESH:C572449', (47, 54))	('enhanced', 'PosReg', (81, 89))	('tumor', 'Disease', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('CHP100 (ES) tumor', 'Disease', 'MESH:C563168', (13, 30))	('rapamycin', 'Chemical', 'MESH:D020123', (127, 136))	('MLN0128', 'Var', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('ES', 'Phenotype', 'HP:0012254', (21, 23))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
180302	25519700	Similar to in vitro studies, only MLN0128 but not rapamycin treatment resulted in inhibition of p4EBP1 in vivo (Figure 5A) Given the apoptotic potential of MLN0128 in RMS model in vitro (Figure 3B-C), we next investigated MLN0128's in vivo anti-tumor effects in Rh30 xenografts.	('MLN0128', 'Var', (34, 41))	('RMS', 'Phenotype', 'HP:0002859', (167, 170))	('4EBP1', 'Gene', '1978', (97, 102))	('MLN0128', 'Chemical', 'MESH:C572449', (222, 229))	('rapamycin', 'Chemical', 'MESH:D020123', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('Rh30', 'Gene', (262, 266))	('4EBP1', 'Gene', (97, 102))	('MLN0128', 'Chemical', 'MESH:C572449', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('inhibition', 'NegReg', (82, 92))	('Rh30', 'Gene', '6007', (262, 266))	('tumor', 'Disease', (245, 250))	('MLN0128', 'Chemical', 'MESH:C572449', (156, 163))
180303	25519700	MLN0128 resulted in significant tumor suppression when compared to rapamycin (Figure 5B, p<0.001) as well as resulted in significant inhibition of downstream targets such as pS6 and p4EBP1 (Figure 5B).	('MLN0128', 'Var', (0, 7))	('4EBP1', 'Gene', '1978', (183, 188))	('pS6', 'Gene', '338413', (174, 177))	('4EBP1', 'Gene', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('rapamycin', 'Chemical', 'MESH:D020123', (67, 76))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('inhibition', 'NegReg', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('pS6', 'Gene', (174, 177))
180305	25519700	The present study reports the in vitro and in vivo pre-clinical characterization of MLN0128, a potent and orally bioavailable pan-mTOR kinase inhibitor, in a broad range of sarcoma subtypes.	('sarcoma subtypes', 'Disease', 'MESH:D012509', (173, 189))	('sarcoma subtypes', 'Disease', (173, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('MLN0128', 'Var', (84, 91))	('mTOR', 'Gene', (130, 134))	('mTOR', 'Gene', '2475', (130, 134))	('MLN0128', 'Chemical', 'MESH:C572449', (84, 91))
180306	25519700	MLN0128 exerts potent anti-proliferative effect and has a molecular signaling profile distinct from that of rapamycin in vitro and in vivo.	('MLN0128', 'Var', (0, 7))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('rapamycin', 'Chemical', 'MESH:D020123', (108, 117))	('anti-proliferative effect', 'CPA', (22, 47))
180307	25519700	MLN0128 induces apoptosis in models of rhabdomyosarcoma, and provides superior anti-tumor effect when compared with rapamycin in in vivo rhabdomyosarcoma and Ewing sarcoma models.	('MLN0128', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('apoptosis', 'CPA', (16, 25))	('rhabdomyosarcoma and Ewing sarcoma', 'Disease', 'MESH:C563168', (137, 171))	('rhabdomyosarcoma', 'Disease', (39, 55))	('rhabdomyosarcoma', 'Disease', (137, 153))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (39, 55))	('tumor', 'Disease', (84, 89))	('rapamycin', 'Chemical', 'MESH:D020123', (116, 125))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (137, 153))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (158, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (39, 55))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (137, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
180310	25519700	Second, aberrant upstream signals from PDGFR, IGF1R, VEGFR, FGFR pathways and others have been shown to contribute to dysregulation of the PI3K/AKT/mTOR axis in various sarcoma subtypes.	('sarcoma subtypes', 'Disease', (169, 185))	('IGF1R', 'Gene', '3480', (46, 51))	('VEGFR', 'Gene', (53, 58))	('mTOR', 'Gene', (148, 152))	('AKT', 'Gene', (144, 147))	('dysregulation', 'MPA', (118, 131))	('mTOR', 'Gene', '2475', (148, 152))	('VEGFR', 'Gene', '3791', (53, 58))	('PDGFR', 'Gene', (39, 44))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (169, 185))	('PDGFR', 'Gene', '5159', (39, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('aberrant', 'Var', (8, 16))	('AKT', 'Gene', '207', (144, 147))	('FGFR pathways', 'Gene', (60, 73))	('contribute', 'Reg', (104, 114))	('IGF1R', 'Gene', (46, 51))
180311	25519700	Lastly, more recently discovered discrete genetic mutations in or clustered around the PI3K/AKT/mTOR axis, document vulnerabilities in the genetic landscapes of sarcoma that can be exploited via mTOR inhibition.	('sarcoma', 'Disease', (161, 168))	('mTOR', 'Gene', (96, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('mutations', 'Var', (50, 59))	('AKT', 'Gene', '207', (92, 95))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('mTOR', 'Gene', '2475', (195, 199))	('AKT', 'Gene', (92, 95))	('mTOR', 'Gene', '2475', (96, 100))	('mTOR', 'Gene', (195, 199))
180314	25519700	MLN0128 potently inhibits proliferation of all sarcoma cell lines tested in a dose-dependent fashion with IC50 values in the low nanomolar range (2-130 nM).	('MLN0128', 'Var', (0, 7))	('inhibits', 'NegReg', (17, 25))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('sarcoma', 'Disease', (47, 54))	('proliferation', 'CPA', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
180315	25519700	While differences in sensitivity between various cell lines tested are not well explained by the biomarkers used in this study (Figure 1C), we can hypothesize that related pathway components, phosphatase and tensin homolog (PTEN) or v-raf murine sarcoma viral oncogene homolog B (BRAF) status, for example A673 which carries a BRAF V600E mutation, could play a role in sensitivity to anti-proliferative effects of the drug.	('BRAF', 'Gene', (327, 331))	('BRAF', 'Gene', (280, 284))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (233, 278))	('V600E', 'Mutation', 'rs113488022', (332, 337))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', (233, 278))	('PTEN', 'Gene', '19211', (224, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('BRAF', 'Gene', '109880', (327, 331))	('V600E', 'Var', (332, 337))	('play', 'Reg', (354, 358))	('PTEN', 'Gene', (224, 228))	('BRAF', 'Gene', '109880', (280, 284))
180319	25519700	These anti-proliferative and molecular signaling events justify the unequal concentrations used to compare MLN0128 and rapamycin in the current work, although we have additionally shown that equivalent concentrations up to 1muM of each agent do not alter outcomes.	('muM', 'Gene', '56925', (224, 227))	('MLN0128', 'Var', (107, 114))	('MLN0128', 'Chemical', 'MESH:C572449', (107, 114))	('muM', 'Gene', (224, 227))	('rapamycin', 'Chemical', 'MESH:D020123', (119, 128))
180320	25519700	In all conditions tested in vitro, MLN0128 provides profound anti-proliferative effect that is superior to that of rapamycin.	('anti-proliferative', 'MPA', (61, 79))	('rapamycin', 'Chemical', 'MESH:D020123', (115, 124))	('MLN0128', 'Var', (35, 42))	('MLN0128', 'Chemical', 'MESH:C572449', (35, 42))
180321	25519700	In all sarcoma subtypes tested, MLN0128 successfully inhibited both of the major regulators of protein synthesis downstream of mTORC1, p70-S6K1 and 4EBP1 in a dose-dependent fashion.	('p70-S6K1 and 4EBP1', 'Gene', '84959;6198', (135, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('inhibited', 'NegReg', (53, 62))	('mTORC1', 'Gene', '382056', (127, 133))	('MLN0128', 'Var', (32, 39))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (7, 23))	('sarcoma subtypes', 'Disease', (7, 23))	('mTORC1', 'Gene', (127, 133))	('MLN0128', 'Chemical', 'MESH:C572449', (32, 39))
180323	25519700	In other tumor types, there is emerging evidence that 4EBP1 is critical to the response to both rapalogues and mTOR kinase inhibition, making MLN0128's effective down-regulation of particular importance.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('mTOR', 'Gene', '2475', (111, 115))	('down-regulation', 'NegReg', (162, 177))	('mTOR', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('MLN0128', 'Var', (142, 149))	('tumor', 'Disease', (9, 14))	('4EBP1', 'Gene', '1978', (54, 59))	('4EBP1', 'Gene', (54, 59))	('MLN0128', 'Chemical', 'MESH:C572449', (142, 149))
180324	25519700	The exact role that 4EBP1 plays in mediating the anti-proliferative effects of MLN0128 and other mTOR kinase inhibitors in sarcomas remains under investigation, and will be indispensable to better understand the role of mTOR inhibition in sarcoma.	('mTOR', 'Gene', '2475', (220, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('sarcomas', 'Disease', (123, 131))	('mTOR', 'Gene', '2475', (97, 101))	('sarcoma', 'Disease', 'MESH:D012509', (239, 246))	('MLN0128', 'Var', (79, 86))	('mTOR', 'Gene', (97, 101))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('sarcoma', 'Disease', (239, 246))	('MLN0128', 'Chemical', 'MESH:C572449', (79, 86))	('sarcomas', 'Disease', 'MESH:D012509', (123, 131))	('4EBP1', 'Gene', '1978', (20, 25))	('anti-proliferative', 'MPA', (49, 67))	('4EBP1', 'Gene', (20, 25))	('sarcoma', 'Disease', (123, 130))	('mTOR', 'Gene', (220, 224))
180325	25519700	MLN0128 potently inhibited phosphorylation of AKT at Ser473 in all sarcoma subtypes tested.	('MLN0128', 'Var', (0, 7))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (67, 83))	('AKT', 'Gene', '207', (46, 49))	('sarcoma subtypes', 'Disease', (67, 83))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('phosphorylation', 'MPA', (27, 42))	('Ser473', 'Chemical', '-', (53, 59))	('AKT', 'Gene', (46, 49))	('inhibited', 'NegReg', (17, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))
180326	25519700	Analysis of phosphorylation on AKT at Thr308 was limited due to weak signal and detection of non-specific proteins in many of the sarcoma cell lines studied, but when detectable, MLN0128 did inhibit this PDK1 phosphorylation site (Supplemental Figure 1A).	('PDK1', 'Gene', '5163', (204, 208))	('MLN0128', 'Var', (179, 186))	('PDK1', 'Gene', (204, 208))	('Thr308', 'Chemical', '-', (38, 44))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('inhibit', 'NegReg', (191, 198))	('AKT', 'Gene', (31, 34))	('MLN0128', 'Chemical', 'MESH:C572449', (179, 186))	('sarcoma', 'Disease', (130, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('AKT', 'Gene', '207', (31, 34))
180328	25519700	Genetic knockout of SIN1 or RICTOR, however, is noted to completely suppress Ser473, but not Thr308 phosphorylation, suggesting that MLN0128 may have additional signaling effects not mediated through mTORC2 that down-regulate phosphorylation of AKT at Thr308.	('MLN0128', 'Chemical', 'MESH:C572449', (133, 140))	('MLN0128', 'Var', (133, 140))	('AKT', 'Gene', '207', (245, 248))	('down-regulate', 'NegReg', (212, 225))	('phosphorylation', 'MPA', (226, 241))	('SIN1', 'Gene', (20, 24))	('Ser473', 'MPA', (77, 83))	('AKT', 'Gene', (245, 248))	('Ser473', 'Chemical', '-', (77, 83))	('suppress', 'NegReg', (68, 76))	('Thr308', 'Chemical', '-', (93, 99))	('mTORC2', 'Gene', (200, 206))	('SIN1', 'Gene', '79109', (20, 24))	('RICTOR', 'Gene', (28, 34))	('Thr308', 'Chemical', '-', (252, 258))	('mTORC2', 'Gene', '74343', (200, 206))	('RICTOR', 'Gene', '253260', (28, 34))
180331	25519700	MLN0128 inhibited the phosphorylation of NDRG1 in a dose-dependent fashion in all cell lines tested, corroborating the anticipated mTORC2 kinase inhibition.	('MLN0128', 'Var', (0, 7))	('mTORC2', 'Gene', '74343', (131, 137))	('inhibited', 'NegReg', (8, 17))	('NDRG1', 'Gene', (41, 46))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('NDRG1', 'Gene', '10397', (41, 46))	('mTORC2', 'Gene', (131, 137))	('phosphorylation', 'MPA', (22, 37))
180333	25519700	MLN0128 was well-tolerated in vivo and resulted in dose-dependent growth inhibition in a broad range of sarcoma xenograft models.	('MLN0128', 'Var', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('sarcoma xenograft', 'Disease', 'MESH:D012509', (104, 121))	('sarcoma xenograft', 'Disease', (104, 121))	('growth inhibition', 'CPA', (66, 83))
180334	25519700	At a dosing schedule of 3 mg/kg BID by oral gavage three times weekly, MLN0128 provided significantly better tumor suppression when compared with rapamycin in tumor xenograft models of rhabdomyosarcoma (p < 0.001) and Ewing sarcoma (p<0.01).	('better', 'PosReg', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('BID', 'Gene', (32, 35))	('rhabdomyosarcoma', 'Disease', (185, 201))	('MLN0128', 'Chemical', 'MESH:C572449', (71, 78))	('Ewing sarcoma', 'Disease', (218, 231))	('BID', 'Gene', '637', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (185, 201))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (185, 201))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (218, 231))	('MLN0128', 'Var', (71, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (218, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('rapamycin', 'Chemical', 'MESH:D020123', (146, 155))	('tumor', 'Disease', (109, 114))
180335	25519700	Additionally, MLN0128 was able to induce apoptosis seen as increased cleaved caspase both in vitro and in vivo model of rhabdomyosarcoma (Rh30).	('induce', 'PosReg', (34, 40))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (120, 136))	('MLN0128', 'Var', (14, 21))	('cleaved caspase', 'MPA', (69, 84))	('Rh30', 'Gene', (138, 142))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (120, 136))	('rhabdomyosarcoma', 'Disease', (120, 136))	('MLN0128', 'Chemical', 'MESH:C572449', (14, 21))	('Rh30', 'Gene', '6007', (138, 142))	('increased', 'PosReg', (59, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
180337	25519700	In summary, MLN0128 is a potent and orally bioavailable pan-mTOR kinase inhibitor with effects on both mTORC1 and mTORC2 and their downstream effectors, and has a molecular signaling profile distinct from that of rapamycin.	('mTORC2', 'Gene', (114, 120))	('mTOR', 'Gene', (103, 107))	('mTORC2', 'Gene', '74343', (114, 120))	('effects', 'Reg', (87, 94))	('mTORC1', 'Gene', '382056', (103, 109))	('mTOR', 'Gene', '2475', (114, 118))	('MLN0128', 'Var', (12, 19))	('mTOR', 'Gene', '2475', (60, 64))	('mTOR', 'Gene', (114, 118))	('mTOR', 'Gene', (60, 64))	('rapamycin', 'Chemical', 'MESH:D020123', (213, 222))	('mTORC1', 'Gene', (103, 109))	('MLN0128', 'Chemical', 'MESH:C572449', (12, 19))	('mTOR', 'Gene', '2475', (103, 107))
180338	25519700	MLN0128 induces dose-dependent inhibition of tumor growth superior to that of rapamycin in a broad range of sarcoma models in vitro.	('MLN0128', 'Var', (0, 7))	('inhibition', 'NegReg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('sarcoma', 'Disease', (108, 115))	('tumor', 'Disease', (45, 50))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('rapamycin', 'Chemical', 'MESH:D020123', (78, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
180339	25519700	In models of rhabdomyosarcoma, MLN0128 induces apoptosis.	('MLN0128', 'Var', (31, 38))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (13, 29))	('apoptosis', 'CPA', (47, 56))	('MLN0128', 'Chemical', 'MESH:C572449', (31, 38))	('rhabdomyosarcoma', 'Disease', (13, 29))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (13, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('induces', 'Reg', (39, 46))
180340	25519700	Finally, in in vivo models of rhabdomyosarcoma and Ewing sarcoma, MLN0128 provides superior anti-tumor effect when compared with that of rapamycin.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (30, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('MLN0128', 'Var', (66, 73))	('rhabdomyosarcoma and Ewing sarcoma', 'Disease', 'MESH:C563168', (30, 64))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('MLN0128', 'Chemical', 'MESH:C572449', (66, 73))	('rapamycin', 'Chemical', 'MESH:D020123', (137, 146))	('tumor', 'Disease', (97, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
180341	25519700	MLN0128 warrants further evaluation as a potential therapy for sarcoma.	('MLN0128', 'Var', (0, 7))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('MLN0128', 'Chemical', 'MESH:C572449', (0, 7))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
180364	21681405	For the current analyses, we only included individuals who had been diagnosed with a pelvic or lower extremity (International Classification of Disease - Oncology (ICD-O) site codes C40.2, C40.3, C41.4, C41.8, C49.2, C49.5) bone or soft tissue sarcoma who were alive and completed the 2003 physical activity follow-up questionnaire, and who consented to medical record abstraction (Figure 1).	('C49.2', 'Var', (210, 215))	('C40.2', 'Var', (182, 187))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (232, 251))	('pelvic', 'Disease', (85, 91))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (232, 251))	('C49.5', 'Var', (217, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('soft tissue sarcoma', 'Disease', (232, 251))	('Oncology', 'Phenotype', 'HP:0002664', (154, 162))	('C40.3', 'Var', (189, 194))	('C41.4', 'Var', (196, 201))	('C41.8', 'Var', (203, 208))	('lower extremity', 'Phenotype', 'HP:0006385', (95, 110))
180378	21681405	Participants with T-scores of 63 or higher on the Brief Symptom Inventory-18 (BSI-18) were classified as depressed.	('T-scores', 'Var', (18, 26))	('Participants', 'Species', '9606', (0, 12))	('depressed', 'Disease', (105, 114))	('BSI-18', 'Gene', (78, 84))
180432	31516788	Sarcomas have two origins: they may be breast primary or appear secondary to various associated clinical conditions such as chronic lymphedema, exposure to chest wall radiotherapy, and in patients with genetic disorders such as neurofibromatosis (mutation in NF1gene), Li-Fraumeni syndrome (mutation in TP53 gene) and familial adenomatous polyposis.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('chronic lymphedema', 'Disease', (124, 142))	('Li-Fraumeni syndrome', 'Disease', (269, 289))	('mutation', 'Var', (291, 299))	('patients', 'Species', '9606', (188, 196))	('familial adenomatous polyposis', 'Disease', (318, 348))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (269, 289))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (318, 348))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (327, 348))	('NF1gene', 'Gene', (259, 266))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (228, 245))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('TP53', 'Gene', (303, 307))	('genetic disorders', 'Disease', 'MESH:D030342', (202, 219))	('neurofibromatosis', 'Disease', 'MESH:C537392', (228, 245))	('mutation in', 'Var', (247, 258))	('lymphedema', 'Phenotype', 'HP:0001004', (132, 142))	('Sarcomas', 'Disease', (0, 8))	('genetic disorders', 'Disease', (202, 219))	('chronic lymphedema', 'Disease', 'MESH:D008209', (124, 142))	('neurofibromatosis', 'Disease', (228, 245))
180543	31052611	The MET-dependent cancer cells became blocked in the late S/G2 phase by MR.	('S/G2', 'SUBSTITUTION', 'None', (58, 62))	('MET', 'Chemical', 'MESH:D008715', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('S/G2', 'Var', (58, 62))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
180544	31052611	The addition of DOX during MR enhanced its activity as the cells were trapped in S/G2, where they are most sensitive to DOX.	('DOX', 'Chemical', 'MESH:D004317', (120, 123))	('enhanced', 'PosReg', (30, 38))	('activity', 'MPA', (43, 51))	('DOX', 'Chemical', 'MESH:D004317', (16, 19))	('S/G2', 'Var', (81, 85))	('S/G2', 'SUBSTITUTION', 'None', (81, 85))
180545	31052611	In a subsequent in vivo study, using fluorescence ubiquitination-based cell cycle indicator (FUCCI)-expressing cancer cells:where color-coded genetic reporters indicate the phase of the cell cycle:rMETase was used to trap cells in S/G2 and enhanced the efficacy of the chemotherapy.	('rMETase', 'Gene', (197, 204))	('enhanced', 'PosReg', (240, 248))	('S/G2', 'Var', (231, 235))	('rMETase', 'Gene', '29252', (197, 204))	('S/G2', 'SUBSTITUTION', 'None', (231, 235))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('efficacy of', 'CPA', (253, 264))
180546	31052611	The growth arrest of MET-dependent cancer cells under MR resulted in a reduction in the percentage of mitotic cells in the cell population and the cancer cells were arrested in the S/G2 phases of the cell cycle under MR.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MET', 'Chemical', 'MESH:D008715', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('reduction', 'NegReg', (71, 80))	('growth arrest', 'Disease', 'MESH:D006323', (4, 17))	('growth arrest', 'Disease', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('S/G2', 'Var', (181, 185))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (147, 153))	('S/G2', 'SUBSTITUTION', 'None', (181, 185))	('growth arrest', 'Phenotype', 'HP:0001510', (4, 17))	('cancer', 'Disease', (35, 41))
180547	31052611	The S/G2 block by MR is responsible for the high efficacy of the combination of rMETase and chemotherapy.	('S/G2', 'Var', (4, 8))	('rMETase', 'Gene', '29252', (80, 87))	('rMETase', 'Gene', (80, 87))	('S/G2', 'SUBSTITUTION', 'None', (4, 8))
180554	31052611	S. typhimurium A1-R decoyed cancer cells in tumors to cycle from the G0/G1 to S/G2/M phases.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('S/G2', 'Var', (78, 82))	('S/G2', 'SUBSTITUTION', 'None', (78, 82))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('S. typhimurium', 'Species', '90371', (0, 14))	('cancer', 'Disease', (28, 34))
180555	31052611	When the cancer cells were subsequently treated with rMETase, they were selectively trapped in S/G2.	('cancer', 'Disease', (9, 15))	('rMETase', 'Gene', (53, 60))	('rMETase', 'Gene', '29252', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('S/G2', 'Var', (95, 99))	('S/G2', 'SUBSTITUTION', 'None', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
180556	31052611	We showed using sequential treatment of tumors with S. typhimurium A1-R to decoy quiescent cancer cells to cycle and rMETase to selectively trap the decoyed cancer cells in the S/G2 phase, that subsequent chemotherapy could eradicate tumors in mouse models of human stomach cancer and a metastasis osteosarcoma PDOX model.	('rMETase', 'Gene', (117, 124))	('S. typhimurium', 'Species', '90371', (52, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (303, 310))	('S/G2', 'Var', (177, 181))	('eradicate', 'NegReg', (224, 233))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('S/G2', 'SUBSTITUTION', 'None', (177, 181))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('stomach cancer', 'Disease', (266, 280))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('DOX', 'Chemical', 'MESH:D004317', (312, 315))	('tumors', 'Disease', (40, 46))	('mouse', 'Species', '10090', (244, 249))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('metastasis osteosarcoma', 'Disease', 'MESH:D009362', (287, 310))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('metastasis osteosarcoma', 'Disease', (287, 310))	('stomach cancer', 'Disease', 'MESH:D013274', (266, 280))	('cancer', 'Disease', (157, 163))	('stomach cancer', 'Phenotype', 'HP:0012126', (266, 280))	('human', 'Species', '9606', (260, 265))	('osteosarcoma', 'Phenotype', 'HP:0002669', (298, 310))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (91, 97))	('tumors', 'Disease', (234, 240))	('cancer', 'Disease', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('rMETase', 'Gene', '29252', (117, 124))
180638	29757258	In this line, cell death induced by the combination of FVP with both formulations of TRAIL was exclusively dependent of TRAIL since blocking TRAIL-signaling with the TRAIL-blocking antibody RIK2 entirely abrogated apoptosis induced by combination of FVP with both sTRAIL and LUV-TRAIL (Figure 6b).	('apoptosis', 'CPA', (214, 223))	('TRAIL', 'Gene', (85, 90))	('TRAIL', 'Gene', '8743', (279, 284))	('TRAIL', 'Gene', '8743', (141, 146))	('TRAIL', 'Gene', (120, 125))	('abrogated', 'NegReg', (204, 213))	('TRAIL', 'Gene', '8743', (166, 171))	('TRAIL', 'Gene', '8743', (265, 270))	('FVP', 'Chemical', 'MESH:C077990', (55, 58))	('TRAIL', 'Gene', (166, 171))	('TRAIL', 'Gene', (141, 146))	('blocking', 'Var', (132, 140))	('TRAIL', 'Gene', (265, 270))	('TRAIL', 'Gene', (279, 284))	('TRAIL', 'Gene', '8743', (120, 125))	('LUV', 'Chemical', '-', (275, 278))	('TRAIL', 'Gene', '8743', (85, 90))	('FVP', 'Chemical', 'MESH:C077990', (250, 253))
180676	29757258	Altogether, these data indicate that combination of FVP with LUV-TRAIL was a caspase-dependent apoptotic process through the activation of the extrinsic apoptotic pathway.	('activation', 'PosReg', (125, 135))	('TRAIL', 'Gene', '8743', (65, 70))	('apoptotic', 'CPA', (95, 104))	('FVP', 'Var', (52, 55))	('TRAIL', 'Gene', (65, 70))	('LUV', 'Chemical', '-', (61, 64))	('extrinsic apoptotic pathway', 'Pathway', (143, 170))	('FVP', 'Chemical', 'MESH:C077990', (52, 55))	('combination', 'Var', (37, 48))
180679	29757258	Several mechanisms have been described to explain FVP-induced TRAIL-sensitization, among them up-regulation of DR expression or inactivation of anti-apoptotic proteins such as FLIP, XIAP, Mcl-1, or survivin.	('FVP-induced', 'Var', (50, 61))	('XIAP', 'Gene', (182, 186))	('XIAP', 'Gene', '331', (182, 186))	('TRAIL', 'Gene', '8743', (62, 67))	('up-regulation', 'PosReg', (94, 107))	('Mcl-1', 'Gene', (188, 193))	('TRAIL', 'Gene', (62, 67))	('inactivation', 'NegReg', (128, 140))	('FVP', 'Chemical', 'MESH:C077990', (50, 53))	('Mcl-1', 'Gene', '4170', (188, 193))
180685	29757258	In agreement with previous studies, we observed that FVP induced a clear decrease of FLIP in all sarcoma cell lines tested.	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('FLIP', 'MPA', (85, 89))	('FVP', 'Var', (53, 56))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('decrease', 'NegReg', (73, 81))	('FVP', 'Chemical', 'MESH:C077990', (53, 56))
180686	29757258	In fact, FVP induced a clear down-regulation of the short isoform of cFLIP (cFLIPS), while no changes were observed for the long isoform of cFLIP (cFLIPL), with the exception of A673 cells.	('cFLIPS', 'Gene', (76, 82))	('down-regulation', 'NegReg', (29, 44))	('FVP', 'Var', (9, 12))	('FVP', 'Chemical', 'MESH:C077990', (9, 12))	('cFLIPS', 'Gene', '8837', (76, 82))	('short isoform', 'MPA', (52, 65))
180762	29471212	On Magnetic Resonance Imaging, nodular fasciitis has been described as inhomogeneous, hypointense to muscle on T1-weighted images, and hyperintense to fat on T2-weighted images, with variable enhancement.	('men', 'Species', '9606', (199, 202))	('nodular fasciitis', 'Disease', (31, 48))	('fasciitis', 'Phenotype', 'HP:0100537', (39, 48))	('hyperintense', 'Var', (135, 147))	('nodular fasciitis', 'Disease', 'MESH:D020518', (31, 48))
180784	22744906	High birth weight has been associated with both osteosarcoma and Ewing sarcoma risk.	('High birth weight', 'Phenotype', 'HP:0001520', (0, 17))	('High birth weight', 'Var', (0, 17))	('associated', 'Reg', (27, 37))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('osteosarcoma and Ewing sarcoma', 'Disease', 'MESH:C563168', (48, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))
180802	22744906	The PVF distributions are those having the Laplace transform with nu > 0, eta > - 1 and etarho > 0.	('eta > - 1', 'Gene', (74, 83))	('eta > - 1', 'Gene', '6696', (74, 83))	('eta', 'Gene', '1909', (88, 91))	('eta', 'Gene', '1909', (74, 77))	('eta', 'Gene', (74, 77))	('eta', 'Gene', (88, 91))	('nu > 0', 'Var', (66, 72))
180910	21392384	The poorly differentiated type shares features of both the monophasic or biphasic types, and has varying proportions of poorly differentiated areas characterised by high cellularity, pleomorphism, numerous mitoses and often necrosis.	('pleomorphism', 'Var', (183, 195))	('necrosis', 'Disease', 'MESH:D009336', (224, 232))	('necrosis', 'Disease', (224, 232))	('mitoses', 'CPA', (206, 213))
180917	21392384	The presence of metastases, a tumor size greater than 5 cm, invasiveness, high histological grade, positive surgical margins and poor histological differentiation are all associated with adverse prognostic significance.	('high', 'Var', (74, 78))	('metastases', 'Disease', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('metastases', 'Disease', 'MESH:D009362', (16, 26))	('invasiveness', 'CPA', (60, 72))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
180938	31391762	These irradiated cells with defective DNA repair mechanism accumulate further mutations and progress to develop secondary carcinomas and sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('develop', 'PosReg', (104, 111))	('mutations', 'Var', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('carcinomas and sarcoma', 'Disease', 'MESH:D012509', (122, 144))
181015	30106161	The RNA sequences used are as follows: EWS-FLI-1-specific siRNA, sense 5'-GUACCCUUCUGACAUCUCCUTT-3', antisense 5'-AGGAGUGUCAGAAGGGUACTT-3'; and non-silencing control siRNA, sense 5'-UUCUCCGAACGUGUCACGUTT-3' and antisense 5'-ACGUGACACGUUCGGAGAATT-3'.	('antisense', 'Var', (211, 220))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	('FLI-1', 'Gene', (43, 48))	('FLI-1', 'Gene', '2313', (43, 48))
181017	30106161	MI0000742) or complementary miR-34b sequence (miRBase accession no.	('miR', 'Gene', (46, 49))	('miR-34b', 'Gene', (28, 35))	('miR', 'Gene', '220972', (28, 31))	('MI0000742', 'Var', (0, 9))	('miR', 'Gene', (28, 31))	('miR-34b', 'Gene', '407041', (28, 35))	('miR', 'Gene', '220972', (46, 49))
181018	30106161	PMUL217000742 and PMDL159000685, respectively) to up- or downregulate miR-34b expression as previously described.	('expression', 'MPA', (78, 88))	('downregulate', 'NegReg', (57, 69))	('PMUL217000742', 'Var', (0, 13))	('PMDL159000685', 'Var', (18, 31))	('miR-34b', 'Gene', (70, 77))	('up-', 'PosReg', (50, 53))	('miR-34b', 'Gene', '407041', (70, 77))
181040	30106161	Similarly, a fragment representing mutant Notch1 3'-UTR, harbouring the change of the seven miRNA34b-binding sites (ACU GCC U UGA CGG A), was cloned into the pmiR-RB-REPORT vector as a control.	('Notch1', 'Gene', (42, 48))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('Notch1', 'Gene', '4851', (42, 48))	('mutant', 'Var', (35, 41))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))
181043	30106161	A large proportion (85-90%) of Ewing's sarcoma cases are characterized by the EWS-FLI1 fusion gene.	('characterized by', 'Reg', (57, 73))	('fusion gene', 'Var', (87, 98))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (31, 46))	("Ewing's sarcoma", 'Disease', (31, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (31, 46))	('EWS', 'Gene', '2130', (78, 81))	('EWS', 'Gene', (78, 81))	('FLI1', 'Gene', '2313', (82, 86))	('FLI1', 'Gene', (82, 86))
181078	30106161	These results suggested that the EWS-FLI1 fusion gene mayinactivate the Notch1 signaling pathway in Ewing's sarcoma via miR-34b.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (100, 115))	('Notch1', 'Gene', (72, 78))	("Ewing's sarcoma", 'Disease', (100, 115))	('fusion', 'Var', (42, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('miR-34b', 'Gene', (120, 127))	('mayinactivate', 'NegReg', (54, 67))	('Notch1', 'Gene', '4851', (72, 78))	('EWS', 'Gene', '2130', (33, 36))	('EWS', 'Gene', (33, 36))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (100, 115))	('FLI1', 'Gene', (37, 41))	('miR-34b', 'Gene', '407041', (120, 127))	('FLI1', 'Gene', '2313', (37, 41))
181080	30106161	Fragments containing the miR-34b binding sequence or mutated sequence in the 3'-UTR of the Notch1 mRNA were cloned into the pmiR-RB-REPORT luciferase reporter vector to generate the pmiR-RB-REPORT-NOTCH1-3'UTR and pmiR-RB-REPORT-NOTCH1-3'UTR-MUT plasmids, respectively.	('Notch1', 'Gene', '4851', (91, 97))	('miR-34b', 'Gene', '407041', (25, 32))	('NOTCH1', 'Gene', '4851', (229, 235))	('miR', 'Gene', '220972', (215, 218))	('NOTCH1', 'Gene', '4851', (197, 203))	('NOTCH1', 'Gene', (197, 203))	('miR', 'Gene', '220972', (183, 186))	('NOTCH1', 'Gene', (229, 235))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('mutated', 'Var', (53, 60))	('miR-34b', 'Gene', (25, 32))	('Notch1', 'Gene', (91, 97))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (183, 186))	('miR', 'Gene', (125, 128))	('miR', 'Gene', (215, 218))
181097	30106161	These results indicated that miR-34b may be upregulated in Ewing's sarcoma biopsy samples, particularly those harboring the EWS-FLI1 fusion gene, and Ewing's sarcoma cell lines.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (150, 165))	('EWS', 'Gene', '2130', (124, 127))	('miR-34b', 'Gene', (29, 36))	('EWS', 'Gene', (124, 127))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (59, 74))	('upregulated', 'PosReg', (44, 55))	("Ewing's sarcoma", 'Disease', (59, 74))	('FLI1', 'Gene', '2313', (128, 132))	('miR-34b', 'Gene', '407041', (29, 36))	('FLI1', 'Gene', (128, 132))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (59, 74))	('fusion gene', 'Var', (133, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (150, 165))	("Ewing's sarcoma", 'Disease', (150, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
181099	30106161	Studies have demonstrated that miRNAs can act as oncogenes or tumor suppressor genes, and that widespread alterations in miRNA expression patterns are highly associated with various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('associated', 'Reg', (158, 168))	('expression', 'MPA', (127, 137))	('human', 'Species', '9606', (182, 187))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('tumor', 'Disease', (62, 67))	('cancers', 'Disease', (188, 195))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('alterations', 'Var', (106, 117))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
181110	30106161	Previous studies have demonstrated that suppression of EWS-FLI1 reactivates Notch signaling in ESFT cells, resulting in cell cycle arrest, and using microarray analysis, Notch signaling has been revealed to be crucial for the metastatic phenotype.	('FLI1', 'Gene', (59, 63))	('EWS', 'Gene', '2130', (55, 58))	('EWS', 'Gene', (55, 58))	('FLI1', 'Gene', '2313', (59, 63))	('suppression', 'Var', (40, 51))	('reactivates', 'NegReg', (64, 75))	('cell cycle arrest', 'CPA', (120, 137))	('Notch signaling', 'MPA', (76, 91))
181115	30106161	In the present study, the observation was made that the mRNA and protein expression levels of Hes1 and Hey1 were downregulated by miR-34b, indicating that the EWS-FLI1 fusion gene may suppress the Notch1 signaling pathway, at least in part via miR-34b.	('miR-34b', 'Gene', (130, 137))	('Hes1', 'Gene', '3280', (94, 98))	('EWS', 'Gene', (159, 162))	('EWS', 'Gene', '2130', (159, 162))	('downregulated', 'NegReg', (113, 126))	('miR-34b', 'Gene', '407041', (244, 251))	('fusion', 'Var', (168, 174))	('suppress', 'NegReg', (184, 192))	('miR-34b', 'Gene', '407041', (130, 137))	('FLI1', 'Gene', (163, 167))	('Hey1', 'Gene', '23462', (103, 107))	('Hey1', 'Gene', (103, 107))	('FLI1', 'Gene', '2313', (163, 167))	('miR-34b', 'Gene', (244, 251))	('Notch1', 'Gene', (197, 203))	('Notch1', 'Gene', '4851', (197, 203))	('Hes1', 'Gene', (94, 98))
181120	30106161	Using a dual-luciferase reporter assay, it was revealed that miR-34b may directly modulate the expression of Notch1 by binding to the 3'-UTR region (sequence 181-187) of Notch1.	('Notch1', 'Gene', '4851', (109, 115))	('miR-34b', 'Gene', (61, 68))	('modulate', 'Reg', (82, 90))	('binding', 'Interaction', (119, 126))	('miR-34b', 'Gene', '407041', (61, 68))	('Notch1', 'Gene', (170, 176))	('sequence 181-187', 'Var', (149, 165))	('Notch1', 'Gene', (109, 115))	('Notch1', 'Gene', '4851', (170, 176))	('expression', 'MPA', (95, 105))
181142	29212731	The improved diagnostic accuracy enabled by detection of the characteristic translocation, and recognition that DSRCT molecularly resembles Ewing sarcoma (ES) and other EWSR1 translocation-positive sarcomas, led to a paradigm shift over the last 2 decades in how these tumors are treated.	('DSRCT', 'Disease', (112, 117))	('ES', 'Phenotype', 'HP:0012254', (155, 157))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('Ewing sarcoma', 'Disease', (140, 153))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('sarcomas', 'Disease', 'MESH:D012509', (198, 206))	('translocation', 'Var', (76, 89))	('EWSR1', 'Gene', (169, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (140, 153))	('tumors', 'Disease', (269, 275))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('sarcomas', 'Phenotype', 'HP:0100242', (198, 206))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (140, 153))	('EWSR1', 'Gene', '2130', (169, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('sarcomas', 'Disease', (198, 206))
181224	29212731	In the salvage setting, our study demonstrated that pazopanib was well tolerated and has the potential to prolong OS, even in heavily pretreated patients.	('patients', 'Species', '9606', (145, 153))	('prolong', 'PosReg', (106, 113))	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('pazopanib', 'Var', (52, 61))
181286	28363372	A 48 year old woman was diagnosed with ER+/PR+/Her2+ left breast cancer four years prior to presentation.	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('woman', 'Species', '9606', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('ER+/PR+/Her2+', 'Var', (39, 52))
181353	28363372	They also found that incomplete surgical remission, metastases at presentation, microscopic tumor necrosis and central tumor site were significant adverse prognostic factors.	('metastases', 'Disease', (52, 62))	('tumor', 'Disease', (119, 124))	('metastases', 'Disease', 'MESH:D009362', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor necrosis', 'Disease', 'MESH:D009336', (92, 106))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', (92, 97))	('microscopic', 'Var', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor necrosis', 'Disease', (92, 106))
181403	24137450	The tumors show a common and unique chromosomal translocation, t(11;22)(q24;q12).	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Disease', (4, 10))	('t(11;22)(q24;q12', 'Var', (63, 79))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
181478	24137450	In the case of patients with a high risk of recurrence (central tumors >=100 cm3), the chemotherapeutic regimen used included vincristine, actinomycin D, ifosfamide (IFM) and ADM (VAIA).	('tumors', 'Disease', (64, 70))	('IFM', 'Chemical', 'MESH:D007069', (166, 169))	('patients', 'Species', '9606', (15, 23))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('actinomycin D', 'Chemical', 'MESH:D003609', (139, 152))	('ADM', 'Var', (175, 178))	('vincristine', 'Chemical', 'MESH:D014750', (126, 137))	('ADM', 'Chemical', 'MESH:D004317', (175, 178))	('ifosfamide', 'Chemical', 'MESH:D007069', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('VAIA', 'Chemical', '-', (180, 184))
181513	21437224	70% aRMS present a specific translocation of the transcription factor Pax3 at the 3'end of FOXO1, creating a potent transcription factor able to induce myogenesis and survival.	('Pax3', 'Gene', '5077', (70, 74))	('FOXO1', 'Gene', (91, 96))	('translocation', 'Var', (28, 41))	('Pax3', 'Gene', (70, 74))	('survival', 'CPA', (167, 175))	('myogenesis', 'CPA', (152, 162))	('induce', 'PosReg', (145, 151))	('potent transcription factor', 'MPA', (109, 136))	('RMS', 'Phenotype', 'HP:0002859', (5, 8))	('FOXO1', 'Gene', '2308', (91, 96))
181597	21437224	This revealed that the mTOR pathway was inhibited by RAD-001 in chondrosarcoma cells contrary to 15-47 cells, in particular eIF4G and p70 S6 kinase whose phosphorylation level was decreased (Figure 3(b)).	('mTOR pathway', 'Pathway', (23, 35))	('RAD', 'Gene', '6236', (53, 56))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (64, 78))	('inhibited', 'NegReg', (40, 49))	('eIF4G', 'Gene', (124, 129))	('phosphorylation level', 'MPA', (154, 175))	('decreased', 'NegReg', (180, 189))	('p70 S6', 'Var', (134, 140))	('eIF4G', 'Gene', '1981', (124, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('chondrosarcoma', 'Disease', 'MESH:D002813', (64, 78))	('RAD', 'Gene', (53, 56))	('chondrosarcoma', 'Disease', (64, 78))
181620	21437224	Although we could not rule out that some trans-acting proteins could be deregulated consequently to these aberrations, this suggested that all tumours were homogeneous and that an increase in some miRNAs in sensitive tumours were due to their upregulation and not to a genetic amplification.	('rat', 'Species', '10116', (110, 113))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('increase', 'PosReg', (180, 188))	('tumours', 'Phenotype', 'HP:0002664', (217, 224))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('tumours', 'Disease', 'MESH:D009369', (143, 150))	('miRNAs', 'MPA', (197, 203))	('upregulation', 'PosReg', (243, 255))	('tumours', 'Disease', (217, 224))	('tumours', 'Disease', 'MESH:D009369', (217, 224))	('tumours', 'Disease', (143, 150))	('aberrations', 'Var', (106, 117))
181644	21437224	The miRNAs deregulated in response to this drug in sensitive cells, effectively targeted the mTOR pathway, in particular the downstream proteins eIF4G and p70 S6 kinase (Figure 3(b)), and potentially RICTOR, ATG1 and HIF1a, which might be validated by qPCR analysis (Figure 5).	('p70', 'Var', (155, 158))	('HIF1a', 'Gene', '3091', (217, 222))	('RICTOR', 'Gene', '253260', (200, 206))	('ATG1', 'Gene', (208, 212))	('ATG1', 'Gene', '8408', (208, 212))	('HIF1a', 'Gene', (217, 222))	('deregulated', 'Var', (11, 22))	('eIF4G', 'Gene', (145, 150))	('targeted', 'Reg', (80, 88))	('eIF4G', 'Gene', '1981', (145, 150))	('mTOR pathway', 'Pathway', (93, 105))	('RICTOR', 'Gene', (200, 206))
181653	21437224	Even if some proteins involved in the regulation of miRNA expression (trans-acting factors or epigenetic regulating factors) could be deregulated following these mutations, the miRNA profiles observed in rat tumours might be correlated to the effects of the cytotoxic drugs on the miRNA machinery and no to upstream DNA rearrangements.	('tumours', 'Phenotype', 'HP:0002664', (208, 215))	('mutations', 'Var', (162, 171))	('miRNA profiles', 'MPA', (177, 191))	('deregulated', 'PosReg', (134, 145))	('tumours', 'Disease', 'MESH:D009369', (208, 215))	('tumours', 'Disease', (208, 215))	('rat', 'Species', '10116', (204, 207))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('proteins', 'Protein', (13, 21))
181686	32722129	Genome-wide analyses revealed several functional cancer-associated mutations within the noncoding genome.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('mutations', 'Var', (67, 76))
181695	32722129	On the contrary, cancer cells harbor mutations in oncogenes that constitutively activate mitogenic signaling pathways and/or acquire the ability to synthesize growth factors by themselves, thus establishing a positive feedback loop indicated as autocrine stimulation.	('oncogenes', 'Gene', (50, 59))	('ability', 'MPA', (137, 144))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('positive feedback loop', 'MPA', (209, 231))	('mitogenic signaling pathways', 'Pathway', (89, 117))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (17, 23))	('activate', 'PosReg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
181711	32722129	FUS/TLS contains two glycine-arginine rich (RGG) domains in its C-terminal region, which are directly involved in the binding to pncRNA-D. Methylation of arginine R-476 disrupts the pncRNA-D-FUS/TLS interaction, thus leading to cyclin D1 upregulation through the rescue of CBP/p300 histone acetyl-transferase (HAT) activity.	('arginine', 'Chemical', 'MESH:D001120', (29, 37))	('CBP/p300', 'Gene', '1387;2033', (273, 281))	('upregulation', 'PosReg', (238, 250))	('interaction', 'Interaction', (199, 210))	('FUS/TLS', 'Gene', '2521', (191, 198))	('FUS/TLS', 'Gene', '2521', (0, 7))	('FUS/TLS', 'Gene', (191, 198))	('ncRNA', 'Gene', (130, 135))	('arginine', 'Chemical', 'MESH:D001120', (154, 162))	('FUS/TLS', 'Gene', (0, 7))	('ncRNA', 'Gene', '54719', (130, 135))	('cyclin D1', 'Gene', (228, 237))	('CBP/p300', 'Gene', (273, 281))	('ncRNA', 'Gene', (183, 188))	('activity', 'MPA', (315, 323))	('glycine', 'Chemical', 'MESH:D005998', (21, 28))	('cyclin D1', 'Gene', '595', (228, 237))	('ncRNA', 'Gene', '54719', (183, 188))	('Methylation', 'Var', (139, 150))	('disrupts', 'NegReg', (169, 177))
181712	32722129	Furthermore, pncRNA-D is susceptible to m6A methylation and its methylation was dramatically decreased after osmotic stress or irradiation in HeLa cells.	('decreased', 'NegReg', (93, 102))	('m6A', 'Var', (40, 43))	('ncRNA', 'Gene', (14, 19))	('methylation', 'MPA', (64, 75))	('ncRNA', 'Gene', '54719', (14, 19))	('HeLa', 'CellLine', 'CVCL:0030', (142, 146))
181713	32722129	Notably, it has been reported that the inhibition of methylation enhances the stability of pncRNA-D, thus promoting its interaction with FUS/TLS.	('FUS/TLS', 'Gene', '2521', (137, 144))	('inhibition', 'Var', (39, 49))	('interaction', 'Interaction', (120, 131))	('methylation', 'Protein', (53, 64))	('ncRNA', 'Gene', (92, 97))	('enhances', 'PosReg', (65, 73))	('FUS/TLS', 'Gene', (137, 144))	('ncRNA', 'Gene', '54719', (92, 97))	('stability', 'MPA', (78, 87))	('promoting', 'PosReg', (106, 115))
181734	32722129	In line with this notion, transcriptional silencing of MYC was shown as an effective strategy to block maintenance and proliferation of prostate cancer stem cells both in cell cultures and in tumor xenografts.	('tumor', 'Disease', (192, 197))	('MYC', 'Gene', (55, 58))	('prostate cancer', 'Disease', (136, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('block', 'NegReg', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('transcriptional silencing', 'Var', (26, 51))
181735	32722129	In particular, MYC silencing was associated with reduced self-renewal and tumor-initiating capability.	('self-renewal', 'CPA', (57, 69))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('reduced', 'NegReg', (49, 56))	('silencing', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('MYC', 'Protein', (15, 18))
181755	32722129	The inhibition of Eleanors by resveratrol treatment as well as pa-Eleanor(S) knockdown affects the formation of the cloud and represses ESR1 gene expression, whereas FOXO3 expression is maintained.	('ESR1', 'Gene', (136, 140))	('formation', 'MPA', (99, 108))	('FOXO3', 'Gene', '2309', (166, 171))	('knockdown', 'Var', (77, 86))	('pa-Eleanor', 'Chemical', '-', (63, 73))	('Eleanors', 'Chemical', '-', (18, 26))	('ESR1', 'Gene', '2099', (136, 140))	('FOXO3', 'Gene', (166, 171))	('affects', 'Reg', (87, 94))	('resveratrol', 'Chemical', 'MESH:D000077185', (30, 41))	('expression', 'MPA', (146, 156))	('represses', 'NegReg', (126, 135))
181765	32722129	In line with this observation, depletion of Khps1 renders tumor cells more sensitive to tamoxifen-induced apoptosis, suggesting its therapeutic potential for the implementation of anticancer strategies.	('cancer', 'Disease', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tamoxifen', 'Chemical', 'MESH:D013629', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Khps1', 'Gene', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('depletion', 'Var', (31, 40))	('more', 'PosReg', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('sensitive to tamoxifen-induced apoptosis', 'MPA', (75, 115))
181769	32722129	By contrast, tumor cells prevent telomere loss by aberrantly upregulating telomerase.	('tumor', 'Disease', (13, 18))	('upregulating', 'PosReg', (61, 73))	('telomerase', 'Enzyme', (74, 84))	('telomere', 'Var', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
181770	32722129	Telomerase activity is strictly dependent on the availability of the telomerase reverse transcriptase (hTERT) and the enzymatic component of telomerase, and expression of the this enzyme is tightly regulated at the transcriptional level through epigenetic modifications in the promoter region.	('hTERT', 'Gene', '7015', (103, 108))	('hTERT', 'Gene', (103, 108))	('epigenetic modifications', 'Var', (245, 269))	('regulated', 'Reg', (198, 207))
181771	32722129	In line with its regulatory role, recurrent mutations in the promoter region of hTERT are among the most common somatic mutations in many types of cancer, including melanomas, glioblastoma multiforme, hepatocellular carcinomas, and bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('hTERT', 'Gene', '7015', (80, 85))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (201, 226))	('bladder cancers', 'Phenotype', 'HP:0009725', (232, 247))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('hepatocellular carcinomas', 'Disease', (201, 226))	('cancer', 'Disease', (240, 246))	('bladder cancer', 'Phenotype', 'HP:0009725', (232, 246))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('hTERT', 'Gene', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('bladder cancers', 'Disease', 'MESH:D001749', (232, 247))	('bladder cancers', 'Disease', (232, 247))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('melanomas', 'Disease', 'MESH:D008545', (165, 174))	('glioblastoma multiforme', 'Disease', (176, 199))	('glioblastoma', 'Phenotype', 'HP:0012174', (176, 188))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (176, 199))	('melanomas', 'Disease', (165, 174))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (201, 226))	('mutations', 'Var', (44, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('cancer', 'Disease', (147, 153))
181774	32722129	Overexpression of hTAPAS pancRNA downregulates hTERT, whereas its knockdown induces the upregulation of hTERT expression.	('downregulates', 'NegReg', (33, 46))	('ncRNA', 'Gene', '54719', (27, 32))	('hTERT', 'Gene', '7015', (104, 109))	('hTAPAS', 'Gene', (18, 24))	('upregulation', 'PosReg', (88, 100))	('hTERT', 'Gene', '7015', (47, 52))	('hTERT', 'Gene', (104, 109))	('ncRNA', 'Gene', (27, 32))	('knockdown', 'Var', (66, 75))	('hTERT', 'Gene', (47, 52))
181817	32722129	Thus, knockdown of paRCDH1-AS leads to CDH1 repression by switching the chromatin engagement of the repressive complex.	('leads to', 'Reg', (30, 38))	('CDH1', 'Gene', '999', (22, 26))	('switching', 'Reg', (58, 67))	('repression', 'NegReg', (44, 54))	('chromatin engagement of the repressive complex', 'MPA', (72, 118))	('knockdown', 'Var', (6, 15))	('CDH1', 'Gene', (22, 26))	('CDH1', 'Gene', (39, 43))	('CDH1', 'Gene', '999', (39, 43))
181820	32722129	Abolishment of pncRNA-D binding caused conformational remodeling in the FUS/TLS protein, reducing the affinity to CBP/p300.	('FUS/TLS', 'Gene', '2521', (72, 79))	('ncRNA', 'Gene', (16, 21))	('reducing', 'NegReg', (89, 97))	('binding', 'Interaction', (24, 31))	('CBP/p300', 'Gene', (114, 122))	('ncRNA', 'Gene', '54719', (16, 21))	('Abolishment', 'Var', (0, 11))	('affinity', 'Interaction', (102, 110))	('CBP/p300', 'Gene', '1387;2033', (114, 122))	('conformational', 'MPA', (39, 53))	('FUS/TLS', 'Gene', (72, 79))
181822	32722129	Cui and colleagues show that PRMT1 (Protein Arginine Methyltransferase 1) catalyzes di-methylation on the Arg-476 of FUS/TLS; this posttranslational modification inhibits FUS/TLS binding to RNA, thus inducing the release of the CBP/p300 HAT activity from the FUS/TLS driven inhibition.	('RNA', 'Protein', (190, 193))	('Protein Arginine Methyltransferase 1', 'Gene', (36, 72))	('inducing', 'Reg', (200, 208))	('Arg', 'Chemical', 'MESH:D001120', (106, 109))	('binding', 'Interaction', (179, 186))	('CBP/p300', 'Gene', (228, 236))	('FUS/TLS', 'Gene', '2521', (117, 124))	('inhibits', 'NegReg', (162, 170))	('Protein Arginine Methyltransferase 1', 'Gene', '3276', (36, 72))	('PRMT1', 'Gene', '3276', (29, 34))	('FUS/TLS', 'Gene', '2521', (259, 266))	('PRMT1', 'Gene', (29, 34))	('FUS/TLS', 'Gene', '2521', (171, 178))	('FUS/TLS', 'Gene', (117, 124))	('CBP/p300', 'Gene', '1387;2033', (228, 236))	('FUS/TLS', 'Gene', (259, 266))	('release', 'MPA', (213, 220))	('FUS/TLS', 'Gene', (171, 178))	('Arg', 'Chemical', 'MESH:D001120', (44, 47))	('modification', 'Var', (149, 161))
181830	32722129	Tyrosine phosphorylation is known to lower the affinity of Sam68 for RNA, and IGF-1-induced activation of SRC promotes Sam68 phosphorylation and the release of the pncCCND1_B.	('Sam68', 'Gene', '10657', (119, 124))	('Tyrosine', 'Var', (0, 8))	('Sam68', 'Gene', '10657', (59, 64))	('IGF-1', 'Gene', '3479', (78, 83))	('Sam68', 'Gene', (119, 124))	('IGF-1', 'Gene', (78, 83))	('CCND1', 'Gene', (167, 172))	('Sam68', 'Gene', (59, 64))	('affinity', 'MPA', (47, 55))	('SRC', 'Gene', '6714', (106, 109))	('SRC', 'Gene', (106, 109))	('phosphorylation', 'MPA', (125, 140))	('lower', 'NegReg', (37, 42))	('release', 'MPA', (149, 156))	('CCND1', 'Gene', '595', (167, 172))
181831	32722129	Thus, tyrosine phosphorylation of Sam68 upon mitogenic stimuli mimics Sam68 silencing by impairing the ability of pncCCND1_B to repress the CCND1 promoter, leading to the upregulation of cyclin D1 expression (Figure 2C).	('CCND1', 'Gene', '595', (140, 145))	('tyrosine', 'Chemical', 'MESH:D014443', (6, 14))	('impairing', 'NegReg', (89, 98))	('cyclin D1', 'Gene', '595', (187, 196))	('repress', 'MPA', (128, 135))	('tyrosine', 'Var', (6, 14))	('CCND1', 'Gene', '595', (117, 122))	('cyclin D1', 'Gene', (187, 196))	('Sam68', 'Gene', (34, 39))	('Sam68', 'Gene', '10657', (34, 39))	('CCND1', 'Gene', (140, 145))	('Sam68', 'Gene', '10657', (70, 75))	('upregulation', 'PosReg', (171, 183))	('Sam68', 'Gene', (70, 75))	('CCND1', 'Gene', (117, 122))	('ability', 'MPA', (103, 110))	('expression', 'MPA', (197, 207))
181843	32722129	Interestingly, degradation of this pancRNA by antisense phosphorothioate oligodeoxynucleotides (ODN) exhibited high specificity, since it did not affect EF1alpha mRNA transcript.	('ncRNA', 'Gene', (37, 42))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (73, 94))	('ODN', 'Chemical', 'MESH:D009838', (96, 99))	('antisense', 'Var', (46, 55))	('EF1alpha', 'Gene', '1917', (153, 161))	('phosphorothioate', 'Chemical', '-', (56, 72))	('EF1alpha', 'Gene', (153, 161))	('degradation', 'MPA', (15, 26))	('ncRNA', 'Gene', '54719', (37, 42))
181851	32722129	Notably, analysis of the promoter chromatin feature after dsRNA treatment revealed a general enrichment of H3 dimethyl-K4, a histone mark associated with actively transcribed promoters, and H3 dimethyl-K9 residues, a modification present at inactive promoters, only at the targeted CDH1 promoter.	('H3 dimethyl-K9 residues', 'Var', (190, 213))	('H3 dimethyl-K4', 'Var', (107, 121))	('CDH1', 'Gene', (282, 286))	('CDH1', 'Gene', '999', (282, 286))
181859	32722129	Notably, knockdown of hnRNPA2/B1 blocks the saRNA-mediated p21 induction.	('knockdown', 'Var', (9, 18))	('hnRNPA2/B1', 'Gene', '3181', (22, 32))	('hnRNPA2/B1', 'Gene', (22, 32))	('saRNA-mediated p21 induction', 'MPA', (44, 72))	('blocks', 'NegReg', (33, 39))
181868	32722129	Recent advances showed that pancRNAs are targetable molecules and that modulation of their expression can be used for therapeutic purpose.	('modulation', 'Var', (71, 81))	('ncRNA', 'Gene', (30, 35))	('ncRNA', 'Gene', '54719', (30, 35))
181931	31160689	Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells causes high-grade sarcoma with a dedifferentiated liposarcoma-like morphology Amplification and overexpression of MDM2 and CDK4 are well-known diagnostic criteria for well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS).	('liposarcoma', 'Phenotype', 'HP:0012034', (262, 273))	('overexpression', 'PosReg', (171, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (303, 310))	('CDK4', 'Gene', '1019', (198, 202))	('MDM2', 'Gene', '4193', (189, 193))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('liposarcoma', 'Disease', 'MESH:D008080', (262, 273))	('liposarcoma', 'Phenotype', 'HP:0012034', (299, 310))	('sarcoma', 'Disease', 'MESH:D012509', (266, 273))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('sarcoma', 'Disease', (93, 100))	('LPS', 'Disease', (314, 317))	('MDM2', 'Gene', (17, 21))	('human', 'Species', '9606', (46, 51))	('sarcoma', 'Disease', (266, 273))	('LPS', 'Phenotype', 'HP:0012034', (277, 280))	('liposarcoma (WDLPS)/dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (262, 310))	('LPS', 'Disease', 'MESH:D008080', (277, 280))	('liposarcoma', 'Disease', 'MESH:D008080', (299, 310))	('expression', 'Species', '29278', (3, 13))	('liposarcoma', 'Disease', 'MESH:D008080', (125, 136))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('MDM2', 'Gene', '4193', (17, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('CDK4', 'Gene', (26, 30))	('liposarcoma', 'Disease', (262, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('sarcoma', 'Disease', (129, 136))	('sarcoma', 'Disease', 'MESH:D012509', (303, 310))	('expression', 'Species', '29278', (175, 185))	('sarcoma', 'Disease', (303, 310))	('CDK4', 'Gene', (198, 202))	('LPS', 'Phenotype', 'HP:0012034', (314, 317))	('CDK4', 'Gene', '1019', (26, 30))	('Co-expression', 'Var', (0, 13))	('MDM2', 'Gene', (189, 193))	('liposarcoma', 'Disease', (299, 310))	('LPS', 'Disease', 'MESH:D008080', (314, 317))	('liposarcoma', 'Disease', (125, 136))	('LPS', 'Disease', (277, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
181933	31160689	We examined whether MDM2 and/or CDK4 cause WDLPS/DDLPS, using two types of transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRASv12).	('TP53', 'Gene', (187, 191))	('expression', 'Species', '29278', (166, 176))	('overexpression', 'PosReg', (162, 176))	('LPS', 'Disease', (51, 54))	('hTERT', 'Gene', '7015', (180, 185))	('expression', 'Species', '29278', (251, 261))	('MDM2', 'Var', (20, 24))	('human', 'Species', '9606', (87, 92))	('inactivation', 'NegReg', (208, 220))	('cause', 'Reg', (37, 42))	('LPS', 'Phenotype', 'HP:0012034', (45, 48))	('c-MYC', 'Gene', '4609', (222, 227))	('CDK4', 'Gene', (32, 36))	('TP53', 'Gene', '7157', (187, 191))	('LPS', 'Disease', 'MESH:D008080', (45, 48))	('degradation', 'NegReg', (192, 203))	('hTERT', 'Gene', (180, 185))	('c-MYC', 'Gene', (222, 227))	('2H', 'Chemical', 'MESH:D006859', (125, 127))	('LPS', 'Phenotype', 'HP:0012034', (51, 54))	('LPS', 'Disease', 'MESH:D008080', (51, 54))	('LPS', 'Disease', (45, 48))
181935	31160689	Using mouse xenograft models, we found that the co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can cause proliferative sarcoma with a DDLPS-like morphology in vivo.	('LPS', 'Phenotype', 'HP:0012034', (177, 180))	('LPS', 'Disease', (177, 180))	('co-overexpression', 'Var', (48, 65))	('cause', 'Reg', (140, 145))	('CDK4', 'Gene', (78, 82))	('proliferative sarcoma', 'Disease', 'MESH:D012509', (146, 167))	('expression', 'Species', '29278', (55, 65))	('LPS', 'Disease', 'MESH:D008080', (177, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('mutations', 'Var', (126, 135))	('proliferative sarcoma', 'Disease', (146, 167))	('MDM2', 'Gene', (69, 73))	('mouse', 'Species', '10090', (6, 11))
181938	31160689	The authors found that co-overexpression of MDM2 and CDK4 causes high-grade sarcoma with a dedifferentiated liposarcoma-like morphology.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('liposarcoma', 'Phenotype', 'HP:0012034', (108, 119))	('MDM2', 'Gene', (44, 48))	('liposarcoma', 'Disease', 'MESH:D008080', (108, 119))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('causes', 'Reg', (58, 64))	('CDK4', 'Gene', (53, 57))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcoma', 'Disease', (112, 119))	('liposarcoma', 'Disease', (108, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('co-overexpression', 'Var', (23, 40))	('expression', 'Species', '29278', (30, 40))
181942	31160689	Amplification and overexpression of MDM2 and CDK4 are generally accepted as the current diagnostic criteria for WDLPS/DDLPS.	('MDM2', 'Gene', (36, 40))	('LPS', 'Disease', (114, 117))	('Amplification', 'Var', (0, 13))	('LPS', 'Disease', 'MESH:D008080', (120, 123))	('LPS', 'Phenotype', 'HP:0012034', (114, 117))	('overexpression', 'PosReg', (18, 32))	('LPS', 'Disease', 'MESH:D008080', (114, 117))	('CDK4', 'Gene', (45, 49))	('expression', 'Species', '29278', (22, 32))	('LPS', 'Phenotype', 'HP:0012034', (120, 123))	('LPS', 'Disease', (120, 123))
181948	31160689	Despite their potency as driving factors, whether MDM2 and CDK4 induce WDLPS/DDLPS tumorigenesis remains unclear.	('induce', 'Reg', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LPS', 'Phenotype', 'HP:0012034', (73, 76))	('LPS', 'Disease', (73, 76))	('tumor', 'Disease', (83, 88))	('LPS', 'Disease', 'MESH:D008080', (79, 82))	('LPS', 'Disease', 'MESH:D008080', (73, 76))	('MDM2', 'Var', (50, 54))	('CDK4', 'Gene', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('LPS', 'Phenotype', 'HP:0012034', (79, 82))	('LPS', 'Disease', (79, 82))
181949	31160689	It has been well-established that the genetic manipulation of important tumor suppressor genes and oncogenes induces the transformation of human BMSCs to various sarcomas in vitro or in vivo.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('transformation', 'CPA', (121, 135))	('sarcomas', 'Disease', 'MESH:D012509', (162, 170))	('tumor', 'Disease', (72, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('genetic manipulation', 'Var', (38, 58))	('human', 'Species', '9606', (139, 144))	('sarcomas', 'Disease', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('induces', 'Reg', (109, 116))
181954	31160689	found that the immunoexpression of MDM2 or CDK4, MDM2, and CDK4 was 100% (44/44), 90.9% (40/44), and 90.9% (40/44) in WDLPS and 95.1% (58/61), 91.8% (56/61), and 90.2% (55/61) in DDLPS, respectively.	('LPS', 'Disease', 'MESH:D008080', (120, 123))	('expression', 'Species', '29278', (21, 31))	('LPS', 'Disease', 'MESH:D008080', (181, 184))	('CDK4', 'Gene', (43, 47))	('MDM2', 'Var', (49, 53))	('MDM2', 'Var', (35, 39))	('CDK4', 'Var', (59, 63))	('LPS', 'Phenotype', 'HP:0012034', (181, 184))	('LPS', 'Phenotype', 'HP:0012034', (120, 123))	('LPS', 'Disease', (181, 184))	('LPS', 'Disease', (120, 123))
181977	31160689	pLenti6.3/3XFLAG-MDM2 or 3XFLAG-CDK4 expression vectors were transfected into 293FT cells using ViraPower Packaging Mix (Invitrogen) to produce lentiviruses expressing MDM2 or CDK4.	('Mix', 'Gene', '83881', (116, 119))	('CDK4', 'Var', (176, 180))	('expression vectors', 'Species', '29278', (37, 55))	('FLAG', 'Chemical', 'MESH:C085706', (12, 16))	('MDM2', 'Var', (168, 172))	('FLAG', 'Chemical', 'MESH:C085706', (27, 31))	('Mix', 'Gene', (116, 119))
181988	31160689	To examine whether the co-overexpression of MDM2 and CDK4 drives WDLPS/DDLPS tumorigenesis, we used two types of transformed BMSCs (2H and 5H cells) containing two to five different oncogenic mutations (Fig.	('LPS', 'Phenotype', 'HP:0012034', (73, 76))	('mutations', 'Var', (192, 201))	('LPS', 'Disease', (73, 76))	('2H', 'Chemical', 'MESH:D006859', (132, 134))	('LPS', 'Phenotype', 'HP:0012034', (67, 70))	('LPS', 'Disease', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CDK4', 'Gene', (53, 57))	('LPS', 'Disease', 'MESH:D008080', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('LPS', 'Disease', 'MESH:D008080', (67, 70))	('tumor', 'Disease', (77, 82))	('expression', 'Species', '29278', (30, 40))
182001	31160689	To establish cells co-overexpressing MDM2 and CDK4, 2H and 5H cells were infected with either LacZ- (beta-galactosidase, control) or MDM2- and/or CDK4-expresssing lentiviral particles.	('beta-galactosidase', 'Gene', '2720', (101, 119))	('beta-galactosidase', 'Gene', (101, 119))	('2H', 'Chemical', 'MESH:D006859', (52, 54))	('MDM2', 'Var', (37, 41))	('MDM2-', 'Var', (133, 138))
182007	31160689	CDK4 expression in the transduced 2H and 5H cells was more than twofold higher than that in both LP6 and LIPO-863B cells (Fig.	('transduced', 'Var', (23, 33))	('expression', 'MPA', (5, 15))	('2H', 'Chemical', 'MESH:D006859', (34, 36))	('LIPO', 'Gene', (105, 109))	('CDK4', 'Gene', (0, 4))	('higher', 'PosReg', (72, 78))	('LIPO', 'Gene', '8091', (105, 109))	('expression', 'Species', '29278', (5, 15))
182008	31160689	Morphologically, both 2H and 5H cells co-overexpressing MDM2 and CKD4 were much longer and thinner than those solely expressing MDM2, CDK4, or LacZ (Fig.	('thinner', 'NegReg', (91, 98))	('2H', 'Chemical', 'MESH:D006859', (22, 24))	('CKD4', 'Var', (65, 69))	('MDM2', 'Var', (56, 60))
182013	31160689	To evaluate the TP53 expression levels in the established cells expressing MDM2 and/or CDK4 that had been transduced with E6, we compared the TP53 expression levels in these cells with those in BMSCs and LIPO-863-B and LP6 cells (Supplementary Fig.	('MDM2', 'Var', (75, 79))	('expression', 'Species', '29278', (147, 157))	('TP53', 'Gene', '7157', (142, 146))	('expression', 'Species', '29278', (21, 31))	('TP53', 'Gene', (142, 146))	('LIPO', 'Gene', '8091', (204, 208))	('TP53', 'Gene', '7157', (16, 20))	('LIPO', 'Gene', (204, 208))	('TP53', 'Gene', (16, 20))	('CDK4', 'Gene', (87, 91))
182015	31160689	It is noteworthy that both 2H and 5H cells expressing MDM2 and/or CDK4 showed decreased TP53 expression levels (Supplementary Fig.	('CDK4', 'Var', (66, 70))	('2H', 'Chemical', 'MESH:D006859', (27, 29))	('expression', 'Species', '29278', (93, 103))	('TP53', 'Gene', '7157', (88, 92))	('decreased', 'NegReg', (78, 87))	('TP53', 'Gene', (88, 92))	('MDM2', 'Var', (54, 58))
182024	31160689	Next, we analyzed the expression levels of genes serially induced during adipogenesis by real-time PCR: C/EBPbeta (in the early step), C/EBPalpha, and PPARgamma (from the middle to late steps), C/SREBP1 (full step), and ADIPSIN and LPL (late step).	('N', 'Chemical', 'MESH:D009584', (226, 227))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('C/EBPbeta', 'Var', (104, 113))	('C/EBPalpha', 'Var', (135, 145))	('expression', 'Species', '29278', (22, 32))	('PPARgamma', 'Gene', (151, 160))
182025	31160689	4b, cells expressing only MDM2 or co-overexpressing MDM2 and CDK4 showed relatively downregulated expression levels of these genes in comparison with those in both 2H-LacZ and 2H-CDK4 cells; the expression levels of all genes except C/EBPbeta in these cells were similar to those in the LP6 cells.	('downregulated', 'NegReg', (84, 97))	('2H', 'Chemical', 'MESH:D006859', (164, 166))	('MDM2', 'Var', (52, 56))	('2H', 'Chemical', 'MESH:D006859', (176, 178))	('expression levels', 'MPA', (98, 115))	('expression', 'Species', '29278', (98, 108))	('expression', 'Species', '29278', (195, 205))
182027	31160689	Notably, co-overexpression of MDM2 and CDK4 decreased the expression of all adipogenesis-related genes, showing levels similar to those in LP6 cells (Fig.	('expression', 'Species', '29278', (58, 68))	('MDM2', 'Var', (30, 34))	('expression', 'MPA', (58, 68))	('adipogenesis-related', 'MPA', (76, 96))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('CDK4', 'Gene', (39, 43))	('expression', 'Species', '29278', (16, 26))	('decreased', 'NegReg', (44, 53))
182028	31160689	Collectively, these data suggest that co-expression of MDM2 and CDK4 blocks the differentiation of adipogenesis from the early to late stages.	('expression', 'Species', '29278', (41, 51))	('differentiation of adipogenesis', 'MPA', (80, 111))	('CDK4', 'Gene', (64, 68))	('co-expression', 'Var', (38, 51))	('blocks', 'NegReg', (69, 75))	('MDM2', 'Gene', (55, 59))
182029	31160689	To verify the in vivo tumorigenic potential of the transformed BMSCs, nude mice were subcutaneously inoculated with 2H and 5H cells co-overexpressing MDM2 and CDK4.	('CDK4', 'Gene', (159, 163))	('MDM2', 'Var', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('nude mice', 'Species', '10090', (70, 79))	('2H', 'Chemical', 'MESH:D006859', (116, 118))
182032	31160689	However, the 5H-MDM2 and CDK4 cells developed tumors larger than those observed in the LacZ control cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('CDK4', 'Var', (25, 29))	('tumors', 'Disease', (46, 52))	('5H-MDM2', 'Var', (13, 20))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
182037	31160689	The 5H-MDM2 and CDK4 cell-derived tumors exhibited more proliferative features with high cellularity and higher expression of Ki-67 than did the 5H-LacZ-derived tumors (Fig.	('5H-MDM2', 'Var', (4, 11))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', (161, 167))	('higher', 'PosReg', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('CDK4 cell-derived', 'Var', (16, 33))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('proliferative features', 'CPA', (56, 78))	('expression', 'Species', '29278', (112, 122))	('Ki-67', 'Gene', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('expression', 'MPA', (112, 122))
182040	31160689	These findings indicate that co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can result in the development of proliferative sarcoma with a DDLPS-like morphology in vivo.	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('MDM2', 'Gene', (50, 54))	('mutations', 'Var', (107, 116))	('LPS', 'Disease', 'MESH:D008080', (181, 184))	('proliferative sarcoma', 'Disease', (150, 171))	('CDK4', 'Gene', (59, 63))	('expression', 'Species', '29278', (36, 46))	('LPS', 'Phenotype', 'HP:0012034', (181, 184))	('LPS', 'Disease', (181, 184))	('proliferative sarcoma', 'Disease', 'MESH:D012509', (150, 171))	('result in', 'Reg', (121, 130))
182043	31160689	Although amplification and overexpression of MDM2 and CDK4 are hallmark events of WDLPS/DDLPS, whether MDM2 and CDK4 drive WDLPS/DDLPS tumorigenesis remains unclear.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('LPS', 'Disease', (125, 128))	('expression', 'Species', '29278', (31, 41))	('LPS', 'Disease', (84, 87))	('LPS', 'Disease', (90, 93))	('LPS', 'Disease', (131, 134))	('overexpression', 'PosReg', (27, 41))	('amplification', 'Var', (9, 22))	('LPS', 'Phenotype', 'HP:0012034', (125, 128))	('tumor', 'Disease', (135, 140))	('LPS', 'Phenotype', 'HP:0012034', (84, 87))	('LPS', 'Disease', 'MESH:D008080', (125, 128))	('LPS', 'Disease', 'MESH:D008080', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('LPS', 'Phenotype', 'HP:0012034', (90, 93))	('LPS', 'Phenotype', 'HP:0012034', (131, 134))	('CDK4', 'Gene', (54, 58))	('LPS', 'Disease', 'MESH:D008080', (90, 93))	('MDM2', 'Gene', (45, 49))	('LPS', 'Disease', 'MESH:D008080', (131, 134))
182047	31160689	However, the genetic introduction of tumor-suppressor genes such as TP53 and RB, and other oncogenes, such as the SV40 T antigen and HRAS, promoted BMSC transformation.	('SV40', 'Species', '1891767', (114, 118))	('promoted', 'PosReg', (139, 147))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('SV40', 'Var', (114, 118))	('TP53', 'Gene', '7157', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('BMSC transformation', 'CPA', (148, 167))	('TP53', 'Gene', (68, 72))
182050	31160689	According to a study by Taylor et al., HDAC1, MAPKAP1, PTPN9, and DAZAP2 were mutated in DDLPS tissue samples by next-generation sequencing analysis.	('PTPN9', 'Gene', '5780', (55, 60))	('HDAC1', 'Gene', (39, 44))	('MAPKAP1', 'Gene', (46, 53))	('HDAC1', 'Gene', '3065', (39, 44))	('PTPN9', 'Gene', (55, 60))	('LPS', 'Phenotype', 'HP:0012034', (91, 94))	('LPS', 'Disease', (91, 94))	('MAPKAP1', 'Gene', '79109', (46, 53))	('mutated', 'Var', (78, 85))	('DAZAP2', 'Gene', (66, 72))	('LPS', 'Disease', 'MESH:D008080', (91, 94))	('DAZAP2', 'Gene', '9802', (66, 72))
182055	31160689	Here, 2H cells with two oncogenic hits, TERT and HPV-16 E6 (TP53 degradation), did not develop into tumors, while 5H cells harboring three additional oncogenic hits, HPV-16 E7 (RB family inactivation), SV40-ST (c-MYC stabilization), and HRASv12 (mitogenic signal activation), generated tumors in vivo.	('c-MYC', 'Gene', '4609', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumors', 'Disease', (286, 292))	('c-MYC', 'Gene', (211, 216))	('SV40-ST', 'Var', (202, 209))	('TP53', 'Gene', (60, 64))	('HRASv12', 'Var', (237, 244))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('SV40', 'Species', '1891767', (202, 206))	('HPV-16', 'Species', '333760', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (100, 106))	('TP53', 'Gene', '7157', (60, 64))	('TERT', 'Gene', (40, 44))	('TERT', 'Gene', '7015', (40, 44))	('HPV-16', 'Species', '333760', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('2H', 'Chemical', 'MESH:D006859', (6, 8))
182059	31160689	Thus, our model showed that co-expression of MDM2 and CDK4 in transformed human BMSCs increases the tendency of high-grade sarcoma with a DDLPS-like morphology.	('human', 'Species', '9606', (74, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('LPS', 'Phenotype', 'HP:0012034', (140, 143))	('LPS', 'Disease', 'MESH:D008080', (140, 143))	('increases', 'PosReg', (86, 95))	('CDK4', 'Gene', (54, 58))	('expression', 'Species', '29278', (31, 41))	('co-expression', 'Var', (28, 41))	('MDM2', 'Gene', (45, 49))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('LPS', 'Disease', (140, 143))	('sarcoma', 'Disease', (123, 130))
182061	31160689	MDM2 and CDK4 overexpression through gene amplification is an early event in liposarcoma tumorigenesis.	('CDK4', 'Gene', (9, 13))	('liposarcoma', 'Disease', (77, 88))	('expression', 'Species', '29278', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('liposarcoma', 'Phenotype', 'HP:0012034', (77, 88))	('liposarcoma', 'Disease', 'MESH:D008080', (77, 88))	('MDM2', 'Gene', (0, 4))	('gene amplification', 'Var', (37, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('overexpression', 'PosReg', (14, 28))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
182062	31160689	However, it was reported that increased MDM2 amplification was closely associated with histological grade in liposarcomas.	('MDM2', 'Gene', (40, 44))	('liposarcomas', 'Disease', 'MESH:D008080', (109, 121))	('liposarcomas', 'Phenotype', 'HP:0012034', (109, 121))	('liposarcoma', 'Phenotype', 'HP:0012034', (109, 120))	('liposarcomas', 'Disease', (109, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('increased', 'PosReg', (30, 39))	('associated', 'Reg', (71, 81))	('amplification', 'Var', (45, 58))
182063	31160689	We previously reported that the high CDK4 amplification group exhibited significantly poorer prognosis relative to the low CDK4 amplification group in human WDLPS and DDLPS.	('high', 'Var', (32, 36))	('LPS', 'Phenotype', 'HP:0012034', (159, 162))	('LPS', 'Disease', (159, 162))	('LPS', 'Phenotype', 'HP:0012034', (169, 172))	('LPS', 'Disease', (169, 172))	('human', 'Species', '9606', (151, 156))	('CDK4', 'Gene', (37, 41))	('LPS', 'Disease', 'MESH:D008080', (159, 162))	('poorer', 'NegReg', (86, 92))	('LPS', 'Disease', 'MESH:D008080', (169, 172))
182074	31160689	In summary, co-overexpression of MDM2 and CDK4 causes high-grade sarcoma with a DDLLPS-like morphology in transformed human BMSCs by accelerating cell growth and migration, and the blockage of adipogenic potential, after cooperation with multiple genetic factors.	('MDM2', 'Gene', (33, 37))	('LPS', 'Disease', (83, 86))	('cell growth', 'CPA', (146, 157))	('sarcoma', 'Disease', (65, 72))	('causes', 'Reg', (47, 53))	('CDK4', 'Gene', (42, 46))	('accelerating', 'PosReg', (133, 145))	('LPS', 'Phenotype', 'HP:0012034', (83, 86))	('adipogenic potential', 'MPA', (193, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('LPS', 'Disease', 'MESH:D008080', (83, 86))	('blockage', 'NegReg', (181, 189))	('human', 'Species', '9606', (118, 123))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('co-overexpression', 'Var', (12, 29))	('expression', 'Species', '29278', (19, 29))
182076	30680066	Chromosomal translocation t(X;18)(p11;q11) results in the formation of SS18/SSX by gene fusion of the SS18 gene on chromosome 18 to either SSX1, SSX2, or SSX4 gene located on chromosome X, which is detected in more than 95% of SSs.	('SSX', 'Gene', '6757', (154, 157))	('SSX', 'Gene', '6757', (145, 148))	('SSX', 'Gene', '6757', (76, 79))	('SSX', 'Gene', '6757', (139, 142))	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('SSX', 'Gene', (154, 157))	('SSX1', 'Gene', '6756', (139, 143))	('SSX', 'Gene', (145, 148))	('SSX', 'Gene', (76, 79))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (26, 42))	('SSX1', 'Gene', (139, 143))	('SSX', 'Gene', (139, 142))	('SS', 'Phenotype', 'HP:0012570', (102, 104))	('SSX4', 'Gene', (154, 158))	('SS18', 'Gene', (102, 106))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('SS', 'Phenotype', 'HP:0012570', (139, 141))	('SSX2', 'Gene', (145, 149))	('SSX4', 'Gene', '6759', (154, 158))	('gene fusion', 'Var', (83, 94))	('SSX2', 'Gene', '6757', (145, 149))	('SS', 'Phenotype', 'HP:0012570', (145, 147))
182079	30680066	Isobaric tags for relative and absolute quantitation (i-TRAQ) analyses identified approximate 1700-2,000 proteins regulated by the SS18/SSX fusion in each SS cell line.	('SS', 'Phenotype', 'HP:0012570', (136, 138))	('fusion', 'Var', (140, 146))	('SSX', 'Gene', '6757', (136, 139))	('proteins', 'Protein', (105, 113))	('SSX', 'Gene', (136, 139))	('SS', 'Phenotype', 'HP:0012570', (131, 133))	('SS', 'Phenotype', 'HP:0012570', (155, 157))
182083	30680066	In addition, we found that expression of TAGLN inhibited cell viability in SS cell lines.	('TAGLN', 'Gene', (41, 46))	('inhibited', 'NegReg', (47, 56))	('TAGLN', 'Gene', '6876', (41, 46))	('cell viability in', 'CPA', (57, 74))	('expression', 'Var', (27, 37))	('SS', 'Phenotype', 'HP:0012570', (75, 77))
182089	30680066	SS is characterized by recurrent chromosomal translocation of t(X;18)(p11.2;q11.2), which results in the fusion of the SS18 gene on chromosome 18 to either SSX1, SSX2 or SSX4 gene located on chromosome X, giving the fusion protein product SS18/SSX.	('SS', 'Phenotype', 'HP:0012570', (170, 172))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (23, 58))	('SSX', 'Gene', '6757', (156, 159))	('SSX', 'Gene', (244, 247))	('SSX1', 'Gene', '6756', (156, 160))	('SSX', 'Gene', '6757', (162, 165))	('SSX1', 'Gene', (156, 160))	('SSX', 'Gene', (156, 159))	('SSX', 'Gene', '6757', (170, 173))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (62, 82))	('SS', 'Phenotype', 'HP:0012570', (119, 121))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SS18', 'Gene', (119, 123))	('SSX2', 'Gene', (162, 166))	('SSX4', 'Gene', (170, 174))	('fusion', 'Var', (105, 111))	('SSX', 'Gene', (162, 165))	('SSX', 'Gene', (170, 173))	('SSX2', 'Gene', '6757', (162, 166))	('SSX4', 'Gene', '6759', (170, 174))	('SS', 'Phenotype', 'HP:0012570', (156, 158))	('SS', 'Phenotype', 'HP:0012570', (162, 164))	('SSX', 'Gene', '6757', (244, 247))
182091	30680066	Multiple lines of evidence have suggested that the SS18/SSX fusion is an oncogene and the central genetic "driver" in SS; (i) its presence as a sole cytogenetic anomaly in up to one-third of cases, (ii) the low frequency of additional mutations, (iii) its preservation in metastatic and advanced lesions, (iv) the death of synovial sarcoma cells upon SS18/SSX knockdown, and (v) its ability to induce tumors in conditional mouse models with appropriate histology, gene expression, and immunophenotype with 100% penetrance.	('SSX', 'Gene', (56, 59))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (323, 339))	('SSX', 'Gene', (356, 359))	('SS', 'Phenotype', 'HP:0012570', (56, 58))	('tumors', 'Phenotype', 'HP:0002664', (401, 407))	('SS', 'Phenotype', 'HP:0012570', (356, 358))	('anomaly', 'Disease', 'MESH:D000014', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('knockdown', 'Var', (360, 369))	('SS', 'Phenotype', 'HP:0012570', (118, 120))	('death of synovial sarcoma', 'Disease', 'MESH:D013584', (314, 339))	('sarcoma', 'Phenotype', 'HP:0100242', (332, 339))	('tumors', 'Disease', (401, 407))	('SSX', 'Gene', '6757', (56, 59))	('anomaly', 'Disease', (161, 168))	('tumors', 'Disease', 'MESH:D009369', (401, 407))	('induce', 'Reg', (394, 400))	('mouse', 'Species', '10090', (423, 428))	('SSX', 'Gene', '6757', (356, 359))	('SS', 'Phenotype', 'HP:0012570', (351, 353))	('SS', 'Phenotype', 'HP:0012570', (51, 53))	('death of synovial sarcoma', 'Disease', (314, 339))
182105	30680066	In the SS cells with knockdown of SS18/SSX (Figure 1 and Supplementary Tables 1-3), analyses showed 33 downregulated proteins associated with SS18/SSX knockdown in HS-SYII, 36 in YaFuSS, and 34 in SYO-1 (p < 0.05).	('SS', 'Phenotype', 'HP:0012570', (39, 41))	('HS-SY', 'CellLine', 'CVCL:8719', (164, 169))	('SSX', 'Gene', '6757', (39, 42))	('proteins', 'Protein', (117, 125))	('SSX', 'Gene', (39, 42))	('SSX', 'Gene', '6757', (147, 150))	('SYO-1', 'Gene', '55027', (197, 202))	('SS', 'Phenotype', 'HP:0012570', (34, 36))	('downregulated', 'NegReg', (103, 116))	('SSX', 'Gene', (147, 150))	('SS', 'Phenotype', 'HP:0012570', (147, 149))	('SYO-1', 'Gene', (197, 202))	('SS', 'Phenotype', 'HP:0012570', (7, 9))	('SS', 'Phenotype', 'HP:0012570', (142, 144))	('knockdown', 'Var', (151, 160))
182106	30680066	Furthermore, analyses showed 72 upregulated proteins associated with SS18/SSX knockdown in HS-SYII, 44 in YaFuSS, and 46 in SYO-1 (p < 0.05).	('SYO-1', 'Gene', '55027', (124, 129))	('SSX', 'Gene', '6757', (74, 77))	('knockdown', 'Var', (78, 87))	('SSX', 'Gene', (74, 77))	('SS', 'Phenotype', 'HP:0012570', (74, 76))	('SYO-1', 'Gene', (124, 129))	('SS', 'Phenotype', 'HP:0012570', (110, 112))	('proteins', 'Protein', (44, 52))	('SS', 'Phenotype', 'HP:0012570', (69, 71))	('HS-SY', 'CellLine', 'CVCL:8719', (91, 96))	('upregulated', 'PosReg', (32, 43))
182109	30680066	We conducted analyses using the proteins associated with SS18/SSX knockdown in SS cell lines.	('SS', 'Phenotype', 'HP:0012570', (57, 59))	('SS', 'Phenotype', 'HP:0012570', (62, 64))	('SSX', 'Gene', '6757', (62, 65))	('SS', 'Phenotype', 'HP:0012570', (79, 81))	('SSX', 'Gene', (62, 65))	('knockdown', 'Var', (66, 75))
182110	30680066	In the network analyses based on the profiles of SS18/SSX knockdown in SS cells, we identified several pathways involving RUNX2 and SMARCA4 that played a critical functional role and acted as upstream regulators of these proteins known to be associated with the SYT/SSX expression in SS cells (Supplementary Tables 4 and Table 5).	('SS', 'Phenotype', 'HP:0012570', (54, 56))	('SS', 'Phenotype', 'HP:0012570', (266, 268))	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('RUNX2', 'Gene', (122, 127))	('SSX', 'Gene', '6757', (54, 57))	('SSX', 'Gene', '6757', (266, 269))	('SSX', 'Gene', (54, 57))	('SSX', 'Gene', (266, 269))	('SYT', 'Gene', '6760', (262, 265))	('SMARCA4', 'Gene', (132, 139))	('SMARCA4', 'Gene', '6597', (132, 139))	('RUNX2', 'Gene', '860', (122, 127))	('SS', 'Phenotype', 'HP:0012570', (49, 51))	('knockdown', 'Var', (58, 67))	('SYT', 'Gene', (262, 265))	('SS', 'Phenotype', 'HP:0012570', (284, 286))
182112	30680066	Regarding TAGLN, the cell lines subjected to siRNA SS18/SSX knockdown showed significantly higher TAGLN expression than control samples (Figure 2A).	('SSX', 'Gene', (56, 59))	('higher', 'PosReg', (91, 97))	('expression', 'MPA', (104, 114))	('knockdown', 'Var', (60, 69))	('TAGLN', 'Gene', (98, 103))	('TAGLN', 'Gene', '6876', (98, 103))	('SS', 'Phenotype', 'HP:0012570', (56, 58))	('SS', 'Phenotype', 'HP:0012570', (51, 53))	('TAGLN', 'Gene', (10, 15))	('SSX', 'Gene', '6757', (56, 59))	('TAGLN', 'Gene', '6876', (10, 15))
182113	30680066	Regarding ACTN4, the cell lines subjected to siRNA SS18/SSX knockdown had significantly higher mRNA levels of ACTN4 than control samples (Figure 2B).	('higher', 'PosReg', (88, 94))	('SSX', 'Gene', (56, 59))	('ACTN4', 'Gene', '81', (110, 115))	('ACTN4', 'Gene', (10, 15))	('mRNA levels', 'MPA', (95, 106))	('knockdown', 'Var', (60, 69))	('SS', 'Phenotype', 'HP:0012570', (56, 58))	('ACTN4', 'Gene', (110, 115))	('ACTN4', 'Gene', '81', (10, 15))	('SS', 'Phenotype', 'HP:0012570', (51, 53))	('SSX', 'Gene', '6757', (56, 59))
182118	30680066	These results indicated that our protein profiles and pathway analyses had correctly identified proteins and transcript pathways that were regulated by SS18/SSX fusion.	('proteins', 'Protein', (96, 104))	('regulated', 'Reg', (139, 148))	('transcript pathways', 'Pathway', (109, 128))	('SS', 'Phenotype', 'HP:0012570', (157, 159))	('fusion', 'Var', (161, 167))	('SSX', 'Gene', (157, 160))	('SSX', 'Gene', '6757', (157, 160))	('SS', 'Phenotype', 'HP:0012570', (152, 154))
182122	30680066	These results revealed that silencing SS18/SSX suppressed SS cell growth in part via activation of TAGLN expression.	('suppressed', 'NegReg', (47, 57))	('SS', 'Phenotype', 'HP:0012570', (43, 45))	('SSX', 'Gene', (43, 46))	('SS', 'Phenotype', 'HP:0012570', (38, 40))	('SSX', 'Gene', '6757', (43, 46))	('activation', 'PosReg', (85, 95))	('SS', 'Phenotype', 'HP:0012570', (58, 60))	('TAGLN', 'Gene', (99, 104))	('silencing', 'Var', (28, 37))	('SS cell growth', 'CPA', (58, 72))	('TAGLN', 'Gene', '6876', (99, 104))
182134	30680066	TAGLN demonstrated the highest fold changes in our protein profile regulated by silencing SS18/SSX.	('SSX', 'Gene', '6757', (95, 98))	('silencing', 'Var', (80, 89))	('SS', 'Phenotype', 'HP:0012570', (95, 97))	('SSX', 'Gene', (95, 98))	('protein profile', 'MPA', (51, 66))	('SS', 'Phenotype', 'HP:0012570', (90, 92))	('TAGLN', 'Gene', (0, 5))	('TAGLN', 'Gene', '6876', (0, 5))
182142	30680066	In addition, in our confirmation studies using qPCR, silencing of SS18/SSX in SS activated the mRNA expression of TAGLN, which suppressed cell proliferation in SS cell lines.	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('SSX', 'Gene', (71, 74))	('mRNA expression', 'MPA', (95, 110))	('TAGLN', 'Gene', (114, 119))	('SSX', 'Gene', '6757', (71, 74))	('SS', 'Phenotype', 'HP:0012570', (160, 162))	('cell proliferation in', 'CPA', (138, 159))	('SS', 'Phenotype', 'HP:0012570', (78, 80))	('suppressed', 'NegReg', (127, 137))	('activated', 'PosReg', (81, 90))	('TAGLN', 'Gene', '6876', (114, 119))	('SS', 'Phenotype', 'HP:0012570', (66, 68))	('silencing', 'Var', (53, 62))
182145	30680066	found that ACTN4, which our protein profiling also identified as upregulated by silencing SS18/SSX, reduced the malignant potential in SS.	('SSX', 'Gene', '6757', (95, 98))	('silencing', 'Var', (80, 89))	('SS', 'Phenotype', 'HP:0012570', (95, 97))	('SSX', 'Gene', (95, 98))	('reduced', 'NegReg', (100, 107))	('ACTN4', 'Gene', (11, 16))	('malignant potential in', 'CPA', (112, 134))	('ACTN4', 'Gene', '81', (11, 16))	('SS', 'Phenotype', 'HP:0012570', (90, 92))	('upregulated', 'PosReg', (65, 76))	('SS', 'Phenotype', 'HP:0012570', (135, 137))
182148	30680066	In addition, ACTN4 is found in the membrane ruffles, and the inhibition of PI3 kinase (PI3K) promotes ACTN4 nuclear translocation in breast cancer and several cancer cell lines.	('cancer', 'Disease', (159, 165))	('breast cancer', 'Disease', (133, 146))	('ACTN4', 'Gene', (102, 107))	('ACTN4', 'Gene', (13, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('inhibition', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (140, 146))	('ACTN4', 'Gene', '81', (13, 18))	('ACTN4', 'Gene', '81', (102, 107))	('nuclear translocation', 'MPA', (108, 129))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('promotes', 'PosReg', (93, 101))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
182153	30680066	In addition, while other gene expression studies on silencing SS18/SSX in SS cells identified COM1 as a critical gene regulated by SS18/SSX and functioning as a cell proliferation regulator in SS, our protein profiling didn't identify show that COM1 was such an abundant protein.	('SS', 'Phenotype', 'HP:0012570', (67, 69))	('SSX', 'Gene', (67, 70))	('COM1', 'Gene', (94, 98))	('COM1', 'Gene', (245, 249))	('silencing', 'Var', (52, 61))	('COM1', 'Gene', '26471', (245, 249))	('SS', 'Phenotype', 'HP:0012570', (136, 138))	('SS', 'Phenotype', 'HP:0012570', (74, 76))	('SS', 'Phenotype', 'HP:0012570', (62, 64))	('SSX', 'Gene', '6757', (136, 139))	('SSX', 'Gene', (136, 139))	('SS', 'Phenotype', 'HP:0012570', (131, 133))	('COM1', 'Gene', '26471', (94, 98))	('SSX', 'Gene', '6757', (67, 70))
182160	30680066	Regarding SMARCA4, the SWI/SNF (BAF) complex includes SMARCA4, and the epigenetic modification of SS18/SSX alters the chromatin remodeling via epigenetic alterations through SWI/SNF(BAF)- and histone deacetylase (HDAC)-associated mechanisms.	('SMARCA4', 'Gene', '6597', (54, 61))	('BAF', 'Gene', (182, 185))	('BAF', 'Gene', '8815', (182, 185))	('SS', 'Phenotype', 'HP:0012570', (98, 100))	('BAF', 'Gene', '8815', (32, 35))	('SMARCA4', 'Gene', (10, 17))	('chromatin remodeling', 'MPA', (118, 138))	('alters', 'Reg', (107, 113))	('SMARCA4', 'Gene', '6597', (10, 17))	('epigenetic', 'MPA', (143, 153))	('SMARCA4', 'Gene', (54, 61))	('SS', 'Phenotype', 'HP:0012570', (103, 105))	('BAF', 'Gene', (32, 35))	('SSX', 'Gene', (103, 106))	('SSX', 'Gene', '6757', (103, 106))	('epigenetic modification', 'Var', (71, 94))
182161	30680066	Recently, Kadoch described the high-affinity binding of SS18/SSX fusion to the core subunits of the SWI/SNF (BAF) complex and SS18 and SS18/SSX incorporate into the core subunits of SWI/SNF (BAF) complex, by dissociating BAF47 from the complex, thereby releasing SNF5, a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('binding', 'Interaction', (45, 52))	('SSX', 'Gene', '6757', (61, 64))	('SSX', 'Gene', '6757', (140, 143))	('SS', 'Phenotype', 'HP:0012570', (56, 58))	('BAF', 'Gene', (221, 224))	('BAF47', 'Gene', (221, 226))	('SNF5', 'Gene', '6598', (263, 267))	('BAF', 'Gene', (109, 112))	('SS', 'Phenotype', 'HP:0012570', (135, 137))	('dissociating', 'NegReg', (208, 220))	('SS', 'Phenotype', 'HP:0012570', (126, 128))	('SSX', 'Gene', (61, 64))	('BAF', 'Gene', '8815', (191, 194))	('SSX', 'Gene', (140, 143))	('releasing', 'PosReg', (253, 262))	('SS', 'Phenotype', 'HP:0012570', (61, 63))	('SS', 'Phenotype', 'HP:0012570', (140, 142))	('BAF', 'Gene', '8815', (221, 224))	('tumor', 'Disease', (271, 276))	('SNF5', 'Gene', (263, 267))	('BAF47', 'Gene', '6598', (221, 226))	('BAF', 'Gene', '8815', (109, 112))	('SS18', 'Var', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('BAF', 'Gene', (191, 194))
182166	30680066	Therefore, based on these functional backgrounds, silencing of co-activator SS18/SSX picked up small amounts of regulated proteins compared to Ewing sarcoma and alveolar rhabdomyosarcoma having either EWS/FLI1 or PAX3/FOXO1 which act as transcriptional factors.	('EWS', 'Gene', (201, 204))	('SS', 'Phenotype', 'HP:0012570', (81, 83))	('FLI1', 'Gene', (205, 209))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (143, 156))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (143, 156))	('PAX3', 'Gene', (213, 217))	('alveolar rhabdomyosarcoma', 'Disease', (161, 186))	('SSX', 'Gene', '6757', (81, 84))	('FLI1', 'Gene', '2313', (205, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('PAX3', 'Gene', '5077', (213, 217))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (170, 186))	('FOXO1', 'Gene', '2308', (218, 223))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (161, 186))	('EWS', 'Gene', '2130', (201, 204))	('Ewing sarcoma', 'Disease', (143, 156))	('SSX', 'Gene', (81, 84))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (161, 186))	('silencing', 'Var', (50, 59))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('FOXO1', 'Gene', (218, 223))
182181	30680066	The membranes were then incubated with either of the following antibodies: rabbit monoclonal antibodies against SS18/SSX (#70929, dilution 1:200; Cell Signaling, Danvers, MA, USA) or mouse monoclonal antibody against GAPDH (#sc-32233, dilution 1: 500; Santa Cruz, Dallas, TX, USA).	('SS', 'Phenotype', 'HP:0012570', (112, 114))	('GAPDH', 'Gene', '2597', (217, 222))	('GAPDH', 'Gene', (217, 222))	('#sc-32233', 'Var', (224, 233))	('rabbit', 'Species', '9986', (75, 81))	('SS', 'Phenotype', 'HP:0012570', (117, 119))	('mouse', 'Species', '10090', (183, 188))	('#70929', 'Var', (122, 128))	('SSX', 'Gene', (117, 120))	('SSX', 'Gene', '6757', (117, 120))
182204	29765618	Fluorescence in situ hybridization studies showed rearrangement of SS18 locus (SYT gene) at 18q:11.2 chromosome within spindle cells pericytomatous blood vessels are present.	('SYT', 'Gene', (79, 82))	('SYT', 'Gene', '6760', (79, 82))	('SS18', 'Gene', (67, 71))	('rearrangement', 'Var', (50, 63))	('SS18', 'Gene', '6760', (67, 71))
182217	29765618	Genetic identification of t(X:18) translocation involving SYT gene on chromosome 18 and the SSX1 or SSX2 gene on the X chromosome, specific for synovial sarcoma is found in over 90% of patients.	('translocation', 'Var', (34, 47))	('synovial sarcoma', 'Disease', 'MESH:D013584', (144, 160))	('SSX1', 'Gene', (92, 96))	('SYT', 'Gene', '6760', (58, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('synovial sarcoma', 'Disease', (144, 160))	('SSX2', 'Gene', '6757', (100, 104))	('SYT', 'Gene', (58, 61))	('patients', 'Species', '9606', (185, 193))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (144, 160))	('SSX2', 'Gene', (100, 104))	('SSX1', 'Gene', '6756', (92, 96))
182233	23956055	Preclinical data suggest that inhibition of the IGF-IR may constitute an important therapeutic target in a variety of pediatric solid tumors, including rhabdomyosarcoma, neuroblastoma and Wilms tumor.	('rhabdomyosarcoma', 'Disease', (152, 168))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('neuroblastoma', 'Disease', (170, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('inhibition', 'Var', (30, 40))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (152, 168))	('Wilms tumor', 'Disease', (188, 199))	('Wilms tumor', 'Disease', 'MESH:D009396', (188, 199))	('Wilms tumor', 'Phenotype', 'HP:0002667', (188, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('IGF-IR', 'Gene', (48, 54))	('pediatric solid tumors', 'Disease', (118, 140))	('neuroblastoma', 'Phenotype', 'HP:0003006', (170, 183))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (152, 168))	('IGF-IR', 'Gene', '3480', (48, 54))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (118, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('neuroblastoma', 'Disease', 'MESH:D009447', (170, 183))
182235	23956055	In preclinical cancer models, cixutumumab has single-agent activity and potentiates the effect of cytotoxic therapy in vitro and in vivo.	('potentiates', 'PosReg', (72, 83))	('cixutumumab', 'Var', (30, 41))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cixutumumab', 'Chemical', 'MESH:C557414', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
182236	23956055	When evaluated by the Pediatric Preclinical Testing Program, cixutumumab demonstrated single-agent activity in osteosarcoma, Ewing sarcoma (ES), neuroblastoma, glioblastoma, and rhabdomyosarcoma models.	('neuroblastoma', 'Disease', (145, 158))	('neuroblastoma', 'Phenotype', 'HP:0003006', (145, 158))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (178, 194))	('neuroblastoma', 'Disease', 'MESH:D009447', (145, 158))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (178, 194))	('cixutumumab', 'Var', (61, 72))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('cixutumumab', 'Chemical', 'MESH:C557414', (61, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('ES', 'Phenotype', 'HP:0012254', (140, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('glioblastoma', 'Disease', (160, 172))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('rhabdomyosarcoma', 'Disease', (178, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('osteosarcoma', 'Disease', (111, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (111, 123))	('Ewing sarcoma', 'Disease', (125, 138))
182313	23956055	In addition, there are several ongoing phase 1 and 2 combination studies of IGFR inhibitors in adults with a variety of solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('inhibitors', 'Var', (81, 91))	('IGFR', 'Gene', (76, 80))	('solid tumors', 'Disease', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('IGFR', 'Gene', '3480', (76, 80))
182325	21907493	Non-brain directed scatter irradiation was associated with elevated risk for migraines and cancer-related pain attribution.	('pain', 'Disease', (106, 110))	('migraine', 'Phenotype', 'HP:0002076', (77, 85))	('migraines', 'Disease', (77, 86))	('Non-brain', 'Var', (0, 9))	('cancer', 'Disease', (91, 97))	('migraines', 'Disease', 'MESH:D008881', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('pain', 'Phenotype', 'HP:0012531', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('migraines', 'Phenotype', 'HP:0002076', (77, 86))	('pain', 'Disease', 'MESH:D010146', (106, 110))
182408	21907493	In a separate model with all factors except diagnosis, survivors who received scatter radiation were more likely to report pain attributed to cancer or its treatment compared to those who did not receive any radiation (Table 4b).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('scatter radiation', 'Var', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pain', 'Phenotype', 'HP:0012531', (123, 127))	('pain', 'Disease', 'MESH:D010146', (123, 127))	('pain', 'Disease', (123, 127))	('cancer', 'Disease', (142, 148))
182420	21907493	Lower income was associated with great risk of using prescription pain medication and attributing pain to cancer.	('pain', 'Phenotype', 'HP:0012531', (66, 70))	('pain', 'Disease', 'MESH:D010146', (66, 70))	('pain', 'Disease', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('Lower income', 'Var', (0, 12))	('pain', 'Phenotype', 'HP:0012531', (98, 102))	('cancer', 'Disease', (106, 112))	('pain', 'Disease', 'MESH:D010146', (98, 102))	('pain', 'Disease', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
182478	33578934	Corresponding International Classification of Diseases codes C40, C41, C45, C46, C47, C48, C49, and the keyword "induced" were used.	('C45', 'Var', (71, 74))	('C47', 'Var', (81, 84))	('C48', 'Gene', (86, 89))	('C46', 'Var', (76, 79))	('C40', 'Gene', (61, 64))	('C49', 'Var', (91, 94))	('C40', 'Gene', '55571', (61, 64))	('C41', 'Var', (66, 69))	('C48', 'Gene', '55755', (86, 89))
182513	33578934	Interestingly, in the current study, RIS localized in the breast and upper extremities were associated with a lower risk of death.	('death', 'Disease', (124, 129))	('RIS localized', 'Var', (37, 50))	('death', 'Disease', 'MESH:D003643', (124, 129))
182515	33578934	However, in our series, obtained surgical margins did not affect patients' survival; whereas, in the aforementioned cohorts, gross positive resection margin was predictive for poorer survival.	('poorer', 'NegReg', (176, 182))	('gross positive', 'Var', (125, 139))	('patients', 'Species', '9606', (65, 73))
182555	30120284	It can be applied to study among others the nucleic acid strands (1000-1250 cm-1), proteins (1500-1560 cm-1, 1600-1700 cm-1), lipids (2800-3000 cm-1) as well as inorganic structures as phosphates (460-1120 cm-1).	('1000-1250 cm-1', 'Var', (66, 80))	('2800-3000 cm-1', 'Var', (134, 148))	('phosphates', 'Chemical', 'MESH:D010710', (185, 195))	('1500-1560 cm-1', 'Var', (93, 107))	('lipids', 'Chemical', 'MESH:D008055', (126, 132))	('460-1120 cm-1', 'Var', (197, 210))
182592	30120284	According to this Analysis we established the following cut-off values: Tb >= 1027 cm-1, Tt - Tb < + 1 cm-1 (what is equal with the shift of the maximum peak wavenumber after neo-CTx to the left or up to 1 cm-1 to the right) and Tb - Tn >= -1 cm-1 (the shift of the normal bone tissue peak to the right or up to 1 cm -1 to the left of the Tb position).	('Tb', 'Chemical', '-', (229, 231))	('Tt - Tb', 'Gene', (89, 96))	('neo-CTx', 'Chemical', '-', (175, 182))	('Tb', 'Chemical', '-', (339, 341))	('>= 1027 cm-1', 'Var', (75, 87))	('Tb', 'Chemical', '-', (72, 74))	('Tb - Tn', 'Chemical', '-', (229, 236))	('Tb', 'Chemical', '-', (94, 96))	('Tb < + 1 cm-1', 'Var', (94, 107))	('Tt - Tb', 'Chemical', '-', (89, 96))
182596	30120284	100% of patients with Tb >= 1027 cm-1 (n = 15) had progressed or relapsed during the 3 yrs follow up period compared to 82% progression-free survival in patients with Tb < 1027 cm-1 in this period (n = 12; log-rank p = 0.00058).	('Tb', 'Chemical', '-', (167, 169))	('patients', 'Species', '9606', (153, 161))	('Tb', 'Chemical', '-', (22, 24))	('Tb >= 1027 cm-1', 'Var', (22, 37))	('relapsed', 'CPA', (65, 73))	('patients', 'Species', '9606', (8, 16))
182629	29512865	In a family in which 2 carrier children had germline SMARCB1 mutations and atypical teratoid rhabdoid tumor, we report malignant progression of a nerve sheath tumor over a 7-year period in an affected adult family member.	('teratoid rhabdoid tumor', 'Disease', 'MESH:C000597569', (84, 107))	('malignant progression', 'CPA', (119, 140))	('nerve sheath tumor', 'Disease', (146, 164))	('malignant progression of a nerve sheath tumor', 'Phenotype', 'HP:0100697', (119, 164))	('children', 'Species', '9606', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutations', 'Var', (61, 70))	('SMARCB1', 'Gene', (53, 60))	('nerve sheath tumor', 'Disease', 'MESH:D010524', (146, 164))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('teratoid rhabdoid tumor', 'Disease', (84, 107))
182630	29512865	Prompt identification of the germline SMARCB1 alteration and the resultant rhabdoid tumor predisposition syndrome can help guide genetic counseling and surveillance in affected family members.	('alteration', 'Var', (46, 56))	('rhabdoid tumor', 'Disease', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('SMARCB1', 'Gene', (38, 45))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (75, 89))
182631	29512865	Somatic alterations of the SMARCB1 gene on chromosome 22q11.2, a core component of the SWI/SNF family of chromatin remodeling complexes, occur in various cancers, including atypical teratoid rhabdoid tumor (ATRT).	('SMARCB1', 'Gene', (27, 34))	('teratoid rhabdoid tumor', 'Disease', (182, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('occur', 'Reg', (137, 142))	('teratoid rhabdoid tumor', 'Disease', 'MESH:C000597569', (182, 205))	('alterations', 'Var', (8, 19))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
182632	29512865	About a third of the patients with rhabdoid tumors (RTs) have heterozygous SMARCB1 germline alteration, leading to rhabdoid tumor predisposition syndrome type I (RTPS1) and increased risk of multifocal and/or familial RTs.	('syndrome type I', 'Disease', (145, 160))	('alteration', 'Var', (92, 102))	('leading to', 'Reg', (104, 114))	('familial RTs', 'Disease', (209, 221))	('RTPS1', 'Gene', '6598', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SMARCB1', 'Gene', (75, 82))	('syndrome type I', 'Disease', 'MESH:D005776', (145, 160))	('patients', 'Species', '9606', (21, 29))	('multifocal', 'Disease', (191, 201))	('rhabdoid tumors', 'Disease', (35, 50))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (35, 49))	('RTPS1', 'Gene', (162, 167))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (35, 50))	('rhabdoid tumor', 'Disease', (115, 129))
182633	29512865	Germline SMARCB1 alterations are also associated with familial schwannomatosis and more aggressive malignancies (e.g., soft tissue or nerve sheath sarcomas).	('associated', 'Reg', (38, 48))	('nerve sheath sarcomas', 'Disease', 'MESH:D010524', (134, 155))	('SMARCB1', 'Gene', (9, 16))	('aggressive malignancies', 'Disease', (88, 111))	('nerve sheath sarcomas', 'Disease', (134, 155))	('aggressive malignancies', 'Disease', 'MESH:D009369', (88, 111))	('familial schwannomatosis', 'Disease', (54, 78))	('soft tissue', 'Disease', (119, 130))	('schwannoma', 'Phenotype', 'HP:0100008', (63, 73))	('alterations', 'Var', (17, 28))	('familial schwannomatosis', 'Disease', 'MESH:C536641', (54, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
182634	29512865	We report ATRT in two children and a peripheral nerve sheath tumor in an adult of a family with a germline SMARCB1 mutation.	('mutation', 'Var', (115, 123))	('SMARCB1', 'Gene', (107, 114))	('peripheral nerve sheath tumor', 'Disease', (37, 66))	('children', 'Species', '9606', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('peripheral nerve sheath tumor', 'Disease', 'MESH:D010524', (37, 66))
182639	29512865	Germline testing of peripheral blood in a commercial lab revealed a pathogenic heterozygous splicing mutation in exon 7 of SMARCB1 (c.986G>C; RefSeq: NM_003073.3).	('c.986G>C', 'Mutation', 'c.986G>C', (132, 140))	('c.986G>C;', 'Var', (132, 141))	('pathogenic', 'Reg', (68, 78))	('SMARCB1', 'Gene', (123, 130))
182650	29512865	Next-generation sequencing and copy number analysis of the tumor at progression by Foundation One Medicine revealed the germline SMARCB1 alteration, a KRAS G12R mutation, and an EWSR1-RHBDD3 fusion with no NF-1 and NF-2 gene alterations.	('NF-1', 'Gene', '4763', (206, 210))	('KRAS', 'Gene', '3845', (151, 155))	('tumor', 'Disease', (59, 64))	('EWSR1', 'Gene', '2130', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('NF-1', 'Gene', (206, 210))	('alteration', 'Var', (137, 147))	('SMARCB1', 'Gene', (129, 136))	('RHBDD3', 'Gene', '25807', (184, 190))	('NF-2', 'Gene', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('KRAS', 'Gene', (151, 155))	('NF-2', 'Gene', '4771', (215, 219))	('G12R', 'Mutation', 'rs121913530', (156, 160))	('RHBDD3', 'Gene', (184, 190))	('EWSR1', 'Gene', (178, 183))
182653	29512865	Subsequent evaluation of our patient's maternal aunt and her child (patient's first cousin) revealed the same germline SMARCB1 mutation (Fig.	('patient', 'Species', '9606', (29, 36))	('patient', 'Species', '9606', (68, 75))	('mutation', 'Var', (127, 135))	('child', 'Species', '9606', (61, 66))	('SMARCB1', 'Gene', (119, 126))
182656	29512865	Germline SMARCB1 alterations are detected in patients with RTPS1 and some patients with familial schwannomatosis.	('SMARCB1', 'Gene', (9, 16))	('patients', 'Species', '9606', (74, 82))	('schwannoma', 'Phenotype', 'HP:0100008', (97, 107))	('detected', 'Reg', (33, 41))	('RTPS1', 'Gene', (59, 64))	('familial schwannomatosis', 'Disease', (88, 112))	('patients', 'Species', '9606', (45, 53))	('alterations', 'Var', (17, 28))	('familial schwannomatosis', 'Disease', 'MESH:C536641', (88, 112))	('RTPS1', 'Gene', '6598', (59, 64))
182657	29512865	In families with RTPS, some members develop a benign tumor-like schwannoma whereas others develop more malignant tumors (e.g., sarcomas or RTs), which highlights incomplete penetrance and variable expressivity of this germline alteration and the phenotypic overlap between RTPS and schwannomatosis.	('benign tumor', 'Disease', 'MESH:D009369', (46, 58))	('schwannoma', 'Disease', 'MESH:D009442', (64, 74))	('sarcomas', 'Disease', (127, 135))	('schwannoma', 'Disease', (282, 292))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('benign tumor', 'Disease', (46, 58))	('schwannomatosis', 'Disease', (282, 297))	('schwannomatosis', 'Disease', 'MESH:C536641', (282, 297))	('schwannoma', 'Disease', 'MESH:D009442', (282, 292))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('schwannoma', 'Phenotype', 'HP:0100008', (64, 74))	('malignant tumors', 'Disease', 'MESH:D018198', (103, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('schwannoma', 'Disease', (64, 74))	('malignant tumors', 'Disease', (103, 119))	('sarcomas', 'Disease', 'MESH:D012509', (127, 135))	('schwannoma', 'Phenotype', 'HP:0100008', (282, 292))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('RTPS', 'Var', (17, 21))
182658	29512865	A SMARCB1 mutation carrier may thus pass through the developmental window wherein RT risk is highest, without developing RT, but later develop other malignancies.	('malignancies', 'Disease', (149, 161))	('SMARCB1', 'Gene', (2, 9))	('malignancies', 'Disease', 'MESH:D009369', (149, 161))	('mutation', 'Var', (10, 18))
182660	29512865	Germline SMARCB1 alterations associated with RT are typically truncating, spare exons 1,8, and 9, and include whole-gene deletions, nonsense mutations, and intragenic deletions/duplications, leading to complete loss of protein expression in the tumor.	('protein expression', 'MPA', (219, 237))	('deletions/duplications', 'Var', (167, 189))	('tumor', 'Disease', (245, 250))	('SMARCB1', 'Gene', (9, 16))	('loss', 'NegReg', (211, 215))	('nonsense mutations', 'Var', (132, 150))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('associated', 'Reg', (29, 39))	('alterations', 'Var', (17, 28))	('truncating', 'MPA', (62, 72))
182661	29512865	In contrast, non-truncating splice site and missense mutations predominantly affecting exon 1 and the 3' untranslated region occur in familial schwannomatosis.	('familial schwannomatosis', 'Disease', 'MESH:C536641', (134, 158))	('non-truncating splice site', 'Var', (13, 39))	('missense mutations', 'Var', (44, 62))	('schwannoma', 'Phenotype', 'HP:0100008', (143, 153))	('familial schwannomatosis', 'Disease', (134, 158))
182664	29512865	Hulsebos and colleagues also observed complete loss of tumor SMARCB1 expression in the presence of a germline SMARCB1 alteration and partial tumor LOH of SMARCB1 in their patient with papillary renal cell carcinoma.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('SMARCB1', 'Gene', (110, 117))	('patient', 'Species', '9606', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('loss of tumor', 'Disease', 'MESH:D009369', (47, 60))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (55, 60))	('expression', 'MPA', (69, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (194, 214))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (184, 214))	('SMARCB1', 'Gene', (61, 68))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (184, 214))	('loss of tumor', 'Disease', (47, 60))	('alteration', 'Var', (118, 128))	('papillary renal cell carcinoma', 'Disease', (184, 214))
182665	29512865	The splice donor site affected by germline mutation in the family we report is also reported in several other families with ATRT, with presumably the same pathogenic consequence of exon 7 skipping during mRNA transcription.	('germline mutation', 'Var', (34, 51))	('donor', 'Species', '9606', (11, 16))	('skipping', 'Var', (188, 196))
182666	29512865	These families include a patient with ATRT with germline mutation (c.986+2T>A), with no details of clinical and family history; a family in which 3 of 4 children had ATRT and the unaffected father had a c.986+1G>C mutation; and a family with posterior fossa brain tumors and an exon 7 donor splice site mutation.	('brain tumor', 'Phenotype', 'HP:0030692', (258, 269))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('c.986+1G>C', 'Mutation', 'rs112038099', (203, 213))	('posterior fossa brain tumors', 'Disease', (242, 270))	('children', 'Species', '9606', (153, 161))	('patient', 'Species', '9606', (25, 32))	('brain tumors', 'Phenotype', 'HP:0030692', (258, 270))	('c.986+1G>C', 'Var', (203, 213))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('posterior fossa brain tumors', 'Disease', 'MESH:D015192', (242, 270))	('c.986+2T>A', 'Mutation', 'c.986+2T>A', (67, 77))	('donor', 'Species', '9606', (285, 290))	('c.986+2T>A', 'Var', (67, 77))
182669	29512865	Activating Ras mutations are oncogenic in several cancers, and a recent study showed that aurora kinase A, a repressed target of SMARCB1, interacts with H-RAS to augment Ras-MAPK signaling.	('Ras-MAPK signaling', 'MPA', (170, 188))	('aurora kinase A, a', 'Gene', '6790', (90, 108))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('H-RAS', 'Gene', (153, 158))	('cancers', 'Disease', (50, 57))	('mutations', 'Var', (15, 24))	('augment', 'PosReg', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('interacts', 'Interaction', (138, 147))	('H-RAS', 'Gene', '3265', (153, 158))
182671	29512865	Although fusions involving EWSR1 can be oncogenic in Ewing sarcoma, the EWSR1-RHBDD3 fusion is not well characterized.	('EWSR1', 'Gene', (27, 32))	('EWSR1', 'Gene', (72, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('fusions', 'Var', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (53, 66))	('EWSR1', 'Gene', '2130', (27, 32))	('RHBDD3', 'Gene', '25807', (78, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('RHBDD3', 'Gene', (78, 84))	('EWSR1', 'Gene', '2130', (72, 77))	('Ewing sarcoma', 'Disease', (53, 66))
182679	29512865	In conclusion, our report highlights the important role of pediatric oncologists in early referral of a child with ATRT and the family for genetic counselling to identify germline SMARCB1 alterations, prompt screening for cancers and close surveillance.	('SMARCB1', 'Gene', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('alterations', 'Var', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('child', 'Species', '9606', (104, 109))
182720	29033609	As shown in Table 2, the AUC was 0.676 (95% confidence interval [CI] 0.585-0.758) for CRP/Alb ratio, 0.634 (95% CI 0.542-0.720) for GPS, 0.618 (95% CI 0.526-0.704) for NLR, 0.613 (95% CI 0.521-0.700) for PLR, 0.574 (95% CI 0.482-0.663) for LMR, and 0.571 (95% CI 0.478-0.660) for NPS.	('GPS', 'Disease', 'MESH:D055652', (132, 135))	('0.571', 'Var', (249, 254))	('0.618', 'Var', (137, 142))	('NPS', 'Disease', 'MESH:D009261', (280, 283))	('Alb', 'Gene', (90, 93))	('0.574', 'Var', (209, 214))	('NPS', 'Disease', (280, 283))	('0.634', 'Var', (101, 106))	('GPS', 'Disease', (132, 135))	('CRP', 'Gene', (86, 89))	('Alb', 'Gene', '213', (90, 93))	('CRP', 'Gene', '1401', (86, 89))
182823	30546886	The patient's history was significant for pT2a prostatic adenocarcinoma (Gleason score 7) in 2011 treated with external radiation therapy (70 Gy) and hormonal treatment six months.	('patient', 'Species', '9606', (4, 11))	('prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (47, 71))	('prostatic adenocarcinoma', 'Disease', (47, 71))	('pT2a', 'Var', (42, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
182858	30546886	Some studies have shown that c-Myc amplification is a recurrent genetic alteration in secondary angiosarcomas, but not in primary angiosarcomas, suggesting distinct pathogenetic mechanisms between them.	('secondary angiosarcomas', 'Disease', (86, 109))	('angiosarcomas', 'Disease', (130, 143))	('amplification', 'Var', (35, 48))	('angiosarcoma', 'Phenotype', 'HP:0200058', (96, 108))	('angiosarcomas', 'Phenotype', 'HP:0200058', (96, 109))	('secondary angiosarcomas', 'Disease', 'MESH:D006394', (86, 109))	('c-Myc', 'Gene', '4609', (29, 34))	('angiosarcomas', 'Disease', 'MESH:D006394', (130, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('angiosarcomas', 'Phenotype', 'HP:0200058', (130, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('angiosarcomas', 'Disease', (96, 109))	('c-Myc', 'Gene', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('angiosarcomas', 'Disease', 'MESH:D006394', (96, 109))	('angiosarcoma', 'Phenotype', 'HP:0200058', (130, 142))
182985	24415941	By utilizing siRNAs to specifically deplete CTCF and Rad21, a cohesin component, we demonstrate that both proteins are potent restriction factors for KSHV replication, with cohesin knockdown leading to hundred-fold increases in viral yield.	('KSHV', 'Species', '37296', (150, 154))	('CTCF', 'Gene', '10664', (44, 48))	('Rad21', 'Gene', (53, 58))	('cohesin', 'Gene', (173, 180))	('Rad21', 'Gene', '5885', (53, 58))	('knockdown', 'Var', (181, 190))	('KS', 'Phenotype', 'HP:0100726', (150, 152))	('increases', 'PosReg', (215, 224))	('CTCF', 'Gene', (44, 48))	('viral yield', 'MPA', (228, 239))
182986	24415941	High-throughput RNA sequencing was used to characterize the transcriptional effects of CTCF and cohesin depletion, and demonstrated that both proteins have complex and global effects on KSHV lytic transcription.	('effects', 'Reg', (175, 182))	('CTCF', 'Gene', (87, 91))	('KSHV', 'Species', '37296', (186, 190))	('KS', 'Phenotype', 'HP:0100726', (186, 188))	('KSHV lytic', 'Gene', (186, 196))	('CTCF', 'Gene', '10664', (87, 91))	('depletion', 'Var', (104, 113))
183019	24415941	Chromosome conformation capture assays have demonstrated that a cohesin/CTCF site in the 5' region of the major latency KSHV transcript forms contacts with a site close to the primary gene necessary for lytic reactivation (ORF50/RTA) and with the 3' region of the latency region.. Mutation of the CTCF site led to increased latency gene expression, suggesting that CTCF and cohesin play a repressive role in latent gene expression.	('KS', 'Phenotype', 'HP:0100726', (120, 122))	('CTCF', 'Gene', '10664', (297, 301))	('increased', 'PosReg', (314, 323))	('Mutation', 'Var', (281, 289))	('CTCF', 'Gene', (72, 76))	('CTCF', 'Gene', (365, 369))	('KSHV', 'Species', '37296', (120, 124))	('CTCF', 'Gene', '10664', (365, 369))	('CTCF', 'Gene', (297, 301))	('ORF50', 'Gene', '4961526', (223, 228))	('latency gene expression', 'MPA', (324, 347))	('CTCF', 'Gene', '10664', (72, 76))	('ORF50', 'Gene', (223, 228))
183020	24415941	Although knockdown of cohesin components led to increased transcription of lytic genes in PEL cells, depletion of CTCF had virtually no such effect.	('increased', 'PosReg', (48, 57))	('CTCF', 'Gene', '10664', (114, 118))	('knockdown', 'Var', (9, 18))	('transcription', 'MPA', (58, 71))	('CTCF', 'Gene', (114, 118))	('lytic genes', 'Gene', (75, 86))	('PEL', 'Phenotype', 'HP:0030069', (90, 93))
183021	24415941	Conversely, mutation of the CTCF site, which would be predicted to disrupt both cohesin and CTCF binding, led to decreased lytic gene expression.	('CTCF', 'Gene', '10664', (92, 96))	('cohesin', 'Protein', (80, 87))	('CTCF', 'Gene', (28, 32))	('mutation', 'Var', (12, 20))	('binding', 'Interaction', (97, 104))	('disrupt', 'NegReg', (67, 74))	('CTCF', 'Gene', '10664', (28, 32))	('CTCF', 'Gene', (92, 96))	('lytic gene', 'Gene', (123, 133))	('decreased', 'NegReg', (113, 122))
183035	24415941	CTCF (L-020165-00-0005), Rad21 (L-006832-00-0005) and negative control On-target plus Smart Pool siRNAs (D-001810-03) were purchased from Thermo Scientific.	('Rad21', 'Gene', '5885', (25, 30))	('CTCF', 'Gene', (0, 4))	('L-006832-00-0005', 'Var', (32, 48))	('CTCF', 'Gene', '10664', (0, 4))	('L-020165-00-0005', 'Var', (6, 22))	('Rad21', 'Gene', (25, 30))
183037	24415941	Similar experiments were also performed with siGENOME Non-Targeting SiRNA #5, D-001210-05-05, SiGENOME human CTCF siRNA, M-020165-02-0005 and SiGENOME human Rad21 siRNA, M-006832-01-0005, purchased from the same manufacturer.	('D-001210-05-05', 'Var', (78, 92))	('CTCF', 'Gene', '10664', (109, 113))	('human', 'Species', '9606', (103, 108))	('Rad21', 'Gene', (157, 162))	('human', 'Species', '9606', (151, 156))	('Rad21', 'Gene', '5885', (157, 162))	('M-020165-02-0005', 'Var', (121, 137))	('CTCF', 'Gene', (109, 113))
183073	24415941	This second normalization step was done to account for increasing KHSV reads over time.	('KHSV reads', 'Var', (66, 76))	('KHSV', 'Chemical', '-', (66, 70))	('increasing', 'PosReg', (55, 65))
183081	24415941	As shown in Figure 1B, CTCF depletion prior to induction of lytic replication led to a marked increase in virion production (20-25 fold), compared to control cells induced to replicate.	('CTCF', 'Gene', '10664', (23, 27))	('increase', 'PosReg', (94, 102))	('virion production', 'MPA', (106, 123))	('depletion', 'Var', (28, 37))	('CTCF', 'Gene', (23, 27))
183083	24415941	Previous investigations of the role of CTCF in KSHV replication in PEL cells detected no effect of CTCF knockdown on KSHV lytic replication.	('CTCF', 'Gene', '10664', (39, 43))	('CTCF', 'Gene', (99, 103))	('PEL', 'Phenotype', 'HP:0030069', (67, 70))	('KS', 'Phenotype', 'HP:0100726', (117, 119))	('KSHV', 'Species', '37296', (117, 121))	('CTCF', 'Gene', '10664', (99, 103))	('KS', 'Phenotype', 'HP:0100726', (47, 49))	('CTCF', 'Gene', (39, 43))	('KSHV', 'Species', '37296', (47, 51))	('knockdown', 'Var', (104, 113))
183086	24415941	Previous studies have reported decreased transcription of several lytic KSHV genes upon partial CTCF knockdown, indicating CTCF-mediated transcriptional activation.	('transcription', 'MPA', (41, 54))	('partial', 'Var', (88, 95))	('CTCF', 'Gene', (96, 100))	('CTCF', 'Gene', '10664', (123, 127))	('KS', 'Phenotype', 'HP:0100726', (72, 74))	('decreased', 'NegReg', (31, 40))	('KSHV', 'Species', '37296', (72, 76))	('CTCF', 'Gene', '10664', (96, 100))	('CTCF', 'Gene', (123, 127))	('lytic KSHV genes', 'Gene', (66, 82))	('knockdown', 'Var', (101, 110))
183090	24415941	While ORF57 (early) and ORF6 (early) lytic mRNA expression were enhanced approximately four-fold by CTCF depletion, there was a less significant increase in other early (ORF59) or late (ORF25) lytic mRNAs (Figure 2 A-D).	('ORF6', 'Gene', (24, 28))	('CTCF', 'Gene', (100, 104))	('ORF57', 'Gene', '4961525', (6, 11))	('ORF57', 'Gene', (6, 11))	('depletion', 'Var', (105, 114))	('CTCF', 'Gene', '10664', (100, 104))	('enhanced', 'PosReg', (64, 72))
183092	24415941	It therefore appeared that CTCF knockdown might enhance expression of KSHV genes in a gene-specific manner, consistent with transcriptional repression due to site-specific binding.	('CTCF', 'Gene', (27, 31))	('CTCF', 'Gene', '10664', (27, 31))	('knockdown', 'Var', (32, 41))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('KSHV', 'Species', '37296', (70, 74))	('enhance', 'PosReg', (48, 55))	('expression', 'MPA', (56, 66))	('KSHV genes', 'Gene', (70, 80))
183108	24415941	Since CTCF depletion alone led to greatly increased KSHV virion production, and cohesin is known to bind to many CTCF sites, it was of interest to determine the effect of cohesin disruption on KSHV replication in our system.	('increased', 'PosReg', (42, 51))	('KSHV', 'Species', '37296', (52, 56))	('CTCF', 'Gene', (6, 10))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('CTCF', 'Gene', '10664', (6, 10))	('disruption', 'Var', (179, 189))	('KSHV', 'Species', '37296', (193, 197))	('CTCF', 'Gene', (113, 117))	('KS', 'Phenotype', 'HP:0100726', (193, 195))	('KSHV virion production', 'MPA', (52, 74))	('CTCF', 'Gene', '10664', (113, 117))
183110	24415941	Depletion of Rad21 effectively disrupts cohesin function in DNA binding and transcriptional regulation.	('disrupts', 'NegReg', (31, 39))	('cohesin', 'Protein', (40, 47))	('function', 'MPA', (48, 56))	('Depletion', 'Var', (0, 9))	('Rad21', 'Gene', (13, 18))	('Rad21', 'Gene', '5885', (13, 18))	('DNA binding', 'Interaction', (60, 71))	('transcriptional regulation', 'MPA', (76, 102))
183112	24415941	Virus production after Rad21 depletion was compared to virus production in cells transfected with control siRNA and revealed that Rad21 depletion enhanced KSHV virion yield even more robustly than CTCF depletion (approximately 90-fold, Figure 4A).	('Rad21', 'Gene', (23, 28))	('CTCF', 'Gene', '10664', (197, 201))	('depletion', 'Var', (136, 145))	('Rad21', 'Gene', '5885', (23, 28))	('Rad21', 'Gene', (130, 135))	('KSHV', 'Species', '37296', (155, 159))	('KS', 'Phenotype', 'HP:0100726', (155, 157))	('KSHV', 'MPA', (155, 159))	('Rad21', 'Gene', '5885', (130, 135))	('enhanced', 'PosReg', (146, 154))	('CTCF', 'Gene', (197, 201))
183113	24415941	In subsequent experiments, CTCF depletion was performed in parallel with Rad21 depletion and confirmed that Rad21 represses KSHV virion production more efficiently than does CTCF (Rad21 depletion enhanced virus production approximately 130-fold versus 20-fold for CTCF depletion, Figure 4B).	('CTCF', 'Gene', (27, 31))	('Rad21', 'Gene', '5885', (180, 185))	('KS', 'Phenotype', 'HP:0100726', (124, 126))	('depletion', 'Var', (186, 195))	('Rad21', 'Gene', '5885', (108, 113))	('CTCF', 'Gene', (264, 268))	('KSHV', 'Species', '37296', (124, 128))	('virus production', 'MPA', (205, 221))	('CTCF', 'Gene', '10664', (174, 178))	('KSHV virion production', 'MPA', (124, 146))	('enhanced', 'PosReg', (196, 204))	('Rad21', 'Gene', (73, 78))	('CTCF', 'Gene', '10664', (27, 31))	('represses', 'NegReg', (114, 123))	('Rad21', 'Gene', (180, 185))	('CTCF', 'Gene', (174, 178))	('Rad21', 'Gene', '5885', (73, 78))	('CTCF', 'Gene', '10664', (264, 268))	('Rad21', 'Gene', (108, 113))
183115	24415941	The results demonstrated that the KSHV copy number in each sample correlated extremely well with the increases in infectious virion titer.	('KS', 'Phenotype', 'HP:0100726', (34, 36))	('KSHV', 'Species', '37296', (34, 38))	('infectious virion titer', 'CPA', (114, 137))	('copy number', 'Var', (39, 50))	('increases', 'PosReg', (101, 110))	('KSHV', 'Gene', (34, 38))
183120	24415941	Since Rad21 depletion appeared to have much more potent effects on KSHV lytic replication than CTCF depletion, it was critical to map the binding of Rad21 during lytic replication and compare its pattern to that of CTCF binding during the same period.	('Rad21', 'Gene', (149, 154))	('effects', 'Reg', (56, 63))	('CTCF', 'Gene', '10664', (95, 99))	('CTCF', 'Gene', (95, 99))	('Rad21', 'Gene', '5885', (149, 154))	('Rad21', 'Gene', (6, 11))	('binding', 'Interaction', (138, 145))	('CTCF', 'Gene', (215, 219))	('KSHV', 'Species', '37296', (67, 71))	('KS', 'Phenotype', 'HP:0100726', (67, 69))	('Rad21', 'Gene', '5885', (6, 11))	('CTCF', 'Gene', '10664', (215, 219))	('depletion', 'Var', (12, 21))
183125	24415941	These are consistent with previously identified cohesin-binding sites but include at least one additional novel Rad21 binding locus at nt 28819-29553 (24,26).	('nt 28819-29553', 'Var', (135, 149))	('Rad21', 'Gene', (112, 117))	('Rad21', 'Gene', '5885', (112, 117))
183132	24415941	The stimulatory effects of CTCF and Rad21 knockdown on KSHV production suggested that both proteins exert restrictive effects on KSHV lytic replication.	('CTCF', 'Gene', (27, 31))	('KSHV', 'Species', '37296', (55, 59))	('lytic replication', 'CPA', (134, 151))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('CTCF', 'Gene', '10664', (27, 31))	('Rad21', 'Gene', (36, 41))	('Rad21', 'Gene', '5885', (36, 41))	('KSHV', 'Species', '37296', (129, 133))	('KS', 'Phenotype', 'HP:0100726', (129, 131))	('knockdown', 'Var', (42, 51))
183133	24415941	Rad21 depletion led to significantly greater increases in KSHV yield, suggesting that Rad21 and CTCF might have unique effects on the transcription of KSHV lytic genes.	('Rad21', 'Gene', '5885', (86, 91))	('KSHV', 'Species', '37296', (151, 155))	('increases', 'PosReg', (45, 54))	('transcription', 'MPA', (134, 147))	('KSHV', 'Species', '37296', (58, 62))	('CTCF', 'Gene', (96, 100))	('KSHV lytic genes', 'Gene', (151, 167))	('KS', 'Phenotype', 'HP:0100726', (151, 153))	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('Rad21', 'Gene', (86, 91))	('Rad21', 'Gene', (0, 5))	('KSHV yield', 'MPA', (58, 68))	('CTCF', 'Gene', '10664', (96, 100))	('depletion', 'Var', (6, 15))	('Rad21', 'Gene', '5885', (0, 5))	('effects', 'Reg', (119, 126))
183136	24415941	48 hours after siRNA transfection, cells were treated with doxycycline to induce KSHV lytic replication, and cells were harvested at 24 and 48 hours after induction of replication.	('KS', 'Phenotype', 'HP:0100726', (81, 83))	('KSHV', 'Gene', (81, 85))	('transfection', 'Var', (21, 33))	('lytic replication', 'CPA', (86, 103))	('doxycycline', 'Chemical', 'MESH:D004318', (59, 70))	('KSHV', 'Species', '37296', (81, 85))
183137	24415941	The effects of both CTCF and Rad21 knockdown on lytic cycle transcription were compared to each other and to the transcriptional profile of induced cells transfected with control siRNA.	('knockdown', 'Var', (35, 44))	('Rad21', 'Gene', (29, 34))	('CTCF', 'Gene', (20, 24))	('Rad21', 'Gene', '5885', (29, 34))	('CTCF', 'Gene', '10664', (20, 24))	('lytic cycle transcription', 'MPA', (48, 73))
183146	24415941	The effect of Rad21 depletion on the transcriptional profile at 48 hours was very similar to that of CTCF, with an increase in expression of most lytic cycle genes (Figure 6C).	('expression', 'MPA', (127, 137))	('CTCF', 'Gene', (101, 105))	('increase', 'PosReg', (115, 123))	('depletion', 'Var', (20, 29))	('Rad21', 'Gene', (14, 19))	('lytic cycle genes', 'Gene', (146, 163))	('CTCF', 'Gene', '10664', (101, 105))	('at 4', 'Species', '1239834', (61, 65))	('Rad21', 'Gene', '5885', (14, 19))
183156	24415941	The magnitude of the overall changes in transcription of individual lytic genes due to CTCF or Rad21 knockdown were reproducible but relatively modest (2-8 fold over control) compared with the increases observed in virion production under the same conditions.	('transcription', 'MPA', (40, 53))	('lytic genes', 'Gene', (68, 79))	('CTCF', 'Gene', (87, 91))	('changes', 'Reg', (29, 36))	('Rad21', 'Gene', (95, 100))	('CTCF', 'Gene', '10664', (87, 91))	('Rad21', 'Gene', '5885', (95, 100))	('knockdown', 'Var', (101, 110))
183171	24415941	Rather CTCF or Rad21 depletion actually resulted in slightly decreased RTA activation function.	('Rad21', 'Gene', (15, 20))	('CTCF', 'Gene', (7, 11))	('decreased', 'NegReg', (61, 70))	('Rad21', 'Gene', '5885', (15, 20))	('CTCF', 'Gene', '10664', (7, 11))	('depletion', 'Var', (21, 30))	('RTA activation function', 'MPA', (71, 94))
183175	24415941	Rad21 appears to exert a greater effect, as Rad21 knockdown resulted in nearly 100-fold increases in virus yield, approximately five times more than the increase caused by CTCF knockdown.	('virus yield', 'MPA', (101, 112))	('knockdown', 'Var', (50, 59))	('CTCF', 'Gene', (172, 176))	('Rad21', 'Gene', (44, 49))	('Rad21', 'Gene', (0, 5))	('CTCF', 'Gene', '10664', (172, 176))	('Rad21', 'Gene', '5885', (44, 49))	('increases', 'PosReg', (88, 97))	('Rad21', 'Gene', '5885', (0, 5))
183182	24415941	The finding that CTCF depletion results in increased virus production is in contrast to those of Chen et.	('CTCF', 'Gene', '10664', (17, 21))	('depletion', 'Var', (22, 31))	('virus production', 'MPA', (53, 69))	('increased', 'PosReg', (43, 52))	('CTCF', 'Gene', (17, 21))
183185	24415941	Our findings that cohesin and CTCF may play distinct roles in regulating KSHV reactivation and virion production are mirrored by the differing effects of their knockdown on KSHV lytic gene transcription.	('knockdown', 'Var', (160, 169))	('KSHV', 'Species', '37296', (73, 77))	('KSHV lytic gene', 'Gene', (173, 188))	('CTCF', 'Gene', '10664', (30, 34))	('KS', 'Phenotype', 'HP:0100726', (73, 75))	('reactivation', 'MPA', (78, 90))	('KS', 'Phenotype', 'HP:0100726', (173, 175))	('CTCF', 'Gene', (30, 34))	('KSHV', 'Species', '37296', (173, 177))	('KSHV', 'Gene', (73, 77))	('virion', 'CPA', (95, 101))
183186	24415941	Consistent with the more profound effects of Rad21 KD on virion production, Rad 21 depletion consistently led to greater increases in KSHV lytic gene expression than did CTCF KD.	('KSHV', 'Species', '37296', (134, 138))	('Rad 21', 'Gene', (76, 82))	('Rad21', 'Gene', '5885', (45, 50))	('increases', 'PosReg', (121, 130))	('CTCF', 'Gene', '10664', (170, 174))	('KSHV lytic gene', 'Gene', (134, 149))	('CTCF', 'Gene', (170, 174))	('depletion', 'Var', (83, 92))	('KS', 'Phenotype', 'HP:0100726', (134, 136))	('Rad21', 'Gene', (45, 50))
183197	24415941	In addition, total levels of RTA protein were not affected by CTCF or Rad21 depletion.	('Rad21', 'Gene', '5885', (70, 75))	('CTCF', 'Gene', (62, 66))	('CTCF', 'Gene', '10664', (62, 66))	('depletion', 'Var', (76, 85))	('Rad21', 'Gene', (70, 75))	('RTA protein', 'Protein', (29, 40))
183205	24415941	The more robust effect of Rad21 depletion on transcription, and especially virus production, suggest that the linking effects of cohesin may be more important in this regard than CTCF.	('CTCF', 'Gene', (179, 183))	('depletion', 'Var', (32, 41))	('Rad21', 'Gene', (26, 31))	('CTCF', 'Gene', '10664', (179, 183))	('transcription', 'MPA', (45, 58))	('cohesin', 'Protein', (129, 136))	('Rad21', 'Gene', '5885', (26, 31))	('virus production', 'MPA', (75, 91))
183208	24415941	An additional insight into the potential role of cohesin in regulating KSHV transcription is provided by an examination of the few genes whose transcript levels are depressed by cohesin depletion and remain suppressed at later times.	('KSHV', 'Gene', (71, 75))	('transcript levels', 'MPA', (143, 160))	('cohesin', 'Protein', (178, 185))	('KSHV', 'Species', '37296', (71, 75))	('KS', 'Phenotype', 'HP:0100726', (71, 73))	('depressed', 'NegReg', (165, 174))	('depletion', 'Var', (186, 195))
183211	24415941	Whether such pausing also occurs at the other KSHV genes whose expression is adversely affected by cohesin depletion (e.g.	('cohesin', 'Protein', (99, 106))	('expression', 'MPA', (63, 73))	('KSHV', 'Species', '37296', (46, 50))	('KS', 'Phenotype', 'HP:0100726', (46, 48))	('depletion', 'Var', (107, 116))	('KSHV genes', 'Gene', (46, 56))
183213	24415941	Cohesin and CTCF appear to initially act as positive factors, facilitating transcription for the majority of KSHV lytic genes, but subsequently their presence limits transcription and virus production, potentially by topological effects on transcription.	('CTCF', 'Gene', '10664', (12, 16))	('limits', 'NegReg', (159, 165))	('CTCF', 'Gene', (12, 16))	('transcription', 'MPA', (166, 179))	('presence', 'Var', (150, 158))	('KSHV', 'Species', '37296', (109, 113))	('KS', 'Phenotype', 'HP:0100726', (109, 111))	('KSHV lytic genes', 'Gene', (109, 125))	('facilitating', 'PosReg', (62, 74))	('transcription', 'MPA', (75, 88))	('virus production', 'CPA', (184, 200))
183291	29254507	We also demonstrate that adoptively-transferred canine NK cells delay the growth of canine patient-derived xenograft (PDX) tumors in vivo and that focal RT increases NK homing to canine sarcoma xenografts.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('delay the growth', 'Phenotype', 'HP:0001510', (64, 80))	('growth', 'CPA', (74, 80))	('canine', 'Species', '9615', (179, 185))	('rat', 'Species', '10116', (15, 18))	('growth of canine', 'Phenotype', 'HP:0012738', (74, 90))	('canine', 'Species', '9615', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('sarcoma', 'Disease', (186, 193))	('NK', 'Chemical', '-', (55, 57))	('NK', 'Chemical', '-', (166, 168))	('patient', 'Species', '9606', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('canine', 'Species', '9615', (84, 90))	('delay', 'NegReg', (64, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('NK homing', 'CPA', (166, 175))	('increases', 'PosReg', (156, 165))	('focal RT', 'Var', (147, 155))
183346	29254507	CD5 depletion lead to a significant reduction in CD5high and CD3+ cells from canine PBMCs, leaving both CD5dim and CD3- populations (Fig.	('depletion', 'Var', (4, 13))	('reduction', 'NegReg', (36, 45))	('leaving', 'Reg', (91, 98))	('canine', 'Species', '9615', (77, 83))	('CD5dim', 'CPA', (104, 110))	('CD3- populations', 'CPA', (115, 131))
183348	29254507	Following CD5 depletion, the remaining cell population was cultured in the presence of an irradiated human feeder cell line (K562C9IL21), which we and others have previously shown to induce robust expansion of human and canine NK cells.	('canine', 'Species', '9615', (220, 226))	('NK', 'Chemical', '-', (227, 229))	('human', 'Species', '9606', (101, 106))	('depletion', 'Var', (14, 23))	('human', 'Species', '9606', (210, 215))	('K562C9IL21', 'Var', (125, 135))
183355	29254507	Overall, we observed the greatest expansion and cytotoxicity using a combination of rh-IL12 (50 mug/mL), rh-IL15 (50 mug/mL), and rh-IL18 (50 mug/mL) compared to other cytokine combinations.	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('50 mug/mL', 'Var', (93, 102))	('50 mug/mL', 'Var', (114, 123))	('cytotoxicity', 'Disease', (48, 60))	('rh-IL12', 'Gene', (84, 91))	('rh-IL18', 'Var', (130, 137))	('expansion', 'CPA', (34, 43))
183356	29254507	With 7 donors of diverse breeds, we observed an average of 1.8 +- 0.2 fold expansion at day 7 with rh-IL12/15/18, and cytotoxicity of these "lymphokine-activated cells" reached a peak of 60 +- 3% at 12.5:1 E:T ratio for the rh-IL12/15/18 combination (P < 0.0001 compared to E:T ratio of 1.6:1 and compared to individual cytokines alone, Additional file 1: Figure S1).	('cytotoxicity', 'Disease', 'MESH:D064420', (118, 130))	('donor', 'Species', '9606', (7, 12))	('rh-IL12/15/18 combination', 'Var', (224, 249))	('rat', 'Species', '10116', (210, 213))	('rat', 'Species', '10116', (278, 281))	('cytotoxicity', 'Disease', (118, 130))
183372	29254507	Mice received 2 intra-tumoral injections 1 week apart, and the group receiving rhIL-2/NK demonstrated significant tumor growth delay (P < 0.01) which persisted until euthanasia of the control mice (Fig.	('mice', 'Species', '10090', (192, 196))	('tumor growth delay', 'Disease', (114, 132))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('NK', 'Chemical', '-', (86, 88))	('intra-tumoral', 'Disease', 'MESH:D009369', (16, 29))	('growth delay', 'Phenotype', 'HP:0001510', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('rhIL-2/NK', 'Var', (79, 88))	('Mice', 'Species', '10090', (0, 4))	('intra-tumoral', 'Disease', (16, 29))	('rat', 'Species', '10116', (96, 99))	('tumor growth delay', 'Disease', 'MESH:D006130', (114, 132))
183438	29254507	We also observed heterogeneity in the magnitude of our NK expansions (while robust cytotoxicity remained fairly reproducible).	('cytotoxicity', 'Disease', (83, 95))	('expansions', 'Var', (58, 68))	('cytotoxicity', 'Disease', 'MESH:D064420', (83, 95))	('NK', 'Chemical', '-', (55, 57))
183489	28743856	Cross-sectional epidemiological studies have determined that seropositivity in HHV-8, now also called Kaposi Sarcoma-Associated Herpesvirus (KSHV), is strongly correlated with the risk of Kaposi sarcoma, and several longitudinal studies have shown that this virus precedes the onset of the disease.	('correlated with', 'Reg', (160, 175))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (188, 202))	('Kaposi Sarcoma-Associated Herpesvirus', 'Disease', (102, 139))	('seropositivity', 'Var', (61, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('Kaposi Sarcoma-Associated Herpesvirus', 'Disease', 'MESH:D012514', (102, 139))	('KSHV', 'Species', '37296', (141, 145))	('Kaposi Sarcoma', 'Phenotype', 'HP:0100726', (102, 116))	('Kaposi sarcoma', 'Disease', (188, 202))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (188, 202))	('HHV-8', 'Gene', (79, 84))	('Sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('HHV-8', 'Species', '37296', (79, 84))
183490	28743856	The presence of HHV-8 and any immune system imbalance are recognized factors that also promote the pathogenesis of this cancer, and a link to HPV infection has also been reported.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('imbalance', 'Phenotype', 'HP:0002172', (44, 53))	('HPV infection', 'Disease', 'MESH:D030361', (142, 155))	('HHV-8', 'Gene', (16, 21))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('HHV-8', 'Species', '37296', (16, 21))	('link', 'Reg', (134, 138))	('HPV infection', 'Disease', (142, 155))	('presence', 'Var', (4, 12))	('promote', 'PosReg', (87, 94))	('immune system imbalance', 'Phenotype', 'HP:0002958', (30, 53))
183493	28743856	Recently, the association of classic Kaposi sarcoma with miR-146a polymorphisms has been shown, but not with miR-149.	('miR-149', 'Gene', (109, 116))	('Kaposi sarcoma', 'Disease', (37, 51))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (37, 51))	('miR-149', 'Gene', '406941', (109, 116))	('association', 'Interaction', (14, 25))	('miR-146a', 'Gene', '406938', (57, 65))	('polymorphisms', 'Var', (66, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (37, 51))	('miR-146a', 'Gene', (57, 65))
183498	28743856	Diagnosis can be achieved through skin biopsies and polymerase-chain reaction (PCR) for HHV-8, or immunostaining for the HHV-8 antigen.	('polymerase-chain reaction', 'Var', (52, 77))	('HHV-8', 'Species', '37296', (121, 126))	('HHV-8', 'Gene', (88, 93))	('HHV-8', 'Species', '37296', (88, 93))	('HHV-8', 'Gene', (121, 126))
183510	27125524	Targeting EZH2-mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in vitro Synovial sarcoma is an aggressive soft tissue sarcoma genetically defined by the fusion oncogene SS18-SSX.	('aggressive soft tissue sarcoma', 'Disease', 'MESH:D012509', (134, 164))	('EZH2', 'Gene', '2146', (10, 14))	('H3K27', 'Protein', (39, 44))	('EZH2', 'Gene', (10, 14))	('methylation', 'Var', (24, 35))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('proliferation', 'CPA', (54, 67))	('Sarcoma', 'Disease', (94, 101))	('sarcoma', 'Disease', (157, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('Sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('inhibits', 'NegReg', (45, 53))	('SS18', 'Gene', (208, 212))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (111, 127))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (85, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('SSX', 'Gene', '6757', (213, 216))	('SS18', 'Gene', '6760', (208, 212))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('SSX', 'Gene', (213, 216))	('aggressive soft tissue sarcoma', 'Disease', (134, 164))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (145, 164))	('Sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('sarcoma', 'Disease', (120, 127))
183517	27125524	Aberrant epigenetic changes are increasingly being recognized as important drivers of malignancy, including altered covalent histone amino tail modifications (e.g.	('Aberrant epigenetic changes', 'Var', (0, 27))	('malignancy', 'Disease', 'MESH:D009369', (86, 96))	('altered', 'Reg', (108, 115))	('malignancy', 'Disease', (86, 96))	('covalent histone amino tail modifications', 'MPA', (116, 157))
183518	27125524	), hyper- or hypo-DNA methylation, and dysregulation of the ATP-dependent chromatin remodeling enzymes that regulate these processes.	('dysregulation', 'Var', (39, 52))	('ATP', 'Chemical', 'MESH:D000255', (60, 63))	('hyper-', 'Var', (3, 9))	('hypo-DNA methylation', 'Var', (13, 33))
183524	27125524	Human tumor sequencing studies have identified multiple alterations in SWI/SNF across a range of malignancies and activating EZH2 mutations in lymphoma (and over-expression in other tumors), and in some these have been correlated with worse clinical outcomes.	('Human', 'Species', '9606', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('alterations', 'Reg', (56, 67))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('malignancies', 'Disease', (97, 109))	('tumors', 'Disease', (182, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (143, 151))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('SWI/SNF', 'Gene', (71, 78))	('EZH2', 'Gene', (125, 129))	('tumor', 'Disease', (6, 11))	('lymphoma', 'Disease', (143, 151))	('tumor', 'Disease', (182, 187))	('lymphoma', 'Disease', 'MESH:D008223', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('mutations', 'Var', (130, 139))	('activating', 'PosReg', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
183527	27125524	In preclinical models of MRT, rescue of INI1 or inhibition of EZH2, and lymphoma (with EZH2 activating mutations), inhibition of EZH2 leads to slowing of tumor growth and apoptosis.	('slowing', 'NegReg', (143, 150))	('MRT', 'Disease', (25, 28))	('mutations', 'Var', (103, 112))	('EZH2', 'Gene', (129, 133))	('tumor', 'Disease', (154, 159))	('INI1', 'Gene', '6598', (40, 44))	('apoptosis', 'CPA', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('lymphoma', 'Disease', (72, 80))	('EZH2', 'Gene', (62, 66))	('inhibition', 'Var', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('lymphoma', 'Disease', 'MESH:D008223', (72, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))	('INI1', 'Gene', (40, 44))
183528	27125524	Moreover, these data are now supported by early phase clinical studies where EZH2 inhibitors have shown clinical responses in MRT and lymphoma (unpublished data).	('EZH2', 'Gene', (77, 81))	('lymphoma', 'Disease', (134, 142))	('lymphoma', 'Disease', 'MESH:D008223', (134, 142))	('inhibitors', 'Var', (82, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (134, 142))	('MRT', 'Disease', (126, 129))
183529	27125524	Could this strategy be relevant to other sarcomas with INI1/EZH2 alteration?	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('INI1', 'Gene', (55, 59))	('alteration', 'Var', (65, 75))	('INI1', 'Gene', '6598', (55, 59))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
183530	27125524	INI1 mutation or loss of expression has been described in connective tissue malignancies, including round cell soft-tissue sarcomas (most were a subset of tumors resembling extraskeletal myxoid chondrosarcoma with rhabdoid features), epithelioid sarcomas, and in poorly differentiated chordoma.	('malignancies', 'Disease', (76, 88))	('chordoma', 'Disease', 'MESH:D002817', (285, 293))	('connective tissue malignancies', 'Phenotype', 'HP:0100242', (58, 88))	('sarcomas', 'Disease', 'MESH:D012509', (246, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (111, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (246, 254))	('loss of expression', 'NegReg', (17, 35))	('sarcomas', 'Disease', (246, 254))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('rhabdoid', 'Disease', (214, 222))	('sarcomas', 'Disease', 'MESH:D012509', (123, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('sarcomas', 'Disease', (123, 131))	('rhabdoid', 'Disease', 'MESH:D018335', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('chordoma', 'Phenotype', 'HP:0010762', (285, 293))	('INI1', 'Gene', (0, 4))	('INI1', 'Gene', '6598', (0, 4))	('tumors', 'Disease', (155, 161))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (234, 254))	('chordoma', 'Disease', (285, 293))	('mutation', 'Var', (5, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (187, 208))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('epithelioid sarcomas', 'Disease', (234, 254))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))	('myxoid chondrosarcoma', 'Disease', (187, 208))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (194, 208))
183540	27125524	In summary evidence suggests that imbalance of SWI/SNF-PRC2/EZH2 can drive oncogenesis in sarcomas.	('oncogenesis', 'CPA', (75, 86))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('drive', 'Reg', (69, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('sarcomas', 'Disease', (90, 98))	('SWI/SNF-PRC2/EZH2', 'Gene', (47, 64))	('imbalance', 'Var', (34, 43))	('imbalance', 'Phenotype', 'HP:0002172', (34, 43))
183542	27125524	We and others hypothesize that inhibition of EZH2 is a potential clinical therapeutic target in synovial sarcoma.	('synovial sarcoma', 'Disease', 'MESH:D013584', (96, 112))	('EZH2', 'Gene', (45, 49))	('synovial sarcoma', 'Disease', (96, 112))	('inhibition', 'Var', (31, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (96, 112))
183550	27125524	The Aska-SS and Yamato-SS cell lines were confirmed to contain the SS18-SSX1 fusion gene variant and the Fuji and SYO-1 cell lines were shown to have the SS18-SSX2 fusion gene variant by quantitative RT-PCR (Supplementary Figure S2).	('variant', 'Var', (176, 183))	('SSX2', 'Gene', (159, 163))	('SS18', 'Gene', '6760', (154, 158))	('SYO-1', 'Gene', '55027', (114, 119))	('SS18', 'Gene', (67, 71))	('variant', 'Var', (89, 96))	('SYO-1', 'Gene', (114, 119))	('SSX1', 'Gene', '6756', (72, 76))	('SS18', 'Gene', (154, 158))	('SSX2', 'Gene', '6757', (159, 163))	('SS18', 'Gene', '6760', (67, 71))	('SSX1', 'Gene', (72, 76))
183560	27125524	EPZ005687 is a specific inhibitor of EZH2, and as such H3K27 trimethylation status is a direct marker of PRC2 activity.	('trimethylation', 'MPA', (61, 75))	('EPZ005687', 'Chemical', 'MESH:C578195', (0, 9))	('EPZ005687', 'Var', (0, 9))	('H3K27', 'Protein', (55, 60))
183562	27125524	Aska-SS and SYO-1 cells were treated with increasing concentrations of EPZ005687 and were then assessed for H3K27me3 status after 72 hours, apoptosis after 72 hours, proliferation after 14 days and migration over 48 hours with 72 hours of constitutive treatment.	('EPZ005687', 'Var', (71, 80))	('EPZ005687', 'Chemical', 'MESH:C578195', (71, 80))	('proliferation', 'CPA', (166, 179))	('SYO-1', 'Gene', '55027', (12, 17))	('apoptosis', 'CPA', (140, 149))	('migration', 'CPA', (198, 207))	('SYO-1', 'Gene', (12, 17))	('H3K27me3', 'Var', (108, 116))
183563	27125524	Western blot and densitometry results demonstrated a dose-dependent inhibition of H3K27me3 with EPZ005687 (Fig.	('EPZ005687', 'Chemical', 'MESH:C578195', (96, 105))	('H3K27me3', 'Protein', (82, 90))	('inhibition', 'NegReg', (68, 78))	('EPZ005687', 'Var', (96, 105))
183565	27125524	Inhibition of cell proliferation by EPZ005687 in each cell line was determined by the MTT assay.	('EPZ005687', 'Var', (36, 45))	('Inhibition', 'NegReg', (0, 10))	('EPZ005687', 'Chemical', 'MESH:C578195', (36, 45))	('cell proliferation', 'CPA', (14, 32))	('MTT', 'Chemical', 'MESH:C070243', (86, 89))
183566	27125524	The IC50 of EPZ005687 in Aska-SS was 0.72 muM, Fuji was 1.5 muM, SYO-1 was 2.1 muM, and Yamato-SS was 3.5 muM (Fig.	('muM', 'Gene', '56925', (106, 109))	('EPZ005687', 'Var', (12, 21))	('muM', 'Gene', (60, 63))	('EPZ005687', 'Chemical', 'MESH:C578195', (12, 21))	('muM', 'Gene', '56925', (42, 45))	('muM', 'Gene', '56925', (79, 82))	('muM', 'Gene', (106, 109))	('muM', 'Gene', (42, 45))	('muM', 'Gene', (79, 82))	('SYO-1', 'Gene', '55027', (65, 70))	('muM', 'Gene', '56925', (60, 63))	('SYO-1', 'Gene', (65, 70))
183569	27125524	Both SYO-1 and Aska-SS cell migration was inhibited with EPZ005687 treatment in a dose-dependent manner with an observable threshold below their IC50s (<1 muM and <0.5 muM, respectively), as compared with untreated control cells (Fig.	('50s', 'Species', '1214577', (147, 150))	('EPZ005687 treatment', 'Var', (57, 76))	('muM', 'Gene', (168, 171))	('EPZ005687', 'Chemical', 'MESH:C578195', (57, 66))	('muM', 'Gene', '56925', (155, 158))	('muM', 'Gene', (155, 158))	('SYO-1', 'Gene', '55027', (5, 10))	('inhibited', 'NegReg', (42, 51))	('SYO-1', 'Gene', (5, 10))	('muM', 'Gene', '56925', (168, 171))
183571	27125524	To examine whether inhibition of EZH2 could sensitize synovial sarcoma cells to chemotherapeutic drugs in vitro, the Aska-SS and SYO-1 cells lines were treated with increasing concentrations of EPZ005687 and etoposide, topotecan, or doxorubicin over 14 days, and IC50s were determined by the MTT assay.	('synovial sarcoma', 'Disease', (54, 70))	('EPZ005687', 'Chemical', 'MESH:C578195', (194, 203))	('50s', 'Species', '1214577', (265, 268))	('topotecan', 'Chemical', 'MESH:D019772', (219, 228))	('inhibition', 'Var', (19, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('etoposide', 'Chemical', 'MESH:D005047', (208, 217))	('MTT', 'Chemical', 'MESH:C070243', (292, 295))	('doxorubicin', 'Chemical', 'MESH:D004317', (233, 244))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (54, 70))	('SYO-1', 'Gene', (129, 134))	('SYO-1', 'Gene', '55027', (129, 134))	('sensitize', 'Reg', (44, 53))	('synovial sarcoma', 'Disease', 'MESH:D013584', (54, 70))
183576	27125524	The IC50 of etoposide alone was 0.066 muM, and 0.029 muM in combination with EPZ005687; topotecan alone was 0.0038 muM, and 0.0025 muM with EPZ005687; and doxorubicin alone was 0.011 muM, and 0.0019 muM together with EPZ005687 (Supplementary Figure S5).	('muM', 'Gene', (53, 56))	('EPZ005687', 'Chemical', 'MESH:C578195', (77, 86))	('0.0025', 'Var', (124, 130))	('muM', 'Gene', '56925', (115, 118))	('EPZ005687', 'Chemical', 'MESH:C578195', (140, 149))	('muM', 'Gene', '56925', (131, 134))	('muM', 'Gene', (115, 118))	('muM', 'Gene', (131, 134))	('muM', 'Gene', '56925', (183, 186))	('muM', 'Gene', (183, 186))	('EPZ005687', 'Chemical', 'MESH:C578195', (217, 226))	('topotecan', 'Chemical', 'MESH:D019772', (88, 97))	('muM', 'Gene', '56925', (199, 202))	('muM', 'Gene', (199, 202))	('etoposide', 'Chemical', 'MESH:D005047', (12, 21))	('doxorubicin', 'Chemical', 'MESH:D004317', (155, 166))	('muM', 'Gene', '56925', (38, 41))	('muM', 'Gene', (38, 41))	('muM', 'Gene', '56925', (53, 56))
183578	27125524	Alterations in SWI/SNF-PRC2/EZH2 are now recognized in a number of tumors and they may correlate with aggressive clinical features.	('SWI/SNF-PRC2/EZH2', 'Gene', (15, 32))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('correlate', 'Reg', (87, 96))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
183586	27125524	EPZ005687 is a high-affinity inhibitor for EZH2.	('EZH2', 'Gene', (43, 47))	('EPZ005687', 'Chemical', 'MESH:C578195', (0, 9))	('EPZ005687', 'Var', (0, 9))
183590	27125524	Indeed, all cell lines had inhibited proliferation with EPZ005687.	('EPZ005687', 'Chemical', 'MESH:C578195', (56, 65))	('EPZ005687', 'Var', (56, 65))	('inhibited', 'NegReg', (27, 36))
183595	27125524	EGR1 expression was found to decrease the metastatic potential in a number of cancers, such as non-small cell lung cancer, hepatocarcinoma, and fibrosarcoma.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (95, 121))	('EGR1', 'Gene', '1958', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (99, 121))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (144, 156))	('decrease', 'NegReg', (29, 37))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (95, 121))	('expression', 'Var', (5, 15))	('hepatocarcinoma', 'Disease', 'None', (123, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('fibrosarcoma', 'Disease', 'MESH:D005354', (144, 156))	('metastatic potential', 'CPA', (42, 62))	('fibrosarcoma', 'Disease', (144, 156))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancers', 'Disease', (78, 85))	('non-small cell lung cancer', 'Disease', (95, 121))	('hepatocarcinoma', 'Disease', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('EGR1', 'Gene', (0, 4))
183596	27125524	EGR1 is repressed by the SS18-SSX fusion protein in synovial sarcoma in that SS18-SSX recruits PcG proteins, including EZH2 and Bmi1, to the EGR1 promoter and correlates with H3K27me3.	('EGR1', 'Gene', '1958', (0, 4))	('synovial sarcoma', 'Disease', 'MESH:D013584', (52, 68))	('SSX', 'Gene', (30, 33))	('H3K27me3', 'Var', (175, 183))	('SS18', 'Gene', (25, 29))	('recruits', 'PosReg', (86, 94))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (52, 68))	('SS18', 'Gene', '6760', (77, 81))	('EGR1', 'Gene', (141, 145))	('SSX', 'Gene', '6757', (82, 85))	('Bmi1', 'Gene', (128, 132))	('EGR1', 'Gene', '1958', (141, 145))	('Bmi1', 'Gene', '648', (128, 132))	('SS18', 'Gene', '6760', (25, 29))	('SSX', 'Gene', (82, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('SSX', 'Gene', '6757', (30, 33))	('SS18', 'Gene', (77, 81))	('synovial sarcoma', 'Disease', (52, 68))	('EGR1', 'Gene', (0, 4))
183597	27125524	It has also been demonstrated that EZH2 activates the Ras and NF-kappaB pathways in prostate cancer.	('EZH2', 'Var', (35, 39))	('prostate cancer', 'Disease', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('activates', 'PosReg', (40, 49))	('NF-kappaB pathways', 'Pathway', (62, 80))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))
183611	27125524	EPZ005687 was dissolved in dimethyl sulfoxide (DMSO) and administered at gradient concentrations to synovial sarcoma cells over 72 hours for wound healing and western blot analysis.	('synovial sarcoma', 'Disease', 'MESH:D013584', (100, 116))	('DMSO', 'Chemical', 'MESH:D004121', (47, 51))	('EPZ005687', 'Var', (0, 9))	('synovial sarcoma', 'Disease', (100, 116))	('EPZ005687', 'Chemical', 'MESH:C578195', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (100, 116))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (27, 45))
183624	27125524	Further evaluation of EZH2 knockdown in synovial sarcoma cells was carried out with lentiviral shRNA (Sigma-Aldrich, SHCLNV-NM_004456).	('synovial sarcoma', 'Disease', (40, 56))	('knockdown', 'Var', (27, 36))	('EZH2', 'Gene', (22, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (40, 56))	('synovial sarcoma', 'Disease', 'MESH:D013584', (40, 56))
183631	27125524	Equal amounts of protein were separated by NuPAGE  4-12% Bis-Tris Gel (Life Technologies), transferred onto nitrocellulose membrane (Bio-Rad), and incubated with specific primary antibodies EZH2 (Cell Signaling, Beverly, MA, dilution 1:1000), H3K27me3 (Active Motif, Carlsbad, CA, dilution 1:1000), and beta-Actin (Sigma-Aldrich, St. Louis, MO, dilution 1:2000) at 4  C overnight.	('Bis-Tris', 'Chemical', 'MESH:C026272', (57, 65))	('H3K27me3', 'Var', (243, 251))	('beta-Actin', 'Gene', (303, 313))	('beta-Actin', 'Gene', '728378', (303, 313))	('Rad', 'Gene', '6236', (137, 140))	('Rad', 'Gene', (137, 140))
183644	27125524	Targeting EZH2-mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in vitro.	('Sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('migration', 'CPA', (72, 81))	('inhibits', 'NegReg', (45, 53))	('H3K27', 'Protein', (39, 44))	('methylation', 'Var', (24, 35))	('proliferation', 'CPA', (54, 67))	('Sarcoma', 'Disease', (94, 101))	('Sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (85, 101))
183657	22587841	It is a pleiomorphic tumour of bone, and based on animal model systems, thought to arise in mesenchymal stem cells in which the mutant proliferating spindle cells produce osteoid or immature bones.	('osteoid', 'CPA', (171, 178))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('immature bones', 'CPA', (182, 196))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('mutant', 'Var', (128, 134))	('tumour of bone', 'Phenotype', 'HP:0010622', (21, 35))	('tumour', 'Disease', (21, 27))
183672	22587841	Ewing sarcoma are diagnostically defined by a Ewing sarcoma EWS (Chromosome 22) translocation resulting in fusion with an ETS transcription factor, the commonest abnormality (85%) being EWS-FLI1 (Chromosome 11) or rarely with a non ETS family partner.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (46, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('Ewing sarcoma', 'Disease', (0, 13))	('FLI1', 'Gene', (190, 194))	('EWS', 'Gene', (60, 63))	('EWS', 'Gene', '2130', (186, 189))	('EWS', 'Gene', (186, 189))	('translocation', 'Var', (80, 93))	('fusion', 'MPA', (107, 113))	('FLI1', 'Gene', '2313', (190, 194))	('Ewing sarcoma', 'Disease', (46, 59))	('EWS', 'Gene', '2130', (60, 63))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))
183707	22587841	For example SARC011, this is a phase II trial of R1507, a recombinant human monoclonal antibody to the Insulin-like growth factor-1 receptor for the treatment of patients with recurrent or refractory Ewing sarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma and other sarcomas.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (200, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('rhabdomyosarcoma', 'Disease', (247, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('osteosarcoma', 'Phenotype', 'HP:0002669', (215, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('sarcomas', 'Disease', 'MESH:D012509', (274, 282))	('Insulin-like growth factor-1 receptor', 'Gene', (103, 140))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (247, 263))	('sarcomas', 'Phenotype', 'HP:0100242', (274, 282))	('Ewing sarcoma', 'Disease', (200, 213))	('sarcomas', 'Disease', (274, 282))	('synovial sarcoma', 'Disease', (229, 245))	('patients', 'Species', '9606', (162, 170))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (247, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('R1507', 'Var', (49, 54))	('human', 'Species', '9606', (70, 75))	('synovial sarcoma', 'Disease', 'MESH:D013584', (229, 245))	('osteosarcoma', 'Disease', (215, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('osteosarcoma', 'Disease', 'MESH:D012516', (215, 227))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (229, 245))	('Insulin-like growth factor-1 receptor', 'Gene', '3480', (103, 140))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (200, 213))
183750	22587841	In Ewing sarcoma the identification of the Insulin-like Growth Factor 1 Receptor (IGF1R) pathway deregulation, as a consequence of the EWS-FLI1 translocation seems to be a new treatment strategy to be explored.	('IGF1R', 'Gene', (82, 87))	('translocation', 'Var', (144, 157))	('Ewing sarcoma', 'Disease', (3, 16))	('EWS', 'Gene', '2130', (135, 138))	('EWS', 'Gene', (135, 138))	('FLI1', 'Gene', '2313', (139, 143))	('IGF1R', 'Gene', '3480', (82, 87))	('Insulin-like Growth Factor 1 Receptor', 'Gene', (43, 80))	('FLI1', 'Gene', (139, 143))	('Insulin-like Growth Factor 1 Receptor', 'Gene', '3480', (43, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('deregulation', 'Reg', (97, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))
183771	30008914	The protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the symmetric dimethylation of arginine residues in histones 4 (H4R3me2s) and 3 (H3R8me2s).	('protein arginine methyltransferase 5', 'Gene', '27374', (4, 40))	('H3R8me2s', 'Chemical', '-', (185, 193))	('PRMT5', 'Gene', '27374', (42, 47))	('H4R3me2s', 'Var', (168, 176))	('arginine', 'Chemical', 'MESH:D001120', (62, 70))	('arginine', 'Chemical', 'MESH:D001120', (135, 143))	('PRMT5', 'Gene', (42, 47))	('arginine', 'Chemical', 'MESH:D001120', (12, 20))	('H4R3me2s', 'Chemical', '-', (168, 176))	('protein arginine methyltransferase 5', 'Gene', (4, 40))
183821	30008914	In addition, AMI-1 increased p53 protein levels, compared with control-treated tumors (Fig.	('AMI-1', 'Chemical', '-', (13, 18))	('p53 protein levels', 'MPA', (29, 47))	('tumors', 'Disease', (79, 85))	('increased', 'PosReg', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('AMI-1', 'Var', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
183822	30008914	PRMT5 is a major type II arginine methyltransferase that catalyzes omega-NG, N'G-symmetric dimethylarginine (H4R3me2s and H3R8me2s).	('H3R8me2s', 'Chemical', '-', (122, 130))	('H3R8me2s', 'Var', (122, 130))	('PRMT5', 'Gene', '27374', (0, 5))	('arginine', 'Chemical', 'MESH:D001120', (25, 33))	('H4R3me2s', 'Chemical', '-', (109, 117))	('arginine', 'Chemical', 'MESH:D001120', (99, 107))	('PRMT5', 'Gene', (0, 5))	('omega-NG', 'Chemical', '-', (67, 75))	('dimethylarginine', 'Chemical', 'MESH:C487735', (91, 107))
183824	30008914	The results demonstrated that AMI-1 treatment significantly decreased the levels of H4R3me2s and H3R8me2s compared with those in the control group (Fig.	('decreased', 'NegReg', (60, 69))	('H4R3me2s', 'MPA', (84, 92))	('H4R3me2s', 'Chemical', '-', (84, 92))	('H3R8me2s', 'Chemical', '-', (97, 105))	('H3R8me2s', 'Var', (97, 105))	('AMI-1', 'Chemical', '-', (30, 35))
183836	30008914	PRMT5 expression or activity is upregulated in various types of cancer and modulation of its expression regulates the viability of cancer cells.	('activity', 'MPA', (20, 28))	('cancer', 'Disease', (131, 137))	('PRMT5', 'Gene', '27374', (0, 5))	('expression', 'MPA', (6, 16))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('PRMT5', 'Gene', (0, 5))	('modulation', 'Var', (75, 85))	('regulates', 'Reg', (104, 113))	('viability', 'CPA', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('upregulated', 'PosReg', (32, 43))
183844	30008914	However, PRMT7 does not catalyze the formation of H3R8me2s (a PRMT5-specific target).	('PRMT7', 'Gene', '214572', (9, 14))	('PRMT5', 'Gene', '27374', (62, 67))	('PRMT7', 'Gene', (9, 14))	('H3R8me2s', 'Chemical', '-', (50, 58))	('H3R8me2s', 'Var', (50, 58))	('PRMT5', 'Gene', (62, 67))
183848	30008914	PRMT5 is responsible for methylating p53 and PRMT5 depletion triggers p53-dependent apoptosis.	('p53-dependent apoptosis', 'CPA', (70, 93))	('PRMT5', 'Gene', '27374', (0, 5))	('triggers', 'Reg', (61, 69))	('PRMT5', 'Gene', (0, 5))	('PRMT5', 'Gene', '27374', (45, 50))	('depletion', 'Var', (51, 60))	('PRMT5', 'Gene', (45, 50))
183949	20472805	Rearrangements of Ig genes are characteristic features of normal B cells and B cell-lineage lymphomas, whereas almost all normal myeloid and T cells are negative.	('B cell-lineage', 'CPA', (77, 91))	('Rearrangements', 'Var', (0, 14))	('Ig genes', 'Gene', (18, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('lymphomas', 'Disease', 'MESH:D008223', (92, 101))	('lymphomas', 'Disease', (92, 101))	('lymphomas', 'Phenotype', 'HP:0002665', (92, 101))	('B cell-lineage lymphomas', 'Phenotype', 'HP:0012191', (77, 101))
183960	20472805	Among the 5 cases with TCRbeta rearrangements, 3 had been diagnosed as HS and 2 as HAL.	('TCRbeta', 'Gene', (23, 30))	('TCRbeta', 'Gene', '21577', (23, 30))	('HAL', 'Chemical', '-', (83, 86))	('rearrangements', 'Var', (31, 45))
183996	20472805	The results of IHC analyses of HAL using antibodies to F4/80, Mac-2, lysozyme, and PAX5 were not remarkably different from those seen with HS.	('Mac-2', 'Gene', '16854', (62, 67))	('PAX5', 'Gene', '18507', (83, 87))	('HAL', 'Chemical', '-', (31, 34))	('F4/80', 'Gene', (55, 60))	('lysozyme', 'Gene', (69, 77))	('antibodies', 'Var', (41, 51))	('F4/80', 'Gene', '13733', (55, 60))	('PAX5', 'Gene', (83, 87))	('Mac-2', 'Gene', (62, 67))	('lysozyme', 'Gene', '4069', (69, 77))
184038	20472805	The etiology of HS in humans is not known, although recent studies indicated that genetic or epigenetic inactivation of PTEN, p16INK4A, and p14ARF may play a role in some cases of both species.	('genetic', 'Var', (82, 89))	('p14ARF', 'Gene', (140, 146))	('humans', 'Species', '9606', (22, 28))	('p16INK4A', 'Gene', (126, 134))	('PTEN', 'Gene', (120, 124))	('epigenetic inactivation', 'Var', (93, 116))	('play', 'Reg', (151, 155))	('PTEN', 'Gene', '5728', (120, 124))	('p14ARF', 'Gene', '1029', (140, 146))	('p16INK4A', 'Gene', '1029', (126, 134))
184057	21209796	Accordingly, cell invasion decreased after treatment with the ROCK inhibitor Y27632, but not with the matrix protease inhibitor Ro 28-2653.	('Ro 28-2653', 'Chemical', 'MESH:C453902', (128, 138))	('Y27632', 'Var', (77, 83))	('cell invasion', 'CPA', (13, 26))	('decreased', 'NegReg', (27, 36))	('Y27632', 'Chemical', 'MESH:C108830', (77, 83))
184060	21209796	Neoplastic transformation is a gradual process, during which cells acquire successive mutations, which mainly cause the loss of proliferation control, the ability to divide indefinitely and invade other tissues.	('mutations', 'Var', (86, 95))	('rat', 'Species', '10116', (135, 138))	('Neoplastic transformation', 'Disease', (0, 25))	('Neoplastic transformation', 'Disease', 'MESH:D002471', (0, 25))	('loss', 'NegReg', (120, 124))	('proliferation control', 'CPA', (128, 149))
184069	21209796	For example, inhibition of matrix proteases or integrins inhibits mesenchymal migration and promotes a transition towards amoeboid movement.	('mesenchymal migration', 'CPA', (66, 87))	('promotes', 'PosReg', (92, 100))	('matrix proteases', 'Protein', (27, 43))	('rat', 'Species', '10116', (81, 84))	('inhibition', 'Var', (13, 23))	('integrins', 'Protein', (47, 56))	('transition towards amoeboid movement', 'CPA', (103, 139))	('inhibits', 'NegReg', (57, 65))
184075	21209796	Studying cells at different phases of transformation, we could show that an early event during transformation was the loss of expression of the CDKN2A locus, followed by inactivation of p53 and overexpression of c-myc.	('c-myc', 'Gene', (212, 217))	('overexpression', 'PosReg', (194, 208))	('expression', 'MPA', (126, 136))	('p53', 'Protein', (186, 189))	('loss of', 'NegReg', (118, 125))	('CDKN2A', 'Gene', (144, 150))	('inactivation', 'Var', (170, 182))	('c-myc', 'Gene', '4609', (212, 217))
184084	21209796	In particular, we used cen3tel cells at five phases of propagation (up to around population doubling (PD) 1000): early cen3tel cells, these cells are at the initial passages after infection with the hTERT containing retrovirus (between PDs 34 and 45) and show a behaviour similar to that of primary cen3 fibroblasts; mid cen3tel cells (around PD 100), these cells are at an early phase of transformation, they are able to grow in the absence of solid support, but are not tumorigenic in nude mice; tumorigenic cen3tel cells, which induce tumors when inoculated subcutaneously into nude mice, were further subdivided in three groups, according to the time required for tumor formation, which decreases at increasing PDs (see first section of the Results), tumorigenic cells of phase I (around PD 160), phase II (around PD 600) and phase III (around PD 1000).	('nude mice', 'Species', '10090', (581, 590))	('cen3', 'Gene', (299, 303))	('cen3', 'Gene', '1070', (299, 303))	('PDs', 'Chemical', 'MESH:D010165', (715, 718))	('tumor', 'Phenotype', 'HP:0002664', (538, 543))	('tumor', 'Disease', (472, 477))	('around PD 600', 'Var', (811, 824))	('tumor', 'Phenotype', 'HP:0002664', (498, 503))	('tumors', 'Phenotype', 'HP:0002664', (538, 544))	('tumor', 'Disease', 'MESH:D009369', (472, 477))	('cen3', 'Gene', (510, 514))	('cen3', 'Gene', '1070', (510, 514))	('cen3', 'Gene', (321, 325))	('tumor', 'Disease', (668, 673))	('cen3', 'Gene', '1070', (321, 325))	('PDs', 'Chemical', 'MESH:D010165', (236, 239))	('tumor', 'Disease', (755, 760))	('tumors', 'Disease', (538, 544))	('tumor', 'Disease', 'MESH:D009369', (668, 673))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('tumor', 'Disease', 'MESH:D009369', (755, 760))	('cen3', 'Gene', '1070', (119, 123))	('cen3', 'Gene', (119, 123))	('tumor', 'Disease', (538, 543))	('tumors', 'Disease', 'MESH:D009369', (538, 544))	('nude mice', 'Species', '10090', (487, 496))	('tumor', 'Disease', (498, 503))	('tumor', 'Disease', 'MESH:D009369', (538, 543))	('tumor', 'Phenotype', 'HP:0002664', (668, 673))	('cen3', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (755, 760))	('cen3', 'Gene', '1070', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (498, 503))
184105	21209796	Total RNA was extracted using the Trizol reagent (Invitrogen) from actively dividing primary fibroblasts (PD 15) and from cen3tel cells representing the five phases of propagation (PD 37, 97, 167, 618, 1032 and 1042; cells at PDs 1032 and 1042 both represent cells of tumorigenic phase III).	('PDs 1032', 'Var', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (268, 273))	('PD', 'Var', (181, 183))	('PDs', 'Chemical', 'MESH:D010165', (226, 229))	('cen3', 'Gene', (122, 126))	('Trizol', 'Chemical', 'MESH:C411644', (34, 40))	('cen3', 'Gene', '1070', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
184127	21209796	In contrast, in the lung of 10 out of 10 mice injected with cen3tel cells around PD 1000, a high number of metastases (always more than 50 metastatic foci per lung) were observed 4 weeks after injection (Figure 1G).	('PD 1000', 'Var', (81, 88))	('mice', 'Species', '10090', (41, 45))	('metastases', 'Disease', 'MESH:D009362', (107, 117))	('cen3', 'Gene', (60, 64))	('cen3', 'Gene', '1070', (60, 64))	('metastases', 'Disease', (107, 117))
184133	21209796	In particular, in cen3tel cells around PD 1000, there was no clear increase in in vitro invasion, that could be related to the acquisition of the metastatic ability.	('cen3', 'Gene', '1070', (18, 22))	('cen3', 'Gene', (18, 22))	('in in vitro invasion', 'CPA', (76, 96))	('PD 1000', 'Var', (39, 46))
184153	21209796	To test the roles of ROCK and metalloproteases on cen3tel cell invasiveness, we analyzed the invasive ability of cen3tel cells at the three stages of tumorigenesis in the presence of the ROCK inhibitor Y27632 or in the presence of the metalloprotease inhibitor Ro 28-2653.	('Ro 28-2653', 'Chemical', 'MESH:C453902', (261, 271))	('Y27632', 'Chemical', 'MESH:C108830', (202, 208))	('cen3', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cen3', 'Gene', (113, 117))	('cen3', 'Gene', '1070', (50, 54))	('Y27632', 'Var', (202, 208))	('cen3', 'Gene', '1070', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
184154	21209796	4B, Y27632 reduced the invasiveness of cen3tel cells at all three different stages (black columns), while the metalloprotease inhibitor did not affect it (grey columns).	('reduced', 'NegReg', (11, 18))	('Y27632', 'Chemical', 'MESH:C108830', (4, 10))	('cen3', 'Gene', (39, 43))	('cen3', 'Gene', '1070', (39, 43))	('Y27632', 'Var', (4, 10))
184177	21209796	In mouse 3T3 fibroblasts a switch to amoeboid movement was observed upon p53 inactivation, while up-regulation of the Rho/ROCK signalling was found in highly metastatic rat sarcoma cells, together with the loss of MMP2 activity and an increased generation of protrusive forces, typical of the amoeboid movement.	('rat', 'Species', '10116', (169, 172))	('up-regulation', 'PosReg', (97, 110))	('activity', 'MPA', (219, 227))	('mouse', 'Species', '10090', (3, 8))	('p53', 'Gene', (73, 76))	('sarcoma', 'Disease', (173, 180))	('Rho/ROCK signalling', 'MPA', (118, 137))	('3T3', 'CellLine', 'CVCL:0594', (9, 12))	('rat', 'Species', '10116', (249, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('MMP2', 'Enzyme', (214, 218))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))	('inactivation', 'Var', (77, 89))	('loss', 'NegReg', (206, 210))
184178	21209796	Moreover, it has been shown that microtubule destabilization through stathmin overexpression can also lead to acquisition of amoeboid movement in sarcoma cells and that the tumor suppressor protein p27kip1 is an important factor for the control of cellular morphology and motility of transformed fibroblasts by regulating microtubule stability.	('stathmin', 'Gene', '3925', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('stathmin', 'Gene', (69, 77))	('regulating', 'Reg', (311, 321))	('microtubule', 'MPA', (33, 44))	('p27kip1', 'Gene', (198, 205))	('sarcoma', 'Disease', (146, 153))	('destabilization', 'NegReg', (45, 60))	('amoeboid movement', 'CPA', (125, 142))	('lead', 'Reg', (102, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('microtubule stability', 'MPA', (322, 343))	('acquisition', 'PosReg', (110, 121))	('overexpression', 'Var', (78, 92))	('p27kip1', 'Gene', '1027', (198, 205))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
184187	21209796	showed that overexpression of Rnd3 in mouse embryonic fibroblasts in which amoeboid migration had been induced by p53 knockdown led to reduced invasion.	('mouse', 'Species', '10090', (38, 43))	('overexpression', 'PosReg', (12, 26))	('p53', 'Gene', (114, 117))	('knockdown', 'Var', (118, 127))	('invasion', 'CPA', (143, 151))	('reduced', 'NegReg', (135, 142))	('amoeboid migration', 'CPA', (75, 93))	('Rnd3', 'Gene', (30, 34))	('rat', 'Species', '10116', (87, 90))
184188	21209796	Our observation that ectopic Rnd3 expression in phase II and III tumorigenic cen3tel cells reduced their invasive capacity points to Rnd3 as a possible regulator of invasion of cells of mesenchymal origin.	('tumor', 'Disease', (65, 70))	('Rnd3', 'Gene', (29, 33))	('invasive capacity', 'CPA', (105, 122))	('ectopic', 'Var', (21, 28))	('reduced', 'NegReg', (91, 98))	('cen3', 'Gene', '1070', (77, 81))	('cen3', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
184189	21209796	In addition, the low levels of myosin phosphorylation in Rnd3 transfected clones is in agreement with the hypothesis that Rnd3 hampers amoeboid movement by inhibiting ROCK kinase activity.	('ROCK kinase activity', 'MPA', (167, 187))	('Rnd3', 'Gene', (57, 61))	('myosin', 'Gene', (31, 37))	('Rnd3', 'Var', (122, 126))	('hampers', 'NegReg', (127, 134))	('myosin', 'Gene', '79784', (31, 37))	('inhibiting', 'NegReg', (156, 166))	('amoeboid movement', 'CPA', (135, 152))
184197	21209796	Recent studies suggest that even normal cells can disseminate and dissemination from primary tumors can actually precede the ability to form metastases; additional genetic or epigenetic changes are then required for the subsequent production of metastases.	('metastases', 'Disease', (245, 255))	('epigenetic changes', 'Var', (175, 193))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('metastases', 'Disease', 'MESH:D009362', (141, 151))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('metastases', 'Disease', 'MESH:D009362', (245, 255))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('metastases', 'Disease', (141, 151))
184313	30558620	Final pathology demonstrated 38x20x18 cm tumor with 70% gross necrosis and R0 resection.	('38x20x18 cm', 'Var', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('necrosis', 'Disease', (62, 70))	('necrosis', 'Disease', 'MESH:D009336', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
184349	29755264	Many soft-tissue tumours are characterised by recurrent chromosomal rearrangements commonly translocations that produce specific gene fusions which allow precise classification of tumours.	('tumours', 'Disease', 'MESH:D009369', (180, 187))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Disease', (180, 187))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('translocations', 'Var', (92, 106))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Disease', (17, 24))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))
184366	29755264	A rearrangement fuses the EWSR1 gene with part of the FLI1 gene forming the EWSR1/FLI1 fusion gene in the vast majority of cases.	('EWSR1', 'Gene', '2130', (26, 31))	('EWSR1', 'Gene', (76, 81))	('FLI1', 'Gene', '2313', (54, 58))	('EWSR1', 'Gene', (26, 31))	('FLI1', 'Gene', (54, 58))	('EWSR1', 'Gene', '2130', (76, 81))	('FLI1', 'Gene', '2313', (82, 86))	('rearrangement', 'Var', (2, 15))	('FLI1', 'Gene', (82, 86))
184398	29755264	In terms of prognosis, there is some data to suggest that metastatic tumours with a PAX7-FOXO1 fusion behave less aggressively than those with a PAX3-FOXO1 fusion as discussed below.	('PAX7', 'Gene', (84, 88))	('tumours', 'Disease', (69, 76))	('PAX3', 'Gene', '5077', (145, 149))	('FOXO1', 'Gene', (150, 155))	('FOXO1', 'Gene', '2308', (150, 155))	('FOXO1', 'Gene', '2308', (89, 94))	('PAX7', 'Gene', '5081', (84, 88))	('FOXO1', 'Gene', (89, 94))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))	('fusion', 'Var', (95, 101))	('PAX3', 'Gene', (145, 149))
184415	29755264	MDM2 is an oncogene and expression of this promotes degradation of the tumour suppressor protein p53.	('tumour', 'Disease', (71, 77))	('p53', 'Gene', (97, 100))	('promotes', 'PosReg', (43, 51))	('degradation of', 'MPA', (52, 66))	('p53', 'Gene', '7157', (97, 100))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('MDM2', 'Gene', (0, 4))	('expression', 'Var', (24, 34))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
184416	29755264	The adjacent gene CDK4 on 12q14.1 is frequently amplified when MDM2 is amplified and its protein product phosphorylates the retinoblastoma 1 protein (RB) which disrupts its interactions with E2F transcription factors allowing progression of the cell cycle form G1 to S phase.	('retinoblastoma 1', 'Gene', (124, 140))	('retinoblastoma 1', 'Gene', '5925', (124, 140))	('cell cycle form G1 to S phase', 'CPA', (245, 274))	('amplified', 'Var', (71, 80))	('retinoblastoma', 'Phenotype', 'HP:0009919', (124, 138))	('RB', 'Protein', (150, 152))	('MDM2', 'Gene', (63, 67))	('interactions', 'Interaction', (173, 185))	('disrupts', 'NegReg', (160, 168))	('CDK4', 'Gene', (18, 22))
184420	29755264	On histology the differential diagnosis includes other lipomatous tumours such as chondroid lipoma or myxolipoma, extraskeletal myxoid chondrosarcoma, myxofibrosarcoma and myxoma Cytogenetic studies have shown that myxoid liposarcoma (MXLS) is characterised by a specific translocation, t(12;16) resulting in the juxtaposition of FUS (fused in sarcoma) and DDIT3 (DNA-damage-inducible transcript 3) or the EWS (Ewing sarcoma breakpoint region 1).	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('myxoid chondrosarcoma', 'Disease', (128, 149))	('juxtaposition', 'MPA', (313, 326))	('fused in sarcoma', 'Gene', (335, 351))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('liposarcoma', 'Phenotype', 'HP:0012034', (222, 233))	('lipoma', 'Phenotype', 'HP:0012032', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('chondroid lipoma or myxolipoma', 'Disease', (82, 112))	('EWS', 'Gene', (406, 409))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (411, 424))	('chondroid lipoma or myxolipoma', 'Disease', 'MESH:D008067', (82, 112))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (135, 149))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (215, 233))	('t(12;16', 'Var', (287, 294))	('lipomatous tumours', 'Disease', (55, 73))	('fused in sarcoma', 'Gene', '2521', (335, 351))	('lipoma', 'Phenotype', 'HP:0012032', (55, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (417, 424))	('lipoma', 'Phenotype', 'HP:0012032', (92, 98))	('myxoid liposarcoma', 'Disease', (215, 233))	('Ewing sarcoma breakpoint region 1', 'Gene', (411, 444))	('FUS', 'Gene', (330, 333))	('lipomatous tumours', 'Disease', 'MESH:D008080', (55, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('DDIT3', 'Gene', '1649', (357, 362))	('DNA-damage-inducible transcript 3', 'Gene', (364, 397))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (215, 233))	('myxofibrosarcoma and myxoma', 'Disease', 'MESH:D009232', (151, 178))	('MXLS', 'Phenotype', 'HP:0012268', (235, 239))	('EWS', 'Gene', '2130', (406, 409))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (411, 444))	('sarcoma', 'Phenotype', 'HP:0100242', (344, 351))	('FUS', 'Gene', '2521', (330, 333))	('lipomatous tumour', 'Phenotype', 'HP:0012031', (55, 72))	('DNA-damage-inducible transcript 3', 'Gene', '1649', (364, 397))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (128, 149))	('DDIT3', 'Gene', (357, 362))
184427	29755264	LGFMS is characterised by a recurrent a t(7;16)(q34;p11).	('t(7;16)(q34;p11', 'Var', (40, 55))	('LGFMS', 'Disease', (0, 5))	('t(7;16)(q34;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (40, 56))
184429	29755264	This is present in about 95% of cases with a smaller number of cases harboring a FUS-CREB3L1 fusion resulting from t(11;16)(p11;p11).	('FUS', 'Gene', (81, 84))	('FUS', 'Gene', '2521', (81, 84))	('t(11;16)(p11;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (115, 132))	('CREB3L1', 'Gene', (85, 92))	('t(11;16)(p11;p11', 'Var', (115, 131))	('CREB3L1', 'Gene', '90993', (85, 92))
184433	29755264	However these proliferations consistently show a t(17;22)(p13;q13) representing a USP6-MYH9 fusion.	('t(17;22)(p13;q13', 'Var', (49, 65))	('t(17;22)(p13;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 66))	('MYH9', 'Gene', '4627', (87, 91))	('MYH9', 'Gene', (87, 91))	('USP6', 'Gene', '9098', (82, 86))	('USP6', 'Gene', (82, 86))
184442	29755264	It has been reported that the presence of a PAX3-FOXO1 fusion carries a worse prognosis than a PAX7-FOXO1 fusion.	('PAX7', 'Gene', (95, 99))	('PAX3', 'Gene', '5077', (44, 48))	('PAX3', 'Gene', (44, 48))	('PAX7', 'Gene', '5081', (95, 99))	('FOXO1', 'Gene', '2308', (49, 54))	('FOXO1', 'Gene', (100, 105))	('presence', 'Var', (30, 38))	('FOXO1', 'Gene', '2308', (100, 105))	('FOXO1', 'Gene', (49, 54))
184444	29755264	Those non-fusion cases are molecularly and clinically indistinguishable from embryonal rhabdomyosarcoma despite their histology.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (77, 103))	('embryonal rhabdomyosarcoma', 'Disease', (77, 103))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (77, 103))	('non-fusion', 'Var', (6, 16))
184447	29755264	Emerging biomarkers at the forefront of active research in this area include MYOD1 mutations, RAS pathway mutations and NCOA2 gene fusions.	('NCOA2', 'Gene', '10499', (120, 125))	('gene fusions', 'Var', (126, 138))	('mutations', 'Var', (83, 92))	('NCOA2', 'Gene', (120, 125))	('MYOD1', 'Gene', '4654', (77, 82))	('mutations', 'Var', (106, 115))	('MYOD1', 'Gene', (77, 82))	('RAS pathway', 'Pathway', (94, 105))
184451	29755264	It has been reported that those patients with an SYT-SSX1 fusion have poorer median survival than those possessing the SYT-SSX2 fusion gene.	('median survival', 'MPA', (77, 92))	('SYT', 'Gene', (49, 52))	('patients', 'Species', '9606', (32, 40))	('SSX2', 'Gene', '6757', (123, 127))	('fusion', 'Var', (58, 64))	('poorer', 'NegReg', (70, 76))	('SYT', 'Gene', '6760', (49, 52))	('SSX1', 'Gene', (53, 57))	('SYT', 'Gene', '6760', (119, 122))	('SSX2', 'Gene', (123, 127))	('SYT', 'Gene', (119, 122))	('SSX1', 'Gene', '6756', (53, 57))
184452	29755264	Indeed in one large study, the median survival was twice that for those with the SSX2 variant.	('SSX2', 'Gene', (81, 85))	('variant', 'Var', (86, 93))	('SSX2', 'Gene', '6757', (81, 85))
184453	29755264	Additionally the presence of the SYT-SSX1 has been reported to double the risk of developing metastatic disease.	('SSX1', 'Gene', '6756', (37, 41))	('SSX1', 'Gene', (37, 41))	('SYT', 'Gene', (33, 36))	('presence', 'Var', (17, 25))	('SYT', 'Gene', '6760', (33, 36))
184455	29755264	Other biomarkers which have been proposed as markers of poor prognosis include aberrant expression of p53 as well as expression of insulin-like growth factor receptors 1 and 2.	('p53', 'Gene', '7157', (102, 105))	('aberrant', 'Var', (79, 87))	('expression', 'MPA', (88, 98))	('p53', 'Gene', (102, 105))
184462	29755264	STAT6 is present in all variants of SFT and is maintained in more aggressive tumours unlike CD34.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('variants', 'Var', (24, 32))	('CD34', 'Gene', (92, 96))	('CD34', 'Gene', '947', (92, 96))	('tumours', 'Disease', (77, 84))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('STAT6', 'Gene', (0, 5))	('SFT', 'Gene', (36, 39))	('STAT6', 'Gene', '6778', (0, 5))
184483	29755264	In particular many soft tissue tumours have distinctive fusion gene products resulting from chromosomal translocations that are most efficiently identified by FISH or RTPCR.	('fusion gene', 'Var', (56, 67))	('chromosomal translocations', 'Var', (92, 118))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('resulting from', 'Reg', (77, 91))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('tumours', 'Disease', (31, 38))
184484	29755264	In some tumours, for example, alveolar rhabdomyosarcoma different gene fusions or absence of these gene fusions has a more significant effect on prognosis than histology such that cytogenetics is now mandatory.	('tumours', 'Disease', (8, 15))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (30, 55))	('gene fusions', 'Var', (66, 78))	('effect', 'Reg', (135, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('alveolar rhabdomyosarcoma', 'Disease', (30, 55))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (30, 55))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (39, 55))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
184488	25614489	Two recent in vivo studies are highlighted, providing additional support for the importance of Wnt signaling in synovial sarcoma: one uses a conditional mouse model where knockout of beta-catenin prevents tumor formation, and another uses a small molecule inhibitor of beta-catenin in xenograft models.	('beta-catenin', 'Protein', (183, 195))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('synovial sarcom', 'Phenotype', 'HP:0012570', (112, 127))	('synovial sarcoma', 'Disease', (112, 128))	('prevents', 'NegReg', (196, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('knockout', 'Var', (171, 179))	('mouse', 'Species', '10090', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (112, 128))	('synovial sarcoma', 'Disease', 'MESH:D013584', (112, 128))
184494	25614489	Multiple lines of evidence implicate SS18-SSX as the central genetic "driver" in this cancer: i) its presence as the sole cytogenetic anomaly in up to a third of cases, ii) the low frequency of additional mutations, iii) its preservation in metastatic and advanced lesions, iv) the death of synovial sarcoma cells upon SS18-SSX knockdown and v) its ability to induce tumors in conditional mouse models with identical histology, orthologous gene expression and immunophenotype, with 100% penetrance.	('tumors', 'Disease', (367, 373))	('mouse', 'Species', '10090', (389, 394))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (291, 307))	('synovial sarcom', 'Phenotype', 'HP:0012570', (291, 306))	('tumors', 'Disease', 'MESH:D009369', (367, 373))	('sarcoma', 'Phenotype', 'HP:0100242', (300, 307))	('knockdown', 'Var', (328, 337))	('death of synovial sarcoma', 'Disease', 'MESH:D013584', (282, 307))	('SSX', 'Gene', '6757', (42, 45))	('cancer', 'Disease', (86, 92))	('anomaly', 'Disease', 'MESH:D000014', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('SSX', 'Gene', '6757', (324, 327))	('SSX', 'Gene', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (367, 373))	('death of synovial sarcoma', 'Disease', (282, 307))	('anomaly', 'Disease', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('SSX', 'Gene', (324, 327))
184497	25614489	Thaete and colleagues showed association of both SS18 and SS18-SSX with the DNA-dependent ATPase BRM, the catalytic subunit of SWI/SNF chromatin remodeling complexes.	('BRM', 'Gene', '6595', (97, 100))	('ATPase', 'Gene', '1769', (90, 96))	('ATPase', 'Gene', (90, 96))	('BRM', 'Gene', (97, 100))	('SSX', 'Gene', '6757', (63, 66))	('SSX', 'Gene', (63, 66))	('association', 'Interaction', (29, 40))	('SS18', 'Var', (49, 53))
184501	25614489	In contrast to the results of Middlejans, these authors observed that expression of the fusion oncogene induced depletion of the BAF47 (SMARCB1) subunit from the SWI-SNF complex, in experiments using transiently expressed GFP-tagged SS18-SSX in a HEK293 background.	('SSX', 'Gene', '6757', (238, 241))	('HEK293', 'CellLine', 'CVCL:0045', (247, 253))	('depletion', 'MPA', (112, 121))	('BAF47', 'Gene', '6598', (129, 134))	('expression', 'Var', (70, 80))	('SSX', 'Gene', (238, 241))	('BAF47', 'Gene', (129, 134))
184503	25614489	Both studies suggest that SMARCB1's association with SWI/SNF may be more labile than for other subunits, and it is conceivable that SMARCB1 is displaced from SWI/SNF by aberrant protein interactions involving SS18-SSX.	('protein', 'Protein', (178, 185))	('SMARCB1', 'Gene', (132, 139))	('SSX', 'Gene', '6757', (214, 217))	('SSX', 'Gene', (214, 217))	('SMARCB1', 'Gene', (26, 33))	('interactions', 'Interaction', (186, 198))	('aberrant', 'Var', (169, 177))
184508	25614489	Of potential importance, synthetic lethalities may be explored by analogy to rhabdoid tumors, where for example tumorigenesis was found to depend on functional BRG1 in the residual SWI/SNF complex.	('BRG1', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('rhabdoid tumors', 'Disease', (77, 92))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (77, 92))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('functional', 'Var', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('BRG1', 'Gene', '6597', (160, 164))	('depend', 'Reg', (139, 145))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
184510	25614489	Importantly, recent exome sequencing studies have found mutations in SWI/SNF complex members in 20% of cases across a broad spectrum of tumor types, surveyed by Kadoch et al, who review the importance of this complex in tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (220, 225))	('found', 'Reg', (50, 55))	('SWI/SNF', 'Gene', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (136, 141))
184512	25614489	SMARCB1 and BRG1 inactivation lead to increased proliferation, at least in part due to impaired transcriptional activation of the CDKN2A/B tumor suppressors.	('impaired', 'NegReg', (87, 95))	('CDKN2A/B', 'Gene', (130, 138))	('inactivation', 'Var', (17, 29))	('transcriptional activation', 'MPA', (96, 122))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('BRG1', 'Gene', (12, 16))	('proliferation', 'CPA', (48, 61))	('BRG1', 'Gene', '6597', (12, 16))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('CDKN2A/B', 'Gene', '1029;1030', (130, 138))	('SMARCB1', 'Gene', (0, 7))	('increased', 'PosReg', (38, 47))
184515	25614489	Other mechanisms of SWI/SNF oncogenesis have been elaborated, including mutations in ARID1A where it has been suggested that functional SWI/SNF is required to execute the p53 transcriptional response.	('mutations', 'Var', (72, 81))	('ARID1A', 'Gene', (85, 91))	('p53', 'Gene', (171, 174))	('p53', 'Gene', '7157', (171, 174))	('ARID1A', 'Gene', '8289', (85, 91))
184516	25614489	Although not shown in synovial sarcoma, such an effect may explain the lack of p53 mutation in the majority of these lesions.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('mutation', 'Var', (83, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (22, 38))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (22, 38))	('synovial sarcoma', 'Disease', (22, 38))	('synovial sarcom', 'Phenotype', 'HP:0012570', (22, 37))
184543	25614489	Expression in later stage Myf6 myoblasts caused myopathy but no tumors, whereas cleavage-stage embryo expression or conditional expression in earlier (Pax3 or Pax7) myoblast populations was embryonic lethal, as was expression of SS18-SSX2 in early ectoderm (Ap2), bone/cartilage (Sox9), endothelial (Flk1; Tie2) or neural (Nestin1) precursor populations.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cartilage', 'Disease', 'MESH:D002357', (269, 278))	('Expression', 'Var', (0, 10))	('Pax7', 'Gene', (159, 163))	('myopathy', 'Disease', (48, 56))	('myopathy', 'Phenotype', 'HP:0003198', (48, 56))	('Tie2', 'Gene', '7010', (306, 310))	('Sox9', 'Gene', (280, 284))	('Pax3', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('caused', 'Reg', (41, 47))	('Ap2', 'Gene', (258, 261))	('Sox9', 'Gene', '6662', (280, 284))	('Myf6', 'Gene', '4618', (26, 30))	('SSX2', 'Gene', (234, 238))	('Myf6', 'Gene', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('SSX2', 'Gene', '6757', (234, 238))	('Flk1', 'Gene', '3791', (300, 304))	('Pax7', 'Gene', '5081', (159, 163))	('Flk1', 'Gene', (300, 304))	('myopathy', 'Disease', 'MESH:D009135', (48, 56))	('cartilage', 'Disease', (269, 278))	('Tie2', 'Gene', (306, 310))	('Ap2', 'Gene', '7020', (258, 261))	('Pax3', 'Gene', '5077', (151, 155))
184557	25614489	Additional genomic copy number changes, which are more common in adult (>18 years) than pediatric patients, are strongly associated with metastatic spread and poor outcomes.	('patients', 'Species', '9606', (98, 106))	('genomic copy number changes', 'Var', (11, 38))	('associated', 'Reg', (121, 131))	('metastatic spread', 'CPA', (137, 154))
184559	25614489	In keeping with the observed chromosomal stability, the most commonly mutated gene in human cancer, TP53, is rarely mutated in synovial sarcoma, occurring in 11 of 92 cases across three published studies; in these studies copy number gains in the p53 suppressing oncogene MDM2 were somewhat more frequent.	('TP53', 'Gene', '7157', (100, 104))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('synovial sarcoma', 'Disease', (127, 143))	('TP53', 'Gene', (100, 104))	('human', 'Species', '9606', (86, 91))	('synovial sarcom', 'Phenotype', 'HP:0012570', (127, 142))	('p53', 'Gene', '7157', (247, 250))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (127, 143))	('MDM2', 'Gene', '4193', (272, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('MDM2', 'Gene', (272, 276))	('copy number gains', 'Var', (222, 239))	('synovial sarcoma', 'Disease', 'MESH:D013584', (127, 143))	('p53', 'Gene', (247, 250))
184561	25614489	Otherwise, targeted sequencing approaches have highlighted mutations in PTEN, CTNNB1 and APC in 8-14% of cases, providing some support for oncogenic activation of the Akt/mTOR and Wnt signaling pathways in this sarcoma (see below).	('APC', 'Disease', 'MESH:D011125', (89, 92))	('PTEN', 'Gene', (72, 76))	('CTNNB1', 'Gene', (78, 84))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('Akt', 'Gene', '207', (167, 170))	('PTEN', 'Gene', '5728', (72, 76))	('APC', 'Disease', (89, 92))	('sarcoma', 'Disease', (211, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('CTNNB1', 'Gene', '1499', (78, 84))	('mutations', 'Var', (59, 68))	('mTOR', 'Gene', (171, 175))	('Akt', 'Gene', (167, 170))	('mTOR', 'Gene', '2475', (171, 175))	('activation', 'PosReg', (149, 159))
184579	25614489	Sanger sequencing studies found canonical activating mutations in CTNNB1, at frequencies of 4% (N=24), 8%(N=49) and 12% (N=16), and APC mutations in 8% (N=49) of cases.	('activating', 'PosReg', (42, 52))	('mutations', 'Var', (53, 62))	('CTNNB1', 'Gene', (66, 72))	('APC', 'Disease', 'MESH:D011125', (132, 135))	('APC', 'Disease', (132, 135))	('CTNNB1', 'Gene', '1499', (66, 72))
184581	25614489	The SYO-1 synovial sarcoma cell line harbors a codon 34 mutation in CTNNB1 (G34L) with concomitant protein accumulation and shows reduced proliferation and impairment in standard invasion and migration assays when transfected with an inhibitory dominant negative LEF1 construct (Saito T, Motoi T, Ladanyi M, unpublished data).	('LEF1', 'Gene', '51176', (263, 267))	('accumulation', 'PosReg', (107, 119))	('synovial sarcoma', 'Disease', (10, 26))	('impairment', 'NegReg', (156, 166))	('SYO-1', 'Gene', '55027', (4, 9))	('SYO-1', 'Gene', (4, 9))	('synovial sarcoma', 'Disease', 'MESH:D013584', (10, 26))	('CTNNB1', 'Gene', (68, 74))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (10, 26))	('LEF1', 'Gene', (263, 267))	('proliferation', 'CPA', (138, 151))	('G34L', 'Mutation', 'p.G34L', (76, 80))	('codon', 'Var', (47, 52))	('mutation', 'Var', (56, 64))	('protein', 'MPA', (99, 106))	('synovial sarcom', 'Phenotype', 'HP:0012570', (10, 25))	('reduced', 'NegReg', (130, 137))	('CTNNB1', 'Gene', '1499', (68, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))
184584	25614489	To confirm this observation in the human setting, they showed that pharmacologic activation of CSNK1A by pyrvinium, known to inhibit beta-catenin signaling, or RNAi knockdown of LRP6 could both impair growth of human synovial sarcoma cell lines.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('inhibit', 'NegReg', (125, 132))	('synovial sarcoma', 'Disease', 'MESH:D013584', (217, 233))	('LRP6', 'Gene', '4040', (178, 182))	('LRP6', 'Gene', (178, 182))	('CSNK1A', 'Gene', (95, 101))	('beta-catenin signaling', 'MPA', (133, 155))	('human', 'Species', '9606', (35, 40))	('synovial sarcom', 'Phenotype', 'HP:0012570', (217, 232))	('activation', 'PosReg', (81, 91))	('synovial sarcoma', 'Disease', (217, 233))	('knockdown', 'Var', (165, 174))	('impair', 'NegReg', (194, 200))	('human', 'Species', '9606', (211, 216))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (217, 233))	('pyrvinium', 'Chemical', 'MESH:C024631', (105, 114))
184587	25614489	In a separate recent study, Trautmann and colleagues found that introduction of SYT-SSX into HEK293 induced activation of Wnt/beta-catenin signaling.	('Wnt/beta-catenin signaling', 'Pathway', (122, 148))	('SSX', 'Gene', '6757', (84, 87))	('SSX', 'Gene', (84, 87))	('introduction', 'Var', (64, 76))	('HEK293', 'CellLine', 'CVCL:0045', (93, 99))	('activation', 'PosReg', (108, 118))
184592	25614489	In light of the recent finding that SYT-SSX may, under certain circumstances, displace SMARCB1 from SWI/SNF chromatin remodeling complexes, it is also notable that loss of SMARCB1 results in activation of Wnt/beta-catenin signaling in mouse and cell culture models, reflecting a role for the SWI/SNF complex in regulating this pathway.	('loss', 'Var', (164, 168))	('SMARCB1', 'Gene', (87, 94))	('displace', 'NegReg', (78, 86))	('SSX', 'Gene', '6757', (40, 43))	('SSX', 'Gene', (40, 43))	('activation', 'PosReg', (191, 201))	('Wnt/beta-catenin signaling', 'MPA', (205, 231))	('mouse', 'Species', '10090', (235, 240))	('SMARCB1', 'Gene', (172, 179))
184594	25614489	At the genetic level, PTEN mutations are only found in a minority of cases and canonical PIK3CA mutations are even more uncommon.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))
184596	25614489	As noted above, apoptosis induction in synovial sarcoma cell lines by HDAC inhibitors is at least partially dependent on derepression of EGR1 and subsequent induction of PTEN, a phenomenon which may help to identify strategic combinations involving these promising therapeutic agents.	('synovial sarcoma', 'Disease', (39, 55))	('inhibitors', 'Var', (75, 85))	('PTEN', 'Gene', (170, 174))	('HDAC', 'Gene', (70, 74))	('apoptosis', 'CPA', (16, 25))	('PTEN', 'Gene', '5728', (170, 174))	('HDAC', 'Gene', '9734', (70, 74))	('synovial sarcom', 'Phenotype', 'HP:0012570', (39, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (39, 55))	('synovial sarcoma', 'Disease', 'MESH:D013584', (39, 55))	('EGR1', 'Gene', (137, 141))	('derepression', 'Var', (121, 133))	('induction', 'Reg', (157, 166))	('EGR1', 'Gene', '1958', (137, 141))
184610	25614489	More closely tied to some of the biological dependencies of synovial sarcoma described above are efforts to test histone deacetylase inhibitors (including vorinostat: NCT01879085, NCT01294670) and IGF1R / mTOR inhibitor combinations (cixutumumab / temsirolimus: NCT01614795).	('NCT01294670', 'Var', (180, 191))	('synovial sarcom', 'Phenotype', 'HP:0012570', (60, 75))	('IGF1R', 'Gene', (197, 202))	('mTOR', 'Gene', (205, 209))	('synovial sarcoma', 'Disease', (60, 76))	('mTOR', 'Gene', '2475', (205, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('vorinostat', 'Chemical', 'MESH:D000077337', (155, 165))	('IGF1R', 'Gene', '3480', (197, 202))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (60, 76))	('synovial sarcoma', 'Disease', 'MESH:D013584', (60, 76))	('cixutumumab', 'Chemical', 'MESH:C557414', (234, 245))
184621	25614489	Potential immunogenic CT antigens expressed in synovial sarcoma but not normal tissues have been identified including NY-ESO-1, an antigen that is the basis for several open trials using strategies such as adoptive T-cell transfer (NCT01477021) or dendritic cell activation (NCT02122861).	('NCT02122861', 'Var', (275, 286))	('NY-ESO-1', 'Gene', '246100', (118, 126))	('synovial sarcoma', 'Disease', (47, 63))	('NY-ESO-1', 'Gene', (118, 126))	('synovial sarcom', 'Phenotype', 'HP:0012570', (47, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (47, 63))	('synovial sarcoma', 'Disease', 'MESH:D013584', (47, 63))	('NCT01477021', 'Var', (232, 243))
184638	25614489	A central role for deregulation of Wnt/beta-catenin signaling in synovial sarcoma has also been strengthened by recent in vivo studies.	('Wnt/beta-catenin', 'MPA', (35, 51))	('synovial sarcoma', 'Disease', 'MESH:D013584', (65, 81))	('synovial sarcom', 'Phenotype', 'HP:0012570', (65, 80))	('synovial sarcoma', 'Disease', (65, 81))	('deregulation', 'Var', (19, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (65, 81))
184664	25207234	Both monophasic and biphasic forms are characterized by a reciprocal chromosomal translocation (x; 18) (p11.2; q11.2) which results from the fusion of the SYT gene on chromosome 18 to either of two genes, SSX1 and SSX2 in the region xp11.	('SYT', 'Gene', (155, 158))	('SSX2', 'Gene', (214, 218))	('fusion', 'Var', (141, 147))	('SYT', 'Gene', '6857', (155, 158))	('results from', 'Reg', (124, 136))	('SSX1', 'Gene', '6756', (205, 209))	('SS', 'Phenotype', 'HP:0012570', (205, 207))	('SSX1', 'Gene', (205, 209))	('SSX2', 'Gene', '6757', (214, 218))	('SS', 'Phenotype', 'HP:0012570', (214, 216))
184679	21801306	Parallel, stable cell line RNAi knockdown of MMP-1 confirmed its role in cellular invasiveness.	('MMP-1', 'Gene', '4312', (45, 50))	('cellular invasiveness', 'CPA', (73, 94))	('knockdown', 'Var', (32, 41))	('MMP-1', 'Gene', (45, 50))
184695	21801306	Inhibition of prenylation has been explored as an anti-neoplastic strategy in various cancers, affecting numerous cellular processes and signalling cascades including Ras.	('Ras', 'Chemical', 'MESH:D011883', (167, 170))	('cellular', 'CPA', (114, 122))	('affecting', 'Reg', (95, 104))	('Ras', 'Disease', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('Inhibition', 'Var', (0, 10))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('prenylation', 'Protein', (14, 25))
184700	21801306	Based on what is known about prenylation and protein trafficking, inhibition of MMP-1 directional traffic is likely to have important effects on cell migration and tumour invasion particularly in human chondrosarcoma.	('chondrosarcoma', 'Disease', 'MESH:D002813', (202, 216))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('chondrosarcoma', 'Disease', (202, 216))	('cell migration', 'CPA', (145, 159))	('directional', 'CPA', (86, 97))	('human', 'Species', '9606', (196, 201))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (202, 216))	('MMP-1', 'Gene', '4312', (80, 85))	('inhibition', 'Var', (66, 76))	('tumour', 'Disease', (164, 170))	('effects', 'Reg', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('MMP-1', 'Gene', (80, 85))
184702	21801306	Inhibition of prenylation affects lamellipodia formation, MMP-1 localization into these structures and secretion.	('lamellipodia formation', 'CPA', (34, 56))	('MMP-1', 'Gene', '4312', (58, 63))	('MMP-1', 'Gene', (58, 63))	('secretion', 'MPA', (103, 112))	('Inhibition', 'Var', (0, 10))	('localization', 'MPA', (64, 76))	('prenylation', 'Protein', (14, 25))
184710	21801306	Stable clones were generated by pHuSH 29mer shRNA constructs targeting MMP-1 (#TR311450; OriGene, Rockville, MD, USA) and established by puromycin selection (Invitrogen; 1.0 mug/ml in the media above) on six-well plates.	('#TR311450;', 'Var', (78, 88))	('MMP-1', 'Gene', (71, 76))	('OriGene', 'Chemical', '-', (89, 96))	('puromycin', 'Chemical', 'MESH:D011691', (137, 146))	('MMP-1', 'Gene', '4312', (71, 76))
184729	21801306	Relative RT-qPCR was performed on AB 7900HT Fast Real-Time System using specific human TaqMan gene expression assays MMP-1 (#Hs00233958_m1), TIMP1 (#Hs00171558_m1), KRAS (#Hs00364282_m1), FNTA (#Hs00357739_m1).	('KRAS', 'Gene', '3845', (165, 169))	('TIMP1', 'Gene', '7076', (141, 146))	('FNTA', 'Gene', (188, 192))	('FNTA', 'Gene', '2339', (188, 192))	('MMP-1', 'Gene', '4312', (117, 122))	('#Hs00171558_m1', 'Var', (148, 162))	('#Hs00233958_m1', 'Var', (124, 138))	('#Hs00364282_m1', 'Var', (171, 185))	('#Hs00357739_m1', 'Var', (194, 208))	('MMP-1', 'Gene', (117, 122))	('human', 'Species', '9606', (81, 86))	('KRAS', 'Gene', (165, 169))	('TIMP1', 'Gene', (141, 146))
184732	21801306	Cells were stained with primary antibody against MMP-1 (#sc-21731; Santa Cruz), counterstained with DAPI (#D21490) and AL647-Phalloidin (#A-22287) both from Invitrogen (Molecular Probes, Eugene, OR, USA) for nuclei and F-actin respectively.	('DAPI', 'Chemical', 'MESH:C007293', (100, 104))	('AL647', 'Chemical', '-', (119, 124))	('MMP-1', 'Gene', '4312', (49, 54))	('Phalloidin', 'Chemical', 'MESH:D010590', (125, 135))	('MMP-1', 'Gene', (49, 54))	('#D21490', 'Var', (106, 113))	('#sc-21731', 'Var', (56, 65))
184733	21801306	The secondary antibody against MMP-1 was AL594 (#A-21201) from Molecular Probes.	('AL594', 'Chemical', '-', (41, 46))	('MMP-1', 'Gene', (31, 36))	('MMP-1', 'Gene', '4312', (31, 36))	('AL594', 'Var', (41, 46))
184742	21801306	FTI-276 prevents Ras farnesylation, efficiently blocking its plasma membrane translocation and consequentially increasing cytoplasmic concentration.	('Ras', 'Chemical', 'MESH:D011883', (17, 20))	('FTI-276', 'Chemical', '-', (0, 7))	('blocking', 'NegReg', (48, 56))	('cytoplasmic concentration', 'MPA', (122, 147))	('plasma membrane translocation', 'MPA', (61, 90))	('increasing', 'PosReg', (111, 121))	('FTI-276', 'Var', (0, 7))
184747	21801306	Farnesyl transferase inhibition decreases MMP-1 extracellular protein levels by 35% and this effect is reversed by FPP to 82% (Fig.	('MMP-1', 'Gene', '4312', (42, 47))	('MMP-1', 'Gene', (42, 47))	('inhibition', 'Var', (21, 31))	('Farnesyl transferase', 'Enzyme', (0, 20))	('decreases', 'NegReg', (32, 41))	('FPP', 'Chemical', 'MESH:C004808', (115, 118))
184768	21801306	3B) show that FPP increases both lamellipodia formation and MMP-1 localization (Fig.	('MMP-1', 'Gene', (60, 65))	('increases', 'PosReg', (18, 27))	('FPP', 'Var', (14, 17))	('localization', 'MPA', (66, 78))	('lamellipodia formation', 'CPA', (33, 55))	('FPP', 'Chemical', 'MESH:C004808', (14, 17))	('MMP-1', 'Gene', '4312', (60, 65))
184769	21801306	The surface area of lamellipodia changed with FTI-276, as did the MMP-1 localization within lamellipodia (Fig.	('MMP-1', 'Gene', '4312', (66, 71))	('FTI-276', 'Var', (46, 53))	('localization', 'MPA', (72, 84))	('changed', 'Reg', (33, 40))	('MMP-1', 'Gene', (66, 71))	('surface area', 'MPA', (4, 16))	('FTI-276', 'Chemical', '-', (46, 53))
184771	21801306	It was observed that FTI-276 results in depletion of MMP-1 in the lamellipodia area by 60% when compared to untreated cells (Fig.	('MMP-1', 'Gene', '4312', (53, 58))	('FTI-276', 'Var', (21, 28))	('MMP-1', 'Gene', (53, 58))	('FTI-276', 'Chemical', '-', (21, 28))
184785	21801306	FTI-276 decreased overall MMP-1 activity and eliminated peripheral foci of degradation which is in agreement with the Western blotting results.	('FTI-276', 'Chemical', '-', (0, 7))	('MMP-1', 'Gene', (26, 31))	('peripheral foci of degradation', 'MPA', (56, 86))	('eliminated', 'NegReg', (45, 55))	('decreased', 'NegReg', (8, 17))	('MMP-1', 'Gene', '4312', (26, 31))	('FTI-276', 'Var', (0, 7))
184786	21801306	Lamellipodia structures in the presence of FTI-276 are associated with less collagenase activity when compared to control or FPP treated cell population (MMP1-S-III, merged Fig.	('FTI-276', 'Chemical', '-', (43, 50))	('MMP1', 'Gene', '4312', (154, 158))	('less', 'NegReg', (71, 75))	('FTI-276', 'Var', (43, 50))	('MMP1', 'Gene', (154, 158))	('collagenase', 'Enzyme', (76, 87))	('FPP', 'Chemical', 'MESH:C004808', (125, 128))
184806	21801306	The MMP-14 levels gradually decreased in the clones (T6-4 > T6-5 > T6-7) and this observation did not correlate with the invasiveness patterns (Fig.	('T6-7', 'Gene', '154754', (67, 71))	('decreased', 'NegReg', (28, 37))	('MMP-14', 'Gene', (4, 10))	('T6-7', 'Gene', (67, 71))	('MMP-14', 'Gene', '4323', (4, 10))	('T6-4 > T6-5', 'Var', (53, 64))
184811	21801306	The fact that farnesylation regulates MMP-1 secretion at least in part at the level of mRNA expression suggests multiple reasons why the effect of FTI-276 on MMP-1 secretion may be delayed.	('MMP-1', 'Gene', '4312', (38, 43))	('MMP-1', 'Gene', '4312', (158, 163))	('FTI-276', 'Chemical', '-', (147, 154))	('MMP-1', 'Gene', (38, 43))	('MMP-1', 'Gene', (158, 163))	('regulates', 'Reg', (28, 37))	('FTI-276', 'Var', (147, 154))
184840	23588365	EWSR1 gene rearrangement is present in nearly all tumors tested, and likely involves a novel fusion partner.	('involves', 'Reg', (76, 84))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('EWSR1', 'Gene', '2130', (0, 5))	('rearrangement', 'Var', (11, 24))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('EWSR1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('men', 'Species', '9606', (20, 23))
184846	23588365	To date, studies have shown that approximately 40-50% of myoepithelial tumors (more often carcinomas) in soft tissue sites harbor EWSR1 rearrangement (and rarely alternate FUS rearrangement), and documented fusion partners include POU5F1, PBX1, and ZNF444.	('men', 'Species', '9606', (145, 148))	('EWSR1', 'Gene', '2130', (130, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('POU5F1', 'Gene', '5460', (231, 237))	('carcinomas', 'Disease', 'MESH:D002277', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (57, 77))	('ZNF444', 'Gene', (249, 255))	('men', 'Species', '9606', (185, 188))	('PBX1', 'Gene', (239, 243))	('men', 'Species', '9606', (200, 203))	('EWSR1', 'Gene', (130, 135))	('PBX1', 'Gene', '5087', (239, 243))	('rearrangement', 'Var', (136, 149))	('POU5F1', 'Gene', (231, 237))	('carcinomas', 'Disease', (90, 100))	('FUS', 'Gene', (172, 175))	('myoepithelial tumors', 'Disease', (57, 77))	('ZNF444', 'Gene', '55311', (249, 255))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('FUS', 'Gene', '2521', (172, 175))
184859	23588365	Two of these cases (cases 26 and 35) and two other cases (cases 17 and 27) had initially been tested for EWSR1 rearrangement at Brigham and Women's Hospital using similar methods.	('men', 'Species', '9606', (142, 145))	('rearrangement', 'Var', (111, 124))	('men', 'Species', '9606', (120, 123))	('EWSR1', 'Gene', (105, 110))	('Women', 'Species', '9606', (140, 145))	('EWSR1', 'Gene', '2130', (105, 110))
184924	23588365	Both lesions are positive for EMA; positivity for pan-keratin and CD34 and negativity for S-100 and GFAP favors epithelioid sarcoma.	('pan-keratin', 'Protein', (50, 61))	('CD34', 'Gene', (66, 70))	('EMA', 'Gene', '4582', (30, 33))	('GFAP', 'Gene', '2670', (100, 104))	('S-100', 'Gene', '6271', (90, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (112, 131))	('positivity', 'Var', (35, 45))	('epithelioid sarcoma', 'Disease', (112, 131))	('GFAP', 'Gene', (100, 104))	('CD34', 'Gene', '947', (66, 70))	('S-100', 'Gene', (90, 95))	('EMA', 'Gene', (30, 33))
184930	23588365	While criteria for malignancy in cutaneous myoepithelial neoplasms have not been well established, myoepithelial tumors in soft tissue with moderate-to-severe cytologic/nuclear atypia show increased risk of recurrence and metastasis and are thus classified as myoepithelial carcinoma.	('myoepithelial tumors', 'Disease', 'MESH:D009208', (99, 119))	('malignancy', 'Disease', (19, 29))	('cutaneous myoepithelial neoplasms', 'Disease', (33, 66))	('myoepithelial tumors', 'Disease', (99, 119))	('recurrence', 'CPA', (207, 217))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (260, 283))	('neoplasms', 'Phenotype', 'HP:0002664', (57, 66))	('myoepithelial neoplasm', 'Phenotype', 'HP:0031492', (43, 65))	('myoepithelial carcinoma', 'Disease', (260, 283))	('moderate-to-severe cytologic/nuclear atypia', 'Var', (140, 183))	('metastasis', 'CPA', (222, 232))	('cutaneous myoepithelial neoplasms', 'Disease', 'MESH:D009208', (33, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('malignancy', 'Disease', 'MESH:D009369', (19, 29))	('myoepithelial neoplasms', 'Phenotype', 'HP:0031492', (43, 66))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('neoplasm', 'Phenotype', 'HP:0002664', (57, 65))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
184936	23588365	In the following two years, Brandal et al reported a balanced translocation t(1;22)(q23;q12) and resultant EWSR1-PBX1 gene fusion in one case of soft tissue myoepithelioma and one myoepithelial carcinoma with translocation t(19;22)(q13;q12) resulting in a chimeric gene EWSR1-ZNF444.	('t(1;22)(q23;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (76, 92))	('EWSR1', 'Gene', '2130', (270, 275))	('PBX1', 'Gene', (113, 117))	('ZNF444', 'Gene', '55311', (276, 282))	('myoepithelioma', 'Disease', (157, 171))	('fusion', 'Var', (123, 129))	('EWSR1', 'Gene', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('myoepithelioma', 'Disease', 'MESH:D009208', (157, 171))	('t(19;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (223, 240))	('EWSR1', 'Gene', '2130', (107, 112))	('PBX1', 'Gene', '5087', (113, 117))	('ZNF444', 'Gene', (276, 282))	('EWSR1', 'Gene', (270, 275))	('myoepithelial carcinoma', 'Disease', (180, 203))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (180, 203))
184937	23588365	In a series of 66 myoepithelial neoplasms in skin, soft tissue, bone, and visceral sites, Antonescu et al identified EWSR1 gene rearrangement in 45% (30/66) of tumors, 47% (14/30) of which were myoepitheliomas and 53% (16/30) of which were malignant.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('neoplasms in skin', 'Phenotype', 'HP:0008069', (32, 49))	('EWSR1', 'Gene', (117, 122))	('myoepithelial neoplasms', 'Phenotype', 'HP:0031492', (18, 41))	('neoplasms', 'Phenotype', 'HP:0002664', (32, 41))	('myoepitheliomas', 'Disease', (194, 209))	('EWSR1', 'Gene', '2130', (117, 122))	('myoepithelial neoplasms', 'Disease', (18, 41))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('myoepithelial neoplasm', 'Phenotype', 'HP:0031492', (18, 40))	('myoepithelial neoplasms in skin', 'Phenotype', 'HP:0030447', (18, 49))	('neoplasm', 'Phenotype', 'HP:0002664', (32, 40))	('rearrangement', 'Var', (128, 141))	('tumors', 'Disease', (160, 166))	('men', 'Species', '9606', (137, 140))	('myoepitheliomas', 'Disease', 'MESH:D009208', (194, 209))	('myoepithelial neoplasms', 'Disease', 'MESH:D009208', (18, 41))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
184940	23588365	Myoepithelial neoplasms showing EWSR1-POU5F1 fusion affected children and young adults and were located in deep soft tissue of the extremities.	('Myoepithelial neoplasms', 'Disease', (0, 23))	('fusion', 'Var', (45, 51))	('neoplasm', 'Phenotype', 'HP:0002664', (14, 22))	('neoplasms', 'Phenotype', 'HP:0002664', (14, 23))	('children', 'Species', '9606', (61, 69))	('EWSR1', 'Gene', (32, 37))	('POU5F1', 'Gene', '5460', (38, 44))	('Myoepithelial neoplasms', 'Disease', 'MESH:D009208', (0, 23))	('Myoepithelial neoplasms', 'Phenotype', 'HP:0031492', (0, 23))	('POU5F1', 'Gene', (38, 44))	('EWSR1', 'Gene', '2130', (32, 37))
184942	23588365	In a 2011 series of 18 cutaneous myoepithelial tumors, Flucke et al reported that seven (7/16; 44%) cases harbored EWSR1 rearrangement, including four mixed tumors, two myoepitheliomas (none of which were reported to be syncytial), and one myoepithelial carcinoma.	('mixed', 'Disease', (151, 156))	('harbored', 'Reg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('myoepithelial carcinoma', 'Disease', (240, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('men', 'Species', '9606', (130, 133))	('tumors', 'Disease', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('EWSR1', 'Gene', (115, 120))	('rearrangement', 'Var', (121, 134))	('cutaneous myoepithelial tumors', 'Disease', (23, 53))	('cutaneous myoepithelial tumors', 'Disease', 'MESH:D009208', (23, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', (157, 163))	('myoepitheliomas', 'Disease', (169, 184))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (240, 263))	('myoepitheliomas', 'Disease', 'MESH:D009208', (169, 184))	('EWSR1', 'Gene', '2130', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
184949	23588365	The presence of EWSR1 gene rearrangement in most cases supports a close relationship to other subsets of myoepithelial tumors, but we were unable to demonstrate any of the known fusion gene partners, suggesting that this morphologically distinctive tumor type may prove to be associated with a novel fusion gene.	('myoepithelial tumors', 'Disease', (105, 125))	('EWSR1', 'Gene', '2130', (16, 21))	('tumor', 'Disease', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('rearrangement', 'Var', (27, 40))	('EWSR1', 'Gene', (16, 21))	('men', 'Species', '9606', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (105, 125))
184988	29292724	Immunohistochemical analysis showed positivity for CD34 (Figure 2g) and negativity for muscular markers and S100.	('CD34', 'Gene', '947', (51, 55))	('S100', 'Gene', (108, 112))	('positivity', 'Var', (36, 46))	('CD34', 'Gene', (51, 55))	('S100', 'Gene', '6271', (108, 112))
185025	29292724	In this regard, the amplification of laptm4a and laptm4b genes has been reported in numerous chemoresistant tumors, including breast and gallbladder cancer.	('laptm4a', 'Gene', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('laptm4a', 'Gene', '9741', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('reported', 'Reg', (72, 80))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('laptm4b', 'Gene', '55353', (49, 56))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('amplification', 'Var', (20, 33))	('laptm4b', 'Gene', (49, 56))	('breast and gallbladder cancer', 'Disease', 'MESH:D005706', (126, 155))
185038	29292724	These data suggest that eribulin induces cell cycle arrest and cell death programming through a caspase-dependent mitochondrial pathway (Figure 5).	('cell death programming', 'CPA', (63, 85))	('cell cycle arrest', 'CPA', (41, 58))	('eribulin', 'Var', (24, 32))	('eribulin', 'Chemical', 'MESH:C490954', (24, 32))	('caspase', 'Gene', (96, 103))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (41, 58))	('caspase', 'Gene', '842', (96, 103))
185091	29162825	Analysis of TCGA data revealed HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations in 112/243 (46%) of patients predominantly HDAC1-11 (41%) alterations.	('RAF', 'Gene', (62, 65))	('PI3K', 'Gene', (37, 41))	('HDAC', 'Gene', (31, 35))	('HER2', 'Gene', (43, 47))	('HDAC', 'Gene', '9734', (31, 35))	('HDAC1-11', 'Gene', '3065;3066;8841;9759;10014;10013;51564;55869;9734;83933;79885', (126, 134))	('HER2', 'Gene', '2064', (43, 47))	('alterations', 'Var', (71, 82))	('HDAC1-11', 'Gene', (126, 134))	('patients', 'Species', '9606', (103, 111))	('HDAC', 'Gene', (126, 130))	('RAF', 'Gene', '22882', (62, 65))	('HDAC', 'Gene', '9734', (126, 130))
185098	29162825	The study was able to meet its primary end point, as pazopanib increased PFS by 3 months over placebo (4.6 months vs 1.6 months, hazard ratio [HR] = 0.31, 95% confidence interval [CI] 0.24 to 0.40; p < 0.0001).	('increased', 'PosReg', (63, 72))	('PFS', 'Disease', (73, 76))	('pazopanib', 'Var', (53, 62))	('pazopanib', 'Chemical', 'MESH:C516667', (53, 62))
185100	29162825	There was a trend towards an increase in overall survival (OS) with pazopanib, but the increase was not statistically significant (p = 0.25).	('OS', 'Chemical', '-', (59, 61))	('pazopanib', 'Chemical', 'MESH:C516667', (68, 77))	('increase', 'PosReg', (29, 37))	('pazopanib', 'Var', (68, 77))	('overall survival', 'MPA', (41, 57))
185101	29162825	Most patients with sarcoma who are on pazopanib ultimately develop resistance to it, leading to progression of disease, and a major challenge in the treatment of advanced soft tissue sarcoma remains a lack of predictive biomarkers to guide further therapy.	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('patients', 'Species', '9606', (5, 13))	('sarcoma', 'Disease', (183, 190))	('resistance', 'MPA', (67, 77))	('pazopanib', 'Chemical', 'MESH:C516667', (38, 47))	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('develop', 'Reg', (59, 66))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (171, 190))	('leading to', 'Reg', (85, 95))	('sarcoma', 'Disease', (19, 26))	('pazopanib', 'Var', (38, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))
185112	29162825	Medical records were retrospectively searched for patients enrolled in the phase 1 trials of pazopanib plus vorinostat (HDAC inhibitor; NCT01339871), pazopanib plus everolimus (mTOR inhibitor; NCT01430572), pazopanib plus lapatinib or trastuzumab (Her2 inhibitor; NCT01454804), and pazopanib plus a MEK inhibitor (NCT01438554).	('Her2', 'Gene', '2064', (248, 252))	('pazopanib', 'Chemical', 'MESH:C516667', (150, 159))	('patients', 'Species', '9606', (50, 58))	('NCT01438554', 'Var', (314, 325))	('MEK', 'Gene', (299, 302))	('MEK', 'Gene', '5609', (299, 302))	('pazopanib', 'Chemical', 'MESH:C516667', (282, 291))	('mTOR', 'Gene', (177, 181))	('vorinostat', 'Chemical', 'MESH:D000077337', (108, 118))	('mTOR', 'Gene', '2475', (177, 181))	('HDAC', 'Gene', '9734', (120, 124))	('pazopanib', 'Chemical', 'MESH:C516667', (93, 102))	('lapatinib', 'Chemical', 'MESH:D000077341', (222, 231))	('HDAC', 'Gene', (120, 124))	('trastuzumab', 'Chemical', 'MESH:D000068878', (235, 246))	('pazopanib', 'Chemical', 'MESH:C516667', (207, 216))	('Her2', 'Gene', (248, 252))	('everolimus', 'Chemical', 'MESH:D000068338', (165, 175))
185119	29162825	We extracted the following information from the patients' medical records for our analysis: histologic diagnosis (all histologic findings had been centrally reviewed at MD Anderson Cancer Center), tumor associated mutations or aberrations, entry date for the trial, date of progression of disease, date of last follow-up at the phase 1 clinic or date of death, ECOG performance status at enrollment, any prior treatment with pazopanib, any dose-limiting toxicity, and any other grade 3 or 4 adverse events within the first 28 days of treatment per Common Terminology Criteria for Adverse Events (CTCAE) v4.0.	('pazopanib', 'Chemical', 'MESH:C516667', (425, 434))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('toxicity', 'Disease', 'MESH:D064420', (454, 462))	('mutations', 'Var', (214, 223))	('Cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Cancer', 'Disease', (181, 187))	('toxicity', 'Disease', (454, 462))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Disease', (197, 202))	('death', 'Disease', 'MESH:D003643', (354, 359))	('patients', 'Species', '9606', (48, 56))	('death', 'Disease', (354, 359))
185128	29162825	Figures were generated to show copy number alterations, and mutations in selected genes namely HDAC, PI3K, HER2, and MAPK/RAS/RAF.	('RAF', 'Gene', (126, 129))	('HER2', 'Gene', '2064', (107, 111))	('copy number alterations', 'Var', (31, 54))	('PI3K', 'Disease', (101, 105))	('mutations', 'Var', (60, 69))	('HDAC', 'Gene', (95, 99))	('RAF', 'Gene', '22882', (126, 129))	('HER2', 'Gene', (107, 111))	('HDAC', 'Gene', '9734', (95, 99))
185161	29162825	The dose-limiting toxicity rate was 20% (95% CI 1% to 72%) for pazopanib-pretreated patients and 28% (95% CI 15% to 45%) for non-pretreated patients.	('patients', 'Species', '9606', (84, 92))	('pazopanib', 'Chemical', 'MESH:C516667', (63, 72))	('toxicity', 'Disease', 'MESH:D064420', (18, 26))	('toxicity', 'Disease', (18, 26))	('patients', 'Species', '9606', (140, 148))	('pazopanib-pretreated', 'Var', (63, 83))
185165	29162825	Next generation sequencing data from the Cancer Genome Atlas (TCGA) revealed copy number alterations, and mutations in 112/243 (46%) of patients in the HDAC, PI3K, HER2, and MAPK/RAS/RAF pathways (Fig.	('HDAC', 'Gene', (152, 156))	('RAF', 'Gene', '22882', (183, 186))	('HDAC', 'Gene', '9734', (152, 156))	('RAF', 'Gene', (183, 186))	('Cancer Genome Atlas', 'Disease', (41, 60))	('HER2', 'Gene', (164, 168))	('patients', 'Species', '9606', (136, 144))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (106, 115))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (41, 60))	('HER2', 'Gene', '2064', (164, 168))	('copy number alterations', 'Var', (77, 100))
185193	29162825	Only the vorinostat and MEK inhibitor combinations led to durable stable disease lasting more than 6 months, which may be an early signal of efficacy with these combinations.	('combinations', 'Var', (38, 50))	('MEK', 'Gene', (24, 27))	('vorinostat', 'Chemical', 'MESH:D000077337', (9, 19))	('MEK', 'Gene', '5609', (24, 27))
185194	29162825	Because these trials were dose escalation trials performed in unselected sarcoma patients, it would be appropriate to assess clinical benefit of the combinations in patients with sarcoma that have these pathway alterations.	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('sarcoma', 'Disease', (73, 80))	('patients', 'Species', '9606', (81, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('alterations', 'Var', (211, 222))	('patients', 'Species', '9606', (165, 173))	('sarcoma', 'Disease', 'MESH:D012509', (179, 186))	('sarcoma', 'Disease', (179, 186))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
185197	29162825	Perhaps selecting patients with respective pathway mutations would improve the response rate of pazopanib combination therapy.	('mutations', 'Var', (51, 60))	('improve', 'PosReg', (67, 74))	('pazopanib', 'Chemical', 'MESH:C516667', (96, 105))	('patients', 'Species', '9606', (18, 26))	('response', 'MPA', (79, 87))
185203	29162825	We were interested in evaluating the validity of this score in sarcoma patients on tyrosine kinase inhibitors.Our analysis revealed that OS was significantly higher in patients with RMH score of 0 compared with those with RMH score of 1 to 3 (58 weeks vs 23 weeks).	('RMH', 'Chemical', '-', (182, 185))	('sarcoma', 'Disease', (63, 70))	('patients', 'Species', '9606', (71, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('higher', 'PosReg', (158, 164))	('patients', 'Species', '9606', (168, 176))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('RMH score of 0', 'Var', (182, 196))	('OS', 'Chemical', '-', (137, 139))	('RMH', 'Chemical', '-', (222, 225))
185213	29162825	The group of patients that received pazopanib less than 400 mg daily most likely had a sub-therapeutic dose and this may have contributed to the poor overall response rate in our study.	('patients', 'Species', '9606', (13, 21))	('pazopanib', 'Gene', (36, 45))	('less than 400 mg', 'Var', (46, 62))	('sub-therapeutic', 'Var', (87, 102))	('pazopanib', 'Chemical', 'MESH:C516667', (36, 45))
185217	29162825	Given that our data from TCGA shows a larger proportion of patients with HDAC pathway (HDAC1-11) alterations further evaluation of epigenetic pathway inhibitor trials are warranted.	('HDAC', 'Gene', (87, 91))	('HDAC', 'Gene', (73, 77))	('HDAC', 'Gene', '9734', (87, 91))	('HDAC', 'Gene', '9734', (73, 77))	('alterations', 'Var', (97, 108))	('patients', 'Species', '9606', (59, 67))	('HDAC1-11', 'Gene', '3065;3066;8841;9759;10014;10013;51564;55869;9734;83933;79885', (87, 95))	('HDAC1-11', 'Gene', (87, 95))
185466	24353976	Although considered to be a lower-grade malignancy, inadequate resection leads to rapid and often unmanageable local recurrence and, rarely, metastatic disease.	('inadequate', 'Var', (52, 62))	('man', 'Species', '9606', (100, 103))	('local recurrence', 'CPA', (111, 127))	('metastatic disease', 'CPA', (141, 159))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('malignancy', 'Disease', (40, 50))
185554	32448829	Serum autoantibodies in DM can indicate a positive or negative risk of malignancy; indeed, antibodies to transcription intermediary factor (TIF)-1 gamma and nuclear matrix protein (NPX)-2 indicate positive risks, while anti-synthetase antibodies, anti-Mi-2 antibody, and anti-signal recognition particle (SRP) antibody indicate negative risks.	('antibodies', 'Var', (91, 101))	('DM', 'Disease', 'MESH:D009223', (24, 26))	('malignancy', 'Disease', 'MESH:D009369', (71, 81))	('malignancy', 'Disease', (71, 81))	('transcription intermediary factor (TIF)-1 gamma', 'Gene', '51592', (105, 152))
185556	32448829	Antibodies to eight different tRNA synthetase have been reported: anti-histidyl (Jo-1), threonyl (PL-7), alanyl (PL-12), glycyl (EJ), isoleucyl (OJ), asparaginyl (KS), phenylalanyl (Zo), and tyrosyl (YRS) tRNA synthetase antibodies.	('YRS', 'Gene', '8565', (200, 203))	('anti-histidyl', 'Var', (66, 79))	('tyrosyl', 'Protein', (191, 198))	('KS', 'Chemical', 'MESH:D011188', (163, 165))	('YRS', 'Gene', (200, 203))
185558	32448829	We herein report the first case of anti-EJ antibody-positive ASS associated with retroperitoneal sarcoma despite ASS being uncommon as a phenotype of paraneoplastic syndrome and sarcoma exceptional as the cause of paraneoplastic syndrome.	('anti-EJ', 'Var', (35, 42))	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('paraneoplastic syndrome', 'Disease', (150, 173))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (150, 173))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('associated', 'Reg', (65, 75))	('retroperitoneal sarcoma', 'Disease', (81, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('retroperitoneal sarcoma', 'Disease', 'MESH:D012186', (81, 104))	('paraneoplastic syndrome', 'Disease', (214, 237))	('sarcoma', 'Disease', (178, 185))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (214, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
185613	32448829	To our knowledge, this is the first reported case of anti-EJ antibody-positive ASS associated with sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('anti-EJ', 'Var', (53, 60))	('associated', 'Reg', (83, 93))	('sarcoma', 'Disease', (99, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
185632	25960901	Ewing sarcoma-primitive neuroectodermal tumor (ES/PNET) constitutes a family of neoplasms characterized by a continuum of neuroectodermal differentiations and by translocations involving EWS-FLI1 genes in approximately 85% of all cases.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (24, 45))	('EWS', 'Gene', '2130', (187, 190))	('EWS', 'Gene', (187, 190))	('Ewing sarcoma-primitive neuroectodermal tumor', 'Disease', 'MESH:C563168', (0, 45))	('neoplasms', 'Disease', (80, 89))	('FLI1', 'Gene', '2313', (191, 195))	('FLI1', 'Gene', (191, 195))	('neoplasms', 'Disease', 'MESH:D009369', (80, 89))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('neoplasm', 'Phenotype', 'HP:0002664', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('neoplasms', 'Phenotype', 'HP:0002664', (80, 89))	('Ewing sarcoma-primitive neuroectodermal tumor', 'Disease', (0, 45))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (14, 45))	('translocations', 'Var', (162, 176))
185649	25960901	Immunostaining revealed a positive reaction for vimentin (+++) and CD99 (+++) (Figure 3(d)) and an evidence for desmin, actin, ML, and CD10.	('vimentin', 'Gene', '7431', (48, 56))	('CD99', 'Gene', (67, 71))	('desmin', 'Gene', '1674', (112, 118))	('vimentin', 'Gene', (48, 56))	('CD10', 'Gene', (135, 139))	('+++', 'Var', (58, 61))	('CD10', 'Gene', '4311', (135, 139))	('CD99', 'Gene', '4267', (67, 71))	('actin', 'Protein', (120, 125))	('ML', 'Disease', 'MESH:C537366', (127, 129))	('desmin', 'Gene', (112, 118))
185656	25960901	Ewing's sarcoma family tumour is a group of small round cell tumors, characterized by the specific translocation t(11;22)(q24;q12) and the specific transcript FLI1/EWS (and by the less common subvariants that involve chromosome 22 and EWS gene, with chromosome 21, 17, or 7).	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (113, 130))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('FLI1', 'Gene', (159, 163))	("Ewing's sarcoma family tumour", 'Disease', (0, 29))	('FLI1', 'Gene', '2313', (159, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('EWS', 'Gene', '2130', (235, 238))	('EWS', 'Gene', (235, 238))	('cell tumors', 'Disease', (56, 67))	('EWS', 'Gene', '2130', (164, 167))	('EWS', 'Gene', (164, 167))	('cell tumors', 'Disease', 'MESH:D005935', (56, 67))	('t(11;22)(q24;q12', 'Var', (113, 129))	("Ewing's sarcoma family tumour", 'Disease', 'MESH:C563168', (0, 29))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
185669	25960901	Immunohistochemically, these tumors usually exhibit positivity for CD99, vimentin, and FLI-1 and in some cases focal positivity for cytokeratins.	('FLI-1', 'Gene', '2313', (87, 92))	('vimentin', 'Gene', '7431', (73, 81))	('FLI-1', 'Gene', (87, 92))	('CD99', 'Gene', (67, 71))	('vimentin', 'Gene', (73, 81))	('cytokeratins', 'Protein', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('positivity', 'Var', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('CD99', 'Gene', '4267', (67, 71))	('tumors', 'Disease', (29, 35))
185671	25960901	Diagnosis of Ewing sarcoma should be based on positive immunohistochemical reactions for vimentin (+++) and CD99 (+++) and negative reaction for desmin, actin, ML, and CD10, associated as in our experience with a high (90%) proliferative index Ki67.	('vimentin', 'Gene', (89, 97))	('CD10', 'Gene', '4311', (168, 172))	('+++', 'Var', (99, 102))	('CD99', 'Gene', '4267', (108, 112))	('Ewing sarcoma', 'Disease', (13, 26))	('ML', 'Disease', 'MESH:C537366', (160, 162))	('Ki67', 'Chemical', '-', (244, 248))	('actin', 'Protein', (153, 158))	('desmin', 'Gene', (145, 151))	('+++', 'Var', (114, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('CD99', 'Gene', (108, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))	('desmin', 'Gene', '1674', (145, 151))	('vimentin', 'Gene', '7431', (89, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))	('CD10', 'Gene', (168, 172))
185796	33009876	Sections underwent antigen retrieval with ER2 buffer (pH 8.0) for 20 minutes at 97 C. After treatment with endogenous peroxidase blocking for 10 minutes, sections were incubated with NUT antibody (C52B1, 1:50, Cell Signaling Technology, Danvers, Massachusetts) for 15 minutes, and Bond Polymer Refine Detection (DS9800, Leica Biosystems, Melbourne, Australia) as a secondary antibody for 10 minutes.	('men', 'Species', '9606', (97, 100))	('ER2 buffer', 'Chemical', '-', (42, 52))	('DS9800', 'Var', (312, 318))	('NUT antibody', 'Phenotype', 'HP:0410331', (183, 195))	('NUT', 'Gene', (183, 186))	('NUT', 'Gene', '256646', (183, 186))
185800	33009876	20  The result of NUT gene (NUTM1) translocation, break-apart fluorescence in situ hybridization (FISH) was acquired as a generous gift from Dr Yoon Kyung Jeon (Seoul National University).	('NUTM1', 'Gene', '256646', (28, 33))	('NUTM1', 'Gene', (28, 33))	('translocation', 'Var', (35, 48))	('NUT', 'Gene', '256646', (28, 31))	('NUT', 'Gene', '256646', (18, 21))	('NUT', 'Gene', (28, 31))	('NUT', 'Gene', (18, 21))
185840	33009876	Case 1, which showed spindle cell morphology, showed positivity for CD34, p63, STAT6, and TTF-1, with negativity for CK (AE1/AE3).	('p63', 'Gene', '8626', (74, 77))	('TTF-1', 'Gene', (90, 95))	('STAT6', 'Gene', '6778', (79, 84))	('CD34', 'Gene', (68, 72))	('CD34', 'Gene', '947', (68, 72))	('CK (AE1/AE3', 'Gene', '6521;6508', (117, 128))	('TTF-1', 'Gene', '7270', (90, 95))	('positivity', 'Var', (53, 63))	('p63', 'Gene', (74, 77))	('STAT6', 'Gene', (79, 84))
185858	33009876	Further studies are needed to explore whether aberrant expression of CD34 and STAT6 expression in NUT carcinoma is clinically significant.	('CD34', 'Gene', '947', (69, 73))	('NUT carcinoma', 'Disease', (98, 111))	('NUT carcinoma', 'Disease', 'MESH:D009369', (98, 111))	('STAT6', 'Gene', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('aberrant', 'Var', (46, 54))	('STAT6', 'Gene', '6778', (78, 83))	('CD34', 'Gene', (69, 73))
185915	32683393	Overall, 40 182 AS events and 18 996 corresponding genes were detected in the sarcoma cohort, including 15 311 Exon Skip (ES), 8287 AT, 7837 AP, 3196 AA, 2815 AD, 2572 RI, and 164 ME (Figure 1A, 1B).	('AD', 'Disease', (159, 161))	('3196 AA', 'Var', (145, 152))	('8287 AT', 'Var', (127, 134))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('sarcoma', 'Disease', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('AD', 'Disease', 'MESH:D000544', (159, 161))
185927	32683393	Moreover, as a DFS-related AS event, TMEM189-59769-AP can be regulated by MBNL1 and PTBP2.	('MBNL1', 'Gene', (74, 79))	('PTBP2', 'Gene', '58155', (84, 89))	('MBNL1', 'Gene', '4154', (74, 79))	('PTBP2', 'Gene', (84, 89))	('TMEM189-59769-AP', 'Var', (37, 53))
185942	32683393	In addition, many predictive models for sarcoma patients have been constructed based on clinicopathologic data, lncRNA, plasmacytoma variant translocation 1, and other predictors, but the discriminative ability of the previous models was low, with AUC or C-statistic less than 0.800.	('plasmacytoma', 'Phenotype', 'HP:0011857', (120, 132))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('sarcoma', 'Disease', (40, 47))	('variant', 'Var', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('patients', 'Species', '9606', (48, 56))
186109	31010432	RNA sequencing detected a PHF1 rearrangement.	('PHF1', 'Gene', '5252', (26, 30))	('rearrangement', 'Var', (31, 44))	('PHF1', 'Gene', (26, 30))	('detected', 'Reg', (15, 23))
186130	31010432	Testing confirmed the presence of PHF1 gene rearrangement (NM_024165.2).	('PHF1', 'Gene', (34, 38))	('PHF1', 'Gene', '5252', (34, 38))	('NM_024165.2', 'Var', (59, 70))
186140	31010432	Other chromosomal rearrangements reported in uterine ESSs include PHF1 gene rearrangements resulting from t(6;10)(p21;p11) and t(6;7)(p21;p15), with fusion of EPC1-PHF1 and JAZF1-PHF1, respectively.	('JAZF1', 'Gene', (173, 178))	('PHF1', 'Gene', (179, 183))	('t(6;7)(p21;p15)', 'STRUCTURAL_ABNORMALITY', 'None', (127, 142))	('PHF1', 'Gene', (164, 168))	('ESSs', 'Gene', '54539', (53, 57))	('PHF1', 'Gene', '5252', (179, 183))	('t(6;7)(p21;p15', 'Var', (127, 141))	('PHF1', 'Gene', (66, 70))	('t(6;10)(p21;p11', 'Var', (106, 121))	('PHF1', 'Gene', '5252', (164, 168))	('uterine ESS', 'Phenotype', 'HP:0000139', (45, 56))	('JAZF1', 'Gene', '221895', (173, 178))	('PHF1', 'Gene', '5252', (66, 70))	('ESSs', 'Gene', (53, 57))	('t(6;10)(p21;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (106, 122))	('EPC1', 'Gene', '80314', (159, 163))	('resulting from', 'Reg', (91, 105))	('EPC1', 'Gene', (159, 163))
186143	31010432	JAZF1-SUZ12 fusions, EPC1-PHF1 fusion, and PHF1 rearrangement with no putative partner have been reported in extra-uterine low-grade endometrial stromal sarcomas.	('fusions', 'Var', (12, 19))	('PHF1', 'Gene', '5252', (26, 30))	('PHF1', 'Gene', '5252', (43, 47))	('SUZ12', 'Gene', '23512', (6, 11))	('SUZ12', 'Gene', (6, 11))	('JAZF1', 'Gene', '221895', (0, 5))	('JAZF1', 'Gene', (0, 5))	('rearrangement', 'Var', (48, 61))	('endometrial stromal sarcomas', 'Disease', (133, 161))	('EPC1', 'Gene', (21, 25))	('reported', 'Reg', (97, 105))	('EPC1', 'Gene', '80314', (21, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (133, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('PHF1', 'Gene', (26, 30))	('PHF1', 'Gene', (43, 47))
186145	31010432	The presence of a PHF1 gene rearrangement, in a tumor with a multi-nodular growth pattern, comprising uniform round to oval tumor cells embedded in a fibro-myxoid stroma, outside the uterus, raises the possibility of ossifying fibromyxoid tumor (OFMT).	('tumor', 'Disease', (48, 53))	('oval tumor', 'Disease', 'MESH:D054092', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('PHF1', 'Gene', (18, 22))	('rearrangement', 'Var', (28, 41))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('oval tumor', 'Disease', (119, 129))	('PHF1', 'Gene', '5252', (18, 22))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
186147	31010432	Furthermore, PHF1 gene rearrangements in OFMT are characterized by fusion to EP400 in the majority of cases, and fusion to MEAF6 and EPC1 in a minority of cases, whereas in ESS, PHF1 rearrangements are typically fused with either JAZF1 or EPC1.	('EPC1', 'Gene', '80314', (239, 243))	('EPC1', 'Gene', (133, 137))	('EPC1', 'Gene', (239, 243))	('PHF1', 'Gene', '5252', (13, 17))	('PHF1', 'Gene', (178, 182))	('fusion', 'Reg', (67, 73))	('EPC1', 'Gene', '80314', (133, 137))	('EP400', 'Gene', (77, 82))	('PHF1', 'Gene', '5252', (178, 182))	('JAZF1', 'Gene', (230, 235))	('rearrangements', 'Var', (23, 37))	('MEAF6', 'Gene', '64769', (123, 128))	('JAZF1', 'Gene', '221895', (230, 235))	('EP400', 'Gene', '57634', (77, 82))	('MEAF6', 'Gene', (123, 128))	('PHF1', 'Gene', (13, 17))
186166	28984429	Recent in vitro studies showed that suboptimal doses of RAL could lead to the generation of aberrant proviruses during the strand transfer reaction, with significant rearrangements of the host genome, including duplications, inversions, deletions and, occasionally, acquisition of sequences from other chromosomes 14, 15.	('RAL', 'Gene', (56, 59))	('suboptimal', 'Var', (36, 46))	('deletions', 'Var', (237, 246))	('inversions', 'CPA', (225, 235))	('lead to', 'Reg', (66, 73))	('RAL', 'Chemical', 'MESH:D000068898', (56, 59))	('rearrangements', 'MPA', (166, 180))	('men', 'Species', '9606', (175, 178))	('duplications', 'Var', (211, 223))
186167	28984429	Based on what is known about the activation of oncogenes in human tumours, it is possible that rearrangements in the host DNA (so far observed only in in vitro models) as a result of potential aberrant HIV DNA integrations could increase the chance that HIV integrations could lead to the development of cancer.	('men', 'Species', '9606', (296, 299))	('HIV DNA', 'Protein', (202, 209))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('men', 'Species', '9606', (104, 107))	('cancer', 'Disease', (304, 310))	('lead to', 'Reg', (277, 284))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('aberrant', 'Var', (193, 201))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('tumours', 'Disease', (66, 73))	('human', 'Species', '9606', (60, 65))
186265	28984429	Finally, there is little evidence that the serum lipid profile is modified by RAL, especially when compared with regimens containing older PIs and also efavirenz.	('RAL', 'Chemical', 'MESH:D000068898', (78, 81))	('modified', 'Reg', (66, 74))	('men', 'Species', '9606', (117, 120))	('lipid', 'Chemical', 'MESH:D008055', (49, 54))	('RAL', 'Var', (78, 81))	('efavirenz', 'Chemical', 'MESH:C098320', (152, 161))	('serum lipid profile', 'MPA', (43, 62))
186291	28984429	Neither host DNA or INSTI resistance data were available to evaluate the prevalence of RAL-induced mutations potentially associated with an increased risk of cancer.	('associated', 'Reg', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('RAL-induced', 'Gene', (87, 98))	('RAL', 'Chemical', 'MESH:D000068898', (87, 90))	('cancer', 'Disease', (158, 164))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
186336	27747121	Diffuse and strong nuclear HHV8 positivity was the diagnostic clue (Figure 3(d)).	('positivity', 'Var', (32, 42))	('HHV8', 'Species', '37296', (27, 31))	('nuclear HHV8', 'Protein', (19, 31))
186379	27747121	Spindle and epithelioid cell morphology with some degree of pleomorphism and increased mitotic count raised a suspicion of sarcoma or melanoma, but immunohistochemistry including desmin, CD 99, calretinin, and Melan-A was not supportive.	('calretinin', 'Gene', '794', (194, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('CD 99', 'Gene', (187, 192))	('pleomorphism', 'Var', (60, 72))	('mitotic count', 'CPA', (87, 100))	('sarcoma or melanoma', 'Disease', (123, 142))	('calretinin', 'Gene', (194, 204))	('CD 99', 'Gene', '4267', (187, 192))	('desmin', 'Gene', (179, 185))	('sarcoma or melanoma', 'Disease', 'MESH:D008545', (123, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('desmin', 'Gene', '1674', (179, 185))	('increased', 'PosReg', (77, 86))
186393	26788073	However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line.	('inhibition', 'NegReg', (9, 19))	('TKI', 'Var', (29, 32))	('cell viability of the hMSC-TERT20-CE8 cell line', 'CPA', (85, 132))	('dasatinib', 'Chemical', 'MESH:D000069439', (33, 42))	('decreased', 'NegReg', (75, 84))
186395	26788073	Sarcomas are suggested to develop from stromal (also known as mesenchymal) stem cells with acquired genetic mutations leading to cellular transformation.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('mutations', 'Var', (108, 117))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
186431	26788073	It has previously been shown in breast carcinoma cell lines that inhibition of SRC family kinases prevents the phosphorylation of MAPK induced by stimulation of EGFR.	('EGFR', 'Gene', (161, 165))	('MAPK', 'Protein', (130, 134))	('breast carcinoma', 'Phenotype', 'HP:0003002', (32, 48))	('prevents', 'NegReg', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('inhibition', 'Var', (65, 75))	('breast carcinoma', 'Disease', (32, 48))	('stimulation', 'PosReg', (146, 157))	('phosphorylation', 'MPA', (111, 126))	('breast carcinoma', 'Disease', 'MESH:D001943', (32, 48))
186553	31624330	NKF-NK cells exhibited markedly increased cytotoxic activity against a wide variety of cancer cell lines as compared to IL-2-NK cells (Fig.	('cancer', 'Disease', (87, 93))	('NKF-NK', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('increased', 'PosReg', (32, 41))	('cytotoxic activity', 'CPA', (42, 60))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
186568	31624330	NKF expansion led to a decrease in CXCR4, a receptor reported to sequester NK cells in the bone marrow (Fig.	('CXCR4', 'Gene', (35, 40))	('decrease', 'NegReg', (23, 31))	('expansion', 'Var', (4, 13))	('CXCR4', 'Gene', '7852', (35, 40))	('NKF', 'Gene', (0, 3))
186576	31624330	Consistent with enhanced NK cell proliferation, the proliferation marker Ki67 was upregulated on NKF-NK cells as compared to OCI-NK cells (p = 0.038).	('proliferation', 'CPA', (52, 65))	('Ki67', 'Gene', '17345', (73, 77))	('upregulated', 'PosReg', (82, 93))	('rat', 'Species', '10116', (40, 43))	('NKF-NK', 'Var', (97, 103))	('NK cell proliferation', 'CPA', (25, 46))	('rat', 'Species', '10116', (59, 62))	('Ki67', 'Gene', (73, 77))	('enhanced', 'PosReg', (16, 24))
186588	31624330	While NKF-NK cells demonstrate a marked increase in cytotoxic activity as compared to non-feeder expanded cells (Fig.	('NKF-NK', 'Var', (6, 12))	('cytotoxic activity', 'CPA', (52, 70))	('rat', 'Species', '10116', (26, 29))	('increase', 'PosReg', (40, 48))
186593	31624330	In this model, not only did we observe a reduction in the growth of the primary sarcoma tumor with NKF-NK cell administration, but there was a dramatic reduction in tumor metastases to the lung (Fig.	('sarcoma tumor', 'Disease', 'MESH:D012509', (80, 93))	('sarcoma tumor', 'Disease', (80, 93))	('tumor metastases', 'Disease', (165, 181))	('rat', 'Species', '10116', (119, 122))	('NKF-NK cell administration', 'Var', (99, 125))	('growth', 'MPA', (58, 64))	('tumor metastases', 'Disease', 'MESH:D009362', (165, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('reduction', 'NegReg', (152, 161))	('reduction', 'NegReg', (41, 50))
186594	31624330	Ki67 staining of lung specimens from vehicle-treated mice and NKF-NK-treated mice revealed decreases in proliferation of tumor cells in NKF-NK-treated mice as compared to vehicle-treated mice (p = 0.023) (Fig.	('mice', 'Species', '10090', (77, 81))	('rat', 'Species', '10116', (111, 114))	('mice', 'Species', '10090', (151, 155))	('Ki67', 'Gene', '17345', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('proliferation', 'CPA', (104, 117))	('tumor', 'Disease', (121, 126))	('mice', 'Species', '10090', (187, 191))	('Ki67', 'Gene', (0, 4))	('decreases', 'NegReg', (91, 100))	('NKF-NK-treated', 'Var', (136, 150))	('mice', 'Species', '10090', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
186626	31624330	Interestingly, NK expansion by the parental OCI-AML3 feeder cells that lack mbIL-21 led to partial activation of the STAT3/cMyc pathway likely due to the fact that the activation of many other receptor signaling pathways also can lead to minimal STAT3 activation.	('STAT3', 'Gene', '6774', (246, 251))	('cMyc', 'Gene', (123, 127))	('cMyc', 'Gene', '4609', (123, 127))	('IL-21', 'Gene', '59067', (78, 83))	('STAT3', 'Gene', (246, 251))	('AML3', 'Gene', '860', (48, 52))	('activation', 'PosReg', (99, 109))	('AML3', 'Gene', (48, 52))	('STAT3', 'Gene', '6774', (117, 122))	('NK expansion', 'Var', (15, 27))	('IL-21', 'Gene', (78, 83))	('STAT3', 'Gene', (117, 122))
186678	30171420	This resulted in the characterization of translocations that have been found in leukemia as well as in solid tumors such as Ewing and other sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Ewing', 'Disease', 'MESH:C563168', (124, 129))	('translocations', 'Var', (41, 55))	('sarcomas', 'Disease', (140, 148))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('solid tumors', 'Disease', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('leukemia', 'Disease', (80, 88))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('leukemia', 'Disease', 'MESH:D007938', (80, 88))	('sarcomas', 'Disease', 'MESH:D012509', (140, 148))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))	('Ewing', 'Disease', (124, 129))
186679	30171420	Moreover quantitative genomic alterations can be characteristic of certain cancers like the amplification of the super-enhancer MYCN (myelocytomatosis oncogene of neuroblastoma), a member of the MYC superfamily and of the 450 Ma old MYC interactom, driving most notably high risk neuroblastomas.	('MYC', 'Gene', (195, 198))	('neuroblastomas', 'Disease', 'MESH:D009447', (280, 294))	('MYCN', 'Gene', '4613', (128, 132))	('amplification', 'Var', (92, 105))	('MYC', 'Gene', (128, 131))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('MYC', 'Gene', (233, 236))	('MYC', 'Gene', '4609', (233, 236))	('MYC', 'Gene', '4609', (195, 198))	('myelocytomatosis oncogene of neuroblastoma', 'Disease', (134, 176))	('MYCN', 'Gene', (128, 132))	('MYC', 'Gene', '4609', (128, 131))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('neuroblastomas', 'Phenotype', 'HP:0003006', (280, 294))	('cancers', 'Disease', (75, 82))	('neuroblastoma', 'Phenotype', 'HP:0003006', (280, 293))	('neuroblastoma', 'Phenotype', 'HP:0003006', (163, 176))	('alterations', 'Var', (30, 41))	('neuroblastomas', 'Disease', (280, 294))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('myelocytomatosis oncogene of neuroblastoma', 'Disease', 'MESH:D009447', (134, 176))
186681	30171420	The translocation t(9;22) results in the BCR-ABL (breakpoint cluster region:Abelson murine leukemia viral oncogene homolog 1) fusion gene.	('murine', 'Species', '10090', (84, 90))	('fusion', 'Var', (126, 132))	('results in', 'Reg', (26, 36))	('ABL', 'Gene', '25', (45, 48))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('leukemia', 'Disease', 'MESH:D007938', (91, 99))	('BCR', 'Gene', (41, 44))	('BCR', 'Gene', '613', (41, 44))	('leukemia', 'Disease', (91, 99))	('ABL', 'Gene', (45, 48))
186692	30171420	We have learned, for instance, that neuroblastoma bearing activating anaplastic lymphoma kinase (ALK) mutations respond much less efficiently upon crizotinib treatment than ALK translocations in lymphoma or lung cancer.	('lymphoma', 'Disease', 'MESH:D008223', (80, 88))	('neuroblastoma', 'Disease', 'MESH:D009447', (36, 49))	('lymphoma', 'Disease', (195, 203))	('lymphoma', 'Disease', 'MESH:D008223', (195, 203))	('mutations', 'Var', (102, 111))	('crizotinib', 'Chemical', 'MESH:D000077547', (147, 157))	('respond', 'MPA', (112, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('lymphoma', 'Phenotype', 'HP:0002665', (80, 88))	('lymphoma or lung cancer', 'Disease', 'MESH:D008175', (195, 218))	('ALK', 'Gene', '238', (97, 100))	('ALK', 'Gene', (97, 100))	('less', 'NegReg', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('activating', 'PosReg', (58, 68))	('lymphoma or lung cancer', 'Disease', (195, 218))	('ALK', 'Gene', '238', (173, 176))	('neuroblastoma', 'Disease', (36, 49))	('neuroblastoma', 'Phenotype', 'HP:0003006', (36, 49))	('lymphoma', 'Phenotype', 'HP:0002665', (195, 203))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (69, 88))	('lymphoma', 'Disease', (80, 88))	('ALK', 'Gene', (173, 176))
186698	30171420	It has been shown in six independent studies that 5-10% of patients have germ-line mutations that predispose to cancer.	('mutations', 'Var', (83, 92))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('predispose', 'Reg', (98, 108))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
186699	30171420	This is all the more surprising because these mutations affect primarily patients from families where there is no increased susceptibility for cancer, i.e., high incidence of malignant diseases or cancer in adolescence.	('affect', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('malignant diseases', 'Disease', 'MESH:D009369', (175, 193))	('malignant diseases', 'Disease', (175, 193))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('patients', 'Species', '9606', (73, 81))
186700	30171420	Another take home message from these trials is the significant difference in the number of mutations between cancer in childhood and adolescence vs. cancer in adults.	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mutations', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
186702	30171420	In a lot of cancers the aberrant expression, overexpression and deregulated activation of certain genes is causative.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('deregulated', 'Var', (64, 75))	('genes', 'Gene', (98, 103))	('cancers', 'Disease', (12, 19))	('activation', 'MPA', (76, 86))	('aberrant expression', 'Var', (24, 43))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('overexpression', 'PosReg', (45, 59))
186703	30171420	Genomic rearrangements in non-coding regions may lead to massive activation of oncogenes, such as GFI1 (growth factor independent 1 transcriptional factor) in medulloblastoma or TERT (telomerase reverse transcriptase) in neuroblastoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (159, 174))	('neuroblastoma', 'Disease', (221, 234))	('telomerase reverse transcriptase', 'Gene', (184, 216))	('TERT', 'Gene', (178, 182))	('neuroblastoma', 'Phenotype', 'HP:0003006', (221, 234))	('medulloblastoma', 'Disease', 'MESH:D008527', (159, 174))	('telomerase reverse transcriptase', 'Gene', '7015', (184, 216))	('GFI1', 'Gene', '2672', (98, 102))	('TERT', 'Gene', '7015', (178, 182))	('rearrangements', 'Var', (8, 22))	('Genomic', 'Var', (0, 7))	('oncogenes', 'Gene', (79, 88))	('activation', 'PosReg', (65, 75))	('GFI1', 'Gene', (98, 102))	('medulloblastoma', 'Disease', (159, 174))	('neuroblastoma', 'Disease', 'MESH:D009447', (221, 234))
186708	30171420	A hallmark of cancer is the activation of genes forcing cells into proliferation or maintaining survival under stress while blocking differentiation and cell death.	('cancer', 'Disease', (14, 20))	('blocking', 'NegReg', (124, 132))	('survival', 'CPA', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('genes', 'Var', (42, 47))	('activation', 'PosReg', (28, 38))	('differentiation', 'CPA', (133, 148))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cell death', 'CPA', (153, 163))
186710	30171420	Deregulated activation of tyrosine kinases is characteristic of most cancers (Fig.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('Deregulated', 'Var', (0, 11))	('activation', 'PosReg', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('tyrosine', 'Chemical', 'MESH:D014443', (26, 34))	('cancers', 'Disease', (69, 76))	('tyrosine kinases', 'Enzyme', (26, 42))
186713	30171420	There are interesting examples of genetic alterations that were initially identified in different adult cancers and are now being targeted in pediatric oncology.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('adult cancers', 'Disease', 'MESH:C535836', (98, 111))	('adult cancers', 'Disease', (98, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('genetic alterations', 'Var', (34, 53))	('oncology', 'Phenotype', 'HP:0002664', (152, 160))
186728	30171420	In medulloblastoma, there are four clearly distinguishable, molecularly defined subgroups with different genetic alterations that result in deregulated signal transduction, i.e., WNT (wingless), SHH (sonic hedgehog) (both named for altered signal transduction pathways), group, 3 and group 4.	('SHH', 'Gene', (195, 198))	('medulloblastoma', 'Disease', 'MESH:D008527', (3, 18))	('SHH', 'Gene', '6469', (195, 198))	('medulloblastoma', 'Phenotype', 'HP:0002885', (3, 18))	('deregulated signal transduction', 'MPA', (140, 171))	('medulloblastoma', 'Disease', (3, 18))	('alterations', 'Var', (113, 124))	('sonic hedgehog', 'Gene', (200, 214))	('sonic hedgehog', 'Gene', '6469', (200, 214))
186733	30171420	In many cases, tumors show extensive genetic heterogeneity, e.g., structural heterogeneity in osteosarcoma due to mutations in DNA repair.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('DNA repair', 'Gene', (127, 137))	('mutations', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('osteosarcoma', 'Disease', (94, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (94, 106))	('osteosarcoma', 'Disease', 'MESH:D012516', (94, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('tumors', 'Disease', (15, 21))
186762	30171420	ADCC and CDC mediate the antitumor effect of the anti-GD2 antibody.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('anti-GD2', 'Var', (49, 57))
186781	30171420	With this approach, they identified mutant antigens expressed on autologous tumor cells and recognized by TIL lines of melanoma patients, who experienced tumor regression after adoptive T-cell transfer.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('mutant', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('patients', 'Species', '9606', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (154, 159))
186783	30171420	Due to the generally low mutational load of childhood cancers, its relevance here may be restricted, e.g., to DNA repair deficiency syndromes.	('mutational', 'Var', (25, 35))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('childhood cancers', 'Disease', (44, 61))	('deficiency syndromes', 'Disease', 'MESH:D013577', (121, 141))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('deficiency syndromes', 'Disease', (121, 141))	('childhood cancers', 'Disease', 'MESH:C536928', (44, 61))
186810	30171420	However, affinity enhanced TCR mutants are prone to cross-reactivity with unforeseeable and fatal side effects.	('TCR', 'Gene', (27, 30))	('TCR', 'Gene', '6962', (27, 30))	('mutants', 'Var', (31, 38))	('enhanced', 'PosReg', (18, 26))
186818	30171420	The centennial success of pediatric oncology was based on the multidisciplinary approach involving less mutilating surgery in a neo-adjuvant setting as well the cytotoxic modalities of mutagenic cell toxins (e.g., war-agent derivatives) and ionizing radiation with ensuing long-term toxicity in cancer survivors.	('toxicity', 'Disease', 'MESH:D064420', (283, 291))	('toxicity', 'Disease', (283, 291))	('mutagenic', 'Var', (185, 194))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('mutilating surgery', 'Phenotype', 'HP:0000742', (104, 122))	('cancer', 'Disease', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('oncology', 'Phenotype', 'HP:0002664', (36, 44))
186844	29108279	Additionally, RNA was extracted from the CTCs for molecular analysis including demonstration of an EWS-FLI1 translocation, identification of a previously unrecognized p53 mutation in a patient with Ewing sarcoma, and single cell RNA sequencing of CTC from a child with alveolar rhabdomyosarcoma.	('translocation', 'Reg', (108, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	('mutation', 'Var', (171, 179))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (198, 211))	('alveolar rhabdomyosarcoma', 'Disease', (269, 294))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (198, 211))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (269, 294))	('patient', 'Species', '9606', (185, 192))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (278, 294))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (269, 294))	('p53', 'Gene', '7157', (167, 170))	('EWS-FLI1', 'Gene', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('EWS-FLI1', 'Gene', '2130;2313', (99, 107))	('Ewing sarcoma', 'Disease', (198, 211))	('child', 'Species', '9606', (258, 263))	('CTC', 'Gene', (247, 250))	('p53', 'Gene', (167, 170))
186845	29108279	In mouse xenograft models, the presence of CTC correlates with disease burden and with clinically silent metastases.	('mouse', 'Species', '10090', (3, 8))	('metastases', 'Disease', (105, 115))	('CTC', 'Gene', (43, 46))	('disease burden', 'CPA', (63, 77))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('presence', 'Var', (31, 39))
186862	29108279	We also present proof of principle analyses suggesting that the presence of CTCs in patients with no radiographic evidence of disease predicts imminent relapse.	('presence', 'Var', (64, 72))	('patients', 'Species', '9606', (84, 92))	('CTCs', 'Gene', (76, 80))
186911	29108279	To demonstrate the feasibility of molecular analysis of the filter-captured CTCs, we used RT-PCR and Sanger sequencing to detect two genetic markers, the EWS-FL11 translocation and TP53 mutation, in CTCs collected from both mouse and human patient blood samples.	('TP53', 'Gene', (181, 185))	('human', 'Species', '9606', (234, 239))	('mouse', 'Species', '10090', (224, 229))	('translocation', 'Var', (163, 176))	('patient', 'Species', '9606', (240, 247))	('EWS-FL11', 'Gene', (154, 162))	('mutation', 'Var', (186, 194))
186918	29108279	Each of these clones contained a previously described, but not previously suspected, point mutation (TP53 p.E198K/c.592G>A).	('c.592G>A', 'Mutation', 'rs730882004', (114, 122))	('TP53', 'Gene', (101, 105))	('p.E198K/c.592G>A', 'Var', (106, 122))	('p.E198K', 'Mutation', 'p.E198K', (106, 113))
186924	29108279	Although the patient had a known PAX3-FOXO1 translocation, this was not detected due to technical limitations of the 3' priming and short-read sequencing that characterize the 10x Genomics platform.	('PAX3', 'Gene', '5077', (33, 37))	('PAX3', 'Gene', (33, 37))	('patient', 'Species', '9606', (13, 20))	('FOXO1', 'Gene', '2308', (38, 43))	('FOXO1', 'Gene', (38, 43))	('translocation', 'Var', (44, 57))
186996	28404944	By selecting for methionine independence, it is possible to select for cells, which became less malignant, indicating further a linkage between altered methionine metabolism and oncogenic transformation.	('altered', 'Var', (144, 151))	('oncogenic transformation', 'CPA', (178, 202))	('linkage', 'Interaction', (128, 135))	('methionine', 'Chemical', 'MESH:D008715', (17, 27))	('methionine', 'Chemical', 'MESH:D008715', (152, 162))
187003	28404944	Previously, a tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a PDOX model.	("Ewing's sarcoma", 'Disease', (42, 57))	('tumor', 'Disease', (14, 19))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (42, 57))	('CDKN2A/B', 'Gene', (103, 111))	('CDKN2A/B', 'Gene', '1029;1030', (103, 111))	('loss', 'NegReg', (113, 117))	('patient', 'Species', '9606', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('2A/B', 'Var', (97, 101))	('nude mice', 'Species', '10090', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('2A/B', 'Var', (107, 111))	('2A/B', 'SUBSTITUTION', 'None', (97, 101))	('2A/B', 'SUBSTITUTION', 'None', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (42, 57))
187068	26760230	Genetic engineering of the MTM-producing bacterium Streptomyces argillaceus to inactivate the gene mtmW encoding the enzyme catalyzing the final step of the MTM biosynthetic pathway, the ketoreductase MtmW, yielded derivatives MTM SA, MTM SK, and MTM SDK.	('mtmW', 'Gene', (99, 103))	('MTM', 'Chemical', 'MESH:D008926', (235, 238))	('keto', 'Chemical', '-', (187, 191))	('inactivate', 'Var', (79, 89))	('Streptomyces argillaceus', 'Species', '41951', (51, 75))	('MTM', 'Chemical', 'MESH:D008926', (157, 160))	('MTM', 'Chemical', 'MESH:D008926', (247, 250))	('MTM', 'Chemical', 'MESH:D008926', (27, 30))	('SA', 'Chemical', '-', (231, 233))	('MTM', 'Chemical', 'MESH:D008926', (227, 230))
187069	26760230	These MTM analogues all contained shortened 3-side chains, which had been shown by previous NMR studies of MTM to interact with the sugar-phosphate backbone of DNA.	('shortened', 'Var', (34, 43))	('sugar-phosphate', 'Chemical', 'MESH:D013403', (132, 147))	('3-side', 'Protein', (44, 50))	('MTM', 'Chemical', 'MESH:D008926', (6, 9))	('MTM', 'Chemical', 'MESH:D008926', (107, 110))
187142	26760230	In agreement with a previous report, Fe2+ is a more potent MTM dimerizer, with Kd at least 100-fold smaller than in Mg2+ (Table 1).	('Fe2+', 'Chemical', 'MESH:C038178', (37, 41))	('Fe2+', 'Var', (37, 41))	('Mg2+', 'Chemical', '-', (116, 120))	('smaller', 'NegReg', (100, 107))	('MTM', 'Chemical', 'MESH:D008926', (59, 62))
187186	26760230	The observed molecular weight of the sample (1249.5181) matched the calculated molecular weight of MTM SA-Trp ([C61H82N2O24Na]+ = 1249.5155) (Supplementary Fig.	('1249.5181', 'Var', (45, 54))	('MTM', 'Chemical', 'MESH:D008926', (99, 102))	('1H', 'Chemical', '-', (114, 116))	('[C61H82N2O24Na]+ = 1249.5155', 'Var', (111, 139))	('SA-Trp', 'Chemical', '-', (103, 109))
187196	21602936	CD133+ sorted cells were subsequently shown to be more tumorigenic and more resistant to commonly used chemotherapeutics.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CD133+', 'Var', (0, 6))	('tumor', 'Disease', (55, 60))	('more', 'PosReg', (50, 54))
187211	21602936	Furthermore, CD133+ glioma stem cells are more resistant to chemotherapy and radiation than bulk and the CD133 negative population.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('CD133+', 'Var', (13, 19))	('resistant', 'CPA', (47, 56))	('glioma', 'Disease', (20, 26))
187216	21602936	CD133+ cells characterize a subpopulation which is more tumorigenic and resistant to chemotherapy than the negative population.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CD133+ cells', 'Var', (0, 12))	('tumor', 'Disease', (56, 61))	('more', 'PosReg', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
187235	21602936	Quantitative Real-Time PCR was performed using validated TaqMan Gene Expression Assays (Applied Biosystems) for POU5F1/OCT3-4 (Hs02397400_g1), NANOG (Hs02387400_g1), SOX2 (Hs01053049_s1), CMYC (Hs00153408_m1), PAX3 (Hs00992437_m1), NMYC (Hs00232074_m1), PROM1/CD133 (Hs01009261_m1) and GAPDH (Hs99999905_m1) as an endogenous housekeeping gene for normalization.	('OCT3-4', 'Gene', (119, 125))	('PROM1', 'Gene', (254, 259))	('Hs99999905_m1', 'Var', (293, 306))	('PROM1', 'Gene', '8842', (254, 259))	('GAPDH', 'Gene', '2597', (286, 291))	('CMYC', 'Gene', '4609', (188, 192))	('NMYC', 'Gene', (232, 236))	('POU5F1', 'Gene', (112, 118))	('PAX3', 'Gene', (210, 214))	('Hs00992437_m1', 'Var', (216, 229))	('Hs00232074_m1', 'Var', (238, 251))	('GAPDH', 'Gene', (286, 291))	('SOX2', 'Gene', '6657', (166, 170))	('SOX2', 'Gene', (166, 170))	('PAX3', 'Gene', '5077', (210, 214))	('NMYC', 'Gene', '4613', (232, 236))	('Hs01009261_m1', 'Var', (267, 280))	('Hs01053049_s1', 'Var', (172, 185))	('CMYC', 'Gene', (188, 192))	('POU5F1', 'Gene', '5460', (112, 118))	('Hs00153408_m1', 'Var', (194, 207))	('NANOG', 'Gene', '79923', (143, 148))	('Hs02397400_g1', 'Var', (127, 140))	('NANOG', 'Gene', (143, 148))	('Hs02387400_g1', 'Var', (150, 163))	('OCT3-4', 'Gene', '5460', (119, 125))
187277	21602936	In contrast, we could detect at least one tumor in the CD133+ injected mice in three out of four dilutions (Figure 4B).	('mice', 'Species', '10090', (71, 75))	('tumor', 'Disease', (42, 47))	('CD133+', 'Var', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
187282	21602936	Therefore, rhabdospheres are enriched for a CD133+ population being more tumorigenic and resistant to cisPlatin and Chlorambucil.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('CD133+', 'Var', (44, 50))	('more', 'PosReg', (68, 72))	('Chlorambucil', 'Chemical', 'MESH:D002699', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('cisPlatin', 'Chemical', 'MESH:D002945', (102, 111))
187286	21602936	ERMS patients showing no or low to intermediate CD133 expression showed an overall survival around 75% which is comparable with the survival rate of translocation negative RMS patients.	('CD133', 'Gene', (48, 53))	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (5, 13))	('ERMS', 'Disease', 'None', (0, 4))	('ERMS', 'Disease', (0, 4))	('low', 'Var', (28, 31))
187306	21602936	Moreover, a CD133+ population was identified as a CSC population in sarcomas such as Ewing's sarcoma and osteosarcoma which was more resistant to chemotherapy and radiation.	("Ewing's sarcoma", 'Disease', (85, 100))	('sarcomas', 'Disease', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (85, 100))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('CD133+', 'Var', (12, 18))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (85, 100))
187308	21602936	It has been reported that expression of FGFR3 might mark a tumorigenic subpopulation in RMS.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('FGFR3', 'Gene', (40, 45))	('expression', 'Var', (26, 36))	('RMS', 'Disease', (88, 91))	('FGFR3', 'Gene', '2261', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
187316	21602936	Patients with high positivity for CD133 were found to have the worst overall survival, which could be explained by a higher recurrence.	('overall survival', 'MPA', (69, 85))	('Patients', 'Species', '9606', (0, 8))	('high positivity', 'Var', (14, 29))	('CD133', 'Gene', (34, 39))	('worst', 'NegReg', (63, 68))
187331	33478436	Herein, we diagnosed a rare case of primary CCS of the bone by detecting EWSR1/ATF1 fusion gene using RT-PCR and direct sequencing.	('ATF1', 'Gene', (79, 83))	('ATF1', 'Gene', '466', (79, 83))	('EWSR1', 'Gene', (73, 78))	('fusion gene', 'Var', (84, 95))	('EWSR1', 'Gene', '2130', (73, 78))	('detecting', 'Reg', (63, 72))
187342	33478436	detected EWS/ATF1 fusion transcripts in 38 paraffin-embedded CCS tissues out of 41 interpretable samples (93 %) in 2006.	('paraffin', 'Chemical', 'MESH:D010232', (43, 51))	('fusion transcripts', 'Var', (18, 36))	('EWS/ATF1', 'Gene', (9, 17))	('EWS/ATF1', 'Gene', '466', (9, 17))
187386	33478436	Although they confirmed rearrangement of the EWS gene localized on chromosome 22q12 using FISH, fusion transcripts were not detected.	('EWS', 'Gene', (45, 48))	('EWS', 'Gene', '2130', (45, 48))	('rearrangement', 'Var', (24, 37))
187457	30217299	Among 526 homologous sarcoma cases, presence of SD was significantly associated with decreased PFS (unadjusted-HR 1.48, 95%CI 1.13-1.93, P = 0.004) and CSS (unadjusted-HR 1.67, 95%CI 1.22-2.28, P = 0.001).	('decreased', 'NegReg', (85, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('presence', 'Var', (36, 44))	('CSS', 'CPA', (152, 155))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('SD', 'Chemical', '-', (48, 50))	('PFS', 'CPA', (95, 98))	('sarcoma', 'Disease', (21, 28))
187461	30217299	When tumors had SD, postoperative radiotherapy was significantly associated with improved PFS (adjusted-HR: 0.49 for homo/dominance, and 0.36 for hetero/dominance) and CSS (adjusted-HR: 0.37 for homo/dominance, and 0.35 for hetero/dominance) regardless of sarcoma types (all, P < 0.05; Table 4).	('improved', 'PosReg', (81, 89))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('SD', 'Chemical', '-', (16, 18))	('sarcoma', 'Disease', 'MESH:D012509', (256, 263))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CSS', 'MPA', (168, 171))	('PFS', 'MPA', (90, 93))	('sarcoma', 'Disease', (256, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('radiotherapy', 'Var', (34, 46))
187479	30217299	This clearly indicates that presence of SD impacts survival more in homologous type than heterologous type.	('survival', 'CPA', (51, 59))	('SD impacts', 'Disease', 'MESH:D029461', (40, 50))	('presence', 'Var', (28, 36))	('SD impacts', 'Disease', (40, 50))
187571	29285586	All four tumors manifested the diagnostic EWSR1 mutation and were treated with an Ewing sarcoma regimen.	('Ewing sarcoma', 'Disease', (82, 95))	('EWSR1', 'Gene', '2130', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (82, 95))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('mutation', 'Var', (48, 56))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('EWS', 'Phenotype', 'HP:0012254', (42, 45))	('EWSR1', 'Gene', (42, 47))
187574	29285586	Testing for the EWSR1 mutation confirms the diagnosis of Ewing sarcoma and excludes other types of embryonal CNS tumors.	('EWSR1', 'Gene', '2130', (16, 21))	('Ewing sarcoma', 'Disease', (57, 70))	('mutation', 'Var', (22, 30))	('embryonal CNS tumors', 'Disease', (99, 119))	('EWS', 'Phenotype', 'HP:0012254', (16, 19))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('embryonal CNS tumors', 'Disease', 'MESH:D009373', (99, 119))	('EWSR1', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
187585	29285586	Polymerase chain reaction (PCR) testing detected EWSR1 rearrangement diagnostic of EWS.	('EWS', 'Gene', '2130', (49, 52))	('EWS', 'Gene', (49, 52))	('EWS', 'Gene', (83, 86))	('EWS', 'Gene', '2130', (83, 86))	('EWS', 'Phenotype', 'HP:0012254', (83, 86))	('EWSR1', 'Gene', (49, 54))	('EWSR1', 'Gene', '2130', (49, 54))	('rearrangement', 'Var', (55, 68))	('EWS', 'Phenotype', 'HP:0012254', (49, 52))
187597	29285586	Fluorescence in situ hybridization (FISH) was positive for the EWSR1 rearrangement diagnostic of EWS (Fig.	('EWS', 'Gene', '2130', (63, 66))	('EWS', 'Gene', (63, 66))	('EWS', 'Gene', (97, 100))	('EWS', 'Phenotype', 'HP:0012254', (97, 100))	('rearrangement', 'Var', (69, 82))	('EWS', 'Gene', '2130', (97, 100))	('EWSR1', 'Gene', '2130', (63, 68))	('EWS', 'Phenotype', 'HP:0012254', (63, 66))	('EWSR1', 'Gene', (63, 68))
187612	29285586	FISH showed the EWSR1 rearrangement diagnostic for EWS (Fig.	('EWSR1', 'Gene', '2130', (16, 21))	('EWS', 'Gene', (51, 54))	('EWS', 'Gene', '2130', (51, 54))	('EWS', 'Phenotype', 'HP:0012254', (16, 19))	('EWS', 'Gene', '2130', (16, 19))	('EWS', 'Gene', (16, 19))	('EWSR1', 'Gene', (16, 21))	('rearrangement', 'Var', (22, 35))	('EWS', 'Phenotype', 'HP:0012254', (51, 54))
187617	29285586	Upon tumor biopsy, pathology revealed a small round cell tumor with FISH testing demonstrating rearrangement of the ESWR1 locus, confirming the diagnosis of EWS (Fig.	('revealed', 'Reg', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('EWS', 'Phenotype', 'HP:0012254', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (57, 62))	('EWS', 'Gene', (157, 160))	('ESWR1', 'Gene', (116, 121))	('rearrangement', 'Var', (95, 108))	('EWS', 'Gene', '2130', (157, 160))
187625	29285586	Although EWS is a type of "small round blue cell tumor," it is unrelated to medulloblastoma, CNS embryonal tumors, or embryonal tumors with multilayered rosettes, C19MC altered.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('EWS', 'Gene', (9, 12))	('medulloblastoma', 'Disease', 'MESH:D008527', (76, 91))	('embryonal tumors', 'Phenotype', 'HP:0002898', (97, 113))	('blue cell tumor', 'Disease', (39, 54))	('embryonal tumors', 'Disease', (97, 113))	('medulloblastoma', 'Phenotype', 'HP:0002885', (76, 91))	('embryonal tumors', 'Disease', 'MESH:D009373', (97, 113))	('C19MC altered', 'Var', (163, 176))	('medulloblastoma', 'Disease', (76, 91))	('EWS', 'Phenotype', 'HP:0012254', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('rosettes', 'Phenotype', 'HP:0031925', (153, 161))	('embryonal tumors', 'Phenotype', 'HP:0002898', (118, 134))	('embryonal tumors', 'Disease', (118, 134))	('embryonal tumors', 'Disease', 'MESH:D009373', (118, 134))	('EWS', 'Gene', '2130', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('blue cell tumor', 'Disease', 'MESH:D005935', (39, 54))
187628	29285586	While translocations involving a number of genes can be identified in EWS, the most common involves the FLI1 gene located on 11q24, which creates a t(11;22)(q24;q12) translocation.	('FLI1', 'Gene', (104, 108))	('EWS', 'Phenotype', 'HP:0012254', (70, 73))	('EWS', 'Gene', '2130', (70, 73))	('EWS', 'Gene', (70, 73))	('FLI1', 'Gene', '2313', (104, 108))	('t(11;22)(q24;q12', 'Var', (148, 164))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (148, 165))
187631	29285586	By utilizing either fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (rtPCR), it is possible to detect translocations diagnostic for EWS, specifically the EWSR1 rearrangement, with 91-100% sensitivity and specificity.	('EWS', 'Gene', '2130', (199, 202))	('EWS', 'Gene', (199, 202))	('EWS', 'Phenotype', 'HP:0012254', (177, 180))	('EWS', 'Gene', '2130', (177, 180))	('EWS', 'Gene', (177, 180))	('EWSR1', 'Gene', '2130', (199, 204))	('rearrangement', 'Var', (205, 218))	('EWS', 'Phenotype', 'HP:0012254', (199, 202))	('EWSR1', 'Gene', (199, 204))	('translocations', 'Var', (147, 161))
187697	29061935	One of the strengths of the dog in comparative oncology is the relatively genetically homogenous breeds (compared to humans) with breed predispositions to different cancers, simplifying identification of genetic signatures related to cancer predisposition (for example, DNA repair deficiency in Golden Retrievers associated with higher risk of lymphoma).	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('oncology', 'Phenotype', 'HP:0002664', (47, 55))	('lymphoma', 'Disease', (344, 352))	('associated', 'Reg', (313, 323))	('humans', 'Species', '9606', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (165, 171))	('lymphoma', 'Disease', 'MESH:D008223', (344, 352))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancer', 'Disease', (234, 240))	('DNA', 'Gene', (270, 273))	('cancers', 'Disease', (165, 172))	('lymphoma', 'Phenotype', 'HP:0002665', (344, 352))	('dog', 'Species', '9615', (28, 31))	('deficiency', 'Var', (281, 291))
187719	29061935	As well as clinical features, feline oral SCC shares many molecular features with HHNC, including high frequency of epidermal growth factor (EGFR) over-expression (although not proven to be prognostic in cats), altered p53 expression, dysregulated CK2 expression, markers of angiogenesis and cyclooxygenase and lipoxygenase enzyme overexpression.	('over-expression', 'PosReg', (147, 162))	('epidermal growth factor', 'Gene', '493978', (116, 139))	('cats', 'Species', '9685', (204, 208))	('overexpression', 'PosReg', (331, 345))	('SCC', 'Gene', (42, 45))	('expression', 'MPA', (223, 233))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('altered', 'Reg', (211, 218))	('dysregulated', 'Var', (235, 247))	('SCC', 'Gene', '6317', (42, 45))	('epidermal growth factor', 'Gene', (116, 139))	('CK2', 'Protein', (248, 251))	('expression', 'MPA', (252, 262))	('HHNC', 'Disease', (82, 86))	('p53', 'Gene', (219, 222))
187728	29061935	Inhibition of CK2 is effective in rodent xenograft models of human prostate and head and neck cancers and small molecule CK2 inhibitors are in early clinical trials.	('prostate', 'Disease', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Inhibition', 'Var', (0, 10))	('head and neck cancer', 'Phenotype', 'HP:0012288', (80, 100))	('head and neck cancers', 'Disease', 'MESH:D006258', (80, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('human', 'Species', '9606', (61, 66))	('head and neck cancers', 'Phenotype', 'HP:0012288', (80, 101))	('CK2', 'Gene', (14, 17))
187733	29061935	Potential avenues for comparative investigations in feline SCC include new EGFR inhibitors, including in the setting of gefitinib-resistance, CK2 inhibition alone and in combination with chemo- or radio-therapy, novel COX/LOX inhibitors, methods to reverse hypoxia in combination with other therapies, and anti-angiogenic therapies.	('SCC', 'Gene', (59, 62))	('inhibition', 'NegReg', (146, 156))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('hypoxia', 'Disease', 'MESH:D000860', (257, 264))	('SCC', 'Gene', '6317', (59, 62))	('hypoxia', 'Disease', (257, 264))	('CK2', 'Protein', (142, 145))	('gefitinib', 'Chemical', 'MESH:D000077156', (120, 129))	('EGFR', 'Gene', (75, 79))	('inhibitors', 'Var', (80, 90))
187741	29061935	Germline mutations in BRCA1 and BRCA2 genes are associated with familial breast cancer risk in women, although the majority of breast cancers are sporadic in nature.	('Germline mutations', 'Var', (0, 18))	('breast cancers', 'Phenotype', 'HP:0003002', (127, 141))	('breast cancers', 'Disease', 'MESH:D001943', (127, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('breast cancers', 'Disease', (127, 141))	('associated', 'Reg', (48, 58))	('BRCA2', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('familial breast cancer', 'Disease', 'MESH:D001943', (64, 86))	('women', 'Species', '9606', (95, 100))	('BRCA1', 'Gene', '672', (22, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('BRCA2', 'Gene', '675', (32, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('familial breast cancer', 'Disease', (64, 86))	('BRCA1', 'Gene', (22, 27))
187742	29061935	BRCA mutations have not been found in cats with mammary cancer.	('BRCA', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (5, 14))	('cats', 'Species', '9685', (38, 42))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
187756	29061935	When considering cats as a model for HER2-targeted therapies however, strong consideration needs to be given to the methodologies used to assess HER2 protein expression due to variability between studies, as well as the recently identified sequence variants in HER2 which may impact its affinity for targeted therapies such as trastuzumab, as is seen in humans.	('humans', 'Species', '9606', (354, 360))	('impact', 'Reg', (276, 282))	('HER2', 'Protein', (145, 149))	('cats', 'Species', '9685', (17, 21))	('affinity', 'MPA', (287, 295))	('trastuzumab', 'Chemical', 'MESH:D000068878', (327, 338))	('variants', 'Var', (249, 257))	('HER2', 'Gene', (261, 265))
187784	26337082	Additionally, pharmacologic inhibition of CDK4 with selective CDK4/6 inhibitors led to cytostasis and cell death of Ewing sarcoma cell lines in vitro and growth delay in an in vivo Ewing sarcoma xenograft model.	('death of Ewing sarcoma', 'Disease', (107, 129))	('Ewing sarcoma', 'Disease', (181, 194))	('CDK4/6', 'Gene', '1019;1021', (62, 68))	('growth delay', 'Phenotype', 'HP:0001510', (154, 166))	('cytostasis', 'CPA', (87, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('pharmacologic', 'Var', (14, 27))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (181, 194))	('CDK4/6', 'Gene', (62, 68))	('death of Ewing sarcoma', 'Disease', 'MESH:C563168', (107, 129))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (181, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('growth delay', 'CPA', (154, 166))	('CDK4', 'Gene', (42, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
187788	26337082	The primary known oncogenic event in Ewing sarcoma is a somatic chromosomal translocation, most commonly between chromosomes 11 and 22, which results in a fusion between the 5' region of the EWS gene and the 3' region of the ETS family gene, FLI1.	('Ewing sarcoma', 'Disease', (37, 50))	('results in', 'Reg', (142, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (37, 50))	('EWS', 'Gene', '2130', (191, 194))	('EWS', 'Gene', (191, 194))	('FLI1', 'Gene', (242, 246))	('fusion', 'Var', (155, 161))	('FLI1', 'Gene', '2313', (242, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
187792	26337082	With the characterization of the genomic landscapes of tumors, it has become clear that there is activation of oncogenic drivers, mutations in tumor suppressors, as well as epigenetic changes that contribute to the hallmarks of tumor cells.	('epigenetic changes', 'Var', (173, 191))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('oncogenic', 'Gene', (111, 120))	('activation', 'PosReg', (97, 107))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (130, 139))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
187807	26337082	Therefore, we hypothesized that epigenetic contributions to tumor initiation and maintenance may be especially important in Ewing tumors.	('Ewing tumors', 'Disease', (124, 136))	('important', 'Reg', (111, 120))	('epigenetic', 'Var', (32, 42))	('tumor initiation', 'Disease', 'MESH:D009369', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Ewing tumors', 'Disease', 'MESH:C563168', (124, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor initiation', 'Disease', (60, 76))	('Ewing tumors', 'Phenotype', 'HP:0012254', (124, 136))
187814	26337082	It showed that the average ChIP-seq signal of EWS/FLI1 and H3K27Ac spanning and flanking the super-enhancers was considerably higher as compared to typical enhancers in TC32 and TC71 Ewing sarcoma cells (Figure 1B and Supplementary Figure S1C, respectively).	('TC71', 'CellLine', 'CVCL:2213', (178, 182))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (183, 196))	('ChIP-seq signal', 'MPA', (27, 42))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (183, 196))	('higher', 'PosReg', (126, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('EWS', 'Gene', '2130', (46, 49))	('EWS', 'Gene', (46, 49))	('FLI1', 'Gene', '2313', (50, 54))	('TC32', 'CellLine', 'CVCL:7151', (169, 173))	('FLI1', 'Gene', (50, 54))	('H3K27Ac', 'Var', (59, 66))	('Ewing sarcoma', 'Disease', (183, 196))
187816	26337082	The amounts of an active mark H3K4me3 and a repressive mark H3K27me3 in the gene body of CAV1/2 and CCND1 are comparable to those in the gene body of a typical enhancer-associated gene SMARCA4.	('CCND1', 'Gene', (100, 105))	('SMARCA4', 'Gene', (185, 192))	('H3K4me3', 'Var', (30, 37))	('CCND1', 'Gene', '595', (100, 105))	('H3K27me3', 'Var', (60, 68))	('CAV1/2', 'Gene', (89, 95))	('SMARCA4', 'Gene', '6597', (185, 192))	('CAV1/2', 'Gene', '775;857;858', (89, 95))
187820	26337082	Consistent with previous literature showing that GGAA microsatellites are a DNA binding motif of EWS/FLI1, we found that GGAA microsatellites within EWS/FLI1 peaks have more GGAA repeat counts than those residing in regions outside of the EWS/FLI1 peaks (Figure 1E).	('EWS', 'Gene', '2130', (149, 152))	('EWS', 'Gene', (149, 152))	('microsatellites', 'Var', (126, 141))	('EWS', 'Gene', (97, 100))	('EWS', 'Gene', '2130', (97, 100))	('FLI1', 'Gene', '2313', (101, 105))	('FLI1', 'Gene', (101, 105))	('FLI1', 'Gene', '2313', (153, 157))	('EWS', 'Gene', (239, 242))	('EWS', 'Gene', '2130', (239, 242))	('GGAA repeat counts', 'MPA', (174, 192))	('FLI1', 'Gene', (153, 157))	('FLI1', 'Gene', (243, 247))	('FLI1', 'Gene', '2313', (243, 247))	('more', 'PosReg', (169, 173))
187821	26337082	Furthermore, in light of a recent paper reporting a role for EWS/FLI1 as a pioneer factor at enhancer elements, we hypothesized that super-enhancers would be enriched with GGAA microsatellites.	('FLI1', 'Gene', '2313', (65, 69))	('FLI1', 'Gene', (65, 69))	('microsatellites', 'Var', (177, 192))	('EWS', 'Gene', '2130', (61, 64))	('EWS', 'Gene', (61, 64))
187822	26337082	We compared the distributions of GGAA microsatellites within super-enhancers and typical enhancers in the Ewing genome and found that the percentage of super-enhancers containing GGAA microsatellites is significantly higher than the percentage of typical-enhancers containing GGAA microsatellites (Figure 1F).	('higher', 'PosReg', (217, 223))	('Ewing genome', 'Disease', (106, 118))	('Ewing genome', 'Disease', 'MESH:C563168', (106, 118))	('microsatellites', 'Var', (184, 199))
187839	26337082	EWS/FLI1 knockdown significantly reduced the EWS/FLI1 binding, as well as the H3K27Ac, at super-enhancer marked genes CAV1 and CCND1, without significant effects on the SMARCA4 typical enhancer (Figure 2D).	('EWS', 'Gene', (45, 48))	('EWS', 'Gene', '2130', (45, 48))	('CCND1', 'Gene', '595', (127, 132))	('FLI1', 'Gene', (4, 8))	('CAV1', 'Gene', (118, 122))	('FLI1', 'Gene', (49, 53))	('knockdown', 'Var', (9, 18))	('FLI1', 'Gene', '2313', (4, 8))	('FLI1', 'Gene', '2313', (49, 53))	('H3K27Ac', 'Var', (78, 85))	('CAV1', 'Gene', '857', (118, 122))	('SMARCA4', 'Gene', (169, 176))	('reduced', 'NegReg', (33, 40))	('SMARCA4', 'Gene', '6597', (169, 176))	('CCND1', 'Gene', (127, 132))	('binding', 'Interaction', (54, 61))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
187850	26337082	In this data set, 634 cancer cell lines were treated with small molecules and the effects on cell viability measured.	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (22, 28))	('small molecules', 'Var', (58, 73))	('cancer', 'Disease', 'MESH:D009369', (22, 28))
187852	26337082	While there were no GSK-3alpha isoform-selective inhibitors in the data set, we did evaluate response to the pan-GSK-3 inhibitors, including SB216763 and CHIR-99021.	('GSK-3alpha', 'Gene', '2931', (20, 30))	('GSK-3alpha', 'Gene', (20, 30))	('SB216763', 'Var', (141, 149))
187854	26337082	PD0332991, a well-validated small-molecule inhibitor of CDK4/6, and thus an indirect inhibitor of activated cyclin D1, was also profiled in the data set.	('PD0332991', 'Chemical', 'MESH:C500026', (0, 9))	('CDK4/6', 'Gene', (56, 62))	('PD0332991', 'Var', (0, 9))	('CDK4/6', 'Gene', '1019;1021', (56, 62))
187855	26337082	The IC50 of PD0332991 in the Ewing cell lines was significantly lower than that of the other cancer cell lines tested in this dataset.	('cancer', 'Disease', (93, 99))	('IC50', 'MPA', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('lower', 'NegReg', (64, 69))	('PD0332991', 'Chemical', 'MESH:C500026', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PD0332991', 'Var', (12, 21))
187856	26337082	In addition, the expression of EWS/FLI1 in Ewing sarcoma was a significant marker of increased drug sensitivity (P-value = 0.0307, Mann-Whitney test, Figure 3C and 3D).	('EWS', 'Gene', (31, 34))	('Ewing sarcoma', 'Disease', (43, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('drug sensitivity', 'Phenotype', 'HP:0020174', (95, 111))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('drug sensitivity', 'MPA', (95, 111))	('FLI1', 'Gene', '2313', (35, 39))	('FLI1', 'Gene', (35, 39))	('expression', 'Var', (17, 27))	('increased', 'PosReg', (85, 94))	('EWS', 'Gene', '2130', (31, 34))
187859	26337082	We analyzed the data for copy number changes in CDK4 or chromosomal amplifications and found chromosomal arm level amplification resulting in three copies of CDK4 in 25% of tumors, which coincided with a modest increase in CDK4 expression, but none of the cell lines had a copy gain in CDK4.	('increase', 'PosReg', (211, 219))	('resulting in', 'Reg', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('chromosomal arm level amplification', 'Var', (93, 128))	('CDK4', 'Gene', (158, 162))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('CDK4', 'Gene', (223, 227))	('expression', 'MPA', (228, 238))
187873	26337082	To complement these shRNA studies, we tested the effects of a selective small-molecule inhibitor of CDK4/6, LEE011, in Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (119, 132))	('LEE011', 'Var', (108, 114))	('CDK4/6', 'Gene', '1019;1021', (100, 106))	('tested', 'Reg', (38, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (119, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (119, 132))	('CDK4/6', 'Gene', (100, 106))	('LEE011', 'Chemical', 'MESH:C000589651', (108, 114))
187874	26337082	A panel of Ewing sarcoma cell lines was cultured with serially diluted concentrations of LEE011 and cell viability measured following five days of treatment.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('LEE011', 'Chemical', 'MESH:C000589651', (89, 95))	('Ewing sarcoma', 'Disease', (11, 24))	('LEE011', 'Var', (89, 95))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (11, 24))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (11, 24))
187876	26337082	Sensitivity to LEE011 was correlated with sensitivity to PD0332991 (Supplementary Figure S4A) and was not based on intrinsic cell growth properties of the various Ewing lines tested (Supplementary Figure S4B).	('PD0332991', 'Var', (57, 66))	('LEE011', 'Chemical', 'MESH:C000589651', (15, 21))	('LEE011', 'Var', (15, 21))	('PD0332991', 'Chemical', 'MESH:C500026', (57, 66))
187877	26337082	Because CDK4/6 inhibitors primarily induce a G1 cell cycle arrest in cancer cells with a functional Rb protein, we examined the effect of CDK4/6 inhibition on cell cycle in Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (173, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('CDK4/6', 'Gene', (138, 144))	('CDK4/6', 'Gene', (8, 14))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (173, 186))	('arrest', 'Disease', (59, 65))	('Rb', 'Chemical', 'MESH:D012413', (100, 102))	('CDK4/6', 'Gene', '1019;1021', (138, 144))	('CDK4/6', 'Gene', '1019;1021', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('induce', 'Reg', (36, 42))	('inhibitors', 'Var', (15, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (48, 65))	('cancer', 'Disease', (69, 75))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
187881	26337082	In addition, when treated with 1 muM LEE011, Ewing sarcoma cell lines had decreased growth in methylcellulose, as demonstrated by smaller and fewer colonies formed in the presence of LEE011 compared to DMSO (Figure 6E-6F).	('LEE011', 'Chemical', 'MESH:C000589651', (183, 189))	('fewer', 'NegReg', (142, 147))	('growth in methylcellulose', 'MPA', (84, 109))	('methylcellulose', 'Chemical', 'MESH:D008747', (94, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('colonies formed', 'CPA', (148, 163))	('DMSO', 'Chemical', 'MESH:D004121', (202, 206))	('LEE011', 'Var', (37, 43))	('LEE011', 'Chemical', 'MESH:C000589651', (37, 43))	('LEE011', 'Var', (183, 189))	('decreased growth', 'Phenotype', 'HP:0001510', (74, 90))	('Ewing sarcoma', 'Disease', (45, 58))	('decreased', 'NegReg', (74, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('smaller', 'NegReg', (130, 137))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 58))
187882	26337082	These studies establish LEE011 as a potent inducer of cell cycle arrest and cell death in a subset of Ewing sarcoma cell lines.	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('Ewing sarcoma', 'Disease', (102, 115))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('LEE011', 'Chemical', 'MESH:C000589651', (24, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('arrest', 'Disease', (65, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('cell death', 'CPA', (76, 86))	('inducer', 'PosReg', (43, 50))	('LEE011', 'Var', (24, 30))
187883	26337082	Following the in vitro validation of cyclin D1 and CDK4 through shRNA-mediated knockdown and small-molecule inhibition, we next assessed the efficacy of LEE011 in vivo.	('LEE011', 'Chemical', 'MESH:C000589651', (153, 159))	('LEE011', 'Var', (153, 159))	('CDK4', 'Gene', (51, 55))
187887	26337082	In addition, there was a statistically significant difference in tumor volume in LEE011 versus vehicle treatment (Figure 7B).	('tumor', 'Disease', (65, 70))	('LEE011', 'Chemical', 'MESH:C000589651', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('LEE011', 'Var', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
187888	26337082	Notably, at the highest dose of LEE011 treatment there was even a modest regression of tumor size.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('LEE011', 'Var', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('LEE011', 'Chemical', 'MESH:C000589651', (32, 38))
187890	26337082	Ki67 staining was significantly decreased in animals treated with the highest dose of LEE011, indicative of decreased cell proliferation (Figure 7D and 7E).	('Ki67 staining', 'Protein', (0, 13))	('LEE011', 'Var', (86, 92))	('Ki67', 'Chemical', '-', (0, 4))	('decreased', 'NegReg', (108, 117))	('LEE011', 'Chemical', 'MESH:C000589651', (86, 92))	('cell proliferation', 'CPA', (118, 136))	('decreased', 'NegReg', (32, 41))
187891	26337082	In summary, these data demonstrate the in vivo efficacy of LEE011 in a Ewing sarcoma model.	('Ewing sarcoma', 'Disease', (71, 84))	('LEE011', 'Var', (59, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (71, 84))	('LEE011', 'Chemical', 'MESH:C000589651', (59, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
187895	26337082	Although the promise of targeted, individualized therapies has begun to positively impact some patients with cancer, success has largely been in targeting mutated kinases.	('mutated', 'Var', (155, 162))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
187902	26337082	We demonstrate that inhibition of CDK4 leads to cytostasis in a panel of Ewing sarcoma cell lines and cell death in a subset of these.	('inhibition', 'Var', (20, 30))	('cell death', 'CPA', (102, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('CDK4', 'Protein', (34, 38))	('Ewing sarcoma', 'Disease', (73, 86))	('cytostasis', 'MPA', (48, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (73, 86))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (73, 86))
187912	26337082	Deregulation of the cyclin D1/CDK4/6/Rb pathway leads to increased cell proliferation; this signaling axis is one of the most frequently mutated pathways in cancers.	('CDK4/6', 'Gene', '1019;1021', (30, 36))	('Rb', 'Chemical', 'MESH:D012413', (37, 39))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Deregulation', 'Var', (0, 12))	('CDK4/6', 'Gene', (30, 36))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('increased', 'PosReg', (57, 66))	('cell proliferation', 'CPA', (67, 85))
187914	26337082	First, cancer genome sequencing has demonstrated disruption of this pathway through CDKN2A deletion, a potential biomarker of sensitivity to CDK4/6 inhibitors, in approximately 13-30 percent of Ewing sarcoma tumors.	('Ewing sarcoma tumors', 'Disease', (194, 214))	('disruption', 'Reg', (49, 59))	('deletion', 'Var', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (194, 207))	('CDK4/6', 'Gene', '1019;1021', (141, 147))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (194, 214))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('CDK4/6', 'Gene', (141, 147))
187922	26337082	Importantly, from a clinical perspective, mutations in RB are the strongest known predictor of resistance to CDK4/6 inhibitors, and Ewing sarcomas rarely contain RB mutations.	('CDK4/6', 'Gene', '1019;1021', (109, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (132, 145))	('Ewing sarcomas', 'Disease', (132, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (132, 146))	('CDK4/6', 'Gene', (109, 115))	('resistance', 'MPA', (95, 105))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (132, 146))	('mutations', 'Var', (42, 51))
187923	26337082	LEE011 and other orally available CDK4/6 inhibitors, such as PD0332991, are currently in clinical trials, and these CDK4/6 inhibitors have had promising pre-clinical activity in many different tumor types, including pediatric neuroblastoma and rhabdomyosarcoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (226, 239))	('CDK4/6', 'Gene', '1019;1021', (34, 40))	('LEE011', 'Var', (0, 6))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (244, 260))	('neuroblastoma', 'Disease', 'MESH:D009447', (226, 239))	('CDK4/6', 'Gene', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('PD0332991', 'Chemical', 'MESH:C500026', (61, 70))	('neuroblastoma', 'Disease', (226, 239))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('rhabdomyosarcoma', 'Disease', (244, 260))	('CDK4/6', 'Gene', (34, 40))	('LEE011', 'Chemical', 'MESH:C000589651', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('tumor', 'Disease', (193, 198))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (244, 260))	('CDK4/6', 'Gene', '1019;1021', (116, 122))
187928	26337082	Indeed, there are emerging reports suggesting that synergy can be achieved with the combination of CDK4/6 inhibitors and PI3K inhibitors in breast cancer or with insulin-like growth factor receptor 1 (IGF1R) inhibitors in pancreatic cancer.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('IGF1R', 'Gene', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('pancreatic cancer', 'Disease', 'MESH:D010190', (222, 239))	('breast cancer', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('CDK4/6', 'Gene', (99, 105))	('combination', 'Interaction', (84, 95))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (222, 239))	('IGF1R', 'Gene', '3480', (201, 206))	('inhibitors', 'Var', (106, 116))	('pancreatic cancer', 'Disease', (222, 239))	('PI3K', 'Gene', (121, 125))	('CDK4/6', 'Gene', '1019;1021', (99, 105))
187929	26337082	Because Ewing sarcoma has been shown to have susceptibility to IGF1R inhibitors, with modest activity observed in clinical trials, this novel combination may prove interesting in Ewing sarcoma and will be the focus of future investigation.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (8, 21))	('Ewing sarcoma', 'Disease', (179, 192))	('susceptibility to IGF1R', 'Phenotype', 'HP:0030269', (45, 68))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (8, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('IGF1R', 'Gene', '3480', (63, 68))	('IGF1R', 'Gene', (63, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (179, 192))	('inhibitors', 'Var', (69, 79))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (179, 192))	('Ewing sarcoma', 'Disease', (8, 21))
187934	26337082	All Ewing sarcoma cell lines were confirmed to have an EWS/FLI1 or EWS/ERG rearrangement by RNA sequencing.	('FLI1', 'Gene', (59, 63))	('EWS', 'Gene', '2130', (55, 58))	('EWS', 'Gene', (55, 58))	('FLI1', 'Gene', '2313', (59, 63))	('Ewing sarcoma', 'Disease', (4, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('EWS', 'Gene', '2130', (67, 70))	('EWS', 'Gene', (67, 70))	('ERG', 'Gene', '2078', (71, 74))	('ERG', 'Gene', (71, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (4, 17))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (4, 17))	('rearrangement', 'Var', (75, 88))
187935	26337082	Ewing sarcoma cell lines were treated with the CDK4/6 inhibitor LEE011, kindly provided by Novartis Oncology, and PD0332991 (Selleck Chemicals).	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('CDK4/6', 'Gene', '1019;1021', (47, 53))	('LEE011', 'Chemical', 'MESH:C000589651', (64, 70))	('PD0332991', 'Chemical', 'MESH:C500026', (114, 123))	('Ewing sarcoma', 'Disease', (0, 13))	('CDK4/6', 'Gene', (47, 53))	('PD0332991', 'Var', (114, 123))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Oncology', 'Phenotype', 'HP:0002664', (100, 108))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('LEE011', 'Var', (64, 70))
187936	26337082	The following antibodies were used for ChIP on the two human Ewing sarcoma cell lines TC32 and TC71: EWS/FLI1: anti-FLI1 antibody SC-356X (Santa Cruz Biotechnology), H3K27Ac: ab4729 (Abcam), H3K4me3: ab8580 (Abcam) and H3K27me3: 07-449 (EMD Millipore).	('TC71', 'CellLine', 'CVCL:2213', (95, 99))	('Ewing sarcoma', 'Disease', (61, 74))	('H3K27me3: 07-449', 'Var', (219, 235))	('TC32', 'CellLine', 'CVCL:7151', (86, 90))	('human', 'Species', '9606', (55, 60))	('EWS', 'Gene', '2130', (101, 104))	('EWS', 'Gene', (101, 104))	('ab4729', 'Var', (175, 181))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (61, 74))	('FLI1', 'Gene', (105, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('FLI1', 'Gene', '2313', (105, 109))	('H3K27Ac: ab4729', 'Var', (166, 181))	('H3K4me3: ab8580', 'Var', (191, 206))	('FLI1', 'Gene', '2313', (116, 120))	('FLI1', 'Gene', (116, 120))
187940	26337082	Colony formation assays were performed after Ewing sarcoma cell lines were transduced with shRNAs targeting CDK4 and CCND1 or treatment with LEE011 or a DMSO control.	('LEE011', 'Var', (141, 147))	('DMSO', 'Chemical', 'MESH:D004121', (153, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('CCND1', 'Gene', '595', (117, 122))	('LEE011', 'Chemical', 'MESH:C000589651', (141, 147))	('Ewing sarcoma', 'Disease', (45, 58))	('CDK4', 'Gene', (108, 112))	('CCND1', 'Gene', (117, 122))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 58))
187941	26337082	The effect of LEE011 treatment on Ewing sarcoma cell cycling was measured at 72 and 120 hours post-treatment.	('LEE011', 'Var', (14, 20))	('Ewing sarcoma', 'Disease', (34, 47))	('LEE011', 'Chemical', 'MESH:C000589651', (14, 20))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (34, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (34, 47))
187948	26337082	Animals bearing engrafted tumors of 100-250 mm3 were randomized to oral gavage treatment with 75 mg/kg (n = 13) or 250 mg/kg (n = 13) LEE011 in 0.5% methylcellulose or vehicle (n = 13) for a total of 21 days.	('methylcellulose', 'Chemical', 'MESH:D008747', (149, 164))	('LEE011', 'Chemical', 'MESH:C000589651', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('LEE011', 'Var', (134, 140))	('tumors', 'Disease', (26, 32))
187952	26337082	These Ki67 stained slides were then imaged in three different fields per tumor using a Nikon microscope, IHC images were quantified, and then the average of the three images per slide and per treatment group were quantified using the Immunoratio software program.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Ki67', 'Chemical', '-', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Ki67', 'Var', (6, 10))	('tumor', 'Disease', (73, 78))
187957	23524973	The randomized, double-blind, placebo-controlled, Phase III PALETTE (pazopanib for metastatic soft-tissue sarcoma) study demonstrated improved progression-free survival in patients receiving pazopanib compared with placebo.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('improved', 'PosReg', (134, 142))	('pazopanib', 'Var', (191, 200))	('pazopanib', 'Chemical', 'MESH:C516667', (69, 78))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (94, 113))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('pazopanib', 'Chemical', 'MESH:C516667', (191, 200))	('patients', 'Species', '9606', (172, 180))	('progression-free survival', 'CPA', (143, 168))	('sarcoma', 'Disease', (106, 113))
187969	23524973	Indeed, high VEGF expression is an independent and prognostic indicator for increased risk of metastases and decreased overall survival.	('metastases', 'Disease', (94, 104))	('decreased', 'NegReg', (109, 118))	('high', 'Var', (8, 12))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('expression', 'MPA', (18, 28))	('overall', 'MPA', (119, 126))	('VEGF', 'Protein', (13, 17))
188007	23524973	However, pazopanib undergoes significantly less renal elimination than sorafenib and sunitinib.	('pazopanib', 'Var', (9, 18))	('less', 'NegReg', (43, 47))	('sorafenib', 'Chemical', 'MESH:D000077157', (71, 80))	('renal elimination', 'MPA', (48, 65))	('pazopanib', 'Chemical', 'MESH:C516667', (9, 18))	('sunitinib', 'Chemical', 'MESH:D000077210', (85, 94))
188022	23524973	The progression-free survival in patients receiving pazopanib was superior to that in those receiving placebo, with a median of 4.6 months and 1.6 months, respectively (hazard ratio = 0.31; P < 0.0001).	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('progression-free', 'CPA', (4, 20))	('patients', 'Species', '9606', (33, 41))	('pazopanib', 'Var', (52, 61))
188024	23524973	A trend towards improved overall survival was also seen in the pazopanib arm (12.5 months versus 10.7 months; hazard ratio 0.86, P = 0.25), but this was not statistically significant.	('improved', 'PosReg', (16, 24))	('pazopanib', 'Chemical', 'MESH:C516667', (63, 72))	('overall survival', 'MPA', (25, 41))	('pazopanib', 'Var', (63, 72))
188048	23524973	The presence of multiple non-VEGF factors has been correlated with in vitro resistance to VEGF inhibition in renal cell carcinoma and colon cancer cell lines.	('renal cell carcinoma', 'Disease', (109, 129))	('colon cancer', 'Disease', (134, 146))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('colon cancer', 'Phenotype', 'HP:0003003', (134, 146))	('colon cancer', 'Disease', 'MESH:D015179', (134, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (109, 129))	('presence', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('resistance', 'MPA', (76, 86))
188053	23524973	Inhibition of these pathways may results in excessive but nonproductive angiogenesis and thereby reduced tumor growth.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('reduced', 'NegReg', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (105, 110))
188060	23524973	Although tumors frequently overcome cytotoxic chemotherapy by acquisition of genetic mutations leading to decreased target binding or increased drug efflux, there is currently no evidence for such a mechanism leading to pazopanib resistance.	('decreased', 'NegReg', (106, 115))	('pazopanib', 'Chemical', 'MESH:C516667', (220, 229))	('target binding', 'Interaction', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('genetic mutations', 'Var', (77, 94))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('increased', 'PosReg', (134, 143))	('drug efflux', 'MPA', (144, 155))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
188197	21403832	Although the role of p53 in CHS pathobiology remains obscure, the presence of overexpression of the p53 protein, 17p1 alterations, and TP53 mutations mainly in almost all high-grade CHSs suggest that the p53 mutation is a late event involved in CHS progression.	('CHS', 'Phenotype', 'HP:0006765', (182, 185))	('CHS', 'Disease', (245, 248))	('protein', 'Protein', (104, 111))	('overexpression', 'PosReg', (78, 92))	('CHS', 'Phenotype', 'HP:0006765', (245, 248))	('TP53', 'Gene', '7157', (135, 139))	('CHS', 'Disease', 'MESH:D002609', (182, 185))	('CHS', 'Disease', (28, 31))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', '7157', (100, 103))	('CHS', 'Phenotype', 'HP:0006765', (28, 31))	('17p1', 'Gene', (113, 117))	('CHS', 'Disease', 'MESH:D002609', (245, 248))	('p53', 'Gene', '7157', (204, 207))	('mutations', 'Var', (140, 149))	('p53', 'Gene', (21, 24))	('p53', 'Gene', (100, 103))	('alterations', 'Var', (118, 129))	('CHS', 'Disease', (182, 185))	('p53', 'Gene', (204, 207))	('TP53', 'Gene', (135, 139))	('CHS', 'Disease', 'MESH:D002609', (28, 31))
188198	21403832	Amplification of 12q13 and loss of 9p21 are some of the few consistent genetic aberrations found in conventional CHS.	('Amplification', 'Var', (0, 13))	('genetic aberrations', 'Disease', (71, 90))	('CHS', 'Disease', (113, 116))	('9p21', 'Protein', (35, 39))	('12q13', 'Gene', (17, 22))	('CHS', 'Disease', 'MESH:D002609', (113, 116))	('genetic aberrations', 'Disease', 'MESH:D030342', (71, 90))	('CHS', 'Phenotype', 'HP:0006765', (113, 116))	('loss', 'NegReg', (27, 31))
188254	21403832	HME is caused by mutations in either of two genes: exostosin-1 (EXT1), which is located on chromosome 8q24.11-q24.13, and exostosin-2 (EXT2), which is located on chromosome 11p11-12.	('exostosin-1', 'Gene', (51, 62))	('exostosin-2', 'Gene', '2132', (122, 133))	('HME', 'Disease', (0, 3))	('EXT2', 'Gene', '2132', (135, 139))	('EXT1', 'Gene', (64, 68))	('exostosin-1', 'Gene', '2131', (51, 62))	('EXT1', 'Gene', '2131', (64, 68))	('caused by', 'Reg', (7, 16))	('exostosin-2', 'Gene', (122, 133))	('mutations', 'Var', (17, 26))	('EXT2', 'Gene', (135, 139))
188255	21403832	Most of the mutations in these two genes are inactivating mutations (nonsense, frame shift, or splice-site mutations), causing premature termination of the EXT proteins and the loss of protein function.	('protein', 'Protein', (185, 192))	('EXT', 'Gene', '2131', (156, 159))	('frame shift', 'Var', (79, 90))	('EXT', 'Gene', (156, 159))	('mutations', 'Var', (12, 21))	('loss', 'NegReg', (177, 181))	('premature termination', 'MPA', (127, 148))
188260	21403832	In the growth plate, IHH regulates chondrocyte proliferation and differentiation in a tightly regulated paracrine feedback loop, together with PTHLH, and deregulated IHH signaling has been implicated in the pathogenesis of osteochondromas.	('osteochondromas', 'Disease', (223, 238))	('chondrocyte proliferation', 'CPA', (35, 60))	('deregulated', 'Var', (154, 165))	('differentiation', 'CPA', (65, 80))	('IHH', 'Gene', (166, 169))	('PTHLH', 'Gene', (143, 148))	('PTHLH', 'Gene', '5744', (143, 148))	('osteochondromas', 'Disease', 'MESH:D015831', (223, 238))	('osteochondroma', 'Phenotype', 'HP:0030431', (223, 237))	('IHH', 'Gene', '3549', (21, 24))	('regulates', 'Reg', (25, 34))	('IHH', 'Gene', (21, 24))	('IHH', 'Gene', '3549', (166, 169))	('osteochondromas', 'Phenotype', 'HP:0030431', (223, 238))	('implicated', 'Reg', (189, 199))
188279	21403832	The exact cause of Ollier disease and Maffucci syndrome remains to be elucidated, although mutation in the PTHR1 gene, c.448C>T (p.R150C), has been suggested to cause enchondromatosis.	('Maffucci syndrome', 'Disease', 'MESH:D004687', (38, 55))	('enchondromatosis', 'Disease', 'MESH:D004687', (167, 183))	('c.448C>T', 'Var', (119, 127))	('cause', 'Reg', (161, 166))	('enchondromatosis', 'Disease', (167, 183))	('enchondroma', 'Phenotype', 'HP:0030038', (167, 178))	('p.R150C', 'Mutation', 'rs121434601', (129, 136))	('c.448C>T', 'Mutation', 'rs121434601', (119, 127))	('PTHR1', 'Gene', (107, 112))	('PTHR1', 'Gene', '5745', (107, 112))	('Ollier disease', 'Disease', (19, 33))	('Ollier disease', 'Phenotype', 'HP:0500045', (19, 33))	('Maffucci syndrome', 'Disease', (38, 55))
188280	21403832	A mutation in PTHR1 disrupts the normal IHH-PTHLH feedback loop, causing constitutive hedgehog signaling (Figure 8(c)).	('PTHLH', 'Gene', (44, 49))	('mutation', 'Var', (2, 10))	('causing', 'Reg', (65, 72))	('disrupts', 'NegReg', (20, 28))	('PTHR1', 'Gene', (14, 19))	('PTHLH', 'Gene', '5744', (44, 49))	('IHH', 'Gene', '3549', (40, 43))	('IHH', 'Gene', (40, 43))	('PTHR1', 'Gene', '5745', (14, 19))	('constitutive hedgehog signaling', 'MPA', (73, 104))
188300	21403832	So far, no specific aberrations seem to be associated with dedifferentiated CHS, although dedifferentiated component tends to show aneuploidy, loss of heterozygosity, and amplification and deletion more frequently.	('CHS', 'Disease', (76, 79))	('CHS', 'Disease', 'MESH:D002609', (76, 79))	('aneuploidy', 'Disease', (131, 141))	('loss of heterozygosity', 'Var', (143, 165))	('CHS', 'Phenotype', 'HP:0006765', (76, 79))	('amplification', 'Var', (171, 184))	('aneuploidy', 'Disease', 'MESH:D000782', (131, 141))	('dedifferentiated', 'Disease', (59, 75))
188301	21403832	Recently an array-based comparative genomic hybridization (Array-CGH) study demonstrated statistically significant association between high-grade tumor (grade III and dedifferentiated) and the recurrent genetic deletions at 5q14.2~q21.3, 6q16~q25.3, 9p24.2~q12, and 9p21.3.	('9p24.2~q12', 'Var', (250, 260))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('6q16~q25.3', 'Var', (238, 248))	('significant association', 'Reg', (103, 126))	('9p21.3', 'Var', (266, 272))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
188351	21403832	Recent molecular genetic studies show that genetic alterations of p53 are infrequent in clear cell CHS in spite of substantial overexpression of p53.	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('CHS', 'Disease', (99, 102))	('overexpression', 'PosReg', (127, 141))	('CHS', 'Disease', 'MESH:D002609', (99, 102))	('genetic alterations', 'Var', (43, 62))	('CHS', 'Phenotype', 'HP:0006765', (99, 102))	('p53', 'Gene', (66, 69))
188463	29445312	However, the median PFS was superior for doxorubicin/ifosfamide (15.4 months) compared to gemcitabine/docetaxel (5.0 months), platinum-based regimens (5.7 mo), or other doxorubicin-based regimens (6.5 months).	('platinum', 'Chemical', 'MESH:D010984', (126, 134))	('PFS', 'MPA', (20, 23))	('ifosfamide', 'Chemical', 'MESH:D007069', (53, 63))	('doxorubicin/ifosfamide', 'Var', (41, 63))
188527	27193096	DNA may be modified through direct binding (cyclophosphamide, cisplatin), incorporation into DNA (cytosine arabinoside) or modification of DNA metabolizing enzymes such as topoisomerases (topotecan, etoposide), leading to induction of repair processes, and activation of TP53-dependent and TP53-independent pathways leading to cell death or survival.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('cell death', 'CPA', (327, 337))	('etoposide', 'Chemical', 'MESH:D005047', (199, 208))	('TP53', 'Gene', (271, 275))	('modification', 'Var', (123, 135))	('cytosine arabinoside', 'Chemical', 'MESH:D003561', (98, 118))	('TP53', 'Gene', '7157', (271, 275))	('repair processes', 'CPA', (235, 251))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (44, 60))	('TP53', 'Gene', '7157', (290, 294))	('TP53', 'Gene', (290, 294))	('survival', 'CPA', (341, 349))	('induction', 'Reg', (222, 231))	('activation', 'PosReg', (257, 267))	('topotecan', 'Chemical', 'MESH:D019772', (188, 197))
188529	27193096	However, it is now becoming clear that tumor responsiveness may be a consequence of defects in DNA damage repair processes that lead to hypersensitivity (e.g., BRCA1/2 mutations).	('DNA', 'MPA', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('BRCA1/2', 'Gene', (160, 167))	('defects', 'NegReg', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('hypersensitivity', 'Disease', 'MESH:D004342', (136, 152))	('tumor', 'Disease', (39, 44))	('BRCA1/2', 'Gene', '672;675', (160, 167))	('hypersensitivity', 'Disease', (136, 152))	('lead to', 'Reg', (128, 135))	('mutations', 'Var', (168, 177))
188549	27193096	However, it is clear that all tubulin binders do not have significant biologic activity, as demonstrated by the lack of antitumor activity of BAL101553 in these models.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('BAL101553', 'Var', (142, 151))	('lack', 'NegReg', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
188555	27193096	These T cell leukemia models had high levels of an aldo-keto reductase (AKR1C3), and antileukemic activity of PR104 was highly correlated with AKR1C3 activity, suggesting that this agent may have utility in T cell ALL.	('T cell leukemia', 'Disease', 'MESH:D015458', (6, 21))	('AKR1C3', 'Gene', '8644', (143, 149))	('leukemia', 'Phenotype', 'HP:0001909', (13, 21))	('AKR1C3', 'Gene', (143, 149))	('AKR1C3', 'Gene', (72, 78))	('aldo-keto reductase', 'MPA', (51, 70))	('AKR1C3', 'Gene', '8644', (72, 78))	('antileukemic activity', 'MPA', (85, 106))	('PR104', 'Var', (110, 115))	('T cell leukemia', 'Disease', (6, 21))	('activity', 'MPA', (150, 158))
188556	27193096	As mentioned above, sensitivity of tumor cells to DNA damaging agents may be a consequence of deficiencies in DNA repair pathways, for example cisplatin sensitivity in homologous recombination-defective cells due to BRCA1-2 mutations.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('cisplatin sensitivity', 'MPA', (143, 164))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('DNA repair pathways', 'Pathway', (110, 129))	('deficiencies', 'NegReg', (94, 106))	('tumor', 'Disease', (35, 40))	('BRCA1-2', 'Disease', (216, 223))	('BRCA1-2', 'Disease', 'OMIM:612555', (216, 223))	('mutations', 'Var', (224, 233))
188559	27193096	One of these has a PALB2 mutation that compromises homologous recombination.	('PALB2', 'Gene', (19, 24))	('PALB2', 'Gene', '79728', (19, 24))	('homologous recombination', 'MPA', (51, 75))	('mutation', 'Var', (25, 33))	('compromises', 'NegReg', (39, 50))
188571	27193096	Two exceptions were the aurora kinase A inhibitor alisertib (MLN8237) and the polo-like kinase-1 (PLK-1) inhibitor volasertib (BI6727), both of which act on the mitotic cycle and caused complete tumor regressions in multiple xenograft models.	('polo-like kinase-1', 'Gene', '5347', (78, 96))	('tumor', 'Disease', (195, 200))	('PLK-1', 'Gene', '5347', (98, 103))	('MLN8237', 'Chemical', 'MESH:C550258', (61, 68))	('BI6727', 'Chemical', 'MESH:C541363', (127, 133))	('MLN8237', 'Var', (61, 68))	('PLK-1', 'Gene', (98, 103))	('alisertib', 'Chemical', 'MESH:C550258', (50, 59))	('polo-like kinase-1', 'Gene', (78, 96))	('aurora kinase A', 'Gene', '6790', (24, 39))	('aurora kinase A', 'Gene', (24, 39))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('volasertib', 'Chemical', 'MESH:C541363', (115, 125))
188575	27193096	As mutations of the TP53 tumor suppressor gene are less prevalent in pediatric compared with adult cancers, it suggests that a larger proportion of pediatric patients may benefit from pharmacological upregulation of wild-type TP53 that could initiate an apoptotic cascade.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TP53', 'Gene', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('upregulation', 'PosReg', (200, 212))	('tumor', 'Disease', (25, 30))	('apoptotic', 'CPA', (254, 263))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('initiate', 'Reg', (242, 250))	('adult cancers', 'Disease', 'MESH:C535836', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (158, 166))	('adult cancers', 'Disease', (93, 106))	('TP53', 'Gene', '7157', (226, 230))	('mutations', 'Var', (3, 12))	('TP53', 'Gene', (226, 230))	('TP53', 'Gene', '7157', (20, 24))
188576	27193096	TP53 mutations are reported to occur at a higher frequency in relapsed patients, and where present have been associated with aggressive and chemo-refractory disease.	('associated', 'Reg', (109, 119))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (71, 79))	('mutations', 'Var', (5, 14))	('relapsed', 'Disease', (62, 70))
188582	27193096	In the PPTP screen, in vitro sensitivity to the MDM2 inhibitors RG7112 and MK-8242 correlated well with wild-type TP53 status, with TP53 mutant cell lines being 10- to 40-fold less sensitive.	('mutant', 'Var', (137, 143))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('TP53', 'Gene', '7157', (114, 118))	('MDM2', 'Gene', (48, 52))	('TP53', 'Gene', (114, 118))	('MK-8242', 'Chemical', '-', (75, 82))	('PPTP', 'Chemical', '-', (7, 11))
188585	27193096	Of note, clinically MDM2 inhibitors induce prolonged thrombocytopenia not seen in the mouse, again highlighting a deficiency in the preclinical models.	('thrombocytopenia', 'Disease', (53, 69))	('mouse', 'Species', '10090', (86, 91))	('deficiency', 'Disease', (114, 124))	('thrombocytopenia', 'Disease', 'MESH:D013921', (53, 69))	('inhibitors', 'Var', (25, 35))	('deficiency', 'Disease', 'MESH:D007153', (114, 124))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (53, 69))	('MDM2', 'Gene', (20, 24))
188587	27193096	This appears to be an on-target toxicity as RG7112 has been shown to promote apoptosis of megakaryocyte progenitor cells and also affected mature megakaryocytes by blocking DNA synthesis during endomitosis impairing platelet production.	('RG7112', 'Var', (44, 50))	('blocking', 'NegReg', (164, 172))	('endomitosis', 'Disease', 'None', (194, 205))	('DNA synthesis', 'MPA', (173, 186))	('platelet production', 'MPA', (216, 235))	('apoptosis', 'CPA', (77, 86))	('affected', 'Reg', (130, 138))	('impairing', 'NegReg', (206, 215))	('endomitosis', 'Disease', (194, 205))	('promote', 'PosReg', (69, 76))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('toxicity', 'Disease', (32, 40))
188593	27193096	Mutation of cysteine-528 confers high-level resistance to selinexor, confirming specificity for XPO1 as the mechanism of action.	('high-level resistance to selinexor', 'MPA', (33, 67))	('cysteine', 'Chemical', 'MESH:D003545', (12, 20))	('cysteine-528', 'Gene', (12, 24))	('Mutation', 'Var', (0, 8))	('XPO1', 'Gene', '7514', (96, 100))	('selinexor', 'Chemical', 'MESH:C585161', (58, 67))	('XPO1', 'Gene', (96, 100))
188609	27193096	Two SMAC mimetics, LCL161 and TL32711 (birinapant, unpublished data), have been evaluated in the PPTP models.	('LCL161', 'Chemical', 'MESH:C574246', (19, 25))	('SMAC', 'Gene', (4, 8))	('TL32711', 'Var', (30, 37))	('birinapant', 'Chemical', 'MESH:C582429', (39, 49))	('TL32711', 'Chemical', 'MESH:C582429', (30, 37))	('SMAC', 'Gene', '56616', (4, 8))	('LCL161', 'Var', (19, 25))	('PPTP', 'Chemical', '-', (97, 101))
188612	27193096	TL32711 (birinapant) did not induce significant differences in EFS distribution compared to control in the evaluable solid tumor xenografts, but did retard progression in 2 of 2 of the evaluable ALL xenografts.	('progression', 'CPA', (156, 167))	('birinapant', 'Chemical', 'MESH:C582429', (9, 19))	('solid tumor', 'Disease', (117, 128))	('retard', 'NegReg', (149, 155))	('TL32711', 'Var', (0, 7))	('TL32711', 'Chemical', 'MESH:C582429', (0, 7))	('solid tumor', 'Disease', 'MESH:D009369', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
188614	27193096	The mechanism(s) for intrinsic resistance in solid tumors remains unknown; however, methylation silencing of the caspase-8 gene has been reported in MYCN amplified neuroblastoma with high frequencies in other pediatric tumors, including rhabdomyosarcoma, medulloblastoma and retinoblastoma.	('caspase-8', 'Gene', '841', (113, 122))	('solid tumors', 'Disease', (45, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('reported', 'Reg', (137, 145))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('retinoblastoma', 'Phenotype', 'HP:0009919', (275, 289))	('rhabdomyosarcoma', 'Disease', (237, 253))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('caspase-8', 'Gene', (113, 122))	('retinoblastoma', 'Disease', (275, 289))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('methylation', 'Var', (84, 95))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (237, 253))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('neuroblastoma', 'Disease', (164, 177))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (237, 253))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('neuroblastoma', 'Phenotype', 'HP:0003006', (164, 177))	('medulloblastoma', 'Disease', 'MESH:D008527', (255, 270))	('medulloblastoma', 'Phenotype', 'HP:0002885', (255, 270))	('pediatric tumors', 'Disease', 'MESH:D063766', (209, 225))	('neuroblastoma', 'Disease', 'MESH:D009447', (164, 177))	('pediatric tumors', 'Disease', (209, 225))	('medulloblastoma', 'Disease', (255, 270))	('retinoblastoma', 'Disease', 'MESH:D012175', (275, 289))
188632	27193096	For example, the MMTV-Her2 mammary carcinoma is inhibited by ERBB1/2 small molecule inhibitors, as would be anticipated, and afatinib, an irreversible inhibitor of mutant EGFR, was active in transgenic mouse models with L858/T790M-driven lung cancer.	('EGFR', 'Gene', (171, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (27, 44))	('carcinoma', 'Disease', (35, 44))	('T790M', 'Mutation', 'rs121434569', (225, 230))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('Her2', 'Gene', '2064', (22, 26))	('afatinib', 'Chemical', 'MESH:D000077716', (125, 133))	('MMTV', 'Species', '11757', (17, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('carcinoma', 'Disease', 'MESH:D002277', (35, 44))	('Her2', 'Gene', (22, 26))	('transgenic', 'Species', '10090', (191, 201))	('ERBB1/2', 'Gene', (61, 68))	('inhibited', 'NegReg', (48, 57))	('L858/T790M-driven', 'Var', (220, 237))	('mutant', 'Var', (164, 170))	('mouse', 'Species', '10090', (202, 207))	('lung cancer', 'Disease', (238, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
188641	27193096	CBL-0137 results in simultaneous NF-kB suppression, heat shock factor 1 suppression and p53 activation.	('heat', 'MPA', (52, 56))	('suppression', 'NegReg', (72, 83))	('activation', 'PosReg', (92, 102))	('p53', 'Protein', (88, 91))	('NF-kB', 'Protein', (33, 38))	('shock', 'Phenotype', 'HP:0031273', (57, 62))	('CBL-0137', 'Var', (0, 8))	('suppression', 'NegReg', (39, 50))	('CBL-0137', 'Chemical', 'MESH:C000600493', (0, 8))
188646	27193096	The Sonic hedgehog model of medulloblastoma, driven by Pcth/p53 mutations that mimic tumors developed in Gorlin syndrome, was instrumental in development of vismodegib for treatment of group 2 medulloblastoma characterized by SHH pathway activation.	('medulloblastoma', 'Disease', (193, 208))	('Pcth/p53', 'Gene', (55, 63))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('medulloblastoma', 'Disease', (28, 43))	('SHH', 'Gene', '6469', (226, 229))	('medulloblastoma', 'Disease', 'MESH:D008527', (28, 43))	('mutations', 'Var', (64, 73))	('medulloblastoma', 'Phenotype', 'HP:0002885', (28, 43))	('medulloblastoma', 'Phenotype', 'HP:0002885', (193, 208))	('medulloblastoma', 'Disease', 'MESH:D008527', (193, 208))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('SHH', 'Gene', (226, 229))	('tumors', 'Disease', (85, 91))
188658	27193096	One additional issue that may limit the value of these models in accurately translating to clinical efficacy is illustrated for the MDM2 inhibitors, where the inhibitory molecules are optimized for human proteins and hence may not reveal the toxic effects on murine tissues but maintain high-level activity in these preclinical models.	('murine', 'Species', '10090', (259, 265))	('human', 'Species', '9606', (198, 203))	('MDM2', 'Gene', (132, 136))	('inhibitors', 'Var', (137, 147))
188661	25050197	In particular, CIK cells killed a putative sarcoma stem cell population that may underlie disease relapse and chemoresistance.	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('CIK', 'Var', (15, 18))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))
188690	23664540	SS is molecularly associated with a t(X;18) translocation, resulting in a fusion protein combining SS18 with SSX1, SSX2, or rarely SSX4.	('SSX4', 'Gene', (131, 135))	('SS', 'Phenotype', 'HP:0012570', (99, 101))	('SSX2', 'Gene', (115, 119))	('SSX1', 'Gene', (109, 113))	('SS', 'Phenotype', 'HP:0012570', (109, 111))	('SS', 'Phenotype', 'HP:0012570', (115, 117))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SS', 'Phenotype', 'HP:0012570', (131, 133))	('SS18', 'Var', (99, 103))	('SSX1', 'Gene', '6756', (109, 113))	('SSX2', 'Gene', '6757', (115, 119))	('SSX4', 'Gene', '6759', (131, 135))
188691	23664540	The FGFR4 Arg388Gly polymorphism associated with prolonged activation of the receptor, as well as FGFR4 RNA expression level and mutations in tumors, have been related to more aggressive disease and poor prognosis in a variety of soft tissue sarcomas.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FGFR4', 'Gene', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('activation', 'PosReg', (59, 69))	('aggressive disease', 'Disease', (176, 194))	('soft tissue sarcomas', 'Disease', (230, 250))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (230, 249))	('sarcomas', 'Phenotype', 'HP:0100242', (242, 250))	('tumors', 'Disease', (142, 148))	('Arg388Gly', 'SUBSTITUTION', 'None', (10, 19))	('aggressive disease', 'Disease', 'MESH:D001523', (176, 194))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (230, 250))	('Arg388Gly', 'Var', (10, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('mutations', 'Var', (129, 138))	('more', 'PosReg', (171, 175))	('related to', 'Reg', (160, 170))	('FGFR4', 'Gene', (4, 9))	('RNA expression level', 'MPA', (104, 124))
188709	23664540	This is not the only malignancy to have improved prognosis associated with FGFR3 expression.	('malignancy', 'Disease', (21, 31))	('malignancy', 'Disease', 'MESH:D009369', (21, 31))	('FGFR3', 'Gene', (75, 80))	('expression', 'Var', (81, 91))
188715	23664540	Additionally, one study found FGFR4 expression to be related to poor prognosis in humans and development of metastases in mice and the FGFR4 Gly388Arg polymorphism, has been associated with poor prognosis in combined sarcoma patients.	('mice', 'Species', '10090', (122, 126))	('Gly388Arg', 'SUBSTITUTION', 'None', (141, 150))	('associated', 'Reg', (174, 184))	('related', 'Reg', (53, 60))	('FGFR4', 'Gene', (135, 140))	('humans', 'Species', '9606', (82, 88))	('FGFR4', 'Gene', (30, 35))	('combined sarcoma', 'Disease', (208, 224))	('Gly388Arg', 'Var', (141, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))
188725	21666687	By FISH analysis two cases showed deletion 17p in both components, while 4 cases had normal cytogenetic findings by FISH in the CLL/SLL cells, but acquired cytogenetic abnormalities in the corresponding histiocytic and dendritic tumors.	('deletion 17p', 'Var', (34, 46))	('CLL/SLL', 'Gene', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('dendritic tumors', 'Disease', 'MESH:D007635', (219, 235))	('dendritic tumors', 'Disease', (219, 235))	('CLL/SLL', 'Gene', '347734', (128, 135))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))
188726	21666687	Chromosome 17p abnormalities were the most common cytogenetic abnormality detected in the sarcomas, seen in 5 of 6 cases studied.	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Chromosome 17p abnormalities', 'Var', (0, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('sarcomas', 'Disease', (90, 98))
188744	21666687	Chromosome 17p abnormalities were the most frequent cytogenetic abnormality detected by FISH in the sarcomas, and were also increased in frequency in the underlying CLL/SLL.	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('CLL/SLL', 'Gene', '347734', (165, 172))	('sarcomas', 'Disease', (100, 108))	('increased', 'PosReg', (124, 133))	('Chromosome 17p abnormalities', 'Var', (0, 28))	('CLL/SLL', 'Gene', (165, 172))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
188745	21666687	Therefore, chromosome 17p changes may be a potential risk factor for the transformation of CLL/SLL to histiocytic or dendritic cell sarcoma.	('risk', 'Reg', (53, 57))	('dendritic cell sarcoma', 'Disease', 'MESH:D054740', (117, 139))	('dendritic cell sarcoma', 'Disease', (117, 139))	('histiocytic', 'Disease', (102, 113))	('CLL/SLL', 'Gene', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('CLL/SLL', 'Gene', '347734', (91, 98))	('chromosome 17p changes', 'Var', (11, 33))
188770	21666687	Probes included centromere 6 (D6Z1) (Abbott) and c-MYB (6q23) (Mayo homebrew), centromere 11(D11Z1) and ATM (11q22.3) (both Abbott), centromere 12 (D12Z3) (Abbott) and MDM2 (12q15) (Mayo homebrew), D13S319 (13q14.3) and LAMP1 (13q34) (both Abbott), and p53 (17p13) and centromere 17 (D17Z1) (both Abbott).	('Mayo', 'Species', '162683', (63, 67))	('Mayo', 'Species', '162683', (182, 186))	('13q34', 'Var', (227, 232))	('p53', 'Gene', (253, 256))	('p53', 'Gene', '7157', (253, 256))	('D13S319 (13q14.3', 'Var', (198, 214))
188810	21666687	In all cases, the CLL/SLL and histiocytic/dendritic sarcoma showed identical clonal IgH or IgK gene rearrangements by PCR.	('dendritic sarcoma', 'Disease', 'MESH:D054740', (42, 59))	('CLL/SLL', 'Gene', (18, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('rearrangements', 'Var', (100, 114))	('IgK', 'Gene', '50802', (91, 94))	('CLL/SLL', 'Gene', '347734', (18, 25))	('IgK', 'Gene', (91, 94))	('dendritic sarcoma', 'Disease', (42, 59))	('IgH', 'Gene', '3492', (84, 87))	('IgH', 'Gene', (84, 87))
188812	21666687	FISH analysis was performed on paraffin embedded tissue sections in 6 of 7 cases using the CLL panel probes for detection of deletions 11q, 13q, 17p, 6p and trisomy 12.	('trisomy 12', 'Var', (157, 167))	('paraffin', 'Chemical', 'MESH:D010232', (31, 39))	('deletions 11q', 'Var', (125, 138))
188814	21666687	Two cases (3 and 7) showed deletion 17p in both the CLL/SLL and corresponding histiocytic/dendritic tumor.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CLL/SLL', 'Gene', (52, 59))	('dendritic tumor', 'Disease', 'MESH:D007635', (90, 105))	('CLL/SLL', 'Gene', '347734', (52, 59))	('dendritic tumor', 'Disease', (90, 105))	('deletion 17p', 'Var', (27, 39))
188815	21666687	The second most common genomic abnormality in the histiocytic/dendritic tumors was deletion 13q, which was observed in 3 cases (1, 4, and 7).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('deletion 13q', 'Var', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('dendritic tumors', 'Disease', (62, 78))	('dendritic tumors', 'Disease', 'MESH:D007635', (62, 78))
188825	21666687	A clonal relationship between the CLL/SLL and the histiocytic/dendritic cell tumors was demonstrated by identical clonal IGH@ or IGK@ gene rearrangements in all 7 patients, with the sequence identity of the corresponding V-D-J junctions confirmed in 5 patients.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (163, 171))	('CLL/SLL', 'Gene', (34, 41))	('CLL/SLL', 'Gene', '347734', (34, 41))	('patients', 'Species', '9606', (252, 260))	('IGK@', 'Gene', (129, 133))	('IGH@', 'Gene', (121, 125))	('rearrangements', 'Var', (139, 153))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('IGH@', 'Gene', '3492', (121, 125))	('IGK@', 'Gene', '50802', (129, 133))	('dendritic cell tumors', 'Disease', (62, 83))	('dendritic cell tumors', 'Disease', 'MESH:D054740', (62, 83))
188826	21666687	FISH analysis demonstrated chromosome 17p deletion or aneusomy in the histiocytic or dendritic cell sarcomas in 5 patients, and 17p deletion in the corresponding CLL/SLL in 2 patients.	('chromosome 17p deletion', 'Var', (27, 50))	('17p deletion', 'Var', (128, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('CLL/SLL', 'Gene', (162, 169))	('patients', 'Species', '9606', (175, 183))	('aneusomy', 'Var', (54, 62))	('CLL/SLL', 'Gene', '347734', (162, 169))	('histiocytic', 'Disease', (70, 81))	('dendritic cell sarcomas', 'Disease', 'MESH:D054740', (85, 108))	('dendritic cell sarcomas', 'Disease', (85, 108))	('patients', 'Species', '9606', (114, 122))
188833	21666687	Of note, sequence analysis showed preferential usage of the IGHV4-39 gene segment in the V-D-J rearrangements of the CLL/SLL and corresponding tumors.	('rearrangements', 'Var', (95, 109))	('IGHV4-39', 'Gene', '28394', (60, 68))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('CLL/SLL', 'Gene', (117, 124))	('tumors', 'Disease', (143, 149))	('CLL/SLL', 'Gene', '347734', (117, 124))	('IGHV4-39', 'Gene', (60, 68))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
188840	21666687	In the hematopoietic system, deletion of the master regulator of B-cell development, PAX5, in mature B-cells led to de-differentiation into uncommitted progenitor cells and subsequent differentiation along the T-cell lineage.	('deletion', 'Var', (29, 37))	('de-differentiation', 'CPA', (116, 134))	('PAX5', 'Gene', '5079', (85, 89))	('PAX5', 'Gene', (85, 89))	('differentiation', 'CPA', (184, 199))
188871	21666687	In our series, the most common cytogenetic changes associated with CLL, such as deletion 13q, deletion 11q, deletion 6q, and trisomy 12 were not present in the CLL/SLL cells by FISH in the 6 cases studied.	('deletion 6q', 'Var', (108, 119))	('deletion 13q', 'Var', (80, 92))	('deletion 11q', 'Var', (94, 106))	('CLL', 'Disease', (67, 70))	('CLL/SLL', 'Gene', (160, 167))	('CLL/SLL', 'Gene', '347734', (160, 167))
188872	21666687	reported trisomy 12 in both the CLL/SLL and interdigitating dendritic cell sarcoma in their case, representing case 5 in our series.	('interdigitating dendritic cell sarcoma', 'Disease', 'MESH:D054739', (44, 82))	('CLL/SLL', 'Gene', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('CLL/SLL', 'Gene', '347734', (32, 39))	('trisomy 12', 'Var', (9, 19))	('interdigitating dendritic cell sarcoma', 'Disease', (44, 82))
188874	21666687	17p abnormalities were also very common in the histiocytic/dendritic sarcomas, identified in 5/6 cases studied (83%).	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('dendritic sarcomas', 'Disease', (59, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('common', 'Reg', (33, 39))	('dendritic sarcomas', 'Disease', 'MESH:D054740', (59, 77))	('17p abnormalities', 'Var', (0, 17))
188875	21666687	These findings suggest that chromosome 17p abnormalities may be a potential risk factor for transformation of CLL/SLL.	('chromosome', 'Var', (28, 38))	('risk', 'Reg', (76, 80))	('CLL/SLL', 'Gene', (110, 117))	('CLL/SLL', 'Gene', '347734', (110, 117))
188877	21666687	The two cases with 17p13 deletion in the CLL/SLL component cells (cases 3 and 7) were stained for p53.	('CLL/SLL', 'Gene', (41, 48))	('17p13', 'Gene', (19, 24))	('CLL/SLL', 'Gene', '347734', (41, 48))	('deletion', 'Var', (25, 33))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))
189000	30637261	The immunohistochemical test results included the following: CD21(+), CD23(+), CD35(+), S-100(partial+), BC12(+), BC16(+), CDepsilon(T+), CD5(+), CD20(B+), CD38(little+), CD43(T+), Cyclind1(+), Ki67(20%+), Mum(partial+), CD10(-), Pax5(-), EBER(-).	('BC12(+', 'Var', (105, 111))	('CD23', 'Gene', '2208', (70, 74))	('Pax5', 'Gene', (230, 234))	('CD43', 'Gene', (171, 175))	('CD20', 'Gene', (146, 150))	('CD38', 'Gene', '952', (156, 160))	('CD35', 'Gene', '1378', (79, 83))	('CD20', 'Gene', '54474', (146, 150))	('CD35', 'Gene', (79, 83))	('S-100', 'Gene', (88, 93))	('CD10', 'Gene', '4311', (221, 225))	('BC16(+', 'Var', (114, 120))	('CD43', 'Gene', '6693', (171, 175))	('CD38', 'Gene', (156, 160))	('S-100', 'Gene', '6271', (88, 93))	('Pax5', 'Gene', '5079', (230, 234))	('CD21', 'Gene', (61, 65))	('CD10', 'Gene', (221, 225))	('CD23', 'Gene', (70, 74))	('CD21', 'Gene', '1380', (61, 65))
189021	30637261	For prognosis, it is known that age (< 40-years-old), large tumor size (> 6 cm), mitotic counts (> 5/10 high-power field), positive Ki-67, and large areas of coagulative necrosis are indicators of a poor prognosis.	('positive', 'Var', (123, 131))	('mitotic counts', 'CPA', (81, 95))	('Ki-67', 'Protein', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('necrosis', 'Disease', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('necrosis', 'Disease', 'MESH:D009336', (170, 178))	('tumor', 'Disease', (60, 65))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (158, 178))
189045	29262551	The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient.	('doxorubicin', 'Chemical', 'MESH:D004317', (383, 394))	('DOX', 'Chemical', 'MESH:D004317', (116, 119))	('ERG', 'Gene', '2078', (468, 471))	("Ewing's sarcoma", 'Disease', (151, 166))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (416, 431))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('ERG', 'Gene', '13876', (178, 181))	('FUS', 'Gene', '2521', (464, 467))	('ERG', 'Gene', (178, 181))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (416, 431))	('mouse', 'Species', '10090', (126, 131))	('CDKN2A', 'Gene', '12578', (193, 199))	('patient', 'Species', '9606', (563, 570))	('CDKN2A', 'Gene', (193, 199))	('FUS', 'Gene', (174, 177))	('FUS', 'Gene', '233908', (464, 467))	('patient', 'Species', '9606', (317, 324))	('patient', 'Species', '9606', (77, 84))	('doxorubicin', 'Chemical', 'MESH:D004317', (55, 66))	('ERG', 'Gene', '2078', (178, 181))	('irinotecan', 'Chemical', 'MESH:D000077146', (32, 42))	("Ewing's sarcoma", 'Disease', (416, 431))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (151, 166))	('deletion', 'Var', (490, 498))	('FUS', 'Gene', '2521', (174, 177))	('ERG', 'Gene', '13876', (468, 471))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (151, 166))	('patient', 'Species', '9606', (235, 242))	('DOX', 'Chemical', 'MESH:D004317', (356, 359))	('CDKN2A', 'Gene', '12578', (483, 489))	('CDKN2A', 'Gene', (483, 489))	('ERG', 'Gene', (468, 471))	('FUS', 'Gene', '233908', (174, 177))	('FUS', 'Gene', (464, 467))	('mouse', 'Species', '10090', (366, 371))	('sarcoma', 'Phenotype', 'HP:0100242', (424, 431))	('temozolomide', 'Chemical', 'MESH:D000077204', (19, 31))
189046	29262551	Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin.	('IGF-1R', 'Gene', (111, 117))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (152, 167))	('inhibitors', 'Var', (119, 129))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (152, 167))	('DOX', 'Chemical', 'MESH:D004317', (169, 172))	('CDK4/6', 'Gene', (60, 66))	('insulin-like growth factor-1 receptor', 'Gene', (72, 109))	("Ewing's sarcoma", 'Disease', (152, 167))	('patient', 'Species', '9606', (210, 217))	('cyclin-dependent kinase 4/6', 'Gene', (31, 58))	('doxorubicin', 'Chemical', 'MESH:D004317', (234, 245))	('cyclin-dependent kinase 4/6', 'Gene', '1019;1021', (31, 58))	('IGF-1R', 'Gene', '3480', (111, 117))	('doxorubicin', 'Chemical', 'MESH:D004317', (182, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (72, 109))	('CDK4/6', 'Gene', '1019;1021', (60, 66))
189135	26221551	Our molecular understanding of these tumors is still in progress and the identification of genetic alterations has increased our ability to distinguish the endometrial stromal neoplasms.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('increased', 'PosReg', (115, 124))	('endometrial stromal neoplasms', 'Disease', (156, 185))	('genetic alterations', 'Var', (91, 110))	('endometrial stromal neoplasms', 'Disease', 'MESH:D036821', (156, 185))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('neoplasm', 'Phenotype', 'HP:0002664', (176, 184))	('tumors', 'Disease', (37, 43))	('neoplasms', 'Phenotype', 'HP:0002664', (176, 185))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
189189	28435400	Patients with large (> 5 cm), deep, and high-grade extremity STS are known to be at significant risk for distant metastasis and sarcoma-related death.	('sarcoma', 'Disease', 'MESH:D012509', (128, 135))	('sarcoma', 'Disease', (128, 135))	('distant metastasis', 'CPA', (105, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Patients', 'Species', '9606', (0, 8))	('STS', 'Phenotype', 'HP:0030448', (61, 64))	('high-grade', 'Var', (40, 50))
189281	28435400	However, the study did not specifically include high-risk STS patients, and the median tumour size was markedly higher in the neoadjuvant CRT arm.	('tumour', 'Disease', (87, 93))	('higher', 'PosReg', (112, 118))	('STS', 'Phenotype', 'HP:0030448', (58, 61))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('neoadjuvant', 'Var', (126, 137))	('patients', 'Species', '9606', (62, 70))
189294	27393385	The Cox proportional hazard model adjusted for histologic subtype, initial metastasis, and PD-L1 expression showed that PD-L1 expression was significantly associated with shorter overall survival (P = 0.037, HR 2.57, 95 % CI 1.060-6.231).	('shorter', 'NegReg', (171, 178))	('PD-L1', 'Gene', (91, 96))	('expression', 'Var', (126, 136))	('PD-L1', 'Gene', (120, 125))	('PD-L1', 'Gene', '29126', (91, 96))	('PD-L1', 'Gene', '29126', (120, 125))	('overall survival', 'MPA', (179, 195))
189297	27393385	With strikingly variable genetic aberrations, various sarcomas have abnormal fusion proteins arising from translocations.	('genetic aberrations', 'Disease', 'MESH:D030342', (25, 44))	('fusion proteins', 'Protein', (77, 92))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('translocations', 'Var', (106, 120))	('genetic aberrations', 'Disease', (25, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcomas', 'Disease', (54, 62))
189304	27393385	Recent studies have indicated that high expression of PD-L1 is associated with poor prognosis in non-small cell lung cancer (NSCLC), ovarian cancer, and kidney cancer.	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('kidney cancer', 'Disease', 'MESH:D007680', (153, 166))	('high expression', 'Var', (35, 50))	('ovarian cancer', 'Disease', (133, 147))	('non-small cell lung cancer', 'Disease', (97, 123))	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('NSCLC', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('kidney cancer', 'Phenotype', 'HP:0009726', (153, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('kidney cancer', 'Disease', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('PD-L1', 'Gene', (54, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (97, 123))	('PD-L1', 'Gene', '29126', (54, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (101, 123))	('ovarian cancer', 'Disease', 'MESH:D010051', (133, 147))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (97, 123))
189323	27393385	The staining intensity was graded as negative (0), weak to moderate (1), or strong (2), and the proportion was categorized by the percentage of positive cells as 0, no positive tumor cells; 1+, less than 10 %; 2+, 10-50 %; and 3+, >50 %.	('less than 10 %', 'Var', (194, 208))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('negative', 'NegReg', (37, 45))
189324	27393385	Based on the multiplication score, a score of 0 or 1 was considered as negative PD-L1 expression, whereas scores greater than 2 were considered positive PD-L1 expression.	('PD-L1', 'Gene', (80, 85))	('PD-L1', 'Gene', (153, 158))	('PD-L1', 'Gene', '29126', (80, 85))	('PD-L1', 'Gene', '29126', (153, 158))	('expression', 'MPA', (86, 96))	('score', 'Var', (37, 42))	('negative', 'NegReg', (71, 79))
189342	27393385	There was a trend toward a worse RFS for the positive PD-L1 expression group compared to the negative group (Fig.	('RFS', 'Disease', 'MESH:D005198', (33, 36))	('PD-L1', 'Gene', (54, 59))	('positive', 'Var', (45, 53))	('PD-L1', 'Gene', '29126', (54, 59))	('RFS', 'Disease', (33, 36))
189366	27393385	Moreover, PD-L1 expression was reported in half of the gastric cancer and lung cancer cases and was an independent negative prognostic factor for OS.	('gastric cancer', 'Disease', (55, 69))	('lung cancer', 'Disease', (74, 85))	('expression', 'Var', (16, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('PD-L1', 'Gene', (10, 15))	('PD-L1', 'Gene', '29126', (10, 15))
189396	26398108	Two responding xenografts had FBXW7 mutations at R465 and two had SMARCA4 mutations.	('FBXW7', 'Gene', '55294', (30, 35))	('FBXW7', 'Gene', (30, 35))	('SMARCA4', 'Gene', (66, 73))	('SMARCA4', 'Gene', '6597', (66, 73))	('mutations at R465', 'Var', (36, 53))
189404	26398108	Consistent with a role for XPO1 in cancer, XPO1 is upregulated in a range of hematologic and solid tumors, and overexpression is associated with poor prognosis.	('XPO1', 'Gene', '7514', (43, 47))	('XPO1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('XPO1', 'Gene', '7514', (27, 31))	('XPO1', 'Gene', (27, 31))	('overexpression', 'Var', (111, 125))	('solid tumors', 'Disease', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('upregulated', 'PosReg', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', (35, 41))	('hematologic', 'Disease', (77, 88))	('solid tumors', 'Disease', 'MESH:D009369', (93, 105))
189405	26398108	Because alterations in nuclear-cytoplasmic trafficking may lead to the cytoplasmic mislocalization of proteins involved in cell cycle, cell survival or tumor suppression, forcing their nuclear localization may have potential as a cancer therapeutics strategy.	('nuclear localization', 'MPA', (185, 205))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cytoplasmic mislocalization', 'MPA', (71, 98))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('alterations', 'Var', (8, 19))	('tumor', 'Disease', (152, 157))	('lead to', 'Reg', (59, 66))	('nuclear-cytoplasmic trafficking', 'MPA', (23, 54))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('proteins', 'Protein', (102, 110))
189421	26398108	CB17SC scid-/- female mice (Taconic Farms, Germantown NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('osteosarcoma', 'Disease', (148, 160))	('glioma', 'Phenotype', 'HP:0009733', (269, 275))	('brain tumors', 'Phenotype', 'HP:0030692', (217, 229))	('osteosarcoma', 'Disease', 'MESH:D012516', (148, 160))	('mice', 'Species', '10090', (22, 26))	('non-glioblastoma brain tumors', 'Disease', 'MESH:D005909', (200, 229))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (162, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (162, 178))	('neuroblastoma', 'Disease', (181, 194))	('mice', 'Species', '10090', (250, 254))	('rhabdoid tumors', 'Disease', (114, 129))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (114, 129))	('neuroblastoma', 'Phenotype', 'HP:0003006', (181, 194))	('non-glioblastoma brain tumors', 'Disease', (200, 229))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('neuroblastoma', 'Disease', 'MESH:D009447', (181, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (148, 160))	('sarcomas', 'Disease', (131, 139))	('CB17SC', 'Var', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('glioma', 'Disease', (269, 275))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('glioma', 'Disease', 'MESH:D005910', (269, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('rhabdomyosarcoma', 'Disease', (162, 178))
189463	26398108	Interestingly those were very prominent in Rh28, the alveolar rhabdomyosarcoma tumor that showed poor response at the end of the 4 week in vivo study (Supplemental Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (53, 78))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (62, 78))	('Rh28', 'Var', (43, 47))	('alveolar rhabdomyosarcoma tumor', 'Disease', (53, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('alveolar rhabdomyosarcoma tumor', 'Disease', 'MESH:D018232', (53, 84))
189474	26398108	KT-10 tumor cells express a non-clinically important p53 mutation (R290H) with wild type transcriptional activity, and therefore p53 would be expected to be enriched in the nucleus in the treated cells.	('R290H', 'Mutation', 'rs55819519', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('p53', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('R290H', 'Var', (67, 72))
189475	26398108	However, p53 proteins, either wild type in CHLA258 and Rh28 tumors or mutant in Rh30 tumors were sensitive to XPO1 inhibition and showed nuclear accumulation upon selinexor treatment in these three cases (Supplemental Figure 3).	('XPO1', 'Gene', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('selinexor', 'Chemical', 'MESH:C585161', (163, 172))	('nuclear accumulation', 'MPA', (137, 157))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', (85, 91))	('mutant', 'Var', (70, 76))	('CHLA258', 'Chemical', '-', (43, 50))	('Rh30 tumors', 'Disease', (80, 91))	('p53 proteins', 'Protein', (9, 21))	('Rh30 tumors', 'Disease', 'MESH:D009369', (80, 91))	('XPO1', 'Gene', '7514', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Disease', (60, 66))	('sensitive', 'MPA', (97, 106))	('proteins', 'Protein', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
189478	26398108	For FBXW7, known oncogenic mutations were identified for both BT-50 (R465H) and ALL-8 (R465C).	('ALL', 'Phenotype', 'HP:0006721', (80, 83))	('FBXW7', 'Gene', '55294', (4, 9))	('BT-50', 'Gene', (62, 67))	('FBXW7', 'Gene', (4, 9))	('R465C', 'Var', (87, 92))	('R465H', 'Mutation', 'rs1057519895', (69, 74))	('R465H', 'Var', (69, 74))	('R465C', 'Mutation', 'rs867384286', (87, 92))
189479	26398108	One additional tested xenograft (ALL-31) had an FBXW7 mutation, but it was in the N-terminal region in the nuclear localization signal domain (c.45_46insCCT; p.15_16TR>TLR).	('ALL', 'Phenotype', 'HP:0006721', (33, 36))	('c.45_46insCCT', 'Mutation', 'rs541979458', (143, 156))	('c.45_46insCCT;', 'Var', (143, 157))	('FBXW7', 'Gene', '55294', (48, 53))	('FBXW7', 'Gene', (48, 53))
189480	26398108	For SMARCA4, the R1189Q mutation, which is predicted to be deleterious by both SIFT and and PolyPhen, was observed in BT-45 and ALL-8.	('R1189Q', 'Mutation', 'p.R1189Q', (17, 23))	('SMARCA4', 'Gene', (4, 11))	('SIFT', 'Disease', 'None', (79, 83))	('SMARCA4', 'Gene', '6597', (4, 11))	('ALL', 'Phenotype', 'HP:0006721', (128, 131))	('R1189Q', 'Var', (17, 23))	('SIFT', 'Disease', (79, 83))
189481	26398108	KT-10 has a PALB2 mutation that leads to defective homologous recombination and to sensitivity to PARP inhibition.	('PARP', 'Gene', '1302', (98, 102))	('PARP', 'Gene', (98, 102))	('homologous recombination', 'MPA', (51, 75))	('PALB2', 'Gene', (12, 17))	('PALB2', 'Gene', '79728', (12, 17))	('mutation', 'Var', (18, 26))	('defective', 'NegReg', (41, 50))
189493	26398108	The responding Wilms tumor xenograft (KT-10) is known to be defective in homologous recombination as a result of biallelic PALB2 mutation.	('Wilms tumor', 'Disease', (15, 26))	('mutation', 'Var', (129, 137))	('Wilms tumor', 'Disease', 'MESH:D009396', (15, 26))	('Wilms tumor', 'Phenotype', 'HP:0002667', (15, 26))	('biallelic', 'Var', (113, 122))	('PALB2', 'Gene', (123, 128))	('result', 'Reg', (103, 109))	('PALB2', 'Gene', '79728', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
189498	26398108	Regarding the xenografts exhibiting objective responses, the Wilms tumor xenograft (KT-10) with the most pronounced solid tumor response is known to be defective in homologous recombination as a result of biallelic PALB2 mutation.	('mutation', 'Var', (221, 229))	('PALB2', 'Gene', '79728', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('biallelic', 'Var', (205, 214))	('Wilms tumor', 'Disease', (61, 72))	('PALB2', 'Gene', (215, 220))	('Wilms tumor', 'Disease', 'MESH:D009396', (61, 72))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Wilms tumor', 'Phenotype', 'HP:0002667', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (67, 72))	('result of', 'Reg', (195, 204))	('tumor', 'Disease', (122, 127))
189499	26398108	Evaluations of additional models will be required to determine whether defective homologous recombination in general (or specific to PALB2 loss of function) sensitizes to SINE compounds.	('PALB2', 'Gene', '79728', (133, 138))	('PALB2', 'Gene', (133, 138))	('SINE', 'Disease', (171, 175))	('sensitizes', 'Reg', (157, 167))	('loss of function', 'NegReg', (139, 155))	('SINE', 'Disease', 'None', (171, 175))	('defective', 'Var', (71, 80))
189500	26398108	The identification of mutated PALB2 in sensitive selinexor tumors is potentially more interesting in light of the recent report that SINE compounds inhibit the expression of DNA damage repair proteins.	('expression', 'MPA', (160, 170))	('inhibit', 'NegReg', (148, 155))	('PALB2', 'Gene', '79728', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('SINE', 'Disease', (133, 137))	('PALB2', 'Gene', (30, 35))	('tumors', 'Disease', (59, 65))	('mutated', 'Var', (22, 29))	('selinexor', 'Chemical', 'MESH:C585161', (49, 58))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('SINE', 'Disease', 'None', (133, 137))	('DNA damage', 'Protein', (174, 184))
189502	26398108	The only two models tested that harbor FBXW7 "hot spot" mutations showed objective responses.	('FBXW7', 'Gene', (39, 44))	('mutations', 'Var', (56, 65))	('FBXW7', 'Gene', '55294', (39, 44))
189503	26398108	These hot spot mutations occur in the WD40 substrate-binding domain of FBXW7.	('mutations', 'Var', (15, 24))	('FBXW7', 'Gene', (71, 76))	('FBXW7', 'Gene', '55294', (71, 76))
189506	26398108	FBXW7 with hot spot mutations acts in a dominant-negative fashion, such that when mutations are heterozygous (as for BT-50 and ALL-8) they exert a marked effect on levels of FBXW7 target proteins as a result of their inhibition of wildtype FBXW7 in heterodimers.	('FBXW7', 'Gene', '55294', (0, 5))	('FBXW7', 'Gene', '55294', (174, 179))	('FBXW7', 'Gene', '55294', (240, 245))	('ALL', 'Phenotype', 'HP:0006721', (127, 130))	('FBXW7', 'Gene', (0, 5))	('FBXW7', 'Gene', (240, 245))	('FBXW7', 'Gene', (174, 179))	('mutations', 'Var', (82, 91))	('heterodimers', 'Interaction', (249, 261))	('inhibition', 'NegReg', (217, 227))	('mutations', 'Var', (20, 29))	('levels', 'MPA', (164, 170))
189507	26398108	SINE compounds have been shown to enhance nuclear localization of FBXW7 in pancreatic cancer cells, and it is plausible that in xenografts with FBXW7 hot spot mutations they are able to elevate the level of active wildtype homodimers sufficiently so that target oncogenic proteins are degraded leading to anticancer activity.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('FBXW7', 'Gene', (144, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('mutations', 'Var', (159, 168))	('degraded', 'NegReg', (285, 293))	('FBXW7', 'Gene', '55294', (66, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))	('cancer', 'Disease', (309, 315))	('cancer', 'Disease', (86, 92))	('FBXW7', 'Gene', '55294', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Disease', (75, 92))	('SINE', 'Disease', (0, 4))	('level', 'MPA', (198, 203))	('elevate', 'PosReg', (186, 193))	('SINE', 'Disease', 'None', (0, 4))	('nuclear localization', 'MPA', (42, 62))	('enhance', 'PosReg', (34, 41))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('FBXW7', 'Gene', (66, 71))
189509	26398108	A consequence of this mutation is the cytoplasmic, rather than nuclear, localization of FBXW7alpha.	('cytoplasmic', 'MPA', (38, 49))	('FBXW7', 'Gene', '55294', (88, 93))	('mutation', 'Var', (22, 30))	('FBXW7', 'Gene', (88, 93))
189510	26398108	Hence, the cellular effects and response to SINE compounds for cancer cells with this mutation are likely distinctive from the effects observed for cells with FBXW7 mutations in the WD40 substrate-binding domain.	('SINE', 'Disease', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('FBXW7', 'Gene', '55294', (159, 164))	('SINE', 'Disease', 'None', (44, 48))	('mutation', 'Var', (86, 94))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('FBXW7', 'Gene', (159, 164))	('cancer', 'Disease', (63, 69))
189511	26398108	Further testing will be required to define the relationship between FBXW7 hot spot mutations and sensitivity to SINE compounds.	('mutations', 'Var', (83, 92))	('FBXW7', 'Gene', '55294', (68, 73))	('FBXW7', 'Gene', (68, 73))	('SINE', 'Disease', (112, 116))	('SINE', 'Disease', 'None', (112, 116))
189513	26398108	SMARCA4 mutations were present in a medulloblastoma xenograft (BT-45) and in a T-cell ALL xenograft (ALL-8).	('SMARCA4', 'Gene', (0, 7))	('SMARCA4', 'Gene', '6597', (0, 7))	('mutations', 'Var', (8, 17))	('ALL', 'Phenotype', 'HP:0006721', (86, 89))	('medulloblastoma xenograft', 'Disease', (36, 61))	('medulloblastoma xenograft', 'Disease', 'MESH:D008527', (36, 61))	('medulloblastoma', 'Phenotype', 'HP:0002885', (36, 51))	('ALL', 'Phenotype', 'HP:0006721', (101, 104))
189514	26398108	Germline mutations in SMARCA4 predispose to rhabdoid tumor and to small cell carcinoma of the ovary, hypercalcemic type (malignant rhabdoid tumor of the ovary).	('Germline mutations', 'Var', (0, 18))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('carcinoma of the ovary', 'Disease', (77, 99))	('rhabdoid tumor', 'Disease', (44, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('hypercalcemic type (malignant rhabdoid tumor of the ovary', 'Disease', 'MESH:D018335', (101, 158))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (131, 145))	('predispose', 'Reg', (30, 40))	('rhabdoid tumor', 'Disease', (131, 145))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (66, 86))	('SMARCA4', 'Gene', (22, 29))	('tumor of the ovary', 'Phenotype', 'HP:0100615', (140, 158))	('SMARCA4', 'Gene', '6597', (22, 29))	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (77, 99))
189515	26398108	Somatic mutations of SMARCA4 have been reported at relatively low frequency in a number of cancers, including medulloblastoma, mantle cell lymphoma, Burkitt lymphoma, T-cell ALL, and others.	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (149, 165))	('cell lymphoma', 'Phenotype', 'HP:0012191', (134, 147))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('SMARCA4', 'Gene', '6597', (21, 28))	('T-cell ALL', 'Disease', (167, 177))	('medulloblastoma', 'Phenotype', 'HP:0002885', (110, 125))	('medulloblastoma', 'Disease', 'MESH:D008527', (110, 125))	('medulloblastoma', 'Disease', (110, 125))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('ALL', 'Phenotype', 'HP:0006721', (174, 177))	('mutations', 'Var', (8, 17))	('Burkitt lymphoma', 'Disease', (149, 165))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (127, 147))	('SMARCA4', 'Gene', (21, 28))	('mantle cell lymphoma', 'Disease', (127, 147))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (149, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (157, 165))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
189517	26398108	Pharmacodynamic effects were documented using the 10 mg/kg dose, with protein levels of p53 and p21 increased in some, but not all, tumors; similarly, PARP cleavage was induced in three of the studied tumors.	('PARP', 'Gene', '1302', (151, 155))	('protein levels', 'MPA', (70, 84))	('increased', 'PosReg', (100, 109))	('p21', 'Gene', (96, 99))	('p53', 'Var', (88, 91))	('PARP', 'Gene', (151, 155))	('p21', 'Gene', '644914', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
189521	26398108	This included phosphorylated ERK, which is associated with growth suppression signals.	('ERK', 'Gene', '5594', (29, 32))	('phosphorylated', 'Var', (14, 28))	('ERK', 'Gene', (29, 32))
189532	26398108	MDM2 inhibitors or kinase inhibitors being other examples.	('MDM2', 'Gene', '4193', (0, 4))	('inhibitors', 'Var', (5, 15))	('MDM2', 'Gene', (0, 4))
189611	29862013	The above case describes a patient with a MPNST of the thigh with pathologically confirmed metastases to the adrenal gland, yet without evidence of pulmonary metastases.	('metastases', 'Disease', (91, 101))	('pulmonary metastases', 'Disease', 'MESH:D009362', (148, 168))	('pulmonary metastases', 'Disease', (148, 168))	('patient', 'Species', '9606', (27, 34))	('metastases', 'Disease', (158, 168))	('MPNST', 'Phenotype', 'HP:0100697', (42, 47))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('MPNST', 'Var', (42, 47))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
189637	29862013	The patients with NF type-1 have increased risk for pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (52, 68))	('pheochromocytoma', 'Disease', 'MESH:D010673', (52, 68))	('NF type-1', 'Var', (18, 27))	('patients', 'Species', '9606', (4, 12))	('pheochromocytoma', 'Disease', (52, 68))
189684	28239280	The authors suggest that inhibition of this leukemia invadosome could be a potential treatment target.	('leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('leukemia', 'Disease', 'MESH:D007938', (44, 52))	('inhibition', 'Var', (25, 35))	('leukemia', 'Disease', (44, 52))
189709	28239280	The risk factors, which have been so far reported, include: a history of extramedullary disease, FAB class M4 or M5 AML, advanced disease status at the time of HSCT and high-risk cytogenetics which includes such abnormalities as chromosome 5q and 7q deletions and FLT-3 mutations.	('FLT-3', 'Gene', (264, 269))	('FLT-3', 'Gene', '2322', (264, 269))	('FAB', 'Gene', '2187', (97, 100))	('mutations', 'Var', (270, 279))	('extramedullary disease', 'Disease', (73, 95))	('FAB', 'Gene', (97, 100))	('AML', 'Disease', 'MESH:D015470', (116, 119))	('AML', 'Phenotype', 'HP:0004808', (116, 119))	('AML', 'Disease', (116, 119))
189756	28239280	Translocation (8;21) which results in AML1-ETO fusion gene, is especially frequent in MS of orbital localization.	('AML1', 'Gene', '861', (38, 42))	('Translocation', 'Var', (0, 13))	('frequent', 'Reg', (74, 82))	('ETO', 'Gene', (43, 46))	('AML1', 'Gene', (38, 42))	('results in', 'Reg', (27, 37))	('ETO', 'Gene', '862', (43, 46))	('AML', 'Phenotype', 'HP:0004808', (38, 41))
189758	28239280	In infants with extramedullary involvement, 11q23 is frequently found.	('11q23', 'Var', (44, 49))	('found', 'Reg', (64, 69))	('infants', 'Species', '9606', (3, 10))
189760	28239280	Some of authors reported increased frequency of the nuclephosmin1 (NPM1) mutation.	('mutation', 'Var', (73, 81))	('NPM', 'Gene', '4869', (67, 70))	('NPM', 'Gene', (67, 70))
189761	28239280	detected NPM1 mutation in 15% of 181 analyzed samples.	('NPM', 'Gene', (9, 12))	('mutation', 'Var', (14, 22))	('NPM', 'Gene', '4869', (9, 12))	('detected', 'Reg', (0, 8))
189923	24501463	These flaps include composite flaps (multiple tissue components served by single vascular source), conjoined flap (multiple flap territory with physical interconnections each retaining independent vascular supply) and chimeric flap (multiple flap territory without interconnections, receiving independent blood supply).	('flap', 'Gene', '241', (30, 34))	('flap', 'Gene', (227, 231))	('flap', 'Gene', (124, 128))	('chimeric', 'Var', (218, 226))	('flap', 'Gene', (242, 246))	('flap', 'Gene', '241', (6, 10))	('flap', 'Gene', (109, 113))	('flap', 'Gene', '241', (124, 128))	('flap', 'Gene', '241', (227, 231))	('conjoined', 'Disease', (99, 108))	('flap', 'Gene', (30, 34))	('flap', 'Gene', (6, 10))	('flap', 'Gene', '241', (242, 246))	('flap', 'Gene', '241', (109, 113))
189926	24501463	All these flap modifications and in combination with available conventional flaps have enormously increased the microsurgical coverage options of composite defects.	('flap', 'Gene', (76, 80))	('microsurgical coverage options', 'CPA', (112, 142))	('flap', 'Gene', '241', (10, 14))	('modifications', 'Var', (15, 28))	('flap', 'Gene', '241', (76, 80))	('increased', 'PosReg', (98, 107))	('flap', 'Gene', (10, 14))
189942	31621900	We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('metastasis', 'CPA', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('delta133p53', 'Var', (50, 61))	('tumor', 'Disease', (97, 102))	('induced', 'Reg', (62, 69))	('expression', 'Species', '29278', (36, 46))	('HGF secretion', 'MPA', (70, 83))
189946	31621900	Together, our findings warrant the development of novel CAR-T-cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c-MET pathway.	('EWS', 'Phenotype', 'HP:0012254', (173, 176))	('c-MET', 'Gene', '17295', (232, 237))	('tumors', 'Disease', (189, 195))	('c-MET', 'Gene', (232, 237))	('HGF', 'Protein', (94, 97))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('CAR-T', 'Chemical', '-', (56, 61))	('EWS', 'Disease', (173, 176))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('neutralizing', 'Var', (107, 119))	('improve', 'PosReg', (132, 139))	('therapeutic potency', 'MPA', (140, 159))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('activation', 'PosReg', (210, 220))
189958	31621900	Cancers frequently evade the potent antitumor surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins.	('dysfunctional', 'Disease', (172, 185))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('mutated', 'Var', (187, 194))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('human', 'Species', '9606', (142, 147))	('mutation', 'Var', (85, 93))	('malignancies', 'Disease', 'MESH:D009369', (148, 160))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('evade', 'NegReg', (19, 24))	('TP53', 'Gene', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('malignancies', 'Disease', (148, 160))	('dysfunctional', 'Disease', 'MESH:D009461', (172, 185))
189960	31621900	Therefore, specific efforts focused on mechanistic understanding and biologic consequences of dysregulation of these isoforms in cancer will help develop new therapeutic approaches.	('dysregulation', 'Var', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
189967	31621900	We thus sought to determine if inhibition of HGF signaling by neutralizing antibody (AMG102) modifies the tumor microenvironment and improves the therapeutic efficacy of CAR-transduced T-cells in a preclinical model of EWS.	('improves', 'PosReg', (133, 141))	('EWS', 'Disease', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('inhibition', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('AMG102', 'Chemical', 'MESH:C524459', (85, 91))	('EWS', 'Phenotype', 'HP:0012254', (219, 222))	('modifies', 'Reg', (93, 101))	('tumor', 'Disease', (106, 111))	('therapeutic efficacy', 'CPA', (146, 166))
189982	31621900	Nitrocellulose membranes were incubated overnight with the following primary antibodies: beta-Actin (Santa Cruz), anti-human HGF (Abcam, cat.	('beta-Actin', 'Gene', (89, 99))	('beta-Actin', 'Gene', '728378', (89, 99))	('anti-human', 'Var', (114, 124))	('human', 'Species', '9606', (119, 124))
189987	31621900	shRNAs sequences for the targeting human HGF, Delta133p53 or scrambled (shCtr) were cloned into the lentiviral expression vector pLKO.1 or Tet-pLKO.1 (Addgene).	('human', 'Species', '9606', (35, 40))	('expression', 'Species', '29278', (111, 121))	('Delta133p53', 'Var', (46, 57))	('HGF', 'Gene', (41, 44))
189991	31621900	Primary antibodies against anti-human CD3 (dilution,1:30; NCL-L-CD3-565) and anti-human CD8 (dilution,1:30; cat.	('anti-human', 'Var', (77, 87))	('CD8', 'Gene', '925', (88, 91))	('CD3', 'Gene', (64, 67))	('CD3', 'Gene', '12503', (64, 67))	('CD3', 'Gene', (38, 41))	('CD3', 'Gene', '12503', (38, 41))	('human', 'Species', '9606', (32, 37))	('human', 'Species', '9606', (82, 87))	('CD8', 'Gene', (88, 91))
189997	31621900	Lentivirus was produced by HEK293FT cells transfected with pMD2.G, pCMV-dR8.91 and pHR-scFvGD2-CAR using TransIT-293 Transfection Reagent (Mirus Bio LLC).	('pHR-scFvGD2-CAR', 'Var', (83, 98))	('pCMV-dR8.91', 'Var', (67, 78))	('pMD2.G', 'Var', (59, 65))	('HEK293FT', 'CellLine', 'CVCL:6911', (27, 35))	('IT-293', 'CellLine', 'CVCL:0045', (110, 116))
190026	31621900	Mice demonstrating >10% weight loss or eBCS <8 were euthanized and lungs harvested, insufflated and fixed in 10% neutral buffered formalin, then embedded and processed for the routine histological examination.	('weight loss', 'Disease', 'MESH:D015431', (24, 35))	('eBCS <8', 'Var', (39, 46))	('formalin', 'Chemical', 'MESH:D005557', (130, 138))	('weight loss', 'Disease', (24, 35))	('weight loss', 'Phenotype', 'HP:0001824', (24, 35))	('Mice', 'Species', '10090', (0, 4))
190036	31621900	Aberrant activation of hepatocyte growth factor (HGF) and its receptor, cMET, triggers cell proliferation, angiogenesis, invasion and metastasis in a wide variety of cancers .	('activation', 'PosReg', (9, 19))	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('Aberrant', 'Var', (0, 8))	('cMET', 'Gene', '17295', (72, 76))	('cMET', 'Gene', (72, 76))	('HGF', 'Gene', (49, 52))	('triggers', 'Reg', (78, 86))	('cell proliferation', 'CPA', (87, 105))	('hepatocyte growth factor', 'Gene', '15234', (23, 47))	('metastasis', 'CPA', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('invasion', 'CPA', (121, 129))	('hepatocyte growth factor', 'Gene', (23, 47))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('angiogenesis', 'CPA', (107, 119))
190037	31621900	We therefore examined whether deregulation of this pathway contributes to EWS tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('EWS', 'Phenotype', 'HP:0012254', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('EWS', 'Disease', (74, 77))	('deregulation', 'Var', (30, 42))
190047	31621900	Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing sarcomas, with the majority of these sarcomas expressing a functional wild-type p53 .	('Ewing sarcomas', 'Disease', (76, 90))	('sarcomas', 'Disease', (119, 127))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (76, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('TP53', 'Gene', (38, 42))	('observed', 'Reg', (57, 65))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (76, 90))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('genetic lesions', 'Var', (15, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcomas', 'Disease', 'MESH:D012509', (82, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcomas', 'Disease', (82, 90))
190051	31621900	Cells were maintained in doxycycline (200ng/ml) to turn-off Delta133p53 expression in media containing 1% FBS for 48 hr.	('doxycycline', 'Chemical', 'MESH:D004318', (25, 36))	('Delta133p53', 'Var', (60, 71))	('turn-off', 'Reg', (51, 59))	('expression', 'Species', '29278', (72, 82))
190053	31621900	As shown in Figures 2B-C, inhibition of Delta133p53 expression in EWS cells significantly reduced HGF expression and secretion.	('expression', 'Species', '29278', (102, 112))	('reduced', 'NegReg', (90, 97))	('expression', 'Species', '29278', (52, 62))	('inhibition', 'NegReg', (26, 36))	('HGF expression', 'MPA', (98, 112))	('secretion', 'MPA', (117, 126))	('EWS', 'Phenotype', 'HP:0012254', (66, 69))	('Delta133p53 expression', 'Var', (40, 62))
190054	31621900	To confirm our findings further, we genetically engineered human mesenchymal stem cell (hMSC), thought to be the cellular origin of EWS, by overexpressing Delta133p53 or EWS/FLI (Supplementary Figure 2F).	('human', 'Species', '9606', (59, 64))	('FLI', 'Gene', '2314', (174, 177))	('EWS', 'Phenotype', 'HP:0012254', (132, 135))	('EWS', 'Phenotype', 'HP:0012254', (170, 173))	('FLI', 'Gene', (174, 177))	('Delta133p53', 'Var', (155, 166))	('overexpressing', 'PosReg', (140, 154))
190055	31621900	As shown in Figures 2D-E, in contrast to EWS/FLI-1 expression, only overexpression of Delta133p53 in hMSC significantly increased both HGF expression and secretion.	('FLI-1', 'Gene', (45, 50))	('FLI-1', 'Gene', '2313', (45, 50))	('expression', 'Species', '29278', (72, 82))	('secretion', 'MPA', (154, 163))	('expression', 'Species', '29278', (51, 61))	('Delta133p53', 'Var', (86, 97))	('HGF', 'Protein', (135, 138))	('expression', 'Species', '29278', (139, 149))	('EWS', 'Phenotype', 'HP:0012254', (41, 44))	('expression', 'MPA', (139, 149))	('increased', 'PosReg', (120, 129))
190056	31621900	Furthermore, we confirmed by two different profiler antibody arrays that only Delta133p53 expression altered HGF expression in hMSC (Figures 2F-G) and induced the activity of the HGF promoter (Supplementary Figure 3).	('expression', 'MPA', (113, 123))	('induced', 'PosReg', (151, 158))	('HGF', 'Protein', (179, 182))	('expression', 'Species', '29278', (90, 100))	('activity', 'MPA', (163, 171))	('altered', 'Reg', (101, 108))	('expression', 'Species', '29278', (113, 123))	('Delta133p53 expression', 'Var', (78, 100))	('HGF', 'Protein', (109, 112))
190057	31621900	Taken together, our data demonstrate that high level of HGF expression and secretion are driven by Delta133p53 and independent of EWS/FLI1 expression.	('expression', 'MPA', (60, 70))	('Delta133p53', 'Var', (99, 110))	('secretion', 'MPA', (75, 84))	('FLI', 'Gene', '2314', (134, 137))	('driven by', 'Reg', (89, 98))	('FLI', 'Gene', (134, 137))	('HGF', 'Protein', (56, 59))	('expression', 'Species', '29278', (139, 149))	('EWS', 'Phenotype', 'HP:0012254', (130, 133))	('expression', 'Species', '29278', (60, 70))
190060	31621900	Depletion of HGF expression in EWS cells abolished both cellular angiogenesis (Supplementary Figure 4B), and invasion (Figure 4A).	('HGF', 'Protein', (13, 16))	('invasion', 'CPA', (109, 117))	('expression', 'Species', '29278', (17, 27))	('abolished', 'NegReg', (41, 50))	('Depletion', 'Var', (0, 9))	('cellular angiogenesis', 'CPA', (56, 77))	('EWS', 'Phenotype', 'HP:0012254', (31, 34))
190067	31621900	In addition, we demonstrated that inhibition of HGF in EWS cell lines significantly reduced primary tumor growth in an orthotopic mouse model (Figure 3E-F).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('EWS', 'Phenotype', 'HP:0012254', (55, 58))	('inhibition', 'Var', (34, 44))	('tumor', 'Disease', (100, 105))	('HGF', 'Protein', (48, 51))	('reduced', 'NegReg', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mouse', 'Species', '10090', (130, 135))
190068	31621900	Taken together, our data established elevated HGF secretion driven by Delta133p53 in EWS stimulates primary tumor growth in the bone and metastasis to the lung.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('stimulates', 'PosReg', (89, 99))	('elevated', 'PosReg', (37, 45))	('metastasis to the lung', 'CPA', (137, 159))	('EWS', 'Phenotype', 'HP:0012254', (85, 88))	('tumor', 'Disease', (108, 113))	('HGF', 'Protein', (46, 49))	('Delta133p53', 'Var', (70, 81))
190071	31621900	As shown in Figure 4, AMG102 treatment only moderately decreased tumor burden in the lungs and increased the survival of mice receiving AMG102 relative to control treatment groups (Figure 4C).	('AMG102', 'Chemical', 'MESH:C524459', (136, 142))	('AMG102', 'Gene', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('decreased tumor', 'Disease', (55, 70))	('decreased tumor', 'Disease', 'MESH:D002303', (55, 70))	('mice', 'Species', '10090', (121, 125))	('increased', 'PosReg', (95, 104))	('AMG102', 'Chemical', 'MESH:C524459', (22, 28))	('AMG102', 'Var', (136, 142))	('survival', 'CPA', (109, 117))
190074	31621900	Similar to the drug effects on lung metastasis, AMG102 treatment only moderately decreased tumor burden in the bone and increased the survival of mice receiving AMG102 relative to control treatment groups (Figure 4D) suggesting targeting of c-Met/HGF signaling extends survival rate without tumor regression (Figure 4E).	('c-Met', 'Gene', (241, 246))	('AMG102', 'Chemical', 'MESH:C524459', (161, 167))	('AMG102', 'Chemical', 'MESH:C524459', (48, 54))	('survival', 'CPA', (134, 142))	('AMG102', 'Var', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('c-Met', 'Gene', '17295', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('survival rate', 'CPA', (269, 282))	('mice', 'Species', '10090', (146, 150))	('decreased tumor', 'Disease', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('increased', 'PosReg', (120, 129))	('tumor', 'Disease', (91, 96))	('decreased tumor', 'Disease', 'MESH:D002303', (81, 96))	('tumor', 'Disease', (291, 296))
190107	31621900	As shown in Supplementary Figure 7, both CD3 and CD8 staining were higher in CAR-T + AMG102 treatment group.	('CAR-T', 'Chemical', '-', (77, 82))	('higher', 'PosReg', (67, 73))	('CD3', 'Gene', (41, 44))	('CD3', 'Gene', '12503', (41, 44))	('CD8', 'Gene', (49, 52))	('CD8', 'Gene', '925', (49, 52))	('CAR-T + AMG102', 'Var', (77, 91))	('AMG102', 'Chemical', 'MESH:C524459', (85, 91))
190108	31621900	These data can be integrated into a coherent model in which inhibition of c-Met/HGF signaling in tumor environment facilitates CAR-T infiltration into the tumor mass, thereby improving its antitumor activity (Supplementary Figure 8).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('c-Met', 'Gene', '17295', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('inhibition', 'Var', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (155, 160))	('c-Met', 'Gene', (74, 79))	('tumor', 'Disease', (97, 102))	('improving', 'PosReg', (175, 184))	('CAR-T', 'Chemical', '-', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('facilitates', 'PosReg', (115, 126))
190110	31621900	Our data demonstrate that EWS cell lines and PDX tumors express elevated levels of HGF, with shRNA depletion abolishing tumorigenic properties of EWS cells in vivo.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('abolishing', 'NegReg', (109, 119))	('EWS', 'Phenotype', 'HP:0012254', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PDX tumors', 'Disease', (45, 55))	('EWS', 'Phenotype', 'HP:0012254', (26, 29))	('depletion', 'Var', (99, 108))	('HGF', 'Protein', (83, 86))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('PDX tumors', 'Disease', 'MESH:D009369', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
190113	31621900	Abrogation of the p53 pathway through mutation is typically associated with enhanced tumor invasive and metastatic capabilities, and poorer patient survival rates.	('Abrogation', 'Var', (0, 10))	('p53 pathway', 'Pathway', (18, 29))	('tumor invasive', 'Disease', (85, 99))	('patient', 'Species', '9606', (140, 147))	('enhanced', 'PosReg', (76, 84))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor invasive', 'Disease', 'MESH:D009361', (85, 99))
190115	31621900	Our data showed that aberrant expression of Delta133p53 drives HGF gene expression resulting in angiogenesis, invasion and metastasis.	('Delta133p53', 'Var', (44, 55))	('HGF gene', 'Gene', (63, 71))	('expression', 'Species', '29278', (72, 82))	('expression', 'MPA', (72, 82))	('angiogenesis', 'CPA', (96, 108))	('invasion', 'CPA', (110, 118))	('expression', 'Species', '29278', (30, 40))
190116	31621900	Together, the precise molecular mechanism of Delta133p53 induced HGF expression warrants further investigation.	('expression', 'Species', '29278', (69, 79))	('HGF', 'Protein', (65, 68))	('induced', 'Reg', (57, 64))	('Delta133p53', 'Var', (45, 56))	('expression', 'MPA', (69, 79))
190123	31621900	However, we do not exclude other possibilities that AMG102 could enhance the efficacy of CAR-T cell therapy through other mechanisms.	('efficacy', 'CPA', (77, 85))	('AMG102', 'Var', (52, 58))	('enhance', 'PosReg', (65, 72))	('CAR-T', 'Chemical', '-', (89, 94))	('AMG102', 'Chemical', 'MESH:C524459', (52, 58))
190126	31621900	EWS Ewing Sarcoma delta133p53 an oncogenic p53 isoform HGF Hepatocyte growth factor AMG102 a HGF neutralizing antibody cMET tyrosine-protein kinase Met, hepatocyte growth factor receptor GD2 disialoganglioside, a sialic acid-containing glycosphingolipid CAR-T Chimeric Antigen Receptor T cells TIL tumor infiltrating lymphocytes IL-2 Interleukin 2 IFN-gamma Interferon gamma TNF-alpha Tumor Necrosis Factor alpha We identified that an oncogenic p53 isoform, delta133p53, drives high level of HGF secretion in Ewing Sarcoma.	('Hepatocyte growth factor', 'Gene', '15234', (59, 83))	('glycosphingolipid', 'Chemical', 'MESH:D006028', (236, 253))	('Sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('Tumor Necrosis Factor alpha', 'Disease', (385, 412))	('cMET', 'Gene', (119, 123))	('AMG102', 'Chemical', 'MESH:C524459', (84, 90))	('Ewing Sarcoma', 'Disease', (509, 522))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (509, 522))	('tumor', 'Disease', (298, 303))	('Sarcoma', 'Phenotype', 'HP:0100242', (515, 522))	('sialic acid', 'Chemical', 'MESH:D019158', (213, 224))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (509, 522))	('cMET', 'Gene', '17295', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('hepatocyte growth factor', 'Gene', '15234', (153, 177))	('tyrosine-protein kinase Met', 'Gene', (124, 151))	('TIL', 'Gene', '21897', (294, 297))	('tyrosine-protein kinase Met', 'Gene', '17295', (124, 151))	('Ewing Sarcoma', 'Disease', (4, 17))	('TNF-alpha', 'Gene', (375, 384))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (4, 17))	('EWS', 'Phenotype', 'HP:0012254', (0, 3))	('hepatocyte growth factor', 'Gene', (153, 177))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('Hepatocyte growth factor', 'Gene', (59, 83))	('TNF-alpha', 'Gene', '21926', (375, 384))	('TIL', 'Gene', (294, 297))	('delta133p53', 'Var', (458, 469))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (4, 17))	('disialoganglioside', 'Chemical', 'MESH:C025447', (191, 209))	('CAR-T', 'Chemical', '-', (254, 259))	('Tumor', 'Phenotype', 'HP:0002664', (385, 390))	('HGF secretion', 'MPA', (492, 505))	('Tumor Necrosis Factor alpha', 'Disease', 'MESH:D005935', (385, 412))
190129	28009602	EWSR1 fusions with CREB family transcription factors define a novel myxoid mesenchymal tumor with predilection for intracranial location Recurrent gene fusions involving EWSR1 with members of the cAMP response element binding protein (CREB) family (ATF1 and CREB1) have been reported in a diverse group of tumors including angiomatoid fibrous histiocytoma (AFH), soft tissue and gastrointestinal clear cell sarcoma (CCS), primary pulmonary myxoid sarcoma (PPMS) and hyalinizing clear cell carcinoma of salivary gland.	('CREB', 'Gene', '1385', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('EWSR1', 'Gene', '2130', (0, 5))	('EWSR1', 'Gene', (170, 175))	('primary pulmonary myxoid sarcoma', 'Disease', (422, 454))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('histiocytoma', 'Phenotype', 'HP:0012315', (343, 355))	('gastrointestinal clear cell sarcoma', 'Disease', (379, 414))	('CREB', 'Gene', (235, 239))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (323, 355))	('CREB1', 'Gene', (258, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (489, 498))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('cAMP response element binding protein', 'Gene', '1385', (196, 233))	('carcinoma of salivary gland', 'Disease', (489, 516))	('CREB', 'Gene', (258, 262))	('tumors', 'Disease', (306, 312))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (68, 92))	('primary pulmonary myxoid sarcoma', 'Disease', 'MESH:D045888', (422, 454))	('gastrointestinal clear cell sarcoma', 'Disease', 'MESH:D018227', (379, 414))	('carcinoma of salivary gland', 'Phenotype', 'HP:0100684', (489, 516))	('angiomatoid fibrous histiocytoma', 'Disease', (323, 355))	('EWSR1', 'Gene', (0, 5))	('CREB1', 'Gene', '1385', (258, 263))	('CREB', 'Gene', (19, 23))	('CREB', 'Gene', '1385', (235, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (447, 454))	('fusions', 'Var', (152, 159))	('myxoid mesenchymal tumor', 'Disease', (68, 92))	('reported', 'Reg', (275, 283))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (407, 414))	('EWSR1', 'Gene', '2130', (170, 175))	('CREB', 'Gene', '1385', (258, 262))	('cAMP response element binding protein', 'Gene', (196, 233))	('carcinoma of salivary gland', 'Disease', 'MESH:D012468', (489, 516))
190130	28009602	We have recently encountered a group of 5 myxoid mesenchymal tumors positive for EWSR1 fusions with one of the CREB family member (ATF1, CREB1 and CREM), with histologic features distinct from any of the previously described pathologic entities.	('fusions', 'Var', (87, 94))	('positive', 'Reg', (68, 76))	('CREB', 'Gene', (137, 141))	('myxoid mesenchymal tumors', 'Disease', 'MESH:C535700', (42, 67))	('CREM', 'Gene', '1390', (147, 151))	('CREM', 'Gene', (147, 151))	('myxoid mesenchymal tumors', 'Disease', (42, 67))	('CREB', 'Gene', '1385', (137, 141))	('CREB', 'Gene', (111, 115))	('CREB1', 'Gene', '1385', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('EWSR1', 'Gene', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('CREB', 'Gene', '1385', (111, 115))	('CREB1', 'Gene', (137, 142))
190139	28009602	About one third of all soft tissue tumor entities are characterized by specific recurrent chromosomal translocations, usually encoding aberrant chimeric transcription factors.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('chromosomal translocations', 'Var', (90, 116))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (23, 40))	('tumor', 'Disease', (35, 40))
190142	28009602	One such example is the presence of EWSR1-CREB1 and/or EWSR1-ATF1 fusions in a diverse group of tumors, including angiomatoid fibrous histiocytoma (AFH), soft tissue and GI clear cell sarcoma (CCS), primary pulmonary myxoid sarcoma (PPMS) and hyalinizing clear cell carcinoma of salivary gland.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('angiomatoid fibrous histiocytoma', 'Disease', (114, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('tumors', 'Disease', (96, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('carcinoma of salivary gland', 'Disease', 'MESH:D012468', (266, 293))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('GI clear cell sarcoma', 'Disease', 'MESH:D018227', (170, 191))	('fusions', 'Var', (66, 73))	('EWSR1-ATF1', 'Gene', (55, 65))	('primary pulmonary myxoid sarcoma', 'Disease', (199, 231))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (114, 146))	('CREB1', 'Gene', (42, 47))	('carcinoma of salivary gland', 'Disease', (266, 293))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('GI clear cell sarcoma', 'Disease', (170, 191))	('carcinoma of salivary gland', 'Phenotype', 'HP:0100684', (266, 293))	('GI clear cell sarcoma', 'Phenotype', 'HP:0006770', (170, 191))	('CREB1', 'Gene', '1385', (42, 47))	('primary pulmonary myxoid sarcoma', 'Disease', 'MESH:D045888', (199, 231))	('histiocytoma', 'Phenotype', 'HP:0012315', (134, 146))	('soft tissue', 'Disease', (154, 165))
190145	28009602	To date, only EWSR1-ATF1 fusion has been detected in hyalinizing clear cell carcinoma, while only EWSR1-CREB1 was reported in PPMS.	('carcinoma', 'Disease', 'MESH:D002277', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('fusion', 'Var', (25, 31))	('CREB1', 'Gene', (104, 109))	('carcinoma', 'Disease', (76, 85))	('CREB1', 'Gene', '1385', (104, 109))	('EWSR1-ATF1', 'Gene', (14, 24))	('detected', 'Reg', (41, 49))
190147	28009602	In this study, we describe a group of tumors displaying a unique histomorphology and harboring fusions involving EWSR1 with one the CREB gene family (CREB1, ATF1 or CREM).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('CREM', 'Gene', (165, 169))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('CREB', 'Gene', (150, 154))	('CREB1', 'Gene', '1385', (150, 155))	('fusions', 'Var', (95, 102))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('CREB', 'Gene', '1385', (150, 154))	('CREB', 'Gene', (132, 136))	('CREB', 'Gene', '1385', (132, 136))	('EWSR1', 'Gene', (113, 118))	('CREB1', 'Gene', (150, 155))	('CREM', 'Gene', '1390', (165, 169))
190164	28009602	The fusion involving EWSR1 exon 15 with either CREM transcripts resulted in in-frame products, while EWSR1 exon 14 resulted in a frameshift regardless of the CREM variant.	('CREM', 'Gene', (47, 51))	('resulted in', 'Reg', (115, 126))	('CREM', 'Gene', '1390', (158, 162))	('CREM', 'Gene', (158, 162))	('resulted in', 'Reg', (64, 75))	('in-frame products', 'MPA', (76, 93))	('frameshift', 'Var', (129, 139))	('CREM', 'Gene', '1390', (47, 51))
190167	28009602	A number of other samples were investigated as control showing a low level of CREM expression, except for an Ewing sarcoma with EWSR1-ERG fusion and a myoepithelial tumor with EWSR1-PBX3 fusion (Fig.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('Ewing sarcoma', 'Disease', (109, 122))	('PBX3', 'Gene', (182, 186))	('PBX3', 'Gene', '5090', (182, 186))	('myoepithelial tumor', 'Disease', 'MESH:D009208', (151, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('CREM', 'Gene', '1390', (78, 82))	('CREM', 'Gene', (78, 82))	('myoepithelial tumor', 'Disease', (151, 170))	('EWSR1-ERG', 'Var', (128, 137))
190174	28009602	EWSR1 fusions with CREM, CREB1 or ATF1, and showing a similar morphology of an unclassified myxoid mesenchymal neoplasm (Table 1).	('myxoid mesenchymal neoplasm', 'Disease', 'MESH:D045888', (92, 119))	('CREB1', 'Gene', (25, 30))	('CREB1', 'Gene', '1385', (25, 30))	('neoplasm', 'Phenotype', 'HP:0002664', (111, 119))	('CREM', 'Gene', '1390', (19, 23))	('myxoid mesenchymal neoplasm', 'Disease', (92, 119))	('EWSR1', 'Gene', (0, 5))	('CREM', 'Gene', (19, 23))	('fusions', 'Var', (6, 13))	('myxoid mesenchymal neoplasm', 'Phenotype', 'HP:0006769', (92, 119))
190187	28009602	The additional 4 cases harbored similar gene fusions involving EWSR1 with CREM/CREB1/ATF1 as demonstrated by break-apart FISH assays (Table 1, Supplementary Figure 1).	('CREB1', 'Gene', (79, 84))	('CREM', 'Gene', '1390', (74, 78))	('gene fusions', 'Var', (40, 52))	('CREB1', 'Gene', '1385', (79, 84))	('CREM', 'Gene', (74, 78))	('EWSR1', 'Gene', (63, 68))
190192	28009602	Two such remarkable examples are the EWSR1-ATF1 and/or EWSR1-CREB1 fusions identified in tumor types otherwise unrelated clinically or immunophenotypically.	('EWSR1-ATF1', 'Gene', (37, 47))	('fusions', 'Var', (67, 74))	('CREB1', 'Gene', '1385', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('CREB1', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
190202	28009602	Their genetic hallmark was the presence of EWSR1 fusions with members of the CREB (cAMP response element binding protein) gene family, including CREM, CREB1 and ATF1.	('CREB', 'Gene', (77, 81))	('cAMP response element binding protein', 'Gene', (83, 120))	('CREB1', 'Gene', (151, 156))	('CREB', 'Gene', '1385', (77, 81))	('CREB', 'Gene', (151, 155))	('CREB', 'Gene', '1385', (151, 155))	('CREM', 'Gene', '1390', (145, 149))	('cAMP response element binding protein', 'Gene', '1385', (83, 120))	('EWSR1', 'Gene', (43, 48))	('CREM', 'Gene', (145, 149))	('CREB1', 'Gene', '1385', (151, 156))	('fusions', 'Var', (49, 56))
190208	28009602	Our findings do not refute the existence of intracranial AFH, as two well-documented examples have been reported in the literature showing EWSR1-ATF1 fusion in the occipital lobe of a 25 year-old man and an EWSR1 rearrangement in the temporal lobe of a 35 year-old man.	('EWSR1-ATF1', 'Gene', (139, 149))	('fusion', 'Var', (150, 156))	('man', 'Species', '9606', (196, 199))	('man', 'Species', '9606', (265, 268))
190214	28009602	Extraskeletal myxoid chondrosarcoma (EMC) and soft tissue myoepithelial tumors are also frequently considered in the differential diagnosis of myxoid neoplasms with EWSR1 gene rearrangements.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('gene rearrangements', 'Var', (171, 190))	('neoplasm', 'Phenotype', 'HP:0002664', (150, 158))	('Extraskeletal myxoid chondrosarcoma', 'Disease', (0, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('neoplasms', 'Phenotype', 'HP:0002664', (150, 159))	('myxoid neoplasms', 'Phenotype', 'HP:0006769', (143, 159))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (58, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (21, 35))	('myoepithelial tumors', 'Disease', (58, 78))	('myxoid neoplasms', 'Disease', 'MESH:D045888', (143, 159))	('EWSR1', 'Gene', (165, 170))	('Extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (0, 35))	('myxoid neoplasms', 'Disease', (143, 159))
190216	28009602	Furthermore, EMC lack desmin reactivity and the overwhelming majority harbor NR4A3 gene fusions with or without the EWSR1 partner.	('NR4A3', 'Gene', '8013', (77, 82))	('desmin', 'Gene', '1674', (22, 28))	('lack desmin', 'Phenotype', 'HP:0100300', (17, 28))	('fusions', 'Var', (88, 95))	('reactivity', 'MPA', (29, 39))	('desmin', 'Gene', (22, 28))	('lack', 'NegReg', (17, 21))	('NR4A3', 'Gene', (77, 82))
190219	28009602	EWSR1 fusions have been identified in half of soft tissue myoepithelial tumors with various fusion partners, including POU5F1, PBX1, PBX3, ZNF444, and KLF17.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('identified', 'Reg', (24, 34))	('PBX1', 'Gene', (127, 131))	('KLF17', 'Gene', '128209', (151, 156))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (58, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('ZNF444', 'Gene', (139, 145))	('POU5F1', 'Gene', '5460', (119, 125))	('POU5F1', 'Gene', (119, 125))	('myoepithelial tumors', 'Disease', (58, 78))	('KLF17', 'Gene', (151, 156))	('PBX1', 'Gene', '5087', (127, 131))	('EWSR1', 'Gene', (0, 5))	('ZNF444', 'Gene', '55311', (139, 145))	('fusions', 'Var', (6, 13))	('PBX3', 'Gene', (133, 137))	('PBX3', 'Gene', '5090', (133, 137))
190236	28009602	In our previous studies using Affymetrix microarray analysis there was no up-regulation of CREB1 and ATF1 expressions in either AFH with EWSR1-CREB1 fusion or CCS with EWSR1-ATF1 fusion.	('CREB1', 'Gene', (143, 148))	('CREB1', 'Gene', '1385', (91, 96))	('up-regulation', 'PosReg', (74, 87))	('ATF1', 'Gene', (101, 105))	('fusion', 'Var', (149, 155))	('CREB1', 'Gene', (91, 96))	('CREB1', 'Gene', '1385', (143, 148))
190238	28009602	Furthermore, no significant fusion transcript variability was noted among the different pathologic entities with EWSR1-ATF1/CREB1 fusions, with consistent breakpoints occurring in a given gene regardless of the tumor phenotypes, except possibly for HCCC, where the breakpoints occurred in EWSR1 exon 11 and ATF1 exon 3, which are different from other tumor types (Supplementary Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', (351, 356))	('fusions', 'Var', (130, 137))	('CREB1', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('CREB1', 'Gene', '1385', (124, 129))
190242	28009602	Collectively, they show a unique spectrum of histologic features and are genetically characterized by recurrent fusions between EWSR1 and CREB gene family of transcription factors.	('EWSR1', 'Gene', (128, 133))	('CREB', 'Gene', (138, 142))	('CREB', 'Gene', '1385', (138, 142))	('fusions', 'Var', (112, 119))
190247	26922091	Furthermore, X-rays combined with genistein inhibited the activity of DNA-PKcs, so DNA-injured sites were dominated by Ku70/80, leading to incompleteness of homologous recombination (HR) and non-homologous end-joining (NHEJ) repairs and the eventual occurrence of cell apoptosis.	('DNA-PKcs', 'Enzyme', (70, 78))	('Ku70', 'Gene', '14375', (119, 123))	('activity', 'MPA', (58, 66))	('genistein', 'Chemical', 'MESH:D019833', (34, 43))	('inhibited', 'NegReg', (44, 53))	('incompleteness', 'NegReg', (139, 153))	('homologous', 'Var', (157, 167))	('cell apoptosis', 'CPA', (264, 278))	('rays', 'Species', '255564', (15, 19))	('Ku70', 'Gene', (119, 123))
190254	26922091	One of the most important mechanisms in the effect of radiotherapy on cancers is damage to DNA, leading to DNA double-strand breaks (DSBs).	('DSB', 'Chemical', '-', (133, 136))	('DNA double-strand breaks', 'MPA', (107, 131))	('damage', 'Var', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
190320	26922091	However, in the D+IR group, the excised tumor shape was more regular and had a pale-red color.	('D+IR', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('more', 'PosReg', (56, 60))	('pale-red', 'MPA', (79, 87))	('tumor', 'Disease', (40, 45))
190321	26922091	Moreover, the weight and volume of the tumor tissues in the D+IR group were significantly less than those in the other groups (P < 0.01), as shown in Fig.	('less', 'NegReg', (90, 94))	('D+IR', 'Var', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
190322	26922091	3C and D; significantly smaller tumor volumes (1.8-fold) were observed in the D+IR group compared with the IR group (0.38 +- 0.14 cm3 vs 0.68 +- 0.16 cm3, P < 0.01, Fig.	('D+IR', 'Var', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('smaller', 'NegReg', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
190323	26922091	The results indicate that genistein enhances in vivo radiosensitivity in the Balb/c xenograft model.	('enhances', 'PosReg', (36, 44))	('vivo radiosensitivity', 'Phenotype', 'HP:0010997', (48, 69))	('radiosensitivity', 'CPA', (53, 69))	('genistein', 'Var', (26, 35))	('genistein', 'Chemical', 'MESH:D019833', (26, 35))
190349	26922091	Additionally, genistein has also been shown to enhance the radiosensitivity of human breast and esophageal cancer cells in vitro.	('enhance', 'PosReg', (47, 54))	('human', 'Species', '9606', (79, 84))	('genistein', 'Chemical', 'MESH:D019833', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('genistein', 'Var', (14, 23))	('radiosensitivity', 'CPA', (59, 75))
190369	26922091	Previous studies have reported that small interfering RNA (siRNA) to DNA-PKcs increases the sensitivity of human cancer cells to IR, inhibiting DNA-PKcs activity and abrogating DNA DSB repair.	('abrogating', 'NegReg', (166, 176))	('small interfering', 'Var', (36, 53))	('sensitivity', 'MPA', (92, 103))	('inhibiting', 'NegReg', (133, 143))	('DSB', 'Chemical', '-', (181, 184))	('human', 'Species', '9606', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('DNA DSB repair', 'MPA', (177, 191))	('cancer', 'Disease', (113, 119))	('activity', 'MPA', (153, 161))	('DNA-PKcs', 'Enzyme', (144, 152))	('increases', 'PosReg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
190389	25870694	The mutations at the level of the tumor suppressing genes can have a dominant-negative effect, by the producing modified protein that enters in competition with the normal one, obstructing its activity (an example is P53 protein, controlled by the suppressing gene TP53).	('P53', 'Gene', (266, 269))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('P53', 'Gene', '7157', (266, 269))	('TP53', 'Gene', '7157', (265, 269))	('activity', 'MPA', (193, 201))	('protein', 'Protein', (121, 128))	('TP53', 'Gene', (265, 269))	('mutations', 'Var', (4, 13))	('obstructing', 'NegReg', (177, 188))	('P53', 'Gene', '7157', (217, 220))	('P53', 'Gene', (217, 220))
190391	25870694	Tumor markers associated with the modifications at the genes' level (TP53, RAS, HER-2/neu, RET, BCL2, BCL1-PRAD1-CCND1, REL, MYC, BCL6, p16-INK4a-CDKN2A).	('RET', 'Gene', (91, 94))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RAS', 'Disease', (75, 78))	('PRAD1', 'Gene', (107, 112))	('BCL6', 'Gene', '604', (130, 134))	('HER-2/neu', 'Gene', (80, 89))	('BCL1', 'Gene', (102, 106))	('CCND1', 'Gene', '595', (113, 118))	('CDKN2A', 'Gene', (146, 152))	('BCL2', 'Gene', '596', (96, 100))	('TP53', 'Var', (69, 73))	('INK4a', 'Gene', (140, 145))	('MYC', 'Gene', '4609', (125, 128))	('CCND1', 'Gene', (113, 118))	('BCL1', 'Gene', '595', (102, 106))	('CDKN2A', 'Gene', '1029', (146, 152))	('INK4a', 'Gene', '1029', (140, 145))	('p16', 'Gene', (136, 139))	('BCL2', 'Gene', (96, 100))	('RET', 'Gene', '5979', (91, 94))	('p16', 'Gene', '1029', (136, 139))	('PRAD1', 'Gene', '595', (107, 112))	('BCL6', 'Gene', (130, 134))	('HER-2/neu', 'Gene', '2064', (80, 89))	('MYC', 'Gene', (125, 128))
190393	25870694	Markers related to clonation (clone markers): inactivity of chromosome X, determining the heavy chains of immunoglobulin (igH), modification of receptors at the level of T lymphocytes (rearrangement of the genes controlling the synthesis of receptors from the level of T lymphocytes - TCR genes).	('igH', 'Gene', '3492', (122, 125))	('inactivity', 'Var', (46, 56))	('modification', 'Var', (128, 140))	('igH', 'Gene', (122, 125))
190394	25870694	The specific translocations were initially identified in hematological tumors, and then these were also proved at the level of some solid neoplasm.	('solid neoplasm', 'Disease', (132, 146))	('hematological tumors', 'Disease', 'MESH:D006402', (57, 77))	('solid neoplasm', 'Disease', 'MESH:D018250', (132, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('hematological tumors', 'Disease', (57, 77))	('translocations', 'Var', (13, 27))
190397	25870694	EWS-FL1 1, t(11, 22) (q24; q12)  The analysis of the cariotip revealed a chromosomal translocation t(11, 22) (q24; q12) specific for a tumor - Ewing sarcoma type, or of primitive neuroectodermal tumors (PNET) type (in 86% from the above mentioned cases).	('t(11, 22) (q24; q12', 'Var', (99, 118))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (179, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (169, 201))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (143, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('tumor - Ewing sarcoma type', 'Disease', (135, 161))	('primitive neuroectodermal tumors', 'Disease', (169, 201))	('tumor - Ewing sarcoma type', 'Disease', 'MESH:C563168', (135, 161))
190401	25870694	The molecular detection of translocation t(11; 22) is valuable in the differential diagnosis of the tumors with small cells - round and in stadialization and prognostic of Ewing sarcomas .	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (172, 186))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (172, 185))	('translocation t', 'Var', (27, 42))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Ewing sarcomas', 'Disease', (172, 186))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (172, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (178, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
190402	25870694	From the EWS - FLI 1 translocation perspective, the positive cells have amplifications of RT - PCR in the hematogenous bone marrow and peripheral blood, for patients with metastasis and also for those without metastasis suffering from Ewing sarcomas and primitive neuroectodermal tumors .	('sarcoma', 'Phenotype', 'HP:0100242', (241, 248))	('sarcomas', 'Phenotype', 'HP:0100242', (241, 249))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (235, 248))	('RT - PCR', 'Gene', (90, 98))	('Ewing sarcomas', 'Disease', (235, 249))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (264, 286))	('patients', 'Species', '9606', (157, 165))	('amplifications', 'Var', (72, 86))	('primitive neuroectodermal tumors', 'Disease', (254, 286))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (235, 249))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (254, 286))
190409	25870694	EWS-E1AF, t(17; 22) (q12; q12) The chromosomal translocation t(17; 22) leads to the fusion of EWS genes with E1AF and was described in a non-differentiated sarcoma of a child .	('EWS', 'Gene', (94, 97))	('child', 'Species', '9606', (169, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('non-differentiated sarcoma', 'Disease', (137, 163))	('E1AF', 'Gene', (109, 113))	('t(17; 22', 'Var', (61, 69))	('fusion', 'Var', (84, 90))	('leads to', 'Reg', (71, 79))
190411	25870694	The EWS-ATF1 translocation is frequent and specific for the malign melanoma of soft tissues (sarcoma with clear cells).	('translocation', 'Var', (13, 26))	('malign melanoma of soft', 'Disease', (60, 83))	('malign melanoma of soft', 'Disease', 'MESH:D008545', (60, 83))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('EWS-ATF1', 'Gene', (4, 12))
190412	25870694	EWS-WT1, t(11; 22) (p13; q12)  This repetitive translocation associated with the desmoplastic sarcoma with small round cells results from the fusion of the EWS gene with the gene of the Wilms tumor on the chromosome 11p13.	('Wilms tumor', 'Disease', 'MESH:D009396', (186, 197))	('Wilms tumor', 'Phenotype', 'HP:0002667', (186, 197))	('Wilms tumor', 'Disease', (186, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('EWS', 'Gene', (156, 159))	('desmoplastic sarcoma', 'Disease', 'MESH:D012509', (81, 101))	('fusion', 'Var', (142, 148))	('results from', 'Reg', (125, 137))	('associated', 'Reg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('desmoplastic sarcoma', 'Disease', (81, 101))
190423	25870694	After the rearrangements, the so-called ARN binding domain of FUS is replaced by the entire tail region of CHOP gene that contains the basic domain, based on the "zipper" motif of leucynes or leucynes zippers.	('CHOP gene', 'Gene', (107, 116))	('rearrangements', 'Var', (10, 24))	('leucyne', 'Chemical', '-', (180, 187))	('leucyne', 'Chemical', '-', (192, 199))
190427	25870694	SYT-SSX (t(x; 18) (p11.2; q11.2)  SYT-SSX fusion gene results in following the chromosomal translocation t(x; 18) (p11; q11) and is present in over 80% of the synovial sarcomas.	('synovial sarcomas', 'Disease', (159, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (159, 175))	('synovial sarcoma', 'Disease', 'MESH:D013584', (159, 175))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('t(x; 18) (p11; q11', 'Var', (105, 123))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (159, 176))	('t(x; 18) (p11.2', 'Var', (9, 24))	('SYT-SSX', 'Gene', (34, 41))	('synovial sarcomas', 'Disease', 'MESH:D013584', (159, 176))
190429	25870694	SYT-SSX 1 or SYT-SSX2 fusion protein present at the C-terminal end of Syt, amino acids replaced by the amino acids of SSX proteins from their C-terminal end .	('SSX 1', 'Gene', '6756', (4, 9))	('SYT-SSX 1', 'Gene', '6760;6756', (0, 9))	('Syt', 'Gene', '6760', (70, 73))	('Syt', 'Gene', (70, 73))	('SYT-SSX2', 'Gene', (13, 21))	('amino acids', 'Var', (75, 86))	('SYT-SSX 1', 'Gene', (0, 9))
190431	25870694	- the SYT-SSX 1 translocations in biphasic sarcomas  - the SYT-SSX 2 translocations in monophasic synovial sarcomas.	('synovial sarcomas', 'Phenotype', 'HP:0012570', (98, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('biphasic sarcomas', 'Disease', 'MESH:D012509', (34, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('translocations', 'Var', (16, 30))	('biphasic sarcomas', 'Disease', (34, 51))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (98, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
190696	33627110	A bone marrow biopsy showed bone marrow proliferation activity, erythroid hyperplasia, and immunotyping for CD34 (+) and CD117 (+).	('CD', 'Chemical', 'MESH:D002104', (108, 110))	('erythroid hyperplasia', 'Phenotype', 'HP:0012132', (64, 85))	('bone marrow proliferation activity', 'CPA', (28, 62))	('CD117', 'Gene', '3815', (121, 126))	('erythroid hyperplasia', 'Disease', 'MESH:D006965', (64, 85))	('CD117', 'Gene', (121, 126))	('erythroid hyperplasia', 'Disease', (64, 85))	('CD34 (+', 'Var', (108, 115))	('CD', 'Chemical', 'MESH:D002104', (121, 123))
190697	33627110	Monocytes accounted for 3.1% and the proportion was normal, mainly comprising CD14 (+) and CD64 (+) mature monocytes.	('CD', 'Chemical', 'MESH:D002104', (78, 80))	('CD', 'Chemical', 'MESH:D002104', (91, 93))	('CD14 (+', 'Var', (78, 85))	('CD64 (+', 'Var', (91, 98))
190705	33627110	The diagnosis of MS in the present case was made based on the positive expression of MPO, CD33, Ki67, CD68, the above findings were the surface antigens expression and immunophenotype of immature myeloid cells.	('MPO', 'Gene', '4353', (85, 88))	('CD33', 'Gene', (90, 94))	('Ki67', 'Var', (96, 100))	('CD', 'Chemical', 'MESH:D002104', (102, 104))	('CD68', 'Gene', (102, 106))	('MPO', 'Gene', (85, 88))	('CD', 'Chemical', 'MESH:D002104', (90, 92))
190725	33627110	The common positive cell surface antigens of MS include myeloperoxidase (MPO), lysozyme, CD68-kp1, CD117, CD99, CD33, CD34, CD56, CD163, TDT, CD61, CD30, blood group glycoprotein and CD4.	('CD', 'Chemical', 'MESH:D002104', (148, 150))	('CD117', 'Gene', (99, 104))	('CD99', 'Var', (106, 110))	('TDT', 'Gene', '1791', (137, 140))	('CD', 'Chemical', 'MESH:D002104', (130, 132))	('CD', 'Chemical', 'MESH:D002104', (99, 101))	('myeloperoxidase', 'Gene', (56, 71))	('myeloperoxidase', 'Gene', '4353', (56, 71))	('TDT', 'Gene', (137, 140))	('lysozyme', 'Gene', (79, 87))	('CD163', 'Gene', '9332', (130, 135))	('CD33', 'Var', (112, 116))	('CD56', 'Var', (124, 128))	('CD', 'Chemical', 'MESH:D002104', (112, 114))	('blood group glycoprotein', 'Protein', (154, 178))	('CD', 'Chemical', 'MESH:D002104', (89, 91))	('CD68-kp1', 'Var', (89, 97))	('MPO', 'Gene', '4353', (73, 76))	('CD', 'Chemical', 'MESH:D002104', (106, 108))	('lysozyme', 'Gene', '4069', (79, 87))	('CD', 'Chemical', 'MESH:D002104', (183, 185))	('MPO', 'Gene', (73, 76))	('CD163', 'Gene', (130, 135))	('CD4', 'Gene', '920', (183, 186))	('CD61', 'Gene', (142, 146))	('CD117', 'Gene', '3815', (99, 104))	('CD', 'Chemical', 'MESH:D002104', (142, 144))	('CD', 'Chemical', 'MESH:D002104', (118, 120))	('CD34', 'Var', (118, 122))	('CD30', 'Var', (148, 152))	('CD4', 'Gene', (183, 186))	('CD', 'Chemical', 'MESH:D002104', (124, 126))
190726	33627110	In addition, the positive expression of CD13, CD33, CD117 and MPO often indicates myeloid differentiation of tumor cells, and the positive expression of CD14, CD163 and CD11c indicates the differentiation of monocytes.	('indicates', 'Reg', (72, 81))	('differentiation of monocytes', 'CPA', (189, 217))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CD', 'Chemical', 'MESH:D002104', (169, 171))	('indicates', 'Reg', (175, 184))	('CD', 'Chemical', 'MESH:D002104', (153, 155))	('CD33', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CD', 'Chemical', 'MESH:D002104', (159, 161))	('CD117', 'Gene', '3815', (52, 57))	('MPO', 'Gene', '4353', (62, 65))	('CD', 'Chemical', 'MESH:D002104', (40, 42))	('CD163', 'Gene', '9332', (159, 164))	('CD14', 'Var', (153, 157))	('MPO', 'Gene', (62, 65))	('CD13', 'Gene', (40, 44))	('CD117', 'Gene', (52, 57))	('CD', 'Chemical', 'MESH:D002104', (46, 48))	('CD', 'Chemical', 'MESH:D002104', (52, 54))	('CD163', 'Gene', (159, 164))	('CD11c', 'Gene', '3687', (169, 174))	('tumor', 'Disease', (109, 114))	('CD11c', 'Gene', (169, 174))
190743	33062546	Pertinently, a strong association between the development of breast sarcomas and TP53 mutations has been established.	('mutations', 'Var', (86, 95))	('breast sarcomas', 'Disease', (61, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('breast sarcomas', 'Disease', 'MESH:D001943', (61, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
190784	32351889	The analysis confirmed the reliability of NGS RNA-based approaches in detecting sarcoma-specific rearrangements.	('rearrangements', 'Var', (97, 111))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcoma', 'Disease', (80, 87))
190788	32351889	Indeed, the identification of histotype-specific (pathognomonic) gene alterations is of paramount importance in the differential diagnosis among sarcoma variants, between malignant and benign mimics, as well as between sarcoma and other tumor types.	('sarcoma', 'Disease', (219, 226))	('alterations', 'Var', (70, 81))	('sarcoma', 'Disease', (145, 152))	('tumor', 'Disease', (237, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('sarcoma', 'Disease', 'MESH:D012509', (219, 226))	('variants', 'Var', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))
190789	32351889	In particular, about one third of all sarcomas presents pathognomonic chromosome rearrangements (translocations, deletions, insertions) that result in fusion genes and corresponding expression of fusion transcripts.	('result in', 'Reg', (141, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('expression', 'MPA', (182, 192))	('deletions', 'Var', (113, 122))	('fusion genes', 'Var', (151, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('sarcomas', 'Disease', (38, 46))	('insertions', 'Var', (124, 134))	('fusion transcripts', 'MPA', (196, 214))	('sarcomas', 'Disease', 'MESH:D012509', (38, 46))
190791	32351889	Moreover, the detection of NTRK fusions in a broad range of malignancies, including sarcomas, has gaining much attention due to the recent demonstration of therapeutic efficacy of a new class of tyrosine kinase inhibitors in NTRK rearranged tumors.	('malignancies', 'Disease', (60, 72))	('fusions', 'Var', (32, 39))	('NTRK', 'Gene', (225, 229))	('tumors', 'Disease', (241, 247))	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('rearranged', 'Var', (230, 240))	('NTRK', 'Gene', (27, 31))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('sarcomas', 'Disease', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
190802	32351889	In a subset of samples, a customized version of the AMP-FPS panel was used to detect PAX3 fusion transcripts.	('AMP', 'Chemical', 'MESH:D000249', (52, 55))	('PAX3', 'Gene', '5077', (85, 89))	('fusion transcripts', 'Var', (90, 108))	('PAX3', 'Gene', (85, 89))
190813	32351889	All three targeted RNA-sequencing panels permit the identification of common and known fusions involved in sarcomas, but also the discovery of novel fusions.	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('fusions', 'Var', (87, 94))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('sarcomas', 'Disease', (107, 115))	('involved', 'Reg', (95, 103))
190822	32351889	With the exception of case #27, for which no algorithm detected, as high confidence calls, fusions involving the CIC gene, apparently rearranged according to FISH, at least one fusion caller was capable of detecting, among others, a fusion transcript involving the target gene in cases previously scored negative with the BaseSpace RNA-Seq Alignment tool, emphasizing the importance of software sensitivity in data analysis (Supplemental Tables 1-3).	('CIC', 'Gene', '23152', (113, 116))	('CIC', 'Gene', (113, 116))	('fusions', 'Var', (91, 98))
190835	32351889	For instance, in two tumors (one endometrial stromal sarcoma and one sarcoma NOS) FISH indicated a rearrangement of the BCOR gene with an unknown partner.	('sarcoma NOS', 'Disease', (69, 80))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (33, 60))	('sarcoma NOS', 'Disease', 'MESH:D012509', (69, 80))	('rearrangement', 'Var', (99, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('BCOR', 'Gene', (120, 124))	('endometrial stromal sarcoma', 'Disease', (33, 60))	('BCOR', 'Gene', '54880', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
190841	32351889	Although in these cases no prior investigation (FISH or RT-PCR) was performed, this tumor is known to be typified by gene fusions involving the PAX3 gene.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('gene fusions', 'Var', (117, 129))	('PAX3', 'Gene', (144, 148))	('tumor', 'Disease', (84, 89))	('PAX3', 'Gene', '5077', (144, 148))
190842	32351889	Since the PAX3 gene is not covered by the commercial AMP-FPS panel, we commissioned a customization of the assay by spiking-in primers to cover PAX3 fusions.	('fusions', 'Var', (149, 156))	('PAX3', 'Gene', (144, 148))	('AMP', 'Chemical', 'MESH:D000249', (53, 56))	('PAX3', 'Gene', '5077', (10, 14))	('PAX3', 'Gene', '5077', (144, 148))	('PAX3', 'Gene', (10, 14))
190844	32351889	Interestingly, a rare EWSR1-PATZ1 fusion was detected by AMP-FPS in one EWSR1 FISH-positive Ewing sarcoma (case #34).	('detected', 'Reg', (45, 53))	('EWSR1', 'Gene', '2130', (22, 27))	('EWSR1', 'Gene', (72, 77))	('fusion', 'Var', (34, 40))	('PATZ1', 'Gene', (28, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('EWSR1', 'Gene', (22, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('PATZ1', 'Gene', '23598', (28, 33))	('EWSR1', 'Gene', '2130', (72, 77))	('AMP', 'Chemical', 'MESH:D000249', (57, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('Ewing sarcoma', 'Disease', (92, 105))
190847	32351889	In addition, 2/5 tumors negative for EWSR1 rearrangements according to FISH, turned out to express a CIC-DUX4 fusion, leading to the diagnosis of CIC-DUX4 fusion-positive undifferentiated round cell sarcoma.	('CIC', 'Gene', '23152', (101, 104))	('CIC', 'Gene', '23152', (146, 149))	('DUX4', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('DUX4', 'Gene', '100288687', (150, 154))	('CIC', 'Gene', (101, 104))	('CIC', 'Gene', (146, 149))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('DUX4', 'Gene', (105, 109))	('fusion', 'Var', (110, 116))	('EWSR1', 'Gene', (37, 42))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('DUX4', 'Gene', '100288687', (105, 109))	('EWSR1', 'Gene', '2130', (37, 42))	('sarcoma', 'Disease', (199, 206))
190850	32351889	In line with recent reports, our study corroborates the robustness of NGS, and in particular of AMP-FPS profiling, for the detection of clinically relevant fusions in sarcomas.	('sarcomas', 'Disease', (167, 175))	('fusions', 'Var', (156, 163))	('sarcomas', 'Disease', 'MESH:D012509', (167, 175))	('AMP', 'Chemical', 'MESH:D000249', (96, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (167, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
190854	32351889	Moreover, when dealing with sarcoma variants expressing uncommon fusions, the presence of primers for the target genes should be verified prior to setting up the profiling because the lack of appropriate primers will yield a false negative result.	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('sarcoma', 'Disease', (28, 35))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))	('variants', 'Var', (36, 44))
190880	30425775	Tumor morphology and IHC suggested synovial sarcoma and therefore the specimen was sent for additional molecular testing which confirmed the presence of SS18/SSX1 fusion transcript as detected by RT-DNA amplification consistent with synovial sarcoma.	('synovial sarcoma', 'Disease', 'MESH:D013584', (35, 51))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SS18', 'Gene', (153, 157))	('synovial sarcoma', 'Disease', (233, 249))	('SSX1', 'Gene', '6756', (158, 162))	('synovial sarcoma', 'Disease', (35, 51))	('SSX1', 'Gene', (158, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('fusion', 'Var', (163, 169))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (233, 249))	('SS18', 'Gene', '6760', (153, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (35, 51))	('synovial sarcoma', 'Disease', 'MESH:D013584', (233, 249))
190903	30425775	Definitive diagnosis is confirmed by positive IHC staining for TLE1, cytokeratins, EMA, BCL, and CD99 and the presence of the chromosomal translocation t(X;18)(p11:q11) involving the SS18 gene and SSX1, SSX2, or SSX4.	('t(X;18)(p11:q11)', 'STRUCTURAL_ABNORMALITY', 'None', (152, 168))	('CD99', 'Gene', '4267', (97, 101))	('SSX4', 'Gene', '6759', (212, 216))	('SSX1', 'Gene', (197, 201))	('SSX4', 'Gene', (212, 216))	('SS18', 'Gene', '6760', (183, 187))	('TLE1', 'Gene', '7088', (63, 67))	('SSX2', 'Gene', '6757', (203, 207))	('CD99', 'Gene', (97, 101))	('SSX2', 'Gene', (203, 207))	('SS18', 'Gene', (183, 187))	('SSX1', 'Gene', '6756', (197, 201))	('t(X;18)(p11:q11', 'Var', (152, 167))	('TLE1', 'Gene', (63, 67))
190916	27579539	Interestingly, most of the phenotypes of p27 null mice are reverted by the concomitant knock-out of the microtubules (MT)-destabilizing stathmin, demonstrating that p27/stathmin interaction plays a role in the control not only of cell motility but also of cell proliferation.	('cell motility', 'CPA', (230, 243))	('p27', 'Var', (41, 44))	('mice', 'Species', '10090', (50, 54))	('cell proliferation', 'CPA', (256, 274))
190917	27579539	Mechanistically, we recently showed that p27 controls H-Ras-driven proliferation acting on its intracellular recycling and mono- bi-ubiquitination.	('H-Ras-driven', 'Protein', (54, 66))	('mono- bi-ubiquitination', 'MPA', (123, 146))	('p27', 'Var', (41, 44))	('cyclin', 'Gene', '18538', (111, 117))	('cyclin', 'Gene', (111, 117))
190921	27579539	In tumors driven by K-Ras mutations, such as the urethane-induced or K-RasG12D-induced lung cancers, p27 acts as a haploinsufficient tumor suppressor gene and the loss of one allele is sufficient to induce the maximum oncogenic cooperation.	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutations', 'Var', (26, 35))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (115, 138))	('induce', 'Reg', (199, 205))	('lung cancers', 'Disease', 'MESH:D008175', (87, 99))	('p27', 'Gene', (101, 104))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('lung cancers', 'Disease', (87, 99))	('oncogenic cooperation', 'CPA', (218, 239))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('K-Ras', 'Gene', '16653', (69, 74))	('K-Ras', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('lung cancers', 'Phenotype', 'HP:0100526', (87, 99))	('urethane', 'Chemical', 'MESH:D014520', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('tumors', 'Disease', (3, 9))	('haploinsufficient tumor', 'Disease', (115, 138))	('K-Ras', 'Gene', (20, 25))	('K-Ras', 'Gene', '16653', (20, 25))
190922	27579539	Conversely, in H-Ras-driven tumorigenesis, such as the MMTV-H-RasV12-induced breast and salivary gland cancers or the DMBA/TPA skin carcinogenesis model, p27 acts as a classical tumor suppressor gene and loss of one p27 allele does not result in enhanced tumor growth.	('MMTV', 'Species', '11757', (55, 59))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', (28, 33))	('p27', 'Var', (154, 157))	('skin carcinogenesis', 'Disease', (127, 146))	('tumor', 'Disease', (255, 260))	('DMBA', 'Chemical', 'MESH:C082386', (118, 122))	('TPA', 'Chemical', '-', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (127, 146))	('breast and salivary gland cancers', 'Disease', 'MESH:D012468', (77, 110))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
190924	27579539	Accordingly, it has been postulated that p27 controls cell H-RasV12-driven transformation via not only the inhibition of the cyclin/CDK/RB pathway but also via RB-independent pathways.	('cell', 'Disease', (54, 58))	('p27', 'Var', (41, 44))	('inhibition', 'NegReg', (107, 117))	('cyclin', 'Gene', '18538', (125, 131))	('cyclin', 'Gene', (125, 131))
190927	27579539	We previously observed that p27 null cells and mice displayed higher Ras activity, due to different recycling and decreased mono-bi-ubiquitination.	('Ras', 'Protein', (69, 72))	('mono-bi-ubiquitination', 'MPA', (124, 146))	('decreased', 'NegReg', (114, 123))	('higher', 'PosReg', (62, 68))	('cyclin', 'Gene', '18538', (102, 108))	('p27', 'Var', (28, 31))	('cyclin', 'Gene', (102, 108))	('mice', 'Species', '10090', (47, 51))
190928	27579539	Subcutaneous injection of 1x106 WT H-RasV12 cells in nude mice (n = 5) were not sufficient to give rise to tumors, while the same number of p27KO H-RasV12 cells determined the appearance of tumor masses within 10-12 days (data not shown).	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('nude mice', 'Species', '10090', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('p27KO', 'Var', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
190929	27579539	Using 2x106 cells, all mice injected with WT H-RasV12 cells developed slow growing tumors within 15-17 days, but p27KO H-RasV12 cells formed fast growing tumors within 5-10 days (Figure 1F) as evidenced by differences in the explanted tumor masses (p < 0.0001, n = 5/clone), with no appreciable difference among the clones utilized (Figure 1G).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (235, 240))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('p27KO', 'Var', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mice', 'Species', '10090', (23, 27))	('tumor', 'Disease', (154, 159))
190930	27579539	In vitro experiments using growth curves (Figure 2A) and soft agar assays (Figure 2B) and in vivo experiments (Figure 2C) using subcutaneous injections, showed that p27KO H-RasV12 fibroblasts re-expressing p27WT or p271-170 were barely (in vitro) or not (in vivo) affected in their growth by either p27WT or p271-170.	('p27WT', 'Var', (299, 304))	('p271-170', 'Var', (215, 223))	('p271-170', 'Var', (308, 316))	('p27WT', 'Var', (206, 211))	('agar', 'Chemical', 'MESH:D000362', (62, 66))	('p27KO', 'Var', (165, 170))
190931	27579539	However, p27WT, but not p271-170, reduced the ability of p27KO H-RasV12 transformed fibroblasts to move in 3D-Matrigel (Figure 2D) and to intravasate, extravasate and settle at distant sites in nude mice, as demonstrated by the presence of cells expressing the H-RasV12 transgene in the blood and in the lungs of mice bearing subcutaneous tumors (5 mice/cell clone) (Figure 2E and 2F).	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('reduced', 'NegReg', (34, 41))	('mice', 'Species', '10090', (199, 203))	('nude mice', 'Species', '10090', (194, 203))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (326, 345))	('mice', 'Species', '10090', (313, 317))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (326, 345))	('extravasate', 'MPA', (151, 162))	('p27WT', 'Var', (9, 14))	('p27KO', 'Var', (57, 62))	('move', 'CPA', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('subcutaneous tumors', 'Disease', (326, 345))	('ability', 'MPA', (46, 53))	('mice', 'Species', '10090', (349, 353))
190932	27579539	Growth curve experiments confirmed that transformed p27KO cells grew much faster than WT cells and showed that DKO H-RasV12 cells displayed an intermediate growth rate (Figure 3A) and western blot analyses demonstrated higher ERK phosphorylation in p27KO H-RasV12 than in WT and DKO fibroblasts, both in basal conditions (Supplemental Figure S2A) and following serum (FBS) or Epidermal Growth Factor (EGF) stimulation (Figure 3B).	('p27KO', 'Var', (52, 57))	('FBS', 'Disease', (368, 371))	('Epidermal Growth Factor', 'Gene', '13645', (376, 399))	('EGF', 'Gene', (401, 404))	('p27KO', 'Var', (249, 254))	('higher', 'PosReg', (219, 225))	('FBS', 'Disease', 'MESH:D005198', (368, 371))	('Epidermal Growth Factor', 'Gene', (376, 399))	('EGF', 'Gene', '13645', (401, 404))	('ERK phosphorylation', 'MPA', (226, 245))
190935	27579539	To distinguish the effects of p27 on H-Ras and RhoA we pharmacologically inhibited H-Ras (FTI-276) or ROCK1 (Y27632).	('FTI-276', 'Var', (90, 97))	('H-Ras', 'CPA', (83, 88))	('ROCK1', 'Gene', '19877', (102, 107))	('Y27632', 'Var', (109, 115))	('ROCK1', 'Gene', (102, 107))	('RhoA', 'Gene', (47, 51))	('inhibited', 'NegReg', (73, 82))	('FTI-276', 'Chemical', 'MESH:C404062', (90, 97))	('RhoA', 'Gene', '11848', (47, 51))	('Y27632', 'Chemical', 'MESH:C108830', (109, 115))
190936	27579539	FTI-276 treatment abrogated the differences in ERK phosphorylation between the different genotypes, while Y27632 treatment did not (Figure 3C).	('Y27632', 'Chemical', 'MESH:C108830', (106, 112))	('FTI-276', 'Chemical', 'MESH:C404062', (0, 7))	('Y27632', 'Var', (106, 112))	('ERK phosphorylation', 'MPA', (47, 66))	('abrogated', 'NegReg', (18, 27))
190937	27579539	However, only FTI-276 inhibitor abrogated the differences in cell proliferation between p27KO and DKO cells (Figure 3D).	('FTI-276', 'Chemical', 'MESH:C404062', (14, 21))	('abrogated', 'NegReg', (32, 41))	('p27KO', 'Var', (88, 93))	('cell proliferation', 'CPA', (61, 79))
190939	27579539	If this was really the case, then no difference in cell transformation should be observed between p27KO and DKO fibroblasts transformed with K-Ras4BV12 oncogene.	('p27KO', 'Var', (98, 103))	('K-Ras', 'Gene', (141, 146))	('BV12', 'CellLine', 'CVCL:0182', (147, 151))	('K-Ras', 'Gene', '16653', (141, 146))
190943	27579539	K-Ras4BV12 p27KO and DKO transformed cells displayed similar levels of ERK1/2 phosphorylation (Figure 5A) and proliferated fairly at the same extent but significantly faster than WT cells (Figure 5B).	('proliferated', 'CPA', (110, 122))	('p27KO', 'Var', (11, 16))	('phosphorylation', 'MPA', (78, 93))	('ERK1/2', 'Protein', (71, 77))	('K-Ras', 'Gene', (0, 5))	('faster', 'PosReg', (167, 173))	('K-Ras', 'Gene', '16653', (0, 5))	('BV12', 'CellLine', 'CVCL:0182', (6, 10))
190944	27579539	No substantial difference in the transformation efficiency was detectable by soft agar assay between p27KO and DKO K-Ras4BV12 cells (Figure 5C).	('agar', 'Chemical', 'MESH:D000362', (82, 86))	('p27KO', 'Var', (101, 106))	('K-Ras', 'Gene', '16653', (115, 120))	('BV12', 'CellLine', 'CVCL:0182', (121, 125))	('K-Ras', 'Gene', (115, 120))
190945	27579539	We next analyzed, by pull down assay, the levels of GTP-bound active Ras proteins in WT, p27KO and DKO cells transformed with H-RasV12 or with K-Ras4BV12, in basal conditions and after stimulation with serum.	('Ras', 'Protein', (69, 72))	('BV12', 'CellLine', 'CVCL:0182', (149, 153))	('K-Ras', 'Gene', (143, 148))	('GTP', 'Chemical', 'MESH:D006160', (52, 55))	('K-Ras', 'Gene', '16653', (143, 148))	('H-RasV12', 'Var', (126, 134))
190946	27579539	However, basal and serum-stimulated H-RasV12 (but not K-Ras4BV12) activities were significantly higher in p27KO when compared to WT and DKO transformed cells (Figure 5D), supporting the possibility that regulation of H-Ras ubiquitination by p27 and stathmin participated in the control of its activity.	('activities', 'MPA', (66, 76))	('K-Ras', 'Gene', (54, 59))	('BV12', 'CellLine', 'CVCL:0182', (60, 64))	('K-Ras', 'Gene', '16653', (54, 59))	('p27KO', 'Var', (106, 111))	('higher', 'PosReg', (96, 102))	('H-RasV12', 'Enzyme', (36, 44))
190950	27579539	To exclude species-specific effects due to the use of human p27 (h-p27WT) in rescue-experiments, we re-performed some of the same assays in p27 null H-RasV12 transformed cells, reintroducing the mouse p27, either wild type (m-p27WT) or mutated in the binding to Cyclin/CDKs complexes (m-p27CK-) (Supplementary Figure S3A and B).	('Cyclin', 'Gene', (262, 268))	('binding', 'Interaction', (251, 258))	('CDKs', 'Gene', '1017;12566', (269, 273))	('mutated', 'Var', (236, 243))	('m-p27CK-', 'Var', (285, 293))	('CDKs', 'Gene', (269, 273))	('Cyclin', 'Gene', '18538', (262, 268))	('human', 'Species', '9606', (54, 59))	('mouse', 'Species', '10090', (195, 200))	('S3A and B', 'Gene', '252903;11778', (317, 326))
190951	27579539	In line with the results obtained with the human protein, m-p27WT and mp27CK- proteins only slightly affected the ability of H-RasV12 transformed cells to grow in culture or in soft agar (Supplementary Figure S3C and D) but significantly reduced cell motility (Supplementary Figure S3E).	('cell motility', 'CPA', (246, 259))	('mp27CK- proteins', 'Var', (70, 86))	('reduced', 'NegReg', (238, 245))	('m-p27WT', 'Var', (58, 65))	('H-RasV12', 'Gene', (125, 133))	('agar', 'Chemical', 'MESH:D000362', (182, 186))	('affected', 'Reg', (101, 109))	('human', 'Species', '9606', (43, 48))
190952	27579539	To avoid the possible bias due to clonal selection and in the generation of 3T3 cells we next concomitantly transduced with and SV40 Large TAg (LgTAg) and with H-RasV12 (Figure 6A) or K-Ras4BV12 (Figure 6B) primary MEF of the different genotypes.	('K-Ras', 'Gene', '16653', (184, 189))	('K-Ras', 'Gene', (184, 189))	('H-RasV12', 'Var', (160, 168))	('MEF', 'Disease', (215, 218))	('BV12', 'CellLine', 'CVCL:0182', (190, 194))	('MEF', 'Disease', 'None', (215, 218))
190953	27579539	Since SV40 LgTAg oncogene simultaneously inactivates p53 and RB, we anticipated that in this model the relevance of CDK-inhibition by p27 would be less pronounced.	('p53', 'Gene', '22060', (53, 56))	('p53', 'Gene', (53, 56))	('SV40', 'Var', (6, 10))	('inactivates', 'NegReg', (41, 52))
190955	27579539	Similarly, tumors from LgTAg/H-RasV12 transformed p27KO MEF had significantly higher volume (Figure 7A) and number of Ki67 positive cells (Figure 7B and 7C), when compared to both WT and DKO counterparts.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('MEF', 'Disease', (56, 59))	('Ki67', 'Gene', (118, 122))	('MEF', 'Disease', 'None', (56, 59))	('higher', 'PosReg', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('Ki67', 'Gene', '17345', (118, 122))	('p27KO', 'Var', (50, 55))
190957	27579539	In explanted tumors, the expression of the Ras-ERK downstream targets Egr-1, c-Fos and Jun-B was higher in p27KO cells only in the presence of H-RasV12 (Figure 7E).	('higher', 'PosReg', (97, 103))	('p27KO', 'Var', (107, 112))	('tumors', 'Disease', (13, 19))	('Jun-B', 'Gene', '16477', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('c-Fos', 'Gene', (77, 82))	('expression', 'MPA', (25, 35))	('Jun-B', 'Gene', (87, 92))	('Egr-1', 'Gene', '13653', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('c-Fos', 'Gene', '14281', (77, 82))	('Egr-1', 'Gene', (70, 75))
190960	27579539	Using HT1080 cells, (a STS cell line harboring the N-RasQ61K mutation and a well-known model for Ras-driven transformation) we next shown that Ras activity was reduced by one third by the overexpression of p27WT or p27CK- (Figure 8C).	('Ras', 'CPA', (143, 146))	('p27WT', 'Var', (206, 211))	('p27CK-', 'Var', (215, 221))	('overexpression', 'PosReg', (188, 202))	('reduced', 'NegReg', (160, 167))	('HT1080', 'CellLine', 'CVCL:0317', (6, 12))	('activity', 'MPA', (147, 155))
190965	27579539	SK-BR-3 and MDA-MB-453 in Supplementary Figure S4C), we consistently detected an inverse correlation between p27/stathmin cytoplasmic ratio and the activation of ERK1/2 and the expression of EGR-1 (Supplementary Figure S4A-C).	('MDA-MB-453', 'CellLine', 'CVCL:0418', (12, 22))	('ERK1/2', 'Protein', (162, 168))	('inverse', 'NegReg', (81, 88))	('activation', 'PosReg', (148, 158))	('EGR-1', 'Gene', (191, 196))	('EGR-1', 'Gene', '13653', (191, 196))	('p27/stathmin', 'Var', (109, 121))	('SK-BR-3', 'CellLine', 'CVCL:0033', (0, 7))	('expression', 'MPA', (177, 187))
190966	27579539	Importantly, knock-down of p27 in SK-BR-3 cells increased ERK1/2 phosphorylation (Figure S4D) and low cytoplasmic p27/stathmin ratio was significantly associated with a higher level of ERK1/2 phosphorylation in primary breast carcinomas (Supplementary Table S1 and Supplementary Figure S4E).	('carcinomas', 'Phenotype', 'HP:0030731', (226, 236))	('increased', 'PosReg', (48, 57))	('higher', 'PosReg', (169, 175))	('knock-down', 'Var', (13, 23))	('low', 'NegReg', (98, 101))	('p27', 'Gene', (27, 30))	('breast carcinomas', 'Disease', 'MESH:D001943', (219, 236))	('breast carcinomas', 'Disease', (219, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('phosphorylation', 'MPA', (65, 80))	('breast carcinomas', 'Phenotype', 'HP:0003002', (219, 236))	('ERK1/2 phosphorylation', 'MPA', (185, 207))	('ERK1/2', 'Protein', (58, 64))	('SK-BR-3', 'CellLine', 'CVCL:0033', (34, 41))
190968	27579539	The most salient observation regards the susceptibility of WT or p27-null immortalized fibroblasts to the transforming activity of H-RasV12 and K-RasV12.	('H-RasV12', 'Var', (131, 139))	('K-Ras', 'Gene', '16653', (144, 149))	('transforming activity', 'MPA', (106, 127))	('K-Ras', 'Gene', (144, 149))
190973	27579539	A second interesting finding is the different potential displayed by p27 in restraining H-RasV12 versus K-RasV12-4B induced transformation.	('K-Ras', 'Gene', '16653', (104, 109))	('H-RasV12', 'Var', (88, 96))	('K-Ras', 'Gene', (104, 109))
190977	27579539	p27 expression was also reported to be necessary to mediate the inhibition of H-Ras-induced transformation induced either by STAT1 or by dominant negative Rho, likely in a RB-independent or partially dependent manner.	('H-Ras-induced transformation', 'CPA', (78, 106))	('STAT1', 'Gene', '20846', (125, 130))	('STAT1', 'Gene', (125, 130))	('Rho', 'Protein', (155, 158))	('inhibition', 'NegReg', (64, 74))	('dominant negative', 'Var', (137, 154))
190978	27579539	More recent evidences demonstrated that in MEFs and in urinary bladder HT1197 cells, carrying a N-Ras Q61R mutation, p27 inhibits cell motility likely by reducing ERK activation, independently supporting our findings.	('activation', 'MPA', (167, 177))	('MEFs', 'CellLine', 'CVCL:9115', (43, 47))	('cell motility', 'CPA', (130, 143))	('reducing', 'NegReg', (154, 162))	('ERK', 'Protein', (163, 166))	('inhibits', 'NegReg', (121, 129))	('Q61R', 'Mutation', 'rs11554290', (102, 106))	('p27', 'Var', (117, 120))	('HT1197', 'CellLine', 'CVCL:1291', (71, 77))
190981	27579539	It is interesting to note that, at least in MEN syndrome, breast cancer, intestine neuroendocrine tumors and prostate cancer, the CDKN1B gene (encoding for p27) is frequently mutated in the C-terminal portion of the protein.	('MEN syndrome', 'Disease', 'MESH:D018813', (44, 56))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Disease', (109, 124))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('CDKN1B', 'Gene', '1027', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('intestine neuroendocrine tumors', 'Disease', (73, 104))	('breast cancer', 'Disease', (58, 71))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CDKN1B', 'Gene', (130, 136))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('mutated', 'Var', (175, 182))	('MEN syndrome', 'Disease', (44, 56))	('intestine neuroendocrine tumors', 'Disease', 'MESH:D018358', (73, 104))
190982	27579539	One of the mutations, repeatedly identified in human breast cancers, is the E171 Stop that results in a truncated protein (p271-170) that we have characterized here and in previous publications.	('human', 'Species', '9606', (47, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('p271-170', 'Var', (123, 131))	('results in', 'Reg', (91, 101))	('breast cancers', 'Phenotype', 'HP:0003002', (53, 67))	('truncated', 'MPA', (104, 113))	('E171 Stop', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancers', 'Disease', 'MESH:D001943', (53, 67))	('breast cancers', 'Disease', (53, 67))
190985	27579539	In the presence of K-Ras mutations, p27 acts invariably as a haploinsufficient tumor suppressor gene.	('K-Ras', 'Gene', (19, 24))	('mutations', 'Var', (25, 34))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (61, 84))	('K-Ras', 'Gene', '16653', (19, 24))	('haploinsufficient tumor', 'Disease', (61, 84))	('p27', 'Gene', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
190986	27579539	In the presence of H-Ras, the complete loss of p27 is necessary to favor tumor growth in mice, suggesting that the presence of one p27 allele is still able to restrain cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('restrain', 'NegReg', (159, 167))	('p27', 'Gene', (47, 50))	('cell proliferation', 'CPA', (168, 186))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('presence', 'Var', (115, 123))	('tumor', 'Disease', (73, 78))	('loss', 'NegReg', (39, 43))
191040	27567955	Hypoalbuminemia was defined as albumin levels < 36 g/l or < 542 mumol/l.	('Hypoalbuminemia', 'Disease', (0, 15))	('Hypoalbuminemia', 'Phenotype', 'HP:0003073', (0, 15))	('Hypoalbuminemia', 'Disease', 'MESH:D034141', (0, 15))	('< 542 mumol/l', 'Var', (58, 71))	('albumin levels', 'MPA', (31, 45))
191057	27567955	To evaluate the value of the ACBS, we have tested the Cox proportional hazard model with the ACBS against the model without the ACBS using likelihood-ratio test.	('tested', 'Reg', (43, 49))	('Cox', 'Disease', (54, 57))	('ACBS', 'Var', (93, 97))	('ACBS', 'Chemical', '-', (93, 97))	('ACBS', 'Chemical', '-', (128, 132))	('ACBS', 'Chemical', '-', (29, 33))
191076	27567955	There was a clear trend of increased 5-year overall mortality with increasing ASBC, from 15% (95% CI: 9-23) in patients with score of 0 to 47% (95% CI: 32-65) in patients with score of 1 and to 61% (95% CI: 46-77) in patients with score of 2.	('patients', 'Species', '9606', (162, 170))	('score', 'Var', (176, 181))	('ASBC', 'Chemical', '-', (78, 82))	('patients', 'Species', '9606', (217, 225))	('ASBC', 'Gene', (78, 82))	('patients', 'Species', '9606', (111, 119))
191137	25267074	For BRAF mutation analysis, paraffin-embedded tissue samples were macrodissected to remove stromal contamination and to ensure tumor cellularity of >=80%.	('mutation', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('paraffin', 'Chemical', 'MESH:D010232', (28, 36))	('tumor', 'Disease', (127, 132))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
191138	25267074	Briefly, DNA extracted from the case was amplified and sequenced, using the BRAF Pyro Kit (QIAGEN) designed to detect mutations in codon 600.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutations in', 'Var', (118, 130))
191149	25267074	FISH analysis for synovial sarcoma showed negative result since more than 90% of the counted cells didn't show separated green and orange signals indicative of rearrangement of the SYT gene.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (18, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('synovial sarcoma', 'Disease', 'MESH:D013584', (18, 34))	('SYT', 'Gene', '6857', (181, 184))	('synovial sarcoma', 'Disease', (18, 34))	('rearrangement', 'Var', (160, 173))	('SYT', 'Gene', (181, 184))
191150	25267074	Mutation analysis showed that no BRAF V600E mutations were detected in this case.	('V600E', 'Var', (38, 43))	('BRAF', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (33, 37))	('V600E', 'Mutation', 'rs113488022', (38, 43))
191160	25267074	confirmed BRAF V600E mutations were present in approximately 90% of all MA cases, serving as a potential valuable diagnostic tool in the differential diagnosis, but there was no BRAF mutation in our case.	('BRAF', 'Gene', (178, 182))	('V600E', 'Mutation', 'rs113488022', (15, 20))	('V600E', 'Var', (15, 20))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('BRAF', 'Gene', '673', (178, 182))
191172	25267074	FISH analysis showed no rearrangement of the SYT gene, which did not support the diagnosis of synovial sarcoma either.	('rearrangement', 'Var', (24, 37))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (94, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('synovial sarcoma', 'Disease', 'MESH:D013584', (94, 110))	('SYT', 'Gene', '6857', (45, 48))	('synovial sarcoma', 'Disease', (94, 110))	('SYT', 'Gene', (45, 48))
191179	23360213	Therefore, the aim was to stimulate intratumoral IL-12 production by gene electrotransfer of plasmid coding for mouse IL-12 (mIL-12) into the tumors, in order to explore its radiosensitizing effect after single or multiple intratumoral gene electrotransfer.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (41, 46))	('stimulate', 'PosReg', (26, 35))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mIL-12', 'Chemical', '-', (125, 131))	('tumors', 'Disease', (142, 148))	('tumor', 'Disease', (228, 233))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('mIL-12', 'Gene', (125, 131))	('mouse', 'Species', '10090', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('gene electrotransfer', 'Var', (69, 89))
191184	23360213	Single intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral but not serum mIL-12 and mIFNgamma concentrations, and had good antitumor (7.1% tumor cures) and radiosensitizing effect (21.4% tumor cures).	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (211, 216))	('mIL-12', 'Gene', (20, 26))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('mIL-12', 'Chemical', '-', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('increased', 'PosReg', (60, 69))	('radiosensitizing', 'CPA', (180, 196))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mIFNgamma', 'Gene', (108, 117))	('mIFNgamma', 'Gene', '15978', (108, 117))	('tumor', 'Disease', (151, 156))	('gene electrotransfer', 'Var', (27, 47))	('mIL-12', 'Chemical', '-', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
191186	23360213	Single or multiple intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral mIL-12 and mIFNgamma cytokine level, and may provide an efficient treatment modality for soft tissue sarcoma as single or adjuvant therapy to tumor irradiation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mIL-12', 'Chemical', '-', (32, 38))	('mIL-12', 'Chemical', '-', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (184, 203))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (184, 203))	('soft tissue sarcoma', 'Disease', (184, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', (87, 92))	('gene electrotransfer', 'Var', (39, 59))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (237, 242))	('increased', 'PosReg', (72, 81))	('mIL-12', 'Gene', (32, 38))	('mIFNgamma', 'Gene', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('mIFNgamma', 'Gene', '15978', (106, 115))
191194	23360213	IL-12 gene electrotransfer can be performed either intratumorally, with a predominantly local effect, or into the muscle, with a systemic effect on primary tumors and metastases.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (56, 61))	('metastases', 'Disease', (167, 177))	('metastases', 'Disease', 'MESH:D009362', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('electrotransfer', 'Var', (11, 26))	('gene electrotransfer', 'Var', (6, 26))	('tumors', 'Disease', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('IL-12', 'Gene', (0, 5))
191216	23360213	Separate experiments were performed combining gene electrotransfer with 10 Gy tumor irradiation using 9-15 animals per treatment group (Tables 1 and 2).	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('gene electrotransfer', 'Var', (46, 66))	('tumor', 'Disease', (78, 83))
191217	23360213	Based on our previous study, gene electrotransfer was performed on day 0 for single, and days 0, 2 and 4 for multiple treatments and tumors were irradiated on day 1.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('gene', 'Var', (29, 33))
191234	23360213	A new set of experiments was performed in order to evaluate the histology of tumors in the control group and after intratumoral mIL12 gene electrotransfer alone or combined with tumor irradiation.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('electrotransfer', 'Var', (139, 154))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('gene electrotransfer', 'Var', (134, 154))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mIL12', 'Gene', (128, 133))	('tumor', 'Disease', (77, 82))	('mIL', 'Chemical', 'MESH:C048042', (128, 131))	('tumor', 'Disease', (120, 125))
191239	23360213	Single intratumoral mIL-12 gene electrotransfer in murine SA-1 sarcoma tumors resulted in 7.1% (1/14) tumor cures and when combined with tumor irradiation in 21.4% (3/14) tumor cures.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mIL-12', 'Gene', (20, 26))	('tumor', 'Disease', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('mIL-12', 'Chemical', '-', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('sarcoma tumors', 'Disease', 'MESH:D012509', (63, 77))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (102, 107))	('murine', 'Species', '10090', (51, 57))	('sarcoma tumors', 'Disease', (63, 77))	('gene electrotransfer', 'Var', (27, 47))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
191240	23360213	In both treatment groups, a temporary and transitory increase in the complete response rate was observed 2-5 weeks after the treatment, reaching 21.4% after mIL-12 gene electrotransfer alone, and 71.4% after the combined treatment (Figure 1A).	('increase', 'PosReg', (53, 61))	('electrotransfer', 'Var', (169, 184))	('mIL-12', 'Chemical', '-', (157, 163))	('mIL-12', 'Gene', (157, 163))
191247	23360213	Significantly elevated concentrations of mIL-12 and mIFNgamma (p < 0.05) were detected in the tumors treated with mIL-12 gene electrotransfer alone (1027 +- 400 pg/g and 6509 +- 1018 pg/g, respectively) and combined with tumor irradiation (1671 +- 529 pg/g and 7191 +- 1283 pg/g, respectively).	('mIFNgamma', 'Gene', '15978', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('6509 +- 1018 pg/g', 'Var', (170, 187))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('concentrations', 'MPA', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (94, 99))	('mIL-12', 'Chemical', '-', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mIL-12', 'Chemical', '-', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('elevated', 'PosReg', (14, 22))	('mIFNgamma', 'Gene', (52, 61))	('mIL-12', 'Gene', (114, 120))
191250	23360213	In order to further elaborate the cytokine dynamics, serum and tumor concentrations of mIL-12 and mIFNgamma were measured at different time points after mIL-12 gene electrotransfer alone or combined with tumor irradiation (Figure 2).	('mIL-12', 'Chemical', '-', (87, 93))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('mIL-12', 'Gene', (153, 159))	('gene electrotransfer', 'Var', (160, 180))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mIFNgamma', 'Gene', (98, 107))	('mIFNgamma', 'Gene', '15978', (98, 107))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('electrotransfer', 'Var', (165, 180))	('mIL-12', 'Chemical', '-', (153, 159))
191256	23360213	Cells with nuclear polymorphism were seen in this part of the tumor, as well as some apoptotic cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', (62, 67))	('nuclear polymorphism', 'Var', (11, 31))
191259	23360213	After mIL-12 gene electrotransfer combined with irradiation, tumors were overall smaller than tumors treated with mIL-12 gene electrotransfer but the viable tumor area was almost 90% of the tumor.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mIL-12', 'Gene', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mIL-12', 'Chemical', '-', (6, 12))	('tumors', 'Disease', (61, 67))	('gene electrotransfer', 'Var', (13, 33))	('tumor', 'Disease', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mIL-12', 'Chemical', '-', (114, 120))	('tumor', 'Disease', (157, 162))	('smaller', 'NegReg', (81, 88))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (61, 66))
191266	23360213	Multiple intratumoral mIL-12 gene electrotransfer resulted in 50% tumor cures, with a temporary increase of the complete response percentage up to 57.1% at day 15 (Figure 1B).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (14, 19))	('mIL-12', 'Chemical', '-', (22, 28))	('tumor', 'Disease', (66, 71))	('gene electrotransfer', 'Var', (29, 49))	('mIL-12', 'Gene', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('increase', 'PosReg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('complete response', 'MPA', (112, 129))
191269	23360213	Cured mice receiving multiple mIL-12 gene electrotransfer alone (7/14) or combined with tumor irradiation (13/15) were resistant to secondary challenge with SA-1 sarcoma cells (Table 2).	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('sarcoma', 'Disease', (162, 169))	('mIL-12', 'Chemical', '-', (30, 36))	('mice', 'Species', '10090', (6, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('mIL-12', 'Gene', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('electrotransfer', 'Var', (42, 57))
191272	23360213	Our study demonstrates that single intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral but not serum mIL-12 and mIFNgamma concentrations, and induced pronounced antitumor and radiosensitizing effects in murine SA-1 sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mIFNgamma', 'Gene', (136, 145))	('mIFNgamma', 'Gene', '15978', (136, 145))	('mIL-12', 'Chemical', '-', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('murine', 'Species', '10090', (227, 233))	('tumor', 'Disease', (103, 108))	('increased', 'PosReg', (88, 97))	('electrotransfer', 'Var', (60, 75))	('tumor', 'Disease', (40, 45))	('mIL-12', 'Gene', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (189, 194))	('sarcoma', 'Disease', 'MESH:D012509', (239, 246))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('radiosensitizing effects', 'CPA', (199, 223))	('mIL-12', 'Chemical', '-', (48, 54))	('sarcoma', 'Disease', (239, 246))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
191279	23360213	Single mIL-12 gene transfer before tumor irradiation resulted in 21.4% tumor cures, while an additional two transfections after irradiation contributed to overall response, resulting in 86.7% tumor cures.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('gene transfer', 'Var', (14, 27))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mIL-12', 'Chemical', '-', (7, 13))	('mIL-12', 'Gene', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
191280	23360213	The high level of complete responses obtained is comparable to the study in murine fibrosarcoma AG104A, in which single intratumoral adenoviral mIL-12 gene transfer increased the tumor cure rate of fractionated radiation (5 fractions of 5 Gy) from 26% to 59%.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (83, 95))	('fibrosarcoma', 'Disease', 'MESH:D005354', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('gene transfer', 'Var', (151, 164))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('mIL-12', 'Chemical', '-', (144, 150))	('fibrosarcoma', 'Disease', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('increased', 'PosReg', (165, 174))	('murine', 'Species', '10090', (76, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('tumor', 'Disease', (179, 184))
191290	23360213	In our study the type of lymphocytes was not identified however previous publications using immunohistochemistry have demonstrated presence of both CD4+ and CD8+ T cells in the tumors after intratumoral mIL-12 gene electrotransfer.	('tumor', 'Disease', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('mIL-12', 'Chemical', '-', (203, 209))	('mIL-12', 'Gene', (203, 209))	('CD4+', 'Var', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('CD8+', 'Var', (157, 161))	('tumors', 'Disease', (177, 183))	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
191291	23360213	Infiltration with CD8+ T cells is necessary for complete tumor eradication and CD4+ T cells help in achieving adaptive immune response.	('adaptive immune response', 'CPA', (110, 134))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CD4+', 'Var', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
191298	23360213	One of the three tumors cured with single mIL-12 gene electrotransfer combined with tumor irradiation was resistant to secondary challenge which indicates on long-term immunity.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('electrotransfer', 'Var', (54, 69))	('tumor', 'Disease', (84, 89))	('mIL-12', 'Chemical', '-', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('mIL-12', 'Gene', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
191299	23360213	All the mice cured by multiple mIL-12 gene electrotransfer alone or combined with radiation were also resistant to secondary challenge, however the same phenomena was observed with mice treated with treatments used as pertinent controls (multiple therapies with electric pulse application or plasmid coding for dsRed combined with tumor irradiation) that resulted in tumors cures, due to their immunogenicity.	('tumors', 'Phenotype', 'HP:0002664', (367, 373))	('tumor', 'Disease', (367, 372))	('mice', 'Species', '10090', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('tumors', 'Disease', (367, 373))	('tumors', 'Disease', 'MESH:D009369', (367, 373))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('tumor', 'Disease', (331, 336))	('electrotransfer', 'Var', (43, 58))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('mIL-12', 'Chemical', '-', (31, 37))	('mIL-12', 'Gene', (31, 37))	('mice', 'Species', '10090', (8, 12))
191300	23360213	This indicates that multiple mIL-12 gene electrotransfer alone or combined with irradiation and also treatments used as pertinent controls might have either increased the immunogenicity of SA-1 sarcoma (increased tumor antigen availability after radiation induced apoptosis) or stimulated the immune cells (control plasmid coding for immunogenic protein) leading to a better tumor immunosurveillance and prevention of tumor outgrowth after secondary challenge.	('mIL-12', 'Gene', (29, 35))	('tumor', 'Disease', (418, 423))	('tumor', 'Disease', 'MESH:D009369', (418, 423))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('increased', 'PosReg', (203, 212))	('mIL-12', 'Chemical', '-', (29, 35))	('tumor', 'Disease', (375, 380))	('better', 'PosReg', (368, 374))	('tumor', 'Phenotype', 'HP:0002664', (418, 423))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('immunogenicity', 'MPA', (171, 185))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('sarcoma', 'Disease', (194, 201))	('stimulated', 'PosReg', (278, 288))	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('increased', 'PosReg', (157, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('electrotransfer', 'Var', (41, 56))
191303	23360213	Intratumoral gene therapy with IL-12 may in such cases, as demonstrated in this study, contribute to the antitumor effectiveness of radiotherapy for effective local tumor control.	('contribute', 'Reg', (87, 97))	('gene therapy', 'Var', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('IL-12', 'Gene', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', (165, 170))
191306	23360213	Multiple intramuscular mIL-12 gene electrotransfer resulted in a radiosensitizing effect, resulting in 44% tumor cures compared to 28% of tumor cures after mIL-12 gene electrotransfer only.	('mIL-12', 'Chemical', '-', (156, 162))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('radiosensitizing effect', 'MPA', (65, 88))	('gene electrotransfer', 'Var', (30, 50))	('mIL-12', 'Chemical', '-', (23, 29))	('mIL-12', 'Gene', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('electrotransfer', 'Var', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
191308	23360213	The result is also superior to the dose modifying factor that we obtained in our previous studies on an LPB sarcoma tumor model, in which irradiation was combined with increased chemotherapeutic drug content in the tumors due to electrotransfer (electrochemotherapy).	('sarcoma tumor', 'Disease', 'MESH:D012509', (108, 121))	('increased', 'PosReg', (168, 177))	('sarcoma tumor', 'Disease', (108, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('electrotransfer', 'Var', (229, 244))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', (215, 221))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', 'MESH:D009369', (215, 221))
191310	23360213	Our study provides a proof of concept regarding the therapeutic efficiency of intratumoral mIL-12 gene electrotransfer combined with single dose tumor irradiation.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (83, 88))	('mIL-12', 'Gene', (91, 97))	('mIL-12', 'Chemical', '-', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('gene electrotransfer', 'Var', (98, 118))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
191311	23360213	Single or multiple intratumoral mIL-12 gene electrotransfer results in increased intratumoral mIL-12 and mIFNgamma cytokine levels, and may provide an efficient treatment modality for soft tissue sarcoma as a single or adjuvant therapy to tumor irradiation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mIL-12', 'Chemical', '-', (32, 38))	('mIFNgamma', 'Gene', (105, 114))	('mIFNgamma', 'Gene', '15978', (105, 114))	('mIL-12', 'Chemical', '-', (94, 100))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (184, 203))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (184, 203))	('soft tissue sarcoma', 'Disease', (184, 203))	('tumor', 'Disease', (239, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('gene electrotransfer', 'Var', (39, 59))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (86, 91))	('mIL-12', 'Gene', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('increased', 'PosReg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
191313	23360213	Furthermore, repetitive gene electrotransfer compared to single one, further potentiated antitumor and radiosensitizing effects as well as increased the resistance to secondary challenge.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('repetitive gene electrotransfer', 'Var', (13, 44))	('increased', 'PosReg', (139, 148))	('tumor', 'Disease', (93, 98))	('radiosensitizing effects', 'CPA', (103, 127))	('potentiated', 'PosReg', (77, 88))	('resistance to secondary challenge', 'CPA', (153, 186))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
191339	32034283	NTRK3 Overexpression in Undifferentiated Sarcomas with YWHAE and BCOR Genetic Alterations The BCOR family of tumors includes a number of undifferentiated sarcomas, occurring in various age groups and anatomic sites, characterized by a spindle and round cell phenotype and diffuse immunoreactivity for BCOR.	('NTRK3', 'Gene', (0, 5))	('BCOR', 'Gene', '54880', (65, 69))	('Sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('Undifferentiated Sarcomas', 'Disease', (24, 49))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('Alterations', 'Var', (78, 89))	('BCOR', 'Gene', (65, 69))	('YWHAE', 'Gene', (55, 60))	('BCOR', 'Gene', '54880', (301, 305))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (137, 162))	('Genetic Alterations', 'Var', (70, 89))	('tumors', 'Disease', (109, 115))	('YWHAE', 'Gene', '7531', (55, 60))	('BCOR', 'Gene', '54880', (94, 98))	('BCOR', 'Gene', (301, 305))	('Undifferentiated Sarcomas', 'Disease', 'MESH:D002277', (24, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (154, 162))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('BCOR', 'Gene', (94, 98))	('Overexpression', 'PosReg', (6, 20))	('NTRK3', 'Gene', '4916', (0, 5))	('undifferentiated sarcomas', 'Disease', (137, 162))
191344	32034283	Most soft tissue undifferentiated round cell sarcomas with YWHAE or BCOR rearrangements or BCOR internal tandem duplications (ITD) showed NTRK3, but not NTRK1 or NTRK2, up-regulation by RNA sequencing data analysis.	('BCOR', 'Gene', '54880', (91, 95))	('NTRK2', 'Gene', '4915', (162, 167))	('rearrangements', 'Var', (73, 87))	('up-regulation', 'PosReg', (169, 182))	('BCOR', 'Gene', (91, 95))	('NTRK1', 'Gene', '4914', (153, 158))	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcomas', 'Disease', (45, 53))	('NTRK1', 'Gene', (153, 158))	('NTRK2', 'Gene', (162, 167))	('NTRK3', 'Gene', '4916', (138, 143))	('YWHAE', 'Gene', (59, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('NTRK3', 'Gene', (138, 143))	('YWHAE', 'Gene', '7531', (59, 64))	('BCOR', 'Gene', '54880', (68, 72))	('BCOR', 'Gene', (68, 72))	('internal tandem duplications', 'Var', (96, 124))
191349	32034283	Sarcomas with BCOR and YWHAE gene alterations encompass different pathologic entities sharing an undifferentiated round to spindle morphology and BCOR upregulation.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('BCOR', 'Gene', '54880', (14, 18))	('YWHAE', 'Gene', (23, 28))	('BCOR', 'Gene', '54880', (146, 150))	('YWHAE', 'Gene', '7531', (23, 28))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('upregulation', 'PosReg', (151, 163))	('alterations', 'Var', (34, 45))	('BCOR', 'Gene', (14, 18))	('Sarcomas', 'Disease', (0, 8))	('BCOR', 'Gene', (146, 150))
191350	32034283	Two categories of BCOR genetic events have been described including BCOR internal tandem duplications (ITD) and BCOR fusions, often involving the CCNB3 gene and occasionally less common partners (MAML3, ZC3H7B).	('fusions', 'Var', (117, 124))	('BCOR', 'Gene', (18, 22))	('CCNB3', 'Gene', (146, 151))	('ZC3H7B', 'Gene', (203, 209))	('MAML3', 'Gene', '55534', (196, 201))	('BCOR', 'Gene', '54880', (18, 22))	('MAML3', 'Gene', (196, 201))	('ZC3H7B', 'Gene', '23264', (203, 209))	('BCOR', 'Gene', (112, 116))	('BCOR', 'Gene', (68, 72))	('CCNB3', 'Gene', '85417', (146, 151))	('BCOR', 'Gene', '54880', (68, 72))	('BCOR', 'Gene', '54880', (112, 116))	('internal tandem duplications', 'Var', (73, 101))
191356	32034283	In this study we investigate a large spectrum of tumors with BCOR genetic alterations and other sarcoma types for expression of NTRK3 at both the mRNA and protein levels.	('BCOR', 'Gene', '54880', (61, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('NTRK3', 'Gene', '4916', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('NTRK3', 'Gene', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('BCOR', 'Gene', (61, 65))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('genetic alterations', 'Var', (66, 85))	('sarcoma', 'Disease', (96, 103))
191367	32034283	In a small subset of cases additional immunostains were applied including NTRK1 (Ab76291, 1:1,500, ABCAM), H3K27me3 (C36B11 (1:200 dilution; Cell Signaling Technology, Danvers, MA) and TLE1 (Santa Cruz Biotech, clone Poly; sc-9121; 1:100 dilution) .	('NTRK1', 'Gene', '4914', (74, 79))	('C36B11', 'Var', (117, 123))	('TLE1', 'Gene', '7088', (185, 189))	('NTRK1', 'Gene', (74, 79))	('TLE1', 'Gene', (185, 189))
191372	32034283	The mRNA levels of BCOR, NTRK1/2/3, and NTF3 expression were evaluated in round cell sarcomas with BCOR ITD, BCOR fusions, or YWHAE fusions using RNA sequencing (RNAseq) data and compared to other sarcoma types available on the same platforms.	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('sarcoma', 'Disease', (197, 204))	('ITD', 'Var', (104, 107))	('BCOR', 'Gene', (19, 23))	('BCOR', 'Gene', (99, 103))	('sarcoma', 'Disease', (85, 92))	('YWHAE', 'Gene', (126, 131))	('YWHAE', 'Gene', '7531', (126, 131))	('NTRK1/2/3', 'Gene', '4914;4915;4916', (25, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('BCOR', 'Gene', '54880', (109, 113))	('sarcomas', 'Disease', 'MESH:D012509', (85, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('fusions', 'Var', (114, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('sarcomas', 'Disease', (85, 93))	('BCOR', 'Gene', (109, 113))	('NTF3', 'Gene', (40, 44))	('NTRK1/2/3', 'Gene', (25, 34))	('BCOR', 'Gene', '54880', (19, 23))	('NTF3', 'Gene', '4908', (40, 44))	('BCOR', 'Gene', '54880', (99, 103))
191377	32034283	Among the tumors with YWHAE and BCOR ITD abnormalities, pan-Trk immuno-staining was positive in all 3 tumors with YWHAE rearrangements (2 infantile soft tissue tumors and 1 adult soft tissue) with a diffuse (>=90%) and moderate cytoplasmic pattern (Fig 1A, Table 1); 80% of soft tissue round cell sarcomas with BCOR ITD (Fig.	('rearrangements', 'Var', (120, 134))	('YWHAE', 'Gene', '7531', (114, 119))	('tumors', 'Disease', (10, 16))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (148, 166))	('BCOR', 'Gene', '54880', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('BCOR', 'Gene', '54880', (311, 315))	('BCOR', 'Gene', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('pan', 'Gene', '51816', (56, 59))	('ITD abnormalities', 'Disease', (37, 54))	('BCOR', 'Gene', (311, 315))	('YWHAE', 'Gene', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('ITD abnormalities', 'Disease', 'MESH:D018376', (37, 54))	('tumors', 'Disease', (102, 108))	('pan', 'Gene', (56, 59))	('YWHAE', 'Gene', '7531', (22, 27))	('sarcomas', 'Disease', 'MESH:D012509', (297, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (297, 304))	('sarcomas', 'Phenotype', 'HP:0100242', (297, 305))	('Trk', 'Gene', '4914', (60, 63))	('sarcomas', 'Disease', (297, 305))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('YWHAE', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('Trk', 'Gene', (60, 63))
191431	32034283	In both cases with KMT2D-BCOR fusions, the FISH assay could not identify the presence of BCOR gene abnormalities, likely due to cryptic gene rearrangements.	('BCOR', 'Gene', '54880', (25, 29))	('BCOR', 'Gene', '54880', (89, 93))	('KMT2D', 'Gene', (19, 24))	('KMT2D', 'Gene', '8085', (19, 24))	('fusions', 'Var', (30, 37))	('gene abnormalities', 'Disease', (94, 112))	('BCOR', 'Gene', (25, 29))	('gene abnormalities', 'Disease', 'MESH:D006623', (94, 112))	('BCOR', 'Gene', (89, 93))
191445	32034283	With the remarkable clinical benefit of targeted therapy in tumors harboring NTRK-related fusions, the screening strategies and correct diagnosis of these tumors have become critical.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('TRK', 'Gene', (78, 81))	('TRK', 'Gene', '4914', (78, 81))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('fusions', 'Var', (90, 97))	('tumors', 'Disease', (60, 66))
191451	32034283	Further investigation is warranted to explore if these NTRK specific inhibitors may also show clinical benefit in the tumors with BCOR and NTRK3 co-expression in the absence of NTRK fusions.	('TRK', 'Gene', '4914', (56, 59))	('NTRK3', 'Gene', '4916', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('TRK', 'Gene', (178, 181))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('TRK', 'Gene', (140, 143))	('TRK', 'Gene', '4914', (178, 181))	('BCOR', 'Gene', (130, 134))	('NTRK3', 'Gene', (139, 144))	('co-expression', 'Var', (145, 158))	('TRK', 'Gene', '4914', (140, 143))	('tumors', 'Disease', (118, 124))	('BCOR', 'Gene', '54880', (130, 134))	('TRK', 'Gene', (56, 59))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
191452	32034283	In the context of NTRK fusion positive tumors, the truncated TRK proteins acquire the ability of ligand-independent activation, whereas the consequence of overexpression of wild-type TRK-C as seen in these BCOR-upregulated tumors remains unclear.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('truncated', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('TRK', 'Gene', (61, 64))	('tumors', 'Disease', (39, 45))	('TRK-C', 'Gene', '4916', (183, 188))	('BCOR', 'Gene', '54880', (206, 210))	('TRK', 'Gene', (19, 22))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('TRK', 'Gene', '4914', (61, 64))	('TRK', 'Gene', (183, 186))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('BCOR', 'Gene', (206, 210))	('TRK-C', 'Gene', (183, 188))	('TRK', 'Gene', '4914', (19, 22))	('TRK', 'Gene', '4914', (183, 186))	('ligand-independent', 'Interaction', (97, 115))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('activation', 'PosReg', (116, 126))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
191453	32034283	In a prior array-based study, infantile fibrosarcomas with ETV6-NTRK3 fusion showed up-regulation of the truncated NTRK3 as well as several other genes encoding for receptor tyrosine kinase pathway inhibitors, such as SPRY4 and DUSP6, while a group of CCSK showed only up-regulation of NTRK3 but not SPRY4 and DUSP6.	('receptor tyrosine kinase', 'Gene', (165, 189))	('CCSK', 'Chemical', '-', (252, 256))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (40, 52))	('ETV6', 'Gene', '2120', (59, 63))	('DUSP6', 'Gene', (228, 233))	('NTRK3', 'Gene', (286, 291))	('SPRY4', 'Gene', (300, 305))	('NTRK3', 'Gene', '4916', (64, 69))	('truncated', 'Var', (105, 114))	('NTRK3', 'Gene', (64, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('SPRY4', 'Gene', '81848', (300, 305))	('SPRY4', 'Gene', (218, 223))	('ETV6', 'Gene', (59, 63))	('NTRK3', 'Gene', '4916', (115, 120))	('infantile fibrosarcomas', 'Disease', 'MESH:D005354', (30, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('DUSP6', 'Gene', '1848', (310, 315))	('NTRK3', 'Gene', (115, 120))	('up-regulation', 'PosReg', (84, 97))	('SPRY4', 'Gene', '81848', (218, 223))	('receptor tyrosine kinase', 'Gene', '5979', (165, 189))	('DUSP6', 'Gene', (310, 315))	('infantile fibrosarcomas', 'Disease', (30, 53))	('fusion', 'Var', (70, 76))	('DUSP6', 'Gene', '1848', (228, 233))	('NTRK3', 'Gene', '4916', (286, 291))
191456	32034283	In vitro experiments using TRK targeting strategies, including RNA interference and TRK inhibitor, have shown reduced colony formation and proliferation of cultured cells from CYLD mutant tumors.	('colony formation', 'CPA', (118, 134))	('mutant', 'Var', (181, 187))	('TRK', 'Gene', (84, 87))	('tumors', 'Disease', (188, 194))	('reduced', 'NegReg', (110, 117))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('TRK', 'Gene', '4914', (84, 87))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('CYLD', 'Gene', '1540', (176, 180))	('proliferation', 'CPA', (139, 152))	('TRK', 'Gene', (27, 30))	('CYLD', 'Gene', (176, 180))	('TRK', 'Gene', '4914', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('RNA interference', 'MPA', (63, 79))
191457	32034283	However, a phase 2 clinical trial exploring the usage of topical pegcantratinib, a potent TRKA inhibitor which also has activity against TRKB and TRKC, in the treatment of cutaneous CYLD defective tumors shows lack of response, which might be attributable to low drug concentration achieved in the tumors.	('pegcantratinib', 'Var', (65, 79))	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('TRKB', 'Gene', '4915', (137, 141))	('TRKA', 'Gene', '4914', (90, 94))	('cutaneous CYLD defective tumors', 'Disease', (172, 203))	('activity', 'MPA', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('TRKC', 'Gene', '4916', (146, 150))	('TRKC', 'Gene', (146, 150))	('TRKA', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('low drug concentration', 'Phenotype', 'HP:0020171', (259, 281))	('tumors', 'Disease', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('pegcantratinib', 'Chemical', 'MESH:C000626556', (65, 79))	('cutaneous CYLD defective tumors', 'Disease', 'MESH:D030342', (172, 203))	('TRKB', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Disease', (298, 304))
191458	32034283	The current study provides further evidence of genetic heterogeneity among undifferentiated sarcomas with BCOR fusions by reporting a novel BCOR-CHD9 and the second case with KMT2D-BCOR fusion.	('undifferentiated sarcomas', 'Disease', (75, 100))	('BCOR', 'Gene', '54880', (181, 185))	('BCOR', 'Gene', (106, 110))	('BCOR', 'Gene', '54880', (140, 144))	('fusions', 'Var', (111, 118))	('CHD9', 'Gene', '80205', (145, 149))	('KMT2D', 'Gene', (175, 180))	('KMT2D', 'Gene', '8085', (175, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (75, 100))	('BCOR', 'Gene', (181, 185))	('CHD9', 'Gene', (145, 149))	('BCOR', 'Gene', (140, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('BCOR', 'Gene', '54880', (106, 110))
191463	32034283	In the novel BCOR-CHD9 fusion identified in this study, exon 1 of BCOR was fused to exon 2 of CHD9, which was associated with lack of BCOR expression.	('BCOR', 'Gene', (66, 70))	('BCOR', 'Gene', '54880', (134, 138))	('fusion', 'Var', (23, 29))	('BCOR', 'Gene', '54880', (66, 70))	('CHD9', 'Gene', '80205', (18, 22))	('CHD9', 'Gene', '80205', (94, 98))	('CHD9', 'Gene', (18, 22))	('BCOR', 'Gene', (13, 17))	('CHD9', 'Gene', (94, 98))	('BCOR', 'Gene', (134, 138))	('BCOR', 'Gene', '54880', (13, 17))
191464	32034283	Intriguingly, up-regulated NTRK3 mRNA expression was demonstrated in all of the 4 tumors with KMT2D-BCOR (n=2), BCOR-CHD9 (n=1), or CIITA-BCOR (n=1) fusions.	('BCOR', 'Gene', (138, 142))	('CIITA', 'Gene', '4261', (132, 137))	('fusions', 'Var', (149, 156))	('tumors', 'Disease', (82, 88))	('CHD9', 'Gene', '80205', (117, 121))	('CHD9', 'Gene', (117, 121))	('BCOR', 'Gene', '54880', (112, 116))	('CIITA', 'Gene', (132, 137))	('up-regulated', 'PosReg', (14, 26))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('BCOR', 'Gene', (112, 116))	('KMT2D', 'Gene', (94, 99))	('BCOR', 'Gene', '54880', (100, 104))	('mRNA expression', 'MPA', (33, 48))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('NTRK3', 'Gene', '4916', (27, 32))	('BCOR', 'Gene', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('NTRK3', 'Gene', (27, 32))	('BCOR', 'Gene', '54880', (138, 142))	('KMT2D', 'Gene', '8085', (94, 99))
191466	32034283	Of note, in all tumors reported to date with KMT2D-BCOR, BCOR-CHD9, or CIITA-BCOR fusions, reciprocal fusion transcripts have been identified.	('CIITA', 'Gene', '4261', (71, 76))	('BCOR', 'Gene', '54880', (57, 61))	('tumors', 'Disease', (16, 22))	('KMT2D', 'Gene', '8085', (45, 50))	('BCOR', 'Gene', '54880', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('CHD9', 'Gene', '80205', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('fusions', 'Var', (82, 89))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('CHD9', 'Gene', (62, 66))	('BCOR', 'Gene', (57, 61))	('BCOR', 'Gene', (77, 81))	('BCOR', 'Gene', (51, 55))	('BCOR', 'Gene', '54880', (77, 81))	('KMT2D', 'Gene', (45, 50))	('CIITA', 'Gene', (71, 76))
191468	32034283	Diagnostic challenges might occur in diagnosing these rare BCOR fusions due to the lack of BCOR staining by immunohistochemistry, as in our BCOR-CHD9 case, as well as due to false negative FISH results for BCOR rearrangement, likely due to cryptic fusions, as seen in both our KMT2D-BCOR fusion cases and the reported CIITA-BCOR tumor.	('BCOR', 'Gene', '54880', (91, 95))	('BCOR', 'Gene', (91, 95))	('CIITA', 'Gene', '4261', (318, 323))	('tumor', 'Disease', (329, 334))	('BCOR', 'Gene', '54880', (206, 210))	('KMT2D', 'Gene', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('CIITA', 'Gene', (318, 323))	('BCOR', 'Gene', (206, 210))	('CHD9', 'Gene', '80205', (145, 149))	('BCOR', 'Gene', '54880', (324, 328))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('CHD9', 'Gene', (145, 149))	('BCOR', 'Gene', '54880', (283, 287))	('BCOR', 'Gene', '54880', (59, 63))	('BCOR', 'Gene', '54880', (140, 144))	('KMT2D', 'Gene', '8085', (277, 282))	('BCOR', 'Gene', (324, 328))	('BCOR', 'Gene', (283, 287))	('rearrangement', 'Var', (211, 224))	('BCOR', 'Gene', (59, 63))	('BCOR', 'Gene', (140, 144))
191470	32034283	Our results demonstrate that in the setting of an undifferentiated round to spindle cell neoplasm showing positivity for pan-Trk at immunohistochemical level, the differential diagnosis may include not only tumors with NTRK fusions, but also a large spectrum of sarcomas with BCOR genetic alterations as well as other BCOR expressing tumors, specifically SFT, and subsets of synovial sarcoma and Ewing sarcoma.	('sarcomas', 'Disease', 'MESH:D012509', (262, 270))	('sarcomas', 'Phenotype', 'HP:0100242', (262, 270))	('SFT', 'Disease', (355, 358))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('pan', 'Gene', '51816', (121, 124))	('tumors', 'Disease', (334, 340))	('sarcomas', 'Disease', (262, 270))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('TRK', 'Gene', '4914', (220, 223))	('genetic alterations', 'Var', (281, 300))	('tumors', 'Disease', (207, 213))	('BCOR', 'Gene', '54880', (318, 322))	('synovial sarcoma', 'Disease', (375, 391))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (396, 409))	('neoplasm', 'Disease', 'MESH:D009369', (89, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (396, 409))	('pan', 'Gene', (121, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (262, 269))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('synovial sarcoma', 'Disease', 'MESH:D013584', (375, 391))	('BCOR', 'Gene', '54880', (276, 280))	('BCOR', 'Gene', (318, 322))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('neoplasm', 'Disease', (89, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (402, 409))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (375, 391))	('BCOR', 'Gene', (276, 280))	('Trk', 'Gene', '4914', (125, 128))	('Ewing sarcoma', 'Disease', (396, 409))	('fusions', 'Var', (224, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (384, 391))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('TRK', 'Gene', (220, 223))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('Trk', 'Gene', (125, 128))
191480	28945501	A diagnosis of cancer in the past 5 years was more commonly reported by male General Practice Patient Survey responders who endorsed gay or bisexual orientation compared with heterosexual men (odds ratio [OR], 1.31; 95% CI, 1.15 to 1.49; P < .001) without evidence of a difference between lesbian or bisexual compared with heterosexual women (OR, 1.14; 95% CI, 0.94 to 1.37; P = .19).	('gay or bisexual orientation', 'Var', (133, 160))	('Patient', 'Species', '9606', (94, 101))	('men', 'Species', '9606', (338, 341))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('bisexual orientation', 'Phenotype', 'HP:0030214', (140, 160))	('women', 'Species', '9606', (336, 341))	('men', 'Species', '9606', (188, 191))	('heterosexual men', 'Phenotype', 'HP:0030214', (175, 191))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
191696	25999350	Aberrant activation of Wnt/beta-catenin signaling drives proliferation of bone sarcoma cells Bone sarcomas such as osteosarcoma and chondrosarcoma are frequently refractory to conventional chemotherapy and radiotherapy that exhibit poor prognosis.	('bone sarcoma cells Bone sarcomas', 'Phenotype', 'HP:0002669', (74, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('activation', 'PosReg', (9, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('sarcomas', 'Disease', (98, 106))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', '1499', (27, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('bone sarcoma', 'Disease', 'MESH:D001847', (74, 86))	('bone sarcoma', 'Phenotype', 'HP:0002669', (74, 86))	('osteosarcoma and chondrosarcoma', 'Disease', 'MESH:D002813', (115, 146))	('sarcomas', 'Disease', 'MESH:D012509', (98, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (115, 127))	('bone sarcoma', 'Disease', (74, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('beta-catenin', 'Gene', (27, 39))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (132, 146))
191712	25999350	Abnormalities in Wnt signaling are implicated in a variety of human tumors by mechanisms such as inactivating aberrations of APC, CTNNB1, or Axin1 (deletion), and through autocrine Wnt signaling recently recognized.	('aberrations', 'Var', (110, 121))	('tumors', 'Disease', (68, 74))	('Axin1', 'Gene', '8312', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('human', 'Species', '9606', (62, 67))	('CTNNB1', 'Gene', (130, 136))	('CTNNB1', 'Gene', '1499', (130, 136))	('Axin1', 'Gene', (141, 146))	('APC', 'Disease', 'MESH:D011125', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('inactivating aberrations', 'Var', (97, 121))	('implicated', 'Reg', (35, 45))	('APC', 'Disease', (125, 128))
191750	25999350	We also observed a marked increase in proliferation rates of SW1353 and U2OS cells after stimulation of Wnt3a (Figure 3D).	('Wnt3a', 'Gene', '89780', (104, 109))	('SW1353', 'Var', (61, 67))	('SW1353', 'CellLine', 'CVCL:0543', (61, 67))	('U2OS cells', 'CPA', (72, 82))	('U2OS', 'CellLine', 'CVCL:0042', (72, 76))	('Wnt3a', 'Gene', (104, 109))	('increase', 'PosReg', (26, 34))	('proliferation rates', 'CPA', (38, 57))
191754	25999350	Thus, inhibition of this activity allows beta-catenin to accumulate in the nucleus and activate TCF/LEF-dependent transcription.	('TCF/LEF', 'Gene', '3172', (96, 103))	('activate', 'PosReg', (87, 95))	('accumulate', 'PosReg', (57, 67))	('inhibition', 'Var', (6, 16))	('TCF/LEF', 'Gene', (96, 103))	('beta-catenin', 'Protein', (41, 53))
191755	25999350	In bone sarcoma SW1353 and U2OS cells, the GSK-3beta inhibitor SB-216763 substantially upregulated active beta-catenin while total beta-catenin had no detected change (Figure 4A), and enhanced reporter gene activity (Figure 4B).	('reporter gene activity', 'MPA', (193, 215))	('U2OS', 'CellLine', 'CVCL:0042', (27, 31))	('bone sarcoma', 'Disease', (3, 15))	('SW1353', 'CellLine', 'CVCL:0543', (16, 22))	('bone sarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('GSK-3beta', 'Gene', (43, 52))	('SB-216763', 'Var', (63, 72))	('SB-216763', 'Chemical', 'MESH:C417521', (63, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('bone sarcoma', 'Disease', 'MESH:D001847', (3, 15))	('GSK-3beta', 'Gene', '2932', (43, 52))	('upregulated', 'PosReg', (87, 98))	('active beta-catenin', 'MPA', (99, 118))	('enhanced', 'PosReg', (184, 192))
191756	25999350	Moreover, incubation of SW1353 and U2OS cells with the GSK-3beta inhibitor improved the survival in culture (Figure 4C), and attenuated apoptotic cell death (Figure 4D, 4E).	('improved', 'PosReg', (75, 83))	('survival in culture', 'CPA', (88, 107))	('inhibitor', 'Var', (65, 74))	('attenuated', 'NegReg', (125, 135))	('GSK-3beta', 'Gene', (55, 64))	('GSK-3beta', 'Gene', '2932', (55, 64))	('apoptotic cell death', 'CPA', (136, 156))	('U2OS', 'CellLine', 'CVCL:0042', (35, 39))	('SW1353', 'CellLine', 'CVCL:0543', (24, 30))
191761	25999350	Analyses of cell cycle profiles of bone sarcoma cells expressing dnTCF4 or siLEF indicated that growth inhibition was achieved either via G1 or G2 arrest (Figure 5E, 5F).	('dnTCF4', 'Chemical', '-', (65, 71))	('bone sarcoma', 'Phenotype', 'HP:0002669', (35, 47))	('G2 arrest', 'CPA', (144, 153))	('bone sarcoma cells', 'Disease', (35, 53))	('dnTCF4', 'Gene', (65, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('growth inhibition', 'CPA', (96, 113))	('siLEF', 'Var', (75, 80))	('bone sarcoma cells', 'Disease', 'MESH:D001847', (35, 53))
191766	25999350	Thus, disruption of autocrine activation of Wnt/beta-catenin signaling could be a novel attractive therapeutic target for bone sarcomas.	('bone sarcomas', 'Disease', 'MESH:D001847', (122, 135))	('bone sarcoma', 'Phenotype', 'HP:0002669', (122, 134))	('bone sarcomas', 'Disease', (122, 135))	('bone sarcomas', 'Phenotype', 'HP:0002669', (122, 135))	('disruption', 'Var', (6, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
191783	25999350	However, contradictory to these findings, the Wnt/beta-catenin pathway was inactivated in osteosarcoma and that the loss of Wnt-beta-catenin activity induces osteosarcoma development.	('Wnt/beta-catenin pathway', 'Pathway', (46, 70))	('osteosarcoma', 'Phenotype', 'HP:0002669', (158, 170))	('osteosarcoma', 'Disease', (158, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('osteosarcoma', 'Disease', 'MESH:D012516', (158, 170))	('osteosarcoma', 'Disease', (90, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('Wnt-beta-catenin', 'Protein', (124, 140))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))	('loss', 'Var', (116, 120))	('inactivated', 'NegReg', (75, 86))	('induces', 'Reg', (150, 157))
191794	25999350	Regarding as the relationship among Wnt6, Wnt7b and Wnt11, the noncanonical Wnt signaling, and tumorigenesis, Galbraith RL et al have reported that the polymorphisms in Wnt6 was associated with increased risk of colorectal adenoma, suggesting that Wnt6 may involve in tumorigenesis by initiating the noncanonical Wnt signaling.	('Wnt7b', 'Gene', (42, 47))	('Wnt6', 'Gene', (36, 40))	('Wnt7b', 'Gene', '7477', (42, 47))	('noncanonical', 'MPA', (300, 312))	('Wnt6', 'Gene', '7475', (248, 252))	('Wnt6', 'Gene', '7475', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('involve', 'Reg', (257, 264))	('polymorphisms', 'Var', (152, 165))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('colorectal adenoma', 'Disease', 'MESH:D015179', (212, 230))	('Wnt6', 'Gene', (248, 252))	('Wnt6', 'Gene', (169, 173))	('Wnt6', 'Gene', '7475', (36, 40))	('tumor', 'Disease', (95, 100))	('Wnt11', 'Gene', (52, 57))	('Wnt11', 'Gene', '7481', (52, 57))	('tumor', 'Disease', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('colorectal adenoma', 'Disease', (212, 230))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
191808	25999350	Independent evidence in support of this conclusion derived from the use of siRNAs directed against LRP6 that was markedly higher in bone sarcoma cells as shown in Figure 1H.	('LRP6', 'Gene', (99, 103))	('bone sarcoma', 'Phenotype', 'HP:0002669', (132, 144))	('bone sarcoma cells', 'Disease', 'MESH:D001847', (132, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('higher', 'PosReg', (122, 128))	('bone sarcoma cells', 'Disease', (132, 150))	('siRNAs', 'Var', (75, 81))	('LRP6', 'Gene', '4040', (99, 103))
191810	25999350	In contrast to human colon carcinomas and a variety of other tumors, in which Wnt activation involves genetic mutations in downstream signaling components, APC or beta-catenin, resulting in upregulation of this pathway, our findings have implied that an autocrine Wnt signaling loop plays a role in the etiology of human bone sarcomas.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('bone sarcoma', 'Phenotype', 'HP:0002669', (321, 333))	('bone sarcomas', 'Disease', 'MESH:D001847', (321, 334))	('bone sarcomas', 'Disease', (321, 334))	('bone sarcomas', 'Phenotype', 'HP:0002669', (321, 334))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (326, 333))	('upregulation', 'PosReg', (190, 202))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('human', 'Species', '9606', (15, 20))	('APC', 'Disease', 'MESH:D011125', (156, 159))	('APC', 'Disease', (156, 159))	('tumors', 'Disease', (61, 67))	('mutations', 'Var', (110, 119))	('colon carcinomas', 'Disease', (21, 37))	('colon carcinomas', 'Disease', 'MESH:D015179', (21, 37))	('human', 'Species', '9606', (315, 320))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (326, 334))
191812	25999350	In addition, the recent report has identified epigenetic silencing of WIF1 in some human osteosarcomas associated with upregulation of Wnt signaling.	('osteosarcomas', 'Disease', (89, 102))	('osteosarcomas', 'Phenotype', 'HP:0002669', (89, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcomas', 'Disease', 'MESH:D012516', (89, 102))	('WIF1', 'Gene', (70, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('human', 'Species', '9606', (83, 88))	('upregulation', 'PosReg', (119, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('epigenetic silencing', 'Var', (46, 66))	('WIF1', 'Gene', '11197', (70, 74))	('Wnt signaling', 'Pathway', (135, 148))
191813	25999350	Thus, whether autocrine Wnt signaling in bone sarcoma cells attributed to Wnt misexpression, aberrant upregulation of other components, or deregulation of Wnt antagonists remains to be elucidated.	('bone sarcoma cells', 'Disease', (41, 59))	('bone sarcoma', 'Phenotype', 'HP:0002669', (41, 53))	('upregulation', 'PosReg', (102, 114))	('misexpression', 'Var', (78, 91))	('bone sarcoma cells', 'Disease', 'MESH:D001847', (41, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
191814	25999350	However, our findings have identified autocrine Wnt signaling loop in bone sarcomas, providing a novel target for therapeutic intervention with DKK1 and FRP1 antagonists or other modalities and aiming interfering with cell surface interactions involving Wnts and their receptors.	('bone sarcomas', 'Phenotype', 'HP:0002669', (70, 83))	('FRP1', 'Gene', (153, 157))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))	('FRP1', 'Gene', '6422', (153, 157))	('cell surface', 'MPA', (218, 230))	('DKK1', 'Gene', '22943', (144, 148))	('DKK1', 'Gene', (144, 148))	('autocrine', 'MPA', (38, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('interfering', 'NegReg', (201, 212))	('antagonists', 'Var', (158, 169))	('interactions', 'Interaction', (231, 243))	('bone sarcomas', 'Disease', 'MESH:D001847', (70, 83))	('bone sarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('bone sarcomas', 'Disease', (70, 83))
191815	25999350	Our current study indicates that aberrant Wnt signaling drives the proliferation of bone sarcoma cells and could represent an important step in the pathogenesis of bone sarcomas.	('bone sarcomas', 'Phenotype', 'HP:0002669', (164, 177))	('bone sarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('bone sarcoma cells', 'Disease', 'MESH:D001847', (84, 102))	('Wnt signaling', 'Pathway', (42, 55))	('drives', 'PosReg', (56, 62))	('bone sarcoma cells', 'Disease', (84, 102))	('bone sarcomas', 'Disease', 'MESH:D001847', (164, 177))	('proliferation', 'CPA', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('bone sarcoma', 'Phenotype', 'HP:0002669', (164, 176))	('bone sarcomas', 'Disease', (164, 177))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('aberrant', 'Var', (33, 41))
191820	25999350	These findings were also supported by the previous study that inhibitions of GSK-3beta activate beta-catenin and attenuate the regulation of the mutant FLT3 receptor on the beta-catenin activity in leukemogenesis.	('FLT3', 'Gene', '2322', (152, 156))	('GSK-3beta', 'Gene', (77, 86))	('mutant', 'Var', (145, 151))	('FLT3', 'Gene', (152, 156))	('beta-catenin activity', 'MPA', (173, 194))	('leukemogenesis', 'Disease', (198, 212))	('activate', 'PosReg', (87, 95))	('attenuate', 'NegReg', (113, 122))	('GSK-3beta', 'Gene', '2932', (77, 86))	('regulation', 'MPA', (127, 137))	('beta-catenin', 'Protein', (96, 108))	('inhibitions', 'Var', (62, 73))
191830	25999350	Our findings are partly consistent with the observed effects of TCF downregulation on c-Myc levels in CRC lines mutant for APC or beta-catenin.	('c-Myc', 'Gene', '4609', (86, 91))	('CRC lines', 'Gene', (102, 111))	('APC', 'Disease', 'MESH:D011125', (123, 126))	('APC', 'Disease', (123, 126))	('c-Myc', 'Gene', (86, 91))	('downregulation', 'NegReg', (68, 82))	('mutant', 'Var', (112, 118))	('TCF', 'Gene', (64, 67))	('TCF', 'Gene', '3172', (64, 67))
191835	25999350	Autocrine activation of the canonical Wnt/beta-catenin signaling drives the proliferation of bone sarcoma cells, whereas antagonism of this pathway decreased the proliferation and induced cell cycle arrest.	('induced', 'Reg', (180, 187))	('bone sarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('bone sarcoma cells', 'Disease', (93, 111))	('decreased', 'NegReg', (148, 157))	('proliferation', 'CPA', (162, 175))	('antagonism', 'Var', (121, 131))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (188, 205))	('cell cycle arrest', 'CPA', (188, 205))	('bone sarcoma cells', 'Disease', 'MESH:D001847', (93, 111))
191836	25999350	Our findings have implied that aberrant activation of the Wnt/beta-catenin pathway drives the proliferation of bone sarcomas and identify the autocrine Wnt/beta-catenin signaling as a potential novel therapeutic target in bone sarcomas.	('bone sarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('bone sarcomas', 'Disease', 'MESH:D001847', (222, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('bone sarcoma', 'Phenotype', 'HP:0002669', (222, 234))	('aberrant', 'Var', (31, 39))	('bone sarcomas', 'Disease', (222, 235))	('bone sarcomas', 'Phenotype', 'HP:0002669', (111, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (227, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('activation', 'PosReg', (40, 50))	('Wnt/beta-catenin pathway', 'Pathway', (58, 82))	('proliferation', 'CPA', (94, 107))	('bone sarcomas', 'Phenotype', 'HP:0002669', (222, 235))	('bone sarcomas', 'Disease', 'MESH:D001847', (111, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('bone sarcomas', 'Disease', (111, 124))
191862	26152121	It commonly demonstrates reproducible staining of CD99 and translocations of the EWS gene.	('CD99', 'Gene', '4267', (50, 54))	('EWS', 'Gene', '2130', (81, 84))	('EWS', 'Gene', (81, 84))	('CD99', 'Gene', (50, 54))	('translocations', 'Var', (59, 73))
191888	26152121	A histology of small round cell bone tumor can be further confirmed as ES by immunohistochemical and cytogenetic analysis, which shows consistent chromosomal anomaly, the reciprocal translocation t(11; 22)(q24; q12).	('bone tumor', 'Disease', (32, 42))	('bone tumor', 'Phenotype', 'HP:0010622', (32, 42))	('bone tumor', 'Disease', 'MESH:D001859', (32, 42))	('ES', 'Phenotype', 'HP:0012254', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('chromosomal anomaly', 'Disease', (146, 165))	('t(11; 22)(q24; q12', 'Var', (196, 214))	('chromosomal anomaly', 'Disease', 'MESH:D002869', (146, 165))
192078	26604682	Considering two subgroup of patients with GMI <=1.33 and GMI >1.33, the median OS was 12.27 and 22.33 months, respectively, and GMI >1.33 was associated with a significant improvement of OS (P=0.03; Figure 4).	('GMI >1.33', 'Var', (128, 137))	('GMI >1.33', 'Var', (57, 66))	('GMI', 'Chemical', '-', (42, 45))	('GMI', 'Chemical', '-', (57, 60))	('GMI <=1.33', 'Var', (42, 52))	('OS', 'Chemical', '-', (79, 81))	('GMI', 'Chemical', '-', (128, 131))	('OS', 'Chemical', '-', (187, 189))	('patients', 'Species', '9606', (28, 36))	('improvement', 'PosReg', (172, 183))
192101	26604682	This data suggest that chimeric oncoproteins deriving from typical sarcoma translocations represent a potential therapeutic target more than a predictive factor.	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('chimeric', 'Var', (23, 31))	('sarcoma', 'Disease', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('oncoproteins', 'Protein', (32, 44))
192102	26604682	Indeed, the randomized Phase III trial of trabectedin vs standard doxorubicin-based chemotherapy as first-line therapy in 88 patients with pathologically confirmed translocation-related sarcomas did not show a significant superiority of any treatment.	('trabectedin', 'Chemical', 'MESH:D000077606', (42, 53))	('sarcomas', 'Disease', 'MESH:D012509', (186, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('sarcomas', 'Disease', (186, 194))	('translocation-related', 'Var', (164, 185))	('patients', 'Species', '9606', (125, 133))
192115	26604682	In our study, a GMI >1.33, considered to be an indicator of treatment activity, was associated with a significant improvement of OS (9.06 months, P=0.03).	('OS', 'Chemical', '-', (129, 131))	('improvement', 'PosReg', (114, 125))	('GMI', 'Chemical', '-', (16, 19))	('GMI >1.33', 'Var', (16, 25))
192140	22654630	The host response is also less effective because of the mismatch in major histocompatibility antigens between the organ donor and host, which reduces the efficacy of direct pathway antiviral cellular immune responses.	('donor', 'Species', '9606', (120, 125))	('mismatch', 'Var', (56, 64))	('direct pathway', 'Pathway', (166, 180))	('reduces', 'NegReg', (142, 149))
192163	22654630	On a pathological level, CMV can replicate in the kidney tissues and cause acute allograft dysfunction which usually improves with ganciclovir treatment and reduction of immunosuppression.	('acute allograft dysfunction', 'Disease', (75, 102))	('ganciclovir', 'Chemical', 'MESH:D015774', (131, 142))	('CMV', 'Var', (25, 28))	('acute allograft dysfunction', 'Disease', 'MESH:D065290', (75, 102))	('cause', 'Reg', (69, 74))
192164	22654630	Infection with CMV has also been implicated in chronic allograft nephropathy which is the major reason for the loss of renal allografts after the first year after transplantation.	('nephropathy', 'Disease', 'MESH:D007674', (65, 76))	('implicated in', 'Reg', (33, 46))	('chronic allograft nephropathy', 'Phenotype', 'HP:0004743', (47, 76))	('nephropathy', 'Phenotype', 'HP:0000112', (65, 76))	('nephropathy', 'Disease', (65, 76))	('CMV', 'Gene', (15, 18))	('Infection', 'Var', (0, 9))
192212	22654630	Other potential therapeutic agents for multidrug-resistant CMV include immunoglobulins, leflunomide and artesunate although data supporting their use remains anecdotal.	('CMV', 'Disease', (59, 62))	('artesunate', 'Chemical', 'MESH:D000077332', (104, 114))	('multidrug-resistant', 'Var', (39, 58))	('leflunomide', 'Chemical', 'MESH:D000077339', (88, 99))
192232	22654630	Acyclovir resistance may arise from mutations in the genes for thymidine kinase or DNA polymerase.	('arise from', 'Reg', (25, 35))	('Acyclovir resistance', 'MPA', (0, 20))	('Acyclovir', 'Chemical', 'MESH:D000212', (0, 9))	('mutations', 'Var', (36, 45))
192256	22654630	Since ninety percent of adults have antibodies to EBV by age 40, symptomatic infection is most commonly seen in pediatric populations.	('antibodies', 'Var', (36, 46))	('EBV', 'Chemical', '-', (50, 53))	('infection', 'Disease', (77, 86))	('EBV', 'Protein', (50, 53))	('infection', 'Disease', 'MESH:D007239', (77, 86))
192309	22654630	It is thought that sirolimus inhibits not only production of VEGF but also dampens its effects on endothelial cells, and it has been suggested that sirolimus inhibits the progression of Kaposi's sarcoma in kidney-transplant recipients while exerting an antirejection effect on organ allografts.	('VEGF', 'Gene', '7422', (61, 65))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (186, 202))	('inhibits', 'NegReg', (158, 166))	('sirolimus', 'Chemical', 'MESH:D020123', (148, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('sirolimus', 'Var', (148, 157))	('effects on endothelial cells', 'MPA', (87, 115))	("Kaposi's sarcoma", 'Disease', (186, 202))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (186, 202))	('dampens', 'NegReg', (75, 82))	('sirolimus', 'Chemical', 'MESH:D020123', (19, 28))	('VEGF', 'Gene', (61, 65))	('inhibits', 'NegReg', (29, 37))
192317	22654630	Accordingly, mismatched BKV serostatus between donor graft and recipient is significantly less frequent than cytomegalovirus mismatches and, in the absence of change, cannot explain the emergence of PVAN in the last decade.	('less', 'NegReg', (90, 94))	('BKV', 'Species', '1891762', (24, 27))	('mismatched', 'Var', (13, 23))	('donor', 'Species', '9606', (47, 52))
192339	22654630	Definitive diagnosis of BKVN requires a biopsy and demonstration of BKV inclusions in tubular epithelial or Bowman's capsular epithelial cells.	('BKV', 'Gene', (68, 71))	('inclusions', 'Var', (72, 82))	('BKV', 'Species', '1891762', (68, 71))	('BKV', 'Species', '1891762', (24, 27))
192372	22654630	Fabrizi and colleagues, in a subsequent meta-analysis, showed that HBsAg seropositive status was an independent risk factor for death.	('death', 'Disease', 'MESH:D003643', (128, 133))	('death', 'Disease', (128, 133))	('seropositive', 'Var', (73, 85))	('HBsAg', 'Gene', (67, 72))
192385	22654630	Reactivation may cause necroinflammatory liver injury with biochemical dysfunction.	('liver injury', 'Disease', 'MESH:D056486', (41, 53))	('biochemical dysfunction', 'Disease', (59, 82))	('cause', 'Reg', (17, 22))	('Reactivation', 'Var', (0, 12))	('liver injury', 'Disease', (41, 53))
192388	22654630	Another theory is the loss of protective immunity and infection by a mutated strain.	('mutated', 'Var', (69, 76))	('loss', 'NegReg', (22, 26))	('infection', 'Disease', (54, 63))	('infection', 'Disease', 'MESH:D007239', (54, 63))	('protective immunity', 'CPA', (30, 49))
192389	22654630	Naturally occurring mutations in the preC region and core promoter region are found in patients with long-standing chronic HBV infection.	('chronic HBV infection', 'Disease', (115, 136))	('found', 'Reg', (78, 83))	('chronic HBV infection', 'Disease', 'MESH:D006509', (115, 136))	('long-standing', 'Phenotype', 'HP:0003698', (101, 114))	('patients', 'Species', '9606', (87, 95))	('mutations', 'Var', (20, 29))
192392	22654630	Vaccination against HBV is recommended for all susceptible patients on dialysis (i.e., those having anti-hepatitis B surface titers b10 IU/mL).	('hepatitis B', 'Disease', (105, 116))	('b10 IU/mL', 'Var', (132, 141))	('HBV', 'Species', '10407', (20, 23))	('patients', 'Species', '9606', (59, 67))	('hepatitis', 'Phenotype', 'HP:0012115', (105, 114))	('hepatitis B', 'Disease', 'MESH:D006509', (105, 116))
192454	22654630	These viruses can lead to upper respiratory tract disease, as well as bronchitis, pneumonitis, and pneumonia.	('upper respiratory tract disease', 'Disease', (26, 57))	('pneumonitis', 'Disease', 'MESH:D011014', (82, 93))	('bronchitis', 'Phenotype', 'HP:0012387', (70, 80))	('upper respiratory tract disease', 'Disease', 'MESH:D012141', (26, 57))	('upper respiratory tract disease', 'Phenotype', 'HP:0002087', (26, 57))	('viruses', 'Var', (6, 13))	('bronchitis', 'Disease', (70, 80))	('pneumonia', 'Phenotype', 'HP:0002090', (99, 108))	('pneumonia', 'Disease', (99, 108))	('pneumonitis', 'Disease', (82, 93))	('lead to', 'Reg', (18, 25))	('pneumonia', 'Disease', 'MESH:D011014', (99, 108))	('bronchitis', 'Disease', 'MESH:D001991', (70, 80))
192455	22654630	Adenovirus can cause a multitude of complications including gastroenteritis, cystitis, and necrotizing hepatitis in addition to respiratory illness.	('gastroenteritis', 'Disease', 'MESH:D005759', (60, 75))	('necrotizing hepatitis', 'Disease', 'MESH:D047508', (91, 112))	('respiratory illness', 'Disease', 'MESH:D012131', (128, 147))	('hepatitis', 'Phenotype', 'HP:0012115', (103, 112))	('cystitis', 'Disease', (77, 85))	('cystitis', 'Disease', 'MESH:D003556', (77, 85))	('necrotizing hepatitis', 'Disease', (91, 112))	('gastroenteritis', 'Disease', (60, 75))	('Adenovirus', 'Var', (0, 10))	('respiratory illness', 'Disease', (128, 147))	('respiratory illness', 'Phenotype', 'HP:0011947', (128, 147))	('cause', 'Reg', (15, 20))
192460	22654630	In the renal transplant recipient, adenovirus can also cause nephritis, which presents with fever, renal dysfunction and liver function test abnormalities.	('adenovirus', 'Var', (35, 45))	('nephritis', 'Disease', 'MESH:D009393', (61, 70))	('renal dysfunction', 'Disease', 'MESH:D007674', (99, 116))	('nephritis', 'Disease', (61, 70))	('fever', 'Disease', 'MESH:D005334', (92, 97))	('nephritis', 'Phenotype', 'HP:0000123', (61, 70))	('fever', 'Disease', (92, 97))	('liver function test abnormalities', 'Phenotype', 'HP:0002910', (121, 154))	('fever', 'Phenotype', 'HP:0001945', (92, 97))	('renal dysfunction', 'Phenotype', 'HP:0000083', (99, 116))	('liver function test abnormalities', 'MPA', (121, 154))	('cause', 'Reg', (55, 60))	('renal dysfunction', 'Disease', (99, 116))
192487	33335731	Malignant gastrointestinal neuroectodermal tumor with BRAF mutation and a history of malignant melanoma: A case report Malignant gastrointestinal neuroectodermal tumors (GNETs), also called clear-cell sarcoma-like tumors of the gastrointestinal tract, are rare and highly aggressive tumors originating in the gastrointestinal tract.	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('mutation', 'Var', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('malignant melanoma', 'Disease', (85, 103))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('Malignant gastrointestinal neuroectodermal tumor', 'Disease', 'MESH:D017599', (119, 167))	('Malignant gastrointestinal neuroectodermal tumor', 'Disease', 'MESH:D017599', (0, 48))	('clear-cell sarcoma-like tumors', 'Disease', (190, 220))	('aggressive tumors', 'Disease', (272, 289))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Malignant gastrointestinal neuroectodermal tumors', 'Disease', 'MESH:D017599', (119, 168))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (146, 167))	('clear-cell sarcoma-like tumors', 'Disease', 'MESH:D018227', (190, 220))	('tumors of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (214, 250))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('aggressive tumors', 'Disease', 'MESH:D001523', (272, 289))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (146, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('malignant melanoma', 'Phenotype', 'HP:0002861', (85, 103))	('malignant melanoma', 'Disease', 'MESH:D008545', (85, 103))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (27, 48))	('Malignant gastrointestinal neuroectodermal tumor', 'Disease', (0, 48))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('Malignant gastrointestinal neuroectodermal tumors', 'Disease', (119, 168))	('tumors originating in the gastrointestinal tract', 'Phenotype', 'HP:0007378', (283, 331))
192491	33335731	The present case reports a woman with a history of desmoplastic malignant melanoma exhibiting a BRAF mutation, which later transformed into a GNET of the small intestine with both a BRAF mutation and two subtypes of EWSR1-ATF1 fusion genes.	('ATF1', 'Gene', '466', (222, 226))	('EWSR1', 'Gene', '2130', (216, 221))	('ATF1', 'Gene', (222, 226))	('mutation', 'Var', (101, 109))	('desmoplastic malignant melanoma', 'Disease', 'MESH:D008545', (51, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('BRAF', 'Gene', '673', (182, 186))	('BRAF', 'Gene', (96, 100))	('woman', 'Species', '9606', (27, 32))	('BRAF', 'Gene', '673', (96, 100))	('desmoplastic malignant melanoma', 'Disease', (51, 82))	('BRAF', 'Gene', (182, 186))	('malignant melanoma', 'Phenotype', 'HP:0002861', (64, 82))	('EWSR1', 'Gene', (216, 221))
192495	33335731	Furthermore, there is no report of GNET exhibiting both a BRAF mutation and an EWSR1-ATF1 fusion gene.	('EWSR1', 'Gene', (79, 84))	('ATF1', 'Gene', '466', (85, 89))	('EWSR1', 'Gene', '2130', (79, 84))	('mutation', 'Var', (63, 71))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))	('ATF1', 'Gene', (85, 89))
192496	33335731	Further accumulation of similar cases is necessary to elucidate the pathological significance of this GNET having a BRAF mutation.	('BRAF', 'Gene', '673', (116, 120))	('mutation', 'Var', (121, 129))	('BRAF', 'Gene', (116, 120))
192503	33335731	Here, we present a unique case of a GNET that has a history of desmoplastic malignant melanoma exhibiting a BRAF mutation, which later transformed into a GNET of the small intestine with both a BRAF mutation and two subtypes of the EWSR1-ATF1 fusion gene.	('mutation', 'Var', (113, 121))	('BRAF', 'Gene', '673', (194, 198))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('desmoplastic malignant melanoma', 'Disease', 'MESH:D008545', (63, 94))	('BRAF', 'Gene', (194, 198))	('malignant melanoma', 'Phenotype', 'HP:0002861', (76, 94))	('EWSR1', 'Gene', (232, 237))	('desmoplastic malignant melanoma', 'Disease', (63, 94))	('BRAF', 'Gene', '673', (108, 112))	('ATF1', 'Gene', (238, 242))	('ATF1', 'Gene', '466', (238, 242))	('EWSR1', 'Gene', '2130', (232, 237))	('BRAF', 'Gene', (108, 112))
192524	33335731	In June 2018, the histological diagnosis of the previous samples at the time of recurrence of MM was finally established as desmoplastic MM with a BRAF mutation.	('desmoplastic MM', 'Disease', 'MESH:D018220', (124, 139))	('desmoplastic MM', 'Disease', (124, 139))	('BRAF', 'Gene', '673', (147, 151))	('BRAF', 'Gene', (147, 151))	('mutation', 'Var', (152, 160))
192525	33335731	Therefore, the BRAF gene status of the small intestinal and left forearm tumors were checked, and both tissues were found to exhibit a BRAF mutation.	('BRAF', 'Gene', '673', (15, 19))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('BRAF', 'Gene', '673', (135, 139))	('BRAF', 'Gene', (15, 19))	('BRAF', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutation', 'Var', (140, 148))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))
192526	33335731	Her GNET was diagnosed as double-positive for BRAF mutation and EWSR1-ATF1 fusion transcript.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('EWSR1', 'Gene', '2130', (64, 69))	('ATF1', 'Gene', (70, 74))	('mutation', 'Var', (51, 59))	('ATF1', 'Gene', '466', (70, 74))	('EWSR1', 'Gene', (64, 69))
192541	33335731	Other immunohistochemical findings were as follows: CK AE1/3(+, focal), CK CAM5.2(+, focal), CD56(+, focal; Fig.	('CK AE1/3', 'Var', (52, 60))	('CD56', 'Gene', (93, 97))	('CD56', 'Gene', '4684', (93, 97))
192545	33335731	All BRAF mutation analyses were consigned to LSI Medience Corporation (Tokyo) and were performed using real-time PCR techniques.	('mutation', 'Var', (9, 17))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))
192546	33335731	BRAF mutations (V600E) were detected in Samples 2, 3 and 4.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Mutation', 'rs113488022', (16, 21))	('V600E', 'Var', (16, 21))
192557	33335731	Thway and Fisher reviewed the clinicopathological and molecular features of five diverse neoplasms that frequently exhibit EWSR1-CREB1 or EWSR1-ATF1 genetic fusion: Angiomatoid fibrous histiocytoma, conventional CCS (of tendons and aponeuroses), CCSLGT, hyalinizing CCS of the salivary gland and primary pulmonary myxoid sarcoma.	('EWSR1', 'Gene', '2130', (123, 128))	('Angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (165, 197))	('genetic', 'Var', (149, 156))	('ATF1', 'Gene', (144, 148))	('neoplasms', 'Disease', (89, 98))	('EWSR1', 'Gene', (138, 143))	('ATF1', 'Gene', '466', (144, 148))	('CCSLGT', 'Disease', (246, 252))	('histiocytoma', 'Phenotype', 'HP:0012315', (185, 197))	('EWSR1', 'Gene', (123, 128))	('Angiomatoid fibrous histiocytoma', 'Disease', (165, 197))	('pulmonary myxoid sarcoma', 'Disease', (304, 328))	('neoplasms', 'Phenotype', 'HP:0002664', (89, 98))	('CREB1', 'Gene', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (321, 328))	('conventional CCS', 'Disease', (199, 215))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('CREB1', 'Gene', '1385', (129, 134))	('EWSR1', 'Gene', '2130', (138, 143))	('pulmonary myxoid sarcoma', 'Disease', 'MESH:D012509', (304, 328))	('hyalinizing CCS of the salivary gland', 'Disease', (254, 291))	('neoplasms', 'Disease', 'MESH:D009369', (89, 98))
192566	33335731	In addition, this tumor exhibited both a BRAF mutation and EWSR1-ATF1 fusion.	('EWSR1', 'Gene', (59, 64))	('exhibited', 'Reg', (24, 33))	('tumor', 'Disease', (18, 23))	('EWSR1', 'Gene', '2130', (59, 64))	('ATF1', 'Gene', (65, 69))	('ATF1', 'Gene', '466', (65, 69))	('BRAF', 'Gene', '673', (41, 45))	('BRAF', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mutation', 'Var', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
192567	33335731	Such cases have rarely been reported with CCS; however, to the best of our knowledge, no case report of a GNET with both a BRAF mutation and EWSR1-ATF1 fusion gene exists so far.	('ATF1', 'Gene', (147, 151))	('ATF1', 'Gene', '466', (147, 151))	('EWSR1', 'Gene', (141, 146))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('EWSR1', 'Gene', '2130', (141, 146))	('mutation', 'Var', (128, 136))
192570	33335731	It should be noted that the patient's past MM and GNET are morphologically and immunohistochemically different neoplasms, but both tumors exhibited BRAF mutations.	('exhibited', 'Reg', (138, 147))	('mutations', 'Var', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('neoplasms', 'Disease', 'MESH:D009369', (111, 120))	('neoplasms', 'Disease', (111, 120))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('neoplasm', 'Phenotype', 'HP:0002664', (111, 119))	('patient', 'Species', '9606', (28, 35))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('BRAF', 'Gene', '673', (148, 152))	('neoplasms', 'Phenotype', 'HP:0002664', (111, 120))	('BRAF', 'Gene', (148, 152))
192571	33335731	Therefore, our case suggests one hypothesis for the pathogenetic process of her GNET: Her desmoplastic MM exhibiting a BRAF mutation acquired an additional EWSR1-ATF1 fusion gene and changed its morphology to a GNET-like one.	('EWSR1', 'Gene', '2130', (156, 161))	('ATF1', 'Gene', (162, 166))	('changed', 'Reg', (183, 190))	('BRAF', 'Gene', '673', (119, 123))	('desmoplastic MM', 'Disease', 'MESH:D018220', (90, 105))	('desmoplastic MM', 'Disease', (90, 105))	('BRAF', 'Gene', (119, 123))	('ATF1', 'Gene', '466', (162, 166))	('EWSR1', 'Gene', (156, 161))	('morphology', 'MPA', (195, 205))	('mutation', 'Var', (124, 132))
192573	33335731	Therefore, the combination of BRAF mutation analysis and EWSR1 fusion gene detection has attracted a significant amount of attention as a means of differentiating CCS from MM.	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('EWSR1', 'Gene', (57, 62))	('CCS', 'Disease', (163, 166))	('mutation analysis', 'Var', (35, 52))	('EWSR1', 'Gene', '2130', (57, 62))
192574	33335731	Our patient's GNET exhibited both a BRAF mutation and EWSR1-ATF1 fusion genes, and combination therapy with dabrafenib mesylate and trametinib dimethyl sulfoxide proved to be temporarily effective.	('dabrafenib mesylate', 'Chemical', '-', (108, 127))	('BRAF', 'Gene', (36, 40))	('EWSR1', 'Gene', '2130', (54, 59))	('patient', 'Species', '9606', (4, 11))	('exhibited', 'Reg', (19, 28))	('mutation', 'Var', (41, 49))	('EWSR1', 'Gene', (54, 59))	('ATF1', 'Gene', (60, 64))	('trametinib dimethyl sulfoxide', 'Chemical', '-', (132, 161))	('BRAF', 'Gene', '673', (36, 40))	('ATF1', 'Gene', '466', (60, 64))
192575	33335731	In summary, we reported the case of a woman with a history of desmoplastic MM exhibiting a BRAF mutation, which later transformed into a GNET exhibiting both a BRAF mutation and two subtypes of EWSR1-ATF1 fusion genes.	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('desmoplastic MM', 'Disease', 'MESH:D018220', (62, 77))	('desmoplastic MM', 'Disease', (62, 77))	('BRAF', 'Gene', '673', (91, 95))	('mutation', 'Var', (96, 104))	('BRAF', 'Gene', (91, 95))	('EWSR1', 'Gene', (194, 199))	('ATF1', 'Gene', (200, 204))	('ATF1', 'Gene', '466', (200, 204))	('woman', 'Species', '9606', (38, 43))	('EWSR1', 'Gene', '2130', (194, 199))
192642	30781855	Third, sarcomas have high complexity at the molecular level, classifying them into two groups: genetically simple sarcomas, such as those bearing specific genetic alterations, and sarcomas with multiple, complex karyotypic abnormalities with no specific pattern.	('genetic alterations', 'Var', (155, 174))	('sarcomas', 'Disease', 'MESH:D012509', (7, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (7, 15))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', (114, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('sarcomas', 'Disease', (180, 188))	('sarcomas', 'Disease', (7, 15))
192649	30781855	For example, a tyrosine kinase inhibitor, imatinib mesylate, was originally developed for the treatment of chronic myelocytic leukemia, which has a unique chromosome translocation; later, imatinib mesylate was repurposed to gastrointestinal stromal tumor (GIST), which is characterized by mutations or overexpression of c-kit and PDGFR.	('chronic myelocytic leukemia', 'Phenotype', 'HP:0005506', (107, 134))	('PDGFR', 'Gene', (330, 335))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (188, 205))	('chronic myelocytic leukemia', 'Disease', 'MESH:D015464', (107, 134))	('PDGFR', 'Gene', '5159', (330, 335))	('mutations', 'Var', (289, 298))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (224, 254))	('GIST', 'Phenotype', 'HP:0100723', (256, 260))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (42, 59))	('c-kit', 'Gene', '3815', (320, 325))	('c-kit', 'Gene', (320, 325))	('chronic myelocytic leukemia', 'Disease', (107, 134))	('overexpression', 'PosReg', (302, 316))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (224, 254))	('myelocytic leukemia', 'Phenotype', 'HP:0012324', (115, 134))	('gastrointestinal stromal tumor', 'Disease', (224, 254))
192688	30781855	By searching the Ximbio website, three cell lines were additionally recognized in the cell bank: 2C4 gamma1A/JAK2 (fibrosarcoma), S_M6R1 (osteosarcoma), and S_N40R2 (osteosarcoma).	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (115, 127))	('fibrosarcoma', 'Disease', 'MESH:D005354', (115, 127))	('S_N40R2', 'Var', (157, 164))	('JAK2', 'Gene', (109, 113))	('osteosarcoma', 'Phenotype', 'HP:0002669', (138, 150))	('osteosarcoma', 'Disease', (138, 150))	('osteosarcoma', 'Phenotype', 'HP:0002669', (166, 178))	('osteosarcoma', 'Disease', (166, 178))	('osteosarcoma', 'Disease', 'MESH:D012516', (138, 150))	('osteosarcoma', 'Disease', 'MESH:D012516', (166, 178))	('fibrosarcoma', 'Disease', (115, 127))	('S_M6R1', 'Var', (130, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('JAK2', 'Gene', '3717', (109, 113))
192769	29878363	Similarly, an R2 resection (HR = 6.52, P = 0.032) was independently associated with inferior OS along with the presence of tumor thrombus (HR 4.91, P = 0.025) (Table 4).	('inferior OS', 'Disease', (84, 95))	('associated', 'Reg', (68, 78))	('tumor thrombus', 'Disease', (123, 137))	('tumor thrombus', 'Disease', 'MESH:D013927', (123, 137))	('R2 resection', 'Var', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
192784	29878363	Previous reports have associated a higher risk of VTE with polytetrafluoroethylene (PTFE) graft reconstruction compared to patch or primary repair.	('PTFE', 'Chemical', 'MESH:D011138', (84, 88))	('polytetrafluoroethylene', 'Chemical', 'MESH:D011138', (59, 82))	('VTE', 'Disease', 'MESH:D054556', (50, 53))	('polytetrafluoroethylene', 'Var', (59, 82))	('VTE', 'Disease', (50, 53))
192813	29878363	Within the cohort of IVC resected patients, positive margins and increasing concomitant multivisceral resections were associated with inferior survival.	('positive margins', 'Var', (44, 60))	('patients', 'Species', '9606', (34, 42))	('inferior', 'NegReg', (134, 142))
192962	32245786	In multivariable logistic regression analyses, synovial sarcoma was more frequent in Hispanics compared with non-Hispanic whites [OR, 1.48; 95% confidence interval (CI), 1.06-2.08].	('Hispanics', 'Var', (85, 94))	('synovial sarcoma', 'Disease', (47, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (47, 63))	('synovial sarcoma', 'Disease', 'MESH:D013584', (47, 63))
192969	32245786	A primary characterizing feature of synovial sarcoma is the t(X;18; p11;q11) translocation resulting in a fusion between the entire coding region of the SS18 gene and a portion of an SSX gene (SSX1, SSX2, or SSX4; ref.	('SSX4', 'Gene', '6759', (208, 212))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (36, 52))	('SSX2', 'Gene', '6757', (199, 203))	('translocation', 'Var', (77, 90))	('SSX', 'Gene', '6757', (193, 196))	('SS18', 'Gene', (153, 157))	('fusion', 'Interaction', (106, 112))	('SSX1', 'Gene', '6756', (193, 197))	('SSX', 'Gene', '6757', (183, 186))	('SSX1', 'Gene', (193, 197))	('SSX', 'Gene', (193, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('SSX', 'Gene', '6757', (208, 211))	('SSX', 'Gene', '6757', (199, 202))	('SS18', 'Gene', '6760', (153, 157))	('synovial sarcoma', 'Disease', (36, 52))	('SSX', 'Gene', (183, 186))	('SSX4', 'Gene', (208, 212))	('SSX', 'Gene', (208, 211))	('synovial sarcoma', 'Disease', 'MESH:D013584', (36, 52))	('SSX', 'Gene', (199, 202))	('SSX2', 'Gene', (199, 203))
192981	32245786	Similar analyses were performed for comparison on additional sarcomas including Ewing sarcoma (ICD-O-3 code 9260; 353 cases), osteosarcoma (ICD-O-3 codes: 9180-83, 9185-87, and 9192-95; 576 cases), and rhabdomyosarcoma (ICD-O-3 codes: 8900-02, 8910, 8912, 8920, and 8991; 719 cases).	('osteosarcoma', 'Disease', (126, 138))	('8912', 'Var', (250, 254))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (202, 218))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (202, 218))	('sarcomas', 'Disease', 'MESH:D012509', (61, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('sarcomas', 'Disease', (61, 69))	('8910', 'Var', (244, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('Ewing sarcoma', 'Disease', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('9185-87', 'Var', (164, 171))	('rhabdomyosarcoma', 'Disease', (202, 218))
192982	32245786	Of the 244 cases with synovial sarcoma, 94 were recorded with ICD-O-3 code 9040 (synovial, not otherwise specified), 92 with ICD-O-3 code 9041 (spindle cell), one with ICD-O-3 code 9042 (epithelioid), and 57 with ICD-O-3 code 9043 (biphasic).	('ICD-O-3 code 9041', 'Var', (125, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('ICD-O-3 code 9040', 'Var', (62, 79))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (22, 38))	('synovial sarcoma', 'Disease', 'MESH:D013584', (22, 38))	('synovial sarcoma', 'Disease', (22, 38))
192992	32245786	For instance, paternal age over 40 years was associated with an OR of 1.90 (95% CI, 1.07-3.35; Table 2) when adjusting for maternal age and other covariates for synovial sarcoma overall.	('synovial sarcoma', 'Disease', (161, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('paternal age', 'Var', (14, 26))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (161, 177))	('synovial sarcoma', 'Disease', 'MESH:D013584', (161, 177))
193013	32245786	Paternal age is associated with epigenetic changes, DNA mutations, and aneuploidy, which are all characteristics of cancer cells and as such may contribute to risk should such features be contributed to the germline.	('associated', 'Reg', (16, 26))	('epigenetic changes', 'Var', (32, 50))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('aneuploidy', 'Disease', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('contribute', 'Reg', (145, 155))	('DNA mutations', 'Var', (52, 65))	('aneuploidy', 'Disease', 'MESH:D000782', (71, 81))
193035	32351891	Overall, sarcomas can be classified in two comprehensive genetic groups depending on the chromosomal aberration occurring in the genome: those harboring specific genetic alterations like activating mutations and/or translocations showing simple karyotypes (which represent almost 30% of all sarcomas) and those with more complexity on karyotypes.	('activating', 'Gene', (187, 197))	('sarcomas', 'Disease', (291, 299))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('translocations', 'Var', (215, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('sarcomas', 'Disease', 'MESH:D012509', (291, 299))	('sarcomas', 'Disease', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (291, 299))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (89, 111))
193036	32351891	The gene fusions resulting from specific translocations encoding chimeric transcription factors affecting transcriptional regulation of target genes are frequently detected in sarcomas, while others encode chimeric growth factors or protein tyrosine kinases.	('translocations', 'Var', (41, 55))	('sarcomas', 'Disease', 'MESH:D012509', (176, 184))	('transcriptional regulation', 'MPA', (106, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('sarcomas', 'Disease', (176, 184))	('detected', 'Reg', (164, 172))
193045	32351891	Genetic variability harboring in the germline genome of the patient can influence systemic pharmacokinetics and pharmacodynamics of the treatments, acting as prognostic biomarkers for drug-induced toxicity and treatment efficacy.	('patient', 'Species', '9606', (60, 67))	('Genetic variability', 'Var', (0, 19))	('influence', 'Reg', (72, 81))	('systemic pharmacokinetics', 'MPA', (82, 107))	('pharmacodynamics', 'MPA', (112, 128))	('toxicity', 'Disease', 'MESH:D064420', (197, 205))	('toxicity', 'Disease', (197, 205))
193046	32351891	Instead, the aberrations in cancer somatic genome mostly function as drug targets and they can be used to select treatment or to be predictive of response to treatment.	('aberrations', 'Var', (13, 24))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))
193047	32351891	Very penetrant predisposed mutations and frequent genetic variants particularly single-nucleotide polymorphisms (SNPs) which heredity pass between the generations represent the mostly germline variations that are considered as useful biomarkers for ADR and drug response.	('mutations', 'Var', (27, 36))	('ADR', 'Gene', (249, 252))	('single-nucleotide polymorphisms', 'Var', (80, 111))	('ADR', 'Gene', '231', (249, 252))
193055	32351891	Additionally, the association of BRCA mutational status with improved clinical response to trabectedin explains the specific sensitivity of STS patients to this drug.	('improved', 'PosReg', (61, 69))	('mutational status', 'Var', (38, 55))	('trabectedin', 'Chemical', 'MESH:D000077606', (91, 102))	('patients', 'Species', '9606', (144, 152))	('BRCA', 'Gene', '672', (33, 37))	('STS', 'Phenotype', 'HP:0030448', (140, 143))	('BRCA', 'Gene', (33, 37))	('clinical response', 'MPA', (70, 87))
193056	32351891	Several clinical studies confirmed an improved prognosis and overall survival in patients carrying germline mutation or absence of BRCA compared to non-carriers.	('improved', 'PosReg', (38, 46))	('prognosis', 'CPA', (47, 56))	('absence', 'NegReg', (120, 127))	('BRCA', 'Gene', '672', (131, 135))	('patients', 'Species', '9606', (81, 89))	('germline mutation', 'Var', (99, 116))	('BRCA', 'Gene', (131, 135))	('overall survival', 'CPA', (61, 77))
193061	32351891	The authors revealed a complete rapid response following trabectedin treatment linking this positive effect to the loss of heterozygosity (LOH) of the mutated BRCA2 gene.	('trabectedin', 'Chemical', 'MESH:D000077606', (57, 68))	('BRCA2', 'Gene', (159, 164))	('BRCA2', 'Gene', '675', (159, 164))	('mutated', 'Var', (151, 158))
193062	32351891	These analyses corroborate the assumption that different DNA repair defects existing in tumors positively conditioned the response to trabectedin and that BRCAness malignant genotype is significant in influencing the effectiveness of treatment including trabectedin.	('conditioned', 'Reg', (106, 117))	('trabectedin', 'Chemical', 'MESH:D000077606', (254, 265))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('response to trabectedin', 'MPA', (122, 145))	('trabectedin', 'Chemical', 'MESH:D000077606', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('defects', 'Var', (68, 75))	('tumors', 'Disease', (88, 94))	('BRCAness malignant', 'Disease', (155, 173))	('BRCAness malignant', 'Disease', 'MESH:D009369', (155, 173))
193064	32351891	Mutation in tyrosine protein kinase KIT and platelet-derived growth factor receptors (PDGFRA) genes are present in 75-80% and 5-10% of GISTs, respectively with their consequent constitutive activation.	('activation', 'PosReg', (190, 200))	('KIT', 'Gene', '3815', (36, 39))	('PDGFRA', 'Gene', '5156', (86, 92))	('PDGFRA', 'Gene', (86, 92))	('Mutation', 'Var', (0, 8))	('KIT', 'Gene', (36, 39))	('GIST', 'Phenotype', 'HP:0100723', (135, 139))
193068	32351891	Commonly, GISTs harbor KIT mutation in exon 11 and less frequently in exon 13 in imatinib-naive patients, while exon 9 mutation reduces sensitivity and the rare KIT exon 17 mutations (e.g., D816V) exert resistance to imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (217, 225))	('exert', 'Reg', (197, 202))	('KIT', 'Gene', '3815', (23, 26))	('reduces', 'NegReg', (128, 135))	('KIT', 'Gene', (23, 26))	('KIT', 'Gene', '3815', (161, 164))	('GIST', 'Phenotype', 'HP:0100723', (10, 14))	('D816V', 'Var', (190, 195))	('imatinib', 'Chemical', 'MESH:D000068877', (81, 89))	('patients', 'Species', '9606', (96, 104))	('D816V', 'Mutation', 'rs121913507', (190, 195))	('sensitivity', 'MPA', (136, 147))	('KIT', 'Gene', (161, 164))	('resistance to imatinib', 'MPA', (203, 225))
193069	32351891	Moreover, the common D842V mutation in PDGRFA gene is correlated to imatinib, sunitinib, and regorafenib resistance, whereas wild-type GISTs negative for KIT/PDGRFA mutations are insensitive to imatinib.	('D842V', 'Var', (21, 26))	('KIT', 'Gene', '3815', (154, 157))	('imatinib', 'Chemical', 'MESH:D000068877', (194, 202))	('regorafenib resistance', 'MPA', (93, 115))	('D842V', 'Mutation', 'p.D842V', (21, 26))	('KIT', 'Gene', (154, 157))	('sunitinib', 'MPA', (78, 87))	('sunitinib', 'Chemical', 'MESH:D000077210', (78, 87))	('correlated', 'Reg', (54, 64))	('imatinib', 'Chemical', 'MESH:D000068877', (68, 76))	('regorafenib', 'Chemical', 'MESH:C559147', (93, 104))	('PDGRFA', 'Gene', (39, 45))	('GIST', 'Phenotype', 'HP:0100723', (135, 139))	('imatinib', 'MPA', (68, 76))
193071	32351891	Analysis of SNPs variant in VEGFRA2, VEGFA, and Solute Carrier Organic Anion Transporter Family Member 1B3 (SLCO1B3) display a correlation of these SNPs with PFS in patients with advanced GIST receiving imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (203, 211))	('VEGFA', 'Gene', '7422', (37, 42))	('SLCO1B3', 'Gene', '28234', (108, 115))	('GIST', 'Phenotype', 'HP:0100723', (188, 192))	('VEGFR', 'Gene', '3791', (28, 33))	('VEGFA', 'Gene', (37, 42))	('PFS', 'Disease', (158, 161))	('correlation', 'Reg', (127, 138))	('variant', 'Var', (17, 24))	('VEGFR', 'Gene', (28, 33))	('Solute Carrier Organic Anion Transporter Family Member 1B3', 'Gene', '28234', (48, 106))	('patients', 'Species', '9606', (165, 173))	('SLCO1B3', 'Gene', (108, 115))
193075	32351891	More specifically, PFS was significantly extended in carriers rs1056878 (TT genotype) in Cytochrome p450 oxidoreductase (POR).	('rs1056878', 'Var', (62, 71))	('POR', 'Gene', (121, 124))	('Cytochrome p450 oxidoreductase', 'Gene', '5447', (89, 119))	('rs1056878', 'Mutation', 'rs1056878', (62, 71))	('POR', 'Gene', '5447', (121, 124))	('extended', 'PosReg', (41, 49))	('Cytochrome p450 oxidoreductase', 'Gene', (89, 119))
193076	32351891	Otherwise, the presence in patients carrying the T-allele in SLCO1B3 rs4149117, the CCC-CCC alleles in SLC22A5 haplotype, and the GC-GC alleles in the IL4 R haplotype were predictive for OS.	('SLC22A5', 'Gene', '6584', (103, 110))	('SLC22A5', 'Gene', (103, 110))	('rs4149117', 'Mutation', 'rs4149117', (69, 78))	('IL4 R', 'Gene', '3566', (151, 156))	('IL4 R', 'Gene', (151, 156))	('patients', 'Species', '9606', (27, 35))	('SLCO1B3', 'Gene', (61, 68))	('rs4149117', 'Var', (69, 78))	('SLCO1B3', 'Gene', '28234', (61, 68))
193080	32351891	Recent data provide innovative understanding connecting the pazopanib-associated hepatotoxicity to an immune-mediated mechanism in some patients, demonstrating that HLA-B*57:01 allele carriage is correlated with elevated ALT values in these patients and identifying genetic PGx predicting liver damage.	('HLA-B', 'Gene', '3106', (165, 170))	('hepatotoxicity', 'Disease', 'MESH:D056486', (81, 95))	('pazopanib', 'Chemical', 'MESH:C516667', (60, 69))	('elevated ALT', 'Phenotype', 'HP:0031964', (212, 224))	('elevated', 'PosReg', (212, 220))	('hepatotoxicity', 'Disease', (81, 95))	('liver damage', 'Disease', (289, 301))	('patients', 'Species', '9606', (136, 144))	('ALT values', 'MPA', (221, 231))	('liver damage', 'Disease', 'MESH:D056486', (289, 301))	('HLA-B', 'Gene', (165, 170))	('patients', 'Species', '9606', (241, 249))	('carriage', 'Var', (184, 192))
193081	32351891	Whole-exome sequencing (WES) data analysis of 206 sarcomas of different histotypes identifies TP53, ATRX, and RB1 significantly mutated genes across sarcoma histotypes where TP53 mutations were most prevalent in leiomyosarcoma and RB1 mutations were seen in leiomyosarcoma, undifferentiated pleomorphic sarcoma, and myxofibrosarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (258, 272))	('RB1', 'Gene', (110, 113))	('TP53', 'Gene', (174, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (303, 310))	('sarcoma', 'Disease', (149, 156))	('ATRX', 'Gene', (100, 104))	('myxofibrosarcoma', 'Disease', 'None', (316, 332))	('TP53', 'Gene', (94, 98))	('ATRX', 'Gene', '546', (100, 104))	('undifferentiated pleomorphic sarcoma', 'Disease', (274, 310))	('sarcoma', 'Disease', 'MESH:D012509', (219, 226))	('RB1', 'Gene', '5925', (231, 234))	('prevalent', 'Reg', (199, 208))	('sarcoma', 'Disease', (219, 226))	('leiomyosarcoma', 'Disease', (258, 272))	('RB1', 'Gene', '5925', (110, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('leiomyosarcoma', 'Disease', (212, 226))	('seen', 'Reg', (250, 254))	('sarcoma', 'Disease', 'MESH:D012509', (265, 272))	('TP53', 'Gene', '7157', (174, 178))	('sarcoma', 'Disease', (265, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('myxofibrosarcoma', 'Disease', (316, 332))	('mutations', 'Var', (235, 244))	('sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('TP53', 'Gene', '7157', (94, 98))	('sarcoma', 'Disease', (50, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('mutations', 'Var', (179, 188))	('sarcoma', 'Disease', 'MESH:D012509', (303, 310))	('sarcomas', 'Disease', (50, 58))	('sarcoma', 'Disease', (303, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('RB1', 'Gene', (231, 234))	('sarcoma', 'Disease', 'MESH:D012509', (325, 332))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (274, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('sarcoma', 'Disease', (325, 332))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (258, 272))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (212, 226))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (212, 226))
193084	32351891	Although all loss-of-function mutational status of TP53 detected (missense mutation of DNA binding and/or tetramerization domain, or homozygous deletion) was not correlated to outcome of patients treated with pazopanib, TP53 mutations were shown to have significant association with a longer PFS respect to TP53 wild-type.	('patients', 'Species', '9606', (187, 195))	('TP53', 'Gene', '7157', (220, 224))	('TP53', 'Gene', (220, 224))	('pazopanib', 'Chemical', 'MESH:C516667', (209, 218))	('TP53', 'Gene', (51, 55))	('mutations', 'Var', (225, 234))	('PFS', 'MPA', (292, 295))	('TP53', 'Gene', '7157', (307, 311))	('TP53', 'Gene', (307, 311))	('TP53', 'Gene', '7157', (51, 55))
193091	32351891	Not only germline variants as discussed before but also somatic alterations in the homologous repair system are reported to be responsible for a deeper and longer activity of trabectedin in STS patients where drug response is inversely correlated with the BRCA1 mRNA levels.	('BRCA1', 'Gene', (256, 261))	('patients', 'Species', '9606', (194, 202))	('STS', 'Phenotype', 'HP:0030448', (190, 193))	('trabectedin', 'Chemical', 'MESH:D000077606', (175, 186))	('activity', 'MPA', (163, 171))	('alterations', 'Var', (64, 75))	('deeper', 'PosReg', (145, 151))	('BRCA1', 'Gene', '672', (256, 261))	('longer', 'PosReg', (156, 162))
193092	32351891	In this clinical report, the investigators established that low levels of mRNA BRCA1 expression statistically significant associate with an improved outcome of patients in terms of disease control rate (48 vs. 26%, p < 0.01) and longer median survival (15.4 vs. 7.1 months, p < 0.002).	('low levels', 'Var', (60, 70))	('improved', 'PosReg', (140, 148))	('BRCA1', 'Gene', '672', (79, 84))	('patients', 'Species', '9606', (160, 168))	('mRNA', 'Var', (74, 78))	('disease control', 'CPA', (181, 196))	('BRCA1', 'Gene', (79, 84))	('median survival', 'CPA', (236, 251))	('longer', 'PosReg', (229, 235))
193093	32351891	Interestingly, patients with decreased level of mRNA BRCA1 showed a better median PFS (4.7 vs. 2.0 months, p = 0.002) and a progression-free at 6-months (PFS-6) after treatment (43 vs. 23%, p < 0.012).	('patients', 'Species', '9606', (15, 23))	('PFS', 'MPA', (82, 85))	('BRCA1', 'Gene', '672', (53, 58))	('decreased', 'NegReg', (29, 38))	('mRNA', 'Var', (48, 52))	('BRCA1', 'Gene', (53, 58))
193102	32351891	This study demonstrated the association of the mutational board of cell cycle regulators (RB1, CDKN2A, CDKN2B, CCND1, and CDK6) with a worse overall survival as well as TP53 alteration and KRAS amplification.	('CCND1', 'Gene', (111, 116))	('KRAS', 'Gene', (189, 193))	('RB1', 'Gene', (90, 93))	('KRAS', 'Gene', '3845', (189, 193))	('overall survival', 'CPA', (141, 157))	('CCND1', 'Gene', '595', (111, 116))	('CDKN2A', 'Gene', (95, 101))	('CDK6', 'Gene', (122, 126))	('TP53', 'Gene', '7157', (169, 173))	('RB1', 'Gene', '5925', (90, 93))	('CDK6', 'Gene', '1021', (122, 126))	('CDKN2A', 'Gene', '1029', (95, 101))	('mutational', 'Var', (47, 57))	('CDKN2B', 'Gene', '1030', (103, 109))	('TP53', 'Gene', (169, 173))	('CDKN2B', 'Gene', (103, 109))	('association', 'Reg', (28, 39))
193103	32351891	Thus, considering as PGx markers in a specific subset of these tumors genetic alterations in the Rb pathway, comprising CCND1 or CDK6 amplification, these data will contribute to knowledge for the use of novel therapeutic approaches such as CDK4/6 inhibitors.	('Rb pathway', 'Pathway', (97, 107))	('CDK6', 'Gene', (129, 133))	('CDK6', 'Gene', '1021', (129, 133))	('CDK4/6', 'Gene', '1019;1021', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('CCND1', 'Gene', (120, 125))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('CDK4/6', 'Gene', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('genetic alterations', 'Var', (70, 89))	('CCND1', 'Gene', '595', (120, 125))
193155	31893185	evaluated TLE1 and CD99 expression in various carcinomas and evaluated the expression of the SS18 (SYT) gene rearrangement in tumors with TLE1 and/or CD99 expression in 100 various carcinomas.	('carcinomas', 'Disease', (181, 191))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('CD99', 'Gene', '4267', (19, 23))	('SS18', 'Gene', '6760', (93, 97))	('TLE1', 'Gene', '7088', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('carcinomas', 'Disease', (46, 56))	('SYT', 'Gene', '6760', (99, 102))	('tumors', 'Disease', (126, 132))	('TLE1', 'Gene', '7088', (10, 14))	('carcinomas', 'Disease', 'MESH:D009369', (181, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('CD99', 'Gene', (150, 154))	('carcinomas', 'Disease', 'MESH:D009369', (46, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('CD99', 'Gene', '4267', (150, 154))	('SS18', 'Gene', (93, 97))	('TLE1', 'Gene', (138, 142))	('SYT', 'Gene', (99, 102))	('CD99', 'Gene', (19, 23))	('rearrangement', 'Var', (109, 122))	('TLE1', 'Gene', (10, 14))
193205	25335527	Clinical diagnosis based on 2-[18F]fluoro-2 deoxy-D glucose uptake is sometimes limited by the fact that 2-[18F]fluoro-2 deoxy-D glucose is taken up by not only malignant tumor cells but also macrophages and tissues with granulation or inflammation.	('2-[18F]fluoro-2 deoxy-D glucose', 'Chemical', 'MESH:D019788', (105, 136))	('2-[18F]fluoro-2 deoxy-D glucose', 'Chemical', 'MESH:D019788', (28, 59))	('malignant tumor', 'Disease', 'MESH:D018198', (161, 176))	('inflammation', 'Disease', 'MESH:D007249', (236, 248))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('inflammation', 'Disease', (236, 248))	('malignant tumor', 'Disease', (161, 176))	('2-[18F]fluoro-2', 'Var', (105, 120))
193304	26722357	Development of Soft Tissue Sarcomas in Ribosomal Proteins L5 and S24 Heterozygous Mice Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with ribosomal protein (RP) gene mutations.	('anemia', 'Disease', 'MESH:D000740', (104, 110))	('anemia', 'Disease', (104, 110))	('mutations', 'Var', (206, 215))	('Sarcomas', 'Disease', 'MESH:D012509', (27, 35))	('bone marrow failure', 'Phenotype', 'HP:0005528', (133, 152))	('anemia', 'Phenotype', 'HP:0001903', (104, 110))	('RP', 'Gene', (197, 199))	('associated', 'Reg', (162, 172))	('Sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('bone marrow failure syndrome', 'Disease', (133, 161))	('Soft Tissue Sarcomas', 'Phenotype', 'HP:0030448', (15, 35))	('bone marrow failure syndrome', 'Disease', 'MESH:D000080983', (133, 161))	('Sarcomas', 'Disease', (27, 35))
193309	26722357	Heterozygous point mutations and large deletions in 16 ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL5, RPL11, RPL35A, RPS7, RPS10, RPS26, RPL26, RPL15, RPS28, RPS29, RPL31, RPS27, and RPL27 have been considered the underlying cause of disease in about 65% of patients .	('RPS10', 'Gene', (133, 138))	('RPS7', 'Gene', '6201', (127, 131))	('RPS19', 'Gene', '6223', (85, 90))	('Heterozygous', 'Var', (0, 12))	('RPL15', 'Gene', (154, 159))	('RPS17', 'Gene', (99, 104))	('RPL26', 'Gene', (147, 152))	('RPS19', 'Gene', (85, 90))	('RPL15', 'Gene', '6138', (154, 159))	('RPL11', 'Gene', (112, 117))	('patients', 'Species', '9606', (268, 276))	('RPL27', 'Gene', (193, 198))	('RPL31', 'Gene', '6160', (175, 180))	('RPS7', 'Gene', (127, 131))	('RPL31', 'Gene', (175, 180))	('RPS28', 'Gene', (161, 166))	('RPL11', 'Gene', '6135', (112, 117))	('cause', 'Reg', (235, 240))	('RPS29', 'Gene', (168, 173))	('RPS27', 'Gene', '6232', (182, 187))	('RPS10', 'Gene', '6204', (133, 138))	('RPS26', 'Gene', '6231', (140, 145))	('RPL35A', 'Gene', '6165', (119, 125))	('RPS28', 'Gene', '6234', (161, 166))	('RPS17', 'Gene', '6218', (99, 104))	('RPL27', 'Gene', '6155', (193, 198))	('RPL35A', 'Gene', (119, 125))	('RPS27', 'Gene', (182, 187))	('RPS24', 'Gene', (92, 97))	('RP', 'Gene', (74, 76))	('RPS29', 'Gene', '6235', (168, 173))	('RPS26', 'Gene', (140, 145))	('RPL5', 'Gene', (106, 110))	('RPL26', 'Gene', '6154', (147, 152))
193319	26722357	Recently, we reported the detection of Rps24 and RpL5 mutations in patients with DBA, and have generated mouse models to further address the effect of these mutations in developing anemia and cancer.	('anemia', 'Phenotype', 'HP:0001903', (181, 187))	('patients', 'Species', '9606', (67, 75))	('DBA', 'Disease', (81, 84))	('Rps24', 'Gene', (39, 44))	('mutations', 'Var', (54, 63))	('RpL5', 'Gene', '6125', (49, 53))	('RpL5', 'Gene', (49, 53))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('anemia', 'Disease', 'MESH:D000740', (181, 187))	('anemia', 'Disease', (181, 187))	('mouse', 'Species', '10090', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
193320	26722357	In this study, we characterized the Rpl5+/- and Rps24+/- mice models for DBA.	('mice', 'Species', '10090', (57, 61))	('Rpl5', 'Gene', '100503670', (36, 40))	('Rps24+/-', 'Var', (48, 56))	('DBA', 'Disease', (73, 76))	('Rpl5', 'Gene', (36, 40))
193323	26722357	Generation of the C57BL/6 Rpl5+/- and Rps24+/- mice was carried out by InGenious Targeting Laboratory (iTL; Ronkonkoma, NY, USA), and all animal studies were approved by Boston Children's Hospital's Institutional Animal Care and Use Committee.	('Rps24+/-', 'Var', (38, 46))	('Rpl5', 'Gene', (26, 30))	('Rpl5', 'Gene', '100503670', (26, 30))	('C57BL/6', 'Var', (18, 25))	('Children', 'Species', '9606', (177, 185))	('mice', 'Species', '10090', (47, 51))	('Ronkonkoma', 'Disease', (108, 118))	('Ronkonkoma', 'Disease', 'None', (108, 118))
193326	26722357	All the Rps24-/- and Rpl5-/- mice died by E11-12 despite there being a normal Mendelian distribution of heterozygous, homozygous, and wild-type blastocysts.	('blastocysts', 'Disease', (144, 155))	('Rpl5', 'Gene', (21, 25))	('Rpl5', 'Gene', '100503670', (21, 25))	('blastocysts', 'Disease', 'MESH:D020964', (144, 155))	('mice', 'Species', '10090', (29, 33))	('Rps24-/-', 'Var', (8, 16))
193329	26722357	Real-time PCR and immunoblot analysis also showed similar expression levels of Rpl5 and Rps24 mRNA, and RPL5 and RPS24 proteins in both heterozygous and wild-type mice (Table S2 and Figure S2).	('RPS24', 'Var', (113, 118))	('Rps24', 'Protein', (88, 93))	('RPL5', 'Var', (104, 108))	('Rpl5', 'Gene', (79, 83))	('mice', 'Species', '10090', (163, 167))	('Rpl5', 'Gene', '100503670', (79, 83))
193330	26722357	These observations are similar to previously reported findings for Rps19+/- mice suggesting that one wild-type copy of these ribosomal proteins is sufficient to prevent the development of anemia.	('anemia', 'Phenotype', 'HP:0001903', (188, 194))	('Rps19', 'Gene', (67, 72))	('Rps19', 'Gene', '20085', (67, 72))	('prevent', 'NegReg', (161, 168))	('anemia', 'Disease', (188, 194))	('mice', 'Species', '10090', (76, 80))	('anemia', 'Disease', 'MESH:D000740', (188, 194))	('copy', 'Var', (111, 115))
193331	26722357	We also investigated the risk of cancer development in aging Rpl5+/- and Rps24+/- male and female mice by monitoring them for up to 36 months after birth (Table S3).	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('Rps24+/-', 'Var', (73, 81))	('Rpl5', 'Gene', (61, 65))	('Rpl5', 'Gene', '100503670', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mice', 'Species', '10090', (98, 102))
193333	26722357	Similarly, out of 23 Rps24+/- mice (between15 and 30 months of age), one female mouse developed a 2 cm tumor spanning from upper left ear to the head/neck region at 17 months of age (Figure S3).	('mice', 'Species', '10090', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('mouse', 'Species', '10090', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('Rps24+/-', 'Var', (21, 29))
193339	26722357	In contrast, ribosomal protein gene mutations in zebrafish have resulted in developmental defects of varying degrees similar to the symptoms detected in patients with DBA.	('resulted in', 'Reg', (64, 75))	('patients', 'Species', '9606', (153, 161))	('mutations', 'Var', (36, 45))	('developmental defects', 'Disease', (76, 97))	('zebrafish', 'Species', '7955', (49, 58))	('developmental defects', 'Disease', 'MESH:D003147', (76, 97))	('ribosomal protein gene', 'Gene', (13, 35))
193340	26722357	Similar to mice, some of these mutations have predisposed fish to cancer development by 2 years of age, which is considered late in the life span of zebrafish.	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('zebrafish', 'Species', '7955', (149, 158))	('predisposed', 'Reg', (46, 57))	('mice', 'Species', '10090', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
193342	26722357	To determine the nature of tumors, we performed histological and immunohistochemical studies on tumor and normal skin tissues from Rpl5+/- and Rps24+/- mice as well as normal skin tissue of wild-type mice (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Rpl5', 'Gene', '100503670', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (27, 32))	('tumors', 'Disease', (27, 33))	('tumor', 'Disease', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mice', 'Species', '10090', (152, 156))	('mice', 'Species', '10090', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('Rps24+/-', 'Var', (143, 151))	('Rpl5', 'Gene', (131, 135))
193347	26722357	In all the studies, wild-type, Rpl5+/-, and Rps24+/- normal skin tissues were histologically unremarkable (Figure 1).	('Rpl5', 'Gene', (31, 35))	('Rps24+/-', 'Var', (44, 52))	('Rpl5', 'Gene', '100503670', (31, 35))
193350	26722357	The proposed mechanisms for sarcoma development are either a mutation in the p53 gene, which is considered to be a low incidence in sarcoma, or an overexpression of one of the p53 inhibitors such as MDM2.	('MDM2', 'Gene', '17246', (199, 203))	('sarcoma', 'Disease', (28, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('p53', 'Gene', (176, 179))	('mutation', 'Var', (61, 69))	('sarcoma', 'Disease', (132, 139))	('p53', 'Gene', '22059', (176, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('p53', 'Gene', (77, 80))	('MDM2', 'Gene', (199, 203))	('overexpression', 'PosReg', (147, 161))	('p53', 'Gene', '22059', (77, 80))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
193353	26722357	To investigate if the presence of a mutation in p53 gene or a change in p53 expression level was the potential mechanism for sarcoma formation in our mouse model, we performed DNA sequencing of the Tp53 gene in DNA isolated from tumors and normal skin (control).	('p53', 'Gene', '22059', (199, 202))	('p53', 'Gene', '22059', (48, 51))	('change', 'Reg', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('p53', 'Gene', '22059', (72, 75))	('mouse', 'Species', '10090', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('sarcoma', 'Disease', (125, 132))	('Tp53', 'Gene', (198, 202))	('tumors', 'Disease', (229, 235))	('Tp53', 'Gene', '22059', (198, 202))	('p53', 'Gene', (48, 51))	('p53', 'Gene', (199, 202))	('p53', 'Gene', (72, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('expression level', 'MPA', (76, 92))	('mutation', 'Var', (36, 44))
193354	26722357	This could be due to the low number of tumors studied in this experiment or a low incidence of p53 mutations in sarcomas.	('sarcomas', 'Disease', (112, 120))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutations', 'Var', (99, 108))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '22059', (95, 98))	('sarcomas', 'Disease', 'MESH:D012509', (112, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('tumors', 'Disease', (39, 45))
193357	26722357	As it has been reported previously, ribosomal proteins use different signaling pathways to regulate p53 expression and activity, which may account for the differences detected in the p53 expression between the Rps24+/- and Rpl5+/- tissues.	('Rps24+/-', 'Var', (210, 218))	('p53', 'Gene', '22059', (100, 103))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '22059', (183, 186))	('Rpl5', 'Gene', (223, 227))	('expression', 'MPA', (104, 114))	('Rpl5', 'Gene', '100503670', (223, 227))	('activity', 'MPA', (119, 127))	('p53', 'Gene', (100, 103))
193358	26722357	also reported that knock-down of RPS24 in human colon cancer cells in vitro significantly decreased cell proliferation and migration and induced cell cycle arrest, which suggested the possible role of RPS24 in cell growth possibly through regulating the cell cycle.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (145, 162))	('RPS24', 'Gene', (33, 38))	('RPS24', 'Gene', (201, 206))	('regulating', 'Reg', (239, 249))	('colon cancer', 'Disease', (48, 60))	('human', 'Species', '9606', (42, 47))	('arrest', 'Disease', 'MESH:D006323', (156, 162))	('decreased', 'NegReg', (90, 99))	('induced', 'Reg', (137, 144))	('cell proliferation', 'CPA', (100, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (48, 60))	('arrest', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('colon cancer', 'Disease', 'MESH:D015179', (48, 60))	('knock-down', 'Var', (19, 29))
193360	26722357	In conclusion, even though Rpl5+/- and Rps24+/- mice did not have anemia, they became more susceptible to cancer development when compared with wild-type mice.	('mice', 'Species', '10090', (154, 158))	('anemia', 'Phenotype', 'HP:0001903', (66, 72))	('susceptible', 'Reg', (91, 102))	('mice', 'Species', '10090', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('Rpl5', 'Gene', (27, 31))	('Rps24+/-', 'Var', (39, 47))	('cancer', 'Disease', (106, 112))	('Rpl5', 'Gene', '100503670', (27, 31))	('anemia', 'Disease', (66, 72))	('anemia', 'Disease', 'MESH:D000740', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
193415	28118409	The epigenetic modifications are thought to determine the fate of KSHV infection.	('KS', 'Phenotype', 'HP:0100726', (66, 68))	('determine', 'Reg', (44, 53))	('KSHV infection', 'Disease', (66, 80))	('epigenetic modifications', 'Var', (4, 28))	('KSHV infection', 'Disease', 'MESH:C537372', (66, 80))
193418	28118409	We examined AcH3 and H3K27me3 histone modifications on KSHV genome, as well as the genome-wide binding sites of latency associated nuclear antigen (LANA).	('LANA', 'Gene', '4961527', (148, 152))	('KSHV', 'Species', '37296', (55, 59))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('H3K27me3', 'Var', (21, 29))	('AcH3', 'Chemical', '-', (12, 16))	('LANA', 'Gene', (148, 152))
193423	28118409	Epigenetic modifications are thought to determine the fate of KSHV infection.	('KSHV infection', 'Disease', (62, 76))	('KS', 'Phenotype', 'HP:0100726', (62, 64))	('Epigenetic modifications', 'Var', (0, 24))	('KSHV infection', 'Disease', 'MESH:C537372', (62, 76))	('determine', 'Reg', (40, 49))
193426	28118409	In this study, we performed ChIP-Seq experiments in classic KS tissues and mapped out the AcH3 and H3K27me3 histone modifications on KSHV genome, as well as the genome-wide LANA binding sites.	('LANA', 'Gene', (173, 177))	('AcH3', 'Chemical', '-', (90, 94))	('AcH3', 'Gene', (90, 94))	('LANA', 'Gene', '4961527', (173, 177))	('H3K27me3', 'Var', (99, 107))	('KSHV', 'Species', '37296', (133, 137))	('KS', 'Phenotype', 'HP:0100726', (60, 62))	('KS', 'Phenotype', 'HP:0100726', (133, 135))
193438	28118409	It has been demonstrated that activating histone modifications like acetylation of histones (AcH3) are only enriched in several loci while repressive histone modifications like H3K27me3 are widespread across the viral genome, which well explained the expression pattern of viral genes during latency.	('H3K27me3', 'Var', (177, 185))	('acetylation', 'MPA', (68, 79))	('activating', 'PosReg', (30, 40))	('AcH3', 'Chemical', '-', (93, 97))
193445	28118409	Specifically, we examined AcH3 and H3K27me3 histone modifications on KSHV genome, as well as the genome-wide LANA binding sites.	('LANA', 'Gene', (109, 113))	('KSHV', 'Species', '37296', (69, 73))	('LANA', 'Gene', '4961527', (109, 113))	('AcH3', 'Var', (26, 30))	('KS', 'Phenotype', 'HP:0100726', (69, 71))	('AcH3', 'Chemical', '-', (26, 30))	('H3K27me3', 'Var', (35, 43))
193446	28118409	Our results demonstrated that the enriched AcH3 histone modifications were mainly restricted at latent locus while H3K27me3 histone modifications were widespread on KSHV genome in classic KS tissues.	('KS', 'Phenotype', 'HP:0100726', (188, 190))	('H3K27me3', 'Var', (115, 123))	('KS', 'Phenotype', 'HP:0100726', (165, 167))	('AcH3', 'Gene', (43, 47))	('AcH3', 'Chemical', '-', (43, 47))	('KSHV', 'Species', '37296', (165, 169))
193450	28118409	Previous studies on the epigenetic landscape of KSHV genome using in vitro cell culture systems have systemically determined genome-wide distributions of four well-known histone modifications by ChIP-on-ChIP, including AcH3, H3K4me3, H3K27me3 and H3K9me3.	('H3K4me3', 'Var', (225, 232))	('AcH3', 'Chemical', '-', (219, 223))	('KS', 'Phenotype', 'HP:0100726', (48, 50))	('KSHV', 'Species', '37296', (48, 52))	('H3K9me3', 'Var', (247, 254))	('AcH3', 'Var', (219, 223))	('H3K27me3', 'Var', (234, 242))
193454	28118409	Each experiment was divided into five experimental groups which are input, IgG, LANA, AcH3 and H3K27me3.	('H3K27me3', 'Var', (95, 103))	('AcH3', 'Chemical', '-', (86, 90))	('LANA', 'Gene', (80, 84))	('LANA', 'Gene', '4961527', (80, 84))
193455	28118409	The purified ChIP product from input, LANA, AcH3 and H3K27me3 groups were subjected to next generation-sequencing.	('AcH3', 'Chemical', '-', (44, 48))	('LANA', 'Gene', (38, 42))	('LANA', 'Gene', '4961527', (38, 42))	('H3K27me3', 'Var', (53, 61))
193462	28118409	As shown in Fig 2, the enriched AcH3 histone modifications were mainly restricted to the latent locus while H3K27me3 histone modifications were widespread on the KSHV genome.	('AcH3', 'Var', (32, 36))	('KSHV', 'Species', '37296', (162, 166))	('AcH3', 'Chemical', '-', (32, 36))	('KS', 'Phenotype', 'HP:0100726', (162, 164))	('H3K27me3', 'Var', (108, 116))
193467	28118409	In the meantime, we observed a unique peak of H3K27me3 at the promoter region of the LANA gene only in the first case (Fig 4).	('LANA', 'Gene', (85, 89))	('H3K27me3', 'Var', (46, 54))	('LANA', 'Gene', '4961527', (85, 89))
193468	28118409	The higher level of AcH3 and the unique peak of H3K27me3 at the promoter region of the LANA gene in the first case provides supporting evidence for the repressive role of LANA on viral gene expression as previously reported.	('LANA', 'Gene', (171, 175))	('higher', 'PosReg', (4, 10))	('LANA', 'Gene', (87, 91))	('LANA', 'Gene', '4961527', (171, 175))	('LANA', 'Gene', '4961527', (87, 91))	('H3K27me3', 'Var', (48, 56))	('AcH3', 'Chemical', '-', (20, 24))
193471	28118409	10 Kb; 20-30 Kb; 87 Kb) in in vitro cell culture systems (BCBL-1 and KSHV infected SLK) were not observed in classic KS tissues while the landscape of H3K27me3 histone modifications in in vitro cell culture systems was much similar to the one in KS tissues.	('KSHV infected SLK', 'Disease', 'MESH:C537372', (69, 86))	('KS', 'Phenotype', 'HP:0100726', (117, 119))	('KS', 'Phenotype', 'HP:0100726', (69, 71))	('H3K27me3', 'Var', (151, 159))	('KS', 'Phenotype', 'HP:0100726', (246, 248))	('KSHV infected SLK', 'Disease', (69, 86))
193491	28118409	The epigenetic status in RTA region may reflect the state of KSHV infection.	('epigenetic status', 'Var', (4, 21))	('KSHV infection', 'Disease', 'MESH:C537372', (61, 75))	('KSHV infection', 'Disease', (61, 75))	('reflect', 'Reg', (40, 47))	('KS', 'Phenotype', 'HP:0100726', (61, 63))
193493	28118409	The GAPDH region exhibited enrichments of AcH3 and little or no H3K27me3 histone modifications, which was the experimental control for the specificity of LANA, AcH3 and H3K27me3 antibodies (Fig 6B).	('GAPDH', 'Gene', (4, 9))	('AcH3', 'Chemical', '-', (42, 46))	('AcH3', 'Chemical', '-', (160, 164))	('LANA', 'Gene', (154, 158))	('AcH3', 'Var', (42, 46))	('LANA', 'Gene', '4961527', (154, 158))	('H3K27me3 histone', 'Protein', (64, 80))	('GAPDH', 'Gene', '2597', (4, 9))
193500	28118409	TR region contains the latent replication origin of KSHV genome, thus hypoacetylation of histone H3 at the TR region might affect the latent replication of KSHV genome, hampering the maintenance of KSHV episomes.	('KSHV', 'Species', '37296', (52, 56))	('KS', 'Phenotype', 'HP:0100726', (198, 200))	('maintenance', 'MPA', (183, 194))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('hampering', 'NegReg', (169, 178))	('KSHV', 'Species', '37296', (156, 160))	('latent replication', 'MPA', (134, 152))	('KSHV episome', 'Disease', 'MESH:C537372', (198, 210))	('hypoacetylation', 'Var', (70, 85))	('KSHV', 'Species', '37296', (198, 202))	('affect', 'Reg', (123, 129))	('KS', 'Phenotype', 'HP:0100726', (156, 158))	('KSHV', 'Gene', (156, 160))	('KSHV episome', 'Disease', (198, 210))
193508	28118409	We additionally determined the epigenetic histone modifications of KSHV genome in one case of AIDS-related KS tissue by ChIP-qPCR.	('epigenetic histone', 'Var', (31, 49))	('KS', 'Phenotype', 'HP:0100726', (107, 109))	('KSHV genome', 'Gene', (67, 78))	('KS', 'Phenotype', 'HP:0100726', (67, 69))	('KSHV', 'Species', '37296', (67, 71))	('AIDS', 'Disease', (94, 98))	('AIDS', 'Disease', 'MESH:D000163', (94, 98))
193515	28118409	The distinct AcH3 histone modifications at the TR and vIRF3 coding regions in classic KS tissues provided important clues about the progression of KS disease, which would be a helpful reference for doctors to diagnose clinical patients using epigenetic targeted strategies.	('KS', 'Phenotype', 'HP:0100726', (147, 149))	('KS disease', 'Disease', 'MESH:D004194', (147, 157))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('clinical', 'Species', '191496', (218, 226))	('modifications', 'Var', (26, 39))	('KS disease', 'Disease', (147, 157))	('AcH3', 'Gene', (13, 17))	('AcH3', 'Chemical', '-', (13, 17))	('patients', 'Species', '9606', (227, 235))
193613	24204937	Additionally, apoptosis was induced after HMME-PDT in a three-dimensional culture of osteosarcoma cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('HMME', 'Chemical', 'MESH:C494379', (42, 46))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('HMME-PDT', 'Var', (42, 50))	('apoptosis', 'CPA', (14, 23))	('induced', 'Reg', (28, 35))
193621	24204937	These results indicate that HMME-PDT has a potent killing effect on osteosarcoma cells in vitro and significantly inhibits tumor growth in vivo, which is associated with the caspase-dependent pathway.	('HMME', 'Chemical', 'MESH:C494379', (28, 32))	('tumor', 'Disease', (123, 128))	('osteosarcoma', 'Disease', 'MESH:D012516', (68, 80))	('HMME-PDT', 'Var', (28, 36))	('osteosarcoma', 'Phenotype', 'HP:0002669', (68, 80))	('inhibits', 'NegReg', (114, 122))	('caspase', 'Gene', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('killing effect', 'CPA', (50, 64))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('caspase', 'Gene', '834;839;841;842', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('osteosarcoma', 'Disease', (68, 80))
193645	24204937	The results of the MTT assay showed that HMME-PDT significantly decreased sarcoma cell viability, whereas photo-damage to cells increased with increasing dose of HMME and light intensity.	('HMME-PDT', 'Var', (41, 49))	('HMME', 'Chemical', 'MESH:C494379', (162, 166))	('MTT', 'Chemical', 'MESH:C070243', (19, 22))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('sarcoma', 'Disease', (74, 81))	('HMME', 'Chemical', 'MESH:C494379', (41, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('decreased', 'NegReg', (64, 73))
193652	24204937	These results show that the apoptosis rate of LM8, MG63, and Saos-2 cells were markedly increased in groups treated with HMME-PDT (10 and 20 microg/mL) compared with the control groups (P<0.05; Fig.	('HMME', 'Chemical', 'MESH:C494379', (121, 125))	('HMME-PDT', 'Var', (121, 129))	('LM8', 'Chemical', '-', (46, 49))	('increased', 'PosReg', (88, 97))	('apoptosis rate', 'CPA', (28, 42))	('Saos-2', 'CellLine', 'CVCL:0548', (61, 67))
193665	24204937	The cleaved caspase-3 (17 kDa) and caspase-9 (35 kDa) were markedly increased in the HMME-PDT group by 2.10- and 3.27-fold compared to the control group at HMME doses of 20 microg/mL.	('caspase-3', 'Enzyme', (12, 21))	('caspase-9', 'Gene', (35, 44))	('HMME', 'Chemical', 'MESH:C494379', (156, 160))	('cleaved', 'MPA', (4, 11))	('HMME', 'Chemical', 'MESH:C494379', (85, 89))	('increased', 'PosReg', (68, 77))	('HMME-PDT', 'Var', (85, 93))
193668	24204937	These results further suggest that the caspase pathway plays an important role in the initiation of the apoptosis cascade after HMME-PDT in OS cells.	('HMME-PDT', 'Var', (128, 136))	('HMME', 'Chemical', 'MESH:C494379', (128, 132))	('caspase', 'Gene', (39, 46))	('caspase', 'Gene', '834;839;841;842', (39, 46))
193672	24204937	These results indicate that HMME-PDT significantly inhibits tumor growth.	('HMME', 'Chemical', 'MESH:C494379', (28, 32))	('inhibits', 'NegReg', (51, 59))	('HMME-PDT', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
193675	24204937	Additionally, the expression of these proteins was significantly increased in the HMME-PDT group compared with the control group (Fig.	('HMME', 'Chemical', 'MESH:C494379', (82, 86))	('increased', 'PosReg', (65, 74))	('expression', 'MPA', (18, 28))	('HMME-PDT', 'Var', (82, 90))
193680	24204937	Liu demonstrated that HMME-PDT can induce apoptosis of canine breast cancer cells.	('canine', 'Species', '9615', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('apoptosis', 'CPA', (42, 51))	('breast cancer', 'Disease', (62, 75))	('HMME', 'Chemical', 'MESH:C494379', (22, 26))	('HMME-PDT', 'Var', (22, 30))
193681	24204937	Zhan reported that HMME-PDT inhibits the growth of glioma and prolongs survival time in vivo.	('glioma', 'Disease', (51, 57))	('growth', 'CPA', (41, 47))	('inhibits', 'NegReg', (28, 36))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('HMME', 'Chemical', 'MESH:C494379', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('prolongs', 'NegReg', (62, 70))	('HMME-PDT', 'Var', (19, 27))	('survival time', 'CPA', (71, 84))
193686	24204937	Additionally, our data suggest that HMME-PDT markedly inhibits sarcoma cell growth, and photodynamic damage of HMME on sarcoma cells increases with the HMME does and light intensity.	('sarcoma', 'Disease', (63, 70))	('HMME', 'Chemical', 'MESH:C494379', (111, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('HMME', 'Chemical', 'MESH:C494379', (152, 156))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('HMME', 'Chemical', 'MESH:C494379', (36, 40))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('inhibits', 'NegReg', (54, 62))	('increases', 'PosReg', (133, 142))	('HMME-PDT', 'Var', (36, 44))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
193690	24204937	It was previously demonstrated by preclinical research that PDT can induce apoptosis in tumor cells in vitro, whereas cell-killing effects mediated by PDT depend on PS concentrations and laser energy density.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('apoptosis', 'CPA', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('PDT', 'Var', (60, 63))
193707	24204937	Liu indicated that the caspase-3/-8 cascade pathway plays a key role in apoptosis of prostate cancer cells induced by PDT.	('caspase-3/-8 cascade pathway', 'Pathway', (23, 51))	('prostate cancer', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('apoptosis', 'CPA', (72, 81))	('PDT', 'Var', (118, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))
193715	24204937	In vivo, PDT can effectively reduce local recurrence rates and inhibit tumor growth.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('PDT', 'Var', (9, 12))	('tumor', 'Disease', (71, 76))	('inhibit', 'NegReg', (63, 70))	('reduce', 'NegReg', (29, 35))	('local recurrence rates', 'CPA', (36, 58))
193716	24204937	Recently, PDT was shown to have a significant effect on reducing the local recurrence rate, providing excellent limb function, and prolonging the median survival time of patients with surgical therapy combined with PDT.	('patients', 'Species', '9606', (170, 178))	('local', 'CPA', (69, 74))	('prolonging', 'PosReg', (131, 141))	('limb function', 'CPA', (112, 125))	('PDT', 'Var', (10, 13))	('reducing', 'NegReg', (56, 64))
193720	24204937	Our data also showed that tumor volume was markedly reduced in the PDT group.	('reduced', 'NegReg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('PDT', 'Var', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
193725	24204937	A wavelength of 635 nm was selected to excite the HMME for the following reasons: First, the absorption peak of HMME is 405, 504, 540, 560, 630 nm while the wavelength of 635 nm can have the best penetration into the tissue.	('405', 'Var', (120, 123))	('HMME', 'Gene', (112, 116))	('HMME', 'Chemical', 'MESH:C494379', (112, 116))	('HMME', 'Chemical', 'MESH:C494379', (50, 54))
193733	24204937	In conclusion, HMME-PDT can significantly inhibit the viability of OS cells, and the photodynamic damage of HMME on cells was increased with HMME dosage and laser power intensity.	('HMME', 'Chemical', 'MESH:C494379', (141, 145))	('HMME', 'Chemical', 'MESH:C494379', (108, 112))	('photodynamic damage', 'CPA', (85, 104))	('HMME-PDT', 'Var', (15, 23))	('HMME', 'Chemical', 'MESH:C494379', (15, 19))	('viability of OS cells', 'CPA', (54, 75))	('inhibit', 'NegReg', (42, 49))	('increased', 'PosReg', (126, 135))
193767	24204937	To evaluate the mechanism of PDT-mediated cell death after HMME-PDT, an irreversible inhibitor of caspase (Z-VAD-FMK) and necrosis (Nec-1) conjugate PDT was used to detect cell viability.	('HMME-PDT', 'Var', (59, 67))	('necrosis', 'Disease', 'MESH:D009336', (122, 130))	('caspase', 'Gene', (98, 105))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (107, 116))	('Nec-1', 'Gene', '5122', (132, 137))	('caspase', 'Gene', '834;839;841;842', (98, 105))	('Nec-1', 'Gene', (132, 137))	('HMME', 'Chemical', 'MESH:C494379', (59, 63))	('necrosis', 'Disease', (122, 130))
193818	22759737	Thus, inflammatory markers, including interleukin 6 (IL-6), C-reactive protein (CRP), and D-dimer, remain elevated among persons on ART, although a recent study comparing demographically similar HIV-infected and uninfected veterans of similar comorbidity status found elevated IL-6 and D-dimer only among HIV-infected veterans with HIV RNA 500 copies/ml or more or CD4 cell count less than 200 cells/mul, and found elevated soluble CD14 (a biomarker of monocyte activation) only among HIV-infected veterans with CD4 cell count less than 200 cells/mul.	('HIV-infected', 'Disease', (195, 207))	('CRP', 'Gene', (80, 83))	('HIV-infected', 'Disease', 'MESH:D015658', (195, 207))	('IL-6', 'Gene', (277, 281))	('IL-6', 'Gene', '3569', (53, 57))	('CD4', 'Gene', (365, 368))	('C-reactive protein', 'Gene', (60, 78))	('elevated IL-6', 'Phenotype', 'HP:0030783', (268, 281))	('persons', 'Species', '9606', (121, 128))	('HIV-infected', 'Disease', (305, 317))	('HIV-infected', 'Disease', 'MESH:D015658', (305, 317))	('CD14', 'Gene', (432, 436))	('HIV-infected', 'Disease', (485, 497))	('CD14', 'Gene', '929', (432, 436))	('IL-6', 'Gene', (53, 57))	('interleukin 6', 'Gene', (38, 51))	('HIV-infected', 'Disease', 'MESH:D015658', (485, 497))	('HIV-infected veterans', 'Disease', 'MESH:D015658', (485, 506))	('C-reactive protein', 'Gene', '1401', (60, 78))	('elevated', 'PosReg', (415, 423))	('CD4', 'Gene', '920', (512, 515))	('CD4 cell count less than 200', 'Phenotype', 'HP:0005407', (365, 393))	('HIV-infected veterans', 'Disease', (305, 326))	('HIV RNA 500 copies/ml', 'Var', (332, 353))	('CRP', 'Gene', '1401', (80, 83))	('CD4', 'Gene', (512, 515))	('D-dimer', 'MPA', (286, 293))	('interleukin 6', 'Gene', '3569', (38, 51))	('HIV-infected veterans', 'Disease', (485, 506))	('CD4 cell count less than 200', 'Phenotype', 'HP:0005407', (512, 540))	('ART', 'Chemical', '-', (132, 135))	('IL-6', 'Gene', '3569', (277, 281))	('CD4', 'Gene', '920', (365, 368))	('HIV-infected veterans', 'Disease', 'MESH:D015658', (305, 326))	('elevated', 'PosReg', (268, 276))
193831	22759737	One study found longer exposure to CD4 cell count less than 200 cells/mul, but not lower current CD4, to be independently associated with increased NADC (grouped) risk.	('CD4 cell count less than 200', 'Phenotype', 'HP:0005407', (35, 63))	('CD4', 'Gene', (35, 38))	('CD4', 'Gene', (97, 100))	('CD4', 'Gene', '920', (35, 38))	('less than 200 cells/mul', 'Var', (50, 73))	('NADC', 'Chemical', '-', (148, 152))	('CD4', 'Gene', '920', (97, 100))
193848	22759737	We should note that for oral cavity/pharynx cancer, in one study the elevated risk among PLWHA compared with uninfected persons was no longer significant after adjusting for smoking and alcohol/drug abuse.	('drug abuse', 'Disease', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('persons', 'Species', '9606', (120, 127))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('drug abuse', 'Disease', 'MESH:D019966', (194, 204))	('PLWHA', 'Var', (89, 94))	('pharynx cancer', 'Phenotype', 'HP:0100638', (36, 50))	('alcohol', 'Chemical', 'MESH:D000438', (186, 193))
193952	20602747	Several studies suggest that the omission of cyclosporine might lead to tumor remission.	('omission', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('lead', 'Reg', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cyclosporine', 'Chemical', 'MESH:D016572', (45, 57))
193966	33419470	Multivariate analysis indicated that nuclear expression of IL4Ralpha and IL13Ralpha1 were independent indicators of shorter overall survival (IL4Ralpha; p = 0.002, IL13Ralpha1; p = 0.016) and relapse-free survival (IL4Ralpha; p = 0.022, IL13Ralpha1; p < 0.001) of soft-tissue sarcoma patients.	('shorter', 'NegReg', (116, 123))	('overall survival', 'CPA', (124, 140))	('IL13Ralpha1', 'Var', (73, 84))	('patients', 'Species', '9606', (284, 292))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (264, 283))	('sarcoma', 'Disease', 'MESH:D012509', (276, 283))	('sarcoma', 'Disease', (276, 283))	('relapse-free survival', 'CPA', (192, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('IL4Ralpha', 'Var', (59, 68))
193967	33419470	Moreover, the co-expression pattern of nuclear IL4Ralpha and IL13Ralpha1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001).	('patients', 'Species', '9606', (145, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (125, 144))	('IL4Ralpha', 'Var', (47, 56))	('IL13Ralpha1', 'Var', (61, 72))	('survival', 'MPA', (113, 121))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('shorter', 'NegReg', (105, 112))	('nuclear IL4Ralpha', 'Var', (39, 56))	('sarcoma', 'Disease', (137, 144))
193968	33419470	This study suggests IL4Ralpha and IL13Ralpha1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Ralpha and IL13Ralpha1 might be novel prognostic indicators of soft-tissue sarcoma patients.	('sarcoma', 'Disease', (206, 213))	('IL13Ralpha1', 'Var', (142, 153))	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('patients', 'Species', '9606', (214, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('IL4Ralpha', 'Var', (128, 137))	('sarcoma', 'Disease', (97, 104))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (194, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcoma', 'Disease', 'MESH:D012509', (206, 213))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (85, 104))	('associated', 'Reg', (50, 60))
193974	33419470	Higher expression of IL4Ralpha and IL13Ralpha1 was observed in various types of human cancers such as colorectal, breast, pancreatic, bladder, brain, and ovarian cancers.	('cancers', 'Disease', (162, 169))	('ovarian cancers', 'Phenotype', 'HP:0100615', (154, 169))	('colorectal', 'Disease', 'MESH:D015179', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('IL13Ralpha1', 'Var', (35, 46))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('pancreatic', 'Disease', (122, 132))	('cancers', 'Disease', (86, 93))	('brain', 'Disease', (143, 148))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('ovarian cancers', 'Disease', (154, 169))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('expression', 'MPA', (7, 17))	('breast', 'Disease', (114, 120))	('ovarian cancers', 'Disease', 'MESH:D010051', (154, 169))	('colorectal', 'Disease', (102, 112))	('IL4Ralpha', 'Var', (21, 30))	('bladder', 'Disease', (134, 141))	('Higher', 'PosReg', (0, 6))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
193975	33419470	In addition, elevated expression of IL4Ralpha and/or IL13Ralpha1 were associated with poor prognosis of glioblastoma, mesothelioma, breast cancer, renal cell carcinoma, and oral cavity squamous cell carcinoma patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('renal cell carcinoma', 'Disease', (147, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('glioblastoma', 'Disease', (104, 116))	('patients', 'Species', '9606', (209, 217))	('mesothelioma', 'Disease', (118, 130))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('oral cavity squamous cell carcinoma', 'Disease', (173, 208))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('expression', 'MPA', (22, 32))	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (147, 167))	('oral cavity squamous cell carcinoma', 'Disease', 'MESH:D002294', (173, 208))	('IL13Ralpha1', 'Var', (53, 64))	('elevated', 'PosReg', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('IL4Ralpha', 'Var', (36, 45))
194001	33419470	Positivity for nIL4Ralpha was significantly associated with age (p = 0.033), higher tumor stage (p < 0.001), lymph node metastasis (p = 0.034), higher histologic grade (p = 0.002), increased mitotic count (p < 0.001), presence of tumor necrosis (p = 0.020), and expression of cIL4Ralpha (p < 0.001), nIL13Ralpha1 (p < 0.001), and cIL13Ralpha1 (p = 0.003) (Table 2).	('tumor', 'Disease', (230, 235))	('nIL13Ralpha1', 'Var', (300, 312))	('higher histologic grade', 'CPA', (144, 167))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('nIL4Ralpha', 'Gene', (15, 25))	('tumor necrosis', 'Disease', (230, 244))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('mitotic count', 'CPA', (191, 204))	('lymph node metastasis', 'CPA', (109, 130))	('cIL13Ralpha1', 'Var', (330, 342))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor necrosis', 'Disease', 'MESH:D009336', (230, 244))	('Positivity', 'Var', (0, 10))	('increased', 'PosReg', (181, 190))
194002	33419470	Positivity for cIL4Ralpha was significantly associated with higher tumor stage (p = 0.012), lymph node metastasis (p = 0.027), higher histologic grade (p < 0.001), increased mitotic count (p = 0.003), presence of tumor necrosis (p = 0.022), and expression of nIL13Ralpha1 (p < 0.001) and cIL13Ralpha1 (p < 0.001) (Table 2).	('tumor', 'Disease', (213, 218))	('cIL13Ralpha1', 'Gene', (288, 300))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('lymph node metastasis', 'CPA', (92, 113))	('tumor necrosis', 'Disease', (213, 227))	('cIL4Ralpha', 'Gene', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor necrosis', 'Disease', 'MESH:D009336', (213, 227))	('higher', 'PosReg', (127, 133))	('Positivity', 'Var', (0, 10))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('mitotic count', 'CPA', (174, 187))	('increased', 'PosReg', (164, 173))
194005	33419470	The nIL4Ralpha-positivity predicted a 5.249-fold [95% CI (95% confidential interval); 2.398-11.493] greater risk of death and a 3.750-fold (95% CI; 2.051-6.855) greater risk of relapse or death of STS patients (Table 3).	('patients', 'Species', '9606', (201, 209))	('death', 'Disease', 'MESH:D003643', (116, 121))	('death', 'Disease', (116, 121))	('relapse', 'CPA', (177, 184))	('death', 'Disease', 'MESH:D003643', (188, 193))	('STS', 'Phenotype', 'HP:0030448', (197, 200))	('death', 'Disease', (188, 193))	('nIL4Ralpha-positivity', 'Var', (4, 25))
194006	33419470	The cIL4Ralpha-positivity predicted a 4.099-fold (95% CI; 1.799-9.339) greater risk of death and a 3.394-fold (95% CI; 1.782-6.464) greater risk of relapse or death of STS patients (Table 3).	('cIL4Ralpha-positivity', 'Var', (4, 25))	('relapse', 'CPA', (148, 155))	('death', 'Disease', 'MESH:D003643', (87, 92))	('death', 'Disease', 'MESH:D003643', (159, 164))	('STS', 'Phenotype', 'HP:0030448', (168, 171))	('death', 'Disease', (87, 92))	('patients', 'Species', '9606', (172, 180))	('death', 'Disease', (159, 164))
194007	33419470	The nIL13Ralpha1-positivity predicted a 9.451-fold (95% CI; 3.938-22.683) greater risk of death and a 6.546-fold (95% CI; 3.499-12.248) greater risk of relapse or death of STS patients (Table 3).	('relapse', 'CPA', (152, 159))	('patients', 'Species', '9606', (176, 184))	('STS', 'Phenotype', 'HP:0030448', (172, 175))	('nIL13Ralpha1-positivity', 'Var', (4, 27))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', (90, 95))	('death', 'Disease', 'MESH:D003643', (163, 168))	('death', 'Disease', (163, 168))
194008	33419470	The cIL13Ralpha1-positivity predicted a 2.902-fold (95% CI; 1.510-5.579) greater risk of death and a 2.305-fold (95% CI; 1.353-3.924) greater risk of relapse or death of STS patients (Table 3).	('cIL13Ralpha1-positivity', 'Var', (4, 27))	('death', 'Disease', 'MESH:D003643', (161, 166))	('death', 'Disease', 'MESH:D003643', (89, 94))	('death', 'Disease', (161, 166))	('relapse', 'CPA', (150, 157))	('STS', 'Phenotype', 'HP:0030448', (170, 173))	('death', 'Disease', (89, 94))	('patients', 'Species', '9606', (174, 182))
194009	33419470	Multivariate analysis was performed with the factors significantly associated with OS or RFS, which were age, tumor stage, lymph node metastasis, distant metastasis, histologic grade, tumor necrosis, and the expression of nIL4Ralpha, cIL4Ralpha, nIL13Ralpha1, and cIL13Ralpha1.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor necrosis', 'Disease', 'MESH:D009336', (184, 198))	('nIL13Ralpha1', 'Var', (246, 258))	('distant metastasis', 'CPA', (146, 164))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cIL13Ralpha1', 'Var', (264, 276))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (184, 189))	('nIL4Ralpha', 'Var', (222, 232))	('cIL4Ralpha', 'Var', (234, 244))	('tumor necrosis', 'Disease', (184, 198))	('lymph node metastasis', 'CPA', (123, 144))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
194010	33419470	Multivariate analysis revealed distant metastasis, nIL4Ralpha expression, and nIL13Ralpha1 expression as independent prognostic indicators of OS and RFS of STS patients (Table 4).	('patients', 'Species', '9606', (160, 168))	('nIL4Ralpha expression', 'Var', (51, 72))	('STS', 'Phenotype', 'HP:0030448', (156, 159))	('nIL13Ralpha1 expression', 'Var', (78, 101))	('RFS of STS', 'Disease', (149, 159))
194013	33419470	In multivariate analysis, the expression of nIL4Ralpha and nIL13Ralpha1 were the independent indicators of OS and RFS of STS patients.	('STS', 'Phenotype', 'HP:0030448', (121, 124))	('RFS', 'Disease', (114, 117))	('nIL4Ralpha', 'Var', (44, 54))	('nIL13Ralpha1', 'Var', (59, 71))	('patients', 'Species', '9606', (125, 133))
194015	33419470	Furthermore, there was a positive correlation between the expression of mRNA IL4Ralpha and IL13Ralpha1 in glioblastoma multiform.	('mRNA IL4Ralpha', 'Var', (72, 86))	('glioblastoma', 'Disease', (106, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('IL13Ralpha1', 'Gene', (91, 102))	('positive correlation', 'Reg', (25, 45))
194020	33419470	Consistently, although nuclear and cytoplasmic expression were not analyzed separately, higher expression of IL4Ralpha and IL13Ralpha1 were significantly associated with shorter cancer-specific survival and RFS of clear cell renal cell carcinoma patients.	('higher', 'PosReg', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (246, 254))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (225, 245))	('RFS of clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (207, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (214, 245))	('IL4Ralpha', 'Var', (109, 118))	('shorter', 'NegReg', (170, 177))	('IL13Ralpha1', 'Var', (123, 134))	('expression', 'MPA', (95, 105))	('RFS of clear cell renal cell carcinoma', 'Disease', (207, 245))
194029	33419470	In renal cell carcinoma cells, knock-down of IL4Ralpha or IL13Ralpha1 induced cell cycle arrest and apoptosis by suppressing JAK2-mediated phosphorylation of FOXO3.	('arrest', 'Disease', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('IL4Ralpha', 'Var', (45, 54))	('suppressing', 'NegReg', (113, 124))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('FOXO3', 'Gene', (158, 163))	('knock-down', 'Var', (31, 41))	('renal cell carcinoma', 'Disease', (3, 23))	('FOXO3', 'Gene', '2309', (158, 163))	('JAK2', 'Gene', '3717', (125, 129))	('arrest', 'Disease', 'MESH:D006323', (89, 95))	('IL13Ralpha1', 'Var', (58, 69))	('apoptosis', 'CPA', (100, 109))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))	('JAK2', 'Gene', (125, 129))
194031	33419470	In 4 T1 breast cancer cells, IL4Ralpha enhanced tumor growth by mediating IL4-related enhancement of glucose and glutamine metabolism.	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('enhancement', 'PosReg', (86, 97))	('tumor', 'Disease', (48, 53))	('IL4Ralpha', 'Var', (29, 38))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('glutamine', 'Chemical', 'MESH:D005973', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('4 T1', 'CellLine', 'CVCL:0125', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))	('enhanced', 'PosReg', (39, 47))
194032	33419470	The silencing of IL4Ralpha inhibited the growth and invasiveness of pancreatic cancer cells by suppressing the STAT3 and Akt pathways.	('invasiveness of pancreatic cancer', 'Disease', (52, 85))	('suppressing', 'NegReg', (95, 106))	('Akt', 'Gene', (121, 124))	('STAT3', 'Gene', (111, 116))	('invasiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (52, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('IL4Ralpha', 'Protein', (17, 26))	('inhibited', 'NegReg', (27, 36))	('STAT3', 'Gene', '6774', (111, 116))	('Akt', 'Gene', '207', (121, 124))	('silencing', 'Var', (4, 13))
194035	33419470	In a transgenic mouse model with overexpression of IL4, IL4/IL4Ralpha suppressed the development of melanoma through activation of the P21-mediated STAT6 pathway and inhibition of anti-apoptotic BCL2 expression.	('BCL2', 'Gene', (195, 199))	('inhibition', 'NegReg', (166, 176))	('P21', 'Gene', '12575', (135, 138))	('IL4/IL4Ralpha', 'Var', (56, 69))	('development of', 'CPA', (85, 99))	('P21', 'Gene', (135, 138))	('suppressed', 'NegReg', (70, 80))	('BCL2', 'Gene', '12043', (195, 199))	('expression', 'MPA', (200, 210))	('mouse', 'Species', '10090', (16, 21))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('activation', 'PosReg', (117, 127))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
194041	33419470	In addition, the expression of IL4Ralpha and/or IL13Ralpha1 was observed in both the cytoplasm and nuclei of human cancer tissue samples, such as clear cell renal cell carcinoma, squamous cell carcinoma, and lung cancer.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('observed', 'Reg', (64, 72))	('clear cell renal cell carcinoma', 'Disease', (146, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('squamous cell carcinoma', 'Disease', (179, 202))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (146, 177))	('cancer', 'Disease', (213, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('IL4Ralpha', 'Var', (31, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('IL13Ralpha1', 'Var', (48, 59))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (146, 177))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))	('lung cancer', 'Disease', (208, 219))
194054	33419470	In rhabdomyosarcoma cells, IL4 and IL13 activate cellular proliferation through the JAK/STAT signaling pathway, and blocking IL4R with a neutralizing antibody suppressed tumor progression.	('JAK', 'Gene', '3716;3717;3718', (84, 87))	('IL4R', 'Gene', (125, 129))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (3, 19))	('tumor', 'Disease', (170, 175))	('suppressed', 'NegReg', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (3, 19))	('IL4', 'Gene', (27, 30))	('STAT', 'Gene', (88, 92))	('IL13', 'Gene', '3596', (35, 39))	('blocking', 'Var', (116, 124))	('JAK', 'Gene', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('activate', 'PosReg', (40, 48))	('STAT', 'Gene', '6774;6778;20852', (88, 92))	('rhabdomyosarcoma', 'Disease', (3, 19))	('IL13', 'Gene', (35, 39))	('cellular proliferation', 'CPA', (49, 71))
194055	33419470	Blocking of IL4Ralpha also induced the apoptosis of breast cancer cells.	('IL4Ralpha', 'Protein', (12, 21))	('apoptosis', 'CPA', (39, 48))	('Blocking', 'Var', (0, 8))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('induced', 'Reg', (27, 34))
194056	33419470	In renal cell carcinoma cells, knock-down of IL4Ralpha or IL13Ralpha1 and pharmacological inhibition of JAK2 induced cell cycle arrest and apoptosis of cancer cells.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('IL13Ralpha1', 'Gene', (58, 69))	('cancer', 'Disease', (152, 158))	('arrest', 'Disease', 'MESH:D006323', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('JAK2', 'Gene', '3717', (104, 108))	('knock-down', 'Var', (31, 41))	('arrest', 'Disease', (128, 134))	('renal cell carcinoma', 'Disease', (3, 23))	('JAK2', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('apoptosis', 'CPA', (139, 148))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))
194057	33419470	Similarly, inhibition of JAK2, which is downstream of IL4R, delayed tumor growth in an osteosarcoma xenograft model.	('tumor', 'Disease', (68, 73))	('JAK2', 'Gene', '3717', (25, 29))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('osteosarcoma', 'Disease', (87, 99))	('osteosarcoma', 'Disease', 'MESH:D012516', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('JAK2', 'Gene', (25, 29))	('inhibition', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('delayed', 'NegReg', (60, 67))
194063	33419470	Therefore, when considering the shorter survival of STS patients expressing IL4Ralpha and IL13Ralpha1, therapeutics targeting IL4Ralpha and IL13Ralpha1 might be novel therapeutic strategems for the treatment of STSs.	('patients', 'Species', '9606', (56, 64))	('STS', 'Phenotype', 'HP:0030448', (211, 214))	('IL4Ralpha', 'Var', (76, 85))	('STS', 'Phenotype', 'HP:0030448', (52, 55))	('IL13Ralpha1', 'Var', (140, 151))	('IL4Ralpha', 'Var', (126, 135))	('IL13Ralpha1', 'Var', (90, 101))
194066	33419470	In addition, this study suggests that blocking of the IL4Ralpha/IL13Ralpha1 pathway might be a novel therapeutic stratagem for STSs.	('IL4Ralpha/IL13Ralpha1', 'Gene', '3566;3597', (54, 75))	('IL4Ralpha/IL13Ralpha1', 'Gene', (54, 75))	('blocking', 'Var', (38, 46))	('STS', 'Phenotype', 'HP:0030448', (127, 130))	('STSs', 'Disease', (127, 131))
194150	26586129	The epidemiological data concerning Neoscytalidium superficial infection obtained in our hospital over a 2-year analysis period (January 1, 2010 to December 31, 2011) were consistent with those of previous epidemiological studies performed in Paris and London with respectively 67 and 73 % of cases of neoscytalidiosis due to Neoscytalidium dimidiatum.	('Neoscytalidium', 'Var', (326, 340))	('infection', 'Disease', (63, 72))	('infection', 'Disease', 'MESH:D007239', (63, 72))	('Neoscytalidium dimidiatum', 'Species', '108428', (326, 351))	('neoscytalidiosis', 'Disease', (302, 318))
194195	26502919	The disruption of Akt signaling plays an important role in tumor progression.	('tumor', 'Disease', (59, 64))	('Akt', 'Gene', (18, 21))	('Akt', 'Gene', '207', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('disruption', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
194211	26502919	PTEN antagonizes PI3K function, and the loss of PTEN activates the Akt/mTOR pathway.	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('Akt', 'Gene', (67, 70))	('activates', 'PosReg', (53, 62))	('PI3K function', 'Pathway', (17, 30))	('mTOR', 'Gene', '2475', (71, 75))	('loss', 'Var', (40, 44))	('mTOR', 'Gene', (71, 75))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('Akt', 'Gene', '207', (67, 70))
194241	26502919	We used rabbit antibodies for phosphorylated (p) Akt (p-Akt) (serine 473 [Ser473]; 1:50 dilution), p-mTOR (Ser2448; 1:100 dilution), p-S6 (Ser235/236; 1:100 dilution), p-4E-BP1 (threonine 37/46 [Thr37/46]; 1:400 dilution), p- mitogen-activated protein kinase1/2 (p-MEK1/2) (Ser217/221; 1:100 dilution), p-extracellular signal-regulated kinase (p-ERK1/2) (Thr202/Tyr204; 1:400 dilution), PTEN (1:50 dilution) and HSP90 (1:400 dilution) (Cell Signaling Technology, Danvers, MA).	('Thr202/Tyr204', 'Var', (355, 368))	('mTOR', 'Gene', '2475', (101, 105))	('Akt', 'Gene', (56, 59))	('p-Akt', 'Gene', (54, 59))	('p-S6', 'Gene', '338413', (133, 137))	('p-S6', 'Gene', (133, 137))	('Akt', 'Gene', '207', (56, 59))	('PTEN', 'Gene', '5728', (387, 391))	('HSP90', 'Gene', (412, 417))	('mitogen-activated protein kinase1', 'Gene', (226, 259))	('mitogen-activated protein kinase1', 'Gene', '5594', (226, 259))	('rabbit', 'Species', '9986', (8, 14))	('HSP90', 'Gene', '3320', (412, 417))	('p-Akt', 'Gene', '207', (54, 59))	('Akt', 'Gene', (49, 52))	('mTOR', 'Gene', (101, 105))	('p-4', 'Gene', (168, 171))	('Akt', 'Gene', '207', (49, 52))	('p-4', 'Gene', '201780', (168, 171))	('PTEN', 'Gene', (387, 391))
194254	26502919	For p-MEK1/2 and p-Erk1/2, the comparison of protein expression between tumor tissue and normal muscular tissue was not made because the MAPK pathway may be activated under a state of perioperative stress in skeletal muscle.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Erk1/2', 'Gene', (19, 25))	('tumor', 'Disease', (72, 77))	('activated', 'PosReg', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Erk1/2', 'Gene', '5595;5594', (19, 25))	('p-MEK1/2', 'Var', (4, 12))	('MAPK pathway', 'Pathway', (137, 149))
194272	26502919	Seven of the 32 (21.9 %) undifferentiated pleomorphic sarcomas with MDM2 amplification were excluded because their biological character is similar to that of DDLS.	('MDM2', 'Gene', '4193', (68, 72))	('MDM2', 'Gene', (68, 72))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (25, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('undifferentiated pleomorphic sarcomas', 'Disease', (25, 62))	('amplification', 'Var', (73, 86))
194281	26502919	The positive ratios were as follows: p-Akt, 57.3 %; p-mTOR, 51.9 %; p-S6RP, 54.5 %; p-4EBP, 57.1 %; p-MEK1/2, 48.6 %; p-ERK1/2, 74.0 %; PTEN, 77.3 %; and HSP90, 56.4 %.	('HSP90', 'Gene', (154, 159))	('p-Akt', 'Gene', (37, 42))	('p-4', 'Gene', (84, 87))	('HSP90', 'Gene', '3320', (154, 159))	('p-S6', 'Gene', '338413', (68, 72))	('mTOR', 'Gene', '2475', (54, 58))	('p-4', 'Gene', '201780', (84, 87))	('p-S6', 'Gene', (68, 72))	('mTOR', 'Gene', (54, 58))	('p-Akt', 'Gene', '207', (37, 42))	('p-MEK1/2', 'Var', (100, 108))	('PTEN', 'Gene', (136, 140))	('p-ERK1/2', 'Var', (118, 126))	('PTEN', 'Gene', '5728', (136, 140))
194286	26502919	The positivities for p-MEK1/2 and p-Erk1/2 were significantly correlated with each other (p = 0.021).	('Erk1/2', 'Gene', (36, 42))	('Erk1/2', 'Gene', '5595;5594', (36, 42))	('p-MEK1/2', 'Var', (21, 29))	('correlated', 'Reg', (62, 72))
194287	26502919	The positivity for p-MEK1/2 was correlated with the elevated expression of HSP90 (p = 0.0195).	('elevated', 'PosReg', (52, 60))	('HSP90', 'Gene', '3320', (75, 80))	('p-MEK1/2', 'Gene', (19, 27))	('positivity', 'Var', (4, 14))	('expression', 'MPA', (61, 71))	('HSP90', 'Gene', (75, 80))
194288	26502919	Clinicopathologically, the positivity for p-mTOR was correlated with the existence of metastasis (p = 0.003), tumor necrosis (p = 0.0007) and >10 % MIB-1 labeling index (LI) (p = 0.0038).	('positivity', 'Var', (27, 37))	('tumor necrosis', 'Disease', 'MESH:D009336', (110, 124))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('MIB-1', 'Gene', (148, 153))	('>10 %', 'Var', (142, 147))	('mTOR', 'Gene', (44, 48))	('mTOR', 'Gene', '2475', (44, 48))	('tumor necrosis', 'Disease', (110, 124))	('MIB-1', 'Gene', '57534', (148, 153))	('metastasis', 'CPA', (86, 96))
194290	26502919	p-4EBP was correlated with large tumor size (p = 0.0316), the existence of metastasis (p = 0.0014), >10 % MIB-1 LI (p = 0.0095), and higher AJCC stage (p = 0.0173).	('AJCC', 'Disease', (140, 144))	('MIB-1', 'Gene', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('MIB-1', 'Gene', '57534', (106, 111))	('>10 %', 'Var', (100, 105))	('p-4', 'Gene', (0, 3))	('metastasis', 'CPA', (75, 85))	('tumor', 'Disease', (33, 38))	('p-4', 'Gene', '201780', (0, 3))
194292	26502919	In the univariate analysis, the positivities for p-Akt, p-mTOR, p-S6RP and p-4EBP and elevated HSP90 expression were significant risk factors for a poor prognosis.	('elevated', 'PosReg', (86, 94))	('mTOR', 'Gene', (58, 62))	('p-4', 'Gene', (75, 78))	('HSP90', 'Gene', (95, 100))	('p-S6', 'Gene', '338413', (64, 68))	('HSP90', 'Gene', '3320', (95, 100))	('p-S6', 'Gene', (64, 68))	('p-4', 'Gene', '201780', (75, 78))	('p-Akt', 'Gene', '207', (49, 54))	('positivities', 'Var', (32, 44))	('p-Akt', 'Gene', (49, 54))	('expression', 'MPA', (101, 111))	('mTOR', 'Gene', '2475', (58, 62))
194302	26502919	In the Matrigel invasion assay, 17-DMAG caused a decrease in the invasiveness of both cell lines, FPS-1 (p = 0.009) and FU-MFH-2 (p = 0.041) (Fig.	('17-DMAG', 'Chemical', 'MESH:C448659', (32, 39))	('MFH', 'Gene', '27086', (123, 126))	('decrease', 'NegReg', (49, 57))	('Matrigel invasion assay', 'CPA', (7, 30))	('17-DMAG', 'Var', (32, 39))	('invasiveness', 'CPA', (65, 77))	('MFH', 'Gene', (123, 126))
194304	26502919	The Western blotting showed decreased expressions of p-Akt, p-mTOR, p-S6RP, p-MEK1/2 and p-ERK1/2 in both cell lines (Fig.	('p-Akt', 'Gene', (53, 58))	('p-MEK1/2', 'Var', (76, 84))	('mTOR', 'Gene', '2475', (62, 66))	('mTOR', 'Gene', (62, 66))	('decreased', 'NegReg', (28, 37))	('expressions', 'MPA', (38, 49))	('p-S6', 'Gene', '338413', (68, 72))	('p-S6', 'Gene', (68, 72))	('p-ERK1/2', 'Var', (89, 97))	('p-Akt', 'Gene', '207', (53, 58))
194306	26502919	The p-Akt expression was decreased at 6 h and at 12 h after the treatment with 17-DMAG, and the p-mTOR and p-S6RP expressions were decreased at 12 h. This sequential alternation indicated that the inhibition of HSP90-Akt binding blocked the Akt/ mTOR signaling pathway.	('blocked', 'NegReg', (229, 236))	('p-Akt', 'Gene', (4, 9))	('mTOR', 'Gene', (98, 102))	('Akt', 'Gene', (6, 9))	('Akt', 'Gene', '207', (6, 9))	('mTOR', 'Gene', '2475', (98, 102))	('17-DMAG', 'Chemical', 'MESH:C448659', (79, 86))	('p-S6', 'Gene', '338413', (107, 111))	('Akt', 'Gene', (241, 244))	('p-S6', 'Gene', (107, 111))	('Akt', 'Gene', '207', (241, 244))	('mTOR', 'Gene', (246, 250))	('HSP90', 'Gene', (211, 216))	('Akt', 'Gene', (217, 220))	('p-Akt', 'Gene', '207', (4, 9))	('inhibition', 'Var', (197, 207))	('binding', 'Interaction', (221, 228))	('mTOR', 'Gene', '2475', (246, 250))	('Akt', 'Gene', '207', (217, 220))	('HSP90', 'Gene', '3320', (211, 216))
194314	26502919	Amplification of MDM2, the driving genes in 12q13-15, can frequently be detected by FISH.	('Amplification', 'Var', (0, 13))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))
194315	26502919	Representative sarcomas with adipocytic differentiation that show MDM2 gene amplifications are defined as DDLS.	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('amplifications', 'Var', (76, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('MDM2', 'Gene', '4193', (66, 70))	('sarcomas', 'Disease', (15, 23))	('MDM2', 'Gene', (66, 70))
194316	26502919	However, a recent study reported that peripheral UPS with MDM2 gene amplification is considered DDLS even if there is no well-differentiated liposarcoma area.	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('gene amplification', 'Var', (63, 81))	('liposarcoma', 'Disease', (141, 152))	('MDM2', 'Gene', '4193', (58, 62))	('MDM2', 'Gene', (58, 62))	('DDLS', 'Disease', (96, 100))	('liposarcoma', 'Phenotype', 'HP:0012034', (141, 152))	('liposarcoma', 'Disease', 'MESH:D008080', (141, 152))
194326	26502919	Akt is a serine/threonine kinase activated by PI3K, and activated AKT initiates a cascade of downstream signaling.	('AKT', 'Gene', (66, 69))	('Akt', 'Gene', '207', (0, 3))	('PI3K', 'Var', (46, 50))	('AKT', 'Gene', '207', (66, 69))	('Akt', 'Gene', (0, 3))
194333	26502919	Abnormalities of several molecules could be responsible for the activation of the Akt/mTOR pathway.	('mTOR', 'Gene', '2475', (86, 90))	('Abnormalities', 'Var', (0, 13))	('Akt', 'Gene', '207', (82, 85))	('mTOR', 'Gene', (86, 90))	('activation', 'PosReg', (64, 74))	('Akt', 'Gene', (82, 85))
194334	26502919	Some studies have revealed that gene mutations in PI3KCA or AKT1 activate the Akt/mTOR pathway.	('Akt', 'Gene', '207', (78, 81))	('activate', 'PosReg', (65, 73))	('mutations', 'Var', (37, 46))	('mTOR', 'Gene', (82, 86))	('Akt', 'Gene', (78, 81))	('PI3KCA', 'Gene', (50, 56))	('mTOR', 'Gene', '2475', (82, 86))	('AKT1', 'Gene', '207', (60, 64))	('AKT1', 'Gene', (60, 64))
194336	26502919	PTEN antagonizes PI3K function, and the loss of PTEN increases PI3K-AKT signaling.	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('PTEN', 'Gene', '5728', (0, 4))	('PI3K function', 'Pathway', (17, 30))	('AKT', 'Gene', '207', (68, 71))	('loss', 'Var', (40, 44))	('increases', 'PosReg', (53, 62))	('PTEN', 'Gene', (0, 4))	('AKT', 'Gene', (68, 71))
194337	26502919	In the present study, we investigated the status of PTEN in UPSs, and our immunohistochemical analysis showed that the loss of PTEN was not correlated with the activation of the Akt/mTOR pathway.	('mTOR', 'Gene', (182, 186))	('mTOR', 'Gene', '2475', (182, 186))	('loss', 'Var', (119, 123))	('PTEN', 'Gene', '5728', (127, 131))	('PTEN', 'Gene', (52, 56))	('PTEN', 'Gene', '5728', (52, 56))	('Akt', 'Gene', '207', (178, 181))	('PTEN', 'Gene', (127, 131))	('Akt', 'Gene', (178, 181))
194341	26502919	This may have occurred because there is cross-talk between the AKT/mTOR and MAPK pathways, and MAPK pathway signaling can be enhanced by mTOR inhibition.	('AKT', 'Gene', (63, 66))	('cross-talk', 'Reg', (40, 50))	('MAPK pathway signaling', 'Pathway', (95, 117))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', (137, 141))	('mTOR', 'Gene', '2475', (67, 71))	('mTOR', 'Gene', '2475', (137, 141))	('MAPK pathways', 'Pathway', (76, 89))	('AKT', 'Gene', '207', (63, 66))	('enhanced', 'PosReg', (125, 133))	('inhibition', 'Var', (142, 152))
194350	26502919	Our in vitro study yielded evidence that 17-DMAG decreased the viability and the invasiveness of UPS cells, and 17-DMAG inactivated the kinase activity of the Akt/mTOR and MAPK pathways although the cell motility remained unchanged.	('Akt', 'Gene', (159, 162))	('inactivated', 'NegReg', (120, 131))	('17-DMAG', 'Var', (112, 119))	('invasiveness of UPS cells', 'CPA', (81, 106))	('viability', 'CPA', (63, 72))	('mTOR', 'Gene', '2475', (163, 167))	('MAPK pathways', 'Pathway', (172, 185))	('mTOR', 'Gene', (163, 167))	('17-DMAG', 'Chemical', 'MESH:C448659', (112, 119))	('decreased', 'NegReg', (49, 58))	('kinase activity', 'MPA', (136, 151))	('Akt', 'Gene', '207', (159, 162))	('17-DMAG', 'Chemical', 'MESH:C448659', (41, 48))
194353	26502919	We did not verify the immediate cause of decreased invasiveness induced by 17-DMAG.	('decreased invasiveness', 'Disease', (41, 63))	('decreased invasiveness', 'Disease', 'MESH:D009362', (41, 63))	('17-DMAG', 'Var', (75, 82))	('17-DMAG', 'Chemical', 'MESH:C448659', (75, 82))
194389	26140238	We also confirmed T-cell receptor excision circles and robust proliferative responses to mitogens (not shown).	('excision circles', 'Var', (34, 50))	('proliferative', 'CPA', (62, 75))	('T-cell receptor', 'Gene', (18, 33))	('T-cell receptor', 'Gene', '328483', (18, 33))
194396	26140238	Subsequently, mice were treated weekly for 5 weeks with FcIL-7 alone (control), NHS-IL12/FcIL-7, or NHS-IL12/IL-2MAB602 (Fig.	('IL-2MAB602', 'Gene', (109, 119))	('IL-2MAB602', 'Gene', '16183', (109, 119))	('mice', 'Species', '10090', (14, 18))	('FcIL-7', 'Chemical', '-', (89, 95))	('FcIL-7', 'Chemical', '-', (56, 62))	('NHS-IL12/FcIL-7', 'Var', (80, 95))
194411	26140238	SPECT/CT biodistribution studies with 123I-labeled NHS-IL12 revealed significant in vivo enrichment of NHS-IL12 inside the sarcoma microenvironment (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('123I', 'Chemical', 'MESH:C000614958', (38, 42))	('sarcoma', 'Disease', (123, 130))	('NHS-IL12', 'Var', (103, 111))
194415	26140238	To understand the differences underlying the therapeutic efficacy of the different treatment protocols, we performed histologic, immunohistochemical, and extensive molecular and functional characterization of the human immune cells infiltrating the A204 sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (254, 262))	('human', 'Species', '9606', (213, 218))	('sarcomas', 'Phenotype', 'HP:0100242', (254, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('A204', 'Var', (249, 253))	('sarcomas', 'Disease', (254, 262))
194421	26140238	We found the activating receptors NKG2E, NKp44, and NKp46 only in tumors of mice treated with NHS-IL12/FcIL-7, whereas NKp30 expression was restricted to sarcomas of NHS-IL12/IL-2MAB602-treated and NHS-IL12/FcIL-7 long-term treated mice (Fig.	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('NKp44', 'Gene', (41, 46))	('NHS-IL12/FcIL-7', 'Var', (94, 109))	('NKG2E', 'Gene', (34, 39))	('IL-2MAB602', 'Gene', '16183', (175, 185))	('NKp46', 'Gene', '17086', (52, 57))	('NKG2E', 'Gene', '58179', (34, 39))	('mice', 'Species', '10090', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('sarcomas of NHS-IL12', 'Disease', 'MESH:C538336', (154, 174))	('NKp46', 'Gene', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('mice', 'Species', '10090', (232, 236))	('sarcomas', 'Phenotype', 'HP:0100242', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('IL-2MAB602', 'Gene', (175, 185))	('sarcomas of NHS-IL12', 'Disease', (154, 174))	('tumors', 'Disease', (66, 72))	('FcIL-7', 'Chemical', '-', (103, 109))	('FcIL-7', 'Chemical', '-', (207, 213))
194437	26140238	The T-bet/RORC ratio was <0.05 in the FcIL-7-only cohort, but was 19-fold higher (0.8) and 44-fold (2.2) higher in mice receiving NHS-IL12 with either FcIL-7 or IL-2MAB602 (Fig.	('RORC', 'Gene', (10, 14))	('higher', 'PosReg', (105, 111))	('higher', 'PosReg', (74, 80))	('IL-2MAB602', 'Gene', (161, 171))	('IL-2MAB602', 'Gene', '16183', (161, 171))	('RORC', 'Gene', '19885', (10, 14))	('FcIL-7', 'Chemical', '-', (151, 157))	('FcIL-7', 'Chemical', '-', (38, 44))	('T-bet', 'Gene', (4, 9))	('NHS-IL12', 'Var', (130, 138))	('mice', 'Species', '10090', (115, 119))	('T-bet', 'Gene', '57765', (4, 9))
194438	26140238	In line with the T-bet/RORC expression, Foxp3 expression was approximately 10-fold lower in both NHS-IL12 groups than in the FcIL-7-only cohort (Fig.	('T-bet', 'Gene', '57765', (17, 22))	('NHS-IL12', 'Var', (97, 105))	('lower', 'NegReg', (83, 88))	('Foxp3', 'Gene', (40, 45))	('FcIL-7', 'Chemical', '-', (125, 131))	('expression', 'MPA', (46, 56))	('Foxp3', 'Gene', '20371', (40, 45))	('T-bet', 'Gene', (17, 22))	('RORC', 'Gene', '19885', (23, 27))	('RORC', 'Gene', (23, 27))
194453	26140238	In sharp contrast, up to 70% of the sarcoma cells from mice treated with either NHS-IL12/IL-2MAB602 or NHS-IL12/FcIL-7 expressed the senescence marker p-HP1gamma or p16INK4a (Fig.	('senescence', 'MPA', (133, 143))	('FcIL-7', 'Chemical', '-', (112, 118))	('HP1gamma', 'Gene', (153, 161))	('p16INK4a', 'Var', (165, 173))	('IL-2MAB602', 'Gene', (89, 99))	('HP1gamma', 'Gene', '12417', (153, 161))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('IL-2MAB602', 'Gene', '16183', (89, 99))	('mice', 'Species', '10090', (55, 59))	('sarcoma', 'Disease', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('NHS-IL12/FcIL-7', 'Var', (103, 118))
194461	26140238	Accordingly, A204 sarcomas showed neither the cross-striation that characterizes myocytes nor expression of desmin prior to transplantation (not shown).	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcomas', 'Disease', (18, 26))	('A204', 'Var', (13, 17))
194470	26140238	Additionally, sarcoma cells morphed into beta-galactosidase+ elongated multinucleate cells and formed multinucleate syncytia (Fig.	('sarcoma', 'Disease', (14, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))	('formed', 'Reg', (95, 101))	('multinucleate syncytia', 'Phenotype', 'HP:0031387', (102, 124))	('morphed', 'Var', (28, 35))	('beta-galactosidase', 'Gene', '12091', (41, 59))	('beta-galactosidase', 'Gene', (41, 59))	('multinucleate', 'CPA', (102, 115))
194493	26140238	While investigating the underlying mechanism, we found that IL-12-associated TH1-immunity induced a senescence-defining growth arrest, mirrored by abrogated expression of the proliferation marker Ki67, nuclear p-HP1gamma, and p16INK4a in up to 75% of all tumor cells.	('abrogated', 'NegReg', (147, 156))	('Ki67', 'Gene', '17345', (196, 200))	('p16INK4a', 'Var', (226, 234))	('tumor', 'Disease', (255, 260))	('expression', 'MPA', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('Ki67', 'Gene', (196, 200))	('senescence-defining growth arrest', 'CPA', (100, 133))	('HP1gamma', 'Gene', (212, 220))	('HP1gamma', 'Gene', '12417', (212, 220))	('IL-12-associated', 'Gene', (60, 76))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('growth arrest', 'Phenotype', 'HP:0001510', (120, 133))
194494	26140238	In humans, p16INK4a-established stable G1 cell cycle arrest can be enforced by the irreversible block of cytokinesis, as the p16INK4a/Rb-pathway synergizes with mitogenic signals in reducing the level of a mitotic exit network kinase required for cytokinesis.	('p16INK4a/Rb-pathway', 'Var', (125, 144))	('humans', 'Species', '9606', (3, 9))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (42, 59))	('level of a mitotic exit network kinase required', 'MPA', (195, 242))
194496	26140238	p21CIP1/WAF, an effector molecule downstream of p16INK4a, collaborates with p16INK4a in establishing growth arrest, and functions as a coordinator of cell cycle exit and differentiation when induced independently from p53, such as by IFN-gamma.	('growth arrest', 'Phenotype', 'HP:0001510', (101, 114))	('establishing growth arrest', 'Disease', (88, 114))	('establishing growth arrest', 'Disease', 'MESH:D006323', (88, 114))	('p21CIP1/WAF', 'Var', (0, 11))
194531	26140238	Primary antibodies against the following proteins were used: CD3 (SP7, 1:50; DCS Innovative Diagnostic Systeme GmBH, Germany); monoclonal rabbit anti human CD4 (SP35, 1:50, Zytomed Systems); CD8 (C8/144B, 1:100), CD56 (123C3-D5, 1:20), CD68 (PG-M1, 1:150), HLA-DR-alpha (TAL.1B5, 1:200), desmin (D33, 1:100) (DAKO, Germany); perforin (5810, 1:200, Novocastra/Leica, Germany).	('human', 'Species', '9606', (150, 155))	('CD3', 'Gene', (61, 64))	('CD8', 'Gene', '925', (191, 194))	('rabbit', 'Species', '9986', (138, 144))	('CD3', 'Gene', '28134', (61, 64))	('CD56', 'Gene', (213, 217))	('SP7', 'Gene', (66, 69))	('CD68', 'Gene', '12514', (236, 240))	('CD68', 'Gene', (236, 240))	('CD8', 'Gene', (191, 194))	('CD56', 'Gene', '17967', (213, 217))	('SP7', 'Gene', '170574', (66, 69))	('5810', 'Var', (335, 339))
194535	26140238	After 3 washes, the sections were incubated with Cy3- or Cy5-conjugated donkey anti-rabbit antibody and Cy3- or Cy5-conjugated donkey anti-mouse antibody (all from Dianova, Germany).	('Cy3', 'Chemical', '-', (104, 107))	('donkey', 'Species', '9793', (72, 78))	('rabbit', 'Species', '9986', (84, 90))	('Cy5-conjugated', 'Var', (57, 71))	('mouse', 'Species', '10090', (139, 144))	('Cy5', 'Chemical', 'MESH:C085321', (112, 115))	('Cy5', 'Chemical', 'MESH:C085321', (57, 60))	('Cy3', 'Chemical', '-', (49, 52))	('Cy3-', 'Var', (49, 53))	('Cy3- or Cy5-conjugated', 'Var', (104, 126))	('donkey', 'Species', '9793', (127, 133))
194604	22174684	Antagonists of integrin alphaVbeta3 inhibit tumor angiogenesis and tumor growth in a variety of animal models of cancer.	('Antagonists', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('integrin alphaVbeta3', 'Gene', (15, 35))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('inhibit', 'NegReg', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (67, 72))	('integrin alphaVbeta3', 'Gene', '3685', (15, 35))	('tumor', 'Disease', (44, 49))
194617	22174684	In primary endothelial cells (ECs), KSHV induced a 3.5-fold increase in integrin beta3 expression over mock infection.	('integrin beta3', 'Protein', (72, 86))	('increase', 'PosReg', (60, 68))	('expression', 'MPA', (87, 97))	('KSHV', 'Species', '37296', (36, 40))	('KSHV', 'Var', (36, 40))	('KS', 'Phenotype', 'HP:0100726', (36, 38))
194619	22174684	In TIME cells latently infected with KSHV, total cellular integrin beta3 was significantly increased as visualized by Western blot analysis with an antibody specific to integrin beta3 (Figure 1B).	('increased', 'PosReg', (91, 100))	('KS', 'Phenotype', 'HP:0100726', (37, 39))	('KSHV', 'Species', '37296', (37, 41))	('KSHV', 'Var', (37, 41))
194629	22174684	Furthermore, Src is also phosphorylated more heavily on tyrosine 416 in KSHV-infected cells.	('KSHV-infected', 'Disease', (72, 85))	('KSHV-infected', 'Disease', 'MESH:C537372', (72, 85))	('Src', 'Gene', (13, 16))	('tyrosine', 'Chemical', 'MESH:D014443', (56, 64))	('phosphorylated', 'MPA', (25, 39))	('Src', 'Gene', '6714', (13, 16))	('KS', 'Phenotype', 'HP:0100726', (72, 74))	('tyrosine 416', 'Var', (56, 68))
194670	22174684	Figure 6 (C and D) shows that the expression of alphaVbeta3 integrin complexes is significantly reduced upon transfection of integrin beta3 siRNA.	('beta3', 'Gene', '27319', (134, 139))	('transfection', 'Var', (109, 121))	('expression', 'MPA', (34, 44))	('beta3', 'Gene', (54, 59))	('beta3', 'Gene', '27319', (54, 59))	('beta3', 'Gene', (134, 139))	('reduced', 'NegReg', (96, 103))
194683	22174684	Su6656 had a similar effect on KSHV-infected cells as SKI-1 (Figure 6G and H).	('SKI-1', 'Gene', '55733', (54, 59))	('KS', 'Phenotype', 'HP:0100726', (31, 33))	('SKI-1', 'Gene', (54, 59))	('Su6656', 'Var', (0, 6))	('Su6656', 'Chemical', 'MESH:C416927', (0, 6))	('KSHV-infected', 'Disease', 'MESH:C537372', (31, 44))	('KSHV-infected', 'Disease', (31, 44))
194693	22174684	Furthermore, inhibition of integrins, and in particular alphaVbeta3, can inhibit angiogenesis and promote regression of tumors by inducing apoptosis of endothelial cells.	('regression', 'CPA', (106, 116))	('beta3', 'Gene', (62, 67))	('tumors', 'Disease', (120, 126))	('promote', 'PosReg', (98, 105))	('integrins', 'Protein', (27, 36))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('beta3', 'Gene', '27319', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('inhibition', 'Var', (13, 23))	('angiogenesis', 'CPA', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('inducing', 'NegReg', (130, 138))	('apoptosis', 'CPA', (139, 148))	('inhibit', 'NegReg', (73, 80))
194698	22174684	However, knock-in expression of a mutant beta3 that lacks phosphorylation sites blocks VEGF-induced pathological angiogenesis in these mice.	('beta3', 'Gene', (41, 46))	('beta3', 'Gene', '27319', (41, 46))	('VEGF-induced', 'Disease', (87, 99))	('mice', 'Species', '10090', (135, 139))	('blocks', 'NegReg', (80, 86))	('mutant', 'Var', (34, 40))
194702	22174684	Inhibition of integrin signaling and alphaVbeta3 had small effects on the ability of uninfected endothelial cells to form capillary-like structures on Matrigel.	('beta3', 'Gene', (43, 48))	('integrin', 'Protein', (14, 22))	('Inhibition', 'Var', (0, 10))	('beta3', 'Gene', '27319', (43, 48))
194718	22174684	Inhibition of integrins and integrin signaling has been proposed as a target for tumor therapy through inhibition of tumor cell growth itself and through inhibition of neo-angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('integrins', 'Protein', (14, 23))	('tumor', 'Disease', (117, 122))	('neo-angiogenesis', 'CPA', (168, 184))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('inhibition', 'NegReg', (154, 164))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (81, 86))	('inhibition', 'NegReg', (103, 113))
194732	22174684	One hundred or 500 ng of total RNA was used in a SuperScript III, Platinum SYBR green, one-step, quantitative reverse transcription PCR (RT-PCR; Invitrogen) according to manufacturer's protocols with the primers for either GAPDH (glyceraldehyde-3-phosphate dehydrogenase) (forward, 5'-AAG GTG AAG GTC GGA GTC AAC G-3'; reverse, 5'-TGG AAG ATG GTG ATG GGA TTT C-3') or integrin beta3 (forward, 5'-GCA AGG ATG CAG TGA ATT GT-3'; reverse, 5'-CTT GGG ACA CTC TGG CTC TT-3').	('AAC', 'Gene', (309, 312))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (230, 270))	('AAC', 'Gene', '10249', (309, 312))	('GAPDH', 'Gene', '2597', (223, 228))	('GAPDH', 'Gene', (223, 228))	('reverse', 'Var', (427, 434))	("C-3') or integrin beta3", 'Gene', '3690', (359, 382))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (230, 270))
194765	22174684	For inhibition studies, GRADSPK or GRGDSPK peptides, SKI-1 (Calbiochem), or su6656 (Sigma) were added at the time of plating on Matrigel.	('su6656', 'Chemical', 'MESH:C416927', (76, 82))	('RAD', 'Disease', 'MESH:C535729', (25, 28))	('SKI-1', 'Gene', (53, 58))	('su6656', 'Var', (76, 82))	('SKI-1', 'Gene', '55733', (53, 58))	('RAD', 'Disease', (25, 28))
194775	33659920	Consequently, ALT, WDLPS, and DDLPS share a common cytogenetic feature characterized by supernumerary ringed chromosomes and amplification of specific oncogenes located in the 12q13-15 amplicon, often including MDM2, FRS2, CDK4, HMGA2, YEATS2, and NAV3.	('MDM2', 'Gene', (211, 215))	('amplification', 'Var', (125, 138))	('FRS2', 'Gene', (217, 221))	('HMGA2', 'Gene', (229, 234))	('NAV3', 'Gene', (248, 252))	('NAV3', 'Gene', '89795', (248, 252))	('YEATS2', 'Gene', '55689', (236, 242))	('FRS2', 'Gene', '10818', (217, 221))	('YEATS2', 'Gene', (236, 242))	('oncogenes', 'Gene', (151, 160))	('CDK4', 'Gene', '1019', (223, 227))	('CDK4', 'Gene', (223, 227))	('MDM2', 'Gene', '4193', (211, 215))	('HMGA2', 'Gene', '8091', (229, 234))
194794	33659920	Subsequently, a planned subgroup analysis revealed the improvement in OS with eribulin was limited to the liposarcoma cohort when compared to dacarbazine (15.6 versus 8.4 months).	('eribulin', 'Var', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('liposarcoma', 'Disease', (106, 117))	('liposarcoma', 'Disease', 'MESH:D008080', (106, 117))	('dacarbazine', 'Chemical', 'MESH:D003606', (142, 153))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))
194800	33659920	CDK4 amplification is present in over 90% of WDLPS and DDLPS and drives the overexpression of CDK4 and cell cycle progression through dysregulated phosphorylation of retinoblastoma (Rb) protein.	('CDK4', 'Gene', (94, 98))	('retinoblastoma', 'Disease', 'MESH:D012175', (166, 180))	('cell cycle progression', 'CPA', (103, 125))	('retinoblastoma', 'Disease', (166, 180))	('CDK4', 'Gene', '1019', (94, 98))	('amplification', 'Var', (5, 18))	('dysregulated phosphorylation', 'MPA', (134, 162))	('Rb', 'Phenotype', 'HP:0009919', (182, 184))	('Rb', 'Protein', (182, 184))	('CDK4', 'Gene', (0, 4))	('retinoblastoma', 'Phenotype', 'HP:0009919', (166, 180))	('CDK4', 'Gene', '1019', (0, 4))	('overexpression', 'PosReg', (76, 90))
194801	33659920	CDK4/6 inhibitors induce growth arrest, upregulate the chromatin remodeling enzyme ATRX, and decrease expression of the negative P53 regulator, MDM2, resulting in cell senescence.	('cell senescence', 'CPA', (163, 178))	('expression', 'MPA', (102, 112))	('P53', 'Gene', (129, 132))	('upregulate', 'PosReg', (40, 50))	('ATRX', 'Gene', (83, 87))	('P53', 'Gene', '7157', (129, 132))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('inhibitors', 'Var', (7, 17))	('MDM2', 'Gene', '4193', (144, 148))	('growth arrest', 'Disease', (25, 38))	('MDM2', 'Gene', (144, 148))	('decrease', 'NegReg', (93, 101))	('growth arrest', 'Disease', 'MESH:D006323', (25, 38))	('ATRX', 'Gene', '546', (83, 87))	('CDK4/6', 'Gene', (0, 6))	('growth arrest', 'Phenotype', 'HP:0001510', (25, 38))
194810	33659920	Early phase clinical trials investigating MDM2 inhibitors in various malignancies with MDM2 overexpression or amplification showed manageable toxicity and some activity (mainly stable disease and a few partial responses) in WDLPS/DDLPS.	('stable disease', 'Disease', (177, 191))	('amplification', 'Var', (110, 123))	('overexpression', 'PosReg', (92, 106))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('activity', 'MPA', (160, 168))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('toxicity', 'Disease', (142, 150))	('MDM2', 'Gene', '4193', (42, 46))	('MDM2', 'Gene', '4193', (87, 91))	('MDM2', 'Gene', (42, 46))	('MDM2', 'Gene', (87, 91))	('malignancies', 'Disease', (69, 81))	('WDLPS/DDLPS', 'Disease', (224, 235))
194831	33659920	MLPS represent approximately 20-30% of the liposarcoma subfamily and are defined by the fusion oncogene FUS-DDIT3 resulting from the genetic translocation t(12:16)(q13:p11) or less frequently EWSR1-DDIT3 resulting from t(12;22)(q13;q12).	('DDIT3', 'Gene', '1649', (108, 113))	('FUS', 'Gene', (104, 107))	('DDIT3', 'Gene', (108, 113))	('MLPS', 'Disease', 'None', (0, 4))	('EWSR1', 'Gene', '2130', (192, 197))	('liposarcoma', 'Disease', (43, 54))	('MLPS', 'Phenotype', 'HP:0012268', (0, 4))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (219, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('FUS', 'Gene', '2521', (104, 107))	('resulting from', 'Reg', (114, 128))	('MLPS', 'Disease', (0, 4))	('t(12;22)(q13;q12', 'Var', (219, 235))	('liposarcoma', 'Phenotype', 'HP:0012034', (43, 54))	('DDIT3', 'Gene', '1649', (198, 203))	('t(12:16)(q13:p11', 'Var', (155, 171))	('EWSR1', 'Gene', (192, 197))	('DDIT3', 'Gene', (198, 203))	('t(12:16)(q13:p11)', 'STRUCTURAL_ABNORMALITY', 'None', (155, 172))	('liposarcoma', 'Disease', 'MESH:D008080', (43, 54))
194861	33659920	Furthermore, activating PIK3CA mutations are present in up to 18% of MLPS, providing a rationale for several targeted therapies, including mTOR inhibitors and PI3K inhibitors.	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('activating', 'PosReg', (13, 23))	('mTOR', 'Gene', (139, 143))	('MLPS', 'Disease', 'None', (69, 73))	('mTOR', 'Gene', '2475', (139, 143))	('PIK3CA', 'Gene', '5290', (24, 30))	('MLPS', 'Disease', (69, 73))	('MLPS', 'Phenotype', 'HP:0012268', (69, 73))
194878	33659920	Common genomic alterations include mutations in TP53 (17%), NF1 (8%), RB1 (4%), PIK3CA (4%), SYK (4%), PTK2B (4%), EPHA5 (4%), and ERBB4 (4%), and deletions of TP53, RB1, and NF1 are also common.	('RB1', 'Gene', (166, 169))	('TP53', 'Gene', '7157', (160, 164))	('mutations', 'Var', (35, 44))	('NF1', 'Gene', (175, 178))	('PIK3CA', 'Gene', '5290', (80, 86))	('SYK', 'Gene', '6850', (93, 96))	('TP53', 'Gene', '7157', (48, 52))	('RB1', 'Gene', (70, 73))	('NF1', 'Gene', '4763', (60, 63))	('EPHA5', 'Gene', '2044', (115, 120))	('deletions', 'Var', (147, 156))	('PTK2B', 'Gene', (103, 108))	('RB1', 'Gene', '5925', (166, 169))	('NF1', 'Gene', (60, 63))	('ERBB4', 'Gene', '2066', (131, 136))	('PIK3CA', 'Gene', (80, 86))	('TP53', 'Gene', (160, 164))	('RB1', 'Gene', '5925', (70, 73))	('ERBB4', 'Gene', (131, 136))	('EPHA5', 'Gene', (115, 120))	('TP53', 'Gene', (48, 52))	('NF1', 'Gene', '4763', (175, 178))	('SYK', 'Gene', (93, 96))	('PTK2B', 'Gene', '2185', (103, 108))
194881	33659920	Notably, in the phase III trial comparing eribulin with dacarbazine, eribulin demonstrated an improvement in OS (22.2 versus 6.7 months) and a non-significant trend toward improved PFS (4.4 versus 1.4 months) in the PLPS subgroup.	('improvement', 'PosReg', (94, 105))	('dacarbazine', 'Chemical', 'MESH:D003606', (56, 67))	('improved', 'PosReg', (172, 180))	('PFS', 'MPA', (181, 184))	('PLPS', 'Disease', (216, 220))	('eribulin', 'Var', (69, 77))
194925	33499774	analyzed whole-genome miRNA microarray data of patients with gastric cancer and found the most related molecules were miR-19b-3p and miR-16-5p, providing new avenues for the diagnosis and treatment of gastric cancer.	('gastric cancer', 'Disease', (201, 215))	('gastric cancer', 'Disease', 'MESH:D013274', (201, 215))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (47, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('miR-16-5p', 'Var', (133, 142))	('miR-19b-3p', 'Var', (118, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (201, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
194955	33499774	Variations in molecular functions were enriched in nucleotide binding, cytoskeletal protein binding, purine nucleotide binding, purine ribonucleotide binding, and ribonucleotide binding (Table 2).	('ribonucleotide', 'Chemical', 'MESH:D012265', (163, 177))	('ribonucleotide', 'Chemical', 'MESH:D012265', (135, 149))	('ribonucleotide binding', 'MPA', (163, 185))	('purine nucleotide', 'Chemical', 'MESH:D011685', (101, 118))	('purine ribonucleotide', 'Chemical', '-', (128, 149))	('purine ribonucleotide binding', 'MPA', (128, 157))	('cytoskeletal', 'MPA', (71, 83))	('Variations', 'Var', (0, 10))	('purine nucleotide binding', 'MPA', (101, 126))	('nucleotide binding', 'MPA', (51, 69))
194989	33499774	Abnormal expression of MYBPC2 may be involved in the occurrence and development of many diseases.	('MYBPC2', 'Gene', '4606', (23, 29))	('MYBPC2', 'Gene', (23, 29))	('Abnormal', 'Var', (0, 8))	('involved', 'Reg', (37, 45))
194995	33499774	studied the relationship between FHL1 protein deletion and the progression of hereditary myopathy; they found that autophagy plays an important role in the development of hereditary myopathy and that MYBPC2 may be involved in its regulation.	('hereditary myopathy', 'Disease', (78, 97))	('deletion', 'Var', (46, 54))	('hereditary myopathy', 'Disease', (171, 190))	('FHL1', 'Gene', '2273', (33, 37))	('autophagy', 'CPA', (115, 124))	('myopathy', 'Phenotype', 'HP:0003198', (89, 97))	('myopathy', 'Phenotype', 'HP:0003198', (182, 190))	('MYBPC2', 'Gene', '4606', (200, 206))	('MYBPC2', 'Gene', (200, 206))	('FHL1', 'Gene', (33, 37))	('hereditary myopathy', 'Disease', 'MESH:D009135', (78, 97))	('hereditary myopathy', 'Disease', 'MESH:D009135', (171, 190))
194999	33499774	Our survival analysis showed that patients with rhabdomyosarcoma showing high expression of MYBPC2 had a poor prognosis.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (48, 64))	('patients', 'Species', '9606', (34, 42))	('high expression', 'Var', (73, 88))	('rhabdomyosarcoma', 'Disease', (48, 64))	('MYBPC2', 'Gene', '4606', (92, 98))	('MYBPC2', 'Gene', (92, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (48, 64))
195006	33499774	found that abnormal MYL1 may cause structural and functional abnormalities of myosin, which in turn may lead to congenital myopathy, suggesting that MYL1 may be a potential target for the diagnosis and treatment of congenital myopathy.	('myopathy', 'Phenotype', 'HP:0003198', (226, 234))	('congenital myopathy', 'Disease', 'MESH:D009224', (215, 234))	('congenital myopathy', 'Disease', 'MESH:D009224', (112, 131))	('functional abnormalities of myosin', 'Disease', 'MESH:C564253', (50, 84))	('abnormal', 'Var', (11, 19))	('functional abnormalities of myosin', 'Disease', (50, 84))	('structural', 'MPA', (35, 45))	('congenital myopathy', 'Disease', (112, 131))	('myopathy', 'Phenotype', 'HP:0003198', (123, 131))	('lead to', 'Reg', (104, 111))	('MYL1', 'Gene', (20, 24))	('cause', 'Reg', (29, 34))	('congenital myopathy', 'Disease', (215, 234))
195154	32206111	When we compared the different parameters and adjusted for size, ADCmean values were the best predictors of malignancy with an AUC of 0.99, followed closely by SUV-ratio, hilum enhancement pattern and R2* values (AUC= 0.98, 0.97, 0.93, respectively).	('ADCmean', 'Var', (65, 72))	('malignancy', 'Disease', 'MESH:D009369', (108, 118))	('malignancy', 'Disease', (108, 118))
195211	28166781	The molecular diagnostic marker is the t(11;22)(p13;q12) translocation, which creates an aberrant transcription factor, EWS-WT1, that underlies the oncogenesis of DSRCT.	('EWS-WT1', 'Gene', (120, 127))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (39, 56))	('t(11', 'Var', (39, 43))	('EWS-WT1', 'Gene', '7490', (120, 127))
195220	28166781	The JN-DSRCT-1 cell line, in vitro, is sensitive to trabectedin: after drug exposure, EWS-WT1 chimera expression decreases as well as binding on its target promoters.	('decreases', 'NegReg', (113, 122))	('EWS-WT1', 'Gene', '7490', (86, 93))	('trabectedin', 'Chemical', 'MESH:D000077606', (52, 63))	('expression', 'MPA', (102, 112))	('EWS-WT1', 'Gene', (86, 93))	('JN-DSRCT-1', 'CellLine', 'CVCL:9W68', (4, 14))	('binding', 'Interaction', (134, 141))	('chimera', 'Var', (94, 101))
195223	28166781	All cases of DSRCT harbor the t(11;22)(p13;q12) translocation, leading to fusion of the N-terminal domain of Ewing's sarcoma gene (EWS) to the C-terminal DNA binding domain of Wilms tumor suppressor gene (WT1).	('Wilms tumor', 'Phenotype', 'HP:0002667', (176, 187))	("Ewing's sarcoma gene", 'Gene', (109, 129))	('fusion', 'Var', (74, 80))	('Wilms tumor', 'Disease', (176, 187))	('EWS', 'Gene', '2130', (131, 134))	('EWS', 'Gene', (131, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('Wilms tumor', 'Disease', 'MESH:D009396', (176, 187))	("Ewing's sarcoma gene", 'Gene', '2130', (109, 129))	('WT1', 'Gene', '7490', (205, 208))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 47))	('WT1', 'Gene', (205, 208))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (109, 124))	('binding', 'Interaction', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
195240	28166781	Alternative splicing in exon 9 of WT1 and EWS-WT1 generates an insertion of three aminoacids -lysine, threonine and serine (KTS)- between zinc fingers 3 and 4, producing + KTS and -KTS isoforms.	('WT1', 'Gene', (46, 49))	('serine', 'MPA', (116, 122))	('lysine', 'Chemical', 'MESH:D008239', (94, 100))	('isoforms', 'MPA', (185, 193))	('EWS-WT1', 'Gene', '7490', (42, 49))	('WT1', 'Gene', '7490', (34, 37))	('EWS-WT1', 'Gene', (42, 49))	('insertion', 'MPA', (63, 72))	('WT1', 'Gene', (34, 37))	('WT1', 'Gene', '7490', (46, 49))	('threonine', 'MPA', (102, 111))	('Alternative splicing', 'Var', (0, 20))	('threonine', 'Chemical', 'MESH:D013912', (102, 111))	('serine', 'Chemical', 'MESH:D012694', (116, 122))
195265	28166781	To have a pure solution of each transcript variant for the Sanger sequencing, a small amount of each band was picked up from gel with a p200 pipette-tip, eluted for at least 3 h in 20 mul of PCR-grade ddH2O and subjected, individually, to Touchdown PCR amplification as described above (using 1 mul of each eluted product as template).	('pipette-tip', 'Disease', (141, 152))	('pipette-tip', 'Disease', 'MESH:D060725', (141, 152))	('ddH2', 'Gene', (201, 205))	('variant', 'Var', (43, 50))	('ddH2', 'Gene', '102775567', (201, 205))
195278	28166781	1b, where nuclei in interphase of JN-DSRCT-1 cells clearly reveal the t(11;22)(p13;q12) translocation, leading to the fusion protein EWS-WT1.	('EWS-WT1', 'Gene', (133, 140))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (70, 87))	('t(11;22)(p13;q12', 'Var', (70, 86))	('JN-DSRCT-1', 'CellLine', 'CVCL:9W68', (34, 44))	('leading to', 'Reg', (103, 113))	('EWS-WT1', 'Gene', '7490', (133, 140))
195289	28166781	Analysis of transcript b showed that almost 50% of this variant contained a small deletion (3 bp: AGC = > Ser) in the 5' end of Exon 9 of EWS gene, marked as (c).	('EWS', 'Gene', '2130', (138, 141))	('EWS', 'Gene', (138, 141))	('variant', 'Var', (56, 63))	('Ser', 'Chemical', 'MESH:D012694', (106, 109))	('contained', 'Reg', (64, 73))
195310	28166781	We have confirmed that JN-DSRCT-1 cells, which are one of the in vitro model of DSRCT, harbor the t(11;22)(p13;q12) translocation, which underlies this tumor and genetic events triggering malignant transformation.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('JN-DSRCT-1', 'CellLine', 'CVCL:9W68', (23, 33))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (98, 115))	('t(11;22)(p13', 'Var', (98, 110))
195314	28166781	We found that EWS-WT1 transcript levels are affected by trabectedin treatment, to a slight but significative degree, and that the drug causes a quantitative decrease in the binding of the aberrant trascription factor to its target promoters.	('affected', 'Reg', (44, 52))	('aberrant', 'Var', (188, 196))	('trabectedin', 'Chemical', 'MESH:D000077606', (56, 67))	('EWS-WT1', 'Gene', '7490', (14, 21))	('decrease', 'NegReg', (157, 165))	('EWS-WT1', 'Gene', (14, 21))	('transcript levels', 'MPA', (22, 39))	('binding', 'Interaction', (173, 180))	('trascription factor', 'Gene', (197, 216))
195363	32225029	Currently, a wide range of GFs and GF variants have been described in ES, although the vast majority of ES harbors the fusion of the EWSR1 gene (a member of the FET family comprising FUS, EWSR1, TAF15 genes which contain an RNA-binding domain) with the FLI1 gene (a member of the ETS transcription factor family) on 11q24.	('FUS', 'Gene', (183, 186))	('EWSR1', 'Gene', '2130', (133, 138))	('FUS', 'Gene', '2521', (183, 186))	('variants', 'Var', (38, 46))	('ES', 'Phenotype', 'HP:0012254', (70, 72))	('ES', 'Phenotype', 'HP:0012254', (104, 106))	('EWSR1', 'Gene', '2130', (188, 193))	('TAF15', 'Gene', (195, 200))	('EWSR1', 'Gene', (133, 138))	('FLI1', 'Gene', '2313', (253, 257))	('FLI1', 'Gene', (253, 257))	('EWSR1', 'Gene', (188, 193))	('TAF15', 'Gene', '8148', (195, 200))
195371	32225029	The targeted-RNA sequencing method based on Anchored Multiplex PCR (AMP) (Archer FusionPlex Sarcoma assay) is commonly used today, preferring RNA to DNA as starting material because most of the GFs arise due to breaks within large introns.	('arise due to', 'Reg', (198, 210))	('breaks', 'Var', (211, 217))	('Archer FusionPlex Sarcoma', 'Disease', (74, 99))	('Archer FusionPlex Sarcoma', 'Disease', 'MESH:D012509', (74, 99))	('Sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('GFs', 'Disease', (194, 197))
195374	32225029	The study cohort comprised 212 cases, 96 of which showed fusion gene expression by the NanoString assay, including all 20 ES, 11 synovial sarcomas, and 5 myxoid liposarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (129, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('synovial sarcomas', 'Disease', 'MESH:D013584', (129, 146))	('synovial sarcomas', 'Disease', (129, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (154, 173))	('liposarcomas', 'Phenotype', 'HP:0012034', (161, 173))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (154, 172))	('ES', 'Phenotype', 'HP:0012254', (122, 124))	('myxoid liposarcomas', 'Disease', (154, 173))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (129, 145))	('fusion gene expression', 'Var', (57, 79))	('liposarcoma', 'Phenotype', 'HP:0012034', (161, 172))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (154, 173))
195380	32225029	Genomic alterations such as the loss of 16q and gain of chromosome 8 in 50% of the cases, 1q gains in 25% of the cases, and the microdeletion of p16 and mutation of TP53 and CDKN2A in around 20% of cases have been extensively described in the literature and are reviewed comprehensively by Grunewald et al..	('gains', 'PosReg', (93, 98))	('p16', 'Gene', '1029', (145, 148))	('gain', 'PosReg', (48, 52))	('TP53', 'Gene', (165, 169))	('microdeletion', 'Var', (128, 141))	('CDKN2A', 'Gene', (174, 180))	('16q', 'Gene', (40, 43))	('p16', 'Gene', (145, 148))	('loss', 'Var', (32, 36))	('CDKN2A', 'Gene', '1029', (174, 180))	('TP53', 'Gene', '7157', (165, 169))	('mutation', 'Var', (153, 161))
195383	32225029	More recently, using NGS, three studies described the presence of STAG2 (cohesin subunit SA-2 protein) mutations or rearrangements in a subgroup of ES cases.	('mutations', 'Var', (103, 112))	('STAG2', 'Gene', '10735', (66, 71))	('STAG2', 'Gene', (66, 71))	('ES', 'Phenotype', 'HP:0012254', (148, 150))	('cohesin subunit SA-2', 'Gene', '10735', (73, 93))	('cohesin subunit SA-2', 'Gene', (73, 93))	('rearrangements', 'Var', (116, 130))
195384	32225029	Crompton and colleagues showed that STAG2 mutation, resulting in a loss of expression, was associated with metastatic disease.	('loss', 'NegReg', (67, 71))	('mutation', 'Var', (42, 50))	('STAG2', 'Gene', (36, 41))	('STAG2', 'Gene', '10735', (36, 41))	('of expression', 'MPA', (72, 85))	('metastatic disease', 'Disease', (107, 125))	('associated', 'Reg', (91, 101))
195386	32225029	Apart from STAG2, previously described mutations in TP53 (tumor protein p53) and CDKN2A (cyclin dependent kinase inhibitor 2A) were also found, both in tumors and cell lines, in accordance with what had already been described.	('STAG2', 'Gene', (11, 16))	('tumors', 'Disease', (152, 158))	('tumor', 'Disease', (58, 63))	('CDKN2A', 'Gene', (81, 87))	('p53', 'Gene', '7157', (72, 75))	('tumor', 'Disease', (152, 157))	('mutations', 'Var', (39, 48))	('TP53', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('cyclin dependent kinase inhibitor 2A', 'Gene', (89, 125))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('p53', 'Gene', (72, 75))	('CDKN2A', 'Gene', '1029', (81, 87))	('STAG2', 'Gene', '10735', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TP53', 'Gene', '7157', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (89, 125))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
195389	32225029	Again, the presence of STAG2 and CDKN2A mutations was detected in a small set of patients (17% and 12%), and these were mutually exclusive.	('CDKN2A', 'Gene', (33, 39))	('CDKN2A', 'Gene', '1029', (33, 39))	('patients', 'Species', '9606', (81, 89))	('STAG2', 'Gene', (23, 28))	('mutations', 'Var', (40, 49))	('STAG2', 'Gene', '10735', (23, 28))
195391	32225029	In these cases, STAG2 mutations were detected with higher allelic fractions than in the primary tumor at diagnosis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('STAG2', 'Gene', (16, 21))	('STAG2', 'Gene', '10735', (16, 21))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
195393	32225029	Authors found that, once more, a loss of expression of STAG2 by mutation was observed in 21.5% of the cases and in 44.4% of cell lines.	('mutation', 'Var', (64, 72))	('STAG2', 'Gene', '10735', (55, 60))	('STAG2', 'Gene', (55, 60))	('expression', 'MPA', (41, 51))	('loss', 'NegReg', (33, 37))
195395	32225029	The loss of STAG2 seems to have a critical biological role in the development of metastasis, hence affecting disease progression.	('affecting', 'Reg', (99, 108))	('STAG2', 'Gene', (12, 17))	('STAG2', 'Gene', '10735', (12, 17))	('disease progression', 'CPA', (109, 128))	('loss', 'Var', (4, 8))
195397	32225029	This process has been previously described in prostate cancer by the presence of TMPRSS2-ERG.	('ERG', 'Gene', (89, 92))	('TMPRSS2', 'Gene', (81, 88))	('presence', 'Var', (69, 77))	('prostate cancer', 'Disease', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TMPRSS2', 'Gene', '7113', (81, 88))	('ERG', 'Gene', '2078', (89, 92))	('prostate cancer', 'Disease', 'MESH:D011471', (46, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))
195404	32225029	Likewise, patients with metastasis at diagnosis presented higher ITH when compared to patients with local disease.	('metastasis', 'Var', (24, 34))	('ITH', 'MPA', (65, 68))	('higher', 'PosReg', (58, 64))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (86, 94))
195405	32225029	Until now, the presence of high levels of the EWSR1-FLI1 had been associated with the presence of malignant phenotype.	('malignant', 'Disease', (98, 107))	('EWSR1', 'Gene', (46, 51))	('FLI1', 'Gene', '2313', (52, 56))	('FLI1', 'Gene', (52, 56))	('associated', 'Reg', (66, 76))	('presence', 'Var', (15, 23))	('EWSR1', 'Gene', '2130', (46, 51))
195412	32225029	Krumbholz and colleagues showed by studying xenograft models and patient s samples, the detection of EWSR1 fusions ctDNA and its correlation with tumor burden.	('ctDNA', 'Disease', (115, 120))	('fusions', 'Var', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('EWSR1', 'Gene', (101, 106))	('tumor', 'Disease', (146, 151))	('patient', 'Species', '9606', (65, 72))	('EWSR1', 'Gene', '2130', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
195413	32225029	In 20 ES patients, ctDNA was evaluated during the treatment by droplet digital PCR (ddPCR) using as a probe the specific GF variant present in the primary tumor.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('patients', 'Species', '9606', (9, 17))	('ES', 'Phenotype', 'HP:0012254', (6, 8))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('variant', 'Var', (124, 131))
195422	32225029	Similarly, also here, STAG2 and TP53 mutations (in 3 and 4 patients, respectively) were detected using these methods, along with the presence of a novel translocation (EWSR1-CSMD2).	('EWSR1', 'Gene', (168, 173))	('CSMD2', 'Gene', '114784', (174, 179))	('TP53', 'Gene', '7157', (32, 36))	('EWSR1', 'Gene', '2130', (168, 173))	('CSMD2', 'Gene', (174, 179))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (32, 36))	('STAG2', 'Gene', (22, 27))	('STAG2', 'Gene', '10735', (22, 27))	('patients', 'Species', '9606', (59, 67))
195424	32225029	A robust method using ddPCR detected different EWSR1-FLI1 transcript variants in the 5 primary tumors and in 4 blood samples.	('EWSR1', 'Gene', '2130', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('variants', 'Var', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('FLI1', 'Gene', '2313', (53, 57))	('EWSR1', 'Gene', (47, 52))	('FLI1', 'Gene', (53, 57))	('tumors', 'Disease', (95, 101))
195444	32225029	Amongst them, YK-4-279 (also known as TK216) was able to reduce ES tumor growth in vitro and in PDX models.	('reduce', 'NegReg', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('YK-4-279', 'Var', (14, 22))	('tumor', 'Disease', (67, 72))	('ES', 'Phenotype', 'HP:0012254', (64, 66))
195447	32225029	The phenotypic plasticity of ES tumor cells upon changes in the GF level needs further confirmation, as it may have an important impact in the clinical management.	('ES', 'Phenotype', 'HP:0012254', (29, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('changes', 'Var', (49, 56))	('impact', 'Reg', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
195450	32225029	Massive drug tests, global tumor mutations and epigenetics analysis, single-cell multiple omics, and CRISPR-Cas9-based screenings have emerged as important tools to identify therapeutic targets.	('epigenetics', 'Var', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
195453	32225029	Poly (ADP-ribose) polymerase 1 (PARP1) plays a crucial role in the repair of different kinds of DNA damage including single and double-strand breaks (SSBs, DSBs).	('Poly (ADP-ribose) polymerase 1', 'Gene', '142', (0, 30))	('single', 'Var', (117, 123))	('PARP1', 'Gene', '142', (32, 37))	('PARP1', 'Gene', (32, 37))	('DSBs', 'Chemical', 'MESH:C007563', (156, 160))	('Poly (ADP-ribose) polymerase 1', 'Gene', (0, 30))
195454	32225029	The detection of lesions by PARP1 triggers a fast-cellular response involving the recruitment of several repair factors.	('PARP1', 'Gene', (28, 33))	('lesions', 'Var', (17, 24))	('fast-cellular response', 'MPA', (45, 67))	('triggers', 'Reg', (34, 42))	('PARP1', 'Gene', '142', (28, 33))
195457	32225029	As a consequence, tumors with mutations in DSBs repair factors such as BRCA1/2, which are members of the homologous recombination (HR) pathway, are especially sensitive to PARP inhibitors (PARPi).	('PARP', 'Gene', '142', (172, 176))	('BRCA1/2', 'Gene', (71, 78))	('DSBs', 'Gene', (43, 47))	('PARP', 'Gene', (172, 176))	('PARP', 'Gene', (189, 193))	('tumors', 'Disease', (18, 24))	('sensitive', 'Reg', (159, 168))	('mutations', 'Var', (30, 39))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('PARP', 'Gene', '142', (189, 193))	('BRCA1/2', 'Gene', '672;675', (71, 78))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('DSBs', 'Chemical', 'MESH:C007563', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
195459	32225029	This effect is also related to an HR deficiency in the absence of BRCA mutations.	('mutations', 'Var', (71, 80))	('HR deficiency in the absence of BRCA', 'Disease', (34, 70))	('HR deficiency in the absence of BRCA', 'Disease', 'MESH:D001919', (34, 70))
195468	32225029	As indicated above, mutations in STAG2 are detected in 15%-20% of ES patients and have also been associated with poor prognosis.	('STAG2', 'Gene', (33, 38))	('STAG2', 'Gene', '10735', (33, 38))	('detected', 'Reg', (43, 51))	('patients', 'Species', '9606', (69, 77))	('associated', 'Reg', (97, 107))	('mutations', 'Var', (20, 29))	('ES', 'Phenotype', 'HP:0012254', (66, 68))
195469	32225029	STAG2 interacts with replication intermediates, and its absence induces replication fork collapse and DNA damage accumulation.	('STAG2', 'Gene', '10735', (0, 5))	('induces', 'Reg', (64, 71))	('STAG2', 'Gene', (0, 5))	('absence', 'Var', (56, 63))	('replication fork collapse', 'CPA', (72, 97))	('DNA damage accumulation', 'MPA', (102, 125))
195470	32225029	STAG2 loss-of-function mutations sensitize cancer cells to inhibitors of DNA repair factors (ATR, PARP1) and increase sensitivity to select cytotoxic chemotherapeutic agents.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('STAG2', 'Gene', '10735', (0, 5))	('cancer', 'Disease', (43, 49))	('increase', 'PosReg', (109, 117))	('loss-of-function', 'NegReg', (6, 22))	('sensitivity', 'MPA', (118, 129))	('mutations', 'Var', (23, 32))	('PARP1', 'Gene', '142', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('PARP1', 'Gene', (98, 103))	('STAG2', 'Gene', (0, 5))
195474	32225029	Mutations in CDKs and their regulators are related with uncontrolled proliferation and chromosomal instability.	('CDKs', 'Gene', (13, 17))	('related', 'Reg', (43, 50))	('chromosomal instability', 'Phenotype', 'HP:0040012', (87, 110))	('Mutations', 'Var', (0, 9))	('chromosomal instability', 'CPA', (87, 110))	('CDKs', 'Gene', '12566;1019;1021;1022;51755;8621', (13, 17))	('uncontrolled proliferation', 'CPA', (56, 82))
195483	32225029	The inhibition of MDM2 (involved in p53 degradation) or MDM4 (a p53 inhibitor) enhances p53 activation, reducing tumor growth in "in vivo" models.	('tumor', 'Disease', (113, 118))	('p53', 'Gene', (36, 39))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (36, 39))	('MDM4', 'Gene', '4194', (56, 60))	('reducing', 'NegReg', (104, 112))	('inhibition', 'Var', (4, 14))	('p53', 'Gene', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('p53', 'Gene', '7157', (88, 91))	('MDM2', 'Gene', '4193', (18, 22))	('MDM4', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('MDM2', 'Gene', (18, 22))	('enhances', 'PosReg', (79, 87))	('activation', 'MPA', (92, 102))	('p53', 'Gene', '7157', (64, 67))
195504	32225029	An obvious proposal is that all future patients with ES can benefit from the determination of STAG2, 1q gains, and 16q losses, among others.	('16q losses', 'Var', (115, 125))	('STAG2', 'Gene', (94, 99))	('patients', 'Species', '9606', (39, 47))	('gains', 'PosReg', (104, 109))	('STAG2', 'Gene', '10735', (94, 99))	('ES', 'Phenotype', 'HP:0012254', (53, 55))
195507	32225029	EdA's laboratory is supported by the AECC project (GCB13-1578), ISCIIIFEDER (PI14/01466, PI17/00464), CIBERONC (CB16/12/00361) and Fundacion CRIS Contra el Cancer.	('PI17/00464', 'Var', (89, 99))	('Cancer', 'Disease', 'MESH:D009369', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('EdA', 'Gene', (0, 3))	('CB16/12/00361', 'Var', (112, 125))	('EdA', 'Gene', '1896', (0, 3))	('PI14/01466', 'Var', (77, 87))	('Cancer', 'Disease', (156, 162))
195508	32225029	AMP Anchored Multiplex PCR  CRISPR Clustered Regularly Interspaced Short Palindromic Repeats  CTC Circulating tumor cells  ctDNA Circulating tumor DNA  ctRNA Circulating tumor RNA  ddPCR Droplet digital PCR  DSBs Double Strand Breaks  DSRCT Desmoplastic Small Round Blue Cell Tumors  ELS Ewing-like Sarcoma  ES Ewing Sarcoma  EVs Extracellular Vesicles  FISH Fluorescence In Situ Hybridization  HR Homologous Recombination  IHC Immunohistochemistry  ITH Intratumoral heterogeneity  LB Liquid biopsy  MSC Mesenchymal Stem Cells  NGS Next Generation Sequencing  ORF Open Reading Frames  PARPi PARP inhibitors  PDX Patient Derived Xenografts  PET Positron Emission Tomography  RT-PCR Reverse Transcriptase-PCR  shRNA Short hairpin RNA  SNP Single nucleotide polymorphism  SNV Single-Nucleotide Variants  SSBs Single Strand Breaks  WGS Whole Genome Sequencing	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('PARP', 'Gene', '142', (585, 589))	('Single nucleotide polymorphism', 'Var', (737, 767))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('Tumor', 'Phenotype', 'HP:0002664', (276, 281))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (311, 324))	('tumor', 'Disease', (170, 175))	('PARP', 'Gene', (585, 589))	('Tumors', 'Phenotype', 'HP:0002664', (276, 282))	('tumoral', 'Disease', (459, 466))	('tumoral', 'Disease', 'MESH:D009369', (459, 466))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('Sarcoma', 'Phenotype', 'HP:0100242', (317, 324))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('PARP', 'Gene', '142', (591, 595))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('PARP', 'Gene', (591, 595))	('Sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (459, 464))	('DSBs', 'Chemical', 'MESH:C007563', (208, 212))	('ES', 'Phenotype', 'HP:0012254', (308, 310))	('Tumors  ELS Ewing-like Sarcoma  ES Ewing Sarcoma  EVs', 'Disease', 'MESH:C563168', (276, 329))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('Patient', 'Species', '9606', (612, 619))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (141, 146))	('Single-Nucleotide Variants', 'Var', (773, 799))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
195524	30394521	Inhibition of the VEGF receptor tyrosine kinases (RTKs) has emerged as an anticancer strategy in adults with renal and hepatic carcinomas as well as soft tissue sarcomas.	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcomas', 'Disease', (161, 169))	('VEGF', 'Gene', '7422', (18, 22))	('renal and hepatic carcinomas', 'Disease', 'MESH:D002292', (109, 137))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (149, 169))	('Inhibition', 'Var', (0, 10))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('tyrosine', 'Chemical', 'None', (32, 40))	('VEGF', 'Gene', (18, 22))
195542	30394521	Organ function requirements included absolute neutrophil count (ANC) >= 1000/mm3, platelet count >= 100,000/mm3, hemoglobin >= 8 gm/dL; creatinine clearance or radioisotope GFR >=70mL/min/1.73 m2 or age-appropriate serum creatinine; bilirubin <= 1.5 times upper limit of normal (ULN) for age, SGPT (ALT) <= 110 U/L, SGOT (AST) <= 125 U/L, serum albumin >= 2 g/dL; lipase <= 1.5 x ULN; and shortening fraction >= 27% by echocardiogram or ejection fraction >= 50% by gated radionuclide study.	('bilirubin', 'Chemical', 'MESH:D001663', (233, 242))	('ejection', 'MPA', (437, 445))	('creatinine', 'Chemical', 'MESH:D003404', (221, 231))	('shortening', 'MPA', (389, 399))	('creatinine', 'Chemical', 'MESH:D003404', (136, 146))	('>= 27', 'Var', (409, 414))
195624	30285733	We hypothesized that pazopanib is associated with a higher risk of SSP in patients with evidence of metastatic sarcoma to the lungs.	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('pazopanib', 'Chemical', 'MESH:C516667', (21, 30))	('patients', 'Species', '9606', (74, 82))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('pazopanib', 'Var', (21, 30))	('SSP', 'Phenotype', 'HP:0002108', (67, 70))	('SSP', 'Disease', (67, 70))
195630	30285733	These were identified with use of the following International Classification of Diseases (ICD) diagnostic codes: ICD9 (512.89, 512.83, 512.81, 512.82, and 512.0) and ICD10 (J93, J93.9, J93.83, J93.81, J93.12, and J93.11) (Fig.	('512.0', 'Var', (155, 160))	('J93.11', 'Var', (213, 219))	('ICD', 'Disease', (166, 169))	('J93', 'CellLine', 'CVCL:M891', (185, 188))	('J93.9', 'CellLine', 'CVCL:M891', (178, 183))	('512.81', 'Var', (135, 141))	('ICD', 'Disease', 'OMIM:252500', (166, 169))	('J93.12', 'CellLine', 'CVCL:M891', (201, 207))	('J93', 'CellLine', 'CVCL:M891', (213, 216))	('512.89', 'Var', (119, 125))	('J93', 'CellLine', 'CVCL:M891', (173, 176))	('ICD', 'Disease', (90, 93))	('512.82', 'Var', (143, 149))	('J93.81', 'Var', (193, 199))	('ICD', 'Disease', (113, 116))	('ICD', 'Disease', 'OMIM:252500', (90, 93))	('J93', 'CellLine', 'CVCL:M891', (178, 181))	('ICD', 'Disease', 'OMIM:252500', (113, 116))	('J93.12', 'Var', (201, 207))	('J93.9', 'Var', (178, 183))	('J93.83', 'Var', (185, 191))	('J93', 'CellLine', 'CVCL:M891', (201, 204))	('J93', 'CellLine', 'CVCL:M891', (193, 196))
195673	30285733	On the basis of our findings we conclude that pazopanib does not increase the pneumothorax risk in patients with sarcoma and evidence of metastatic disease to the chest however the study may have been underpowered to detect a difference.	('pazopanib', 'Var', (46, 55))	('pneumothorax', 'Disease', (78, 90))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('patients', 'Species', '9606', (99, 107))	('sarcoma', 'Disease', (113, 120))	('pazopanib', 'Chemical', 'MESH:C516667', (46, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('pneumothorax', 'Phenotype', 'HP:0002107', (78, 90))
195680	23520471	Inhibition of Wee1 by MK1775 has been reported to enhance the cytotoxic effect of DNA damaging agents in different types of carcinomas.	('Wee1', 'Gene', (14, 18))	('Wee1', 'Gene', '7465', (14, 18))	('Inhibition', 'NegReg', (0, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('carcinomas', 'Disease', 'MESH:D002277', (124, 134))	('cytotoxic effect', 'CPA', (62, 78))	('carcinomas', 'Disease', (124, 134))	('MK1775', 'Chemical', 'MESH:C549567', (22, 28))	('MK1775', 'Var', (22, 28))	('enhance', 'PosReg', (50, 57))
195681	23520471	In this study we investigated the therapeutic efficacy of MK1775 in various sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo both alone and in combination with gemcitabine, which is frequently used in the treatment of sarcomas.	('MK1775', 'Var', (58, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (182, 193))	('sarcoma cell lines', 'Disease', 'MESH:D012509', (76, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('sarcoma cell lines', 'Disease', (76, 94))	('sarcomas', 'Disease', (240, 248))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('patient', 'Species', '9606', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('tumor', 'Disease', (112, 117))	('sarcomas', 'Disease', 'MESH:D012509', (240, 248))	('MK1775', 'Chemical', 'MESH:C549567', (58, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (240, 248))
195683	23520471	Additionally, MK1775 significantly enhances the cytotoxic effect of gemcitabine in sarcoma cells lines with different p53 mutational status.	('MK1775', 'Chemical', 'MESH:C549567', (14, 20))	('sarcoma', 'Disease', (83, 90))	('p53', 'Gene', (118, 121))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('MK1775', 'Var', (14, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('cytotoxic effect', 'CPA', (48, 64))	('enhances', 'PosReg', (35, 43))	('gemcitabine', 'Chemical', 'MESH:C056507', (68, 79))
195684	23520471	In patient-derived bone and soft tissue sarcoma samples we showed that MK1775 alone and in combination with gemcitabine causes significant apoptotic cell death.	('apoptotic cell death', 'CPA', (139, 159))	('patient', 'Species', '9606', (3, 10))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('gemcitabine', 'Chemical', 'MESH:C056507', (108, 119))	('MK1775', 'Chemical', 'MESH:C549567', (71, 77))	('sarcoma', 'Disease', (40, 47))	('MK1775', 'Var', (71, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (28, 47))
195685	23520471	Magnetic resonance imaging (MRI) and histopathologic studies showed that MK1775 induces significant cell death and terminal differentiation in a patient-derived xenograft mouse model of osteosarcoma in vivo.	('MK1775', 'Chemical', 'MESH:C549567', (73, 79))	('terminal differentiation', 'CPA', (115, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('cell death', 'CPA', (100, 110))	('patient', 'Species', '9606', (145, 152))	('MK1775', 'Var', (73, 79))	('osteosarcoma', 'Disease', (186, 198))	('osteosarcoma', 'Phenotype', 'HP:0002669', (186, 198))	('mouse', 'Species', '10090', (171, 176))	('osteosarcoma', 'Disease', 'MESH:D012516', (186, 198))	('induces', 'Reg', (80, 87))
195696	23520471	MK-1775 has been reported to induce anti-tumorigenic effects in different cancer types that harbor p53 mutations when combined with cytotoxic agents.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (103, 112))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('MK-1775', 'Chemical', 'MESH:C549567', (0, 7))	('p53', 'Gene', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
195697	23520471	We have previously shown that MK-1775 has a cytotoxic effect on sarcomas as a single agent independent of p53 mutation status.	('MK-1775', 'Var', (30, 37))	('MK-1775', 'Chemical', 'MESH:C549567', (30, 37))	('sarcomas', 'Disease', 'MESH:D012509', (64, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcomas', 'Disease', (64, 72))	('cytotoxic effect', 'CPA', (44, 60))
195709	23520471	Briefly, tumor explants were exposed to vehicle, MK-1775 (500 nM), gemcitabine (3 microM), or a combination of MK-1775 and gemcitabine for 18 hours, and tissue fragments were collected for Western blot and morphological studies.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('gemcitabine', 'Chemical', 'MESH:C056507', (123, 134))	('MK-1775', 'Chemical', 'MESH:C549567', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('MK-1775', 'Var', (49, 56))	('gemcitabine', 'Chemical', 'MESH:C056507', (67, 78))	('MK-1775', 'Chemical', 'MESH:C549567', (49, 56))	('MK-1775', 'Var', (111, 118))
195713	23520471	When tumors reached a volume of 500 mm3, mice were individually identified and randomly assigned to treatment groups of 4 mice (6-8 evaluable tumors) in each group: 1) control; 2) MK-1775 (30 mg/kg p.o., twice daily on days 1, 3, 8, and 10); 3) gemcitabine (100 mg/kg i.p., once daily on days 1, 3, 8, 10); or 4) MK-1775 and gemcitabine in the above-mentioned doses.	('tumors', 'Disease', (5, 11))	('mice', 'Species', '10090', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MK-1775', 'Chemical', 'MESH:C549567', (180, 187))	('mice', 'Species', '10090', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('gemcitabine', 'Chemical', 'MESH:C056507', (325, 336))	('MK-1775', 'Var', (313, 320))	('gemcitabine', 'Chemical', 'MESH:C056507', (245, 256))	('MK-1775', 'Chemical', 'MESH:C549567', (313, 320))
195738	23520471	We have previously shown that MK-1775 as a single agent induces marked cell death in sarcoma cell lines.	('cell death', 'CPA', (71, 81))	('MK-1775', 'Var', (30, 37))	('MK-1775', 'Chemical', 'MESH:C549567', (30, 37))	('sarcoma cell lines', 'Disease', (85, 103))	('sarcoma cell lines', 'Disease', 'MESH:D012509', (85, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
195739	23520471	To determine whether combination of MK-1775 with gemcitabine potentiates its cytotoxic effects in sarcoma cells, asynchronously growing MG63, U20S, A673, and HT1080 cell lines were treated with MK-1775 (500 nM) and gemcitabine (3 microM) at clinically relevant doses for 24 hours, and cell extracts were evaluated by Western blot analysis.	('MG63', 'CellLine', 'CVCL:0426', (136, 140))	('MK-1775', 'Var', (36, 43))	('MK-1775', 'Chemical', 'MESH:C549567', (36, 43))	('MK-1775', 'Var', (194, 201))	('MK-1775', 'Chemical', 'MESH:C549567', (194, 201))	('gemcitabine', 'Chemical', 'MESH:C056507', (49, 60))	('HT1080', 'CellLine', 'CVCL:0317', (158, 164))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('combination', 'Interaction', (21, 32))	('cytotoxic effects', 'CPA', (77, 94))	('sarcoma', 'Disease', (98, 105))	('gemcitabine', 'Chemical', 'MESH:C056507', (215, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('U20S', 'CellLine', 'CVCL:0042', (142, 146))
195740	23520471	To assess the activation of DNA damage response by MK-1775 and gemcitabine, we determined the phosphorylation status of histone H2AX (gammaH2AX) that occurs rapidly after genotoxic stress.	('gemcitabine', 'Chemical', 'MESH:C056507', (63, 74))	('gammaH2AX', 'Chemical', '-', (134, 143))	('histone H2AX', 'Gene', '3014', (120, 132))	('histone H2AX', 'Gene', (120, 132))	('MK-1775', 'Var', (51, 58))	('MK-1775', 'Chemical', 'MESH:C549567', (51, 58))
195743	23520471	In contrary, MK-1775 alone caused DNA damage with increased gammaH2AX expression and apoptosis.	('increased', 'PosReg', (50, 59))	('gammaH2AX', 'Protein', (60, 69))	('apoptosis', 'CPA', (85, 94))	('MK-1775', 'Var', (13, 20))	('expression', 'MPA', (70, 80))	('MK-1775', 'Chemical', 'MESH:C549567', (13, 20))	('gammaH2AX', 'Chemical', '-', (60, 69))
195744	23520471	Interestingly, in cells treated with MK-1775 and gemcitabine together, there was increased apoptotic cell death.	('apoptotic cell death', 'CPA', (91, 111))	('gemcitabine', 'Chemical', 'MESH:C056507', (49, 60))	('MK-1775', 'Var', (37, 44))	('MK-1775', 'Chemical', 'MESH:C549567', (37, 44))	('increased', 'PosReg', (81, 90))
195750	23520471	Interestingly, in all cell lines tested, Cyclin A expression was found to be lowest in the presence of MK1775 and gemcitabine combination compared to other treatment groups, which was accompanied by a simultaneous decrease in inhibitory phosphorylation of CDC2.	('CDC2', 'Gene', (256, 260))	('lowest', 'NegReg', (77, 83))	('inhibitory phosphorylation', 'MPA', (226, 252))	('Cyclin A', 'Gene', '890', (41, 49))	('MK1775', 'Chemical', 'MESH:C549567', (103, 109))	('MK1775', 'Var', (103, 109))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('Cyclin A', 'Gene', (41, 49))	('expression', 'MPA', (50, 60))	('decrease', 'NegReg', (214, 222))	('CDC2', 'Gene', '983', (256, 260))
195754	23520471	Our results are supported by a recent study demonstrating that MK-1775 overcomes S-phase arrest in response to gemcitabine treatment in breast cancer cells.	('overcomes', 'NegReg', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('gemcitabine', 'Chemical', 'MESH:C056507', (111, 122))	('S-phase arrest', 'MPA', (81, 95))	('MK-1775', 'Var', (63, 70))	('MK-1775', 'Chemical', 'MESH:C549567', (63, 70))
195757	23520471	As shown in Figure 1B, exposure of sarcoma cells to the combination of MK-1775 and gemcitabine exerted a strong synergistic effect with CI values of 0.5, 0.2, 0.6, and 0.1 for U2OS, MG63, A673, and HT1080 cells, respectively, indicative of a synergistic to strong synergistic effect (CI range 0.1-0.3 = ++++strong synergism, 0.3-0.7 = +++synergism; Table 1).	('MK-1775', 'Var', (71, 78))	('sarcoma', 'Disease', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('MK-1775', 'Chemical', 'MESH:C549567', (71, 78))	('MG63', 'CellLine', 'CVCL:0426', (182, 186))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('U2OS', 'CellLine', 'CVCL:0042', (176, 180))	('synergistic effect', 'MPA', (112, 130))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('HT1080', 'CellLine', 'CVCL:0317', (198, 204))
195758	23520471	Previous studies showed that pharmacological inhibition of Wee1 enhances the cytotoxic effect of DNA-damaging agents, particularly in cancer cells harboring p53 mutations, likely because p53-deficient cells are largely dependent on G2/M arrest to repair DNA damage caused by cytotoxic agents.	('Wee1', 'Gene', (59, 63))	('Wee1', 'Gene', '7465', (59, 63))	('enhances', 'PosReg', (64, 72))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mutations', 'Var', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('p53', 'Gene', (157, 160))	('cytotoxic effect', 'CPA', (77, 93))
195759	23520471	Based on these findings, p53 mutation has been proposed as a predictor of tumor response to Wee1 inhibitors in clinical trials.	('p53', 'Gene', (25, 28))	('mutation', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Wee1', 'Gene', (92, 96))	('tumor', 'Disease', (74, 79))	('Wee1', 'Gene', '7465', (92, 96))
195761	23520471	As shown in Figure 1C, a synergy is observed between MK-1775 and gemcitabine in all cell lines independent of their p53 status.	('MK-1775', 'Chemical', 'MESH:C549567', (53, 60))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('MK-1775', 'Var', (53, 60))	('synergy', 'MPA', (25, 32))
195764	23520471	As illustrated in Figure 2, compared to vehicle-treated control samples, ex vivo treatment of tumor explants with gemcitabine alone showed only limited cell death in all tumors, whereas MK-1775 (500 nM) caused marked cell death accompanied by increased DNA damage, and activation of CDC2, while no changes were observed in total CDC2 levels (data not shown).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('tumor', 'Disease', (170, 175))	('increased', 'PosReg', (243, 252))	('CDC2', 'Gene', (283, 287))	('MK-1775 (500 nM', 'Var', (186, 201))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('CDC2', 'Gene', '983', (283, 287))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CDC2', 'Gene', '983', (329, 333))	('CDC2', 'Gene', (329, 333))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('activation', 'PosReg', (269, 279))	('MK-1775', 'Chemical', 'MESH:C549567', (186, 193))	('tumor', 'Disease', (94, 99))	('DNA damage', 'MPA', (253, 263))	('tumors', 'Disease', (170, 176))
195770	23520471	Here and in our previous studies, we showed that MK-1775 alone causes cell death in osteosarcoma cell lines at clinically achievable concentrations.	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('cell death', 'CPA', (70, 80))	('osteosarcoma', 'Disease', (84, 96))	('MK-1775', 'Var', (49, 56))	('MK-1775', 'Chemical', 'MESH:C549567', (49, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('sarcoma cell lines', 'Disease', (89, 107))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))	('sarcoma cell lines', 'Disease', 'MESH:D012509', (89, 107))
195775	23520471	As illustrated in Figure 3A, treatment with MK-1775 alone and in combination with gemcitabine caused activation of CDC2 while no changes were observed in vehicle-treated control and gemcitabine groups demonstrating that MK-1775 effectively inhibits the activity of Wee1 at the early stage of treatment and gemcitabine does not interfere with its mode of action when combined in vivo.	('gemcitabine', 'Chemical', 'MESH:C056507', (182, 193))	('inhibits', 'NegReg', (240, 248))	('activation', 'PosReg', (101, 111))	('MK-1775', 'Var', (44, 51))	('MK-1775', 'Chemical', 'MESH:C549567', (44, 51))	('Wee1', 'Gene', (265, 269))	('gemcitabine', 'Chemical', 'MESH:C056507', (306, 317))	('activity', 'MPA', (253, 261))	('Wee1', 'Gene', '7465', (265, 269))	('CDC2', 'Gene', '983', (115, 119))	('CDC2', 'Gene', (115, 119))	('MK-1775', 'Var', (220, 227))	('MK-1775', 'Chemical', 'MESH:C549567', (220, 227))	('gemcitabine', 'Chemical', 'MESH:C056507', (82, 93))
195790	23520471	Additionally, the tumor cells in the MK-1775 alone and MK-1775+ gemcitabine groups exhibited increased cell size with abundant eosinophilic cytoplasm and significant osteoid production, consistent with differentiation (Figure 4B); results for the gemcitabine-treated group, however, were more similar to the those of the control group, where tumor cells were more spindled with scant cytoplasm.	('gemcitabine', 'Chemical', 'MESH:C056507', (247, 258))	('eosin', 'Chemical', 'MESH:D004801', (127, 132))	('MK-1775', 'Chemical', 'MESH:C549567', (55, 62))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('increased', 'PosReg', (93, 102))	('osteoid production', 'CPA', (166, 184))	('MK-1775', 'Var', (37, 44))	('gemcitabine', 'Chemical', 'MESH:C056507', (64, 75))	('cell size', 'CPA', (103, 112))	('MK-1775', 'Chemical', 'MESH:C549567', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('MK-1775+', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (342, 347))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
195793	23520471	As illustrated in Figure 4B, tumors treated with MK-1775 alone and with MK-1775+ gemcitabine had an increased Ki67 index of 73% and 79%, respectively, compared to tumors treated with gemcitabine and with vehicle (Ki67 index of 13% and 76%, respectively).	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('MK-1775+', 'Var', (72, 80))	('Ki67', 'Gene', (110, 114))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))	('increased', 'PosReg', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('gemcitabine', 'Chemical', 'MESH:C056507', (183, 194))	('Ki67', 'Gene', (213, 217))	('MK-1775', 'Var', (49, 56))	('tumors', 'Disease', (29, 35))	('Ki67', 'Gene', '17345', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('Ki67', 'Gene', '17345', (213, 217))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('MK-1775', 'Chemical', 'MESH:C549567', (49, 56))	('MK-1775', 'Chemical', 'MESH:C549567', (72, 79))
195797	23520471	As illustrated in Figure 4, combination of MK-1775 and gemcitabine caused an increased cytotoxic response, with 34% of cells showing cleaved caspase 3 that was accompanied by a Ki67 index of 79% and gammaH2AX index of 80%.	('Ki67', 'Gene', (177, 181))	('cleaved', 'MPA', (133, 140))	('gemcitabine', 'Chemical', 'MESH:C056507', (55, 66))	('caspase 3', 'Protein', (141, 150))	('MK-1775', 'Var', (43, 50))	('MK-1775', 'Chemical', 'MESH:C549567', (43, 50))	('Ki67', 'Gene', '17345', (177, 181))	('increased', 'PosReg', (77, 86))	('gammaH2AX', 'Chemical', '-', (199, 208))	('combination', 'Interaction', (28, 39))	('cytotoxic response', 'CPA', (87, 105))
195798	23520471	These results show that MK-1775 is capable of overcoming gemcitabine-induced growth arrest and causes enhanced cytotoxicty in osteosarcoma cells in vivo.	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('enhanced', 'PosReg', (102, 110))	('osteosarcoma', 'Disease', (126, 138))	('growth arrest', 'Disease', 'MESH:D006323', (77, 90))	('growth arrest', 'Disease', (77, 90))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('MK-1775', 'Var', (24, 31))	('growth arrest', 'Phenotype', 'HP:0001510', (77, 90))	('cytotoxicty', 'CPA', (111, 122))	('overcoming', 'PosReg', (46, 56))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('MK-1775', 'Chemical', 'MESH:C549567', (24, 31))
195799	23520471	In the cell line studies above we showed that MK-1775 disrupts gemcitabine-induced S-phase arrest and leads to mitotic entry and cell death (Figure 1A).	('S-phase arrest', 'CPA', (83, 97))	('cell death', 'CPA', (129, 139))	('MK-1775', 'Var', (46, 53))	('gemcitabine-induced', 'MPA', (63, 82))	('MK-1775', 'Chemical', 'MESH:C549567', (46, 53))	('mitotic entry', 'CPA', (111, 124))	('gemcitabine', 'Chemical', 'MESH:C056507', (63, 74))	('disrupts', 'NegReg', (54, 62))	('leads to', 'Reg', (102, 110))
195800	23520471	Next, we tested whether MK-1775 can overcome gemcitabine mediated S-phase arrest to enhance cell death in this patient-derived osteosarcoma model in vivo.	('cell death', 'CPA', (92, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (127, 139))	('MK-1775', 'Chemical', 'MESH:C549567', (24, 31))	('enhance', 'PosReg', (84, 91))	('osteosarcoma', 'Disease', 'MESH:D012516', (127, 139))	('gemcitabine', 'Chemical', 'MESH:C056507', (45, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('MK-1775', 'Var', (24, 31))	('patient', 'Species', '9606', (111, 118))	('tested', 'Reg', (9, 15))	('osteosarcoma', 'Disease', (127, 139))
195802	23520471	As shown in panel E, compared to control group, gemcitabine treatment led to a 2-fold increase in the number of Cyclin A positive cells (13.5 vs 27.3%), while combination of MK-1775 with gemcitabine markedly decreased Cyclin A expressing cells (3%), which is similar to the MK-1775 treatment group (2.9%).	('Cyclin A', 'Gene', '890', (112, 120))	('Cyclin A', 'Gene', '890', (218, 226))	('increase', 'PosReg', (86, 94))	('Cyclin A', 'Gene', (218, 226))	('MK-1775', 'Var', (174, 181))	('Cyclin A', 'Gene', (112, 120))	('gemcitabine', 'Chemical', 'MESH:C056507', (48, 59))	('MK-1775', 'Chemical', 'MESH:C549567', (274, 281))	('MK-1775', 'Chemical', 'MESH:C549567', (174, 181))	('gemcitabine', 'Chemical', 'MESH:C056507', (187, 198))	('decreased', 'NegReg', (208, 217))
195803	23520471	These findings together with enhanced CDC2 activity are most consistent with a model where inhibition of Wee1 activity disrupts gemcitabine induced S-phase arrest and forces cells into mitosis with damaged DNA causing mitotic cell death.	('forces', 'Reg', (167, 173))	('inhibition', 'Var', (91, 101))	('CDC2', 'Gene', (38, 42))	('CDC2', 'Gene', '983', (38, 42))	('gemcitabine', 'Chemical', 'MESH:C056507', (128, 139))	('Wee1', 'Gene', (105, 109))	('mitotic cell death', 'CPA', (218, 236))	('Wee1', 'Gene', '7465', (105, 109))	('gemcitabine induced S-phase arrest', 'MPA', (128, 162))	('mitosis', 'Disease', 'None', (185, 192))	('mitosis', 'Disease', (185, 192))	('disrupts', 'NegReg', (119, 127))
195804	23520471	Although certain genetic conditions and alterations increase the risk of developing osteosarcoma, the molecular pathogenesis is not well understood.	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('alterations', 'Var', (40, 51))	('osteosarcoma', 'Disease', (84, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))
195810	23520471	Our data demonstrated that MK-1775 alone and in combination with gemcitabine induces significant terminal differentiation and cell death in high-grade osteosarcoma cells, laying an important foundation for future clinical trials with this well-tolerated readily available targeted drug.	('osteosarcoma', 'Disease', (151, 163))	('terminal differentiation', 'CPA', (97, 121))	('cell death', 'CPA', (126, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('MK-1775', 'Var', (27, 34))	('MK-1775', 'Chemical', 'MESH:C549567', (27, 34))
195811	21212061	Racial differences in the incidence of mesenchymal tumors associated with EWSR1 translocation The incidence of Ewing sarcoma varies by race, with very low rates among persons of African and East Asian ancestry.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('persons', 'Species', '9606', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('EWSR1', 'Gene', (74, 79))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (39, 57))	('Ewing sarcoma', 'Disease', (111, 124))	('translocation', 'Var', (80, 93))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('EWSR1', 'Gene', '2130', (74, 79))	('mesenchymal tumors', 'Disease', (39, 57))
195812	21212061	The incidence by race of other mesenchymal tumors that also harbor EWSR1 translocations has not been studied.	('EWSR1', 'Gene', '2130', (67, 72))	('translocations', 'Var', (73, 87))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (31, 49))	('mesenchymal tumors', 'Disease', (31, 49))	('EWSR1', 'Gene', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))
195813	21212061	The SEER database was queried to find cases of mesenchymal tumors associated with EWSR1 translocations: Ewing sarcoma; clear cell sarcoma; extraskeletal myxoid chondrosarcoma; myxoid liposarcoma; desmoplastic small round cell tumor and myoepithelial tumor.	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (153, 174))	('mesenchymal tumors', 'Disease', (47, 65))	('translocations', 'Var', (88, 102))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (176, 194))	('myxoid chondrosarcoma', 'Disease', (153, 174))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (104, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('myxoid liposarcoma', 'Disease', (176, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('EWSR1', 'Gene', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (176, 194))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (119, 137))	('myoepithelial tumor', 'Disease', 'MESH:D009208', (236, 255))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (196, 231))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (160, 174))	('desmoplastic small round cell tumor', 'Disease', (196, 231))	('myoepithelial tumor', 'Disease', (236, 255))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('Ewing sarcoma', 'Disease', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (47, 65))	('associated', 'Reg', (66, 76))	('liposarcoma', 'Phenotype', 'HP:0012034', (183, 194))	('clear cell sarcoma', 'Disease', (119, 137))	('EWSR1', 'Gene', '2130', (82, 87))
195818	21212061	Tumors associated with EWSR1 translocation are not uniformly more common in people of European ancestry.	('people', 'Species', '9606', (76, 82))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('EWSR1', 'Gene', (23, 28))	('translocation', 'Var', (29, 42))	('EWSR1', 'Gene', '2130', (23, 28))
195821	21212061	Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue characterized by genetic translocations involving the Ewing sarcoma breakpoint region (EWSR1) in 95% of cases.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (118, 131))	('EWSR1', 'Gene', (151, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('Ewing sarcoma', 'Disease', (0, 13))	('tumor of bone', 'Phenotype', 'HP:0010622', (34, 47))	('EWSR1', 'Gene', '2130', (151, 156))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('genetic translocations', 'Var', (81, 103))	('Ewing sarcoma', 'Disease', (118, 131))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
195825	21212061	The impact of race on the incidence of other mesenchymal tumors associated with EWSR1 translocations has not been studied.	('translocations', 'Var', (86, 100))	('EWSR1', 'Gene', (80, 85))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (45, 63))	('mesenchymal tumors', 'Disease', (45, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('EWSR1', 'Gene', '2130', (80, 85))
195826	21212061	Given the difference in ES incidence between people of European, East Asian, and African ancestry, we hypothesized that race might also have an impact on the incidence of other mesenchymal tumors associated with EWSR1 translocation.	('people', 'Species', '9606', (45, 51))	('EWSR1', 'Gene', '2130', (212, 217))	('impact', 'Reg', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (177, 195))	('EWSR1', 'Gene', (212, 217))	('mesenchymal tumors', 'Disease', (177, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('translocation', 'Var', (218, 231))
195828	21212061	To evaluate for incidence differences among patients diagnosed with mesenchymal tumors associated with EWSR1 translocation, we performed a secondary data analysis of all cases of these tumors registered on the Surveillance, Epidemiology, and End Results (SEER) public-access database collected from various geographic areas in the United States.	('EWSR1', 'Gene', (103, 108))	('patients', 'Species', '9606', (44, 52))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (68, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('mesenchymal tumors', 'Disease', (68, 86))	('EWSR1', 'Gene', '2130', (103, 108))	('associated', 'Reg', (87, 97))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('translocation', 'Var', (109, 122))
195834	21212061	While angiomatoid fibrous histiocytoma (AFH) is also reported to harbor EWSR1 translocations, cases of AFH were only rarely reported in SEER (n=4) and therefore AFH was not further analyzed in this study.	('EWSR1', 'Gene', (72, 77))	('histiocytoma', 'Phenotype', 'HP:0012315', (26, 38))	('angiomatoid fibrous histiocytoma', 'Disease', (6, 38))	('EWSR1', 'Gene', '2130', (72, 77))	('translocations', 'Var', (78, 92))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (6, 38))
195838	21212061	The search for mesenchymal tumors associated with EWSR1 translocation in the SEER database identified a total of 2893 cases.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('EWSR1', 'Gene', '2130', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('translocation', 'Var', (56, 69))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (15, 33))	('EWSR1', 'Gene', (50, 55))	('mesenchymal tumors', 'Disease', (15, 33))
195850	21212061	EWSR1 translocations are present in a very high percentage of both of these tumors.	('EWSR1', 'Gene', '2130', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('EWSR1', 'Gene', (0, 5))	('translocations', 'Var', (6, 20))
195861	21212061	In contrast, this assumption may be less appropriate for ME and particularly MLPS, which harbor EWSR1 gene rearrangements in only in a minority of cases.	('EWSR1', 'Gene', (96, 101))	('MLPS', 'Disease', (77, 81))	('rearrangements', 'Var', (107, 121))	('EWSR1', 'Gene', '2130', (96, 101))	('MLPS', 'Disease', 'None', (77, 81))
195862	21212061	ME and MLPS were included in the current analysis to provide a complete evaluation of the role of race in tumors reported to be associated with EWSR1 translocation.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('EWSR1', 'Gene', '2130', (144, 149))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('MLPS', 'Disease', 'None', (7, 11))	('MLPS', 'Disease', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('EWSR1', 'Gene', (144, 149))	('translocation', 'Var', (150, 163))
195863	21212061	Despite the low frequency of EWSR1 translocation in MLPS, our findings of differences in incidence according to race should prompt further investigations into their genetic epidemiology.	('MLPS', 'Disease', 'None', (52, 56))	('EWSR1', 'Gene', (29, 34))	('translocation', 'Var', (35, 48))	('MLPS', 'Disease', (52, 56))	('EWSR1', 'Gene', '2130', (29, 34))
195865	21212061	However, these tumors do not appear to share common racial differences in the propensity for EWSR1 translocation.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('translocation', 'Var', (99, 112))	('EWSR1', 'Gene', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('EWSR1', 'Gene', '2130', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
195914	32102348	Conversely to cytotoxic cells infiltrates, which exert a tumor suppressive action, the presence of TAMs and Tregs in the TME of different sarcoma types correlate with a worse prognosis.	('TAMs', 'Chemical', '-', (99, 103))	('sarcoma', 'Disease', (138, 145))	('presence', 'Var', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Tregs', 'CPA', (108, 113))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('tumor', 'Disease', (57, 62))	('TAMs', 'Protein', (99, 103))
195918	32102348	demonstrated that the recruited macrophages were polarized toward M2 subtype and tumor growth was strongly inhibited by the specific deletion of this cell population.	('deletion', 'Var', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('inhibited', 'NegReg', (107, 116))	('tumor', 'Disease', (81, 86))
195920	32102348	In OS patients, the progression of the disease has been associated with the presence of the suppressive receptor PD1 on peripheral CD4+ and CD8+ T cells.	('presence', 'Var', (76, 84))	('CD8', 'Gene', (140, 143))	('CD8', 'Gene', '925', (140, 143))	('associated', 'Reg', (56, 66))	('patients', 'Species', '9606', (6, 14))	('PD1', 'Gene', (113, 116))
195931	32102348	Indeed, deregulation of acidity, especially lactic acidosis, is crucial to promote tumor growth and metastasis, as already reported for sarcomas and other cancer types.	('sarcomas', 'Disease', (136, 144))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('acidity', 'MPA', (24, 31))	('lactic acidosis', 'Disease', 'MESH:D000140', (44, 59))	('lactic', 'Chemical', '-', (44, 50))	('metastasis', 'CPA', (100, 110))	('lactic acidosis', 'Disease', (44, 59))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('lactic acid', 'Chemical', 'MESH:D019344', (44, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('cancer', 'Disease', (155, 161))	('acidosis', 'Phenotype', 'HP:0001941', (51, 59))	('promote', 'PosReg', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('deregulation', 'Var', (8, 20))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('lactic acidosis', 'Phenotype', 'HP:0003128', (44, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))
195942	32102348	It has been shown that MCT1 inhibition successfully prevents tumor cell growth.	('MCT1', 'Gene', '6566', (23, 27))	('inhibition', 'Var', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MCT1', 'Gene', (23, 27))	('prevents', 'NegReg', (52, 60))	('tumor', 'Disease', (61, 66))
195944	32102348	In agreement, CD147 silencing reduces pancreatic tumor malignancy both in vivo and in vitro and CD147 gene ablation leads to a downregulation in MCT1 and MCT4 expression and to a consequent decrease of lactate export in non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Disease', (220, 246))	('decrease', 'NegReg', (190, 198))	('lactate export', 'MPA', (202, 216))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('pancreatic tumor malignancy', 'Disease', (38, 65))	('downregulation', 'NegReg', (127, 141))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (220, 246))	('CD147', 'Gene', '682', (96, 101))	('expression', 'MPA', (159, 169))	('MCT1', 'Gene', (145, 149))	('silencing', 'Var', (20, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (224, 246))	('NSCLC', 'Disease', 'MESH:D002289', (248, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))	('CD147', 'Gene', '682', (14, 19))	('pancreatic tumor malignancy', 'Disease', 'MESH:D010190', (38, 65))	('lactate', 'Chemical', 'MESH:D019344', (202, 209))	('CD147', 'Gene', (96, 101))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (220, 246))	('reduces', 'NegReg', (30, 37))	('MCT1', 'Gene', '6566', (145, 149))	('NSCLC', 'Disease', (248, 253))	('MCT4', 'Gene', (154, 158))	('CD147', 'Gene', (14, 19))	('MCT4', 'Gene', '9123', (154, 158))
195949	32102348	In keeping, antibodies directed against CAIX results in a substantial decrease of lactate export and in a consequent reduction of cancer cell proliferation.	('antibodies', 'Var', (12, 22))	('reduction', 'NegReg', (117, 126))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CAIX', 'Gene', (40, 44))	('cancer', 'Disease', (130, 136))	('lactate', 'Chemical', 'MESH:D019344', (82, 89))	('CAIX', 'Gene', '768', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('decrease', 'NegReg', (70, 78))	('lactate export', 'MPA', (82, 96))
195973	32102348	In turn, PHD2 impairment leads to increased stability of HIF-1alpha, which stimulates VEGF accumulation in tumor cells.	('stimulates', 'PosReg', (75, 85))	('PHD2', 'Gene', '54583', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('PHD2', 'Gene', (9, 13))	('HIF-1alpha', 'Gene', '3091', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('impairment', 'Var', (14, 24))	('HIF-1alpha', 'Gene', (57, 67))	('VEGF accumulation', 'MPA', (86, 103))	('increased', 'PosReg', (34, 43))	('stability', 'MPA', (44, 53))
195975	32102348	In keeping, MCT1 inhibition blocks tumor angiogenesis.	('MCT1', 'Gene', '6566', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('blocks tumor', 'Disease', 'MESH:D006327', (28, 40))	('inhibition', 'Var', (17, 27))	('blocks tumor', 'Disease', (28, 40))	('MCT1', 'Gene', (12, 16))
195991	32102348	Both in MCF7 and L6 cells, exposure to lactate profoundly alters the transcriptional profile, upregulating respectively 4131 and 673 genes, including MCT1.	('MCF7', 'CellLine', 'CVCL:0031;0.07065536906780479', (8, 12))	('L6', 'CellLine', 'CVCL:0385;0.02512529577910998', (17, 19))	('MCT1', 'Gene', (150, 154))	('transcriptional profile', 'MPA', (69, 92))	('lactate', 'Chemical', 'MESH:D019344', (39, 46))	('alters', 'Reg', (58, 64))	('MCT1', 'Gene', '6566', (150, 154))	('4131', 'Var', (120, 124))	('upregulating', 'PosReg', (94, 106))
195994	32102348	Since MCT1 silencing hampers lactate-induced c-Myc activation, MCT1 inhibitors could be useful to indirectly impede also glutamine uptake and metabolism in oxidative cancer cells.	('silencing', 'Var', (11, 20))	('cancer', 'Disease', (166, 172))	('glutamine', 'Chemical', 'MESH:D005973', (121, 130))	('lactate', 'Chemical', 'MESH:D019344', (29, 36))	('metabolism', 'MPA', (142, 152))	('MCT1', 'Gene', (6, 10))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('MCT1', 'Gene', (63, 67))	('c-Myc', 'Gene', (45, 50))	('MCT1', 'Gene', '6566', (6, 10))	('MCT1', 'Gene', '6566', (63, 67))	('impede', 'NegReg', (109, 115))	('hampers', 'NegReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('glutamine uptake', 'MPA', (121, 137))	('c-Myc', 'Gene', '4609', (45, 50))
195998	32102348	Physiologically, GPR81 activation reduces lipolysis through the decrease of cAMP levels in adipose cells.	('GPR81', 'Gene', (17, 22))	('GPR81', 'Gene', '27198', (17, 22))	('decrease', 'NegReg', (64, 72))	('reduces', 'NegReg', (34, 41))	('cAMP levels in adipose cells', 'MPA', (76, 104))	('lipolysis', 'MPA', (42, 51))	('activation', 'Var', (23, 33))	('cAMP', 'Chemical', '-', (76, 80))
196044	32154027	GLS measurement increased diagnostic sensitivity and were associated with the risk of left ventricular dysfunction in patients treated with the anthracycline epirubicin.	('left ventricular dysfunction', 'Phenotype', 'HP:0005162', (86, 114))	('measurement', 'Var', (4, 15))	('associated with', 'Reg', (58, 73))	('GLS', 'Chemical', '-', (0, 3))	('ventricular dysfunction', 'Disease', 'MESH:D018754', (91, 114))	('increased', 'PosReg', (16, 25))	('diagnostic sensitivity', 'MPA', (26, 48))	('anthracycline epirubicin', 'Chemical', '-', (144, 168))	('GLS', 'Gene', (0, 3))	('patients', 'Species', '9606', (118, 126))	('ventricular dysfunction', 'Disease', (91, 114))
196305	29147292	In our case, the high FDG uptake with SUVmax of 25.2 has highly suspected pulmonary artery sarcoma, but not thromboembolism.	('thromboembolism', 'Disease', 'MESH:D013923', (108, 123))	('thromboembolism', 'Phenotype', 'HP:0001907', (108, 123))	('high', 'Var', (17, 21))	('FDG', 'Chemical', 'MESH:D019788', (22, 25))	('thromboembolism', 'Disease', (108, 123))	('pulmonary artery sarcoma', 'Disease', (74, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('pulmonary artery sarcoma', 'Disease', 'MESH:D000071079', (74, 98))
196374	26705227	The immunohistochemistry results were calponin (+); desmin (+); smooth muscle actin (SMA) (dispersive +); vimentin (+); CKpan (focal +); CD117 (-); CD34 (+-); Ki67 (the positive rate was low); and S-100 (-).	('CD117 (-', 'Var', (137, 145))	('CKpan', 'Var', (120, 125))	('S-100', 'Var', (197, 202))	('CD34', 'Gene', '947', (148, 152))	('desmin', 'Gene', (52, 58))	('men', 'Species', '9606', (108, 111))	('desmin', 'Gene', '1674', (52, 58))	('Ki67', 'Var', (159, 163))	('CD34', 'Gene', (148, 152))
196441	21352917	In addition, ET-1, ET-3, S6c, IRL-1620 and BQ-3020 were all potent at initiating contractions in the isolated bronchus, but only IRL-1620 and BQ-3020 contractions were blocked by BQ-788, despite S6c and ET-3 also being ETB-selective agonists.	('BQ', 'Chemical', 'MESH:C063469', (179, 181))	('ET-1, ET-3', 'Gene', '13614;13616', (13, 23))	('BQ-788', 'Chemical', 'MESH:C086539', (179, 185))	('BQ', 'Chemical', 'MESH:C063469', (142, 144))	('BQ-3020', 'Var', (43, 50))	('BQ', 'Chemical', 'MESH:C063469', (43, 45))	('S6c', 'Var', (25, 28))
196443	21352917	In rat brain, [125I]-ET-1 was found to more clearly recognize ETA receptors when used in conjunction with S6c.	('[125I]-ET-1', 'Var', (14, 25))	('ETA receptors', 'Protein', (62, 75))	('rat', 'Species', '10116', (3, 6))
196452	21352917	Binding experiments in these cells showed that the presence of BQ-123 increased the affinity of the ETB ligands BQ-3020 and BQ-788.	('increased', 'PosReg', (70, 79))	('affinity', 'Interaction', (84, 92))	('BQ-123', 'Gene', (63, 69))	('ETB', 'Gene', (100, 103))	('BQ', 'Chemical', 'MESH:C063469', (124, 126))	('BQ', 'Chemical', 'MESH:C063469', (63, 65))	('BQ-788', 'Chemical', 'MESH:C086539', (124, 130))	('BQ-123', 'Chemical', 'MESH:C072247', (63, 69))	('BQ', 'Chemical', 'MESH:C063469', (112, 114))	('presence', 'Var', (51, 59))
196470	21352917	In freshly dissociated mouse DRG neurons, 10 nM ET-1 induced a very small intracellular calcium increase from intracellular stores which was blocked by BQ-123 but not by BQ-788.	('ET-1', 'Gene', (48, 52))	('BQ-123', 'Var', (152, 158))	('intracellular calcium increase', 'Phenotype', 'HP:0003575', (74, 104))	('calcium', 'Chemical', 'MESH:D002118', (88, 95))	('mouse', 'Species', '10090', (23, 28))	('BQ-788', 'Chemical', 'MESH:C086539', (170, 176))	('BQ-123', 'Chemical', 'MESH:C072247', (152, 158))
196471	21352917	Conversely, in satellite cells the large intracellular calcium increase induced by 10 nM ET-1 was blocked by BQ-788 but not BQ-123.	('BQ-123', 'Chemical', 'MESH:C072247', (124, 130))	('intracellular calcium increase', 'Phenotype', 'HP:0003575', (41, 71))	('BQ-788', 'Var', (109, 115))	('BQ-788', 'Chemical', 'MESH:C086539', (109, 115))	('ET-1', 'Gene', (89, 93))	('calcium', 'Chemical', 'MESH:D002118', (55, 62))
196475	21352917	Recently, it was reported that the tissue specific ablation of ETA receptors in nociceptors expressing the sodium channel NaV 1.8 completely suppressed tactile allodynia as well as late phase thermal hyperalgesia resulting from ET-1 injection into the plantar region without affecting "physiological" nociception (i.e.	('hyperalgesia', 'Phenotype', 'HP:0031005', (200, 212))	('tactile allodynia', 'Disease', 'MESH:D006930', (152, 169))	('thermal hyperalgesia', 'Disease', 'MESH:D006930', (192, 212))	('NaV 1.8', 'Gene', '20264', (122, 129))	('plantar region', 'Phenotype', 'HP:0010612', (252, 266))	('suppressed', 'NegReg', (141, 151))	('thermal hyperalgesia', 'Disease', (192, 212))	('NaV 1.8', 'Gene', (122, 129))	('allodynia', 'Phenotype', 'HP:0012533', (160, 169))	('ablation', 'Var', (51, 59))	('tactile allodynia', 'Disease', (152, 169))
196485	21352917	Thermal and mechanical hyperalgesia as well as tactile allodynia are well documented pain states induced by subcutaneous injection of a low concentration of ET-1 (30nM, 3pmol - 200uM, 2nmol).	('allodynia', 'Phenotype', 'HP:0012533', (55, 64))	('mechanical hyperalgesia', 'Disease', (12, 35))	('hyperalgesia', 'Phenotype', 'HP:0031005', (23, 35))	('tactile allodynia', 'Disease', (47, 64))	('mechanical hyperalgesia', 'Disease', 'MESH:D006930', (12, 35))	('pain', 'Phenotype', 'HP:0012531', (85, 89))	('rat', 'Species', '10116', (147, 150))	('30nM', 'Var', (163, 167))	('ET-1', 'Gene', (157, 161))	('tactile allodynia', 'Disease', 'MESH:D006930', (47, 64))	('pain', 'Disease', 'MESH:D010146', (85, 89))	('pain', 'Disease', (85, 89))	('Thermal and', 'Disease', (0, 11))
196493	21352917	ET-1 also can raise intracellular calcium in neurons independent of TRPV1, but how such elevation of calcium affects the TRPV1 response is not known.	('intracellular calcium in neurons', 'MPA', (20, 52))	('calcium', 'Chemical', 'MESH:D002118', (101, 108))	('ET-1', 'Var', (0, 4))	('calcium', 'Chemical', 'MESH:D002118', (34, 41))	('raise intracellular calcium', 'Phenotype', 'HP:0003575', (14, 41))	('raise', 'PosReg', (14, 19))
196495	21352917	Interestingly, heterologous expression of ETB receptors with TRPV1 in HEK293 cells showed that ETB was also able to elicit potentiation of TRPV1 responses, although less effectively than ETA.	('ETB', 'Var', (95, 98))	('elicit', 'Reg', (116, 122))	('potentiation', 'MPA', (123, 135))	('HEK293', 'CellLine', 'CVCL:0045', (70, 76))	('TRPV1', 'Protein', (139, 144))
196509	21352917	The pain-like behavior induced by 10 muM ET-1 was reduced by local inhibitors of phospholipase C, but not protein kinase C. ET-1, at a concentration (300 nM, 3pmol) that did not induce significant pain on its own, enhanced nociception from the TRPA1 agonist, cinnamaldehyde.	('inhibitors', 'Var', (67, 77))	('pain', 'Disease', 'MESH:D010146', (4, 8))	('nociception', 'MPA', (223, 234))	('pain', 'Disease', (4, 8))	('TRPA1', 'Gene', (244, 249))	('pain', 'Phenotype', 'HP:0012531', (197, 201))	('pain', 'Disease', 'MESH:D010146', (197, 201))	('reduced', 'NegReg', (50, 57))	('pain', 'Disease', (197, 201))	('TRPA1', 'Gene', '277328', (244, 249))	('cinnamaldehyde', 'Chemical', 'MESH:C012843', (259, 273))	('pain', 'Phenotype', 'HP:0012531', (4, 8))	('rat', 'Species', '10116', (142, 145))	('enhanced', 'PosReg', (214, 222))
196546	21352917	After CCI, increased levels of ET-1 and SP, but not CGRP, were found in traumatized sciatic nerves in NEP KO mice, suggesting a role for ET-1 (and/or SP) in the pathogenesis of CRPS with nerve injury.	('nerve injury', 'Disease', 'MESH:D000080902', (187, 199))	('trauma', 'Disease', (72, 78))	('CCI', 'Chemical', '-', (6, 9))	('CCI', 'Var', (6, 9))	('SP', 'Gene', '21333', (40, 42))	('mice', 'Species', '10090', (109, 113))	('SP', 'Gene', '21333', (150, 152))	('trauma', 'Disease', 'MESH:D014947', (72, 78))	('nerve injury', 'Disease', (187, 199))
196548	21352917	CPIP mice also exhibited increased sensitivity to an intraplantar injection of ET-1 (3nM, 0.3pmol - 20uM, 200pmol).	('mice', 'Species', '10090', (5, 9))	('CPIP', 'Var', (0, 4))	('sensitivity', 'MPA', (35, 46))	('increased', 'PosReg', (25, 34))
196550	21352917	Conversely, the ETB receptor antagonist BQ-788 significantly enhanced cold allodynia in CPIP, but not sham mice, although the ETB receptor agonist IRL-1620 was without effect.	('allodynia', 'Disease', (75, 84))	('enhanced', 'PosReg', (61, 69))	('allodynia', 'Phenotype', 'HP:0012533', (75, 84))	('allodynia', 'Disease', 'MESH:D006930', (75, 84))	('BQ-788', 'Chemical', 'MESH:C086539', (40, 46))	('mice', 'Species', '10090', (107, 111))	('BQ-788', 'Gene', (40, 46))	('CPIP', 'Var', (88, 92))
196551	21352917	In contrast, IRL-1620 reduced mechanical allodynia in CPIP mice, and this anti-nociceptive effect appeared naloxone-insensitive, unlike the ETB mediated analgesic mechanism in the epidermis.	('mechanical allodynia', 'Disease', 'MESH:D006930', (30, 50))	('mice', 'Species', '10090', (59, 63))	('mechanical allodynia', 'Disease', (30, 50))	('naloxone', 'Chemical', 'MESH:D009270', (107, 115))	('allodynia', 'Phenotype', 'HP:0012533', (41, 50))	('reduced', 'NegReg', (22, 29))	('IRL-1620', 'Var', (13, 21))
196553	21352917	The ETB receptor agonist IRL-1620 was anti-nociceptive for SNB in CPIP, but not sham mice.	('mice', 'Species', '10090', (85, 89))	('CPIP', 'Var', (66, 70))	('anti-nociceptive', 'MPA', (38, 54))
196588	21352917	Interestingly, the ETB receptor-mediated opioid mechanism in SC carcinoma was found to be modulated by ETA receptor antagonism with BQ-123.	('modulated', 'Reg', (90, 99))	('antagonism', 'Var', (116, 126))	('SC carcinoma', 'Disease', 'MESH:D000755', (61, 73))	('ETA receptor', 'Protein', (103, 115))	('SC carcinoma', 'Disease', (61, 73))	('ETB receptor-mediated opioid', 'MPA', (19, 47))	('BQ-123', 'Chemical', 'MESH:C072247', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
196595	21352917	Mechanical allodynia evoked in naive mice by intraplantar injection of tumor extract (paw-grown melanoma, B16-BL6 cells) was reduced by local inhibitors of ETB receptors, as well as by antagonists of ETA receptors.	('inhibitors', 'Var', (142, 152))	('ETB receptors', 'Protein', (156, 169))	('Mechanical allodynia', 'Disease', 'MESH:D006930', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('B16-BL6', 'CellLine', 'CVCL:0157', (106, 113))	('reduced', 'NegReg', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('allodynia', 'Phenotype', 'HP:0012533', (11, 20))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('tumor', 'Disease', (71, 76))	('melanoma', 'Disease', (96, 104))	('Mechanical allodynia', 'Disease', (0, 20))	('mice', 'Species', '10090', (37, 41))
196597	21352917	Stosser and colleagues used mice with a conditional deletion of ETA receptors in peripheral nociceptors (NaV1.8- ETA-/- mice) to obtain strong evidence for a significant role of ETA receptors expressed on peripheral nociceptors in tumor associated hyperalgesia.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('mice', 'Species', '10090', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('NaV1.8', 'Gene', '20264', (105, 111))	('mice', 'Species', '10090', (28, 32))	('NaV1.8', 'Gene', (105, 111))	('tumor', 'Disease', (231, 236))	('hyperalgesia', 'Disease', 'MESH:D006930', (248, 260))	('hyperalgesia', 'Disease', (248, 260))	('deletion', 'Var', (52, 60))	('hyperalgesia', 'Phenotype', 'HP:0031005', (248, 260))
196598	21352917	In this study, lung carcinoma cells were injected subcutaneously in the hind paws of the mutant mice and of their control littermates (ETA fl/fl mice).	('lung carcinoma', 'Disease', 'MESH:D008175', (15, 29))	('mice', 'Species', '10090', (96, 100))	('lung carcinoma', 'Disease', (15, 29))	('mice', 'Species', '10090', (145, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('mutant', 'Var', (89, 95))
196610	21352917	The spontaneous activity of C-nociceptors in tumor-bearing mice was reduced, although not fully abolished, by injection of BQ-123 into their receptive field.	('BQ-123', 'Gene', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('injection', 'Var', (110, 119))	('C-nociceptors', 'Protein', (28, 41))	('mice', 'Species', '10090', (59, 63))	('BQ-123', 'Chemical', 'MESH:C072247', (123, 129))	('tumor', 'Disease', (45, 50))	('spontaneous activity', 'MPA', (4, 24))	('reduced', 'NegReg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
196759	29986386	Additionally, cellular KAP-1 associates with RTA-dependent lytic promoters and represses their expression, and depletion of KAP-1 is sufficient to induce KSHV reactivation.	('KS', 'Phenotype', 'HP:0100726', (154, 156))	('KSHV', 'MPA', (154, 158))	('induce', 'Reg', (147, 153))	('represses', 'NegReg', (79, 88))	('associates', 'Interaction', (29, 39))	('KSHV', 'Species', '37296', (154, 158))	('depletion', 'Var', (111, 120))	('expression', 'MPA', (95, 105))
196765	29986386	Loss of FUS leads to enhanced viral RNA and protein expression, resulting in an increase in the production of infectious virions.	('FUS', 'Gene', (8, 11))	('FUS', 'Gene', '2521', (8, 11))	('increase', 'PosReg', (80, 88))	('enhanced', 'PosReg', (21, 29))	('production of infectious virions', 'MPA', (96, 128))	('Loss', 'Var', (0, 4))
196769	29986386	Consistent with this, FUS knockdown increases RNAP II phosphorylation and increases nascent RNA expression of RTA, thus enhancing viral reactivation.	('enhancing', 'PosReg', (120, 129))	('FUS', 'Gene', (22, 25))	('FUS', 'Gene', '2521', (22, 25))	('knockdown', 'Var', (26, 35))	('increases', 'PosReg', (74, 83))	('increases', 'PosReg', (36, 45))	('viral reactivation', 'MPA', (130, 148))	('RTA', 'Gene', (110, 113))	('RNAP II', 'Protein', (46, 53))	('nascent RNA expression', 'MPA', (84, 106))
196814	29986386	FUS depletion resulted in a significant increase in the steady state levels of several KSHV-encoded mRNAs as well as the long noncoding RNA PAN (Figure 1B).	('KSHV', 'Species', '37296', (87, 91))	('increase', 'PosReg', (40, 48))	('depletion', 'Var', (4, 13))	('PAN', 'Gene', '51816', (140, 143))	('KS', 'Phenotype', 'HP:0100726', (87, 89))	('FUS', 'Gene', (0, 3))	('PAN', 'Gene', (140, 143))	('FUS', 'Gene', '2521', (0, 3))	('KSHV-encoded', 'Gene', (87, 99))
196818	29986386	Given the increase in viral lytic gene expression, we predicted that knockdown of FUS would affect virion production.	('virion production', 'MPA', (99, 116))	('FUS', 'Gene', (82, 85))	('affect', 'Reg', (92, 98))	('FUS', 'Gene', '2521', (82, 85))	('expression', 'MPA', (39, 49))	('increase', 'PosReg', (10, 18))	('knockdown', 'Var', (69, 78))	('viral lytic gene', 'Gene', (22, 38))
196820	29986386	Indeed, knockdown of FUS resulted in an increase in viral production (Figure 1E).	('viral production', 'MPA', (52, 68))	('knockdown', 'Var', (8, 17))	('increase', 'PosReg', (40, 48))	('FUS', 'Gene', '2521', (21, 24))	('FUS', 'Gene', (21, 24))
196828	29986386	FUS depletion resulted in a marked increase in the number of RFP positive cells, suggesting more efficient entry into the lytic cycle (Figure 2B).	('RFP', 'Gene', (61, 64))	('FUS', 'Gene', '2521', (0, 3))	('increase', 'PosReg', (35, 43))	('RFP', 'Gene', '5987', (61, 64))	('more efficient', 'PosReg', (92, 106))	('depletion', 'Var', (4, 13))	('FUS', 'Gene', (0, 3))	('entry', 'CPA', (107, 112))
196831	29986386	To test whether the observed FUS phenotype was due to off-target effects of siRNA-mediated knockdown, we examined the effect of a second FUS-siRNA on KSHV reactivation.	('KSHV', 'Species', '37296', (150, 154))	('FUS', 'Gene', (29, 32))	('knockdown', 'Var', (91, 100))	('FUS', 'Gene', '2521', (29, 32))	('FUS', 'Gene', (137, 140))	('FUS', 'Gene', '2521', (137, 140))	('KS', 'Phenotype', 'HP:0100726', (150, 152))
196868	29986386	Interestingly, during lytic reactivation, the levels of FUS decreased at ORF57 and PAN, while quantitatively it was not significantly altered at the RTA and vIL6 loci.	('PAN', 'Gene', (83, 86))	('FUS', 'Gene', (56, 59))	('decreased', 'NegReg', (60, 69))	('FUS', 'Gene', '2521', (56, 59))	('levels', 'MPA', (46, 52))	('PAN', 'Gene', '51816', (83, 86))	('ORF57', 'Var', (73, 78))
196883	29986386	Consistent with FUS negatively affecting Ser2 CTD phosphorylation, siRNA-mediated knockdown of FUS robustly stimulates RTA nascent RNA production.	('Ser2', 'Gene', (41, 45))	('Ser2', 'Gene', '3714', (41, 45))	('RTA nascent RNA production', 'MPA', (119, 145))	('FUS', 'Gene', (16, 19))	('FUS', 'Gene', (95, 98))	('FUS', 'Gene', '2521', (16, 19))	('knockdown', 'Var', (82, 91))	('FUS', 'Gene', '2521', (95, 98))	('stimulates', 'PosReg', (108, 118))
196894	29986386	However, P-TEFb has been demonstrated to be present on the viral genome, and thus FUS inhibition of Ser2 CTD phosphorylation at viral genes may occur through P-TEFb inhibition, as proposed for select cellular genes.	('Ser2', 'Gene', '3714', (100, 104))	('TEFb', 'Chemical', '-', (11, 15))	('Ser2', 'Gene', (100, 104))	('TEFb', 'Chemical', '-', (160, 164))	('FUS', 'Gene', (82, 85))	('FUS', 'Gene', '2521', (82, 85))	('inhibition', 'NegReg', (165, 175))	('P-TEFb', 'Var', (158, 164))	('inhibition', 'NegReg', (86, 96))
196898	29986386	Furthermore, mutations in FUS are associated with a range of diseases including cancer and amyotrophic lateral sclerosis (ALS).	('ALS', 'Phenotype', 'HP:0007354', (122, 125))	('associated', 'Reg', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('FUS', 'Gene', (26, 29))	('amyotrophic lateral sclerosis', 'Disease', (91, 120))	('FUS', 'Gene', '2521', (26, 29))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (91, 120))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (80, 86))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (91, 120))
196899	29986386	In the case of ALS, FUS mutations have been described that promote its relocalization to the cytoplasm.	('relocalization to the cytoplasm', 'MPA', (71, 102))	('promote', 'PosReg', (59, 66))	('FUS', 'Gene', (20, 23))	('ALS', 'Phenotype', 'HP:0007354', (15, 18))	('mutations', 'Var', (24, 33))	('FUS', 'Gene', '2521', (20, 23))
196901	29986386	Thus, we would predict KSHV reactivation would be significantly enhanced within cells harboring FUS mutations associated with ALS.	('mutations', 'Var', (100, 109))	('KS', 'Phenotype', 'HP:0100726', (23, 25))	('ALS', 'Phenotype', 'HP:0007354', (126, 129))	('KSHV', 'Gene', (23, 27))	('ALS', 'Disease', (126, 129))	('KSHV', 'Species', '37296', (23, 27))	('FUS', 'Gene', (96, 99))	('FUS', 'Gene', '2521', (96, 99))	('enhanced', 'PosReg', (64, 72))
196918	29080385	In medulloblastoma, co-expression of ERBB2 and ERBB4 occurs in 10-50% of high-grade glial cells and co-expression demonstrated independent prognostic significance.	('ERBB2', 'Gene', (37, 42))	('ERBB2', 'Gene', '2064', (37, 42))	('ERBB4', 'Gene', (47, 52))	('medulloblastoma', 'Disease', 'MESH:D008527', (3, 18))	('co-expression', 'Var', (20, 33))	('medulloblastoma', 'Phenotype', 'HP:0002885', (3, 18))	('medulloblastoma', 'Disease', (3, 18))	('ERBB4', 'Gene', '2066', (47, 52))
196920	29080385	ERBB3 is expressed in rhabdomyosarcoma, particularly the alveolar subtype, and has been proposed as a therapeutic target as RNAi mediated knockdown of ERBB3 in RD embryonal rhabdomyosarcoma cells suppresses proliferation.	('knockdown', 'Var', (138, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('rhabdomyosarcoma', 'Disease', (22, 38))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (173, 189))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (163, 189))	('embryonal rhabdomyosarcoma', 'Disease', (163, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (22, 38))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (163, 189))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (173, 189))	('ERBB3', 'Gene', (151, 156))	('suppresses', 'NegReg', (196, 206))	('alveolar subtype', 'Disease', 'MESH:C535673', (57, 73))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (22, 38))	('alveolar subtype', 'Disease', (57, 73))	('rhabdomyosarcoma', 'Disease', (173, 189))
196924	29080385	In adult cancers, therapeutic efficacy of targeted drugs such as lapatinib or trastuzumab occurs when the target gene is amplified (as in ERBB2/Her2 amplified breast cancer), and where there exists an activating mutation (imatinib in treatment of chronic myelogenous leukemia).	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (247, 275))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('imatinib', 'Chemical', 'MESH:D000068877', (222, 230))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('Her2', 'Gene', (144, 148))	('breast cancer', 'Disease', (159, 172))	('trastuzumab', 'Chemical', 'MESH:D000068878', (78, 89))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('amplified', 'Var', (121, 130))	('adult cancers', 'Disease', (3, 16))	('leukemia', 'Phenotype', 'HP:0001909', (267, 275))	('chronic myelogenous leukemia', 'Disease', (247, 275))	('lapatinib', 'Chemical', 'MESH:D000077341', (65, 74))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (247, 275))	('activating mutation', 'PosReg', (201, 220))	('ERBB2', 'Gene', (138, 143))	('adult cancers', 'Disease', 'MESH:C535836', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (255, 275))	('ERBB2', 'Gene', '2064', (138, 143))	('Her2', 'Gene', '2064', (144, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))
196925	29080385	In pediatric cancers certain mutations in ALK in neuroblastoma and activation of ALK through t(2;5)(p23;q35) chromosomal translocation, amplification or mutation confer sensitivity to crizotinib Although ERBB3 does not signal directly it heterodimerizes with and allosterically activates ERBB1 and ERBB2.	('activates', 'PosReg', (278, 287))	('ERBB2', 'Gene', '2064', (298, 303))	('sensitivity', 'MPA', (169, 180))	('heterodimerizes', 'MPA', (238, 253))	('neuroblastoma', 'Disease', (49, 62))	('ERBB1', 'Gene', (288, 293))	('neuroblastoma', 'Phenotype', 'HP:0003006', (49, 62))	('t(2;5)(p23;q35)', 'STRUCTURAL_ABNORMALITY', 'None', (93, 108))	('pediatric cancers', 'Disease', (3, 20))	('ALK', 'Gene', '238', (81, 84))	('neuroblastoma', 'Disease', 'MESH:D009447', (49, 62))	('crizotinib', 'Chemical', 'MESH:D000077547', (184, 194))	('mutation', 'Var', (153, 161))	('ALK', 'Gene', (81, 84))	('ALK', 'Gene', '238', (42, 45))	('ERBB1', 'Gene', '1956', (288, 293))	('mutations', 'Var', (29, 38))	('pediatric cancers', 'Disease', 'MESH:D009369', (3, 20))	('ALK', 'Gene', (42, 45))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('amplification', 'Var', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('ERBB2', 'Gene', (298, 303))
196927	29080385	Additionally, anti-ERBB3 therapy was also been reported to sensitize erlotinib refractory non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('anti-ERBB3', 'Var', (14, 24))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('cell lung cancer', 'Disease', (100, 116))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cell lung cancer', 'Disease', 'MESH:D008175', (100, 116))	('erlotinib', 'Chemical', 'MESH:D000069347', (69, 78))
196930	29080385	While resistance to IGF1R-targeted antibodies was associated with expression of the insulin receptor, this did not explain the intrinsic resistance present in many tumor models.	('insulin receptor', 'Gene', '3643', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('expression', 'MPA', (66, 76))	('IGF1R', 'Gene', (20, 25))	('antibodies', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('insulin receptor', 'Gene', (84, 100))	('associated', 'Reg', (50, 60))	('IGF1R', 'Gene', '3480', (20, 25))
196938	29080385	For ES-4 cells, that showed the highest levels of phospho-ERBB3, the effect of patritumab was studied after 24 Hr exposure to 5-20 mug/mL antibody.	('ES-4', 'Gene', '13884', (4, 8))	('phospho-ERBB3', 'Var', (50, 63))	('patritumab', 'Chemical', 'MESH:C585471', (79, 89))	('ES-4', 'Gene', (4, 8))
196942	29080385	Antibodies used were against ERBB3 (D22C5 Rabbit mAb), phospho-ERBB3 (Y1289; D1B5 Rabbit mAb), Heregulin (#2573 Rabbit Ab) and GAPDH (D16H11 rabbit Mab; loading control), purchased from Cell Signaling Tecnology (Danvers, MA).	('Rabbit', 'Species', '9986', (112, 118))	('Rabbit', 'Species', '9986', (82, 88))	('Rabbit', 'Species', '9986', (42, 48))	('ERBB3', 'Gene', (29, 34))	('Y1289; D1B5', 'Var', (70, 81))	('rabbit', 'Species', '9986', (141, 147))
196981	29080385	For ES-2 xenografts only cyclophosphamide or cyclophosphamide + P significantly inhibited tumor growth (P<0.001).	('cyclophosphamide', 'Var', (25, 41))	('cyclophosphamide', 'Var', (45, 61))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('cyclophosphamide + P', 'Chemical', '-', (45, 65))	('ES-2', 'Gene', '8220', (4, 8))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (25, 41))	('inhibited', 'NegReg', (80, 89))	('ES-2', 'Gene', (4, 8))
196990	29080385	However, in both ES-4 and Rh18 models the combination of P+E with dosed-reduced cyclophosphamide was significantly inferior (P=0.002, and <0.001, respectively) to cyclophosphamide administered at its MTD, Figure 3.	('cyclophosphamide', 'MPA', (80, 96))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (163, 179))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (80, 96))	('ES-4', 'Gene', '13884', (17, 21))	('P+E', 'Var', (57, 60))	('inferior', 'NegReg', (115, 123))	('ES-4', 'Gene', (17, 21))
196996	29080385	As shown in Figure 4, phospho-ERBB3(Tyr1289) was detected in control tumors (n=3), with some variability, but was completely suppressed by patritumab treatment.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('phospho-ERBB3', 'Var', (22, 35))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('suppressed', 'NegReg', (125, 135))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('Tyr1289', 'Chemical', '-', (36, 43))	('patritumab', 'Chemical', 'MESH:C585471', (139, 149))
196998	29080385	In contrast, erlotinib did not decrease phospho-ERBB3, but decreased phosphor-ERK1/2, but also appeared to increase phosphorylation of Akt.	('Akt', 'Gene', '207', (135, 138))	('increase', 'PosReg', (107, 115))	('phosphorylation', 'MPA', (116, 131))	('erlotinib', 'Var', (13, 22))	('Akt', 'Gene', (135, 138))	('phosphor-ERK1/2', 'MPA', (69, 84))	('erlotinib', 'Chemical', 'MESH:D000069347', (13, 22))
197002	29080385	For example combination of dabrafenib with trametinib in treatment of melanoma results in increased progression-free survival, and in a preclinical model trametinib-resistant astrocytoma, combination with a STAT3 inhibitor results in re-sensitization to trametinib.	('melanoma', 'Disease', (70, 78))	('trametinib', 'Chemical', 'MESH:C560077', (43, 53))	('progression-free survival', 'CPA', (100, 125))	('trametinib', 'Chemical', 'MESH:C560077', (154, 164))	('STAT3', 'Gene', '6774', (207, 212))	('increased', 'PosReg', (90, 99))	('astrocytoma', 'Phenotype', 'HP:0009592', (175, 186))	('re-sensitization', 'MPA', (234, 250))	('trametinib', 'Chemical', 'MESH:C560077', (254, 264))	('combination', 'Interaction', (188, 199))	('combination', 'Var', (12, 23))	('clinical', 'Species', '191496', (139, 147))	('STAT3', 'Gene', (207, 212))	('dabrafenib', 'Chemical', 'MESH:C561627', (27, 37))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
197010	29080385	Our studies showed that relative to other pediatric xenografts and cell lines developed in the PPTP, ERBB1 mRNA was high in embryonal rhabdomyosarcoma lines (Rh18 and RD) whereas ERBB3 mRNA was highly expressed in alveolar rhabdomyosarcoma xenografts (Rh10, Rh28, Rh30, Rh41 and Rh65), consistent with clinical samples.	('Rh41', 'Var', (270, 274))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (214, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (134, 150))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (124, 150))	('alveolar rhabdomyosarcoma xenografts', 'Disease', (214, 250))	('Rh30', 'Gene', (264, 268))	('clinical samples', 'Species', '191496', (302, 318))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (223, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('embryonal rhabdomyosarcoma lines', 'Disease', 'MESH:D018233', (124, 156))	('ERBB1', 'Gene', '1956', (101, 106))	('PPTP', 'Chemical', '-', (95, 99))	('embryonal rhabdomyosarcoma lines', 'Disease', (124, 156))	('alveolar rhabdomyosarcoma xenografts', 'Disease', 'MESH:D018232', (214, 250))	('Rh10', 'Var', (252, 256))	('Rh30', 'Gene', '6007', (264, 268))	('ERBB1', 'Gene', (101, 106))
197011	29080385	ERBB3 protein was elevated in Rh5, Rh10 and Rh41 alveolar rhabdomyosarcoma cell lines, although phosphorylation was not detected.	('protein', 'Protein', (6, 13))	('ERBB3', 'Gene', (0, 5))	('Rh41', 'Var', (44, 48))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (49, 74))	('Rh10', 'Var', (35, 39))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (58, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (49, 74))	('alveolar rhabdomyosarcoma', 'Disease', (49, 74))	('elevated', 'PosReg', (18, 26))
197148	30782663	In the current studies, we have found that EphA4 promotes KSHV glycoprotein H/glycoprotein L (gH/gL)-mediated fusion and infection better than does ephrin A2 (EphA2) in HEK293T cells, indicating that EphA4 is a new KSHV entry receptor.	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('KSHV', 'Species', '37296', (58, 62))	('gL', 'Chemical', 'MESH:C015905', (97, 99))	('promotes', 'PosReg', (49, 57))	('infection', 'Disease', (121, 130))	('infection', 'Disease', 'MESH:D007239', (121, 130))	('KSHV', 'Species', '37296', (215, 219))	('EphA4', 'Var', (43, 48))	('KS', 'Phenotype', 'HP:0100726', (215, 217))	('HEK293T', 'CellLine', 'CVCL:0063', (169, 176))
197150	30782663	We found that both EphA2 and EphA4 play a role in KSHV fusion and infection, since EphA2-EphA4 double-knockout cells had the greatest decrease in fusion activity and infection compared to single-knockout cells.	('decrease', 'NegReg', (134, 142))	('infection', 'Disease', (66, 75))	('fusion activity', 'CPA', (146, 161))	('infection', 'Disease', 'MESH:D007239', (66, 75))	('KSHV', 'Species', '37296', (50, 54))	('infection', 'Disease', (166, 175))	('infection', 'Disease', 'MESH:D007239', (166, 175))	('KS', 'Phenotype', 'HP:0100726', (50, 52))	('EphA2-EphA4', 'Gene', (83, 94))	('double-knockout', 'Var', (95, 110))
197151	30782663	Fusion and infection of KSHV were rescued in the EphA2-EphA4 double-knockout cells upon overexpression of EphA2 and/or EphA4.	('EphA2-EphA4', 'Gene', (49, 60))	('overexpression', 'PosReg', (88, 102))	('infection of KSHV', 'Disease', (11, 28))	('Fusion', 'CPA', (0, 6))	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('infection of KSHV', 'Disease', 'MESH:C537372', (11, 28))	('EphA2', 'Var', (106, 111))	('EphA4', 'Var', (119, 124))
197174	30782663	Overexpression of EphA2 and EphA4 has been reported in gastric cancer, breast cancer, colon cancer, and prostate cancer.	('EphA2', 'Protein', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('reported', 'Reg', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', (71, 84))	('gastric cancer', 'Disease', (55, 69))	('colon cancer', 'Disease', (86, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('prostate cancer', 'Disease', (104, 119))	('EphA4', 'Var', (28, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))
197188	30782663	To further examine if EphA4 is sufficient to induce fusion for KSHV gH/gL, we examined fusion activity using a split green fluorescent protein (GFP) fusion assay and readily detected fusion; this was monitored by the appearance of green cells indicative of fusion activity only when KSHV gH/gL- and EBV gB-expressing cells were overlaid with cells that overexpress EphA2 or EphA4 (Fig.	('KSHV', 'Species', '37296', (63, 67))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('EphA2', 'Var', (365, 370))	('KS', 'Phenotype', 'HP:0100726', (283, 285))	('gL', 'Chemical', 'MESH:C015905', (71, 73))	('gL', 'Chemical', 'MESH:C015905', (291, 293))	('gB', 'Chemical', '-', (303, 305))	('KSHV', 'Species', '37296', (283, 287))	('EBV', 'Species', '10376', (299, 302))	('EphA4', 'Var', (374, 379))
197189	30782663	Similarly, EphA4 induced more fusion activity than did EphA2, consistent with our observation of greater fusion in HEK293T cells transfected with EphA4.	('fusion activity', 'MPA', (30, 45))	('HEK293T', 'CellLine', 'CVCL:0063', (115, 122))	('EphA4', 'Var', (11, 16))
197190	30782663	To examine the effect of EphA4 on KSHV infection of epithelial cells, we transfected HEK293T cells with control plasmid, EphA2, EphA4, and EphA2-EphA4 and then infected the cells with KSHV virus expressing GFP.	('KS', 'Phenotype', 'HP:0100726', (34, 36))	('KSHV', 'Species', '37296', (34, 38))	('EphA2-EphA4', 'Var', (139, 150))	('HEK293T', 'CellLine', 'CVCL:0063', (85, 92))	('KS', 'Phenotype', 'HP:0100726', (184, 186))	('KSHV', 'Species', '37296', (184, 188))	('KSHV infection', 'Disease', 'MESH:C537372', (34, 48))	('KSHV infection', 'Disease', (34, 48))
197191	30782663	Flow cytometry showed increased infection of KSHV in the presence of either EphA2 or EphA4 and higher levels of fusion when both EphA2 and EphA4 were transfected (Fig.	('infection of KSHV', 'Disease', 'MESH:C537372', (32, 49))	('EphA2', 'Var', (76, 81))	('KS', 'Phenotype', 'HP:0100726', (45, 47))	('higher', 'PosReg', (95, 101))	('increased', 'PosReg', (22, 31))	('infection of KSHV', 'Disease', (32, 49))	('EphA4', 'Var', (85, 90))	('fusion', 'MPA', (112, 118))
197198	30782663	We next examined the effect of EphA2 and EphA4 knockout on KSHV fusion.	('KSHV', 'Species', '37296', (59, 63))	('EphA2', 'Gene', (31, 36))	('KS', 'Phenotype', 'HP:0100726', (59, 61))	('knockout', 'Var', (47, 55))	('EphA4', 'Gene', (41, 46))
197222	30782663	To investigate if the kinase function was also nonessential for KSHV cell-cell fusion, we constructed three EphA4 kinase-dead mutants based on previous studies, similar to the EphA2 constructs that we used in our previous study with EBV.	('KS', 'Phenotype', 'HP:0100726', (64, 66))	('KSHV', 'Species', '37296', (64, 68))	('EphA4', 'Gene', (108, 113))	('EBV', 'Species', '10376', (233, 236))	('mutants', 'Var', (126, 133))
197226	30782663	Moreover, we found that EphA4 functions better than EphA2, since overexpression of EphA4 enhances KSHV fusion by approximately 33% and KSHV infection by 163% compared to EphA2 (Fig.	('KS', 'Phenotype', 'HP:0100726', (98, 100))	('KSHV fusion', 'CPA', (98, 109))	('KSHV infection', 'Disease', 'MESH:C537372', (135, 149))	('EphA4', 'Var', (83, 88))	('KSHV infection', 'Disease', (135, 149))	('KS', 'Phenotype', 'HP:0100726', (135, 137))	('KSHV', 'Species', '37296', (135, 139))	('overexpression', 'PosReg', (65, 79))	('enhances', 'PosReg', (89, 97))	('KSHV', 'Species', '37296', (98, 102))
197228	30782663	Interestingly, EphA4 but not EphA2 is expressed in B cells, suggesting that EphA4 might play a key role in KSHV B cell infection exclusively compared to EphA2.	('infection', 'Disease', (119, 128))	('KSHV', 'Species', '37296', (107, 111))	('KS', 'Phenotype', 'HP:0100726', (107, 109))	('EphA4', 'Var', (76, 81))	('infection', 'Disease', 'MESH:D007239', (119, 128))
197229	30782663	Knockout of both EphA2 and EphA4 greatly decreased fusion and infection of KSHV, while overexpression of EphA2 and EphA4 alone or together rescued the fusion and infection of EphA2-EphA4 double-knockout cells (Fig.	('fusion', 'CPA', (151, 157))	('infection of KSHV', 'Disease', (62, 79))	('fusion', 'CPA', (51, 57))	('decreased', 'NegReg', (41, 50))	('infection', 'Disease', (162, 171))	('infection', 'Disease', (62, 71))	('EphA4', 'Gene', (27, 32))	('infection', 'Disease', 'MESH:D007239', (62, 71))	('Knockout', 'Var', (0, 8))	('infection', 'Disease', 'MESH:D007239', (162, 171))	('infection of KSHV', 'Disease', 'MESH:C537372', (62, 79))	('KS', 'Phenotype', 'HP:0100726', (75, 77))	('EphA2', 'Gene', (17, 22))
197247	30782663	We found that while only EphA2 can enhance the fusion activity of EBV gH/gL, both EphA2 and EphA4 can enhance the fusion activity of KSHV gH/gL (Fig.	('EBV', 'Species', '10376', (66, 69))	('fusion activity', 'MPA', (47, 62))	('gL', 'Chemical', 'MESH:C015905', (141, 143))	('enhance', 'PosReg', (102, 109))	('gL', 'Chemical', 'MESH:C015905', (73, 75))	('enhance', 'PosReg', (35, 42))	('fusion activity', 'MPA', (114, 129))	('EphA2', 'Var', (82, 87))	('EphA4', 'Var', (92, 97))	('KSHV', 'Species', '37296', (133, 137))	('KS', 'Phenotype', 'HP:0100726', (133, 135))
197250	30782663	In WT HEK293T cells, overexpression of either EphA2 or EphA4 or both can also enhance KSHV infection (Fig.	('enhance', 'PosReg', (78, 85))	('KSHV infection', 'Disease', (86, 100))	('EphA2', 'Var', (46, 51))	('EphA4', 'Var', (55, 60))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('overexpression', 'PosReg', (21, 35))	('HEK293T', 'CellLine', 'CVCL:0063', (6, 13))	('KSHV infection', 'Disease', 'MESH:C537372', (86, 100))
197252	30782663	Transfection of the double-knockout cells with EphA2 or EphA4, and especially both EphA2 and EphA4, rescued infection (Fig.	('EphA2', 'Var', (83, 88))	('EphA4', 'Var', (93, 98))	('infection', 'Disease', (108, 117))	('infection', 'Disease', 'MESH:D007239', (108, 117))	('rescued', 'PosReg', (100, 107))
197253	30782663	These results together indicate that both EphA2 and EphA4 play a role in KSHV fusion.	('EphA4', 'Var', (52, 57))	('KSHV', 'Species', '37296', (73, 77))	('KS', 'Phenotype', 'HP:0100726', (73, 75))	('KSHV fusion', 'Disease', (73, 84))	('EphA2', 'Var', (42, 47))
197261	30782663	Mutation of the ELEFN motif in RRV and KSHV is sufficient for detargeting of KSHV from Eph family receptors and reduces infection of susceptible cells.	('detargeting', 'NegReg', (62, 73))	('KSHV', 'Gene', (39, 43))	('infection', 'Disease', 'MESH:D007239', (120, 129))	('KSHV', 'Gene', (77, 81))	('Eph', 'Gene', '2041', (87, 90))	('RRV', 'Species', '703611', (31, 34))	('Mutation', 'Var', (0, 8))	('Eph', 'Gene', (87, 90))	('KS', 'Phenotype', 'HP:0100726', (39, 41))	('KSHV', 'Species', '37296', (39, 43))	('KS', 'Phenotype', 'HP:0100726', (77, 79))	('KSHV', 'Species', '37296', (77, 81))	('reduces', 'NegReg', (112, 119))	('infection', 'Disease', (120, 129))
197265	30782663	Our results showed that EphA4 promotes KSHV fusion approximately 33% better than does EphA2 (Fig.	('KSHV fusion', 'CPA', (39, 50))	('EphA4', 'Var', (24, 29))	('promotes', 'PosReg', (30, 38))	('KS', 'Phenotype', 'HP:0100726', (39, 41))	('KSHV', 'Species', '37296', (39, 43))
197269	30782663	Previously, we examined if the kinase activity of EphA2 is important for the fusion of EBV gH/gL and did not observe any loss of fusion function for the kinase-dead EphA2 mutants.	('EBV', 'Species', '10376', (87, 90))	('gL', 'Chemical', 'MESH:C015905', (94, 96))	('EphA2', 'Gene', (165, 170))	('important', 'Reg', (59, 68))	('mutants', 'Var', (171, 178))
197273	30782663	Both EphA2 and EphA4 are overexpressed in numerous malignancies, including gastric cancer, breast cancer, colon cancer, and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (106, 118))	('EphA2', 'Var', (5, 10))	('EphA4', 'Var', (15, 20))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colon cancer', 'Disease', 'MESH:D015179', (106, 118))	('numerous malignancies', 'Disease', 'MESH:D009369', (42, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('gastric cancer', 'Disease', (75, 89))	('overexpressed', 'PosReg', (25, 38))	('numerous malignancies', 'Disease', (42, 63))	('colon cancer', 'Disease', (106, 118))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Disease', (91, 104))	('prostate cancer', 'Disease', 'MESH:D011471', (124, 139))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('prostate cancer', 'Disease', (124, 139))
197282	30782663	A total of 2.5 x 105 HEK293-T14-Cas9 cells per well in a 12-well plate were infected with lentivirus, including control sgRNA, EphA2 sgRNA, or EphA4 sgRNA, either individually or combined.	('infected', 'Reg', (76, 84))	('EphA4', 'Var', (143, 148))	('HEK293-T14-Cas9', 'CellLine', 'CVCL:0063', (21, 36))
197322	29352211	Therefore, disruption of cholesterol signalling may be an effective strategy in hedgehog-driven cancers, including medulloblastoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (115, 130))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('medulloblastoma', 'Disease', (115, 130))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('disruption', 'Var', (11, 21))	('cholesterol', 'Chemical', 'MESH:D002784', (25, 36))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('medulloblastoma', 'Disease', 'MESH:D008527', (115, 130))	('cancers', 'Disease', (96, 103))
197336	29352211	Furthermore, analysis of patient samples revealed an enrichment of several hedgehog pathway genes, such as GLI2, GLI3 and HHIP in cells from medulloblastoma patients expressing high SCARB1 levels (Fig.	('medulloblastoma', 'Disease', (141, 156))	('GLI2', 'Gene', (107, 111))	('hedgehog pathway genes', 'Gene', (75, 97))	('GLI2', 'Gene', '2736', (107, 111))	('high', 'Var', (177, 181))	('patient', 'Species', '9606', (157, 164))	('SCARB1', 'Gene', '949', (182, 188))	('GLI3', 'Gene', '2737', (113, 117))	('patients', 'Species', '9606', (157, 165))	('medulloblastoma', 'Disease', 'MESH:D008527', (141, 156))	('HHIP', 'Gene', '64399', (122, 126))	('patient', 'Species', '9606', (25, 32))	('GLI3', 'Gene', (113, 117))	('medulloblastoma', 'Phenotype', 'HP:0002885', (141, 156))	('HHIP', 'Gene', (122, 126))	('SCARB1', 'Gene', (182, 188))
197340	29352211	High expression of SCARB1 was associated with shorter overall survival in medulloblastoma patients (Fig.	('medulloblastoma', 'Phenotype', 'HP:0002885', (74, 89))	('High', 'Var', (0, 4))	('overall survival', 'MPA', (54, 70))	('medulloblastoma', 'Disease', (74, 89))	('SCARB1', 'Gene', (19, 25))	('shorter', 'NegReg', (46, 53))	('patients', 'Species', '9606', (90, 98))	('medulloblastoma', 'Disease', 'MESH:D008527', (74, 89))	('SCARB1', 'Gene', '949', (19, 25))
197360	29352211	After treatment with the HDL NPs, we found a marked decrease in the number of ALDEFLUOR positive (ALDH+) cells (Fig.	('HDL', 'Var', (25, 28))	('ALDEFLUOR', 'Chemical', '-', (78, 87))	('decrease', 'NegReg', (52, 60))
197370	29352211	Importantly, HDL NPs reduce the number of ALDH+ cells and disrupt stem cell frequencies in the SHH-driven medulloblastoma and Ewing sarcoma cell lines indicative of potent inhibitory effects on the CSC populations in these cancers.	('ALDH+', 'Protein', (42, 47))	('SHH', 'Gene', '6469', (95, 98))	('disrupt', 'NegReg', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('reduce', 'NegReg', (21, 27))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (126, 139))	('SHH', 'Gene', (95, 98))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (126, 139))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancers', 'Disease', (223, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('NPs', 'Var', (17, 20))	('medulloblastoma', 'Disease', 'MESH:D008527', (106, 121))	('Ewing sarcoma', 'Disease', (126, 139))	('medulloblastoma', 'Phenotype', 'HP:0002885', (106, 121))	('HDL NPs', 'Var', (13, 20))	('medulloblastoma', 'Disease', (106, 121))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('stem cell frequencies', 'CPA', (66, 87))
197449	29264173	The polymorphism (EGR2-gene on 10q21.3) associated with the increased risk is found at a much higher frequency in whites than in blacks or Asians, possibly explaining the epidemiology of the relative infrequency of Ewing sarcoma in the latter populations.	('Ewing sarcoma', 'Disease', (215, 228))	('EGR2', 'Gene', '1959', (18, 22))	('EGR2', 'Gene', (18, 22))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (215, 228))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (215, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('polymorphism', 'Var', (4, 16))
197502	28321306	ASPL-TFE3 is the fusion gene product of the chromosomal translocation, der(17)t(X;17)(p11;q25), and is considered to be the most reliable diagnostic feature of ASPS.	('ASPS', 'Phenotype', 'HP:0012218', (160, 164))	('TFE3', 'Gene', (5, 9))	('der(17)t(X;17)(p11;q25', 'Var', (71, 93))	('der(17)t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (71, 94))	('ASPL', 'Gene', '79058', (0, 4))	('ASPS', 'Gene', (160, 164))	('ASPL', 'Gene', (0, 4))	('ASPS', 'Gene', '79058', (160, 164))	('TFE3', 'Gene', '7030', (5, 9))
197522	32601077	When compared to immune responsive tumors, STS demonstrated a median tumor mutational burden (TMB) of 2 mutations per DNA megabase (Mb), CD8+ expression was 23+-13 % and the PD-L1 expression was 6.6% in the largest series.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (69, 74))	('CD8', 'Gene', (137, 140))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('TMB', 'Chemical', '-', (94, 97))	('tumor', 'Disease', (35, 40))	('CD8', 'Gene', '925', (137, 140))	('tumors', 'Disease', (35, 41))	('PD-L1', 'Gene', (174, 179))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PD-L1', 'Gene', '29126', (174, 179))
197523	32601077	In contrast, the expression in melanoma, a paradigmatic immune sensitive tumor, was 14 mutations per DNA Mb in TMB, 42 +- 23 % for CD8+ lymphocytes and 35% for PD-L1.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PD-L1', 'Gene', (160, 165))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('PD-L1', 'Gene', '29126', (160, 165))	('tumor', 'Disease', (73, 78))	('TMB', 'Chemical', '-', (111, 114))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('DNA Mb', 'Gene', (101, 107))	('melanoma', 'Disease', (31, 39))	('CD8', 'Gene', (131, 134))	('mutations', 'Var', (87, 96))	('CD8', 'Gene', '925', (131, 134))
197529	32601077	The mean and standard deviation of number of cells per gram of weight were as follows: 72+-15 for CD3+ and 42+-23 for CD8+ in melanoma while there were 35+-9 for CD3+ and 23+-13 for CD8+ in sarcoma, respectively.	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('CD8', 'Gene', (182, 185))	('CD8', 'Gene', '925', (182, 185))	('sarcoma', 'Disease', (190, 197))	('CD3+', 'Var', (98, 102))	('CD8', 'Gene', '925', (118, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('CD8', 'Gene', (118, 121))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))
197530	32601077	In a meta-analysis carried out to examine the prognostic role of high TIL population in different cancers, including 52 studies and 12447 patients, the authors reported a positive effect on prognosis for high CD3+ and CD8+ TILs.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('CD8', 'Gene', (218, 221))	('CD8', 'Gene', '925', (218, 221))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('TIL', 'Gene', '7096', (223, 226))	('TIL', 'Gene', '7096', (70, 73))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('prognosis', 'MPA', (190, 199))	('TIL', 'Gene', (223, 226))	('high CD3+', 'Var', (204, 213))	('cancers', 'Disease', (98, 105))	('TIL', 'Gene', (70, 73))	('patients', 'Species', '9606', (138, 146))
197532	32601077	In contrast, in series including several STS subtypes, the prognostic role of CD3+ or CD8+ seems less prominent.	('CD3+', 'Var', (78, 82))	('CD8', 'Gene', '925', (86, 89))	('CD8', 'Gene', (86, 89))
197539	32601077	Besides, the largest series exploring the prognostic impact of TIL in sarcoma, included 809 samples of STS and GIST, did not find any prognostic correlation among the translocation-associated sarcomas.	('translocation-associated', 'Var', (167, 191))	('sarcomas', 'Disease', (192, 200))	('sarcoma', 'Disease', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('TIL', 'Gene', '7096', (63, 66))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('TIL', 'Gene', (63, 66))	('sarcomas', 'Disease', 'MESH:D012509', (192, 200))	('sarcoma', 'Disease', (192, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
197540	32601077	By contrast the authors reported a significant better prognostic for OS (p=0.02) and PFS (p=0.01), with increasing lymphocyte infiltration among the non-translocation-associated sarcomas.	('sarcomas', 'Disease', (178, 186))	('OS', 'Gene', '17451', (69, 71))	('non-translocation-associated', 'Var', (149, 177))	('sarcomas', 'Disease', 'MESH:D012509', (178, 186))	('increasing', 'PosReg', (104, 114))	('lymphocyte infiltration', 'CPA', (115, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (178, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
197541	32601077	Additional, the OS was significantly worse with increasing CD56+ (p=0.03) or PD-1+ (p=0.05) TIL.	('TIL', 'Gene', (92, 95))	('CD56', 'Gene', (59, 63))	('OS', 'Gene', '17451', (16, 18))	('CD56', 'Gene', '4684', (59, 63))	('worse', 'NegReg', (37, 42))	('PD-1+', 'Var', (77, 82))	('TIL', 'Gene', '7096', (92, 95))
197542	32601077	Of note, patients with positive immunostaining for both CD8 and FOXP3 had better OS compared with those negative for FOXP3 in dedifferentiated liposarcoma (p=0.002) or MPNST (p=0.002).	('better', 'PosReg', (74, 80))	('patients', 'Species', '9606', (9, 17))	('liposarcoma', 'Disease', (143, 154))	('FOXP3', 'Gene', (117, 122))	('FOXP3', 'Gene', '50943', (64, 69))	('positive immunostaining', 'Var', (23, 46))	('CD8', 'Gene', (56, 59))	('FOXP3', 'Gene', '50943', (117, 122))	('OS', 'Gene', '17451', (81, 83))	('CD8', 'Gene', '925', (56, 59))	('liposarcoma', 'Phenotype', 'HP:0012034', (143, 154))	('liposarcoma', 'Disease', 'MESH:D008080', (143, 154))	('FOXP3', 'Gene', (64, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
197552	32601077	In general, M1-polarized macrophages mediates anticancer effects through adaptive immunity mechanisms and M2-polarized macrophages suppress adaptive immunity, favoring tumor progression, tumor angiogenesis, increase extracellular matrix breakdown and tumor invasion.	('favoring', 'PosReg', (159, 167))	('tumor', 'Disease', (251, 256))	('cancer', 'Disease', (50, 56))	('suppress', 'NegReg', (131, 139))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('adaptive immunity', 'CPA', (73, 90))	('increase extracellular matrix', 'Phenotype', 'HP:0009025', (207, 236))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('extracellular matrix breakdown', 'MPA', (216, 246))	('tumor', 'Disease', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('increase', 'PosReg', (207, 215))	('M2-polarized', 'Var', (106, 118))	('adaptive immunity', 'CPA', (140, 157))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
197570	32601077	PD-L1 high expression had 5-year MFS of 61% (95% CI 50-73) while PD-L1 low expression had 5-year MFS of 72% (95% CI 63-83), p=0.0037.	('low', 'NegReg', (71, 74))	('high expression', 'Var', (6, 21))	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', (65, 70))	('PD-L1', 'Gene', '29126', (0, 5))	('PD-L1', 'Gene', '29126', (65, 70))
197600	32601077	In this latter study, a mismatch-repair deficiency signature was associated with the activity of anti-PD-L1 in ASPS, however, further studied in larger series of cases are required to validate these observations.	('ASPS', 'Gene', (111, 115))	('PD-L1', 'Gene', (102, 107))	('associated', 'Reg', (65, 75))	('ASPS', 'Gene', '79058', (111, 115))	('PD-L1', 'Gene', '29126', (102, 107))	('activity', 'MPA', (85, 93))	('mismatch-repair deficiency', 'Var', (24, 50))
197629	32601077	T cells expressing MC.7.G5 TCR are able to kill a broad spectrum of tumor cell lines regardless of their HLA allomorph.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('MC.7.G5 TCR', 'Var', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
197635	32601077	On the other hand, and in these immunocompetent mouse models, anti-TIM-3 antibodies were more effective in combination with anti-CTLA-4 or anti-PD-1 antibodies, in comparison to monotherapy.	('combination', 'Interaction', (107, 118))	('antibodies', 'Var', (73, 83))	('anti-TIM-3', 'Gene', (62, 72))	('mouse', 'Species', '10090', (48, 53))
197719	28819402	In univariate analysis, PD-L1 expression was significantly associated with high tumor grade and the age of patients, while the presence of FOXP3+ in tumor infiltrating Tregs was significantly associated with the age of patients, high tumor stage, higher tumor grade and tumor depth.	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('associated', 'Reg', (192, 202))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PD-L1', 'Gene', (24, 29))	('high tumor', 'Disease', (229, 239))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('presence', 'Var', (127, 135))	('high tumor', 'Disease', 'MESH:D009369', (229, 239))	('PD-L1', 'Gene', '29126', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('high tumor', 'Disease', (75, 85))	('patients', 'Species', '9606', (219, 227))	('high tumor', 'Disease', 'MESH:D009369', (75, 85))	('patients', 'Species', '9606', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('FOXP3+', 'Var', (139, 145))	('associated', 'Reg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
197728	28819402	Overexpression of PD-L1 in tumors has been shown to inhibit T-cell activation and proliferation while inducing apoptosis in the T-effector cells, leading to diminished immune responses and the impairment of protective immunity against cancer.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('inducing', 'Reg', (102, 110))	('inhibit', 'NegReg', (52, 59))	('diminished immune responses', 'Phenotype', 'HP:0002721', (157, 184))	('PD-L1 in tumors', 'Disease', 'MESH:D010300', (18, 33))	('cancer', 'Disease', (235, 241))	('immune responses', 'CPA', (168, 184))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('T-cell activation', 'CPA', (60, 77))	('diminished', 'NegReg', (157, 167))	('impairment', 'NegReg', (193, 203))	('Overexpression', 'Var', (0, 14))	('proliferation', 'CPA', (82, 95))	('PD-L1 in tumors', 'Disease', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('apoptosis', 'CPA', (111, 120))
197755	28819402	The Kaplan-Meier method and log-rank test were used to estimate the distribution of DFS and OS by the PD-L1 positivity and FOXP3 positivity.	('FOXP3', 'Gene', (123, 128))	('PD-L1', 'Gene', (102, 107))	('positivity', 'Var', (108, 118))	('PD-L1', 'Gene', '29126', (102, 107))	('positivity', 'Var', (129, 139))
197757	28819402	The association of PD-L1 positivity or FOXP3+ Treg infiltration expression with variable clinicopathological factors of STS is summarized in Table 1 and Table 2.	('positivity', 'Var', (25, 35))	('PD-L1', 'Gene', (19, 24))	('FOXP3+', 'Gene', (39, 45))	('PD-L1', 'Gene', '29126', (19, 24))
197764	28819402	The expression of PD-L1 predicted shorter OS (HR:3.101, 95%CI: 1.570-6.125, p=0.001) and DFS (HR:2.575; 95%CI: 1.493-4.442, p=0.001) (Table 4).	('DFS', 'MPA', (89, 92))	('shorter', 'NegReg', (34, 41))	('expression', 'Var', (4, 14))	('PD-L1', 'Gene', (18, 23))	('PD-L1', 'Gene', '29126', (18, 23))
197765	28819402	Intra-tumoral high infiltration of FOXP3+ Tregs also predicted shorter OS (HR:2.259; 95%CI: 1.249-4.084; p=0.007) and DFS (HR:1.587, 95%CI: 1.015-2.483, p=0.043) (Table 4).	('FOXP3+', 'Var', (35, 41))	('DFS', 'CPA', (118, 121))	('shorter', 'NegReg', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
197791	28819402	Preclinical work in implanted fibrosarcoma mouse models has shown anti-tumor activity of anti-PD-1 therapy.	('anti-PD-1', 'Var', (89, 98))	('fibrosarcoma', 'Disease', (30, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (30, 42))	('fibrosarcoma', 'Disease', 'MESH:D005354', (30, 42))	('tumor', 'Disease', (71, 76))	('mouse', 'Species', '10090', (43, 48))
197795	28819402	Furthermore, perhaps CTLA-4 inhibition alone is not enough to elicit an anti-tumor response, but combination with other therapies may make a difference.	('CTLA-4', 'Gene', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('inhibition', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CTLA-4', 'Gene', '1493', (21, 27))	('tumor', 'Disease', (77, 82))
197800	27137987	This unique dual phenotype stems from recurrent rearrangements in PAX3, a transcription factor that promotes commitment along both lineages.	('PAX3', 'Gene', '496377', (66, 70))	('PAX3', 'Gene', (66, 70))	('rearrangements', 'Var', (48, 62))
197801	27137987	While identification of PAX3 rearrangements by fluorescence in situ hybridization (FISH) can confirm a BSNS diagnosis, this assay is not widely available.	('PAX3', 'Gene', '496377', (24, 28))	('rearrangements', 'Var', (29, 43))	('PAX3', 'Gene', (24, 28))	('BSNS', 'Disease', (103, 107))
197806	27137987	This unique dual phenotype stems from recurrent rearrangements in PAX3, a transcription factor that normally promotes neural crest and skeletal muscle differentiation, and is particularly important in the normal development of nasal structures.	('PAX3', 'Gene', (66, 70))	('PAX3', 'Gene', '496377', (66, 70))	('promotes', 'PosReg', (109, 117))	('rearrangements', 'Var', (48, 62))
197807	27137987	The original and predominant translocation identified in BSNS is t(2;4)(q35;q31.1), which results in a PAX3-MAML3 fusion protein and activation of PAX3 response elements.	('PAX3', 'Gene', '496377', (147, 151))	('t(2;4)(q35;q31.1', 'Var', (65, 81))	('PAX3', 'Gene', '496377', (103, 107))	('PAX3', 'Gene', (147, 151))	('activation', 'PosReg', (133, 143))	('PAX3', 'Gene', (103, 107))	('t(2;4)(q35;q31.1)', 'STRUCTURAL_ABNORMALITY', 'None', (65, 82))	('results in', 'Reg', (90, 100))
197808	27137987	Other molecular alterations have also been recently reported in a subset of BSNS, including PAX3-NCOA1 and PAX3-FOXO1 fusions.	('PAX3', 'Gene', '496377', (92, 96))	('fusions', 'Var', (118, 125))	('PAX3', 'Gene', (92, 96))	('BSNS', 'Disease', (76, 80))	('alterations', 'Var', (16, 27))	('reported', 'Reg', (52, 60))	('PAX3', 'Gene', '496377', (107, 111))	('PAX3', 'Gene', (107, 111))
197809	27137987	Still other cases of BSNS have PAX3 rearrangements with yet unidentified partners (PAX3-X).	('PAX3', 'Gene', '496377', (83, 87))	('PAX3', 'Gene', '496377', (31, 35))	('PAX3', 'Gene', (83, 87))	('rearrangements', 'Var', (36, 50))	('PAX3', 'Gene', (31, 35))	('BSNS', 'Disease', (21, 25))
197811	27137987	While identification of PAX3 rearrangements by fluorescence in situ hybridization (FISH) can confirm a diagnosis of BSNS, this assay is not available in most diagnostic surgical pathology laboratories.	('BSNS', 'Disease', (116, 120))	('PAX3', 'Gene', '496377', (24, 28))	('rearrangements', 'Var', (29, 43))	('PAX3', 'Gene', (24, 28))
197812	27137987	The surgical pathology archives at The Johns Hopkins Hospital were searched for all sinonasal tumors diagnosed as cellular schwannoma, synovial sarcoma, low-grade malignant peripheral nerve sheath tumor, low-grade fibrosarcoma, or low-grade sarcoma, not otherwise specified.	('sarcoma', 'Disease', (144, 151))	('sinonasal tumors', 'Disease', (84, 100))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (163, 202))	('schwannoma', 'Phenotype', 'HP:0100008', (123, 133))	('sarcoma', 'Disease', 'MESH:D012509', (219, 226))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('sarcoma', 'Disease', (219, 226))	('schwannoma', 'Disease', (123, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (214, 226))	('low-grade', 'Var', (153, 162))	('sheath tumor', 'Disease', 'MESH:D010524', (190, 202))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('sarcoma', 'Disease', 'MESH:D012509', (241, 248))	('sarcoma', 'Disease', (241, 248))	('synovial sarcoma', 'Disease', (135, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('schwannoma', 'Disease', 'MESH:D009442', (123, 133))	('fibrosarcoma', 'Disease', 'MESH:D005354', (214, 226))	('synovial sarcoma', 'Disease', 'MESH:D013584', (135, 151))	('fibrosarcoma', 'Disease', (214, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (241, 248))	('sinonasal tumors', 'Disease', 'MESH:C537344', (84, 100))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (135, 151))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('sinonasal tumors', 'Phenotype', 'HP:0030072', (84, 100))	('sheath tumor', 'Disease', (190, 202))
197816	27137987	Diagnosis of BSNS and inclusion in this study was based on either identification of PAX3 alterations by fluorescent in situ hybridization (FISH) or diagnostic histologic and immunohistochemical findings for BSNS.	('BSNS', 'Disease', (13, 17))	('alterations', 'Var', (89, 100))	('PAX3', 'Gene', '496377', (84, 88))	('PAX3', 'Gene', (84, 88))
197846	27137987	PAX3 alterations were identified in all eight cases for which FISH testing could be successfully completed.	('PAX3', 'Gene', (0, 4))	('PAX3', 'Gene', '496377', (0, 4))	('alterations', 'Var', (5, 16))
197852	27137987	It is characterized histologically by a hypercellular proliferation of uniform spindled cells, immunohistochemically by positivity for both S100 and SMA, and molecular genetically by translocations involving the PAX3 gene.	('translocations', 'Var', (183, 197))	('PAX3', 'Gene', (212, 216))	('PAX3', 'Gene', '496377', (212, 216))
197857	27137987	While identification of PAX3 rearrangements using FISH can confirm the diagnosis of BSNS, this test is not available for most diagnostic pathology laboratories.	('BSNS', 'Disease', (84, 88))	('PAX3', 'Gene', '496377', (24, 28))	('rearrangements', 'Var', (29, 43))	('PAX3', 'Gene', (24, 28))
197862	27137987	One reported case of a BSNS detected an inactivating mutation in CDC73 - a tumor suppressor gene and an important transcriptional regulator of WNT/beta-catenin signaling.	('inactivating mutation', 'Var', (40, 61))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CDC73', 'Gene', (65, 70))	('tumor', 'Disease', (75, 80))
197866	27137987	Immunohistochemistry for PAX3 was also attempted, in an attempt to determine whether the PAX3 rearrangements of BSNS resulted in a detectable alteration of protein expression.	('PAX3', 'Gene', '496377', (25, 29))	('PAX3', 'Gene', '496377', (89, 93))	('alteration', 'Reg', (142, 152))	('rearrangements', 'Var', (94, 108))	('PAX3', 'Gene', (25, 29))	('PAX3', 'Gene', (89, 93))	('protein expression', 'MPA', (156, 174))
197877	27137987	The consistent positivity for beta-catenin and negativity for SOX10 described here can prove very useful at distinguishing BSNS from low-grade nerve sheath tumors.	('negativity', 'Var', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('BSNS', 'Disease', (123, 127))	('beta-catenin', 'Protein', (30, 42))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('SOX10', 'Gene', (62, 67))	('nerve sheath tumors', 'Disease', 'MESH:D010524', (143, 162))	('nerve sheath tumors', 'Disease', (143, 162))
197894	21647307	In addition to the important role of Cx43 in bone development and differentiation, dysregulation of Cx expression is believed to have a role in carcinogenesis.	('Cx43', 'Gene', '2697', (37, 41))	('Cx43', 'Gene', (37, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (144, 158))	('carcinogenesis', 'Disease', (144, 158))	('dysregulation', 'Var', (83, 96))
197940	21647307	This result indicates that the patient group with metastasis had significantly higher failure rate compared to the group without metastasis.	('higher', 'PosReg', (79, 85))	('patient', 'Species', '9606', (31, 38))	('failure rate', 'CPA', (86, 98))	('metastasis', 'Var', (50, 60))
197951	21647307	Furthermore, previous studies suggested that aberrant cytoplasmic localization and disturbance of GJ intercellular communication play an important role in carcinogenesis, invasion, and metastasis in some human malignancies including carcinomas, melanoma, and leukemia.	('carcinomas', 'Disease', 'MESH:D002277', (233, 243))	('invasion', 'CPA', (171, 179))	('carcinogenesis', 'Disease', (155, 169))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('leukemia', 'Phenotype', 'HP:0001909', (259, 267))	('carcinomas', 'Disease', (233, 243))	('aberrant', 'Var', (45, 53))	('GJ intercellular communication', 'MPA', (98, 128))	('human', 'Species', '9606', (204, 209))	('leukemia', 'Disease', (259, 267))	('leukemia', 'Disease', 'MESH:D007938', (259, 267))	('metastasis', 'CPA', (185, 195))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('malignancies', 'Disease', 'MESH:D009369', (210, 222))	('communication play', 'Phenotype', 'HP:0010529', (115, 133))	('malignancies', 'Disease', (210, 222))	('carcinomas', 'Phenotype', 'HP:0030731', (233, 243))
197979	21647307	Understanding the role of aberrant Cx43 expression in EWS/PNET may help explain the ontogeny of EWS, identify an important step in oncogenesis in a subset of tumors, and eventually serve as a therapeutic target.	('tumors', 'Disease', (158, 164))	('EWS', 'Gene', '2130', (96, 99))	('EWS', 'Gene', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('aberrant', 'Var', (26, 34))	('Cx43', 'Gene', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('PNET', 'Phenotype', 'HP:0030065', (58, 62))	('EWS', 'Phenotype', 'HP:0012254', (54, 57))	('EWS', 'Gene', '2130', (54, 57))	('EWS', 'Gene', (54, 57))	('EWS', 'Phenotype', 'HP:0012254', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Cx43', 'Gene', '2697', (35, 39))
197980	21647307	Given the important role of Cx43 in tissue development, differentiation, and carcinogenesis, especially in bone cells, alterations in the expression of Cx43 may influence cell-cell communication and may serve as a potential prognostic marker as well as a target for novel agents in Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (282, 295))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('Cx43', 'Gene', (152, 156))	('carcinogenesis', 'Disease', (77, 91))	('influence', 'Reg', (161, 170))	('Ewing sarcoma', 'Disease', (282, 295))	('Cx43', 'Gene', '2697', (28, 32))	('alterations', 'Var', (119, 130))	('cell-cell communication', 'CPA', (171, 194))	('Cx43', 'Gene', (28, 32))	('Cx43', 'Gene', '2697', (152, 156))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (282, 295))
198039	32591592	After 4 h/24 h, propranolol did not alter the expression of P-gp on the plasma membrane; instead, doxorubicin induced a time-dependent increase that was stronger in SW-872 cells than in SK-LMS-1 cells (eightfold vs. fourfold).	('SK-LMS-1', 'CellLine', 'CVCL:0628', (186, 194))	('LMS', 'Phenotype', 'HP:0100243', (189, 192))	('increase', 'PosReg', (135, 143))	('P-gp', 'Gene', (60, 64))	('doxorubicin', 'Chemical', 'MESH:D004317', (98, 109))	('SW-872', 'CellLine', 'CVCL:1730', (165, 171))	('propranolol', 'Chemical', 'MESH:D011433', (16, 27))	('P-gp', 'Gene', '5243', (60, 64))	('doxorubicin', 'Var', (98, 109))
198125	30431433	Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (114, 130))	('BRD9', 'Gene', (70, 74))	('bromodomain', 'Var', (55, 66))	('synovial sarcoma', 'Disease', 'MESH:D013584', (114, 130))	('synovial sarcoma', 'Disease', (114, 130))
198129	30431433	Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo.	('tumour', 'Disease', (94, 100))	('inhibits', 'NegReg', (85, 93))	('Degradation', 'Var', (0, 11))	('oncogenic', 'CPA', (46, 55))	('BRD9', 'Gene', (15, 19))	('downregulation', 'NegReg', (28, 42))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
198130	30431433	We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease.	('BRD9', 'Gene', (144, 148))	('SSX', 'Gene', '6757', (75, 78))	('SSX', 'Gene', (75, 78))	('synovial sarcoma', 'Disease', (89, 105))	('fusion', 'Var', (79, 85))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (89, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('synovial sarcoma', 'Disease', 'MESH:D013584', (89, 105))
198142	30431433	The SS18-SSX rearrangement is often the only genetic abnormality in synovial sarcoma tumours; suggesting that it is the primary driver of disease.	('SSX', 'Gene', (9, 12))	('SSX', 'Gene', '6757', (9, 12))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('rearrangement', 'Var', (13, 26))	('genetic abnormality', 'Disease', 'MESH:D030342', (45, 64))	('synovial sarcoma tumours', 'Disease', (68, 92))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (68, 84))	('genetic abnormality', 'Disease', (45, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('synovial sarcoma tumours', 'Disease', 'MESH:D013584', (68, 92))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
198143	30431433	Indeed, conditional expression of SS18-SSX in muscle progenitor cells leads to development of a fully penetrant synovial sarcoma like disease in mice.	('synovial sarcoma like disease', 'Disease', 'MESH:D013584', (112, 141))	('synovial sarcoma like disease', 'Disease', (112, 141))	('SSX', 'Gene', '6757', (39, 42))	('SSX', 'Gene', (39, 42))	('leads to', 'Reg', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('mice', 'Species', '10090', (145, 149))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (112, 128))	('conditional expression', 'Var', (8, 30))
198156	30431433	Here using a custom CRISPR/Cas9 based functional genomics approach focused on chromatin regulatory genes we identify the bromodomain of BRD9 as a vulnerability in synovial sarcoma cells.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (163, 179))	('bromodomain', 'Var', (121, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('synovial sarcoma', 'Disease', 'MESH:D013584', (163, 179))	('synovial sarcoma', 'Disease', (163, 179))	('BRD9', 'Gene', (136, 140))
198170	30431433	Using an independent shRNA-based approach we observed similar synovial sarcoma specific effects following knockdown of BRD9 protein levels (Figure 1:figure supplement 1D-G).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (62, 78))	('synovial sarcoma', 'Disease', 'MESH:D013584', (62, 78))	('protein', 'Protein', (124, 131))	('knockdown', 'Var', (106, 115))	('synovial sarcoma', 'Disease', (62, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('BRD9', 'Gene', (119, 123))
198172	30431433	We generated a full-length human BRD9 cDNA containing silent point mutations within the sgRNA recognition sequence, conferring resistance to Cas9 targeting (Figure 1:figure supplement 1H).	('eq', 'Chemical', '-', (107, 109))	('sgRNA', 'Gene', (88, 93))	('human', 'Species', '9606', (27, 32))	('silent point mutations', 'Var', (54, 76))	('Cas9 targeting', 'MPA', (141, 155))	('1H', 'Chemical', '-', (184, 186))	('resistance', 'MPA', (127, 137))
198204	30431433	To test the feasibility of small-molecule mediated targeting of the BRD9 bromodomain as a therapeutic approach in synovial sarcoma we performed dose response experiments using two independent BRD9 inhibitors, BI7273 and I-BRD9.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (114, 130))	('synovial sarcoma', 'Disease', 'MESH:D013584', (114, 130))	('BI7273', 'Var', (209, 215))	('BI7273', 'Chemical', '-', (209, 215))	('synovial sarcoma', 'Disease', (114, 130))	('BRD9', 'Gene', (192, 196))
198207	30431433	Significantly, the ability of BRD9 to incorporate into the BAF complex is required for chromatin association, since deleting the BAF complex interaction domain (aa311-345) leads to a similar reduction in chromatin binding as bromodomain deletion (Figure 4C and Figure 4:source data 1).	('BAF', 'Gene', '8815', (59, 62))	('BAF', 'Gene', (59, 62))	('deleting', 'Var', (116, 124))	('reduction', 'NegReg', (191, 200))	('aa311-345', 'Var', (161, 170))	('eq', 'Chemical', '-', (75, 77))	('BAF', 'Gene', '8815', (129, 132))	('BAF', 'Gene', (129, 132))	('chromatin binding', 'MPA', (204, 221))
198211	30431433	Importantly, dBRD9-A is a highly specific binder of the BRD9 bromodomain (Figure 4E); and elicits near complete BRD9 degradation at low nanomolar concentrations (Figure 4F).	('elicits', 'Reg', (90, 97))	('dBRD9-A', 'Chemical', '-', (13, 20))	('binder', 'Interaction', (42, 48))	('BRD9 degradation', 'MPA', (112, 128))	('dBRD9-A', 'Var', (13, 20))
198212	30431433	ChIP-Rx experiments demonstrate a far more robust loss of BRD9 binding across the genome following dBRD9-A treatment; compared to BI7273 treatment (Figure 4G).	('BRD9', 'Protein', (58, 62))	('dBRD9-A', 'Chemical', '-', (99, 106))	('binding', 'Interaction', (63, 70))	('loss', 'NegReg', (50, 54))	('dBRD9-A treatment', 'Var', (99, 116))	('BI7273', 'Chemical', '-', (130, 136))
198214	30431433	Moreover, consistent with our genetic data other pediatric sarcoma subtypes are unaffected by BRD9 degradation (Figure 4:figure supplement 1E-F).	('degradation', 'Var', (99, 110))	('sarcoma', 'Disease', (59, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('BRD9', 'Gene', (94, 98))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))
198217	30431433	This suggests that BRD9 is essential for the proper assembly of GBAF complexes; and that BRD9 degradation specifically disrupts this subclass of SS18-SSX containing complexes.	('BRD9', 'Gene', (89, 93))	('SSX', 'Gene', '6757', (150, 153))	('GBAF', 'Chemical', '-', (64, 68))	('SSX', 'Gene', (150, 153))	('degradation', 'Var', (94, 105))	('disrupts', 'NegReg', (119, 127))
198219	30431433	Synovial sarcoma cells treated with dBRD9-A undergo a progressive cell cycle arrest (Figure 5A and Figure 5:source data 1), which is further associated with an increase in Annexin-V positivity (Figure 5B and Figure 5:source data 3).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('dBRD9-A', 'Chemical', '-', (36, 43))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('increase', 'PosReg', (160, 168))	('cell cycle arrest', 'CPA', (66, 83))	('sarcoma', 'Disease', (9, 16))	('dBRD9-A', 'Var', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Annexin-V', 'Gene', '308', (172, 181))	('Annexin-V', 'Gene', (172, 181))	('positivity', 'MPA', (182, 192))
198220	30431433	Consistent with the on-target activity of dBRD9-A, swapping the BRD9 bromodomain for the closely related BRD7 bromodomain (63%, sequence identity) renders BRD9 and synovial sarcoma cells insensitive to dBRD9-A treatment (Figure 5:figure supplement 1A-B and Figure 5:figure supplement 1:source data 1).	('synovial sarcoma', 'Disease', 'MESH:D013584', (164, 180))	('insensitive', 'NegReg', (187, 198))	('BRD7', 'Gene', (105, 109))	('BRD7', 'Gene', '29117', (105, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('dBRD9-A', 'Chemical', '-', (202, 209))	('synovial sarcoma', 'Disease', (164, 180))	('dBRD9-A', 'Chemical', '-', (42, 49))	('eq', 'Chemical', '-', (129, 131))	('swapping', 'Var', (51, 59))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (164, 180))
198221	30431433	Using an in vivo synovial sarcoma xenograft model, we found that treatment of mice with dBRD9-A over 24 days inhibited tumour progression (Figure 5C).	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('dBRD9-A', 'Chemical', '-', (88, 95))	('inhibited', 'NegReg', (109, 118))	('synovial sarcoma', 'Disease', (17, 33))	('tumour', 'Disease', (119, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (17, 33))	('dBRD9-A', 'Var', (88, 95))	('synovial sarcoma', 'Disease', 'MESH:D013584', (17, 33))	('mice', 'Species', '10090', (78, 82))
198223	30431433	Mice treated with dBRD9-A did not suffer any overt side effects associated with treatment, retaining a normal body weight and blood counts (Figure 5:figure supplement 1C-D and and Figure 5:figure supplement 1:source datas 2-3).	('dBRD9-A', 'Var', (18, 25))	('body weight', 'CPA', (110, 121))	('blood counts', 'CPA', (126, 138))	('Mice', 'Species', '10090', (0, 4))	('dBRD9-A', 'Chemical', '-', (18, 25))
198230	30431433	SEs have higher BRD9 and SS18-SSX1 occupancy levels compared to typical enhancers (Figure 5:figure supplement 1E); and BRD9 degradation leads to a preferential downregulation of SE associated gene expression (Figure 5G).	('downregulation', 'NegReg', (160, 174))	('SSX1', 'Gene', '6756', (30, 34))	('SSX1', 'Gene', (30, 34))	('degradation', 'Var', (124, 135))	('SEs', 'Chemical', 'MESH:D012643', (0, 3))	('BRD9', 'Gene', (119, 123))	('SE associated gene', 'Gene', (178, 196))	('higher', 'PosReg', (9, 15))
198231	30431433	Significantly, these genes depend on SS18-SSX1 to maintain their expression, since shRNA mediated knockdown of SS18-SSX1 leads to a collapse of SE associated gene expression (Figure 5H).	('SSX1', 'Gene', '6756', (116, 120))	('knockdown', 'Var', (98, 107))	('SSX1', 'Gene', '6756', (42, 46))	('SSX1', 'Gene', (42, 46))	('SSX1', 'Gene', (116, 120))	('collapse', 'NegReg', (132, 140))	('SE associated gene expression', 'MPA', (144, 173))
198232	30431433	dBRD9-A treatment and consequential downregulation of transcription is further associated with reductions in SS18-SSX1 binding at SEs (Figure 5I and Figure 5:figure supplement 1F).	('dBRD9-A', 'Var', (0, 7))	('downregulation', 'NegReg', (36, 50))	('SSX1', 'Gene', (114, 118))	('reductions', 'NegReg', (95, 105))	('dBRD9-A', 'Chemical', '-', (0, 7))	('eq', 'Chemical', '-', (26, 28))	('SEs', 'Chemical', 'MESH:D012643', (130, 133))	('SSX1', 'Gene', '6756', (114, 118))	('transcription', 'MPA', (54, 67))	('binding', 'Interaction', (119, 126))
198234	30431433	However, these data demonstrate that BRD9 is required to maintain the SE associated oncogenic transcriptional program driven by SS18-SSX and the phenotypic impact of BRD9 degradation underlines the functional importance of this gene cohort.	('degradation', 'Var', (171, 182))	('oncogenic transcriptional program', 'MPA', (84, 117))	('SSX', 'Gene', '6757', (133, 136))	('SSX', 'Gene', (133, 136))	('eq', 'Chemical', '-', (46, 48))	('BRD9', 'Gene', (166, 170))
198239	30431433	BRD9 may promote and/or stabilize binding of SS18-SSX containing complexes at acetylated chromatin regions; since loss of BRD9 can lead to reduced fusion protein occupancy at some super enhancers.	('fusion protein', 'Protein', (147, 161))	('SSX', 'Gene', '6757', (50, 53))	('SSX', 'Gene', (50, 53))	('loss', 'Var', (114, 118))	('reduced', 'NegReg', (139, 146))	('BRD9', 'Gene', (122, 126))
198250	30431433	Since SNF5 is absent in BRD9 containing complexes it is tempting to speculate that loss of SNF5 (by genetic or biochemical means) shifts the balance of BAF complex assembly to a more GBAF-like state.	('SNF5', 'Gene', '6598', (91, 95))	('SNF5', 'Gene', (6, 10))	('loss', 'Var', (83, 87))	('SNF5', 'Gene', '6598', (6, 10))	('BAF', 'Gene', '8815', (152, 155))	('BAF', 'Gene', '8815', (184, 187))	('BAF', 'Gene', (152, 155))	('BAF', 'Gene', (184, 187))	('shifts', 'Reg', (130, 136))	('SNF5', 'Gene', (91, 95))	('GBAF', 'Chemical', '-', (183, 187))
198252	30431433	Several additional cancers, including bladder cancer and uterine corpus endometrial carcinoma, have a high frequency of mutations effecting the genes encoding ARID1A/B.	('ARID1A/B', 'Gene', (159, 167))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (72, 93))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('cancers', 'Disease', (19, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('endometrial carcinoma', 'Disease', (72, 93))	('eq', 'Chemical', '-', (109, 111))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (72, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('bladder cancer', 'Disease', (38, 52))	('mutations', 'Var', (120, 129))	('ARID1A/B', 'Gene', '8289', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
198253	30431433	Loss of function mutations in these components could potentially shift the dynamics of BAF complex assembly toward a GBAF-like state.	('GBAF', 'Chemical', '-', (117, 121))	('BAF', 'Gene', '8815', (87, 90))	('BAF', 'Gene', '8815', (118, 121))	('BAF', 'Gene', (87, 90))	('Loss of function', 'NegReg', (0, 16))	('BAF', 'Gene', (118, 121))	('mutations', 'Var', (17, 26))
198254	30431433	Therefore, it will be important to test the efficacy of BRD9 targeting in other cancers with BAF complex mutations.	('BAF', 'Gene', '8815', (93, 96))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('BRD9', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('BAF', 'Gene', (93, 96))	('mutations', 'Var', (105, 114))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
198259	30431433	This study provides a rationale for development of BRD9 degradation as a novel therapeutic approach and potentially assessment in patients suffering with this disease.	('patients', 'Species', '9606', (130, 138))	('BRD9', 'Gene', (51, 55))	('degradation', 'Var', (56, 67))
198260	30431433	We demonstrate that degradation of BRD9, a member of an oncogenic multi-protein complex in synovial sarcoma, has a more profound effect on cancer cell survival than small-molecule mediated inhibition.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('synovial sarcoma', 'Disease', (91, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('degradation', 'Var', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BRD9', 'Gene', (35, 39))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (91, 107))	('synovial sarcoma', 'Disease', 'MESH:D013584', (91, 107))	('cancer', 'Disease', (139, 145))
198262	30431433	Importantly, the potent and selective small-molecule inhibitors that already exist for proteins such as EZH2 and DOT1L will provide a basis for the development of novel protein degraders targeting these proteins.	('degraders', 'NegReg', (177, 186))	('EZH2', 'Gene', '2146', (104, 108))	('EZH2', 'Gene', (104, 108))	('small-molecule', 'Var', (38, 52))	('DOT1L', 'Gene', (113, 118))	('DOT1L', 'Gene', '84444', (113, 118))	('protein', 'MPA', (169, 176))
198328	30431433	Lcms: 239 (M) Sarcosyl tert-butyl ester hydrochloride (556 mg, 3.06 mmol, 1.5 eq) was dissolved in a solution of NaOAc (251 mg, 3.06 mmol, 1.5 eq), in DCM (8.2 mL), before 167 muL AcOH (2.04 mmol, 1.0 eq) was added, followed by 4-bromo-2,6-dimethoxybenzaldehyde (500 mg, 2.04 mmol, 1.0 eq).	('eq', 'Chemical', '-', (286, 288))	('NaOAc', 'Chemical', '-', (113, 118))	('tert', 'Gene', (23, 27))	('eq', 'Chemical', '-', (201, 203))	('DCM', 'Disease', 'MESH:D002311', (151, 154))	('556 mg', 'Var', (55, 61))	('DCM', 'Disease', (151, 154))	('eq', 'Chemical', '-', (78, 80))	('tert', 'Gene', '7015', (23, 27))	('eq', 'Chemical', '-', (143, 145))	('AcOH', 'Chemical', 'MESH:D019342', (180, 184))	('4-bromo-2,6-dimethoxybenzaldehyde', 'Chemical', '-', (228, 261))
198356	30431433	Thank you for submitting your article "Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma" for consideration by eLife.	('synovial sarcoma', 'Disease', (106, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('degradation', 'Var', (48, 59))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (106, 122))	('reverses', 'NegReg', (68, 76))	('oncogenic gene expression', 'MPA', (77, 102))	('synovial sarcoma', 'Disease', 'MESH:D013584', (106, 122))	('BRD9', 'Gene', (63, 67))
198365	30431433	2) Does BRD9 inhibition alter the stability or composition of either the GBAF or core BAF complexes?	('BAF', 'Gene', '8815', (86, 89))	('stability', 'MPA', (34, 43))	('inhibition', 'Var', (13, 23))	('BRD9', 'Gene', (8, 12))	('BAF', 'Gene', (86, 89))	('BAF', 'Gene', '8815', (74, 77))	('alter', 'Reg', (24, 29))	('composition', 'MPA', (47, 58))	('GBAF', 'Chemical', '-', (73, 77))	('BAF', 'Gene', (74, 77))
198376	30431433	We find that BRD9 degradation leads to an at least partial disassembly of GBAF complexes (Figure 4:figure supplement 1H).	('GBAF complexes', 'Protein', (74, 88))	('GBAF', 'Chemical', '-', (74, 78))	('1H', 'Chemical', '-', (117, 119))	('degradation', 'Var', (18, 29))	('BRD9', 'Gene', (13, 17))	('disassembly', 'MPA', (59, 70))
198378	30431433	These findings suggest that degradation of BRD9 primarily effects GBAF complex assembly but does not appear to shift the dynamics of other non-GBAF forms of the complex.	('effects', 'Reg', (58, 65))	('GBAF', 'Protein', (66, 70))	('degradation', 'Var', (28, 39))	('GBAF', 'Chemical', '-', (143, 147))	('BRD9', 'Gene', (43, 47))	('GBAF', 'Chemical', '-', (66, 70))
198477	27190730	SS includes a characteristic translocation (X; 18) (p11; q11), resulting in the fusion of SYT and SSX1 or SSX2 genes.	('SYT', 'Gene', (90, 93))	('SSX1', 'Gene', '6756', (98, 102))	('SSX2', 'Gene', '6757', (106, 110))	('SS', 'Phenotype', 'HP:0012570', (98, 100))	('SYT', 'Gene', '6760', (90, 93))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SS', 'Phenotype', 'HP:0012570', (106, 108))	('SSX1', 'Gene', (98, 102))	('SSX2', 'Gene', (106, 110))	('fusion', 'Var', (80, 86))
198549	26293323	Nevertheless, the low grade fibromyxoid sarcoma has potential for late local recurrence and distant metastasis.	('distant metastasis', 'CPA', (92, 110))	('low grade', 'Var', (18, 27))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (28, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('fibromyxoid sarcoma', 'Disease', (28, 47))
198572	26293323	In addition, low grade fibromyxoid sarcomas have one of two distinct chromosomal translocations - t(7;16)(q34;p11) or t(11;16)(p11;p11) - that results in the fused in sarcoma (FUS)-CREB3L2 and FUS-CREB3L1 gene fusions.	('FUS', 'Gene', (193, 196))	('fibromyxoid sarcoma', 'Disease', (23, 42))	('CREB3L1', 'Gene', '90993', (197, 204))	('t(7;16)(q34;p11', 'Var', (98, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('FUS', 'Gene', (176, 179))	('FUS', 'Gene', '2521', (193, 196))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (23, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('sarcoma', 'Disease', (35, 42))	('FUS', 'Gene', '2521', (176, 179))	('sarcomas', 'Disease', (35, 43))	('CREB3L2', 'Gene', '64764', (181, 188))	('t(11;16)(p11;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (118, 135))	('results in', 'Reg', (143, 153))	('CREB3L2', 'Gene', (181, 188))	('CREB3L1', 'Gene', (197, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('t(7;16)(q34;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (98, 114))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('sarcoma', 'Disease', (167, 174))	('t(11;16)(p11;p11) -', 'Var', (118, 137))
198591	26293323	Although low grade fibromyxoid sarcoma has the possibility of distant metastasis, it is likely that this patient may have a favorable prognosis with long-term close follow up because the tumor was solitary, well capsulated, confined to the localized area, and did not show severe mitosis in histology.	('patient', 'Species', '9606', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (19, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('fibromyxoid sarcoma', 'Disease', (19, 38))	('mitosis', 'Disease', (280, 287))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mitosis', 'Disease', 'None', (280, 287))	('tumor', 'Disease', (187, 192))	('low grade', 'Var', (9, 18))
198639	24719120	The 5-year disease-specific survival rate was 26% in patients who had positive lymph nodes compared with 64.2% in patients who had negative lymph nodes (p<0.001).	('positive lymph nodes', 'Var', (70, 90))	('patients', 'Species', '9606', (114, 122))	('disease-specific survival', 'CPA', (11, 36))	('patients', 'Species', '9606', (53, 61))
198677	33911820	In conclusion, this case demonstrates the clinical diversity of deep dermatomycosis in an immunocompromised patient, caused by C. guilliermondii.	('deep dermatomycosis', 'Disease', 'MESH:D003881', (64, 83))	('C. guilliermondii', 'Var', (127, 144))	('C. guilliermondii', 'Species', '4929', (127, 144))	('deep dermatomycosis', 'Disease', (64, 83))	('patient', 'Species', '9606', (108, 115))	('caused by', 'Reg', (117, 126))
198685	32126619	Our case emphasizes that patients with neurofibromatosis type I may develop malignant tumors Neurofibromatosis type I (NF I) or von Recklinghausen disease, is an autosomal dominant disorder caused by inactivating mutations in the germline of the NF I gene.	('neurofibromatosis', 'Disease', (39, 56))	('inactivating mutations in', 'Var', (200, 225))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (162, 189))	('NF I', 'Gene', (246, 250))	('von Recklinghausen disease', 'Disease', 'MESH:D009456', (128, 154))	('caused by', 'Reg', (190, 199))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('autosomal dominant disorder', 'Disease', (162, 189))	('von Recklinghausen disease', 'Disease', (128, 154))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (39, 56))	('patients', 'Species', '9606', (25, 33))	('neurofibromatosis', 'Disease', 'MESH:D017253', (39, 56))	('malignant tumors', 'Disease', 'MESH:D009369', (76, 92))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (93, 110))	('malignant tumors', 'Disease', (76, 92))	('develop', 'PosReg', (68, 75))
198725	31676869	Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs Approximately 60-70% of EWSR1-negative small blue round cell sarcomas harbour a rearrangement of CIC, most commonly CIC-DUX4.	('CIC', 'Gene', (31, 34))	('DUX4', 'Gene', '100288687', (35, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('CIC', 'Gene', '23152', (238, 241))	('DUX4', 'Gene', (261, 265))	('human', 'Species', '9606', (25, 30))	('sarcoma', 'Disease', 'MESH:D012509', (202, 209))	('CIC', 'Gene', '23152', (31, 34))	('sarcomas', 'Disease', 'MESH:D012509', (202, 210))	('CIC', 'Gene', (257, 260))	('sarcoma', 'Disease', (202, 209))	('sarcomas', 'Phenotype', 'HP:0100242', (202, 210))	('sarcomas', 'Disease', (202, 210))	('EWSR1', 'Gene', '2130', (165, 170))	('IGF-1R', 'Gene', '3480', (85, 91))	('DUX4', 'Gene', '100288687', (261, 265))	('IGF-1R', 'Gene', (85, 91))	('rearrangement', 'Var', (221, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('CIC', 'Gene', (238, 241))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('sarcoma', 'Disease', (40, 47))	('CIC', 'Gene', '23152', (257, 260))	('DUX4', 'Gene', (35, 39))	('EWSR1', 'Gene', (165, 170))	('small blue round', 'CPA', (180, 196))
198734	31676869	CIC rearrangement is the genetic abnormality that is generally detected in approximately 60-70% of EWSR1-negative small blue round cell sarcomas.	('detected', 'Reg', (63, 71))	('CIC', 'Gene', (0, 3))	('EWSR1', 'Gene', '2130', (99, 104))	('rearrangement', 'Var', (4, 17))	('sarcomas', 'Disease', (136, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('genetic abnormality', 'Disease', 'MESH:D030342', (25, 44))	('CIC', 'Gene', '23152', (0, 3))	('genetic abnormality', 'Disease', (25, 44))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('EWSR1', 'Gene', (99, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))
198735	31676869	This rearrangement most commonly connects CIC (19q13) to DUX4 (4q35 or 10q26); some tumours harbour CIC rearrangements with non-DUX4 partner genes, including FOXO4, LEUTX, NUTM1, and NUTM2A.	('LEUTX', 'Gene', '342900', (165, 170))	('NUTM2A', 'Gene', '728118', (183, 189))	('CIC', 'Gene', (100, 103))	('CIC', 'Gene', (42, 45))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('rearrangements', 'Var', (104, 118))	('NUTM1', 'Gene', '256646', (172, 177))	('NUTM1', 'Gene', (172, 177))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('FOXO4', 'Gene', (158, 163))	('CIC', 'Gene', '23152', (100, 103))	('CIC', 'Gene', '23152', (42, 45))	('LEUTX', 'Gene', (165, 170))	('NUTM2A', 'Gene', (183, 189))	('FOXO4', 'Gene', '4303', (158, 163))
198739	31676869	The CIC-DUX4 fusion gene is implicated in oncogenesis, tumour development, and metastatic capability.	('tumour', 'Disease', (55, 61))	('fusion', 'Var', (13, 19))	('implicated', 'Reg', (28, 38))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('CIC', 'Gene', '23152', (4, 7))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('metastatic capability', 'CPA', (79, 100))	('CIC', 'Gene', (4, 7))
198765	31676869	3a, lane 2, CIC-DUX4 fusions were observed in Kitra-SRS cells.	('CIC', 'Gene', '23152', (12, 15))	('CIC', 'Gene', (12, 15))	('fusions', 'Var', (21, 28))
198771	31676869	In chromosomal analysis employing multiplex fluorescence in situ hybridization (M-FISH), six out of ten metaphase cells from Kitra-SRS cells at passage 20 showed the following karyotype: 48, XX, del(1)(p32), +8, t(12;19)(q13;q13), +20 (Fig.	('t(12;19)(q13;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (212, 229))	('M-FISH', 'Species', '119488', (80, 86))	('t(12;19)(q13;q13', 'Var', (212, 228))	('del(1)(p32', 'Var', (195, 205))
198774	31676869	Notably, three chromosome breakpoints within 19q13.2 were demonstrated using the bacterial artificial chromosome cloning system, located within the bacterial artificial chromosome clones CTD-3049I13, RP11-374A11 (or CTD-2278A8), and RP11-780O11 (or CTD-2278A8) (Fig.	('RP11', 'Gene', (233, 237))	('RP11', 'Gene', '26121', (233, 237))	('RP11', 'Gene', (200, 204))	('RP11', 'Gene', '26121', (200, 204))	('CTD-3049I13', 'Var', (187, 198))
198775	31676869	CTD-3049I13 covered the approximately 200-kb region within 19q13.2 and contained CIC.	('CIC', 'Gene', (81, 84))	('CIC', 'Gene', '23152', (81, 84))	('CTD-3049I13', 'Var', (0, 11))
198776	31676869	These results suggest that complex chromosomal rearrangements occurred in Kitra-SRS cells with insertion of a chromosome region including a DUX4 pseudogene after the breakpoint of CIC on chromosome 19q13, resulting in generation of the CIC-DUX4 fusion gene.	('CIC', 'Gene', '23152', (180, 183))	('CIC', 'Gene', '23152', (236, 239))	('DUX4', 'Gene', (140, 144))	('insertion', 'Var', (95, 104))	('CIC', 'Gene', (180, 183))	('CIC', 'Gene', (236, 239))
198833	31676869	recently used FISH and documented the clinicopathologic features of a large cohort of 115 cases with a CIC break-apart signal; only 65 cases were positive for fusion to DUX4 on 4q35 or 10q26; in the remaining 50 cases, a fusion partner could not be identified.	('CIC', 'Gene', (103, 106))	('DUX4', 'Protein', (169, 173))	('fusion', 'Var', (159, 165))	('positive', 'Reg', (146, 154))	('CIC', 'Gene', '23152', (103, 106))
198835	31676869	Therefore, the CIC-DUX4 fusion is likely generated by a variety of chromosome rearrangements including translocations and insertions.	('CIC', 'Gene', (15, 18))	('insertions', 'Var', (122, 132))	('translocations', 'Var', (103, 117))	('CIC', 'Gene', '23152', (15, 18))
198836	31676869	The presence of multiple CIC-DUX4 fusion variants has been reported.	('variants', 'Var', (41, 49))	('CIC', 'Gene', (25, 28))	('CIC', 'Gene', '23152', (25, 28))
198843	31676869	Thus, C-terminal truncated CIC may play a key role in the oncogenesis of CDS.	('C-terminal truncated', 'Var', (6, 26))	('CIC', 'Gene', (27, 30))	('play', 'Reg', (35, 39))	('CDS', 'Disease', (73, 76))	('CIC', 'Gene', '23152', (27, 30))
198963	25136525	More cases (30.7%) revealed weak or no Bax expression with high VEGF expression compared to only 23.8% of strong Bax expression with high VEGF expression.	('Bax', 'Gene', '581', (113, 116))	('Bax', 'Gene', (113, 116))	('Bax', 'Gene', (39, 42))	('VEGF', 'Gene', (64, 68))	('high', 'Var', (59, 63))	('VEGF', 'Gene', '7422', (138, 142))	('Bax', 'Gene', '581', (39, 42))	('expression', 'MPA', (43, 53))	('VEGF', 'Gene', '7422', (64, 68))	('VEGF', 'Gene', (138, 142))
198969	25136525	In this study, apoptotic activity was higher in the TCs compared to anti-apoptotic activity, which is consistent with the findings reported by Sabah et al.	('TCs', 'Var', (52, 55))	('apoptotic activity', 'CPA', (15, 33))	('TCs', 'Chemical', '-', (52, 55))	('higher', 'PosReg', (38, 44))
199111	31485091	Bayesian Semiparametric Estimation of Cancer-specific Age-at-onset Penetrance with Application to Li-Fraumeni Syndrome Penetrance, which plays a key role in genetic research, is defined as the proportion of individuals with the genetic variants (i.e., genotype) that cause a particular trait and who have clinical symptoms of the trait (i.e., phenotype).	('cause', 'Reg', (267, 272))	('Li-Fraumeni', 'Disease', (98, 109))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (98, 109))	('variants', 'Var', (236, 244))
199116	31485091	It is characterized by autosomal dominant mutation inheritance with frequent occurrence of several cancer types: soft tissue/bone sarcoma, breast cancer, lung cancer, and other types of cancer that are grouped together as "other cancers".	('autosomal', 'Var', (23, 32))	('cancer', 'Disease', (146, 152))	('bone sarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', (159, 165))	('occurrence', 'Reg', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bone sarcoma', 'Disease', (125, 137))	('soft tissue/bone sarcoma', 'Phenotype', 'HP:0030448', (113, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('lung cancer', 'Disease', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (229, 235))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cancers', 'Disease', (229, 236))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', (139, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Disease', (186, 192))	('bone sarcoma', 'Disease', 'MESH:D001847', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (99, 105))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
199117	31485091	A majority of LFS is caused by germline mutations in the TP53 tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('LFS', 'Disease', (14, 17))	('caused by', 'Reg', (21, 30))	('germline mutations', 'Var', (31, 49))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
199120	31485091	Considering the prevalence of TP53 mutations in a general population is as low as 0.0001 to 0.003, this dataset provides a specially enriched collection of TP53 mutations, which then allow us to characterize its effect on a diverse cancer outcomes.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (30, 34))	('cancer', 'Disease', (232, 238))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('mutations', 'Var', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('effect', 'Reg', (212, 218))
199124	31485091	The primary objective here is to estimate the cancer-specific age-at-onset penetrance as a measure of the risk of experiencing a specific cancer for a person with a specific genotype(i.e., TP53 mutation status).	('TP53', 'Gene', '7157', (189, 193))	('cancer', 'Disease', (138, 144))	('person', 'Species', '9606', (151, 157))	('mutation', 'Var', (194, 202))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('TP53', 'Gene', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
199144	31485091	As LFS is autosomal dominant, we use G = 1 to denote genotype Aa or AA, and G = 0 to denote genotype aa, where A and a denote the (minor) mutated and wildtype alleles in the TP53 tumor suppressor gene, respectively.	('TP53', 'Gene', (174, 178))	('mutated', 'Var', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('TP53', 'Gene', '7157', (174, 178))	('tumor', 'Disease', (179, 184))
199158	31485091	In our application, the TP53 mutation prevalence is independent of X = gender i.e., Pr(G X) = Pr(G), and can be calculated on the basis of the mutated allele frequency phiA, i.e., Pr(G = 0) = (1 - phiA)2 and Pr(G = 1) = 1 - (1 - phiA)2.	('TP53', 'Gene', (24, 28))	('mutation', 'Var', (29, 37))	('TP53', 'Gene', '7157', (24, 28))
199159	31485091	The prevalence of a germline TP53 mutation in the Western population is estimated as phiA = 0.0006.	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))
199162	31485091	Given G, we then simulate his/her true time to cancer, Tk, k = 1, 2, from the following cancer-specific frailty model:  with beta1 = 4, beta2 = 10, lambda0,1(t) = 0.1, lambda0,2(t) = 0.0005, , and .	('cancer', 'Disease', (88, 94))	('beta2', 'Gene', '10383', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('k = 1', 'Gene', '3848', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('beta2', 'Gene', (136, 141))	('cancer', 'Disease', (47, 53))	('k = 1', 'Gene', (59, 64))	('beta1', 'Var', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
199173	31485091	Genotype has a strong effect on the incidence of all cancer types, with TP53 mutation carriers being more likely to have cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Disease', (53, 59))	('TP53', 'Gene', '7157', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mutation', 'Var', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TP53', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
199181	31485091	It is not surprising that the TP53 mutation carriers (G = 1) have higher risk of developing cancer than the non-carriers (G = 0), regardless of cancer type.	('TP53', 'Gene', (30, 34))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('mutation', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TP53', 'Gene', '7157', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
199183	31485091	It is of clinical interest that there is a sizable chance that the female TP53 mutation carrier will develop breast cancer before 20 years of age, which is rarely seen in females with BRCA1 and BRCA2 mutations (two well-known susceptibility gene mutations for breast cancer).	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('breast cancer', 'Disease', (109, 122))	('BRCA2', 'Gene', (194, 199))	('breast cancer', 'Disease', (260, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('BRCA1', 'Gene', '672', (184, 189))	('develop', 'PosReg', (101, 108))	('TP53', 'Gene', '7157', (74, 78))	('BRCA2', 'Gene', '675', (194, 199))	('mutation', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRCA1', 'Gene', (184, 189))	('TP53', 'Gene', (74, 78))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
199184	31485091	This suggests that early-onset breast cancer is an important feature of TP53 mutation.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('TP53', 'Gene', '7157', (72, 76))	('mutation', 'Var', (77, 85))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('TP53', 'Gene', (72, 76))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))
199187	31485091	The overall age-at-onset penetrance quantifies the probability of having any type of cancer by a certain age for carriers of TP53 mutations.	('TP53', 'Gene', '7157', (125, 129))	('type of cancer', 'Disease', 'MESH:D009369', (77, 91))	('carriers', 'Reg', (113, 121))	('TP53', 'Gene', (125, 129))	('mutations', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('type of cancer', 'Disease', (77, 91))
199188	31485091	Among the non-carriers, females have lower cancer risk than males; whereas the female mutation carrier has higher risk than the male mutation carrier due to the excessively high risk of the female carrier developing breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', (216, 229))	('cancer', 'Disease', (43, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (86, 94))	('cancer', 'Disease', (223, 229))
199189	31485091	Overall, TP53 mutation carriers have very high lifetime risk of developing cancer, demonstrating the importance of the accurate detection of TP53 germline mutations.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutation', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
199197	31485091	Family 1 does not carry the mutated allele and has three cases of cancer (two breast and one other cancers), and family 2 carries the mutated allele with four cases of cancer (one breast, two sarcoma and one other cancers).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast', 'Disease', (180, 186))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Disease', (168, 174))	('breast', 'Disease', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('one breast', 'Phenotype', 'HP:0012813', (176, 186))	('cancers', 'Disease', (214, 221))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('sarcoma', 'Disease', (192, 199))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Disease', (99, 105))	('mutated', 'Var', (134, 141))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', (66, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
199239	30150410	EBV abundantly expressed both exon-only and exon-intron circRNAs from the BamHI A rightward transcript (BART) locus (circBARTs) formed from a spliced BART transcript and excluding the EBV miRNA region.	('BART', 'Gene', '23568', (121, 125))	('BART', 'Gene', (150, 154))	('EBV', 'Species', '10376', (184, 187))	('BART', 'Gene', (104, 108))	('BART', 'Gene', (121, 125))	('circBARTs', 'Chemical', '-', (117, 126))	('exon-intron', 'Var', (44, 55))	('BART', 'Gene', '23568', (150, 154))	('EBV', 'Species', '10376', (0, 3))	('BART', 'Gene', '23568', (104, 108))
199245	30150410	In EBV and KSHV coinfected cells, exon-only EBV circBARTs were located more in the cytoplasm, whereas the intron-retaining circBARTs were found in the nuclear fraction.	('KSHV', 'Species', '37296', (11, 15))	('circBARTs', 'Chemical', '-', (123, 132))	('EBV', 'Species', '10376', (44, 47))	('nuclear', 'Gene', (151, 158))	('circBARTs', 'Chemical', '-', (48, 57))	('nuclear', 'Gene', '4000', (151, 158))	('exon-only', 'Var', (34, 43))	('EBV', 'Species', '10376', (3, 6))
199251	30150410	KSHV causes Kaposi's sarcoma:an endothelial cell tumor:and two hematolymphoid malignancies: primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD).	('KSHV', 'Species', '37296', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('effusion lymphoma', 'Disease', (100, 117))	('hematolymphoid malignancies', 'Disease', 'MESH:D009369', (63, 90))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (12, 28))	('PEL', 'Phenotype', 'HP:0030069', (119, 122))	('MCD', 'Disease', 'MESH:D012514', (162, 165))	('MCD', 'Disease', (162, 165))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (12, 28))	('KSHV', 'Var', (0, 4))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (92, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (109, 117))	("Kaposi's sarcoma", 'Disease', (12, 28))	("multicentric Castleman's disease", 'Disease', 'MESH:C537372', (128, 160))	('tumor', 'Disease', (49, 54))	('effusion lymphoma', 'Disease', 'MESH:D054685', (100, 117))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('hematolymphoid malignancies', 'Disease', (63, 90))	("multicentric Castleman's disease", 'Disease', (128, 160))
199262	30150410	While Merkel cell polyomavirus was identified by poly(A) DTS, no other human cancer viruses since have been found by this approach.	('poly(A) DTS', 'Var', (49, 60))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('poly(A) DTS', 'Chemical', '-', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Merkel cell polyomavirus', 'Disease', (6, 30))	('Merkel cell polyomavirus', 'Species', '493803', (6, 30))	('human', 'Species', '9606', (71, 76))
199283	30150410	We detected three to four bands migrating between 400 bp and 700 bp in all samples except the EBV-uninfected HK1 control cells and the B95-8 cell line, which has a 12-kb deletion within the BART locus from position 139,724 to 151,554 (NC_007605).	('EBV', 'Species', '10376', (94, 97))	('HK1', 'Gene', '3098', (109, 112))	('HK1', 'Gene', (109, 112))	('BART', 'Gene', '23568', (190, 194))	('BART', 'Gene', (190, 194))	('deletion', 'Var', (170, 178))
199325	30150410	In NaB/TPA-treated BC1 and BCBL1 cells, additional candidate BSJ reads were found at low abundance from K4, ORF49, ORF69, K12, ORF71, and ORF72 and from newly described transcripts K1.3, K4.5, K4.7, and K12.5 (Dataset S2).	('K12', 'Var', (122, 125))	('ORF49', 'Var', (108, 113))	('ORF71', 'Var', (127, 132))	('ORF69', 'Var', (115, 120))	('NaB/TPA', 'Chemical', '-', (3, 10))	('BSJ', 'Gene', (61, 64))
199344	30150410	EBV genome sequencing revealed the spontaneous occurrence of a BART deletion eliminating miRNA and circBART expression in 1 of 50 lymphoblastoid cell lines (AFB1), suggesting that neither circBARTs nor BART miRNA are obligatory for the maintenance of the EBV genome in cell culture or to achieve in vitro immortalization of B cells.	('BART', 'Gene', '23568', (63, 67))	('BART', 'Gene', (192, 196))	('circBART', 'Chemical', '-', (188, 196))	('BART', 'Gene', '23568', (103, 107))	('miRNA', 'MPA', (89, 94))	('BART', 'Gene', (202, 206))	('circBART', 'Chemical', '-', (99, 107))	('circBARTs', 'Chemical', '-', (188, 197))	('BART', 'Gene', (63, 67))	('BART', 'Gene', (103, 107))	('deletion', 'Var', (68, 76))	('eliminating', 'NegReg', (77, 88))	('BART', 'Gene', '23568', (202, 206))	('BART', 'Gene', '23568', (192, 196))	('EBV', 'Species', '10376', (255, 258))	('EBV', 'Species', '10376', (0, 3))
199481	29449896	In September 2013, the patient underwent an atypical resection of the bilateral lung lesions, the histological report confirming the presence of adenocarcinoma of the lung, pT2a N0 LV0 G2 R0 staging with mutated K-ras and wild type EGFR.	('EGFR', 'Gene', '1956', (232, 236))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (150, 171))	('mutated', 'Var', (204, 211))	('K-ras', 'Gene', '3845', (212, 217))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (145, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('adenocarcinoma of the lung', 'Disease', (145, 171))	('K-ras', 'Gene', (212, 217))	('EGFR', 'Gene', (232, 236))	('patient', 'Species', '9606', (23, 30))
199483	29449896	In February 2015, a new thigh lesion was surgically removed, the histology report indicating a relapse of high-grade myxofibrosarcoma; Ki67 70%; mitotic index 19 mitoses/10 high power fields (HPFs).	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('myxofibrosarcoma', 'Disease', (117, 133))	('myxofibrosarcoma', 'Disease', 'None', (117, 133))	('mitotic index', 'Var', (145, 158))	('Ki67', 'Chemical', '-', (135, 139))
199552	29449896	Interestingly, CD109 overexpression was markedly higher in the primary tumor MF3 (663-fold higher compared with the normal tissue) than in local recurrences MF1 and MF2 (24- and 72-fold higher than that of normal tissue) [Figure 2(a) and (c)].	('MF1', 'Gene', '2237', (157, 160))	('primary tumor', 'Disease', (63, 76))	('higher', 'PosReg', (91, 97))	('CD109', 'Gene', '135228', (15, 20))	('primary tumor', 'Disease', 'MESH:D009369', (63, 76))	('overexpression', 'PosReg', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('MF3', 'Var', (77, 80))	('higher', 'PosReg', (49, 55))	('MF1', 'Gene', (157, 160))	('CD109', 'Gene', (15, 20))
199568	29449896	Notably, the MF2 specimen was characterized by the presence of markedly pleomorphic areas (Figure 1) and a higher expression of TGF- beta than the other two specimens [Figure 2(b)], which could explain its lower sensitivity to chemotherapy.	('TGF- beta', 'Gene', '7040', (128, 137))	('MF2', 'Var', (13, 16))	('expression', 'MPA', (114, 124))	('higher', 'PosReg', (107, 113))	('TGF- beta', 'Gene', (128, 137))
199574	29449896	Trabectedin showed a higher cytotoxic activity in MF1 and MF3 than in MF2 cultures.	('MF3', 'Var', (58, 61))	('higher', 'PosReg', (21, 27))	('MF1', 'Gene', (50, 53))	('cytotoxic activity', 'CPA', (28, 46))	('MF1', 'Gene', '2237', (50, 53))
199621	25639868	These genomic data provide the foundation to launch new research efforts to address one of the fundamental questions in cancer biology:why are some cells more susceptible to malignant transformation by particular genetic lesions at discrete developmental stages than others?	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('genetic lesions', 'Var', (213, 228))	('lesions', 'Var', (221, 228))
199646	25639868	For example, RB1 inactivation contributes to retinoblastoma initiation by promoting cell cycle progression, but the RB1 protein is also required for rod photoreceptor differentiation.	('inactivation', 'Var', (17, 29))	('RB1', 'Gene', '5925', (13, 16))	('RB1', 'Gene', '5925', (116, 119))	('RB1', 'Gene', (13, 16))	('retinoblastoma initiation', 'Disease', 'MESH:D012175', (45, 70))	('cell cycle progression', 'CPA', (84, 106))	('retinoblastoma', 'Phenotype', 'HP:0009919', (45, 59))	('promoting', 'PosReg', (74, 83))	('RB1', 'Gene', (116, 119))	('retinoblastoma initiation', 'Disease', (45, 70))
199650	25639868	When a tumor-initiating mutation occurs in those distinct progenitor cell populations, the consequence may vary dramatically depending on the competence of that cell at that particular stage of development.	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('mutation', 'Var', (24, 32))	('tumor', 'Disease', (7, 12))
199651	25639868	For example, in one cell population, an oncogenic mutation may result in a tumor with cellular features of skeletal muscle such as rhabdomyosarcoma, whereas in another, the same mutation may lead to rapid cell death or a tumor with osteogenic features (Figure 2).	('lead to', 'Reg', (191, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('mutation', 'Var', (50, 58))	('osteogenic features', 'CPA', (232, 251))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('death', 'Disease', 'MESH:D003643', (210, 215))	('death', 'Disease', (210, 215))	('result in', 'Reg', (63, 72))	('tumor', 'Disease', (75, 80))	('rhabdomyosarcoma', 'Disease', (131, 147))
199652	25639868	Indeed, recent studies in genetically engineered mouse models show that perturbations in the hedgehog pathway in the adipose lineage can lead to rhabdomyosarcoma with features of skeletal muscle typical of human rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (145, 161))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (212, 228))	('rhabdomyosarcoma', 'Disease', (145, 161))	('human', 'Species', '9606', (206, 211))	('lead to', 'Reg', (137, 144))	('hedgehog pathway', 'Pathway', (93, 109))	('mouse', 'Species', '10090', (49, 54))	('rhabdomyosarcoma', 'Disease', (212, 228))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (145, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (212, 228))	('perturbations', 'Var', (72, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))
199653	25639868	Thus, the competence of individual progenitor cells and the specific oncogenic mutations affect when and where pediatric solid tumors arise during development.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('pediatric solid tumors', 'Disease', (111, 133))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (111, 133))	('affect', 'Reg', (89, 95))	('mutations', 'Var', (79, 88))
199654	25639868	The interplay between the specific tumor mutations and differentiation programs, combined with the dynamic intrinsic cellular competence, make it difficult to pinpoint a cell of origin from the molecular or cellular features of the resulting tumors.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (242, 247))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))
199666	25639868	It was previously thought that this was due to the requirement of secondary and tertiary genetic lesions after inactivation of the Rb1 gene.	('Rb1', 'Gene', (131, 134))	('inactivation', 'Var', (111, 123))	('Rb1', 'Gene', '5925', (131, 134))
199681	25639868	The majority of TP53 mutations in osteosarcomas are translocations in the first intron of the gene.	('osteosarcomas', 'Disease', (34, 47))	('osteosarcomas', 'Phenotype', 'HP:0002669', (34, 47))	('osteosarcoma', 'Phenotype', 'HP:0002669', (34, 46))	('osteosarcomas', 'Disease', 'MESH:D012516', (34, 47))	('TP53', 'Gene', '7157', (16, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
199683	25639868	To the best of our knowledge, this type of TP53 mutation occurs only in a rare subset of prostate cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancers', 'Disease', 'MESH:D011471', (89, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('prostate cancers', 'Phenotype', 'HP:0012125', (89, 105))	('prostate cancers', 'Disease', (89, 105))	('mutation', 'Var', (48, 56))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
199685	25639868	Careful analysis of mutant allele frequency and tumor heterogeneity showed that TP53 mutations are initiating genetic events in osteosarcoma.	('tumor', 'Disease', (48, 53))	('TP53', 'Gene', '7157', (80, 84))	('osteosarcoma', 'Disease', (128, 140))	('TP53', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('osteosarcoma', 'Phenotype', 'HP:0002669', (128, 140))	('osteosarcoma', 'Disease', 'MESH:D012516', (128, 140))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
199686	25639868	In many tumor types, inactivation of the p53 pathway can lead to an increase in translocations and other chromosomal events because of perturbations in DNA damage checkpoint control.	('p53', 'Gene', '7157', (41, 44))	('inactivation', 'Var', (21, 33))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('chromosomal events', 'CPA', (105, 123))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('increase', 'PosReg', (68, 76))	('tumor', 'Disease', (8, 13))	('DNA damage checkpoint control', 'MPA', (152, 181))	('translocations', 'MPA', (80, 94))	('p53', 'Gene', (41, 44))
199687	25639868	However, many pediatric osteosarcomas are initiated through a structural variation occurring at very high frequency in TP53 itself.	('initiated through', 'Reg', (42, 59))	('osteosarcomas', 'Disease', (24, 37))	('osteosarcomas', 'Phenotype', 'HP:0002669', (24, 37))	('osteosarcoma', 'Phenotype', 'HP:0002669', (24, 36))	('osteosarcomas', 'Disease', 'MESH:D012516', (24, 37))	('structural variation', 'Var', (62, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
199689	25639868	One intriguing possibility is that the cell of origin for osteosarcoma has a higher rate of chromosomal lesions and structural variations than do other cellular lineages.	('osteosarcoma', 'Disease', (58, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))	('chromosomal', 'Var', (92, 103))	('structural variations', 'CPA', (116, 137))
199695	25639868	Translocations that are predicted to produce in-frame fusion proteins are rare in retinoblastoma.	('retinoblastoma', 'Gene', (82, 96))	('retinoblastoma', 'Gene', '5925', (82, 96))	('Translocations', 'Var', (0, 14))	('retinoblastoma', 'Phenotype', 'HP:0009919', (82, 96))
199696	25639868	In contrast, osteosarcomas have 266 SVs per tumor (range 47-1135), 50% of their genome is involved in CNVs (range 3-89%) and have 46 single nucleotide variations in coding regions (range 16-237).	('osteosarcoma', 'Phenotype', 'HP:0002669', (13, 25))	('osteosarcomas', 'Disease', (13, 26))	('single nucleotide variations', 'Var', (133, 161))	('osteosarcomas', 'Phenotype', 'HP:0002669', (13, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('osteosarcomas', 'Disease', 'MESH:D012516', (13, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('involved', 'Reg', (90, 98))	('tumor', 'Disease', (44, 49))
199697	25639868	On average, 8.5 translocations per tumor (median value) produce a novel fusion protein in osteosarcoma.	('fusion protein', 'Protein', (72, 86))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('translocations', 'Var', (16, 30))	('osteosarcoma', 'Disease', (90, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))
199713	25639868	Ewing sarcomas are initiated by EWS-FLI1 translocations, and WGS of 112 tumors and matched germline tissue revealed that the tumors have very few secondary genetic lesions.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', (72, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))	('translocations', 'Var', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('EWS', 'Gene', (32, 35))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('FLI1', 'Gene', (36, 40))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (0, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('FLI1', 'Gene', '2313', (36, 40))	('Ewing sarcomas', 'Disease', (0, 14))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (0, 14))	('initiated', 'Reg', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('EWS', 'Gene', '2130', (32, 35))
199714	25639868	Similarly, ARMS are initiated by PAX3/7-FOXO translocations and have few secondary genetic lesions.	('PAX3', 'Gene', '5077', (33, 37))	('ARMS', 'Disease', (11, 15))	('PAX3', 'Gene', (33, 37))	('initiated', 'Reg', (20, 29))	('ARMS', 'Phenotype', 'HP:0006779', (11, 15))	('translocations', 'Var', (45, 59))
199716	25639868	In addition to these striking differences in the genomic landscape of oncogenic fusion protein-driven pediatric solid tumors, several other unique patterns of DNA mutations contribute to our understanding of cellular origins and the unique developmental context that predisposes some cellular lineages to malignant transformation.	('mutations', 'Var', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('DNA', 'Gene', (159, 162))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('pediatric solid tumors', 'Disease', (102, 124))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (102, 124))
199730	25639868	All tumors with the kataegis pattern carried mutated TP53.	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('mutated', 'Var', (45, 52))	('TP53', 'Gene', '7157', (53, 57))	('carried', 'Reg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TP53', 'Gene', (53, 57))
199735	25639868	Unlike chromothripsis, there is no evidence supporting that mutations associated with kataegis contribute to tumor initiation or progression in pediatric solid tumors.	('pediatric solid tumors', 'Disease', (144, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('contribute', 'Reg', (95, 105))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (144, 166))	('progression', 'CPA', (129, 140))	('chromothripsis', 'Disease', 'MESH:D000072837', (7, 21))	('tumor initiation', 'Disease', 'MESH:D009369', (109, 125))	('kataegis', 'Gene', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor initiation', 'Disease', (109, 125))	('mutations', 'Var', (60, 69))	('chromothripsis', 'Disease', (7, 21))
199743	25639868	It is possible that a single oncogenic event, such as formation of the EWS-FLI1 oncogene, promotes the formation of Ewing sarcoma in a stochastic manner through active epigenetic reprogramming, as seen in the formation of induced pluripotent stem cells from somatic cells (Figure 2).	('Ewing sarcoma', 'Disease', (116, 129))	('EWS', 'Gene', '2130', (71, 74))	('EWS', 'Gene', (71, 74))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('promotes', 'PosReg', (90, 98))	('FLI1', 'Gene', (75, 79))	('epigenetic', 'Var', (168, 178))	('FLI1', 'Gene', '2313', (75, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
199748	25639868	One of the most important advances resulting from the genomic analysis of pediatric cancer over the past 5 years was the discovery that epigenetics plays a major role in tumor initiation and progression.	('pediatric cancer', 'Disease', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor initiation', 'Disease', 'MESH:D009369', (170, 186))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pediatric cancer', 'Disease', 'MESH:D009369', (74, 90))	('tumor initiation', 'Disease', (170, 186))	('epigenetics', 'Var', (136, 147))
199751	25639868	An integrated analysis of DNA methylation, gene expression and histone modification in retinoblastoma showed that the expression of several oncogenes and tumor suppressor genes was altered through epigenetic mechanisms.	('altered', 'Reg', (181, 188))	('retinoblastoma', 'Gene', (87, 101))	('retinoblastoma', 'Gene', '5925', (87, 101))	('retinoblastoma', 'Phenotype', 'HP:0009919', (87, 101))	('epigenetic', 'Var', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('oncogenes', 'Gene', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('expression', 'MPA', (118, 128))	('tumor', 'Disease', (154, 159))
199754	25639868	Another unexpected discovery that highlighted the importance of epigenetics in solid tumor progression was that of recurrent mutations in the epigenetic modulators themselves.	('mutations', 'Var', (125, 134))	('tumor', 'Disease', (85, 90))	('epigenetic', 'Gene', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
199757	25639868	During development, BCOR is thought to maintain tissue homeostasis and gene silencing through epigenetic mechanisms.	('gene', 'Var', (71, 75))	('BCOR', 'Gene', '54880', (20, 24))	('BCOR', 'Gene', (20, 24))
199760	25639868	Further analyses of the epigenome of retinoblastomas with wild-type and mutant BCOR are required to identify the key target genes for tumor progression.	('retinoblastoma', 'Phenotype', 'HP:0009919', (37, 51))	('BCOR', 'Gene', '54880', (79, 83))	('mutant', 'Var', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('retinoblastomas', 'Disease', 'MESH:D012175', (37, 52))	('retinoblastomas', 'Disease', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('retinoblastomas', 'Phenotype', 'HP:0009919', (37, 52))	('tumor', 'Disease', (134, 139))	('BCOR', 'Gene', (79, 83))
199765	25639868	In neuroblastomas, ATRX mutations are associated with age at diagnosis, which is highly predictive of overall survival.21,32 In adrenocortical carcinomas, ATRX mutations, which occurred in tumors harboring TP53 mutations, are associated with genome instability, advanced tumor stage and poor outcomes.	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('genome instability', 'CPA', (242, 260))	('mutations', 'Var', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('adrenocortical carcinomas', 'Disease', (128, 153))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('TP53', 'Gene', '7157', (206, 210))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (128, 152))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('ATRX', 'Gene', (155, 159))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (128, 153))	('ATRX', 'Gene', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('ATRX', 'Gene', '546', (155, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('ATRX', 'Gene', '546', (19, 23))	('tumor', 'Disease', (271, 276))	('tumors', 'Disease', (189, 195))	('neuroblastomas', 'Phenotype', 'HP:0003006', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('neuroblastomas', 'Disease', (3, 17))	('tumor', 'Disease', (189, 194))	('TP53', 'Gene', (206, 210))	('associated', 'Reg', (226, 236))	('mutations', 'Var', (211, 220))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('neuroblastomas', 'Disease', 'MESH:D009447', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (128, 153))
199766	25639868	Interestingly, ATRX mutations have never been found in combination with MYCN amplification in neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (94, 107))	('ATRX', 'Gene', '546', (15, 19))	('neuroblastoma', 'Disease', (94, 107))	('MYCN', 'Gene', (72, 76))	('neuroblastoma', 'Phenotype', 'HP:0003006', (94, 107))	('ATRX', 'Gene', (15, 19))	('MYCN', 'Gene', '4613', (72, 76))	('mutations', 'Var', (20, 29))
199767	25639868	Further comprehensive studies are required to determine whether ATRX mutations are an independent prognostic risk factor for neuroblastoma.	('mutations', 'Var', (69, 78))	('ATRX', 'Gene', (64, 68))	('neuroblastoma', 'Disease', (125, 138))	('ATRX', 'Gene', '546', (64, 68))	('neuroblastoma', 'Phenotype', 'HP:0003006', (125, 138))	('neuroblastoma', 'Disease', 'MESH:D009447', (125, 138))
199768	25639868	In most tumors with ATRX mutations, cells have longer telomeres as a result of alternative lengthening of telomeres, which is a mechanism of telomere maintenance in cancer.	('mutations', 'Var', (25, 34))	('longer', 'PosReg', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ATRX', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('lengthening', 'MPA', (91, 102))	('tumors', 'Disease', (8, 14))	('cancer', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('ATRX', 'Gene', '546', (20, 24))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
199771	25639868	Germline ATRX mutations lead to the X-linked alpha thalassemia/mental retardation syndrome, which is associated with diverse developmental defects.	('thalassemia/mental retardation syndrome', 'Disease', (51, 90))	('mutations', 'Var', (14, 23))	('ATRX', 'Gene', '546', (9, 13))	('developmental defects', 'Disease', (125, 146))	('developmental defects', 'Disease', 'MESH:D003147', (125, 146))	('thalassemia/mental retardation syndrome', 'Disease', 'MESH:C538258', (51, 90))	('lead to', 'Reg', (24, 31))	('ATRX', 'Gene', (9, 13))	('mental retardation', 'Phenotype', 'HP:0001249', (63, 81))
199772	25639868	Although alternative lengthening of telomeres and telomere maintenance are important for tumorigenesis, inactivation of ATRX may also contribute to perturbations in other cellular pathways through epigenetic mechanisms.	('ATRX', 'Gene', (120, 124))	('contribute', 'Reg', (134, 144))	('ATRX', 'Gene', '546', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inactivation', 'Var', (104, 116))	('perturbations', 'NegReg', (148, 161))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
199776	25639868	Epigenetics has emerged as a major focus area in pediatric solid tumor research because of the striking changes in the epigenetic landscape after inactivation of tumor suppressor genes such as RB1 and the identification of recurrent mutations in epigenetic regulators such as BCOR and ATRX.	('epigenetic landscape', 'MPA', (119, 139))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (65, 70))	('RB1', 'Gene', (193, 196))	('BCOR', 'Gene', (276, 280))	('tumor', 'Disease', (162, 167))	('inactivation', 'NegReg', (146, 158))	('BCOR', 'Gene', '54880', (276, 280))	('ATRX', 'Gene', (285, 289))	('mutations', 'Var', (233, 242))	('ATRX', 'Gene', '546', (285, 289))	('RB1', 'Gene', '5925', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('changes', 'Reg', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
199777	25639868	By integrating these tumor data with epigenomic profiling of normal cells during development, we can develop a new framework to understand why some oncogenic mutations cause specific types of tumors in restricted cell lineages during development.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('cause', 'Reg', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('mutations', 'Var', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
199780	25639868	Therefore, the effect of tumor suppressor gene inactivation or proto-oncogene activation on tumor initiation and progression is also likely to be dependent on cellular lineage and developmental stage.	('inactivation', 'Var', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor initiation', 'Disease', 'MESH:D009369', (92, 108))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor initiation', 'Disease', (92, 108))
199782	25639868	Specifically, it is possible that individual oncogenic lesions in a particular cellular lineage at a unique developmental stage lead to cancer but other combinations of mutation, lineage and stage are not tolerated.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('lesions', 'Var', (55, 62))	('lead to', 'Reg', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
199786	25639868	Although all partitioned domains are not likely to be maintained in the tumor cells because of changes associated with age and/or genetic mutations in cancer cells, a sufficient number may remain to identify the developmental- and lineage-specific remnants of the cell of origin.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', (72, 77))	('genetic mutations', 'Var', (130, 147))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutations', 'Var', (138, 147))
199793	25639868	One prediction is that oncogenic pathways that are required for malignant transformation will be epigenetically poised in the cell that gives rise to that tumor.	('epigenetically', 'Var', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('oncogenic pathways', 'Pathway', (23, 41))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))
199799	25639868	For example, pediatric cancer is rare, and it may be difficult to establish the statistical significance of new therapies for rare subsets of patients receiving individualized treatment based on the mutations found in their tumors.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('pediatric cancer', 'Disease', (13, 29))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('mutations', 'Var', (199, 208))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('pediatric cancer', 'Disease', 'MESH:D009369', (13, 29))
199801	25639868	Unfortunately, with our current understanding of pediatric solid tumor genomes and available molecular targeted therapies, only 12% of patients (46/380) with pediatric solid tumor patients likely have 'druggable' mutations.	('tumor', 'Disease', (174, 179))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('mutations', 'Var', (213, 222))	('patients', 'Species', '9606', (180, 188))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
199803	25639868	For example, activating mutations in the ALK gene are thought to be druggable with molecular targeted therapeutics such as crizotinib.	('ALK', 'Gene', (41, 44))	('ALK', 'Gene', '238', (41, 44))	('activating mutations', 'Var', (13, 33))	('crizotinib', 'Chemical', 'MESH:D000077547', (123, 133))
199805	25639868	The inclusion criteria for the Phase I/II study includes patients whose tumors have ALK gene fusions, mutations and amplifications (>fourfold).	('amplifications', 'Var', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ALK', 'Gene', (84, 87))	('patients', 'Species', '9606', (57, 65))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (102, 111))	('ALK', 'Gene', '238', (84, 87))
199806	25639868	In neuroblastomas with ALK mutations, it is not known whether some mutations confer greater sensitivity to crizotinib than others.	('mutations', 'Var', (27, 36))	('neuroblastomas', 'Disease', (3, 17))	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('ALK', 'Gene', (23, 26))	('neuroblastomas', 'Phenotype', 'HP:0003006', (3, 17))	('neuroblastomas', 'Disease', 'MESH:D009447', (3, 17))	('ALK', 'Gene', '238', (23, 26))	('crizotinib', 'Chemical', 'MESH:D000077547', (107, 117))
199810	25639868	For example, RAS is mutated in a subset of intermediate- and high-risk rhabdomyosarcomas, but none of the nearly 100 drugs that target this pathway show any differential activity on tumors from patients with RAS mutant rhabdomyosarcomas versus those with wild-type RAS.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (71, 87))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (219, 235))	('tumors', 'Disease', (182, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('sarcomas', 'Phenotype', 'HP:0100242', (228, 236))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (71, 88))	('rhabdomyosarcomas', 'Disease', (71, 88))	('patients', 'Species', '9606', (194, 202))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (71, 88))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (219, 236))	('mutant', 'Var', (212, 218))	('rhabdomyosarcomas', 'Disease', (219, 236))	('RAS', 'Gene', (208, 211))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (219, 236))
199813	25639868	However, clinical genomics will provide a more complete catalog of germline and somatic mutations in pediatric solid tumors and contribute important insights into tumor heterogeneity and the clonal evolution of cancer.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('cancer', 'Disease', (211, 217))	('pediatric solid tumors', 'Disease', (101, 123))	('mutations', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (101, 123))	('tumor', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
199869	26101678	Further, the presence of the translocation t(X:18) on fluorescent in situ hybridization is also confirmatory of synovial sarcoma.	('synovial sarcoma', 'Disease', (112, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (112, 128))	('synovial sarcoma', 'Disease', 'MESH:D013584', (112, 128))	('translocation t', 'Var', (29, 44))
199892	23651186	Recently, we demonstrated that immunoselection by CD8+ T cells of tumor variants lacking strong tumor-specific antigens represents one mechanism by which cancer cells escape tumor immunity and points toward the future of personalized cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('CD8', 'Gene', (50, 53))	('tumor', 'Disease', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('escape', 'NegReg', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (96, 101))	('variants', 'Var', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CD8', 'Gene', '925', (50, 53))	('cancer', 'Disease', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
199905	23651186	It has been proposed that some of these mutations result in the expression of tumor-specific proteins that are, in turn, tumor-specific antigens for T cells.	('result in', 'Reg', (50, 59))	('expression', 'MPA', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('proteins', 'Protein', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
199906	23651186	Recent work from our laboratory used a novel from of exome sequencing (cDNA capture sequencing or cDNA CapSeq) to define the mutational profile of two independent, unedited MCA sarcomas (d42m1 and H31m1).	('H31m1', 'Var', (197, 202))	('d42m1', 'Var', (187, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (177, 185))	('MCA sarcomas', 'Disease', 'MESH:D020244', (173, 185))	('MCA sarcomas', 'Disease', (173, 185))
199907	23651186	By pipelining the sequencing data for one of these tumors (d42m1) into major histocompatibility complex (MHC) class I epitope prediction algorithms, we identified a potential mutational antigen of the unedited d42m1cells, validated its identity as the major rejection antigen using expressing cloning techniques, and showed that antigen loss via a T cell-dependent immunoselection process represents the mechanism underlying cancer immunoediting of this tumor.	('d42m1cells', 'Var', (210, 220))	('tumor', 'Phenotype', 'HP:0002664', (454, 459))	('cancer', 'Phenotype', 'HP:0002664', (425, 431))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('loss', 'NegReg', (337, 341))	('tumor', 'Disease', (454, 459))	('tumor', 'Disease', (51, 56))	('cancer', 'Disease', (425, 431))	('tumors', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (425, 431))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (454, 459))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
199909	23651186	Interestingly, both d42m1 and H31m1 had activating mutations in codon 12 of the Kras proto-oncogene and inactivating mutations in the tumor suppressor gene Trp53.	('activating', 'PosReg', (40, 50))	('Kras', 'Gene', '3845', (80, 84))	('Trp53', 'Gene', '7157', (156, 161))	('H31m1', 'Var', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('d42m1', 'Var', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('inactivating', 'NegReg', (104, 116))	('Trp53', 'Gene', (156, 161))	('Kras', 'Gene', (80, 84))	('tumor', 'Disease', (134, 139))
199910	23651186	When comparing the sequence data of d42m1 and H31m1 sarcoma cells to those of human cancer genomes we found that the former most closely resemble genomes of carcinogen-induced lung cancers from smokers in both the number and type of mutations (e.g., C/A or G/T transversions).	('G/T transversions', 'Var', (257, 274))	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (176, 188))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('sarcoma', 'Disease', (52, 59))	('cancer', 'Disease', (84, 90))	('C/A', 'Var', (250, 253))	('lung cancers', 'Disease', (176, 188))	('lung cancers', 'Disease', 'MESH:D008175', (176, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancer', 'Disease', (181, 187))	('human', 'Species', '9606', (78, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
199914	23651186	Furthermore, cell lines derived from escape tumors of parental d42m1 (d42m1-es1, d42m1-es2, and d42m1-es3) consistently formed progressively growing tumors when transplanted into naive syngeneic recipients.	('d42m1-es2', 'Var', (81, 90))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('d42m1-es3', 'Var', (96, 105))
199917	23651186	To identify tumor-specific antigens for CD8+ T cells, we used the data from the cancer exome mutational analysis to identify the antigenic targets of d42m1-specific CD8+ cytotoxic T lymphocytes (CTLs).	('cancer', 'Disease', (80, 86))	('CD8', 'Gene', '925', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CD8', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CD8', 'Gene', '925', (165, 168))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', (12, 17))	('d42m1-specific', 'Var', (150, 164))	('CD8', 'Gene', (40, 43))
199919	23651186	The d42m1- specific C3 CTL clone was stimulated by parental d42m1 tumor cells and with all regressor d42m1 tumor cell variants; but it was not stimulated by progressor d42m1 tumor cell variants or unrelated MCA sarcoma cells.	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('stimulated', 'PosReg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (66, 71))	('MCA sarcoma', 'Disease', 'MESH:D020244', (207, 218))	('variants', 'Var', (118, 126))	('MCA sarcoma', 'Disease', (207, 218))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
199921	23651186	And together with the fact that recognition of all d42m1 regressor variants by the CTL clone was restricted by H-2Db, we predicted that an R913L mutation in spectrin-beta2 represented the most likely rejection antigen candidate because of its high affinity for H-2Db.	('H-2Db', 'Chemical', '-', (261, 266))	('R913L', 'Var', (139, 144))	('H-2Db', 'Chemical', '-', (111, 116))	('spectrin-beta2', 'Gene', (157, 171))	('R913L', 'Mutation', 'p.R913L', (139, 144))	('spectrin-beta2', 'Gene', '20742', (157, 171))	('affinity', 'Interaction', (248, 256))
199922	23651186	Next, we established that C3 CTL cells could discriminate between the mutant and wild- type spectrin-beta2 peptide sequence 905-913 when presented on H-2Db.	('spectrin-beta2', 'Gene', '20742', (92, 106))	('mutant', 'Var', (70, 76))	('spectrin-beta2', 'Gene', (92, 106))	('H-2Db', 'Chemical', '-', (150, 155))
199923	23651186	To document that the anti-R913L spectrin-beta2 response occurred under physiologic conditions, we used labeled H-2Db tetramers carrying the mutant spectrin-beta2 905-913 peptide to identify tumor antigen specific CD8+ T cells in d42m1 tumors.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('CD8', 'Gene', '925', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('spectrin-beta2', 'Gene', '20742', (32, 46))	('spectrin-beta2', 'Gene', (32, 46))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('CD8', 'Gene', (213, 216))	('d42m1', 'Gene', (229, 234))	('tumor', 'Disease', (190, 195))	('spectrin-beta2', 'Gene', '20742', (147, 161))	('tumors', 'Disease', (235, 241))	('mutant', 'Var', (140, 146))	('R913L', 'Mutation', 'p.R913L', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('spectrin-beta2', 'Gene', (147, 161))	('H-2Db', 'Chemical', '-', (111, 116))	('tumor', 'Disease', (235, 240))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
199924	23651186	Mutant spectrin-beta2-specific CD8+ T cells were detected in parental d42m1 tumors and draining lymph nodes and increased in numbers to peak values just prior to tumor rejection.	('spectrin-beta2', 'Gene', '20742', (7, 21))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('spectrin-beta2', 'Gene', (7, 21))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CD8', 'Gene', (31, 34))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('CD8', 'Gene', '925', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
199926	23651186	These data demonstrate that a mutated gene expressed selectively in unedited d42m1 tumor cells gives rise to a mutant protein that evokes a naturally occurring T cell response in naive wild-type mice.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mice', 'Species', '10090', (195, 199))	('mutant', 'Var', (111, 117))	('tumor', 'Disease', (83, 88))	('T cell response', 'MPA', (160, 175))	('protein', 'Protein', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('evokes', 'Reg', (131, 137))
199927	23651186	Thus, mutant spectrin-beta2 is a genuine tumor-specific antigen of d42m1 sarcoma cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutant', 'Var', (6, 12))	('tumor', 'Disease', (41, 46))	('sarcoma', 'Disease', (73, 80))	('spectrin-beta2', 'Gene', (13, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('spectrin-beta2', 'Gene', '20742', (13, 27))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
199928	23651186	In order to explore whether mutant spectrin-beta2 represented the major rejection antigen of parental d42m1 tumor cells, we enforced expression of either the mutant or wild type forms of spectrin-beta2 into cells of one of the d42m1 escape variants, d42m1-es3.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('spectrin-beta2', 'Gene', '20742', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('spectrin-beta2', 'Gene', '20742', (187, 201))	('tumor', 'Disease', (108, 113))	('spectrin-beta2', 'Gene', (35, 49))	('mutant', 'Var', (158, 164))	('spectrin-beta2', 'Gene', (187, 201))
199930	23651186	In contrast, d42m1-es3 tumor cell clones expressing mutant spectrin-beta2 were rejected in wild-type but not Rag2-/- mice.	('Rag2', 'Gene', (109, 113))	('spectrin-beta2', 'Gene', '20742', (59, 73))	('mutant', 'Var', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('spectrin-beta2', 'Gene', (59, 73))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Rag2', 'Gene', '19374', (109, 113))	('tumor', 'Disease', (23, 28))
199931	23651186	Furthermore, CD8+ T cells specific for mutant spectrin-beta2 were detected by tetramer staining of d42m1-es3 tumors that had been reconstituted with mutant spectrin-beta2.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('CD8', 'Gene', (13, 16))	('CD8', 'Gene', '925', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('spectrin-beta2', 'Gene', '20742', (156, 170))	('spectrin-beta2', 'Gene', '20742', (46, 60))	('mutant', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('spectrin-beta2', 'Gene', (156, 170))	('tumors', 'Disease', (109, 115))	('spectrin-beta2', 'Gene', (46, 60))
199932	23651186	These results demonstrate that expression of mutant spectrin-beta2 is both necessary and sufficient for the rejection of d42m1 tumors, and thus validate it as a major rejection antigen of d42m1 sarcoma cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutant', 'Var', (45, 51))	('spectrin-beta2', 'Gene', '20742', (52, 66))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('spectrin-beta2', 'Gene', (52, 66))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('sarcoma', 'Disease', (194, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))
199934	23651186	This possibility is consistent with our finding that every d42m1 clone that expresses mutant spectrin- beta2 was rejected, while every clone or variant that lacks mutant spectrin-beta2 formed progressively growing tumors.	('spectrin- beta2', 'Gene', (93, 108))	('mutant', 'Var', (86, 92))	('spectrin-beta2', 'Gene', '20742', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('spectrin-beta2', 'Gene', (170, 184))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('tumors', 'Disease', 'MESH:D009369', (214, 220))
199935	23651186	To formally test this hypothesis, we assessed the in vivo behavior of a disproportionate mixture of cells consisting of a majority of highly immunogenic d42m1 tumor cells expressing mutant spectrin-beta2 (i.e., d42m1-T2) and a minority a d42m1 tumor cell clone lacking mutant spectrin-beta2 (i.e., d42m1-T3).	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('spectrin-beta2', 'Gene', (189, 203))	('tumor', 'Disease', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('spectrin-beta2', 'Gene', '20742', (189, 203))	('tumor', 'Disease', (159, 164))	('spectrin-beta2', 'Gene', '20742', (276, 290))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('spectrin-beta2', 'Gene', (276, 290))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mutant', 'Var', (182, 188))
199937	23651186	Furthermore, tumors that grew out in wild-type mice consisted of 98% d42m1-T3 tumor cells and lacked mutant spectrin-beta2.	('tumor', 'Disease', (13, 18))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('spectrin-beta2', 'Gene', '20742', (108, 122))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('spectrin-beta2', 'Gene', (108, 122))	('lacked', 'NegReg', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('d42m1-T3', 'Var', (69, 77))	('mice', 'Species', '10090', (47, 51))
199939	23651186	For d42m1 tumor cells, we show that an immunoselection process acting on an oligoclonal parental tumor cell population leads to the outgrowth of tumor cell variants that lack the major tumor rejection antigen, in this case mutant spectrin-beta2.	('tumor rejection antigen', 'Gene', '55578', (185, 208))	('spectrin-beta2', 'Gene', (230, 244))	('tumor', 'Disease', (185, 190))	('mutant', 'Var', (223, 229))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('oligoclonal parental tumor', 'Disease', 'MESH:D063129', (76, 102))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('outgrowth', 'CPA', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor rejection antigen', 'Gene', (185, 208))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('spectrin-beta2', 'Gene', '20742', (230, 244))	('oligoclonal parental tumor', 'Disease', (76, 102))
199941	23651186	However, this finding does not rule out the possibility that similar immunoediting mechanisms might select for mutations in critical components of the MHC class I antigen processing and presentation pathway, such as the class I heavy chain, beta2 microglobulin, or components of IFN-gamma receptor signaling, all of which are known to regulate tumor cell recognition by tumor-specific CD8+ T cells.	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumor', 'Disease', (344, 349))	('tumor', 'Disease', 'MESH:D009369', (370, 375))	('CD8', 'Gene', (385, 388))	('regulate', 'Reg', (335, 343))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('CD8', 'Gene', '925', (385, 388))	('MHC class I antigen', 'Gene', '100507703', (151, 170))	('beta2 microglobulin', 'Gene', '567', (241, 260))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('tumor', 'Disease', (370, 375))	('MHC class I antigen', 'Gene', (151, 170))	('beta2 microglobulin', 'Gene', (241, 260))
199942	23651186	For cancer, most genome sequencing studies have focused on identifying new driver mutations that promote neoplastic development and metastasis, in the hope of obtaining insights that lead to novel cancer-targeted therapeutics or that provide prognostic value.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('metastasis', 'CPA', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (197, 203))	('neoplastic development', 'CPA', (105, 127))	('mutations', 'Var', (82, 91))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (4, 10))	('promote', 'PosReg', (97, 104))
199943	23651186	However, we have shown that this same technology, when combined with an in silico epitope prediction algorithm, can be used to identify expressed mutations in a cancer cells that result in expression of tumor-specific antigens that can be targets for immune-mediated elimination.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutations', 'Var', (146, 155))	('expression', 'MPA', (189, 199))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (161, 167))
199948	23651186	We suggest that patients who respond to checkpoint blockade immunotherapy may have more immunogenic, tumor- specific mutations, and that these antigens can be identified using cancer exome sequencing and high-throughput bioinformatics; in other words, the genomics approach may provide a mechanism to stratify those patients who would benefit most from this type of therapy.	('mutations', 'Var', (117, 126))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Disease', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('patients', 'Species', '9606', (316, 324))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
199954	23651186	These results thus not only provide definitive evidence for at least one mechanism underlying the cancer immunoediting process, but also demonstrate the key role that tumor-specific mutations play in the development of a tumor's immunogenic phenotype and subsequent fate.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (182, 191))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
199956	23651186	Many factors may contribute to the immunodominance of mutant spectrin-beta2.	('mutant', 'Var', (54, 60))	('spectrin-beta2', 'Gene', (61, 75))	('spectrin-beta2', 'Gene', '20742', (61, 75))
199957	23651186	On the basis of in silico analysis, the mutant 905-913 sequence is predicted to interact with H-2Db with very high affinity in contrast to the corresponding wild-type sequence, which is predicted to bind only weakly.	('H-2Db', 'Chemical', '-', (94, 99))	('H-2Db', 'Protein', (94, 99))	('mutant 905-913', 'Var', (40, 54))	('interact', 'Interaction', (80, 88))
199958	23651186	However, several other factors may also contribute to the immunodominance of mutant spectrin-beta2, including antigen abundance, antigen cross presentability, T cell repertoire, or presence of epitopes recognized by regulatory T cells.	('mutant', 'Var', (77, 83))	('spectrin-beta2', 'Gene', '20742', (84, 98))	('spectrin-beta2', 'Gene', (84, 98))
199962	23651186	We speculate that oncogene-driven models of cancer, which harbor fewer passenger mutations than spontaneous cancers, may not be as readily eradicated or controlled by anti-tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('tumor', 'Disease', (172, 177))	('cancers', 'Disease', (108, 115))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (81, 90))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
199963	23651186	demonstrated a key role of dominant antigens in the cancer immunoediting process by using a sarcoma model driven by Kras activation and Trp53 inactivation.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Trp53', 'Gene', '7157', (136, 141))	('Kras', 'Gene', (116, 120))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('Kras', 'Gene', '3845', (116, 120))	('inactivation', 'Var', (142, 154))	('sarcoma', 'Disease', (92, 99))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('activation', 'PosReg', (121, 131))	('Trp53', 'Gene', (136, 141))
200023	33580206	Consistent with these findings, our results showed that amongst several clinical variables examined, only the presence of microscopic positive margins was independently correlated with worse OS (HR 2.60, 95% CI 1.06-6.36, p = 0.0367) and RFS (HR 3.25, 95% CI 1.43-7.38, p = 0.0047) (Supplementary Fig.	('worse OS', 'Disease', (185, 193))	('men', 'Species', '9606', (289, 292))	('RFS', 'Disease', (238, 241))	('microscopic positive', 'Var', (122, 142))
200066	33580206	Similar to peripheral blood NLR, high tNLR scores conferred worse survival outcomes (OS: HR 2.23, 95% CI 0.98-5.06, p = 0.0551); DSS: HR 2.65, 95% CI 1.11-6.36, p = 0.0286) in this subcohort of patients with both non-metastatic (n = 26) and metastatic disease (n = 9) (Fig.	('DSS', 'Chemical', '-', (129, 132))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (194, 202))	('non-metastatic', 'Disease', (213, 227))	('survival outcomes', 'MPA', (66, 83))	('metastatic disease', 'Disease', (241, 259))	('tNLR', 'Gene', (38, 42))	('worse', 'NegReg', (60, 65))
200069	33580206	In terms of pathway scores, scores for angiogenesis (p = 0.0259), matrix remodeling and metastasis (p = 0.0203), cytokine and chemokine signaling (p = 0.005), and myeloid compartment (p = 0.0068) were all significantly higher in non-responders compared to responders, in keeping with observations with tNLR (Fig.	('cytokine', 'Gene', (113, 121))	('angiogenesis', 'CPA', (39, 51))	('cytokine', 'Gene', '943', (113, 121))	('higher', 'PosReg', (219, 225))	('non-responders', 'Var', (229, 243))	('myeloid compartment', 'CPA', (163, 182))	('men', 'Species', '9606', (178, 181))	('pathway', 'Pathway', (12, 19))
200092	33580206	Confirming our previous result, we showed that high NLR was significantly correlated with worse OS, and could be incorporated into a prognostic score for patient risk stratification.	('high', 'Var', (47, 51))	('patient', 'Species', '9606', (154, 161))	('worse OS', 'Disease', (90, 98))	('NLR', 'Gene', (52, 55))
200096	33580206	Mutations in angiogenesis signaling genes such as KDR, PTPRB, and PLCG1, as well as the expression of angiogenic growth factors are known to occur in angiosarcomas.	('angiosarcomas', 'Disease', (150, 163))	('KDR', 'Gene', '3791', (50, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('PLCG1', 'Gene', (66, 71))	('angiosarcomas', 'Disease', 'MESH:D006394', (150, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('angiosarcomas', 'Phenotype', 'HP:0200058', (150, 163))	('Mutations', 'Var', (0, 9))	('occur', 'Reg', (141, 146))	('PLCG1', 'Gene', '5335', (66, 71))	('KDR', 'Gene', (50, 53))	('PTPRB', 'Gene', (55, 60))	('PTPRB', 'Gene', '5787', (55, 60))	('expression', 'MPA', (88, 98))	('angiosarcoma', 'Phenotype', 'HP:0200058', (150, 162))
200104	33580206	In an ovarian cancer mouse model, the depletion of macrophages with CSF1R inhibitors restored sensitivity to bevacizumab and paclitaxel in the setting of adaptive resistance.	('CSF1R', 'Gene', '12978', (68, 73))	('paclitaxel', 'Chemical', 'MESH:D017239', (125, 135))	('restored', 'PosReg', (85, 93))	('age', 'Gene', (58, 61))	('mouse', 'Species', '10090', (21, 26))	('inhibitors', 'Var', (74, 84))	('sensitivity to bevacizumab', 'MPA', (94, 120))	('bevacizumab', 'Chemical', 'MESH:D000068258', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (6, 20))	('ovarian cancer', 'Phenotype', 'HP:0100615', (6, 20))	('CSF1R', 'Gene', (68, 73))	('age', 'Gene', '5973', (58, 61))	('ovarian cancer', 'Disease', (6, 20))
200399	23661945	Recently, a specific unbalanced translocation, der (17)t (X: 17)(p11;p25), resulting in the formation of ASPL-TFE3 fusion gene has been demonstrated in ASPS.	('TFE3', 'Gene', '7030', (110, 114))	('p25', 'Gene', (69, 72))	('ASPS', 'Gene', (152, 156))	('ASPL', 'Gene', (105, 109))	('p11', 'Gene', (65, 68))	('der (17)t (X: 17', 'Var', (47, 63))	('ASPS', 'Gene', '79058', (152, 156))	('TFE3', 'Gene', (110, 114))	('p25', 'Gene', '11076', (69, 72))	('p11', 'Gene', '6281', (65, 68))	('ASPL', 'Gene', '79058', (105, 109))	('ASPS', 'Phenotype', 'HP:0012218', (152, 156))
200416	21467166	Previous studies showed that introduction of the ApcMin mutation into the Ts65Dn mouse model of DS by interbreeding caused formation of intestinal adenomas at a significantly reduced incidence compared to control (euploid) animals that did not have trisomy.	('ApcMin', 'Gene', (49, 55))	('reduced', 'NegReg', (175, 182))	('intestinal adenomas', 'Disease', (136, 155))	('Ts65Dn', 'Gene', (74, 80))	('intestinal adenomas', 'Disease', 'MESH:D000236', (136, 155))	('Ts65Dn', 'Gene', '21101', (74, 80))	('mouse', 'Species', '10090', (81, 86))	('mutation', 'Var', (56, 64))
200417	21467166	To a large degree, this reduction was determined to reflect an increased dosage of the Ets2 tumor repressor gene due to trisomy.	('increased', 'PosReg', (63, 72))	('Ets2', 'Gene', '23872', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Ets2', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('reduction', 'NegReg', (24, 33))	('dosage', 'MPA', (73, 79))	('trisomy', 'Var', (120, 127))
200419	21467166	To confirm and extend these findings, we employed the complex cancer mouse model, NPcis, which is heterozygous for the Trp53 and Nf1 genes and through loss of heterozygosity develops lymphomas, sarcomas or carcinomas with 100% penetrance.	('loss of heterozygosity', 'Var', (151, 173))	('Nf1', 'Gene', '18015', (129, 132))	('Trp53', 'Gene', '22059', (119, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (183, 191))	('Trp53', 'Gene', (119, 124))	('sarcomas or carcinomas', 'Disease', 'MESH:D012509', (194, 216))	('lymphomas', 'Disease', (183, 192))	('mouse', 'Species', '10090', (69, 74))	('cancer', 'Disease', (62, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('Nf1', 'Gene', (129, 132))	('lymphomas', 'Disease', 'MESH:D008223', (183, 192))	('lymphomas', 'Phenotype', 'HP:0002665', (183, 192))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('sarcomas or carcinomas', 'Disease', (194, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('develops', 'PosReg', (174, 182))
200420	21467166	In this aggressive model, trisomy did not prevent cancer but it nevertheless extended host survival relative to euploid littermates.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('extended', 'PosReg', (77, 85))	('trisomy', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('host survival', 'CPA', (86, 99))
200423	21467166	Down syndrome (DS), a genetic disorder resulting from trisomy for human chromosome 21 (Hsa21), affects all cells in the body.	('human', 'Species', '9606', (66, 71))	('genetic disorder', 'Disease', 'MESH:D030342', (22, 38))	('trisomy', 'Var', (54, 61))	('Hsa21', 'Gene', (87, 92))	('genetic disorder', 'Disease', (22, 38))	('Down syndrome', 'Disease', (0, 13))
200426	21467166	The observation that the incidence of many different types of cancer may be reduced in DS suggests that there might be a general mechanism by which trisomy affects tumorigenesis.	('tumor', 'Disease', (164, 169))	('affects', 'Reg', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('trisomy', 'Var', (148, 155))	('reduced', 'NegReg', (76, 83))	('cancer', 'Disease', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
200434	21467166	Although the role of Rcan1 in regulating VEGF to control angiogenesis has been known for some time, its contributions to this process in trisomic xenografts are unclear because Tc1 mice have normal dosage (2 copies) of Rcan1, but show the same reduction in xenograft angiogenesis as do Ts65Dn mice with three copies.	('Ts65Dn', 'Gene', '21101', (286, 292))	('dosage', 'MPA', (198, 204))	('Rcan1', 'Gene', '54720', (21, 26))	('Tc1', 'Var', (177, 180))	('mice', 'Species', '10090', (181, 185))	('Rcan1', 'Gene', '54720', (219, 224))	('VEGF', 'Gene', '22339', (41, 45))	('Rcan1', 'Gene', (21, 26))	('Rcan1', 'Gene', (219, 224))	('mice', 'Species', '10090', (293, 297))	('reduction', 'NegReg', (244, 253))	('xenograft angiogenesis', 'CPA', (257, 279))	('VEGF', 'Gene', (41, 45))	('Ts65Dn', 'Gene', (286, 292))
200470	21467166	Survival curves for NP and NP65 mice showed that life span was extended significantly in trisomic mice (median survival was 145 and 188 days, log-rank test, P = 2.4e-5, n = 102 and 28, respectively) (Fig.	('life span', 'CPA', (49, 58))	('trisomic', 'Var', (89, 97))	('mice', 'Species', '10090', (32, 36))	('extended', 'PosReg', (63, 71))	('mice', 'Species', '10090', (98, 102))
200471	21467166	Thus, trisomy has a protective effect against mortality from cancer in this complex model.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('trisomy', 'Var', (6, 13))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
200476	21467166	Trisomic female NP65 mice survived significantly longer than did euploid NP females (p<0.0002) (Supplementary Fig.	('NP65', 'Var', (16, 20))	('mice', 'Species', '10090', (21, 25))	('survived', 'CPA', (26, 34))	('longer', 'PosReg', (49, 55))	('Trisomic', 'Var', (0, 8))
200485	21467166	The incidence of sarcoma in trisomic mice was significantly reduced (Fisher's exact test, P = 0.0001).	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcoma', 'Disease', 'MESH:D012509', (17, 24))	('trisomic', 'Var', (28, 36))	('reduced', 'NegReg', (60, 67))	('sarcoma', 'Disease', (17, 24))	('mice', 'Species', '10090', (37, 41))
200486	21467166	Eleven out of 32 (34.4%) tumors were sarcomas in the trisomy group, while in the euploid group, 92 out of 126 (73%) were sarcoma (Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('sarcoma', 'Disease', (121, 128))	('sarcoma', 'Disease', 'MESH:D012509', (37, 44))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('trisomy', 'Var', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('sarcoma', 'Disease', (37, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcomas', 'Disease', (37, 45))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))
200488	21467166	Ts65Dn didn't extend survival of mice with sarcoma (median survival of 142 and 145 days in NP and NP65 respectively, Fig.	('NP65', 'Var', (98, 102))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('mice', 'Species', '10090', (33, 37))	('Ts65Dn', 'Gene', (0, 6))	('sarcoma', 'Disease', (43, 50))	('Ts65Dn', 'Gene', '21101', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
200489	21467166	3), but did extend survival significantly in mice with other cancers (median survival of 178 days and 214 days in NP and NP65, respectively) (Fig.	('mice', 'Species', '10090', (45, 49))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('NP65', 'Var', (121, 125))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
200490	21467166	The median survival time was longer in NP65 than in NP for each non-sarcoma tumor type (Supplementary Table 3).	('survival', 'MPA', (11, 19))	('NP65', 'Var', (39, 43))	('non-sarcoma tumor', 'Disease', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('longer', 'PosReg', (29, 35))	('non-sarcoma tumor', 'Disease', 'MESH:D012509', (64, 81))
200494	21467166	The incidence of adrenal tumors as a percent of total was significantly higher in trisomic NP65 mice compared to euploid (Fisher's exact test, P = 0.0014).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mice', 'Species', '10090', (96, 100))	('NP65', 'Var', (91, 95))	('adrenal tumors', 'Disease', 'MESH:D000310', (17, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('higher', 'PosReg', (72, 78))	('adrenal tumors', 'Disease', (17, 31))	('trisomic NP65', 'Var', (82, 95))
200495	21467166	Among the NP65 group, 11 out of 32 (34.4%) were adrenal tumors while the frequency for euploid mice was 12 out of 126 (10%) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mice', 'Species', '10090', (95, 99))	('adrenal tumors', 'Disease', 'MESH:D000310', (48, 62))	('NP65', 'Var', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('adrenal tumors', 'Disease', (48, 62))
200500	21467166	Trisomy did not significantly alter the incidence of lymphoma (11% in euploid, 18.8% in trisomy, P = 0.24 by Fisher's exact test).	('lymphoma', 'Disease', (53, 61))	('lymphoma', 'Disease', 'MESH:D008223', (53, 61))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('Trisomy', 'Disease', (0, 7))	('trisomy', 'Var', (88, 95))	('Trisomy', 'Disease', 'MESH:D014314', (0, 7))
200509	21467166	Extended survival of NP65 mice compared to their euploid counterparts can be explained in part by the shift in tumor types away from sarcoma and toward adrenal tumors, since median survival time with sarcoma was significantly shorter.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('shorter', 'NegReg', (226, 233))	('adrenal tumors', 'Disease', (152, 166))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('sarcoma', 'Disease', (133, 140))	('NP65', 'Var', (21, 25))	('sarcoma', 'Disease', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('tumor', 'Disease', (111, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('adrenal tumors', 'Disease', 'MESH:D000310', (152, 166))	('tumor', 'Disease', (160, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('mice', 'Species', '10090', (26, 30))
200511	21467166	Tumor mass was highly variable even within a given type of tumor, so although some trends were recognized, tumor size was not significantly different between the NP and NP65 groups (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('NP65', 'Var', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
200512	21467166	Proliferation, measured as percent Ki67+ cells, was significantly reduced in sarcomas that occurred in trisomic mice compared to euploid (P =0.023).	('reduced', 'NegReg', (66, 73))	('Ki67', 'Gene', (35, 39))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('Ki67', 'Gene', '17345', (35, 39))	('trisomic', 'Var', (103, 111))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('mice', 'Species', '10090', (112, 116))
200515	21467166	The average mass of adrenal tumors was somewhat lower in NP65 mice, although this trend was not statistically significant.	('NP65', 'Var', (57, 61))	('adrenal tumors', 'Disease', 'MESH:D000310', (20, 34))	('lower', 'NegReg', (48, 53))	('mass', 'CPA', (12, 16))	('mice', 'Species', '10090', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('adrenal tumors', 'Disease', (20, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
200516	21467166	Extended survival time of trisomic NPcis mice, the observation that trisomic mice carrying the ApcMin mutation form fewer intestinal tumors and the reduction in mortality from cancer in individuals with DS raises the question of whether loss of the extra chromosome is required as an early step in order for cells to become transformed.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('mice', 'Species', '10090', (77, 81))	('reduction', 'NegReg', (148, 157))	('mice', 'Species', '10090', (41, 45))	('mutation', 'Var', (102, 110))	('intestinal tumors', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ApcMin', 'Gene', (95, 101))	('intestinal tumors', 'Disease', 'MESH:D007414', (122, 139))	('fewer', 'NegReg', (116, 121))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
200520	21467166	Since tumors are initiated by loss of heterozygosity, deleting the single copies of these genes, their presence is indicative of contamination of the tumor sample by non-transformed cells.	('deleting', 'Var', (54, 62))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('loss', 'Var', (30, 34))	('tumor', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('heterozygosity', 'MPA', (38, 52))
200529	21467166	Jam2:Apob ratios were 1.1 in euploid and 1.4 in trisomic brain, with a ratio of 1.6 in trisomic tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Apob', 'Gene', (5, 9))	('trisomic brain', 'Disease', (48, 62))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('trisomic tumors', 'Disease', (87, 102))	('Jam2', 'Gene', '67374', (0, 4))	('Jam2', 'Gene', (0, 4))	('Apob', 'Gene', '238055', (5, 9))	('euploid', 'Var', (29, 36))	('trisomic tumors', 'Disease', 'MESH:D009369', (87, 102))
200533	21467166	Even if some cells lose the marker chromosome, the observation that the overall ratio in trisomic tumors is significantly higher than that in euploid in all three comparisons and the results from FISH of primary tumor cells indicate that loss of the extra chromosome is not a necessary or frequent early event in tumors arising from trisomic cells.	('tumors', 'Disease', (98, 104))	('tumor', 'Disease', (313, 318))	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('loss', 'Var', (238, 242))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('trisomic tumors', 'Disease', 'MESH:D009369', (89, 104))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('higher', 'PosReg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('trisomic tumors', 'Disease', (89, 104))	('tumor', 'Disease', (212, 217))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumors', 'Disease', (313, 319))
200535	21467166	NP65 mice provided the opportunity to examine angiogenesis in endogenous tumors arising in NP and NP65 mice, where not only the microenvironment, but also the transformed cells themselves were trisomic.	('NP65', 'Var', (98, 102))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('mice', 'Species', '10090', (5, 9))
200538	21467166	Contrary to expectations from previous xenograft experiments, we observed no difference in MVD between either sarcomas or adrenal tumors that arose in trisomic hosts compared to euploid (Fig.	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcomas or adrenal tumors', 'Disease', 'MESH:D000310', (110, 136))	('trisomic', 'Var', (151, 159))	('sarcomas or adrenal tumors', 'Disease', (110, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
200540	21467166	We performed the xenograft assay using B16F10 cells (ATCC) to produce 14 xenografts in euploid and 16 in Ts65Dn mice.	('Ts65Dn', 'Gene', (105, 111))	('Ts65Dn', 'Gene', '21101', (105, 111))	('B16F10', 'CellLine', 'CVCL:0159', (39, 45))	('euploid', 'Var', (87, 94))	('mice', 'Species', '10090', (112, 116))
200550	21467166	Epidemiological studies of DS suggest that trisomic individuals are protected against multiple types of cancer.	('trisomic', 'Var', (43, 51))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
200557	21467166	Repression of tumorigenesis by trisomy could involve any of a number of mechanisms, and two possible sources of protection have been described previously.	('tumor', 'Disease', (14, 19))	('trisomy', 'Var', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Repression', 'NegReg', (0, 10))
200560	21467166	Instead, we observed that reduced xenograft mass in trisomic hosts was correlated with reduced cell proliferation relative to the same tumors in euploid mice.	('cell proliferation', 'CPA', (95, 113))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('reduced', 'NegReg', (87, 94))	('tumors', 'Disease', (135, 141))	('reduced', 'NegReg', (26, 33))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('trisomic', 'Var', (52, 60))	('mice', 'Species', '10090', (153, 157))	('xenograft mass', 'CPA', (34, 48))
200571	21467166	Lifespan was significantly extended in trisomic mice with a variety of cancers and this extension was independent of known mechanisms of trisomic tumor repression.	('trisomic tumor', 'Disease', 'MESH:D009369', (137, 151))	('Lifespan', 'CPA', (0, 8))	('trisomic', 'Var', (39, 47))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancers', 'Disease', (71, 78))	('mice', 'Species', '10090', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('extended', 'PosReg', (27, 35))	('trisomic tumor', 'Disease', (137, 151))
200605	20634933	For the vast majority of cases, the aetiology is unknown, although there are certain genetic associations, such as the 10% lifetime risk of malignant peripheral nerve sheath tumour (MPNST) in individuals with familial neurofibromatosis, caused by mutations in the NF1 gene.	('NF1', 'Gene', '4763', (264, 267))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('malignant peripheral nerve sheath tumour', 'Disease', 'MESH:D018319', (140, 180))	('familial neurofibromatosis', 'Disease', (209, 235))	('malignant peripheral nerve sheath tumour', 'Disease', (140, 180))	('malignant peripheral nerve sheath tumour', 'Phenotype', 'HP:0100697', (140, 180))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (218, 235))	('MPNST', 'Phenotype', 'HP:0100697', (182, 187))	('caused by', 'Reg', (237, 246))	('mutations', 'Var', (247, 256))	('NF1', 'Gene', (264, 267))	('familial neurofibromatosis', 'Disease', 'MESH:C537392', (209, 235))
200606	20634933	Another example is the increased risk of sarcomas, both bone and soft tissue, in patients who have had a familial retinoblastoma, caused by inherited mutations in the RB gene.	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('patients', 'Species', '9606', (81, 89))	('caused by', 'Reg', (130, 139))	('familial retinoblastoma', 'Disease', (105, 128))	('mutations', 'Var', (150, 159))	('retinoblastoma', 'Phenotype', 'HP:0009919', (114, 128))	('familial retinoblastoma', 'Disease', 'MESH:D012175', (105, 128))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
200607	20634933	Similarly, there is an increased risk of sarcomas, and other cancers in families with Li-Fraumeni syndrome who have inherited mutations in the TP53 tumour suppressor gene.	('TP53', 'Gene', (143, 147))	('tumour', 'Disease', (148, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('TP53', 'Gene', '7157', (143, 147))	('Li-Fraumeni syndrome', 'Disease', (86, 106))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (86, 106))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
200620	20634933	In addition, certain translocation-driven sarcomas have a relatively uniform cellular morphology and, as such, can be misleadingly scored as intermediate, rather than high grade.	('sarcomas', 'Disease', 'MESH:D012509', (42, 50))	('translocation-driven', 'Var', (21, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('sarcomas', 'Disease', (42, 50))
200666	20634933	Pre-operative radiotherapy in limb sarcoma has been shown to be associated with increased postoperative complications compared to the standard postoperative treatment but less late toxicity (reflecting the lower pre-operative dose of 50 Gy compared with the postoperative dose of 66 Gy and a smaller treatment volume), with equivalent tumour control.	('tumour', 'Phenotype', 'HP:0002664', (335, 341))	('equivalent tumour', 'Disease', (324, 341))	('toxicity', 'Disease', 'MESH:D064420', (181, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('toxicity', 'Disease', (181, 189))	('limb sarcoma', 'Disease', (30, 42))	('limb sarcoma', 'Disease', 'MESH:D012509', (30, 42))	('less', 'NegReg', (171, 175))	('radiotherapy', 'Var', (14, 26))	('equivalent tumour', 'Disease', 'MESH:D064386', (324, 341))
200682	20634933	Whilst most events will arise in the first five years following diagnosis, low grade tumours in particular may relapse late.	('low grade', 'Var', (75, 84))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('tumours', 'Disease', (85, 92))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
200775	20634933	Sporadic cases of fibromatosis are commonly liked to mutations in CTNNB1, the gene for beta-catenin.	('fibromatosis', 'Disease', 'MESH:D005350', (18, 30))	('beta-catenin', 'Gene', (87, 99))	('liked', 'Reg', (44, 49))	('mutations', 'Var', (53, 62))	('fibromatosis', 'Disease', (18, 30))	('beta-catenin', 'Gene', '1499', (87, 99))	('CTNNB1', 'Gene', (66, 72))	('CTNNB1', 'Gene', '1499', (66, 72))
200818	28765612	For example, often in drug studies, one studies co-regulation patterns via the differential expression of genes that are induced through a knockdown of separate gene (e.g., PI3K inhibition of BYL719 induces expression of estrogen receptor function in breast cancer).	('induces', 'PosReg', (199, 206))	('PI3K inhibition', 'Var', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('estrogen receptor', 'Gene', (221, 238))	('breast cancer', 'Disease', (251, 264))	('estrogen receptor', 'Gene', '2099', (221, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('expression', 'MPA', (207, 217))	('BYL719', 'Gene', (192, 198))
200862	26929181	The presence of ReT was an independent poor prognostic predictor for DSS, MFS, and LRFS with hazard ratios of 2.02 (95% confidence interval (CI), 1.25-3.26), 1.62 (95% CI, 1.05-2.51) and 1.94 (95% CI, 1.05-3.59), respectively.	('LRFS', 'Disease', (83, 87))	('DSS', 'Chemical', '-', (69, 72))	('MFS', 'Disease', (74, 77))	('DSS', 'Disease', (69, 72))	('presence', 'Var', (4, 12))
200925	26929181	In this regard, this study identified that the proportion of small and superficial tumors was significantly higher in unplanned excisions as compared to planned excisions.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('small', 'Disease', (61, 66))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('unplanned excisions', 'Var', (118, 137))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('higher', 'PosReg', (108, 114))
200955	26189059	CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation.	('formation of vasculogenic structures', 'CPA', (37, 73))	('repressed', 'PosReg', (114, 123))	('facilitated', 'PosReg', (21, 32))	('migration', 'CPA', (124, 133))	('expression', 'Var', (5, 15))	('CD44', 'Gene', '960', (0, 4))	('CD44', 'Gene', '960', (87, 91))	('CD44', 'Gene', (0, 4))	('CD44', 'Gene', (87, 91))	('vascular network formation', 'CPA', (138, 164))
200977	26189059	The observation that tumor cells adopt mechanisms of angiogenic endothelial cells to increase their chances to survive is important and suggests that targeting of CD44 is a promising anti-cancer approach.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CD44', 'Gene', (163, 167))	('tumor', 'Disease', (21, 26))	('targeting', 'Var', (150, 159))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('chances to survive', 'CPA', (100, 118))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('increase', 'PosReg', (85, 93))	('CD44', 'Gene', '960', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
200990	26189059	We also performed qRT-PCR analysis for the CD44 variants and found overexpression of variants 3, 5, 6 and 10 in vasculogenic cells (Figure 2a).	('overexpression', 'PosReg', (67, 81))	('CD44', 'Gene', '960', (43, 47))	('CD44', 'Gene', (43, 47))	('variants', 'Var', (48, 56))
201003	26189059	Using siRNA knockdown, CD44 was suppressed by 50-75% at the RNA level, while surface protein expression was approximately 40% in the EW7 cells (Figure 4a, 4b, 4h).	('CD44', 'Gene', '960', (23, 27))	('surface protein expression', 'MPA', (77, 103))	('EW7', 'CellLine', 'CVCL:1217', (133, 136))	('CD44', 'Gene', (23, 27))	('knockdown', 'Var', (12, 21))	('suppressed', 'NegReg', (32, 42))
201005	26189059	Transferring the transfected cells to Matrigel revealed that patterned vasculogenic network formation by CD44 knockdown EW7 cells was suppressed as networks were less refined compared to those formed by control cells (Figure 4e).	('less', 'NegReg', (162, 166))	('knockdown', 'Var', (110, 119))	('suppressed', 'NegReg', (134, 144))	('networks', 'CPA', (148, 156))	('CD44', 'Gene', (105, 109))	('EW7', 'CellLine', 'CVCL:1217', (120, 123))	('patterned vasculogenic network formation', 'CPA', (61, 101))	('CD44', 'Gene', '960', (105, 109))
201006	26189059	The average mesh area of vascular networks formed by CD44 knockdown EW7 cells was significantly larger compared to the mesh area in vasculogenic structures formed by control cells (Figure 4f, 4i).	('CD44', 'Gene', '960', (53, 57))	('EW7', 'CellLine', 'CVCL:1217', (68, 71))	('CD44', 'Gene', (53, 57))	('mesh area', 'CPA', (12, 21))	('knockdown', 'Var', (58, 67))	('larger', 'PosReg', (96, 102))
201007	26189059	We also counted the number of branch points to validate that sprouting indeed is reduced when CD44 is knocked down in EW7 cells (Figure 4g, 4j).	('CD44', 'Gene', (94, 98))	('knocked down', 'Var', (102, 114))	('sprouting', 'CPA', (61, 70))	('CD44', 'Gene', '960', (94, 98))	('reduced', 'NegReg', (81, 88))	('EW7', 'CellLine', 'CVCL:1217', (118, 121))
201018	26189059	Indeed, knockdown of CD44 resulted in reduced tumor cell migration and suppressed network formation in vitro.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('reduced', 'NegReg', (38, 45))	('knockdown', 'Var', (8, 17))	('CD44', 'Gene', '960', (21, 25))	('tumor', 'Disease', (46, 51))	('CD44', 'Gene', (21, 25))	('network formation in vitro', 'CPA', (82, 108))	('suppressed', 'NegReg', (71, 81))
201034	26189059	Several reports have described the capacity of CD44 variants to promote or increase c-Met activation.	('promote', 'PosReg', (64, 71))	('CD44', 'Gene', '960', (47, 51))	('CD44', 'Gene', (47, 51))	('variants', 'Var', (52, 60))	('c-Met', 'Gene', (84, 89))	('c-Met', 'Gene', '4233', (84, 89))	('increase', 'PosReg', (75, 83))
201041	26189059	Secondly, targeting CD44 would attenuate tumor angiogenesis, thus decreasing blood and nutrient supply to the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('CD44', 'Gene', '960', (20, 24))	('attenuate', 'NegReg', (31, 40))	('targeting', 'Var', (10, 19))	('CD44', 'Gene', (20, 24))	('decreasing', 'NegReg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
201042	26189059	The combination of angiogenesis inhibition and CD44 targeting would prevent resistance, by means of VM, against the angiostatic compound.	('CD44', 'Gene', '960', (47, 51))	('prevent', 'NegReg', (68, 75))	('angiogenesis', 'CPA', (19, 31))	('CD44', 'Gene', (47, 51))	('targeting', 'Var', (52, 61))	('resistance', 'MPA', (76, 86))
201058	26189059	Although various studies have correlated the expression of CD44 to increased tumor malignancy, some studies did not find a positive association between CD44 expression or activation and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('expression', 'Var', (45, 55))	('CD44', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('increased tumor malignancy', 'Disease', 'MESH:D018198', (67, 93))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CD44', 'Gene', '960', (59, 63))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CD44', 'Gene', (59, 63))	('tumor', 'Disease', (77, 82))	('CD44', 'Gene', '960', (152, 156))	('increased tumor malignancy', 'Disease', (67, 93))
201068	26189059	Our findings offer new opportunities for future treatment strategies, as targeting CD44 may not only affect VM, but may also inhibit tumor angiogenesis and target the cancer stem cell population.	('target', 'Reg', (156, 162))	('inhibit', 'NegReg', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('affect', 'Reg', (101, 107))	('CD44', 'Gene', '960', (83, 87))	('tumor', 'Disease', (133, 138))	('targeting', 'Var', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('CD44', 'Gene', (83, 87))
201081	26189059	After trypsinization, cells were fixed in 1% paraformaldehyde for 30 minutes at room temperature and incubated with primary antibodies directed to CD44s or CD44 variants appropriately diluted in PBS/0.1% bovine serum albumin.	('variants', 'Var', (161, 169))	('CD44', 'Gene', (156, 160))	('CD44', 'Gene', '960', (147, 151))	('CD44', 'Gene', (147, 151))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (45, 61))	('bovine', 'Species', '9913', (204, 210))	('CD44', 'Gene', '960', (156, 160))	('PBS', 'Disease', 'MESH:D011535', (195, 198))	('PBS', 'Disease', (195, 198))
201121	33467481	Different OS neoplastic clones develop, during tumor growth, from normal cells that earn the first cancer-promoting mutations to start tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancer', 'Disease', (99, 105))	('mutations', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (47, 52))	('OS', 'Phenotype', 'HP:0002669', (10, 12))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
201124	33467481	The resulting significant genetic instability of operating system cells leads to the development of several different cell types within the same tumor, with consequent changes in cellular behavior.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('genetic instability', 'Var', (26, 45))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('changes', 'Reg', (168, 175))	('leads to', 'Reg', (72, 80))	('cellular behavior', 'MPA', (179, 196))
201125	33467481	These changes may be responsible for the aggressiveness of cancer cells and result in the emergence of resistance to ChT treatment.	('aggressiveness of cancer', 'Disease', 'MESH:D009369', (41, 65))	('resistance to ChT treatment', 'MPA', (103, 130))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('changes', 'Var', (6, 13))	('responsible', 'Reg', (21, 32))	('aggressiveness of cancer', 'Disease', (41, 65))	('aggressiveness', 'Phenotype', 'HP:0000718', (41, 55))
201126	33467481	Several chromosomal and genetic syndromes, like Li-Fraumeni or hereditary retinoblastoma, have been linked to OS as well as 6p21, 8q24, and 12q14 chromosome amplifications and loss of heterozygosity of 10q21.1, described as the most common genomic alteration in OS.	('OS', 'Phenotype', 'HP:0002669', (262, 264))	('Li-Fraumeni or hereditary retinoblastoma', 'Disease', (48, 88))	('retinoblastoma', 'Phenotype', 'HP:0009919', (74, 88))	('genetic syndromes', 'Disease', 'MESH:D030342', (24, 41))	('linked', 'Reg', (100, 106))	('6p21', 'Var', (124, 128))	('loss of heterozygosity', 'Var', (176, 198))	('genetic syndromes', 'Disease', (24, 41))	('8q24', 'Var', (130, 134))	('10q21.1', 'Gene', (202, 209))	('12q14 chromosome amplifications', 'Var', (140, 171))	('OS', 'Phenotype', 'HP:0002669', (110, 112))	('Li-Fraumeni or hereditary retinoblastoma', 'Disease', 'MESH:D012175', (48, 88))
201127	33467481	Mutations in both the p53 or Rb suppressor genes have also been implicated in OS pathogenesis, but without evidence that they impact tumor behavior.	('Rb suppressor genes', 'Gene', (29, 48))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('p53', 'Gene', (22, 25))	('OS', 'Phenotype', 'HP:0002669', (78, 80))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('impact', 'Reg', (126, 132))	('Mutations', 'Var', (0, 9))	('implicated', 'Reg', (64, 74))	('p53', 'Gene', '7157', (22, 25))	('tumor', 'Disease', (133, 138))
201129	33467481	Amplification of Myc, a transcription factor that exerts its effects in the nucleus promoting cell growth and division, has been involved in OS pathogenesis and resistance to chemotherapeutics.	('Amplification', 'Var', (0, 13))	('involved', 'Reg', (129, 137))	('Myc', 'Gene', '4609', (17, 20))	('Myc', 'Gene', (17, 20))	('OS', 'Phenotype', 'HP:0002669', (141, 143))	('cell growth', 'CPA', (94, 105))
201138	33467481	Readjustment of the actin cytoskeleton, crucial for endothelial cell migration, develops via phosphorylation of T cell-specific adapter and interaction with Src, a protein kinase.	('Src', 'Gene', (157, 160))	('phosphorylation', 'Var', (93, 108))	('interaction', 'Interaction', (140, 151))	('Src', 'Gene', '6714', (157, 160))
201150	33467481	Among these are rearrangements resulting from chromothripsis (20-89%) and mutation clusters known as kataegis (50-85% of cases), which result in a significant degree of genomic instability, with a predicted elevated burden of antigens and neoantigens that may provide immunogenic potential in OS.	('OS', 'Phenotype', 'HP:0002669', (293, 295))	('genomic', 'MPA', (169, 176))	('chromothripsis', 'Disease', (46, 60))	('burden', 'MPA', (216, 222))	('rearrangements', 'Var', (16, 30))	('chromothripsis', 'Disease', 'MESH:D000072837', (46, 60))	('mutation clusters', 'Var', (74, 91))
201185	33467481	In addition, dual PI3K/mTOR inhibition has shown promising results in treating OS (Table 1) and this anti-tumor activity can be enhanced by MEK/Erk inhibition.	('Erk', 'Gene', (144, 147))	('MEK', 'Gene', (140, 143))	('MEK', 'Gene', '5609', (140, 143))	('Erk', 'Gene', '5594', (144, 147))	('inhibition', 'Var', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('OS', 'Phenotype', 'HP:0002669', (79, 81))	('tumor', 'Disease', (106, 111))
201194	33467481	miR-26a blocks the Jagged 1/Notch signaling pathway, and Notch2, a key receptor in this pathway that promotes OS cell proliferation, migration, and invasion, is repressed by miR-1296-5p.	('Notch', 'Gene', (57, 62))	('promotes', 'PosReg', (101, 109))	('miR-26a', 'Gene', '407015', (0, 7))	('invasion', 'CPA', (148, 156))	('Notch', 'Gene', '4851;4853;4854;4855', (57, 62))	('Notch', 'Gene', (28, 33))	('miR-26a', 'Gene', (0, 7))	('Jagged 1', 'Gene', (19, 27))	('Notch2', 'Gene', '4853', (57, 63))	('Jagged 1', 'Gene', '182', (19, 27))	('miR-1296-5p', 'Var', (174, 185))	('migration', 'CPA', (133, 142))	('Notch', 'Gene', '4851;4853;4854;4855', (28, 33))	('OS', 'Phenotype', 'HP:0002669', (110, 112))	('blocks', 'NegReg', (8, 14))	('OS cell proliferation', 'CPA', (110, 131))	('miR-1296-5p', 'Chemical', '-', (174, 185))	('Notch2', 'Gene', (57, 63))
201195	33467481	Two other miRNA molecules:miR-34 and miR-200:seem to have an oncosupressor function through Notch1 downregulation and their levels are low in OS.	('OS', 'Phenotype', 'HP:0002669', (142, 144))	('miR-200', 'Var', (37, 44))	('downregulation', 'NegReg', (99, 113))	('levels', 'MPA', (124, 130))	('miR-34', 'Gene', (26, 32))	('oncosupressor function', 'MPA', (61, 83))	('Notch1', 'Gene', (92, 98))	('miR-34', 'Gene', '407040', (26, 32))	('Notch1', 'Gene', '4851', (92, 98))
201200	33467481	Some have been shown to have a protective role, preventing metastases development such as miR-491 and miR-223-3p, while others promote lung metastases such as miR-19a.	('metastases', 'Disease', 'MESH:D009362', (140, 150))	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('promote', 'PosReg', (127, 134))	('lung metastases', 'Disease', (135, 150))	('miR-19a', 'Gene', (159, 166))	('lung metastases', 'Disease', 'MESH:D009362', (135, 150))	('metastases', 'Disease', (140, 150))	('miR-491', 'Gene', '574444', (90, 97))	('miR-223-3p', 'Var', (102, 112))	('miR-491', 'Gene', (90, 97))	('preventing', 'NegReg', (48, 58))	('metastases', 'Disease', (59, 69))	('miR-19a', 'Gene', '406979', (159, 166))
201202	33467481	Other mechanisms contributing to OS development and progression in which miRNA molecules are involved include microenvironment and extracellular matrix targeting, angiogenesis through dysregulation of VEGF ligands and receptors and IL-6 receptor, and TGF-beta signaling.	('angiogenesis', 'CPA', (163, 175))	('TGF-beta', 'Gene', (251, 259))	('VEGF', 'Gene', (201, 205))	('OS', 'Phenotype', 'HP:0002669', (33, 35))	('TGF-beta', 'Gene', '7039', (251, 259))	('IL-6', 'Gene', (232, 236))	('IL-6', 'Gene', '3569', (232, 236))	('VEGF', 'Gene', '7422', (201, 205))	('dysregulation', 'Var', (184, 197))
201212	33467481	Suppression of this cascade leads to lower levels of Yap1 and its knock-down leads to OS progression inhibition, suggesting that the Hh pathway and Yap1 protein are potential therapeutic targets, along with long-non-coding RNA (lncRNA) H19, which is also abnormally overexpressed in OS tissues.	('Yap1', 'Gene', (53, 57))	('OS', 'Phenotype', 'HP:0002669', (283, 285))	('Yap1', 'Gene', '10413', (53, 57))	('H19', 'Gene', '283120', (236, 239))	('levels', 'MPA', (43, 49))	('OS progression', 'CPA', (86, 100))	('knock-down', 'Var', (66, 76))	('H19', 'Gene', (236, 239))	('Yap1', 'Gene', '10413', (148, 152))	('lower', 'NegReg', (37, 42))	('Yap1', 'Gene', (148, 152))	('OS', 'Phenotype', 'HP:0002669', (86, 88))
201228	33467481	Preclinical studies have shown that Notch1 may be related to chemoresistance, as in vitro regulation of Notch1 (activation/inhibition) altered cisplatin-induced apoptosis, probably through the activity of the Caspase family of proteases.	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('regulation', 'Var', (90, 100))	('Notch1', 'Gene', (104, 110))	('altered', 'Reg', (135, 142))	('Notch1', 'Gene', '4851', (104, 110))	('Notch1', 'Gene', (36, 42))	('cisplatin-induced', 'MPA', (143, 160))	('Notch1', 'Gene', '4851', (36, 42))
201254	33467481	As previously mentioned, the high levels of genomic instability with potentially associated high mutational load in OS have raised interest in targeting immune checkpoint pathways in this tumor.	('tumor', 'Disease', (188, 193))	('genomic instability', 'MPA', (44, 63))	('high', 'Var', (92, 96))	('OS', 'Phenotype', 'HP:0002669', (116, 118))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mutational load', 'MPA', (97, 112))
201442	24455645	Nearly all synovial sarcomas have a specific chromosomal translocation t (X; 18)(p11.2;q11.2).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (11, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (11, 28))	('t (X; 18)(p11.2;q11.2', 'Var', (71, 92))	('synovial sarcomas', 'Disease', 'MESH:D013584', (11, 28))	('synovial sarcomas', 'Disease', (11, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
201462	24455645	Failure to achieve a complete resection, large tumor size (>5 cm), male gender, older age (>20 years) high-grade tumor, presence of necrosis, neurovascular invasion, high mitotic rate (>10 per 10 high power fields), and SYT-SSX1 variant portend a poor prognosis.	('neu', 'Gene', '2064', (142, 145))	('neu', 'Gene', (142, 145))	('tumor', 'Disease', (113, 118))	('SSX1', 'Gene', '6756', (224, 228))	('necrosis', 'Disease', (132, 140))	('variant', 'Var', (229, 236))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('high mitotic rate', 'CPA', (166, 183))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('SYT', 'Gene', '6857', (220, 223))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SSX1', 'Gene', (224, 228))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('necrosis', 'Disease', 'MESH:D009336', (132, 140))	('tumor', 'Disease', (47, 52))	('SYT', 'Gene', (220, 223))
201466	24173190	The definitive diagnosis is made by positivity for the immunohistochemical markers CD163, CD68, CD4 and lysozyme.	('CD4', 'Gene', (96, 99))	('lysozyme', 'Gene', '4069', (104, 112))	('CD68', 'Gene', (90, 94))	('CD4', 'Gene', '920', (96, 99))	('CD68', 'Gene', '968', (90, 94))	('CD163', 'Gene', '9332', (83, 88))	('CD163', 'Gene', (83, 88))	('lysozyme', 'Gene', (104, 112))	('positivity', 'Var', (36, 46))
201503	21559261	While GISTs represent only about 5% of all sarcomas, the efficacy of treatment with KIT kinase small-molecule inhibitors suggests that other kinases may represent targets in more prevalent sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (189, 197))	('sarcomas', 'Disease', (43, 51))	('small-molecule', 'Var', (95, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('sarcomas', 'Disease', (189, 197))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcomas', 'Disease', 'MESH:D012509', (189, 197))
201512	21559261	Mirk knockdown by shRNA or by synthetic RNAi duplexes induced apoptosis in each of 3 osteosarcoma lines tested as well as an osteosarcoma in primary culture.	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('induced', 'Reg', (54, 61))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('knockdown', 'Var', (5, 14))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('apoptosis', 'CPA', (62, 71))	('osteosarcoma', 'Disease', (125, 137))	('Mirk', 'Gene', (0, 4))	('osteosarcoma', 'Disease', 'MESH:D012516', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
201541	21559261	Depletion of Mirk from C2C12 myoblasts also led to an increase in ROS (Deng and Friedman, manuscript in preparation), consistent with ROS control being a major role of Mirk in muscle development and function.	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('ROS', 'Chemical', 'MESH:D017382', (66, 69))	('increase', 'PosReg', (54, 62))	('C2C12', 'Var', (23, 28))	('Mirk', 'Protein', (13, 17))	('Depletion', 'MPA', (0, 9))	('ROS', 'MPA', (66, 69))
201546	21559261	This possibility was tested, and depletion of Mirk increased cellular ROS levels in each of 4 ovarian cancer cell lines.	('ovarian cancer', 'Disease', (94, 108))	('depletion', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Mirk', 'Protein', (46, 50))	('increased', 'PosReg', (51, 60))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('increased cellular ROS levels', 'Phenotype', 'HP:0025464', (51, 80))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('cellular ROS levels', 'MPA', (61, 80))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))
201555	21559261	Mirk is activated by oncogenic K-ras and H-ras and is an active kinase in pancreatic cancers, which exhibit a very high rate of K-ras mutation, almost 100% in advanced lesions.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('activated', 'PosReg', (8, 17))	('K-ras', 'Gene', (31, 36))	('K-ras', 'Gene', '3845', (31, 36))	('Mirk', 'Enzyme', (0, 4))	('K-ras', 'Gene', (128, 133))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (74, 92))	('mutation', 'Var', (134, 142))	('K-ras', 'Gene', '3845', (128, 133))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('H-ras', 'Gene', '3265', (41, 46))	('pancreatic cancers', 'Disease', 'MESH:D010190', (74, 92))	('pancreatic cancers', 'Disease', (74, 92))	('H-ras', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
201556	21559261	Mutant K-ras signaling through Mirk/dyrk1B blocked autocrine Hedgehog signaling to Gli1 within pancreatic cancer cells, only allowing Hedgehog signaling to Gli1 in stromal cells, which do not have mutant K-ras.	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('K-ras', 'Gene', '3845', (7, 12))	('Gli1', 'Gene', (83, 87))	('K-ras', 'Gene', (204, 209))	('Gli1', 'Gene', (156, 160))	('blocked', 'NegReg', (43, 50))	('Gli1', 'Gene', '2735', (83, 87))	('K-ras', 'Gene', '3845', (204, 209))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('Gli1', 'Gene', '2735', (156, 160))	('pancreatic cancer', 'Disease', (95, 112))	('Mutant', 'Var', (0, 6))	('Hedgehog signaling', 'MPA', (134, 152))	('K-ras', 'Gene', (7, 12))	('Mirk/dyrk1B', 'Gene', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
201561	21559261	One may be Han11, which binds to Dyrk1A, Dyrk1B/Mirk, the related kinase HIPK2, and the mitogen-activated protein kinase kinase kinase1 (MEKK1).	('HIPK2', 'Gene', (73, 78))	('Han11', 'Gene', '10238', (11, 16))	('mitogen-activated protein kinase kinase kinase1', 'Gene', (88, 135))	('Han11', 'Gene', (11, 16))	('mitogen-activated protein kinase kinase kinase1', 'Gene', '4214', (88, 135))	('Dyrk1A', 'Gene', '1859', (33, 39))	('MEKK1', 'Gene', (137, 142))	('MEKK1', 'Gene', '4214', (137, 142))	('Dyrk1A', 'Gene', (33, 39))	('HIPK2', 'Gene', '28996', (73, 78))	('Dyrk1B/Mirk', 'Var', (41, 52))
201570	30489320	Novel PLAG1 Gene Rearrangement Distinguishes a Subset of Uterine Myxoid Leiomyosarcoma from Other Uterine Myxoid Mesenchymal Tumors Genetic alterations in uterine myxoid leiomyosarcoma are unknown.	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (72, 86))	('PLAG1', 'Gene', (6, 11))	('Tumors', 'Phenotype', 'HP:0002664', (125, 131))	('myxoid leiomyosarcoma', 'Disease', 'MESH:D007890', (163, 184))	('Distinguishes', 'Reg', (31, 44))	('Mesenchymal Tumors', 'Disease', (113, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('PLAG1', 'Gene', '5324', (6, 11))	('Tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Myxoid Leiomyosarcoma', 'Disease', 'MESH:D007890', (65, 86))	('Rearrangement', 'Var', (17, 30))	('Myxoid Leiomyosarcoma', 'Disease', (65, 86))	('myxoid leiomyosarcoma', 'Disease', (163, 184))	('Mesenchymal Tumors', 'Disease', 'MESH:C535700', (113, 131))	('uterine myxoid leiomyosarcoma', 'Phenotype', 'HP:0002891', (155, 184))	('Uterine Myxoid Mesenchymal Tumors', 'Phenotype', 'HP:0000131', (98, 131))	('Uterine Myxoid Leiomyosarcoma', 'Phenotype', 'HP:0002891', (57, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (170, 184))
201578	30489320	Novel TRPS1-PLAG1 or RAD51B-PLAG1 fusions were detected by sequencing in four tumors, three of which were also confirmed by FISH.	('RAD51B', 'Gene', '5890', (21, 27))	('tumors', 'Disease', (78, 84))	('PLAG1', 'Gene', (28, 33))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('PLAG1', 'Gene', '5324', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PLAG1', 'Gene', '5324', (28, 33))	('PLAG1', 'Gene', (12, 17))	('fusions', 'Var', (34, 41))	('detected', 'Reg', (47, 55))	('RAD51B', 'Gene', (21, 27))
201579	30489320	Diffuse PLAG1 expression was seen in seven tumors, including four with PLAG1 rearrangement.	('rearrangement', 'Var', (77, 90))	('PLAG1', 'Gene', '5324', (8, 13))	('PLAG1', 'Gene', '5324', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PLAG1', 'Gene', (8, 13))	('tumors', 'Disease', (43, 49))	('PLAG1', 'Gene', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
201582	30489320	Based on sequencing and FISH results, PLAG1 rearrangements resulting in PLAG1 expression underpin ~25% of myxoid leiomyosarcomas and may serve as a useful diagnostic biomarker.	('myxoid leiomyosarcomas', 'Disease', 'MESH:D007890', (106, 128))	('myxoid leiomyosarcomas', 'Disease', (106, 128))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (113, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('expression', 'MPA', (78, 88))	('PLAG1', 'Gene', (38, 43))	('PLAG1', 'Gene', (72, 77))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (113, 127))	('PLAG1', 'Gene', '5324', (38, 43))	('PLAG1', 'Gene', '5324', (72, 77))	('rearrangements', 'Var', (44, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
201592	30489320	Since gene rearrangements are frequently found among endometrial stromal sarcomas, inflammatory myofibroblastic tumors, and a subset of uterine leiomyomas, we surmise that uterine myxoid leiomyosarcoma could potentially harbor fusions that may serve as diagnostic biomarkers.	('myofibroblastic tumors', 'Disease', (96, 118))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (187, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('gene rearrangements', 'Var', (6, 25))	('myxoid leiomyosarcoma', 'Disease', (180, 201))	('found', 'Reg', (41, 46))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (96, 117))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (96, 118))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (96, 118))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (53, 81))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('uterine myxoid leiomyosarcoma', 'Phenotype', 'HP:0002891', (172, 201))	('leiomyomas', 'Disease', (144, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('endometrial stromal sarcomas', 'Disease', (53, 81))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (136, 154))	('leiomyomas', 'Disease', 'MESH:D007889', (144, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('myxoid leiomyosarcoma', 'Disease', 'MESH:D007890', (180, 201))
201601	30489320	Any tumors found to harbor BCOR and ALK rearrangements were excluded from the study.	('BCOR', 'Gene', '54880', (27, 31))	('tumors', 'Disease', (4, 10))	('ALK', 'Gene', '238', (36, 39))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('BCOR', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('rearrangements', 'Var', (40, 54))	('ALK', 'Gene', (36, 39))
201608	30489320	PLAG1 immunohistochemistry was specifically selected to study PLAG1 expression patterns in tumors harboring or lacking PLAG1 rearrangement by fluorescence in situ hybridization or targeted RNA sequencing.	('tumors', 'Disease', (91, 97))	('PLAG1', 'Gene', (119, 124))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('PLAG1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('PLAG1', 'Gene', (62, 67))	('PLAG1', 'Gene', '5324', (0, 5))	('rearrangement', 'Var', (125, 138))	('PLAG1', 'Gene', '5324', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PLAG1', 'Gene', '5324', (62, 67))
201629	30489320	Rearrangements involving the PLAG1 gene were identified in four of eight (50%) tumors sequenced (cases 1-4) (Table 2).	('Rearrangements', 'Var', (0, 14))	('PLAG1', 'Gene', '5324', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('PLAG1', 'Gene', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
201632	30489320	PLAG1 rearrangement was also confirmed by FISH in three of these tumors for which additional material was available.	('PLAG1', 'Gene', (0, 5))	('rearrangement', 'Var', (6, 19))	('PLAG1', 'Gene', '5324', (0, 5))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
201635	30489320	After exclusion of tumors harboring BCOR and ALK fusions and based on both sequencing and FISH results, PLAG1 rearrangement was found in 4 of 15 (26%) myxoid leiomyosarcomas.	('ALK', 'Gene', '238', (45, 48))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('myxoid leiomyosarcomas', 'Disease', 'MESH:D007890', (151, 173))	('myxoid leiomyosarcomas', 'Disease', (151, 173))	('BCOR', 'Gene', (36, 40))	('found', 'Reg', (128, 133))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (158, 173))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PLAG1', 'Gene', (104, 109))	('ALK', 'Gene', (45, 48))	('rearrangement', 'Var', (110, 123))	('BCOR', 'Gene', '54880', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('PLAG1', 'Gene', '5324', (104, 109))
201637	30489320	Strong nuclear PLAG1 expression in >95% of tumor cells was confirmed in three tumors (cases 1, 2, and 4) harboring PLAG1 rearrangement for which additional tumor tissue material was available (Figure 1).	('tumors', 'Disease', (78, 84))	('PLAG1', 'Gene', '5324', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('PLAG1', 'Gene', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('rearrangement', 'Var', (121, 134))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PLAG1', 'Gene', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (43, 48))	('PLAG1', 'Gene', '5324', (115, 120))
201638	30489320	PLAG1 immunohistochemistry was not performed on the fourth tumor (case 3) harboring TRPS1-PLAG1 fusion for which all available tumor tissue sections were subjected to sequencing.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('PLAG1', 'Gene', (0, 5))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (127, 132))	('fusion', 'Var', (96, 102))	('PLAG1', 'Gene', '5324', (0, 5))	('PLAG1', 'Gene', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('PLAG1', 'Gene', '5324', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
201639	30489320	Moderate to strong nuclear PLAG1 expression in >95% of tumor cells was also seen in 3 of 11 (27%) tumors that lacking gene fusions by targeted RNA sequencing and/or PLAG1, HMGA2, BCOR, and ALK rearrangements by FISH.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumors', 'Disease', (98, 104))	('PLAG1', 'Gene', (165, 170))	('ALK', 'Gene', '238', (189, 192))	('ALK', 'Gene', (189, 192))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('PLAG1', 'Gene', '5324', (165, 170))	('HMGA2', 'Gene', (172, 177))	('PLAG1', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BCOR', 'Gene', (179, 183))	('BCOR', 'Gene', '54880', (179, 183))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('HMGA2', 'Gene', '8091', (172, 177))	('tumor', 'Disease', (55, 60))	('rearrangements', 'Var', (193, 207))	('PLAG1', 'Gene', '5324', (27, 32))
201644	30489320	By targeted RNA sequencing and FISH, we identified PLAG1 gene rearrangements resulting in PLAG1 overexpression in 26% of bona fide myxoid leiomyosarcomas after exclusion of tumors harboring BCOR and ALK rearrangements.	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('PLAG1', 'Gene', '5324', (90, 95))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (138, 152))	('rearrangements', 'Var', (62, 76))	('BCOR', 'Gene', '54880', (190, 194))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('BCOR', 'Gene', (190, 194))	('PLAG1', 'Gene', (51, 56))	('PLAG1', 'Gene', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('overexpression', 'PosReg', (96, 110))	('resulting in', 'Reg', (77, 89))	('ALK', 'Gene', '238', (199, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('ALK', 'Gene', (199, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('myxoid leiomyosarcomas', 'Disease', 'MESH:D007890', (131, 153))	('myxoid leiomyosarcomas', 'Disease', (131, 153))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (138, 153))	('PLAG1', 'Gene', '5324', (51, 56))
201645	30489320	PLAG1 rearrangement may serve as a useful biomarker in distinguishing a significant subset of myxoid leiomyosarcomas from other myxoid uterine mesenchymal tumors.	('PLAG1', 'Gene', (0, 5))	('rearrangement', 'Var', (6, 19))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (143, 161))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (101, 115))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('mesenchymal tumors', 'Disease', (143, 161))	('PLAG1', 'Gene', '5324', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('myxoid leiomyosarcomas', 'Disease', 'MESH:D007890', (94, 116))	('myxoid leiomyosarcomas', 'Disease', (94, 116))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (101, 116))
201646	30489320	Uterine myxoid leiomyosarcomas is one of a variety of soft tissue and salivary gland tumors that often exhibit myxoid matrix and harbor rearrangement of the Pleomorphic Adenoma Gene 1 (PLAG1), a developmentally regulated zinc finger proto-oncogene located on chromosome 8q12.	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (15, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('rearrangement', 'Var', (136, 149))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (70, 91))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (15, 29))	('salivary gland tumors', 'Disease', 'MESH:D008949', (70, 91))	('salivary gland tumors', 'Disease', (70, 91))	('PLAG1', 'Gene', '5324', (185, 190))	('Adenoma', 'Disease', (169, 176))	('Uterine myxoid leiomyosarcomas', 'Phenotype', 'HP:0002891', (0, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('myxoid leiomyosarcomas', 'Disease', 'MESH:D007890', (8, 30))	('myxoid leiomyosarcomas', 'Disease', (8, 30))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('Adenoma', 'Disease', 'MESH:D000236', (169, 176))	('PLAG1', 'Gene', (185, 190))
201647	30489320	PLAG1 rearrangements have been previously reported in pleomorphic adenoma, carcinoma ex-pleomorphic adenoma, skin and soft tissue myoepithelioma, and lipoblastoma.	('lipoblastoma', 'Disease', (150, 162))	('PLAG1', 'Gene', (0, 5))	('rearrangements', 'Var', (6, 20))	('myoepithelioma', 'Disease', 'MESH:D009208', (130, 144))	('reported', 'Reg', (42, 50))	('PLAG1', 'Gene', '5324', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('myoepithelioma', 'Disease', (130, 144))	('pleomorphic adenoma, carcinoma ex-pleomorphic adenoma', 'Disease', 'MESH:D008949', (54, 107))	('lipoblastoma', 'Disease', 'MESH:D062689', (150, 162))
201650	30489320	While LIFR-PLAG1 fusion has been detected in one soft tissue myoepithelioma, the fusion partner has not been identified in the vast majority of skin and soft tissue myoepitheliomas.	('myoepithelioma', 'Disease', 'MESH:D009208', (61, 75))	('myoepitheliomas', 'Disease', 'MESH:D009208', (165, 180))	('PLAG1', 'Gene', (11, 16))	('fusion', 'Var', (17, 23))	('myoepithelioma', 'Disease', (61, 75))	('detected', 'Reg', (33, 41))	('myoepithelioma', 'Disease', 'MESH:D009208', (165, 179))	('PLAG1', 'Gene', '5324', (11, 16))	('myoepithelioma', 'Disease', (165, 179))	('myoepitheliomas', 'Disease', (165, 180))
201656	30489320	Strong and diffuse PLAG1 immunoexpression in all PLAG1-rearranged myxoid leiomyosarcomas tested provides evidence that PLAG1 rearrangement affects PLAG1 transcriptional up-regulation in these tumors.	('PLAG1', 'Gene', (119, 124))	('tumors', 'Disease', (192, 198))	('myxoid leiomyosarcomas', 'Disease', (66, 88))	('up-regulation', 'PosReg', (169, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('myxoid leiomyosarcomas', 'Disease', 'MESH:D007890', (66, 88))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (73, 88))	('PLAG1', 'Gene', '5324', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('PLAG1', 'Gene', '5324', (119, 124))	('PLAG1', 'Gene', (19, 24))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (73, 87))	('PLAG1', 'Gene', (147, 152))	('PLAG1', 'Gene', '5324', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('transcriptional', 'MPA', (153, 168))	('PLAG1', 'Gene', (49, 54))	('rearrangement', 'Var', (125, 138))	('PLAG1', 'Gene', '5324', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
201657	30489320	Diffuse PLAG1 expression in rare myxoid leiomyosarcomas lacking PLAG1 rearrangement may occur as a result of alternate mechanisms such as PLAG1 point mutations or HMGA1 rearrangement that may contribute to PLAG1 transcriptional up-regulation.	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (40, 55))	('PLAG1', 'Gene', (64, 69))	('PLAG1', 'Gene', (138, 143))	('point mutations', 'Var', (144, 159))	('PLAG1', 'Gene', '5324', (8, 13))	('PLAG1', 'Gene', (206, 211))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (40, 54))	('PLAG1', 'Gene', '5324', (64, 69))	('up-regulation', 'PosReg', (228, 241))	('PLAG1', 'Gene', '5324', (138, 143))	('PLAG1', 'Gene', (8, 13))	('transcriptional', 'MPA', (212, 227))	('myxoid leiomyosarcomas', 'Disease', 'MESH:D007890', (33, 55))	('myxoid leiomyosarcomas', 'Disease', (33, 55))	('PLAG1', 'Gene', '5324', (206, 211))	('rearrangement', 'Var', (169, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
201671	30489320	Frequent identification of genetic abnormalities driving oncogenesis, particularly gene fusions, among uterine mesenchymal tumors suggests that molecular methods are increasingly necessary in the routine diagnostic evaluation of these lesions.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('gene fusions', 'Var', (83, 95))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (111, 129))	('genetic abnormalities', 'Disease', 'MESH:D030342', (27, 48))	('mesenchymal tumors', 'Disease', (111, 129))	('genetic abnormalities', 'Disease', (27, 48))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
201674	30489320	Limited clinical history also hinders our ability to draw conclusions regarding the behavior of PLAG1 fusion-positive sarcomas compared to fusion-negative tumors.	('sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('PLAG1', 'Gene', (96, 101))	('hinders', 'NegReg', (30, 37))	('fusion-positive', 'Var', (102, 117))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcomas', 'Disease', (118, 126))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('PLAG1', 'Gene', '5324', (96, 101))
201675	30489320	Despite these limitations, we identified PLAG1 gene rearrangements in a significant subset of uterine myxoid leiomyosarcomas.	('uterine myxoid leiomyosarcoma', 'Phenotype', 'HP:0002891', (94, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('rearrangements', 'Var', (52, 66))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (109, 123))	('PLAG1', 'Gene', (41, 46))	('uterine myxoid leiomyosarcomas', 'Phenotype', 'HP:0002891', (94, 124))	('PLAG1', 'Gene', '5324', (41, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('myxoid leiomyosarcomas', 'Disease', 'MESH:D007890', (102, 124))	('myxoid leiomyosarcomas', 'Disease', (102, 124))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (109, 124))
201678	30489320	Targeted RNA sequencing and FISH are helpful in identifying gene fusions that may aid in the classification of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('gene fusions', 'Var', (60, 72))	('aid', 'Reg', (82, 85))
201698	28158190	Due to methodological limitations (in particular due to the selection process, retrospective analysis ...), none of these studies has conclusively demonstrated the benefits of CPGs in terms of progression-free survival (PFS) and overall survival (OS).	('OS', 'Chemical', '-', (247, 249))	('progression-free survival', 'CPA', (193, 218))	('overall survival', 'CPA', (229, 245))	('CPGs', 'Var', (176, 180))
201746	28158190	In multivariate analysis, surgical conformity significantly improved the PFS of patients with liposarcoma (HR: 0 32; 95% CI [0 16-0 61]), along with age at diagnosis <= 60 years (HR: 0 42; 95% CI [0 21-0 83]), grade (low vs. high, HR: 0 16, 95% CI [0 07-0 37]; intermediate vs. high, HR: 0 8, 95% CI [0 34-1 85]) and tumor site (limbs vs. abdominopelvic and retroperitoneal tumors HR: 0 49, 95% CI [0 24-1 01]; head, neck and thoracic vs. abdominal and retroperitoneal tumors HR: 0 12, 95% CI [0 02-0 93]).	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('patients', 'Species', '9606', (80, 88))	('liposarcoma', 'Phenotype', 'HP:0012034', (94, 105))	('surgical conformity', 'Var', (26, 45))	('liposarcoma', 'Disease', 'MESH:D008080', (94, 105))	('tumors', 'Phenotype', 'HP:0002664', (469, 475))	('tumor', 'Disease', (469, 474))	('tumor', 'Disease', 'MESH:D009369', (469, 474))	('tumor', 'Disease', (374, 379))	('tumor', 'Disease', (317, 322))	('PFS', 'MPA', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (374, 379))	('improved', 'PosReg', (60, 68))	('liposarcoma', 'Disease', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('abdominal and retroperitoneal tumors HR', 'Disease', 'MESH:C535553', (439, 478))	('tumors', 'Phenotype', 'HP:0002664', (374, 380))	('tumor', 'Phenotype', 'HP:0002664', (469, 474))	('abdominopelvic and retroperitoneal tumors HR', 'Disease', 'MESH:D012186', (339, 383))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))
201747	28158190	Multivariate analyses revealed that the OS of STS patients was strongly influenced by adherence to CPGs for surgery (Fig 3A), with an interaction according to the organizational setting in which patients underwent surgery (Fig 3B).	('patients', 'Species', '9606', (50, 58))	('OS', 'Chemical', '-', (40, 42))	('patients', 'Species', '9606', (195, 203))	('adherence', 'Var', (86, 95))	('influenced', 'Reg', (72, 82))
201763	28158190	A recent study using the same methodology conducted on a sample of 151 sarcoma patients prospectively enrolled for two years in an Italian region (Veneto) within the frame of the European CONnective TIssue CAncer NETwork (CONTICANET), demonstrated that incomplete adherence to CPGs for the loco regional treatment of sarcomas was also associated with worse prognosis in patients with localized tumors.	('CAncer', 'Disease', (206, 212))	('sarcomas', 'Disease', 'MESH:D012509', (317, 325))	('CAncer', 'Phenotype', 'HP:0002664', (206, 212))	('sarcoma', 'Disease', (317, 324))	('sarcomas', 'Phenotype', 'HP:0100242', (317, 325))	('sarcomas', 'Disease', (317, 325))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('tumors', 'Phenotype', 'HP:0002664', (394, 400))	('incomplete adherence', 'Var', (253, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (317, 324))	('patients', 'Species', '9606', (370, 378))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('CAncer', 'Disease', 'MESH:D009369', (206, 212))	('localized tumors', 'Disease', 'MESH:D009364', (384, 400))	('CONnective TIssue CAncer', 'Phenotype', 'HP:0100242', (188, 212))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('localized tumors', 'Disease', (384, 400))	('sarcoma', 'Disease', (71, 78))	('patients', 'Species', '9606', (79, 87))	('sarcoma', 'Disease', 'MESH:D012509', (317, 324))
201851	21421714	For the 5 patients with completed studies, the initial transport of 11C-verapamil (K1), which is associated with P-gp activity, ranged from 0.074 to 0.293 mL/g/min (mean, 0.149 mL/g/min; COV, 53%) for the studies before therapy and from 0.038 to 0.093 mL/g/min (mean, 0.069 mL/g/min; COV, 30%) for the studies after therapy.	('P-gp', 'Gene', (113, 117))	('COV', 'Disease', 'None', (187, 190))	('COV', 'Disease', 'None', (284, 287))	('COV', 'Disease', (187, 190))	('11C-verapamil', 'Chemical', '-', (68, 81))	('COV', 'Disease', (284, 287))	('P-gp', 'Gene', '5243', (113, 117))	('patients', 'Species', '9606', (10, 18))	('0.074', 'Var', (140, 145))
201982	32022102	Three MRI sequences are commonly used in clinical practice for cases of bone sarcoma: T1WI, T2WI with fat suppression, and T1WI FS GD.	('bone sarcoma', 'Disease', 'MESH:D012509', (72, 84))	('T1WI', 'Var', (86, 90))	('FS GD', 'Disease', 'MESH:D018223', (128, 133))	('bone sarcoma', 'Disease', (72, 84))	('fat suppression', 'MPA', (102, 117))	('T2WI', 'Var', (92, 96))	('FS GD', 'Disease', (128, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('bone sarcoma', 'Phenotype', 'HP:0002669', (72, 84))
202015	32022102	studied a model of osteosarcoma xenograft in mice and response after MK1175 and gemcitabine therapy.	('osteosarcoma xenograft', 'Disease', 'MESH:D012516', (19, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('gemcitabine', 'Chemical', 'MESH:C056507', (80, 91))	('osteosarcoma xenograft', 'Disease', (19, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('MK1175', 'Var', (69, 75))
202173	31016866	Patients were required to have adequate bone marrow, liver, and renal function (absolute neutrophil count [ANC] >1500/mm3, platelet count > 100 000/mm3, total bilirubin <1.5 x ULN, ALT or AST < 2.5 x ULN [upper limit of normal; for subjects with documented liver metastases, ALT and AST < 5 x ULN], serum creatinine < 1.5 x ULN, international normalized ratio [INR] or activated partial thromboplastin time [PTT] <=1.5 x ULN, if not therapeutically anticoagulated and serum albumin > 3.0 gm/dL).	('bone marrow', 'Disease', (40, 51))	('liver metastases', 'Disease', (257, 273))	('bone marrow', 'Disease', 'MESH:D001855', (40, 51))	('activated partial thromboplastin time', 'MPA', (369, 406))	('liver metastases', 'Disease', 'MESH:D009362', (257, 273))	('Patients', 'Species', '9606', (0, 8))	('activated partial thromboplastin time', 'Phenotype', 'HP:0003645', (369, 406))	('> 100 000/mm3', 'Var', (138, 151))	('international normalized ratio [', 'MPA', (329, 361))	('serum creatinine', 'MPA', (299, 315))
202210	31016866	GPX-150 was not associated with significant alopecia or mucositis beyond grade 1 or with grade 3 or 4 nausea and vomiting.	('mucositis', 'Disease', (56, 65))	('vomiting', 'Phenotype', 'HP:0002013', (113, 121))	('GPX-150', 'Var', (0, 7))	('nausea', 'Disease', (102, 108))	('alopecia', 'Disease', 'MESH:D000505', (44, 52))	('nausea', 'Phenotype', 'HP:0002018', (102, 108))	('vomiting', 'Disease', (113, 121))	('mucositis', 'Disease', 'MESH:D052016', (56, 65))	('nausea', 'Disease', 'MESH:D009325', (102, 108))	('vomiting', 'Disease', 'MESH:D014839', (113, 121))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (102, 121))	('alopecia', 'Disease', (44, 52))	('GPX-150', 'Chemical', 'MESH:C000604876', (0, 7))	('alopecia', 'Phenotype', 'HP:0001596', (44, 52))
202228	31016866	Table 5 shows the IC50 values for DOX and GPX-150 to inhibit topoisomerase IIalpha and IIbeta.	('topoisomerase IIalpha', 'Enzyme', (61, 82))	('GPX-150', 'Chemical', 'MESH:C000604876', (42, 49))	('inhibit', 'NegReg', (53, 60))	('DOX', 'Chemical', 'MESH:D004317', (34, 37))	('GPX-150', 'Var', (42, 49))	('IIbeta', 'Enzyme', (87, 93))
202231	31016866	Thus, utilizing this methodology up to the concentration of 100 mumol/L, GPX-150 was selective to inhibit topoisomerase IIalpha while DOX inhibited both topoisomerase IIalpha and IIbeta isoforms.	('topoisomerase IIalpha', 'Enzyme', (106, 127))	('GPX-150', 'Chemical', 'MESH:C000604876', (73, 80))	('DOX', 'Chemical', 'MESH:D004317', (134, 137))	('inhibit', 'NegReg', (98, 105))	('GPX-150', 'Var', (73, 80))	('inhibited', 'NegReg', (138, 147))
202256	31016866	Despite some subjects receiving GPX-150 for up to 16 cycles, effects on cardiac function were of no clinical significance and there was no evidence of irreversible heart failure in any subject.	('cardiac function', 'MPA', (72, 88))	('heart failure', 'Disease', 'MESH:D006333', (164, 177))	('GPX-150', 'Chemical', 'MESH:C000604876', (32, 39))	('heart failure', 'Disease', (164, 177))	('GPX-150', 'Var', (32, 39))	('heart failure', 'Phenotype', 'HP:0001635', (164, 177))
202291	30237969	A total number of 8394 bone malignancies (C40 and C41codes of the International Classification of Disease, 10th revision (ICD-10) constituting approximately 1.2% of all cancers were registered in the NCRP.	('cancers', 'Disease', (169, 176))	('bone malignancies', 'Phenotype', 'HP:0010622', (23, 40))	('bone malignancies', 'Disease', (23, 40))	('C41codes', 'Var', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('C40', 'Gene', (42, 45))	('bone malignancies', 'Disease', 'MESH:D001859', (23, 40))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('C40', 'Gene', '55571', (42, 45))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
202325	29952132	Importantly, 50 muCi of 211At-OTSA101 suppressed tumor growth immediately after injection, whereas this effect required several days in the case of 90Y-OTSA101.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('suppressed', 'NegReg', (38, 48))	('tumor', 'Disease', (49, 54))	('211At-OTSA101', 'Var', (24, 37))
202346	29952132	Radioimmunotherapy was performed as described previously.14 Briefly, SS xenograft mice received a single injection of 12.5, 25 or 50 muCi of 211At-OTSA101 or 90Y-OTSA101 into the tail vein.	('211At-OTSA101', 'Var', (141, 154))	('90Y-OTSA101', 'Var', (158, 169))	('SS', 'Phenotype', 'HP:0012570', (69, 71))	('mice', 'Species', '10090', (82, 86))
202349	29952132	The tumor-absorbed and tissue-absorbed doses for radiolabeled antibodies were estimated from the biodistribution data as previously described.19 Briefly, the area under the curve (AUC) was calculated based on the biodistribution data and the absorbed dose was then estimated using the AUC and the mean energy emitted per transition of 90Y, or 211At and a daughter nuclide 211Po with a correction for the branching ratio.20  Histological analyses were performed as described previously.19 Briefly, SS xenografts were sampled from the model mice at 1, 3 and 7 days post-injection with either 211At-OTSA101 (50 muCi) or 90Y-OTSA101 (50 muCi) and fixed with 10% (v/v) formalin and embedded in paraffin.	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (539, 543))	('SS', 'Phenotype', 'HP:0012570', (497, 499))	('formalin', 'Chemical', 'MESH:D005557', (664, 672))	('90Y-OTSA101', 'Var', (617, 628))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('paraffin', 'Chemical', 'MESH:D010232', (689, 697))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('211At-OTSA101', 'Var', (590, 603))
202354	29952132	We observed increased tumor uptake for both of the radiolabeled OTSA101 molecules over time but to different maximum levels of 5.1 +- 1.9%ID/g up to 1-day post-injection for 211At-OTSA101 compared with 14.6 +- 3.3%ID/g for 111In-OTSA101 at the same timepoint.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('increased', 'PosReg', (12, 21))	('tumor', 'Disease', (22, 27))	('211At-OTSA101', 'Var', (174, 187))
202356	29952132	Figure 2 shows the measured therapeutic efficacy (ie tumor suppression and survival time) of RIT using 211At-OTSA101 and 90Y-OTSA101.	('survival time', 'CPA', (75, 88))	('211At-OTSA101', 'Var', (103, 116))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
202357	29952132	A single injection of 25 and 50 muCi of 211At-OTSA101 and of 50 muCi of 90Y-OTSA101 significantly suppressed the growth of SYO-1 xenografts compared to treatment with intact OTSA101 in our SS mouse model.	('SYO-1', 'Gene', '55027', (123, 128))	('mouse', 'Species', '10090', (192, 197))	('suppressed', 'NegReg', (98, 108))	('SS', 'Phenotype', 'HP:0012570', (189, 191))	('SYO-1', 'Gene', (123, 128))	('211At-OTSA101', 'Var', (40, 53))	('growth', 'CPA', (113, 119))
202358	29952132	Twenty-five muCi of 90Y-OTSA101 and 12.5 muCi each of both types of radiolabeled OTSA101 moderately suppressed the SS tumor growth but not to a significant level.	('SS', 'Phenotype', 'HP:0012570', (115, 117))	('90Y-OTSA101', 'Var', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('suppressed', 'NegReg', (100, 110))	('SS tumor', 'Disease', (115, 123))	('SS tumor', 'Disease', 'MESH:D009369', (115, 123))
202359	29952132	Notably, SYO-1 tumors treated with a 50 muCi dose of 211At-OTSA101 suppressed tumor growth immediately after injection, whereas tumors continued to grow after a 50-muCi injection of 90Y-OTSA101 and only started to shrink from several days after this treatment.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('SYO-1 tumors', 'Disease', 'MESH:D009369', (9, 21))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (15, 21))	('211At-OTSA101', 'Var', (53, 66))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (128, 133))	('suppressed', 'NegReg', (67, 77))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('SYO-1 tumors', 'Disease', (9, 21))
202366	29952132	The tumor absorbed doses up to 1-day post-injection were almost equivalent for 211At-OTSA101 and 90Y-OTSA101 at 3.3 and 3.0 Gy, respectively.	('211At-OTSA101', 'Var', (79, 92))	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
202377	29952132	Spindle cell proliferation was found in tumors treated with both alpha-RIT and beta-RIT by day 7 post-injection, although there were still some damaged cells observed (Figure 4F,G).	('alpha-RIT', 'Var', (65, 74))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('alpha-RIT', 'Chemical', '-', (65, 74))	('beta-RIT', 'Chemical', '-', (79, 87))	('beta-RIT', 'Var', (79, 87))	('Spindle cell proliferation', 'CPA', (0, 26))	('tumors', 'Disease', (40, 46))
202379	29952132	We found in our present analyses that 211At-OTSA101, an alpha-emitting anti-FZD10 antibody, effectively suppresses the growth of SS xenografts in a mouse model without apparent toxicity.	('suppresses', 'NegReg', (104, 114))	('FZD10', 'Gene', '93897', (76, 81))	('211At-OTSA101', 'Var', (38, 51))	('toxicity', 'Disease', (177, 185))	('FZD10', 'Gene', (76, 81))	('SS', 'Phenotype', 'HP:0012570', (129, 131))	('mouse', 'Species', '10090', (148, 153))	('toxicity', 'Disease', 'MESH:D064420', (177, 185))	('growth of', 'CPA', (119, 128))
202382	29952132	Our current data show that a 25-muCi dose of 211At-OTSA101 significantly suppresses SS tumor growth but that this does not occur with the same dose of 90Y-OTSA101, a beta-emitting anti-FZD10 antibody.	('SS tumor', 'Disease', (84, 92))	('SS tumor', 'Disease', 'MESH:D009369', (84, 92))	('SS', 'Phenotype', 'HP:0012570', (84, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('211At-OTSA101', 'Var', (45, 58))	('FZD10', 'Gene', '93897', (185, 190))	('FZD10', 'Gene', (185, 190))	('suppresses', 'NegReg', (73, 83))
202383	29952132	Our biodistribution data indicate that both 111In-OTSA101 and 211At-OTSA101 have similar pharmacokinetics in SS xenograft mice other than in the stomach.	('mice', 'Species', '10090', (122, 126))	('111In-OTSA101', 'Var', (44, 57))	('SS', 'Phenotype', 'HP:0012570', (109, 111))	('211At-OTSA101', 'Var', (62, 75))
202384	29952132	The tumor uptake of 211At-OTSA101 was found to be approximately 3-fold lower than that of the 111In-anti-FZD10 antibody at 1-day post-injection.	('tumor', 'Disease', (4, 9))	('FZD10', 'Gene', '93897', (105, 110))	('FZD10', 'Gene', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('lower', 'NegReg', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('211At-OTSA101', 'Var', (20, 33))
202386	29952132	Consistent with these observations, our histopathological analyses indicated more severe tumoricidal effects at an earlier stage of alpha-RIT with 211At-OTSA101 compared with beta-RIT using 90Y-OTSA101.	('alpha-RIT', 'Chemical', '-', (132, 141))	('beta-RIT', 'Chemical', '-', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('211At-OTSA101', 'Var', (147, 160))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
202387	29952132	These dramatic tumoricidal effects were assumed to be complete even at 1 day after 211At-OTSA101 injection, while only relatively mild pathological changes were observed in the SS xenografts at 1 day after the administration of 90Y-OTSA101.	('211At-OTSA101', 'Var', (83, 96))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('SS', 'Phenotype', 'HP:0012570', (177, 179))
202388	29952132	Interestingly, our calculations showed that the absorbed dose by the SS tumor cells up to 1-day post-injection was almost equivalent between 211At-OTSA101 (3.3 Gy) and 90Y-OTSA101 (3.0 Gy).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('211At-OTSA101', 'Var', (141, 154))	('90Y-OTSA101', 'Var', (168, 179))	('SS tumor', 'Disease', (69, 77))	('SS tumor', 'Disease', 'MESH:D009369', (69, 77))	('SS', 'Phenotype', 'HP:0012570', (69, 71))
202390	29952132	Notably, the tumor vessels in our model mice were little affected by 211At-OTSA101 at day 1, suggesting that this radiolabeled antibody specifically targets SS cells that are positive for FZD10.	('tumor', 'Disease', (13, 18))	('211At-OTSA101', 'Var', (69, 82))	('SS', 'Phenotype', 'HP:0012570', (157, 159))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('FZD10', 'Gene', '93897', (188, 193))	('FZD10', 'Gene', (188, 193))	('mice', 'Species', '10090', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
202391	29952132	No apparent systemic toxicities were evident in our model mice treated with 211At-OTSA101, although the calculated absorbed doses were considerably higher in all tissues examined at 1 day after the injection of 211At-OTSA101 compared with 90Y-OTSA101.	('toxicities', 'Disease', (21, 31))	('211At-OTSA101', 'Var', (76, 89))	('211At-OTSA101', 'Var', (211, 224))	('mice', 'Species', '10090', (58, 62))	('toxicities', 'Disease', 'MESH:D064420', (21, 31))	('absorbed doses', 'MPA', (115, 129))	('higher', 'PosReg', (148, 154))
202392	29952132	The body weights of the mice tended to be lower in the groups treated with both 211At-OTSA101 and 90Y-OTSA101 compared to the control mice, but no severe body weight loss was observed in the RIT groups and all varied within a normal range.	('mice', 'Species', '10090', (134, 138))	('severe body weight loss', 'Phenotype', 'HP:0001525', (147, 170))	('weight loss', 'Disease', 'MESH:D015431', (159, 170))	('mice', 'Species', '10090', (24, 28))	('lower', 'NegReg', (42, 47))	('211At-OTSA101', 'Var', (80, 93))	('weight loss', 'Disease', (159, 170))	('body weights', 'CPA', (4, 16))	('weight loss', 'Phenotype', 'HP:0001824', (159, 170))
202394	29952132	Previous studies have also reported that alpha-RIT is superior to beta-RIT in treating solid tumors because alpha-particles with a higher LET may have huge advantages in terms of cytotoxicity compared to beta-particles with a lower LET.15, 16 Given that solid tumors including SS lesions are generally chemo-resistant and radio-resistant, alpha-RIT using 211At-OTSA101 could become a more viable therapeutic option than beta-RIT with 90Y-OTSA101 for the treatment of SS, especially in cases of unresectable, conventional chemotherapy or radiotherapy-resistant lesions.	('beta-RIT', 'Chemical', '-', (420, 428))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('211At-OTSA101', 'Var', (355, 368))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))	('SS', 'Phenotype', 'HP:0012570', (277, 279))	('SS', 'Phenotype', 'HP:0012570', (467, 469))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('cytotoxicity', 'Disease', (179, 191))	('solid tumors', 'Disease', (87, 99))	('solid tumors', 'Disease', (254, 266))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('beta-RIT', 'Chemical', '-', (66, 74))	('alpha-RIT', 'Chemical', '-', (339, 348))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('cytotoxicity', 'Disease', 'MESH:D064420', (179, 191))	('alpha-RIT', 'Chemical', '-', (41, 50))	('solid tumors', 'Disease', 'MESH:D009369', (254, 266))
202396	29952132	Although our present analyses indicate that alpha-RIT using 211At-OTSA101 has therapeutic potential for the treatment of SS, there were several noteworthy limitations of our current study.	('alpha-RIT', 'Protein', (44, 53))	('SS', 'Phenotype', 'HP:0012570', (121, 123))	('alpha-RIT', 'Chemical', '-', (44, 53))	('211At-OTSA101', 'Var', (60, 73))
202400	29952132	In conclusion, alpha-RIT using 211At-OTSA101 effectively suppresses the growth of SS xenografts in a preclinical mouse model with no apparent toxicities and with more efficiency than beta-RIT using 211Y-OTSA101.	('alpha-RIT', 'Chemical', '-', (15, 24))	('211At-OTSA101', 'Var', (31, 44))	('growth of', 'CPA', (72, 81))	('suppresses', 'NegReg', (57, 67))	('SS', 'Phenotype', 'HP:0012570', (82, 84))	('toxicities', 'Disease', (142, 152))	('toxicities', 'Disease', 'MESH:D064420', (142, 152))	('mouse', 'Species', '10090', (113, 118))	('beta-RIT', 'Chemical', '-', (183, 191))
202479	25536954	Phase I Study of Oral Abexinostat, a Histone Deacetylase Inhibitor, in Combination with Doxorubicin in Patients with Metastatic Sarcoma Several inhibitors of histone deacetylase have been shown to enhance chemotherapy induced apoptosis and reduce sarcoma tumor volume in preclinical models.	('sarcoma tumor', 'Disease', (247, 260))	('histone deacetylase', 'Gene', '9734', (158, 177))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('Metastatic Sarcoma', 'Disease', 'MESH:C538445', (117, 135))	('Sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Doxorubicin', 'Chemical', 'MESH:D004317', (88, 99))	('histone deacetylase', 'Gene', (158, 177))	('Metastatic Sarcoma', 'Disease', (117, 135))	('inhibitors', 'Var', (144, 154))	('reduce', 'NegReg', (240, 246))	('Histone Deacetylase', 'Gene', (37, 56))	('sarcoma tumor', 'Disease', 'MESH:D012509', (247, 260))	('enhance', 'PosReg', (197, 204))	('chemotherapy induced apoptosis', 'CPA', (205, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (247, 254))	('Patients', 'Species', '9606', (103, 111))	('Histone Deacetylase', 'Gene', '9734', (37, 56))
202563	25536954	HDAC inhibitors can increase accessibility of cytotoxic agents to DNA by altering chromatin structure, thereby allowing DNA alkylating and intercalating agents to interact with DNA more directly.	('HDAC', 'Gene', (0, 4))	('accessibility', 'MPA', (29, 42))	('chromatin structure', 'MPA', (82, 101))	('HDAC', 'Gene', '9734', (0, 4))	('inhibitors', 'Var', (5, 15))	('altering', 'Reg', (73, 81))	('increase', 'PosReg', (20, 28))
202564	25536954	HDAC inhibition has been shown in vitro to enhance the toxicity of several anticancer drugs that target DNA (e.g., etoposide, doxorubicin, cisplatin).	('HDAC', 'Gene', (0, 4))	('etoposide', 'Chemical', 'MESH:D005047', (115, 124))	('doxorubicin', 'MPA', (126, 137))	('HDAC', 'Gene', '9734', (0, 4))	('inhibition', 'Var', (5, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('toxicity', 'Disease', 'MESH:D064420', (55, 63))	('toxicity', 'Disease', (55, 63))	('doxorubicin', 'Chemical', 'MESH:D004317', (126, 137))	('enhance', 'PosReg', (43, 50))
202591	25686274	Doxorubicin and ifosfamide have shown consistent activity, and recently, the anti-angiogenic agent, pazopanib, has been approved based on the results of a randomized, placebo-controlled phase III trial showing a significant, but modest, benefit in progression-free survival (PFS) for patients treated with pazopanib.	('activity', 'MPA', (49, 57))	('patients', 'Species', '9606', (284, 292))	('progression-free survival', 'CPA', (248, 273))	('pazopanib', 'Chemical', 'MESH:C516667', (100, 109))	('pazopanib', 'Chemical', 'MESH:C516667', (306, 315))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('ifosfamide', 'Chemical', 'MESH:D007069', (16, 26))	('pazopanib', 'Var', (306, 315))
202597	25686274	Evidence shows that disruption of DNA by trabectedin ultimately causes apoptosis and sensitization of cancer cells to Fas-mediated cell death.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('causes', 'Reg', (64, 70))	('apoptosis', 'CPA', (71, 80))	('disruption', 'Var', (20, 30))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('sensitization', 'CPA', (85, 98))	('trabectedin', 'Chemical', 'MESH:D000077606', (41, 52))
202602	25686274	The most common translocation in the disease is t(12;16)(q13;p11), creating a FUS-CHOP fusion gene, and rarely, a t(12;22)(q13;q12) translocation takes place resulting in a EWS-CHOP fusion gene.	('CHOP', 'Gene', '1649', (177, 181))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (114, 131))	('t(12;16)(q13;p11', 'Var', (48, 64))	('CHOP', 'Gene', '1649', (82, 86))	('CHOP', 'Gene', (177, 181))	('CHOP', 'Gene', (82, 86))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (48, 65))
202641	25686274	Another phase III trial randomized 121 patients with translocation-related sarcomas to receive trabectedin or doxorubicin in the first-line setting with progression-free survival as the primary end point.	('sarcomas', 'Disease', (75, 83))	('patients', 'Species', '9606', (39, 47))	('translocation-related', 'Var', (53, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (110, 121))	('trabectedin', 'Chemical', 'MESH:D000077606', (95, 106))	('sarcomas', 'Disease', 'MESH:D012509', (75, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
202643	25686274	The response rate according to RECIST 1.0 was significantly higher in the doxorubicin (27%) compared to the trabectedin (5.9%) arm of the trial.	('trabectedin', 'Chemical', 'MESH:D000077606', (108, 119))	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('higher', 'PosReg', (60, 66))	('response', 'MPA', (4, 12))	('doxorubicin', 'Var', (74, 85))
202774	23346417	In this regard, endothelial, mesodermal, epithelial, neural, and mesenchymal cells have all been hypothesized as an origin, but there is substantial research indicating that mesenchymal stem cells (MSC) may be the original progenitor of Ewing tumor proliferation, and Ewing tumors most often harbor nonrandom balanced chromosomal translocations of the EWS gene on chromosome 22 and any one of several ETS family genes.	('Ewing tumor', 'Phenotype', 'HP:0012254', (268, 279))	('EWS', 'Gene', (352, 355))	('Ewing tumors', 'Disease', (268, 280))	('Ewing tumor', 'Disease', (237, 248))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('Ewing tumor', 'Disease', 'MESH:C563168', (237, 248))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('harbor', 'Reg', (292, 298))	('nonrandom balanced chromosomal translocations', 'Var', (299, 344))	('Ewing tumors', 'Disease', 'MESH:C563168', (268, 280))	('Ewing tumor', 'Disease', 'MESH:C563168', (268, 279))	('Ewing tumors', 'Phenotype', 'HP:0012254', (268, 280))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('Ewing tumor', 'Phenotype', 'HP:0012254', (237, 248))
202775	23346417	Since the t(11;22)(q24;12) translocation is most frequent, its protein product has been suggested as a main component of ES malignancies.	('ES malignancies', 'Disease', (121, 136))	('ES', 'Phenotype', 'HP:0012254', (121, 123))	('ES malignancies', 'Disease', 'MESH:C563168', (121, 136))	('t(11;22)(q24;12', 'Var', (10, 25))
202778	23346417	suggests that Ewing's sarcoma is characterized by EWS fusions with FLI1 in 90-95% of cases, ERG in 5-10% of cases, and that FEV, ETV1, and ETV4 fusions occur in less than 1% of cases.	('ETV1', 'Gene', '2115', (129, 133))	("Ewing's sarcoma", 'Disease', (14, 29))	('fusions', 'Var', (54, 61))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (14, 29))	('ETV1', 'Gene', (129, 133))	('ETV4', 'Gene', (139, 143))	('FLI1', 'Gene', (67, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('ETV4', 'Gene', '2118', (139, 143))
202780	23346417	On the other hand, EWS-FLI1 tends to suppress genes involved in apoptosis and cell cycle arrest including IGFBP3, p57kip, p21, and TGFB2.	('IGFBP3', 'Gene', (106, 112))	('p21', 'Gene', (122, 125))	('p21', 'Gene', '644914', (122, 125))	('apoptosis', 'CPA', (64, 73))	('IGFBP3', 'Gene', '3486', (106, 112))	('suppress', 'NegReg', (37, 45))	('TGFB2', 'Gene', '7042', (131, 136))	('genes', 'MPA', (46, 51))	('p57kip', 'Var', (114, 120))	('TGFB2', 'Gene', (131, 136))	('cell cycle arrest', 'CPA', (78, 95))
202781	23346417	There are also a number of secondary events, such as mutations of p53, which have been correlated with prognosis.	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (66, 69))	('mutations', 'Var', (53, 62))
202798	23346417	Therapeutics based on antisense cDNA and siRNA have been shown to reduce EWS-FLI1 expression and increase survival rates in mice with ESFTs present.	('increase', 'PosReg', (97, 105))	('expression', 'MPA', (82, 92))	('mice', 'Species', '10090', (124, 128))	('antisense', 'Var', (22, 31))	('survival rates', 'CPA', (106, 120))	('ES', 'Phenotype', 'HP:0012254', (134, 136))	('reduce', 'NegReg', (66, 72))	('EWS-FLI1', 'Gene', (73, 81))
202801	23346417	It has also been suggested that combining IGF-1R inhibitors with mTOR inhibitors may improve efficacy.	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('improve', 'PosReg', (85, 92))	('efficacy', 'MPA', (93, 101))	('inhibitors', 'Var', (49, 59))	('IGF-1R', 'Gene', (42, 48))
202830	22187115	NBS may be isointense or hypointense on T1-weighted images and does not enhance.	('hypointense', 'MPA', (25, 36))	('NBS', 'Phenotype', 'HP:0008643', (0, 3))	('isointense', 'Var', (11, 21))	('NBS', 'Disease', 'MESH:D049932', (0, 3))	('NBS', 'Disease', (0, 3))
202844	22187115	A WT gene mutation has been identified in 10-15% of sporadic cases of Wilms tumour.	('Wilms tumour', 'Disease', 'MESH:D009396', (70, 82))	('WT', 'Disease', 'MESH:C536751', (2, 4))	('Wilms tumour', 'Disease', (70, 82))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('mutation', 'Var', (10, 18))	('Wilms tumour', 'Phenotype', 'HP:0002667', (70, 82))
202875	22187115	The AREN0533 arm of the current Children's Oncology Group (COG) trial uses central staging and a response-based approach to pulmonary lesions whereby only those that do not respond to 6 weeks of chemotherapy and are biopsy positive will be treated with whole lung radiotherapy.	('pulmonary lesions', 'Disease', (124, 141))	('Oncology', 'Phenotype', 'HP:0002664', (43, 51))	('AREN0533', 'Var', (4, 12))	('COG', 'Chemical', '-', (59, 62))	('Children', 'Species', '9606', (32, 40))	('pulmonary lesions', 'Disease', 'MESH:D008171', (124, 141))
202968	22187115	As in neuroblastoma, high copy number and overexpression of MycN confers a poor prognosis in RMS.	('neuroblastoma', 'Phenotype', 'HP:0003006', (6, 19))	('RMS', 'Disease', (93, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (6, 19))	('RMS', 'Phenotype', 'HP:0002859', (93, 96))	('overexpression', 'PosReg', (42, 56))	('high copy number', 'Var', (21, 37))	('MycN', 'Gene', '4613', (60, 64))	('neuroblastoma', 'Disease', (6, 19))	('MycN', 'Gene', (60, 64))
203003	22187115	A retrospective study of 19 paediatric sarcoma patients (7 with RMS) comparing FDG-PET/CT with conventional imaging found that FDG-PET/CT was sensitive for local relapse and complementary to conventional imaging in the detection of distant metastases.	('metastases', 'Disease', (240, 250))	('FDG', 'Chemical', 'MESH:D019788', (79, 82))	('RMS', 'Phenotype', 'HP:0002859', (64, 67))	('metastases', 'Disease', 'MESH:D009362', (240, 250))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('FDG-PET/CT', 'Var', (127, 137))	('patients', 'Species', '9606', (47, 55))	('local', 'CPA', (156, 161))	('sarcoma', 'Disease', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('FDG', 'Chemical', 'MESH:D019788', (127, 130))
203004	22187115	A further retrospective study of 43 childhood sarcomas (including 5 cases of RMS) found PET/CT had a greater sensitivity than PET alone for the detection of distant metastases but was not superior to CT.	('metastases', 'Disease', 'MESH:D009362', (165, 175))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('child', 'Species', '9606', (36, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('PET/CT', 'Var', (88, 94))	('sarcomas', 'Disease', (46, 54))	('RMS', 'Phenotype', 'HP:0002859', (77, 80))	('metastases', 'Disease', (165, 175))
203124	32493964	In STS, the high sPD-L1 (>44.26 pg/mL) group had significantly lower metastasis-free survival (MS) and lower overall survival (OS) than the low sPD-L1 group (<=44.26 pg/mL) at 5 years using the log-rank test.	('>44.26', 'Var', (25, 31))	('lower', 'NegReg', (63, 68))	('metastasis-free survival', 'CPA', (69, 93))	('lower', 'NegReg', (103, 108))	('STS', 'Phenotype', 'HP:0030448', (3, 6))	('sPD-L1', 'Chemical', '-', (144, 150))	('overall', 'MPA', (109, 116))	('sPD-L1', 'Chemical', '-', (17, 23))
203125	32493964	On multivariate Cox proportional hazard analysis, the high sPD-L1 group had significant differences in MS and OS compared to the low sPD-L1 group.	('sPD-L1', 'Chemical', '-', (59, 65))	('differences', 'Reg', (88, 99))	('high sPD-L1', 'Var', (54, 65))	('sPD-L1', 'Chemical', '-', (133, 139))
203133	32493964	Some studies reported that high PD-L1 expression in tumor tissues was related to a poor prognosis in various malignant tumors, including non-small cell lung cancer, ovarian cancer, renal cell carcinoma, melanoma, breast cancer, and STS.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('malignant tumors', 'Disease', (109, 125))	('malignant tumors', 'Disease', 'MESH:D009369', (109, 125))	('tumor', 'Disease', (52, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ovarian cancer', 'Disease', (165, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('PD-L1', 'Gene', (32, 37))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('STS', 'Disease', (232, 235))	('melanoma, breast cancer', 'Disease', 'MESH:D001943', (203, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (181, 201))	('STS', 'Phenotype', 'HP:0030448', (232, 235))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (141, 163))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (137, 163))	('ovarian cancer', 'Disease', 'MESH:D010051', (165, 179))	('renal cell carcinoma', 'Disease', (181, 201))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))	('related', 'Reg', (70, 77))	('lung cancer', 'Disease', (152, 163))
203137	32493964	High sPD-L1 is related to a poor prognosis in various cancers, such as renal cell carcinoma, hepatocellular carcinoma, esophageal cancer, lung cancer, gastric cancer, rectal cancer, and lymphoma.	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (93, 117))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('rectal cancer', 'Phenotype', 'HP:0100743', (167, 180))	('sPD-L1', 'Chemical', '-', (5, 11))	('High sPD-L1', 'Var', (0, 11))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (71, 91))	('gastric cancer', 'Disease', (151, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (93, 117))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', (143, 149))	('lymphoma', 'Disease', (186, 194))	('lymphoma', 'Disease', 'MESH:D008223', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('hepatocellular carcinoma', 'Disease', (93, 117))	('renal cell carcinoma', 'Disease', (71, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('cancer', 'Disease', (54, 60))	('lung cancer', 'Disease', (138, 149))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('cancer', 'Disease', (130, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lymphoma', 'Phenotype', 'HP:0002665', (186, 194))
203168	32493964	In only high-grade tumors, RS showed no significant difference (5 years: low sPD-L1 = 64.5%, high sPD-L1 = 58.9%, P = 0.653, Supplementary Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('sPD-L1', 'Chemical', '-', (77, 83))	('sPD-L1', 'Chemical', '-', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('high', 'Var', (93, 97))
203169	32493964	The high-sPD-L1 group had significantly lower MS (5 years: low sPD-L1 88.4%, high sPD-L1 42.4%, P < 0.001) (Fig.	('sPD-L1', 'Chemical', '-', (63, 69))	('sPD-L1', 'Chemical', '-', (9, 15))	('high-sPD-L1', 'Var', (4, 15))	('high sPD-L1', 'Var', (77, 88))	('sPD-L1', 'Chemical', '-', (82, 88))	('lower', 'NegReg', (40, 45))
203170	32493964	In only high-grade tumors, MS showed a significant difference (5 years: low sPD-L1 = 79.9%, high sPD-L1 = 29.5%, P = 0.003, Supplementary Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('high', 'Var', (92, 96))	('sPD-L1', 'Chemical', '-', (76, 82))	('sPD-L1', 'Chemical', '-', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
203171	32493964	For OS, the high-sPD-L1 group had a significantly worse prognosis (5 years: low sPD-L1 = 89.2%, high sPD-L1 = 64.1%, P = 0.011) (Fig.	('sPD-L1', 'Chemical', '-', (80, 86))	('low', 'Var', (76, 79))	('sPD-L1', 'Chemical', '-', (101, 107))	('high', 'Var', (96, 100))	('sPD-L1', 'Chemical', '-', (17, 23))	('high-sPD-L1', 'Var', (12, 23))
203172	32493964	In only high-grade tumors, OS showed a significant difference (5 years: low sPD-L1 = 81.4%, high sPD-L1 = 5%, P = 0.040, Supplementary Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('high', 'Var', (92, 96))	('sPD-L1', 'Chemical', '-', (76, 82))	('sPD-L1', 'Chemical', '-', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
203186	32493964	The signal pathway of IFN-gamma/JAK2/IFN, PI3K, and MEK/ERK/STAT1 can upregulate them.	('ERK', 'Gene', '5594', (56, 59))	('JAK2', 'Gene', (32, 36))	('IFN', 'Gene', (22, 25))	('signal pathway', 'Pathway', (4, 18))	('ERK', 'Gene', (56, 59))	('IFN', 'Gene', (37, 40))	('PI3K', 'Var', (42, 46))	('IFN', 'Gene', '3439', (22, 25))	('MEK', 'Gene', (52, 55))	('IFN-gamma', 'Gene', '3458', (22, 31))	('IFN-gamma', 'Gene', (22, 31))	('upregulate', 'PosReg', (70, 80))	('MEK', 'Gene', '5609', (52, 55))	('JAK2', 'Gene', '3717', (32, 36))	('STAT1', 'Gene', (60, 65))	('STAT1', 'Gene', '6772', (60, 65))	('IFN', 'Gene', '3439', (37, 40))
203193	32493964	The results of the present study successfully demonstrated the relationship between elevated sPD-L1 and a poor prognosis in STS.	('STS', 'Phenotype', 'HP:0030448', (124, 127))	('elevated', 'Var', (84, 92))	('sPD-L1', 'Gene', (93, 99))	('sPD-L1', 'Chemical', '-', (93, 99))
203210	32493964	Several studies supported the notion that exosomal PD-L1 inhibited IL-2 release and killing of tumor cells by T cells.	('exosomal', 'Var', (42, 50))	('IL-2', 'Gene', (67, 71))	('inhibited', 'NegReg', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('release', 'MPA', (72, 79))	('IL-2', 'Gene', '3558', (67, 71))	('tumor', 'Disease', (95, 100))	('PD-L1', 'Gene', (51, 56))
203215	32493964	Thus, the notion that circulating sPD-L1 has the potential to induce systemic immune suppression has been supported.	('sPD-L1', 'Chemical', '-', (34, 40))	('systemic immune suppression', 'CPA', (69, 96))	('induce', 'PosReg', (62, 68))	('sPD-L1', 'Var', (34, 40))
203217	32493964	Once the combination of high sPD-L1 and malignancy occurred, it led to worse MFS and OS in the high-sPD-L1 group than in the low-sPD-L1 group.	('high sPD-L1', 'Var', (24, 35))	('high-sPD-L1', 'Var', (95, 106))	('sPD-L1', 'Chemical', '-', (100, 106))	('sPD-L1', 'Chemical', '-', (29, 35))	('worse', 'NegReg', (71, 76))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('sPD-L1', 'Chemical', '-', (129, 135))	('malignancy', 'Disease', (40, 50))
203219	32493964	High sPD-L1 was strongly related to metastasis and a poor prognosis.	('metastasis', 'CPA', (36, 46))	('High sPD-L1', 'Var', (0, 11))	('sPD-L1', 'Chemical', '-', (5, 11))	('related', 'Reg', (25, 32))
203220	32493964	Thus, sPD-L1 may have potential to exacerbate tumor behavior in STS.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('exacerbate', 'PosReg', (35, 45))	('tumor', 'Disease', (46, 51))	('STS', 'Phenotype', 'HP:0030448', (64, 67))	('sPD-L1', 'Var', (6, 12))	('sPD-L1', 'Chemical', '-', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
203260	30416685	Indeed, ZSTK474 inhibited PI3K-downstream pathways, in parallel to growth inhibition, in all cell lines examined, showing proof-of-concept of PI3K inhibition.	('PI3K-downstream pathways', 'Pathway', (26, 50))	('ZSTK474', 'Chemical', 'MESH:C510150', (8, 15))	('inhibited', 'NegReg', (16, 25))	('ZSTK474', 'Var', (8, 15))
203261	30416685	In addition, ZSTK474 induced apoptosis selectively in Ewing's sarcoma (RD-ES and A673), alveolar rhabdomyosarcoma (SJCRH30) and synovial sarcoma (SYO-1, Aska-SS and Yamato-SS) cell lines, all of which harbor chromosomal translocation and resulting oncogenic fusion genes, EWSR1-FLI1, PAX3-FOXO1 and SS18-SSX, respectively.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('PAX3', 'Gene', (284, 288))	('FLI1', 'Gene', (278, 282))	('SS', 'Phenotype', 'HP:0012570', (304, 306))	('EWSR1', 'Gene', '2130', (272, 277))	('SS18', 'Gene', '6760', (299, 303))	('ES', 'Phenotype', 'HP:0012254', (74, 76))	("Ewing's sarcoma", 'Disease', (54, 69))	('synovial sarcoma', 'Disease', (128, 144))	('ZSTK474', 'Var', (13, 20))	('apoptosis', 'CPA', (29, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('SSX', 'Gene', '6757', (304, 307))	('SYO-1', 'Gene', (146, 151))	('SYO-1', 'Gene', '55027', (146, 151))	('PAX3', 'Gene', '5077', (284, 288))	('FLI1', 'Gene', '2313', (278, 282))	('synovial sarcoma', 'Disease', 'MESH:D013584', (128, 144))	('SS', 'Phenotype', 'HP:0012570', (158, 160))	('alveolar rhabdomyosarcoma', 'Disease', (88, 113))	('EWSR1', 'Gene', (272, 277))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (128, 144))	('SSX', 'Gene', (304, 307))	('ZSTK474', 'Chemical', 'MESH:C510150', (13, 20))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (97, 113))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (88, 113))	('induced', 'Reg', (21, 28))	('SS', 'Phenotype', 'HP:0012570', (172, 174))	('SS', 'Phenotype', 'HP:0012570', (299, 301))	('FOXO1', 'Gene', '2308', (289, 294))	('SS18', 'Gene', (299, 303))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (54, 69))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (88, 113))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (54, 69))	('SJCRH30', 'Chemical', '-', (115, 122))	('FOXO1', 'Gene', (289, 294))
203263	30416685	These results suggest that ZSTK474 could be a promising drug candidate for treating sarcomas, especially those harboring chromosomal translocation.	('treating sarcomas', 'Disease', 'MESH:D012509', (75, 92))	('treating sarcomas', 'Disease', (75, 92))	('ZSTK474', 'Gene', (27, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('chromosomal translocation', 'Var', (121, 146))	('ZSTK474', 'Chemical', 'MESH:C510150', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))
203267	30416685	Another group is consisted of sarcomas harboring complex karyotypic abnormalities, accompanied by multiple gene mutations, gene amplifications and chromosomal aberrations, which frequently include the impairment of cell cycle checkpoint genes.	('accompanied', 'Reg', (83, 94))	('sarcomas', 'Disease', (30, 38))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (147, 170))	('cell cycle checkpoint genes', 'Gene', (215, 242))	('mutations', 'Var', (112, 121))	('sarcomas', 'Disease', 'MESH:D012509', (30, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
203278	30416685	Interestingly, there were four sarcoma recipients in the overall cohort and three of these were included in the prolonged SD group, suggesting that ZSTK474 could be useful in sarcoma therapy.	('sarcoma', 'Disease', (175, 182))	('sarcoma', 'Disease', (31, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('ZSTK474', 'Var', (148, 155))	('sarcoma', 'Disease', 'MESH:D012509', (175, 182))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))	('ZSTK474', 'Chemical', 'MESH:C510150', (148, 155))
203283	30416685	A total of 24 anticancer agents including ZSTK474, other PI3K inhibitors, and those clinically used for sarcoma treatment were examined with respect to their antitumor profiles across the panel of sarcoma cell lines in terms of effects on tumor growth, PI3K-downstream signaling pathway alterations and apoptosis induction in vitro and in vivo.	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('tumor', 'Disease', (162, 167))	('sarcoma', 'Disease', (197, 204))	('ZSTK474', 'Chemical', 'MESH:C510150', (42, 49))	('cancer', 'Disease', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('tumor', 'Disease', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('PI3K-downstream signaling pathway', 'Pathway', (253, 286))	('alterations', 'Reg', (287, 298))	('apoptosis induction', 'CPA', (303, 322))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('ZSTK474', 'Var', (42, 49))	('sarcoma', 'Disease', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))
203286	30416685	Of note, eleven of the 14 cell lines had mutations in TP53, which was the most frequently mutated gene among the genes examined.	('mutations', 'Var', (41, 50))	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))
203287	30416685	In addition, gain of function mutations, which gave new activity or enhancement of its activity to the proteins, were commonly found in KIT (M541L, four cell lines), BRAF (V600E, three cell lines) and NRAS (Q61K/H, two cell lines) genes.	('BRAF', 'Gene', (166, 170))	('NRAS', 'Gene', (201, 205))	('activity', 'MPA', (56, 64))	('M541L', 'Mutation', 'rs3822214', (141, 146))	('NRAS', 'Gene', '4893', (201, 205))	('gain of function', 'PosReg', (13, 29))	('mutations', 'Var', (30, 39))	('enhancement', 'PosReg', (68, 79))	('V600E', 'Mutation', 'rs113488022', (172, 177))	('KIT', 'Gene', (136, 139))	('BRAF', 'Gene', '673', (166, 170))	('Q61K', 'SUBSTITUTION', 'None', (207, 211))	('Q61K', 'Var', (207, 211))	('activity to the proteins', 'MPA', (87, 111))
203288	30416685	In contrast, none of the cell lines in this panel harbored known gain of function mutations in the PIK3CA gene at the hotspot residues (E542, E545 and H1047).	('H1047', 'Var', (151, 156))	('E542', 'Var', (136, 140))	('PIK3CA', 'Gene', '5290', (99, 105))	('E545', 'Var', (142, 146))	('gain of function', 'PosReg', (65, 81))	('PIK3CA', 'Gene', (99, 105))
203289	30416685	Missense mutations were not observed in the PTEN gene in these cell lines, while intronic deletions were observed in the HT-1080, RD and RD-ES cell lines.	('HT-1080', 'CellLine', 'CVCL:0317', (121, 128))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('ES', 'Phenotype', 'HP:0012254', (140, 142))	('Missense mutations', 'Var', (0, 18))
203291	30416685	Baseline expression of phosphorylated AKT (S473 and T308) and S6 (S235/236) were detected in most of the cell lines examined, suggesting substantial activation of AKT consistent with previous findings.	('S235/236', 'Gene', (66, 74))	('T308', 'Var', (52, 56))	('S6', 'Gene', '6194', (62, 64))	('S235/236', 'Gene', '6194', (66, 74))	('S473', 'Var', (43, 47))	('AKT', 'Pathway', (163, 166))	('activation', 'PosReg', (149, 159))
203293	30416685	Interestingly, cell lines harboring a gain of function mutation in either NRAS, KRAS or BRAF genes expressed phosphorylated MEK and ERK proteins at a significantly higher level than wild-type cell lines (Figure 1B and 1C), whereas no such association was observed regarding phosphorylated AKT nor S6 (data not shown).	('ERK', 'Gene', '5594', (132, 135))	('KRAS', 'Gene', (80, 84))	('BRAF', 'Gene', (88, 92))	('ERK', 'Gene', (132, 135))	('BRAF', 'Gene', '673', (88, 92))	('NRAS', 'Gene', (74, 78))	('higher', 'PosReg', (164, 170))	('gain of function', 'PosReg', (38, 54))	('MEK', 'Gene', (124, 127))	('KRAS', 'Gene', '3845', (80, 84))	('NRAS', 'Gene', '4893', (74, 78))	('MEK', 'Gene', '5609', (124, 127))	('mutation', 'Var', (55, 63))	('phosphorylated', 'MPA', (109, 123))	('S6', 'Gene', '6194', (297, 299))
203300	30416685	PI3K inhibitors including derivatives of ZSTK474 (ZSTK778, ZSTK534 and ZSTK1741), pictilisib (GDC-0941), buparlisib (BKM120) and alpelisib (BYL-719) were highly ranked, and everolimus, an allosteric inhibitor of mTOR, appeared after the PI3K inhibitors.	('ZSTK474', 'Var', (41, 48))	('alpelisib', 'Chemical', 'MESH:C585539', (129, 138))	('mTOR', 'Gene', '2475', (212, 216))	('pictilisib', 'Chemical', 'MESH:C532162', (82, 92))	('ZSTK1741', 'Chemical', '-', (71, 79))	('BYL-719', 'Chemical', 'MESH:C585539', (140, 147))	('ZSTK778', 'Chemical', '-', (50, 57))	('everolimus', 'Chemical', 'MESH:D000068338', (173, 183))	('GDC-0941', 'Chemical', 'MESH:C532162', (94, 102))	('ZSTK534', 'Chemical', '-', (59, 66))	('BKM120', 'Chemical', 'MESH:C571178', (117, 123))	('ZSTK474', 'Chemical', 'MESH:C510150', (41, 48))	('ZSTK1741', 'Var', (71, 79))	('mTOR', 'Gene', (212, 216))	('ZSTK534', 'Var', (59, 66))	('buparlisib', 'Chemical', 'MESH:C571178', (105, 115))
203301	30416685	In fact, ZSTK474 was broadly effective across the 14 cell lines tested and the GI50 concentrations were distributed within a 10-fold range (0.1 to 1 muM; Supplementary Figures 1D and 2).	('ZSTK474', 'Var', (9, 16))	('muM', 'Gene', '56925', (149, 152))	('muM', 'Gene', (149, 152))	('ZSTK474', 'Chemical', 'MESH:C510150', (9, 16))
203309	30416685	The most prominent association identified in this screen was found between efficacy of the MEK inhibitor selumetinib and the gain of function mutation in either NRAS, KRAS or BRAF genes (Supplementary Figure 3).	('NRAS', 'Gene', '4893', (161, 165))	('KRAS', 'Gene', '3845', (167, 171))	('BRAF', 'Gene', (175, 179))	('gain of function', 'PosReg', (125, 141))	('BRAF', 'Gene', '673', (175, 179))	('NRAS', 'Gene', (161, 165))	('KRAS', 'Gene', (167, 171))	('selumetinib', 'Chemical', 'MESH:C517975', (105, 116))	('mutation', 'Var', (142, 150))	('MEK', 'Gene', (91, 94))	('MEK', 'Gene', '5609', (91, 94))
203311	30416685	As expected, three of the cell lines which harbored a BRAF V600E mutation, namely SW982, SW872 and GCT, exhibited sensitivity to the mutant selective BRAF inhibitor, vemurafenib.	('SW872', 'CellLine', 'CVCL:1730', (89, 94))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('SW982', 'CellLine', 'CVCL:1734', (82, 87))	('exhibited', 'Reg', (104, 113))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('sensitivity', 'MPA', (114, 125))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('vemurafenib', 'Chemical', 'MESH:D000077484', (166, 177))	('V600E', 'Var', (59, 64))
203313	30416685	Instead, we found significant negative correlations between phosphorylated AKT (T308) and sensitivity to pazopanib (r = -0.70), docetaxel (r = -0.63) or gemcitabine (r = -0.57).	('pazopanib', 'Chemical', 'MESH:C516667', (105, 114))	('negative', 'NegReg', (30, 38))	('T308', 'Var', (80, 84))	('gemcitabine', 'Chemical', 'MESH:C056507', (153, 164))	('sensitivity', 'MPA', (90, 101))	('docetaxel', 'Chemical', 'MESH:D000077143', (128, 137))
203316	30416685	As shown in Figure 3, the expression levels of phosphorylated AKT (S473) and phosphorylated S6 protein (S235/236) were downregulated upon treatment with ZSTK474 at a concentration required for 50% growth inhibition in each of 14 sarcoma cell lines within 30 min and 6 h, respectively.	('14 sarcoma', 'Disease', (226, 236))	('S6', 'Gene', '6194', (92, 94))	('ZSTK474', 'Var', (153, 160))	('14 sarcoma', 'Disease', 'MESH:D012509', (226, 236))	('downregulated', 'NegReg', (119, 132))	('S235/236', 'Gene', '6194', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('S473', 'Var', (67, 71))	('expression levels', 'MPA', (26, 43))	('ZSTK474', 'Chemical', 'MESH:C510150', (153, 160))	('S235/236', 'Gene', (104, 112))
203317	30416685	These results clearly indicated the proof of concept that ZSTK474 certainly inhibited the PI3K-downstream signaling pathway in sarcoma cells, in parallel to growth inhibition.	('PI3K-downstream signaling pathway', 'Pathway', (90, 123))	('ZSTK474', 'Chemical', 'MESH:C510150', (58, 65))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('sarcoma', 'Disease', (127, 134))	('ZSTK474', 'Var', (58, 65))	('inhibited', 'NegReg', (76, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
203318	30416685	Given that PI3K inhibitors showed antiproliferative activity in sarcoma cell lines in vitro, we next exploited sarcoma xenograft models to determine antitumor activity of ZSTK474 in vivo.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('antiproliferative activity', 'MPA', (34, 60))	('ZSTK474', 'Chemical', 'MESH:C510150', (171, 178))	('sarcoma', 'Disease', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('PI3K inhibitors', 'Var', (11, 26))
203320	30416685	Therefore, we examined the effect of ZSTK474 on growth of xenografted tumors derived from these cell lines, and compared it with that affected by doxorubicin and pazopanib.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ZSTK474', 'Chemical', 'MESH:C510150', (37, 44))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('pazopanib', 'Chemical', 'MESH:C516667', (162, 171))	('ZSTK474', 'Var', (37, 44))	('doxorubicin', 'Chemical', 'MESH:D004317', (146, 157))
203323	30416685	Immunohistochemistry (IHC) revealed that ZSTK474 efficiently suppressed expression of phosphorylated S6 protein, a PI3K-downstream signaling molecule, whereas neither doxorubicin nor pazopanib suppressed phosphorylated S6 protein.	('ZSTK474', 'Var', (41, 48))	('suppressed', 'NegReg', (61, 71))	('doxorubicin', 'Chemical', 'MESH:D004317', (167, 178))	('S6', 'Gene', '6194', (219, 221))	('expression', 'MPA', (72, 82))	('ZSTK474', 'Chemical', 'MESH:C510150', (41, 48))	('pazopanib', 'Chemical', 'MESH:C516667', (183, 192))	('S6', 'Gene', '6194', (101, 103))
203324	30416685	The results provided the proof of concept that ZSTK474 certainly exerted antitumor effects via inhibiting the PI3K signaling pathway in vivo, as well as in vitro.	('inhibiting', 'NegReg', (95, 105))	('ZSTK474', 'Chemical', 'MESH:C510150', (47, 54))	('ZSTK474', 'Var', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('PI3K signaling pathway', 'Pathway', (110, 132))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
203326	30416685	In the present study, to investigate the involvement of apoptosis in the antitumor effects of ZSTK474 in sarcoma cells, 14 sarcoma cell lines were treated with ZSTK474 at a higher concentration than GI50 for an extended period (48 h, Supplementary Figure 4).	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('14 sarcoma', 'Disease', 'MESH:D012509', (120, 130))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('ZSTK474', 'Var', (160, 167))	('sarcoma', 'Disease', (105, 112))	('ZSTK474', 'Gene', (94, 101))	('ZSTK474', 'Chemical', 'MESH:C510150', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('tumor', 'Disease', (77, 82))	('sarcoma', 'Disease', (123, 130))	('ZSTK474', 'Chemical', 'MESH:C510150', (160, 167))	('14 sarcoma', 'Disease', (120, 130))
203330	30416685	Dephosphorylation of PI3K-downstream signaling proteins, including AKT (on S473 and T308 residues), ribosomal S6 protein (on S235/236 residues) and 4E-BP1 (on T37/46 residues) were observed within 6 h following ZSTK474 treatment, with effects lasting at least 48 h after drug exposure.	('ZSTK474', 'Chemical', 'MESH:C510150', (211, 218))	('Dephosphorylation', 'MPA', (0, 17))	('S235/236', 'Gene', (125, 133))	('E-BP1', 'Gene', (149, 154))	('E-BP1', 'Gene', '4790', (149, 154))	('S235/236', 'Gene', '6194', (125, 133))	('T308 residues', 'Var', (84, 97))	('S6', 'Gene', '6194', (110, 112))	('ZSTK474', 'Gene', (211, 218))	('AKT', 'Pathway', (67, 70))
203331	30416685	Interestingly, cleaved PARP was detected within 6 h after exposure of ZSTK474 at a concentration of 1 muM or more, suggesting that progression of apoptosis started earlier than 6 h. As expected, apoptotic cells increased in a dose-dependent manner in both Ewing's sarcoma cell lines following ZSTK474 treatment.	('PARP', 'Gene', (23, 27))	('muM', 'Gene', (102, 105))	('apoptotic cells', 'CPA', (195, 210))	('ZSTK474', 'Var', (293, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (256, 271))	('ZSTK474', 'Chemical', 'MESH:C510150', (70, 77))	('PARP', 'Gene', '142', (23, 27))	('ZSTK474', 'Chemical', 'MESH:C510150', (293, 300))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (256, 271))	("Ewing's sarcoma", 'Disease', (256, 271))	('muM', 'Gene', '56925', (102, 105))
203332	30416685	From these results, we concluded that Ewing's sarcoma cells underwent apoptosis upon treatment with ZSTK474 in vitro.	("Ewing's sarcoma", 'Disease', (38, 53))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (38, 53))	('ZSTK474', 'Var', (100, 107))	('ZSTK474', 'Chemical', 'MESH:C510150', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('apoptosis', 'CPA', (70, 79))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (38, 53))
203333	30416685	The most common chromosomal translocation found in Ewing's sarcoma, t(11;22)(q24;q12), generates an aberrant transcription factor EWSR1-FLI1 fusion gene.	('t(11;22)(q24;q12', 'Var', (68, 84))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (51, 66))	('EWSR1', 'Gene', '2130', (130, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (68, 85))	("Ewing's sarcoma", 'Disease', (51, 66))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (51, 66))	('EWSR1', 'Gene', (130, 135))	('FLI1', 'Gene', '2313', (136, 140))	('FLI1', 'Gene', (136, 140))
203337	30416685	Instead, we found that ZSTK474 reduced the expression level of Id2, which was transcriptionally regulated by EWSR1-FLI1, in the Ewing's sarcoma cell lines.	('EWSR1', 'Gene', '2130', (109, 114))	('ZSTK474', 'Chemical', 'MESH:C510150', (23, 30))	('reduced', 'NegReg', (31, 38))	('Id2', 'Gene', '3398', (63, 66))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (128, 143))	('Id2', 'Gene', (63, 66))	("Ewing's sarcoma", 'Disease', (128, 143))	('FLI1', 'Gene', (115, 119))	('expression level', 'MPA', (43, 59))	('FLI1', 'Gene', '2313', (115, 119))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (128, 143))	('ZSTK474', 'Var', (23, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('EWSR1', 'Gene', (109, 114))
203341	30416685	This result suggested that downregulation of Id2 protein expression observed in Ewing's sarcoma cell lines upon treatment with ZSTK474 could be mediated via transcriptional inactivation of EWSR1-FLI1 from the Id2 promoter.	('FLI1', 'Gene', (195, 199))	('expression', 'MPA', (57, 67))	('Id2', 'Gene', '3398', (45, 48))	('Id2', 'Gene', (209, 212))	('protein', 'Protein', (49, 56))	('EWSR1', 'Gene', '2130', (189, 194))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (80, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('ZSTK474', 'Chemical', 'MESH:C510150', (127, 134))	("Ewing's sarcoma", 'Disease', (80, 95))	('Id2', 'Gene', (45, 48))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (80, 95))	('Id2', 'Gene', '3398', (209, 212))	('downregulation', 'NegReg', (27, 41))	('inactivation', 'NegReg', (173, 185))	('ZSTK474', 'Var', (127, 134))	('FLI1', 'Gene', '2313', (195, 199))	('EWSR1', 'Gene', (189, 194))
203345	30416685	Immunoblot analysis of tumor samples resected from nude mice revealed that administration of ZSTK474 for two weeks downregulated the PI3K-downstream signaling pathway, as determined by dephosphorylation of AKT and ribosomal S6 protein (Figure 6B).	('dephosphorylation', 'MPA', (185, 202))	('PI3K-downstream signaling pathway', 'Pathway', (133, 166))	('ZSTK474', 'Var', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('S6', 'Gene', '6194', (224, 226))	('ribosomal', 'Protein', (214, 223))	('AKT', 'Pathway', (206, 209))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('ZSTK474', 'Chemical', 'MESH:C510150', (93, 100))	('tumor', 'Disease', (23, 28))	('downregulated', 'NegReg', (115, 128))	('nude mice', 'Species', '10090', (51, 60))
203346	30416685	Moreover, cleaved PARP was selectively detected from the samples that had been derived from ZSTK474 administrated-animals, suggesting that A673 cells underwent apoptosis upon ZSTK474 administration in vivo.	('ZSTK474', 'Var', (175, 182))	('apoptosis', 'CPA', (160, 169))	('ZSTK474', 'Chemical', 'MESH:C510150', (92, 99))	('ZSTK474', 'Chemical', 'MESH:C510150', (175, 182))	('PARP', 'Gene', (18, 22))	('underwent', 'Reg', (150, 159))	('PARP', 'Gene', '142', (18, 22))
203351	30416685	In SYO-1 and Aska-SS cells, protein expression of SS18-SSX, as well as SS18, was reduced upon treatment with ZSTK474, while no significant reduction was observed in Yamato-SS cells.	('SS18', 'Gene', '6760', (71, 75))	('ZSTK474', 'Chemical', 'MESH:C510150', (109, 116))	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('SYO-1', 'Gene', (3, 8))	('SS18', 'Gene', (50, 54))	('protein expression', 'MPA', (28, 46))	('treatment', 'Interaction', (94, 103))	('SS18', 'Gene', '6760', (50, 54))	('SS18', 'Gene', (71, 75))	('SS', 'Phenotype', 'HP:0012570', (172, 174))	('SSX', 'Gene', '6757', (55, 58))	('ZSTK474', 'Var', (109, 116))	('reduced', 'NegReg', (81, 88))	('SS', 'Phenotype', 'HP:0012570', (55, 57))	('SSX', 'Gene', (55, 58))	('SS', 'Phenotype', 'HP:0012570', (18, 20))	('SYO-1', 'Gene', '55027', (3, 8))	('SS', 'Phenotype', 'HP:0012570', (50, 52))
203353	30416685	As expected, ZSTK474 suppressed the growth of SYO-1 tumors (T/C = 29.2%, Figure 7C).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('growth', 'MPA', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('suppressed', 'NegReg', (21, 31))	('ZSTK474', 'Chemical', 'MESH:C510150', (13, 20))	('SYO-1 tumors', 'Disease', (46, 58))	('ZSTK474', 'Var', (13, 20))	('SYO-1 tumors', 'Disease', 'MESH:D009369', (46, 58))
203354	30416685	Immunoblot analysis of tumor samples revealed that ZSTK474 certainly downregulated the PI3K-downstream signaling pathway and induced apoptosis, as determined by detection of cleaved PARP (Figure 7D).	('ZSTK474', 'Var', (51, 58))	('apoptosis', 'CPA', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('ZSTK474', 'Chemical', 'MESH:C510150', (51, 58))	('downregulated', 'NegReg', (69, 82))	('PARP', 'Gene', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('induced', 'PosReg', (125, 132))	('tumor', 'Disease', (23, 28))	('PI3K-downstream signaling pathway', 'Pathway', (87, 120))	('PARP', 'Gene', '142', (182, 186))
203362	30416685	These results suggested that ZSTK474 efficiently inhibited angiogenesis in sarcoma xenografts in vivo to a similar extent to pazopanib.	('angiogenesis in', 'CPA', (59, 74))	('ZSTK474', 'Chemical', 'MESH:C510150', (29, 36))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('sarcoma', 'Disease', (75, 82))	('ZSTK474', 'Var', (29, 36))	('pazopanib', 'Chemical', 'MESH:C516667', (125, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('inhibited', 'NegReg', (49, 58))
203365	30416685	The results strongly supported our hypothesis that these compounds shared a specific mode of action, i.e., similarity of their fingerprints was as a result of PI3K inhibition against sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('sarcoma', 'Disease', (183, 190))	('PI3K', 'Var', (159, 163))
203366	30416685	In fact, ZSTK474 effectively suppressed tumor cell growth at submicromolar concentrations, with the variance of GI50 concentrations across the 14 cell lines being small (within a 10-fold range) compared to the MEK inhibitor selumetinib (~1000-fold range).	('selumetinib', 'Chemical', 'MESH:C517975', (224, 235))	('MEK', 'Gene', (210, 213))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('MEK', 'Gene', '5609', (210, 213))	('ZSTK474', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('ZSTK474', 'Chemical', 'MESH:C510150', (9, 16))	('suppressed', 'NegReg', (29, 39))
203367	30416685	These results suggested that ZSTK474 effectively suppressed tumor growth in sarcoma cell lines irrespective of their subtype.	('ZSTK474', 'Chemical', 'MESH:C510150', (29, 36))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ZSTK474', 'Var', (29, 36))	('sarcoma', 'Disease', (76, 83))	('suppressed', 'NegReg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('tumor', 'Disease', (60, 65))
203369	30416685	In our previous study using the JFCR39 carcinoma cell line panel, gain of function mutations of the KRAS or BRAF genes and overexpression of IGF1R were found to be negative predictors whereas high expression of phosphorylated AKT was observed to be a positive predictor for ZSTK474 efficacy; however, neither gain of function mutations of KRAS/NRAS/BRAF nor overexpression of IGFR/phosphorylated AKT displayed any significant correlation with ZSTK474 efficacy in the sarcoma panel assessed here.	('sarcoma', 'Disease', (467, 474))	('KRAS', 'Gene', (100, 104))	('KRAS', 'Gene', '3845', (339, 343))	('BRAF', 'Gene', '673', (349, 353))	('BRAF', 'Gene', (349, 353))	('mutations', 'Var', (326, 335))	('KRAS', 'Gene', (339, 343))	('sarcoma', 'Phenotype', 'HP:0100242', (467, 474))	('NRAS', 'Gene', (344, 348))	('ZSTK474', 'Chemical', 'MESH:C510150', (443, 450))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('BRAF', 'Gene', '673', (108, 112))	('carcinoma', 'Disease', (39, 48))	('BRAF', 'Gene', (108, 112))	('IGF1R', 'Gene', '3480', (141, 146))	('IGFR', 'Gene', '3480', (376, 380))	('IGF1R', 'Gene', (141, 146))	('mutations', 'Var', (83, 92))	('ZSTK474', 'Chemical', 'MESH:C510150', (274, 281))	('KRAS', 'Gene', '3845', (100, 104))	('carcinoma', 'Disease', 'MESH:D002277', (39, 48))	('NRAS', 'Gene', '4893', (344, 348))	('IGFR', 'Gene', (376, 380))	('sarcoma', 'Disease', 'MESH:D012509', (467, 474))
203370	30416685	HT-1080, one of the less effective cell lines examined, harbored gain of function mutation of NRAS, suggesting that NRAS mutation could be involved ZSTK474 inefficacy; however, RD, another NRAS mutant cell line, responded to ZSTK474 at a moderate level.	('NRAS', 'Gene', (94, 98))	('ZSTK474', 'Chemical', 'MESH:C510150', (225, 232))	('NRAS', 'Gene', '4893', (189, 193))	('HT-1080', 'CellLine', 'CVCL:0317', (0, 7))	('mutation', 'Var', (82, 90))	('NRAS', 'Gene', '4893', (94, 98))	('NRAS', 'Gene', (116, 120))	('mutation', 'Var', (121, 129))	('gain of function', 'PosReg', (65, 81))	('NRAS', 'Gene', '4893', (116, 120))	('NRAS', 'Gene', (189, 193))	('ZSTK474', 'Chemical', 'MESH:C510150', (148, 155))
203371	30416685	Further studies are needed to clarify whether NRAS mutation predicts ZSTK474 inefficacy.	('NRAS', 'Gene', (46, 50))	('NRAS', 'Gene', '4893', (46, 50))	('ZSTK474', 'Chemical', 'MESH:C510150', (69, 76))	('mutation', 'Var', (51, 59))	('ZSTK474', 'Gene', (69, 76))
203372	30416685	In addition, we could not determine whether PIK3CA mutation could predict the efficacy of ZSTK474, since none of the 14 sarcoma cell lines examined harbored a gain of function mutation of PIK3CA despite gain of function mutations in this genes being commonly found in in 18-25% of patients with liposarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('PIK3CA', 'Gene', (44, 50))	('PIK3CA', 'Gene', (188, 194))	('14 sarcoma', 'Disease', 'MESH:D012509', (117, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (299, 307))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('14 sarcoma', 'Disease', (117, 127))	('PIK3CA', 'Gene', '5290', (44, 50))	('patients', 'Species', '9606', (281, 289))	('liposarcomas', 'Phenotype', 'HP:0012034', (295, 307))	('PIK3CA', 'Gene', '5290', (188, 194))	('liposarcomas', 'Disease', 'MESH:D008080', (295, 307))	('gain of function', 'PosReg', (203, 219))	('liposarcomas', 'Disease', (295, 307))	('ZSTK474', 'Chemical', 'MESH:C510150', (90, 97))	('mutation', 'Var', (176, 184))	('gain of function', 'PosReg', (159, 175))
203376	30416685	We additionally examined the effect of ZSTK474 in another Ewing's sarcoma cell line, A673, and found that it also induced apoptosis in this context.	('ZSTK474', 'Chemical', 'MESH:C510150', (39, 46))	("Ewing's sarcoma", 'Disease', (58, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (58, 73))	('apoptosis', 'CPA', (122, 131))	('ZSTK474', 'Var', (39, 46))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (58, 73))	('induced', 'Reg', (114, 121))
203378	30416685	The rest of the 12 sarcoma cell lines used in this study did not undergo apoptosis following ZSTK474 treatment, except that a slight increase was observed in the Saos-2 osteosarcoma cell line.	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('ZSTK474', 'Var', (93, 100))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('sarcoma', 'Disease', (19, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('increase', 'PosReg', (133, 141))	('ZSTK474', 'Chemical', 'MESH:C510150', (93, 100))	('sarcoma', 'Disease', (174, 181))	('osteosarcoma', 'Disease', (169, 181))	('osteosarcoma', 'Disease', 'MESH:D012516', (169, 181))	('osteosarcoma', 'Phenotype', 'HP:0002669', (169, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))
203379	30416685	This cell line has not been reported to express an oncogenic fusion gene generated by specific chromosomal translocation, corroborating our hypothesis that ZSTK474 could preferentially induce apoptosis in chromosomal translocation-positive sarcomas.	('ZSTK474', 'Chemical', 'MESH:C510150', (156, 163))	('preferentially', 'PosReg', (170, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('sarcomas', 'Disease', (240, 248))	('induce', 'PosReg', (185, 191))	('ZSTK474', 'Var', (156, 163))	('apoptosis', 'CPA', (192, 201))	('sarcomas', 'Disease', 'MESH:D012509', (240, 248))	('sarcomas', 'Phenotype', 'HP:0100242', (240, 248))
203380	30416685	Here, we demonstrated that ZSTK474 partially downregulated transcriptional activity of the EWSR1-FLI1 transcription factor from the Id2 promoter via a reporter assay, and suppressed expression of the Id2 protein in both of the Ewing's sarcoma cell lines examined.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (227, 242))	('FLI1', 'Gene', '2313', (97, 101))	('Id2', 'Gene', (132, 135))	("Ewing's sarcoma", 'Disease', (227, 242))	('transcriptional activity', 'MPA', (59, 83))	('Id2', 'Gene', '3398', (132, 135))	('EWSR1', 'Gene', (91, 96))	('ZSTK474', 'Var', (27, 34))	('suppressed', 'NegReg', (171, 181))	('expression', 'MPA', (182, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('protein', 'Protein', (204, 211))	('Id2', 'Gene', (200, 203))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (227, 242))	('FLI1', 'Gene', (97, 101))	('Id2', 'Gene', '3398', (200, 203))	('downregulated', 'NegReg', (45, 58))	('ZSTK474', 'Chemical', 'MESH:C510150', (27, 34))	('EWSR1', 'Gene', '2130', (91, 96))
203381	30416685	Actually, a previous study demonstrated that the EWSR1-FLI1 fusion could transform cells, and downregulation of EWSR1-FLI1 by RNA interference could induce growth arrest in Ewing's sarcoma.	('FLI1', 'Gene', (55, 59))	("Ewing's sarcoma", 'Disease', (173, 188))	('EWSR1', 'Gene', '2130', (112, 117))	('downregulation', 'NegReg', (94, 108))	('fusion', 'Var', (60, 66))	('FLI1', 'Gene', '2313', (55, 59))	('FLI1', 'Gene', (118, 122))	('EWSR1', 'Gene', '2130', (49, 54))	('growth arrest', 'Phenotype', 'HP:0001510', (156, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('induce', 'Reg', (149, 155))	('EWSR1', 'Gene', (112, 117))	('FLI1', 'Gene', '2313', (118, 122))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (173, 188))	('RNA interference', 'MPA', (126, 142))	('growth arrest', 'Disease', 'MESH:D006323', (156, 169))	('EWSR1', 'Gene', (49, 54))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (173, 188))	('cells', 'CPA', (83, 88))	('transform', 'Reg', (73, 82))	('growth arrest', 'Disease', (156, 169))
203382	30416685	The precise mechanisms by which ZSTK474 downregulated EWSR1-FLI1, and by which mechanism their downregulation rendered cells susceptible to ZSTK474-induced apoptosis remains to be elucidated.	('EWSR1', 'Gene', '2130', (54, 59))	('downregulated', 'NegReg', (40, 53))	('ZSTK474', 'Chemical', 'MESH:C510150', (140, 147))	('ZSTK474', 'Var', (32, 39))	('downregulation', 'NegReg', (95, 109))	('EWSR1', 'Gene', (54, 59))	('FLI1', 'Gene', (60, 64))	('FLI1', 'Gene', '2313', (60, 64))	('ZSTK474', 'Chemical', 'MESH:C510150', (32, 39))
203383	30416685	Similarly, it has been reported that SS18-SSX fusion genes are capable of transforming cells and knockdown of SS18-SSX expression can greatly reduce viability of synovial sarcoma cells, as determined by colony formation assays.	('synovial sarcoma', 'Disease', 'MESH:D013584', (162, 178))	('reduce', 'NegReg', (142, 148))	('SSX', 'Gene', '6757', (115, 118))	('SS18', 'Gene', '6760', (37, 41))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (162, 178))	('viability', 'CPA', (149, 158))	('SS', 'Phenotype', 'HP:0012570', (110, 112))	('SSX', 'Gene', '6757', (42, 45))	('SS18', 'Gene', (110, 114))	('SS', 'Phenotype', 'HP:0012570', (37, 39))	('SSX', 'Gene', (115, 118))	('knockdown', 'Var', (97, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('SSX', 'Gene', (42, 45))	('SS18', 'Gene', (37, 41))	('SS18', 'Gene', '6760', (110, 114))	('SS', 'Phenotype', 'HP:0012570', (42, 44))	('synovial sarcoma', 'Disease', (162, 178))	('SS', 'Phenotype', 'HP:0012570', (115, 117))
203386	30416685	It was reported that the synovial sarcoma Aska-SS cell line expressed an activated ALK variant and showed sensitivity to ALK inhibitors, while another synovial sarcoma cell line Yamato-SS overexpressed MET protein and exhibited sensitivity to the ALK/MET dual inhibitor, crizotinib.	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('SS', 'Phenotype', 'HP:0012570', (185, 187))	('synovial sarcoma', 'Disease', (25, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('synovial sarcoma', 'Disease', 'MESH:D013584', (25, 41))	('sensitivity', 'MPA', (106, 117))	('ALK', 'Gene', '238', (83, 86))	('MET protein', 'Protein', (202, 213))	('synovial sarcoma', 'Disease', (151, 167))	('ALK', 'Gene', (83, 86))	('activated', 'PosReg', (73, 82))	('ALK', 'Gene', '238', (247, 250))	('variant', 'Var', (87, 94))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (25, 41))	('synovial sarcoma', 'Disease', 'MESH:D013584', (151, 167))	('ALK', 'Gene', '238', (121, 124))	('SS', 'Phenotype', 'HP:0012570', (47, 49))	('ALK', 'Gene', (247, 250))	('crizotinib', 'Chemical', 'MESH:D000077547', (271, 281))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (151, 167))	('overexpressed', 'PosReg', (188, 201))	('ALK', 'Gene', (121, 124))
203388	30416685	We also examined the expression of PAX3-FOXO1 after ZSTK474 treatment in SJCRH30 (Supplementary Figure 6).	('PAX3', 'Gene', (35, 39))	('FOXO1', 'Gene', (40, 45))	('FOXO1', 'Gene', '2308', (40, 45))	('ZSTK474', 'Var', (52, 59))	('SJCRH30', 'Chemical', '-', (73, 80))	('examined', 'Reg', (8, 16))	('ZSTK474', 'Chemical', 'MESH:C510150', (52, 59))	('PAX3', 'Gene', '5077', (35, 39))
203391	30416685	However, the causality between these events observed in chromosomal translocation positive sarcoma cells and the induction of apoptosis were unclear in the context of this study.	('sarcoma', 'Disease', (91, 98))	('chromosomal translocation positive', 'Var', (56, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))
203392	30416685	In fact, we detected neither common nor specific changes in the expression levels of Bcl-2 and IAP (inhibitor of apoptosis) family proteins in these cells upon treatment with ZSTK474 (data not shown).	('Bcl-2', 'Gene', '596', (85, 90))	('ZSTK474', 'Var', (175, 182))	('ZSTK474', 'Chemical', 'MESH:C510150', (175, 182))	('Bcl-2', 'Gene', (85, 90))
203395	30416685	ZSTK474 exerted a significant in vivo antitumor effect against all of sarcoma cell lines examined, comparable to the existing antitumor drugs doxorubicin and pazopanib.	('sarcoma', 'Disease', (70, 77))	('tumor', 'Disease', (42, 47))	('pazopanib', 'Chemical', 'MESH:C516667', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('ZSTK474', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ZSTK474', 'Chemical', 'MESH:C510150', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('tumor', 'Disease', (130, 135))	('doxorubicin', 'Chemical', 'MESH:D004317', (142, 153))
203398	30416685	Moreover, we clearly demonstrated that ZSTK474 suppressed the number of CD31-positive cells and inhibited blood vessel formation within the tumors, suggestive of an anti-angiogenic effect, in agreement with our previous finding using carcinoma cells.	('ZSTK474', 'Chemical', 'MESH:C510150', (39, 46))	('suppressed', 'NegReg', (47, 57))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('carcinoma', 'Disease', (234, 243))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CD31', 'Gene', '5175', (72, 76))	('anti-angiogenic effect', 'CPA', (165, 187))	('inhibited', 'NegReg', (96, 105))	('ZSTK474', 'Var', (39, 46))	('carcinoma', 'Disease', 'MESH:D002277', (234, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('CD31', 'Gene', (72, 76))
203401	30416685	In fact, our previous studies revealed that ZSTK474 induce G1 arrest of cell cycle but hardly induce apoptosis in various carcinoma cell lines both in vitro and in vivo.	('ZSTK474', 'Chemical', 'MESH:C510150', (44, 51))	('carcinoma', 'Disease', 'MESH:D002277', (122, 131))	('ZSTK474', 'Var', (44, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('G1 arrest of cell cycle', 'CPA', (59, 82))	('carcinoma', 'Disease', (122, 131))
203402	30416685	In contrast, chromosomal translocation-positive sarcomas underwent apoptosis upon administration of ZSTK474 in vivo as well as in vitro, as demonstrated in the present study.	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('apoptosis', 'CPA', (67, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('ZSTK474', 'Gene', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('sarcomas', 'Disease', (48, 56))	('ZSTK474', 'Chemical', 'MESH:C510150', (100, 107))	('chromosomal translocation-positive', 'Var', (13, 47))
203403	30416685	ZSTK474 has not yet administered to patients with such types of sarcoma; but the present results suggest that ZSTK474 would exert potential clinical benefits on them via tumor shrinkage in addition to inhibition of tumor proliferation and warrant further clinical development.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('ZSTK474', 'Var', (110, 117))	('inhibition', 'NegReg', (201, 211))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('ZSTK474', 'Chemical', 'MESH:C510150', (0, 7))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('sarcoma', 'Disease', (64, 71))	('ZSTK474', 'Chemical', 'MESH:C510150', (110, 117))	('tumor', 'Disease', (215, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
203417	30416685	Sequencing library construction and Ion torrent amplicon sequencing were performed via the TaKaRa Amplicon sequencing service by using the Ion Ampliseq Cancer Hotspot Panel v2, which includes primer sets to amplify 207 amplicons covering approximately 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes using human hg19 reference genome as described in the manufacturer's web site (https://www.thermofisher.com/order/catalog/product/4475346).	('Cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (152, 158))	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (265, 274))	('human', 'Species', '9606', (326, 331))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', (297, 302))
203431	30416685	Antitumor effects were evaluated for 14 days in SJCRH30-, 14 days in SK-UT-1-, 10 days MES-SA-, 10 days in MES-SA/Dx5-, 14 days in A673-, 14 days in SYO-1- xenografted mice.	('tumor', 'Disease', (4, 9))	('Dx5', 'Gene', '16398', (114, 117))	('MES-SA', 'Chemical', '-', (107, 113))	('ES', 'Phenotype', 'HP:0012254', (108, 110))	('MES-SA', 'Chemical', '-', (87, 93))	('SK-UT-1', 'Chemical', '-', (69, 76))	('mice', 'Species', '10090', (168, 172))	('SYO-1', 'Gene', (149, 154))	('SJCRH30', 'Chemical', '-', (48, 55))	('SYO-1', 'Gene', '55027', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('ES', 'Phenotype', 'HP:0012254', (88, 90))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SJCRH30-', 'Var', (48, 56))	('Dx5', 'Gene', (114, 117))
203436	30416685	Targeted antigens were detected by incubating with anti-phospho AKT (Ser473) antibody, anti-phospho AKT (Thr308) antibody, anti-pan AKT antibody, anti-phospho S6 antibody, anti-S6 antibody, anti-phospho IGF-1R beta (Tyr1135/1136) antibody, anti-phospho MEK 1/2 (Ser217/221) antibody, anti-phospho ERK 1/2 (Thr203/Tyr204) antibody, anti-phospho 4E-BP1 (Thr37/46), anti-AKT antibody, anti-S6 antibody, anti-cleaved PARP at Asp214 antibody, anti-PTEN antibody, anti-Id2 antibody, anti-GAPDH antibody (Cell Signaling Technologies, MA, USA), anti-phospho IGF-1R antibody (Abcam, Cambridge, UK) or anti-alpha tubulin antibody (Sigma-Aldrich, MO, USA), followed by fluorescently tagged secondary antibodies (Thermo Fisher Scientific, CA, USA).	('GAPDH', 'Gene', (482, 487))	('S6', 'Gene', '6194', (387, 389))	('ERK 1/2', 'Gene', (297, 304))	('ERK 1/2', 'Gene', '5595', (297, 304))	('PTEN', 'Gene', '5728', (443, 447))	('Id2', 'Gene', (463, 466))	('E-BP1', 'Gene', '4790', (345, 350))	('MEK 1/2', 'Gene', '5604;5605', (253, 260))	('S6', 'Gene', '6194', (177, 179))	('Id2', 'Gene', '3398', (463, 466))	('PARP', 'Gene', '142', (413, 417))	('E-BP1', 'Gene', (345, 350))	('S6', 'Gene', '6194', (159, 161))	('MEK 1/2', 'Gene', (253, 260))	('IGF-1R', 'Gene', (203, 209))	('SA', 'Chemical', 'MESH:C012546', (732, 734))	('GAPDH', 'Gene', '2597', (482, 487))	('PARP', 'Gene', (413, 417))	('IGF-1R', 'Gene', '3480', (203, 209))	('SA', 'Chemical', 'MESH:C012546', (532, 534))	('anti-phospho', 'Var', (537, 549))	('SA', 'Chemical', 'MESH:C012546', (641, 643))	('IGF-1R', 'Gene', '3480', (550, 556))	('PTEN', 'Gene', (443, 447))	('IGF-1R', 'Gene', (550, 556))
203692	28137790	Estimating TP53 Mutation Carrier Probability in Families with Li-Fraumeni Syndrome Using LFSPRO Li-Fraumeni syndrome (LFS) is associated with germline TP53 mutations and a very high lifetime cancer risk.	('associated', 'Reg', (126, 136))	('cancer', 'Disease', (191, 197))	('Li-Fraumeni', 'Disease', (62, 73))	('TP53', 'Gene', (151, 155))	('Li-Fraumeni syndrome', 'Disease', (96, 116))	('TP53', 'Gene', '7157', (11, 15))	('mutations', 'Var', (156, 165))	('TP53', 'Gene', (11, 15))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (96, 107))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Li-Fraumeni', 'Disease', (96, 107))	('germline', 'Var', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (96, 116))	('TP53', 'Gene', '7157', (151, 155))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (62, 73))
203694	28137790	The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making for TP53 mutation testing and LFS management.	('TP53', 'Gene', '7157', (136, 140))	('mutation', 'Var', (141, 149))	('TP53', 'Gene', (136, 140))
203695	28137790	Based on a Mendelian model, LFSPRO estimates TP53 mutation probability through the Elston-Stewart algorithm, and consequently estimates future risk of cancer.	('TP53', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('TP53', 'Gene', '7157', (45, 49))	('mutation', 'Var', (50, 58))
203696	28137790	LFSPRO accurately predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center (MDACC) in the US, the observed to expected ratio (OE) = 1.35 (95%CI, 0.99 to 1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75 to 0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study (ISKS) in Australia, OE = 1.62 (1.03 to 2.55); AUC = 0.67 (0.54 to 0.79); and the NCI LFS study cohort, OE = 1.28 (1.17 to 1.39); AUC = 0.82 (0.78 to 0.86).	('TP53', 'Gene', '7157', (28, 32))	('mutation', 'Var', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcoma cohort', 'Disease', 'MESH:D012509', (300, 314))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (86, 104))	('sarcoma cohort', 'Disease', 'MESH:D012509', (66, 80))	('Sarcoma', 'Phenotype', 'HP:0100242', (338, 345))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TP53', 'Gene', (28, 32))	('pediatric sarcoma', 'Disease', (56, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (300, 307))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (56, 73))	('MD Anderson Cancer', 'Disease', (86, 104))	('sarcoma cohort', 'Disease', (66, 80))	('Sarcoma', 'Disease', (338, 345))	('Sarcoma', 'Disease', 'MESH:D012509', (338, 345))	('sarcoma cohort', 'Disease', (300, 314))
203697	28137790	LFSPRO shows good performance in predicting TP53 mutations in individuals and families in varied situations.	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('mutations', 'Var', (49, 58))
203699	28137790	Germline mutations in the tumor suppressor gene TP53 are present in about 70% of families meeting classic LFS criteria (Figure S1).	('Germline mutations', 'Var', (0, 18))	('TP53', 'Gene', '7157', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('TP53', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
203700	28137790	In these families, the lifetime cancer penetrance for TP53 mutation carriers is 90%, increasing to nearly 100% for women by age 70 years, mostly because of breast cancer.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('TP53', 'Gene', '7157', (54, 58))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('mutation', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('breast cancer', 'Disease', (156, 169))	('TP53', 'Gene', (54, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('women', 'Species', '9606', (115, 120))
203701	28137790	Given this extremely high lifetime cancer risk, tools to identify who to test for germline TP53 mutations may be useful.	('TP53', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('TP53', 'Gene', '7157', (91, 95))	('cancer', 'Disease', (35, 41))	('mutations', 'Var', (96, 105))
203702	28137790	One study demonstrated significantly improved survival of TP53 mutation carriers using clinical surveillance and whole-body imaging.	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('survival', 'MPA', (46, 54))	('mutation', 'Var', (63, 71))	('improved', 'PosReg', (37, 45))
203703	28137790	Classic LFS criteria have high specificity for predicting TP53 mutations, but low sensitivity.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))
203704	28137790	Further criteria assist in identifying potential germline TP53 mutation carriers, but are relatively insensitive to de novo mutations.	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))	('mutation', 'Var', (63, 71))
203705	28137790	Chompret criteria (Figure S1) have evolved to identify de novo TP53 mutations, which may affect up to 20% of carriers.	('mutations', 'Var', (68, 77))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))
203708	28137790	LFSPRO estimates the probability of any designated family member carrying a TP53 mutation based on a detailed family cancer history (Table S1) and values of two sets of parameters, the prevalence and penetrance for TP53, respectively.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('TP53', 'Gene', '7157', (76, 80))	('mutation', 'Var', (81, 89))	('TP53', 'Gene', '7157', (215, 219))	('TP53', 'Gene', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('TP53', 'Gene', (215, 219))
203709	28137790	The prevalence of TP53 mutations is expressed as Pr(G), where G denotes genotype, which could be wildtype (denoted as 0), a heterozygous mutation (denoted as 1) or a homozygous mutation (denoted as 2).	('mutations', 'Var', (23, 32))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))
203710	28137790	The penetrance is the probability of developing cancer at a given age, for TP53 mutation carriers and noncarriers, respectively.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('TP53', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (75, 79))	('mutation', 'Var', (80, 88))
203716	28137790	However, LFSPRO accounts for the occurrence of de novo mutations: when neither parent carries a TP53 mutation, we still consider a transmission probability of 2a that their child may become a carrier of a TP53 germline mutation, where a denotes the probability of obtaining a new mutated allele.	('child', 'Species', '9606', (173, 178))	('TP53', 'Gene', (96, 100))	('TP53', 'Gene', '7157', (205, 209))	('TP53', 'Gene', (205, 209))	('mutation', 'Var', (101, 109))	('TP53', 'Gene', '7157', (96, 100))
203718	28137790	We used previous penetrance estimates for TP53 mutation carriers and noncarriers from six large pediatric sarcoma families at the University of Texas MD Anderson Cancer Center (MDACC), which are not included in the test cohort.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('TP53', 'Gene', '7157', (42, 46))	('pediatric sarcoma', 'Disease', (96, 113))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (96, 113))	('TP53', 'Gene', (42, 46))	('mutation', 'Var', (47, 55))	('Texas MD Anderson Cancer', 'Disease', (144, 168))	('Texas MD Anderson Cancer', 'Disease', 'MESH:C535460', (144, 168))	('Cancer', 'Phenotype', 'HP:0002664', (162, 168))
203723	28137790	To compare the true prevalence of TP53 mutations in clinic populations to that in the general population, we modeled LFSPRO outputs, assuming the above prevalence estimates.	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))
203724	28137790	estimated the proportion of de novo mutations within germline mutations of TP53 as 7%-20%, with paternal or maternal origin.	('TP53', 'Gene', '7157', (75, 79))	('germline mutations', 'Var', (53, 71))	('TP53', 'Gene', (75, 79))	('mutations', 'Var', (36, 45))
203725	28137790	We used both 7% and 20% to calculate the prevalence of de novo TP53 mutations from the three sets of prevalence data described above.	('mutations', 'Var', (68, 77))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))
203729	28137790	Eleven of the 183 kindreds had at least one individual with a confirmed germline TP53 mutation; the rest had no confirmed mutation carriers.	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('mutation', 'Var', (86, 94))
203733	28137790	Nineteen of the kindreds had at least one individual with a confirmed TP53 mutation.	('TP53', 'Gene', '7157', (70, 74))	('TP53', 'Gene', (70, 74))	('mutation', 'Var', (75, 83))
203734	28137790	iii) The National Cancer Institute (NCI) LFS cohort (NCT01443468) is from a long-term prospective, natural history study that started in 2011, and includes individuals meeting classic LFS or modified criteria, having a pathogenic germline TP53 mutation or a first- or second-degree relative with a mutation, or a personal history of choroid plexus carcinoma, adrenocortical carcinoma, or at least 3 primary cancers.	('cancers', 'Phenotype', 'HP:0002664', (407, 414))	('cancers', 'Disease', (407, 414))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('TP53', 'Gene', '7157', (239, 243))	('pathogenic', 'Reg', (219, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (374, 383))	('choroid plexus carcinoma', 'Disease', (333, 357))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (359, 383))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (333, 357))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (407, 414))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (359, 383))	('Cancer', 'Disease', (18, 24))	('TP53', 'Gene', (239, 243))	('adrenocortical carcinoma', 'Disease', (359, 383))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (333, 357))	('mutation', 'Var', (244, 252))	('Cancer', 'Disease', 'MESH:D009369', (18, 24))
203739	28137790	At MDACC, if a TP53 mutation was identified, then all first-degree relatives of the proband (affected and unaffected by cancer) and any other family member at risk of carrying the familial mutation were tested.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutation', 'Var', (20, 28))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('tested', 'Reg', (203, 209))
203741	28137790	No testing was offered to relatives if the proband tested negative for a TP53 mutation.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('mutation', 'Var', (78, 86))
203743	28137790	We used LFSPRO to calculate the carrier probabilities of TP53 mutations for all tested individuals (TP53 positive and negative).	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (100, 104))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
203744	28137790	A high area under the ROC curve (AUC) indicates that we can find a point on the ROC curve for determining the TP53 mutation carrier with a high true positive rate and low false positive rate.	('mutation', 'Var', (115, 123))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))
203745	28137790	The OE is the ratio between the number of observed TP53 mutation carriers and the summation of the estimated probability of TP53 mutation carriers.	('TP53', 'Gene', '7157', (124, 128))	('TP53', 'Gene', (51, 55))	('TP53', 'Gene', (124, 128))	('mutation', 'Var', (56, 64))	('TP53', 'Gene', '7157', (51, 55))
203748	28137790	Four scenarios of a hypothetical pedigree illustrate how LFSPRO estimates TP53 mutation probability (Figure 1, Table 3).	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))
203749	28137790	Figure 1A shows four family members diagnosed with early-onset cancers in each of four generations, suggesting a germline TP53 mutation.	('TP53', 'Gene', (122, 126))	('mutation', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('TP53', 'Gene', '7157', (122, 126))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
203751	28137790	Given the high mutation probability, when asymptomatic, the counselee has an elevated risk of developing cancer compared to the population: respectively 31% vs. 2% at age 40 years and 43% vs. 9% at age 70 years.	('mutation', 'Var', (15, 23))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
203753	28137790	Early cancer in a grandmother within the counselee's direct lineage provides stronger evidence that the counselee may have inherited a germline mutation in TP53, and her carrier probability increases to 82%.	('germline mutation', 'Var', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))
203755	28137790	In these three scenarios, the Mendelian transmission of a germline mutation in TP53 likely occurred via the counselee's maternal line.	('germline mutation', 'Var', (58, 75))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))
203756	28137790	Both of the counselee's maternal great-grandparents stayed healthy until death at an advanced age, while the counselee's mother had early-onset breast cancer, likely due to de novo TP53 mutation.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('TP53', 'Gene', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('TP53', 'Gene', '7157', (181, 185))	('mutation', 'Var', (186, 194))
203757	28137790	Three independent cohorts, comprising 867 families and 22,206 individuals, and 1,353 individuals tested for TP53 mutations, were used to assess the performance of LFSPRO (Tables 1, 2) using six settings of the prevalence values for deleterious germline and de novo TP53 mutations (Table S2).	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('TP53', 'Gene', '7157', (265, 269))	('mutations', 'Var', (270, 279))	('TP53', 'Gene', (265, 269))
203758	28137790	Clinical populations like our cohorts are likely to have enriched TP53 mutations compared to that in the general population.	('TP53', 'Gene', (66, 70))	('mutations', 'Var', (71, 80))	('TP53', 'Gene', '7157', (66, 70))
203759	28137790	The closest data we can reliably use to estimate a population undergoing genetic testing is that provided by Myriad Genetics, which showed the prevalence of germline mutations in TP53 as 0.0006 (see Materials and Methods).	('germline mutations', 'Var', (157, 175))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (179, 183))
203760	28137790	For the MDACC dataset, classic LFS criteria were highly specific at predicting TP53 mutation carrier status, but had 12.5% sensitivity; whereas Chompret criteria had higher sensitivity (50%), with a slightly higher false positive rate (7%).	('mutation carrier status', 'Var', (84, 107))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))
203762	28137790	Classic LFS criteria's low sensitivity makes it difficult to detect TP53 mutation carriers, but its high specificity reduces false positives.	('mutation', 'Var', (73, 81))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('reduces', 'NegReg', (117, 124))
203766	28137790	We have developed a probabilistic prediction algorithm, LFSPRO, for TP53 germline mutations and personalized cancer risk associated with LFS (Table S1 describes LFSPRO software).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('LFS', 'Var', (137, 140))	('TP53', 'Gene', '7157', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('TP53', 'Gene', (68, 72))
203768	28137790	Ideally, information on affected family members should improve the sensitivity of TP53 mutation probability prediction by LFSPRO, while information about unaffected family members should lower high false positive rates.	('TP53', 'Gene', (82, 86))	('improve', 'PosReg', (55, 62))	('lower', 'NegReg', (187, 192))	('TP53', 'Gene', '7157', (82, 86))	('mutation', 'Var', (87, 95))
203771	28137790	LFSPRO performs best with the MDACC cohort (ascertainment through a specific tumor type and age, i.e., pediatric sarcoma) and the NCI cohort (ascertainment through a specific type of family history, i.e., families of LFS type), as TP53 germline mutations are the dominant cause of cancer in both cohorts.	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (103, 120))	('germline mutations', 'Var', (236, 254))	('pediatric sarcoma', 'Disease', (103, 120))	('cancer', 'Disease', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('TP53', 'Gene', '7157', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('TP53', 'Gene', (231, 235))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', (77, 82))
203774	28137790	Many of these families did not display the classic LFS family history of cancer, rather subsequent sequencing identified a group of participants that carried germline TP53 mutations.	('TP53', 'Gene', (167, 171))	('mutations', 'Var', (172, 181))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (167, 171))	('participants', 'Species', '9606', (132, 144))
203775	28137790	In this case, LFSPRO may still be used, but in conjunction with risk prediction models for other genes when possible (e.g., BRCAPRO for BRCA1/2 mutations in early-onset breast cancer), in order to help identify portions of the phenotype that are caused by TP53 mutations or other mutations, as people are increasingly identified as carrying TP53 mutations by non-traditional methods.	('mutations', 'Var', (261, 270))	('BRCA', 'Gene', '672', (124, 128))	('TP53', 'Gene', '7157', (341, 345))	('TP53', 'Gene', (341, 345))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('caused', 'Reg', (246, 252))	('BRCA', 'Gene', (124, 128))	('BRCA1/2', 'Gene', (136, 143))	('BRCA', 'Gene', '672', (136, 140))	('TP53', 'Gene', '7157', (256, 260))	('people', 'Species', '9606', (294, 300))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('mutations', 'Var', (144, 153))	('BRCA1/2', 'Gene', '672;675', (136, 143))	('breast cancer', 'Disease', (169, 182))	('TP53', 'Gene', (256, 260))	('BRCA', 'Gene', (136, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
203776	28137790	The practice of testing for TP53 mutations has changed over time and is not always 100% accurate.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
203778	28137790	We consider the deleterious del/dups in TP53 to be rare and the difference in sensitivity across these datasets is likely to be small.	('TP53', 'Gene', '7157', (40, 44))	('del/dups', 'Var', (28, 36))	('TP53', 'Gene', (40, 44))
203784	28137790	LFSPRO well discriminated mutation carriers from non-carriers (evaluated by AUCs) under six sets of assumed prevalence values for germline and de novo TP53 mutations.	('TP53', 'Gene', (151, 155))	('mutation', 'Var', (26, 34))	('mutations', 'Var', (156, 165))	('discriminated', 'Reg', (12, 25))	('TP53', 'Gene', '7157', (151, 155))
203788	28137790	As more clinical genetic testing with large gene panels becomes routine, LFSPRO will potentially aid in the interpretation of genetic variants in TP53 of unknown significance and prove useful in the management of Li-Fraumeni syndrome.	('variants', 'Var', (134, 142))	('TP53', 'Gene', '7157', (146, 150))	('Li-Fraumeni syndrome', 'Disease', (213, 233))	('aid', 'Reg', (97, 100))	('TP53', 'Gene', (146, 150))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (213, 233))
203880	28484655	Another study of tumor flare occurrence and its prognostic role after discontinuing anti-VEGF receptor TKIs investigated patients with metastatic renal cell carcinoma, similarly concluding that TKI discontinuation accelerates tumor growth rate and negatively affects prognosis.	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('affects', 'Reg', (259, 266))	('metastatic renal cell carcinoma', 'Disease', (135, 166))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (135, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (146, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('prognosis', 'MPA', (267, 276))	('tumor', 'Disease', (17, 22))	('accelerates', 'PosReg', (214, 225))	('VEGF', 'Gene', '7422', (89, 93))	('negatively', 'NegReg', (248, 258))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('VEGF', 'Gene', (89, 93))	('TKI', 'Gene', (194, 197))	('patients', 'Species', '9606', (121, 129))	('discontinuation', 'Var', (198, 213))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (226, 231))
203900	25792975	CD70+ primary cultures were derived from CD70+ osteosarcoma lesions.	('osteosarcoma lesions', 'Disease', (47, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('osteosarcoma lesions', 'Disease', 'MESH:D012516', (47, 67))	('CD70+', 'Var', (41, 46))	('osteosarcoma', 'Phenotype', 'HP:0002669', (47, 59))
203906	25792975	In patients with CD70+ tumors, CD70 may represent a novel candidate for antibody-based targeted immunotherapy.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('CD70+', 'Var', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (3, 11))	('CD70', 'Var', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
203919	25792975	On human NK cells CD27 is acquired during maturation in lymphoid organs but down-regulated in terminal maturation stages; in peripheral blood CD27+ NK cells are functionally closely related to CD56bright NK cells, whereas CD27- NK cells correspond to CD56dim NK cells.	('rat', 'Species', '10116', (46, 49))	('human', 'Species', '9606', (3, 8))	('CD56', 'Gene', (251, 255))	('CD56', 'Gene', '4684', (193, 197))	('CD27+', 'Var', (142, 147))	('CD56', 'Gene', (193, 197))	('CD56', 'Gene', '4684', (251, 255))	('rat', 'Species', '10116', (107, 110))
203922	25792975	In addition, CD70 on cancer cells is an attractive candidate for targeted immunotherapy due to its restricted expression on non-malignant cells.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (21, 27))	('CD70', 'Var', (13, 17))
203963	25792975	Of the tumor-primary culture combinations, parental tissue of L2531 (p363) exhibited CD70-expressing cells in focal regions.	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('L2531 (p363', 'Var', (62, 73))	('tumor', 'Disease', (7, 12))
203966	25792975	In the residual four patients with combinations of consecutive tumor specimens, one metastatic tumor (L437, p47) contained CD70-expressing cells, while there were no CD70-expressing cells detectable in the primary tumor (L1046) of the same patient (Table 1).	('p47', 'Gene', (108, 111))	('tumor', 'Disease', (63, 68))	('CD70-expressing', 'Var', (123, 138))	('patient', 'Species', '9606', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('p47', 'Gene', '3621', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('patient', 'Species', '9606', (240, 247))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (95, 100))
203970	25792975	Thus because cell lines were homogenously positive for CD70 even if they grew from tumors in which not all cells expressed CD70, these results suggest that CD70+ cells in the tumor preferentially grow out to CD70+ primary patient-derived cultures.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (175, 180))	('CD70+', 'Var', (156, 161))	('tumor', 'Disease', (83, 88))	('patient', 'Species', '9606', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('preferentially', 'PosReg', (181, 195))	('grow out', 'CPA', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
203979	25792975	Strong immunofluorescent staining for CD70 was confined to tumor cells and did not co-localize with the T cell marker CD3 (Figure 4, panel B).	('tumor', 'Disease', (59, 64))	('CD70', 'Var', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('S', 'Chemical', 'MESH:D013455', (0, 1))
203980	25792975	In contrast to CD70, its receptor CD27 was detected neither in CD70+ nor CD70- osteosarcoma lesions and was not expressed by infiltrating T cells (Figure 4, panel C and data not shown).	('rat', 'Species', '10116', (131, 134))	('CD70-', 'Var', (73, 78))	('osteosarcoma', 'Phenotype', 'HP:0002669', (79, 91))	('osteosarcoma lesions', 'Disease', (79, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('osteosarcoma lesions', 'Disease', 'MESH:D012516', (79, 99))
203983	25792975	In the remaining 70 patients, the occurrence of overt metastasis (metastasis-free survival) during ten years of follow-up was not statistically different between patients with high or low CD70 gene expression (log-rank chi2 = 0.29, p = 0.59) (Figure 3, panel C).	('patients', 'Species', '9606', (162, 170))	('low', 'NegReg', (184, 187))	('CD70', 'Gene', (188, 192))	('patients', 'Species', '9606', (20, 28))	('high', 'Var', (176, 180))
203985	25792975	In conclusion, high CD70 expression in osteosarcoma tumors is not associated with better or worse metastasis-free survival.	('CD70', 'Protein', (20, 24))	('high', 'Var', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (39, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('expression', 'MPA', (25, 35))	('osteosarcoma tumors', 'Disease', (39, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (39, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))
203996	25792975	Acute challenge with CD70+ tumor cells was shown to induce anti-tumor T cell-mediated immunity.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (27, 32))	('CD70+', 'Var', (21, 26))	('induce', 'PosReg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
203998	25792975	On the contrary, co-culture of CD70+ tumor cells and CD27+ immune cells was shown to inhibit alloreactive T cell proliferation and induce T cell apoptosis.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('T cell apoptosis', 'CPA', (138, 154))	('alloreactive T cell proliferation', 'CPA', (93, 126))	('inhibit', 'NegReg', (85, 92))	('CD70+', 'Var', (31, 36))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('rat', 'Species', '10116', (120, 123))	('induce', 'PosReg', (131, 137))
204000	25792975	In line with the latter observations, CD70+ tumor cells in renal cell carcinoma and B cell lymphoma may promote depletion of naive CD27+ T cells and induce regulatory T cells in the tumor, respectively.	('B cell lymphoma', 'Phenotype', 'HP:0012191', (84, 99))	('promote', 'PosReg', (104, 111))	('renal cell carcinoma', 'Disease', (59, 79))	('tumor', 'Disease', (44, 49))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (59, 79))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('B cell lymphoma', 'Disease', (84, 99))	('depletion', 'MPA', (112, 121))	('CD70+', 'Var', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('induce', 'PosReg', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('B cell lymphoma', 'Disease', 'MESH:D016393', (84, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (59, 79))	('tumor', 'Disease', (182, 187))	('regulatory T cells', 'CPA', (156, 174))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
204003	25792975	In our cohort of osteosarcoma patients, CD70 gene expression at the time of diagnosis did not correlate with metastasis-free survival, suggesting that at least in osteosarcoma, CD70 expression does not promote tumor progression.	('CD70', 'Var', (177, 181))	('osteosarcoma', 'Disease', (17, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('osteosarcoma', 'Disease', 'MESH:D012516', (17, 29))	('osteosarcoma', 'Disease', (163, 175))	('tumor', 'Disease', (210, 215))	('osteosarcoma', 'Phenotype', 'HP:0002669', (163, 175))	('patients', 'Species', '9606', (30, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (163, 175))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
204008	25792975	In preclinical studies, anti-CD70 antibodies demonstrated indirect anti-tumor efficacy mediated by NK cells and macrophages involving antibody-dependent cellular cytotoxicity and tumor cell phagocytosis, respectively, as we have similarly recently reported using the clinically-approved anti-epidermal growth factor receptor antibody cetuximab.	('rat', 'Species', '10116', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('epidermal growth factor receptor', 'Gene', (292, 324))	('cytotoxicity', 'Disease', 'MESH:D064420', (162, 174))	('tumor', 'Disease', (72, 77))	('cetuximab', 'Chemical', 'MESH:D000068818', (334, 343))	('antibodies', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('epidermal growth factor receptor', 'Gene', '1956', (292, 324))	('anti-CD70 antibodies', 'Var', (24, 44))	('cytotoxicity', 'Disease', (162, 174))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (179, 184))
204009	25792975	In addition, if conjugated to cytotoxic drugs anti-CD70 antibodies can mediate direct anti-tumor effects.	('antibodies', 'Protein', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('anti-CD70', 'Var', (46, 55))	('tumor', 'Disease', (91, 96))
204014	24458261	Unlike other anti-IGF1R antibodies, BIIB022 has no effector functions.	('BIIB022', 'Chemical', 'MESH:C000594951', (36, 43))	('BIIB022', 'Var', (36, 43))	('IGF1R', 'Gene', (18, 23))	('IGF1R', 'Gene', '3480', (18, 23))
204028	24458261	Perturbation with an anti-IGF-1R antibody of IGF-1R axis is therefore hypothesized to have therapeutic value.	('IGF-1R', 'Gene', (45, 51))	('IGF-1R', 'Gene', (26, 32))	('IGF-1R', 'Gene', '3480', (26, 32))	('IGF-1R', 'Gene', '3480', (45, 51))	('Perturbation', 'Var', (0, 12))
204031	24458261	BIIB022 blocks both IGF-1 and IGF-2 induced phosphorylation of IGF-1R and downstream substrates, thereby inhibiting ligand-mediated receptor signaling.	('inhibiting', 'NegReg', (105, 115))	('phosphorylation', 'MPA', (44, 59))	('BIIB022', 'Var', (0, 7))	('ligand-mediated receptor signaling', 'MPA', (116, 150))	('IGF-1', 'Gene', '3479', (20, 25))	('IGF-1', 'Gene', (20, 25))	('IGF-1', 'Gene', '3479', (63, 68))	('IGF-1', 'Gene', (63, 68))	('blocks', 'NegReg', (8, 14))	('IGF-2', 'Gene', (30, 35))	('IGF-1R', 'Gene', '3480', (63, 69))	('IGF-2', 'Gene', '3481', (30, 35))	('BIIB022', 'Chemical', 'MESH:C000594951', (0, 7))	('IGF-1R', 'Gene', (63, 69))
204032	24458261	Additionally, BIIB022 was designed without Fc effector function and C1q binding and therefore cannot activate antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), features that may limit toxicity associated with this agent.	('toxicity', 'Disease', 'MESH:D064420', (231, 239))	('BIIB022', 'Chemical', 'MESH:C000594951', (14, 21))	('cytotoxicity', 'Disease', 'MESH:D064420', (187, 199))	('cytotoxicity', 'Disease', (143, 155))	('toxicity', 'Disease', 'MESH:D064420', (147, 155))	('toxicity', 'Disease', (147, 155))	('BIIB022', 'Var', (14, 21))	('toxicity', 'Disease', 'MESH:D064420', (191, 199))	('C1q', 'Gene', '712', (68, 71))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('C1q', 'Gene', (68, 71))	('cytotoxicity', 'Disease', (187, 199))	('toxicity', 'Disease', (191, 199))	('toxicity', 'Disease', (231, 239))
204033	24458261	In vitro studies demonstrated evidence of decreased cell growth following treatment with BIIB022 in lung, pancreas and colon cancer cell lines in the presence of IGF-1 or IGF-2 in culture media.	('BIIB022', 'Var', (89, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('cell growth', 'CPA', (52, 63))	('decreased', 'NegReg', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreas and colon cancer', 'Disease', 'MESH:D010190', (106, 131))	('IGF-2', 'Gene', (171, 176))	('BIIB022', 'Chemical', 'MESH:C000594951', (89, 96))	('IGF-1', 'Gene', '3479', (162, 167))	('IGF-1', 'Gene', (162, 167))	('IGF-2', 'Gene', '3481', (171, 176))
204038	24458261	Other eligibility criteria included adequate hematologic, renal, and hepatic function; no history of diabetes mellitus; and hemoglobin A1c <= 6.	('diabetes mellitus', 'Phenotype', 'HP:0000819', (101, 118))	('hemoglobin', 'Var', (124, 134))	('diabetes mellitus', 'Disease', (101, 118))	('diabetes mellitus', 'Disease', 'MESH:D003920', (101, 118))	('hemoglobin A1c', 'Phenotype', 'HP:0040217', (124, 138))	('hepatic function', 'MPA', (69, 85))
204047	24458261	Extra electro-cardiograms were added in response to a DLT of QTc prolongation in this study and routine audiometry assessments were added in response to an ototoxicity DLT seen in contemporaneous phase I clinical trials of other anti-IGF-1R antibodies.	('DLT', 'Var', (54, 57))	('ototoxicity', 'Disease', 'MESH:D006311', (156, 167))	('IGF-1R', 'Gene', '3480', (234, 240))	('QTc prolongation', 'Disease', 'MESH:D011273', (61, 77))	('IGF-1R', 'Gene', (234, 240))	('ototoxicity', 'Disease', (156, 167))	('QTc prolongation', 'Disease', (61, 77))
204048	24458261	Therapy with BIIB022 was continued until disease progression, unacceptable toxicity, or subject withdrawal.	('toxicity', 'Disease', 'MESH:D064420', (75, 83))	('BIIB022', 'Chemical', 'MESH:C000594951', (13, 20))	('toxicity', 'Disease', (75, 83))	('BIIB022', 'Var', (13, 20))
204050	24458261	The BED was defined as the dose at which BIIB022 serum exposure had reached a plateau in 2 successive dose cohorts (indicating receptor saturating exposure), or the BIIB022 dose resulting in human exposure approximately 10 times higher than serum levels associated with maximal anti-tumor activity in animal xenograft models.	('BIIB022', 'Chemical', 'MESH:C000594951', (41, 48))	('BIIB022', 'Gene', (41, 48))	('higher', 'PosReg', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('BIIB022', 'Var', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumor', 'Disease', (283, 288))	('human', 'Species', '9606', (191, 196))	('BIIB022', 'Chemical', 'MESH:C000594951', (165, 172))
204087	24458261	Although the GI bleed was most likely related to the tumor, a contribution from BIIB022 could not be ruled out, and it was considered a DLT based on the definitions set forth in the protocol.	('GI bleed', 'Phenotype', 'HP:0002239', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('GI bleed', 'Disease', 'MESH:D006470', (13, 21))	('BIIB022', 'Chemical', 'MESH:C000594951', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('BIIB022', 'Var', (80, 87))	('GI bleed', 'Disease', (13, 21))
204092	24458261	Serum exposure increased in a dose-dependent manner, but BIIB022 demonstrated nonlinear PK, as indicated by the plot of AUCinf versus Dose in Fig.	('BIIB022', 'Chemical', 'MESH:C000594951', (57, 64))	('BIIB022', 'Var', (57, 64))	('nonlinear', 'MPA', (78, 87))
204113	24458261	His FDG uptake on day 43, after 2 BIIB022 doses, had decreased by 40 % compared with baseline.	('BIIB022', 'Var', (34, 41))	('FDG uptake', 'MPA', (4, 14))	('decreased', 'NegReg', (53, 62))	('FDG', 'Chemical', 'MESH:D019788', (4, 7))	('BIIB022', 'Chemical', 'MESH:C000594951', (34, 41))
204120	24458261	BIIB022 has a unique structure compared with other antibodies targeting IGF-1R.	('IGF-1R', 'Gene', (72, 78))	('IGF-1R', 'Gene', '3480', (72, 78))	('BIIB022', 'Chemical', 'MESH:C000594951', (0, 7))	('BIIB022', 'Var', (0, 7))
204121	24458261	Ganitumab (AMG-479), R1507, and daltuzumab (MK-0646) are humanized IgG1 antibodies while figitumimab (CP-751,871) is a humanized IgG2 antibody.	('R1507', 'Var', (21, 26))	('AMG', 'Gene', '265', (11, 14))	('Ganitumab', 'Chemical', 'MESH:C545764', (0, 9))	('AMG', 'Gene', (11, 14))	('human', 'Species', '9606', (57, 62))	('human', 'Species', '9606', (119, 124))
204122	24458261	By contrast, BIIB022 is a non-glycosylated human IgG4 monoclonal antibody that lacks Fc effector and C1q binding domains.	('BIIB022', 'Var', (13, 20))	('C1q', 'Gene', '712', (101, 104))	('C1q', 'Gene', (101, 104))	('BIIB022', 'Chemical', 'MESH:C000594951', (13, 20))	('human', 'Species', '9606', (43, 48))
204127	24458261	Unlike the other antibodies in development, BIIB022 interferes with receptor function via an allosteric mechanism, as it binds an epitope on the fibronectin III-1 domain of IGF-1R that is distinct from the IGF-1 and IGF-2 binding regions.	('IGF-2', 'Gene', '3481', (216, 221))	('receptor function', 'MPA', (68, 85))	('IGF-1', 'Gene', '3479', (173, 178))	('IGF-1', 'Gene', (173, 178))	('IGF-1R', 'Gene', '3480', (173, 179))	('interferes', 'NegReg', (52, 62))	('IGF-1R', 'Gene', (173, 179))	('binds', 'Interaction', (121, 126))	('BIIB022', 'Chemical', 'MESH:C000594951', (44, 51))	('allosteric', 'MPA', (93, 103))	('BIIB022', 'Var', (44, 51))	('IGF-1', 'Gene', '3479', (206, 211))	('IGF-1', 'Gene', (206, 211))	('IGF-2', 'Gene', (216, 221))
204128	24458261	Thus, BIIB022 can engage IGF-1R in the presence of ligands and is hypothesized to cause a conformational change that significantly reduces ligand affinity for the receptor.	('BIIB022', 'Var', (6, 13))	('ligand affinity', 'MPA', (139, 154))	('reduces', 'NegReg', (131, 138))	('engage', 'Interaction', (18, 24))	('conformational change', 'MPA', (90, 111))	('IGF-1R', 'Gene', '3480', (25, 31))	('IGF-1R', 'Gene', (25, 31))	('BIIB022', 'Chemical', 'MESH:C000594951', (6, 13))
204130	24458261	While toxicities (all grades) were reported in all patients, the proportion of patients with grade 3 toxicities related to BIIB022 was only 21 %.	('BIIB022', 'Var', (123, 130))	('toxicities', 'Disease', (101, 111))	('toxicities', 'Disease', 'MESH:D064420', (6, 16))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (51, 59))	('BIIB022', 'Chemical', 'MESH:C000594951', (123, 130))	('toxicities', 'Disease', 'MESH:D064420', (101, 111))	('toxicities', 'Disease', (6, 16))
204132	24458261	We did note some cardiovascular effects that may have been attributable to BIIB022, including one patient with hypertension and a second with asymptomatic EKG changes including T-wave inversion and QTc prolongation.	('hypertension', 'Disease', (111, 123))	('T-wave inversion', 'Disease', (177, 193))	('hypertension', 'Phenotype', 'HP:0000822', (111, 123))	('patient', 'Species', '9606', (98, 105))	('QTc prolongation', 'Disease', 'MESH:D011273', (198, 214))	('T-wave inversion', 'Phenotype', 'HP:0010872', (177, 193))	('hypertension', 'Disease', 'MESH:D006973', (111, 123))	('QTc prolongation', 'Disease', (198, 214))	('BIIB022', 'Chemical', 'MESH:C000594951', (75, 82))	('T-wave', 'Phenotype', 'HP:0005135', (177, 183))	('BIIB022', 'Var', (75, 82))	('cardiovascular', 'Disease', (17, 31))
204136	24458261	We note that cerebral ischemia was reported in a patient treated with R1507.	('R1507', 'Var', (70, 75))	('patient', 'Species', '9606', (49, 56))	('cerebral ischemia', 'Phenotype', 'HP:0002637', (13, 30))	('cerebral ischemia', 'Disease', (13, 30))	('cerebral ischemia', 'Disease', 'MESH:D002545', (13, 30))
204137	24458261	It seems unlikely that either of these events were drug related as there are no data to date showing that inhibition of IGF-1R perturbs coagulation and patients with metastatic cancers are known to be hypercoagulable.	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('inhibition', 'Var', (106, 116))	('IGF-1R', 'Gene', (120, 126))	('IGF-1R', 'Gene', '3480', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('perturbs coagulation', 'Disease', 'MESH:C536875', (127, 147))	('patients', 'Species', '9606', (152, 160))	('perturbs coagulation', 'Disease', (127, 147))
204144	24458261	We did not observe any RECIST responses, although 9/32 (28 %) patients treated with BIIB022 had a metabolic response as defined by the EORTC criteria.	('BIIB022', 'Chemical', 'MESH:C000594951', (84, 91))	('BIIB022', 'Var', (84, 91))	('patients', 'Species', '9606', (62, 70))	('metabolic response', 'MPA', (98, 116))
204146	24458261	Although a quantitative link between BIIB022 exposure required for efficacy in animals and humans has not been established, at a dose of 20 mg/kg IV q 3 weeks, BIIB022 achieved trough serum levels in human subjects comparable to levels that consistently demonstrated anti-tumor activity in several mouse xenograft tumor models.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Disease', (272, 277))	('humans', 'Species', '9606', (91, 97))	('BIIB022', 'Chemical', 'MESH:C000594951', (160, 167))	('tumor', 'Disease', (314, 319))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('human', 'Species', '9606', (200, 205))	('BIIB022', 'Var', (160, 167))	('BIIB022', 'Chemical', 'MESH:C000594951', (37, 44))	('mouse', 'Species', '10090', (298, 303))	('human', 'Species', '9606', (91, 96))
204155	24458261	For example, at the 9 mg/kg dose of R1507, IGF-1 increased by 250 % from baseline and after 7 doses the mean percentage ranged from 100 to 350 % for all dose levels.	('R1507', 'Var', (36, 41))	('increased', 'PosReg', (49, 58))	('IGF-1', 'Gene', '3479', (43, 48))	('IGF-1', 'Gene', (43, 48))
204157	24458261	A key difference may be that BIIB022, unlike all the other IGF-1R antibodies, is not a competitive inhibitor of the ligand binding sites, which might explain the lack of alteration of these levels.	('BIIB022', 'Var', (29, 36))	('BIIB022', 'Chemical', 'MESH:C000594951', (29, 36))	('IGF-1R', 'Gene', (59, 65))	('IGF-1R', 'Gene', '3480', (59, 65))
204162	24458261	The toxicity profile was similar to other anti-IGF-1R mAbs with the exception of hyperglycemia, which was not observed in our study, and our observation of prolonged QTc associated with a transient wall motion abnormality in one patient receiving BIIB022.	('prolonged QTc', 'Phenotype', 'HP:0005184', (156, 169))	('BIIB022', 'Var', (247, 254))	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('hyperglycemia', 'Disease', 'MESH:D006943', (81, 94))	('motion abnormality', 'Disease', (203, 221))	('IGF-1R', 'Gene', '3480', (47, 53))	('IGF-1R', 'Gene', (47, 53))	('toxicity', 'Disease', (4, 12))	('hyperglycemia', 'Disease', (81, 94))	('motion abnormality', 'Disease', 'MESH:D009041', (203, 221))	('QTc', 'MPA', (166, 169))	('hyperglycemia', 'Phenotype', 'HP:0003074', (81, 94))	('BIIB022', 'Chemical', 'MESH:C000594951', (247, 254))	('patient', 'Species', '9606', (229, 236))	('wall', 'MPA', (198, 202))
204164	24458261	This suggests that IGF-1R inhibitors may yet play a role in the anti-cancer armamentarium, if a reliable biomarker of disease sensitivity can be found in order to allow for rational patient selection and optimization of the risk:benefit ratio.	('IGF-1R', 'Gene', '3480', (19, 25))	('inhibitors', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('IGF-1R', 'Gene', (19, 25))	('patient', 'Species', '9606', (182, 189))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
204183	31893067	The diagnosis of a benign intramuscular myxoma could be established by excluding the S-100 staining and rearrangement of the FUS gene, which is diagnostic for fibromyxoid sarcoma.	('FUS', 'Gene', '2521', (125, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('S-100', 'Gene', (85, 90))	('FUS', 'Gene', (125, 128))	('myxoma', 'Disease', 'MESH:D009232', (40, 46))	('rearrangement', 'Var', (104, 117))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (159, 178))	('fibromyxoid sarcoma', 'Disease', (159, 178))	('myxoma', 'Disease', (40, 46))	('S-100', 'Gene', '6271', (85, 90))	('intramuscular myxoma', 'Phenotype', 'HP:0031461', (26, 46))
204212	30058346	An early study of 430 cases of osteogenic sarcoma reported higher 5-year survival rates (~23%) for patients undergoing amputations than those receiving other therapies.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('patients', 'Species', '9606', (99, 107))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (31, 49))	('osteogenic sarcoma', 'Disease', (31, 49))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (31, 49))	('higher', 'PosReg', (59, 65))	('amputations', 'Var', (119, 130))
204215	30058346	Major limb amputations can potentially decrease the quality of life of patients because of prolonged recovery, interference with bodily functions, high associated morbidity and/or mortality, possibility of disability, and long-term psychological distress.	('Major limb amputations', 'Phenotype', 'HP:0200083', (0, 22))	('psychological distress', 'Disease', (232, 254))	('quality of life', 'CPA', (52, 67))	('amputations', 'Var', (11, 22))	('decrease', 'NegReg', (39, 47))	('Major', 'Var', (0, 5))	('patients', 'Species', '9606', (71, 79))	('interference', 'NegReg', (111, 123))	('psychological distress', 'Disease', 'MESH:D005316', (232, 254))	('bodily functions', 'CPA', (129, 145))
204216	30058346	suggested that patients with osteosarcoma having LSS had significantly better 5-year survival rates and lower rates of metastases than those undergoing limb amputations.	('patients', 'Species', '9606', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('LSS', 'Var', (49, 52))	('metastases', 'Disease', 'MESH:D009362', (119, 129))	('lower', 'NegReg', (104, 109))	('metastases', 'Disease', (119, 129))	('osteosarcoma', 'Disease', (29, 41))	('better', 'PosReg', (71, 77))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))
204217	30058346	revealed significantly lower 5-year survival rates in amputees than those receiving LSS; also, Musculoskeletal Tumor Society (MSTS) scores, which indicate functional outcomes, were significantly lower for amputees than those receiving LSS.	('amputees', 'Var', (205, 213))	('lower', 'NegReg', (195, 200))	('Tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Musculoskeletal Tumor', 'Disease', 'MESH:D009140', (95, 116))	('Musculoskeletal Tumor', 'Disease', (95, 116))	('lower', 'NegReg', (23, 28))
204220	30058346	In these patients who had low chances of survival, amputations improved the ability to carry on daily activities, significantly alleviated pain, improved emotional, sexual, and social lives, and increased the overall quality of life.	('patients', 'Species', '9606', (9, 17))	('improved', 'PosReg', (63, 71))	('alleviated', 'NegReg', (128, 138))	('pain', 'Phenotype', 'HP:0012531', (139, 143))	('amputations', 'Var', (51, 62))	('pain', 'Disease', 'MESH:D010146', (139, 143))	('emotional', 'CPA', (154, 163))	('pain', 'Disease', (139, 143))	('improved', 'PosReg', (145, 153))	('quality of life', 'CPA', (217, 232))	('increased', 'PosReg', (195, 204))	('ability', 'CPA', (76, 83))	('alleviated pain', 'Phenotype', 'HP:0007328', (128, 143))
204274	30058346	Our study did not investigate phantom limb pain; nevertheless, a previous study showed great improvement in outcomes of amputees with phantom limb pain, with little recurrence after 1 year of surgery.	('limb pain', 'Disease', 'MESH:D010146', (38, 47))	('limb pain', 'Phenotype', 'HP:0009763', (38, 47))	('improvement', 'PosReg', (93, 104))	('limb pain', 'Disease', 'MESH:D010146', (142, 151))	('pain', 'Phenotype', 'HP:0012531', (43, 47))	('limb pain', 'Disease', (38, 47))	('limb pain', 'Phenotype', 'HP:0009763', (142, 151))	('outcomes', 'MPA', (108, 116))	('pain', 'Phenotype', 'HP:0012531', (147, 151))	('limb pain', 'Disease', (142, 151))	('phantom', 'Var', (134, 141))
204298	29357838	We used lentiviral over-expression and knockdown assays to examine how changes of AZGP1 expressions might affect cellular migration and invasion.	('changes', 'Var', (71, 78))	('AZGP1', 'Gene', (82, 87))	('affect', 'Reg', (106, 112))	('cellular migration', 'CPA', (113, 131))	('AZGP1', 'Gene', '563', (82, 87))
204302	29357838	Over-expression of AZGP1 significantly decreased RD cellular migration and invasion by 64% and 78%, respectively.	('AZGP1', 'Gene', (19, 24))	('invasion', 'CPA', (75, 83))	('RD', 'Phenotype', 'HP:0002859', (49, 51))	('RD cellular migration', 'CPA', (49, 70))	('Over-expression', 'Var', (0, 15))	('decreased', 'NegReg', (39, 48))	('AZGP1', 'Gene', '563', (19, 24))
204303	29357838	HT1080 cells migration was inhibited by 2-fold, whereas their invasion was repressed by 7-fold after AZGP1 knockdown.	('knockdown', 'Var', (107, 116))	('AZGP1', 'Gene', (101, 106))	('AZGP1', 'Gene', '563', (101, 106))	('inhibited', 'NegReg', (27, 36))	('HT1080', 'CellLine', 'CVCL:0317', (0, 6))
204366	29357838	The results suggest that patients with low expression of AZGP1 are more prone to metastasis and disease-specific death.	('prone', 'Reg', (72, 77))	('AZGP1', 'Gene', (57, 62))	('death', 'Disease', 'MESH:D003643', (113, 118))	('death', 'Disease', (113, 118))	('metastasis', 'CPA', (81, 91))	('patients', 'Species', '9606', (25, 33))	('low expression', 'Var', (39, 53))	('AZGP1', 'Gene', '563', (57, 62))
204379	29357838	4a and b, the expression of AZGP1 mRNA and protein was decreased by 55% for sh150 and 80% for sh368 compared with the control (scramble oligo).	('sh368', 'Var', (94, 99))	('AZGP1', 'Gene', '563', (28, 33))	('mRNA and', 'MPA', (34, 42))	('decreased', 'NegReg', (55, 64))	('expression', 'MPA', (14, 24))	('AZGP1', 'Gene', (28, 33))	('sh150', 'Var', (76, 81))
204400	29357838	Inhibition of fatty acid synthesis, which is overexpressed in MPNST cells lines, can effectively reduce MPNST survival and delay tumor growth in vivo.	('delay tumor', 'Disease', (123, 134))	('fatty acid', 'Chemical', 'MESH:D005227', (14, 24))	('fatty acid synthesis', 'MPA', (14, 34))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MPNST survival', 'CPA', (104, 118))	('MPNST', 'Phenotype', 'HP:0100697', (62, 67))	('Inhibition', 'Var', (0, 10))	('delay tumor', 'Disease', 'MESH:D009369', (123, 134))	('MPNST', 'Phenotype', 'HP:0100697', (104, 109))	('reduce', 'NegReg', (97, 103))
204407	29357838	In addition, AZGP1 expression was linked with PTEN deletion and might regulate the phosphatidylinositol-3 kinase (PI3K/AKT) pathway, which can trigger a cascade of responses to drive cell proliferation and tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('AZGP1', 'Gene', '563', (13, 18))	('tumor', 'Disease', (206, 211))	('PTEN', 'Gene', (46, 50))	('trigger', 'Reg', (143, 150))	('AKT', 'Gene', '207', (119, 122))	('PTEN', 'Gene', '5728', (46, 50))	('AZGP1', 'Gene', (13, 18))	('drive cell proliferation', 'CPA', (177, 201))	('regulate', 'Reg', (70, 78))	('AKT', 'Gene', (119, 122))	('deletion', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('linked', 'Reg', (34, 40))
204447	30473763	Due to adverse effects that led to a deep thrombocytopenia (50 G/L), sunitinib was stopped.	('sunitinib', 'Chemical', 'MESH:D000077210', (69, 78))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (42, 58))	('deep thrombocytopenia', 'Disease', 'MESH:D013921', (37, 58))	('50 G/L', 'Var', (60, 66))	('deep thrombocytopenia', 'Disease', (37, 58))	('50 G/L', 'SUBSTITUTION', 'None', (60, 66))
204647	23482406	Junior by immunohistochemical analysis founded positivity for p53 in 52% of the cases, 24% for MDM2, 84% for CDK4, 92% for PCNA, and 88% for Ki-67.	('PCNA', 'Gene', (123, 127))	('CDK4', 'Gene', (109, 113))	('p53', 'Gene', '7157', (62, 65))	('MDM2', 'Gene', '4193', (95, 99))	('MDM2', 'Gene', (95, 99))	('CDK4', 'Gene', '1019', (109, 113))	('PCNA', 'Gene', '5111', (123, 127))	('p53', 'Gene', (62, 65))	('positivity', 'Var', (47, 57))
204937	23226965	EW is characterised by a group of translocations which oppose a gene from the EWS family with a gene from the ETS family arising in cells of mesenchymal origin.	('translocations', 'Var', (34, 48))	('EW', 'Phenotype', 'HP:0012254', (78, 80))	('EWS', 'Gene', '2130', (78, 81))	('EWS', 'Gene', (78, 81))	('EW', 'Phenotype', 'HP:0012254', (0, 2))
204945	23226965	Decreased EWS-FLI1 expression by antisense oligonucleotides or RNA, small interference RNA (siRNA) through nanoparticles, inhibits cell proliferation and tumour growth of EW xenografts.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('EW', 'Phenotype', 'HP:0012254', (10, 12))	('expression', 'MPA', (19, 29))	('tumour growth', 'Disease', (154, 167))	('inhibits', 'NegReg', (122, 130))	('tumour growth', 'Disease', 'MESH:D006130', (154, 167))	('oligonucleotides', 'Chemical', 'MESH:D009841', (43, 59))	('Decreased', 'NegReg', (0, 9))	('antisense oligonucleotides', 'Var', (33, 59))	('EWS-FLI1', 'Gene', (10, 18))	('cell proliferation', 'CPA', (131, 149))	('EW', 'Phenotype', 'HP:0012254', (171, 173))	('EWS-FLI1', 'Gene', '2130;2313', (10, 18))
205001	23226965	Furthermore, there is increasing information that mTOR inhibition can reverse resistance to growth receptor inhibition in other solid tumours including breast cancer.	('solid tumours', 'Disease', 'MESH:D009369', (128, 141))	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('mTOR', 'Gene', (50, 54))	('resistance to growth receptor inhibition', 'MPA', (78, 118))	('solid tumours', 'Disease', (128, 141))	('mTOR', 'Gene', '2475', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('inhibition', 'Var', (55, 65))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
205005	23226965	The Aurora A inhibitor, MLN8237, led to prolonged CR in in vivo EW/OS models.	('prolonged', 'PosReg', (40, 49))	('Aurora A', 'Gene', '6790', (4, 12))	('OS', 'Phenotype', 'HP:0002669', (67, 69))	('MLN8237', 'Chemical', 'MESH:C550258', (24, 31))	('Aurora A', 'Gene', (4, 12))	('CR', 'Chemical', '-', (50, 52))	('MLN8237', 'Var', (24, 31))	('EW', 'Phenotype', 'HP:0012254', (64, 66))
205006	23226965	Two Aurora A inhibitors, MLN8237 (NCT01154816/NCT00739427) and AT9283 (NCT00985868/NCT01431664), are under development in paediatric phase I/II studies.	('Aurora A', 'Gene', '6790', (4, 12))	('NCT00985868/NCT01431664', 'Var', (71, 94))	('AT9283 (NCT00985868/NCT01431664', 'Var', (63, 94))	('MLN8237 (NCT01154816/NCT00739427', 'Var', (25, 57))	('MLN8237', 'Chemical', 'MESH:C550258', (25, 32))	('Aurora A', 'Gene', (4, 12))
205011	23226965	An adult phase I of an oral MDM2 inhibitor (RO5503781) is ongoing in solid cancers (NCT01462175) and a study in sarcoma in preparation.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('RO5503781', 'Var', (44, 53))	('MDM2', 'Gene', '4193', (28, 32))	('MDM2', 'Gene', (28, 32))	('sarcoma', 'Disease', (112, 119))	('solid cancers', 'Disease', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('RO5503781', 'Chemical', 'MESH:C586849', (44, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('solid cancers', 'Disease', 'MESH:D009369', (69, 82))
205022	23226965	The Smac mimetic, LCL161, increases survival of paediatric in vivo models, including 5/6 OS and glioblastomas.	('glioblastomas', 'Disease', (96, 109))	('LCL161', 'Var', (18, 24))	('Smac', 'Gene', '56616', (4, 8))	('OS', 'Phenotype', 'HP:0002669', (89, 91))	('glioblastomas', 'Phenotype', 'HP:0012174', (96, 109))	('Smac', 'Gene', (4, 8))	('glioblastomas', 'Disease', 'MESH:D005909', (96, 109))	('increases', 'PosReg', (26, 35))	('survival', 'CPA', (36, 44))
205026	23226965	Inhibition of survivin induces apoptosis and reverts CT resistance (etoposide, cisplatin, and doxorubicin) in OS cell lines.	('induces', 'Reg', (23, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('survivin', 'Protein', (14, 22))	('doxorubicin', 'Chemical', 'MESH:D004317', (94, 105))	('Inhibition', 'Var', (0, 10))	('etoposide', 'Chemical', 'MESH:D005047', (68, 77))	('apoptosis', 'CPA', (31, 40))	('reverts', 'NegReg', (45, 52))	('OS', 'Phenotype', 'HP:0002669', (110, 112))
205061	23226965	In OS, GIN, the GSK3beta inhibitor stimulates the Wnt/beta-catenin pathway and induces intranuclear passage of beta-catenin.	('beta-catenin', 'Gene', (111, 123))	('induces', 'PosReg', (79, 86))	('inhibitor', 'Var', (25, 34))	('GSK3beta', 'Gene', (16, 24))	('beta-catenin', 'Gene', (54, 66))	('beta-catenin', 'Gene', '1499', (111, 123))	('OS', 'Phenotype', 'HP:0002669', (3, 5))	('GSK3beta', 'Gene', '2932', (16, 24))	('beta-catenin', 'Gene', '1499', (54, 66))	('stimulates', 'PosReg', (35, 45))
205062	23226965	A phase I of the LY2090314 (GSK3 inhibitor)/pemetrexed/carboplatin combination is ongoing in adults with progressive solid tumours, with good tolerance and restoration of beta-catenin expression.	('LY2090314', 'Var', (17, 26))	('LY2090314', 'Chemical', 'MESH:C584053', (17, 26))	('solid tumours', 'Disease', (117, 130))	('beta-catenin', 'Gene', '1499', (171, 183))	('pemetrexed', 'Chemical', 'MESH:D000068437', (44, 54))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('carboplatin', 'Chemical', 'MESH:D016190', (55, 66))	('expression', 'MPA', (184, 194))	('beta-catenin', 'Gene', (171, 183))	('solid tumours', 'Disease', 'MESH:D009369', (117, 130))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
205063	23226965	DDK1 inhibitors interfere with the Wnt pathway and bone metabolism.	('interfere', 'NegReg', (16, 25))	('DDK1', 'Gene', (0, 4))	('DDK1', 'Gene', '92667', (0, 4))	('inhibitors', 'Var', (5, 15))	('bone metabolism', 'CPA', (51, 66))	('Wnt pathway', 'Pathway', (35, 46))
205064	23226965	Adult phase I studies with monoclonal anti-DDK1 antibodies (LY2812176, NCT01457417; BHQ880, NCT00741377) are ongoing.	('DDK1', 'Gene', (43, 47))	('DDK1', 'Gene', '92667', (43, 47))	('BHQ880', 'Chemical', 'MESH:C557618', (84, 90))	('LY2812176', 'Var', (60, 69))	('LY2812176', 'Chemical', '-', (60, 69))
205073	23226965	Their inactivation is sufficient to revert the metastatic phenotype, but not inactivation of beta1 integrin.	('beta1 integrin', 'Gene', '3688', (93, 107))	('revert', 'Reg', (36, 42))	('inactivation', 'Var', (6, 18))	('beta1 integrin', 'Gene', (93, 107))	('metastatic phenotype', 'CPA', (47, 67))
205090	23226965	Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, GD2-specific cytolytic responses to allogeneic and autologous EW, including tumour cells grown as multicellular, anchorage-independent spheres.	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('patient', 'Species', '9606', (81, 88))	('GD2-specific cytolytic responses', 'MPA', (105, 137))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('EW', 'Phenotype', 'HP:0012254', (167, 169))	('tumour', 'Disease', (181, 187))	('chimeric', 'Var', (10, 18))	('GD2', 'Chemical', '-', (105, 108))
205112	23226965	In preclinical OS models, inhibition of RANKL signalling by a decoy receptor OPG or with a soluble form of its membranous receptor RANK (RANK-Fc) inhibits tumour-associated osteolysis and reduces tumour incidence, local growth, invasion, migration, and lung metastases, leading to increased survival in animals.	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('invasion', 'CPA', (228, 236))	('OS', 'Phenotype', 'HP:0002669', (15, 17))	('RANKL', 'Gene', '8600', (40, 45))	('tumour', 'Disease', 'MESH:D009369', (196, 202))	('migration', 'CPA', (238, 247))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('lung metastases', 'Disease', (253, 268))	('tumour', 'Disease', (196, 202))	('local growth', 'CPA', (214, 226))	('OPG', 'Gene', (77, 80))	('tumour', 'Disease', (155, 161))	('osteolysis', 'Disease', (173, 183))	('inhibition', 'Var', (26, 36))	('osteolysis', 'Disease', 'MESH:D010014', (173, 183))	('increased', 'PosReg', (281, 290))	('survival', 'CPA', (291, 299))	('RANKL', 'Gene', (40, 45))	('inhibits', 'NegReg', (146, 154))	('reduces', 'NegReg', (188, 195))	('lung metastases', 'Disease', 'MESH:D009362', (253, 268))	('osteolysis', 'Phenotype', 'HP:0002797', (173, 183))	('OPG', 'Gene', '4982', (77, 80))
205119	23226965	BHQ880 is currently being investigated in adult phase I/II trials for multiple myeloma, alone (NCT01302886; NCT01337752) or associated with zoledronic acid (NCT00741377).	('NCT01302886; NCT01337752', 'Var', (95, 119))	('multiple myeloma', 'Phenotype', 'HP:0006775', (70, 86))	('multiple myeloma', 'Disease', 'MESH:D009101', (70, 86))	('multiple myeloma', 'Disease', (70, 86))	('BHQ880', 'Chemical', 'MESH:C557618', (0, 6))	('associated', 'Interaction', (124, 134))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (140, 155))
205133	23226965	HDAC inhibition restores HAT activity, inhibits cell growth, and induces apoptosis.	('HDAC', 'Gene', (0, 4))	('cell growth', 'CPA', (48, 59))	('HDAC', 'Gene', '9734', (0, 4))	('inhibition', 'Var', (5, 15))	('restores', 'PosReg', (16, 24))	('induces', 'Reg', (65, 72))	('HAT activity', 'MPA', (25, 37))	('apoptosis', 'CPA', (73, 82))	('inhibits', 'NegReg', (39, 47))
205139	23226965	HSP90 inhibitors induce proteasome-mediated degradation of many oncogenic proteins involved in all hallmark characteristics of cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('inhibitors', 'Var', (6, 16))	('cancer', 'Disease', (127, 133))	('proteasome-mediated degradation', 'MPA', (24, 55))
205158	20598147	For example, myogenin and myoD1 are specific and sensitive for the diagnosis of rhabdomyosarcoma and lymphoid markers such as CD20, CD3, CD30 and CD45 are very useful in the diagnosis of lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (187, 195))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (80, 96))	('myogenin', 'Gene', '4656', (13, 21))	('rhabdomyosarcoma', 'Disease', (80, 96))	('CD20', 'Gene', '54474', (126, 130))	('CD20', 'Gene', (126, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('CD30', 'Gene', '943', (137, 141))	('CD3', 'Gene', (132, 135))	('lymphoma', 'Disease', (187, 195))	('CD30', 'Gene', (137, 141))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (80, 96))	('myogenin', 'Gene', (13, 21))	('CD45', 'Var', (146, 150))	('lymphoma', 'Disease', 'MESH:D008223', (187, 195))
205161	20598147	EWSR1 gene rearrangement is characteristic of EFT, but is also present in extraskeletal myxoid chondrosarcoma, desmoplastic small round cell tumor, and a subset of myxoid/round cell liposarcomas.	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (74, 109))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (95, 109))	('rearrangement', 'Var', (11, 24))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (111, 146))	('desmoplastic small round cell tumor', 'Disease', (111, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('liposarcomas', 'Disease', (182, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('liposarcomas', 'Phenotype', 'HP:0012034', (182, 194))	('liposarcomas', 'Disease', 'MESH:D008080', (182, 194))	('myxoid/round cell liposarcomas', 'Phenotype', 'HP:0012268', (164, 194))	('EWSR1', 'Gene', (0, 5))	('extraskeletal myxoid chondrosarcoma', 'Disease', (74, 109))	('present in', 'Reg', (63, 73))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (164, 193))	('liposarcoma', 'Phenotype', 'HP:0012034', (182, 193))
205214	20598147	This minor difference could be explained by the fact that not all the studies were intended to cover all the transcript variants, and the negative cases may well represent tumors with overlooked alternative chimeric transcripts.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('variants', 'Var', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', (172, 178))
205216	20598147	This case supports the fact that EWSR1-CREB1 is not a translocation variant exclusive to clear cell sarcomas arising in the gastrointestinal tract.	('gastrointestinal tract', 'Disease', 'MESH:D004067', (124, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Disease', (100, 108))	('EWSR1-CREB1', 'Var', (33, 44))	('gastrointestinal tract', 'Disease', (124, 146))	('clear cell sarcoma', 'Disease', (89, 107))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (89, 107))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
205223	20598147	An "in-house" dual-color, dual-fusion EWSR1-CREB1 probe was prepared to confirm the reciprocal t(2;22)(q34;q12) using BACs RP11-135B21/RP11-354H1 (chromosome 2) and RP11-945M21/RP11-1126O13 (chromosome 22).	('t(2;22)(q34;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (95, 111))	('BACs RP11-135B21/RP11-354H1', 'Var', (118, 145))	('RP11-945M21/RP11-1126O13', 'Var', (165, 189))
205261	31448166	Hemangioma is intensely hyperintense on T2 and hypointense on T1 unless have a hemorrhage or fatty replacement [Figure 1] Usually, they demonstrate homogenous enhancement after gadolinium administration.	('hemorrhage', 'Disease', (79, 89))	('Hemangioma', 'Disease', (0, 10))	('homogenous enhancement', 'MPA', (148, 170))	('Hemangioma', 'Disease', 'MESH:D006391', (0, 10))	('hemorrhage', 'Disease', 'MESH:D006470', (79, 89))	('Hemangioma', 'Phenotype', 'HP:0001028', (0, 10))	('fat', 'Gene', (93, 96))	('gadolinium', 'Chemical', 'MESH:D005682', (177, 187))	('fat', 'Gene', '2195', (93, 96))	('hypointense', 'Var', (47, 58))
205291	31448166	Involvement of median nerve frequently causes carpal tunnel syndrome.	('causes', 'Reg', (39, 45))	('Involvement', 'Var', (0, 11))	('carpal tunnel syndrome', 'Disease', 'MESH:D002349', (46, 68))	('carpal tunnel', 'Phenotype', 'HP:0009702', (46, 59))	('carpal tunnel syndrome', 'Phenotype', 'HP:0012185', (46, 68))	('carpal tunnel syndrome', 'Disease', (46, 68))
205297	31448166	Traumatic neuroma is the non-neoplastic proliferation of the injured or transected (completely or partially) proximal segment of the nerve.	('Traumatic neuroma', 'Disease', (0, 17))	('neuroma', 'Phenotype', 'HP:0030430', (10, 17))	('Traumatic neuroma', 'Disease', 'MESH:D009463', (0, 17))	('neoplastic proliferation', 'Phenotype', 'HP:0002664', (29, 53))	('transected', 'Var', (72, 82))
205309	31448166	A positive Tinel's sign can be elicited, i.e., percussion to the mass will result in tingling and pain on the nerve distribution.	('percussion', 'Var', (47, 57))	('Tinel', 'Disease', (11, 16))	('result in', 'Reg', (75, 84))	('pain', 'Phenotype', 'HP:0012531', (98, 102))	('pain', 'Disease', 'MESH:D010146', (98, 102))	('pain', 'Disease', (98, 102))	('tingling', 'CPA', (85, 93))	('tingling', 'Phenotype', 'HP:0003401', (85, 93))
205506	23028325	To investigate a role of the KSHV K15 protein in KSHV-mediated angiogenesis, we carried out a genome wide gene expression analysis on primary endothelial cells infected with KSHV wildtype (KSHVwt) and a KSHV K15 deletion mutant (KSHVDeltaK15).	('KS', 'Phenotype', 'HP:0100726', (174, 176))	('KSHV', 'Species', '37296', (49, 53))	('KS', 'Phenotype', 'HP:0100726', (203, 205))	('KSHV', 'Species', '37296', (203, 207))	('KSHV', 'Species', '37296', (189, 193))	('expression', 'Species', '29278', (111, 121))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('KS', 'Phenotype', 'HP:0100726', (189, 191))	('KSHV', 'Species', '37296', (229, 233))	('KSHV', 'Species', '37296', (29, 33))	('KS', 'Phenotype', 'HP:0100726', (29, 31))	('deletion mutant', 'Var', (212, 227))	('KSHV K15', 'Gene', (203, 211))	('KSHV', 'Species', '37296', (174, 178))
205509	23028325	We found that K15 directly recruits PLCgamma1, and thereby activates Calcineurin/NFAT1-dependent RCAN1 expression which results in the formation of angiogenic tubes.	('PLCgamma1', 'Gene', '5335', (36, 45))	('NFAT1', 'Gene', (81, 86))	('expression', 'Species', '29278', (103, 113))	('expression', 'MPA', (103, 113))	('PLCgamma1', 'Gene', (36, 45))	('results in', 'Reg', (120, 130))	('RCAN1', 'Gene', (97, 102))	('K15', 'Var', (14, 17))	('angiogenic tubes', 'CPA', (148, 164))	('activates', 'PosReg', (59, 68))	('NFAT1', 'Gene', '4773', (81, 86))	('RCAN1', 'Gene', '1827', (97, 102))
205514	23028325	The K15 protein of KSHV upregulates the host factor RCAN1/DSCR1.	('KSHV', 'Gene', (19, 23))	('DSCR1', 'Gene', (58, 63))	('K15', 'Var', (4, 7))	('RCAN1', 'Gene', '1827', (52, 57))	('RCAN1', 'Gene', (52, 57))	('KSHV', 'Species', '37296', (19, 23))	('KS', 'Phenotype', 'HP:0100726', (19, 21))	('upregulates', 'PosReg', (24, 35))	('DSCR1', 'Gene', '1827', (58, 63))
205516	23028325	In this study we show that the increased expression of RCAN1/DSCR1 in KSHV-infected endothelial cells depends on K15 and that K15, by recruiting PLCgamma1, activates PLCgamma1, Calcineurin and NFAT1 to induce RCAN1/DSCR1 expression and capillary tube formation.	('RCAN1', 'Gene', (209, 214))	('K15', 'Var', (126, 129))	('increased', 'PosReg', (31, 40))	('induce', 'PosReg', (202, 208))	('expression', 'Species', '29278', (221, 231))	('PLCgamma1', 'Gene', '5335', (145, 154))	('Calcineurin', 'MPA', (177, 188))	('DSCR1', 'Gene', '1827', (215, 220))	('DSCR1', 'Gene', (215, 220))	('NFAT1', 'Gene', (193, 198))	('capillary tube formation', 'CPA', (236, 260))	('activates', 'PosReg', (156, 165))	('PLCgamma1', 'Gene', (145, 154))	('expression', 'MPA', (41, 51))	('PLCgamma1', 'Gene', '5335', (166, 175))	('DSCR1', 'Gene', '1827', (61, 66))	('RCAN1', 'Gene', '1827', (55, 60))	('NFAT1', 'Gene', '4773', (193, 198))	('DSCR1', 'Gene', (61, 66))	('KSHV-infected', 'Disease', 'MESH:C537372', (70, 83))	('PLCgamma1', 'Gene', (166, 175))	('RCAN1', 'Gene', (55, 60))	('expression', 'MPA', (221, 231))	('recruiting', 'PosReg', (134, 144))	('expression', 'Species', '29278', (41, 51))	('RCAN1', 'Gene', '1827', (209, 214))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('KSHV-infected', 'Disease', (70, 83))
205517	23028325	Deleting the K15 gene from the viral genome, or silencing its expression with siRNA, reduces the ability of KSHV to induce angiogenesis in infected endothelial cells in tissue culture.	('expression', 'Species', '29278', (62, 72))	('KSHV', 'Species', '37296', (108, 112))	('KS', 'Phenotype', 'HP:0100726', (108, 110))	('expression', 'MPA', (62, 72))	('K15', 'Gene', (13, 16))	('angiogenesis', 'CPA', (123, 135))	('Deleting', 'Var', (0, 8))	('reduces', 'NegReg', (85, 92))	('ability', 'MPA', (97, 104))	('silencing', 'NegReg', (48, 57))
205536	23028325	Knockdown of RCAN1 has been shown to inhibit VEGF-mediated migration of endothelial cells in vitro, angiogenesis in vivo and thereby tumor growth.	('RCAN1', 'Gene', (13, 18))	('Knockdown', 'Var', (0, 9))	('RCAN1', 'Gene', '1827', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('VEGF', 'Gene', '7422', (45, 49))	('inhibit', 'NegReg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('angiogenesis', 'CPA', (100, 112))	('VEGF', 'Gene', (45, 49))
205538	23028325	The main K15 protein is predicted to feature 12 transmembrane segments and a C-terminal cytoplasmic domain, which contains several putative signaling motifs such as two SH2-binding sites (Y431ASIL and Y481EEVL), a proline-rich SH3-binding site (P387PLP) and a tumor necrosis factor receptor-associated factor (TRAF)-binding site (A473TQPTDD).	('tumor necrosis', 'Disease', (260, 274))	('PLP', 'Gene', '5354', (249, 252))	('SH2-binding', 'Interaction', (169, 180))	('Y481EEVL', 'Mutation', 'p.Y481EEVL', (201, 209))	('Y481EEVL', 'Var', (201, 209))	('tumor necrosis', 'Disease', 'MESH:D009336', (260, 274))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('Y431ASIL', 'Mutation', 'p.Y431ASIL', (188, 196))	('PLP', 'Gene', (249, 252))	('Y431ASIL', 'Var', (188, 196))	('proline', 'Chemical', 'MESH:D011392', (214, 221))
205543	23028325	We further found that K15 directly interacts with PLCgamma1 to activate the PLCgamma1-Calcineurin-NFAT pathway and induces RCAN1/DSCR1 expression and thereby tubular morphogenesis in KSHV-infected human umbilical vein endothelial cells (HUVECs).	('PLCgamma1', 'Gene', (76, 85))	('KSHV-infected', 'Disease', (183, 196))	('RCAN1', 'Gene', (123, 128))	('KSHV-infected', 'Disease', 'MESH:C537372', (183, 196))	('PLCgamma1', 'Gene', (50, 59))	('activate', 'PosReg', (63, 71))	('tubular morphogenesis', 'CPA', (158, 179))	('RCAN1', 'Gene', '1827', (123, 128))	('expression', 'Species', '29278', (135, 145))	('induces', 'PosReg', (115, 122))	('PLCgamma1', 'Gene', '5335', (76, 85))	('DSCR1', 'Gene', '1827', (129, 134))	('KS', 'Phenotype', 'HP:0100726', (183, 185))	('PLCgamma1', 'Gene', '5335', (50, 59))	('expression', 'MPA', (135, 145))	('human', 'Species', '9606', (197, 202))	('DSCR1', 'Gene', (129, 134))	('K15', 'Var', (22, 25))
205544	23028325	Deletion of K15 from the viral genome, or silencing its expression with siRNA, reduces the ability of KSHV to induce angiogenesis in cultured endothelial cells.	('ability', 'MPA', (91, 98))	('KS', 'Phenotype', 'HP:0100726', (102, 104))	('reduces', 'NegReg', (79, 86))	('expression', 'Species', '29278', (56, 66))	('Deletion', 'Var', (0, 8))	('expression', 'MPA', (56, 66))	('KSHV', 'Species', '37296', (102, 106))	('silencing', 'NegReg', (42, 51))	('K15', 'Gene', (12, 15))
205569	23028325	Subsequently, retroviral vector plasmids pSF91-IRES-GFP or pSF91-K15-IRES-GFP (5 microg) were co-transfected with packaging plasmids pM57DAW gag/pol (15 microg) and pRD114 vector (5 microg) expressing the envelope protein, using the calcium-phosphate transfection method.	('SF9', 'CellLine', 'CVCL:0549', (60, 63))	('pSF91-IRES-GFP', 'Var', (41, 55))	('calcium-phosphate', 'Chemical', 'MESH:C020243', (233, 250))	('SF9', 'CellLine', 'CVCL:0549', (42, 45))	('pSF91-K15-IRES-GFP', 'Var', (59, 77))
205571	23028325	Protein lysates from HUVECs were prepared in SDS sample buffer (62.5 mM Tris-HCl, pH 6.8, 2% (w/v) SDS, 10% glycerol, 50 mM DTT, 0.01% (w/v) bromophenol blue) containing beta- mercaptoethanol for the detection of both PLCgamma1 and phospho PLCgamma1.	('PLCgamma1', 'Gene', '5335', (240, 249))	('PLCgamma1', 'Gene', (218, 227))	('Tris', 'Chemical', '-', (72, 76))	('HCl', 'Chemical', '-', (77, 80))	('SDS', 'Chemical', 'MESH:D012967', (99, 102))	('bromophenol blue', 'Chemical', 'MESH:D001978', (141, 157))	('DTT', 'Chemical', 'MESH:D004229', (124, 127))	('glycerol', 'Chemical', 'MESH:D005990', (108, 116))	('SDS', 'Chemical', 'MESH:D012967', (45, 48))	('beta- mercaptoethanol', 'Chemical', 'MESH:D008623', (170, 191))	('phospho', 'Var', (232, 239))	('PLCgamma1', 'Gene', '5335', (218, 227))	('PLCgamma1', 'Gene', (240, 249))
205587	23028325	The following TaqMan gene expression assays (Applied Biosystems: #4331182) were used: Hs01120954_m1 (RCAN1); Hs00173626_m1 (VEGFA); Hs99999905_m1 (GAPDH).	('Hs01120954_m1', 'Var', (86, 99))	('Hs99999905_m1', 'Var', (132, 145))	('RCAN1', 'Gene', '1827', (101, 106))	('RCAN1', 'Gene', (101, 106))	('VEGF', 'Gene', '7422', (124, 128))	('Hs00173626_m1', 'Var', (109, 122))	('expression', 'Species', '29278', (26, 36))	('VEGF', 'Gene', (124, 128))
205588	23028325	For most siRNA transfection experiments, HUVECs were transduced with pSF91-IRES-GFP (control vector) or pSF91-K15-IRES-GFP.	('pSF91-K15-IRES-GFP', 'Var', (104, 122))	('pSF91-IRES-GFP', 'Var', (69, 83))	('SF9', 'CellLine', 'CVCL:0549', (70, 73))	('SF9', 'CellLine', 'CVCL:0549', (105, 108))	('transduced', 'Reg', (53, 63))
205589	23028325	The following siRNAs (siGENOME SMARTpool) were ordered from Dharmacon: Control siRNA (Non-Targeting siRNA pool #1, D-001206-13-05), siRCAN1 (M-004268-02), siNFATc2 (M-003603-02), siPLCG1 (M-003559-01), siRELA/p65 (M-003533-02), siCalcineurin (PPP3CA) (M-008300-02), siFLT1 (M-003136-03), siFLT4 (M-003138-02) and siKDR (M-003148-01).	('M-003559-01', 'Var', (188, 199))	('M-003603-02', 'Var', (165, 176))	('M-003148-01', 'Var', (320, 331))	('RCAN1', 'Gene', '1827', (134, 139))	('KDR', 'Gene', '3791', (315, 318))	('M-008300-02', 'Var', (252, 263))	('RCAN1', 'Gene', (134, 139))	('FLT4', 'Gene', (290, 294))	('siRELA/p65', 'Gene', '5970', (202, 212))	('FLT1', 'Gene', (268, 272))	('FLT4', 'Gene', '2324', (290, 294))	('M-003136-03', 'Var', (274, 285))	('FLT1', 'Gene', '2321', (268, 272))	('siRELA/p65', 'Gene', (202, 212))	('M-004268-02', 'Var', (141, 152))	('PPP3CA', 'Gene', '5530', (243, 249))	('M-003533-02', 'Var', (214, 225))	('PPP3CA', 'Gene', (243, 249))	('M-003138-02', 'Var', (296, 307))	('KDR', 'Gene', (315, 318))
205591	23028325	The RCAN1.4 isoform was specifically targeted by siRNA against exon 4 of RCAN1 (AGUGAUAUCUUCAGCGAAAUU).	('RCAN1', 'Gene', (4, 9))	('RCAN1', 'Gene', '1827', (4, 9))	('RCAN1', 'Gene', (73, 78))	('siRNA', 'Var', (49, 54))	('RCAN1', 'Gene', '1827', (73, 78))
205592	23028325	HUVECs were transduced with pSF91-K15-IRES-GFP or pSF91-IRES-GFP retrovirus stocks.	('SF9', 'CellLine', 'CVCL:0549', (29, 32))	('SF9', 'CellLine', 'CVCL:0549', (51, 54))	('pSF91-IRES-GFP', 'Var', (50, 64))	('pSF91-K15-IRES-GFP', 'Var', (28, 46))	('stocks', 'Species', '3724', (76, 82))
205595	23028325	For drug treatment experiments, cells were resuspended in medium containing 1 microM Cyclosporin A (Calcineurin inhibitor, Calbiochem) or 20 microM U73122 (PLCgamma inhibitor, Calbiochem).	('Calcineurin inhibitor', 'Gene', (100, 121))	('U73122', 'Chemical', 'MESH:C060229', (148, 154))	('Calcineurin inhibitor', 'Gene', '23523', (100, 121))	('Cyclosporin A', 'Chemical', 'MESH:D016572', (85, 98))	('U73122', 'Var', (148, 154))
205600	23028325	The cells were transiently transfected with retroviral vector plasmids pSF91-IRES-GFP, pSF91K15-IRES-GFP, pSF91K15/YF-IRES-GFP, pSF91K15/DeltaSH3-IRES-GFP, pSF91K15/YF/DeltaSH3-IRES-GFP (5 microg) using Fugene 6 transfection reagent (Promega) according to manufacturer's instructions.	('SF9', 'CellLine', 'CVCL:0549', (88, 91))	('pSF91K15-IRES-GFP', 'Var', (87, 104))	('SF9', 'CellLine', 'CVCL:0549', (129, 132))	('SF9', 'CellLine', 'CVCL:0549', (157, 160))	('pSF91K15/YF/DeltaSH3-IRES-GFP', 'Var', (156, 185))	('pSF91K15/YF-IRES-GFP', 'Var', (106, 126))	('SF9', 'CellLine', 'CVCL:0549', (107, 110))	('pSF91K15/DeltaSH3-IRES-GFP', 'Var', (128, 154))	('SF9', 'CellLine', 'CVCL:0549', (72, 75))
205612	23028325	To this end, we compared the cellular transcriptome of primary human umbilical vein endothelial cells (HUVECs) infected with a recombinant KSHVwt, derived from the BAC36 genome or a K15 deletion mutant of BAC36, KSHVDeltaK15.	('human', 'Species', '9606', (63, 68))	('KS', 'Phenotype', 'HP:0100726', (212, 214))	('BAC36', 'Gene', (205, 210))	('KS', 'Phenotype', 'HP:0100726', (139, 141))	('KSHV', 'Species', '37296', (139, 143))	('K15 deletion', 'Var', (182, 194))	('KSHV', 'Species', '37296', (212, 216))
205615	23028325	Data were filtered for mRNAs showing an at least two-fold induction by K15 overexpression relative to empty vector transduced cells in each of two independent experiments performed.	('expression', 'Species', '29278', (79, 89))	('overexpression', 'Var', (75, 89))	('K15', 'Gene', (71, 74))
205623	23028325	We first confirmed the upregulation of RCAN1/DSCR1 by K15 in endothelial cells using quantitative PCR and the samples tested by gene expression microarray.	('K15', 'Var', (54, 57))	('RCAN1', 'Gene', '1827', (39, 44))	('DSCR1', 'Gene', '1827', (45, 50))	('DSCR1', 'Gene', (45, 50))	('upregulation', 'PosReg', (23, 35))	('RCAN1', 'Gene', (39, 44))	('expression', 'Species', '29278', (133, 143))
205625	23028325	Expression of K15 in HUVECs from a retroviral vector resulted in a marked increase in the mRNA levels of RCAN1 (15 and 19 fold in two experiments; see figure 1C), while in KSHVwt-infected cells we observed an increase of 3.2 and 6.4 fold relative to cells exposed to heat inactivated virus (figure 1D).	('RCAN1', 'Gene', '1827', (105, 110))	('mRNA levels', 'MPA', (90, 101))	('KS', 'Phenotype', 'HP:0100726', (172, 174))	('KSHV', 'Species', '37296', (172, 176))	('increase', 'PosReg', (74, 82))	('K15', 'Var', (14, 17))	('Expression', 'Species', '29278', (0, 10))	('RCAN1', 'Gene', (105, 110))
205630	23028325	These observations could suggest that K15 might induce RCAN1/DSCR1 expression in a VEGF-independent manner.	('VEGF', 'Gene', (83, 87))	('induce', 'PosReg', (48, 54))	('K15', 'Var', (38, 41))	('RCAN1', 'Gene', (55, 60))	('VEGF', 'Gene', '7422', (83, 87))	('expression', 'Species', '29278', (67, 77))	('DSCR1', 'Gene', '1827', (61, 66))	('RCAN1', 'Gene', '1827', (55, 60))	('expression', 'MPA', (67, 77))	('DSCR1', 'Gene', (61, 66))
205635	23028325	As compared to untransduced cells and the cells transduced with the control vector, cells expressing K15 could form tubes even in the absence of exogenously supplied VEGF (figure 2A) and the angiogenic index showed a statistically significant increase for K15-transduced cells relative to the control vector-transduced cells in the absence of VEGF (figure 2B, 3B, 4C, 5A, 5C, 6C, 7C).	('K15-transduced', 'Var', (256, 270))	('VEGF', 'Gene', (166, 170))	('VEGF', 'Gene', (343, 347))	('increase', 'PosReg', (243, 251))	('VEGF', 'Gene', '7422', (166, 170))	('K15', 'Var', (101, 104))	('angiogenic index', 'CPA', (191, 207))	('VEGF', 'Gene', '7422', (343, 347))
205637	23028325	K15, on the other hand, could upregulate both isoforms of RCAN1 even in the absence of exogenously supplied VEGF (lane 6 relative to lanes 2,4).	('VEGF', 'Gene', (108, 112))	('RCAN1', 'Gene', (58, 63))	('K15', 'Var', (0, 3))	('VEGF', 'Gene', '7422', (108, 112))	('upregulate', 'PosReg', (30, 40))	('RCAN1', 'Gene', '1827', (58, 63))
205641	23028325	Taken together with the fact that expression of K15 in primary endothelial cells does not consistently induce expression of the VEGF-A gene (figure 1), this observation is compatible with the interpretation that K15 does not increase RCAN1 expression nor induces capillary tube formation by augmenting VEGF secretion.	('capillary tube formation', 'CPA', (263, 287))	('VEGF', 'Gene', (128, 132))	('RCAN1', 'Gene', (234, 239))	('VEGF', 'Gene', (302, 306))	('RCAN1', 'Gene', '1827', (234, 239))	('K15', 'Var', (212, 215))	('expression', 'Species', '29278', (240, 250))	('expression', 'Species', '29278', (110, 120))	('induces', 'Reg', (255, 262))	('VEGF', 'Gene', '7422', (128, 132))	('VEGF-A', 'Gene', '7422', (128, 134))	('VEGF', 'Gene', '7422', (302, 306))	('augmenting', 'PosReg', (291, 301))	('VEGF-A', 'Gene', (128, 134))	('expression', 'Species', '29278', (34, 44))
205644	23028325	In HUVECs transduced with a GFP expressing retroviral vector pSF91, knockdown of RCAN1 significantly abrogates VEGF-induced tube formation in contrast to cells transfected with a scrambled siRNA (not shown) in line with earlier reports that RCAN1 is required for VEGF-induced capillary tube formation in HUVECs.	('VEGF', 'Gene', (111, 115))	('abrogates', 'NegReg', (101, 110))	('RCAN1', 'Gene', '1827', (81, 86))	('RCAN1', 'Gene', (241, 246))	('SF9', 'CellLine', 'CVCL:0549', (62, 65))	('RCAN1', 'Gene', '1827', (241, 246))	('VEGF', 'Gene', (263, 267))	('knockdown', 'Var', (68, 77))	('VEGF', 'Gene', '7422', (111, 115))	('RCAN1', 'Gene', (81, 86))	('VEGF', 'Gene', '7422', (263, 267))
205645	23028325	Knockdown of RCAN1 also abrogated K15-induced capillary tube formation in the absence of VEGF (figure 3A and 3B).	('K15-induced capillary tube formation', 'CPA', (34, 70))	('RCAN1', 'Gene', (13, 18))	('Knockdown', 'Var', (0, 9))	('RCAN1', 'Gene', '1827', (13, 18))	('VEGF', 'Gene', '7422', (89, 93))	('abrogated', 'NegReg', (24, 33))	('VEGF', 'Gene', (89, 93))
205646	23028325	The Western blot in figure 3C confirms the knockdown of RCAN1.	('RCAN1', 'Gene', '1827', (56, 61))	('RCAN1', 'Gene', (56, 61))	('knockdown', 'Var', (43, 52))
205648	23028325	As shown in figure 3A-C, expression of RCAN1.1 and RCAN 1.4 could be reduced selectively, and the absence of either isoform reduced the ability of K15 to induce angiogenic tube formation.	('angiogenic tube formation', 'CPA', (161, 186))	('expression', 'Species', '29278', (25, 35))	('reduced', 'NegReg', (124, 131))	('ability', 'MPA', (136, 143))	('reduced', 'NegReg', (69, 76))	('expression', 'MPA', (25, 35))	('RCAN 1', 'Gene', '1827', (51, 57))	('absence', 'Var', (98, 105))	('RCAN 1', 'Gene', (51, 57))	('RCAN1', 'Gene', (39, 44))	('RCAN1', 'Gene', '1827', (39, 44))
205651	23028325	Following VEGF-A stimulation, phosphorylation of the tyrosine 1175 site in VEGFR-2 allows the binding and subsequent phosphorylation of PLCgamma1.	('phosphorylation', 'MPA', (30, 45))	('VEGF-A', 'Gene', '7422', (10, 16))	('binding', 'Interaction', (94, 101))	('VEGF-A', 'Gene', (10, 16))	('phosphorylation', 'MPA', (117, 132))	('VEGFR-2', 'Gene', '3791', (75, 82))	('tyrosine 1175', 'Var', (53, 66))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('PLCgamma1', 'Gene', (136, 145))	('VEGFR-2', 'Gene', (75, 82))	('PLCgamma1', 'Gene', '5335', (136, 145))
205653	23028325	DAG is a physiological activator of PKC, whilst IP3 acts upon the endoplasmic reticulum to release calcium, thus inducing a rise in intracellular calcium (Ca2+).	('IP3', 'Var', (48, 51))	('calcium', 'Chemical', 'MESH:D002118', (146, 153))	('IP3', 'Chemical', 'MESH:D015544', (48, 51))	('DAG', 'Chemical', 'MESH:D004075', (0, 3))	('rise', 'PosReg', (124, 128))	('Ca2+', 'Chemical', 'MESH:D000069285', (155, 159))	('calcium', 'Chemical', 'MESH:D002118', (99, 106))	('inducing', 'Reg', (113, 121))
205657	23028325	As expected from previous reports, we could inhibit VEGF-induced capillary tube formation in HUVEC (figure 4A), NFAT1 dephosphorylation and the resulting increased RCAN1.1/1.4 expression (figure 4B) with chemical inhibitors of Calcineurin (cyclosporin A; CsA) and PLCgamma (U73122).	('VEGF', 'Gene', (52, 56))	('U73122', 'Var', (274, 280))	('NFAT1', 'Gene', (112, 117))	('cyclosporin A', 'Chemical', 'MESH:D016572', (240, 253))	('inhibit', 'NegReg', (44, 51))	('RCAN1', 'Gene', (164, 169))	('RCAN1', 'Gene', '1827', (164, 169))	('expression', 'Species', '29278', (176, 186))	('VEGF', 'Gene', '7422', (52, 56))	('capillary tube formation', 'CPA', (65, 89))	('CsA', 'Chemical', 'MESH:D016572', (255, 258))	('expression', 'MPA', (176, 186))	('U73122', 'Chemical', 'MESH:C060229', (274, 280))	('dephosphorylation', 'MPA', (118, 135))	('NFAT1', 'Gene', '4773', (112, 117))	('increased', 'PosReg', (154, 163))
205658	23028325	In addition, as shown in figure 4C, K15-induced capillary tube formation was significantly abrogated in the presence of CsA and U73122, suggesting that it follows the same pathway as VEGF.	('VEGF', 'Gene', (183, 187))	('CsA', 'Gene', (120, 123))	('U73122', 'Chemical', 'MESH:C060229', (128, 134))	('CsA', 'Chemical', 'MESH:D016572', (120, 123))	('K15-induced', 'Var', (36, 47))	('VEGF', 'Gene', '7422', (183, 187))	('abrogated', 'NegReg', (91, 100))	('U73122', 'Var', (128, 134))
205659	23028325	Western blot analysis (figure 4D) showed that K15 induced PLCgamma1 phosphorylation and dephosphorylation of NFAT1.	('PLCgamma1', 'Gene', (58, 67))	('NFAT1', 'Gene', (109, 114))	('PLCgamma1', 'Gene', '5335', (58, 67))	('dephosphorylation', 'MPA', (88, 105))	('K15', 'Var', (46, 49))	('NFAT1', 'Gene', '4773', (109, 114))
205660	23028325	Treatment with CsA and U73122 reduced the levels of K15-induced RCAN1.1/1.4 expression, abolished dephosphorylation of NFAT1 and (in the case of U73122) reduced levels of PLCgamma1 phosphorylated on Tyr 783.	('reduced', 'NegReg', (153, 160))	('U73122', 'Chemical', 'MESH:C060229', (23, 29))	('abolished', 'NegReg', (88, 97))	('U73122', 'Var', (145, 151))	('dephosphorylation', 'MPA', (98, 115))	('RCAN1', 'Gene', '1827', (64, 69))	('expression', 'Species', '29278', (76, 86))	('CsA', 'Chemical', 'MESH:D016572', (15, 18))	('RCAN1', 'Gene', (64, 69))	('U73122', 'Chemical', 'MESH:C060229', (145, 151))	('NFAT1', 'Gene', (119, 124))	('reduced', 'NegReg', (30, 37))	('NFAT1', 'Gene', '4773', (119, 124))	('levels', 'MPA', (42, 48))	('PLCgamma1', 'Gene', '5335', (171, 180))	('U73122', 'Var', (23, 29))	('Tyr', 'Chemical', 'MESH:D014443', (199, 202))	('PLCgamma1', 'Gene', (171, 180))	('expression', 'MPA', (76, 86))	('levels', 'MPA', (161, 167))
205663	23028325	Western blots of the same samples (figure 5B) showed again that K15 expression led to an enhanced dephosphorylation of NFAT1 and that this effect was abolished by silencing the expression of Calcineurin by means of siRNA.	('expression', 'Species', '29278', (68, 78))	('enhanced', 'PosReg', (89, 97))	('NFAT1', 'Gene', (119, 124))	('K15 expression', 'Var', (64, 78))	('expression', 'Species', '29278', (177, 187))	('NFAT1', 'Gene', '4773', (119, 124))	('dephosphorylation', 'MPA', (98, 115))
205664	23028325	Silencing of NFAT1 and Calcineurin also reduced K15-induced RCAN1.1 and RCAN1.4 levels (figure 5B).	('NFAT1', 'Gene', '4773', (13, 18))	('RCAN1', 'Gene', (60, 65))	('NFAT1', 'Gene', (13, 18))	('RCAN1', 'Gene', '1827', (72, 77))	('RCAN1', 'Gene', (72, 77))	('reduced', 'NegReg', (40, 47))	('Silencing', 'Var', (0, 9))	('RCAN1', 'Gene', '1827', (60, 65))
205666	23028325	As shown in figure 5C, knockdown of PLCgamma1 decreased VEGF-induced capillary tube formation in the absence of K15 (pSF91-transduced cells in figure 5C), as well as K15-induced capillary tube formation (figure 5C) and RCAN1.1/1.4 expression (figure 5D) in the absence of VEGF.	('VEGF', 'Gene', (272, 276))	('PLCgamma1', 'Gene', '5335', (36, 45))	('VEGF', 'Gene', (56, 60))	('RCAN1', 'Gene', (219, 224))	('K15-induced', 'Var', (166, 177))	('knockdown', 'Var', (23, 32))	('VEGF', 'Gene', '7422', (272, 276))	('PLCgamma1', 'Gene', (36, 45))	('RCAN1', 'Gene', '1827', (219, 224))	('expression', 'Species', '29278', (231, 241))	('decreased', 'NegReg', (46, 55))	('VEGF', 'Gene', '7422', (56, 60))	('SF9', 'CellLine', 'CVCL:0549', (118, 121))
205667	23028325	We have shown earlier that K15, through its cytoplasmic C terminal domain activates the NFkappaB pathway and that this involves the NFkappaB component RelA/p65 (unpublished).	('NFkappaB', 'Gene', '4790', (132, 140))	('p65', 'Gene', (156, 159))	('NFkappaB', 'Gene', (88, 96))	('p65', 'Gene', '5970', (156, 159))	('K15', 'Var', (27, 30))	('NFkappaB', 'Gene', '4790', (88, 96))	('activates', 'PosReg', (74, 83))	('RelA', 'Gene', (151, 155))	('RelA', 'Gene', '5970', (151, 155))	('NFkappaB', 'Gene', (132, 140))
205668	23028325	To investigate the involvement of the NFkappaB pathway in K15-induced capillary tube formation, we silenced RelA/p65 using siRNA.	('silenced', 'Var', (99, 107))	('p65', 'Gene', (113, 116))	('NFkappaB', 'Gene', (38, 46))	('p65', 'Gene', '5970', (113, 116))	('NFkappaB', 'Gene', '4790', (38, 46))	('RelA', 'Gene', (108, 112))	('RelA', 'Gene', '5970', (108, 112))
205669	23028325	As shown in figure 5C and 5D, silencing of RelA/p65 does not antagonize RCAN1 expression and capillary tube formation induced by K15.	('RelA', 'Gene', (43, 47))	('p65', 'Gene', '5970', (48, 51))	('expression', 'MPA', (78, 88))	('antagonize', 'NegReg', (61, 71))	('RCAN1', 'Gene', '1827', (72, 77))	('RelA', 'Gene', '5970', (43, 47))	('RCAN1', 'Gene', (72, 77))	('capillary tube formation', 'CPA', (93, 117))	('p65', 'Gene', (48, 51))	('silencing', 'Var', (30, 39))	('expression', 'Species', '29278', (78, 88))	('K15', 'Var', (129, 132))
205670	23028325	Taken together, these results suggest that the activation of the PLCgamma1-Calcineurin-NFAT pathway is required for the K15-induced tube formation and that this effect is independent of the NFkappaB pathway.	('NFkappaB', 'Gene', (190, 198))	('NFkappaB', 'Gene', '4790', (190, 198))	('PLCgamma1', 'Gene', '5335', (65, 74))	('tube formation', 'CPA', (132, 146))	('K15-induced', 'Var', (120, 131))	('PLCgamma1', 'Gene', (65, 74))
205671	23028325	We next studied the kinetics of the activation of the PLCgamma1 pathway by K15.	('PLCgamma1', 'Gene', (54, 63))	('K15', 'Var', (75, 78))	('PLCgamma1', 'Gene', '5335', (54, 63))
205672	23028325	We found that, in contrast to VEGF, which induces a transient increase in PLCgamma1 phosphorylation that peaks at 5-10 minutes and disappears after approx 30 minutes (figure 6A), the K15-induced PLCgamma1 phosphorylation lasted for up to 48 hours (figure 6B).	('PLCgamma1', 'Gene', '5335', (195, 204))	('VEGF', 'Gene', '7422', (30, 34))	('PLCgamma1', 'Gene', (74, 83))	('K15-induced', 'Var', (183, 194))	('VEGF', 'Gene', (30, 34))	('PLCgamma1', 'Gene', (195, 204))	('PLCgamma1', 'Gene', '5335', (74, 83))	('phosphorylation', 'MPA', (205, 220))
205677	23028325	K15, on the other hand, as seen in figure 6B, activates PLCgamma1 and RCAN1 expression in a protracted constitutive manner.	('PLCgamma1', 'Gene', (56, 65))	('K15', 'Var', (0, 3))	('RCAN1', 'Gene', (70, 75))	('activates', 'PosReg', (46, 55))	('expression', 'Species', '29278', (76, 86))	('PLCgamma1', 'Gene', '5335', (56, 65))	('RCAN1', 'Gene', '1827', (70, 75))	('expression', 'MPA', (76, 86))
205681	23028325	The cytoplasmic domain of the P-type of K15 used here contains two SH2-binding sites (Y431ASIL and Y481EEVL), a proline-rich SH3-binding site (P387PLP) and a TRAF-binding site (A473TQPTDD).	('proline', 'Chemical', 'MESH:D011392', (112, 119))	('PLP', 'Gene', (147, 150))	('PLP', 'Gene', '5354', (147, 150))	('Y431ASIL', 'Mutation', 'p.Y431ASIL', (86, 94))	('Y431ASIL', 'Var', (86, 94))	('SH2-binding', 'Interaction', (67, 78))	('SH3-binding', 'Interaction', (125, 136))	('Y481EEVL', 'Mutation', 'p.Y481EEVL', (99, 107))	('SH2-binding', 'Gene', (67, 78))	('Y481EEVL', 'Var', (99, 107))
205682	23028325	The Y481EEVL motif has been shown to activate various signaling pathways such as MAPK, JNK, NFkappaB.	('activate', 'PosReg', (37, 45))	('JNK', 'Gene', (87, 90))	('signaling pathways', 'Pathway', (54, 72))	('MAPK', 'Gene', (81, 85))	('Y481EEVL', 'Mutation', 'p.Y481EEVL', (4, 12))	('NFkappaB', 'Gene', (92, 100))	('JNK', 'Gene', '5599', (87, 90))	('NFkappaB', 'Gene', '4790', (92, 100))	('MAPK', 'Gene', '5594', (81, 85))	('Y481EEVL', 'Var', (4, 12))
205683	23028325	To test which of these domains is involved in the activation of the PLCgamma1 pathway, we used previously reported mutants of SH2 and SH3 binding motifs in which the tyrosine at position 481 had been changed to phenylalanine (YEEVL to FEEVL), or all the prolines in the SH3 binding motif had been changed to alanine (PPLP to AALA).	('PLP', 'Gene', (318, 321))	('PLCgamma1', 'Gene', '5335', (68, 77))	('changed', 'Reg', (297, 304))	('changed', 'Reg', (200, 207))	('alanine', 'Chemical', 'MESH:D000409', (308, 315))	('mutants', 'Var', (115, 122))	('prolines', 'Chemical', 'MESH:D011392', (254, 262))	('PLCgamma1', 'Gene', (68, 77))	('tyrosine at position 481 had been changed to phenylalanine', 'Mutation', 'p.Y481F', (166, 224))	('SH2', 'Gene', (126, 129))	('PLP', 'Gene', '5354', (318, 321))	('alanine', 'Chemical', 'MESH:D000409', (217, 224))
205684	23028325	We tested these mutants for their ability to induce capillary tube formation and to activate PLCgamma1 phosphorylation.	('PLCgamma1', 'Gene', (93, 102))	('induce', 'PosReg', (45, 51))	('mutants', 'Var', (16, 23))	('tested', 'Reg', (3, 9))	('PLCgamma1', 'Gene', '5335', (93, 102))	('phosphorylation', 'MPA', (103, 118))	('capillary tube formation', 'CPA', (52, 76))	('activate', 'PosReg', (84, 92))
205685	23028325	As shown in figure 7B, wildtype K15 and the DeltaSH3 mutant could induce PLCgamma1 phosphorylation and increase RCAN1.1/1.4 expression, whereas the tyrosine 481 (YF) mutant of K15 could not.	('increase', 'PosReg', (103, 111))	('tyrosine', 'Chemical', 'MESH:D014443', (148, 156))	('PLCgamma1', 'Gene', '5335', (73, 82))	('RCAN1', 'Gene', '1827', (112, 117))	('induce', 'PosReg', (66, 72))	('expression', 'Species', '29278', (124, 134))	('expression', 'MPA', (124, 134))	('mutant', 'Var', (53, 59))	('DeltaSH3', 'Gene', (44, 52))	('PLCgamma1', 'Gene', (73, 82))	('RCAN1', 'Gene', (112, 117))
205686	23028325	This observation suggests that the tyrosine residue at position 481 in the YEEV motif is important for activation of the PLCgamma1 pathway, induction of RCAN1 and capillary tube formation.	('tyrosine', 'Chemical', 'MESH:D014443', (35, 43))	('tyrosine', 'Var', (35, 43))	('PLCgamma1', 'Gene', '5335', (121, 130))	('RCAN1', 'Gene', '1827', (153, 158))	('capillary tube formation', 'CPA', (163, 187))	('RCAN1', 'Gene', (153, 158))	('activation', 'PosReg', (103, 113))	('PLCgamma1', 'Gene', (121, 130))
205688	23028325	Since we had found that activation of PLCgamma1 by K15 requires the K15 Y481 residue, which had been previously shown to be phosphorylated by Src family tyrosine kinases, we next investigated if K15 can directly recruit PLCgamma1 via its Y481EEV SH2 binding site.	('PLCgamma1', 'Gene', '5335', (38, 47))	('PLCgamma1', 'Gene', '5335', (220, 229))	('Y481', 'Var', (72, 76))	('K15', 'Var', (195, 198))	('K15', 'Var', (51, 54))	('Y481EEV', 'Var', (238, 245))	('tyrosine', 'Chemical', 'MESH:D014443', (153, 161))	('recruit', 'Interaction', (212, 219))	('Src', 'Gene', (142, 145))	('Src', 'Gene', '6714', (142, 145))	('activation', 'PosReg', (24, 34))	('PLCgamma1', 'Gene', (38, 47))	('PLCgamma1', 'Gene', (220, 229))
205690	23028325	We found that K15 can interact with PLCgamma1 (figure 8A), and that the K15YF mutant and the K15DeltaSH3 mutants showed a reduced interaction with PLCgamma1.	('PLCgamma1', 'Gene', '5335', (36, 45))	('PLCgamma1', 'Gene', (147, 156))	('K15YF mutant', 'Var', (72, 84))	('K15DeltaSH3', 'Gene', (93, 104))	('PLCgamma1', 'Gene', '5335', (147, 156))	('PLCgamma1', 'Gene', (36, 45))	('interact', 'Interaction', (22, 30))	('mutants', 'Var', (105, 112))	('interaction', 'Interaction', (130, 141))	('reduced', 'NegReg', (122, 129))	('mutant', 'Var', (78, 84))
205691	23028325	This suggests that K15 interacts with PLCgamma1, and that the SH2 binding site (Y481EEV) as well as the SH3 binding site (P387LPP) contribute to the interaction.	('PLCgamma1', 'Gene', '5335', (38, 47))	('interacts', 'Interaction', (23, 32))	('binding', 'Interaction', (66, 73))	('interaction', 'Interaction', (149, 160))	('P387LPP', 'Var', (122, 129))	('Y481EEV', 'Var', (80, 87))	('contribute', 'Reg', (131, 141))	('PLCgamma1', 'Gene', (38, 47))
205693	23028325	In this assay, the Y481F and DeltaSH3 mutants also showed a decreased interaction while virtually no interaction could be seen in the case of the double mutant (YFDeltaSH3).	('decreased', 'NegReg', (60, 69))	('interaction', 'Interaction', (70, 81))	('DeltaSH3', 'Gene', (29, 37))	('Y481F', 'Var', (19, 24))	('Y481F', 'Mutation', 'p.Y481F', (19, 24))
205695	23028325	As shown in figure 8C, D, both K15-P and K15-M co-immunoprecipitate with PLCgamma1 and interact with PLCgamma1 in a GST pull-down assay.	('PLCgamma1', 'Gene', (101, 110))	('K15-P', 'Var', (31, 36))	('PLCgamma1', 'Gene', '5335', (73, 82))	('interact', 'Interaction', (87, 95))	('PLCgamma1', 'Gene', '5335', (101, 110))	('K15-M', 'Gene', '3866', (41, 46))	('K15-M', 'Gene', (41, 46))	('PLCgamma1', 'Gene', (73, 82))
205696	23028325	In addition, transfection of both K15-P and K15-M induces phosphorylation of PLCgamma1 on tyrosine 783 (figure 8E).	('K15-P', 'Var', (34, 39))	('K15-M', 'Gene', (44, 49))	('K15-M', 'Gene', '3866', (44, 49))	('tyrosine', 'Chemical', 'MESH:D014443', (90, 98))	('phosphorylation', 'MPA', (58, 73))	('PLCgamma1', 'Gene', (77, 86))	('PLCgamma1', 'Gene', '5335', (77, 86))	('induces', 'Reg', (50, 57))
205703	23028325	This supports our previous result (figure 1C, 2D and 6C) that K15-induced tube formation is independent of VEGF.	('tube formation', 'CPA', (74, 88))	('K15-induced', 'Var', (62, 73))	('VEGF', 'Gene', (107, 111))	('VEGF', 'Gene', '7422', (107, 111))
205704	23028325	To explore if Src family kinase members are involved in the K15-mediated activation of PLCgamma1, we treated K15-transduced HUVECs with the Src family kinase inhibitors Su6656, PP1, PP2 and MNS.	('PP2', 'Gene', (182, 185))	('PP2', 'Gene', '4888', (182, 185))	('Su6656', 'Chemical', 'MESH:C416927', (169, 175))	('PLCgamma1', 'Gene', '5335', (87, 96))	('Src', 'Gene', (140, 143))	('Src', 'Gene', '6714', (140, 143))	('PP1', 'Gene', '5540', (177, 180))	('PP1', 'Gene', (177, 180))	('Src', 'Gene', (14, 17))	('Src', 'Gene', '6714', (14, 17))	('Su6656', 'Var', (169, 175))	('PLCgamma1', 'Gene', (87, 96))
205706	23028325	The identity of the tyrosine kinase involved in the phosphorylation of K15 tyrosine 481 (required for PLCgamma1 docking) or PLCgamma1 tyrosine 783 therefore remains to be established.	('tyrosine', 'Chemical', 'MESH:D014443', (20, 28))	('PLCgamma1', 'Gene', (124, 133))	('PLCgamma1', 'Gene', '5335', (124, 133))	('PLCgamma1', 'Gene', (102, 111))	('tyrosine', 'Chemical', 'MESH:D014443', (75, 83))	('tyrosine', 'Chemical', 'MESH:D014443', (134, 142))	('K15', 'Var', (71, 74))	('PLCgamma1', 'Gene', '5335', (102, 111))
205715	23028325	As shown in panel 4 of figure 10C, induction of the lytic replication cycle results in increased PLCgamma1 phosphorylation, which, along with capillary tube formation, is strongly suppressed by silencing of K15.	('PLCgamma1', 'Gene', (97, 106))	('increased', 'PosReg', (87, 96))	('K15', 'Gene', (207, 210))	('silencing', 'Var', (194, 203))	('suppressed', 'NegReg', (180, 190))	('PLCgamma1', 'Gene', '5335', (97, 106))	('capillary tube formation', 'CPA', (142, 166))	('lytic replication cycle', 'CPA', (52, 75))
205719	23028325	As shown in figure 10 D, E, BAC-derived KSHV induced moderate angiogenic tube formation in latently infected compared to uninfected cells, and more extensive angiogenic tube formation following activation of the lytic cycle, whereas the angiogenic index was reduced in KSHVDeltaK15- relative to KSHVwt-infected lytically induced cells.	('angiogenic tube formation', 'CPA', (158, 183))	('angiogenic index', 'CPA', (237, 253))	('reduced', 'NegReg', (258, 265))	('angiogenic tube formation', 'CPA', (62, 87))	('KSHV', 'Species', '37296', (269, 273))	('KSHV', 'Species', '37296', (40, 44))	('KS', 'Phenotype', 'HP:0100726', (269, 271))	('KSHVDeltaK15-', 'Var', (269, 282))	('KS', 'Phenotype', 'HP:0100726', (295, 297))	('KSHV', 'Species', '37296', (295, 299))	('KS', 'Phenotype', 'HP:0100726', (40, 42))
205720	23028325	Western blots (figure 10F) confirmed the absence of K15 protein in KSHVDeltaK15- compared to KSHVwt-infected cells (top panel) and comparable levels of lytic glycoprotein K8.1 expression in KSHVwt and KSHVDeltaK15-infected cells following lytic cycle activation.	('K15 protein', 'Protein', (52, 63))	('KSHV', 'Species', '37296', (93, 97))	('expression', 'Species', '29278', (176, 186))	('KS', 'Phenotype', 'HP:0100726', (190, 192))	('KSHV', 'Species', '37296', (190, 194))	('absence', 'NegReg', (41, 48))	('KSHV', 'Species', '37296', (201, 205))	('KS', 'Phenotype', 'HP:0100726', (67, 69))	('KSHV', 'Species', '37296', (67, 71))	('KS', 'Phenotype', 'HP:0100726', (201, 203))	('KS', 'Phenotype', 'HP:0100726', (93, 95))	('KSHVDeltaK15-', 'Var', (67, 80))
205721	23028325	These results suggest that the increased formation of capillary tubes that occurs in KSHV infected endothelial cells depends to a significant extent on K15 and the K15-dependent activation of the PLCgamma1-NFAT1-RCAN1 pathway.	('increased formation of capillary tubes', 'Phenotype', 'HP:0030005', (31, 69))	('RCAN1', 'Gene', '1827', (212, 217))	('KSHV', 'Species', '37296', (85, 89))	('RCAN1', 'Gene', (212, 217))	('formation of capillary tubes', 'CPA', (41, 69))	('K15-dependent', 'Var', (164, 177))	('increased', 'PosReg', (31, 40))	('PLCgamma1', 'Gene', '5335', (196, 205))	('NFAT1', 'Gene', '4773', (206, 211))	('KSHV', 'Gene', (85, 89))	('NFAT1', 'Gene', (206, 211))	('activation', 'PosReg', (178, 188))	('K15', 'Var', (152, 155))	('KS', 'Phenotype', 'HP:0100726', (85, 87))	('PLCgamma1', 'Gene', (196, 205))
205727	23028325	KSHV induces a transcriptional reprogramming of vascular endothelial cells towards a pattern typical of lymphatic endothelial cells, as well as inducing cellular genes typical of vascular endothelial cells in infected lymphatic endothelial cells In addition, KSHV causes endothelial to mesenchymal transition (EndoMT) in infected lymphatic endothelial cells, thereby accounting for the expression of mesenchymal markers frequently observed on KS spindle cells.	('KS', 'Phenotype', 'HP:0100726', (443, 445))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('KS', 'Phenotype', 'HP:0100726', (259, 261))	('KSHV', 'Species', '37296', (259, 263))	('expression', 'Species', '29278', (386, 396))	('KSHV', 'Var', (259, 263))	('endothelial to mesenchymal transition', 'CPA', (271, 308))	('causes', 'Reg', (264, 270))
205732	23028325	Starting from an earlier observation, that transfection of K15 into epithelial cells induced the expression of cellular genes that are known to be activated by VEGF, but did not appear to induce VEGF expression itself, we compared the effect of expressing K15 in primary endothelial cells on cellular gene expression with the pattern of cellular genes induced by infecting endothelial cells with KSHV, or a KSHV K15 deletion mutant.	('VEGF', 'Gene', '7422', (195, 199))	('expression', 'Species', '29278', (306, 316))	('VEGF', 'Gene', (160, 164))	('KSHV K15', 'Gene', (407, 415))	('KSHV', 'Species', '37296', (396, 400))	('K15', 'Gene', (412, 415))	('expression', 'Species', '29278', (200, 210))	('expression', 'Species', '29278', (97, 107))	('KS', 'Phenotype', 'HP:0100726', (396, 398))	('VEGF', 'Gene', (195, 199))	('KSHV', 'Species', '37296', (407, 411))	('deletion mutant', 'Var', (416, 431))	('KS', 'Phenotype', 'HP:0100726', (407, 409))	('VEGF', 'Gene', '7422', (160, 164))	('expression', 'MPA', (97, 107))
205735	23028325	Cellular genes that are differentially regulated between endothelial cells infected with KSHVwt and a KSHV deletion mutant are likely to be those whose expression is most strongly affected by the deleted viral gene in the context of the entire virus genome.	('KS', 'Phenotype', 'HP:0100726', (89, 91))	('KSHV', 'Species', '37296', (89, 93))	('KS', 'Phenotype', 'HP:0100726', (102, 104))	('KSHV', 'Gene', (102, 106))	('expression', 'Species', '29278', (152, 162))	('KSHV', 'Species', '37296', (102, 106))	('expression', 'MPA', (152, 162))	('deletion mutant', 'Var', (107, 122))
205736	23028325	In this study we found RCAN1/DSCR1, a regulator of the Calcineurin-NFAT pathway, to be differentially expressed in endothelial cells infected with KSHVwt and KSHVDeltaK15.	('KSHV', 'Species', '37296', (147, 151))	('KS', 'Phenotype', 'HP:0100726', (147, 149))	('DSCR1', 'Gene', '1827', (29, 34))	('KSHVDeltaK15', 'Var', (158, 170))	('DSCR1', 'Gene', (29, 34))	('KS', 'Phenotype', 'HP:0100726', (158, 160))	('RCAN1', 'Gene', (23, 28))	('RCAN1', 'Gene', '1827', (23, 28))	('KSHV', 'Species', '37296', (158, 162))
205737	23028325	The activation of RCAN1 by K15 in KSHVwt- but not in KSHVDeltaK15-infected endothelial cells, as well as in endothelial cells transduced with K15, is not accompanied by a consistently increased expression of VEGF family members (figure 1A-D).	('KS', 'Phenotype', 'HP:0100726', (34, 36))	('KSHV', 'Species', '37296', (34, 38))	('RCAN1', 'Gene', (18, 23))	('K15', 'Var', (27, 30))	('RCAN1', 'Gene', '1827', (18, 23))	('VEGF', 'Gene', (208, 212))	('expression', 'Species', '29278', (194, 204))	('KS', 'Phenotype', 'HP:0100726', (53, 55))	('KSHV', 'Species', '37296', (53, 57))	('VEGF', 'Gene', '7422', (208, 212))	('activation', 'PosReg', (4, 14))
205739	23028325	Similarly, RCAN1 expression is required for K15-induced angiogenesis in the absence of exogenously added VEGF (figure 3B,C).	('expression', 'Species', '29278', (17, 27))	('RCAN1', 'Gene', (11, 16))	('VEGF', 'Gene', (105, 109))	('RCAN1', 'Gene', '1827', (11, 16))	('K15-induced', 'Var', (44, 55))	('VEGF', 'Gene', '7422', (105, 109))
205740	23028325	Although the expression of RCAN1 is normally regulated by the binding of VEGF to its receptor, the subsequent activation (phosphorylation) of PLCgamma1 and the ensuing influx of Ca2+, our observations suggest that the K15-induced expression of RCAN1 and angiogenic tube formation is not dependent on VEGF.	('PLCgamma1', 'Gene', (142, 151))	('angiogenic tube formation', 'CPA', (254, 279))	('activation', 'PosReg', (110, 120))	('expression', 'Species', '29278', (13, 23))	('Ca2+', 'Chemical', 'MESH:D000069285', (178, 182))	('VEGF', 'Gene', (300, 304))	('RCAN1', 'Gene', (27, 32))	('RCAN1', 'Gene', (244, 249))	('expression', 'Species', '29278', (230, 240))	('PLCgamma1', 'Gene', '5335', (142, 151))	('RCAN1', 'Gene', '1827', (244, 249))	('RCAN1', 'Gene', '1827', (27, 32))	('VEGF', 'Gene', '7422', (73, 77))	('VEGF', 'Gene', '7422', (300, 304))	('K15-induced', 'Var', (218, 229))	('influx of Ca2+', 'MPA', (168, 182))	('VEGF', 'Gene', (73, 77))
205741	23028325	The expression of VEGF-A is not consistently increased by overexpressed K15 whereas, the expression of RCAN1 is (figure 1C).	('expression', 'MPA', (89, 99))	('expression', 'Species', '29278', (4, 14))	('RCAN1', 'Gene', (103, 108))	('expression', 'MPA', (4, 14))	('VEGF-A', 'Gene', '7422', (18, 24))	('RCAN1', 'Gene', '1827', (103, 108))	('VEGF-A', 'Gene', (18, 24))	('K15', 'Var', (72, 75))	('expression', 'Species', '29278', (89, 99))
205742	23028325	Conditioned supernatants from K15 transduced cells do not induce the angiogenic tube formation caused by VEGF (figure 2D) and the silencing of any of the three VEGF receptors FLT1, KDR, FLT4 by siRNA does not reduce K15-induced angiogenic tube formation while VEGF-induced angiogenesis is inhibited by silencing KDR (figure 9A,B).	('KDR', 'Gene', (181, 184))	('VEGF', 'Gene', '7422', (260, 264))	('angiogenic tube formation', 'CPA', (69, 94))	('FLT1', 'Gene', '2321', (175, 179))	('VEGF', 'Gene', (160, 164))	('VEGF', 'Gene', (105, 109))	('KDR', 'Gene', '3791', (312, 315))	('KDR', 'Gene', '3791', (181, 184))	('angiogenic tube formation', 'CPA', (228, 253))	('FLT4', 'Gene', (186, 190))	('VEGF', 'Gene', (260, 264))	('VEGF', 'Gene', '7422', (160, 164))	('FLT1', 'Gene', (175, 179))	('silencing', 'Var', (130, 139))	('KDR', 'Gene', (312, 315))	('FLT4', 'Gene', '2324', (186, 190))	('VEGF', 'Gene', '7422', (105, 109))
205743	23028325	We therefore conclude that K15-induced angiogenesis is independent of VEGF and VEGF receptors, in spite of K15-induced angiogenesis requiring several of the downstream components of the VEGF signaling pathway.	('VEGF', 'Gene', (70, 74))	('VEGF', 'Gene', (186, 190))	('K15-induced', 'Var', (107, 118))	('VEGF', 'Gene', '7422', (79, 83))	('VEGF', 'Gene', '7422', (70, 74))	('VEGF', 'Gene', '7422', (186, 190))	('VEGF', 'Gene', (79, 83))
205745	23028325	Both RCAN1 isoforms RCAN1.1 and RCAN1.4 appear to contribute to K15-induced angiogenic tube formation.	('RCAN1', 'Gene', '1827', (20, 25))	('RCAN1', 'Gene', (20, 25))	('contribute', 'Reg', (50, 60))	('angiogenic tube formation', 'CPA', (76, 101))	('K15-induced', 'Var', (64, 75))	('RCAN1', 'Gene', (5, 10))	('RCAN1', 'Gene', (32, 37))	('RCAN1', 'Gene', '1827', (5, 10))	('RCAN1', 'Gene', '1827', (32, 37))
205746	23028325	These results suggest that K15 activates a PLCgamma1-Calcineurin-NFAT1-dependent pathway, normally utilized by VEGF.	('VEGF', 'Gene', (111, 115))	('activates', 'PosReg', (31, 40))	('K15', 'Var', (27, 30))	('NFAT1', 'Gene', (65, 70))	('PLCgamma1', 'Gene', (43, 52))	('VEGF', 'Gene', '7422', (111, 115))	('PLCgamma1', 'Gene', '5335', (43, 52))	('NFAT1', 'Gene', '4773', (65, 70))
205747	23028325	In contrast to VEGF, which induces a short burst of PLCgamma1 phosphorylation and a transient RCAN1 expression, K15 activates PLCgamma1 phosphorylation and RCAN1 expression in a protracted manner (figure 6).	('PLCgamma1', 'Gene', (52, 61))	('phosphorylation', 'MPA', (136, 151))	('PLCgamma1', 'Gene', '5335', (126, 135))	('K15', 'Var', (112, 115))	('expression', 'Species', '29278', (100, 110))	('VEGF', 'Gene', (15, 19))	('expression', 'Species', '29278', (162, 172))	('PLCgamma1', 'Gene', '5335', (52, 61))	('activates', 'PosReg', (116, 125))	('expression', 'MPA', (162, 172))	('RCAN1', 'Gene', '1827', (94, 99))	('RCAN1', 'Gene', (94, 99))	('PLCgamma1', 'Gene', (126, 135))	('VEGF', 'Gene', '7422', (15, 19))	('RCAN1', 'Gene', '1827', (156, 161))	('RCAN1', 'Gene', (156, 161))
205748	23028325	Whether this is due to K15 not being subject to the same negative feedback regulation that operates in the case of VEGFR-dependent signaling, or to other mechanisms, remains to be established.	('VEGFR', 'Gene', (115, 120))	('VEGFR', 'Gene', '3791', (115, 120))	('K15', 'Var', (23, 26))
205749	23028325	Whatever the molecular basis of this observation, a constitutive activation of PLCgamma1 by K15 could contribute to the sustained angiogenic phenotype seen in KS lesions.	('K15', 'Var', (92, 95))	('KS lesions', 'Disease', 'MESH:D051437', (159, 169))	('PLCgamma1', 'Gene', '5335', (79, 88))	('KS', 'Phenotype', 'HP:0100726', (159, 161))	('KS lesions', 'Disease', (159, 169))	('activation', 'PosReg', (65, 75))	('PLCgamma1', 'Gene', (79, 88))
205750	23028325	In K15-expressing cells, the PLCgamma1-Calcineurin-NFAT pathway seems to be fully activated and cannot be further enhanced by exogenous VEGF, in keeping with the interpretation that K15 and VEGF use the same pathway.	('VEGF', 'Gene', '7422', (136, 140))	('VEGF', 'Gene', (190, 194))	('PLCgamma1', 'Gene', (29, 38))	('VEGF', 'Gene', (136, 140))	('K15-expressing', 'Var', (3, 17))	('PLCgamma1', 'Gene', '5335', (29, 38))	('VEGF', 'Gene', '7422', (190, 194))	('K15 and VEGF', 'Gene', '3866;7422', (182, 194))
205751	23028325	In an attempt to understand how K15 would achieve the activation of this VEGF-dependent pathway without involving VEGF or VEGF receptors, we found that K15, a membrane protein, can directly interact with PLCgamma1 (figure 8A,B).	('VEGF', 'Gene', '7422', (122, 126))	('PLCgamma1', 'Gene', (204, 213))	('VEGF', 'Gene', (114, 118))	('interact', 'Interaction', (190, 198))	('VEGF', 'Gene', '7422', (73, 77))	('K15', 'Var', (152, 155))	('VEGF', 'Gene', (122, 126))	('PLCgamma1', 'Gene', '5335', (204, 213))	('VEGF', 'Gene', '7422', (114, 118))	('VEGF', 'Gene', (73, 77))
205752	23028325	Both allelic isoforms of K15, K15-P and K15-M, are able to recruit and activate PLCgamma1 (figure 8C-E), suggesting that KSHV isolates with divergent K15 variants are able to activate angiogenesis through the mechanism described in this report.	('K15-M', 'Gene', '3866', (40, 45))	('activate', 'PosReg', (175, 183))	('angiogenesis', 'CPA', (184, 196))	('K15-M', 'Gene', (40, 45))	('variants', 'Var', (154, 162))	('PLCgamma1', 'Gene', (80, 89))	('K15', 'Gene', (150, 153))	('KSHV', 'Species', '37296', (121, 125))	('KS', 'Phenotype', 'HP:0100726', (121, 123))	('PLCgamma1', 'Gene', '5335', (80, 89))
205756	23028325	Since silencing of VEGF receptors does not affect K15-induced angiogenesis and since several Src kinase inhibitors did not show a strong effect on K15-induced PLCgamma1 phosphorylation and angiogenic tube formation (data not shown), the phosphorylation of PLCgamma1 recruited to K15 most likely involves another, yet to be determined, tyrosine kinase.	('PLCgamma1', 'Gene', '5335', (256, 265))	('PLCgamma1', 'Gene', (159, 168))	('Src', 'Gene', '6714', (93, 96))	('VEGF', 'Gene', (19, 23))	('PLCgamma1', 'Gene', (256, 265))	('PLCgamma1', 'Gene', '5335', (159, 168))	('Src', 'Gene', (93, 96))	('K15', 'Gene', (279, 282))	('tyrosine', 'Chemical', 'MESH:D014443', (335, 343))	('silencing', 'Var', (6, 15))	('VEGF', 'Gene', '7422', (19, 23))
205757	23028325	The ability of K15 to induce the phosphorylation of PLCgamma1 and to induce angiogenic tube formation is relevant in virus-infected cells, since silencing of K15 by siRNA in HUVEC infected with recombinant KSHV, KSHV.219, inhibited phosphorylation of PLCgamma1, NFAT1 dephosphorylation, RCAN1.1/1.4 expression and angiogenic tube formation following activation of the lytic cycle (figure 10).	('PLCgamma1', 'Gene', (52, 61))	('KSHV', 'Species', '37296', (206, 210))	('PLCgamma1', 'Gene', (251, 260))	('KS', 'Phenotype', 'HP:0100726', (212, 214))	('KSHV', 'Species', '37296', (212, 216))	('RCAN1', 'Gene', (287, 292))	('expression', 'Species', '29278', (299, 309))	('NFAT1', 'Gene', (262, 267))	('NFAT1', 'Gene', '4773', (262, 267))	('K15', 'Gene', (158, 161))	('angiogenic tube formation', 'CPA', (314, 339))	('KS', 'Phenotype', 'HP:0100726', (206, 208))	('silencing', 'Var', (145, 154))	('inhibited', 'NegReg', (222, 231))	('PLCgamma1', 'Gene', '5335', (52, 61))	('PLCgamma1', 'Gene', '5335', (251, 260))	('dephosphorylation', 'MPA', (268, 285))	('expression', 'MPA', (299, 309))	('RCAN1', 'Gene', '1827', (287, 292))	('phosphorylation', 'MPA', (232, 247))
205758	23028325	Furthermore, KSHVDeltaK15-infected HUVECs showed a significantly reduced angiogenic tube formation compared to KSHVwt-infected cells (figure 10 D-F).	('KS', 'Phenotype', 'HP:0100726', (13, 15))	('reduced', 'NegReg', (65, 72))	('angiogenic tube formation', 'CPA', (73, 98))	('KSHV', 'Species', '37296', (111, 115))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('KSHV', 'Species', '37296', (13, 17))	('KSHVDeltaK15-infected', 'Var', (13, 34))
205759	23028325	We therefore conclude that, in addition to previously reported viral mediators of angiogenesis such as K1 and vGPCR, the membrane protein K15 contributes to KSHV-induced angiogenesis.	('KS', 'Phenotype', 'HP:0100726', (157, 159))	('angiogenesis', 'CPA', (170, 182))	('K15', 'Var', (138, 141))	('K1 and vGPCR', 'Gene', '4961465', (103, 115))	('KSHV-induced', 'Gene', (157, 169))	('contributes', 'Reg', (142, 153))	('KSHV', 'Species', '37296', (157, 161))
205761	23028325	Recruitment and activation of PLCgamma1 by K15 may represent an upstream signaling event that not only feeds into IP3/Ca2+ influx-mediated activation of Calcineurin and subsequent NFAT activation (figure 11), but could also be responsible, via DAG (figure 11), for the previously reported activation of the MEK/ERK and JNK pathways by K15.	('K15', 'Var', (43, 46))	('activation', 'PosReg', (16, 26))	('IP3', 'Chemical', 'MESH:D015544', (114, 117))	('activation', 'PosReg', (139, 149))	('PLCgamma1', 'Gene', '5335', (30, 39))	('ERK', 'Gene', '5594', (311, 314))	('Calcineurin', 'MPA', (153, 164))	('DAG', 'Chemical', 'MESH:D004075', (244, 247))	('JNK', 'Gene', (319, 322))	('ERK', 'Gene', (311, 314))	('MEK', 'Gene', (307, 310))	('MEK', 'Gene', '5609', (307, 310))	('PLCgamma1', 'Gene', (30, 39))	('Ca2+', 'Chemical', 'MESH:D000069285', (118, 122))	('JNK', 'Gene', '5599', (319, 322))	('IP3/Ca2+ influx-mediated', 'MPA', (114, 138))	('NFAT', 'MPA', (180, 184))
205762	23028325	Although we can detect K15 expression at the mRNA (figure 1) and protein (figure 10) level in KSHV-infected endothelial cells prior to the induction of the lytic cycle, we only observed moderate, or no, angiogenic tube formation in HUVECs that were infected with, respectively, BAC36-derived KSHVwt (figure 10 D, E) or rKSHV.219 (figure 10 A, B) prior to the activation of the lytic cycle.	('KS', 'Phenotype', 'HP:0100726', (292, 294))	('KSHV-infected', 'Disease', (94, 107))	('KSHV-infected', 'Disease', 'MESH:C537372', (94, 107))	('angiogenic tube formation', 'CPA', (203, 228))	('expression', 'Species', '29278', (27, 37))	('KSHV', 'Species', '37296', (292, 296))	('KS', 'Phenotype', 'HP:0100726', (94, 96))	('K15', 'Gene', (23, 26))	('KSHV', 'Species', '37296', (94, 98))	('KSHV', 'Species', '37296', (320, 324))	('KS', 'Phenotype', 'HP:0100726', (320, 322))	('rKSHV.219', 'Var', (319, 328))
205764	23028325	We therefore assessed the impact of K15, using siRNA and a KSHV K15 deletion mutant, in infected cells following activation of the lytic cycle in order to obtain more robust measurements.	('deletion mutant', 'Var', (68, 83))	('KSHV K15', 'Gene', (59, 67))	('KSHV', 'Species', '37296', (59, 63))	('KS', 'Phenotype', 'HP:0100726', (59, 61))
205769	23028325	The K15 locus in the KSHV genome appears to be occupied by 'active' chromatin characterized by specific histone acetylation and methylation patterns (H3K9/K14ac, H3K4me3) and K15 was originally described as expressed during latency, but upregulated during lytic replication.	('KS', 'Phenotype', 'HP:0100726', (21, 23))	('H3K9/K14ac', 'Var', (150, 160))	('K15', 'Gene', (175, 178))	('upregulated', 'PosReg', (237, 248))	('methylation', 'MPA', (128, 139))	('acetylation', 'MPA', (112, 123))	('H3K4me3', 'Var', (162, 169))	('KSHV', 'Species', '37296', (21, 25))
205771	23028325	K15 may therefore exert its angiogenic effect in the early stages of KS (when aberrant angiogenesis rather than spindle cells dominate the histology and limited lytic gene expression may play a role) or in a subpopulation of cells showing a restricted pattern of lytic gene expression.	('angiogenic effect', 'CPA', (28, 45))	('K15', 'Var', (0, 3))	('KS', 'Phenotype', 'HP:0100726', (69, 71))	('expression', 'Species', '29278', (172, 182))	('expression', 'Species', '29278', (274, 284))
205773	23028325	Our observation that K15 'usurps' the PLCgamma1-Calcineurin-NFAT pathway and renders K15-expressing cells refractory to additional stimulation by VEGF (figure 6C) does not argue against an effect of VEGF, induced by other viral proteins, on KSHV-infected or neighbouring cells that do not express K15.	('PLCgamma1', 'Gene', '5335', (38, 47))	('VEGF', 'Gene', (146, 150))	('K15', 'Var', (21, 24))	("'usurps'", 'PosReg', (25, 33))	('KS', 'Phenotype', 'HP:0100726', (241, 243))	('VEGF', 'Gene', '7422', (199, 203))	('VEGF', 'Gene', '7422', (146, 150))	('KSHV-infected', 'Disease', (241, 254))	('PLCgamma1', 'Gene', (38, 47))	('KSHV-infected', 'Disease', 'MESH:C537372', (241, 254))	('VEGF', 'Gene', (199, 203))
205774	23028325	Our results therefore do not exclude other, paracrine effects mediated by KSHV and K15, e.g.	('KSHV', 'Species', '37296', (74, 78))	('KS', 'Phenotype', 'HP:0100726', (74, 76))	('KSHV', 'Gene', (74, 78))	('K15', 'Var', (83, 86))
205787	22662320	The major driver of ES, the EWS-FLI1 gene fusion, was discovered exactly 20 years ago (Delattre et al.,), and there is ample experimental evidence that inhibition of EWS-FLI1 interferes with tumor growth.	('EWS-FLI1', 'Gene', (166, 174))	('EWS-FLI1', 'Gene', '2130;2313', (28, 36))	('EWS-FLI1', 'Gene', '2130;2313', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('EWS-FLI1', 'Gene', (28, 36))	('interferes', 'NegReg', (175, 185))	('inhibition', 'Var', (152, 162))
205789	22662320	Several labs use EWS-FLI1 signature based approaches to screen for potential therapeutic drugs which mimic the effects of EWS-FLI1 knockdown, as pioneered by Stegmaier et al..	('knockdown', 'Var', (131, 140))	('EWS-FLI1', 'Gene', (122, 130))	('EWS-FLI1', 'Gene', (17, 25))	('EWS-FLI1', 'Gene', '2130;2313', (17, 25))	('EWS-FLI1', 'Gene', '2130;2313', (122, 130))
205793	22662320	Schafer reported on a particularly active novel drug, PKC412 (Midostaurin, previously shown to modify phosphorylation of PAX-FKHR in alveolar rhabdomyosarcoma), and presented data on in vitro apoptosis induction and in vivo growth reduction of ES cell lines in xenografts (Boro et al.,) (Table 1).	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('growth', 'CPA', (224, 230))	('FKHR', 'Gene', (125, 129))	('apoptosis induction', 'CPA', (192, 211))	('phosphorylation', 'MPA', (102, 117))	('reduction', 'NegReg', (231, 240))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (133, 158))	('Midostaurin', 'Chemical', 'MESH:C059539', (62, 73))	('modify', 'Reg', (95, 101))	('FKHR', 'Gene', '2308', (125, 129))	('PKC412', 'Var', (54, 60))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (142, 158))	('alveolar rhabdomyosarcoma', 'Disease', (133, 158))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (133, 158))
205806	22662320	Lessnick provided evidence for the involvement of proteins that modulate epigenetic alterations in EWS/FLI mediated direct repression of critical target genes in Ewing's sarcoma.	('epigenetic alterations', 'Var', (73, 95))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (162, 177))	("Ewing's sarcoma", 'Disease', (162, 177))	('repression', 'NegReg', (123, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('FLI', 'Gene', '2314', (103, 106))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (162, 177))	('FLI', 'Gene', (103, 106))
205813	22662320	TARDBP on chromosomal region 1p36.22 is of particular interest since its product, TDP-43, associates with FET (FUS, EWS, TAF15) proteins, and is frequently mutated in amyotrophic lateral sclerosis (as is FUS, for review Ince et al.,).	('amyotrophic lateral sclerosis', 'Disease', (167, 196))	('associates', 'Interaction', (90, 100))	('FET', 'Protein', (106, 109))	('TAF15', 'Gene', '8148', (121, 126))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (167, 196))	('FUS', 'Gene', (111, 114))	('FUS', 'Gene', (204, 207))	('TDP-43', 'Gene', '23435', (82, 88))	('FUS', 'Gene', '2521', (111, 114))	('TARDBP', 'Gene', '23435', (0, 6))	('FUS', 'Gene', '2521', (204, 207))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (167, 196))	('mutated', 'Var', (156, 163))	('TAF15', 'Gene', (121, 126))	('TDP-43', 'Gene', (82, 88))	('TARDBP', 'Gene', (0, 6))
205816	22662320	Based on results on the FUS-DDIT3 gene fusion in myxoid liposarcoma, Aman hypothesized that there might exist a critical intermediate FET fusion protein expression level defining a transformation window, while high expression results in senescence and/or apoptosis.	('expression', 'Species', '29278', (215, 225))	('myxoid liposarcoma', 'Disease', (49, 67))	('liposarcoma', 'Phenotype', 'HP:0012034', (56, 67))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (49, 67))	('high expression', 'Var', (210, 225))	('expression', 'Species', '29278', (153, 163))	('apoptosis', 'CPA', (255, 264))	('results in', 'Reg', (226, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (49, 67))	('FUS', 'Gene', (24, 27))	('senescence', 'CPA', (237, 247))	('FUS', 'Gene', '2521', (24, 27))
205828	22662320	Ultimately, they will investigate if HERV sequences have an impact on patient survival or immune response, or may be used as markers for minimal residual disease detection.	('sequences', 'Var', (42, 51))	('HERV', 'Protein', (37, 41))	('impact', 'Reg', (60, 66))	('patient', 'Species', '9606', (70, 77))	('patient survival', 'CPA', (70, 86))	('immune response', 'CPA', (90, 105))	('HERV', 'Species', '11827', (37, 41))
205839	22662320	Therefore, if one wants to adopt therapy to progression-associated mutations it is essential to collect tumor material at a time right before any change in therapy is initiated, as Lee Helman pointed out.	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('mutations', 'Var', (67, 76))
205849	22662320	Kovar's group found that EWS-FLI1 knockdown decreases AGO2 expression in ES cells, and Gunther Richter (Department of Pediatrics, Technical University, Munich, Germany) reported that EWS-FLI1 induced EZH2 up-regulates AGO2, and experimental AGO2 suppression results in decreased ES tumor growth and metastasis in mice, while AGO1 knockdown enhances tumorigenicity.	('decreased ES tumor', 'Disease', 'MESH:C563168', (269, 287))	('EWS-FLI1', 'Gene', '2130;2313', (183, 191))	('tumor', 'Disease', (282, 287))	('suppression', 'NegReg', (246, 257))	('EZH2', 'Gene', (200, 204))	('EZH2', 'Gene', '2146', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('knockdown', 'Var', (330, 339))	('AGO2', 'Protein', (54, 58))	('mice', 'Species', '10090', (313, 317))	('AGO1', 'Gene', (325, 329))	('knockdown', 'Var', (34, 43))	('decreases', 'NegReg', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('expression', 'Species', '29278', (59, 69))	('EWS-FLI1', 'Gene', (25, 33))	('enhances', 'PosReg', (340, 348))	('AGO1', 'Gene', '236511', (325, 329))	('EWS-FLI1', 'Gene', (183, 191))	('tumor', 'Disease', (349, 354))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('decreased ES tumor', 'Disease', (269, 287))	('up-regulates', 'PosReg', (205, 217))	('AGO2', 'MPA', (218, 222))	('EWS-FLI1', 'Gene', '2130;2313', (25, 33))
205863	22662320	He provided in vitro evidence that treatment with oncostatin M results in decreased cell adhesion and the activation of several stemness transcription factors.	('oncostatin M', 'Var', (50, 62))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (74, 97))	('stemness', 'Disease', 'MESH:D020295', (128, 136))	('stemness', 'Disease', (128, 136))	('decreased', 'NegReg', (74, 83))	('cell adhesion', 'CPA', (84, 97))	('activation', 'PosReg', (106, 116))
205868	22662320	Comparing clinical data in patients with in vivo data in the xenograft models demonstrated the limitations of mouse models: in patients, high STEAP1 expression is associated with better survival (Grunewald et al.,) while in the mouse it promotes tumor cell invasion.	('better', 'PosReg', (179, 185))	('high', 'Var', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('mouse', 'Species', '10090', (110, 115))	('expression', 'Species', '29278', (149, 159))	('promotes', 'PosReg', (237, 245))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('STEAP1', 'Gene', '26872', (142, 148))	('STEAP1', 'Gene', (142, 148))	('mouse', 'Species', '10090', (228, 233))	('tumor', 'Disease', (246, 251))	('survival', 'CPA', (186, 194))
205890	22662320	High-levels of LGR5 are also associated with tumor initiation, cancer stem cells, and early relapse in colorectal cancer (Merlos-Suarez et al.,; Walker et al.,).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('LGR5', 'Gene', (15, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('LGR5', 'Gene', '8549', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor initiation', 'Disease', (45, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('early relapse', 'CPA', (86, 99))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('High-levels', 'Var', (0, 11))	('tumor initiation', 'Disease', 'MESH:D009369', (45, 61))	('associated with', 'Reg', (29, 44))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', (114, 120))
205902	22662320	In addition she demonstrated that ectopic soluble RANKL receptor osteoprotegerin (OPG), soluble TNF receptor, and DKK1 inhibitors (BHQ880, Novartis) inhibit ES growth by stimulating osteoblastogenesis (as monitored by increased bone marker expression) (Table 1).	('stimulating', 'PosReg', (170, 181))	('inhibit', 'NegReg', (149, 156))	('BHQ880', 'Chemical', 'MESH:C557618', (131, 137))	('RANKL', 'Gene', '8600', (50, 55))	('RANKL', 'Gene', (50, 55))	('expression', 'Species', '29278', (240, 250))	('ES growth', 'CPA', (157, 166))	('ectopic', 'Var', (34, 41))	('DKK1', 'Gene', (114, 118))	('osteoblastogenesis', 'CPA', (182, 200))	('DKK1', 'Gene', '13380', (114, 118))
205907	22662320	Redini described a novel TRAIL receptor isoform on ES cells, a truncated DR4.	('DR4', 'Gene', '8797', (73, 76))	('DR4', 'Gene', (73, 76))	('truncated', 'Var', (63, 72))
205925	22662320	The top candidate kinase sensitizing to IGF1R inhibitors was found to be MST1R (RON), a cMET related receptor tyrosine kinase (RTK; Potratz et al.,) (Table 1).	('inhibitors', 'Var', (46, 56))	('IGF1R', 'Gene', (40, 45))	('RON', 'Gene', (80, 83))	('MST1R', 'Gene', (73, 78))	('RON', 'Gene', '4486', (80, 83))	('IGF1R', 'Gene', '3480', (40, 45))	('MST1R', 'Gene', '4486', (73, 78))
205936	22662320	Other drugs and pathways of relevance to ES that were addressed during the meeting but not mentioned above comprise the PKC inhibitor Enzastaurin (F. Tirode), the NEDD8 inhibitor MLN4294, and protein ubiquitin ligase inhibitors (E. De Alava) (Table 1).	('ubiquitin ligase', 'Gene', '84585', (200, 216))	('PKC', 'Enzyme', (120, 123))	('Enzastaurin', 'Chemical', 'MESH:C504878', (134, 145))	('MLN4294', 'Chemical', '-', (179, 186))	('ubiquitin ligase', 'Gene', (200, 216))	('NEDD8', 'Gene', (163, 168))	('protein', 'Protein', (192, 199))	('NEDD8', 'Gene', '4738', (163, 168))	('MLN4294', 'Var', (179, 186))
205940	22662320	Clinically well annotated retrospective ES tumor banks, partly with genomic data (gene expression), already exist in Munster, Leeds, and Paris with samples from the European ES studies EICESS92 and EuroE.W.I.N.G.99.	('ES tumor', 'Disease', 'MESH:C563168', (40, 48))	('ES tumor', 'Disease', (40, 48))	('expression', 'Species', '29278', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('EICESS92', 'Var', (185, 193))
206005	21498392	G7765)/PBST before an overnight incubation with a 1:100 dilution of anti-rabbit RXRalpha antibody (Santa Cruz Biotechnology, Santa Cruz, CA, cat.	('RXRalpha', 'Gene', (80, 88))	('rabbit', 'Species', '9986', (73, 79))	('PBS', 'Chemical', 'MESH:D007854', (7, 10))	('RXRalpha', 'Gene', '20181', (80, 88))	('G7765', 'Var', (0, 5))
206106	20587042	A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62), anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44), and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72).	('anthracycline', 'Var', (174, 187))	('anthracycline', 'Chemical', 'MESH:D018943', (103, 116))	('cardiotoxicity', 'Disease', 'MESH:D066126', (41, 55))	('men', 'Species', '9606', (121, 124))	('clinical', 'Disease', (32, 40))	('anthracycline', 'Chemical', 'MESH:D018943', (71, 84))	('anthracycline', 'Chemical', 'MESH:D018943', (283, 296))	('cardiotoxicity', 'Disease', (41, 55))	('anthracycline', 'Chemical', 'MESH:D018943', (174, 187))	('anthracycline', 'Var', (71, 84))	('mitoxantrone', 'Chemical', 'MESH:D008942', (195, 207))
206107	20587042	Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78), liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38) and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33).	('lower', 'NegReg', (50, 55))	('cardiotoxicity', 'Disease', 'MESH:D066126', (17, 31))	('cardiotoxicity', 'Disease', (17, 31))	('epirubicin', 'Chemical', 'MESH:D015251', (61, 71))	('doxorubicin', 'Chemical', 'MESH:D004317', (79, 90))	('doxorubicin', 'Chemical', 'MESH:D004317', (169, 180))	('liposomal', 'Var', (138, 147))
206108	20587042	A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent.	('doxorubicin', 'Chemical', 'MESH:D004317', (225, 236))	('men', 'Species', '9606', (138, 141))	('epirubicin', 'Var', (203, 213))	('subclinical', 'MPA', (44, 55))	('epirubicin', 'Chemical', 'MESH:D015251', (203, 213))	('cardiotoxicity', 'Disease', 'MESH:D066126', (56, 70))	('cardiotoxicity', 'Disease', (56, 70))	('liposomal doxorubicin', 'Var', (215, 236))	('lower', 'NegReg', (187, 192))	('anthracycline', 'Chemical', 'MESH:D018943', (109, 122))	('doxorubicin', 'Chemical', 'MESH:D004317', (244, 255))	('epirubicin', 'Chemical', 'MESH:D015251', (264, 274))	('anthracycline', 'Var', (109, 122))
206121	20587042	Anthracyclines are the drug class most closely associated with acute and late cardiac toxicity.	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('associated', 'Reg', (47, 57))	('cardiac toxicity', 'Disease', (78, 94))	('cardiac toxicity', 'Disease', 'MESH:D066126', (78, 94))	('Anthracyclines', 'Var', (0, 14))
206122	20587042	It has been known since the 1970s that anthracycline treatment is associated with an increased risk of heart failure, and that this is dependent on cumulative dose and schedule.	('heart failure', 'Disease', 'MESH:D006333', (103, 116))	('heart failure', 'Phenotype', 'HP:0001635', (103, 116))	('heart failure', 'Disease', (103, 116))	('anthracycline', 'Chemical', 'MESH:D018943', (39, 52))	('anthracycline', 'Var', (39, 52))	('men', 'Species', '9606', (58, 61))
206123	20587042	While the anti-cancer effects of anthracyclines are mediated primarily through inhibition of DNA synthesis, transcription and replication, they also generate oxygen-derived free radicals using iron as a co-factor and the mitochondrial respiratory chain.	('anthracyclines', 'Chemical', 'MESH:D018943', (33, 47))	('generate', 'Reg', (149, 157))	('transcription', 'CPA', (108, 121))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('replication', 'CPA', (126, 137))	('iron', 'Chemical', 'MESH:D007501', (193, 197))	('oxygen-derived free radicals', 'MPA', (158, 186))	('inhibition', 'NegReg', (79, 89))	('anthracyclines', 'Var', (33, 47))	('DNA synthesis', 'MPA', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('oxygen-derived free radicals', 'Chemical', '-', (158, 186))
206173	20587042	For any cardiotoxic event (clinical and sub-clinical) the pooled result is highly dependent on the choice of summary statistic; the Peto OR showed a significant increase in odds of cardiotoxicity with anthracycline compared with non-anthracycline: 2.27 (95% CI: 1.50, 3.43, p < 0.0001), whereas, the RR while higher, was not statistically significant, 4.23 (95% CI: 0.93, 19.38; p = 0.08).	('cardiotoxic', 'Disease', 'MESH:D066126', (181, 192))	('cardiotoxic', 'Disease', (8, 19))	('anthracycline', 'Chemical', 'MESH:D018943', (201, 214))	('cardiotoxicity', 'Disease', (181, 195))	('anthracycline', 'Chemical', 'MESH:D018943', (233, 246))	('anthracycline', 'Var', (201, 214))	('cardiotoxic', 'Disease', 'MESH:D066126', (8, 19))	('cardiotoxic', 'Disease', (181, 192))	('cardiotoxicity', 'Disease', 'MESH:D066126', (181, 195))
206175	20587042	Meta-analysis of four studies showed cardiac related deaths, though infrequent, were significantly higher with an anthracycline OR 4.94 (95% CI: 1.23, 19.87; p = 0.025; I2 = 19.3%).	('anthracycline', 'Var', (114, 127))	('anthracycline', 'Chemical', 'MESH:D018943', (114, 127))	('cardiac', 'Disease', (37, 44))	('higher', 'PosReg', (99, 105))
206200	20587042	Four studies compared liposomal doxorubicin with conventional doxorubicin in women with metastatic breast cancer, and in men and women with multiple myeloma.	('men', 'Species', '9606', (79, 82))	('multiple myeloma', 'Disease', (140, 156))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('men', 'Species', '9606', (121, 124))	('breast cancer', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('men', 'Species', '9606', (131, 134))	('liposomal', 'Var', (22, 31))	('women', 'Species', '9606', (129, 134))	('women', 'Species', '9606', (77, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('multiple myeloma', 'Phenotype', 'HP:0006775', (140, 156))	('doxorubicin', 'Chemical', 'MESH:D004317', (62, 73))	('multiple myeloma', 'Disease', 'MESH:D009101', (140, 156))	('doxorubicin', 'Chemical', 'MESH:D004317', (32, 43))
206206	20587042	Liposomal doxorubicin compared with conventional doxorubicin decreased the risk of clinical cardiotoxicity OR 0.18 (0.08, 0.38; p < 0.0001; I2 = 0%), subclinical cardiotoxicity RR 0.31 (0.20, 0.48; p < 0.0001; I2 = 48.5%) and any cardiotoxic event (clinical and sub-clinical) RR 0.30 (0.21, 0.43; p < 0.0001; I2 = 32.2%).	('cardiotoxic', 'Disease', 'MESH:D066126', (230, 241))	('cardiotoxic', 'Disease', (92, 103))	('cardiotoxicity', 'Disease', 'MESH:D066126', (162, 176))	('doxorubicin', 'Chemical', 'MESH:D004317', (49, 60))	('subclinical', 'Disease', (150, 161))	('cardiotoxic', 'Disease', 'MESH:D066126', (162, 173))	('cardiotoxicity', 'Disease', (162, 176))	('cardiotoxic', 'Disease', (230, 241))	('doxorubicin', 'Chemical', 'MESH:D004317', (10, 21))	('cardiotoxicity', 'Disease', 'MESH:D066126', (92, 106))	('decreased', 'NegReg', (61, 70))	('cardiotoxic', 'Disease', 'MESH:D066126', (92, 103))	('cardiotoxicity', 'Disease', (92, 106))	('cardiotoxic', 'Disease', (162, 173))	('Liposomal', 'Var', (0, 9))
206209	20587042	There was no evidence that suggests a difference in tumour response rate or survival between liposomal doxorubicin and doxorubicin, and whilst time to treatment failure and time to disease progression were significantly longer with liposomal doxorubicin than with epirubicin at equimolar concentrations, survival was comparable.	('failure', 'Disease', (161, 168))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('men', 'Species', '9606', (156, 159))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('doxorubicin', 'Chemical', 'MESH:D004317', (119, 130))	('liposomal', 'Var', (232, 241))	('failure', 'Disease', 'MESH:D017093', (161, 168))	('longer', 'PosReg', (220, 226))	('tumour', 'Disease', (52, 58))	('doxorubicin', 'Chemical', 'MESH:D004317', (242, 253))	('doxorubicin', 'Chemical', 'MESH:D004317', (103, 114))	('epirubicin', 'Chemical', 'MESH:D015251', (264, 274))
206223	20587042	Our analyses demonstrate that anthracyclines increased the risk of clinical cardiotoxicity by 5.43 fold, subclinical cardiotoxicity by 6.25 fold, any cardiotoxicity by 2.27 fold and the risk of cardiac death by 4.94 fold compared with non-anthracycline regimens.	('men', 'Species', '9606', (257, 260))	('cardiotoxicity', 'Disease', (150, 164))	('anthracyclines', 'Chemical', 'MESH:D018943', (30, 44))	('cardiotoxicity', 'Disease', 'MESH:D066126', (117, 131))	('cardiac death', 'Disease', (194, 207))	('cardiotoxicity', 'Disease', 'MESH:D066126', (76, 90))	('cardiac death', 'Phenotype', 'HP:0001645', (194, 207))	('cardiotoxicity', 'Disease', (117, 131))	('cardiac death', 'Disease', 'MESH:D003643', (194, 207))	('any', 'MPA', (146, 149))	('anthracycline', 'Chemical', 'MESH:D018943', (239, 252))	('anthracycline', 'Chemical', 'MESH:D018943', (30, 43))	('cardiotoxicity', 'Disease', (76, 90))	('cardiotoxicity', 'Disease', 'MESH:D066126', (150, 164))	('anthracyclines', 'Var', (30, 44))
206225	20587042	The risk was also 22% lower with liposomal doxorubicin, which allows a more favourable tumour to normal tissue concentration ratio.	('tumour', 'Disease', (87, 93))	('liposomal', 'Var', (33, 42))	('doxorubicin', 'Chemical', 'MESH:D004317', (43, 54))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('lower', 'NegReg', (22, 27))
206240	20587042	The rates were significantly higher for anthracycline regimens compared with non-anthracycline chemotherapy -adjusted hazard ratio (HR) 1.26 (95% CI: 1.12, 1.42).	('higher', 'PosReg', (29, 35))	('anthracycline', 'Var', (40, 53))	('rates', 'MPA', (4, 9))	('anthracycline', 'Chemical', 'MESH:D018943', (40, 53))	('anthracycline', 'Chemical', 'MESH:D018943', (81, 94))	('men', 'Species', '9606', (58, 61))
206295	33489999	The fluorescence in situ hybridization (FISH) identified the translocation of EWS gene, consequently confirming the diagnosis of Ewing sarcoma (Figure 3).	('translocation', 'Var', (61, 74))	('Ewing sarcoma', 'Disease', (129, 142))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (129, 142))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (129, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('EWS', 'Gene', '2130', (78, 81))	('EWS', 'Gene', (78, 81))
206313	33489999	More than 85% of patients with Ewing sarcoma harbor the reciprocal translocation between the EWS and FLI1 genes, t(11;22) (q24;q12), resulting in the EWSR1-FLI1 fusion transcript.	('t(11;22) (q24;q12', 'Var', (113, 130))	('EWS', 'Gene', '2130', (93, 96))	('EWS', 'Gene', (93, 96))	('EWSR1', 'Gene', '2130', (150, 155))	('FLI1', 'Gene', '2313', (101, 105))	('FLI1', 'Gene', (156, 160))	('Ewing sarcoma harbor', 'Disease', (31, 51))	('FLI1', 'Gene', (101, 105))	('EWS', 'Gene', '2130', (150, 153))	('EWS', 'Gene', (150, 153))	('FLI1', 'Gene', '2313', (156, 160))	('Ewing sarcoma harbor', 'Disease', 'MESH:C563168', (31, 51))	('patients', 'Species', '9606', (17, 25))	('fusion', 'Interaction', (161, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('EWSR1', 'Gene', (150, 155))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (31, 44))
206368	32899796	Ewing's sarcoma is characterized by the presence of chromosome translocation, which causes the chimeric fusions; the t(11;22) chromosomal rearrangement causes the fusion of the EWSR1 gene on chromosome 22 with the FLI-1 gene on chromosome 11.	("Ewing's sarcoma", 'Disease', (0, 15))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('FLI-1', 'Gene', (214, 219))	('FLI-1', 'Gene', '2313', (214, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('fusion', 'Var', (163, 169))	('EWSR1', 'Gene', (177, 182))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('causes', 'Reg', (152, 158))	('EWSR1', 'Gene', '2130', (177, 182))
206380	32899796	The clinical significance of genetic mutations depends on the cancer types, being influenced by the lineage and differentiation of tumor precursor cells.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('genetic mutations', 'Var', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', (131, 136))	('influenced', 'Reg', (82, 92))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
206384	32899796	Large-scale drug sensitivity screening using cell lines revealed the links between drug sensitivity and genetic alterations, leading to novel indications for anticancer agents and discovery of candidate predictive biomarkers.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('genetic alterations', 'Var', (104, 123))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('links', 'Reg', (69, 74))	('drug sensitivity', 'Phenotype', 'HP:0020174', (83, 99))	('drug sensitivity', 'Phenotype', 'HP:0020174', (12, 28))
206440	32899796	The antitumor effects of palbociclib, a CDK4/6 inhibitor, and listinib, an inhibitor of insulin receptor and insulin growth factor receptors, were examined using PDOXs of Ewing's sarcoma with Fusion involved in t(12;16) in malignant liposarcoma-ETS-related gene fusion and cyclin-dependent kinase inhibitor 2A/B loss.	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('insulin receptor', 'Gene', '3643', (88, 104))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (171, 186))	('palbociclib', 'Chemical', 'MESH:C500026', (25, 36))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('malignant liposarcoma', 'Disease', (223, 244))	('malignant liposarcoma', 'Disease', 'MESH:D008080', (223, 244))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('loss', 'NegReg', (312, 316))	('liposarcoma', 'Phenotype', 'HP:0012034', (233, 244))	('tumor', 'Disease', (8, 13))	('2A/B', 'SUBSTITUTION', 'None', (307, 311))	('2A/B', 'Var', (307, 311))	('listinib', 'Chemical', '-', (62, 70))	('insulin receptor', 'Gene', (88, 104))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (171, 186))	("Ewing's sarcoma", 'Disease', (171, 186))
206442	32899796	Methionine addiction is a common feature of cancer, and methionine restriction causes cell cycle arrest.	('methionine restriction', 'Var', (56, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('Methionine addiction', 'Disease', (0, 20))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('arrest', 'Disease', (97, 103))	('methionine', 'Chemical', 'MESH:D008715', (56, 66))	('causes', 'Reg', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
206464	32561656	High-grade sarcomas were generated with Cre recombinase technology using mice with conditional mutations in Kras and Trp53 (KP) genes.	('Trp53', 'Gene', (117, 122))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('mice', 'Species', '10090', (73, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcomas', 'Disease', (11, 19))	('Kras', 'Gene', '16653', (108, 112))	('Trp53', 'Gene', '22059', (117, 122))	('mutations', 'Var', (95, 104))	('Kras', 'Gene', (108, 112))
206468	32561656	Remarkably, CRISPR/Cas9 mediated knockout of Neat1 suppressed the ability of KP tumor cells to colonize the lungs.	('CRISPR', 'Gene', '70873', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('knockout', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('ability', 'CPA', (66, 73))	('CRISPR', 'Gene', (12, 18))	('suppressed', 'NegReg', (51, 61))	('Neat1', 'Gene', (45, 50))
206511	32561656	To analyze the correlation of the altered (copy number alteration > 1, mutated, mRNA median z-score > 2 or < -2) KHSRP or SMC2 and the prognosis of STS patients, we used the TCGA dataset.	('KHSRP', 'Gene', (113, 118))	('mutated', 'Var', (71, 78))	('copy number alteration > 1', 'Var', (43, 69))	('patients', 'Species', '9606', (152, 160))	('STS', 'Phenotype', 'HP:0030448', (148, 151))
206519	32561656	p53 mutational status in sarcoma patients presented in the Table S2.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('sarcoma', 'Disease', (25, 32))	('patients', 'Species', '9606', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcoma', 'Disease', 'MESH:D012509', (25, 32))	('mutational', 'Var', (4, 14))
206520	32561656	Human NEAT1 (#411531) and NEAT_2 (#411541-C2) probes were purchased from Advanced Cell Diagnostics (ACD).	('Human', 'Species', '9606', (0, 5))	('#411541-C2', 'Var', (34, 44))	('#411531', 'Var', (13, 20))
206535	32561656	Membranes were washed three times in TBS-T for 5 minutes and then incubated with secondary antibodies goat anti-rabbit IRDye800 (Li-Cor Biosciences, P/N 925-32211) and goat anti-mouse IRDye680 (Li-Cor Biosciences, P/N 925-68070) both at 1:20,000 dilution in TBS-T for 1 hour at room temperature.	('mouse', 'Species', '10090', (178, 183))	('TBS-T', 'Disease', (258, 263))	('P/N 925', 'Var', (214, 221))	('TBS-T', 'Disease', 'MESH:D001260', (37, 42))	('TBS-T', 'Disease', (37, 42))	('Li-Cor', 'Chemical', '-', (194, 200))	('P/N 925', 'SUBSTITUTION', 'None', (149, 156))	('TBS-T', 'Disease', 'MESH:D001260', (258, 263))	('Li-Cor', 'Chemical', '-', (129, 135))	('P/N 925', 'SUBSTITUTION', 'None', (214, 221))	('P/N 925', 'Var', (149, 156))
206541	32561656	Cre activates the expression of a mutant KrasG12D and deletes both alleles of Trp53 gene (Figure 1A).	('mutant KrasG12D', 'Var', (34, 49))	('deletes', 'NegReg', (54, 61))	('Trp53', 'Gene', '22059', (78, 83))	('KrasG12D', 'Var', (41, 49))	('expression', 'MPA', (18, 28))	('activates', 'PosReg', (4, 13))	('Trp53', 'Gene', (78, 83))
206564	32561656	CRISPR/Cas9 mediated knockdown of Neat1 in both cell lines decreased the area of lung with colonization of sarcoma (Figure 4D).	('CRISPR', 'Gene', (0, 6))	('decreased', 'NegReg', (59, 68))	('sarcoma', 'Disease', (107, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('CRISPR', 'Gene', '70873', (0, 6))	('Neat1', 'Gene', (34, 39))	('knockdown', 'Var', (21, 30))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))
206565	32561656	The short Neat1_1 isoform has been shown to be a critical modulator of prostate cancer progression and metastasis, leading us to evaluate whether depletion of Neat1_1 alone is sufficient to represses sarcoma lung colonization.	('prostate cancer', 'Disease', (71, 86))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('sarcoma', 'Disease', (200, 207))	('represses', 'NegReg', (190, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('depletion', 'Var', (146, 155))
206566	32561656	Having confirmed the deletion of the short isoform, we injected these Neat1_1 knockout (KO) clones #2 and #3, into nude mice via the tail vein.	('Neat1_1', 'Gene', (70, 77))	('nude mice', 'Species', '10090', (115, 124))	('deletion', 'Var', (21, 29))
206571	32561656	Cre mediated recombination activates mutant KrasG12D and deletes both alleles of Ink4a/Arf, effectively inactivating oncogene induced tumor suppression, yet maintaining wildtype Trp53.	('mutant KrasG12D', 'Var', (37, 52))	('Ink4a/Arf', 'Gene', '12578', (81, 90))	('oncogene', 'MPA', (117, 125))	('Ink4a/Arf', 'Gene', (81, 90))	('wildtype', 'MPA', (169, 177))	('Trp53', 'Gene', '22059', (178, 183))	('tumor suppression', 'Disease', 'MESH:D009369', (134, 151))	('deletes', 'Var', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('inactivating', 'NegReg', (104, 116))	('KrasG12D', 'Var', (44, 52))	('tumor suppression', 'Disease', (134, 151))	('Trp53', 'Gene', (178, 183))	('activates', 'PosReg', (27, 36))
206574	32561656	Together these results suggest that regardless of Trp53 status, depletion of Neat1_1 region is sufficient to repress lung colonization.	('Trp53', 'Gene', '22059', (50, 55))	('depletion', 'Var', (64, 73))	('Trp53', 'Gene', (50, 55))	('repress', 'NegReg', (109, 116))	('lung colonization', 'CPA', (117, 134))	('Neat1_1', 'Gene', (77, 84))
206575	32561656	Among the proteins identified to interact with Neat1_1, alterations of far upstream element-binding protein 2 (KHSRP) (Figure 7A) and structural maintenance of chromosomes protein 2 (SMC-2) (Figure S10A) were both previously associated with poor prognosis in STS.	('SMC-2', 'Gene', '14211', (183, 188))	('structural maintenance of chromosomes protein 2', 'Gene', (134, 181))	('alterations', 'Var', (56, 67))	('S10A', 'SUBSTITUTION', 'None', (198, 202))	('STS', 'Phenotype', 'HP:0030448', (259, 262))	('far upstream element-binding protein 2', 'Gene', '16549', (71, 109))	('structural maintenance of chromosomes protein 2', 'Gene', '14211', (134, 181))	('STS', 'Disease', (259, 262))	('KHSRP', 'Gene', (111, 116))	('far upstream element-binding protein 2', 'Gene', (71, 109))	('associated', 'Reg', (225, 235))	('S10A', 'Var', (198, 202))	('SMC-2', 'Gene', (183, 188))
206576	32561656	We first used Neat1_1 RNA pull down combined with western blotting to confirm that KHSRP (Figure 7B) and SMC2 (Figure S10B) specifically interact with the Neat1_1 sense RNA.	('S10B', 'Var', (118, 122))	('SMC2', 'Gene', (105, 109))	('KHSRP', 'Gene', (83, 88))	('S10B', 'SUBSTITUTION', 'None', (118, 122))	('interact', 'Interaction', (137, 145))
206579	32561656	The protein expression of KHSRP (Figure 7C) or SMC2 (Figure S10C) in their respective cell lines was significantly decreased following CRISPR/Cas9 editing.	('protein expression', 'MPA', (4, 22))	('KHSRP', 'Gene', (26, 31))	('CRISPR', 'Gene', (135, 141))	('decreased', 'NegReg', (115, 124))	('SMC2', 'Gene', (47, 51))	('editing', 'Var', (147, 154))	('S10C', 'Mutation', 'p.S10C', (60, 64))	('CRISPR', 'Gene', '70873', (135, 141))
206583	32561656	Interestingly, when the pathway analysis was performed in wild type and Neat1 knockout MEFs, we observed that RNA splicing pathways are significantly upregulated in Neat1 knockout MEFs (Figure S11).	('upregulated', 'PosReg', (150, 161))	('Neat1', 'Gene', (165, 170))	('knockout', 'Var', (171, 179))	('MEFs', 'CellLine', 'CVCL:9115', (87, 91))	('RNA splicing pathways', 'Pathway', (110, 131))	('MEFs', 'CellLine', 'CVCL:9115', (180, 184))
206598	32561656	We determined that knockout of the Neat1_1 locus significantly repressed sarcoma lung colonization regardless of Trp53 status in both KP and KI cell lines.	('repressed', 'NegReg', (63, 72))	('knockout', 'Var', (19, 27))	('sarcoma', 'Disease', (73, 80))	('Trp53', 'Gene', '22059', (113, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('Neat1_1', 'Gene', (35, 42))	('Trp53', 'Gene', (113, 118))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
206599	32561656	Our findings suggest that Neat1, or at least the short isoform Neat1_1, may promote sarcoma lung metastasis via dysregulation of mRNA splicing.	('sarcoma lung metastasis', 'Disease', (84, 107))	('promote', 'PosReg', (76, 83))	('sarcoma lung metastasis', 'Disease', 'MESH:D009362', (84, 107))	('mRNA splicing', 'MPA', (129, 142))	('Neat1', 'Var', (26, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))
206600	32561656	However, our results cannot rule out the possibility that truncation of Neat1_2 also plays a role in suppressing sarcoma metastasis.	('Neat1_2', 'Gene', (72, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('truncation', 'Var', (58, 68))	('sarcoma metastasis', 'Disease', 'MESH:D009362', (113, 131))	('sarcoma metastasis', 'Disease', (113, 131))	('suppressing', 'NegReg', (101, 112))
206603	32561656	Through alternative splicing of multiple genes, a cancer cell clone could acquire more aggressive phenotypes to survive and colonize a distant organ.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('alternative splicing', 'Var', (8, 28))
206606	32561656	Remarkably, RNA splicing pathways are significantly downregulated in lung metastases compared to paired KP primary tumors, but significantly upregulated in Neat1 knockout MEFs.	('lung metastases', 'Disease', (69, 84))	('lung metastases', 'Disease', 'MESH:D009362', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('MEFs', 'CellLine', 'CVCL:9115', (171, 175))	('Neat1', 'Gene', (156, 161))	('downregulated', 'NegReg', (52, 65))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('upregulated', 'PosReg', (141, 152))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('RNA splicing pathways', 'Pathway', (12, 33))	('knockout', 'Var', (162, 170))
206607	32561656	We further found that one protein interacting with Neat1 is the splicing regulator KHSRP whose alteration correlates with poor prognosis in sarcoma patients.	('patients', 'Species', '9606', (148, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('alteration', 'Var', (95, 105))	('KHSRP', 'Gene', (83, 88))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('sarcoma', 'Disease', (140, 147))
206610	32561656	Through modulation of Neat1 expression, we determined that Neat1 can promote lung colonization of sarcoma cells.	('Neat1', 'Gene', (22, 27))	('modulation', 'Var', (8, 18))	('Neat1', 'Gene', (59, 64))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcoma', 'Disease', (98, 105))	('promote', 'PosReg', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
206619	31595587	This case illustrates the utility of targeted RNA-sequencing in the classification of challenging tumors with deceptive morphology and identification of novel gene fusion variants.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('variants', 'Var', (171, 179))
206630	31595587	At this writing, only one other synovial sarcoma variant gene fusion has been reported: an SS18L1-SSX1 fusion resulting from a t(X;20)(p11;q13).	('SSX1', 'Gene', '6756', (98, 102))	('synovial sarcoma', 'Disease', (32, 48))	('SS18L1', 'Gene', (91, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (32, 48))	('SSX1', 'Gene', (98, 102))	('resulting from', 'Reg', (110, 124))	('synovial sarcoma', 'Disease', 'MESH:D013584', (32, 48))	('t(X;20)(p11;q13', 'Var', (127, 142))	('t(X;20)(p11;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (127, 143))	('SS18L1', 'Gene', '26039', (91, 97))
206631	31595587	We report herein a novel gene fusion in synovial sarcoma between SS18 and the NEDD4 gene at chromosome 15q21, identified by RNA sequencing and confirmed by fluorescence in situ hybridization (FISH).	('synovial sarcoma', 'Disease', (40, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('gene fusion', 'Var', (25, 36))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (40, 56))	('SS18', 'Gene', '6760', (65, 69))	('synovial sarcoma', 'Disease', 'MESH:D013584', (40, 56))	('NEDD4', 'Gene', (78, 83))	('SS18', 'Gene', (65, 69))	('NEDD4', 'Gene', '4734', (78, 83))
206647	31595587	There was no evidence of a BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (32, 37))	('V600E', 'Var', (32, 37))	('BRAF', 'Gene', (27, 31))	('BRAF', 'Gene', '673', (27, 31))
206673	31595587	All of the members of this family are associated with BRAF V600E mutations.	('associated', 'Reg', (38, 48))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('V600E', 'Var', (59, 64))
206674	31595587	In the current case, the lack of CD34 immunoreactivity and BRAF V600E mutation argue against a metanephric stromal tumor.	('CD34', 'Protein', (33, 37))	('lack', 'NegReg', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('metanephric stromal tumor', 'Disease', (95, 120))	('BRAF', 'Gene', (59, 63))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('BRAF', 'Gene', '673', (59, 63))	('metanephric stromal tumor', 'Disease', 'MESH:D036821', (95, 120))	('V600E', 'Var', (64, 69))
206683	31595587	Structural alterations of NEDD4 in cancer are uncommon.	('NEDD4', 'Gene', '4734', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('NEDD4', 'Gene', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('Structural alterations', 'Var', (0, 22))	('cancer', 'Disease', (35, 41))
206684	31595587	Mutations in NEDD4 are extremely rare, found in less than 5% of all cancers except uterine cancers in which it is seen in 8% of cases (www.cbioportal.org).	('NEDD4', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('NEDD4', 'Gene', '4734', (13, 18))	('cancers', 'Disease', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('uterine cancers', 'Phenotype', 'HP:0010784', (83, 98))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
206685	31595587	Well-characterized cancer-associated gene fusions involving NEDD4 have not previously been reported.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('NEDD4', 'Gene', '4734', (60, 65))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('fusions', 'Var', (42, 49))	('NEDD4', 'Gene', (60, 65))
206686	31595587	Three analyses of thousands of tumors profiled in The Cancer Genome Atlas (TCGA) project identifies 6 potential NEDD4 gene fusions.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', (54, 60))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('fusions', 'Var', (123, 130))	('NEDD4', 'Gene', (112, 117))	('NEDD4', 'Gene', '4734', (112, 117))
206687	31595587	These include a fusion with RDH10 in a squamous cell carcinoma of the lung, a fusion with GABRA5 in a bladder cancer, fusions with RFX7, ADMATSL3 and RAB27A in breast cancers, and a fusion with MY05A in a sarcoma.	('fusions', 'Var', (118, 125))	('fusion', 'Var', (78, 84))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('RAB27A', 'Gene', '5873', (150, 156))	('sarcoma', 'Disease', (205, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('GABRA5', 'Gene', '2558', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('RDH10', 'Gene', '157506', (28, 33))	('RFX7', 'Gene', '64864', (131, 135))	('RAB27A', 'Gene', (150, 156))	('RFX7', 'Gene', (131, 135))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('RDH10', 'Gene', (28, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('GABRA5', 'Gene', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', (39, 62))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (53, 74))	('fusion', 'Var', (16, 22))	('breast cancers', 'Disease', 'MESH:D001943', (160, 174))	('breast cancers', 'Disease', (160, 174))	('fusion', 'Var', (182, 188))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (39, 74))	('breast cancers', 'Phenotype', 'HP:0003002', (160, 174))
206691	31595587	Although the function of fusion protein is not entirely clear, we postulate that NEDD4, like SSX1 or SSX2, fuses to SS18 and converts this transcriptional coactivator to a transcriptional repressor, yielding a phenotype consistent with myxoid monophasic synovial sarcoma.	('SS18', 'Gene', '6760', (116, 120))	('NEDD4', 'Gene', '4734', (81, 86))	('fuses', 'Var', (107, 112))	('SSX2', 'Gene', (101, 105))	('converts', 'Reg', (125, 133))	('yielding', 'Reg', (199, 207))	('SS18', 'Gene', (116, 120))	('synovial sarcoma', 'Disease', (254, 270))	('SSX2', 'Gene', '6757', (101, 105))	('SSX1', 'Gene', '6756', (93, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('NEDD4', 'Gene', (81, 86))	('SSX1', 'Gene', (93, 97))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (254, 270))	('synovial sarcoma', 'Disease', 'MESH:D013584', (254, 270))
206693	31595587	We considered the possibility that this neoplasm, despite the SS18 rearrangement, might not represent a synovial sarcoma, just as not all neoplasms harboring EWSR1 gene fusions represent Ewing sarcoma.	('neoplasm', 'Disease', (138, 146))	('SS18', 'Gene', '6760', (62, 66))	('synovial sarcoma', 'Disease', (104, 120))	('Ewing sarcoma', 'Disease', (187, 200))	('neoplasm', 'Disease', 'MESH:D009369', (40, 48))	('neoplasms', 'Phenotype', 'HP:0002664', (138, 147))	('rearrangement', 'Var', (67, 80))	('synovial sarcoma', 'Disease', 'MESH:D013584', (104, 120))	('neoplasm', 'Phenotype', 'HP:0002664', (138, 146))	('neoplasm', 'Disease', (40, 48))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (104, 120))	('EWSR1', 'Gene', '2130', (158, 163))	('neoplasms', 'Disease', 'MESH:D009369', (138, 147))	('neoplasm', 'Phenotype', 'HP:0002664', (40, 48))	('SS18', 'Gene', (62, 66))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (187, 200))	('neoplasms', 'Disease', (138, 147))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (187, 200))	('neoplasm', 'Disease', 'MESH:D009369', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('EWSR1', 'Gene', (158, 163))
206697	31595587	reported a t(X;20)(p11;q13) translocation resulting in a fusion of the related SS18L1 gene (which is highly homologous with SS18) with SSX1 in a biphasic intraneural synovial sarcoma of the leg in a 36 year old male.	('SS18', 'Gene', (124, 128))	('SSX1', 'Gene', (135, 139))	('t(X;20)(p11;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (11, 27))	('biphasic intraneural synovial sarcoma', 'Disease', 'MESH:D013584', (145, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (166, 182))	('SS18L1', 'Gene', '26039', (79, 85))	('SS18', 'Gene', '6760', (79, 83))	('SS18', 'Gene', '6760', (124, 128))	('SS18L1', 'Gene', (79, 85))	('biphasic intraneural synovial sarcoma', 'Disease', (145, 182))	('SSX1', 'Gene', '6756', (135, 139))	('fusion', 'Var', (57, 63))	('SS18', 'Gene', (79, 83))
206698	31595587	also reported a SS18L1-SSX1 gene fusion in a monophasic spindle cell intraneural synovial sarcoma of the ankle of a 29-year-old female.	('SSX1', 'Gene', '6756', (23, 27))	('SSX1', 'Gene', (23, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('fusion', 'Var', (33, 39))	('synovial sarcoma', 'Disease', (81, 97))	('SS18L1', 'Gene', '26039', (16, 22))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (81, 97))	('SS18L1', 'Gene', (16, 22))	('synovial sarcoma', 'Disease', 'MESH:D013584', (81, 97))
206703	31595587	Based on these findings the authors suggest that undifferentiated tumors with SS18-CRTC1 fusion variants most likely do not represent molecular variants of poorly differentiated synovial sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('undifferentiated tumors', 'Disease', 'MESH:D002277', (49, 72))	('variants', 'Var', (96, 104))	('SS18', 'Gene', (78, 82))	('synovial sarcoma', 'Disease', (178, 194))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('CRTC1', 'Gene', (83, 88))	('CRTC1', 'Gene', '23373', (83, 88))	('SS18', 'Gene', '6760', (78, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (178, 194))	('undifferentiated tumors', 'Disease', (49, 72))	('synovial sarcoma', 'Disease', 'MESH:D013584', (178, 194))
206805	31127406	In this study, decreased functionality was detected for patients who received an amputation compared to patients who underwent limb-sparing procedures which was also found in other studies.	('patients', 'Species', '9606', (56, 64))	('amputation', 'Var', (81, 91))	('decreased', 'NegReg', (15, 24))	('functionality', 'MPA', (25, 38))	('patients', 'Species', '9606', (104, 112))
206999	32103242	Potential sources of heterogeneity include cell-type composition , cellular contamination, technical issues, allele- and strand-specific DNA methylation (ASM and hemimethylation), and DNA methylation erosion, i.e.	('erosion', 'NegReg', (200, 207))	('DNA', 'Var', (184, 187))	('ASM', 'Gene', '283120', (154, 157))	('methylation', 'Var', (141, 152))	('ASM', 'Gene', (154, 157))
207037	32103242	qFDRP, FDRP, Epipolymorphism and Entropy quantified increased heterogeneity within the THR when we introduced between 0 and  cell type contamination in silico.	('THR', 'Chemical', '-', (87, 90))	('qFDRP', 'Chemical', '-', (0, 5))	('increased', 'PosReg', (52, 61))	('Epipolymorphism', 'Var', (13, 28))	('heterogeneity', 'MPA', (62, 75))
207039	32103242	Correlating the mean WSH score with the simulated sample purity level per region, we found significant negative associations for FDRP (-0.47), qFDRP (-0.48), Epipolymorphism (-0.26) and Entropy (-0.47), but not for DNA methylation, PDR and MHL (Supplementary Data 1, Figure S3).	('FDRP', 'Var', (129, 133))	('Epipolymorphism', 'Var', (158, 173))	('qFDRP', 'Chemical', '-', (143, 148))	('negative', 'NegReg', (103, 111))	('qFDRP', 'Var', (143, 148))	('associations', 'Interaction', (112, 124))
207044	32103242	However, we detected negative correlations between gamma, the replication parameter specifying how often a particular pattern is found in the reads, and FDRP, qFDRP, Epipolymorphism and Entropy as expected, but not for PDR.	('FDRP', 'Gene', (153, 157))	('negative', 'NegReg', (21, 29))	('qFDRP', 'Chemical', '-', (159, 164))	('Entropy', 'MPA', (186, 193))	('Epipolymorphism', 'Var', (166, 181))
207060	32103242	While Epipolymorphism and Entropy were highly correlated to qFDRP and FDRP, we found that qFDRP and FDRP captured more than twice as many regions (Supplementary Data 1, Table S4).	('qFDRP', 'Chemical', '-', (60, 65))	('Entropy', 'MPA', (26, 33))	('Epipolymorphism', 'Var', (6, 21))	('qFDRP', 'Chemical', '-', (90, 95))
207062	32103242	Unexpectedly, Epipolymorphism showed a negative association with coverage and MHL showed a strictly bimodal distribution (Supplementary Data 1, Figure S12).	('S12', 'Gene', (151, 154))	('S12', 'Gene', '6268', (151, 154))	('Epipolymorphism', 'Var', (14, 29))	('negative', 'NegReg', (39, 47))	('coverage', 'Disease', (65, 73))
207082	32103242	MHL identifies DNA methylation haplotype blocks in bisulfite sequencing reads and might thus not be suitable for capturing WSH according to our definition.	('methylation', 'Var', (19, 30))	('bisulfite', 'Chemical', 'MESH:C042345', (51, 60))	('MHL', 'Gene', (0, 3))
207180	31672491	Furthermore, among the ten most well conserved and universal hypoxia targets, 7 of them were up-regulated by metformin in TC7l cells, and 4 out of the 7 were variably attenuated by imatinib (Fig.	('metformin', 'Var', (109, 118))	('up-regulated', 'PosReg', (93, 105))	('hypoxia', 'Disease', 'MESH:D000860', (61, 68))	('metformin', 'Chemical', 'MESH:D008687', (109, 118))	('hypoxia', 'Disease', (61, 68))	('TC7l', 'CellLine', 'CVCL:Z706', (122, 126))	('imatinib', 'Chemical', 'MESH:D000068877', (181, 189))
207191	31672491	Taken together, our experimental data demonstrate that metformin augments the cellular hypoxic response in EwS cells, limiting its therapeutic effects, and this situation can be attenuated by concurrent imatinib treatment.	('metformin', 'Chemical', 'MESH:D008687', (55, 64))	('imatinib', 'Chemical', 'MESH:D000068877', (203, 211))	('therapeutic effects', 'MPA', (131, 150))	('EwS', 'Phenotype', 'HP:0012254', (107, 110))	('limiting', 'NegReg', (118, 126))	('cellular hypoxic response', 'MPA', (78, 103))	('metformin', 'Var', (55, 64))	('augments', 'PosReg', (65, 73))
207206	31672491	Others include mTOR signaling pathway (p=0.007) and skeletal muscle hypertrophy regulated via AKT/mTOR pathway (p=0.009), GOs: 0044237/cellular metabolic process (p=0.004) and 0009058/biosynthetic process (p=0.005).	('AKT', 'Gene', '207', (94, 97))	('skeletal muscle hypertrophy', 'Disease', (52, 79))	('skeletal muscle hypertrophy', 'Phenotype', 'HP:0003712', (52, 79))	('AKT', 'Gene', (94, 97))	('mTOR', 'Gene', (15, 19))	('0044237/cellular metabolic process', 'CPA', (127, 161))	('mTOR', 'Gene', '2475', (15, 19))	('mTOR', 'Gene', '2475', (98, 102))	('skeletal muscle hypertrophy', 'Disease', 'MESH:C536106', (52, 79))	('mTOR', 'Gene', (98, 102))	('0009058/biosynthetic', 'Var', (176, 196))
207243	31672491	Extensive data demonstrate that molecular signals within a tumor are transmitted through a network of proteins rather than hierarchical signaling pathways, providing the rationale that targeting a single component in a canonical pathway instead of simultaneously inhibiting network proteins is insufficient for cancer treatment.	('tumor', 'Disease', (59, 64))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('targeting', 'Var', (185, 194))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inhibiting', 'NegReg', (263, 273))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
207264	29472530	Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma Sarcomas are rare tumors with generally poor prognosis, for which current therapies have shown limited efficacy.	('ITF2357', 'Var', (30, 37))	('human', 'Species', '9606', (120, 125))	('rare tumors', 'Disease', 'MESH:D035583', (147, 158))	('ITF2357', 'Chemical', 'MESH:C502418', (30, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('rare tumors', 'Disease', (147, 158))	('cytotoxicity', 'Disease', (82, 94))	('apoptosis', 'CPA', (47, 56))	('enhances', 'PosReg', (61, 69))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('Sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('doxorubicin', 'Chemical', 'MESH:D004317', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('Sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('sarcoma', 'Disease', (126, 133))	('Sarcomas', 'Disease', (134, 142))
207266	29472530	By using established and patient-derived sarcoma cells with different subtypes, we showed that the pan-HDACi, ITF2357, potently inhibited in vitro survival in a p53-independent manner.	('sarcoma', 'Disease', (41, 48))	('HDAC', 'Gene', '9734', (103, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('p53', 'Gene', '7157', (161, 164))	('patient', 'Species', '9606', (25, 32))	('ITF2357', 'Var', (110, 117))	('ITF2357', 'Chemical', 'MESH:C502418', (110, 117))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('p53', 'Gene', (161, 164))	('inhibited', 'NegReg', (128, 137))	('HDAC', 'Gene', (103, 107))
207268	29472530	ITF2357 also induced autophagy, which protected sarcoma cells from apoptotic cell death.	('autophagy', 'CPA', (21, 30))	('ITF2357', 'Var', (0, 7))	('sarcoma', 'Disease', (48, 55))	('induced', 'Reg', (13, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('ITF2357', 'Chemical', 'MESH:C502418', (0, 7))	('sarcoma', 'Disease', 'MESH:D012509', (48, 55))
207269	29472530	ITF2357 activated forkhead box (FOXO) 1 and 3a transcription factors and their downstream target genes, however, silencing of both FOXO1 and 3a did not protect sarcoma cells against ITF2357-induced apoptosis and upregulated FOXO4 and 6.	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('FOXO4', 'Gene', '4303', (224, 229))	('ITF2357-induced', 'Var', (182, 197))	('FOXO1 and 3a', 'Gene', '2308;2309', (131, 143))	('ITF2357', 'Chemical', 'MESH:C502418', (182, 189))	('upregulated', 'PosReg', (212, 223))	('FOXO) 1', 'Gene', (32, 39))	('sarcoma', 'Disease', (160, 167))	('ITF2357', 'Chemical', 'MESH:C502418', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('silencing', 'Var', (113, 122))	('FOXO4', 'Gene', (224, 229))
207270	29472530	Notably, ITF2357 synergized with Doxorubicin to induce cell death of established and patient-derived sarcoma cells.	('patient', 'Species', '9606', (85, 92))	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('Doxorubicin', 'Chemical', 'MESH:D004317', (33, 44))	('sarcoma', 'Disease', (101, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('cell death', 'CPA', (55, 65))	('ITF2357', 'Var', (9, 16))	('ITF2357', 'Chemical', 'MESH:C502418', (9, 16))
207271	29472530	Furthermore, combination treatment strongly impaired xenograft tumor growth in vivo, when compared to single treatments, suggesting that combination of ITF2357 with Doxorubicin has the potential to enhance sensitization in different preclinical models of sarcoma.	('sensitization', 'MPA', (206, 219))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('combination', 'Var', (137, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('Doxorubicin', 'Chemical', 'MESH:D004317', (165, 176))	('impaired xenograft tumor', 'Disease', (44, 68))	('impaired xenograft tumor', 'Disease', 'MESH:D015417', (44, 68))	('ITF2357', 'Var', (152, 159))	('sarcoma', 'Disease', 'MESH:D012509', (255, 262))	('ITF2357', 'Chemical', 'MESH:C502418', (152, 159))	('enhance', 'PosReg', (198, 205))	('sarcoma', 'Disease', (255, 262))
207282	29472530	ITF2357 is a safe and tolerable pan-HDACi with broad anti-inflammatory properties.	('ITF2357', 'Var', (0, 7))	('ITF2357', 'Chemical', 'MESH:C502418', (0, 7))	('HDAC', 'Gene', (36, 40))	('HDAC', 'Gene', '9734', (36, 40))
207285	29472530	We discovered that targeting HDACs by ITF2357 induces a mitochondrial apoptosis in human sarcoma cells.	('ITF2357', 'Var', (38, 45))	('human', 'Species', '9606', (83, 88))	('HDAC', 'Gene', (29, 33))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('mitochondrial apoptosis', 'CPA', (56, 79))	('HDAC', 'Gene', '9734', (29, 33))	('sarcoma', 'Disease', (89, 96))	('ITF2357', 'Chemical', 'MESH:C502418', (38, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('induces', 'Reg', (46, 53))
207286	29472530	More importantly, ITF2357 enhances in vitro Doxorubicin (Doxo) cytotoxicity in both established and patient-derived sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('Doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('cytotoxicity', 'Disease', (63, 75))	('patient', 'Species', '9606', (100, 107))	('ITF2357', 'Var', (18, 25))	('enhances', 'PosReg', (26, 34))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('Doxo', 'Chemical', 'MESH:D004317', (44, 48))	('sarcoma', 'Disease', (116, 123))	('ITF2357', 'Chemical', 'MESH:C502418', (18, 25))	('Doxo', 'Chemical', 'MESH:D004317', (57, 61))	('cytotoxicity', 'Disease', 'MESH:D064420', (63, 75))
207287	29472530	Furthermore, combination treatment strongly impaired xenografts tumor growth in vivo, when compared to single treatments.	('impaired xenografts tumor', 'Disease', 'MESH:D015417', (44, 69))	('impaired xenografts tumor', 'Disease', (44, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('combination', 'Var', (13, 24))
207289	29472530	1 suppl., ITF2357 strongly reduced sarcoma cell viability regardless of p53 status, with IC50 values ranging from 3 microM in the p53 null line SaOS2, to 0.57-0.97 microM in p53-mutant lines (SW872, SKLMS) and 0.63-0.88 microM in wild-type (wt) p53 lines (U2OS, SW982, HT1080, A204).	('reduced', 'NegReg', (27, 34))	('SW982', 'CellLine', 'CVCL:1734', (262, 267))	('p53', 'Gene', (130, 133))	('HT1080', 'Gene', (269, 275))	('p53', 'Gene', '7157', (174, 177))	('U2OS', 'CellLine', 'CVCL:0042', (256, 260))	('HT1080', 'Gene', '8872', (269, 275))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', '7157', (245, 248))	('p53', 'Gene', (174, 177))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('SW872', 'CellLine', 'CVCL:1730', (192, 197))	('SaOS2', 'CellLine', 'CVCL:0548', (144, 149))	('sarcoma', 'Disease', (35, 42))	('p53', 'Gene', (245, 248))	('p53', 'Gene', (72, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('ITF2357', 'Var', (10, 17))	('ITF2357', 'Chemical', 'MESH:C502418', (10, 17))	('p53', 'Gene', '7157', (130, 133))
207291	29472530	Of note, ITF2357 suppressed colony growth in a dose-dependent manner (Fig.	('suppressed', 'NegReg', (17, 27))	('colony growth', 'CPA', (28, 41))	('ITF2357', 'Var', (9, 16))	('ITF2357', 'Chemical', 'MESH:C502418', (9, 16))
207293	29472530	Furthermore, exposure to ITF2357 markedly increased histone H3 and alpha-tubulin protein acetylation in a dose-dependent manner in sarcoma cell lines (Fig.	('increased', 'PosReg', (42, 51))	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('sarcoma', 'Disease', (131, 138))	('ITF2357', 'Var', (25, 32))	('ITF2357', 'Chemical', 'MESH:C502418', (25, 32))	('alpha-tubulin', 'Gene', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('histone H3', 'Protein', (52, 62))	('alpha-tubulin', 'Gene', '10376', (67, 80))
207294	29472530	By using HT1080, SW872, and SaOS2 representative cell lines, to study in depth molecular mechanisms of ITF2357 we evaluated whether growth inhibition by ITF2357 was due to apoptosis induction.	('HT1080', 'Gene', (9, 15))	('SW872', 'CellLine', 'CVCL:1730', (17, 22))	('HT1080', 'Gene', '8872', (9, 15))	('SaOS2', 'CellLine', 'CVCL:0548', (28, 33))	('ITF2357', 'Chemical', 'MESH:C502418', (153, 160))	('ITF2357', 'Var', (153, 160))	('ITF2357', 'Chemical', 'MESH:C502418', (103, 110))	('growth', 'MPA', (132, 138))
207298	29472530	Focusing our attention on HT1080 cells, we explored whether treatment with ITF2357 induced caspase-dependent apoptosis by using the pan-caspase inhibitor, zVAD-fmk (zVAD).	('zVAD-fmk', 'Chemical', 'MESH:C096713', (155, 163))	('ITF2357', 'Chemical', 'MESH:C502418', (75, 82))	('caspase-dependent', 'MPA', (91, 108))	('HT1080', 'Gene', (26, 32))	('zVAD', 'Chemical', '-', (155, 159))	('induced', 'Reg', (83, 90))	('HT1080', 'Gene', '8872', (26, 32))	('ITF2357', 'Var', (75, 82))	('zVAD', 'Chemical', '-', (165, 169))
207299	29472530	1f, ITF2357 triggered the cleavage of poly(ADP ribose) polymerase (PARP), a typical caspases substrate.	('PARP', 'Gene', (67, 71))	('poly(ADP ribose) polymerase', 'Gene', (38, 65))	('cleavage', 'MPA', (26, 34))	('ITF2357', 'Var', (4, 11))	('PARP', 'Gene', '142', (67, 71))	('poly(ADP ribose) polymerase', 'Gene', '142', (38, 65))	('ITF2357', 'Chemical', 'MESH:C502418', (4, 11))
207300	29472530	We found that about 40% of ITF2357-treated cells were positive for active caspase-3 staining, whereas <5% of zVAD-pretreated cells, as well as, untreated cells were positive for caspase-3 staining (Fig.	('caspase-3', 'Gene', '836', (178, 187))	('zVAD', 'Chemical', '-', (109, 113))	('caspase-3', 'Gene', (74, 83))	('ITF2357', 'Chemical', 'MESH:C502418', (27, 34))	('active', 'MPA', (67, 73))	('caspase-3', 'Gene', (178, 187))	('ITF2357-treated', 'Var', (27, 42))	('caspase-3', 'Gene', '836', (74, 83))	('positive', 'Reg', (54, 62))
207306	29472530	Treatment with ITF2357 resulted in a dose-dependent upregulation of Bim isoforms (BimEL, BimL, and BimS).	('ITF2357', 'Chemical', 'MESH:C502418', (15, 22))	('upregulation', 'PosReg', (52, 64))	('Bim', 'Gene', (82, 85))	('Bim', 'Gene', (68, 71))	('Bim', 'Gene', (99, 102))	('Bim', 'Gene', '10018', (99, 102))	('Bim', 'Gene', (89, 92))	('Bim', 'Gene', '10018', (89, 92))	('Bim', 'Gene', '10018', (82, 85))	('Bim', 'Gene', '10018', (68, 71))	('ITF2357', 'Var', (15, 22))
207307	29472530	In addition, ITF2357 induced Noxa, Bax, and Puma expression and triggered the cleavage of BH3-only protein Bid (tBid), suggesting tBid recruitment at mitochondria and its involvement in ITF2357-mediated apoptosis.	('Bax', 'Gene', '581', (35, 38))	('recruitment', 'MPA', (135, 146))	('involvement', 'Reg', (171, 182))	('Puma expression', 'MPA', (44, 59))	('Noxa', 'Gene', '5366', (29, 33))	('Bid', 'Gene', (107, 110))	('Bid', 'Gene', (131, 134))	('ITF2357', 'Var', (13, 20))	('Bid', 'Gene', (113, 116))	('ITF2357', 'Chemical', 'MESH:C502418', (13, 20))	('tBid', 'Chemical', '-', (130, 134))	('Noxa', 'Gene', (29, 33))	('induced', 'Reg', (21, 28))	('tBid', 'Chemical', '-', (112, 116))	('Bid', 'Gene', '637', (107, 110))	('Bid', 'Gene', '637', (131, 134))	('ITF2357', 'Chemical', 'MESH:C502418', (186, 193))	('cleavage', 'MPA', (78, 86))	('Bid', 'Gene', '637', (113, 116))	('Bax', 'Gene', (35, 38))
207308	29472530	Notably, ITF2357 also transcriptionally upregulated pro-apoptotic BH3-only proteins in SW872 cell line, harboring p53 mutation (Fig.	('BH3-only', 'Protein', (66, 74))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('SW872', 'CellLine', 'CVCL:1730', (87, 92))	('pro-apoptotic', 'MPA', (52, 65))	('mutation', 'Var', (118, 126))	('ITF2357', 'Var', (9, 16))	('upregulated', 'PosReg', (40, 51))	('ITF2357', 'Chemical', 'MESH:C502418', (9, 16))
207311	29472530	Accordingly, ITF2357 induced a decrease of mut-p53 protein levels in SW872 cells, while no accumulation of p53 was observed after ITF2357 treatment of either HT1080 cells, bearing wt-p53, or p53 null SaOS2 cells (Fig.	('ITF2357', 'Chemical', 'MESH:C502418', (130, 137))	('ITF2357', 'Var', (13, 20))	('SW872', 'CellLine', 'CVCL:1730', (69, 74))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('decrease', 'NegReg', (31, 39))	('ITF2357', 'Chemical', 'MESH:C502418', (13, 20))	('HT1080', 'Gene', (158, 164))	('p53', 'Gene', (191, 194))	('p53', 'Gene', '7157', (191, 194))	('SaOS2', 'CellLine', 'CVCL:0548', (200, 205))	('HT1080', 'Gene', '8872', (158, 164))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
207312	29472530	Overall, these data indicate that ITF2357 induces apoptosis in a caspase- and bcl-2-dependent manner, through a p53-independent transcriptional mechanism.	('bcl-2', 'Gene', '596', (78, 83))	('ITF2357', 'Var', (34, 41))	('induces', 'Reg', (42, 49))	('ITF2357', 'Chemical', 'MESH:C502418', (34, 41))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (112, 115))	('bcl-2', 'Gene', (78, 83))	('apoptosis', 'CPA', (50, 59))
207313	29472530	Because it has been shown that ITF2357 induces autophagy in other cancer models, we investigated the effect of ITF2357 on autophagy also in sarcoma cell lines.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ITF2357', 'Var', (31, 38))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('ITF2357', 'Chemical', 'MESH:C502418', (31, 38))	('ITF2357', 'Chemical', 'MESH:C502418', (111, 118))	('induces', 'Reg', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('autophagy', 'CPA', (47, 56))	('sarcoma', 'Disease', (140, 147))	('cancer', 'Disease', (66, 72))
207314	29472530	In HT1080 cells, the induction of autophagy by ITF2357 was confirmed based on the increase of autophagosomes formation, maturation, and degradation, as well as the increase of lipidated form of LC3B (LC3B-II) and the degradation of p62/SQTSM1, indicating that the autophagic process is progressing to completion.	('LC3B-II', 'Gene', (200, 207))	('degradation', 'CPA', (136, 147))	('LC3B', 'Gene', (194, 198))	('ITF2357', 'Var', (47, 54))	('ITF2357', 'Chemical', 'MESH:C502418', (47, 54))	('LC3B', 'Gene', '81631', (194, 198))	('maturation', 'CPA', (120, 130))	('LC3B', 'Gene', (200, 204))	('LC3B-II', 'Gene', '81631', (200, 207))	('degradation', 'MPA', (217, 228))	('increase', 'PosReg', (164, 172))	('LC3B', 'Gene', '81631', (200, 204))	('HT1080', 'Gene', (3, 9))	('increase', 'PosReg', (82, 90))	('p62', 'Gene', '8878', (232, 235))	('p62', 'Gene', (232, 235))	('HT1080', 'Gene', '8872', (3, 9))	('autophagy', 'CPA', (34, 43))	('autophagosomes formation', 'CPA', (94, 118))
207316	29472530	3a, b, a time- and dose-dependent enhancement of punctate vesicular structures was observed in ITF2357-treated cells when compared to untreated ones.	('enhancement', 'PosReg', (34, 45))	('ITF2357-treated', 'Var', (95, 110))	('ITF2357', 'Chemical', 'MESH:C502418', (95, 102))	('punctate vesicular structures', 'MPA', (49, 78))
207318	29472530	Notably, ITF2357 treatment induced the autophagosome-lysosome fusion and complete autophagosome maturation (Fig.	('induced', 'PosReg', (27, 34))	('autophagosome-lysosome fusion', 'CPA', (39, 68))	('autophagosome maturation', 'CPA', (82, 106))	('ITF2357', 'Var', (9, 16))	('ITF2357', 'Chemical', 'MESH:C502418', (9, 16))
207319	29472530	According with these results, we also found by western blot analysis an increase of LC3B-II form and a decrease of p62/SQTSM1 protein level upon treatment with ITF2357 (Fig.	('ITF2357', 'Chemical', 'MESH:C502418', (160, 167))	('increase', 'PosReg', (72, 80))	('LC3B-II', 'Gene', (84, 91))	('p62', 'Gene', '8878', (115, 118))	('LC3B-II', 'Gene', '81631', (84, 91))	('decrease', 'NegReg', (103, 111))	('p62', 'Gene', (115, 118))	('ITF2357', 'Var', (160, 167))
207321	29472530	Interestingly, only ATG12 and MAP1LC3B messenger RNA (mRNA) were substantially upregulated in ITF2357-treated cells, while the expression level of BECN1 mRNA was superimposable in untreated and treated cells (Fig.	('BECN1', 'Gene', '8678', (147, 152))	('ATG12', 'Gene', (20, 25))	('BECN1', 'Gene', (147, 152))	('MAP1LC3B', 'Gene', (30, 38))	('MAP1LC3B', 'Gene', '81631', (30, 38))	('ITF2357', 'Chemical', 'MESH:C502418', (94, 101))	('upregulated', 'PosReg', (79, 90))	('ITF2357-treated', 'Var', (94, 109))	('ATG12', 'Gene', '9140', (20, 25))
207323	29472530	3e, quantification of cell viability showed an increased cell death when ITF2357 was combined with CQ.	('cell death', 'CPA', (57, 67))	('CQ', 'Chemical', 'MESH:D002738', (99, 101))	('ITF2357', 'Var', (73, 80))	('ITF2357', 'Chemical', 'MESH:C502418', (73, 80))	('combined', 'Interaction', (85, 93))
207324	29472530	Similarly, ITF2357 treatment induced autophagy also in SW872 cells harboring mut-p53, as evidenced by analysis of LC3 puncta formation in SW872/EGFP-LC3B cells (Fig.	('LC3B', 'Gene', '81631', (149, 153))	('SW872', 'CellLine', 'CVCL:1730', (138, 143))	('induced', 'Reg', (29, 36))	('SW872', 'CellLine', 'CVCL:1730', (55, 60))	('ITF2357', 'Var', (11, 18))	('LC3 puncta formation', 'MPA', (114, 134))	('ITF2357', 'Chemical', 'MESH:C502418', (11, 18))	('p53', 'Gene', (81, 84))	('autophagy', 'CPA', (37, 46))	('p53', 'Gene', '7157', (81, 84))	('LC3B', 'Gene', (149, 153))
207325	29472530	These results indicate that ITF2357 induces a canonical autophagic process both in wt- and mut-p53 sarcoma cells and that ITF2357-induced autophagy shows a cell survival mechanism.	('autophagy', 'CPA', (138, 147))	('canonical autophagic process', 'CPA', (46, 74))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('ITF2357', 'Var', (28, 35))	('ITF2357', 'Chemical', 'MESH:C502418', (122, 129))	('ITF2357', 'Chemical', 'MESH:C502418', (28, 35))	('induces', 'PosReg', (36, 43))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('sarcoma', 'Disease', (99, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
207328	29472530	4a, FOXO1 and FOXO3a mRNA levels were increased in three different sarcoma cell lines treated with ITF2357.	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('ITF2357', 'Chemical', 'MESH:C502418', (99, 106))	('FOXO1', 'Gene', (4, 9))	('FOXO1', 'Gene', '2308', (4, 9))	('sarcoma', 'Disease', (67, 74))	('FOXO3a', 'Gene', '2309', (14, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('FOXO3a', 'Gene', (14, 20))	('mRNA levels', 'MPA', (21, 32))	('increased', 'PosReg', (38, 47))	('ITF2357', 'Var', (99, 106))
207330	29472530	As reported by immunofluorescence analysis, a similar localization of FOXO1 and FOXO3a was observed in HT1080 cells after ITF2357 treatment (Fig.	('FOXO3a', 'Gene', (80, 86))	('HT1080', 'Gene', '8872', (103, 109))	('ITF2357', 'Var', (122, 129))	('FOXO3a', 'Gene', '2309', (80, 86))	('ITF2357', 'Chemical', 'MESH:C502418', (122, 129))	('FOXO1', 'Gene', '2308', (70, 75))	('FOXO1', 'Gene', (70, 75))	('HT1080', 'Gene', (103, 109))
207331	29472530	In particular, ITF2357-treated cells showed a more evident nuclear localization of FOXO3a in comparison to untreated ones.	('ITF2357', 'Chemical', 'MESH:C502418', (15, 22))	('nuclear localization', 'MPA', (59, 79))	('ITF2357-treated', 'Var', (15, 30))	('FOXO3a', 'Gene', '2309', (83, 89))	('FOXO3a', 'Gene', (83, 89))
207333	29472530	4c, an increased expression of the two transcripts was observed after ITF2357 treatment.	('ITF2357', 'Var', (70, 77))	('expression', 'MPA', (17, 27))	('ITF2357', 'Chemical', 'MESH:C502418', (70, 77))	('increased', 'PosReg', (7, 16))
207335	29472530	Thus, we proceeded to confirm the relevance of FOXOs in ITF2357-mediated apoptosis by testing the consequences of siRNA-mediated knockdown of FOXO1 and FOXO3a, alone and in combination (Fig.	('knockdown', 'Var', (129, 138))	('FOXO1', 'Gene', (142, 147))	('FOXO1', 'Gene', '2308', (142, 147))	('ITF2357', 'Chemical', 'MESH:C502418', (56, 63))	('FOXO3a', 'Gene', '2309', (152, 158))	('FOXO3a', 'Gene', (152, 158))	('testing', 'Reg', (86, 93))
207336	29472530	Surprisingly, knockdown of FOXO1 or FOXO3a is not associated with a decrease of apoptotic rates in HT1080 cells treated with ITF2357.	('HT1080', 'Gene', (99, 105))	('apoptotic rates', 'CPA', (80, 95))	('FOXO1', 'Gene', (27, 32))	('FOXO1', 'Gene', '2308', (27, 32))	('HT1080', 'Gene', '8872', (99, 105))	('knockdown', 'Var', (14, 23))	('FOXO3a', 'Gene', '2309', (36, 42))	('ITF2357', 'Chemical', 'MESH:C502418', (125, 132))	('FOXO3a', 'Gene', (36, 42))
207337	29472530	Notably, similar results were obtained in HT1080 cells after simultaneous knockdown of both FOXO1 and 3a (Fig.	('HT1080', 'Gene', (42, 48))	('FOXO1 and 3a', 'Gene', '2308;2309', (92, 104))	('knockdown', 'Var', (74, 83))	('HT1080', 'Gene', '8872', (42, 48))
207338	29472530	These results were also corroborated by analysis of Bim expression in HT1080 cells upon FOXOs silencing and ITF2357 treatment.	('HT1080', 'Gene', (70, 76))	('silencing', 'Var', (94, 103))	('HT1080', 'Gene', '8872', (70, 76))	('FOXOs', 'Gene', (88, 93))	('ITF2357', 'Chemical', 'MESH:C502418', (108, 115))	('Bim', 'Gene', (52, 55))	('Bim', 'Gene', '10018', (52, 55))
207339	29472530	Indeed, after FOXOs silencing, Bim expression was still upregulated in response to ITF2357 (Fig.	('Bim', 'Gene', (31, 34))	('ITF2357', 'Chemical', 'MESH:C502418', (83, 90))	('Bim', 'Gene', '10018', (31, 34))	('FOXOs', 'Gene', (14, 19))	('silencing', 'Var', (20, 29))	('upregulated', 'PosReg', (56, 67))
207340	29472530	Interestingly, we found that mRNA of other two FOXO members, FOXO4 and FOXO6, were upregulated in response to ITF2357 when FOXO1 and 3a were downregulated.	('FOXO6', 'Gene', (71, 76))	('mRNA', 'MPA', (29, 33))	('FOXO4', 'Gene', (61, 66))	('ITF2357', 'Var', (110, 117))	('upregulated', 'PosReg', (83, 94))	('ITF2357', 'Chemical', 'MESH:C502418', (110, 117))	('FOXO4', 'Gene', '4303', (61, 66))	('FOXO1 and 3a', 'Gene', '2308;2309', (123, 135))	('FOXO6', 'Gene', '100132074', (71, 76))
207342	29472530	Based on these data, we decided to explore the effect of ITF2357 in combination with conventional sarcoma chemotherapy, such as Doxo, a topoisomerase II inhibitor frequently used as first-line chemotherapeutic for sarcomas.	('ITF2357', 'Var', (57, 64))	('ITF2357', 'Chemical', 'MESH:C502418', (57, 64))	('sarcoma', 'Disease', 'MESH:D012509', (214, 221))	('Doxo', 'Chemical', 'MESH:D004317', (128, 132))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcomas', 'Disease', 'MESH:D012509', (214, 222))	('sarcoma', 'Disease', (214, 221))	('sarcoma', 'Disease', (98, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (214, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('sarcomas', 'Disease', (214, 222))
207346	29472530	In particular, in HT1080 cells, the combination of ITF2357 (0.5 muM) and Doxo (0.1 muM) caused a growth reduction of about 90% +- 4.7, while single treatments resulted in 50% +- 3 and 63% +- 10 growth reduction after treatment with ITF2357 or Doxo, respectively.	('ITF2357', 'Chemical', 'MESH:C502418', (232, 239))	('HT1080', 'Gene', (18, 24))	('reduction', 'NegReg', (104, 113))	('muM', 'Gene', (64, 67))	('Doxo', 'Chemical', 'MESH:D004317', (73, 77))	('HT1080', 'Gene', '8872', (18, 24))	('muM', 'Gene', '56925', (83, 86))	('ITF2357', 'Var', (51, 58))	('ITF2357', 'Chemical', 'MESH:C502418', (51, 58))	('muM', 'Gene', (83, 86))	('muM', 'Gene', '56925', (64, 67))	('Doxo', 'Chemical', 'MESH:D004317', (243, 247))	('growth', 'MPA', (97, 103))
207349	29472530	Notably, a significant growth-inhibitory effect of ITF2357 in vitro and a synergistic interaction with Doxo was also evidenced in two-patient-derived sarcoma cell lines (LSP1, 4052), while the effect of the two drugs was additive in 3844B patient-derived sarcoma cell line (Table 1, Fig.	('patient', 'Species', '9606', (239, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('Doxo', 'Chemical', 'MESH:D004317', (103, 107))	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('ITF2357', 'Var', (51, 58))	('ITF2357', 'Chemical', 'MESH:C502418', (51, 58))	('sarcoma', 'Disease', (150, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcoma', 'Disease', 'MESH:D012509', (255, 262))	('growth-inhibitory effect', 'MPA', (23, 47))	('patient', 'Species', '9606', (134, 141))	('sarcoma', 'Disease', (255, 262))
207356	29472530	In vivo experiments were also performed in HT1080 xenografts in which treatment with either Doxo or ITF2357 alone slightly affects xenografts growth (about 15% of inhibition).	('xenografts growth', 'CPA', (131, 148))	('HT1080', 'Gene', (43, 49))	('affects', 'Reg', (123, 130))	('ITF2357', 'Var', (100, 107))	('HT1080', 'Gene', '8872', (43, 49))	('ITF2357', 'Chemical', 'MESH:C502418', (100, 107))	('Doxo', 'Chemical', 'MESH:D004317', (92, 96))
207358	29472530	Accordingly, with in vitro data, immunohistochemical analysis of SW982 tumor xenografts showed an increased percentage of apoptotic cells in combination treatments when compared to single ones (Fig.	('apoptotic cells', 'CPA', (122, 137))	('combination', 'Var', (141, 152))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('SW982', 'CellLine', 'CVCL:1734', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
207359	29472530	In particular, TUNEL-positive staining nuclei revealed an apoptotic index of 5% for control, 13.6% for Doxo, 13.4% for ITF2357, and 23.6% for the combination.	('ITF2357', 'Var', (119, 126))	('ITF2357', 'Chemical', 'MESH:C502418', (119, 126))	('Doxo', 'Chemical', 'MESH:D004317', (103, 107))	('apoptotic index', 'CPA', (58, 73))
207360	29472530	These results indicate that ITF2357 sensitizes sarcoma from different histologic subtypes and p53 mutational status to Doxo both in vitro and in vivo.	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('sensitizes', 'Reg', (36, 46))	('mutational', 'Var', (98, 108))	('ITF2357', 'Var', (28, 35))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('ITF2357', 'Chemical', 'MESH:C502418', (28, 35))	('sarcoma', 'Disease', (47, 54))	('Doxo', 'Chemical', 'MESH:D004317', (119, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
207362	29472530	Using in vitro and in vivo sarcoma models, here we demonstrate that the HDACi, ITF2357, decreases cell viability, activates apoptosis, and increases the growth-inhibitory efficacy of Doxo.	('sarcoma', 'Disease', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('HDAC', 'Gene', (72, 76))	('growth-inhibitory efficacy', 'MPA', (153, 179))	('activates', 'PosReg', (114, 123))	('HDAC', 'Gene', '9734', (72, 76))	('Doxo', 'Chemical', 'MESH:D004317', (183, 187))	('increases', 'PosReg', (139, 148))	('ITF2357', 'Var', (79, 86))	('decreases', 'NegReg', (88, 97))	('ITF2357', 'Chemical', 'MESH:C502418', (79, 86))	('cell viability', 'CPA', (98, 112))	('apoptosis', 'CPA', (124, 133))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))
207365	29472530	In agreement with other groups demonstrating p53-independent transcriptional regulation of some pro-apoptotic BH3-only genes, we found that ITF2357 transcriptionally upregulated, in a dose-dependent manner, Bax, Puma, Noxa, and Bim in cells harboring mutant or wt p53, thus indicating a p53-independent mechanism.	('upregulated', 'PosReg', (166, 177))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('mutant', 'Var', (251, 257))	('p53', 'Gene', (264, 267))	('p53', 'Gene', '7157', (264, 267))	('Bax', 'Gene', (207, 210))	('Noxa', 'Gene', (218, 222))	('ITF2357', 'Chemical', 'MESH:C502418', (140, 147))	('p53', 'Gene', '7157', (287, 290))	('ITF2357', 'Gene', (140, 147))	('Puma', 'CPA', (212, 216))	('Bax', 'Gene', '581', (207, 210))	('Bim', 'Gene', (228, 231))	('p53', 'Gene', (287, 290))	('Bim', 'Gene', '10018', (228, 231))	('Noxa', 'Gene', '5366', (218, 222))
207367	29472530	Interestingly, we also found that ITF2357 induces a canonical autophagic process, and that inhibition of autophagy strongly increased apoptosis induced by ITF2357, suggesting that in our models, autophagy shows a pro-survival effect.	('canonical autophagic process', 'CPA', (52, 80))	('increased', 'PosReg', (124, 133))	('apoptosis', 'CPA', (134, 143))	('inhibition', 'NegReg', (91, 101))	('ITF2357', 'Var', (34, 41))	('induces', 'Reg', (42, 49))	('ITF2357', 'Var', (155, 162))	('ITF2357', 'Chemical', 'MESH:C502418', (34, 41))	('ITF2357', 'Chemical', 'MESH:C502418', (155, 162))	('autophagy', 'CPA', (105, 114))
207369	29472530	We previously reported that ITF2357 in combination with Pemetrexed caused a toxic form of autophagy that subsequently activated a caspase-dependent apoptotic program in lung cancer models.	('activated', 'PosReg', (118, 127))	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (56, 66))	('autophagy', 'CPA', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('ITF2357', 'Var', (28, 35))	('ITF2357', 'Chemical', 'MESH:C502418', (28, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('caused', 'Reg', (67, 73))	('lung cancer', 'Disease', (169, 180))	('caspase-dependent apoptotic program', 'CPA', (130, 165))
207371	29472530	They act as tumor suppressor genes and their alterations have been reported in some human cancers, including rhabdomyosarcoma and osteosarcoma.	('alterations', 'Var', (45, 56))	('cancers', 'Disease', (90, 97))	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('human', 'Species', '9606', (84, 89))	('rhabdomyosarcoma and osteosarcoma', 'Disease', 'MESH:D012516', (109, 142))	('reported', 'Reg', (67, 75))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('tumor', 'Disease', (12, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (109, 125))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
207372	29472530	We reported that HDAC inhibition by ITF2357, induced FOXO1/3 upregulation, FOXO proteins nuclear accumulation, and transcriptional activation of FOXO-target genes, such as BH3-only proteins Puma, Noxa, and Bim, thus altering the equlibrium between anti-apoptotic and pro-apoptotic proteins belonging to bcl-2 family, which in turn culminates into mitochondrial alteration, caspases activation, and DNA fragmentation.	('Noxa', 'Gene', '5366', (196, 200))	('Bim', 'Gene', (206, 209))	('equlibrium', 'MPA', (229, 239))	('caspases', 'CPA', (373, 381))	('bcl-2', 'Gene', (303, 308))	('HDAC', 'Gene', (17, 21))	('FOXO1', 'Gene', '2308', (53, 58))	('inhibition', 'NegReg', (22, 32))	('Noxa', 'Gene', (196, 200))	('mitochondrial alteration', 'Phenotype', 'HP:0012103', (347, 371))	('ITF2357', 'Var', (36, 43))	('FOXO1', 'Gene', (53, 58))	('ITF2357', 'Chemical', 'MESH:C502418', (36, 43))	('bcl-2', 'Gene', '596', (303, 308))	('altering', 'Reg', (216, 224))	('activation', 'PosReg', (382, 392))	('upregulation', 'PosReg', (61, 73))	('Bim', 'Gene', '10018', (206, 209))	('mitochondrial alteration', 'CPA', (347, 371))	('HDAC', 'Gene', '9734', (17, 21))
207374	29472530	Also the expression of other downstream targets of FOXOs, including CDKN1A/p21 and TP53PIN1, was found to be upregulated in response to ITF2357 in sarcoma models.	('ITF2357', 'Var', (136, 143))	('upregulated', 'PosReg', (109, 120))	('TP53PIN1', 'Gene', (83, 91))	('ITF2357', 'Chemical', 'MESH:C502418', (136, 143))	('p21', 'Gene', '1026', (75, 78))	('CDKN1A', 'Gene', (68, 74))	('expression', 'MPA', (9, 19))	('CDKN1A', 'Gene', '1026', (68, 74))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('p21', 'Gene', (75, 78))	('sarcoma', 'Disease', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('FOXOs', 'Gene', (51, 56))
207377	29472530	Since we also observed that in silenced cells, ITF2357 treatment upregulated other two members of FOXO family, FOXO4 and FOXO6, we might hypothesize that FOXO4 and FOXO6 upregulation might sustains ITF2357-mediated apoptosis through upregulation of pro-apoptotic BH3-only protein Bim.	('FOXO4', 'Gene', (111, 116))	('ITF2357', 'Chemical', 'MESH:C502418', (198, 205))	('Bim', 'Gene', '10018', (280, 283))	('FOXO6', 'Gene', '100132074', (164, 169))	('FOXO4', 'Gene', '4303', (111, 116))	('upregulation', 'PosReg', (170, 182))	('ITF2357-mediated', 'Var', (198, 214))	('FOXO6', 'Gene', (164, 169))	('ITF2357', 'Chemical', 'MESH:C502418', (47, 54))	('FOXO4', 'Gene', (154, 159))	('FOXO6', 'Gene', '100132074', (121, 126))	('FOXO6', 'Gene', (121, 126))	('upregulated', 'PosReg', (65, 76))	('FOXO4', 'Gene', '4303', (154, 159))	('upregulation', 'PosReg', (233, 245))	('Bim', 'Gene', (280, 283))
207378	29472530	Overall, our results evidence similar FOXO-dependent apoptotic mechanisms in response to ITF2357 in sarcoma cells with wt or mutated p53 status.	('sarcoma', 'Disease', (100, 107))	('ITF2357', 'Chemical', 'MESH:C502418', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('mutated', 'Var', (125, 132))	('p53', 'Gene', '7157', (133, 136))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))	('ITF2357', 'Gene', (89, 96))	('p53', 'Gene', (133, 136))	('apoptotic', 'CPA', (53, 62))
207382	29472530	Taken together, our data indicate that ITF2357 may represent an important potential therapeutic agent against human sarcoma regardless of p53 status, and that the pharmacological combination of ITF2357 with Doxo has the potential to enhance sensitization in different preclinical models of sarcoma.	('ITF2357', 'Var', (194, 201))	('ITF2357', 'Var', (39, 46))	('p53', 'Gene', (138, 141))	('ITF2357', 'Chemical', 'MESH:C502418', (194, 201))	('ITF2357', 'Chemical', 'MESH:C502418', (39, 46))	('enhance', 'PosReg', (233, 240))	('p53', 'Gene', '7157', (138, 141))	('sarcoma', 'Disease', 'MESH:D012509', (290, 297))	('Doxo', 'Chemical', 'MESH:D004317', (207, 211))	('sarcoma regardless', 'Disease', (116, 134))	('human', 'Species', '9606', (110, 115))	('sarcoma regardless', 'Disease', 'MESH:D012509', (116, 134))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('sarcoma', 'Disease', (290, 297))	('sarcoma', 'Disease', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('sensitization', 'MPA', (241, 254))
207383	29472530	Based on these results, the potential clinical value of ITF2357, over other HDACi agents previously assessed in sarcoma, deserves further studies in the future.	('HDAC', 'Gene', (76, 80))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('HDAC', 'Gene', '9734', (76, 80))	('ITF2357', 'Var', (56, 63))	('sarcoma', 'Disease', (112, 119))	('ITF2357', 'Chemical', 'MESH:C502418', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
207386	29472530	EGFP-LC3B, ptf-LC3, and GFP-bcl-2 stable clones, obtained as previously described, were cultured in the presence of geneticin (800 mug/ml, Sigma-Aldrich, St. Louis, MO).	('LC3B', 'Gene', '81631', (5, 9))	('LC3B', 'Gene', (5, 9))	('bcl-2', 'Gene', (28, 33))	('bcl-2', 'Gene', '596', (28, 33))	('800 mug/ml', 'Var', (127, 137))
207443	27170917	Other factors are male gender, extensive tumor necrosis, high grade, large number of mitotic figures (>10/hpf) and syt-ssx1 variant.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor necrosis', 'Disease', 'MESH:D009336', (41, 55))	('syt', 'Gene', '6857', (115, 118))	('syt', 'Gene', (115, 118))	('tumor necrosis', 'Disease', (41, 55))	('ssx1', 'Gene', (119, 123))	('ssx1', 'Gene', '6756', (119, 123))	('variant', 'Var', (124, 131))
17740	27170917	SYT-SSX1 variant is associated with more aggressive phenotype and more tumor cell proliferation.	('tumor cell proliferation', 'CPA', (71, 95))	('variant', 'Var', (9, 16))	('SSX1', 'Gene', '6756', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('more', 'PosReg', (66, 70))	('SSX1', 'Gene', (4, 8))
207683	30925179	The weights of the resected tumors of mice in the pazopanib group were significantly lower than those of tumors from mice in the control group (Fig 7C).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('pazopanib', 'Var', (50, 59))	('lower', 'NegReg', (85, 90))	('mice', 'Species', '10090', (38, 42))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('pazopanib', 'Chemical', 'MESH:C516667', (50, 59))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
207709	30925179	In the current study, pazopanib significantly suppressed the proliferation of incubated PIS-1 cells as well as the growth of xenografted tumors.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('pazopanib', 'Var', (22, 31))	('PIS', 'Chemical', '-', (88, 91))	('proliferation', 'CPA', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))	('suppressed', 'NegReg', (46, 56))
207810	28663959	In the light of this recent information, specific targeting of ASPL-TFE3 mutation is deemed vital in order to control the disease and prolong the lifetime of patients.	('control', 'Disease', (110, 117))	('TFE3', 'Gene', (68, 72))	('ASPL', 'Gene', '79058', (63, 67))	('prolong', 'PosReg', (134, 141))	('ASPL', 'Gene', (63, 67))	('patients', 'Species', '9606', (158, 166))	('TFE3', 'Gene', '7030', (68, 72))	('mutation', 'Var', (73, 81))
207915	26061213	For example, in a report from MGH of 29 patients treated with preoperative radiation (45 Gy) and complete gross resection, those who also received IOERT (10-20 Gy) had 83% local control at 5 years, compared to 61% for those who did not receive IOERT.	('patients', 'Species', '9606', (40, 48))	('10-20 Gy', 'Var', (154, 162))	('local control', 'CPA', (172, 185))
207943	20300555	While some cooperative genetic events have been identified, such as mutations in TP53 or deletions of the CDKN2A locus, these appear to be absent in the vast majority of cases.	('CDKN2A', 'Gene', '1029', (106, 112))	('deletions', 'Var', (89, 98))	('CDKN2A', 'Gene', (106, 112))	('mutations', 'Var', (68, 77))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
207945	20300555	One method to discover such mutations is to identify familial cases of Ewing's sarcoma and to then map the susceptibility locus using traditional genetic mapping techniques.	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (71, 86))	("Ewing's sarcoma", 'Disease', (71, 86))	('mutations', 'Var', (28, 37))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (71, 86))
207950	20300555	Some hereditary cancer syndromes, such as Li-Fraumeni Syndrome, are caused by the mutation of critical tumor suppressor genes (TP53) and lead to wide-spread tumorigenesis including many different tumor types.	('hereditary cancer syndromes', 'Disease', (5, 32))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (196, 201))	('caused by', 'Reg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('TP53', 'Gene', '7157', (127, 131))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (5, 32))	('mutation', 'Var', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (103, 108))	('lead to', 'Reg', (137, 144))	('Li-Fraumeni Syndrome', 'Disease', (42, 62))	('TP53', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (157, 162))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (42, 62))	('tumor', 'Disease', 'MESH:D009369', (157, 162))
207951	20300555	However, other hereditary cancer syndromes appear to have a more limited tumor spectrum.For example, individuals with syndromes such as WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation syndrome) and Denys-Drash Syndrome have mutations in the WT1 gene, and these patients are primarily at risk for Wilms tumor.	('mutations', 'Var', (257, 266))	('Wilms tumor', 'Phenotype', 'HP:0002667', (329, 340))	('Denys-Drash Syndrome', 'Disease', (231, 251))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('WT1', 'Gene', '7490', (274, 277))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('Wilms tumor', 'Disease', (329, 340))	('aniridia', 'Disease', (155, 163))	('mental retardation syndrome', 'Disease', 'MESH:D008607', (198, 225))	('WAGR', 'Disease', (136, 140))	('genitourinary abnormalities', 'Phenotype', 'HP:0000119', (165, 192))	('Wilms tumor', 'Disease', 'MESH:D009396', (142, 153))	('tumor', 'Disease', (335, 340))	('WAGR', 'Disease', 'MESH:D017624', (136, 140))	('mental retardation syndrome', 'Disease', (198, 225))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('tumor', 'Disease', (73, 78))	('Wilms tumor', 'Phenotype', 'HP:0002667', (142, 153))	('aniridia', 'Disease', 'MESH:D015783', (155, 163))	('hereditary cancer syndromes', 'Disease', (15, 42))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('genitourinary abnormalities', 'Disease', 'MESH:D014564', (165, 192))	('mental retardation', 'Phenotype', 'HP:0001249', (198, 216))	('patients', 'Species', '9606', (294, 302))	('tumor', 'Disease', (148, 153))	('Wilms tumor', 'Disease', 'MESH:D009396', (329, 340))	('aniridia', 'Phenotype', 'HP:0000526', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (15, 42))	('genitourinary abnormalities', 'Disease', (165, 192))	('Wilms tumor', 'Disease', (142, 153))	('Denys-Drash Syndrome', 'Disease', 'MESH:D030321', (231, 251))	('WT1', 'Gene', (274, 277))
207952	20300555	The identification of an underlying genetic mutation or predisposition to develop specific cancers is helpful not only to family members with that syndrome, but also to many other individuals who develop cancer without known risk factors.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('mutation', 'Var', (44, 52))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
207961	20300555	The most common of these, t(11;22)(q24;q12), is found in approximately 85% of cases, while t(21;22)(q22;q12) is found in 10% of cases.	('t(11;22)(q24;q12', 'Var', (26, 42))	('t(21;22)(q22;q12', 'Var', (91, 107))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (91, 108))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (26, 43))
207962	20300555	These translocations fuse the EWSR1 gene on chromosome 22 with an ETS family member, most commonly the FLI1 gene on chromosome 11.	('EWSR1', 'Gene', '2130', (30, 35))	('FLI1', 'Gene', (103, 107))	('FLI1', 'Gene', '2313', (103, 107))	('EWSR1', 'Gene', (30, 35))	('fuse', 'NegReg', (21, 25))	('translocations', 'Var', (6, 20))
207966	20300555	The presence of EWS/ETS translocations is specific to Ewing's sarcoma, and the presence of an EWS/ETS fusion protein can be used clinically to diagnose patients with Ewing's sarcoma who have small round blue cell tumors.	('EWS', 'Gene', '2130', (94, 97))	('diagnose', 'Reg', (143, 151))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	("Ewing's sarcoma", 'Disease', (166, 181))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	("Ewing's sarcoma", 'Disease', (54, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('translocations', 'Var', (24, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('EWS', 'Gene', (16, 19))	('blue cell tumors', 'Disease', 'MESH:D005935', (203, 219))	('EWS', 'Gene', (94, 97))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (166, 181))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (54, 69))	('patients', 'Species', '9606', (152, 160))	('EWS', 'Gene', '2130', (16, 19))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (166, 181))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (54, 69))	('blue cell tumors', 'Disease', (203, 219))
207967	20300555	Two main cooperating mutations have been identified in Ewing's sarcoma: p53 and RB pathway mutations.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (55, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	("Ewing's sarcoma", 'Disease', (55, 70))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (55, 70))	('RB pathway', 'Pathway', (80, 90))	('mutations', 'Var', (91, 100))
207968	20300555	Mutations in TP53 (encoding the p53 protein) occur with a frequency of 5%-20% in Ewing's sarcoma, amplifications of MDM2 occur in 0%-10% of cases, and deletions of the CDKN2A locus (encoding overlapping p16INK4A and p14ARF transcripts) occur in about 15% of cases.	('p14ARF', 'Gene', '1029', (216, 222))	('TP53', 'Gene', (13, 17))	('MDM2', 'Gene', '4193', (116, 120))	('MDM2', 'Gene', (116, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('p14ARF', 'Gene', (216, 222))	('p53', 'Gene', (32, 35))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (81, 96))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', (168, 174))	('deletions', 'Var', (151, 160))	('p16INK4A', 'Gene', (203, 211))	("Ewing's sarcoma", 'Disease', (81, 96))	('p53', 'Gene', '7157', (32, 35))	('TP53', 'Gene', '7157', (13, 17))	('p16INK4A', 'Gene', '1029', (203, 211))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (81, 96))	('CDKN2A', 'Gene', '1029', (168, 174))
207971	20300555	Alterations in these pathways may be required to bypass a growth inhibitory effect mediated by the EWS/ETS fusion protein.	('growth', 'MPA', (58, 64))	('Alterations', 'Var', (0, 11))	('EWS', 'Gene', '2130', (99, 102))	('EWS', 'Gene', (99, 102))
207972	20300555	Although alterations in the p53 and/or RB pathways may cooperate with EWS/ETS fusion proteins to induce Ewing's sarcoma, this disease is not traditionally considered to be a part of the Li-Fraumeni syndrome and has rarely been reported as a second tumor in patients with heritable retinoblastoma.	('p53', 'Gene', (28, 31))	('retinoblastoma', 'Disease', 'MESH:D012175', (281, 295))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('tumor', 'Disease', (248, 253))	('EWS', 'Gene', '2130', (70, 73))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (104, 119))	('induce', 'Reg', (97, 103))	('patients', 'Species', '9606', (257, 265))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('retinoblastoma', 'Phenotype', 'HP:0009919', (281, 295))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (104, 119))	('RB pathways', 'Pathway', (39, 50))	('alterations', 'Var', (9, 20))	('retinoblastoma', 'Disease', (281, 295))	('Li-Fraumeni syndrome', 'Disease', (186, 206))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('EWS', 'Gene', (70, 73))	('p53', 'Gene', '7157', (28, 31))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (186, 206))	("Ewing's sarcoma", 'Disease', (104, 119))
208015	20300555	They speculate that the increased risk of cancer in older mothers could be due to age-related increases in de novo epimutations in oocyte genes transmitted to offspring.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('epimutations', 'Var', (115, 127))	('oocyte', 'Gene', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (42, 48))
208040	20300555	speculated that these microsatellite polymorphisms may contribute to differences in individual and population susceptibility to Ewing's sarcoma, and that this may also be true of other diseases mediated by ETS transcription factors.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (128, 143))	("Ewing's sarcoma", 'Disease', (128, 143))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (128, 143))	('contribute', 'Reg', (55, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('microsatellite polymorphisms', 'Var', (22, 50))
208067	30447212	The incidence of unexpected sarcoma progressively increased with higher uterine weight with an incidence of 0.03% (1/2,993) among women with a uterine weight <250 grams versus 15.4% (2/13) with a uterine weight >=2,000 grams.	('sarcoma', 'Disease', (28, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('<250 grams', 'Var', (158, 168))	('women', 'Species', '9606', (130, 135))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))
208115	30447212	Similar to the incidence of unexpected sarcoma, the incidence of any sarcoma progressively increased among all hysterectomy with increasing uterine weight from 0.09% among women with uterine weight < 250 grams to 0.7%, 1.4%, 6.3%, 11.1%, and 14.3%, among women with uterine weight 250-499, 500-999, 1000-1499, 1500-1999, and >=2000 grams, respectively (p<0.001).	('sarcoma', 'Disease', (69, 76))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('< 250 grams', 'Var', (198, 209))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcoma', 'Disease', (39, 46))	('increased', 'PosReg', (91, 100))	('women', 'Species', '9606', (255, 260))	('women', 'Species', '9606', (172, 177))
208145	30273195	UTERINE TUMOR RESEMBLING OVARIAN SEX CORD TUMOR: A DISTINCT ENTITY CHARACTERIZED BY RECURRENT NCOA2/3 GENE FUSIONS Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare and distinctive neoplasm of unclear histogenesis, and uncertain malignant potential.	('NCOA2', 'Gene', '10499', (94, 99))	('ovarian sex cord tumor', 'Disease', (140, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (123, 128))	('neoplasm', 'Disease', 'MESH:D009369', (199, 207))	('TUMOR', 'Phenotype', 'HP:0002664', (42, 47))	('ovarian sex cord tumor', 'Disease', 'MESH:D010051', (140, 162))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('NCOA2', 'Gene', (94, 99))	('neoplasm', 'Disease', (199, 207))	('OVARIAN', 'Disease', (25, 32))	('Uterine tumor', 'Phenotype', 'HP:0010784', (115, 128))	('TUMOR', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('ovarian sex cord tumor', 'Phenotype', 'HP:0031918', (140, 162))	('tumor', 'Disease', (157, 162))	('neoplasm', 'Phenotype', 'HP:0002664', (199, 207))	('OVARIAN SEX CORD TUMOR', 'Phenotype', 'HP:0031918', (25, 47))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('OVARIAN', 'Disease', 'MESH:D010049', (25, 32))	('FUSIONS', 'Var', (107, 114))	('UTERINE TUMOR', 'Phenotype', 'HP:0010784', (0, 13))
208150	30273195	RNA-Sequencing was performed in all cases, revealing an ESR1-NCOA3 fusion in 2 cases and one case each with related ESR1-NCOA2 and GREB1-NCOA2 fusions.	('N', 'Chemical', 'MESH:D009584', (61, 62))	('NCOA2', 'Gene', '10499', (137, 142))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('NCOA3', 'Gene', (61, 66))	('NCOA2', 'Gene', (137, 142))	('NCOA2', 'Gene', '10499', (121, 126))	('NCOA3', 'Gene', '8202', (61, 66))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('NCOA2', 'Gene', (121, 126))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('fusion', 'Var', (67, 73))
208152	30273195	Our results demonstrate UTROSCT are defined by recurrent fusions involving NCOA2 or NCOA3, a finding that is directly amenable to diagnostic evaluation.	('UTROSCT', 'Disease', (24, 31))	('NCOA3', 'Gene', (84, 89))	('NCOA2', 'Gene', (75, 80))	('NCOA3', 'Gene', '8202', (84, 89))	('fusions', 'Var', (57, 64))	('NCOA2', 'Gene', '10499', (75, 80))
208161	30273195	In contrast to endometrial stromal sarcoma with sex-cord-like differentiation, UTROSCT lacks evidence of either JAZF1-SUZ12 fusion genes, or PHF1 rearrangement.	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (15, 42))	('UTROSCT', 'Disease', (79, 86))	('JAZF1', 'Gene', (112, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('fusion genes', 'Var', (124, 136))	('PHF1', 'Gene', (141, 145))	('JAZF1', 'Gene', '221895', (112, 117))	('SUZ12', 'Gene', '23512', (118, 123))	('rearrangement', 'Var', (146, 159))	('PHF1', 'Gene', '5252', (141, 145))	('SUZ12', 'Gene', (118, 123))	('endometrial stromal sarcoma', 'Disease', (15, 42))
208162	30273195	Furthermore, these tumors lack FOXL2 and DICER1 mutations typical of ovarian adult granulosa cell tumor and Sertoli-Leydig cell tumor, respectively.	('tumors', 'Disease', (19, 25))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (108, 133))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (108, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('adult granulosa cell tumor', 'Phenotype', 'HP:0031919', (77, 103))	('lack', 'NegReg', (26, 30))	('ovarian adult granulosa cell tumor', 'Disease', (69, 103))	('DICER1', 'Gene', '23405', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (116, 133))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('DICER1', 'Gene', (41, 47))	('ovarian adult granulosa cell tumor', 'Disease', 'MESH:D010051', (69, 103))	('FOXL2', 'Gene', '668', (31, 36))	('Sertoli-Leydig cell tumor', 'Disease', (108, 133))	('FOXL2', 'Gene', (31, 36))
208196	30273195	The tumors with NCOA3 rearrangement involved either exon 14 or 15 (NCBI Reference Sequence: NM_181659.2), which was fused to ESR1 exon 3 (NM_000125.3).	('N', 'Chemical', 'MESH:D009584', (67, 68))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('NCOA3', 'Gene', (16, 21))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('NCOA3', 'Gene', '8202', (16, 21))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('rearrangement', 'Var', (22, 35))
208197	30273195	Two cases with NCOA2 rearrangement involved exon 14 (NM_001321703.1), which was fused with either ESR1 exon 3 (NM_000125.3), or GREB1 exon 2 (NM_014668.3).	('N', 'Chemical', 'MESH:D009584', (53, 54))	('NM_014668.3', 'Var', (142, 153))	('NCOA2', 'Gene', '10499', (15, 20))	('NCOA2', 'Gene', (15, 20))	('rearrangement', 'Var', (21, 34))	('NM_001321703.1', 'Var', (53, 67))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('N', 'Chemical', 'MESH:D009584', (15, 16))
208210	30273195	The relationship of Group I tumors to endometrial stromal sarcoma has recently been confirmed molecularly, where six cases were found to harbor PHF1 rearrangement.	('PHF1', 'Gene', (144, 148))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('endometrial stromal sarcoma', 'Disease', (38, 65))	('PHF1', 'Gene', '5252', (144, 148))	('harbor', 'Reg', (137, 143))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (38, 65))	('rearrangement', 'Var', (149, 162))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
208217	30273195	Following the incidental discovery of an ESR1-NCOA3 fusion gene in a patient with UTROSCT in the course of routine diagnostic RNA-Seq testing, we examined three additional cases by RNA-Seq (N=4) to further assess their molecular pathogenesis.	('N', 'Chemical', 'MESH:D009584', (190, 191))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('NCOA3', 'Gene', (46, 51))	('NCOA3', 'Gene', '8202', (46, 51))	('N', 'Chemical', 'MESH:D009584', (182, 183))	('N', 'Chemical', 'MESH:D009584', (127, 128))	('patient', 'Species', '9606', (69, 76))	('fusion gene', 'Var', (52, 63))
208219	30273195	Notably, NCOA2/3 fusions have previously been identified in uterine neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (68, 77))	('NCOA2', 'Gene', (9, 14))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('neoplasms', 'Phenotype', 'HP:0002664', (68, 77))	('uterine neoplasms', 'Phenotype', 'HP:0010784', (60, 77))	('fusions', 'Var', (17, 24))	('NCOA2', 'Gene', '10499', (9, 14))	('identified', 'Reg', (46, 56))	('neoplasm', 'Phenotype', 'HP:0002664', (68, 76))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('neoplasms', 'Disease', (68, 77))
208220	30273195	A GREB1-NCOA2 fusion gene was recently reported in a uterine tumor designated 'sarcoma, not otherwise classifiable.'	('NCOA2', 'Gene', (8, 13))	('sarcoma', 'Disease', (79, 86))	('uterine tumor', 'Phenotype', 'HP:0010784', (53, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('uterine tumor', 'Disease', 'MESH:D014594', (53, 66))	('fusion', 'Var', (14, 20))	('uterine tumor', 'Disease', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('reported', 'Reg', (39, 47))	('NCOA2', 'Gene', '10499', (8, 13))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
208224	30273195	identified two cases with ESR1 rearrangement:one partnered with NCOA2 and the other NCOA3.	('NCOA3', 'Gene', (84, 89))	('NCOA2', 'Gene', '10499', (64, 69))	('rearrangement', 'Var', (31, 44))	('NCOA3', 'Gene', '8202', (84, 89))	('NCOA2', 'Gene', (64, 69))	('ESR1', 'Gene', (26, 30))
208230	30273195	Fusion genes involving NCOA2 have been reported in several soft tissue tumors, including: mesenchymal chondrosarcoma (HEY1-NCOA2 fusion), soft tissue angiofibroma (NCOA2 fused to various partners e.g., AHRR, GTF2I), congenital spindle cell rhabdomyosarcoma (NCOA2 fused with SRF, TEAD1, VGLL2), and rare examples of alveolar rhabdomyosarcoma (PAX3-NCOA2).	('TEAD1', 'Gene', (280, 285))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (316, 341))	('sarcoma', 'Phenotype', 'HP:0100242', (334, 341))	('AHRR', 'Gene', '57491', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('NCOA2', 'Gene', '10499', (348, 353))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (316, 341))	('TEAD1', 'Gene', '7003', (280, 285))	('NCOA2', 'Gene', (23, 28))	('SRF', 'Gene', '6722', (275, 278))	('NCOA2', 'Gene', '10499', (164, 169))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (59, 77))	('NCOA2', 'Gene', '10499', (258, 263))	('GTF2I', 'Gene', '2969', (208, 213))	('HEY1', 'Gene', '23462', (118, 122))	('SRF', 'Gene', (275, 278))	('HEY1', 'Gene', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('VGLL2', 'Gene', '245806', (287, 292))	('mesenchymal chondrosarcoma', 'Disease', (90, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('congenital spindle cell rhabdomyosarcoma', 'Disease', (216, 256))	('congenital spindle cell rhabdomyosarcoma', 'Disease', 'MESH:D002277', (216, 256))	('NCOA2', 'Gene', (348, 353))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (102, 116))	('GTF2I', 'Gene', (208, 213))	('NCOA2', 'Gene', '10499', (123, 128))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (240, 256))	('PAX3', 'Gene', (343, 347))	('NCOA2', 'Gene', (164, 169))	('NCOA2', 'Gene', (258, 263))	('angiofibroma', 'Disease', (150, 162))	('reported', 'Reg', (39, 47))	('tissue angiofibroma', 'Phenotype', 'HP:0010615', (143, 162))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (325, 341))	('AHRR', 'Gene', (202, 206))	('Fusion genes', 'Var', (0, 12))	('alveolar rhabdomyosarcoma', 'Disease', (316, 341))	('VGLL2', 'Gene', (287, 292))	('angiofibroma', 'Disease', 'MESH:D018322', (150, 162))	('PAX3', 'Gene', '5077', (343, 347))	('mesenchymal chondrosarcoma', 'Disease', 'MESH:D018211', (90, 116))	('NCOA2', 'Gene', (123, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('NCOA2', 'Gene', '10499', (23, 28))
208238	30273195	Pbx is an essential Hox cofactor and is required for Hox activity, they cooperatively promote cell proliferation and have been implicated as proto-oncogenes in human leukemia, and associated with epigenetic regulation in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (221, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('associated', 'Reg', (180, 190))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('promote', 'PosReg', (86, 93))	('epigenetic regulation', 'Var', (196, 217))	('Pbx', 'Gene', (0, 3))	('leukemia', 'Disease', 'MESH:D007938', (166, 174))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (221, 234))	('leukemia', 'Disease', (166, 174))	('cell proliferation', 'CPA', (94, 112))	('Ewing sarcoma', 'Disease', (221, 234))	('human', 'Species', '9606', (160, 165))
208246	30273195	The cases were found to contain fusion genes involving ESR1-NCOA3 (N=2), ESR1-NCOA2 (N=1) and GREB1-NCOA2 (N=1).	('N', 'Chemical', 'MESH:D009584', (67, 68))	('NCOA2', 'Gene', '10499', (78, 83))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('NCOA2', 'Gene', (78, 83))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('NCOA3', 'Gene', (60, 65))	('NCOA2', 'Gene', '10499', (100, 105))	('NCOA2', 'Gene', (100, 105))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('NCOA3', 'Gene', '8202', (60, 65))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('fusion', 'Var', (32, 38))
208351	27303489	Cytogenetic analysis confirmed the diagnosis of synovial sarcoma by demonstrating a variant X;18 translocation.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (48, 64))	('synovial sarcoma', 'Disease', 'MESH:D013584', (48, 64))	('variant X;18 translocation', 'Var', (84, 110))	('synovial sarcoma', 'Disease', (48, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
208402	27303489	The characteristic chromosomal translocation t(X;18)(SYT-SSX) is present in 80%-90% of these tumors and is considered specific for the diagnosis.	('t(X;18', 'Var', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('SYT', 'Gene', (53, 56))	('SSX', 'Gene', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('SSX', 'Gene', '727837', (57, 60))	('tumors', 'Disease', (93, 99))	('SYT', 'Gene', '6760', (53, 56))
208464	26977231	Chemotherapy may also worsen the performance status of the patient.	('performance', 'MPA', (33, 44))	('worsen', 'NegReg', (22, 28))	('Chemotherapy', 'Var', (0, 12))	('patient', 'Species', '9606', (59, 66))
208537	26155093	It was shown that in the presence of heparin, beta-sitosterol stimulated neovascularization in the mouse Matrigen plug assay, and the motility of human umbilical vein endothelial cells in an in vitro wound migration assay.	('beta-sitosterol', 'Chemical', 'MESH:C025473', (46, 61))	('motility', 'CPA', (134, 142))	('mouse', 'Species', '10090', (99, 104))	('neovascularization', 'CPA', (73, 91))	('heparin', 'Chemical', 'MESH:D006493', (37, 44))	('beta-sitosterol', 'Var', (46, 61))	('human', 'Species', '9606', (146, 151))	('stimulated', 'PosReg', (62, 72))
208593	25025207	High expression of FGFR4 has been associated with advanced-stage in RMS cancer and a poor survival rate.	('associated', 'Reg', (34, 44))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('RMS cancer', 'Disease', (68, 78))	('FGFR4', 'Gene', '2264', (19, 24))	('FGFR4', 'Gene', (19, 24))	('RMS cancer', 'Disease', 'MESH:D009369', (68, 78))	('RMS', 'Phenotype', 'HP:0002859', (68, 71))
208595	25025207	Over-expression of FGFR4 may stimulate the expression of TNNT1; the regulator for striated muscle contraction, despite the fact that a negative interaction between these 2 genes was detected.	('FGFR4', 'Gene', '2264', (19, 24))	('FGFR4', 'Gene', (19, 24))	('Over-expression', 'Var', (0, 15))	('TNNT1', 'Gene', (57, 62))	('expression', 'MPA', (43, 53))	('stimulate', 'PosReg', (29, 38))	('TNNT1', 'Gene', '7138', (57, 62))
208596	25025207	Low expression of FHL3, RXRG, MYL1 and RND3 may also promote the mutation of TNNT1 genes due to a suppression of the anti-proliferative effects of RA in the RMS cells.	('MYL1', 'Gene', '4632', (30, 34))	('RND3', 'Gene', (39, 43))	('RMS', 'Phenotype', 'HP:0002859', (157, 160))	('RA', 'Chemical', 'MESH:D014212', (147, 149))	('MYL1', 'Gene', (30, 34))	('RXRG', 'Gene', '6258', (24, 28))	('FHL3', 'Gene', '2275', (18, 22))	('FHL3', 'Gene', (18, 22))	('RND3', 'Gene', '390', (39, 43))	('mutation', 'Var', (65, 73))	('TNNT1', 'Gene', (77, 82))	('anti-proliferative effects', 'CPA', (117, 143))	('suppression', 'NegReg', (98, 109))	('RXRG', 'Gene', (24, 28))	('TNNT1', 'Gene', '7138', (77, 82))	('promote', 'PosReg', (53, 60))
208599	25025207	The high expression value in mutated TNNT1 genes suggests that RMS tumors may be congenital.	('RMS tumors', 'Disease', (63, 73))	('RMS', 'Phenotype', 'HP:0002859', (63, 66))	('RMS tumors', 'Disease', 'MESH:D009369', (63, 73))	('TNNT1', 'Gene', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('expression', 'MPA', (9, 19))	('mutated', 'Var', (29, 36))	('TNNT1', 'Gene', '7138', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))
208603	25025207	Over-expression of TNNT2 has been correlated to myocardial stunning in hemodialysis patients, and the disruption of this gene could lead to impaired cardiac development in the embryo and infant.	('cardiac development', 'CPA', (149, 168))	('Over-expression', 'PosReg', (0, 15))	('correlated to', 'Reg', (34, 47))	('TNNT2', 'Gene', '7139', (19, 24))	('patients', 'Species', '9606', (84, 92))	('TNNT2', 'Gene', (19, 24))	('disruption', 'Var', (102, 112))	('infant', 'Species', '9606', (187, 193))	('myocardial stunning', 'Disease', (48, 67))	('impaired', 'NegReg', (140, 148))	('lead to', 'Reg', (132, 139))
208604	25025207	Deficiency of the BIN1 gene has been correlated with cardiomyopathy.	('cardiomyopathy', 'Disease', (53, 67))	('BIN1', 'Gene', '274', (18, 22))	('myopathy', 'Phenotype', 'HP:0003198', (59, 67))	('correlated', 'Reg', (37, 47))	('cardiomyopathy', 'Disease', 'MESH:D009202', (53, 67))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (53, 67))	('BIN1', 'Gene', (18, 22))	('Deficiency', 'Var', (0, 10))
208623	25025207	Mutation of this gene decreases its ability to mediate the expressions of VEGF and PITX2C genes, suggesting that it may play a role in the development of congenital heart disease.	('VEGF', 'Gene', '7422', (74, 78))	('ability', 'MPA', (36, 43))	('congenital heart disease', 'Phenotype', 'HP:0001627', (154, 178))	('PITX2C genes', 'Gene', (83, 95))	('expressions', 'MPA', (59, 70))	('Mutation', 'Var', (0, 8))	('VEGF', 'Gene', (74, 78))	('play', 'Reg', (120, 124))	('congenital heart disease', 'Disease', (154, 178))	('congenital heart', 'Phenotype', 'HP:0001627', (154, 170))	('role', 'Reg', (127, 131))	('decreases', 'NegReg', (22, 31))	('congenital heart disease', 'Disease', 'MESH:D006331', (154, 178))
208626	25025207	Over-expression of this gene promotes metastasis on Ewing tumor.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Ewing tumor', 'Phenotype', 'HP:0012254', (52, 63))	('Ewing tumor', 'Disease', (52, 63))	('Over-expression', 'Var', (0, 15))	('Ewing tumor', 'Disease', 'MESH:C563168', (52, 63))	('promotes', 'PosReg', (29, 37))
208628	25025207	Runx2 is the master regulator of osteoblast differentiation and study reviewed that blockade of this gene by EWS-FLI induce osteoblast specification of a mesenchymal progenitor cell and thus, disrupting interactions between Runx2 and EWS-FLI may promote differentiation of the tumor cell.	('interactions', 'Interaction', (203, 215))	('Runx2', 'Gene', '860', (224, 229))	('FLI', 'Gene', '2314', (238, 241))	('EWS', 'Gene', '2130', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('EWS', 'Phenotype', 'HP:0012254', (234, 237))	('promote', 'PosReg', (246, 253))	('blockade', 'Var', (84, 92))	('EWS', 'Gene', '2130', (234, 237))	('disrupting', 'Var', (192, 202))	('induce', 'PosReg', (117, 123))	('EWS', 'Gene', (109, 112))	('tumor', 'Disease', (277, 282))	('Runx2', 'Gene', (0, 5))	('FLI', 'Gene', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('Runx2', 'Gene', (224, 229))	('EWS', 'Phenotype', 'HP:0012254', (109, 112))	('FLI', 'Gene', (238, 241))	('Runx2', 'Gene', '860', (0, 5))	('FLI', 'Gene', '2314', (113, 116))	('EWS', 'Gene', (234, 237))
208633	25025207	Although its actual function in human SMA is unknown, a study has claimed that the mutation of this gene does not contribute significantly to the cause of human SMA, rather that it associated with chromosomal rearrangement in chronic lymphatic leukemia.	('associated', 'Reg', (181, 191))	('chronic lymphatic leukemia', 'Phenotype', 'HP:0005550', (226, 252))	('lymphatic leukemia', 'Phenotype', 'HP:0005526', (234, 252))	('SMA', 'Phenotype', 'HP:0007269', (161, 164))	('leukemia', 'Phenotype', 'HP:0001909', (244, 252))	('human', 'Species', '9606', (155, 160))	('mutation', 'Var', (83, 91))	('SMA', 'Phenotype', 'HP:0007269', (38, 41))	('human', 'Species', '9606', (32, 37))	('lymphatic leukemia', 'Disease', 'MESH:D015451', (234, 252))	('lymphatic leukemia', 'Disease', (234, 252))
208642	25025207	Deficiency of this gene due to hypoxia leads to an accumulation of GAGs protein in lysosomes, resulting to mucopolysaccharidosis.	('GAGs protein', 'Protein', (67, 79))	('accumulation', 'PosReg', (51, 63))	('mucopolysaccharidosis', 'Disease', 'MESH:D008059', (107, 128))	('hypoxia', 'Disease', (31, 38))	('hypoxia', 'Disease', 'MESH:D000860', (31, 38))	('mucopolysaccharidosis', 'Disease', (107, 128))	('Deficiency', 'Var', (0, 10))
208683	23554566	Locally recurrent or metastatic synovial sarcoma with RECIST defined measurable disease, who failed or refused standard treatment; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; laboratory constraints: absolute neutrophil count >=1.0 x 109/L; hemoglobin >=8 g/dL; platelet count >=75 x 109/L; serum creatinine <=2 mg/dL; ALT, AST <= 5 x institutional upper limit of normal (ULN); alkaline phosphatase, total bilirubin <= 2.5 x ULN.	('ALT', 'MPA', (340, 343))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('total bilirubin', 'MPA', (421, 436))	('AST', 'Gene', (345, 348))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (32, 48))	('alkaline phosphatase', 'MPA', (399, 419))	('>=75', 'Var', (298, 302))	('Oncology', 'Phenotype', 'HP:0002664', (151, 159))	('serum creatinine', 'MPA', (312, 328))	('AST', 'Gene', '26503', (345, 348))
208688	23554566	All patients underwent delayed type hypersensitivity (DTH) skin testing with NY-ESO-1 protein, NY-ESO-1b, and DP4 peptides and had analysis for ANA and human anti-human antibody production (HAHA).	('HAHA', 'Disease', 'None', (190, 194))	('delayed type hypersensitivity', 'Disease', (23, 52))	('human', 'Species', '9606', (163, 168))	('NY-ESO-1b', 'Var', (95, 104))	('human', 'Species', '9606', (152, 157))	('DP4', 'Var', (110, 113))	('HAHA', 'Disease', (190, 194))
208712	22570737	Several sarcomas have specific chromosomal translocations and resultant fusion genes.	('sarcomas', 'Disease', 'MESH:D012509', (8, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('fusion genes', 'Var', (72, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('sarcomas', 'Disease', (8, 16))
208716	22570737	A significant proportion of MLS has a cytogenetic hallmark of chromosomal translocation, t(12;16)(q13;p11).	('MLS', 'Disease', 'MESH:C537466', (28, 31))	('MLS', 'Disease', (28, 31))	('MLS', 'Phenotype', 'HP:0012268', (28, 31))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (89, 106))	('t(12;16)(q13;p11', 'Var', (89, 105))
208717	22570737	This translocation leads to fusion of translocated in liposarcoma (TLS; also known as fused in sarcoma, FUS) and DNA damage-inducible transcript 3 (DDIT3; also known as CCAAT/enhancer-binding protein (C/EBP) homologous protein, CHOP; originally named as growth arrest- and DNA damage- inducible gene 153, GADD153) genes, resulting in the production of the TLS-DDIT3 fusion protein.	('GADD153', 'Gene', '13198', (305, 312))	('fusion', 'Var', (28, 34))	('liposarcoma', 'Phenotype', 'HP:0012034', (54, 65))	('C/EBP', 'Gene', '12606', (201, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('CHOP', 'Gene', '13198', (228, 232))	('translocated in liposarcoma', 'Gene', '233908', (38, 65))	('GADD153', 'Gene', (305, 312))	('FUS', 'Gene', (104, 107))	('TLS-DDIT3', 'Gene', (356, 365))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('DNA damage-inducible transcript 3', 'Gene', '13198', (113, 146))	('sarcoma', 'Disease', (58, 65))	('FUS', 'Gene', '233908', (104, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('DNA damage-inducible transcript 3', 'Gene', (113, 146))	('CHOP', 'Gene', (228, 232))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('sarcoma', 'Disease', (95, 102))	('growth arrest-', 'Phenotype', 'HP:0031164', (254, 268))	('leads to', 'Reg', (19, 27))	('C/EBP', 'Gene', (201, 206))	('translocated in liposarcoma', 'Gene', (38, 65))
208719	22570737	If MLS originates from multipotent mesenchymal cells, EWSR1-DDIT3 may act as an aberrant transcription factor and affect the phenotypic selection of uncommitted target cells.	('MLS', 'Disease', 'MESH:C537466', (3, 6))	('MLS', 'Disease', (3, 6))	('phenotypic selection of uncommitted target cells', 'CPA', (125, 173))	('affect', 'Reg', (114, 120))	('MLS', 'Phenotype', 'HP:0012268', (3, 6))	('EWSR1-DDIT3', 'Var', (54, 65))
208720	22570737	To test this hypothesis, we analyzed whether EWSR1-DDIT3 affected the transcriptional potential of lineage-specific marker genes in mouse multipotent mesenchymal C3H10T1/2 cells.	('affected', 'Reg', (57, 65))	('EWSR1-DDIT3', 'Var', (45, 56))	('transcriptional potential', 'MPA', (70, 95))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (162, 171))	('mouse', 'Species', '10090', (132, 137))
208733	22570737	On the other hand, Ppar-gamma2 promoter activity was not significantly affected by EWSR1-DDIT3 or EWSR1 overexpression, but it was very mildly repressed by wild-type DDIT3 (Figure 2D).	('EWSR1-DDIT3', 'Var', (83, 94))	('Ppar-gamma2', 'Gene', (19, 30))	('Ppar-gamma2', 'Gene', '19016', (19, 30))	('expression', 'Species', '29278', (108, 118))	('EWSR1', 'Gene', (98, 103))	('activity', 'MPA', (40, 48))
208739	22570737	To test the possibility that EWSR1-DDIT3 affects Opn and Col11a2 promoters by binding to potential target sites within them, two forms of mutant EWSR1-DDIT3 expression vectors were generated.	('binding', 'Interaction', (78, 85))	('Opn', 'Gene', (49, 52))	('Col11a2', 'Gene', (57, 64))	('EWSR1-DDIT3', 'Gene', (145, 156))	('mutant', 'Var', (138, 144))	('promoters', 'MPA', (65, 74))	('expression vectors', 'Species', '29278', (157, 175))	('affects', 'Reg', (41, 48))	('rat', 'Species', '10116', (185, 188))
208742	22570737	Consequent cotransfection experiments in C3H10T1/2 cells documented that Opn and Col11a2 promoter activities were significantly increased by overexpression of EWSR1-DDIT3 del LZ or EWSR1-DDIT3 mut LZ than of EWSR1-DDIT3 (Figure 3B and 3C).	('EWSR1-DDIT3 del LZ', 'Var', (159, 177))	('Col11a2', 'Gene', (81, 88))	('Opn', 'Gene', (73, 76))	('expression', 'Species', '29278', (145, 155))	('increased', 'PosReg', (128, 137))	('EWSR1-DDIT3 mut', 'Var', (181, 196))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (41, 50))	('overexpression', 'PosReg', (141, 155))	('DDIT3 del', 'Mutation', 'c.3delDDIT', (165, 174))
208748	22570737	Mutating the inverted CCAAT box in the Opn promoter construct to aaAAT (Opn mut) and the C/EBP half-site in the Col11a2 promoter construct to GCccT (Col11a2 mut) significantly reduced the luciferase activity by 84% and 70%, respectively, when transiently transfected into C3H10T1/2 cells (Figure 4A and 4B).	('Mutating', 'Var', (0, 8))	('activity', 'MPA', (199, 207))	('C/EBP', 'Gene', '12606', (89, 94))	('C/EBP', 'Gene', (89, 94))	('reduced', 'NegReg', (176, 183))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (272, 281))	('luciferase', 'Enzyme', (188, 198))
208749	22570737	In contrast, Ppar-gamma2 promoter activity was not significantly influenced by deleting tandem repeats of C/EBP-binding sites located between -615 to -320, which were shown to mediate glucocorticoid-induced adipocytic differentiation of C3H10T1/2 cells (Figure 4C).	('C3H10T1/2', 'CellLine', 'CVCL:0190', (237, 246))	('C/EBP', 'Gene', (106, 111))	('Ppar-gamma2', 'Gene', (13, 24))	('mediate', 'Reg', (176, 183))	('deleting', 'Var', (79, 87))	('Ppar-gamma2', 'Gene', '19016', (13, 24))	('C/EBP', 'Gene', '12606', (106, 111))
208751	22570737	Further experiments using hMSCs showed that mutating the putative C/EBP-binding sites significantly decreased transcriptional activities from Opn, Col11a2, and Ppar-gamma2 promoters (Figure S1A-C).	('Ppar-gamma2', 'Gene', '19016', (160, 171))	('mutating', 'Var', (44, 52))	('C/EBP', 'Gene', '12606', (66, 71))	('decreased', 'NegReg', (100, 109))	('C/EBP', 'Gene', (66, 71))	('transcriptional activities', 'MPA', (110, 136))	('Ppar-gamma2', 'Gene', (160, 171))
208756	22570737	Importantly, mutation of the potential C/EBP site within each construct eliminated the binding of wild-type EWSR1-DDIT3 to the promoter.	('mutation', 'Var', (13, 21))	('binding', 'Interaction', (87, 94))	('eliminated', 'NegReg', (72, 82))	('C/EBP', 'Gene', '12606', (39, 44))	('C/EBP', 'Gene', (39, 44))
208759	22570737	Based on our earlier observations showing the critical role of C/EBP-binding sites within Opn and Col11a2 promoters for gene transcription in innate mouse multipotent mesenchymal C3H10T1/2 cells and in vivo binding of EWSR1-DDIT3 to C/EBP-binding sites within Opn and Col11a2 promoters, we speculated that EWSR1-DDIT3 might affect the function of endogenous C/EBP protein family of transcription factors.	('C3H10T1/2', 'CellLine', 'CVCL:0190', (179, 188))	('function', 'MPA', (335, 343))	('affect', 'Reg', (324, 330))	('EWSR1-DDIT3', 'Var', (306, 317))	('C/EBP', 'Gene', '12606', (63, 68))	('C/EBP', 'Gene', '12606', (233, 238))	('C/EBP', 'Gene', (233, 238))	('C/EBP', 'Gene', (63, 68))	('C/EBP', 'Gene', '12606', (358, 363))	('mouse', 'Species', '10090', (149, 154))	('C/EBP', 'Gene', (358, 363))
208765	22570737	Collectively, these data could indicate that EWSR1-DDIT3 represses Opn and Col11a2 gene transcription by interfering, at least in part, with endogenous C/EBPbeta function.	('EWSR1-DDIT3', 'Var', (45, 56))	('C/EBPbeta', 'Gene', (152, 161))	('endogenous', 'MPA', (141, 151))	('Opn', 'Gene', (67, 70))	('C/EBPbeta', 'Gene', '12608', (152, 161))	('interfering', 'NegReg', (105, 116))	('represses', 'NegReg', (57, 66))	('transcription', 'MPA', (88, 101))	('Col11a2 gene', 'Gene', (75, 87))
208772	22570737	This observation implies that EWSR1-DDIT3 may interfere with HAT activity of certain promoters at the site of transcription in C3H10T1/2 cells.	('promoters', 'MPA', (85, 94))	('HAT activity', 'MPA', (61, 73))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (127, 136))	('EWSR1-DDIT3', 'Var', (30, 41))	('interfere', 'NegReg', (46, 55))
208782	22570737	The ratio of acetylated H3K9 to trimethylated H3K9 around Opn and Col11a2 promoter segments was significantly decreased by EWSR1-DDIT3 (Figure 9C), which reflected epigenetic silencing of gene transcription.	('acetylated', 'MPA', (13, 23))	('Col11a2', 'Gene', (66, 73))	('decreased', 'NegReg', (110, 119))	('rat', 'Species', '10116', (4, 7))	('EWSR1-DDIT3', 'Var', (123, 134))
208785	22570737	In this study, we showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells.	('transcriptional activity', 'MPA', (159, 183))	('repressed', 'NegReg', (145, 154))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (46, 64))	('liposarcoma', 'Phenotype', 'HP:0012034', (53, 64))	('myxoid liposarcoma', 'Disease', (46, 64))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (249, 258))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (46, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('EWSR1-DDIT3', 'Var', (34, 45))
208805	22570737	Variants of pGL3-Opn (pGL3-Opn mut) and pGL3-Col11a2 (pGL3-Col11a2 mut) were created by mutating potential C/EBP-binding sites using the Gene Editor  Site-Directed Mutagenesis kit (Promega), and successful mutagenesis was confirmed by DNA sequencing.	('Variants', 'Var', (0, 8))	('pGL3-Opn', 'Gene', '20750', (12, 20))	('pGL3-Col11a2', 'Gene', (40, 52))	('pGL3-Opn', 'Gene', '20750', (22, 30))	('mutating', 'Var', (88, 96))	('C/EBP', 'Gene', '12606', (107, 112))	('C/EBP', 'Gene', (107, 112))	('pGL3-Opn', 'Gene', (12, 20))	('pGL3-Opn', 'Gene', (22, 30))
208811	22570737	Two forms of mutant EWSR1-DDIT3 expression vectors were generated by mutating pFLG-CMV4 EWSR1-DDIT3 using the Gene Editor  Site-Directed Mutagenesis kit (Promega), and successful mutagenesis was confirmed by DNA sequencing.	('mutating', 'Var', (69, 77))	('CMV4', 'Gene', (83, 87))	('expression vectors', 'Species', '29278', (32, 50))	('rat', 'Species', '10116', (60, 63))	('CMV4', 'Gene', '100035301', (83, 87))	('EWSR1-DDIT3', 'Gene', (88, 99))
208812	22570737	pFLAG-CMV4 EWSR1-DDIT3 del LZ contained a stop codon just 5' to the codon for the first leucine residue of the dimer forming LZ domain, so that the entire LZ domain, composed of 38 C-terminal amino acid residues, was deleted.	('DDIT3 del', 'Mutation', 'c.3delDDIT', (17, 26))	('CMV4', 'Gene', (6, 10))	('deleted', 'Var', (217, 224))	('CMV4', 'Gene', '100035301', (6, 10))	('leucine', 'Chemical', 'MESH:D007930', (88, 95))
209026	23739700	These include variants associated with ectatic lymphatics (as lymphangioma-like and lymphangiectatic KS), and variants with subepidermal and intraepidermal edema (as bullous KS).	('ectatic lymphatics', 'Phenotype', 'HP:0001004', (39, 57))	('lymphangioma', 'Disease', (62, 74))	('KS', 'Phenotype', 'HP:0100726', (174, 176))	('ectatic lymphatics', 'Disease', (39, 57))	('lymphangioma', 'Disease', 'MESH:D008202', (62, 74))	('variants', 'Var', (14, 22))	('variants', 'Var', (110, 118))	('edema', 'Phenotype', 'HP:0000969', (156, 161))	('lymphangioma', 'Phenotype', 'HP:0100764', (62, 74))	('KS', 'Phenotype', 'HP:0100726', (101, 103))	('associated', 'Reg', (23, 33))
209053	23984145	Cytogenetics contribute greatly to the diagnosis of SS as 90% harbour a specific translocation between the SYT gene on chromosome 18 and either the SSX1 or SSX2 gene on the X chromosome.	('translocation', 'Var', (81, 94))	('SSX2', 'Gene', (156, 160))	('SYT', 'Gene', (107, 110))	('SS', 'Phenotype', 'HP:0100242', (52, 54))	('SYT', 'Gene', '6760', (107, 110))	('SSX1', 'Gene', '6756', (148, 152))	('SS', 'Phenotype', 'HP:0100242', (148, 150))	('SSX2', 'Gene', '6757', (156, 160))	('SSX1', 'Gene', (148, 152))	('SS', 'Phenotype', 'HP:0100242', (156, 158))
209062	23880362	Deregulation of P53- Retinoblastoma-, PI3K-AKT-and MAPK pathways has been implicated in transformation of MSCs.	('MSCs', 'Disease', (106, 110))	('Deregulation', 'Var', (0, 12))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (21, 35))	('AKT', 'Gene', '11651', (43, 46))	('implicated', 'Reg', (74, 84))	('MAPK pathways', 'Pathway', (51, 64))	('AKT', 'Gene', (43, 46))	('Retinoblastoma', 'Disease', 'MESH:D012175', (21, 35))	('Retinoblastoma', 'Disease', (21, 35))
209080	23880362	Transformation of mouse MSCs has been induced by an array of manipulations, including knockout of tumour suppressor genes, overexpression of oncogenes and drug administration to affect signaling pathways.	('knockout', 'Var', (86, 94))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('mouse', 'Species', '10090', (18, 23))	('signaling pathways', 'Pathway', (185, 203))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('rat', 'Species', '10116', (168, 171))	('induced', 'Reg', (38, 45))	('affect', 'Reg', (178, 184))
209082	23880362	In one study, loss of tumour suppressor P21 and Tp53 in mouse adipose derived MSCs (AMSC) induced in vitro transformation and in vivo so-called fibrosarcoma formation after transplantation.	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('loss', 'Var', (14, 18))	('tumour', 'Disease', (22, 28))	('mouse', 'Species', '10090', (56, 61))	('Tp53', 'Gene', (48, 52))	('fibrosarcoma', 'Disease', (144, 156))	('P21', 'Gene', '12575', (40, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('Tp53', 'Gene', '22059', (48, 52))	('P21', 'Gene', (40, 43))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('induced', 'Reg', (90, 97))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (144, 156))	('fibrosarcoma', 'Disease', 'MESH:D005354', (144, 156))
209087	23880362	A conditional mouse model with Tp53 homozygous deletion has been created by crossing Prx1-Cre transgenic mice to mice bearing alleles of Tp53 flanked by loxP.	('Tp53', 'Gene', (137, 141))	('transgenic mice', 'Species', '10090', (94, 109))	('mouse', 'Species', '10090', (14, 19))	('Tp53', 'Gene', '22059', (137, 141))	('Tp53', 'Gene', (31, 35))	('deletion', 'Var', (47, 55))	('Tp53', 'Gene', '22059', (31, 35))	('mice', 'Species', '10090', (113, 117))	('mice', 'Species', '10090', (105, 109))
209091	23880362	However, loss of RB accelerated tumorigenesis in P53-deficient mice.	('tumorigenesis', 'CPA', (32, 45))	('rat', 'Species', '10116', (26, 29))	('mice', 'Species', '10090', (63, 67))	('RB', 'Chemical', 'MESH:D012413', (17, 19))	('loss', 'Var', (9, 13))	('accelerated', 'PosReg', (20, 31))
209096	23880362	The Fos overexpression transgenic mice resulted in the development of bone tumours, with chondrosarcomas as the main type.	('overexpression', 'PosReg', (8, 22))	('chondrosarcomas', 'Disease', 'MESH:D002813', (89, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('bone tumours', 'Disease', 'MESH:D001859', (70, 82))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (89, 103))	('chondrosarcomas', 'Disease', (89, 104))	('Fos', 'Gene', (4, 7))	('bone tumour', 'Phenotype', 'HP:0010622', (70, 81))	('transgenic', 'Var', (23, 33))	('transgenic mice', 'Species', '10090', (23, 38))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (89, 104))	('bone tumours', 'Disease', (70, 82))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
209111	23880362	For instance, the introduction of SV40-LT, which perturbs both P53 and RB proteins potently promoted human MSC transformation.	('P53', 'Protein', (63, 66))	('RB', 'Chemical', 'MESH:D012413', (71, 73))	('RB proteins', 'Protein', (71, 82))	('promoted', 'PosReg', (92, 100))	('SV40-LT', 'Var', (34, 41))	('human', 'Species', '9606', (101, 106))	('human MSC', 'Disease', (101, 110))
209117	23880362	Based on genetic profiles, sarcomas can be categorized into two groups, one with relatively simple genetic alterations, either being associated with point mutations or reciprocal translocations, and the other with extensive genetic changes.	('rat', 'Species', '10116', (111, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcomas', 'Disease', (27, 35))	('point mutations', 'Var', (149, 164))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))	('associated', 'Reg', (133, 143))
209127	23880362	It is a type of a poorly differentiated tumour known to be associated with a the expression of EWSR1-ETS fusions or rarely other chimeras.	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (40, 46))	('fusions', 'Var', (105, 112))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('EWSR1-ETS', 'Gene', (95, 104))
209132	23880362	Moreover, the knockdown of EWS-FLI1 expression in Ewing sarcoma cell lines restored the in vitro trilineage differentiation ability of the cells.	('restored', 'PosReg', (75, 83))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (50, 63))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (50, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('EWS-FLI1', 'Gene', (27, 35))	('knockdown', 'Var', (14, 23))	('Ewing sarcoma', 'Disease', (50, 63))
209148	23880362	On the other hand, fusion gene silencing in primary synovial sarcoma cells restored both the trilineage differentiation capacity and the MSC marker expression, strongly suggesting cells of MSC lineage as the origin of synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (52, 68))	('restored', 'PosReg', (75, 83))	('synovial sarcoma', 'Disease', (218, 234))	('fusion gene silencing', 'Var', (19, 40))	('synovial sarcoma', 'Disease', 'MESH:D013584', (52, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('trilineage differentiation capacity', 'CPA', (93, 128))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (218, 234))	('synovial sarcoma', 'Disease', 'MESH:D013584', (218, 234))	('synovial sarcoma', 'Disease', (52, 68))	('expression', 'MPA', (148, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
209153	23880362	A third soft tissue sarcoma model is that of clear cell sarcoma, characterized by melanoma-like features and an EWSR1/ATF1 translocation.	('translocation', 'Var', (123, 136))	('sarcoma', 'Disease', (20, 27))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (45, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcoma', 'Disease', (56, 63))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('EWSR1/ATF1', 'Gene', (112, 122))	('melanoma', 'Disease', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('clear cell sarcoma', 'Disease', (45, 63))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (8, 27))
209154	23880362	Conditional expression of the human EWSR1/ATF1 fusion gene in mouse gives rise to tumorigenesis with extreme brief latency.	('human', 'Species', '9606', (30, 35))	('fusion', 'Var', (47, 53))	('mouse', 'Species', '10090', (62, 67))	('tumorigenesis', 'CPA', (82, 95))	('EWSR1/ATF1', 'Gene', (36, 46))
209266	31927711	Postoperative pathological shows left breast invasive carcinoma, non-specific, histologic grade II, scores 7 (glandular component scores 3, nuclear atypia scores 2, fission scores 2) (modified black nuclear classification method).	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (38, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('breast invasive carcinoma', 'Disease', (38, 63))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (38, 63))	('scores 7', 'Var', (100, 108))
209294	31927711	The relative risk of radiation doses above 44 Gy is 30.6 compared to doses below 15 Gy.The incidence of radiosarcoma is also affected by a variety of other factors, such as BRCA1 gene mutations, hereditary diseases (such as Gardner syndrome and Li-Fraumeni syndrome), chemotherapy with alkylating agents.	('Gardner syndrome', 'Disease', 'MESH:D005736', (224, 240))	('Gardner syndrome', 'Disease', (224, 240))	('affected by', 'Reg', (125, 136))	('mutations', 'Var', (184, 193))	('radiosarcoma', 'Disease', 'None', (104, 116))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (245, 265))	('BRCA1', 'Gene', '672', (173, 178))	('hereditary diseases', 'Disease', (195, 214))	('Li-Fraumeni syndrome', 'Disease', (245, 265))	('radiosarcoma', 'Disease', (104, 116))	('BRCA1', 'Gene', (173, 178))	('hereditary diseases', 'Disease', 'MESH:D030342', (195, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))
209301	31927711	In most cases, post-radiation leiomyosarcoma is different from other breast or thoracic wall sarcomas, and it is less invasive and has a better prognosis.	('post-radiation', 'Var', (15, 29))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('leiomyosarcoma', 'Disease', (30, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (30, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcomas', 'Disease', (93, 101))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (30, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
209317	32257368	Role of rat sarcoma virus mutations in cancer and potential target for cancer therapy The prevalence of oncogenic rat sarcoma virus (RAS) mutations has made RAS a popular target for cancer therapies.	('RAS', 'Gene', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (71, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('rat sarcoma virus', 'Species', '11848', (114, 131))	('RAS', 'Gene', 'None', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('cancer', 'Disease', (182, 188))	('RAS', 'Gene', 'None', (157, 160))	('rat sarcoma virus', 'Species', '11848', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('RAS', 'Gene', (133, 136))	('mutations', 'Var', (138, 147))
209318	32257368	Significant discoveries have been reported regarding cancer molecular biology following the study of RAS mutations.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('RAS', 'Gene', 'None', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('RAS', 'Gene', (101, 104))	('mutations', 'Var', (105, 114))
209322	32257368	Therefore, the development of targeted therapies will require a detailed understanding of the properties and dependencies of specific cancers to a RAS mutation.	('RAS', 'Gene', (147, 150))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('mutation', 'Var', (151, 159))	('cancers', 'Disease', (134, 141))	('RAS', 'Gene', 'None', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
209323	32257368	This review provides an overview of RAS mutations and their relationship with cancer and discusses their potential as therapeutic targets.	('RAS', 'Gene', 'None', (36, 39))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (40, 49))	('RAS', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
209325	32257368	Significant discoveries regarding genetic mutations have provided new opportunities for development of targeted cancer therapies.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (112, 118))
209332	32257368	A point-mutated RAS keeps the molecule in an active, GTP-bound state, causing abnormal cell signaling.	('causing', 'Reg', (70, 77))	('RAS', 'Gene', 'None', (16, 19))	('point-mutated', 'Var', (2, 15))	('cell', 'CPA', (87, 91))	('RAS', 'Gene', (16, 19))	('GTP', 'Chemical', 'MESH:D006160', (53, 56))
209337	32257368	The guanine nucleotide exchange factors (GEFs) carry GTP to the RAS molecule, which becomes activated upon the changing of GDP for GTP.	('changing', 'Var', (111, 119))	('RAS', 'Gene', 'None', (64, 67))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (4, 22))	('GTP', 'Chemical', 'MESH:D006160', (131, 134))	('GTP', 'Chemical', 'MESH:D006160', (53, 56))	('RAS', 'Gene', (64, 67))	('GDP', 'Chemical', 'MESH:D006153', (123, 126))
209339	32257368	RAS mutations also cause an accumulation of reactive oxygen species, leading to DNA damage in cells.	('DNA damage', 'MPA', (80, 90))	('RAS', 'Gene', (0, 3))	('reactive oxygen species', 'MPA', (44, 67))	('accumulation', 'PosReg', (28, 40))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (44, 67))	('mutations', 'Var', (4, 13))	('RAS', 'Gene', 'None', (0, 3))	('leading to', 'Reg', (69, 79))
209340	32257368	The cell checkpoint feature that typically inhibit cells with DNA damage from proceeding to mitosis does not function in the light of the RAS mutation, allowing genetically injured cells to proceed through the G1 and G2 phases of cell growth.	('mutation', 'Var', (142, 150))	('RAS', 'Gene', 'None', (138, 141))	('RAS', 'Gene', (138, 141))
209341	32257368	The cells that lack the p53 tumor suppressor gene are particularly affected by these consequences of RAS mutations, as p53 functions against the RAS oncogene.	('tumor', 'Disease', (28, 33))	('affected', 'Reg', (67, 75))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('RAS', 'Gene', 'None', (101, 104))	('RAS', 'Gene', (145, 148))	('p53', 'Gene', '7157', (119, 122))	('RAS', 'Gene', (101, 104))	('mutations', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('p53', 'Gene', (119, 122))	('RAS', 'Gene', 'None', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
209342	32257368	It has been determined that RAS mutations are more prevalent in certain cancers but less likely associated with others, such as breast cancer.	('prevalent', 'Reg', (51, 60))	('RAS', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (32, 41))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('breast cancer', 'Disease', (128, 141))	('cancers', 'Disease', (72, 79))	('RAS', 'Gene', 'None', (28, 31))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
209348	32257368	However, the mutant K-RAS gene produces high levels of the P19ARF tumor suppressor gene that activates the p53 tumor suppressor gene, which leads to cellular apoptosis.	('mutant', 'Var', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('leads to', 'Reg', (140, 148))	('activates', 'PosReg', (93, 102))	('tumor', 'Disease', (66, 71))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('cellular apoptosis', 'CPA', (149, 167))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
209350	32257368	Colon, pancreatic and lung cancers are prime examples for K-RAS mutations.	('pancreatic', 'Disease', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('lung cancers', 'Disease', 'MESH:D008175', (22, 34))	('lung cancers', 'Phenotype', 'HP:0100526', (22, 34))	('Colon', 'Disease', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('mutations', 'Var', (64, 73))	('pancreatic', 'Disease', 'MESH:D010195', (7, 17))	('lung cancers', 'Disease', (22, 34))
209352	32257368	In a colon cancer mouse model, K-RAS, and not N-RAS, was able to proliferate epithelial colon cancer.	('N-RAS', 'Gene', (46, 51))	('rat', 'Species', '10116', (72, 75))	('proliferate', 'CPA', (65, 76))	('colon cancer', 'Phenotype', 'HP:0003003', (88, 100))	('colon cancer', 'Disease', 'MESH:D015179', (5, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (5, 17))	('mouse', 'Species', '10090', (18, 23))	('N-RAS', 'Gene', '4893', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('colon cancer', 'Disease', 'MESH:D015179', (88, 100))	('epithelial colon cancer', 'Disease', (77, 100))	('colon cancer', 'Disease', (5, 17))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('K-RAS', 'Var', (31, 36))	('epithelial colon cancer', 'Disease', 'MESH:D015179', (77, 100))
209354	32257368	Although the isoforms exhibit a high degree of similarity, K-RAS has been shown to be the most frequently mutated isoform in most cancers; for example, 90% of pancreatic tumors harbor K-RAS mutations.	('pancreatic tumors', 'Disease', 'MESH:D010190', (159, 176))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancers', 'Disease', (130, 137))	('mutations', 'Var', (190, 199))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('K-RAS', 'Protein', (184, 189))	('pancreatic tumors', 'Disease', (159, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (159, 176))
209355	32257368	By contrast, N-RAS mutations are strongly associated with hematopoietic tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (58, 78))	('associated', 'Reg', (42, 52))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('hematopoietic tumors', 'Disease', (58, 78))	('N-RAS', 'Gene', (13, 18))	('N-RAS', 'Gene', '4893', (13, 18))
209365	32257368	The inactivity of GAP results in a buildup of RAS-GTP.	('RAS-GTP', 'Chemical', '-', (46, 53))	('RAS-GTP', 'MPA', (46, 53))	('inactivity', 'Var', (4, 14))	('buildup', 'PosReg', (35, 42))
209368	32257368	Approximately 30% of all human tumors express a mutant form of RAS that is locked in the active form as result of being insensitive to GAPs.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutant', 'Var', (48, 54))	('RAS', 'Gene', (63, 66))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('human', 'Species', '9606', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('human', 'Disease', (25, 30))	('RAS', 'Gene', 'None', (63, 66))
209371	32257368	An additional accumulation of GEFs allows for the removal of GDP and the addition of GTP to RAS, which can then hyper-activate downstream proteins in its pathway.	('GTP', 'Chemical', 'MESH:D006160', (85, 88))	('GDP', 'Chemical', 'MESH:D006153', (61, 64))	('RAS', 'Gene', 'None', (92, 95))	('GDP', 'Var', (61, 64))	('hyper-activate', 'PosReg', (112, 126))	('downstream proteins in its pathway', 'Pathway', (127, 161))	('RAS', 'Gene', (92, 95))
209377	32257368	The various cancers related to RAS mutations include non-small-cell lung carcinoma, colorectal carcinoma and pancreatic carcinoma.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('RAS', 'Gene', (31, 34))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (57, 82))	('cancers', 'Disease', (12, 19))	('colorectal carcinoma', 'Disease', (84, 104))	('pancreatic carcinoma', 'Disease', (109, 129))	('lung carcinoma', 'Disease', 'MESH:D008175', (68, 82))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (109, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('lung carcinoma', 'Disease', (68, 82))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (84, 104))	('RAS', 'Gene', 'None', (31, 34))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (53, 82))	('mutations', 'Var', (35, 44))
209378	32257368	For K-RAS, they are caused by a substitution of the amino acid glycine by aspartate or valine at codon 12 and by aspartate at codon 13 on the exon 1 fragment of the K-RAS gene.	('substitution', 'Var', (32, 44))	('K-RAS', 'Gene', (4, 9))	('valine', 'Chemical', 'MESH:D014633', (87, 93))	('aspartate', 'Chemical', 'MESH:D001224', (74, 83))	('glycine', 'Chemical', 'MESH:D005998', (63, 70))	('aspartate', 'Chemical', 'MESH:D001224', (113, 122))	('caused by', 'Reg', (20, 29))
209379	32257368	The K-RAS mutations are present in a significant amount of colorectal cancers, while N-RAS mutations are only present in a small amount of cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('N-RAS', 'Gene', (85, 90))	('colorectal cancers', 'Disease', 'MESH:D015179', (59, 77))	('K-RAS mutations', 'Var', (4, 19))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('colorectal cancers', 'Disease', (59, 77))	('N-RAS', 'Gene', '4893', (85, 90))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
209380	32257368	Both K-RAS and N-RAS mutations affect codons 12, 13 and 61 in colorectal cancer.	('affect', 'Reg', (31, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('N-RAS', 'Gene', (15, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('N-RAS', 'Gene', '4893', (15, 20))	('K-RAS', 'Protein', (5, 10))	('colorectal cancer', 'Disease', (62, 79))	('codons 12', 'Var', (38, 47))	('mutations', 'Var', (21, 30))
209381	32257368	The RAS mutations at these sites commonly inhibit binding between RAS and GAPs, thus preventing GTP hydrolysis.	('RAS', 'Gene', 'None', (66, 69))	('RAS', 'Gene', (4, 7))	('RAS', 'Gene', (66, 69))	('GTP hydrolysis', 'MPA', (96, 110))	('GAPs', 'Protein', (74, 78))	('mutations', 'Var', (8, 17))	('GTP', 'Chemical', 'MESH:D006160', (96, 99))	('RAS', 'Gene', 'None', (4, 7))	('preventing', 'NegReg', (85, 95))	('inhibit', 'NegReg', (42, 49))	('binding', 'Interaction', (50, 57))
209382	32257368	In mice, it has been shown that acute myeloid leukemia may be induced through oncogenic K-RAS as well as a deficiency of the Nf1 gene.	('myeloid leukemia', 'Disease', (38, 54))	('mice', 'Species', '10090', (3, 7))	('Nf1', 'Gene', '4763', (125, 128))	('deficiency', 'Var', (107, 117))	('induced', 'Reg', (62, 69))	('Nf1', 'Gene', (125, 128))	('myeloid leukemia', 'Disease', 'MESH:D007951', (38, 54))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (38, 54))	('leukemia', 'Phenotype', 'HP:0001909', (46, 54))	('K-RAS', 'Protein', (88, 93))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (32, 54))
209390	32257368	The results of the study concluded that melanoma cells featuring RAS mutations had an increase in phosphorylated, active CAS protein distribution to the cytoplasm of the cells.	('mutations', 'Var', (69, 78))	('increase', 'PosReg', (86, 94))	('RAS', 'Gene', (65, 68))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('CAS', 'Gene', '1434', (121, 124))	('phosphorylated', 'MPA', (98, 112))	('CAS', 'Gene', (121, 124))	('RAS', 'Gene', 'None', (65, 68))
209394	32257368	Ovarian cancers of the epithelial tissue form are linked to RAS mutations as well.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('RAS', 'Gene', 'None', (60, 63))	('linked', 'Reg', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (64, 73))	('Ovarian cancers', 'Phenotype', 'HP:0100615', (0, 15))	('RAS', 'Gene', (60, 63))
209395	32257368	There is evidence of K-RAS mutations, varying in the degree of prevalence, in ovarian carcinomas and borderline tumors, varying in the degree of prevalence in these cancers.	('mutations', 'Var', (27, 36))	('K-RAS', 'Protein', (21, 26))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (78, 96))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ovarian carcinomas', 'Disease', (78, 96))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('cancers', 'Disease', (165, 172))	('tumors', 'Disease', (112, 118))
209396	32257368	Studies suggest that K-RAS mutations are a common early occurrence in ovarian tumor formation.	('mutations', 'Var', (27, 36))	('K-RAS', 'Protein', (21, 26))	('ovarian tumor', 'Disease', 'MESH:D010051', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ovarian tumor', 'Disease', (70, 83))	('ovarian tumor', 'Phenotype', 'HP:0100615', (70, 83))
209397	32257368	K-RAS mutations then stimulate the RAS downstream cellular signaling pathway.	('RAS', 'Gene', 'None', (2, 5))	('RAS', 'Gene', (35, 38))	('stimulate', 'PosReg', (21, 30))	('RAS', 'Gene', (2, 5))	('RAS', 'Gene', 'None', (35, 38))	('mutations', 'Var', (6, 15))
209398	32257368	Type 1 ovarian cancers typically exhibit K-RAS mutations, while type 2 ovarian cancers do not exhibit RAS mutations but are associated with mutations in TP53 gene.	('ovarian cancer', 'Phenotype', 'HP:0100615', (7, 21))	('TP53', 'Gene', '7157', (153, 157))	('Type 1 ovarian cancers', 'Disease', (0, 22))	('RAS', 'Gene', (102, 105))	('mutations', 'Var', (47, 56))	('RAS', 'Gene', 'None', (43, 46))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('ovarian cancers', 'Phenotype', 'HP:0100615', (71, 86))	('type 2 ovarian cancers', 'Disease', 'MESH:C564499', (64, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('associated', 'Reg', (124, 134))	('ovarian cancers', 'Phenotype', 'HP:0100615', (7, 22))	('exhibit', 'Reg', (33, 40))	('mutations', 'Var', (140, 149))	('TP53', 'Gene', (153, 157))	('RAS', 'Gene', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('Type 1 ovarian cancers', 'Disease', 'OMIM:233300', (0, 22))	('type 2 ovarian cancers', 'Disease', (64, 86))	('RAS', 'Gene', 'None', (102, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))
209399	32257368	Hepatocellular carcinoma is another cancer of interest with regards to RAS mutation and the RAS pathway dysfunction.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('RAS', 'Gene', 'None', (71, 74))	('mutation', 'Var', (75, 83))	('cancer', 'Disease', (36, 42))	('RAS', 'Gene', 'None', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('RAS', 'Gene', (71, 74))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('RAS', 'Gene', (92, 95))
209401	32257368	A significant amount of cases of hepatocellular carcinoma are attributed to a B-Raf gene mutation or deletion, which subsequently activates an oncogenic RAS, as well as K-RAS, H-RAS and N-RAS mutations.	('B-Raf', 'Gene', '673', (78, 83))	('RAS', 'Gene', 'None', (178, 181))	('oncogenic', 'MPA', (143, 152))	('RAS', 'Gene', 'None', (171, 174))	('hepatocellular carcinoma', 'Disease', (33, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('RAS', 'Gene', (188, 191))	('N-RAS', 'Gene', '4893', (186, 191))	('RAS', 'Gene', (178, 181))	('RAS', 'Gene', (171, 174))	('deletion', 'Var', (101, 109))	('B-Raf', 'Gene', (78, 83))	('H-RAS', 'Gene', (176, 181))	('mutation', 'Var', (89, 97))	('RAS', 'Gene', 'None', (153, 156))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (33, 57))	('activates', 'PosReg', (130, 139))	('H-RAS', 'Gene', '3265', (176, 181))	('N-RAS', 'Gene', (186, 191))	('RAS', 'Gene', 'None', (188, 191))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (33, 57))	('RAS', 'Gene', (153, 156))
209402	32257368	The prevalence of oncogenic RAS mutations has made RAS a popular target for cancer therapies.	('RAS', 'Gene', 'None', (51, 54))	('RAS', 'Gene', (51, 54))	('RAS', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (32, 41))	('RAS', 'Gene', 'None', (28, 31))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
209403	32257368	Significant discoveries are reported regarding cancer molecular biology as a result of the study of oncogenic RAS mutations.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('mutations', 'Var', (114, 123))	('cancer', 'Disease', (47, 53))	('RAS', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('RAS', 'Gene', 'None', (110, 113))
209405	32257368	RAS mutations are one of the most common oncogenic drivers in human cancer and there are ongoing efforts to find a clinically effective Ras inhibitor.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('RAS', 'Gene', (0, 3))	('human', 'Species', '9606', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('mutations', 'Var', (4, 13))	('RAS', 'Gene', 'None', (0, 3))
209410	32257368	A structural study has taught that guanosine nucleotides dictate these states primarily by altering the conformation of two dynamic loops within the RAS proteins called switch I and switch II.	('conformation', 'MPA', (104, 116))	('RAS', 'Gene', (149, 152))	('dictate', 'Reg', (57, 64))	('guanosine', 'Var', (35, 44))	('altering', 'Reg', (91, 99))	('RAS', 'Gene', 'None', (149, 152))	('guanosine nucleotides', 'Chemical', '-', (35, 56))
209411	32257368	Furthermore, the most common RAS mutations occur at codons 12, 13 and 61.	('RAS', 'Gene', 'None', (29, 32))	('RAS', 'Gene', (29, 32))	('mutations', 'Var', (33, 42))
209412	32257368	These mutations surround the guanine nucleotide-binding pocket suggesting that the most common mechanism by which activating RAS mutations function is to influence aspects of how nucleotides interact with RAS, be it binding, exchange, hydrolysis or control of protein dynamics.	('hydrolysis', 'MPA', (235, 245))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (29, 47))	('binding', 'Interaction', (216, 223))	('RAS', 'Gene', 'None', (205, 208))	('RAS', 'Gene', 'None', (125, 128))	('exchange', 'MPA', (225, 233))	('mutations', 'Var', (129, 138))	('influence', 'Reg', (154, 163))	('nucleotides interact', 'MPA', (179, 199))	('activating', 'PosReg', (114, 124))	('RAS', 'Gene', (125, 128))	('RAS', 'Gene', (205, 208))	('protein', 'Protein', (260, 267))	('mutations', 'Var', (6, 15))
209413	32257368	If the mechanisms that underlie the functional classes of RAS mutations can be defined, it follows that strategies to address these classes may be customized.	('RAS', 'Gene', 'None', (58, 61))	('RAS', 'Gene', (58, 61))	('mutations', 'Var', (62, 71))	('rat', 'Species', '10116', (106, 109))
209420	32257368	One study has demonstrated that the combination of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as well as MEK inhibitors is an effective drug combination therapy.	('PARP', 'Gene', (98, 102))	('MEK', 'Gene', (126, 129))	('MEK', 'Gene', '5609', (126, 129))	('rat', 'Species', '10116', (21, 24))	('inhibitors', 'Var', (104, 114))
209421	32257368	Both inhibitors function harmoniously to induce cellular apoptosis in tumors exhibiting RAS mutations.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('RAS', 'Gene', 'None', (88, 91))	('induce', 'PosReg', (41, 47))	('mutations', 'Var', (92, 101))	('tumors', 'Disease', (70, 76))	('cellular apoptosis', 'CPA', (48, 66))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('RAS', 'Gene', (88, 91))
209439	32257368	Research using organoids of K-RAS-related colon cancer showed that drug combination therapy of Afatinib and Selumetinib was partially successful in K-RAS-mutated colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('Afatinib', 'Chemical', 'MESH:D000077716', (95, 103))	('colon cancer', 'Disease', (162, 174))	('K-RAS-mutated', 'Var', (148, 161))	('Selumetinib', 'Chemical', 'MESH:C517975', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (162, 174))	('colon cancer', 'Disease', 'MESH:D015179', (162, 174))	('colon cancer', 'Disease', (42, 54))
209447	32257368	The frequency of RAS mutations is among the highest for any gene in human cancers and development of inhibitors of Ras-mitogen activated protein kinase pathway as potential anticancer agents is a very promising pharmacologic strategy.	('rat', 'Species', '10116', (227, 230))	('cancer', 'Disease', (177, 183))	('human', 'Species', '9606', (68, 73))	('RAS', 'Gene', (17, 20))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Disease', (74, 80))	('cancers', 'Disease', (74, 81))	('RAS', 'Gene', 'None', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (21, 30))
209451	32257368	Therefore, the development of targeted therapies will require a detailed understanding of the properties and dependencies of specific cancer to RAS mutation.	('RAS', 'Gene', (144, 147))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('RAS', 'Gene', 'None', (144, 147))	('mutation', 'Var', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
209454	32257368	Prevalence of RAS (rat sarcoma virus) protein mutations has provided a popular target for the development of novel cancer therapeutics.	('cancer', 'Disease', (115, 121))	('mutations', 'Var', (46, 55))	('RAS', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rat sarcoma virus', 'Species', '11848', (19, 36))	('RAS', 'Gene', 'None', (14, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
209455	32257368	Mutations in the RAS protein in the different types of cancers are discussed.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('RAS', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Mutations', 'Var', (0, 9))	('RAS', 'Gene', 'None', (17, 20))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
209465	30610505	Cell cycle arrest was observed at G0/G1 (TA) or G2/M (VCR and TA+VCR).	('VCR', 'Chemical', 'MESH:D014750', (54, 57))	('VCR', 'Chemical', 'MESH:D014750', (65, 68))	('Cell cycle arrest', 'Phenotype', 'HP:0011018', (0, 17))	('Cell cycle arrest', 'CPA', (0, 17))	('G2/M', 'Var', (48, 52))
209473	30610505	VCR is known to induce G2-M cell cycle arrest accompanied by rise and fall of Cyclin B1.	('fall', 'NegReg', (70, 74))	('VCR', 'Chemical', 'MESH:D014750', (0, 3))	('Cyclin B1', 'Gene', '891', (78, 87))	('G2-M cell cycle arrest', 'CPA', (23, 45))	('VCR', 'Var', (0, 3))	('fall', 'Phenotype', 'HP:0002527', (70, 74))	('rise', 'PosReg', (61, 65))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (28, 45))	('Cyclin B1', 'Gene', (78, 87))
209555	30610505	Although there are no previous reports of the modulation of Sp1 in response to VCR treatment, our results revealed that VCR treatment caused a moderate downregulation of Sp1 in CHLA-9 cells but not in TC-32 cells (Figure 3).	('downregulation', 'NegReg', (152, 166))	('VCR', 'Var', (120, 123))	('VCR', 'Chemical', 'MESH:D014750', (120, 123))	('VCR', 'Chemical', 'MESH:D014750', (79, 82))	('Sp1', 'Gene', (170, 173))	('CHLA-9', 'CellLine', 'CVCL:M150', (177, 183))	('TC-32', 'CellLine', 'CVCL:7151', (201, 206))
209584	30610505	TA+VCR caused higher anti-proliferative response in TC-32 cells as seen in Annexin V apoptosis and cell cycle analysis than in CHLA-9 cells.	('Annexin V', 'Gene', (75, 84))	('CHLA-9', 'CellLine', 'CVCL:M150', (127, 133))	('VCR', 'Chemical', 'MESH:D014750', (3, 6))	('TA+VCR', 'Var', (0, 6))	('TC-32', 'CellLine', 'CVCL:7151', (52, 57))	('anti-proliferative response', 'CPA', (21, 48))	('Annexin V', 'Gene', '308', (75, 84))	('cell cycle analysis', 'CPA', (99, 118))	('higher', 'PosReg', (14, 20))
209588	29862022	Case Report: Exome sequencing reveals recurrent RETSAT mutations and a loss-of-function POLDIP2 mutation in a rare undifferentiated tongue sarcoma Soft tissue sarcoma of the tongue represents a very rare head and neck cancer with connective tissue features, and the genetics underlying this rare cancer are largely unknown.	('RETSAT', 'Gene', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('Soft tissue sarcoma', 'Phenotype', 'HP:0030448', (147, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('POLDIP2', 'Gene', '26073', (88, 95))	('head and neck cancer', 'Phenotype', 'HP:0012288', (204, 224))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('POLDIP2', 'Gene', (88, 95))	('mutation', 'Var', (96, 104))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('head and neck cancer', 'Disease', 'MESH:D006258', (204, 224))	('mutations', 'Var', (55, 64))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('cancer with connective tissue', 'Phenotype', 'HP:0100242', (218, 247))	('sarcoma', 'Disease', (139, 146))	('sarcoma of the tongue', 'Phenotype', 'HP:0030415', (159, 180))	('sarcoma', 'Disease', 'MESH:D012509', (159, 166))	('tongue sarcoma', 'Phenotype', 'HP:0030415', (132, 146))	('RETSAT', 'Gene', '54884', (48, 54))	('loss-of-function', 'NegReg', (71, 87))	('cancer', 'Disease', (218, 224))	('sarcoma', 'Disease', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('cancer', 'Disease', (296, 302))
209591	29862022	Yet, among the few genes that are somatically mutated in this HPV-negative undifferentiated tongue sarcoma, a noticeable deleterious frameshift mutation (with a very high allele frequency of >93%) of a gene for DNA replication and repair, namely  POLDIP2 (DNA polymerase delta interacting protein 2), and two recurrent mutations of the adipogenesis and adipocyte differentiation gene RETSAT (retinol saturase), were identified.	('adipogenesis', 'Gene', (336, 348))	('tongue sarcoma', 'Phenotype', 'HP:0030415', (92, 106))	('tongue sarcoma', 'Disease', 'MESH:D014060', (92, 106))	('RETSAT', 'Gene', '54884', (384, 390))	('POLDIP2', 'Gene', (247, 254))	('tongue sarcoma', 'Disease', (92, 106))	('frameshift mutation', 'Var', (133, 152))	('POLDIP2', 'Gene', '26073', (247, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('RETSAT', 'Gene', (384, 390))	('HPV', 'Species', '10566', (62, 65))
209618	29862022	The very low rate of non-synonymous mutations is uncommon in HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC) , and is slightly lower than that of reported sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (183, 191))	('neck squamous cell carcinoma', 'Disease', (100, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (100, 128))	('sarcomas', 'Disease', (183, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('HPV', 'Species', '10566', (78, 81))	('HPV', 'Species', '10566', (61, 64))	('non-synonymous mutations', 'Var', (21, 45))
209621	29862022	This suggests that major somatic mutations of this rare tumor appear to affect DNA replication and mitosis, consistent with an aggressive phenotype.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('affect', 'Reg', (72, 78))	('DNA replication', 'CPA', (79, 94))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (33, 42))	('mitosis', 'Disease', (99, 106))	('mitosis', 'Disease', 'None', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
209622	29862022	Of note, the patient's tumor carried a 93% allele frequency of the POLDIP2 S28fs mutation, which is a hotspot mutation in multiple cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('S28fs', 'Mutation', 'p.S28fsX', (75, 80))	('cancers', 'Disease', (131, 138))	('patient', 'Species', '9606', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('POLDIP2', 'Gene', '26073', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('S28fs', 'Var', (75, 80))	('POLDIP2', 'Gene', (67, 74))
209623	29862022	In addition, the MCC gene was also mutated in this rare tumor ( MCC p.G20S) at a high allele frequency of 28%, indicating its likely role as a driver event for tumorigenesis.	('mutated', 'Var', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('p.G20S', 'Mutation', 'p.G20S', (68, 74))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('MCC gene', 'Gene', (17, 25))
209624	29862022	Interestingly, the PRR21 mutation is also found to be mutated at high frequencies in TCGA HNSCC cohort with a hotspot mutation S86Gfs*291 and M48Tfs*329 mutation, while in this tumor, PRR21 mutation occurred at G114C, a position near to these two hotspot mutations in HNSCC.	('M48Tfs*329', 'Mutation', 'rs1387860684', (142, 152))	('PRR21', 'Gene', '643905', (184, 189))	('PRR21', 'Gene', (184, 189))	('G114C', 'Var', (211, 216))	('G114C', 'Mutation', 'rs201132375', (211, 216))	('PRR21', 'Gene', '643905', (19, 24))	('M48Tfs*329 mutation', 'Var', (142, 161))	('PRR21', 'Gene', (19, 24))	('S86Gfs', 'Mutation', 'p.S86,FSG', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('S86Gfs*291', 'Var', (127, 137))	('tumor', 'Disease', (177, 182))
209625	29862022	Most strikingly, among all the somatic mutations identified in this patient, we found that recurrent somatic events of RETSAT ( RETSAT p.A533V and p.G536R mutations), a gene known to be important for the promotion of adipogenesis and normal adipocyte differentiation.	('p.A533V', 'Mutation', 'rs4832169', (135, 142))	('adipogenesis', 'MPA', (217, 229))	('RETSAT', 'Gene', (119, 125))	('p.G536R', 'Mutation', 'rs4832168', (147, 154))	('patient', 'Species', '9606', (68, 75))	('promotion', 'PosReg', (204, 213))	('RETSAT', 'Gene', '54884', (128, 134))	('p.A533V', 'Var', (135, 142))	('RETSAT', 'Gene', (128, 134))	('p.G536R mutations', 'Var', (147, 164))	('RETSAT', 'Gene', '54884', (119, 125))
209626	29862022	It is plausible that RETSAT mutations may affect adipocyte adipogenesis and differentiation, related to the sarcoma features of this rare tumor.	('affect', 'Reg', (42, 48))	('RETSAT', 'Gene', '54884', (21, 27))	('sarcoma', 'Disease', (108, 115))	('tumor', 'Disease', (138, 143))	('RETSAT', 'Gene', (21, 27))	('differentiation', 'CPA', (76, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('adipocyte adipogenesis', 'MPA', (49, 71))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
209628	29862022	The common CNA events in sarcomas including aberrations of the MDM2-p53 and p16-cyclin dependent kinase 4 (CDK4)-retinoblastoma-associated protein pathways, deletion of TP53 (tumor protein p53), CDKN2A (cyclin dependent kinase inhibitor 2A), as well as chr.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('TP53', 'Gene', '7157', (169, 173))	('CDKN2A', 'Gene', '1029', (195, 201))	('CDK4', 'Gene', (107, 111))	('deletion', 'Var', (157, 165))	('cyclin dependent kinase inhibitor 2A', 'Gene', (203, 239))	('retinoblastoma-associated protein', 'Gene', (113, 146))	('tumor', 'Disease', (175, 180))	('CDK4', 'Gene', '1019', (107, 111))	('p53', 'Gene', '7157', (189, 192))	('retinoblastoma-associated protein', 'Gene', '5925', (113, 146))	('TP53', 'Gene', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('p53', 'Gene', '7157', (68, 71))	('MDM2', 'Gene', (63, 67))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('p53', 'Gene', (189, 192))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (203, 239))	('retinoblastoma', 'Phenotype', 'HP:0009919', (113, 127))	('sarcomas', 'Disease', (25, 33))	('CDKN2A', 'Gene', (195, 201))	('p16-cyclin dependent kinase 4', 'Gene', '1019', (76, 105))	('p16-cyclin dependent kinase 4', 'Gene', (76, 105))	('p53', 'Gene', (68, 71))	('MDM2', 'Gene', '4193', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
209632	29862022	Importantly, we found that this patient carried multiple germline mutational events of TP53, including a missense mutation of TP53 p.P72R (100% allele frequency), 2 mutations at the immediate 5'-UTR, likely in the promoter region of TP53 (c.-112G>A; and c.-123C>G; both with 100% allele frequencies), as well as two other intron variants with unknown effects ( Table 2).	('p.P72R', 'Mutation', 'rs1042522', (131, 137))	('patient', 'Species', '9606', (32, 39))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (126, 130))	('TP53', 'Gene', (233, 237))	('TP53', 'Gene', (87, 91))	('c.-123C>G', 'Var', (254, 263))	('p.P72R', 'Var', (131, 137))	('c.-123C>G', 'Mutation', 'rs1642785', (254, 263))	('c.-112G>A;', 'Var', (239, 249))	('c.-112G>A', 'Mutation', 'rs2909430', (239, 248))	('TP53', 'Gene', '7157', (126, 130))	('TP53', 'Gene', '7157', (233, 237))
209634	29862022	In addition, a 5'-UTR mutation, likely at the promoter region of CDKN2A, was identified (c.*193G>C), with an allele frequency of 100%.	('CDKN2A', 'Gene', '1029', (65, 71))	('CDKN2A', 'Gene', (65, 71))	('c.*193G>C', 'Mutation', 'rs11515', (89, 98))	('c.*193G>C', 'Var', (89, 98))
209635	29862022	A CASP8 (caspase 8) missense mutation, CASP8 p.L14R, was also found in this patient's blood with a 46.7% allele frequency.	('CASP8', 'Gene', '841', (39, 44))	('caspase 8', 'Gene', '841', (9, 18))	('p.L14R', 'Var', (45, 51))	('CASP8', 'Gene', '841', (2, 7))	('p.L14R', 'Mutation', 'p.L14R', (45, 51))	('caspase 8', 'Gene', (9, 18))	('patient', 'Species', '9606', (76, 83))	('CASP8', 'Gene', (2, 7))	('CASP8', 'Gene', (39, 44))
209640	29862022	The presence of a rare soft tissue sarcoma in a young patient provided the evidence to evaluate for germline mutations in addition to the somatic mutations, leading to the discovery of multiple germline TP53 mutations, as well as multiple CDKN2A, and potentially multiple NOTCH1 mutations of unclear functions.	('patient', 'Species', '9606', (54, 61))	('TP53', 'Gene', '7157', (203, 207))	('sarcoma', 'Disease', (35, 42))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (23, 42))	('TP53', 'Gene', (203, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('mutations', 'Var', (208, 217))	('CDKN2A', 'Gene', (239, 245))	('CDKN2A', 'Gene', '1029', (239, 245))	('NOTCH1', 'Gene', '4851', (272, 278))	('NOTCH1', 'Gene', (272, 278))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))
209641	29862022	Notably, a CASP8 mutation was also found in his germline.	('CASP8', 'Gene', '841', (11, 16))	('CASP8', 'Gene', (11, 16))	('mutation', 'Var', (17, 25))
209643	29862022	Furthermore, unlike the genetic profile of soft tissue sarcomas, our sarcoma patient lacked the common somatic mutations in TP53, PTEN (phosphatase and tensin homolog) and CDKN2A , .	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('sarcoma', 'Disease', (55, 62))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (43, 63))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (43, 62))	('TP53', 'Gene', (124, 128))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (43, 63))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('CDKN2A', 'Gene', '1029', (172, 178))	('mutations', 'Var', (111, 120))	('sarcoma', 'Disease', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('PTEN', 'Gene', (130, 134))	('patient', 'Species', '9606', (77, 84))	('TP53', 'Gene', '7157', (124, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('PTEN', 'Gene', '5728', (130, 134))	('lacked', 'NegReg', (85, 91))	('CDKN2A', 'Gene', (172, 178))	('soft tissue sarcomas', 'Disease', (43, 63))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))
209645	29862022	This was partly contributed to by his heavy germline mutations of some of these key tumor suppressor genes, including TP53 and CDKN2A, which are commonly mutated in both sarcoma and HNSCC, usually somatically.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('sarcoma', 'Disease', 'MESH:D012509', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('sarcoma', 'Disease', (170, 177))	('germline mutations', 'Var', (44, 62))	('tumor', 'Disease', (84, 89))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('CDKN2A', 'Gene', (127, 133))	('CDKN2A', 'Gene', '1029', (127, 133))
209646	29862022	Furthermore, his germline events also carried CASP8 and NOTCH1 mutations, which are commonly somatically mutated in HNSCC rather than in the germline.	('mutations', 'Var', (63, 72))	('CASP8', 'Gene', (46, 51))	('CASP8', 'Gene', '841', (46, 51))	('NOTCH1', 'Gene', '4851', (56, 62))	('NOTCH1', 'Gene', (56, 62))	('carried', 'Reg', (38, 45))
209648	29862022	Germline mutations in TP53 are associated with familial clustering of early onset carcinomas, including pre-menopausal breast cancer, soft tissue sarcomas, adrenal cortical carcinomas or choroid plexus carcinomas, which together are classified as Li-Fraumeni syndrome based on Chompret criteria - .	('Germline mutations', 'Var', (0, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('carcinomas', 'Disease', 'MESH:D002277', (202, 212))	('-menopausal breast cancer', 'Phenotype', 'HP:0008209', (107, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('adrenal cortical carcinomas or choroid plexus carcinomas', 'Disease', 'MESH:D020288', (156, 212))	('carcinomas', 'Disease', (173, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('TP53', 'Gene', (22, 26))	('carcinomas', 'Disease', 'MESH:D002277', (82, 92))	('adrenal cortical carcinomas', 'Phenotype', 'HP:0006744', (156, 183))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (134, 153))	('breast cancer', 'Disease', (119, 132))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('soft tissue sarcomas', 'Disease', (134, 154))	('carcinomas', 'Disease', (202, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('carcinomas', 'Disease', 'MESH:D002277', (173, 183))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (134, 154))	('TP53', 'Gene', '7157', (22, 26))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (134, 154))	('carcinomas', 'Disease', (82, 92))	('Li-Fraumeni syndrome', 'Disease', (247, 267))	('choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (187, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (247, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
209651	29862022	Our case highlights the importance of considering TP53 mutations in early onset soft tissue sarcomas, even in those without familial histories, as this offers the potential to appropriately manage the patient and possibly the family.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (80, 100))	('mutations', 'Var', (55, 64))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (80, 100))	('TP53', 'Gene', '7157', (50, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('soft tissue sarcomas', 'Disease', (80, 100))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (80, 99))	('TP53', 'Gene', (50, 54))	('patient', 'Species', '9606', (201, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
209653	29862022	The early detection of these mutations can be useful in treating these patients, given the consideration that radiation wherever possible should be avoided to prevent the development of radiation-induced second malignancies - .	('patients', 'Species', '9606', (71, 79))	('malignancies', 'Disease', 'MESH:D009369', (211, 223))	('mutations', 'Var', (29, 38))	('malignancies', 'Disease', (211, 223))
209659	29862022	Genomic DNA of the patient's tumor and buffy coat were used for WES using the Agilent SureSelect Human All Exon V5 Kit, with sequencing performed using the Illumina HiSeq 4000 platform (Macrogen, Korea) with a goal coverage of x200 for tumor and x100 for the blood (buffy coat) sample of the same patient.	('patient', 'Species', '9606', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('x100', 'Var', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (29, 34))	('Human', 'Species', '9606', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('x200', 'Var', (227, 231))	('patient', 'Species', '9606', (297, 304))	('tumor', 'Disease', (236, 241))
209665	29862022	Immunohistochemical staining was performed with the following antibodies: Melan A (M7196, Dako, Denmark), HMB34 (M0634, Dako, Denmark), ALK-1 (M7195, Dako, Denmark), HHV8 (NCL-HHV8-LNA, Novo, UK), MIC-2 (M3601, Dako, Denmark), SOX-10 (ACI3099, Biocare, USA), Calp (M3556, Dako, Denmark), INI1 (612110, DB transduction, USA), Vimentin (M0725, Dako, Denmark), p16 (805-4713, Ventana, USA), SMA (M0851, Dako, Denmark), p53 (M7001, Dako, Denmark), TLE1 (401M-16, Cell Marque, USA), p63 (M7317, Dako, Denmark), EMA (MS348, Thermo, UK), AE1/3 (M3515, Dako, Denmark), c-kit (A4502, Dako, Denmark), S100 (NCL-S100p, Leica, UK), CD31 (M0823, Dako, Denmark), CD34 (NCL-L-END, Leica, UK), Desmin (M0760, Dako, Denmark) and Myogenin (M3559, Dako, Denmark).	('M0823', 'Var', (626, 631))	('p53', 'Gene', '7157', (416, 419))	('INI1', 'Gene', (288, 292))	('INI1', 'Gene', '6598', (288, 292))	('Myogenin', 'CPA', (712, 720))	('M3559', 'Var', (722, 727))	('M0760', 'Var', (686, 691))	('HHV8', 'Species', '37296', (176, 180))	('p53', 'Gene', (416, 419))	('HHV8', 'Species', '37296', (166, 170))
209676	29862022	They identified a fairly low mutation rate, with mutations in POLDIP2, a gene important in DNA replication and repair, and RETSAT, a gene involved in adipogenesis.	('RETSAT', 'Gene', (123, 129))	('mutations', 'Var', (49, 58))	('POLDIP2', 'Gene', (62, 69))	('RETSAT', 'Gene', '54884', (123, 129))	('POLDIP2', 'Gene', '26073', (62, 69))
209677	29862022	WES analysis of the patient's blood DNA revealed mutations in TP53, CDKN2A, CASP8, and NOTCH1.	('TP53', 'Gene', '7157', (62, 66))	('mutations', 'Var', (49, 58))	('TP53', 'Gene', (62, 66))	('CDKN2A', 'Gene', (68, 74))	('patient', 'Species', '9606', (20, 27))	('CASP8', 'Gene', (76, 81))	('CDKN2A', 'Gene', '1029', (68, 74))	('CASP8', 'Gene', '841', (76, 81))	('NOTCH1', 'Gene', '4851', (87, 93))	('NOTCH1', 'Gene', (87, 93))
209684	29862022	10.5256/f1000research.15650.r33489 Yang Tsung Lin 2018 A rare undifferentiated tongue sarcoma showing recurrent  RETSAT mutations and a loss-of-function  POLDIP2 mutation was presented in this case report.	('loss-of-function', 'NegReg', (136, 152))	('tongue sarcoma', 'Disease', (79, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('POLDIP2', 'Gene', (154, 161))	('tongue sarcoma', 'Phenotype', 'HP:0030415', (79, 93))	('tongue sarcoma', 'Disease', 'MESH:D014060', (79, 93))	('POLDIP2', 'Gene', '26073', (154, 161))	('mutation', 'Var', (162, 170))	('RETSAT', 'Gene', (113, 119))	('RETSAT', 'Gene', '54884', (113, 119))
209689	29862022	Although this case might provide a chance to evaluate the mutual influence between the germline and somatic mutation, evidences are required to confirm whether the heavy germline mutation indeed affect the incidence of common somatic mutation found in this patient.	('affect', 'Reg', (195, 201))	('heavy germline mutation', 'Var', (164, 187))	('patient', 'Species', '9606', (257, 264))
209692	28961825	In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.	('mutational analysis', 'Var', (74, 93))	('desmoid-type fibromatosis', 'Disease', (97, 122))	('patients', 'Species', '9606', (123, 131))	('desmoid-type fibromatosis', 'Disease', 'MESH:C535944', (97, 122))
209704	28961825	Noteworthy, nuclear accumulation of beta-catenin on immunostaining has been observed in non-DF soft tissue neoplasms as well, while activating mutations in CTNNB1 (the gene encoding beta-catenin) were confined to DF in the differential diagnostic setting compared with other soft tissue neoplasms.	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (95, 116))	('beta-catenin', 'Gene', '1499', (182, 194))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (275, 296))	('nuclear accumulation', 'MPA', (12, 32))	('neoplasms', 'Disease', 'MESH:D009369', (107, 116))	('neoplasms', 'Disease', (107, 116))	('beta-catenin', 'Gene', '1499', (36, 48))	('neoplasms', 'Disease', (287, 296))	('CTNNB1', 'Gene', '1499', (156, 162))	('neoplasms', 'Phenotype', 'HP:0002664', (287, 296))	('beta-catenin', 'Gene', (36, 48))	('neoplasms', 'Phenotype', 'HP:0002664', (107, 116))	('neoplasms', 'Disease', 'MESH:D009369', (287, 296))	('activating', 'PosReg', (132, 142))	('CTNNB1', 'Gene', (156, 162))	('mutations', 'Var', (143, 152))	('beta-catenin', 'Gene', (182, 194))
209705	28961825	Approximately 85%-90% of DF harbors mutations in the beta-catenin gene, leading to nuclear accumulation of beta-catenin protein (Figure 2).	('beta-catenin', 'Gene', (107, 119))	('mutations', 'Var', (36, 45))	('beta-catenin', 'Gene', (53, 65))	('beta-catenin', 'Gene', '1499', (107, 119))	('beta-catenin', 'Gene', '1499', (53, 65))	('nuclear accumulation', 'MPA', (83, 103))
209706	28961825	beta-Catenin mutations and APC mutations appear to be mutually exclusive in DF, thus, detection of a somatic beta-catenin mutation may help to exclude a syndromal condition.	('APC', 'Disease', 'MESH:D011125', (27, 30))	('mutation', 'Var', (122, 130))	('beta-catenin', 'Gene', (109, 121))	('APC', 'Disease', (27, 30))	('beta-Catenin', 'Gene', (0, 12))	('beta-Catenin', 'Gene', '1499', (0, 12))	('beta-catenin', 'Gene', '1499', (109, 121))
209707	28961825	Vice versa, beta-catenin wildtype status in DF should raise suspicion for FAP, with more extensive diagnostic clinical work-up (e.g.	('beta-catenin', 'Gene', (12, 24))	('wildtype status', 'Var', (25, 40))	('FAP', 'Disease', (74, 77))	('beta-catenin', 'Gene', '1499', (12, 24))	('FAP', 'Disease', 'MESH:C567782', (74, 77))
209708	28961825	Mutation analysis of beta-catenin has been proposed as a specific diagnostic tool for establishing DF diagnosis, particularly in challenging or diagnostically ambiguous cases.	('beta-catenin', 'Gene', (21, 33))	('Mutation analysis', 'Var', (0, 17))	('beta-catenin', 'Gene', '1499', (21, 33))
209710	28961825	Mutations of beta-catenin in DF cluster in the N-terminal region comprising codons 32-45 encoded by exon 3.	('beta-catenin', 'Gene', (13, 25))	('Mutations', 'Var', (0, 9))	('beta-catenin', 'Gene', '1499', (13, 25))
209711	28961825	Although T41A and S45F are by far the most common mutations in DF accounting for roughly 50% and 25%, respectively, S45P is the third most common mutation at around 9% and very rare missense mutations and deletions affecting codons 32-49 have been observed as well.	('S45P', 'Mutation', 'rs121913407', (116, 120))	('deletions', 'Var', (205, 214))	('S45F', 'Var', (18, 22))	('T41A', 'SUBSTITUTION', 'None', (9, 13))	('S45F', 'Mutation', 'rs121913409', (18, 22))	('missense mutations', 'Var', (182, 200))	('S45P', 'Var', (116, 120))	('T41A', 'Var', (9, 13))
209713	28961825	A significant correlation between beta-catenin S45F mutation and an increased risk of recurrence after resection was observed in four independent studies, and S45F mutations were overrepresented in a clinical trial of DF patients with RECIST progressive disease.	('patients', 'Species', '9606', (221, 229))	('S45F', 'Gene', (159, 163))	('S45F mutation', 'Var', (47, 60))	('beta-catenin', 'Gene', '1499', (34, 46))	('S45F', 'Mutation', 'rs121913409', (159, 163))	('mutation', 'Var', (52, 60))	('S45F', 'Mutation', 'rs121913409', (47, 51))	('mutations', 'Var', (164, 173))	('beta-catenin', 'Gene', (34, 46))
209714	28961825	Notably, in that trial DF with S45F mutation showed the highest progression arrest rate of 85% when treated with 2 years of imatinib 800 mg/day, compared with only 43% progression arrest rate in DF with beta-catenin wild-type status.	('beta-catenin', 'Gene', (203, 215))	('imatinib', 'Chemical', 'MESH:D000068877', (124, 132))	('S45F', 'Mutation', 'rs121913409', (31, 35))	('beta-catenin', 'Gene', '1499', (203, 215))	('S45F mutation', 'Var', (31, 44))	('progression arrest', 'CPA', (64, 82))	('mutation', 'Var', (36, 44))
209715	28961825	Taken together, these findings strongly encourage mutation analysis of beta-catenin in DF to identify patients with a probably more aggressive course, and to estimate response to imatinib therapy.	('mutation analysis', 'Var', (50, 67))	('patients', 'Species', '9606', (102, 110))	('beta-catenin', 'Gene', (71, 83))	('imatinib', 'Chemical', 'MESH:D000068877', (179, 187))	('beta-catenin', 'Gene', '1499', (71, 83))
209716	28961825	However, to date there are no prospective data on the prognostic value of beta-catenin (CTNNB1) mutation status at the time of first diagnosis, but studies addressing this point are ongoing.	('CTNNB1', 'Gene', (88, 94))	('CTNNB1', 'Gene', '1499', (88, 94))	('mutation', 'Var', (96, 104))	('beta-catenin', 'Gene', (74, 86))	('beta-catenin', 'Gene', '1499', (74, 86))
209748	28961825	Pegylated liposomal doxorubicin has been reported in uncontrolled patient series to have significant activity with acceptable toxicity and, importantly in this young patient population, less cardiac toxicity than conventional doxorubicin.	('toxicity', 'Disease', 'MESH:D064420', (126, 134))	('Pegylated liposomal', 'Var', (0, 19))	('toxicity', 'Disease', 'MESH:D064420', (199, 207))	('toxicity', 'Disease', (126, 134))	('toxicity', 'Disease', (199, 207))	('activity', 'MPA', (101, 109))	('doxorubicin', 'Chemical', 'MESH:D004317', (20, 31))	('cardiac toxicity', 'Disease', 'MESH:D066126', (191, 207))	('patient', 'Species', '9606', (66, 73))	('cardiac toxicity', 'Disease', (191, 207))	('doxorubicin', 'Chemical', 'MESH:D004317', (226, 237))	('patient', 'Species', '9606', (166, 173))
209792	27006472	Targeting the epigenetic readers in Ewing Sarcoma inhibits the oncogenic transcription factor EWS/Fli1 Ewing Sarcoma is a rare bone and soft tissue malignancy affecting children and young adults.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (36, 49))	('soft tissue malignancy', 'Phenotype', 'HP:0031459', (136, 158))	('EWS', 'Gene', '2130', (94, 97))	('EWS', 'Gene', (94, 97))	('malignancy', 'Disease', (148, 158))	('Sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Ewing Sarcoma', 'Disease', (36, 49))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('malignancy', 'Disease', 'MESH:D009369', (148, 158))	('children', 'Species', '9606', (169, 177))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (103, 116))	('Sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('Ewing Sarcoma', 'Disease', (103, 116))	('inhibits', 'NegReg', (50, 58))	('epigenetic readers', 'Var', (14, 32))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (103, 116))
209793	27006472	Chromosomal translocations in this cancer produce fusion oncogenes as characteristic molecular signatures of the disease.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Chromosomal translocations', 'Var', (0, 26))	('fusion oncogenes', 'MPA', (50, 66))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
209794	27006472	The most common case is the translocation t (11; 22) (q24;q12) which yields the EWS-Fli1 chimeric transcription factor.	('yields', 'Reg', (69, 75))	('EWS-Fli1', 'Gene', '2130', (80, 88))	('translocation t (11; 22) (q24;q12', 'Var', (28, 61))	('EWS-Fli1', 'Gene', (80, 88))
209799	27006472	Taken together, our data indicate that inhibiting the BET bromodomains interferes with EWS-FLi1 transcription and could be a promising strategy in the Ewing tumors context.	('Ewing tumor', 'Phenotype', 'HP:0012254', (151, 162))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('Ewing tumors', 'Disease', 'MESH:C563168', (151, 163))	('transcription', 'MPA', (96, 109))	('inhibiting', 'Var', (39, 49))	('FLi1', 'Gene', '2313', (91, 95))	('Ewing tumors', 'Phenotype', 'HP:0012254', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('interferes', 'NegReg', (71, 81))	('FLi1', 'Gene', (91, 95))	('Ewing tumors', 'Disease', (151, 163))
209810	27006472	EWS-Fli1 has also a transcriptional repressor role, as it is able to directly inhibit the expression of some tumor suppressor genes such as p21, p57kip , TGF-betaRII and IGFBP3, often associated with development, differentiation and cell communication.	('TGF-betaRII', 'Gene', '7048', (154, 165))	('TGF-betaRII', 'Gene', (154, 165))	('p21', 'Gene', '644914', (140, 143))	('p57kip', 'Var', (145, 151))	('IGFBP3', 'Gene', '3486', (170, 176))	('inhibit', 'NegReg', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('expression', 'MPA', (90, 100))	('IGFBP3', 'Gene', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('EWS-Fli1', 'Gene', '2130', (0, 8))	('EWS-Fli1', 'Gene', (0, 8))	('tumor', 'Disease', (109, 114))	('p21', 'Gene', (140, 143))
209821	27006472	From this perspective, the small cell-permeable thieno-triazolo-1, 4-diazepine, JQ1, which is a potent BET inhibitor, has recently been shown to exhibit anti-cancer effects in various cancer models such as NMC (NUT midline carcinoma), hematopoietic malignancies lung cancer, prostate cancer and Osteosarcoma.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (211, 232))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('thieno-triazolo-1, 4-diazepine', 'Chemical', '-', (48, 78))	('Osteosarcoma', 'Disease', (295, 307))	('Osteosarcoma', 'Disease', 'MESH:D012516', (295, 307))	('hematopoietic malignancies lung cancer', 'Disease', (235, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('N', 'Chemical', 'MESH:D009584', (211, 212))	('JQ1', 'Var', (80, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (300, 307))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('hematopoietic malignancies lung cancer', 'Disease', 'MESH:D019337', (235, 273))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (295, 307))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('prostate cancer', 'Disease', 'MESH:D011471', (275, 290))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('prostate cancer', 'Phenotype', 'HP:0012125', (275, 290))	('NUT midline carcinoma', 'Disease', (211, 232))	('NMC', 'Disease', (206, 209))	('prostate cancer', 'Disease', (275, 290))	('N', 'Chemical', 'MESH:D009584', (206, 207))
209824	27006472	We further uncover that through targeting EWS-Fli1, the BET bromodomain inhibitor JQ1 consequently modulates the expression level of the downstream EWS-Fli1 network genes in Ewing sarcoma cell lines and in in vivo tumor models.	('modulates', 'Reg', (99, 108))	('EWS-Fli1', 'Gene', (42, 50))	('EWS-Fli1', 'Gene', '2130', (42, 50))	('targeting', 'Var', (32, 41))	('Ewing sarcoma', 'Disease', (174, 187))	('EWS-Fli1', 'Gene', (148, 156))	('EWS-Fli1', 'Gene', '2130', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (174, 187))	('expression level', 'MPA', (113, 129))	('tumor', 'Disease', (214, 219))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (174, 187))
209826	27006472	Taken together and considering the EWS-Fli1 oncogene addiction of the Ewing Sarcoma cells, our findings indicate that targeting the BET bromodomain signaling pathway in Ewing tumor can effectively disrupt the progression of this cancer through transcriptional repression of its main oncogenic driver.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('EWS-Fli1', 'Gene', '2130', (35, 43))	('EWS-Fli1', 'Gene', (35, 43))	('progression', 'CPA', (209, 220))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('Ewing tumor', 'Phenotype', 'HP:0012254', (169, 180))	('Ewing tumor', 'Disease', 'MESH:C563168', (169, 180))	('Sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('disrupt', 'NegReg', (197, 204))	('Ewing tumor', 'Disease', (169, 180))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (70, 83))	('Ewing Sarcoma', 'Disease', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('transcriptional repression', 'Var', (244, 270))	('targeting', 'Var', (118, 127))
209840	27006472	The A673 cells come from a female donor of 15 years old presenting a tumor localized on muscle whereas the TC71 cells come from a 22 years old male patient, displaying a recurrent humerus sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('TC71', 'CellLine', 'CVCL:2213', (107, 111))	('humerus sarcoma', 'Disease', (180, 195))	('humerus sarcoma', 'Disease', 'MESH:C566022', (180, 195))	('donor', 'Species', '9606', (34, 39))	('patient', 'Species', '9606', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('A673', 'Var', (4, 8))
209841	27006472	In order to evaluate the functional effects of the BET proteins inhibition in vitro, we performed a colony formation assay in presence of DMSO alone, JQ1(+) or JQ1(-).	('JQ1(+', 'Var', (150, 155))	('colony formation assay', 'CPA', (100, 122))	('DMSO', 'Chemical', 'MESH:D004121', (138, 142))	('JQ1(-', 'Var', (160, 165))
209842	27006472	A 2-days treatment with 4 muM of JQ1(+) significantly reduces the clonogenic abilities by 48% in TC71 (Figure 2A) and 45% in A673 cells (Supplementary Figure S2A) compared to the same amount of DMSO alone or the same concentration of JQ1(-).	('muM', 'Gene', (26, 29))	('DMSO', 'Chemical', 'MESH:D004121', (194, 198))	('clonogenic abilities', 'CPA', (66, 86))	('TC71', 'CellLine', 'CVCL:2213', (97, 101))	('JQ1', 'Var', (33, 36))	('muM', 'Gene', '56925', (26, 29))	('reduces', 'NegReg', (54, 61))
209846	27006472	The differences obtained between the two cell lines could probably be due to the cell-relative sensitivity to JQ1(+), the A673 displaying a higher GI50 than the TC71.	('GI50', 'MPA', (147, 151))	('TC71', 'CellLine', 'CVCL:2213', (161, 165))	('A673', 'Var', (122, 126))	('higher', 'PosReg', (140, 146))
209847	27006472	The time-course experiment performed during 3, 6, 24 or 30 hours with 4 muM of JQ1(+) shows that the phosphorylated form of the Rb protein (P-Rb), not inhibiting E2F, is shortly activated after 3 and 6 hours of JQ1(+) treatment and then reduced after 24 hours in the TC71, whereas the total Rb protein expression level remains stable for TC71.	('Rb', 'Chemical', 'MESH:D012413', (291, 293))	('TC71', 'CellLine', 'CVCL:2213', (338, 342))	('JQ1', 'Var', (211, 214))	('muM', 'Gene', '56925', (72, 75))	('phospho', 'Chemical', 'MESH:D004099', (101, 108))	('activated', 'PosReg', (178, 187))	('TC71', 'CellLine', 'CVCL:2213', (267, 271))	('muM', 'Gene', (72, 75))	('Rb', 'Chemical', 'MESH:D012413', (142, 144))	('P-Rb', 'Gene', (140, 144))	('Rb', 'Chemical', 'MESH:D012413', (128, 130))	('reduced', 'NegReg', (237, 244))	('P-Rb', 'Gene', '5925', (140, 144))
209852	27006472	In addition, the same methods also confirm that JQ1(+) induces a dose-dependent apoptosis both in the TC71and the A673 cell lines (Figure 2G, 2H and Supplementary Figure S2G, S2H).	('induces', 'Reg', (55, 62))	('2H', 'Chemical', 'MESH:D003903', (176, 178))	('JQ1(+', 'Var', (48, 53))	('TC71', 'CellLine', 'CVCL:2213', (102, 106))	('apoptosis', 'CPA', (80, 89))	('2H', 'Chemical', 'MESH:D003903', (142, 144))
209854	27006472	The BET bromodomains inhibition-induced apoptosis was thus confirmed both in A673 and in TC71 to be caspase-3/7-dependent.	('A673', 'Var', (77, 81))	('TC71', 'CellLine', 'CVCL:2213', (89, 93))	('caspase-3', 'Gene', (100, 109))	('caspase-3', 'Gene', '836', (100, 109))
209855	27006472	Finally, confirmation of cell death induction was obtained when TC71 and A673 cells were treated with 4 muM JQ1(+) or JQ1(-) during 3, 6, 24, 30 or 48 hours and a time-dependent induction of cell death could be observed when the number of dead cells was evaluated by manual counting after Trypan blue exclusion (Supplementary Figure S2I, S2J).	('JQ1', 'Var', (108, 111))	('muM', 'Gene', '56925', (104, 107))	('Trypan blue', 'Chemical', 'MESH:D014343', (289, 300))	('muM', 'Gene', (104, 107))	('TC71', 'CellLine', 'CVCL:2213', (64, 68))	('JQ1(-', 'Var', (118, 123))
209856	27006472	EWS-Fli1 expression is considered as the molecular signature of the Ewing Sarcoma cells and it is now well established that inhibiting this chimeric factor source of oncogene addiction impacts the aggressiveness and the cancerous features of these cells.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('aggressiveness', 'Phenotype', 'HP:0000718', (197, 211))	('cancerous', 'Disease', 'MESH:D009369', (220, 229))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (68, 81))	('addiction impacts the aggressiveness', 'Disease', 'MESH:D004834', (175, 211))	('inhibiting', 'Var', (124, 134))	('Ewing Sarcoma', 'Disease', (68, 81))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('Sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('cancerous', 'Disease', (220, 229))	('addiction impacts the aggressiveness', 'Disease', (175, 211))	('EWS-Fli1', 'Gene', '2130', (0, 8))	('EWS-Fli1', 'Gene', (0, 8))
209858	27006472	In all the Ewing Sarcoma cell lines tested, JQ1(+) treatment decreased the EWS-Fli1 mRNA expression in a dose-dependent manner (Figure 3A).	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (11, 24))	('JQ1', 'Var', (44, 47))	('Sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (11, 24))	('Ewing Sarcoma', 'Disease', (11, 24))	('decreased', 'NegReg', (61, 70))	('N', 'Chemical', 'MESH:D009584', (86, 87))	('EWS-Fli1', 'Gene', '2130', (75, 83))	('EWS-Fli1', 'Gene', (75, 83))
209859	27006472	Indeed, after twenty-four hours of 10 muM JQ1(+), the mRNA expression was decreased by 57.1% in the A673 cell line and by 39.9% with 4 muM JQ1(+) in the TC71 cell line.	('muM', 'Gene', '56925', (38, 41))	('mRNA expression', 'MPA', (54, 69))	('TC71', 'CellLine', 'CVCL:2213', (153, 157))	('muM', 'Gene', (38, 41))	('muM', 'Gene', '56925', (135, 138))	('decreased', 'NegReg', (74, 83))	('muM', 'Gene', (135, 138))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('JQ1', 'Var', (42, 45))
209869	27006472	Furthermore, treatment of these cells with JQ1(+) induces the release of BRD4 from the promoter-binding sites.	('JQ1(+', 'Var', (43, 48))	('BRD4', 'Gene', '23476', (73, 77))	('release', 'MPA', (62, 69))	('BRD4', 'Gene', (73, 77))
209876	27006472	Taken together, those data emphasise and support the BET bromodomains implication in the EWS-Fli1 expression activation and supports the fact that JQ1 has an EWS-Fli1-dependent activity in our model.	('EWS-Fli1', 'Gene', (158, 166))	('activation', 'PosReg', (109, 119))	('JQ1', 'Var', (147, 150))	('EWS-Fli1', 'Gene', '2130', (158, 166))	('EWS-Fli1', 'Gene', '2130', (89, 97))	('EWS-Fli1', 'Gene', (89, 97))	('expression', 'MPA', (98, 108))
209881	27006472	In addition, the expression of two of the EWS-Fli1's indirect target-genes FOXM1 and VEGFA was also reduced consequently to a JQ1(+) treatment (Figure 4B and Supplementary Figure S4B).	('EWS-Fli1', 'Gene', '2130', (42, 50))	('EWS-Fli1', 'Gene', (42, 50))	('reduced', 'NegReg', (100, 107))	('VEGFA', 'Gene', '7422', (85, 90))	('expression', 'MPA', (17, 27))	('FOXM1', 'Gene', '2305', (75, 80))	('FOXM1', 'Gene', (75, 80))	('JQ1', 'Var', (126, 129))	('VEGFA', 'Gene', (85, 90))
209885	27006472	EWS-Fli1 knock-down in these cells results in the inhibition of Gli1, NR0B1, FOXM1, VEGFA and CCND1 expression as well as the induction of p21 one (Supplementary Figure S4, S4I, S4J, S4K).	('VEGFA', 'Gene', '7422', (84, 89))	('CCND1', 'Gene', (94, 99))	('NR0B1', 'Gene', (70, 75))	('induction', 'PosReg', (126, 135))	('inhibition', 'NegReg', (50, 60))	('p21', 'Gene', '644914', (139, 142))	('FOXM1', 'Gene', (77, 82))	('expression', 'MPA', (100, 110))	('VEGFA', 'Gene', (84, 89))	('Gli1', 'Gene', (64, 68))	('FOXM1', 'Gene', '2305', (77, 82))	('NR0B1', 'Gene', '190', (70, 75))	('knock-down', 'Var', (9, 19))	('CCND1', 'Gene', '595', (94, 99))	('p21', 'Gene', (139, 142))	('EWS-Fli1', 'Gene', '2130', (0, 8))	('EWS-Fli1', 'Gene', (0, 8))	('Gli1', 'Gene', '2735', (64, 68))
209888	27006472	Particularly, it was previously reported that the ERK1/2 proteins are constitutively activated in NIH3T3 cells transformed by an artificial expression of EWS-Fli1.	('artificial expression', 'Var', (129, 150))	('ERK1/2 proteins', 'Protein', (50, 65))	('activated', 'PosReg', (85, 94))	('proteins', 'Protein', (57, 65))	('EWS-Fli1', 'Gene', '2130', (154, 162))	('EWS-Fli1', 'Gene', (154, 162))	('NIH3T3', 'CellLine', 'CVCL:0594', (98, 104))
209889	27006472	Indeed, an EWS-Fli1 knockdown in the ASP14 cells consequently reduces the ERK1/2 phosphorylation-marks, witnesses of the MAPK/ERK pathway activation (Supplementary Figure S4L).	('reduces', 'NegReg', (62, 69))	('ERK', 'Gene', '5594', (74, 77))	('EWS-Fli1', 'Gene', (11, 19))	('EWS-Fli1', 'Gene', '2130', (11, 19))	('ASP14', 'Chemical', '-', (37, 42))	('ERK', 'Gene', (74, 77))	('ERK', 'Gene', '5594', (126, 129))	('phospho', 'Chemical', 'MESH:D004099', (81, 88))	('knockdown', 'Var', (20, 29))	('ERK', 'Gene', (126, 129))
209890	27006472	In accordance with these results, a dose- as well as a time-dependent inhibition of the ERK1/2 signaling was observed in both the TC71 and the A673 cell lines consequently to a JQ1(+) treatment (Figure 4G, 4H and Supplementary Figure S4G, S4H).	('inhibition', 'NegReg', (70, 80))	('JQ1(+', 'Var', (177, 182))	('TC71', 'CellLine', 'CVCL:2213', (130, 134))	('ERK1/2 signaling', 'Pathway', (88, 104))
209893	27006472	The gene expression signature and the modulation of the EWS-Fli1's related-pathways finally observed after EWS-Fli1 knock-down are in full agreement with the ones resulting from the BET bromodomain inhibition, reinforcing the assertion that JQ1(+) directly inhibits the Ewing Sarcoma malignant features through EWS-Fli1 signaling.	('inhibits', 'NegReg', (257, 265))	('EWS-Fli1', 'Gene', (107, 115))	('knock-down', 'Var', (116, 126))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (270, 283))	('EWS-Fli1', 'Gene', '2130', (56, 64))	('EWS-Fli1', 'Gene', (56, 64))	('Ewing Sarcoma', 'Disease', (270, 283))	('EWS-Fli1', 'Gene', '2130', (107, 115))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (270, 283))	('Sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('EWS-Fli1', 'Gene', '2130', (311, 319))	('EWS-Fli1', 'Gene', (311, 319))
209896	27006472	JQ1(+) treatment significantly reduced the average tumor growth in our model (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('reduced', 'NegReg', (31, 38))	('tumor', 'Disease', (51, 56))	('JQ1', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
209901	27006472	As expected, Gli1, FOXM1, VEGFA and CCND1 expression were significantly decreased in the JQ1(+) treated group, whereas the one of p21 was increased.	('Gli1', 'Gene', '2735', (13, 17))	('p21', 'Gene', (130, 133))	('p21', 'Gene', '644914', (130, 133))	('FOXM1', 'Gene', (19, 24))	('VEGFA', 'Gene', '7422', (26, 31))	('decreased', 'NegReg', (72, 81))	('expression', 'MPA', (42, 52))	('CCND1', 'Gene', (36, 41))	('FOXM1', 'Gene', '2305', (19, 24))	('JQ1(+', 'Var', (89, 94))	('Gli1', 'Gene', (13, 17))	('CCND1', 'Gene', '595', (36, 41))	('VEGFA', 'Gene', (26, 31))
209904	27006472	Tumor biopsies from JQ1(+)-treated mice display a statistically significant decreased cell proliferation compared with their untreated counterparts (Figure 5E).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('decreased', 'NegReg', (76, 85))	('cell proliferation', 'CPA', (86, 104))	('mice', 'Species', '10090', (35, 39))	('JQ1', 'Var', (20, 23))
209906	27006472	Immunohistochemical staining for the caspase-3 activity was also assessed in these samples and the results show an higher induction of apoptosis in the JQ1(+) cohort (Figure 5F).	('apoptosis', 'CPA', (135, 144))	('JQ1(+', 'Var', (152, 157))	('caspase-3', 'Gene', (37, 46))	('caspase-3', 'Gene', '836', (37, 46))
209908	27006472	Collectively, these in vivo data suggest that the potent anti-tumor activity of JQ1(+) in Ewing Sarcoma is mediated through its inhibitory effects on the EWS-Fli1oncogene expression and its transcriptional targets.	('expression', 'MPA', (171, 181))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('Sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('JQ1', 'Var', (80, 83))	('tumor', 'Disease', (62, 67))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (90, 103))	('Ewing Sarcoma', 'Disease', (90, 103))	('EWS-Fli1', 'Gene', '2130', (154, 162))	('EWS-Fli1', 'Gene', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
209910	27006472	Impairing its activity through a direct inhibition of its transcript is indeed a seducing strategy to reduce the malignant features of the Ewing Sarcoma cells.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (139, 152))	('activity', 'MPA', (14, 22))	('Sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('reduce', 'NegReg', (102, 108))	('inhibition', 'NegReg', (40, 50))	('transcript', 'MPA', (58, 68))	('Impairing', 'Var', (0, 9))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (139, 152))	('Ewing Sarcoma', 'Disease', (139, 152))
209915	27006472	We herein demonstrated that treating Ewing Sarcoma cells with JQ1, a BET bromodomain inhibitor reduces their viability, their clonogenic features as well as their migratory capabilities.	('clonogenic features', 'CPA', (126, 145))	('Ewing Sarcoma', 'Disease', (37, 50))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('Sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('JQ1', 'Var', (62, 65))	('migratory capabilities', 'CPA', (163, 185))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (37, 50))	('reduces', 'NegReg', (95, 102))	('viability', 'CPA', (109, 118))
209922	27006472	Interestingly, it was recently reported that the H3K27Ac were the histone marks the most strongly inhibited by EWS-Fli1 knockdown.	('inhibited', 'NegReg', (98, 107))	('EWS-Fli1', 'Gene', '2130', (111, 119))	('EWS-Fli1', 'Gene', (111, 119))	('H3K27Ac', 'Protein', (49, 56))	('knockdown', 'Var', (120, 129))
209926	27006472	The antitumor effects of JQ1(+) on Ewing Sarcoma were also confirmed in vivo, as intra-peritoneal administrations of JQ1(+) significantly improve the overall survival of tumor-bearing nude mice through delaying the tumor growth.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('nude mice', 'Species', '10090', (184, 193))	('Sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('delaying', 'NegReg', (202, 210))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (170, 175))	('improve', 'PosReg', (138, 145))	('tumor', 'Disease', (8, 13))	('JQ1(+', 'Var', (117, 122))	('Ewing Sarcoma', 'Disease', (35, 48))
209952	27006472	Ewing Sarcoma cells were seeded at a density of 1000 cells per well in 6-well plate and treated with 4 muM of JQ1(+), JQ1(-) or the corresponding amount of DMSO for 48 hours.	('Sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('muM', 'Gene', '56925', (103, 106))	('Ewing Sarcoma', 'Disease', (0, 13))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('JQ1(-', 'Var', (118, 123))	('muM', 'Gene', (103, 106))	('JQ1(+', 'Var', (110, 115))	('DMSO', 'Chemical', 'MESH:D004121', (156, 160))
209954	27006472	Ewing Sarcoma cells were cultured or not in presence of JQ1(+) during 24 hours and 20 000 cells were then plated in 8 mum-pored Boyden Chambers (Falcon), always in presence of JQ1(+), in 1% FBS growth medium for additional 48 hours.	('Sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('FBS', 'Disease', 'MESH:D005198', (190, 193))	('JQ1', 'Var', (176, 179))	('mum', 'Gene', (118, 121))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('Ewing Sarcoma', 'Disease', (0, 13))	('FBS', 'Disease', (190, 193))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('mum', 'Gene', '56925', (118, 121))
210060	25881607	Since IkappaBalpha is one of calpain's hydrolysis substrates and also the inhibitor of nuclear factor-kappaB (NF-kappaB), the suppressed osteoclastogenesis after calpain inhibition could be due to the reduction of IkappaBalpha hydrolysis, leading to the inhibition of RANKL-induced NF-kappaB activation, as proved by Lee et al.	('osteoclastogenesis', 'CPA', (137, 155))	('pain', 'Disease', (165, 169))	('reduction', 'NegReg', (201, 210))	('NF-kappaB', 'Protein', (282, 291))	('suppressed', 'NegReg', (126, 136))	('IkappaBalpha', 'Gene', (6, 18))	('inhibition', 'Var', (170, 180))	('pain', 'Phenotype', 'HP:0012531', (32, 36))	('pain', 'Disease', 'MESH:D010146', (32, 36))	('pain', 'Disease', (32, 36))	('pain', 'Phenotype', 'HP:0012531', (165, 169))	('inhibition', 'NegReg', (254, 264))	('IkappaBalpha', 'Gene', '25493', (214, 226))	('activation', 'PosReg', (292, 302))	('IkappaBalpha', 'Gene', (214, 226))	('rat', 'Species', '10116', (55, 58))	('IkappaBalpha', 'Gene', '25493', (6, 18))	('pain', 'Disease', 'MESH:D010146', (165, 169))
210061	25881607	Similar with our previous in vitro study, TRAP-positive cells in the tibia were significantly decreased after calpain inhibition, indicating that the osteoclastogenesis process can also be interfered with by a calpain inhibitor in vivo.	('pain', 'Disease', 'MESH:D010146', (213, 217))	('TRAP', 'Gene', (42, 46))	('pain', 'Disease', (213, 217))	('calpain inhibitor', 'Gene', '25403', (210, 227))	('calpain inhibitor', 'Gene', (210, 227))	('pain', 'Phenotype', 'HP:0012531', (113, 117))	('decreased', 'NegReg', (94, 103))	('pain', 'Disease', 'MESH:D010146', (113, 117))	('pain', 'Disease', (113, 117))	('pain', 'Phenotype', 'HP:0012531', (213, 217))	('osteoclastogenesis process', 'CPA', (150, 176))	('inhibition', 'Var', (118, 128))	('TRAP', 'Gene', '25732', (42, 46))
210096	23230561	The stage of tumor using the standard tumor-node-metastasis staging system was T4N0M0.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('T4N0M0', 'Var', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
210119	23230561	None of these are absolutely specific to smooth muscle and positivity for two of these markers were more supportive of leiomyosarcoma than positivity for one alone.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('leiomyosarcoma', 'Disease', (119, 133))	('positivity', 'Var', (59, 69))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (119, 133))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (119, 133))
210400	25633912	Furthermore, the 60-90 minute half lives of Ki-67 and TCII are relatively short in comparison to the 8 h half life of TCII-R, thereby affecting the ability to uniformly capture timing of peak expression for each protein.	('TCII', 'Gene', '6948', (54, 58))	('TCII', 'Gene', '6948', (118, 122))	('affecting', 'Reg', (134, 143))	('Ki-67', 'Chemical', '-', (44, 49))	('TCII', 'Gene', (118, 122))	('TCII', 'Gene', (54, 58))	('timing', 'MPA', (177, 183))	('Ki-67', 'Var', (44, 49))	('ability', 'MPA', (148, 155))
210450	21298745	In vivo BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested, but in none of the ALL xenografts studied.	('solid tumor', 'Disease', 'MESH:D009369', (114, 125))	('differences', 'Reg', (39, 50))	('BMS-754807', 'Var', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('EFS distribution', 'MPA', (54, 70))	('solid tumor', 'Disease', (114, 125))
210460	21298745	Phosphorylation of IRS-1 activates the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) ultimately leading to conversion of phosphatidylinositol-4,5-biphoshate (PIP2) to phosphatidylinositol-3,4,5-biphoshate (PIP3).	('conversion', 'MPA', (124, 134))	('activates', 'PosReg', (25, 34))	('phosphatidylinositol-3,4,5-biphoshate', 'Chemical', '-', (184, 221))	('IRS-1', 'Gene', '3667', (19, 24))	('Phosphorylation', 'Var', (0, 15))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (65, 85))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (138, 158))	('leading to', 'Reg', (113, 123))	('IRS-1', 'Gene', (19, 24))	('PIP3', 'Chemical', '-', (223, 227))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (184, 204))	('phosphatidylinositol-4,5-biphoshate', 'Chemical', '-', (138, 173))	('PIP2', 'Chemical', 'MESH:D019269', (175, 179))
210461	21298745	PIP3 activates phosphoinositide-dependent kinase-1 (PDK1), resulting in phosphorylation and activation of the serine/threonine kinase Akt.	('activation', 'PosReg', (92, 102))	('Akt', 'Gene', '207', (134, 137))	('activates', 'PosReg', (5, 14))	('phosphorylation', 'MPA', (72, 87))	('PDK1', 'Gene', '5163', (52, 56))	('phosphoinositide-dependent kinase-1', 'Gene', '5163', (15, 50))	('PIP3', 'Chemical', '-', (0, 4))	('phosphoinositide-dependent kinase-1', 'Gene', (15, 50))	('PDK1', 'Gene', (52, 56))	('Akt', 'Gene', (134, 137))	('PIP3', 'Var', (0, 4))
210462	21298745	Akt enhances intracellular metabolism through glycogen synthase kinase-3 (GSK3); protein synthesis and cell growth through the mammalian target of rapamycin (mTOR); cell survival through BAD (a Bcl-2 family member); and cell proliferation through p28Kip1 (reviewed in Refs.).	('intracellular metabolism', 'MPA', (13, 37))	('cell survival', 'CPA', (165, 178))	('cell growth', 'CPA', (103, 114))	('mammalian target of rapamycin', 'Gene', '2475', (127, 156))	('cell proliferation', 'CPA', (220, 238))	('mammalian target of rapamycin', 'Gene', (127, 156))	('protein synthesis', 'MPA', (81, 98))	('glycogen synthase', 'MPA', (46, 63))	('Akt', 'Gene', '207', (0, 3))	('p28Kip1', 'Var', (247, 254))	('enhances', 'PosReg', (4, 12))	('Akt', 'Gene', (0, 3))	('mTOR', 'Gene', (158, 162))	('mTOR', 'Gene', '2475', (158, 162))
210467	21298745	Small molecule inhibitors of IGF-1R have the advantage of oral bioavailability, and unlike the anti-IGF-1R antibodies, small molecule inhibitors of IGF-1R may also target the insulin receptor (IR) and the hybrid IGF-1R/IR receptor.	('IGF-1R', 'Gene', (148, 154))	('inhibitors', 'Var', (134, 144))	('insulin receptor (IR', 'Gene', (175, 195))	('IR', 'Gene', '3643', (219, 221))	('insulin receptor (IR)', 'Gene', '3643', (175, 196))	('target', 'Reg', (164, 170))	('hybrid', 'Protein', (205, 211))	('IR', 'Gene', '3643', (193, 195))	('small', 'Var', (119, 124))
210473	21298745	In the current report we have evaluated BMS-754807 against a panel of pediatric tumors, in vitro and in vivo, through the NCI-supported Pediatric Preclinical Testing Program (PPTP).	('pediatric tumors', 'Disease', 'MESH:D063766', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('pediatric tumors', 'Disease', (70, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('PPTP', 'Chemical', '-', (175, 179))	('BMS-754807', 'Var', (40, 50))
210475	21298745	Cells were incubated in the presence of BMS-754807 for 96 hr at concentrations from 1 nM to 10 muM and analyzed as previously described.	('muM', 'Gene', '56925', (95, 98))	('BMS-754807', 'Var', (40, 50))	('muM', 'Gene', (95, 98))
210477	21298745	CB17SC-M scid-/- female mice (Taconic Farms, Germantown, NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described.	('neuroblastoma', 'Disease', (184, 197))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (165, 181))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('neuroblastoma', 'Phenotype', 'HP:0003006', (184, 197))	('CB17SC-M', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioma', 'Disease', (272, 278))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('non-glioblastoma brain tumors', 'Disease', (203, 232))	('neuroblastoma', 'Disease', 'MESH:D009447', (184, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('sarcomas', 'Disease', (134, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('glioma', 'Disease', 'MESH:D005910', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('brain tumors', 'Phenotype', 'HP:0030692', (220, 232))	('rhabdomyosarcoma', 'Disease', (165, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('non-glioblastoma brain tumors', 'Disease', 'MESH:D005909', (203, 232))	('osteosarcoma', 'Disease', (151, 163))	('mice', 'Species', '10090', (24, 28))	('glioblastoma', 'Phenotype', 'HP:0012174', (207, 219))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('rhabdoid tumors', 'Disease', (117, 132))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (117, 132))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (165, 181))	('mice', 'Species', '10090', (253, 257))
210488	21298745	The median EC50 value for BMS-754807 for the five cell lines with the greatest response to the anti-IGF-1R monoclonal antibody mAb391 (all with inhibition >30%) was 0.12 muM, while the median EC50 for the 10 cell lines with the least evidence of mAb391 treatment effect was approximately 10-fold higher at 1.0 muM (P = 0.0017).	('muM', 'Gene', '56925', (170, 173))	('muM', 'Gene', '56925', (310, 313))	('BMS-754807', 'Var', (26, 36))	('muM', 'Gene', (310, 313))	('muM', 'Gene', (170, 173))
210491	21298745	Four solid tumor xenografts were inevaluable because of toxicity (GBM2, BT-39, and D456 from the GBM panel; CHLA-258 from the Ewing sarcoma panel) and a medulloblastoma xenograft (BT-50) was inevaluable because of inadequate growth of tumors in control animals.	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('solid tumor', 'Disease', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Ewing sarcoma panel', 'Disease', (126, 145))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('solid tumor', 'Disease', 'MESH:D009369', (5, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('toxicity', 'Disease', 'MESH:D064420', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (126, 139))	('medulloblastoma', 'Phenotype', 'HP:0002885', (153, 168))	('medulloblastoma xenograft', 'Disease', 'MESH:D008527', (153, 178))	('toxicity', 'Disease', (56, 64))	('Ewing sarcoma panel', 'Disease', 'MESH:C563168', (126, 145))	('inadequate growth', 'Phenotype', 'HP:0001510', (214, 231))	('D456', 'Var', (83, 87))	('tumors', 'Disease', (235, 241))	('medulloblastoma xenograft', 'Disease', (153, 178))
210494	21298745	BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested as shown (Table II).	('BMS-754807', 'Var', (0, 10))	('solid tumor', 'Disease', (106, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('differences', 'Reg', (31, 42))	('EFS distribution', 'MPA', (46, 62))	('solid tumor', 'Disease', 'MESH:D009369', (106, 117))
210503	21298745	Typical tumor responses are shown in Figure 3 (KT14 (rhabdoid), KT5 (Wilms), Rh28 (rhabdomyosarcoma), OS1 (osteosarcoma)).	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('OS1', 'Gene', '2487', (102, 105))	('rhabdoid', 'Disease', 'MESH:D018335', (53, 61))	('OS1', 'Gene', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('rhabdoid', 'Disease', (53, 61))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (83, 99))	('osteosarcoma', 'Disease', (107, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('rhabdomyosarcoma', 'Disease', (83, 99))	('Rh28', 'Var', (77, 81))	('tumor', 'Disease', (8, 13))	('Wilms', 'Disease', (69, 74))	('Wilms', 'Disease', 'MESH:D009396', (69, 74))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (83, 99))
210505	21298745	In alveolar rhabdomyosarcoma, the PAX3-FKHR or PAX7-FKHR chimeric transcription factors associated with t(2;13)(q35;q14) and t(1;13)(q36;q14), enhance transcription IGF-1R.	('enhance', 'PosReg', (143, 150))	('PAX7', 'Gene', (47, 51))	('transcription IGF-1R', 'MPA', (151, 171))	('t(2;13)(q35;q14', 'Var', (104, 119))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (12, 28))	('FKHR', 'Gene', '2308', (39, 43))	('alveolar rhabdomyosarcoma', 'Disease', (3, 28))	('FKHR', 'Gene', (52, 56))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (104, 120))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (3, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('FKHR', 'Gene', '2308', (52, 56))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (3, 28))	('PAX3', 'Gene', (34, 38))	('t(1;13)(q36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (125, 141))	('PAX3', 'Gene', '5077', (34, 38))	('FKHR', 'Gene', (39, 43))	('PAX7', 'Gene', '5081', (47, 51))	('t(1;13)(q36;q14', 'Var', (125, 140))
210509	21298745	EWS-FLI1 silencing leads to increased levels of insulin-like growth factor binding protein 3 gene (IGFBP-3), a major regulator of IGF-1.	('increased', 'PosReg', (28, 37))	('FLI1', 'Gene', '2313', (4, 8))	('FLI1', 'Gene', (4, 8))	('insulin-like growth factor binding protein 3', 'Gene', (48, 92))	('insulin-like growth factor binding protein 3', 'Gene', '3486', (48, 92))	('silencing', 'Var', (9, 18))	('IGF-1', 'Gene', '3479', (130, 135))	('levels of', 'MPA', (38, 47))	('IGF-1', 'Gene', (130, 135))	('IGFBP-3', 'Gene', '3486', (99, 106))	('IGFBP-3', 'Gene', (99, 106))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
210517	21298745	Results for the murine anti-IGF-1R monoclonal antibody mAb391 show consistency with those for BMS-754807, as the EC50 for BMS-754807 is 10-fold lower in the mAb391-sensitive lines compared to the mAb391-resistant lines.	('BMS-754807', 'Var', (122, 132))	('murine', 'Species', '10090', (16, 22))	('EC50', 'MPA', (113, 117))	('lower', 'NegReg', (144, 149))
210519	21298745	For example, using biochemical assays of kinase inhibition, BMS-754807 shows low nanomolar activity against Met, TrkA, TrkB, and AurA, with IC50 values two- to fivefold greater than those observed for IGF-1R and IR.	('Met', 'Protein', (108, 111))	('IC50', 'MPA', (140, 144))	('TrkA', 'Gene', (113, 117))	('AurA', 'Disease', (129, 133))	('TrkB', 'Gene', '4915', (119, 123))	('TrkA', 'Gene', '4914', (113, 117))	('IR', 'Gene', '3643', (212, 214))	('BMS-754807', 'Var', (60, 70))	('TrkB', 'Gene', (119, 123))	('nanomolar activity', 'MPA', (81, 99))
210523	21298745	In published studies antibodies that block ligand binding to IGF-1R induced regressions of tumors whereas BMS-754807 induced growth inhibition.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('growth', 'CPA', (125, 131))	('regressions', 'CPA', (76, 87))	('IGF-1R', 'Gene', (61, 67))	('antibodies', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
210550	25003665	The correlation between mTOR pathway abnormalities and carcinogenesis has been extensively reported.	('abnormalities', 'Var', (37, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))	('carcinogenesis', 'Disease', (55, 69))
210567	25003665	Adequate bone marrow, hepatic and renal function were mandatory and were defined as: absolute neutrophil count >=1.5 x 109 l-1, platelets >=100 x 109 l-1, bilirubin, aspartate aminotranferase (AST), alanine aminotransferase and creatinine <=1.5 x upper limit of normal and creatinine clearance >=60 ml min-1.	('creatinine clearance', 'MPA', (273, 293))	('AST', 'Gene', '26503', (193, 196))	('bilirubin', 'Chemical', 'MESH:D001663', (155, 164))	('creatinine', 'Chemical', 'MESH:D003404', (228, 238))	('AST', 'Gene', (193, 196))	('min-1', 'Gene', '966', (302, 307))	('min-1', 'Gene', (302, 307))	('aspartate aminotranferase', 'Gene', '26503', (166, 191))	('>=1.5', 'Var', (111, 116))	('creatinine', 'Chemical', 'MESH:D003404', (273, 283))	('>=100 x 109 l-1', 'Var', (138, 153))	('alanine', 'MPA', (199, 206))	('aspartate aminotranferase', 'Gene', (166, 191))
210582	25003665	Dose-limiting toxicity was defined as any of the following within 3 weeks after the administration of the first cycle: absolute neutrophil count <0.5 x 109 l-1 over >=5 days or associated with fever >=38.5 C, platelets <50 x 109 l-1, any grade 3-4 non-haematological toxicity (excluding nausea and vomiting non-refractory to antiemetic treatment) or skin rash grade 2 related to treatment and not controlled with support medication.	('fever', 'Phenotype', 'HP:0001945', (193, 198))	('nausea', 'Disease', (287, 293))	('platelets <50 x 109 l-1', 'Var', (209, 232))	('vomiting', 'Disease', 'MESH:D014839', (298, 306))	('toxicity', 'Disease', 'MESH:D064420', (14, 22))	('skin rash', 'Disease', (350, 359))	('toxicity', 'Disease', 'MESH:D064420', (267, 275))	('nausea', 'Disease', 'MESH:D009325', (287, 293))	('non-haematological', 'Disease', (248, 266))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (287, 306))	('vomiting', 'Phenotype', 'HP:0002013', (298, 306))	('vomiting', 'Disease', (298, 306))	('toxicity', 'Disease', (14, 22))	('grade', 'Disease', (238, 243))	('toxicity', 'Disease', (267, 275))	('skin rash', 'Disease', 'MESH:D005076', (350, 359))	('fever', 'Disease', 'MESH:D005334', (193, 198))	('fever', 'Disease', (193, 198))	('skin rash', 'Phenotype', 'HP:0000988', (350, 359))	('nausea', 'Phenotype', 'HP:0002018', (287, 293))	('<0.5 x 109 l-1', 'Var', (145, 159))
210592	25003665	Sirolimus and its internal standard ([13C2D4]-everolimus) were detected in multiple reaction monitoring mode using mass-to-charge (m/z) transition of 931.9 864.4 and 981.9 914.4, respectively.	('everolimus', 'Chemical', 'MESH:D000068338', (46, 56))	('Sirolimus', 'Chemical', 'MESH:D020123', (0, 9))	('981.9 914.4', 'Var', (166, 177))	('931.9 864.4', 'Var', (150, 161))
210595	25003665	Two sarcoma cell lines acquired from Cell Lines Service (CLS, Eppelheim, Germany) were used to assess the in vitro efficacy of the treatment: SKLMS-1 and SW982 (leiomyosarcoma and synovial sarcoma, respectively).	('CLS', 'Disease', (57, 60))	('CLS', 'Disease', 'MESH:D038921', (57, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (180, 196))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))	('sarcoma', 'Disease', (189, 196))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (161, 175))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (161, 175))	('sarcoma', 'Disease', (4, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('SW982', 'Var', (154, 159))	('synovial sarcoma', 'Disease', (180, 196))	('sarcoma', 'Disease', (168, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('synovial sarcoma', 'Disease', 'MESH:D013584', (180, 196))	('SW982', 'CellLine', 'CVCL:1734', (154, 159))	('leiomyosarcoma', 'Disease', (161, 175))
210660	25003665	In agreement with this hypothesis, several reports demonstrate that inhibition of antiapoptotic bcl-2 family members sensitises tumour cells to gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (144, 155))	('inhibition', 'Var', (68, 78))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('bcl-2', 'Gene', (96, 101))	('sensitises tumour', 'Disease', 'MESH:D009369', (117, 134))	('sensitises tumour', 'Disease', (117, 134))	('bcl-2', 'Gene', '596', (96, 101))
210677	22551002	Earlier cytogenetic studies in limited cases demonstrated that UESL is associated with a recurrent translocation t(11;19)(q11;q13.3-q13.4) or add(19)(q13.4).	('t(11;19)(q11;q13.3-q13.4', 'Var', (113, 137))	('add(19)(q13.4', 'Var', (142, 155))	('associated', 'Reg', (71, 81))	('SL', 'Disease', 'MESH:C564794', (65, 67))
210678	22551002	In this report, we present our array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) findings, and a missense mutation of TP53 gene by DNA sequencing in a 19-year-old patient with UESL.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('patient', 'Species', '9606', (203, 210))	('SL', 'Disease', 'MESH:C564794', (218, 220))	('missense mutation', 'Var', (137, 154))
210684	22551002	Multiple cytogenetic studies of sporadic cases demonstrated that UESL frequently harbors chromosomal rearrangements of 19q13.4, including the translocation t(11;19)(q11;q13.3/13.4) and add(19)(q13.4).	('19q13.4', 'Gene', (119, 126))	('SL', 'Disease', 'MESH:C564794', (67, 69))	('t(11;19)(q11;q13.3/13.4', 'Var', (156, 179))	('add(19)(q13.4', 'Var', (185, 198))	('chromosomal rearrangements', 'Var', (89, 115))
210685	22551002	used a conventional CGH technique to investigate chromosomal imbalances in six patients with UESL and reported losses or gains of whole chromosomes or partial chromosomal regions.	('gains', 'PosReg', (121, 126))	('losses', 'NegReg', (111, 117))	('partial chromosomal regions', 'Var', (151, 178))	('whole', 'Protein', (130, 135))	('patients', 'Species', '9606', (79, 87))	('SL', 'Disease', 'MESH:C564794', (95, 97))	('imbalances', 'Phenotype', 'HP:0002172', (61, 71))
210687	22551002	Point mutations of the TP53 gene were also detected in three UESL cases.	('SL', 'Disease', 'MESH:C564794', (63, 65))	('Point mutations', 'Var', (0, 15))	('detected', 'Reg', (43, 51))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
210708	22551002	The tumor had losses of multiple chromosomal regions, including 1p13.1, several regions on 2q, 3p, 4q, and alternating deletions on 5q, 8q24.12-qter, 9p24.1, 9q34.11, 9q34.3, 10pter-q22.1, 11pter-p15.4, 14q12-qter, 15q, 16pter-p13.3, 17pter-p12, 19p13.3-13.11, 20q13.32-qter, 22q12.3, and 22q13.1-qter.	('tumor', 'Disease', (4, 9))	('losses', 'NegReg', (14, 20))	('p12', 'Gene', (241, 244))	('p13', 'Gene', (248, 251))	('deletions', 'Var', (119, 128))	('p13', 'Gene', (65, 68))	('p13', 'Gene', (227, 230))	('p15', 'Gene', (196, 199))	('p15', 'Gene', '1030', (196, 199))	('p13', 'Gene', '440926', (65, 68))	('p13', 'Gene', '440926', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('p12', 'Gene', '56655', (241, 244))	('p13', 'Gene', '440926', (248, 251))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
210712	22551002	A point mutation (C>T) in TP53 gene exon 7 at nucleotide 13379 (g.13379 C>T) resulting in the substitution of an arginine for a methionine at codon 248 (R248W) was identified in this case (Figure 3).	('TP53', 'Gene', (26, 30))	('substitution', 'Var', (94, 106))	('arginine for a methionine at codon 248', 'Mutation', 'p.M248R', (113, 151))	('g.13379 C>T', 'Mutation', 'g.13379C>T', (64, 75))	('R248W', 'Mutation', 'rs121912651', (153, 158))	('g.13379 C>T', 'Var', (64, 75))	('TP53', 'Gene', '7157', (26, 30))
210714	22551002	Our investigation of this single UESL case identified multiple unreported genomic imbalances involving gains of regions on chromosome 2 (2pter-p25.3 and 2q14.1), 19p13.11, 21q22.13-q22.3, and 22q13.1, as well as deletions of 1p13.1, alternating deletions on 5q (5q21.2-5q33.3), 8q24.12-qter, 9q (9q34.11 and 9q34.3), 15q11.2-qter, 16pter-p13.3, 17pter-p12, 19p13.3-p13.11, 20q13.32-qter, and 22q (22q12.3 and 22q13.1-qter).	('p13', 'Gene', (164, 167))	('p13', 'Gene', (226, 229))	('p12', 'Gene', '56655', (352, 355))	('deletions', 'Var', (212, 221))	('SL', 'Disease', 'MESH:C564794', (35, 37))	('p13', 'Gene', '440926', (164, 167))	('p13', 'Gene', (338, 341))	('p13', 'Gene', '440926', (226, 229))	('imbalances', 'Phenotype', 'HP:0002172', (82, 92))	('p13', 'Gene', '440926', (338, 341))	('p12', 'Gene', (352, 355))	('p13', 'Gene', (359, 362))	('p13', 'Gene', (365, 368))	('p25', 'Gene', (143, 146))	('p25', 'Gene', '54732', (143, 146))	('p13', 'Gene', '440926', (359, 362))	('p13', 'Gene', '440926', (365, 368))	('deletions', 'Var', (245, 254))
210719	22551002	The same is true for the deletions on chromosome 8q (8q24.12-qter) and 17p (17pter-p12) detected in our study as opposed to the duplications reported by Sowery et al.	('deletions', 'Var', (25, 34))	('p12', 'Gene', '56655', (83, 86))	('p12', 'Gene', (83, 86))
210722	22551002	To our knowledge, this is the fourth UESL case reported to carry the TP53 gene mutation.	('TP53', 'Gene', (69, 73))	('SL', 'Disease', 'MESH:C564794', (39, 41))	('mutation', 'Var', (79, 87))	('TP53', 'Gene', '7157', (69, 73))
210723	22551002	This particular mutation, as a somatic or germline change, has been reported in a variety of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (93, 105))	('mutation', 'Var', (16, 24))	('solid tumors', 'Disease', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('reported', 'Reg', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
210724	22551002	Interestingly, all these mutations, identified in cases with UESL, namely, K120M, V216M, S245G, and R248W (our case) are located in the sequence-specific DNA binding domain (amino acid residues 102-292 out of the 393 of the p53 protein), where the hot spots of mutations are located.	('V216M', 'Mutation', 'rs730882025', (82, 87))	('p53', 'Gene', (224, 227))	('p53', 'Gene', '7157', (224, 227))	('R248W', 'Mutation', 'rs121912651', (100, 105))	('K120M', 'Mutation', 'p.K120M', (75, 80))	('SL', 'Disease', 'MESH:C564794', (63, 65))	('R248W', 'Var', (100, 105))	('K120M', 'Var', (75, 80))	('S245G', 'Mutation', 'rs28934575', (89, 94))	('V216M', 'Var', (82, 87))	('S245G', 'Var', (89, 94))
210725	22551002	The major consequence of these mutations in this domain is loss of sequence-specific DNA binding to the canonical p53-binding site and loss of the ability to induce cell cycle arrest or apoptosis.	('mutations', 'Var', (31, 40))	('p53', 'Gene', (114, 117))	('arrest', 'Disease', 'MESH:D006323', (176, 182))	('loss', 'NegReg', (135, 139))	('p53', 'Gene', '7157', (114, 117))	('arrest', 'Disease', (176, 182))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (165, 182))	('loss', 'NegReg', (59, 63))	('DNA binding', 'Interaction', (85, 96))	('apoptosis', 'CPA', (186, 195))	('induce', 'Reg', (158, 164))
210726	22551002	It has been reported that ellipticine may restore the DNA binding domain and transcription function in transfected p53 mutants cells with different mutations in this sequence-specific DNA binding domain.	('DNA binding domain', 'MPA', (54, 72))	('transcription function', 'MPA', (77, 99))	('mutations', 'Var', (148, 157))	('restore', 'PosReg', (42, 49))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('mutants', 'Var', (119, 126))	('ellipticine', 'Chemical', 'MESH:C034192', (26, 37))
210729	22551002	Although loss of chromosome 14 has been reported in rhabdomyosarcoma and neuroblastoma and associated with poor outcomes in clear-cell renal cell carcinoma, it is unclear whether the loss of chromosome 14 plays an important role in UESL initiation or progression.	('clear-cell renal cell carcinoma', 'Disease', (124, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('SL', 'Disease', 'MESH:C564794', (234, 236))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 155))	('neuroblastoma', 'Phenotype', 'HP:0003006', (73, 86))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (52, 68))	('loss', 'Var', (9, 13))	('rhabdomyosarcoma and neuroblastoma', 'Disease', 'MESH:D009447', (52, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
210734	22551002	FGFR3 amplification and/or overexpression was reported in rhabdomyosarcoma and bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('FGFR3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (58, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('amplification', 'Var', (6, 19))	('overexpression', 'PosReg', (27, 41))	('bladder cancer', 'Disease', (79, 93))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (58, 74))	('rhabdomyosarcoma', 'Disease', (58, 74))	('FGFR3', 'Gene', '2261', (0, 5))
210738	22551002	Over the past few years, three cases of UESL have been reported to develop within MHL, displaying similar genetic rearrangements involving either an add(19)(q13.4) or t(11;19)(q11;q13.3-13.4), nearly identical to the genetic rearrangements observed in previous solitary cases of MHL.	('add(19)(q13.4', 'Var', (149, 162))	('t(11;19)(q11;q13.3-13.4', 'Var', (167, 190))	('SL', 'Disease', 'MESH:C564794', (42, 44))
210744	22551002	In addition, we also emphasized the inactivation of TP53 gene through the loss of heterozygosity and a pathogenic mutation of the remaining allele.	('pathogenic', 'Reg', (103, 113))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))	('loss of', 'NegReg', (74, 81))	('mutation', 'Var', (114, 122))
210770	31435477	On immunohistochemistry, the tumor cells express CD35, CD23, and CD21 (Figs.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('CD21', 'Gene', '1380', (65, 69))	('CD21', 'Gene', (65, 69))	('CD35', 'Gene', '1378', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CD23', 'Var', (55, 59))	('CD35', 'Gene', (49, 53))	('tumor', 'Disease', (29, 34))
210815	28955656	Sarcomas of the genetically simple category (hypomutated) are characterized by only one disease-specific "driver" aberration such as a translocation or mutation (Table 2) and are more common in younger patients.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('translocation', 'Var', (135, 148))	('patients', 'Species', '9606', (202, 210))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('mutation', 'Var', (152, 160))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
210816	28955656	For example, detecting the amplification of MDM2 helps to confirm the diagnosis of a well-differentiated or dedifferentiated liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('MDM2', 'Gene', '4193', (44, 48))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('liposarcoma', 'Disease', 'MESH:D008080', (125, 136))	('MDM2', 'Gene', (44, 48))	('liposarcoma', 'Disease', (125, 136))	('amplification', 'Var', (27, 40))
210817	28955656	The genetically complex group (hypermutated) is made up by more or less chaotic karyotypes with high mutation frequencies in key oncogenes and tumor suppressor genes like TP53 or RB1.	('TP53', 'Gene', (171, 175))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('RB1', 'Gene', '5925', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutation', 'Var', (101, 109))	('RB1', 'Gene', (179, 182))	('TP53', 'Gene', '7157', (171, 175))
210824	28955656	An important improvement in the management of this neoplasm was achieved in 1998 due to the discovery of oncogenic mutations in the tyrosine kinase KIT.	('neoplasm', 'Disease', (51, 59))	('mutations', 'Var', (115, 124))	('neoplasm', 'Disease', 'MESH:D009369', (51, 59))	('neoplasm', 'Phenotype', 'HP:0002664', (51, 59))
210826	28955656	In some cases, a specific treatment can now be selected to target a mutation in a molecular pathway if a drug targeting this pathway is available, even if this drug was originally approved for a different tumor type.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mutation', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('molecular pathway', 'Pathway', (82, 99))
210835	28955656	Increasing evidence indicates that sarcomagenesis might be initiated by an aberration in a multipotent cell, and this hypothesis is currently favored by most researchers in the field.	('aberration', 'Var', (75, 85))	('sarcoma', 'Disease', (35, 42))	('initiated by', 'Reg', (59, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))
210843	28955656	Genetic approaches aimed to knock out tumor suppressor genes and overexpress specific oncogenes have been used to induce MSCs transformation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('MSCs transformation', 'Disease', (121, 140))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('induce', 'Reg', (114, 120))	('knock', 'Var', (28, 33))
210846	28955656	By using hMSC, they established cell lines by serially introducing these genetic alterations, and the effect of this manipulation on cellular phenotype, gene expression profiles, karyotype, and multilineage differentiation capacity was compared to osteosarcoma.	('genetic alterations', 'Var', (73, 92))	('osteosarcoma', 'Disease', (248, 260))	('osteosarcoma', 'Phenotype', 'HP:0002669', (248, 260))	('osteosarcoma', 'Disease', 'MESH:D012516', (248, 260))	('alterations', 'Var', (81, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))
210850	28955656	They identified aneuploidization, translocation, and homozygous loss of the cdkn2 region as the key mediators of MSC transformation.	('aneuploidization', 'Var', (16, 32))	('translocation', 'Var', (34, 47))	('cdkn2', 'Gene', '1029', (76, 81))	('cdkn2', 'Gene', (76, 81))	('MSC', 'Disease', (113, 116))
210865	28955656	This underlines the importance of sarcoma molecular characterization and demonstrates that molecular testing could significantly increase diagnostic accuracy.	('sarcoma', 'Disease', (34, 41))	('diagnostic', 'MPA', (138, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('increase', 'PosReg', (129, 137))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('molecular testing', 'Var', (91, 108))
210867	28955656	Considering this heterogeneity, searching for actionable mutations using only next-generation sequencing techniques may be very challenging, and the treatment of tumor cells with specific mutations by targeted therapy could select for specific subpopulations resistant to the initial therapy, making the combination of multiple drugs with different targets the most promising approach, aiming at the inhibition of tumor growth at multiple levels.	('tumor', 'Disease', 'MESH:D009369', (414, 419))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (414, 419))	('mutations', 'Var', (188, 197))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
210886	28955656	Moreover, they highlighted a discrepancy between CDKN2A homozygous deletions in osteosarcoma and EWS cell lines (42 and 36%, respectively) compared to primary sarcoma samples, in which the frequency of this deletion is expected to be lower.	('CDKN2A', 'Gene', '1029', (49, 55))	('EWS', 'Phenotype', 'HP:0012254', (97, 100))	('EWS', 'Gene', (97, 100))	('deletions', 'Var', (67, 76))	('sarcoma', 'Disease', (159, 166))	('EWS', 'Gene', '2130', (97, 100))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('osteosarcoma', 'Disease', (80, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcoma', 'Disease', (85, 92))	('CDKN2A', 'Gene', (49, 55))	('sarcoma', 'Disease', 'MESH:D012509', (159, 166))
210897	28955656	Since little is known about the molecular biology of sarcomas including unknown contextual cross talk between signaling pathways and other components presumably including epigenetic modifications and regulatory RNA sequences, patient-derived sarcoma tumor models are desirable tools to fulfill the promises of personalized medicine.	('epigenetic modifications', 'Var', (171, 195))	('sarcoma tumor', 'Disease', 'MESH:D012509', (242, 255))	('patient', 'Species', '9606', (226, 233))	('sarcoma tumor', 'Disease', (242, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcomas', 'Disease', (53, 61))
210908	28955656	Taken together, these data demonstrated that EWS 3D models are useful and reliable tools for evaluating new IGF-1R antagonists not only as single agents but also in combined strategies.	('EWS', 'Gene', (45, 48))	('IGF-1R', 'Gene', (108, 114))	('IGF-1R', 'Gene', '3480', (108, 114))	('antagonists', 'Var', (115, 126))	('EWS', 'Phenotype', 'HP:0012254', (45, 48))	('EWS', 'Gene', '2130', (45, 48))
210933	28955656	These results were then validated in a second study-set of 160 tumors confirming the presence of subtype-specific mutations in several genes such as PIK3CA in myxoid/round cell liposarcoma, TP53 in pleomorphic liposarcoma, and NF1 in myxofibrosarcoma and pleomorphic liposarcoma.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (238, 250))	('liposarcoma', 'Disease', (267, 278))	('mutations', 'Var', (114, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('liposarcoma', 'Disease', (210, 221))	('liposarcoma', 'Disease', (177, 188))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (198, 221))	('TP53', 'Gene', '7157', (190, 194))	('tumors', 'Disease', (63, 69))	('liposarcoma', 'Phenotype', 'HP:0012034', (267, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('myxofibrosarcoma and pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (234, 278))	('PIK3CA', 'Gene', '5290', (149, 155))	('NF1', 'Gene', '4763', (227, 230))	('pleomorphic liposarcoma', 'Disease', (255, 278))	('liposarcoma', 'Phenotype', 'HP:0012034', (210, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('liposarcoma', 'Phenotype', 'HP:0012034', (177, 188))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('liposarcoma', 'Disease', 'MESH:D008080', (267, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('liposarcoma', 'Disease', 'MESH:D008080', (210, 221))	('NF1', 'Gene', (227, 230))	('liposarcoma', 'Disease', 'MESH:D008080', (177, 188))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (255, 278))	('TP53', 'Gene', (190, 194))	('PIK3CA', 'Gene', (149, 155))	('pleomorphic liposarcoma', 'Disease', (198, 221))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
210943	28955656	Even if specific mutations have been associated with certain sarcoma subtypes, their etiology remain largely unknown.	('sarcoma subtypes', 'Disease', 'MESH:D012509', (61, 77))	('sarcoma subtypes', 'Disease', (61, 77))	('associated', 'Reg', (37, 47))	('mutations', 'Var', (17, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
210960	28955656	Integrating these profiling systems, it is possible to correlate the presence of tumor-specific mutations to functional alterations in intracellular pathways.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('intracellular pathways', 'Pathway', (135, 157))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', (81, 86))
210963	28955656	As mentioned before, several sarcoma types are characterized by the presence of chromosomal translocations that cause the production of altered transcription factors.	('chromosomal translocations', 'Var', (80, 106))	('sarcoma type', 'Disease', 'MESH:D012509', (29, 41))	('transcription factors', 'MPA', (144, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('sarcoma type', 'Disease', (29, 41))
210966	28955656	To this aim, Grohar and coworkers screened more than 50,000 compounds in TC32 EWS cells for the ability of altering the expression level of the EWS/FLI1 downstream target NR0B1, that was prior transfected with a luciferase construct.	('TC32', 'Gene', (73, 77))	('NR0B1', 'Gene', '190', (171, 176))	('FLI1', 'Gene', (148, 152))	('compounds', 'Var', (60, 69))	('TC32 EWS', 'CellLine', 'CVCL:7151', (73, 81))	('FLI1', 'Gene', '2313', (148, 152))	('EWS', 'Gene', '2130', (144, 147))	('EWS', 'Phenotype', 'HP:0012254', (78, 81))	('altering', 'Reg', (107, 115))	('expression level', 'MPA', (120, 136))	('EWS', 'Gene', '2130', (78, 81))	('EWS', 'Gene', (78, 81))	('EWS', 'Phenotype', 'HP:0012254', (144, 147))	('NR0B1', 'Gene', (171, 176))	('EWS', 'Gene', (144, 147))
211040	27893764	We found that the mutant MCPIP1, D141N, which lacks RNase activity, significantly inhibited degradation of both human and viral pre-miRNAs indicating that the RNase activity of MCPIP1 is responsible for cleavage of the pre-miRNAs (Fig 1C and 1D).	('inhibited', 'NegReg', (82, 91))	('MCPIP1', 'Gene', (25, 31))	('degradation', 'MPA', (92, 103))	('lacks', 'NegReg', (46, 51))	('miR', 'Gene', '220972', (223, 226))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (223, 226))	('D141N', 'Var', (33, 38))	('miR', 'Gene', (132, 135))	('D141N', 'Mutation', 'rs775252087', (33, 38))	('human', 'Species', '9606', (112, 117))
211047	27893764	Expression of hsa-miR-135b is also significantly reduced in the presence of MCPIP1 while there is no decrease in pri-hsa-miR135b expression in concordance with Suzuki et al.	('miR135b', 'Gene', '442891', (121, 128))	('reduced', 'NegReg', (49, 56))	('Expression', 'MPA', (0, 10))	('MCPIP1', 'Gene', (76, 82))	('miR135b', 'Gene', (121, 128))	('presence', 'Var', (64, 72))	('miR-135b', 'Gene', (18, 26))	('miR-135b', 'Gene', '442891', (18, 26))
211048	27893764	A similar experiment with the MCPIP1 D141N mutant results in no decrease in mature KSHV miRNA expression levels, supporting our results from the in vitro cleavage assays (Figs 2G, 1D and S2A Fig).	('miR', 'Gene', (88, 91))	('MCPIP1', 'Gene', (30, 36))	('decrease', 'NegReg', (64, 72))	('KSHV', 'Species', '37296', (83, 87))	('KS', 'Phenotype', 'HP:0100726', (83, 85))	('D141N mutant', 'Var', (37, 49))	('D141N', 'Mutation', 'rs775252087', (37, 42))	('miR', 'Gene', '220972', (88, 91))
211055	27893764	These data demonstrate not only that reduced MCPIP1 expression increases mature miRNA levels, but that this effect is primarily due to MCPIP1-mediated effects on pre-miRNAs during miRNA biogenesis as opposed to mature RISC-associated miRNA.	('miR', 'Gene', '220972', (80, 83))	('increases', 'PosReg', (63, 72))	('effects', 'Reg', (151, 158))	('miR', 'Gene', (80, 83))	('miR', 'Gene', '220972', (166, 169))	('MCPIP1-mediated', 'Gene', (135, 150))	('miR', 'Gene', (166, 169))	('MCPIP1', 'Gene', (45, 51))	('miR', 'Gene', '220972', (234, 237))	('miR', 'Gene', (234, 237))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (180, 183))	('reduced', 'Var', (37, 44))
211066	27893764	We found that MCPIP1 mRNA expression is reduced in infected MC116.219 cells, while Dicer and TRBP expression were both increased upon KSHV infection (S3 Fig).	('Dicer', 'Gene', (83, 88))	('KS', 'Phenotype', 'HP:0100726', (134, 136))	('TRBP', 'Gene', (93, 97))	('KSHV infection', 'Disease', 'MESH:C537372', (134, 148))	('TRBP', 'Gene', '6895', (93, 97))	('MC116.219', 'Var', (60, 69))	('Dicer', 'Gene', '23405', (83, 88))	('MCPIP1', 'Gene', (14, 20))	('reduced', 'NegReg', (40, 47))	('KSHV infection', 'Disease', (134, 148))	('mRNA expression', 'MPA', (21, 36))	('MC116.219', 'CellLine', 'CVCL:1399', (60, 69))	('increased', 'PosReg', (119, 128))	('expression', 'MPA', (98, 108))
211079	27893764	We found that expression of MCPIP1 was increased in the iSLK miRNA cluster mutant as compared to the wild type KSHV infected iSLK cells (Fig 4E), highlighting the importance of KSHV miRNA expression in the down-regulation of MCPIP1 expression.	('KSHV infected', 'Disease', 'MESH:C537372', (111, 124))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('miR', 'Gene', '220972', (182, 185))	('MCPIP1', 'Gene', (28, 34))	('miR', 'Gene', (182, 185))	('KSHV', 'Species', '37296', (111, 115))	('expression', 'MPA', (14, 24))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('increased', 'PosReg', (39, 48))	('mutant', 'Var', (75, 81))	('KS', 'Phenotype', 'HP:0100726', (177, 179))	('KSHV infected', 'Disease', (111, 124))	('KSHV', 'Species', '37296', (177, 181))
211081	27893764	Following the mutation of this predicted binding site, KSHV-miR-1 no longer repressed MCPIP1 3' UTR reporter expression, while reporter plasmids with the KSHV-miR-1 mutation could still be repressed by KSHV-miR-7 (Fig 4F).	('miR', 'Gene', '220972', (60, 63))	('KSHV', 'Species', '37296', (55, 59))	('miR-1', 'Gene', (159, 164))	('miR-1', 'Gene', '4961486', (159, 164))	('KS', 'Phenotype', 'HP:0100726', (154, 156))	('KS', 'Phenotype', 'HP:0100726', (202, 204))	('miR', 'Gene', (60, 63))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', '220972', (207, 210))	('KSHV', 'Species', '37296', (202, 206))	('miR', 'Gene', (159, 162))	('miR-1', 'Gene', (60, 65))	('miR-1', 'Gene', '4961486', (60, 65))	('KSHV', 'Species', '37296', (154, 158))	('miR', 'Gene', (207, 210))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('mutation', 'Var', (165, 173))	('MCPIP1', 'Gene', (86, 92))	('mutation', 'Var', (14, 22))
211086	27893764	We mutated either the 5' miRNA region (mut1) or the 3' target site (mut2) and observed that KSHV-miR-7 could no longer repress either of these reporter constructs indicating that both of these interactions are critical for KSHV-miR-7 directed MCPIP1 repression (Fig 4G).	('MCPIP1', 'Gene', (243, 249))	('miR', 'Gene', (228, 231))	('KS', 'Phenotype', 'HP:0100726', (92, 94))	('KS', 'Phenotype', 'HP:0100726', (223, 225))	('KSHV', 'Species', '37296', (223, 227))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('KSHV', 'Species', '37296', (92, 96))	('miR', 'Gene', '220972', (228, 231))	('miR', 'Gene', (97, 100))	('mutated', 'Var', (3, 10))
211097	27893764	Deletion of the KSHV miRNA cluster in the iSLK DeltamiRNA mutant cell line resulted in decreased expression of Dicer and TRBP as compared to the wild type KSHV infected iSLK cells (Fig 5C).	('Dicer', 'Gene', '23405', (111, 116))	('decreased', 'NegReg', (87, 96))	('Dicer', 'Gene', (111, 116))	('TRBP', 'Gene', (121, 125))	('KSHV', 'Gene', (16, 20))	('miR', 'Gene', '220972', (21, 24))	('KSHV infected', 'Disease', 'MESH:C537372', (155, 168))	('miR', 'Gene', (21, 24))	('TRBP', 'Gene', '6895', (121, 125))	('KSHV', 'Species', '37296', (155, 159))	('miR', 'Gene', '220972', (52, 55))	('KS', 'Phenotype', 'HP:0100726', (155, 157))	('KS', 'Phenotype', 'HP:0100726', (16, 18))	('KSHV', 'Species', '37296', (16, 20))	('miR', 'Gene', (52, 55))	('KSHV infected', 'Disease', (155, 168))	('expression', 'MPA', (97, 107))	('Deletion', 'Var', (0, 8))
211104	27893764	Conversely, the knockdown of Dicer has no effect on MCPIP1 expression (S4 Fig).	('MCPIP1', 'Gene', (52, 58))	('Dicer', 'Gene', '23405', (29, 34))	('Dicer', 'Gene', (29, 34))	('knockdown', 'Var', (16, 25))	('expression', 'MPA', (59, 69))
211129	27893764	Together, this data shows that modulation of MCPIP1 in the context of KSHV infection can result in significant changes in expression for its mRNA and miRNA targets and supports a role for MCPIP1 in KSHV pathogenesis.	('expression for', 'MPA', (122, 136))	('KSHV infection', 'Disease', 'MESH:C537372', (70, 84))	('miR', 'Gene', (150, 153))	('miR', 'Gene', '220972', (150, 153))	('modulation', 'Var', (31, 41))	('KSHV infection', 'Disease', (70, 84))	('MCPIP1', 'Gene', (45, 51))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('KSHV', 'Species', '37296', (70, 74))	('KSHV', 'Species', '37296', (198, 202))	('KS', 'Phenotype', 'HP:0100726', (198, 200))	('changes', 'Reg', (111, 118))
211133	27893764	Together with our data, this suggests that reduced MCPIP1 expression increases mature miRNA levels (Fig 2H) and is primarily due to MCPIP1-mediated effects during miRNA biogenesis as opposed to mature RISC-associated miRNA.	('increases', 'PosReg', (69, 78))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('effects', 'Reg', (148, 155))	('expression', 'Var', (58, 68))	('MCPIP1', 'Gene', (51, 57))	('miR', 'Gene', '220972', (217, 220))	('miR', 'Gene', (217, 220))	('miR', 'Gene', '220972', (163, 166))	('reduced', 'NegReg', (43, 50))	('miR', 'Gene', (163, 166))
211149	27893764	Multiple pieces of evidence suggest that MCPIP1 may inhibit miRNA biogenesis during other viral infections as well.	('inhibit', 'NegReg', (52, 59))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('MCPIP1', 'Var', (41, 47))	('viral infections', 'Disease', 'MESH:D001102', (90, 106))	('viral infections', 'Disease', (90, 106))
211177	27893764	The cytokines IL-1beta, TNFalpha and TWEAK were purchased from Peprotech and used at a working concentration as follows: IL-1beta (15 ng/ul), TNFalpha (15 ng/ul) and TWEAK (500 ng/ul).	('IL-1beta', 'Gene', '3553', (14, 22))	('IL-1beta', 'Gene', '3553', (121, 129))	('TNFalpha', 'Gene', (24, 32))	('TNFalpha', 'Gene', (142, 150))	('TWEAK', 'Gene', (166, 171))	('15 ng/ul', 'Var', (152, 160))	('TNFalpha', 'Gene', '7124', (24, 32))	('TWEAK', 'Gene', '8742', (166, 171))	('15 ng/ul', 'Var', (131, 139))	('TWEAK', 'Gene', (37, 42))	('TNFalpha', 'Gene', '7124', (142, 150))	('TWEAK', 'Gene', '8742', (37, 42))	('IL-1beta', 'Gene', (14, 22))	('IL-1beta', 'Gene', (121, 129))
211220	27893764	Primary antibodies include: mouse anti-Dicer (ab14601, Abcam), rabbit anti-TRBP (ab42018, Abcam), mouse anti-MCPIP (sc-515275, Santa Cruz).	('MCPIP', 'Gene', '80149', (109, 114))	('MCPIP', 'Gene', (109, 114))	('rabbit', 'Species', '9986', (63, 69))	('mouse', 'Species', '10090', (28, 33))	('ab42018', 'Var', (81, 88))	('Dicer', 'Gene', '23405', (39, 44))	('Dicer', 'Gene', (39, 44))	('TRBP', 'Gene', (75, 79))	('mouse', 'Species', '10090', (98, 103))	('ab14601', 'Var', (46, 53))	('TRBP', 'Gene', '6895', (75, 79))
211221	27893764	The following secondary antibodies conjugated to infrared (IR) fluorescing dyes were obtained from LI-COR: goat anti-rabbit antibody IR800CW, goat anti-mouse antibody IR680, and goat anti-mouse antibody IR800CW.	('rabbit', 'Species', '9986', (117, 123))	('mouse', 'Species', '10090', (188, 193))	('IR800CW', 'Var', (203, 210))	('mouse', 'Species', '10090', (152, 157))	('goat', 'Species', '9925', (178, 182))	('goat', 'Species', '9925', (142, 146))	('goat', 'Species', '9925', (107, 111))	('IR800CW', 'Var', (133, 140))
211235	22223258	This effect was associated with the induction of potent tumor antigen-specific CD8+ T-cell responses, as well as the infiltration of tumors with CD4+ and CD8+ T cells but not with the cytotoxic activity of DCs.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('CD8+', 'Var', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
211269	22223258	The mutant p53-derived peptide binds the MHC class I molecule and therefore is recognized by CD8+ T cells.	('p53', 'Gene', (11, 14))	('mutant', 'Var', (4, 10))	('binds', 'Interaction', (31, 36))	('MHC class I molecule', 'Protein', (41, 61))	('p53', 'Gene', '22060', (11, 14))
211280	22223258	In contrast, treatment of mice with DC-IL-12 and AL resulted in a substantial slow down of the tumor growth (Fig.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('DC-IL-12', 'Var', (36, 44))	('AL', 'Chemical', '-', (49, 51))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('slow down', 'NegReg', (78, 87))	('tumor', 'Disease', (95, 100))	('mice', 'Species', '10090', (26, 30))
211289	22223258	Thus, DC-IL-12, DC-IL-21, and DC-IFN-alpha provided significant antitumor activity against RENCA-bearing mice.	('tumor', 'Disease', (68, 73))	('IFN-alpha', 'Gene', (33, 42))	('RENCA', 'Phenotype', 'HP:0005584', (91, 96))	('IFN-alpha', 'Gene', '111654', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('IL-21', 'Gene', '60505', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mice', 'Species', '10090', (105, 109))	('IL-21', 'Gene', (19, 24))	('DC-IL-12', 'Var', (6, 14))
211328	22223258	Therefore, we hypothesized that using DC-IL-12 as the primary step of treatment would sensitize mice to the antitumor effects of IFN-alpha leading to increased efficacy and decreased toxicity.	('DC-IL-12', 'Var', (38, 46))	('tumor', 'Disease', (112, 117))	('efficacy', 'MPA', (160, 168))	('IFN-alpha', 'Gene', (129, 138))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('IFN-alpha', 'Gene', '111654', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('toxicity', 'Disease', 'MESH:D064420', (183, 191))	('toxicity', 'Disease', (183, 191))	('increased', 'PosReg', (150, 159))	('decreased', 'NegReg', (173, 182))
211338	25691401	ES tumors often express a balanced translocation involving the EWS gene on chromosome 22 and a member of the ETS family of transcription factors.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('EWS', 'Gene', '2130', (63, 66))	('EWS', 'Gene', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('balanced translocation', 'Var', (26, 48))
211355	25691401	As the abovementioned small round cell tumors; i.e., ES, PNET, neuroepithelioma, and Askin's tumor, exhibit similar types of chromosomal translocation, e.g., t(11;22)(q24;q12), they are classified as a single disease entity; i.e., the ES family of tumors.	("Askin's tumor", 'Disease', 'MESH:C563168', (85, 98))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('t(11;22)(q24;q12', 'Var', (158, 174))	('ES', 'Phenotype', 'HP:0012254', (53, 55))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	("Askin's tumor", 'Disease', (85, 98))	('tumors', 'Disease', (248, 254))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (158, 175))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('PNET', 'Phenotype', 'HP:0030065', (57, 61))	('neuroepithelioma', 'Disease', 'MESH:C563168', (63, 79))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('ES', 'Phenotype', 'HP:0012254', (235, 237))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('neuroepithelioma', 'Disease', (63, 79))	('tumors', 'Disease', (39, 45))
211381	25691401	Immunohistochemically, positivity for neural markers such as S-100 protein and PGP9.5 is sometimes detected, and vimentin positivity is also commonly observed.	('S-100 protein', 'Protein', (61, 74))	('PGP9.5', 'Gene', '7345', (79, 85))	('vimentin', 'Gene', '7431', (113, 121))	('PGP9.5', 'Gene', (79, 85))	('vimentin', 'Gene', (113, 121))	('positivity', 'Var', (23, 33))
211382	25691401	In over 90 % of ES cases, positivity for CD99, a product of the MIC2 gene, is detected on the cytoplasmic membrane (Fig.	('MIC2', 'Gene', '4267', (64, 68))	('positivity', 'Var', (26, 36))	('CD99', 'Gene', (41, 45))	('MIC2', 'Gene', (64, 68))	('ES', 'Phenotype', 'HP:0012254', (16, 18))	('CD99', 'Gene', '4267', (41, 45))
211392	25691401	In addition, in a study by the Memorial Sloan Kettering Cancer Center the 64 patients with the type 1 fusion gene exhibited a better prognosis than the 35 patients with other types of fusion gene.	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (155, 163))	('Cancer', 'Disease', (56, 62))	('fusion gene', 'Var', (102, 113))	('patients', 'Species', '9606', (77, 85))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))
211430	25691401	The treatment protocols included many different regimens such as the T-11 and modified T-11 regimens in 47 patients, V(A)CD + IE-based regimens in 41 patients, the VAID/EVAID regimen in 22/3 patients, and VACD-based regimens in 22 patients, etc.	('CD +', 'Chemical', 'MESH:D002104', (121, 125))	('T-11', 'Gene', '914', (69, 73))	('patients', 'Species', '9606', (191, 199))	('patients', 'Species', '9606', (231, 239))	('modified', 'Var', (78, 86))	('T-11', 'Gene', (69, 73))	('T-11', 'Gene', (87, 91))	('VAID', 'Chemical', '-', (164, 168))	('patients', 'Species', '9606', (150, 158))	('VACD', 'Chemical', '-', (205, 209))	('patients', 'Species', '9606', (107, 115))	('T-11', 'Gene', '914', (87, 91))	('VAID', 'Chemical', '-', (170, 174))	('EVAID', 'Chemical', '-', (169, 174))
211500	25229618	Yaa mice have a mutation characterized by translocation of a portion of the X chromosome (which contains the gene encoding Tlr7) onto the Y chromosome, and male BXSB/Yaa mice develop severe autoimmune disease consistent with SLE, with approximately 90% of mice developing fatal immune glomerulonephritis by 8 to 9 months of age.	('glomerulonephritis', 'Phenotype', 'HP:0000099', (285, 303))	('autoimmune disease', 'Disease', 'MESH:D001327', (190, 208))	('SLE', 'Disease', 'MESH:D008180', (225, 228))	('SLE', 'Disease', (225, 228))	('SLE', 'Phenotype', 'HP:0002725', (225, 228))	('mice', 'Species', '10090', (4, 8))	('autoimmune disease', 'Phenotype', 'HP:0002960', (190, 208))	('mice', 'Species', '10090', (170, 174))	('Yaa', 'Gene', '107944', (0, 3))	('glomerulonephritis', 'Disease', 'MESH:D005921', (285, 303))	('Tlr7', 'Gene', (123, 127))	('Yaa', 'Gene', '107944', (166, 169))	('to 9', 'Species', '1214577', (309, 313))	('mutation', 'Var', (16, 24))	('glomerulonephritis', 'Disease', (285, 303))	('mice', 'Species', '10090', (256, 260))	('Yaa', 'Gene', (0, 3))	('nephritis', 'Phenotype', 'HP:0000123', (294, 303))	('Yaa', 'Gene', (166, 169))	('autoimmune disease', 'Disease', (190, 208))
211501	25229618	Male Tlr7 -/-/Yaa mice develop less severe lupus nephritis than Tlr7+/Yaa B6.Nba2 congenic mice suggesting that increased copy number results in increased disease progression.	('less', 'NegReg', (31, 35))	('mice', 'Species', '10090', (91, 95))	('disease progression', 'CPA', (155, 174))	('nephritis', 'Phenotype', 'HP:0000123', (49, 58))	('lupus nephritis', 'Disease', 'MESH:D008181', (43, 58))	('Nba2', 'Gene', (77, 81))	('Yaa', 'Gene', '107944', (14, 17))	('Nba2', 'Gene', '110273', (77, 81))	('Yaa', 'Gene', '107944', (70, 73))	('increased', 'PosReg', (145, 154))	('mice', 'Species', '10090', (18, 22))	('copy number', 'Var', (122, 133))	('Yaa', 'Gene', (14, 17))	('Yaa', 'Gene', (70, 73))	('lupus nephritis', 'Disease', (43, 58))
211503	25229618	Similarly, deletion of mouse Tlr8 was associated with autoimmunity and a reciprocal increase in the expression of Tlr7 and decreased marginal zone B cells as well as peritoneal B1 B cells.	('autoimmunity', 'Disease', 'MESH:D001327', (54, 66))	('autoimmunity', 'Phenotype', 'HP:0002960', (54, 66))	('Tlr7', 'Gene', (114, 118))	('marginal zone B cells', 'CPA', (133, 154))	('associated', 'Reg', (38, 48))	('decreased', 'NegReg', (123, 132))	('autoimmunity', 'Disease', (54, 66))	('decreased marginal zone B cells', 'Phenotype', 'HP:0030384', (123, 154))	('Tlr8', 'Gene', (29, 33))	('expression', 'MPA', (100, 110))	('peritoneal B1 B cells', 'CPA', (166, 187))	('increase', 'PosReg', (84, 92))	('mouse', 'Species', '10090', (23, 28))	('deletion', 'Var', (11, 19))
211509	25229618	Mice transgenic for human bacterial artificial chromosomes (BACs) encoding TLR4 and its coreceptor MD-2 (which together form the LPS receptor complex) have also been crossed with mice containing targeted deletions of the mouse Tlr4/MD-2 to create a humanized TLR4/MD-2 mouse.	('Tlr4', 'Gene', '21898', (227, 231))	('human', 'Species', '9606', (20, 25))	('mice', 'Species', '10090', (179, 183))	('Tlr4', 'Gene', (227, 231))	('mouse', 'Species', '10090', (221, 226))	('mouse', 'Species', '10090', (269, 274))	('Mice', 'Species', '10090', (0, 4))	('human', 'Species', '9606', (249, 254))	('deletions', 'Var', (204, 213))	('TLR4', 'Gene', (75, 79))
211517	25229618	Human genomic bacterial artificial chromosome (BAC) RP11-1047N23 (BAC#1) and RP11-1137P1 (BAC#2) were obtained from The BACPAC Resource Center (CHORI, Oakland, CA) (Figure 1).	('RP11-1047N23', 'Var', (52, 64))	('RP11-1137P1', 'Var', (77, 88))	('Human', 'Species', '9606', (0, 5))
211518	25229618	Positive pups were identified by PCR (primer sequences shown in Table 1) and intercrossed with mice containing a targeted deletion of both mouse Tlr7 and Tlr8 (VelociGene Modified Allele ID #144), obtained from Regeneron, to generate humanized TLR7/8 mice (Table 2).	('mice', 'Species', '10090', (251, 255))	('mice', 'Species', '10090', (95, 99))	('human', 'Species', '9606', (234, 239))	('rat', 'Species', '10116', (229, 232))	('deletion', 'Var', (122, 130))	('mouse', 'Species', '10090', (139, 144))	('TLR7/8', 'Gene', (244, 250))	('Tlr7', 'Gene', (145, 149))	('Tlr8', 'Gene', (154, 158))	('TLR7/8', 'Gene', '170743;170744', (244, 250))
211556	25229618	Mice transgenic for human BACs encoding TLR7 and TLR8 were intercrossed with mice containing targeted deletions of both mouse Tlr7 and Tlr8, thereby replacing the mouse receptors with the human receptors.	('mice', 'Species', '10090', (77, 81))	('human', 'Species', '9606', (20, 25))	('human', 'Species', '9606', (188, 193))	('Tlr7', 'Gene', (126, 130))	('deletions', 'Var', (102, 111))	('Tlr8', 'Gene', (135, 139))	('mouse', 'Species', '10090', (163, 168))	('Mice', 'Species', '10090', (0, 4))	('mouse', 'Species', '10090', (120, 125))
211563	25229618	Unlike the BAC #1 lines, these mice survived long enough to reproduce; however, BAC+ mice routinely developed clinical signs including blepharitis (Figure 2B-C), corneal ulceration, hunching, and loss of condition which required euthanasia by 4 to 7 months of age.	('mice', 'Species', '10090', (85, 89))	('blepharitis', 'Disease', 'MESH:D001762', (135, 146))	('hunching', 'Disease', (182, 190))	('corneal ulceration', 'Disease', 'MESH:D003320', (162, 180))	('to 7', 'Species', '1214577', (245, 249))	('mice', 'Species', '10090', (31, 35))	('blepharitis', 'Disease', (135, 146))	('loss of condition', 'Disease', (196, 213))	('corneal ulceration', 'Phenotype', 'HP:0012804', (162, 180))	('corneal ulceration', 'Disease', (162, 180))	('blepharitis', 'Phenotype', 'HP:0000498', (135, 146))	('condition', 'Disease', (204, 213))	('BAC+', 'Var', (80, 84))
211589	25229618	Fluorescent activated cell sorting (FACS) analysis of spleens from huTLR7/8 BAC+ mice and their wild type controls showed that all of the cell types tested (T-cells, B-cells, pDCs, cDCs, and mac/monos) were significantly increased in number in the huTLR7/8 BAC+ mice versus the wild type control mice (Figure 6), as shown for muTlr7 BAC+ mice.	('mice', 'Species', '10090', (81, 85))	('increased', 'PosReg', (221, 230))	('TLR7/8', 'Gene', '170743;170744', (250, 256))	('mice', 'Species', '10090', (262, 266))	('mice', 'Species', '10090', (296, 300))	('mice', 'Species', '10090', (338, 342))	('BAC+', 'Var', (257, 261))	('TLR7/8', 'Gene', (250, 256))	('TLR7/8', 'Gene', (69, 75))	('TLR7/8', 'Gene', '170743;170744', (69, 75))
211599	25229618	The greatest response was observed in the macrophage/monocyte population in response to R848 (resiquimod), which stimulates both TLR7 and TLR8, although the % of cells responding in the humanized TLR7/8 cells was greatly reduced compared to C57BL/6 cells (Figure 8A).	('TLR7', 'Gene', (129, 133))	('stimulates', 'PosReg', (113, 123))	('TLR7/8', 'Gene', (196, 202))	('TLR8', 'Gene', (138, 142))	('reduced', 'NegReg', (221, 228))	('human', 'Species', '9606', (186, 191))	('TLR7/8', 'Gene', '170743;170744', (196, 202))	('R848', 'Var', (88, 92))
211602	25229618	CL075 that stimulates TLR8 preferentially, but not guardiquimod (GDQ) that stimulates TLR7 preferentially, stimulated the humanized TLR7/8 macrophage/monocyte population (and to a lesser extent cDC) even though both compounds stimulated B6 cells to an equivalent extent (Figure 8A and Figure 8B).	('human', 'Species', '9606', (122, 127))	('TLR7/8', 'Gene', '170743;170744', (132, 138))	('GDQ', 'Chemical', '-', (65, 68))	('CL075', 'Var', (0, 5))	('CL075', 'Chemical', 'MESH:C551788', (0, 5))	('stimulated', 'PosReg', (107, 117))	('TLR7/8', 'Gene', (132, 138))	('TLR8', 'Gene', (22, 26))
211603	25229618	Only R848, however, and not GDQ, stimulated huTLR7/8 BAC+ splenic pDC (Figure 8C), despite expression of human TLR7 RNA in bone-marrow derived pDC (Figure 7).	('TLR7/8', 'Gene', (46, 52))	('GDQ', 'Chemical', '-', (28, 31))	('TLR7/8', 'Gene', '170743;170744', (46, 52))	('R848', 'Var', (5, 9))	('human', 'Species', '9606', (105, 110))	('TLR7', 'Gene', (111, 115))
211604	25229618	Finally, to determine whether these mice might be useful for our vaccine studies, we measured serum cytokine production 1 and 3 hr following systemic administration of R848 (Figure 9).	('rat', 'Species', '10116', (158, 161))	('mice', 'Species', '10090', (36, 40))	('serum cytokine production', 'MPA', (94, 119))	('R848', 'Var', (168, 172))
211606	25229618	Wild-type C57BL/6 mice clearly induced TNF, IL-12 p40 and p70, IL-6, and IL-10 cytokines in response to R848 to levels greater than those induced in huTLR7/8 BAC+ mice.	('induced', 'Reg', (31, 38))	('TNF', 'Gene', '21926', (39, 42))	('IL-10', 'Gene', (73, 78))	('IL-6', 'Gene', '16193', (63, 67))	('IL-12 p40', 'Gene', '16160', (44, 53))	('R848', 'Var', (104, 108))	('TLR7/8', 'Gene', (151, 157))	('mice', 'Species', '10090', (18, 22))	('p70', 'Gene', (58, 61))	('mice', 'Species', '10090', (163, 167))	('IL-12 p40', 'Gene', (44, 53))	('TNF', 'Gene', (39, 42))	('IL-6', 'Gene', (63, 67))	('IL-10', 'Gene', '16153', (73, 78))	('p70', 'Gene', '16185', (58, 61))	('TLR7/8', 'Gene', '170743;170744', (151, 157))
211607	25229618	Even though IL-12p40 and IL-10 were significantly increased in huTLR7/8 BAC+ mice compared to Tlr7/8 DKO mice, the control uninjected huTLR7/8 BAC+ mice also showed a trend towards higher levels than the DKO mice suggesting that human TLR7 or TLR8 might be constitutively activated in the BAC+ mice.	('mice', 'Species', '10090', (105, 109))	('mice', 'Species', '10090', (77, 81))	('TLR7/8', 'Gene', '170743;170744', (65, 71))	('TLR7/8', 'Gene', (136, 142))	('IL-12p40', 'Gene', '16160', (12, 20))	('mice', 'Species', '10090', (208, 212))	('IL-12p40', 'Gene', (12, 20))	('increased', 'PosReg', (50, 59))	('mice', 'Species', '10090', (148, 152))	('IL-10', 'Gene', '16153', (25, 30))	('TLR7/8', 'Gene', '170743;170744', (136, 142))	('TLR7/8', 'Gene', (65, 71))	('human', 'Species', '9606', (229, 234))	('BAC+', 'Var', (72, 76))	('mice', 'Species', '10090', (294, 298))	('IL-10', 'Gene', (25, 30))
211613	25229618	The median lesion severity score at 3 months of age for the BAC+ MyD88 wild type mice was significantly higher than for the BAC+ MyD88 knockout mice for meninges (p = 0.03), eyelids (p = 0.02), and pancreas (p = 0.02) (Figure 10).	('BAC+ MyD88', 'Var', (60, 70))	('mice', 'Species', '10090', (81, 85))	('mice', 'Species', '10090', (144, 148))	('lesion severity score', 'MPA', (11, 32))	('higher', 'PosReg', (104, 110))
211614	25229618	Lesion severity scores were intermediate for the BAC+ MyD88 heterozygous mice compared to the other two groups, although this difference was not statistically significant, presumably due to the small sample size.	('mice', 'Species', '10090', (73, 77))	('Lesion', 'MPA', (0, 6))	('BAC+ MyD88', 'Var', (49, 59))
211616	25229618	Activation of B cells via TLR7 signaling has been implicated in the pathogenesis of autoimmune disease such as SLE, and Tlr7 deficient MRL/MpJ-Faslpr (MRL/lpr) mice do not produce anti-Smith (sm) antigen antibodies and show lessened immune activation and clinical disease.	('lpr', 'Gene', '14102', (155, 158))	('Tlr7', 'Gene', (120, 124))	('lpr', 'Gene', (146, 149))	('deficient', 'Var', (125, 134))	('autoimmune disease', 'Disease', (84, 102))	('lessened immune activation', 'Phenotype', 'HP:0002721', (224, 250))	('autoimmune disease', 'Disease', 'MESH:D001327', (84, 102))	('implicated', 'Reg', (50, 60))	('lpr', 'Gene', '14102', (146, 149))	('clinical disease', 'CPA', (255, 271))	('lessened', 'NegReg', (224, 232))	('immune activation', 'CPA', (233, 250))	('autoimmune disease', 'Phenotype', 'HP:0002960', (84, 102))	('SLE', 'Disease', 'MESH:D008180', (111, 114))	('SLE', 'Disease', (111, 114))	('SLE', 'Phenotype', 'HP:0002725', (111, 114))	('MRL/lpr', 'Gene', (151, 158))	('mice', 'Species', '10090', (160, 164))	('MRL/lpr', 'Gene', '14102', (151, 158))	('lpr', 'Gene', (155, 158))
211617	25229618	In previous studies of a murine lupus model, the selective deletion of MyD88 from B cells in MRL/lpr mice, dendritic cells in Lynflox/floxCd11c-cre+ mice, and complete deletion of the MyD88 gene in MRL/lpr mice also prevented the generation of ANA antibodies and resolved the glomerulonephritis phenotype, but not the dermatitis phenotype.	('resolved', 'Reg', (263, 271))	('glomerulonephritis', 'Phenotype', 'HP:0000099', (276, 294))	('MRL/lpr', 'Gene', '14102', (93, 100))	('mice', 'Species', '10090', (101, 105))	('mice', 'Species', '10090', (149, 153))	('dermatitis', 'Phenotype', 'HP:0011123', (318, 328))	('deletion', 'Var', (168, 176))	('ANA antibodies', 'MPA', (244, 258))	('glomerulonephritis', 'Disease', 'MESH:D005921', (276, 294))	('MyD88', 'Gene', (184, 189))	('rat', 'Species', '10116', (234, 237))	('deletion', 'Var', (59, 67))	('prevented', 'NegReg', (216, 225))	('MRL/lpr', 'Gene', (198, 205))	('mice', 'Species', '10090', (206, 210))	('glomerulonephritis', 'Disease', (276, 294))	('dermatitis', 'Disease', 'MESH:D003872', (318, 328))	('dermatitis', 'Disease', (318, 328))	('MyD88', 'Gene', (71, 76))	('MRL/lpr', 'Gene', (93, 100))	('murine', 'Species', '10090', (25, 31))	('MRL/lpr', 'Gene', '14102', (198, 205))	('nephritis', 'Phenotype', 'HP:0000123', (285, 294))
211618	25229618	Other models of autoimmune disease, such as traditional induction of autoimmune encephalomyelitis by administration of MOG35-55 peptide, have been shown to be dependent on MyD88 gene function as well.	('autoimmune disease', 'Disease', (16, 34))	('MyD88', 'Gene', (172, 177))	('autoimmune disease', 'Phenotype', 'HP:0002960', (16, 34))	('MOG35-55', 'Var', (119, 127))	('autoimmune disease', 'Disease', 'MESH:D001327', (16, 34))	('rat', 'Species', '10116', (109, 112))	('autoimmune encephalomyelitis', 'Disease', (69, 97))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (69, 97))
211619	25229618	However, in a spontaneous mouse model of experimental autoimmune encephalomyelitis, development of disease was not prevented by loss of the MyD88 gene.	('autoimmune encephalomyelitis', 'Disease', (54, 82))	('loss', 'Var', (128, 132))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (54, 82))	('mouse', 'Species', '10090', (26, 31))	('MyD88', 'Gene', (140, 145))
211631	25229618	A previous study has shown enhanced neuroinflammation following TLR9 agonist administration and suggested a role of normal TLR7, and potentially TLR 8 signaling, in modulating TLR9 related meningitis and neuroinflammation.	('TLR9', 'Gene', (176, 180))	('meningitis', 'Disease', (189, 199))	('modulating', 'Reg', (165, 175))	('TLR9', 'Gene', (64, 68))	('enhanced', 'PosReg', (27, 35))	('TLR9', 'Gene', '81897', (176, 180))	('rat', 'Species', '10116', (85, 88))	('TLR 8', 'Gene', (145, 150))	('agonist', 'Var', (69, 76))	('inflammation', 'Disease', 'MESH:D007249', (209, 221))	('meningitis', 'Phenotype', 'HP:0001287', (189, 199))	('TLR9', 'Gene', '81897', (64, 68))	('inflammation', 'Disease', 'MESH:D007249', (41, 53))	('meningitis', 'Disease', 'MESH:D008581', (189, 199))	('inflammation', 'Disease', (209, 221))	('TLR 8', 'Gene', '170744', (145, 150))	('inflammation', 'Disease', (41, 53))
211635	25229618	Further, the human TLR8 chimeras developed more significant disease in the kidney than the mice in the current report, and some TLR8 chimeras developed significant clinical and histologic evidence of joint disease.	('mice', 'Species', '10090', (91, 95))	('joint disease', 'Phenotype', 'HP:0001367', (200, 213))	('human', 'Species', '9606', (13, 18))	('chimeras', 'Var', (24, 32))	('joint disease', 'Disease', (200, 213))	('TLR8', 'Gene', (128, 132))	('developed', 'Reg', (142, 151))	('disease in the kidney', 'MPA', (60, 81))	('TLR8', 'Gene', (19, 23))	('joint disease', 'Disease', 'MESH:D007592', (200, 213))	('developed', 'Reg', (33, 42))
211637	25229618	It has been proposed that activation of human TLR8 may cause a distinct pattern of disease than activation of TLR7, and it appears likely that activation of human TLR7 and TLR8 also results in a novel distribution and type of inflammatory infiltrate than activation of mouse TLR7 or human TLR8 alone.	('disease', 'Disease', (83, 90))	('human', 'Species', '9606', (283, 288))	('human', 'Species', '9606', (40, 45))	('human', 'Species', '9606', (157, 162))	('rat', 'Species', '10116', (245, 248))	('TLR8', 'Gene', (172, 176))	('distribution', 'MPA', (201, 213))	('mouse', 'Species', '10090', (269, 274))	('TLR8', 'Gene', (46, 50))	('results in', 'Reg', (182, 192))	('cause', 'Reg', (55, 60))	('activation', 'Var', (26, 36))	('TLR7', 'Gene', (163, 167))
211645	25229618	Most likely, the pathogenesis of autoimmune disease differs between traditional lupus models, in which loss of B and T cell tolerance to self antigen leads to antibody-antigen immune complex deposition in end-organs, and the mice in this report that develop a florid multisystemic histiocytic infiltrate.	('leads to', 'Reg', (150, 158))	('autoimmune disease', 'Disease', (33, 51))	('antibody-antigen immune complex deposition', 'MPA', (159, 201))	('autoimmune disease', 'Disease', 'MESH:D001327', (33, 51))	('loss', 'Var', (103, 107))	('autoimmune disease', 'Phenotype', 'HP:0002960', (33, 51))	('immune complex deposition', 'Phenotype', 'HP:0012224', (176, 201))	('mice', 'Species', '10090', (225, 229))	('rat', 'Species', '10116', (299, 302))
211655	25229618	Activating mutations in MyD88 have been described in human lymphomas, suggesting that constitutive human TLR7 or TLR8 signaling in our mice could be driving proliferation.	('mutations', 'Var', (11, 20))	('MyD88', 'Gene', (24, 29))	('lymphomas', 'Phenotype', 'HP:0002665', (59, 68))	('mice', 'Species', '10090', (135, 139))	('human', 'Species', '9606', (53, 58))	('lymphomas', 'Disease', 'MESH:D008223', (59, 68))	('rat', 'Species', '10116', (164, 167))	('lymphomas', 'Disease', (59, 68))	('human', 'Species', '9606', (99, 104))
211664	25229618	The resolution of lesions in the huTRL7/8 mice when the MyD88 gene was knocked out may be consistent with an inflammatory etiology with inappropriate and exuberant MyD88 dependent signaling through the humanized TLR7 and TLR8 receptors.	('MyD88', 'Gene', (56, 61))	('knocked out', 'Var', (71, 82))	('mice', 'Species', '10090', (42, 46))	('human', 'Species', '9606', (202, 207))	('TLR8', 'Gene', (221, 225))
211666	25229618	In conclusion, this report summarizes a novel phenotype, presumably related to replacement of the murine Tlr7 and Tlr8 genes with the human genes, and abnormal signaling through these TLR receptors in mice.	('human', 'Species', '9606', (134, 139))	('replacement', 'Var', (79, 90))	('Tlr8', 'Gene', (114, 118))	('murine', 'Species', '10090', (98, 104))	('mice', 'Species', '10090', (201, 205))	('Tlr7', 'Gene', (105, 109))
211768	31188901	While iSLK.219 cells are of clear cell renal cell carcinoma origin and thus of lesser biological relevance, the iSLK system has proven invaluable to KSHV research as it is routinely used in studies addressing viral gene function through bacterial artificial chromosome (BAC) mutagenesis.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (28, 59))	('mutagenesis', 'Var', (275, 286))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (34, 59))	('cell renal cell carcinoma', 'Disease', (34, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('KSHV', 'Species', '37296', (149, 153))
211787	31188901	TREx-BCBL1 cells have been the subject of extensive investigation regarding the presence and location of various chromatin modifications, including the activating mark H3K4me3 and the repressive mark H3K27me3, as well as the KSHV latent protein LANA and cellular RNAP II.	('LANA', 'Gene', (245, 249))	('H3K27me3', 'Var', (200, 208))	('LANA', 'Gene', '4961527', (245, 249))	('H3K4me3', 'Var', (168, 175))	('KSHV', 'Species', '37296', (225, 229))	('activating', 'PosReg', (152, 162))
211814	31188901	Interestingly, when all cellular TSCs are ranked by expression the presence of a downstream GG motif is associated with higher expression (S7 Fig).	('TSC', 'Gene', (33, 36))	('expression', 'MPA', (127, 137))	('higher', 'PosReg', (120, 126))	('presence', 'Var', (67, 75))	('TSC', 'Gene', '6559', (33, 36))
211874	31188901	While it would likely be unfavorable for the virus to activate the expression of an interferon via the viral initiation complex, we hypothesize that cellular promoters that harbor TATT motifs contain sequences that recruit additional factors that are required for their expression.	('AT', 'Disease', 'None', (181, 183))	('motifs', 'Var', (185, 191))	('recruit', 'PosReg', (215, 222))
211910	31188901	hg38 and GQ994935.1 genomes were applied as background.	('hg38', 'Gene', (0, 4))	('hg38', 'Gene', '8549', (0, 4))	('GQ994935.1', 'Var', (9, 19))
211911	31188901	CTCF ChIP-seq (SRR503420), FAIRE-seq (SRR965330, SRR965331), and RTA ChIP-seq (SRR5676584, SRR5676585, SRR8324529, SRR8324530), LANA (SRR1030378, SRR1030385, SRR1030386, SRR1030387, SRR1030388), PolII (SRR1030375), H3K27me3 (SRR1030374) and H3K4me3 (SRR1030370, SRR1030371, SRR1030372, SRR1030373) were downloaded from Sequence Read Archive (SRA) use sra-tools (https://www.ncbi.nlm.nih.gov/sra).	('LANA', 'Gene', '4961527', (128, 132))	('SRR1030387', 'Var', (170, 180))	('CTCF', 'Gene', (0, 4))	('CTCF', 'Gene', '10664', (0, 4))	('SRR1030371', 'Var', (262, 272))	('SRR1030386', 'Var', (158, 168))	('SRR1030373', 'Var', (286, 296))	('SRR1030370', 'Var', (250, 260))	('SRR1030372', 'Var', (274, 284))	('LANA', 'Gene', (128, 132))	('SRR1030378', 'Var', (134, 144))
211912	31188901	Processed fastq reads were mapped to GQ994935.1 and GRCh38 genome using default STAR parameters, and peaks identified using MACS2.	('GQ994935.1', 'Var', (37, 47))	('STAR', 'Gene', (80, 84))	('STAR', 'Gene', '6770', (80, 84))	('GRCh38', 'Gene', (52, 58))
211915	29415665	Prognostic implications of polycomb proteins ezh2, suz12, and eed1 and histone modification by H3K27me3 in sarcoma Polycomb repressive complex 2 (PRC2; formed by EZH2, SUZ12, and EED protein subunits) and PRC1 (BMI1 protein) induce gene silencing through histone modification by H3K27me3.	('SUZ12', 'Gene', '23512', (168, 173))	('gene', 'MPA', (232, 236))	('EED', 'Gene', (179, 182))	('PRC', 'Gene', '23082', (146, 149))	('PRC', 'Gene', (205, 208))	('ezh2', 'Gene', (45, 49))	('ezh2', 'Gene', '2146', (45, 49))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))	('BMI1', 'Gene', (211, 215))	('histone modification', 'MPA', (255, 275))	('sarcoma', 'Disease', (107, 114))	('EED', 'Gene', '8726', (179, 182))	('PRC1', 'Gene', (205, 209))	('PRC1', 'Gene', '9055', (205, 209))	('suz12', 'Gene', (51, 56))	('suz12', 'Gene', '23512', (51, 56))	('PRC', 'Gene', '23082', (205, 208))	('SUZ12', 'Gene', (168, 173))	('PRC', 'Gene', (146, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('EZH2', 'Gene', (162, 166))	('EZH2', 'Gene', '2146', (162, 166))	('H3K27me3', 'Var', (279, 287))	('BMI1', 'Gene', '648', (211, 215))
211921	29415665	Overall survival (OS) was significantly poor for SUZ12 high (P = 0.001), EED1 high (P = 0.279), and H3K27me3 high (P = 0.009).	('poor', 'NegReg', (40, 44))	('high', 'Var', (78, 82))	('SUZ12', 'Gene', '23512', (49, 54))	('SUZ12', 'Gene', (49, 54))	('H3K27me3 high', 'Var', (100, 113))	('EED', 'Gene', '8726', (73, 76))	('Overall survival', 'CPA', (0, 16))	('EED', 'Gene', (73, 76))
211923	29415665	In the Cox proportional hazard model adjusted for stage, histologic grade, surgery, margin and initial metastasis, SUZ12 expression (P = 0.020, HR 29.069, 95% CI 1.690-500.007), H3K27me3 (P = 0.010, HR 3.743, 95% CI 1.370-10.228) expression was significantly associated with shorter OS.	('SUZ12', 'Gene', '23512', (115, 120))	('shorter OS', 'Disease', (275, 285))	('SUZ12', 'Gene', (115, 120))	('H3K27me3', 'Var', (178, 186))
211947	29415665	The primary antibodies used in this study were as follows: EZH2 (#18-7395, dilution 1:100, clone ZMD.309; Invitrogen, Carlsbad, CA, USA), SUZ12 (dilution 1:50, clone SUZ220A, Abcam, Cambridge, MA, USA), EED1 (dilution 1:100, clone 163C, Abcam), H3K27me3 (dilution 1:100, clone C36B11; Cell Signaling Technology, Danvers, MA, USA).	('SUZ12', 'Gene', '23512', (138, 143))	('EZH2', 'Gene', '2146', (59, 63))	('H3K27me3', 'Var', (245, 253))	('SUZ12', 'Gene', (138, 143))	('EED', 'Gene', '8726', (203, 206))	('EZH2', 'Gene', (59, 63))	('EED', 'Gene', (203, 206))
211950	29415665	EZH2, SUZ12, EED1, and H3K27me3 showed nuclear expression.	('EED', 'Gene', '8726', (13, 16))	('nuclear expression', 'MPA', (39, 57))	('EZH2', 'Gene', '2146', (0, 4))	('SUZ12', 'Gene', (6, 11))	('H3K27me3', 'Var', (23, 31))	('EZH2', 'Gene', (0, 4))	('EED', 'Gene', (13, 16))	('SUZ12', 'Gene', '23512', (6, 11))
211963	29415665	c-d, e-f and g-h were diagnosed as osteosarcoma but showed high grade and low grade expression in SUZ12, EED1 and H3K27me3 expression, respectively.	('SUZ12', 'Gene', (98, 103))	('osteosarcoma', 'Phenotype', 'HP:0002669', (35, 47))	('osteosarcoma', 'Disease', (35, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (35, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('SUZ12', 'Gene', '23512', (98, 103))	('H3K27me3', 'Var', (114, 122))	('EED', 'Gene', '8726', (105, 108))	('EED', 'Gene', (105, 108))
211967	29415665	shows that EZH2 and H3K27me3 are low at the same time, one of them is high or both are high, and EZH2 high or H3K27me3 high occupies a high ratio as shown by the relatively low H3K27me3.	('H3K27me3', 'Protein', (20, 28))	('EZH2', 'Gene', (11, 15))	('EZH2', 'Gene', '2146', (97, 101))	('EZH2', 'Gene', '2146', (11, 15))	('EZH2', 'Gene', (97, 101))	('H3K27me3', 'Protein', (177, 185))	('H3K27me3', 'Var', (110, 118))
211968	29415665	SUZ12 and H3K27me3 are low at the same time, one of them is high, and both of them are high, and SUZ12 non-high and H3K27me non-high occupies a high ratio.	('SUZ12', 'Gene', (0, 5))	('H3K27me non-high', 'Var', (116, 132))	('SUZ12', 'Gene', '23512', (97, 102))	('SUZ12', 'Gene', (97, 102))	('H3K27me3', 'Var', (10, 18))	('SUZ12', 'Gene', '23512', (0, 5))
211970	29415665	For the same reason, EED1 high or H3K27me3 high seems to occupy a high percentage.The expression patterns of EZH2, SUZ12, EED1, and H3K27me3 were most distinctive; EZH2high and EED1high were frequently observed in all subtypes.	('EZH2', 'Gene', '2146', (164, 168))	('EED', 'Gene', '8726', (21, 24))	('EZH2', 'Gene', (164, 168))	('EED', 'Gene', '8726', (122, 125))	('EED', 'Gene', (21, 24))	('SUZ12', 'Gene', '23512', (115, 120))	('EED', 'Gene', (122, 125))	('SUZ12', 'Gene', (115, 120))	('EED', 'Gene', '8726', (177, 180))	('EZH2', 'Gene', '2146', (109, 113))	('H3K27me3', 'Var', (132, 140))	('EZH2', 'Gene', (109, 113))	('EED', 'Gene', (177, 180))
211971	29415665	SUZ12high and H3K27me3high were uniformly infrequent across all subtypes, whereas H3K27me3high was frequent in Ewing's sarcoma.	('SUZ12', 'Gene', (0, 5))	('H3K27me3high', 'Var', (82, 94))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (111, 126))	('frequent', 'Reg', (99, 107))	('H3K27me3high', 'Var', (14, 26))	("Ewing's sarcoma", 'Disease', (111, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (111, 126))	('SUZ12', 'Gene', '23512', (0, 5))
211980	29415665	The Cox proportional hazard model was adjusted for stage, histologic grade, initial metastasis, surgery, margin status, and EZH2, SUZ12, H3K27me3, and all PRC2.	('SUZ12', 'Gene', (130, 135))	('PRC', 'Gene', (155, 158))	('PRC', 'Gene', '23082', (155, 158))	('EZH2', 'Gene', '2146', (124, 128))	('H3K27me3', 'Var', (137, 145))	('EZH2', 'Gene', (124, 128))	('SUZ12', 'Gene', '23512', (130, 135))
211981	29415665	Initial metastasis (P = 0.013, HR 3.365, 95% CI 1.295-8.745), SUZ12 expression (P = 0.020, HR 29.069, 95% CI 1.690-500.007), and H3K27me3 (P = 0.010, HR 3.743, 95% CI 1.370-10.228) expression were significantly associated with a shorter OS (Table 2).	('Initial metastasis', 'CPA', (0, 18))	('H3K27me3', 'Var', (129, 137))	('SUZ12', 'Gene', '23512', (62, 67))	('SUZ12', 'Gene', (62, 67))	('shorter', 'Disease', (229, 236))
211986	29415665	reported that high EZH2 expression was associated with poor prognosis in colorectal cancer, whereas EZH2 expression was associated with relapse-free survival in another study.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('expression', 'MPA', (24, 34))	('EZH2', 'Gene', '2146', (100, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('EZH2', 'Gene', (100, 104))	('high', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('EZH2', 'Gene', '2146', (19, 23))	('EZH2', 'Gene', (19, 23))
211990	29415665	Co-expression of EZH2 and BMI1 was found to be a poor prognostic factor.	('BMI1', 'Gene', '648', (26, 30))	('EZH2', 'Gene', (17, 21))	('BMI1', 'Gene', (26, 30))	('Co-expression', 'Var', (0, 13))	('EZH2', 'Gene', '2146', (17, 21))
211994	29415665	To obtain additional prognostic information regarding epigenetic pathways, we performed multivariate analyses using combined expression of PRC2 proteins and the association with histone modification H3K27me3.	('association', 'Interaction', (161, 172))	('histone modification', 'MPA', (178, 198))	('PRC', 'Gene', (139, 142))	('H3K27me3', 'Var', (199, 207))	('PRC', 'Gene', '23082', (139, 142))	('proteins', 'Protein', (144, 152))
211997	29415665	Synovial sarcoma is defined by a characteristic translocation t(X;18)(p11.2;q11.2), which is observed in > 95% of cases and results in the fusion of SS18 to the SSX1, SSX2, or SSX4 genes.	('SSX4', 'Gene', (176, 180))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('SSX2', 'Gene', '6757', (167, 171))	('SSX1', 'Gene', '6756', (161, 165))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (62, 82))	('SS18', 'Gene', (149, 153))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('SSX2', 'Gene', (167, 171))	('SSX1', 'Gene', (161, 165))	('SS18', 'Gene', '6760', (149, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SSX4', 'Gene', '6759', (176, 180))	('fusion', 'Var', (139, 145))
211998	29415665	Thus, SS18-SSX fusion leads to disease development by disrupting the epigenetic regulation of gene expression.	('fusion', 'Var', (15, 21))	('leads to', 'Reg', (22, 30))	('disrupting', 'NegReg', (54, 64))	('SS18', 'Gene', '6760', (6, 10))	('SSX', 'Gene', '6757', (11, 14))	('epigenetic regulation of gene expression', 'MPA', (69, 109))	('SSX', 'Gene', (11, 14))	('disease development', 'CPA', (31, 50))	('SS18', 'Gene', (6, 10))
212003	29415665	reports that malignant peripheral nerve sheath tumors with loss of H3K27 tri-methylation showed inferior survival compared to malignant peripheral nerve sheath tumors with intact H3K27 tri-methylation.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (126, 166))	('tri-methylation', 'Var', (73, 88))	('malignant peripheral nerve sheath tumors', 'Disease', (126, 166))	('malignant peripheral nerve sheath tumors', 'Disease', (13, 53))	('H3K27', 'Protein', (67, 72))	('inferior', 'NegReg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (126, 166))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (13, 53))	('loss', 'NegReg', (59, 63))	('survival', 'CPA', (105, 113))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (13, 53))
212014	29415665	Tazemetostat, CPI-1205, and GSK2816126, are currently performed in the clinical trials in different cancer types, including lymphomas, kidney tumors, synovial sarcoma, epitheliod sarcoma, mesothelioma, advanced solid tumors, and ovarian cancer.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('epitheliod sarcoma', 'Disease', (168, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('CPI-1205', 'Chemical', 'MESH:C000619999', (14, 22))	('ovarian cancer', 'Disease', (229, 243))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('solid tumors', 'Disease', (211, 223))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('CPI-1205', 'Var', (14, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (229, 243))	('synovial sarcoma', 'Disease', (150, 166))	('lymphomas', 'Disease', 'MESH:D008223', (124, 133))	('GSK2816126', 'Var', (28, 38))	('synovial sarcoma', 'Disease', 'MESH:D013584', (150, 166))	('lymphomas', 'Phenotype', 'HP:0002665', (124, 133))	('kidney tumors', 'Disease', (135, 148))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('solid tumors', 'Disease', 'MESH:D009369', (211, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('Tazemetostat', 'Chemical', 'MESH:C000593333', (0, 12))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (150, 166))	('cancer', 'Disease', (100, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))	('mesothelioma', 'Disease', (188, 200))	('ovarian cancer', 'Disease', 'MESH:D010051', (229, 243))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('lymphomas', 'Disease', (124, 133))	('epitheliod sarcoma', 'Disease', 'MESH:D012509', (168, 186))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mesothelioma', 'Disease', 'MESH:D008654', (188, 200))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('GSK2816126', 'Chemical', '-', (28, 38))	('kidney tumors', 'Disease', 'MESH:D007674', (135, 148))	('kidney tumors', 'Phenotype', 'HP:0009726', (135, 148))
212064	28512407	There may also be preferential uptake of 18F-FDG into muscles in hyperinsulinemic states, for example after the use of corticosteroids.	('18F-FDG', 'Var', (41, 48))	('preferential', 'PosReg', (18, 30))	('hyperinsulinemic', 'Disease', (65, 81))	('hyperinsulinemic', 'Disease', 'MESH:D044903', (65, 81))	('18F-FDG', 'Chemical', 'MESH:D019788', (41, 48))	('uptake', 'MPA', (31, 37))
212092	26828206	Moreover, laparoscopic myomectomy is associated with a lower tumorigenesis rate in uterine fibroids.	('uterine fibroids', 'Phenotype', 'HP:0000131', (83, 99))	('laparoscopic', 'Var', (10, 22))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('uterine fibroids', 'Disease', (83, 99))	('lower', 'NegReg', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
212124	26828206	A separate analysis of the impact of the laparoscopic approach on survival rates revealed that the 1- and 3-year RFS rates for patients were 66.7% and 41.7%, respectively, in the laparoscopy-FM group; the corresponding OS rates were 83.3% and 66.7%, respectively.	('OS', 'Chemical', '-', (219, 221))	('RFS', 'Chemical', '-', (113, 116))	('patients', 'Species', '9606', (127, 135))	('RFS', 'CPA', (113, 116))	('laparoscopy-FM', 'Var', (179, 193))
212150	26828206	In particular, for young patients, laparoscopic myomectomy prevents the formation of pelvic adhesions and reduces the prevalence of infertility compared with the transabdominal and transvaginal approaches.	('laparoscopic', 'Var', (35, 47))	('reduces', 'NegReg', (106, 113))	('infertility', 'Phenotype', 'HP:0000789', (132, 143))	('infertility', 'Disease', 'MESH:D007247', (132, 143))	('infertility', 'Disease', (132, 143))	('prevents', 'NegReg', (59, 67))	('patients', 'Species', '9606', (25, 33))	('formation of pelvic adhesions', 'CPA', (72, 101))
212151	26828206	Because transabdominal fibroid morcellation is associated with the risk of tumor seeding at the abdominal incision, it is necessary to fully evaluate and choose the appropriate approach prior to surgery in patients with rapid growth of uterine fibroids and rich blood flow signals on ultrasound or MRI (indicating higher probability of malignancy) to avoid the negative impact potentially brought about by fibroid morcellation (including during laparoscopic, transvaginal and transabdominal approaches).	('malignancy', 'Disease', 'MESH:D009369', (336, 346))	('malignancy', 'Disease', (336, 346))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('patients', 'Species', '9606', (206, 214))	('uterine fibroids', 'Phenotype', 'HP:0000131', (236, 252))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('morcellation', 'Var', (31, 43))	('tumor', 'Disease', (75, 80))
212156	30086788	Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants.	('Li-Fraumeni-like', 'Disease', (32, 48))	('TP53', 'Gene', '7157', (103, 107))	('TP53', 'Gene', (103, 107))	('variants', 'Var', (108, 116))
212159	30086788	We identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels.	('variants', 'Var', (58, 66))	('patients', 'Species', '9606', (74, 82))	('single-nucleotide variants', 'Var', (150, 176))	('pathogenic', 'Reg', (38, 48))	('pathogenic', 'Reg', (17, 27))
212161	30086788	In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM).	('hereditary breast cancer', 'Disease', (99, 123))	('ATM', 'Gene', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (99, 123))	('CHEK2', 'Gene', (159, 164))	('CHEK2', 'Gene', '11200', (159, 164))	('ATM', 'Gene', '472', (166, 169))	('PALB2', 'Gene', (152, 157))	('variants', 'Var', (75, 83))	('PALB2', 'Gene', '79728', (152, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('patients', 'Species', '9606', (8, 16))
212162	30086788	Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14ARF, and RUNX1).	('Fanconi pathway genes', 'Gene', (172, 193))	('RUNX1', 'Gene', '861', (233, 238))	('CDKN2A', 'Gene', (214, 220))	('RECQ family genes', 'Gene', (195, 212))	('und', 'Gene', (53, 56))	('CDKN2A', 'Gene', '1029', (214, 220))	('patients', 'Species', '9606', (13, 21))	('p14ARF', 'Gene', '1029', (221, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('und', 'Gene', '7373', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('RUNX1', 'Gene', (233, 238))	('p14ARF', 'Gene', (221, 227))	('variants', 'Var', (78, 86))
212166	30086788	Germline pathogenic variants (PVs) in the tumor suppressor gene TP53 are primarily responsible for this autosomal dominantly inherited disease; however, because TP53 PVs can be confirmed in only about 70% of suspected families, diagnosis of LFS is usually based on clinical evaluation and conformance to stringent criteria independent of mutational status.	('TP53', 'Gene', (161, 165))	('tumor', 'Disease', (42, 47))	('variants', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('LFS', 'Disease', (241, 244))	('inherited disease', 'Disease', (125, 142))	('TP53', 'Gene', '7157', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('TP53', 'Gene', (64, 68))	('TP53', 'Gene', '7157', (161, 165))	('responsible', 'Reg', (83, 94))	('inherited disease', 'Disease', 'MESH:D030342', (125, 142))
212169	30086788	Penetrance is remarkably high in carriers of germline TP53 PVs, with 84% of female carriers and 41% of male carriers developing a tumor by age 45 years.	('germline', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('TP53', 'Gene', '7157', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('TP53', 'Gene', (54, 58))	('tumor', 'Disease', (130, 135))	('high', 'Reg', (25, 29))
212172	30086788	Because patients with BC harboring germline TP53 PVs typically present with very early age of onset, routine TP53 testing has been suggested for women who develop BC before the age of 30 years, independent of family history, and TP53 detection rates within cohorts of patients with early-onset BC have been reported to be between 4% and 8%.	('BC', 'Phenotype', 'HP:0003002', (22, 24))	('BC', 'Phenotype', 'HP:0003002', (294, 296))	('TP53', 'Gene', '7157', (109, 113))	('germline', 'Var', (35, 43))	('TP53', 'Gene', '7157', (229, 233))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (109, 113))	('TP53', 'Gene', (229, 233))	('BC', 'Phenotype', 'HP:0003002', (163, 165))	('patients', 'Species', '9606', (268, 276))	('women', 'Species', '9606', (145, 150))	('TP53', 'Gene', (44, 48))	('patients', 'Species', '9606', (8, 16))
212175	30086788	While not all germline TP53 mutation carriers may be covered by LFS/LFL criteria, many families who do clinically conform to LFS/LFL criteria lack detectable germline TP53 PVs, which is demonstrated by TP53 mutation detection rates ranging from ~ 55% to 70% in classic LFS criteria, ~ 25% to 30% in LFL criteria, and ~ 20% to 35% in Chompret criteria.	('TP53', 'Gene', (202, 206))	('LFS', 'Disease', (269, 272))	('lack', 'NegReg', (142, 146))	('TP53', 'Gene', '7157', (167, 171))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutation', 'Var', (207, 215))	('TP53', 'Gene', (167, 171))	('TP53', 'Gene', '7157', (202, 206))
212178	30086788	Moreover, germline PVs in CHEK2 have continuously but controversially been implicated in LFL phenotypes.	('germline PVs', 'Var', (10, 22))	('LFL', 'Disease', (89, 92))	('implicated', 'Reg', (75, 85))	('CHEK2', 'Gene', '11200', (26, 31))	('CHEK2', 'Gene', (26, 31))
212182	30086788	Prior to study inclusion, all patients had a negative test result for pathogenic single-nucleotide variants or small indels (Sanger sequencing) as well as gross genomic rearrangements (multiplex ligation-dependent probe amplification [MLPA], SALSA MLPA kits [MRC Holland, Amsterdam, The Netherlands], P002B/P087 for BRCA1, P045-B3/P077 for BRCA2, and P056-C1 for TP53) within the genes BRCA1, BRCA2, and TP53.	('BRCA1', 'Gene', (386, 391))	('P045-B3/P077', 'Var', (323, 335))	('BRCA2', 'Gene', '675', (340, 345))	('BRCA2', 'Gene', (393, 398))	('P002B/P087', 'Var', (301, 311))	('BRCA1', 'Gene', '672', (316, 321))	('TP53', 'Gene', '7157', (404, 408))	('P056-C1', 'Var', (351, 358))	('BRCA1', 'Gene', (316, 321))	('patients', 'Species', '9606', (30, 38))	('TP53', 'Gene', '7157', (363, 367))	('BRCA2', 'Gene', (340, 345))	('BRCA1', 'Gene', '672', (386, 391))	('TP53', 'Gene', (404, 408))	('TP53', 'Gene', (363, 367))	('BRCA2', 'Gene', '675', (393, 398))
212184	30086788	Classification into LFS/LFL and Chompret criteria was performed either on the particular proband undergoing mutation analysis or on another index case within the same family.	('LFS/LFL', 'Disease', (20, 27))	('und', 'Gene', (97, 100))	('und', 'Gene', '7373', (97, 100))	('mutation analysis', 'Var', (108, 125))
212191	30086788	Variants were further filtered with the software GSvar (part of ngs-bits) to identify frameshift, nonsense, splice site, missense, inframe insertion/deletion, and 3'/5' untranslated region (UTR) variants that had a minor allele frequency (MAF) at or below 0.1% in the 1000 Genomes Project, ExAC, and Kaviar databases and were located in the ROI as defined above.	('frameshift', 'Var', (86, 96))	('variants', 'Var', (195, 203))	('insertion/deletion', 'Var', (139, 157))	('GS', 'Disease', 'MESH:D011125', (49, 51))
212192	30086788	As a second measure, via GSvar analysis, we filtered all variants that were predicted to be pathogenic by at least 2 of 4 in silico prediction tools (i.e., MetaLR, Sift, PolyPhen-2 HVAR, and PolyPhen-2 HDIV) or that were documented as pathogenic in either the ClinVar or HGMD database, as long as they were neither listed n > 2 in the FLOSSIES database of healthy older women, nor classified as class 1-2 variants according to a consented expert decision within the German HBOC Consortium, nor reported as predominantly benign or likely benign in ClinVar.	('GS', 'Disease', 'MESH:D011125', (25, 27))	('variants', 'Var', (57, 65))	('women', 'Species', '9606', (370, 375))	('pathogenic', 'Reg', (235, 245))
212194	30086788	In addition, and with particular relevance to potential TP53 variants of reduced penetrance or hypomorphic alleles, all variants detected within the TP53 gene (including synonymous and intronic variants) were analyzed.	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', '7157', (149, 153))	('TP53', 'Gene', (56, 60))	('TP53', 'Gene', (149, 153))	('variants', 'Var', (61, 69))
212196	30086788	For detection of copy number changes, a custom-made eArray covering the identical set of genes targeted by Illumina's TruSight Cancer Panel was used (SureDesign 069100, 8x60K; Agilent Technologies, Santa Clara, CA, USA).	('copy', 'Var', (17, 21))	('Cancer', 'Disease', 'MESH:D009369', (127, 133))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Cancer', 'Disease', (127, 133))
212198	30086788	Verification of detected copy number variations with a second independent method was performed either via MLPA, if probe sets were commercially available for the relevant region (SALSA MLPA kits [MRC Holland], P042-B1 for ATM; P056 for CHEK2; P008-C1 for PMS2), and/or via next-generation sequencing (NGS)-based copy number evaluation using CnvHunter, which is part of ngs-bits.	('PMS2', 'Gene', (255, 259))	('ATM', 'Gene', (222, 225))	('P056', 'Var', (227, 231))	('PMS2', 'Gene', '5395', (255, 259))	('P042-B1', 'Var', (210, 217))	('ATM', 'Gene', '472', (222, 225))	('variations', 'Var', (37, 47))	('CHEK2', 'Gene', '11200', (236, 241))	('GS', 'Disease', 'MESH:D011125', (302, 304))	('CHEK2', 'Gene', (236, 241))
212201	30086788	Within the cohort of 83 subjects with BC, we detected 13 pathogenic or likely pathogenic heterozygous germline variants (ACMG class 4-5; i.e., nonsense, frameshift, missense, [consensus] splice site variants, or copy number aberrations) in 10 unrelated patients and 9 genes [ATM (n = 3), CDKN2A (n = 1), CHEK2 (n = 1), FANCI (n = 1), PALB2 (n = 2), PMS2 (n = 1), RECQL4 (n = 2), RUNX1 (n = 1), and WRN (n = 1)].	('RUNX1', 'Gene', (379, 384))	('RUNX1', 'Gene', '861', (379, 384))	('patients', 'Species', '9606', (253, 261))	('FANCI', 'Gene', (319, 324))	('CHEK2', 'Gene', (304, 309))	('FA', 'Phenotype', 'HP:0001994', (319, 321))	('PALB2', 'Gene', '79728', (334, 339))	('ATM', 'Gene', '472', (275, 278))	('PMS2', 'Gene', '5395', (349, 353))	('frameshift', 'Var', (153, 163))	('FANCI', 'Gene', '55215', (319, 324))	('CDKN2A', 'Gene', (288, 294))	('CHEK2', 'Gene', '11200', (304, 309))	('RECQL4', 'Gene', '9401', (363, 369))	('BC', 'Phenotype', 'HP:0003002', (38, 40))	('variants', 'Var', (111, 119))	('pathogenic', 'Reg', (57, 67))	('CDKN2A', 'Gene', '1029', (288, 294))	('nonsense', 'Var', (143, 151))	('ATM', 'Gene', (275, 278))	('WRN', 'Gene', (398, 401))	('WRN', 'Gene', '7486', (398, 401))	('RECQL4', 'Gene', (363, 369))	('PMS2', 'Gene', (349, 353))	('missense', 'Var', (165, 173))	('PALB2', 'Gene', (334, 339))
212204	30086788	Half of the 10 mutation carriers (5 of 83; 6% of the entire cohort) were found to harbor PVs in widely accepted BC susceptibility genes (i.e., PALB2, ATM, and CHEK2), whereas the remaining half (5 of 83; 6% of the entire cohort) carried PVs in candidate genes for which no firm association with BC incidence has yet been established in a heterozygous germline setting (CDKN2A, RUNX1, FANCI, WRN, and RECQL4).	('CDKN2A', 'Gene', (369, 375))	('FANCI', 'Gene', '55215', (384, 389))	('RECQL4', 'Gene', (400, 406))	('PALB2', 'Gene', (143, 148))	('BC', 'Phenotype', 'HP:0003002', (112, 114))	('CDKN2A', 'Gene', '1029', (369, 375))	('ATM', 'Gene', (150, 153))	('BC', 'Phenotype', 'HP:0003002', (295, 297))	('PALB2', 'Gene', '79728', (143, 148))	('RUNX1', 'Gene', (377, 382))	('RUNX1', 'Gene', '861', (377, 382))	('CHEK2', 'Gene', (159, 164))	('und', 'Gene', '7373', (75, 78))	('WRN', 'Gene', (391, 394))	('WRN', 'Gene', '7486', (391, 394))	('und', 'Gene', (75, 78))	('mutation', 'Var', (15, 23))	('CHEK2', 'Gene', '11200', (159, 164))	('ATM', 'Gene', '472', (150, 153))	('FANCI', 'Gene', (384, 389))	('RECQL4', 'Gene', '9401', (400, 406))	('FA', 'Phenotype', 'HP:0001994', (384, 386))
212206	30086788	An overview of all index patients carrying (likely) pathogenic germline variants, including their personal and family histories as well as available clinical data and LFS/LFL classification, is given in Table 3, and respective pedigrees can be accessed in Additional file 3.	('patients', 'Species', '9606', (25, 33))	('person', 'Species', '9606', (98, 104))	('pathogenic', 'Reg', (52, 62))	('variants', 'Var', (72, 80))
212207	30086788	Via array-based CGH, we identified a duplication of exons 1-21 of the BLM gene, which currently ranks as a class 3 variant owing to a lack of more precise breakpoint information.	('BLM', 'Gene', '641', (70, 73))	('duplication of', 'Var', (37, 51))	('BLM', 'Gene', (70, 73))
212208	30086788	Via NGS-based sequencing, we detected 46 missense or disruptive inframe deletion and 2 splice region VUS with an MAF <= 0.1% occurring in 35 of the 94 investigated genes.	('missense', 'Var', (41, 49))	('GS', 'Disease', 'MESH:D011125', (5, 7))	('disruptive', 'NegReg', (53, 63))
212209	30086788	Among this list of VUS, we observed an unexpected frequency of very rare FANCA missense variants that were linked to either very early-onset BC or exceptionally Li-Fraumeni-suggestive family/personal history.	('linked', 'Reg', (107, 113))	('FANCA', 'Gene', (73, 78))	('person', 'Species', '9606', (191, 197))	('FA', 'Phenotype', 'HP:0001994', (73, 75))	('missense variants', 'Var', (79, 96))	('BC', 'Phenotype', 'HP:0003002', (141, 143))	('FANCA', 'Gene', '2175', (73, 78))
212212	30086788	A list of all detected TP53 variants is accessible in Additional file 4.	('TP53', 'Gene', (23, 27))	('variants', 'Var', (28, 36))	('TP53', 'Gene', '7157', (23, 27))
212216	30086788	Two women (subjects 7, 76) carry previously described, protein-truncating, heterozygous PALB2 frameshift variants.	('PALB2', 'Gene', '79728', (88, 93))	('protein-truncating', 'NegReg', (55, 73))	('PALB2', 'Gene', (88, 93))	('women', 'Species', '9606', (4, 9))	('frameshift variants', 'Var', (94, 113))
212217	30086788	The variant PALB2:p.(Gln60Argfs*7), occurring in patient 76, has previously been detected in several unrelated patients with BC, whereas the variant PALB2:p.(Arg170Ilefs*14) in patient 7 is a known Polish founder mutation.	('PALB2:p.(Gln60Argfs*7)', 'FRAMESHIFT', 'None', (12, 34))	('PALB2:p.(Arg170Ilefs*14)', 'FRAMESHIFT', 'None', (149, 173))	('und', 'Gene', '7373', (207, 210))	('patient', 'Species', '9606', (49, 56))	('patient', 'Species', '9606', (111, 118))	('PALB2:p.(Gln60Argfs*7', 'Var', (12, 33))	('BC', 'Phenotype', 'HP:0003002', (125, 127))	('PALB2:p.(Arg170Ilefs*14', 'Var', (149, 172))	('patient', 'Species', '9606', (177, 184))	('und', 'Gene', (207, 210))	('patients', 'Species', '9606', (111, 119))
212218	30086788	Notably, patient 76 developed hormone receptor-positive BC disease at the age of 33 years and contralateral BC at age 39 years, whereas patient 7 presented with triple-negative BC, which is in line with studies reporting breast tumors of PALB2 mutation carriers to be triple-negative in about 34% of these patients.	('BC', 'Phenotype', 'HP:0003002', (177, 179))	('PALB2', 'Gene', '79728', (238, 243))	('breast tumors', 'Disease', 'MESH:D001943', (221, 234))	('patient', 'Species', '9606', (136, 143))	('PALB2', 'Gene', (238, 243))	('BC disease', 'Disease', (56, 66))	('breast tumors', 'Disease', (221, 234))	('hormone', 'Disease', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('BC', 'Phenotype', 'HP:0003002', (56, 58))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('BC', 'Phenotype', 'HP:0003002', (108, 110))	('mutation', 'Var', (244, 252))	('patient', 'Species', '9606', (9, 16))	('breast tumors', 'Phenotype', 'HP:0100013', (221, 234))	('patient', 'Species', '9606', (306, 313))	('patients', 'Species', '9606', (306, 314))
212219	30086788	Furthermore, 3 women of our cohort carry heterozygous PVs in ATM, one of whom additionally harbors a PV in CHEK2.	('CHEK2', 'Gene', '11200', (107, 112))	('women', 'Species', '9606', (15, 20))	('CHEK2', 'Gene', (107, 112))	('PVs', 'Var', (54, 57))	('ATM', 'Gene', (61, 64))	('ATM', 'Gene', '472', (61, 64))
212220	30086788	A deletion of the last 2 exons of ATM (62-63) was detected in patient 32.	('ATM', 'Gene', (34, 37))	('deletion', 'Var', (2, 10))	('patient', 'Species', '9606', (62, 69))	('ATM', 'Gene', '472', (34, 37))
212221	30086788	Deletions of exon 63 or exons 62-63 of the ATM gene have previously been reported in patients with ataxia telangiectasia and are considered to be functionally relevant.	('ataxia', 'Phenotype', 'HP:0001251', (99, 105))	('ATM', 'Gene', (43, 46))	('ataxia telangiectasia', 'Disease', (99, 120))	('reported', 'Reg', (73, 81))	('patients', 'Species', '9606', (85, 93))	('Deletions of exon', 'Var', (0, 17))	('ATM', 'Gene', '472', (43, 46))	('telangiectasia', 'Phenotype', 'HP:0001009', (106, 120))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (99, 120))
212222	30086788	In two further patients (60, 40), we detected previously described ATM nonsense variants; the variant ATM:p.(Glu1978*) has been reported in BC cases before, whereas the variant ATM:p.(Cys2931*) has been described as a class 5 variant in a patient with ataxia telangiectasia.	('patient', 'Species', '9606', (15, 22))	('ATM', 'Gene', (177, 180))	('patient', 'Species', '9606', (239, 246))	('patients', 'Species', '9606', (15, 23))	('telangiectasia', 'Phenotype', 'HP:0001009', (259, 273))	('ataxia', 'Phenotype', 'HP:0001251', (252, 258))	('ataxia telangiectasia', 'Disease', (252, 273))	('ATM', 'Gene', '472', (67, 70))	('BC', 'Phenotype', 'HP:0003002', (140, 142))	('ATM', 'Gene', (102, 105))	('ATM', 'Gene', '472', (177, 180))	('ATM', 'Gene', (67, 70))	('ATM:p.(Cys2931*)', 'SUBSTITUTION', 'None', (177, 193))	('ATM:p.(Glu1978*)', 'SUBSTITUTION', 'None', (102, 118))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (252, 273))	('ATM:p.(Glu1978*', 'Var', (102, 117))	('ATM', 'Gene', '472', (102, 105))	('ATM:p.(Cys2931*', 'Var', (177, 192))
212225	30086788	While monoallelic ATM germline PVs have been described in patients with ovarian cancer, heterozygous ATM variants have been associated predominantly with elevated BC incidence rather than other cancer types.	('ATM', 'Gene', (101, 104))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (194, 200))	('BC', 'Phenotype', 'HP:0003002', (163, 165))	('ATM', 'Gene', '472', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('ATM', 'Gene', '472', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('variants', 'Var', (105, 113))	('elevated', 'PosReg', (154, 162))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('ovarian cancer', 'Disease', (72, 86))	('ATM', 'Gene', (18, 21))	('cancer', 'Disease', (80, 86))
212226	30086788	One woman (patient 58), who is additionally affected by the class 4 splice donor site variant RECQL4:c.1390+1G>C, was identified to carry a CDKN2A/p14ARF nonsense variant in exon 2 of 3 total exons [CDKN2A:p.(Arg98*)].	('CDKN2A:p.(Arg98*', 'Var', (199, 215))	('RECQL4:c.1390+1G>C', 'Var', (94, 112))	('CDKN2A', 'Gene', (140, 146))	('woman', 'Species', '9606', (4, 9))	('donor', 'Species', '9606', (75, 80))	('p14ARF', 'Gene', (147, 153))	('patient', 'Species', '9606', (11, 18))	('CDKN2A', 'Gene', '1029', (140, 146))	('CDKN2A', 'Gene', (199, 205))	('RECQL4:c.1390+1G>C', 'SUBSTITUTION', 'None', (94, 112))	('CDKN2A:p.(Arg98*)', 'SUBSTITUTION', 'None', (199, 216))	('CDKN2A', 'Gene', '1029', (199, 205))	('p14ARF', 'Gene', '1029', (147, 153))
212231	30086788	PVs in human p14ARF exon 2 have been reported to disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and TP53.	('TP53', 'Gene', (143, 147))	('disrupt', 'NegReg', (49, 56))	('ability', 'MPA', (99, 106))	('p14ARF', 'Gene', (13, 19))	('nucleolar localization', 'MPA', (61, 83))	('block', 'NegReg', (110, 115))	('MDM2', 'Gene', '4193', (134, 138))	('human', 'Species', '9606', (7, 12))	('MDM2', 'Gene', (134, 138))	('impair', 'NegReg', (88, 94))	('TP53', 'Gene', '7157', (143, 147))	('nuclear export', 'MPA', (116, 130))	('p14ARF', 'Gene', '1029', (13, 19))	('PVs', 'Var', (0, 3))
212232	30086788	The exon 2 variant in our cohort was identified in an index patient whose grandfather was diagnosed with hypopharyngeal carcinoma, which is in line with CDKN2A PVs predisposing to tobacco-related cancers such as orolaryngeal cancer, next to its predominant role in hereditary melanoma, pancreatic cancer, and further tumor entities [MIM:600160].	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('pancreatic cancer', 'Disease', (286, 303))	('orolaryngeal cancer', 'Disease', 'MESH:D009369', (212, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tobacco', 'Species', '4097', (180, 187))	('CDKN2A', 'Gene', (153, 159))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('hypopharyngeal carcinoma', 'Disease', 'MESH:D007012', (105, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (286, 303))	('orolaryngeal cancer', 'Disease', (212, 231))	('hypopharyngeal carcinoma', 'Disease', (105, 129))	('tumor', 'Disease', (317, 322))	('CDKN2A', 'Gene', '1029', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancers', 'Disease', (196, 203))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('hereditary melanoma', 'Disease', (265, 284))	('patient', 'Species', '9606', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('pancreatic cancer', 'Disease', 'MESH:D010190', (286, 303))	('hereditary melanoma', 'Disease', 'MESH:D008545', (265, 284))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('variant', 'Var', (11, 18))	('hypopharyngeal carcinoma', 'Phenotype', 'HP:0012182', (105, 129))
212234	30086788	Conversely, however, sarcomas are rare in CDKN2A mutation carriers, and the affected family of our cohort also does not present with sarcoma cases.	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('sarcomas', 'Disease', (21, 29))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('mutation', 'Var', (49, 57))	('CDKN2A', 'Gene', (42, 48))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('CDKN2A', 'Gene', '1029', (42, 48))	('sarcoma', 'Disease', (133, 140))	('sarcomas', 'Disease', 'MESH:D012509', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('sarcoma', 'Disease', (21, 28))
212236	30086788	In index patient 30, we detected a splice donor site variant in RUNX1 (RUNX1:c.97+1G>A) predicted deleterious by 4 of 5 splice prediction programs owing to complete loss of the native splice site.	('native splice site', 'MPA', (177, 195))	('RUNX1:c.97+1G>A', 'SUBSTITUTION', 'None', (71, 86))	('RUNX1:c.97+1G>A', 'Var', (71, 86))	('RUNX1', 'Gene', (71, 76))	('RUNX1', 'Gene', '861', (71, 76))	('RUNX1', 'Gene', (64, 69))	('donor', 'Species', '9606', (42, 47))	('patient', 'Species', '9606', (9, 16))	('loss', 'NegReg', (165, 169))	('RUNX1', 'Gene', '861', (64, 69))
212242	30086788	A conclusive role for RUNX1 germline variations in BC pathogenesis cannot be assessed currently and needs further clarification.	('BC', 'Phenotype', 'HP:0003002', (51, 53))	('germline', 'Var', (28, 36))	('RUNX1', 'Gene', (22, 27))	('RUNX1', 'Gene', '861', (22, 27))
212243	30086788	The nonsense FANCI variant FANCI:p.(Arg1285*) in exon 37 of 38 total exons, located within the last 72 bp of the second to last exon and therefore imprecise in regard to NMD, was detected in patient 65, who was additionally found to carry a deletion of exons 3-8 of the PMS2 gene, which was verified by MLPA analysis.	('FANCI', 'Gene', (27, 32))	('FANCI:p.(Arg1285*)', 'SUBSTITUTION', 'None', (27, 45))	('FA', 'Phenotype', 'HP:0001994', (13, 15))	('PMS2', 'Gene', '5395', (270, 274))	('FA', 'Phenotype', 'HP:0001994', (27, 29))	('und', 'Gene', (226, 229))	('FANCI', 'Gene', '55215', (13, 18))	('PMS2', 'Gene', (270, 274))	('FANCI', 'Gene', '55215', (27, 32))	('FANCI:p.(Arg1285*', 'Var', (27, 44))	('FANCI', 'Gene', (13, 18))	('patient', 'Species', '9606', (191, 198))	('deletion', 'Var', (241, 249))	('und', 'Gene', '7373', (226, 229))
212244	30086788	Because the maternal lineage includes two colorectal carcinomas in two of the index person's second-degree relatives, diagnosed at 37 and 70 years of age, the PMS2 variant is primarily suggestive of being responsible for the familial cancer phenotypes.	('responsible', 'Reg', (205, 216))	('familial cancer', 'Disease', 'MESH:D009369', (225, 240))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('person', 'Species', '9606', (84, 90))	('PMS2', 'Gene', (159, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('PMS2', 'Gene', '5395', (159, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('colorectal carcinomas', 'Disease', (42, 63))	('variant', 'Var', (164, 171))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (42, 63))	('familial cancer', 'Disease', (225, 240))
212245	30086788	Nonetheless, the FANCI variant concerns a highly conserved arginine, has previously been described in patients with Fanconi anemia (FA), and has been found to impair DNA binding and ubiquitination of the ID2 complex, a dimeric complex formed by FANCI and FANCD2, which is relevant for DNA crosslink repair.	('ID2', 'Gene', (204, 207))	('patients', 'Species', '9606', (102, 110))	('und', 'Gene', '7373', (152, 155))	('arginine', 'Chemical', 'MESH:D001120', (59, 67))	('FANCI', 'Gene', (17, 22))	('und', 'Gene', (152, 155))	('FA', 'Phenotype', 'HP:0001994', (17, 19))	('FA', 'Phenotype', 'HP:0001994', (255, 257))	('FANCI', 'Gene', (245, 250))	('Fanconi anemia', 'Disease', (116, 130))	('FANCI', 'Gene', '55215', (17, 22))	('Fanconi anemia', 'Disease', 'MESH:D005199', (116, 130))	('FANCI', 'Gene', '55215', (245, 250))	('FANCD2', 'Gene', (255, 261))	('ubiquitination', 'MPA', (182, 196))	('variant', 'Var', (23, 30))	('anemia', 'Phenotype', 'HP:0001903', (124, 130))	('FA', 'Phenotype', 'HP:0001994', (245, 247))	('FANCD2', 'Gene', '2177', (255, 261))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (116, 130))	('DNA binding', 'Interaction', (166, 177))	('FA', 'Phenotype', 'HP:0001994', (132, 134))	('impair', 'NegReg', (159, 165))	('ID2', 'Gene', '3398', (204, 207))
212246	30086788	Because the paternal lineage also shows incidence of malignant disease, it is conceivable that the FANCI and PMS2 variants may jointly combine in the index person's genome, leading to a more severe phenotype, such as earlier age of onset of disease.	('malignant disease', 'Disease', (53, 70))	('leading to', 'Reg', (173, 183))	('FANCI', 'Gene', '55215', (99, 104))	('person', 'Species', '9606', (156, 162))	('variants', 'Var', (114, 122))	('PMS2', 'Gene', (109, 113))	('FANCI', 'Gene', (99, 104))	('PMS2', 'Gene', '5395', (109, 113))	('FA', 'Phenotype', 'HP:0001994', (99, 101))	('malignant disease', 'Disease', 'MESH:D009369', (53, 70))
212247	30086788	Furthermore, 6 patients of our cohort were identified to carry 5 very rare FANCA VUS: FANCA:p.(Trp22Gly) twice, FANCA:p.(Pro497Ala), FANCA:p.(Pro667Arg), FANCA:p.(Arg1144Trp), and FANCA:p.(Leu1230Val).	('patients', 'Species', '9606', (15, 23))	('FA', 'Phenotype', 'HP:0001994', (154, 156))	('FANCA', 'Gene', '2175', (112, 117))	('FANCA:p.(Leu1230Val)', 'SUBSTITUTION', 'None', (180, 200))	('FANCA', 'Gene', (75, 80))	('FANCA', 'Gene', (154, 159))	('FANCA:p.(Pro497Ala)', 'SUBSTITUTION', 'None', (112, 131))	('FA', 'Phenotype', 'HP:0001994', (112, 114))	('FANCA', 'Gene', '2175', (133, 138))	('FANCA', 'Gene', (112, 117))	('FANCA:p.(Pro667Arg', 'Var', (133, 151))	('FANCA', 'Gene', '2175', (180, 185))	('FANCA', 'Gene', '2175', (86, 91))	('FANCA:p.(Pro667Arg)', 'SUBSTITUTION', 'None', (133, 152))	('FA', 'Phenotype', 'HP:0001994', (86, 88))	('FANCA', 'Gene', (133, 138))	('FA', 'Phenotype', 'HP:0001994', (133, 135))	('FANCA', 'Gene', (86, 91))	('FANCA:p.(Arg1144Trp', 'Var', (154, 173))	('FANCA:p.(Trp22Gly)', 'SUBSTITUTION', 'None', (86, 104))	('FANCA:p.(Trp22Gly', 'Var', (86, 103))	('FANCA', 'Gene', (180, 185))	('FANCA:p.(Arg1144Trp)', 'SUBSTITUTION', 'None', (154, 174))	('FANCA', 'Gene', '2175', (75, 80))	('FANCA', 'Gene', '2175', (154, 159))	('FANCA:p.(Leu1230Val', 'Var', (180, 199))	('FA', 'Phenotype', 'HP:0001994', (75, 77))	('FANCA:p.(Pro497Ala', 'Var', (112, 130))
212253	30086788	Heterozygous parents and siblings of patients with FA have not been found to exhibit an elevated incidence of malignant disease; however, monoallelic FANCA variants have been investigated only sparsely in a disease context, and with inconsistent results.	('patients', 'Species', '9606', (37, 45))	('FA', 'Phenotype', 'HP:0001994', (51, 53))	('und', 'Gene', '7373', (70, 73))	('FANCA', 'Gene', '2175', (150, 155))	('variants', 'Var', (156, 164))	('FANCA', 'Gene', (150, 155))	('malignant disease', 'Disease', 'MESH:D009369', (110, 127))	('FA', 'Phenotype', 'HP:0001994', (150, 152))	('und', 'Gene', (70, 73))	('malignant disease', 'Disease', (110, 127))
212254	30086788	Considering the rarity of each FANCA VUS detected in the present study, and given the possibility of differing FANCA missense variants conferring vastly diverse effects on protein function, the disproportionate occurrence of these rare variants appears to be worthy of further investigation.	('effects', 'Reg', (161, 168))	('FANCA', 'Gene', (31, 36))	('variants', 'Var', (126, 134))	('FANCA', 'Gene', (111, 116))	('FA', 'Phenotype', 'HP:0001994', (31, 33))	('missense', 'Var', (117, 125))	('protein function', 'MPA', (172, 188))	('FA', 'Phenotype', 'HP:0001994', (111, 113))	('FANCA', 'Gene', '2175', (111, 116))	('FANCA', 'Gene', '2175', (31, 36))
212259	30086788	Whereas biallelic impairment is considered mandatory for the full spectrum of the syndromes to develop, WRN and BLM have additionally been suggested as BC susceptibility genes in a monoallelic setting, and dominant-negative effects or gain-of-function processes have previously been proposed for specific missense mutant WRN or BLM proteins.	('WRN', 'Gene', '7486', (104, 107))	('gain-of-function', 'PosReg', (235, 251))	('BLM', 'Gene', '641', (112, 115))	('WRN', 'Gene', (104, 107))	('BLM', 'Gene', '641', (328, 331))	('WRN', 'Gene', '7486', (321, 324))	('WRN', 'Gene', (321, 324))	('BLM', 'Gene', (112, 115))	('BLM', 'Gene', (328, 331))	('BC', 'Phenotype', 'HP:0003002', (152, 154))	('missense mutant', 'Var', (305, 320))
212267	30086788	Associations have been suggested for LFS-associated brain tumors with nonsense PVs in CASP9 (caspase-9), for a POT1 (protection of telomeres 1) missense variant with cardiac and breast angiosarcomas, and, as mentioned above, for CDKN2A PVs with hereditary sarcoma cases.	('brain tumor', 'Phenotype', 'HP:0030692', (52, 63))	('CASP9', 'Gene', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('CDKN2A', 'Gene', '1029', (229, 235))	('CASP9', 'Gene', '842', (86, 91))	('angiosarcomas', 'Phenotype', 'HP:0200058', (185, 198))	('sarcomas', 'Phenotype', 'HP:0100242', (190, 198))	('caspase-9', 'Gene', (93, 102))	('POT1', 'Gene', (111, 115))	('brain tumors', 'Disease', (52, 64))	('Associations', 'Reg', (0, 12))	('breast angiosarcomas', 'Disease', 'MESH:C536368', (178, 198))	('missense variant', 'Var', (144, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('LFS-associated', 'Gene', (37, 51))	('hereditary sarcoma', 'Disease', 'MESH:D012509', (245, 263))	('cardiac', 'Disease', (166, 173))	('brain tumors', 'Phenotype', 'HP:0030692', (52, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('nonsense PVs', 'Var', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('hereditary sarcoma', 'Disease', (245, 263))	('CDKN2A', 'Gene', (229, 235))	('caspase-9', 'Gene', '842', (93, 102))	('breast angiosarcomas', 'Disease', (178, 198))	('brain tumors', 'Disease', 'MESH:D001932', (52, 64))	('POT1', 'Gene', '25913', (111, 115))
212269	30086788	Whereas the severe phenotype known for LFS is expected to result predominantly from missense or isoform-specific variants conferring a dominant-negative effect of the mutated over the wild-type proteins, TP53 haploinsufficiency (e.g., loss of function or gene dosage effects due to splice variants or 3' UTR variants and deletions, respectively) is emerging as a likely mechanism for a more subtle phenotype, one that may in fact be described as LFL, as has previously been suggested.	('LFS', 'Disease', (39, 42))	('variants', 'Var', (113, 121))	('deletions', 'Var', (321, 330))	('gene dosage', 'Var', (255, 266))	('haploinsufficiency', 'Disease', 'MESH:D058495', (209, 227))	('TP53', 'Gene', '7157', (204, 208))	('haploinsufficiency', 'Disease', (209, 227))	('TP53', 'Gene', (204, 208))	('loss of function', 'NegReg', (235, 251))
212270	30086788	Testing patients without variants in coding TP53 regions, such as the ones in our cohort, for the above-mentioned variants would constitute a crucial future undertaking.	('variants', 'Var', (25, 33))	('und', 'Gene', (157, 160))	('TP53', 'Gene', '7157', (44, 48))	('und', 'Gene', '7373', (157, 160))	('TP53', 'Gene', (44, 48))	('patients', 'Species', '9606', (8, 16))
212274	30086788	Notably, our study further reveals that there remains a large portion of unexplained LFS/LFL cases and emphasizes the necessity of advanced research on novel susceptibility genes as well as noncoding TP53 variants in patients with negative test results for TP53 variants in coding regions.	('TP53', 'Gene', (257, 261))	('TP53', 'Gene', '7157', (200, 204))	('TP53', 'Gene', (200, 204))	('variants', 'Var', (205, 213))	('LFS/LFL', 'Disease', (85, 92))	('patients', 'Species', '9606', (217, 225))	('TP53', 'Gene', '7157', (257, 261))
212275	30086788	ACMG American College of Medical Genetics and Genomics BC Breast cancer bp Base pair(s) CGH Comparative genomic hybridization FA Fanconi anemia HBOC Hereditary breast and ovarian cancer HMGU Helmholtz Zentrum Munchen - Deutsches Forschungszentrum fur Gesundheit und Umwelt IGV Integrative Genomics Viewer LFL Li-Fraumeni-like syndrome LFS Li-Fraumeni syndrome MAF Minor allele frequency MLPA Multiplex ligation-dependent probe amplification NGS Next-generation sequencing NMD Nonsense-mediated RNA decay PV Pathogenic variant ROI Region of interest UTR Untranslated region VAF Variant allele frequency VUS Variant of unknown significance JP contributed to conception and design, data generation, data interpretation and statistical analysis, critical review and discussion, and the writing of the manuscript.	('Li-Fraumeni-like syndrome', 'Disease', (309, 334))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('variant', 'Var', (518, 525))	('ovarian cancer', 'Phenotype', 'HP:0100615', (171, 185))	('Li-Fraumeni syndrome', 'Disease', (339, 359))	('und', 'Gene', '7373', (262, 265))	('und', 'Gene', '7373', (254, 257))	('Nonsense-mediated', 'Var', (476, 493))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (309, 334))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (339, 359))	('und', 'Gene', (262, 265))	('und', 'Gene', (254, 257))	('FA', 'Phenotype', 'HP:0001994', (126, 128))	('GS', 'Disease', 'MESH:D011125', (442, 444))	('Breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('Hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (149, 185))	('BC', 'Phenotype', 'HP:0003002', (55, 57))	('Breast cancer', 'Disease', (58, 71))	('VAF', 'Chemical', '-', (573, 576))	('Breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('Fanconi anemia', 'Disease', (129, 143))	('Fanconi anemia', 'Disease', 'MESH:D005199', (129, 143))	('anemia', 'Phenotype', 'HP:0001903', (137, 143))
212486	29184796	Chemotherapy also impacts female fertility, as alkylating agents such as ifosfamide, commonly used in the treatment of sarcoma, have been associated to a high risk of amenorrhea and infertility.	('amenorrhea and infertility', 'Disease', 'MESH:D000568', (167, 193))	('high risk of amenorrhea', 'Phenotype', 'HP:0000869', (154, 177))	('men', 'Species', '9606', (111, 114))	('risk of amenorrhea', 'Phenotype', 'HP:0000869', (159, 177))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('alkylating', 'Var', (47, 57))	('female fertility', 'CPA', (26, 42))	('ifosfamide', 'Chemical', 'MESH:D007069', (73, 83))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('amenorrhea', 'Phenotype', 'HP:0000141', (167, 177))	('men', 'Species', '9606', (168, 171))	('impacts', 'Reg', (18, 25))	('infertility', 'Phenotype', 'HP:0000789', (182, 193))
212566	26837714	Epigenetic re-expression of HIF-2alpha suppresses soft tissue sarcoma growth In soft tissue sarcomas (STS), low intratumoural O2 (hypoxia) is a poor prognostic indicator.	('hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('STS', 'Phenotype', 'HP:0030448', (102, 105))	('O2', 'Chemical', 'MESH:D010100', (126, 128))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (80, 99))	('Epigenetic re-expression', 'Var', (0, 24))	('HIF-2alpha', 'Gene', (28, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('soft tissue sarcomas', 'Disease', (80, 100))	('sarcoma', 'Disease', (92, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('suppresses', 'NegReg', (39, 49))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (80, 100))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (80, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('hypoxia', 'Disease', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('HIF-2alpha', 'Gene', '13819', (28, 38))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('tumour', 'Disease', (117, 123))	('sarcoma', 'Disease', (62, 69))	('soft', 'Disease', (50, 54))
212568	26837714	Surprisingly, here we show that HIF-2alpha inhibits high-grade STS cell growth in vivo, as loss of HIF-2alpha promotes sarcoma proliferation and increases calcium and mTORC1 signalling in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.	('liposarcoma', 'Disease', (246, 257))	('HIF-2alpha promotes sarcoma proliferation', 'Disease', (99, 140))	('liposarcoma', 'Disease', 'MESH:D008080', (246, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('mTORC1', 'Gene', (167, 173))	('HIF-2alpha promotes sarcoma proliferation', 'Disease', 'MESH:D012509', (99, 140))	('liposarcoma', 'Phenotype', 'HP:0012034', (246, 257))	('increases', 'PosReg', (145, 154))	('STS', 'Phenotype', 'HP:0030448', (63, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (188, 224))	('loss', 'Var', (91, 95))	('undifferentiated pleomorphic sarcoma', 'Disease', (188, 224))	('mTORC1', 'Gene', '382056', (167, 173))	('calcium', 'Chemical', 'MESH:D002118', (155, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))
212572	26837714	Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2alpha deletion, implicating HIF-2alpha as a biomarker for Vorinostat efficacy in STS.	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour growth', 'Disease', (24, 37))	('tumour growth', 'Disease', 'MESH:D006130', (24, 37))	('deletion', 'Var', (75, 83))	('inhibits', 'NegReg', (11, 19))	('STS', 'Phenotype', 'HP:0030448', (150, 153))	('Vorinostat', 'Chemical', 'MESH:D000077337', (127, 137))	('Vorinostat', 'Chemical', 'MESH:D000077337', (0, 10))	('HIF-2alpha', 'Gene', (64, 74))	('STS', 'Phenotype', 'HP:0030448', (20, 23))
212574	26837714	show that paradoxically HIF-2alpha is epigenetically silenced during the progression of multiple sarcoma subtypes, and when reexpressed, blocks tumour growth in vivo.	('multiple sarcoma subtypes', 'Disease', 'MESH:D012509', (88, 113))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour growth', 'Disease', (144, 157))	('epigenetically', 'Var', (38, 52))	('tumour growth', 'Disease', 'MESH:D006130', (144, 157))	('silenced', 'NegReg', (53, 61))	('multiple sarcoma subtypes', 'Disease', (88, 113))	('blocks tumour', 'Disease', 'MESH:D006327', (137, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('HIF-2alpha', 'Gene', (24, 34))	('blocks tumour', 'Disease', (137, 150))
212587	26837714	In this study, using a genetically engineered UPS mouse model that faithfully recapitulates human disease, as well as fibrosarcoma and liposarcoma xenografts, we found that HIF-2alpha expression surprisingly suppresses tumourigenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('suppresses', 'NegReg', (208, 218))	('fibrosarcoma and liposarcoma', 'Disease', 'MESH:D005354', (118, 146))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (118, 130))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('liposarcoma', 'Phenotype', 'HP:0012034', (135, 146))	('tumour', 'Disease', (219, 225))	('mouse', 'Species', '10090', (50, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('human', 'Species', '9606', (92, 97))	('HIF-2alpha', 'Var', (173, 183))
212588	26837714	Loss of HIF-2alpha (encoded by the EPAS1 gene) increased sarcoma tumour cell proliferation.	('HIF-2alpha', 'Gene', (8, 18))	('sarcoma tumour', 'Disease', 'MESH:D012509', (57, 71))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('increased', 'PosReg', (47, 56))	('sarcoma tumour', 'Disease', (57, 71))	('EPAS1', 'Gene', (35, 40))	('Loss', 'Var', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
212591	26837714	mTORC1 senses nutrient availability, and regulates cellular growth, biosynthetic activity and ribosomal biogenesis; as such, disregulation of this pathway occurs in a variety of cancer types, including sarcomas.	('disregulation', 'Var', (125, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (202, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('sarcomas', 'Disease', (202, 210))	('mTORC1', 'Gene', '382056', (0, 6))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('mTORC1', 'Gene', (0, 6))	('sarcomas', 'Disease', 'MESH:D012509', (202, 210))
212593	26837714	These data suggest that EPAS1 expression is suppressed by epigenetic mechanisms in multiple sarcoma subtypes.	('EPAS1', 'Protein', (24, 29))	('suppressed', 'NegReg', (44, 54))	('expression', 'MPA', (30, 40))	('multiple sarcoma subtypes', 'Disease', (83, 108))	('multiple sarcoma subtypes', 'Disease', 'MESH:D012509', (83, 108))	('epigenetic', 'Var', (58, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
212594	26837714	Altered epigenetics have been observed in many cancers, with dysregulation of the epigenome proposed as an important mechanism whereby tumours progress.	('dysregulation', 'Var', (61, 74))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('cancers', 'Disease', (47, 54))	('observed', 'Reg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('epigenetics', 'MPA', (8, 19))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
212595	26837714	Of note, treatment with the chromatin modifying agent suberanilohydroxamic acid (SAHA, Sigma-Aldrich, St Louis, MO, USA; Vorinostat), a clinically approved histone deacetylase inhibitor (HDACi), significantly increased HIF-2alpha expression in several STS, and inhibited growth in a HIF-2alpha dependent manner.	('suberanilohydroxamic acid', 'Chemical', 'MESH:D000077337', (54, 79))	('HIF-2alpha', 'Protein', (219, 229))	('STS', 'Phenotype', 'HP:0030448', (252, 255))	('expression', 'MPA', (230, 240))	('SAHA', 'Chemical', 'MESH:D000077337', (81, 85))	('Vorinostat', 'Chemical', 'MESH:D000077337', (121, 131))	('growth', 'MPA', (271, 277))	('inhibited', 'NegReg', (261, 270))	('suberanilohydroxamic acid', 'Var', (54, 79))	('increased', 'PosReg', (209, 218))
212599	26837714	PCR analysis confirmed efficient Epas1 deletion in KPH2 tumours (Supplementary Fig.	('Epas1', 'Gene', (33, 38))	('KPH2 tumours', 'Disease', 'MESH:D009369', (51, 63))	('deletion', 'Var', (39, 47))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('KPH2 tumours', 'Disease', (51, 63))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))
212600	26837714	Both KP and KPH2 samples displayed a similar heterogeneous, multinucleated appearance consistent with UPS and local muscle invasion was also observed, albeit more extensively in the KPH2 than KP tumours (Supplementary Fig.	('KPH2', 'Var', (182, 186))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('KP tumours', 'Disease', 'MESH:D009369', (192, 202))	('KP tumours', 'Disease', (192, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
212606	26837714	To rule out the possibility that the effects of HIF-2alpha deficiency in vivo were due to compensatory HIF-1alpha activity, we deleted Arnt, the obligate binding partner of both HIF-1alpha and HIF-2alpha.	('deleted', 'Var', (127, 134))	('Arnt', 'Gene', (135, 139))	('HIF-1alpha', 'Gene', (103, 113))	('HIF-1alpha', 'Gene', '15251', (103, 113))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (178, 203))	('Arnt', 'Gene', '11863', (135, 139))	('HIF-2alpha deficiency', 'Disease', (48, 69))	('HIF-2alpha deficiency', 'Disease', 'MESH:D007153', (48, 69))	('HIF-1alpha', 'Gene', '15251', (178, 188))	('HIF-1alpha', 'Gene', (178, 188))
212609	26837714	1d), indicating that the effects of HIF-2alpha deletion are not due to HIF-1alpha-mediated compensation.	('HIF-2alpha', 'Gene', (36, 46))	('deletion', 'Var', (47, 55))	('HIF-1alpha', 'Gene', '15251', (71, 81))	('HIF-1alpha', 'Gene', (71, 81))
212610	26837714	Together, these data indicate that HIF-2alpha suppresses UPS tumourigenesis, in contrast to HIF-1alpha which has no effect on primary tumour growth in this model.	('tumour growth', 'Disease', (134, 147))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('suppresses', 'NegReg', (46, 56))	('tumour growth', 'Disease', 'MESH:D006130', (134, 147))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('tumour', 'Disease', (61, 67))	('tumour', 'Disease', (134, 140))	('HIF-1alpha', 'Gene', '15251', (92, 102))	('HIF-1alpha', 'Gene', (92, 102))	('HIF-2alpha', 'Var', (35, 45))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
212619	26837714	Furthermore, HIF-2alpha depletion promoted growth of HT-1080 fibrosarcoma tumour xenografts in vivo (Fig.	('HT-1080 fibrosarcoma tumour', 'Disease', (53, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('HIF-2alpha', 'Protein', (13, 23))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (61, 73))	('depletion', 'Var', (24, 33))	('promoted', 'PosReg', (34, 42))	('growth', 'CPA', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('HT-1080 fibrosarcoma tumour', 'Disease', 'MESH:D005354', (53, 80))
212621	26837714	These results demonstrate that inhibition of HIF-2alpha in vivo accelerates growth of multiple STS, including UPS, fibrosarcoma and liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('fibrosarcoma and liposarcoma', 'Disease', 'MESH:D005354', (115, 143))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (115, 127))	('accelerates', 'PosReg', (64, 75))	('liposarcoma', 'Phenotype', 'HP:0012034', (132, 143))	('STS', 'Phenotype', 'HP:0030448', (95, 98))	('UPS', 'Disease', (110, 113))	('HIF-2alpha', 'Protein', (45, 55))	('inhibition', 'Var', (31, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('growth', 'MPA', (76, 82))
212622	26837714	To define mechanism(s) whereby HIF-2alpha opposes sarcomagenesis using an unbiased approach, we performed RNA-seq analysis of KP (n=3) and KPH2 (n=4) tumours.	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumours', 'Disease', (150, 157))	('sarcoma', 'Disease', (50, 57))	('opposes', 'NegReg', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('HIF-2alpha', 'Var', (31, 41))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
212636	26837714	Phosphorylated 4E-BP1 levels were elevated in KPH2 tumour-derived cells as compared with KP tumour-derived cells (Supplementary Fig.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour', 'Disease', (92, 98))	('KP tumour', 'Disease', 'MESH:D009369', (89, 98))	('4E-BP1', 'Gene', '13685', (15, 21))	('KP tumour', 'Disease', (89, 98))	('4E-BP1', 'Gene', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('elevated', 'PosReg', (34, 42))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('KPH2', 'Var', (46, 50))	('tumour', 'Disease', (51, 57))
212638	26837714	Similar increases in phosphorylated 4E-BP1, S6K1 and S6 were apparent in HIF-2alpha knockdown LPS246 xenografts (Fig.	('phosphorylated', 'MPA', (21, 35))	('HIF-2alpha', 'Gene', (73, 83))	('4E-BP1', 'Gene', '13685', (36, 42))	('knockdown', 'Var', (84, 93))	('4E-BP1', 'Gene', (36, 42))	('S6K1', 'Gene', '72508', (44, 48))	('increases', 'PosReg', (8, 17))	('LPS246', 'Chemical', '-', (94, 100))	('S6K1', 'Gene', (44, 48))
212654	26837714	As expected, CaCCinh-A01 treatment reduced phosphorylated CaMKIIalpha levels more effectively in KPH2 compared with KP cells (Fig.	('reduced', 'NegReg', (35, 42))	('CaMKII', 'Gene', '12323', (58, 64))	('CaMKII', 'Gene', (58, 64))	('CaCCinh-A01', 'Chemical', 'MESH:C000607369', (13, 24))	('KPH2', 'Var', (97, 101))
212655	26837714	Moreover, CaCCinh-A01 diminished mTORC1 activation (Fig.	('diminished', 'NegReg', (22, 32))	('CaCCinh-A01', 'Chemical', 'MESH:C000607369', (10, 21))	('mTORC1', 'Gene', (33, 39))	('mTORC1', 'Gene', '382056', (33, 39))	('CaCCinh-A01', 'Var', (10, 21))
212659	26837714	Similar to our in vitro data, inhibition of ANO1 reduced tumour growth in KPH2 but not KP allografts (Fig.	('tumour growth', 'Disease', 'MESH:D006130', (57, 70))	('inhibition', 'Var', (30, 40))	('reduced', 'NegReg', (49, 56))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('ANO1', 'Gene', '101772', (44, 48))	('ANO1', 'Gene', (44, 48))	('tumour growth', 'Disease', (57, 70))
212660	26837714	Collectively, these data suggest that loss of HIF-2alpha increases ANO1 accumulation, activating CaMKII and mTORC1 signalling in UPS tumours, enhancing their growth (see below for further discussion).	('loss', 'Var', (38, 42))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('CaMKII', 'Gene', (97, 103))	('UPS tumours', 'Disease', (129, 140))	('UPS tumours', 'Disease', 'MESH:D017118', (129, 140))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('growth', 'MPA', (158, 164))	('HIF-2alpha', 'Gene', (46, 56))	('ANO1', 'Gene', '101772', (67, 71))	('activating', 'PosReg', (86, 96))	('enhancing', 'PosReg', (142, 151))	('increases', 'PosReg', (57, 66))	('ANO1', 'Gene', (67, 71))	('mTORC1', 'Gene', '382056', (108, 114))	('CaMKII', 'Gene', '12323', (97, 103))	('mTORC1', 'Gene', (108, 114))
212698	26837714	SAHA significantly slowed the growth of control tumours, while HIF-2alpha inhibition abrogated this effect in a dose-dependent manner (Fig.	('slowed', 'NegReg', (19, 25))	('inhibition', 'Var', (74, 84))	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('HIF-2alpha', 'Protein', (63, 73))	('SAHA', 'Chemical', 'MESH:D000077337', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('growth', 'CPA', (30, 36))	('abrogated', 'NegReg', (85, 94))	('tumours', 'Disease', 'MESH:D009369', (48, 55))
212716	26837714	One major obstacle to developing better treatment regimens has been the myriad of unique subtypes with distinct genetic alterations, coupled with the relatively low incidence of these malignancies.	('malignancies', 'Disease', (184, 196))	('genetic alterations', 'Var', (112, 131))	('malignancies', 'Disease', 'MESH:D009369', (184, 196))
212726	26837714	Although mTORC2 signalling has been shown to promote HIF-2alpha accumulation in cancers like renal cell carcinoma, our results suggest that HIF-2alpha inhibits mTORC1 signalling in at least the high-grade STS subtypes examined.	('mTORC2', 'Gene', '74343', (9, 15))	('inhibits', 'NegReg', (151, 159))	('STS', 'Phenotype', 'HP:0030448', (205, 208))	('HIF-2alpha accumulation in cancers like renal cell carcinoma', 'Disease', 'MESH:C538614', (53, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (93, 113))	('mTORC1', 'Gene', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('HIF-2alpha', 'Var', (140, 150))	('mTORC1', 'Gene', '382056', (160, 166))	('mTORC2', 'Gene', (9, 15))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
212728	26837714	For UPS tumours, loss of HIF-2alpha increases ANO1, promoting CaMKII and mTORC1 activity (Fig.	('mTORC1', 'Gene', (73, 79))	('promoting', 'PosReg', (52, 61))	('HIF-2alpha', 'Protein', (25, 35))	('ANO1', 'Gene', '101772', (46, 50))	('UPS tumours', 'Disease', (4, 15))	('UPS tumours', 'Disease', 'MESH:D017118', (4, 15))	('CaMKII', 'Gene', '12323', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('mTORC1', 'Gene', '382056', (73, 79))	('ANO1', 'Gene', (46, 50))	('CaMKII', 'Gene', (62, 68))	('increases', 'PosReg', (36, 45))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('loss', 'Var', (17, 21))
212729	26837714	Interestingly, a previous study demonstrated that HIF-1alpha inhibition increased ANO1 mRNA expression in renal cysts, yet we are the first to connect HIF-2alpha loss with increased ANO1 in UPS.	('renal cysts', 'Disease', (106, 117))	('ANO1', 'Gene', (182, 186))	('increased', 'PosReg', (72, 81))	('HIF-2alpha loss', 'Disease', (151, 166))	('inhibition', 'Var', (61, 71))	('HIF-2alpha loss', 'Disease', 'MESH:D015431', (151, 166))	('renal cysts', 'Phenotype', 'HP:0000107', (106, 117))	('HIF-1alpha', 'Gene', (50, 60))	('ANO1', 'Gene', '101772', (82, 86))	('HIF-1alpha', 'Gene', '15251', (50, 60))	('ANO1', 'Gene', '101772', (182, 186))	('renal cysts', 'Disease', 'MESH:D007674', (106, 117))	('ANO1', 'Gene', (82, 86))
212731	26837714	Given the multitude of targets and biological processes HIF-2alpha controls, the mechanism whereby HIF-2alpha inhibition increases ANO1 levels remains to be elucidated.	('ANO1', 'Gene', '101772', (131, 135))	('increases', 'PosReg', (121, 130))	('ANO1', 'Gene', (131, 135))	('HIF-2alpha', 'Gene', (99, 109))	('inhibition', 'Var', (110, 120))
212747	26837714	These results suggest that HDACi therapies will be most effective against sarcomas that have epigenetically suppressed HIF-2alpha expression, and not genomic deletion of the locus.	('sarcomas', 'Disease', (74, 82))	('HIF-2alpha', 'Protein', (119, 129))	('expression', 'MPA', (130, 140))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('epigenetically', 'Var', (93, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
212785	26837714	Subsequently, the lysates were transferred to nitrocellulose membranes and probed with the following antibodies and concentrations: HIF-2alpha 1:1,000 (Novus #NB100-122), HIF-1alpha 1:1,000 (Cayman Chemicals #1006421), caspase-3 1:1,000 (Cell Signaling #9662 Danvers, MA, USA), GAPDH 1:2,000 (Cell Signaling #2118), beta-tubulin 1:1,500 (Cell Signaling #2146), phospho-4E-BP1 1:1,000 (S65, Cell Signaling #9451), 4E-BP1 1:1,000 (Cell Signaling #9452), phospho-S6K1 1:1,000 (T389, Cell Signaling #9205), c-Myc 1:5,000 (Abcam #32072), S6K1 1:1,000 (Cell Signaling #2708), phospho-AKT 1:1,000 (S473, Cell Signaling #9271), AKT 1:1,000 (Cell Signaling #9272), phospho-EGFR 1:1,000 (Y1068, Cell Signaling #3777), EGFR 1:1,000 (Cell Signaling #4267) ANO1 1:500 (Abcam ab64085), phospho-CAMKIIalpha 1:1,000 (T286, Cell Signaling #12716) and CAMKII 1:1,000 (Cell Signaling #11945).	('AKT', 'Gene', (578, 581))	('HIF-1alpha', 'Gene', (171, 181))	('T286', 'Var', (801, 805))	('4E-BP1', 'Gene', '13685', (413, 419))	('EGFR', 'Gene', '13649', (708, 712))	('4E-BP1', 'Gene', (413, 419))	('AKT', 'Gene', '11651', (620, 623))	('CAMKII', 'Gene', (780, 786))	('EGFR', 'Gene', (708, 712))	('S6K1', 'Gene', (533, 537))	('Myc', 'Gene', (505, 508))	('AKT', 'Gene', '11651', (578, 581))	('CAMKII', 'Gene', (834, 840))	('S6K1', 'Gene', '72508', (533, 537))	('S6K1', 'Gene', (460, 464))	('caspase-3 1:1,000', 'Gene', '12362', (219, 236))	('GAPDH', 'Gene', (278, 283))	('Myc', 'Gene', '17869', (505, 508))	('S6K1', 'Gene', '72508', (460, 464))	('CAMKII', 'Gene', '12323', (780, 786))	('ANO1', 'Gene', (744, 748))	('4E-BP1', 'Gene', (369, 375))	('GAPDH', 'Gene', '14433', (278, 283))	('4E-BP1', 'Gene', '13685', (369, 375))	('AKT', 'Gene', (620, 623))	('EGFR', 'Gene', (664, 668))	('EGFR', 'Gene', '13649', (664, 668))	('HIF-1alpha', 'Gene', '15251', (171, 181))	('CAMKII', 'Gene', '12323', (834, 840))	('ANO1', 'Gene', '101772', (744, 748))
212791	26837714	The following primary antibodies and concentrations were used for immunohistochemistry: anti-BrdU 1:40 (Abcam #ab6326), anti-cleaved caspase-3 Asp 175 1:300 (Cell Signaling #9661) anti-Ki67 1:100 (Abcam #ab15580), anti-phospho-S6 (S235/236, Cell Signaling #4858) and anti-HIF-2alpha (ThermoPierce #PA1-16510).	('Asp', 'Chemical', 'MESH:D001224', (143, 146))	('Ki67', 'Chemical', '-', (185, 189))	('anti-HIF-2alpha', 'Var', (267, 282))	('anti-Ki67', 'Var', (180, 189))	('caspase-3', 'Gene', (133, 142))	('BrdU', 'Chemical', 'MESH:D001973', (93, 97))	('caspase-3', 'Gene', '12367', (133, 142))
212818	26837714	Epigenetic re-expression of HIF-2alpha suppresses soft tissue sarcoma growth.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('suppresses', 'NegReg', (39, 49))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('sarcoma growth', 'Disease', 'MESH:D006130', (62, 76))	('Epigenetic re-expression', 'Var', (0, 24))	('HIF-2alpha', 'Gene', (28, 38))	('sarcoma growth', 'Disease', (62, 76))
212877	25662589	Interestingly, they show that the bulk luminal K14 negative cells can be induced to become K14+ and lead invasion and that knocking down the K14 gene in tumor organoids inhibits collective invasion both in vitro and in vivo.	('invasion', 'CPA', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('K14', 'Gene', (141, 144))	('K14', 'Gene', '3861', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('K14', 'Gene', '3861', (141, 144))	('K14', 'Gene', (91, 94))	('inhibits', 'NegReg', (169, 177))	('K14', 'Gene', (47, 50))	('collective invasion', 'CPA', (178, 197))	('K14', 'Gene', '3861', (91, 94))	('knocking down', 'Var', (123, 136))
212881	25662589	The introduction of combinations of genes (APC-null, KRASG12D, p53 ShRNA, SMAD4 ShRNA) was shown to convert primary colon organoids to adenocarcinoma.	('colon organoids to adenocarcinoma', 'Disease', (116, 149))	('KRASG12D', 'Var', (53, 61))	('SMAD4', 'Gene', (74, 79))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('SMAD4', 'Gene', '4089', (74, 79))	('colon organoids to adenocarcinoma', 'Disease', 'MESH:D003110', (116, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('convert', 'Reg', (100, 107))
213005	25662589	Additional requirements include rigorous validation in drug studies, by using IC50 and EC50 values, and comparing these to the corresponding plasma levels measured in patients.	('IC50', 'MPA', (78, 82))	('patients', 'Species', '9606', (167, 175))	('EC50', 'Var', (87, 91))
213042	22031808	Radiological studies, including computed tomography (CT) and positron emission tomography-CT (PET-CT), were conducted, and PET-CT showed faint fluorodeoxyglucose uptake in the area of the left breast that corresponded to the lesion seen on the CT scan (Figure 4).	('fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (143, 161))	('fluorodeoxyglucose uptake', 'MPA', (143, 168))	('PET-CT', 'Var', (123, 129))
213091	22031808	Immunohistochemically, fibromatosis exhibits positivity for SMA and vimentin and negativity for CK, estrogen, progesterone and androgen receptors.	('vimentin', 'Gene', (68, 76))	('positivity', 'Var', (45, 55))	('fibromatosis', 'Disease', 'MESH:D005350', (23, 35))	('vimentin', 'Gene', '7431', (68, 76))	('androgen', 'Protein', (127, 135))	('fibromatosis', 'Disease', (23, 35))	('SMA', 'Protein', (60, 63))
213102	30179902	Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney We describe two cases of a distinct sarcoma characterized by a novel MEIS1-NCOA2 gene fusion.	('NCOA2', 'Gene', (169, 174))	('MEIS1', 'Gene', (163, 168))	('NCOA2', 'Gene', (12, 17))	('Sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('Sarcoma of the Kidney', 'Disease', 'MESH:D012509', (72, 93))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('MEIS1', 'Gene', '4211', (6, 11))	('MEIS1', 'Gene', (6, 11))	('Sarcoma of the Kidney', 'Disease', (72, 93))	('sarcoma', 'Disease', (130, 137))	('Fusions', 'Var', (23, 30))	('NCOA2', 'Gene', '10499', (169, 174))	('Sarcoma of the Kidney', 'Phenotype', 'HP:0008663', (72, 93))	('NCOA2', 'Gene', '10499', (12, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('MEIS1', 'Gene', '4211', (163, 168))
213115	30179902	In this report we describe two cases of primary renal sarcoma harboring a novel MEIS1-NCOA2 gene fusion.	('renal sarcoma', 'Disease', 'MESH:D007674', (48, 61))	('renal sarcoma', 'Phenotype', 'HP:0008663', (48, 61))	('renal sarcoma', 'Disease', (48, 61))	('NCOA2', 'Gene', '10499', (86, 91))	('NCOA2', 'Gene', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('MEIS1', 'Gene', '4211', (80, 85))	('MEIS1', 'Gene', (80, 85))	('gene fusion', 'Var', (92, 103))
213130	30179902	For comparison of mRNA expression profiles, we included two mesenchymal chondrosarcomas with known HEY1-NCOA2 gene rearrangements, and one soft tissue angiofibroma with a known AHRR-NCOA2 gene fusion.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (72, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('mesenchymal chondrosarcomas', 'Disease', (60, 87))	('angiofibroma', 'Disease', 'MESH:D018322', (151, 163))	('rearrangements', 'Var', (115, 129))	('NCOA2', 'Gene', '10499', (182, 187))	('N', 'Chemical', 'MESH:D009584', (182, 183))	('gene rearrangements', 'Var', (110, 129))	('NCOA2', 'Gene', (182, 187))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (72, 86))	('NCOA2', 'Gene', '10499', (104, 109))	('tissue angiofibroma', 'Phenotype', 'HP:0010615', (144, 163))	('angiofibroma', 'Disease', (151, 163))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (60, 87))	('N', 'Chemical', 'MESH:D009584', (104, 105))	('NCOA2', 'Gene', (104, 109))
213131	30179902	In addition, unsupervised clustering was performed including the renal index case (Case 1), three other control cases with NCOA2 gene fusions (2 mesenchymal chondrosarcomas, 1 soft tissue angiofibroma), and over 100 other sarcomas available on the same targeted RNA-sequencing platform.	('sarcomas', 'Disease', 'MESH:D012509', (222, 230))	('sarcomas', 'Phenotype', 'HP:0100242', (222, 230))	('sarcomas', 'Disease', (222, 230))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('sarcomas', 'Disease', 'MESH:D012509', (164, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('N', 'Chemical', 'MESH:D009584', (263, 264))	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('NCOA2', 'Gene', '10499', (123, 128))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (145, 172))	('sarcomas', 'Disease', (164, 172))	('angiofibroma', 'Disease', (188, 200))	('gene fusions', 'Var', (129, 141))	('mesenchymal chondrosarcomas', 'Disease', (145, 172))	('angiofibroma', 'Disease', 'MESH:D018322', (188, 200))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (157, 171))	('NCOA2', 'Gene', (123, 128))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (157, 172))	('tissue angiofibroma', 'Phenotype', 'HP:0010615', (181, 200))
213136	30179902	Second, we also studied 4 cases of mesenchymal chondrosarcoma and 1 angiofibroma with proven NCOA2 gene rearrangements but unknown partner from the consultation files of one author (CRA).	('mesenchymal chondrosarcoma', 'Disease', 'MESH:D018211', (35, 61))	('angiofibroma', 'Disease', 'MESH:D018322', (68, 80))	('1 angiofibroma', 'Phenotype', 'HP:0010615', (66, 80))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (47, 61))	('NCOA2', 'Gene', '10499', (93, 98))	('angiofibroma', 'Disease', (68, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('mesenchymal chondrosarcoma', 'Disease', (35, 61))	('NCOA2', 'Gene', (93, 98))	('gene rearrangements', 'Var', (99, 118))
213156	30179902	FISH analysis also validated the RNA sequencing candidate fusions in MEIS1-NCOA2 renal sarcoma case 1 (not shown).	('renal sarcoma', 'Phenotype', 'HP:0008663', (81, 94))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('NCOA2', 'Gene', (75, 80))	('renal sarcoma', 'Disease', (81, 94))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('fusions', 'Var', (58, 65))	('MEIS1', 'Gene', '4211', (69, 74))	('MEIS1', 'Gene', (69, 74))	('renal sarcoma', 'Disease', 'MESH:D007674', (81, 94))	('NCOA2', 'Gene', '10499', (75, 80))
213160	30179902	Furthermore, we investigated the differential expression of NCOA2 gene, which showed high expression of 3'NCOA2 exons participating in the fusion (exons 13-23) in tumors showing NCOA2 gene fusion regardless of its partners (Fig.	('NCOA2', 'Gene', '10499', (106, 111))	('NCOA2', 'Gene', '10499', (60, 65))	('NCOA2', 'Gene', '10499', (178, 183))	('NCOA2', 'Gene', (106, 111))	('NCOA2', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('NCOA2', 'Gene', (178, 183))	('fusion', 'Var', (189, 195))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))
213162	30179902	However, none of the 4 mesenchymal chondrosarcomas with known NCOA2 gene rearrangement demonstrated MEIS1 gene rearrangements.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (35, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('rearrangement', 'Var', (73, 86))	('NCOA2', 'Gene', '10499', (62, 67))	('mesenchymal chondrosarcomas', 'Disease', (23, 50))	('MEIS1', 'Gene', '4211', (100, 105))	('MEIS1', 'Gene', (100, 105))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (23, 50))	('NCOA2', 'Gene', (62, 67))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (35, 49))
213165	30179902	However, none of these neoplasms demonstrated evidence of NCOA2 or MEIS1 gene rearrangements.	('MEIS1', 'Gene', '4211', (67, 72))	('MEIS1', 'Gene', (67, 72))	('neoplasms', 'Phenotype', 'HP:0002664', (23, 32))	('NCOA2', 'Gene', '10499', (58, 63))	('NCOA2', 'Gene', (58, 63))	('neoplasms', 'Disease', (23, 32))	('neoplasm', 'Phenotype', 'HP:0002664', (23, 31))	('neoplasms', 'Disease', 'MESH:D009369', (23, 32))	('rearrangements', 'Var', (78, 92))
213173	30179902	While occasional cases of acute myeloid leukemia have been associated with either MYST3-NCOA2 or ETV6-NCOA2 gene fusion, a larger number of mesenchymal neoplasms have been shown to be associated with NCOA2 gene fusions.	('NCOA2', 'Gene', (200, 205))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (26, 48))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (140, 161))	('NCOA2', 'Gene', '10499', (102, 107))	('mesenchymal neoplasms', 'Disease', (140, 161))	('NCOA2', 'Gene', (88, 93))	('acute myeloid leukemia', 'Disease', (26, 48))	('NCOA2', 'Gene', (102, 107))	('neoplasm', 'Phenotype', 'HP:0002664', (152, 160))	('associated', 'Reg', (59, 69))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (26, 48))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (32, 48))	('NCOA2', 'Gene', '10499', (200, 205))	('neoplasms', 'Phenotype', 'HP:0002664', (152, 161))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))	('NCOA2', 'Gene', '10499', (88, 93))	('gene fusions', 'Var', (206, 218))
213178	30179902	NCOA2 gene fusions are also characteristic of congenital/infantile spindle cell rhabdomyosarcoma, with various partners, including VGLL2, SRF, or TEAD1, which represent critical transcription factors or co-activators involved in muscle development and regulation.	('NCOA2', 'Gene', '10499', (0, 5))	('congenital/infantile spindle cell rhabdomyosarcoma', 'Disease', (46, 96))	('congenital/infantile spindle cell rhabdomyosarcoma', 'Disease', 'MESH:D002277', (46, 96))	('SRF', 'Gene', '6722', (138, 141))	('NCOA2', 'Gene', (0, 5))	('TEAD1', 'Gene', '7003', (146, 151))	('TEAD1', 'Gene', (146, 151))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (80, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('fusions', 'Var', (11, 18))	('SRF', 'Gene', (138, 141))
213179	30179902	Of note, NCOA2-fusion positive infantile spindle cell rhabdomyosarcomas have a favorable prognosis compared to the older childhood and adult sclerosing/spindle cell rhabdomyosarcomas associated with MYOD1 mutations.	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (165, 182))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (54, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('rhabdomyosarcomas', 'Disease', (165, 182))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (165, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('mutations', 'Var', (205, 214))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (165, 182))	('associated', 'Reg', (183, 193))	('NCOA2', 'Gene', '10499', (9, 14))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (54, 71))	('rhabdomyosarcomas', 'Disease', (54, 71))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (54, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('NCOA2', 'Gene', (9, 14))	('MYOD1', 'Gene', (199, 204))
213180	30179902	Rare cases of alveolar rhabdomyosarcoma have been associated with PAX3-NCOA2 gene fusions.	('alveolar rhabdomyosarcoma', 'Disease', (14, 39))	('NCOA2', 'Gene', (71, 76))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (14, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (14, 39))	('associated', 'Reg', (50, 60))	('NCOA2', 'Gene', '10499', (71, 76))	('gene fusions', 'Var', (77, 89))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (23, 39))
213182	30179902	Another soft tissue tumor recently shown to harbor recurrent NCOA2 gene rearrangements is the so-called soft tissue angiofibroma, characterized by an AHRR-NCOA2 gene fusion, with occasional cases demonstrating a GTF21-NCOA2 gene fusion.	('NCOA2', 'Gene', (218, 223))	('angiofibroma', 'Disease', 'MESH:D018322', (116, 128))	('NCOA2', 'Gene', (61, 66))	('gene fusion', 'Var', (161, 172))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (8, 25))	('rearrangements', 'Var', (72, 86))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('NCOA2', 'Gene', '10499', (155, 160))	('tissue angiofibroma', 'Phenotype', 'HP:0010615', (109, 128))	('angiofibroma', 'Disease', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('NCOA2', 'Gene', (155, 160))	('NCOA2', 'Gene', '10499', (218, 223))	('tumor', 'Disease', (20, 25))	('NCOA2', 'Gene', '10499', (61, 66))
213187	30179902	MEIS1 stands for 'myeloid ectopic viral integration site-1' and its overexpression, induced by retroviral integration, leads to myeloid leukemia.	('leads to', 'Reg', (119, 127))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('MEIS1', 'Gene', '4211', (0, 5))	('MEIS1', 'Gene', (0, 5))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (128, 144))	('myeloid leukemia', 'Disease', (128, 144))	('overexpression', 'PosReg', (68, 82))	('myeloid leukemia', 'Disease', 'MESH:D007951', (128, 144))	('retroviral integration', 'Var', (95, 117))
213197	30179902	One of our MEIS1-NCOA2 renal sarcomas was positive for BCOR: while this neoplasm demonstrated moderate-strong reactivity in approximately 60% of nuclei, it was less than the diffuse strong labeling typically seen in sarcomas harboring BCOR genetic alterations, such as BCOR internal tandem duplication or the BCOR-CCNB3 gene fusion.	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('reactivity', 'MPA', (110, 120))	('renal sarcomas', 'Disease', (23, 37))	('MEIS1', 'Gene', '4211', (11, 16))	('MEIS1', 'Gene', (11, 16))	('NCOA2', 'Gene', (17, 22))	('renal sarcomas', 'Phenotype', 'HP:0008663', (23, 37))	('BCOR', 'Gene', '54880', (55, 59))	('BCOR', 'Gene', '54880', (309, 313))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('neoplasm', 'Disease', 'MESH:D009369', (72, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcomas', 'Disease', (29, 37))	('BCOR', 'Gene', (309, 313))	('BCOR', 'Gene', (55, 59))	('renal sarcomas', 'Disease', 'MESH:D007674', (23, 37))	('neoplasm', 'Disease', (72, 80))	('internal', 'Var', (274, 282))	('BCOR', 'Gene', '54880', (269, 273))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('BCOR', 'Gene', '54880', (235, 239))	('renal sarcoma', 'Phenotype', 'HP:0008663', (23, 36))	('sarcomas', 'Disease', 'MESH:D012509', (216, 224))	('sarcomas', 'Phenotype', 'HP:0100242', (216, 224))	('sarcomas', 'Disease', (216, 224))	('BCOR', 'Gene', (269, 273))	('BCOR', 'Gene', (235, 239))	('NCOA2', 'Gene', '10499', (17, 22))	('neoplasm', 'Phenotype', 'HP:0002664', (72, 80))	('N', 'Chemical', 'MESH:D009584', (316, 317))
213203	30179902	The recently described CIC-rearranged renal sarcomas also enter into the differential diagnosis, and these may also be immunoreactive for WT1 in approximately 50% of cases.	('renal sarcoma', 'Phenotype', 'HP:0008663', (38, 51))	('renal sarcomas', 'Phenotype', 'HP:0008663', (38, 52))	('renal sarcomas', 'Disease', 'MESH:D007674', (38, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('renal sarcomas', 'Disease', (38, 52))	('enter', 'Reg', (58, 63))	('CIC-rearranged', 'Var', (23, 37))
213210	30179902	In summary, we describe a distinctive sarcoma subtype in the kidney harboring novel MEIS1-NCOA2 gene fusions, characterized by plump spindle cells with variable amounts of eosinophilic cytoplasm demonstrating prominent nodular variations in cellularity.	('fusions', 'Var', (101, 108))	('gene fusions', 'Var', (96, 108))	('sarcoma', 'Disease', (38, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('NCOA2', 'Gene', '10499', (90, 95))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))	('MEIS1', 'Gene', '4211', (84, 89))	('MEIS1', 'Gene', (84, 89))	('NCOA2', 'Gene', (90, 95))
213294	26512574	The main inclusion criteria were unresectable or metastatic STS with previous treatment with anthracyclines-based regimen, 18-75 years old, at least one extracranial measurable lesion by MRI or CT according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), Eastern Cooperative Oncology Group performance status of 0-2, <= 1 prior regimen of chemotherapy for advanced disease, no anticancer treatment for at least 4 weeks prior to enrollment in the study, a life expectancy >=3 months, adequate hematologic, renal, and hepatic function, as indicated by hemoglobin >=8 g/dL, absolute neutrophil count (ANC) >=1.5 x 109 /L, platelet count >=80 x 109 /L, total serum bilirubin <=1.5 x upper limit of normal (ULN), AST/ALT <=2.5 x ULN (<=5 x ULN if hepatic disease involvement present), alkaline phosphatase <=2.5 x ULN (<=5 x ULN if hepatic disease involvement present and <=10 x ULN if bone disease involvement present), serum creatinine <=1.25 x ULN or calculated creatinine clearance >=65 ml/min.	('hepatic disease', 'Phenotype', 'HP:0001392', (850, 865))	('AST', 'Gene', '26503', (731, 734))	('ALT <=2', 'Gene', (735, 742))	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('>=80', 'Var', (657, 661))	('ALT <=2', 'Gene', '84706', (735, 742))	('Solid Tumors', 'Disease', (242, 254))	('Solid Tumors', 'Disease', 'MESH:D009369', (242, 254))	('anthracyclines', 'Chemical', 'MESH:D018943', (93, 107))	('AST', 'Gene', (731, 734))	('Oncology', 'Phenotype', 'HP:0002664', (298, 306))	('cancer', 'Disease', (404, 410))	('hepatic disease', 'Disease', (765, 780))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('alkaline phosphatase', 'MPA', (803, 823))	('hepatic disease', 'Disease', (850, 865))	('bone disease', 'Disease', (904, 916))	('calculated creatinine clearance', 'MPA', (972, 1003))	('hepatic disease', 'Disease', 'MESH:D056486', (765, 780))	('hepatic disease', 'Phenotype', 'HP:0001392', (765, 780))	('serum creatinine', 'MPA', (939, 955))	('bone disease', 'Disease', 'MESH:D001847', (904, 916))	('total serum bilirubin', 'Phenotype', 'HP:0003573', (672, 693))	('hepatic disease', 'Disease', 'MESH:D056486', (850, 865))	('Tumors', 'Phenotype', 'HP:0002664', (248, 254))
213494	24249545	Fenestrations in the catheter between the two occlusion balloons allow for venous outflow from the hepatic veins to be shunted extracorporeally, and using a perfusion bypass machine the venoveno bypass circuit passes blood through the chemotherapy filtration device, and then returns it via the IJ venous catheter thus completing the veno-veno bypass circuit.	('occlusion balloons', 'Disease', 'MESH:D054549', (46, 64))	('Fenestrations', 'Var', (0, 13))	('venous outflow from the', 'MPA', (75, 98))	('occlusion balloons', 'Disease', (46, 64))
213597	25598687	The patient underwent a re-staging PET-CT scan, which showed no other skeletal or visceral metastasis, and the lesion in the proximal meta-diaphyseal region of the femur had a decreased SUV value compared to that of the previous staging PET-CT, and it now measured 1.2.	('visceral metastasis', 'Disease', 'MESH:D009362', (82, 101))	('lesion', 'Var', (111, 117))	('patient', 'Species', '9606', (4, 11))	('decreased', 'NegReg', (176, 185))	('SUV value', 'MPA', (186, 195))	('visceral metastasis', 'Disease', (82, 101))
213657	24294990	what is more, Immunohistochemical studies for EMA and CK showed strong positivity, The fusion gene SYT-SSX and translocation t(X; 18) are the special marker for synovial sarcoma, which is not seen in any other spindle cell tumors.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('SYT', 'Gene', '6857', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('synovial sarcoma', 'Disease', (161, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('SYT', 'Gene', (99, 102))	('translocation t', 'Var', (111, 126))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (161, 177))	('synovial sarcoma', 'Disease', 'MESH:D013584', (161, 177))
213673	24294990	Immunohistochemically, the tumor cells demonstrate positivity for vimentin, MSA, SMA and cytokeratin.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('vimentin', 'Gene', '7431', (66, 74))	('tumor', 'Disease', (27, 32))	('vimentin', 'Gene', (66, 74))	('positivity', 'Var', (51, 61))	('cytokeratin', 'Protein', (89, 100))	('MSA', 'Gene', (76, 79))	('SMA', 'Gene', '6606', (81, 84))	('SMA', 'Gene', (81, 84))	('MSA', 'Gene', '7173', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
213696	24279718	Concomitant occurrence of EGFR (epidermal growth factor receptor) and KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations in an ALK (anaplastic lymphoma kinase)-positive lung adenocarcinoma patient with acquired resistance to crizotinib: a case report Anaplastic lymphoma kinase-positive non-small cell lung carcinoma patients are generally highly responsive to the dual anaplastic lymphoma kinase and MET tyrosine kinase inhibitor crizotinib.	('lymphoma', 'Phenotype', 'HP:0002665', (162, 170))	('lymphoma', 'Phenotype', 'HP:0002665', (400, 408))	('patient', 'Species', '9606', (336, 343))	('KRAS', 'Gene', (70, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (281, 289))	('Anaplastic lymphoma kinase', 'Gene', (270, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('crizotinib', 'Chemical', 'MESH:D000077547', (450, 460))	('crizotinib', 'Chemical', 'MESH:D000077547', (244, 254))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (270, 289))	('anaplastic lymphoma kinase', 'Gene', '266802', (151, 177))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (188, 207))	('patient', 'Species', '9606', (208, 215))	('rat', 'Species', '10116', (94, 97))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (306, 335))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (188, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('non-small cell lung carcinoma', 'Disease', (306, 335))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (310, 335))	('ALK', 'Gene', (146, 149))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (389, 408))	('occurrence', 'Reg', (12, 22))	('EGFR', 'Gene', (26, 30))	('KRAS', 'Gene', '24525', (70, 74))	('EGFR', 'Gene', '24329', (26, 30))	('patients', 'Species', '9606', (336, 344))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (151, 170))	('sarcoma', 'Disease', (98, 105))	('Anaplastic lymphoma kinase', 'Gene', '238', (270, 296))	('epidermal growth factor receptor', 'Gene', '24329', (32, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('ALK', 'Gene', '266802', (146, 149))	('anaplastic lymphoma kinase', 'Gene', (389, 415))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (306, 335))	('mutations', 'Var', (130, 139))	('epidermal growth factor receptor', 'Gene', (32, 64))	('anaplastic lymphoma kinase', 'Gene', (151, 177))	('lung adenocarcinoma', 'Disease', (188, 207))	('anaplastic lymphoma kinase', 'Gene', '266802', (389, 415))
213699	24279718	Thus, we report on an anaplastic lymphoma kinase-positive non-small cell lung carcinoma patient with concomitant occurrence of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations upon development of crizotinib-resistance.	('patient', 'Species', '9606', (88, 95))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (58, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (22, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('non-small cell lung carcinoma', 'Disease', (58, 87))	('sarcoma viral', 'Disease', 'MESH:D001102', (186, 199))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (62, 87))	('rat', 'Species', '10116', (182, 185))	('crizotinib', 'Chemical', 'MESH:D000077547', (247, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('sarcoma viral', 'Disease', (186, 199))	('mutations', 'Var', (217, 226))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (58, 87))
213702	24279718	Biopsies from new metastases revealed development of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations concomitant with the original anaplastic lymphoma kinase gene rearrangement and without signs of anaplastic lymphoma kinase fusion gene amplification or secondary anaplastic lymphoma kinase mutations.	('rat', 'Species', '10116', (108, 111))	('lymphoma', 'Phenotype', 'HP:0002665', (194, 202))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (250, 269))	('sarcoma viral', 'Disease', (112, 125))	('metastases', 'Disease', (18, 28))	('metastases', 'Disease', 'MESH:D009362', (18, 28))	('anaplastic lymphoma kinase gene', 'Gene', (183, 214))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (316, 335))	('sarcoma viral', 'Disease', 'MESH:D001102', (112, 125))	('lymphoma', 'Phenotype', 'HP:0002665', (261, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (327, 335))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (183, 202))	('mutations', 'Var', (143, 152))	('rearrangement', 'Var', (215, 228))
213703	24279718	To our knowledge, this is the first report of an anaplastic lymphoma kinase-positive pulmonary adenocarcinoma, which upon emergence of crizotinib resistance acquired 2 new somatic mutations in the epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog genes, respectively, concomitant with the original anaplastic lymphoma kinase rearrangement.	('pulmonary adenocarcinoma', 'Disease', (85, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('mutations', 'Var', (180, 189))	('rat', 'Species', '10116', (252, 255))	('lymphoma', 'Phenotype', 'HP:0002665', (349, 357))	('lymphoma', 'Phenotype', 'HP:0002665', (60, 68))	('sarcoma viral', 'Disease', (256, 269))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (85, 109))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (338, 357))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 109))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (49, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('sarcoma viral', 'Disease', 'MESH:D001102', (256, 269))	('crizotinib', 'Chemical', 'MESH:D000077547', (135, 145))
213704	24279718	Thus, these 3 driver mutations, usually considered mutually exclusive, may coexist in advanced non-small cell lung carcinoma that becomes resistant to crizotinib, presumably because heterogeneous tumor clones utilize epidermal growth factor receptor and/or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog signaling to circumvent the inhibition of anaplastic lymphoma kinase-mediated signaling by crizotinib.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (352, 371))	('non-small cell lung carcinoma', 'Disease', (95, 124))	('tumor', 'Disease', (196, 201))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (99, 124))	('crizotinib', 'Chemical', 'MESH:D000077547', (401, 411))	('sarcoma viral', 'Disease', 'MESH:D001102', (279, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (363, 371))	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('anaplastic lymphoma kinase-mediated signaling', 'Pathway', (352, 397))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (95, 124))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (95, 124))	('crizotinib', 'Chemical', 'MESH:D000077547', (151, 161))	('sarcoma viral', 'Disease', (279, 292))	('rat', 'Species', '10116', (275, 278))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('mutations', 'Var', (21, 30))
213708	24279718	However, subsets of NSCLC harboring specific driver mutations affecting EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) genes can obtain remarkable benefit from therapies targeting these oncogenic drivers.	('mutations', 'Var', (52, 61))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('EGFR', 'Gene', '1956', (72, 76))	('ALK', 'Gene', '238', (116, 119))	('ALK', 'Gene', (116, 119))	('EGFR', 'Gene', (72, 76))	('benefit', 'PosReg', (177, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (121, 140))	('NSCLC', 'Disease', (20, 25))
213709	24279718	Oncogenic ALK gene fusions were identified in a distinct subpopulation (approximately 5%) of NSCLC patients typically characterized by adenocarcinoma histology, young age, no- or light-smoking history, and in the vast majority of cases, lack of concomitant mutations in EGFR- or KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) genes or amplification of MET (mesenchymal-epithelial transition) gene.	('rat', 'Species', '10116', (303, 306))	('amplification', 'Var', (348, 361))	('mutations', 'Var', (257, 266))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('adenocarcinoma', 'Disease', 'MESH:D000230', (135, 149))	('NSCLC', 'Disease', (93, 98))	('KRAS', 'Gene', '3845', (279, 283))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('EGFR', 'Gene', (270, 274))	('KRAS', 'Gene', (279, 283))	('ALK', 'Gene', '238', (10, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (307, 314))	('ALK', 'Gene', (10, 13))	('patients', 'Species', '9606', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('sarcoma viral', 'Disease', 'MESH:D001102', (307, 320))	('EGFR', 'Gene', '1956', (270, 274))	('sarcoma viral', 'Disease', (307, 320))	('adenocarcinoma', 'Disease', (135, 149))
213712	24279718	Moreover, a recent prospective randomized phase III trial has shown that crizotinib provides longer progression-free survival, higher response rates, and better quality of life than chemotherapy when used as second-line in patients with advanced, previously chemotherapy-treated, ALK-positive NSCLC.	('response rates', 'MPA', (134, 148))	('ALK', 'Gene', (280, 283))	('patients', 'Species', '9606', (223, 231))	('NSCLC', 'Phenotype', 'HP:0030358', (293, 298))	('progression-free survival', 'CPA', (100, 125))	('crizotinib', 'Var', (73, 83))	('ALK', 'Gene', '238', (280, 283))	('NSCLC', 'Disease', (293, 298))	('rat', 'Species', '10116', (143, 146))	('higher', 'PosReg', (127, 133))	('NSCLC', 'Disease', 'MESH:D002289', (293, 298))	('longer', 'PosReg', (93, 99))	('crizotinib', 'Chemical', 'MESH:D000077547', (73, 83))
213713	24279718	ALK rearrangements typically consist of a small inversion on chromosome 2p23-21, resulting in the fusion between exon 20-29 of the ALK gene (encoding the kinase-domain) and exons 1-13 (different variants due to different breakpoints) in the N-terminal portion of the Echinoderm Microtubule-associated protein-Like 4 (EML4) gene.	('Echinoderm Microtubule-associated protein-Like 4', 'Gene', (267, 315))	('fusion', 'Var', (98, 104))	('Echinoderm Microtubule-associated protein-Like 4', 'Gene', '27436', (267, 315))	('ALK', 'Gene', '238', (0, 3))	('ALK', 'Gene', '238', (131, 134))	('ALK', 'Gene', (0, 3))	('EML4', 'Gene', (317, 321))	('EML4', 'Gene', '27436', (317, 321))	('ALK', 'Gene', (131, 134))
213715	24279718	Cases of atypical translocation with partial loss of chromosomal material, resulting in so called single-red signals by fluorescence in-situ hybridization (FISH) analysis of ALK gene rearrangements in tumor cell nuclei, may also occur.	('ALK', 'Gene', (174, 177))	('translocation', 'Var', (18, 31))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('single-red signals', 'MPA', (98, 116))	('rearrangements', 'Var', (183, 197))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('ALK', 'Gene', '238', (174, 177))
213716	24279718	These different types of ALK rearrangements result in the expression of stabilized chimeric ALK fusion-proteins with constitutive kinase activity and oncogenic properties.	('ALK', 'Gene', (92, 95))	('expression', 'MPA', (58, 68))	('ALK', 'Gene', (25, 28))	('result in', 'Reg', (44, 53))	('rearrangements', 'Var', (29, 43))	('ALK', 'Gene', '238', (92, 95))	('ALK', 'Gene', '238', (25, 28))
213720	24279718	In some ALK-positive NSCLC patients the development of secondary point mutations in the ALK kinase domain or ALK fusion gene amplification have been shown to be responsible for the acquired resistance to crizotinib.	('ALK', 'Gene', (88, 91))	('NSCLC', 'Disease', (21, 26))	('ALK', 'Gene', (109, 112))	('ALK', 'Gene', '238', (8, 11))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('point mutations', 'Var', (65, 80))	('patients', 'Species', '9606', (27, 35))	('ALK', 'Gene', '238', (109, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('responsible', 'Reg', (161, 172))	('ALK', 'Gene', (8, 11))	('ALK', 'Gene', '238', (88, 91))	('crizotinib', 'Chemical', 'MESH:D000077547', (204, 214))
213722	24279718	Patients, such as the one reported here, acquiring resistance to ALK-TKI by developing mutations in different genes, could help clarify the mechanism involved in this process and the strategies to overcome it.	('ALK', 'Gene', '238', (65, 68))	('Patients', 'Species', '9606', (0, 8))	('ALK', 'Gene', (65, 68))	('rat', 'Species', '10116', (185, 188))	('mutations', 'Var', (87, 96))
213727	24279718	All together, the TNM stage was T4N3M1b.	('T4N3M1b', 'Var', (32, 39))	('TNM', 'Gene', (18, 21))	('TNM', 'Gene', '10178', (18, 21))
213728	24279718	A small transbronchial biopsy of the pulmonary infiltrate showed a histology and immunohistochemistry (IHC) profile (mucin stain+, CK7+, TTF1+, CK5/6-, p63-) of primary adenocarcinoma (data not shown).	('p63', 'Gene', '8626', (152, 155))	('TTF1', 'Gene', (137, 141))	('adenocarcinoma', 'Disease', 'MESH:D000230', (169, 183))	('TTF1', 'Gene', '7270', (137, 141))	('CK7+', 'Var', (131, 135))	('rat', 'Species', '10116', (53, 56))	('p63', 'Gene', (152, 155))	('mucin', 'Var', (117, 122))	('pulmonary infiltrate', 'Phenotype', 'HP:0002113', (37, 57))	('adenocarcinoma', 'Disease', (169, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('CK5/6-', 'Var', (144, 150))
213730	24279718	One of the right inguinal lymph nodes was excised and corresponding formalin-fixed paraffin-embedded (FFPE) sections were used to histologically and immunohistochemically confirm that the metastatic tumor tissue originated from the pulmonary adenocarcinoma (same morphology of mucin-producing adenocarcinoma and IHC-profile with CK7+, TTF1+, CK20-, CDX2-, PSA-).	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (232, 256))	('CK7+', 'Var', (329, 333))	('adenocarcinoma', 'Disease', (293, 307))	('CK20', 'Gene', (342, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('paraffin', 'Chemical', 'MESH:D010232', (83, 91))	('TTF1', 'Gene', '7270', (335, 339))	('CDX2', 'Gene', '1045', (349, 353))	('CK20', 'Gene', '54474', (342, 346))	('adenocarcinoma', 'Disease', (242, 256))	('tumor', 'Disease', (199, 204))	('adenocarcinoma', 'Disease', 'MESH:D000230', (293, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('CDX2', 'Gene', (349, 353))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('adenocarcinoma', 'Disease', 'MESH:D000230', (242, 256))	('TTF1', 'Gene', (335, 339))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (232, 256))	('formalin', 'Chemical', 'MESH:D005557', (68, 76))	('pulmonary adenocarcinoma', 'Disease', (232, 256))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('PSA-', 'Disease', (356, 360))
213735	24279718	FISH analysis of the specimen with dual-color break-apart rearrangement probe (Vysis LSI ALK; Abbott Molecular), detected ALK rearrangement in 40% of the analyzed tumor cell nuclei (100 tumor cell nuclei analyzed with a cut-off of 15%).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('ALK', 'Gene', (89, 92))	('rearrangement', 'Var', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (186, 191))	('ALK', 'Gene', (122, 125))	('tumor', 'Disease', (163, 168))	('ALK', 'Gene', '238', (89, 92))	('ALK', 'Gene', '238', (122, 125))
213736	24279718	The cell nuclei with rearrangement appeared with one normal fusion signal and an abnormal single red signal for ALK, characteristic for ALK gene fusion with partial deletion of genetic material.	('ALK', 'Gene', '238', (136, 139))	('ALK', 'Gene', (112, 115))	('single red signal', 'MPA', (90, 107))	('rearrangement', 'Var', (21, 34))	('ALK', 'Gene', (136, 139))	('ALK', 'Gene', '238', (112, 115))	('fusion signal', 'MPA', (60, 73))
213744	24279718	The histology and IHC-profile were the same as in the primary lung adenocarcinoma and in the previous biopsy from inguinal metastasis (same histological appearance, mucin stain+, CK7+, TTF1+, CK20-, CDX2-, PSA-; data not shown).	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('primary lung adenocarcinoma', 'Disease', (54, 81))	('TTF1', 'Gene', (185, 189))	('CK7+', 'Var', (179, 183))	('primary lung adenocarcinoma', 'Disease', 'MESH:D000077192', (54, 81))	('TTF1', 'Gene', '7270', (185, 189))	('CDX2', 'Gene', (199, 203))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('CK20', 'Gene', (192, 196))	('CDX2', 'Gene', '1045', (199, 203))	('CK20', 'Gene', '54474', (192, 196))
213749	24279718	However, mutations in codon 13 of KRAS gene (c.38G > A, p.G13D) (Figure 4) and in exon 21 of EGFR gene (c.2585 T > G, p.L862R) were detected in the relapsed metastasis (Figure 5).	('c.2585 T > G', 'Mutation', 'c.2585T>G', (104, 116))	('c.2585 T > G', 'Var', (104, 116))	('KRAS', 'Gene', '3845', (34, 38))	('EGFR', 'Gene', '1956', (93, 97))	('p.L862R', 'Var', (118, 125))	('detected', 'Reg', (132, 140))	('p.L862R', 'Mutation', 'p.L862R', (118, 125))	('c.38G > A', 'Mutation', 'rs112445441', (45, 54))	('EGFR', 'Gene', (93, 97))	('c.38G > A', 'Var', (45, 54))	('p.G13D', 'Mutation', 'rs112445441', (56, 62))	('KRAS', 'Gene', (34, 38))	('relapsed', 'Disease', (148, 156))
213753	24279718	Similarly, the co-existence of KRAS and EGFR mutations in the same tumor tissue could be interpreted as either double mutation in the crizotinib-resistant tumor cells or more likely as the occurrence of two different tumor subpopulations with constitutive activation of either the EGFR or the KRAS signaling pathway as different mechanisms of acquired crizotinib-resistance.	('KRAS', 'Gene', (31, 35))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (67, 72))	('EGFR', 'Gene', (281, 285))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('EGFR', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('crizotinib', 'Chemical', 'MESH:D000077547', (352, 362))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('KRAS', 'Gene', '3845', (293, 297))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EGFR', 'Gene', '1956', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('KRAS', 'Gene', (293, 297))	('mutations', 'Var', (45, 54))	('crizotinib', 'Chemical', 'MESH:D000077547', (134, 144))	('KRAS', 'Gene', '3845', (31, 35))	('EGFR', 'Gene', '1956', (40, 44))
213754	24279718	The EGFR mutation L862R has to our knowledge not previously been described in the literature, but given its proximity to mutations known to be sensitive to EGFR-TKI (L858R and L861X), tumor clones bearing the L862R mutation could also be potentially responsive to EGFR-TKI.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('EGFR', 'Gene', (4, 8))	('L862R', 'Var', (209, 214))	('EGFR', 'Gene', (264, 268))	('EGFR', 'Gene', '1956', (156, 160))	('EGFR', 'Gene', '1956', (264, 268))	('L861X', 'Mutation', 'p.L861X', (176, 181))	('L862R', 'Mutation', 'p.L862R', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('EGFR', 'Gene', (156, 160))	('L862R', 'Var', (18, 23))	('responsive', 'Reg', (250, 260))	('L858R', 'Mutation', 'rs121434568', (166, 171))	('rat', 'Species', '10116', (86, 89))	('L862R', 'Mutation', 'p.L862R', (209, 214))	('EGFR', 'Gene', '1956', (4, 8))
213759	24279718	Re-biopsy of relapsed metastatic tumor tissue showed newly emerged somatic mutations in both the KRAS and the EGFR gene, while the tumor cells still carried the original ALK rearrangement but without signs of ALK fusion gene amplification or secondary ALK mutations.	('ALK', 'Gene', (252, 255))	('EGFR', 'Gene', '1956', (110, 114))	('tumor', 'Disease', (131, 136))	('ALK', 'Gene', '238', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('KRAS', 'Gene', '3845', (97, 101))	('ALK', 'Gene', (209, 212))	('ALK', 'Gene', '238', (170, 173))	('tumor', 'Disease', (33, 38))	('ALK', 'Gene', (170, 173))	('carried', 'Reg', (149, 156))	('KRAS', 'Gene', (97, 101))	('EGFR', 'Gene', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('rearrangement', 'Var', (174, 187))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ALK', 'Gene', '238', (252, 255))	('mutations', 'Var', (75, 84))
213761	24279718	loss of ALK rearrangement, amplification of ALK fusion gene, or secondary ALK mutations, but was most likely due to the emergence of concurrent EGFR and KRAS mutations.	('ALK', 'Gene', (74, 77))	('EGFR', 'Gene', (144, 148))	('ALK', 'Gene', (44, 47))	('ALK', 'Gene', '238', (8, 11))	('KRAS', 'Gene', (153, 157))	('mutations', 'Var', (78, 87))	('ALK', 'Gene', '238', (44, 47))	('KRAS', 'Gene', '3845', (153, 157))	('ALK', 'Gene', '238', (74, 77))	('ALK', 'Gene', (8, 11))	('rearrangement', 'Var', (12, 25))	('EGFR', 'Gene', '1956', (144, 148))	('amplification', 'Var', (27, 40))	('loss', 'NegReg', (0, 4))
213762	24279718	To our knowledge, this is the first report of a concomitant presence of ALK gene rearrangement, EGFR mutation, and KRAS mutation in the same NSCLC patient.	('EGFR', 'Gene', (96, 100))	('patient', 'Species', '9606', (147, 154))	('KRAS', 'Gene', (115, 119))	('ALK', 'Gene', '238', (72, 75))	('mutation', 'Var', (120, 128))	('NSCLC', 'Disease', (141, 146))	('KRAS', 'Gene', '3845', (115, 119))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('rearrangement', 'Var', (81, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('mutation', 'Var', (101, 109))	('ALK', 'Gene', (72, 75))	('EGFR', 'Gene', '1956', (96, 100))
213765	24279718	In contrast, the initial biopsy from the metastatic tumor in the current case showed only ALK rearrangement and wild-type EGFR and KRAS, while re-biopsy from a new metastasis at progression after 8 months of crizotinib treatment revealed the appearance of EGFR and KRAS mutations in addition to an unchanged ALK rearrangement.	('crizotinib', 'Chemical', 'MESH:D000077547', (208, 218))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('KRAS', 'Gene', (131, 135))	('ALK', 'Gene', (308, 311))	('KRAS', 'Gene', (265, 269))	('ALK', 'Gene', '238', (90, 93))	('KRAS', 'Gene', '3845', (265, 269))	('mutations', 'Var', (270, 279))	('KRAS', 'Gene', '3845', (131, 135))	('ALK', 'Gene', (90, 93))	('EGFR', 'Gene', '1956', (256, 260))	('rearrangement', 'Var', (94, 107))	('ALK', 'Gene', '238', (308, 311))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))	('EGFR', 'Gene', (256, 260))
213766	24279718	This suggests that these 3 mutations, typically considered mutually exclusive, can coexist in some cases of NSCLC that become resistant to crizotinib in vivo, presumably because the tumor cells or heterogeneous tumor clones utilize EGFR and/or KRAS signaling to circumvent the inhibition of ALK-mediated signaling by crizotinib.	('mutations', 'Var', (27, 36))	('crizotinib', 'Chemical', 'MESH:D000077547', (317, 327))	('crizotinib', 'Chemical', 'MESH:D000077547', (139, 149))	('KRAS', 'Gene', '3845', (244, 248))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('ALK', 'Gene', (291, 294))	('NSCLC', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('EGFR', 'Gene', '1956', (232, 236))	('EGFR', 'Gene', (232, 236))	('ALK', 'Gene', '238', (291, 294))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('KRAS', 'Gene', (244, 248))
213767	24279718	The emergence of either EGFR or KRAS mutations have been reported in single NSCLC cases acquiring resistance to crizotinib, both with and without concomitant loss of ALK gene rearrangement.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('ALK', 'Gene', '238', (166, 169))	('KRAS', 'Gene', (32, 36))	('NSCLC', 'Disease', (76, 81))	('crizotinib', 'Chemical', 'MESH:D000077547', (112, 122))	('KRAS', 'Gene', '3845', (32, 36))	('mutations', 'Var', (37, 46))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('ALK', 'Gene', (166, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
213773	24279718	In this case, however, the presence of the G13D KRAS mutation could render the patient resistant to an EGFR-targeting therapy.	('resistant', 'MPA', (87, 96))	('KRAS', 'Gene', (48, 52))	('EGFR', 'Gene', '1956', (103, 107))	('KRAS', 'Gene', '3845', (48, 52))	('EGFR', 'Gene', (103, 107))	('G13D', 'Var', (43, 47))	('patient', 'Species', '9606', (79, 86))	('G13D', 'Mutation', 'rs112445441', (43, 47))
213776	24279718	Indeed, even if the co-existence of KRAS and EGFR mutations could be interpreted as double mutation occurring in the crizotinib-resistant tumor cells, the possibility of different tumor clones with activation of EGFR and KRAS signaling as different mechanisms of crizotinib-resistance appeared to be an alternative, perhaps more likely explanation.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('crizotinib', 'Chemical', 'MESH:D000077547', (263, 273))	('EGFR', 'Gene', (45, 49))	('tumor', 'Disease', (138, 143))	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('KRAS', 'Gene', (221, 225))	('tumor', 'Disease', (180, 185))	('KRAS', 'Gene', (36, 40))	('KRAS', 'Gene', '3845', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('KRAS', 'Gene', '3845', (36, 40))	('crizotinib', 'Chemical', 'MESH:D000077547', (117, 127))	('EGFR', 'Gene', '1956', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('EGFR', 'Gene', '1956', (212, 216))	('EGFR', 'Gene', (212, 216))
213777	24279718	Furthermore, the identified L862R EGFR mutation, although not reported before, was located near mutations known to be sensitive to EGFR-TKI, such as L858R and L861X.	('L858R', 'Mutation', 'rs121434568', (149, 154))	('L862R', 'Mutation', 'p.L862R', (28, 33))	('EGFR', 'Gene', (34, 38))	('L861X', 'Mutation', 'p.L861X', (159, 164))	('L862R', 'Var', (28, 33))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('L858R', 'Var', (149, 154))	('L861X', 'Var', (159, 164))	('EGFR', 'Gene', '1956', (34, 38))
213778	24279718	Therefore, the tumor clone bearing this EGFR mutation could have been potentially responsive to EGR-TKI therapy.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('EGFR', 'Gene', '1956', (40, 44))	('mutation', 'Var', (45, 53))	('tumor', 'Disease', (15, 20))	('EGFR', 'Gene', (40, 44))
213779	24279718	However, a previously described single case of L862V EGFR mutation was associated with lack of response to gefitinib and the same could have been the scenario with the L862R EGFR mutation.	('EGFR', 'Gene', (174, 178))	('L862V', 'Var', (47, 52))	('L862R', 'Mutation', 'p.L862R', (168, 173))	('gefitinib', 'Chemical', 'MESH:D000077156', (107, 116))	('L862R', 'Var', (168, 173))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('L862V', 'Mutation', 'p.L862V', (47, 52))	('EGFR', 'Gene', '1956', (174, 178))
213780	24279718	Functional characterization of this and other rare EGFR mutations is needed in order to elucidate their impact on treatment with TKI.	('mutations', 'Var', (56, 65))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', (51, 55))
213781	24279718	The appearance of new EGFR and KRAS mutations could indicate a shift in the oncogenic survival and proliferation dependency from the ALK signaling pathway to EGFR and/or KRAS pathways in the ALK-TKI resistant cells.	('KRAS', 'Gene', (31, 35))	('EGFR', 'Gene', (158, 162))	('KRAS', 'Gene', (170, 174))	('ALK', 'Gene', (133, 136))	('rat', 'Species', '10116', (106, 109))	('KRAS', 'Gene', '3845', (31, 35))	('mutations', 'Var', (36, 45))	('ALK', 'Gene', '238', (191, 194))	('oncogenic survival', 'CPA', (76, 94))	('shift', 'Reg', (63, 68))	('KRAS', 'Gene', '3845', (170, 174))	('EGFR', 'Gene', '1956', (22, 26))	('ALK', 'Gene', '238', (133, 136))	('EGFR', 'Gene', '1956', (158, 162))	('ALK', 'Gene', (191, 194))	('proliferation', 'CPA', (99, 112))	('EGFR', 'Gene', (22, 26))
213784	24279718	KIT amplification, auto-phosphorylation of EGFR, and aberrant expression of other receptor tyrosine kinases have also been postulated by in vitro experiments to cause resistance to crizotinib in ALK-rearranged cancer cells.	('cause', 'Reg', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('aberrant', 'Var', (53, 61))	('resistance', 'MPA', (167, 177))	('crizotinib', 'Chemical', 'MESH:D000077547', (181, 191))	('KIT amplification', 'Var', (0, 17))	('ALK', 'Gene', (195, 198))	('EGFR', 'Gene', '1956', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('EGFR', 'Gene', (43, 47))	('cancer', 'Disease', (210, 216))	('auto-phosphorylation', 'Var', (19, 39))	('ALK', 'Gene', '238', (195, 198))
213788	24279718	Whether separate oncogenic driver subclones with EGFR and KRAS mutations can arise completely independently, they share a common progenitor that acquires these drivers independently as later events, or both drivers coexist within the same cell, and then one or other is lost in subclonal evolution is still unclear.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (49, 53))	('KRAS', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (58, 62))	('rat', 'Species', '10116', (12, 15))	('EGFR', 'Gene', (49, 53))
213791	24279718	Moreover, our case indicates that ALK-rearranged NSCLC may possibly acquire resistance to crizotinib through the emergence of concurrent somatic mutations in both EGFR and KRAS genes.	('KRAS', 'Gene', (172, 176))	('ALK', 'Gene', '238', (34, 37))	('KRAS', 'Gene', '3845', (172, 176))	('NSCLC', 'Disease', (49, 54))	('mutations', 'Var', (145, 154))	('resistance to', 'MPA', (76, 89))	('EGFR', 'Gene', '1956', (163, 167))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('acquire', 'PosReg', (68, 75))	('ALK', 'Gene', (34, 37))	('EGFR', 'Gene', (163, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('crizotinib', 'Chemical', 'MESH:D000077547', (90, 100))
213792	24279718	The concomitant occurrence of EGFR and KRAS mutations with ALK rearrangement upon crizotinib resistance suggests that the most effective therapeutic strategy for ALK-positive lung cancers may ultimately require combined strategies targeting not only ALK gene fusions and ALK resistance mutations, but also other driver mutations that activate alternative TKI-resistance pathways.	('EGFR', 'Gene', (30, 34))	('ALK', 'Gene', '238', (250, 253))	('rat', 'Species', '10116', (151, 154))	('ALK', 'Gene', '238', (59, 62))	('ALK', 'Gene', (250, 253))	('ALK', 'Gene', '238', (162, 165))	('rat', 'Species', '10116', (222, 225))	('lung cancers', 'Disease', 'MESH:D008175', (175, 187))	('ALK', 'Gene', (59, 62))	('ALK', 'Gene', (162, 165))	('EGFR', 'Gene', '1956', (30, 34))	('lung cancers', 'Disease', (175, 187))	('ALK', 'Gene', '238', (271, 274))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('ALK', 'Gene', (271, 274))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('crizotinib', 'Chemical', 'MESH:D000077547', (82, 92))	('lung cancers', 'Phenotype', 'HP:0100526', (175, 187))	('KRAS', 'Gene', '3845', (39, 43))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))	('TKI-resistance pathways', 'Pathway', (355, 378))
213808	27785071	LPS variants exhibit different aggressive potentials reflecting their morphologic diversity.	('LPS', 'Disease', 'MESH:C536528', (0, 3))	('variants', 'Var', (4, 12))	('aggressive potentials', 'CPA', (31, 52))	('LPS', 'Phenotype', 'HP:0012034', (0, 3))	('LPS', 'Disease', (0, 3))
213817	27785071	Recent studies on LPS molecular pathways and genetic mutations have identified new treatment targets with promising results.	('LPS', 'Disease', (18, 21))	('LPS', 'Disease', 'MESH:C536528', (18, 21))	('LPS', 'Phenotype', 'HP:0012034', (18, 21))	('mutations', 'Var', (53, 62))
213823	27785071	In particular, molecular cytogenetic analysis and immunohistochemistry staining have assessed the prognostic value of CDK4 amplification, which seems to be significantly associated with a worse prognosis in DDLPS (88.2% in DDLPS vs 58.9% in ALT/WDLPS).	('LPS', 'Disease', 'MESH:C536528', (209, 212))	('CDK4', 'Gene', (118, 122))	('LPS', 'Disease', 'MESH:C536528', (247, 250))	('LPS', 'Disease', (247, 250))	('ALT', 'Gene', (241, 244))	('LPS', 'Disease', (225, 228))	('LPS', 'Phenotype', 'HP:0012034', (225, 228))	('LPS', 'Disease', 'MESH:C536528', (225, 228))	('ALT', 'Gene', '76282', (241, 244))	('LPS', 'Phenotype', 'HP:0012034', (209, 212))	('LPS', 'Disease', (209, 212))	('amplification', 'Var', (123, 136))	('LPS', 'Phenotype', 'HP:0012034', (247, 250))	('associated', 'Reg', (170, 180))
213832	27785071	Although the etiology of ALT/WDLPS and DDLPS is still unclear, the characteristic presence of 12q13-15 amplification suggests a role in tumor pathogenesis.	('12q13-15', 'Gene', (94, 102))	('LPS', 'Disease', 'MESH:C536528', (41, 44))	('LPS', 'Phenotype', 'HP:0012034', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('LPS', 'Disease', 'MESH:C536528', (31, 34))	('ALT', 'Gene', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('ALT', 'Gene', '76282', (25, 28))	('LPS', 'Phenotype', 'HP:0012034', (41, 44))	('LPS', 'Disease', (41, 44))	('tumor', 'Disease', (136, 141))	('amplification', 'Var', (103, 116))	('LPS', 'Disease', (31, 34))
213842	27785071	In line with these findings, overall survival (OS) at 5 years is ~90% in MLPS poor in round cells versus 50% in MLPS rich in round cells.	('MLPS', 'Disease', 'None', (112, 116))	('poor in', 'Var', (78, 85))	('MLPS', 'Disease', (112, 116))	('MLPS', 'Disease', 'None', (73, 77))	('LPS', 'Phenotype', 'HP:0012034', (113, 116))	('LPS', 'Phenotype', 'HP:0012034', (74, 77))	('MLPS', 'Disease', (73, 77))	('OS', 'Chemical', '-', (47, 49))
213843	27785071	In addition to round cell component, high MIB-1 labeling index, p53 missense mutation, reduction of p14 protein expression and p53 mutation are the adverse prognostic factors.	('p14', 'Gene', (100, 103))	('MIB-1', 'Gene', (42, 47))	('p53', 'Gene', '7157', (64, 67))	('p14', 'Gene', '1029', (100, 103))	('MIB-1', 'Gene', '57534', (42, 47))	('missense mutation', 'Var', (68, 85))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (127, 130))	('reduction', 'NegReg', (87, 96))	('p53', 'Gene', (127, 130))	('mutation', 'Var', (131, 139))
213844	27785071	The most important molecular genetic abnormality of MLPS is the recurrent translocation of the t(12;16)(q13;p11) region, which results in the aberrant fusion gene, FUS-CHOP/DDIT3, currently used for the diagnosis of MLPS.	('LPS', 'Phenotype', 'HP:0012034', (217, 220))	('MLPS', 'Disease', 'None', (216, 220))	('DDIT3', 'Gene', (173, 178))	('MLPS', 'Disease', 'None', (52, 56))	('CHOP', 'Gene', (168, 172))	('MLPS', 'Disease', (216, 220))	('MLPS', 'Disease', (52, 56))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (95, 112))	('results in', 'Reg', (127, 137))	('DDIT3', 'Gene', '1649', (173, 178))	('CHOP', 'Gene', '1649', (168, 172))	('LPS', 'Phenotype', 'HP:0012034', (53, 56))	('translocation', 'Var', (74, 87))	('t(12', 'Gene', (95, 99))
213845	27785071	In rare cases, another translocation, (t12;22)(q13;q12), is reported that results in a fusion gene arrangement between EWS and CHOP.	('t12;22)(q13;q12', 'Var', (39, 54))	('CHOP', 'Gene', '1649', (127, 131))	('results in', 'Reg', (74, 84))	('fusion gene arrangement', 'MPA', (87, 110))	('CHOP', 'Gene', (127, 131))	('EWS', 'Gene', '2130', (119, 122))	('EWS', 'Gene', (119, 122))
213846	27785071	FUS-CHOP fusion transcripts are classified into three categories: type I (exons 7-2), type II (exons 5-2), and type III (exons 8-2).	('CHOP', 'Gene', (4, 8))	('exons', 'Var', (95, 100))	('CHOP', 'Gene', '1649', (4, 8))
213848	27785071	Moreover, four types of less-frequent EWS-CHOP fusion transcripts have been identified: type I (exons 7-2), type II (exons 20-2), type III (exons 13-2), and type IV (exons 13-3).	('exons', 'Var', (140, 145))	('EWS', 'Gene', '2130', (38, 41))	('EWS', 'Gene', (38, 41))	('exons', 'Var', (117, 122))	('CHOP', 'Gene', '1649', (42, 46))	('CHOP', 'Gene', (42, 46))
213862	27785071	Recent studies have hypothesized the role of p14ARF methylation in the origin and growth of PLS.	('PLS', 'Disease', 'MESH:D010214', (92, 95))	('p14ARF', 'Gene', (45, 51))	('methylation', 'Var', (52, 63))	('PLS', 'Disease', (92, 95))	('growth', 'CPA', (82, 88))	('p14ARF', 'Gene', '1029', (45, 51))
213982	27785071	Inactivation of p53 pathway results in the inhibition of cell cycle arrest and apoptosis.	('arrest', 'Disease', (68, 74))	('inhibition', 'NegReg', (43, 53))	('p53', 'Gene', (16, 19))	('p53', 'Gene', '7157', (16, 19))	('apoptosis', 'CPA', (79, 88))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('Inactivation', 'Var', (0, 12))
213983	27785071	Amplification of MDM2 is seen in many tumors, especially in ALT/WDLPS and DDLPS.	('ALT', 'Gene', (60, 63))	('LPS', 'Phenotype', 'HP:0012034', (66, 69))	('LPS', 'Disease', (66, 69))	('Amplification', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('LPS', 'Phenotype', 'HP:0012034', (76, 79))	('LPS', 'Disease', 'MESH:C536528', (66, 69))	('LPS', 'Disease', (76, 79))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('MDM2', 'Gene', (17, 21))	('ALT', 'Gene', '76282', (60, 63))	('LPS', 'Disease', 'MESH:C536528', (76, 79))	('seen', 'Reg', (25, 29))
213984	27785071	For this reason, the presence of MDM2 amplification is a useful tool for diagnosis in these LPS histologic subgroups.	('MDM2', 'Gene', (33, 37))	('LPS', 'Disease', 'MESH:C536528', (92, 95))	('LPS', 'Phenotype', 'HP:0012034', (92, 95))	('LPS', 'Disease', (92, 95))	('amplification', 'Var', (38, 51))
213985	27785071	Moreover, inhibition of MDM2 interaction with p53 tumor suppressor protein represents a new strategic approach to cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('p53', 'Gene', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('p53', 'Gene', '7157', (46, 49))	('MDM2', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('interaction', 'Interaction', (29, 40))	('inhibition', 'Var', (10, 20))	('tumor', 'Disease', (50, 55))	('cancer', 'Disease', (114, 120))
213991	27785071	Although RG7112 was well tolerated, out of 20 patients, six experienced grade 4 neutropenia, three experienced thrombocytopenia, and almost all patients had nausea, vomiting, and fatigue.	('patients', 'Species', '9606', (46, 54))	('thrombocytopenia', 'Disease', 'MESH:D013921', (111, 127))	('fatigue', 'Disease', (179, 186))	('neutropenia', 'Disease', (80, 91))	('nausea', 'Phenotype', 'HP:0002018', (157, 163))	('nausea', 'Disease', (157, 163))	('nausea', 'Disease', 'MESH:D009325', (157, 163))	('fatigue', 'Phenotype', 'HP:0012378', (179, 186))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (111, 127))	('vomiting', 'Phenotype', 'HP:0002013', (165, 173))	('RG7112', 'Var', (9, 15))	('neutropenia', 'Disease', 'MESH:D009503', (80, 91))	('patients', 'Species', '9606', (144, 152))	('vomiting', 'Disease', (165, 173))	('vomiting', 'Disease', 'MESH:D014839', (165, 173))	('neutropenia', 'Phenotype', 'HP:0001875', (80, 91))	('thrombocytopenia', 'Disease', (111, 127))	('fatigue', 'Disease', 'MESH:D005221', (179, 186))
213995	27785071	CDK4 inactivation may represent a potential approach to cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CDK4', 'Protein', (0, 4))	('inactivation', 'Var', (5, 17))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
213997	27785071	Preclinical studies in STS have shown that CDK4 inhibitors may act as potentiators of cytotoxic CT agent, doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (106, 117))	('inhibitors', 'Var', (48, 58))	('CDK4', 'Protein', (43, 47))
214002	27785071	The study enrolled 48 patients with advanced ALT/WDLPS and DDLPS (44 of 48 had CDK4 amplification; 41 of 44 were Rb positive).	('LPS', 'Phenotype', 'HP:0012034', (51, 54))	('Rb', 'Phenotype', 'HP:0009919', (113, 115))	('amplification', 'Var', (84, 97))	('patients', 'Species', '9606', (22, 30))	('LPS', 'Disease', 'MESH:C536528', (51, 54))	('ALT', 'Gene', (45, 48))	('LPS', 'Disease', 'MESH:C536528', (61, 64))	('LPS', 'Phenotype', 'HP:0012034', (61, 64))	('LPS', 'Disease', (61, 64))	('CDK4', 'Gene', (79, 83))	('ALT', 'Gene', '76282', (45, 48))	('LPS', 'Disease', (51, 54))
214005	27785071	Although the treatment schedule was well tolerated, PD0332991 was associated with hematological toxicity including anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%).	('anemia', 'Disease', 'MESH:D000740', (115, 121))	('PD0332991', 'Chemical', 'MESH:C500026', (52, 61))	('thrombocytopenia', 'Disease', (129, 145))	('anemia', 'Disease', (115, 121))	('neutropenia', 'Disease', (153, 164))	('PD0332991', 'Var', (52, 61))	('anemia', 'Phenotype', 'HP:0001903', (115, 121))	('thrombocytopenia', 'Disease', 'MESH:D013921', (129, 145))	('febrile neutropenia', 'Disease', (176, 195))	('neutropenia', 'Disease', (184, 195))	('febrile neutropenia', 'Disease', 'MESH:D009503', (176, 195))	('neutropenia', 'Disease', 'MESH:D009503', (153, 164))	('hematological toxicity', 'Disease', 'MESH:D006402', (82, 104))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (129, 145))	('hematological toxicity', 'Disease', (82, 104))	('neutropenia', 'Phenotype', 'HP:0001875', (153, 164))	('neutropenia', 'Disease', 'MESH:D009503', (184, 195))	('neutropenia', 'Phenotype', 'HP:0001875', (184, 195))
214007	27785071	Other CDK4 inhibitors, including LY2835219 and LEE001, are currently under evaluation in clinical trials.	('LY2835219', 'Var', (33, 42))	('LY2835219', 'Chemical', 'MESH:C000590451', (33, 42))	('LEE001', 'Var', (47, 53))	('CDK4', 'Protein', (6, 10))
214008	27785071	These agents showed different profiles of toxicity; gastrointestinal adverse effects were associated with LY2835219, and neutropenia and QT prolongation were mostly recorded with LEE001.	('LY2835219', 'Var', (106, 115))	('LEE001', 'Var', (179, 185))	('LY2835219', 'Chemical', 'MESH:C000590451', (106, 115))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('neutropenia', 'Phenotype', 'HP:0001875', (121, 132))	('gastrointestinal adverse effects', 'Disease', (52, 84))	('toxicity', 'Disease', (42, 50))	('neutropenia and QT prolongation', 'Disease', 'MESH:D008133', (121, 152))
214022	27785071	Alterations in SREBP-1 expression result in a clinical syndrome of lipodystrophy, which is characterized by abnormal adopigenesis, peripheral fat atrophy, and bizarre lipid distribution.	('lipodystrophy', 'Disease', (67, 80))	('atrophy', 'Disease', 'MESH:D001284', (146, 153))	('atrophy', 'Disease', (146, 153))	('SREBP-1', 'Gene', '6720', (15, 22))	('Alterations', 'Var', (0, 11))	('SREBP-1', 'Gene', (15, 22))	('fat atrophy', 'Phenotype', 'HP:0100578', (142, 153))	('lipodystrophy', 'Phenotype', 'HP:0009125', (67, 80))	('result in', 'Reg', (34, 43))	('lipodystrophy', 'Disease', 'MESH:D008060', (67, 80))	('lipid', 'Chemical', 'MESH:D008055', (167, 172))
214078	33189003	This is mostly related to vaso-occlusion and sickling of red blood cells causing bone ischemia.	('related', 'Reg', (15, 22))	('bone ischemia', 'Disease', 'MESH:D007511', (81, 94))	('bone ischemia', 'Disease', (81, 94))	('sickling of red blood cells', 'Phenotype', 'HP:0008346', (45, 72))	('vaso-occlusion', 'Disease', 'MESH:D001157', (26, 40))	('vaso-occlusion', 'Disease', (26, 40))	('sickling', 'Var', (45, 53))
214175	33173008	For example, the continuous induction of inflammatory cytokines and cytotoxic mediators, such as reactive oxygen or nitrogen species, can, over time, cause damage to the cellular genome, resulting in cellular mutations that lead to dysregulated cell proliferation and cancer development.	('cancer', 'Disease', (268, 274))	('cause', 'Reg', (150, 155))	('nitrogen', 'Chemical', 'MESH:D009584', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('lead to', 'Reg', (224, 231))	('mutations', 'Var', (209, 218))	('rat', 'Species', '10116', (257, 260))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('dysregulated cell proliferation', 'CPA', (232, 263))
214197	33173008	However, P. aeruginosa can cause severe infection in individuals with immunosuppression.	('infection', 'Disease', (40, 49))	('infection', 'Disease', 'MESH:D007239', (40, 49))	('P. aeruginosa', 'Species', '287', (9, 22))	('cause', 'Reg', (27, 32))	('P. aeruginosa', 'Var', (9, 22))	('severe infection', 'Phenotype', 'HP:0032169', (33, 49))
214207	33173008	P. aeruginosa increased the proliferation of KMM cells but did not have any significant effect on MM cells (Fig.	('increased', 'PosReg', (14, 23))	('proliferation', 'CPA', (28, 41))	('P. aeruginosa', 'Var', (0, 13))	('rat', 'Species', '10116', (35, 38))	('P. aeruginosa', 'Species', '287', (0, 13))
214208	33173008	Both P. aeruginosa and LPS also increased the sizes and efficiency of colony formation in soft agar of KMM cells (Fig.	('agar', 'Chemical', 'MESH:D000362', (95, 99))	('P. aeruginosa', 'Species', '287', (5, 18))	('sizes', 'CPA', (46, 51))	('increased', 'PosReg', (32, 41))	('colony formation in', 'CPA', (70, 89))	('P. aeruginosa', 'Var', (5, 18))	('LPS', 'Var', (23, 26))
214209	33173008	These results indicated that, similar to LPS, P. aeruginosa stimulated the proliferation and cellular transformation of KMM cells.	('cellular transformation', 'CPA', (93, 116))	('P. aeruginosa', 'Species', '287', (46, 59))	('stimulated', 'PosReg', (60, 70))	('rat', 'Species', '10116', (82, 85))	('P. aeruginosa', 'Var', (46, 59))	('proliferation', 'CPA', (75, 88))
214215	33173008	Additionally, we analyzed the cytokines tumor necrosis factor alpha (TNF-alpha) and CXCL-1, as P. aeruginosa increased levels of these inflammatory cytokines in mice.	('tumor necrosis', 'Disease', (40, 54))	('CXCL-1', 'Gene', (84, 90))	('P. aeruginosa', 'Var', (95, 108))	('CXCL-1', 'Gene', '81503', (84, 90))	('mice', 'Species', '10090', (161, 165))	('TNF-alpha', 'Gene', (69, 78))	('tumor necrosis', 'Disease', 'MESH:D009336', (40, 54))	('P. aeruginosa', 'Species', '287', (95, 108))	('levels', 'MPA', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('increased', 'PosReg', (109, 118))	('TNF-alpha', 'Gene', '24835', (69, 78))
214217	33173008	In contrast, cytokines IL-6, IL-1beta, IL-18, TNF-alpha, and CXCL-1 were not significantly upregulated in MM cells by P. aeruginosa (Fig.	('IL-1beta', 'Gene', (29, 37))	('CXCL-1', 'Gene', '81503', (61, 67))	('CXCL-1', 'Gene', (61, 67))	('P. aeruginosa', 'Species', '287', (118, 131))	('TNF-alpha', 'Gene', '24835', (46, 55))	('IL-18', 'Gene', '29197', (39, 44))	('TNF-alpha', 'Gene', (46, 55))	('IL-18', 'Gene', (39, 44))	('IL-1beta', 'Gene', '24493', (29, 37))	('P. aeruginosa', 'Var', (118, 131))	('cytokines', 'MPA', (13, 22))
214226	33173008	The levels of induced proinflammatory cytokines IL-6, IL-1beta, TNF-alpha, and CXCL-1 by P. aeruginosa were significantly decreased in KMM cells by CLI095; however, they remained significantly higher than those of the unstimulated KMM cells (Fig.	('levels of induced proinflammatory cytokines IL-6', 'MPA', (4, 52))	('IL-1beta', 'Gene', (54, 62))	('TNF-alpha', 'Gene', (64, 73))	('P. aeruginosa', 'Var', (89, 102))	('IL-1beta', 'Gene', '24493', (54, 62))	('CXCL-1', 'Gene', '81503', (79, 85))	('CXCL-1', 'Gene', (79, 85))	('CLI095', 'Chemical', '-', (148, 154))	('P. aeruginosa', 'Species', '287', (89, 102))	('TNF-alpha', 'Gene', '24835', (64, 73))	('decreased', 'NegReg', (122, 131))	('higher', 'PosReg', (193, 199))
214227	33173008	As expected, induction of inflammatory cytokines by LPS was completely blocked by CLI095 in KMM cells, with levels similar to those of the unstimulated cells or cells treated with CLI095 alone (Fig.	('blocked', 'NegReg', (71, 78))	('induction', 'MPA', (13, 22))	('CLI095', 'Chemical', '-', (82, 88))	('inflammatory cytokines', 'MPA', (26, 48))	('CLI095', 'Var', (82, 88))	('LPS', 'Gene', (52, 55))	('CLI095', 'Chemical', '-', (180, 186))
214228	33173008	These results indicated that, besides LPS, another P. aeruginosa PAMP(s) also contributes to P. aeruginosa-induced inflammation in KMM cells.	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('P. aeruginosa', 'Species', '287', (51, 64))	('P. aeruginosa', 'Species', '287', (93, 106))	('P. aeruginosa-induced', 'Var', (93, 114))	('inflammation', 'Disease', (115, 127))
214230	33173008	While PAO1 and PAO1DeltafliC strains at 1 x 107 CFU/ml induced inflammatory cytokines in KMM cells, the levels of induction were significantly lower in KMM cells stimulated with the PAO1DeltafliC than PAO1 strain (Fig.	('inflammatory cytokines', 'MPA', (63, 85))	('PAO1DeltafliC', 'Var', (182, 195))	('lower', 'NegReg', (143, 148))	('PAO1', 'Species', '208964', (182, 186))	('PAO1', 'Species', '208964', (6, 10))	('PAO1', 'Species', '208964', (201, 205))	('PAO1', 'Species', '208964', (15, 19))	('induced', 'Reg', (55, 62))
214234	33173008	In contrast, PAO1DeltafliC strain induction of inflammatory cytokines was completely abolished by CLI095 (Fig.	('PAO1', 'Species', '208964', (13, 17))	('abolished', 'NegReg', (85, 94))	('CLI095', 'Chemical', '-', (98, 104))	('inflammatory cytokines', 'MPA', (47, 69))	('PAO1DeltafliC strain', 'Var', (13, 33))
214235	33173008	No significant effect was observed on MM cells with either the PAO1DeltafliC or PAO1 strain (Fig.	('PAO1', 'Species', '208964', (63, 67))	('PAO1', 'Species', '208964', (80, 84))	('PAO1 strain', 'Var', (80, 91))	('PAO1DeltafliC', 'Var', (63, 76))
214240	33173008	Hence, at least LPS and flagellin contributed to P. aeruginosa induction of inflammation in KMM cells.	('inflammation', 'Disease', (76, 88))	('P. aeruginosa', 'Var', (49, 62))	('P. aeruginosa', 'Species', '287', (49, 62))	('inflammation', 'Disease', 'MESH:D007249', (76, 88))
214242	33173008	While all three MAPK pathways were activated in KMM cells by PAO1, the activation levels were reduced in cells stimulated with the PAO1DeltafliC strain (Fig.	('PAO1', 'Species', '208964', (61, 65))	('PAO1', 'Var', (61, 65))	('PAO1DeltafliC', 'Var', (131, 144))	('PAO1', 'Species', '208964', (131, 135))	('activated', 'PosReg', (35, 44))	('MAPK pathways', 'Pathway', (16, 29))
214246	33173008	As expected, flagellin alone indeed activated the p38 and ERK1/2 pathways, and treatment with CLI095 had no effect on flagellin activation of these two pathways, although the reduction of ERK1/2 activation by CLI095 in P. aeruginosa-stimulated KMM cells was less pronounced in this experiment, indicating possible variation of P. aeruginosa LPS effect on ERK1/2 activation (Fig.	('aeruginosa LPS', 'Disease', (330, 344))	('p38', 'Gene', '5594', (50, 53))	('P. aeruginosa', 'Species', '287', (327, 340))	('aeruginosa LPS', 'Disease', 'MESH:C536528', (330, 344))	('CLI095', 'Chemical', '-', (209, 215))	('p38', 'Gene', (50, 53))	('CLI095', 'Var', (209, 215))	('P. aeruginosa', 'Species', '287', (219, 232))	('ERK1/2 pathways', 'Pathway', (58, 73))	('CLI095', 'Chemical', '-', (94, 100))
214255	33173008	p38 inhibitor (SB203580) or ERK1/2 inhibitor (U0126) alone had no effect on flagellin induction of inflammatory cytokines (Fig.	('SB203580', 'Var', (15, 23))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('p38', 'Gene', '5594', (0, 3))	('inflammatory cytokines', 'MPA', (99, 121))	('p38', 'Gene', (0, 3))	('SB203580', 'Chemical', 'MESH:C093642', (15, 23))
214259	33173008	While P. aeruginosa flagellin stimulated the proliferation of KMM cells by 20%, SB203580 or U0126 alone or in combination completely abolished this effect (Fig.	('rat', 'Species', '10116', (52, 55))	('proliferation', 'CPA', (45, 58))	('U0126', 'Var', (92, 97))	('aeruginosa flagellin', 'Disease', (9, 29))	('stimulated', 'PosReg', (30, 40))	('U0126', 'Chemical', 'MESH:C113580', (92, 97))	('SB203580', 'Chemical', 'MESH:C093642', (80, 88))	('P. aeruginosa', 'Species', '287', (6, 19))	('SB203580', 'Var', (80, 88))	('aeruginosa flagellin', 'Disease', 'MESH:D011552', (9, 29))
214275	33173008	It would be interesting to further confirm the roles of P. aeruginosa in KS development in AIDS-KS patients.	('AIDS-KS', 'Disease', (91, 98))	('P. aeruginosa', 'Species', '287', (56, 69))	('KS development', 'Disease', (73, 87))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('KS', 'Phenotype', 'HP:0100726', (73, 75))	('patients', 'Species', '9606', (99, 107))	('P. aeruginosa', 'Var', (56, 69))	('AIDS-KS', 'Disease', 'MESH:D000163', (91, 98))
214281	33173008	In this study, we demonstrate that both P. aeruginosa LPS and flagellin activate the MAPK pathways and that inhibition of MAPK pathways decreases expression of inflammatory cytokines, cell proliferation, and cellular transformation (Fig.	('MAPK pathways', 'Pathway', (85, 98))	('cellular transformation', 'CPA', (208, 231))	('MAPK pathways', 'Pathway', (122, 135))	('rat', 'Species', '10116', (196, 199))	('inflammatory cytokines', 'MPA', (160, 182))	('aeruginosa LPS', 'Disease', (43, 57))	('aeruginosa LPS', 'Disease', 'MESH:C536528', (43, 57))	('cell proliferation', 'CPA', (184, 202))	('P. aeruginosa', 'Species', '287', (40, 53))	('rat', 'Species', '10116', (25, 28))	('inhibition', 'Var', (108, 118))	('expression', 'MPA', (146, 156))	('decreases', 'NegReg', (136, 145))
214287	33173008	As previously reported, we confirmed the induction of TNF-alpha and CXCL-1 by P. aeruginosa.	('CXCL-1', 'Gene', '81503', (68, 74))	('CXCL-1', 'Gene', (68, 74))	('TNF-alpha', 'Gene', '24835', (54, 63))	('P. aeruginosa', 'Species', '287', (78, 91))	('TNF-alpha', 'Gene', (54, 63))	('P. aeruginosa', 'Var', (78, 91))
214295	33173008	The proportions of the types of TLRs expressed (TLR2 versus TLR4, for example) may also affect the cellular response.	('affect', 'Reg', (88, 94))	('TLR4', 'Gene', '7099', (60, 64))	('TLR2', 'Var', (48, 52))	('cellular response', 'CPA', (99, 116))	('TLR4', 'Gene', (60, 64))
214298	33173008	Lastly, we focused on the effects of P. aeruginosa on MAPK activation, showing that P. aeruginosa stimulation of KMM cells resulted in the activation of p38, ERK1/2, and JNK pathways.	('p38', 'Gene', '5594', (153, 156))	('JNK', 'Gene', (170, 173))	('activation', 'PosReg', (139, 149))	('ERK1/2', 'Pathway', (158, 164))	('p38', 'Gene', (153, 156))	('P. aeruginosa', 'Species', '287', (84, 97))	('P. aeruginosa', 'Species', '287', (37, 50))	('JNK', 'Gene', '5599', (170, 173))	('P. aeruginosa', 'Var', (84, 97))
214301	33173008	Primary infection of KSHV results in activation of p38, ERK1/2, and JNK activation, and inhibition of the MAPK pathways can reduce KSHV infectivity and induction of IL-6.	('activation', 'PosReg', (72, 82))	('MAPK pathways', 'Pathway', (106, 119))	('Primary infection', 'Disease', 'MESH:D007239', (0, 17))	('p38', 'Gene', (51, 54))	('KS', 'Phenotype', 'HP:0100726', (21, 23))	('JNK', 'Gene', '5599', (68, 71))	('activation', 'PosReg', (37, 47))	('IL-6', 'MPA', (165, 169))	('KSHV', 'Species', '37296', (131, 135))	('JNK', 'Gene', (68, 71))	('p38', 'Gene', '5594', (51, 54))	('KS', 'Phenotype', 'HP:0100726', (131, 133))	('KSHV', 'Species', '37296', (21, 25))	('Primary infection', 'Disease', (0, 17))	('ERK1/2', 'Pathway', (56, 62))	('KSHV', 'Gene', (131, 135))	('reduce', 'NegReg', (124, 130))	('inhibition', 'Var', (88, 98))
214303	33173008	Our results identify the important role of P. aeruginosa-induced inflammation in cell proliferation and cellular transformation while providing further evidence on the therapeutic value of inhibiting the MAPK pathways in KS patients.	('cell proliferation', 'CPA', (81, 99))	('inflammation', 'Disease', (65, 77))	('inhibiting', 'NegReg', (189, 199))	('P. aeruginosa', 'Species', '287', (43, 56))	('KS', 'Phenotype', 'HP:0100726', (221, 223))	('patients', 'Species', '9606', (224, 232))	('inflammation', 'Disease', 'MESH:D007249', (65, 77))	('P. aeruginosa-induced', 'Var', (43, 64))	('MAPK pathways', 'Pathway', (204, 217))	('cellular transformation', 'CPA', (104, 127))	('rat', 'Species', '10116', (93, 96))
214310	33173008	Besides LPS and flagellin, P. aeruginosa consists of many additional PAMPs that can induce inflammation, such as peptidoglycans and lipoproteins.	('peptidoglycans', 'MPA', (113, 127))	('PAMPs', 'Gene', (69, 74))	('lipoproteins', 'MPA', (132, 144))	('inflammation', 'Disease', (91, 103))	('inflammation', 'Disease', 'MESH:D007249', (91, 103))	('P. aeruginosa', 'Var', (27, 40))	('PAMPs', 'Gene', 'None', (69, 74))	('induce', 'PosReg', (84, 90))	('P. aeruginosa', 'Species', '287', (27, 40))
214324	33173008	Primary antibodies included mouse monoclonal antibodies to beta-tubulin and rabbit polyclonal antibodies to glyceraldehyde-3-phosphate dehydrogenase (5174S; Cell Signaling Technology), JNK (9252S; Cell Signaling Technology), phospho-JNK (4668S; Cell Signaling Technology), p38 (8690S; Cell Signaling Technology), phospho-p38 (4511S; Cell Signaling Technology), ERK1/2 (4695S; Cell Signaling Technology), and phospho-ERK1/2 (4370S; Cell Signaling Technology).	('JNK', 'Gene', '5599', (233, 236))	('p38', 'Gene', '5594', (273, 276))	('p38', 'Gene', '5594', (321, 324))	('JNK', 'Gene', '5599', (185, 188))	('p38', 'Gene', (321, 324))	('4511S', 'Var', (326, 331))	('p38', 'Gene', (273, 276))	('JNK', 'Gene', (233, 236))	('JNK', 'Gene', (185, 188))
214328	26843990	In transgenic mice, either overexpressing the mutated human Cu/Zn-superoxide dismutase (hSOD1G93A) gene or deficient in GABAergic/glycinergic synaptic transmission (gephyrin, GAD-67, or VGAT gene knockout), hypoglossal motoneurons develop excitatory glutamatergic synaptic hyperactivity.	('synaptic hyperactivity', 'Disease', (264, 286))	('GAD-67', 'Gene', '2571', (175, 181))	('GABA', 'Chemical', 'MESH:D005680', (120, 124))	('synaptic hyperactivity', 'Disease', 'MESH:D012183', (264, 286))	('GAD-67', 'Gene', (175, 181))	('hyperactivity', 'Phenotype', 'HP:0000752', (273, 286))	('Cu/Zn-superoxide dismutase', 'Gene', (60, 86))	('develop', 'PosReg', (231, 238))	('deficient', 'Var', (107, 116))	('glycine', 'Chemical', 'MESH:D005998', (130, 137))	('transgenic mice', 'Species', '10090', (3, 18))	('Cu/Zn-superoxide dismutase', 'Gene', '6647', (60, 86))	('hSOD1', 'Gene', '6647', (88, 93))	('hypoglossal motoneurons', 'CPA', (207, 230))	('hSOD1', 'Gene', (88, 93))	('human', 'Species', '9606', (54, 59))	('glutamate', 'Chemical', 'MESH:D018698', (250, 259))	('GABAergic/glycinergic synaptic transmission', 'MPA', (120, 163))
214361	26843990	Dendritic elongation and branching abnormalities of lumbar motoneurons were reported in mutated human Cu/Zn-superoxide dismutase (hSOD1G85R) overexpressing mice compared to wild-type mice at P3-P9.	('hSOD1', 'Gene', '6647', (130, 135))	('Dendritic elongation and branching abnormalities of lumbar motoneurons', 'Disease', 'MESH:C563613', (0, 70))	('human', 'Species', '9606', (96, 101))	('mice', 'Species', '10090', (183, 187))	('Cu/Zn-superoxide dismutase', 'Gene', (102, 128))	('mutated', 'Var', (88, 95))	('mice', 'Species', '10090', (156, 160))	('Cu/Zn-superoxide dismutase', 'Gene', '6647', (102, 128))	('hSOD1', 'Gene', (130, 135))
214366	26843990	We have been using voltage pulses to electroporate the membrane in giga-seal or semiloose seal modes, instead of direct and variable suction that can damage the plasma membrane and intracellular organelles.	('damage', 'Reg', (150, 156))	('electroporate', 'Var', (37, 50))	('plasma membrane', 'CPA', (161, 176))	('rat', 'Species', '10116', (46, 49))
214377	26843990	Dendritic spines can also structurally restrict access of dyes, especially larger molecules such as HRP (MW ~ 44 kilo Dalton (kDa)) compared to small size Neurobiotin (MW = 323) (Kanjhan, unpublished observations).	('Neurobiotin', 'Chemical', 'MESH:C070614', (155, 166))	('access', 'MPA', (48, 54))	('HRP', 'Protein', (100, 103))	('Dendritic spines', 'Disease', (0, 16))	('restrict', 'NegReg', (39, 47))	('Dendritic spines', 'Disease', 'MESH:D007635', (0, 16))	('MW ~ 44 kilo', 'Var', (105, 117))
214378	26843990	Furthermore, the intensity of dye is always much higher in dendritic shafts, particularly in distal dendrites, compared to spines protruding from them, even with smaller dyes Neurobiotin, biocytin (MW = 372), Lucifer Yellow (MW = 522), and Alexa Fluor (MW = 570).	('biocytin', 'Chemical', 'MESH:C013411', (188, 196))	('Alexa Fluor', 'Chemical', '-', (240, 251))	('intensity', 'MPA', (17, 26))	('higher', 'PosReg', (49, 55))	('Neurobiotin', 'Chemical', 'MESH:C070614', (175, 186))	('MW', 'Var', (198, 200))
214397	26843990	However, a number of manipulations have also been shown to induce filopodia growth including high-frequency focal synaptic stimulation by activation of glutamatergic NMDA receptors, overexpression of glutamatergic AMPA receptor subtype 2 (GluR2) and the transmembrane agrin (TM-agrin), proteolytic cleavage of agrin by neurotrypsin, or activation of the small conductance Ca2+-activated K+ channel subtype 3 (SK3).	('induce', 'PosReg', (59, 65))	('GluR2', 'Gene', '14800', (239, 244))	('NMDA', 'Chemical', 'MESH:D016202', (166, 170))	('SK3', 'Gene', '140493', (409, 412))	('activation', 'PosReg', (138, 148))	('neurotrypsin', 'Gene', '19142', (319, 331))	('Ca2', 'Gene', '12349', (372, 375))	('glutamatergic', 'Protein', (152, 165))	('GluR2', 'Gene', (239, 244))	('SK3', 'Gene', (409, 412))	('activation', 'PosReg', (336, 346))	('glutamatergic AMPA receptor subtype 2', 'Gene', '14800', (200, 237))	('neurotrypsin', 'Gene', (319, 331))	('agrin', 'Gene', (278, 283))	('filopodia growth', 'CPA', (66, 82))	('manipulations', 'Var', (21, 34))	('agrin', 'Gene', (310, 315))	('agrin', 'Gene', '11603', (278, 283))	('agrin', 'Gene', '11603', (310, 315))	('agrin', 'Gene', (268, 273))	('Ca2', 'Gene', (372, 375))	('glutamate', 'Chemical', 'MESH:D018698', (152, 161))	('glutamate', 'Chemical', 'MESH:D018698', (200, 209))	('overexpression', 'PosReg', (182, 196))	('agrin', 'Gene', '11603', (268, 273))	('glutamatergic AMPA receptor subtype 2', 'Gene', (200, 237))
214412	26843990	Somatic patch-clamp recordings show that at E18 wild-type (WT) mice hypoglossal motoneurons receive both glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic/glycinergic inhibitory postsynaptic currents (IPSCs) under voltage clamp (Figure 4(a)).	('glycine', 'Chemical', 'MESH:D005998', (174, 181))	('GABA', 'Chemical', 'MESH:D005680', (164, 168))	('mice', 'Species', '10090', (63, 67))	('E18', 'Var', (44, 47))	('glutamatergic excitatory postsynaptic currents', 'MPA', (105, 151))	('glutamate', 'Chemical', 'MESH:D018698', (105, 114))
214415	26843990	Inhibitory postsynaptic currents are mostly lost in mice that lack GAD-67, while there is an increase in the frequency of excitatory synaptic inputs (Figure 4(b)).	('lost', 'NegReg', (44, 48))	('GAD-67', 'Gene', (67, 73))	('increase', 'PosReg', (93, 101))	('Inhibitory postsynaptic currents', 'MPA', (0, 32))	('mice', 'Species', '10090', (52, 56))	('frequency of excitatory synaptic inputs', 'MPA', (109, 148))	('GAD-67', 'Gene', '2571', (67, 73))	('lack', 'Var', (62, 66))
214421	26843990	In current-clamp recordings, IPSPs were significantly reduced in amplitude and frequency in hypoglossal motoneurons from the mice deficient in inhibitory synaptic transmission; instead an increase in the frequency and amplitude of EPSPs was observed, which increased the action potential firing probability and reduced the interspike interval (Figures 4(f) and 4(h)).	('interspike interval', 'MPA', (323, 342))	('increased', 'PosReg', (257, 266))	('deficient', 'Var', (130, 139))	('mice', 'Species', '10090', (125, 129))	('reduced', 'NegReg', (54, 61))	('increase', 'PosReg', (188, 196))	('reduced', 'NegReg', (311, 318))	('action potential firing probability', 'MPA', (271, 306))
214426	26843990	In the spinal cord, nerve endings from Ia/II proprioceptive sensory neurons, directly contacting alpha motoneurons, are preferentially affected in ALS and degenerate much earlier than those from Ib sensory neurons in SOD1G93A and transactivation response element (TAR) deoxyribonucleic acid- (DNA-) binding protein-43 (TDP-43A315T) mutant mice.	('ALS', 'Phenotype', 'HP:0007354', (147, 150))	('ALS', 'Gene', (147, 150))	('mice', 'Species', '10090', (339, 343))	('degenerate', 'NegReg', (155, 165))	('rat', 'Species', '10116', (161, 164))	('TDP-43', 'Gene', '230908', (319, 325))	('TDP-43', 'Gene', (319, 325))	('ALS', 'Gene', '6647', (147, 150))	('affected', 'Reg', (135, 143))	('mutant', 'Var', (332, 338))
214428	26843990	In motoneuronal somatodendritic domain, the mushroom-shaped pedunculated spines were less frequent than the stubby (sessile) and thin and filopodia-like spines (Figure 1(c)), the sessile (stubby) spines being most common at P30.	('mushroom-shaped pedunculated spines', 'CPA', (44, 79))	('soma', 'Disease', (16, 20))	('soma', 'Disease', 'None', (16, 20))	('P30', 'Var', (224, 227))	('mushroom', 'Species', '5341', (44, 52))
214429	26843990	In consistency with previous studies on other parts of the brain, such as the pyramidal cells from the rat visual cortex where transiently appearing filopodia mostly disappear after P12, there was a gradual developmental decrease in the filopodia density on the soma and dendrites of motoneurons at P15 (Figures 5(d) and 6(c)) and P30 (Figures 5(c) and 6(e)) compared to E17/P0 WT mice (Figures 3(c)-3(d), 5(a), and 6(a)-6(b)).	('developmental decrease', 'Phenotype', 'HP:0001263', (207, 229))	('P15', 'Var', (299, 302))	('filopodia', 'CPA', (237, 246))	('mice', 'Species', '10090', (381, 385))	('rat', 'Species', '10116', (103, 106))	('P30', 'Var', (331, 334))	('E17', 'Gene', (371, 374))	('soma and dendrites', 'Disease', 'MESH:D007635', (262, 280))	('P12', 'Var', (182, 185))	('E17', 'Gene', '100035255', (371, 374))	('decrease', 'NegReg', (221, 229))
214431	26843990	Spine density on the other hand increased, especially on the distal dendrites at P15 (Figures 5(d) and 6(c)), but then showed a decline at P30 WT mice (Figures 5(c) and 6(e)), especially on soma and proximal dendrites (Figure 6(e)).	('decline', 'NegReg', (128, 135))	('P30', 'Var', (139, 142))	('Spine density', 'CPA', (0, 13))	('soma', 'Disease', 'None', (190, 194))	('soma', 'Disease', (190, 194))	('P15', 'Var', (81, 84))	('mice', 'Species', '10090', (146, 150))
214434	26843990	In mutant mice strains with impaired inhibitory synaptic transmission (lacking VGAT, GAD-67, or gephyrin), we saw an increase in the density and length of filopodia and spine-like structures on the soma and primary dendrites (Figure 5(b)) compared to WT littermates at E18-P0 (Figure 5(a)).	('mutant', 'Var', (3, 9))	('increase', 'PosReg', (117, 125))	('gephyrin', 'Protein', (96, 104))	('mice', 'Species', '10090', (10, 14))	('GAD-67', 'Gene', (85, 91))	('soma', 'Disease', (198, 202))	('soma', 'Disease', 'None', (198, 202))	('VGAT', 'Protein', (79, 83))	('lacking', 'NegReg', (71, 78))	('inhibitory synaptic transmission', 'MPA', (37, 69))	('GAD-67', 'Gene', '2571', (85, 91))
214441	26843990	This is consistent with patch-clamp recordings showing significant decrease in the frequency and amplitude of inhibitory postsynaptic currents and potentials and a significant increase in the frequency of excitatory postsynaptic currents and potentials in mutant mice compared to their WT littermates (Figure 4).	('increase', 'PosReg', (176, 184))	('decrease', 'NegReg', (67, 75))	('mutant', 'Var', (256, 262))	('frequency', 'MPA', (83, 92))	('mice', 'Species', '10090', (263, 267))
214442	26843990	These findings fit with significant increases in hypoglossal nerve output in brainstem-spinal cord preparations of gephyrin knockout mice, compared to WT littermates.	('mice', 'Species', '10090', (133, 137))	('hypoglossal nerve output', 'Disease', 'MESH:D020437', (49, 73))	('hypoglossal nerve output', 'Disease', (49, 73))	('gephyrin', 'Gene', (115, 123))	('increases', 'PosReg', (36, 45))	('knockout', 'Var', (124, 132))	('hypoglossal nerve', 'Phenotype', 'HP:0011394', (49, 66))	('rat', 'Species', '10116', (104, 107))
214444	26843990	Interestingly, mice overexpressing the mutated hSOD1G93A gene, widely used as a mouse model of inherited ALS, also show increased density of filopodia and spine-like structures in their soma (Figures 5(e)-5(f)) and dendrites (Figures 6(d) and 6(f)) at P15-P30 of presymptomatic age, compared to WT littermates at P15 (Figures 5(c) and 5(d)) and P30 (Figures 6(c) and 6(d)).	('filopodia', 'CPA', (141, 150))	('density', 'CPA', (130, 137))	('soma', 'Disease', 'None', (186, 190))	('ALS', 'Gene', '6647', (105, 108))	('soma', 'Disease', (186, 190))	('mutated', 'Var', (39, 46))	('mouse', 'Species', '10090', (80, 85))	('ALS', 'Phenotype', 'HP:0007354', (105, 108))	('ALS', 'Gene', (105, 108))	('mice', 'Species', '10090', (15, 19))	('increased', 'PosReg', (120, 129))	('hSOD1', 'Gene', '6647', (47, 52))	('hSOD1', 'Gene', (47, 52))
214446	26843990	We have found that increased filopodia and spine-like processes were usually associated with increased dendritic length and branching in hSOD1G93A mutants and inhibitory synaptic transmission deficient strains of mice including gephyrin, GAD67, and VGAT knockout mice compared to WT littermates.	('hSOD1', 'Gene', '6647', (137, 142))	('hSOD1', 'Gene', (137, 142))	('mice', 'Species', '10090', (213, 217))	('increased', 'PosReg', (93, 102))	('branching', 'CPA', (124, 133))	('dendritic length', 'CPA', (103, 119))	('increased', 'PosReg', (19, 28))	('mice', 'Species', '10090', (263, 267))	('mutants', 'Var', (147, 154))
214447	26843990	In WT mice, dendritic growth and branching and increases in spine density continued until about P15, when the filopodia density was high; after loss of filopodia, the growth of the motoneuronal dendritic length and branching, as well as increases in dendritic spine density, were reduced.	('loss', 'Var', (144, 148))	('increases', 'PosReg', (237, 246))	('mice', 'Species', '10090', (6, 10))	('dendritic spine density', 'CPA', (250, 273))	('reduced', 'NegReg', (280, 287))	('growth', 'CPA', (167, 173))	('filopodia', 'Protein', (152, 161))	('branching', 'CPA', (215, 224))
214448	26843990	Taken together these findings suggest that at least some of the filopodia may be involved in dendritic lengthening and branching and increased spine density during normal motoneuron development and that exaggerated filopodial formation leads to increased structural responses in hSOD1G93A, gephyrin, GAD67, and VGAT mutants compared to WT mice.	('spine density', 'CPA', (143, 156))	('structural responses', 'CPA', (255, 275))	('branching', 'CPA', (119, 128))	('mutants', 'Var', (316, 323))	('mice', 'Species', '10090', (339, 343))	('hSOD1', 'Gene', (279, 284))	('increased', 'PosReg', (245, 254))	('filopodial formation', 'CPA', (215, 235))	('rat', 'Species', '10116', (209, 212))	('hSOD1', 'Gene', '6647', (279, 284))	('dendritic lengthening', 'CPA', (93, 114))	('increased', 'PosReg', (133, 142))	('increased spine density', 'Phenotype', 'HP:0004563', (133, 156))
214461	26843990	Activation of BDNF-TrkB complex has been implicated in motoneuron vulnerability to SOD1G37R mutations and toxicity.	('toxicity', 'Disease', 'MESH:D064420', (106, 114))	('toxicity', 'Disease', (106, 114))	('motoneuron vulnerability', 'MPA', (55, 79))	('mutations', 'Var', (92, 101))	('Activation', 'PosReg', (0, 10))	('SOD1G37R', 'Gene', (83, 91))	('implicated', 'Reg', (41, 51))	('BDNF', 'Gene', '12064', (14, 18))	('BDNF', 'Gene', (14, 18))
214470	26843990	The complexity of dendritic arbor and branching of spinal motoneurons are refined in an activity-dependent manner that is sensitive to blockade of NMDA receptors during postnatal development, but not during late-adult postnatal life.	('NMDA', 'Gene', (147, 151))	('dendritic arbor', 'Disease', (18, 33))	('NMDA', 'Chemical', 'MESH:D016202', (147, 151))	('dendritic arbor', 'Disease', 'MESH:D007635', (18, 33))	('blockade', 'Var', (135, 143))
214477	26843990	Using genetic manipulations of plasma membrane K+ channel expression in Drosophila, it has previously been shown that increased intrinsic neuronal excitability can cause increased dendritic branch formation, whereas decreased intrinsic excitability can cause increased dendrite branch elongation of motoneurons.	('decreased', 'NegReg', (216, 225))	('increased', 'PosReg', (259, 268))	('increased', 'PosReg', (170, 179))	('intrinsic neuronal excitability', 'MPA', (128, 159))	('increased', 'PosReg', (118, 127))	('dendritic branch', 'Disease', 'MESH:D007635', (180, 196))	('dendrite branch elongation', 'Disease', 'MESH:C538010', (269, 295))	('intrinsic excitability', 'MPA', (226, 248))	('dendrite branch elongation', 'Disease', (269, 295))	('Drosophila', 'Species', '7227', (72, 82))	('genetic manipulations', 'Var', (6, 27))	('manipulations', 'Var', (14, 27))	('dendritic branch', 'Disease', (180, 196))
214479	26843990	Since increases in excitatory synaptic inputs were common to motoneurons in all mutant mice used in our studies (Figures 4 and 7), we think it is likely that increases in dendritic branching, filopodia, and spine numbers reported here in mice overexpressing hSOD1G93A and in mice with impaired inhibitory synaptic transmission (VGAT, GAD-67, and gephyrin knockouts) may be driven by increases in glutamatergic synaptic inputs onto motoneurons.	('filopodia', 'CPA', (192, 201))	('mutant', 'Var', (80, 86))	('mice', 'Species', '10090', (275, 279))	('hSOD1', 'Gene', (258, 263))	('hSOD1', 'Gene', '6647', (258, 263))	('mice', 'Species', '10090', (87, 91))	('GAD-67', 'Gene', '2571', (334, 340))	('increases', 'PosReg', (383, 392))	('glutamatergic synaptic inputs', 'MPA', (396, 425))	('dendritic branching', 'Disease', 'MESH:D007635', (171, 190))	('glutamate', 'Chemical', 'MESH:D018698', (396, 405))	('dendritic branching', 'Disease', (171, 190))	('overexpressing', 'PosReg', (243, 257))	('GAD-67', 'Gene', (334, 340))	('inhibitory synaptic transmission', 'MPA', (294, 326))	('mice', 'Species', '10090', (238, 242))	('spine numbers', 'CPA', (207, 220))	('increases', 'PosReg', (158, 167))
214489	26843990	Significant loss of Dscam1 function in Drosophila prevented stable dendrites from being formed and mutant motoneurons were devoid of mature dendritic branches, instead of displaying a dense meshwork of filopodia-like and lamellipodia-like processes, normally seen during early pupal development.	('Drosophila', 'Species', '7227', (39, 49))	('function', 'MPA', (27, 35))	('loss', 'NegReg', (12, 16))	('dendritic branches', 'Disease', 'MESH:D007635', (140, 158))	('Dscam1', 'Gene', (20, 26))	('mutant', 'Var', (99, 105))	('Dscam1', 'Gene', '35652', (20, 26))	('devoid', 'NegReg', (123, 129))	('dendritic branches', 'Disease', (140, 158))	('prevented', 'NegReg', (50, 59))	('stable dendrites', 'CPA', (60, 76))
214493	26843990	Dendritic translation of Dscam1 is regulated by NMDA receptor activation, and impairment of NMDA-mediated regulation of Dscam1 has been implicated in alterations in dendritic morphology and synaptic plasticity in Down's syndrome.	('impairment', 'Var', (78, 88))	("Down's syndrome", 'Disease', (213, 228))	('rat', 'Species', '10116', (154, 157))	('Dscam1', 'Gene', (120, 126))	('Dscam1', 'Gene', '35652', (120, 126))	('implicated', 'Reg', (136, 146))	('alterations', 'Reg', (150, 161))	('NMDA', 'Chemical', 'MESH:D016202', (48, 52))	('Dscam1', 'Gene', (25, 31))	('Dendritic', 'MPA', (0, 9))	('Dscam1', 'Gene', '35652', (25, 31))	('dendritic morphology', 'CPA', (165, 185))	('NMDA', 'Chemical', 'MESH:D016202', (92, 96))
214506	26843990	These are important functions as loss of spine stability has been implicated in a number of neurodegenerative diseases.	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (92, 118))	('neurodegenerative diseases', 'Disease', (92, 118))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (92, 118))	('loss', 'Var', (33, 37))	('loss of spine stability', 'Phenotype', 'HP:0003306', (33, 56))	('spine stability', 'CPA', (41, 56))	('implicated', 'Reg', (66, 76))
214515	26843990	Recent studies have found that alterations or disturbances in the cytoskeletal actin pathway in motoneurons and redox alterations in the inflammatory compartment contribute to ALS pathogenesis and disease outcome.	('alterations', 'Var', (31, 42))	('redox alterations', 'MPA', (112, 129))	('ALS', 'Gene', '6647', (176, 179))	('rat', 'Species', '10116', (35, 38))	('ALS', 'Phenotype', 'HP:0007354', (176, 179))	('cytoskeletal actin pathway', 'Pathway', (66, 92))	('ALS', 'Gene', (176, 179))	('rat', 'Species', '10116', (122, 125))	('contribute', 'Reg', (162, 172))	('disturbances', 'Var', (46, 58))
214516	26843990	Profilin 1 (PFN-1) is crucial for the conversation of monomeric (globular) G-actin to polymer microfilament (filamentous) F-actin in response to extracellular signals, and mutations in PFN-1 gene are shown to cause familial ALS.	('mutations', 'Var', (172, 181))	('cause', 'Reg', (209, 214))	('PFN-1', 'Gene', '18643', (185, 190))	('Profilin 1', 'Gene', '18643', (0, 10))	('familial ALS', 'Disease', 'MESH:C565957', (215, 227))	('ALS', 'Phenotype', 'HP:0007354', (224, 227))	('Profilin 1', 'Gene', (0, 10))	('PFN-1', 'Gene', (12, 17))	('PFN-1', 'Gene', '18643', (12, 17))	('familial ALS', 'Disease', (215, 227))	('PFN-1', 'Gene', (185, 190))
214517	26843990	Primary motoneurons expressing mutant PFN-1 display smaller growth cones with a reduced F/G-actin ratio.	('mutant', 'Var', (31, 37))	('growth cones', 'CPA', (60, 72))	('PFN-1', 'Gene', (38, 43))	('PFN-1', 'Gene', '18643', (38, 43))	('reduced', 'NegReg', (80, 87))	('smaller', 'NegReg', (52, 59))	('rat', 'Species', '10116', (98, 101))	('F/G-actin ratio', 'MPA', (88, 103))
214519	26843990	SMA is due to gene mutations or deletions in the survival motor neuron 1 (smn1) gene, decreasing the availability of SMN protein, which in turn leads to an early degeneration of lower motor neurons in children.	('deletions', 'Var', (32, 41))	('smn1', 'Gene', '6606', (74, 78))	('leads to', 'Reg', (144, 152))	('degeneration', 'NegReg', (162, 174))	('children', 'Species', '9606', (201, 209))	('SMA', 'Disease', (0, 3))	('survival motor neuron 1', 'Gene', '6606', (49, 72))	('SMA', 'Phenotype', 'HP:0007269', (0, 3))	('rat', 'Species', '10116', (168, 171))	('lower', 'CPA', (178, 183))	('smn1', 'Gene', (74, 78))	('survival motor neuron 1', 'Gene', (49, 72))	('availability of SMN', 'MPA', (101, 120))	('decreasing', 'NegReg', (86, 96))
214520	26843990	Small GTPase Rac1 dysregulation or alterations in structure and function have also been implicated in the pathogenesis of ALS and SMA.	('ALS', 'Phenotype', 'HP:0007354', (122, 125))	('ALS', 'Gene', (122, 125))	('implicated', 'Reg', (88, 98))	('alterations', 'Reg', (35, 46))	('SMA', 'Disease', (130, 133))	('SMA', 'Phenotype', 'HP:0007269', (130, 133))	('rat', 'Species', '10116', (39, 42))	('dysregulation', 'Var', (18, 31))	('structure', 'MPA', (50, 59))	('ALS', 'Gene', '6647', (122, 125))	('Small GTPase Rac1', 'Protein', (0, 17))	('function', 'MPA', (64, 72))
214523	26843990	At all age groups, in particular at P15 and P30, the frequency of EPSCs is significantly higher in large-sized hypoglossal motoneurons from hSOD1G93A transgenic mice (Figure 7(b)), compared to age-matched WT mice (Figure 7(a)).	('hSOD1', 'Gene', (140, 145))	('mice', 'Species', '10090', (161, 165))	('EPSCs', 'Disease', (66, 71))	('P15', 'Var', (36, 39))	('P30', 'Var', (44, 47))	('transgenic mice', 'Species', '10090', (150, 165))	('higher', 'PosReg', (89, 95))	('transgenic', 'Var', (150, 160))	('mice', 'Species', '10090', (208, 212))	('hSOD1', 'Gene', '6647', (140, 145))
214524	26843990	Amplitude of EPSCs was slightly larger in hSOD1G93A overexpressing motoneurons than WT motoneurons, but not as dramatic as changes in EPSC frequency (Figure 7).	('hSOD1', 'Gene', (42, 47))	('EPSCs', 'MPA', (13, 18))	('hSOD1', 'Gene', '6647', (42, 47))	('larger', 'PosReg', (32, 38))	('Amplitude', 'MPA', (0, 9))	('overexpressing', 'Var', (52, 66))
214548	26843990	The Sotelo model, based on data from cerebellar Purkinje cells of normal and mutant mice, contradicts the Miller/Peters model; as Purkinje cells from mutant mice lacking parallel fibers form abundant spine, the Sotelo model proposes that the presynaptic axonal terminal has only a minor role in spinogenesis.	('lacking', 'NegReg', (162, 169))	('mutant', 'Var', (150, 156))	('mice', 'Species', '10090', (84, 88))	('mice', 'Species', '10090', (157, 161))
214566	26843990	Most cases of ALS are sporadic with no known genetic linkage, while approximately 10% are associated with familial forms, presenting mutations in over 20 genes encoding for distinct proteins with varied functions, including SOD1, fused in sarcoma (FUS), TDP-43, chromosome 9 open reading frame 72 (C9ORF72), PFN-1, vacuolar protein sorting-associated protein 9- (VPS9-) ankyrin repeat protein (VARP), alsin, ataxin-2, and matrin-3.	('fused in sarcoma', 'Gene', '233908', (230, 246))	('C9ORF72', 'Gene', (298, 305))	('vacuolar protein sorting-associated protein 9- (VPS9-) ankyrin repeat protein', 'Gene', '245886', (315, 392))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('PFN-1', 'Gene', (308, 313))	('VARP', 'Gene', (394, 398))	('ALS', 'Gene', (14, 17))	('alsin', 'Gene', (401, 406))	('mutations', 'Var', (133, 142))	('TDP-43', 'Gene', (254, 260))	('fused in sarcoma', 'Gene', (230, 246))	('ataxin-2', 'Gene', '20239', (408, 416))	('TDP-43', 'Gene', '230908', (254, 260))	('PFN-1', 'Gene', '18643', (308, 313))	('familial forms', 'Disease', (106, 120))	('ALS', 'Gene', '6647', (14, 17))	('C9ORF72', 'Gene', '203228', (298, 305))	('ataxin-2', 'Gene', (408, 416))	('alsin', 'Gene', '74018', (401, 406))	('matrin-3', 'Gene', (422, 430))	('SOD1', 'Gene', (224, 228))	('matrin-3', 'Gene', '17184', (422, 430))	('ALS', 'Phenotype', 'HP:0007354', (14, 17))	('VARP', 'Gene', '245886', (394, 398))
214567	26843990	Mutations in these proteins may increase the susceptibility for the dysregulated intracellular Ca2+-mediated degenerative processes to occur, suggesting existence of a common pathogenic pathway centered around intracellular Ca2+ and its handling.	('rat', 'Species', '10116', (115, 118))	('Ca2', 'Gene', (224, 227))	('Ca2', 'Gene', '12349', (95, 98))	('Mutations', 'Var', (0, 9))	('Ca2', 'Gene', (95, 98))	('Ca2', 'Gene', '12349', (224, 227))
214568	26843990	Consistent with glutamate-mediated excitotoxicity hypothesis, our studies of motoneurons from hSOD1G93A mutant mice show that increases in dendritic spine density compared to age-matched littermates are associated with increased frequency of EPSCs, as well as an enhanced developmental increase in EPSC amplitudes (Figure 7(b)).	('increases', 'PosReg', (126, 135))	('dendritic spine density', 'CPA', (139, 162))	('toxicity', 'Disease', 'MESH:D064420', (41, 49))	('increase', 'PosReg', (286, 294))	('toxicity', 'Disease', (41, 49))	('mutant', 'Var', (104, 110))	('mice', 'Species', '10090', (111, 115))	('hSOD1', 'Gene', (94, 99))	('EPSCs', 'Disease', (242, 247))	('developmental', 'CPA', (272, 285))	('hSOD1', 'Gene', '6647', (94, 99))	('EPSC amplitudes', 'MPA', (298, 313))	('enhanced', 'PosReg', (263, 271))	('glutamate', 'Chemical', 'MESH:D018698', (16, 25))
214569	26843990	Increased frequency of excitatory and inhibitory synaptic inputs to hypoglossal motoneurons, together with increased intrinsic persistent sodium currents resulting in increased action potential firing rates, was previously reported in hSOD1G93A mutant mice as early as P4 to P10.	('mice', 'Species', '10090', (252, 256))	('rat', 'Species', '10116', (201, 204))	('increased', 'PosReg', (107, 116))	('increased', 'PosReg', (167, 176))	('intrinsic persistent sodium currents', 'MPA', (117, 153))	('hSOD1', 'Gene', (235, 240))	('mutant', 'Var', (245, 251))	('Increased', 'PosReg', (0, 9))	('action potential firing rates', 'MPA', (177, 206))	('hSOD1', 'Gene', '6647', (235, 240))	('sodium', 'Chemical', 'MESH:D012964', (138, 144))
214571	26843990	Such longer depolarizations may in turn reduce the excitability and firing properties of motoneurons, by depolarization block or partial inactivation of the voltage-gated sodium channels.	('depolarizations', 'Var', (12, 27))	('sodium', 'Chemical', 'MESH:D012964', (171, 177))	('reduce', 'NegReg', (40, 46))	('depolarization block', 'NegReg', (105, 125))	('excitability', 'MPA', (51, 63))	('firing properties of motoneurons', 'CPA', (68, 100))	('voltage-gated sodium channels', 'Pathway', (157, 186))	('partial inactivation', 'NegReg', (129, 149))
214572	26843990	This may be the mechanism of hypoexcitability of lumbar motoneurons reported in adult hSOD1G93A mutant mice.	('mice', 'Species', '10090', (103, 107))	('hSOD1', 'Gene', (86, 91))	('mutant', 'Var', (96, 102))	('hSOD1', 'Gene', '6647', (86, 91))
214575	26843990	The excitability of large F-type motoneurons was unchanged in the mSOD1G93A mutant neonatal mice, but, surprisingly, the small S-type motoneurons displayed intrinsic hyperexcitability.	('intrinsic hyperexcitability', 'Disease', (156, 183))	('mutant', 'Var', (76, 82))	('intrinsic hyperexcitability', 'Disease', 'MESH:D020919', (156, 183))	('mSOD1G93A', 'Gene', (66, 75))	('mice', 'Species', '10090', (92, 96))
214576	26843990	Another study using two-photon imaging found that calcium transients in motoneuron dendrites of hSOD1G93A mutants are smaller, compared to WT mice at P4-P11.	('hSOD1', 'Gene', '6647', (96, 101))	('calcium', 'Chemical', 'MESH:D002118', (50, 57))	('hSOD1', 'Gene', (96, 101))	('mice', 'Species', '10090', (142, 146))	('smaller', 'NegReg', (118, 125))	('calcium transients', 'MPA', (50, 68))	('mutants', 'Var', (106, 113))
214594	26843990	Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders.	('neurological disorders', 'Disease', (87, 109))	('implicated', 'Reg', (39, 49))	('mitochondrial transport', 'MPA', (11, 34))	('Defects', 'Var', (0, 7))	('neurological disorders', 'Disease', 'MESH:D009422', (87, 109))
214600	26843990	Miro1 is essential for development of cranial motor nuclei and maintenance of upper motor neurons, and neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits.	('neurological deficits', 'Phenotype', 'HP:0000707', (213, 234))	('neurological deficits', 'Disease', (213, 234))	('Miro1', 'Gene', (127, 132))	('progressive neurological deficits', 'Phenotype', 'HP:0002344', (201, 234))	('neurological deficits', 'Disease', 'MESH:D009461', (213, 234))	('loss', 'Var', (119, 123))	('depletion of mitochondria', 'MPA', (140, 165))
214601	26843990	Defects in Miro1-mediated mitochondrial motility and distribution are sufficient to cause neurological disease such as upper motoneuron disease.	('neurological disease', 'Phenotype', 'HP:0000707', (90, 110))	('Miro1-mediated', 'Gene', (11, 25))	('Defects', 'Var', (0, 7))	('upper motoneuron disease', 'Disease', (119, 143))	('upper motoneuron disease', 'Disease', 'MESH:D012141', (119, 143))	('cause', 'Reg', (84, 89))	('neurological disease', 'Disease', (90, 110))	('neurological disease', 'Disease', 'MESH:D019636', (90, 110))
214607	26843990	Motoneurons derived from induced pluripotent stem cells (iPS cells) from ALS patients, harboring SOD1, C9orf72, and fused-in-sarcoma (FUS) mutations, have been reported to display reduced delayed-rectifier K+ current (Kv7 or M-current) amplitudes relative to control-derived motor neurons.	('Motoneurons', 'CPA', (0, 11))	('fused-in-sarcoma', 'Gene', '2521', (116, 132))	('SOD1', 'Gene', (97, 101))	('C9orf72', 'Gene', (103, 110))	('mutations', 'Var', (139, 148))	('ALS', 'Phenotype', 'HP:0007354', (73, 76))	('ALS', 'Gene', (73, 76))	('ALS', 'Gene', '6647', (73, 76))	('reduced', 'NegReg', (180, 187))	('patients', 'Species', '9606', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('C9orf72', 'Gene', '203228', (103, 110))	('iPS', 'Chemical', '-', (57, 60))	('fused-in-sarcoma', 'Gene', (116, 132))
214608	26843990	The M-current activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS patient iPS cell-derived motoneurons in culture.	('blocks the hyperexcitability', 'Disease', 'MESH:D006327', (40, 68))	('ALS', 'Phenotype', 'HP:0007354', (140, 143))	('SOD1', 'Gene', (128, 132))	('blocks the hyperexcitability', 'Disease', (40, 68))	('retigabine', 'Chemical', 'MESH:C101866', (24, 34))	('patient', 'Species', '9606', (144, 151))	('ALS', 'Gene', '6647', (140, 143))	('iPS', 'Chemical', '-', (152, 155))	('motor neuron survival', 'CPA', (82, 103))	('improves', 'PosReg', (73, 81))	('mutant', 'Var', (133, 139))	('ALS', 'Gene', (140, 143))
214609	26843990	A more recent study also reported initial hyperexcitability followed by progressive loss of action potential output and synaptic activity, due to a progressive decrease in voltage-activated Na+ and K+ currents, in patient iPS cell-derived motoneurons, harboring transactivation response element (TAR) DNA-binding protein (TARDBP) or C9ORF72 ALS-causing mutations.	('decrease', 'NegReg', (160, 168))	('patient', 'Species', '9606', (214, 221))	('ALS', 'Gene', '6647', (341, 344))	('loss', 'NegReg', (84, 88))	('hyperexcitability', 'PosReg', (42, 59))	('C9ORF72', 'Gene', '203228', (333, 340))	('TARDBP', 'Gene', (322, 328))	('ALS', 'Phenotype', 'HP:0007354', (341, 344))	('ALS', 'Gene', (341, 344))	('C9ORF72', 'Gene', (333, 340))	('mutations', 'Var', (353, 362))	('iPS', 'Chemical', '-', (222, 225))	('synaptic activity', 'MPA', (120, 137))
214613	26843990	Neuroinflammation is evident in rodent models of inherited ALS overexpressing mutant SOD1 and in ALS human patients.	('patients', 'Species', '9606', (107, 115))	('ALS', 'Gene', (59, 62))	('ALS', 'Gene', '6647', (59, 62))	('overexpressing', 'PosReg', (63, 77))	('ALS', 'Gene', '6647', (97, 100))	('ALS', 'Phenotype', 'HP:0007354', (59, 62))	('inflammation', 'Disease', 'MESH:D007249', (5, 17))	('ALS', 'Phenotype', 'HP:0007354', (97, 100))	('ALS', 'Gene', (97, 100))	('human', 'Species', '9606', (101, 106))	('inflammation', 'Disease', (5, 17))	('SOD1', 'Gene', (85, 89))	('mutant', 'Var', (78, 84))
214616	26843990	Therefore deficits or changes in microglial function may contribute to synaptic abnormalities seen in neurodegenerative and neurodevelopmental diseases.	('changes', 'Reg', (22, 29))	('synaptic abnormalities', 'Phenotype', 'HP:0012535', (71, 93))	('contribute', 'Reg', (57, 67))	('microglial function', 'CPA', (33, 52))	('neurodegenerative and neurodevelopmental diseases', 'Disease', 'MESH:D019636', (102, 151))	('synaptic abnormalities', 'MPA', (71, 93))	('deficits', 'Var', (10, 18))
214618	26843990	Selective changes in motoneuronal activity, such as synaptic hyperactivity in hSOD1G93A mutants (Figure 7(b)), or pharmacologic block of the inhibitory synaptic transmission leading to disinhibited motoneuron bursting will increase metabolic and energy demand by depleting intracellular ATP (see above) and this will subsequently activate microglia to attack and phagocytose the motoneuronal soma and dendrites (Figure 9).	('increase', 'PosReg', (223, 231))	('ATP', 'Chemical', 'MESH:D000255', (287, 290))	('activate', 'PosReg', (330, 338))	('microglia', 'CPA', (339, 348))	('depleting', 'NegReg', (263, 272))	('synaptic hyperactivity', 'Disease', (52, 74))	('motoneuronal soma and dendrites', 'Disease', 'MESH:D007635', (379, 410))	('synaptic hyperactivity', 'Disease', 'MESH:D012183', (52, 74))	('hyperactivity', 'Phenotype', 'HP:0000752', (61, 74))	('hSOD1', 'Gene', (78, 83))	('mutants', 'Var', (88, 95))	('hSOD1', 'Gene', '6647', (78, 83))
214619	26843990	Microglial attack and phagocytosis were seen in presymptomatic hSOD1G93A mutant mice in a minority (~5%) of cells dye-filled with Neurobiotin (Figures 9(a)-9(b)).	('hSOD1', 'Gene', (63, 68))	('hSOD1', 'Gene', '6647', (63, 68))	('seen', 'Reg', (40, 44))	('Neurobiotin', 'Chemical', 'MESH:C070614', (130, 141))	('mutant', 'Var', (73, 79))	('mice', 'Species', '10090', (80, 84))	('Microglial attack', 'CPA', (0, 17))	('phagocytosis', 'CPA', (22, 34))
214624	26843990	In support of this idea, a recent study has shown that the modulation of microglial activation by Fasudil, a Rho kinase inhibitor drug, prolongs survival and improves motor function in hSOD1G93A mice.	('hSOD1', 'Gene', (185, 190))	('motor function', 'CPA', (167, 181))	('mice', 'Species', '10090', (195, 199))	('modulation', 'Var', (59, 69))	('hSOD1', 'Gene', '6647', (185, 190))	('Fasudil', 'Chemical', 'MESH:C049347', (98, 105))	('improves', 'PosReg', (158, 166))	('prolongs', 'PosReg', (136, 144))	('survival', 'CPA', (145, 153))	('microglial activation', 'CPA', (73, 94))
214629	26843990	Any significant and prolonged changes to the balance of excitatory-inhibitory synaptic inputs can result in synaptic hyperactivity and changes in intrinsic membrane properties (i.e., hyperexcitability), with associated changes in neuronal dendritic tree, filopodia, and spine morphology.	('changes', 'Reg', (135, 142))	('spine morphology', 'CPA', (270, 286))	('filopodia', 'CPA', (255, 264))	('changes', 'Var', (30, 37))	('neuronal dendritic tree', 'CPA', (230, 253))	('changes', 'Reg', (219, 226))	('synaptic hyperactivity', 'Disease', 'MESH:D012183', (108, 130))	('synaptic hyperactivity', 'Disease', (108, 130))	('intrinsic membrane properties', 'MPA', (146, 175))	('balance', 'MPA', (45, 52))	('hyperactivity', 'Phenotype', 'HP:0000752', (117, 130))
214630	26843990	Remodeling of synaptic, intrinsic membrane, and morphological properties of motoneurons can ultimately lead to excitotoxicity and subsequent motoneuronal damage.	('Remodeling', 'Var', (0, 10))	('motoneuronal damage', 'Disease', (141, 160))	('motoneuronal damage', 'Disease', 'MESH:D004194', (141, 160))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('toxicity', 'Disease', (117, 125))	('lead to', 'Reg', (103, 110))
214639	23616767	Quantitatively we found a clear inverse relationship between cardiac connexin expression (Cx43, Cx40, or Cx45) and increased Ki-67 expression (Cx43: p < 0.0001, Cx45: p < 0.03, Cx40: p < 0.014).	('Cx45', 'Var', (105, 109))	('expression', 'MPA', (78, 88))	('connexin', 'Gene', '100128922', (69, 77))	('connexin', 'Gene', (69, 77))	('increased', 'PosReg', (115, 124))	('Ki-67', 'Gene', (125, 130))	('expression', 'MPA', (131, 141))	('Cx43', 'Var', (90, 94))	('Cx40', 'Var', (96, 100))
214655	23616767	In contrast, various scientific groups observed, that MSC could promote metastasis (Karnoub et al.,) and enhance tumor growth (Gunn et al.,; Zhu et al.,; Spaeth et al.,), which is assumed to be attributable to for instance immunosuppression (Djouad et al.,) or drug resistance (Kurtova et al.,).	('tumor', 'Disease', (113, 118))	('promote', 'PosReg', (64, 71))	('metastasis', 'CPA', (72, 82))	('drug resistance', 'Phenotype', 'HP:0020174', (261, 276))	('MSC', 'Var', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('enhance', 'PosReg', (105, 112))
214660	23616767	showed in commercially available human MSC that these cells can express Cx43, Cx40, and Cx45, and found punctuate Cx43 and Cx40 staining in regions of close cell-cell contact, while Cx45 was mostly found cytoplasmically.	('Cx45', 'Var', (88, 92))	('Cx40', 'Var', (78, 82))	('human', 'Species', '9606', (33, 38))	('Cx40', 'Var', (123, 127))	('Cx43', 'Var', (72, 76))
214664	23616767	This tumor showed an interesting reverse relationship between proliferation and expression of the cardiac connexins Cx43, Cx40, and Cx45.	('Cx40', 'Var', (122, 126))	('connexin', 'Gene', '100128922', (106, 114))	('connexin', 'Gene', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('Cx43', 'Protein', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('expression', 'MPA', (80, 90))	('Cx45', 'Var', (132, 136))	('rat', 'Species', '10116', (69, 72))
214674	23616767	For cBM-MSC (passage 6) we could validate the manufacturer's descriptions (CD29+, CD44+, CD90+, CD106+ (>70%), CD11b-, CD34-, CD45- (<5%) and adipogenic-, chondrogenic-, and osteogenic-differentiation).	('CD34-', 'Var', (119, 124))	('CD29+', 'Var', (75, 80))	('CD90+', 'Var', (89, 94))	('CD11b', 'Gene', '25021', (111, 116))	('CD44', 'Gene', '25406', (82, 86))	('CD11b', 'Gene', (111, 116))	('CD44', 'Gene', (82, 86))	('adipogenic-', 'CPA', (142, 153))	('chondrogenic-', 'CPA', (155, 168))
214729	23616767	By comparing the fluorescence signals of the three connexins, we recognized that most cells stained positive for Cx43, while a smaller percentage expressed Cx45 and Cx40.	('Cx40', 'Var', (165, 169))	('connexin', 'Gene', (51, 59))	('Cx43', 'Protein', (113, 117))	('connexin', 'Gene', '100128922', (51, 59))
214739	23616767	At the tumor-heart border all cells expressing Ki-67 were negative for Cx43 and Cx40, and only 2% co-expressed Ki-67 and Cx45 (Figure 6B).	('negative', 'NegReg', (58, 66))	('tumor-heart border', 'Disease', 'MESH:D001882', (7, 25))	('Cx43', 'MPA', (71, 75))	('tumor-heart border', 'Disease', (7, 25))	('Cx40', 'MPA', (80, 84))	('Ki-67', 'Var', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
214740	23616767	As a main finding we observed an inverse relationship between the expression of connexins, i.e., Cx43, Cx40, or Cx45, and of cell proliferation marker Ki-67 (which is not present in G0 phase).	('inverse', 'NegReg', (33, 40))	('Cx45', 'Var', (112, 116))	('rat', 'Species', '10116', (137, 140))	('cell proliferation', 'CPA', (125, 143))	('Cx43', 'Var', (97, 101))	('connexin', 'Gene', (80, 88))	('connexin', 'Gene', '100128922', (80, 88))	('Cx40', 'Var', (103, 107))
214845	23243358	t(x;18)(p11.2;q11.2), has greatly increased the sensitivity and specificity of diagnosing synovial sarcoma, especially at unusual locations like the lung.	('t(x;18)(p11.2;q11.2', 'Var', (0, 19))	('synovial sarcoma', 'Disease', 'MESH:D013584', (90, 106))	('t(x;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (0, 20))	('synovial sarcoma', 'Disease', (90, 106))	('increased', 'PosReg', (34, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (90, 106))
214867	23243358	The overall 5-year survival rate is 50%, and poor prognostic risk factors include an age of more than 20 years, female sex, incomplete resection, tumor size greater than 5 cm, extensive tumor necrosis, high number of mitoses (>10 per 10 high power fields), neurovascular invasion, and recently, SYT-SSX1 variant.	('SYT', 'Gene', '6760', (295, 298))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor necrosis', 'Disease', 'MESH:D009336', (186, 200))	('tumor', 'Disease', (146, 151))	('SSX1', 'Gene', '6756', (299, 303))	('neurovascular invasion', 'CPA', (257, 279))	('variant', 'Var', (304, 311))	('tumor', 'Disease', (186, 191))	('tumor necrosis', 'Disease', (186, 200))	('SYT', 'Gene', (295, 298))	('SSX1', 'Gene', (299, 303))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
214875	22185463	Interestingly, two novel 19-bp insertions in the U3 region in the LTR and 5' UTR, most likely derived from other retroviruses, were found in all the three isolates, thereby separately introducing one E2BP binding site in the U3 region in the LTR and RNA polymerase II transcription factor IIB and core promoter motif ten elements in the 5' UTR.	('E2BP', 'MPA', (200, 204))	('insertions', 'Var', (31, 41))	('c', 'Chemical', 'MESH:D002244', (297, 298))	('binding', 'Interaction', (205, 212))	('c', 'Chemical', 'MESH:D002244', (191, 192))	('introducing', 'Reg', (184, 195))	('c', 'Chemical', 'MESH:D002244', (284, 285))	('c', 'Chemical', 'MESH:D002244', (273, 274))
214876	22185463	Meanwhile, two binding sites in the U3 LTRs of the three isolates for NFAP-1 and AIB REP1 were lost, and a 1-base deletion in the E element of the 3' UTR of JL093-1 and SD09DP03 introduced a binding site for c-Ets-1.	('NFAP-1', 'Gene', (70, 76))	('REP1', 'Gene', (85, 89))	('lost', 'NegReg', (95, 99))	('introduced', 'Reg', (178, 188))	('c', 'Chemical', 'MESH:D002244', (185, 186))	('SD09DP03', 'Var', (169, 177))	('REP1', 'Gene', '1121', (85, 89))	('c', 'Chemical', 'MESH:D002244', (208, 209))	('binding', 'Interaction', (191, 198))	('binding', 'Interaction', (15, 22))
214878	22185463	Our study is the first to discovery the coexistence of two novel insertions in the U3 region in the LTR and the 5' UTR of ALV-J associated with hemangioma symptoms, and the transcriptional regulatory elements introduced should be taken into consideration in the occurrence of hemangioma.	('hemangioma', 'Disease', (276, 286))	('c', 'Chemical', 'MESH:D002244', (216, 217))	('c', 'Chemical', 'MESH:D002244', (49, 50))	('hemangioma symptoms', 'Disease', (144, 163))	('hemangioma', 'Phenotype', 'HP:0001028', (144, 154))	('ALV-J', 'Gene', (122, 127))	('c', 'Chemical', 'MESH:D002244', (40, 41))	('hemangioma', 'Disease', 'MESH:D006391', (144, 154))	('c', 'Chemical', 'MESH:D002244', (270, 271))	('hemangioma symptoms', 'Disease', 'MESH:D006391', (144, 163))	('ALV-J', 'Species', '1401444', (122, 127))	('c', 'Chemical', 'MESH:D002244', (29, 30))	('associated with', 'Reg', (128, 143))	('hemangioma', 'Phenotype', 'HP:0001028', (276, 286))	('insertions', 'Var', (65, 75))	('hemangioma', 'Disease', (144, 154))	('hemangioma', 'Disease', 'MESH:D006391', (276, 286))	('c', 'Chemical', 'MESH:D002244', (132, 133))	('c', 'Chemical', 'MESH:D002244', (264, 265))	('c', 'Chemical', 'MESH:D002244', (178, 179))	('c', 'Chemical', 'MESH:D002244', (241, 242))	('c', 'Chemical', 'MESH:D002244', (263, 264))
214890	22185463	This type of tumor may be induced in chickens by an avian leukosis retrovirus (ALV) variant that contains the erb-B oncogene.	('c', 'Chemical', 'MESH:D002244', (30, 31))	('tumor', 'Disease', (13, 18))	('variant', 'Var', (84, 91))	('leukosis retrovirus', 'Disease', (58, 77))	('c', 'Chemical', 'MESH:D002244', (97, 98))	('c', 'Chemical', 'MESH:D002244', (118, 119))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('c', 'Chemical', 'MESH:D002244', (37, 38))	('chickens', 'Species', '9031', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('leukosis retrovirus', 'Disease', 'MESH:D012192', (58, 77))	('c', 'Chemical', 'MESH:D002244', (40, 41))
214895	22185463	These insertions introduced one E2BP binding site in the U3 LTR and RNA polymerase II transcription factor IIB and core promoter motif ten elements in the 5' UTR.	('binding', 'Interaction', (37, 44))	('c', 'Chemical', 'MESH:D002244', (24, 25))	('insertions', 'Var', (6, 16))	('c', 'Chemical', 'MESH:D002244', (91, 92))	('c', 'Chemical', 'MESH:D002244', (115, 116))	('c', 'Chemical', 'MESH:D002244', (102, 103))
214896	22185463	Meanwhile, the binding sites for NFAP-1 and AIB REP1 in the U3 LTR of the three isolates were lost, and a 1-base deletion in the E element of the 3' UTR of JL093-1 and SD09DP03 introduced a binding site for c-Ets-1.	('SD09DP03', 'Var', (168, 176))	('REP1', 'Gene', '1121', (48, 52))	('NFAP-1', 'Gene', (33, 39))	('REP1', 'Gene', (48, 52))	('lost', 'NegReg', (94, 98))	('JL093-1', 'Var', (156, 163))	('c', 'Chemical', 'MESH:D002244', (184, 185))	('c', 'Chemical', 'MESH:D002244', (207, 208))	('introduced', 'Reg', (177, 187))	('binding', 'Interaction', (15, 22))	('binding', 'Interaction', (190, 197))
214924	22185463	The whole genome sequences of the three isolates were aligned with DNASTAR (version 5.01), and the sequences were submitted to GenBank with the accession numbers as follows: HLJ09MDJ-1 (JN624878), SD09DP03 (JN624880), and JL093-1 (JN624879).	('JN624878', 'Var', (186, 194))	('c', 'Chemical', 'MESH:D002244', (145, 146))	('JN624880', 'Var', (207, 215))	('c', 'Chemical', 'MESH:D002244', (146, 147))	('HLJ09MDJ-1', 'CellLine', 'CVCL:N271', (174, 184))	('JN624879', 'Var', (231, 239))	('c', 'Chemical', 'MESH:D002244', (23, 24))	('c', 'Chemical', 'MESH:D002244', (105, 106))
214925	22185463	The full-length proviral genome sequences of JL093-1, SD09DP03 and HLJ09MDJ-1 were 7670, 7670 and 7633 nt in length, respectively.	('c', 'Chemical', 'MESH:D002244', (122, 123))	('JL093-1', 'Var', (45, 52))	('HLJ09MDJ-1', 'CellLine', 'CVCL:N271', (67, 77))	('c', 'Chemical', 'MESH:D002244', (38, 39))	('HLJ09MDJ-1', 'Var', (67, 77))
214935	22185463	In contrast with ML strains, in the three isolates, the NFAP-1 and AIB REP1 components were lost due to the mutation and deletion of base pairs, which was also observed in the hemangioma strain SCDY1.	('NFAP-1', 'Gene', (56, 62))	('c', 'Chemical', 'MESH:D002244', (3, 4))	('hemangioma', 'Disease', 'MESH:D006391', (176, 186))	('REP1', 'Gene', '1121', (71, 75))	('deletion', 'Var', (121, 129))	('REP1', 'Gene', (71, 75))	('c', 'Chemical', 'MESH:D002244', (76, 77))	('base', 'Protein', (133, 137))	('c', 'Chemical', 'MESH:D002244', (148, 149))	('mutation', 'Var', (108, 116))	('hemangioma', 'Disease', (176, 186))	('lost', 'NegReg', (92, 96))	('hemangioma', 'Phenotype', 'HP:0001028', (176, 186))
214936	22185463	An E2BP binding site was introduced by the 19 bp-insertion.	('E2BP', 'Var', (3, 7))	('binding', 'Interaction', (8, 15))	('c', 'Chemical', 'MESH:D002244', (32, 33))
214941	22185463	Interestingly, the 19-bp insertion was predicted to introduce RNA polymerase II transcription factor II B and core promoter motif ten elements, which are also present in two hemangioma strains, SCAU-HN06 and JS09GY6.	('c', 'Chemical', 'MESH:D002244', (44, 45))	('c', 'Chemical', 'MESH:D002244', (59, 60))	('c', 'Chemical', 'MESH:D002244', (147, 148))	('c', 'Chemical', 'MESH:D002244', (96, 97))	('SCAU-HN06', 'Disease', 'None', (194, 203))	('introduce', 'PosReg', (52, 61))	('insertion', 'Var', (25, 34))	('c', 'Chemical', 'MESH:D002244', (110, 111))	('hemangioma', 'Phenotype', 'HP:0001028', (174, 184))	('SCAU-HN06', 'Disease', (194, 203))	('hemangioma', 'Disease', (174, 184))	('hemangioma', 'Disease', 'MESH:D006391', (174, 184))	('c', 'Chemical', 'MESH:D002244', (85, 86))
214946	22185463	Deletion of most of the rTM Consistent with ML strains, most of the rTMs of the three isolates were deleted, as observed in other hemangioma strains such as SCAU-HN06 and JS09GY6 and the ML strain ADOL-7501.	('c', 'Chemical', 'MESH:D002244', (151, 152))	('hemangioma', 'Phenotype', 'HP:0001028', (130, 140))	('hemangioma', 'Disease', (130, 140))	('SCAU-HN06', 'Disease', 'None', (157, 166))	('hemangioma', 'Disease', 'MESH:D006391', (130, 140))	('SCAU-HN06', 'Disease', (157, 166))	('Deletion', 'Var', (0, 8))
214948	22185463	The deletion of the rTM is common in current ALV-J isolates, suggesting that this region might be dispensable for viral fitness.	('viral fitness', 'Disease', (114, 127))	('c', 'Chemical', 'MESH:D002244', (27, 28))	('rTM', 'Gene', (20, 23))	('deletion', 'Var', (4, 12))	('ALV-J', 'Species', '1401444', (45, 50))	('c', 'Chemical', 'MESH:D002244', (37, 38))	('viral fitness', 'Disease', 'MESH:D001102', (114, 127))
214953	22185463	For example, the E elements of JL093-1 and SD09DP03 had a 1-base deletion (between 7387 and 7389 according to the HPRS-103 sequence); this deletion was also present in JS09GY6, JS09GY3, JS09GY5 and SCAU-HN06.	('c', 'Chemical', 'MESH:D002244', (129, 130))	('SCAU-HN06', 'Disease', 'None', (198, 207))	('SD09DP03', 'Var', (43, 51))	('SCAU-HN06', 'Disease', (198, 207))	('c', 'Chemical', 'MESH:D002244', (98, 99))	('c', 'Chemical', 'MESH:D002244', (99, 100))
214954	22185463	The deletion introduced a specific distinct binding site for c-Ets-1 according motif analysis; this binding protein is associated with vascular endothelial cell differentiation.	('c', 'Chemical', 'MESH:D002244', (20, 21))	('c', 'Chemical', 'MESH:D002244', (123, 124))	('associated with', 'Reg', (119, 134))	('c', 'Chemical', 'MESH:D002244', (138, 139))	('c', 'Chemical', 'MESH:D002244', (41, 42))	('c', 'Chemical', 'MESH:D002244', (70, 71))	('c', 'Chemical', 'MESH:D002244', (61, 62))	('c', 'Chemical', 'MESH:D002244', (29, 30))	('deletion', 'Var', (4, 12))	('c', 'Chemical', 'MESH:D002244', (71, 72))	('binding', 'Interaction', (44, 51))	('c', 'Chemical', 'MESH:D002244', (33, 34))	('c', 'Chemical', 'MESH:D002244', (156, 157))	('vascular', 'CPA', (135, 143))
214956	22185463	For example, in the USA, the E element of ML strains have been reported to have substantial deletions in >50% of ALV-Js, and the E element has been completely deleted in earlier Chinese ML isolates such as YZ9902 and NX0101 and the recent strain JS-nt.	('c', 'Chemical', 'MESH:D002244', (234, 235))	('ALV-J', 'Species', '1401444', (113, 118))	('c', 'Chemical', 'MESH:D002244', (200, 201))	('c', 'Chemical', 'MESH:D002244', (148, 149))	('ALV-Js', 'Disease', (113, 119))	('deletions', 'Var', (92, 101))
214958	22185463	Although the three isolates were collected from different sick layers in three separate provinces of China, they all contained special sequences such as modifications of the LTRs and 5' UTRs that seem to be molecular markers of some hemangioma strains.	('c', 'Chemical', 'MESH:D002244', (38, 39))	('c', 'Chemical', 'MESH:D002244', (147, 148))	('c', 'Chemical', 'MESH:D002244', (117, 118))	('c', 'Chemical', 'MESH:D002244', (159, 160))	('c', 'Chemical', 'MESH:D002244', (141, 142))	('c', 'Chemical', 'MESH:D002244', (94, 95))	('modifications', 'Var', (153, 166))	('hemangioma', 'Phenotype', 'HP:0001028', (233, 243))	('hemangioma', 'Disease', (233, 243))	('c', 'Chemical', 'MESH:D002244', (211, 212))	('c', 'Chemical', 'MESH:D002244', (33, 34))	('c', 'Chemical', 'MESH:D002244', (130, 131))	('hemangioma', 'Disease', 'MESH:D006391', (233, 243))	('c', 'Chemical', 'MESH:D002244', (60, 61))
214979	22185463	Moreover, the insertion in the U3 introduced an E2BP binding site.	('c', 'Chemical', 'MESH:D002244', (41, 42))	('insertion', 'Var', (14, 23))	('E2BP', 'MPA', (48, 52))
214980	22185463	E2BP was first found in hepatitis B virus (HBV) and influences the liver specificity of HBV replication through the combination with an enhancer, EII.	('c', 'Chemical', 'MESH:D002244', (59, 60))	('hepatitis', 'Phenotype', 'HP:0012115', (24, 33))	('HBV', 'Species', '10407', (43, 46))	('hepatitis B virus', 'Species', '10407', (24, 41))	('replication', 'MPA', (92, 103))	('c', 'Chemical', 'MESH:D002244', (97, 98))	('combination', 'Interaction', (116, 127))	('influences', 'Reg', (52, 62))	('c', 'Chemical', 'MESH:D002244', (76, 77))	('c', 'Chemical', 'MESH:D002244', (141, 142))	('c', 'Chemical', 'MESH:D002244', (80, 81))	('liver specificity', 'MPA', (67, 84))	('c', 'Chemical', 'MESH:D002244', (116, 117))	('E2BP', 'Var', (0, 4))	('HBV', 'Gene', (88, 91))	('HBV', 'Species', '10407', (88, 91))
214981	22185463	The additional DNA binding site for E2BP introduced in the U3 may be related to viral tropism.	('DNA', 'MPA', (15, 18))	('viral tropism', 'Disease', (80, 93))	('E2BP', 'Var', (36, 40))	('c', 'Chemical', 'MESH:D002244', (48, 49))	('viral tropism', 'Disease', 'MESH:D001102', (80, 93))
214982	22185463	The insertion or deletion of transcription regulatory elements may severely impact the transcriptional activity of the LTR in hemangioma isolates, thereby affecting the replication or infection capability of this virus.	('c', 'Chemical', 'MESH:D002244', (159, 160))	('c', 'Chemical', 'MESH:D002244', (104, 105))	('c', 'Chemical', 'MESH:D002244', (80, 81))	('LTR', 'Protein', (119, 122))	('c', 'Chemical', 'MESH:D002244', (174, 175))	('hemangioma', 'Phenotype', 'HP:0001028', (126, 136))	('infection capability', 'CPA', (184, 204))	('affecting', 'Reg', (155, 164))	('impact', 'NegReg', (76, 82))	('c', 'Chemical', 'MESH:D002244', (92, 93))	('hemangioma', 'Disease', 'MESH:D006391', (126, 136))	('c', 'Chemical', 'MESH:D002244', (188, 189))	('insertion', 'Var', (4, 13))	('c', 'Chemical', 'MESH:D002244', (194, 195))	('c', 'Chemical', 'MESH:D002244', (34, 35))	('hemangioma', 'Disease', (126, 136))	('transcriptional activity', 'MPA', (87, 111))	('deletion', 'Var', (17, 25))	('replication', 'MPA', (169, 180))
214987	22185463	Early studies found that the rTM exists in the majority ALV-J trains in China; however, deletion of the rTM has been observed in a large number of ALV-J strains in recent years.	('deletion', 'Var', (88, 96))	('c', 'Chemical', 'MESH:D002244', (166, 167))	('ALV-J', 'Species', '1401444', (147, 152))	('ALV-J', 'Species', '1401444', (56, 61))	('rTM', 'Gene', (104, 107))
214993	22185463	For the hemangioma ALV-Js examined, a binding site for c-Ets-1, introduced in JL093-1 and SD09DP03 due to a 1-bp deletion, was associated with the development of hemangiomas.	('hemangioma', 'Phenotype', 'HP:0001028', (8, 18))	('associated with', 'Reg', (127, 142))	('hemangiomas', 'Disease', 'MESH:D006391', (162, 173))	('deletion', 'Var', (113, 121))	('binding', 'Interaction', (38, 45))	('hemangiomas', 'Disease', (162, 173))	('c', 'Chemical', 'MESH:D002244', (55, 56))	('hemangiomas', 'Phenotype', 'HP:0001028', (162, 173))	('c', 'Chemical', 'MESH:D002244', (131, 132))	('hemangioma ALV-Js', 'Disease', (8, 25))	('c-Ets-1', 'Gene', (55, 62))	('hemangioma', 'Phenotype', 'HP:0001028', (162, 172))	('hemangioma ALV-Js', 'Disease', 'MESH:D006391', (8, 25))	('c', 'Chemical', 'MESH:D002244', (71, 72))
214996	22185463	In conclusion, our study is the first to discovery the coexistence of two novel insertions in the U3 region in the LTR and the 5' UTR of ALV-J associated with hemangioma symptoms, and the transcriptional regulatory elements introduced should be taken into consideration in the occurrence of hemangioma.	('c', 'Chemical', 'MESH:D002244', (256, 257))	('c', 'Chemical', 'MESH:D002244', (278, 279))	('hemangioma', 'Disease', (291, 301))	('c', 'Chemical', 'MESH:D002244', (279, 280))	('hemangioma symptoms', 'Disease', (159, 178))	('hemangioma', 'Phenotype', 'HP:0001028', (159, 169))	('c', 'Chemical', 'MESH:D002244', (64, 65))	('c', 'Chemical', 'MESH:D002244', (6, 7))	('hemangioma', 'Disease', 'MESH:D006391', (159, 169))	('c', 'Chemical', 'MESH:D002244', (55, 56))	('c', 'Chemical', 'MESH:D002244', (285, 286))	('hemangioma symptoms', 'Disease', 'MESH:D006391', (159, 178))	('ALV-J', 'Gene', (137, 142))	('hemangioma', 'Phenotype', 'HP:0001028', (291, 301))	('associated with', 'Reg', (143, 158))	('ALV-J', 'Species', '1401444', (137, 142))	('hemangioma', 'Disease', 'MESH:D006391', (291, 301))	('insertions', 'Var', (80, 90))	('c', 'Chemical', 'MESH:D002244', (44, 45))	('hemangioma', 'Disease', (159, 169))	('c', 'Chemical', 'MESH:D002244', (3, 4))	('c', 'Chemical', 'MESH:D002244', (147, 148))	('c', 'Chemical', 'MESH:D002244', (231, 232))	('c', 'Chemical', 'MESH:D002244', (193, 194))
215255	27897234	Molecular studies has proven that TCDD is a potent a carcinogen which could disrupt multiple endocrine pathways via aryl-hydrocarbon receptors (AhR) widely present in animals and humans.	('AhR', 'Gene', (144, 147))	('AhR', 'Gene', '196', (144, 147))	('endocrine pathways', 'Pathway', (93, 111))	('aryl-hydrocarbon receptors', 'Gene', (116, 142))	('aryl-hydrocarbon receptors', 'Gene', '196', (116, 142))	('disrupt', 'NegReg', (76, 83))	('TCDD', 'Chemical', 'MESH:D000072317', (34, 38))	('TCDD', 'Var', (34, 38))	('humans', 'Species', '9606', (179, 185))
215326	27897234	Furthermore, TCDD may also up-regulate drug-metabolizing enzymes, thus increasing the presence of highly reactive intermediates that form during metabolic activation and/or transformation of several key hormones.	('increasing', 'PosReg', (71, 81))	('up-regulate', 'PosReg', (27, 38))	('TCDD', 'Chemical', 'MESH:D000072317', (13, 17))	('TCDD', 'Var', (13, 17))	('drug-metabolizing enzymes', 'Enzyme', (39, 64))	('presence of highly reactive intermediates', 'MPA', (86, 127))
215382	20414330	Knockdown of TLR3 prior to KSHV infection significantly reduced the activation of TLR3 and its downstream effectors (Figure 1).	('TLR3', 'Gene', '7098', (82, 86))	('TLR3', 'Gene', '7098', (13, 17))	('activation', 'MPA', (68, 78))	('KSHV infection', 'Disease', (27, 41))	('Knockdown', 'Var', (0, 9))	('reduced', 'NegReg', (56, 63))	('TLR3', 'Gene', (82, 86))	('TLR3', 'Gene', (13, 17))	('KSHV infection', 'Disease', 'MESH:C537372', (27, 41))
215394	20414330	In addition, a dominant negative IRF-7 mutant protein significantly inhibited latent primary effusion lymphoma cells from being able to reactivate and produce virus after TLR7/8 stimulation.	('reactivate', 'MPA', (136, 146))	('primary effusion lymphoma', 'Disease', (85, 110))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (85, 110))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (85, 110))	('produce', 'MPA', (151, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('TLR7', 'Gene', (171, 175))	('negative', 'NegReg', (24, 32))	('inhibited', 'NegReg', (68, 77))	('TLR7', 'Gene', '51284', (171, 175))	('mutant', 'Var', (39, 45))	('IRF-7', 'Gene', '3665', (33, 38))	('protein', 'Protein', (46, 53))	('IRF-7', 'Gene', (33, 38))
215395	20414330	It also represents a new role for TLR stimulation in the context of KSHV and suggests that KSHV takes advantage of a TLR-mediated 'death' signal to reproduce itself and leave a cell that is fated to die.	('KSHV', 'Var', (91, 95))	('leave', 'Reg', (169, 174))	('KSHV', 'Species', '37296', (91, 95))	('KSHV', 'Species', '37296', (68, 72))
215402	20414330	Opsonization leads to increased phagocytosis and humoral response to infection.	('infection', 'Disease', (69, 78))	('infection', 'Disease', 'MESH:D007239', (69, 78))	('phagocytosis', 'CPA', (32, 44))	('increased', 'PosReg', (22, 31))	('Opsonization', 'Var', (0, 12))
215407	20414330	KCP has been shown to inhibit the complement response in three ways: it enhances the decay of C3 convertase; it prevents depositing of C3b on the surface of sensitized cells, preventing opsonization; and KCP acts as a cofactor for factor I-mediated inactivation of C3b and C4b (Figure 2).	('C3b', 'Gene', '718', (265, 268))	('C3b', 'Gene', '718', (135, 138))	('C4b', 'Gene', (273, 276))	('inhibit', 'NegReg', (22, 29))	('complement', 'CPA', (34, 44))	('prevents', 'NegReg', (112, 120))	('depositing', 'MPA', (121, 131))	('C4b', 'Gene', '721', (273, 276))	('KCP', 'Var', (0, 3))	('preventing', 'NegReg', (175, 185))	('decay', 'MPA', (85, 90))	('opsonization', 'MPA', (186, 198))	('C3b', 'Gene', (265, 268))	('C3 convertase', 'Enzyme', (94, 107))	('enhances', 'PosReg', (72, 80))	('C3b', 'Gene', (135, 138))
215437	20414330	Activation of p53 often leads to apoptosis and tumor suppression.	('apoptosis', 'CPA', (33, 42))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('leads to', 'Reg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Activation', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
215454	20414330	In 2005, Pattingre demonstrated that KSHV vBcl-2 can inhibit the process of autophagy by binding to Beclin-1, a protein which promotes autophagy and inhibits tumorigenesis (Figure 2).	('binding', 'Interaction', (89, 96))	('tumor', 'Disease', (158, 163))	('inhibit', 'NegReg', (53, 60))	('promotes', 'PosReg', (126, 134))	('Beclin-1', 'Gene', (100, 108))	('inhibits', 'NegReg', (149, 157))	('autophagy', 'CPA', (135, 144))	('Beclin-1', 'Gene', '8678', (100, 108))	('process of autophagy', 'CPA', (65, 85))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('KSHV', 'Species', '37296', (37, 41))	('KSHV', 'Var', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
215484	20414330	Yet another mechanism has been reported by which KSHV downregulates the type I IFN response, in this case specifically the IFN-beta response.	('IFN-beta', 'Gene', '3456', (123, 131))	('downregulates', 'NegReg', (54, 67))	('IFN', 'Gene', '3439', (123, 126))	('KSHV', 'Var', (49, 53))	('KSHV', 'Species', '37296', (49, 53))	('IFN', 'Gene', '3439', (79, 82))	('IFN', 'Gene', (123, 126))	('IFN-beta', 'Gene', (123, 131))	('IFN', 'Gene', (79, 82))
215493	20414330	K3/K5 have also been shown to reduce surface expression of MHC class I chains, which allows KSHV to evade recognition by the host immune system, in this case specifically recognition by cytotoxic T lymphocytes, which typically recognize viral peptides presented on the surface of infected cells (Figure 2).	('MHC class', 'Gene', (59, 68))	('reduce', 'NegReg', (30, 36))	('surface expression', 'MPA', (37, 55))	('K3/K5', 'Var', (0, 5))	('KSHV', 'Species', '37296', (92, 96))
215533	20414330	Open reading frame 50 can induce IRF-7 degradation via ubiquitination.	('Open reading frame', 'Var', (0, 18))	('ubiquitination', 'MPA', (55, 69))	('IRF-7', 'Gene', '3665', (33, 38))	('induce', 'Reg', (26, 32))	('IRF-7', 'Gene', (33, 38))
215581	33468992	We evaluated their contribution to the maintenance of CD133(+) cancer stem-like cells (CSCs) and spheroid-forming cells in patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma, SK-LMS-1 leiomyosarcoma, and DDLS8817 dedifferentiated liposarcoma.	('human', 'Species', '9606', (161, 166))	('SK-LMS-1 leiomyosarcoma', 'Disease', 'MESH:C537878', (206, 229))	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('sarcoma', 'Disease', (197, 204))	('sarcoma', 'Disease', 'MESH:D012509', (222, 229))	('fibrosarcoma', 'Disease', 'MESH:D005354', (192, 204))	('sarcoma', 'Disease', (222, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('liposarcoma', 'Disease', 'MESH:D008080', (261, 272))	('fibrosarcoma', 'Disease', (192, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('sarcoma', 'Disease', 'MESH:D012509', (265, 272))	('SK-LMS-1 leiomyosarcoma', 'Disease', (206, 229))	('cancer', 'Disease', (63, 69))	('sarcoma', 'Disease', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('sarcoma', 'Disease', (265, 272))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (215, 229))	('liposarcoma', 'Disease', (261, 272))	('patient', 'Species', '9606', (123, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (192, 204))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('HT1080', 'CellLine', 'CVCL:0317', (185, 191))	('HT1080', 'Var', (185, 191))	('liposarcoma', 'Phenotype', 'HP:0012034', (261, 272))
215582	33468992	Levels of Nanog and activated Akt were significantly higher in sarcoma cells grown as spheroids or sorted for CD133 expression to enrich for CSCs.	('Akt', 'Gene', '207', (30, 33))	('higher', 'PosReg', (53, 59))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Akt', 'Gene', (30, 33))	('Nanog', 'Var', (10, 15))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
215583	33468992	shRNA knockdown of Nanog decreased spheroid formation 10- to 14-fold, and reversed resistance to both doxorubicin and radiation in vitro and in H1080 flank xenografts.	('spheroid formation', 'CPA', (35, 53))	('resistance to', 'MPA', (83, 96))	('decreased', 'NegReg', (25, 34))	('doxorubicin', 'Chemical', 'MESH:D004317', (102, 113))	('Nanog', 'Gene', (19, 24))	('knockdown', 'Var', (6, 15))	('reversed', 'NegReg', (74, 82))
215584	33468992	In the HT1080 xenograft model, doxorubicin and Nanog knockdown reduced tumor growth by 34% and 45%, respectively, and the combination reduced tumor growth by 74%.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('reduced', 'NegReg', (63, 70))	('tumor', 'Disease', (142, 147))	('knockdown', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('Nanog', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('HT1080', 'CellLine', 'CVCL:0317', (7, 13))	('reduced', 'NegReg', (134, 141))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
215586	33468992	Pharmacologic inhibition of Akt using LY294002 and Akt1/2 knockdown using shRNA in sarcoma CSCs decreased Nanog expression and spheroid formation and reversed chemotherapy resistance.	('Akt', 'Gene', (28, 31))	('LY294002', 'Var', (38, 46))	('Akt', 'Gene', (51, 54))	('sarcoma CSCs', 'Disease', 'MESH:D012509', (83, 95))	('decreased', 'NegReg', (96, 105))	('reversed', 'Reg', (150, 158))	('Nanog expression', 'CPA', (106, 122))	('sarcoma CSCs', 'Disease', (83, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('chemotherapy resistance', 'CPA', (159, 182))	('Akt', 'Gene', '207', (51, 54))	('Akt', 'Gene', '207', (28, 31))	('LY294002', 'Chemical', 'MESH:C085911', (38, 46))	('spheroid formation', 'CPA', (127, 145))
215602	33468992	In keeping with that conclusion, we previously showed that inhibition of PI3K significantly reduced expression of the CSC marker CD44 and the mesenchymal transdifferentiation controller Slug in gastric CSCs.	('CD44', 'Gene', '960', (129, 133))	('gastric CSCs', 'Disease', (194, 206))	('CD44', 'Gene', (129, 133))	('expression', 'MPA', (100, 110))	('gastric CSCs', 'Disease', 'MESH:D013274', (194, 206))	('Slug', 'Gene', (186, 190))	('inhibition', 'Var', (59, 69))	('reduced', 'NegReg', (92, 99))	('Slug', 'Gene', '6591', (186, 190))	('PI3K', 'Gene', (73, 77))
215610	33468992	We finally confirmed the association of CD133 and Nanog gene mutations and copy number alterations in sarcomas with patient survival data in four publicly available databases (http://cancergenome.nih.gov).	('sarcomas', 'Disease', (102, 110))	('cancer', 'Disease', (183, 189))	('patient', 'Species', '9606', (116, 123))	('association', 'Interaction', (25, 36))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('CD133', 'Gene', (40, 45))	('sarcomas', 'Disease', 'MESH:D012509', (102, 110))	('Nanog gene', 'Gene', (50, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('copy number alterations', 'Var', (75, 98))
215611	33468992	Patients whose sarcomas had gene mutation or gene amplification of both CD133 and Nanog had significantly worse disease-free survival compared to patients whose sarcomas did not have gene mutation or gene amplification of CD133 and Nanog (Fig.	('worse', 'NegReg', (106, 111))	('CD133', 'Gene', (72, 77))	('sarcomas', 'Disease', (15, 23))	('disease-free survival', 'CPA', (112, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcomas', 'Disease', (161, 169))	('gene amplification', 'Var', (45, 63))	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('Patients', 'Species', '9606', (0, 8))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('Nanog', 'Gene', (82, 87))	('gene mutation', 'Var', (28, 41))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('patients', 'Species', '9606', (146, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))
215630	33468992	Nanog shRNA and doxorubicin reduced tumor growth by 45% and 35%, respectively, while the combination of Nanog shRNA and doxorubicin inhibited tumor growth by 84% (Fig.	('inhibited', 'NegReg', (132, 141))	('doxorubicin', 'Chemical', 'MESH:D004317', (16, 27))	('reduced', 'NegReg', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('doxorubicin', 'Chemical', 'MESH:D004317', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Nanog', 'Var', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', (36, 41))
215631	33468992	The combination of Nanog shRNA and doxorubicin reduced proliferation as measured by Ki76 immunofluorescence in tumors after 14 days of treatment by only 28.4% compared to control tumors (Fig.	('Nanog', 'Var', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (179, 185))	('proliferation', 'CPA', (55, 68))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))	('reduced', 'NegReg', (47, 54))
215632	33468992	In contrast, this combination reduced expression of CD133 and Nanog by >90% compared with controls and increased apoptosis by 17.5-fold as measured by cleaved caspase-3 expression, corresponding to 90% reduced expression of the anti-apoptotic protein Bcl-2(+) cells.	('Bcl-2', 'Gene', (251, 256))	('reduced', 'NegReg', (202, 209))	('Bcl-2', 'Gene', '596', (251, 256))	('caspase-3', 'Gene', (159, 168))	('increased', 'PosReg', (103, 112))	('apoptosis', 'CPA', (113, 122))	('expression', 'MPA', (38, 48))	('CD133', 'Protein', (52, 57))	('expression', 'MPA', (210, 220))	('caspase-3', 'Gene', '836', (159, 168))	('reduced', 'NegReg', (30, 37))	('expression', 'MPA', (169, 179))	('cleaved', 'MPA', (151, 158))	('Nanog', 'Var', (62, 67))
215636	33468992	We confirmed that the PI3K/Akt pathway is highly activated in sarcoma spheroid-forming cells by western blot for phosphorylated Akt (T308 or S473) and total Akt1/2; phosphorylation was higher in sarcoma cells grown as spheroids compared with monolayers (Suppl.	('Akt', 'Gene', (157, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcoma spheroid', 'Disease', 'MESH:D012509', (62, 78))	('Akt', 'Gene', '207', (157, 160))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('Akt', 'Gene', (27, 30))	('sarcoma', 'Disease', (195, 202))	('Akt', 'Gene', '207', (27, 30))	('phosphorylation', 'MPA', (165, 180))	('activated', 'PosReg', (49, 58))	('S473', 'Var', (141, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('Akt', 'Gene', (128, 131))	('T308', 'Var', (133, 137))	('Akt', 'Gene', '207', (128, 131))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('higher', 'PosReg', (185, 191))	('sarcoma spheroid', 'Disease', (62, 78))	('sarcoma', 'Disease', (62, 69))
215637	33468992	Akt shRNA knockdown or pharmacologic inhibition using LY294002 dramatically reduced levels of CD133 and Nanog but had no effect on levels of other stemness factors such as Sox2, Oct4, and c-Myc (Fig.	('Nanog', 'MPA', (104, 109))	('c-Myc', 'Gene', (188, 193))	('CD133', 'MPA', (94, 99))	('LY294002', 'Chemical', 'MESH:C085911', (54, 62))	('Sox2', 'Gene', (172, 176))	('Oct4', 'Gene', (178, 182))	('c-Myc', 'Gene', '4609', (188, 193))	('Akt', 'Gene', '207', (0, 3))	('reduced', 'NegReg', (76, 83))	('LY294002', 'Var', (54, 62))	('Oct4', 'Gene', '5460', (178, 182))	('Akt', 'Gene', (0, 3))	('Sox2', 'Gene', '6657', (172, 176))
215638	33468992	Furthermore, following separation of spheroids into CD133+ and CD133- cells, PI3K inhibition with LY294002 reduced the expression of CD133 and Nanog in CD133+ cells from all sarcoma lines (Suppl.	('expression', 'MPA', (119, 129))	('LY294002', 'Chemical', 'MESH:C085911', (98, 106))	('reduced', 'NegReg', (107, 114))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('PI3K', 'Enzyme', (77, 81))	('Nanog', 'Var', (143, 148))	('sarcoma', 'Disease', (174, 181))	('CD133', 'Protein', (133, 138))	('LY294002', 'Var', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))
215639	33468992	Inhibition of the PI3K/Akt signaling pathway with LY294002 or Akt1/2 shRNA in CD133+ cells reduced spheroid formation under standard conditions (Fig.	('LY294002', 'Chemical', 'MESH:C085911', (50, 58))	('Akt', 'Gene', '207', (23, 26))	('Akt', 'Gene', '207', (62, 65))	('Akt', 'Gene', (23, 26))	('spheroid formation', 'CPA', (99, 117))	('LY294002', 'Var', (50, 58))	('reduced', 'NegReg', (91, 98))	('Akt', 'Gene', (62, 65))
215641	33468992	The PI3K inhibitor LY294002 inhibited growth by 31-35%, doxorubicin by 11-16%, and the combination by 77-84% (Suppl.	('LY294002', 'Chemical', 'MESH:C085911', (19, 27))	('doxorubicin', 'MPA', (56, 67))	('growth', 'MPA', (38, 44))	('inhibited', 'NegReg', (28, 37))	('LY294002', 'Var', (19, 27))	('doxorubicin', 'Chemical', 'MESH:D004317', (56, 67))
215642	33468992	LY294002 combined with doxorubicin led to significant induction of apoptosis, as measured by western blotting for cleaved caspase-3 and Bcl-2, in HT1080 spheroid cells (Suppl.	('LY294002', 'Var', (0, 8))	('HT1080', 'CellLine', 'CVCL:0317', (146, 152))	('caspase-3', 'Gene', '836', (122, 131))	('apoptosis', 'CPA', (67, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (23, 34))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('caspase-3', 'Gene', (122, 131))	('Bcl-2', 'Gene', (136, 141))	('Bcl-2', 'Gene', '596', (136, 141))
215644	33468992	Similar to results with doxorubicin, sh.Akt1/2 combined with radiation led to significant induction of apoptosis in HT1080 spheroid cells (Suppl.	('HT1080', 'CellLine', 'CVCL:0317', (116, 122))	('sh.Akt1/2', 'Var', (37, 46))	('doxorubicin', 'Chemical', 'MESH:D004317', (24, 35))	('apoptosis', 'CPA', (103, 112))
215646	33468992	To evaluate the efficacy of combining Akt1/2 inhibition with doxorubicin, we xenografted HT1080 cells stably transduced with Akt1/2 shRNA or control shRNA into the flanks of immunodeficient mice following confirmation of stable knockdown (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (61, 72))	('immunodeficient', 'Disease', 'MESH:D007153', (174, 189))	('immunodeficient', 'Disease', (174, 189))	('HT1080', 'CellLine', 'CVCL:0317', (89, 95))	('Akt1/2', 'Var', (125, 131))	('mice', 'Species', '10090', (190, 194))
215650	33468992	The combination of Akt1/2 shRNA and doxorubicin resulted in a 13-fold increase in the apoptosis marker cleaved caspase-3 compared with control, and >=90% decreases in expression of the CSC markers CD133 and Nanog and in the anti-apoptosis marker Bcl-2 as measured by immunofluorescence (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (36, 47))	('caspase-3', 'Gene', (111, 120))	('increase', 'PosReg', (70, 78))	('anti-apoptosis', 'MPA', (224, 238))	('caspase-3', 'Gene', '836', (111, 120))	('doxorubicin', 'Var', (36, 47))	('Bcl-2', 'Gene', (246, 251))	('Bcl-2', 'Gene', '596', (246, 251))	('Akt1/2 shRNA', 'Var', (19, 31))	('CD133', 'Protein', (197, 202))	('expression', 'MPA', (167, 177))	('decreases', 'NegReg', (154, 163))
215652	33468992	Levels of CD133, Nanog, and phospho-Akt were 1.8-6.8-fold higher in tumor tissue compared with normal tissue (Fig.	('tumor', 'Disease', (68, 73))	('Akt', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Nanog', 'Var', (17, 22))	('higher', 'PosReg', (58, 64))	('CD133', 'Var', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Akt', 'Gene', '207', (36, 39))
215655	33468992	In the HT1080 flank xenograft model, inhibition of Nanog synergized with doxorubicin to reduce tumor growth, and histologic examination of treated tumors found dramatic increases in tumor cell apoptosis and depletion of CD133+ cells.	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('HT1080', 'CellLine', 'CVCL:0317', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('doxorubicin', 'Chemical', 'MESH:D004317', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', (147, 152))	('increases', 'PosReg', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('depletion of CD133+ cells', 'MPA', (207, 232))	('reduce', 'NegReg', (88, 94))	('tumor', 'Disease', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('inhibition', 'Var', (37, 47))	('tumor', 'Disease', (182, 187))	('tumors', 'Disease', (147, 153))	('Nanog', 'Gene', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
215656	33468992	Moreover, pharmacologic inhibition or knockdown of Akt in sarcoma CSCs reduced expression of Nanog, reduced spheroid formation, and reversed therapy resistance.	('Akt', 'Gene', (51, 54))	('sarcoma CSCs', 'Disease', (58, 70))	('therapy resistance', 'CPA', (141, 159))	('expression', 'MPA', (79, 89))	('spheroid formation', 'CPA', (108, 126))	('reduced', 'NegReg', (100, 107))	('sarcoma CSCs', 'Disease', 'MESH:D012509', (58, 70))	('reduced', 'NegReg', (71, 78))	('Akt', 'Gene', '207', (51, 54))	('knockdown', 'Var', (38, 47))	('reversed', 'Reg', (132, 140))	('Nanog', 'Protein', (93, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
215663	33468992	Our results implicate Nanog in the resistance of sarcoma CSCs to chemotherapy and radiation; we found that Nanog in spheroid-forming cells reduced chemo- and radiotherapy resistance, increased apoptosis, and attenuated the tumor growth of flank xenografts.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('sarcoma CSCs', 'Disease', (49, 61))	('tumor', 'Disease', (223, 228))	('apoptosis', 'CPA', (193, 202))	('sarcoma CSCs', 'Disease', 'MESH:D012509', (49, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('increased', 'PosReg', (183, 192))	('attenuated', 'NegReg', (208, 218))	('reduced', 'NegReg', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('Nanog', 'Var', (107, 112))
215665	33468992	Our phospho-kinase array analysis revealed that Akt1/2 is more highly activated in CD133(+) vs. CD133(-) sarcoma cells and spheroid vs. monolayer sarcoma cells.	('CD133(+', 'Var', (83, 90))	('activated', 'PosReg', (70, 79))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('Akt1/2', 'Pathway', (48, 54))	('sarcoma', 'Disease', (146, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('sarcoma', 'Disease', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
215680	33468992	Cells were resuspended in spheroid media, comprised of DMEM/F12 containing epidermal growth factor (EGF, E9644; Sigma-Aldrich, St. Louis, MO), basic fibroblast growth factor (bFGF, 341583; Sigma-Aldrich), N-2 supplement (A13707-01; Thermo Fisher Scientific, Waltham, MA), and B27 (0080085SA; Sigma-Aldrich), and then plated on Ultra-Low Attachment culture dishes (Corning Life Sciences, Tewksbury, MA).	('basic fibroblast growth factor', 'Gene', '2247', (143, 173))	('bFGF', 'Gene', '2247', (175, 179))	('DMEM', 'Chemical', '-', (55, 59))	('bFGF', 'Gene', (175, 179))	('F12', 'Chemical', 'MESH:C007782', (60, 63))	('B27', 'Gene', (276, 279))	('B27', 'Gene', '56246', (276, 279))	('basic fibroblast growth factor', 'Gene', (143, 173))	('EGF', 'Gene', (100, 103))	('epidermal growth factor', 'Gene', (75, 98))	('A13707-01;', 'Var', (221, 231))	('epidermal growth factor', 'Gene', '1950', (75, 98))	('EGF', 'Gene', '1950', (100, 103))
215689	33468992	Nanog and Akt1/2 expression was silenced via lentiviral transduction of human Nanog shRNA (sc-43958-V; Santa Cruz) and human Akt1/2 shRNA (sc-43609-V; Santa Cruz) per the manufacturer's protocol.	('Akt1/2', 'Gene', (10, 16))	('silenced', 'NegReg', (32, 40))	('sc-43609-V', 'Var', (139, 149))	('expression', 'MPA', (17, 27))	('human', 'Species', '9606', (72, 77))	('Nanog', 'Gene', (0, 5))	('human', 'Species', '9606', (119, 124))
215697	33468992	Following cell fixation, cells were incubated with antibodies recognizing CD133 (MBS462020; MyBioSource), Nanog (#4893; Cell Signaling), and gamma-H2AX (05-636; Millipore) in a solution of PBS with 1% FBS and 0.1% Triton X-100 at 4  C overnight.	('gamma-H2AX', 'Var', (141, 151))	('PBS', 'Gene', (189, 192))	('PBS', 'Gene', '1131', (189, 192))	('CD133', 'Gene', (74, 79))	('Triton X-100', 'Chemical', 'MESH:D017830', (214, 226))
215699	33468992	To generate subcutaneous flank tumors, 2 x 106 HT1080 cells (following shRNA knockdown of Nanog or Akt1/2 where indicated) were resuspended in 100 muL of Hank's balanced salt solution (HBSS) and injected subcutaneously into the right flank of athymic 6-8-week-old male BALB/c nu/nu mice (Taconic, Hudson, NY) following isoflurane anesthesia.	('HBSS', 'Chemical', '-', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('HT1080', 'CellLine', 'CVCL:0317', (47, 53))	('mice', 'Species', '10090', (282, 286))	('Akt1/2', 'Gene', (99, 105))	('knockdown', 'Var', (77, 86))	('isoflurane', 'Chemical', 'MESH:D007530', (319, 329))	("Hank's balanced salt solution", 'Chemical', '-', (154, 183))	('flank tumors', 'Disease', (25, 37))	('flank tumors', 'Disease', 'MESH:D021501', (25, 37))
215703	33468992	Paraffin-embedded sections were deparaffinized, and then incubated with one or more of the following primary antibodies recognizing Sox2 (ab93689), Oct4 (ab18976), Nanog (ab80892), c-Myc (ab125275; Abcam), Ki67 (ab15580) (all from Abcam), cleaved caspase-3 (#9661; Cell Signaling), Bcl-2 (Santa Cruz, sc-65392), or CD133 (MBS462020; MyBioSource) in a solution of PBS with 1% FBS and 0.1% Triton X-100 at 4  C overnight.	('Bcl-2', 'Gene', (282, 287))	('Sox2', 'Gene', '6657', (132, 136))	('Bcl-2', 'Gene', '596', (282, 287))	('paraffin', 'Chemical', 'MESH:D010232', (34, 42))	('caspase-3', 'Gene', '836', (247, 256))	('MBS462020', 'Var', (322, 331))	('Triton X-100', 'Chemical', 'MESH:D017830', (388, 400))	('Sox2', 'Gene', (132, 136))	('Oct4', 'Gene', (148, 152))	('PBS', 'Gene', (363, 366))	('cleaved', 'Var', (239, 246))	('c-Myc', 'Gene', '4609', (181, 186))	('Oct4', 'Gene', '5460', (148, 152))	('caspase-3', 'Gene', (247, 256))	('PBS', 'Gene', '1131', (363, 366))	('ab15580', 'Var', (212, 219))	('c-Myc', 'Gene', (181, 186))
215707	33468992	Staining was visualized using secondary antibodies tagged with Alexa Fluor 488 (A32766, A10042) and Alexa Fluor 594 (A32744, A32754), from Thermo Fisher, with nuclear counterstaining using DAPI.	('A32754', 'Var', (125, 131))	('Alexa Fluor 488', 'Chemical', '-', (63, 78))	('A32766', 'Var', (80, 86))	('DAPI', 'Chemical', 'MESH:C007293', (189, 193))	('A10042', 'Var', (88, 94))	('A32744', 'Var', (117, 123))	('Alexa Fluor 594', 'Chemical', '-', (100, 115))
215832	23819111	The term "CSC" has been interpreted to imply that the CSC may originate from normal tissue stem cells that acquire genetic and epigenetic changes conferring a malignant, tumorigenic phenotype (Nowell,; Clarke et al.,; Baylin and Jones,).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('epigenetic changes', 'Var', (127, 145))	('tumor', 'Disease', (170, 175))	('malignant', 'CPA', (159, 168))
215833	23819111	The cells that comprise a given tumor may then undergo a process of clonal evolution that gives rise to different subpopulations of cells with variable biologic properties as a result of selection pressure influenced by the genetic and epigenetic changes acquired by the parental CSC.	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('epigenetic changes', 'Var', (236, 254))
215842	23819111	Subsequent work by numerous investigators have identified several other candidate CSC cell surface markers (e.g., CD34, CD44, CD90, CD117, CD133, CD20) in a variety of different solid tumors including brain, breast, prostate, melanoma, colon, lung, liver, and sarcomas (Al-Hajj et al.,; Singh et al.,; Collins et al.,; Fang et al.,; Eramo et al.,; Tirino et al.,).	('colon', 'Disease', (236, 241))	('CD133', 'Var', (139, 144))	('brain', 'Disease', (201, 206))	('CD117', 'Var', (132, 137))	('CD20', 'Gene', (146, 150))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('CD90', 'Gene', '7070', (126, 130))	('CD34', 'Gene', (114, 118))	('solid tumors', 'Disease', (178, 190))	('CD44', 'Gene', '960', (120, 124))	('CD20', 'Gene', '54474', (146, 150))	('CD44', 'Gene', (120, 124))	('sarcomas', 'Disease', 'MESH:D012509', (260, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('sarcomas', 'Phenotype', 'HP:0100242', (260, 268))	('liver', 'Disease', (249, 254))	('sarcomas', 'Disease', (260, 268))	('solid tumors', 'Disease', 'MESH:D009369', (178, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('breast', 'Disease', (208, 214))	('lung', 'Disease', (243, 247))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('CD34', 'Gene', '947', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('colon', 'Disease', 'MESH:D015179', (236, 241))	('prostate', 'Disease', (216, 224))	('CD90', 'Gene', (126, 130))
215848	23819111	Prospective validation of CD133 positivity as a marker for sarcoma CSCs in other sarcoma subtypes would need to be performed in the future and perhaps be combined with other assays for the identification and isolation of putative sarcoma CSCs.	('sarcoma CSCs', 'Disease', 'MESH:D012509', (59, 71))	('sarcoma', 'Disease', (59, 66))	('sarcoma CSCs', 'Disease', (230, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcoma CSCs', 'Disease', (59, 71))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('sarcoma', 'Disease', 'MESH:D012509', (230, 237))	('CD133', 'Gene', (26, 31))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('positivity', 'Var', (32, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('sarcoma CSCs', 'Disease', 'MESH:D012509', (230, 242))	('sarcoma', 'Disease', (230, 237))
215887	23819111	Examination of osteosarcoma cell lines identified a subpopulation of CD133+ cells which exhibited self-renewal properties, higher proliferative rates, spherical colony formation, and expression of the stem cell-associated gene OCT3/4.	('OCT3/4', 'Gene', '5460', (227, 233))	('osteosarcoma cell lines', 'Disease', 'MESH:D012516', (15, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('colon', 'Disease', (161, 166))	('self-renewal properties', 'CPA', (98, 121))	('higher', 'PosReg', (123, 129))	('OCT3/4', 'Gene', (227, 233))	('colon', 'Disease', 'MESH:D015179', (161, 166))	('CD133+', 'Var', (69, 75))	('osteosarcoma cell lines', 'Disease', (15, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (15, 27))
215893	23819111	Adhikari and colleagues examined the expression of two mesenchymal stem cell markers, CD117 and Stro-1, and discovered that mouse and human osteosarcoma cell lines positive for both CD117 and Stro-1 (DP or double positive cells) readily formed spherical colonies, more readily formed tumors in a nude mouse model in comparison to cells negative for both CD117 and Stro-1 (DN or double negative cells), had higher metastatic potential in an orthotopic NOD/SCID mouse model, exhibited increased chemoresistance when exposed to the chemotherapy agent doxorubicin, retained multipotent differentiation ability, and able to reconstitute DP and DN populations upon serial transplantation (Adhikari et al.,).	('Stro-1', 'Var', (192, 198))	('higher', 'PosReg', (406, 412))	('mouse', 'Species', '10090', (301, 306))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('SCID', 'Disease', 'MESH:D053632', (455, 459))	('DP', 'Chemical', '-', (632, 634))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('colon', 'Disease', 'MESH:D015179', (254, 259))	('osteosarcoma cell lines', 'Disease', (140, 163))	('SCID', 'Disease', (455, 459))	('tumors', 'Disease', (284, 290))	('human', 'Species', '9606', (134, 139))	('metastatic potential', 'CPA', (413, 433))	('colon', 'Disease', (254, 259))	('osteosarcoma cell lines', 'Disease', 'MESH:D012516', (140, 163))	('mouse', 'Species', '10090', (124, 129))	('DP', 'Chemical', '-', (200, 202))	('osteosarcoma', 'Phenotype', 'HP:0002669', (140, 152))	('CD117', 'Var', (182, 187))	('tumors', 'Disease', 'MESH:D009369', (284, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('chemoresistance', 'CPA', (493, 508))	('mouse', 'Species', '10090', (460, 465))
215899	23819111	Interestingly, it has been recently shown that blockade of developmentally important signaling pathways, specifically hedgehog and Notch, in the MFH SP fraction abrogated its proliferative and tumorigenic capacities potentially implicating these pathways in the process of stem cell renewal and presenting a rationale for future therapeutic targeting (Wang et al.,).	('blockade', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('SP', 'Chemical', '-', (149, 151))	('Notch', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('hedgehog', 'Gene', (118, 126))	('tumor', 'Disease', (193, 198))	('abrogated', 'NegReg', (161, 170))
215926	23819111	They showed that CD133+ cells were capable of initiating and forming tumors in NOD/SCID mice and were capable of recapitulating the parental tumor phenotype upon serial transplantation in NOD/SCID mice.	('initiating', 'PosReg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('CD133+', 'Var', (17, 23))	('SCID', 'Disease', 'MESH:D053632', (192, 196))	('SCID', 'Disease', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('parental tumor', 'Disease', (132, 146))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('parental tumor', 'Disease', 'MESH:D063129', (132, 146))	('SCID', 'Disease', (83, 87))	('SCID', 'Disease', 'MESH:D053632', (83, 87))	('mice', 'Species', '10090', (88, 92))	('mice', 'Species', '10090', (197, 201))
215931	23819111	With the exception of one cell line, STA-ET-8.2, no differences in chemoresistance or tumorigenic potential was observed between CD133+ and CD133- subpopulations.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('chemoresistance', 'CPA', (67, 82))	('CD133+', 'Var', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
215945	23819111	Interestingly, a selective inhibitor of EWS/FLI-1 (YK-4-279) was effective in inhibiting the growth and tumorigenic capacity of both ALDHHigh and ALDHLow cells indicating the dependence of the ALDHHigh population on EWS/FLI-1 oncogene expression (Awad et al.,).	('ALDH', 'Gene', '216', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ALDH', 'Gene', (133, 137))	('inhibiting', 'NegReg', (78, 88))	('inhibitor', 'Var', (27, 36))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('ALDH', 'Gene', '216', (133, 137))	('ALDH', 'Gene', '216', (146, 150))	('EWS/FLI-1', 'Gene', (40, 49))	('ALDH', 'Gene', (146, 150))	('ALDH', 'Gene', (193, 197))
215949	23819111	Similar to Ewing sarcoma, ~20-30% of RMS cases involve the presence characteristic chromosomal translocations resulting in the production of an aberrant fusion oncogene.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('aberrant', 'Var', (144, 152))	('production', 'MPA', (127, 137))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (11, 24))	('Ewing sarcoma', 'Disease', (11, 24))	('RMS', 'Disease', (37, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (11, 24))	('chromosomal translocations', 'Var', (83, 109))	('RMS', 'Phenotype', 'HP:0002859', (37, 40))
215955	23819111	The CD133+ cells, in contrast to CD133- and unsorted cells, were able to generate tumors in NOD/SCID mice at lower cell densities and were more resistant to treatment with the chemotherapy drugs cisplatin and chlorambucil.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('CD133+', 'Var', (4, 10))	('mice', 'Species', '10090', (101, 105))	('SCID', 'Disease', 'MESH:D053632', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SCID', 'Disease', (96, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('chlorambucil', 'Chemical', 'MESH:D002699', (209, 221))
215956	23819111	Furthermore, analysis of CD133+ expression in patient-derived tissue samples revealed that high CD133+ expression correlated with inferior survival compared to low or intermediate expression levels in patients with the embryonal RMS variant.	('patient', 'Species', '9606', (46, 53))	('patients', 'Species', '9606', (201, 209))	('high', 'Var', (91, 95))	('inferior', 'NegReg', (130, 138))	('survival', 'MPA', (139, 147))	('CD133+ expression', 'MPA', (96, 113))	('RMS', 'Phenotype', 'HP:0002859', (229, 232))	('patient', 'Species', '9606', (201, 208))
215961	23819111	Cells doubly positive for CD133 and ALDHHigh were more clonogenic and tumorigenic when compared to parental cells or cells singly positive for either CD133 or ALDHHigh.	('ALDH', 'Gene', (36, 40))	('ALDH', 'Gene', (159, 163))	('clonogenic', 'CPA', (55, 65))	('ALDH', 'Gene', '216', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CD133', 'Var', (26, 31))	('ALDH', 'Gene', '216', (36, 40))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('more', 'PosReg', (50, 54))
215978	33327223	The most common mutation associated with both systemic mastocytosis and myeloid sarcoma is mutation in Kit.	('mutation', 'Var', (91, 99))	('Kit', 'Gene', (103, 106))	('associated', 'Reg', (25, 35))	('systemic mastocytosis and myeloid sarcoma', 'Disease', 'MESH:D034721', (46, 87))	('Kit', 'Gene', '3815', (103, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('mastocytosis', 'Phenotype', 'HP:0100495', (55, 67))
215979	33327223	Here, we identified the novel KIT D816V and ARID1A G1254S mutations co-occurring in systemic mastocytosis with myeloid sarcoma.	('co-occurring', 'Reg', (68, 80))	('ARID1A', 'Gene', '8289', (44, 50))	('G1254S', 'Mutation', 'rs139907456', (51, 57))	('mastocytosis', 'Phenotype', 'HP:0100495', (93, 105))	('ARID1A', 'Gene', (44, 50))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (84, 105))	('systemic mastocytosis', 'Disease', (84, 105))	('D816V', 'Mutation', 'rs121913507', (34, 39))	('KIT', 'Gene', '3815', (30, 33))	('KIT', 'Gene', (30, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (111, 126))	('G1254S', 'Var', (51, 57))	('myeloid sarcoma', 'Disease', (111, 126))
215983	33327223	Codon 816 KIT mutation D816V and codon 1245 ARID1A mutation G1254S were found in peripheral blood.	('ARID1A', 'Gene', '8289', (44, 50))	('ARID1A', 'Gene', (44, 50))	('G1254S', 'Var', (60, 66))	('KIT', 'Gene', '3815', (10, 13))	('G1254S', 'Mutation', 'rs139907456', (60, 66))	('D816V', 'Var', (23, 28))	('D816V', 'Mutation', 'rs121913507', (23, 28))	('KIT', 'Gene', (10, 13))
215991	33327223	Mutations of Kit and Arid1a emphasis the importance to notice possibility of various tumors occurring in patients with multiple mutations.	('patients', 'Species', '9606', (105, 113))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('Mutations', 'Var', (0, 9))	('Arid1a', 'Gene', '8289', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('Kit', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Arid1a', 'Gene', (21, 27))	('Kit', 'Gene', '3815', (13, 16))	('tumors', 'Disease', (85, 91))
215996	33327223	According to 2008 World Health Organization diagnosis criteria, to diagnose SM requires either the major criteria of multifocal dense infiltrations of mast cells in extracutaneous organs (more than 15 mast cells aggregating) with 1 of 4 minor criteria (more than 25% mast cells in extracutaneous organs show an abnormal morphology; codon 816 KIT mutation D816V detected in extracutaneous organs; mast cells in bone marrow express CD2, CD25 or both; more than 20 ng/mL serum tryptase) or 3 minor criteria.	('CD2', 'Gene', '914', (430, 433))	('CD2', 'Gene', (430, 433))	('CD25', 'Gene', (435, 439))	('KIT', 'Gene', '3815', (342, 345))	('D816V', 'Var', (355, 360))	('D816V', 'Mutation', 'rs121913507', (355, 360))	('KIT', 'Gene', (342, 345))	('CD25', 'Gene', '3559', (435, 439))	('CD2', 'Gene', (435, 438))	('CD2', 'Gene', '914', (435, 438))
216004	33327223	Multiple mutations have been reported to be linked with myeloid sarcoma.	('mutations', 'Var', (9, 18))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (56, 71))	('linked', 'Reg', (44, 50))	('myeloid sarcoma', 'Disease', (56, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
216006	33327223	Other mutations in Kit, Idh2, and Braf genes were also identified in myeloid sarcoma.	('Idh2', 'Gene', (24, 28))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (69, 84))	('identified', 'Reg', (55, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('Kit', 'Gene', (19, 22))	('Idh2', 'Gene', '3418', (24, 28))	('Kit', 'Gene', '3815', (19, 22))	('myeloid sarcoma', 'Disease', (69, 84))	('Braf', 'Gene', (34, 38))	('mutations', 'Var', (6, 15))	('Braf', 'Gene', '673', (34, 38))
216007	33327223	Herein we reported a case of SM co-occurring with myeloid myeloma whose genetic profiles showed a cooccurrence of KIT D816V and ARID1A G1254S mutations.	('myeloid myeloma', 'Disease', 'MESH:D009101', (50, 65))	('G1254S', 'Var', (135, 141))	('KIT', 'Gene', (114, 117))	('G1254S', 'Mutation', 'rs139907456', (135, 141))	('D816V', 'Mutation', 'rs121913507', (118, 123))	('ARID1A', 'Gene', '8289', (128, 134))	('ARID1A', 'Gene', (128, 134))	('myeloid myeloma', 'Disease', (50, 65))	('KIT', 'Gene', '3815', (114, 117))
216015	33327223	Mutation screening tests from peripheral blood revealed codon 816 KIT mutation D816V and codon 1245 ARID1A mutation G1254S.	('KIT', 'Gene', (66, 69))	('D816V', 'Var', (79, 84))	('G1254S', 'Var', (116, 122))	('D816V', 'Mutation', 'rs121913507', (79, 84))	('ARID1A', 'Gene', '8289', (100, 106))	('ARID1A', 'Gene', (100, 106))	('G1254S', 'Mutation', 'rs139907456', (116, 122))	('KIT', 'Gene', '3815', (66, 69))
216043	33327223	Biopsy in multiple sites and codon 816 KIT mutation D816V confirmed the diagnosis of SM-AHNMD.	('SM-AHNMD', 'Disease', (85, 93))	('D816V', 'Var', (52, 57))	('KIT', 'Gene', '3815', (39, 42))	('D816V', 'Mutation', 'rs121913507', (52, 57))	('KIT', 'Gene', (39, 42))
216046	33327223	In this case, the patient carried heterozygous Kit mutation which was known to be related to mastocytosis.	('mastocytosis', 'Phenotype', 'HP:0100495', (93, 105))	('related', 'Reg', (82, 89))	('mutation', 'Var', (51, 59))	('mastocytosis', 'Disease', (93, 105))	('mastocytosis', 'Disease', 'MESH:D008415', (93, 105))	('patient', 'Species', '9606', (18, 25))	('Kit', 'Gene', (47, 50))	('Kit', 'Gene', '3815', (47, 50))
216048	33327223	Researches have shown KIT D816V mutation, which was identified in more than 80% of patients with SM, induced autophosphorylation of KIT receptor.	('KIT', 'Gene', '3815', (132, 135))	('D816V mutation', 'Var', (26, 40))	('KIT', 'Gene', '3815', (22, 25))	('autophosphorylation', 'MPA', (109, 128))	('KIT', 'Gene', (132, 135))	('D816V', 'Mutation', 'rs121913507', (26, 31))	('KIT', 'Gene', (22, 25))	('patients', 'Species', '9606', (83, 91))	('induced', 'Reg', (101, 108))
216049	33327223	In addition, the mutation of AT-rich interaction domain 1A (Arid1a) was found in the patient.	('patient', 'Species', '9606', (85, 92))	('AT-rich interaction domain 1A', 'Gene', '8289', (29, 58))	('AT-rich interaction domain 1A', 'Gene', (29, 58))	('mutation', 'Var', (17, 25))	('Arid1a', 'Gene', '8289', (60, 66))	('Arid1a', 'Gene', (60, 66))
216052	33327223	The mutation of Arid1a was associated with a broad spectrum of cancers, such as lung adenocarcinoma, ovarian cancer, and gastric cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('associated with', 'Reg', (27, 42))	('mutation', 'Var', (4, 12))	('cancers', 'Disease', (129, 136))	('gastric cancers', 'Disease', (121, 136))	('gastric cancers', 'Disease', 'MESH:D013274', (121, 136))	('lung adenocarcinoma, ovarian cancer', 'Disease', 'MESH:D000077192', (80, 115))	('gastric cancers', 'Phenotype', 'HP:0012126', (121, 136))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Arid1a', 'Gene', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Arid1a', 'Gene', '8289', (16, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
216053	33327223	Interestingly, mutations of Kit and Arid1a have been found in various types of tumors.	('Kit', 'Gene', (28, 31))	('found', 'Reg', (53, 58))	('Arid1a', 'Gene', '8289', (36, 42))	('mutations', 'Var', (15, 24))	('Kit', 'Gene', '3815', (28, 31))	('Arid1a', 'Gene', (36, 42))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
216055	33327223	Therefore, it is likely to assume that both Arid1a and Kit mutations contribute to myeloid sarcoma co-occurring mastocytosis in our patient.	('mastocytosis', 'Disease', 'MESH:D008415', (112, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('mastocytosis', 'Disease', (112, 124))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (83, 98))	('Arid1a', 'Gene', '8289', (44, 50))	('Kit', 'Gene', '3815', (55, 58))	('Arid1a', 'Gene', (44, 50))	('mastocytosis', 'Phenotype', 'HP:0100495', (112, 124))	('mutations', 'Var', (59, 68))	('contribute', 'Reg', (69, 79))	('myeloid sarcoma', 'Disease', (83, 98))	('patient', 'Species', '9606', (132, 139))	('Kit', 'Gene', (55, 58))
216056	33327223	Indeed, a whole-exome sequencing analysis detected both Kit and Arid1a mutations in 69 hepatocellular carcinoma samples.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (87, 111))	('Kit', 'Gene', (56, 59))	('hepatocellular carcinoma', 'Disease', (87, 111))	('Arid1a', 'Gene', '8289', (64, 70))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (87, 111))	('Arid1a', 'Gene', (64, 70))	('mutations', 'Var', (71, 80))	('Kit', 'Gene', '3815', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('detected', 'Reg', (42, 50))
216057	33327223	As it demonstrated that Kit mutated in a fully clonal manner and Arid1a mutated heterogeneously, Kit mutation may precede Arid1a mutation.	('Kit', 'Gene', (97, 100))	('Arid1a', 'Gene', '8289', (122, 128))	('Kit', 'Gene', '3815', (24, 27))	('Arid1a', 'Gene', (122, 128))	('Kit', 'Gene', '3815', (97, 100))	('Arid1a', 'Gene', '8289', (65, 71))	('mutation', 'Var', (101, 109))	('Kit', 'Gene', (24, 27))	('Arid1a', 'Gene', (65, 71))
216058	33327223	Moreover, while Kit mutated universally in gastrointestinal stromal tumors (GIST), only a portion of GIST harbored mutations of Arid1a, indicating ARID1A may act as a downstream protein of KIT-related pathways.	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (43, 74))	('KIT', 'Gene', (189, 192))	('Arid1a', 'Gene', (128, 134))	('mutations', 'Var', (115, 124))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('ARID1A', 'Gene', '8289', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('ARID1A', 'Gene', (147, 153))	('Kit', 'Gene', (16, 19))	('GIST', 'Phenotype', 'HP:0100723', (76, 80))	('gastrointestinal stromal tumors', 'Disease', (43, 74))	('GIST', 'Phenotype', 'HP:0100723', (101, 105))	('Kit', 'Gene', '3815', (16, 19))	('KIT', 'Gene', '3815', (189, 192))	('Arid1a', 'Gene', '8289', (128, 134))	('mutated', 'Var', (20, 27))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (43, 74))
216060	33327223	Since mutations of Kit and Arid1a coexisted in various cancers, it is critical to notice if there could be any signs of other tumorigenesis in our patient during follow-up therapy.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('coexisted', 'Reg', (34, 43))	('patient', 'Species', '9606', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Kit', 'Gene', (19, 22))	('Arid1a', 'Gene', '8289', (27, 33))	('Kit', 'Gene', '3815', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('Arid1a', 'Gene', (27, 33))	('mutations', 'Var', (6, 15))	('cancers', 'Disease', (55, 62))	('tumor', 'Disease', (126, 131))
216063	33327223	Researches have demonstrated KIT mutation D816V as one of the most common resistance to imatinib and sunitinib, while dasatinib has been shown to overcome the resistance.	('D816V', 'Var', (42, 47))	('KIT', 'Gene', '3815', (29, 32))	('D816V', 'Mutation', 'rs121913507', (42, 47))	('sunitinib', 'Chemical', 'MESH:D000077210', (101, 110))	('KIT', 'Gene', (29, 32))	('imatinib', 'Chemical', 'MESH:D000068877', (88, 96))	('dasatinib', 'Chemical', 'MESH:D000069439', (118, 127))
216072	33327223	Cysteinyl leukotrienes and platelet-acting factors released by mast cells can increase vascular permeability and vasodilation, thus causing severe anaphylaxis in patients.	('patients', 'Species', '9606', (162, 170))	('anaphylaxis', 'Disease', (147, 158))	('anaphylaxis', 'Disease', 'MESH:D000707', (147, 158))	('causing', 'Reg', (132, 139))	('increase', 'PosReg', (78, 86))	('anaphylaxis', 'Phenotype', 'HP:0100845', (147, 158))	('vasodilation', 'CPA', (113, 125))	('Cysteinyl leukotrienes', 'Chemical', 'MESH:C112381', (0, 22))	('vascular permeability', 'MPA', (87, 108))	('Cysteinyl', 'Var', (0, 9))	('increase vascular permeability', 'Phenotype', 'HP:0030005', (78, 108))
216077	33327223	Mutations of KIT D816V and ARID1A G1254S both contributed to carcinogenesis, which highlighted the power of genetic analysis in patients with SM-AHNMD.	('D816V', 'Var', (17, 22))	('D816V', 'Mutation', 'rs121913507', (17, 22))	('carcinogenesis', 'Disease', (61, 75))	('ARID1A', 'Gene', '8289', (27, 33))	('contributed', 'Reg', (46, 57))	('ARID1A', 'Gene', (27, 33))	('KIT', 'Gene', '3815', (13, 16))	('G1254S', 'Var', (34, 40))	('KIT', 'Gene', (13, 16))	('G1254S', 'Mutation', 'rs139907456', (34, 40))	('patients', 'Species', '9606', (128, 136))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
216078	33327223	Physicians should be careful about onsets of various tumors in SM-AHNMD patients with mutations of multiple tumor suppressor genes.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('tumors', 'Disease', (53, 59))	('patients', 'Species', '9606', (72, 80))
216082	32504042	Here, we develop FUDGE (FUsion Detection from Gene Enrichment) to accurately and impartially identify fusions.	('fusions', 'Var', (102, 109))	('FUsion', 'Disease', 'MESH:D000069337', (24, 30))	('FUsion', 'Disease', (24, 30))
216085	32504042	Fusion genes are a hallmarks of cancer, though breakpoint-position promiscuity restricts diagnostic detection.	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Fusion genes', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
216086	32504042	Fusion genes are hallmarks of many human cancers.	('Fusion genes', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('human', 'Species', '9606', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
216087	32504042	Recent studies suggest that up to 16% of cancers are driven by a fusion gene.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('driven by', 'Reg', (53, 62))	('fusion gene', 'Var', (65, 76))	('cancers', 'Disease', (41, 48))
216091	32504042	Whereas fusion detection is pathognomonic for some cancer types, it is a determinant of prognosis or treatment choices in other cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('pathognomonic', 'Reg', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('fusion', 'Var', (8, 14))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (128, 134))
216102	32504042	2b), 142x and 101x (EWSR1) (Fig.	('101x', 'Var', (14, 18))	('EWSR1', 'Gene', (20, 25))	('142x', 'Var', (5, 9))	('EWSR1', 'Gene', '2130', (20, 25))
216103	32504042	2c), 117x and 118x (SS18) (Fig.	('SS18', 'Gene', (20, 24))	('117x', 'Var', (5, 9))	('SS18', 'Gene', '6760', (20, 24))
216111	32504042	This produced a mean genome coverage of 0.24x (A4573), 0.15x (CHP-100), and 0.015x (HS-SYII) (Fig.	('CHP', 'Gene', (62, 65))	('CHP', 'Gene', '11261', (62, 65))	('0.015x', 'Var', (76, 82))
216113	32504042	This relates to an overall on-target fold-enrichment of 342x (A4573), 443x (CHP-100), and 735x (HS-SYII) (Fig.	('735x', 'Var', (90, 94))	('CHP', 'Gene', (76, 79))	('342x', 'Var', (56, 60))	('CHP', 'Gene', '11261', (76, 79))	('443x', 'Var', (70, 74))
216122	32504042	Rhabdomyosarcomas are characterized by breaks in the second intron of FOXO1 (104 kb) which then fuses to either PAX3 or PAX7 (ref.	('PAX7', 'Gene', (120, 124))	('Rhabdomyosarcomas', 'Disease', (0, 17))	('breaks in', 'Var', (39, 48))	('PAX3', 'Gene', '5077', (112, 116))	('Rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (0, 17))	('PAX3', 'Gene', (112, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('FOXO1', 'Gene', (70, 75))	('FOXO1', 'Gene', '2308', (70, 75))	('PAX7', 'Gene', '5081', (120, 124))	('Rhabdomyosarcomas', 'Disease', 'MESH:D012208', (0, 17))
216127	32504042	4a, d), a BCR-ABL1 fusion within the major-cluster (CML, 22 reads) (Fig.	('CML', 'Disease', (52, 55))	('fusion', 'Var', (19, 25))	('ABL1', 'Gene', (14, 18))	('CML', 'Disease', 'MESH:D015464', (52, 55))	('CML', 'Phenotype', 'HP:0005506', (52, 55))	('ABL1', 'Gene', '25', (14, 18))	('BL', 'Phenotype', 'HP:0030080', (15, 17))
216129	32504042	4B), a BCR-ABL1 fusion within the minor-cluster (ALL1, 27 reads) (Fig.	('ABL1', 'Gene', '25', (11, 15))	('ALL1', 'Gene', '100310785', (49, 53))	('ABL1', 'Gene', (11, 15))	('ALL', 'Phenotype', 'HP:0006721', (49, 52))	('BL', 'Phenotype', 'HP:0030080', (12, 14))	('ALL1', 'Gene', (49, 53))	('fusion', 'Var', (16, 22))
216131	32504042	The on-target enrichment was 498x (ES1), 930x (RH1), 611x (CML), 347x (BL), 679 (ALL1), and 3492 (ALL2) and the breakpoint-spanning enrichment was 406x (ES1), 838x (RH1), 598x (CML), 81x (BL), 633x (ALL1), and 3601x (ALL2) (Fig.	('ALL', 'Phenotype', 'HP:0006721', (81, 84))	('ALL', 'Phenotype', 'HP:0006721', (98, 101))	('ALL', 'Phenotype', 'HP:0006721', (217, 220))	('ALL1', 'Gene', '100310785', (81, 85))	('ALL1', 'Gene', '100310785', (199, 203))	('CML', 'Phenotype', 'HP:0005506', (59, 62))	('ALL', 'Phenotype', 'HP:0006721', (199, 202))	('838x', 'Var', (159, 163))	('CML', 'Phenotype', 'HP:0005506', (177, 180))	('ALL1', 'Gene', (81, 85))	('ALL1', 'Gene', (199, 203))	('BL', 'Phenotype', 'HP:0030080', (71, 73))	('3601x', 'Var', (210, 215))	('RH', 'Phenotype', 'HP:0002859', (47, 49))	('406x', 'Var', (147, 151))	('RH', 'Phenotype', 'HP:0002859', (165, 167))	('3492', 'Var', (92, 96))	('BL', 'Phenotype', 'HP:0030080', (188, 190))	('CML', 'Disease', 'MESH:D015464', (59, 62))	('CML', 'Disease', 'MESH:D015464', (177, 180))	('CML', 'Disease', (59, 62))	('CML', 'Disease', (177, 180))
216132	32504042	From this, a fusion-specific enrichment of 270x (ES1), 258x (RH1), 188x (CML), 61x (BL), 197x (ALL1), and 3382x (ALL2) was achieved (Fig.	('3382x', 'Var', (106, 111))	('ALL', 'Phenotype', 'HP:0006721', (95, 98))	('ALL', 'Phenotype', 'HP:0006721', (113, 116))	('RH', 'Phenotype', 'HP:0002859', (61, 63))	('ALL1', 'Gene', (95, 99))	('CML', 'Disease', 'MESH:D015464', (73, 76))	('CML', 'Phenotype', 'HP:0005506', (73, 76))	('ALL1', 'Gene', '100310785', (95, 99))	('BL', 'Phenotype', 'HP:0030080', (84, 86))	('CML', 'Disease', (73, 76))
216136	32504042	In summary, this demonstrates the ability of FUDGE to detect known and reciprocal fusion genes and genomic rearrangements from patient samples irrespective of tumor type.	('genomic rearrangements', 'Var', (99, 121))	('patient', 'Species', '9606', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('fusion genes', 'Var', (82, 94))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
216140	32504042	The B2 sample was randomly chosen out of a pool of six tumor samples (four ALL, one BL, one Burkitt's-ALL) which could potentially harbor a BCR-ABL1, IGH/MYC, or CRLF2-P2RY8 rearrangement.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CRLF2', 'Gene', (162, 167))	('BL', 'Phenotype', 'HP:0030080', (145, 147))	('ABL1', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('IGH', 'Gene', '3492', (150, 153))	('P2RY8', 'Gene', (168, 173))	('MYC', 'Gene', '4609', (154, 157))	('ABL1', 'Gene', '25', (144, 148))	('harbor', 'Reg', (131, 137))	('CRLF2', 'Gene', '64109', (162, 167))	('ALL', 'Phenotype', 'HP:0006721', (102, 105))	('BL', 'Phenotype', 'HP:0030080', (84, 86))	('P2RY8', 'Gene', '286530', (168, 173))	('ALL', 'Phenotype', 'HP:0006721', (75, 78))	('rearrangement', 'Var', (174, 187))	('IGH', 'Gene', (150, 153))	('tumor', 'Disease', (55, 60))	('MYC', 'Gene', (154, 157))
216147	32504042	Therefore, we sequenced WGA-DNA of two colon cancer samples (C1 and C2), known to harbor BRAF fusions (AGAP3-BRAF and TRIM24-BRAF, respectively), a sarcoma sample with a SS18-SSX1 fusion (S1) and a PDX sarcoma sample with unknown fusion status (S2).	('SS18', 'Gene', (170, 174))	('BRAF', 'Gene', '673', (89, 93))	('colon cancer', 'Disease', (39, 51))	('BRAF', 'Gene', (89, 93))	('AGAP3', 'Gene', '116988', (103, 108))	('TRIM24', 'Gene', (118, 124))	('BRAF', 'Gene', (109, 113))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('BRAF', 'Gene', '673', (109, 113))	('sarcoma', 'Disease', (148, 155))	('sarcoma', 'Disease', 'MESH:D012509', (202, 209))	('SS18', 'Gene', '6760', (170, 174))	('BRAF', 'Gene', '673', (125, 129))	('BRAF', 'Gene', (125, 129))	('sarcoma', 'Disease', (202, 209))	('colon cancer', 'Phenotype', 'HP:0003003', (39, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('TRIM24', 'Gene', '8805', (118, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('SSX1', 'Gene', '6756', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('colon cancer', 'Disease', 'MESH:D015179', (39, 51))	('SSX1', 'Gene', (175, 179))	('AGAP3', 'Gene', (103, 108))	('fusions', 'Var', (94, 101))
216152	32504042	In addition, for the BRAF fusions, the breakpoint junction locations were 6.5 kb apart (Fig.	('fusions', 'Var', (26, 33))	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', '673', (21, 25))
216163	32504042	We successfully identified fusion genes from genomic DNA independent of cancer type or fusion gene configuration and/or breakpoint-positions.	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('fusion', 'Var', (27, 33))	('cancer', 'Disease', (72, 78))
216196	32504042	To select a minimum number of supporting reads used in the detection of fusion genes, we ran NanoFG on a number of samples (CHP-100, ES1, C1-WGA, and C2-WGA) with a minimum of one supporting read.	('C2-WGA', 'Var', (150, 156))	('CHP', 'Gene', '11261', (124, 127))	('CHP', 'Gene', (124, 127))	('C1-WGA', 'Var', (138, 144))
216217	32132106	In a similar setting for L-type STS, eribulin significantly improved OS compared with dacarbazine (median 13.5 vs 11.5 months; HR=0.77; p=0.0169).	('eribulin', 'Var', (37, 45))	('dacarbazine', 'Chemical', 'MESH:D003606', (86, 97))	('STS', 'Phenotype', 'HP:0030448', (32, 35))	('improved', 'PosReg', (60, 68))
216221	32132106	Furthermore, the discovery of epidermal growth factor receptor (EGFR) mutations and the outstanding response from EGFR tyrosine kinase inhibitors in non-small-cell lung cancer have transformed the treatment paradigm for some patients with lung cancer, steering away from the use of cytotoxic chemotherapy as front-line treatment.	('lung cancer', 'Disease', (239, 250))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (149, 175))	('transformed', 'Reg', (181, 192))	('epidermal growth factor receptor', 'Gene', (30, 62))	('lung cancer', 'Disease', (164, 175))	('epidermal growth factor receptor', 'Gene', '1956', (30, 62))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('EGFR', 'Gene', (114, 118))	('EGFR', 'Gene', (64, 68))	('mutations', 'Var', (70, 79))	('patients', 'Species', '9606', (225, 233))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('EGFR', 'Gene', '1956', (114, 118))	('EGFR', 'Gene', '1956', (64, 68))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (153, 175))
216222	32132106	Moreover, in the past decade, driver mutations were found in certain types of STS (table 1), and this has reshaped a part of the paradigm of sarcoma treatment.	('sarcoma', 'Disease', (141, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('STS', 'Phenotype', 'HP:0030448', (78, 81))	('mutations', 'Var', (37, 46))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))
216224	32132106	No effective systemic treatment existed for GISTs until 1998, when KIT and PDGFRA mutations of the interstitial cells of Cajal were found to drive GIST development.	('GIST', 'Disease', 'MESH:D046152', (147, 151))	('GISTs', 'Disease', (44, 49))	('GIST', 'Disease', (147, 151))	('KIT', 'Gene', (67, 70))	('mutations', 'Var', (82, 91))	('GIST', 'Disease', 'MESH:D046152', (44, 48))	('drive', 'PosReg', (141, 146))	('PDGFRA', 'Gene', (75, 81))	('PDGFRA', 'Gene', '5156', (75, 81))	('GIST', 'Disease', (44, 48))	('GISTs', 'Disease', 'MESH:D046152', (44, 49))	('KIT', 'Gene', '3815', (67, 70))
216227	32132106	For PDGFRA mutant GISTs, patients with the PDGFRA exon 18 D842V mutation were resistant to imatinib therapy, whereas patients with exon 4, exon 12 and non-D842V exon 18 mutations may still respond to imatinib, with the overall response rate of 38% and PFS of 28.5 months in a retrospective study.	('D842V', 'Mutation', 'rs121908585', (58, 63))	('mutant', 'Var', (11, 17))	('PDGFRA', 'Gene', '5156', (4, 10))	('D842V', 'Mutation', 'rs121908585', (155, 160))	('PDGFRA', 'Gene', (4, 10))	('D842V', 'Var', (58, 63))	('GISTs', 'Disease', 'MESH:D046152', (18, 23))	('imatinib', 'Chemical', 'MESH:D000068877', (91, 99))	('GISTs', 'Disease', (18, 23))	('imatinib', 'Chemical', 'MESH:D000068877', (200, 208))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (25, 33))	('resistant', 'MPA', (78, 87))	('PDGFRA', 'Gene', (43, 49))	('PDGFRA', 'Gene', '5156', (43, 49))	('respond to imatinib', 'MPA', (189, 208))
216228	32132106	Despite the promising efficiency, imatinib resistance can occur within a median of 2-3 years due to secondary mutations in KIT.	('mutations', 'Var', (110, 119))	('occur', 'Reg', (58, 63))	('KIT', 'Gene', '3815', (123, 126))	('KIT', 'Gene', (123, 126))	('imatinib resistance', 'MPA', (34, 53))	('imatinib', 'Chemical', 'MESH:D000068877', (34, 42))	('due to', 'Reg', (93, 99))
216229	32132106	In contrast to primary KIT mutations that are predominately in the juxtamembrane regions encoded by exons 9 and 11, secondary mutations mainly occur in two regions of imatinib binding sites.	('mutations', 'Var', (27, 36))	('KIT', 'Gene', '3815', (23, 26))	('occur', 'Reg', (143, 148))	('KIT', 'Gene', (23, 26))	('imatinib', 'Chemical', 'MESH:D000068877', (167, 175))
216235	32132106	KIT exon 17 mutations account for 30%-40% of KIT secondary mutations and are responsible for resistance to imatinib or sunitinib.	('KIT', 'Gene', (45, 48))	('imatinib', 'Chemical', 'MESH:D000068877', (107, 115))	('resistance to imatinib', 'MPA', (93, 115))	('responsible', 'Reg', (77, 88))	('mutations', 'Var', (12, 21))	('KIT', 'Gene', '3815', (0, 3))	('KIT', 'Gene', '3815', (45, 48))	('KIT', 'Gene', (0, 3))	('sunitinib', 'Chemical', 'MESH:D000077210', (119, 128))
216237	32132106	A prospective phase II trial tested the efficacy of regorafenib in GIST patients with exon 17 mutations and showed an ORR of 30% (6/15) and the median PFS of 22.1 months.	('mutations', 'Var', (94, 103))	('exon 17', 'Gene', (86, 93))	('GIST', 'Disease', 'MESH:D046152', (67, 71))	('regorafenib', 'Chemical', 'MESH:C559147', (52, 63))	('GIST', 'Disease', (67, 71))	('patients', 'Species', '9606', (72, 80))
216238	32132106	Avapritinib (formerly known as BLU-285) had broad activity against primary or secondary KIT and PDGFRA mutations, including PDGFRA D842V.	('mutations', 'Var', (103, 112))	('Avapritinib', 'Chemical', '-', (0, 11))	('PDGFRA', 'Gene', (96, 102))	('D842V', 'Mutation', 'rs121908585', (131, 136))	('KIT', 'Gene', '3815', (88, 91))	('PDGFRA', 'Gene', '5156', (96, 102))	('PDGFRA', 'Gene', '5156', (124, 130))	('PDGFRA', 'Gene', (124, 130))	('D842V', 'Var', (131, 136))	('KIT', 'Gene', (88, 91))	('BLU', 'Gene', (31, 34))	('BLU', 'Gene', '51364', (31, 34))
216239	32132106	In a phase I study of avapritinib in patients with advanced GIST (the NAVIGATOR trial), patients who had received at least three prior therapies, including PDGFRA exon 18 mutations patients, were treated at the maximal tolerated dose (400 mg) or recommended phase II dose (RP2D) 300 mg per day.	('avapritinib', 'Chemical', '-', (22, 33))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (88, 96))	('PDGFRA', 'Gene', (156, 162))	('patients', 'Species', '9606', (181, 189))	('PDGFRA', 'Gene', '5156', (156, 162))	('mutations', 'Var', (171, 180))	('GIST', 'Disease', (60, 64))	('GIST', 'Disease', 'MESH:D046152', (60, 64))
216241	32132106	Remarkably, in patients with PDGFRA exon 18 mutation, the response rate was 86%, and the disease control rate was 95%.	('PDGFRA', 'Gene', '5156', (29, 35))	('patients', 'Species', '9606', (15, 23))	('mutation', 'Var', (44, 52))	('PDGFRA', 'Gene', (29, 35))
216253	32132106	Approximately 10%-15% of GIST patients do not harbour KIT and PDGFRA mutations, and these GISTs are called wild-type GISTs.	('mutations', 'Var', (69, 78))	('GIST', 'Disease', 'MESH:D046152', (25, 29))	('GIST', 'Disease', (25, 29))	('PDGFRA', 'Gene', '5156', (62, 68))	('PDGFRA', 'Gene', (62, 68))	('GIST', 'Disease', 'MESH:D046152', (117, 121))	('KIT', 'Gene', '3815', (54, 57))	('GIST', 'Disease', 'MESH:D046152', (90, 94))	('GIST', 'Disease', (117, 121))	('GISTs', 'Disease', 'MESH:D046152', (117, 122))	('GISTs', 'Disease', (117, 122))	('KIT', 'Gene', (54, 57))	('patients', 'Species', '9606', (30, 38))	('GIST', 'Disease', (90, 94))	('GISTs', 'Disease', 'MESH:D046152', (90, 95))	('GISTs', 'Disease', (90, 95))
216256	32132106	Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation promotes the response of alkylating agents in several cancer types including gliomas, colorectal cancer and diffuse large B cell lymphoma.	('promotes', 'PosReg', (102, 110))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (27, 65))	('cancer', 'Disease', (199, 205))	('response of alkylating agents', 'MPA', (115, 144))	('gliomas', 'Disease', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('lymphoma', 'Phenotype', 'HP:0002665', (231, 239))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('MGMT', 'Gene', (67, 71))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (224, 239))	('Epigenetic inactivation', 'Var', (0, 23))	('gliomas', 'Disease', 'MESH:D005910', (179, 186))	('colorectal cancer', 'Disease', (188, 205))	('O6-methylguanine-DNA methyltransferase', 'Gene', (27, 65))	('large B cell', 'Phenotype', 'HP:0005404', (218, 230))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('lymphoma', 'Disease', (231, 239))	('lymphoma', 'Disease', 'MESH:D008223', (231, 239))	('cancer', 'Disease', (156, 162))	('MGMT', 'Gene', '4255', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('promoter methylation', 'Var', (81, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))
216262	32132106	In wild-type GIST patients with competent SDH, 4%-13% carried the BRAF V600E mutation.	('GIST', 'Disease', (13, 17))	('SDH', 'Gene', '6390', (42, 45))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('SDH', 'Gene', (42, 45))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', '673', (66, 70))	('patients', 'Species', '9606', (18, 26))	('GIST', 'Disease', 'MESH:D046152', (13, 17))	('BRAF', 'Gene', (66, 70))
216264	32132106	The introduction of imatinib has single-handedly transformed the treatment paradigm of GIST but in the past few years we have a much better understanding of other non-KIT genetic alterations in GIST such as PDGFR, BRAF, SDH and neurofibromatosis type 1 (NF1).	('GIST', 'Disease', 'MESH:D046152', (87, 91))	('KIT', 'Gene', '3815', (167, 170))	('NF1', 'Gene', (254, 257))	('alterations', 'Var', (179, 190))	('BRAF', 'Gene', '673', (214, 218))	('PDGFR', 'Gene', (207, 212))	('BRAF', 'Gene', (214, 218))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (228, 245))	('PDGFR', 'Gene', '5159', (207, 212))	('GIST', 'Disease', (194, 198))	('neurofibromatosis type 1', 'Gene', '4763', (228, 252))	('imatinib', 'Chemical', 'MESH:D000068877', (20, 28))	('SDH', 'Gene', '6390', (220, 223))	('GIST', 'Disease', 'MESH:D046152', (194, 198))	('neurofibroma', 'Phenotype', 'HP:0001067', (228, 240))	('KIT', 'Gene', (167, 170))	('GIST', 'Disease', (87, 91))	('SDH', 'Gene', (220, 223))	('neurofibromatosis type 1', 'Gene', (228, 252))	('NF1', 'Gene', '4763', (254, 257))
216265	32132106	It is recommended that every GIST patient should be tested for at least KIT and PDGFRA mutations as these are both prognostic and guidance for treatment selection.	('KIT', 'Gene', (72, 75))	('PDGFRA', 'Gene', (80, 86))	('PDGFRA', 'Gene', '5156', (80, 86))	('GIST', 'Disease', 'MESH:D046152', (29, 33))	('patient', 'Species', '9606', (34, 41))	('GIST', 'Disease', (29, 33))	('mutations', 'Var', (87, 96))	('KIT', 'Gene', '3815', (72, 75))
216266	32132106	For GIST patients who are KIT and PDGFRA mutation negative, BRAF, SDH and NF1 status should be investigated.	('patients', 'Species', '9606', (9, 17))	('SDH', 'Gene', '6390', (66, 69))	('GIST', 'Disease', 'MESH:D046152', (4, 8))	('NF1', 'Gene', (74, 77))	('GIST', 'Disease', (4, 8))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('KIT', 'Gene', '3815', (26, 29))	('NF1', 'Gene', '4763', (74, 77))	('SDH', 'Gene', (66, 69))	('mutation', 'Var', (41, 49))	('KIT', 'Gene', (26, 29))	('negative', 'NegReg', (50, 58))	('PDGFRA', 'Gene', '5156', (34, 40))	('PDGFRA', 'Gene', (34, 40))
216267	32132106	The recently approved PDGFRA D842V-targeted avapritinib by the US FDA is a manifest that molecular-targeted therapy in GIST is still under evolution and the optimal treatment for every subtype of GIST is fully anticipated.	('GIST', 'Disease', (196, 200))	('avapritinib', 'Chemical', '-', (44, 55))	('D842V', 'Mutation', 'rs121908585', (29, 34))	('PDGFRA', 'Gene', '5156', (22, 28))	('PDGFRA', 'Gene', (22, 28))	('GIST', 'Disease', 'MESH:D046152', (119, 123))	('D842V-targeted', 'Var', (29, 43))	('GIST', 'Disease', 'MESH:D046152', (196, 200))	('GIST', 'Disease', (119, 123))
216275	32132106	A significant number of PEComas are associated with TSC gene alteration, either as sporadic cases or in patients with TSC.	('PEComas', 'Disease', (24, 31))	('gene alteration', 'Var', (56, 71))	('PEComas', 'Disease', 'MESH:D054973', (24, 31))	('TSC', 'Gene', (52, 55))	('associated', 'Reg', (36, 46))	('patients', 'Species', '9606', (104, 112))
216280	32132106	This may be related to the higher prevalence of TFE3 translocation in gynecologic PEComas, and PEComas harbouring TFE3 gene rearrangements lack the TSC2 alteration characteristics of conventional PEComas and possibly show insensitivity to mTOR inhibition.	('PEComas', 'Disease', (82, 89))	('TFE3', 'Gene', '7030', (48, 52))	('PEComas', 'Disease', (196, 203))	('TFE3', 'Gene', (114, 118))	('TSC2', 'Gene', '7249', (148, 152))	('PEComas', 'Disease', 'MESH:D054973', (95, 102))	('PEComas', 'Disease', 'MESH:D054973', (82, 89))	('rearrangements', 'Var', (124, 138))	('mTOR', 'Gene', (239, 243))	('TSC2', 'Gene', (148, 152))	('TFE3', 'Gene', '7030', (114, 118))	('mTOR', 'Gene', '2475', (239, 243))	('PEComas', 'Disease', 'MESH:D054973', (196, 203))	('lack', 'NegReg', (139, 143))	('PEComas', 'Disease', (95, 102))	('translocation', 'Var', (53, 66))	('TFE3', 'Gene', (48, 52))
216283	32132106	However, most of the responders in the study showed either TSC1/TSC2 mutations or strong expression of pS6, a downstream signal of mTOR activation, whereas patients without either TSC1 or TSC2 mutations are less likely to derive benefits from ABI-009.	('TSC1', 'Gene', (180, 184))	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (156, 164))	('expression', 'MPA', (89, 99))	('pS6', 'Gene', (103, 106))	('ABI-009', 'Chemical', '-', (243, 250))	('mTOR', 'Gene', (131, 135))	('mTOR', 'Gene', '2475', (131, 135))	('TSC1', 'Gene', '7248', (59, 63))	('TSC2', 'Gene', '7249', (64, 68))	('pS6', 'Gene', '338413', (103, 106))	('TSC2', 'Gene', '7249', (188, 192))	('TSC1', 'Gene', (59, 63))	('TSC1', 'Gene', '7248', (180, 184))	('TSC2', 'Gene', (64, 68))	('TSC2', 'Gene', (188, 192))
216304	32132106	Genetic alterations of ALK, ROS-1 and NTRK should be examined either sequentially or simultaneously to determine the optimal genomic-guided treatment.	('Genetic alterations', 'Var', (0, 19))	('ROS-1', 'Gene', '6098', (28, 33))	('ALK', 'Gene', (23, 26))	('ALK', 'Gene', '238', (23, 26))	('ROS-1', 'Gene', (28, 33))	('NTRK', 'Gene', (38, 42))
216308	32132106	Fibrosarcomatous areas occasionally arise in DFSP, which is associated with increased metastasis risk, gains of p53 mutations and increased proliferative activity.	('Fibrosarcomatous', 'Disease', 'MESH:D018223', (0, 16))	('DFSP', 'Disease', (45, 49))	('Fibrosarcomatous', 'Disease', (0, 16))	('DFSP', 'Disease', 'MESH:D018223', (45, 49))	('mutations', 'Var', (116, 125))	('p53', 'Gene', (112, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('p53', 'Gene', '7157', (112, 115))	('gains', 'PosReg', (103, 108))	('metastasis', 'CPA', (86, 96))
216311	32132106	DFSP is characterised by the reciprocal translocation t(17;22)(q22;q13), resulting in the fusion of the genes collagen type 1 alpha 1 (COL1A1) on chromosome 17q21-22 and platelet-derived growth factor beta (PDGFB) on 22q13.	('DFSP', 'Disease', (0, 4))	('COL1A1', 'Gene', '1277', (135, 141))	('COL1A1', 'Gene', (135, 141))	('PDGFB', 'Gene', '5155', (207, 212))	('PDGFB', 'Gene', (207, 212))	('DFSP', 'Disease', 'MESH:D018223', (0, 4))	('fusion', 'Var', (90, 96))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (54, 71))
216313	32132106	Two independently conducted phase II clinical trials, one in the USA by the Southwest Oncology Group(SWOG-S0345) and one in Europe by the European organisation for Research and Treatent of Cancer(EORTC 62027), were designed to test imatinib (400-800 mg daily) in patients with locally advanced or metastatic DFSP with PDGFB rearrangement (EORTC trial) or t(17;22) (SWOG study).	('PDGFB', 'Gene', '5155', (318, 323))	('patients', 'Species', '9606', (263, 271))	('PDGFB', 'Gene', (318, 323))	('imatinib', 'Chemical', 'MESH:D000068877', (232, 240))	('rearrangement', 'Var', (324, 337))	('locally advanced', 'Disease', (277, 293))	('Cancer', 'Disease', (189, 195))	('Cancer', 'Disease', 'MESH:D009369', (189, 195))	('Cancer', 'Phenotype', 'HP:0002664', (189, 195))	('DFSP', 'Disease', (308, 312))	('Oncology', 'Phenotype', 'HP:0002664', (86, 94))	('DFSP', 'Disease', 'MESH:D018223', (308, 312))
216332	32132106	The primary endpoint:the proportion of patients who achieved objective responses:was significantly higher for pexidartinib than for placebo at week 25 with RECIST (24 (39%) of 61 vs none of 59; absolute difference: 39% (95% CI 27 to 53); p<0.0001).	('pexidartinib', 'Chemical', 'MESH:C000600259', (110, 122))	('pexidartinib', 'Var', (110, 122))	('patients', 'Species', '9606', (39, 47))	('higher', 'PosReg', (99, 105))
216344	32132106	Further evidence supporting that WDLPS and DDLPS are similar concatenate are that both WDLPS and DDLPS have high-level amplifications in the chromosomal 12q14-15 region, which includes the MDM2 and cyclin-dependent kinase 4 (CDK4) oncogenes.	('LPS', 'Gene', (99, 102))	('amplifications', 'Var', (119, 133))	('LPS', 'Gene', '3664', (35, 38))	('CDK4', 'Gene', (225, 229))	('LPS', 'Gene', (45, 48))	('LPS', 'Gene', (35, 38))	('CDK4', 'Gene', '1019', (225, 229))	('LPS', 'Gene', '3664', (89, 92))	('cyclin-dependent kinase 4', 'Gene', '1019', (198, 223))	('MDM2', 'Gene', '4193', (189, 193))	('LPS', 'Gene', '3664', (99, 102))	('MDM2', 'Gene', (189, 193))	('cyclin-dependent kinase 4', 'Gene', (198, 223))	('LPS', 'Gene', (89, 92))	('LPS', 'Gene', '3664', (45, 48))
216349	32132106	The first study of the MDM2 inhibitor RG7112 was a proof-of-mechanism study performed in the neoadjuvant setting.	('MDM2', 'Gene', (23, 27))	('RG7112', 'Var', (38, 44))	('MDM2', 'Gene', '4193', (23, 27))
216350	32132106	Twenty patients with WDLPS or DDLPS were treated with RG7112 for 3 months before surgical resection or a tumour biopsy if unresectable.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumour', 'Disease', (105, 111))	('RG7112', 'Var', (54, 60))	('LPS', 'Gene', '3664', (32, 35))	('LPS', 'Gene', '3664', (23, 26))	('LPS', 'Gene', (32, 35))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (7, 15))	('LPS', 'Gene', (23, 26))
216357	32132106	In another phase I trial of another MDM2 inhibitor DS-3032b in patients with WDLPS/DDLPS, solid tumours and lymphomas, partial responses were found in DDLPS and synovial sarcoma.	('MDM2', 'Gene', (36, 40))	('LPS', 'Gene', (79, 82))	('synovial sarcoma', 'Disease', (161, 177))	('solid tumours', 'Disease', 'MESH:D009369', (90, 103))	('synovial sarcoma', 'Disease', 'MESH:D013584', (161, 177))	('MDM2', 'Gene', '4193', (36, 40))	('LPS', 'Gene', (85, 88))	('DS-3032b', 'Var', (51, 59))	('lymphomas', 'Disease', 'MESH:D008223', (108, 117))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('LPS', 'Gene', '3664', (153, 156))	('lymphomas', 'Phenotype', 'HP:0002665', (108, 117))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (161, 177))	('LPS', 'Gene', '3664', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('LPS', 'Gene', '3664', (85, 88))	('lymphoma', 'Phenotype', 'HP:0002665', (108, 116))	('solid tumours', 'Disease', (90, 103))	('lymphomas', 'Disease', (108, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('patients', 'Species', '9606', (63, 71))	('LPS', 'Gene', (153, 156))
216375	32132106	However, the optimal doses of these agents, especially MDM2 inhibitors because of the strong bone marrow suppression activity, have been the limiting step for the full-scale exploration of these agents.	('bone marrow suppression', 'Phenotype', 'HP:0005528', (93, 116))	('bone marrow suppression activity', 'CPA', (93, 125))	('inhibitors', 'Var', (60, 70))	('MDM2', 'Gene', '4193', (55, 59))	('MDM2', 'Gene', (55, 59))
216376	32132106	NF1, an autosomal dominant disorder caused by germ line alterations in the NF1 tumour suppressor gene, is characterised by pigmentary skin lesions (cafe-au-lait macules) and dermal neurofibromas.	('cafe-au-lait macules', 'Phenotype', 'HP:0000957', (148, 168))	('dermal neurofibromas', 'Disease', (174, 194))	('neurofibromas', 'Phenotype', 'HP:0001067', (181, 194))	('caused by', 'Reg', (36, 45))	('NF1', 'Gene', (0, 3))	('dermal neurofibromas', 'Disease', 'MESH:D009455', (174, 194))	('NF1', 'Gene', '4763', (75, 78))	('macules', 'Phenotype', 'HP:0012733', (161, 168))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (8, 35))	('neurofibroma', 'Phenotype', 'HP:0001067', (181, 193))	('NF1', 'Gene', (75, 78))	('pigmentary skin lesions', 'Disease', 'MESH:D012871', (123, 146))	('pigmentary skin lesions', 'Disease', (123, 146))	('alterations', 'Var', (56, 67))	('autosomal dominant disorder', 'Disease', (8, 35))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('NF1', 'Gene', '4763', (0, 3))	('tumour', 'Disease', (79, 85))
216379	32132106	GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, thus reducing RAS-mediated growth signalling.	('RAS-mediated growth signalling', 'MPA', (105, 135))	('GAP', 'Var', (0, 3))	('reducing', 'NegReg', (96, 104))	('GTP', 'Chemical', 'MESH:D006160', (45, 48))	('accelerates', 'PosReg', (4, 15))	('conversion', 'MPA', (20, 30))	('RAS', 'Protein', (55, 58))	('GDP', 'Chemical', 'MESH:D006153', (75, 78))
216380	32132106	In NF1 mutated patients, RAS transmits its pro-tumoural signal through the AKT-mTOR and MEK-extracellular signal-regulated kinase effector pathways.	('mTOR', 'Gene', (79, 83))	('MEK', 'Gene', '5609', (88, 91))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('mTOR', 'Gene', '2475', (79, 83))	('patients', 'Species', '9606', (15, 23))	('AKT', 'Gene', '207', (75, 78))	('tumour', 'Disease', (47, 53))	('NF1', 'Gene', (3, 6))	('AKT', 'Gene', (75, 78))	('NF1', 'Gene', '4763', (3, 6))	('MEK', 'Gene', (88, 91))	('mutated', 'Var', (7, 14))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
216394	32132106	Gain-of-function alterations of EZH2 or loss of function of the SWI/SNF components, such as SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, also known as INI-1) or SMARCA4, is linked to many cancer types.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1', 'Gene', '6598', (101, 194))	('SMARCA4', 'Gene', (220, 227))	('SMARCA4', 'Gene', '6597', (220, 227))	('INI-1', 'Gene', '6598', (210, 215))	('INI-1', 'Gene', (210, 215))	('EZH2', 'Gene', (32, 36))	('cancer', 'Disease', (247, 253))	('Gain-of-function', 'PosReg', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('SMARCB1', 'Gene', '6598', (92, 99))	('EZH2', 'Gene', '2146', (32, 36))	('SMARCB1', 'Gene', (92, 99))	('alterations', 'Var', (17, 28))	('loss of function', 'NegReg', (40, 56))
216396	32132106	The loss of INI-1 enhances unopposed EZH2 function and portend susceptibility to EZH2 inhibition.	('EZH2', 'Gene', (81, 85))	('EZH2', 'Gene', '2146', (81, 85))	('INI-1', 'Gene', (12, 17))	('EZH2', 'Gene', (37, 41))	('INI-1', 'Gene', '6598', (12, 17))	('EZH2', 'Gene', '2146', (37, 41))	('enhances', 'PosReg', (18, 26))	('loss', 'Var', (4, 8))
216406	32132106	Similarly, Sen et al reported that patients with sarcoma enrolled into phase I studies based on NGS results had significantly better PFS and OS than those who were enrolled into non-genomic-guided phase I clinical trials.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('better', 'PosReg', (126, 132))	('PFS', 'CPA', (133, 136))	('NGS', 'Var', (96, 99))	('patients', 'Species', '9606', (35, 43))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('sarcoma', 'Disease', (49, 56))
216411	32132106	For instance, the National Comprehensive Cancer Network Guideline recommended mutation testing for all GIST patients scheduled for imatinib treatment.	('GIST', 'Disease', 'MESH:D046152', (103, 107))	('imatinib', 'Chemical', 'MESH:D000068877', (131, 139))	('mutation testing', 'Var', (78, 94))	('GIST', 'Disease', (103, 107))	('Cancer', 'Disease', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('patients', 'Species', '9606', (108, 116))
216412	32132106	To test the mutations, although NGS is helpful, a valid but less expensive diagnostic procedure such as PCR for KIT and PDGFRA mutations is readily available.	('KIT', 'Gene', '3815', (112, 115))	('KIT', 'Gene', (112, 115))	('mutations', 'Var', (127, 136))	('PDGFRA', 'Gene', '5156', (120, 126))	('PDGFRA', 'Gene', (120, 126))
216500	26437730	For all other infectious agents considered here (HBV, HCV, HIV, H. pylori), we used the standard formula to estimate the PAF and number of cancers attributable to infection with these agents, as: where px is the proportion of the population in exposure level x and ERRx the excess relative risk (RRx-1) associated with exposure level x.	('HIV', 'Species', '12721', (59, 62))	('number of cancers', 'Disease', 'MESH:D009369', (129, 146))	('ERRx', 'Var', (265, 269))	('H. pylori', 'Species', '210', (64, 73))	('PAF', 'Chemical', '-', (121, 124))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('HBV', 'Species', '10407', (49, 52))	('number of cancers', 'Disease', (129, 146))	('infection', 'Disease', (163, 172))	('infection', 'Disease', 'MESH:D007239', (163, 172))	('HCV', 'Species', '11103', (54, 57))
216616	24348836	An immunochemistry examination revealed the following results: EMA(+), Vim(+), S100(+), CD99(+), Ki-67(+), CD117(-), CD34(-), SAM(-), HMB(-), CK(-) and p53(-) (Figs.	('CD99', 'Gene', (88, 92))	('CD34', 'Gene', '947', (117, 121))	('CD117(-', 'Var', (107, 114))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('Vim', 'Gene', (71, 74))	('CD99', 'Gene', '4267', (88, 92))	('Vim', 'Gene', '7431', (71, 74))	('CD34', 'Gene', (117, 121))
216638	24348836	With regard to a genetic diagnosis, cellular and molecular genetic studies have shown that the translocation t(X;18)(p11.2; q11.2) exists in >90% of synovial sarcomas.	('synovial sarcomas', 'Disease', 'MESH:D013584', (149, 166))	('synovial sarcomas', 'Disease', (149, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (149, 165))	('translocation t(X', 'Var', (95, 112))	('p11', 'Gene', (117, 120))	('t(X', 'Var', (109, 112))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (149, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('p11', 'Gene', '6281', (117, 120))
216650	24348836	However, adjuvant radiotherapy showed a marked impact on patients with marginally resected disease, as in the 71 patients who received partial surgical excision, the 5-year LRFS rate was 57.4% for patients who received radiotherapy and only 7.1% for patients who had not.	('patients', 'Species', '9606', (197, 205))	('patients', 'Species', '9606', (57, 65))	('LRFS', 'CPA', (173, 177))	('patients', 'Species', '9606', (250, 258))	('patients', 'Species', '9606', (113, 121))	('radiotherapy', 'Var', (219, 231))
216688	29300189	In contrast to ES, BCS shows consistent BCOR overexpression, and preliminary evidence suggests that these tumors share morphologic features with other tumors harboring BCOR genetic alterations, including BCOR internal tandem duplication (ITD) and BCOR-MAML3.	('BCOR', 'Gene', '54880', (247, 251))	('internal tandem duplication', 'Var', (209, 236))	('tumors', 'Disease', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('BCOR', 'Gene', '54880', (40, 44))	('BCOR', 'Gene', (247, 251))	('MAML3', 'Gene', (252, 257))	('BCOR', 'Gene', '54880', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', (151, 157))	('BCOR', 'Gene', (40, 44))	('MAML3', 'Gene', '55534', (252, 257))	('BCOR', 'Gene', (168, 172))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('ES', 'Phenotype', 'HP:0012254', (15, 17))	('BCOR', 'Gene', '54880', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('BCOR', 'Gene', (204, 208))
216698	29300189	Unsupervised clustering by RNA sequencing data revealed that tumors with BCOR genetic alterations, including BCOR-CCNB3, BCOR-MAML3 and BCOR ITD, formed a tight genomic group distinct from ES and CIC-rearranged sarcomas.	('CIC-rearranged sarcomas', 'Disease', 'MESH:D012509', (196, 219))	('MAML3', 'Gene', (126, 131))	('BCOR', 'Gene', '54880', (73, 77))	('BCOR', 'Gene', '54880', (121, 125))	('BCOR', 'Gene', '54880', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('BCOR', 'Gene', (73, 77))	('MAML3', 'Gene', '55534', (126, 131))	('BCOR', 'Gene', (121, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (211, 219))	('BCOR', 'Gene', (136, 140))	('BCOR', 'Gene', '54880', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('BCOR-CCNB3', 'Gene', (109, 119))	('tumors', 'Disease', (61, 67))	('BCOR', 'Gene', (109, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('genetic alterations', 'Var', (78, 97))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ES', 'Phenotype', 'HP:0012254', (189, 191))	('BCOR-CCNB3', 'Gene', '54880;85417', (109, 119))	('CIC-rearranged sarcomas', 'Disease', (196, 219))
216700	29300189	The genetic abnormality involves a paracentric inversion on the short arm of chromosome X, resulting in the fusion of 2 nearby genes BCOR and CCNB3 (10 Mb apart) and leading to the overexpression of CCNB3.	('CCNB3', 'Gene', (142, 147))	('CCNB3', 'Gene', '85417', (199, 204))	('overexpression', 'PosReg', (181, 195))	('short arm', 'Phenotype', 'HP:0009824', (64, 73))	('CCNB3', 'Gene', '85417', (142, 147))	('genetic abnormality', 'Disease', 'MESH:D030342', (4, 23))	('BCOR', 'Gene', (133, 137))	('fusion', 'Var', (108, 114))	('CCNB3', 'Gene', (199, 204))	('genetic abnormality', 'Disease', (4, 23))	('BCOR', 'Gene', '54880', (133, 137))
216709	29300189	were searched for primitive round and spindle cell sarcomas that had molecular confirmation of BCOR-CCNB3 fusion by fluorescence in situ hybridization (FISH) or RNA sequencing (RNAseq).	('BCOR-CCNB3', 'Gene', '54880;85417', (95, 105))	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Disease', (51, 59))	('fusion', 'Var', (106, 112))	('BCOR-CCNB3', 'Gene', (95, 105))
216714	29300189	Custom FISH probes were prepared using bacterial artificial chromosomes (BAC) flanking BCOR (telomeric: RP11-21D3, RP11-1105N2; centromeric: RP11-37K20, RP11-973F20) and CCNB3 (telomeric: RP11-58H17; centromeric: RP11-168F22, RP11-96H3).	('RP11-1105N2', 'Var', (115, 126))	('CCNB3', 'Gene', (170, 175))	('BCOR', 'Gene', (87, 91))	('BCOR', 'Gene', '54880', (87, 91))	('RP11-96H3', 'Var', (226, 235))	('CCNB3', 'Gene', '85417', (170, 175))	('RP11-973F20', 'Var', (153, 164))	('RP11-37K20', 'Var', (141, 151))
216716	29300189	To compare the expression profile of BCOR-CCNB3 sarcomas (BCS) with morphologically similar tumors, including ES and SS, we have downloaded publicly available expression array data from GEO, including: 10 BCS (GSE34800) and 4 ES (GSE34800) from the study by Pierron et al, 34 SS (GSE20196), and a control group of normal tissues (GSE7307) on Affymetrix Human Genome U133A Plus 2 platform.	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('ES', 'Phenotype', 'HP:0012254', (226, 228))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('sarcomas', 'Disease', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('GSE34800', 'Var', (230, 238))	('GSE7307', 'Chemical', '-', (330, 337))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('BCOR-CCNB3', 'Gene', (37, 47))	('tumors', 'Disease', (92, 98))	('GSE20196', 'Var', (280, 288))	('ES', 'Phenotype', 'HP:0012254', (110, 112))	('BCOR-CCNB3', 'Gene', '54880;85417', (37, 47))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('GSE34800', 'Var', (210, 218))	('Human', 'Species', '9606', (353, 358))	('SS', 'Phenotype', 'HP:0100242', (117, 119))	('SS', 'Phenotype', 'HP:0100242', (276, 278))
216745	29300189	FISH results typically showed inversions of both BCOR and CCNB3 and fusion of centromeric BCOR (5') to centromeric CCNB3 (3') (Fig.	('CCNB3', 'Gene', (58, 63))	('BCOR', 'Gene', (49, 53))	('CCNB3', 'Gene', (115, 120))	('BCOR', 'Gene', (90, 94))	('BCOR', 'Gene', '54880', (49, 53))	('BCOR', 'Gene', '54880', (90, 94))	('CCNB3', 'Gene', '85417', (58, 63))	('inversions', 'Var', (30, 40))	('CCNB3', 'Gene', '85417', (115, 120))
216746	29300189	In some cases, additional unbalanced alterations were observed, such as deletion of telomeric BCOR (3') signals, additional regional breaks, or deletion of the other allele.	('telomeric', 'Protein', (84, 93))	('BCOR', 'Gene', (94, 98))	('BCOR', 'Gene', '54880', (94, 98))	('deletion', 'Var', (144, 152))	('regional breaks', 'CPA', (124, 139))	('deletion', 'Var', (72, 80))
216747	29300189	Four cases evaluated by RNAseq confirmed the BCOR-CCNB3 fusion, with a similar BCOR exon 15 to CCNB3 exon 5 transcript as previously reported (Fig.	('BCOR', 'Gene', '54880', (45, 49))	('BCOR', 'Gene', '54880', (79, 83))	('CCNB3', 'Gene', '85417', (50, 55))	('CCNB3', 'Gene', '85417', (95, 100))	('BCOR-CCNB3', 'Gene', (45, 55))	('fusion', 'Var', (56, 62))	('CCNB3', 'Gene', (50, 55))	('CCNB3', 'Gene', (95, 100))	('BCOR-CCNB3', 'Gene', '54880;85417', (45, 55))	('BCOR', 'Gene', (45, 49))	('BCOR', 'Gene', (79, 83))
216777	29300189	No significant prognostic difference was found in patients with mitotic rates >=10/10 high power fields versus those with < 10/10 high power fields (p-value=1.000).	('>=10/10', 'Var', (78, 85))	('mitotic', 'CPA', (64, 71))	('patients', 'Species', '9606', (50, 58))
216787	29300189	Subsequently, BCOR was found to be a core component of a variant PRC1.1 complex associated with chromatin remodeling and histone modification.	('BCOR', 'Gene', '54880', (14, 18))	('PRC1', 'Gene', (65, 69))	('PRC1', 'Gene', '9055', (65, 69))	('variant', 'Var', (57, 64))	('associated', 'Reg', (80, 90))	('BCOR', 'Gene', (14, 18))
216793	29300189	BCOR-related translocations have also been described in hematoproliferative disorders involving different mechanisms, such as recurrent BCOR-RARA fusions (exon 12 of BCOR to exon 3 of RARA) in a small subset of acute promyelocytic leukemia; resulting in chimeric transcripts lack the PUFD domain at the C-terminus.	('acute promyelocytic leukemia', 'Disease', (211, 239))	('PUFD domain at the', 'MPA', (284, 302))	('RARA', 'Gene', '5914', (184, 188))	('hematoproliferative disorders', 'Phenotype', 'HP:0005523', (56, 85))	('BCOR', 'Gene', '54880', (136, 140))	('BCOR', 'Gene', '54880', (0, 4))	('BCOR', 'Gene', '54880', (166, 170))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (211, 239))	('hematoproliferative disorders', 'Disease', 'MESH:D030342', (56, 85))	('RARA', 'Gene', (184, 188))	('BCOR', 'Gene', (136, 140))	('BCOR', 'Gene', (0, 4))	('fusions', 'Var', (146, 153))	('RARA', 'Gene', '5914', (141, 145))	('BCOR', 'Gene', (166, 170))	('chimeric transcripts', 'MPA', (254, 274))	('lack', 'NegReg', (275, 279))	('hematoproliferative disorders', 'Disease', (56, 85))	('RARA', 'Gene', (141, 145))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (211, 239))	('leukemia', 'Phenotype', 'HP:0001909', (231, 239))
216794	29300189	BCOR inactivating mutations have also been identified in rhabdomyosarcomas and several hematologic malignancies, while germline BCOR mutation results in the oculofaciocardiodental syndrome.	('results in', 'Reg', (142, 152))	('mutation', 'Var', (133, 141))	('hematologic malignancies', 'Disease', (87, 111))	('oculofaciocardiodental syndrome', 'Disease', (157, 188))	('BCOR', 'Gene', (128, 132))	('BCOR', 'Gene', '54880', (0, 4))	('BCOR', 'Gene', '54880', (128, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (57, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (57, 74))	('identified', 'Reg', (43, 53))	('oculofaciocardiodental syndrome', 'Disease', 'MESH:C537465', (157, 188))	('hematologic malignancies', 'Disease', 'MESH:D019337', (87, 111))	('inactivating mutations', 'Var', (5, 27))	('BCOR', 'Gene', (0, 4))	('rhabdomyosarcomas', 'Disease', (57, 74))
216799	29300189	Recent data from our group have suggested that undifferentiated sarcomas characterized by BCOR genetic alterations, spanning both gene fusions and ITD, share similarities at the morphologic and immunohistochemical level, despite the wide spectrum of clinical presentations and pathologic entities involved.	('BCOR', 'Gene', (90, 94))	('genetic alterations', 'Var', (95, 114))	('BCOR', 'Gene', '54880', (90, 94))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (47, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('undifferentiated sarcomas', 'Disease', (47, 72))
216812	29300189	A further pitfall was recently revealed in a SS18-negative spindle cell sarcoma showing diffuse BCOR expression and morphologically suspected to represent a BCOR-alteration sarcoma, however, RNA sequencing found a rare SS18L1-SSX variant fusion, diagnostic of SS.	('BCOR', 'Gene', '54880', (96, 100))	('SS18', 'Gene', '6760', (45, 49))	('SS', 'Phenotype', 'HP:0100242', (260, 262))	('SS', 'Phenotype', 'HP:0100242', (219, 221))	('sarcoma', 'Disease', (173, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('SS', 'Phenotype', 'HP:0100242', (45, 47))	('BCOR', 'Gene', (96, 100))	('SS18', 'Gene', '6760', (219, 223))	('SS18L1', 'Gene', (219, 225))	('SS', 'Phenotype', 'HP:0100242', (226, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('variant', 'Var', (230, 237))	('BCOR', 'Gene', '54880', (157, 161))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('BCOR', 'Gene', (157, 161))	('SS18', 'Gene', (45, 49))	('found', 'Reg', (206, 211))	('SS18L1', 'Gene', '26039', (219, 225))	('sarcoma', 'Disease', (72, 79))	('SS18', 'Gene', (219, 223))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))
216819	29300189	As BCS often presents as an intra-osseous lesion with a round cell/undifferentiated phenotype, expression of SATB2 might suggest an osteoblastic line of differentiation and be misinterpreted as a small cell osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('SATB2', 'Gene', (109, 114))	('BCS', 'Disease', (3, 6))	('suggest', 'Reg', (121, 128))	('expression', 'Var', (95, 105))	('intra-osseous lesion', 'Disease', 'MESH:D001845', (28, 48))	('SATB2', 'Gene', '23314', (109, 114))	('osteoblastic line of differentiation', 'CPA', (132, 168))	('small cell osteosarcoma', 'Disease', (196, 219))	('osteosarcoma', 'Phenotype', 'HP:0002669', (207, 219))	('intra-osseous lesion', 'Disease', (28, 48))	('small cell osteosarcoma', 'Disease', 'MESH:D012516', (196, 219))
216830	29300189	Our study analyzed the clinical outcome of 22 BCS patients (mean follow-up: 38 months) showing that the overall survival of BCS (3-year: 93%, 5-year: 72%), is superior to CIC-rearranged sarcomas, while not statistically different from ES and SS.	('CIC-rearranged sarcomas', 'Disease', 'MESH:D012509', (171, 194))	('patients', 'Species', '9606', (50, 58))	('BCS', 'Var', (124, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('CIC-rearranged sarcomas', 'Disease', (171, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('ES', 'Phenotype', 'HP:0012254', (235, 237))	('SS', 'Phenotype', 'HP:0100242', (242, 244))	('superior', 'PosReg', (159, 167))
216844	29300189	HOX abnormalities have also been reported in various cancer types, including carcinomas of breast, colon, prostate, and lung.	('carcinomas of breast, colon', 'Disease', 'MESH:D015179', (77, 104))	('HOX', 'Gene', (0, 3))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('prostate', 'Disease', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('reported', 'Reg', (33, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('lung', 'Disease', (120, 124))	('abnormalities', 'Var', (4, 17))
216847	29300189	In conclusion, we report a large series of 36 BCS, highlighting the significant morphologic, immunohistochemical and transcriptional overlap with other primitive round/spindle cell sarcomas with BCOR gene alterations, despite differences in their demographics and clinical presentations.	('sarcomas', 'Disease', 'MESH:D012509', (181, 189))	('BCOR', 'Gene', '54880', (195, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('sarcomas', 'Disease', (181, 189))	('alterations', 'Var', (205, 216))	('BCOR', 'Gene', (195, 199))
216863	27105519	S. typhimurium A1-R was able to inhibit or eradicate primary and metastatic tumors as monotherapy in nude mouse models of major cancers, including prostate, breast, lung, pancreatic, ovarian stomach, and cervical cancer, as well as sarcoma cell lines and glioma, all of which are highly aggressive tumor models.	('inhibit', 'NegReg', (32, 39))	('eradicate', 'NegReg', (43, 52))	('tumor', 'Disease', (76, 81))	('pancreatic', 'Disease', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('cervical cancer', 'Disease', (204, 219))	('cervical cancer', 'Disease', 'MESH:D002583', (204, 219))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Disease', (298, 303))	('breast', 'Disease', (157, 163))	('cancers', 'Disease', (128, 135))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('S. typhimurium', 'Species', '90371', (0, 14))	('glioma', 'Disease', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('lung', 'Disease', (165, 169))	('sarcoma', 'Disease', 'MESH:D012509', (232, 239))	('glioma', 'Disease', 'MESH:D005910', (255, 261))	('sarcoma', 'Disease', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('prostate', 'Disease', (147, 155))	('tumors', 'Disease', (76, 82))	('A1-R', 'Var', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('mouse', 'Species', '10090', (106, 111))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('ovarian stomach', 'Disease', (183, 198))	('pancreatic', 'Disease', 'MESH:D010195', (171, 181))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('ovarian stomach', 'Disease', 'MESH:D013274', (183, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('tumors', 'Disease', 'MESH:D009369', (76, 82))
216865	27105519	However, S. typhimurium A1-R significantly inhibited tumor growth compared to the untreated mice.	('inhibited', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('S. typhimurium', 'Species', '90371', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('S. typhimurium', 'Var', (9, 23))	('mice', 'Species', '10090', (92, 96))
216866	27105519	These results suggest tumor-targeting S. typhimurium A1-R is a promising treatment for chemo-resistant soft tissue sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('sarcoma', 'Disease', (115, 122))	('S. typhimurium', 'Var', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('tumor', 'Disease', (22, 27))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (103, 122))	('S. typhimurium', 'Species', '90371', (38, 52))
216868	27105519	This sarcoma PDOX was sensitive to DOX and S. typhimurium A1-R followed by DOX, could eradicate this tumor.	('DOX', 'Chemical', 'MESH:D004317', (35, 38))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('DOX', 'Chemical', 'MESH:D004317', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('sarcoma', 'Disease', (5, 12))	('S. typhimurium', 'Species', '90371', (43, 57))	('DOX', 'Chemical', 'MESH:D004317', (75, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('S. typhimurium', 'Var', (43, 57))
216879	27105519	The tumor-volume ratio in Group 5, S. typhimurium A1-R (3.11 +- 2.05, p < 0.01); Group 6, S. typhimurium A1-R and DOX (2.80 +- 1.72, p < 0.01); and Group 7, S. typhimurium A1-R and BEZ (3.28 +- 4.62, p < 0.05) were significantly lower than in Group 1, untreated control (19.44 +- 6.70) (Figure 3B).	('tumor', 'Disease', (4, 9))	('S. typhimurium', 'Species', '90371', (35, 49))	('S. typhimurium A1-R', 'Var', (157, 176))	('BEZ', 'Chemical', '-', (181, 184))	('S. typhimurium', 'Species', '90371', (90, 104))	('DOX', 'Chemical', 'MESH:D004317', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('lower', 'NegReg', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('S. typhimurium', 'Species', '90371', (157, 171))
216882	27105519	The goal of this experiment was to determine if S. typhimurium A1-R could sensitize the tumor by decoying the quiescent cells in the tumor to begin to cycle and therefore become more responsive to the chemotherapy.	('S. typhimurium', 'Species', '90371', (48, 62))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('A1-R', 'Var', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('S. typhimurium A1-R', 'Var', (48, 67))	('quiescent cells in the', 'MPA', (110, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('more', 'PosReg', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (88, 93))	('decoying', 'NegReg', (97, 105))
216892	27105519	Since S. typhimurium A1-R is a facultative anaerobe, unlike C. novyi-NT which is an obligate anaerobe, it may have more broad application for cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('C. novyi-NT', 'Species', '386415', (60, 71))	('S. typhimurium', 'Var', (6, 20))	('S. typhimurium', 'Species', '90371', (6, 20))
216896	27105519	The results of the present study suggest S. typhimurium A1-R is a candidate for clinical trial to treat DOX-resistant FDCS.	('DOX-resistant FDCS', 'Disease', (104, 122))	('DOX', 'Chemical', 'MESH:D004317', (104, 107))	('S. typhimurium', 'Species', '90371', (41, 55))	('S. typhimurium', 'Var', (41, 55))
217001	33680643	On the molecular level, ES is associated with deletions and cytogenic translocations between short arms of chromosomes 12 and 22 t(12;22)(q13;q12) that are associated with the chimeric fusion EWSR1/ATF1 gene transcript and promotes growth of the tumor.	('EWSR1', 'Gene', '2130', (192, 197))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (129, 146))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('promotes', 'PosReg', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('associated', 'Reg', (156, 166))	('ATF1', 'Gene', (198, 202))	('growth', 'CPA', (232, 238))	('chimeric fusion', 'Var', (176, 191))	('short arms', 'Phenotype', 'HP:0009824', (93, 103))	('tumor', 'Disease', (246, 251))	('deletions', 'Var', (46, 55))	('ATF1', 'Gene', '466', (198, 202))	('EWSR1', 'Gene', (192, 197))
217014	33680643	Koulaxouzidis et al documented higher recurrence for patients undergoing R1 microscopic incomplete resection compared with R0 complete resection, which punctuates the need for a tumor-free resection.	('recurrence', 'MPA', (38, 48))	('tumor', 'Disease', (178, 183))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('R1 microscopic', 'Var', (73, 87))	('higher', 'PosReg', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
217031	33214228	Abnormal NLR and PLR levels were associated with higher all-cause mortality (NLR: HR 1.698, p<0.001, 95% CI 1.424 to 2.025; PLR: HR 1.346, p<0.001, 95% CI 1.164 to 1.555) and cancer-related mortality (NLR: HR 1.648, p<0.001, 95% CI 1.341 to 2.024; PLR: HR 1.430, p<0.001, 95% CI 1.205 to 1.697).	('mortality', 'Disease', (190, 199))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('mortality', 'Disease', 'MESH:D003643', (66, 75))	('Abnormal', 'Var', (0, 8))	('mortality', 'Disease', 'MESH:D003643', (190, 199))	('higher', 'PosReg', (49, 55))	('mortality', 'Disease', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
217065	33214228	Abnormal serum LDH was defined by (1) for men, <106 U/L or >218 U/L; (2) for women, <103 U/L or >199 U/L.	('men', 'Species', '9606', (79, 82))	('men', 'Species', '9606', (42, 45))	('women', 'Species', '9606', (77, 82))	('<103 U/L', 'Var', (84, 92))	('<106 U/L', 'Var', (47, 55))
217090	33214228	CCI >=7 led to 2.391 times risks of all-cause mortality (p=0.001).	('CCI >=7', 'Var', (0, 7))	('mortality', 'Disease', (46, 55))	('mortality', 'Disease', 'MESH:D003643', (46, 55))
217091	33214228	Patients with abnormal NLR, PLR and serum LDH were under the risk of all-cause mortality by 1.698 (p<0.001), 1.346 (p<0.001) and 1.355 (p<0.001) times, respectively.	('NLR', 'Gene', (23, 26))	('serum LDH', 'Gene', (36, 45))	('abnormal', 'Var', (14, 22))	('LDH', 'Gene', (42, 45))	('mortality', 'Disease', 'MESH:D003643', (79, 88))	('Patients', 'Species', '9606', (0, 8))	('mortality', 'Disease', (79, 88))
217108	33214228	The HR for all-cause mortality in patients with abnormal NLR and abnormal PLR vs normal NLR and PLR were 1.698 (95% CI 1.42 to 2.025) and 1.346 (95% CI 1.164 to 1.555), respectively.	('abnormal', 'Var', (65, 73))	('abnormal', 'Var', (48, 56))	('mortality', 'Disease', 'MESH:D003643', (21, 30))	('patients', 'Species', '9606', (34, 42))	('mortality', 'Disease', (21, 30))
217109	33214228	Similar results are also seen in cancer-specific mortality (Abnormal NLR: HR 1.648 (95% CI 1.341 to 2.204) and Abnormal PLR: 1.430 (95% CI 1.205 to 1.697)).	('Abnormal', 'Var', (111, 119))	('mortality', 'Disease', (49, 58))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mortality', 'Disease', 'MESH:D003643', (49, 58))
217138	33214228	A total of 121 within the 3358 patients who met eligibility criteria (3.6%) were concurrently coded for ICD-9-CM 170.x as well as ICD-9-CM 171.x, indicating the presence of both bone & articular cartilage as well as connective and STS.	('ICD-9-CM 171.x', 'Var', (130, 144))	('patients', 'Species', '9606', (31, 39))	('ICD-9-CM 170.x', 'Var', (104, 118))
217163	31086240	In a meta-analysis from 2008, the combination of doxorubicin and ifosfamide was associated with an overall survival (OS) benefit and an absolute risk reduction of 11%.	('OS', 'Chemical', '-', (117, 119))	('doxorubicin', 'Var', (49, 60))	('ifosfamide', 'Chemical', 'MESH:D007069', (65, 75))	('overall survival', 'MPA', (99, 115))	('benefit', 'PosReg', (121, 128))	('reduction', 'NegReg', (150, 159))	('doxorubicin', 'Chemical', 'MESH:D004317', (49, 60))
217278	29580035	Many soft tissue tumors show recurrent genetic mutations that are now being used as diagnostic markers.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('genetic mutations', 'Var', (39, 56))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (5, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
217283	29580035	EWS gene fusion was detected in 7 out of 8 cases of Ewing sarcoma and the X: 18 translocation was positive in 3 of the 8 cases of synovial sarcoma.	('detected', 'Reg', (20, 28))	('synovial sarcoma', 'Disease', (130, 146))	('gene fusion', 'Var', (4, 15))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))	('Ewing sarcoma', 'Disease', (52, 65))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (130, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('synovial sarcoma', 'Disease', 'MESH:D013584', (130, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('EWS', 'Gene', (0, 3))
217297	29580035	FISH studies related to soft tissue sarcomas which we use in our department are EWSR1 gene fusion for Ewing sarcoma family of tumors, FOXO1 for Alveolar rhabdomyosarcoma, MDM2 gene amplification for atypical lipomatous tumors/well differentiated liposarcoma and dedifferentiated liposarcoma and X:18 translocation for synovial sarcoma.	('liposarcoma', 'Disease', 'MESH:D008080', (279, 290))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('liposarcoma', 'Disease', 'MESH:D008080', (246, 257))	('atypical lipomatous tumors', 'Disease', (199, 225))	('lipomatous tumors', 'Phenotype', 'HP:0012031', (208, 225))	('lipoma', 'Phenotype', 'HP:0012032', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (126, 132))	('synovial sarcoma', 'Disease', (318, 334))	('soft tissue sarcomas', 'Disease', (24, 44))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('FOXO1', 'Gene', (134, 139))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('Alveolar rhabdomyosarcoma', 'Disease', (144, 169))	('synovial sarcoma', 'Disease', 'MESH:D013584', (318, 334))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('liposarcoma', 'Disease', (279, 290))	('MDM', 'Disease', 'MESH:D007645', (171, 174))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (24, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (283, 290))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (24, 44))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('liposarcoma', 'Disease', (246, 257))	('X:18 translocation', 'Var', (295, 313))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (219, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('MDM', 'Disease', (171, 174))	('Alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (144, 169))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (318, 334))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (153, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('liposarcoma', 'Phenotype', 'HP:0012034', (279, 290))	('Ewing sarcoma', 'Disease', (102, 115))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('EWSR1', 'Gene', (80, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('Alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (144, 169))	('liposarcoma', 'Phenotype', 'HP:0012034', (246, 257))	('lipomatous tumor', 'Phenotype', 'HP:0012031', (208, 224))	('atypical lipomatous tumors', 'Disease', 'MESH:D008080', (199, 225))
217312	29580035	Detection of X:18 translocation, specific to synovial sarcoma can help in differentiating it from its mimickers (Foo et al., 2011; Terry et al., 2005).	('X:18 translocation', 'Var', (13, 31))	('synovial sarcoma', 'Disease', (45, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (45, 61))	('synovial sarcoma', 'Disease', 'MESH:D013584', (45, 61))
217374	29580035	Three cases in our study showed break apart of SYT gene confirming the diagnosis of synovial sarcoma.	('synovial sarcoma', 'Disease', (84, 100))	('SYT gene', 'Gene', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('break apart', 'Var', (32, 43))	('synovial sarcoma', 'Disease', 'MESH:D013584', (84, 100))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (84, 100))	('break apart', 'Phenotype', 'HP:0001061', (32, 43))
217376	29580035	Terry et al found X:18 chromosomal translocation in 22 out of 23 synovial sarcomas diagnosed histologically, while none of the other sarcomas tested were positive for this translocation.	('sarcomas', 'Disease', (74, 82))	('sarcomas', 'Disease', (133, 141))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (65, 81))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (65, 82))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('synovial sarcomas', 'Disease', 'MESH:D013584', (65, 82))	('synovial sarcomas', 'Disease', (65, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('chromosomal translocation', 'Var', (23, 48))
217460	23180926	Although the exact pathogenesis remains speculative, emerging evidence regards AA as an organ-specific autoimmune disease mediated by either CD4+ or CD8+ T cells.	('autoimmune disease', 'Disease', 'MESH:D001327', (103, 121))	('CD8+', 'Var', (149, 153))	('autoimmune disease', 'Disease', (103, 121))	('autoimmune disease', 'Phenotype', 'HP:0002960', (103, 121))
217608	26718692	BRAF, TP53, KRAS, KIT, ERBB2, MET, RET, ATM, and EGFR mutations were detected in 4 of the 5 tissue samples.	('EGFR', 'Gene', '1956', (49, 53))	('ERBB2', 'Gene', (23, 28))	('ERBB2', 'Gene', '2064', (23, 28))	('detected', 'Reg', (69, 77))	('KIT', 'Gene', (18, 21))	('TP53', 'Gene', (6, 10))	('ATM', 'Gene', (40, 43))	('RET', 'Gene', '5979', (35, 38))	('EGFR', 'Gene', (49, 53))	('TP53', 'Gene', '7157', (6, 10))	('mutations', 'Var', (54, 63))	('KRAS', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (0, 4))	('RET', 'Gene', (35, 38))	('KRAS', 'Gene', '3845', (12, 16))	('ATM', 'Gene', '472', (40, 43))	('BRAF', 'Gene', (0, 4))	('MET', 'Gene', (30, 33))
217695	26718692	In the El Ghatany study, the survival duration was shorter in patients with <GTR, metastatic disease, and age <1 year at diagnosis.	('survival', 'MPA', (29, 37))	('shorter', 'NegReg', (51, 58))	('metastatic disease', 'CPA', (82, 100))	('patients', 'Species', '9606', (62, 70))	('<GTR', 'Var', (76, 80))
217696	26718692	reported a trend toward a poorer outcome in patients with <GTR and sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('patients', 'Species', '9606', (44, 52))	('sarcoma', 'Disease', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('<GTR', 'Var', (58, 62))
217697	26718692	In our series, patients who had GTR of the tumor had a trend towards superior survival.	('patients', 'Species', '9606', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('GTR', 'Var', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('superior', 'PosReg', (69, 77))
217700	26718692	KIT and MET mutations were reported to play a role in tumorigenesis in osteosarcoma and rhabdomyosarcoma, with prognostic implications.	('osteosarcoma and rhabdomyosarcoma', 'Disease', 'MESH:D012516', (71, 104))	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('MET', 'Gene', (8, 11))	('tumor', 'Disease', (54, 59))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (88, 104))	('KIT', 'Gene', (0, 3))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))
217701	26718692	TP53 mutations are more common in osteosarcoma than in rhabdomyosarcoma and Ewing sarcoma.	('TP53', 'Gene', '7157', (0, 4))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('TP53', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('osteosarcoma', 'Phenotype', 'HP:0002669', (34, 46))	('osteosarcoma', 'Disease', (34, 46))	('osteosarcoma', 'Disease', 'MESH:D012516', (34, 46))	('mutations', 'Var', (5, 14))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (55, 71))	('Ewing sarcoma', 'Disease', (76, 89))	('common', 'Reg', (24, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (55, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('rhabdomyosarcoma', 'Disease', (55, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (76, 89))
217703	26718692	reported the presence of BRAF and KRAS mutations in Ewing sarcoma and rhabdomyosarcoma, indicating a role for RAS pathway activation in sarcoma tumorigenesis.	('sarcoma', 'Disease', (79, 86))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (70, 86))	('Ewing sarcoma', 'Disease', (52, 65))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (70, 86))	('KRAS', 'Gene', '3845', (34, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('mutations', 'Var', (39, 48))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('sarcoma', 'Disease', (58, 65))	('KRAS', 'Gene', (34, 38))	('presence', 'Reg', (13, 21))	('tumor', 'Disease', (144, 149))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('sarcoma', 'Disease', (136, 143))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('rhabdomyosarcoma', 'Disease', (70, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
217711	26718692	Inhibition of PDGFRA had a dramatic effect on tumor cell growth, both in vitro and in vivo, and has proven beneficial in several types of sarcomas.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('PDGFRA', 'Gene', (14, 20))	('tumor', 'Disease', (46, 51))	('PDGFRA', 'Gene', '5156', (14, 20))	('effect', 'Reg', (36, 42))	('sarcomas', 'Disease', (138, 146))	('Inhibition', 'Var', (0, 10))	('beneficial', 'PosReg', (107, 117))
217712	26718692	The most common mutations in our cohort involved KIT and TP53 (2 of the 4 samples); other mutations involved BRAF, RET, KRAS, ATM, EGFR, ERBB2, and MET (details in Table 2).	('ATM', 'Gene', '472', (126, 129))	('KRAS', 'Gene', '3845', (120, 124))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('mutations', 'Var', (16, 25))	('ERBB2', 'Gene', (137, 142))	('ERBB2', 'Gene', '2064', (137, 142))	('RET', 'Gene', '5979', (115, 118))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('ATM', 'Gene', (126, 129))	('KRAS', 'Gene', (120, 124))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('MET', 'Gene', (148, 151))	('RET', 'Gene', (115, 118))	('KIT', 'Gene', (49, 52))
217754	24213507	The ploidy status as defined by FCM-base histograms (Figure 1) was normal (diploid) in all non-malignant lesions except one lipoma with a small (10% of all nuclei) aneuploid peak (DI 1.20).	('lipoma', 'Disease', 'MESH:D008067', (124, 130))	('lipoma', 'Phenotype', 'HP:0012032', (124, 130))	('aneuploid', 'Var', (164, 173))	('lipoma', 'Disease', (124, 130))
217757	24213507	There were 42 aneuploid cases out of 77 primary malignant tumors (55%), and four (5%) PD cases.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('aneuploid', 'Var', (14, 23))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('PD', 'Disease', 'MESH:D010300', (86, 88))	('malignant tumors', 'Disease', (48, 64))	('malignant tumors', 'Disease', 'MESH:D018198', (48, 64))
217772	24213507	Aneuploid STS more often had metastases than diploid STS (p = 0.0092).	('metastases', 'Disease', 'MESH:D009362', (29, 39))	('metastases', 'Disease', (29, 39))	('Aneuploid STS', 'Var', (0, 13))
217781	24213507	As in earlier studies in mammary malignant tumors in dogs and in humans, we were also able to demonstrate a relation between ploidy status and risk of metastases in STS.	('dogs', 'Species', '9615', (53, 57))	('malignant tumors', 'Disease', (33, 49))	('malignant tumors', 'Disease', 'MESH:D018198', (33, 49))	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('ploidy status', 'Var', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('humans', 'Species', '9606', (65, 71))	('metastases', 'Disease', (151, 161))
217783	24213507	Striking was the absolute lack of a relation between ploidy status and risk of metastasis in OS, which is in contrast to OS in humans.	('metastasis', 'CPA', (79, 89))	('ploidy', 'Var', (53, 59))	('humans', 'Species', '9606', (127, 133))
217784	24213507	In diploid cases within particular types of cancer more detailed cytogenetic analyses are required to discern those changes that predict metastatic behavior.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('metastatic behavior', 'CPA', (137, 156))	('diploid', 'Var', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
217798	24213507	More subtle and sometimes balanced chromosomal gains and losses have been observed by cytogenetic analysis in some such human cancers including sarcomas, and also in canine sarcomas and carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (120, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (144, 152))	('chromosomal gains', 'Var', (35, 52))	('sarcomas and carcinomas', 'Disease', 'MESH:D012509', (173, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('sarcomas', 'Disease', (144, 152))	('canine', 'Species', '9615', (166, 172))	('losses', 'NegReg', (57, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('sarcomas', 'Disease', 'MESH:D012509', (173, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (173, 181))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('sarcomas', 'Disease', (173, 181))	('sarcomas', 'Disease', 'MESH:D012509', (144, 152))
217803	24213507	In cancers that harbour significant chromosomal alterations, even if not recognized as DNA-aneuploid, the cause underlying this chromosomal instability has been subject of study and aberrations in many pathways, in particular those related to sister chromatid cohesion and segregation have been suggested as possible causes.	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('chromosomal alterations', 'Var', (36, 59))	('cancers', 'Disease', (3, 10))	('chromosomal instability', 'Phenotype', 'HP:0040012', (128, 151))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('aberrations', 'Var', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
217805	24213507	Although it must be recognized that analysis for P53 mutations concerns only part of the many elements involved in the P53 pathway, our results are in clear contrast with a study in human sarcomas that demonstrated a relation between the presence of P53 mutations and DNA-aneuploidy.	('P53', 'Gene', (250, 253))	('sarcomas', 'Disease', (188, 196))	('aneuploidy', 'Disease', (272, 282))	('human', 'Species', '9606', (182, 187))	('aneuploidy', 'Disease', 'MESH:D000782', (272, 282))	('mutations', 'Var', (53, 62))	('P53', 'Gene', (49, 52))	('sarcomas', 'Disease', 'MESH:D012509', (188, 196))	('sarcomas', 'Phenotype', 'HP:0100242', (188, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('mutations', 'Var', (254, 263))
217809	24213507	There is no doubt that many malignancies with full malignant potential are aneuploid, reflecting gross quantitative genomic destabilization.	('malignancies', 'Disease', (28, 40))	('aneuploid', 'Var', (75, 84))	('malignancies', 'Disease', 'MESH:D009369', (28, 40))
217811	24213507	Functional changes that may allow malignant behavior in such cancers may include P53 inactivation or MDM2 amplification as well as many other genetic alterations.	('P53', 'Gene', (81, 84))	('MDM2', 'Gene', '403693', (101, 105))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('allow', 'Reg', (28, 33))	('amplification', 'Var', (106, 119))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('MDM2', 'Gene', (101, 105))
217812	24213507	To some extent and for some types of sarcomas (such as MPNST and leiomyosarcoma), a diploid status is then related to low metastatic potential.	('diploid status', 'Var', (84, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (65, 79))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('leiomyosarcoma', 'Disease', (65, 79))	('low metastatic potential', 'CPA', (118, 142))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (65, 79))	('MPNST', 'Disease', (55, 60))	('sarcomas', 'Disease', (37, 45))
217816	24213507	Sometimes, haploidization or duplication of such stemlines occurs, with variation between metastases.	('haploidization', 'Var', (11, 25))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('metastases', 'Disease', (90, 100))	('duplication', 'Var', (29, 40))
217843	24213507	In two earlier studies, part of the sarcomas had been analyzed for the presence of p53 mutations.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '403869', (83, 86))	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('sarcomas', 'Disease', (36, 44))	('mutations', 'Var', (87, 96))
217846	24213507	Only mutations predicted to affect the amino-acid sequence of the p53 gene including point mutations, deletions and insertions, and mutations of the splice site were counted.	('insertions', 'Var', (116, 126))	('point mutations', 'Var', (85, 100))	('deletions', 'Var', (102, 111))	('p53', 'Gene', '403869', (66, 69))	('p53', 'Gene', (66, 69))
217901	31380289	In brief, the cancers described in this manuscript include all sarcomas from soft tissue and from bone, including ICD-O-3 M codes 8800-8935, 8910, 8920, 8936, 8940, 8950-8959, 8963-8964, 8990-8991, 9020-9044, 9120-9133, 9150, 9170, 9180-9251, 9260-9261, 9364-9372, 9540-9581 combined with all ICD-O-3 T codes (C00-C80).	('9540-9581', 'Var', (265, 274))	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('sarcomas', 'Disease', (63, 71))	('8940', 'Var', (159, 163))	('9364-9372', 'Var', (254, 263))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('9150', 'Var', (220, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('8936', 'Var', (153, 157))	('9170', 'Var', (226, 230))	('sarcomas from soft tissue', 'Phenotype', 'HP:0100242', (63, 88))	('8963-8964', 'Var', (176, 185))	('9180-9251', 'Var', (232, 241))	('8800-8935', 'Var', (130, 139))	('8950-8959', 'Var', (165, 174))	('9020-9044', 'Var', (198, 207))	('9120-9133', 'Var', (209, 218))	('8910', 'Var', (141, 145))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancers', 'Disease', (14, 21))	('8920', 'Var', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('8990-8991', 'Var', (187, 196))	('9260-9261', 'Var', (243, 252))	('sarcomas', 'Disease', 'MESH:D012509', (63, 71))
217942	31380289	A previous report in Beijing on STS, only including the cases diagnosed with sites of C47 and C49, showed that the incidence was lower than our findings, with CR and ASR 1.2/105 and 0.9/105, respectively.	('STS', 'Phenotype', 'HP:0030448', (32, 35))	('C49', 'Var', (94, 97))	('CR', 'Chemical', 'MESH:D002857', (159, 161))	('C47', 'Var', (86, 89))	('ASR', 'Chemical', '-', (166, 169))
218099	23878485	Ionizing radiation has been shown to cause genetic defects including defects in p53 expression which may predispose to cancer.	('defects', 'Var', (69, 76))	('genetic defects', 'Disease', 'MESH:D030342', (43, 58))	('Ionizing radiation', 'Disease', (0, 18))	('p53', 'Gene', (80, 83))	('genetic defects', 'Disease', (43, 58))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('Ionizing radiation', 'Disease', 'MESH:D004194', (0, 18))	('cancer', 'Disease', (119, 125))	('p53', 'Gene', '7157', (80, 83))	('predispose', 'Reg', (105, 115))	('expression', 'MPA', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
218178	31861000	Angiogenesis is essential for the growth and progression of solid tumors, and inhibition of VEGF signaling, which plays a key role in angiogenesis, has been a promising anticancer approach.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('solid tumors', 'Disease', 'MESH:D009369', (60, 72))	('inhibition', 'Var', (78, 88))	('VEGF', 'Gene', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('VEGF', 'Gene', '7422', (92, 96))	('solid tumors', 'Disease', (60, 72))
218191	31861000	One major challenge to conventional antineoplastic drug therapy is multidrug resistance (MDR), which greatly decreases the efficacy of cancer chemotherapy.	('cancer', 'Disease', (135, 141))	('multidrug', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('decreases', 'NegReg', (109, 118))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('efficacy', 'CPA', (123, 131))
218240	29849658	The highest values of D95% for PTV50 and PTV66 are obtained by IMRT and RA, respectively.	('D95', 'Var', (22, 25))	('PTV50', 'Var', (31, 36))	('PTV66', 'Var', (41, 46))	('RA', 'Chemical', '-', (72, 74))
218243	29849658	The mean doses to the heart increased with IMRT and RA, compared to 3D-CRT.	('doses', 'MPA', (9, 14))	('IMRT', 'Var', (43, 47))	('increased', 'PosReg', (28, 37))	('RA', 'Chemical', '-', (52, 54))
218346	27911942	Furthermore, several studies demonstrated a correlation between a high cortactin expression and a poor prognosis in several types of human neoplasms such as oesophageal squamous cell carcinoma, pancreatic and colorectal adenocarcinoma and laryngeal carcinoma.	('oesophageal squamous cell carcinoma', 'Disease', (157, 192))	('neoplasms', 'Phenotype', 'HP:0002664', (139, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('cortactin', 'Gene', (71, 80))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (157, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (239, 258))	('human', 'Species', '9606', (133, 138))	('neoplasms', 'Disease', 'MESH:D009369', (139, 148))	('neoplasms', 'Disease', (139, 148))	('high', 'Var', (66, 70))	('neoplasm', 'Phenotype', 'HP:0002664', (139, 147))	('pancreatic and colorectal adenocarcinoma and laryngeal carcinoma', 'Disease', 'MESH:D010190', (194, 258))	('expression', 'MPA', (81, 91))
218424	27863505	A specific translocation, t(11;22)(p13;q12), resulting in EWS and WT1 gene fusion is the only recurrent molecular hallmark and no other genetic factor has been associated to this aggressive tumor.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('resulting in', 'Reg', (45, 57))	('WT1', 'Gene', '7490', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('WT1', 'Gene', (66, 69))	('tumor', 'Disease', (190, 195))	('t(11;22)(p13;q12', 'Var', (26, 42))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (26, 43))	('EWS', 'Gene', (58, 61))	('EWS', 'Gene', '2130', (58, 61))
218427	27863505	The deletions at 11p and 22q indicated the presence of the classic translocation, t(11;22)(p13;q12).	('t(11;22)(p13;q12', 'Var', (82, 98))	('deletions', 'Var', (4, 13))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (82, 99))
218437	27863505	Variants of unknown clinical significance were reported in ARID1A and RUNX1 genes in one patient, whereas in another study, no mutations were detected in a panel of 29 genes evaluated in a cohort of 24 DSRCT cases.	('Variants', 'Var', (0, 8))	('patient', 'Species', '9606', (89, 96))	('RUNX1', 'Gene', '861', (70, 75))	('ARID1A', 'Gene', '8289', (59, 65))	('ARID1A', 'Gene', (59, 65))	('RUNX1', 'Gene', (70, 75))
218440	27863505	We identified somatic mutations in a genomic background of rare germline variants either homozygous or as compound heterozygous inheritance, which can improve the understanding of the genetic basis of this rare tumor.	('variants', 'Var', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (211, 216))
218457	27863505	Copy number alterations were detected using the bioinformatics packages Excavator (version 2.2) and cn.mops (version 1.8.9) by comparing exome data from the tumor to leukocyte from the patient.	('tumor', 'Disease', (157, 162))	('exome', 'MPA', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('patient', 'Species', '9606', (185, 192))	('Copy number alterations', 'Var', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
218479	27863505	The analysis of the tumor revealed 15 somatic acquired mutations, 12 of which were protein-affecting variants (validated by capillary sequencing) including one non-sense mutation in the ZNF808 gene, one nucleotide change at the 3' splice site of RIMS4, and 10 missense mutations considered disease associated by at least one pathogenicity prediction program (Table 1).	('RIMS4', 'Gene', '140730', (246, 251))	('missense mutations', 'Var', (260, 278))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('ZNF808', 'Gene', '388558', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ZNF808', 'Gene', (186, 192))	('RIMS4', 'Gene', (246, 251))	('tumor', 'Disease', (20, 25))
218480	27863505	Gene ontology enrichment analysis of the 12 genes harboring protein-affecting somatic mutations revealed several biological processes such as muscle tissue/organ development (ZFPM2 and MEGF10), which is related to the mesothelium origin of this tumor, cell adhesion (DPP4, CDH9, CNTNAP4, MEGF10), response to mechanic stimulus (MEIS2, TRPA4), and response to abiotic stimulus (DPP4, MEIS2, TRPA1) (Additional file 3: Table S2).	('ZFPM2', 'Gene', '23414', (175, 180))	('ZFPM2', 'Gene', (175, 180))	('MEGF10', 'Gene', '84466', (185, 191))	('CDH9', 'Gene', (273, 277))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('DPP4', 'Gene', '1803', (267, 271))	('CDH9', 'Gene', '1007', (273, 277))	('DPP4', 'Gene', '1803', (377, 381))	('MEIS2', 'Gene', '4212', (328, 333))	('CNTNAP4', 'Gene', (279, 286))	('MEIS2', 'Gene', (328, 333))	('CNTNAP4', 'Gene', '85445', (279, 286))	('cell adhesion', 'CPA', (252, 265))	('TRPA1', 'Gene', (390, 395))	('MEIS2', 'Gene', '4212', (383, 388))	('mutations', 'Var', (86, 95))	('DPP4', 'Gene', (267, 271))	('MEIS2', 'Gene', (383, 388))	('DPP4', 'Gene', (377, 381))	('tumor', 'Disease', (245, 250))	('MEGF10', 'Gene', (288, 294))	('TRPA1', 'Gene', '8989', (390, 395))	('muscle tissue/organ development', 'CPA', (142, 173))	('MEGF10', 'Gene', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('MEGF10', 'Gene', '84466', (288, 294))
218481	27863505	Intriguingly, biological network analysis obtained using Ingenuity Pathway Analysis (IPA) interconnected the 15 genes harboring somatic mutations in a single network associated with cell death and survival, cell damage or degeneration, and nervous system development and function (Fig.	('degeneration', 'Disease', (222, 234))	('degeneration', 'Disease', 'MESH:D009410', (222, 234))	('mutations', 'Var', (136, 145))	('associated', 'Reg', (166, 176))	('nervous system development', 'CPA', (240, 266))
218482	27863505	In an attempt to identify de novo germline mutations and inherited variants potentially associated with DSRCT, we performed whole-exome sequencing of the leukocyte DNA from the patient's parents (Additional file 2: Table S1).	('associated', 'Reg', (88, 98))	('patient', 'Species', '9606', (177, 184))	('variants', 'Var', (67, 75))	('DSRCT', 'Disease', (104, 109))
218490	27863505	The detection of copy number losses affecting terminal segments of 11p and 22q suggested the presence of the chromosomal translocation t(11;22)(p13;q12) involving EWSR1 and WT1 genes.	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (135, 152))	('EWSR1', 'Gene', (163, 168))	('WT1', 'Gene', '7490', (173, 176))	('t(11;22)(p13;q12', 'Var', (135, 151))	('copy number losses', 'Var', (17, 35))	('WT1', 'Gene', (173, 176))	('EWSR1', 'Gene', '2130', (163, 168))
218491	27863505	Additionally, we used NGS data from the WES of the tumor and patient's leukocyte to search for CNAs, and 98.4% of the events detected by array CGH were validated, demonstrating the efficacy of WES for identification of a wide range of somatic events, besides point mutations and indels (Fig.	('point mutations', 'Var', (259, 274))	('patient', 'Species', '9606', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('CGH', 'Gene', (143, 146))	('CGH', 'Gene', '3342', (143, 146))	('indels', 'Var', (279, 285))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
218492	27863505	The genomic translocation t(11;22)(p13;q12), which is considered the molecular hallmark of this tumor type, was initially detected by FISH analysis for diagnostic purposes.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('t(11;22)(p13;q12', 'Var', (26, 42))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (26, 43))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
218506	27863505	More recently, a study based on targeted exome sequencing of six adult patients with pediatric-type malignancies found AURKB and MCL1 amplifications and variants of unknown clinical significance in ARID1A and RUNX1 genes in one DSRCT.	('DSRCT', 'Disease', (228, 233))	('AURKB', 'Gene', '9212', (119, 124))	('MCL1', 'Gene', (129, 133))	('AURKB', 'Gene', (119, 124))	('patients', 'Species', '9606', (71, 79))	('RUNX1', 'Gene', (209, 214))	('variants', 'Var', (153, 161))	('pediatric-type malignancies', 'Disease', (85, 112))	('pediatric-type malignancies', 'Disease', 'MESH:D063766', (85, 112))	('ARID1A', 'Gene', (198, 204))	('ARID1A', 'Gene', '8289', (198, 204))	('RUNX1', 'Gene', '861', (209, 214))	('MCL1', 'Gene', '4170', (129, 133))
218513	27863505	Another interesting finding is that among the set of somatically mutated genes, 8 showed to be mutated in desmoplastic melanoma samples from TCGA project, in frequencies ranging from 5 to 25% of the 20 samples interrogated.	('mutated', 'Var', (95, 102))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (106, 127))	('desmoplastic melanoma', 'Disease', (106, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))
218514	27863505	This data suggests that mutation in these genes might be involved with the desmoplastic phenotype, seen in both tumor types.	('desmoplastic', 'Disease', 'MESH:D018220', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutation', 'Var', (24, 32))	('desmoplastic', 'Disease', (75, 87))	('tumor', 'Disease', (112, 117))	('involved', 'Reg', (57, 65))
218515	27863505	Additionally, 7 out of 15 genes harboring somatic mutations (CHL1, MEGF10, MEIS2, MYH8, RIMS4, TBPL1, and ZFPM2) are regulated by the same transcription factor, LEF1 (p < 0.001 by enrichment analysis), which, in turn, is regulated by WT1.	('WT1', 'Gene', (234, 237))	('TBPL1', 'Gene', '9519', (95, 100))	('TBPL1', 'Gene', (95, 100))	('MYH8', 'Gene', (82, 86))	('WT1', 'Gene', '7490', (234, 237))	('MEIS2', 'Gene', (75, 80))	('MEIS2', 'Gene', '4212', (75, 80))	('LEF1', 'Gene', (161, 165))	('MEGF10', 'Gene', (67, 73))	('CHL1', 'Gene', (61, 65))	('MYH8', 'Gene', '4626', (82, 86))	('RIMS4', 'Gene', (88, 93))	('MEGF10', 'Gene', '84466', (67, 73))	('regulated', 'Reg', (117, 126))	('ZFPM2', 'Gene', '23414', (106, 111))	('CHL1', 'Gene', '10752', (61, 65))	('RIMS4', 'Gene', '140730', (88, 93))	('ZFPM2', 'Gene', (106, 111))	('mutations', 'Var', (50, 59))	('LEF1', 'Gene', '51176', (161, 165))
218519	27863505	Detection of tumor-specific genomic rearrangements has been shown as a sensitive and specific method for monitoring of disease status of cancer patients and has clear advantages over point mutations concerning the specificity of detection.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('genomic rearrangements', 'Var', (28, 50))	('patients', 'Species', '9606', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Disease', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
218527	27863505	CGH Comparative genomic hybridization CNA Copy number alterations COSMIC Catalogue of Somatic Mutations in Cancer CT Computed tomography ctDNA Circulating tumor DNA ddPCR Digital droplet PCR DSRCT Desmoplastic small round cell tumor GATK Genome Analysis Toolkit HIPEC Hyperthermic intraperitoneal chemotherapy ICE Ifosfamide, carboplatin, and etoposide Indel Small insertions and deletions IPA Ingenuity pathway analysis MAF Minor allele frequency PET Positron emission tomography SNP Simple nucleotide polymorphism TCGA The cancer genome atlas VAC Vincristine, cyclophosphamide, and doxorubicin WES Whole-sequencing	('MAF', 'Gene', (421, 424))	('tumor', 'Disease', (227, 232))	('cancer', 'Disease', (525, 531))	('tumor', 'Disease', (155, 160))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (562, 578))	('MAF', 'Gene', '4094', (421, 424))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (525, 531))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('CGH', 'Gene', '3342', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('Desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (197, 232))	('carboplatin', 'Chemical', 'MESH:D016190', (326, 337))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (525, 531))	('VAC', 'Chemical', '-', (545, 548))	('Vincristine', 'Chemical', 'MESH:D014750', (549, 560))	('CGH', 'Gene', (0, 3))	('Ifosfamide', 'Chemical', 'MESH:D007069', (314, 324))	('ICE', 'Chemical', '-', (310, 313))	('deletions', 'Var', (380, 389))	('Desmoplastic small round cell tumor', 'Disease', (197, 232))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('doxorubicin', 'Chemical', 'MESH:D004317', (584, 595))	('etoposide', 'Chemical', 'MESH:D005047', (343, 352))
218531	27656422	Current techniques for isolating sarcoma CTCs are based on size criteria, the identification of circulating cells that express either common mesenchymal markers, sarcoma-specific markers, such as CD99, CD81, or PAX3, and chromosomal translocations found in certain sarcoma subtypes, such as EWS-FLI1 in Ewing's sarcoma, detection of osteoblast-related genes, or measurement of the activity of specific metabolic enzymes.	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('CD81', 'Gene', '975', (202, 206))	('activity', 'MPA', (381, 389))	('FLI1', 'Gene', '2313', (295, 299))	('PAX3', 'Gene', (211, 215))	('chromosomal translocations', 'Var', (221, 247))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (303, 318))	('EWS', 'Gene', '2130', (291, 294))	('sarcoma', 'Disease', 'MESH:D012509', (265, 272))	('PAX3', 'Gene', '5077', (211, 215))	('sarcoma', 'Disease', (265, 272))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('CD99', 'Gene', (196, 200))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (303, 318))	('sarcoma', 'Disease', (162, 169))	('sarcoma', 'Disease', 'MESH:D012509', (311, 318))	('sarcoma', 'Disease', (311, 318))	('metabolic enzymes', 'Enzyme', (402, 419))	('CD99', 'Gene', '4267', (196, 200))	('osteoblast-related genes', 'Gene', (333, 357))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	("Ewing's sarcoma", 'Disease', (303, 318))	('CD81', 'Gene', (202, 206))	('sarcoma', 'Disease', (33, 40))	('EWS', 'Gene', (291, 294))	('sarcoma', 'Phenotype', 'HP:0100242', (311, 318))	('FLI1', 'Gene', (295, 299))
218536	27656422	This observation is strengthened by recent publications identifying a specific subgroup of thoracic sarcomas based on SMARC4A inactivation and a "BRCA-ness" signature in osteosarcomas.	('inactivation', 'Var', (126, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Disease', (175, 183))	('sarcomas', 'Disease', (100, 108))	('BRCA', 'Gene', '672', (146, 150))	('SMARC4A', 'Gene', (118, 125))	('BRCA', 'Gene', (146, 150))	('osteosarcomas', 'Disease', (170, 183))	('osteosarcomas', 'Phenotype', 'HP:0002669', (170, 183))	('osteosarcoma', 'Phenotype', 'HP:0002669', (170, 182))	('sarcomas', 'Disease', 'MESH:D012509', (175, 183))	('osteosarcomas', 'Disease', 'MESH:D012516', (170, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (175, 183))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
218537	27656422	These molecular signatures include sarcoma-specific translocations that result in oncogenic fusion genes, which are believed to be necessary for malignant transformation and are utilized for molecular-based subgrouping.	('translocations', 'Var', (52, 66))	('sarcoma', 'Disease', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('oncogenic', 'Gene', (82, 91))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('result in', 'Reg', (72, 81))
218544	27656422	Nevertheless, these methodologies show also important disadvantages such as (i) exposure to ionizing radiation (X-ray or gamma rays) with potential risks of secondary cancer; (ii) injection of a contrast medium (dye) can cause kidney problems or result in allergic/injection-site reactions in some patients; and (iii) some procedures require anesthesia.	('rays', 'Species', '255564', (127, 131))	('injection', 'Var', (180, 189))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('kidney problems', 'Phenotype', 'HP:0000112', (227, 242))	('result in', 'Reg', (246, 255))	('cancer', 'Disease', (167, 173))	('patients', 'Species', '9606', (298, 306))	('allergic', 'Disease', 'MESH:D004342', (256, 264))	('kidney problems', 'MPA', (227, 242))	('allergic', 'Disease', (256, 264))	('cause', 'Reg', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
218557	27656422	After isolation, CTCs are also characterized by immunocytochemistry and more specifically by the absence of (i) white blood cell markers, such as anti-CD45 (leukocyte common antigen) or anti-CD34 (hematopoietic and vascular-associated tissue marker), and (ii) the absence of epithelial-related markers, such as anti-Pan CK.	('CD45', 'Gene', (151, 155))	('anti-CD34', 'Var', (186, 195))	('CD45', 'Gene', '5788', (151, 155))	('absence', 'NegReg', (97, 104))
218562	27656422	Circulating tumor cells can more easily be identified in sarcoma subtypes associated with specific chromosomal translocations leading to the expression of a unique fusion product, which is found in tumor cells but not in normal cells.	('sarcoma', 'Disease', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('leading to', 'Reg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('chromosomal translocations', 'Var', (99, 125))	('expression', 'MPA', (141, 151))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (12, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('associated', 'Reg', (74, 84))
218567	27656422	found that the presence of PAX3-FOX1 and PAX7-FOXO1 fusions in CTCs located in bone marrow correlated with clinical outcome in alveolar rhabdomyosarcoma.	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (127, 152))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (136, 152))	('FOX1', 'Gene', (32, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (127, 152))	('PAX7', 'Gene', (41, 45))	('FOX1', 'Gene', '54715', (32, 36))	('PAX3', 'Gene', '5077', (27, 31))	('FOXO1', 'Gene', '2308', (46, 51))	('PAX3', 'Gene', (27, 31))	('alveolar rhabdomyosarcoma', 'Disease', (127, 152))	('FOXO1', 'Gene', (46, 51))	('correlated with', 'Reg', (91, 106))	('PAX7', 'Gene', '5081', (41, 45))	('fusions', 'Var', (52, 59))
218571	27656422	This model was characterized by a splicing variant of the transcription factor Osf2 restricted to bone and osteosarcoma.	('bone', 'Disease', (98, 102))	('splicing variant', 'Var', (34, 50))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('Osf2', 'Gene', (79, 83))	('osteosarcoma', 'Disease', (107, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
218602	27656422	In sarcomas characterized by chromosomal translocations, where aberrant gene fusion products are constitutively present, this is a relatively straightforward task.	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('sarcomas', 'Disease', (3, 11))	('chromosomal', 'Var', (29, 40))
218764	25035576	In rats, a fibroma of desmoid type (also known as fibromatosis-type) has been described as postoperative lesion in Bhd gene mutant rats (Kouchi et al.	('fibroma', 'Phenotype', 'HP:0010614', (11, 18))	('Bhd', 'Gene', '303185', (115, 118))	('fibroma of desmoid type', 'Disease', (11, 34))	('mutant', 'Var', (124, 130))	('fibroma', 'Phenotype', 'HP:0010614', (50, 57))	('fibromatosis-type', 'Disease', 'MESH:D005350', (50, 67))	('fibroma of desmoid type', 'Disease', 'MESH:C535944', (11, 34))	('Bhd', 'Gene', (115, 118))	('fibroma of desmoid', 'Phenotype', 'HP:0100245', (11, 29))	('fibromatosis-type', 'Disease', (50, 67))
218830	31675134	Only in a handful of these reports, the presence of EWSR1 or FUS gene rearrangements has been documented.	('EWSR1', 'Gene', (52, 57))	('rearrangements', 'Var', (70, 84))	('FUS', 'Gene', '2521', (61, 64))	('EWSR1', 'Gene', '2130', (52, 57))	('FUS', 'Gene', (61, 64))
218841	31675134	Transcript IDs used in this study were ENST00000397938.6 (EWSR1), ENST00000621158.4 (CREB3L1), and ENST00000330387.11 (CREB3L2).	('ENST00000397938.6', 'Var', (39, 56))	('ENST00000621158.4', 'Var', (66, 83))	('ENST00000330387.11', 'Var', (99, 117))	('CREB3L2', 'Gene', '64764', (119, 126))	('EWSR1', 'Gene', '2130', (58, 63))	('CREB3L1', 'Gene', (85, 92))	('CREB3L1', 'Gene', '90993', (85, 92))	('CREB3L2', 'Gene', (119, 126))	('EWSR1', 'Gene', (58, 63))
218873	31675134	FISH revealed EWSR1 gene rearrangements in all 7 cases tested.	('rearrangements', 'Var', (25, 39))	('EWSR1', 'Gene', '2130', (14, 19))	('EWSR1', 'Gene', (14, 19))
218876	31675134	MSK-IMPACT also identified copy number amplification of CHECK2, and copy number losses of the NF2, RAC2, EP300, and CRKL genes.	('losses', 'NegReg', (80, 86))	('RAC2', 'Gene', '5880', (99, 103))	('RAC2', 'Gene', (99, 103))	('CRKL', 'Gene', (116, 120))	('copy number', 'Var', (68, 79))	('NF2', 'Gene', (94, 97))	('copy number amplification', 'Var', (27, 52))	('CRKL', 'Gene', '1399', (116, 120))	('CHECK2', 'Gene', (56, 62))	('NF2', 'Gene', '4771', (94, 97))	('CHECK2', 'CellLine', 'CVCL:BT07', (56, 62))	('EP300', 'Gene', (105, 110))	('EP300', 'Gene', '2033', (105, 110))
218884	31675134	Three cases showed EWSR1 rearrangement and one case showed FUS rearrangement.	('FUS', 'Gene', '2521', (59, 62))	('rearrangement', 'Var', (25, 38))	('EWSR1', 'Gene', (19, 24))	('EWSR1', 'Gene', '2130', (19, 24))	('FUS', 'Gene', (59, 62))
218908	28811969	K27M-mutant histone-3 as a novel target for glioma immunotherapy Mutation-specific vaccines have become increasingly important in glioma immunotherapy; however, shared neoepitopes are rare.	('histone-3', 'Protein', (12, 21))	('K27M', 'SUBSTITUTION', 'None', (0, 4))	('glioma', 'Disease', (130, 136))	('glioma', 'Disease', (44, 50))	('K27M', 'Var', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
218909	28811969	For diffuse gliomas, a driver mutation in the gene for isocitrate dehydrogenase type-1 has been shown to produce an immunogenic epitope currently targeted in clinical trials.	('gliomas', 'Disease', (12, 19))	('immunogenic epitope', 'Disease', 'MESH:C538237', (116, 135))	('mutation', 'Var', (30, 38))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('produce', 'Reg', (105, 112))	('rat', 'Species', '10116', (61, 64))	('immunogenic epitope', 'Disease', (116, 135))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))
218910	28811969	For highly aggressive midline gliomas, a recurrent point mutation in the histone-3 gene (H3F3A) causes an amino acid change from lysine to methionine at position 27 (K27M).	('lysine to methionine at position 27', 'Mutation', 'p.K27M', (129, 164))	('amino acid change', 'MPA', (106, 123))	('H3F3A', 'Gene', (89, 94))	('midline gliomas', 'Disease', (22, 37))	('point mutation', 'Var', (51, 65))	('midline gliomas', 'Disease', 'MESH:D005910', (22, 37))	('causes', 'Reg', (96, 102))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('K27M', 'Mutation', 'p.K27M', (166, 170))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
218911	28811969	Here, we demonstrate that a peptide vaccine against K27M-mutant histone-3 is capable of inducing effective, mutation-specific, cytotoxic T-cell- and T-helper-1-cell-mediated immune responses in a major histocompatibility complex (MHC)-humanized mouse model.	('rat', 'Species', '10116', (16, 19))	('K27M-mutant', 'Var', (52, 63))	('inducing', 'PosReg', (88, 96))	('mouse', 'Species', '10090', (245, 250))	('histone-3', 'Gene', (64, 73))	('K27M', 'Mutation', 'p.K27M', (52, 56))	('human', 'Species', '9606', (235, 240))	('T-helper-1-cell-mediated immune responses', 'CPA', (149, 190))	('cytotoxic T-cell-', 'CPA', (127, 144))
218912	28811969	By proving an immunologically effective presentation of the driver mutation H3K27M on MHC class II in human H3K27M-mutant gliomas, our data provide a basis for the further clinical development of vaccine-based or cell-based immunotherapeutic approaches targeting H3K27M.	('K27M', 'Mutation', 'p.K27M', (78, 82))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('K27M', 'Mutation', 'p.K27M', (110, 114))	('gliomas', 'Disease', (122, 129))	('K27M', 'Mutation', 'p.K27M', (265, 269))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('H3K27M-mutant', 'Var', (108, 121))	('human', 'Species', '9606', (102, 107))
218915	28811969	Vaccines targeting one or multiple immunogenic neoepitopes originating from oncogenic driver mutations may best meet the obvious challenge of inducing an effective anti-glioma immune response for two main reasons: (i) they represent tumor antigens, specifically expressed in tumor cells thus reducing the risk of central T-cell tolerance or autoimmune reactions and (ii) they are homogeneously expressed, therefore preventing immune escape.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('mutations', 'Var', (93, 102))	('glioma', 'Disease', (169, 175))	('autoimmune reactions', 'Phenotype', 'HP:0002960', (341, 361))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('reducing', 'NegReg', (292, 300))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('immunogenic neoepitope', 'Disease', 'None', (35, 57))	('immunogenic neoepitope', 'Disease', (35, 57))	('preventing', 'NegReg', (415, 425))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('immune escape', 'CPA', (426, 439))
218916	28811969	One example is a peptide vaccine targeting mutant isocitrate dehydrogenase-1 (IDH1R132H) that induced a CD4-driven mutation-specific immune response in a major histocompatibility complex (MHC)-humanized mouse model and reduced growth of IDH1R132H-overexpressing tumors.	('reduced', 'NegReg', (219, 226))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('growth', 'CPA', (227, 233))	('rat', 'Species', '10116', (56, 59))	('mouse', 'Species', '10090', (203, 208))	('CD4', 'Gene', (104, 107))	('IDH1R132H', 'Gene', (78, 87))	('induced', 'PosReg', (94, 101))	('tumors', 'Disease', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('mutant', 'Var', (43, 49))	('CD4', 'Gene', '12504', (104, 107))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('human', 'Species', '9606', (193, 198))
218917	28811969	This and a similar vaccine are currently tested in two phase I clinical trials in patients with IDH1 R132H-mutated gliomas.	('IDH1', 'Gene', '3417', (96, 100))	('gliomas', 'Disease', (115, 122))	('patients', 'Species', '9606', (82, 90))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('R132H', 'Mutation', 'rs121913500', (101, 106))	('R132H-mutated', 'Var', (101, 114))	('IDH1', 'Gene', (96, 100))
218918	28811969	Another example of a recently discovered oncogenic mutation occurring especially in pediatric high-grade midline and diffuse intrinsic pontine gliomas is a point mutation in the histone-3 gene (H3F3A).	('H3F3A', 'Gene', (194, 199))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('midline', 'Disease', (105, 112))	('gliomas', 'Disease', (143, 150))	('midline', 'Disease', 'MESH:D009436', (105, 112))	('point mutation', 'Var', (156, 170))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))
218919	28811969	An amino acid exchange from lysine to methionine at position 27 (K27M) leads to the reduction of H3K27 trimethylation resulting in a distinct global methylation and gene expression pattern.	('H3K27', 'Protein', (97, 102))	('lysine to methionine at position 27', 'Mutation', 'p.K27M', (28, 63))	('reduction', 'NegReg', (84, 93))	('gene expression', 'MPA', (165, 180))	('K27M', 'Mutation', 'p.K27M', (65, 69))	('trimethylation', 'MPA', (103, 117))	('global methylation', 'MPA', (142, 160))	('K27M', 'Var', (65, 69))
218920	28811969	Besides, gliomas harboring H3K27M lack hallmark cytogenetic aberrations usually found in high-grade gliomas and are characterized by an exceptionally aggressive tumor progression.	('aggressive tumor', 'Disease', (150, 166))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('gliomas', 'Disease', (9, 16))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('rat', 'Species', '10116', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('H3K27M', 'Var', (27, 33))	('K27M', 'Mutation', 'p.K27M', (29, 33))	('aggressive tumor', 'Disease', 'MESH:D001523', (150, 166))	('gliomas', 'Disease', (100, 107))
218921	28811969	From a clinical point of view, H3K27M represents:due to its significance for glioma biology:a promising target also for immunotherapeutic approaches.	('glioma', 'Disease', (77, 83))	('H3K27M', 'Var', (31, 37))	('K27M', 'Mutation', 'p.K27M', (33, 37))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
218925	28811969	In vivo, vaccination of MHC-humanized mice expressing HLA-A*0201 HLA-DRA*0101 HLA-DRB1*0101 while lacking mouse MHC class I and II (A2.DR1 mice) with H3K27M p26-35 induced mutation-specific cytotoxic T-cell responses confirming H3K27M as a glioma neoepitope restricted to human MHC class I (Fig.	('glioma neoepitope', 'Disease', 'MESH:D005910', (240, 257))	('HLA-A', 'Gene', '3105', (54, 59))	('human', 'Species', '9606', (272, 277))	('mice', 'Species', '10090', (38, 42))	('HLA-A', 'Gene', (54, 59))	('HLA-DRB1', 'Gene', (78, 86))	('human', 'Species', '9606', (28, 33))	('HLA-DRB1', 'Gene', '116749', (78, 86))	('K27M', 'Mutation', 'p.K27M', (230, 234))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('H3K27M', 'Var', (150, 156))	('mice', 'Species', '10090', (139, 143))	('K27M', 'Mutation', 'p.K27M', (152, 156))	('glioma neoepitope', 'Disease', (240, 257))	('mouse', 'Species', '10090', (106, 111))
218930	28811969	Indeed, vaccination of A2.DR1 mice with H3K27M p14-40 resulted in enhanced mutation-specific IFNgamma responses.	('p14', 'Gene', (47, 50))	('mice', 'Species', '10090', (30, 34))	('IFNgamma', 'Gene', '15978', (93, 101))	('H3K27M', 'Var', (40, 46))	('enhanced', 'PosReg', (66, 74))	('K27M', 'Mutation', 'p.K27M', (42, 46))	('IFNgamma', 'Gene', (93, 101))	('p14', 'Gene', '20202', (47, 50))
218931	28811969	Intracellular flow cytometry after application of HLA-ABC as well as HLA-DR blocking antibodies during splenocyte re-stimulation substantiated both, H3K27M-specific class I-dependent CD8+-driven as well as class II-dependent CD4+-mediated immune responses (Figs.	('HLA-A', 'Gene', '3105', (50, 55))	('K27M', 'Mutation', 'p.K27M', (151, 155))	('HLA-A', 'Gene', (50, 55))	('CD4', 'Gene', (225, 228))	('H3K27M-specific', 'Var', (149, 164))	('CD8', 'Gene', (183, 186))	('CD4', 'Gene', '12504', (225, 228))	('CD8', 'Gene', '925', (183, 186))
218934	28811969	The presence of H3K27M-specific IFNgamma-secreting CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs) in tumors of mice treated with the H3K27M peptide vaccine confirmed induction of an effective cytotoxic and T-helper-1 antitumor immune response (Figs.	('tumors', 'Disease', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('CD8', 'Gene', (51, 54))	('K27M', 'Mutation', 'p.K27M', (18, 22))	('tumor', 'Disease', (106, 111))	('mice', 'Species', '10090', (116, 120))	('tumor', 'Disease', (65, 70))	('rat', 'Species', '10116', (77, 80))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('CD4', 'Gene', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('H3K27M', 'Var', (138, 144))	('IFNgamma', 'Gene', '15978', (32, 40))	('CD8', 'Gene', '925', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('CD4', 'Gene', '12504', (60, 63))	('IFNgamma', 'Gene', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('K27M', 'Mutation', 'p.K27M', (140, 144))	('tumor', 'Disease', (226, 231))
218935	28811969	Finally, in situ proximity ligation assay (PLA), a method that we have previously established to prove cancer neoepitope presentation on MHC molecules, demonstrated specific H3K27M epitope co-localization with HLA-DR in H3K27M-mutant human glioma tissue (Figs.	('K27M', 'Mutation', 'p.K27M', (176, 180))	('K27M', 'Mutation', 'p.K27M', (222, 226))	('glioma', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('human', 'Species', '9606', (234, 239))	('H3K27M-mutant', 'Var', (220, 233))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('H3K27M', 'Protein', (174, 180))	('cancer neoepitope', 'Disease', (103, 120))	('cancer neoepitope', 'Disease', 'MESH:D009369', (103, 120))	('co-localization', 'Interaction', (189, 204))	('rat', 'Species', '10116', (159, 162))
218936	28811969	Using a mutation-specific HLA class I multimer, H3K27M-specific cytotoxic T cells were exclusively detected in peripheral blood mononuclear cell (PBMC) samples of 3/3 patients with H3K27M-mutant gliomas after ex vivo expansion, indicating that H3K27M is an immunogenic epitope in patients with H3K27M-mutated gliomas capable of inducing spontaneous mutation-specific T-cell responses (Figs.	('gliomas', 'Disease', 'MESH:D005910', (309, 316))	('glioma', 'Phenotype', 'HP:0009733', (309, 315))	('K27M', 'Mutation', 'p.K27M', (296, 300))	('K27M', 'Mutation', 'p.K27M', (183, 187))	('inducing', 'PosReg', (328, 336))	('gliomas', 'Disease', (195, 202))	('immunogenic epitope', 'Disease', (257, 276))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('gliomas', 'Phenotype', 'HP:0009733', (309, 316))	('H3K27M-mutant', 'Var', (181, 194))	('gliomas', 'Disease', 'MESH:D005910', (195, 202))	('K27M', 'Mutation', 'p.K27M', (246, 250))	('patients', 'Species', '9606', (280, 288))	('H3K27M-mutated', 'Var', (294, 308))	('gliomas', 'Disease', (309, 316))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))	('patients', 'Species', '9606', (167, 175))	('immunogenic epitope', 'Disease', 'MESH:C538237', (257, 276))	('K27M', 'Mutation', 'p.K27M', (50, 54))
218937	28811969	In summary, we identified H3K27M as an immunogenic neoepitope targetable by a mutation-specific peptide vaccine.	('K27M', 'Mutation', 'p.K27M', (28, 32))	('immunogenic neoepitope', 'Disease', (39, 61))	('immunogenic neoepitope', 'Disease', 'None', (39, 61))	('H3K27M', 'Var', (26, 32))
218938	28811969	In an MHC-humanized mouse model, vaccination with a H3K27M 27mer induced both cytotoxic T-cell-driven as well as T-helper-1-cell-driven IFNgamma immune responses suggesting in vivo processing of the peptide vaccine resulting in presentation of the histone point mutation H3K27M on both HLA class I and HLA class II.	('mouse', 'Species', '10090', (20, 25))	('K27M', 'Mutation', 'p.K27M', (273, 277))	('human', 'Species', '9606', (10, 15))	('IFNgamma', 'Gene', (136, 144))	('IFNgamma', 'Gene', '15978', (136, 144))	('H3K27M', 'Var', (52, 58))	('H3K27M', 'Var', (271, 277))	('K27M', 'Mutation', 'p.K27M', (54, 58))
218943	28811969	However, proximity ligation assay verified presentation of H3K27M on MHC class II in human gliomas and detection of spontaneous mutation-specific CD8+ T cells in patients with H3K27M-mutant gliomas substantiated an immunologically effective recognition by the human immune system.	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('presentation', 'Reg', (43, 55))	('K27M', 'Mutation', 'p.K27M', (178, 182))	('CD8', 'Gene', (146, 149))	('MHC class II', 'Gene', (69, 81))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('H3K27M', 'Var', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('patients', 'Species', '9606', (162, 170))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('CD8', 'Gene', '925', (146, 149))	('human', 'Species', '9606', (260, 265))	('human', 'Species', '9606', (85, 90))	('K27M', 'Mutation', 'p.K27M', (61, 65))	('gliomas', 'Disease', (190, 197))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('H3K27M-mutant', 'Var', (176, 189))
218945	28811969	While most somatic point mutations are unique to the individual patient requiring extensive molecular analyses to manufacture individually tailored vaccines, H3K27M is an early genetic event occurring in essentially all tumor cells of each individual patient and can easily be detected by immunohistochemistry of glioma tissue during the routine diagnostic process.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('glioma', 'Disease', (313, 319))	('patient', 'Species', '9606', (64, 71))	('tumor', 'Disease', (220, 225))	('patient', 'Species', '9606', (251, 258))	('glioma', 'Disease', 'MESH:D005910', (313, 319))	('glioma', 'Phenotype', 'HP:0009733', (313, 319))	('H3K27M', 'Var', (158, 164))	('K27M', 'Mutation', 'p.K27M', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
218946	28811969	Taken together, our results provide evidence for a further clinical translation of a vaccine targeting H3K27M as part of a personalized (combinatorial) immunotherapeutic approach for HLA-A*02-positive patients with H3K27M-mutant gliomas.	('patients', 'Species', '9606', (201, 209))	('HLA-A', 'Gene', (183, 188))	('H3K27M-mutant', 'Var', (215, 228))	('gliomas', 'Disease', (229, 236))	('K27M', 'Mutation', 'p.K27M', (217, 221))	('gliomas', 'Disease', 'MESH:D005910', (229, 236))	('gliomas', 'Phenotype', 'HP:0009733', (229, 236))	('H3K27M', 'Var', (103, 109))	('HLA-A', 'Gene', '3105', (183, 188))	('K27M', 'Mutation', 'p.K27M', (105, 109))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))
218962	28811969	A2.DR1 mice were immunized with 100 mug H3K27M p14-40 or p26-35 in PBS emulsified with equal volume of Montanide-ISA51 (Seppic) to 1 mg/mL.	('p14', 'Gene', (47, 50))	('p26-35 in', 'Var', (57, 66))	('Montanide-ISA51', 'Chemical', 'MESH:C477385', (103, 118))	('mice', 'Species', '10090', (7, 11))	('K27M', 'Mutation', 'p.K27M', (42, 46))	('PBS', 'Chemical', 'MESH:D007854', (67, 70))	('p14', 'Gene', '20202', (47, 50))
218979	28811969	For characterization of H3K27M-specific CD8+ T cells, splenocytes of vaccinated A2.DR1 mice were stimulated ex vivo with 10 microg/mL H3K27M p26-35 or wild type p26-35 in a U-bottom 96-well-plate.	('K27M', 'Mutation', 'p.K27M', (26, 30))	('CD8', 'Gene', '925', (40, 43))	('K27M', 'Mutation', 'p.K27M', (136, 140))	('mice', 'Species', '10090', (87, 91))	('H3K27M p26-35', 'Var', (134, 147))	('CD8', 'Gene', (40, 43))
218992	28811969	H3K27M-expressing or wild type A2.DR1 sarcoma cells were seeded on glass coverslips, grown until 70-90% confluent and fixed and permeabilized with Cytofixx Pump Spray (Cell Path) at -20  C and subsequent 4% PFA at room temperature.	('K27M', 'Mutation', 'p.K27M', (2, 6))	('sarcoma', 'Disease', (38, 45))	('PFA', 'Chemical', 'MESH:D017245', (207, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('H3K27M-expressing', 'Var', (0, 17))	('rat', 'Species', '10116', (224, 227))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))
218993	28811969	Primary antibody was rabbit anti-human K27M-mutant histone-H3 antibody (ABE419, Merck Millipore), and secondary antibody was goat anti-rabbit Alexa Fluor 546 (Molecular Probes, Invitrogen, A-11010).	('rabbit', 'Species', '9986', (135, 141))	('K27M', 'Mutation', 'p.K27M', (39, 43))	('histone-H3', 'Protein', (51, 61))	('human', 'Species', '9606', (33, 38))	('Alexa Fluor 546', 'Chemical', 'MESH:C481052', (142, 157))	('goat', 'Species', '9925', (125, 129))	('K27M-mutant', 'Var', (39, 50))	('rabbit', 'Species', '9986', (21, 27))
218995	28811969	Formalin-fixed paraffin-embedded H3K27M-mutant and H3 wild type glioma tissue was obtained from the archives of the Department of Neuropathology, Institute of Pathology, Heidelberg.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('H3K27M-mutant', 'Var', (33, 46))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('glioma', 'Disease', (64, 70))	('K27M', 'Mutation', 'p.K27M', (35, 39))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
218996	28811969	H3K27M-expressing A2.DR1 mouse tumor tissue was fixed with Roti-Histofix 4.5% and paraffin embedded.	('K27M', 'Mutation', 'p.K27M', (2, 6))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('mouse', 'Species', '10090', (25, 30))	('H3K27M-expressing', 'Var', (0, 17))	('paraffin', 'Chemical', 'MESH:D010232', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
219020	26837430	This results in the aberrant and strong nuclear expression of TFE3 which is seen almost exclusively in tumours harbouring the TFE3 gene fusions, such as ASPSs and rare paediatric renal carcinomas.	('results in', 'Reg', (5, 15))	('renal carcinomas', 'Disease', (179, 195))	('ASPS', 'Gene', '79058', (153, 157))	('ASPS', 'Phenotype', 'HP:0012218', (153, 157))	('nuclear expression', 'MPA', (40, 58))	('renal carcinomas', 'Phenotype', 'HP:0005584', (179, 195))	('tumours', 'Disease', (103, 110))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('fusions', 'Var', (136, 143))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('TFE3', 'Gene', (126, 130))	('TFE3', 'Gene', (62, 66))	('TFE3', 'Gene', '7030', (126, 130))	('tumours', 'Disease', 'MESH:D009369', (103, 110))	('TFE3', 'Gene', '7030', (62, 66))	('ASPS', 'Gene', (153, 157))	('renal carcinomas', 'Disease', 'MESH:C538614', (179, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))
219039	26837430	Because of immunohistochemical and ultrastructural features, such as focal immunoreactivity to muscle-specific markers (actin, desmin, caldesmin), negativity to other makers, strong and diffuse nuclear positivity to TFE3 and the presence of cytoplasmic crystal inclusions, the final pathologic diagnosis was primary uterine alveolar soft part sarcoma of uterine corpus.	('TFE3', 'Gene', '7030', (216, 220))	('muscle-specific', 'Gene', (95, 110))	('desmin', 'Gene', (127, 133))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (324, 350))	('alveolar soft part sarcoma', 'Disease', (324, 350))	('desmin', 'Gene', (138, 144))	('desmin', 'Gene', '1674', (127, 133))	('TFE3', 'Gene', (216, 220))	('muscle-specific', 'Gene', '27335', (95, 110))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (324, 350))	('negativity', 'Var', (147, 157))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (333, 350))	('sarcoma', 'Phenotype', 'HP:0100242', (343, 350))	('desmin', 'Gene', '1674', (138, 144))
219049	26837430	The correct pathological diagnosis has been made by immunohistochemical and ultrastructural features, which revealed focal immunoreactivity to muscle-specific markers (actin, desmin, caldesmon), negativity to other makers, strong and diffuse nuclear positivity to TFE3 and the presence of cytoplasmic crystal inclusions.	('caldesmon', 'Gene', (183, 192))	('caldesmon', 'Gene', '800', (183, 192))	('TFE3', 'Gene', '7030', (264, 268))	('muscle-specific', 'Gene', (143, 158))	('desmin', 'Gene', '1674', (175, 181))	('negativity', 'Var', (195, 205))	('immunoreactivity', 'MPA', (123, 139))	('TFE3', 'Gene', (264, 268))	('actin', 'Protein', (168, 173))	('desmin', 'Gene', (175, 181))	('muscle-specific', 'Gene', '27335', (143, 158))
219187	24470939	Otitis externa, on the other hand, is usually caused by Pseudomonas aeruginosa, whilst Candida albicans is often the cause of otomycosis.	('caused by', 'Reg', (46, 55))	('Pseudomonas aeruginosa', 'Var', (56, 78))	('Pseudomonas aeruginosa', 'Species', '287', (56, 78))	('Otitis externa', 'Phenotype', 'HP:0410017', (0, 14))	('otomycosis', 'Disease', (126, 136))	('Otitis externa', 'Disease', 'MESH:D010032', (0, 14))	('otomycosis', 'Disease', 'MESH:D059249', (126, 136))	('Candida albicans', 'Species', '5476', (87, 103))	('Otitis externa', 'Disease', (0, 14))
219257	20368795	The molecular changes in type I endometrial carcinomas include mutations in PTEN, PIK3CA, KRAS, and beta-catenin, along with microsatellite instability, whereas type II endometrial carcinomas are characterized by genetic alterations in p53, HER2/neu, p16, and E-cadherin.	('E-cadherin', 'Gene', (260, 270))	('type II endometrial carcinomas', 'Disease', 'MESH:D016889', (161, 191))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (169, 191))	('PIK3CA', 'Gene', '5290', (82, 88))	('E-cadherin', 'Gene', '999', (260, 270))	('HER2/neu', 'Gene', '2064', (241, 249))	('type I endometrial carcinomas', 'Disease', 'MESH:D016889', (25, 54))	('mutations', 'Var', (63, 72))	('type II endometrial carcinomas', 'Disease', (161, 191))	('PTEN', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (90, 94))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (32, 54))	('p53', 'Gene', '7157', (236, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('type I endometrial carcinomas', 'Disease', (25, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('beta-catenin', 'Gene', (100, 112))	('PIK3CA', 'Gene', (82, 88))	('beta-catenin', 'Gene', '1499', (100, 112))	('KRAS', 'Gene', (90, 94))	('p53', 'Gene', (236, 239))	('PTEN', 'Gene', '5728', (76, 80))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (32, 53))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (169, 190))	('HER2/neu', 'Gene', (241, 249))	('p16', 'Gene', (251, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('p16', 'Gene', '1029', (251, 254))
219258	20368795	For endometrial neoplasms with a malignant mesenchymal component, C-MYC mutations and loss of heterozygosity are frequently seen in carcinosarcomas, and a fusion gene, JAZF1/JJAZ1, is distinctive for endometrial stromal sarcoma.	('seen', 'Reg', (124, 128))	('endometrial stromal sarcoma', 'Disease', (200, 227))	('C-MYC', 'Gene', '4609', (66, 71))	('mutations', 'Var', (72, 81))	('C-MYC', 'Gene', (66, 71))	('JJAZ1', 'Gene', '23512', (174, 179))	('JAZF1', 'Gene', '221895', (168, 173))	('JJAZ1', 'Gene', (174, 179))	('carcinosarcomas', 'Disease', 'MESH:D002296', (132, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('JAZF1', 'Gene', (168, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('endometrial neoplasms', 'Disease', 'MESH:D016889', (4, 25))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (200, 227))	('carcinosarcomas', 'Disease', (132, 147))	('endometrial neoplasms', 'Disease', (4, 25))	('neoplasms', 'Phenotype', 'HP:0002664', (16, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (16, 24))
219259	20368795	In addition, p53 mutations may play an important role in tumorigenesis of undifferentiated endometrial sarcoma.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (91, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('endometrial sarcoma', 'Disease', (91, 110))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p53', 'Gene', (13, 16))	('tumor', 'Disease', (57, 62))	('play', 'Reg', (31, 35))	('mutations', 'Var', (17, 26))	('p53', 'Gene', '7157', (13, 16))
219289	20368795	The two distinct histological types of carcinomas are associated with genetic alterations of independent sets of genes.	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('carcinomas', 'Disease', (39, 49))	('carcinomas', 'Disease', 'MESH:D002277', (39, 49))	('genetic alterations', 'Var', (70, 89))
219292	20368795	According to this model, normal endometrial cells would transform into endometrioid endometrial carcinoma through 5 different molecular changes, including, mutations of PTEN, PIK3CA, KRAS, and CTNNB1 (beta-catenin) genes and microsatellite instability (MSI) while non-endometrioid endometrial carcinoma is frequently related to alterations of p53 and chromosomal instability.	('MSI', 'Disease', (253, 256))	('CTNNB1', 'Gene', '1499', (193, 199))	('PIK3CA', 'Gene', '5290', (175, 181))	('p53', 'Gene', (343, 346))	('transform', 'Reg', (56, 65))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (84, 105))	('microsatellite', 'MPA', (225, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('KRAS', 'Gene', '3845', (183, 187))	('CTNNB1', 'Gene', (193, 199))	('PIK3CA', 'Gene', (175, 181))	('endometrioid endometrial carcinoma', 'Disease', (71, 105))	('KRAS', 'Gene', (183, 187))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (281, 302))	('mutations', 'Var', (156, 165))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (71, 105))	('PTEN', 'Gene', (169, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('endometrioid endometrial carcinoma', 'Disease', (268, 302))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (268, 302))	('beta-catenin', 'Gene', (201, 213))	('PTEN', 'Gene', '5728', (169, 173))	('chromosomal instability', 'Phenotype', 'HP:0040012', (351, 374))	('p53', 'Gene', '7157', (343, 346))	('beta-catenin', 'Gene', '1499', (201, 213))	('MSI', 'Disease', 'None', (253, 256))
219294	20368795	Furthermore, none of the five main alterations of endometrioid endometrial carcinoma (mutations of PTEN, PIK3CA, KRAS, and CTNNB1 genes and MSI) plays a major role in non-endometrioid endometrial carcinoma.	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (50, 84))	('endometrioid endometrial carcinoma', 'Disease', (50, 84))	('PIK3CA', 'Gene', '5290', (105, 111))	('KRAS', 'Gene', '3845', (113, 117))	('MSI', 'Disease', 'None', (140, 143))	('CTNNB1', 'Gene', (123, 129))	('MSI', 'Disease', (140, 143))	('KRAS', 'Gene', (113, 117))	('PTEN', 'Gene', (99, 103))	('PIK3CA', 'Gene', (105, 111))	('mutations', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (184, 205))	('PTEN', 'Gene', '5728', (99, 103))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (171, 205))	('endometrioid endometrial carcinoma', 'Disease', (171, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (63, 84))	('CTNNB1', 'Gene', '1499', (123, 129))
219296	20368795	described the development of non-endometrioid endometrial carcinoma through these possible pathways: (i) de novo, through p53 mutations, loss of heterozygosity (LOH) at several loci, and some other still unknown gene alterations; or (ii) through dedifferentiation of a pre-existing endometrioid carcinoma.	('endometrioid endometrial carcinoma', 'Disease', (33, 67))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (33, 67))	('loss of heterozygosity', 'Var', (137, 159))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (282, 304))	('p53', 'Gene', '7157', (122, 125))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (282, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('endometrioid carcinoma', 'Disease', (282, 304))	('mutations', 'Var', (126, 135))	('alterations', 'Var', (217, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (46, 67))	('p53', 'Gene', (122, 125))
219305	20368795	PTEN may be inactivated by several mechanisms such as mutation, LOH, and promoter hypermethylation.	('promoter hypermethylation', 'Var', (73, 98))	('mutation', 'Var', (54, 62))	('LOH', 'Var', (64, 67))	('inactivated', 'NegReg', (12, 23))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
219306	20368795	Somatic PTEN mutations are common in endometrial carcinoma, and they are almost exclusively restricted to endometrioid endometrial carcinomas, occurring up to 83% of them.	('endometrial carcinoma', 'Disease', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (119, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('PTEN', 'Gene', (8, 12))	('endometrioid endometrial carcinomas', 'Disease', (106, 141))	('PTEN', 'Gene', '5728', (8, 12))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (119, 140))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (119, 141))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (37, 58))	('mutations', 'Var', (13, 22))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (106, 141))	('common', 'Reg', (27, 33))
219307	20368795	Germline mutations of PTEN are responsible for Cowden syndrome.	('Germline mutations', 'Var', (0, 18))	('Cowden syndrome', 'Disease', 'MESH:D006223', (47, 62))	('Cowden syndrome', 'Disease', (47, 62))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))	('responsible', 'Reg', (31, 42))
219308	20368795	PTEN may be also inactivated by deletion, as shown by LOH in 40% of endometrial carcinomas.	('deletion', 'Var', (32, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (68, 89))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (68, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('endometrial carcinomas', 'Disease', (68, 90))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (68, 90))
219309	20368795	Promoter hypermethylation leading to PTEN inactivation, is found in about 20% of tumors, most of which are high-stage.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('inactivation', 'NegReg', (42, 54))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('Promoter hypermethylation', 'Var', (0, 25))
219310	20368795	PTEN mutations have been detected in 15-55% of endometrial hyperplasias with and without atypia.	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (47, 70))	('mutations', 'Var', (5, 14))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (47, 71))	('endometrial hyperplasias', 'Disease', (47, 71))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (47, 71))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('detected', 'Reg', (25, 33))
219312	20368795	This suggests that PTEN could be a target for mutations in the context of DNA repair deficiency.	('PTEN', 'Gene', (19, 23))	('mutations', 'Var', (46, 55))	('PTEN', 'Gene', '5728', (19, 23))
219313	20368795	In addition, identical PTEN mutations have been also identified in hyperplasias coexisting with MSI-positive endometrioid endometrial carcinoma, which suggests that PTEN mutations are early events in their development.	('MSI-positive endometrioid endometrial carcinoma', 'Disease', (96, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (122, 143))	('PTEN', 'Gene', (165, 169))	('PTEN', 'Gene', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('hyperplasias', 'Disease', (67, 79))	('identified', 'Reg', (53, 63))	('PTEN', 'Gene', '5728', (23, 27))	('MSI-positive endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 143))	('mutations', 'Var', (28, 37))	('hyperplasias', 'Disease', 'MESH:D006965', (67, 79))	('PTEN', 'Gene', '5728', (165, 169))
219314	20368795	On the other hand, identical PTEN mutations have been detected in MSI-negative endometrial hyperplasia with coexisting MSI-positive endometrioid endometrial carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('MSI', 'Disease', 'None', (66, 69))	('MSI-positive endometrioid endometrial carcinomas', 'Disease', (119, 167))	('MSI', 'Disease', (119, 122))	('endometrial hyperplasia', 'Disease', (79, 102))	('PTEN', 'Gene', (29, 33))	('MSI-positive endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (119, 167))	('PTEN', 'Gene', '5728', (29, 33))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (79, 102))	('MSI', 'Disease', (66, 69))	('detected', 'Reg', (54, 62))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (145, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (79, 102))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (145, 166))	('mutations', 'Var', (34, 43))	('MSI', 'Disease', 'None', (119, 122))
219315	20368795	Thus, some PTEN mutations may precede MSI, and coexistence of both alterations does not necessarily mean a cause-effect relationship.	('PTEN', 'Gene', (11, 15))	('PTEN', 'Gene', '5728', (11, 15))	('MSI', 'Disease', 'None', (38, 41))	('mutations', 'Var', (16, 25))	('MSI', 'Disease', (38, 41))
219319	20368795	In addition, recent data suggest that only PTEN mutations outside exons 5-7 may predict favorable survival, independent of the clinical and pathological features of the tumors.	('favorable survival', 'CPA', (88, 106))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('predict', 'Reg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))	('mutations', 'Var', (48, 57))
219323	20368795	Activation of PI3K produces the second messenger PIP3 which subsequently activates various down-stream pathways such as AKT.	('AKT', 'Gene', (120, 123))	('PI3K', 'Var', (14, 18))	('down-stream pathways', 'Pathway', (91, 111))	('AKT', 'Gene', '207', (120, 123))	('activates', 'PosReg', (73, 82))
219325	20368795	Mutations in AKT family members and their correlation with other gene alterations are found in endometrial carcinoma, including AKT2 (D399N), AKT2 (D32H) and AKT3 (E438D) mutations.	('AKT3', 'Gene', '10000', (158, 162))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (95, 116))	('D399N', 'Mutation', 'rs1319165364', (134, 139))	('AKT', 'Gene', (142, 145))	('AKT', 'Gene', '207', (128, 131))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (95, 116))	('AKT3', 'Gene', (158, 162))	('AKT', 'Gene', (13, 16))	('D32H', 'Mutation', 'p.D32H', (148, 152))	('AKT2', 'Gene', '208', (128, 132))	('AKT', 'Gene', '207', (158, 161))	('AKT', 'Gene', '207', (142, 145))	('E438D', 'Mutation', 'p.E438D', (164, 169))	('AKT2', 'Gene', (128, 132))	('D32H', 'Var', (148, 152))	('AKT2', 'Gene', '208', (142, 146))	('AKT', 'Gene', '207', (13, 16))	('E438D) mutations', 'Var', (164, 180))	('AKT2', 'Gene', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('endometrial carcinoma', 'Disease', (95, 116))	('AKT', 'Gene', (128, 131))	('AKT', 'Gene', (158, 161))
219326	20368795	Mutations of AKT3 (E438D) also have amplification of and a mutation in PIK3CA .	('E438D', 'Var', (19, 24))	('amplification', 'MPA', (36, 49))	('PIK3CA', 'Gene', '5290', (71, 77))	('E438D', 'Mutation', 'p.E438D', (19, 24))	('AKT3', 'Gene', (13, 17))	('AKT3', 'Gene', '10000', (13, 17))	('PIK3CA', 'Gene', (71, 77))
219327	20368795	AKT1 E17K mutation is not associated with either PTEN or PIK3CA genomic alteration.	('PTEN', 'Gene', '5728', (49, 53))	('AKT1', 'Gene', '207', (0, 4))	('PIK3CA', 'Gene', '5290', (57, 63))	('AKT1', 'Gene', (0, 4))	('E17K', 'Mutation', 'rs121434592', (5, 9))	('E17K', 'Var', (5, 9))	('PTEN', 'Gene', (49, 53))	('PIK3CA', 'Gene', (57, 63))
219328	20368795	In vitro studies showed that activating mutations of PIK3CA in combination with PTEN mutations led to an additional increase in phosphorylated AKT when compared with cells with only inactivated PTEN.	('PTEN', 'Gene', (80, 84))	('PIK3CA', 'Gene', '5290', (53, 59))	('PTEN', 'Gene', '5728', (80, 84))	('PTEN', 'Gene', (194, 198))	('PIK3CA', 'Gene', (53, 59))	('phosphorylated', 'MPA', (128, 142))	('PTEN', 'Gene', '5728', (194, 198))	('AKT', 'Gene', '207', (143, 146))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (85, 94))	('increase', 'PosReg', (116, 124))	('activating', 'PosReg', (29, 39))	('AKT', 'Gene', (143, 146))
219329	20368795	Some investigators have claimed that PIK3CA mutations are mutually exclusive of PTEN mutations, suggesting that tumorigenic signaling through this pathway can occur either through activation of PIK3CA or inactivation of PTEN.	('PIK3CA', 'Gene', '5290', (194, 200))	('PIK3CA', 'Gene', (37, 43))	('PIK3CA', 'Gene', '5290', (37, 43))	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PIK3CA', 'Gene', (194, 200))	('inactivation', 'Var', (204, 216))	('tumor', 'Disease', (112, 117))	('PTEN', 'Gene', (220, 224))	('PTEN', 'Gene', '5728', (220, 224))	('activation', 'PosReg', (180, 190))
219330	20368795	Recently, interactions between the PI3K/AKT and p53 signaling pathways have been described in which activation of the PI3K/AKT pathway through PTEN or PIK3CA mutations, together with p53 inactivation, results in malignant transformation.	('p53', 'Gene', (48, 51))	('results in', 'Reg', (201, 211))	('p53', 'Gene', '7157', (48, 51))	('interactions', 'Interaction', (10, 22))	('PIK3CA', 'Gene', (151, 157))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('PTEN', 'Gene', '5728', (143, 147))	('AKT', 'Gene', '207', (40, 43))	('malignant transformation', 'CPA', (212, 236))	('AKT', 'Gene', '207', (123, 126))	('PIK3CA', 'Gene', '5290', (151, 157))	('PTEN', 'Gene', (143, 147))	('AKT', 'Gene', (40, 43))	('activation', 'PosReg', (100, 110))	('mutations', 'Var', (158, 167))	('AKT', 'Gene', (123, 126))
219331	20368795	Moreover, patients with dysregulation of PI3K/AKT signaling pathway and p53 alterations had shorter survival than patients with only p53 alterations.	('survival', 'MPA', (100, 108))	('alterations', 'Var', (76, 87))	('AKT', 'Gene', '207', (46, 49))	('p53', 'Gene', '7157', (133, 136))	('dysregulation', 'Var', (24, 37))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('AKT', 'Gene', (46, 49))	('patients', 'Species', '9606', (10, 18))	('p53', 'Gene', (133, 136))	('patients', 'Species', '9606', (114, 122))	('shorter', 'NegReg', (92, 99))
219332	20368795	Mutations were more common in mixed endometrioid-nonendometrioid adenocarcinomas (44%) than in pure endometrioid adenocarcinomas (28%) or pure nonendometrioid adenocarcinomas (21%).	('endometrioid adenocarcinomas', 'Disease', (146, 174))	('endometrioid adenocarcinomas', 'Disease', (52, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('Mutations', 'Var', (0, 9))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (100, 128))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (52, 80))	('common', 'Reg', (20, 26))	('endometrioid adenocarcinomas', 'Disease', (100, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
219333	20368795	In fact, PIK3CA mutations are usually missense and cluster in exons 9 (helical domain) and 20 (kinase domain).	('PIK3CA', 'Gene', '5290', (9, 15))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))
219334	20368795	The tumors carrying exon 9 PIK3CA mutations are more likely to be low-grade carcinomas; in contrast, carcinomas with exon 20 mutations or PIK3CA mRNA overexpression are often high-grade carcinomas associated with myometrial invasion and tended to have lymphovascular invasion.	('myometrial invasion', 'Disease', (213, 232))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('carcinomas', 'Disease', (76, 86))	('PIK3CA', 'Gene', (27, 33))	('PIK3CA', 'Gene', (138, 144))	('carcinomas', 'Disease', (186, 196))	('carcinomas', 'Disease', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('associated', 'Reg', (197, 207))	('mutations', 'Var', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('exon 9', 'Var', (20, 26))	('lymphovascular invasion', 'CPA', (252, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('tumors', 'Disease', (4, 10))	('carcinomas', 'Disease', 'MESH:D002277', (76, 86))	('overexpression', 'PosReg', (150, 164))	('carcinomas', 'Disease', 'MESH:D002277', (186, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('carcinomas', 'Disease', 'MESH:D002277', (101, 111))	('PIK3CA', 'Gene', '5290', (27, 33))	('PIK3CA', 'Gene', '5290', (138, 144))
219335	20368795	Furthermore, in high-grade endometrioid adenocarcinomas and mixed carcinomas, PIK3CA mutations in exon 20 coexist with p53 alterations more frequently than in nonendometrioid adenocarcinomas.	('PIK3CA', 'Gene', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (66, 76))	('carcinomas', 'Disease', (180, 190))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (27, 55))	('p53', 'Gene', '7157', (119, 122))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (162, 190))	('alterations', 'Var', (123, 134))	('carcinomas', 'Disease', (45, 55))	('mutations in', 'Var', (85, 97))	('mixed', 'Disease', (60, 65))	('p53', 'Gene', (119, 122))	('carcinomas', 'Disease', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('PIK3CA', 'Gene', '5290', (78, 84))	('endometrioid adenocarcinomas', 'Disease', (27, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('endometrioid adenocarcinomas', 'Disease', (162, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('carcinomas', 'Disease', 'MESH:D002277', (45, 55))
219337	20368795	PIK3CA mutations did not correlate with MSI or beta-catenin/CTNNB1 mutations.	('beta-catenin', 'Gene', '1499', (47, 59))	('CTNNB1', 'Gene', (60, 66))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (67, 76))	('PIK3CA', 'Gene', '5290', (0, 6))	('beta-catenin', 'Gene', (47, 59))	('MSI', 'Disease', 'None', (40, 43))	('CTNNB1', 'Gene', '1499', (60, 66))	('MSI', 'Disease', (40, 43))	('mutations', 'Var', (7, 16))
219338	20368795	PIK3CA mutations, particularly exon 20 mutations or PIK3CA mRNA overexpression, are frequent in endometrioid endometrial carcinoma in association with invasion and adverse prognostic factors such as blood vessel invasion.	('blood vessel invasion', 'CPA', (199, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('exon 20 mutations', 'Var', (31, 48))	('frequent', 'Reg', (84, 92))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (109, 130))	('PIK3CA', 'Gene', (52, 58))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 130))	('endometrioid endometrial carcinoma', 'Disease', (96, 130))	('PIK3CA', 'Gene', '5290', (52, 58))	('mRNA', 'MPA', (59, 63))	('mutations', 'Var', (7, 16))
219340	20368795	KRAS mutations have been identified in 10-30% of endometrioid endometrial carcinomas while some investigators have reported an almost complete absence of KRAS mutations in serous and clear cell carcinomas of endometrium.	('KRAS', 'Gene', '3845', (154, 158))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (62, 84))	('clear cell carcinomas', 'Disease', (183, 204))	('identified', 'Reg', (25, 35))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (49, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (62, 83))	('endometrioid endometrial carcinomas', 'Disease', (49, 84))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (183, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', (154, 158))	('KRAS', 'Gene', '3845', (0, 4))
219341	20368795	Some studies found a higher frequency of KRAS mutations in MSI-positive carcinomas than in MSI-negative tumors suggesting that both events may occur simultaneously before clonal expansion.	('MSI', 'Disease', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('KRAS', 'Gene', '3845', (41, 45))	('mutations', 'Var', (46, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('MSI', 'Disease', 'None', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MSI-positive carcinomas', 'Disease', 'MESH:D002277', (59, 82))	('MSI-positive carcinomas', 'Disease', (59, 82))	('MSI', 'Disease', (59, 62))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('MSI', 'Disease', 'None', (91, 94))	('KRAS', 'Gene', (41, 45))
219342	20368795	KRAS mutations were detected in endometrial hyperplasias at a similar rate to that observed in endometrioid endometrial carcinomas, suggesting that KRAS mutations are early events in endometrial carcinogensis.	('KRAS', 'Gene', (148, 152))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (32, 55))	('endometrial hyperplasias', 'Disease', (32, 56))	('endometrioid endometrial carcinomas', 'Disease', (95, 130))	('mutations', 'Var', (153, 162))	('endometrial carcinogensis', 'Disease', (183, 208))	('endometrial carcinogensis', 'Disease', 'MESH:D014591', (183, 208))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (32, 56))	('endometrial carcinogensis', 'Phenotype', 'HP:0012114', (183, 208))	('KRAS', 'Gene', '3845', (148, 152))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (108, 130))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (32, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (95, 130))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (108, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
219343	20368795	No relationship has been found between KRAS mutations and tumor stage, histologic grade, depth of myometrial invasion, age, or clinical outcome in endometrioid endometrial carcinomas.	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (147, 182))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('endometrioid endometrial carcinomas', 'Disease', (147, 182))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (160, 182))	('KRAS', 'Gene', '3845', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (160, 181))
219347	20368795	Mutations in exon 3 of CTNNB1 result in stabilization of a protein that resists degradation, leading to nuclear accumulation of beta-catenin, have been described in endometrioid endometrial carcinoma.	('CTNNB1', 'Gene', (23, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('described', 'Reg', (152, 161))	('beta-catenin', 'Gene', (128, 140))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (178, 199))	('stabilization', 'MPA', (40, 53))	('beta-catenin', 'Gene', '1499', (128, 140))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (165, 199))	('endometrioid endometrial carcinoma', 'Disease', (165, 199))	('Mutations in', 'Var', (0, 12))	('CTNNB1', 'Gene', '1499', (23, 29))
219350	20368795	By comparison in colonic adenocarcinomas, elevated beta-catenin levels caused by mutations in CTNNB1 or APC result in activation of the Wnt/beta-catenin/LEF1 pathway through a LEF1 binding site in the cyclin D1 promotor, triggering cyclin D1 gene expression, and subsequently, uncontrolled progression of tumor cells into the cell cycle.	('cyclin D1', 'Gene', '595', (201, 210))	('colonic adenocarcinomas', 'Disease', (17, 40))	('binding', 'Interaction', (181, 188))	('cyclin D1', 'Gene', (232, 241))	('mutations', 'Var', (81, 90))	('tumor', 'Disease', (305, 310))	('triggering', 'Reg', (221, 231))	('expression', 'MPA', (247, 257))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('cyclin D1', 'Gene', '595', (232, 241))	('elevated', 'PosReg', (42, 50))	('colonic adenocarcinomas', 'Disease', 'MESH:D003110', (17, 40))	('LEF1', 'Gene', (176, 180))	('LEF1', 'Gene', (153, 157))	('CTNNB1', 'Gene', '1499', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('beta-catenin', 'Gene', (51, 63))	('beta-catenin', 'Gene', (140, 152))	('activation', 'PosReg', (118, 128))	('beta-catenin', 'Gene', '1499', (140, 152))	('cyclin D1', 'Gene', (201, 210))	('beta-catenin', 'Gene', '1499', (51, 63))	('APC', 'Disease', 'MESH:D011125', (104, 107))	('APC', 'Disease', (104, 107))	('LEF1', 'Gene', '51176', (153, 157))	('CTNNB1', 'Gene', (94, 100))	('LEF1', 'Gene', '51176', (176, 180))
219352	20368795	The reported frequency of CTNNB1 mutations in endometrioid endometrial carcinoma ranges from 14-44%.	('CTNNB1', 'Gene', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutations', 'Var', (33, 42))	('CTNNB1', 'Gene', '1499', (26, 32))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (59, 80))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (46, 80))	('endometrioid endometrial carcinoma', 'Disease', (46, 80))
219354	20368795	In all cases, the mutations were homogeneously distributed in different areas of the tumors suggesting that they play a role in early steps of endometrial tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('play', 'Reg', (113, 117))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('role', 'Reg', (120, 124))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (18, 27))
219355	20368795	Alterations in beta-catenin have been reported in endometrial hyperplasias with squamous metaplasia.	('squamous metaplasia', 'Phenotype', 'HP:0002860', (80, 99))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (50, 73))	('reported', 'Reg', (38, 46))	('endometrial hyperplasias', 'Disease', (50, 74))	('Alterations', 'Var', (0, 11))	('endometrial hyperplasias', 'Disease', 'MESH:D004714', (50, 74))	('beta-catenin', 'Gene', (15, 27))	('endometrial hyperplasias', 'Phenotype', 'HP:0040298', (50, 74))	('beta-catenin', 'Gene', '1499', (15, 27))	('squamous metaplasia', 'Disease', (80, 99))	('squamous metaplasia', 'Disease', 'MESH:D008679', (80, 99))
219356	20368795	Although there was a good correlation between CTNNB1 mutations and beta-catenin nuclear immunostaining, the presence of cytoplasmic and nuclear beta-catenin immunoreactivity in some endometrial carcinomas without CTNNB mutation suggests that the changes of other genes in the Wnt/beta-catenin/LEF-1 pathway may be responsible for the stabilization and putative transcription activator role of beta-catenin.	('CTNNB', 'Gene', '1499', (213, 218))	('endometrial carcinomas', 'Disease', (182, 204))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (182, 203))	('CTNNB', 'Gene', (213, 218))	('beta-catenin', 'Gene', (144, 156))	('LEF-1', 'Gene', '51176', (293, 298))	('beta-catenin', 'Gene', '1499', (144, 156))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (182, 204))	('LEF-1', 'Gene', (293, 298))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (182, 204))	('CTNNB', 'Gene', (46, 51))	('beta-catenin', 'Gene', (393, 405))	('mutations', 'Var', (53, 62))	('beta-catenin', 'Gene', '1499', (393, 405))	('CTNNB1', 'Gene', '1499', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('beta-catenin', 'Gene', (280, 292))	('CTNNB', 'Gene', '1499', (46, 51))	('beta-catenin', 'Gene', (67, 79))	('beta-catenin', 'Gene', '1499', (280, 292))	('beta-catenin', 'Gene', '1499', (67, 79))	('CTNNB1', 'Gene', (46, 52))
219357	20368795	Endometrioid endometrial carcinomas with CTNNB1 mutations are characteristically early stage tumors associated with favorable prognosis.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (13, 34))	('stage tumors', 'Disease', 'MESH:D062706', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (13, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('CTNNB1', 'Gene', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('endometrial carcinomas', 'Disease', (13, 35))	('stage tumors', 'Disease', (87, 99))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (13, 35))	('mutations', 'Var', (48, 57))	('CTNNB1', 'Gene', '1499', (41, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))
219366	20368795	In sporadic endometrial carcinoma, epigenetic cause of MSI is more common involving MLH1 promotor hypermethylation which is the main cause of MMR deficiency.	('MMR deficiency', 'Disease', (142, 156))	('epigenetic', 'Var', (35, 45))	('MLH1', 'Gene', '4292', (84, 88))	('MLH1', 'Gene', (84, 88))	('MMR deficiency', 'Disease', 'MESH:C536143', (142, 156))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (12, 33))	('MSI', 'Disease', 'None', (55, 58))	('common', 'Reg', (67, 73))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (12, 33))	('MSI', 'Disease', (55, 58))	('cause', 'Reg', (46, 51))	('endometrial carcinoma', 'Disease', (12, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('hypermethylation', 'Var', (98, 114))
219367	20368795	This epigenetic inactivation usually occurs in atypical hyperplasia, most of which coexists with carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (47, 67))	('atypical hyperplasia', 'Disease', (47, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('carcinomas', 'Disease', (97, 107))	('carcinomas', 'Disease', 'MESH:D002277', (97, 107))	('occurs', 'Reg', (37, 43))	('epigenetic inactivation', 'Var', (5, 28))
219368	20368795	Thus, MLH1 hypermethylation is an early event in the pathogenesis of endometrioid endometrial carcinoma, which precedes the development of MSI.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('MSI', 'Disease', (139, 142))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (82, 103))	('hypermethylation', 'Var', (11, 27))	('MLH1', 'Gene', '4292', (6, 10))	('MLH1', 'Gene', (6, 10))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (69, 103))	('endometrioid endometrial carcinoma', 'Disease', (69, 103))	('MSI', 'Disease', 'None', (139, 142))
219369	20368795	The remaining unmethylated MLH1 cases reveal MSH2 mutations (15%) and MSH6 mutations (60%), of which almost half are germline mutations.	('mutations', 'Var', (50, 59))	('MSH2', 'Gene', (45, 49))	('MSH6', 'Gene', (70, 74))	('MLH1', 'Gene', '4292', (27, 31))	('MSH2', 'Gene', '4436', (45, 49))	('MLH1', 'Gene', (27, 31))	('MSH6', 'Gene', '2956', (70, 74))	('mutations', 'Var', (75, 84))
219370	20368795	Thus, MSH6 mutations seem to be a frequent cause of MSI.	('mutations', 'Var', (11, 20))	('cause', 'Reg', (43, 48))	('MSI', 'Disease', 'None', (52, 55))	('MSH6', 'Gene', '2956', (6, 10))	('MSI', 'Disease', (52, 55))	('MSH6', 'Gene', (6, 10))
219371	20368795	Tumors with MSI of CpG island methylation in the promoter region have been identified in some other genes, for example, p16, PTEN, and E-cadherin (CDH1), suggesting altered methylation may be a coexisting independent early change.	('methylation', 'Var', (30, 41))	('PTEN', 'Gene', (125, 129))	('CDH1', 'Gene', '999', (147, 151))	('PTEN', 'Gene', '5728', (125, 129))	('p16', 'Gene', (120, 123))	('E-cadherin', 'Gene', '999', (135, 145))	('MSI', 'Disease', 'None', (12, 15))	('methylation', 'MPA', (173, 184))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p16', 'Gene', '1029', (120, 123))	('CDH1', 'Gene', (147, 151))	('E-cadherin', 'Gene', (135, 145))	('MSI', 'Disease', (12, 15))
219372	20368795	The presentation of some small short-tandem repeats such as mononucleotide repeats located within the coding sequence of important genes for example, transforming growth factor beta receptor type II (TGF-betaRII), BAX, insulin-like growth factor II receptor (IGFIIR), MSH3, MSH6, caspase-5, and PTEN may promote MSI-positive endometrial carcinoma.	('mononucleotide', 'Chemical', '-', (60, 74))	('promote', 'PosReg', (304, 311))	('caspase-5', 'Gene', '838', (280, 289))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (325, 346))	('short-tandem repeats', 'Var', (31, 51))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (325, 346))	('MSH3', 'Gene', (268, 272))	('insulin-like growth factor II receptor', 'Gene', '3482', (219, 257))	('MSH3', 'Gene', '4437', (268, 272))	('MSH6', 'Gene', (274, 278))	('TGF-betaRII', 'Gene', '7048', (200, 211))	('MSI', 'Disease', 'None', (312, 315))	('BAX', 'Gene', (214, 217))	('MSH6', 'Gene', '2956', (274, 278))	('insulin-like growth factor II receptor', 'Gene', (219, 257))	('BAX', 'Gene', '581', (214, 217))	('MSI', 'Disease', (312, 315))	('caspase-5', 'Gene', (280, 289))	('PTEN', 'Gene', (295, 299))	('transforming growth factor beta receptor type II', 'Gene', '7048', (150, 198))	('TGF-betaRII', 'Gene', (200, 211))	('endometrial carcinoma', 'Disease', (325, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (337, 346))	('mononucleotide repeats', 'Var', (60, 82))	('transforming growth factor beta receptor type II', 'Gene', (150, 198))	('IGFIIR', 'Gene', '3482', (259, 265))	('PTEN', 'Gene', '5728', (295, 299))	('IGFIIR', 'Gene', (259, 265))
219377	20368795	While p53 mutations occur in 90% of non-endometrioid endometrial carcinoma, they are only present in 10-20% of endometrioid endometrial carcinoma, which are mostly high-grade.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (111, 145))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (53, 74))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (40, 74))	('endometrioid endometrial carcinoma', 'Disease', (40, 74))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (124, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('mutations', 'Var', (10, 19))	('endometrioid endometrial carcinoma', 'Disease', (111, 145))
219378	20368795	The abnormal p53 expression has been found in 11% of grade 1 endometrioid endometrial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (74, 95))	('abnormal', 'Var', (4, 12))	('endometrioid endometrial carcinoma', 'Disease', (61, 95))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 95))	('found', 'Reg', (37, 42))	('expression', 'MPA', (17, 27))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (13, 16))
219379	20368795	This finding supports that p53 mutations may influence progression of endometrioid endometrial carcinomas to non-endometrioid endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('mutations', 'Var', (31, 40))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (70, 105))	('p53', 'Gene', '7157', (27, 30))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (83, 105))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (126, 147))	('endometrioid endometrial carcinomas', 'Disease', (113, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (83, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('influence', 'Reg', (45, 54))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (113, 148))	('endometrioid endometrial carcinomas', 'Disease', (70, 105))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (126, 148))	('p53', 'Gene', (27, 30))
219380	20368795	In fact, p53 mutation is the most characteristic genetic alteration of non-endometrioid endometrial carcinomas and may be useful in their distinction from endometrioid endometrial carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (88, 109))	('endometrioid endometrial carcinomas', 'Disease', (75, 110))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (155, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('mutation', 'Var', (13, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (168, 189))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (88, 110))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (75, 110))	('endometrioid endometrial carcinomas', 'Disease', (155, 190))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (168, 190))
219385	20368795	p53 mutations produce a non-functional protein that resists degradation and can be visualized by immunostaining.	('mutations', 'Var', (4, 13))	('p53', 'Gene', '7157', (0, 3))	('non-functional protein', 'MPA', (24, 46))	('p53', 'Gene', (0, 3))
219386	20368795	However, loss of function of p53 resulting from LOH may not correlate with protein overexpression.	('LOH', 'Var', (48, 51))	('loss of function', 'NegReg', (9, 25))	('p53', 'Gene', '7157', (29, 32))	('p53', 'Gene', (29, 32))
219387	20368795	In addition, frameshift mutations and stop codons lead to a truncated protein, which is not detected by antibodies and leads to negative immunohistochemistry After DNA damage, nuclear p53 accumulates and causes cell cycle arrest by inhibiting cyclin D1 phosphorylation of the Rb gene and thereby promoting apoptosis.	('phosphorylation', 'MPA', (253, 268))	('lead to', 'Reg', (50, 57))	('promoting', 'PosReg', (296, 305))	('truncated', 'MPA', (60, 69))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (211, 228))	('p53', 'Gene', (184, 187))	('cyclin D1', 'Gene', '595', (243, 252))	('p53', 'Gene', '7157', (184, 187))	('accumulates', 'PosReg', (188, 199))	('cyclin D1', 'Gene', (243, 252))	('cell cycle arrest', 'CPA', (211, 228))	('frameshift mutations', 'Var', (13, 33))	('causes', 'Reg', (204, 210))	('apoptosis', 'CPA', (306, 315))	('inhibiting', 'NegReg', (232, 242))
219388	20368795	Overexpression of p53 is associated with high histological grade and advanced stage as well as unfavorable prognosis.	('p53', 'Gene', '7157', (18, 21))	('advanced stage', 'CPA', (69, 83))	('Overexpression', 'Var', (0, 14))	('p53', 'Gene', (18, 21))
219391	20368795	Mutations of p53 are also found in 75-80% of EIC.	('found', 'Reg', (26, 31))	('Mutations', 'Var', (0, 9))	('EIC', 'Disease', (45, 48))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (13, 16))
219392	20368795	It is postulated that mutation in one allele occurs early during the development of serous carcinoma, and loss of the second normal allele occurs late in the progression to carcinoma.	('mutation', 'Var', (22, 30))	('serous carcinoma', 'Disease', (84, 100))	('carcinoma', 'Disease', 'MESH:D002277', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('serous carcinoma', 'Disease', 'MESH:D018284', (84, 100))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Disease', (173, 182))	('carcinoma', 'Disease', (91, 100))
219393	20368795	p53 mutations are almost always associated with aneuploidy and do not seem to occur with PTEN mutations in the same tumor.	('p53', 'Gene', (0, 3))	('aneuploidy', 'Disease', (48, 58))	('p53', 'Gene', '7157', (0, 3))	('aneuploidy', 'Disease', 'MESH:D000782', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('associated with', 'Reg', (32, 47))	('mutations', 'Var', (4, 13))	('PTEN', 'Gene', (89, 93))	('tumor', 'Disease', (116, 121))	('PTEN', 'Gene', '5728', (89, 93))
219395	20368795	HER2/neu overexpression or amplification is more frequently found in non-endometrioid endometrial carcinoma (18-80%) than in grade 2 and 3 endometrioid carcinoma (10-30%) and has been associated with adverse prognostic parameters including advanced stage, high histologic grade, and low overall survival.	('endometrioid carcinoma', 'Disease', (139, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('overexpression', 'PosReg', (9, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (139, 161))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (73, 107))	('endometrioid endometrial carcinoma', 'Disease', (73, 107))	('HER2/neu', 'Gene', '2064', (0, 8))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (139, 161))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (86, 107))	('amplification', 'Var', (27, 40))	('HER2/neu', 'Gene', (0, 8))
219398	20368795	p16 inactivation can lead to uncontrolled cell growth.	('uncontrolled cell growth', 'CPA', (29, 53))	('inactivation', 'Var', (4, 16))	('p16', 'Gene', (0, 3))	('lead to', 'Reg', (21, 28))	('p16', 'Gene', '1029', (0, 3))
219399	20368795	Inactivation of p16 is more frequent in non-endometrioid endometrial carcinoma (40-45%) than in endometrioid endometrial carcinoma (10%).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (109, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (57, 78))	('p16', 'Gene', '1029', (16, 19))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (44, 78))	('endometrioid endometrial carcinoma', 'Disease', (44, 78))	('frequent', 'Reg', (28, 36))	('endometrioid endometrial carcinoma', 'Disease', (96, 130))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 130))	('p16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))
219400	20368795	Loss of p16 expression is correlated with KRAS and p53 mutations and is associated with high stage, high grade, and poor survival.	('high stage', 'CPA', (88, 98))	('KRAS', 'Gene', (42, 46))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('p16', 'Gene', '1029', (8, 11))	('KRAS', 'Gene', '3845', (42, 46))	('mutations', 'Var', (55, 64))	('associated', 'Reg', (72, 82))	('Loss', 'NegReg', (0, 4))	('p16', 'Gene', (8, 11))	('expression', 'MPA', (12, 22))	('high grade', 'CPA', (100, 110))
219402	20368795	It is thought to be a tumor suppressor gene, the loss of which has been demonstrated to promote tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss', 'Var', (49, 53))	('metastasis', 'CPA', (115, 125))	('promote', 'PosReg', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
219407	20368795	p53 mutations are only present in about 30-40% of clear cell carcinomas compared to 90% of serous carcinomas.	('p53', 'Gene', '7157', (0, 3))	('serous carcinomas', 'Disease', (91, 108))	('p53', 'Gene', (0, 3))	('clear cell carcinomas', 'Disease', (50, 71))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (50, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('mutations', 'Var', (4, 13))	('serous carcinomas', 'Disease', 'MESH:D018284', (91, 108))
219408	20368795	However, the frequency of MSI and PTEN alterations in clear cell carcinoma is higher than in serous carcinoma (15% versus <5 for MSI and 30% versus 10% for PTEN) but lower compared with endometrioid carcinoma (20-40% and 35-50%, resp.).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('PTEN', 'Gene', (156, 160))	('serous carcinoma', 'Disease', 'MESH:D018284', (93, 109))	('endometrioid carcinoma', 'Disease', (186, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('PTEN', 'Gene', '5728', (156, 160))	('MSI', 'Disease', 'None', (26, 29))	('PTEN', 'Gene', (34, 38))	('MSI', 'Disease', 'None', (129, 132))	('MSI', 'Disease', (129, 132))	('MSI', 'Disease', (26, 29))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (186, 208))	('lower', 'NegReg', (166, 171))	('PTEN', 'Gene', '5728', (34, 38))	('clear cell carcinoma', 'Disease', (54, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('serous carcinoma', 'Disease', (93, 109))	('alterations', 'Var', (39, 50))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (186, 208))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (54, 74))
219409	20368795	A recent molecular study demonstrated that the majority of pure clear cell carcinomas do not show mutations in either PTEN or p53, the most commonly altered genes in type I and type II tumors, respectively.	('type II tumors', 'Disease', (177, 191))	('p53', 'Gene', '7157', (126, 129))	('type II tumors', 'Disease', 'MESH:D009369', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('PTEN', 'Gene', '5728', (118, 122))	('clear cell carcinomas', 'Disease', (64, 85))	('mutations', 'Var', (98, 107))	('PTEN', 'Gene', (118, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('p53', 'Gene', (126, 129))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (64, 85))
219425	20368795	One study found STK15 amplification in 9 of 15 (60%) non-endometrioid endometrial carcinomas but in none of endometrioid endometrial carcinomas.	('STK15', 'Gene', (16, 21))	('STK15', 'Gene', '6790', (16, 21))	('endometrioid endometrial carcinomas', 'Disease', (57, 92))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (121, 143))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (108, 143))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (70, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('amplification', 'Var', (22, 35))	('endometrioid endometrial carcinomas', 'Disease', 'MESH:D016889', (57, 92))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (121, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (70, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('endometrioid endometrial carcinomas', 'Disease', (108, 143))
219436	20368795	In addition, the number of chromosomal aberrations in complex hyperplasia is significantly higher than simple hyperplasia and close to the number found in atypical hyperplasia.	('hyperplasia', 'Disease', 'MESH:D006965', (164, 175))	('hyperplasia', 'Disease', (110, 121))	('chromosomal aberrations', 'Var', (27, 50))	('higher', 'PosReg', (91, 97))	('hyperplasia', 'Disease', 'MESH:D006965', (62, 73))	('hyperplasia', 'Disease', 'MESH:D006965', (110, 121))	('atypical hyperplasia', 'Disease', (155, 175))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (27, 50))	('hyperplasia', 'Disease', (164, 175))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (155, 175))	('hyperplasia', 'Disease', (62, 73))
219439	20368795	However, PTEN and KRAS mutations seem to occur earlier, since they were found in simple hyperplasia, partially associated with monoclonality.	('hyperplasia', 'Disease', 'MESH:D006965', (88, 99))	('found', 'Reg', (72, 77))	('KRAS', 'Gene', (18, 22))	('PTEN', 'Gene', (9, 13))	('KRAS', 'Gene', '3845', (18, 22))	('PTEN', 'Gene', '5728', (9, 13))	('hyperplasia', 'Disease', (88, 99))	('mutations', 'Var', (23, 32))
219441	20368795	The inactivation of E-cadherin gene by methylation seems to play a role during progression of endometrioid carcinoma, since it is most frequently found in grade 3 and least frequently in grade 1 tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('methylation', 'Var', (39, 50))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (94, 116))	('E-cadherin', 'Gene', (20, 30))	('E-cadherin', 'Gene', '999', (20, 30))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (94, 116))	('endometrioid carcinoma', 'Disease', (94, 116))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('inactivation', 'NegReg', (4, 16))
219442	20368795	Furthermore, p53 mutations, HER2/neu overexpression or amplification, and p16 inactivation are considered in late events during carcinogenesis of endometrioid carcinoma, since they are predominantly identified in grade 3 tumors, but rarely in grade 1 tumors, and are absent in atypical hyperplastic lesions.	('overexpression', 'PosReg', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('mutations', 'Var', (17, 26))	('p16', 'Gene', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinogenesis of endometrioid carcinoma', 'Disease', (128, 168))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('p16', 'Gene', '1029', (74, 77))	('p53', 'Gene', '7157', (13, 16))	('tumors', 'Disease', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('HER2/neu', 'Gene', (28, 36))	('tumors', 'Disease', (251, 257))	('p53', 'Gene', (13, 16))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('inactivation', 'NegReg', (78, 90))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (146, 168))	('carcinogenesis of endometrioid carcinoma', 'Disease', 'MESH:D016889', (128, 168))	('HER2/neu', 'Gene', '2064', (28, 36))
219443	20368795	Hypothetically, p53 mutations and HER2/neu amplification might also be early events in de novo poorly differentiated endometrioid carcinomas (Figure 2).	('HER2/neu', 'Gene', (34, 42))	('endometrioid carcinomas', 'Disease', (117, 140))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (117, 139))	('p53', 'Gene', (16, 19))	('amplification', 'Var', (43, 56))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (117, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('p53', 'Gene', '7157', (16, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (117, 140))	('HER2/neu', 'Gene', '2064', (34, 42))	('mutations', 'Var', (20, 29))
219444	20368795	Endometrial pre-cancers (e.g., EIC) have been postulated to share common genetic alterations with endometrioid endometrial carcinoma, including PTEN mutations and MSI.	('cancers', 'Disease', (16, 23))	('mutations', 'Var', (149, 158))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (98, 132))	('endometrioid endometrial carcinoma', 'Disease', (98, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('MSI', 'Disease', 'None', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('PTEN', 'Gene', (144, 148))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (111, 132))	('MSI', 'Disease', (163, 166))	('PTEN', 'Gene', '5728', (144, 148))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
219445	20368795	Mutations of p53 were found in approximately 80% of EIC, but in contrast to most serous carcinomas, there is no LOH at the locus TP53.	('EIC', 'Disease', (52, 55))	('serous carcinomas', 'Disease', (81, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('TP53', 'Gene', '7157', (129, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('TP53', 'Gene', (129, 133))	('p53', 'Gene', '7157', (13, 16))	('serous carcinomas', 'Disease', 'MESH:D018284', (81, 98))
219446	20368795	Thus, it is hypothesized that p53 mutation of one allele occurs early, whereas loss of the normal second allele accompanies progression into serous carcinoma.	('serous carcinoma', 'Disease', (141, 157))	('serous carcinoma', 'Disease', 'MESH:D018284', (141, 157))	('mutation', 'Var', (34, 42))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
219447	20368795	The alterations of E-cadherin, p16, and HER2/neu seem to affect the progression from EIC to serous carcinoma.	('p16', 'Gene', '1029', (31, 34))	('alterations', 'Var', (4, 15))	('HER2/neu', 'Gene', '2064', (40, 48))	('E-cadherin', 'Gene', (19, 29))	('HER2/neu', 'Gene', (40, 48))	('affect', 'Reg', (57, 63))	('serous carcinoma', 'Disease', (92, 108))	('EIC', 'Disease', (85, 88))	('p16', 'Gene', (31, 34))	('serous carcinoma', 'Disease', 'MESH:D018284', (92, 108))	('E-cadherin', 'Gene', '999', (19, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))
219448	20368795	Another group hypothesized that serous carcinoma may develop from endometrioid carcinoma through p53 mutation based on findings in mixed endometrioid and serous carcinomas.	('serous carcinomas', 'Disease', 'MESH:D018284', (154, 171))	('serous carcinoma', 'Disease', 'MESH:D018284', (154, 170))	('serous carcinomas', 'Disease', (154, 171))	('p53', 'Gene', (97, 100))	('serous carcinoma', 'Disease', (32, 48))	('mutation', 'Var', (101, 109))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (66, 88))	('p53', 'Gene', '7157', (97, 100))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (66, 88))	('serous carcinoma', 'Disease', 'MESH:D018284', (32, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('endometrioid carcinoma', 'Disease', (66, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('develop', 'Reg', (53, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))
219452	20368795	It is an autosomal dominant syndrome that predisposes its carriers to multiple malignancies particularly colorectal, and endometrial carcinomas, caused by a germline mutation in one of the DNA MMR genes occurring in 30-60% of cases.	('DNA MMR', 'Gene', (189, 196))	('caused by', 'Reg', (145, 154))	('malignancies particularly colorectal', 'Disease', 'MESH:D009369', (79, 115))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (121, 143))	('autosomal dominant syndrome', 'Disease', (9, 36))	('germline mutation', 'Var', (157, 174))	('malignancies particularly colorectal', 'Disease', (79, 115))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (121, 143))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (9, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (121, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('endometrial carcinomas', 'Disease', (121, 143))
219455	20368795	The frequency of germline DNA MMR gene mutations among unselected patients with endometrial carcinoma has been found to be 1.8-2.1%, which is similar to the frequency of HNPCC in colorectal carcinoma.	('HNPCC in colorectal carcinoma', 'Disease', 'MESH:D015179', (170, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('HNPCC', 'Phenotype', 'HP:0006716', (170, 175))	('HNPCC in colorectal carcinoma', 'Disease', (170, 199))	('DNA MMR', 'Gene', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (80, 101))	('mutations', 'Var', (39, 48))	('endometrial carcinoma', 'Disease', (80, 101))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('patients', 'Species', '9606', (66, 74))
219456	20368795	Patients with endometrial carcinoma in the HNPCC population have an inherited germline mutation in MLH1, MSH2, MSH6, or PMS2 (first hit) but endometrial carcinoma develops only after the initiation of a deletion or mutation in the contralateral MLH1, MSH2, MSH6, or PMS2 allele (second hit) in endometrial cells.	('MLH1', 'Gene', (245, 249))	('MSH2', 'Gene', '4436', (105, 109))	('MSH6', 'Gene', (111, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (14, 35))	('PMS2', 'Gene', (266, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (141, 162))	('MSH6', 'Gene', '2956', (111, 115))	('HNPCC', 'Disease', 'None', (43, 48))	('HNPCC', 'Disease', (43, 48))	('MLH1', 'Gene', '4292', (245, 249))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (14, 35))	('MSH2', 'Gene', (251, 255))	('PMS2', 'Gene', '5395', (120, 124))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (141, 162))	('Patients', 'Species', '9606', (0, 8))	('MSH6', 'Gene', (257, 261))	('mutation', 'Var', (215, 223))	('MSH6', 'Gene', '2956', (257, 261))	('MSH2', 'Gene', '4436', (251, 255))	('MLH1', 'Gene', (99, 103))	('HNPCC', 'Phenotype', 'HP:0006716', (43, 48))	('deletion', 'Var', (203, 211))	('PMS2', 'Gene', '5395', (266, 270))	('mutation', 'Var', (87, 95))	('PMS2', 'Gene', (120, 124))	('MSH2', 'Gene', (105, 109))	('MLH1', 'Gene', '4292', (99, 103))	('endometrial carcinoma', 'Disease', (14, 35))	('endometrial carcinoma', 'Disease', (141, 162))
219458	20368795	Unlike HNPCC associated colorectal carcinoma, which appears to frequently have MLH1 and MSH2 mutations, endometrial carcinomas have a higher probability of MSH2 and MSH6 mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (24, 44))	('MLH1', 'Gene', '4292', (79, 83))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (104, 126))	('HNPCC', 'Phenotype', 'HP:0006716', (7, 12))	('MSH6', 'Gene', (165, 169))	('MSH2', 'Gene', '4436', (88, 92))	('MSH6', 'Gene', '2956', (165, 169))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (104, 126))	('MSH2', 'Gene', (156, 160))	('mutations', 'Var', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('endometrial carcinomas', 'Disease', (104, 126))	('MSH2', 'Gene', '4436', (156, 160))	('HNPCC', 'Disease', (7, 12))	('HNPCC', 'Disease', 'None', (7, 12))	('mutations', 'Var', (170, 179))	('MLH1', 'Gene', (79, 83))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (104, 125))	('colorectal carcinoma', 'Disease', (24, 44))	('MSH2', 'Gene', (88, 92))
219459	20368795	Women with HNPCC who carry MSH2 and MSH6 mutations have a higher chance to present initially with endometrial rather than colorectal cancer.	('mutations', 'Var', (41, 50))	('HNPCC', 'Disease', 'None', (11, 16))	('HNPCC', 'Phenotype', 'HP:0006716', (11, 16))	('HNPCC', 'Disease', (11, 16))	('Women', 'Species', '9606', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('colorectal cancer', 'Disease', (122, 139))	('MSH2', 'Gene', (27, 31))	('MSH6', 'Gene', (36, 40))	('MSH2', 'Gene', '4436', (27, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('MSH6', 'Gene', '2956', (36, 40))	('endometrial', 'Disease', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
219468	20368795	PTEN inactivation by mutation seems to also be involved in tumorigenesis, since it occurs in about 90% of type I carcinomas.	('type I carcinomas', 'Disease', 'MESH:D017827', (106, 123))	('tumor', 'Disease', (59, 64))	('involved', 'Reg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutation', 'Var', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('inactivation', 'NegReg', (5, 17))	('type I carcinomas', 'Disease', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
219471	20368795	studied serial endometrial biopsy samples taken during a 10-year followup of HPNCC mutation carriers and found abnormal MMR protein expression, MSI, or tumor suppressor promotor hypermethylation in various endometrial histologies, including normal and hyperplastic endometria.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('MSI', 'Disease', 'None', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('hyperplastic endometria', 'Phenotype', 'HP:0040298', (252, 275))	('hypermethylation', 'Var', (178, 194))	('HPNCC', 'Gene', (77, 82))	('tumor', 'Disease', (152, 157))	('MSI', 'Disease', (144, 147))	('mutation', 'Var', (83, 91))	('abnormal', 'Reg', (111, 119))	('MMR protein', 'Protein', (120, 131))
219472	20368795	The most frequently methylated genes were CDH13, RASSF1A, and GSTP1.	('methylated', 'Var', (20, 30))	('CDH13', 'Gene', '1012', (42, 47))	('RASSF1A', 'Gene', (49, 56))	('GSTP1', 'Gene', (62, 67))	('RASSF1A', 'Gene', '11186', (49, 56))	('CDH13', 'Gene', (42, 47))	('GSTP1', 'Gene', '2950', (62, 67))
219474	20368795	PTEN hamartoma tumor syndrome, caused by a germline mutation in PTEN gene on chromosome 10q, comprises a group of disorders including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, Proteus-like syndrome, and autism spectrum disorder with macrocephaly.	('Cowden syndrome', 'Disease', (134, 149))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('autism', 'Phenotype', 'HP:0000717', (231, 237))	('hamartoma', 'Phenotype', 'HP:0010566', (5, 14))	('macrocephaly', 'Disease', (261, 273))	('Proteus-like syndrome', 'Disease', 'MESH:D016715', (204, 225))	('autism spectrum disorder', 'Disease', 'MESH:D000067877', (231, 255))	('macrocephaly', 'Disease', 'MESH:D058627', (261, 273))	('Proteus syndrome', 'Disease', (186, 202))	('hamartoma tumor syndrome', 'Disease', (5, 29))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', 'MESH:D006223', (151, 184))	('autism spectrum disorder', 'Disease', (231, 255))	('Proteus-like syndrome', 'Disease', (204, 225))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (231, 255))	('PTEN', 'Gene', (64, 68))	('Proteus syndrome', 'Disease', 'MESH:D016715', (186, 202))	('PTEN', 'Gene', (0, 4))	('caused by', 'Reg', (31, 40))	('macrocephaly', 'Phenotype', 'HP:0000256', (261, 273))	('Cowden syndrome', 'Disease', 'MESH:D006223', (134, 149))	('hamartoma tumor syndrome', 'Disease', 'MESH:D006222', (5, 29))	('germline mutation', 'Var', (43, 60))	('PTEN', 'Gene', '5728', (64, 68))	('PTEN', 'Gene', '5728', (0, 4))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', (151, 184))
219478	20368795	PTEN mutations in exon 5, coding for the active site and flanking amino acids, is a common site for mutations in patients with Cowden syndrome, and missense mutations are only found in this active area.	('mutations', 'Var', (100, 109))	('Cowden syndrome', 'Disease', 'MESH:D006223', (127, 142))	('patients', 'Species', '9606', (113, 121))	('Cowden syndrome', 'Disease', (127, 142))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
219479	20368795	However, germline PTEN mutation has been detected in approximately 80% of Cowden syndrome patients.	('Cowden syndrome', 'Disease', 'MESH:D006223', (74, 89))	('PTEN', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))	('PTEN', 'Gene', '5728', (18, 22))	('Cowden syndrome', 'Disease', (74, 89))	('patients', 'Species', '9606', (90, 98))	('detected', 'Reg', (41, 49))
219493	20368795	Many carcinosarcomas contained aberrations on chromosome 8 and 20 detected by FISH.	('aberrations', 'Var', (31, 42))	('carcinosarcomas', 'Disease', 'MESH:D002296', (5, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('carcinosarcomas', 'Disease', (5, 20))
219495	20368795	Gains or amplifications of 8q are the most common genetic aberration in carcinosarcomas.	('Gains', 'Var', (0, 5))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('carcinosarcomas', 'Disease', 'MESH:D002296', (72, 87))	('carcinosarcomas', 'Disease', (72, 87))
219499	20368795	p53 mutations and LOH for TP53 occur frequently in both carcinosarcoma components which are associated with frequent protein overexpression.	('TP53', 'Gene', (26, 30))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('carcinosarcoma', 'Disease', 'MESH:D002296', (56, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('carcinosarcoma', 'Disease', (56, 70))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (4, 13))
219532	20368795	In contrast to epithelial endometrial carcinoma, endometrial stromal tumors are characterized by distinct cytogenetic abnormalities, particularly translocations leading to gene fusion.	('epithelial endometrial carcinoma', 'Disease', 'MESH:D016889', (15, 47))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('endometrial stromal tumors', 'Disease', 'MESH:D036821', (49, 75))	('translocations', 'Var', (146, 160))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (26, 47))	('epithelial endometrial carcinoma', 'Disease', (15, 47))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('endometrial stromal tumors', 'Disease', (49, 75))	('gene fusion', 'MPA', (172, 183))	('genetic abnormalities', 'Disease', 'MESH:D030342', (110, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('genetic abnormalities', 'Disease', (110, 131))
219533	20368795	Cytogenetic studies reported to-date are primarily for low grade endometrial stromal sarcomas, mostly showing rearrangement of chromosomes 6, 7, and 17.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (65, 93))	('rearrangement', 'Var', (110, 123))	('endometrial stromal sarcomas', 'Disease', (65, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
219534	20368795	Loss of chromosome arm 7p (55.6% of the cases) is the most frequent aberration and may play a role in tumor development and progression.	('tumor', 'Disease', (102, 107))	('role', 'Reg', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Loss', 'Var', (0, 4))	('play', 'Reg', (87, 91))
219546	20368795	A major subgroup of endometrial stromal sarcomas has been found to have translocations involving short arm of chromosome 6, particularly band 6p21.	('p21', 'Gene', (143, 146))	('translocations', 'Var', (72, 86))	('p21', 'Gene', '644914', (143, 146))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (20, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('endometrial stromal sarcomas', 'Disease', (20, 48))	('short arm', 'Phenotype', 'HP:0009824', (97, 106))
219548	20368795	introduced that a low-grade endometrial stromal sarcoma cell line carrying a der(7)t(6;7)(p21;p22) also harbors a JAZF1/PHF1 fusion.	('PHF1', 'Gene', (120, 124))	('der(7)t(6;7)(p21;p22', 'Var', (77, 97))	('JAZF1', 'Gene', '221895', (114, 119))	('PHF1', 'Gene', '5252', (120, 124))	('endometrial stromal sarcoma', 'Disease', (28, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('der(7)t(6;7)(p21;p22)', 'STRUCTURAL_ABNORMALITY', 'None', (77, 98))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (28, 55))	('JAZF1', 'Gene', (114, 119))
219550	20368795	Additionally, few endometrial stromal sarcoma cases were reported with a t(X;17)(p11.2;q23) and a t(10;17)(q22;p13).	('t(10;17)(q22;p13', 'Var', (98, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('endometrial stromal sarcoma', 'Disease', (18, 45))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (98, 115))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (18, 45))	('t(X;17)(p11.2;q23', 'Var', (73, 90))	('t(X;17)(p11.2;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (73, 91))
219566	20368795	The importance of p53 mutations for the development of undifferentiated endometrial sarcomas is not evident, but p53 overexpression was detected in three of four high-grade stromal sarcomas.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('undifferentiated endometrial sarcomas', 'Disease', (55, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('p53', 'Gene', '7157', (113, 116))	('overexpression', 'PosReg', (117, 131))	('mutations', 'Var', (22, 31))	('stromal sarcomas', 'Disease', (173, 189))	('p53', 'Gene', (113, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('stromal sarcomas', 'Disease', 'MESH:D046152', (173, 189))	('undifferentiated endometrial sarcomas', 'Disease', 'MESH:D018203', (55, 92))
219567	20368795	have recently found frequent nuclear accumulation of p53 and TP53 gene missense mutations in undifferentiated endometrial sarcoma with nuclear pleomorphism, 3 (50%) of 6 cases.	('missense mutations', 'Var', (71, 89))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (110, 129))	('endometrial sarcoma', 'Disease', (110, 129))	('nuclear accumulation', 'MPA', (29, 49))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
219569	20368795	p53 alteration may be one different pathway that contributes the tumorigenesis of undifferentiated endometrial sarcoma.	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('alteration', 'Var', (4, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('endometrial sarcoma', 'Disease', 'MESH:D018203', (99, 118))	('endometrial sarcoma', 'Disease', (99, 118))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
219576	20368795	Dysregulation of these pathways allows beta-catenin to accumulate and translocate to the nucleus, where it forms complexes with T-cell factor/lymphoid enhancing factor (TCF/LEF) leading to uncontrolled cell growth and carcinogenesis.	('TCF/LEF', 'Gene', '3172', (169, 176))	('complexes', 'Interaction', (113, 122))	('Dysregulation', 'Var', (0, 13))	('accumulate', 'PosReg', (55, 65))	('carcinogenesis', 'Disease', (218, 232))	('uncontrolled cell growth', 'CPA', (189, 213))	('beta-catenin', 'Gene', '1499', (39, 51))	('beta-catenin', 'Gene', (39, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (218, 232))	('TCF/LEF', 'Gene', (169, 176))
219580	20368795	Therefore, we can exploit our knowledge of the dualistic model and their typical gene mutations and use the immunoprofile as a diagnostic tool, in concert with the histomorphologic features to specify the tumor type, particularly in difficult cases such as in the differentiation between high-grade endometrioid carcinoma and serous carcinoma (Table 3).	('mutations', 'Var', (86, 95))	('endometrioid carcinoma and serous carcinoma', 'Disease', 'MESH:D016889', (299, 342))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (299, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))
219581	20368795	The distinct molecular alteration described in the majority of endometrial stromal sarcomas is the t(7;17)(p15;q21) leading to the formation of fusion gene JAZF1/JJAZ1, which can be detected by RT-PCR or FISH assays.	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('JAZF1', 'Gene', (156, 161))	('JJAZ1', 'Gene', '23512', (162, 167))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (63, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('t(7;17)(p15;q21', 'Var', (99, 114))	('t(7;17)(p15;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (99, 115))	('JJAZ1', 'Gene', (162, 167))	('JAZF1', 'Gene', '221895', (156, 161))	('endometrial stromal sarcomas', 'Disease', (63, 91))
219590	20368795	By CGH, leiomyosarcomas have the most frequent losses including 10q, 11q, 13q, and 2p while the most common gains are Xp, 1q, 5p, 8q, 12q, 17p and 19p.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (8, 22))	('leiomyosarcomas', 'Disease', (8, 23))	('10q', 'Var', (64, 67))	('losses', 'NegReg', (47, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (8, 23))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (8, 23))
219591	20368795	There are a variety of genetic changes and mutations inclusive of TP53 and MDM2 expression associated with progression of leiomyosarcomas.	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (122, 137))	('MDM2', 'Gene', '4193', (75, 79))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (122, 137))	('MDM2', 'Gene', (75, 79))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (122, 136))	('mutations', 'Var', (43, 52))	('leiomyosarcomas', 'Disease', (122, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('associated', 'Reg', (91, 101))
219592	20368795	LOH of 10q is found in more than half of leiomyosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (41, 56))	('LOH of 10q', 'Var', (0, 10))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (41, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('leiomyosarcomas', 'Disease', (41, 56))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (41, 55))
219595	20368795	Drug targets may focus on genes that affect apoptosis, signal transduction, epigenetic modification, drug resistance, protein folding and degradation, cell cycle progression, hormone receptor activity, and angiogenesis.	('hormone receptor', 'Gene', (175, 191))	('degradation', 'MPA', (138, 149))	('drug resistance', 'MPA', (101, 116))	('hormone receptor', 'Gene', '3164', (175, 191))	('cell cycle', 'CPA', (151, 161))	('apoptosis', 'CPA', (44, 53))	('affect', 'Reg', (37, 43))	('epigenetic modification', 'Var', (76, 99))	('drug resistance', 'Phenotype', 'HP:0020174', (101, 116))	('angiogenesis', 'CPA', (206, 218))	('protein folding', 'MPA', (118, 133))
219599	20368795	In in vitro studies, cells with PTEN inactivation in endometrioid carcinoma are sensitive to mTOR inhibitors, since the loss of PTEN leads to constitutive activation of downstream components, which in turn up-regulates mTOR activity.	('mTOR', 'Gene', (219, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('up-regulates', 'PosReg', (206, 218))	('mTOR', 'Gene', (93, 97))	('PTEN', 'Gene', (128, 132))	('mTOR', 'Gene', '2475', (93, 97))	('PTEN', 'Gene', (32, 36))	('constitutive', 'MPA', (142, 154))	('PTEN', 'Gene', '5728', (128, 132))	('PTEN', 'Gene', '5728', (32, 36))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (53, 75))	('mTOR', 'Gene', '2475', (219, 223))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (53, 75))	('loss', 'Var', (120, 124))	('activation', 'PosReg', (155, 165))	('endometrioid carcinoma', 'Disease', (53, 75))
219626	20368795	They are associated with a number of well-described genetic alterations including mutations of PTEN, KRAS, beta-catenin, PIK3CA, and inactivation of DNA mismatch repair.	('beta-catenin', 'Gene', (107, 119))	('KRAS', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (101, 105))	('associated', 'Reg', (9, 19))	('beta-catenin', 'Gene', '1499', (107, 119))	('PIK3CA', 'Gene', (121, 127))	('mutations', 'Var', (82, 91))	('PTEN', 'Gene', (95, 99))	('PIK3CA', 'Gene', '5290', (121, 127))	('PTEN', 'Gene', '5728', (95, 99))	('DNA mismatch repair', 'Protein', (149, 168))	('inactivation', 'Var', (133, 145))
219629	20368795	Mutations of p53 are present in approximately 90% of this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('p53', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('p53', 'Gene', '7157', (13, 16))
219630	20368795	Carcinosarcoma is considered to be a high-grade carcinoma with sarcomatous differentiation and a high frequency of C-MYC mutations and LOH of p53.	('Carcinosarcoma', 'Disease', 'MESH:D002296', (0, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('C-MYC', 'Gene', '4609', (115, 120))	('sarcomatous', 'Disease', (63, 74))	('p53', 'Gene', (142, 145))	('carcinoma', 'Disease', (48, 57))	('p53', 'Gene', '7157', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Carcinosarcoma', 'Disease', (0, 14))	('LOH', 'Var', (135, 138))	('sarcomatous', 'Disease', 'MESH:D018316', (63, 74))	('C-MYC', 'Gene', (115, 120))	('carcinoma', 'Disease', 'MESH:D002277', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
219642	29513652	Despite extensive research on the transcription targets of the fusion of EWSR1 and FLI1 (EWS-FLI1), factors that mediate the chemosensitivity of Ewing sarcoma or the effect of EWSR1 have not been well characterized.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (145, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (145, 158))	('FLI1', 'Gene', (83, 87))	('EWSR1', 'Gene', (176, 181))	('FLI1', 'Gene', (93, 97))	('FLI1', 'Gene', '2130', (83, 87))	('EWSR1', 'Gene', (73, 78))	('EWS-FLI1', 'Gene', (89, 97))	('EWSR1', 'Gene', '2130', (176, 181))	('fusion', 'Var', (63, 69))	('EWSR1', 'Gene', '2130', (73, 78))	('FLI1', 'Gene', '2130', (93, 97))	('Ewing sarcoma', 'Disease', (145, 158))	('EWS-FLI1', 'Gene', '2130;2313', (89, 97))
219645	29513652	Conversely, EWS-FLI1 expression increased chemosensitivity in U2OS osteosarcoma cells (Extended Data Fig.	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('expression', 'Species', '29278', (21, 31))	('U2OS', 'CellLine', 'CVCL:0042', (62, 66))	('EWS-FLI1', 'Gene', '2130;2313', (12, 20))	('chemosensitivity', 'MPA', (42, 58))	('increased', 'PosReg', (32, 41))	('expression', 'Var', (21, 31))	('osteosarcoma', 'Disease', (67, 79))	('EWS-FLI1', 'Gene', (12, 20))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
219658	29513652	EWSR1 depletion in U2OS cells increased RNAPII phosphorylation, confirming the results of the kinase assay (Fig.	('EWSR1', 'Gene', '2130', (0, 5))	('RNAPII phosphorylation', 'MPA', (40, 62))	('increased', 'PosReg', (30, 39))	('depletion', 'Var', (6, 15))	('EWSR1', 'Gene', (0, 5))	('U2OS', 'CellLine', 'CVCL:0042', (19, 23))
219661	29513652	Notably, wild-type EWSR1 levels were not affected by EWS-FLI1 knockdown.	('EWS-FLI1', 'Gene', (53, 61))	('EWS-FLI1', 'Gene', '2130;2313', (53, 61))	('EWSR1', 'Gene', (19, 24))	('EWSR1', 'Gene', '2130', (19, 24))	('knockdown', 'Var', (62, 71))
219666	29513652	Unlike IMR90 cells, which displayed a characteristic decrease in EU incorporation two hours post-damage followed by recovery, TC32 Ewing sarcoma cells showed a significantly higher basal transcription level, similar to that seen in EWSR1-depleted cells (Extended Data Fig.	('basal transcription level', 'MPA', (181, 206))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (131, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (131, 144))	('rat', 'Species', '10116', (75, 78))	('higher', 'PosReg', (174, 180))	('TC32', 'Var', (126, 130))	('IMR90', 'CellLine', 'CVCL:0347', (7, 12))	('EWSR1', 'Gene', (232, 237))	('EU', 'Chemical', '-', (65, 67))	('Ewing sarcoma', 'Disease', (131, 144))	('TC32', 'CellLine', 'CVCL:7151', (126, 130))	('EWSR1', 'Gene', '2130', (232, 237))
219674	29513652	A DNA-binding mutant EWS-FLI1 (Extended Data Fig.	('EWS-FLI1', 'Gene', '2130;2313', (21, 29))	('mutant', 'Var', (14, 20))	('EWS-FLI1', 'Gene', (21, 29))
219695	29513652	Given the similarity in phenotypes between Ewing sarcoma and BRCA1/2 mutant breast cancer (Extended Data Table 2), we investigated whether BRCA1 function was altered in Ewing sarcoma.	('BRCA1', 'Gene', (61, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (169, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (169, 182))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('BRCA1', 'Gene', '672', (139, 144))	('altered', 'Reg', (158, 165))	('BRCA1/2', 'Gene', '672;675', (61, 68))	('BRCA1', 'Gene', (139, 144))	('Ewing sarcoma', 'Disease', (43, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('Ewing sarcoma', 'Disease', (169, 182))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('mutant', 'Var', (69, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('BRCA1/2', 'Gene', (61, 68))	('BRCA1', 'Gene', '672', (61, 66))
219703	29513652	Mutation of TP53BP1 circumvents the need for BRCA1 in homologous recombination, partially restoring homologous recombination and conferring some resistance to chemotherapy.	('TP53BP1', 'Gene', (12, 19))	('BRCA1', 'Gene', '672', (45, 50))	('TP53BP1', 'Gene', '7158', (12, 19))	('homologous recombination', 'MPA', (100, 124))	('restoring', 'PosReg', (90, 99))	('Mutation', 'Var', (0, 8))	('BRCA1', 'Gene', (45, 50))	('resistance to chemotherapy', 'MPA', (145, 171))
219707	29513652	Together, our data indicate that Ewing sarcoma phenocopies BRCA1-deficient tumours and suggests that secondary mutations in TP53BP1 are a potential chemoresistance mechanism.	('mutations', 'Var', (111, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (33, 46))	('Ewing sarcoma phenocopies BRCA1-deficient tumours', 'Disease', 'MESH:C563168', (33, 82))	('Ewing sarcoma phenocopies BRCA1-deficient tumours', 'Disease', (33, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('TP53BP1', 'Gene', '7158', (124, 131))	('TP53BP1', 'Gene', (124, 131))
219709	29513652	Sequestration of BRCA1 with transcription complexes could prevent its redistribution to exogenous damage and therefore explain its functional absence in Ewing sarcoma.	('BRCA1', 'Gene', '672', (17, 22))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('prevent', 'NegReg', (58, 65))	('BRCA1', 'Gene', (17, 22))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (153, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('rat', 'Species', '10116', (7, 10))	('redistribution to exogenous damage', 'MPA', (70, 104))	('Sequestration', 'Var', (0, 13))	('Ewing sarcoma', 'Disease', (153, 166))
219713	29513652	3i), but was substantially reduced by EWS-FLI1 knockdown.	('knockdown', 'Var', (47, 56))	('reduced', 'NegReg', (27, 34))	('EWS-FLI1', 'Gene', (38, 46))	('EWS-FLI1', 'Gene', '2130;2313', (38, 46))
219727	29513652	Conversely, we also confirmed the presence of R-loops at BRCA1 binding sites (Extended Data Fig.	('BRCA1', 'Gene', (57, 62))	('binding', 'Interaction', (63, 70))	('BRCA1', 'Gene', '672', (57, 62))	('R-loops', 'Var', (46, 53))
219737	29513652	Mutations in EWSR1 and its homologues are associated with several therapeutically challenging cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('EWSR1', 'Gene', '2130', (13, 18))	('associated', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('EWSR1', 'Gene', (13, 18))	('cancers', 'Disease', (94, 101))
219739	29513652	We envision the use of agents that induce transcription or replication stress as potentially effective augmentative treatment strategies in various tumours associated with EWSR1 translocations.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('EWSR1', 'Gene', (172, 177))	('EWSR1', 'Gene', '2130', (172, 177))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('translocations', 'Var', (178, 192))	('rat', 'Species', '10116', (128, 131))
219749	29513652	For some experiments, lentiviral transduction of TC32 cells with control short hairpin RNA (shCtrl) (clone RHZ4743, Life Technologies) or shFLI1 (clone V2THS227524 or V3THS414176, Life Technologies) was performed.	('FLI1', 'Gene', '2130', (140, 144))	('FLI1', 'Gene', (140, 144))	('TC32', 'CellLine', 'CVCL:7151', (49, 53))	('V3THS414176', 'Var', (167, 178))
219757	29513652	Chemicals used in cell viability experiments include etoposide (E1383, Sigma), camptothecin (C9911, Sigma), VE-821 (ATR inhibitor, Selleck Chemicals) and Olaparib (PARP1 inhibitor, Selleck Chemicals).	('C9911', 'Var', (93, 98))	('PARP1', 'Gene', (164, 169))	('camptothecin', 'Chemical', 'MESH:D002166', (79, 91))	('E1383', 'Chemical', '-', (64, 69))	('ATR', 'Gene', '545', (116, 119))	('ATR', 'Gene', (116, 119))	('Olaparib', 'Chemical', 'MESH:C531550', (154, 162))	('etoposide', 'Chemical', 'MESH:D005047', (53, 62))	('E1383', 'Var', (64, 69))	('VE-821', 'Chemical', 'MESH:C560580', (108, 114))	('PARP1', 'Gene', '142', (164, 169))
219767	29513652	The following purified recombinant proteins were purchased: RNAPII CTD fragment (POLR2A-1149H, Creative BioMart), EWSR1 (TP303709, Origene), FUS (TP301808, Origene) and CDK9/cyclin T1 (PV4131, ThermoFisher Scientific).	('FUS', 'Gene', (141, 144))	('CDK9', 'Gene', (169, 173))	('cyclin T1', 'Gene', (174, 183))	('POLR2A', 'Gene', '5430', (81, 87))	('FUS', 'Gene', '2521', (141, 144))	('EWSR1', 'Gene', (114, 119))	('TP303709', 'Var', (121, 129))	('CDK9', 'Gene', '1025', (169, 173))	('EWSR1', 'Gene', '2130', (114, 119))	('POLR2A', 'Gene', (81, 87))	('TP301808', 'Var', (146, 154))	('cyclin T1', 'Gene', '904', (174, 183))	('Origene', 'Var', (156, 163))	('PV4131', 'Var', (185, 191))
219768	29513652	The template used for kinase activity was either 50 muM CDK7/9tide (triheptad repeat peptide) provided in the kit (PV5090, ThermoFisher Scientific), or 12 ng RNAPII CTD fragment.	('CDK7', 'Gene', '1022', (56, 60))	('PV5090', 'Var', (115, 121))	('CDK7', 'Gene', (56, 60))
219799	29513652	The remaining pre-cleared lysates were used for overnight immunoprecipitation with either BRCA1 antibody (A300-000, Bethyl Labs) or IgG control (ab37415, Abcam) and pre-washed beads.	('BRCA1', 'Gene', '672', (90, 95))	('A300-000', 'Disease', 'MESH:C564120', (106, 114))	('BRCA1', 'Gene', (90, 95))	('ab37415', 'Var', (145, 152))	('A300-000', 'Disease', (106, 114))
219840	29513652	a, Differentially upregulated processes in IMR90 but not Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (57, 70))	('IMR90', 'CellLine', 'CVCL:0347', (43, 48))	('IMR90', 'Var', (43, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('processes', 'CPA', (30, 39))	('upregulated', 'PosReg', (18, 29))
219841	29513652	b, Differentially downregulated processes in IMR90 but not Ewing sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('IMR90', 'Var', (45, 50))	('Ewing sarcoma', 'Disease', (59, 72))	('downregulated', 'NegReg', (18, 31))	('IMR90', 'CellLine', 'CVCL:0347', (45, 50))	('processes', 'CPA', (32, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))
219845	22072439	As rare examples of EWSR1-negative SBRCT have been shown to carry rearrangements for FUS and CIC genes, we undertook a systematic screening for these two genes.	('CIC', 'Gene', '23152', (93, 96))	('SBRCT', 'Chemical', '-', (35, 40))	('CIC', 'Gene', (93, 96))	('EWSR1', 'Gene', '2130', (20, 25))	('rearrangements', 'Var', (66, 80))	('FUS', 'Gene', (85, 88))	('FUS', 'Gene', '2521', (85, 88))	('EWSR1', 'Gene', (20, 25))
219848	22072439	Subsequent FISH analysis confirmed fused signals of CIC with either 4q35 or 10q26.3 region in six cases each.	('CIC', 'Gene', '23152', (52, 55))	('4q35', 'Var', (68, 72))	('CIC', 'Gene', (52, 55))
219853	22072439	These results suggest the possibility of a newly defined subgroup of primitive round cell sarcomas characterized by CIC rearrangements, distinct from Ewing sarcoma family of tumors.	('rearrangements', 'Var', (120, 134))	('Ewing sarcoma family of tumors', 'Disease', (150, 180))	('Ewing sarcoma family of tumors', 'Disease', 'MESH:C563168', (150, 180))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('CIC', 'Gene', '23152', (116, 119))	('sarcomas', 'Disease', (90, 98))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (150, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('CIC', 'Gene', (116, 119))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
219857	22072439	A subset of tumors resembling microscopically Ewing sarcoma family of tumors (EFT), being composed mainly of primitive small round cells and occurring in children or young adults, remain unclassified, being negative for EWSR1, SS18(SYT), DDIT3(CHOP) and FOXO1(FKHR) gene rearrangements by FISH/RT-PCR, which constitute most of the known SBRCT-related translocations in this age group.	('SS18', 'Gene', (227, 231))	('rearrangements', 'Var', (271, 285))	('SYT', 'Gene', (232, 235))	('FOXO1', 'Gene', (254, 259))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Ewing sarcoma family of tumors', 'Disease', (46, 76))	('FKHR', 'Gene', (260, 264))	('Ewing sarcoma family of tumors', 'Disease', 'MESH:C563168', (46, 76))	('children', 'Species', '9606', (154, 162))	('SBRCT', 'Chemical', '-', (337, 342))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('EWSR1', 'Gene', (220, 225))	('CHOP', 'Gene', '1649', (244, 248))	('SS18', 'Gene', '6760', (227, 231))	('tumors', 'Disease', (70, 76))	('SYT', 'Gene', '6760', (232, 235))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('FKHR', 'Gene', '2308', (260, 264))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('DDIT3', 'Gene', '1649', (238, 243))	('tumors', 'Disease', (12, 18))	('negative', 'NegReg', (207, 215))	('CHOP', 'Gene', (244, 248))	('DDIT3', 'Gene', (238, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('EWSR1', 'Gene', '2130', (220, 225))	('FOXO1', 'Gene', '2308', (254, 259))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
219875	22072439	Additional FISH studies to exclude rearrangements in SS18 in 5 cases and DDIT3 in 2 cases were performed at the time of diagnosis.	('DDIT3', 'Gene', (73, 78))	('rearrangements', 'Var', (35, 49))	('SS18', 'Gene', (53, 57))	('DDIT3', 'Gene', '1649', (73, 78))	('SS18', 'Gene', '6760', (53, 57))
219902	22072439	The most likely explanation for this failure was the D4Z4 repetitive sequence of DUX4.	('DUX4', 'Gene', (81, 85))	('DUX4', 'Gene', '100288687', (81, 85))	('D4Z4 repetitive sequence', 'Var', (53, 77))
219903	22072439	However, by LR-PCR, the amplified 1.3 kb product confirmed the fusion of the 5'portion of CIC exon 20 to exon 1 of DUX4, located within the D4Z4 repeat and part of the coding sequence region of DUX4 on chromosome 4 (Fig.	('CIC', 'Gene', (90, 93))	('DUX4', 'Gene', '100288687', (115, 119))	('DUX4', 'Gene', (115, 119))	('fusion', 'Var', (63, 69))	('CIC', 'Gene', '23152', (90, 93))	('DUX4', 'Gene', (194, 198))	('DUX4', 'Gene', '100288687', (194, 198))
219909	22072439	At the DNA level, LR-PCR further confirmed the fusion of CIC exon 20 with DUX4 exon 1 at the 135497789 genomic position (Fig.	('DUX4', 'Gene', '100288687', (74, 78))	('fusion', 'Var', (47, 53))	('CIC', 'Gene', '23152', (57, 60))	('CIC', 'Gene', (57, 60))	('DUX4', 'Gene', (74, 78))
219915	22072439	There was no significant difference between tumors harboring a t(4;19) and t(10;19) in terms of histological features, clinical presentation or outcome.	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('t(4;19', 'Var', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
219944	22072439	In fact one of their cases of undifferentiated primitive sarcoma, arising in the chest wall of 5 year-old boy was associated with a 4q35 rearrangement, a der(4)t(4;?8)(q35;q22).	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('boy', 'Species', '9606', (106, 109))	('der(4)t(4;?8)(q35;q22', 'Var', (154, 175))	('associated', 'Reg', (114, 124))	('sarcoma', 'Disease', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
219957	22072439	The contraction of the D4Z4 macrosatellite repeat array in the subtelomeric region of 4q35, but not 10q26, causes fascioscapular muscular dystrophy (FSMD).	('muscular dystrophy', 'Phenotype', 'HP:0003560', (129, 147))	('contraction', 'Var', (4, 15))	('causes', 'Reg', (107, 113))	('FSMD', 'Disease', 'None', (149, 153))	('fascioscapular muscular dystrophy', 'Disease', (114, 147))	('FSMD', 'Disease', (149, 153))	('D4Z4', 'Gene', (23, 27))	('fascioscapular muscular dystrophy', 'Disease', 'MESH:D009136', (114, 147))
219958	22072439	However, this contraction is pathogenic only in certain permissive configurations, such as the formation of a canonical polyadenylation signal for transcripts derived from DUX4, by single nucleotide polymorphisms distal to the last D4Z4 repeat.	('formation', 'MPA', (95, 104))	('single nucleotide polymorphisms', 'Var', (181, 212))	('DUX4', 'Gene', (172, 176))	('DUX4', 'Gene', '100288687', (172, 176))	('canonical polyadenylation signal', 'MPA', (110, 142))
219961	22072439	As a consequence of fusion with the C-terminal of DUX4, the transcriptional activity of CIC is enhanced, suggesting a deregulation of downstream targets.	('fusion', 'Var', (20, 26))	('deregulation', 'MPA', (118, 130))	('CIC', 'Gene', '23152', (88, 91))	('transcriptional activity', 'MPA', (60, 84))	('CIC', 'Gene', (88, 91))	('DUX4', 'Gene', (50, 54))	('DUX4', 'Gene', '100288687', (50, 54))	('enhanced', 'PosReg', (95, 103))
219970	22072439	The identification of a subgroup of undifferentiated sarcomas characterized by a fusion between genes which are not related to EWSR1 or the ETS family may have significant clinical implications.	('EWSR1', 'Gene', (127, 132))	('fusion', 'Var', (81, 87))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (36, 61))	('EWSR1', 'Gene', '2130', (127, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('undifferentiated sarcomas', 'Disease', (36, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))
219978	22072439	Therefore, we believe that our results showing a high prevalence of rearrangement of CIC in EWSR1-negative SBRCT support the routine testing of this gene in this group of tumor.	('SBRCT', 'Chemical', '-', (107, 112))	('EWSR1', 'Gene', '2130', (92, 97))	('rearrangement', 'Var', (68, 81))	('CIC', 'Gene', '23152', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('EWSR1', 'Gene', (92, 97))	('CIC', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
220075	21785569	Thus, MEKK3-/- BM-transplanted mice have impaired vasculogenesis but normal angiogenesis.	('vasculogenesis', 'CPA', (50, 64))	('angiogenesis', 'CPA', (76, 88))	('MEKK3-/- BM-transplanted', 'Var', (6, 30))	('mice', 'Species', '10090', (31, 35))	('impaired', 'NegReg', (41, 49))
220076	21785569	The growth of both TC71 and A4573 Ewing's sarcoma tumors was significantly inhibited in MEKK3-/- BM-transplanted mice compared to tumors in control transplanted mice.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('mice', 'Species', '10090', (161, 165))	('growth', 'CPA', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (34, 49))	("Ewing's sarcoma tumors", 'Disease', (34, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('A4573', 'Var', (28, 33))	('TC71', 'Gene', (19, 23))	('inhibited', 'NegReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	("Ewing's sarcoma tumors", 'Disease', 'MESH:C563168', (34, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('mice', 'Species', '10090', (113, 117))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
220093	21785569	Tumors from mice treated with DC101 had reduced numbers of BM-derived pericytes/vSMCs, reduced microvessel density, and importantly, significantly-inhibited tumor growth.	('tumor', 'Disease', (157, 162))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('reduced', 'NegReg', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('significantly-inhibited', 'NegReg', (133, 156))	('DC101', 'Var', (30, 35))	('Tumors', 'Disease', (0, 6))	('reduced', 'NegReg', (40, 47))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (12, 16))	('microvessel density', 'CPA', (95, 114))
220115	21785569	In both A4573 and TC71 tumors, immunohistochemical analysis demonstrated co-localization between DLL4 and GFP, as well as DLL4 and the pericyte/vSMC markers desmin, NG2, and alpha-SMA.	('DLL4', 'Gene', '54567', (97, 101))	('GFP', 'Gene', (106, 109))	('co-localization', 'Interaction', (73, 88))	('DLL4', 'Gene', (122, 126))	('desmin', 'Gene', (157, 163))	('NG2', 'Gene', '1464', (165, 168))	('TC71 tumors', 'Disease', 'MESH:D009369', (18, 29))	('desmin', 'Gene', '1674', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('DLL4', 'Gene', (97, 101))	('DLL4', 'Gene', '54567', (122, 126))	('A4573', 'Var', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('NG2', 'Gene', (165, 168))	('TC71 tumors', 'Disease', (18, 29))
220118	21785569	The loss of BM-derived pericytes/vSMC after DLL4 inhibition substantiates the critical role of DLL4 in the formation of BM-derived pericytes/vSMCs, and a functional vasculature.	('DLL4', 'Gene', (95, 99))	('inhibition', 'Var', (49, 59))	('DLL4', 'Gene', '54567', (44, 48))	('DLL4', 'Gene', '54567', (95, 99))	('loss', 'NegReg', (4, 8))	('DLL4', 'Gene', (44, 48))
220130	21785569	While inhibition of DLL4 leads to ablation of the functional vascular network, inhibition of VEGF can, in some cases, lead to a transient stage of vessel normalization.	('lead to', 'Reg', (118, 125))	('VEGF', 'Gene', (93, 97))	('functional vascular network', 'CPA', (50, 77))	('DLL4', 'Gene', (20, 24))	('inhibition', 'Var', (79, 89))	('VEGF', 'Gene', '7422', (93, 97))	('inhibition', 'Var', (6, 16))	('ablation', 'NegReg', (34, 42))	('vessel normalization', 'MPA', (147, 167))	('DLL4', 'Gene', '54567', (20, 24))
220137	21785569	Therefore, inhibition of VEGF or DLL4, both of which are important for BM cell participation in vasculogenesis, after chemotherapy may prove to be useful in preventing disease relapse or metastasis.	('DLL4', 'Gene', '54567', (33, 37))	('VEGF', 'Gene', '7422', (25, 29))	('disease relapse', 'CPA', (168, 183))	('inhibition', 'Var', (11, 21))	('DLL4', 'Gene', (33, 37))	('VEGF', 'Gene', (25, 29))
220139	21785569	Additionally, genetic targeting of vasculogenesis, but not angiogenesis, via MEKK3 knockout has shown that vasculogenesis is essential for the growth of Ewing's sarcoma in vivo .	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('MEKK3', 'Gene', (77, 82))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (153, 168))	('genetic', 'Var', (14, 21))	("Ewing's sarcoma", 'Disease', (153, 168))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (153, 168))
220160	30112112	For example one randomized neoadjuvant trial of ifosfamide, doxorubicin, mesna showed no significant benefit in high risk tumors (over 8 cm of any grade or grade II/III less than 8 cm) in overall survival (OS) or disease free survival (DFS).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('doxorubicin', 'Chemical', 'MESH:D004317', (60, 71))	('ifosfamide', 'Chemical', 'MESH:D007069', (48, 58))	('mesna', 'Chemical', 'MESH:D015080', (73, 78))	('overall survival', 'CPA', (188, 204))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('over', 'Var', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('disease free survival', 'CPA', (213, 234))
220161	30112112	In another study with a similar ifosfamide, doxorubicin protocol however there was a disease specific survival benefit in high grade tumors >10 cm but not in smaller tumors with no overall survival benefit.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('high grade', 'Var', (122, 132))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('benefit', 'PosReg', (111, 118))	('ifosfamide', 'Chemical', 'MESH:D007069', (32, 42))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
220165	30112112	For example, in the EORTC trial combination doxo/ifos was associated with 47% grade III/IV toxicity, most commonly neutropenia (39%).	('neutropenia', 'Phenotype', 'HP:0001875', (115, 126))	('doxo/ifos', 'Var', (44, 53))	('grade III/IV', 'Disease', (78, 90))	('neutropenia', 'Disease', (115, 126))	('doxo', 'Chemical', '-', (44, 48))	('toxicity', 'Disease', 'MESH:D064420', (91, 99))	('neutropenia', 'Disease', 'MESH:D009503', (115, 126))	('toxicity', 'Disease', (91, 99))
220173	30112112	Neo-antigens are the result of mutations in coding regions of the DNA, thus tumors with a higher mutation load would be more likely to be identified and destroyed by engaged CD8 T cells once exposed to checkpoint inhibitors.	('mutations', 'Var', (31, 40))	('CD8', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CD8', 'Gene', '925', (174, 177))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
220174	30112112	One such condition is tumors with mutations in the mismatch repair genes.	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mismatch repair genes', 'Gene', (51, 72))	('mutations', 'Var', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
220187	30112112	PDL-1 staining was positive in four of eleven tumors employing the Abcam antibody while all 11 samples had a negative staining with the Dako antibody.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PDL-1', 'Gene', '29126', (0, 5))	('positive', 'Reg', (19, 27))	('PDL-1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('Abcam', 'Var', (67, 72))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
220203	30112112	Loss of PMS2 is the least common deficiency identified in MMR-D tumors from various origins, and is associated in most cases with loss of MLH1.	('PMS2', 'Gene', '5395', (8, 12))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('PMS2', 'Gene', (8, 12))	('MLH1', 'Gene', '4292', (138, 142))	('MLH1', 'Gene', (138, 142))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('MMR-D', 'Gene', (58, 63))
220205	30112112	All samples in our analysis had CD8+ lymphocytic infiltration within the tumor; however, In our homogenous series of primary LMS, lack of peri-tumoral CD8 infiltration, together with an absence of PD-L1 staining was in fact associated with the best clinical subset- alive and recurrence free in contrast to the patients in our series who had strong positive PD-L1 staining who had the poorest outcome.	('CD8', 'Gene', '925', (32, 35))	('lymphocytic infiltration within the tumor', 'Disease', 'MESH:D001929', (37, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CD8', 'Gene', '925', (151, 154))	('associated', 'Reg', (224, 234))	('lymphocytic infiltration within the tumor', 'Disease', (37, 78))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('PD-L1', 'Gene', (358, 363))	('PD-L1', 'Gene', '29126', (358, 363))	('CD8', 'Gene', (32, 35))	('PD-L1', 'Gene', (197, 202))	('CD8', 'Gene', (151, 154))	('tumor', 'Disease', (73, 78))	('PD-L1', 'Gene', '29126', (197, 202))	('recurrence free', 'CPA', (276, 291))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (143, 148))	('lack', 'Var', (130, 134))	('patients', 'Species', '9606', (311, 319))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
220221	30112112	Contrary to our findings, it might be expected that MMR-D tumors harboring a high mutational load would exhibit a rich lymphocytic infiltration; this discrepancy could be the result of T cell exclusion.	('mutational load', 'Var', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('lymphocytic infiltration', 'CPA', (119, 143))
220228	30112112	Our initial results in primary LMS tumors suggest that patients with positive CD8 and PD-L1 staining have a poor prognosis and as such might benefit from intensified adjuvant/neoadjuvant therapy.	('benefit', 'Reg', (141, 148))	('CD8', 'Gene', (78, 81))	('LMS tumors', 'Disease', 'MESH:C535903', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('PD-L1', 'Gene', '29126', (86, 91))	('CD8', 'Gene', '925', (78, 81))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('positive', 'Var', (69, 77))	('patients', 'Species', '9606', (55, 63))	('LMS tumors', 'Disease', (31, 41))	('PD-L1', 'Gene', (86, 91))
220251	30112112	LMS Leiomyosarcoma TIL tumor lymphocytic infiltration PD-L1 programed cell death ligand-1 MMR-D mismatch repair deficiency ULMS uterine LMS STS soft tissue sarcomas NSCLC non-small cell lung cancer LMS EU-LMS extra-uterine IDO indoleamine-pyrrole 2,3-dioxygenase	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('IDO', 'Chemical', '-', (223, 226))	('Leiomyosarcoma', 'Disease', (4, 18))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (144, 163))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (144, 163))	('tumor lymphocytic infiltration', 'Disease', 'MESH:D017254', (23, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (171, 197))	('soft tissue sarcoma', 'Disease', (144, 163))	('NSCLC', 'Disease', (165, 170))	('sarcomas', 'Disease', 'MESH:D012509', (156, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (175, 197))	('sarcomas', 'Disease', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (144, 164))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (171, 197))	('PD-L1', 'Gene', (54, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('PD-L1', 'Gene', '29126', (54, 59))	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (4, 18))	('deficiency', 'Var', (112, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('non-small cell lung cancer', 'Disease', (171, 197))	('tumor lymphocytic infiltration', 'Disease', (23, 53))	('Leiomyosarcoma', 'Disease', 'MESH:D007890', (4, 18))
220348	26001368	GIST diagnosis was confirmed by immunohistochemistry or PCR-based DNA sequencing analysis to detect mutations in PDGFRalpha (exon 18) or c-KIT (exons 9, 11, 13, and 17).	('mutations', 'Var', (100, 109))	('c-KIT', 'Gene', (137, 142))	('c-KIT', 'Gene', '3815', (137, 142))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('PDGFRalpha', 'Gene', '5156', (113, 123))	('PDGFRalpha', 'Gene', (113, 123))
220359	26001368	Subgroup analysis showed that patients with GIST who received imatinib had a higher 5-year RFS rate than patients with GIST who underwent surgical resection alone (47.1% vs 9.5%; p = 0.013; Figure 3a).	('GIST', 'Phenotype', 'HP:0100723', (44, 48))	('imatinib', 'Var', (62, 70))	('imatinib', 'Chemical', 'MESH:D000068877', (62, 70))	('patients', 'Species', '9606', (105, 113))	('GIST', 'Phenotype', 'HP:0100723', (119, 123))	('higher', 'PosReg', (77, 83))	('RFS', 'CPA', (91, 94))	('patients', 'Species', '9606', (30, 38))
220364	26001368	The 5-year OS rates and median survival times did not differ significantly by pathological type, although there was a clear trend towards better 5-year survival for patients with GIST (Table 3).	('GIST', 'Phenotype', 'HP:0100723', (179, 183))	('better', 'PosReg', (138, 144))	('GIST', 'Var', (179, 183))	('patients', 'Species', '9606', (165, 173))
220365	26001368	However, the 10-year OS rate was significantly better in patients with GIST (52.5%) than in patients with LMS (9.2%) or SRC (23.0%; Figure 2b; p = 0.016).	('LMS', 'Phenotype', 'HP:0100243', (106, 109))	('better', 'PosReg', (47, 53))	('GIST', 'Phenotype', 'HP:0100723', (71, 75))	('GIST', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (92, 100))	('SRC', 'Gene', '6714', (120, 123))	('SRC', 'Gene', (120, 123))
220366	26001368	In univariate analyses (Table 4), after resection of liver metastases from GIST, age greater than 55 years (HR, 2.798; p = 0.027) was associated with reduced OS, male sex (HR, 0.447; p = 0.071) exhibited a trend towards increased OS, and concomitant RFA (HR, 2.179; p = 0.085) and R1 resection (HR, 4.100; p = 0.066) exhibited trends towards reduced OS.	('increased', 'PosReg', (220, 229))	('liver metastases', 'Disease', 'MESH:D009362', (53, 69))	('male sex', 'Var', (162, 170))	('GIST', 'Phenotype', 'HP:0100723', (75, 79))	('reduced', 'NegReg', (150, 157))	('liver metastases', 'Disease', (53, 69))
220368	26001368	After resection of SRC, R1 resection (HR, 12.97; p < 0.001) was associated with decreased OS, and male sex (HR, 1.962; p = 0.076) exhibited a trend towards decreased OS (Table 4).	('decreased', 'NegReg', (80, 89))	('SRC', 'Gene', '6714', (19, 22))	('SRC', 'Gene', (19, 22))	('R1 resection', 'Var', (24, 36))
220383	26001368	In GIST, the principal pathological genetic defect has been identified as mutation in the c-KIT proto-oncogene or in the platelet-derived growth factor receptor-alpha (PDGFRalpha) gene, both leading to expression of proteins causing constitutive activation of tyrosine kinase receptors.	('platelet-derived growth factor receptor-alpha', 'Gene', (121, 166))	('proteins', 'Protein', (216, 224))	('mutation', 'Var', (74, 82))	('PDGFRalpha', 'Gene', (168, 178))	('PDGFRalpha', 'Gene', '5156', (168, 178))	('genetic defect', 'Disease', (36, 50))	('genetic defect', 'Disease', 'MESH:D030342', (36, 50))	('tyrosine kinase receptors', 'MPA', (260, 285))	('activation', 'PosReg', (246, 256))	('leading to', 'Reg', (191, 201))	('expression', 'MPA', (202, 212))	('c-KIT', 'Gene', (90, 95))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (121, 166))	('GIST', 'Phenotype', 'HP:0100723', (3, 7))	('c-KIT', 'Gene', '3815', (90, 95))
220423	33801580	Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis.	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('rat', 'Species', '10116', (157, 160))	('CrkL', 'Gene', (52, 56))	('tumor', 'Disease', (256, 261))	('epithelial-mesenchymal transition', 'CPA', (175, 208))	('knockout', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cell proliferation', 'CPA', (118, 136))	('migration', 'CPA', (154, 163))	('resistance to chemotherapy', 'CPA', (210, 236))	('tumor', 'Disease', (86, 91))	('transformation', 'CPA', (138, 152))	('invasion', 'CPA', (165, 173))	('Crk', 'Gene', (44, 47))	('rat', 'Species', '10116', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('suppress', 'NegReg', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
220441	33801580	Moreover, the heterozygous inactive mutation in CrkL in humans has been reported to cause congenital kidney anomalies of DiGeorge syndrome.	('congenital kidney anomalies of DiGeorge syndrome', 'Disease', (90, 138))	('congenital kidney anomalies of DiGeorge syndrome', 'Disease', 'MESH:D004062', (90, 138))	('kidney anomalies', 'Phenotype', 'HP:0000077', (101, 117))	('CrkL', 'Gene', (48, 52))	('heterozygous inactive mutation', 'Var', (14, 44))	('humans', 'Species', '9606', (56, 62))	('cause', 'Reg', (84, 89))
220456	33801580	Overexpression of T47D breast cancer epithelial cells with CrkII also caused dispersal of colonies.	('breast cancer', 'Disease', (23, 36))	('dispersal of colonies', 'CPA', (77, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('caused', 'Reg', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('T47D', 'Var', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('T47', 'CellLine', 'CVCL:3945', (18, 21))
220457	33801580	CrkII overexpression in NIH3T3 cells made cells larger with enhanced lamellipodium formation.	('NIH3T3', 'CellLine', 'CVCL:0594', (24, 30))	('overexpression', 'Var', (6, 20))	('lamellipodium formation', 'CPA', (69, 92))	('cells larger', 'CPA', (42, 54))	('enhanced', 'PosReg', (60, 68))
220460	33801580	Crk knockdown in NIH3T3 cells resulted in a slower rate of cell spreading, more filopodia formation, and reduced focal adhesion formation in the early stages of cell spreading onto fibronectin-coated surfaces.	('cell spreading', 'CPA', (59, 73))	('focal adhesion formation', 'CPA', (113, 137))	('slower', 'NegReg', (44, 50))	('NIH3T3', 'CellLine', 'CVCL:0594', (17, 23))	('filopodia formation', 'CPA', (80, 99))	('more', 'PosReg', (75, 79))	('rat', 'Species', '10116', (51, 54))	('reduced', 'NegReg', (105, 112))	('knockdown', 'Var', (4, 13))	('Crk', 'Gene', (0, 3))
220461	33801580	Furthermore, Crk/CrkL double knockdown, but not Crk or CrkL single knockdown, in NIH3T3 cells led to nearly complete inhibition of focal adhesion formation in the absence of PDGF.	('focal adhesion formation', 'CPA', (131, 155))	('double knockdown', 'Var', (22, 38))	('inhibition', 'NegReg', (117, 127))	('NIH3T3', 'CellLine', 'CVCL:0594', (81, 87))
220463	33801580	In addition, ablation of both Crk and CrkL from mouse embryonic fibroblasts resulted in a decrease in focal adhesion sites, reduced actin stress fibers, and a collapse of microtubule structures.	('reduced', 'NegReg', (124, 131))	('mouse', 'Species', '10090', (48, 53))	('collapse', 'NegReg', (159, 167))	('Crk', 'Protein', (30, 33))	('focal', 'CPA', (102, 107))	('CrkL', 'Gene', (38, 42))	('ablation', 'Var', (13, 21))	('actin stress', 'MPA', (132, 144))	('microtubule structures', 'MPA', (171, 193))	('decrease', 'NegReg', (90, 98))
220466	33801580	Crk knockdown resulted in decreased spreading of a breast cancer cell line onto a fibronectin substrate with decreases in focal adhesions and actin stress fibers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('knockdown', 'Var', (4, 13))	('spreading', 'CPA', (36, 45))	('actin stress fibers', 'CPA', (142, 161))	('focal adhesions', 'CPA', (122, 137))	('rat', 'Species', '10116', (99, 102))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('decreased', 'NegReg', (26, 35))	('decreases', 'NegReg', (109, 118))	('Crk', 'Gene', (0, 3))
220467	33801580	In addition, knockdown of both Crk and CrkL in the breast cancer cell line resulted in defective lamellipodia formation and delayed cell spreading on fibronectin.	('Crk', 'Gene', (31, 34))	('CrkL', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lamellipodia formation', 'CPA', (97, 119))	('cell spreading on fibronectin', 'CPA', (132, 161))	('delayed', 'NegReg', (124, 131))	('defective', 'NegReg', (87, 96))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('knockdown', 'Var', (13, 22))
220468	33801580	In a glioblastoma cell line, both CrkL knockdown and Crk/CrkL double knockdown caused cells to shrink and become rounded.	('glioblastoma', 'Disease', (5, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (5, 17))	('knockdown', 'Var', (39, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (5, 17))	('shrink', 'NegReg', (95, 101))	('knockdown', 'Var', (69, 78))
220474	33801580	Ablation of endogenous Crk and CrkL from immortalized fibroblasts using Cre-loxP recombination-mediated gene knockout caused a blockage of cell proliferation and arrest of the cell cycle at the G1-S transition.	('Ablation', 'Var', (0, 8))	('arrest', 'Disease', 'MESH:D006323', (162, 168))	('Crk', 'Protein', (23, 26))	('cell proliferation', 'CPA', (139, 157))	('arrest', 'Disease', (162, 168))	('blockage', 'NegReg', (127, 135))	('rat', 'Species', '10116', (151, 154))	('CrkL', 'Protein', (31, 35))
220475	33801580	While loss of either Crk or CrkL alone conferred a much more modest reduction in cell proliferation, reintroduction of CrkI, CrkII, or CrkL individually rescued cell proliferation in the absence of the endogenous Crk and CrkL, suggesting overlapping functions of Crk and CrkL in fibroblast proliferation.	('cell proliferation', 'CPA', (81, 99))	('CrkI', 'Gene', (125, 129))	('loss', 'Var', (6, 10))	('rat', 'Species', '10116', (173, 176))	('rat', 'Species', '10116', (297, 300))	('cell proliferation', 'CPA', (161, 179))	('CrkI', 'Gene', (119, 123))	('CrkI', 'Gene', '12928', (125, 129))	('rescued', 'PosReg', (153, 160))	('reduction', 'NegReg', (68, 77))	('Crk', 'Gene', (21, 24))	('CrkI', 'Gene', '12928', (119, 123))	('rat', 'Species', '10116', (93, 96))
220477	33801580	Reduction in CrkII and CrkI protein levels by Crk knockdown led to inhibition of cell proliferation in MCAS and SKOV3 ovarian cancer and synovial sarcoma cell lines (Table 1).	('cell proliferation', 'CPA', (81, 99))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('CrkI', 'Gene', '12928', (13, 17))	('inhibition', 'NegReg', (67, 77))	('synovial sarcoma', 'Disease', (137, 153))	('knockdown', 'Var', (50, 59))	('CrkI', 'Gene', (23, 27))	('CrkI', 'Gene', (13, 17))	('Crk', 'Gene', (46, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('Reduction', 'NegReg', (0, 9))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (137, 153))	('synovial sarcoma', 'Disease', 'MESH:D013584', (137, 153))	('CrkI', 'Gene', '12928', (23, 27))	('MCAS and SKOV3 ovarian cancer', 'Disease', 'MESH:D010051', (103, 132))	('rat', 'Species', '10116', (93, 96))
220478	33801580	CrkL knockdown also inhibited cell proliferation in rhabdomyosarcoma, MDA-MB-453 breast cancer, MKN-45 gastric cancer, hepatocellular carcinoma, and HeLa cell lines.	('breast cancer', 'Disease', (81, 94))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (20, 29))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('hepatocellular carcinoma', 'Disease', (119, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (52, 68))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (52, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('cell proliferation', 'CPA', (30, 48))	('CrkL', 'Gene', (0, 4))	('HeLa', 'CellLine', 'CVCL:0030', (149, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('gastric cancer', 'Disease', (103, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))	('rhabdomyosarcoma', 'Disease', (52, 68))	('rat', 'Species', '10116', (42, 45))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
220480	33801580	In addition, individual and combined knockdown of Crk and CrkL in U-118MG glioblastoma cells demonstrated that CrkL knockdown and Crk/CrkL double knockdown, but not Crk knockdown, inhibited cell proliferation.	('glioblastoma', 'Disease', (74, 86))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('knockdown', 'Var', (116, 125))	('U-118MG', 'CellLine', 'CVCL:0633', (66, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('cell proliferation', 'CPA', (190, 208))	('rat', 'Species', '10116', (202, 205))	('inhibited', 'NegReg', (180, 189))	('CrkL', 'Protein', (111, 115))	('rat', 'Species', '10116', (100, 103))
220483	33801580	Crk knockdown and CrkL knockdown induced arrest of the cell cycle at G1 in synovial sarcoma and gastric cancer cells, respectively.	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('synovial sarcoma', 'Disease', (75, 91))	('knockdown', 'Var', (23, 32))	('arrest', 'Disease', (41, 47))	('CrkL', 'Gene', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (75, 91))	('gastric cancer', 'Disease', (96, 110))	('knockdown', 'Var', (4, 13))	('arrest', 'Disease', 'MESH:D006323', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('synovial sarcoma', 'Disease', 'MESH:D013584', (75, 91))	('Crk', 'Gene', (0, 3))
220488	33801580	Systematic comparison among individual and combined knockdown in various cancer cell lines would provide in-depth insights into this question.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('knockdown', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
220499	33801580	Crk knockdown in human ovarian cancer cells and glioblastoma cells inhibited colony formation on soft agar.	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('colony formation on soft agar', 'CPA', (77, 106))	('inhibited', 'NegReg', (67, 76))	('agar', 'Chemical', 'MESH:D000362', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('human', 'Species', '9606', (17, 22))	('ovarian cancer', 'Disease', (23, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('glioblastoma', 'Disease', (48, 60))	('knockdown', 'Var', (4, 13))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))	('Crk', 'Gene', (0, 3))
220500	33801580	CrkL knockdown also inhibited colony formation of glioma and cervical cancer cell lines on soft agar.	('cervical cancer', 'Disease', 'MESH:D002583', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CrkL', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('cervical cancer', 'Disease', (61, 76))	('agar', 'Chemical', 'MESH:D000362', (96, 100))	('glioma', 'Disease', (50, 56))	('inhibited', 'NegReg', (20, 29))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
220501	33801580	Ablation of CrkII, CrkI, and CrkL altogether suppressed anchorage-independent growth of MDA-231 breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CrkI', 'Gene', (19, 23))	('CrkI', 'Gene', (12, 16))	('Ablation', 'Var', (0, 8))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('CrkI', 'Gene', '12928', (19, 23))	('suppressed', 'NegReg', (45, 55))	('MDA-231', 'CellLine', 'CVCL:0062', (88, 95))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('anchorage-independent growth', 'CPA', (56, 84))	('CrkI', 'Gene', '12928', (12, 16))
220506	33801580	Crk knockdown in ovarian cancer, glioblastoma, breast cancer, and bladder cancer cells resulted in decreased tumor growth in nude mice.	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (66, 80))	('knockdown', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('decreased tumor', 'Disease', 'MESH:D002303', (99, 114))	('breast cancer', 'Disease', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (17, 31))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('decreased tumor', 'Disease', (99, 114))	('Crk', 'Gene', (0, 3))	('nude mice', 'Species', '10090', (125, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('ovarian cancer', 'Disease', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('glioblastoma', 'Disease', (33, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('bladder cancer', 'Disease', 'MESH:D001749', (66, 80))	('bladder cancer', 'Disease', (66, 80))
220507	33801580	CrkL knockdown also inhibited in vivo tumor growth in head and neck squamous cell carcinoma, rhabdomyosarcoma, hepatocellular carcinoma, and colorectal cancer cells.	('knockdown', 'Var', (5, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (111, 135))	('inhibited', 'NegReg', (20, 29))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('hepatocellular carcinoma', 'Disease', (111, 135))	('neck squamous cell carcinoma', 'Disease', (63, 91))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (63, 91))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('colorectal cancer', 'Disease', (141, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('tumor', 'Disease', (38, 43))	('rhabdomyosarcoma', 'Disease', (93, 109))	('CrkL', 'Gene', (0, 4))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (111, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (93, 109))
220508	33801580	In addition to suppressing tumor growth at the primary injection sites in nude mice, Crk or CrkL knockdown reduced metastatic tumor burden.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CrkL', 'Gene', (92, 96))	('knockdown', 'Var', (97, 106))	('suppressing', 'NegReg', (15, 26))	('tumor', 'Disease', (27, 32))	('reduced', 'NegReg', (107, 114))	('nude mice', 'Species', '10090', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Crk', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', (126, 131))
220509	33801580	Bone metastasis in vivo following intra-cardiac injection of basal breast cancer cells was reduced by Crk knockdown.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('Bone metastasis', 'CPA', (0, 15))	('knockdown', 'Var', (106, 115))	('reduced', 'NegReg', (91, 98))	('Crk', 'Gene', (102, 105))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
220510	33801580	Crk knockdown reduced metastatic tumor burden in blood, liver, and lung together with reductions in tumor volume at the primary site and the number of circulating tumor cells following orthotopic injection of bladder cancer cells under the bladder muscle layer.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('reduced', 'NegReg', (14, 21))	('bladder cancer', 'Phenotype', 'HP:0009725', (209, 223))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (209, 223))	('bladder cancer', 'Disease', (209, 223))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (33, 38))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('reductions', 'NegReg', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('Crk', 'Gene', (0, 3))
220516	33801580	Antoku and Mayer reported that PDGF-induced motility of NIH3T3 cells was decreased with Crk knockdown or CrkL knockdown and completely blocked with Crk/CrkL double knockdown.	('knockdown', 'Var', (110, 119))	('CrkL', 'Protein', (105, 109))	('blocked', 'NegReg', (135, 142))	('decreased', 'NegReg', (73, 82))	('knockdown', 'Var', (92, 101))	('NIH3T3', 'CellLine', 'CVCL:0594', (56, 62))	('Crk', 'Protein', (88, 91))
220517	33801580	Ablation of both Crk and CrkL in mouse embryonic fibroblasts resulted in a decrease in cell motility.	('decrease', 'NegReg', (75, 83))	('Ablation', 'Var', (0, 8))	('CrkL', 'Protein', (25, 29))	('cell motility', 'CPA', (87, 100))	('mouse', 'Species', '10090', (33, 38))	('Crk', 'Protein', (17, 20))
220520	33801580	In contrast, Crk knockdown enhanced endothelial cell migration under intermittent hypoxia.	('rat', 'Species', '10116', (56, 59))	('enhanced', 'PosReg', (27, 35))	('hypoxia', 'Disease', (82, 89))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('Crk', 'Gene', (13, 16))	('knockdown', 'Var', (17, 26))	('endothelial cell migration', 'CPA', (36, 62))
220522	33801580	Expression of CrkII with a mutated SH2 domain inhibited insulin-induced migration and invasion of COS-7 cells.	('invasion of COS-7 cells', 'CPA', (86, 109))	('mutated', 'Var', (27, 34))	('rat', 'Species', '10116', (75, 78))	('SH2 domain', 'Gene', (35, 45))	('inhibited', 'NegReg', (46, 55))	('COS-7', 'CellLine', 'CVCL:0224', (98, 103))
220525	33801580	reported that Crk knockdown led to inhibition of cell migration and invasion in breast cancer, cervical carcinoma, and non-small cell lung carcinoma.	('non-small cell lung carcinoma', 'Disease', (119, 148))	('knockdown', 'Var', (18, 27))	('cervical carcinoma', 'Disease', (95, 113))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (123, 148))	('Crk', 'Gene', (14, 17))	('cell migration', 'CPA', (49, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('invasion', 'CPA', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cervical carcinoma', 'Disease', 'MESH:D002583', (95, 113))	('rat', 'Species', '10116', (57, 60))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (119, 148))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (119, 148))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('inhibition', 'NegReg', (35, 45))
220526	33801580	Furthermore, Crk knockdown inhibited hepatocyte growth factor (HGF)-induced migration of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('hepatocyte growth factor', 'Gene', '3082', (37, 61))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('HGF', 'Gene', (63, 66))	('rat', 'Species', '10116', (79, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('HGF', 'Gene', '3082', (63, 66))	('inhibited', 'NegReg', (27, 36))	('knockdown', 'Var', (17, 26))	('Crk', 'Gene', (13, 16))	('hepatocyte growth factor', 'Gene', (37, 61))
220527	33801580	Since then, Crk knockdown has been demonstrated to result in decreases in cancer cell migration and invasion in ovarian cancer, synovial cell carcinoma, glioblastoma, oral squamous cell carcinoma, prostate cancer, breast cancer, gastric cancer, bladder cancer, and pancreatic ductal adenocarcinoma cells.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('pancreatic ductal adenocarcinoma', 'Disease', (265, 297))	('decreases', 'NegReg', (61, 70))	('breast cancer', 'Disease', (214, 227))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 195))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (245, 259))	('bladder cancer', 'Disease', (245, 259))	('gastric cancer', 'Disease', (229, 243))	('oral squamous cell carcinoma', 'Disease', (167, 195))	('bladder cancer', 'Phenotype', 'HP:0009725', (245, 259))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', (237, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (265, 297))	('synovial cell carcinoma', 'Disease', 'MESH:C538614', (128, 151))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (229, 243))	('cancer', 'Disease', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('prostate cancer', 'Disease', 'MESH:D011471', (197, 212))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('synovial cell carcinoma', 'Disease', (128, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (197, 212))	('glioblastoma', 'Disease', (153, 165))	('prostate cancer', 'Disease', (197, 212))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('Crk', 'Gene', (12, 15))	('invasion in ovarian cancer', 'Disease', (100, 126))	('knockdown', 'Var', (16, 25))	('rat', 'Species', '10116', (89, 92))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('invasion in ovarian cancer', 'Disease', 'MESH:D009362', (100, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (229, 243))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (265, 297))	('synovial cell carcinoma', 'Phenotype', 'HP:0012570', (128, 151))	('rat', 'Species', '10116', (42, 45))
220528	33801580	CrkL knockdown also inhibited cell motility in head and neck squamous cell carcinoma and migration and invasion of cervical cancer cells.	('cervical cancer', 'Disease', 'MESH:D002583', (115, 130))	('cervical cancer', 'Disease', (115, 130))	('knockdown', 'Var', (5, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rat', 'Species', '10116', (92, 95))	('neck squamous cell carcinoma', 'Disease', (56, 84))	('CrkL', 'Protein', (0, 4))	('inhibited', 'NegReg', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (56, 84))	('cell motility in', 'CPA', (30, 46))
220529	33801580	Furthermore, CrkL knockdown led to inhibition of TGF-beta1-induced cell motility in glioma and ovarian cancer cells.	('knockdown', 'Var', (18, 27))	('glioma and ovarian cancer', 'Disease', 'MESH:D005910', (84, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TGF-beta1', 'Gene', '7040', (49, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))	('CrkL', 'Protein', (13, 17))	('TGF-beta1', 'Gene', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('inhibition', 'NegReg', (35, 45))	('cell motility', 'CPA', (67, 80))
220530	33801580	CrkL knockdown also resulted in a decrease in CCL20-induced migration and invasion of gastric cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('CCL20', 'Gene', '6364', (46, 51))	('invasion', 'CPA', (74, 82))	('knockdown', 'Var', (5, 14))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('decrease', 'NegReg', (34, 42))	('CrkL', 'Protein', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))	('migration', 'CPA', (60, 69))	('rat', 'Species', '10116', (63, 66))	('CCL20', 'Gene', (46, 51))
220531	33801580	However, it was not clear whether the other protein between Crk and CrkL play similar roles because all the studies investigated effects by either Crk knockdown or CrkL knockdown in the given cancer cell type.	('knockdown', 'Var', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('CrkL', 'Gene', (164, 168))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('investigated effects', 'Reg', (116, 136))	('Crk', 'Gene', (147, 150))	('knockdown', 'Var', (151, 160))
220532	33801580	demonstrated that loss of Crk or CrkL alone using CRISPR/Cas9 substantially inhibited migration and invasion of colorectal cancer cells, while loss of both Crk and CrkL completely blocked cell migration and invasion.	('cell migration', 'CPA', (188, 202))	('blocked', 'NegReg', (180, 187))	('colorectal cancer', 'Disease', (112, 129))	('CrkL', 'Protein', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('loss', 'Var', (18, 22))	('Crk', 'Protein', (26, 29))	('rat', 'Species', '10116', (89, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('rat', 'Species', '10116', (7, 10))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('rat', 'Species', '10116', (196, 199))	('inhibited', 'NegReg', (76, 85))	('invasion', 'CPA', (207, 215))
220533	33801580	Crk/CrkL double knockout also inhibited pancreatic cancer cell migration and invasion.	('Crk/CrkL', 'Protein', (0, 8))	('double knockout', 'Var', (9, 24))	('inhibited', 'NegReg', (30, 39))	('invasion', 'CPA', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('pancreatic cancer', 'Disease', (40, 57))	('rat', 'Species', '10116', (66, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))
220534	33801580	To investigate distinct and overlapping functions of Crk and CrkL, individual and combined knockdown of Crk and CrkL were induced in U-118MG glioblastoma cells, and cell migration and invasion were analyzed in real-time.	('CrkL', 'Gene', (112, 116))	('rat', 'Species', '10116', (173, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('Crk', 'Gene', (104, 107))	('U-118MG', 'CellLine', 'CVCL:0633', (133, 140))	('knockdown', 'Var', (91, 100))	('glioblastoma', 'Disease', (141, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))
220535	33801580	While CrkL knockdown reduced glioblastoma cell migration, Crk knockdown delayed the cell migration.	('reduced', 'NegReg', (21, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('rat', 'Species', '10116', (50, 53))	('delayed', 'NegReg', (72, 79))	('rat', 'Species', '10116', (92, 95))	('cell migration', 'CPA', (84, 98))	('CrkL', 'Protein', (6, 10))	('knockdown', 'Var', (11, 20))	('glioblastoma', 'Disease', (29, 41))
220536	33801580	When knockdown of both Crk and CrkL was induced, cell migration was completely blocked, suggesting the unique and overlapping functions of Crk and CrkL in glioblastoma cells.	('cell migration', 'CPA', (49, 63))	('knockdown', 'Var', (5, 14))	('glioblastoma', 'Disease', (155, 167))	('rat', 'Species', '10116', (57, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('blocked', 'NegReg', (79, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))
220537	33801580	On the other hand, CrkL knockdown, but not Crk knockdown, inhibited glioblastoma cell invasion, and Crk/CrkL double knockdown completely blocked cell invasion.	('glioblastoma', 'Disease', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('cell invasion', 'CPA', (145, 158))	('blocked', 'NegReg', (137, 144))	('inhibited', 'NegReg', (58, 67))	('knockdown', 'Var', (24, 33))
220538	33801580	These findings indicate that individual and combined ablation of Crk and CrkL are required to address their unique and overlapping functions in tumor cells.	('tumor', 'Disease', (144, 149))	('ablation', 'Var', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CrkL', 'Protein', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Crk', 'Protein', (65, 68))
220549	33801580	Abl-induced phosphorylation of CrkII on Tyr221 and subsequent intramolecular binding of the SH2 domain to the phosphorylated Tyr221 are known to disrupt the association of CrkII to its SH2 target proteins.	('Tyr221', 'Chemical', '-', (40, 46))	('disrupt', 'NegReg', (145, 152))	('phosphorylation', 'Var', (12, 27))	('association', 'Interaction', (157, 168))	('Tyr221', 'Chemical', '-', (125, 131))	('binding', 'Interaction', (77, 84))
220552	33801580	Whereas overexpression with CrkII-Y239F, like wild-type CrkII, increased migration of Crk-null fibroblasts and Hs683 glioblastoma cells, CrkII-Y239F, unlike wild-type CrkII, failed to increase migration of 4T1 breast cancer cells.	('CrkII-Y239F', 'Var', (137, 148))	('migration', 'CPA', (73, 82))	('increased', 'PosReg', (63, 72))	('rat', 'Species', '10116', (76, 79))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('4T1', 'CellLine', 'CVCL:0125', (206, 209))	('Y239F', 'Mutation', 'p.Y239F', (34, 39))	('Y239F', 'Mutation', 'p.Y239F', (143, 148))	('breast cancer', 'Disease', (210, 223))	('glioblastoma', 'Disease', (117, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('glioblastoma', 'Disease', 'MESH:D005909', (117, 129))	('rat', 'Species', '10116', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
220553	33801580	Phosphorylation of CrkII on Tyr251 that is located on the C-terminal SH3 domain promoted motility of Crk-null mouse fibroblasts towards epidermal growth factor (EGF).	('motility', 'CPA', (89, 97))	('epidermal growth factor', 'Gene', '13645', (136, 159))	('promoted', 'PosReg', (80, 88))	('Tyr251', 'Var', (28, 34))	('EGF', 'Gene', (161, 164))	('Tyr251', 'Chemical', '-', (28, 34))	('mouse', 'Species', '10090', (110, 115))	('epidermal growth factor', 'Gene', (136, 159))	('EGF', 'Gene', '13645', (161, 164))
220554	33801580	On the other hand, CrkII-Ser41Gly expression decreased motility of NSCLC cells while wild-type CrkII expression increased the cell motility, suggesting that phosphorylation of CrkII on serine 41 by PAK1 promotes cell motility and invasion.	('PAK1', 'Gene', '5058', (198, 202))	('PAK1', 'Gene', (198, 202))	('cell motility', 'CPA', (212, 225))	('cell motility', 'CPA', (126, 139))	('Ser41Gly', 'SUBSTITUTION', 'None', (25, 33))	('decreased', 'NegReg', (45, 54))	('promotes', 'PosReg', (203, 211))	('serine', 'Chemical', 'MESH:D012694', (185, 191))	('Ser41Gly', 'Var', (25, 33))	('increased', 'PosReg', (112, 121))	('invasion', 'CPA', (230, 238))	('phosphorylation', 'Var', (157, 172))	('NSCLC', 'Disease', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
220557	33801580	In most of these studies, loss of either Crk or CrkL resulted in decreases in tumor cell migration and invasion, suggesting that tumor cell migration and invasion are highly demanding cellular processes that require both Crk and CrkL to reorganize the cellular cytoskeletal network.	('CrkL', 'Protein', (48, 52))	('decreases', 'NegReg', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('rat', 'Species', '10116', (92, 95))	('invasion', 'CPA', (154, 162))	('rat', 'Species', '10116', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Crk', 'Protein', (41, 44))	('loss', 'Var', (26, 30))	('tumor', 'Disease', (129, 134))	('invasion', 'CPA', (103, 111))
220559	33801580	Furthermore, recent studies indicate that cell migration and invasion depend on Crk and CrkL in a dose-dependent manner since the loss of both Crk and CrkL led to more severe defects than the loss of one protein.	('cell migration', 'CPA', (42, 56))	('rat', 'Species', '10116', (50, 53))	('invasion', 'CPA', (61, 69))	('CrkL', 'Protein', (151, 155))	('Crk', 'Protein', (143, 146))	('loss', 'Var', (130, 134))
220568	33801580	CrkL knockdown also suppressed CCL19/CCR7-induced EMT marker expression and extracellular signal-regulated kinase (ERK) phosphorylation in epithelial ovarian carcinoma cells by decreasing expression of N-cadherin, Snail, and MMP9 and increasing E-cadherin expression.	('knockdown', 'Var', (5, 14))	('EMT marker', 'Gene', (50, 60))	('ERK', 'Gene', (115, 118))	('E-cadherin expression', 'MPA', (245, 266))	('extracellular signal-regulated kinase', 'Gene', (76, 113))	('CCL19', 'Gene', '6363', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('CCR7', 'Gene', (37, 41))	('decreasing', 'NegReg', (177, 187))	('extracellular signal-regulated kinase', 'Gene', '5594', (76, 113))	('suppressed', 'NegReg', (20, 30))	('Snail', 'Protein', (214, 219))	('epithelial ovarian carcinoma', 'Disease', (139, 167))	('increasing', 'PosReg', (234, 244))	('MMP9', 'Gene', '4318', (225, 229))	('MMP9', 'Gene', (225, 229))	('CCL19', 'Gene', (31, 36))	('CCR7', 'Gene', '1236', (37, 41))	('expression', 'MPA', (188, 198))	('CrkL', 'Gene', (0, 4))	('N-cadherin', 'Protein', (202, 212))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (150, 167))	('epithelial ovarian carcinoma', 'Disease', 'MESH:D010051', (139, 167))	('ERK', 'Gene', '5594', (115, 118))
220569	33801580	CrkL knockdown inhibited CCL20/CCR6-induced EMT marker expression and ERK phosphorylation in gastric cancer cells by decreasing expression of N-cadherin, vimentin, and MMP2.	('CCL20', 'Gene', '6364', (25, 30))	('ERK', 'Gene', (70, 73))	('knockdown', 'Var', (5, 14))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('vimentin', 'Gene', '7431', (154, 162))	('CCL20', 'Gene', (25, 30))	('vimentin', 'Gene', (154, 162))	('CCR6', 'Gene', (31, 35))	('expression', 'MPA', (128, 138))	('gastric cancer', 'Disease', (93, 107))	('N-cadherin', 'Protein', (142, 152))	('MMP2', 'Gene', (168, 172))	('EMT', 'MPA', (44, 47))	('ERK', 'Gene', '5594', (70, 73))	('CCR6', 'Gene', '1235', (31, 35))	('inhibited', 'NegReg', (15, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('CrkL', 'Gene', (0, 4))	('decreasing', 'NegReg', (117, 127))	('MMP2', 'Gene', '4313', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
220570	33801580	While CrkL knockout blocked SASH1 deficiency-induced EMT in HCT116 colon cancer cells, Crk/CrkL double knockout inhibited Src activation-induced EMT.	('inhibited', 'NegReg', (112, 121))	('SASH1', 'Gene', '23328', (28, 33))	('HCT116', 'CellLine', 'CVCL:0291', (60, 66))	('colon cancer', 'Disease', 'MESH:D015179', (67, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (67, 79))	('Src', 'Gene', (122, 125))	('Src', 'Gene', '6714', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('deficiency-induced', 'Var', (34, 52))	('EMT', 'CPA', (53, 56))	('colon cancer', 'Disease', (67, 79))	('SASH1', 'Gene', (28, 33))
220571	33801580	Increased E-cadherin expression and decreased ZEB1 expression were observed by knockout of Crk, CrkL, or both in colon cancer cells and by Crk/CrkL double in pancreatic cancer cells.	('E-cadherin', 'Protein', (10, 20))	('pancreatic cancer', 'Disease', (158, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('ZEB1', 'Gene', (46, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (158, 175))	('ZEB1', 'Gene', '6935', (46, 50))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('expression', 'MPA', (21, 31))	('colon cancer', 'Disease', (113, 125))	('Crk', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Increased', 'PosReg', (0, 9))	('expression', 'MPA', (51, 61))	('CrkL', 'Protein', (96, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (158, 175))	('knockout', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('decreased', 'NegReg', (36, 45))
220574	33801580	demonstrated that suppression of EMT in pancreatic ductal adenocarcinoma mouse models by genetic ablation of EMT-inducing transcription factors such as Snail or Twist enhanced expression of nucleoside transporters in tumors, leading to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice.	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('suppression', 'NegReg', (18, 29))	('mouse', 'Species', '10090', (73, 78))	('rat', 'Species', '10116', (7, 10))	('mice', 'Species', '10090', (316, 320))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('expression of nucleoside transporters', 'MPA', (176, 213))	('enhanced', 'PosReg', (167, 175))	('Twist', 'Gene', (161, 166))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (40, 72))	('ablation', 'Var', (97, 105))	('Twist', 'Gene', '22160', (161, 166))	('pancreatic ductal adenocarcinoma', 'Disease', (40, 72))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('enhanced', 'PosReg', (236, 244))	('gemcitabine', 'Chemical', 'MESH:C056507', (260, 271))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (217, 223))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (40, 72))	('increased', 'PosReg', (286, 295))	('sensitivity to gemcitabine treatment', 'MPA', (245, 281))
220575	33801580	demonstrated that breast cancer cells with EMT contribute to recurrent lung metastasis after chemotherapy, and that inhibition of EMT by overexpressing miR-200 abrogated the chemoresistance to cyclophosphamide treatment, leading to reduced lung metastasis.	('chemoresistance to cyclophosphamide treatment', 'MPA', (174, 219))	('inhibition', 'Var', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('lung metastasis', 'CPA', (71, 86))	('abrogated', 'NegReg', (160, 169))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (193, 209))	('breast cancer', 'Disease', (18, 31))	('overexpressing', 'PosReg', (137, 151))	('miR-200', 'Gene', (152, 159))	('reduced', 'NegReg', (232, 239))	('rat', 'Species', '10116', (7, 10))	('miR-200', 'Chemical', '-', (152, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('lung metastasis', 'CPA', (240, 255))
220585	33801580	Analysis of the curated set of non-redundant studies in The Cancer Genome Atlas (TCGA) using the cBioPortal platform indicates that only 0.5% and 1% of cancer patients showed copy number increases for CRK and CRKL, respectively.	('rat', 'Species', '10116', (18, 21))	('CRKL', 'Protein', (209, 213))	('cancer', 'Disease', (152, 158))	('CRK', 'Protein', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('copy number', 'Var', (175, 186))	('increases', 'PosReg', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (159, 167))
220589	33801580	Nevertheless, lower survival was observed for the patients with amplification of CRK or CRKL transcripts (46.78 and 53.92 months for the median months overall, respectively, compared to 118.30 months with the unaltered group) (Figure 3 and Table 2).	('patients', 'Species', '9606', (50, 58))	('CRKL', 'Gene', (88, 92))	('lower', 'NegReg', (14, 19))	('amplification', 'Var', (64, 77))	('survival', 'MPA', (20, 28))	('CRK', 'Gene', (81, 84))
220595	33801580	A similar analysis using cBioPortal of a smaller subset for lung, breast, and gastric cancer patients combined did not exhibit any apparent difference in overall survival among the patients with amplification of CRK and CRKL transcripts (data not shown).	('breast', 'Disease', (66, 72))	('CRKL', 'Protein', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('gastric cancer', 'Disease', (78, 92))	('patients', 'Species', '9606', (181, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))	('amplification', 'Var', (195, 208))	('patients', 'Species', '9606', (93, 101))	('CRK', 'Protein', (212, 215))
220596	33801580	Therefore, accumulation of more datasets, together with correlation studies between copy number alterations and protein level changes in cancer tissue, would provide a more concrete explanation of whether copy number alterations of CRK and CRKL contribute to overall patient survival in individual cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('patient', 'Species', '9606', (267, 274))	('rat', 'Species', '10116', (221, 224))	('CRKL', 'Protein', (240, 244))	('CRK', 'Protein', (232, 235))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (298, 304))	('cancer', 'Disease', (137, 143))	('copy number alterations', 'Var', (205, 228))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('rat', 'Species', '10116', (100, 103))	('contribute', 'Reg', (245, 255))
220604	33801580	FGFR2 was highly expressed in many pancreatic ductal adenocarcinoma (PDAC) tissues, and knockdown of FGFR2 IIIb and IIIc in PDAC cells inhibited cell proliferation, migration, invasion, and in vivo tumor formation.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (35, 67))	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('knockdown', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('rat', 'Species', '10116', (168, 171))	('cell proliferation', 'CPA', (145, 163))	('rat', 'Species', '10116', (157, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('tumor', 'Disease', (198, 203))	('FGFR2', 'Gene', (0, 5))	('pancreatic ductal adenocarcinoma', 'Disease', (35, 67))	('inhibited', 'NegReg', (135, 144))	('FGFR2', 'Gene', '2263', (0, 5))	('invasion', 'CPA', (176, 184))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (35, 67))
220605	33801580	FGF8 was elevated in colorectal cancer tissues, and high FGF8 expression in colorectal cancer cells led to EMT marker expression, enhanced proliferation and invasion, and in vivo tumor growth and metastasis in a YAP1-dependent manner.	('enhanced', 'PosReg', (130, 138))	('EMT marker', 'CPA', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('YAP1', 'Gene', '10413', (212, 216))	('colorectal cancer', 'Phenotype', 'HP:0003003', (21, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('YAP1', 'Gene', (212, 216))	('expression', 'MPA', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('proliferation', 'CPA', (139, 152))	('high', 'Var', (52, 56))	('FGF8', 'Gene', '2253', (57, 61))	('FGF8', 'Gene', (57, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (21, 38))	('FGF8', 'Gene', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('FGF8', 'Gene', '2253', (0, 4))	('rat', 'Species', '10116', (146, 149))	('invasion', 'CPA', (157, 165))	('colorectal cancer', 'Disease', (21, 38))	('colorectal cancer', 'Disease', (76, 93))	('tumor', 'Disease', (179, 184))
220607	33801580	FGFR4 expression was elevated in nasopharyngeal carcinoma tissues, and FGFR4 knockdown reduced proliferation and migration of nasopharyngeal carcinoma cells.	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (126, 150))	('knockdown', 'Var', (77, 86))	('FGFR4', 'Gene', '2264', (0, 5))	('proliferation', 'CPA', (95, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('carcinoma', 'Disease', (48, 57))	('FGFR4', 'Gene', '2264', (71, 76))	('rat', 'Species', '10116', (102, 105))	('FGFR4', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('reduced', 'NegReg', (87, 94))	('carcinoma', 'Disease', (141, 150))	('carcinoma', 'Disease', 'MESH:D009369', (48, 57))	('rat', 'Species', '10116', (116, 119))	('FGFR4', 'Gene', (71, 76))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (33, 57))	('expression', 'MPA', (6, 16))	('elevated', 'PosReg', (21, 29))	('carcinoma', 'Disease', 'MESH:D009369', (141, 150))
220617	33801580	Overall, knockdown or knockout of Crk or CrkL suppressed tumor cell growth in vitro and in vivo, whereas overexpression of Crk or CrkL promoted tumor cell growth.	('Crk', 'Gene', (34, 37))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CrkL', 'Gene', (41, 45))	('knockout', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (57, 62))	('suppressed', 'NegReg', (46, 56))
220618	33801580	Cancer cell migration and invasion were also inhibited by Crk or CrkL knockdown and promoted by Crk or CrkL overexpression.	('promoted', 'PosReg', (84, 92))	('knockdown', 'Var', (70, 79))	('rat', 'Species', '10116', (15, 18))	('invasion', 'CPA', (26, 34))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Crk', 'Protein', (58, 61))	('inhibited', 'NegReg', (45, 54))	('CrkL', 'Protein', (65, 69))
220629	33801580	No inhibitory effect on cell migration and less pronounced inhibitory effects on cell invasion by transient, individual knockdown of Crk and CrkL indirectly suggest potentially overlapping functions of Crk and CrkL.	('cell migration', 'CPA', (24, 38))	('rat', 'Species', '10116', (32, 35))	('knockdown', 'Var', (120, 129))	('CrkL', 'Gene', (141, 145))	('Crk', 'Gene', (133, 136))	('cell invasion', 'CPA', (81, 94))
220630	33801580	induced individual and combined knockout of Crk and CrkL in colorectal cancer cells.	('CrkL', 'Protein', (52, 56))	('knockout', 'Var', (32, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('Crk', 'Gene', (44, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('combined', 'Interaction', (23, 31))	('colorectal cancer', 'Disease', (60, 77))
220633	33801580	induced individual and combined knockdown of Crk and CrkL in a glioblastoma cell line and demonstrated a predominant role of CrkL and overlapping roles of Crk and CrkL in glioblastoma cell migration.	('rat', 'Species', '10116', (97, 100))	('glioblastoma', 'Disease', (171, 183))	('glioblastoma', 'Disease', (63, 75))	('knockdown', 'Var', (32, 41))	('glioblastoma', 'Disease', 'MESH:D005909', (171, 183))	('rat', 'Species', '10116', (192, 195))	('glioblastoma', 'Phenotype', 'HP:0012174', (171, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('Crk', 'Protein', (45, 48))	('CrkL', 'Protein', (125, 129))
220639	33801580	The peptides inhibited the binding of Crk to DOCK180, to SoS, and to C3G in vitro.	('SoS', 'Gene', '64132', (57, 60))	('SoS', 'Gene', (57, 60))	('binding', 'Interaction', (27, 34))	('inhibited', 'NegReg', (13, 22))	('peptides', 'Var', (4, 12))	('DOCK180', 'Gene', (45, 52))	('DOCK180', 'Gene', '1793', (45, 52))	('Crk', 'Protein', (38, 41))
220698	30626819	However, a common characteristic gene translocation that results in the expression of a fusion gene product has been identified, and the above tumors are now all considered subtypes of the same disease.	('translocation', 'Var', (38, 51))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('fusion gene product', 'MPA', (88, 107))	('tumors', 'Disease', (143, 149))	('results in', 'Reg', (57, 67))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('expression', 'MPA', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
220706	30626819	Thus, a significant 3-month advantage with regard to the PFS was observed in the pazopanib arm.	('advantage', 'PosReg', (28, 37))	('pazopanib', 'Var', (81, 90))	('pazopanib', 'Chemical', 'MESH:C516667', (81, 90))
220850	25379845	A primary tumor was resected in 133 patients [69 (90.8%) EIA + RHT vs. 64 (87.7%) EIA, P = 0.54].	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Disease', (10, 15))	('EIA + RHT', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
220869	25379845	Patients treated with RHT and EIA had increased LPFS and DFS compared to patients treated with EIA alone.	('EIA', 'Var', (30, 33))	('LPFS', 'CPA', (48, 52))	('RHT', 'Var', (22, 25))	('Patients', 'Species', '9606', (0, 8))	('DFS', 'CPA', (57, 60))	('patients', 'Species', '9606', (73, 81))	('increased', 'PosReg', (38, 47))
220877	25379845	The tumor response rate after 4 cycles of systemic therapy with EIA + RHT was more than twice as high (34.7% vs 15.6%, P = 0.0034) when compared to chemotherapy alone.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('EIA + RHT', 'Var', (64, 73))
220881	25379845	In the EIA + RHT group, liposarcoma as a histological subtype was slightly more frequent and there were a few more primary tumors (vs recurrent tumors) and wide excisions (vs local tumor resections), although none of these differences was statistically significant.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('liposarcoma', 'Phenotype', 'HP:0012034', (24, 35))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('EIA', 'Var', (7, 10))	('primary tumors', 'Disease', (115, 129))	('liposarcoma', 'Disease', (24, 35))	('local tumor', 'Disease', (175, 186))	('primary tumors', 'Disease', 'MESH:D009369', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('local tumor', 'Disease', 'MESH:D009364', (175, 186))	('liposarcoma', 'Disease', 'MESH:D008080', (24, 35))
220897	25379845	We propose the use of EIA and RHT for patients with G2/G3 retroperitoneal sarcomas as part of a differentiated approach tailored to the risk of an individual patient.	('patient', 'Species', '9606', (158, 165))	('G2/G3', 'Var', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('patient', 'Species', '9606', (38, 45))	('retroperitoneal sarcomas', 'Disease', (58, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('patients', 'Species', '9606', (38, 46))	('retroperitoneal sarcomas', 'Disease', 'MESH:D012186', (58, 82))	('retroperitoneal sarcomas', 'Phenotype', 'HP:0006729', (58, 82))
220938	33937098	Particularly relevant for the present study are the early demonstrations that TIME cells are highly susceptible to infection by cell-free KSHV virions; the infected cells can be induced to transition from latent to lytic phase and production of infectious virus by treatment with phorbol ester or by ectopic expression of the KSHV replication and transcriptional activator (K-RTA), the lytic switch protein product of the viral ORF50 gene.	('infected', 'Disease', (156, 164))	('ORF50', 'Gene', '4961526', (428, 433))	('K-RTA', 'Gene', (374, 379))	('KSHV', 'Species', '37296', (138, 142))	('phorbol ester', 'Chemical', 'MESH:D010703', (280, 293))	('ORF50', 'Gene', (428, 433))	('infected', 'Disease', 'MESH:D007239', (156, 164))	('infection', 'Disease', (115, 124))	('infection', 'Disease', 'MESH:D007239', (115, 124))	('KSHV', 'Species', '37296', (326, 330))	('ectopic expression', 'Var', (300, 318))
220995	33937098	Immunofluorescence microscopy and flow cytometry revealed that KSHV glycoproteins K8.1 ( Figure 2D  upper panels) and gH ( Figure 2D  lower panels) were minimally detectable in uninduced iTIME.219 cells; upon induction with Dox + SB, the expression of both glycoproteins appeared to increase in the majority of cells, as evidenced by the shifted populations.	('KSHV', 'Species', '37296', (63, 67))	('SB', 'Chemical', 'MESH:D020148', (230, 232))	('Dox', 'Chemical', 'MESH:D004318', (224, 227))	('iTIME', 'Chemical', '-', (187, 192))	('K8.1', 'Gene', (82, 86))	('increase', 'PosReg', (283, 291))	('Dox + SB', 'Var', (224, 232))	('expression', 'MPA', (238, 248))	('K8.1', 'Gene', '3887', (82, 86))
221022	33937098	There is precedent for such relationships among both animal and human gammaherpesviruses, whereby cell type-specific variations in viral glycoprotein expression result in complex effects on tropism.	('human', 'Species', '9606', (64, 69))	('effects', 'Reg', (179, 186))	('tropism', 'MPA', (190, 197))	('variations', 'Var', (117, 127))	('glycoprotein', 'Protein', (137, 149))
221024	33937098	For the human pathogen Epstein-Barr virus, epithelial cells produce virus expressing glycoprotein complexes containing gp42, whose binding to cell surface HLA II is essential for virus fusion/entry into B lymphocytes.	('binding', 'Interaction', (131, 138))	('Epstein-Barr virus', 'Species', '10376', (23, 41))	('HLA II', 'Chemical', '-', (155, 161))	('human', 'Species', '9606', (8, 13))	('gp42', 'Var', (119, 123))
221028	33937098	This finding complemented extensive evidence in the literature demonstrating the tropism involvement of proteins encoded by positionally homologous genes in cell tropism of other gammaherpesviruses, as described above for gp180 of bovineherpesvirus-4, as well as for gp350/320 of Epstein-Barr virus.	('Epstein-Barr virus', 'Species', '10376', (280, 298))	('gp350/320', 'Var', (267, 276))	('gp180', 'Gene', '5788', (222, 227))	('gp180', 'Gene', (222, 227))
221032	32806571	MiR-155-5p and MiR-203a-3p Are Prognostic Factors in Soft Tissue Sarcoma Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with a five-year survival rate of approximately 50%.	('Sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('MiR-203a-3p', 'Var', (15, 26))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('MiR-155', 'Gene', '406947', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('Sarcoma', 'Disease', (65, 72))	('Soft Tissue Sarcoma', 'Phenotype', 'HP:0030448', (53, 72))	('Soft tissue sarcoma', 'Phenotype', 'HP:0030448', (73, 92))	('MiR-155', 'Gene', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('sarcoma', 'Disease', (85, 92))	('malignancies', 'Disease', (132, 144))	('STS', 'Phenotype', 'HP:0030448', (94, 97))
221042	32806571	Furthermore, there is a multitude of studies showing a considerable impact of the dysregulation of certain microRNAs in all major malignancies on the prognosis of patients.	('patients', 'Species', '9606', (163, 171))	('dysregulation', 'Var', (82, 95))	('malignancies', 'Disease', (130, 142))	('impact', 'Reg', (68, 74))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))
221054	32806571	MiR-203 was identified to be downregulated both in rhabdomyosarcoma (RMS) cell lines and in rhabdomyosarcoma patient samples due to promoter hypermethylation.	('promoter hypermethylation', 'Var', (132, 157))	('patient', 'Species', '9606', (109, 116))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (51, 67))	('rhabdomyosarcoma', 'Disease', (92, 108))	('RMS', 'Phenotype', 'HP:0002859', (69, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (92, 108))	('MiR-203', 'Gene', '406986', (0, 7))	('MiR-203', 'Gene', (0, 7))	('rhabdomyosarcoma', 'Disease', (51, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (51, 67))	('downregulated', 'NegReg', (29, 42))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (92, 108))
221098	32806571	Additionally, we found a correlation between miR-155 expression and p53 mutation status.	('miR-155', 'Gene', '406947', (45, 52))	('mutation status', 'Var', (72, 87))	('correlation', 'Interaction', (25, 36))	('miR-155', 'Gene', (45, 52))	('p53', 'Gene', (68, 71))	('expression', 'MPA', (53, 63))	('p53', 'Gene', '7157', (68, 71))
221100	32806571	However, an upregulation of miR-155 through mutant p53 or mutant BRCA1 has been reported (reviewed in).	('mutant', 'Var', (58, 64))	('p53', 'Gene', (51, 54))	('BRCA1', 'Gene', '672', (65, 70))	('p53', 'Gene', '7157', (51, 54))	('miR-155', 'Gene', '406947', (28, 35))	('upregulation', 'PosReg', (12, 24))	('BRCA1', 'Gene', (65, 70))	('miR-155', 'Gene', (28, 35))	('mutant', 'Var', (44, 50))
221104	32806571	However, oncogenic p53 mutants exhibit a significant loss or total ablation of this repressing activity.	('p53', 'Gene', (19, 22))	('loss', 'NegReg', (53, 57))	('p53', 'Gene', '7157', (19, 22))	('ablation', 'NegReg', (67, 75))	('mutants', 'Var', (23, 30))	('repressing activity', 'MPA', (84, 103))
221128	32806571	Siu et al suggested that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and tyrosine kinase inhibitor (TKI) resistance characterized by high EGFR ligand output and antiapoptotic protein activation.	('prostate cancer', 'Disease', (87, 102))	('activation', 'PosReg', (228, 238))	('EGFR', 'Gene', '1956', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EGFR', 'Gene', (183, 187))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('miR-203', 'Gene', (37, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('loss', 'Var', (29, 33))	('miR-203', 'Gene', '406986', (37, 44))	('tyrosine kinase inhibitor', 'MPA', (118, 143))
221135	32806571	MiR-155 inhibition by MRG106/cobomarsen was recently tested in a clinical phase 1 study in different leukemia and lymphoma patients (NCT02580552) and in two clinical phase 2 studies in cutaneous T-cell lymphoma/mycosis fungoides patients (NCT03837457, NCT03713320).	('cobomarsen', 'Chemical', '-', (29, 39))	('patients', 'Species', '9606', (229, 237))	('inhibition', 'NegReg', (8, 18))	('MRG106', 'Chemical', '-', (22, 28))	('lymphoma', 'Disease', (202, 210))	('lymphoma', 'Disease', 'MESH:D008223', (202, 210))	('patients', 'Species', '9606', (123, 131))	('MiR-155', 'Gene', '406947', (0, 7))	('cutaneous T-cell lymphoma/mycosis', 'Disease', 'MESH:D016410', (185, 218))	('lymphoma', 'Disease', (114, 122))	('lymphoma', 'Disease', 'MESH:D008223', (114, 122))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('MRG106/cobomarsen', 'Var', (22, 39))	('cutaneous T-cell lymphoma/mycosis', 'Disease', (185, 218))	('leukemia', 'Disease', (101, 109))	('leukemia', 'Disease', 'MESH:D007938', (101, 109))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (195, 210))	('lymphoma', 'Phenotype', 'HP:0002665', (202, 210))	('MiR-155', 'Gene', (0, 7))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (185, 210))
221136	32806571	Our results suggest that inhibition of miR-155 could also have potential as a future treatment option for STS patients.	('miR-155', 'Gene', (39, 46))	('STS', 'Phenotype', 'HP:0030448', (106, 109))	('miR-155', 'Gene', '406947', (39, 46))	('inhibition', 'Var', (25, 35))	('patients', 'Species', '9606', (110, 118))
221157	32806571	; Formal analysis, T.G., H.-J.H., P.W., and H.T.	('P.W.', 'Var', (34, 38))	('H.T', 'Disease', 'MESH:D000848', (44, 47))	('H.T', 'Disease', (44, 47))
221278	32468287	Cancer predisposition syndromes comprise entities characterized by a risk of development of specific tumors or co-occurrence of tumors caused by a germ-line mutation in one or more cancer-related genes.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutation', 'Var', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (181, 187))	('tumors', 'Disease', (101, 107))
221279	32468287	At least 10% of children with cancer harbor a disease-associated pathogenic variant in a known cancer predisposition gene.	('pathogenic', 'Reg', (65, 75))	('variant', 'Var', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer harbor a disease', 'Disease', (30, 53))	('cancer', 'Disease', (95, 101))	('cancer harbor a disease', 'Disease', 'MESH:D009369', (30, 53))	('children', 'Species', '9606', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
221294	32468287	reported in 2016 that long-term compliance with a comprehensive surveillance protocol in individuals with pathogenic TP53 variants is associated with improved long-term survival.	('variants', 'Var', (122, 130))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('long-term survival', 'CPA', (159, 177))	('improved', 'PosReg', (150, 158))
221299	32468287	False-positive findings can be a potential risk in whole-body MRI surveillance of cancer predisposition syndromes.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('False-positive', 'Var', (0, 14))	('cancer', 'Disease', (82, 88))
221319	29893768	Prospective cohort Veterans Health Administration HIV+ (N = 42,441) and demographically-matched uninfected Veterans (N = 104,712) from 1999-2015 Standardized cancer incidence rates (IR) and Poisson regression rate ratios (RR, HIV-infected versus uninfected persons) by viral suppression status (unsuppressed: person-time with HIV RNA >= 500 copies/mL; early-suppressed: initial two years with HIV RNA <500 copies/mL; long-term-suppressed: person-time after early suppression with HIV RNA <500 copies/mL).	('HIV-infected versus uninfected persons', 'Disease', (226, 264))	('person', 'Species', '9606', (257, 263))	('person', 'Species', '9606', (309, 315))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('person', 'Species', '9606', (439, 445))	('HIV-infected versus uninfected persons', 'Disease', 'MESH:D015658', (226, 264))	('cancer', 'Disease', (158, 164))	('HIV', 'Var', (326, 329))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
221330	29893768	The benefits of ART include suppressed HIV viral load (as measured by plasma HIV-1 RNA [HIV RNA]), improved immune function (as measured by increasing CD4+ T-cell count [CD4 count]), and reduced inflammation.	('CD4', 'Gene', (151, 154))	('CD4', 'Gene', '920', (151, 154))	('improved', 'PosReg', (99, 107))	('increasing', 'PosReg', (140, 150))	('improved immune function', 'Phenotype', 'HP:0002721', (99, 123))	('HIV viral load', 'MPA', (39, 53))	('HIV-1', 'Species', '11676', (77, 82))	('suppressed', 'NegReg', (28, 38))	('reduced', 'NegReg', (187, 194))	('CD4', 'Gene', (170, 173))	('immune function', 'MPA', (108, 123))	('inflammation', 'Disease', 'MESH:D007249', (195, 207))	('inflammation', 'Disease', (195, 207))	('CD4', 'Gene', '920', (170, 173))	('ART', 'Var', (16, 19))
221334	29893768	We compared cancer risk among HIV+ persons, stratified by viral suppression status, to cancer risk among demographically-similar uninfected persons using the incidence rate ratio, a measure of relative risk.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('persons', 'Species', '9606', (140, 147))	('HIV+', 'Var', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('persons', 'Species', '9606', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
221397	29893768	In the Strategic Timing of Antiretroviral Treatment trial (52 cancers), among persons with CD4 count >500 cells/mL, immediate ART initiation (versus deferred initiation) was associated with significant decreased risk of all cancer, infection-related cancer (mostly ADC), and Kaposi sarcoma.	('decreased', 'NegReg', (202, 211))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (275, 289))	('Kaposi sarcoma', 'Disease', (275, 289))	('CD4', 'Gene', '920', (91, 94))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('CD4', 'Gene', (91, 94))	('cancers', 'Disease', (62, 69))	('ADC', 'Disease', 'MESH:D009369', (265, 268))	('persons', 'Species', '9606', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('men', 'Species', '9606', (47, 50))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (275, 289))	('ADC', 'Disease', (265, 268))	('cancer', 'Disease', (250, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('>500', 'Var', (101, 105))	('cancers', 'Disease', 'MESH:D009369', (62, 69))
221398	29893768	Consistent with our results, previous observational studies found various cumulative measures of viral suppression to be associated with ADC, non-Hodgkin lymphoma, Kaposi sarcoma, and anal cancer risk, but not liver cancer risk.	('ADC', 'Disease', (137, 140))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (164, 178))	('non-Hodgkin lymphoma', 'Disease', (142, 162))	('anal cancer', 'Phenotype', 'HP:0032186', (184, 195))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (142, 162))	('lymphoma', 'Phenotype', 'HP:0002665', (154, 162))	('viral', 'Var', (97, 102))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (142, 162))	('liver cancer', 'Phenotype', 'HP:0002896', (210, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('suppression', 'NegReg', (103, 114))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (164, 178))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('ADC', 'Disease', 'MESH:D009369', (137, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('Kaposi sarcoma', 'Disease', (164, 178))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (146, 162))
221402	29893768	Nevertheless, the mechanism underlying the association between viral suppression and decreased cancer risk is of considerable interest.	('decreased cancer', 'Disease', 'MESH:D009369', (85, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('decreased cancer', 'Disease', (85, 101))	('viral suppression', 'Var', (63, 80))
221406	29893768	Beneficial effects of viral suppression on cancer risk over and above its beneficial effect on CD4 count could include reduced (if not ideal) levels of inflammation, lessened immune-senescence, or decreased presence of pro-oncogenic HIV-encoded proteins.	('inflammation', 'Disease', 'MESH:D007249', (152, 164))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('HIV-encoded', 'Protein', (233, 244))	('cancer', 'Disease', (43, 49))	('inflammation', 'Disease', (152, 164))	('reduced', 'NegReg', (119, 126))	('CD4', 'Gene', (95, 98))	('viral suppression', 'Var', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('decreased', 'NegReg', (197, 206))	('immune-senescence', 'MPA', (175, 192))	('CD4', 'Gene', '920', (95, 98))	('presence', 'MPA', (207, 215))	('lessened', 'NegReg', (166, 174))
221408	29893768	Prior meta-analyses, which included studies from the pre-ART era, reported a 30% decreased risk of prostate cancer in HIV+ men compared with the general population, consistent with our finding of a 20% decreased risk among unsuppressed compared with uninfected men.	('decreased', 'NegReg', (81, 90))	('men', 'Species', '9606', (261, 264))	('prostate cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('men', 'Species', '9606', (123, 126))	('HIV+', 'Var', (118, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('decreased risk of prostate', 'Phenotype', 'HP:0008687', (81, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
221411	29893768	However, one study found that screening differences could not explain lower prostate cancer risk in HIV+ compared to uninfected men during the ART era.	('lower prostate cancer', 'Disease', 'MESH:D011471', (70, 91))	('lower prostate', 'Phenotype', 'HP:0008687', (70, 84))	('lower prostate cancer', 'Disease', (70, 91))	('HIV+', 'Var', (100, 104))	('men', 'Species', '9606', (128, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
221412	29893768	A major strength of this investigation was the use of a large national cohort of HIV+ and demographically-similar uninfected persons followed over a 16-year period in the modern ART-era, and thus sufficient cancer events to comprehensively explore the relationship between viral suppression and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('HIV+', 'Var', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('persons', 'Species', '9606', (125, 132))
221421	31651363	The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear.	('tumor', 'Disease', (86, 91))	('gene-modified', 'Var', (28, 41))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
221426	31651363	The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('response', 'Disease', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('associated', 'Reg', (75, 85))	('tumor', 'Disease', (128, 133))	('patients', 'Species', '9606', (103, 111))	('gene-modified', 'Var', (17, 30))	('NY-ESO-1', 'Gene', (136, 144))	('NY-ESO-1', 'Gene', '246100', (136, 144))
221436	31651363	Most SS occur as a result of a translocation between the X chromosome and chromosome 18 resulting in SS18-SSX1, SS18-SSX2, and/or SS18-SSX4 fusion proteins.	('SS', 'Phenotype', 'HP:0012570', (112, 114))	('SSX4', 'Gene', (135, 139))	('SS', 'Disease', 'MESH:D013584', (106, 108))	('SS', 'Phenotype', 'HP:0012570', (106, 108))	('translocation', 'Var', (31, 44))	('SS18', 'Gene', (130, 134))	('SS', 'Disease', 'MESH:D013584', (135, 137))	('SS18', 'Gene', '6760', (101, 105))	('SS', 'Phenotype', 'HP:0100242', (101, 103))	('SSX4', 'Gene', '6759', (135, 139))	('SS', 'Phenotype', 'HP:0100242', (5, 7))	('SSX2', 'Gene', (117, 121))	('SS', 'Disease', 'MESH:D013584', (117, 119))	('SS', 'Phenotype', 'HP:0012570', (117, 119))	('SSX2', 'Gene', '6757', (117, 121))	('SS18', 'Gene', (112, 116))	('SS', 'Phenotype', 'HP:0100242', (112, 114))	('SS18', 'Gene', '6760', (130, 134))	('SSX1', 'Gene', '6756', (106, 110))	('SS', 'Phenotype', 'HP:0100242', (106, 108))	('SSX1', 'Gene', (106, 110))	('SS', 'Disease', 'MESH:D013584', (101, 103))	('SS', 'Phenotype', 'HP:0012570', (101, 103))	('SS', 'Disease', 'MESH:D013584', (130, 132))	('SS', 'Disease', 'MESH:D013584', (5, 7))	('SS18', 'Gene', (101, 105))	('SS18', 'Gene', '6760', (112, 116))	('SS', 'Phenotype', 'HP:0012570', (5, 7))	('SS', 'Phenotype', 'HP:0100242', (117, 119))	('result of', 'Reg', (19, 28))	('SS', 'Disease', 'MESH:D013584', (112, 114))
221440	31651363	PD-1/PD-L1 (programmed cell death) pathway inhibitors have shown durable clinical benefit in tumor histologies that exhibit T-cell infiltration, elevated levels of PD-L1 expression, and higher levels of nonsynonymous somatic mutation burden.	('elevated', 'PosReg', (145, 153))	('PD-L1', 'Gene', '29126', (164, 169))	('inhibitors', 'Var', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PD-L1', 'Gene', (5, 10))	('tumor', 'Disease', (93, 98))	('PD-L1', 'Gene', '29126', (5, 10))	('T-cell infiltration', 'CPA', (124, 143))	('levels', 'MPA', (154, 160))	('PD-L1', 'Gene', (164, 169))	('higher', 'PosReg', (186, 192))	('expression', 'MPA', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
221449	31651363	In this cohort, we observed 50% response rate with a durable (30.9 weeks median duration of response) in patients with high intra-tumoral NY-ESO-1 expression.	('NY-ESO-1', 'Gene', '246100', (138, 146))	('patients', 'Species', '9606', (105, 113))	('NY-ESO-1', 'Gene', (138, 146))	('high', 'Var', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
221467	31651363	Laboratory assessments for eligibility were as follows: absolute neutrophil count >=1000/mm3, platelet count >=75,000/mm3, serum bilirubin < 2 mg/dl, alanine aminotransferase and aspartate aminotransferase <=2.5 x upper limit of normal, and creatinine clearance of >=60 ml/min.	('aspartate', 'Chemical', 'None', (179, 188))	('creatinine clearance', 'MPA', (241, 261))	('creatinine', 'Chemical', 'MESH:D003404', (241, 251))	('platelet count', 'CPA', (94, 108))	('aspartate aminotransferase', 'MPA', (179, 205))	('bilirubin', 'Chemical', 'MESH:D001663', (129, 138))	('alanine', 'Chemical', 'MESH:D000409', (150, 157))	('serum bilirubin', 'MPA', (123, 138))	('>=1000/mm3', 'Var', (82, 92))
221474	31651363	Vector was produced at the City of Hope (Duarte, CA) using transient transfection with four plasmids expressing the transfer vector, rev, VSV-G, and gag/pol, in 293 T cells.	('VSV-G', 'Var', (138, 143))	('gag/pol', 'Gene', (149, 156))	('gag/pol', 'Gene', '100616496', (149, 156))
221476	31651363	The following antibodies were used: cluster of differentiation (CD)4 BV605, CD8 BV650, CCR7 PE-CF594 (Becton Dickinson), CD45RA PECy7, CD28 BV421, CD127 BV711, PD-1 PerCP-Cy5.5, CD95 APC, CD62L BV785 (BioLegend, Dedham, MA), CD3 AF700, CD45RO FITC, CD27 APC-ef780 (eBioscience, San Diego, CA).	('CD45', 'Gene', '5788', (236, 240))	('CD27', 'Gene', (249, 253))	('CCR7', 'Gene', (87, 91))	('APC', 'Disease', 'MESH:D011125', (254, 257))	('APC', 'Disease', (254, 257))	('CD8', 'Gene', (76, 79))	('BioLegend', 'Disease', (201, 210))	('CD45', 'Gene', (121, 125))	('CD27', 'Gene', '939', (249, 253))	('eBioscience', 'Disease', (265, 276))	('CCR7', 'Gene', '1236', (87, 91))	('BioLegend', 'Disease', 'None', (201, 210))	('CD62L', 'Gene', '6402', (188, 193))	('CD127', 'Gene', (147, 152))	('CD45', 'Gene', '5788', (121, 125))	('CD28', 'Gene', (135, 139))	('CD95', 'Gene', '355', (178, 182))	('CD62L', 'Gene', (188, 193))	('CD127', 'Gene', '3575', (147, 152))	('CF594', 'Chemical', 'MESH:C011571', (95, 100))	('FITC', 'Chemical', 'MESH:D016650', (243, 247))	('eBioscience', 'Disease', 'None', (265, 276))	('CD8', 'Gene', '925', (76, 79))	('CD3 AF700', 'Var', (225, 234))	('CD28', 'Gene', '940', (135, 139))	('CD45', 'Gene', (236, 240))	('APC', 'Disease', 'MESH:D011125', (183, 186))	('CD95', 'Gene', (178, 182))	('APC', 'Disease', (183, 186))
221489	31651363	In cohort 2, which consisted of patients with low antigen expression, the BOR was SD in five patients, PD in one patient, and PR in four patients (Fig.	('patient', 'Species', '9606', (113, 120))	('patients', 'Species', '9606', (32, 40))	('low', 'Var', (46, 49))	('patients', 'Species', '9606', (93, 101))	('patient', 'Species', '9606', (137, 144))	('BOR', 'Disease', (74, 77))	('patients', 'Species', '9606', (137, 145))	('patient', 'Species', '9606', (93, 100))	('patient', 'Species', '9606', (32, 39))	('antigen', 'Protein', (50, 57))
221509	31651363	While there was not a significant difference in immune infiltration patterns across all biopsies after infusion, we did observe a trend towards an increased presence of CD3+ and CD8+ T cells at 8 weeks post infusion for a subset of patients, although the overall amount of infiltration remained quite low (<=5%) (Fig.	('CD8', 'Gene', (178, 181))	('CD8', 'Gene', '925', (178, 181))	('patients', 'Species', '9606', (232, 240))	('CD3+', 'Var', (169, 173))
221537	31651363	SS is an ideal tumor target, since the fundamental oncogenic mechanisms of this translocation-related sarcoma drive aberrant expression of NY-ESO-1 through the defective SWI/SNF complex, which results in abnormal function of polycomb repressor complexes modulating gene expression.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('SS', 'Disease', 'MESH:D013584', (0, 2))	('function', 'MPA', (213, 221))	('modulating', 'Reg', (254, 264))	('SS', 'Phenotype', 'HP:0100242', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('expression', 'MPA', (125, 135))	('NY-ESO-1', 'Gene', '246100', (139, 147))	('tumor', 'Disease', (15, 20))	('polycomb', 'Protein', (225, 233))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('NY-ESO-1', 'Gene', (139, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcoma', 'Disease', (102, 109))	('defective', 'NegReg', (160, 169))	('SWI/SNF complex', 'Protein', (170, 185))	('aberrant', 'Var', (116, 124))
221565	31651363	Our data demonstrate that loss of NY-ESO-1 protein or mRNA in SS patients treated with SPEAR T cells is not a widespread phenomenon, possibly due to the aberrant epigenetic mechanisms in SS tumors caused by the defective SWI/SNF complex.	('NY-ESO-1', 'Gene', '246100', (34, 42))	('SS', 'Phenotype', 'HP:0012570', (187, 189))	('SS', 'Disease', 'MESH:D013584', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('SS', 'Phenotype', 'HP:0100242', (62, 64))	('mRNA', 'MPA', (54, 58))	('SS', 'Phenotype', 'HP:0012570', (62, 64))	('SS', 'Phenotype', 'HP:0100242', (187, 189))	('SS', 'Disease', 'MESH:D013584', (187, 189))	('patients', 'Species', '9606', (65, 73))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('NY-ESO-1', 'Gene', (34, 42))	('defective', 'Var', (211, 220))
221573	31651363	Specific loss or mutations of the HLA-A*02 allele or defects in SLLMWITQC peptide loading onto HLA-A*02 have not yet been ruled out as mechanisms of resistance in our study.	('HLA-A', 'Gene', '3105', (95, 100))	('HLA-A', 'Gene', '3105', (34, 39))	('defects', 'NegReg', (53, 60))	('HLA-A', 'Gene', (95, 100))	('loss', 'NegReg', (9, 13))	('HLA-A', 'Gene', (34, 39))	('mutations', 'Var', (17, 26))
221587	31651363	Moreover, the therapeutic efficacy may be enhanced through use of a high dose fludarabine-containing preparative lymphodepletion regimen, by promoting greater engraftment at the tumor site, and through modulation of TAM.	('tumor', 'Disease', (178, 183))	('modulation', 'Var', (202, 212))	('promoting greater', 'PosReg', (141, 158))	('enhanced', 'PosReg', (42, 50))	('fludarabine', 'Chemical', 'MESH:C024352', (78, 89))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('therapeutic efficacy', 'CPA', (14, 34))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TAM', 'Protein', (216, 219))
221595	31651363	Equity in Allogene, Vor, PACT, Unum, Lyell.	('PACT', 'Gene', '5930', (25, 29))	('PACT', 'Gene', (25, 29))	('Allogene', 'Var', (10, 18))
221616	26886614	The larger one of the masses in left anterior mediastinum (black asterisk in Figure 2) was measured about 15.0 x 9.0 x 8.0 cm, which showed broad contact with the left chest wall anteriorly, mass effect with compression resulting in contour deformity of the adjacent left cardiac chambers posteromedially on axial scan (Figure 2B) and inversion of the left diaphragm inferiorly on coronal scan (Figure 2C).	('left diaphragm inferiorly', 'CPA', (352, 377))	('contour deformity', 'Disease', 'MESH:D009140', (233, 250))	('contour deformity', 'Disease', (233, 250))	('mass effect', 'Var', (191, 202))
221639	26886614	The family of ES/PNET tumors can be united as a tumor entity by the presence of a reciprocal translocation of the long arms of chromosomes 11 and 22, t (11;22)(q24;q12), so-called EWS (Ewing sarcoma protein)-friend leukemia virus integration-1 (FLI-1) fusion gene.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('FLI-1', 'Gene', '2313', (245, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('leukemia', 'Disease', 'MESH:D007938', (215, 223))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('leukemia', 'Disease', (215, 223))	('PNET tumors', 'Disease', (17, 28))	('EWS', 'Gene', '2130', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Ewing sarcoma', 'Disease', (185, 198))	('FLI-1', 'Gene', (245, 250))	('tumor', 'Disease', (48, 53))	('PNET tumors', 'Disease', 'MESH:D008527', (17, 28))	('t (11;22)(q24;q12', 'Var', (150, 167))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('EWS', 'Gene', (180, 183))	('leukemia', 'Phenotype', 'HP:0001909', (215, 223))	('tumor', 'Disease', (22, 27))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (185, 198))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (185, 198))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
221648	26886614	Identification of the t (11;22)(q24;q12) chromosomal translocation (EWS-FLI1 gene fusion) is highly specific for ES/PNET, because >90% of the tumors show this gene rearrangement.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FLI1', 'Gene', (72, 76))	('FLI1', 'Gene', '2313', (72, 76))	('t (11;22)(q24;q12', 'Var', (22, 39))	('ES/PNET', 'Disease', (113, 120))	('EWS', 'Gene', '2130', (68, 71))	('tumors', 'Disease', (142, 148))	('EWS', 'Gene', (68, 71))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
221684	27606299	The studies from TMH suggest that fluorescence in situ hybridization is a sensitive test for detecting EWSR1 rearrangements as compared to polymerase chain reaction.	('rearrangements', 'Var', (109, 123))	('EWS', 'Phenotype', 'HP:0012254', (103, 106))	('EWSR1', 'Gene', (103, 108))	('EWSR1', 'Gene', '2130', (103, 108))
221750	32204428	The sequence complementary to the EWS/FLI1 fusion oncogene (siAS) is: sense strands 5'-GCAGCAGAACCCUUCUUAUd(GA)-3' and antisense strand 5'-AUAAGAAGGGUUCUGCUGCd(CC)-3'.	('siAS', 'Disease', (60, 64))	('antisense', 'Var', (119, 128))	('siAS', 'Disease', 'None', (60, 64))
221798	32204428	Looking at the zeta potentials of each solution (Figure 2b), we observed that for mass ratios lower than 10, the surface charge is negative (around -30 mV) corresponding to an excess of siRNA covering nanodiamonds.	('siRNA', 'MPA', (186, 191))	('negative', 'NegReg', (131, 139))	('as', 'Chemical', 'MESH:D001151', (83, 85))	('lower', 'Var', (94, 99))	('excess', 'PosReg', (176, 182))	('surface charge', 'MPA', (113, 127))
221802	32204428	Sonication have no effect on surface charge but promote smaller aggregates, as observed on the DLS profiles (Figure 2a).	('aggregates', 'MPA', (64, 74))	('as', 'Chemical', 'MESH:D001151', (76, 78))	('Sonication', 'Var', (0, 10))
221850	32204428	H-DND positive charge favored electrostatic attachment of siRNA onto the nanoparticles and the measured DLS size larger than the 7-nm primary size indicated some aggregation.	('positive charge', 'Var', (6, 21))	('favored', 'PosReg', (22, 29))	('H-DND', 'Chemical', '-', (0, 5))	('aggregation', 'MPA', (162, 173))	('as', 'Chemical', 'MESH:D001151', (97, 99))	('electrostatic attachment', 'MPA', (30, 54))
221892	32204428	Finally, regarding the silencing efficacy of EWS-FLI1 in Ewing sarcoma cells xenografted tumor by siRNA delivered by T-DND, we observed a 50% inhibition by the antisense siRNA compared to irrelevant siRNA.	('Ewing sarcoma', 'Disease', (57, 70))	('EWS-FLI1', 'Gene', '14030;14247', (45, 53))	('antisense', 'Var', (160, 169))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('T-DND', 'Chemical', '-', (117, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('EWS-FLI1', 'Gene', (45, 53))	('silencing', 'MPA', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
221918	30653119	The preoperative serum levels of cancer antigen (CA)-125, CA19-9, CA72-4, human epididymis protein 4, carcinoembryonic antigen, and alpha-fetoprotein were all within the normal range.	('cancer antigen (CA)-125', 'Gene', '94025', (33, 56))	('cancer antigen (CA)-125', 'Gene', (33, 56))	('alpha-fetoprotein', 'Gene', '174', (132, 149))	('CA72-4', 'Var', (66, 72))	('carcinoembryonic antigen', 'MPA', (102, 126))	('CA19-9', 'Var', (58, 64))	('epididymis', 'Disease', 'MESH:D004823', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('human', 'Species', '9606', (74, 79))	('alpha-fetoprotein', 'Gene', (132, 149))	('epididymis', 'Disease', (80, 90))
221984	28985760	Importantly, we demonstrated that although leukemic stem cell activity is enriched and mediated by CD34+CD117+ subpopulation, CD34+CD117- subpopulation can acquire CD34+CD117+ phenotype through de-differentiation.	('de-differentiation', 'CPA', (194, 212))	('CD34+CD117-', 'Var', (126, 137))	('leukemic', 'Disease', (43, 51))	('leukemic', 'Disease', 'MESH:D007938', (43, 51))	('CD34+CD117+ phenotype', 'CPA', (164, 185))
222011	28985760	Patients with AML were diagnosed using the French-American-British (FAB) classification system; subtype M1 (patients Leu 32 and BMI 1786), M4 (patient BMI 1808), M5 (patient BMI 1690), and M5a (patients Leu 14, Leu 29, and Leu 33).	('Leu 33', 'Var', (223, 229))	('Leu', 'Chemical', 'MESH:D007930', (203, 206))	('patient', 'Species', '9606', (194, 201))	('AML', 'Phenotype', 'HP:0004808', (14, 17))	('patients', 'Species', '9606', (194, 202))	('AML', 'Disease', (14, 17))	('patient', 'Species', '9606', (143, 150))	('Leu', 'Chemical', 'MESH:D007930', (117, 120))	('Leu 29', 'Var', (211, 217))	('Leu', 'Chemical', 'MESH:D007930', (223, 226))	('Leu', 'Chemical', 'MESH:D007930', (211, 214))	('patient', 'Species', '9606', (166, 173))	('Patients', 'Species', '9606', (0, 8))	('patient', 'Species', '9606', (108, 115))	('patients', 'Species', '9606', (108, 116))	('AML', 'Disease', 'MESH:D015470', (14, 17))	('FAB', 'Chemical', '-', (68, 71))
222016	28985760	One to 3-day-old NSG pups were sub-lethally irradiated at 1Gy and engrafted with 8.7 x 104-7.9 x 105 of CD3-depleted AML mononuclear cells from seven AML patients (Leu 14, Leu 29, Leu 32, Leu 33, BMI 1690, BMI 1786, and BMI 1808) via intrahepatic injection route.	('Leu', 'Chemical', 'MESH:D007930', (172, 175))	('AML', 'Disease', (117, 120))	('AML', 'Disease', 'MESH:D015470', (150, 153))	('AML', 'Phenotype', 'HP:0004808', (117, 120))	('CD3', 'Gene', (104, 107))	('Leu', 'Chemical', 'MESH:D007930', (180, 183))	('patients', 'Species', '9606', (154, 162))	('AML', 'Disease', (150, 153))	('AML', 'Phenotype', 'HP:0004808', (150, 153))	('Leu 33', 'Var', (188, 194))	('Leu 29', 'Var', (172, 178))	('CD3', 'Gene', '12501', (104, 107))	('Leu', 'Chemical', 'MESH:D007930', (188, 191))	('Leu 32', 'Var', (180, 186))	('AML', 'Disease', 'MESH:D015470', (117, 120))	('Leu', 'Chemical', 'MESH:D007930', (164, 167))
222030	28985760	Primary antibodies including anti-human CD45 (cat# ab781), anti-human MPO (cat# ab134132), and anti-human c-kit (cat# ab32363) monoclonal antibodies were purchased from Abcam and used for immunohistochemistry.	('c-kit', 'Gene', (106, 111))	('human', 'Species', '9606', (64, 69))	('human', 'Species', '9606', (34, 39))	('c-kit', 'Gene', '16590', (106, 111))	('cat', 'Var', (75, 78))	('human', 'Species', '9606', (100, 105))
222035	28985760	It is well documented that flow cytometric analysis using CD45/SSC gating can distinguish leukemic blast cells (low CD45 expression) from normal hematopoietic cell types (high CD45 expression).	('leukemic', 'Disease', 'MESH:D007938', (90, 98))	('leukemic', 'Disease', (90, 98))	('CD45', 'Gene', (116, 120))	('low', 'Var', (112, 115))
222036	28985760	As shown by previous publications, CD33 (myeloid cell marker), CD34 (primitive stem cell marker), CD117 (c-kit receptor), and CD38 (cell activation marker) are key AML leukemic blasts-associated markers.	('CD38', 'Var', (126, 130))	('c-kit', 'Gene', '16590', (105, 110))	('AML leukemic blasts', 'Disease', (164, 183))	('CD33', 'Gene', (35, 39))	('AML leukemic blasts', 'Disease', 'MESH:D015470', (164, 183))	('CD117', 'Var', (98, 103))	('key AML leukemic', 'Disease', 'MESH:D015470', (160, 176))	('CD33', 'Gene', '12489', (35, 39))	('CD34', 'Gene', (63, 67))	('AML', 'Phenotype', 'HP:0004808', (164, 167))	('c-kit', 'Gene', (105, 110))	('key AML leukemic', 'Disease', (160, 176))
222037	28985760	To confirm the presence of AML leukemic blasts in seven individuals with AML, BM mononuclear cells were isolated, labeled with anti-human CD34, CD117, CD38, CD33, and CD45 monoclonal antibodies, and analyzed using flow cytometry (Additional file 1: Figure S1a and Table 1).	('AML', 'Phenotype', 'HP:0004808', (27, 30))	('AML', 'Disease', 'MESH:D015470', (73, 76))	('CD38', 'Var', (151, 155))	('AML leukemic blasts', 'Disease', (27, 46))	('AML', 'Disease', (73, 76))	('AML', 'Phenotype', 'HP:0004808', (73, 76))	('CD33', 'Gene', '12489', (157, 161))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('human', 'Species', '9606', (132, 137))	('AML leukemic blasts', 'Disease', 'MESH:D015470', (27, 46))	('AML', 'Disease', (27, 30))	('CD117', 'Var', (144, 149))	('CD33', 'Gene', (157, 161))
222039	28985760	Although all samples expressed CD33, only three samples (Leu 14, BMI 1690, and BMI 1808) expressed CD33 within the CD45lo compartment, suggesting that Leu 14, BMI 1690, and BMI 1808 are positive for AML leukemic blasts (Additional file 1: Figure S1a).	('CD33', 'Gene', (99, 103))	('AML leukemic blasts', 'Disease', (199, 218))	('Leu', 'Chemical', 'MESH:D007930', (57, 60))	('CD33', 'Gene', (31, 35))	('CD33', 'Gene', '12489', (99, 103))	('Leu 14', 'Var', (151, 157))	('AML leukemic blasts', 'Disease', 'MESH:D015470', (199, 218))	('CD33', 'Gene', '12489', (31, 35))	('positive', 'Reg', (186, 194))	('Leu', 'Chemical', 'MESH:D007930', (151, 154))	('AML', 'Phenotype', 'HP:0004808', (199, 202))
222045	28985760	Phenotypic analysis revealed that NSG recipient mice injected with Leu 14, BMI 1690, or BMI 1808 were successfully engrafted, with more than 10% AML engraftment detected in the peripheral blood (Fig.	('AML', 'Phenotype', 'HP:0004808', (145, 148))	('AML', 'Disease', (145, 148))	('mice', 'Species', '10090', (48, 52))	('Leu', 'Chemical', 'MESH:D007930', (67, 70))	('Leu 14', 'Var', (67, 73))	('AML', 'Disease', 'MESH:D015470', (145, 148))
222047	28985760	The frequency of periphery AML cells in Leu 14 and BMI 1690 recipient mice increased with time, with more than 50% AML cells detected at endpoint (week 12-14 post-engraftment; Fig.	('AML', 'Phenotype', 'HP:0004808', (27, 30))	('Leu 14', 'Var', (40, 46))	('AML', 'Disease', 'MESH:D015470', (115, 118))	('AML', 'Phenotype', 'HP:0004808', (115, 118))	('AML', 'Disease', (115, 118))	('Leu', 'Chemical', 'MESH:D007930', (40, 43))	('mice', 'Species', '10090', (70, 74))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('AML', 'Disease', (27, 30))
222049	28985760	Consistent with peripheral blood, high frequency of AML cells were detected in spleen (range 16.6-99.1%) and BM (range 63.4-99.9%) of Leu 14, BMI 1690, and BMI 1808 recipient mice at endpoint (Fig.	('mice', 'Species', '10090', (175, 179))	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('AML', 'Disease', (52, 55))	('Leu', 'Var', (134, 137))	('Leu', 'Chemical', 'MESH:D007930', (134, 137))	('AML', 'Disease', 'MESH:D015470', (52, 55))
222053	28985760	In comparison, BM harbors the highest frequency of human CD45+ cells, accompanied by the greatest level of CD117 expression, as opposed to spleen and peripheral blood (Additional file 2: Figure S2).	('CD45+ cells', 'Var', (57, 68))	('human', 'Species', '9606', (51, 56))	('CD117 expression', 'MPA', (107, 123))
222060	28985760	While no solid tumors were detected, spleen enlargement and massive accumulation of green soft tissue resembling soft tissue sarcoma with increased vascularization at the trunk, abdomen, limbs, and kidneys were observed in CD34+ secondary engrafted NSG mice (Fig.	('mice', 'Species', '10090', (253, 257))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('increased', 'PosReg', (138, 147))	('solid tumors', 'Disease', 'MESH:D009369', (9, 21))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (113, 132))	('spleen enlargement', 'Phenotype', 'HP:0001744', (37, 55))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('sarcoma', 'Disease', (125, 132))	('spleen', 'CPA', (37, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('CD34+', 'Var', (223, 228))	('solid tumors', 'Disease', (9, 21))	('enlargement', 'PosReg', (44, 55))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
222062	28985760	Although AML cell engraftment was detected in all secondary NSG recipient mice, engraftment levels were significantly higher in mice engrafted with CD34+ than CD34- cells in peripheral blood, spleen, and BM (Fig.	('higher', 'PosReg', (118, 124))	('AML', 'Disease', 'MESH:D015470', (9, 12))	('AML', 'Disease', (9, 12))	('mice', 'Species', '10090', (128, 132))	('engraftment levels', 'MPA', (80, 98))	('AML', 'Phenotype', 'HP:0004808', (9, 12))	('mice', 'Species', '10090', (74, 78))	('CD34+', 'Var', (148, 153))
222063	28985760	The frequency of AML cells was ~ 80 fold, 25 fold, and 100 fold greater in CD34+ engrafted mice compared to CD34- engrafted mice in the peripheral blood, spleen, and BM, respectively (Fig.	('mice', 'Species', '10090', (91, 95))	('CD34+ engrafted', 'Var', (75, 90))	('mice', 'Species', '10090', (124, 128))	('AML', 'Disease', 'MESH:D015470', (17, 20))	('AML', 'Phenotype', 'HP:0004808', (17, 20))	('AML', 'Disease', (17, 20))	('greater', 'PosReg', (64, 71))
222076	28985760	The absolute number of human CD45+ and CD34+ AML cells was significantly greater in the peripheral blood and spleen but not in the BM of NSG newborn pups compared to adult mice (Fig.	('AML', 'Phenotype', 'HP:0004808', (45, 48))	('greater', 'PosReg', (73, 80))	('CD34+', 'Var', (39, 44))	('mice', 'Species', '10090', (172, 176))	('CD45+', 'Var', (29, 34))	('AML', 'Disease', 'MESH:D015470', (45, 48))	('human', 'Species', '9606', (23, 28))	('AML', 'Disease', (45, 48))
222080	28985760	Given that CD117 is expressed on leukemic blasts of Leu 14, BMI 1690, and BMI 1808 among the seven AML patients (Additional file 1: Figure S1), we hypothesized that CD117 is essential for successful engraftment (Fig.	('Leu', 'Var', (52, 55))	('leukemic', 'Disease', (33, 41))	('AML', 'Disease', 'MESH:D015470', (99, 102))	('Leu', 'Chemical', 'MESH:D007930', (52, 55))	('AML', 'Phenotype', 'HP:0004808', (99, 102))	('leukemic', 'Disease', 'MESH:D007938', (33, 41))	('AML', 'Disease', (99, 102))	('patients', 'Species', '9606', (103, 111))
222082	28985760	Although peripheral blood engraftment was detected in both CD34+CD117+ and CD34+CD117- NSG recipient mice at week 12 post-engraftment, the frequency and absolute count of AML cells were significantly greater in CD34+CD117+ NSG recipient mice in a dose-dependent manner (Fig.	('absolute count', 'CPA', (153, 167))	('AML', 'Disease', 'MESH:D015470', (171, 174))	('mice', 'Species', '10090', (237, 241))	('mice', 'Species', '10090', (101, 105))	('greater', 'PosReg', (200, 207))	('CD34+CD117+ NSG', 'Var', (211, 226))	('AML', 'Phenotype', 'HP:0004808', (171, 174))	('AML', 'Disease', (171, 174))
222084	28985760	Significantly greater engraftment was observed in the peripheral blood, spleen, and BM of CD34+CD117+ NSG recipient mice (Fig.	('greater', 'PosReg', (14, 21))	('engraftment', 'CPA', (22, 33))	('mice', 'Species', '10090', (116, 120))	('CD34+CD117+ NSG', 'Var', (90, 105))
222085	28985760	Although either CD34+CD117+ or CD34+CD117- cells were used for engraftment, CD34-CD117-, CD34-CD117+, CD34+CD117+, and CD34+CD117- subsets were present in all NSG recipient mice (Fig.	('CD34+CD117+', 'Var', (102, 113))	('CD34-CD117-', 'Var', (76, 87))	('mice', 'Species', '10090', (173, 177))	('CD34-CD117+', 'Var', (89, 100))
222086	28985760	Interestingly, significantly greater frequency of CD34+CD117+ subset (but not absolute count) was detected in mice engrafted with CD34+CD117- (Fig.	('greater', 'PosReg', (29, 36))	('CD34+CD117-', 'Var', (130, 141))	('CD34+CD117+ subset', 'CPA', (50, 68))	('mice', 'Species', '10090', (110, 114))
222087	28985760	Despite significant increase in engraftment, CD34+CD117+ NSG recipient mice did not exhibit more severe pathological outcome than CD34+CD117- NSG recipient mice (data not shown).	('mice', 'Species', '10090', (71, 75))	('CD34+CD117+ NSG', 'Var', (45, 60))	('engraftment', 'CPA', (32, 43))	('mice', 'Species', '10090', (156, 160))	('increase', 'PosReg', (20, 28))
222116	28985760	Consistent with a recent report, we have demonstrated, through both in vitro and in vivo studies, that leukemic stem cells are enriched in the CD34+ population and in particular CD34+CD117+ fraction, while CD34+CD117- fraction is more mature and less potent in proliferation.	('leukemic', 'Disease', 'MESH:D007938', (103, 111))	('leukemic', 'Disease', (103, 111))	('CD34+CD117+', 'Var', (178, 189))
222117	28985760	Interestingly, CD34+CD117- engrafted mice gave rise to both CD117- and CD117+ cells; therefore, it is not clear if leukemogenesis and pathological outcomes observed in CD34+CD117- engrafted mice are driven by CD117- or CD117+ cells.	('mice', 'Species', '10090', (190, 194))	('mice', 'Species', '10090', (37, 41))	('leukemogenesis', 'Disease', (115, 129))	('CD34+CD117-', 'Var', (168, 179))
222118	28985760	Given the heterogeneity and plasticity of leukemic stem cells, these results raise the possibility that the engrafted CD34+CD117- cells can de-differentiate to give rise to CD34+CD117+ cells and acquire an immature, stem cell-like property to drive the disease progression.	('leukemic', 'Disease', 'MESH:D007938', (42, 50))	('CD34+CD117+', 'Var', (173, 184))	('drive', 'Reg', (243, 248))	('de-differentiate', 'CPA', (140, 156))	('disease progression', 'CPA', (253, 272))	('leukemic', 'Disease', (42, 50))	('CD34+CD117-', 'Var', (118, 129))	('immature', 'CPA', (206, 214))
222120	28985760	It is possible that the leukemic stem cell activity is mediated by the CD34+CD38+ population as majority of the CD34+ cells from Leu 14, BMI 1690, and BMI 1808 patients express high levels of CD38.	('patients', 'Species', '9606', (160, 168))	('leukemic', 'Disease', 'MESH:D007938', (24, 32))	('Leu', 'Var', (129, 132))	('CD38', 'MPA', (192, 196))	('leukemic', 'Disease', (24, 32))	('Leu', 'Chemical', 'MESH:D007930', (129, 132))
222125	28985760	In addition, the discrepancies in engraftment potential as shown by the "low engrafters" (Leu 32 and Leu 1786) despite the presence of CD45lo leukemic blasts can possibly be a reflection of their in vivo proliferative ability, or alternatively, an indication of prognosis.	('Leu', 'Chemical', 'MESH:D007930', (90, 93))	('leukemic', 'Disease', 'MESH:D007938', (142, 150))	('Leu 1786', 'Var', (101, 109))	('Leu', 'Chemical', 'MESH:D007930', (101, 104))	('engraftment potential', 'CPA', (34, 55))	('leukemic', 'Disease', (142, 150))	('CD45lo', 'Var', (135, 141))
222126	28985760	It was reported in previous studies that AML cells from patients with poor prognosis features such as the presence of FLT3 mutations, high white blood cell count at diagnosis, or chromosomal rearrangements would tend to engraft more efficiently in mice than AML cells isolated from patients with good prognostic features.	('AML', 'Phenotype', 'HP:0004808', (41, 44))	('patients', 'Species', '9606', (56, 64))	('AML', 'Disease', (258, 261))	('FLT3', 'Gene', '2322', (118, 122))	('more efficiently', 'PosReg', (228, 244))	('AML', 'Phenotype', 'HP:0004808', (258, 261))	('mice', 'Species', '10090', (248, 252))	('engraft', 'CPA', (220, 227))	('FLT3', 'Gene', (118, 122))	('AML', 'Disease', 'MESH:D015470', (41, 44))	('presence', 'Var', (106, 114))	('AML', 'Disease', 'MESH:D015470', (258, 261))	('chromosomal rearrangements', 'Var', (179, 205))	('patients', 'Species', '9606', (282, 290))	('AML', 'Disease', (41, 44))	('mutations', 'Var', (123, 132))
222164	27516790	Recent cytogenetic studies have taken a leading role for definitive diagnosis of synovial sarcoma, identifying a translocation t(X;18) (p11.2;q11.2) resulting from fusion of the SYT gene on chromosome 18 to SSX1 or SSX2 on chromosome X.	('SSX1', 'Gene', (207, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('fusion', 'Var', (164, 170))	('synovial sarcoma', 'Disease', (81, 97))	('SSX2', 'Gene', (215, 219))	('SYT', 'Gene', '6857', (178, 181))	('SSX1', 'Gene', '6756', (207, 211))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (81, 97))	('SYT', 'Gene', (178, 181))	('SSX2', 'Gene', '6757', (215, 219))	('synovial sarcoma', 'Disease', 'MESH:D013584', (81, 97))
222172	27516790	The expression of SYT-SSX1 variants has been associated with worse behavior.	('variants', 'Var', (27, 35))	('SYT', 'Gene', (18, 21))	('worse behavior', 'Disease', (61, 75))	('SSX1', 'Gene', (22, 26))	('associated', 'Reg', (45, 55))	('SYT', 'Gene', '6857', (18, 21))	('SSX1', 'Gene', '6756', (22, 26))
222222	26959007	In another skin cancer xenograft model using 92.1 uveal melanoma cells, about 29% of mice treated with withaferin-A exhibited a complete clinical response, while 43% of the animals showed cancer progression upon discontinuation of treatment.	('mice', 'Species', '10090', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('withaferin-A', 'Var', (103, 115))	('cancer', 'Disease', (16, 22))	('skin cancer', 'Disease', (11, 22))	('skin cancer', 'Phenotype', 'HP:0008069', (11, 22))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('skin cancer', 'Disease', 'MESH:D012878', (11, 22))	('cancer', 'Disease', (188, 194))	('uveal melanoma', 'Disease', (50, 64))	('withaferin-A', 'Chemical', 'MESH:C009684', (103, 115))
222236	26959007	Since the neoplastic transformation of cells involves oxidative and/or inflammatory stress-induced modifications of cellular macromolecules, such as DNA, RNA and proteins, and subsequent dysfunction of cellular biochemical pathways, the tumorigenesis process can be prevented by relieving cells from oxidative stress load and inflammatory insults.	('tumor', 'Disease', (237, 242))	('cellular biochemical pathways', 'Pathway', (202, 231))	('proteins', 'Protein', (162, 170))	('modifications', 'Reg', (99, 112))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('cellular macromolecules', 'MPA', (116, 139))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('dysfunction', 'Var', (187, 198))	('oxidative stress', 'Phenotype', 'HP:0025464', (300, 316))	('neoplastic transformation', 'CPA', (10, 35))
222244	26959007	Genetic ablation of several of these cytoprotective enzymes or that Nrf2 have been reported to increase the susceptibility of animals to carcinogens in various mouse model of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (175, 189))	('Nrf2', 'Gene', (68, 72))	('increase', 'PosReg', (95, 103))	('susceptibility', 'MPA', (108, 122))	('carcinogenesis', 'Disease', (175, 189))	('Genetic ablation', 'Var', (0, 16))	('mouse', 'Species', '10090', (160, 165))
222247	26959007	The antioxidant activity of withaferin-A was first reported by Bhattacharya et al., who showed that treatment with withaferin-A increased SOD, CAT and GPX activity in rat brain frontal cortex and striatal concentrations.	('antioxidant activity', 'MPA', (4, 24))	('SOD', 'Gene', (138, 141))	('withaferin-A', 'Var', (115, 127))	('increased', 'PosReg', (128, 137))	('rat', 'Species', '10116', (212, 215))	('increased SOD', 'Phenotype', 'HP:0410246', (128, 141))	('withaferin-A', 'Chemical', 'MESH:C009684', (28, 40))	('rat', 'Species', '10116', (167, 170))	('SOD', 'Gene', '6647', (138, 141))	('CAT and', 'MPA', (143, 150))	('GPX', 'Enzyme', (151, 154))	('withaferin-A', 'Chemical', 'MESH:C009684', (115, 127))
222263	26959007	Thus, inhibition of aberrant expression of COX-2 and iNOS may prevent the promotion and progression of cancer.	('progression of', 'CPA', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aberrant expression', 'Var', (20, 39))	('COX-2', 'Gene', (43, 48))	('prevent', 'NegReg', (62, 69))	('iNOS', 'Gene', (53, 57))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('inhibition', 'NegReg', (6, 16))	('promotion', 'CPA', (74, 83))
222282	26959007	Incubation of temozolomide-resistant glioblastoma multiforme (U251TMZ and U87TMZ) cells with withaferin-A also resulted in G2/M phase cell cycle arrest as revealed by increased expression of cyclin B1, which was accompanied by the depletion of tyrosine kinase cell surface receptors c-Met, epidermal growth factor receptor (EGFR), and Her-2, and reduced phosphorylation of cell survival kinases, such as Akt, mTOR and p70 S6K.	('p70 S6K', 'Gene', '6198', (418, 425))	('G2/M phase cell cycle arrest', 'CPA', (123, 151))	('c-Met', 'Gene', (283, 288))	('p70 S6K', 'Gene', (418, 425))	('mTOR', 'Gene', '2475', (409, 413))	('expression', 'MPA', (177, 187))	('Her-2', 'Gene', (335, 340))	('glioblastoma multiforme', 'Disease', (37, 60))	('tyrosine', 'Chemical', 'MESH:D014443', (244, 252))	('U87TMZ', 'Var', (74, 80))	('depletion', 'MPA', (231, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('EGFR', 'Gene', '1956', (324, 328))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (37, 60))	('U87TMZ', 'CellLine', 'CVCL:0022', (74, 80))	('withaferin-A', 'Chemical', 'MESH:C009684', (93, 105))	('epidermal growth factor receptor', 'Gene', (290, 322))	('epidermal growth factor receptor', 'Gene', '1956', (290, 322))	('temozolomide', 'Chemical', 'MESH:D000077204', (14, 26))	('increased', 'PosReg', (167, 176))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (134, 151))	('phosphorylation', 'MPA', (354, 369))	('c-Met', 'Gene', '4233', (283, 288))	('tyrosine kinase cell', 'MPA', (244, 264))	('mTOR', 'Gene', (409, 413))	('Akt', 'Pathway', (404, 407))	('EGFR', 'Gene', (324, 328))	('cyclin B1', 'Gene', '891', (191, 200))	('cyclin B1', 'Gene', (191, 200))	('Her-2', 'Gene', '2064', (335, 340))	('cell survival kinases', 'Pathway', (373, 394))	('reduced', 'NegReg', (346, 353))
222310	26959007	As compared to the treatment with withaferin-A or hyperthermia alone, exposure of hyperthermia-stimulated HeLa cells to withaferin-A resulted in decreased intracellular GSH/GSSG ratio and caspase-3 activation, which was significantly inhibited by a cell permeable glutathione precursor.	('hyperthermia', 'Phenotype', 'HP:0001945', (50, 62))	('withaferin-A', 'Chemical', 'MESH:C009684', (120, 132))	('decreased', 'NegReg', (145, 154))	('HeLa', 'CellLine', 'CVCL:0030', (106, 110))	('hyperthermia', 'Phenotype', 'HP:0001945', (82, 94))	('GSSG', 'Chemical', 'MESH:D019803', (173, 177))	('glutathione', 'Chemical', 'MESH:D005978', (264, 275))	('hyperthermia', 'Disease', (50, 62))	('hyperthermia', 'Disease', (82, 94))	('caspase-3', 'Gene', '836', (188, 197))	('activation', 'PosReg', (198, 208))	('GSH', 'Chemical', '-', (169, 172))	('caspase-3', 'Gene', (188, 197))	('rat', 'Species', '10116', (178, 181))	('hyperthermia', 'Disease', 'MESH:D005334', (50, 62))	('hyperthermia', 'Disease', 'MESH:D005334', (82, 94))	('intracellular GSH/GSSG ratio', 'MPA', (155, 183))	('withaferin-A', 'Chemical', 'MESH:C009684', (34, 46))	('withaferin-A', 'Var', (120, 132))
222319	26959007	Similarly, the induction of apoptosis of U251TMZ and U87TMZ cells by withaferin-A was mediated through the activation of both extrinsic and intrinsic pathways through ROS-dependent manner.	('U87TMZ', 'Var', (53, 59))	('intrinsic pathways', 'Pathway', (140, 158))	('U87TMZ', 'CellLine', 'CVCL:0022', (53, 59))	('extrinsic', 'Pathway', (126, 135))	('U251TMZ', 'Var', (41, 48))	('apoptosis', 'CPA', (28, 37))	('withaferin-A', 'Chemical', 'MESH:C009684', (69, 81))	('ROS', 'Chemical', 'MESH:D017382', (167, 170))
222324	26959007	The inactivation of p53, a tumor suppressor protein, is a key event in the pathogenesis of many cancers.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('inactivation', 'Var', (4, 16))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('tumor', 'Disease', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('cancers', 'Disease', (96, 103))
222325	26959007	Numerous studies have shown that restoration of p53 function leads to the cell cycle arrest and apoptosis in cancer cells.	('p53', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('p53', 'Gene', '7157', (48, 51))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('cancer', 'Disease', (109, 115))	('apoptosis', 'CPA', (96, 105))	('cell cycle arrest', 'CPA', (74, 91))	('restoration', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rat', 'Species', '10116', (38, 41))
222341	26959007	Silencing of Par-4 by small interfering RNAs increased the proliferation of cholangiocarcinoma cells in culture.	('proliferation', 'CPA', (59, 72))	('small interfering', 'Var', (22, 39))	('increased', 'PosReg', (45, 54))	('Par-4', 'Gene', (13, 18))	('rat', 'Species', '10116', (66, 69))	('cholangiocarcinoma', 'Disease', (76, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Silencing', 'Var', (0, 9))	('RNAs', 'Protein', (40, 44))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
222361	26959007	Although withaferin-A-induced LC3 expression remained unaffected upon treatment of cells with pharmacological inhibitors of canonical autophagy, silencing of BAG3 led to suppression of withaferin-A-induced LC3 expression and cell death, suggesting that the compound induced BAG3-mediated autophagy that protects PC3 cells against withaferin-A-induced apoptosis.	('cell death', 'CPA', (225, 235))	('silencing', 'Var', (145, 154))	('LC3', 'Gene', '84557', (206, 209))	('LC3', 'Gene', (206, 209))	('LC3', 'Gene', '84557', (30, 33))	('suppression', 'NegReg', (170, 181))	('expression', 'MPA', (210, 220))	('BAG3', 'Gene', '9531', (158, 162))	('BAG3', 'Gene', '9531', (274, 278))	('withaferin-A', 'Chemical', 'MESH:C009684', (185, 197))	('BAG3', 'Gene', (274, 278))	('withaferin-A', 'Chemical', 'MESH:C009684', (330, 342))	('LC3', 'Gene', (30, 33))	('withaferin-A', 'Chemical', 'MESH:C009684', (9, 21))	('BAG3', 'Gene', (158, 162))
222375	26959007	Whereas treatment of MCF-7 and MDA-MB-231 cells with withaferin-A elevated the level of E-cadherin protein, the expression of vimentin was decreased in the MDA-MB-231 cells xenografts as well as in MMTV-neu tumors from withaferin-A-treated mice.	('expression', 'MPA', (112, 122))	('E-cadherin', 'Gene', (88, 98))	('E-cadherin', 'Gene', '999', (88, 98))	('withaferin-A', 'Chemical', 'MESH:C009684', (53, 65))	('MCF-7', 'CellLine', 'CVCL:0031', (21, 26))	('mice', 'Species', '10090', (240, 244))	('MDA-MB-231', 'Var', (156, 166))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('decreased', 'NegReg', (139, 148))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (156, 166))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('withaferin-A', 'Chemical', 'MESH:C009684', (219, 231))	('MMTV-neu tumors', 'Disease', (198, 213))	('MMTV-neu tumors', 'Disease', 'MESH:C537366', (198, 213))	('vimentin', 'Protein', (126, 134))	('elevated', 'PosReg', (66, 74))
222382	26959007	Withaferin-A directly interacted with residues Gly26, Ser27, Gly30, Lys31, Gln34, Gln83 and Ser85 of KH3 domain of hnRNP-K via hydrogen bonds and hydrophobic interactions, thereby masking the ability of hnRNP-K to bind with ssDNA.	('Ser27', 'Var', (54, 59))	('hydrogen bonds', 'Protein', (127, 141))	('hnRNP-K', 'Gene', '3190', (115, 122))	('hnRNP-K', 'Gene', (203, 210))	('Gln83', 'Chemical', '-', (82, 87))	('Ser85', 'Chemical', '-', (92, 97))	('KH3', 'Chemical', 'MESH:C033990', (101, 104))	('hnRNP-K', 'Gene', (115, 122))	('hydrophobic', 'CPA', (146, 157))	('Lys31', 'Chemical', '-', (68, 73))	('Ser27', 'Chemical', '-', (54, 59))	('ability', 'MPA', (192, 199))	('Ser85', 'Var', (92, 97))	('Withaferin-A', 'Chemical', 'MESH:C009684', (0, 12))	('interacted', 'Interaction', (22, 32))	('Gln83', 'Var', (82, 87))	('Gly26', 'Chemical', '-', (47, 52))	('Lys31', 'Var', (68, 73))	('Gln34', 'Chemical', '-', (75, 80))	('bind', 'Interaction', (214, 218))	('masking', 'NegReg', (180, 187))	('Gly30', 'Var', (61, 66))	('Gln34', 'Var', (75, 80))	('Gly30', 'Chemical', '-', (61, 66))	('hydrogen', 'Chemical', 'MESH:D006859', (127, 135))	('Gly26', 'Var', (47, 52))	('hnRNP-K', 'Gene', '3190', (203, 210))
222388	26959007	Withaferin-A-mediated inhibition of MDA-MB-231 cell migration was significantly augmented by knockdown of Notch-2 and Notch-4 protein, suggesting that the Notch-2 and Notch-4 activation by withaferin-A impairs its inhibitory effect on breast cancer cell migration.	('knockdown', 'Var', (93, 102))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (36, 46))	('Notch-2', 'Gene', '4853', (155, 162))	('rat', 'Species', '10116', (55, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('activation', 'PosReg', (175, 185))	('Withaferin-A', 'Chemical', 'MESH:C009684', (0, 12))	('impairs', 'NegReg', (202, 209))	('breast cancer', 'Disease', 'MESH:D001943', (235, 248))	('Notch-2', 'Gene', (155, 162))	('withaferin-A', 'Chemical', 'MESH:C009684', (189, 201))	('breast cancer', 'Disease', (235, 248))	('Notch-4', 'Gene', '4855', (167, 174))	('inhibitory effect', 'MPA', (214, 231))	('Notch-4', 'Gene', (167, 174))	('Notch-4', 'Gene', '4855', (118, 125))	('Notch-2', 'Gene', '4853', (106, 113))	('rat', 'Species', '10116', (257, 260))	('Notch-4', 'Gene', (118, 125))	('MDA-MB-231', 'Gene', (36, 46))	('Notch-2', 'Gene', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
222394	26959007	Treatment of doxorubicin-resistant human leukemia cells (K562/Adr) with withaferin-A resulted in caspase-mediated apoptosis induction, which was associated with decreased expression of Bcl-2, Bim and p-Bad.	('expression', 'MPA', (171, 181))	('K562', 'CellLine', 'CVCL:0004', (57, 61))	('leukemia', 'Phenotype', 'HP:0001909', (41, 49))	('decreased', 'NegReg', (161, 170))	('Bim', 'Gene', (192, 195))	('leukemia', 'Disease', 'MESH:D007938', (41, 49))	('Bim', 'Gene', '10018', (192, 195))	('leukemia', 'Disease', (41, 49))	('human', 'Species', '9606', (35, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (13, 24))	('caspase-mediated apoptosis induction', 'CPA', (97, 133))	('withaferin-A', 'Chemical', 'MESH:C009684', (72, 84))	('Bcl-2', 'Gene', (185, 190))	('p-Bad', 'Var', (200, 205))	('Bcl-2', 'Gene', '596', (185, 190))
222405	26959007	reported that the overexpression of nestin, a stem cell marker, in pancreatic ductal adenocarcinoma cells increased cell motility and induced phenotypic changes associated with the EMT, whereas knockdown of endogenous nestin expression reduced cell migration and helped cells to retain epithelial phenotype.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (67, 99))	('cell motility', 'CPA', (116, 129))	('pancreatic ductal adenocarcinoma', 'Disease', (67, 99))	('rat', 'Species', '10116', (252, 255))	('knockdown', 'Var', (194, 203))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (67, 99))	('induced', 'Reg', (134, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('nestin', 'Gene', (36, 42))	('cell migration', 'CPA', (244, 258))	('phenotypic', 'MPA', (142, 152))	('helped', 'PosReg', (263, 269))	('reduced', 'NegReg', (236, 243))	('increased', 'PosReg', (106, 115))	('overexpression', 'PosReg', (18, 32))
222413	26959007	The antitumor effects of withaferin-A alone or in combination with cisplatin in mice bearing ovarian tumors were attributed to the elimination of cells expressing cancer stem cells markers, such as CD44, CD24, CD34, CD117 and Oct4, and the downregulation of Notch-1, Hes1 and Hey1 genes.	('CD117', 'Gene', (216, 221))	('ovarian tumors', 'Disease', (93, 107))	('Hes1', 'Gene', '15205', (267, 271))	('elimination', 'NegReg', (131, 142))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ovarian tumors', 'Disease', 'MESH:D010051', (93, 107))	('ovarian tumor', 'Phenotype', 'HP:0100615', (93, 106))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('CD34', 'Gene', '12490', (210, 214))	('Hes1', 'Gene', (267, 271))	('CD24', 'Gene', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('downregulation', 'NegReg', (240, 254))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('CD117', 'Gene', '16590', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('Hey1', 'Gene', '15213', (276, 280))	('ovarian tumors', 'Phenotype', 'HP:0100615', (93, 107))	('CD24', 'Gene', '12484', (204, 208))	('Notch-1', 'Gene', (258, 265))	('tumor', 'Disease', (8, 13))	('Hey1', 'Gene', (276, 280))	('CD44', 'Var', (198, 202))	('cancer', 'Disease', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('mice', 'Species', '10090', (80, 84))	('withaferin-A', 'Chemical', 'MESH:C009684', (25, 37))	('CD34', 'Gene', (210, 214))	('Oct4', 'Gene', (226, 230))
222430	26959007	Mutation of cysteine-179 abrogated the NF-kappaB suppressing effect of withaferin-A.	('abrogated', 'NegReg', (25, 34))	('Mutation', 'Var', (0, 8))	('cysteine-179', 'Gene', (12, 24))	('NF-kappaB', 'Protein', (39, 48))	('cysteine', 'Chemical', 'MESH:D003545', (12, 20))	('withaferin-A', 'Chemical', 'MESH:C009684', (71, 83))	('suppressing', 'NegReg', (49, 60))
222436	26959007	Withaferin-A caused direct covalent binding with cysreine-302 residue of beta-tubulin, thereby inducing cell cycle arrest in MCF-7 cells.	('beta-tubulin', 'Protein', (73, 85))	('covalent', 'MPA', (27, 35))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('Withaferin-A', 'Chemical', 'MESH:C009684', (0, 12))	('cysreine', 'Chemical', '-', (49, 57))	('MCF-7', 'CellLine', 'CVCL:0031', (125, 130))	('inducing', 'PosReg', (95, 103))	('cysreine-302', 'Var', (49, 61))	('cell cycle arrest', 'CPA', (104, 121))	('binding', 'Interaction', (36, 43))
222439	26959007	In contrast, withaferin-A has been shown to bind with the cysteine-9, but not the cysteine-133, residue located on the N-terminal domain of annexin-A2.	('cysteine', 'Chemical', 'MESH:D003545', (58, 66))	('cysteine-9', 'Var', (58, 68))	('annexin-A2', 'Gene', (140, 150))	('withaferin-A', 'Chemical', 'MESH:C009684', (13, 25))	('bind', 'Interaction', (44, 48))	('cysteine', 'Chemical', 'MESH:D003545', (82, 90))	('annexin-A2', 'Gene', '302', (140, 150))
222490	26578536	Since HIV infection is a strong risk factor for zoster and also increases the risk of certain cancers, we identified all individuals who had at least one Medicare claim for HIV (ICD-9 codes 042.0, 042.1, 042.2, 042.9, or V08) any time before death or the last follow-up.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('death', 'Disease', (242, 247))	('HIV infection', 'Disease', (6, 19))	('HIV', 'Species', '12721', (6, 9))	('zoster', 'Disease', (48, 54))	('HIV', 'Species', '12721', (173, 176))	('cancers', 'Disease', (94, 101))	('HIV infection', 'Disease', 'MESH:D015658', (6, 19))	('042.0', 'Var', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('042.2', 'Var', (204, 209))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('increases', 'PosReg', (64, 73))	('death', 'Disease', 'MESH:D003643', (242, 247))
222531	26578536	Of interest, monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis are asymptomatic premalignant conditions that can precede by several years the development of multiple myeloma, lymphoplasmacytic lymphoma, and CLL/SLL.	('SLL', 'Gene', (248, 251))	('CLL', 'Disease', (244, 247))	('lymphoplasmacytic lymphoma', 'Disease', 'MESH:D008223', (212, 238))	('monoclonal', 'Var', (68, 78))	('lymphoma', 'Phenotype', 'HP:0002665', (230, 238))	('lymphoplasmacytic lymphoma', 'Disease', (212, 238))	('multiple myeloma', 'Phenotype', 'HP:0006775', (194, 210))	('multiple myeloma', 'Disease', 'MESH:D009101', (194, 210))	('SLL', 'Gene', '347734', (248, 251))	('multiple myeloma', 'Disease', (194, 210))	('CLL', 'Disease', 'MESH:D015451', (244, 247))	('lymphocytosis', 'Phenotype', 'HP:0100827', (86, 99))	('monoclonal gammopathy of undetermined', 'Disease', (13, 50))
222584	26484141	Modulation of the activity of Sp transcription factors by Mithramycin analogues had shown promising results for treatment of metastatic prostate cancer.	('Modulation', 'Var', (0, 10))	('activity', 'MPA', (18, 26))	('prostate cancer', 'Disease', (136, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Mithramycin', 'Chemical', 'MESH:D008926', (58, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))
222604	25905041	Do translocation-bearing sarcomas have specific weaknesses in their cell death signaling networks?	('weaknesses', 'NegReg', (48, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('cell death signaling networks', 'Pathway', (68, 97))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('translocation-bearing', 'Var', (3, 24))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))
222620	25905041	Some sarcomas rely on the presence of specific aberrant fusion proteins, generated after chromosomal rearrangements.	('aberrant', 'Var', (47, 55))	('fusion proteins', 'Protein', (56, 71))	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('sarcomas', 'Disease', (5, 13))
222621	25905041	Deregulation of gene expression in sarcomas driven by these chimeric oncoproteins can occur at different levels (epigenetic silencing, transcription activity, messenger processing, etc.)	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('sarcomas', 'Disease', (35, 43))	('epigenetic silencing', 'Var', (113, 133))	('transcription activity', 'MPA', (135, 157))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))	('messenger processing', 'MPA', (159, 179))
222625	25905041	Furthermore, certain translocation-bearing sarcomas are also characterized by failure to complete tissue differentiation (i.e., RMS to skeletal muscle, liposarcoma to adipocytes) in a process mediated by their specific fusion protein and linked to the inhibition of apoptosis induction.	('tissue differentiation', 'CPA', (98, 120))	('liposarcoma', 'Disease', 'MESH:D008080', (152, 163))	('translocation-bearing', 'Var', (21, 42))	('liposarcoma', 'Phenotype', 'HP:0012034', (152, 163))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('failure', 'NegReg', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('specific fusion protein', 'Protein', (210, 233))	('liposarcoma', 'Disease', (152, 163))	('sarcomas', 'Disease', (43, 51))
222633	25905041	p53 re-activator agents as Nutlin-3 and/or PRIMA-1 are able to induce apoptosis successfully through Noxa, Puma, or p21 upregulation in both mutant and wild-type p53 sarcoma cell lines.	('p53', 'Gene', (0, 3))	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('p21', 'Gene', (116, 119))	('p53', 'Gene', '7157', (0, 3))	('mutant', 'Var', (141, 147))	('p53', 'Gene', (162, 165))	('sarcoma', 'Disease', (166, 173))	('upregulation', 'PosReg', (120, 132))	('p53', 'Gene', '7157', (162, 165))	('PRIMA-1', 'Gene', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('induce', 'PosReg', (63, 69))	('p21', 'Gene', '1026', (116, 119))	('apoptosis', 'CPA', (70, 79))	('Noxa', 'Gene', '5366', (101, 105))	('PRIMA-1', 'Gene', '145270', (43, 50))	('Noxa', 'Gene', (101, 105))
222639	25905041	Also, inhibition of endogenous tyrosine kinase B (TrkB) signaling suppresses cell proliferation and increases apoptosis in cultured leiomyosarcoma cells.	('leiomyosarcoma', 'Disease', (132, 146))	('TrkB', 'Gene', '4915', (50, 54))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (132, 146))	('tyrosine kinase B', 'Gene', (31, 48))	('increases', 'PosReg', (100, 109))	('TrkB', 'Gene', (50, 54))	('tyrosine kinase B', 'Gene', '4915', (31, 48))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (132, 146))	('inhibition', 'Var', (6, 16))	('suppresses', 'NegReg', (66, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('apoptosis', 'CPA', (110, 119))	('cell proliferation', 'CPA', (77, 95))
222648	25905041	Accordingly, Hsp-90 antagonists had been shown to induce transient growth arrest and apoptosis in RMS cells.	('antagonists', 'Var', (20, 31))	('Hsp-90', 'Gene', '3320', (13, 19))	('growth arrest', 'Disease', 'MESH:D006323', (67, 80))	('growth arrest', 'Disease', (67, 80))	('apoptosis', 'CPA', (85, 94))	('growth arrest', 'Phenotype', 'HP:0001510', (67, 80))	('Hsp-90', 'Gene', (13, 19))	('induce', 'Reg', (50, 56))
222651	25905041	The lack of attachment activates signals from the plasma membrane, mostly by integrins and the focal adhesion kinase (FAK) that regulate the BH3-only proteins through the mitochondrial commitment to cell suicide (Figure 2).	('FAK', 'Gene', (118, 121))	('FAK', 'Gene', '5747', (118, 121))	('focal adhesion kinase', 'Gene', (95, 116))	('BH3-only proteins', 'Protein', (141, 158))	('activates', 'PosReg', (23, 32))	('lack', 'Var', (4, 8))	('focal adhesion kinase', 'Gene', '5747', (95, 116))	('mitochondrial commitment', 'CPA', (171, 195))
222654	25905041	Anoikis resistance in sarcomas has been described to be associated with integrins, Bcl-2 and caspase-8, CD99 isoforms, RANK, and ERK.	('sarcomas', 'Disease', (22, 30))	('integrins', 'Protein', (72, 81))	('ERK', 'Var', (129, 132))	('Anoikis resistance', 'Disease', (0, 18))	('caspase-8', 'Gene', (93, 102))	('associated', 'Reg', (56, 66))	('caspase-8', 'Gene', '841', (93, 102))	('sarcomas', 'Disease', 'MESH:D012509', (22, 30))	('CD99', 'Protein', (104, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('Bcl-2', 'Protein', (83, 88))
222657	25905041	Impairment of IGF-1R signaling (by neutralizing antibodies or siRNAs expression) led to a lower survival in anchorage-independent growth conditions and a decrease on metastatic ability.	('IGF-1R', 'Gene', (14, 20))	('survival', 'CPA', (96, 104))	('signaling', 'MPA', (21, 30))	('decrease', 'NegReg', (154, 162))	('lower', 'NegReg', (90, 95))	('neutralizing', 'Var', (35, 47))	('siRNAs', 'Gene', (62, 68))	('Impairment', 'Var', (0, 10))	('IGF-1R', 'Gene', '3480', (14, 20))	('metastatic ability', 'CPA', (166, 184))
222676	25905041	Sensitization to apoptosis has also been achieved by re-expressing caspase-8 through demethylation or gene transfer.	('re-expressing', 'Reg', (53, 66))	('demethylation', 'Var', (85, 98))	('caspase-8', 'Gene', (67, 76))	('caspase-8', 'Gene', '841', (67, 76))	('gene transfer', 'Var', (102, 115))
222697	25905041	Plk1 is another major component of MC signaling: siRNA inhibition of Plk1 killed RMS cells and the chemical inhibitor BI 2536 induced G2/M arrest and cell death in OS cell lines.	('BI 2536', 'Chemical', 'MESH:C518477', (118, 125))	('cell death', 'CPA', (150, 160))	('M arrest', 'Disease', 'MESH:D006323', (137, 145))	('Plk1', 'Gene', '5347', (0, 4))	('M arrest', 'Disease', (137, 145))	('Plk1', 'Gene', '5347', (69, 73))	('OS', 'Phenotype', 'HP:0002669', (164, 166))	('MC', 'Chemical', '-', (35, 37))	('inhibition', 'Var', (55, 65))	('Plk1', 'Gene', (0, 4))	('Plk1', 'Gene', (69, 73))
222698	25905041	Inhibitors of Aurora kinases block the formation of the cleavage furrow, disrupting cytokinesis, and killing leiomyosarcoma and synovial sarcoma cells.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (109, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (128, 144))	('leiomyosarcoma', 'Disease', (109, 123))	('killing', 'NegReg', (101, 108))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (109, 123))	('synovial sarcoma', 'Disease', 'MESH:D013584', (128, 144))	('Inhibitors', 'Var', (0, 10))	('block', 'NegReg', (29, 34))	('cytokinesis', 'CPA', (84, 95))	('synovial sarcoma', 'Disease', (128, 144))	('disrupting', 'NegReg', (73, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
222748	23543869	Later, the genomic copy number gain at chromosome 8q22, which contains the MTDH/AEG-1 gene, was recognized as a defining event in both metastasis and chemoresistance in breast cancer patients, providing evidence for a role for MTDH in both of these oncogenic processes.	('metastasis', 'CPA', (135, 145))	('copy number gain', 'Var', (19, 35))	('MTDH', 'Gene', (227, 231))	('MTDH', 'Gene', '92140', (75, 79))	('chemoresistance', 'CPA', (150, 165))	('AEG-1', 'Gene', '92140', (80, 85))	('AEG-1', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('MTDH', 'Gene', (75, 79))	('breast cancer', 'Disease', (169, 182))	('MTDH', 'Gene', '92140', (227, 231))	('patients', 'Species', '9606', (183, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
222755	23543869	Conversely, loss of HOTAIR reduces cancer cell viability and invasion and increases sensitivity to cisplatin and doxorubicin.	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('reduces', 'NegReg', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('doxorubicin', 'Chemical', 'MESH:D004317', (113, 124))	('invasion', 'CPA', (61, 69))	('loss', 'Var', (12, 16))	('HOTAIR', 'Gene', (20, 26))	('increases', 'PosReg', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('HOTAIR', 'Gene', '100124700', (20, 26))	('cancer', 'Disease', (35, 41))
222789	23543869	However, some subjects with high MTDH/AEG-1 or HOTAIR expression in the collected sample demonstrated a favorable response to treatment or no evidence of disease after treatment.	('AEG-1', 'Gene', '92140', (38, 43))	('AEG-1', 'Gene', (38, 43))	('MTDH', 'Gene', '92140', (33, 37))	('HOTAIR', 'Gene', (47, 53))	('MTDH', 'Gene', (33, 37))	('HOTAIR', 'Gene', '100124700', (47, 53))	('high', 'Var', (28, 32))
222795	23543869	It was interesting to see an expression level of HOTAIR that correlated with the percent necrosis in tumor samples exposed to chemotherapy and/or radiation, being high when minimal necrosis is present (#0796) or low with maximum necrosis (#0703) present.	('necrosis', 'Disease', (181, 189))	('necrosis', 'Disease', (89, 97))	('HOTAIR', 'Gene', '100124700', (49, 55))	('necrosis', 'Disease', 'MESH:D009336', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('necrosis', 'Disease', (229, 237))	('#0703', 'Var', (239, 244))	('necrosis', 'Disease', 'MESH:D009336', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('HOTAIR', 'Gene', (49, 55))	('necrosis', 'Disease', 'MESH:D009336', (229, 237))	('#0796', 'Var', (202, 207))
222834	33484281	If not indicated elsewhere, HuARLT, BFP-HuARLT, and rKSHV-HuARLT cells were cultivated on plates coated with 0.5% gelatin (G1393-100ML, Sigma) in endothelial growth medium (CC-3124, Lonza) in a humidified normoxic atmosphere at 37  C with 5% CO2 and in the presence of 2 mug/ml doxycycline to facilitate proliferation.	('G1393-100ML', 'Var', (123, 134))	('doxycycline', 'Chemical', 'MESH:D004318', (278, 289))	('BFP', 'Gene', (36, 39))	('KSHV', 'Species', '37296', (53, 57))	('CO2', 'Chemical', 'MESH:D002245', (242, 245))	('KS', 'Phenotype', 'HP:0100726', (53, 55))	('BFP', 'Gene', '7732', (36, 39))
222838	33484281	Six to 8 spheroids were suspended per 50 mul of 0.7 mg/ml fibrin (341576, Calbiochem), 0.4% methylcellulose (M0512, Sigma), and 0.5 U/ml thrombin (605190-100 U, Merck Millipore) in EGM medium supplemented with 2 mug/ml doxycycline.	('605190-100 U', 'Var', (147, 159))	('EGM medium', 'Chemical', '-', (181, 191))	('thrombin', 'Gene', (137, 145))	('doxycycline', 'Chemical', 'MESH:D004318', (219, 230))	('341576', 'Var', (66, 72))	('thrombin', 'Gene', '2147', (137, 145))
222879	33484281	The primary antibodies used for Western blot analysis are as follows: RAD50 (ab89, Abcam), MRE11A (GTX70212, GeneTex) NBN (GTX103229, GeneTex), gammaH2AX S139 (R20244, NSJ Bioreagent), and beta-actin (5441, Sigma).	('NBN', 'Gene', '4683', (118, 121))	('RAD50', 'Gene', (70, 75))	('RAD50', 'Gene', '10111', (70, 75))	('NBN', 'Gene', (118, 121))	('MRE11A', 'Gene', (91, 97))	('R20244', 'Var', (160, 166))	('gammaH2AX', 'Chemical', '-', (144, 153))	('beta-actin', 'Protein', (189, 199))	('GTX103229', 'Var', (123, 132))	('MRE11A', 'Gene', '4361', (91, 97))
222880	33484281	Secondary antibodies are as follows: donkey anti-mouse IgG-HRP (GENA9310, GE Healthcare, now Merck), donkey anti-rabbit IgG-HRP (GENA9340, GE Healthcare).	('mouse', 'Species', '10090', (49, 54))	('GENA9340', 'Var', (129, 137))	('GENA9310', 'Var', (64, 72))
222930	33484281	qRT-PCR analysis confirmed a moderate but statistically significant upregulation of PI3K, Notch, Hes1, S6K, Jak2, TLR 2/4, and cRaf in 3D culture (Fig.	('Jak2', 'Gene', '3717', (108, 112))	('Hes1', 'Gene', '3280', (97, 101))	('S6K', 'Gene', (103, 106))	('TLR 2/4', 'Gene', (114, 121))	('upregulation', 'PosReg', (68, 80))	('PI3K', 'Var', (84, 88))	('cRaf', 'Gene', (127, 131))	('Hes1', 'Gene', (97, 101))	('cRaf', 'Gene', '5894', (127, 131))	('Jak2', 'Gene', (108, 112))	('TLR 2/4', 'Gene', '7097;7099', (114, 121))	('S6K', 'Gene', '6198', (103, 106))
222931	33484281	Furthermore, to elucidate the relevance of PI3K/mTOR pathway for KSHV maintenance in 3D culture, we specifically blocked PI3K and mTOR activities in virus infected rKSHV-HuARLT cells by small molecules, LY294002 and rapamycin, respectively.	('mTOR', 'Gene', '2475', (48, 52))	('KSHV', 'Species', '37296', (65, 69))	('mTOR', 'Gene', (48, 52))	('LY294002', 'Var', (203, 211))	('PI3K', 'Enzyme', (121, 125))	('KS', 'Phenotype', 'HP:0100726', (165, 167))	('activities', 'MPA', (135, 145))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('blocked', 'NegReg', (113, 120))	('virus infected', 'Disease', (149, 163))	('rapamycin', 'Chemical', 'MESH:D020123', (216, 225))	('LY294002', 'Chemical', 'MESH:C085911', (203, 211))	('mTOR', 'Gene', (130, 134))	('mTOR', 'Gene', '2475', (130, 134))	('KSHV', 'Species', '37296', (165, 169))	('virus infected', 'Disease', 'MESH:D001102', (149, 163))
222933	33484281	As a result, treatment with LY294002 and rapamycin led to a statistically significant reduction in the viral copy number in 3D culture of up to 20%, whereas the treatment with FK506, which shares a number of molecular targets with rapamycin, except for mTOR, showed no effect.	('reduction', 'NegReg', (86, 95))	('rapamycin', 'Chemical', 'MESH:D020123', (231, 240))	('LY294002', 'Var', (28, 36))	('FK506', 'Chemical', 'MESH:D016559', (176, 181))	('mTOR', 'Gene', (253, 257))	('mTOR', 'Gene', '2475', (253, 257))	('LY294002', 'Chemical', 'MESH:C085911', (28, 36))	('viral copy', 'MPA', (103, 113))	('rapamycin', 'Chemical', 'MESH:D020123', (41, 50))
222934	33484281	This observation was confirmed when we used other chemical inhibitors such as IC87114, a specific inhibitor of PI3Kdelta inhibitor, and TGX-221, an inhibitor of PI3K p110beta (Fig.	('IC87114', 'Var', (78, 85))	('p110beta', 'Gene', '5291', (166, 174))	('p110beta', 'Gene', (166, 174))	('IC87114', 'Chemical', 'MESH:C477872', (78, 85))	('PI3Kdelta', 'Gene', (111, 120))	('TGX-221', 'Chemical', 'MESH:C504718', (136, 143))	('PI3Kdelta', 'Gene', '5293', (111, 120))
222946	33484281	Moreover, when we blocked PI3K activity by Ly294002 or ATM activity by Ku55933, we could abolish the increase in gammaH2AX protein expression in 3D cultures of KSHV-infected endothelial cells.	('ATM', 'Gene', '472', (55, 58))	('KSHV-infected', 'Disease', (160, 173))	('gammaH2AX protein', 'Protein', (113, 130))	('PI3K', 'Protein', (26, 30))	('Ku55933', 'Chemical', 'MESH:C495818', (71, 78))	('gammaH2AX', 'Chemical', '-', (113, 122))	('Ly294002', 'Chemical', 'MESH:C085911', (43, 51))	('abolish', 'NegReg', (89, 96))	('ATM', 'Gene', (55, 58))	('KS', 'Phenotype', 'HP:0100726', (160, 162))	('KSHV-infected', 'Disease', 'MESH:D007239', (160, 173))	('Ku55933', 'Var', (71, 78))	('Ly294002', 'Var', (43, 51))
222975	33484281	Our inhibitor studies thus confirmed the relevance of this pathway for the maintenance of episomal virus genomes in 3D cultures: both, inhibitors of PI3K as well as of mTOR, triggered a notable decrease in the viral copy number.	('mTOR', 'Gene', (168, 172))	('PI3K', 'Gene', (149, 153))	('mTOR', 'Gene', '2475', (168, 172))	('inhibitors', 'Var', (135, 145))	('viral copy number', 'MPA', (210, 227))	('decrease', 'NegReg', (194, 202))
222977	33484281	Histological studies indicated that markers of DNA damage response, such as gammaH2AX, pT-Chk2, and 53BP1, are activated in early KSHV lesions.	('Chk2', 'Gene', '11200', (90, 94))	('activated', 'PosReg', (111, 120))	('Chk2', 'Gene', (90, 94))	('53BP1', 'Gene', (100, 105))	('53BP1', 'Gene', '7158', (100, 105))	('KSHV', 'Disease', (130, 134))	('KS', 'Phenotype', 'HP:0100726', (130, 132))	('KSHV', 'Species', '37296', (130, 134))	('gammaH2AX', 'Chemical', '-', (76, 85))	('gammaH2AX', 'Var', (76, 85))
222986	33484281	Moreover, DNA damage response is modulated by PI3K, e.g., by enhancing in MRE11 expression and stimulating DNA-PK.	('DNA-PK', 'Gene', (107, 113))	('MRE11', 'Gene', '4361', (74, 79))	('stimulating', 'Reg', (95, 106))	('MRE11', 'Gene', (74, 79))	('DNA-PK', 'Gene', '5591', (107, 113))	('PI3K', 'Var', (46, 50))	('expression', 'MPA', (80, 90))	('enhancing', 'PosReg', (61, 70))
223010	33542674	More patients with T3-4 received chemotherapy compared with T1-2.	('T1-2', 'Gene', '923;9173;292', (60, 64))	('chemotherapy', 'CPA', (33, 45))	('T3-4', 'Var', (19, 23))	('T1-2', 'Gene', (60, 64))
223109	26675762	Alterations in gastrointestinal function can alter visceral receptor function, leading to altered secretion of gastrointestinal peptides, e.g.	('visceral receptor function', 'MPA', (51, 77))	('secretion of gastrointestinal peptides', 'MPA', (98, 136))	('altered', 'Reg', (90, 97))	('Alterations', 'Var', (0, 11))	('alter', 'Reg', (45, 50))	('rat', 'Species', '10116', (4, 7))	('Alterations in gastrointestinal function', 'Phenotype', 'HP:0012719', (0, 40))
223111	26675762	Peripherally, chemotherapy can alter taste perception and cause nausea, vomiting, mucositis, abdominal cramping, bleeding, and ileus.	('nausea', 'Disease', (64, 70))	('nausea', 'Disease', 'MESH:D009325', (64, 70))	('vomiting', 'Disease', 'MESH:D014839', (72, 80))	('abdominal cramping', 'Phenotype', 'HP:0032155', (93, 111))	('vomiting', 'Phenotype', 'HP:0002013', (72, 80))	('ileus', 'Disease', (127, 132))	('taste perception', 'MPA', (37, 53))	('bleeding', 'Disease', 'MESH:D006470', (113, 121))	('ileus', 'Phenotype', 'HP:0002595', (127, 132))	('abdominal cramping', 'Disease', (93, 111))	('bleeding', 'Disease', (113, 121))	('cause', 'Reg', (58, 63))	('chemotherapy', 'Var', (14, 26))	('mucositis', 'Disease', (82, 91))	('alter', 'Reg', (31, 36))	('mucositis', 'Disease', 'MESH:D052016', (82, 91))	('nausea', 'Phenotype', 'HP:0002018', (64, 70))	('vomiting', 'Disease', (72, 80))
223121	26675762	Methotrexate leads to a decrease in proopiomelanocortin (POMC) messenger RNA (mRNA) (potentially decreasing opioid-mediated feeding) and activation of brain pathways associated with dehydration.	('decreasing', 'NegReg', (97, 107))	('proopiomelanocortin', 'Gene', (36, 55))	('proopiomelanocortin', 'Gene', '5443', (36, 55))	('dehydration', 'Phenotype', 'HP:0001944', (182, 193))	('dehydration', 'Disease', 'MESH:D003681', (182, 193))	('Methotrexate', 'Var', (0, 12))	('decrease', 'NegReg', (24, 32))	('brain pathways', 'Pathway', (151, 165))	('activation', 'PosReg', (137, 147))	('Methotrexate', 'Chemical', 'MESH:D008727', (0, 12))	('dehydration', 'Disease', (182, 193))
223134	26675762	Antibodies to IL-1 enhance food intake in tumour-bearing rodents.	('IL-1', 'Gene', '3552', (14, 18))	('Antibodies', 'Var', (0, 10))	('IL-1', 'Gene', (14, 18))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour-bearing', 'Disease', 'MESH:C565129', (42, 56))	('tumour-bearing', 'Disease', (42, 56))	('food intake', 'CPA', (27, 38))	('enhance', 'PosReg', (19, 26))
223137	26675762	The anorectic effect of IL-1 can be partially blocked by antibodies to CRF.	('antibodies', 'Var', (57, 67))	('IL-1', 'Gene', (24, 28))	('CRF', 'Gene', (71, 74))	('anorectic effect', 'MPA', (4, 20))	('IL-1', 'Gene', '3552', (24, 28))
223144	26675762	An inhibitor of TNFalpha increased food intake in anorectic tumour-bearing rats.	('increased', 'PosReg', (25, 34))	('tumour-bearing', 'Disease', (60, 74))	('inhibitor', 'Var', (3, 12))	('tumour-bearing', 'Disease', 'MESH:C565129', (60, 74))	('rats', 'Species', '10116', (75, 79))	('TNFalpha', 'Gene', (16, 24))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('food intake', 'CPA', (35, 46))
223145	26675762	The TNFalpha rs800629 single-nucleotide polymorphism is associated with anorexia in patients with non-small-cell lung cancer.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('TNFalpha', 'Gene', (4, 12))	('lung cancer', 'Disease', (113, 124))	('rs800629', 'Mutation', 'rs800629', (13, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('patients', 'Species', '9606', (84, 92))	('rs800629 single-nucleotide polymorphism', 'Var', (13, 52))	('anorexia', 'Phenotype', 'HP:0002039', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('anorexia', 'Gene', (72, 80))	('anorexia', 'Gene', '11743', (72, 80))	('associated with', 'Reg', (56, 71))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))
223162	26675762	In addition, prostate cancer cells with exogenous expression of visfatin genes show rapid tumour cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('exogenous expression', 'Var', (40, 60))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('prostate cancer', 'Disease', (13, 28))	('rat', 'Species', '10116', (109, 112))	('visfatin genes', 'Gene', (64, 78))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('tumour', 'Disease', (90, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))
223165	26675762	The decrease in food intake was prevented by the administration of SHU9119, an inhibitor of melanocortin receptor 3 and melanocortin receptor 4 (MC4R).	('melanocortin receptor 3', 'Gene', (92, 115))	('melanocortin receptor 4', 'Gene', (120, 143))	('food intake', 'CPA', (16, 27))	('SHU9119', 'Var', (67, 74))	('decrease', 'NegReg', (4, 12))	('melanocortin receptor 4', 'Gene', '4160', (120, 143))	('melanocortin receptor 3', 'Gene', '4159', (92, 115))	('rat', 'Species', '10116', (57, 60))
223184	26675762	Dichloroacetate enhances pyruvate dehydrogenase, leading to a reduction of lactate.	('Dichloroacetate', 'Var', (0, 15))	('pyruvate', 'Chemical', 'MESH:D019289', (25, 33))	('enhances', 'PosReg', (16, 24))	('lactate', 'Chemical', 'MESH:D019344', (75, 82))	('Dichloroacetate', 'Chemical', 'MESH:D003999', (0, 15))	('lactate', 'MPA', (75, 82))	('pyruvate dehydrogenase', 'Enzyme', (25, 47))	('reduction', 'NegReg', (62, 71))
223207	26675762	Finally, in humans with cancer, small increases of food intake have been seen with the serotonin antagonist cyproheptadine, the serotonergic-3-receptor blocker, ondansetron, ramosetron, and granisetron.	('serotonin', 'Chemical', 'MESH:D012701', (87, 96))	('increases', 'PosReg', (38, 47))	('food intake', 'CPA', (51, 62))	('cyproheptadine', 'Var', (108, 122))	('cyproheptadine', 'Chemical', 'MESH:D003533', (108, 122))	('granisetron', 'Chemical', 'MESH:D017829', (190, 201))	('ondansetron', 'Chemical', 'MESH:D017294', (161, 172))	('humans', 'Species', '9606', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('ramosetron', 'Chemical', 'MESH:C071315', (174, 184))
223246	26675762	found that acetylated alpha-MSH decreased food intake after central administration.	('food intake', 'CPA', (42, 53))	('rat', 'Species', '10116', (76, 79))	('acetylated', 'Var', (11, 21))	('alpha-MSH', 'Gene', (22, 31))	('alpha-MSH', 'Gene', '5443', (22, 31))	('decreased', 'NegReg', (32, 41))
223252	26675762	AGRP has also been shown to prevent a decrease in food intake in sarcoma-bearing mice.	('sarcoma', 'Disease', (65, 72))	('mice', 'Species', '10090', (81, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('food intake', 'CPA', (50, 61))	('decrease', 'NegReg', (38, 46))	('AGRP', 'Var', (0, 4))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))
223266	26675762	In HEK293 cells, dominant negative mutants of dynamin-1 prevent internalization of the MC4R when it is stimulated by alpha-MSH.	('negative', 'NegReg', (26, 34))	('mutants', 'Var', (35, 42))	('internalization', 'MPA', (64, 79))	('HEK293', 'CellLine', 'CVCL:0045', (3, 9))	('alpha-MSH', 'Gene', '5443', (117, 126))	('prevent', 'NegReg', (56, 63))	('alpha-MSH', 'Gene', (117, 126))	('MC4R', 'Protein', (87, 91))	('dynamin-1', 'Gene', (46, 55))
223267	26675762	Stimulation of MCR4 leads to anorexia.	('MCR4', 'Gene', (15, 19))	('Stimulation', 'Var', (0, 11))	('anorexia', 'Phenotype', 'HP:0002039', (29, 37))	('anorexia', 'Gene', (29, 37))	('anorexia', 'Gene', '11743', (29, 37))
223270	26675762	Cyclooxygenase-1 inhibition reduces cancer-induced anorexia.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('anorexia', 'Gene', '11743', (51, 59))	('Cyclooxygenase-1', 'Gene', (0, 16))	('reduces', 'NegReg', (28, 35))	('anorexia', 'Phenotype', 'HP:0002039', (51, 59))	('cancer', 'Disease', (36, 42))	('anorexia', 'Gene', (51, 59))	('inhibition', 'Var', (17, 27))	('Cyclooxygenase-1', 'Gene', '5742', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
223273	26675762	Central administration of an antisense to a guanine nucleotide-binding protein (Galphao) subunit slows weight recovery in rats following starvation.	('weight recovery', 'CPA', (103, 118))	('antisense', 'Var', (29, 38))	('rats', 'Species', '10116', (122, 126))	('rat', 'Species', '10116', (16, 19))	('slows', 'NegReg', (97, 102))	('Galphao', 'Gene', '14681', (80, 87))	('rat', 'Species', '10116', (122, 125))	('Galphao', 'Gene', (80, 87))
223283	26675762	There are several mechanisms of zinc deficiency in cancer patients: low albumin reducing zinc binding, anorexia contributing to low intake, ubiquitin-proteasome activation causing accumulation and wasting in muscle cells, gastrointestinal loss, diversion of zinc away from muscle production, and increased urinary excretion of zinc.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('low', 'Var', (68, 71))	('anorexia', 'Gene', (103, 111))	('zinc deficiency', 'Phenotype', 'HP:0031831', (32, 47))	('ubiquitin-proteasome', 'Protein', (140, 160))	('albumin', 'Protein', (72, 79))	('urinary excretion of zinc', 'MPA', (306, 331))	('gastrointestinal loss', 'Disease', 'MESH:D005767', (222, 243))	('reducing', 'NegReg', (80, 88))	('activation', 'PosReg', (161, 171))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('gastrointestinal loss', 'Disease', (222, 243))	('increased', 'PosReg', (296, 305))	('zinc', 'MPA', (89, 93))	('patients', 'Species', '9606', (58, 66))	('wasting in muscle', 'Phenotype', 'HP:0003202', (197, 214))	('low albumin', 'Phenotype', 'HP:0003073', (68, 79))	('increased urinary excretion', 'Phenotype', 'HP:0002914', (296, 323))	('zinc deficiency', 'Disease', (32, 47))	('zinc deficiency', 'Disease', 'MESH:C564286', (32, 47))	('binding', 'Interaction', (94, 101))	('anorexia', 'Gene', '11743', (103, 111))	('anorexia', 'Phenotype', 'HP:0002039', (103, 111))	('diversion', 'Reg', (245, 254))	('accumulation', 'PosReg', (180, 192))	('cancer', 'Disease', (51, 57))
223302	26675762	Normal doses of megestrol used to enhance appetite are between 600 and 800 mg. A Cochrane meta-analysis found that megestrol increased weight [risk ratio 1.55 (1.06-2.26), appetite 2.57 (1.48-4.49)] and quality of life (1.02-3.59) in cancer patients.	('appetite', 'CPA', (172, 180))	('rat', 'Species', '10116', (148, 151))	('increased', 'PosReg', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('weight [', 'CPA', (135, 143))	('megestrol', 'Var', (115, 124))	('enhance appetite', 'Phenotype', 'HP:0002591', (34, 50))	('increased weight', 'Phenotype', 'HP:0004324', (125, 141))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('megestrol', 'Chemical', 'MESH:D008535', (115, 124))	('megestrol', 'Chemical', 'MESH:D008535', (16, 25))	('cancer', 'Disease', (234, 240))	('patients', 'Species', '9606', (241, 249))	('quality of life', 'CPA', (203, 218))
223320	26675762	In patients with AIDS anorexia, dronabinol improved appetite and mood and decreased nausea compared with placebo.	('improved appetite', 'Phenotype', 'HP:0004396', (43, 60))	('anorexia', 'Phenotype', 'HP:0002039', (22, 30))	('appetite', 'CPA', (52, 60))	('nausea', 'Disease', 'MESH:D009325', (84, 90))	('patients', 'Species', '9606', (3, 11))	('nausea', 'Disease', (84, 90))	('dronabinol', 'Chemical', 'MESH:D013759', (32, 42))	('decreased', 'NegReg', (74, 83))	('dronabinol', 'Var', (32, 42))	('improved', 'PosReg', (43, 51))	('nausea', 'Phenotype', 'HP:0002018', (84, 90))	('mood', 'CPA', (65, 69))	('AIDS anorexia', 'Disease', (17, 30))	('AIDS anorexia', 'Disease', 'MESH:D000855', (17, 30))
223349	24058630	Simultaneous Activation of Kras and Inactivation of p53 Induces Soft Tissue Sarcoma and Bladder Urothelial Hyperplasia The development of the Cre recombinase-controlled (Cre/LoxP) technique allows the manipulation of specific tumorigenic genes, temporarily and spatially.	('Sarcoma and Bladder Urothelial Hyperplasia', 'Disease', 'MESH:D001745', (76, 118))	('Soft Tissue Sarcoma', 'Phenotype', 'HP:0030448', (64, 83))	('Induces', 'Reg', (56, 63))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '22059', (52, 55))	('Sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Bladder Urothelial Hyperplasia', 'Phenotype', 'HP:0008635', (88, 118))	('Inactivation', 'Var', (36, 48))	('Kras', 'Gene', (27, 31))	('Kras', 'Gene', '16653', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (226, 231))
223350	24058630	Our original intention of this study was to investigate the role of Kras and p53 in the development of urinary bladder cancer.	('urinary bladder cancer', 'Disease', 'MESH:D001749', (103, 125))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '22059', (77, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('urinary bladder cancer', 'Disease', (103, 125))	('Kras', 'Var', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
223359	24058630	In conclusion, we observed that the simultaneous inactivation of p53 and activation of Kras induces quick formation of spindle-cell sarcoma in the soft tissues adjacent to the bladder but slow formation of urothelial hyperplasia inside the bladder.	('activation', 'PosReg', (73, 83))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '22059', (65, 68))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))	('sarcoma', 'Disease', (132, 139))	('inactivation', 'Var', (49, 61))	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (206, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('Kras', 'Gene', (87, 91))	('urothelial hyperplasia', 'Disease', (206, 228))
223363	24058630	p53 is a nuclear phosphoprotein that plays a central role in controlling cell growth, and its mutations are commonly observed in high-grade urothelial carcinoma.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '22059', (0, 3))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (140, 160))	('mutations', 'Var', (94, 103))	('urothelial carcinoma', 'Disease', (140, 160))	('observed', 'Reg', (117, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
223364	24058630	Interestingly, p53 dysfunction is not common in non-invasive, superficial urothelial tumors, suggesting a role for p53 mutations in promoting tumor invasion.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('urothelial tumors', 'Disease', (74, 91))	('tumor', 'Disease', (142, 147))	('promoting', 'PosReg', (132, 141))	('p53', 'Gene', (15, 18))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '22059', (115, 118))	('p53', 'Gene', '22059', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutations', 'Var', (119, 128))	('urothelial tumors', 'Disease', 'MESH:D001749', (74, 91))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
223365	24058630	In mouse models, it has been shown that p53 deficiency by itself predisposes the urothelium to proliferate, but this alone is not sufficient for bladder tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('deficiency', 'Var', (44, 54))	('mouse', 'Species', '10090', (3, 8))	('p53', 'Gene', (40, 43))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('p53', 'Gene', '22059', (40, 43))	('urothelium', 'CPA', (81, 91))
223366	24058630	On the other hand, the loss of p53 in the context of simultaneously activated Hras is sufficient to promote urothelial tumorigenesis.	('p53', 'Gene', (31, 34))	('tumor', 'Disease', (119, 124))	('p53', 'Gene', '22059', (31, 34))	('promote', 'PosReg', (100, 107))	('Hras', 'Gene', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Hras', 'Gene', '15461', (78, 82))	('loss', 'Var', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
223367	24058630	Previous investigations have reported 4 to 29% in incidence rate of Kras mutations in human urothelial carcinomas.	('urothelial carcinomas', 'Disease', 'MESH:D014526', (92, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('Kras', 'Gene', (68, 72))	('human', 'Species', '9606', (86, 91))	('urothelial carcinomas', 'Disease', (92, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('mutations', 'Var', (73, 82))
223369	24058630	Kras mutations may cooperate with beta-catenin activation to induce urothelial cell carcinoma, consistent with our broad understanding of the Knudson "multiple-hit" hypothesis of tumorigenesis.	('urothelial cell carcinoma', 'Disease', (68, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('Kras', 'Gene', (0, 4))	('beta-catenin', 'Gene', '12387', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('induce', 'Reg', (61, 67))	('urothelial cell carcinoma', 'Disease', 'MESH:C538614', (68, 93))	('beta-catenin', 'Gene', (34, 46))	('tumor', 'Disease', (179, 184))
223370	24058630	Furthermore, the mutant Kras induces neoplastic changes in a wide variety of tumor types, including squamous cell carcinoma of the oral cavity and skin cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('induces', 'Reg', (29, 36))	('skin cancer', 'Phenotype', 'HP:0008069', (147, 158))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (100, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('skin cancer', 'Disease', (147, 158))	('squamous cell carcinoma', 'Disease', (100, 123))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Kras', 'Gene', (24, 28))	('neoplastic changes', 'CPA', (37, 55))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('skin cancer', 'Disease', 'MESH:D012878', (147, 158))	('carcinoma of the oral cavity', 'Phenotype', 'HP:0100649', (114, 142))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('neoplastic changes', 'Phenotype', 'HP:0002664', (37, 55))	('tumor', 'Disease', (77, 82))	('mutant', 'Var', (17, 23))
223385	24058630	Interestingly, as shown in these figures, the dynamic change of beta-galactosidase activity peaked at day 7 after a single intravesical administration of Adeno-Cre (Figure 1B) and eventually faded over the next two (Figure 1C) to four weeks (image not shown).	('activity', 'MPA', (83, 91))	('Adeno-Cre', 'Var', (154, 163))	('beta-galactosidase', 'Gene', (64, 82))	('beta-galactosidase', 'Gene', '12091', (64, 82))	('Adeno-Cre', 'Chemical', '-', (154, 163))
223386	24058630	The level of beta-galactosidase activity observed was dose dependent, as demonstrated by the administration of a half dose of Adeno-Cre (4.23x108 pfu per mouse) (Figure 1D) compared to the dose of 8.46x108 pfu per mouse post 7 days (Figure 1B).	('mouse', 'Species', '10090', (154, 159))	('mouse', 'Species', '10090', (214, 219))	('activity', 'MPA', (32, 40))	('beta-galactosidase', 'Gene', (13, 31))	('4.23x108 pfu', 'Var', (137, 149))	('beta-galactosidase', 'Gene', '12091', (13, 31))	('Adeno-Cre', 'Gene', (126, 135))	('Adeno-Cre', 'Chemical', '-', (126, 135))
223399	24058630	B6.129S4-Kras tm4Tyj/J mice have the point mutation G12D in the Kras gene.	('G12D', 'Var', (52, 56))	('G12D', 'Mutation', 'rs121913529', (52, 56))	('Kras', 'Gene', (64, 68))	('mice', 'Species', '10090', (23, 27))
223403	24058630	Cre-mediated recombination deletes these exons, functionally abolishing p53 function.	('abolishing', 'NegReg', (61, 71))	('deletes', 'Var', (27, 34))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '22059', (72, 75))	('function', 'MPA', (76, 84))
223406	24058630	p53 fl/fl mouse as shown in Upper Figure 4, making it possible to simultaneously manipulate both p53 and Kras genes.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '22059', (0, 3))	('mouse', 'Species', '10090', (10, 15))	('p53', 'Gene', (97, 100))	('manipulate', 'Reg', (81, 91))	('Kras genes', 'Gene', (105, 115))	('p53', 'Gene', '22059', (97, 100))	('fl/fl', 'Var', (4, 9))
223438	24058630	Finally, to detect the status of Kras and p53 in both sarcoma tumors and hyperplastic bladder tissue, PCR analysis was performed.	('p53', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('p53', 'Gene', '22059', (42, 45))	('hyperplastic bladder tissue', 'Phenotype', 'HP:0008635', (73, 100))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('sarcoma tumors', 'Disease', (54, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('Kras', 'Var', (33, 37))	('sarcoma tumors', 'Disease', 'MESH:D012509', (54, 68))
223447	24058630	B6.129S4-Gt(ROSA) 26Sor tmlSor/J (#003474), B6.129S4-Kras tm4Tyj/J (#008179), B6.129P2-Trp53 tm1Brn/J (#008462), and C57BL/6J (#000664) mice were purchased from Jackson Laboratory (Bar Harbor, ME, USA).	('mice', 'Species', '10090', (136, 140))	('B6.129S4-Kras', 'Var', (44, 57))	('#008462', 'Var', (103, 110))	('Trp53', 'Gene', (87, 92))	('#008179', 'Var', (68, 75))	('Trp53', 'Gene', '22059', (87, 92))	('#003474', 'Var', (34, 41))
223488	24058630	Transgenic models of bladder carcinogenesis, using the uroplakin II gene (UPII) to drive urothelium specific expression of SV40T antigen crossed with a cre transgenic strain model, developed by Dr. Wu and his coworkers, has been described.	('transgenic', 'Species', '10090', (156, 166))	('Transgenic', 'Species', '10090', (0, 10))	('uroplakin II', 'Gene', '22269', (55, 67))	('uroplakin II', 'Gene', (55, 67))	('UPII', 'Gene', '22269', (74, 78))	('SV40T', 'Var', (123, 128))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (21, 43))	('bladder carcinogenesis', 'Disease', (21, 43))	('UPII', 'Gene', (74, 78))
223490	24058630	Recently, a two hit (Kras activation and p53 inactivation) transgenic mice model has been reported to accelerate formation of oral and lung cancers.	('formation', 'CPA', (113, 122))	('lung cancers', 'Phenotype', 'HP:0100526', (135, 147))	('accelerate', 'PosReg', (102, 112))	('inactivation', 'Var', (45, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('lung cancers', 'Disease', (135, 147))	('p53', 'Gene', '22059', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancers', 'Disease', 'MESH:D008175', (135, 147))	('p53', 'Gene', (41, 44))	('transgenic mice', 'Species', '10090', (59, 74))
223491	24058630	Using a laparotomy technique for the delivery of Adeno-Cre, another group has reported gene deletion exclusively in the epithelium of the bladder by inducing "invasive bladder cancer."	('bladder cancer', 'Phenotype', 'HP:0009725', (168, 182))	('Adeno-Cre', 'Chemical', '-', (49, 58))	('gene deletion', 'Var', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('inducing', 'Reg', (149, 157))	('invasive bladder', 'Phenotype', 'HP:0100645', (159, 175))	('bladder cancer', 'Disease', 'MESH:D001749', (168, 182))	('bladder cancer', 'Disease', (168, 182))
223500	24058630	This observation is in accordance with a previous study that direct delivery of Adeno-Cre into soft tissue of Kras LSLG12D/+ p53 fl/fl mice induces sarcoma formation.	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('induces', 'Reg', (140, 147))	('sarcoma', 'Disease', (148, 155))	('Adeno-Cre', 'Chemical', '-', (80, 89))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '22059', (125, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('G12D', 'Mutation', 'rs121913529', (118, 122))	('mice', 'Species', '10090', (135, 139))	('Adeno-Cre', 'Var', (80, 89))
223510	24058630	Interestingly, results from other studies demonstrated that the combinations of p53 with pRb and Kras with beta-catenin were sufficient to drive bladder tumorigenesis.	('combinations', 'Var', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('beta-catenin', 'Gene', (107, 119))	('pRb', 'Gene', '19645', (89, 92))	('p53', 'Gene', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('pRb', 'Gene', (89, 92))	('p53', 'Gene', '22059', (80, 83))	('beta-catenin', 'Gene', '12387', (107, 119))	('drive bladder', 'Phenotype', 'HP:0100645', (139, 152))	('bladder', 'Disease', (145, 152))	('drive', 'PosReg', (139, 144))
223511	24058630	Supporting our proposed microenvironment hypothesis, a recent study from the same research group using mice with Kras or beta-catenin and FGFR-3 mutations plus the uroplakin II Cre promoter, demonstrated expontaneous induction of tumorigenesis in the skin (UroIICre+ Fgfr 3+/K644E Kras G12D/+ mice) and lung skin (UroIICre+ Fgfr 3+/K644E beta-catenin exon3/+ mice) but not in the urinary bladder when animals were 1 year old.	('mutations', 'Var', (145, 154))	('beta-catenin', 'Gene', (121, 133))	('FGFR-3', 'Gene', '14184', (138, 144))	('K644E', 'Mutation', 'p.K644E', (275, 280))	('uroplakin II', 'Gene', (164, 176))	('FGFR-3', 'Gene', (138, 144))	('uroplakin II', 'Gene', '22269', (164, 176))	('beta-catenin', 'Gene', '12387', (338, 350))	('tumor', 'Disease', (230, 235))	('G12D', 'Mutation', 'rs121913529', (286, 290))	('beta-catenin', 'Gene', (338, 350))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('mice', 'Species', '10090', (359, 363))	('mice', 'Species', '10090', (103, 107))	('mice', 'Species', '10090', (293, 297))	('K644E', 'Mutation', 'p.K644E', (332, 337))	('tumorigenesis in the skin', 'Phenotype', 'HP:0008069', (230, 255))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('beta-catenin', 'Gene', '12387', (121, 133))
223524	20588273	Mutational analysis could be performed in 106 tumour samples (74%), and 71 (67%) had exon 11 mutations.	('exon 11 mutations', 'Var', (85, 102))	('tumour', 'Disease', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
223525	20588273	PDGFRA mutations were found in 16% of cases, which is twice as high as previously reported for advanced GIST.	('PDGFRA', 'Gene', (0, 6))	('PDGFRA', 'Gene', '5156', (0, 6))	('found', 'Reg', (22, 27))	('GIST', 'Phenotype', 'HP:0100723', (104, 108))	('mutations', 'Var', (7, 16))
223526	20588273	Data indicate that PDGFRA mutations in localised GIST may be twice as high as what was previously reported in patients with advanced disease.	('mutations', 'Var', (26, 35))	('GIST', 'Phenotype', 'HP:0100723', (49, 53))	('PDGFRA', 'Gene', (19, 25))	('PDGFRA', 'Gene', '5156', (19, 25))	('patients', 'Species', '9606', (110, 118))
223530	20588273	These activating mutations affect primarily the exons 9 and 11 of KIT, but may also be found on exons 8, 13 and 17 of KIT and exons 12, 14 and 18 of PDGFRA.	('KIT', 'Gene', (66, 69))	('activating', 'PosReg', (6, 16))	('PDGFRA', 'Gene', '5156', (149, 155))	('PDGFRA', 'Gene', (149, 155))	('mutations', 'Var', (17, 26))	('affect', 'Reg', (27, 33))
223531	20588273	The relative frequency of the different KIT and PDGFRA mutations in patients with advanced GIST has been previously reported.	('PDGFRA', 'Gene', '5156', (48, 54))	('GIST', 'Phenotype', 'HP:0100723', (91, 95))	('PDGFRA', 'Gene', (48, 54))	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (68, 76))	('KIT', 'Gene', (40, 43))
223532	20588273	The frequency of KIT and PDGFRA mutations in localised GIST has been reported in a single-institution study from Italy.	('PDGFRA', 'Gene', (25, 31))	('PDGFRA', 'Gene', '5156', (25, 31))	('mutations', 'Var', (32, 41))	('GIST', 'Phenotype', 'HP:0100723', (55, 59))	('KIT', 'Gene', (17, 20))
223533	20588273	Other preliminary reports indicate that PDGFRA mutations may be higher in localised than metastatic GIST, which may reflect their more favourable prognosis.	('mutations', 'Var', (47, 56))	('metastatic GIST', 'Disease', (89, 104))	('higher', 'Reg', (64, 70))	('GIST', 'Phenotype', 'HP:0100723', (100, 104))	('PDGFRA', 'Gene', (40, 46))	('localised', 'Disease', (74, 83))	('PDGFRA', 'Gene', '5156', (40, 46))
223534	20588273	Two recent autopsy series have shown that the incidence of GIST may be as high as 50% in stomach specimens; in one of these series, canonical KIT or PDGFRA mutations were found in 50% of assessable tumours.	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('tumours', 'Disease', 'MESH:D009369', (198, 205))	('mutations', 'Var', (156, 165))	('PDGFRA', 'Gene', '5156', (149, 155))	('PDGFRA', 'Gene', (149, 155))	('GIST', 'Phenotype', 'HP:0100723', (59, 63))	('tumours', 'Disease', (198, 205))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))
223561	20588273	The majority of samples harboured KIT mutations (n=71 of 106, 67%), and no KIT or PDGFRA mutations was found in 18 patients (17%).	('PDGFRA', 'Gene', (82, 88))	('patients', 'Species', '9606', (115, 123))	('harboured', 'Reg', (24, 33))	('mutations', 'Var', (38, 47))	('KIT', 'Gene', (34, 37))	('PDGFRA', 'Gene', '5156', (82, 88))
223562	20588273	Seventeen tumours (16%) harboured PDGFRA mutations, 15 tumours originated from the stomach (14 with PDGFRA exon 18 and one PDGFRA exon 12), one from the peritoneum (omentum, PDGFRA exon 18 mutation) and one from the small bowel (PDGFRA exon 12 mutation).	('PDGFRA', 'Gene', '5156', (229, 235))	('PDGFRA', 'Gene', (229, 235))	('mutations', 'Var', (41, 50))	('tumours', 'Disease', (10, 17))	('PDGFRA', 'Gene', '5156', (100, 106))	('small bowel', 'Disease', (216, 227))	('PDGFRA', 'Gene', (100, 106))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('small bowel', 'Disease', 'MESH:D015212', (216, 227))	('PDGFRA', 'Gene', '5156', (123, 129))	('PDGFRA', 'Gene', '5156', (34, 40))	('PDGFRA', 'Gene', (123, 129))	('PDGFRA', 'Gene', (34, 40))	('tumours', 'Disease', (55, 62))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('15 tumours', 'Disease', (52, 62))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Disease', 'MESH:D009369', (55, 62))	('PDGFRA', 'Gene', (174, 180))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('15 tumours', 'Disease', 'MESH:C567447', (52, 62))	('PDGFRA', 'Gene', '5156', (174, 180))
223563	20588273	In addition, 10 patients (9%) had tumours with exon 9 mutations, 8 of which originated from the small bowel (including the duodenum), one from the rectum and one from the pelvis.	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (16, 24))	('small bowel', 'Disease', (96, 107))	('originated', 'Reg', (76, 86))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('exon 9 mutations', 'Var', (47, 63))	('tumours', 'Disease', (34, 41))	('small bowel', 'Disease', 'MESH:D015212', (96, 107))
223564	20588273	The relative frequencies of KIT exon 11, KIT exon 9 and PDGFRA mutations are described in Table 3.	('mutations', 'Var', (63, 72))	('KIT exon 11', 'Gene', (28, 39))	('PDGFRA', 'Gene', '5156', (56, 62))	('PDGFRA', 'Gene', (56, 62))	('KIT exon 9', 'Gene', (41, 51))
223565	20588273	When considering only patients with localised disease for whom molecular data were available (n=94), KIT exon 9, 11, 13 and 17 mutations were found in 9 (10%), 49 (52%), 3 (3%) and 1 (1%) patient, respectively, whereas PDGFRA mutations were found in 14 (15%) patients (exon 18, n=12 and exon 12, n=2), and 18 (19%) patients had KIT and PDGFRA wild-type tumours.	('tumours', 'Phenotype', 'HP:0002664', (353, 360))	('tumours', 'Disease', 'MESH:D009369', (353, 360))	('PDGFRA', 'Gene', '5156', (219, 225))	('PDGFRA', 'Gene', (219, 225))	('tumour', 'Phenotype', 'HP:0002664', (353, 359))	('patients', 'Species', '9606', (259, 267))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (315, 323))	('mutations', 'Var', (127, 136))	('found', 'Reg', (142, 147))	('patient', 'Species', '9606', (22, 29))	('patient', 'Species', '9606', (315, 322))	('patient', 'Species', '9606', (188, 195))	('mutations', 'Var', (226, 235))	('patient', 'Species', '9606', (259, 266))	('PDGFRA', 'Gene', (336, 342))	('PDGFRA', 'Gene', '5156', (336, 342))	('tumours', 'Disease', (353, 360))	('exon', 'Var', (287, 291))
223566	20588273	Of the 14 PDGFRA exon 18 mutations, 13 (93%) involved codon 842, and 10 were D842V substitutions (11%).	('mutations', 'Var', (25, 34))	('PDGFRA', 'Gene', '5156', (10, 16))	('PDGFRA', 'Gene', (10, 16))	('involved', 'Reg', (45, 53))	('D842V', 'Mutation', 'rs121908585', (77, 82))	('D842V', 'Var', (77, 82))
223570	20588273	This was true for all mutations types except for PDGFRA mutants in which 50% of the patients were reclassified as low risk, leaving only 7% of patients in the high-risk group of the AFIP classification (vs 57% when using the NIH classification; Table 4).	('patients', 'Species', '9606', (84, 92))	('PDGFRA', 'Gene', (49, 55))	('mutants', 'Var', (56, 63))	('PDGFRA', 'Gene', '5156', (49, 55))	('patients', 'Species', '9606', (143, 151))
223571	20588273	The distribution of PDGFRA mutant tumours between the low- and high-risk categories was significantly different from that of KIT mutant or wild-type tumours when using the AFIP classification (P=0.005, Kruskal-Wallis test), but not when using the NIH classification (P=0.452, Kruskal-Wallis test).	('tumours', 'Disease', 'MESH:D009369', (149, 156))	('tumours', 'Disease', (149, 156))	('mutant', 'Var', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('PDGFRA', 'Gene', '5156', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('different', 'Reg', (102, 111))	('tumours', 'Disease', (34, 41))	('PDGFRA', 'Gene', (20, 26))
223572	20588273	This difference of distributions is likely the consequence of the association of PDGFRA mutations with tumours of gastric origin.	('tumours', 'Disease', 'MESH:D009369', (103, 110))	('tumours', 'Disease', (103, 110))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (88, 97))	('association', 'Reg', (66, 77))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('PDGFRA', 'Gene', (81, 87))	('PDGFRA', 'Gene', '5156', (81, 87))	('tumours of gastric origin', 'Phenotype', 'HP:0006753', (103, 128))
223575	20588273	One of the key findings is the differences in the frequency of PDGFRA mutations that seem almost twice as high as that reported in patients with advanced disease (Table 5), including in patients with localised disease.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (70, 79))	('PDGFRA', 'Gene', (63, 69))	('PDGFRA', 'Gene', '5156', (63, 69))	('patients', 'Species', '9606', (186, 194))
223576	20588273	These differences may be because of the more indolent behaviour of tumours bearing mutant PDGFRA, whereas some KIT exon 11 and KIT exon 9 mutations have a higher risk of relapse after surgical excision.	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('mutant', 'Var', (83, 89))	('tumours', 'Disease', (67, 74))	('PDGFRA', 'Gene', '5156', (90, 96))	('PDGFRA', 'Gene', (90, 96))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
223577	20588273	Other recently reported series have found somewhat lower frequencies of PDGFRA mutations: reported frequencies of 7.3% in patients with completely resected GIST in a specific population from Brazil.	('PDGFRA', 'Gene', '5156', (72, 78))	('PDGFRA', 'Gene', (72, 78))	('patients', 'Species', '9606', (122, 130))	('GIST', 'Phenotype', 'HP:0100723', (156, 160))	('mutations', 'Var', (79, 88))
223578	20588273	recently reported a large series of GIST with molecular epidemiology and found that PDGFRA mutation were twice as high in localised GIST than that previously reported for patients with advanced disease.	('GIST', 'Phenotype', 'HP:0100723', (36, 40))	('mutation', 'Var', (91, 99))	('localised GIST', 'MPA', (122, 136))	('high', 'Reg', (114, 118))	('patients', 'Species', '9606', (171, 179))	('PDGFRA', 'Gene', '5156', (84, 90))	('PDGFRA', 'Gene', (84, 90))	('GIST', 'Phenotype', 'HP:0100723', (132, 136))
223580	20588273	Furthermore, in contrast with what found, the frequency of KIT exon 9 mutations in patients with localised disease in our series was comparable to that previously reported in patients with advanced disease (approximately 10%) Although the predictive role of KIT mutations have been studied and reported in patients with advanced disease, the precise role of mutations in the biology of localised GISTs and their correlation with prognosis remains debated, although PDGFRA mutations seem associated with a rather indolent course, whereas deletions of KIT exon 11 encompassing codons 557 and 558 were found to have poor prognosis.	('GIST', 'Phenotype', 'HP:0100723', (396, 400))	('KIT exon 11', 'Gene', (550, 561))	('mutations', 'Var', (472, 481))	('patients', 'Species', '9606', (175, 183))	('deletions', 'Var', (537, 546))	('patients', 'Species', '9606', (83, 91))	('PDGFRA', 'Gene', '5156', (465, 471))	('PDGFRA', 'Gene', (465, 471))	('patients', 'Species', '9606', (306, 314))
223582	20588273	PDGFRA exon 18 mutations (D842V), which affect the activation loop of the PDGFRalpha kinase, are biochemically less sensitive to imatinib than the more common KIT exon 11 mutations.	('activation loop', 'MPA', (51, 66))	('sensitive to imatinib', 'MPA', (116, 137))	('PDGFRA', 'Gene', (0, 6))	('PDGFRA', 'Gene', '5156', (0, 6))	('imatinib', 'Chemical', 'MESH:D000068877', (129, 137))	('PDGFRalpha', 'Gene', (74, 84))	('mutations (D842V', 'Var', (15, 31))	('PDGFRalpha', 'Gene', '5156', (74, 84))	('D842V', 'Mutation', 'rs121908585', (26, 31))	('less', 'NegReg', (111, 115))
223584	20588273	It is noteworthy that although 57% of the tumours with PDGFRA mutations in our series were classified as intermediate or high risk according to the NIH consensus, most of these tumours were classified as low or very low risk according to the AFIP risk classification.	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumours', 'Disease', (177, 184))	('PDGFRA', 'Gene', (55, 61))	('PDGFRA', 'Gene', '5156', (55, 61))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))	('mutations', 'Var', (62, 71))
223585	20588273	The main reason for this shift is likely the gastric origin of most of the tumours harbouring PDGFRA mutations (15 of 17, 88%).	('mutations', 'Var', (101, 110))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (75, 82))	('PDGFRA', 'Gene', '5156', (94, 100))	('PDGFRA', 'Gene', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
223678	30601401	Delaying HIV diagnosis among this pediatric population was significantly associated with HIV-associated malignancies, possibly due to immune suppression and high viral load.	('Delaying', 'Var', (0, 8))	('HIV', 'Disease', (9, 12))	('HIV-associated malignancies', 'Disease', (89, 116))	('associated', 'Reg', (73, 83))	('HIV-associated malignancies', 'Disease', 'MESH:D009369', (89, 116))
223736	27501793	Eight patients (five females); 2 solitary fibrous tumor (SFT), 2 undifferentiated pleomorphic sarcoma (UPS), 1 uterine leiomyosarcoma (ULMS), 1 leiomyosarcoma (LMS), 1 desmoplastic small round cell tumor (DSRCT), 1 undifferentiated uterine sarcoma (UUS) between the ages of 36-74 received P + S in combination, following escape from response to P of at least 4 months and one patient with grade II metastatic chondrosarcoma received the combination without initial P (Table 1).	('S', 'Chemical', 'MESH:D013455', (206, 207))	('sarcoma', 'Disease', (94, 101))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (168, 203))	('P + S', 'Var', (289, 294))	('leiomyosarcoma', 'Disease', (119, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('desmoplastic small round cell tumor', 'Disease', (168, 203))	('S', 'Chemical', 'MESH:D013455', (293, 294))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('patients', 'Species', '9606', (6, 14))	('sarcoma', 'Disease', (126, 133))	('S', 'Chemical', 'MESH:D013455', (251, 252))	('S', 'Chemical', 'MESH:D013455', (138, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (65, 101))	('S', 'Chemical', 'MESH:D013455', (162, 163))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (232, 247))	('solitary fibrous tumor', 'Disease', (33, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcoma', 'Disease', 'MESH:D012509', (416, 423))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (144, 158))	('chondrosarcoma', 'Disease', 'MESH:D002813', (409, 423))	('ULMS', 'Phenotype', 'HP:0002891', (135, 139))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (144, 158))	('chondrosarcoma', 'Disease', (409, 423))	('sarcoma', 'Disease', (416, 423))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('P + S', 'Chemical', 'MESH:D010758', (289, 294))	('undifferentiated pleomorphic sarcoma', 'Disease', (65, 101))	('solitary fibrous tumor', 'Disease', 'MESH:D054364', (33, 55))	('patient', 'Species', '9606', (6, 13))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (119, 133))	('LMS', 'Phenotype', 'HP:0100243', (160, 163))	('S', 'Chemical', 'MESH:D013455', (57, 58))	('S', 'Chemical', 'MESH:D013455', (105, 106))	('sarcoma', 'Disease', 'MESH:D012509', (240, 247))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (119, 133))	('LMS', 'Phenotype', 'HP:0100243', (136, 139))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (111, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (416, 423))	('sarcoma', 'Disease', (240, 247))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (409, 423))	('leiomyosarcoma', 'Disease', (144, 158))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patient', 'Species', '9606', (376, 383))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('sarcoma', 'Disease', (151, 158))
223747	27501793	Three months later, chest CT demonstrated a new RML lesion and treatment with P + S was resumed (P 200 mg + S 4 mg).	('RML lesion', 'Disease', (48, 58))	('S', 'Chemical', 'MESH:D013455', (108, 109))	('P + S', 'Chemical', 'MESH:D010758', (78, 83))	('RML lesion', 'Disease', 'MESH:D051437', (48, 58))	('S', 'Chemical', 'MESH:D013455', (82, 83))	('P 200 mg + S', 'Var', (97, 109))
223753	27501793	This study was not designed to delineate efficacy by STS subtype, but rather serve as a proof of concept that P + S is an effective way to combat resistance to P and prolong PFS.	('P + S', 'Chemical', 'MESH:D010758', (110, 115))	('S', 'Chemical', 'MESH:D013455', (176, 177))	('PFS', 'MPA', (174, 177))	('P + S', 'Var', (110, 115))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('S', 'Chemical', 'MESH:D013455', (114, 115))	('prolong', 'PosReg', (166, 173))	('STS', 'Phenotype', 'HP:0030448', (53, 56))	('S', 'Chemical', 'MESH:D013455', (53, 54))	('resistance to P', 'MPA', (146, 161))
223773	27501793	Abrogating the mTOR pathway ameliorates angiogenesis induced by FGF2.	('FGF2', 'Gene', (64, 68))	('angiogenesis', 'CPA', (40, 52))	('Abrogating', 'Var', (0, 10))	('mTOR', 'Gene', (15, 19))	('FGF2', 'Gene', '2247', (64, 68))	('mTOR', 'Gene', '2475', (15, 19))	('ameliorates', 'PosReg', (28, 39))
223788	27501793	This patient underwent next generation sequencing (NGS) using the Foundation One test which showed a mutation in TSC2 splice site 2545.	('patient', 'Species', '9606', (5, 12))	('S', 'Chemical', 'MESH:D013455', (114, 115))	('TSC2', 'Gene', '7249', (113, 117))	('S', 'Chemical', 'MESH:D013455', (53, 54))	('TSC2', 'Gene', (113, 117))	('mutation', 'Var', (101, 109))
223791	27501793	A mutation in TSC1 or TSC2 can lead to loss of function and constant activation of the mTORC complex.	('mTOR', 'Gene', (87, 91))	('mTOR', 'Gene', '2475', (87, 91))	('mutation', 'Var', (2, 10))	('TSC1', 'Gene', '7248', (14, 18))	('loss', 'NegReg', (39, 43))	('TSC1', 'Gene', (14, 18))	('TSC2', 'Gene', '7249', (22, 26))	('TSC2', 'Gene', (22, 26))	('activation', 'PosReg', (69, 79))
223792	27501793	This patient had a specific TSC2 mutation that had not been described in malignant tissue in COSMIC as of February 2016.	('patient', 'Species', '9606', (5, 12))	('mutation', 'Var', (33, 41))	('TSC2', 'Gene', '7249', (28, 32))	('TSC2', 'Gene', (28, 32))	('S', 'Chemical', 'MESH:D013455', (29, 30))	('S', 'Chemical', 'MESH:D013455', (95, 96))
223793	27501793	However, it is known that TSC2 splice site alteration affects exon 22 and causes protein truncation.	('causes', 'Reg', (74, 80))	('alteration', 'Var', (43, 53))	('affects', 'Reg', (54, 61))	('protein truncation', 'MPA', (81, 99))	('TSC2', 'Gene', '7249', (26, 30))	('exon 22', 'MPA', (62, 69))	('TSC2', 'Gene', (26, 30))
223813	27501793	Resistance to P eventually develops and the addition of S serves to prolong the chemotherapy-free window.	('addition', 'Var', (44, 52))	('chemotherapy-free window', 'CPA', (80, 104))	('S', 'Chemical', 'MESH:D013455', (56, 57))	('prolong', 'PosReg', (68, 75))
223815	27501793	We suggest that the current results serve as proof of concept for the use of combination P + S after escape from P and should be explored prospectively in a large randomized control trial to evaluate the efficacy of combination therapy in different sarcoma subtypes.	('P + S', 'Chemical', 'MESH:D010758', (89, 94))	('sarcoma subtype', 'Disease', (249, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('P + S', 'Var', (89, 94))	('sarcoma subtype', 'Disease', 'MESH:D012509', (249, 264))
223866	26022107	However, as already shown for colorectal cancer, the overall survival rate seems to be not significantly influenced by the margin width but more by the presence of residual disease (R1-R2 versus R0).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('colorectal cancer', 'Disease', (30, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (30, 47))	('R1-R2', 'Var', (182, 187))	('colorectal cancer', 'Phenotype', 'HP:0003003', (30, 47))
223966	25624890	The immunoreactivity profile of ALK reflects rearrangements in the ALK gene, which is located on chromosome 2p23 and encodes a tyrosine kinase receptor.	('ALK', 'Gene', (32, 35))	('ALK', 'Gene', '238', (67, 70))	('rearrangements', 'Var', (45, 59))	('ALK', 'Gene', '238', (32, 35))	('ALK', 'Gene', (67, 70))
223972	24260303	Inhibition of Survivin Influences the Biological Activities of Canine Histiocytic Sarcoma Cell Lines Canine histiocytic sarcoma (CHS) is an aggressive malignant neoplasm that originates from histiocytic lineage cells, including dendritic cells and macrophages, and is characterized by progressive local infiltration and a very high metastatic potential.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('Histiocytic Sarcoma', 'Disease', 'MESH:D054747', (70, 89))	('Biological', 'MPA', (38, 48))	('Survivin', 'Gene', '442936', (14, 22))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (108, 127))	('neoplasm', 'Phenotype', 'HP:0002664', (161, 169))	('Canine', 'Species', '9615', (63, 69))	('malignant neoplasm', 'Disease', 'MESH:D009369', (151, 169))	('histiocytic sarcoma', 'Disease', (108, 127))	('CHS', 'Disease', (129, 132))	('CHS', 'Disease', 'MESH:D002609', (129, 132))	('Canine', 'Species', '9615', (101, 107))	('Survivin', 'Gene', (14, 22))	('Inhibition', 'Var', (0, 10))	('Sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('Histiocytic Sarcoma', 'Disease', (70, 89))	('malignant neoplasm', 'Disease', (151, 169))
223977	24260303	After transfection with survivin siRNA, apoptosis, cell growth inhibition, enhanced chemosensitivity, and weakened phagocytic activities were observed in all CHS cell lines.	('cell growth inhibition', 'CPA', (51, 73))	('enhanced', 'PosReg', (75, 83))	('apoptosis', 'CPA', (40, 49))	('survivin', 'Gene', '442936', (24, 32))	('survivin', 'Gene', (24, 32))	('transfection', 'Var', (6, 18))	('phagocytic activities', 'CPA', (115, 136))	('weakened', 'NegReg', (106, 114))	('CHS', 'Disease', (158, 161))	('CHS', 'Disease', 'MESH:D002609', (158, 161))	('chemosensitivity', 'CPA', (84, 100))
223978	24260303	In contrast, normal canine fibroblasts were not significantly affected by survivin knockdown.	('survivin', 'Gene', '442936', (74, 82))	('knockdown', 'Var', (83, 92))	('survivin', 'Gene', (74, 82))	('canine', 'Species', '9615', (20, 26))
223991	24260303	Such RNAi-mediated knockdown of gene expression has been successfully observed in human and canine cells cultured in vitro, and inhibition of survivin expression has been achieved using this technology.	('gene expression', 'MPA', (32, 47))	('inhibition', 'NegReg', (128, 138))	('survivin', 'Gene', '442936', (142, 150))	('knockdown', 'Var', (19, 28))	('survivin', 'Gene', (142, 150))	('expression', 'MPA', (151, 161))	('canine', 'Species', '9615', (92, 98))	('human', 'Species', '9606', (82, 87))
224066	24260303	After transfection with survivin siRNA, the viability of all CHS cells was significantly decreased as compared to that of the control.	('viability', 'CPA', (44, 53))	('survivin', 'Gene', '442936', (24, 32))	('survivin', 'Gene', (24, 32))	('transfection', 'Var', (6, 18))	('CHS', 'Disease', (61, 64))	('CHS', 'Disease', 'MESH:D002609', (61, 64))	('decreased', 'NegReg', (89, 98))
224068	24260303	Of the CHS cell lines, CTT and LHS cells exhibited the greatest difference in cell viability in response to survivin knockdown when compared to the other 2 CHS cell lines.	('survivin', 'Gene', '442936', (108, 116))	('CHS', 'Disease', 'MESH:D002609', (156, 159))	('survivin', 'Gene', (108, 116))	('CHS', 'Disease', (7, 10))	('CHS', 'Disease', 'MESH:D002609', (7, 10))	('knockdown', 'Var', (117, 126))	('cell viability', 'CPA', (78, 92))	('CHS', 'Disease', (156, 159))
224077	24260303	In addition, survivin knock-down weakened the Hoechst efflux activity that Hoechst 33342 staining intensity increased in the nuclear and cell membrane of all CHS cell lines as compared to control and scrambled siRNA-transfected cells (Fig.	('knock-down', 'Var', (22, 32))	('Hoechst 33342 staining intensity', 'MPA', (75, 107))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (75, 88))	('Hoechst', 'Chemical', '-', (75, 82))	('Hoechst', 'Chemical', '-', (46, 53))	('weakened', 'NegReg', (33, 41))	('survivin', 'Gene', '442936', (13, 21))	('increased', 'PosReg', (108, 117))	('CHS', 'Disease', (158, 161))	('CHS', 'Disease', 'MESH:D002609', (158, 161))	('Hoechst efflux activity', 'MPA', (46, 69))	('survivin', 'Gene', (13, 21))
224080	24260303	After transfection with survivin siRNA, total number of phagocytosed latex beads in 2 of the 4 CHS cell lines (CHS-4 and DH82) was significantly decreased as compared to control cells (median values; 58% and 36% of control cells, respectively).	('survivin', 'Gene', '442936', (24, 32))	('CHS', 'Disease', (95, 98))	('CHS', 'Disease', 'MESH:D002609', (111, 114))	('survivin', 'Gene', (24, 32))	('transfection', 'Var', (6, 18))	('CHS', 'Disease', 'MESH:D002609', (95, 98))	('decreased', 'NegReg', (145, 154))	('latex', 'Chemical', 'MESH:D007840', (69, 74))	('CHS', 'Disease', (111, 114))
224088	24260303	Cell viability was significantly decreased in all CHS cell lines, but not normal canine fibroblasts, following transfection with survivin siRNA.	('CHS', 'Disease', (50, 53))	('canine', 'Species', '9615', (81, 87))	('Cell viability', 'CPA', (0, 14))	('CHS', 'Disease', 'MESH:D002609', (50, 53))	('survivin', 'Gene', '442936', (129, 137))	('decreased', 'NegReg', (33, 42))	('survivin', 'Gene', (129, 137))	('transfection', 'Var', (111, 123))
224090	24260303	Therefore, inhibition of survivin could preferentially block cell division.	('survivin', 'Gene', '442936', (25, 33))	('survivin', 'Gene', (25, 33))	('block', 'NegReg', (55, 60))	('cell division', 'CPA', (61, 74))	('inhibition', 'Var', (11, 21))
224091	24260303	In the present study, differences in the viabilities of 4 CHS cell lines were detected at 24 h after transfection with survivin siRNA, while other phenomena, including enhanced chemosensitivities and decreased phagocytic activity, were detected at 48 h after transfection.	('phagocytic activity', 'CPA', (210, 229))	('enhanced', 'PosReg', (168, 176))	('chemosensitivities', 'CPA', (177, 195))	('decreased', 'NegReg', (200, 209))	('CHS', 'Disease', (58, 61))	('CHS', 'Disease', 'MESH:D002609', (58, 61))	('transfection', 'Var', (101, 113))	('survivin', 'Gene', '442936', (119, 127))	('survivin', 'Gene', (119, 127))
224092	24260303	Thus, we suggested that inhibition of survivin might induce a preferential decrease in cell viability by apoptosis and delay the progressive pathological process of CHS cells, which have comparatively high cell growth potential in different types of CHS cells.	('CHS', 'Disease', (250, 253))	('decrease', 'NegReg', (75, 83))	('cell viability', 'CPA', (87, 101))	('delay', 'NegReg', (119, 124))	('apoptosis', 'CPA', (105, 114))	('survivin', 'Gene', (38, 46))	('survivin', 'Gene', '442936', (38, 46))	('CHS', 'Disease', 'MESH:D002609', (250, 253))	('progressive pathological process', 'CPA', (129, 161))	('inhibition', 'Var', (24, 34))	('CHS', 'Disease', (165, 168))	('CHS', 'Disease', 'MESH:D002609', (165, 168))
224093	24260303	After transfection with survivin siRNA, the sensitivities of CHS cells to CCNU and DOX were significantly increased as compared to that of control cells.	('CCNU', 'Gene', (74, 78))	('sensitivities', 'MPA', (44, 57))	('survivin', 'Gene', '442936', (24, 32))	('survivin', 'Gene', (24, 32))	('transfection', 'Var', (6, 18))	('CHS', 'Disease', (61, 64))	('CCNU', 'Gene', '487208', (74, 78))	('DOX', 'Chemical', 'MESH:D004317', (83, 86))	('CHS', 'Disease', 'MESH:D002609', (61, 64))	('increased', 'PosReg', (106, 115))
224095	24260303	Some research groups have reported that inhibition of survivin may prevent acquisition of chemoresistance by anti-apoptotic mechanisms or enhancement of cytological telomerase activity, which prolongs the apoptotic process.	('inhibition', 'Var', (40, 50))	('cytological telomerase', 'CPA', (153, 175))	('enhancement', 'PosReg', (138, 149))	('activity', 'MPA', (176, 184))	('prolongs', 'PosReg', (192, 200))	('apoptotic process', 'CPA', (205, 222))	('survivin', 'Gene', (54, 62))	('acquisition of chemoresistance', 'CPA', (75, 105))	('survivin', 'Gene', '442936', (54, 62))	('anti-apoptotic mechanisms', 'CPA', (109, 134))	('prevent', 'NegReg', (67, 74))
224104	24260303	After transfection with survivin siRNA, phagocytic activity was decreased in all CHS cell lines, and significant differences were observed in 2 of the 4 CHS cells.	('CHS', 'Disease', (153, 156))	('CHS', 'Disease', (81, 84))	('survivin', 'Gene', '442936', (24, 32))	('survivin', 'Gene', (24, 32))	('transfection', 'Var', (6, 18))	('CHS', 'Disease', 'MESH:D002609', (153, 156))	('CHS', 'Disease', 'MESH:D002609', (81, 84))	('phagocytic activity', 'CPA', (40, 59))	('decreased', 'NegReg', (64, 73))
224108	24260303	Thus, the weakened phagocytic activity resulting from survivin knockdown in CHS cell lines may be the indirect result of survivin inhibition rather than a direct consequence of survivin inhibition.	('CHS', 'Disease', (76, 79))	('CHS', 'Disease', 'MESH:D002609', (76, 79))	('survivin', 'Gene', '442936', (121, 129))	('survivin', 'Gene', (121, 129))	('inhibition', 'NegReg', (130, 140))	('survivin', 'Gene', '442936', (177, 185))	('weakened', 'NegReg', (10, 18))	('survivin', 'Gene', (54, 62))	('survivin', 'Gene', (177, 185))	('phagocytic activity', 'CPA', (19, 38))	('survivin', 'Gene', '442936', (54, 62))	('knockdown', 'Var', (63, 72))
224109	24260303	However, not all cell lines responded to knockdown of survivin to the same extent; CTT and LHS cells had low phagocytic activity before survivin knockdown compared to other cell lines.	('survivin', 'Gene', '442936', (136, 144))	('low', 'NegReg', (105, 108))	('knockdown', 'Var', (145, 154))	('survivin', 'Gene', (136, 144))	('survivin', 'Gene', '442936', (54, 62))	('survivin', 'Gene', (54, 62))	('phagocytic activity', 'CPA', (109, 128))
224112	24260303	One such inhibitor is YM155, a small-molecule suppressor of survivin activity, and phase II clinical trials are currently underway YM155 in human cancer patients.	('YM155', 'Var', (131, 136))	('cancer', 'Disease', (146, 152))	('human', 'Species', '9606', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('patients', 'Species', '9606', (153, 161))	('YM155', 'Chemical', 'MESH:C523798', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('survivin', 'Gene', '442936', (60, 68))	('YM155', 'Chemical', 'MESH:C523798', (131, 136))	('survivin', 'Gene', (60, 68))
224115	24260303	In this study, we demonstrated that knockdown of survivin using siRNA induced changes in cell appearance and cell viability in all CHS cell lines tested, which were established from several different sites of primary lesions; moreover, knockdown of survivin also affected DH82 cells, which originated from macrophages.	('affected', 'Reg', (263, 271))	('survivin', 'Gene', '442936', (49, 57))	('cell viability', 'CPA', (109, 123))	('CHS', 'Disease', 'MESH:D002609', (131, 134))	('survivin', 'Gene', (49, 57))	('changes', 'Reg', (78, 85))	('knockdown', 'Var', (236, 245))	('cell appearance', 'CPA', (89, 104))	('survivin', 'Gene', '442936', (249, 257))	('survivin', 'Gene', (249, 257))	('CHS', 'Disease', (131, 134))
224116	24260303	In contrast, normal canine fibroblasts were unaffected by inhibition of survivin expression.	('survivin', 'Gene', (72, 80))	('inhibition', 'Var', (58, 68))	('survivin', 'Gene', '442936', (72, 80))	('canine', 'Species', '9615', (20, 26))
224117	24260303	Therefore, these data suggested that survivin inhibitors, including YM155 and EZN-3042, have the potential to be efficacious against CHS.	('EZN-3042', 'Chemical', 'MESH:C552302', (78, 86))	('CHS', 'Disease', (133, 136))	('YM155', 'Chemical', 'MESH:C523798', (68, 73))	('CHS', 'Disease', 'MESH:D002609', (133, 136))	('EZN-3042', 'Gene', (78, 86))	('YM155', 'Var', (68, 73))	('survivin', 'Gene', '442936', (37, 45))	('survivin', 'Gene', (37, 45))
224119	24260303	In conclusion, the present study demonstrated that inhibition of survivin expression decreased cell viability through the induction of apoptosis, enhancement of chemosensitivity, and weakening of phagocytic activities in CHS cell lines.	('CHS', 'Disease', (221, 224))	('chemosensitivity', 'CPA', (161, 177))	('apoptosis', 'CPA', (135, 144))	('decreased', 'NegReg', (85, 94))	('survivin', 'Gene', '442936', (65, 73))	('survivin', 'Gene', (65, 73))	('enhancement', 'PosReg', (146, 157))	('weakening', 'NegReg', (183, 192))	('CHS', 'Disease', 'MESH:D002609', (221, 224))	('inhibition', 'Var', (51, 61))	('cell viability', 'CPA', (95, 109))
224129	21772794	In the first paper of the special issue, "Epigenetic regulation of apoptosis and cell cycle in osteosarcoma," Kleinerman and K. Rao-Bindal critically discuss frequency and prognostic impact of epigenetic inactivation of p16/p14ARF, HIC1, and RASSF1A in this disease, as well as the possible role of histone H3 lysine 27 monomethylation in osteosarcoma apoptosis.	('p16', 'Gene', '1029', (220, 223))	('RASSF1A', 'Gene', (242, 249))	('osteosarcoma apoptosis', 'Disease', (339, 361))	('osteosarcoma', 'Phenotype', 'HP:0002669', (95, 107))	('HIC1', 'Gene', (232, 236))	('osteosarcoma apoptosis', 'Disease', 'MESH:D012516', (339, 361))	('osteosarcoma', 'Disease', (339, 351))	('osteosarcoma', 'Disease', 'MESH:D012516', (339, 351))	('epigenetic inactivation', 'Var', (193, 216))	('p14ARF', 'Gene', '1029', (224, 230))	('HIC1', 'Gene', '3090', (232, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('osteosarcoma', 'Disease', (95, 107))	('osteosarcoma', 'Disease', 'MESH:D012516', (95, 107))	('lysine', 'Chemical', 'MESH:D008239', (310, 316))	('p16', 'Gene', (220, 223))	('osteosarcoma', 'Phenotype', 'HP:0002669', (339, 351))	('p14ARF', 'Gene', (224, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (344, 351))	('RASSF1A', 'Gene', '11186', (242, 249))
224130	21772794	This provides unique insights into the role of epigenetics as a molecular basis for osteosarcoma development.	('epigenetics', 'Var', (47, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('osteosarcoma', 'Disease', (84, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))
224146	21772794	Savage and L. Mirabello, provides a comprehensive review of the epidemiology of osteosarcoma, and also reviews the known genomic mutations and variants that are associated with osteosarcoma development.	('osteosarcoma', 'Disease', 'MESH:D012516', (177, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('osteosarcoma', 'Disease', (80, 92))	('variants', 'Var', (143, 151))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))	('osteosarcoma', 'Phenotype', 'HP:0002669', (177, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('osteosarcoma', 'Disease', (177, 189))
224148	21772794	Transcription factor fusions involving the EWS gene or one of its relatives FUS or TAF15 in sarcomas or rare leukemias are considered dominant oncogenes.	('leukemias', 'Disease', 'MESH:D007938', (109, 118))	('sarcomas', 'Disease', (92, 100))	('FUS', 'Gene', (76, 79))	('TAF15', 'Gene', '8148', (83, 88))	('FUS', 'Gene', '2521', (76, 79))	('TAF15', 'Gene', (83, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('EWS', 'Gene', '2130', (43, 46))	('EWS', 'Gene', (43, 46))	('leukemias', 'Disease', (109, 118))	('fusions', 'Var', (21, 28))	('leukemias', 'Phenotype', 'HP:0001909', (109, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
224149	21772794	However, since EWS family proteins are ubiquitously expressed housekeeping proteins, allelic rearrangements may result in haploinsufficiency or even a dominant negative effect on the remaining expressed allele.	('haploinsufficiency', 'Disease', 'MESH:D058495', (122, 140))	('EWS', 'Gene', '2130', (15, 18))	('EWS', 'Gene', (15, 18))	('rearrangements', 'Var', (93, 107))	('haploinsufficiency', 'Disease', (122, 140))	('result in', 'Reg', (112, 121))	('negative', 'NegReg', (160, 168))
224153	21772794	In the next article, "Copy number alterations (CNAs) and methylation in Ewing's sarcoma," M. S. Jahromi et al., provide a comprehensive literature review of available data reporting copy number alterations (CNA's), alterations in mitochondrial DNA, and gene silencing by methylation for Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (72, 87))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (287, 302))	('copy number alterations', 'Var', (182, 205))	("Ewing's sarcoma", 'Disease', (72, 87))	('gene', 'Gene', (253, 257))	('methylation', 'Var', (271, 282))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (72, 87))	('alterations', 'Reg', (215, 226))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (287, 302))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	("Ewing's sarcoma", 'Disease', (287, 302))	('mitochondrial DNA', 'MPA', (230, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (295, 302))
224154	21772794	The potential implication of trisomy 8 and 12, gains on chromosome 2q, and deletion or methylation silencing of the CDKN2A (p16-INK4a) locus, or genes involved in the extrinsic death pathway for patient outcome are reviewed.	('p16', 'Gene', '1029', (124, 127))	('CDKN2A', 'Gene', (116, 122))	('patient', 'Species', '9606', (195, 202))	('deletion', 'Var', (75, 83))	('CDKN2A', 'Gene', '1029', (116, 122))	('methylation silencing', 'Var', (87, 108))	('p16', 'Gene', (124, 127))	('INK4a', 'Gene', '1029', (128, 133))	('INK4a', 'Gene', (128, 133))
224179	21772794	The eighteenth article, "Human chondrosarcoma cells acquire an epithelial-like gene expression pattern via an epigenetic switch: evidence for mesenchymal-epithelial transition during sarcomagenesis," by M. P. Fitzgerald et al., provides evidence for epigenetic activation of a set of epithelial markers in chondrosarcomas, and downregulation of snail, as compared to chondrocytes.	('downregulation', 'NegReg', (327, 341))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('chondrosarcomas', 'Disease', 'MESH:D002813', (306, 321))	('Human', 'Species', '9606', (25, 30))	('epigenetic', 'Var', (250, 260))	('snail', 'Gene', '6615', (345, 350))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))	('chondrosarcoma', 'Disease', (31, 45))	('sarcoma', 'Disease', (38, 45))	('chondrosarcoma', 'Disease', 'MESH:D002813', (31, 45))	('chondrosarcomas', 'Disease', (306, 321))	('sarcoma', 'Disease', 'MESH:D012509', (313, 320))	('snail', 'Gene', (345, 350))	('sarcoma', 'Disease', (313, 320))	('sarcomas', 'Phenotype', 'HP:0100242', (313, 321))	('chondrosarcoma', 'Disease', (306, 320))	('chondrosarcoma', 'Disease', 'MESH:D002813', (306, 320))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (31, 45))	('activation', 'PosReg', (261, 271))	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('sarcoma', 'Disease', (183, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (313, 320))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (306, 320))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (306, 321))
224182	21772794	Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous-origin sarcoma associated with constitutive activation of the receptor tyrosine kinase (RTK) PDGFR by chromosomal rearrangement with the collagen gene COL1A1.	('DFSP', 'Disease', 'MESH:D018223', (33, 37))	('Dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (0, 31))	('PDGFR', 'Gene', (152, 157))	('RTK', 'Gene', '5979', (147, 150))	('PDGFR', 'Gene', '5159', (152, 157))	('DFSP', 'Disease', (33, 37))	('chromosomal rearrangement', 'Var', (161, 186))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('sarcoma', 'Disease', (12, 19))	('receptor tyrosine kinase', 'Gene', '5979', (121, 145))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('activation', 'PosReg', (103, 113))	('COL1A1', 'Gene', '1277', (210, 216))	('sarcoma', 'Disease', (66, 73))	('Dermatofibrosarcoma protuberans', 'Disease', (0, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('receptor tyrosine kinase', 'Gene', (121, 145))	('COL1A1', 'Gene', (210, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('RTK', 'Gene', (147, 150))
224191	21772794	In some cases, these molecular changes (such as amplification of MDM2 and CDK4) suggest rational therapeutic approaches for these diseases, which are also reviewed.	('CDK4', 'Gene', '1019', (74, 78))	('CDK4', 'Gene', (74, 78))	('MDM2', 'Gene', '4193', (65, 69))	('MDM2', 'Gene', (65, 69))	('amplification', 'Var', (48, 61))
224271	21317715	ERG has been recently studied immunohisto-chemically in prostate carcinoma, subsets of which have oncogenic TMPRSS2-ERG gene fusions and express ERG protein, and in human tissues, vascular endothelial cells also consistently express ERG.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('human', 'Species', '9606', (165, 170))	('TMPRSS2', 'Gene', '7113', (108, 115))	('fusions', 'Var', (125, 132))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (56, 74))	('prostate carcinoma', 'Disease', (56, 74))	('prostate carcinoma', 'Disease', 'MESH:D011471', (56, 74))	('TMPRSS2', 'Gene', (108, 115))
224274	21317715	Known other entities for ERG-gene fusions, acute myeloid leukemia and Ewing sarcoma, are among rare exceptions on positive non-endothelial neoplasms.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('acute myeloid leukemia', 'Disease', (43, 65))	('neoplasms', 'Phenotype', 'HP:0002664', (139, 148))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (43, 65))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (49, 65))	('neoplasms', 'Disease', 'MESH:D009369', (139, 148))	('Ewing sarcoma', 'Disease', (70, 83))	('neoplasms', 'Disease', (139, 148))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (43, 65))	('ERG-gene', 'Gene', (25, 33))	('fusions', 'Var', (34, 41))	('leukemia', 'Phenotype', 'HP:0001909', (57, 65))
224288	21317715	Monoclonal antibody JC70A to CD31 (Dako Cytomation, Carpinteria, CA), diluted 1:100, with similar epitope retrieval as employed for ERG, was used in the characterization of vascular tumors.	('vascular tumors', 'Phenotype', 'HP:0100742', (173, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('CD31', 'Gene', (29, 33))	('vascular tumors', 'Disease', (173, 188))	('CD31', 'Gene', '5175', (29, 33))	('JC70A', 'Var', (20, 25))	('vascular tumors', 'Disease', 'MESH:D019043', (173, 188))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
224342	21317715	Also, the presence of CD31 in platelets can cause diffuse immunoreactivity in areas of hemorrhage and necrosis, complicating the interpretation of CD31 immunostaining in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cause', 'Reg', (44, 49))	('necrosis', 'Disease', 'MESH:D009336', (102, 110))	('hemorrhage', 'Disease', 'MESH:D006470', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CD31', 'Gene', (22, 26))	('hemorrhage', 'Disease', (87, 97))	('CD31', 'Gene', (147, 151))	('tumor', 'Disease', (170, 175))	('CD31', 'Gene', '5175', (22, 26))	('diffuse immunoreactivity', 'MPA', (50, 74))	('necrosis', 'Disease', (102, 110))	('presence', 'Var', (10, 18))	('CD31', 'Gene', '5175', (147, 151))
224350	21317715	A subset of acute myeloid leukemias (AML) contains ERG-involving gene fusions and express ERG (as measured by mRNA content), and these especially include poor prognosis AMLs.	('myeloid leukemias', 'Phenotype', 'HP:0012324', (18, 35))	('leukemia', 'Phenotype', 'HP:0001909', (26, 34))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (18, 34))	('AML', 'Phenotype', 'HP:0004808', (169, 172))	('gene fusions', 'Var', (65, 77))	('AML', 'Disease', (169, 172))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('AML', 'Disease', 'MESH:D015470', (37, 40))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (12, 35))	('leukemias', 'Phenotype', 'HP:0001909', (26, 35))	('acute myeloid leukemias', 'Disease', (12, 35))	('AML', 'Phenotype', 'HP:0004808', (37, 40))	('AML', 'Disease', (37, 40))	('ERG-involving', 'Gene', (51, 64))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (12, 34))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (12, 35))	('AML', 'Disease', 'MESH:D015470', (169, 172))
224356	21317715	ERG involving gene fusions have been also detected in a rare subset of myxoid liposarcoma.	('gene fusions', 'Var', (14, 26))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (71, 89))	('myxoid liposarcoma', 'Disease', (71, 89))	('liposarcoma', 'Phenotype', 'HP:0012034', (78, 89))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (71, 89))	('ERG involving', 'Gene', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('detected', 'Reg', (42, 50))
224364	21317715	The significance of these observations remains unclear, but possible mechanisms could include sporadic ERG-involving translocations or other gene rearrangements inducing ERG overexpression in non-prostatic carcinomas.	('non-prostatic carcinomas', 'Disease', (192, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('prostatic carcinoma', 'Phenotype', 'HP:0012125', (196, 215))	('overexpression', 'PosReg', (174, 188))	('ERG-involving', 'Gene', (103, 116))	('non-prostatic carcinomas', 'Disease', 'MESH:D011471', (192, 216))	('translocations', 'Var', (117, 131))
224365	21317715	ERG-involving translocations have also been detected in uterine cervical carcinoma lines.	('translocations', 'Var', (14, 28))	('carcinoma', 'Disease', (73, 82))	('ERG-involving', 'Gene', (0, 13))	('detected', 'Reg', (44, 52))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
224379	30581471	Interphase FISH was performed and was positive for a rearrangement involving SYT gene (18q11) consistent with a synovial sarcoma.	('SYT', 'Gene', '6857', (77, 80))	('synovial sarcoma', 'Disease', (112, 128))	('SYT', 'Gene', (77, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (112, 128))	('synovial sarcoma', 'Disease', 'MESH:D013584', (112, 128))	('rearrangement', 'Var', (53, 66))
224385	30581471	Advances in cytogenetics have revealed that the definitive diagnosis of synovial sarcoma can be made only by evidence of a translocation t(X : 18) characterized by fusion of the SYT gene (Figure 5) on chromosome 18 with SSX genes on X chromosome resulting in a chimeric protein.	('SSX', 'Gene', '727837', (220, 223))	('translocation t', 'Var', (123, 138))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (72, 88))	('fusion', 'Var', (164, 170))	('synovial sarcoma', 'Disease', 'MESH:D013584', (72, 88))	('SYT', 'Gene', '6857', (178, 181))	('chimeric protein', 'MPA', (261, 277))	('SSX', 'Gene', (220, 223))	('SYT', 'Gene', (178, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('synovial sarcoma', 'Disease', (72, 88))
224439	30328319	After comparing the two groups (PORT vs. no-PORT), we found no significant differences in patient characteristics, although resection margin showed a marginal difference: rate of R1 or R2 resection was higher in PORT group (p=0.053).	('R2 resection', 'CPA', (185, 197))	('higher', 'PosReg', (202, 208))	('PORT', 'Var', (212, 216))	('patient', 'Species', '9606', (90, 97))
224441	30328319	Radiation dose tended to be higher in patients with R1 or R2 resection than in those with R0 resection (Table 2).	('higher', 'PosReg', (28, 34))	('Radiation dose', 'MPA', (0, 14))	('patients', 'Species', '9606', (38, 46))	('R2 resection', 'Var', (58, 70))
224451	30328319	Patients who did not receive PORT, despite R1 or R2 resection, experienced more recurrences compared to those treated with PORT: 78% versus 47% in patients with R1 resection and 100% versus 67% in those with R2 resection for no-PORT and PORT groups, respectively.	('recurrences', 'CPA', (80, 91))	('patients', 'Species', '9606', (147, 155))	('R2 resection', 'Var', (49, 61))	('Patients', 'Species', '9606', (0, 8))
224473	30328319	Although PORT significantly improved LFFS, the benefit did not lead to improved OS in our study.	('PORT', 'Var', (9, 13))	('OS', 'Chemical', '-', (80, 82))	('LFFS', 'MPA', (37, 41))	('improved', 'PosReg', (28, 36))
224497	30328319	Our results suggest that a radiation dose >45 Gy is necessary to achieve local control, considering that most of the infield recurrences occurred in patients who received <=45 Gy to tumor bed, even in R0 patients, while patients who received radiation >45 Gy had marginal or outfield recurrences only.	('patients', 'Species', '9606', (204, 212))	('patients', 'Species', '9606', (149, 157))	('<=45 Gy', 'Var', (171, 178))	('tumor', 'Disease', (182, 187))	('patients', 'Species', '9606', (220, 228))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
224499	30328319	Four of the five patients who received <=54 Gy had local recurrence (infield in three patients, marginal recurrence in one patient), while only one marginal recurrence occurred among those who received >=65 Gy.	('<=54 Gy', 'Var', (39, 46))	('patient', 'Species', '9606', (123, 130))	('patient', 'Species', '9606', (17, 24))	('local recurrence', 'CPA', (51, 67))	('patient', 'Species', '9606', (86, 93))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (86, 94))
224669	25812730	It is yet uncertain whether SRCTs showing aberrant translocation should be included as a specific entity or be left as undifferentiated or high-grade sarcomas.	('sarcomas', 'Disease', (150, 158))	('SRCTs', 'Disease', (28, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))	('aberrant translocation', 'Var', (42, 64))
224694	25812730	As up to 30% of soft tissue tumors show chromosomal alterations, integration of molecular study in the diagnosis of soft tissue tumors has been recommended.	('soft tissue tumors', 'Disease', (16, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('soft tissue tumors', 'Disease', 'MESH:D012983', (16, 34))	('soft tissue tumors', 'Disease', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('soft tissue tumors', 'Disease', 'MESH:D012983', (116, 134))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (16, 34))	('chromosomal alterations', 'Var', (40, 63))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
224695	25812730	However, accumulating data on these molecular alterations sometimes further complicates the molecular diagnoses of some soft tissue tumors.	('complicates', 'Reg', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('alterations', 'Var', (46, 57))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('soft tissue tumors', 'Disease', (120, 138))	('soft tissue tumors', 'Disease', 'MESH:D012983', (120, 138))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (120, 138))
224721	25812730	Monophasic synovial sarcoma showing epithelial membrane antigen-negative and cytokeratin-negative poorly differentiated one, requires either molecular cytogenetic study to evaluate the specific translocation t(X;18)(p11;q11) or EM examination.	('t(X;18)(p11;q11', 'Var', (208, 223))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (11, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('synovial sarcoma', 'Disease', 'MESH:D013584', (11, 27))	('synovial sarcoma', 'Disease', (11, 27))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (208, 224))
224743	24958807	Recently, preclinical studies have demonstrated an association between ETS gene fusions and components of the DNA damage response pathway, such as poly (ADP)-ribose polymerase 1 (PARP1), the catalytic subunit of DNA protein kinase (DNA-PK), and histone deactylase 1 (HDAC1), and have suggested that ETS fusions may confer sensitivity to inhibitors of these DNA repair proteins.	('HDAC1', 'Gene', (267, 272))	('fusions', 'Var', (80, 87))	('HDAC1', 'Gene', '3065', (267, 272))	('histone deactylase 1', 'Gene', '3065', (245, 265))	('ETS', 'Gene', (71, 74))	('association', 'Interaction', (51, 62))	('DNA-PK', 'Gene', (232, 238))	('clinical', 'Species', '191496', (13, 21))	('histone deactylase 1', 'Gene', (245, 265))	('DNA damage response pathway', 'Pathway', (110, 137))	('DNA-PK', 'Gene', '5591', (232, 238))
224744	24958807	In this review, we discuss the role of ETS fusions in cancer, the preclinical rationale for targeting ETS fusions with inhibitors of PARP1, DNAPK, and HDAC1, as well as ongoing clinical trials targeting ETS gene fusions.	('clinical', 'Species', '191496', (69, 77))	('DNAPK', 'Gene', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('DNAPK', 'Gene', '5591', (140, 145))	('cancer', 'Disease', (54, 60))	('HDAC1', 'Gene', (151, 156))	('PARP1', 'Gene', (133, 138))	('ETS', 'Gene', (102, 105))	('fusions', 'Var', (106, 113))	('clinical', 'Species', '191496', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('HDAC1', 'Gene', '3065', (151, 156))
224747	24958807	Prostate cancer frequently harbors rearrangements of ETS genes, in which ERG (50% of all prostate cancers) and ETV1 (5%) are fused to the androgen-regulated promoter and 5' untranslated region of the TMPRSS2 gene.	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('prostate cancers', 'Disease', 'MESH:D011471', (89, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('rearrangements', 'Var', (35, 49))	('Prostate cancer', 'Disease', (0, 15))	('prostate cancers', 'Phenotype', 'HP:0012125', (89, 105))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('ERG', 'Gene', (73, 76))	('prostate cancers', 'Disease', (89, 105))	('ETS genes', 'Gene', (53, 62))	('ETV1', 'Gene', (111, 115))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('TMPRSS2', 'Gene', (200, 207))
224748	24958807	In addition, almost all Ewing's sarcomas contain an ETS rearrangement, including EWS-FLI1 (~90%) or EWS-ERG (~5-10%) gene fusions, which encode a chimeric protein notable for several features, including: 1) provision of an activation domain (from the EWS gene) to the ETS fusion and 2) replacement of the N-terminus of the ETS protein by an RNA binding domain from the EWS protein that enhances post-transcriptional splicing of ETS target genes (Figure 1).	('enhances', 'PosReg', (386, 394))	('ETS', 'Gene', (52, 55))	('post-transcriptional splicing', 'MPA', (395, 424))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (24, 40))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (24, 39))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (24, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('EWS-FLI1', 'Gene', (81, 89))	('replacement', 'Var', (286, 297))	('EWS-FLI1', 'Gene', '2130;2313', (81, 89))	("Ewing's sarcomas", 'Disease', (24, 40))
224753	24958807	Interestingly, TMPRSS2-ERG overexpression leads to increased self-renewal over multiple plating generations in Sca-1hi/EpCAM+ basal/progenitor cells isolated from genetically engineered mice suggesting a role for ETS fusions in prostate cancer progenitor populations.	('EpCAM', 'Gene', '17075', (119, 124))	('prostate cancer', 'Disease', (228, 243))	('overexpression', 'Var', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('self-renewal', 'CPA', (61, 73))	('increased', 'PosReg', (51, 60))	('prostate cancer', 'Disease', 'MESH:D011471', (228, 243))	('prostate cancer', 'Phenotype', 'HP:0012125', (228, 243))	('mice', 'Species', '10090', (186, 190))	('TMPRSS2-ERG', 'Gene', (15, 26))	('EpCAM', 'Gene', (119, 124))
224755	24958807	Despite this impediment, EWS-FLI1 overexpression has been shown to induce leukemic phenotypes when expressed in hematoepoetic stem cells, to induce skeletal disruption when expressed in mesenchymal progenitors using a PRX1 promoter, and to accelerate tumor formation in conjunction with TP53 deletion.	('skeletal disruption', 'CPA', (148, 167))	('overexpression', 'Var', (34, 48))	('tumor', 'Disease', (251, 256))	('leukemic', 'Disease', (74, 82))	('PRX1', 'Gene', (218, 222))	('induce', 'Reg', (141, 147))	('skeletal disruption', 'Phenotype', 'HP:0000924', (148, 167))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('EWS-FLI1', 'Gene', (25, 33))	('leukemic', 'Disease', 'MESH:D007938', (74, 82))	('accelerate', 'PosReg', (240, 250))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('TP53', 'Gene', '7157', (287, 291))	('EWS-FLI1', 'Gene', '2130;2313', (25, 33))	('PRX1', 'Gene', '5396', (218, 222))	('induce', 'PosReg', (67, 73))	('TP53', 'Gene', (287, 291))
224757	24958807	RNA interference-mediated disruption of either TMPRSS2-ERG or EWS-FLI1 expression inhibits cell proliferation, invasion, metastasis and xenograft growth of prostate cancer or Ewing's sarcoma cell line models that harbor the respective fusions.	("Ewing's sarcoma", 'Disease', (175, 190))	('metastasis', 'CPA', (121, 131))	('EWS-FLI1', 'Gene', '2130;2313', (62, 70))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('disruption', 'Var', (26, 36))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (175, 190))	('growth of prostate cancer', 'Disease', 'MESH:D011471', (146, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('TMPRSS2-ERG', 'Gene', (47, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('EWS-FLI1', 'Gene', (62, 70))	('growth of prostate cancer', 'Disease', (146, 171))	('invasion', 'CPA', (111, 119))	('inhibits', 'NegReg', (82, 90))	('cell proliferation', 'CPA', (91, 109))
224758	24958807	Recently, our group found that both prostate cancer and Ewing's sarcoma ETS gene fusions induce DNA double strand breaks.	('induce', 'Reg', (89, 95))	('prostate cancer', 'Disease', (36, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('DNA double strand breaks', 'MPA', (96, 120))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (56, 71))	('fusions', 'Var', (81, 88))	("Ewing's sarcoma", 'Disease', (56, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (36, 51))	('prostate cancer', 'Phenotype', 'HP:0012125', (36, 51))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (56, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
224768	24958807	Using patient specimens from smaller phase I/II studies of metastatic patients treated with abiraterone, Attard et al found that the presence of the predominant ETS fusion, the TMPRSS2:ERG rearrangement, in circulating tumor cells (CTCs) correlated with prostate-specific antigen (PSA) response.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('patients', 'Species', '9606', (70, 78))	('abiraterone', 'Chemical', 'MESH:C089740', (92, 103))	('prostate-specific antigen', 'Disease', (254, 279))	('tumor', 'Disease', (219, 224))	('rearrangement', 'Var', (189, 202))	('patient', 'Species', '9606', (70, 77))	('patient', 'Species', '9606', (6, 13))	('correlated with', 'Reg', (238, 253))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
224769	24958807	In this study, 38% of patients with ERG fusion-positive CTCs had a >90% decline in PSA level with abiraterone, compared to 7% of patients with ERG-fusion-negative CTCs.	('decline', 'NegReg', (72, 79))	('to 7', 'Species', '1214577', (120, 124))	('abiraterone', 'Chemical', 'MESH:C089740', (98, 109))	('ERG fusion-positive', 'Var', (36, 55))	('patients', 'Species', '9606', (129, 137))	('PSA level', 'MPA', (83, 92))	('patients', 'Species', '9606', (22, 30))
224777	24958807	Preclinical experiments demonstrated that ETS transcription factor activity was dependent on PARP1 expression and that inhibition of PARP1 could potentiate ETS-induced DNA damage leading to a long term loss of cell viability.	('PARP1', 'Gene', (93, 98))	('inhibition', 'Var', (119, 129))	('cell viability', 'CPA', (210, 224))	('potentiate', 'PosReg', (145, 155))	('PARP1', 'Gene', (133, 138))	('loss', 'NegReg', (202, 206))	('clinical', 'Species', '191496', (3, 11))
224781	24958807	Subsequent independent validation of the finding that the EWS-FLI1 fusion is associated with response to PARP1 inhibitors was performed via a high-throughput screen of 639 cell lines against 130 drugs under clinical or preclinical evaluation; this screen likely could not detect similar associations with prostate cancer ETS fusions as it included only one cell line harboring such a fusion.	('EWS-FLI1', 'Gene', '2130;2313', (58, 66))	('prostate cancer', 'Disease', (305, 320))	('clinical', 'Species', '191496', (207, 215))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('PARP1', 'Gene', (105, 110))	('EWS-FLI1', 'Gene', (58, 66))	('clinical', 'Species', '191496', (222, 230))	('prostate cancer', 'Disease', 'MESH:D011471', (305, 320))	('prostate cancer', 'Phenotype', 'HP:0012125', (305, 320))	('fusion', 'Var', (67, 73))	('associated', 'Reg', (77, 87))
224783	24958807	These studies proposed that PARP1 inhibitors cause replication forks to collapse leading to increased DNA damage, which goes unrepaired in the absence of HR, and early clinical studies have suggested that the PARP1 inhibitor olaparib has activity on the context of BRCA mutant cancers.	('PARP1', 'Gene', (28, 33))	('replication forks', 'CPA', (51, 68))	('activity', 'MPA', (238, 246))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('BRCA', 'Gene', '672', (265, 269))	('inhibitors', 'Var', (34, 44))	('collapse', 'NegReg', (72, 80))	('cancers', 'Disease', (277, 284))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('increased', 'PosReg', (92, 101))	('BRCA', 'Gene', (265, 269))	('DNA damage', 'MPA', (102, 112))	('olaparib', 'Chemical', 'MESH:C531550', (225, 233))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('clinical', 'Species', '191496', (168, 176))
224794	24958807	In addition to this study, several Phase I studies including PARP1 inhibitors are currently underway or near completion for patients with any solid tumor; these include the agents BMN-673(NCT01286987), CEP-9722 (NCT01311713), E7016 (NCT01127178), and rucaparib (AG-014699/PF-01367338) (NCT01009190).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Disease', (148, 153))	('NCT01286987', 'Var', (188, 199))	('E7016 (NCT01127178', 'Var', (226, 244))	('NCT01311713', 'Var', (212, 223))	('PARP1', 'Gene', (61, 66))	('rucaparib', 'Chemical', 'MESH:C531549', (251, 260))	('AG-014699/PF-01367338', 'Var', (262, 283))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
224798	24958807	This suggests that certain PARP1 inhibitors may be more effective than others for treating ETS-positive cancers; however, to address this concern, more investigation is needed into the mechanism by which PARP1 inhibitors are cytotoxic in the context of ETS rearrangements.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PARP1', 'Gene', (204, 209))	('inhibitors', 'Var', (210, 220))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('ETS-positive', 'Disease', (91, 103))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
224809	24958807	Given the recently demonstrated cross-talk between androgen receptor signaling and the PI3K pathway in PTEN-deficient prostate cancers, the associations between ERG fusions and PTEN deletion in prostate cancer, and the cooperativity between ERG overexpression and PTEN loss in carcinogenesis, dual targeting of DNA-PK and MTOR has intriguing potential in ETS-positive prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('carcinogenesis', 'Disease', 'MESH:D063646', (277, 291))	('PI3K pathway', 'Pathway', (87, 99))	('PTEN', 'Gene', '5728', (103, 107))	('PTEN-deficient prostate cancers', 'Disease', 'MESH:D006223', (103, 134))	('prostate cancer', 'Disease', 'MESH:D011471', (368, 383))	('prostate cancer', 'Phenotype', 'HP:0012125', (368, 383))	('prostate cancer', 'Disease', 'MESH:D011471', (194, 209))	('prostate cancer', 'Phenotype', 'HP:0012125', (194, 209))	('PTEN loss', 'Disease', 'MESH:D006223', (264, 273))	('DNA-PK', 'Gene', '5591', (311, 317))	('prostate cancer', 'Disease', (368, 383))	('cross-talk', 'Reg', (32, 42))	('prostate cancer', 'Disease', (194, 209))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('deletion', 'Var', (182, 190))	('PTEN', 'Gene', (264, 268))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ERG', 'Gene', (161, 164))	('PTEN loss', 'Disease', (264, 273))	('deficient prostate', 'Phenotype', 'HP:0008687', (108, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (118, 133))	('PTEN', 'Gene', (177, 181))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('prostate cancers', 'Phenotype', 'HP:0012125', (118, 134))	('PTEN-deficient prostate cancers', 'Disease', (103, 134))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('PTEN', 'Gene', (103, 107))	('PTEN', 'Gene', '5728', (264, 268))	('androgen receptor', 'Gene', (51, 68))	('MTOR', 'Gene', (322, 326))	('carcinogenesis', 'Disease', (277, 291))	('PTEN', 'Gene', '5728', (177, 181))	('DNA-PK', 'Gene', (311, 317))	('androgen receptor', 'Gene', '367', (51, 68))	('MTOR', 'Gene', '2475', (322, 326))	('associations', 'Interaction', (140, 152))
224810	24958807	In addition, since mTOR inhibition downregulates the EWS-FLI1 protein and has been demonstrated to synergize with antisense oligonucleotides against EWS-FLI1 (reviewed in), the dual activity of CC-115 provides theoretical advantages in the treatment of Ewing's sarcoma as well.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (253, 268))	('protein', 'Protein', (62, 69))	('CC-115', 'Chemical', 'MESH:C000601954', (194, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('EWS-FLI1', 'Gene', (53, 61))	('EWS-FLI1', 'Gene', '2130;2313', (149, 157))	('mTOR', 'Gene', '2475', (19, 23))	('EWS-FLI1', 'Gene', '2130;2313', (53, 61))	('mTOR', 'Gene', (19, 23))	('inhibition', 'Var', (24, 34))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (253, 268))	('oligonucleotides', 'Chemical', 'MESH:D009841', (124, 140))	('downregulates', 'NegReg', (35, 48))	("Ewing's sarcoma", 'Disease', (253, 268))	('EWS-FLI1', 'Gene', (149, 157))
224813	24958807	In addition, inhibition of HDAC1 repressed ERG and was preferentially sensitive in ERG-positive cell lines.	('HDAC1', 'Gene', '3065', (27, 32))	('inhibition', 'Var', (13, 23))	('HDAC1', 'Gene', (27, 32))	('ERG', 'CPA', (43, 46))
224817	24958807	While recent advances have been made in the preclinical space of targeting ETS fusions with clinically available agents, such as inhibitors of PARP1, DNAPK, and HDAC1, these findings need to be validated in clinical trials.	('DNAPK', 'Gene', (150, 155))	('inhibitors', 'Var', (129, 139))	('HDAC1', 'Gene', (161, 166))	('DNAPK', 'Gene', '5591', (150, 155))	('clinical', 'Species', '191496', (207, 215))	('HDAC1', 'Gene', '3065', (161, 166))	('clinical', 'Species', '191496', (92, 100))	('clinical', 'Species', '191496', (47, 55))	('PARP1', 'Gene', (143, 148))
224827	23320191	Risk factors for tumor development include human immunodeficiency virus (HIV) infection, high anti-HHV-8 antibody titers, HHV-8 viremia, inherited variation in immuno-modulating genes, immunosuppression with steroids or other immuno-suppressants, and absence of tobacco use.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('immunodeficiency', 'Phenotype', 'HP:0002721', (49, 65))	('tumor development', 'CPA', (17, 34))	('HHV-8 viremia', 'Disease', 'MESH:D014766', (122, 135))	('tobacco', 'Species', '4097', (262, 269))	('human immunodeficiency virus (HIV) infection', 'Disease', 'MESH:D015658', (43, 87))	('viremia', 'Phenotype', 'HP:0020071', (128, 135))	('inherited variation', 'Var', (137, 156))	('steroids', 'Chemical', 'MESH:D013256', (208, 216))	('HHV-8 viremia', 'Disease', (122, 135))
224833	23320191	However, an underlying genetic polymorphism contributing to improved survival must be considered, as there is evidence that differences in KS survival among ethnic groups can be explained by a TP53 polymorphism at codon 72.	('TP53', 'Gene', '7157', (193, 197))	('KS', 'Phenotype', 'HP:0100726', (139, 141))	('TP53', 'Gene', (193, 197))	('polymorphism at', 'Var', (198, 213))	('explained by', 'Reg', (178, 190))
225000	20151216	For this central tumor in a young patient, PBRT allowed marked sparing of liver, spinal cord, stomach/duodenum, kidneys, and colon compared to IMRT (Fig.	('tumor', 'Disease', (17, 22))	('PBRT', 'Var', (43, 47))	('sparing', 'NegReg', (63, 70))	('patient', 'Species', '9606', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
225019	20151216	Some have recently argued that more aggressive surgery leads to lower recurrence rates, while others have argued that sacrificing some dispensable organs (e.g., colon and kidney) while leaving other less easily resected organs (e.g., duodenum and aorta) may not be sufficient to clear all margins of microscopic disease.	('lower', 'NegReg', (64, 69))	('recurrence rates', 'MPA', (70, 86))	('sacrificing', 'Var', (118, 129))	('colon and kidney', 'Disease', 'MESH:D007674', (161, 177))
225033	20151216	Thus, PBRT reduces the radiation of adjacent normal organs and tissues by approximately 60% and allows delivery of the prescription dose to the tumor with much greater sparing of adjacent organs and structures than is possible with photons.	('tumor', 'Disease', (144, 149))	('reduces', 'NegReg', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('radiation', 'MPA', (23, 32))	('PBRT', 'Var', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
225063	28135248	Five percent of cases, mostly with undetectable TERT, harbored ATRX or DAXX alterations, demonstrated elongated telomeres and increased telomeric repeat containing RNA (TERRA).	('alterations', 'Var', (76, 87))	('elongated', 'PosReg', (102, 111))	('ATRX', 'Gene', (63, 67))	('DAXX', 'Gene', '1616', (71, 75))	('TERT', 'Gene', (48, 52))	('telomeric repeat containing RNA', 'MPA', (136, 167))	('ATRX', 'Gene', '546', (63, 67))	('TERT', 'Gene', '7015', (48, 52))	('increased', 'PosReg', (126, 135))	('DAXX', 'Gene', (71, 75))	('telomeres', 'CPA', (112, 121))
225065	28135248	In this group, telomere length positively correlated with TP53 and RB1 mutations.	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('RB1', 'Gene', (67, 70))	('mutations', 'Var', (71, 80))	('correlated', 'Reg', (42, 52))	('telomere length', 'MPA', (15, 30))
225070	28135248	The telomerase enzymatic subunit is encoded by TERT, and while it is transcriptionally silent in most non-neoplastic cells, reactivation may endow a small population of cells with the ability to survive crisis, at which point they become immortalized.	('TERT', 'Gene', (47, 51))	('reactivation', 'Var', (124, 136))	('TERT', 'Gene', '7015', (47, 51))	('ran', 'Gene', (70, 73))	('ran', 'Gene', '5901', (70, 73))
225074	28135248	Deactivating mutations in ATRX and its binding partner DAXX were found tightly correlated with long telomeres in pancreatic neuroendocrine tumors and glioma.	('ATRX', 'Gene', (26, 30))	('long telomeres', 'MPA', (95, 109))	('DAXX', 'Gene', (55, 59))	('Deactivating mutations', 'Var', (0, 22))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (124, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('ATRX', 'Gene', '546', (26, 30))	('glioma', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('correlated', 'Reg', (79, 89))	('pancreatic neuroendocrine tumors', 'Disease', (113, 145))	('DAXX', 'Gene', '1616', (55, 59))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (113, 145))
225075	28135248	Recent evidence suggested that loss of ATRX may contribute to ALT by promoting sustained sister telomere cohesion and chromatid exchange.	('ATRX', 'Gene', (39, 43))	('promoting', 'PosReg', (69, 78))	('ATRX', 'Gene', '546', (39, 43))	('loss', 'Var', (31, 35))	('contribute', 'Reg', (48, 58))	('ALT', 'Disease', (62, 65))	('chromatid exchange', 'CPA', (118, 136))
225087	28135248	We curated a core sample set that consisted of 473 T/N pairs with the most comprehensive molecular profiling and an extended set that consisted of 6,835 T/N pairs with varying numbers of cases profiled by each individual platform (Figure 1a, Online Methods).	('835 T/N', 'Var', (149, 156))	('835 T/N', 'SUBSTITUTION', 'None', (149, 156))	('473 T/N', 'Var', (47, 54))	('473 T/N', 'SUBSTITUTION', 'None', (47, 54))
225088	28135248	TERT promoter (TERTp) mutations, predominantly C250T and C228T, were detected in 27% of the extended set for the cases where TERTp status could be determined (n=1,581).	('C250T', 'Var', (47, 52))	('TERT', 'Gene', '7015', (15, 19))	('C250T', 'Mutation', 'c.250C>T', (47, 52))	('C228T', 'Mutation', 'c.228C>T', (57, 62))	('TERTp', 'Gene', (125, 130))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERTp', 'Gene', '7015', (125, 130))	('TERTp', 'Gene', (15, 20))	('TERT', 'Gene', (125, 129))	('C228T', 'Var', (57, 62))	('TERTp', 'Gene', '7015', (15, 20))	('TERT', 'Gene', '7015', (125, 129))	('TERT', 'Gene', (15, 19))
225089	28135248	In agreement with previous reports; high incidence of TERTp mutations was found in bladder cancer (42/60, 70%), liver cancer (73/162, 45%), melanoma (93/129, 72%), lower grade glioma (127/285, 45%) and glioblastoma (25/28, 89%, Supplementary Figure 4a).	('glioblastoma', 'Disease', 'MESH:D005909', (202, 214))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('TERTp', 'Gene', (54, 59))	('TERTp', 'Gene', '7015', (54, 59))	('glioma', 'Disease', (176, 182))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioblastoma', 'Disease', (202, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('liver cancer', 'Disease', 'MESH:D006528', (112, 124))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('liver cancer', 'Phenotype', 'HP:0002896', (112, 124))	('bladder cancer', 'Disease', (83, 97))	('liver cancer', 'Disease', (112, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (60, 69))
225095	28135248	In the majority of TERTp structural variants (65%), at least one predicted super enhancer was found to directly overlap with the juxtaposed position (Supplementary Table 3).	('TERTp', 'Gene', (19, 24))	('TERTp', 'Gene', '7015', (19, 24))	('variants', 'Var', (36, 44))
225104	28135248	Taken together, we found somatic TERT alterations including TERTp mutations, TERT amplifications and TERT structural variants involving gene promoter or gene body in 32% of core set samples.	('TERT', 'Gene', '7015', (101, 105))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (60, 64))	('TERT', 'Gene', '7015', (77, 81))	('variants', 'Var', (117, 125))	('TERT', 'Gene', (101, 105))	('TERTp', 'Gene', (60, 65))	('TERTp', 'Gene', '7015', (60, 65))	('TERT', 'Gene', (60, 64))
225110	28135248	As previously described in pediatric brain tumors, TERT promoter probe cg11625005 demonstrated a strong correlation with TERT expression (Rho=0.52, FDR<0.0001).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('brain tumors', 'Phenotype', 'HP:0030692', (37, 49))	('pediatric brain tumors', 'Disease', (27, 49))	('TERT', 'Gene', (51, 55))	('correlation', 'Interaction', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cg11625005', 'Var', (71, 81))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', (121, 125))	('TERT', 'Gene', '7015', (121, 125))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (27, 49))
225115	28135248	TERTp methylation (two-sided t-test P<0.05) and TERTp mutations (two-sided t-test P<0.0001) were associated with relative TL shortening compared to other types of TERT alterations (Supplementary Figure 5c).	('TERTp', 'Gene', '7015', (0, 5))	('TERT', 'Gene', '7015', (163, 167))	('TERTp', 'Gene', (48, 53))	('TERTp', 'Gene', '7015', (48, 53))	('mutations', 'Var', (54, 63))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', (48, 52))	('shortening', 'NegReg', (125, 135))	('TERT', 'Gene', '7015', (0, 4))	('methylation', 'Var', (6, 17))	('TERT', 'Gene', (163, 167))	('TERT', 'Gene', '7015', (48, 52))	('TERTp', 'Gene', (0, 5))
225119	28135248	Focal TERC amplifications were associated with increased TERC expression (two-sided t-test P<0.0001) (Supplementary Figure 5d), and were enriched in TERT expressing samples (Odds Ratio (OR) 2.59, Fisher's Exact P<0.0001).	('TERT', 'Gene', '7015', (149, 153))	('TERC', 'Gene', (57, 61))	('TERC', 'Gene', (6, 10))	('amplifications', 'Var', (11, 25))	('TERC', 'Gene', '7012', (57, 61))	('increased', 'PosReg', (47, 56))	('TERT', 'Gene', (149, 153))	('TERC', 'Gene', '7012', (6, 10))
225129	28135248	TERC amplification was additionally associated with higher telomerase signature scores compared to non-amplified samples (two-sided t-test, P<0.0001), which may in part be explained by the co-expression patterns of TERT and TERC.	('TERT', 'Gene', '7015', (215, 219))	('amplification', 'Var', (5, 18))	('TERC', 'Gene', (0, 4))	('TERC', 'Gene', (224, 228))	('higher', 'PosReg', (52, 58))	('telomerase signature scores', 'MPA', (59, 86))	('TERC', 'Gene', '7012', (0, 4))	('TERT', 'Gene', (215, 219))	('TERC', 'Gene', '7012', (224, 228))
225132	28135248	We found alterations of ATRX and IDH1 as the most significantly associated with relative TL elongation (both FDR<0.0001; Figure 3a).	('associated', 'Reg', (64, 74))	('relative TL elongation', 'CPA', (80, 102))	('IDH1', 'Gene', (33, 37))	('ATRX', 'Gene', (24, 28))	('alterations', 'Var', (9, 20))	('IDH1', 'Gene', '3417', (33, 37))	('ATRX', 'Gene', '546', (24, 28))
225133	28135248	Since IDH1 mutations frequently co-occur with ATRX in glioma, we tested a model with both tumor type and IDH1 as covariates, and found IDH1 no longer associated with TL ratio (two-sided t-test P=0.15).	('associated', 'Reg', (150, 160))	('IDH1', 'Gene', '3417', (6, 10))	('mutations', 'Var', (11, 20))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('ATRX', 'Gene', '546', (46, 50))	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1', 'Gene', '3417', (135, 139))	('IDH1', 'Gene', '3417', (105, 109))	('glioma', 'Disease', (54, 60))	('ATRX', 'Gene', (46, 50))	('IDH1', 'Gene', (6, 10))	('TL ratio', 'MPA', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
225135	28135248	Alterations of the VHL were found to be associated with relative TL shortening (TL ratio 0.7, 95%CI 0.61-0.8, FDR<0.0001).	('relative TL shortening', 'MPA', (56, 78))	('Alterations', 'Var', (0, 11))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('VHL', 'Disease', (19, 22))
225138	28135248	A linear regression model showed that in addition to older age, positive TERRA expression, TP53 deletion, TP53 mutations, ATRX deletion, ATRX structural variants and absent/undetectable TERT expression were all independently associated with relative TL elongation (Figure 3b-c).	('mutations', 'Var', (111, 120))	('TP53', 'Gene', (91, 95))	('ATRX', 'Gene', (137, 141))	('positive', 'PosReg', (64, 72))	('TP53', 'Gene', '7157', (106, 110))	('ATRX', 'Gene', (122, 126))	('ATRX', 'Gene', '546', (122, 126))	('TP53', 'Gene', '7157', (91, 95))	('ATRX', 'Gene', '546', (137, 141))	('deletion', 'Var', (127, 135))	('deletion', 'Var', (96, 104))	('variants', 'Var', (153, 161))	('associated', 'Reg', (225, 235))	('TERT', 'Gene', (186, 190))	('relative TL elongation', 'CPA', (241, 263))	('TERT', 'Gene', '7015', (186, 190))	('TP53', 'Gene', (106, 110))
225139	28135248	Although DAXX has been linked to telomere length and ALT, DAXX mutations (n=51/6,835) and deletions (n=5/6,835) did not associate with TL.	('mutations', 'Var', (63, 72))	('DAXX', 'Gene', (58, 62))	('DAXX', 'Gene', '1616', (9, 13))	('deletions', 'Var', (90, 99))	('DAXX', 'Gene', (9, 13))	('DAXX', 'Gene', '1616', (58, 62))
225141	28135248	In addition to non-synonymous mutations and deletions, we detected ATRX structural variants from WGS data in 5% of the core set samples (n=26/473).	('variants', 'Var', (83, 91))	('ATRX', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (67, 71))
225147	28135248	We observed a significant decrease in ATRX expression in samples showing mutations, deletions, fusions and structural variants compared to cases with wild type ATRX (Figure 4a).	('ATRX', 'Gene', '546', (160, 164))	('decrease', 'NegReg', (26, 34))	('structural variants', 'Var', (107, 126))	('ATRX', 'Gene', (38, 42))	('fusions', 'Var', (95, 102))	('ATRX', 'Gene', (160, 164))	('ATRX', 'Gene', '546', (38, 42))	('expression', 'MPA', (43, 53))	('mutations', 'Var', (73, 82))	('deletions', 'Var', (84, 93))
225148	28135248	We found that all of types of ATRX alteration associated with significantly longer TL compared to wild type ATRX, consistent with the previously established association between ATRX deactivation and ALT (Figure 4b).	('ATRX', 'Gene', (30, 34))	('ATRX', 'Gene', '546', (177, 181))	('ATRX', 'Gene', (108, 112))	('longer', 'PosReg', (76, 82))	('ATRX', 'Gene', '546', (30, 34))	('alteration', 'Var', (35, 45))	('ATRX', 'Gene', '546', (108, 112))	('ATRX', 'Gene', (177, 181))
225149	28135248	Recent studies found that ATRX knockdown resulted in elevated levels of telomeric repeat containing RNA (TERRA).	('ATRX', 'Gene', '546', (26, 30))	('ATRX', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))	('elevated', 'PosReg', (53, 61))
225150	28135248	Our results demonstrate a significantly higher fraction of TERRA expressing samples in all groups of ATRX altered samples (Figure 4c, Fisher's Exact test P<0.05) compared to the group of ATRX wild type samples.	('ATRX', 'Gene', '546', (187, 191))	('higher', 'PosReg', (40, 46))	('TERRA expressing', 'MPA', (59, 75))	('ATRX', 'Gene', (187, 191))	('ATRX', 'Gene', (101, 105))	('ATRX', 'Gene', '546', (101, 105))	('altered', 'Var', (106, 113))
225154	28135248	ATRX/DAXX mutations were found in 210 TERT expressing samples, representing 3% of the cohort.	('ATRX', 'Gene', (0, 4))	('DAXX', 'Gene', '1616', (5, 9))	('TERT', 'Gene', (38, 42))	('DAXX', 'Gene', (5, 9))	('ATRX', 'Gene', '546', (0, 4))	('TERT', 'Gene', '7015', (38, 42))	('mutations', 'Var', (10, 19))
225155	28135248	These events were in majority non-truncating, while ATRX/DAXX mutations in TERT-negative cases were mostly truncating (Supplementary Methods, Supplementary Figure 9a).	('non-truncating', 'MPA', (30, 44))	('mutations', 'Var', (62, 71))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('DAXX', 'Gene', '1616', (57, 61))	('ATRX', 'Gene', (52, 56))	('ATRX', 'Gene', '546', (52, 56))	('DAXX', 'Gene', (57, 61))
225156	28135248	TERT-expressing ATRX/DAXX mutants showed higher telomerase signature scores compared to ATRX/DAXX altered samples lacking TERT expression (Supplementary Figure 9b).	('TERT', 'Gene', (122, 126))	('DAXX', 'Gene', '1616', (93, 97))	('TERT', 'Gene', '7015', (122, 126))	('DAXX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (88, 92))	('ATRX', 'Gene', '546', (16, 20))	('TERT', 'Gene', (0, 4))	('DAXX', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (0, 4))	('mutants', 'Var', (26, 33))	('telomerase signature scores', 'MPA', (48, 75))	('higher', 'PosReg', (41, 47))	('DAXX', 'Gene', '1616', (21, 25))	('ATRX', 'Gene', (88, 92))	('ATRX', 'Gene', (16, 20))
225170	28135248	In addition to IDH1 and TP53, RB1 (TL ratio 1.5, 95%CI 1.2-1.87, FDR=0.001) and MDM2 (TL ratio 1.51, 95%CI 1.14-2, FDR=0.01) were revealed to associate with relatively long TLs.	('MDM2', 'Gene', (80, 84))	('IDH1', 'Gene', (15, 19))	('TP53', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (15, 19))	('RB1', 'Var', (30, 33))	('MDM2', 'Gene', '4193', (80, 84))	('TP53', 'Gene', '7157', (24, 28))
225171	28135248	The finding of RB1 is consistent with experimental data demonstrating markedly elongated telomeres in Rb1 deficient mice independent of telomerase.	('mice', 'Species', '10090', (116, 120))	('telomeres', 'CPA', (89, 98))	('deficient', 'Var', (106, 115))	('elongated', 'PosReg', (79, 88))	('Rb1', 'Gene', (102, 105))	('Rb1', 'Gene', '19645', (102, 105))
225172	28135248	In the opposite direction, somatic alterations in PBRM1 (TL ratio 0.67, 95%CI 0.55-0.83, FDR=0.001), NRAS (TL ratio 0.68, 95%CI 0.52-0.9, FDR=0.02) and VHL (TL ratio 0.7, 95%CI 0.57-0.85, FDR=0.002) were associated with relative TL shortening (Figure 5d).	('NRAS', 'Gene', (101, 105))	('PBRM1', 'Gene', (50, 55))	('alterations', 'Var', (35, 46))	('PBRM1', 'Gene', '55193', (50, 55))	('NRAS', 'Gene', '4893', (101, 105))	('VHL', 'Disease', (152, 155))	('VHL', 'Disease', 'MESH:D006623', (152, 155))
225182	28135248	This paradoxical association between TERT promoter methylation and increased TERT expression may result from loss of CTCF binding, a transcriptional repressor reported to bind to the unmethylated TERT promoter.	('TERT', 'Gene', (37, 41))	('binding', 'Interaction', (122, 129))	('ran', 'Gene', (134, 137))	('TERT', 'Gene', (77, 81))	('ran', 'Gene', '5901', (134, 137))	('TERT', 'Gene', '7015', (37, 41))	('TERT', 'Gene', '7015', (77, 81))	('CTCF', 'Gene', (117, 121))	('TERT', 'Gene', (196, 200))	('loss', 'NegReg', (109, 113))	('TERT', 'Gene', '7015', (196, 200))	('increased', 'PosReg', (67, 76))	('methylation', 'Var', (51, 62))	('CTCF', 'Gene', '10664', (117, 121))
225183	28135248	Structural TERT variants have been documented and we detected these across several novel cancer types, including sarcoma, prostate and liver carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('liver carcinoma', 'Phenotype', 'HP:0001402', (135, 150))	('liver carcinoma', 'Disease', (135, 150))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('prostate', 'Disease', (122, 130))	('liver carcinoma', 'Disease', 'MESH:D006528', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('detected', 'Reg', (53, 61))	('cancer', 'Disease', (89, 95))	('sarcoma', 'Disease', (113, 120))	('TERT', 'Gene', (11, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('TERT', 'Gene', '7015', (11, 15))	('variants', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
225184	28135248	Hepatitis B virus and adeno-associated virus type 2 integration in TERT was found in about 5% of hepatocellular carcinomas.	('TERT', 'Gene', (67, 71))	('integration', 'Var', (52, 63))	('found', 'Reg', (76, 81))	('TERT', 'Gene', '7015', (67, 71))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (97, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (97, 121))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (97, 122))	('Hepatitis B virus', 'Species', '10407', (0, 17))	('adeno-associated virus type 2', 'Species', '10804', (22, 51))	('hepatocellular carcinomas', 'Disease', (97, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('Hepatitis B virus', 'Disease', (0, 17))
225189	28135248	An estimated 5-10% of TERC and TERRA carry the poly-A tails required for oligo-dT primer based RNA sequencing quantification.	('poly-A', 'Chemical', 'MESH:D011061', (47, 53))	('TERC', 'Gene', '7012', (22, 26))	('TERC', 'Gene', (22, 26))	('poly-A tails', 'Var', (47, 59))
225194	28135248	Deactivation of ATRX and/or DAXX has been related to ALT, and was observed in five percent of the cases in our core set.	('Deactivation', 'Var', (0, 12))	('ATRX', 'Gene', '546', (16, 20))	('DAXX', 'Gene', (28, 32))	('ALT', 'Disease', (53, 56))	('DAXX', 'Gene', '1616', (28, 32))	('related', 'Reg', (42, 49))	('ATRX', 'Gene', (16, 20))
225195	28135248	A detailed review of ATRX somatic changes revealed a large spectrum of potentially protein truncating changes, including inactivating mutations, deletions and structural variants.	('inactivating mutations', 'Var', (121, 143))	('structural variants', 'Var', (159, 178))	('protein truncating changes', 'MPA', (83, 109))	('ATRX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (21, 25))	('deletions', 'Var', (145, 154))
225197	28135248	Our analysis reinforced the association of inactivate ATRX/DAXX and ALT, demonstrating relative TL elongation in samples affected by somatic alterations in one of these two genes and a higher frequency of TERRA expression in tumors with these alterations.	('alterations', 'Var', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('DAXX', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ATRX', 'Gene', '546', (54, 58))	('TL elongation', 'CPA', (96, 109))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('affected', 'Reg', (121, 129))	('DAXX', 'Gene', '1616', (59, 63))	('tumors', 'Disease', (225, 231))	('ATRX', 'Gene', (54, 58))	('inactivate', 'Var', (43, 53))
225200	28135248	Such mechanisms may involve some RB1 and TP53 alterations, as somatic changes in these genes were associated with telomere elongation within this group.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('telomere elongation', 'CPA', (114, 133))	('RB1', 'Gene', (33, 36))	('changes', 'Var', (70, 77))	('associated', 'Reg', (98, 108))
225219	28135248	There was sufficient coverage for TERTp mutation calling in 903 samples, and we detected TERTp mutations in n=183, including C228T (n=128), C250T (n=49), C242/243T (n=5) and C169T (n=1).	('TERTp', 'Gene', '7015', (89, 94))	('C250T', 'Var', (140, 145))	('C250T', 'Mutation', 'c.250C>T', (140, 145))	('TERTp', 'Gene', '7015', (34, 39))	('C228T', 'Var', (125, 130))	('C169T', 'Var', (174, 179))	('detected', 'Reg', (80, 88))	('C169T', 'Mutation', 'c.169C>T', (174, 179))	('C242/243T', 'Var', (154, 163))	('C228T', 'Mutation', 'c.228C>T', (125, 130))	('TERTp', 'Gene', (89, 94))	('TERTp', 'Gene', (34, 39))
225222	28135248	Because we were only interested in variants involving TERT (chr5:1253287-1315162, including 20kb upstream of the TSS) and ATRX (chrX:76760356-77041719), variants not overlapping one of these regions were excluded.	('ATRX', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (54, 58))	('variants', 'Var', (35, 43))	('chr5:1253287-1315162', 'STRUCTURAL_ABNORMALITY', 'None', (60, 80))	('chrX:76760356-77041719', 'STRUCTURAL_ABNORMALITY', 'None', (128, 150))	('ATRX', 'Gene', '546', (122, 126))	('TERT', 'Gene', (54, 58))
225233	28135248	This analysis found overlapping super-enhancers in 11/17 TERTp structural variants, and this was significantly more than expected by chance (Chi-Square test P=0.001).	('super-enhancers', 'PosReg', (32, 47))	('variants', 'Var', (74, 82))	('TERTp', 'Gene', (57, 62))	('TERTp', 'Gene', '7015', (57, 62))
225234	28135248	For each structural variant proximal (adjacent to the TERT promoter) and distal breakpoint (juxtaposed to the TERT promoter) we calculated the number of reads mapping to each of three histone marks (H3K27ac, H3K27me3 and H3Kme1) individually within each tissue and cell/type.	('H3Kme1', 'Var', (221, 227))	('H3K27ac', 'Var', (199, 206))	('H3K27me3', 'Var', (208, 216))	('TERT', 'Gene', '7015', (54, 58))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('TERT', 'Gene', (54, 58))
225246	28135248	Spearman correlation was used to associate TERT expression and methylation, and to correlate gene expression and TL.	('TERT', 'Gene', (43, 47))	('methylation', 'Var', (63, 74))	('TERT', 'Gene', '7015', (43, 47))
225314	28938025	Deletion of the K15 gene from the viral genome or its depletion by siRNA lead to reduced virus reactivation, as evidenced by the decreased expression levels of KSHV lytic proteins RTA, K-bZIP, ORF 45 and K8.1 as well as reduced release of infectious virus.	('RTA', 'Gene', (180, 183))	('K15', 'Gene', (16, 19))	('release of infectious virus', 'MPA', (228, 255))	('reduced', 'NegReg', (220, 227))	('depletion', 'MPA', (54, 63))	('virus reactivation', 'MPA', (89, 107))	('Deletion', 'Var', (0, 8))	('expression levels', 'MPA', (139, 156))	('KSHV', 'Species', '37296', (160, 164))	('RTA', 'Gene', '23543', (180, 183))	('KS', 'Phenotype', 'HP:0100726', (160, 162))	('reduced', 'NegReg', (81, 88))	('ORF 45', 'Gene', '4961474', (193, 199))	('decreased', 'NegReg', (129, 138))	('ORF 45', 'Gene', (193, 199))
225315	28938025	Deleting either K15 or K1 from the viral genome also compromised the ability of KSHV to activate PLCgamma1, Erk1/2 and Akt1.	('PLCgamma1', 'Gene', (97, 106))	('Akt1', 'Gene', '207', (119, 123))	('Erk1/2', 'Pathway', (108, 114))	('KS', 'Phenotype', 'HP:0100726', (80, 82))	('KSHV', 'Species', '37296', (80, 84))	('Deleting', 'Var', (0, 8))	('PLCgamma1', 'Gene', '5335', (97, 106))	('compromised', 'NegReg', (53, 64))	('K15', 'Var', (16, 19))	('Akt1', 'Gene', (119, 123))	('ability', 'MPA', (69, 76))	('activate', 'PosReg', (88, 96))
225316	28938025	In infected primary lymphatic endothelial (LEC-rKSHV) cells, which have previously been shown to spontaneously display a viral lytic transcription pattern, transfection of siRNA against K15, but not K1, abolished viral lytic replication as well as KSHV-induced spindle cell formation.	('abolished', 'NegReg', (203, 212))	('KSHV-induced spindle cell formation', 'CPA', (248, 283))	('KSHV', 'Species', '37296', (248, 252))	('KSHV', 'Species', '37296', (48, 52))	('KS', 'Phenotype', 'HP:0100726', (48, 50))	('KS', 'Phenotype', 'HP:0100726', (248, 250))	('LEC', 'Gene', '6360', (43, 46))	('viral lytic replication', 'CPA', (213, 236))	('LEC', 'Gene', (43, 46))	('K15', 'Var', (186, 189))
225334	28938025	Blocking the activation of protein kinase C (PKC) isoforms by using GF 109203X or the PKCdelta isoform specifically decreases TPA-induced KSHV reactivation; while intracellular calcium mobilization elicits KSHV lytic replication through the activation of the Ca++ dependent calcineurin-NFAT pathway independently of PKC activation.	('Ca++ dependent calcineurin-NFAT pathway', 'Pathway', (259, 298))	('KSHV', 'Species', '37296', (206, 210))	('protein kinase C', 'Enzyme', (27, 43))	('GF 109203X', 'Var', (68, 78))	('KS', 'Phenotype', 'HP:0100726', (206, 208))	('intracellular calcium mobilization', 'MPA', (163, 197))	('calcium', 'Chemical', 'MESH:D002118', (177, 184))	('TPA', 'Chemical', '-', (126, 129))	('KSHV', 'Species', '37296', (138, 142))	('KS', 'Phenotype', 'HP:0100726', (138, 140))	('TPA-induced KSHV reactivation', 'MPA', (126, 155))	('decreases', 'NegReg', (116, 125))	('elicits', 'Reg', (198, 205))	('KSHV lytic replication', 'CPA', (206, 228))
225339	28938025	Upon ectopic expression, K15 recruits and constitutively activates the phospholipase C gamma1 (PLCgamma1) protein by using a constitutively phosphorylated tyrosine residue at its second SH2-binding site (Y481EEVL) and one of two SH2 domains of PLCgamma1.	('PLCgamma1', 'Gene', '5335', (95, 104))	('tyrosine', 'Chemical', 'MESH:D014443', (155, 163))	('K15', 'Var', (25, 28))	('phospholipase C gamma1', 'Gene', '5335', (71, 93))	('PLCgamma1', 'Gene', '5335', (244, 253))	('Y481EEVL', 'Mutation', 'p.Y481EEVL', (204, 212))	('Y481EEVL', 'Var', (204, 212))	('activates', 'PosReg', (57, 66))	('PLCgamma1', 'Gene', (95, 104))	('phospholipase C gamma1', 'Gene', (71, 93))	('PLCgamma1', 'Gene', (244, 253))
225340	28938025	K15 also induces the activation of the two MAP-kinases Erk2 and JNK, calcineurin-NFAT as well as NF-kappaB pathways leading to the activation of the NFAT and AP-1 transcription factors and expression of proangiogenic and proinflammatory factors such as Dscr-1, interleukin (IL)-6, IL-8, IL-1alpha/beta, CCL20, CCL2, CXCl3 and Cox-2 as well as intracellular calcium ion (Ca++) mobilization.	('activation', 'PosReg', (131, 141))	('CCL20', 'Gene', '6364', (303, 308))	('IL-8', 'Gene', (281, 285))	('Cox-2', 'Gene', (326, 331))	('NF-kappaB', 'Gene', '4790', (97, 106))	('JNK', 'Gene', (64, 67))	('CCL2', 'Gene', '6347', (303, 307))	('JNK', 'Gene', '5599', (64, 67))	('CCL20', 'Gene', (303, 308))	('calcineurin-NFAT', 'Pathway', (69, 85))	('NFAT and', 'Pathway', (149, 157))	('CCL2', 'Gene', '6347', (310, 314))	('CXCl3', 'Gene', '2921', (316, 321))	('Dscr-1', 'Gene', (253, 259))	('IL-1alpha', 'Gene', '3552', (287, 296))	('CXCl3', 'Gene', (316, 321))	('IL-8', 'Gene', '3576', (281, 285))	('Cox-2', 'Gene', '4513', (326, 331))	('AP-1', 'Gene', (158, 162))	('CCL2', 'Gene', (303, 307))	('Dscr-1', 'Gene', '1827', (253, 259))	('calcium', 'Chemical', 'MESH:D002118', (357, 364))	('Erk2', 'Gene', '5594', (55, 59))	('K15', 'Var', (0, 3))	('expression', 'MPA', (189, 199))	('IL-1alpha', 'Gene', (287, 296))	('CCL2', 'Gene', (310, 314))	('activation', 'PosReg', (21, 31))	('Erk2', 'Gene', (55, 59))	('NF-kappaB', 'Gene', (97, 106))
225341	28938025	Depletion of K15 from the infected cell or its deletion from the viral genome reduces the invasiveness of KSHV infected endothelial cells and their ability to form capillary tubes in a PLCgamma1 dependent manner, linking its activation of PLCgamma1-dependent signaling pathways to KSHV induced angiogenesis.	('KS', 'Phenotype', 'HP:0100726', (106, 108))	('PLCgamma1', 'Gene', '5335', (185, 194))	('ability', 'CPA', (148, 155))	('invasiveness of KSHV infected', 'Disease', 'MESH:C537372', (90, 119))	('KS', 'Phenotype', 'HP:0100726', (281, 283))	('angiogenesis', 'CPA', (294, 306))	('PLCgamma1', 'Gene', (239, 248))	('K15', 'Gene', (13, 16))	('KSHV', 'Species', '37296', (281, 285))	('deletion', 'Var', (47, 55))	('PLCgamma1', 'Gene', (185, 194))	('PLCgamma1', 'Gene', '5335', (239, 248))	('invasiveness of KSHV infected', 'Disease', (90, 119))	('KSHV', 'Species', '37296', (106, 110))	('reduces', 'NegReg', (78, 85))
225342	28938025	K15 has also been shown to interact with the anti-apoptotic protein HAX1 and induce the expression of a number of anti-apoptotic genes including birc2, brc3, bf, A20 and bcl2a1 which can provide a survival advantage to the infected cell.	('interact', 'Interaction', (27, 35))	('induce', 'PosReg', (77, 83))	('HAX1', 'Gene', '10456', (68, 72))	('birc2', 'Gene', '329', (145, 150))	('brc3', 'Gene', (152, 156))	('A20', 'Gene', (162, 165))	('HAX1', 'Gene', (68, 72))	('K15', 'Var', (0, 3))	('anti-apoptotic genes', 'Gene', (114, 134))	('bcl2a1', 'Gene', (170, 176))	('survival advantage', 'CPA', (197, 215))	('birc2', 'Gene', (145, 150))	('bcl2a1', 'Gene', '597', (170, 176))	('A20', 'Gene', '7128', (162, 165))	('expression', 'MPA', (88, 98))
225344	28938025	Our results revealed that the expression of the K15 protein in the infected cell is crucial for KSHV lytic replication and its reactivation from latency; K15 also contributes to the activation of PLCgamma1, Erk1/2 and Akt1 signaling during viral lytic replication.	('Akt1', 'Gene', '207', (218, 222))	('KSHV', 'Species', '37296', (96, 100))	('PLCgamma1', 'Gene', '5335', (196, 205))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('Erk1/2', 'Pathway', (207, 213))	('activation', 'PosReg', (182, 192))	('Akt1', 'Gene', (218, 222))	('PLCgamma1', 'Gene', (196, 205))	('K15', 'Var', (154, 157))
225347	28938025	Previously, our group has established BJAB-rKSHV cells, a B cell line stably infected with rKSHV.219, in which the KSHV lytic cycle can be activated by cross-linking the B-cell receptor (BCR) using an antibody to IgM.	('KS', 'Phenotype', 'HP:0100726', (92, 94))	('KSHV', 'CPA', (115, 119))	('BJAB', 'CellLine', 'CVCL:5711', (38, 42))	('BCR', 'Gene', (187, 190))	('KSHV', 'Species', '37296', (115, 119))	('KSHV', 'Species', '37296', (44, 48))	('KSHV', 'Species', '37296', (92, 96))	('KS', 'Phenotype', 'HP:0100726', (115, 117))	('antibody to IgM', 'Phenotype', 'HP:0003496', (201, 216))	('cross-linking', 'Var', (152, 165))	('KS', 'Phenotype', 'HP:0100726', (44, 46))
225352	28938025	In contrast, knock down of K15 from these cells led to reduced expression of early lytic viral proteins including the master lytic switch protein RTA as well as ORF 45, indicating that K15 expression is required at an early step during KSHV reactivation; the expression of the late lytic structural glycoprotein K8.1 was also inhibited in response to K15 depletion.	('reduced', 'NegReg', (55, 62))	('ORF 45', 'Gene', '4961474', (161, 167))	('expression', 'MPA', (63, 73))	('ORF 45', 'Gene', (161, 167))	('RTA', 'Gene', '23543', (146, 149))	('K15', 'Gene', (27, 30))	('knock down', 'Var', (13, 23))	('KS', 'Phenotype', 'HP:0100726', (236, 238))	('KSHV', 'Species', '37296', (236, 240))	('RTA', 'Gene', (146, 149))
225359	28938025	The integrity of the wild type as well as the two KSHV-Bac36 deletion mutant constructs was first validated by deep sequencing of the complete genome (S1 Fig).	('deletion mutant', 'Var', (61, 76))	('mutant', 'Var', (70, 76))	('KSHV-Bac36', 'Gene', (50, 60))	('KSHV', 'Species', '37296', (50, 54))	('KS', 'Phenotype', 'HP:0100726', (50, 52))
225360	28938025	The increased sequence coverage of the region between ORFs K4.2 and ORF 19 is due to the duplication of this region in the TR of this Bac.	('duplication', 'Var', (89, 100))	('sequence', 'MPA', (14, 22))	('ORF 19', 'Gene', (68, 74))	('ORF 19', 'Gene', '79783', (68, 74))	('increased', 'PosReg', (4, 13))
225364	28938025	In agreement with our K15 knock down results in the Bjab-rKSHV system above (Fig 1) and with a recent report using a K1 deletion virus, the absence of either the K1 or K15 gene reduced the ability of KSHV to reactivate from latency, as evidenced by the decreased expression level of KSHV early lytic proteins K-bZIP and ORF45 as well as reduced levels of infectious virus released into the supernatant of these cultures (Fig 2B and 2C).	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('KSHV', 'Species', '37296', (283, 287))	('KSHV', 'Species', '37296', (58, 62))	('latency', 'MPA', (224, 231))	('KS', 'Phenotype', 'HP:0100726', (200, 202))	('expression level', 'MPA', (263, 279))	('reduced', 'NegReg', (177, 184))	('KSHV', 'Species', '37296', (200, 204))	('reduced', 'NegReg', (337, 344))	('absence', 'Var', (140, 147))	('ORF45', 'Gene', '4961474', (320, 325))	('K15', 'Gene', (168, 171))	('reactivate', 'MPA', (208, 218))	('ORF45', 'Gene', (320, 325))	('KS', 'Phenotype', 'HP:0100726', (283, 285))	('decreased', 'NegReg', (253, 262))
225365	28938025	To extend our investigation to endothelial cells, which are thought to be targets of KSHV infection in vivo and relevant to KS pathogenesis, HuARLT2 cells (an immortalized endothelial cell line) were stably infected with the wild type or either of the deletion mutant viruses as described in materials and methods (Fig 2D), and the KSHV lytic cycle was induced using a cocktail of RTA and SB.	('KS', 'Phenotype', 'HP:0100726', (332, 334))	('deletion mutant', 'Var', (252, 267))	('RTA', 'Gene', '23543', (381, 384))	('KSHV infection', 'Disease', 'MESH:C537372', (85, 99))	('KS', 'Phenotype', 'HP:0100726', (124, 126))	('SB', 'Chemical', 'MESH:D020148', (389, 391))	('RTA', 'Gene', (381, 384))	('KSHV infection', 'Disease', (85, 99))	('KSHV', 'Species', '37296', (332, 336))	('KS', 'Phenotype', 'HP:0100726', (85, 87))	('KSHV', 'Species', '37296', (85, 89))
225373	28938025	Upon ectopic expression, K15 has been shown to activate the PLCgamma1-calcineurin-NFAT, MAP-Kinase as well as the NF-kappaB pathways (Fig 3A), which are crucial both during KSHV primary infection as well as during its reactivation from latency (see Introduction).	('NF-kappaB', 'Gene', '4790', (114, 123))	('activate', 'PosReg', (47, 55))	('MAP-Kinase', 'Pathway', (88, 98))	('NF-kappaB', 'Gene', (114, 123))	('PLCgamma1', 'Gene', '5335', (60, 69))	('K15', 'Var', (25, 28))	('ectopic expression', 'Var', (5, 23))	('PLCgamma1', 'Gene', (60, 69))	('KSHV primary infection', 'Disease', 'MESH:C537372', (173, 195))	('KS', 'Phenotype', 'HP:0100726', (173, 175))	('KSHV primary infection', 'Disease', (173, 195))
225374	28938025	As a first step in investigating the role of K15-dependent signaling pathways in KSHV lytic reactivation, we transfected HEK-293 cells with a K15 expression vector and measured the phosphorylation levels of PLCgamma1(Tyr783), Akt1 (Ser473) and Erk1/2(Thr202/Tyr204) on western blots by using phospho-specific antibodies against the indicated residues.	('Akt1', 'Gene', (226, 230))	('Ser473', 'Var', (232, 238))	('PLCgamma1', 'Gene', (207, 216))	('Ser473', 'Chemical', '-', (232, 238))	('Tyr204', 'Chemical', '-', (258, 264))	('Thr202', 'Chemical', '-', (251, 257))	('HEK-293', 'CellLine', 'CVCL:0045', (121, 128))	('Akt1', 'Gene', '207', (226, 230))	('phosphorylation', 'MPA', (181, 196))	('Tyr783', 'Chemical', '-', (217, 223))	('KS', 'Phenotype', 'HP:0100726', (81, 83))	('KSHV', 'Species', '37296', (81, 85))	('PLCgamma1', 'Gene', '5335', (207, 216))
225375	28938025	In line with experiments reported earlier, in which co-transfection of Erk2 together with K15 had been shown to increase Erk2 kinase activity as measured by the increased phosphorylation of the myelin basic protein (MBP) in an in vitro kinase assay, we found that endogenous Erk1/2 protein is phosphorylated on Thr202 and Tyr204 residues in response to K15 expression (Fig 3B).	('Erk2', 'Gene', (121, 125))	('myelin basic protein', 'Gene', (194, 214))	('Erk2', 'Gene', (71, 75))	('MBP', 'Gene', '4155', (216, 219))	('Thr202', 'Var', (311, 317))	('Erk2', 'Gene', '5594', (121, 125))	('K15', 'Gene', (353, 356))	('Tyr204 residues', 'Var', (322, 337))	('MBP', 'Gene', (216, 219))	('increase', 'PosReg', (112, 120))	('phosphorylated', 'MPA', (293, 307))	('protein', 'Protein', (282, 289))	('myelin basic protein', 'Gene', '4155', (194, 214))	('Erk2', 'Gene', '5594', (71, 75))	('Thr202', 'Chemical', '-', (311, 317))	('Tyr204', 'Chemical', '-', (322, 328))
225376	28938025	Consistent with previous results in endothelial cells from our group, K15 expression in HEK-293 cells also induced the activation of the PLCgamma1 pathway as evidenced by its increased phosphorylation on Tyr783; in contrast, we did not observe any activation of the PI3K-Akt pathway in these cells in response to K15 expression as shown by the lack of increased Akt1 phosphorylation on Ser473 (Fig 3B).	('Tyr783', 'Chemical', '-', (204, 210))	('phosphorylation on Tyr783', 'MPA', (185, 210))	('Akt', 'Gene', (362, 365))	('Akt', 'Gene', '207', (362, 365))	('expression', 'Var', (74, 84))	('Akt', 'Gene', '207', (271, 274))	('Ser473', 'Chemical', '-', (386, 392))	('Akt1', 'Gene', (362, 366))	('PLCgamma1', 'Gene', (137, 146))	('HEK-293', 'CellLine', 'CVCL:0045', (88, 95))	('activation', 'PosReg', (119, 129))	('Akt1', 'Gene', '207', (362, 366))	('increased', 'PosReg', (175, 184))	('PLCgamma1', 'Gene', '5335', (137, 146))	('Akt', 'Gene', (271, 274))	('K15', 'Gene', (70, 73))	('increased Akt1 phosphorylation', 'Phenotype', 'HP:0003240', (352, 382))
225378	28938025	Deleting either K1 or K15 from the viral genome compromised the ability of KSHV to activate PLCgamma1, Akt1 and Erk1/2 upon lytic reactivation in HEK-293 cells (Fig 3C).	('Erk1/2', 'Gene', (112, 118))	('Akt1', 'Gene', (103, 107))	('ability', 'MPA', (64, 71))	('activate', 'PosReg', (83, 91))	('HEK-293', 'CellLine', 'CVCL:0045', (146, 153))	('PLCgamma1', 'Gene', '5335', (92, 101))	('PLCgamma1', 'Gene', (92, 101))	('compromised', 'NegReg', (48, 59))	('Deleting', 'Var', (0, 8))	('Akt1', 'Gene', '207', (103, 107))	('KS', 'Phenotype', 'HP:0100726', (75, 77))	('KSHV', 'Species', '37296', (75, 79))	('K15', 'Var', (22, 25))
225379	28938025	The fact that the lack of K15 in the infected cell abolished Akt1 phosphorylation in response to reactivation (Fig 3C), even though K15 did not activate this pathway directly when expressed in isolation in these cells (Fig 3B) could be due to the decreased lytic replication which results in decreased expression of other KSHV lytic proteins such as vGPCR and K1 that are known to activate the PI3K-Akt pathway directly (reviewed in).	('Akt1', 'Gene', (61, 65))	('decreased', 'NegReg', (247, 256))	('K15', 'Gene', (26, 29))	('Akt1', 'Gene', '207', (61, 65))	('vGPCR', 'Gene', '4961465', (350, 355))	('Akt', 'Gene', (399, 402))	('decreased', 'NegReg', (292, 301))	('Akt', 'Gene', '207', (61, 64))	('expression', 'MPA', (302, 312))	('abolished', 'NegReg', (51, 60))	('lytic replication', 'CPA', (257, 274))	('Akt', 'Gene', '207', (399, 402))	('lack', 'Var', (18, 22))	('Akt', 'Gene', (61, 64))	('response', 'MPA', (85, 93))	('KSHV', 'Species', '37296', (322, 326))	('vGPCR', 'Gene', (350, 355))	('KS', 'Phenotype', 'HP:0100726', (322, 324))
225380	28938025	In contrast, K15 activates phosphorylation of Erk1/2 and PLCgamma1 directly (Fig 3B), and the decreased levels of Erk1/2 and PLCgamma1 phosphorylation in cells infected with the K1 or K15 deletion viruses could therefore be the direct result of the absence or reduced expression of K15 in the case of the K1 deletion virus.	('K15', 'Var', (13, 16))	('PLCgamma1', 'Gene', (125, 134))	('K15', 'Gene', (184, 187))	('Erk1/2', 'Gene', (46, 52))	('PLCgamma1', 'Gene', (57, 66))	('expression', 'MPA', (268, 278))	('PLCgamma1', 'Gene', '5335', (125, 134))	('phosphorylation', 'MPA', (27, 42))	('deletion', 'Var', (188, 196))	('decreased', 'NegReg', (94, 103))	('phosphorylation', 'MPA', (135, 150))	('activates', 'PosReg', (17, 26))	('PLCgamma1', 'Gene', '5335', (57, 66))
225383	28938025	Similar to the HEK-293 cells, deleting either K1 or K15 from the viral genome also compromised the ability of KSHV to activate PLCgamma1 and Akt1 (Fig 3D) upon lytic reactivation in the HuARLT2 cells.	('KSHV', 'Species', '37296', (110, 114))	('PLCgamma1', 'Gene', '5335', (127, 136))	('Akt1', 'Gene', '207', (141, 145))	('deleting', 'Var', (30, 38))	('Akt1', 'Gene', (141, 145))	('compromised', 'NegReg', (83, 94))	('HEK-293', 'CellLine', 'CVCL:0045', (15, 22))	('KS', 'Phenotype', 'HP:0100726', (110, 112))	('activate', 'PosReg', (118, 126))	('K15', 'Var', (52, 55))	('PLCgamma1', 'Gene', (127, 136))
225384	28938025	However, unlike either PLCgamma1 or Akt1, the basal level of Erk1/2 phosphorylation on Thr202/Tyr204 is already abundant in the uninfected HuARLT2 cells (Fig 3D), which could be due to the hTERT and SV40 large T antigen used for immortalization of these cells (see Materials and methods).	('Akt1', 'Gene', '207', (36, 40))	('Erk1/2', 'Gene', (61, 67))	('phosphorylation', 'MPA', (68, 83))	('PLCgamma1', 'Gene', (23, 32))	('Akt1', 'Gene', (36, 40))	('Thr202', 'Chemical', '-', (87, 93))	('Tyr204', 'Chemical', '-', (94, 100))	('SV40', 'Species', '1891767', (199, 203))	('PLCgamma1', 'Gene', '5335', (23, 32))	('Thr202/Tyr204', 'Var', (87, 100))
225385	28938025	We also observed an increased Erk1/2 (Thr202/Tyr204) phosphorylation without induction of the lytic cycle in these endothelial cells infected with viruses lacking either the K1 or K15 gene which decreased upon lytic reactivation (Fig 3D).Taken together, our results so far indicate that the K1 and K15 proteins play an important role during KSHV lytic replication and its activation of cellular signaling pathways and that the absence of K1 or K15 affects the PI3K-Akt and MEK/Erk pathways in endothelial cells in a manner that would not have been predicted from the outcome of experiments involving overexpression of these proteins.	('absence', 'Var', (427, 434))	('Akt', 'Gene', '207', (465, 468))	('affects', 'Reg', (448, 455))	('Erk', 'Gene', '5594', (477, 480))	('Thr202', 'Chemical', '-', (38, 44))	('KSHV', 'Species', '37296', (341, 345))	('K15', 'Gene', (444, 447))	('Tyr204', 'Chemical', '-', (45, 51))	('cellular signaling pathways', 'Pathway', (386, 413))	('Akt', 'Gene', (465, 468))	('Erk', 'Gene', (30, 33))	('KS', 'Phenotype', 'HP:0100726', (341, 343))	('Erk', 'Gene', '5594', (30, 33))	('Erk', 'Gene', (477, 480))
225386	28938025	To investigate this in the context of viral infection (in stably infected HuARLT2-rKSHV cells after lytic induction), an immunofluorescence assay (IFA) was performed using monoclonal antibodies to K1 and K15; examples of cells expressing K15 (shown in green) alone or together with K1 (shown in red) are shown in Fig 4A.	('KSHV', 'Species', '37296', (83, 87))	('viral infection', 'Disease', (38, 53))	('KS', 'Phenotype', 'HP:0100726', (83, 85))	('K15', 'Var', (238, 241))	('viral infection', 'Disease', 'MESH:D001102', (38, 53))
225391	28938025	Using this biochemical assay, we showed previously that the K15 protein expressed from a transfected plasmid associates with lipid rafts in Cos7 cells.	('K15', 'Var', (60, 63))	('lipid', 'Chemical', 'MESH:D008055', (125, 130))	('lipid rafts', 'MPA', (125, 136))	('associates', 'Interaction', (109, 119))
225396	28938025	Further analysis of the intracellular localization of K15 in stably infected HuARLT2-rKSHV cells by IFA staining using markers specific for different cytoplasmic compartments revealed the presence of K15 in vesicular structures in the perinuclear area.	('presence', 'Reg', (188, 196))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('KSHV', 'Species', '37296', (86, 90))	('K15', 'Var', (200, 203))	('vesicular', 'Species', '11276', (207, 216))
225397	28938025	Here, K15 co-localized with a cis-Golgi network marker GM130 as well as a late endosome marker LAMP1 (Fig 4D).	('LAMP1', 'Gene', '3916', (95, 100))	('K15', 'Var', (6, 9))	('GM130', 'Chemical', '-', (55, 60))	('LAMP1', 'Gene', (95, 100))
225399	28938025	In order to get further mechanistic insight into the role of K15-induced signaling in KSHV reactivation, BJAB-rKSHV.219 cells were treated with pharmacological inhibitors for the PLCgamma (U73122), MAPK (U0126) and PI3K/Akt (Ly294002) pathways and the KSHV lytic cycle was induced by using anti-hIgM antibody.	('U73122', 'Chemical', 'MESH:C060229', (189, 195))	('PLCgamma', 'Pathway', (179, 187))	('KSHV lytic cycle', 'CPA', (252, 268))	('Ly294002', 'Chemical', 'MESH:C085911', (225, 233))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('KSHV', 'Species', '37296', (86, 90))	('U73122', 'Var', (189, 195))	('MAPK', 'Pathway', (198, 202))	('U0126', 'Chemical', 'MESH:C113580', (204, 209))	('Akt', 'Gene', '207', (220, 223))	('KSHV', 'Species', '37296', (111, 115))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('IgM antibody', 'Phenotype', 'HP:0003496', (296, 308))	('KS', 'Phenotype', 'HP:0100726', (252, 254))	('KSHV', 'Species', '37296', (252, 256))	('BJAB-rKSHV.219', 'CellLine', 'CVCL:5711', (105, 119))	('Akt', 'Gene', (220, 223))	('U0126', 'Var', (204, 209))
225400	28938025	Treatment of these cells with 2 muM of U73122 decreased PLCgamma1 phosphorylation in reactivated cultures; this was accompanied by reduced viral lytic gene expression and infectious virus release (Fig 5A-5C).	('viral lytic gene expression', 'MPA', (139, 166))	('PLCgamma1', 'Gene', (56, 65))	('infectious virus release', 'CPA', (171, 195))	('PLCgamma1', 'Gene', '5335', (56, 65))	('reduced', 'NegReg', (131, 138))	('U73122', 'Chemical', 'MESH:C060229', (39, 45))	('decreased', 'NegReg', (46, 55))	('U73122', 'Var', (39, 45))
225401	28938025	Similarly, consistent with the literature (see Introduction), 12.5 muM of the MAPK inhibitor U0126 as well as 10 muM of the PI3K-Akt inhibitor Ly294002 efficiently inhibited KSHV lytic replication as shown both by the dramatic reduction in lytic gene expression as well as infectious virus production (Fig 5D-5F).	('U0126', 'Var', (93, 98))	('KS', 'Phenotype', 'HP:0100726', (174, 176))	('Ly294002', 'Var', (143, 151))	('Akt', 'Gene', '207', (129, 132))	('rat', 'Species', '10116', (35, 38))	('lytic gene expression', 'MPA', (240, 261))	('U0126', 'Chemical', 'MESH:C113580', (93, 98))	('inhibited', 'NegReg', (164, 173))	('KSHV lytic replication', 'CPA', (174, 196))	('Akt', 'Gene', (129, 132))	('infectious virus production', 'MPA', (273, 300))	('KSHV', 'Species', '37296', (174, 178))	('Ly294002', 'Chemical', 'MESH:C085911', (143, 151))	('MAPK', 'Gene', (78, 82))	('inhibitor U0126', 'Var', (83, 98))	('reduction', 'NegReg', (227, 236))
225402	28938025	In accordance with the results of the these experiments, depleting PLCgamma1 from the stably infected HuARLT2-rKSHV cells by siRNA affected the ability of the virus to reactivate from latency as shown by the reduced number of RFP positive cells as well as lytic gene expression (S2 Fig).	('lytic gene expression', 'MPA', (256, 277))	('RFP', 'Gene', '5987', (226, 229))	('RFP', 'Gene', (226, 229))	('reactivate', 'MPA', (168, 178))	('KSHV', 'Species', '37296', (111, 115))	('PLCgamma1', 'Gene', (67, 76))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('reduced', 'NegReg', (208, 215))	('PLCgamma1', 'Gene', '5335', (67, 76))	('depleting', 'Var', (57, 66))
225406	28938025	Expression of the PLCgamma2-cSH2 domain in these cells inhibited virus reactivation as shown by the decreased expression level of the KSHV lytic proteins K-bZIP, ORF45 and K15 itself (Fig 6A), which was accompanied by reduced infectious virus release (Fig 6B).	('expression level', 'MPA', (110, 126))	('cSH2', 'Gene', '1443', (28, 32))	('virus reactivation', 'CPA', (65, 83))	('KSHV', 'Species', '37296', (134, 138))	('K15', 'Var', (172, 175))	('cSH2', 'Gene', (28, 32))	('PLCgamma2', 'Gene', (18, 27))	('infectious virus release', 'MPA', (226, 250))	('ORF45', 'Gene', '4961474', (162, 167))	('ORF45', 'Gene', (162, 167))	('decreased', 'NegReg', (100, 109))	('reduced', 'NegReg', (218, 225))	('PLCgamma2', 'Gene', '5336', (18, 27))	('KS', 'Phenotype', 'HP:0100726', (134, 136))	('inhibited', 'NegReg', (55, 64))
225407	28938025	Transfection of the isolated PLCgamma2-cSH2 domain also inhibited the activation of PLCgamma1 (phosphorylation on Tyr783), Akt1 (Ser473) and Erk2 (Thr202/Tyr204) after induction of the KSHV lytic cycle compared to KSHV-carrying cells transfected with the empty vector (Fig 6C).	('Akt1', 'Gene', '207', (123, 127))	('Erk2', 'Gene', '5594', (141, 145))	('KSHV', 'Species', '37296', (214, 218))	('Thr202/Tyr204', 'Var', (147, 160))	('Erk2', 'Gene', (141, 145))	('cSH2', 'Gene', (39, 43))	('Ser473', 'Chemical', '-', (129, 135))	('Tyr204', 'Chemical', '-', (154, 160))	('KS', 'Phenotype', 'HP:0100726', (185, 187))	('Thr202', 'Chemical', '-', (147, 153))	('KS', 'Phenotype', 'HP:0100726', (214, 216))	('cSH2', 'Gene', '1443', (39, 43))	('inhibited', 'NegReg', (56, 65))	('PLCgamma1', 'Gene', '5335', (84, 93))	('activation', 'PosReg', (70, 80))	('Akt1', 'Gene', (123, 127))	('Tyr783', 'Chemical', '-', (114, 120))	('KSHV', 'Species', '37296', (185, 189))	('PLCgamma2', 'Gene', '5336', (29, 38))	('PLCgamma1', 'Gene', (84, 93))	('PLCgamma2', 'Gene', (29, 38))
225409	28938025	Similar to the results in the epithelial cells, expression of the isolated PLCgamma2-cSH2 domain abolished virus reactivation as shown by the reduced number of RFP (expressed under the control of the lytic PAN promoter) expressing cells (S3A Fig), and decreased K-bZIP and ORF 45 expression (S3B Fig), as well as reduced infectious virus release (S3C Fig) compared to cells transduced with an empty vector control.	('infectious virus release', 'MPA', (321, 345))	('cSH2', 'Gene', (85, 89))	('reduced', 'NegReg', (313, 320))	('K-bZIP and ORF 45', 'Gene', '4961474', (262, 279))	('reduced', 'NegReg', (142, 149))	('PLCgamma2', 'Gene', '5336', (75, 84))	('abolished', 'NegReg', (97, 106))	('virus reactivation', 'MPA', (107, 125))	('expression', 'Var', (48, 58))	('cSH2', 'Gene', '1443', (85, 89))	('RFP', 'Gene', (160, 163))	('PLCgamma2', 'Gene', (75, 84))	('RFP', 'Gene', '5987', (160, 163))	('decreased', 'NegReg', (252, 261))
225417	28938025	Microscopic examination of the infected cells revealed that KSHV induced extensive spindling in LEC cells, which was already visible after 48 hours of infection (see images taken 7 days after infection shown in Fig 7A), while HuAR2T-rKSHV cells did not show an obvious change in their morphology; the level of infection is shown by the expression of GFP in both cell populations (Fig 7A).	('KSHV', 'Species', '37296', (234, 238))	('LEC', 'Gene', (96, 99))	('LEC', 'Gene', '6360', (96, 99))	('KS', 'Phenotype', 'HP:0100726', (234, 236))	('spindling', 'CPA', (83, 92))	('KSHV', 'Species', '37296', (60, 64))	('KSHV', 'Var', (60, 64))	('KS', 'Phenotype', 'HP:0100726', (60, 62))
225425	28938025	In contrast, the majority of the LEC-rKSHV cells were expressing the K15 protein while the number of K1 expressing cells is negligible (Fig 7C) in agreement with the absence of detectable K1 mRNA expression in the previously reported KSHV tiling microarray study on KSHV-LECs.	('KSHV', 'Species', '37296', (234, 238))	('KS', 'Phenotype', 'HP:0100726', (38, 40))	('LEC', 'Gene', (33, 36))	('LEC', 'Gene', (271, 274))	('KSHV', 'Species', '37296', (38, 42))	('LEC', 'Gene', '6360', (271, 274))	('KS', 'Phenotype', 'HP:0100726', (234, 236))	('K15', 'Var', (69, 72))	('KSHV', 'Species', '37296', (266, 270))	('KS', 'Phenotype', 'HP:0100726', (266, 268))	('LEC', 'Gene', '6360', (33, 36))
225428	28938025	Interestingly, ORF 59 staining was evident only in the K15 expressing cells, while the reverse is not true (representative IF images of cells expressing K15 alone or together with ORF 59 are shown in Fig 7D upper and lower panel respectively), in agreement with the greater number of cells (10%) expressing the K15 protein compared to the number of cells expressing ORF 59 (6%) during lytic replication (Fig 7C).	('ORF 59', 'Gene', '4961492', (366, 372))	('ORF 59', 'Gene', '4961492', (15, 21))	('ORF 59', 'Gene', (366, 372))	('K15', 'Var', (55, 58))	('ORF 59', 'Gene', '4961492', (180, 186))	('ORF 59', 'Gene', (180, 186))	('K15', 'Var', (311, 314))	('ORF 59', 'Gene', (15, 21))
225434	28938025	The result (Fig 8A) shows that silencing the K15 mRNA in LEC-rKSHV cells results in a pronounced decrease of K-bZIP and ORF 45 expression as well as the low molecular weight isoform of LANA, while the higher molecular weight isoforms of LANA were unaffected.	('LEC', 'Gene', (57, 60))	('silencing', 'Var', (31, 40))	('LANA', 'Gene', '4961527', (237, 241))	('LEC', 'Gene', '6360', (57, 60))	('expression', 'MPA', (127, 137))	('KSHV', 'Species', '37296', (62, 66))	('KS', 'Phenotype', 'HP:0100726', (62, 64))	('K15', 'Var', (45, 48))	('LANA', 'Gene', (185, 189))	('K-bZIP and ORF 45', 'Gene', '4961474', (109, 126))	('LANA', 'Gene', (237, 241))	('low molecular weight isoform', 'MPA', (153, 181))	('decrease', 'NegReg', (97, 105))	('LANA', 'Gene', '4961527', (185, 189))
225438	28938025	Phosphorylation at the indicated residues of PLCgamma1, Akt1 and Erk1/2 was reduced in response to K15 silencing but not in cells transfected with siRNAs against either K1 or ORF 26 (Fig 8C).	('silencing', 'Var', (103, 112))	('PLCgamma1', 'Gene', (45, 54))	('K15', 'Gene', (99, 102))	('Akt1', 'Gene', (56, 60))	('Phosphorylation', 'MPA', (0, 15))	('PLCgamma1', 'Gene', '5335', (45, 54))	('reduced', 'NegReg', (76, 83))	('Erk1/2', 'Gene', (65, 71))	('Akt1', 'Gene', '207', (56, 60))
225439	28938025	Interestingly, in addition to inhibiting the lytic transcription in the stably infected LEC-rKSHV cells, K15 depletion also led to the loss of the pronounced spindle cell morphology induced by KSHV infection (Fig 8D); in contrast, we did not observe an obvious phenotypic change after transfecting siRNAs against either K1 or ORF 26 (Fig 8D).	('inhibiting', 'NegReg', (30, 40))	('K15 depletion', 'Var', (105, 118))	('KSHV infection', 'Disease', 'MESH:C537372', (193, 207))	('loss', 'NegReg', (135, 139))	('KSHV', 'Species', '37296', (93, 97))	('depletion', 'Var', (109, 118))	('spindle cell morphology', 'CPA', (158, 181))	('LEC', 'Gene', '6360', (88, 91))	('KSHV infection', 'Disease', (193, 207))	('KSHV', 'Species', '37296', (193, 197))	('KS', 'Phenotype', 'HP:0100726', (193, 195))	('KS', 'Phenotype', 'HP:0100726', (93, 95))	('LEC', 'Gene', (88, 91))	('lytic transcription', 'MPA', (45, 64))
225440	28938025	In support of a role for K15 in spindle cell formation, we also show that ectopic expression of K15 alone in LECs can induce morphological change similar to KSHV infection (Fig 9A) and this is accompanied by the activation of PLCgamma1, Akt1 and Erk1/2 signaling pathways (Fig 9B).	('PLCgamma1', 'Gene', '5335', (226, 235))	('KS', 'Phenotype', 'HP:0100726', (157, 159))	('morphological change', 'CPA', (125, 145))	('Akt1', 'Gene', (237, 241))	('ectopic expression', 'Var', (74, 92))	('K15', 'Gene', (96, 99))	('KSHV infection', 'Disease', 'MESH:C537372', (157, 171))	('PLCgamma1', 'Gene', (226, 235))	('Akt1', 'Gene', '207', (237, 241))	('LEC', 'Gene', '6360', (109, 112))	('activation', 'PosReg', (212, 222))	('KSHV infection', 'Disease', (157, 171))	('LEC', 'Gene', (109, 112))	('Erk1/2 signaling pathways', 'Pathway', (246, 271))
225442	28938025	We could also show that inhibiting the K15-PLCgamma1 interaction by transducing the retroviral vector for the PLCgamma2-cSH2 domain (see above) as a dominant negative inhibitor can reduce the phosphorylation of PLCgamma1, and, to a lower extent, Akt1 and Erk1/2 (Fig 9C), viral lytic protein expression (Fig 9D) and infectious virus release (Fig 9E) in the stably infected LEC-rKSHV cells, consistent with our results obtained with the HEK-293-Bac36 and HuARLT2-rKSHV cells (see above).	('inhibiting', 'Var', (24, 34))	('LEC', 'Gene', '6360', (373, 376))	('phosphorylation', 'MPA', (192, 207))	('PLCgamma1', 'Gene', (211, 220))	('PLCgamma1', 'Gene', (43, 52))	('cSH2', 'Gene', (120, 124))	('viral lytic', 'MPA', (272, 283))	('HEK-293', 'CellLine', 'CVCL:0045', (436, 443))	('KS', 'Phenotype', 'HP:0100726', (463, 465))	('LEC', 'Gene', (373, 376))	('reduce', 'NegReg', (181, 187))	('cSH2', 'Gene', '1443', (120, 124))	('infectious virus release', 'MPA', (316, 340))	('Akt1', 'Gene', (246, 250))	('KSHV', 'Species', '37296', (378, 382))	('PLCgamma2', 'Gene', '5336', (110, 119))	('KSHV', 'Species', '37296', (463, 467))	('Akt1', 'Gene', '207', (246, 250))	('PLCgamma2', 'Gene', (110, 119))	('PLCgamma1', 'Gene', '5335', (211, 220))	('PLCgamma1', 'Gene', '5335', (43, 52))	('KS', 'Phenotype', 'HP:0100726', (378, 380))
225455	28938025	Interestingly, we were also able to detect the K15M protein using our monoclonal antibody in a KS biopsy that was positive for the K15M allele (Fig 10B last panel).	('K15M', 'Mutation', 'p.K15M', (131, 135))	('K15M', 'Var', (47, 51))	('K15M', 'Mutation', 'p.K15M', (47, 51))	('detect', 'Reg', (36, 42))	('KS', 'Phenotype', 'HP:0100726', (95, 97))	('K15M', 'Var', (131, 135))
225459	28938025	Indeed, both K15P and M proteins were recognized by our monoclonal antibody clone 18E5 (S5C Fig).	('K15P', 'Var', (13, 17))	('K15P', 'Mutation', 'p.K15P', (13, 17))	('M proteins', 'Protein', (22, 32))
225468	28938025	Both by siRNA-mediated silencing as well as deleting the K15 gene from the viral genome we show, in a variety of KSHV infected cells, that the expression of K15 is crucial for reactivation from latency, early viral gene expression and virus production (Figs 1, 2 and 8).	('deleting', 'Var', (44, 52))	('reactivation', 'MPA', (176, 188))	('silencing', 'Var', (23, 32))	('KSHV', 'Species', '37296', (113, 117))	('K15', 'Gene', (157, 160))	('KS', 'Phenotype', 'HP:0100726', (113, 115))
225469	28938025	K15 expression is required earlier during lytic replication as demonstrated by the reduced expression of immediate early lytic viral proteins including the master lytic switch protein RTA, ORF 45 and K-bZIP upon K15 knock down in stably infected cells or when K15 is deleted from the viral genome (Figs 1A, 2B and 2E).	('expression', 'MPA', (91, 101))	('RTA', 'Gene', (184, 187))	('rat', 'Species', '10116', (70, 73))	('reduced', 'NegReg', (83, 90))	('ORF 45', 'Gene', '4961474', (189, 195))	('K15', 'Gene', (212, 215))	('ORF 45', 'Gene', (189, 195))	('RTA', 'Gene', '23543', (184, 187))	('knock down', 'Var', (216, 226))
225470	28938025	The decreased expression of these immediate-early/ early viral proteins RTA, ORF 45 and K-bZIP in the absence of K15 can further affect the expression of late lytic proteins, such as the envelope glycoprotein K8.1 (Fig 1A) and therefore lead to reduced virus production (Figs 1B, 2C and 2F).	('decreased', 'NegReg', (4, 13))	('expression', 'MPA', (140, 150))	('ORF 45', 'Gene', (77, 83))	('RTA', 'Gene', '23543', (72, 75))	('expression', 'MPA', (14, 24))	('virus production', 'MPA', (253, 269))	('affect', 'Reg', (129, 135))	('reduced', 'NegReg', (245, 252))	('K-bZIP', 'Var', (88, 94))	('ORF 45', 'Gene', '4961474', (77, 83))	('RTA', 'Gene', (72, 75))
225475	28938025	In cultured endothelial cells, the number of K15 positive cells vastly exceeds that of cells undergoing lytic viral DNA replication, as indicated by expression of the viral polymerase-associated factor encoded by ORF 59; in addition, ORF 59-positive cells are always positive for K15, while the reverse is not the case (Fig 7).	('ORF 59', 'Gene', (213, 219))	('ORF 59', 'Gene', '4961492', (213, 219))	('ORF 59', 'Gene', '4961492', (234, 240))	('ORF 59', 'Gene', (234, 240))	('K15', 'Var', (280, 283))	('positive', 'Reg', (267, 275))
225478	28938025	We show here that the absence of K15 impedes the activation of PLCgamma1, Erk1/2 and Akt1 (Figs 3C, 3D and 8C), and that these pathways are also directly activated by K15, at least in the lymphatic endothelial cells (Figs 3B and 9B).	('K15', 'Var', (167, 170))	('impedes', 'NegReg', (37, 44))	('absence', 'Var', (22, 29))	('K15', 'Gene', (33, 36))	('PLCgamma1', 'Gene', '5335', (63, 72))	('Akt1', 'Gene', '207', (85, 89))	('activated', 'PosReg', (154, 163))	('activation', 'MPA', (49, 59))	('Erk1/2', 'Pathway', (74, 80))	('PLCgamma1', 'Gene', (63, 72))	('Akt1', 'Gene', (85, 89))
225483	28938025	Not only did K15 depletion affect viral replication in KSHV-infected lymphatic endothelial cells, it also reversed the virus-induced endothelial cell spindling (Fig 8D), and K15 overexpression in these cells recapitulates KSHV infection with regard to spindle cell formation (Fig 9A).	('viral replication', 'CPA', (34, 51))	('spindle cell formation', 'CPA', (252, 274))	('KSHV infection', 'Disease', 'MESH:C537372', (222, 236))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('overexpression', 'PosReg', (178, 192))	('K15 depletion', 'Var', (13, 26))	('depletion', 'Var', (17, 26))	('KSHV infection', 'Disease', (222, 236))	('KSHV-infected', 'Disease', 'MESH:C537372', (55, 68))	('KS', 'Phenotype', 'HP:0100726', (222, 224))	('affect', 'Reg', (27, 33))	('KSHV-infected', 'Disease', (55, 68))
225485	28938025	K15 can also mediate NF-kappaB activation, suggesting that K15 induced LEC spindling may also be the result of NF-kappaB activation.	('NF-kappaB', 'Gene', '4790', (21, 30))	('K15', 'Var', (59, 62))	('NF-kappaB', 'Gene', '4790', (111, 120))	('LEC', 'Gene', '6360', (71, 74))	('NF-kappaB', 'Gene', (21, 30))	('LEC', 'Gene', (71, 74))	('NF-kappaB', 'Gene', (111, 120))
225487	28938025	In view of our observation (Figs 7 and 8) that, the absence of K15 also impedes the spontaneous lytic reactivation observed in KSHV-infected lymphatic endothelial cells, we explored if K15 might serve as a potential therapeutic target to interfere with KSHV early gene expression and lytic replication.	('absence', 'Var', (52, 59))	('KSHV-infected', 'Disease', 'MESH:C537372', (127, 140))	('KS', 'Phenotype', 'HP:0100726', (127, 129))	('spontaneous lytic reactivation', 'CPA', (84, 114))	('impedes', 'NegReg', (72, 79))	('K15', 'Gene', (63, 66))	('KSHV-infected', 'Disease', (127, 140))	('KS', 'Phenotype', 'HP:0100726', (253, 255))	('KSHV', 'Species', '37296', (253, 257))	('KSHV', 'Species', '37296', (127, 131))
225494	28938025	Primary antibodies rabbit anti-GAPDH (#14C10), rabbit anti-S-Tag (#8476), rabbit anti-PLCgamma1 (#2822), rabbit anti-phospho PLCgamma1 (Tyr783; #2821), mouse anti-phospho MAP-Kinase p44/42 (Thr202/Tyr204; #91062), rabbit anti-phospho Akt1 (Ser473; #4058), mouse anti-Akt1 (#2967) and mouse anti-MAP-Kinas p44/42 (#9107) were purchased from Cell Signaling Technology; mouse anti-Erk2 (D-2) (sc-1647), mouse anti-KSHV ORF 45 (sc-53883) and mouse anti-KSHV K-bZIP (sc-69797), were purchased from Santa Cruz Biotechnolocy Inc.; mouse anti KSHV K8.1 (A2B) (13-212-100), rat anti-KSHV ORF73 (LNA-1;13-210-100) and mouse anti-KSHV ORF 59 (13-211-100) were purchased from Advanced Biotechnology Inc.; mouse anti-HHV-8 ORF26 (LS-C41403) was purchased from LifeSpan Biosciences Inc.; mouse anti-beta-actin (A5441) was purchased from Sigma Aldrich; and rabbit anti-caveolin (610060) was purchased from BD Transduction Laboratories.	('mouse', 'Species', '10090', (367, 372))	('p44', 'Gene', (305, 308))	('ORF 59', 'Gene', '4961492', (624, 630))	('D-2', 'Gene', (384, 387))	('Akt1', 'Gene', '207', (267, 271))	('rat', 'Species', '10116', (565, 568))	('KS', 'Phenotype', 'HP:0100726', (411, 413))	('ORF 45', 'Gene', '4961474', (416, 422))	('Akt1', 'Gene', '207', (234, 238))	('p44', 'Gene', '10561', (305, 308))	('KSHV', 'Species', '37296', (619, 623))	('KS', 'Phenotype', 'HP:0100726', (535, 537))	('KS', 'Phenotype', 'HP:0100726', (449, 451))	('KSHV', 'Species', '37296', (411, 415))	('Tyr204', 'Chemical', '-', (197, 203))	('mouse', 'Species', '10090', (524, 529))	('Erk2', 'Gene', '5594', (378, 382))	('ORF 59', 'Gene', (624, 630))	('rabbit', 'Species', '9986', (74, 80))	('rabbit', 'Species', '9986', (105, 111))	('rabbit', 'Species', '9986', (19, 25))	('KS', 'Phenotype', 'HP:0100726', (574, 576))	('Erk2', 'Gene', (378, 382))	('KSHV', 'Species', '37296', (449, 453))	('Ser473', 'Chemical', '-', (240, 246))	('rat', 'Species', '10116', (911, 914))	('mouse', 'Species', '10090', (284, 289))	('mouse', 'Species', '10090', (608, 613))	('rabbit', 'Species', '9986', (842, 848))	('GAPDH', 'Gene', '2597', (31, 36))	('PLCgamma1', 'Gene', '5335', (125, 134))	('rabbit', 'Species', '9986', (214, 220))	('ORF26', 'Gene', (710, 715))	('mouse', 'Species', '10090', (400, 405))	('p44', 'Gene', (182, 185))	('mouse', 'Species', '10090', (774, 779))	('PLCgamma1', 'Gene', '5335', (86, 95))	('D-2', 'Gene', '28503', (384, 387))	('rabbit', 'Species', '9986', (47, 53))	('610060', 'Var', (864, 870))	('mouse', 'Species', '10090', (693, 698))	('ORF26', 'Gene', '440829', (710, 715))	('KS', 'Phenotype', 'HP:0100726', (619, 621))	('Akt1', 'Gene', (267, 271))	('KSHV', 'Species', '37296', (535, 539))	('p44', 'Gene', '10561', (182, 185))	('HHV-8', 'Species', '37296', (704, 709))	('Akt1', 'Gene', (234, 238))	('PLCgamma1', 'Gene', (125, 134))	('PLCgamma1', 'Gene', (86, 95))	('Tyr783', 'Chemical', '-', (136, 142))	('GAPDH', 'Gene', (31, 36))	('KSHV', 'Species', '37296', (574, 578))	('mouse', 'Species', '10090', (152, 157))	('ORF 45', 'Gene', (416, 422))	('mouse', 'Species', '10090', (438, 443))	('Thr202', 'Chemical', '-', (190, 196))	('mouse', 'Species', '10090', (256, 261))
225495	28938025	HRP-conjugated secondary antibodies: goat anti-rabbit IgG (P0448), rabbit anti-mouse IgG (P0260) and goat anti-mouse IgG (P0447) were purchased from DAKO; goat anti-rat IgG (#3050-05) was purchased from SouthernBiotech.	('mouse', 'Species', '10090', (79, 84))	('P0260', 'Var', (90, 95))	('goat', 'Species', '9925', (37, 41))	('P0447', 'Var', (122, 127))	('mouse', 'Species', '10090', (111, 116))	('rabbit', 'Species', '9986', (67, 73))	('rabbit', 'Species', '9986', (47, 53))	('goat', 'Species', '9925', (155, 159))	('rat', 'Species', '10116', (165, 168))	('P0448', 'Var', (59, 64))	('goat', 'Species', '9925', (101, 105))
225517	28938025	For inhibitor treatment, 8 x 105 BJAB-rKSHV.219 cells were plated per well of a 12 well plate and treated with 1mug per ml of anti-human IgM antibody plus the individual inhibitors for the PLCgamma (U73122), MAPK (U126) and PI3K/Akt (Ly294002) pathways at their respective concentrations.	('Akt', 'Gene', '207', (229, 232))	('U73122', 'Var', (199, 205))	('IgM antibody', 'Phenotype', 'HP:0003496', (137, 149))	('PLCgamma', 'Pathway', (189, 197))	('MAPK', 'Pathway', (208, 212))	('rat', 'Species', '10116', (280, 283))	('human', 'Species', '9606', (131, 136))	('BJAB-rKSHV.219', 'CellLine', 'CVCL:5711', (33, 47))	('Akt', 'Gene', (229, 232))	('KS', 'Phenotype', 'HP:0100726', (39, 41))	('U126', 'Var', (214, 218))	('U73122', 'Chemical', 'MESH:C060229', (199, 205))	('Ly294002', 'Chemical', 'MESH:C085911', (234, 242))
225530	28938025	A semi-confluent culture of HEK-293 cells was then transfected with 2 mug of Bac DNA per well of a 6 well plate per each construct (KSHV-Bac36Wt, KSHV-Bac36DeltaK1 or KSHV-Bac36DeltaK15) using the Fugene 6 transfection reagent.	('HEK-293', 'CellLine', 'CVCL:0045', (28, 35))	('KSHV', 'Species', '37296', (132, 136))	('KSHV', 'Species', '37296', (146, 150))	('KS', 'Phenotype', 'HP:0100726', (146, 148))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('KSHV-Bac36Wt', 'Var', (132, 144))	('KS', 'Phenotype', 'HP:0100726', (167, 169))	('KSHV', 'Species', '37296', (167, 171))	('KSHV-Bac36DeltaK1', 'Var', (146, 163))
225536	28938025	To establish a stably infected HuARLT2 cell line, recombinant viruses were produced from the stably transfected HEK-293-KSHV-BAC36Wt/DeltaK1/DeltaK15 cells.	('DeltaK1', 'Var', (133, 140))	('DeltaK15', 'DELETION', 'None', (141, 149))	('DeltaK1', 'Var', (141, 148))	('DeltaK15', 'Var', (141, 149))	('DeltaK1', 'DELETION', 'None', (133, 140))	('HEK-293', 'CellLine', 'CVCL:0045', (112, 119))	('DeltaK1', 'DELETION', 'None', (141, 148))	('293-KSHV', 'CellLine', 'CVCL:0045', (116, 124))	('KS', 'Phenotype', 'HP:0100726', (120, 122))
225540	28938025	Three days after infection, 100 mug/ml of Hygromycin-B was added and cells were grown and maintained until a fully selected, stably infected, polyclonal population was obtained for each virus (HuARLT2-KSHV-Bac36Wt, HuARLT2-KSHV-Bac36DeltaK1 or HuARLT2-KSHV-Bac36DeltaK15).	('HuARLT2-KSHV-Bac36Wt', 'Var', (193, 213))	('KS', 'Phenotype', 'HP:0100726', (223, 225))	('KSHV', 'Species', '37296', (223, 227))	('KSHV', 'Species', '37296', (201, 205))	('HuARLT2-KSHV-Bac36DeltaK15', 'Var', (244, 270))	('Hygromycin-B', 'Chemical', 'MESH:D006921', (42, 54))	('KS', 'Phenotype', 'HP:0100726', (201, 203))	('KS', 'Phenotype', 'HP:0100726', (252, 254))	('KSHV', 'Species', '37296', (252, 256))	('HuARLT2-KSHV-Bac36DeltaK1', 'Var', (215, 240))
225543	28938025	Retroviruses containing the pSF91-PLCgamma2-cSH2-IRES-GFP, pSF91-sK15-IRES-GFP or the empty vector control pSF91-IRES-GFP were produced in HEK-293T cells after calcium-phosphate co-transfection of the respective vector constructs together with packaging plasmids pM57DAW (gag/pol) and pRD114 (env) as described before.	('PLCgamma2', 'Gene', (34, 43))	('HEK-293T', 'CellLine', 'CVCL:0063', (139, 147))	('calcium', 'Chemical', 'MESH:D002118', (160, 167))	('pSF91-sK15-IRES-GFP', 'Var', (59, 78))	('cSH2', 'Gene', '1443', (44, 48))	('cSH2', 'Gene', (44, 48))	('PLCgamma2', 'Gene', '5336', (34, 43))	('phosphate', 'Chemical', 'MESH:D010710', (168, 177))
225561	28938025	After 3 washes in 1xPBS cells were permeablized with 0.2% Triton X-100 for 10 minutes at RT, blocked with 10% FBS in PBS for an hour at 37 C and incubated with the respective primary antibody in blocking solution for an hour at 37 C. After another 3 washes, cells were incubated with the corresponding fluorescently labeled secondary antibody for an hour at 37 C. Plasmid constructs used include pFJ-K15P/M (encoding either K15P or M).	('FBS', 'Disease', 'MESH:D005198', (110, 113))	('FBS', 'Disease', (110, 113))	('Triton X-100', 'Chemical', 'MESH:D017830', (58, 70))	('pFJ-K15P/M', 'Gene', (396, 406))	('1xPBS', 'Chemical', '-', (18, 23))	('K15P', 'Mutation', 'p.K15P', (400, 404))	('PBS', 'Chemical', 'MESH:D007854', (20, 23))	('K15P', 'Mutation', 'p.K15P', (424, 428))	('K15P', 'Var', (424, 428))	('PBS', 'Chemical', 'MESH:D007854', (117, 120))
225578	22467249	The cytogenetic hallmark of Ewing sarcoma is balanced translocation t(11;22)(q24;q12), first described by Aurias et al and Turc-Carel et al.	('Aurias', 'Disease', (106, 112))	('balanced translocation t', 'Var', (45, 69))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (68, 85))	('Aurias', 'Disease', 'None', (106, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('Ewing sarcoma', 'Disease', (28, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (28, 41))
225579	22467249	The t(11;22)(q24;q12) was the first sarcoma associated translocation to be characterized at the molecular level.	('t(11;22)(q24;q12', 'Var', (4, 20))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 21))	('sarcoma', 'Disease', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))
225582	22467249	The protein encoded by FLI1 is a member of the E-twenty six (ETS) family of transcription factors that target deoxyribonucleic acid (DNA) sequences through structural motif in their DNA binding region (Riggi et al,).	('binding', 'Interaction', (186, 193))	('structural motif', 'Var', (156, 172))	('FLI1', 'Gene', '2313', (23, 27))	('FLI1', 'Gene', (23, 27))
225583	22467249	The t(11;22)(q24;q12) joins the 5'portion of the EWSR1 gene to the DNA binding region of FLI1, thus resulting in the replacement of its transcription activation domain by EWSR1 sequences.	('FLI1', 'Gene', (89, 93))	('EWSR1', 'Gene', '2130', (171, 176))	('FLI1', 'Gene', '2313', (89, 93))	('replacement', 'Var', (117, 128))	('EWSR1', 'Gene', (49, 54))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 21))	('transcription activation domain', 'MPA', (136, 167))	('EWSR1', 'Gene', '2130', (49, 54))	('EWSR1', 'Gene', (171, 176))
225584	22467249	The breakpoints in the two genes vary, but the most common fusions are between EWSR1 exon 7 and FLI1 exon 5 or 6.	('EWSR1', 'Gene', (79, 84))	('FLI1', 'Gene', (96, 100))	('FLI1', 'Gene', '2313', (96, 100))	('EWSR1', 'Gene', '2130', (79, 84))	('fusions', 'Var', (59, 66))
225586	22467249	These alternate translocations result in fusions of the EWSR1 gene with one of four different ETS genes including ERG (ETS-related gene), ETV1 (ETS-variant gene 1), ETV4 (ETS variant gene 4) or FEV (fifth Ewing sarcoma variant).	('ETS variant gene 4', 'Gene', (171, 189))	('ETV1', 'Gene', (138, 142))	('ETS variant gene 4', 'Gene', '2118', (171, 189))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (205, 218))	('ETV4', 'Gene', (165, 169))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (205, 218))	('ERG', 'Gene', (114, 117))	('EWSR1', 'Gene', '2130', (56, 61))	('ETV1', 'Gene', '2115', (138, 142))	('ETS-variant gene 1', 'Gene', (144, 162))	('ERG', 'Gene', '2078', (114, 117))	('ETV4', 'Gene', '2118', (165, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('Ewing sarcoma', 'Disease', (205, 218))	('fusions', 'Var', (41, 48))	('FEV', 'Gene', '54738', (194, 197))	('EWSR1', 'Gene', (56, 61))	('ETS-variant gene 1', 'Gene', '2115', (144, 162))	('FEV', 'Gene', (194, 197))	('result in', 'Reg', (31, 40))
225591	22467249	Chromosomal translocations between the EWSR1 gene and various genes encoding transcription factors result in the production of chimeric proteins that are involved in tumorigenesis through theirs function as an aberrant transcription factor.	('involved', 'Reg', (154, 162))	('Chromosomal translocations', 'Var', (0, 26))	('EWSR1', 'Gene', (39, 44))	('result in', 'Reg', (99, 108))	('chimeric', 'Var', (127, 135))	('EWSR1', 'Gene', '2130', (39, 44))
225592	22467249	In addition, rare cases of Ewing sarcoma where EWSR1 becomes fused to another type of transcription factor have been reported: inv(22)(q12q12) resulted in an EWSR1-PATZ1 (POZ/BTB and A-T-hook containing zinc finger 1) fusion gene, t(6;22)(p21;q12) fused EWSR1-POU5F1 (POU class 5 homeobox 1) chimera, t(2;22)(q31;q12) resulted in an EWSR1-SP3 fusion, and t(20;22)(q13;q12) achieved an EWSR1-NFATc2 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2) (Mastrangelo et al,; Szuhai et al,).	('PATZ1', 'Gene', (164, 169))	('EWSR1', 'Gene', '2130', (385, 390))	('t(20;22)(q13;q12', 'Var', (355, 371))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (27, 40))	('POU class 5 homeobox 1', 'Gene', '5460', (268, 290))	('EWSR1', 'Gene', '2130', (254, 259))	('POU5F1', 'Gene', '5460', (260, 266))	('NFATc2', 'Gene', '4773', (391, 397))	('Ewing sarcoma', 'Disease', (27, 40))	('nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2', 'Gene', '4773', (399, 472))	('EWSR1', 'Gene', '2130', (47, 52))	('EWSR1', 'Gene', '2130', (333, 338))	('EWSR1', 'Gene', '2130', (158, 163))	('EWSR1', 'Gene', (385, 390))	('t(2;22)(q31;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (301, 317))	('t(20;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (355, 372))	('EWSR1', 'Gene', (254, 259))	('POU class 5 homeobox 1', 'Gene', (268, 290))	('POU5F1', 'Gene', (260, 266))	('PATZ1', 'Gene', '23598', (164, 169))	('t(6;22)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (231, 247))	('EWSR1', 'Gene', (47, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (27, 40))	('EWSR1', 'Gene', (333, 338))	('EWSR1', 'Gene', (158, 163))	('NFATc2', 'Gene', (391, 397))
225597	22467249	In addition to many reported TET-ETS translocation, a number of other fusion event have been described: t(4;19)(q35;13), t(15;19)(q13;q13) and ins(4;X)(q31-32;p11p22) (Kawamura-Saito et al,; Mertens et al,; Surace et al,).	('TET', 'Chemical', '-', (29, 32))	('p11', 'Gene', '8909', (159, 162))	('p11', 'Gene', (159, 162))	('t(15;19)(q13;q13', 'Var', (121, 137))	('t(4;19)(q35;13', 'Var', (104, 118))	('t(15;19)(q13;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (121, 138))
225604	22467249	This method is useful to detect translocations from patients' fresh tumour specimens, cell lines, frozen tumours and formalin fixed tumours.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumour', 'Disease', (132, 138))	('tumours', 'Disease', (132, 139))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumour', 'Disease', (105, 111))	('tumours', 'Disease', (105, 112))	('translocations', 'Var', (32, 46))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (52, 60))
225605	22467249	The main advantage of this method is that ADOT is capable of detecting known or unknown translocations in biological samples, including those most commonly encountered during the diagnostic work-up of a patient.	('patient', 'Species', '9606', (203, 210))	('detecting', 'Reg', (61, 70))	('translocations', 'Var', (88, 102))
225606	22467249	Furthermore with additional design, ADOT could also be used in different types of cancer to detect chromosomal translocations.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('chromosomal translocations', 'Var', (99, 125))	('cancer', 'Disease', (82, 88))
225612	22701332	Identification of specific chromosomal translocations, some important pathways characterization such as mTOR pathway or the insulin-like growth factor pathway, the stunning development in angiogenesis knowledge, and brand new agents like viruses have lead to the development of new therapeutic options with promising results.	('insulin-like growth factor pathway', 'Pathway', (124, 158))	('mTOR', 'Gene', '2475', (104, 108))	('chromosomal translocations', 'Var', (27, 53))	('mTOR', 'Gene', (104, 108))
225640	22701332	Thus, patients with absent or faint VEGF expression had higher 5-year DFS than patients with a strong VEGF expression (83.3% versus 13.2%, resp.).	('VEGF', 'Gene', '7422', (102, 106))	('VEGF', 'Gene', (36, 40))	('VEGF', 'Gene', (102, 106))	('higher', 'PosReg', (56, 62))	('VEGF', 'Gene', '7422', (36, 40))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (79, 87))	('faint', 'Var', (30, 35))	('DFS', 'MPA', (70, 73))
225643	22701332	The analysis showed that patients with a strong or moderate expression of HIF-1alpha had poorer OS than those with a weak or negative expression.	('poorer', 'NegReg', (89, 95))	('HIF-1alpha', 'Gene', '3091', (74, 84))	('patients', 'Species', '9606', (25, 33))	('HIF-1alpha', 'Gene', (74, 84))	('moderate expression', 'Var', (51, 70))
225645	22701332	Thus, in a work by Comandone et al., patients with high MVD had worse OS and DFS than patients with lower MVD.	('worse', 'NegReg', (64, 69))	('DFS', 'MPA', (77, 80))	('high MVD', 'Var', (51, 59))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (86, 94))
225714	22701332	Due to the many functions that mTOR regulates, its abnormal activity leads to a number of malignancies including sarcomas.	('sarcomas', 'Disease', (113, 121))	('malignancies', 'Disease', (90, 102))	('abnormal', 'Var', (51, 59))	('mTOR', 'Gene', (31, 35))	('mTOR', 'Gene', '2475', (31, 35))	('leads to', 'Reg', (69, 77))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
225715	22701332	The upregulation of growth factors or mutations in tyrosine kinase receptors that belongs to the mTOR network have been reported to be involved in the development of various sarcomas.	('mTOR', 'Gene', '2475', (97, 101))	('sarcomas', 'Disease', (174, 182))	('mTOR', 'Gene', (97, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('mutations', 'Var', (38, 47))	('upregulation', 'PosReg', (4, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('growth', 'Protein', (20, 26))	('tyrosine kinase receptors', 'Protein', (51, 76))
225716	22701332	Furthermore, deletions of some mTOR pathway tumor suppressors such as tuberous sclerosis complex 1 and 2 (TSC1 and TSC2) and neurofibromatosis type 1 (NF1) are associated with both, benign and malignant mesenchymal tumors.	('malignant mesenchymal tumors', 'Disease', (193, 221))	('tuberous sclerosis', 'Disease', (70, 88))	('mTOR', 'Gene', '2475', (31, 35))	('deletions', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('NF1', 'Gene', (151, 154))	('neurofibromatosis type 1', 'Gene', (125, 149))	('tumor', 'Disease', (44, 49))	('associated', 'Reg', (160, 170))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('TSC2', 'Gene', '7249', (115, 119))	('TSC1', 'Gene', (106, 110))	('TSC1', 'Gene', '7248', (106, 110))	('TSC2', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('neurofibromatosis type 1', 'Gene', '4763', (125, 149))	('tumor', 'Disease', (215, 220))	('mTOR', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('malignant mesenchymal tumors', 'Disease', 'MESH:C535700', (193, 221))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (70, 88))	('NF1', 'Gene', '4763', (151, 154))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
225739	22701332	Results recently reported showed a 28% reduction in the risk of progression in ridaforolimus arm compared with placebo arm and a 3.1-week improvement in PFS.	('ridaforolimus', 'Chemical', 'MESH:C515074', (79, 92))	('PFS', 'MPA', (153, 156))	('reduction', 'NegReg', (39, 48))	('ridaforolimus', 'Var', (79, 92))
225742	22701332	Dysfunction in tumor suppressors TSC1 and 2 and the subsequent upregulation of mTORC1 seems to be a crucial step in the development of this disease.	('Dysfunction', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('TSC1 and 2', 'Gene', '7248;7249', (33, 43))	('mTORC1', 'Gene', '382056', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('mTORC1', 'Gene', (79, 85))	('upregulation', 'PosReg', (63, 75))
225748	22701332	These translocations are an early step in carcinogenesis, promoting some of the processes that finally lead to the appearance of sarcomas.	('promoting', 'PosReg', (58, 67))	('carcinogenesis', 'Disease', 'MESH:D063646', (42, 56))	('carcinogenesis', 'Disease', (42, 56))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcomas', 'Disease', (129, 137))	('translocations', 'Var', (6, 20))
225754	22701332	Clear cell sarcoma is also associated with a specific chromosomal translocation, t(12; 22)(q13; q12) in most of the cases.	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('Clear cell sarcoma', 'Disease', 'MESH:D018227', (0, 18))	('t(12; 22)(q13; q12', 'Var', (81, 99))	('Clear cell sarcoma', 'Disease', (0, 18))
225769	22701332	The most studied double-inhibition-targeted therapies are those related with IGFR-1 pathway, with preclinical evidences of activity in sarcoma models.	('IGFR-1', 'Gene', '100132417', (77, 83))	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('sarcoma', 'Disease', (135, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('IGFR-1', 'Gene', (77, 83))	('double-inhibition-targeted', 'Var', (17, 43))
225805	21716856	Based on early studies of a potential benefit of liposomal MTP in sarcoma, the Children's Oncology Group's Intergroup-0133 conducted a randomized trial in patients with newly diagnosed osteosarcoma.	('sarcoma', 'Disease', (66, 73))	('osteosarcoma', 'Disease', (185, 197))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('liposomal', 'Var', (49, 58))	('Children', 'Species', '9606', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (185, 197))	('osteosarcoma', 'Disease', 'MESH:D012516', (185, 197))	('sarcoma', 'Disease', (190, 197))	('MTP', 'Chemical', 'MESH:C037144', (59, 62))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('patients', 'Species', '9606', (155, 163))	('Oncology', 'Phenotype', 'HP:0002664', (90, 98))
225819	21716856	The largest dendritic cell vaccine trial to date enrolled 52 patients with t(2;13) or t(11;22) translocation positive, recurrent, or metastatic Ewing's sarcoma family of tumors or alveolar rhabdomyosarcoma.	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (180, 205))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (189, 205))	('translocation positive', 'Var', (95, 117))	('alveolar rhabdomyosarcoma', 'Disease', (180, 205))	('t(11', 'Gene', (86, 90))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (180, 205))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (144, 159))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	("Ewing's sarcoma", 'Disease', (144, 159))	('tumors', 'Disease', (170, 176))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (144, 159))
225834	21716856	HLA mismatch was not generally associated with a greater antitumor effect.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (61, 66))	('mismatch', 'Var', (4, 12))
225846	21716856	A number of different approaches have been so far employed to obtain tumor-specific T cells, such as: ex vivo selection TIL based on their capacity to recognize autologous tumor cells, repeated in vitro stimulation with tumor-associated antigens (TAA)/whole tumor cells, or, more recently, genetic modification of T-cells using T-cell receptors encoding retroviruses, that can convert normal lymphocytes into cells with specific anti-cancer activity.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('cancer', 'Disease', (434, 440))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', (69, 74))	('TIL', 'Gene', (120, 123))	('TIL', 'Gene', '7096', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (434, 440))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('genetic modification', 'Var', (290, 310))	('cancer', 'Disease', 'MESH:D009369', (434, 440))
225889	33247209	We performed a 9-year, single sarcoma network, double-blind, unmatched cohort study, comparing post-operative histology outcomes (benign versus non-benign) versus 15 signs across three domains: Clinical (size of tumour, depth, growth noticed by patient, previous lipoma, patient felt pain), Ultrasonographic (size, depth, vascularity, heterogenous features septae) and MRI (size, depth, vascularity, heterogenous features, septae, complete fat signal suppression).	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('pain', 'Phenotype', 'HP:0012531', (284, 288))	('lipoma', 'Disease', (263, 269))	('patient', 'Species', '9606', (271, 278))	('lipoma', 'Disease', 'MESH:D008067', (263, 269))	('lipoma', 'Phenotype', 'HP:0012032', (263, 269))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('previous lipoma', 'Phenotype', 'HP:0001012', (254, 269))	('heterogenous', 'Var', (400, 412))	('tumour', 'Disease', (212, 218))	('sarcoma', 'Disease', (30, 37))	('pain', 'Disease', 'MESH:D010146', (284, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('pain', 'Disease', (284, 288))	('patient', 'Species', '9606', (245, 252))
225925	32770382	CFI-400945 and centrinone elicited cell death in p53 wild-type and mutant Ewing's sarcoma cells.	('centrinone', 'Chemical', 'MESH:C000599097', (15, 25))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (74, 89))	('CFI', 'Gene', (0, 3))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (74, 89))	('mutant', 'Var', (67, 73))	('cell death', 'CPA', (35, 45))	('CFI', 'Gene', '3426', (0, 3))	("Ewing's sarcoma", 'Disease', (74, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('elicited', 'Reg', (26, 34))
225927	32770382	In addition, the PLK4 inhibitors induced a G2/M cell cycle arrest, particularly when cell killing was attenuated by the pan-caspase inhibitor z-VAD-fmk.	('inhibitors', 'Var', (22, 32))	('induced', 'Reg', (33, 40))	('arrest', 'Disease', (59, 65))	('z-VAD-fmk', 'Chemical', 'MESH:C096713', (142, 151))	('PLK4', 'Gene', (17, 21))	('PLK4', 'Gene', '10733', (17, 21))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (48, 65))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
225929	32770382	Our findings show that PLK4 inhibitors were effective against Ewing's sarcoma cells in vitro and thus provide a rationale for their evaluation in vivo.	("Ewing's sarcoma", 'Disease', (62, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (62, 77))	('PLK4', 'Gene', (23, 27))	('rat', 'Species', '10116', (112, 115))	('inhibitors', 'Var', (28, 38))	('PLK4', 'Gene', '10733', (23, 27))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (62, 77))
225931	32770382	The pathognomonic feature of ES is the gene fusion of a member of the FET gene family (consisting of FUS, EWSR1 and TAF15), by far most frequently EWSR1 (EWS RNA binding protein 1), with a member of the ETS gene family of transcription factors, most commonly FLI1.	('EWSR1', 'Gene', '2130', (106, 111))	('TAF15', 'Gene', (116, 121))	('EWSR1', 'Gene', (147, 152))	('FUS', 'Gene', (101, 104))	('gene fusion', 'Var', (39, 50))	('FUS', 'Gene', '2521', (101, 104))	('ES', 'Phenotype', 'HP:0012254', (29, 31))	('EWSR1', 'Gene', '2130', (147, 152))	('EWS RNA binding protein 1', 'Gene', (154, 179))	('FLI1', 'Gene', '2313', (259, 263))	('EWS RNA binding protein 1', 'Gene', '2130', (154, 179))	('FLI1', 'Gene', (259, 263))	('TAF15', 'Gene', '8148', (116, 121))	('EWSR1', 'Gene', (106, 111))	('FET gene', 'Gene', (70, 78))
226000	32770382	Since a study on melanoma cells observed that centrinone-B was less effective in cells with mutant p53 (Denu et al.	('p53', 'Gene', (99, 102))	('centrinone-B', 'Chemical', 'MESH:C000599098', (46, 58))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('mutant', 'Var', (92, 98))	('p53', 'Gene', '7157', (99, 102))
226001	32770382	), we used three ES cell lines with different TP53 status, i.e., wild-type p53 WE-68 cells, mutant p53 (C176F) SK-ES-1 cells (Sonnemann et al.)	('SK-ES-1', 'CellLine', 'CVCL:0627', (111, 118))	('C176F', 'Mutation', 'rs786202962', (104, 109))	('C176F', 'Var', (104, 109))	('TP53', 'Gene', '7157', (46, 50))	('ES', 'Phenotype', 'HP:0012254', (114, 116))	('p53', 'Gene', (75, 78))	('TP53', 'Gene', (46, 50))	('p53', 'Gene', '7157', (75, 78))	('mutant', 'Var', (92, 98))	('p53', 'Gene', (99, 102))	('p53', 'Gene', '7157', (99, 102))	('ES', 'Phenotype', 'HP:0012254', (17, 19))
226064	32770382	CFI-400945 and centrinone thus may be useful for the treatment of ES with curtailed apoptotic responsiveness due to defects in the caspase system.	('centrinone', 'Chemical', 'MESH:C000599097', (15, 25))	('caspase system', 'Pathway', (131, 145))	('apoptotic responsiveness', 'MPA', (84, 108))	('CFI', 'Gene', (0, 3))	('CFI', 'Gene', '3426', (0, 3))	('defects', 'Var', (116, 123))	('ES', 'Phenotype', 'HP:0012254', (66, 68))
226066	32770382	This finding is in contrast to results obtained in melanoma cells, in which centrinone-B was found to be less effective in cells with mutant TP53 (Denu et al.	('centrinone-B', 'Chemical', 'MESH:C000599098', (76, 88))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('mutant', 'Var', (134, 140))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
226069	32770382	In any case, the evidently p53-independent action of CFI-400945 and centrinone in ES cells is a welcome finding from the clinical perspective: TP53 mutations are relatively rare in ES though (Grunewald et al.	('TP53', 'Gene', (143, 147))	('ES', 'Phenotype', 'HP:0012254', (181, 183))	('mutations', 'Var', (148, 157))	('p53', 'Gene', '7157', (27, 30))	('centrinone', 'Chemical', 'MESH:C000599097', (68, 78))	('CFI', 'Gene', (53, 56))	('CFI', 'Gene', '3426', (53, 56))	('ES', 'Phenotype', 'HP:0012254', (82, 84))	('TP53', 'Gene', '7157', (143, 147))	('p53', 'Gene', (27, 30))
226070	32770382	), the subset of patients with mutant TP53 has a considerably poorer outcome than average (Crompton et al.	('TP53', 'Gene', (38, 42))	('mutant', 'Var', (31, 37))	('patients', 'Species', '9606', (17, 25))	('TP53', 'Gene', '7157', (38, 42))
226111	28654633	We did not see translocation-associated sarcomas, such as synovial sarcoma in this cohort.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (58, 74))	('synovial sarcoma', 'Disease', 'MESH:D013584', (58, 74))	('translocation-associated', 'Var', (15, 39))	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('synovial sarcoma', 'Disease', (58, 74))	('sarcomas', 'Disease', (40, 48))
226123	28654633	Isolating their data of 125 patients, chemotherapy was again associated with a shortened time to development of RIS (HR 1.82; 95% CI: 1.24-2.69; P=0.002).	('chemotherapy', 'Var', (38, 50))	('shortened', 'NegReg', (79, 88))	('RIS', 'Disease', (112, 115))	('patients', 'Species', '9606', (28, 36))	('RIS', 'Chemical', '-', (112, 115))
226128	28654633	Patients given anthracyclines had a shorter interval to RIS than those not treated with an anthracycline (HR 2.56; 95% CI: 1.62-4.07; P<0.001; Figure 1B1).	('anthracyclines', 'Chemical', 'MESH:D018943', (15, 29))	('interval', 'MPA', (44, 52))	('anthracycline', 'Chemical', 'MESH:D018943', (15, 28))	('Patients', 'Species', '9606', (0, 8))	('RIS', 'Chemical', '-', (56, 59))	('anthracyclines', 'Var', (15, 29))	('anthracycline', 'Chemical', 'MESH:D018943', (91, 104))	('RIS', 'MPA', (56, 59))	('shorter', 'NegReg', (36, 43))
226143	28654633	In the Childhood Cancer Survivor study, anthracycline use was associated with an RR of 3.5 for developing a secondary sarcoma.	('anthracycline', 'Var', (40, 53))	('sarcoma', 'Disease', (118, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('anthracycline', 'Chemical', 'MESH:D018943', (40, 53))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
226154	28654633	In pre-clinical studies, anthracyclines and alkylating agents have been shown to induce neoplastic transformation by disruption of DNA function both in vitro and in vivo.	('induce', 'PosReg', (81, 87))	('anthracyclines', 'Var', (25, 39))	('neoplastic transformation', 'CPA', (88, 113))	('anthracyclines', 'Chemical', 'MESH:D018943', (25, 39))	('DNA function', 'MPA', (131, 143))	('disruption', 'NegReg', (117, 127))
226156	28654633	Anthracyclines may be more likely to lead to RIS compared to other topoisomerase II inhibitors due to free radical formation.	('lead', 'Reg', (37, 41))	('RIS', 'Disease', (45, 48))	('RIS', 'Chemical', '-', (45, 48))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('free', 'MPA', (102, 106))	('Anthracyclines', 'Var', (0, 14))
226158	28654633	Even in the absence of radiation, anthracyclines and alkylating agents have been associated with increased risks of developing other SMNs, such as breast, lung, and various gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (173, 197))	('breast', 'Disease', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('anthracyclines', 'Var', (34, 48))	('lung', 'Disease', (155, 159))	('anthracyclines', 'Chemical', 'MESH:D018943', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('SMN', 'Chemical', '-', (133, 136))	('gastrointestinal cancers', 'Disease', (173, 197))
226164	28654633	Breast cancers and sarcomas are both associated with Li Fraumeni syndrome, and related syndromes with mutations in the tumour suppressor gene TP53, which could be one explanation for this finding.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('TP53', 'Gene', '7157', (142, 146))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('TP53', 'Gene', (142, 146))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('sarcomas', 'Disease', 'MESH:D012509', (19, 27))	('tumour', 'Disease', (119, 125))	('mutations', 'Var', (102, 111))	('Fraumeni syndrome', 'Disease', 'MESH:D016864', (56, 73))	('Breast cancers', 'Disease', (0, 14))	('associated', 'Reg', (37, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))	('sarcomas', 'Disease', (19, 27))	('Fraumeni syndrome', 'Disease', (56, 73))
226170	28654633	These patients may have had a germline mutation in certain tumour suppressor or DNA repair genes, which not only predisposed them to their aggressive primary cancer, but also placed them at higher risk and at a shorter time to development of an RIS.	('aggressive primary cancer', 'Disease', (139, 164))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Disease', (59, 65))	('aggressive primary cancer', 'Disease', 'MESH:D009369', (139, 164))	('germline mutation', 'Var', (30, 47))	('patients', 'Species', '9606', (6, 14))	('RIS', 'Chemical', '-', (245, 248))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('DNA repair genes', 'Gene', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('predisposed', 'Reg', (113, 124))
226182	26214589	Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging.	('EGR2', 'Gene', (68, 72))	('variants', 'Var', (175, 183))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('Ewing sarcoma', 'Gene', '2130', (34, 47))	('cancer', 'Disease', (205, 211))	('EWSR1', 'Gene', (9, 14))	('Ewing sarcoma', 'Gene', (34, 47))	('regulates', 'Reg', (20, 29))	('FLI1', 'Gene', (15, 19))	('FLI1', 'Gene', '2313', (15, 19))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (34, 47))	('EWSR1', 'Gene', '2130', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('promote', 'PosReg', (197, 204))	('EGR2', 'Gene', '1959', (68, 72))
226183	26214589	Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', '2130', (50, 55))	('bind', 'Interaction', (178, 182))	('EWSR1', 'Gene', (100, 105))	('Ewing sarcoma', 'Gene', '2130', (0, 13))	('Ewing sarcoma', 'Gene', (0, 13))	('EWSR1', 'Gene', '2130', (100, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('EWSR1', 'Gene', (50, 55))	('FLI1', 'Gene', (106, 110))	('fusions', 'Var', (34, 41))	('FLI1', 'Gene', '2313', (106, 110))
226184	26214589	A recent genome-wide association study identified susceptibility variants near EGR2.	('EGR2', 'Gene', '1959', (79, 83))	('variants', 'Var', (65, 73))	('EGR2', 'Gene', (79, 83))	('susceptibility', 'Reg', (50, 64))
226185	26214589	Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts.	('EGR2', 'Gene', '1959', (19, 23))	('Ewing sarcoma', 'Gene', '2130', (130, 143))	('Ewing sarcoma', 'Gene', (130, 143))	('clonogenicity', 'CPA', (59, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (130, 143))	('inhibited', 'NegReg', (34, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('regression', 'CPA', (116, 126))	('knockdown', 'Var', (24, 33))	('EGR2', 'Gene', (19, 23))	('spheroidal growth', 'CPA', (77, 94))	('proliferation', 'CPA', (44, 57))
226187	26214589	At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element.	('increasing', 'PosReg', (132, 142))	('enhancer activity', 'PosReg', (215, 232))	('FLI1', 'Gene', (200, 204))	('FLI1', 'Gene', '2313', (200, 204))	('EWSR1', 'Gene', (194, 199))	('rs79965208', 'Var', (3, 13))	('EWSR1', 'Gene', '2130', (194, 199))	('rs79965208', 'Mutation', 'rs79965208', (3, 13))
226189	26214589	Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (139, 152))	('Ewing sarcomagenesis', 'Phenotype', 'HP:0012254', (139, 159))	('variant', 'Var', (98, 105))	('Ewing sarcomagenesis', 'Disease', (139, 159))	('Ewing sarcomagenesis', 'Disease', 'MESH:C563168', (139, 159))
226191	26214589	It is driven by oncogenic fusions between EWSR1 and genes in the ETS family (mostly FLI1).	('EWSR1', 'Gene', '2130', (42, 47))	('fusions', 'Var', (26, 33))	('FLI1', 'Gene', (84, 88))	('FLI1', 'Gene', '2313', (84, 88))	('EWSR1', 'Gene', (42, 47))
226203	26214589	Interestingly, the Ewing sarcoma risk-associated rs1848797, which was genotyped in all data sets, was associated with higher EGR2 and ADO expression only in Ewing sarcoma, and not in EWSR1-FLI1-negative tissues (Table 1, Supplementary Data and Supplementary Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('Ewing sarcoma', 'Gene', '2130', (157, 170))	('ADO', 'Gene', '84890', (134, 137))	('expression', 'MPA', (138, 148))	('Ewing sarcoma', 'Gene', (19, 32))	('higher', 'PosReg', (118, 124))	('ADO', 'Gene', (134, 137))	('FLI1', 'Gene', (189, 193))	('EGR2', 'Gene', '1959', (125, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('rs1848797', 'Var', (49, 58))	('EWSR1', 'Gene', '2130', (183, 188))	('Ewing sarcoma', 'Gene', '2130', (19, 32))	('FLI1', 'Gene', '2313', (189, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('EGR2', 'Gene', (125, 129))	('Ewing sarcoma', 'Gene', (157, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (19, 32))	('EWSR1', 'Gene', (183, 188))	('rs1848797', 'Mutation', 'rs1848797', (49, 58))
226204	26214589	Moreover, ectopic EWSR1-FLI1 expression in human MSCs specifically induced EGR2 expression (Fig.	('FLI1', 'Gene', '2313', (24, 28))	('EWSR1', 'Gene', (18, 23))	('induced', 'Reg', (67, 74))	('FLI1', 'Gene', (24, 28))	('EGR2', 'Gene', (75, 79))	('EGR2', 'Gene', '1959', (75, 79))	('EWSR1', 'Gene', '2130', (18, 23))	('expression', 'MPA', (80, 90))	('ectopic', 'Var', (10, 17))	('human', 'Species', '9606', (43, 48))
226208	26214589	Knockdown experiments showed that inhibition of EGR2, but not of ADO, impaired proliferation and clonogenicity of four different Ewing sarcoma cell lines, reduced cell cycle progression through S-phase and reduced cell viability (Fig.	('proliferation', 'CPA', (79, 92))	('Ewing sarcoma', 'Gene', (129, 142))	('reduced', 'NegReg', (206, 213))	('Ewing sarcoma', 'Gene', '2130', (129, 142))	('reduced', 'NegReg', (155, 162))	('inhibition', 'Var', (34, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (129, 142))	('EGR2', 'Gene', '1959', (48, 52))	('EGR2', 'Gene', (48, 52))	('ADO', 'Gene', (65, 68))	('clonogenicity', 'CPA', (97, 110))	('ADO', 'Gene', '84890', (65, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('cell viability', 'CPA', (214, 228))	('cell cycle progression through S-phase', 'CPA', (163, 201))	('impaired', 'NegReg', (70, 78))
226210	26214589	Long-term EGR2 knockdown not only dramatically reduced anchorage-independent spheroidal growth in vitro but, even more strikingly, also induced regression of Ewing sarcoma xenografts in vivo (Fig.	('knockdown', 'Var', (15, 24))	('EGR2', 'Gene', '1959', (10, 14))	('EGR2', 'Gene', (10, 14))	('Ewing sarcoma', 'Gene', '2130', (158, 171))	('Ewing sarcoma', 'Gene', (158, 171))	('anchorage-independent spheroidal growth', 'CPA', (55, 94))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (158, 171))	('regression', 'NegReg', (144, 154))	('reduced', 'NegReg', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
226217	26214589	To fine-map the chr10 susceptibility locus and to identify variants that potentially contribute to EGR2 overexpression, we performed targeted deep sequencing across the chr10 susceptibility locus, including the flanking haplotype blocks, in the germline DNA of 343 individuals with Ewing sarcoma cases and 251 genetically matched controls (median target-region coverage >=10X, 91.35%; median nucleotide coverage, 217X).	('EGR2', 'Gene', (99, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (282, 295))	('variants', 'Var', (59, 67))	('chr10', 'Gene', (169, 174))	('Ewing sarcoma', 'Gene', '2130', (282, 295))	('Ewing sarcoma', 'Gene', (282, 295))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('EGR2', 'Gene', '1959', (99, 103))
226226	26214589	This activity corresponded to EWSR1-FLI1-dependent activating chromatin marks H3K4me1 and H3K27ac (Fig.	('EWSR1', 'Gene', '2130', (30, 35))	('H3K27ac', 'Var', (90, 97))	('H3K4me1', 'Protein', (78, 85))	('FLI1', 'Gene', '2313', (36, 40))	('FLI1', 'Gene', (36, 40))	('activating', 'PosReg', (51, 61))	('EWSR1', 'Gene', (30, 35))
226227	26214589	3a) and was consistent with recent evidence suggesting that EWSR1-FLI1 can act as a pioneer transcription factor to create de novo enhancers at GGAA microsatellites.	('EWSR1', 'Gene', '2130', (60, 65))	('FLI1', 'Gene', '2313', (66, 70))	('microsatellites', 'Var', (149, 164))	('FLI1', 'Gene', (66, 70))	('enhancers', 'PosReg', (131, 140))	('EWSR1', 'Gene', (60, 65))
226230	26214589	This yielded 1,158 analyzable mSat2 sequences, which revealed another SNP, rs79965208, in strong LD (D' = 0.97) with the nearby rs6479860, one of the strongest sentinel SNPs from our GWAS (Fig.	('rs6479860', 'Var', (128, 137))	('rs79965208', 'Var', (75, 85))	('mSat2', 'Gene', (30, 35))	('rs79965208', 'Mutation', 'rs79965208', (75, 85))	('mSat2', 'Gene', '69215', (30, 35))	('rs6479860', 'Mutation', 'rs6479860', (128, 137))
226231	26214589	The significant association of the A allele of rs79965208 with Ewing sarcoma (P = 0.022, logistic regression) was replicated in two independent cohorts, the first based on direct sequencing of this SNP in 156 additional Ewing sarcoma subjects and 184 controls of European descent (P = 6.15 x 10-3, logistic regression), and the second on imputation from the 1000 Genomes Project Phase 3 reference panel of 162 individuals with first primary Ewing sarcoma from the Childhood Cancer Survivor Study genotyped on Illumina HumanOmni5Exome arrays and 435 cancer-free controls from the Division of Cancer Epidemiology and Genetics (P = 9.33 x 10-6, logistic regression) (Supplementary Data).	('Human', 'Species', '9606', (518, 523))	('Ewing sarcoma', 'Gene', '2130', (220, 233))	('cancer', 'Disease', (549, 555))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('Cancer', 'Disease', (474, 480))	('Cancer', 'Disease', (591, 597))	('Ewing sarcoma', 'Gene', '2130', (441, 454))	('cancer', 'Phenotype', 'HP:0002664', (549, 555))	('Cancer', 'Phenotype', 'HP:0002664', (474, 480))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (220, 233))	('rs79965208', 'Mutation', 'rs79965208', (47, 57))	('Cancer', 'Disease', 'MESH:D009369', (591, 597))	('Cancer', 'Disease', 'MESH:D009369', (474, 480))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (441, 454))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('cancer', 'Disease', 'MESH:D009369', (549, 555))	('Ewing sarcoma', 'Gene', (63, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (447, 454))	('Ewing sarcoma', 'Gene', (220, 233))	('rs79965208', 'Var', (47, 57))	('Ewing sarcoma', 'Gene', '2130', (63, 76))	('Cancer', 'Phenotype', 'HP:0002664', (591, 597))	('Ewing sarcoma', 'Gene', (441, 454))
226233	26214589	The A allele at rs79965208 therefore increases the median number of consecutive GGAA motifs from 11 to 16.	('increases', 'PosReg', (37, 46))	('rs79965208', 'Mutation', 'rs79965208', (16, 26))	('rs79965208', 'Var', (16, 26))
226236	26214589	We subsequently examined the enhancer properties of mSat2 corresponding to the reference sequence (hg19) containing either the T or A allele at rs79965208 in a luciferase assay.	('mSat2', 'Gene', (52, 57))	('rs79965208', 'Mutation', 'rs79965208', (144, 154))	('rs79965208', 'Var', (144, 154))	('mSat2', 'Gene', '69215', (52, 57))
226238	26214589	This transcription-activation property was observed in two Ewing sarcoma cell lines and was strictly dependent on EWSR1-FLI1, as its doxycycline-induced knockdown abrogated luciferase activity (Fig.	('knockdown', 'Var', (153, 162))	('luciferase', 'Enzyme', (173, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('EWSR1', 'Gene', (114, 119))	('activity', 'MPA', (184, 192))	('abrogated', 'NegReg', (163, 172))	('Ewing sarcoma', 'Gene', '2130', (59, 72))	('Ewing sarcoma', 'Gene', (59, 72))	('EWSR1', 'Gene', '2130', (114, 119))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('doxycycline', 'Chemical', 'MESH:D004318', (133, 144))	('FLI1', 'Gene', (120, 124))	('FLI1', 'Gene', '2313', (120, 124))
226241	26214589	10), indicating that EWSR1-FLI1 preferentially bound to the A allele of rs79965208.	('rs79965208', 'Mutation', 'rs79965208', (72, 82))	('EWSR1', 'Gene', (21, 26))	('FLI1', 'Gene', '2313', (27, 31))	('EWSR1', 'Gene', '2130', (21, 26))	('preferentially', 'PosReg', (32, 46))	('rs79965208', 'Var', (72, 82))	('FLI1', 'Gene', (27, 31))	('bound', 'Interaction', (47, 52))
226242	26214589	Moreover, taking advantage of a transcribed SNP in the 3' UTR of EGR2 (rs61865883), we assessed allele-specific EGR2 expression via targeted RNA deep sequencing.	('rs61865883', 'Var', (71, 81))	('EGR2', 'Gene', '1959', (65, 69))	('EGR2', 'Gene', (65, 69))	('rs61865883', 'Mutation', 'rs61865883', (71, 81))	('EGR2', 'Gene', '1959', (112, 116))	('EGR2', 'Gene', (112, 116))
226243	26214589	Across 45 individuals with heterozygosity for rs61865883, the transcriptional allelic imbalance was significantly higher in 16 tumors heterozygous for rs79965208 (A/T) than in 29 tumors homozygous (A/A or T/T) for this locus (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('rs79965208', 'Mutation', 'rs79965208', (151, 161))	('rs61865883', 'Var', (46, 56))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('transcriptional allelic imbalance', 'MPA', (62, 95))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('imbalance', 'Phenotype', 'HP:0002172', (86, 95))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('rs61865883', 'Mutation', 'rs61865883', (46, 56))	('higher', 'PosReg', (114, 120))	('rs79965208', 'Var', (151, 161))
226245	26214589	Importantly, we noted that the chr10 signal was strongly reduced when we performed association testing conditionally on rs79965208, which indicated that this SNP is a major functional variant at this locus.	('rs79965208', 'Var', (120, 130))	('reduced', 'NegReg', (57, 64))	('chr10', 'Gene', (31, 36))	('rs79965208', 'Mutation', 'rs79965208', (120, 130))
226248	26214589	However, we could not test whether Ewing sarcoma cells with a T/T genotype at rs79965208 have decreased sensitivity to EGR2 knockdown, as the T/T genotype was not observed across 21 different Ewing sarcoma cell lines (Supplementary Data).	('EGR2', 'Gene', '1959', (119, 123))	('EGR2', 'Gene', (119, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('Ewing sarcoma', 'Gene', '2130', (35, 48))	('Ewing sarcoma', 'Gene', '2130', (192, 205))	('Ewing sarcoma', 'Gene', (192, 205))	('rs79965208', 'Var', (78, 88))	('sensitivity', 'MPA', (104, 115))	('decreased', 'NegReg', (94, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('knockdown', 'MPA', (124, 133))	('Ewing sarcoma', 'Gene', (35, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (192, 205))	('rs79965208', 'Mutation', 'rs79965208', (78, 88))
226249	26214589	As the incidence of Ewing sarcoma is higher in Europeans than in Africans, we investigated the frequency of the A allele at rs79965208 across human populations, as determined by the 1000 Genomes Project (Supplementary Data).	('rs79965208', 'Mutation', 'rs79965208', (124, 134))	('Ewing sarcoma', 'Gene', '2130', (20, 33))	('human', 'Species', '9606', (142, 147))	('Ewing sarcoma', 'Gene', (20, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('rs79965208', 'Var', (124, 134))
226250	26214589	Strikingly, the A risk allele is highly significantly more frequent in non-African human populations (mean, 0.64; range, 0.57-0.70; n = 1,886) than in Africans (0.25; n = 691) (P = 2.20 x 10-16, Fisher's exact test), which suggests that rs79965208 underwent a recent expansion in non-Africans and that it might contribute to the variable susceptibility to Ewing sarcoma across populations.	('Ewing sarcoma', 'Gene', '2130', (356, 369))	('human', 'Species', '9606', (83, 88))	('Ewing sarcoma', 'Gene', (356, 369))	('sarcoma', 'Phenotype', 'HP:0100242', (362, 369))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (356, 369))	('rs79965208', 'Var', (237, 247))	('rs79965208', 'Mutation', 'rs79965208', (237, 247))
226251	26214589	To our knowledge, this constitutes one of the first reports of how a germline variant highly correlated with the reported GWAS signal can inform our understanding of a cancer-specific acquired genetic abnormality.	('genetic abnormality', 'Disease', 'MESH:D030342', (193, 212))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('genetic abnormality', 'Disease', (193, 212))	('inform', 'Reg', (138, 144))	('variant', 'Var', (78, 85))	('GWAS', 'MPA', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))
226252	26214589	Moreover, they illustrate the contribution of a common germline variant that alters one or more key biological pathways in Ewing sarcoma through the modification of transcription regulatory elements that mediate the effects of a dominant oncogene.	('modification', 'Reg', (149, 161))	('alters', 'Reg', (77, 83))	('transcription regulatory elements', 'MPA', (165, 198))	('Ewing sarcoma', 'Gene', (123, 136))	('variant', 'Var', (64, 71))	('Ewing sarcoma', 'Gene', '2130', (123, 136))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('key biological pathways', 'Pathway', (96, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
226254	26214589	A673-TR-shEF1 and SK-N-MC-TR-shEF1 harbor a doxycycline-inducible shRNA against EWSR1-FLI1 (ref.	('A673-TR-shEF1', 'Var', (0, 13))	('EWSR1', 'Gene', (80, 85))	('FLI1', 'Gene', (86, 90))	('FLI1', 'Gene', '2313', (86, 90))	('doxycycline', 'Chemical', 'MESH:D004318', (44, 55))	('SK-N-MC-TR-shEF1', 'CellLine', 'CVCL:1E45', (18, 34))	('EWSR1', 'Gene', '2130', (80, 85))
226286	26214589	Doxycycline (1 mug/ml) was added for induction of EGR2 knockdown.	('knockdown', 'Var', (55, 64))	('EGR2', 'Gene', '1959', (50, 54))	('Doxycycline', 'Chemical', 'MESH:D004318', (0, 11))	('EGR2', 'Gene', (50, 54))
226299	26214589	Doxycycline-induced EGR2 knockdown was confirmed by qRT-PCR 72 h after the start of doxycycline treatment in aliquots of the injected cells that were grown in parallel in vitro.	('EGR2', 'Gene', '1959', (20, 24))	('EGR2', 'Gene', (20, 24))	('doxycycline', 'Chemical', 'MESH:D004318', (84, 95))	('knockdown', 'Var', (25, 34))	('Doxycycline', 'Chemical', 'MESH:D004318', (0, 11))
226312	26214589	LD and haplotype analyses were done with PLINK and HaploView as described by Gabriel et al.. Association testing conditional to rs79965208 was done with PLINK with a logistic regression including significant PCA eigenvectors (EV1, EV5 and EV6) and the 'condition' command option.	('EV1', 'Gene', (226, 229))	('rs79965208', 'Var', (128, 138))	('rs79965208', 'Mutation', 'rs79965208', (128, 138))	('EV5', 'Chemical', '-', (231, 234))	('EV6', 'Chemical', '-', (239, 242))	('EV1', 'Gene', '11322', (226, 229))
226317	26214589	In this cohort, the mSat2 region containing rs79965208 was directly sequenced in an Illumina MiSeq instrument.	('mSat2', 'Gene', (20, 25))	('mSat2', 'Gene', '69215', (20, 25))	('rs79965208', 'Mutation', 'rs79965208', (44, 54))	('rs79965208', 'Var', (44, 54))
226318	26214589	A second replication of the association of rs79965208 with Ewing sarcoma was conducted in an independent sample of individuals of European descent from the United States.	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('rs79965208', 'Var', (43, 53))	('Ewing sarcoma', 'Gene', '2130', (59, 72))	('Ewing sarcoma', 'Gene', (59, 72))	('rs79965208', 'Mutation', 'rs79965208', (43, 53))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))
226325	26214589	Allele-specific EGR2 expression was assessed via targeted RNA sequencing (Illumina HiSeq2500) in 45 individuals with Ewing sarcoma who were heterozygous in constitutional DNA for rs61865883 (located in the EGR2 3' UTR), serving as transcribed allelic marker.	('rs61865883', 'Mutation', 'rs61865883', (179, 189))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (117, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('EGR2', 'Gene', '1959', (206, 210))	('EGR2', 'Gene', (206, 210))	('rs61865883', 'Var', (179, 189))	('Ewing sarcoma', 'Gene', '2130', (117, 130))	('Ewing sarcoma', 'Gene', (117, 130))	('EGR2', 'Gene', '1959', (16, 20))	('EGR2', 'Gene', (16, 20))
226327	26214589	For each of these 45 subjects, we statistically compared the raw rs61865883 allele fractions of 16 tumors heterozygous for rs79965208 (A/T) with those of 29 tumors that were homozygous for rs79965208 (A/A or T/T) using a parametric two-tailed Student's t-test.	('rs79965208', 'Mutation', 'rs79965208', (189, 199))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('rs61865883', 'Mutation', 'rs61865883', (65, 75))	('rs79965208', 'Var', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('rs79965208', 'Mutation', 'rs79965208', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('rs61865883', 'Var', (65, 75))
226328	26214589	ENCODE SK-N-MC DNase-Seq (GSM736570) and RNA Pol II ChIP-Seq (GSM1010793), together with the FAIRE-Seq data, were analyzed within the Nebula environment using Model-based Analysis of ChIP-Seq v1.4.2 (MACS) and converted to *.wig format for display in the UCSC Genome Browser.	('iron', 'Chemical', 'MESH:D007501', (144, 148))	('GSM1010793', 'Var', (62, 72))	('GSM736570', 'Chemical', '-', (26, 35))	('SK-N-MC', 'Chemical', '-', (7, 14))	('GSM736570', 'Var', (26, 35))
226329	26214589	Samples used were: GSM1517544 SK-N-MC_shGFP_48h_FLI1, GSM1517553 SK-N-MC_shFLI1_48h_FLI1, GSM1517569 A673_shGFP_48h_FLI1, GSM1517572 A673_shFLI1_48h_FLI1, GSM1517548 SK-N-MC_shGFP_96h_H3K4me1, GSM1517557 SK-N-MC_shFLI1_96h_H3K4me1, GSM1517545 SK-N-MC_shGFP_48h_H3K27ac, and GSM1517554 SK-N-MC_shFLI1_48h_H3K27ac.	('FLI1', 'Gene', (48, 52))	('FLI1', 'Gene', (214, 218))	('SK-N-MC', 'Chemical', '-', (65, 72))	('FLI1', 'Gene', '2313', (295, 299))	('GSM1517545', 'Var', (232, 242))	('FLI1', 'Gene', '2313', (48, 52))	('FLI1', 'Gene', (149, 153))	('FLI1', 'Gene', (84, 88))	('FLI1', 'Gene', '2313', (214, 218))	('SK-N-MC', 'Chemical', '-', (285, 292))	('FLI1', 'Gene', (116, 120))	('FLI1', 'Gene', (140, 144))	('SK-N-MC', 'Chemical', '-', (166, 173))	('SK-N-MC', 'Chemical', '-', (30, 37))	('FLI1', 'Gene', '2313', (149, 153))	('FLI1', 'Gene', '2313', (84, 88))	('FLI1', 'Gene', (75, 79))	('FLI1', 'Gene', '2313', (116, 120))	('FLI1', 'Gene', '2313', (140, 144))	('SK-N-MC', 'Chemical', '-', (204, 211))	('SK-N-MC', 'Chemical', '-', (243, 250))	('FLI1', 'Gene', (295, 299))	('FLI1', 'Gene', '2313', (75, 79))
226341	32948771	We demonstrate that dTAGV-1 degrades fusion proteins recalcitrant to CRBN-mediated degradation, exemplified by EWS/FLI, a driver of Ewing sarcoma.	('FLI', 'Gene', (115, 118))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (132, 145))	('dTAGV-1', 'Var', (20, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (132, 145))	('fusion proteins', 'Protein', (37, 52))	('EWS', 'Gene', '2130', (111, 114))	('EWS', 'Gene', (111, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('dTAGV-1', 'Chemical', '-', (20, 27))	('FLI', 'Gene', '2314', (115, 118))	('degrades', 'NegReg', (28, 36))	('Ewing sarcoma', 'Disease', (132, 145))
226358	32948771	KRASG12V degradation was rescued by pre-treatment with proteasome-inhibitor carfilzomib or Nedd8 activating enzyme inhibitor MLN4924, and by VHL knockout, consistent with the mechanism-of-action of a VHL-recruiting degrader (Fig.	('Nedd8', 'Gene', (91, 96))	('knockout', 'Var', (145, 153))	('MLN4924', 'Chemical', 'MESH:C539933', (125, 132))	('MLN4924', 'Var', (125, 132))	('degradation', 'MPA', (9, 20))	('KRASG12V', 'Gene', (0, 8))	('KRASG12V', 'Chemical', '-', (0, 8))	('Nedd8', 'Gene', '4738', (91, 96))	('carfilzomib', 'Chemical', 'MESH:C524865', (76, 87))
226369	32948771	Ewing sarcoma is driven by the translocation of EWSR1 and members of the ETS transcription factors, most commonly FLI, giving rise to a fusion transcription factor oncoprotein that activates an aberrant transcriptional program.	('EWSR1', 'Gene', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('transcriptional', 'MPA', (203, 218))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('driven by', 'Reg', (17, 26))	('Ewing sarcoma', 'Disease', (0, 13))	('translocation', 'Var', (31, 44))	('EWSR1', 'Gene', '2130', (48, 53))	('activates', 'PosReg', (181, 190))	('FLI', 'Gene', '2314', (114, 117))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('FLI', 'Gene', (114, 117))
226377	32948771	dTAGV-1 led to a decrease in downstream EWS/FLI targets such as NKX2-2, and Gene Set Enrichment Analysis (GSEA) of the differentially regulated target proteins (FDR < 0.05) identified known EWS/FLI and Ewing sarcoma signatures (Fig.	('FLI', 'Gene', '2314', (44, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('FLI', 'Gene', (194, 197))	('FLI', 'Gene', (44, 47))	('dTAGV-1', 'Var', (0, 7))	('NKX2-2', 'Gene', '4821', (64, 70))	('dTAGV-1', 'Chemical', '-', (0, 7))	('EWS', 'Gene', '2130', (190, 193))	('EWS', 'Gene', (190, 193))	('decrease', 'NegReg', (17, 25))	('EWS', 'Gene', (40, 43))	('Ewing sarcoma', 'Disease', (202, 215))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (202, 215))	('EWS', 'Gene', '2130', (40, 43))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (202, 215))	('FLI', 'Gene', '2314', (194, 197))	('NKX2-2', 'Gene', (64, 70))
226382	32948771	Treatment of FKBP12F36V-EWS/FLI; EWS/FLI-/- cells with dTAG-63 led to marginal degradation of FKBP12F36V-EWS/FLI, limited changes in NKX2-2 protein levels and modest antiproliferative effects relative to dTAGV-1 (Supplementary Fig.	('EWS', 'Gene', '2130', (24, 27))	('EWS', 'Gene', (105, 108))	('FLI', 'Gene', (109, 112))	('EWS', 'Gene', (33, 36))	('FKBP12', 'Gene', (94, 100))	('dTAG-', 'Chemical', '-', (55, 60))	('FKBP12', 'Gene', '2284', (94, 100))	('FLI', 'Gene', '2314', (109, 112))	('antiproliferative', 'MPA', (166, 183))	('dTAG-63', 'Var', (55, 62))	('EWS', 'Gene', (24, 27))	('FLI', 'Gene', (37, 40))	('FKBP12', 'Gene', (13, 19))	('FKBP12', 'Gene', '2284', (13, 19))	('EWS', 'Gene', '2130', (105, 108))	('FLI', 'Gene', (28, 31))	('FLI', 'Gene', '2314', (37, 40))	('dTAGV-1', 'Chemical', '-', (204, 211))	('NKX2-2', 'Gene', '4821', (133, 139))	('FLI', 'Gene', '2314', (28, 31))	('changes', 'Reg', (122, 129))	('EWS', 'Gene', '2130', (33, 36))	('degradation', 'NegReg', (79, 90))	('NKX2-2', 'Gene', (133, 139))
226392	32948771	Through evaluation of mutant KRAS degradation in PDAC models, we show that either CRBN or VHL can be co-opted to alleviate the aberrant signaling coordinated by this oncoprotein.	('aberrant signaling coordinated', 'MPA', (127, 157))	('alleviate', 'NegReg', (113, 122))	('KRAS', 'Gene', (29, 33))	('mutant', 'Var', (22, 28))	('KRAS', 'Gene', '3845', (29, 33))	('PDAC', 'Phenotype', 'HP:0006725', (49, 53))	('PD', 'Disease', 'MESH:D010300', (49, 51))	('VHL', 'Gene', (90, 93))
226397	32948771	Employing dTAGV-1 to study EWS/FLI, we demonstrate that VHL-mediated degradation of EWS/FLI rapidly alters downstream target protein expression and leads to pronounced growth defects in Ewing sarcoma cells, providing a powerful model system to investigate immediate consequences of EWS/FLI loss.	('FLI', 'Gene', (88, 91))	('VHL-mediated', 'Gene', (56, 68))	('EWS', 'Gene', (282, 285))	('dTAGV-1', 'Chemical', '-', (10, 17))	('FLI', 'Gene', (31, 34))	('alters', 'Reg', (100, 106))	('Ewing sarcoma', 'Disease', (186, 199))	('FLI', 'Gene', (286, 289))	('FLI', 'Gene', '2314', (88, 91))	('FLI', 'Gene', '2314', (31, 34))	('EWS', 'Gene', '2130', (84, 87))	('FLI', 'Gene', '2314', (286, 289))	('EWS', 'Gene', '2130', (27, 30))	('EWS', 'Gene', '2130', (282, 285))	('degradation', 'Var', (69, 80))	('growth', 'MPA', (168, 174))	('leads to', 'Reg', (148, 156))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (186, 199))	('downstream target protein expression', 'MPA', (107, 143))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (186, 199))	('EWS', 'Gene', (84, 87))	('EWS', 'Gene', (27, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
226404	32948771	In brief, to first generate pDONR221-EWS/FLI, EWS/FLI was cloned into pDONR221 using BP clonase (Invitrogen) after PCR with the following primers containing BP overhangs: Forward-N-E/F-dTAG, 5'-ggggacaagtttgtacaaaaaagcaggcttcgcgtccacggattacagtacct-3' and Reverse-N-E/F-dTAG, 5'-ggggaccactttgtacaagaaagctgggtcctagtagtagctgcctaagtgtgaaggc-3'.	('dTAG', 'Chemical', '-', (269, 273))	('FLI', 'Gene', (50, 53))	('Reverse-N-E/F-dTAG', 'Var', (255, 273))	('FLI', 'Gene', '2314', (41, 44))	('EWS', 'Gene', '2130', (46, 49))	('EWS', 'Gene', (46, 49))	('FLI', 'Gene', (41, 44))	('EWS', 'Gene', '2130', (37, 40))	('EWS', 'Gene', (37, 40))	('FLI', 'Gene', '2314', (50, 53))	('dTAG', 'Chemical', '-', (185, 189))
226443	32948771	Spectral searches were performed using a 2020 Uniprot Human database including canonical isoforms (96,788 total entries) fasta formatted database which included custom sequences for LACZ-FKBP12F36V and FKBP12F36V-EWS/FLI, common contaminants, reversed sequences (Uniprot Human, 2020) and the following parameters: 50 ppm precursor tolerance, fully tryptic peptides, fragment ion tolerance of 0.9 Da and a static modification of TMT (+229.163 Da) on lysine and peptide N-termini, carbamidomethylation of cysteine residues (+57.021 Da) were set as static modifications, while oxidation of methionine residues (+15.995 Da) was set as a variable modification.	('FKBP12', 'Gene', '2284', (187, 193))	('FKBP12', 'Gene', (202, 208))	('FLI', 'Gene', '2314', (217, 220))	('FKBP12', 'Gene', '2284', (202, 208))	('Human', 'Species', '9606', (271, 276))	('EWS', 'Gene', '2130', (213, 216))	('EWS', 'Gene', (213, 216))	('FKBP12', 'Gene', (187, 193))	('+57.021 Da', 'Var', (522, 532))	('Human', 'Species', '9606', (54, 59))	('FLI', 'Gene', (217, 220))
226463	32948771	are inventors on patent applications related to the dTAG system (WO/2017/024318, WO/2017/024319, WO/2018/148440 and WO/2018/148443).	('WO/2017/024319', 'Var', (81, 95))	('WO/2018/148440', 'Var', (97, 111))	('WO/2017/024318', 'Var', (65, 79))	('WO/2018/148443', 'Var', (116, 130))	('dTAG', 'Chemical', '-', (52, 56))
226562	27807504	A recent large retrospective series 39 which included 684 patients with primary, nonmetastatic extremity STS showed in multivariate analysis that the predictors of local recurrence are positive/close margins, high grade, age &gt; 50, size &gt; 5 cm, and unfavourable histology .	('patients', 'Species', '9606', (58, 66))	('local recurrence', 'CPA', (164, 180))	('age &gt', 'Var', (221, 228))	('high grade', 'Var', (209, 219))
226629	32489430	Finally, the typical cardiotoxicity of anthracyclines, which represent the preferred chemotherapeutic choice for sarcomas, could limit their use in neoadjuvant/adjuvant or advanced settings in these cases.	('sarcomas', 'Disease', (113, 121))	('anthracyclines', 'Chemical', 'MESH:D018943', (39, 53))	('cardiotoxicity', 'Disease', 'MESH:D066126', (21, 35))	('cardiotoxicity', 'Disease', (21, 35))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('anthracyclines', 'Var', (39, 53))	('limit', 'NegReg', (129, 134))
226639	32489430	Molecular aberrations detected in cardiac AS often involve KDR and KIT and homozygous deletion of CDKN2A.	('KDR', 'Gene', (59, 62))	('KIT', 'Gene', (67, 70))	('cardiac', 'Disease', (34, 41))	('CDKN2A', 'Gene', (98, 104))	('KDR', 'Gene', '3791', (59, 62))	('involve', 'Reg', (51, 58))	('CDKN2A', 'Gene', '1029', (98, 104))	('AS', 'Phenotype', 'HP:0200058', (42, 44))	('deletion', 'Var', (86, 94))	('KIT', 'Gene', '3815', (67, 70))
226640	32489430	In particular these mutations involve KDR (kinase insert domain receptor encoding for one of the vascular endothelial growth factor receptor tyrosine kinases), PLCG1 (phospholipase C gamma 1 encoding for a tyrosine kinase signal transducer within the phosphoinositide signaling pathway), and PTPRB (protein tyrosine phosphatase receptor type B encoding for a negative regulator of vascular growth factor tyrosine kinases).	('phospholipase C gamma 1', 'Gene', (167, 190))	('phospholipase C gamma 1', 'Gene', '5335', (167, 190))	('PLCG1', 'Gene', '5335', (160, 165))	('KDR', 'Gene', (38, 41))	('PTPRB', 'Gene', '5787', (292, 297))	('PLCG1', 'Gene', (160, 165))	('KDR', 'Gene', '3791', (38, 41))	('PTPRB', 'Gene', (292, 297))	('mutations', 'Var', (20, 29))	('phosphoinositide', 'Chemical', 'MESH:D010716', (251, 267))
226641	32489430	Indeed, KDR mutations are present in about 7-10% of soft tissue AS, and three KDR-mutated cases have been reported in cardiac AS: one case harbored a mutation in the transmembrane domain (p.T771K) while the other two in the immunoglobulin domain (p.G681R and p.R720W) of the protein.	('p.G681R', 'Mutation', 'p.G681R', (247, 254))	('p.R720W', 'Var', (259, 266))	('p.T771K', 'Var', (188, 195))	('p.R720W', 'Mutation', 'p.R720W', (259, 266))	('KDR', 'Gene', (8, 11))	('KDR', 'Gene', '3791', (78, 81))	('AS', 'Phenotype', 'HP:0200058', (126, 128))	('AS', 'Phenotype', 'HP:0200058', (64, 66))	('KDR', 'Gene', '3791', (8, 11))	('p.T771K', 'Mutation', 'p.T771K', (188, 195))	('KDR', 'Gene', (78, 81))	('p.G681R', 'Var', (247, 254))
226642	32489430	Similarly, PLCG1 mutations were reported in about 10% of soft tissue AS, predominantly affecting the highly conserved auto-inhibitory Src homology 2 (cSH2) domain within exon 18 (p.R707Q or p.R707L), with rarer mutations involving exon 11.	('cSH2', 'Gene', (150, 154))	('p.R707Q', 'Mutation', 'p.R707Q', (179, 186))	('PLCG1', 'Gene', (11, 16))	('AS', 'Phenotype', 'HP:0200058', (69, 71))	('p.R707L', 'Var', (190, 197))	('PLCG1', 'Gene', '5335', (11, 16))	('affecting', 'Reg', (87, 96))	('p.R707L', 'Mutation', 'p.R707L', (190, 197))	('mutations', 'Var', (17, 26))	('p.R707Q', 'Var', (179, 186))
226643	32489430	Among cardiac cases, p.R707Q has been reported in a minority of cases and functional studies demonstrate that this mutation confers KDR-independent PLCG1 activation, probably causing primary resistance against VEGF/KDR-directed therapies.	('p.R707Q', 'Mutation', 'p.R707Q', (21, 28))	('causing', 'Reg', (175, 182))	('KDR', 'Gene', '3791', (215, 218))	('PLCG1', 'Gene', (148, 153))	('KDR', 'Gene', (132, 135))	('VEGF', 'Gene', '7422', (210, 214))	('activation', 'PosReg', (154, 164))	('KDR', 'Gene', (215, 218))	('PLCG1', 'Gene', '5335', (148, 153))	('p.R707Q', 'Var', (21, 28))	('KDR', 'Gene', '3791', (132, 135))	('VEGF', 'Gene', (210, 214))
226645	32489430	However, PTPRB mutations have yet to be reported in cardiac AS, although they are present in up to 26% of soft tissue AS, exclusively in the setting of secondary or MYC-amplified AS and often in association with PLCG1 mutations.	('AS', 'Phenotype', 'HP:0200058', (179, 181))	('AS', 'Phenotype', 'HP:0200058', (118, 120))	('MYC', 'Gene', (165, 168))	('PLCG1', 'Gene', '5335', (212, 217))	('mutations', 'Var', (15, 24))	('AS', 'Phenotype', 'HP:0200058', (60, 62))	('MYC', 'Gene', '4609', (165, 168))	('PLCG1', 'Gene', (212, 217))	('PTPRB', 'Gene', '5787', (9, 14))	('PTPRB', 'Gene', (9, 14))
226648	32489430	Alterations of TP53, commonly observed in sarcoma with complex karyotypes, are rare events in all AS, with an estimated frequency of 4%.	('sarcoma', 'Disease', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Alterations', 'Var', (0, 11))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('AS', 'Phenotype', 'HP:0200058', (98, 100))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))
226649	32489430	In cardiac AS, the exact frequency and significance of TP53 mutations remain unclear, given the limited literature on the subject.	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('cardiac', 'Disease', (3, 10))	('AS', 'Phenotype', 'HP:0200058', (11, 13))	('mutations', 'Var', (60, 69))
226652	32489430	In cardiac AS, p.G13S and p.Q61K mutations have been reported in few cases.	('p.G13S', 'Var', (15, 21))	('p.G13S', 'Mutation', 'rs121913535', (15, 21))	('p.Q61K', 'Var', (26, 32))	('cardiac', 'Disease', (3, 10))	('AS', 'Phenotype', 'HP:0200058', (11, 13))	('p.Q61K', 'Mutation', 'rs121913238', (26, 32))
226653	32489430	Other mutated genes detected in soft tissue AS (CIC fusions and mutations, PIK3CA, FLT4, TIE1) have not yet been investigated in the cardiac AS.	('PIK3CA', 'Gene', (75, 81))	('PIK3CA', 'Gene', '5290', (75, 81))	('FLT4', 'Gene', (83, 87))	('AS', 'Phenotype', 'HP:0200058', (44, 46))	('mutations', 'Var', (64, 73))	('TIE1', 'Gene', (89, 93))	('FLT4', 'Gene', '2324', (83, 87))	('AS', 'Phenotype', 'HP:0200058', (141, 143))	('TIE1', 'Gene', '7075', (89, 93))
226654	32489430	For example, inactivating mutations of the lysine methyltransferase 2D (KMT2D), a gene found altered in a large number of different cancers (including diffuse large B-cell lymphoma, follicular lymphoma, and medulloblastoma), have been reported in cardiac AS but not in extra-cardiac AS: one in concomitance with KDR p.R707Q and one together with Protection of Telomeres 1 (POT1) inactivating mutation.	('medulloblastoma', 'Phenotype', 'HP:0002885', (207, 222))	('inactivating mutations', 'Var', (13, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (193, 201))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (165, 180))	('medulloblastoma', 'Disease', (207, 222))	('AS', 'Phenotype', 'HP:0200058', (283, 285))	('POT1', 'Gene', (373, 377))	('lysine methyltransferase 2D', 'Gene', (43, 70))	('cardiac AS', 'Disease', (247, 257))	('KMT2D', 'Gene', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('p.R707Q', 'Mutation', 'p.R707Q', (316, 323))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (165, 180))	('lymphoma', 'Disease', (172, 180))	('lymphoma', 'Disease', 'MESH:D008223', (172, 180))	('lymphoma', 'Disease', (193, 201))	('lysine methyltransferase 2D', 'Gene', '8085', (43, 70))	('Protection of Telomeres 1', 'Gene', '25913', (346, 371))	('KDR', 'Gene', (312, 315))	('lymphoma', 'Disease', 'MESH:D008223', (193, 201))	('Protection of Telomeres 1', 'Gene', (346, 371))	('B-cell lymphoma', 'Disease', (165, 180))	('AS', 'Phenotype', 'HP:0200058', (255, 257))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('KMT2D', 'Gene', '8085', (72, 77))	('cancers', 'Disease', (132, 139))	('POT1', 'Gene', '25913', (373, 377))	('KDR', 'Gene', '3791', (312, 315))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (172, 180))	('reported', 'Reg', (235, 243))	('medulloblastoma', 'Disease', 'MESH:D008527', (207, 222))
226655	32489430	With regards to the latter, POT1 alterations occur in 27% of Li-Fraumeni-like (LFL) family with members affected with AS, and in 11.4% of sporadic cardiac AS.	('AS', 'Phenotype', 'HP:0200058', (118, 120))	('occur', 'Reg', (45, 50))	('alterations', 'Var', (33, 44))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (61, 72))	('POT1', 'Gene', '25913', (28, 32))	('AS', 'Phenotype', 'HP:0200058', (155, 157))	('Li-Fraumeni', 'Disease', (61, 72))	('POT1', 'Gene', (28, 32))
226656	32489430	Up to now, different POT1 mutations have been identified in cardiac AS: one p.G301* and 3 cases of p.R117C in LFL families, and a p.P116L and a p.R432* in two sporadic cases.	('p.R432*', 'Var', (144, 151))	('p.G301*', 'Var', (76, 83))	('p.R432*', 'Mutation', 'p.R432*', (144, 151))	('p.G301*', 'Mutation', 'p.G301fsX', (76, 83))	('p.R117C', 'Mutation', 'rs780936436', (99, 106))	('p.P116L', 'Var', (130, 137))	('POT1', 'Gene', '25913', (21, 25))	('AS', 'Phenotype', 'HP:0200058', (68, 70))	('POT1', 'Gene', (21, 25))	('p.R117C', 'Var', (99, 106))	('p.P116L', 'Mutation', 'p.P116L', (130, 137))
226678	32489430	Endoglin is also expressed directly on tumor cells in AS and is upregulated following VEGF inhibition.	('inhibition', 'Var', (91, 101))	('AS', 'Phenotype', 'HP:0200058', (54, 56))	('VEGF', 'Gene', (86, 90))	('upregulated', 'PosReg', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Endoglin', 'Gene', (0, 8))	('VEGF', 'Gene', '7422', (86, 90))	('tumor', 'Disease', (39, 44))	('Endoglin', 'Gene', '2022', (0, 8))
226679	32489430	The rationale was that TRC105, targeting a pathway upregulated following VEGF inhibition, could complement and potentiate VEGFR TKIs, resulting in more effective angiogenesis inhibition and improved clinical efficacy when compared with pazopanib alone.	('VEGFR', 'Gene', '3791', (122, 127))	('VEGF', 'Gene', '7422', (122, 126))	('pazopanib', 'Chemical', 'MESH:C516667', (236, 245))	('more', 'PosReg', (147, 151))	('inhibition', 'Var', (78, 88))	('VEGFR', 'Gene', (122, 127))	('potentiate', 'PosReg', (111, 121))	('clinical efficacy', 'CPA', (199, 216))	('VEGF', 'Gene', '7422', (73, 77))	('VEGF', 'Gene', (122, 126))	('improved', 'PosReg', (190, 198))	('TRC105', 'Chemical', 'MESH:C579557', (23, 29))	('upregulated', 'PosReg', (51, 62))	('angiogenesis inhibition', 'CPA', (162, 185))	('men', 'Species', '9606', (102, 105))	('VEGF', 'Gene', (73, 77))
226680	32489430	An interim analysis following enrollment of 123 patients showed no meaningful efficacy for TRC105/pazopanib combination versus pazopanib alone in the face of greater toxicity especially concerning anemia, headache, and epistaxis.	('pazopanib', 'Chemical', 'MESH:C516667', (98, 107))	('headache', 'Disease', 'MESH:D006261', (205, 213))	('pazopanib', 'Chemical', 'MESH:C516667', (127, 136))	('anemia', 'Disease', (197, 203))	('anemia', 'Disease', 'MESH:D000740', (197, 203))	('men', 'Species', '9606', (36, 39))	('TRC105/pazopanib', 'Var', (91, 107))	('toxicity', 'Disease', 'MESH:D064420', (166, 174))	('epistaxis', 'Disease', (219, 228))	('headache', 'Disease', (205, 213))	('toxicity', 'Disease', (166, 174))	('anemia', 'Phenotype', 'HP:0001903', (197, 203))	('epistaxis', 'Phenotype', 'HP:0000421', (219, 228))	('TRC105', 'Chemical', 'MESH:C579557', (91, 97))	('patients', 'Species', '9606', (48, 56))	('headache', 'Phenotype', 'HP:0002315', (205, 213))
226684	32489430	Some authors have proposed intimal sarcoma as a distinct subtype of cardiac sarcoma, characterized by MDM2 amplification and overexpression.	('amplification', 'Var', (107, 120))	('cardiac sarcoma', 'Disease', 'MESH:D006331', (68, 83))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('sarcoma', 'Disease', (35, 42))	('MDM2', 'Gene', '4193', (102, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('MDM2', 'Gene', (102, 106))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('cardiac sarcoma', 'Disease', (68, 83))	('cardiac sarcoma', 'Phenotype', 'HP:0031350', (68, 83))
226688	32489430	Whilst amplification of MDM2 is the most frequent event, other recurrent chromosomal imbalances have been detected, such as 4q12 amplification including KIT and PDGFRA, gain in 7p12 region including EGFR and loss of 9p21 region targeting CDKN2A.	('CDKN2A', 'Gene', (238, 244))	('imbalances', 'Phenotype', 'HP:0002172', (85, 95))	('PDGFRA', 'Gene', (161, 167))	('KIT', 'Gene', '3815', (153, 156))	('CDKN2A', 'Gene', '1029', (238, 244))	('EGFR', 'Gene', (199, 203))	('PDGFRA', 'Gene', '5156', (161, 167))	('KIT', 'Gene', (153, 156))	('gain', 'PosReg', (169, 173))	('loss', 'NegReg', (208, 212))	('7p12', 'Protein', (177, 181))	('MDM2', 'Gene', (24, 28))	('MDM2', 'Gene', '4193', (24, 28))	('amplification', 'Var', (7, 20))	('EGFR', 'Gene', '1956', (199, 203))
226691	32489430	In one of these, a novel inherited loss of functional mutation of FH (p.E404D) and a recurrent somatic hotspot mutation of PIK3CA (p.H1047R) were detected.	('p.E404D', 'Mutation', 'p.E404D', (70, 77))	('PIK3CA', 'Gene', (123, 129))	('p.E404D', 'Var', (70, 77))	('PIK3CA', 'Gene', '5290', (123, 129))	('p.H1047R', 'Var', (131, 139))	('loss of functional', 'NegReg', (35, 53))	('p.H1047R', 'Mutation', 'rs121913279', (131, 139))
226692	32489430	In the other two cases, PDGFRB activating mutations (p.R709H and a p.E472D) have been identified, concurrent with PDGFRA amplification.	('PDGFRB', 'Gene', (24, 30))	('p.E472D', 'Mutation', 'rs947086492', (67, 74))	('PDGFRA', 'Gene', '5156', (114, 120))	('p.R709H', 'Mutation', 'rs759436020', (53, 60))	('PDGFRA', 'Gene', (114, 120))	('activating', 'PosReg', (31, 41))	('p.E472D', 'Var', (67, 74))	('PDGFRB', 'Gene', '5159', (24, 30))	('p.R709H', 'Var', (53, 60))
226693	32489430	In a cohort of 21 large arterial blood vessel IS, PDGFRA amplification was the most frequent abnormality (81% of cases), followed by MDM2 amplification (65% of cases) and EGFR amplification or aneuploidy (both accounting for 76% of cases).	('EGFR', 'Gene', (171, 175))	('MDM2', 'Gene', '4193', (133, 137))	('aneuploidy', 'Disease', 'MESH:D000782', (193, 203))	('amplification', 'Var', (57, 70))	('aneuploidy', 'Disease', (193, 203))	('MDM2', 'Gene', (133, 137))	('PDGFRA', 'Gene', '5156', (50, 56))	('PDGFRA', 'Gene', (50, 56))	('EGFR', 'Gene', '1956', (171, 175))	('amplification', 'Var', (138, 151))	('amplification', 'Var', (176, 189))
226695	32489430	PDGFRB mutations and kinase activation have been also identified in a small subgroup of IS.	('PDGFRB', 'Gene', (0, 6))	('PDGFRB', 'Gene', '5159', (0, 6))	('mutations', 'Var', (7, 16))
226698	32489430	It is worth noting that other druggable mutations involving ALK, ATM/ATR and PTCH1 have been described in IS of the pulmonary artery, which can occasionally extend to the heart.	('ATM', 'Gene', '472', (65, 68))	('ALK', 'Gene', (60, 63))	('PTCH1', 'Gene', (77, 82))	('described', 'Reg', (93, 102))	('pulmonary artery', 'Disease', (116, 132))	('mutations', 'Var', (40, 49))	('ATR', 'Gene', '545', (69, 72))	('ATR', 'Gene', (69, 72))	('PTCH1', 'Gene', '5727', (77, 82))	('ALK', 'Gene', '238', (60, 63))	('pulmonary artery', 'Disease', 'MESH:D000071079', (116, 132))	('ATM', 'Gene', (65, 68))
226709	32489430	The median survival time was 14 months, with major risk factors related to a poor prognosis represented by tumors >=40 mm in size or with high-grade.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('high-grade', 'Var', (138, 148))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
226710	32489430	Regarding molecular information, some studies identified MFS as genetically highly complex and heterogeneous tumors, lacking specific or recurrent genetic fingerprints, with frequent gross amplifications and deletions.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('MFS', 'Disease', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('deletions', 'Var', (208, 217))
226711	32489430	On the contrary, the abundance of point mutations is relatively low, with TP53 signaling and cell cycle checkpoint genes as more frequently altered pathways.	('altered', 'Reg', (140, 147))	('point mutations', 'Var', (34, 49))	('cell cycle checkpoint genes', 'Gene', (93, 120))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))
226712	32489430	We have recently reported a case of an elderly woman affected by MFS of the left atrium, describing its molecular features by whole transcriptome sequencing.	('affected by', 'Reg', (53, 64))	('MFS', 'Var', (65, 68))	('woman', 'Species', '9606', (47, 52))
226719	32489430	Hundreds of genomic rearrangements have been identified in osteosarcomas, including recurrent rearrangements of TP53, RB1, MDM2 and CDKN2A gene fusions.	('CDKN2A', 'Gene', (132, 138))	('osteosarcomas', 'Disease', (59, 72))	('MDM2', 'Gene', '4193', (123, 127))	('CDKN2A', 'Gene', '1029', (132, 138))	('osteosarcoma', 'Phenotype', 'HP:0002669', (59, 71))	('MDM2', 'Gene', (123, 127))	('RB1', 'Gene', (118, 121))	('men', 'Species', '9606', (103, 106))	('osteosarcomas', 'Phenotype', 'HP:0002669', (59, 72))	('osteosarcomas', 'Disease', 'MESH:D012516', (59, 72))	('rearrangements', 'Var', (94, 108))	('men', 'Species', '9606', (29, 32))	('RB1', 'Gene', '5925', (118, 121))	('TP53', 'Gene', '7157', (112, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('TP53', 'Gene', (112, 116))
226720	32489430	Up to 80% of tumors carry TP53 biallelic inactivation, predominantly through structural variations in intron 1.	('TP53', 'Gene', (26, 30))	('structural variations', 'Var', (77, 98))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('biallelic inactivation', 'Var', (31, 53))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('TP53', 'Gene', '7157', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
226721	32489430	On the contrary, low rates of single nucleotide variations (mainly involving TP53 and RB1) are reported.	('RB1', 'Gene', (86, 89))	('single nucleotide variations', 'Var', (30, 58))	('RB1', 'Gene', '5925', (86, 89))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
226726	32489430	Molecular analysis of only one case of cardiac RMS, harboring a KRAS mutation (codon 13 G>A transition), has been reported.	('cardiac RMS', 'Disease', (39, 50))	('RMS', 'Phenotype', 'HP:0002859', (47, 50))	('cardiac RMS', 'Disease', 'MESH:D006331', (39, 50))	('KRAS', 'Gene', (64, 68))	('13 G>A', 'SUBSTITUTION', 'None', (85, 91))	('AS', 'Phenotype', 'HP:0200058', (66, 68))	('13 G>A', 'Var', (85, 91))	('KRAS', 'Gene', '3845', (64, 68))
226727	32489430	Similarly, alteration of RAS pathway (H/K/N-RAS) has been detected in extra-cardiac RMS, together with mutations of TP53, PIK3CA, CTNNB1, FGFR4, BCOR and FBXW7, and loss of heterozygosity at 11p15.5.	('FGFR4', 'Gene', (138, 143))	('BCOR', 'Gene', '54880', (145, 149))	('AS', 'Phenotype', 'HP:0200058', (45, 47))	('FBXW7', 'Gene', '55294', (154, 159))	('RMS', 'Phenotype', 'HP:0002859', (84, 87))	('CTNNB1', 'Gene', (130, 136))	('PIK3CA', 'Gene', (122, 128))	('mutations', 'Var', (103, 112))	('TP53', 'Gene', (116, 120))	('cardiac RMS', 'Disease', (76, 87))	('BCOR', 'Gene', (145, 149))	('RAS pathway', 'Pathway', (25, 36))	('alteration', 'Reg', (11, 21))	('N-RAS', 'Gene', '4893', (42, 47))	('detected', 'Reg', (58, 66))	('AS', 'Phenotype', 'HP:0200058', (26, 28))	('TP53', 'Gene', '7157', (116, 120))	('FGFR4', 'Gene', '2264', (138, 143))	('FBXW7', 'Gene', (154, 159))	('PIK3CA', 'Gene', '5290', (122, 128))	('CTNNB1', 'Gene', '1499', (130, 136))	('N-RAS', 'Gene', (42, 47))	('cardiac RMS', 'Disease', 'MESH:D006331', (76, 87))
226734	32489430	Generally, defects in DNA repair and chromosomal maintenance (including mutations of TP53, ATM, RB1, and ATRX) are central to the biology of LMS.	('chromosomal maintenance', 'CPA', (37, 60))	('LMS', 'Disease', (141, 144))	('mutations', 'Var', (72, 81))	('TP53', 'Gene', (85, 89))	('DNA', 'MPA', (22, 25))	('ATRX', 'Gene', '546', (105, 109))	('LMS', 'Phenotype', 'HP:0100243', (141, 144))	('ATM', 'Gene', (91, 94))	('RB1', 'Gene', '5925', (96, 99))	('ATM', 'Gene', '472', (91, 94))	('TP53', 'Gene', '7157', (85, 89))	('defects', 'NegReg', (11, 18))	('ATRX', 'Gene', (105, 109))	('RB1', 'Gene', (96, 99))
226738	32489430	From the molecular point of view, SS have a relatively stable genome and they are characterized by the pathognomonic reciprocal chromosomal translocation t(X;18) (p11.2;q11.2), which results in the fusion of the SS18 (formerly SYT) gene on chromosome 18 with one of the SSX genes on chromosome X (SSX1, SSX2, or rarely SSX4).	('SYT', 'Gene', (227, 230))	('SSX', 'Gene', '6757', (297, 300))	('SS18', 'Gene', '6760', (212, 216))	('SS', 'Phenotype', 'HP:0100242', (212, 214))	('SSX4', 'Gene', '6759', (319, 323))	('p11', 'Gene', '8909', (163, 166))	('p11', 'Gene', (163, 166))	('SS', 'Phenotype', 'HP:0100242', (297, 299))	('SSX', 'Gene', (297, 300))	('SS', 'Phenotype', 'HP:0100242', (34, 36))	('SYT', 'Gene', '6760', (227, 230))	('SSX', 'Gene', '6757', (319, 322))	('SSX', 'Gene', '6757', (303, 306))	('SSX1', 'Gene', '6756', (297, 301))	('SSX1', 'Gene', (297, 301))	('SSX', 'Gene', (319, 322))	('SSX', 'Gene', '6757', (270, 273))	('SS18', 'Gene', (212, 216))	('SS', 'Phenotype', 'HP:0100242', (303, 305))	('fusion', 'Var', (198, 204))	('SSX2', 'Gene', (303, 307))	('SS', 'Phenotype', 'HP:0100242', (270, 272))	('SSX', 'Gene', (303, 306))	('SSX', 'Gene', (270, 273))	('SSX4', 'Gene', (319, 323))	('SSX2', 'Gene', '6757', (303, 307))
226739	32489430	It was demonstrated that SS18-SSX fusion associates with SWI/SNF and Polycomb chromatin complexes to dysregulate gene expression through the disruption of epigenetic regulation.	('disruption', 'NegReg', (141, 151))	('SS18', 'Gene', '6760', (25, 29))	('fusion', 'Var', (34, 40))	('SS', 'Phenotype', 'HP:0100242', (30, 32))	('gene expression', 'MPA', (113, 128))	('SSX', 'Gene', '6757', (30, 33))	('SSX', 'Gene', (30, 33))	('SS', 'Phenotype', 'HP:0100242', (25, 27))	('epigenetic regulation', 'MPA', (155, 176))	('SS18', 'Gene', (25, 29))	('associates', 'Interaction', (41, 51))	('dysregulate', 'PosReg', (101, 112))
226755	32489430	Most of these genes induce proliferation and angiogenesis through the activation of PI3K/AKT, PLCG1/PKC, and RAS pathways.	('AS', 'Phenotype', 'HP:0200058', (110, 112))	('induce', 'PosReg', (20, 26))	('PKC', 'Gene', (100, 103))	('PKC', 'Gene', '112476', (100, 103))	('PLCG1', 'Gene', (94, 99))	('proliferation', 'CPA', (27, 40))	('AKT', 'Gene', '207', (89, 92))	('genes', 'Var', (14, 19))	('RAS pathways', 'Pathway', (109, 121))	('angiogenesis', 'CPA', (45, 57))	('PLCG1', 'Gene', '5335', (94, 99))	('AKT', 'Gene', (89, 92))	('activation', 'PosReg', (70, 80))
226808	30567503	However, considering that the other typical FD characteristics such as hypo- to isointense lesion on T1W and a sclerotic rim as a hypointense area that surrounds the lesion could not be observed in our patient, FD was excluded as a differential diagnosis.	('sclerotic rim', 'Disease', 'MESH:C538213', (111, 124))	('sclerotic rim', 'Disease', (111, 124))	('patient', 'Species', '9606', (202, 209))	('FD', 'Disease', 'MESH:D004402', (211, 213))	('FD', 'Disease', 'MESH:D004402', (44, 46))	('hypo- to', 'Var', (71, 79))
226811	30567503	It is seen on MRI as a well-defined expansive mass with lobulated contours that is T1W-hypointense and T2W-hyperintense with possible hypointense foci that match calcifications.	('hypointense foci', 'Disease', (134, 150))	('T1W-hypointense', 'Var', (83, 98))	('T2W-hyperintense', 'Var', (103, 119))	('hypointense foci', 'Disease', 'MESH:C565785', (134, 150))
226817	30567503	Heterogenous appearance and hypo- to isointensity on T1W are typical characteristics of Ewing sarcoma that partially matched our case with mostly high signal intensity on T1W.	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('hypo- to isointensity', 'Var', (28, 49))	('Ewing sarcoma', 'Disease', (88, 101))
226992	23553917	The mechanism of inhibition of microtubule dynamic instability by eribulin is distinctive from that of other tubulin-binding antimitotic agents in that eribulin suppresses the growth parameters at microtubule plus ends without affecting microtubule shortening parameters.	('microtubule', 'MPA', (31, 42))	('eribulin', 'Var', (152, 160))	('growth parameters at microtubule plus ends', 'MPA', (176, 218))	('suppresses', 'NegReg', (161, 171))	('eribulin', 'Chemical', 'MESH:C490954', (152, 160))	('eribulin', 'Chemical', 'MESH:C490954', (66, 74))
227005	23553917	CB17SC scid-/- female mice (Taconic Farms, Germantown, NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing sarcoma, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described.	('osteosarcoma', 'Disease', (157, 169))	('osteosarcoma', 'Disease', 'MESH:D012516', (157, 169))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (171, 187))	('glioblastoma', 'Phenotype', 'HP:0012174', (213, 225))	('non-glioblastoma brain tumors', 'Disease', 'MESH:D005909', (209, 238))	('mice', 'Species', '10090', (259, 263))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (142, 155))	('mice', 'Species', '10090', (22, 26))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (142, 155))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (171, 187))	('sarcomas', 'Disease', 'MESH:D012509', (132, 140))	('neuroblastoma', 'Disease', (190, 203))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('neuroblastoma', 'Phenotype', 'HP:0003006', (190, 203))	('sarcomas', 'Disease', (132, 140))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('non-glioblastoma brain tumors', 'Disease', (209, 238))	('glioma', 'Disease', (278, 284))	('rhabdoid tumors', 'Disease', (115, 130))	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('neuroblastoma', 'Disease', 'MESH:D009447', (190, 203))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (115, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('glioma', 'Disease', 'MESH:D005910', (278, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('Ewing sarcoma', 'Disease', (142, 155))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('CB17SC', 'Var', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('brain tumors', 'Phenotype', 'HP:0030692', (226, 238))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('rhabdomyosarcoma', 'Disease', (171, 187))
227021	23553917	Twenty-four of 30 (80%) solid tumor models evaluable for the EFS T/C activity metric demonstrated EFS T/C >2.0, with seven lines showing intermediate activity and 17 showing high activity.	('EFS T/C', 'Var', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('solid tumor', 'Disease', (24, 35))	('solid tumor', 'Disease', 'MESH:D009369', (24, 35))
227030	23553917	Hence, the PPTP results in SCID mice are similar to those previously reported for eriubulin.	('PPTP', 'Chemical', '-', (11, 15))	('PPTP', 'Var', (11, 15))	('SCID', 'Disease', 'MESH:D053632', (27, 31))	('SCID', 'Disease', (27, 31))	('mice', 'Species', '10090', (32, 36))
227039	23553917	Additionally, activity for eribulin for rhabdomyosarcoma appears to be greater than that observed for vincristine (6 of 7 with MCR for eribulin vs. 2 MCR/1 PR out of 7 for vincristine).	('MCR', 'Chemical', '-', (150, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (40, 56))	('MCR', 'Chemical', '-', (127, 130))	('activity', 'MPA', (14, 22))	('rhabdomyosarcoma', 'Disease', (40, 56))	('vincristine', 'Chemical', 'MESH:D014750', (102, 113))	('vincristine', 'Chemical', 'MESH:D014750', (172, 183))	('eribulin', 'Chemical', 'MESH:C490954', (27, 35))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (40, 56))	('MCR', 'Var', (127, 130))	('eribulin', 'Chemical', 'MESH:C490954', (135, 143))
227077	23553917	Combinations with a topoisomerase I inhibitor would have general applicability, given the activity of these agents for several childhood solid tumors and given evidence for supra-additive effects for topoisomerase I inhibitors with vincristine.	('solid tumors', 'Disease', (137, 149))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('activity', 'MPA', (90, 98))	('Combinations', 'Var', (0, 12))	('solid tumors', 'Disease', 'MESH:D009369', (137, 149))	('vincristine', 'Chemical', 'MESH:D014750', (232, 243))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
227120	24216979	Early data showing that HIF1alpha expression was correlated with aberrant p53 accumulation and cell proliferation in various solid tumors and their metastasis indicated the important role that HIFs may play in human cancer progression.	('aberrant', 'Var', (65, 73))	('HIF', 'Gene', (24, 27))	('p53', 'Gene', (74, 77))	('human', 'Species', '9606', (210, 215))	('cancer', 'Disease', (216, 222))	('solid tumors', 'Disease', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('HIF1alpha', 'Gene', '3091', (24, 33))	('HIF', 'Gene', '405', (24, 27))	('cell proliferation', 'CPA', (95, 113))	('correlated', 'Reg', (49, 59))	('solid tumors', 'Disease', 'MESH:D009369', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HIF1alpha', 'Gene', (24, 33))	('metastasis', 'CPA', (148, 158))	('HIF', 'Gene', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('accumulation', 'PosReg', (78, 90))	('HIF', 'Gene', '405', (193, 196))	('p53', 'Gene', '7157', (74, 77))
227125	24216979	More recently, pharmacological targeting of the HIF1alpha signaling pathway has been shown to inhibit rhabdomyosarcoma growth in xenograft models.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (102, 118))	('pharmacological', 'Var', (15, 30))	('rhabdomyosarcoma', 'Disease', (102, 118))	('HIF1alpha', 'Gene', (48, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('HIF1alpha', 'Gene', '3091', (48, 57))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (102, 118))	('inhibit', 'NegReg', (94, 101))
227155	24216979	Studies in breast and head and neck cancers have shown that hypoxia-induced lysyl oxidase (LOX) is essential for tumor metastasis as LOX covalently modifies collagens to increase focal adhesion kinase activity, cell migration, and metastasis.	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('metastasis', 'CPA', (231, 241))	('lysyl oxidase', 'Gene', (76, 89))	('cell migration', 'CPA', (211, 225))	('modifies', 'Var', (148, 156))	('LOX', 'Gene', '4015', (133, 136))	('tumor', 'Disease', (113, 118))	('collagens', 'Protein', (157, 166))	('increase', 'PosReg', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('LOX', 'Gene', '4015', (91, 94))	('focal adhesion kinase', 'Pathway', (179, 200))	('LOX', 'Gene', (133, 136))	('lysyl oxidase', 'Gene', '4015', (76, 89))	('hypoxia', 'Disease', (60, 67))	('activity', 'MPA', (201, 209))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('neck cancers', 'Disease', (31, 43))	('head and neck cancers', 'Phenotype', 'HP:0012288', (22, 43))	('neck cancers', 'Disease', 'MESH:D006258', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LOX', 'Gene', (91, 94))
227168	24216979	Inhibition of HIF-2alpha leads to tumor cell death and enhances the response to radiation treatment.	('HIF-2alpha', 'Gene', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor cell death', 'Disease', 'MESH:D003643', (34, 50))	('response to radiation treatment', 'CPA', (68, 99))	('HIF-2alpha', 'Gene', '2034', (14, 24))	('Inhibition', 'Var', (0, 10))	('enhances', 'PosReg', (55, 63))	('tumor cell death', 'Disease', (34, 50))
227174	24216979	Furthermore, HIF1 activity may contribute to resistance to more targeted therapies, such as imatinib, through metabolic reprogramming.	('HIF1', 'Gene', (13, 17))	('activity', 'Var', (18, 26))	('imatinib', 'Chemical', 'MESH:D000068877', (92, 100))	('metabolic reprogramming', 'CPA', (110, 133))	('contribute', 'Reg', (31, 41))	('resistance', 'MPA', (45, 55))	('HIF1', 'Gene', '3091', (13, 17))
227180	24216979	Updated results of phase 2 clinical trial involving 91 metastatic or locally advanced unresectable STS reported at 2012 Connective Tissue Oncology Society meeting in Prague showed that TH-302 boosted the response rate to 36% with a median progression-free survival of 6.7 months.	('TH-302', 'Chemical', 'MESH:C552526', (185, 191))	('TH-302', 'Var', (185, 191))	('response', 'MPA', (204, 212))	('Connective Tissue Oncology', 'Phenotype', 'HP:0100242', (120, 146))	('Oncology', 'Phenotype', 'HP:0002664', (138, 146))	('boosted', 'PosReg', (192, 199))
227244	22698085	For examples, following polyethylene and metal wear debris, hip arthroplasties have characteristic radiographic features including eccentric polyethylene wear, osteolysis, or a radiolucency outlining the effective joint space termed the "bubble sign".	('polyethylene', 'Chemical', 'MESH:D020959', (24, 36))	('metal', 'Chemical', 'MESH:D008670', (41, 46))	('osteolysis', 'Disease', (160, 170))	('eccentric polyethylene', 'Var', (131, 153))	('polyethylene', 'Chemical', 'MESH:D020959', (141, 153))	('hip arthroplasties', 'Disease', (60, 78))	('osteolysis', 'Disease', 'MESH:D010014', (160, 170))	('wear debris', 'Disease', (47, 58))	('wear debris', 'Disease', 'MESH:D057085', (47, 58))	('osteolysis', 'Phenotype', 'HP:0002797', (160, 170))	('hip arthroplasties', 'Disease', 'MESH:D006618', (60, 78))
227252	22698085	Many of the specimens contained polyethylene debris suggesting that a hypersensitivity reaction to wear particles may be responsible for cyst formation.	('contained', 'Reg', (22, 31))	('cyst', 'Disease', (137, 141))	('hypersensitivity', 'Disease', (70, 86))	('hypersensitivity', 'Disease', 'MESH:D004342', (70, 86))	('polyethylene', 'Chemical', 'MESH:D020959', (32, 44))	('polyethylene', 'Var', (32, 44))
227265	22698085	Furthermore, excision relieves the potential compressive effect of the mass on surrounding neurovascular structures including, as in this case, the sciatic nerve.	('excision', 'Var', (13, 21))	('compressive effect', 'MPA', (45, 63))	('neurovascular', 'Disease', (91, 104))	('neurovascular', 'Disease', 'MESH:D013901', (91, 104))	('relieves', 'NegReg', (22, 30))
227275	20856679	The multimembrane photodestruction and cell necrosis induced by photoactivation of 2 and 5 are directly associated with membrane permeabilization caused by lipid photodamage.	('lipid', 'Chemical', 'MESH:D008055', (156, 161))	('multimembrane photodestruction', 'CPA', (4, 34))	('necrosis', 'Disease', 'MESH:D009336', (44, 52))	('photoactivation', 'Var', (64, 79))	('associated', 'Reg', (104, 114))	('necrosis', 'Disease', (44, 52))	('membrane permeabilization', 'MPA', (120, 145))
227293	20856679	In a cell free system, photoactivation of 2 or 5 caused damage to membranes of artificial vesicles manifested in their leakage, strongly suggesting that lipid membrane permeabilization is a key factor of an instant cell death induced by the novel chlorin e6 based photosensitizers.	('chlorin e6', 'Chemical', 'MESH:C062985', (247, 257))	('photoactivation', 'Var', (23, 38))	('membranes', 'MPA', (66, 75))	('leakage', 'MPA', (119, 126))	('lipid', 'Chemical', 'MESH:D008055', (153, 158))
227341	20856679	These data indicated that necrosis was the primary mechanism of cell death upon photoactivation of 5.	('photoactivation', 'Var', (80, 95))	('necrosis', 'Disease', (26, 34))	('necrosis', 'Disease', 'MESH:D009336', (26, 34))
227343	20856679	LI of C6 glioma cells loaded with DCFH-DA and 5 caused bright green fluorescence (Figure 5).	('DCFH-DA', 'Chemical', 'MESH:C029569', (34, 41))	('C6 glioma', 'Disease', 'MESH:C567307', (6, 15))	('C6 glioma', 'Disease', (6, 15))	('bright green fluorescence', 'MPA', (55, 80))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('DCFH-DA', 'Var', (34, 41))
227346	20856679	Trolox has been reported to quench singlet oxygen and photosensitizer triplet states as well as to scavenge lipid peroxyl radicals.	('peroxyl radicals', 'Chemical', 'MESH:C049375', (114, 130))	('scavenge', 'NegReg', (99, 107))	('Trolox', 'Var', (0, 6))	('lipid peroxyl radicals', 'MPA', (108, 130))	('lipid', 'Chemical', 'MESH:D008055', (108, 113))	('singlet oxygen', 'Chemical', 'MESH:D026082', (35, 49))	('quench', 'NegReg', (28, 34))	('Trolox', 'Chemical', 'MESH:C010643', (0, 6))
227355	20856679	Importantly, NaN3, a singlet oxygen quencher, abrogated liposome photodamage (Figure 6, curve 5).	('singlet oxygen', 'Chemical', 'MESH:D026082', (21, 35))	('abrogated', 'NegReg', (46, 55))	('liposome photodamage', 'CPA', (56, 76))	('NaN3', 'Var', (13, 17))	('NaN3', 'Chemical', 'MESH:D019810', (13, 17))
227364	20856679	As shown in Figure 8, photoactivation of 5 led to fast dye leakage from liposomes made of unsaturated EggPC.	('unsaturated', 'Chemical', '-', (90, 101))	('dye leakage', 'MPA', (55, 66))	('photoactivation', 'Var', (22, 37))
227371	20856679	These findings strongly suggest that a higher therapeutic potency of boronated compound 5 compared to boron-free 2 is associated with the ability of 5 to penetrate through lipid membranes.	('higher', 'PosReg', (39, 45))	('lipid', 'Chemical', 'MESH:D008055', (172, 177))	('boron', 'Chemical', 'MESH:D001895', (102, 107))	('therapeutic potency', 'MPA', (46, 65))	('boron', 'Chemical', 'MESH:D001895', (69, 74))	('rat', 'Species', '10116', (159, 162))	('boronated', 'Var', (69, 78))
227373	20856679	Studies of mechanisms of antitumor efficacy revealed that photoactivation of 5 triggered intracellular ROS generation followed by rapid (within the initial minutes after LI) damage of multiple membrane organelles, leading to cell necrosis.	('rat', 'Species', '10116', (111, 114))	('damage', 'MPA', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('necrosis', 'Disease', 'MESH:D009336', (230, 238))	('ROS', 'Protein', (103, 106))	('photoactivation', 'Var', (58, 73))	('tumor', 'Disease', (29, 34))	('necrosis', 'Disease', (230, 238))
227384	20856679	According to these patterns of intracellular drug distribution, photoactivation of 5 followed by ROS generation caused damage to these organelles.	('photoactivation', 'Var', (64, 79))	('rat', 'Species', '10116', (105, 108))	('damage', 'MPA', (119, 125))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('ROS generation', 'MPA', (97, 111))
227396	20856679	The loss of the plasma membrane integrity, a hallmark of necrosis, can be mediated via energy starvation and subsequent disappearance of the ionic transmembrane gradient due to inactivation of ATP-dependent transporters.	('plasma membrane integrity', 'MPA', (16, 41))	('necrosis', 'Disease', (57, 65))	('loss', 'NegReg', (4, 8))	('disappearance of the ionic transmembrane gradient', 'MPA', (120, 169))	('ATP-dependent transporters', 'MPA', (193, 219))	('inactivation', 'Var', (177, 189))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
227459	31234291	IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients (1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor.	('Brain Tumor', 'Disease', (59, 70))	('alteration', 'Var', (173, 183))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (111, 132))	('BCOR', 'Gene', '54880', (191, 195))	('HGNET-BCOR', 'Gene', (48, 58))	('IGF1R', 'Gene', '3480', (0, 5))	('HGNET-BCOR', 'Gene', '54880', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Brain Tumor', 'Phenotype', 'HP:0030692', (59, 70))	('BCOR', 'Gene', '54880', (168, 172))	('BCOR', 'Gene', (191, 195))	('IGF1R', 'Gene', (0, 5))	('BCOR', 'Gene', '54880', (54, 58))	('malignant tumor', 'Disease', (209, 224))	('BCOR', 'Gene', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('HGNET-BCOR', 'Gene', '54880', (48, 58))	('malignant tumor', 'Disease', 'MESH:D018198', (209, 224))	('BCOR', 'Gene', (54, 58))	('Brain Tumor', 'Disease', 'MESH:D001932', (59, 70))	('tumor of the central nervous system', 'Phenotype', 'HP:0100006', (127, 162))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (111, 132))	('Tumor', 'Phenotype', 'HP:0002664', (65, 70))	('HGNET-BCOR', 'Gene', (185, 195))	('neuroepithelial tumor', 'Disease', (111, 132))
227476	31234291	HGNET-BCOR primarily affects children and is characterized by somatic internal tandem duplications (ITDs) within the C-terminus of the BCL-6 co-repressor (BCOR) gene and by BCOR overexpression.	('BCOR', 'Gene', (155, 159))	('HGNET-BCOR', 'Gene', '54880', (0, 10))	('BCOR', 'Gene', '54880', (6, 10))	('children', 'Species', '9606', (29, 37))	('BCOR', 'Gene', '54880', (155, 159))	('HGNET-BCOR', 'Gene', (0, 10))	('overexpression', 'PosReg', (178, 192))	('BCOR', 'Gene', (173, 177))	('BCL-6 co-repressor', 'Gene', (135, 153))	('BCL-6 co-repressor', 'Gene', '54880', (135, 153))	('BCOR', 'Gene', '54880', (173, 177))	('BCOR', 'Gene', (6, 10))	('internal tandem duplications', 'Var', (70, 98))
227485	31234291	In spite of promising preclinical data, IGF1R inhibitors have not had success as single agents in clinical trials, and no formally approved drugs are available.	('IGF1R', 'Gene', '3480', (40, 45))	('inhibitors', 'Var', (46, 56))	('IGF1R', 'Gene', (40, 45))
227506	31234291	Hepatoblastoma have a high IGF2 expression due to genetic and epigenetic alterations in the IGF2-H19 region.	('IGF2', 'Gene', (27, 31))	('genetic', 'Var', (50, 57))	('IGF2', 'Gene', '3481', (92, 96))	('Hepatoblastoma', 'Disease', (0, 14))	('Hepatoblastoma', 'Phenotype', 'HP:0002884', (0, 14))	('high IGF2', 'Phenotype', 'HP:0030269', (22, 31))	('high', 'PosReg', (22, 26))	('IGF2', 'Gene', '3481', (27, 31))	('IGF2', 'Gene', (92, 96))	('epigenetic alterations', 'Var', (62, 84))	('expression', 'MPA', (32, 42))	('Hepatoblastoma', 'Disease', 'MESH:D018197', (0, 14))
227513	31234291	For our drug screening in the PhKh1 model, we selected 11 compounds, including chemotherapeutics that we previously selected for our personalized treatment of HGNET-BCOR and three IGF1R kinase inhibitors, namely, linsitinib, picropodophyllin, and PQ401.	('PQ401', 'Var', (247, 252))	('IGF1R', 'Gene', '3480', (180, 185))	('PhKh1', 'CellLine', 'CVCL:B231', (30, 35))	('HGNET-BCOR', 'Gene', '54880', (159, 169))	('PQ401', 'Chemical', 'MESH:C569479', (247, 252))	('picropodophyllin', 'Chemical', 'MESH:C415032', (225, 241))	('HGNET-BCOR', 'Gene', (159, 169))	('linsitinib', 'Chemical', 'MESH:C551528', (213, 223))	('IGF1R', 'Gene', (180, 185))
227531	31234291	A cluster of three tyrosine residues, located at position Tyr1131, Tyr1135, and Tyr1136 within the kinase domain, is critical for receptor autophosphorylation.	('Tyr1131', 'Var', (58, 65))	('Tyr1131', 'Chemical', '-', (58, 65))	('Tyr1136', 'Var', (80, 87))	('Tyr1135', 'Var', (67, 74))	('Tyr1136', 'Chemical', '-', (80, 87))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))	('Tyr1135', 'Chemical', '-', (67, 74))
227606	31234291	The following antibodies were obtained from Cell Signaling Technology (MA, USA): GAPDH (14C10) (cat # 2118, 1:1000 dilution), Lamin B1 (D4Q4Z) (cat# 12586, 1:1000 dilution) (Cell Signaling Technology), IGF1 Receptor beta (D23H3) XP  (cat # 9750, 1:1000 dilution), Phospho-IGF1 Receptor beta (Tyr1131)/Insulin Receptor beta (Tyr1146) (cat # 3021, 1:1000 dilution), AKT (cat # 9272, 1:1000 dilution), Phospho-AKT (Ser473) (cat # 9271, 1:1000 dilution).	('GAPDH', 'Gene', (81, 86))	('IGF1 Receptor', 'Gene', '3480', (272, 285))	('Lamin B1', 'Gene', '4001', (126, 134))	('Insulin', 'Gene', '3630', (301, 308))	('Insulin', 'Gene', (301, 308))	('IGF1 Receptor', 'Gene', '3480', (202, 215))	('Tyr1131', 'Chemical', '-', (292, 299))	('IGF1 Receptor', 'Gene', (272, 285))	('Lamin B1', 'Gene', (126, 134))	('cat # 3021', 'Var', (334, 344))	('GAPDH', 'Gene', '2597', (81, 86))	('IGF1 Receptor', 'Gene', (202, 215))	('cat # 9750', 'Var', (234, 244))	('cat # 9272', 'Var', (369, 379))
227607	31234291	The antibodies ERK1/ERK2 (cat # MAB1576, 0.5 microg/mL dilution) and Phospho-ERK1 (T202/Y204)/ERK2 (T185/Y187) (cat # MAB1018, 0.5 microg/mL dilution) were obtained from R&D Systems Inc. (MN, USA).	('ERK2', 'Gene', '5594', (94, 98))	('ERK1', 'Gene', (15, 19))	('ERK1', 'Gene', (77, 81))	('T185/Y187', 'Var', (100, 109))	('ERK1', 'Gene', '5595', (77, 81))	('ERK2', 'Gene', (20, 24))	('T202/Y204', 'Var', (83, 92))	('ERK2', 'Gene', (94, 98))	('ERK2', 'Gene', '5594', (20, 24))	('MN', 'CellLine', 'CVCL:U508', (188, 190))	('ERK1', 'Gene', '5595', (15, 19))
227609	31234291	The HRP-linked secondary antibodies were obtained from Cell Signaling Technology (MA, USA) (anti-mouse IgG (cat# 7076)) and Sera Care (MA, USA) (anti-rabbit IgG (cat# 074-1516)).	('mouse', 'Species', '10090', (97, 102))	('rabbit', 'Species', '9986', (150, 156))	('cat# 7076', 'Var', (108, 117))	('HRP-linked', 'Protein', (4, 14))
227621	30389743	Her medical history was significant for AML with trisomy 8.	('AML', 'Phenotype', 'HP:0004808', (40, 43))	('AML', 'Disease', 'MESH:D015470', (40, 43))	('AML', 'Disease', (40, 43))	('trisomy 8', 'Var', (49, 58))
227780	29552283	We show that pediatric sarcomas are highly sensitive to EGFATFKDEL (at subnanomolar concentrations) in vitro.	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('EGFATFKDEL', 'Var', (56, 66))	('pediatric sarcomas', 'Disease', (13, 31))	('EGFATFKDEL', 'Chemical', '-', (56, 66))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (13, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('sensitive', 'Reg', (43, 52))
227796	29552283	Aberrant epidermal growth factor receptor (EGFR) expression and signaling promotes the proliferation, migration and invasion of malignant cells, and is frequently associated with metastasis and an overall poor prognosis.	('promotes', 'PosReg', (74, 82))	('Aberrant', 'Var', (0, 8))	('proliferation', 'CPA', (87, 100))	('signaling', 'MPA', (64, 73))	('expression', 'MPA', (49, 59))	('associated with', 'Reg', (163, 178))	('invasion of malignant cells', 'CPA', (116, 143))	('metastasis', 'CPA', (179, 189))	('epidermal growth factor receptor', 'Gene', '13649', (9, 41))	('migration', 'CPA', (102, 111))	('epidermal growth factor receptor', 'Gene', (9, 41))	('EGFR', 'Gene', (43, 47))
227797	29552283	EGFR is overexpressed, mutated, or dysregulated in numerous cancers and hence, is an attractive target for many malignancies.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('EGFR', 'Gene', (0, 4))	('malignancies', 'Disease', (112, 124))	('dysregulated in numerous cancers', 'Disease', (35, 67))	('overexpressed', 'PosReg', (8, 21))	('mutated', 'Var', (23, 30))	('malignancies', 'Disease', 'MESH:D009369', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('dysregulated in numerous cancers', 'Disease', 'MESH:D009369', (35, 67))
227826	29552283	Similar differences between RH30 and TC-71 persisted at day 7 when cells were treated at 100 nM (100% loss vs. 70%), 10 nM (88% loss vs. 62%), 1 nM (78% loss vs. 61%), 0.1 nM (88% loss vs. 53%) and 0.01 nM (78% loss vs 46%) (p<0.001 for all).	('loss', 'NegReg', (128, 132))	('loss', 'NegReg', (180, 184))	('loss', 'NegReg', (211, 215))	('loss', 'NegReg', (153, 157))	('0.1 nM', 'Var', (168, 174))	('TC-71', 'Chemical', '-', (37, 42))	('RH30', 'Gene', (28, 32))	('RH30', 'Gene', '6007', (28, 32))	('loss', 'NegReg', (102, 106))	('0.01 nM', 'Var', (198, 205))	('TC-71', 'Gene', (37, 42))	('1 nM', 'Var', (143, 147))
227832	29552283	Overall, few mice in this established tumor model showed sustained complete responses, however significantly more of the bispecific targeted RH30 tumor bearing mice vs. monospecific targeted TC-71 mice did achieve this (17% vs 0%, p=0.04).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mice', 'Species', '10090', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('TC-71', 'Chemical', '-', (191, 196))	('mice', 'Species', '10090', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('RH30', 'Gene', (141, 145))	('RH30', 'Gene', '6007', (141, 145))	('mice', 'Species', '10090', (197, 201))	('bispecific', 'Var', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
227848	29552283	A similar study of canine hemangiosarcoma, which express both EGFR and uPAR, showed that EGFATFKDEL effectively killed both hemangiosarcoma cells in monolayer as well as hemangiospheres enriched for cancer stem cells at subnanamolar doses over 72 hours.	('EGFATFKDEL', 'Var', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('hemangiosarcoma', 'Disease', (26, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (124, 139))	('canine', 'Species', '9615', (19, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (26, 41))	('cancer', 'Disease', (199, 205))	('hemangiosarcoma', 'Disease', (124, 139))	('EGFATFKDEL', 'Chemical', '-', (89, 99))
227851	29552283	Collectively, our data show that mice bearing tumors expressing both EGFR and uPAR (i.e., RH30) had a greater effect on tumor growth over time, along with a higher number of complete responses to the toxin, compared to the TC-71 bearing mice that only expressed uPAR.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mice', 'Species', '10090', (237, 241))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('RH30', 'Gene', (90, 94))	('greater', 'PosReg', (102, 109))	('uPAR', 'Var', (78, 82))	('higher', 'PosReg', (157, 163))	('tumors', 'Disease', (46, 52))	('RH30', 'Gene', '6007', (90, 94))	('tumor', 'Disease', (120, 125))	('TC-71', 'Chemical', '-', (223, 228))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('mice', 'Species', '10090', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('EGFR', 'Gene', (69, 73))	('responses to the toxin', 'MPA', (183, 205))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
227852	29552283	Future studies will use shRNA to knock-down each receptor in RH30 cells to more precisely address this topic in a single cell line.	('knock-down', 'Var', (33, 43))	('RH30', 'Gene', (61, 65))	('RH30', 'Gene', '6007', (61, 65))
227889	29552283	PE38 was modified by adding Lys-Asp-Glu-Leu (KDEL) C-terminus signal that prevents secretion of the protein from the ER and enhances anticancer activity.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Lys-Asp-Glu-Leu', 'Var', (28, 43))	('prevents', 'NegReg', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('secretion of the protein', 'MPA', (83, 107))	('cancer', 'Disease', (137, 143))	('enhances', 'PosReg', (124, 132))
228065	27510467	By validating the performance of current staging system in PBS, our results supported the changes made in AJCC 7 regarding T, N and M, and identified additional risk groups by refining tumor size (<= 2, 2-5, 5-10 and >10 cm).	('tumor', 'Disease', (185, 190))	('PBS', 'Chemical', '-', (59, 62))	('AJCC 7', 'Gene', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('changes', 'Var', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
228197	34012291	Breast Cancer Adjuvant Radiotherapy in BRCA1/2, TP53, ATM Genes Mutations: Are There Solved Issues?	('TP53', 'Gene', '7157', (48, 52))	('ATM', 'Gene', (54, 57))	('TP53', 'Gene', (48, 52))	('Breast Cancer', 'Disease', (0, 13))	('BRCA1/2', 'Gene', (39, 46))	('Mutations', 'Var', (64, 73))	('Breast Cancer', 'Disease', 'MESH:D001943', (0, 13))	('ATM', 'Gene', '472', (54, 57))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('BRCA1/2', 'Gene', '672;675', (39, 46))	('Breast Cancer', 'Phenotype', 'HP:0003002', (0, 13))
228198	34012291	BRCA1, BRCA2, TP53 and ATM gene mutations are the most studied tumour suppressor genes (TSGs) influencing the loco-regional approach to breast cancer (BC).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('BRCA1', 'Gene', (0, 5))	('TP53', 'Gene', (14, 18))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('BRCA2', 'Gene', '675', (7, 12))	('breast cancer', 'Disease', (136, 149))	('influencing', 'Reg', (94, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('TSG', 'Gene', (88, 91))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (32, 41))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('ATM gene', 'Gene', (23, 31))	('BRCA1', 'Gene', '672', (0, 5))	('TSG', 'Gene', '57045', (88, 91))	('BRCA2', 'Gene', (7, 12))	('tumour', 'Disease', (63, 69))
228199	34012291	Due to altered radio sensitivity of mutated cancer cells, mastectomy has always been advised in most patients with BC linked to TSGs mutations in order to avoid or minimize the use of adjuvant radiotherapy (ART).	('patients', 'Species', '9606', (101, 109))	('TSG', 'Gene', (128, 131))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('TSG', 'Gene', '57045', (128, 131))	('mutations', 'Var', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
228200	34012291	In this review, we have highlighted the impact of these mutations on local control, toxicities, second tumors, and contralateral breast cancers (CBCs) after ART to solve remaining doubts and encourage the safe use of ART when indicated.	('mutations', 'Var', (56, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('toxicities', 'Disease', (84, 94))	('contralateral breast cancers', 'Disease', (115, 143))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('toxicities', 'Disease', 'MESH:D064420', (84, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (129, 143))	('contralateral breast cancers', 'Disease', 'MESH:D001943', (115, 143))
228201	34012291	The genetic basis of breast cancer (BC) is linked to several high- and/or moderate-penetrance mutations in BC susceptibility genes.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (94, 103))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))
228202	34012291	Among them, mutations in the BRCA1, BRCA2, TP53 and ATM genes are the most studied tumour suppressor genes (TSGs) influencing the therapeutic approach to BC.	('tumour', 'Disease', (83, 89))	('TSG', 'Gene', (108, 111))	('mutations', 'Var', (12, 21))	('BRCA2', 'Gene', (36, 41))	('BRCA1', 'Gene', '672', (29, 34))	('TSG', 'Gene', '57045', (108, 111))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('BRCA2', 'Gene', '675', (36, 41))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('BRCA1', 'Gene', (29, 34))	('TP53', 'Gene', (43, 47))	('ATM', 'Gene', (52, 55))
228205	34012291	An impaired radiation response has been observed in vitro and evocated in vivo for patients with BC carrying these TSGs mutations, leading to limitations of ART, regardless of the clinical indications.	('TSG', 'Gene', (115, 118))	('patients', 'Species', '9606', (83, 91))	('TSG', 'Gene', '57045', (115, 118))	('impaired radiation response', 'Phenotype', 'HP:0011133', (3, 30))	('mutations', 'Var', (120, 129))	('impaired', 'NegReg', (3, 11))	('radiation response', 'CPA', (12, 30))
228207	34012291	Based on the above advice and literature certainties, we have focused this review on the impact of ART on TSGs mutations in breast cancer in terms of local control, acute toxicities, second tumours, and contralateral breast cancers (CBCs) in order to achieve a quick reference guidance in the context of a multidisciplinary team approach.	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('mutations', 'Var', (111, 120))	('TSG', 'Gene', '57045', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Disease', (124, 137))	('TSG', 'Gene', (106, 109))	('contralateral breast cancers', 'Disease', (203, 231))	('breast cancers', 'Phenotype', 'HP:0003002', (217, 231))	('tumours', 'Disease', (190, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))	('toxicities', 'Disease', 'MESH:D064420', (171, 181))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('tumours', 'Disease', 'MESH:D009369', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('toxicities', 'Disease', (171, 181))	('contralateral breast cancers', 'Disease', 'MESH:D001943', (203, 231))
228210	34012291	Germline mutations in BRCA1 or BRCA2 are found in 3% to 4% of all women with BC.	('found', 'Reg', (41, 46))	('Germline mutations', 'Var', (0, 18))	('BRCA2', 'Gene', (31, 36))	('BRCA2', 'Gene', '675', (31, 36))	('BRCA1', 'Gene', '672', (22, 27))	('women', 'Species', '9606', (66, 71))	('BRCA1', 'Gene', (22, 27))
228211	34012291	The lifetime risk of BC among BRCA mutation carriers is approximately 70%, within a range of 50% to 90% depending on the studied population, genetic tests and methods of analysis.	('BRCA', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))	('BRCA', 'Gene', '672', (30, 34))
228212	34012291	These mutations, when associated with the autosomal dominant pathway, cause hereditary breast and ovarian cancer (HBOC) syndrome.	('hereditary breast and ovarian cancer (HBOC) syndrome', 'Disease', 'MESH:D061325', (76, 128))	('cause', 'Reg', (70, 75))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
228213	34012291	Mutations in the BRCA1 gene are mainly associated with the development of high-grade and "triple-negative" BC, while BRCA2 seems to usually correlate with higher-grade BC compared to sporadic BC.	('associated with', 'Reg', (39, 54))	('BRCA1', 'Gene', '672', (17, 22))	('BRCA2', 'Gene', '675', (117, 122))	('high-grade', 'Disease', (74, 84))	('BRCA1', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('BRCA2', 'Gene', (117, 122))
228214	34012291	BRCA gene mutations predispose patients to a younger age of BC development with a worse prognosis than sporadic BC in terms of overall survival (OS) and BC-specific survival, as confirmed by a meta-analysis by Beretta et al.	('mutations', 'Var', (10, 19))	('patients', 'Species', '9606', (31, 39))	('BRCA', 'Gene', (0, 4))	('BRCA', 'Gene', '672', (0, 4))
228215	34012291	Furthermore, as found in the POSH study, although patients with young-onset BC who carry a BRCA mutation show similar survival to noncarriers at any time point (2-5-10 years), in patients with BRCA mutation triple-negative BC, the survival advantage seems to be only during the first few years after diagnosis when compared with noncarriers.	('BRCA', 'Gene', (91, 95))	('patients', 'Species', '9606', (50, 58))	('POSH', 'Gene', (29, 33))	('mutation', 'Var', (96, 104))	('POSH', 'Gene', '57630', (29, 33))	('BRCA', 'Gene', '672', (193, 197))	('patients', 'Species', '9606', (179, 187))	('BRCA', 'Gene', (193, 197))	('BRCA', 'Gene', '672', (91, 95))
228218	34012291	Germline TP53 mutations are associated with Li-Fraumeni syndrome, first described in 1969 by Li and Fraumeni, who reported a high incidence of soft tissue sarcomas and BC in young women belonging to four families.	('women', 'Species', '9606', (180, 185))	('sarcomas', 'Disease', 'MESH:D012509', (155, 163))	('associated', 'Reg', (28, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (143, 163))	('sarcomas', 'Disease', (155, 163))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (44, 64))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (143, 162))	('TP53', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('Li-Fraumeni syndrome', 'Disease', (44, 64))
228220	34012291	Mutations in TP53 correlate with a more aggressive tumour phenotype, characterized by genomic instability, a high mitotic index, high Ki-67 and cyclin E expression.	('TP53', 'Gene', (13, 17))	('genomic instability', 'CPA', (86, 105))	('aggressive tumour', 'Disease', 'MESH:D009369', (40, 57))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('Mutations', 'Var', (0, 9))	('cyclin E expression', 'MPA', (144, 163))	('aggressive tumour', 'Disease', (40, 57))
228222	34012291	However, single nucleotide polymorphisms (SNPs) are also associated with altered p53 function and with an increased cancer risk, rapid progression or an altered response to treatments.	('function', 'MPA', (85, 93))	('altered', 'Reg', (73, 80))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('single nucleotide polymorphisms', 'Var', (9, 40))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
228223	34012291	In this regard, in a cohort study by Overgaard J on 294 patients with BC, TP53 mutation was associated with a significantly poorer outcome with univariate odds ratios for local failure of 2.04 (1.43-2.91, 95% confidence limit), distant metastasis of 3.56 (2.65-4.77), any failure or death (disease-free survival) 2.51 (1.89-3.32) and death 3.99 (2.97-5.37).	('patients', 'Species', '9606', (56, 64))	('distant metastasis', 'CPA', (228, 246))	('death', 'Disease', 'MESH:D003643', (334, 339))	('death', 'Disease', 'MESH:D003643', (283, 288))	('mutation', 'Var', (79, 87))	('local failure', 'CPA', (171, 184))	('poorer', 'NegReg', (124, 130))	('any failure', 'CPA', (268, 279))	('death', 'Disease', (334, 339))	('TP53', 'Gene', (74, 78))	('death', 'Disease', (283, 288))
228224	34012291	Patients with TP53 mutations had an overall survival (OS) probability of 52% at 5 years compared with 82% in wild-type (WT) carriers (p < 0.0001).	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))
228225	34012291	In node negative, patients' OS was 89% in WT vs 64% in TP53 mutations carriers (p = 0.0002); in node positive, patients' OS was 72% in WT vs 44% TP53 mutation carriers (p= 0.003).	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', (145, 149))	('patients', 'Species', '9606', (18, 26))	('mutations', 'Var', (60, 69))	('patients', 'Species', '9606', (111, 119))
228227	34012291	ATM gene mutations predispose patients to a rare autosomal recessive disorder named ataxia-telangiectasia (AT) and its variants.	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (84, 105))	('mutations', 'Var', (9, 18))	('telangiectasia', 'Phenotype', 'HP:0001009', (91, 105))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (49, 77))	('patients', 'Species', '9606', (30, 38))	('ataxia-telangiectasia', 'Disease', (84, 105))	('predispose', 'Reg', (19, 29))	('AT', 'Disease', 'None', (0, 2))	('ataxia', 'Phenotype', 'HP:0001251', (84, 90))	('AT', 'Disease', 'None', (107, 109))	('autosomal recessive disorder', 'Disease', (49, 77))
228231	34012291	In another study on patients with familial BC, a 2.37 relative risk of BC development was shown among ATM heterozygotes mutation occurring in any functional domain of the ATM gene.	('mutation', 'Var', (120, 128))	('patients', 'Species', '9606', (20, 28))	('ATM', 'Gene', (102, 105))
228232	34012291	All of these genes are involved in the DNA damage repair machinery after IR, impacting cell cycle recruitment, proliferation and apoptosis in various ways through impaired DNA DSBs repair pathways and, consequently, altered radiosensitivity, which is still a debated matter.	('radiosensitivity', 'MPA', (224, 240))	('DSBs', 'Chemical', '-', (176, 180))	('impacting', 'Reg', (77, 86))	('apoptosis', 'CPA', (129, 138))	('impaired', 'NegReg', (163, 171))	('proliferation', 'CPA', (111, 124))	('DNA DSBs repair pathways', 'Pathway', (172, 196))	('genes', 'Var', (13, 18))	('cell cycle recruitment', 'CPA', (87, 109))	('altered', 'Reg', (216, 223))
228233	34012291	Myths from retrospective data with a limited follow-up regarding local outcome assessment supported by the theory of genome instability have generated conflicting results and doubts about the efficacy of ART in patients with BC carrying BRCA1/2 mutations.	('mutations', 'Var', (245, 254))	('patients', 'Species', '9606', (211, 219))	('BRCA1/2', 'Gene', (237, 244))	('BRCA1/2', 'Gene', '672;675', (237, 244))
228237	34012291	Irradiated lymphoblastoid cell lines heterozygous for BRCA1/2 mutations showed a significantly higher number of chromatid breaks per cell than control cells, while irradiated BRCA1-/- MEFs were found to be highly sensitive to IR, as were HCC1937 human cancer cells with truncated BRCA1 expression.	('BRCA1', 'Gene', (280, 285))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('chromatid breaks', 'Phenotype', 'HP:0040012', (112, 128))	('cancer', 'Disease', (252, 258))	('BRCA1', 'Gene', (175, 180))	('higher', 'PosReg', (95, 101))	('BRCA1', 'Gene', '672', (175, 180))	('BRCA1/2', 'Gene', (54, 61))	('HCC1937', 'CellLine', 'CVCL:0290', (238, 245))	('BRCA1', 'Gene', '672', (54, 59))	('BRCA1', 'Gene', '672', (280, 285))	('chromatid breaks', 'CPA', (112, 128))	('human', 'Species', '9606', (246, 251))	('MEFs', 'CellLine', 'CVCL:9115', (184, 188))	('BRCA1/2', 'Gene', '672;675', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('mutations', 'Var', (62, 71))	('BRCA1', 'Gene', (54, 59))
228238	34012291	Most likely, BRCA 1 and 2 mutated cells show different radiosensitivity, as investigated by Baert et al, in two different studies, but no confirmations have been achieved in clinical reports.	('BRCA 1 and 2', 'Gene', '672;675', (13, 25))	('mutated', 'Var', (26, 33))	('radiosensitivity', 'MPA', (55, 71))
228240	34012291	Additionally, the retrospective study of Pierce et al showed no diversity in OS, local recurrence or cancer-specific survival between BRCA1/2 mutated vs nonmutated patients with stage I/II BC treated with surgery followed by ART at a median follow-up time of 5.3 years.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('mutated', 'Var', (142, 149))	('BRCA1/2', 'Gene', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA1/2', 'Gene', '672;675', (134, 141))	('patients', 'Species', '9606', (164, 172))
228242	34012291	Similarly, Kyrova et al found no significant differences in the recurrence rate (p=0.47) among patients with BC treated with surgery followed by ART carrying or not carrying BRCA1/2 mutations.	('BRCA1/2', 'Gene', (174, 181))	('BRCA1/2', 'Gene', '672;675', (174, 181))	('mutations', 'Var', (182, 191))	('patients', 'Species', '9606', (95, 103))
228245	34012291	As concluded by Vallard et al, from a radiation oncologist's point of view, there is no radiosensitivity difference sufficient to discourage the use of ART in patients with BC carrying BRCA1/2 mutations, although long-term data are needed.	('mutations', 'Var', (193, 202))	('patients', 'Species', '9606', (159, 167))	('BRCA1/2', 'Gene', (185, 192))	('BRCA1/2', 'Gene', '672;675', (185, 192))
228248	34012291	These results support the theory that WT p53 function is required for the sensitivity of tumour cells to DNA-damaging agents, such as IR, and that the loss of p53 function in certain human tumour cells can lead to resistance to IR.	('loss', 'Var', (151, 155))	('p53', 'Gene', '7157', (41, 44))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('tumour', 'Disease', (89, 95))	('lead to', 'Reg', (206, 213))	('human', 'Species', '9606', (183, 188))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('resistance to IR', 'MPA', (214, 230))	('tumour', 'Disease', (189, 195))	('p53', 'Gene', (41, 44))
228249	34012291	In carefully controlled radiotherapy studies, the presence of mutant p53, regardless of the missense and nonmissense mutational condition, has been associated with decreased local control following radiotherapy and a worse prognosis.	('mutant', 'Var', (62, 68))	('decreased', 'NegReg', (164, 173))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('presence', 'Var', (50, 58))	('local control', 'CPA', (174, 187))
228250	34012291	Nowadays, the current literature agrees with the theory of minimizing radiation exposure and avoiding high-dose schedules and re-irradiation in patients carrying TP53 mutations.	('patients', 'Species', '9606', (144, 152))	('TP53', 'Gene', (162, 166))	('mutations', 'Var', (167, 176))
228253	34012291	Based on experiments in mice and cell culture of dermal fibroblasts, increased radiosensitivity in mutation carrier cells has been recorded linked to a downregulation of ATM protein levels, as also observed in a published case report.	('downregulation', 'NegReg', (152, 166))	('increased', 'PosReg', (69, 78))	('mice', 'Species', '10090', (24, 28))	('radiosensitivity', 'MPA', (79, 95))	('ATM protein levels', 'MPA', (170, 188))	('mutation', 'Var', (99, 107))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (69, 95))
228254	34012291	In vivo studies suggest a wide response spectrum in favour of the effectiveness of radiation in patients with BC carriers of a pathogenic ATM variant due to their deficiency in DNA mismatch repair mechanisms.	('deficiency', 'NegReg', (163, 173))	('variant', 'Var', (142, 149))	('ATM', 'Gene', (138, 141))	('patients', 'Species', '9606', (96, 104))
228257	34012291	In the study by Meyer et al on a cohort of 138 patients with BC who received ART following BCS with 20 patient carriers of important sequence variants in the ATM gene, no difference was found in the actuarial 7-year local relapse-free survival of carriers vs noncarriers (88 vs 94% P=0.34).	('patient', 'Species', '9606', (47, 54))	('local relapse-free survival', 'CPA', (216, 243))	('variants', 'Var', (142, 150))	('patients', 'Species', '9606', (47, 55))	('ATM', 'Gene', (158, 161))	('patient', 'Species', '9606', (103, 110))	('carriers', 'Var', (247, 255))
228260	34012291	In this study, five patients with breast cancer and varying germline heterozygous ATM mutations, after RT, remained recurrence-free with a median duration of 18 months.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('ATM', 'Gene', (82, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('patients', 'Species', '9606', (20, 28))
228261	34012291	Radiotherapy-induced acute and late toxicities are considered not only a consequence of irradiation techniques but also of patient-related factors, such as age and altered genetic background as occurs in BC related to TSGs mutations leading to several uncertainties on ART benefit.	('TSG', 'Gene', '57045', (218, 221))	('patient', 'Species', '9606', (123, 130))	('toxicities', 'Disease', (36, 46))	('TSG', 'Gene', (218, 221))	('mutations', 'Var', (223, 232))	('toxicities', 'Disease', 'MESH:D064420', (36, 46))
228265	34012291	In a study by Pierce et al, with a median follow-up of 5.3 years, no difference in late normal tissue toxicities was found in irradiated patients with BC and mutation carriers.	('mutation', 'Var', (158, 166))	('toxicities', 'Disease', 'MESH:D064420', (102, 112))	('toxicities', 'Disease', (102, 112))	('patients', 'Species', '9606', (137, 145))
228267	34012291	Furthermore, ethnicity does not seem to influence toxicity in BRCA mutations, as demonstrated by Park et al in a Korean study on 213 patients with BC undergoing ART, 20% of whom had BRCA1 and/or BRCA2 mutations.	('BRCA2', 'Gene', '675', (195, 200))	('BRCA', 'Gene', '672', (182, 186))	('BRCA1', 'Gene', '672', (182, 187))	('mutations', 'Var', (201, 210))	('BRCA', 'Gene', (195, 199))	('BRCA', 'Gene', '672', (62, 66))	('BRCA', 'Gene', (182, 186))	('patients', 'Species', '9606', (133, 141))	('BRCA1', 'Gene', (182, 187))	('BRCA', 'Gene', (62, 66))	('BRCA2', 'Gene', (195, 200))	('toxicity', 'Disease', 'MESH:D064420', (50, 58))	('toxicity', 'Disease', (50, 58))	('BRCA', 'Gene', '672', (195, 199))
228269	34012291	In the report by Huzno et al, no significant differences in terms of early acute and severe skin toxicity or complications requiring treatment discontinuation were observed among patients with BC carriers of BRCA mutation vs noncarriers (3% vs 4% p=0.880 and 0% vs 1% p = 0.860, respectively).	('mutation', 'Var', (213, 221))	('BRCA', 'Gene', (208, 212))	('BRCA', 'Gene', '672', (208, 212))	('patients', 'Species', '9606', (179, 187))	('skin toxicity', 'Disease', (92, 105))	('skin toxicity', 'Disease', 'MESH:D012871', (92, 105))
228270	34012291	By in vitro studies, modified irradiation apoptosis (IA) in association with several TP53 polymorphisms has been related to late radiation-induced toxicity.	('TP53', 'Gene', (85, 89))	('related', 'Reg', (113, 120))	('toxicity', 'Disease', 'MESH:D064420', (147, 155))	('toxicity', 'Disease', (147, 155))	('modified irradiation apoptosis', 'Disease', (21, 51))	('polymorphisms', 'Var', (90, 103))
228273	34012291	IA in patients with toxicity appeared to be lower than that in the control patients only in TP53Arg/Arg patients (P= 0.077).	('lower', 'NegReg', (44, 49))	('TP53Arg/Arg', 'Var', (92, 103))	('toxicity', 'Disease', 'MESH:D064420', (20, 28))	('patients', 'Species', '9606', (75, 83))	('toxicity', 'Disease', (20, 28))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (104, 112))
228275	34012291	Tan et al compared the acute radiation toxicity in TP53 72 (TP53 Arg72Pro) Pro carriers with that in noncarriers.	('toxicity', 'Disease', 'MESH:D064420', (39, 47))	('Arg72Pro', 'Var', (65, 73))	('toxicity', 'Disease', (39, 47))	('Arg72Pro', 'SUBSTITUTION', 'None', (65, 73))
228280	34012291	The RT-induced toxicity spectrum in patients with BC carrying ATM mutations is controversial because of the wide variety of ATM mutations acting alone or in combination.	('mutations', 'Var', (66, 75))	('toxicity', 'Disease', (15, 23))	('toxicity', 'Disease', 'MESH:D064420', (15, 23))	('patients', 'Species', '9606', (36, 44))
228283	34012291	For example, the condition of heterozygosity for truncating ATM mutations has been related to devastating normal tissue toxicity induced by RT, as reported in an overview by Pollard et al.	('toxicity', 'Disease', 'MESH:D064420', (120, 128))	('toxicity', 'Disease', (120, 128))	('mutations', 'Var', (64, 73))	('truncating', 'Var', (49, 59))	('related', 'Reg', (83, 90))
228285	34012291	Moreover, the concomitant presence of two pathogenic gene variants seems to be linked with grade 3-4 late subcutaneous toxicity, as reported by Iannuzzi et al among 3 out 6 ATM-mutated patients with BC carrying more than one missense variant in the ATM gene.	('toxicity', 'Disease', 'MESH:D064420', (119, 127))	('toxicity', 'Disease', (119, 127))	('linked', 'Reg', (79, 85))	('ATM', 'Gene', (249, 252))	('variants', 'Var', (58, 66))	('patients', 'Species', '9606', (185, 193))	('missense variant', 'Var', (225, 241))
228286	34012291	Gly2891Asp and a c.1A4G substitution) have been linked to a severe reaction after ART in breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('Gly2891Asp', 'SUBSTITUTION', 'None', (0, 10))	('patients', 'Species', '9606', (103, 111))	('c.1A4G', 'Var', (17, 23))	('linked to', 'Reg', (48, 57))	('Gly2891Asp', 'Var', (0, 10))
228287	34012291	This SNP, also known as G5557A or D1853N, due to a nonconservative substitution of aspartic acid for asparagine at amino acid position 1853 in an exon is the most studied variant related to skin toxicity in breast cancer radiotherapy.	('G5557A', 'Mutation', 'g.5557G>A', (24, 30))	('substitution', 'Var', (67, 79))	('skin toxicity', 'Disease', (190, 203))	('D1853N', 'Var', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('related', 'Reg', (179, 186))	('skin toxicity', 'Disease', 'MESH:D012871', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('D1853N', 'Mutation', 'rs1801516', (34, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('breast cancer', 'Disease', (207, 220))	('aspartic acid for asparagine at amino acid position 1853', 'Mutation', 'rs1801516', (83, 139))
228290	34012291	Two of them recorded a significantly increased risk of acute toxicity and radiation-induced fibrosis among carriers of rs1801516.	('rs1801516', 'Var', (119, 128))	('toxicity', 'Disease', 'MESH:D064420', (61, 69))	('fibrosis', 'Disease', (92, 100))	('toxicity', 'Disease', (61, 69))	('fibrosis', 'Disease', 'MESH:D005355', (92, 100))	('rs1801516', 'Mutation', 'rs1801516', (119, 128))
228291	34012291	In this paper, pooled analyses of two cohorts revealed no association of ATM rs1801516 with radiation-induced telangiectasia (P = 0.316) but a significant correlation with radiation-induced fibrosis (P = 0.049).	('ATM', 'Gene', (73, 76))	('telangiectasia', 'Disease', (110, 124))	('telangiectasia', 'Phenotype', 'HP:0001009', (110, 124))	('telangiectasia', 'Disease', 'MESH:D013684', (110, 124))	('correlation', 'Interaction', (155, 166))	('rs1801516', 'Mutation', 'rs1801516', (77, 86))	('rs1801516', 'Var', (77, 86))	('fibrosis', 'Disease', 'MESH:D005355', (190, 198))	('fibrosis', 'Disease', (190, 198))
228295	34012291	The incidence of ART-SPMs seems quite different among BC related to TSGs mutations.	('TSG', 'Gene', '57045', (68, 71))	('TSG', 'Gene', (68, 71))	('mutations', 'Var', (73, 82))	('ART-SPMs', 'Disease', (17, 25))
228298	34012291	The hypothesis of an increased incidence of radiation-induced second tumours, particularly in young patients who are carriers of genetic mutations, is actually based on data on young patients subjected to early intensive screening with mammography and chest X-rays.	('tumours', 'Disease', (69, 76))	('mutations', 'Var', (137, 146))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (100, 108))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('patients', 'Species', '9606', (183, 191))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
228299	34012291	The published data are controversial, although they seem to support the hypothesis that radiation exposure at an early age (<30 years) may be a risk factor for BC development in patients carrying BRCA1 mutations, as reported by Pijpe et al and Andriew et al.	('BRCA1', 'Gene', '672', (196, 201))	('BRCA1', 'Gene', (196, 201))	('patients', 'Species', '9606', (178, 186))	('risk', 'Reg', (144, 148))	('mutations', 'Var', (202, 211))
228300	34012291	Thus, there is uniform agreement in replacing mammography screening by magnetic resonance imaging for patients carrying BRCA1 mutations.	('BRCA1', 'Gene', '672', (120, 125))	('patients', 'Species', '9606', (102, 110))	('BRCA1', 'Gene', (120, 125))	('mutations', 'Var', (126, 135))
228306	34012291	In a study by Kadoury et al, of 470 patients with BRCA mutations, seven developed a sarcoma in the radiation field, five in the chest wall and two in other sites.	('patients', 'Species', '9606', (36, 44))	('mutations', 'Var', (55, 64))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('developed', 'Reg', (72, 81))	('sarcoma', 'Disease', (84, 91))	('BRCA', 'Gene', '672', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('BRCA', 'Gene', (50, 54))
228307	34012291	Genetic evaluation revealed BRCA1 mutations in two additional patients and BRCA2 mutations in another patient.	('BRCA1', 'Gene', '672', (28, 33))	('revealed', 'Reg', (19, 27))	('patient', 'Species', '9606', (102, 109))	('BRCA1', 'Gene', (28, 33))	('patient', 'Species', '9606', (62, 69))	('BRCA2', 'Gene', (75, 80))	('mutations', 'Var', (81, 90))	('BRCA2', 'Gene', '675', (75, 80))	('patients', 'Species', '9606', (62, 70))	('mutations', 'Var', (34, 43))
228309	34012291	It is well acknowledged that patients with TP53 mutations have an increased risk of other cancers other than primary or secondary BC, regardless of radiation exposure.	('cancers', 'Disease', (90, 97))	('patients', 'Species', '9606', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('primary', 'Disease', (109, 116))	('secondary BC', 'Disease', (120, 132))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
228310	34012291	With this regard, mouse models have confirmed that TP53 mutations enable cells to repair DNA damage induced by IR, leading to a significantly higher risk of tumour development.	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('mouse', 'Species', '10090', (18, 23))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('tumour', 'Disease', (157, 163))	('higher', 'PosReg', (142, 148))
228312	34012291	Related aggressiveness has been reported in a case showing a de novo TP 53 mutation such as c.G841C, p.D281N, responsible for dramatic development 40 months after radiotherapy of a malignant fibrous histiocytoma of the right clavicle and another primary left BC in a 27-year-old woman treated with RT for bilateral BC.	('TP 53', 'Gene', '7157', (69, 74))	('aggressiveness', 'Phenotype', 'HP:0000718', (8, 22))	('histiocytoma', 'Phenotype', 'HP:0012315', (199, 211))	('malignant fibrous histiocytoma', 'Disease', 'MESH:D051677', (181, 211))	('TP 53', 'Gene', (69, 74))	('c.G841C', 'Var', (92, 99))	('malignant fibrous histiocytoma', 'Disease', (181, 211))	('aggressiveness', 'Disease', 'MESH:D001523', (8, 22))	('p.D281N', 'Var', (101, 108))	('p.D281N', 'Mutation', 'rs764146326', (101, 108))	('woman', 'Species', '9606', (279, 284))	('c.G841C', 'Mutation', 'rs764146326', (92, 99))	('aggressiveness', 'Disease', (8, 22))
228316	34012291	Petry et al reported particularly high RT-induced damage in specific TP53 pathogenic germline variants, namely, those characterized by the c.1010G>A mutation in exon 10 (p. Arg337His, R337H), which is frequent in southern and south-eastern Brazil.	('Arg337His', 'Var', (173, 182))	('RT-induced damage', 'MPA', (39, 56))	('Arg337His', 'SUBSTITUTION', 'None', (173, 182))	('c.1010G>A', 'Mutation', 'rs121912664', (139, 148))	('TP53', 'Gene', (69, 73))	('R337H', 'Var', (184, 189))	('pathogenic', 'Reg', (74, 84))	('R337H', 'Mutation', 'rs121912664', (184, 189))	('c.1010G>A', 'Var', (139, 148))
228320	34012291	This issue has been widely questioned in case of ART applied in patients with BC carrying TSGs mutations.	('TSG', 'Gene', (90, 93))	('patients', 'Species', '9606', (64, 72))	('TSG', 'Gene', '57045', (90, 93))	('mutations', 'Var', (95, 104))
228321	34012291	It is well acknowledged that patients with BC carrying BRCA mutations per se show a high risk of developing CBC.	('patients', 'Species', '9606', (29, 37))	('BRCA', 'Gene', '672', (55, 59))	('BRCA', 'Gene', (55, 59))	('mutations', 'Var', (60, 69))	('CBC', 'Disease', (108, 111))
228324	34012291	For information, sequence variants corresponding to deleterious mutations have been defined according the Breast Cancer Information Core (BIC) criteria: (1) all frameshift and nonsense variants with the exception of the neutral stop codon BRCA2 c.9976A>T (BIC: K3326X) and other variants located 3' thereof; (2) all alterations in non-coding intervening sequences (IVS variants) occurring in the consensus splice acceptor or donor sequence sites, either within 2 bp of exon-intron junctions or when experimentally demonstrated to result in abnormal mRNA transcript processing; (3) missense variants that have been conclusively demonstrated, on the basis of data from linkage analysis of high-risk families, functional assays or biochemical evidence, to have a deleterious effect on known functional regions.	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Breast Cancer', 'Disease', (106, 119))	('BRCA2', 'Gene', (239, 244))	('Breast Cancer', 'Disease', 'MESH:D001943', (106, 119))	('mRNA transcript processing', 'MPA', (549, 575))	('BRCA2', 'Gene', '675', (239, 244))	('Breast Cancer', 'Phenotype', 'HP:0003002', (106, 119))	('missense variants', 'Var', (581, 598))	('c.9976A>T', 'Mutation', 'rs11571833', (245, 254))	('K3326X', 'Mutation', 'rs11571833', (261, 267))
228325	34012291	However, data derived from retrospective studies have provided no clear evidence that patients with BC carriers of BRCA1/2 mutations are more predisposed to radiation-induced CBC than patients with sporadic breast cancer.	('patients', 'Species', '9606', (184, 192))	('BRCA1/2', 'Gene', (115, 122))	('predisposed', 'Reg', (142, 153))	('radiation-induced CBC', 'Disease', (157, 178))	('sporadic breast cancer', 'Disease', (198, 220))	('BRCA1/2', 'Gene', '672;675', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (198, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('mutations', 'Var', (123, 132))	('patients', 'Species', '9606', (86, 94))
228326	34012291	In a recent multicentric study, the 10-year cumulative risk of developing CBC was found to be 25.1% (95% CI 19.6-31.9) for patients with BC carrying BRCA1 mutations, 13.5% (95% CI 9.2-19.1) for those carrying BRCA2 mutations and 3.6% (95% CI 2.2-5.7) for noncarriers.	('BRCA2', 'Gene', '675', (209, 214))	('mutations', 'Var', (155, 164))	('patients', 'Species', '9606', (123, 131))	('CBC', 'Disease', (74, 77))	('mutations', 'Var', (215, 224))	('BRCA1', 'Gene', '672', (149, 154))	('BRCA2', 'Gene', (209, 214))	('BRCA1', 'Gene', (149, 154))
228329	34012291	Regarding the effect of the low doses received by the contralateral breast, a population-based nested case-control study conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC) with all women tested for BRCA1 and BRCA2 mutations yielded interesting findings.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('BRCA1', 'Gene', '672', (227, 232))	('unilateral breast cancer', 'Disease', (170, 194))	('BRCA2', 'Gene', '675', (237, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('BRCA1', 'Gene', (227, 232))	('mutations', 'Var', (243, 252))	('BRCA2', 'Gene', (237, 242))	('unilateral breast cancer', 'Disease', 'MESH:D001943', (170, 194))	('unilateral breast', 'Phenotype', 'HP:0012813', (170, 187))	('women', 'Species', '9606', (210, 215))
228331	34012291	The risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR=4.5, confidence interval, CI=3.0-6.8) and among those treated with RT (RR=1.2, CI=1.0-1.6).	('BRCA2', 'Gene', (84, 89))	('CBC', 'Disease', (23, 26))	('BRCA1', 'Gene', '672', (78, 83))	('BRCA2', 'Gene', '675', (84, 89))	('mutation', 'Var', (90, 98))	('BRCA1', 'Gene', (78, 83))	('women', 'Species', '9606', (46, 51))
228335	34012291	Broeks et al reported that there is a nonsignificant increase in the risk of developing CBC among patients with BC who carry ATM missense variants not treated with ART (OR 0.77, 95% CI).	('CBC', 'Disease', (88, 91))	('missense variants', 'Var', (129, 146))	('patients', 'Species', '9606', (98, 106))
228336	34012291	Patients developing CBC with an ATM missense variant had a mean interval between the first and second breast tumours of ~101 months, compared to 122 months for patients who were noncarriers of ATM mutations (p = 0.085).	('breast tumour', 'Phenotype', 'HP:0100013', (102, 115))	('patients', 'Species', '9606', (160, 168))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('breast tumours', 'Disease', (102, 116))	('breast tumours', 'Disease', 'MESH:D001943', (102, 116))	('Patients', 'Species', '9606', (0, 8))	('CBC', 'Disease', (20, 23))	('missense variant', 'Var', (36, 52))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
228337	34012291	Interestingly, the combination of radiation treatment and a missense variant resulted in an even shorter mean interval of 92 months in patients with CBC compared with 136 months for those who did not receive RT and did not carry a germline variant (p = 0.029).	('patients', 'Species', '9606', (135, 143))	('CBC', 'Disease', (149, 152))	('shorter', 'NegReg', (97, 104))	('missense variant', 'Var', (60, 76))
228338	34012291	Bernstein et al performed a case-control study on a sample of 2105 women, analysing the association between ATM gene variants and the risk of developing synchronous CBC.	('ATM gene', 'Gene', (108, 116))	('women', 'Species', '9606', (67, 72))	('variants', 'Var', (117, 125))
228339	34012291	They found no significant increase in the diagnosis of CBC among BC patients who carried any of the different types of ATM mutations compared with patients who were WT-ATM.	('ATM', 'Gene', (119, 122))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (147, 155))	('mutations', 'Var', (123, 132))	('CBC', 'Disease', (55, 58))
228341	34012291	Bernstein et al noted that in women with BC who carried ATM missense variants, those with radiation exposure levels of 1.0 Gy or higher had a significantly increased risk of CBC compared with patients with BC who were WT for ATM and who were unexposed to radiation (RR = 2.0, 95% CI = 1.1 to 3.9).	('patients', 'Species', '9606', (192, 200))	('women', 'Species', '9606', (30, 35))	('CBC', 'Disease', (174, 177))	('missense variants', 'Var', (60, 77))
228342	34012291	Therefore, although the increased risk of radiation-related CBC associated with specific ATM mutations is not a key determinant in the treatment choice in breast cancer for most patients, it might warrant consideration with regard to a family history of A-T and for the adsorbed dose to the contralateral breast.	('mutations', 'Var', (93, 102))	('ATM', 'Gene', (89, 92))	('patients', 'Species', '9606', (178, 186))	('A-T', 'Disease', (254, 257))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('A-T', 'Disease', 'MESH:D001260', (254, 257))
228343	34012291	The lack of Phase II-III studies assessing the effect of ART in patients with BC carrying TSGs mutations like BRCA1/2, TP53 and ATM induces controversial data and uncertainties concerning the benefit of ART in these patients, supporting mastectomy as the preferred choice.	('TSG', 'Gene', (90, 93))	('BRCA1/2', 'Gene', (110, 117))	('patients', 'Species', '9606', (64, 72))	('TSG', 'Gene', '57045', (90, 93))	('BRCA1/2', 'Gene', '672;675', (110, 117))	('patients', 'Species', '9606', (216, 224))	('mutations', 'Var', (95, 104))	('TP53', 'Gene', (119, 123))
228344	34012291	In light of recent literature data, the issues of ART in patients with BC carrying TSGs mutations seem to be solved in favour of a safe effect of ART when several conditions occur.	('TSG', 'Gene', '57045', (83, 86))	('patients', 'Species', '9606', (57, 65))	('mutations', 'Var', (88, 97))	('TSG', 'Gene', (83, 86))
228349	34012291	Useful and a quick guidance with information related to ART safety in patients with BC carrying TSGs mutations are summarized below in Table 1.	('patients', 'Species', '9606', (70, 78))	('TSG', 'Gene', (96, 99))	('mutations', 'Var', (101, 110))	('TSG', 'Gene', '57045', (96, 99))
228351	33173419	Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('overexpression', 'PosReg', (37, 51))	('AKT', 'Gene', (24, 27))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('mTOR', 'Gene', '2475', (19, 23))	('sarcoma', 'Disease', (111, 118))	('Hyperactivation', 'Var', (0, 15))	('carcinosarcoma', 'Disease', (123, 137))	('mTOR', 'Gene', (19, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', (130, 137))	('PI3', 'Gene', '5266', (28, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('AKT', 'Gene', '207', (24, 27))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (103, 118))	('PI3', 'Gene', (28, 31))	('carcinosarcoma', 'Disease', 'MESH:D002296', (123, 137))
228409	33173419	GEM+MLN combination showed additivity also in ESS-1, in this cell line addition was also deteted in combinations: GEM+RAP and MLN+RAP.	('GEM', 'Chemical', 'MESH:C056507', (114, 117))	('RAP', 'Chemical', '-', (118, 121))	('ESS-1', 'Gene', '7046', (46, 51))	('ESS-1', 'Gene', (46, 51))	('MLN', 'Gene', (4, 7))	('MLN', 'Gene', (126, 129))	('GEM+RAP', 'Var', (114, 121))	('RAP', 'Chemical', '-', (130, 133))	('MLN', 'Gene', '4295', (126, 129))	('MLN', 'Gene', '4295', (4, 7))	('GEM', 'Chemical', 'MESH:C056507', (0, 3))
228410	33173419	Additivity was observed for MLN+RAP and GAM+RAP.	('MLN', 'Gene', '4295', (28, 31))	('RAP', 'Chemical', '-', (32, 35))	('RAP', 'Chemical', '-', (44, 47))	('MLN', 'Gene', (28, 31))	('GAM+RAP', 'Var', (40, 47))
228437	33173419	The rest of tested combinations gave much more optimistic results, we noted additive effect between both GEM-RAP and MLN-RAP.	('GEM-RAP', 'Chemical', '-', (105, 112))	('MLN-RAP', 'Var', (117, 124))	('MLN-RAP', 'Chemical', '-', (117, 124))	('additive', 'Interaction', (76, 84))
228502	31676003	The finalized pathologic stage was T3aN0M0 based on the American Joint Committee on Cancer (AJCC) definition and accepted as stage II according to the updated National Wilms Tumor Study 5 (NWTS-5) definition.	('Cancer', 'Disease', 'MESH:D009369', (84, 90))	('Tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Wilms Tumor', 'Disease', 'MESH:D009396', (168, 179))	('T3aN0M0', 'Var', (35, 42))	('Wilms Tumor', 'Disease', (168, 179))	('Wilms Tumor', 'Phenotype', 'HP:0002667', (168, 179))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Disease', (84, 90))
228556	31676003	reported that diffuse and strong positivity of CD56 is characteristic of CCSK.	('CD56', 'Gene', (47, 51))	('CCSK', 'Disease', (73, 77))	('CCSK', 'Phenotype', 'HP:0006770', (73, 77))	('CD56', 'Gene', '4684', (47, 51))	('positivity', 'Var', (33, 43))
228568	31676003	The BCL-6 corepressor (BCOR) gene was found to regulate mesenchymal stem cell function by epigenetic mechanisms.	('epigenetic', 'Var', (90, 100))	('mesenchymal stem cell function', 'CPA', (56, 86))	('regulate', 'Reg', (47, 55))	('BCL-6 corepressor', 'Gene', (4, 21))	('BCL-6 corepressor', 'Gene', '54880', (4, 21))	('BCOR', 'Gene', (23, 27))	('BCOR', 'Gene', '54880', (23, 27))
228569	31676003	Ueno-Yokohata found 100% internal tandem duplications (ITDs) in exon 15 of the BCOR gene in 20 cases of CCSK.	('BCOR', 'Gene', '54880', (79, 83))	('CCSK', 'Disease', (104, 108))	('CCSK', 'Phenotype', 'HP:0006770', (104, 108))	('internal tandem duplications', 'Var', (25, 53))	('BCOR', 'Gene', (79, 83))
228579	31676003	The hypermethylation of TCF21, a transcription factor known to be active early in renal development, might lie within the pathogenic pathway of most CCSKs.	('CCSKs', 'Disease', (149, 154))	('TCF21', 'Gene', (24, 29))	('lie', 'Reg', (107, 110))	('CCSK', 'Phenotype', 'HP:0006770', (149, 153))	('TCF21', 'Gene', '6943', (24, 29))	('hypermethylation', 'Var', (4, 20))
228580	31676003	The status of BCOR ITDs, YWHAE-NUTM2B/E fusion and hypermethylation of TCF21 in adult CCSKs is not clear.	('NUTM2B', 'Gene', (31, 37))	('BCOR', 'Gene', '54880', (14, 18))	('hypermethylation', 'Var', (51, 67))	('YWHAE', 'Gene', (25, 30))	('NUTM2B', 'Gene', '729262', (31, 37))	('TCF21', 'Gene', '6943', (71, 76))	('CCSK', 'Phenotype', 'HP:0006770', (86, 90))	('YWHAE', 'Gene', '7531', (25, 30))	('BCOR', 'Gene', (14, 18))	('TCF21', 'Gene', (71, 76))
228645	31160249	After observation of a prolonged partial remission with cediranib in a patient with locally advanced and metastatic ASPS treated in a phase 2, hypertension management study (NCT00264004), an opportunity arose to treat a further six patients with ASPS who were treated in a cediranib pharmacodynamic study of patients with soft-tissue sarcoma, most of whom had gastrointestinal stromal tumours (D8480C00046).	('cediranib', 'Chemical', 'MESH:C500926', (56, 65))	('patients', 'Species', '9606', (308, 316))	('men', 'Species', '9606', (162, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (334, 341))	('tumours', 'Phenotype', 'HP:0002664', (385, 392))	('ASPS', 'Gene', (246, 250))	('gastrointestinal stromal tumours', 'Disease', (360, 392))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (322, 341))	('patient', 'Species', '9606', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (385, 391))	('ASPS', 'Gene', (116, 120))	('hypertension', 'Disease', 'MESH:D006973', (143, 155))	('patient', 'Species', '9606', (308, 315))	('ASPS', 'Gene', '79058', (246, 250))	('ASPS', 'Phenotype', 'HP:0012218', (246, 250))	('hypertension', 'Disease', (143, 155))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (360, 392))	('cediranib', 'Chemical', 'MESH:C500926', (273, 282))	('sarcoma', 'Disease', 'MESH:D012509', (334, 341))	('ASPS', 'Gene', '79058', (116, 120))	('sarcoma', 'Disease', (334, 341))	('patients', 'Species', '9606', (232, 240))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (360, 391))	('ASPS', 'Phenotype', 'HP:0012218', (116, 120))	('hypertension', 'Phenotype', 'HP:0000822', (143, 155))	('D8480C00046', 'Var', (394, 405))	('patient', 'Species', '9606', (232, 239))
228650	31160249	In 40 patients with ASPS and a rearrangement of the TFE3 gene treated with the serine/threonine-protein kinase Haspin homolog ALK1 and hepatocyte growth factor receptor (MET) inhibitor crizotinib, one patient had a partial response and 35 had stable disease as their best response, with 1-year progression-free survival of 37 5% (95% CI 22 9-52 1).	('rearrangement', 'Var', (31, 44))	('patient', 'Species', '9606', (6, 13))	('ASPS', 'Gene', '79058', (20, 24))	('ALK1', 'Gene', (126, 130))	('hepatocyte growth factor receptor', 'Gene', '4233', (135, 168))	('crizotinib', 'Chemical', 'MESH:D000077547', (185, 195))	('ALK1', 'Gene', '94', (126, 130))	('men', 'Species', '9606', (40, 43))	('patients', 'Species', '9606', (6, 14))	('ASPS', 'Phenotype', 'HP:0012218', (20, 24))	('TFE3', 'Gene', (52, 56))	('hepatocyte growth factor receptor', 'Gene', (135, 168))	('patient', 'Species', '9606', (201, 208))	('ASPS', 'Gene', (20, 24))
228661	31160249	Patients were required to have measurable metastatic disease that had progressed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the previous 6 months; an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function (absolute neutrophil count >1 5 x 109 per L; platelet count >100x109 per L; serum bilirubin <1 5 x upper limit of normal [ULN], unless proven Gilbert's syndrome; alanine transaminase or aspartate transaminase <2 5 x ULN or <5 x ULN if liver metastases present; serum creatinine <1 5 x ULN or creatinine clearance >50 mL per min).	('>100x109 per L', 'Var', (378, 392))	('Tumors', 'Phenotype', 'HP:0002664', (136, 142))	('alanine transaminase', 'MPA', (480, 500))	("Gilbert's syndrome", 'Disease', (460, 478))	('<5 x ULN', 'Var', (541, 549))	('Solid Tumors', 'Disease', 'MESH:D009369', (130, 142))	('Solid Tumors', 'Disease', (130, 142))	('aspartate transaminase <2', 'Gene', (504, 529))	('Patients', 'Species', '9606', (0, 8))	('metastases', 'Disease', (559, 569))	('aspartate transaminase <2', 'Gene', '2806', (504, 529))	('serum creatinine', 'MPA', (579, 595))	('creatinine clearance', 'MPA', (610, 630))	("Gilbert's syndrome", 'Disease', 'MESH:D005878', (460, 478))	('serum bilirubin', 'MPA', (394, 409))	('metastases', 'Disease', 'MESH:D009362', (559, 569))
228731	31160249	Similar results were obtained in the sensitivity analysis in the cediranib-naive population (42 [88%] of 48 participants): median percentage change in the sum of the longest diameters (or shortest if nodal disease) of target marker lesions at 24 weeks was -4 4% (IQR -26 3 to 6 0) with cediranib versus 14 4% (1 1 to 22 6) with placebo (one-sided p=0 0019) and best percentage change was -15 0% (IQR -26 3 to -2 4) with cediranib versus 1 3% (-2 5 to 11 8) with placebo (one-sided p=0 00010).	('nodal disease', 'Disease', 'MESH:D013611', (200, 213))	('cediranib', 'Chemical', 'MESH:C500926', (65, 74))	('cediranib', 'Chemical', 'MESH:C500926', (286, 295))	('cediranib', 'Chemical', 'MESH:C500926', (420, 429))	('nodal disease', 'Disease', (200, 213))	('participants', 'Species', '9606', (108, 120))	('cediranib', 'Var', (420, 429))
228735	31160249	14 (50%) of 28 participants in the cediranib group and seven (44%) of 16 in the placebo group had stable disease at 24 weeks; thus the proportion of participants with clinical benefit at 24 weeks was 61% (17 of 28) for cediranib and 44% (seven of 16) for placebo (post-hoc analysis).	('participants', 'Species', '9606', (15, 27))	('cediranib', 'Chemical', 'MESH:C500926', (35, 44))	('stable', 'Disease', (98, 104))	('cediranib', 'Var', (219, 228))	('participants', 'Species', '9606', (149, 161))	('cediranib', 'Chemical', 'MESH:C500926', (219, 228))
228793	31160249	Whether or not the spectrum of receptor tyrosine kinases inhibited by cediranib is substantially different from that of other drugs that are active in this disease (eg, sunitinib) is unclear.	('inhibited', 'NegReg', (57, 66))	('cediranib', 'Var', (70, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (169, 178))	('cediranib', 'Chemical', 'MESH:C500926', (70, 79))
228816	30496486	Therefore, characterization of epigenomic deregulation in Ewing sarcoma may provide innovative insights into the pathophysiology of this cancer and offer new therapeutic approaches.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('epigenomic deregulation', 'Var', (31, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('Ewing sarcoma', 'Disease', (58, 71))	('cancer', 'Disease', (137, 143))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (58, 71))
228818	30496486	Histone marks such as H3K27ac, H3K4me1 and the transcription cofactor p300 often are used to define super-enhancers.	('H3K4me1', 'Var', (31, 38))	('H3K27ac', 'Var', (22, 29))	('p300', 'Gene', '2033', (70, 74))	('p300', 'Gene', (70, 74))
228826	30496486	The following antibodies were used in the current study: CDK7 (Cell Signaling Technology, 2916), RNAPII CTD S2 (Bethyl, A300-654A), RNAPII CTD S5 (Bethyl, A300-655A), RNAPII CTD S7 (Cell Signaling Technology, 13780), RNAPII (Santa Cruz, sc-899), MEIS1 (Abcam, ab19867), APCDD1 (Novus Biologicals, NB110-92756SS), FLI-1 (Santa Cruz Biotechnology, sc-53826), GAPDH (Cell Signaling Technology, 5174), anti-mouse IgG-HRP (Santa Cruz Biotechnology, sc-2005), anti-rabbit IgG-HRP (Santa Cruz Biotechnology, sc-2004) and rabbit IgG Isotype Control (Invitrogen, 02-6102).	('FLI-1', 'Gene', '2313', (313, 318))	('anti-mouse', 'Var', (398, 408))	('APCDD1', 'Gene', (270, 276))	('GAPDH', 'Gene', (357, 362))	('FLI-1', 'Gene', (313, 318))	('rabbit', 'Species', '9986', (459, 465))	('CDK7', 'Gene', (57, 61))	('rabbit', 'Species', '9986', (514, 520))	('APCDD1', 'Gene', '147495', (270, 276))	('mouse', 'Species', '10090', (403, 408))	('CDK7', 'Gene', '1022', (57, 61))	('GAPDH', 'Gene', '2597', (357, 362))
228849	30496486	H3K27ac ChIP-seq raw data generated in four Ewing sarcoma cell lines and three primary tumors were retrieved from NCBI Gene Expression Omnibus (GEO) or generously shared by Dr Kimberly Stegmaier (Harvard Medical School).	('H3K27ac', 'Var', (0, 7))	('Ewing sarcoma', 'Disease', (44, 57))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('NCBI', 'Gene', (114, 118))	('primary tumors', 'Disease', (79, 93))	('primary tumors', 'Disease', 'MESH:D009369', (79, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (44, 57))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (44, 57))
228868	30496486	Of note, compared to high-dose treatment, low-dose THZ1 elicited transcriptional inhibition in a more selective manner (Figure 2C, D; Supplementary Dataset S1).	('THZ1', 'Chemical', '-', (51, 55))	('low-dose', 'Var', (42, 50))	('THZ1', 'Gene', (51, 55))	('transcriptional', 'MPA', (65, 80))
228875	30496486	Moreover, preferential downregulation of transcripts associated with super-enhancers, but not typical-enhancers, was observed upon THZ1 treatment (Figure 3C).	('downregulation', 'NegReg', (23, 37))	('THZ1', 'Chemical', '-', (131, 135))	('THZ1', 'Var', (131, 135))	('transcripts', 'MPA', (41, 52))
228885	30496486	Importantly, enhancer profiles were highly similar between Ewing sarcoma cell lines and primary tumors, which were also supported by additional markers such as H3K4me1 (Figures 4A, B and 6C; Supplementary Figure S2A, B).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Ewing sarcoma', 'Disease', (59, 72))	('H3K4me1', 'Var', (160, 167))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('primary tumors', 'Disease', (88, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))	('primary tumors', 'Disease', 'MESH:D009369', (88, 102))
228900	30496486	Importantly, silencing of MEIS1 significantly inhibited xenograft tumor growth (Figure 5F, G; Supplementary Figure S6), corroborating the in vitro results.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('MEIS1', 'Gene', (26, 31))	('xenograft tumor', 'Disease', 'MESH:D009369', (56, 71))	('xenograft tumor', 'Disease', (56, 71))	('inhibited', 'NegReg', (46, 55))	('silencing', 'Var', (13, 22))
228907	30496486	Through further integration with RNA-seq data in the presence of silencing EWS-FLI1, we also found that a significant fraction (13.8%, 71 of 513) of 'EWS-FLI1 direct target genes' (genes bound by EWS-FLI1 and changed in expression by more than 2-fold in response to EWS-FLI1 knockdown, Supplementary Figure S7) were co-occupied by MEIS1 (Supplementary Figure S8 and Dataset S10).	('FLI1', 'Gene', (79, 83))	('FLI1', 'Gene', '2313', (200, 204))	('FLI1', 'Gene', '2313', (270, 274))	('changed', 'Reg', (209, 216))	('EWS', 'Gene', '2130', (196, 199))	('knockdown', 'Var', (275, 284))	('FLI1', 'Gene', '2313', (79, 83))	('EWS', 'Gene', '2130', (266, 269))	('EWS', 'Gene', (150, 153))	('EWS', 'Gene', '2130', (75, 78))	('EWS', 'Gene', (196, 199))	('FLI1', 'Gene', (154, 158))	('silencing', 'Var', (65, 74))	('expression', 'MPA', (220, 230))	('FLI1', 'Gene', (200, 204))	('EWS', 'Gene', (266, 269))	('EWS', 'Gene', '2130', (150, 153))	('EWS', 'Gene', (75, 78))	('FLI1', 'Gene', (270, 274))	('FLI1', 'Gene', '2313', (154, 158))
228914	30496486	Binding peaks of MEIS1 and EWS-FLI1 on APCDD1 (which were validated by ChIP-qPCR assays, Figure 6D, E) were flanked with high levels of H3K4me1 and H3K27ac modifications (Figure 6C), strongly suggesting the positive regulation of MEIS1 and EWS-FLI1 on APCDD1 transcription.	('EWS', 'Gene', (240, 243))	('APCDD1', 'Gene', (39, 45))	('APCDD1', 'Gene', (252, 258))	('FLI1', 'Gene', (244, 248))	('FLI1', 'Gene', (31, 35))	('FLI1', 'Gene', '2313', (244, 248))	('APCDD1', 'Gene', '147495', (39, 45))	('FLI1', 'Gene', '2313', (31, 35))	('APCDD1', 'Gene', '147495', (252, 258))	('H3K27ac', 'Var', (148, 155))	('MEIS1', 'Gene', (17, 22))	('H3K4me1', 'Var', (136, 143))	('EWS', 'Gene', '2130', (27, 30))	('EWS', 'Gene', (27, 30))	('EWS', 'Gene', '2130', (240, 243))
228919	30496486	Moreover, both the mRNA and protein expressions of APCDD1 were substantially suppressed when silencing MEIS1 or EWS-FLI1 (Figure 7A, B).	('suppressed', 'NegReg', (77, 87))	('silencing', 'Var', (93, 102))	('EWS', 'Gene', '2130', (112, 115))	('EWS', 'Gene', (112, 115))	('APCDD1', 'Gene', (51, 57))	('MEIS1', 'Gene', (103, 108))	('FLI1', 'Gene', '2313', (116, 120))	('FLI1', 'Gene', (116, 120))	('APCDD1', 'Gene', '147495', (51, 57))
228922	30496486	Similar to MEIS1 silencing, APCDD1 depletion reduced cell proliferation and anchorage-independent growth of Ewing sarcoma cells (Figure 7C, D).	('anchorage-independent growth', 'CPA', (76, 104))	('reduced', 'NegReg', (45, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('APCDD1', 'Gene', '147495', (28, 34))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('APCDD1', 'Gene', (28, 34))	('Ewing sarcoma', 'Disease', (108, 121))	('cell proliferation', 'CPA', (53, 71))	('depletion', 'Var', (35, 44))
228923	30496486	Moreover, APCDD1 depletion potently inhibited the growth of Ewing sarcoma xenografts (Supplementary Figures S6, 13).	('inhibited', 'NegReg', (36, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (60, 73))	('APCDD1', 'Gene', (10, 16))	('depletion', 'Var', (17, 26))	('growth', 'CPA', (50, 56))	('APCDD1', 'Gene', '147495', (10, 16))	('Ewing sarcoma', 'Disease', (60, 73))
228938	30496486	Besides, super-enhancer-associated transcripts were enriched among genes whose expression exhibited the most profound changes following EWS-FLI1 depletion (Figure 3F).	('changes', 'Reg', (118, 125))	('FLI1', 'Gene', (140, 144))	('expression', 'MPA', (79, 89))	('depletion', 'Var', (145, 154))	('EWS', 'Gene', '2130', (136, 139))	('EWS', 'Gene', (136, 139))	('FLI1', 'Gene', '2313', (140, 144))
228956	30496486	In this study, we showed that APCDD1 knockdown increased the expression of CDC25A, LRP6, LEF1 and NKD1, which are confirmed targets of the canonical Wnt pathway in Ewing sarcoma (Supplementary Figure S14), implying that APCDD1 might act as a Wnt inhibitor in this cancer.	('Supplementary Figure S1', 'Disease', (179, 202))	('CDC25A', 'Gene', (75, 81))	('Ewing sarcoma', 'Disease', (164, 177))	('knockdown', 'Var', (37, 46))	('LEF1', 'Gene', '51176', (89, 93))	('APCDD1', 'Gene', '147495', (30, 36))	('APCDD1', 'Gene', '147495', (220, 226))	('cancer', 'Disease', (264, 270))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (179, 202))	('APCDD1', 'Gene', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('APCDD1', 'Gene', (220, 226))	('NKD1', 'Gene', (98, 102))	('LEF1', 'Gene', (89, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (164, 177))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (164, 177))	('expression', 'MPA', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('LRP6', 'Gene', '4040', (83, 87))	('CDC25A', 'Gene', '993', (75, 81))	('LRP6', 'Gene', (83, 87))	('NKD1', 'Gene', '85407', (98, 102))	('increased', 'PosReg', (47, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))
229036	27683125	P-gp expression was elevated in Dox-resistant cells as compared to Dox-sensitive cells (Figure 1A).	('P-gp', 'Gene', '5243', (0, 4))	('expression', 'MPA', (5, 15))	('Dox', 'Chemical', 'MESH:D004317', (67, 70))	('Dox', 'Chemical', 'MESH:D004317', (32, 35))	('P-gp', 'Gene', (0, 4))	('elevated', 'PosReg', (20, 28))	('Dox-resistant', 'Var', (32, 45))
229054	27683125	In this study, arginine deprivation appeared to induce autophagy in Dox-resistant cells (Figure 3).	('arginine', 'Chemical', 'MESH:D001120', (15, 23))	('induce', 'PosReg', (48, 54))	('autophagy', 'CPA', (55, 64))	('Dox', 'Chemical', 'MESH:D004317', (68, 71))	('arginine deprivation', 'Var', (15, 35))
229126	31065111	Based on these results, eribulin was evaluated in an international phase 3 study of patients with unresectable or metastatic advanced LPS or LMS, in which eribulin significantly improved OS compared with dacarbazine in the total study population (13.5 vs 11.5 months, hazard ratio [HR] 0.77 [0.62-0.95], P = 0.017).	('improved', 'PosReg', (178, 186))	('LMS', 'Disease', (141, 144))	('LMS', 'Phenotype', 'HP:0100243', (141, 144))	('LPS', 'Disease', 'MESH:C536528', (134, 137))	('patients', 'Species', '9606', (84, 92))	('eribulin', 'Var', (155, 163))	('eribulin', 'Chemical', 'MESH:C490954', (155, 163))	('eribulin', 'Chemical', 'MESH:C490954', (24, 32))	('LPS', 'Disease', (134, 137))	('dacarbazine', 'Chemical', 'MESH:D003606', (204, 215))	('LPS', 'Phenotype', 'HP:0012034', (134, 137))
229150	31065111	Male patients treated with eribulin had numerically longer OS compared with male patients taking dacarbazine (14.2 vs 9.7 months, respectively) (Fig.	('patients', 'Species', '9606', (5, 13))	('eribulin', 'Var', (27, 35))	('eribulin', 'Chemical', 'MESH:C490954', (27, 35))	('patients', 'Species', '9606', (81, 89))	('longer', 'PosReg', (52, 58))	('dacarbazine', 'Chemical', 'MESH:D003606', (97, 108))
229154	31065111	Male patients treated with eribulin had numerically (but not statistically significantly) longer PFS compared with male patients taking dacarbazine (4.0 vs 2.6 months, respectively) (Fig.	('dacarbazine', 'Chemical', 'MESH:D003606', (136, 147))	('patients', 'Species', '9606', (5, 13))	('eribulin', 'Var', (27, 35))	('eribulin', 'Chemical', 'MESH:C490954', (27, 35))	('longer', 'PosReg', (90, 96))	('patients', 'Species', '9606', (120, 128))	('PFS', 'MPA', (97, 100))
229160	31065111	Grade >=3 neutropenia and leukopenia occurred more frequently in patients treated with eribulin, whereas grade >=3 anaemia and thrombocytopenia occurred more frequently in patients treated with dacarbazine (Table 3).	('anaemia', 'Disease', 'MESH:D000740', (115, 122))	('thrombocytopenia', 'Disease', (127, 143))	('dacarbazine', 'Chemical', 'MESH:D003606', (194, 205))	('anaemia', 'Phenotype', 'HP:0001903', (115, 122))	('leukopenia', 'Phenotype', 'HP:0001882', (26, 36))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (127, 143))	('neutropenia', 'Phenotype', 'HP:0001875', (10, 21))	('neutropenia', 'Disease', 'MESH:D009503', (10, 21))	('eribulin', 'Var', (87, 95))	('patients', 'Species', '9606', (65, 73))	('leukopenia', 'Disease', (26, 36))	('eribulin', 'Chemical', 'MESH:C490954', (87, 95))	('patients', 'Species', '9606', (172, 180))	('thrombocytopenia', 'Disease', 'MESH:D013921', (127, 143))	('leukopenia', 'Disease', 'MESH:D007970', (26, 36))	('neutropenia', 'Disease', (10, 21))	('anaemia', 'Disease', (115, 122))
229205	30906647	The latent heat of the melted PCM inside TINY keeps the system isothermal for over an hour in-case of power outages when heated by electricity, or in-case of variable cloud coverage when heated via sunlight.	('TINY', 'Gene', '319583', (41, 45))	('power outages', 'Var', (102, 115))	('TINY', 'Gene', (41, 45))
229263	30906647	Furthermore, when threshold times were grouped by patient, the resulting clustering shows that quantification by TINY is possible across all locations and heating methods, as the variation in threshold time was consistent with the expected variation from the LAMP assay itself (Fig.	('TINY', 'Gene', (113, 117))	('patient', 'Species', '9606', (50, 57))	('variation', 'Var', (179, 188))	('TINY', 'Gene', '319583', (113, 117))
229366	29718840	PET/CT is not sensitive to prostate sarcoma, because it is a qualitative analysis method based on the uptake of glucose in tumors, very limited literature reported that compared with FDG-PET, PET/CT improves especially in the lesion localization as well as characterization.	('glucose in tumors', 'Disease', (112, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('lesion localization', 'MPA', (226, 245))	('PET/CT', 'Var', (192, 198))	('prostate sarcoma', 'Disease', 'MESH:D011472', (27, 43))	('glucose in tumors', 'Disease', 'MESH:D009369', (112, 129))	('improves', 'PosReg', (199, 207))	('prostate sarcoma', 'Disease', (27, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('characterization', 'MPA', (257, 273))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
229380	29718840	The MRI detection and display of prostate carcinoma are mainly based on T2WI, which mainly manifested as a hypointense defect area in the peripheral zone, where it is significantly different from hyperintense of normal prostate tissue in peripheral zone.	('man', 'Species', '9606', (91, 94))	('hypointense defect', 'Disease', 'MESH:D005128', (107, 125))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (33, 51))	('T2WI', 'Var', (72, 76))	('prostate carcinoma', 'Disease', (33, 51))	('hypointense defect', 'Disease', (107, 125))	('prostate carcinoma', 'Disease', 'MESH:D011472', (33, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
229396	27186713	Animals with bone cancer pain treated with anti-P2X3 showed a reduction in skin hypersensitivity but no attenuation of skeletal pain behaviors.	('pain', 'Phenotype', 'HP:0012531', (128, 132))	('skeletal pain', 'Phenotype', 'HP:0002653', (119, 132))	('bone cancer pain', 'Disease', 'MESH:D001859', (13, 29))	('skeletal pain behaviors', 'Disease', (119, 142))	('hypersensitivity', 'Disease', (80, 96))	('hypersensitivity', 'Disease', 'MESH:D004342', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('anti-P2X3', 'Var', (43, 52))	('bone cancer pain', 'Disease', (13, 29))	('pain', 'Phenotype', 'HP:0012531', (25, 29))	('bone cancer pain', 'Phenotype', 'HP:0002653', (13, 29))	('skeletal pain behaviors', 'Disease', 'MESH:D013001', (119, 142))	('reduction in skin hypersensitivity', 'Phenotype', 'HP:0002972', (62, 96))	('reduction', 'NegReg', (62, 71))
229397	27186713	Whereas animals with bone cancer pain treated with anti-NGF showed a reduction in both skin hypersensitivity and skeletal pain behaviors.	('hypersensitivity', 'Disease', 'MESH:D004342', (92, 108))	('skeletal pain', 'Phenotype', 'HP:0002653', (113, 126))	('pain', 'Phenotype', 'HP:0012531', (33, 37))	('skeletal pain behaviors', 'Disease', (113, 136))	('reduction', 'NegReg', (69, 78))	('bone cancer pain', 'Disease', 'MESH:D001859', (21, 37))	('skeletal pain behaviors', 'Disease', 'MESH:D013001', (113, 136))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('pain', 'Phenotype', 'HP:0012531', (122, 126))	('hypersensitivity', 'Disease', (92, 108))	('bone cancer pain', 'Disease', (21, 37))	('bone cancer pain', 'Phenotype', 'HP:0002653', (21, 37))	('anti-NGF', 'Var', (51, 59))
229415	27186713	Using this approach we found that anti-P2X3 significantly reduced hypersensitivity of skin, but had no significant effect on attenuating skeletal pain-related behaviors.	('pain', 'Phenotype', 'HP:0012531', (146, 150))	('skeletal pain', 'Phenotype', 'HP:0002653', (137, 150))	('skeletal pain', 'Disease', (137, 150))	('attenuating', 'NegReg', (125, 136))	('skeletal pain', 'Disease', 'MESH:D010146', (137, 150))	('hypersensitivity of', 'Disease', (66, 85))	('hypersensitivity of', 'Disease', 'MESH:D004342', (66, 85))	('reduced hypersensitivity', 'Phenotype', 'HP:0002972', (58, 82))	('reduced', 'NegReg', (58, 65))	('anti-P2X3', 'Var', (34, 43))
229416	27186713	In contrast, anti-NGF, which has been shown to reduce skeletal pain in both humans and animals models, attenuated both mechanical hypersensitivity of the skin and skeletal pain-related behaviors.	('hypersensitivity of the', 'Disease', 'MESH:D004342', (130, 153))	('skeletal pain', 'Disease', (54, 67))	('attenuated', 'NegReg', (103, 113))	('pain', 'Phenotype', 'HP:0012531', (63, 67))	('reduce', 'NegReg', (47, 53))	('skeletal pain', 'Disease', 'MESH:D010146', (54, 67))	('skeletal pain', 'Disease', 'MESH:D010146', (163, 176))	('pain', 'Phenotype', 'HP:0012531', (172, 176))	('anti-NGF', 'Var', (13, 21))	('skeletal pain', 'Phenotype', 'HP:0002653', (163, 176))	('humans', 'Species', '9606', (76, 82))	('hypersensitivity of the', 'Disease', (130, 153))	('skeletal pain', 'Disease', (163, 176))	('skeletal pain', 'Phenotype', 'HP:0002653', (54, 67))
229421	27186713	In brief, an arthrotomy was performed following induction of general anesthesia with ketamine/xylazine (100 mg/kg ketamine and 10 mg/kg xylazine; s.c.).	('arthrotomy', 'Disease', 'None', (13, 23))	('ketamine', 'Chemical', 'MESH:D007649', (85, 93))	('xylazine', 'Chemical', 'MESH:D014991', (94, 102))	('ketamine', 'Chemical', 'MESH:D007649', (114, 122))	('arthrotomy', 'Disease', (13, 23))	('100 mg/kg', 'Var', (104, 113))	('xylazine', 'Chemical', 'MESH:D014991', (136, 144))
229428	27186713	We have shown that anti-NGF effectively reduces the skeletal pain associated with malignant bone cancer.	('skeletal pain', 'Disease', 'MESH:D010146', (52, 65))	('malignant bone cancer', 'Disease', (82, 103))	('anti-NGF', 'Var', (19, 27))	('skeletal pain', 'Phenotype', 'HP:0002653', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('pain', 'Phenotype', 'HP:0012531', (61, 65))	('reduces', 'NegReg', (40, 47))	('skeletal pain', 'Disease', (52, 65))	('malignant bone cancer', 'Disease', 'MESH:D001859', (82, 103))
229461	27186713	In order to accomplish this we evaluated the effect of two antibody treatments that bind either P2X3 or NGF on a battery of skeletal pain-related behaviors and on cancer-induced mechanical hypersensitivity of the skin.	('hypersensitivity of the', 'Disease', 'MESH:D004342', (189, 212))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('pain', 'Phenotype', 'HP:0012531', (133, 137))	('hypersensitivity of the', 'Disease', (189, 212))	('skeletal pain', 'Phenotype', 'HP:0002653', (124, 137))	('P2X3', 'Var', (96, 100))	('skeletal pain', 'Disease', (124, 137))	('NGF', 'Gene', (104, 107))	('skeletal pain', 'Disease', 'MESH:D010146', (124, 137))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
229464	27186713	Mechanical hypersensitivity was relieved when sarcoma injected animals were treated with either anti-P2X3 (on days 28 and 35) or anti-NGF (on days 21, 28, and 35) (Figure 1).	('anti-P2X3', 'Var', (96, 105))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('relieved', 'NegReg', (32, 40))	('hypersensitivity', 'Disease', (11, 27))	('hypersensitivity', 'Disease', 'MESH:D004342', (11, 27))	('anti-NGF', 'Var', (129, 137))	('sarcoma', 'Disease', (46, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
229469	27186713	Anti-P2X3 administration in CIBP mice (Figure 2A, dark gray bars) resulted in no difference in spontaneous nocifensive behaviors when compared to tumor-bearing mice treated with vehicle (Figure 2A).	('rat', 'Species', '10116', (18, 21))	('CIBP', 'Chemical', '-', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Anti-P2X3', 'Var', (0, 9))	('tumor', 'Disease', (146, 151))	('mice', 'Species', '10090', (160, 164))	('mice', 'Species', '10090', (33, 37))	('spontaneous', 'CPA', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
229470	27186713	In contrast, sarcoma bearing mice treated with anti-NGF (black bars) showed a significant decrease in spontaneous nocifensive behaviors that was significantly different from sarcoma + vehicle (Figure 2A).	('spontaneous nocifensive behaviors', 'CPA', (102, 135))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('mice', 'Species', '10090', (29, 33))	('sarcoma', 'Disease', 'MESH:D012509', (13, 20))	('anti-NGF', 'Var', (47, 55))	('sarcoma', 'Disease', (174, 181))	('sarcoma', 'Disease', (13, 20))	('decrease', 'NegReg', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))
229471	27186713	The inability of anti-P2X3 treatment to reduce sarcoma-induced skeletal pain-related behaviors was also apparent in the weight bearing of the affected limb (Figure 2B).	('sarcoma-induced skeletal pain', 'Disease', (47, 76))	('pain', 'Phenotype', 'HP:0012531', (72, 76))	('reduce', 'NegReg', (40, 46))	('skeletal pain', 'Phenotype', 'HP:0002653', (63, 76))	('sarcoma-induced skeletal pain', 'Disease', 'MESH:D010146', (47, 76))	('anti-P2X3', 'Var', (17, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
229473	27186713	By day 35 post-sarcoma cell injection, the tumor-bearing hind limb of anti-P2X3 treated animals only bore approximately 20% of the weight borne by the hindlimbs (Figure 2B, dark gray bars).	('anti-P2X3', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcoma', 'Disease', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('tumor', 'Disease', (43, 48))
229477	27186713	To explore why there was an effect of anti-P2X3 treatment on skin pain but not skeletal pain, we analyzed the distribution of neurons in femur innervating ganglia that expressed TrkA, P2X3, and both TrkA and P2X3.	('pain', 'Phenotype', 'HP:0012531', (66, 70))	('P2X3', 'Var', (208, 212))	('skin pain', 'Disease', 'MESH:D010146', (61, 70))	('skin pain', 'Disease', (61, 70))	('skeletal pain', 'Phenotype', 'HP:0002653', (79, 92))	('pain', 'Phenotype', 'HP:0012531', (88, 92))	('TrkA', 'Gene', (178, 182))	('skeletal pain', 'Disease', (79, 92))	('skeletal pain', 'Disease', 'MESH:D010146', (79, 92))	('P2X3', 'Var', (184, 188))
229480	27186713	Others have shown that intrathecal NGF administration increases P2X3 expression in a subset of neurons, however here we show that peripheral expression of NGF (by cancer or stromal cells) does not result in an up-regulation of P2X3 expression in neurons in the dorsal root ganglia that innervate the tumor bearing bone.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('up-regulation', 'PosReg', (210, 223))	('tumor', 'Disease', (300, 305))	('rat', 'Species', '10116', (26, 29))	('NGF', 'Var', (155, 158))	('P2X3', 'MPA', (64, 68))	('rat', 'Species', '10116', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('P2X3', 'Gene', (227, 231))	('expression', 'MPA', (232, 242))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
229492	27186713	Both therapies, anti-P2X3 and anti-NGF, are mouse monoclonal antibodies that do not readily cross the blood brain barrier (BBB) and thus most likely exert their effects outside the BBB.	('anti-P2X3', 'Var', (16, 25))	('anti-NGF', 'Var', (30, 38))	('mouse', 'Species', '10090', (44, 49))
229498	27186713	In light of the data presented above, a major question is what mechanisms might explain how anti-P2X3 could relieve bone cancer-induced hypersensitivity of the skin but not the underlying bone cancer pain itself?	('hypersensitivity of the', 'Disease', 'MESH:D004342', (136, 159))	('relieve', 'PosReg', (108, 115))	('bone cancer pain', 'Disease', 'MESH:D001859', (188, 204))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bone cancer', 'Disease', 'MESH:D001859', (188, 199))	('bone cancer', 'Disease', 'MESH:D001859', (116, 127))	('pain', 'Phenotype', 'HP:0012531', (200, 204))	('bone cancer pain', 'Phenotype', 'HP:0002653', (188, 204))	('anti-P2X3', 'Var', (92, 101))	('bone cancer pain', 'Disease', (188, 204))	('bone cancer', 'Disease', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('hypersensitivity of the', 'Disease', (136, 159))
229504	27186713	Together, the present results suggest that blockade of P2X3 only attenuates skin pain whereas sequestration of NGF attenuates both the skeletal pain itself and the skin pain induced by skeletal pain.	('pain', 'Phenotype', 'HP:0012531', (194, 198))	('attenuates', 'NegReg', (115, 125))	('skeletal pain', 'Disease', (185, 198))	('blockade', 'Var', (43, 51))	('pain', 'Phenotype', 'HP:0012531', (169, 173))	('pain', 'Phenotype', 'HP:0012531', (81, 85))	('pain', 'Phenotype', 'HP:0012531', (144, 148))	('skeletal pain', 'Disease', 'MESH:D010146', (185, 198))	('skeletal pain', 'Disease', (135, 148))	('rat', 'Species', '10116', (101, 104))	('P2X3', 'Enzyme', (55, 59))	('skeletal pain', 'Phenotype', 'HP:0002653', (185, 198))	('attenuates', 'NegReg', (65, 75))	('skin pain', 'Disease', (164, 173))	('skin pain', 'Disease', (76, 85))	('skeletal pain', 'Disease', 'MESH:D010146', (135, 148))	('sequestration', 'Var', (94, 107))	('skin pain', 'Disease', 'MESH:D010146', (164, 173))	('skeletal pain', 'Phenotype', 'HP:0002653', (135, 148))	('skin pain', 'Disease', 'MESH:D010146', (76, 85))
229511	27186713	In contrast, anti-NGF relieved skeletal pain-related behaviors in this model and has been shown to relieve skeletal pain in humans, dogs, rats and mice.	('skeletal pain', 'Disease', 'MESH:D010146', (107, 120))	('mice', 'Species', '10090', (147, 151))	('humans', 'Species', '9606', (124, 130))	('pain', 'Phenotype', 'HP:0012531', (40, 44))	('dogs', 'Species', '9615', (132, 136))	('relieved', 'NegReg', (22, 30))	('rats', 'Species', '10116', (138, 142))	('skeletal pain', 'Phenotype', 'HP:0002653', (31, 44))	('anti-NGF', 'Var', (13, 21))	('skeletal pain', 'Phenotype', 'HP:0002653', (107, 120))	('pain', 'Phenotype', 'HP:0012531', (116, 120))	('skeletal pain', 'Disease', (31, 44))	('skeletal pain', 'Disease', (107, 120))	('relieve', 'NegReg', (99, 106))	('skeletal pain', 'Disease', 'MESH:D010146', (31, 44))
229567	25388523	These chromosomal abnormalities are seen both in the glial as well as in the sarcomatous components, which are also genetically identical in terms of TP53 mutations, PTEN mutations, p16INK4a deletion, CDK4 amplification and MDM2 amplification.	('CDK4', 'Gene', '1019', (201, 205))	('CDK4', 'Gene', (201, 205))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('chromosomal abnormalities', 'Disease', (6, 31))	('PTEN', 'Gene', (166, 170))	('sarcomatous', 'Disease', 'MESH:D018316', (77, 88))	('MDM2', 'Gene', '4193', (224, 228))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (6, 31))	('amplification', 'PosReg', (206, 219))	('MDM2', 'Gene', (224, 228))	('PTEN', 'Gene', '5728', (166, 170))	('p16INK4a', 'Gene', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('mutations', 'Var', (171, 180))	('sarcomatous', 'Disease', (77, 88))	('TP53', 'Gene', '7157', (150, 154))	('p16INK4a', 'Gene', '1029', (182, 190))
229568	25388523	Similarly, in the reported ependymosarcomas, chromosome imbalances, such as gains on chromosome 1q, deletions of 22q and 6p, monosomy 18 and polysomies/polyploidy, were found in both the mesenchymal and glial tissues.	('monosomy 18', 'Var', (125, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('ependymosarcomas', 'Disease', (27, 43))	('polysomies/polyploidy', 'Var', (141, 162))	('gains', 'PosReg', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('22q', 'Gene', (113, 116))	('ependymosarcomas', 'Disease', 'None', (27, 43))	('deletions of', 'Var', (100, 112))	('imbalances', 'Phenotype', 'HP:0002172', (56, 66))
229688	26848307	A subset of patients (6-20 %) co-infected with human herpesvirus 8 (HHV8) may develop Kaposi's sarcoma ("unmasking" Kaposi's sarcoma-associated IRIS, KS-IRIS) or experience acute worsening of pre-existing tumor ("paradoxical" KS-IRIS) within a short interval (2-3 months) after ART initiation.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (86, 102))	('worsening', 'PosReg', (179, 188))	('patients', 'Species', '9606', (12, 20))	("Kaposi's sarcoma", 'Disease', (86, 102))	('HHV8', 'Species', '37296', (68, 72))	('HHV8', 'Gene', (68, 72))	('KS', 'Chemical', 'MESH:D011188', (226, 228))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (116, 132))	('develop', 'PosReg', (78, 85))	('human herpesvirus 8', 'Species', '37296', (47, 66))	('ART', 'Chemical', '-', (278, 281))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (116, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	("Kaposi's sarcoma", 'Disease', (116, 132))	('co-infected', 'Var', (30, 41))	('KS', 'Chemical', 'MESH:D011188', (150, 152))	('tumor', 'Disease', (205, 210))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (86, 102))
229736	21821699	EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo.	('cytostatic ES growth', 'CPA', (63, 83))	('blockade', 'Var', (5, 13))	('EGFR', 'Gene', (0, 4))	('inhibited', 'NegReg', (14, 23))	('EGFR', 'Gene', '1956', (0, 4))
229742	21821699	Recent insights into ES molecular underpinnings suggest that loss of INI1 expression, a component of a chromatin remodeling complex regulating transcription machinery, may be involved in disease inception.	('involved', 'Reg', (175, 183))	('disease', 'Disease', (187, 194))	('INI1', 'Gene', (69, 73))	('INI1', 'Gene', '6598', (69, 73))	('loss', 'Var', (61, 65))
229745	21821699	The rapidly increasing awareness of malignancy-related genetic and epigenetic deregulations has driven the inclusion of biologically-based treatment approaches as an integral and desired component of anti-cancer therapeutic strategies.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('malignancy', 'Disease', 'MESH:D009369', (36, 46))	('epigenetic deregulations', 'Var', (67, 91))	('malignancy', 'Disease', (36, 46))
229748	21821699	Upon ligand binding, EGFR phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions such as proliferation, survival, angiogenesis, etc.. Functional EGFR dysregulation is frequently observed in human cancers, with overexpression and activation by mutations or autocrine/paracrine growth factor loops identified in approximately 50% of epithelial malignancies, suggesting a pivotal role in tumorigenesis and disease progression.	('epithelial malignancies', 'Disease', 'MESH:D002277', (389, 412))	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (203, 207))	('tumor', 'Disease', (443, 448))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('human', 'Species', '9606', (248, 253))	('EGFR', 'Gene', (203, 207))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (389, 412))	('epithelial malignancies', 'Disease', (389, 412))	('overexpression', 'PosReg', (268, 282))	('tumor', 'Disease', 'MESH:D009369', (443, 448))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('cancers', 'Disease', (254, 261))	('cancers', 'Disease', 'MESH:D009369', (254, 261))	('tumor', 'Phenotype', 'HP:0002664', (443, 448))	('dysregulation', 'Var', (208, 221))
229795	21821699	Furthermore, EGFR blockade resulted in a dose-dependent inhibition of pERK in both cell lines tested (Fig 3A).	('inhibition', 'NegReg', (56, 66))	('pERK', 'Gene', (70, 74))	('blockade', 'Var', (18, 26))	('pERK', 'Gene', '9451', (70, 74))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
229796	21821699	Interestingly, while a marked effect on the phosphorylation of AKT and its downstream mTOR-regulated effectors P70S6 kinase and 4EBP1 was observed in Epi544 cells, only a limited effect on this signaling pathway was seen in VAESBJ cells (Fig 3A).	('phosphorylation', 'MPA', (44, 59))	('AKT', 'Gene', (63, 66))	('mTOR', 'Gene', '2475', (86, 90))	('mTOR', 'Gene', (86, 90))	('4EBP1', 'Gene', '1978', (128, 133))	('4EBP1', 'Gene', (128, 133))	('P70S6', 'Var', (111, 116))	('AKT', 'Gene', '207', (63, 66))
229797	21821699	Functionally, a dose dependent decrease in ES cell growth in response to erlotinib (96h) was observed in both cell lines, although more pronouncedly in Epi544 (Fig 3B).	('Epi544', 'Var', (152, 158))	('ES cell growth', 'CPA', (43, 57))	('decrease', 'NegReg', (31, 39))	('erlotinib', 'Chemical', 'MESH:D000069347', (73, 82))
229798	21821699	Similarly, EGFR blockade inhibited the colony formation capacity of ES cells (Fig 3B).	('blockade', 'Var', (16, 24))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('colony formation capacity of ES cells', 'CPA', (39, 76))	('inhibited', 'NegReg', (25, 34))
229803	21821699	Concordantly, increased levels of PARP cleavage were noted in both cell lines in response to EGFR blockade (96h) further confirming the presence of treatment-induced apoptosis.	('increased', 'PosReg', (14, 23))	('blockade', 'Var', (98, 106))	('EGFR', 'Gene', '1956', (93, 97))	('PARP', 'Gene', '1302', (34, 38))	('PARP', 'Gene', (34, 38))	('EGFR', 'Gene', (93, 97))
229806	21821699	Taken together, these results suggest that EGFR blockade results in decreased ES cell proliferation, G1 cell cycle arrest, enhanced apoptosis, and abrogated migration and invasion capacities.	('apoptosis', 'CPA', (132, 141))	('abrogated', 'NegReg', (147, 156))	('enhanced', 'PosReg', (123, 131))	('decreased', 'NegReg', (68, 77))	('ES cell proliferation', 'CPA', (78, 99))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('blockade', 'Var', (48, 56))	('EGFR', 'Gene', '1956', (43, 47))	('decreased ES cell', 'Phenotype', 'HP:0025022', (68, 85))	('EGFR', 'Gene', (43, 47))	('G1 cell cycle arrest', 'CPA', (101, 121))
229816	21821699	Furthermore, as was found in vitro, erlotinib induced a decrease in cyclin D1, MMP2, and MMP9 expression in vivo (Fig 4B).	('MMP9', 'Gene', '4318', (89, 93))	('MMP9', 'Gene', (89, 93))	('MMP2', 'Gene', (79, 83))	('erlotinib', 'Chemical', 'MESH:D000069347', (36, 45))	('cyclin D1', 'Gene', '595', (68, 77))	('expression', 'MPA', (94, 104))	('MMP2', 'Gene', '4313', (79, 83))	('decrease', 'NegReg', (56, 64))	('cyclin D1', 'Gene', (68, 77))	('erlotinib', 'Var', (36, 45))
229817	21821699	Taken together, the impact of EGFR blockade on ES xenografts mirrors the effects noted in cell culture.	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (30, 34))	('blockade', 'Var', (35, 43))
229824	21821699	Phosphorylation of the AKT/mTOR pathway in Epi544 cells is decreased under serum free culture conditions, suggesting that its activation might possibly occur via upstream signaling.	('Epi544', 'Var', (43, 49))	('decreased', 'NegReg', (59, 68))	('AKT', 'Gene', '207', (23, 26))	('activation', 'PosReg', (126, 136))	('Phosphorylation', 'MPA', (0, 15))	('AKT', 'Gene', (23, 26))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))
229830	21821699	These findings suggest that PTEN deregulation is a common molecular aberration in human ES.	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (28, 32))	('human', 'Species', '9606', (82, 87))	('deregulation', 'Var', (33, 45))
229844	21821699	To determine the effect of the therapeutic combination on cell death PI/Annexin V staining FACS analyses were conducted after 96h of treatment: no apoptosis was found in response to rapamycin alone whereas similar to the findings described above, erlotinib did result in ES cell apoptosis.	('erlotinib', 'Var', (247, 256))	('Annexin V', 'Gene', '308', (72, 81))	('Annexin V', 'Gene', (72, 81))	('erlotinib', 'Chemical', 'MESH:D000069347', (247, 256))	('rapamycin', 'Chemical', 'MESH:D020123', (182, 191))
229851	21821699	These data suggest that EGFR blockade in combination with mTOR inhibition results in significant anti-ES effects in vitro and in vivo, a finding of potential clinical utility.	('blockade', 'Var', (29, 37))	('EGFR', 'Gene', '1956', (24, 28))	('mTOR', 'Gene', (58, 62))	('EGFR', 'Gene', (24, 28))	('anti-ES effects', 'MPA', (97, 112))	('mTOR', 'Gene', '2475', (58, 62))
229854	21821699	Most importantly, EGFR blockade was found to inhibit the growth of ES cells in vitro and in vivo, inducing arrested cell cycle progression, enhanced apoptosis, and abrogated tumor cell migration and invasion.	('tumor', 'Disease', (174, 179))	('apoptosis', 'CPA', (149, 158))	('blockade', 'Var', (23, 31))	('enhanced', 'PosReg', (140, 148))	('EGFR', 'Gene', '1956', (18, 22))	('arrested cell cycle progression', 'CPA', (107, 138))	('EGFR', 'Gene', (18, 22))	('growth', 'CPA', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('inhibit', 'NegReg', (45, 52))	('inducing', 'NegReg', (98, 106))	('abrogated', 'NegReg', (164, 173))
229858	21821699	Moreover, it is pertinent that a large body of evidence suggests that despite promising responses to monotherapy EGFR manipulation in multiple preclinical epithelial cancer models in which the receptor is over-expressed, the clinical therapeutic benefit is minimal, even with high levels of EGFR expression within the tumor, and is mostly observed in tumors harboring a genetic deregulation of the receptor, i.e., amplifications and activating mutations.	('EGFR', 'Gene', (291, 295))	('tumors', 'Disease', 'MESH:D009369', (351, 357))	('EGFR', 'Gene', (113, 117))	('epithelial cancer', 'Phenotype', 'HP:0031492', (155, 172))	('epithelial cancer', 'Disease', (155, 172))	('tumor', 'Disease', (351, 356))	('epithelial cancer', 'Disease', 'MESH:D000077216', (155, 172))	('tumor', 'Disease', (318, 323))	('EGFR', 'Gene', '1956', (291, 295))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('activating', 'PosReg', (433, 443))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('EGFR', 'Gene', '1956', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('tumors', 'Disease', (351, 357))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('amplifications', 'Var', (414, 428))	('over-expressed', 'PosReg', (205, 219))	('minimal', 'NegReg', (257, 264))
229859	21821699	Furthermore, even tumors harboring such genetic modifications are bound to develop resistance to EGFR blockade.	('resistance', 'MPA', (83, 93))	('EGFR', 'Gene', '1956', (97, 101))	('genetic modifications', 'Var', (40, 61))	('EGFR', 'Gene', (97, 101))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('develop', 'PosReg', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
229875	21821699	Interestingly, response to EGFR inhibitors has been shown to inversely correlate with PI3K/mTOR signaling over-activation.	('EGFR', 'Gene', '1956', (27, 31))	('inhibitors', 'Var', (32, 42))	('EGFR', 'Gene', (27, 31))	('over-activation', 'PosReg', (106, 121))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))
229877	21821699	Similarly, loss of PTEN has been found to predict resistance to EGFR blockade in colorectal cancer, lung cancer, and glioblastoma; our studies expand these observations to now include ES:a tumor lacking effective systemic treatment.	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('glioblastoma', 'Disease', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))	('colorectal cancer', 'Disease', (81, 98))	('PTEN', 'Gene', (19, 23))	('lung cancer', 'Disease', (100, 111))	('EGFR', 'Gene', (64, 68))	('resistance', 'MPA', (50, 60))	('PTEN', 'Gene', '5728', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('tumor', 'Disease', (189, 194))	('loss', 'Var', (11, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('EGFR', 'Gene', '1956', (64, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (117, 129))
229886	21821699	Studies reported here suggest a role for EGFR activation in promoting the ES aggressive/metastatic phenotype and demonstrate EGFR blockade to induce anti-ES effects including abrogated cell growth, survival, migration and invasion.	('EGFR', 'Gene', (41, 45))	('promoting', 'PosReg', (60, 69))	('invasion', 'CPA', (222, 230))	('blockade', 'Var', (130, 138))	('EGFR', 'Gene', '1956', (125, 129))	('activation', 'PosReg', (46, 56))	('EGFR', 'Gene', (125, 129))	('EGFR', 'Gene', '1956', (41, 45))	('abrogated', 'NegReg', (175, 184))	('ES aggressive/metastatic phenotype', 'CPA', (74, 108))	('cell growth', 'CPA', (185, 196))
229888	21821699	Most importantly, dual targeting of EGFR and mTOR significantly and synergistically abrogates ES growth in vitro and in vivo.	('ES growth', 'CPA', (94, 103))	('dual targeting', 'Var', (18, 32))	('abrogates', 'NegReg', (84, 93))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (45, 49))	('mTOR', 'Gene', (45, 49))
229936	33947445	The pathogenesis of ESS includes gene rearrangement, loss of tumor suppressor genes, microsatellite instability, and loss of heterozygosity.	('ESS', 'Disease', (20, 23))	('loss of heterozygosity', 'Var', (117, 139))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('loss', 'NegReg', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('microsatellite instability', 'Var', (85, 111))	('gene rearrangement', 'Var', (33, 51))	('tumor', 'Disease', (61, 66))
229962	32629987	A high frequency of mutations has been found in SWI/SNF family subunits by exome sequencing in human cancer, and multiple studies support its role in tumor suppression.	('human', 'Species', '9606', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SWI/SNF family', 'Gene', (48, 62))	('tumor', 'Disease', (150, 155))	('mutations', 'Var', (20, 29))
229963	32629987	Recent structural studies of yeast SWI/SNF and its human homolog, BAF (BRG1/BRM associated factor), have provided a model for their complex assembly and their interaction with nucleosomal substrates, revealing the molecular function of individual subunits as well as the potential impact of cancer-associated mutations on the remodeling function.	('BAF', 'Gene', '8815', (66, 69))	('SWI/SNF', 'Gene', (35, 42))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('BRG1/BRM associated factor', 'Gene', '8815;6597', (71, 97))	('BAF', 'Gene', (66, 69))	('human', 'Species', '9606', (51, 56))	('BRG1/BRM associated factor', 'Gene', (71, 97))	('mutations', 'Var', (309, 318))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('yeast', 'Species', '4932', (29, 34))
229967	32629987	The essential role of the SWI/SNF family of remodelers is evident in their conservation from yeast (SWI/SNF and Remodel the Structure of Chromatin or RSC) to humans (BAF and PBAF) and the critical effect of their mutations on organism survival and development.	('Structure', 'MPA', (124, 133))	('BAF', 'Gene', (175, 178))	('BAF', 'Gene', '8815', (166, 169))	('humans', 'Species', '9606', (158, 164))	('BAF', 'Gene', (166, 169))	('yeast', 'Species', '4932', (93, 98))	('mutations', 'Var', (213, 222))	('BAF', 'Gene', '8815', (175, 178))
229968	32629987	Over the last few decades, a series of studies has identified mutations in multiple SWI/SNF subunits within a variety of tumor types, and whole-genome sequencing of cancerous primary tumors revealed that the human BAF complex exhibited a high mutation frequency (~20%).	('BAF', 'Gene', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancerous primary tumors', 'Disease', (165, 189))	('cancerous primary tumors', 'Disease', 'MESH:D009369', (165, 189))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (183, 188))	('SWI/SNF', 'Gene', (84, 91))	('BAF', 'Gene', '8815', (214, 217))	('human', 'Species', '9606', (208, 213))	('mutations', 'Var', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
229969	32629987	For this reason, SWI/SNF subunit mutations have become popular targets for potential biomarkers and cancer therapeutics.	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (33, 42))	('cancer', 'Disease', (100, 106))	('SWI/SNF subunit', 'Gene', (17, 32))
229970	32629987	Mutations in the BAF complex were broadly distributed among tumor types compared to other known tumor suppressors with the exception of TP53.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('BAF', 'Gene', (17, 20))	('TP53', 'Gene', '7157', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (96, 101))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (60, 65))	('TP53', 'Gene', (136, 140))	('BAF', 'Gene', '8815', (17, 20))
229971	32629987	This suggests that BAF complex activity can contribute to general tumor suppression and its mutations facilitate disease progression.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('facilitate', 'PosReg', (102, 112))	('tumor', 'Disease', (66, 71))	('mutations', 'Var', (92, 101))	('disease progression', 'CPA', (113, 132))	('BAF', 'Gene', '8815', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('BAF', 'Gene', (19, 22))
229972	32629987	It is also likely that these mutations can alter the function of SWI/SNF complexes, allowing for dysregulation of chromatin architecture in cancers.	('chromatin architecture', 'MPA', (114, 136))	('alter', 'Reg', (43, 48))	('allowing', 'Reg', (84, 92))	('mutations', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('dysregulation', 'MPA', (97, 110))	('function', 'MPA', (53, 61))
229974	32629987	Recent high-resolution structures of both yeast SWI/SNF (ySWI/SNF) and human BAF (hBAF) complexes provide further mechanistic understanding of the remodeler function when bound to nucleosomes, allowing us to place mutations from these key subunits in context of a 3D model of the full complex.	('BAF', 'Gene', '8815', (83, 86))	('hBAF', 'Gene', (82, 86))	('BAF', 'Gene', (83, 86))	('yeast', 'Species', '4932', (42, 47))	('mutations', 'Var', (214, 223))	('hBAF', 'Gene', '8815', (82, 86))	('BAF', 'Gene', '8815', (77, 80))	('BAF', 'Gene', (77, 80))	('human', 'Species', '9606', (71, 76))
229975	32629987	Here we review the newly determined structures of BAF family complexes and the role of commonly mutated subunits and discuss the functional effects that these mutations have on SWI/SNF chromatin remodelers.	('mutations', 'Var', (159, 168))	('BAF', 'Gene', (50, 53))	('BAF', 'Gene', '8815', (50, 53))
229990	32629987	It has been observed that cancer cell lines are deficient in SMARCA4 and that ectopic expression of SMARCA4 can rescue cell-cycle inhibition.	('SMARCA4', 'Gene', (61, 68))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cell-cycle inhibition', 'CPA', (119, 140))	('ectopic expression', 'Var', (78, 96))	('SMARCA4', 'Gene', (100, 107))	('deficient', 'NegReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('rescue', 'PosReg', (112, 118))
229991	32629987	Null mutations of SMARCA4 lead to death during embryogenesis in mouse models; however, mice with heterozygous mutations of SMARCA4 were instead predisposed to tumor development.	('SMARCA4', 'Gene', (123, 130))	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mice', 'Species', '10090', (87, 91))	('death', 'Disease', 'MESH:D003643', (34, 39))	('death', 'Disease', (34, 39))	('tumor', 'Disease', (159, 164))	('SMARCA4', 'Gene', (18, 25))	('predisposed', 'Reg', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mouse', 'Species', '10090', (64, 69))
229992	32629987	Genetic studies have revealed high frequencies of SMARCA4 mutations in ovarian, thoracic, lung, and prostate cancer.	('mutations', 'Var', (58, 67))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('thoracic', 'Disease', (80, 88))	('lung', 'Disease', (90, 94))	('SMARCA4', 'Gene', (50, 57))	('ovarian', 'Disease', (71, 78))	('prostate cancer', 'Disease', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
229993	32629987	Although cancer-associated mutations are present throughout SMARCA4, mutations to the two ATPase lobes are commonly found in cancer.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (9, 15))	('ATPase', 'Protein', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('found', 'Reg', (116, 121))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('cancer', 'Disease', (125, 131))	('SMARCA4', 'Gene', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
229994	32629987	Immunoprecipitation studies showed that cancer-associated mutations to the SMARCA4 ATPase domain do not prevent its incorporation into the BAF complex.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('BAF', 'Gene', '8815', (139, 142))	('SMARCA4', 'Gene', (75, 82))	('ATP', 'Chemical', 'MESH:D000255', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('incorporation', 'MPA', (116, 129))	('BAF', 'Gene', (139, 142))
229995	32629987	However, the engagement and release of chromatin as well as PRC1 eviction are disrupted by cancer-associated mutations to the ATP recognition cleft or DNA-binding groove of the ATPase domain.	('engagement', 'MPA', (13, 23))	('disrupted', 'NegReg', (78, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('ATP', 'Chemical', 'MESH:D000255', (126, 129))	('ATP', 'Chemical', 'MESH:D000255', (177, 180))	('mutations', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('release', 'MPA', (28, 35))	('PRC1', 'Gene', (60, 64))
230002	32629987	However, deletion of the HSA was shown to disrupt the interaction between SMARCA4 and ARID1A, indicating that other components of the Arp module are insufficient to bridge the interaction between the Body and ATPase modules.	('SMARCA4', 'Gene', (74, 81))	('HSA', 'Gene', (25, 28))	('ATP', 'Chemical', 'MESH:D000255', (209, 212))	('disrupt', 'NegReg', (42, 49))	('deletion', 'Var', (9, 17))	('Arp', 'Gene', '167', (134, 137))	('ARID1A', 'Gene', (86, 92))	('interaction', 'Interaction', (54, 65))	('Arp', 'Gene', (134, 137))
230006	32629987	In silico analysis of cancer-associated mutations of SMARCA4 suggest that they destabilize the HSA alpha-helix.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('mutations', 'Var', (40, 49))	('SMARCA4', 'Gene', (53, 60))	('destabilize', 'NegReg', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('HSA alpha-helix', 'Protein', (95, 110))
230007	32629987	This suggests another mechanism of BAF complex inactivation in cancer wherein truncating or point mutations to the HSA domain can uncouple the Body module from the ATPase module.	('BAF', 'Gene', '8815', (35, 38))	('point mutations', 'Var', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ATP', 'Chemical', 'MESH:D000255', (164, 167))	('BAF', 'Gene', (35, 38))	('truncating', 'Var', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('Body module', 'MPA', (143, 154))	('uncouple', 'MPA', (130, 138))	('cancer', 'Disease', (63, 69))
230009	32629987	The Body module of ySWI/SNF consists of Swi1, Snf5/Swi10, Swi3, Snf12/Swp73, Snf6, and Swp82.	('Snf12/Swp73', 'Var', (64, 75))	('Swi1', 'Gene', (51, 55))	('Swp82', 'Var', (87, 92))	('Swi3', 'Gene', '6599', (58, 62))	('Swi10', 'Gene', '852592', (51, 56))	('Swi1', 'Gene', '856091', (51, 55))	('Swi3', 'Gene', (58, 62))	('Swi1', 'Gene', (40, 44))	('Snf6', 'Var', (77, 81))	('Swi1', 'Gene', '856091', (40, 44))	('Swi10', 'Gene', (51, 56))
230017	32629987	Mutant BAF complexes were evaluated by biochemical fractionation of purified endogenous complexes, and it was found that complex stability was compromised by the deletion of ARID1A.	('deletion', 'Var', (162, 170))	('BAF', 'Gene', '8815', (7, 10))	('compromised', 'NegReg', (143, 154))	('BAF', 'Gene', (7, 10))	('ARID1A', 'Gene', (174, 180))
230018	32629987	Additionally, the Y2254* mutant of ARID1A disrupted the interaction between ARID1A and BAF complex subunits.	('BAF', 'Gene', '8815', (87, 90))	('Y2254*', 'SUBSTITUTION', 'None', (18, 24))	('interaction', 'Interaction', (56, 67))	('BAF', 'Gene', (87, 90))	('ARID1A', 'Gene', (76, 82))	('ARID1A', 'Gene', (35, 41))	('disrupted', 'NegReg', (42, 51))	('Y2254*', 'Var', (18, 24))
230019	32629987	This truncation mutant removed a two-helix bundle that interacts with SMARCD1, another key scaffolding protein, which may explain the drastic effect on complex stability.	('interacts', 'Interaction', (55, 64))	('two-helix bundle', 'MPA', (33, 49))	('SMARCD1', 'Gene', '6602', (70, 77))	('removed', 'NegReg', (23, 30))	('SMARCD1', 'Gene', (70, 77))	('mutant', 'Var', (16, 22))
230020	32629987	Mutations to the C-terminus of ARID1A (including Y2254), which acts as the core of the Body module, are common in cancer (Figure 1) and would be expected to have equally deleterious effects on complex stability.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('common', 'Reg', (104, 110))	('Y2254', 'Var', (49, 54))	('ARID1A', 'Gene', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('complex stability', 'MPA', (193, 210))	('effects', 'Reg', (182, 189))	('cancer', 'Disease', (114, 120))
230021	32629987	The role of ARID1A as a scaffold for BAF complex assembly is especially pertinent as there is a high occurrence of inactivating frameshift mutations in ARID1A in cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('BAF', 'Gene', '8815', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('inactivating frameshift mutations', 'Var', (115, 148))	('ARID1A', 'Gene', (152, 158))	('BAF', 'Gene', (37, 40))
230022	32629987	Point mutations to G2087, one of the most common cancer-associated mutations in hBAF, also increase ubiquitination and decrease protein levels when expressed in human cell lines.	('human', 'Species', '9606', (161, 166))	('decrease', 'NegReg', (119, 127))	('protein levels', 'MPA', (128, 142))	('hBAF', 'Gene', '8815', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ubiquitination', 'MPA', (100, 114))	('increase', 'PosReg', (91, 99))	('G2087', 'Var', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Point mutations', 'Var', (0, 15))	('cancer', 'Disease', (49, 55))	('hBAF', 'Gene', (80, 84))
230024	32629987	This is supported by additional studies of cancer cell lines that showed that partial depletion of ARID1A enhanced cell proliferation and restoring expression of ARID1A in both ARID1A-deficient breast cancer cell lines and mouse ovarian cancer models was sufficient to inhibit cell proliferation.	('ARID1A', 'Gene', (99, 105))	('enhanced', 'PosReg', (106, 114))	('cancer', 'Disease', (201, 207))	('deficient breast', 'Phenotype', 'HP:0003187', (184, 200))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('ARID1A', 'Gene', (162, 168))	('ovarian cancer', 'Phenotype', 'HP:0100615', (229, 243))	('inhibit', 'NegReg', (269, 276))	('partial depletion', 'Var', (78, 95))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('mouse ovarian cancer', 'Disease', 'MESH:D004482', (223, 243))	('cancer', 'Disease', (237, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cell proliferation', 'CPA', (277, 295))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('ARID1A-deficient breast cancer', 'Disease', (177, 207))	('ARID1A-deficient breast cancer', 'Disease', 'MESH:D001943', (177, 207))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cell proliferation', 'CPA', (115, 133))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('expression', 'MPA', (148, 158))	('mouse ovarian cancer', 'Disease', (223, 243))
230025	32629987	The ARID (AT-rich interaction domain) of ARID1A is known to interact with DNA, and mutations to this domain affect nucleosome-binding affinity.	('mutations', 'Var', (83, 92))	('nucleosome-binding affinity', 'MPA', (115, 142))	('ARID', 'Disease', (4, 8))	('ARID', 'Disease', (41, 45))	('affect', 'Reg', (108, 114))	('interact', 'Interaction', (60, 68))	('ARID', 'Disease', 'None', (41, 45))	('ARID', 'Disease', 'None', (4, 8))
230027	32629987	This highlights the possibility of cancer-associated mutations affecting not just SWI/SNF activity but also recruitment of chromatin-modifying complexes.	('recruitment', 'MPA', (108, 119))	('activity', 'MPA', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('SWI/SNF', 'Protein', (82, 89))	('affecting', 'Reg', (63, 72))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
230031	32629987	SMARCB1 demonstrated a low frequency of mutations to coding regions (0.6% of tumors screened) compared to other subunits of the BAF complex.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('BAF', 'Gene', '8815', (128, 131))	('BAF', 'Gene', (128, 131))	('mutations', 'Var', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('SMARCB1', 'Gene', '6598', (0, 7))	('SMARCB1', 'Gene', (0, 7))
230032	32629987	However, loss of SMARCB1 is reported in various cancers including malignant rhabdoid tumors, epithelioid sarcoma, medullary carcinoma, synovial sarcoma, familial schwannomatosis, extraskeletal myxoid chondrosarcoma, and small-cell hepatoblastoma.	('sarcoma', 'Disease', (144, 151))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (193, 214))	('familial schwannomatosis', 'Disease', (153, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (200, 214))	('familial schwannomatosis', 'Disease', 'MESH:C536641', (153, 177))	('carcinoma', 'Disease', 'MESH:D009369', (124, 133))	('myxoid chondrosarcoma', 'Disease', (193, 214))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (231, 245))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('malignant rhabdoid tumors', 'Disease', (66, 91))	('SMARCB1', 'Gene', (17, 24))	('SMARCB1', 'Gene', '6598', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Disease', (48, 55))	('synovial sarcoma', 'Disease', (135, 151))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('synovial sarcoma', 'Disease', 'MESH:D013584', (135, 151))	('sarcoma', 'Disease', (105, 112))	('hepatoblastoma', 'Disease', (231, 245))	('sarcoma', 'Disease', 'MESH:D012509', (207, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (135, 151))	('hepatoblastoma', 'Disease', 'MESH:D018197', (231, 245))	('carcinoma', 'Disease', (124, 133))	('loss', 'Var', (9, 13))	('sarcoma', 'Disease', (207, 214))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (66, 91))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
230033	32629987	In addition, loss of SMARCB1 is the defining genetic change in both synovial sarcoma and malignant rhabdoid tumors (MRTs).	('malignant rhabdoid tumors', 'Disease', (89, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('synovial sarcoma', 'Disease', (68, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('SMARCB1', 'Gene', '6598', (21, 28))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (68, 84))	('synovial sarcoma', 'Disease', 'MESH:D013584', (68, 84))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (89, 114))	('SMARCB1', 'Gene', (21, 28))	('loss', 'Var', (13, 17))
230037	32629987	It is hypothesized that novel interactions with the fusion protein are responsible for relocalization of the mutant BAF complex; however, the mechanism by which this occurs is currently undefined.	('interactions', 'Interaction', (30, 42))	('BAF', 'Gene', (116, 119))	('relocalization', 'MPA', (87, 101))	('mutant', 'Var', (109, 115))	('BAF', 'Gene', '8815', (116, 119))
230038	32629987	SMARCB1 depletion in MRTs leads to a similar loss of PRC2 antagonism.	('depletion', 'Var', (8, 17))	('SMARCB1', 'Gene', '6598', (0, 7))	('PRC2 antagonism', 'MPA', (53, 68))	('loss', 'NegReg', (45, 49))	('SMARCB1', 'Gene', (0, 7))
230039	32629987	Mutations in MRTs consist of inactivating deletions or truncations of SMARCB1, and loss of SMARCB1 leads to a global decrease in its occupancy at enhancer and promoter regions as opposed to the relocalization seen in synovial sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('synovial sarcoma', 'Disease', 'MESH:D013584', (217, 233))	('SMARCB1', 'Gene', '6598', (91, 98))	('MRTs', 'Gene', (13, 17))	('loss', 'Var', (83, 87))	('SMARCB1', 'Gene', (91, 98))	('synovial sarcoma', 'Disease', (217, 233))	('Mutations', 'Var', (0, 9))	('SMARCB1', 'Gene', '6598', (70, 77))	('decrease', 'NegReg', (117, 125))	('SMARCB1', 'Gene', (70, 77))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (217, 233))	('truncations', 'Var', (55, 66))
230042	32629987	While loss of SMARCB1 does not affect the assembly of other modules, it does negatively affect chromatin remodeling.	('SMARCB1', 'Gene', (14, 21))	('loss', 'Var', (6, 10))	('affect', 'Reg', (88, 94))	('negatively', 'NegReg', (77, 87))	('chromatin remodeling', 'MPA', (95, 115))	('SMARCB1', 'Gene', '6598', (14, 21))
230044	32629987	Additionally, mutations to the C-terminal helix of SMARCB1 disrupt nucleosome binding and chromatin remodeling by the BAF complex.	('nucleosome binding', 'MPA', (67, 85))	('disrupt', 'NegReg', (59, 66))	('BAF', 'Gene', '8815', (118, 121))	('SMARCB1', 'Gene', '6598', (51, 58))	('BAF', 'Gene', (118, 121))	('mutations', 'Var', (14, 23))	('SMARCB1', 'Gene', (51, 58))	('chromatin remodeling', 'CPA', (90, 110))
230045	32629987	These studies support the critical function of SMARCB1 in facilitating DNA translocation around the histone octamer and the potential disruption of chromatin remodeling by cancer-associated mutations.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutations', 'Var', (190, 199))	('DNA translocation around the histone octamer', 'MPA', (71, 115))	('SMARCB1', 'Gene', '6598', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('SMARCB1', 'Gene', (47, 54))	('cancer', 'Disease', (172, 178))
230046	32629987	It has been well established that mutations to BAF complex subunits are associated with the progression of multiple cancers.	('BAF', 'Gene', (47, 50))	('associated with', 'Reg', (72, 87))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('BAF', 'Gene', '8815', (47, 50))	('mutations', 'Var', (34, 43))
230047	32629987	Recent additions of high-resolution models of ySWI/SNF and hBAF complexes have provided insight into the molecular roles of individual subunits and can be used to infer the effect that cancer-associated mutations would have on the integrity and activity of the BAF complex.	('BAF', 'Gene', '8815', (261, 264))	('integrity', 'CPA', (231, 240))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('BAF', 'Gene', (261, 264))	('activity', 'MPA', (245, 253))	('BAF', 'Gene', '8815', (60, 63))	('hBAF', 'Gene', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('mutations', 'Var', (203, 212))	('cancer', 'Disease', (185, 191))	('hBAF', 'Gene', '8815', (59, 63))	('BAF', 'Gene', (60, 63))
230081	31002835	The Ewing's sarcoma family of tumors (ESFT) present a small round cell morphology, cell surface expression of CD99, and almost always feature a pathogenic chromosomal translocation of the EWSR1 gene at the N terminus with an ETS gene at the C terminus.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('CD99', 'Gene', '4267', (110, 114))	("Ewing's sarcoma", 'Disease', (4, 19))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (4, 19))	('EWSR1', 'Gene', '2130', (188, 193))	('ESFT', 'Chemical', '-', (38, 42))	('CD99', 'Gene', (110, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('chromosomal translocation', 'Var', (155, 180))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('pathogenic', 'Reg', (144, 154))	('EWSR1', 'Gene', (188, 193))	('ES', 'Phenotype', 'HP:0012254', (38, 40))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (4, 19))
230082	31002835	The EWS-FLI1 translocation is the most common, and can be observed in ~85% of all ESFT.	('ESFT', 'Disease', (82, 86))	('ESFT', 'Chemical', '-', (82, 86))	('EWS-FLI1', 'Var', (4, 12))	('ES', 'Phenotype', 'HP:0012254', (82, 84))
230086	31002835	Transgenic mouse models of ESFT have failed largely due to EWS-FLI1 translocation related embryonic lethality, developmental defects, or failure to cause expression within specific target sites.	('translocation', 'Var', (68, 81))	('mouse', 'Species', '10090', (11, 16))	('ESFT', 'Disease', (27, 31))	('developmental defects, or failure', 'Disease', 'MESH:D006333', (111, 144))	('ES', 'Phenotype', 'HP:0012254', (27, 29))	('ESFT', 'Chemical', '-', (27, 31))	('embryonic lethality', 'Disease', 'MESH:D020964', (90, 109))	('embryonic lethality', 'Disease', (90, 109))	('EWS-FLI1', 'Gene', (59, 67))
230126	31002835	In collagen hydrogels blended with polyacrylamide (PA) substrates with tunable elasticity, HSPC morphology was significantly impacted by biophysical cues, and the cell viability was maximized at the 0.044 kPa substrate stiffness and 100 mug/mL collagen hydrogel concentration.	('HSPC', 'Gene', '5688', (91, 95))	('polyacrylamide', 'Chemical', 'MESH:C016679', (35, 49))	('maximized', 'PosReg', (182, 191))	('rat', 'Species', '10116', (60, 63))	('cell viability', 'CPA', (163, 177))	('impacted', 'Reg', (125, 133))	('rat', 'Species', '10116', (214, 217))	('PA', 'Chemical', 'MESH:C016679', (51, 53))	('0.044', 'Var', (199, 204))	('rat', 'Species', '10116', (269, 272))	('HSPC', 'Gene', (91, 95))
230170	31002835	Biorecognition signals have been included in the form of ECM proteins, collagen 1, or fibronectin, with collagen 1 yielding the most sustainable (8 weeks) leukemic cell culture without the addition of exogenous factors.	('fibronectin', 'Gene', '2335', (86, 97))	('collagen 1', 'Var', (104, 114))	('leukemic cell culture', 'CPA', (155, 176))	('fibronectin', 'Gene', (86, 97))
230174	31002835	Deeper characterization of the cellular profiles suggested that the enrichment of LSCs rather than other progenitors was causing increases in these markers of self-renewal ability.	('increases', 'PosReg', (129, 138))	('LSCs', 'Var', (82, 86))	('rat', 'Species', '10116', (87, 90))
230205	31002835	Abrogation of this pathway using the Bcl-2-specific inhibitor ABT 737 eliminated chemo-resistant advantages.	('Abrogation', 'Var', (0, 10))	('chemo-resistant advantages', 'CPA', (81, 107))	('Bcl-2', 'Gene', (37, 42))	('Bcl-2', 'Gene', '596', (37, 42))	('eliminated', 'NegReg', (70, 80))	('ABT', 'Chemical', 'MESH:C002502', (62, 65))
230226	31002835	The vascular cell adhesion molecule 1 (VCAM1) transfectants were used to activate the VLA-4 - VCAM1 pathway to bortezomib resistance, a novel and promising therapeutic developed against MM.	('VCAM1', 'Gene', '7412', (39, 44))	('vascular cell adhesion molecule 1', 'Gene', '7412', (4, 37))	('vascular cell adhesion molecule 1', 'Gene', (4, 37))	('VCAM1', 'Gene', (94, 99))	('activate', 'PosReg', (73, 81))	('VCAM1', 'Gene', (39, 44))	('bortezomib', 'Chemical', 'MESH:D000069286', (111, 121))	('transfectants', 'Var', (46, 59))	('VCAM1', 'Gene', '7412', (94, 99))
230313	30737998	The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number.	('single nucleotide variants', 'Var', (42, 68))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('insertions/deletions', 'Var', (73, 93))	('microsatellite instability status', 'MPA', (148, 181))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('464', 'Gene', (98, 101))	('tumor', 'Disease', (122, 127))
230317	30737998	Most of these cancer gene panels are based on sequencing the gDNA of target genes isolated either by polymerase chain reaction (PCR)5, 6 or probe hybridization,7, 8, 9, 10 enabling the detection of single nucleotide variants (SNV), small insertions/deletions (indels) and copy number variation (CNV).	('cancer', 'Disease', (14, 20))	('small insertions/deletions', 'Var', (232, 258))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('single nucleotide variants', 'Var', (198, 224))	('copy number variation', 'Var', (272, 293))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
230318	30737998	Examples such as BCR-ABL1 fusion in chronic myeloid leukemia11 or EML4-ALK fusion in non-small-cell lung cancer (NSCLC)12 have led to the development of novel first-line therapies with corresponding tyrosine kinase inhibitors and have improved the outcome of patients harboring these fusions.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('chronic myeloid leukemia11', 'Disease', (36, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (85, 111))	('chronic myeloid leukemia11', 'Phenotype', 'HP:0005506', (36, 62))	('patients', 'Species', '9606', (259, 267))	('lung cancer', 'Disease', (100, 111))	('BCR-ABL1', 'Gene', (17, 25))	('fusion', 'Var', (26, 32))	('led to', 'Reg', (127, 133))	('ALK', 'Gene', '238', (71, 74))	('EML4', 'Gene', (66, 70))	('improved', 'PosReg', (235, 243))	('EML4', 'Gene', '27436', (66, 70))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('BCR-ABL1', 'Gene', '613;25', (17, 25))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('chronic myeloid leukemia11', 'Disease', 'MESH:D015464', (36, 62))	('ALK', 'Gene', (71, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('NSCLC', 'Disease', (113, 118))
230321	30737998	The TOP DNA panel can detect SNV, indels and (CNV) in 464 genes and can infer the tumor mutation burden (TMB) and microsatellite instability (MSI) statuses, while the TOP RNA panel, which uses our original "junction capture method", sensitively and accurately detects gene fusions and exon skipping and provides transcriptome profiling.	('SNV', 'Var', (29, 32))	('gene', 'Protein', (268, 272))	('exon skipping', 'Var', (285, 298))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('indels', 'Var', (34, 40))	('MSI', 'Disease', 'None', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('MSI', 'Disease', (142, 145))	('microsatellite', 'MPA', (114, 128))	('TMB', 'Chemical', '-', (105, 108))	('tumor', 'Disease', (82, 87))
230325	30737998	Prospective TOP testing for patients with advanced cancer was ordered by the treating physician to identify clinically relevant genomic alterations that could potentially inform treatment decisions.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('inform', 'Reg', (171, 177))	('alterations', 'Var', (136, 147))	('patients', 'Species', '9606', (28, 36))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
230329	30737998	After removing the PCR duplicates, SRMA29 was used to improve variant discovery through joint local realignments of tumor and matched normal bam files.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('variant', 'Var', (62, 69))	('tumor', 'Disease', (116, 121))	('improve', 'PosReg', (54, 61))
230330	30737998	Somatic mutations were called using Karkinos (https://github.com/genome-rcast/karkinos), which detects SNV, short indels, chromosomal CNV and tumor purity.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('short indels', 'Var', (108, 120))	('tumor', 'Disease', (142, 147))	('SNV', 'Var', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
230358	30737998	Thus, the DNA panel is capable of detecting all SNV/indels/CNV of 464 genes as well as TERT promoter mutations, MSI and genomic rearrangement in the selected genes.	('MSI', 'Disease', (112, 115))	('TERT', 'Gene', (87, 91))	('464 genes', 'Gene', (66, 75))	('detecting', 'Reg', (34, 43))	('TERT', 'Gene', '7015', (87, 91))	('SNV/indels/CNV', 'Var', (48, 62))	('MSI', 'Disease', 'None', (112, 115))
230364	30737998	In total, V4 can detect 365 fusion transcripts as well as MET exon skipping, and it can evaluate the expression levels of 109 cancer-associated genes (Table S1D,E).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('expression levels', 'MPA', (101, 118))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('MET exon skipping', 'Var', (58, 75))
230369	30737998	We further evaluated the capability of junction capture RNA-seq to detect aberrant transcripts, such as MET exon 14 skipping, which was previously reported to be oncogenic.34, 35 RNA was extracted from FFPE sections of surgically resected tissues from five lung adenocarcinoma cases that had been shown to harbor MET exon 14 skipping by RNA-seq.	('MET', 'Var', (313, 316))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (257, 276))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (257, 276))	('lung adenocarcinoma', 'Disease', (257, 276))
230372	30737998	MET exon 14 skipping, EML4-ALK fusion and CCDC6-RET fusion were detected in 17.1% of the total cases by the TOP RNA panel V3, whereas NF1, ERBB2 or BRAF mutation was found in 14.3% of the total cases by the TOP DNA panel V1 (Figure S5 and Table S4).	('ERBB2', 'Gene', '2064', (139, 144))	('EML4', 'Gene', (22, 26))	('RET', 'Gene', '5979', (48, 51))	('EML4', 'Gene', '27436', (22, 26))	('ALK', 'Gene', (27, 30))	('NF1', 'Gene', (134, 137))	('skipping', 'Var', (12, 20))	('CCDC6', 'Gene', (42, 47))	('NF1', 'Gene', '4763', (134, 137))	('RET', 'Gene', (48, 51))	('BRAF', 'Gene', '673', (148, 152))	('CCDC6', 'Gene', '8030', (42, 47))	('MET exon', 'Var', (0, 8))	('ALK', 'Gene', '238', (27, 30))	('ERBB2', 'Gene', (139, 144))	('BRAF', 'Gene', (148, 152))
230384	30737998	We established a TOP classification (Figure S10), using databases for clinical trials as well as several curated cancer knowledge databases such as OncoKB (http://oncokb.org/) and COSMIC (https://cancer.sanger.ac.uk/cosmic), to group all mutations into tiers of clinical actionability.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('S10', 'Gene', '6204', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (238, 247))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('S10', 'Gene', (44, 47))
230386	30737998	The proportion of actionable mutations in lung cancer, sarcoma, gynecological cancer and colorectal cancer were 43.1%, 13.6%, 52.6% and 13.8%, respectively (Figure S11).	('sarcoma', 'Disease', (55, 62))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('S11', 'Gene', '6267', (164, 167))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('colorectal cancer', 'Disease', (89, 106))	('cancer', 'Disease', (47, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('S11', 'Gene', (164, 167))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (100, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', (42, 53))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))
230388	30737998	Comparisons with matched WES data from 37 tumors in this cohort revealed a high correlation in TMB when the mean depth of TOP sequencing was more than 300 (r = 0.87; Figure S12B).	('S12B', 'SUBSTITUTION', 'None', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('TMB', 'Disease', (95, 98))	('S12B', 'Var', (173, 177))	('TMB', 'Chemical', '-', (95, 98))
230389	30737998	We further assessed the mutation signature of high-TMB specimens (n = 13, 4.1%) and found that tumors with mutations in mismatch-repair (MMR) genes such as MSH2, MSH6 or MLH1 exhibited Signature 6, which is associated with defective DNA mismatch repair and is found in microsatellite unstable tumors36 (Figure S13).	('MSH6', 'Gene', (162, 166))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('mutations', 'Var', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('TMB', 'Chemical', '-', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('MSH6', 'Gene', '2956', (162, 166))	('MSH2', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (293, 299))	('MLH1', 'Gene', '4292', (170, 174))	('tumors', 'Disease', (95, 101))	('MLH1', 'Gene', (170, 174))	('MSH2', 'Gene', '4436', (156, 160))
230390	30737998	Germ line mutations in hereditary cancer genes can predict good response to therapeutic reagents, as shown in the response of cases with BRCA1/2 mutations to PARP inhibitors.37 We have established an IRB-approved process for prospective germ line analysis whereby inherited pathogenic variants of 10 genes (TP53, BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, APC, RB1 and PTEN) detected by the TOP DNA panel are reported to patients who wish to receive this information.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('BRCA2', 'Gene', (320, 325))	('BRCA1', 'Gene', '672', (313, 318))	('TP53', 'Gene', (307, 311))	('BRCA1', 'Gene', (313, 318))	('PARP', 'Gene', (158, 162))	('BRCA1/2', 'Gene', (137, 144))	('RB1', 'Gene', (356, 359))	('PTEN', 'Gene', '5728', (364, 368))	('MSH2', 'Gene', (333, 337))	('BRCA2', 'Gene', '675', (320, 325))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('PMS2', 'Gene', (345, 349))	('pathogenic', 'CPA', (274, 284))	('BRCA1/2', 'Gene', '672;675', (137, 144))	('MSH6', 'Gene', (339, 343))	('BRCA1', 'Gene', '672', (137, 142))	('RB1', 'Gene', '5925', (356, 359))	('TP53', 'Gene', '7157', (307, 311))	('BRCA1', 'Gene', (137, 142))	('variants', 'Var', (285, 293))	('MSH6', 'Gene', '2956', (339, 343))	('MSH2', 'Gene', '4436', (333, 337))	('MLH1', 'Gene', (327, 331))	('patients', 'Species', '9606', (416, 424))	('PARP', 'Gene', '1302', (158, 162))	('cancer', 'Disease', (34, 40))	('MLH1', 'Gene', '4292', (327, 331))	('APC', 'Disease', 'MESH:D011125', (351, 354))	('APC', 'Disease', (351, 354))	('PMS2', 'Gene', '5395', (345, 349))	('PTEN', 'Gene', (364, 368))
230392	30737998	Using the TOP RNA panel, 54 fusion transcripts and one instance of MET exon 14 skipping were identified, and 27.8% of them were clinically relevant (Tier 1 to Tier 5) (Figure S15A).	('skipping', 'NegReg', (79, 87))	('S15A', 'Var', (175, 179))	('S15A', 'SUBSTITUTION', 'None', (175, 179))
230394	30737998	Among 41 patients with sarcoma analyzed prospectively, one patient harbored a TAF15-NR4A3 fusion, consistent with the pathological diagnosis of extraskeletal myxoid chondrosarcoma (Figure S15B).38 Another patient was diagnosed with myxofibrosarcoma due to the proliferation of spindle cells with atypical nuclei and surrounding myxoid interstitial tissue (Figure 5D).	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('TAF15', 'Gene', '8148', (78, 83))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('sarcoma', 'Disease', (23, 30))	('patient', 'Species', '9606', (9, 16))	('extraskeletal myxoid chondrosarcoma', 'Disease', (144, 179))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (144, 179))	('sarcoma', 'Disease', (172, 179))	('NR4A3', 'Gene', (84, 89))	('sarcoma', 'Disease', 'MESH:D012509', (241, 248))	('patient', 'Species', '9606', (205, 212))	('myxofibrosarcoma', 'Disease', (232, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcoma', 'Disease', (241, 248))	('S15B', 'Var', (188, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('patients', 'Species', '9606', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (241, 248))	('patient', 'Species', '9606', (59, 66))	('S15B', 'SUBSTITUTION', 'None', (188, 192))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (165, 179))	('NR4A3', 'Gene', '8013', (84, 89))	('myxofibrosarcoma', 'Disease', 'None', (232, 248))	('TAF15', 'Gene', (78, 83))
230395	30737998	However, the pathological diagnosis was changed after detecting the AHRR-NCOA2 fusion gene, which is known to be specific for angiofibroma of soft tissues (Figure 5D).39 The presence of TAF15-NR4A3 and AHRR-NCOA2 fusions was further confirmed by RT-PCR and sequencing of the PCR products (Figure 5D and Figure S15B).	('AHRR', 'Gene', (202, 206))	('S15B', 'SUBSTITUTION', 'None', (310, 314))	('NCOA2', 'Gene', '10499', (207, 212))	('NCOA2', 'Gene', (207, 212))	('NR4A3', 'Gene', (192, 197))	('AHRR', 'Gene', '57491', (68, 72))	('NR4A3', 'Gene', '8013', (192, 197))	('TAF15', 'Gene', '8148', (186, 191))	('angiofibroma of soft tissues', 'Disease', 'MESH:D018322', (126, 154))	('angiofibroma of soft tissues', 'Disease', (126, 154))	('AHRR', 'Gene', '57491', (202, 206))	('NCOA2', 'Gene', '10499', (73, 78))	('TAF15', 'Gene', (186, 191))	('AHRR', 'Gene', (68, 72))	('S15B', 'Var', (310, 314))	('NCOA2', 'Gene', (73, 78))
230399	30737998	As shown in Figure 6(B), among 80 lung adenocarcinoma specimens, the expression level of MET was highest in a tumor with gene amplification (MET copy number = 14.7).	('expression level', 'MPA', (69, 85))	('gene amplification', 'Var', (121, 139))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (34, 53))	('MET', 'MPA', (89, 92))	('lung adenocarcinoma', 'Disease', (34, 53))	('highest', 'Reg', (97, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (34, 53))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
230406	30737998	In our cohort of stage II or III NSCLC without EGFR/KRAS mutations, the RNA junction capture method successfully identified MET exon skipping and ALK or RET gene fusions in 17.1% of the cases.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('RET', 'Gene', (153, 156))	('KRAS', 'Gene', (52, 56))	('ALK', 'Gene', '238', (146, 149))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('KRAS', 'Gene', '3845', (52, 56))	('MET exon skipping', 'Var', (124, 141))	('RET', 'Gene', '5979', (153, 156))	('NSCLC', 'Disease', (33, 38))	('EGFR', 'Gene', '1956', (47, 51))	('ALK', 'Gene', (146, 149))	('EGFR', 'Gene', (47, 51))
230407	30737998	In contrast, TOP DNA panel analyses on the same cohort identified mutations in BRAF, ERBB2 or NF1 in 14.3% of cases.	('mutations', 'Var', (66, 75))	('NF1', 'Gene', '4763', (94, 97))	('ERBB2', 'Gene', (85, 90))	('ERBB2', 'Gene', '2064', (85, 90))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (79, 83))	('NF1', 'Gene', (94, 97))
230410	30737998	In fact, the versatility of the TOP system was demonstrated in a case in which the detection of an AHRR-NCOA2 fusion changed the diagnosis from myxofibrosarcoma, one of the most aggressive types of soft tissue neoplasms, to angiofibroma of soft tissues, a benign fibrovascular soft tissue tumor.	('changed', 'Reg', (117, 124))	('myxofibrosarcoma', 'Disease', 'None', (144, 160))	('neoplasms', 'Disease', (210, 219))	('angiofibroma of soft tissues', 'Disease', 'MESH:D018322', (224, 252))	('NCOA2', 'Gene', (104, 109))	('tumor', 'Disease', (289, 294))	('AHRR', 'Gene', '57491', (99, 103))	('detection', 'Var', (83, 92))	('neoplasms', 'Phenotype', 'HP:0002664', (210, 219))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('myxofibrosarcoma', 'Disease', (144, 160))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (277, 294))	('angiofibroma of soft tissues', 'Disease', (224, 252))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('neoplasms', 'Disease', 'MESH:D009369', (210, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('fusion', 'Var', (110, 116))	('NCOA2', 'Gene', '10499', (104, 109))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (198, 219))	('AHRR', 'Gene', (99, 103))
230412	30737998	In addition to the detection of somatic mutations such as missense mutations, insertions, deletions and CNVs, the TOP DNA pipeline also implemented MSIsensor for the prediction of MSI status and the calculation of TMB to predict sensitivity to immunocheckpoint inhibitors.	('insertions', 'Var', (78, 88))	('MSI', 'Disease', (148, 151))	('MSI', 'Disease', 'None', (148, 151))	('MSI', 'Disease', 'None', (180, 183))	('MSI', 'Disease', (180, 183))	('deletions', 'Var', (90, 99))	('TMB', 'Chemical', '-', (214, 217))
230418	30737998	We believe that the TOP panel system accelerates personalized medicine and broadens cancer treatment options by precisely detecting fusion oncogenes, abnormal transcripts while evaluating gene expression as well as SNV, indels and CNV in cancer.	('SNV', 'Var', (215, 218))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('CNV', 'Var', (231, 234))	('abnormal', 'Var', (150, 158))	('cancer', 'Disease', (238, 244))	('oncogenes', 'Gene', (139, 148))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', (84, 90))	('accelerates', 'PosReg', (37, 48))	('detecting', 'Reg', (122, 131))	('gene expression', 'MPA', (188, 203))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('indels', 'Var', (220, 226))	('fusion', 'Var', (132, 138))
230674	21437220	Copy Number Alterations and Methylation in Ewing's Sarcoma Ewing's sarcoma is the second most common bone malignancy affecting children and young adults.	('Sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('bone malignancy', 'Disease', 'MESH:D001859', (101, 116))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (59, 74))	('bone malignancy affecting children', 'Phenotype', 'HP:0010622', (101, 135))	('Methylation', 'Var', (28, 39))	("Ewing's sarcoma", 'Disease', (59, 74))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (43, 58))	("Ewing's Sarcoma", 'Disease', (43, 58))	('bone malignancy', 'Disease', (101, 116))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (59, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('Copy Number Alterations', 'Var', (0, 23))	('children', 'Species', '9606', (127, 135))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (43, 58))
230678	21437220	This paper explores in depth two molecular aspects of Ewing's sarcoma: copy number alterations (CNAs) and methylation.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (54, 69))	("Ewing's sarcoma", 'Disease', (54, 69))	('copy number alterations', 'Var', (71, 94))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (54, 69))
230680	21437220	Methylation is thought to be important in oncogenesis and balanced karyotype cancers such as Ewing's, yet it has received only minimal attention in prior studies.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('Methylation', 'Var', (0, 11))	('cancers', 'Disease', (77, 84))	('important', 'Reg', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Ewing', 'Disease', (93, 98))
230688	21437220	Nearly every case of Ewing's sarcoma contains a translocation involving the EWSR1 gene on chromosome 22.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (21, 36))	("Ewing's sarcoma", 'Disease', (21, 36))	('translocation', 'Var', (48, 61))	('EWSR1', 'Gene', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('EWSR1', 'Gene', '2130', (76, 81))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (21, 36))
230694	21437220	Such changes in tumor biology include copy number alterations (CNAs), such as genomic deletions or amplifications, and methylation abnormalities.	('amplifications', 'Var', (99, 113))	('copy number alterations', 'Var', (38, 61))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('methylation', 'CPA', (119, 130))
230695	21437220	As newer technology has become available in recent years, we have learned more about CNAs and methylation in Ewing's sarcoma and possible associations with outcome, disease classification, and tumorigenesis.	('CNAs', 'MPA', (85, 89))	('associations', 'Interaction', (138, 150))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (109, 124))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	("Ewing's sarcoma", 'Disease', (109, 124))	('methylation', 'Var', (94, 105))	('tumor', 'Disease', (193, 198))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (109, 124))
230698	21437220	Literature searches for articles containing "Ewing's sarcoma copy number" and "Ewing's sarcoma methylation" were performed via the PUBMED database.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (45, 60))	('copy number', 'Var', (61, 72))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (79, 94))	("Ewing's sarcoma", 'Disease', (45, 60))	("Ewing's sarcoma", 'Disease', (79, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (45, 60))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (79, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))
230699	21437220	Specific CNAs predict prognosis in several cancers and have been introduced as part of clinical risk stratification for colorectal and breast cancer, neuroblastoma, and brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (169, 181))	('brain tumors', 'Phenotype', 'HP:0030692', (169, 181))	('predict', 'Reg', (14, 21))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('clinical', 'Species', '191496', (87, 95))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('brain tumors', 'Disease', (169, 181))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Disease', (43, 50))	('CNAs', 'Var', (9, 13))	('neuroblastoma', 'Disease', 'MESH:D009447', (150, 163))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('neuroblastoma', 'Disease', (150, 163))	('colorectal and breast cancer', 'Disease', 'MESH:D015179', (120, 148))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('neuroblastoma', 'Phenotype', 'HP:0003006', (150, 163))
230704	21437220	For example, CDKN2A homozygous deletions in pediatric gliomas were recently found to significantly associate with specific BRAFV600E mutations, helping to define a new subset of tumors; the same deletion and mutation were also shown to work together to promote glioma formation in mice, validating the cooperation between CNAs and mutations.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (261, 267))	('BRAFV600E', 'Gene', (123, 132))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('mutations', 'Var', (133, 142))	('pediatric gliomas', 'Disease', 'MESH:D005910', (44, 61))	('mice', 'Species', '10090', (281, 285))	('promote', 'PosReg', (253, 260))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('glioma', 'Disease', (261, 267))	('BRAFV600E', 'Mutation', 'rs113488022', (123, 132))	('tumors', 'Disease', (178, 184))	('glioma', 'Disease', 'MESH:D005910', (261, 267))	('CDKN2A', 'Gene', (13, 19))	('pediatric gliomas', 'Disease', (44, 61))	('glioma', 'Disease', (54, 60))	('deletions', 'Var', (31, 40))
230707	21437220	Copy number assessment in combination with clinical data could be used to identify CNAs in archival tissue and determine their link to the outcome in Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (150, 165))	('clinical', 'Species', '191496', (43, 51))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (150, 165))	("Ewing's sarcoma", 'Disease', (150, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('CNAs', 'Var', (83, 87))
230709	21437220	A large number of novel and recurrent secondary abnormalities in Ewing's tumors relating to copy number already have been discovered (see summary Table 1).	("Ewing's tumors", 'Disease', 'MESH:C563168', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('copy number', 'Var', (92, 103))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (65, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	("Ewing's tumors", 'Disease', (65, 79))
230711	21437220	The most commonly reported CNAs in Ewing's sarcoma are trisomies of chromosomes 8 and 12 followed by the gain of 1q.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (35, 50))	('trisomies', 'Var', (55, 64))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (35, 50))	("Ewing's sarcoma", 'Disease', (35, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
230714	21437220	In contrast to these findings, many studies have not found a statically significant link to survival outcomes in Ewing's sarcoma and trisomy 8.	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (113, 128))	("Ewing's sarcoma", 'Disease', (113, 128))	('trisomy', 'Var', (133, 140))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (113, 128))
230716	21437220	reported that 8p amplifications occurred at higher frequency in relapsed cases compared to primary tumors (P = .04).	('8p amplifications', 'Var', (14, 31))	('relapsed cases', 'Disease', (64, 78))	('primary tumors', 'Disease', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('primary tumors', 'Disease', 'MESH:D009369', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
230719	21437220	Copy number gains of 8 and/or 12 appear more frequently in local recurrences (83% of the time) compared to primary (47%) and metastatic (42%) lesions and are hypothesized to appear with increased frequency during tumor progression or after initial translocation.	('tumor', 'Disease', (213, 218))	('Copy number gains', 'Var', (0, 17))	('local recurrences', 'CPA', (59, 76))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))
230723	21437220	These genes may be indicative of the importance of trisomy 12 and its role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (78, 83))	('trisomy', 'Var', (51, 58))
230724	21437220	Amplifications and trisomies involving chromosomes 8 and 12 have conflicting findings regarding clinical and statistical significance.	('clinical', 'Species', '191496', (96, 104))	('trisomies', 'Var', (19, 28))	('Amplifications', 'Var', (0, 14))
230728	21437220	This is the presumed artifact of an unbalanced translocation in Ewing's sarcoma, der(16)t(1;16).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (64, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('der(16)t(1;16', 'Var', (81, 94))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (64, 79))	("Ewing's sarcoma", 'Disease', (64, 79))
230732	21437220	1q21-1q22 amplification has also been reported in other sarcomas.	('1q21-1q22 amplification', 'Var', (0, 23))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('reported', 'Reg', (38, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcomas', 'Disease', (56, 64))
230734	21437220	In addition to TP53 deletion that is contained within 17p loss, mutation of TP53 has been reported to show an association with poor chemoresponse and overall survival in Ewing's sarcoma (P = .03 and P < .001).	('mutation', 'Var', (64, 72))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (170, 185))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('TP53', 'Gene', (76, 80))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (170, 185))	("Ewing's sarcoma", 'Disease', (170, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
230735	21437220	Deletion of 9p21 encompassing CDKN2A (p16-INK4a) appeared in 10-73% of cases, including Ewing's sarcoma cell lines, with reported homozygous deletions in 8% and 13% of patient samples.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('INK4a', 'Gene', (42, 47))	('CDKN2A', 'Gene', (30, 36))	('INK4a', 'Gene', '1029', (42, 47))	('patient', 'Species', '9606', (168, 175))	('p16', 'Gene', (38, 41))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (88, 103))	("Ewing's sarcoma", 'Disease', (88, 103))	('p16', 'Gene', '1029', (38, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (88, 103))	('Deletion', 'Var', (0, 8))
230736	21437220	This CDKN2A deletion was found to be a negative predictor of disease-specific survival (P = .001): 7 patients with this deletion all died of disease before 36 months, 2 of which had metastases at diagnosis.	('deletion', 'Var', (12, 20))	('patients', 'Species', '9606', (101, 109))	('metastases', 'Disease', 'MESH:D009362', (182, 192))	('CDKN2A', 'Gene', (5, 11))	('metastases', 'Disease', (182, 192))	('negative', 'NegReg', (39, 47))
230737	21437220	The combination of CDKN2A deletion and TP53 mutation was shown to be the most significant negative predictor of overall survival (P < .001).	('mutation', 'Var', (44, 52))	('CDKN2A', 'Gene', (19, 25))	('deletion', 'Var', (26, 34))	('negative', 'NegReg', (90, 98))	('TP53', 'Gene', '7157', (39, 43))	('overall survival', 'MPA', (112, 128))	('TP53', 'Gene', (39, 43))
230739	21437220	Current studies validating the prevalence and prognostic significance of CDKN2A deletions and TP53 mutations in Ewing's sarcoma are underway through the Children's Oncology Group (COG).	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (112, 127))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('Children', 'Species', '9606', (153, 161))	('deletions', 'Var', (80, 89))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (112, 127))	('Oncology', 'Phenotype', 'HP:0002664', (164, 172))	("Ewing's sarcoma", 'Disease', (112, 127))	('CDKN2A', 'Gene', (73, 79))
230745	21437220	Mitochondrial DNA (mtDNA) copy number changes have been associated with increased risk of certain cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('copy number changes', 'Var', (26, 45))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('associated', 'Reg', (56, 66))	('cancers', 'Disease', (98, 105))
230747	21437220	These mutations, in conjunction with quantitative mtDNA changes, have been linked to Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (85, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (85, 100))	('linked', 'Reg', (75, 81))	('mutations', 'Var', (6, 15))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (85, 100))
230748	21437220	While both D-loop mutations and reduced content of mtDNA are at higher instance in Ewing's sarcoma, the greatest statistical significance was determined to be between low mtDNA copy number and tumor metastasis as all of the metastases in the study contained low numbers of mtDNA (P = .029).	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (83, 98))	('D-loop mutations', 'Var', (11, 27))	("Ewing's sarcoma", 'Disease', (83, 98))	('low', 'NegReg', (167, 170))	('metastases', 'Disease', 'MESH:D009362', (224, 234))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mtDNA', 'Gene', (171, 176))	('tumor metastasis', 'Disease', 'MESH:D009362', (193, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('tumor metastasis', 'Disease', (193, 209))	('metastases', 'Disease', (224, 234))
230749	21437220	Methylation is an alternate method by which gene expression is changed in cancer cells.	('changed', 'Reg', (63, 70))	('Methylation', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
230757	21437220	In fact, the relative absence of wild karyotype anomalies and rampant mutations argues that epigenetic modifications such as methylation may be a prominent mechanism of disease in sarcomas bearing balanced translocations such as Ewing's sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('anomalies', 'Disease', (48, 57))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (229, 244))	('sarcomas', 'Disease', (180, 188))	('anomalies', 'Disease', 'MESH:D000014', (48, 57))	('balanced translocations', 'Var', (197, 220))	("Ewing's sarcoma", 'Disease', (229, 244))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (229, 244))	('methylation', 'Var', (125, 136))
230759	21437220	Two studies have assessed genetic alterations in the 9p21 locus in Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (67, 82))	('9p21', 'Gene', (53, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('genetic alterations', 'Var', (26, 45))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (67, 82))	("Ewing's sarcoma", 'Disease', (67, 82))
230762	21437220	The second study found 1 methylated, 1 point-mutated, and 2 homozygous deleted CDKN2A among 24 tumors, as well as 2 methylated and 2 homozygous deleted CDKN2B.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('point-mutated', 'Var', (39, 52))	('CDKN2B', 'Gene', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('methylated', 'Var', (25, 35))	('CDKN2B', 'Gene', '1030', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CDKN2A', 'Gene', (79, 85))	('tumors', 'Disease', (95, 101))
230764	21437220	One study interrogated RASSF1A along with p16, MGMT, GSTP1, APC, DAPK, RARbeta, CDH1, and CDH13 and found only MGMT and CDH1 promoters methylated in 1 of 8 (12.5%) Ewing's sarcoma tumor samples.	('RARbeta', 'Gene', (71, 78))	('CDH1', 'Gene', (80, 84))	('methylated', 'Var', (135, 145))	("Ewing's sarcoma tumor", 'Disease', 'MESH:C563168', (164, 185))	('CDH13', 'Gene', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('MGMT', 'Gene', '4255', (111, 115))	('DAPK', 'Gene', (65, 69))	('p16', 'Gene', (42, 45))	('MGMT', 'Gene', '4255', (47, 51))	('p16', 'Gene', '1029', (42, 45))	('APC', 'Disease', 'MESH:D011125', (60, 63))	('APC', 'Disease', (60, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	("Ewing's sarcoma tumor", 'Disease', (164, 185))	('CDH1', 'Gene', '999', (90, 94))	('DAPK', 'Gene', '1612', (65, 69))	('CDH1', 'Gene', '999', (120, 124))	('MGMT', 'Gene', (111, 115))	('RASSF1A', 'Gene', '11186', (23, 30))	('GSTP1', 'Gene', '2950', (53, 58))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (164, 179))	('CDH13', 'Gene', '1012', (90, 95))	('CDH1', 'Gene', (90, 94))	('MGMT', 'Gene', (47, 51))	('RARbeta', 'Gene', '5915', (71, 78))	('CDH1', 'Gene', '999', (80, 84))	('CDH1', 'Gene', (120, 124))	('RASSF1A', 'Gene', (23, 30))	('GSTP1', 'Gene', (53, 58))
230765	21437220	With respect to RASSF1A, these results are more difficult to reconcile with the high frequency of RASSF1A methylation in a previously published report; Avigad et al.	('methylation', 'Var', (106, 117))	('RASSF1A', 'Gene', '11186', (98, 105))	('RASSF1A', 'Gene', (16, 23))	('RASSF1A', 'Gene', '11186', (16, 23))	('RASSF1A', 'Gene', (98, 105))
230771	21437220	They confirmed the absence of deletions in the caspase 8 gene, as well as the reexpression of caspase 8 upon 5-aza-2' deoxycytidine administration.	('caspase 8', 'Gene', '841', (94, 103))	('reexpression', 'MPA', (78, 90))	('deletions', 'Var', (30, 39))	('caspase 8', 'Gene', (94, 103))	('caspase 8', 'Gene', '841', (47, 56))	('caspase 8', 'Gene', (47, 56))
230776	21437220	We also acknowledge the importance of other molecular changes potentially at work in Ewing's sarcomagenesis such as pleiotropic effects of the chromosomal translocation beyond creation of the specific fusion oncogene, somatic mutations in yet uninterrogated tumor suppressors, increased expression of oncogenes or oncogenic microRNAs, and other epigenetic mechanisms of expression regulation such as histone and chromatin packaging that could not be covered within the scope of this review.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	("Ewing's sarcomagenesis", 'Phenotype', 'HP:0012254', (85, 107))	('tumor', 'Disease', (258, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('mutations', 'Var', (226, 235))	('increased', 'PosReg', (277, 286))	("Ewing's sarcomagenesis", 'Disease', 'MESH:C563168', (85, 107))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	("Ewing's sarcomagenesis", 'Disease', (85, 107))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (85, 100))
230777	21437220	CNAs and methylation changes in Ewing's sarcoma, along with some of these yet unexplored genetic and epigenetic perturbations may be essential to Ewing's tumorigenesis as evidence suggests that the EWS-FLI1 translocation is necessary but not sufficient for Ewing's transformation in vitro; CNAs and methylation changes may form some of the necessary second hits required for Ewing's sarcoma to develop.	("Ewing's tumorigenesis", 'Disease', 'MESH:C563168', (146, 167))	('FLI1', 'Gene', '2313', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (375, 390))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (32, 47))	("Ewing's sarcoma", 'Disease', (375, 390))	("Ewing's transformation", 'Disease', 'MESH:C563168', (257, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (383, 390))	("Ewing's transformation", 'Disease', (257, 279))	('EWS', 'Gene', (198, 201))	('methylation changes', 'Var', (299, 318))	("Ewing's sarcoma", 'Disease', (32, 47))	('EWS', 'Gene', '2130', (198, 201))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (375, 390))	("Ewing's tumorigenesis", 'Disease', (146, 167))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (32, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('FLI1', 'Gene', (202, 206))
230781	21437220	The main copy number recurrences in Ewing's sarcoma included trisomies 8 and 12, along with 1q amplification.	('trisomies 8', 'Var', (61, 72))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (36, 51))	("Ewing's sarcoma", 'Disease', (36, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (36, 51))
230783	21437220	For methylation as a mechanism of sarcomagenesis, two prominent tumor suppressor loci, CDKN2A and RASSF1A, as well as one important apoptosis activator, caspase 8, have been implicated.	('sarcoma', 'Disease', (34, 41))	('tumor', 'Disease', (64, 69))	('caspase 8', 'Gene', '841', (153, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('RASSF1A', 'Gene', '11186', (98, 105))	('caspase 8', 'Gene', (153, 162))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('RASSF1A', 'Gene', (98, 105))	('CDKN2A', 'Gene', (87, 93))
230784	21437220	For these methylation-associated genetic perturbations, therapeutic implications are very direct because the clinical drugs affecting methylation status and downstream histone deacetylation are already available for patient use.	('methylation-associated', 'Var', (10, 32))	('patient', 'Species', '9606', (216, 223))	('clinical', 'Species', '191496', (109, 117))	('perturbations', 'Var', (41, 54))	('genetic perturbations', 'Var', (33, 54))
230944	30134855	The LMNA-NTRK1 fusion was likely the molecular driver of tumorigenesis and metastasis in this patient, and the observed effectiveness of crizotinib treatment provides clinical validation of this molecular target.	('fusion', 'Var', (15, 21))	('NTRK1', 'Gene', '4914', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('LMNA', 'Gene', (4, 8))	('NTRK1', 'Gene', (9, 14))	('crizotinib', 'Chemical', 'MESH:D000077547', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('patient', 'Species', '9606', (94, 101))	('tumor', 'Disease', (57, 62))	('LMNA', 'Gene', '4000', (4, 8))
230988	30134855	However, with crizotinib treatment, the FDG metabolism was significantly reduced in comparison with that seen in the first PET-CT examination.	('reduced', 'NegReg', (73, 80))	('FDG metabolism', 'MPA', (40, 54))	('crizotinib', 'Chemical', 'MESH:D000077547', (14, 24))	('crizotinib', 'Var', (14, 24))
231000	30134855	TrkA does not appear to be an oncogene, but gene fusions involving NTRK1 have been shown to be oncogenic, resulting in constitutive TrkA activation.	('NTRK1', 'Gene', '4914', (67, 72))	('NTRK1', 'Gene', (67, 72))	('TrkA', 'Gene', '4914', (0, 4))	('activation', 'PosReg', (137, 147))	('TrkA', 'Gene', (0, 4))	('gene fusions', 'Var', (44, 56))	('TrkA', 'Gene', '4914', (132, 136))	('TrkA', 'Gene', (132, 136))
231001	30134855	Activation of this receptor initiates several key downstream signal transduction cascades, including the MAPK, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-gamma (PLC-gamma) pathways as well as promotes phosphorylation of the AKT, ERK, and PLC-gamma1 fusion proteins in vitro.	('PLC-gamma1', 'Gene', '5335', (253, 263))	('PI3', 'Gene', (142, 145))	('ERK', 'Protein', (244, 247))	('PLC-gamma1', 'Gene', (253, 263))	('C-gamma', 'Species', '10733', (178, 185))	('C-gamma', 'Species', '10733', (167, 174))	('MAPK', 'Pathway', (105, 109))	('phosphorylation', 'MPA', (216, 231))	('C-gamma', 'Species', '10733', (255, 262))	('PI3', 'Gene', '5266', (142, 145))	('AKT', 'Protein', (239, 242))	('Activation', 'Var', (0, 10))	('promotes', 'PosReg', (207, 215))	('fusion proteins', 'Protein', (264, 279))
231003	30134855	At present, no direct kinase inhibitors with NTRK1 fusions have been approved by the U.S. Food and Drug Administration.	('NTRK1', 'Gene', '4914', (45, 50))	('fusions', 'Var', (51, 58))	('NTRK1', 'Gene', (45, 50))
231004	30134855	reported the case of a 41-year-old woman with an undifferentiated soft tissue sarcoma and lung metastasis harboring a LMNA-NTRK1 gene fusion who consented to treatment with the Trk inhibitor LOXO-101.	('LMNA', 'Gene', (118, 122))	('NTRK1', 'Gene', (123, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('soft tissue sarcoma', 'Disease', (66, 85))	('fusion', 'Var', (134, 140))	('Trk', 'Gene', '4914', (177, 180))	('LMNA', 'Gene', '4000', (118, 122))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (66, 85))	('NTRK1', 'Gene', '4914', (123, 128))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (66, 85))	('Trk', 'Gene', (177, 180))	('LOXO-101', 'Chemical', 'MESH:C000609083', (191, 199))	('lung metastasis', 'Disease', (90, 105))	('woman', 'Species', '9606', (35, 40))	('lung metastasis', 'Disease', 'MESH:D009362', (90, 105))
231007	30134855	Crizotinib is a multi-active kinase inhibitor that blocks TrkA autophosphorylation and cell growth in cells expressing NTRK1 fusion proteins.	('cell growth', 'CPA', (87, 98))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('fusion', 'Var', (125, 131))	('NTRK1', 'Gene', '4914', (119, 124))	('blocks', 'NegReg', (51, 57))	('TrkA', 'Gene', '4914', (58, 62))	('TrkA', 'Gene', (58, 62))	('NTRK1', 'Gene', (119, 124))
231009	30134855	Based on the report of a minor response to crizotinib in a case of non-small cell lung cancer harboring a NTRK1 fusion as well as preclinical data, we started oral administration of crizotinib (450 mg QD) in the UPS patient described in this report.	('crizotinib', 'Chemical', 'MESH:D000077547', (43, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (67, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patient', 'Species', '9606', (216, 223))	('non-small cell lung cancer', 'Disease', (67, 93))	('NTRK1', 'Gene', '4914', (106, 111))	('crizotinib', 'Chemical', 'MESH:D000077547', (182, 192))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (71, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (67, 93))	('NTRK1', 'Gene', (106, 111))	('fusion', 'Var', (112, 118))
231014	30134855	Thus, the detection rate for NTRK1 fusions in STS was less than 1% in their study.	('STS', 'Phenotype', 'HP:0030448', (46, 49))	('NTRK1', 'Gene', '4914', (29, 34))	('fusions', 'Var', (35, 42))	('NTRK1', 'Gene', (29, 34))
231017	30134855	These findings highlight the importance of further large research series with genetic testing of any sarcomatous neoplasm with similar histomorphology features for NTRK1 gene fusion and the application of such testing in the routine clinical diagnostic setting.	('sarcomatous neoplasm', 'Phenotype', 'HP:0100242', (101, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('NTRK1', 'Gene', '4914', (164, 169))	('sarcomatous neoplasm', 'Disease', (101, 121))	('neoplasm', 'Phenotype', 'HP:0002664', (113, 121))	('gene fusion', 'Var', (170, 181))	('sarcomatous neoplasm', 'Disease', 'MESH:D018316', (101, 121))	('NTRK1', 'Gene', (164, 169))
231018	30134855	The tumor regression and clinical response observed in the present case establishes that this LMNA-NTRK1 fusion may be a molecular driver of carcinogenesis in this patient and provides clinical validation of a molecular target in oncology.	('tumor', 'Disease', (4, 9))	('fusion', 'Var', (105, 111))	('LMNA', 'Gene', '4000', (94, 98))	('patient', 'Species', '9606', (164, 171))	('oncology', 'Phenotype', 'HP:0002664', (230, 238))	('carcinogenesis', 'Disease', 'MESH:D063646', (141, 155))	('NTRK1', 'Gene', '4914', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('LMNA', 'Gene', (94, 98))	('NTRK1', 'Gene', (99, 104))	('carcinogenesis', 'Disease', (141, 155))
231046	28556516	The regulation and activation of the EMT-TFs is complex involving pleiotropic and contextual signals and different regulatory layers including negative feedback loops with microRNAs (miRNAs) and alterations in the DNA methylation status, facilitating short time or prolonged induction of the mesenchymal state.	('alterations', 'Var', (195, 206))	('miR', 'Gene', '220972', (183, 186))	('miR', 'Gene', (183, 186))
231072	28556516	ZEB2 is upregulated in GBM cells and suppression of ZEB2 inhibits invasion (Qi et al., 2012) and results in a blockade of resistance against vascular endothelial growth factor (VEGF), which involves inhibition of a hypoxia-inducible factor (HIF)1a-ZEB2-EphrinB2 MT pathway (Depner et al., 2016).	('ZEB2', 'Gene', '9839', (0, 4))	('hypoxia-inducible factor (HIF)1a', 'Gene', '3091', (215, 247))	('blockade', 'NegReg', (110, 118))	('suppression', 'Var', (37, 48))	('vascular endothelial growth factor', 'Gene', '7422', (141, 175))	('EphrinB2', 'Gene', '1948', (253, 261))	('vascular endothelial growth factor', 'Gene', (141, 175))	('resistance', 'MPA', (122, 132))	('invasion', 'CPA', (66, 74))	('ZEB2', 'Gene', (52, 56))	('VEGF', 'Gene', '7422', (177, 181))	('VEGF', 'Gene', (177, 181))	('ZEB2', 'Gene', '9839', (52, 56))	('upregulated', 'PosReg', (8, 19))	('ZEB2', 'Gene', (248, 252))	('ZEB2', 'Gene', '9839', (248, 252))	('inhibition', 'NegReg', (199, 209))	('ZEB2', 'Gene', (0, 4))	('EphrinB2', 'Gene', (253, 261))	('inhibits', 'NegReg', (57, 65))
231077	28556516	Recent work suggests that mesenchymal transformation by STAT3 is controlled through Annexin-A2 (ANXA2) that is inactivated in GBMs that exhibit mutations in the isocitrate dehydrogenase (IDH) gene (Kling et al., 2016).	('STAT3', 'Gene', (56, 61))	('IDH', 'Gene', (187, 190))	('ANXA2', 'Gene', (96, 101))	('isocitrate dehydrogenase', 'Gene', (161, 185))	('IDH', 'Gene', '3417', (187, 190))	('isocitrate dehydrogenase', 'Gene', '3417', (161, 185))	('Annexin-A2', 'Gene', (84, 94))	('mutations', 'Var', (144, 153))	('mesenchymal transformation', 'CPA', (26, 52))	('Annexin-A2', 'Gene', '302', (84, 94))	('ANXA2', 'Gene', '302', (96, 101))	('STAT3', 'Gene', '6774', (56, 61))
231094	28556516	For example, following gamma-radiation of patients SNAI1, EMT markers and invasion were elevated in recurrent GBM samples, and in vitro, SNAI1 knockdown prevented radiation-induced MT leading to reduced cellular invasion (Mahabir et al., 2014).	('SNAI1', 'Gene', (51, 56))	('reduced', 'NegReg', (195, 202))	('prevented', 'NegReg', (153, 162))	('invasion', 'CPA', (74, 82))	('elevated', 'PosReg', (88, 96))	('EMT markers', 'CPA', (58, 69))	('cellular invasion', 'CPA', (203, 220))	('SNAI1', 'Gene', '6615', (51, 56))	('SNAI1', 'Gene', '6615', (137, 142))	('SNAI1', 'Gene', (137, 142))	('knockdown', 'Var', (143, 152))	('patients', 'Species', '9606', (42, 50))	('radiation-induced', 'CPA', (163, 180))
231117	28556516	Modulating miRNA homeostasis gains attraction as a powerful approach in clinical translation in various diseases and may be a very applicable way to target MT in brain cancer oncology (Li and Rana, 2014).	('Modulating', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('homeostasis gains attraction', 'Disease', 'MESH:D015430', (17, 45))	('brain cancer', 'Disease', (162, 174))	('oncology', 'Phenotype', 'HP:0002664', (175, 183))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('brain cancer', 'Disease', 'MESH:D001932', (162, 174))	('brain cancer', 'Phenotype', 'HP:0030692', (162, 174))	('homeostasis gains attraction', 'Disease', (17, 45))
231123	28556516	Also, lncRNA AB073614 can influence the expression of mesenchymal differentiation in glioma cells although no effect on EMT-TFs expression was found (Li et al., 2016).	('expression', 'MPA', (40, 50))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('influence', 'Reg', (26, 35))	('mesenchymal differentiation', 'CPA', (54, 81))	('lncRNA AB073614', 'Var', (6, 21))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
231124	28556516	In summary, blocking (E)MT in cancer cells through targeted modification of the epigenome or the household of lncRNAs may be an attractive therapeutic strategy to impede tumor malignancy.	('modification', 'Reg', (60, 72))	('impede', 'NegReg', (163, 169))	('epigenome', 'Protein', (80, 89))	('tumor malignancy', 'Disease', (170, 186))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor malignancy', 'Disease', 'MESH:D018198', (170, 186))	('blocking', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
231125	28556516	This is particularly promising as epigenetic alterations are reversible and may be applied to transiently make tumors more susceptible to traditional, clinically approved drugs.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('epigenetic alterations', 'Var', (34, 56))
231129	28556516	Recently, it was shown that the MT status of GBM cells can be monitored by determining the intracellular composition of choline derivatives using high resolution of proton nuclear magnetic resonance spectroscopy; the targeting of choline kinase 1a (CHK1a) impaired MT (Koch et al., 2016).	('choline', 'Chemical', 'MESH:D002794', (120, 127))	('choline', 'Chemical', 'MESH:D002794', (230, 237))	('targeting', 'Var', (217, 226))	('impaired', 'NegReg', (256, 264))	('CHK1a', 'Gene', (249, 254))
231141	28556516	Histone mutations as well as gene expression profiling can differentiate diffuse intrinsic pontine glioma (DIPG), one of the most devastating pediatric brain tumors, into molecular subgroups including a mesenchymal branch (Castel et al., 2015; Puget et al., 2012).	('brain tumors', 'Disease', 'MESH:D001932', (152, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('DIPG', 'Chemical', '-', (107, 111))	('brain tumors', 'Disease', (152, 164))	('brain tumor', 'Phenotype', 'HP:0030692', (152, 163))	('mutations', 'Var', (8, 17))	('glioma', 'Disease', (99, 105))	('brain tumors', 'Phenotype', 'HP:0030692', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
231159	28556516	Moreover, ZEB1 contributes to chemoresistance by enhancing expression of drug efflux pathways and consequently silencing of ZEB1, resulting in sensitization to doxorubicin in a xenograft mouse model.	('silencing', 'Var', (111, 120))	('sensitization to doxorubicin', 'MPA', (143, 171))	('doxorubicin', 'Chemical', 'MESH:D004317', (160, 171))	('chemoresistance', 'CPA', (30, 45))	('expression', 'MPA', (59, 69))	('mouse', 'Species', '10090', (187, 192))	('drug efflux pathways', 'Pathway', (73, 93))	('enhancing', 'PosReg', (49, 58))	('ZEB1', 'Gene', (124, 128))
231165	28556516	Interestingly, ZEB1 has been identified as a potent transcriptional repressor of IL-15 and hypermethylation of its binding region in the IL-15 promoter prevents suppression of IL-15 production in CTCL and thus progression (Mishra et al., 2016).	('prevents suppression', 'NegReg', (152, 172))	('IL-15', 'Gene', '3600', (176, 181))	('IL-15', 'Gene', (81, 86))	('IL-15', 'Gene', (137, 142))	('IL-15', 'Gene', '3600', (81, 86))	('IL-15', 'Gene', (176, 181))	('hypermethylation', 'Var', (91, 107))	('IL-15', 'Gene', '3600', (137, 142))	('CTCL', 'Gene', '64061', (196, 200))	('CTCL', 'Gene', (196, 200))
231168	28556516	TWIST1 knockdown decreased invasiveness and sensitized for an ALK inhibitor in cell culture models, thus linking TWIST1 with malignant progression and therapy resistance of this tumor.	('linking', 'Reg', (105, 112))	('tumor', 'Disease', (178, 183))	('TWIST1', 'Gene', (0, 6))	('decreased', 'NegReg', (17, 26))	('TWIST1', 'Gene', '7291', (0, 6))	('ALK', 'Gene', (62, 65))	('ALK', 'Gene', '238', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('invasiveness', 'CPA', (27, 39))	('knockdown', 'Var', (7, 16))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TWIST1', 'Gene', (113, 119))	('TWIST1', 'Gene', '7291', (113, 119))
231171	28556516	Mice with homozygous C-terminal deletions in Zeb1 were among others characterized by small thymus and a reduction in early T-cell progenitors (Higashi et al., 1997).	('reduction', 'NegReg', (104, 113))	('Zeb1', 'Gene', (45, 49))	('small thymus', 'Phenotype', 'HP:0000778', (85, 97))	('early T-cell progenitors', 'CPA', (117, 141))	('C-terminal deletions', 'Var', (21, 41))	('Mice', 'Species', '10090', (0, 4))	('Zeb1', 'Gene', '21417', (45, 49))
231184	28556516	The epigenetic inactivation of TWIST2 also has been reported to modulate disease progression in childhood acute lymphoblastic leukemia.	('acute lymphoblastic leukemia', 'Disease', (106, 134))	('disease progression', 'CPA', (73, 92))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (112, 134))	('modulate', 'Reg', (64, 72))	('epigenetic inactivation', 'Var', (4, 27))	('TWIST2', 'Gene', (31, 37))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (106, 134))	('TWIST2', 'Gene', '117581', (31, 37))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (106, 134))
231186	28556516	(2015), showing that in acute myeloid leukemia (AML) in around 30% of examined cases hypermethylation of TWIST2 occurred leading to reduced expression of both TWIST2 and the cyclin-dependent kinase inhibitor p21.	('hypermethylation', 'Var', (85, 101))	('TWIST2', 'Gene', (105, 111))	('TWIST2', 'Gene', '117581', (105, 111))	('expression', 'MPA', (140, 150))	('AML', 'Disease', (48, 51))	('leukemia', 'Phenotype', 'HP:0001909', (38, 46))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (24, 46))	('reduced', 'NegReg', (132, 139))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (30, 46))	('acute myeloid leukemia', 'Disease', (24, 46))	('TWIST2', 'Gene', '117581', (159, 165))	('p21', 'Gene', (208, 211))	('TWIST2', 'Gene', (159, 165))	('AML', 'Disease', 'MESH:D015470', (48, 51))	('p21', 'Gene', '644914', (208, 211))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (24, 46))
231190	28556516	A link between imatinib resistance and TWIST1 exists, as in vitro knockdown of TWIST1 expression in CML cells resulted in sensitization for imatinib (Cosset et al., 2011).	('TWIST1', 'Gene', '7291', (39, 45))	('TWIST1', 'Gene', (79, 85))	('imatinib', 'Chemical', 'MESH:D000068877', (15, 23))	('CML', 'Disease', 'MESH:D015464', (100, 103))	('TWIST1', 'Gene', '7291', (79, 85))	('TWIST1', 'Gene', (39, 45))	('CML', 'Disease', (100, 103))	('knockdown', 'Var', (66, 75))	('sensitization for imatinib', 'MPA', (122, 148))	('imatinib', 'Chemical', 'MESH:D000068877', (140, 148))
231194	28556516	Downmodulation of TWIST1 reduced their colony-forming capacity, providing further evidence for TWIST1 involvement in leukemia stem cells and disease progression (Wang et al., 2015c).	('reduced', 'NegReg', (25, 32))	('colony-forming capacity', 'CPA', (39, 62))	('TWIST1', 'Gene', (95, 101))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('leukemia', 'Disease', 'MESH:D007938', (117, 125))	('involvement', 'Reg', (102, 113))	('TWIST1', 'Gene', (18, 24))	('TWIST1', 'Gene', '7291', (18, 24))	('leukemia', 'Disease', (117, 125))	('Downmodulation', 'Var', (0, 14))	('TWIST1', 'Gene', '7291', (95, 101))
231196	28556516	Knockdown of ZEB1 reduced the invasive properties of this aggressive tumor (Stavropoulou et al., 2016).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Knockdown', 'Var', (0, 9))	('tumor', 'Disease', (69, 74))	('reduced', 'NegReg', (18, 25))	('ZEB1', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
231205	28556516	Indeed, SNAI1 expression is associated with worse overall survival in sarcomas.	('expression', 'Var', (14, 24))	('SNAI1', 'Gene', '6615', (8, 13))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('SNAI1', 'Gene', (8, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))
231206	28556516	In addition, ectopic expression of SNAI1 has tumorigenic activity in fibroblasts and a role for SNAI1 in the generation of sarcomas has been suggested (Alba-Castellon et al., 2014).	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('sarcomas', 'Disease', (123, 131))	('SNAI1', 'Gene', '6615', (35, 40))	('Alba', 'Gene', (152, 156))	('tumor', 'Disease', (45, 50))	('Alba', 'Gene', '173', (152, 156))	('sarcomas', 'Disease', 'MESH:D012509', (123, 131))	('ectopic expression', 'Var', (13, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('SNAI1', 'Gene', '6615', (96, 101))	('SNAI1', 'Gene', (96, 101))	('SNAI1', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
231224	28556516	An integrated proteomics and genomics analyses in soft tissue leiomyosarcomas identified SNAI2/SLUG as a negative regulator of E-cadherin expression; knockdown of SNAI2 increased E-cadherin and decreased vimentin expression that was associated with a decrease in proliferation and invasion (Yang et al., 2010).	('SNAI2', 'Gene', (89, 94))	('decrease', 'NegReg', (251, 259))	('E-cadherin', 'Gene', (179, 189))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (62, 77))	('E-cadherin', 'Gene', '999', (179, 189))	('leiomyosarcomas', 'Disease', (62, 77))	('SNAI2', 'Gene', '6591', (163, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('SLUG', 'Gene', '6591', (95, 99))	('SNAI2', 'Gene', '6591', (89, 94))	('SLUG', 'Gene', (95, 99))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (62, 77))	('invasion', 'CPA', (281, 289))	('expression', 'MPA', (213, 223))	('increased', 'PosReg', (169, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('SNAI2', 'Gene', (163, 168))	('vimentin', 'Gene', '7431', (204, 212))	('vimentin', 'Gene', (204, 212))	('knockdown', 'Var', (150, 159))	('E-cadherin', 'Gene', (127, 137))	('proliferation', 'CPA', (263, 276))	('decreased', 'NegReg', (194, 203))	('E-cadherin', 'Gene', '999', (127, 137))
231232	28556516	It has been shown in osteosarcoma that the silencing of AMF/PGI reduces the production and secretion of TGF-beta2 and TGF-beta3 resulting in downregulation of SNAI1 that can elevate E-cadherin expression leading to MET.	('PGI', 'Gene', (60, 63))	('osteosarcoma', 'Disease', (21, 33))	('elevate', 'PosReg', (174, 181))	('TGF-beta2', 'Gene', '7042', (104, 113))	('osteosarcoma', 'Disease', 'MESH:D012516', (21, 33))	('TGF-beta3', 'Gene', '7043', (118, 127))	('downregulation', 'NegReg', (141, 155))	('MET', 'Disease', (215, 218))	('expression', 'MPA', (193, 203))	('AMF', 'Gene', (56, 59))	('reduces', 'NegReg', (64, 71))	('SNAI1', 'Gene', '6615', (159, 164))	('SNAI1', 'Gene', (159, 164))	('osteosarcoma', 'Phenotype', 'HP:0002669', (21, 33))	('PGI', 'Gene', '2821', (60, 63))	('silencing', 'Var', (43, 52))	('TGF-beta3', 'Gene', (118, 127))	('TGF-beta2', 'Gene', (104, 113))	('secretion', 'MPA', (91, 100))	('AMF', 'Gene', '2821', (56, 59))	('E-cadherin', 'Gene', (182, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('E-cadherin', 'Gene', '999', (182, 192))
231233	28556516	Thus, silencing of AMF/PGI might contribute toward the loss of malignancy in these cancers through differentiation via MET (Niinaka et al., 2010).	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('AMF', 'Gene', (19, 22))	('loss', 'NegReg', (55, 59))	('PGI', 'Gene', '2821', (23, 26))	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('malignancy', 'Disease', (63, 73))	('MET', 'MPA', (119, 122))	('AMF', 'Gene', '2821', (19, 22))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('silencing', 'Var', (6, 15))	('cancers', 'Disease', (83, 90))	('PGI', 'Gene', (23, 26))
231235	28556516	In Saos-2 osteosarcoma cells, transfection of WNT receptor low-density lipoprotein receptor-related protein 5 (LRP5) caused a marked upregulation of E-cadherin and downregulation of N-cadherin and was associated with reduced activity of the transcription factors SNAI2 and Twist (Guo et al., 2007).	('LRP5', 'Gene', (111, 115))	('osteosarcoma', 'Phenotype', 'HP:0002669', (10, 22))	('SNAI2', 'Gene', '6591', (263, 268))	('Twist', 'Gene', (273, 278))	('upregulation', 'PosReg', (133, 145))	('downregulation', 'NegReg', (164, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('LRP5', 'Gene', '4041', (111, 115))	('transfection', 'Var', (30, 42))	('osteosarcoma', 'Disease', (10, 22))	('osteosarcoma', 'Disease', 'MESH:D012516', (10, 22))	('low-density', 'Var', (59, 70))	('Twist', 'Gene', '7291', (273, 278))	('N-cadherin', 'Gene', (182, 192))	('N-cadherin', 'Gene', '1000', (182, 192))	('activity', 'MPA', (225, 233))	('SNAI2', 'Gene', (263, 268))	('reduced', 'NegReg', (217, 224))	('E-cadherin', 'Gene', (149, 159))	('E-cadherin', 'Gene', '999', (149, 159))
231246	28556516	The proapoptotic response was suppressed following vimentin knockdown or by caspase blockade.	('vimentin', 'Gene', (51, 59))	('proapoptotic response', 'MPA', (4, 25))	('suppressed', 'NegReg', (30, 40))	('knockdown', 'Var', (60, 69))	('caspase', 'Protein', (76, 83))	('vimentin', 'Gene', '7431', (51, 59))
231253	28556516	Correspondingly, biomarkers for MT have been linked with worse clinical outcome in these cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('biomarkers', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
231261	28556516	In conclusion, further studies are required to unravel the mechanisms governing MT/MET in these nonepithelial cancers and for being suitable as prognostic markers or therapeutic targets in order to improve their clinical management.	('epithelial cancers', 'Disease', 'MESH:D000077216', (99, 117))	('MT/MET', 'Var', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('epithelial cancers', 'Disease', (99, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))
231265	27831000	Among the approved inhibitors are crizotinib, erlotinib, afatinib and gefitinib, and side effects are usually mild to intense.	('erlotinib', 'Chemical', 'MESH:D000069347', (46, 55))	('gefitinib', 'Chemical', 'MESH:D000077156', (70, 79))	('crizotinib', 'Chemical', 'MESH:D000077547', (34, 44))	('erlotinib', 'Gene', (46, 55))	('crizotinib', 'Var', (34, 44))	('afatinib', 'Chemical', 'MESH:D000077716', (57, 65))
231275	27831000	Pulmonary carcinoma, mainly adenocarcinoma, has a multifactorial profile and could be related to gene mutations, mainly in epidermal growth factor receptor (EGFR) and rearrangements of the anaplastic lymphoma kinase (ALK) genes.	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('EGFR', 'Gene', '1956', (157, 161))	('Pulmonary carcinoma', 'Disease', 'MESH:D008175', (0, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (200, 208))	('adenocarcinoma', 'Disease', (28, 42))	('mutations', 'Var', (102, 111))	('Pulmonary carcinoma', 'Disease', (0, 19))	('rearrangements', 'Var', (167, 181))	('epidermal growth factor receptor', 'Gene', (123, 155))	('ALK', 'Gene', '238', (217, 220))	('epidermal growth factor receptor', 'Gene', '1956', (123, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (28, 42))	('ALK', 'Gene', (217, 220))	('EGFR', 'Gene', (157, 161))	('anaplastic lymphoma kinase', 'Gene', '238', (189, 215))	('anaplastic lymphoma kinase', 'Gene', (189, 215))	('related', 'Reg', (86, 93))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (189, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
231283	27831000	Crizotinib is a kinase inhibitor that has been shown to be effective in treating tumors involving ALK alterations, while gefitinib, erlotinib, and afatinib are applied to patients with tumors related to mutations in EGFR.	('tumors', 'Disease', (81, 87))	('erlotinib', 'Chemical', 'MESH:D000069347', (132, 141))	('tumors', 'Disease', (185, 191))	('EGFR', 'Gene', (216, 220))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('patients', 'Species', '9606', (171, 179))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('ALK', 'Gene', '238', (98, 101))	('afatinib', 'Chemical', 'MESH:D000077716', (147, 155))	('ALK', 'Gene', (98, 101))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('EGFR', 'Gene', '1956', (216, 220))	('mutations', 'Var', (203, 212))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('gefitinib', 'Chemical', 'MESH:D000077156', (121, 130))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('rat', 'Species', '10116', (106, 109))
231318	27831000	Binding of PD-L1 or PD-L2 to PD-1 inhibits T-cell receptor signaling and down-regulates the expression of anti-apoptotic molecules.	('PD-1', 'Gene', '5133', (29, 33))	('inhibits', 'NegReg', (34, 42))	('PD-L2', 'Var', (20, 25))	('PD-L1', 'Var', (11, 16))	('down-regulates', 'NegReg', (73, 87))	('expression of anti-apoptotic molecules', 'MPA', (92, 130))	('PD-1', 'Gene', (29, 33))	('Binding', 'Interaction', (0, 7))	('T-cell receptor signaling', 'MPA', (43, 68))
231335	27831000	The inhibitors of ALK are able to block the ALK kinase activity and promote tumor reduction.	('ALK', 'Gene', '238', (18, 21))	('block', 'NegReg', (34, 39))	('activity', 'MPA', (55, 63))	('ALK', 'Gene', (44, 47))	('promote', 'PosReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('ALK', 'Gene', '238', (44, 47))	('ALK', 'Gene', (18, 21))	('inhibitors', 'Var', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
231336	27831000	About five percent of NSCLC have a mutation in ALK gene that produces an abnormal protein causing tumor growth.	('abnormal protein', 'MPA', (73, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('ALK', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ALK', 'Gene', '238', (47, 50))	('NSCLC', 'Disease', (22, 27))	('mutation', 'Var', (35, 43))	('SCLC', 'Phenotype', 'HP:0030357', (23, 27))	('tumor', 'Disease', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))
231338	27831000	This biological molecule reduced the tumor size by about 50% to 60% of patients with alterations in the ALK protein, although most of them had been previously treated with chemotherapy.	('reduced', 'NegReg', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('ALK', 'Gene', '238', (104, 107))	('patients', 'Species', '9606', (71, 79))	('rat', 'Species', '10116', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('ALK', 'Gene', (104, 107))	('alterations', 'Var', (85, 96))
231348	27831000	It is used primarily for advanced lung cancer, and may also be used in patients with mutations in the EGFR gene, frequent in 10 to 15% of NSCLC.	('NSCLC', 'Disease', (138, 143))	('lung cancer', 'Disease', (34, 45))	('patients', 'Species', '9606', (71, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('SCLC', 'Phenotype', 'HP:0030357', (139, 143))	('mutations', 'Var', (85, 94))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
231354	27831000	However, the treatment is associated with the detection of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations by an FDA-approved test.	('substitution mutations', 'Var', (101, 123))	('EGFR', 'Gene', (59, 63))	('EGFR', 'Gene', '1956', (59, 63))	('deletions', 'Var', (72, 81))	('exon', 'Var', (64, 68))	('L858R', 'Mutation', 'rs121434568', (94, 99))	('L858R', 'Gene', (94, 99))
231383	27831000	Changes in gene c-MET and MET and HGF aberrations are involved in resistance to inhibitors of the EGFR in NSCLC patients with EGFR mutations.	('EGFR', 'Gene', (98, 102))	('MET', 'Gene', (26, 29))	('mutations', 'Var', (131, 140))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('EGFR', 'Gene', (126, 130))	('HGF', 'Gene', (34, 37))	('rat', 'Species', '10116', (42, 45))	('SCLC', 'Phenotype', 'HP:0030357', (107, 111))	('resistance to inhibitors', 'MPA', (66, 90))	('patients', 'Species', '9606', (112, 120))	('HGF', 'Gene', '3082', (34, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('EGFR', 'Gene', '1956', (98, 102))	('aberrations', 'Var', (38, 49))	('NSCLC', 'Disease', (106, 111))	('involved', 'Reg', (54, 62))	('EGFR', 'Gene', '1956', (126, 130))
231388	27831000	Blocking of RANKL has been demonstrated to prevent tumor-induced osteolysis and skeletal complications.	('skeletal complications', 'CPA', (80, 102))	('RANKL', 'Gene', (12, 17))	('RANKL', 'Gene', '8600', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('skeletal complications', 'Phenotype', 'HP:0000924', (80, 102))	('osteolysis', 'Disease', 'MESH:D010014', (65, 75))	('Blocking', 'Var', (0, 8))	('tumor', 'Disease', (51, 56))	('osteolysis', 'Phenotype', 'HP:0002797', (65, 75))	('rat', 'Species', '10116', (34, 37))	('osteolysis', 'Disease', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
231393	27831000	In an exploratory study, denosumab was associated with increased overall survival compared with ZA, in patients with metastatic lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('increased', 'PosReg', (55, 64))	('ZA', 'Chemical', 'MESH:D000077211', (96, 98))	('denosumab', 'Chemical', 'MESH:D000069448', (25, 34))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('rat', 'Species', '10116', (11, 14))	('denosumab', 'Var', (25, 34))	('patients', 'Species', '9606', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('overall survival', 'MPA', (65, 81))
231396	27831000	Antibodies to CTLA-4 inhibit critical negative T-cell regulators, since they inhibit the costimulatory signaling for T-cells.	('Antibodies', 'Var', (0, 10))	('CTLA-4', 'Gene', (14, 20))	('inhibit', 'NegReg', (77, 84))	('costimulatory signaling for T-cells', 'MPA', (89, 124))	('inhibit', 'NegReg', (21, 28))	('CTLA-4', 'Gene', '1493', (14, 20))
231408	27831000	They act against tumors in people with hereditary BRCA1 or BRCA2 (breast cancer 1, early onset) mutations.	('BRCA2', 'Gene', '675', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('BRCA1', 'Gene', (50, 55))	('people', 'Species', '9606', (27, 33))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('BRCA2', 'Gene', (59, 64))	('breast cancer', 'Disease', (66, 79))	('BRCA1', 'Gene', '672', (50, 55))	('act', 'Reg', (5, 8))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (96, 105))
231481	27262580	Impaired fitness and limited activities of daily living were associated with a suboptimal outcome on the physical component summary of the SF-36; fitness impairment was also associated with scoring < 40 on the role physical subscale of the SF-36.	('activities of daily living', 'Phenotype', 'HP:0031058', (29, 55))	('scoring < 40', 'Var', (190, 202))	('fitness impairment', 'Disease', 'MESH:D004827', (146, 164))	('fitness impairment', 'Disease', (146, 164))	('Impaired fitness', 'Disease', 'MESH:D004827', (0, 16))	('Impaired fitness', 'Disease', (0, 16))	('limited activities of daily living', 'Phenotype', 'HP:0031058', (21, 55))
231607	26044957	We recently demonstrated that global downregulation of miRNAs after deleting dicer can promote development of distant metastases in a mouse model of primary soft tissue sarcoma (STS).	('downregulation', 'NegReg', (37, 51))	('deleting', 'Var', (68, 76))	('metastases', 'Disease', (118, 128))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (157, 176))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('STS', 'Phenotype', 'HP:0030448', (178, 181))	('dicer', 'Gene', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('miR', 'Gene', '735281', (55, 58))	('miR', 'Gene', (55, 58))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (157, 176))	('promote', 'PosReg', (87, 94))	('soft tissue sarcoma', 'Disease', (157, 176))	('mouse', 'Species', '10090', (134, 139))
231612	26044957	In addition, orthotopic transplantation of a sarcoma cell line stably expressing miR-16 into the muscle of immunocompromised mice revealed that restoration of miR-16 can significantly decrease lung metastasis in vivo.	('decrease', 'NegReg', (184, 192))	('decrease lung', 'Phenotype', 'HP:0002089', (184, 197))	('sarcoma', 'Disease', (45, 52))	('lung metastasis', 'CPA', (193, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('miR-16', 'Gene', (159, 165))	('mice', 'Species', '10090', (125, 129))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('restoration', 'Var', (144, 155))	('miR-16', 'Gene', (81, 87))
231614	26044957	However, the loss-of-function experiments in autochthonous tumors indicate that loss of miR-16 is not sufficient to promote metastasis in vivo.	('loss-of-function', 'NegReg', (13, 29))	('metastasis', 'CPA', (124, 134))	('loss', 'Var', (80, 84))	('promote', 'PosReg', (116, 123))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('miR-16', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
231627	26044957	Deregulation of miRNA expression is often associated with a variety of disorders, including human malignancy.	('Deregulation', 'Var', (0, 12))	('associated', 'Reg', (42, 52))	('malignancy', 'Disease', 'MESH:D009369', (98, 108))	('human', 'Species', '9606', (92, 97))	('miR', 'Gene', '735281', (16, 19))	('miR', 'Gene', (16, 19))	('malignancy', 'Disease', (98, 108))
231628	26044957	To study sarcoma metastasis, our lab has developed a genetically engineered mouse model of STS with conditional mutations in Kras and p53 (LSL-KrasG12D; p53flox/flox; known as 'KP' mice).	('p53', 'Gene', '22060', (153, 156))	('mice', 'Species', '10090', (181, 185))	('Kras', 'Gene', (143, 147))	('p53', 'Gene', '22060', (134, 137))	('Kras', 'Gene', '16653', (143, 147))	('sarcoma metastasis', 'Disease', 'MESH:D009362', (9, 27))	('STS', 'Phenotype', 'HP:0030448', (91, 94))	('sarcoma metastasis', 'Disease', (9, 27))	('mouse', 'Species', '10090', (76, 81))	('mutations', 'Var', (112, 121))	('p53', 'Gene', (153, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Kras', 'Gene', (125, 129))	('p53', 'Gene', (134, 137))	('Kras', 'Gene', '16653', (125, 129))
231641	26044957	Notably, however, there was no change in the rate of lung metastasis when miR-16 was deleted in autochthonous tumors (a tumor that forms where it is found rather than being transplanted from elsewhere) in a mouse model of primary STS previously developed by the authors in which sarcomas develop in a spatially and temporally restricted manner and can be surgically resected so that the true metastatic potential of the primary tumor can be determined.	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('tumor', 'Phenotype', 'HP:0002664', (428, 433))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mouse', 'Species', '10090', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Disease', (428, 433))	('deleted', 'Var', (85, 92))	('miR-16', 'Gene', (74, 80))	('sarcomas', 'Disease', 'MESH:D012509', (279, 287))	('sarcomas', 'Phenotype', 'HP:0100242', (279, 287))	('tumor', 'Disease', 'MESH:D009369', (428, 433))	('sarcomas', 'Disease', (279, 287))	('tumor', 'Disease', (110, 115))	('STS', 'Phenotype', 'HP:0030448', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
231644	26044957	The discordant results reported here between the effects of miR-16 overexpression in an orthotopic transplant model in immunocompromised mice and miR-16 deletion in a primary tumor model in immunocompetent mice demonstrate the importance of utilizing complementary gain-of-function and loss-of-function approaches and primary tumor model systems for the study of metastasis.	('tumor', 'Disease', (175, 180))	('deletion', 'Var', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('mice', 'Species', '10090', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('loss-of-function', 'NegReg', (286, 302))	('miR-16', 'Gene', (146, 152))	('gain-of-function', 'PosReg', (265, 281))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (326, 331))	('miR-16', 'Gene', (60, 66))	('mice', 'Species', '10090', (137, 141))
231660	26044957	Interestingly, despite miR-103 being the most downregulated miRNA in both human and mouse metastatic sarcomas, restoration of miR-103 had no effect on either migration or invasion.	('human', 'Species', '9606', (74, 79))	('miR', 'Gene', '735281', (23, 26))	('miR', 'Gene', (23, 26))	('miR', 'Gene', (60, 63))	('sarcomas', 'Disease', 'MESH:D012509', (101, 109))	('miR', 'Gene', '735281', (126, 129))	('miR', 'Gene', (126, 129))	('invasion', 'CPA', (171, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('restoration', 'Var', (111, 122))	('mouse', 'Species', '10090', (84, 89))	('downregulated', 'NegReg', (46, 59))	('sarcomas', 'Disease', (101, 109))	('migration', 'CPA', (158, 167))	('miR', 'Gene', '735281', (60, 63))
231668	26044957	For example, 9/10 mice developed lung metastasis in the vector control group, but only 4/10 mice developed lung metastasis from the sarcoma cells overexpressing miR-16.	('miR-16', 'Var', (161, 167))	('lung metastasis', 'CPA', (107, 122))	('sarcoma', 'Disease', (132, 139))	('lung metastasis', 'CPA', (33, 48))	('mice', 'Species', '10090', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('mice', 'Species', '10090', (92, 96))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
231673	26044957	miR-16flox/flox mice) so that Cre recombinase can delete miR-16 (Fig.	('delete', 'Var', (50, 56))	('mice', 'Species', '10090', (16, 20))	('miR-16', 'Gene', (57, 63))
231674	26044957	We generated primary sarcomas by injecting an adenovirus expressing Cre recombinase (Ad-Cre) into KP mice (miR-16 WT) and into KP miR-16flox/flox mice to generate sarcomas with deletion of miR-16 (miR-16 F/F) (Fig.	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('sarcomas', 'Disease', (21, 29))	('deletion', 'Var', (177, 185))	('miR-16', 'Gene', (189, 195))	('sarcomas', 'Disease', 'MESH:D012509', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('primary sarcomas', 'Disease', 'MESH:D012509', (13, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (163, 171))	('mice', 'Species', '10090', (101, 105))	('mice', 'Species', '10090', (146, 150))	('primary sarcomas', 'Disease', (13, 29))	('sarcomas', 'Disease', (163, 171))	('sarcomas', 'Disease', 'MESH:D012509', (21, 29))
231675	26044957	After Ad-Cre injection, KP mice with miR-16 deletion developed primary sarcomas with similar kinetics to the mice with wild-type miR-16.	('primary sarcomas', 'Disease', (63, 79))	('mice', 'Species', '10090', (27, 31))	('deletion', 'Var', (44, 52))	('miR-16', 'Gene', (37, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('mice', 'Species', '10090', (109, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('primary sarcomas', 'Disease', 'MESH:D012509', (63, 79))	('developed', 'Reg', (53, 62))
231676	26044957	PCR analysis on genomic DNA from primary cell lines generated from sarcomas with or without miR-16 deletion demonstrated efficient recombination of the miR-16 allele in KP sarcomas (Fig.	('recombination', 'MPA', (131, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (172, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('KP sarcomas', 'Disease', (169, 180))	('sarcomas', 'Disease', (172, 180))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('miR-16', 'Gene', (152, 158))	('deletion', 'Var', (99, 107))	('KP sarcomas', 'Disease', 'MESH:D012509', (169, 180))	('miR-16', 'Gene', (92, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('sarcomas', 'Disease', (67, 75))	('sarcomas', 'Disease', 'MESH:D012509', (172, 180))
231677	26044957	Because miR-16 has been shown to suppress cell proliferation in various tissues, we next determined whether deletion of miR-16 had any effect on proliferation of sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('sarcoma', 'Disease', (162, 169))	('cell proliferation in', 'CPA', (42, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('deletion', 'Var', (108, 116))	('miR-16', 'Gene', (120, 126))
231678	26044957	Of note, immunostaining of sarcomas with an antibody directed against Ki-67, which is a marker of cellular proliferation because it is expressed during interphase (G1, S, G2) and mitosis (M), but not in resting G0 cells, showed no difference between the two groups suggesting that miR-16 deletion had no significant impact on proliferation of sarcoma cells in vivo (Fig.	('sarcoma', 'Disease', (27, 34))	('mitosis', 'Disease', 'None', (179, 186))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcomas', 'Disease', (27, 35))	('Ki-67', 'Gene', (70, 75))	('deletion', 'Var', (288, 296))	('sarcoma', 'Disease', 'MESH:D012509', (343, 350))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))	('sarcoma', 'Disease', (343, 350))	('Ki-67', 'Gene', '17345', (70, 75))	('interphase (G1, S, G2', 'Gene', '68197', (152, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (343, 350))	('mitosis', 'Disease', (179, 186))	('miR-16', 'Gene', (281, 287))
231680	26044957	We did not observe a significant change in tumor onset or tumor growth kinetics after deletion of miR-16 in KP tumors (Fig.	('KP tumors', 'Disease', 'MESH:D009369', (108, 117))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('KP tumors', 'Disease', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (43, 48))	('deletion', 'Var', (86, 94))	('miR-16', 'Gene', (98, 104))
231683	26044957	To our surprise, and in contrast to our findings in the orthotopic metastasis assay, we did not observe any change in the rate of lung metastases in the sarcomas with or without deletion of miR-16 (Fig.	('lung metastases in the sarcomas', 'Disease', 'MESH:D009362', (130, 161))	('lung metastases in the sarcomas', 'Disease', (130, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('deletion', 'Var', (178, 186))	('miR-16', 'Gene', (190, 196))
231686	26044957	Deregulation of microRNA expression has been reported in a variety of human diseases, especially cancer.	('cancer', 'Disease', (97, 103))	('reported', 'Reg', (45, 53))	('Deregulation', 'Var', (0, 12))	('human', 'Species', '9606', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('microRNA', 'Protein', (16, 24))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
231691	26044957	We further demonstrate that overexpression of miR-16 decreases metastasis in an orthotopic mouse model in immunocompromised mice, but deletion of miR-16 in primary sarcomas fails to increase metastasis.	('metastasis', 'CPA', (63, 73))	('primary sarcomas', 'Disease', 'MESH:D012509', (156, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('primary sarcomas', 'Disease', (156, 172))	('mice', 'Species', '10090', (124, 128))	('deletion', 'Var', (134, 142))	('miR-16', 'Gene', (146, 152))	('miR-16', 'Gene', (46, 52))	('decreases', 'NegReg', (53, 62))	('mouse', 'Species', '10090', (91, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
231699	26044957	Using novel genetically engineered mice to either delete or overexpress miR-182 in primary sarcomas in vivo, we showed that deletion of miR-182 in primary sarcomas significantly decreased the rate of lung metastasis after amputation of the tumor-bearing limb, whereas overexpression of miR-182 significantly increased the rate of lung metastasis.	('decreased', 'NegReg', (178, 187))	('miR-182', 'Gene', (286, 293))	('miR-182', 'Gene', '387177', (136, 143))	('tumor', 'Disease', (240, 245))	('miR-182', 'Gene', '387177', (72, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('primary sarcomas', 'Disease', (147, 163))	('deletion', 'Var', (124, 132))	('primary sarcomas', 'Disease', (83, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('miR-182', 'Gene', '387177', (286, 293))	('mice', 'Species', '10090', (35, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('miR-182', 'Gene', (136, 143))	('miR-182', 'Gene', (72, 79))	('primary sarcomas', 'Disease', 'MESH:D012509', (147, 163))	('lung metastasis after amputation', 'CPA', (200, 232))	('primary sarcomas', 'Disease', 'MESH:D012509', (83, 99))
231704	26044957	Using miR-16flox/flox mice, we were able to delete two alleles of miR-16 during sarcomagenesis and then follow the mice for the development of lung metastases.	('follow', 'Reg', (104, 110))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('miR-16', 'Gene', (66, 72))	('sarcoma', 'Disease', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('delete', 'Var', (44, 50))	('mice', 'Species', '10090', (115, 119))	('lung metastases', 'Disease', 'MESH:D009362', (143, 158))	('mice', 'Species', '10090', (22, 26))	('lung metastases', 'Disease', (143, 158))
231705	26044957	First, the primary tumor model system examined miR-16 deletion.	('deletion', 'Var', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('miR-16', 'Gene', (47, 53))
231706	26044957	However, it does not rule out the possibility that, in concert with downregulation of other miRNAs, loss of miR-16 could contribute to metastasis.	('metastasis', 'CPA', (135, 145))	('loss', 'Var', (100, 104))	('miR', 'Gene', '735281', (92, 95))	('miR', 'Gene', (92, 95))	('miR', 'Gene', '735281', (108, 111))	('contribute', 'Reg', (121, 131))	('miR', 'Gene', (108, 111))
231707	26044957	Alternatively, the results from the primary tumor experiment might simply reflect the fact that there was an unexpectedly high rate of lung metastasis in the control KP mice, which could be a consequence of the mixed genetic background of the miR-16flox/flox mice.	('lung metastasis', 'CPA', (135, 150))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mice', 'Species', '10090', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mice', 'Species', '10090', (259, 263))	('tumor', 'Disease', (44, 49))	('miR-16flox/flox', 'Var', (243, 258))
231709	26044957	To search for potential targets of miR-16 that can regulate metastasis, we performed a liquid chromatography/mass spectrometry (LC/MS) proteomic screen of cell lines derived from primary sarcomas with (n=3) or without (n=3) miR-16 deletion, as previously described.	('deletion', 'Var', (231, 239))	('miR-16', 'Gene', (224, 230))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('primary sarcomas', 'Disease', 'MESH:D012509', (179, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('primary sarcomas', 'Disease', (179, 195))
231710	26044957	The proteomic screen revealed that ~300 proteins were differentially regulated at least 2-fold between the miR-16-expressing and miR-16-deleted sarcoma cells.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('miR-16-deleted', 'Var', (129, 143))	('miR-16-expressing', 'Var', (107, 124))	('proteins', 'Protein', (40, 48))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))
231722	26044957	However, deletion of miR-16 failed to promote metastasis in a primary tumor model system, which suggests that loss of miR-16 is not sufficient to promote metastasis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('loss', 'Var', (110, 114))	('deletion', 'Var', (9, 17))	('miR-16', 'Gene', (21, 27))	('tumor', 'Disease', (70, 75))	('metastasis', 'CPA', (154, 164))	('miR-16', 'Gene', (118, 124))	('promote', 'PosReg', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
231849	23671375	Trauma, cryptorchidism, and exogenous maternal estrogen (in utero) have all been associated with its development.	('exogenous maternal', 'Var', (28, 46))	('Trauma', 'Disease', (0, 6))	('cryptorchidism', 'Disease', (8, 22))	('cryptorchidism', 'Phenotype', 'HP:0000028', (8, 22))	('Trauma', 'Disease', 'MESH:D014947', (0, 6))	('associated', 'Reg', (81, 91))
231921	32659967	Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC).	('MSH2', 'Gene', '4436', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('Sarcomas', 'Disease', (70, 78))	('epithelial tumors', 'Disease', (244, 261))	('epithelial tumors', 'Disease', 'MESH:D002277', (244, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('carcinomas', 'Phenotype', 'HP:0030731', (309, 319))	('Sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('cancer', 'Disease', (183, 189))	('endometrial carcinomas', 'Disease', (297, 319))	('Sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Lynch syndrome', 'Disease', (147, 161))	('colorectal', 'Disease', (276, 286))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (51, 65))	('Variants', 'Var', (138, 146))	('Sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (297, 319))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('MSH2', 'Gene', (113, 117))	('Lynch syndrome', 'Disease', 'MESH:D003123', (147, 161))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('Patients', 'Species', '9606', (37, 45))	('Lynch Syndrome', 'Disease', (51, 65))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (297, 319))
231926	32659967	Additionally, we reviewed 43 previous reports of sarcomas in patients with LS, which revealed a high frequency (58%) of MSH2 alterations.	('MSH2', 'Gene', (120, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('alterations', 'Var', (125, 136))	('sarcomas', 'Disease', (49, 57))	('patients', 'Species', '9606', (61, 69))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))
231927	32659967	In summary, sarcomas represent a rare clinical manifestation in patients with LS, especially in MSH2 carriers, and the analysis of tumor biological characteristics can be useful for definition of tumor etiology and novel therapeutic options.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (196, 201))	('patients', 'Species', '9606', (64, 72))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('MSH2', 'Gene', (96, 100))	('carriers', 'Var', (101, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('sarcomas', 'Disease', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
231928	32659967	Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, as well as rare deletions in EPCAM that disrupt MSH2 expression.	('MLH1', 'Gene', (135, 139))	('mutations', 'Var', (86, 95))	('hereditary cancer predisposition syndrome', 'Disease', 'MESH:D061325', (25, 66))	('disrupt', 'NegReg', (203, 210))	('deletions', 'Var', (179, 188))	('EPCAM', 'Gene', (192, 197))	('expression', 'MPA', (216, 226))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('EPCAM', 'Gene', '4072', (192, 197))	('MSH2', 'Gene', (141, 145))	('Lynch syndrome', 'Disease', (0, 14))	('caused', 'Reg', (67, 73))	('hereditary cancer predisposition syndrome', 'Disease', (25, 66))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('MSH2', 'Gene', (211, 215))	('MSH6', 'Gene', (147, 151))	('MLH1', 'Gene', '4292', (135, 139))	('PMS2', 'Gene', (157, 161))
231932	32659967	Additionally, in a recent study involving 1162 patients with sarcoma who were unselected with regard to family history of cancer, 20% of patients had pathogenic (P) or likely pathogenic (LP) variants in 72 genes associated with the increased risk of cancer, including 11 patients with P or LP variants in MMR genes.	('LP', 'Chemical', '-', (290, 292))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('associated', 'Reg', (212, 222))	('MMR', 'Gene', (305, 308))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('patients', 'Species', '9606', (137, 145))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('variants', 'Var', (191, 199))	('patients', 'Species', '9606', (271, 279))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('sarcoma', 'Disease', (61, 68))	('LP', 'Chemical', '-', (187, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
231948	32659967	Five patients had been confirmed through previous genetic testing to be carriers of germline pathogenic (P) or likely pathogenic (LP) variants in MMR genes (three in MSH2 and two in MLH1), and two of these patients had the MTS phenotype.	('MTS', 'Disease', (223, 226))	('variants', 'Var', (134, 142))	('patients', 'Species', '9606', (5, 13))	('pathogenic', 'Reg', (118, 128))	('pathogenic', 'Reg', (93, 103))	('MMR', 'Gene', (146, 149))	('MLH1', 'Gene', '4292', (182, 186))	('MLH1', 'Gene', (182, 186))	('patients', 'Species', '9606', (206, 214))	('LP', 'Chemical', '-', (130, 132))
231952	32659967	Case SLS26 was a carrier of the MSH2 pathogenic variant and presented two primary sarcomas:a liposarcoma at 18 years of age and an osteosarcoma at 20 years of age.	('liposarcoma', 'Disease', 'MESH:D008080', (93, 104))	('variant', 'Var', (48, 55))	('liposarcoma', 'Phenotype', 'HP:0012034', (93, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (131, 143))	('osteosarcoma', 'Disease', (131, 143))	('sarcomas', 'Disease', 'MESH:D012509', (82, 90))	('osteosarcoma', 'Disease', 'MESH:D012516', (131, 143))	('MSH2', 'Gene', (32, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('liposarcoma', 'Disease', (93, 104))	('sarcomas', 'Disease', (82, 90))
231955	32659967	We performed a germline multigene panel testing in patient SLS6 and we identified a variant of unknown significance (VUS) in the TP53 gene (p.Asp49His).	('p.Asp49His', 'Var', (140, 150))	('TP53', 'Gene', '7157', (129, 133))	('patient', 'Species', '9606', (51, 58))	('p.Asp49His', 'Mutation', 'rs587780728', (140, 150))	('TP53', 'Gene', (129, 133))
231957	32659967	Although additional germline genetic testing was not done in patient SLS23, the CRC harbored a somatic mutation in BRAF (p.Val600Glu), which is usually associated with somatic MLH1 promoter methylation and the sporadic CRC pathway.	('BRAF', 'Gene', '673', (115, 119))	('patient', 'Species', '9606', (61, 68))	('BRAF', 'Gene', (115, 119))	('p.Val600Glu', 'Mutation', 'rs113488022', (121, 132))	('CRC pathway', 'Pathway', (219, 230))	('p.Val600Glu', 'Var', (121, 132))	('MLH1', 'Gene', '4292', (176, 180))	('MLH1', 'Gene', (176, 180))
231960	32659967	We detected a total of 26 rare variants, including two pathogenic (P) and likely pathogenic (LP) loss of function variants in RAD51C and FANCE in case SLS19 (Table 1) and 24 VUS) in 11 patients (Table S1).	('pathogenic', 'Reg', (55, 65))	('variants', 'Var', (114, 122))	('RAD51C', 'Gene', '5889', (126, 132))	('patients', 'Species', '9606', (185, 193))	('LP', 'Chemical', '-', (93, 95))	('loss of function', 'NegReg', (97, 113))	('RAD51C', 'Gene', (126, 132))	('FANCE', 'Gene', (137, 142))	('FANCE', 'Gene', '2178', (137, 142))
231962	32659967	One of the identified patients (SLS1) had a probably pathogenic germline variant in MSH2 (c.1661+1G>A).	('c.1661+1G>A', 'Mutation', 'rs267607969', (90, 101))	('c.1661+1G>A', 'Var', (90, 101))	('patients', 'Species', '9606', (22, 30))	('pathogenic', 'Reg', (53, 63))	('MSH2', 'Gene', (84, 88))
231963	32659967	We investigated the relation of the patient's sarcoma diagnosis with the germline MSH2 variant through IHC and molecular analysis of the tumor sample.	('patient', 'Species', '9606', (36, 43))	('MSH2', 'Gene', (82, 86))	('tumor', 'Disease', (137, 142))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('sarcoma', 'Disease', (46, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('variant', 'Var', (87, 94))
231965	32659967	We also sought to confirm the pathogenicity of the LP splice site variant in MSH2 identified in this patient, as no confirmatory aberrant transcript has been described in the literature.	('LP splice site', 'Var', (51, 65))	('patient', 'Species', '9606', (101, 108))	('LP', 'Chemical', '-', (51, 53))	('MSH2', 'Gene', (77, 81))
231967	32659967	Sanger sequencing of RT-PCR products revealed an aberrant transcript involving the complete skipping of exon 10 in the tumor and normal tissues (Figure 1C,D), which resulted in a premature stop codon at codon 507 (p.Gly504Alafs*3).	('tumor', 'Disease', (119, 124))	('p.Gly504Alafs*3', 'FRAMESHIFT', 'None', (214, 229))	('p.Gly504Alafs*3', 'Var', (214, 229))	('skipping', 'NegReg', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('exon', 'Gene', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
231969	32659967	Additionally, Sanger sequencing of the tumor and blood DNA revealed significant reduction of the normal allele peak in the tumor, indicating that the second MSH2 inactivation event probably occurred due to deletion of the normal allele, causing loss of heterozygosity (LOH; Figure S2).	('MSH2', 'Gene', (157, 161))	('tumor', 'Disease', (123, 128))	('reduction', 'NegReg', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('inactivation', 'NegReg', (162, 174))	('loss', 'NegReg', (245, 249))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('deletion', 'Var', (206, 214))	('heterozygosity', 'MPA', (253, 267))	('tumor', 'Disease', (39, 44))	('normal allele peak in', 'MPA', (97, 118))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
231973	32659967	Germline mutations in the MSH2 gene (25 patients) were described more frequently than those in other MMR genes (MLH1 in 12 patients, MSH6 in 5 patients and PMS2 in 1 patient).	('Germline mutations', 'Var', (0, 18))	('patient', 'Species', '9606', (40, 47))	('MSH2', 'Gene', (26, 30))	('patient', 'Species', '9606', (123, 130))	('patient', 'Species', '9606', (143, 150))	('MLH1', 'Gene', '4292', (112, 116))	('patients', 'Species', '9606', (40, 48))	('MLH1', 'Gene', (112, 116))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (143, 151))	('patient', 'Species', '9606', (166, 173))
231974	32659967	Remarkably, the concordance of germline pathogenic variants and loss of protein expression or presence of MSI was higher for the MSH2 gene, since 87% (21/24) of sarcomas from MSH2 carriers harbored one of these hallmarks, in contrast to 75% for MLH1 (6/8) and MSH6 (3/4) and 0% for PSM2 (0/1) (Table 3).	('MLH1', 'Gene', '4292', (245, 249))	('MLH1', 'Gene', (245, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('MSH2', 'Gene', (175, 179))	('sarcomas', 'Disease', (161, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('protein expression', 'MPA', (72, 90))	('variants', 'Var', (51, 59))	('loss', 'NegReg', (64, 68))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('MSH2', 'Gene', (129, 133))
231976	32659967	These tumors have been described in families affected by LS and germline variants in MMR genes have also been identified in unselected sarcoma cases, however no definitive association or defined risk related to this syndrome has been established.	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('identified', 'Reg', (110, 120))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('MMR', 'Gene', (85, 88))	('sarcoma', 'Disease', (135, 142))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('germline variants', 'Var', (64, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
231980	32659967	Clinical and pathological or molecular data from reports identified in our literature review suggest that the development of sarcoma is more often associated with MSH2 pathogenic variants than with other LS genes, as 25 out of 43 (58.1%) cases subjected to genetic testing harbored mutations in this gene.	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('variants', 'Var', (179, 187))	('associated', 'Reg', (147, 157))	('sarcoma', 'Disease', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('MSH2', 'Gene', (163, 167))	('mutations', 'Var', (282, 291))	('harbored', 'Reg', (273, 281))
231981	32659967	In our cohort, three of the five patients with LS harbored MSH2 pathogenic variants.	('patients', 'Species', '9606', (33, 41))	('MSH2', 'Gene', (59, 63))	('pathogenic', 'Reg', (64, 74))	('variants', 'Var', (75, 83))	('harbored', 'Reg', (50, 58))
231985	32659967	described a patient with MTS and pleomorphic liposarcoma presenting loss of MSH2/MSH6 expression and a confirmed MSH2 germline pathogenic variant.	('MSH2/MSH6', 'Gene', (76, 85))	('liposarcoma', 'Phenotype', 'HP:0012034', (45, 56))	('variant', 'Var', (138, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('pleomorphic liposarcoma', 'Disease', (33, 56))	('expression', 'MPA', (86, 96))	('loss', 'NegReg', (68, 72))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (33, 56))	('patient', 'Species', '9606', (12, 19))	('MTS', 'Disease', (25, 28))	('MSH2', 'Gene', (113, 117))
231986	32659967	described a patient with an MSI-H soft-tissue sarcoma and sebaceous adenoma who was a carrier of the MSH2 pathogenic variant.	('sebaceous adenoma', 'Phenotype', 'HP:0009720', (58, 75))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('adenoma', 'Disease', (68, 75))	('sarcoma', 'Disease', (46, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('MSH2', 'Gene', (101, 105))	('patient', 'Species', '9606', (12, 19))	('variant', 'Var', (117, 124))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (34, 53))	('adenoma', 'Disease', 'MESH:D000236', (68, 75))
231988	32659967	In this sense, a recent publication based on The Cancer Genome Atlas data for cancer-predisposing variants described the detection of two MSH2 carriers among 255 unselected patients with sarcoma and the classification of MSH2 as potentially associated with sarcoma risk according to variant burden analysis (odds ratio, 9.9; p = 0.02; false discovery rate, 0.09).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('sarcoma', 'Disease', (257, 264))	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('patients', 'Species', '9606', (173, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('associated', 'Reg', (241, 251))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('sarcoma', 'Disease', (187, 194))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('MSH2', 'Gene', (138, 142))	('Cancer', 'Disease', (49, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('sarcoma', 'Disease', 'MESH:D012509', (257, 264))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('variants', 'Var', (98, 106))
231993	32659967	investigated germline causes of 1244 patients with osteosarcoma and identified more germline MSH2 pathogenic variants in cases than in the control cohorts (p < 0.05).	('osteosarcoma', 'Phenotype', 'HP:0002669', (51, 63))	('patients', 'Species', '9606', (37, 45))	('osteosarcoma', 'Disease', (51, 63))	('osteosarcoma', 'Disease', 'MESH:D012516', (51, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('variants', 'Var', (109, 117))	('MSH2', 'Gene', (93, 97))
231996	32659967	This patient was diagnosed with a gastrointestinal stromal tumor (GIST) and rectal adenocarcinoma and carried germline P/LP variants in FANCE and RAD51C.	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (34, 64))	('patient', 'Species', '9606', (5, 12))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('adenocarcinoma', 'Disease', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('RAD51C', 'Gene', (146, 152))	('variants', 'Var', (124, 132))	('RAD51C', 'Gene', '5889', (146, 152))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (34, 64))	('FANCE', 'Gene', (136, 141))	('LP', 'Chemical', '-', (121, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('gastrointestinal stromal tumor', 'Disease', (34, 64))	('FANCE', 'Gene', '2178', (136, 141))
232005	32659967	Sarcoma development has been linked to germline and somatic mutations in MMR genes, not only in patients with clinical phenotype of LS, but also in unselected cohorts of patients.	('patients', 'Species', '9606', (170, 178))	('MMR', 'Gene', (73, 76))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('Sarcoma', 'Disease', (0, 7))	('linked', 'Reg', (29, 35))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('patients', 'Species', '9606', (96, 104))	('germline', 'Var', (39, 47))
232006	32659967	In this sense, MSI and MMR IHC analyses are valuable tools for the identification of tumors originating from MMR pathway defects (both somatic and constitutive), and may aid the detection of undiagnosed LS in patients with unexpected phenotypes.	('defects', 'Var', (121, 128))	('MMR', 'Gene', (109, 112))	('patients', 'Species', '9606', (209, 217))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
232010	32659967	The overall rate of MSI-H or indeterminate MSI in soft-tissue sarcomas was 5.7% (45/785 patients), and 2 of these 45 patients had LS due to MSH2 pathogenic variants.	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (50, 70))	('sarcomas', 'Disease', 'MESH:D012509', (62, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('MSI-H', 'Var', (20, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('MSH2', 'Gene', (140, 144))	('patients', 'Species', '9606', (88, 96))	('variants', 'Var', (156, 164))	('sarcomas', 'Disease', (62, 70))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('patients', 'Species', '9606', (117, 125))
232012	32659967	Somatic mutation analysis identified MMR mutations in all seven patients (four in MSH2 or EPCAM, two in PMS2, and one in MSH6); germline sequencing was performed for three patients and confirmed LS in one patient (a carrier of a MSH2 germline pathogenic variant).	('mutations', 'Var', (41, 50))	('patient', 'Species', '9606', (64, 71))	('EPCAM', 'Gene', '4072', (90, 95))	('patients', 'Species', '9606', (64, 72))	('patient', 'Species', '9606', (172, 179))	('MMR', 'Gene', (37, 40))	('patients', 'Species', '9606', (172, 180))	('patient', 'Species', '9606', (205, 212))	('EPCAM', 'Gene', (90, 95))
232015	32659967	An incidental finding of a germline pathogenic variant in MLH1, identified through whole-exome sequencing, led to the administration of anti-PD-1 antibody treatment (nivolumab), which resulted in a rapid major response.	('variant', 'Var', (47, 54))	('PD-1', 'Gene', '6139', (141, 145))	('PD-1', 'Gene', (141, 145))	('MLH1', 'Gene', '4292', (58, 62))	('pathogenic', 'Reg', (36, 46))	('MLH1', 'Gene', (58, 62))
232027	32659967	Patients who had not undergone previous genetic testing were evaluated to detect germline variants in cancer-predisposing genes.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('germline variants', 'Var', (81, 98))
232029	32659967	For one patient diagnosed with osteosarcoma who had a LP germline variant in MSH2 intron 10 (c.1661+1G>A), a complete molecular analysis of the tumor was performed, including MSI analysis and transcript analysis using Sanger sequencing.	('tumor', 'Disease', (144, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (31, 43))	('osteosarcoma', 'Disease', (31, 43))	('osteosarcoma', 'Disease', 'MESH:D012516', (31, 43))	('c.1661+1G>A', 'Mutation', 'rs267607969', (93, 104))	('c.1661+1G>A', 'Var', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('patient', 'Species', '9606', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('LP', 'Chemical', '-', (54, 56))	('MSH2', 'Gene', (77, 81))
232033	32659967	The following antibodies were used: MLH1 (M1; Ventana), MSH2 (G219-1129; Cell Marque), MSH6 (44; Ventana), and PMS2 (EPR3947; Cell Marque).	('MLH1', 'Gene', '4292', (36, 40))	('MLH1', 'Gene', (36, 40))	('EPR3947', 'Var', (117, 124))
232039	32659967	The transcript analysis was performed using MSH2 gene transcripts of RNA extracted from tissue samples from frozen tumors and normal adjacent tissue of the proband (carrier of MSH2 c.1661+1G>A).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('c.1661+1G>A', 'Var', (181, 192))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('MSH2', 'Gene', (176, 180))	('c.1661+1G>A', 'Mutation', 'rs267607969', (181, 192))	('MSH2 gene', 'Gene', (44, 53))
232071	32165957	In some cases, rearrangements of the glomulin gene (1p21-22) have been found.	('glomulin', 'Gene', '11146', (37, 45))	('glomulin', 'Gene', (37, 45))	('rearrangements', 'Var', (15, 29))	('1p21-22', 'Gene', (52, 59))
232090	32165957	Although CD99 negative, approximately 40% of the tumor cells were positive for EWS RNA binding protein 1 (EWSR1) (22q12) rearrangement on Fluorescent in situ hybridization (FISH).	('CD99', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('EWSR1', 'Gene', '2130', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('rearrangement', 'Var', (121, 134))	('tumor', 'Disease', (49, 54))	('CD99', 'Gene', '4267', (9, 13))	('positive', 'Reg', (66, 74))	('EWS RNA binding protein 1', 'Gene', (79, 104))	('EWS RNA binding protein 1', 'Gene', '2130', (79, 104))	('EWSR1', 'Gene', (106, 111))
232103	32165957	Polymorphisms and silent mutations were detected in five genes (PDGFRA, RET, JAK1, PIK3R1, CHEK2), as well as KDR gene mutation (Q472H) in about 49% of the cells which was not considered a driver mutation.	('Q472H', 'Mutation', 'rs1870377', (129, 134))	('KDR', 'Gene', (110, 113))	('JAK1', 'Gene', (77, 81))	('RET', 'Gene', '5979', (72, 75))	('JAK1', 'Gene', '3716', (77, 81))	('PIK3R1', 'Gene', '5295', (83, 89))	('PDGFRA', 'Gene', (64, 70))	('PIK3R1', 'Gene', (83, 89))	('Q472H', 'Var', (129, 134))	('CHEK2', 'Gene', '11200', (91, 96))	('RET', 'Gene', (72, 75))	('PDGFRA', 'Gene', '5156', (64, 70))	('KDR', 'Gene', '3791', (110, 113))	('CHEK2', 'Gene', (91, 96))
232119	32165957	Glomus tumor should be considered malignant when the tumor is larger than 2 cm, has deep subfascial or visceral location and has histologic features of malignancy, such as atypical mitotic figures or marked nuclear atypia and any level of mitotic activity.	('Glomus tumor', 'Disease', 'MESH:D005918', (0, 12))	('tumor', 'Disease', (7, 12))	('mitotic activity', 'CPA', (239, 255))	('fascia', 'Disease', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Glomus tumor', 'Disease', (0, 12))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('fascia', 'Disease', 'None', (92, 98))	('nuclear atypia', 'CPA', (207, 221))	('atypical', 'Var', (172, 180))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('malignancy', 'Disease', (152, 162))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
232126	32165957	In some cases rearrangements of the glomulin gene (1p21-22) have been documented.	('glomulin', 'Gene', (36, 44))	('rearrangements', 'Var', (14, 28))	('1p21-22', 'Gene', (51, 58))	('glomulin', 'Gene', '11146', (36, 44))
232148	32165957	Our patient started chemotherapy for Ewing's sarcoma after kidney core biopsy showed 40% of the tumor cells positive for EWS RNA binding protein 1 (EWSR1) (22q12) rearrangement on Fluorescent in situ hybridization (FISH).	('EWS RNA binding protein 1', 'Gene', '2130', (121, 146))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('EWSR1', 'Gene', (148, 153))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (37, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('tumor', 'Disease', (96, 101))	('patient', 'Species', '9606', (4, 11))	('rearrangement', 'Var', (163, 176))	('EWSR1', 'Gene', '2130', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (37, 52))	('EWS RNA binding protein 1', 'Gene', (121, 146))	("Ewing's sarcoma", 'Disease', (37, 52))
232154	32165957	This methylation damages the DNA and triggers the death of tumor cells,.	('methylation', 'Var', (5, 16))	('tumor', 'Disease', (59, 64))	('DNA', 'CPA', (29, 32))	('triggers', 'Reg', (37, 45))	('death', 'CPA', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
232178	30042376	Patients with AIDS-related KS with CD4 cell counts <100 cells/mm3 have the worst prognosis.	('<100', 'Var', (51, 55))	('CD4', 'Gene', (35, 38))	('KS', 'Phenotype', 'HP:0100726', (27, 29))	('CD4', 'Gene', '920', (35, 38))	('Patients', 'Species', '9606', (0, 8))	('AIDS', 'Disease', (14, 18))	('AIDS', 'Disease', 'MESH:D000163', (14, 18))
232247	28088687	Hallmarks of DNA methylation abnormalities in UCS included global hypomethylation, especially in repetitive elements, and hypermethylation of tumor suppressor gene promoters.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('abnormalities', 'Var', (29, 42))	('UCS', 'Phenotype', 'HP:0002891', (46, 49))	('hypermethylation', 'MPA', (122, 138))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('global hypomethylation', 'MPA', (59, 81))
232248	28088687	The carcinoma component of UCS was characterized by hypermethylation of promoters of EMILIN1, NEFM, and CLEC14A, genes that are associated with tumor vascularization.	('tumor', 'Disease', (144, 149))	('EMILIN1', 'Gene', '11117', (85, 92))	('NEFM', 'Gene', (94, 98))	('CLEC14A', 'Gene', '161198', (104, 111))	('NEFM', 'Gene', '4741', (94, 98))	('hypermethylation', 'Var', (52, 68))	('CLEC14A', 'Gene', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('EMILIN1', 'Gene', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('carcinoma component of UCS', 'Disease', (4, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (4, 13))	('carcinoma component of UCS', 'Disease', 'MESH:C562869', (4, 30))	('UCS', 'Phenotype', 'HP:0002891', (27, 30))
232251	28088687	Human cancers display abnormal DNA methylation patterns including genome-wide hypomethylation and site-specific hypermethylation.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Disease', (6, 13))	('hypomethylation', 'Var', (78, 93))
232253	28088687	Globally, hypomethylation of most genomic transposable elements (TEs) leads to chromosome instability, whereas alterations in methylation levels of other TEs contribute to tumor initiation or progression.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('methylation', 'MPA', (126, 137))	('tumor initiation', 'Disease', 'MESH:D009369', (172, 188))	('hypomethylation', 'Var', (10, 25))	('chromosome instability', 'Phenotype', 'HP:0040012', (79, 101))	('leads to', 'Reg', (70, 78))	('tumor initiation', 'Disease', (172, 188))	('contribute', 'Reg', (158, 168))	('chromosome instability', 'CPA', (79, 101))
232254	28088687	The scope of aberrant methylation of distal enhancers continues to receive attention in many cancers.	('cancers', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('aberrant methylation', 'Var', (13, 33))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('methylation', 'Var', (22, 33))
232262	28088687	Characteristic mutations in TP53, KRAS, and PIK3CA have been reported in UCS.	('KRAS', 'Gene', '3845', (34, 38))	('PIK3CA', 'Gene', (44, 50))	('TP53', 'Gene', '7157', (28, 32))	('UCS', 'Phenotype', 'HP:0002891', (73, 76))	('mutations', 'Var', (15, 24))	('TP53', 'Gene', (28, 32))	('PIK3CA', 'Gene', '5290', (44, 50))	('UCS', 'Disease', (73, 76))	('KRAS', 'Gene', (34, 38))	('reported', 'Reg', (61, 69))
232291	28088687	In normal endometrium, 80% of the 28M CpGs were methylated (i.e., methylation level >= 0.8), whereas in UCS samples, this ratio fell to 60% to 70% (Supplemental Table 1).	('methylated', 'Var', (48, 58))	('methylation level', 'MPA', (66, 83))	('CpGs', 'Chemical', 'MESH:C015772', (38, 42))	('UCS', 'Phenotype', 'HP:0002891', (104, 107))
232296	28088687	This approach allowed us to discover a total of 7235 recurrent DMRs in at least 2 of the 3 carcinoma components, and 4165 DMRs in the sarcoma components, when compared to normal endometrium.	('DMRs', 'Var', (63, 67))	('DMRs', 'Chemical', '-', (63, 67))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('sarcoma', 'Disease', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('DMRs', 'Chemical', '-', (122, 126))	('carcinoma', 'Disease', (91, 100))
232298	28088687	About 82% of UCS common DMRs were hypermethylated (2490 DMRs), and 18% were hypomethylated (539) (Figure 2C).	('DMRs', 'Chemical', '-', (24, 28))	('UCS', 'Disease', (13, 16))	('DMRs', 'Chemical', '-', (56, 60))	('hypermethylated', 'Var', (34, 49))	('UCS', 'Phenotype', 'HP:0002891', (13, 16))
232311	28088687	Specifically, we found 743 genes with hypermethylated DMRs within 2.5 kb of their transcription start site.	('DMRs', 'Chemical', '-', (54, 58))	('DMRs', 'Var', (54, 58))	('hypermethylated DMRs', 'Var', (38, 58))
232312	28088687	In cancer cells, epigenetic inactivation of tumor-suppressor genes (TSGs) is a key tumorigenic event.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('epigenetic inactivation', 'Var', (17, 40))	('tumor', 'Disease', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
232314	28088687	More specifically, the Wilms' tumor 1 (WT1) gene was one of the TSGs identified as harboring a hypermethylated DMR in its promoter (Figure 3B), and this was validated by TCGA methylation data (Figure 3C).	("Wilms' tumor 1", 'Gene', '7490', (23, 37))	('WT1', 'Gene', (39, 42))	('hypermethylated', 'Var', (95, 110))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (23, 35))	("Wilms' tumor 1", 'Gene', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('WT1', 'Gene', '7490', (39, 42))
232316	28088687	Necdin (NDN) has been reported to be silenced by methylation in urothelial carcinoma.	('NDN', 'Gene', '4692', (8, 11))	('silenced', 'NegReg', (37, 45))	('urothelial carcinoma', 'Disease', (64, 84))	('Necdin', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Necdin', 'Gene', '4692', (0, 6))	('methylation', 'Var', (49, 60))	('NDN', 'Gene', (8, 11))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (64, 84))
232326	28088687	Global hypomethylation of TEs has long been regarded as a hallmark of cancers, with direct implication in cancer genome instability.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Global hypomethylation', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('hallmark of cancers', 'Disease', 'MESH:D009369', (58, 77))	('hallmark of cancers', 'Disease', (58, 77))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('TEs', 'Gene', (26, 29))
232329	28088687	Overall, 15.6% of hypermethylated and 40% of hypomethylated UCS-common DMRs were contributed by TEs (Figure 4B).	('UCS', 'Phenotype', 'HP:0002891', (60, 63))	('UCS-common', 'Disease', (60, 70))	('DMRs', 'Chemical', '-', (71, 75))	('hypermethylated', 'Var', (18, 33))
232330	28088687	For example, LTR12C is an endogenous retroviral element (ERV/LTR) recently reported to produce abnormal transcripts in liver cancer.	('liver cancer', 'Disease', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('LTR12C', 'Var', (13, 19))	('liver cancer', 'Phenotype', 'HP:0002896', (119, 131))	('liver cancer', 'Disease', 'MESH:D006528', (119, 131))
232331	28088687	LTR12C contributed both hypermethylated and hypomethylated DMRs (Figure 4C).	('hypermethylated', 'Var', (24, 39))	('hypomethylated', 'Var', (44, 58))	('DMRs', 'Chemical', '-', (59, 63))	('LTR12C', 'Gene', (0, 6))
232335	28088687	Recurrent hypermethylated protocadherin genes in endometrial cancers occurred within 5q31, spanning three PCDH clusters (PCDHA, PCDHB, and PCDHG; Figure 5A).	('PCDHB', 'Gene', (128, 133))	('PCDHA', 'Gene', (121, 126))	('PCDHA', 'Gene', '56117', (121, 126))	('PCDHB', 'Gene', '56116', (128, 133))	('PCDHG', 'Gene', '56115', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('endometrial cancer', 'Phenotype', 'HP:0012114', (49, 67))	('endometrial cancers', 'Disease', 'MESH:D016889', (49, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('PCDHG', 'Gene', (139, 144))	('endometrial cancers', 'Disease', (49, 68))	('protocadherin genes', 'Gene', (26, 45))	('hypermethylated', 'Var', (10, 25))
232338	28088687	We hypothesized that the presence of DMRs within certain genes might be characteristic of carcinomatous or sarcomatous components of UCS.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('genes', 'Gene', (57, 62))	('carcinomatous or sarcomatous', 'Disease', 'MESH:D055756', (90, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('UCS', 'Phenotype', 'HP:0002891', (133, 136))	('DMRs', 'Chemical', '-', (37, 41))	('carcinomatous or sarcomatous', 'Disease', (90, 118))	('DMRs', 'Var', (37, 41))
232342	28088687	Interestingly, they shared many more hypermethylated DMRs (1582) than hypomethylated DMRs (145).	('DMRs', 'Chemical', '-', (85, 89))	('hypermethylated', 'Var', (37, 52))	('DMRs', 'Chemical', '-', (53, 57))	('1582', 'Var', (59, 63))
232347	28088687	Of 342 genes with CADs located in their promoters, elastic microfibril interface located protein (EMILIN1), neurofilament medium peptide (NEFM), and C-type lectin domain family 14 member A (CLEC14A) showed significant hypermethylation and decreased expression in endometrial carcinoma and carcinomatous components of UCS (Supplementary Figure 2, A and B).	('expression', 'MPA', (249, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('UCS', 'Phenotype', 'HP:0002891', (317, 320))	('EMILIN1', 'Gene', '11117', (98, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('C-type lectin domain family 14 member A', 'Gene', '161198', (149, 188))	('decreased', 'NegReg', (239, 248))	('endometrial carcinoma and carcinomatous', 'Disease', 'MESH:D016889', (263, 302))	('CLEC14A', 'Gene', '161198', (190, 197))	('EMILIN1', 'Gene', (98, 105))	('CLEC14A', 'Gene', (190, 197))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (263, 284))	('hypermethylation', 'Var', (218, 234))	('NEFM', 'Gene', '4741', (138, 142))	('C-type lectin domain family 14 member A', 'Gene', (149, 188))	('NEFM', 'Gene', (138, 142))
232349	28088687	Our DMR analysis revealed a novel connection between epigenetic regulation of miRNAs and the distinction between the sarcomatous and carcinomatous components of UCS.	('sarcomatous', 'Disease', (117, 128))	('carcinomatous', 'Disease', 'MESH:D055756', (133, 146))	('miRNAs', 'Protein', (78, 84))	('carcinomatous', 'Disease', (133, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('epigenetic regulation', 'Var', (53, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('sarcomatous', 'Disease', 'MESH:D018316', (117, 128))	('UCS', 'Phenotype', 'HP:0002891', (161, 164))
232350	28088687	This was highlighted by several DMRs targeting the MIR200 family (MIR200a, MIR200b, MIR200c, MIR141, MIR429) in UCS.	('MIR200', 'Gene', (51, 57))	('MIR429', 'Gene', '554210', (101, 107))	('MIR200a', 'Var', (66, 73))	('MIR200c', 'Gene', (84, 91))	('MIR429', 'Gene', (101, 107))	('MIR141', 'Gene', (93, 99))	('MIR200b', 'Gene', (75, 82))	('DMRs', 'Chemical', '-', (32, 36))	('UCS', 'Phenotype', 'HP:0002891', (112, 115))	('MIR200c', 'Gene', '406985', (84, 91))	('MIR141', 'Gene', '406933', (93, 99))	('MIR200b', 'Gene', '406984', (75, 82))
232357	28088687	Taken together, these results suggest that the methylation pattern of MIR200 family members is an important epigenetic biomarker to distinguish carcinomatous and sarcomatous components of UCS.	('MIR200', 'Gene', (70, 76))	('sarcomatous', 'Disease', 'MESH:D018316', (162, 173))	('carcinomatous', 'Disease', 'MESH:D055756', (144, 157))	('methylation', 'Var', (47, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('sarcomatous', 'Disease', (162, 173))	('carcinomatous', 'Disease', (144, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('UCS', 'Phenotype', 'HP:0002891', (188, 191))
232362	28088687	UCSs with high WT1 and high estrogen receptor beta expression were shown to have decreased survival, supporting a role for WT1 as a biomarker in this tumor type.	('decreased', 'NegReg', (81, 90))	('survival', 'CPA', (91, 99))	('estrogen receptor beta', 'Gene', '2100', (28, 50))	('WT1', 'Gene', '7490', (123, 126))	('WT1', 'Gene', (123, 126))	('high', 'Var', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('UCS', 'Phenotype', 'HP:0002891', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('WT1', 'Gene', '7490', (15, 18))	('tumor', 'Disease', (150, 155))	('estrogen receptor beta', 'Gene', (28, 50))	('WT1', 'Gene', (15, 18))
232366	28088687	Among other candidate genes with a differential methylation pattern between the carcinomatous and sarcomatous components, we noted that EMILIN1 and CLEC4A harbored carcinoma-associated DMRs in their promoters and exhibited decreased expression in carcinoma.	('CLEC4A', 'Gene', '50856', (148, 154))	('expression', 'MPA', (233, 243))	('sarcomatous', 'Disease', 'MESH:D018316', (98, 109))	('carcinoma', 'Disease', 'MESH:D002277', (164, 173))	('carcinomatous', 'Disease', 'MESH:D055756', (80, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('sarcomatous', 'Disease', (98, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Disease', (247, 256))	('decreased', 'NegReg', (223, 232))	('DMRs', 'Chemical', '-', (185, 189))	('CLEC4A', 'Gene', (148, 154))	('carcinoma', 'Disease', (80, 89))	('DMRs', 'Var', (185, 189))	('EMILIN1', 'Gene', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinoma', 'Disease', 'MESH:D002277', (247, 256))	('EMILIN1', 'Gene', '11117', (136, 143))	('carcinoma', 'Disease', 'MESH:D002277', (80, 89))	('carcinoma', 'Disease', (164, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('carcinomatous', 'Disease', (80, 93))
232371	28088687	We identified component-specific DNA methylation abnormalities of MIR200 in UCS-Ca and in UCS-Sa, as well as in other endometrial tumor types.	('UCS-Sa', 'Disease', (90, 96))	('UCS-Ca', 'Disease', (76, 82))	('endometrial tumor', 'Disease', (118, 135))	('methylation abnormalities', 'Var', (37, 62))	('UCS', 'Phenotype', 'HP:0002891', (76, 79))	('UCS', 'Phenotype', 'HP:0002891', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('endometrial tumor', 'Disease', 'MESH:D016889', (118, 135))	('MIR200', 'Gene', (66, 72))
232373	28088687	Compared to pure carcinomas, UCS cases were found to have an increase in histone H2A/H2B mutations; furthermore, a majority of UCSs showed amplification of chromosome arm 6p, harboring the HIST1H histone gene cluster, and 1q22, harboring the HIST2H gene cluster.	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('carcinomas', 'Disease', (17, 27))	('carcinomas', 'Disease', 'MESH:D002277', (17, 27))	('amplification', 'Var', (139, 152))	('mutations', 'Var', (89, 98))	('UCS', 'Phenotype', 'HP:0002891', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('UCS', 'Phenotype', 'HP:0002891', (127, 130))
232383	28088687	There are recurrent epigenetic differences between the carcinomatous and sarcomatous components, in keeping with the phenotypic differences between them.	('sarcomatous', 'Disease', (73, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('carcinomatous', 'Disease', 'MESH:D055756', (55, 68))	('epigenetic differences', 'Var', (20, 42))	('sarcomatous', 'Disease', 'MESH:D018316', (73, 84))	('carcinomatous', 'Disease', (55, 68))
232384	28088687	The preponderance of hypermethylated DMRs in UCS could suggest a role for hypomethylating agents in clinical practice.	('UCS', 'Phenotype', 'HP:0002891', (45, 48))	('UCS', 'Disease', (45, 48))	('DMRs', 'Chemical', '-', (37, 41))	('DMRs', 'Var', (37, 41))	('hypermethylated DMRs', 'Var', (21, 41))
232498	24085323	MMP-2 expression was downregulated by 99% by doxycycline 100 microM in chondrosarcoma by 100% in fibrosarcoma and by 99% in liposarcoma.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (71, 85))	('MMP-2', 'Gene', (0, 5))	('doxycycline 100 microM', 'Var', (45, 67))	('liposarcoma', 'Disease', 'MESH:D008080', (124, 135))	('liposarcoma', 'Phenotype', 'HP:0012034', (124, 135))	('fibrosarcoma', 'Disease', 'MESH:D005354', (97, 109))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (97, 109))	('expression', 'MPA', (6, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('downregulated', 'NegReg', (21, 34))	('chondrosarcoma', 'Disease', (71, 85))	('chondrosarcoma', 'Disease', 'MESH:D002813', (71, 85))	('MMP-2', 'Gene', '4313', (0, 5))	('liposarcoma', 'Disease', (124, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('doxycycline', 'Chemical', 'MESH:D004318', (45, 56))	('fibrosarcoma', 'Disease', (97, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
232499	24085323	MMP-9 expression was downregulated by doxycycline 100 microM in chondrosarcoma and liposarcoma by 96 and 86%, respectively, while fibrosarcoma MMP-9 expression was completely blocked at 25 microM.	('MMP-9', 'Gene', '4318', (143, 148))	('doxycycline 100 microM', 'Var', (38, 60))	('chondrosarcoma and liposarcoma', 'Disease', 'MESH:D002813', (64, 94))	('fibrosarcoma', 'Disease', (130, 142))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (64, 78))	('MMP-9', 'Gene', (143, 148))	('liposarcoma', 'Phenotype', 'HP:0012034', (83, 94))	('expression', 'MPA', (6, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('downregulated', 'NegReg', (21, 34))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (130, 142))	('fibrosarcoma', 'Disease', 'MESH:D005354', (130, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('doxycycline', 'Chemical', 'MESH:D004318', (38, 49))	('MMP-9', 'Gene', '4318', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('MMP-9', 'Gene', (0, 5))
232504	24085323	Synovial sarcoma was most sensitive to NM with block of MMP-2 at 500 microg/ml and MMP-9 at 100 microg/ml.	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('MMP-9', 'Gene', '4318', (83, 88))	('MMP-9', 'Gene', (83, 88))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('MMP-2', 'Gene', (56, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('MMP-2', 'Gene', '4313', (56, 61))	('block', 'Var', (47, 52))
30929	24085323	In addition, lysine contributes to ECM stability as a natural inhibitor of plasmin-induced proteolysis.	('plasmin', 'Gene', (75, 82))	('lysine', 'Var', (13, 19))	('ECM', 'Gene', '22915', (35, 38))	('plasmin', 'Gene', '5340', (75, 82))	('ECM', 'Gene', (35, 38))	('lysine', 'Chemical', 'MESH:D008239', (13, 19))
232542	32751241	Even though both proximal and distant variants belong to SWI/SNF-deficient soft tissue, neoplasms are unified by the presence of monomorphic, undifferentiated epithelioid cells and are characterized by the loss of INI1 expression (Figure 2E).	('INI1', 'Gene', (214, 218))	('INI1', 'Gene', '6598', (214, 218))	('variants', 'Var', (38, 46))	('expression', 'MPA', (219, 229))	('neoplasms', 'Phenotype', 'HP:0002664', (88, 97))	('SNF-deficient soft tissue', 'Disease', 'MESH:D012983', (61, 86))	('neoplasms', 'Disease', 'MESH:D009369', (88, 97))	('neoplasms', 'Disease', (88, 97))	('SNF-deficient soft tissue', 'Disease', (61, 86))	('neoplasm', 'Phenotype', 'HP:0002664', (88, 96))	('loss', 'NegReg', (206, 210))
232553	32751241	Over 90% of ES, both conventional and proximal type, shows a complete SMARC1/INI1 (integrase interactor 1) loss due to the biallelic deletion of the SMARCB1 gene locus or as a consequence of epigenetic dysregulation, which defines both types of epithelioid sarcoma.	('biallelic deletion', 'Var', (123, 141))	('sarcoma', 'Disease', (257, 264))	('SMARCB1', 'Gene', (149, 156))	('INI1', 'Gene', (77, 81))	('loss', 'NegReg', (107, 111))	('INI1', 'Gene', '6598', (77, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('integrase interactor 1', 'Gene', '6598', (83, 105))	('integrase interactor 1', 'Gene', (83, 105))	('sarcoma', 'Disease', 'MESH:D012509', (257, 264))	('epigenetic dysregulation', 'Var', (191, 215))	('SMARCB1', 'Gene', '6598', (149, 156))
232563	32751241	Biallelic inactivation of INI1 occurs in strictly defined malignant rhabdoid tumors of infancy, which confirmed its functions as a tumor-suppressor gene.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('INI1', 'Gene', '6598', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('malignant rhabdoid tumors', 'Disease', (58, 83))	('INI1', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Biallelic inactivation', 'Var', (0, 22))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (58, 83))
232564	32751241	SMARCB1/INI1 inactivation leads to the deregulation of targeted genes, uncontrolled cellular growth, and neoplastic transformation.	('INI1', 'Gene', (8, 12))	('INI1', 'Gene', '6598', (8, 12))	('inactivation', 'Var', (13, 25))	('neoplastic transformation', 'CPA', (105, 130))	('SMARCB1', 'Gene', '6598', (0, 7))	('deregulation of targeted genes', 'MPA', (39, 69))	('SMARCB1', 'Gene', (0, 7))
232565	32751241	The restoration of SMARCB1 resulted in the reduced cell proliferation and migration of the ES VAESBJ cell line.	('SMARCB1', 'Gene', '6598', (19, 26))	('migration of the ES VAESBJ cell line', 'CPA', (74, 110))	('SMARCB1', 'Gene', (19, 26))	('cell proliferation', 'CPA', (51, 69))	('reduced', 'NegReg', (43, 50))	('restoration', 'Var', (4, 15))
232566	32751241	INI1 function can be lost due to the homozygous deletion of SMARCB1, bi- or single-allelic deletion, or point mutations; however, in up to 50% of ES cases, both alleles of the gene are intact, which has led to the discovery that INI1 loss is caused rather at the epigenetic level or interaction with microRNA in the silencing of this gene.	('INI1', 'Gene', '6598', (229, 233))	('INI1', 'Gene', (229, 233))	('lost', 'NegReg', (21, 25))	('SMARCB1', 'Gene', '6598', (60, 67))	('INI1', 'Gene', (0, 4))	('SMARCB1', 'Gene', (60, 67))	('INI1', 'Gene', '6598', (0, 4))	('interaction', 'Reg', (283, 294))	('point mutations', 'Var', (104, 119))	('deletion', 'Var', (48, 56))	('loss', 'NegReg', (234, 238))
232568	32751241	INI1 inactivation results in overactivation of the PRC2 complex, leading to the methylation of histones, promotion of cell proliferation, and silencing the genes responsible for differentiation.	('PRC2', 'Gene', (51, 55))	('genes', 'Gene', (156, 161))	('methylation', 'MPA', (80, 91))	('histones', 'Protein', (95, 103))	('INI1', 'Gene', (0, 4))	('INI1', 'Gene', '6598', (0, 4))	('promotion', 'PosReg', (105, 114))	('cell proliferation', 'CPA', (118, 136))	('inactivation', 'Var', (5, 17))	('overactivation', 'PosReg', (29, 43))	('silencing', 'NegReg', (142, 151))
232569	32751241	It has been confirmed in experimental studies where the blockade of EZH2 could induce apoptosis and significantly retard the growth of INI1-negative solid tumors.	('INI1', 'Gene', (135, 139))	('EZH2', 'Gene', (68, 72))	('INI1', 'Gene', '6598', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('induce', 'Reg', (79, 85))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('retard', 'NegReg', (114, 120))	('blockade', 'Var', (56, 64))	('EZH2', 'Gene', '2146', (68, 72))	('apoptosis', 'CPA', (86, 95))
232570	32751241	Histone deacetylases are the group of enzymes that deacetylase lysine on histone and non-histone proteins inducing changes in chromatin structure and, in the appropriate context, facilitates transcription of the genes involved in cell proliferation, differentiation, and apoptosis.	('lysine', 'Chemical', 'MESH:D008239', (63, 69))	('cell proliferation', 'CPA', (230, 248))	('facilitates', 'PosReg', (179, 190))	('deacetylase lysine', 'Var', (51, 69))	('chromatin structure', 'MPA', (126, 145))	('lysine', 'Var', (63, 69))	('genes', 'Gene', (212, 217))	('transcription', 'MPA', (191, 204))	('changes', 'Reg', (115, 122))
232576	32751241	In addition, EGFR inhibitors showed preclinical efficacy alone and in combination with mTOR inhibitors, as shown by in vivo and in vitro models of ES growth.	('mTOR', 'Gene', '2475', (87, 91))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('inhibitors', 'Var', (18, 28))	('mTOR', 'Gene', (87, 91))
232583	32751241	A variety of other molecular and genetic abnormalities such as the loss of PBRM1 and SYT-SSX1 expression, overexpression of interleukin-2beta, or NRAS mutation were reported in ES; their clinical significance has not been yet established.	('genetic abnormalities', 'Disease', (33, 54))	('PBRM1', 'Gene', (75, 80))	('NRAS', 'Gene', '4893', (146, 150))	('PBRM1', 'Gene', '55193', (75, 80))	('SSX1', 'Gene', '6756', (89, 93))	('mutation', 'Var', (151, 159))	('overexpression', 'PosReg', (106, 120))	('loss', 'NegReg', (67, 71))	('SSX1', 'Gene', (89, 93))	('SYT', 'Gene', (85, 88))	('expression', 'MPA', (94, 104))	('SYT', 'Gene', '6760', (85, 88))	('genetic abnormalities', 'Disease', 'MESH:D030342', (33, 54))	('NRAS', 'Gene', (146, 150))
232634	32751241	Pulled data from 4 EORTC (The European Organisation for Research and Treatment of Cancer) studies (62012, 62043, 62072, 62091) enable identifying 27 patients with ES out of 976 patients treated in those trials.	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (177, 185))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('62012', 'Var', (99, 104))	('Cancer', 'Disease', (82, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))
232707	32751241	Finally, deep axial location compared to superficial axial or appendicular is associated with poorer prognosis and a higher recurrence rate.	('deep axial', 'Var', (9, 19))	('appendicular', 'Disease', (62, 74))	('appendicular', 'Disease', 'MESH:D001259', (62, 74))
232715	25010205	The Genomic Landscape of the Ewing Sarcoma Family of Tumors Reveals Recurrent STAG2 Mutation The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (97, 110))	('STAG2', 'Gene', '10735', (78, 83))	('Tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Mutation', 'Var', (84, 92))	('children', 'Species', '9606', (207, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('blue cell tumors', 'Disease', (177, 193))	('STAG2', 'Gene', (78, 83))	('Tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (29, 42))	('Ewing Sarcoma Family of Tumors', 'Disease', 'MESH:C563168', (29, 59))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('blue cell tumors', 'Disease', 'MESH:D005935', (177, 193))	('Ewing Sarcoma Family of Tumors', 'Disease', (29, 59))	('Sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Ewing sarcoma family of tumors', 'Disease', (97, 127))	('Ewing sarcoma family of tumors', 'Disease', 'MESH:C563168', (97, 127))
232717	25010205	Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%).	('STAG2', 'Gene', (223, 228))	('CDKN2A', 'Gene', '1029', (286, 292))	('deletion', 'Var', (274, 282))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('mutations', 'Var', (182, 191))	('mutations', 'Var', (313, 322))	('TP53', 'Gene', '7157', (326, 330))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('CDKN2A', 'Gene', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('TP53', 'Gene', (326, 330))
232718	25010205	We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006).	('BRCA2', 'Gene', (52, 57))	('patient', 'Species', '9606', (85, 92))	('K3326X', 'Var', (58, 64))	('BRCA2', 'Gene', '675', (52, 57))	('K3326X', 'Mutation', 'rs11571833', (58, 64))
232726	25010205	We find that this cancer is frequently affected by mutations in STAG2, a gene that has recently gained attention due to its importance in the biology of several cancer types.	('mutations', 'Var', (51, 60))	('affected', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('STAG2', 'Gene', (64, 69))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
232734	25010205	In larger centers an EWSR1 break-apart probe is used to detect a fusion event involving this gene, but in most cases this test is not required for a diagnosis of Ewing sarcoma.	('EWSR1', 'Gene', (21, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (162, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (162, 175))	('EWSR1', 'Gene', '2130', (21, 26))	('fusion event', 'Var', (65, 77))	('Ewing sarcoma', 'Disease', (162, 175))
232735	25010205	In previous case series, most EFT cases express one of several reciprocal translocations, most commonly t(11;22)(q24;q12) between the amino terminus of the EWSR1 gene and the carboxy terminus of the FLI1 gene found in 85-90% of cases.	('EWSR1', 'Gene', '2130', (156, 161))	('FLI1', 'Gene', (199, 203))	('FLI1', 'Gene', '2313', (199, 203))	('t(11;22)(q24;q12', 'Var', (104, 120))	('EWSR1', 'Gene', (156, 161))	('EFT', 'Disease', (30, 33))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (104, 121))
232736	25010205	A number of variant translocations between an alternate member of the TET family of RNA-binding proteins and/or an alternate member of the ETS family of transcription factors have also been described.	('variant translocations', 'Var', (12, 34))	('TET', 'Chemical', 'MESH:C010349', (70, 73))	('RNA-binding', 'Protein', (84, 95))
232737	25010205	Recurrent mutations in known tumor suppressor genes have also been described, though with lower frequency.	('mutations', 'Var', (10, 19))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))
232742	25010205	In the whole genome sequenced samples, we detected an average of 361 somatic mutations per tumor in non-repetitive regions and an average of 6 somatic mutations per tumor in protein coding regions (0.15 mutations/Mb of coding sequence), placing EFT at the low end of the mutation rate spectrum compared to previously reported malignancies.	('malignancies', 'Disease', (326, 338))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('malignancies', 'Disease', 'MESH:D009369', (326, 338))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (165, 170))
232743	25010205	Significant findings include previously reported alterations such as the characteristic EWSR1-FLI1 gene fusion detected in all 6 samples, CDKN2A homozygous deletion in 2 samples, and frequent chromosomal gains and losses.	('EWSR1', 'Gene', '2130', (88, 93))	('CDKN2A', 'Gene', (138, 144))	('CDKN2A', 'Gene', '1029', (138, 144))	('losses', 'NegReg', (214, 220))	('chromosomal gains', 'CPA', (192, 209))	('FLI1', 'Gene', (94, 98))	('FLI1', 'Gene', '2313', (94, 98))	('fusion', 'Var', (104, 110))	('EWSR1', 'Gene', (88, 93))	('deletion', 'Var', (156, 164))
232745	25010205	In summary, WGS of 6 EFTs revealed the characteristic EWSR1 fusion genes, low mutational burden and structural variations, but two tumors had loss of STAG2 (frameshift variant in EWS2017 and focal tandem duplication in EWS2020), and two had deletion of CDKN2A (EWS2009 and EWS2020) (Figure 1, Figure S1).	('EWS', 'Gene', (179, 182))	('EWS', 'Gene', '2130', (261, 264))	('EWS', 'Gene', '2130', (54, 57))	('CDKN2A', 'Gene', '1029', (253, 259))	('EWS', 'Gene', (273, 276))	('EWSR1', 'Gene', (54, 59))	('focal tandem duplication', 'Var', (191, 215))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('deletion', 'Var', (241, 249))	('STAG2', 'Gene', (150, 155))	('EWS', 'Gene', '2130', (179, 182))	('EWS', 'Gene', '2130', (219, 222))	('EWS', 'Gene', (261, 264))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('EWS', 'Gene', (54, 57))	('EWS', 'Gene', '2130', (273, 276))	('tumors', 'Disease', (131, 137))	('EWSR1', 'Gene', '2130', (54, 59))	('loss', 'NegReg', (142, 146))	('CDKN2A', 'Gene', (253, 259))	('frameshift variant', 'Var', (157, 175))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('EWS', 'Gene', (219, 222))
232747	25010205	In 62 tumor samples analyzed by RNA sequencing, 55 contained an EWSR1-ETS family fusion including 28 EWSR1-FLI1 type I (51%), 11 EWSR1-FLI1 type II (20%), 11 other EWSR1-FLI1 variants (20%), 3 EWSR1-ERG (5%), and 2 EWSR1-FEV fusions (4%) (Table S5).	('EWSR1', 'Gene', (101, 106))	('FLI1', 'Gene', (135, 139))	('contained', 'Reg', (51, 60))	('EWSR1', 'Gene', '2130', (193, 198))	('EWSR1', 'Gene', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('EWSR1', 'Gene', (129, 134))	('FLI1', 'Gene', '2313', (135, 139))	('EWSR1', 'Gene', '2130', (215, 220))	('variants', 'Var', (175, 183))	('EWSR1', 'Gene', '2130', (64, 69))	('FLI1', 'Gene', (107, 111))	('FLI1', 'Gene', (170, 174))	('EWSR1', 'Gene', (193, 198))	('EWSR1', 'Gene', '2130', (101, 106))	('tumor', 'Disease', (6, 11))	('EWSR1', 'Gene', '2130', (164, 169))	('FLI1', 'Gene', '2313', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('FLI1', 'Gene', '2313', (170, 174))	('EWSR1', 'Gene', (215, 220))	('EWSR1', 'Gene', '2130', (129, 134))	('EWSR1', 'Gene', (64, 69))
232755	25010205	In total, we discovered STAG2 alterations in 30 of 101 (29.7%) of EFT samples including 14 of 65 (21.5%) clinical tumor samples and 16 of 36 (44.4%) cell lines (Table 1, Table S5).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('clinical', 'Species', '191496', (105, 113))	('tumor', 'Disease', (114, 119))	('alterations', 'Var', (30, 41))	('STAG2', 'Gene', (24, 29))
232756	25010205	Mutations were confirmed to be somatic in all tumor samples in which germline DNA from the same patient was available for comparison (7 tumors).	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('patient', 'Species', '9606', (96, 103))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
232757	25010205	The remaining three mutations of unclear functional consequence include a tumor with point mutation in the 3' untranslated (UTR) region, a cell line with a missense mutation, and a cell line with a complex in-frame insertion (1 bp deletion replaced by a 7 bp insertion).	('point mutation', 'Var', (85, 99))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
232758	25010205	Interestingly, 5 samples (4 tumors and 1 cell line) contained the same nonsense mutation, R216X.	('R216X', 'Mutation', 'p.R216X', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('R216X', 'Var', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
232759	25010205	In tumor samples, all evaluable STAG2 mutated samples showed preferential RNA expression of the mutant allele with varying amounts of wild type allele (median variant allele frequency 0.78), likely due to varying amounts of normal tissue contamination.	('tumor', 'Disease', (3, 8))	('mutant', 'Var', (96, 102))	('RNA expression', 'MPA', (74, 88))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('preferential', 'PosReg', (61, 73))
232760	25010205	Seven additional EFT samples (five tumors and two cell lines) in which STAG2 mutation was not identified by our methods also had very low STAG2 expression comparable to samples with a truncating mutation in STAG2 (Figure S4).	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mutation', 'Var', (77, 85))	('expression', 'MPA', (144, 154))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('low', 'NegReg', (134, 137))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('STAG2', 'Gene', (138, 143))
232761	25010205	Immunohistochemistry (IHC) analysis with an antibody that binds to an epitope at the C-terminus of the STAG2 protein confirmed that EFT tumors with truncating STAG2 mutations have absent STAG2 protein expression, while the admixed non-neoplastic stromal and endothelial cells had robust expression (Figure 4).	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('STAG2', 'Gene', (159, 164))	('absent', 'NegReg', (180, 186))	('EFT tumors', 'Disease', (132, 142))	('STAG2', 'Gene', (187, 192))	('protein', 'Protein', (193, 200))	('EFT tumors', 'Disease', 'MESH:D009369', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mutations', 'Var', (165, 174))	('expression', 'MPA', (201, 211))
232765	25010205	We identified TP53 mutation in 4 of 65 (6.2%) EFT tumor samples and in 23 of 32 (71.9%) EFT cell lines tested.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('EFT', 'Disease', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
232766	25010205	Almost all of the TP53 mutations we discovered are previously reported pathologic variants and/or are truncating mutations (nonsense, splice site, or frameshift) (Figure 3B, Table S5).	('splice site', 'Var', (134, 145))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('frameshift', 'Var', (150, 160))
232767	25010205	RNA expression analysis showed that there were 4 additional EFT samples (2 tumors, 2 cell lines) in which TP53 mutation was not identified but had low TP53 expression similar to those with a truncating mutation (Figure S6).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('TP53', 'Gene', (151, 155))	('low', 'NegReg', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutation', 'Var', (111, 119))	('tumors', 'Disease', (75, 81))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', '7157', (151, 155))	('TP53', 'Gene', (106, 110))
232768	25010205	CDKN2A deletion was detected in 9 of 65 (13.8%) EFT tumors and in 16 of 32 (50%) EFT cell lines tested based on DNA and/or RNA sequencing coverage (Figure S7, Figure S8A).	('detected', 'Reg', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('EFT tumors', 'Disease', 'MESH:D009369', (48, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('EFT tumors', 'Disease', (48, 58))	('CDKN2A', 'Gene', (0, 6))	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))
232773	25010205	In the clinical tumor samples, these alterations were typically mutually exclusive in 19 of 26 (65.5%) although several samples had STAG2 mutations in association with TP53 mutations or CDKN2A deletions (Figure 6).	('deletions', 'Var', (193, 202))	('CDKN2A', 'Gene', '1029', (186, 192))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('clinical', 'Species', '191496', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (173, 182))	('tumor', 'Disease', (16, 21))	('CDKN2A', 'Gene', (186, 192))	('mutations', 'Var', (138, 147))
232775	25010205	In addition we discovered the BRCA2 K3326X polymorphism in 5 samples, 4 from patient tumors and one in a cell line (TC-106).	('TC-106', 'CellLine', 'CVCL:F720', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('K3326X', 'Mutation', 'rs11571833', (36, 42))	('BRCA2', 'Gene', (30, 35))	('K3326X', 'Var', (36, 42))	('tumors', 'Disease', (85, 91))	('patient', 'Species', '9606', (77, 84))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('BRCA2', 'Gene', '675', (30, 35))
232777	25010205	In our tumor samples, this polymorphism was mutually exclusive with STAG2, CDKN2A, and TP53 mutations, though overlapped with STAG2 expression loss in one case (Figure 6, Table S5).	('TP53', 'Gene', '7157', (87, 91))	('tumor', 'Disease', (7, 12))	('CDKN2A', 'Gene', (75, 81))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('CDKN2A', 'Gene', '1029', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
232779	25010205	We discovered one additional BRCA2 missense mutation (S2186T) that is previously unreported in dbSNP and is of uncertain clinical significance (Table S7).	('clinical', 'Species', '191496', (121, 129))	('BRCA2', 'Gene', (29, 34))	('BRCA2', 'Gene', '675', (29, 34))	('S2186T', 'Mutation', 'p.S2186T', (54, 60))	('S2186T', 'Var', (54, 60))
232780	25010205	A significant relationship was noted between STAG2 loss and TP53 mutational status in the EFT cell lines.	('STAG2', 'Gene', (45, 50))	('TP53', 'Gene', '7157', (60, 64))	('loss', 'NegReg', (51, 55))	('TP53', 'Gene', (60, 64))	('mutational status', 'Var', (65, 82))
232781	25010205	In the 16 cell lines with deleterious STAG2 alterations (inactivating mutation or loss of expression), there were 14 (87.5%) with TP53 mutations, all missense.	('missense', 'Var', (150, 158))	('mutations', 'Var', (135, 144))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('loss of expression', 'NegReg', (82, 100))
232782	25010205	In the 20 remaining cell lines with intact STAG2, only 9 of the 16 (56.3%) evaluated by sequencing contained a TP53 mutation, 5 of which were truncating and 4 of which were missense.	('truncating', 'Var', (142, 152))	('mutation', 'Var', (116, 124))	('TP53', 'Gene', (111, 115))	('TP53', 'Gene', '7157', (111, 115))
232783	25010205	Congruent with these findings, TP53 transcript levels from RNA sequencing were approximately 4-fold higher in cell lines with deleterious STAG2 alteration (log2 FPKM 5.26 vs. 3.47, p = 0.0023) (Figure S9A).	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('alteration', 'Var', (144, 154))	('higher', 'PosReg', (100, 106))	('STAG2', 'Gene', (138, 143))
232784	25010205	To assess the functional consequence of TP53 overexpression related to STAG2 mutation, we assessed the RNA expression levels of CDKN1A (which encodes p21WAF1/CIP1) as a marker of p53 activity.	('CDKN1A', 'Gene', '1026', (128, 134))	('p21WAF1/CIP1', 'Gene', '1026', (150, 162))	('mutation', 'Var', (77, 85))	('RNA', 'MPA', (103, 106))	('p21WAF1/CIP1', 'Gene', (150, 162))	('STAG2', 'Gene', (71, 76))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('CDKN1A', 'Gene', (128, 134))
232785	25010205	As expected, cell lines with TP53 mutation or expression loss showed lower levels of CDKN1A transcript than TP53 wild type cell lines (log2 FPKM 0.09 vs 4.85, p = 0.0005).	('TP53', 'Gene', '7157', (108, 112))	('CDKN1A', 'Gene', (85, 91))	('TP53', 'Gene', (108, 112))	('mutation', 'Var', (34, 42))	('lower', 'NegReg', (69, 74))	('CDKN1A', 'Gene', '1026', (85, 91))	('TP53', 'Gene', '7157', (29, 33))	('levels', 'MPA', (75, 81))	('TP53', 'Gene', (29, 33))	('loss', 'NegReg', (57, 61))	('expression', 'MPA', (46, 56))
232786	25010205	STAG2 mutation in the EFT cell lines similarly predicted for decreased CDKN1A transcript expression compared to samples without a detected mutation (log2 FPKM -0.20 vs 2.31, p = 0.018) (Figure S9B).	('CDKN1A', 'Gene', (71, 77))	('CDKN1A', 'Gene', '1026', (71, 77))	('mutation', 'Var', (6, 14))	('decreased', 'NegReg', (61, 70))	('STAG2', 'Gene', (0, 5))	('transcript expression', 'MPA', (78, 99))
232787	25010205	Despite a much lower rate of concordant TP53 mutation, there was also a significant association between STAG2 mutation and decreased CDKN1A transcript expression in the tumor cohort (log2 FPKM 4.08 vs 5.18, p = 0.039) (Figure S9C) and a trend towards increased TP53 expression (log2 FPKM 5.51 vs. 5.38, p = 0.19).	('increased', 'PosReg', (251, 260))	('expression', 'MPA', (266, 276))	('transcript expression', 'MPA', (140, 161))	('TP53', 'Gene', '7157', (261, 265))	('decreased', 'NegReg', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('CDKN1A', 'Gene', (133, 139))	('STAG2', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('TP53', 'Gene', (261, 265))	('CDKN1A', 'Gene', '1026', (133, 139))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('mutation', 'Var', (110, 118))	('tumor', 'Disease', (169, 174))
232788	25010205	In summary, STAG2 mutation was associated with higher TP53 and lower CDKN1A expression in both tumors and cell lines and associated with more frequent missense TP53 mutations in cell lines.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('missense', 'Var', (151, 159))	('lower', 'NegReg', (63, 68))	('higher', 'PosReg', (47, 53))	('TP53', 'Gene', '7157', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('STAG2', 'Gene', (12, 17))	('TP53', 'Gene', '7157', (54, 58))	('expression', 'MPA', (76, 86))	('TP53', 'Gene', (160, 164))	('mutation', 'Var', (18, 26))	('CDKN1A', 'Gene', (69, 75))	('mutations', 'Var', (165, 174))	('CDKN1A', 'Gene', '1026', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('TP53', 'Gene', (54, 58))	('tumors', 'Disease', (95, 101))
232793	25010205	We found no significant differences in age, gender, stage, or primary tumor site (extremity vs. non-extremity) between STAG2 mutated and wild-type samples, though numbers were small in these comparisons (Table S9).	('primary tumor', 'Disease', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutated', 'Var', (125, 132))	('primary tumor', 'Disease', 'MESH:D009369', (62, 75))	('STAG2', 'Gene', (119, 124))
232797	25010205	This may be due in part to the shorter amount of time that the precursor cell has to accumulate passenger mutations during normal cell division but may also represent a fundamental difference common to pediatric cancers.	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('pediatric cancers', 'Disease', 'MESH:D009369', (202, 219))	('pediatric cancers', 'Disease', (202, 219))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
232799	25010205	Second, the low mutation rate of Ewing sarcoma even amongst several reported pediatric cancer types may reflect a fundamental characteristic of fusion-driven cancers.	('cancer', 'Disease', (87, 93))	('mutation', 'Var', (16, 24))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (33, 46))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (33, 46))	('cancer', 'Disease', (158, 164))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Ewing sarcoma', 'Disease', (33, 46))	('low', 'NegReg', (12, 15))
232804	25010205	CIC gene rearrangements, particularly CIC-DUX4 fusions, have been described in a group of aggressive undifferentiated small blue round cell sarcomas thought to be distinct from Ewing sarcoma.	('CIC', 'Gene', (38, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('sarcomas', 'Disease', (140, 148))	('described', 'Reg', (66, 75))	('DUX4', 'Gene', (42, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (177, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (177, 190))	('CIC', 'Gene', '23152', (0, 3))	('DUX4', 'Gene', '100288687', (42, 46))	('fusions', 'Var', (47, 54))	('rearrangements', 'Var', (9, 23))	('CIC', 'Gene', '23152', (38, 41))	('Ewing sarcoma', 'Disease', (177, 190))	('sarcomas', 'Disease', 'MESH:D012509', (140, 148))	('CIC', 'Gene', (0, 3))
232810	25010205	In our survey for genetic alterations, we discovered STAG2 mutations in 21.5% of Ewing sarcoma family tumor samples and 44.4% of EFT cell lines tested, the vast majority of which are inactivating mutations.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('STAG2', 'Gene', (53, 58))	('Ewing sarcoma family tumor', 'Disease', (81, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('mutations', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Ewing sarcoma family tumor', 'Disease', 'MESH:C563168', (81, 107))
232812	25010205	While immunohistochemistry will identify all tumors with homozygous deletions and truncating mutations, it will not detect tumors harboring missense mutations, in-frame insertions or deletions, or duplication events.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('deletions', 'Var', (68, 77))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
232813	25010205	STAG2 mutation has previously been reported in one Ewing sarcoma tumor and in multiple EFT cell lines and has additionally been reported as a recurrently mutated tumor suppressor gene in other tumor types including glioblastoma, urothelial carcinoma, and acute myeloid leukemia.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('reported', 'Reg', (35, 43))	('tumor', 'Disease', (162, 167))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (261, 277))	('STAG2', 'Gene', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('Ewing sarcoma tumor', 'Disease', 'MESH:C563168', (51, 70))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (255, 277))	('tumor', 'Disease', (65, 70))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (255, 277))	('urothelial carcinoma', 'Disease', (229, 249))	('leukemia', 'Phenotype', 'HP:0001909', (269, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('Ewing sarcoma tumor', 'Disease', (51, 70))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (215, 227))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (229, 249))	('glioblastoma', 'Disease', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (215, 227))	('mutation', 'Var', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('acute myeloid leukemia', 'Disease', (255, 277))
232814	25010205	Mutations in TP53 and CDKN2A were found in frequencies similar to that previously reported.	('TP53', 'Gene', (13, 17))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (34, 39))	('TP53', 'Gene', '7157', (13, 17))
232815	25010205	In total we found that 40% of EFT clinical tumors and 97% of EFT cell lines have disruption of STAG2, TP53 or CDKN2A.	('CDKN2A', 'Gene', (110, 116))	('TP53', 'Gene', (102, 106))	('disruption', 'Var', (81, 91))	('CDKN2A', 'Gene', '1029', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('STAG2', 'Gene', (95, 100))	('EFT', 'Disease', (30, 33))	('tumors', 'Disease', (43, 49))	('TP53', 'Gene', '7157', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('clinical', 'Species', '191496', (34, 42))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
232816	25010205	The striking difference in mutational frequencies between tumors and cell lines, particularly in TP53, may be a result of culture conditions and the process of immortalization.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TP53', 'Gene', '7157', (97, 101))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('TP53', 'Gene', (97, 101))	('mutational', 'Var', (27, 37))
232817	25010205	In addition to the recurrent mutations in STAG2, TP53 and CDKN2A, we found a high prevalence of the BRCA2 K3326X polymorphism, seen in 7.3% of our clinical tumor samples.	('BRCA2', 'Gene', (100, 105))	('K3326X', 'Var', (106, 112))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('BRCA2', 'Gene', '675', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('CDKN2A', 'Gene', (58, 64))	('tumor', 'Disease', (156, 161))	('K3326X', 'Mutation', 'rs11571833', (106, 112))	('clinical', 'Species', '191496', (147, 155))	('CDKN2A', 'Gene', '1029', (58, 64))
232818	25010205	Occurring in approximately 1% of the general population, this premature stop codon has not been shown to confer an increased risk of breast or ovarian cancer and is classified as a benign variant by the International Agency for Research on Cancer Unclassified Genetic Variants Working Group.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (133, 157))	('Cancer', 'Disease', (240, 246))	('premature stop codon', 'Var', (62, 82))	('Cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Cancer', 'Disease', 'MESH:D009369', (240, 246))	('breast or ovarian cancer', 'Disease', (133, 157))
232821	25010205	In addition to STAG2, other recurrent alterations in subunits of this complex have been reported across a number of cancer types.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('reported', 'Reg', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('alterations', 'Var', (38, 49))
232822	25010205	Potentially, the oncologic mechanism for cohesin mutation is disrupted chromosomal segregation during mitosis leading to accumulation of structural mutations and aneuploidy.	('cohesin', 'Gene', (41, 48))	('structural', 'MPA', (137, 147))	('aneuploidy', 'Disease', (162, 172))	('disrupted', 'NegReg', (61, 70))	('mutation', 'Var', (49, 57))	('chromosomal segregation', 'CPA', (71, 94))	('aneuploidy', 'Disease', 'MESH:D000782', (162, 172))	('accumulation', 'PosReg', (121, 133))	('mitosis', 'Disease', (102, 109))	('mitosis', 'Disease', 'None', (102, 109))
232823	25010205	Though we find EFT to have a low rate of aneuploidy overall in our comprehensively characterized WGS cohort, further work is indicated to clarify whether or not a STAG2 mutation is linked to increased aneuploidy in this tumor histology.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('mutation', 'Var', (169, 177))	('tumor', 'Disease', (220, 225))	('STAG2', 'Gene', (163, 168))	('aneuploidy', 'Disease', (201, 211))	('aneuploidy', 'Disease', 'MESH:D000782', (41, 51))	('aneuploidy', 'Disease', 'MESH:D000782', (201, 211))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('aneuploidy', 'Disease', (41, 51))
232824	25010205	In our evaluation of the cellular impact of STAG2 in EFT, we note a significant intersection of STAG2 mutation with alteration of the TP53 pathway.	('mutation', 'Var', (102, 110))	('TP53', 'Gene', '7157', (134, 138))	('STAG2', 'Gene', (96, 101))	('TP53', 'Gene', (134, 138))
232825	25010205	STAG2 mutated samples also had low RNA expressional levels of CDKN1A (encoding p21WAF1/CIP1), a well-established mediator of p53 tumor suppressor activity.	('CDKN1A', 'Gene', '1026', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('p21WAF1/CIP1', 'Gene', '1026', (79, 91))	('RNA expressional levels', 'MPA', (35, 58))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('p21WAF1/CIP1', 'Gene', (79, 91))	('CDKN1A', 'Gene', (62, 68))	('low', 'NegReg', (31, 34))	('tumor', 'Disease', (129, 134))	('mutated', 'Var', (6, 13))
232826	25010205	Though there was less overlap between STAG2 mutation and TP53 mutation in the sequenced tumor cohort, we noted the same pattern of decreased CDKN1A expression in STAG2 mutant samples.	('STAG2', 'Gene', (162, 167))	('mutation', 'Var', (44, 52))	('mutant', 'Var', (168, 174))	('TP53', 'Gene', '7157', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CDKN1A', 'Gene', '1026', (141, 147))	('decreased', 'NegReg', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CDKN1A', 'Gene', (141, 147))	('expression', 'MPA', (148, 158))	('TP53', 'Gene', (57, 61))	('tumor', 'Disease', (88, 93))	('STAG2', 'Gene', (38, 43))
232828	25010205	Given the significant percentage of tumors harboring a STAG2 mutation in this cancer type, further investigation into the oncogenic mechanism, clinical consequence, as well as strategies for directed therapy are warranted.	('STAG2', 'Gene', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mutation', 'Var', (61, 69))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('clinical', 'Species', '191496', (143, 151))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
232832	25010205	Further studies will be needed to determine if the presence of these additional genetic aberrations will impact the sensitivity/resistance to small molecule inhibitors of EWS-FLI1 or PARP that are currently in development and early phase clinical trials.	('FLI1', 'Gene', '2313', (175, 179))	('impact', 'Reg', (105, 111))	('clinical', 'Species', '191496', (238, 246))	('sensitivity/resistance', 'MPA', (116, 138))	('PARP', 'Gene', (183, 187))	('FLI1', 'Gene', (175, 179))	('EWS', 'Gene', '2130', (171, 174))	('EWS', 'Gene', (171, 174))	('presence', 'Var', (51, 59))
232845	25010205	We determined that more stringent somatic score cut-off was required in our cohort to achieve adequate positive predictive value of variants calls, likely due to the low mutation rate in our tumor type.	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('variants', 'Var', (132, 140))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (191, 196))
232850	25010205	For variant detection, samtools (http://samtools.sourceforge.net/) is used to count the number of reads uniquely mapped to a position found as variant in DNA sequencing of the same sample or a position of interest based on a mutation being present in the TCGA (http://cancergenome.nih.gov/) or compared to the reference genome hg19 in genes of interest.	('cancer', 'Disease', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('variant', 'Var', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('mutation', 'Var', (225, 233))
232855	25010205	Traces with putative mutations were reamplified and sequenced from both tumor and matched normal DNA from blood when available.	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutations', 'Var', (21, 30))
232861	25010205	For the BRCA2 K3326X polymorphism, a two-tailed Fisher Exact Test was used to calculate p-value for the Odds Ratio significantly different from 1.	('BRCA2', 'Gene', '675', (8, 13))	('K3326X', 'Var', (14, 20))	('K3326X', 'Mutation', 'rs11571833', (14, 20))	('BRCA2', 'Gene', (8, 13))
232879	24426787	Thus, dysregulation of miRNA expression may contribute to development of cancer through loss of these controls.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('contribute', 'Reg', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('loss', 'NegReg', (88, 92))	('dysregulation', 'Var', (6, 19))
232880	24426787	These cancer-related changes may represent a means of detection or characterization of malignancy through quantification of miRNA expression or, more importantly, may act as future therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('malignancy', 'Disease', 'MESH:D009369', (87, 97))	('malignancy', 'Disease', (87, 97))	('changes', 'Var', (21, 28))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('miR', 'Gene', '220972', (124, 127))	('cancer', 'Disease', (6, 12))	('miR', 'Gene', (124, 127))
232882	24426787	To date, there is a dearth of research relating to the role of miRNAs in other primary bone tumors, however it is possible that they too are significantly influenced by miRNA-related changes.	('influenced', 'Reg', (155, 165))	('bone tumors', 'Phenotype', 'HP:0010622', (87, 98))	('bone tumors', 'Disease', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('bone tumors', 'Disease', 'MESH:D001859', (87, 98))	('bone tumor', 'Phenotype', 'HP:0010622', (87, 97))	('miR', 'Gene', '220972', (169, 172))	('changes', 'Var', (183, 190))	('miR', 'Gene', (169, 172))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
232894	24426787	miRNA expression is tightly regulated via several mechanisms including specific translational regulation, deoxyribonucleic acid (DNA) methylation, and histone deacetylation, DNA copy alteration, and gene mutations affecting proteins involved in processing and maturation.	('proteins', 'Protein', (224, 232))	('rat', 'Species', '10116', (187, 190))	('deoxyribonucleic acid', 'MPA', (106, 127))	('copy alteration', 'Var', (178, 193))	('histone deacetylation', 'MPA', (151, 172))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('gene mutations', 'Var', (199, 213))	('rat', 'Species', '10116', (264, 267))	('affecting', 'Reg', (214, 223))
232895	24426787	Epigenetic changes such as DNA methylation and histone modification are associated with chromatin remodeling and regulation of gene expression in mammalian development and human diseases, including cancer.	('histone modification', 'Var', (47, 67))	('mammalian', 'Species', '9606', (146, 155))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('human', 'Species', '9606', (172, 177))	('associated', 'Reg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
232896	24426787	While DNA methylation leads to miRNA silencing, histone modification, especially methylation, can either trigger or suppress miRNA expression, depending on the target amino acid residues and the extent of methylation.	('methylation', 'Var', (81, 92))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('methylation', 'Var', (10, 21))	('suppress', 'NegReg', (116, 124))	('miR', 'Gene', '220972', (125, 128))	('trigger', 'PosReg', (105, 112))	('DNA', 'Var', (6, 9))	('miR', 'Gene', (125, 128))
232906	24426787	Aberrant miRNA expression patterns have recently been identified in a range of human diseases including many cancers.	('human', 'Species', '9606', (79, 84))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('identified', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
232907	24426787	This dysregulation of miRNA expression can influence carcinogenesis if the relevant target mRNAs are encoded by tumor suppressor genes or oncogenes.	('dysregulation', 'Var', (5, 18))	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('miR', 'Gene', '220972', (22, 25))	('influence', 'Reg', (43, 52))	('carcinogenesis', 'Disease', (53, 67))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('miR', 'Gene', (22, 25))
232921	24426787	One study found that DATS suppressed cell survival, invasion and angiogenesis in osteosarcoma cells and these effects were associated with decreased expression of Notch-1 and its downstream genes as well as increased expression of a panel of tumor-suppressive microRNAs including miR-34a, miR-143, miR-145, and miR-200b/c that are typically lost in osteosarcoma.	('suppressed', 'NegReg', (26, 36))	('expression', 'MPA', (217, 227))	('miR-34', 'Gene', (280, 286))	('miR-200b', 'Gene', (311, 319))	('tumor', 'Disease', (242, 247))	('angiogenesis', 'CPA', (65, 77))	('invasion', 'CPA', (52, 60))	('Notch-1', 'Gene', '4851', (163, 170))	('osteosarcoma', 'Phenotype', 'HP:0002669', (349, 361))	('miR-143', 'Var', (289, 296))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('miR-145', 'Gene', '406937', (298, 305))	('DATS', 'Chemical', 'MESH:C042577', (21, 25))	('Notch-1', 'Gene', (163, 170))	('miR-200b', 'Gene', '406984', (311, 319))	('sarcoma', 'Phenotype', 'HP:0100242', (354, 361))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('miR-145', 'Gene', (298, 305))	('expression', 'MPA', (149, 159))	('miR-34', 'Gene', '407040', (280, 286))	('osteosarcoma', 'Disease', (349, 361))	('osteosarcoma', 'Disease', 'MESH:D012516', (349, 361))	('osteosarcoma', 'Disease', (81, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('increased', 'PosReg', (207, 216))	('decreased', 'NegReg', (139, 148))	('cell survival', 'CPA', (37, 50))
232933	24426787	One study showed that mir-143 was the most downregulated miRNA in human osteosarcoma cell lines in a mouse model; however, in vitro transfection of miR-143 decreased cell invasiveness and intravenous injection of miR-143 suppressed lung metastasis of 143B sarcoma cells in the mouse model.	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('human', 'Species', '9606', (66, 71))	('mir-143', 'Gene', (22, 29))	('sarcoma', 'Disease', (77, 84))	('mouse', 'Species', '10090', (277, 282))	('miR', 'Gene', (148, 151))	('mir-143', 'Gene', '406935', (22, 29))	('mouse', 'Species', '10090', (101, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (72, 84))	('cell invasiveness', 'CPA', (166, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('transfection', 'Var', (132, 144))	('suppressed', 'NegReg', (221, 231))	('miR', 'Gene', '220972', (213, 216))	('miR', 'Gene', '220972', (57, 60))	('sarcoma', 'Disease', 'MESH:D012509', (256, 263))	('decreased', 'NegReg', (156, 165))	('sarcoma', 'Disease', (256, 263))	('miR', 'Gene', (57, 60))	('miR', 'Gene', (213, 216))	('osteosarcoma', 'Disease', (72, 84))	('osteosarcoma', 'Disease', 'MESH:D012516', (72, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('miR', 'Gene', '220972', (148, 151))
232943	24426787	Overexpression of miR-140 has also been shown to cause chemoresistance to methotrexate and 5-fluorouracil in xenograft models.	('chemoresistance', 'CPA', (55, 70))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (91, 105))	('miR-140', 'Gene', (18, 25))	('Overexpression', 'Var', (0, 14))	('methotrexate', 'Chemical', 'MESH:D008727', (74, 86))	('cause', 'Reg', (49, 54))	('miR-140', 'Gene', '406932', (18, 25))
232951	24426787	In addition, underexpression of the miRNA cluster at the 14q32 chromosomal locus has been shown to be predictive of chemoresponse, recurrence, and survival, as described in the previous section.	('underexpression', 'Var', (13, 28))	('survival', 'CPA', (147, 155))	('chemoresponse', 'CPA', (116, 129))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))	('recurrence', 'CPA', (131, 141))
232953	24426787	Ewing's sarcoma is a member of the Ewing family of tumors (EFT) and, unlike most other primary tumors of bone, has a characteristic translocation most commonly involving chromosomes 11 and 22.	("Ewing's sarcoma", 'Disease', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('primary tumors', 'Disease', (87, 101))	('Ewing family of tumors', 'Disease', 'MESH:C563168', (35, 57))	('tumors of bone', 'Phenotype', 'HP:0010622', (95, 109))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('primary tumors', 'Disease', 'MESH:D009369', (87, 101))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('tumors of bone', 'Disease', 'MESH:D001859', (95, 109))	('Ewing family of tumors', 'Disease', (35, 57))	('translocation', 'Var', (132, 145))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('tumors of bone', 'Disease', (95, 109))
232954	24426787	These translocations give rise to fusion genes comprising of the Ewing's sarcoma breakpoint 1 gene and one of several of its family members of transcription factors.	('give rise to', 'Reg', (21, 33))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (65, 80))	('fusion genes', 'Var', (34, 46))	("Ewing's sarcoma", 'Disease', (65, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (65, 80))	('translocations', 'Var', (6, 20))
232958	24426787	miR-145 is markedly reduced in Ewing's sarcoma cell lines and expression dramatically increases on knockdown of EWS-FLI1.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (31, 46))	("Ewing's sarcoma", 'Disease', (31, 46))	('increases', 'PosReg', (86, 95))	('expression', 'MPA', (62, 72))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (31, 46))	('EWS', 'Gene', '2130', (112, 115))	('EWS', 'Gene', (112, 115))	('knockdown', 'Var', (99, 108))	('miR-145', 'Gene', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('miR-145', 'Gene', '406937', (0, 7))	('FLI1', 'Gene', '2313', (116, 120))	('FLI1', 'Gene', (116, 120))
232992	24426787	In this study, which used colorectal cancer (SW620), melanoma (IGR37), and head and neck cancer (SIHN-011B) cell lines derived from lymph node metastases, reintroduction of miR-148a, miR-34b, and miR-34c into cancer cells with epigenetic inactivation inhibited motility, tumor growth, and metastasis formation in xenograft models, with associated downregulation of miRNA oncogenic target genes such as cMyc, the E2F2 transcription factor, cyclin-dependent kinase 6 (CDK6), and TGIF2.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('SIHN-011B', 'Disease', 'None', (97, 106))	('cMyc', 'Gene', (402, 406))	('miR', 'Gene', (196, 199))	('epigenetic inactivation', 'Var', (227, 250))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('inhibited', 'NegReg', (251, 260))	('cancer', 'Disease', (89, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('downregulation', 'NegReg', (347, 361))	('cyclin-dependent kinase 6', 'Gene', '1021', (439, 464))	('head and neck cancer', 'Phenotype', 'HP:0012288', (75, 95))	('metastasis formation', 'CPA', (289, 309))	('miR-148a', 'Gene', '406940', (173, 181))	('E2F2 transcription', 'Gene', (412, 430))	('miR-148a', 'Gene', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('motility', 'CPA', (261, 269))	('colorectal cancer', 'Disease', (26, 43))	('cMyc', 'Gene', '4609', (402, 406))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('SIHN-011B', 'Disease', (97, 106))	('miR-34b', 'Gene', (183, 190))	('miR', 'Gene', '220972', (183, 186))	('TGIF2', 'Gene', '60436', (477, 482))	('metastases', 'Disease', 'MESH:D009362', (143, 153))	('cancer', 'Disease', (37, 43))	('head and neck cancer', 'Disease', 'MESH:D006258', (75, 95))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('tumor', 'Disease', (271, 276))	('melanoma', 'Disease', (53, 61))	('CDK6', 'Gene', '1021', (466, 470))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('metastases', 'Disease', (143, 153))	('miR', 'Gene', (183, 186))	('miR', 'Gene', '220972', (365, 368))	('miR', 'Gene', '220972', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('miR-34b', 'Gene', '407041', (183, 190))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))	('TGIF2', 'Gene', (477, 482))	('CDK6', 'Gene', (466, 470))	('miR', 'Gene', '220972', (196, 199))	('cancer', 'Disease', (209, 215))	('cyclin-dependent kinase 6', 'Gene', (439, 464))	('SW620', 'CellLine', 'CVCL:0547', (45, 50))	('miR', 'Gene', (365, 368))	('miR', 'Gene', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
232994	24426787	A Chinese study using human small cell lung cancer cells in mouse xenograft models found that levels of miR-335 and mir-29a were reduced in SBC-5 cells (which metastasize to bone) compared to SBC-3 cells (which do not), as were receptor activator of nuclear factor kappa-B ligand (RANKL) and IGF-1R (key mediators in bone metastases).	('mir-29a', 'Gene', (116, 123))	('RANKL', 'Gene', (281, 286))	('SBC-5', 'Gene', (140, 145))	('bone metastases', 'Disease', 'MESH:D009362', (317, 332))	('reduced', 'NegReg', (129, 136))	('receptor activator of nuclear factor kappa-B ligand', 'Gene', '8600', (228, 279))	('lung cancer', 'Disease', (39, 50))	('levels', 'MPA', (94, 100))	('bone metastases', 'Disease', (317, 332))	('IGF-1R', 'Gene', '3480', (292, 298))	('IGF-1R', 'Gene', (292, 298))	('miR-335', 'Var', (104, 111))	('SBC-5', 'CellLine', 'CVCL:1679', (140, 145))	('RANKL', 'Gene', '8600', (281, 286))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('human', 'Species', '9606', (22, 27))	('mouse', 'Species', '10090', (60, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('mir-29a', 'Gene', '387222', (116, 123))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (28, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
232997	24426787	Loss of miR-335 was associated with metastatic osteolytic skeletal lesions.miR-33a expression is also altered in lung cancer and underexpression may be associated with bone metastasis via increased activity of parathyroid hormone related protein (PTHrP) induced osteoclastogenesis.	('parathyroid hormone related protein', 'Gene', (210, 245))	('PTHrP', 'Gene', (247, 252))	('osteoclastogenesis', 'Disease', (262, 280))	('PTHrP', 'Gene', '5744', (247, 252))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('associated', 'Reg', (152, 162))	('parathyroid hormone related protein', 'Gene', '5744', (210, 245))	('increased', 'PosReg', (188, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('bone metastasis', 'CPA', (168, 183))	('activity', 'MPA', (198, 206))	('altered', 'Reg', (102, 109))	('osteolytic skeletal lesions', 'Disease', (47, 74))	('underexpression', 'Var', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('miR-33a', 'Gene', (75, 82))	('lung cancer', 'Disease', (113, 124))	('osteoclastogenesis', 'Disease', 'None', (262, 280))	('osteolytic skeletal lesions', 'Disease', 'MESH:D030981', (47, 74))	('miR-33a', 'Gene', '407039', (75, 82))
233010	24426787	These could include measures to reduce expression of oncogenic miRNAs, such as miRNA silencing, antisense blocking, and miRNA modifications.	('reduce', 'NegReg', (32, 38))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('expression', 'MPA', (39, 49))	('antisense blocking', 'Var', (96, 114))
233122	20224682	Omitting RT in an LSS-approached patient increases the risk of local recurrence.	('Omitting', 'Var', (0, 8))	('local recurrence', 'CPA', (63, 79))	('patient', 'Species', '9606', (33, 40))
233225	33061942	For KEGG pathway analysis, significantly enriched pathways of DEGs were enriched in staphylococcus aureus infection, cell cycle and rheumatoid arthritis signaling pathways (Figure 3D; Table 3).	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (132, 152))	('arthritis', 'Phenotype', 'HP:0001369', (143, 152))	('cell cycle', 'CPA', (117, 127))	('rheumatoid arthritis', 'Disease', (132, 152))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (132, 152))	('aureus infection', 'Disease', 'MESH:D013203', (99, 115))	('aureus infection', 'Disease', (99, 115))	('staphylococcus', 'Disease', (84, 98))	('DEGs', 'Var', (62, 66))	('staphylococcus aureus infection', 'Phenotype', 'HP:0002726', (84, 115))
233236	33061942	As shown in Figure 8, SS patients with high expression of CENPF, KIF11, KIF23, TTK, MKI67, TOP2A, CDC45, MELK, AURKB, and BUB1 had worse overall survival.	('MELK', 'Gene', (105, 109))	('KIF11', 'Gene', (65, 70))	('TOP2A', 'Gene', '7153', (91, 96))	('MKI67', 'Gene', (84, 89))	('overall', 'MPA', (137, 144))	('MKI67', 'Gene', '4288', (84, 89))	('TTK', 'Gene', '7272', (79, 82))	('KIF23', 'Gene', '9493', (72, 77))	('BUB1', 'Gene', '699', (122, 126))	('AURKB', 'Gene', (111, 116))	('BUB1', 'Gene', (122, 126))	('MELK', 'Gene', '9833', (105, 109))	('SS', 'Phenotype', 'HP:0012570', (22, 24))	('CENPF', 'Gene', (58, 63))	('patients', 'Species', '9606', (25, 33))	('CENPF', 'Gene', '1063', (58, 63))	('CDC45', 'Gene', '8318', (98, 103))	('TTK', 'Gene', (79, 82))	('high expression', 'Var', (39, 54))	('CDC45', 'Gene', (98, 103))	('KIF23', 'Gene', (72, 77))	('AURKB', 'Gene', '9212', (111, 116))	('KIF11', 'Gene', '3832', (65, 70))	('TOP2A', 'Gene', (91, 96))
233237	33061942	Moreover, SS patients with high expression of CENPF, KIF11, KIF23, TTK, MKI67, TOP2A, CDC45, MELK, AURKB, and BUB1 predicted worse recurrence-free survival (Figure 9).	('KIF23', 'Gene', '9493', (60, 65))	('AURKB', 'Gene', (99, 104))	('TTK', 'Gene', (67, 70))	('patients', 'Species', '9606', (13, 21))	('worse', 'NegReg', (125, 130))	('SS', 'Phenotype', 'HP:0012570', (10, 12))	('MELK', 'Gene', '9833', (93, 97))	('TOP2A', 'Gene', (79, 84))	('CDC45', 'Gene', '8318', (86, 91))	('recurrence-free survival', 'CPA', (131, 155))	('TOP2A', 'Gene', '7153', (79, 84))	('CDC45', 'Gene', (86, 91))	('AURKB', 'Gene', '9212', (99, 104))	('KIF11', 'Gene', '3832', (53, 58))	('KIF23', 'Gene', (60, 65))	('high', 'Var', (27, 31))	('TTK', 'Gene', '7272', (67, 70))	('KIF11', 'Gene', (53, 58))	('MELK', 'Gene', (93, 97))	('BUB1', 'Gene', '699', (110, 114))	('BUB1', 'Gene', (110, 114))	('MKI67', 'Gene', (72, 77))	('CENPF', 'Gene', (46, 51))	('MKI67', 'Gene', '4288', (72, 77))	('CENPF', 'Gene', '1063', (46, 51))
233252	33061942	Currently, a high MKI67 expression predicts for poor prognosis in patients with retroperitoneal soft tissue sarcomas.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (96, 116))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('retroperitoneal soft tissue sarcomas', 'Disease', 'MESH:D012509', (80, 116))	('MKI67', 'Gene', (18, 23))	('MKI67', 'Gene', '4288', (18, 23))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (96, 115))	('retroperitoneal soft tissue sarcomas', 'Disease', (80, 116))	('patients', 'Species', '9606', (66, 74))
233263	33061942	Recent studies have showed that in the process of carcinogenesis, the cell cycle is critical and dysregulated cell cycle may cause uncontrolled cell proliferation, survival and differentiation which are essential for the early stages of carcinogenesis.	('dysregulated', 'Var', (97, 109))	('carcinogenesis', 'Disease', (50, 64))	('uncontrolled', 'MPA', (131, 143))	('cell cycle', 'CPA', (110, 120))	('survival', 'CPA', (164, 172))	('carcinogenesis', 'Disease', 'MESH:D063646', (237, 251))	('differentiation', 'CPA', (177, 192))	('cause', 'Reg', (125, 130))	('carcinogenesis', 'Disease', (237, 251))	('dysregulated cell cycle', 'Phenotype', 'HP:0011018', (97, 120))	('carcinogenesis', 'Disease', 'MESH:D063646', (50, 64))
233268	33061942	Genetic and epigenetic alterations that occur in tumor cells are likely to contribute to tumor cell invasion and metastasis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('contribute', 'Reg', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('epigenetic alterations', 'Var', (12, 34))	('Genetic', 'Var', (0, 7))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('metastasis', 'CPA', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
233412	30649606	Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1 A broad spectrum of primary sarcoma subtypes are now recognized to occur intracranially, presumably arising from mesenchymal progenitor cells within the meningeal covering of the brain and along perivascular Virchow-Robin spaces.	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('DICER1', 'Gene', (35, 41))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (141, 158))	('neurofibromatosis type 1', 'Disease', 'MESH:D009456', (141, 165))	('neurofibromatosis type 1', 'Disease', (141, 165))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('DICER1', 'Gene', '23405', (35, 41))	('mutation', 'Var', (42, 50))	('sarcoma', 'Disease', (194, 201))	('Robin', 'Species', '9188', (382, 387))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('Primary intracranial sarcomas', 'Disease', 'MESH:D012509', (0, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('perivascular Virchow-Robin spaces', 'Phenotype', 'HP:0012520', (361, 394))	('Primary intracranial sarcomas', 'Disease', (0, 29))	('sarcoma', 'Disease', (21, 28))
233413	30649606	Here we report the clinical, radiologic, histologic, and molecular features of three patients with intracranial sarcomas that are unified by the presence of primary intracranial location with meningeal involvement, pleomorphic morphology, high proliferation index, prominent eosinophilic cytoplasmic globules, focal immunophenotypic evidence of myogenic differentiation, and the combination of DICER1 and TP53 mutations, along with ATRX inactivation and genetic alterations causing activation of the MAP kinase signaling pathway.	('DICER1', 'Gene', (394, 400))	('TP53', 'Gene', (405, 409))	('DICER1', 'Gene', '23405', (394, 400))	('MAP kinase signaling pathway', 'Pathway', (500, 528))	('ATRX', 'Gene', (432, 436))	('high proliferation index', 'CPA', (239, 263))	('mutations', 'Var', (410, 419))	('ATRX', 'Gene', '546', (432, 436))	('intracranial sarcomas', 'Disease', 'MESH:D012509', (99, 120))	('patients', 'Species', '9606', (85, 93))	('intracranial sarcomas', 'Disease', (99, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('myogenic differentiation', 'CPA', (345, 369))	('TP53', 'Gene', '7157', (405, 409))
233436	30649606	All three cases demonstrated hotspot missense mutations in exons 24 or 25 of the DICER1 gene (p.E1705K, p.G1809R, and p.E1813K) located within the Ribonuclease III domain near the C-terminus of the encoded microRNA processing enzyme (Supplemental Table 3 [Online Resource 2]), which have been recurrently seen as confirmed somatic mutations in numerous cystic nephromas, Sertoli-Leydig cell tumors, and other neoplasms known to be driven by DICER1 mutation (Catalog Of Somatic Mutations In Cancer [COSMIC] database, version 87 release).	('p.E1813K', 'Mutation', 'p.E1813K', (118, 126))	('p.G1809R', 'Var', (104, 112))	('p.E1813K', 'Var', (118, 126))	('neoplasms', 'Phenotype', 'HP:0002664', (409, 418))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (371, 397))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (371, 397))	('DICER1', 'Gene', '23405', (441, 447))	('neoplasm', 'Phenotype', 'HP:0002664', (409, 417))	('DICER1', 'Gene', (441, 447))	('DICER1', 'Gene', '23405', (81, 87))	('cystic nephromas', 'Disease', 'MESH:D018201', (353, 369))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (379, 397))	('neoplasms', 'Disease', 'MESH:D009369', (409, 418))	('missense mutations', 'Var', (37, 55))	('p.E1705K', 'Var', (94, 102))	('cystic nephromas', 'Disease', (353, 369))	('DICER1', 'Gene', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('p.G1809R', 'Mutation', 'p.G1809R', (104, 112))	('neoplasms', 'Disease', (409, 418))	('tumors', 'Phenotype', 'HP:0002664', (391, 397))	('Sertoli-Leydig cell tumors', 'Disease', (371, 397))	('Cancer', 'Phenotype', 'HP:0002664', (490, 496))	('p.E1705K', 'Mutation', 'p.E1705K', (94, 102))
233437	30649606	The DICER1 mutation in the tumor from patient #1 was homozygous due to copy-neutral loss of heterozygosity of chromosome 14q that eliminated the remaining wildtype allele.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('DICER1', 'Gene', (4, 10))	('DICER1', 'Gene', '23405', (4, 10))	('tumor', 'Disease', (27, 32))	('loss', 'NegReg', (84, 88))	('patient', 'Species', '9606', (38, 45))	('mutation', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('wildtype', 'MPA', (155, 163))
233438	30649606	In the tumors from patients #2 and #3, there was a second splice site mutation in the DICER1 gene (c.2436+1G>A and c.5365-1G>A) likely to be present in trans and causing inactivation of the remaining wildtype allele.	('patients', 'Species', '9606', (19, 27))	('DICER1', 'Gene', (86, 92))	('DICER1', 'Gene', '23405', (86, 92))	('inactivation', 'MPA', (170, 182))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('c.5365-1G>A', 'Var', (115, 126))	('c.2436+1G>A', 'Mutation', 'c.2436+1G>A', (99, 110))	('c.2436+1G>A', 'Var', (99, 110))	('c.5365-1G>A', 'Mutation', 'c.5365-1G>A', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
233439	30649606	Such inactivating mutations affecting one allele together with a hotspot missense mutation affecting the other allele are commonly seen in tumor types known to be driven by DICER1 mutations.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutations', 'Var', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('DICER1', 'Gene', (173, 179))	('DICER1', 'Gene', '23405', (173, 179))	('inactivating mutations', 'Var', (5, 27))
233440	30649606	Additionally, all three cases demonstrated inactivating mutations affecting the TP53 tumor suppressor gene (p.W91*, p.C238F, and p.E258K) accompanied by loss of the remaining wildtype alleles.	('tumor', 'Disease', (85, 90))	('p.C238F', 'Mutation', 'rs730882005', (116, 123))	('p.W91*', 'Var', (108, 114))	('p.C238F', 'Var', (116, 123))	('p.W91*', 'Mutation', 'p.W91*', (108, 114))	('p.E258K', 'Mutation', 'rs121912652', (129, 136))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('inactivating mutations', 'Var', (43, 65))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p.E258K', 'Var', (129, 136))
233441	30649606	Two cases demonstrated inactivation of the ATRX tumor suppressor gene, one with deep deletion and one with a nonsense mutation (p.W263*).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('deep deletion', 'Var', (80, 93))	('ATRX', 'Gene', '546', (43, 47))	('p.W263*', 'Mutation', 'p.W263*', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('p.W263*', 'Var', (128, 135))	('inactivation', 'Var', (23, 35))	('ATRX', 'Gene', (43, 47))
233442	30649606	The tumor from patient #1 harbored an activating hotspot mutation in the KRAS oncogene (p.G12D), and the tumor from patient #3 harbored a hotspot missense mutation in the PDGFRA oncogene (p.D842Y) located within the intracellular tyrosine kinase domain that has been recurrently seen as a confirmed somatic mutation in numerous gastrointestinal stromal tumors (COSMIC database, version 87 release).	('tumor', 'Disease', (4, 9))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (328, 359))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (328, 359))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('PDGFRA', 'Gene', (171, 177))	('p.D842Y', 'Mutation', 'rs121913265', (188, 195))	('PDGFRA', 'Gene', '5156', (171, 177))	('tumor', 'Disease', (353, 358))	('KRAS', 'Gene', '3845', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('gastrointestinal stromal tumors', 'Disease', (328, 359))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (105, 110))	('patient', 'Species', '9606', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (353, 359))	('p.D842Y', 'Var', (188, 195))	('KRAS', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('patient', 'Species', '9606', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('p.G12D', 'Mutation', 'rs121913529', (88, 94))	('activating hotspot', 'PosReg', (38, 56))
233443	30649606	Patient #2 was found to harbor a heterozygous truncating nonsense mutation in NF1 tumor suppressor gene (p.R192*) in the germline, genetically confirming the clinical diagnosis of NF1.	('NF1', 'Gene', (180, 183))	('p.R192*', 'Var', (105, 112))	('NF1', 'Gene', '4763', (180, 183))	('p.R192*', 'Mutation', 'p.R192*', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('NF1', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('NF1', 'Gene', '4763', (78, 81))	('tumor', 'Disease', (82, 87))	('Patient', 'Species', '9606', (0, 7))
233444	30649606	A second somatic missense mutation in the NF1 gene (p.D2632G) was seen in the tumor, indicating that the sarcoma likely arose, at least in part, due to biallelic NF1 inactivation.	('NF1', 'Gene', (162, 165))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('NF1', 'Gene', '4763', (162, 165))	('p.D2632G', 'Var', (52, 60))	('p.D2632G', 'Mutation', 'p.D2632G', (52, 60))	('inactivation', 'NegReg', (166, 178))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('sarcoma', 'Disease', (105, 112))	('tumor', 'Disease', (78, 83))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', (42, 45))
233445	30649606	As tumor tissue only without a paired normal sample was sequenced for patients #1 and #3, the somatic versus germline status of the identified DICER1 and TP53 mutations could not be determined, but the DICER1 and TP53 mutations in patient #2 were both confirmed to be somatic (tumor-specific).	('DICER1', 'Gene', (202, 208))	('patients', 'Species', '9606', (70, 78))	('DICER1', 'Gene', '23405', (202, 208))	('tumor', 'Disease', (3, 8))	('TP53', 'Gene', (154, 158))	('TP53', 'Gene', (213, 217))	('DICER1', 'Gene', '23405', (143, 149))	('TP53', 'Gene', '7157', (154, 158))	('mutations', 'Var', (218, 227))	('patient', 'Species', '9606', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Disease', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('patient', 'Species', '9606', (231, 238))	('TP53', 'Gene', '7157', (213, 217))	('DICER1', 'Gene', (143, 149))
233447	30649606	Genome-wide DNA methylation profiling was performed on cases #1 and #2 as previously described using the Illumina MethylationEPIC BeadChip (850k array) to further characterize these primary intracranial sarcomas with myogenic differentiation and DICER1 mutation.	('intracranial sarcomas', 'Disease', 'MESH:D012509', (190, 211))	('mutation', 'Var', (253, 261))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('intracranial sarcomas', 'Disease', (190, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('myogenic differentiation', 'CPA', (217, 241))	('DICER1', 'Gene', (246, 252))	('DICER1', 'Gene', '23405', (246, 252))
233451	30649606	Disease recurrence adjacent to the resection cavity in the left parietal lobe was seen on follow-up imaging at four years after initial resection, and a second resection was recently performed confirming recurrent pleomorphic sarcoma with myogenic differentiation and DICER1 mutation.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('DICER1', 'Gene', (268, 274))	('DICER1', 'Gene', '23405', (268, 274))	('mutation', 'Var', (275, 283))	('sarcoma', 'Disease', 'MESH:D012509', (226, 233))	('sarcoma', 'Disease', (226, 233))
233453	30649606	Overall, this series of three primary intracranial sarcomas has significant similarities with the group of "primary intracranial spindle cell sarcomas with rhabdomyosarcoma-like features, DICER1 mutant" that were recently reported including primary intracranial location, immunophenotypic evidence of focal myogenic differentiation, overlapping genome-wide methylation profile, co-occurring DICER1 and TP53 mutations, and alterations activating the MAP kinase signaling pathway.	('DICER1', 'Gene', '23405', (188, 194))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (156, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('mutations', 'Var', (407, 416))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (156, 172))	('DICER1', 'Gene', (188, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('TP53', 'Gene', (402, 406))	('activating', 'Reg', (434, 444))	('intracranial sarcomas', 'Disease', 'MESH:D012509', (38, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('MAP kinase signaling pathway', 'Pathway', (449, 477))	('DICER1', 'Gene', '23405', (391, 397))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('intracranial spindle cell sarcomas', 'Disease', 'MESH:D012509', (116, 150))	('intracranial spindle cell sarcomas', 'Disease', (116, 150))	('focal myogenic differentiation', 'CPA', (301, 331))	('intracranial sarcomas', 'Disease', (38, 59))	('DICER1', 'Gene', (391, 397))	('TP53', 'Gene', '7157', (402, 406))	('rhabdomyosarcoma', 'Disease', (156, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))
233454	30649606	However, the tumors in our series have morphology best characterized as pleomorphic rather than spindled, uniformly lack rhabdomyoblasts and myogenin expression, and demonstrate frequent ATRX inactivation.	('inactivation', 'Var', (192, 204))	('lack', 'NegReg', (116, 120))	('ATRX', 'Gene', '546', (187, 191))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('rhabdomyoblasts', 'Protein', (121, 136))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('myogenin', 'Gene', (141, 149))	('myogenin', 'Gene', '4656', (141, 149))	('ATRX', 'Gene', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
233457	30649606	In addition to the previously reported association with the DICER1 pleuropulmonary blastoma tumor syndrome, we identify that these primary intracranial sarcomas with DICER1 mutation can also occur in the setting of NF1, thereby extending the tumor spectrum associated with this common familial tumor syndrome.	('NF1', 'Gene', (215, 218))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('intracranial sarcomas', 'Disease', (139, 160))	('DICER1', 'Gene', (166, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('tumor', 'Disease', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('DICER1', 'Gene', '23405', (60, 66))	('pleuropulmonary blastoma tumor syndrome', 'Disease', (67, 106))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('DICER1', 'Gene', (60, 66))	('familial tumor syndrome', 'Disease', (285, 308))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (294, 299))	('intracranial sarcomas', 'Disease', 'MESH:D012509', (139, 160))	('NF1', 'Gene', '4763', (215, 218))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('pleuropulmonary blastoma tumor syndrome', 'Disease', 'MESH:C537516', (67, 106))	('familial tumor syndrome', 'Disease', 'MESH:D009386', (285, 308))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('DICER1', 'Gene', '23405', (166, 172))	('tumor', 'Disease', (92, 97))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (67, 91))	('mutation', 'Var', (173, 181))
233505	27428733	BCOR Overexpression is a Highly Sensitive Marker in Round Cell Sarcomas with BCOR Genetic Abnormalities With the advent of next-generation sequencing, an increasing number of novel gene fusions and other abnormalities have emerged recently in the spectrum of EWSR1-negative small blue round cell tumors (SBRCTs).	('Genetic Abnormalities', 'Disease', (82, 103))	('BCOR', 'Gene', '54880', (0, 4))	('cell tumors', 'Disease', 'MESH:D005935', (291, 302))	('Cell Sarcomas', 'Disease', (58, 71))	('fusions', 'Var', (186, 193))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('Genetic Abnormalities', 'Disease', 'MESH:D030342', (82, 103))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('EWSR1', 'Gene', (259, 264))	('BCOR', 'Gene', (77, 81))	('Sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('cell tumors', 'Disease', (291, 302))	('BCOR', 'Gene', '54880', (77, 81))	('EWSR1', 'Gene', '2130', (259, 264))	('BCOR', 'Gene', (0, 4))	('Cell Sarcomas', 'Disease', 'MESH:D012509', (58, 71))
233506	27428733	In this regard, a subset of SBRCTs harboring either BCOR gene fusions (BCOR-CCNB3, BCOR-MAML3), BCOR internal tandem duplications (ITD), or YWHAE-NUTM2B share a transcriptional signature including high BCOR mRNA expression, as well as similar histologic features.	('MAML3', 'Gene', '55534', (88, 93))	('BCOR', 'Gene', (52, 56))	('BCOR', 'Gene', '54880', (96, 100))	('BCOR', 'Gene', (96, 100))	('NUTM2B', 'Gene', '729262', (146, 152))	('CCNB3', 'Gene', '85417', (76, 81))	('BCOR', 'Gene', '54880', (71, 75))	('YWHAE', 'Gene', (140, 145))	('internal tandem duplications', 'Var', (101, 129))	('NUTM2B', 'Gene', (146, 152))	('CCNB3', 'Gene', (76, 81))	('YWHAE', 'Gene', '7531', (140, 145))	('BCOR', 'Gene', (71, 75))	('BCOR', 'Gene', '54880', (202, 206))	('MAML3', 'Gene', (88, 93))	('BCOR', 'Gene', '54880', (52, 56))	('BCOR', 'Gene', '54880', (83, 87))	('BCOR', 'Gene', (202, 206))	('BCOR', 'Gene', (83, 87))
233511	27428733	In addition we included related pathologic entities such as 8 CCSKs and other sarcomas with BCOR gene fusions.	('sarcomas', 'Disease', (78, 86))	('BCOR', 'Gene', (92, 96))	('CCSKs', 'Chemical', '-', (62, 67))	('gene fusions', 'Var', (97, 109))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('CCSK', 'Phenotype', 'HP:0006770', (62, 66))	('BCOR', 'Gene', '54880', (92, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))
233514	27428733	All SBRCTs with BCOR-MAML3 and BCOR-CCNB3 fusions, as well as most with BCOR ITD (93%), and all CCSKs showed strong and diffuse nuclear BCOR immunoreactivity.	('BCOR', 'Gene', (72, 76))	('BCOR', 'Gene', (31, 35))	('CCNB3', 'Gene', '85417', (36, 41))	('BCOR', 'Gene', '54880', (136, 140))	('BCOR', 'Gene', '54880', (31, 35))	('MAML3', 'Gene', '55534', (21, 26))	('CCSK', 'Phenotype', 'HP:0006770', (96, 100))	('BCOR', 'Gene', (16, 20))	('MAML3', 'Gene', (21, 26))	('BCOR', 'Gene', '54880', (16, 20))	('BCOR', 'Gene', '54880', (72, 76))	('CCSKs', 'Chemical', '-', (96, 101))	('CCNB3', 'Gene', (36, 41))	('BCOR', 'Gene', (136, 140))	('fusions', 'Var', (42, 49))
233517	27428733	In conclusion, BCOR immunohistochemical stain is a highly sensitive marker for SBRCTs and CCSKs with BCOR abnormalities and YWHAE rearrangements and can be used as a useful diagnostic marker in these various molecular subsets.	('BCOR', 'Gene', (101, 105))	('YWHAE', 'Gene', '7531', (124, 129))	('BCOR', 'Gene', (15, 19))	('CCSKs', 'Chemical', '-', (90, 95))	('BCOR', 'Gene', '54880', (15, 19))	('BCOR', 'Gene', '54880', (101, 105))	('YWHAE', 'Gene', (124, 129))	('abnormalities', 'Var', (106, 119))	('CCSK', 'Phenotype', 'HP:0006770', (90, 94))
233521	27428733	As a result of the wide application of next generation sequencing to undifferentiated round cell sarcomas, an increasing number of novel genetic abnormalities have been identified including: CIC-DUX4, CIC-FOXO4, BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, YWHAE-NUTM2B gene fusions or BCOR internal tandem duplication (ITD).	('MAML3', 'Gene', (229, 234))	('BCOR', 'Gene', '54880', (224, 228))	('FOXO4', 'Gene', (205, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('MAML3', 'Gene', '55534', (229, 234))	('BCOR', 'Gene', (224, 228))	('CIC', 'Gene', '23152', (191, 194))	('BCOR', 'Gene', '54880', (278, 282))	('NUTM2B', 'Gene', '729262', (255, 261))	('CCNB3', 'Gene', '85417', (217, 222))	('FOXO4', 'Gene', '4303', (205, 210))	('BCOR', 'Gene', '54880', (212, 216))	('BCOR', 'Gene', (278, 282))	('DUX4', 'Gene', (195, 199))	('CIC', 'Gene', (201, 204))	('internal tandem duplication', 'Var', (283, 310))	('BCOR', 'Gene', (212, 216))	('BCOR', 'Gene', '54880', (243, 247))	('YWHAE', 'Gene', (249, 254))	('ZC3H7B', 'Gene', (236, 242))	('NUTM2B', 'Gene', (255, 261))	('genetic abnormalities', 'Disease', 'MESH:D030342', (137, 158))	('CCNB3', 'Gene', (217, 222))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('ZC3H7B', 'Gene', '23264', (236, 242))	('genetic abnormalities', 'Disease', (137, 158))	('DUX4', 'Gene', '100288687', (195, 199))	('YWHAE', 'Gene', '7531', (249, 254))	('CIC', 'Gene', (191, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('BCOR', 'Gene', (243, 247))	('sarcomas', 'Disease', (97, 105))	('CIC', 'Gene', '23152', (201, 204))
233558	27428733	For comparison, we included the expression data of normal human tissues and non-sarcomatous tumoral tissues (randomly selected samples from GSE16515, GSE50161, GSE7307).	('non-sarcomatous tumoral', 'Disease', (76, 99))	('human', 'Species', '9606', (58, 63))	('GSE7307', 'Var', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('GSE7307', 'Chemical', '-', (160, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('non-sarcomatous tumoral', 'Disease', 'MESH:D018316', (76, 99))	('GSE16515', 'Var', (140, 148))	('GSE50161', 'Var', (150, 158))
233559	27428733	After the signal intensities were log2-transformed, the expression levels of BCOR and SATB2 in these samples were evaluated and compared to the round cell sarcomas with BCOR abnormalities or YWHAE fusions and CCSKs.	('SATB2', 'Gene', '23314', (86, 91))	('sarcomas', 'Disease', 'MESH:D012509', (155, 163))	('BCOR', 'Gene', (169, 173))	('CCSKs', 'Chemical', '-', (209, 214))	('CCSK', 'Phenotype', 'HP:0006770', (209, 213))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcomas', 'Disease', (155, 163))	('YWHAE', 'Gene', '7531', (191, 196))	('BCOR', 'Gene', '54880', (169, 173))	('BCOR', 'Gene', (77, 81))	('abnormalities', 'Var', (174, 187))	('BCOR', 'Gene', '54880', (77, 81))	('SATB2', 'Gene', (86, 91))	('YWHAE', 'Gene', (191, 196))
233562	27428733	In addition, as both SSX1 (Xp11.23) or SSX2 (Xp11.22) and BCOR (Xp11.4) are located on the p-arm of chromosome X, we investigated the expression of neighboring genes within a 21.8 MB region (chr X: 31,000,000-52,792,617) for potential coupled upregulation.	('BCOR', 'Gene', (58, 62))	('BCOR', 'Gene', '54880', (58, 62))	('investigated', 'Reg', (117, 129))	('SSX1', 'Gene', '6756', (21, 25))	('Xp11.4', 'Var', (64, 70))	('SSX1', 'Gene', (21, 25))	('SSX2', 'Gene', (39, 43))	('SSX2', 'Gene', '6757', (39, 43))
233564	27428733	All SBRCTs with BCOR ITD, YWHAE-NUTM2B, BCOR-MAML3 and BCOR-CCNB3 fusions showed nuclear expression of BCOR (Fig.	('YWHAE', 'Gene', (26, 31))	('NUTM2B', 'Gene', '729262', (32, 38))	('BCOR', 'Gene', (55, 59))	('CCNB3', 'Gene', '85417', (60, 65))	('BCOR', 'Gene', '54880', (55, 59))	('BCOR', 'Gene', '54880', (103, 107))	('nuclear expression', 'MPA', (81, 99))	('CCNB3', 'Gene', (60, 65))	('BCOR', 'Gene', (40, 44))	('BCOR', 'Gene', (16, 20))	('NUTM2B', 'Gene', (32, 38))	('MAML3', 'Gene', '55534', (45, 50))	('BCOR', 'Gene', '54880', (40, 44))	('YWHAE', 'Gene', '7531', (26, 31))	('MAML3', 'Gene', (45, 50))	('fusions', 'Var', (66, 73))	('BCOR', 'Gene', '54880', (16, 20))	('BCOR', 'Gene', (103, 107))
233589	27428733	Furthermore, no BCOR reactivity was noted in the 3 cases harboring ZC3H7B-BCOR fusion (2 endometrial stromal sarcoma and 1 ossifying fibromyxoid tumor).	('endometrial stromal sarcoma', 'Disease', (89, 116))	('ZC3H7B', 'Gene', '23264', (67, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('fibromyxoid tumor', 'Disease', 'MESH:D009369', (133, 150))	('BCOR', 'Gene', (74, 78))	('BCOR', 'Gene', (16, 20))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (89, 116))	('fusion', 'Var', (79, 85))	('fibromyxoid tumor', 'Disease', (133, 150))	('ZC3H7B', 'Gene', (67, 73))	('BCOR', 'Gene', '54880', (74, 78))	('BCOR', 'Gene', '54880', (16, 20))
233615	27428733	BCOR (BCL-6 interacting corepressor) is a transcriptional corepressor involved in suppressing gene expression by either interacting with BCL-6 or binding to PCGF1 (polycomb-group RING finger homologue 1), as part of a variant Polycomb Repressive Complex 1 (PRC1), and inducing gene silencing via histone modification.	('BCOR', 'Gene', '54880', (0, 4))	('BCL-6 interacting corepressor', 'Gene', '54880', (6, 35))	('PCGF1', 'Gene', (157, 162))	('variant', 'Var', (218, 225))	('inducing', 'Reg', (268, 276))	('suppressing', 'NegReg', (82, 93))	('PCGF1', 'Gene', '84759', (157, 162))	('BCL-6 interacting corepressor', 'Gene', (6, 35))	('BCL-6', 'Gene', (6, 11))	('binding', 'Interaction', (146, 153))	('interacting', 'Interaction', (120, 131))	('gene', 'MPA', (277, 281))	('gene expression', 'MPA', (94, 109))	('BCL-6', 'Gene', (137, 142))	('histone modification', 'MPA', (296, 316))	('BCL-6', 'Gene', '604', (6, 11))	('BCL-6', 'Gene', '604', (137, 142))	('BCOR', 'Gene', (0, 4))
233624	27428733	Specifically, we noted significant up-regulation of BCOR and SATB2 mRNA expression in round cell sarcomas with BCOR alterations (ITD, BCOR-CCNB3, BCOR-MAML3) and YWHAE-NUTM2B fusion, as well as in CCSKs.	('CCSKs', 'Chemical', '-', (197, 202))	('BCOR', 'Gene', (52, 56))	('up-regulation', 'PosReg', (35, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('MAML3', 'Gene', (151, 156))	('alterations', 'Var', (116, 127))	('CCNB3', 'Gene', '85417', (139, 144))	('NUTM2B', 'Gene', '729262', (168, 174))	('BCOR', 'Gene', '54880', (111, 115))	('MAML3', 'Gene', '55534', (151, 156))	('CCSK', 'Phenotype', 'HP:0006770', (197, 201))	('BCOR', 'Gene', (111, 115))	('BCOR', 'Gene', '54880', (134, 138))	('CCNB3', 'Gene', (139, 144))	('YWHAE', 'Gene', (162, 167))	('BCOR', 'Gene', (134, 138))	('NUTM2B', 'Gene', (168, 174))	('YWHAE', 'Gene', '7531', (162, 167))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('BCOR', 'Gene', '54880', (52, 56))	('SATB2', 'Gene', (61, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('BCOR', 'Gene', '54880', (146, 150))	('SATB2', 'Gene', '23314', (61, 66))	('sarcomas', 'Disease', (97, 105))	('mRNA expression', 'MPA', (67, 82))	('BCOR', 'Gene', (146, 150))
233626	27428733	Our results showed that the overwhelming majority of SBRCTs harboring BCOR-ITD, BCOR-CCNB3, BCOR-MAML3, and YWHAE-NUTM2B abnormalities demonstrate strong and diffuse nuclear immunoreactivity to BCOR.	('YWHAE', 'Gene', '7531', (108, 113))	('abnormalities', 'Var', (121, 134))	('NUTM2B', 'Gene', (114, 120))	('CCNB3', 'Gene', (85, 90))	('BCOR', 'Gene', (70, 74))	('BCOR', 'Gene', (80, 84))	('CCNB3', 'Gene', '85417', (85, 90))	('BCOR', 'Gene', '54880', (80, 84))	('BCOR', 'Gene', (194, 198))	('BCOR', 'Gene', (92, 96))	('BCOR', 'Gene', '54880', (70, 74))	('BCOR', 'Gene', '54880', (194, 198))	('NUTM2B', 'Gene', '729262', (114, 120))	('BCOR', 'Gene', '54880', (92, 96))	('YWHAE', 'Gene', (108, 113))	('MAML3', 'Gene', '55534', (97, 102))	('MAML3', 'Gene', (97, 102))
233628	27428733	In addition to BCOR, round cell sarcomas with BCOR-CCNB3 fusion were also shown to have CCNB3 mRNA up-regulation.	('mRNA', 'MPA', (94, 98))	('CCNB3', 'Gene', (51, 56))	('CCNB3', 'Gene', '85417', (88, 93))	('BCOR', 'Gene', (46, 50))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('up-regulation', 'PosReg', (99, 112))	('BCOR', 'Gene', (15, 19))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('BCOR', 'Gene', '54880', (15, 19))	('CCNB3', 'Gene', (88, 93))	('BCOR', 'Gene', '54880', (46, 50))	('CCNB3', 'Gene', '85417', (51, 56))	('sarcomas', 'Disease', (32, 40))	('fusion', 'Var', (57, 63))
233637	27428733	In contrast to the diffuse and strong staining pattern seen in SBRCTs with BCOR-gene alterations, BCOR immunoreactivity in synovial sarcomas was more variable in intensity and extent.	('synovial sarcomas', 'Phenotype', 'HP:0012570', (123, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('BCOR', 'Gene', (98, 102))	('synovial sarcomas', 'Disease', 'MESH:D013584', (123, 140))	('synovial sarcomas', 'Disease', (123, 140))	('BCOR', 'Gene', (75, 79))	('alterations', 'Var', (85, 96))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (123, 139))	('BCOR', 'Gene', '54880', (75, 79))	('BCOR', 'Gene', '54880', (98, 102))
233641	27428733	It is intriguing to speculate that the histologic overlap with mixed round and spindle cell phenotype and BCOR immunoreactivity seen in both synovial sarcoma and SBRCT with BCOR-gene alterations might be related to the BCOR gene upregulation through different pathogenetic mechanisms.	('BCOR', 'Gene', '54880', (106, 110))	('BCOR', 'Gene', '54880', (219, 223))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (141, 157))	('synovial sarcoma', 'Disease', 'MESH:D013584', (141, 157))	('alterations', 'Var', (183, 194))	('upregulation', 'PosReg', (229, 241))	('BCOR', 'Gene', (173, 177))	('BCOR', 'Gene', '54880', (173, 177))	('BCOR', 'Gene', (106, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('BCOR', 'Gene', (219, 223))	('synovial sarcoma', 'Disease', (141, 157))
233643	27428733	Our results showed that only tumors harboring fusions with 5'BCOR partner had BCOR protein overexpression by immunohistochemistry, while tumors with 3'BCOR fusions did not.	('tumors', 'Disease', (137, 143))	('BCOR', 'Gene', '54880', (151, 155))	('overexpression', 'PosReg', (91, 105))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('fusions', 'Var', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BCOR', 'Gene', (78, 82))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('BCOR', 'Gene', '54880', (78, 82))	('BCOR', 'Gene', (61, 65))	('BCOR', 'Gene', (151, 155))	('tumors', 'Disease', (29, 35))	('BCOR', 'Gene', '54880', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
233646	27428733	Furthermore, in contrast to the BCOR-CCNB3 or BCOR-MAML3 positive SBRCTs, our RNA sequencing data showed that tumors with ZC3H7B-BCOR fusion had low levels of BCOR mRNA expression.	('CCNB3', 'Gene', '85417', (37, 42))	('ZC3H7B', 'Gene', '23264', (122, 128))	('BCOR', 'Gene', (129, 133))	('BCOR', 'Gene', '54880', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('BCOR', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('BCOR', 'Gene', '54880', (159, 163))	('CCNB3', 'Gene', (37, 42))	('tumors', 'Disease', (110, 116))	('BCOR', 'Gene', '54880', (46, 50))	('BCOR', 'Gene', (46, 50))	('BCOR', 'Gene', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('MAML3', 'Gene', (51, 56))	('fusion', 'Var', (134, 140))	('MAML3', 'Gene', '55534', (51, 56))	('low', 'NegReg', (145, 148))	('BCOR', 'Gene', '54880', (129, 133))	('ZC3H7B', 'Gene', (122, 128))
233648	27428733	In contrast to the diffuse and consistent staining results in SBRCTs with BCOR-gene abnormalities, BCOR reactivity was present with patchy moderate intensity only in one of the 8 Ewing sarcoma tested.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('BCOR', 'Gene', '54880', (74, 78))	('Ewing sarcoma', 'Disease', (179, 192))	('BCOR', 'Gene', (74, 78))	('abnormalities', 'Var', (84, 97))	('BCOR', 'Gene', (99, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (179, 192))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (179, 192))	('BCOR', 'Gene', '54880', (99, 103))
233655	27428733	Other mechanisms of BCOR overexpression may involve epigenetic regulations.	('BCOR', 'Gene', '54880', (20, 24))	('epigenetic regulations', 'Var', (52, 74))	('BCOR', 'Gene', (20, 24))
233657	27428733	For BCOR ITD tumors, the duplicated BCOR sequences reside in the region encoding the PUFD (PCGF ubiquitin-like fold discriminator) domain of BCOR, which is responsible for the binding with PCGF1 (polycomb group ring finger 1) and the formation of a variant PRC1, involved in histone modification.	('polycomb group ring finger 1', 'Gene', (196, 224))	('polycomb group ring finger 1', 'Gene', '84759', (196, 224))	('PRC1', 'Gene', (257, 261))	('BCOR', 'Gene', (141, 145))	('BCOR', 'Gene', '54880', (4, 8))	('BCOR', 'Gene', (36, 40))	('ITD tumors', 'Disease', 'MESH:D009369', (9, 19))	('variant', 'Var', (249, 256))	('BCOR', 'Gene', '54880', (141, 145))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('PCGF1', 'Gene', (189, 194))	('ITD tumors', 'Disease', (9, 19))	('binding', 'Interaction', (176, 183))	('BCOR', 'Gene', '54880', (36, 40))	('PCGF1', 'Gene', '84759', (189, 194))	('BCOR', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
233669	27428733	In conclusion, we demonstrated BCOR immunohistochemistry as a highly sensitive marker in identifying round cell sarcomas with BCOR abnormality, namely BCOR gene rearrangement or ITD, and YWHAE fusion.	('BCOR', 'Gene', (31, 35))	('sarcomas', 'Disease', (112, 120))	('BCOR', 'Gene', '54880', (126, 130))	('BCOR', 'Gene', '54880', (151, 155))	('BCOR', 'Gene', '54880', (31, 35))	('YWHAE', 'Gene', '7531', (187, 192))	('BCOR', 'Gene', (126, 130))	('sarcomas', 'Disease', 'MESH:D012509', (112, 120))	('BCOR', 'Gene', (151, 155))	('YWHAE', 'Gene', (187, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('abnormality', 'Var', (131, 142))
233689	22898541	Three early genetic observations helped define the problem: First, there are mutants of RSV that instead of transforming the fibroblast host into a rounded cell, induce an elongated, fusiform cell shape.	('RSV', 'Gene', (88, 91))	('RSV', 'Species', '11886', (88, 91))	('induce', 'Reg', (162, 168))	('mutants', 'Var', (77, 84))	('elongated', 'CPA', (172, 181))
233690	22898541	Second, a replication-defective variant of RSV transforms cells without producing infectious progeny, which indicated that the generation of progeny virus is not a prerequisite for oncogenicity.	('replication-defective', 'Reg', (10, 31))	('rat', 'Species', '10116', (131, 134))	('variant', 'Var', (32, 39))	('RSV', 'Species', '11886', (43, 46))	('RSV', 'Gene', (43, 46))
233694	22898541	In 1970, a groundbreaking paper in Nature described a mutant of the replication-competent Schmidt-Ruppin strain of RSV that transforms cells at a low, permissive temperature but fails to transform at an elevated, non-permissive temperature.	('RSV', 'Species', '11886', (115, 118))	('transforms', 'Reg', (124, 134))	('rat', 'Species', '10116', (233, 236))	('rat', 'Species', '10116', (167, 170))	('mutant', 'Var', (54, 60))
233699	22898541	Mutant RSVs that are transformation-defective, but replication-competent, contain a smaller RNA than the parental virus, suggesting that the lost sequences represent the oncogene (Fig.	('Mutant', 'Var', (0, 6))	('RSV', 'Species', '11886', (7, 10))	('RNA', 'MPA', (92, 95))
233702	22898541	One of these tools, subtractive hybridization, was applied to DNA transcripts of non-defective RSV and its replication-defective deletion mutant and resulted in the isolation of src-specific DNA sequences.	('RSV', 'Gene', (95, 98))	('RSV', 'Species', '11886', (95, 98))	('deletion mutant', 'Var', (129, 144))	('src', 'Gene', (178, 181))	('src', 'Gene', '6714', (178, 181))
233716	22898541	The viral Src protein differs from its cellular progenitor by a C-terminal deletion that includes a critical regulatory phosphorylation site and by several point mutations.	('Src', 'Gene', '6714', (10, 13))	('Src', 'Gene', (10, 13))	('point mutations', 'Var', (156, 171))
233722	22898541	In viral Src, these inhibitory interactions are absent because of the C-terminal deletion and point mutations in the SH3 domain, making viral Src constitutively active.	('Src', 'Gene', '6714', (9, 12))	('SH3', 'Gene', (117, 120))	('point mutations', 'Var', (94, 109))	('Src', 'Gene', (142, 145))	('Src', 'Gene', '6714', (142, 145))	('Src', 'Gene', (9, 12))
233744	22898541	The discovery of c-MYC rearrangements in a human lymphoma was the first indication that cellular counterparts of retroviral oncogenes are involved in the pathogenesis of human disease.	('c-MYC', 'Gene', (17, 22))	('lymphoma', 'Disease', (49, 57))	('involved', 'Reg', (138, 146))	('lymphoma', 'Disease', 'MESH:D008223', (49, 57))	('rearrangements', 'Var', (23, 37))	('human', 'Species', '9606', (170, 175))	('c-MYC', 'Gene', '4609', (17, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))	('human', 'Species', '9606', (43, 48))
233746	22898541	Mutations in the coding region of MYC do not play a significant role in human cancer.	('MYC', 'Gene', (34, 37))	('cancer', 'Disease', (78, 84))	('human', 'Species', '9606', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
233762	22898541	Although numerous somatic mutations occur within the catalytic subunit of human PI3K, no mutations have been found in the Ras binding domain, suggesting that interaction with Ras is essential for the function of PI3K.	('interaction', 'Interaction', (158, 169))	('mutations', 'Var', (26, 35))	('PI3K', 'Gene', (80, 84))	('human', 'Species', '9606', (74, 79))
233785	22898541	Finally and most importantly, sequence analysis revealed both close homology to EGFR and a large deletion in the extracellular domain of viral ErbB.	('ErbB', 'Gene', (143, 147))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('ErbB', 'Gene', '1956', (143, 147))	('deletion in', 'Var', (97, 108))
233786	22898541	In addition to the N-terminal truncation, viral ErbB proteins also show mutations in the kinase domain located in the C-terminal cytoplasmic portion of the protein.	('mutations', 'Var', (72, 81))	('ErbB', 'Gene', (48, 52))	('ErbB', 'Gene', '1956', (48, 52))
233788	22898541	The mutations in viral ErbB do not cause a mere quantitative enhancement of the same signaling pathways that are controlled by cellular EGFR but induce qualitative changes in the spectrum of signaling targets.	('spectrum of signaling targets', 'MPA', (179, 208))	('changes', 'Reg', (164, 171))	('ErbB', 'Gene', '1956', (23, 27))	('ErbB', 'Gene', (23, 27))	('mutations', 'Var', (4, 13))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
233790	22898541	Mutations that mechanistically resemble those seen in viral ErbB occur in the EGFR of glioblastoma multiforme and non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (86, 109))	('non-small cell lung cancer', 'Disease', (114, 140))	('ErbB', 'Gene', (60, 64))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (118, 140))	('ErbB', 'Gene', '1956', (60, 64))	('Mutations', 'Var', (0, 9))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (114, 140))	('EGFR', 'Gene', '1956', (78, 82))	('glioblastoma multiforme', 'Disease', (86, 109))	('EGFR', 'Gene', (78, 82))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (114, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
233791	22898541	About 50% of glioblastomas carry the EGFRvIII mutant which has lost a large portion of the extracellular domain and no longer binds ligand but signals constitutively, addressing targets that are different from those of wild-type EGFR.	('glioblastomas', 'Phenotype', 'HP:0012174', (13, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('EGFR', 'Gene', '1956', (37, 41))	('mutant', 'Var', (46, 52))	('EGFR', 'Gene', (229, 233))	('glioblastomas', 'Disease', 'MESH:D005909', (13, 26))	('EGFR', 'Gene', '1956', (229, 233))	('EGFR', 'Gene', (37, 41))	('glioblastomas', 'Disease', (13, 26))	('addressing', 'Reg', (167, 177))
233792	22898541	Such a cancer-specific mutation in a kinase would appear to be an ideal therapeutic target.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Disease', (7, 13))	('mutation', 'Var', (23, 31))
233793	22898541	However, the clinical experience with inhibitors of EGFR in glioblastoma has been uneven, with tumor shrinkage linked to the co-expression of EGFRvIII and of the tumor suppressor PTEN.	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('linked', 'Reg', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('EGFR', 'Gene', '1956', (142, 146))	('tumor', 'Disease', (162, 167))	('EGFR', 'Gene', (142, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('inhibitors', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('PTEN', 'Gene', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', (95, 100))	('PTEN', 'Gene', '5728', (179, 183))
233794	22898541	In non-small cell lung cancer, EGFR mutations are located in the kinase domain and lead to constitutive autophosphorylation and activation.	('activation', 'PosReg', (128, 138))	('EGFR', 'Gene', '1956', (31, 35))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('EGFR', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('constitutive autophosphorylation', 'MPA', (91, 123))	('non-small cell lung cancer', 'Disease', (3, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
233795	22898541	Such cancers, seen mostly in non-smokers, are uniquely sensitive to EGFR inhibitors but regularly develop resistance to these drugs.	('develop', 'Reg', (98, 105))	('inhibitors', 'Var', (73, 83))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('EGFR', 'Gene', '1956', (68, 72))	('resistance', 'MPA', (106, 116))	('sensitive', 'Reg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('EGFR', 'Gene', (68, 72))
233798	22898541	The cell-transforming gene in these experiments was identified as EGFR-related with an activating mutation in the transmembrane domain.	('EGFR', 'Gene', (66, 70))	('activating', 'PosReg', (87, 97))	('mutation in the', 'Var', (98, 113))	('EGFR', 'Gene', '1956', (66, 70))
233805	22898541	Most of these viruses are replication-competent, do not carry an oncogene, and induce tumors (mostly lymphoid leukosis) by insertional activation of a cellular oncogene.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('activation', 'PosReg', (135, 145))	('tumors', 'Disease', (86, 92))	('insertional', 'Var', (123, 134))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('induce', 'PosReg', (79, 85))	('mostly lymphoid leukosis', 'Disease', 'MESH:D016583', (94, 118))	('mostly lymphoid leukosis', 'Disease', (94, 118))
233806	22898541	But occasionally the genetic recombination between virus and host results in the incorporation of an oncogene into the viral genome.	('genetic recombination', 'Var', (21, 42))	('results in', 'Reg', (66, 76))	('incorporation', 'MPA', (81, 94))	('rat', 'Species', '10116', (88, 91))
233810	22898541	Slaughterhouse veterinarians have been the source of several new, rapidly oncogenic retroviruses, and from these viruses, three new oncogenes were isolated: jun, qin and pi3k.	('qin', 'Gene', (162, 165))	('pi3k', 'Var', (170, 174))	('qin', 'Gene', '2290', (162, 165))
233821	22898541	Direct evidence for the oncogenicity of PI3K came with the discovery of an avian hemangiosarcoma virus, ASV16, in a tumor obtained from a chicken processing plant.	('hemangiosarcoma virus', 'Disease', (81, 102))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('chicken', 'Species', '9031', (138, 145))	('hemangiosarcoma virus', 'Disease', 'MESH:D006394', (81, 102))	('PI3K', 'Var', (40, 44))	('tumor', 'Disease', (116, 121))
233823	22898541	The viral pi3k harbors several mutations in the p110alpha coding sequence, but these do not induce a gain of function and are irrelevant for oncogenic activity.	('mutations', 'Var', (31, 40))	('p110alpha', 'Gene', (48, 57))	('p110alpha', 'Gene', '5290', (48, 57))
233826	22898541	Support for this idea comes from the observation that a myristylation signal added to the N-terminus of cellular p110alpha also has a strongly activating effect and makes the protein oncogenic.	('protein', 'Protein', (175, 182))	('makes', 'Reg', (165, 170))	('myristylation', 'Var', (56, 69))	('activating effect', 'MPA', (143, 160))	('p110alpha', 'Gene', (113, 122))	('oncogenic', 'CPA', (183, 192))	('p110alpha', 'Gene', '5290', (113, 122))
233828	22898541	Rather, these N-terminal additions appear to induce a conformational change that mimics activation of p110alpha by upstream signals.	('p110alpha', 'Gene', '5290', (102, 111))	('p110alpha', 'Gene', (102, 111))	('N-terminal', 'Var', (14, 24))	('conformational change', 'MPA', (54, 75))
233829	22898541	A similar mechanism for constitutive activity is seen with cancer-specific mutations that carry an amino acid substitution in the helical domain of p110alpha .	('p110alpha', 'Gene', (148, 157))	('p110alpha', 'Gene', '5290', (148, 157))	('amino acid substitution in', 'Var', (99, 125))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
233830	22898541	In such mutants, the inhibitory interaction with the regulatory subunit p85 is disrupted.	('p85', 'Gene', '5295', (72, 75))	('mutants', 'Var', (8, 15))	('p85', 'Gene', (72, 75))	('disrupted', 'NegReg', (79, 88))	('inhibitory interaction', 'MPA', (21, 43))
233831	22898541	PI3K has moved into the limelight as a cancer target because of frequent cancer-specific genetic and epigenetic changes that result in enhanced activity.	('genetic', 'Var', (89, 96))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('enhanced', 'PosReg', (135, 143))	('epigenetic changes', 'Var', (101, 119))	('activity', 'MPA', (144, 152))
233832	22898541	These include loss of function in the PI3K antagonist and tumor suppressor PTEN, elevated activity and amplification of PI3K and gain-of-function mutations in the catalytic subunit p110alpha.	('p110alpha', 'Gene', '5290', (181, 190))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('gain-of-function', 'PosReg', (129, 145))	('PI3K', 'Protein', (120, 124))	('mutations', 'Var', (146, 155))	('activity', 'MPA', (90, 98))	('loss of function', 'NegReg', (14, 30))	('elevated', 'PosReg', (81, 89))	('PTEN', 'Gene', (75, 79))	('amplification', 'MPA', (103, 116))	('p110alpha', 'Gene', (181, 190))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PTEN', 'Gene', '5728', (75, 79))
233843	22898541	The key discoveries were finding transcriptional activation of c-MYC by chromosomal translocation in Burkitt lymphoma, amplification of N-Myc in neuroblastoma and identification of activated RAS in DNA from human cancer cells (see also Table 2).	('neuroblastoma', 'Disease', (145, 158))	('neuroblastoma', 'Phenotype', 'HP:0003006', (145, 158))	('N-Myc', 'Gene', (136, 141))	('N-Myc', 'Gene', '4613', (136, 141))	('transcriptional', 'MPA', (33, 48))	('neuroblastoma', 'Disease', 'MESH:D009447', (145, 158))	('c-MYC', 'Gene', '4609', (63, 68))	('cancer', 'Disease', (213, 219))	('human', 'Species', '9606', (207, 212))	('Burkitt lymphoma', 'Disease', (101, 117))	('c-MYC', 'Gene', (63, 68))	('activation', 'PosReg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('lymphoma', 'Phenotype', 'HP:0002665', (109, 117))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (101, 117))	('chromosomal translocation', 'Var', (72, 97))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('amplification', 'Var', (119, 132))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (101, 117))
233847	22898541	A comprehensive view of cell-autonomous genetic alterations in cancer further includes tumor suppressors which contribute to the oncogenic phenotype by a loss of function, often as a result of epigenetic changes.	('rat', 'Species', '10116', (52, 55))	('epigenetic changes', 'Var', (193, 211))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('loss of function', 'NegReg', (154, 170))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
233855	22898541	Retroviruses of the subfamily oncovirus that lack an oncogene in their genome are able to induce cancer by insertional mutagenesis.	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('induce', 'PosReg', (90, 96))	('insertional mutagenesis', 'Var', (107, 130))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
233884	28489919	Furthermore, in a recent phase III study, eribulin was shown to prolong OS as compared with dacarbazine (median OS, 13.5 vs. 11.5 months; HR 0.77; P = 0.017), but not PFS (median PFS, 2.6 vs. 2.6 months; HR 0.88; P = 0.23), for the third-line therapy or later of patients with advanced liposarcoma or leiomyosarcoma.	('dacarbazine', 'Chemical', 'MESH:D003606', (92, 103))	('patients', 'Species', '9606', (263, 271))	('liposarcoma or leiomyosarcoma', 'Disease', 'MESH:D007890', (286, 315))	('eribulin', 'Var', (42, 50))	('liposarcoma', 'Phenotype', 'HP:0012034', (286, 297))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (301, 315))	('liposarcoma or leiomyosarcoma', 'Disease', (286, 315))	('prolong', 'PosReg', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('sarcoma', 'Phenotype', 'HP:0100242', (308, 315))
234111	22216245	Central to these changes are alterations in either the expression pattern or activity of integrins, key regulators of the organization of cytoskeleton, cell adhesion and survival.	('expression', 'MPA', (55, 65))	('alterations', 'Reg', (29, 40))	('changes', 'Var', (17, 24))	('rat', 'Species', '10116', (33, 36))	('activity', 'MPA', (77, 85))	('integrins', 'Protein', (89, 98))
234132	22216245	In a previous report, we have shown that EJ-ras expressing NIH3T3 cells (CCR2 cells) acquired the ability to migrate on laminin-111 surfaces, characterizing a dysfunctional pattern of migration.	('rat', 'Species', '10116', (187, 190))	('laminin-111', 'Gene', (120, 131))	('ability', 'MPA', (98, 105))	('NIH3T3', 'CellLine', 'CVCL:0594', (59, 65))	('rat', 'Species', '10116', (112, 115))	('migrate', 'CPA', (109, 116))	('CCR2', 'Gene', '12772', (73, 77))	('NIH3T3 cells', 'Var', (59, 71))	('CCR2', 'Gene', (73, 77))	('EJ', 'CellLine', 'CVCL:7039', (41, 43))	('laminin-111', 'Gene', '16777', (120, 131))
234155	22216245	On the other hand, Sigma12 were less migratory than S11 and S12 cells on laminin-111 substrata (Fig.	('less', 'NegReg', (32, 36))	('S12', 'CellLine', 'CVCL:T291', (60, 63))	('laminin-111', 'Gene', '16777', (73, 84))	('S11', 'Gene', (52, 55))	('migratory', 'CPA', (37, 46))	('rat', 'Species', '10116', (40, 43))	('Sigma12', 'Var', (19, 26))	('S11', 'Gene', '23997', (52, 55))	('laminin-111', 'Gene', (73, 84))	('rat', 'Species', '10116', (90, 93))
234162	22216245	Concomitantly, galectin-3 expressing Sigma12 cells were more migratory in response to laminin-111 than the parental cells (Fig.	('laminin-111', 'Gene', '16777', (86, 97))	('migratory', 'CPA', (61, 70))	('rat', 'Species', '10116', (64, 67))	('Sigma12', 'Var', (37, 44))	('laminin-111', 'Gene', (86, 97))	('galectin-3', 'Protein', (15, 25))	('more', 'PosReg', (56, 60))
234176	22216245	Exposure of cells to extracellular galectin-3 resulted in a significant decrease in the amount of phosphorylated FAK in cell protrusions, followed by an extensive reorganization of cytoskeletal actin and membrane ruffling as compared to control conditions (ctl or LN) or cells exposed to galectin-3 in the presence of lactose (LN+gal-3+lac) (Fig.	('gal-3', 'Gene', '16854', (330, 335))	('amount of phosphorylated FAK in', 'MPA', (88, 119))	('galectin-3', 'Var', (35, 45))	('reorganization', 'MPA', (163, 177))	('LN', 'Gene', '16777', (264, 266))	('cytoskeletal actin', 'MPA', (181, 199))	('decrease', 'NegReg', (72, 80))	('LN', 'Gene', '16777', (327, 329))	('gal-3', 'Gene', (330, 335))	('lactose', 'Chemical', 'MESH:D007785', (318, 325))
234209	22216245	Considering the possibility of a polarized secretion of galectin-3 at the cell leading edge, this de-adhesive state could contribute to cell migration, as galectin-3 led to the destabilization of focal complexes.	('contribute', 'Reg', (122, 132))	('focal complexes', 'CPA', (196, 211))	('galectin-3', 'Var', (155, 165))	('destabilization', 'NegReg', (177, 192))	('rat', 'Species', '10116', (144, 147))	('cell migration', 'CPA', (136, 150))
234214	22216245	In agreement with the phenomenon observed in sarcoma cells, Pierce and colleagues showed that knocking down of MGAT5 expression, which led to decreased synthesis of galectin-3 ligands in molecules such as the EGFR, interfered with the migratory response of breast cancer cells in response to EGF.	('sarcoma', 'Disease', (45, 52))	('EGFR', 'Gene', (209, 213))	('MGAT5', 'Gene', '107895', (111, 116))	('MGAT5', 'Gene', (111, 116))	('synthesis of', 'MPA', (152, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('decreased', 'NegReg', (142, 151))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('migratory response', 'CPA', (235, 253))	('knocking down', 'Var', (94, 107))	('galectin-3', 'Protein', (165, 175))	('breast cancer', 'Disease', (257, 270))	('rat', 'Species', '10116', (238, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('interfered', 'NegReg', (215, 225))	('EGFR', 'Gene', '13649', (209, 213))
234218	22216245	Regardless, exogenous galectin-3 led to decreased phosphorylation of FAK and loss of phosphorylated paxillin from the focal adhesion complexes, favoring sarcoma cell migration.	('paxillin', 'Gene', (100, 108))	('galectin-3', 'Protein', (22, 32))	('rat', 'Species', '10116', (169, 172))	('phosphorylation', 'MPA', (50, 65))	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('paxillin', 'Gene', '19303', (100, 108))	('sarcoma', 'Disease', (153, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('exogenous', 'Var', (12, 21))	('loss', 'NegReg', (77, 81))	('favoring', 'PosReg', (144, 152))	('decreased', 'NegReg', (40, 49))	('phosphorylated', 'MPA', (85, 99))	('FAK', 'Protein', (69, 72))
234220	22216245	FAK can trigger activation of small GTPases, such as Rac and Cdc42, that regulate extension of filopodia and lamellipodia at the leading edge and the formation of focal adhesion complexes during cell migration.	('FAK', 'Var', (0, 3))	('Cdc42', 'Gene', '12540', (61, 66))	('Rac', 'Gene', '19353', (53, 56))	('Cdc42', 'Gene', (61, 66))	('Rac', 'Gene', (53, 56))	('rat', 'Species', '10116', (203, 206))
234285	21494688	Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor.	('mTOR', 'Gene', (52, 56))	('Thr202/Tyr204', 'Var', (94, 107))	('Ser473', 'Var', (75, 81))	('Ser473', 'Chemical', '-', (75, 81))	('Tyr', 'Chemical', 'MESH:D014443', (101, 104))	('tumor', 'Disease', (170, 175))	('Thr202', 'Chemical', '-', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('mTOR', 'Gene', '2475', (52, 56))	('Akt', 'Gene', (70, 73))	('Tyr', 'Chemical', 'MESH:D014443', (131, 134))	('Akt', 'Gene', '207', (70, 73))	('Tyr204', 'Chemical', '-', (101, 107))	('ERK1/2', 'Gene', (86, 92))	('STAT3', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('ERK1/2', 'Gene', '5595;5594', (86, 92))	('Ser2448', 'Chemical', '-', (58, 65))	('STAT3', 'Gene', '6774', (124, 129))	('Ser2448', 'Var', (58, 65))
234296	21494688	Morphoproteomics (morphology+proteomics) involves immunohistochemical assessment of the activation of signaling pathways in cancer cells, and predicting susceptibility to small-molecule inhibitors, specific chemotherapeutic agents, and possibly, differentiating agents.	('cancer', 'Disease', (124, 130))	('activation', 'PosReg', (88, 98))	('signaling pathways', 'Pathway', (102, 120))	('small-molecule', 'Var', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
234309	21494688	A Multiple Ascending Dose Study of R1507 in Patients with Advanced Solid Tumors (now closed and not actively recruiting patients) NCT00400361 (Phase I), 2.	('Patients', 'Species', '9606', (44, 52))	('Advanced Solid Tumors', 'Disease', 'MESH:D009369', (58, 79))	('Tumor', 'Phenotype', 'HP:0002664', (73, 78))	('NCT00400361', 'Var', (130, 141))	('patients', 'Species', '9606', (120, 128))	('Tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Advanced Solid Tumors', 'Disease', (58, 79))
234325	21494688	Fluorescent in situ hybridrization showed a positive result for a clone with an EWSR1 gene rearrangement.	('EWSR1', 'Gene', '2130', (80, 85))	('rearrangement', 'Var', (91, 104))	('EWSR1', 'Gene', (80, 85))
234333	21494688	In December 2006, the patient was started on a Phase I study of R1507 (Roche, Nutley NJ), a fully human IgG1 type monoclonal antibody against IGF1R.	('IGF1R', 'Gene', '3480', (142, 147))	('IGF1R', 'Gene', (142, 147))	('human', 'Species', '9606', (98, 103))	('patient', 'Species', '9606', (22, 29))	('R1507', 'Var', (64, 69))
234339	21494688	Biopsy showed Ewing's sarcoma with a t(11;22) translocation.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (14, 29))	('t(11;22) translocation', 'Var', (37, 59))	("Ewing's sarcoma", 'Disease', (14, 29))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (14, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))
234357	21494688	In contrast, there was apparent upregulation of these analytes in the specimen from the IGF1R-resistant tumor that emerged during IGF1R antibody therapy, with predominant nuclear expression of both p-mTOR (Ser2448) and p-Akt (Ser473), consistent with mTORC2 pathway activation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('upregulation', 'PosReg', (32, 44))	('Akt', 'Gene', (221, 224))	('IGF1R', 'Gene', (130, 135))	('IGF1R', 'Gene', '3480', (88, 93))	('Ser473', 'Var', (226, 232))	('Ser2448', 'Chemical', '-', (206, 213))	('Ser473', 'Chemical', '-', (226, 232))	('Akt', 'Gene', '207', (221, 224))	('IGF1R', 'Gene', (88, 93))	('mTOR', 'Gene', (200, 204))	('mTOR', 'Gene', '2475', (200, 204))	('tumor', 'Disease', (104, 109))	('mTORC2', 'Gene', (251, 257))	('mTOR', 'Gene', (251, 255))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('IGF1R', 'Gene', '3480', (130, 135))	('mTORC2', 'Gene', '74343', (251, 257))	('mTOR', 'Gene', '2475', (251, 255))
234362	21494688	There was constitutive activation of mTOR in the patient's original and recurrent tumor, evidenced by phosphorylation (p) of mTOR in a putative site of activation, Ser2448, with a predominantly nuclear distribution most likely indicating an mTORC2 complex (rictor + p-mTOR), and correlative activation of Akt on Ser473 consistent with the presence of both mTORC2 and dominant expression of p-Akt (Ser473) in tumoral nuclei.	('mTOR', 'Gene', '2475', (268, 272))	('mTOR', 'Gene', '2475', (125, 129))	('patient', 'Species', '9606', (49, 56))	('mTOR', 'Gene', '2475', (37, 41))	('tumor', 'Disease', (82, 87))	('mTORC2', 'Gene', '74343', (241, 247))	('tumor', 'Disease', (408, 413))	('mTOR', 'Gene', (241, 245))	('mTORC2', 'Gene', (356, 362))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Ser2448', 'Chemical', '-', (164, 171))	('Akt', 'Gene', (305, 308))	('tumor', 'Disease', 'MESH:D009369', (408, 413))	('Ser473', 'Chemical', '-', (312, 318))	('Akt', 'Gene', '207', (305, 308))	('mTOR', 'Gene', '2475', (241, 245))	('Ser473', 'Chemical', '-', (397, 403))	('Akt', 'Gene', (392, 395))	('Ser2448', 'Var', (164, 171))	('tumoral', 'Disease', (408, 415))	('tumoral', 'Disease', 'MESH:D009369', (408, 415))	('mTORC2', 'Gene', '74343', (356, 362))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Akt', 'Gene', '207', (392, 395))	('mTOR', 'Gene', (356, 360))	('tumor', 'Phenotype', 'HP:0002664', (408, 413))	('rictor', 'Gene', (257, 263))	('mTOR', 'Gene', (268, 272))	('activation', 'PosReg', (291, 301))	('mTOR', 'Gene', (125, 129))	('rictor', 'Gene', '253260', (257, 263))	('mTOR', 'Gene', (37, 41))	('mTORC2', 'Gene', (241, 247))	('mTOR', 'Gene', '2475', (356, 360))
234379	21494688	In this context, our finding of upregulated p-Akt (Ser473) and p-mTOR (Ser2448) in patient 1's resistant tumor that emerged following IGF1R antibody therapy is consistent with a resistance mechanism that could be related to upregulation of TORC2.	('mTOR', 'Gene', (65, 69))	('Akt', 'Gene', '207', (46, 49))	('mTOR', 'Gene', '2475', (65, 69))	('Ser473', 'Chemical', '-', (51, 57))	('Ser2448', 'Chemical', '-', (71, 78))	('TORC2', 'Gene', (240, 245))	('IGF1R', 'Gene', (134, 139))	('upregulated', 'PosReg', (32, 43))	('Akt', 'Gene', (46, 49))	('TORC2', 'Gene', '200186', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IGF1R', 'Gene', '3480', (134, 139))	('patient', 'Species', '9606', (83, 90))	('tumor', 'Disease', (105, 110))	('Ser473', 'Var', (51, 57))	('Ser2448', 'Var', (71, 78))
234399	21494688	Inhibition of IGF1R and/or IGF1R and mTOR has resulted in significant clinical activity in patients with Ewing's sarcoma.	('IGF1R', 'Gene', '3480', (14, 19))	('patients', 'Species', '9606', (91, 99))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (105, 120))	('IGF1R', 'Gene', (27, 32))	('mTOR', 'Gene', (37, 41))	('Inhibition', 'Var', (0, 10))	('IGF1R', 'Gene', (14, 19))	('mTOR', 'Gene', '2475', (37, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (105, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	("Ewing's sarcoma", 'Disease', (105, 120))	('IGF1R', 'Gene', '3480', (27, 32))
234406	32178691	Our results show that miR-9-5p regulated the expression of both repressor element silencing transcription factor (REST) and mu-opioid receptors (MOR) by targeting REST in primary mouse BMSCs.	('mouse', 'Species', '10090', (179, 184))	('miR-9-5p', 'Var', (22, 30))	('REST', 'MPA', (163, 167))	('expression', 'MPA', (45, 55))	('miR-9-5p', 'Chemical', '-', (22, 30))	('repressor element silencing transcription factor', 'Gene', '19712', (64, 112))	('targeting', 'Reg', (153, 162))	('repressor element silencing transcription factor', 'Gene', (64, 112))
234408	32178691	In addition, miR-9-5p modified BMSCs alleviated cancer pain in the sarcoma-inoculated mouse model.	('sarcoma-inoculated', 'Disease', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer pain', 'Disease', (48, 59))	('mouse', 'Species', '10090', (86, 91))	('alleviated', 'NegReg', (37, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('miR-9-5p modified', 'Var', (13, 30))	('miR-9-5p', 'Chemical', '-', (13, 21))	('sarcoma-inoculated', 'Disease', 'MESH:D002372', (67, 85))	('pain', 'Phenotype', 'HP:0012531', (55, 59))	('cancer pain', 'Disease', 'MESH:D000072716', (48, 59))
234410	32178691	Our results indicate that miR-9-5p modified BMSCs can relieve bone cancer pain via modulating neuroinflammation in the central nervous system, suggesting genetically modified BMSCs could be a promising cell therapy in pain management.	('miR-9-5p', 'Var', (26, 34))	('pain', 'Phenotype', 'HP:0012531', (218, 222))	('pain', 'Phenotype', 'HP:0012531', (74, 78))	('neuroinflammation in the central nervous system', 'MPA', (94, 141))	('relieve', 'NegReg', (54, 61))	('modulating', 'Reg', (83, 93))	('pain', 'Disease', 'MESH:D010146', (218, 222))	('miR-9-5p', 'Chemical', '-', (26, 34))	('pain', 'Disease', (218, 222))	('pain', 'Disease', 'MESH:D010146', (74, 78))	('pain', 'Disease', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('bone cancer pain', 'Disease', 'MESH:D001859', (62, 78))	('bone cancer pain', 'Disease', (62, 78))	('bone cancer pain', 'Phenotype', 'HP:0002653', (62, 78))
234469	32178691	To test whether this predicted miR-9-5p binding site can effectively regulate REST expression, we further designed a mutated 3'-UTR of REST and then cloned the wide type or mutated REST 3'-UTR into a luciferase reporter construct, respectively (Fig.	('mutated', 'Var', (117, 124))	('mutated', 'Var', (173, 180))	('miR-9-5p', 'Chemical', '-', (31, 39))	('regulate', 'Reg', (69, 77))	('REST', 'MPA', (78, 82))
234470	32178691	As expected, miR-9-5p suppressed the luciferase activities expressed by WT-REST but not MUT-REST luciferase construct (Fig.	('suppressed', 'NegReg', (22, 32))	('activities', 'MPA', (48, 58))	('miR-9-5p', 'Var', (13, 21))	('luciferase', 'Enzyme', (37, 47))	('miR-9-5p', 'Chemical', '-', (13, 21))
234474	32178691	1d-g, overexpression of miR-9-5p reduced REST mRNA levels as well as protein expression 24 h post transfection.	('miR-9-5p', 'Chemical', '-', (24, 32))	('REST mRNA levels', 'MPA', (41, 57))	('protein expression', 'MPA', (69, 87))	('miR-9-5p', 'Var', (24, 32))	('reduced', 'NegReg', (33, 40))
234475	32178691	Our results indicated that MOR mRNA level and protein expression increased in BMSCs overexpressing miR-9-5p (Fig.	('increased', 'PosReg', (65, 74))	('MOR mRNA level', 'MPA', (27, 41))	('miR-9-5p', 'Var', (99, 107))	('protein expression', 'MPA', (46, 64))	('miR-9-5p', 'Chemical', '-', (99, 107))
234477	32178691	Taken together, our results indicate that miR-9-5p modulates expressions of REST and MOR, suggesting miR-9-5p might play a key role in pain sensation.	('miR-9-5p', 'Chemical', '-', (42, 50))	('pain', 'Phenotype', 'HP:0012531', (135, 139))	('miR-9-5p', 'Chemical', '-', (101, 109))	('modulates', 'Reg', (51, 60))	('miR-9-5p', 'Var', (42, 50))	('REST', 'MPA', (76, 80))	('MOR', 'MPA', (85, 88))	('pain sensation', 'Disease', (135, 149))	('expressions', 'MPA', (61, 72))	('pain sensation', 'Disease', 'MESH:D010146', (135, 149))
234482	32178691	Consistent with our previous findings that REST is one of the miR-9-5p target genes, overexpression of miR-9-5p reversed the increase of REST expression which resulted from cytokine treatment (Fig.	('miR-9-5p', 'Chemical', '-', (62, 70))	('miR-9-5p', 'Chemical', '-', (103, 111))	('REST expression', 'MPA', (137, 152))	('increase', 'PosReg', (125, 133))	('miR-9-5p', 'Var', (103, 111))
234484	32178691	These positive feedbacks were interrupted by miR-9-5p overexpression (Fig.	('miR-9-5p', 'Var', (45, 53))	('overexpression', 'PosReg', (54, 68))	('miR-9-5p', 'Chemical', '-', (45, 53))
234485	32178691	Furthermore, miR-9-5p overexpression suppressed IL-6- and TNF-alpha-induced cell apoptosis by inhibiting caspase 3 expression (Fig.	('caspase 3', 'Gene', '12367', (105, 114))	('miR-9-5p', 'Var', (13, 21))	('caspase 3', 'Gene', (105, 114))	('overexpression', 'PosReg', (22, 36))	('TNF-alpha', 'Gene', (58, 67))	('expression', 'MPA', (115, 125))	('inhibiting', 'NegReg', (94, 104))	('miR-9-5p', 'Chemical', '-', (13, 21))	('TNF-alpha', 'Gene', '21926', (58, 67))	('IL-6', 'Gene', (48, 52))	('IL-6', 'Gene', '16193', (48, 52))	('suppressed', 'NegReg', (37, 47))
234486	32178691	Therefore, our results indicate that miR-9-5p can modify BMSCs by modulating the cytokine mediating signaling pathways which involve REST.	('BMSCs', 'Disease', (57, 62))	('cytokine mediating signaling pathways', 'Pathway', (81, 118))	('modulating', 'Reg', (66, 76))	('modify', 'Reg', (50, 56))	('miR-9-5p', 'Chemical', '-', (37, 45))	('miR-9-5p', 'Var', (37, 45))
234487	32178691	To investigate whether miR-9-5p modified BMSCs can alleviate cancer pain, we first checked the expression level of REST as well as MOR whose expression has been reported to be closely associated with REST expression in the mouse sarcoma model.	('MOR', 'Gene', (131, 134))	('miR-9-5p', 'Var', (23, 31))	('mouse', 'Species', '10090', (223, 228))	('cancer pain', 'Disease', 'MESH:D000072716', (61, 72))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('pain', 'Phenotype', 'HP:0012531', (68, 72))	('sarcoma', 'Disease', (229, 236))	('cancer pain', 'Disease', (61, 72))	('expression', 'MPA', (141, 151))	('miR-9-5p', 'Chemical', '-', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
234489	32178691	As our previous results showed that miR-9-5p suppressed cytokine expression by targeting REST gene in BMSCs, we hypothesize here that miR-9-5p modified BMSCs can alleviate cancer pain.	('cancer pain', 'Disease', (172, 183))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('miR-9-5p', 'Var', (134, 142))	('cytokine expression', 'MPA', (56, 75))	('miR-9-5p', 'Chemical', '-', (36, 44))	('suppressed', 'NegReg', (45, 55))	('targeting', 'Reg', (79, 88))	('cancer pain', 'Disease', 'MESH:D000072716', (172, 183))	('alleviate', 'NegReg', (162, 171))	('pain', 'Phenotype', 'HP:0012531', (179, 183))	('miR-9-5p', 'Chemical', '-', (134, 142))
234490	32178691	As expected, transfusion of miR-9-5p modified BMSCs into the spinal cord of sarcoma inoculation mouse model significantly alleviated pain-related behaviors (Fig.	('miR-9-5p', 'Chemical', '-', (28, 36))	('mouse', 'Species', '10090', (96, 101))	('alleviated pain', 'Phenotype', 'HP:0007328', (122, 137))	('pain', 'Phenotype', 'HP:0012531', (133, 137))	('alleviated', 'NegReg', (122, 132))	('pain', 'Disease', 'MESH:D010146', (133, 137))	('miR-9-5p modified', 'Var', (28, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('pain', 'Disease', (133, 137))	('sarcoma inoculation', 'Disease', (76, 95))	('sarcoma inoculation', 'Disease', 'MESH:D002372', (76, 95))
234493	32178691	This suppressing capacity of BMSCs is significantly enhanced after modification by miR-9-5p (p < 0.01, Fig.	('suppressing', 'NegReg', (5, 16))	('modification', 'Var', (67, 79))	('miR-9-5p', 'Var', (83, 91))	('enhanced', 'PosReg', (52, 60))	('miR-9-5p', 'Chemical', '-', (83, 91))
234495	32178691	Mir-9-5p modified BMSCs showed significantly stronger inhibiting effects than BMSCs alone (Fig.	('Mir-9-5p', 'Chemical', '-', (0, 8))	('Mir-9-5p modified', 'Var', (0, 17))	('inhibiting', 'NegReg', (54, 64))
234498	32178691	In summary, our results suggest that modifications mediated by miR-9-5p endow BMSCs more properties to alleviate cancer pain.	('miR-9-5p', 'Var', (63, 71))	('cancer pain', 'Disease', 'MESH:D000072716', (113, 124))	('pain', 'Phenotype', 'HP:0012531', (120, 124))	('cancer pain', 'Disease', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('miR-9-5p', 'Chemical', '-', (63, 71))
234501	32178691	Our results demonstrate that microRNA-5-9P modified BMSCs significantly relieved pain-related behaviors by suppressing REST and cytokine expression and enhancing MOR expression (Figs.	('pain', 'Disease', (81, 85))	('relieved', 'NegReg', (72, 80))	('MOR expression', 'MPA', (162, 176))	('enhancing', 'PosReg', (152, 161))	('pain', 'Phenotype', 'HP:0012531', (81, 85))	('suppressing', 'NegReg', (107, 118))	('relieved pain', 'Phenotype', 'HP:0007328', (72, 85))	('pain', 'Disease', 'MESH:D010146', (81, 85))	('microRNA-5-9P', 'Var', (29, 42))
234508	32178691	Furthermore, microRNA-5-9p modified BMSCs can inhibit cytokine expression in the spinal cord of the mouse model with bone cancer pain.	('bone cancer pain', 'Disease', (117, 133))	('bone cancer pain', 'Phenotype', 'HP:0002653', (117, 133))	('inhibit', 'NegReg', (46, 53))	('microRNA-5-9p modified', 'Var', (13, 35))	('mouse', 'Species', '10090', (100, 105))	('pain', 'Phenotype', 'HP:0012531', (129, 133))	('cytokine expression', 'MPA', (54, 73))	('bone cancer pain', 'Disease', 'MESH:D001859', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
234510	32178691	It will be informative to check whether microRNA-5-9p overexpression can modulate TGFbeta release in BMSCs in future studies.	('TGFbeta', 'Gene', (82, 89))	('microRNA-5-9p', 'Var', (40, 53))	('modulate', 'Reg', (73, 81))	('TGFbeta', 'Gene', '21802', (82, 89))
234515	32178691	Recent studies have shown that aberrant regulation of MOR expression might contribute to the pathogenesis of persistent pain in cancer patients.	('pain', 'Disease', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('patients', 'Species', '9606', (135, 143))	('contribute', 'Reg', (75, 85))	('aberrant', 'Var', (31, 39))	('persistent pain', 'Phenotype', 'HP:0012532', (109, 124))	('pain', 'Phenotype', 'HP:0012531', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('pain', 'Disease', 'MESH:D010146', (120, 124))	('MOR', 'Protein', (54, 57))	('cancer', 'Disease', (128, 134))
234517	32178691	Changes in molecular properties caused by microRNA-5-9p overexpression endow BMSCs' robust capacity to relieve pain sensation.	('pain', 'Phenotype', 'HP:0012531', (111, 115))	('overexpression', 'Var', (56, 70))	('microRNA-5-9p overexpression', 'Var', (42, 70))	('pain sensation', 'Disease', (111, 125))	('relieve pain', 'Phenotype', 'HP:0007328', (103, 115))	('pain sensation', 'Disease', 'MESH:D010146', (111, 125))	('molecular properties', 'MPA', (11, 31))	('Changes', 'Reg', (0, 7))
234519	32178691	To summarize, our results show that microRNA-5-9p modified BMSCs can relieve bone cancer pain via modulating neuroinflammation in the central nervous system.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('microRNA-5-9p modified', 'Var', (36, 58))	('bone cancer pain', 'Disease', 'MESH:D001859', (77, 93))	('relieve', 'NegReg', (69, 76))	('bone cancer pain', 'Phenotype', 'HP:0002653', (77, 93))	('bone cancer pain', 'Disease', (77, 93))	('pain', 'Phenotype', 'HP:0012531', (89, 93))	('BMSCs', 'Gene', (59, 64))	('modulating', 'Reg', (98, 108))	('neuroinflammation', 'MPA', (109, 126))
234597	28191343	We also analyzed risk factors for HIV acquisition, and found strong associations with intravenous drug users, having been in prison, low educational level, high-risk sexual behavior, and increased risk of transmission from infected mothers to children.	('HIV', 'Species', '12721', (34, 37))	('sexual behavior', 'Phenotype', 'HP:0030214', (166, 181))	('low educational', 'Var', (133, 148))	('children', 'Species', '9606', (243, 251))	('associations', 'Interaction', (68, 80))
234606	28191343	In geographic areas where KSHV is comparatively common, KSHV prevalence displays the same pattern among IVDUs and the general populations; nevertheless, it seems that most KSHV-positive patients in the present study are injecting drug users; furthermore, as expected, syringe sharing, in addition to increasing the risk of hepatitis B and C, is also a risk factor for KSHV infection.	('KSHV infection', 'Disease', 'MESH:C537372', (368, 382))	('KSHV', 'Species', '37296', (172, 176))	('KSHV', 'Species', '37296', (368, 372))	('hepatitis', 'Phenotype', 'HP:0012115', (323, 332))	('KSHV infection', 'Disease', (368, 382))	('KSHV', 'Species', '37296', (56, 60))	('KSHV', 'Species', '37296', (26, 30))	('hepatitis B', 'Disease', 'MESH:D006509', (323, 334))	('syringe sharing', 'Var', (268, 283))	('hepatitis B', 'Disease', (323, 334))	('patients', 'Species', '9606', (186, 194))
234670	26923635	The immunoprofile is (CD1a+, S100+), and some cells should have the characteristic LC features of grooved nuclei and/or Birbeck granules.	('CD1a', 'Gene', (22, 26))	('S100+', 'Var', (29, 34))	('grooved nuclei', 'CPA', (98, 112))	('Birbeck granules', 'CPA', (120, 136))	('CD1a', 'Gene', '909', (22, 26))
234700	26295973	The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3).	('sarcoma viral', 'Disease', (319, 332))	('sarcoma viral', 'Disease', 'MESH:D001102', (319, 332))	('sarcoma viral', 'Disease', (134, 147))	('rat', 'Species', '10116', (315, 318))	('rat', 'Species', '10116', (130, 133))	('mutations', 'Var', (95, 104))	('sarcoma viral', 'Disease', 'MESH:D001102', (243, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('sarcoma viral', 'Disease', 'MESH:D001102', (134, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (319, 326))	('sarcoma viral', 'Disease', (243, 256))
234705	26295973	Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion.	('GFPT1', 'Gene', (70, 75))	('ALK', 'Gene', '238', (76, 79))	('deletion', 'Var', (165, 173))	('fusion', 'Var', (80, 86))	('GFPT1', 'Gene', '2673', (70, 75))	('ALK', 'Gene', (76, 79))
234707	26295973	In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC.	('ALK', 'Gene', '238', (87, 90))	('mutations', 'Var', (40, 49))	('MTC', 'Gene', (53, 56))	('MTC', 'Phenotype', 'HP:0002865', (53, 56))	('ALK', 'Gene', (87, 90))	('MTC', 'Phenotype', 'HP:0002865', (102, 105))
234708	26295973	Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors.	('ALK', 'Gene', '238', (34, 37))	('EML4', 'Gene', '27436', (29, 33))	('ALK', 'Gene', (109, 112))	('fusion', 'Var', (38, 44))	('MTC', 'Phenotype', 'HP:0002865', (48, 51))	('ALK', 'Gene', (34, 37))	('ALK', 'Gene', '238', (109, 112))	('EML4', 'Gene', (29, 33))
234709	26295973	Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target therapy.	('GFPT1', 'Gene', (17, 22))	('ALK', 'Gene', (23, 26))	('fusion', 'Var', (27, 33))	('GFPT1', 'Gene', '2673', (17, 22))	('ALK', 'Gene', '238', (23, 26))
234712	26295973	For the first time, anaplastic lymphoma kinase (ALK) rearrangements were detected in MTC: one case with a glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK fusion, and another case with an echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion.	('ALK', 'Gene', (253, 256))	('anaplastic lymphoma kinase', 'Gene', '238', (20, 46))	('anaplastic lymphoma kinase', 'Gene', (20, 46))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (20, 39))	('MTC', 'Phenotype', 'HP:0002865', (85, 88))	('glutamine:fructose-6-phosphate transaminase 1', 'Gene', '2673', (106, 151))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('rearrangements', 'Var', (53, 67))	('GFPT1', 'Gene', '2673', (153, 158))	('EML4', 'Gene', (247, 251))	('detected', 'Reg', (73, 81))	('ALK', 'Gene', '238', (160, 163))	('EML4', 'Gene', '27436', (247, 251))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (197, 245))	('ALK', 'Gene', (160, 163))	('ALK', 'Gene', '238', (48, 51))	('GFPT1', 'Gene', (153, 158))	('ALK', 'Gene', '238', (253, 256))	('ALK', 'Gene', (48, 51))	('echinoderm microtubule-associated protein-like 4', 'Gene', (197, 245))	('glutamine:fructose-6-phosphate transaminase 1', 'Gene', (106, 151))
234720	26295973	Genetic and epigenetic alterations play important roles in the progression and prognosis of MTC.	('MTC', 'Disease', (92, 95))	('roles', 'Reg', (50, 55))	('epigenetic alterations', 'Var', (12, 34))	('Genetic', 'Var', (0, 7))	('rat', 'Species', '10116', (27, 30))	('MTC', 'Phenotype', 'HP:0002865', (92, 95))
234721	26295973	In the Mitogen-activated protein kinase (MAPK) pathway, the RAS mutation is another genetic rearrangement that is prevalent in sporadic MTC and other types of thyroid cancer but the prevalence and significance of other genetic mutations including BRAF in MTC remain unclear.	('MTC', 'Phenotype', 'HP:0002865', (255, 258))	('MTC', 'Phenotype', 'HP:0002865', (136, 139))	('thyroid cancer', 'Disease', (159, 173))	('mutation', 'Var', (64, 72))	('BRAF', 'Gene', '673', (247, 251))	('thyroid cancer', 'Phenotype', 'HP:0002890', (159, 173))	('prevalent', 'Reg', (114, 123))	('BRAF', 'Gene', (247, 251))	('thyroid cancer', 'Disease', 'MESH:D013964', (159, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('RAS', 'Gene', (60, 63))
234725	26295973	Recently, the rearrangement of anaplastic lymphoma kinase (ALK) was detected in a small but significant proportion of patients with non-small cell lung cancer (NSCLC).	('ALK', 'Gene', '238', (59, 62))	('non-small cell lung cancer', 'Disease', (132, 158))	('rearrangement', 'Var', (14, 27))	('patients', 'Species', '9606', (118, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('anaplastic lymphoma kinase', 'Gene', '238', (31, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (42, 50))	('ALK', 'Gene', (59, 62))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (31, 50))	('detected', 'Reg', (68, 76))	('anaplastic lymphoma kinase', 'Gene', (31, 57))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('NSCLC', 'Disease', (160, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
234732	26295973	The most common mutation occurred in RET, which was observed in 47 cases, followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3), MET proto-oncogene (N = 3), ATM serine/threonine kinase (N = 2), kinase insert domain receptor (N = 2), adenomatous polyposis coli (APC; N = 2), B-raf proto-oncogene (N = 1), cadherin 1 (N = 1), epidermal growth factor receptor (N = 1), cyclin-dependent kinase inhibitor 2A (CDKN2A, N = 1), Janus kinase 3 (N = 1), protein tyrosine phosphatase, non-receptor type 1 (N = 1), SMAD family member 4 (N = 1) and von Hippel-Lundau tumor suppressor (N = 1).	('epidermal growth factor receptor', 'Gene', '24329', (545, 577))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (454, 480))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '25163', (587, 623))	('sarcoma viral', 'Disease', (234, 247))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (454, 480))	('adenomatous polyposis coli', 'Disease', (454, 480))	('APC', 'Phenotype', 'HP:0005227', (482, 485))	('N = 2', 'Gene', '300711', (487, 492))	('protein tyrosine phosphatase', 'MPA', (665, 693))	('epidermal growth factor receptor', 'Gene', (545, 577))	('N = 2', 'Gene', '300711', (446, 451))	('APC', 'Disease', 'MESH:D011125', (482, 485))	('APC', 'Disease', (482, 485))	('N = 2', 'Gene', '300711', (407, 412))	('cadherin 1', 'Gene', '83502', (525, 535))	('sarcoma', 'Phenotype', 'HP:0100242', (310, 317))	('tumor', 'Phenotype', 'HP:0002664', (775, 780))	('mutations', 'Var', (86, 95))	('ATM serine/threonine kinase (N = 2', 'Gene', '300711', (378, 412))	('von Hippel-Lundau tumor', 'Disease', 'MESH:D006623', (757, 780))	('sarcoma viral', 'Disease', 'MESH:D001102', (310, 323))	('SMAD', 'Disease', (724, 728))	('von Hippel-Lundau tumor', 'Disease', (757, 780))	('SMAD', 'Disease', 'None', (724, 728))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (587, 623))	('sarcoma viral', 'Disease', (310, 323))	('N = 2', 'Gene', (487, 492))	('N = 2', 'Gene', (446, 451))	('cadherin 1', 'Gene', (525, 535))	('rat', 'Species', '10116', (306, 309))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('sarcoma viral', 'Disease', 'MESH:D001102', (125, 138))	('kinase insert domain receptor (N = 2', 'Gene', '25589', (415, 451))	('sarcoma viral', 'Disease', (125, 138))	('CDKN2A', 'Gene', '25163', (625, 631))	('N = 2', 'Gene', (407, 412))	('CDKN2A', 'Gene', (625, 631))	('sarcoma viral', 'Disease', 'MESH:D001102', (234, 247))	('rat', 'Species', '10116', (121, 124))
234735	26295973	Similarly, M918T (N = 19) was the most common RET mutation in our samples, followed by C634Y (N = 7), C634W (N = 4), C634G (N = 4), C630R (N = 4), D631Y (N = 2), and others (N = 7).	('N = 2', 'Gene', (154, 159))	('C634Y', 'Var', (87, 92))	('M918T', 'Var', (11, 16))	('D631Y', 'Var', (147, 152))	('C630R', 'Mutation', 'rs377767404', (132, 137))	('C634W', 'Var', (102, 107))	('C634G', 'Mutation', 'rs1229955390', (117, 122))	('C634G', 'Var', (117, 122))	('C634W', 'SUBSTITUTION', 'None', (102, 107))	('D631Y', 'Mutation', 'rs377767406', (147, 152))	('M918T', 'Mutation', 'rs74799832', (11, 16))	('N = 2', 'Gene', '300711', (154, 159))	('C630R', 'Var', (132, 137))	('C634Y', 'Mutation', 'rs75996173', (87, 92))
234736	26295973	All HRAS mutations occurred in exon 3.	('mutations', 'Var', (9, 18))	('HRAS', 'Gene', '3265', (4, 8))	('HRAS', 'Gene', (4, 8))
234737	26295973	The mutant amino acid sequence in each of the HRAS mutant cases was Q61K (N = 13).	('Q61K', 'Mutation', 'rs28933406', (68, 72))	('HRAS', 'Gene', '3265', (46, 50))	('HRAS', 'Gene', (46, 50))	('Q61K', 'Var', (68, 72))
234738	26295973	KRAS mutations were observed in three cases (Q61R, 2 and G48R, 1), and BRAF mutation was found in only one case.	('BRAF', 'Gene', '673', (71, 75))	('G48R', 'Var', (57, 61))	('Q61R', 'Var', (45, 49))	('BRAF', 'Gene', (71, 75))	('Q61R', 'Mutation', 'rs121913240', (45, 49))	('observed', 'Reg', (20, 28))	('KRAS', 'Gene', (0, 4))	('G48R', 'Mutation', 'p.G48R', (57, 61))	('KRAS', 'Gene', '3845', (0, 4))
234739	26295973	The dominant amino acid sequence in STK11 was F354L (N = 7).	('F354L', 'Var', (46, 51))	('STK11', 'Gene', (36, 41))	('F354L', 'Mutation', 'rs59912467', (46, 51))	('STK11', 'Gene', '6794', (36, 41))
234740	26295973	In the hereditary MTC cases, RET mutations were observed in MTC and their matched normal thyroid tissues: these RET mutation types included C634Y, D631Y, and C634W, which are well known to be associated with the MEN2A.	('MEN2A', 'Gene', (212, 217))	('MEN2A', 'Gene', '5979', (212, 217))	('D631Y', 'Var', (147, 152))	('associated', 'Reg', (192, 202))	('MTC', 'Phenotype', 'HP:0002865', (18, 21))	('C634Y', 'Mutation', 'rs75996173', (140, 145))	('C634W', 'Var', (158, 163))	('D631Y', 'Mutation', 'rs377767406', (147, 152))	('C634W', 'SUBSTITUTION', 'None', (158, 163))	('MTC', 'Phenotype', 'HP:0002865', (60, 63))	('C634Y', 'Var', (140, 145))
234742	26295973	In 16 sporadic MTC group, several RET mutation types (M918T, C630R, C618S and deletion) were detected in MTC tissues, but not in the matched normal thyroid tissues.	('C618S', 'Var', (68, 73))	('C630R', 'Mutation', 'rs377767404', (61, 66))	('M918T', 'Mutation', 'rs74799832', (54, 59))	('MTC', 'Phenotype', 'HP:0002865', (15, 18))	('MTC', 'Phenotype', 'HP:0002865', (105, 108))	('C618S', 'Mutation', 'rs76262710', (68, 73))	('M918T', 'Var', (54, 59))	('C630R', 'Var', (61, 66))
234743	26295973	The M918T RET mutations and Q61K HRAS mutations were observed only in the MTCs of the sporadic or unknown subgroups, suggesting that these mutations are pathognomonic somatic mutation in MTC.	('M918T', 'Var', (4, 9))	('Q61K', 'Mutation', 'rs28933406', (28, 32))	('MTC', 'Phenotype', 'HP:0002865', (187, 190))	('HRAS', 'Gene', '3265', (33, 37))	('RET', 'Gene', (10, 13))	('M918T', 'Mutation', 'rs74799832', (4, 9))	('HRAS', 'Gene', (33, 37))	('Q61K', 'Var', (28, 32))	('MTC', 'Phenotype', 'HP:0002865', (74, 77))
234744	26295973	In addition, two KRAS (G48R, Q61R) and one MET (A986T) mutations were also observed only in MTC tissues.	('Q61R', 'Var', (29, 33))	('Q61R', 'Mutation', 'rs121913240', (29, 33))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', '3845', (17, 21))	('A986T', 'Mutation', 'c.986A>T', (48, 53))	('G48R', 'Mutation', 'p.G48R', (23, 27))	('MTC', 'Phenotype', 'HP:0002865', (92, 95))
234750	26295973	For the two cases harboring ALK break-apart rearrangements, targeted cancer panel sequencing (HiSeq 2500, Illumina, USA) was performed to detect the breakpoints and 5' fusion partner genes of ALK.	('ALK', 'Gene', '238', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ALK', 'Gene', (192, 195))	('ALK', 'Gene', (28, 31))	('ALK', 'Gene', '238', (192, 195))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('rearrangements', 'Var', (44, 58))
234757	26295973	The breakpoints were located in intron 13 of EML4 and intron 19 of ALK, which indicates that this fusion is the most common variant (E13; A20) in NSCLC.	('EML4', 'Gene', (45, 49))	('ALK', 'Gene', '238', (67, 70))	('NSCLC', 'Disease', (146, 151))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('E13; A20', 'Var', (133, 141))	('EML4', 'Gene', '27436', (45, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('ALK', 'Gene', (67, 70))
234768	26295973	Results from the current study suggest that IHC-based screening, along with FISH-based confirmation and targeted NGS, may be a cost-effective and reliable method to detect ALK rearrangements.	('ALK', 'Gene', (172, 175))	('rearrangements', 'Var', (176, 190))	('ALK', 'Gene', '238', (172, 175))
234769	26295973	Most importantly, we detected a novel GFPT1-ALK fusion that has not been reported in any type of cancer.	('GFPT1', 'Gene', (38, 43))	('ALK', 'Gene', (44, 47))	('cancer', 'Disease', (97, 103))	('fusion', 'Var', (48, 54))	('GFPT1', 'Gene', '2673', (38, 43))	('ALK', 'Gene', '238', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
234773	26295973	In the current study, the MTC case harboring the GFPT1-ALK fusion showed strong ALK protein expression and did not exhibit co-existing genetic mutations; both of these factors may support an important role for this fusion gene in the pathogenesis of this MTC case.	('MTC', 'Phenotype', 'HP:0002865', (255, 258))	('ALK', 'Gene', '238', (55, 58))	('GFPT1', 'Gene', (49, 54))	('MTC', 'Disease', (255, 258))	('ALK', 'Gene', '238', (80, 83))	('fusion', 'Var', (59, 65))	('GFPT1', 'Gene', '2673', (49, 54))	('ALK', 'Gene', (55, 58))	('MTC', 'Phenotype', 'HP:0002865', (26, 29))	('ALK', 'Gene', (80, 83))
234778	26295973	Despite the low frequency of ALK rearrangements in MTC, our techniques can be used to detect target genes in other rare diseases.	('ALK', 'Gene', (29, 32))	('MTC', 'Phenotype', 'HP:0002865', (51, 54))	('rearrangements', 'Var', (33, 47))	('MTC', 'Disease', (51, 54))	('ALK', 'Gene', '238', (29, 32))
234780	26295973	However, M918T RET (N = 10), Q61K HRAS (N = 7), KRAS (N = 2), and MET (N = 1) mutations were harbored dominantly in MTCs.	('MTC', 'Phenotype', 'HP:0002865', (116, 119))	('KRAS', 'Gene', (48, 52))	('Q61K', 'Var', (29, 33))	('HRAS', 'Gene', (34, 38))	('M918T', 'Mutation', 'rs74799832', (9, 14))	('KRAS', 'Gene', '3845', (48, 52))	('Q61K', 'Mutation', 'rs28933406', (29, 33))	('M918T', 'Var', (9, 14))	('N = 2', 'Gene', '300711', (54, 59))	('N = 2', 'Gene', (54, 59))	('HRAS', 'Gene', '3265', (34, 38))	('RET', 'Gene', (15, 18))
234781	26295973	identified RET, HRAS, KRAS and STK11 mutations as significant somatic mutations in MTCs, whereas TP53, KDR, KIT, MET, PIK3CA and ATM mutations were classified as nonpathogenic germ-line variants.	('TP53', 'Gene', '7157', (97, 101))	('KDR', 'Gene', (103, 106))	('MTC', 'Phenotype', 'HP:0002865', (83, 86))	('ATM', 'Gene', (129, 132))	('PIK3CA', 'Gene', '5290', (118, 124))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (37, 46))	('STK11', 'Gene', (31, 36))	('MTCs', 'Gene', (83, 87))	('KRAS', 'Gene', (22, 26))	('HRAS', 'Gene', '3265', (16, 20))	('KRAS', 'Gene', '3845', (22, 26))	('ATM', 'Gene', '472', (129, 132))	('PIK3CA', 'Gene', (118, 124))	('KDR', 'Gene', '3791', (103, 106))	('HRAS', 'Gene', (16, 20))	('STK11', 'Gene', '6794', (31, 36))
234782	26295973	Interestingly, however, the F354L STK11 mutation, regarded as significant somatic mutation by Simbolo et al., was observed in both MTCs and control tissues of our seven cases.	('F354L', 'Var', (28, 33))	('STK11', 'Gene', (34, 39))	('MTC', 'Phenotype', 'HP:0002865', (131, 134))	('F354L', 'Mutation', 'rs59912467', (28, 33))	('STK11', 'Gene', '6794', (34, 39))
234783	26295973	Therefore, we presume that the F354L STK11 mutation is a germ-line mutation in MTC.	('MTC', 'Phenotype', 'HP:0002865', (79, 82))	('F354L', 'Var', (31, 36))	('STK11', 'Gene', '6794', (37, 42))	('STK11', 'Gene', (37, 42))	('F354L', 'Mutation', 'rs59912467', (31, 36))
234785	26295973	Furthermore, our results also suggest that the novel GFPT1-ALK fusion can be a potential candidate for molecular target therapy.	('ALK', 'Gene', '238', (59, 62))	('GFPT1', 'Gene', '2673', (53, 58))	('GFPT1', 'Gene', (53, 58))	('ALK', 'Gene', (59, 62))	('fusion', 'Var', (63, 69))
234802	26295973	The PCR products were indicative of fusion points within intron 18 of GFPT1 and exon 20 of ALK, based on target sequencing results.	('ALK', 'Gene', (91, 94))	('GFPT1', 'Gene', (70, 75))	('ALK', 'Gene', '238', (91, 94))	('GFPT1', 'Gene', '2673', (70, 75))	('fusion', 'Var', (36, 42))
234824	22662203	Usually, inhibition of oncogenic TK activity leads to down-regulation of several downstream signaling pathways, including mitogen-activated protein kinase (MAPK) cascades and phosphatidylinositol 3'-kinase (PI3K)/AKT pathway, consequently repressing proliferation, invasion and survival of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('activity', 'MPA', (36, 44))	('cancer', 'Disease', (290, 296))	("phosphatidylinositol 3'-kinase", 'Gene', (175, 205))	('repressing', 'PosReg', (239, 249))	('survival', 'CPA', (278, 286))	('down-regulation', 'NegReg', (54, 69))	('AKT', 'Gene', '207', (213, 216))	('downstream signaling pathways', 'Pathway', (81, 110))	("phosphatidylinositol 3'-kinase", 'Gene', '5290', (175, 205))	('invasion', 'CPA', (265, 273))	('proliferation', 'CPA', (250, 263))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('inhibition', 'Var', (9, 19))	('AKT', 'Gene', (213, 216))
234825	22662203	Accordingly, the TK inhibitor imatinib mesylate (STI571; Gleevec; Novartis) has become first-line therapy for patients with chronic myeloid leukaemia (CML) harbouring BCR/ABL translocation or for those with advanced gastrointestinal stromal tumor (GIST) showing specific mutations in c-KIT or PDGFRalpha genes, which activate these TKs.	('Novartis', 'Disease', 'None', (66, 74))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (30, 47))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (216, 246))	('Novartis', 'Disease', (66, 74))	('PDGFRalpha', 'Gene', (293, 303))	('c-KIT', 'Gene', (284, 289))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (216, 246))	('mutations', 'Var', (271, 280))	('BCR', 'Gene', '613', (167, 170))	('CML', 'Disease', 'MESH:D015464', (151, 154))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (132, 149))	('c-KIT', 'Gene', '3815', (284, 289))	('CML', 'Disease', (151, 154))	('gastrointestinal stromal tumor', 'Disease', (216, 246))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (124, 149))	('BCR', 'Gene', (167, 170))	('ABL', 'Gene', '25', (171, 174))	('PDGFRalpha', 'Gene', '5156', (293, 303))	('ABL', 'Gene', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('chronic myeloid leukaemia', 'Disease', (124, 149))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (124, 149))	('patients', 'Species', '9606', (110, 118))
234850	22662203	Cell populations in the different phases of cell cycle (sub-G1 (cell death), G0/G1, S/G2/M peaks) were determined based on their DNA content in a Beckman Coulter Epics XL flow cytometer.	('S/G2', 'Var', (84, 88))	('S/G2', 'SUBSTITUTION', 'None', (84, 88))	('DNA', 'MPA', (129, 132))
234899	22662203	These results indicate that nilotinib, but not imatinib, enhances intracellular DXR accumulation.	('nilotinib', 'Var', (28, 37))	('DXR', 'Chemical', 'MESH:D004317', (80, 83))	('nilotinib', 'Chemical', 'MESH:C498826', (28, 37))	('enhances', 'PosReg', (57, 65))	('imatinib', 'Chemical', 'MESH:D000068877', (47, 55))	('intracellular DXR accumulation', 'MPA', (66, 96))
234907	22662203	Importantly, incubation of synovial sarcoma cells with DXR (0.1 microM, 72 h) provoked a significant upregulation of P-gp levels (55.2+-21.0%), which is generally considered as the central molecular mechanism of MDR in response to DXR treatment and which was fully blocked by nilotinib (Fig.	('synovial sarcoma cells', 'Disease', (27, 49))	('upregulation', 'PosReg', (101, 113))	('P-gp', 'Gene', '5243', (117, 121))	('DXR', 'Chemical', 'MESH:D004317', (231, 234))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (27, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('P-gp', 'Gene', (117, 121))	('nilotinib', 'Chemical', 'MESH:C498826', (276, 285))	('synovial sarcoma cells', 'Disease', 'MESH:D013584', (27, 49))	('DXR', 'Chemical', 'MESH:D004317', (55, 58))	('DXR', 'Var', (55, 58))
234909	22662203	4) and that inhibition of this kinase reduces MDR in some human cancer cells by modulating P-gp expression, suggested to analyze the effect of nilotinib and DXR on p38 MAPK phosphorylation.	('inhibition', 'Var', (12, 22))	('reduces', 'NegReg', (38, 45))	('human', 'Species', '9606', (58, 63))	('P-gp', 'Gene', (91, 95))	('p38', 'Gene', '5594', (164, 167))	('MDR', 'MPA', (46, 49))	('cancer', 'Disease', (64, 70))	('expression', 'MPA', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('nilotinib', 'Chemical', 'MESH:C498826', (143, 152))	('modulating', 'Reg', (80, 90))	('DXR', 'Chemical', 'MESH:D004317', (157, 160))	('P-gp', 'Gene', '5243', (91, 95))	('p38', 'Gene', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
234925	22662203	In this context, suppression of proliferation by imatinib and nilotinib correlated with their capability to down-regulate AKT and mitogen-activated protein kinases (MAPKs) (Fig.	('nilotinib', 'Var', (62, 71))	('nilotinib', 'Chemical', 'MESH:C498826', (62, 71))	('AKT', 'Gene', '207', (122, 125))	('proliferation', 'CPA', (32, 45))	('mitogen-activated protein kinases', 'Pathway', (130, 163))	('suppression', 'NegReg', (17, 28))	('down-regulate', 'NegReg', (108, 121))	('imatinib', 'Chemical', 'MESH:D000068877', (49, 57))	('AKT', 'Gene', (122, 125))
234931	22662203	Furthermore, nilotinib is more lipophilic and relatively less protonated at physiologic pH than imatinib, thus, facilitating its plasma membrane passage and accessibility of intracellular interaction partners.	('plasma membrane passage', 'MPA', (129, 152))	('nilotinib', 'Var', (13, 22))	('nilotinib', 'Chemical', 'MESH:C498826', (13, 22))	('protonated', 'MPA', (62, 72))	('less', 'NegReg', (57, 61))	('imatinib', 'Chemical', 'MESH:D000068877', (96, 104))	('interaction', 'Interaction', (188, 199))
234954	22662203	Because of the wide substrate profile of P-gp in relation to chemotherapeutic agents, it is tempting to speculate that nilotinib could also enhance the antiproliferative effects of other antitumoral agents affected by MDR, such as paclitaxel or vinblastine.	('enhance', 'PosReg', (140, 147))	('antiproliferative effects', 'CPA', (152, 177))	('nilotinib', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('nilotinib', 'Chemical', 'MESH:C498826', (119, 128))	('P-gp', 'Gene', (41, 45))	('paclitaxel', 'Chemical', 'MESH:D017239', (231, 241))	('vinblastine', 'Chemical', 'MESH:D014747', (245, 256))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('P-gp', 'Gene', '5243', (41, 45))
234966	29572501	These tumors were subjected to methylation profiling and could be assigned to Ewing sarcoma in 14 (47%), to small blue round cell tumors with CIC alteration in 6 (20%), to small blue round cell tumors with BCOR alteration in 4 (13%), to synovial sarcoma and to malignant rhabdoid tumor in 2 cases each.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('CIC', 'Gene', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BCOR', 'Gene', '54880', (206, 210))	('alteration', 'Var', (211, 221))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('synovial sarcoma', 'Disease', (237, 253))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (261, 285))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('BCOR', 'Gene', (206, 210))	('malignant rhabdoid tumor', 'Disease', (261, 285))	('synovial sarcoma', 'Disease', 'MESH:D013584', (237, 253))	('CIC', 'Gene', '23152', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (237, 253))	('tumors', 'Disease', (194, 200))	('Ewing sarcoma', 'Disease', (78, 91))	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumors', 'Disease', 'MESH:D009369', (194, 200))
234968	29572501	12/14 tumors classified as Ewing sarcoma could be verified by demonstrating either a canonical EWS translocation evading initial testing, by identifying rare breakpoints or fusion partners.	('translocation', 'Var', (99, 112))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('Ewing sarcoma', 'Disease', (27, 40))	('tumors', 'Disease', (6, 12))	('EWS', 'Gene', '2130', (95, 98))	('EWS', 'Gene', (95, 98))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (27, 40))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (27, 40))
234976	29572501	A breakthrough in the diagnostics of Ewing sarcoma was the discovery of two highly specific translocations, which both result in a gene fusion between a member of the TET- and ETS- gene families.	('gene fusion', 'MPA', (131, 142))	('Ewing sarcoma', 'Disease', (37, 50))	('TET', 'Chemical', 'MESH:C010349', (167, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('translocations', 'Var', (92, 106))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (37, 50))	('result in', 'Reg', (119, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
234978	29572501	Gene fusions with other TET and ETS family members and rearrangements of EWSR1 with non-ETS family genes have also been described.	('Gene fusions', 'Var', (0, 12))	('TET', 'Chemical', 'MESH:C010349', (24, 27))	('EWSR1', 'Gene', (73, 78))	('rearrangements', 'Var', (55, 69))	('EWSR1', 'Gene', '2130', (73, 78))
234986	29572501	The considerable stability of epigenetic signatures during tumor disease has been demonstrated for many tumors.	('epigenetic signatures', 'Var', (30, 51))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
234992	29572501	The reference set for building a framework of methylation groups comprised a total of 460 prototypical sarcoma cases from primary manifestations and metastases encompassing classic adamantinoma of the tibia with prominent epithelial component (n = 6), alveolar soft part sarcoma (n = 22), mesenchymal chondrosarcoma (n = 9), clear cell sarcoma of the kidney (n = 12), conventional osteosarcoma (n = 82), dermatofibrosarcoma protuberans (n = 39), desmoplastic small round cell tumor (n = 28), epithelioid sarcoma (n = 17), Ewing sarcoma carrying a gene fusion either between EWSR1-FLI1 (n = 41), EWSR1-ERG (n = 3) or FUS-ERG (n = 1), or showing an EWSR1 break-apart signal in the FISH test (n = 12), infantile fibrosarcoma (n = 13), malignant peripheral nerve sheath tumor (n = 22), malignant rhabdoid tumor (n = 18), embryonal rhabdomyosarcoma (n = 31), alveolar rhabdomyosarcoma (n = 33), small blue round cell tumor with BCOR-CCNB3 fusion (n = 8), small blue round cell tumor with an rearrangement of CIC (n = 10), solitary fibrous tumor (n = 22) and synovial sarcoma (n = 31).	('FLI1', 'Gene', (580, 584))	('sarcoma', 'Disease', (714, 721))	('ERG', 'Gene', (601, 604))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('tumor', 'Disease', (972, 977))	('FUS', 'Gene', '2521', (616, 619))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (404, 435))	('tumor', 'Disease', 'MESH:D009369', (972, 977))	('tumor', 'Disease', (1034, 1039))	('osteosarcoma', 'Phenotype', 'HP:0002669', (381, 393))	('sarcoma', 'Disease', 'MESH:D012509', (386, 393))	('infantile fibrosarcoma', 'Disease', (699, 721))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('rearrangement', 'Var', (986, 999))	('tumor', 'Disease', 'MESH:D009369', (1034, 1039))	('sarcoma', 'Disease', (386, 393))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (827, 843))	('tumor', 'Phenotype', 'HP:0002664', (766, 771))	('adamantinoma of the tibia', 'Disease', (181, 206))	('sarcoma', 'Disease', 'MESH:D012509', (271, 278))	('sarcoma', 'Disease', (271, 278))	('mesenchymal chondrosarcoma', 'Disease', 'MESH:D018211', (289, 315))	('osteosarcoma', 'Disease', (381, 393))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (336, 357))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (709, 721))	('malignant rhabdoid tumor', 'Disease', (782, 806))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (817, 843))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (446, 481))	('classic adamantinoma', 'Disease', (173, 193))	('sarcoma', 'Disease', (103, 110))	('desmoplastic small round cell tumor', 'Disease', (446, 481))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (1053, 1069))	('tumor', 'Phenotype', 'HP:0002664', (476, 481))	('fibrous tumor', 'Disease', (1026, 1039))	('malignant peripheral nerve sheath tumor', 'Disease', (732, 771))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (854, 879))	('EWSR1', 'Gene', '2130', (574, 579))	('FLI1', 'Gene', '2313', (580, 584))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (732, 771))	('CCNB3', 'Gene', (928, 933))	('sarcoma', 'Disease', 'MESH:D012509', (504, 511))	('sarcoma', 'Disease', 'MESH:D012509', (528, 535))	('sarcoma of the kidney', 'Disease', (336, 357))	('sarcoma', 'Disease', (504, 511))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (411, 423))	('sarcoma', 'Disease', (528, 535))	('sarcoma', 'Phenotype', 'HP:0100242', (308, 315))	('sarcoma', 'Disease', 'MESH:D012509', (714, 721))	('CIC', 'Gene', (1003, 1006))	('sarcoma', 'Disease', (336, 343))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (325, 357))	('synovial sarcoma', 'Disease', (1053, 1069))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (492, 511))	('synovial sarcoma', 'Disease', 'MESH:D013584', (1053, 1069))	('Ewing sarcoma', 'Disease', (522, 535))	('fibrous tumor', 'Disease', 'MESH:D054364', (1026, 1039))	('CCNB3', 'Gene', '85417', (928, 933))	('CIC', 'Gene', '23152', (1003, 1006))	('sarcoma of the kidney', 'Disease', 'MESH:D012509', (336, 357))	('tumor', 'Phenotype', 'HP:0002664', (801, 806))	('epithelioid sarcoma', 'Disease', (492, 511))	('BCOR', 'Gene', (923, 927))	('sarcoma', 'Disease', 'MESH:D012509', (308, 315))	('tumor', 'Disease', (766, 771))	('tumor', 'Phenotype', 'HP:0002664', (912, 917))	('sarcoma', 'Disease', (308, 315))	('tumor', 'Disease', 'MESH:D009369', (766, 771))	('EWSR1', 'Gene', (647, 652))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (817, 843))	('tumor', 'Phenotype', 'HP:0002664', (972, 977))	('sarcoma', 'Disease', 'MESH:D012509', (836, 843))	('sarcoma', 'Disease', (836, 843))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (732, 771))	('sarcoma', 'Disease', 'MESH:D012509', (336, 343))	('tumor', 'Disease', (476, 481))	('ERG', 'Gene', (620, 623))	('embryonal rhabdomyosarcoma', 'Disease', (817, 843))	('metastases', 'Disease', (149, 159))	('tumor', 'Disease', 'MESH:D009369', (476, 481))	('alveolar rhabdomyosarcoma', 'Disease', (854, 879))	('FUS', 'Gene', (616, 619))	('EWSR1', 'Gene', (595, 600))	('ERG', 'Gene', '2078', (620, 623))	('sarcoma', 'Disease', (872, 879))	('EWSR1', 'Gene', '2130', (647, 652))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (261, 278))	('sarcoma', 'Disease', 'MESH:D012509', (1062, 1069))	('sarcoma', 'Disease', (1062, 1069))	('classic adamantinoma', 'Disease', 'MESH:D050398', (173, 193))	('ERG', 'Gene', '2078', (601, 604))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (854, 879))	('adamantinoma of the tibia', 'Disease', 'MESH:D050398', (181, 206))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (699, 721))	('sarcoma', 'Disease', 'MESH:D012509', (416, 423))	('EWSR1', 'Gene', '2130', (595, 600))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (522, 535))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (522, 535))	('sarcoma', 'Disease', (416, 423))	('mesenchymal chondrosarcoma', 'Disease', (289, 315))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (301, 315))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('EWSR1', 'Gene', (574, 579))	('tumor', 'Disease', (801, 806))	('sarcoma', 'Phenotype', 'HP:0100242', (386, 393))	('tumor', 'Disease', (912, 917))	('tumor', 'Disease', 'MESH:D009369', (801, 806))	('dermatofibrosarcoma protuberans', 'Disease', (404, 435))	('osteosarcoma', 'Disease', 'MESH:D012516', (381, 393))	('tumor', 'Disease', 'MESH:D009369', (912, 917))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (782, 806))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (863, 879))	('sarcoma', 'Disease', 'MESH:D012509', (872, 879))	('BCOR', 'Gene', '54880', (923, 927))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (252, 278))
235003	29572501	BCOR-CCNB3 rearrangements were detected by RT-PCR as well.	('BCOR', 'Gene', '54880', (0, 4))	('rearrangements', 'Var', (11, 25))	('CCNB3', 'Gene', (5, 10))	('BCOR', 'Gene', (0, 4))	('CCNB3', 'Gene', '85417', (5, 10))
235008	29572501	Reads covering the BCOR locus (NM_001123383) were visualized in IGV and assessed manually for alterations.	('BCOR', 'Gene', (19, 23))	('BCOR', 'Gene', '54880', (19, 23))	('NM_001123383', 'Var', (31, 43))
235015	29572501	Unsupervised clustering and t-distributed stochastic neighbor embedding analysis (Figure 1) together with 460 sarcomas from the reference series allotted the 30 small blue round cell tumors not otherwise specified to different methylation classes corresponding to sarcomas with a defined histology and characteristic molecular hallmarks: 14 (47 %) assigned to Ewing sarcoma, six (20 %) to small blue round cell tumors with CIC alteration, four (13 %) to small blue round cell tumors with BCOR alteration, which is a methylation group composed of small blue round cell tumors with BCOR-CCNB3 fusion and clear cell sarcoma of the kidney with BCOR internal tandem duplication, two (7 %) to synovial sarcomas, two (7 %) to malignant rhabdoid tumors and one (3 %) to mesenchymal chondrosarcomas.	('tumors', 'Phenotype', 'HP:0002664', (738, 744))	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (774, 789))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (476, 481))	('mesenchymal chondrosarcomas', 'Disease', (762, 789))	('sarcomas', 'Disease', (110, 118))	('malignant rhabdoid tumors', 'Disease', (719, 744))	('synovial sarcomas', 'Disease', 'MESH:D013584', (687, 704))	('sarcoma of the kidney', 'Disease', 'MESH:D012509', (613, 634))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (360, 373))	('tumors', 'Disease', (183, 189))	('tumors', 'Disease', (476, 482))	('tumor', 'Phenotype', 'HP:0002664', (411, 416))	('BCOR', 'Gene', '54880', (580, 584))	('CIC', 'Gene', '23152', (423, 426))	('tumor', 'Phenotype', 'HP:0002664', (738, 743))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (687, 703))	('tumors', 'Disease', (738, 744))	('tumors', 'Phenotype', 'HP:0002664', (411, 417))	('Ewing sarcoma', 'Disease', (360, 373))	('CCNB3', 'Gene', (585, 590))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('internal tandem duplication', 'Var', (645, 672))	('tumors', 'Phenotype', 'HP:0002664', (568, 574))	('sarcomas', 'Disease', 'MESH:D012509', (696, 704))	('sarcoma', 'Phenotype', 'HP:0100242', (696, 703))	('sarcomas', 'Phenotype', 'HP:0100242', (696, 704))	('BCOR', 'Gene', (580, 584))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (476, 482))	('mesenchymal chondrosarcomas', 'Disease', 'MESH:D018211', (762, 789))	('sarcomas', 'Disease', (696, 704))	('sarcomas', 'Disease', 'MESH:D012509', (781, 789))	('sarcoma of the kidney', 'Disease', (613, 634))	('sarcomas', 'Phenotype', 'HP:0100242', (781, 789))	('tumor', 'Phenotype', 'HP:0002664', (568, 573))	('tumors', 'Disease', 'MESH:D009369', (738, 744))	('tumors', 'Disease', (411, 417))	('sarcomas', 'Disease', (781, 789))	('BCOR', 'Gene', '54880', (640, 644))	('tumors', 'Disease', (568, 574))	('CIC', 'Gene', (423, 426))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (719, 744))	('sarcomas', 'Disease', 'MESH:D012509', (264, 272))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (602, 634))	('BCOR', 'Gene', '54880', (488, 492))	('sarcomas', 'Phenotype', 'HP:0100242', (264, 272))	('tumors', 'Disease', 'MESH:D009369', (411, 417))	('sarcoma', 'Phenotype', 'HP:0100242', (613, 620))	('sarcomas', 'Disease', (264, 272))	('BCOR', 'Gene', (640, 644))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (687, 704))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (568, 574))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (774, 788))	('synovial sarcomas', 'Disease', (687, 704))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (360, 373))	('CCNB3', 'Gene', '85417', (585, 590))	('sarcoma', 'Phenotype', 'HP:0100242', (366, 373))	('tumors', 'Phenotype', 'HP:0002664', (476, 482))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (613, 634))	('BCOR', 'Gene', (488, 492))
235019	29572501	By applying this procedure, six of 14 tumors harbored a gene fusion between EWSR1 and FLI1.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('FLI1', 'Gene', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('EWSR1', 'Gene', (76, 81))	('FLI1', 'Gene', '2313', (86, 90))	('EWSR1', 'Gene', '2130', (76, 81))	('gene fusion', 'Var', (56, 67))
235027	29572501	Cases assigning to the methylation class small blue round cell tumors with BCOR alteration were tested by RT-PCR, total RNA sequencing and panel sequencing of the entire coding region if RNA-based methods were negative.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('BCOR', 'Gene', (75, 79))	('alteration', 'Var', (80, 90))	('BCOR', 'Gene', '54880', (75, 79))
235029	29572501	In the fusion-negative case, a BCOR internal tandem duplication spanning 66 bases in exon 15 was detected (Figure 2).	('BCOR', 'Gene', '54880', (31, 35))	('BCOR', 'Gene', (31, 35))	('internal tandem duplication spanning', 'Var', (36, 72))
235039	29572501	A very similar chromosome 22q alteration was found in one of the six classic adamantinomas.	('classic adamantinomas', 'Disease', (69, 90))	('classic adamantinomas', 'Disease', 'MESH:D050398', (69, 90))	('alteration', 'Var', (30, 40))
235050	29572501	The case matching with the methylation class small blue round cell tumors with CIC alteration had segmental copy number gains on chromosome arm 19q involving the CIC locus, which may have had an adverse effect on the FISH analysis (data not shown).	('CIC', 'Gene', (79, 82))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('CIC', 'Gene', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('gains', 'PosReg', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('alteration', 'Var', (83, 93))	('CIC', 'Gene', '23152', (79, 82))	('tumors', 'Disease', (67, 73))	('copy number', 'Var', (108, 119))	('CIC', 'Gene', '23152', (162, 165))
235055	29572501	The copy number profile of this tumor showed an unusual copy number alteration on chromosome 22q, which was also detected in one reference case classified as classic adamantinoma of the tibia.	('adamantinoma of the tibia', 'Disease', (166, 191))	('copy number alteration', 'Var', (56, 78))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('classic adamantinoma', 'Disease', (158, 178))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('classic adamantinoma', 'Disease', 'MESH:D050398', (158, 178))	('adamantinoma of the tibia', 'Disease', 'MESH:D050398', (166, 191))
235060	29572501	This methylation class is composed of different tumor subtypes sharing the molecular background of BCOR alteration either by rearrangement, internal tandem duplication or mutation.	('tumor', 'Disease', (48, 53))	('mutation', 'Var', (171, 179))	('rearrangement', 'Var', (125, 138))	('BCOR', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('internal tandem duplication', 'Var', (140, 167))	('BCOR', 'Gene', '54880', (99, 103))
235063	29572501	The fourth case, an infant patient with a small blue round cell tumor in the skull, carried a BCOR internal tandem duplication.	('internal tandem duplication', 'Var', (99, 126))	('tumor', 'Disease', (64, 69))	('BCOR', 'Gene', (94, 98))	('BCOR', 'Gene', '54880', (94, 98))	('patient', 'Species', '9606', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
235064	29572501	This case was re-classified as undifferentiated round cell sarcoma of infancy, in which the BCOR internal tandem duplication has been described as a highly recurrent event.	('sarcoma', 'Disease', (59, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('BCOR', 'Gene', (92, 96))	('internal tandem duplication', 'Var', (97, 124))	('BCOR', 'Gene', '54880', (92, 96))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))
235065	29572501	BCOR alterations have been recognized in a growing number of tumor subtypes affecting the soft tissue, the kidney or the central nervous system.	('BCOR', 'Gene', '54880', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('BCOR', 'Gene', (0, 4))
235068	29572501	Furthermore, using an extended set of tumor subtypes for DNA-methylation profiling (data not shown), also central nervous system high-grade neuroepithelial tumors with BCOR alteration fall into this methylation class.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('alteration', 'Var', (173, 183))	('BCOR', 'Gene', '54880', (168, 172))	('neuroepithelial tumors', 'Disease', (140, 162))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (140, 162))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (140, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('fall', 'Phenotype', 'HP:0002527', (184, 188))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('BCOR', 'Gene', (168, 172))
235072	29572501	A deletion of the SMARCB1 locus on chromosome arm 22q, which located juxtaposed to the EWSR1 locus, can result in a false-positive EWSR1 break-apart FISH signal, although the gene integrity is retained.	('SMARCB1', 'Gene', (18, 25))	('EWSR1', 'Gene', (87, 92))	('deletion', 'Var', (2, 10))	('EWSR1', 'Gene', (131, 136))	('EWSR1', 'Gene', '2130', (87, 92))	('EWSR1', 'Gene', '2130', (131, 136))	('SMARCB1', 'Gene', '6598', (18, 25))
235076	29572501	We could demonstrate a CIC rearrangement in four of six cases by break-apart FISH analysis.	('CIC', 'Gene', (23, 26))	('CIC', 'Gene', '23152', (23, 26))	('rearrangement', 'Var', (27, 40))
235081	29572501	Likewise, BCOR overexpression has been proposed as a potential biomarker for diagnosing small blue round cell tumors with BCOR alteration, although diagnostic pitfalls have already been recognized.	('BCOR', 'Gene', '54880', (10, 14))	('BCOR', 'Gene', '54880', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('alteration', 'Var', (127, 137))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('BCOR', 'Gene', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('fall', 'Phenotype', 'HP:0002527', (162, 166))	('BCOR', 'Gene', (10, 14))
235101	32630411	Ontak was a recombinant molecule composed of truncated DT fused with interleukin 2 (IL-2), a cytokine produced by T lymphocytes.	('interleukin 2', 'Gene', (69, 82))	('truncated', 'Var', (45, 54))	('interleukin 2', 'Gene', '3558', (69, 82))	('IL-2', 'Gene', '3558', (84, 88))	('IL-2', 'Gene', (84, 88))
235116	32630411	Further development has focused on reducing the immune response by combining DT2219 with rituximab to deplete B cells and reduce neutralizing antibody formation.	('DT2219', 'Chemical', '-', (77, 83))	('reduce', 'NegReg', (122, 128))	('rituximab', 'Chemical', 'MESH:D000069283', (89, 98))	('deplete B cells', 'MPA', (102, 117))	('neutralizing antibody formation', 'MPA', (129, 160))	('DT2219', 'Var', (77, 83))
235117	32630411	DT2219 proved it has greater cytotoxicity against patient leukemia cells than monomeric LTTs made exclusively with anti-CD19 or anti-CD22 antibodies.	('cytotoxicity', 'Disease', (29, 41))	('DT2219', 'Var', (0, 6))	('CD22', 'Gene', '933', (133, 137))	('CD22', 'Gene', (133, 137))	('CD19', 'Gene', (120, 124))	('leukemia', 'Disease', (58, 66))	('DT2219', 'Chemical', '-', (0, 6))	('leukemia', 'Disease', 'MESH:D007938', (58, 66))	('leukemia', 'Phenotype', 'HP:0001909', (58, 66))	('cytotoxicity', 'Disease', 'MESH:D064420', (29, 41))	('CD19', 'Gene', '930', (120, 124))	('patient', 'Species', '9606', (50, 57))	('LTTs', 'Chemical', '-', (88, 92))
235137	32630411	Though EGFR can be expressed in mutant form or overexpressed in tumors of the mammary glands, lungs, pancreas, intestines, and central nervous system, EGFR can also be found in both healthy tissue and tumors in the wild type form at normal levels.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('EGFR', 'Gene', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutant', 'Var', (32, 38))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('overexpressed', 'PosReg', (47, 60))
235138	32630411	EGFR inhibitors have also been known to cause gastrointestinal, pulmonary, cardiac, ocular, oral, and liver toxicity.	('cause', 'Reg', (40, 45))	('gastrointestinal', 'Disease', (46, 62))	('EGFR', 'Gene', (0, 4))	('cardiac', 'Disease', (75, 82))	('ocular', 'Disease', (84, 90))	('oral', 'Disease', (92, 96))	('inhibitors', 'Var', (5, 15))	('pulmonary', 'Disease', (64, 73))	('liver toxicity', 'Disease', 'MESH:D056486', (102, 116))	('liver toxicity', 'Disease', (102, 116))
235140	32630411	Attempts have been made to reduce the dose-limiting toxicity of EGFR-targeted drugs by combining EGFR inhibitors with antiangiogenic therapeutics.	('EGFR', 'Gene', (97, 101))	('inhibitors', 'Var', (102, 112))	('toxicity', 'Disease', (52, 60))	('toxicity', 'Disease', 'MESH:D064420', (52, 60))
235151	32630411	The cytotoxicity of monospecific ATF LTTs has previously been described in glioma cells in vitro.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('monospecific', 'Var', (20, 32))	('glioma', 'Disease', (75, 81))	('cytotoxicity', 'Disease', (4, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))	('LTTs', 'Chemical', '-', (37, 41))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
235157	32630411	To enhance its cytotoxic activity, four amino acid residues, Lys-Asp-Glu-Leu (KDEL), were cloned at the C-terminus that enhanced toxin retention in the endoplasmic reticulum (ER).	('toxin retention', 'MPA', (129, 144))	('enhance', 'PosReg', (3, 10))	('enhanced', 'PosReg', (120, 128))	('Lys-Asp-Glu-Leu', 'Var', (61, 76))	('Lys-Asp-Glu-Leu', 'Chemical', 'MESH:C073762', (61, 76))	('cytotoxic activity', 'MPA', (15, 33))
235159	32630411	Thus, seven major B cell epitopes that provoked neutralizing antibody formation in mice were identified and mutated in the sequence encoding PE.	('neutralizing antibody formation', 'MPA', (48, 79))	('mutated', 'Var', (108, 115))	('mice', 'Species', '10090', (83, 87))
235167	32630411	Importantly, eBAT killed U87, an aggressive primary glioblastoma cell line, significantly more effectively than the monospecific LTTs of EGF or the ATF cytokine conjugated to PE38KDEL in vitro.	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('PE38KDEL', 'Var', (175, 183))	('aggressive primary glioblastoma', 'Disease', (33, 64))	('eBAT', 'Chemical', '-', (13, 17))	('aggressive primary glioblastoma', 'Disease', 'MESH:D005909', (33, 64))	('LTTs', 'Chemical', '-', (129, 133))
235169	32630411	U87 proved more tumorigenic in nude rats than in nude mice.	('nude mice', 'Species', '10090', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('U87', 'Var', (0, 3))	('rats', 'Species', '10116', (36, 40))
235214	32630411	eBAT was also well-tolerated, supporting our hypothesis that bispecificity reduces the toxicity associated with EGFR-targeting.	('rat', 'Species', '10116', (23, 26))	('toxicity', 'Disease', 'MESH:D064420', (87, 95))	('bispecificity', 'Var', (61, 74))	('toxicity', 'Disease', (87, 95))	('eBAT', 'Chemical', '-', (0, 4))	('reduces', 'NegReg', (75, 82))
235218	32630411	One possible interpretation is that the immune response and the development of a neutralizing antibody following eBAT dampens its efficacy, and chemotherapy may eliminate immune cells and augment potency.	('augment', 'NegReg', (188, 195))	('immune response', 'CPA', (40, 55))	('neutralizing', 'Var', (81, 93))	('eBAT', 'Chemical', '-', (113, 117))	('potency', 'MPA', (196, 203))	('dampens', 'NegReg', (118, 125))	('efficacy', 'MPA', (130, 138))	('eliminate', 'NegReg', (161, 170))	('immune cells', 'CPA', (171, 183))
235235	32630411	LY3164530 is a bispecific antibody that targets mesenchymal-epithelial transition factor (MET) and EGFR for treating advanced and metastatic cancer that recently underwent phase I trials.	('EGFR', 'Gene', (99, 103))	('LY3164530', 'Var', (0, 9))	('LY3164530', 'Chemical', '-', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
235252	32630411	The modifications that improved the potency and reduced the immunogenicity of the toxin will reduce the likelihood of eBAT developing neutralizing antibodies and improve patient outcomes.	('potency', 'MPA', (36, 43))	('reduce', 'NegReg', (93, 99))	('eBAT', 'Chemical', '-', (118, 122))	('reduced', 'NegReg', (48, 55))	('immunogenicity', 'MPA', (60, 74))	('neutralizing antibodies', 'MPA', (134, 157))	('improved', 'PosReg', (23, 31))	('improve', 'PosReg', (162, 169))	('modifications', 'Var', (4, 17))	('patient', 'Species', '9606', (170, 177))
235337	29610388	These studies used high-throughput next-generation sequencing technology (HTS) to reveal single-nucleotide variants (SNVs) and small indels in protein-coding regions that comprise <1% of the human genome.	('human', 'Species', '9606', (191, 196))	('HTS', 'Disease', 'MESH:C537160', (74, 77))	('single-nucleotide variants', 'Var', (89, 115))	('HTS', 'Disease', (74, 77))
235338	29610388	The clinical utility and cost-effectiveness of targeted next-generation sequencing (TGS) cancer panel testing to detect somatically acquired single gene mutations is now established in specific disease areas, such as lung and melanoma, and are illustrated by the efficacy of a number of therapeutics targeting the protein products of specific genes that are altered in human cancer.	('mutations', 'Var', (153, 162))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('lung and melanoma', 'Disease', 'MESH:D008545', (217, 234))	('cancer', 'Disease', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('human', 'Species', '9606', (369, 374))	('cancer', 'Disease', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
235339	29610388	However, the breadth and significance of various mutation types across multiple genes affecting biological pathways relevant to cancer and their potential clinical significance are largely unexplored.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('biological pathways', 'Pathway', (96, 115))	('mutation', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('affecting', 'Reg', (86, 95))	('cancer', 'Disease', (128, 134))
235342	29610388	The possibility that similar mechanisms operate somatically in cancer was highlighted by the discovery of potentially targetable somatic driver substitutions in the TERT gene promoter and more recently in NOTCH1 splice region and a PAX5 enhancer.	('PAX5', 'Gene', (232, 236))	('PAX5', 'Gene', '5079', (232, 236))	('NOTCH1', 'Gene', '4851', (205, 211))	('NOTCH1', 'Gene', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('TERT', 'Gene', (165, 169))	('TERT', 'Gene', '7015', (165, 169))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('substitutions', 'Var', (144, 157))	('cancer', 'Disease', (63, 69))
235343	29610388	The second area addresses complex types of mutations such as copy-number aberrations (CNAs) and translocations that have not been integrated systematically with SNV analyses and linked to clinical outcome or response to therapy such as CN losses and/or SNVs involving the TP53 locus at 17p13.1 in chronic lymphocytic leukemia and translocations.	('translocations', 'Var', (330, 344))	('TP53', 'Gene', '7157', (272, 276))	('TP53', 'Gene', (272, 276))	('SNVs', 'Var', (253, 257))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (297, 325))	('leukemia', 'Phenotype', 'HP:0001909', (317, 325))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (297, 325))	('chronic lymphocytic leukemia', 'Disease', (297, 325))	('CN losses', 'Var', (236, 245))
235346	29610388	For example, synthetic lethality of BRCA1/2 mutations causing defective homologous recombination repair (HRR) is induced by cisplatin or PARP inhibition and has been confirmed in clinical trials.	('homologous recombination repair', 'MPA', (72, 103))	('PARP', 'Gene', (137, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('BRCA1/2', 'Gene', (36, 43))	('PARP', 'Gene', '142', (137, 141))	('defective', 'NegReg', (62, 71))	('mutations', 'Var', (44, 53))	('BRCA1/2', 'Gene', '672;675', (36, 43))	('synthetic lethality', 'CPA', (13, 32))
235347	29610388	Comprehensive analysis of combinations of constitutional and/or somatically acquired base substitution, indels, rearrangements, and CN changes across all genes involved in HRR-based DNA double-strand break repair may yield better predictors of responsiveness to drugs targeting this pathway than BRCA1/2 mutations or promoter methylation alone.	('BRCA1/2', 'Gene', '672;675', (296, 303))	('responsiveness', 'MPA', (244, 258))	('base substitution', 'Var', (85, 102))	('rearrangements', 'Var', (112, 126))	('BRCA1/2', 'Gene', (296, 303))
235348	29610388	In particular, somatic and germline mutations in ATM, ATR, PTEN, PALB2, RAD51C, RAD50, TP53, CHEK2, BRIP1, FANCA, HDAC2, MLH3, ERCC3, MRE11, and NBN have been associated with synthetic lethality after treatment with PARP inhibitors and other emerging potential therapeutics.	('FANCA', 'Gene', (107, 112))	('RAD51C', 'Gene', '5889', (72, 78))	('CHEK2', 'Gene', '11200', (93, 98))	('MRE11', 'Gene', '4361', (134, 139))	('ATM', 'Gene', (49, 52))	('MLH3', 'Gene', '27030', (121, 125))	('MLH3', 'Gene', (121, 125))	('PTEN', 'Gene', (59, 63))	('synthetic lethality', 'MPA', (175, 194))	('RAD51C', 'Gene', (72, 78))	('TP53', 'Gene', '7157', (87, 91))	('ATR', 'Gene', (54, 57))	('ERCC3', 'Gene', '2071', (127, 132))	('associated with', 'Reg', (159, 174))	('RAD50', 'Gene', (80, 85))	('PARP', 'Gene', '142', (216, 220))	('PTEN', 'Gene', '5728', (59, 63))	('NBN', 'Gene', '4683', (145, 148))	('PARP', 'Gene', (216, 220))	('BRIP1', 'Gene', '83990', (100, 105))	('PALB2', 'Gene', (65, 70))	('RAD50', 'Gene', '10111', (80, 85))	('FANCA', 'Gene', '2175', (107, 112))	('HDAC2', 'Gene', (114, 119))	('HDAC2', 'Gene', '3066', (114, 119))	('ATM', 'Gene', '472', (49, 52))	('ATR', 'Gene', '545', (54, 57))	('NBN', 'Gene', (145, 148))	('CHEK2', 'Gene', (93, 98))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (36, 45))	('ERCC3', 'Gene', (127, 132))	('PALB2', 'Gene', '79728', (65, 70))	('MRE11', 'Gene', (134, 139))	('BRIP1', 'Gene', (100, 105))
235349	29610388	These measures are not routinely investigated in the clinical setting yet but can point to particular subtypes of cancer with defective mismatch repair that are associated with favorable prognosis and may benefit from immune checkpoint inhibition.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('defective mismatch repair', 'Var', (126, 151))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
235350	29610388	Recent studies have demonstrated a direct relationship between exonic mutational burden, durable sensitivity to PD-1 and CTLA-4 blockade, and overall survival.	('CTLA-4', 'Gene', (121, 127))	('PD-1', 'Gene', (112, 116))	('PD-1', 'Gene', '9825', (112, 116))	('CTLA-4', 'Gene', '1493', (121, 127))	('exonic mutational burden', 'Var', (63, 87))
235358	29610388	Targeted in silico germline analysis of a predefined list of cancer predisposition genes (Supplemental Table S3) led to identification of multiple germline variants of uncertain significance (data not shown).	('variants', 'Var', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
235359	29610388	One germline variant in RAD51B (Case 4) contributed to a homozygous impairment of a DDR locus and was therefore considered clinically actionable.	('DDR locus', 'Gene', (84, 93))	('variant', 'Var', (13, 20))	('contributed to', 'Reg', (40, 54))	('RAD51B', 'Gene', (24, 30))	('RAD51B', 'Gene', '5890', (24, 30))
235367	29610388	TGS of DNA derived from the metastasis showed a variant in TP53 (c.832C>A, p.Pro278Thr), indicative of poor prognosis.	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', (59, 63))	('p.Pro278Thr', 'Mutation', 'rs17849781', (75, 86))	('c.832C>A', 'Mutation', 'rs17849781', (65, 73))	('p.Pro278Thr', 'Var', (75, 86))	('c.832C>A', 'Var', (65, 73))
235368	29610388	WGS of paired tumor and germline DNA confirmed the somatic tier 1 SNV in TP53 and additionally revealed a cnLOH region of Chromosome 17 (17p13.3-p12) involving TP53, as well as copy-number loss of PTEN and allelic imbalance of BRCA2 (Table 2; Fig.	('TP53', 'Gene', '7157', (73, 77))	('tumor', 'Disease', (14, 19))	('BRCA2', 'Gene', '675', (227, 232))	('TP53', 'Gene', '7157', (160, 164))	('TP53', 'Gene', (73, 77))	('imbalance', 'Phenotype', 'HP:0002172', (214, 223))	('allelic imbalance', 'Var', (206, 223))	('p12', 'Gene', (145, 148))	('PTEN', 'Gene', (197, 201))	('TP53', 'Gene', (160, 164))	('PTEN', 'Gene', '5728', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('copy-number loss', 'Var', (177, 193))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('p12', 'Gene', '56655', (145, 148))	('BRCA2', 'Gene', (227, 232))
235370	29610388	Mutation signature 5 associated with all cancer types was the dominant signature from WGS data (Fig.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('associated', 'Reg', (21, 31))	('Mutation', 'Var', (0, 8))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
235371	29610388	WGS also showed a SETD2 (tier 1) variant (c.5143-1G>A) (Table 2).	('c.5143-1G>A', 'Mutation', 'c.5143-1G>A', (42, 53))	('c.5143-1G>A', 'Var', (42, 53))	('SETD2', 'Gene', (18, 23))	('SETD2', 'Gene', '29072', (18, 23))
235376	29610388	The genome exhibited a complex karyotype, a mutation in DDX3X, and absence of TP53 mutations, all in keeping with HPV-positive squamous cell carcinoma.	('mutations', 'Var', (83, 92))	('DDX3X', 'Gene', (56, 61))	('exhibited', 'Reg', (11, 20))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('HPV-positive squamous cell carcinoma', 'Disease', (114, 150))	('DDX3X', 'Gene', '1654', (56, 61))	('HPV-positive squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 150))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))
235378	29610388	Presence of mutation signature 2 is consistent with the viral etiology of the tumor (Fig.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutation', 'Var', (12, 20))	('tumor', 'Disease', (78, 83))
235381	29610388	Cisplatin was stopped, a decision supported by the absence of a DDR mutation signature and good prognosis features, and the patient was started on concomitant cetuximab (Table 3).	('DDR', 'Gene', (64, 67))	('mutation', 'Var', (68, 76))	('cetuximab', 'Chemical', 'MESH:D000068818', (159, 168))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('absence', 'NegReg', (51, 58))	('patient', 'Species', '9606', (124, 131))
235382	29610388	Reassuringly, WGS confirmed that there were no EGFR resistance mutations to this drug.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))
235384	29610388	The absence of biallelic mutations in DDR genes or in the known cancer predisposition gene EGFR assisted in managing drug side effects and in confirming the choice of an alternative targeted therapy.	('EGFR', 'Gene', (91, 95))	('biallelic mutations', 'Var', (15, 34))	('cancer', 'Disease', (64, 70))	('DDR genes', 'Gene', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('assisted', 'Reg', (96, 104))	('absence', 'NegReg', (4, 11))	('man', 'Species', '9606', (108, 111))	('EGFR', 'Gene', '1956', (91, 95))	('managing drug side effects', 'MPA', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
235396	29610388	Because TGS and WGS showed an activating PIK3CA mutation (c.1633C>G, p.Glu545Gln), the proposed management was to proceed with the PIK3CA inhibitors, taselisib or pictilisib, at disease progression.	('PIK3CA', 'Gene', '5290', (41, 47))	('activating', 'PosReg', (30, 40))	('PIK3CA', 'Gene', '5290', (131, 137))	('PIK3CA', 'Gene', (41, 47))	('man', 'Species', '9606', (96, 99))	('p.Glu545Gln', 'Var', (69, 80))	('c.1633C>G', 'Var', (58, 67))	('PIK3CA', 'Gene', (131, 137))	('taselisib', 'Chemical', 'MESH:C582924', (150, 159))	('pictilisib', 'Chemical', 'MESH:C532162', (163, 173))	('p.Glu545Gln', 'Mutation', 'rs104886003', (69, 80))	('c.1633C>G', 'Mutation', 'rs104886003', (58, 67))
235397	29610388	In addition, WGS revealed two different acquired pathogenic TP53 mutations and an allelic imbalance reflecting either a CN loss or cnLOH involving TP53, BRCA1, BRIP1, RAD51C, and RAD51D (Fig.	('TP53', 'Gene', (147, 151))	('BRIP1', 'Gene', '83990', (160, 165))	('imbalance', 'Phenotype', 'HP:0002172', (90, 99))	('RAD51D', 'Gene', (179, 185))	('BRCA1', 'Gene', '672', (153, 158))	('RAD51D', 'Gene', '5892', (179, 185))	('BRIP1', 'Gene', (160, 165))	('RAD51C', 'Gene', (167, 173))	('RAD51C', 'Gene', '5889', (167, 173))	('loss', 'NegReg', (123, 127))	('TP53', 'Gene', '7157', (60, 64))	('BRCA1', 'Gene', (153, 158))	('TP53', 'Gene', '7157', (147, 151))	('TP53', 'Gene', (60, 64))	('pathogenic', 'Reg', (49, 59))	('mutations', 'Var', (65, 74))
235400	29610388	A germline deletion polymorphism involving APOBEC3A and APOBEC3B on Chromosome 22 is associated with the presence of large numbers of signature 2 and 13 mutations and with predisposition to breast cancer, but this patient did not carry the germline polymorphism.	('patient', 'Species', '9606', (214, 221))	('APOBEC3A', 'Gene', '200315', (43, 51))	('mutations', 'Var', (153, 162))	('APOBEC3B', 'Gene', '9582', (56, 64))	('APOBEC3A', 'Gene', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('APOBEC3B', 'Gene', (56, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('associated', 'Reg', (85, 95))
235412	29610388	WGS identified a tier 1 germline deleterious SNV in RAD51B together with an acquired CN loss of this locus that could be regarded as a second hit and is consistent with impairment of the DDR signaling pathway function (Fig.	('DDR signaling pathway', 'Pathway', (187, 208))	('loss', 'NegReg', (88, 92))	('SNV', 'Var', (45, 48))	('RAD51B', 'Gene', '5890', (52, 58))	('RAD51B', 'Gene', (52, 58))
235413	29610388	Supporting these findings, mutation signature 3 was clearly present in this tumor (Fig.	('mutation', 'Var', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
235414	29610388	Furthermore, WGS showed a tier 1 nonsense mutation in ARID1A (c.4480C>T, p.Gln1494Ter).	('ARID1A', 'Gene', (54, 60))	('p.Gln1494Ter', 'Var', (73, 85))	('c.4480C>T', 'Mutation', 'rs1060501576', (62, 71))	('p.Gln1494Ter', 'Mutation', 'rs1060501576', (73, 85))	('c.4480C>T', 'Var', (62, 71))	('ARID1A', 'Gene', '8289', (54, 60))
235415	29610388	A recent study demonstrated synthetic lethality by targeting EZH2 histone methyltransferase activity in ARID1A-mutated tumors using a clinically applicable small molecule inhibitor, and a clinical trial for patients with mutations in ARID1A is now recruiting and others are planned for which the patient could be eligible.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (207, 215))	('EZH2', 'Gene', (61, 65))	('mutations', 'Var', (221, 230))	('EZH2', 'Gene', '2146', (61, 65))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('patient', 'Species', '9606', (296, 303))	('ARID1A', 'Gene', '8289', (234, 240))	('ARID1A', 'Gene', '8289', (104, 110))	('ARID1A', 'Gene', (234, 240))	('patient', 'Species', '9606', (207, 214))	('ARID1A', 'Gene', (104, 110))	('activity', 'MPA', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
235416	29610388	WGS also revealed tier 2 mutations in HDAC2, NFE2L2, and SMAD4 that are likely to have biological and prognostic significance (Table 2) but are not clinically actionable.	('mutations', 'Var', (25, 34))	('SMAD4', 'Gene', (57, 62))	('HDAC2', 'Gene', '3066', (38, 43))	('NFE2L2', 'Gene', '4780', (45, 51))	('HDAC2', 'Gene', (38, 43))	('NFE2L2', 'Gene', (45, 51))	('SMAD4', 'Gene', '4089', (57, 62))
235426	29610388	As uterine serous carcinoma is frequently associated with the presence of TP53 mutations, molecular testing was performed to identify these and other variants useful in guiding management.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('serous carcinoma', 'Disease', (11, 27))	('serous carcinoma', 'Disease', 'MESH:D018284', (11, 27))	('associated', 'Reg', (42, 52))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('man', 'Species', '9606', (177, 180))	('mutations', 'Var', (79, 88))
235427	29610388	Interestingly, although neither TGS nor WGS detected any TP53 mutation, WGS demonstrated a pathogenic mutation in the exonuclease domain of the replicative DNA polymerase POLE (c.857C>G, p.Pro286Arg) (Table 2), along with the characteristic ultramutated phenotype (Supplemental Fig.	('p.Pro286Arg', 'Mutation', 'p.P286R', (187, 198))	('c.857C>G', 'Var', (177, 185))	('pathogenic', 'Reg', (91, 101))	('c.857C>G', 'Mutation', 'c.857C>G', (177, 185))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
235433	29610388	Moreover, in the event of disease progression, POLE mutations may predict sensitivity to nivolumab or pebrolizumab.	('mutations', 'Var', (52, 61))	('predict', 'Reg', (66, 73))	('nivolumab', 'Chemical', 'MESH:D000077594', (89, 98))	('sensitivity', 'MPA', (74, 85))
235438	29610388	TGS performed on DNA obtained from the rib metastasis showed a pathogenic mutation in TP53.	('TP53', 'Gene', (86, 90))	('mutation', 'Var', (74, 82))	('pathogenic', 'Reg', (63, 73))	('TP53', 'Gene', '7157', (86, 90))
235456	29610388	TGS and WGS revealed a tier 1 mutation in NRAS (c.181C>A, p.Gln61Lys), which indicates lack of response to anti-EGFR antibody therapy or BRAF inhibition and points to MEK-inhibitor therapy.	('EGFR', 'Gene', (112, 116))	('MEK', 'Gene', (167, 170))	('c.181C>A', 'Var', (48, 56))	('NRAS', 'Gene', '4893', (42, 46))	('MEK', 'Gene', '5609', (167, 170))	('lack', 'NegReg', (87, 91))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('c.181C>A', 'Mutation', 'rs121913254', (48, 56))	('p.Gln61Lys', 'Var', (58, 68))	('p.Gln61Lys', 'Mutation', 'rs121913254', (58, 68))	('EGFR', 'Gene', '1956', (112, 116))	('NRAS', 'Gene', (42, 46))
235458	29610388	However, WGS showed a complex karyotype including an acquired homozygous CN loss of CDKN2A (Aurora/VEGF inhibitors), loss of PTEN (mTOR inhibitors), and a somatically acquired loss of NF1, again indicating potential response to MEK inhibition.	('NF1', 'Gene', (184, 187))	('CDKN2A', 'Gene', (84, 90))	('loss', 'NegReg', (176, 180))	('loss', 'NegReg', (76, 80))	('PTEN', 'Gene', (125, 129))	('loss', 'Var', (117, 121))	('NF1', 'Gene', '4763', (184, 187))	('mTOR', 'Gene', (131, 135))	('CDKN2A', 'Gene', '1029', (84, 90))	('mTOR', 'Gene', '2475', (131, 135))	('PTEN', 'Gene', '5728', (125, 129))	('VEGF', 'Gene', '7422', (99, 103))	('MEK', 'Gene', (228, 231))	('MEK', 'Gene', '5609', (228, 231))	('VEGF', 'Gene', (99, 103))
235460	29610388	Interestingly, in a phase 1 trial of abemaciclib, a selective CDK4 and 6 inhibitor, a patient with metastatic melanoma achieved a PR carrying similar molecular alterations (NRAS mutation and copy-number loss at the INK4 locus) to Case 7.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('CDK4', 'Gene', '1019', (62, 66))	('NRAS', 'Gene', (173, 177))	('copy-number loss', 'Var', (191, 207))	('NRAS', 'Gene', '4893', (173, 177))	('patient', 'Species', '9606', (86, 93))	('PR', 'Gene', '5241', (130, 132))	('INK4', 'Gene', '1029', (215, 219))	('INK4', 'Gene', (215, 219))	('CDK4', 'Gene', (62, 66))
235470	29610388	The proliferation index by Ki67 was 5%, indicative of a low-grade lesion.	('Ki67', 'Var', (27, 31))	('Ki67', 'Chemical', '-', (27, 31))	('proliferation index', 'CPA', (4, 23))
235488	29610388	In four patients (Cases 1, 3, 4, and 6) WGS revealed a likely biallelic DDR mutation signature that would have been missed by conventional targeted cancer panel approaches, as it was defined by integration of SNVs, indels, and copy-number losses and analysis of global mutation signatures.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('DDR', 'Gene', (72, 75))	('mutation', 'Var', (76, 84))	('patients', 'Species', '9606', (8, 16))
235495	29610388	For example, we identified acquired copy-number changes in BRCA1/2 that enabled synthetic lethal drugs to be used.	('copy-number changes', 'Var', (36, 55))	('BRCA1/2', 'Gene', (59, 66))	('BRCA1/2', 'Gene', '672;675', (59, 66))	('enabled', 'Reg', (72, 79))
235496	29610388	Similarly, mutations in POLE were originally identified in inherited colorectal cancers but have since been recognized as somatic changes in both colorectal and endometrial cancers.	('mutations', 'Var', (11, 20))	('POLE', 'Gene', (24, 28))	('colorectal and endometrial cancers', 'Disease', 'MESH:D016889', (146, 180))	('identified', 'Reg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('endometrial cancer', 'Phenotype', 'HP:0012114', (161, 179))	('colorectal cancers', 'Disease', 'MESH:D015179', (69, 87))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('colorectal cancers', 'Disease', (69, 87))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
235497	29610388	Finally, Case 4 carried a deleterious germline variant in RAD51B and acquired loss of the other allele in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('loss', 'NegReg', (78, 82))	('germline variant', 'Var', (38, 54))	('RAD51B', 'Gene', (58, 64))	('RAD51B', 'Gene', '5890', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
235502	29610388	In addition to confirming the HPV status, WGS also informed the management of side effects leading to de-escalation and the choice of alternative therapy by confirming lack of DDR mutations and absence of EGFR mutations, which would have conferred resistance to cetuximab.	('absence', 'NegReg', (194, 201))	('cetuximab', 'Chemical', 'MESH:D000068818', (262, 271))	('mutations', 'Var', (210, 219))	('mutations', 'Var', (180, 189))	('man', 'Species', '9606', (64, 67))	('lack', 'NegReg', (168, 172))	('conferred', 'Reg', (238, 247))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (205, 209))	('HPV', 'Species', '10566', (30, 33))	('DDR', 'Gene', (176, 179))
235504	29610388	For noncoding regions, mutations in the promoter of TERT2 gene are well-described, but these did not occur in our cohort.	('mutations', 'Var', (23, 32))	('TERT2', 'Gene', (52, 57))	('TERT2', 'CellLine', 'CVCL:C452', (52, 57))
235512	29610388	Two treatment regimens emerge from this study as being of particular importance: PARP inhibitors for patients with defects in the DDR pathway and PDL1 checkpoint inhibitors for cancers showing hypermutation.	('DDR pathway', 'Pathway', (130, 141))	('patients', 'Species', '9606', (101, 109))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('PARP', 'Gene', (81, 85))	('cancers', 'Disease', (177, 184))	('defects', 'Var', (115, 122))	('PDL1', 'Gene', '29126', (146, 150))	('PARP', 'Gene', '142', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('PDL1', 'Gene', (146, 150))
235533	29610388	Tier 2 variants were defined as those that might contribute to confirming the pathological diagnosis or have established biological relevance and/or those for which a clinical trial or approved therapy in a different tumor type was available.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('variants', 'Var', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (217, 222))
235535	29610388	The tier 1 and tier 2 variants identified in this study have been submitted to ClinVar  and can be found under accession numbers SCV000493830 PTEN Chr 10:85557432-105804295 CN Loss; SCV000493831 BRCA2 Chr 13:32178877-33860144 CN Loss (Homozygous); and SCV000493829 TP53 Chr 17:7573975 NM_000546.5: c1044_1051 delGGAACTCA.	('PTEN', 'Gene', (142, 146))	('BRCA2', 'Gene', '675', (195, 200))	('PTEN', 'Gene', '5728', (142, 146))	('TP53', 'Gene', '7157', (265, 269))	('SCV000493830', 'Var', (129, 141))	('TP53', 'Gene', (265, 269))	('BRCA2', 'Gene', (195, 200))	('SCV000493831', 'Var', (182, 194))	('delGGAACTCA', 'Mutation', 'c.delGGAACTCA', (309, 320))
235536	29610388	designed the study, interpreted results wrote the first draft, and edited the manuscript; H.D., S.J.L.K., T.M., P.A., D.V., K.R., E.M.K., M.M.P., and N.P.	('man', 'Species', '9606', (78, 81))	('D.V.', 'Var', (118, 122))	('T.M.', 'Var', (106, 110))	('P.A.', 'Var', (112, 116))	('E.M.K.', 'Var', (130, 136))	('M.M.P.', 'Var', (138, 144))	('K.R.', 'Var', (124, 128))	('S.J.L.K.', 'Var', (96, 104))
235538	27160069	Searching for the Chokehold of NRAS Mutant Melanoma Up to 18% of melanomas harbor mutations in the neuroblastoma rat-sarcoma homolog (NRAS).	('melanomas', 'Disease', 'MESH:D008545', (65, 74))	('Melanoma', 'Disease', (43, 51))	('neuroblastoma rat-sarcoma', 'Disease', 'MESH:D009447', (99, 124))	('neuroblastoma', 'Phenotype', 'HP:0003006', (99, 112))	('neuroblastoma rat-sarcoma', 'Disease', (99, 124))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('NRAS', 'Gene', '4893', (31, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('melanomas', 'Disease', (65, 74))	('mutations', 'Var', (82, 91))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('NRAS', 'Gene', (134, 138))	('Melanoma', 'Disease', 'MESH:D008545', (43, 51))	('Melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('NRAS', 'Gene', (31, 35))	('NRAS', 'Gene', '4893', (134, 138))
235540	27160069	This review discusses direct and indirect blocking of activated RAS with a focus on current and potential future therapeutic approaches for NRAS mutant melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('mutant', 'Var', (145, 151))	('NRAS', 'Gene', (140, 144))
235543	27160069	Dysregulated RAS signaling, mainly mediated by oncogenic mutations, is found in about one-third of all cancers with NRAS being most frequently mutant in melanoma (18%).	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('found', 'Reg', (71, 76))	('melanoma', 'Disease', (153, 161))	('mutant', 'Reg', (143, 149))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('mutations', 'Var', (57, 66))	('NRAS', 'Gene', (116, 120))	('Dysregulated RAS signaling', 'MPA', (0, 26))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
235545	27160069	To date, indirect inhibition of mutant RAS by downstream pathway interference is one of the clinically most promising strategies.	('RAS', 'Protein', (39, 42))	('mutant', 'Var', (32, 38))	('rat', 'Species', '10116', (120, 123))
235546	27160069	In addition, recent discoveries indicate that RAS activity is also increased by loss of function mutations in the negative regulator of RAS, NF1, which is mutated in approximately 14% of patients with melanoma.	('melanoma', 'Disease', (201, 209))	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (187, 195))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('activity', 'MPA', (50, 58))	('increased', 'PosReg', (67, 76))	('loss of function', 'NegReg', (80, 96))	('NF1', 'Gene', (141, 144))	('RAS', 'CPA', (46, 49))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('NF1', 'Gene', '4763', (141, 144))
235549	27160069	This review aims to give an overview of recent discoveries in direct and indirect targeting of mutant RAS proteins with a focus on NRAS mutant melanoma and discusses opportunities and limitations for their future clinical application.	('RAS proteins', 'Protein', (102, 114))	('NRAS', 'Gene', (131, 135))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('mutant', 'Var', (95, 101))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))
235554	27160069	While mutant NRAS(Q61) disrupts the GTPase activity of RAS, locking it in its active conformation, NRAS(G12) and NRAS(G13) mutations affect the Walker A-motif (p-loop) of the protein, thus decreasing its sensitivity to GAPs (Figure 1).	('mutant', 'Var', (6, 12))	('NRAS(G13', 'Gene', (113, 121))	('sensitivity to GAPs', 'MPA', (204, 223))	('activity', 'MPA', (43, 51))	('GTP', 'Chemical', 'MESH:D006160', (36, 39))	('affect', 'Reg', (133, 139))	('active', 'MPA', (78, 84))	('GTPase', 'Enzyme', (36, 42))	('decreasing', 'NegReg', (189, 199))	('disrupts', 'NegReg', (23, 31))	('mutations', 'Var', (123, 132))
235556	27160069	Mutations in NRAS favor the formation of GTP-bound, active RAS proteins.	('GTP-bound', 'MPA', (41, 50))	('GTP', 'Chemical', 'MESH:D006160', (41, 44))	('RAS proteins', 'Protein', (59, 71))	('formation', 'MPA', (28, 37))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('favor', 'PosReg', (18, 23))
235558	27160069	This is possible as recently exemplified in preclinical models of codon 12 mutant KRAS: Because the intrinsic catalytic capacity of mutant RAS(G12) is not affected, the mutant protein displays a balanced equilibrium of GDP and GTP bound states.	('GDP', 'Chemical', 'MESH:D006153', (219, 222))	('mutant', 'Var', (132, 138))	('GTP', 'Chemical', 'MESH:D006160', (227, 230))	('KRAS', 'Gene', (82, 86))	('KRAS', 'Gene', '3845', (82, 86))	('equilibrium', 'MPA', (204, 215))
235560	27160069	These compounds covalently and specifically bind to cysteine-12 in G12C mutants and block the activation of downstream signaling mediators of RAS including v-akt murine thymoma viral oncogene homolog (AKT) and extracellular signal-regulated kinase (ERK).	('thymoma viral', 'Disease', (169, 182))	('murine', 'Species', '10090', (162, 168))	('thymoma', 'Phenotype', 'HP:0100522', (169, 176))	('akt', 'Gene', (158, 161))	('extracellular signal-regulated kinase', 'Gene', (210, 247))	('thymoma viral', 'Disease', 'MESH:D013945', (169, 182))	('extracellular signal-regulated kinase', 'Gene', '26413', (210, 247))	('akt', 'Gene', '207', (158, 161))	('bind', 'Interaction', (44, 48))	('block', 'NegReg', (84, 89))	('G12C', 'Var', (67, 71))	('activation', 'MPA', (94, 104))	('downstream signaling mediators', 'MPA', (108, 138))	('G12C', 'Mutation', 'rs121913530', (67, 71))	('cysteine-12', 'Chemical', '-', (52, 63))
235561	27160069	Even though this research has been carried out in models of oncogenic KRAS, it is likely that, such compounds will also specifically block codon G12C mutant NRAS given the high structural similarities in the effector lobe of RAS proteins.	('codon G12C mutant', 'Var', (139, 156))	('KRAS', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (70, 74))	('G12C', 'Mutation', 'rs121913530', (145, 149))	('NRAS', 'Gene', (157, 161))	('block', 'NegReg', (133, 138))
235564	27160069	Blocking farnesylation, a post-translational modification step essential for RAS binding to the cell membrane, showed promising results in preclinical models of mutant HRAS; however, clinical testing of farnesyltransferase inhibitors in K- and N-RAS mutant malignancies failed to provide a benefit for patients.	('mutant', 'Var', (161, 167))	('malignancies', 'Disease', 'MESH:D009369', (257, 269))	('HRAS', 'Gene', (168, 172))	('malignancies', 'Disease', (257, 269))	('N-RAS', 'Gene', (244, 249))	('HRAS', 'Gene', '3265', (168, 172))	('patients', 'Species', '9606', (302, 310))	('N-RAS', 'Gene', '4893', (244, 249))
235566	27160069	Similarly, inhibitors of posttranslational palmitoylation, such as palmostatin B, which also aim to disrupt the membrane localization of RAS, were effective in preclinical models of NRAS mutant cells but have not (yet) translated into clinical applications.	('palmostatin B', 'Chemical', 'MESH:C578782', (67, 80))	('disrupt', 'NegReg', (100, 107))	('RAS', 'Protein', (137, 140))	('mutant', 'Var', (187, 193))	('membrane localization', 'MPA', (112, 133))	('NRAS', 'Gene', (182, 186))
235567	27160069	Activated RAS proteins form complexes with regulators controlling RAS cycling (GEFs, GAPs) and effectors mediating downstream signaling (RAF, RAS related GTP binding protein [RAL], PI3K, and others).	('RAS related GTP binding protein', 'Gene', '10890', (142, 173))	('PI3K', 'Var', (181, 185))	('complexes', 'Interaction', (28, 37))	('GEF', 'Gene', '9181', (79, 82))	('RAS related GTP binding protein', 'Gene', (142, 173))	('RAL', 'Gene', (175, 178))	('RAL', 'Gene', '5898', (175, 178))	('GEF', 'Gene', (79, 82))
235569	27160069	Yet, it remains unknown to which extent GEFs contribute to mutant RAS activation and if compounds targeting RAS-GEF interactions might be beneficial in the context of the mutant protein.	('GEF', 'Gene', '9181', (40, 43))	('interactions', 'Interaction', (116, 128))	('GEF', 'Gene', '9181', (112, 115))	('mutant', 'Var', (59, 65))	('RAS', 'Protein', (66, 69))	('GEF', 'Gene', (40, 43))	('GEF', 'Gene', (112, 115))	('activation', 'PosReg', (70, 80))
235571	27160069	Similar to studies mentioned above, most research was carried out in models of mutant HRAS and KRAS, and it remains unclear whether such findings hold promise for NRAS mutant melanoma.	('KRAS', 'Gene', '3845', (95, 99))	('HRAS', 'Gene', '3265', (86, 90))	('mutant', 'Var', (79, 85))	('HRAS', 'Gene', (86, 90))	('KRAS', 'Gene', (95, 99))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('melanoma', 'Disease', (175, 183))
235572	27160069	The most investigated signaling cascades in NRAS mutant melanoma are the MAPK, PI3K/mammalian target of rapamycin (mTOR), and cell-cycle pathways (Figure 2).	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutant', 'Var', (49, 55))	('melanoma', 'Disease', (56, 64))	('cell-cycle pathways', 'Pathway', (126, 145))	('NRAS', 'Gene', (44, 48))	('PI3K/mammalian target of rapamycin', 'Gene', '2475', (79, 113))	('PI3K/mammalian target of rapamycin', 'Gene', (79, 113))
235574	27160069	Several multikinase inhibitors with modest pan-RAF activity were developed but only showed minimal effects in patients with NRAS mutant melanoma.	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('patients', 'Species', '9606', (110, 118))	('mutant', 'Var', (129, 135))	('NRAS', 'Gene', (124, 128))
235575	27160069	More specific RAF inhibitors, such as vemurafenib and dabrafenib, which preferentially target the mutant BRAF(V600) protein, even caused worsening of NRAS mutant disease.	('vemurafenib', 'Chemical', 'MESH:D000077484', (38, 49))	('dabrafenib', 'Chemical', 'MESH:C561627', (54, 64))	('NRAS mutant disease', 'Disease', (150, 169))	('BRAF(V600', 'Gene', '673', (105, 114))	('mutant', 'Var', (98, 104))	('protein', 'Protein', (116, 123))
235576	27160069	This was later found to be due to paradoxical activation of ERK signaling in BRAF wild-type cells caused by enhanced dimerization, conformational changes, and trans-activation of RAF induced by these drugs, as well as the switch from BRAF to CRAF signaling when NRAS is mutant.	('switch', 'Reg', (222, 228))	('BRAF', 'Gene', '673', (77, 81))	('RAF', 'Protein', (179, 182))	('mutant', 'Var', (270, 276))	('activation', 'PosReg', (46, 56))	('BRAF', 'Gene', (77, 81))	('enhanced', 'PosReg', (108, 116))	('trans-activation', 'MPA', (159, 175))	('CRAF', 'Gene', (242, 246))	('ERK signaling', 'MPA', (60, 73))	('BRAF', 'Gene', '673', (234, 238))	('conformational changes', 'MPA', (131, 153))	('CRAF', 'Gene', '5894', (242, 246))	('NRAS', 'Gene', (262, 266))	('dimerization', 'MPA', (117, 129))	('BRAF', 'Gene', (234, 238))
235579	27160069	Inhibition of MAPK/ERK kinase (MEK) with specific, small molecules suppresses MAPK signaling and has shown promising results in patients with NRAS mutant melanoma.	('mutant', 'Var', (147, 153))	('NRAS', 'Gene', (142, 146))	('suppresses', 'NegReg', (67, 77))	('MEK', 'Gene', (31, 34))	('MEK', 'Gene', '5609', (31, 34))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('Inhibition', 'Var', (0, 10))	('MAPK signaling', 'Pathway', (78, 92))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('patients', 'Species', '9606', (128, 136))
235585	27160069	Even though RAF, MEK, and ERK comprise the core of MAPK signaling, we now understand that a one-directional picture of the pathway is insufficient to account for the diverse regulatory mechanisms that ensure mutant NRAS cell homeostasis.	('MEK', 'Gene', (17, 20))	('insufficient', 'Disease', (134, 146))	('insufficient', 'Disease', 'MESH:D000309', (134, 146))	('MEK', 'Gene', '5609', (17, 20))	('mutant', 'Var', (208, 214))
235591	27160069	The important role of MAPK signaling in NRAS mutant cancers and the fact that to date only MEK inhibitors have shown clinical activity in patients with NRAS mutant melanoma are the rationale for using MEK inhibitors as a cornerstone for combinational treatments (Supplementary Table S1).	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutant', 'Var', (157, 163))	('NRAS', 'Gene', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('MEK', 'Gene', (201, 204))	('rat', 'Species', '10116', (181, 184))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('MEK', 'Gene', '5609', (201, 204))	('MEK', 'Gene', (91, 94))	('MEK', 'Gene', '5609', (91, 94))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('patients', 'Species', '9606', (138, 146))	('melanoma', 'Disease', (164, 172))
235595	27160069	Clinical testing of MEK/CDK4 inhibition showed activity in NRAS mutant melanoma; however, the majority of patients still did not respond.	('MEK', 'Gene', (20, 23))	('MEK', 'Gene', '5609', (20, 23))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('CDK4', 'Gene', '1019', (24, 28))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('patients', 'Species', '9606', (106, 114))	('NRAS', 'Gene', (59, 63))	('activity', 'MPA', (47, 55))	('CDK4', 'Gene', (24, 28))	('mutant', 'Var', (64, 70))
235596	27160069	Current research suggests that the efficacy of this combination might be increased when tumor cells also have genetic aberrations increasing CDK4 activity such as loss of p16(INK4a) or amplifications of cyclin D1.	('increased', 'PosReg', (73, 82))	('INK4a', 'Gene', '1029', (175, 180))	('CDK4', 'Gene', '1019', (141, 145))	('amplifications', 'Var', (185, 199))	('p16', 'Gene', (171, 174))	('INK4a', 'Gene', (175, 180))	('activity', 'MPA', (146, 154))	('increasing', 'PosReg', (130, 140))	('loss', 'NegReg', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('p16', 'Gene', '1029', (171, 174))	('rat', 'Species', '10116', (122, 125))	('cyclin D1', 'Gene', '595', (203, 212))	('tumor', 'Disease', (88, 93))	('cyclin D1', 'Gene', (203, 212))	('CDK4', 'Gene', (141, 145))
235597	27160069	Another, yet experimental, combination blocking the MAPK and cell-cycle pathways targets MEK and the cell-cycle regulator Plk1, which effectively reduces growth of NRAS mutant melanoma xenografts independent of p16(INK4a) mutation status.	('INK4a', 'Gene', '1029', (215, 220))	('MEK', 'Gene', (89, 92))	('Plk1', 'Gene', '5347', (122, 126))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('MEK', 'Gene', '5609', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('p16', 'Gene', '1029', (211, 214))	('growth', 'MPA', (154, 160))	('MAPK', 'Gene', (52, 56))	('Plk1', 'Gene', (122, 126))	('reduces', 'NegReg', (146, 153))	('mutant', 'Var', (169, 175))	('NRAS', 'Gene', (164, 168))	('p16', 'Gene', (211, 214))	('INK4a', 'Gene', (215, 220))	('cell-cycle pathways', 'Pathway', (61, 80))
235598	27160069	The rationale for dual inhibition of the MAPK and PI3K/mTOR pathways is supported by effective growth reduction of NRAS mutant melanoma in mouse models and the upregulation of PI3K/mTOR pathway members due to the release of negative feedback to RTKs after single MEK inhibitor treatment.	('PI3K/mTOR pathways', 'Pathway', (50, 68))	('MEK', 'Gene', '5609', (263, 266))	('NRAS', 'Gene', (115, 119))	('growth', 'MPA', (95, 101))	('upregulation', 'PosReg', (160, 172))	('MAPK', 'Pathway', (41, 45))	('mouse', 'Species', '10090', (139, 144))	('reduction', 'NegReg', (102, 111))	('rat', 'Species', '10116', (4, 7))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('PI3K/mTOR pathway', 'Pathway', (176, 193))	('mutant', 'Var', (120, 126))	('MEK', 'Gene', (263, 266))
235600	27160069	In addition, cotargeting of both PI3K and mTOR signaling molecules in combination with MEK inhibition might be necessary for effective NRAS mutant tumor shrinkage.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('NRAS', 'Gene', (135, 139))	('MEK', 'Gene', (87, 90))	('MEK', 'Gene', '5609', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutant', 'Var', (140, 146))
235604	27160069	The overactivation of the hepatocyte growth factor receptor (c-MET) in NRAS mutant melanoma prompted testing of the RAF kinase inhibitor sorafenib in combination with the c-MET inhibitor tivantinib.	('c-MET', 'Gene', '4233', (171, 176))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('c-MET', 'Gene', '4233', (61, 66))	('hepatocyte growth factor receptor', 'Gene', (26, 59))	('mutant', 'Var', (76, 82))	('NRAS', 'Gene', (71, 75))	('overactivation', 'PosReg', (4, 18))	('c-MET', 'Gene', (61, 66))	('sorafenib', 'Chemical', 'MESH:D000077157', (137, 146))	('c-MET', 'Gene', (171, 176))	('tivantinib', 'Chemical', 'MESH:C551661', (187, 197))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('hepatocyte growth factor receptor', 'Gene', '4233', (26, 59))	('melanoma', 'Disease', (83, 91))
235605	27160069	In a first clinical trial, 2 of 8 patients with NRAS mutant melanoma experienced complete or partial response; 2 additional patients had stable disease.	('patients', 'Species', '9606', (124, 132))	('partial', 'NegReg', (93, 100))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('patients', 'Species', '9606', (34, 42))	('mutant', 'Var', (53, 59))	('NRAS', 'Gene', (48, 52))
235607	27160069	Thus, it is possible that in the context of NRAS mutant melanoma, digitoxin (or derivates with comparable characteristics) could be used therapeutically.	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutant', 'Var', (49, 55))	('melanoma', 'Disease', (56, 64))	('digitoxin', 'Chemical', 'MESH:D004074', (66, 75))	('NRAS', 'Gene', (44, 48))
235609	27160069	This concept has proved effective in BRAF mutant melanoma, where combined BRAF/MEK inhibition significantly prolongs overall survival compared with BRAF or MEK inhibition alone.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('mutant', 'Var', (42, 48))	('inhibition', 'NegReg', (83, 93))	('overall survival', 'MPA', (117, 133))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('MEK', 'Gene', (79, 82))	('MEK', 'Gene', '5609', (79, 82))	('BRAF', 'Gene', (37, 41))	('MEK', 'Gene', (156, 159))	('MEK', 'Gene', '5609', (156, 159))	('BRAF', 'Gene', '673', (148, 152))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('prolongs', 'PosReg', (108, 116))	('melanoma', 'Disease', (49, 57))	('BRAF', 'Gene', (148, 152))
235610	27160069	A similar concept might also be effective in NRAS mutant melanoma: As discussed, one of the mechanisms of resistance using MEK inhibitors in NRAS mutant melanoma is the reactivation or inability to fully suppress ERK signaling.	('MEK', 'Gene', (123, 126))	('MEK', 'Gene', '5609', (123, 126))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('ERK', 'MPA', (213, 216))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('mutant', 'Var', (146, 152))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('NRAS', 'Gene', (141, 145))
235611	27160069	In preclinical studies, targeting of MEK and ERK in combination potently suppresses levels of phospho-ERK and induces apoptosis in NRAS mutant cells.	('apoptosis', 'CPA', (118, 127))	('ERK', 'Gene', (45, 48))	('NRAS', 'Gene', (131, 135))	('MEK', 'Gene', '5609', (37, 40))	('targeting', 'Var', (24, 33))	('levels of phospho-ERK', 'MPA', (84, 105))	('induces', 'Reg', (110, 117))	('mutant', 'Var', (136, 142))	('MEK', 'Gene', (37, 40))	('suppresses', 'NegReg', (73, 83))
235614	27160069	To date, combined vertical inhibition of the PI3K/mTOR pathway in melanoma has only been investigated in BRAF mutant cells.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('BRAF', 'Gene', '673', (105, 109))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('BRAF', 'Gene', (105, 109))	('PI3K/mTOR pathway', 'Pathway', (45, 62))	('mutant', 'Var', (110, 116))
235616	27160069	Systemic therapy with targeted molecules also affects cells other than tumor cells, including immune cells.	('affects', 'Reg', (46, 53))	('targeted molecules', 'Var', (22, 40))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
235617	27160069	MEK inhibitors suppress MAPK signaling in all exposed cells, potentially dampening immune cell activity, too.	('immune cell activity', 'CPA', (83, 103))	('suppress', 'NegReg', (15, 23))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('inhibitors', 'Var', (4, 14))	('dampening immune cell', 'Phenotype', 'HP:0002721', (73, 94))	('dampening', 'NegReg', (73, 82))	('MAPK signaling', 'Pathway', (24, 38))
235618	27160069	Still, the successful use of single MEK inhibitors in NRAS mutant melanoma makes it appealing to test the effects of combined MEK and immune-checkpoint inhibition in patients with NRAS mutant melanoma.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('mutant', 'Var', (59, 65))	('MEK', 'Gene', (126, 129))	('NRAS', 'Gene', (54, 58))	('MEK', 'Gene', '5609', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('patients', 'Species', '9606', (166, 174))	('melanoma', 'Disease', (192, 200))	('MEK', 'Gene', (36, 39))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('MEK', 'Gene', '5609', (36, 39))
235619	27160069	In contrast, compounds designed to target mutant BRAF(V600) cause paradox activation of ERK signaling in non-BRAF(V600) mutant cells.	('mutant', 'Var', (42, 48))	('BRAF(V600', 'Gene', '673', (49, 58))	('activation', 'PosReg', (74, 84))	('ERK signaling', 'MPA', (88, 101))	('BRAF(V600', 'Gene', '673', (109, 118))
235620	27160069	NRAS mutations are common in melanoma and are associated with clinical features of poor biological behavior.	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('mutations', 'Var', (5, 14))	('common', 'Reg', (19, 25))	('NRAS', 'Gene', (0, 4))
235621	27160069	It is likely that the complexity of NRAS signaling events and the genetic heterogeneity, such as low-activating BRAF mutations, loss of p16(INK4a) and MITF amplification, will require a diverse set of therapeutics for optimized patient care.	('mutations', 'Var', (117, 126))	('low-activating', 'NegReg', (97, 111))	('INK4a', 'Gene', (140, 145))	('amplification', 'Var', (156, 169))	('loss', 'NegReg', (128, 132))	('INK4a', 'Gene', '1029', (140, 145))	('p16', 'Gene', (136, 139))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('MITF', 'Gene', '4286', (151, 155))	('MITF', 'Gene', (151, 155))	('p16', 'Gene', '1029', (136, 139))	('patient', 'Species', '9606', (228, 235))
235623	27160069	To further complete our picture of RAS-driven melanoma growth, it will be necessary to also take into account other forms of RAS pathway activation, such as loss of function mutations in NF1, or copy number alterations of RAS itself.	('melanoma growth', 'Disease', 'MESH:D008545', (46, 61))	('loss of function', 'NegReg', (157, 173))	('NF1', 'Gene', '4763', (187, 190))	('NF1', 'Gene', (187, 190))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('rat', 'Species', '10116', (211, 214))	('mutations', 'Var', (174, 183))	('melanoma growth', 'Disease', (46, 61))	('copy number alterations', 'Var', (195, 218))
235624	27160069	To date most RAS research has been performed in models of mutant KRAS.	('KRAS', 'Gene', '3845', (65, 69))	('mutant', 'Var', (58, 64))	('KRAS', 'Gene', (65, 69))
235626	27160069	Recent developments in targeting oncogenic RAS function allow for an optimistic yet cautious outlook that effective targeted treatment of NRAS mutant melanoma can be achieved.	('mutant', 'Var', (143, 149))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('NRAS', 'Gene', (138, 142))
235663	25506014	The fact that the tumor must arise in the region of a prior irradiation, having a latency period of at least two years, and proof that the sarcoma is histologically different from the radiated primary lesion are the criteria of postradiation sarcoma modified by Laskin et al.. A high rate of TP53 gene mutation was observed in radiation-induced sarcomas compared to sporadic ones with studies examining mutations in specific genes using polymerase chain reaction followed by direct sequencing (88% versus 20% and 58% versus 16.8% for two different series).	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('sarcoma', 'Disease', 'MESH:D012509', (345, 352))	('sarcoma', 'Disease', 'MESH:D012509', (242, 249))	('tumor', 'Disease', (18, 23))	('TP53', 'Gene', '7157', (292, 296))	('TP53', 'Gene', (292, 296))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('sarcomas', 'Disease', 'MESH:D012509', (345, 353))	('sarcoma', 'Disease', (242, 249))	('sarcoma', 'Disease', (345, 352))	('sarcomas', 'Phenotype', 'HP:0100242', (345, 353))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (345, 352))	('sarcoma', 'Disease', (139, 146))	('sarcomas', 'Disease', (345, 353))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mutation', 'Var', (302, 310))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
235675	25506014	The possibility of our patient having Li-Fraumeni syndrome, who developed a PIS, directed us to chemotherapy while in both situations there is a possibility of TP53 gene mutation increasing the risk of a new PIS formation.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (38, 58))	('Li-Fraumeni syndrome', 'Disease', (38, 58))	('PIS', 'Chemical', '-', (76, 79))	('gene mutation', 'Var', (165, 178))	('PIS', 'Chemical', '-', (208, 211))	('increasing', 'PosReg', (179, 189))	('patient', 'Species', '9606', (23, 30))	('TP53', 'Gene', '7157', (160, 164))	('TP53', 'Gene', (160, 164))	('mutation', 'Var', (170, 178))
235710	23638178	Several studies examining miR alterations in Ewing Sarcoma have identified upregulation of miRs belonging to three paralogous clusters - miR-17~92a, miR-106b~25, and miR-106a~363.	('miR', 'Gene', (91, 94))	('miR-106b', 'Gene', '406900', (149, 157))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', '220972', (137, 140))	('miR-17~92', 'Gene', (137, 146))	('miR-106b', 'Gene', (149, 157))	('miR', 'Gene', (26, 29))	('miR-17~92', 'Gene', '407975', (137, 146))	('miR', 'Gene', (137, 140))	('miR', 'Gene', '220972', (149, 152))	('miR', 'Gene', '220972', (166, 169))	('Ewing Sarcoma', 'Disease', (45, 58))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('Sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (45, 58))	('upregulation', 'PosReg', (75, 87))	('alterations', 'Var', (30, 41))	('miR', 'Gene', (149, 152))	('miR', 'Gene', (166, 169))	('miR', 'Gene', '220972', (91, 94))
235713	23638178	Thus, manipulation of these clusters, or their component miRs, may have therapeutic benefit in Ewing Sarcoma.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (95, 108))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('Ewing Sarcoma', 'Disease', (95, 108))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('Sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('manipulation', 'Var', (6, 18))
235759	23638178	The s-alpha-miR-106a~363 sponge also yielded the most potent inhibition of colony formation in a soft agar assay of anchorage-independent growth (Figure 4c).	('inhibition', 'NegReg', (61, 71))	('agar', 'Chemical', 'MESH:D000362', (102, 106))	('s-alpha-miR-106a~363', 'Var', (4, 24))	('colony formation in a soft agar assay', 'CPA', (75, 112))
235763	23638178	We next tested the inhibitory activity of the s-alpha-miR-106a~363 sponge in additional EWS cell lines.	('tested', 'Reg', (8, 14))	('s-alpha-miR-106a~363', 'Var', (46, 66))	('EWS', 'Gene', '2130', (88, 91))	('EWS', 'Gene', (88, 91))
235764	23638178	Similar to Sk-ES-1 cells, stable expression of s-alpha-miR-106a~363 inhibited both clonogenic and anchorage-independent growth of RD-ES cells (Figure 5a-c).	('Sk-ES-1', 'Chemical', '-', (11, 18))	('s-alpha-miR-106a~363', 'Var', (47, 67))	('anchorage-independent growth', 'CPA', (98, 126))	('inhibited', 'NegReg', (68, 77))
235765	23638178	Introduction of the s-alpha-miR-106a~363 sponge into A673 or TC71 cells, on the other hand, did not affect clonogenic growth.	('TC71', 'CellLine', 'CVCL:2213', (61, 65))	('s-alpha-miR-106a~363', 'Var', (20, 40))	('clonogenic growth', 'CPA', (107, 124))
235766	23638178	Interestingly, both cell lines vulnerable to the sponge effect appeared to restrict sponge expression (Sk-ES-1 and RD-ES), further suggesting that introduction of s-alpha-miR-106a~363 is deleterious in these cells (Figure 5d).	('restrict', 'NegReg', (75, 83))	('s-alpha-miR-106a~363', 'Var', (163, 183))	('Sk-ES-1', 'Chemical', '-', (103, 110))	('sponge expression', 'MPA', (84, 101))
235770	23638178	To probe for relevant mechanisms of action of the s-alpha-miR-106a~363 sponge in Ewing Sarcoma, we examined the expression of a number of targets, and/or related pathway activity, of miR-106a~363, as well as the closely related miR-17~92a, cluster, which have been identified in other cancers as regulators of growth and apoptosis.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('cancers', 'Disease', (285, 292))	('miR-17~92', 'Gene', (228, 237))	('miR-106a~363', 'Var', (183, 195))	('miR-17~92', 'Gene', '407975', (228, 237))	('Sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing Sarcoma', 'Disease', (81, 94))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('cancers', 'Disease', 'MESH:D009369', (285, 292))
235772	23638178	We thus employed an unbiased approach to identify targets and/or pathways affected by s-alpha-miR-106a~363 sponge expression in Ewing Sarcoma.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('s-alpha-miR-106a~363', 'Var', (86, 106))	('Sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('Ewing Sarcoma', 'Disease', (128, 141))
235773	23638178	Expression profiling using Affymetrix whole transcript arrays was performed on Sk-ES-1 cells expressing either s-Neg or s-alpha-miR-106a~363.	('Sk-ES-1', 'Chemical', '-', (79, 86))	('s-Neg', 'Var', (111, 116))	('s-alpha-miR-106a~363', 'Var', (120, 140))
235775	23638178	Subsequent qRT-PCR analysis showed miR-15a to be increased upon s-alpha-miR-106a~363 expression in responsive cell lines (SK-ES-1 and RD-ES), but not in the unresponsive cell lines (TC71 and A673) (Figure 6).	('expression', 'MPA', (85, 95))	('TC71', 'CellLine', 'CVCL:2213', (182, 186))	('miR-15a', 'Gene', (35, 42))	('increased', 'PosReg', (49, 58))	('SK-ES-1', 'CellLine', 'CVCL:0627', (122, 129))	('s-alpha-miR-106a~363', 'Var', (64, 84))
235776	23638178	We thus pursued miR-15a upregulation as a possible mechanism contributing to the s-alpha-miR-106a~363 growth-inhibition phenotype in Ewing Sarcoma cells.	('Ewing Sarcoma', 'Disease', (133, 146))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (133, 146))	('Sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('s-alpha-miR-106a~363', 'Var', (81, 101))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (133, 146))
235777	23638178	In both Sk-ES-1 and RD-ES cells, treatment with LNA-anti-miR-15a resulted in at least partial rescue of growth inhibition by s-alpha-miR-106a~363 (Figure 7).	('growth', 'MPA', (104, 110))	('Sk-ES-1', 'Chemical', '-', (8, 15))	('s-alpha-miR-106a~363', 'Var', (125, 145))
235780	23638178	To further explore the role of miR-15a in Ewing Sarcoma, we asked how miR-15a manipulation affects clonogenic growth in the absence of miR-106a~363 inhibition.	('affects', 'Reg', (91, 98))	('miR-15a', 'Gene', (70, 77))	('clonogenic growth', 'CPA', (99, 116))	('Sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('manipulation', 'Var', (78, 90))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (42, 55))	('Ewing Sarcoma', 'Disease', (42, 55))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (42, 55))
235781	23638178	Inhibition of miR-15a in Sk-ES-1 and RD-ES cells, using the same LNAs as above, resulted in increased clonogenic growth compared to a non-targeting negative control LNA (Figure 8b).	('clonogenic growth', 'CPA', (102, 119))	('miR-15a', 'Gene', (14, 21))	('increased', 'PosReg', (92, 101))	('Inhibition', 'Var', (0, 10))	('Sk-ES-1', 'Chemical', '-', (25, 32))
235782	23638178	As in the rescue experiments above, LNA-anti-miR-15a treatment resulted in a greater increase in colony formation in RD-ES cells compared to Sk-ES-1 cells.	('colony formation', 'CPA', (97, 113))	('increase', 'PosReg', (85, 93))	('LNA-anti-miR-15a', 'Var', (36, 52))	('Sk-ES-1', 'Chemical', '-', (141, 148))
235803	23638178	One possibility is that miR-106a~363 is indeed more important than miR-17~92a in Ewing Sarcoma pathogenesis.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('miR-106a~363', 'Var', (24, 36))	('miR-17~92', 'Gene', '407975', (67, 76))	('Sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing Sarcoma', 'Disease', (81, 94))	('miR-17~92', 'Gene', (67, 76))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (81, 94))
235809	23638178	Furthermore, three members of the miR-17 family (miR-17, miR-106b and miR-106a) each directly inhibit p21 in Diffuse Large B-cell Lymphoma and in Burkitt's Lymphoma to increase cellular proliferation.	('increase', 'PosReg', (168, 176))	('miR-106b', 'Gene', (57, 65))	("Burkitt's Lymphoma", 'Disease', (146, 164))	('cellular proliferation', 'CPA', (177, 199))	('p21', 'Gene', '644914', (102, 105))	("Burkitt's Lymphoma", 'Phenotype', 'HP:0030080', (146, 164))	('Lymphoma', 'Phenotype', 'HP:0002665', (156, 164))	('miR-106b', 'Gene', '406900', (57, 65))	('B-cell Lymphoma', 'Disease', 'MESH:D016393', (123, 138))	('miR-106a', 'Var', (70, 78))	("Burkitt's Lymphoma", 'Disease', 'MESH:D002051', (146, 164))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (123, 138))	('p21', 'Gene', (102, 105))	('inhibit', 'NegReg', (94, 101))	('Lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('B-cell Lymphoma', 'Disease', (123, 138))
235811	23638178	Together, these studies support an important and distinct role for miR-106a in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('miR-106a', 'Var', (67, 75))
235813	23638178	This suggests that inhibition of the entire miR-106a~363 cluster may be required for the growth-inhibitory effects of the s-alpha-miR-106a~363 sponge in Ewing Sarcoma.	('s-alpha-miR-106a~363', 'Var', (122, 142))	('Ewing Sarcoma', 'Disease', (153, 166))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('Sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (153, 166))
235814	23638178	The growth inhibitory effects of s-alpha-miR-106a~363 demonstrate cell specificity, affecting growth of Sk-ES-1 and RD-ES, but not A673 and TC71 cells.	('s-alpha-miR-106a~363', 'Var', (33, 53))	('growth inhibitory effects', 'MPA', (4, 29))	('Sk-ES-1', 'Chemical', '-', (104, 111))	('TC71', 'CellLine', 'CVCL:2213', (140, 144))	('growth', 'MPA', (94, 100))	('affecting', 'Reg', (84, 93))
235825	23638178	In mouse genetic models, miR-15a deletion significantly accelerates the development of Chronic Lymphocytic Leukemia, in part through de-repression of multiple miR-15a-targeted cyclins (Cyclin D1 and D3, Cyclin E), CDK6 and the anti-apoptotic factor Bcl-2.	('miR-15a', 'Gene', (25, 32))	('Cyclin D1 and D3', 'Gene', '12443', (185, 201))	('Chronic Lymphocytic Leukemia', 'Phenotype', 'HP:0005550', (87, 115))	('mouse', 'Species', '10090', (3, 8))	('deletion', 'Var', (33, 41))	('Leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('miR-15a-targeted', 'Gene', (159, 175))	('Chronic Lymphocytic Leukemia', 'Disease', (87, 115))	('Chronic Lymphocytic Leukemia', 'Disease', 'MESH:D015451', (87, 115))	('Cyclin E', 'Protein', (203, 211))	('CDK6', 'Protein', (214, 218))	('accelerates', 'PosReg', (56, 67))	('de-repression', 'NegReg', (133, 146))
235826	23638178	In prostate cancer, inhibition of miR-15a leads to increased anchorage-independent growth and migration in vitro, as well as transforming a non-tumorigenic prostate cell line in vivo.	('miR-15a', 'Gene', (34, 41))	('tumor', 'Disease', (144, 149))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('inhibition', 'Var', (20, 30))	('increased', 'PosReg', (51, 60))	('anchorage-independent growth', 'CPA', (61, 89))	('migration', 'CPA', (94, 103))	('prostate cancer', 'Disease', (3, 18))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('transforming', 'Reg', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
235830	23638178	Finally, in Ewing Sarcoma, treatment with MLN4924, a compound that inhibits neddylation, and subsequent degradation, of cullins in cullin-RING ubiquitin ligase complexes leading degradation of a variety of proteins, leads to a G2 cell cycle arrest and apoptosis.	('degradation', 'MPA', (104, 115))	('inhibits', 'NegReg', (67, 75))	('leads to', 'Reg', (216, 224))	('Ewing Sarcoma', 'Disease', (12, 25))	('apoptosis', 'CPA', (252, 261))	('MLN4924', 'Var', (42, 49))	('neddylation', 'Protein', (76, 87))	('arrest', 'Disease', (241, 247))	('Sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (12, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (230, 247))	('degradation', 'MPA', (178, 189))	('arrest', 'Disease', 'MESH:D006323', (241, 247))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (12, 25))
235834	23638178	Somewhat unexpectedly, many genes in this pathway were overall upregulated by s-alpha-miR-106a~363 expression, including two known miR-15a targets, Cyclin E1 and E2, and E2F1.	('E2F1', 'Gene', '1869', (170, 174))	('E2F1', 'Gene', (170, 174))	('upregulated', 'PosReg', (63, 74))	('Cyclin E1', 'Gene', '898', (148, 157))	('s-alpha-miR-106a~363', 'Var', (78, 98))	('Cyclin E1', 'Gene', (148, 157))
235835	23638178	This is not entirely surprising, however, in light of data from osteosarcoma, where E2F1, Cyclin E, and miR-15a form a complex regulatory loop, whereby E2Fs induce both Cyclin E and miR-15a expression, and miR-15a limits proliferation by inhibiting Cyclin E expression during G1/S.	('osteosarcoma', 'Disease', 'MESH:D012516', (64, 76))	('Cyclin E expression', 'MPA', (249, 268))	('E2F1', 'Gene', '1869', (84, 88))	('induce', 'PosReg', (157, 163))	('limits', 'NegReg', (214, 220))	('E2F1', 'Gene', (84, 88))	('proliferation', 'CPA', (221, 234))	('E2Fs', 'Var', (152, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('miR-15a', 'Var', (206, 213))	('inhibiting', 'NegReg', (238, 248))	('expression', 'MPA', (190, 200))	('Cyclin E', 'MPA', (169, 177))	('osteosarcoma', 'Disease', (64, 76))	('miR-15a', 'Gene', (182, 189))	('osteosarcoma', 'Phenotype', 'HP:0002669', (64, 76))
235841	23638178	In summary, we demonstrate that members of the miR-17~92a, miR-106b~25, and miR-106a~363 clusters are upregulated in EWS.	('EWS', 'Gene', '2130', (117, 120))	('EWS', 'Gene', (117, 120))	('miR-17~92', 'Gene', '407975', (47, 56))	('miR-106b', 'Gene', (59, 67))	('miR-17~92', 'Gene', (47, 56))	('upregulated', 'PosReg', (102, 113))	('miR-106a~363', 'Var', (76, 88))	('miR-106b', 'Gene', '406900', (59, 67))
235844	23638178	Thus, blockade of the miR-106a~363 cluster and/or replacement of miR-15a represent possible new strategies for inhibition of Ewing Sarcoma growth.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('miR-15a', 'Gene', (65, 72))	('Sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Ewing Sarcoma growth', 'Disease', (125, 145))	('Ewing Sarcoma growth', 'Disease', 'MESH:C563168', (125, 145))	('replacement', 'Var', (50, 61))	('miR-106a~363', 'Gene', (22, 34))	('inhibition', 'NegReg', (111, 121))
235857	23638178	For transient miR blockade experiments, cells were transfected with a negative control or specific miR hairpin inhibitors (20 nM; Dharmacon), or, alternatively, negative control or specific miR LNAs (100 nM; Exiqon), using Lipofectamine 2000 reagent in both cases.	('20 nM;', 'Var', (123, 129))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (223, 241))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (190, 193))
235858	23638178	For rescue experiments, cells expressing s-Neg or s-alpha-miR-106a~363 were transfected with 50 nM miR-15a-targeting or negative control LNA (Exiqon) using Lipofectamine 2000 reagent.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (156, 174))	('miR-15a-targeting', 'Gene', (99, 116))	('s-alpha-miR-106a~363', 'Var', (50, 70))
235865	23638178	EWS cells were infected with similar titers of virus and selected with Puromycin (2 microg/ml for A673, and 0.5 microg/ml for Sk-ES-1, TC71, and RD-ES).	('Puromycin', 'Chemical', 'MESH:D011691', (71, 80))	('TC71', 'CellLine', 'CVCL:2213', (135, 139))	('Sk-ES-1', 'Chemical', '-', (126, 133))	('A673', 'Var', (98, 102))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
235866	23638178	Biological triplicates of Sk-ES-1, RD-ES, and TC71 cells stably transduced with either s-CXCR4 or s-alpha-miR-106a~363 were harvested at ~70-80% confluence.	('Sk-ES-1', 'Chemical', '-', (26, 33))	('TC71', 'CellLine', 'CVCL:2213', (46, 50))	('CXCR4', 'Gene', '7852', (89, 94))	('CXCR4', 'Gene', (89, 94))	('s-alpha-miR-106a~363', 'Var', (98, 118))
235894	21871117	Protein functions are altered via backbone fragmentation, side chain group oxidation, cross-linking and unfolding among others that give rise to markers of protein oxidation in human studies.	('backbone', 'MPA', (34, 42))	('Protein', 'Protein', (0, 7))	('unfolding', 'CPA', (104, 113))	('altered', 'Reg', (22, 29))	('cross-linking', 'Var', (86, 99))	('human', 'Species', '9606', (177, 182))	('side chain group oxidation', 'Var', (58, 84))
235982	21871117	When subjected to moderate levels of oxidative stress, oxidation of cysteine residues has been found to cause mixed disulphide formations between protein thiol groups and low-molecular mass thiols (S-thiolation), mainly with GSH (S-glutathionylation).	('mixed disulphide formations', 'MPA', (110, 137))	('thiol', 'Chemical', 'MESH:D013438', (190, 195))	('oxidative stress', 'Phenotype', 'HP:0025464', (37, 53))	('thiols', 'Chemical', 'MESH:D013438', (190, 196))	('thiol', 'Chemical', 'MESH:D013438', (154, 159))	('GSH', 'Chemical', '-', (225, 228))	('protein', 'Protein', (146, 153))	('disulphide', 'Chemical', '-', (116, 126))	('cause', 'Reg', (104, 109))	('oxidation', 'Var', (55, 64))	('cysteine', 'Chemical', 'MESH:D003545', (68, 76))	('thiol', 'Chemical', 'MESH:D013438', (200, 205))
236012	32084007	The key genes were found to be involved in the cell cycle, DNA replication, and various cancer pathways, and gene alterations were associated with a poor prognosis.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('alterations', 'Var', (114, 125))	('involved', 'Reg', (31, 39))	('associated', 'Reg', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cell cycle', 'CPA', (47, 57))
236043	32084007	Camptothecin, daunorubicin, 0175029-0000, resveratrol, and trichostatin A were the top molecules likely to act on the gene targets obtained in our comparison of tumor and normal tissues; these drugs might therefore be particularly useful for treating STS.	('STS', 'Disease', (251, 254))	('STS', 'Disease', 'MESH:D012509', (251, 254))	('0175029-0000', 'Var', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('resveratrol', 'Chemical', 'MESH:D000077185', (42, 53))	('STS', 'Phenotype', 'HP:0030448', (251, 254))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('daunorubicin', 'Chemical', 'MESH:D003630', (14, 26))	('Camptothecin', 'Chemical', 'MESH:D002166', (0, 12))	('trichostatin A', 'Chemical', 'MESH:C012589', (59, 73))	('tumor', 'Disease', (161, 166))
236057	32084007	Additionally, aberrant methylation of FBN2 has been observed in breast cancer, non-small cell lung cancer, and esophageal squamous cell carcinoma; FBN2 methylation might negatively impact STS prognosis as well.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('STS', 'Disease', 'MESH:D012509', (188, 191))	('FBN2', 'Gene', (38, 42))	('STS', 'Phenotype', 'HP:0030448', (188, 191))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (79, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('methylation', 'MPA', (23, 34))	('FBN2', 'Gene', (147, 151))	('negatively', 'NegReg', (170, 180))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal squamous cell carcinoma', 'Disease', (111, 145))	('non-small cell lung cancer', 'Disease', (79, 105))	('aberrant', 'Var', (14, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('observed', 'Reg', (52, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (111, 145))	('impact', 'Reg', (181, 187))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('methylation', 'Var', (152, 163))	('STS', 'Disease', (188, 191))	('breast cancer', 'Disease', (64, 77))
236071	32084007	Finally, a GSEA analysis revealed that the key genes promoted cell proliferation as well as cancer development and progression via different cell cycle, DNA replication, mismatch repair, and cancer-associated pathways (e.g., phosphatidylinositol signaling system, basal cell carcinoma, transforming growth factor beta signaling pathway, WNT signaling pathway, and the p53 signaling pathway).	('progression', 'CPA', (115, 126))	('basal cell carcinoma', 'Disease', (264, 284))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (225, 245))	('GSEA', 'Chemical', '-', (11, 15))	('cancer', 'Disease', (191, 197))	('WNT signaling pathway', 'Pathway', (337, 358))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('promoted', 'PosReg', (53, 61))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (264, 284))	('cancer', 'Disease', (92, 98))	('cell proliferation', 'CPA', (62, 80))	('cell cycle', 'CPA', (141, 151))	('DNA replication', 'CPA', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('transforming growth factor beta signaling pathway', 'Pathway', (286, 335))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('genes', 'Var', (47, 52))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (264, 284))	('phosphatidylinositol signaling system', 'Pathway', (225, 262))	('mismatch repair', 'CPA', (170, 185))
236073	32084007	Finally, these key genes might also affect development and progression of STS through interactions with gene fusion products and miRNAs, which not only play important regulatory roles but can also act as therapeutic targets in sarcoma.	('STS', 'Disease', 'MESH:D012509', (74, 77))	('sarcoma', 'Disease', (227, 234))	('development', 'CPA', (43, 54))	('genes', 'Var', (19, 24))	('STS', 'Phenotype', 'HP:0030448', (74, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('gene fusion products', 'Protein', (104, 124))	('progression', 'CPA', (59, 70))	('interactions', 'Interaction', (86, 98))	('affect', 'Reg', (36, 42))	('STS', 'Disease', (74, 77))	('sarcoma', 'Disease', 'MESH:D012509', (227, 234))
236096	32084007	This database was used to investigate associations between alterations in the key genes and survival in STS patients.	('alterations', 'Var', (59, 70))	('associations', 'Interaction', (38, 50))	('STS', 'Disease', (104, 107))	('STS', 'Disease', 'MESH:D012509', (104, 107))	('STS', 'Phenotype', 'HP:0030448', (104, 107))
236108	29280411	CMB305 also includes a boost from a NY-ESO-1 protein vaccine given along with a potent toll-like-4 receptor agonist, glycopyranosyl lipid A. CMB305 induces NY-ESO-1 specific T cell responses in both SS and MRC patients and these patients had excellent overall survival (OS) outcomes in the initial phase I study.	('CMB305', 'Var', (141, 147))	('patients', 'Species', '9606', (229, 237))	('CMB305', 'Chemical', '-', (0, 6))	('CMB305', 'Chemical', '-', (141, 147))	('SS', 'Phenotype', 'HP:0012570', (199, 201))	('NY-ESO-1', 'Gene', '246100', (36, 44))	('NY-ESO-1', 'Gene', '246100', (156, 164))	('induces', 'PosReg', (148, 155))	('NY-ESO-1', 'Gene', (36, 44))	('NY-ESO-1', 'Gene', (156, 164))	('MRC', 'CellLine', 'CVCL:0440', (206, 209))	('patients', 'Species', '9606', (210, 218))	('overall', 'MPA', (252, 259))	('glycopyranosyl lipid A', 'Chemical', '-', (117, 139))
236120	29280411	MRCL has a similar incidence, comprising approximately 20-30% of liposarcomas and is associated with a characteristic translocation t(12;16)(q13;p11).	('liposarcoma', 'Phenotype', 'HP:0012034', (65, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('t(12;16)(q13;p11', 'Var', (132, 148))	('MRCL', 'Gene', (0, 4))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (132, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('liposarcomas', 'Disease', 'MESH:D008080', (65, 77))	('MRC', 'CellLine', 'CVCL:0440', (0, 3))	('liposarcomas', 'Phenotype', 'HP:0012034', (65, 77))	('MRCL', 'Phenotype', 'HP:0012268', (0, 4))	('associated', 'Reg', (85, 95))	('liposarcomas', 'Disease', (65, 77))
236134	29280411	While third-generation lentivirus vectors with broad tropism (as their envelope derives from vesicular stomatits virus [VSV]) have typically been used in preclinical or clinical studies, they carry risks related to off-target activity and integrational mutagenesis.	('vesicular stomatits', 'Disease', (93, 112))	('mutagenesis', 'Var', (253, 264))	('vesicular stomatits', 'Disease', 'MESH:D012872', (93, 112))
236138	29280411	Through selective mutation of the heparin binding region, a Sindbis envelope was genetically engineered that selectively binds to DC-SIGN.	('DC-SIGN', 'Gene', '30835', (130, 137))	('DC-SIGN', 'Gene', (130, 137))	('heparin', 'Protein', (34, 41))	('binds', 'Interaction', (121, 126))	('Sindbis', 'Species', '11034', (60, 67))	('mutation', 'Var', (18, 26))	('heparin', 'Chemical', 'MESH:D006493', (34, 41))
236140	29280411	Like other third-generation LVs generally regarded as safe for use in gene therapy, ZVex is devoid of all HIV 1-derived accessory proteins, except for Rev, and is encoded by a split genome with a deletion in the U3 region (DeltaU3, for self-inactivation of the 3'LTR).	('HIV 1', 'Species', '11676', (106, 111))	('Rev', 'Gene', '155908', (151, 154))	('Rev', 'Gene', (151, 154))	('deletion', 'Var', (196, 204))
236142	29280411	Further important safety features of ZVex are a genetically modified capsid gene to reduce the risk of recombination, and a genetically inactivated integrase enzyme (D64V mutation), which significantly reduces the risk of integration (Figure 1(b)).	('reduce', 'NegReg', (84, 90))	('reduces', 'NegReg', (202, 209))	('D64V', 'Mutation', 'p.D64V', (166, 170))	('integration', 'MPA', (222, 233))	('D64V mutation', 'Var', (166, 179))
236158	29280411	Notably, high expression of CTAs has been linked to worse prognosis in some tumor types.	('linked', 'Reg', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CTAs', 'Protein', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('high', 'Var', (9, 13))
236174	29280411	A pilot study using peptides spanning the SYT-SSX fusion in SS patients resulted in one transient tumor response and more than a third of patients developed a T-cell response based on staining using MHC-peptide tetramers.	('SS', 'Phenotype', 'HP:0012570', (46, 48))	('SSX', 'Gene', (46, 49))	('SYT', 'Gene', '6760', (42, 45))	('SSX', 'Gene', '727837', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('SS', 'Phenotype', 'HP:0012570', (60, 62))	('T-cell response', 'CPA', (159, 174))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('peptides', 'Var', (20, 28))	('patients', 'Species', '9606', (63, 71))	('tumor', 'Disease', (98, 103))	('patients', 'Species', '9606', (138, 146))	('SYT', 'Gene', (42, 45))
236200	29280411	The patient who had a dramatic response to LV305 had a large peripheral increase in T-cell clones that were detectable in a pretreatment biopsy and the percentage of NYESO-1-specific cells expressing PD-1 also increased following vaccination.	('LV305', 'Var', (43, 48))	('NYESO-1', 'Gene', (166, 173))	('increase', 'PosReg', (72, 80))	('NYESO-1', 'Gene', '246100', (166, 173))	('increased', 'PosReg', (210, 219))	('patient', 'Species', '9606', (4, 11))	('T-cell clones', 'CPA', (84, 97))	('increase in T-cell', 'Phenotype', 'HP:0100828', (72, 90))	('PD-1', 'Gene', (200, 204))
236209	29280411	An analysis of biomarkers for LV305 and CMB305 and their association with clinical outcomes was presented at the 2017 ASCO Annual Meeting.	('CMB305', 'Gene', (40, 46))	('CMB305', 'Chemical', '-', (40, 46))	('LV305', 'Var', (30, 35))
236212	29280411	LV305 and CMB305 induced anti-NY-ESO-1 T-cells in 52% and 68% pts, respectively.	('LV305', 'Var', (0, 5))	('CMB305', 'Chemical', '-', (10, 16))	('NY-ESO-1', 'Gene', '246100', (30, 38))	('NY-ESO-1', 'Gene', (30, 38))	('CMB305', 'Gene', (10, 16))
236214	29280411	As expected, because of the marked activity of GLA-SE on TH1 cells, NY-ESO-1-specific CD4+ T-cell responses increased more in the patients treated with CMB305.	('GLA', 'Gene', (47, 50))	('CD4', 'Gene', (86, 89))	('GLA', 'Gene', '2717', (47, 50))	('increased', 'PosReg', (108, 117))	('CMB305', 'Var', (152, 158))	('CD4', 'Gene', '920', (86, 89))	('patients', 'Species', '9606', (130, 138))	('CMB305', 'Chemical', '-', (152, 158))	('NY-ESO-1', 'Gene', '246100', (68, 76))	('NY-ESO-1', 'Gene', (68, 76))
236215	29280411	Based on both antibody and ELIspot analysis, LV305 and CMB305 induced immune responses against other tumorassociated antigens (so-called 'antigen spreading') in 17% and 36% patients, respectively.	('CMB305', 'Gene', (55, 61))	('patients', 'Species', '9606', (173, 181))	('CMB305', 'Chemical', '-', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('induced', 'Reg', (62, 69))	('LV305', 'Var', (45, 50))	('immune responses', 'MPA', (70, 86))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
236228	29280411	In this context, it is important to note that LV305/CMB305 show signals of clinical activity in multiple independent single-arm Phase 1 trials in these tumor types as well as the randomized C232 study with survival rates comparing favorably to the standard of care chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('CMB305', 'Chemical', '-', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('LV305/CMB305', 'Var', (46, 58))
236232	29280411	Thus, the LV305 and the CMB305 regimens have clear potential to impact the treatment of SS and MRCL and possibly also other STS and other malignancies expressing NY-ESO-1.	('SS', 'Phenotype', 'HP:0012570', (88, 90))	('NY-ESO-1', 'Gene', '246100', (162, 170))	('LV305', 'Var', (10, 15))	('NY-ESO-1', 'Gene', (162, 170))	('STS', 'Disease', (124, 127))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('impact', 'Reg', (64, 70))	('MRC', 'CellLine', 'CVCL:0440', (95, 98))	('MRCL', 'Disease', (95, 99))	('treatment', 'MPA', (75, 84))	('CMB305', 'Gene', (24, 30))	('malignancies', 'Disease', (138, 150))	('MRCL', 'Phenotype', 'HP:0012268', (95, 99))	('CMB305', 'Chemical', '-', (24, 30))	('STS', 'Phenotype', 'HP:0030448', (124, 127))
236233	29280411	During that time, we speculate that a Phase III trial of CMB305 will be completed and that CMB305 ultimately will become integrated into an effective regimen for SS and MRCL, perhaps in combination with a checkpoint inhibitor.	('MRC', 'CellLine', 'CVCL:0440', (169, 172))	('CMB305', 'Gene', (57, 63))	('CMB305', 'Var', (91, 97))	('MRCL', 'Phenotype', 'HP:0012268', (169, 173))	('CMB305', 'Chemical', '-', (57, 63))	('CMB305', 'Chemical', '-', (91, 97))	('SS', 'Phenotype', 'HP:0012570', (162, 164))
236237	29280411	CMB305 is a 'prime-boost' regimen that includes LV305 for priming with a boost of NY-ESO-1 protein and a potent TLR4 agonist adjuvant (G100).	('TLR4', 'Gene', (112, 116))	('CMB305', 'Chemical', '-', (0, 6))	('boost', 'PosReg', (73, 78))	('LV305', 'Var', (48, 53))	('TLR4', 'Gene', '7099', (112, 116))	('NY-ESO-1', 'Gene', '246100', (82, 90))	('NY-ESO-1', 'Gene', (82, 90))
236242	29945296	In addition, murine Ewing sarcoma is highly dependent on EWS-FLI1 expression, indicating that EWS-FLI1 drives the expression of genes important for cell survival and proliferation.	('Ewing sarcoma', 'Disease', (20, 33))	('drives', 'PosReg', (103, 109))	('murine', 'Species', '10090', (13, 19))	('EWS-FLI1', 'Var', (94, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('expression', 'MPA', (114, 124))
236259	29945296	Ewing sarcoma: GSE12102, alveolar soft part sarcoma: GSE32569, osteosarcoma: GSE87437, rhabdomyosarcoma: GSE66533, and synovial sarcoma: GSE20196 were assessed using GeneSpring GX 12.6.	('alveolar soft part sarcoma', 'Disease', (25, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('osteosarcoma', 'Phenotype', 'HP:0002669', (63, 75))	('synovial sarcoma', 'Disease', (119, 135))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (34, 51))	('rhabdomyosarcoma', 'Disease', (87, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', (0, 13))	('GSE66533', 'Var', (105, 113))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (25, 51))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (119, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('osteosarcoma', 'Disease', (63, 75))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (25, 51))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('GSE87437', 'Var', (77, 85))
236266	29945296	Trib1 was identified as a leukemia disease gene that enhances MAPK phosphorylation and degrades C/EBPalpha.22, 23, 24 Nrg1 promotes tumor progression in many cancers such as gastric, lung, and breast cancers.25, 26, 27 Notably, these genes have been previously identified as EWS-FLI1-binding genes in human Ewing sarcoma.4 EWS-FLI1-binding peaks and an H3K27Ac active enhancer mark could be observed 30 kbp upstream from the TSS of Trib1 and 164 kbp downstream from that of Nrg1 (Figure 3A).	('leukemia', 'Phenotype', 'HP:0001909', (26, 34))	('MAPK', 'Gene', '5594', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('C/EBP', 'Gene', (96, 101))	('C/EBP', 'Gene', '1050', (96, 101))	('C/EBPalpha', 'Gene', '1050', (96, 106))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancers', 'Disease', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('H3K27Ac', 'Var', (353, 360))	('cancers', 'Disease', (158, 165))	('leukemia disease', 'Disease', 'MESH:D007938', (26, 42))	('breast cancers', 'Disease', 'MESH:D001943', (193, 207))	('breast cancers', 'Disease', (193, 207))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (307, 320))	('Trib1', 'Gene', (432, 437))	('gastric', 'Disease', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('leukemia disease', 'Disease', (26, 42))	('enhancer', 'PosReg', (368, 376))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('C/EBPalpha', 'Gene', (96, 106))	('gastric', 'Disease', 'MESH:D013274', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (313, 320))	('MAPK', 'Gene', (62, 66))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))
236268	29945296	Furthermore, EdU incorporation was reduced by Trib1 knockdown, whereas no increase of Annexin V-positive pre-apoptotic cells was found (Figure 5C,D).	('Trib1', 'Gene', (46, 51))	('reduced', 'NegReg', (35, 42))	('EdU incorporation', 'CPA', (13, 30))	('Annexin V', 'Gene', '308', (86, 95))	('Annexin V', 'Gene', (86, 95))	('knockdown', 'Var', (52, 61))
236270	29945296	Although C/EBPalpha is not expressed in Ewing sarcoma cells (data not shown), the LAP isoform of C/EBPbeta were increased by Trib1 silencing (Figure 5E).	('Trib1', 'Gene', (125, 130))	('LAP', 'Gene', '7939', (82, 85))	('silencing', 'Var', (131, 140))	('LAP', 'Gene', (82, 85))	('C/EBPbeta', 'Gene', (97, 106))	('C/EBPbeta', 'Gene', '1051', (97, 106))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('increased', 'PosReg', (112, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
236273	29945296	TRIB1 acts as an oncogene with strong transforming activity in acute myelogenous leukemia,22, 23, 37 and Tribbles family genes are also involved in human solid cancers.38 It is therefore notable that Trib1 knockdown suppressed Ewing sarcoma cell growth concomitant with increased levels of C/EBPbeta.	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('myelogenous leukemia', 'Disease', (69, 89))	('Trib1', 'Gene', (200, 205))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (69, 89))	('solid cancers', 'Disease', (154, 167))	('increased', 'PosReg', (270, 279))	('suppressed', 'NegReg', (216, 226))	('solid cancers', 'Disease', 'MESH:D009369', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('Ewing', 'CPA', (227, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('knockdown', 'Var', (206, 215))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (227, 240))
236308	28242986	MPAL with the t (9;22) (q34;q11)/BCR-ABL1 and MPAL with t (v;11q23)/ MLL rearrangement have been recognized as two distinct categories, while the remaining cases are grouped under MPAL, NOS (not otherwise specified).	('BCR-ABL1', 'Gene', (33, 41))	('MLL', 'Gene', '4297', (69, 72))	('MLL', 'Gene', (69, 72))	('BCR-ABL1', 'Gene', '613;25', (33, 41))	('t (v;11q23', 'Var', (56, 66))
236365	27755806	A characteristic balanced translocation between chromosomes X and 18, t (X; 18) (p11.2; q11.2) is shown in most cases of SS, and, as in our case, is confirmed by SYT-SSX gene detection.	('SYT', 'Gene', '6857', (162, 165))	('t (X; 18) (p11.2; q11.2', 'Var', (70, 93))	('SYT', 'Gene', (162, 165))	('balanced translocation', 'Var', (17, 39))	('SSX', 'Gene', '727837', (166, 169))	('SS', 'Phenotype', 'HP:0012570', (121, 123))	('SS', 'Phenotype', 'HP:0012570', (166, 168))	('SSX', 'Gene', (166, 169))
236536	27931750	Key findings of this study include more early-stage disease and less distant metastatic disease in tamoxifen-related uterine carcinosarcomas when compared to tamoxifen-unrelated uterine carcinosarcomas.	('uterine carcinosarcoma', 'Disease', (178, 200))	('carcinosarcomas', 'Disease', (186, 201))	('uterine carcinosarcoma', 'Disease', 'MESH:D002296', (178, 200))	('distant metastatic disease', 'CPA', (69, 95))	('carcinosarcomas', 'Disease', 'MESH:D002296', (125, 140))	('more', 'PosReg', (35, 39))	('age', 'Gene', '5973', (48, 51))	('tamoxifen', 'Chemical', 'MESH:D013629', (158, 167))	('less', 'NegReg', (64, 68))	('tamoxifen-related', 'Var', (99, 116))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (117, 139))	('carcinosarcomas', 'Disease', (125, 140))	('uterine carcinosarcoma', 'Disease', (117, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('uterine carcinosarcoma', 'Disease', 'MESH:D002296', (117, 139))	('carcinosarcomas', 'Disease', 'MESH:D002296', (186, 201))	('tamoxifen', 'Chemical', 'MESH:D013629', (99, 108))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (178, 200))	('age', 'Gene', (48, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))
236558	27931750	Because gynecologic malignancy with the PIK3CA/AKT/mTOR pathway alteration is known to be associated with better prognosis, this may be a possible biological plausibility to support a high proportion of early-stage disease in tamoxifen-related uterine carcinosarcoma.	('mTOR', 'Gene', (51, 55))	('AKT', 'Gene', (47, 50))	('malignancy', 'Disease', (20, 30))	('uterine carcinosarcoma', 'Disease', (244, 266))	('PIK3CA', 'Gene', (40, 46))	('tamoxifen', 'Chemical', 'MESH:D013629', (226, 235))	('age', 'Gene', '5973', (211, 214))	('PIK3CA', 'Gene', '5290', (40, 46))	('better', 'PosReg', (106, 112))	('AKT', 'Gene', '207', (47, 50))	('alteration', 'Var', (64, 74))	('uterine carcinosarcoma', 'Disease', 'MESH:D002296', (244, 266))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (244, 266))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('age', 'Gene', (211, 214))	('mTOR', 'Gene', '2475', (51, 55))	('malignancy', 'Disease', 'MESH:D009369', (20, 30))
236629	32293288	CIC-rearranged sarcoma was first reported in 2006 as Ewing-like sarcoma with CIC-double homeobox protein 4 gene (DUX4) rearrangement by Kawamura-Saito.	('CIC-rearranged sarcoma', 'Disease', (0, 22))	('rearrangement', 'Var', (119, 132))	('CIC', 'Gene', '23152', (77, 80))	('Ewing-like sarcoma', 'Disease', (53, 71))	('CIC', 'Gene', '23152', (0, 3))	('CIC', 'Gene', (77, 80))	('CIC-rearranged sarcoma', 'Disease', 'MESH:D012509', (0, 22))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (53, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('DUX4', 'Gene', (113, 117))	('DUX4', 'Gene', '100288687', (113, 117))	('CIC', 'Gene', (0, 3))
236630	32293288	The CIC gene present on chromosome 19 acts as a strong transcriptional activator by fusion with the DUX4 gene present on chromosome 4 or 10, causing a t (4; 19) or t (10; 19) translocation.	('causing', 'Reg', (141, 148))	('DUX4', 'Gene', (100, 104))	('DUX4', 'Gene', '100288687', (100, 104))	('CIC', 'Gene', '23152', (4, 7))	('fusion', 'Var', (84, 90))	('CIC', 'Gene', (4, 7))
236652	32293288	In this case, both WT1 and ETV4 were positive and the tumor had a rearrangement of the CIC gene in a molecular genetic search with fluorescence in situ hybridization (FISH).	('CIC', 'Gene', '23152', (87, 90))	('CIC', 'Gene', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('rearrangement', 'Var', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
236666	32023846	Poison-Exon Inclusion in DHX9 Reduces Its Expression and Sensitizes Ewing Sarcoma Cells to Chemotherapeutic Treatment Alternative splicing is a combinatorial mechanism by which exons are joined to produce multiple mRNA variants, thus expanding the coding potential and plasticity of eukaryotic genomes.	('Sensitizes', 'Reg', (57, 67))	('Expression', 'MPA', (42, 52))	('DHX9', 'Gene', (25, 29))	('DHX9', 'Gene', '1660', (25, 29))	('Poison-Exon Inclusion', 'Var', (0, 21))	('Reduces', 'NegReg', (30, 37))	('Ewing Sarcoma', 'Disease', (68, 81))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('Sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('Ewing Sarcoma', 'Disease', 'MESH:D012512', (68, 81))
236667	32023846	Defects in alternative splicing regulation are associated with several human diseases, including cancer.	('cancer', 'Disease', (97, 103))	('alternative splicing regulation', 'MPA', (11, 42))	('Defects', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('associated', 'Reg', (47, 57))	('human', 'Species', '9606', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
236672	32023846	Hence, our study suggests that inhibition of hnRNPM and SRSF3 expression or activity could be exploited as a therapeutic tool to enhance the efficacy of chemotherapy in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (169, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('activity', 'MPA', (76, 84))	('inhibition', 'Var', (31, 41))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (169, 182))	('enhance', 'PosReg', (129, 136))	('hnRNPM', 'Protein', (45, 51))	('SRSF3', 'Gene', (56, 61))	('Ewing sarcoma', 'Disease', (169, 182))
236687	32023846	Therefore, our study suggests that inhibition of hnRNPM or SRSF3 expression could be exploited as a therapeutic tool in Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (120, 133))	('Ewing sarcoma', 'Disease', (120, 133))	('SRSF3', 'Gene', (59, 64))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (120, 133))	('inhibition', 'Var', (35, 45))	('hnRNPM', 'Protein', (49, 55))
236703	32023846	Samples were briefly sonicated and incubated with 10 muL of 1/1000 RNase I (Ambion, AM2295, Thermo Fisher Scientific) dilution and 2 muL Turbo DNase (Ambion, AM2238, Thermo Fisher Scientific) for 3 min at 37  C shaking at 1100 rpm, and then centrifuged at 13,000 rpm for 10 min at 4  C. One point five milligrams of the extract was immunoprecipitated overnight using anti-hnRNPM, anti-SRSF1, anti-SRSF3, anti-hnRNPK, anti-FUS antibodies or purified rabbit or mouse IgGs (negative control) in the presence of protein A/G magnetic Dynabeads (Life Technologies-Thermo Fisher Scientific).	('anti-hnRNPK', 'Var', (404, 415))	('anti-hnRNPM', 'Var', (367, 378))	('anti-SRSF3', 'Var', (392, 402))	('rabbit', 'Species', '9986', (449, 455))	('anti-SRSF1', 'Var', (380, 390))	('mouse', 'Species', '10090', (459, 464))
236718	32023846	Analysis of event-free survival and overall survival in a dataset comprising 64 Ewing sarcoma, 4 Askin, and 20 perypheral primitive neuroectodermal tumors, which all belong to the family of Ewing tumors, showed that high DHX9 expression correlates with worse prognosis of the patients (Figure 1A,B).	('patients', 'Species', '9606', (276, 284))	('expression', 'MPA', (226, 236))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (122, 154))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('Ewing tumors', 'Disease', 'MESH:D012512', (190, 202))	('Ewing tumors', 'Disease', (190, 202))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (132, 154))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (80, 93))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (132, 154))	('neuroectodermal tumors', 'Disease', (132, 154))	('Ewing sarcoma', 'Disease', (80, 93))	('Ewing tumors', 'Phenotype', 'HP:0012254', (190, 202))	('high', 'Var', (216, 220))	('DHX9', 'Gene', (221, 225))
236723	32023846	Oligonucleotides to knockdown either SR proteins or hnRNPs were transfected in TC-71 Ewing sarcoma cells, and RNA was extracted 48 h later.	('Ewing sarcoma', 'Disease', (85, 98))	('hnRNP', 'Gene', (52, 57))	('Oligonucleotides', 'Chemical', 'MESH:D009841', (0, 16))	('SR', 'Chemical', '-', (37, 39))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (85, 98))	('hnRNP', 'Gene', '3183', (52, 57))	('SR proteins', 'Protein', (37, 48))	('TC-71', 'CellLine', 'CVCL:2213', (79, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('knockdown', 'Var', (20, 29))
236725	32023846	Increased inclusion of exon 6A was observed upon knockdown of SRSF1, SRSF3, SRSF10, HNRNPM, and HNRNPP (FUS), with respect to cells transfected with a control siRNA.	('exon 6A', 'Protein', (23, 30))	('knockdown', 'Var', (49, 58))	('SRSF10', 'Gene', '10772', (76, 82))	('SRSF10', 'Gene', (76, 82))	('HNRNPM', 'Gene', (84, 90))	('HNRNPP', 'Gene', (96, 102))	('SRSF3', 'Gene', (69, 74))	('SRSF1', 'Gene', (62, 67))
236727	32023846	Collectively, these results suggest that several specific SR proteins and hnRNPs contribute to the regulation of DHX9 alternative splicing in TC-71 cells.	('contribute', 'Reg', (81, 91))	('hnRNP', 'Gene', (74, 79))	('regulation', 'MPA', (99, 109))	('SR proteins', 'Protein', (58, 69))	('hnRNP', 'Gene', '3183', (74, 79))	('SR', 'Chemical', '-', (58, 60))	('TC-71', 'CellLine', 'CVCL:2213', (142, 147))	('alternative splicing', 'Var', (118, 138))	('DHX9', 'Gene', (113, 117))
236736	32023846	A significant decrease (35% for siHNRNPM and 50% for siSRSF3) in the DHX9 protein level was observed upon the silencing of these two splicing factors in TC-71 cells (Figure 5A,B).	('DHX9 protein level', 'MPA', (69, 87))	('silencing', 'Var', (110, 119))	('decrease', 'NegReg', (14, 22))	('TC-71', 'CellLine', 'CVCL:2213', (153, 158))
236737	32023846	Similar results were also obtained in SK-N-MC and LAP-35 Ewing sarcoma cells (Supplementary Figure S3), even though HNRNPM and SRSF3 knockdown in LAP-35 weakly affected DHX9 alternative splicing.	('affected', 'Reg', (160, 168))	('Ewing sarcoma', 'Disease', (57, 70))	('SK-N-MC', 'CellLine', 'CVCL:0530', (38, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('knockdown', 'Var', (133, 142))	('SRSF3', 'Gene', (127, 132))	('HNRNPM', 'Gene', (116, 122))	('DHX9 alternative splicing', 'MPA', (169, 194))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (57, 70))
236738	32023846	As previously reported, disruption of the DHX9-EWS-FLI1 interaction strongly impacts on the EWS-FLI1-driven transcriptional program in Ewing sarcoma cells.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (135, 148))	('impacts', 'Reg', (77, 84))	('EWS-FLI1', 'Gene', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('EWS-FLI1', 'Gene', (47, 55))	('interaction', 'Interaction', (56, 67))	('disruption', 'Var', (24, 34))	('EWS-FLI1', 'Gene', '2130;2313', (47, 55))	('Ewing sarcoma', 'Disease', (135, 148))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (135, 148))	('EWS-FLI1', 'Gene', '2130;2313', (92, 100))
236739	32023846	Thus, we asked whether knockdown of SRSF3 and hnRNPM had a similar effect on EWS-FLI1 target genes.	('SRSF3', 'Gene', (36, 41))	('knockdown', 'Var', (23, 32))	('EWS-FLI1', 'Gene', (77, 85))	('hnRNPM', 'Gene', (46, 52))	('EWS-FLI1', 'Gene', '2130;2313', (77, 85))
236740	32023846	RT-qPCR analysis showed that expression of c-MYC, EZH2, and ID2, was downregulated upon silencing of the two RBPs, with stronger effects elicited by depletion of SRSF3.	('RBP', 'Gene', (109, 112))	('depletion', 'Var', (149, 158))	('c-MYC', 'Gene', '4609', (43, 48))	('RBP', 'Gene', '57794', (109, 112))	('ID2', 'Gene', '3398', (60, 63))	('ID2', 'Gene', (60, 63))	('downregulated', 'NegReg', (69, 82))	('silencing', 'Var', (88, 97))	('c-MYC', 'Gene', (43, 48))	('EZH2', 'Gene', '2146', (50, 54))	('expression', 'MPA', (29, 39))	('EZH2', 'Gene', (50, 54))
236741	32023846	Moreover, expression of NR0B1 and CCND1 was affected only by SRSF3 depletion (Figure 5C).	('NR0B1', 'Gene', (24, 29))	('depletion', 'Var', (67, 76))	('affected', 'Reg', (44, 52))	('CCND1', 'Gene', '595', (34, 39))	('NR0B1', 'Gene', '190', (24, 29))	('expression', 'MPA', (10, 20))	('CCND1', 'Gene', (34, 39))
236742	32023846	To evaluate the effect of these splicing factors on Ewing sarcoma cell proliferation, we performed colony assays with cells transfected with control siRNA or with si-HNRNPM and si-SRSF3 oligonucleotides.	('si-SRSF3', 'Var', (177, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Ewing sarcoma', 'Disease', (52, 65))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (52, 65))	('si-HNRNPM', 'Var', (163, 172))	('oligonucleotides', 'Chemical', 'MESH:D009841', (186, 202))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
236745	32023846	To test whether SRSF3 and HNRNPM depletion had an effect on Ewing sarcoma sensitivity to chemotherapeutic agents, we treated TC-71 cells with doxorubicin.	('depletion', 'Var', (33, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (60, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('Ewing sarcoma', 'Disease', (60, 73))	('effect', 'Reg', (50, 56))	('TC-71', 'CellLine', 'CVCL:2213', (125, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (142, 153))	('HNRNPM', 'Protein', (26, 32))
236747	32023846	Doxorubicin induces DNA double-strand breaks and can cause a nonreversible checkpoint arrest or trigger cell death, thus curbing the rapid proliferation of cancer cells.	('cause', 'Reg', (53, 58))	('curbing', 'NegReg', (121, 128))	('checkpoint arrest', 'Disease', (75, 92))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('Doxorubicin', 'Var', (0, 11))	('cell', 'CPA', (104, 108))	('checkpoint arrest', 'Disease', 'MESH:D006323', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('DNA double-strand breaks', 'MPA', (20, 44))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('induces', 'Reg', (12, 19))
236748	32023846	MTS assays showed a statistically significant decrease in the viability of TC-71 cells silenced for HNRNPM (red) and SRSF3 (blue) versus control (black) (Figure 6A).	('TC-71', 'CellLine', 'CVCL:2213', (75, 80))	('HNRNPM', 'Gene', (100, 106))	('silenced', 'Var', (87, 95))	('SRSF3', 'Gene', (117, 122))	('decrease', 'NegReg', (46, 54))
236752	32023846	The knockdown of hnRNPM and SRSF3 significantly reduced the ability of TC-71 cells to form colonies in the presence of the drug (Figure 6B).	('TC-71', 'CellLine', 'CVCL:2213', (71, 76))	('reduced', 'NegReg', (48, 55))	('SRSF3', 'Gene', (28, 33))	('hnRNPM', 'Gene', (17, 23))	('knockdown', 'Var', (4, 13))
236758	32023846	Notably, although alternative splicing dysregulation has also been reported in Ewing sarcoma, limited information is available regarding the RBPs responsible for this process and their possible association with prognosis.	('Ewing sarcoma', 'Disease', 'MESH:D012512', (79, 92))	('alternative splicing dysregulation', 'Var', (18, 52))	('Ewing sarcoma', 'Disease', (79, 92))	('RBP', 'Gene', (141, 144))	('RBP', 'Gene', '57794', (141, 144))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('reported', 'Reg', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
236763	32023846	Moreover, our work indicates that the silencing of hnRNPM and SRSF3, the strongest repressors of exon 6A, significantly reduces DHX9 expression and Ewing sarcoma cell survival, thus suggesting the functional relevance of their effects on DHX9 splicing regulation.	('hnRNPM', 'Gene', (51, 57))	('expression', 'MPA', (133, 143))	('reduces', 'NegReg', (120, 127))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (148, 161))	('Ewing sarcoma', 'Disease', (148, 161))	('DHX9', 'Gene', (128, 132))	('SRSF3', 'Gene', (62, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (148, 161))	('silencing', 'Var', (38, 47))
236767	32023846	Remarkably, silencing of SRSF3 and HNRNPM, impacts on DHX9 expression as well as on Ewing sarcoma cell viability and proliferation, while it reduces survival of Ewing sarcoma cells to doxorubicin treatment.	('HNRNPM', 'Gene', (35, 41))	('expression', 'MPA', (59, 69))	('SRSF3', 'Gene', (25, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('Ewing sarcoma cell viability', 'Disease', 'MESH:D012512', (84, 112))	('Ewing sarcoma', 'Disease', (161, 174))	('doxorubicin', 'Chemical', 'MESH:D004317', (184, 195))	('proliferation', 'CPA', (117, 130))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (161, 174))	('impacts', 'Reg', (43, 50))	('survival', 'CPA', (149, 157))	('Ewing sarcoma cell viability', 'Disease', (84, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('reduces', 'NegReg', (141, 148))	('silencing', 'Var', (12, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (161, 174))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (84, 97))	('DHX9', 'Gene', (54, 58))
236779	32023846	Notably, the effect of SRSF3 knockdown on DHX9 protein expression and Ewing sarcoma cell viability was stronger than that elicited by hnRNPM, although displaying a milder effect on the inclusion of the alternative poison exon.	('protein', 'Protein', (47, 54))	('SRSF3', 'Gene', (23, 28))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('knockdown', 'Var', (29, 38))	('expression', 'MPA', (55, 65))	('Ewing sarcoma cell viability', 'Disease', 'MESH:D012512', (70, 98))	('DHX9', 'Gene', (42, 46))	('stronger', 'PosReg', (103, 111))	('Ewing sarcoma cell viability', 'Disease', (70, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))
236782	32023846	SRSF3 depletion displayed a stronger effect than HNRNPM depletion on Ewing sarcoma sensitivity to chemotherapy treatment, in line with its stronger impact on DHX9 expression.	('Ewing sarcoma', 'Disease', 'MESH:D012512', (69, 82))	('SRSF3', 'Gene', (0, 5))	('Ewing sarcoma', 'Disease', (69, 82))	('depletion', 'Var', (6, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (69, 82))
236784	32023846	Moreover, the downregulation of SRSF3 by antisense oligonucleotides (ASO) was shown to sensitize oral squamous cell carcinoma and breast cancer cells to paclitaxel treatment.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('SRSF3', 'Gene', (32, 37))	('squamous cell carcinoma', 'Disease', (102, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('antisense oligonucleotides', 'Var', (41, 67))	('paclitaxel', 'Chemical', 'MESH:D017239', (153, 163))	('oligonucleotides', 'Chemical', 'MESH:D009841', (51, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('downregulation', 'NegReg', (14, 28))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('ASO', 'Chemical', 'MESH:D016376', (69, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
236787	32023846	In conclusion, our study shows that DHX9 expression in Ewing sarcoma correlates with worse outcome in patients.	('patients', 'Species', '9606', (102, 110))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (55, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('Ewing sarcoma', 'Disease', (55, 68))	('expression', 'Var', (41, 51))	('DHX9', 'Gene', (36, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (55, 68))
236789	32023846	Thus, we suggest that modulation of SRSF3 and hnRNPM expression and their splicing signature could represent a novel therapeutic opportunity for combined and less aggressive therapy in Ewing sarcoma.	('SRSF3', 'Gene', (36, 41))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (185, 198))	('hnRNPM', 'Gene', (46, 52))	('Ewing sarcoma', 'Disease', (185, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('modulation', 'Var', (22, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (185, 198))
236792	32023846	Depletion of SRSF3 and hnRNPM increases doxorubicin sensitivity of SK-N-MC and LAP-35 Ewing sarcoma cells, Supplementary Table S1 List of oligonucleotides used in the siRNA library, Supplementary Table S2 List of primers.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('doxorubicin', 'Chemical', 'MESH:D004317', (40, 51))	('hnRNPM', 'Protein', (23, 29))	('Depletion', 'Var', (0, 9))	('Ewing sarcoma', 'Disease', (86, 99))	('SRSF3', 'Gene', (13, 18))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (86, 99))	('doxorubicin sensitivity', 'MPA', (40, 63))	('SK-N-MC', 'CellLine', 'CVCL:0530', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('increases', 'PosReg', (30, 39))	('oligonucleotides', 'Chemical', 'MESH:D009841', (138, 154))
236796	31418125	Highlighted findings are mainly on deregulated genes associated with cell adhesion, migration, and tumor cell dissemination.	('tumor', 'Disease', (99, 104))	('cell adhesion', 'CPA', (69, 82))	('migration', 'CPA', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('deregulated', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
236803	31418125	Clearly, genetic and epigenetic changes in tumor cells are of importance for tumor progression and these changes also contribute to modifications of the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('genetic', 'Var', (9, 16))	('modifications', 'Reg', (132, 145))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('epigenetic changes', 'Var', (21, 39))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (77, 82))	('importance', 'Reg', (62, 72))
236829	31418125	Detection of tumor-specific translocations is often diagnostically useful in pediatric sarcomas.	('tumor', 'Disease', (13, 18))	('pediatric sarcomas', 'Disease', (77, 95))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (77, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('translocations', 'Var', (28, 42))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
236830	31418125	EWS-ETS gene fusion variants are found in Ewing sarcomas, and similarly, the most common fusion genes associated with alveolar rhabdomyosarcoma are PAX3-FOXO1 and PAX7-FOXO1.	('variants', 'Var', (20, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (42, 55))	('FOXO1', 'Gene', (168, 173))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (118, 143))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (118, 143))	('PAX3', 'Gene', (148, 152))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (42, 56))	('PAX7', 'Gene', '5081', (163, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('Ewing sarcomas', 'Disease', (42, 56))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (42, 56))	('PAX3', 'Gene', '5077', (148, 152))	('PAX7', 'Gene', (163, 167))	('EWS', 'Gene', (0, 3))	('associated', 'Reg', (102, 112))	('FOXO1', 'Gene', '2308', (153, 158))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (127, 143))	('alveolar rhabdomyosarcoma', 'Disease', (118, 143))	('FOXO1', 'Gene', '2308', (168, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('FOXO1', 'Gene', (153, 158))	('EWS', 'Gene', '2130', (0, 3))
236858	31418125	Importantly, deregulated developmental processes are believed to play a major role in pediatric sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('deregulated', 'Var', (13, 24))	('pediatric sarcomas', 'Disease', (86, 104))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (86, 104))	('developmental processes', 'CPA', (25, 48))
236867	31418125	The traditional linear progression model of metastasis is based on the assumption that genetic mutations accumulate in the tumor over time, and eventually, subclonal populations acquire metastatic features.	('tumor', 'Disease', (123, 128))	('metastatic features', 'CPA', (186, 205))	('acquire', 'Reg', (178, 185))	('accumulate', 'PosReg', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('genetic mutations', 'Var', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
236883	31418125	Both MMP-2 and MMP-9 have been suggested as prognostic markers and associate with metastasis in osteosarcoma.	('metastasis in osteosarcoma', 'Disease', (82, 108))	('metastasis in osteosarcoma', 'Disease', 'MESH:D009362', (82, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (96, 108))	('MMP-9', 'Gene', '4318', (15, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('MMP-2', 'Var', (5, 10))	('associate', 'Reg', (67, 76))	('MMP-9', 'Gene', (15, 20))
236913	31418125	VEGF expression has been associated with vessel density and decreased disease-free survival of osteosarcoma patients.	('osteosarcoma', 'Disease', 'MESH:D012516', (95, 107))	('decreased', 'NegReg', (60, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('VEGF', 'Gene', '7422', (0, 4))	('expression', 'Var', (5, 15))	('disease-free survival', 'CPA', (70, 91))	('VEGF', 'Gene', (0, 4))	('patients', 'Species', '9606', (108, 116))	('osteosarcoma', 'Phenotype', 'HP:0002669', (95, 107))	('osteosarcoma', 'Disease', (95, 107))	('vessel density', 'CPA', (41, 55))
236914	31418125	CTGF was recently shown to promote angiogenesis, increase MMP-2/3 expression and cell migration in osteosarcoma, whereas knockdown of CTGF reduced lung metastasis in an experimental mouse model.	('knockdown', 'Var', (121, 130))	('osteosarcoma', 'Disease', 'MESH:D012516', (99, 111))	('increase', 'PosReg', (49, 57))	('CTGF', 'Gene', (0, 4))	('mouse', 'Species', '10090', (182, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('MMP-2/3', 'Protein', (58, 65))	('promote', 'PosReg', (27, 34))	('cell migration', 'CPA', (81, 95))	('angiogenesis', 'CPA', (35, 47))	('osteosarcoma', 'Phenotype', 'HP:0002669', (99, 111))	('CTGF', 'Gene', (134, 138))	('osteosarcoma', 'Disease', (99, 111))
236927	31418125	Genetic aberrations of PDGF receptors are only detected in about 2% of pediatric cancers .	('pediatric cancers', 'Disease', (71, 88))	('pediatric cancers', 'Disease', 'MESH:D009369', (71, 88))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('Genetic aberrations', 'Var', (0, 19))	('detected', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PDGF', 'Gene', (23, 27))	('PDGF', 'Gene', '56034', (23, 27))
236933	31418125	Another report, from rhabdomyosarcoma, has identified amplified, overexpressed, and constitutively activated PDGFRalpha as an acquired resistance mechanism to an agent targeting insulin-like growth factor I receptor (IGF-IR).	('PDGFRalpha', 'Gene', (109, 119))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (21, 37))	('IGF-IR', 'Gene', (217, 223))	('amplified', 'Var', (54, 63))	('insulin-like growth factor I receptor', 'Gene', (178, 215))	('IGF-IR', 'Gene', '3480', (217, 223))	('rhabdomyosarcoma', 'Disease', (21, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('PDGFRalpha', 'Gene', '5156', (109, 119))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (21, 37))	('insulin-like growth factor I receptor', 'Gene', '3480', (178, 215))
237039	31110820	In particular, the results of CR + PR exceeding 90% have been reported in skin cancer, malignant melanoma, superficial squamous carcinoma, vulva cancer, and scar cancer.	('scar', 'Phenotype', 'HP:0100699', (157, 161))	('squamous carcinoma', 'Disease', 'MESH:D002294', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('vulva cancer', 'Phenotype', 'HP:0030416', (139, 151))	('scar cancer', 'Disease', 'MESH:D002921', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('skin cancer', 'Disease', (74, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('malignant melanoma', 'Phenotype', 'HP:0002861', (87, 105))	('malignant melanoma', 'Disease', 'MESH:D008545', (87, 105))	('scar cancer', 'Disease', (157, 168))	('skin cancer', 'Phenotype', 'HP:0008069', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('vulva cancer', 'Disease', (139, 151))	('squamous carcinoma', 'Disease', (119, 137))	('CR + PR', 'Var', (30, 37))	('skin cancer', 'Disease', 'MESH:D012878', (74, 85))	('malignant melanoma', 'Disease', (87, 105))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (119, 137))	('CR', 'Chemical', 'MESH:D002857', (30, 32))	('vulva cancer', 'Disease', 'MESH:D014846', (139, 151))
237040	31110820	It appears that ECT caused rapid and polar-dependent changes in physiological solutions in cancer tissues, and similar electrochemical processes mediated a decrease in observed tumor growth.	('changes', 'Reg', (53, 60))	('physiological solutions', 'MPA', (64, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ECT', 'Var', (16, 19))	('decrease', 'NegReg', (156, 164))	('tumor', 'Disease', (177, 182))
237049	31110820	's research, hemoglobin is converted into iron (III) protoporphyrin chloride (C34H32ClFIIIN4O4) = chlorohemin which is acidic Hemin on the anode side and iron (III) protoporphyrin (C34H32O4N4FeOH)) = Hematin (hematin) has also been reported to occur.	('C34H32O4N4FeOH', 'Var', (181, 195))	('iron (III) protoporphyrin', 'Chemical', '-', (42, 67))	('chlorohemin', 'Chemical', 'MESH:D006427', (98, 109))	('Hematin', 'Chemical', 'MESH:D006427', (200, 207))	('C34H32ClFIIIN4O4', 'Var', (78, 94))	('C34H32ClFIIIN4O4', 'Chemical', '-', (78, 94))	('Hemin', 'Chemical', 'MESH:D006427', (126, 131))	('iron (III) protoporphyrin chloride', 'Chemical', '-', (42, 76))	('hematin', 'Chemical', 'MESH:D006427', (209, 216))	('C34H32O4N4FeOH', 'Chemical', '-', (181, 195))	('iron (III) protoporphyrin', 'Chemical', '-', (154, 179))
237055	31110820	When Ca2+ becomes excessive, it is thought that Ca2+ plays an important role of killing the cell, since it can cause cell death.	('Ca2+', 'Var', (48, 52))	('Ca2+', 'Chemical', 'MESH:D000069285', (48, 52))	('cell death', 'CPA', (117, 127))	('Ca2+', 'Chemical', 'MESH:D000069285', (5, 9))	('cause', 'Reg', (111, 116))
237058	31110820	In this study, apoptosis antibody staining was performed instead of agarose gel electrophoresis or nick-end labeling method; it was found that after hrs it changed to 10mA x 300secs and 10mA x 600secs group, after 1hr it changed to 10mA x 300secs group, and after 24hrs there was a significant increase in apoptosis in each group compared to the control group.	('agarose', 'Chemical', 'MESH:D012685', (68, 75))	('10mA x 600secs', 'Var', (186, 200))	('apoptosis', 'CPA', (306, 315))
237065	31110820	In this study, the tumor suppressing effect of Scc-7 was observed in the 10mA x 300sec group and the 10mA x 600sec group.	('10mA x 300sec', 'Var', (73, 86))	('Scc-7', 'Gene', (47, 52))	('Scc-7', 'Gene', '109433', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))
237120	28336944	2b), while the production of the DeltaORF34-KSHV was about 100-fold lower.	('production', 'MPA', (15, 25))	('KSHV', 'Species', '37296', (44, 48))	('lower', 'NegReg', (68, 73))	('DeltaORF34-KSHV', 'Var', (33, 48))
237143	28336944	Using these 2xS-ORF34 deletion mutants, the interaction domains of ORF34 with 6xMyc-ORF24 (Fig.	('deletion mutants', 'Var', (22, 38))	('ORF34', 'Gene', (67, 72))	('ORF24', 'Gene', (84, 89))	('Myc', 'Gene', '4609', (80, 83))	('interaction', 'Interaction', (44, 55))	('Myc', 'Gene', (80, 83))	('ORF24', 'Gene', '4961485', (84, 89))
237152	28336944	Because mapping data shows that ORF34 interacts with ORF24 protein via its C-terminal region, we therefore investigated whether this interaction is important for virus production by trans-complementation assay using exogenous ORF34 mutants lacking variable lengths of the C-terminal region.	('ORF24', 'Gene', '4961485', (53, 58))	('ORF34', 'Gene', (32, 37))	('protein', 'Protein', (59, 66))	('lacking', 'NegReg', (240, 247))	('ORF34', 'Gene', (226, 231))	('mutants', 'Var', (232, 239))	('ORF24', 'Gene', (53, 58))	('interacts', 'Interaction', (38, 47))
237173	28336944	Our findings are in line with a previous result that showed ORF34 associated with ORF18, ORF31, and ORF66 by a split luciferase assay.	('ORF34', 'Var', (60, 65))	('ORF31', 'Gene', (89, 94))	('ORF31', 'Gene', '4961498', (89, 94))	('associated', 'Reg', (66, 76))	('ORF66', 'Gene', (100, 105))	('ORF18', 'Gene', '4961499', (82, 87))	('ORF66', 'Gene', '4961523', (100, 105))	('ORF18', 'Gene', (82, 87))
237190	28336944	KSHV BAC16 wild-type (WT-BAC16) and mutants (DeltaORF34-BAC16 and Revertant-BAC16) were transfected to iVero cells by a calcium phosphate method.	('KSHV', 'Species', '37296', (0, 4))	('calcium phosphate', 'Chemical', 'MESH:C020243', (120, 137))	('DeltaORF34-BAC16', 'Var', (45, 61))	('KSHV BAC16', 'Gene', (0, 10))
237203	28336944	The cells were transfected with pCI-neo-2xS as a control plasmid, and 2xS-taggged ORF34 full length and deletion mutant plasmids using Screenfect A plus (Wako, Tokyo, JAPAN) according to the manufacturer's instructions.	('ORF34', 'Gene', (82, 87))	('mutant', 'Var', (113, 119))	('deletion mutant', 'Var', (104, 119))	('pCI-neo-2xS', 'Chemical', '-', (32, 43))
237214	28336944	Cells were incubated with Anti-Myc, Anti-FLAG, Anti-S-probe antibodies.	('Myc', 'Gene', '4609', (31, 34))	('Myc', 'Gene', (31, 34))	('Anti-FLAG', 'Var', (36, 45))	('Anti-S-probe', 'Var', (47, 59))
237218	28336944	Immunoprecipitates containing chromatin and viral DNA were subjected to SYBR green real-time PCR for measuring the levels of promoter DNA of ORF46/47 (E gene) or K8.1 (L gene).	('K8.1', 'Var', (162, 166))	('SYBR green', 'Chemical', '-', (72, 82))	('ORF46/47', 'Var', (141, 149))
237301	24616882	Beyond Breast and Ovarian Cancers: PARP Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical activity in patients with germline BRCA1/2 mutation (gBRCAm)-associated breast and ovarian cancers.	('BRCA', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('Breast and Ovarian Cancers', 'Disease', 'MESH:D010051', (7, 33))	('ovarian cancers', 'Phenotype', 'HP:0100615', (257, 272))	('BRCA', 'Gene', '672', (228, 232))	('BRCA', 'Gene', '672', (84, 88))	('PARP', 'Gene', '142', (147, 151))	('BRCA1/2', 'Gene', '672;675', (209, 216))	('BRCA-Like Solid Tumors', 'Disease', (84, 106))	('BRCA-Like Solid Tumors', 'Disease', 'MESH:D009369', (84, 106))	('PARP', 'Gene', (147, 151))	('mutation', 'Var', (217, 225))	('Tumors', 'Phenotype', 'HP:0002664', (100, 106))	('BRCA', 'Gene', (228, 232))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (246, 272))	('BRCA', 'Gene', (84, 88))	('patients', 'Species', '9606', (186, 194))	('BRCA', 'Gene', '672', (209, 213))	('PARP', 'Gene', '142', (35, 39))	('Poly(ADP-ribose) polymerase', 'Gene', '142', (107, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (257, 271))	('PARP', 'Gene', (35, 39))	('Cancers', 'Phenotype', 'HP:0002664', (26, 33))	('BRCA', 'Gene', '672', (55, 59))	('BRCA', 'Gene', (209, 213))	('Poly(ADP-ribose) polymerase', 'Gene', (107, 134))	('Ovarian Cancers', 'Phenotype', 'HP:0100615', (18, 33))	('BRCA1/2', 'Gene', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('gBRCAm', 'Chemical', '-', (227, 233))
237308	24616882	This approach has been an important step toward individualization of therapy for germline BRCA1/2 mutation (gBRCAm)-associated breast and ovarian cancers.	('BRCA1/2', 'Gene', (90, 97))	('gBRCAm', 'Chemical', '-', (108, 114))	('mutation', 'Var', (98, 106))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (127, 153))	('BRCA1/2', 'Gene', '672;675', (90, 97))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian cancers', 'Phenotype', 'HP:0100615', (138, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
237343	24616882	PARP inhibition has been shown to induce phosphorylation of DNA-dependent protein kinase (DNA-Pk), to further stimulate error-prone NHEJ in HR-deficient cells.	('NHEJ', 'Gene', (132, 136))	('induce', 'PosReg', (34, 40))	('DNA-dependent protein kinase', 'Gene', (60, 88))	('inhibition', 'Var', (5, 15))	('DNA-Pk', 'Gene', (90, 96))	('PARP', 'Gene', (0, 4))	('DNA-Pk', 'Gene', '5591', (90, 96))	('phosphorylation', 'MPA', (41, 56))	('error-prone', 'Reg', (120, 131))	('HR-deficient', 'Disease', (140, 152))	('HR-deficient', 'Disease', 'MESH:D001919', (140, 152))	('stimulate', 'PosReg', (110, 119))	('DNA-dependent protein kinase', 'Gene', '5591', (60, 88))
237355	24616882	Some of the molecular events described in BRCA-like behavior include epigenetic silencing of BRCA1 through promoter methylation and overexpression of EMSY, suppressing BRCA2 transcription.	('BRCA2', 'Gene', '675', (168, 173))	('overexpression', 'PosReg', (132, 146))	('BRCA', 'Gene', '672', (42, 46))	('transcription', 'MPA', (174, 187))	('epigenetic silencing', 'Var', (69, 89))	('BRCA', 'Gene', (168, 172))	('BRCA', 'Gene', '672', (168, 172))	('EMSY', 'Gene', (150, 154))	('promoter', 'MPA', (107, 115))	('BRCA', 'Gene', (42, 46))	('BRCA', 'Gene', '672', (93, 97))	('BRCA', 'Gene', (93, 97))	('BRCA1', 'Gene', '672', (93, 98))	('EMSY', 'Gene', '56946', (150, 154))	('BRCA1', 'Gene', (93, 98))	('BRCA2', 'Gene', (168, 173))	('suppressing', 'NegReg', (156, 167))
237357	24616882	Defects in translesion synthesis (TLS) also contribute to carcinogenesis but confer sensitivity to DNA-damaging agents, requiring further investigation on sensitivity to PARPi.	('translesion', 'MPA', (11, 22))	('contribute', 'Reg', (44, 54))	('Defects', 'Var', (0, 7))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('carcinogenesis', 'Disease', (58, 72))	('sensitivity', 'MPA', (84, 95))
237358	24616882	Homozygous mutation in the PTEN tumor suppressor gene may also lead to HR dysfunction.	('Homozygous mutation', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('HR dysfunction', 'Disease', 'MESH:D006331', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('HR dysfunction', 'Disease', (71, 85))	('lead to', 'Reg', (63, 70))	('PTEN', 'Gene', (27, 31))	('tumor', 'Disease', (32, 37))	('PTEN', 'Gene', '5728', (27, 31))
237359	24616882	Increased PARPi sensitivity was shown in a series of cell lines with PTEN mutation or haploinsufficiency, and confirmed in xenograft models using olaparib.	('mutation', 'Var', (74, 82))	('PTEN', 'Gene', '5728', (69, 73))	('haploinsufficiency', 'Disease', (86, 104))	('PARPi sensitivity', 'MPA', (10, 27))	('haploinsufficiency', 'Disease', 'MESH:D058495', (86, 104))	('olaparib', 'Chemical', 'MESH:C531550', (146, 154))	('PTEN', 'Gene', (69, 73))
237365	24616882	Cutaneous melanoma has been associated with mutations in the BRCA2 gene although there are only a few cases reported for uveal melanoma in BRCA2 mutation carriers.	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('uveal melanoma', 'Disease', (121, 135))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('associated', 'Reg', (28, 38))	('BRCA2', 'Gene', (139, 144))	('BRCA2', 'Gene', (61, 66))	('BRCA2', 'Gene', '675', (139, 144))	('mutations', 'Var', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('BRCA2', 'Gene', '675', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanoma', 'Disease', (0, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (121, 135))
237366	24616882	In recent years, the advent of BRAF V600E inhibitors (e.g., vemurafenib) and anti-CTLA4 antibodies (e.g., ipilimumab) has significantly improved outcomes in patients with metastatic melanoma, with a median duration of response of 8 and 16 months, respectively.	('CTLA4', 'Gene', '1493', (82, 87))	('ipilimumab', 'Chemical', 'MESH:D000074324', (106, 116))	('vemurafenib', 'Chemical', 'MESH:D000077484', (60, 71))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('melanoma', 'Disease', (182, 190))	('BRAF', 'Gene', (31, 35))	('patients', 'Species', '9606', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))	('BRAF', 'Gene', '673', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('antibodies', 'Var', (88, 98))	('CTLA4', 'Gene', (82, 87))	('improved', 'PosReg', (136, 144))
237369	24616882	In the setting of melanoma, altered expression or new mutations in DNA MMR genes, MLH1 and MSH2, have been reported in brain metastases.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('MSH2', 'Gene', (91, 95))	('altered', 'Reg', (28, 35))	('DNA MMR', 'Gene', (67, 74))	('MSH2', 'Gene', '4436', (91, 95))	('MLH1', 'Gene', '4292', (82, 86))	('mutations', 'Var', (54, 63))	('reported', 'Reg', (107, 115))	('MLH1', 'Gene', (82, 86))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('brain metastases', 'Disease', 'MESH:D009362', (119, 135))	('melanoma', 'Disease', (18, 26))	('expression', 'MPA', (36, 46))	('brain metastases', 'Disease', (119, 135))
237371	24616882	PARP inhibition with INO-1001 has been shown to restore sensitivity to TMZ in an MMR-deficient xenograft model of malignant melanoma, and another PARPi, GPI 15427, enhanced TMZ anti-tumor activity in various cancers, including metastatic melanoma in an orthotopic xenograft mouse model.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', (238, 246))	('inhibition', 'Var', (5, 15))	('TMZ', 'Chemical', 'MESH:D000077204', (71, 74))	('malignant melanoma', 'Phenotype', 'HP:0002861', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('restore', 'PosReg', (48, 55))	('malignant melanoma', 'Disease', 'MESH:D008545', (114, 132))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('TMZ', 'Chemical', 'MESH:D000077204', (173, 176))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancers', 'Disease', (208, 215))	('INO-1001', 'Chemical', 'MESH:C491685', (21, 29))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('INO-1001', 'Gene', (21, 29))	('sensitivity', 'MPA', (56, 67))	('mouse', 'Species', '10090', (274, 279))	('malignant melanoma', 'Disease', (114, 132))	('tumor', 'Disease', (182, 187))	('PARP', 'Gene', (0, 4))	('enhanced', 'PosReg', (164, 172))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
237383	24616882	Phase I and II trials evaluating E7016 in combination with TMZ in patients with advanced solid tumors and malignant melanoma are ongoing.	('E7016', 'Var', (33, 38))	('malignant melanoma', 'Disease', (106, 124))	('solid tumors', 'Disease', (89, 101))	('E7016', 'Chemical', 'MESH:C559134', (33, 38))	('malignant melanoma', 'Phenotype', 'HP:0002861', (106, 124))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))	('solid tumors', 'Disease', 'MESH:D009369', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (66, 74))	('malignant melanoma', 'Disease', 'MESH:D008545', (106, 124))
237389	24616882	BRCA2 mutation prevalence in familial pancreatic cancer patients varies between 5 and 19%, and a BRCA2 mutation increases the risk of developing pancreatic cancer by approximately 3.5-fold.	('BRCA2', 'Gene', '675', (0, 5))	('BRCA2', 'Gene', (97, 102))	('patients', 'Species', '9606', (56, 64))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (29, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('pancreatic cancer', 'Disease', 'MESH:D010190', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('pancreatic cancer', 'Disease', (145, 162))	('BRCA2', 'Gene', '675', (97, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('BRCA2', 'Gene', (0, 5))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (38, 55))	('mutation', 'Var', (103, 111))	('increases', 'PosReg', (112, 121))	('familial pancreatic cancer', 'Disease', (29, 55))
237390	24616882	The unique biology of cancer cells with BRCA mutations offers potential therapeutic advantages with agents such as platinums.	('mutations', 'Var', (45, 54))	('advantages', 'PosReg', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('BRCA', 'Gene', '672', (40, 44))	('platinums', 'Chemical', 'MESH:D010984', (115, 124))	('BRCA', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
237393	24616882	Studies are ongoing to examine single-agent and combination PARPi therapy in BRCA2 mutant pancreatic cancers.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('mutant', 'Var', (83, 89))	('BRCA2', 'Gene', (77, 82))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (90, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA2', 'Gene', '675', (77, 82))	('pancreatic cancers', 'Disease', 'MESH:D010190', (90, 108))	('pancreatic cancers', 'Disease', (90, 108))
237403	24616882	Germline BRCA2 mutation confers the highest genetic risk of prostate cancer known to date at 8.6-fold in men <=65 years, whereas the effect of BRCA1 is more modest at 3.4-fold.	('mutation', 'Var', (15, 23))	('BRCA1', 'Gene', '672', (143, 148))	('BRCA2', 'Gene', (9, 14))	('prostate cancer', 'Disease', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA1', 'Gene', (143, 148))	('BRCA2', 'Gene', '675', (9, 14))	('men', 'Species', '9606', (105, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
237412	24616882	Translational studies revealed positive ERG staining by immunohistochemistry, and ERG rearrangements by FISH, as well as either heterozygous or homozygous PTEN allelic loss in all four cases.	('ERG', 'Gene', (82, 85))	('PTEN', 'Gene', (155, 159))	('PTEN', 'Gene', '5728', (155, 159))	('rearrangements', 'Var', (86, 100))	('ERG', 'Gene', '2078', (40, 43))	('men', 'Species', '9606', (95, 98))	('ERG', 'Gene', '2078', (82, 85))	('ERG', 'Gene', (40, 43))	('allelic', 'Var', (160, 167))
237415	24616882	Gene fusion between the ERG proto-oncogene and TMPRSS2 promoter is a major genomic alteration observed in approximately 50% of prostate cancers.	('TMPRSS2', 'Gene', (47, 54))	('ERG', 'Gene', '2078', (24, 27))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('prostate cancers', 'Phenotype', 'HP:0012125', (127, 143))	('ERG', 'Gene', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('prostate cancers', 'Disease', (127, 143))	('TMPRSS2', 'Gene', '7113', (47, 54))	('prostate cancers', 'Disease', 'MESH:D011471', (127, 143))	('Gene fusion', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
237416	24616882	Formation of the TMPRSS2-ERG fusion gene causes aberrant androgen-dependent ERG expression and promotes tumorigenesis.	('ERG', 'Gene', '2078', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ERG', 'Gene', (25, 28))	('TMPRSS2', 'Gene', (17, 24))	('ERG', 'Gene', '2078', (76, 79))	('tumor', 'Disease', (104, 109))	('aberrant', 'Var', (48, 56))	('causes', 'Reg', (41, 47))	('ERG', 'Gene', (76, 79))	('expression', 'MPA', (80, 90))	('TMPRSS2', 'Gene', '7113', (17, 24))	('promotes', 'PosReg', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
237418	24616882	In turn, inhibition of PARP1 reduces ETS-positive, but not ETS-negative, prostate cancer xenograft growth.	('prostate cancer', 'Disease', (73, 88))	('inhibition', 'Var', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PARP1', 'Gene', '142', (23, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('PARP1', 'Gene', (23, 28))	('reduces', 'NegReg', (29, 36))	('ETS-positive', 'Disease', (37, 49))
237421	24616882	The HR/PARP synthetic lethality model may be more widely applicable in prostate cancer with germline or somatic inactivating mutations in the HR DNA repair genes, CHK2, BRIPI/FANCJ, NBS1, BRCA1, and ATM, collectively thought to occur in 20-25% of prostate cancer cases.	('CHK2', 'Gene', (163, 167))	('ATM', 'Gene', '472', (199, 202))	('BRCA1', 'Gene', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('prostate cancer', 'Disease', 'MESH:D011471', (247, 262))	('CHK2', 'Gene', '11200', (163, 167))	('NBS1', 'Gene', '4683', (182, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (247, 262))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Disease', (247, 262))	('ATM', 'Gene', (199, 202))	('NBS1', 'Gene', (182, 186))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('inactivating mutations', 'Var', (112, 134))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('prostate cancer', 'Disease', (71, 86))	('FANCJ', 'Gene', (175, 180))	('FANCJ', 'Gene', '83990', (175, 180))	('BRCA1', 'Gene', '672', (188, 193))
237430	24616882	Preclinical data suggest the utility of PARPi in tumors deficient in HR and displaying microsatellite instability (MSI) due to mutations in the coding microsatellites of the MRE11A and hRAD50 genes involved in DNA DSB repair.	('MRE11A', 'Gene', '4361', (174, 180))	('microsatellite instability', 'MPA', (87, 113))	('hRAD50', 'Gene', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('hRAD50', 'Gene', '10111', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors deficient in HR', 'Disease', 'MESH:D009369', (49, 71))	('MRE11A', 'Gene', (174, 180))	('mutations', 'Var', (127, 136))	('tumors deficient in HR', 'Disease', (49, 71))
237431	24616882	Preferential cytotoxicity to the PARP1 inhibitor ABT-888 was seen in MSI cell lines containing mutant copies of MRE11A, compared with wild-type or microsatellite stable (MSS) cells.	('cytotoxicity', 'Disease', (13, 25))	('PARP1', 'Gene', (33, 38))	('MRE11A', 'Gene', (112, 118))	('PARP1', 'Gene', '142', (33, 38))	('mutant copies', 'Var', (95, 108))	('cytotoxicity', 'Disease', 'MESH:D064420', (13, 25))	('MRE11A', 'Gene', '4361', (112, 118))	('ABT-888', 'Chemical', 'MESH:C521013', (49, 56))
237433	24616882	Another study reporting high correlation between MRE11 mutations and MSI in CRC cell lines as well as primary tumors, found that PARPi preferentially kills MSI cell lines harboring MRE11 mutations.	('MRE11', 'Gene', '4361', (49, 54))	('mutations', 'Var', (55, 64))	('CR', 'Chemical', 'MESH:D002857', (76, 78))	('MRE11', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mutations', 'Var', (187, 196))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('MRE11', 'Gene', '4361', (181, 186))	('MRE11', 'Gene', (181, 186))
237450	24616882	One study showed that BRCA1 silencing increased susceptibility to olaparib treatment in NSCLC cell lines, providing evidence for possible clinical application in this subset of NSCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('susceptibility to olaparib treatment', 'MPA', (48, 84))	('men', 'Species', '9606', (80, 83))	('BRCA1', 'Gene', '672', (22, 27))	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Disease', (88, 93))	('olaparib', 'Chemical', 'MESH:C531550', (66, 74))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('silencing', 'Var', (28, 37))	('BRCA1', 'Gene', (22, 27))
237452	24616882	The role of PTEN mutation and its effect on the susceptibility to PARPi is an area of continued research in lung and other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('PARPi', 'Disease', (66, 71))	('mutation', 'Var', (17, 25))	('malignancies', 'Disease', (123, 135))	('PTEN', 'Gene', (12, 16))	('PTEN', 'Gene', '5728', (12, 16))
237457	24616882	The role of PARPi in patients with EGFR mutant NSCLC has been studied in a phase IB study of olaparib and the EGFR tyrosine kinase inhibitor (TKI) gefitinib.	('gefitinib', 'Chemical', 'MESH:D000077156', (147, 156))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('patients', 'Species', '9606', (21, 29))	('olaparib', 'Chemical', 'MESH:C531550', (93, 101))	('NSCLC', 'Disease', (47, 52))	('mutant', 'Var', (40, 46))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))
237458	24616882	It was noted that high BRCA1 mRNA expression is associated with a shorter PFS in EGFR-mutated patients treated with erlotinib.	('PFS', 'MPA', (74, 77))	('patients', 'Species', '9606', (94, 102))	('mRNA expression', 'MPA', (29, 44))	('BRCA1', 'Gene', (23, 28))	('shorter', 'NegReg', (66, 73))	('erlotinib', 'Chemical', 'MESH:D000069347', (116, 125))	('high', 'Var', (18, 22))	('BRCA1', 'Gene', '672', (23, 28))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
237471	24616882	Gene fusions involving Ewing's sarcoma breakpoint region 1 (EWS) and ETS transcription factors have been implicated in abnormal proliferation, invasion, and tumorigenesis.	('tumor', 'Disease', (157, 162))	('ETS transcription factors', 'Gene', (69, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Gene fusions', 'Var', (0, 12))	('implicated', 'Reg', (105, 115))	('invasion', 'CPA', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('EWS', 'Gene', '2130', (60, 63))	('EWS', 'Gene', (60, 63))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (23, 38))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('abnormal proliferation', 'CPA', (119, 141))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (23, 38))	("Ewing's sarcoma", 'Disease', (23, 38))
237480	24616882	BRCA1/2 somatic mutation or promoter methylation, ATM mutation, MRE11-dominant negative mutations in MMR-deficient cancers, FANCF promotor methylation and PTEN deficiency are all potential biomarkers of sensitivity to PARPi.	('mutation', 'Var', (54, 62))	('PTEN deficiency', 'Disease', (155, 170))	('promoter', 'MPA', (28, 36))	('ATM', 'Gene', (50, 53))	('MMR-deficient cancers', 'Disease', (101, 122))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('MMR-deficient cancers', 'Disease', 'MESH:C536928', (101, 122))	('FANCF', 'Gene', '2188', (124, 129))	('negative', 'NegReg', (79, 87))	('mutations', 'Var', (88, 97))	('PTEN deficiency', 'Disease', 'MESH:D006223', (155, 170))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ATM', 'Gene', '472', (50, 53))	('MRE11', 'Gene', '4361', (64, 69))	('FANCF', 'Gene', (124, 129))	('BRCA1/2', 'Gene', (0, 7))	('MRE11', 'Gene', (64, 69))
237481	24616882	Importantly, not all patients with deficiencies in BRCA1 or 2 are responsive to PARP inhibition.	('responsive', 'Reg', (66, 76))	('deficiencies', 'Var', (35, 47))	('BRCA1', 'Gene', '672', (51, 56))	('patients', 'Species', '9606', (21, 29))	('BRCA1', 'Gene', (51, 56))
237484	24616882	Acquisition of a secondary mutation in BRCA1/2 that allows BRCA1/2 gene read-through and yields a functional protein has been demonstrated in cell lines and some patients; this was correlated with loss of susceptibility to PARPi treatment.	('patients', 'Species', '9606', (162, 170))	('BRCA1/2', 'Gene', (59, 66))	('BRCA1/2', 'Gene', '672;675', (59, 66))	('BRCA1/2', 'Gene', (39, 46))	('men', 'Species', '9606', (234, 237))	('mutation', 'Var', (27, 35))	('functional', 'MPA', (98, 108))	('read-through', 'PosReg', (72, 84))	('protein', 'Protein', (109, 116))	('BRCA1/2', 'Gene', '672;675', (39, 46))
237533	31615564	Almost all cases of ES are negative for ERG gene rearrangement and according to detection by IHC or fluorescence in situ hybridization (FISH), 90% of malignant rhabdoid tumors show nuclear deficiency of INI1, with the inactivation of SMARCB1.	('malignant rhabdoid tumors', 'Disease', (150, 175))	('nuclear deficiency', 'Var', (181, 199))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (150, 175))	('INI1', 'Gene', '6598', (203, 207))	('ERG', 'Gene', '2078', (40, 43))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('INI1', 'Gene', (203, 207))	('SMARCB1', 'Gene', (234, 241))	('ERG', 'Gene', (40, 43))	('SMARCB1', 'Gene', '6598', (234, 241))
237574	30174981	Immunohistochemistry revealed CD10 (Figure 5), estrogen receptor (ER, Figure 6), and progesterone receptor (PR, Figure 7) positivity.	('progesterone receptor', 'Gene', '5241', (85, 106))	('positivity', 'Var', (122, 132))	('estrogen receptor', 'Gene', '2099', (47, 64))	('PR', 'Gene', '5241', (108, 110))	('CD10', 'Gene', '4311', (30, 34))	('CD10', 'Gene', (30, 34))	('progesterone receptor', 'Gene', (85, 106))	('estrogen receptor', 'Gene', (47, 64))
237633	29896199	Finally, three microarray datasets of sarcoma (GSE2719, GSE6481, and GSE 967) were screened and downloaded for analysis.	('GSE', 'Chemical', '-', (69, 72))	('GSE2719', 'Var', (47, 54))	('GSE6481', 'Var', (56, 63))	('sarcoma', 'Disease', (38, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('GSE', 'Chemical', '-', (56, 59))	('GSE2719', 'Chemical', '-', (47, 54))	('GSE6481', 'Chemical', '-', (56, 63))	('GSE', 'Chemical', '-', (47, 50))	('GSE 967', 'Var', (69, 76))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))
237660	29896199	The correlations were then validated by analysis using GSE2719 and GSE6481 datasets of sarcoma (Figure 4A).	('GSE2719', 'Chemical', '-', (55, 62))	('sarcoma', 'Disease', (87, 94))	('GSE6481', 'Var', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('GSE2719', 'Var', (55, 62))	('GSE6481', 'Chemical', '-', (67, 74))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
237697	29896199	However, it has also been reported that IL-33 can promote the accumulation of ST2+ Tregs in tumor lesions and exhibits an immunosuppressive effect; IL-33 can also promote MDSCs to accumulate in the tumor and secrete a large amount of immunosuppressive cytokines, such as TGF-beta1, resulting in tumor metastasis.	('accumulate', 'PosReg', (180, 190))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('TGF-beta1', 'Gene', (271, 280))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('secrete', 'MPA', (208, 215))	('tumor lesions', 'Disease', (92, 105))	('tumor', 'Disease', (295, 300))	('TGF-beta1', 'Gene', '7040', (271, 280))	('tumor metastasis', 'Disease', 'MESH:D009362', (295, 311))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('IL-33', 'Var', (148, 153))	('tumor', 'Disease', (198, 203))	('promote', 'PosReg', (163, 170))	('tumor metastasis', 'Disease', (295, 311))	('tumor lesions', 'Disease', 'MESH:D051437', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (92, 97))
237853	29620641	showed that inhibiting LDH-A expression promoted apoptosis and reduced cell proliferation in vitro, suppressed infection and metastasis, and restored chemosensitivity in vivo.	('reduced', 'NegReg', (63, 70))	('promoted', 'PosReg', (40, 48))	('infection', 'Disease', (111, 120))	('LDH-A', 'Gene', '3939', (23, 28))	('restored', 'PosReg', (141, 149))	('inhibiting', 'Var', (12, 22))	('LDH-A', 'Gene', (23, 28))	('chemosensitivity', 'CPA', (150, 166))	('suppressed', 'NegReg', (100, 110))	('infection', 'Disease', 'MESH:D007239', (111, 120))	('apoptosis', 'CPA', (49, 58))	('cell proliferation', 'CPA', (71, 89))
237856	29620641	Overexpression of LDH-A in cholangiocarcinoma was also correlated with poor prognosis.	('LDH-A', 'Gene', (18, 23))	('cholangiocarcinoma', 'Disease', (27, 45))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('Overexpression', 'Var', (0, 14))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (27, 45))	('LDH-A', 'Gene', '3939', (18, 23))
237857	29620641	The present study provides the basis for the future use of LDH-A inhibitors in leiomyosarcoma of the uterus.	('LDH-A', 'Gene', (59, 64))	('leiomyosarcoma of the uterus', 'Disease', 'MESH:D007890', (79, 107))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (79, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('inhibitors', 'Var', (65, 75))	('leiomyosarcoma of the uterus', 'Disease', (79, 107))	('LDH-A', 'Gene', '3939', (59, 64))
237894	29113426	Here in one rare case of undifferentiated cardiac intimal sarcoma (IS), a next-generation sequencing based assay, MSK-IMPACT (Memorial Sloan Kettering - Integrated Mutation Profiling of Actionable Cancer Targets), identified a somatic, activating mutation in PDGFRB, along with amplification of PDGFRA.	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('mutation', 'Var', (247, 255))	('PDGFRB', 'Gene', '5159', (259, 265))	('PDGFRB', 'Gene', (259, 265))	('PDGFRA', 'Gene', (295, 301))	('undifferentiated cardiac intimal sarcoma', 'Disease', 'MESH:D002277', (25, 65))	('undifferentiated cardiac intimal sarcoma', 'Disease', (25, 65))	('activating', 'PosReg', (236, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('PDGFRA', 'Gene', '5156', (295, 301))
237895	29113426	This E472D mutation of PDGFRB was discovered for the first time in IS.	('PDGFRB', 'Gene', '5159', (23, 29))	('E472D', 'Var', (5, 10))	('E472D', 'Mutation', 'rs947086492', (5, 10))	('PDGFRB', 'Gene', (23, 29))
237896	29113426	These findings suggest that concurrent aberrant PDGFRA and PDGFRB signaling may be a diagnostic biomarker and molecular therapeutic target of IS of the heart.	('PDGFRA', 'Gene', '5156', (48, 54))	('PDGFRB', 'Gene', '5159', (59, 65))	('IS of the heart', 'Disease', (142, 157))	('PDGFRA', 'Gene', (48, 54))	('PDGFRB', 'Gene', (59, 65))	('aberrant', 'Var', (39, 47))
237906	29113426	Previous molecular analysis of the few available IS cases revealed frequent concurrent amplification/activation of PDGFRA, EGFR and MDM2.	('EGFR', 'Gene', (123, 127))	('PDGFRA', 'Gene', '5156', (115, 121))	('PDGFRA', 'Gene', (115, 121))	('amplification/activation', 'Var', (87, 111))	('amplification/activation', 'PosReg', (87, 111))	('EGFR', 'Gene', '1956', (123, 127))	('MDM2', 'Gene', '4193', (132, 136))	('MDM2', 'Gene', (132, 136))
237908	29113426	Genomic screening of 410 key cancer genes using next-generation sequencing based MSKTM-IMPACT revealed somatic alterations in 3 important genes: PDGFRB, KMT2D and MPL, along with amplification or deletion of PDGFRA, MDM2, KIT, CDKN2Ap16INK4A, CDKN2Ap14ARF and CDKN2B.	('KMT2D', 'Gene', (153, 158))	('alterations', 'Reg', (111, 122))	('CDKN2A', 'Gene', (243, 249))	('INK4A', 'Gene', (236, 241))	('amplification', 'Var', (179, 192))	('CDKN2A', 'Gene', '1029', (227, 233))	('MDM2', 'Gene', (216, 220))	('deletion', 'Var', (196, 204))	('CDKN2B', 'Gene', (260, 266))	('CDKN2A', 'Gene', '1029', (243, 249))	('cancer', 'Disease', (29, 35))	('KMT2D', 'Gene', '8085', (153, 158))	('MDM2', 'Gene', '4193', (216, 220))	('PDGFRB', 'Gene', '5159', (145, 151))	('MPL', 'Gene', '4352', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('PDGFRA', 'Gene', (208, 214))	('PDGFRB', 'Gene', (145, 151))	('CDKN2B', 'Gene', '1030', (260, 266))	('PDGFRA', 'Gene', '5156', (208, 214))	('INK4A', 'Gene', '1029', (236, 241))	('KIT', 'Gene', (222, 225))	('CDKN2A', 'Gene', (227, 233))	('MPL', 'Gene', (163, 166))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
237909	29113426	The E472D missense mutation of PDGFRB was identified for the first time in any tumor and was accompanied by elevated levels of activated/phosphorylated PDGFRB.	('PDGFRB', 'Gene', '5159', (31, 37))	('tumor', 'Disease', (79, 84))	('PDGFRB', 'Gene', (31, 37))	('PDGFRB', 'Gene', '5159', (152, 158))	('E472D', 'Mutation', 'rs947086492', (4, 9))	('PDGFRB', 'Gene', (152, 158))	('E472D missense', 'Var', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('elevated', 'PosReg', (108, 116))	('levels of activated/phosphorylated', 'MPA', (117, 151))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
237920	29113426	Surprisingly, somatic mutations involving only 4 genes, PDGFRB, KMT2D, MPL and ZFHX3, were identified, namely, E472D for PDGFRB, A3618P for KMT2D, P453L for MPL, and Q3202-Q3204dup/G3511-G3512del for ZFHX3 (Figure 3).	('ZFHX3', 'Gene', '463', (79, 84))	('ZFHX3', 'Gene', (79, 84))	('KMT2D', 'Gene', '8085', (140, 145))	('MPL', 'Gene', '4352', (71, 74))	('A3618P', 'Mutation', 'p.A3618P', (129, 135))	('P453L', 'Mutation', 'rs750469665', (147, 152))	('A3618P', 'Var', (129, 135))	('KMT2D', 'Gene', (64, 69))	('Q3202-Q3204dup/G3511-G3512del', 'Mutation', 'p.3202,3512delQ3204,G', (166, 195))	('MPL', 'Gene', '4352', (157, 160))	('MPL', 'Gene', (71, 74))	('P453L', 'Var', (147, 152))	('Q3202-Q3204dup/G3511-G3512del', 'Var', (166, 195))	('PDGFRB', 'Gene', '5159', (121, 127))	('E472D', 'Var', (111, 116))	('PDGFRB', 'Gene', (121, 127))	('KMT2D', 'Gene', (140, 145))	('PDGFRB', 'Gene', '5159', (56, 62))	('PDGFRB', 'Gene', (56, 62))	('MPL', 'Gene', (157, 160))	('KMT2D', 'Gene', '8085', (64, 69))	('ZFHX3', 'Gene', '463', (200, 205))	('E472D', 'Mutation', 'rs947086492', (111, 116))	('ZFHX3', 'Gene', (200, 205))
237921	29113426	By comparing against gnomAD.org human SNPs database, we excluded the ZFHX3 mutations as normal variants.	('ZFHX3', 'Gene', '463', (69, 74))	('ZFHX3', 'Gene', (69, 74))	('mutations', 'Var', (75, 84))	('AD', 'Disease', 'MESH:D000544', (25, 27))	('human', 'Species', '9606', (32, 37))	('AD', 'Disease', (25, 27))
237923	29113426	Aberrant PDGFR (A/B) signaling due to gene amplification has been suggested as a potential molecular signature of IS.	('gene amplification', 'Var', (38, 56))	('Aberrant', 'Var', (0, 8))	('PDGFR (A/B', 'Gene', '5156;5159', (9, 19))
237924	29113426	One potentially activating point mutation of PDGFRB has recently been found.	('PDGFRB', 'Gene', '5159', (45, 51))	('PDGFRB', 'Gene', (45, 51))	('activating', 'PosReg', (16, 26))	('point mutation', 'Var', (27, 41))
237933	29113426	Tumors were profiled for genomic alterations in 410 key cancer-associated genes using our custom, deep sequencing MSK-IMPACT assay.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('genomic alterations', 'Var', (25, 44))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
237937	29113426	Unpaired-sample variant calling was performed on tumor sample and control normals to identify point mutations/single nucleotide variants (SNVs) and small insertions/deletion (indels).	('point mutations/single', 'Var', (94, 116))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (49, 54))
237941	29113426	well-characterized hotspot mutations) were considered in a separate class from novel second-tier variants -first-tier variants were filtered using the following criteria: DP >= 20X, AD >= 8 and VF >= 2%, compared to second-tier variants: DP >= 20X, AD >= 10 and VF >= 5%.	('DP', 'Chemical', '-', (171, 173))	('DP >= 20X', 'Var', (171, 180))	('VF', 'Disease', 'MESH:D014693', (262, 264))	('AD', 'Disease', 'MESH:D000544', (249, 251))	('AD', 'Disease', (249, 251))	('VF', 'Disease', 'MESH:D014693', (194, 196))	('AD', 'Disease', 'MESH:D000544', (182, 184))	('DP', 'Chemical', '-', (238, 240))	('AD', 'Disease', (182, 184))
237943	29113426	The E472D missense mutation of PDGFRB was confirmed by genomic locus PCR and Sanger sequencing.	('PDGFRB', 'Gene', (31, 37))	('PDGFRB', 'Gene', '5159', (31, 37))	('E472D', 'Mutation', 'rs947086492', (4, 9))	('E472D missense', 'Var', (4, 18))
237944	29113426	Primers used for PCR and Sanger sequencing are: E472D_1F:TCTGCCTCTACCCCATACGC; E472D_1R: GGGCACATTACCAATTAGGCAG.	('E472D', 'Mutation', 'rs947086492', (79, 84))	('E472D', 'Mutation', 'rs947086492', (48, 53))	('E472D_1F', 'Var', (48, 56))	('E472D_1R', 'Var', (79, 87))
237954	29113426	Five small study series of IS have demonstrated that amplification/activation of PDGFRA/B, EGFR, and MDM2 are common findings in IS.	('EGFR', 'Gene', (91, 95))	('PDGFRA', 'Gene', '5156', (81, 87))	('PDGFRA', 'Gene', (81, 87))	('amplification/activation', 'Var', (53, 77))	('MDM2', 'Gene', '4193', (101, 105))	('EGFR', 'Gene', '1956', (91, 95))	('MDM2', 'Gene', (101, 105))	('amplification/activation', 'PosReg', (53, 77))
237964	29113426	Consistent with previous study results, our gene copy number analysis in this IS case revealed genomic amplification of PDGFRA, MDM2, KIT, and deletion of CDKN2A and CDKN2B, reiterating such variations as molecular characteristics of IS.	('CDKN2A', 'Gene', '1029', (155, 161))	('CDKN2B', 'Gene', (166, 172))	('deletion', 'Var', (143, 151))	('CDKN2B', 'Gene', '1030', (166, 172))	('CDKN2A', 'Gene', (155, 161))	('MDM2', 'Gene', '4193', (128, 132))	('MDM2', 'Gene', (128, 132))	('KIT', 'Gene', (134, 137))	('PDGFRA', 'Gene', '5156', (120, 126))	('PDGFRA', 'Gene', (120, 126))
237965	29113426	The nonsynonymous mutations in PDGFRB, KMT2D and MPL are a unique finding in this study.	('PDGFRB', 'Gene', '5159', (31, 37))	('KMT2D', 'Gene', '8085', (39, 44))	('KMT2D', 'Gene', (39, 44))	('nonsynonymous mutations', 'Var', (4, 27))	('MPL', 'Gene', '4352', (49, 52))	('PDGFRB', 'Gene', (31, 37))	('MPL', 'Gene', (49, 52))
237967	29113426	Aberrant activation of PDGFR signaling due to gene amplification, translocation and activating mutation, has been found in various solid tumors.	('activation', 'PosReg', (9, 19))	('solid tumors', 'Disease', 'MESH:D009369', (131, 143))	('gene amplification', 'Var', (46, 64))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('PDGFR', 'Gene', (23, 28))	('translocation', 'Var', (66, 79))	('PDGFR', 'Gene', '5159', (23, 28))	('activating', 'MPA', (84, 94))	('solid tumors', 'Disease', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
237968	29113426	Limited number of small series studies (7-21 cases), as well as one recent large cohort (100 cases, the largest so far), have identified dysregulated PDGFR (A and B) activity as a possible unique molecular feature of IS.	('activity', 'MPA', (166, 174))	('dysregulated', 'Var', (137, 149))	('PDGFR (A and B', 'Gene', '5156;5159', (150, 164))
237970	29113426	A recent IS case report by Ito et al uncovered a PDGFRB R709H point mutation, which is located in the kinase domain of the protein, implying it may activate PDGFRB signaling.	('PDGFRB', 'Gene', (157, 163))	('PDGFRB', 'Gene', '5159', (49, 55))	('R709H', 'Var', (56, 61))	('PDGFRB', 'Gene', (49, 55))	('activate', 'PosReg', (148, 156))	('R709H', 'Mutation', 'rs759436020', (56, 61))	('PDGFRB', 'Gene', '5159', (157, 163))
237971	29113426	Our current case of IS has identified a novel missense mutation in PDGFRB, E472D.	('PDGFRB', 'Gene', '5159', (67, 73))	('E472D', 'Mutation', 'rs947086492', (75, 80))	('E472D', 'Var', (75, 80))	('PDGFRB', 'Gene', (67, 73))
237972	29113426	We further showed that in this IS tumor, PDGFRB protein was consistently activated (phosphorylated), strongly suggesting E472D be an activating mutation in maintaining aberrant PDGFRB signaling in IS.	('PDGFRB', 'Gene', '5159', (41, 47))	('tumor', 'Disease', (34, 39))	('PDGFRB', 'Gene', (41, 47))	('E472D', 'Var', (121, 126))	('PDGFRB', 'Gene', '5159', (177, 183))	('PDGFRB', 'Gene', (177, 183))	('E472D', 'Mutation', 'rs947086492', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('activated', 'PosReg', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
237975	29113426	We speculate that the replacement of glutamic acid with aspartic acid at position 472 might provide a shorter salt bridge for domain-domain interaction, resulting in persistent activation of downstream signaling.	('shorter', 'NegReg', (102, 109))	('glutamic acid', 'Protein', (37, 50))	('glutamic acid with aspartic acid at position 472', 'Mutation', 'rs947086492', (37, 85))	('activation', 'PosReg', (177, 187))	('downstream signaling', 'MPA', (191, 211))	('replacement', 'Var', (22, 33))	('salt bridge for domain-domain interaction', 'MPA', (110, 151))
237976	29113426	Although PDGFRA was found by others to be predominantly amplified/activated in IS, our discovery of a novel, potentially activating PDGFRB mutation, concurrently with PDGFRA amplification, substantiates the forming concept of considering PDGFR signaling as an IS-specific diagnostic biomarker.	('PDGFR', 'Gene', (9, 14))	('PDGFR', 'Gene', '5159', (9, 14))	('mutation', 'Var', (139, 147))	('PDGFR', 'Gene', (132, 137))	('PDGFR', 'Gene', (238, 243))	('PDGFR', 'Gene', (167, 172))	('activating', 'PosReg', (121, 131))	('PDGFRA', 'Gene', (9, 15))	('PDGFR', 'Gene', '5159', (238, 243))	('PDGFRB', 'Gene', '5159', (132, 138))	('PDGFRA', 'Gene', '5156', (9, 15))	('PDGFR', 'Gene', '5159', (132, 137))	('PDGFRB', 'Gene', (132, 138))	('PDGFRA', 'Gene', '5156', (167, 173))	('PDGFR', 'Gene', '5159', (167, 172))	('PDGFRA', 'Gene', (167, 173))
237980	29113426	Mutations of MPL have been identified in myeloproliferative neoplasms.	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (41, 69))	('identified', 'Reg', (27, 37))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (41, 69))	('MPL', 'Gene', (13, 16))	('neoplasms', 'Phenotype', 'HP:0002664', (60, 69))	('Mutations', 'Var', (0, 9))	('myeloproliferative neoplasms', 'Disease', (41, 69))	('MPL', 'Gene', '4352', (13, 16))	('neoplasm', 'Phenotype', 'HP:0002664', (60, 68))
237981	29113426	The P453L missense mutation, a novel alteration identified in this case of IS, is located in the Ig FN3 domain of MPL protein, implying the interaction of MPL with other factors might be affected.	('missense', 'Var', (10, 18))	('P453L missense', 'Var', (4, 18))	('MPL', 'Gene', '4352', (155, 158))	('MPL', 'Gene', '4352', (114, 117))	('MPL', 'Gene', (155, 158))	('P453L', 'Mutation', 'rs750469665', (4, 9))	('MPL', 'Gene', (114, 117))
237983	29113426	KMT2D inactivating mutations have been found in a variety of solid tumors, including cardiac angiosarcoma.	('cardiac angiosarcoma', 'Disease', 'MESH:D006394', (85, 105))	('solid tumors', 'Disease', (61, 73))	('found', 'Reg', (39, 44))	('cardiac angiosarcoma', 'Disease', (85, 105))	('solid tumors', 'Disease', 'MESH:D009369', (61, 73))	('angiosarcoma', 'Phenotype', 'HP:0200058', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('KMT2D', 'Gene', (0, 5))	('KMT2D', 'Gene', '8085', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('inactivating mutations', 'Var', (6, 28))
237984	29113426	Novel A3618P mutation detected in this case of IS does not fall in any functional domain of KMT2D, and its functional consequence remains to be clarified.	('A3618P', 'Mutation', 'p.A3618P', (6, 12))	('KMT2D', 'Gene', '8085', (92, 97))	('fall', 'Phenotype', 'HP:0002527', (59, 63))	('A3618P', 'Var', (6, 12))	('KMT2D', 'Gene', (92, 97))
238014	28423517	The previously reported EWSR1-NR4A3 translocation was identified in all patient tumors; however, other recurring genomic abnormalities were not detected.	('NR4A3', 'Gene', '8013', (30, 35))	('EWSR1', 'Gene', (24, 29))	('NR4A3', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('EWSR1', 'Gene', '2130', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('patient', 'Species', '9606', (72, 79))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('translocation', 'Var', (36, 49))
238041	28423517	Exome copy number analysis did not detect clinically significant focal amplifications or deletions; however, copy gains of chr1q and 8q, copy losses chr6q and 8p, and one copy loss of ARID1B, MYB, CDKN2A, CDKN2B among others were observed (Figure 2).	('ARID1B', 'Gene', (184, 190))	('loss', 'NegReg', (176, 180))	('CDKN2A', 'Gene', (197, 203))	('MYB', 'Gene', (192, 195))	('chr6q', 'Var', (149, 154))	('CDKN2B', 'Gene', (205, 211))	('gains', 'PosReg', (114, 119))	('CDKN2B', 'Gene', '1030', (205, 211))	('CDKN2A', 'Gene', '1029', (197, 203))	('MYB', 'Gene', '4602', (192, 195))	('ARID1B', 'Gene', '57492', (184, 190))	('copy losses chr6q', 'Var', (137, 154))	('chr1q', 'Gene', (123, 128))
238049	28423517	For example, genomic evaluation of 86 patients with liposarcoma identified amplification of specific genes on chromosome 12q (previously known to be amplified) as well as recurrent mutations in 7 genes, many with downstream pathways that could potentially be targeted.	('liposarcoma', 'Phenotype', 'HP:0012034', (52, 63))	('liposarcoma', 'Disease', 'MESH:D008080', (52, 63))	('amplification', 'MPA', (75, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('man', 'Species', '9606', (203, 206))	('mutations', 'Var', (181, 190))	('patients', 'Species', '9606', (38, 46))	('liposarcoma', 'Disease', (52, 63))
238050	28423517	A similar study of 54 patients with leiomyosarcoma revealed recurrent mutations in TP53 and ATRX genes.	('TP53', 'Gene', '7157', (83, 87))	('ATRX', 'Gene', (92, 96))	('mutations', 'Var', (70, 79))	('leiomyosarcoma', 'Disease', (36, 50))	('ATRX', 'Gene', '546', (92, 96))	('TP53', 'Gene', (83, 87))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (36, 50))	('patients', 'Species', '9606', (22, 30))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (36, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
238054	28423517	Potential explanations include the limited sample size or that a specific class of molecular aberrations in EMC, such as aberrant methylation signatures (not a component of the MI-ONCOSEQ integrative analysis), has not been identified.	('aberrant', 'Var', (121, 129))	('MI-ONCOSEQ', 'Chemical', '-', (177, 187))	('EMC', 'Gene', (108, 111))	('methylation signatures', 'MPA', (130, 152))
238056	28423517	Specifically, EMCs with variant NR4A3 gene fusions demonstrate a clinically more aggressive phenotype than EMCs with the classic EWSR1-NR4A3 fusion.	('aggressive phenotype', 'CPA', (81, 101))	('fusions', 'Var', (43, 50))	('NR4A3', 'Gene', '8013', (135, 140))	('EWSR1', 'Gene', (129, 134))	('NR4A3', 'Gene', '8013', (32, 37))	('NR4A3', 'Gene', (135, 140))	('variant', 'Var', (24, 31))	('more', 'PosReg', (76, 80))	('NR4A3', 'Gene', (32, 37))	('EWSR1', 'Gene', '2130', (129, 134))
238058	28423517	EMCs with variant fusions had increased cellularity, proliferation, and atypia including plasmacytoid/rhabdoid morphology in 50% of cases.	('rhabdoid', 'Disease', 'MESH:D018335', (102, 110))	('variant fusions', 'Var', (10, 25))	('rhabdoid', 'Disease', (102, 110))	('proliferation', 'CPA', (53, 66))	('cellularity', 'CPA', (40, 51))	('increased', 'PosReg', (30, 39))	('atypia', 'CPA', (72, 78))
238060	28423517	The finding of a more aggressive phenotype with the variant fusion corroborates the previously mentioned study of sunitinib in EMC.	('aggressive', 'CPA', (22, 32))	('sunitinib', 'Chemical', 'MESH:D000077210', (114, 123))	('variant fusion', 'Var', (52, 66))
238062	28423517	Given that our study did not include patients with variant fusions, there may be genetic aberrations in these EMCs that we did not identify.	('genetic aberrations', 'Disease', (81, 100))	('patients', 'Species', '9606', (37, 45))	('genetic aberrations', 'Disease', 'MESH:D030342', (81, 100))	('variant', 'Var', (51, 58))
238086	28423517	MI-ONCOSEQ bioinformatic pipelines are used to detect the following classes of mutations: somatic and germline variant calls including single-nucleotide variants and insertion/deletions (indels), copy number alterations, gene fusions and outlier gene expression.	('single-nucleotide variants', 'Var', (135, 161))	('copy number alterations', 'Var', (196, 219))	('insertion/deletions', 'Var', (166, 185))	('gene', 'CPA', (221, 225))	('MI-ONCOSEQ', 'Chemical', '-', (0, 10))
238087	28423517	Potentially actionable mutations are defined as any genomic findings discovered during sequencing that could lead to a (1) change in patient management by providing a targetable molecular aberration; (2) change in diagnosis or risk stratification and/or; (3) cancer-related germline findings that inform about a potential cancer risk to patient family members.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('lead to', 'Reg', (109, 116))	('inform', 'Reg', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('change', 'Reg', (123, 129))	('cancer', 'Disease', (322, 328))	('patient', 'Species', '9606', (133, 140))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('change', 'Reg', (204, 210))	('patient', 'Species', '9606', (337, 344))	('man', 'Species', '9606', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('cancer', 'Disease', (259, 265))
238097	27735949	However, when starvation was simultaneously prolonged by ADI-PEG20 while inhibited by the clinically available drug chloroquine, sarcoma cells died via necroptosis and apoptosis.	('chloroquine', 'Chemical', 'MESH:D002738', (116, 127))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (57, 66))	('apoptosis', 'CPA', (168, 177))	('necroptosis', 'CPA', (152, 163))	('sarcoma', 'Disease', (129, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('ADI-PEG20', 'Var', (57, 66))
238100	27735949	p53 mutations, which affect approximately ~50% of sarcomas, so far remain undruggable.	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (0, 3))	('sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('mutations', 'Var', (4, 13))	('sarcomas', 'Disease', (50, 58))
238104	27735949	As arginine is a semi-essential amino acid, the loss of ASS1 makes cells dependent on extracellular sources of arginine for survival, a state referred to as arginine auxotrophy.	('loss', 'Var', (48, 52))	('ASS1', 'Gene', (56, 60))	('arginine', 'Chemical', 'MESH:D001120', (157, 165))	('ASS1', 'Gene', '445', (56, 60))	('arginine', 'Chemical', 'MESH:D001120', (3, 11))	('arginine', 'Chemical', 'MESH:D001120', (111, 119))
238108	27735949	ADI-PEG20 (pegylated arginine deiminase), a stabilized soluble form of arginine deiminase, depletes available stores of extracellular arginine and induces a metabolic stress in cells that are deficient in ASS1.	('ASS1', 'Gene', '445', (205, 209))	('ASS1', 'Gene', (205, 209))	('arginine', 'Chemical', 'MESH:D001120', (71, 79))	('ADI-PEG20', 'Var', (0, 9))	('induces', 'Reg', (147, 154))	('arginine', 'Chemical', 'MESH:D001120', (134, 142))	('depletes', 'NegReg', (91, 99))	('arginine', 'Chemical', 'MESH:D001120', (21, 29))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (0, 9))	('metabolic stress', 'MPA', (157, 173))
238109	27735949	The consequence of metabolic stress, such as that induced by ADI-PEG20, is usually transient autophagy, a cell survival pathway, which, in the case of arginine auxotrophs, acts primarily as a holding station to apoptosis.	('ADI-PEG20', 'Var', (61, 70))	('arginine', 'Chemical', 'MESH:D001120', (151, 159))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (61, 70))	('cell survival pathway', 'CPA', (106, 127))
238110	27735949	In pre-clinical studies, arginine depletion by ADI-PEG20 alone is lethal in several arginine auxotrophic cancers such as prostate, breast, T-cell lymphoma and mesothelioma.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (139, 154))	('T-cell lymphoma', 'Disease', (139, 154))	('cell lymphoma', 'Phenotype', 'HP:0012191', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('auxotrophic cancers', 'Disease', 'MESH:D009369', (93, 112))	('arginine', 'Chemical', 'MESH:D001120', (25, 33))	('mesothelioma', 'Disease', (159, 171))	('breast', 'Disease', (131, 137))	('mesothelioma', 'Disease', 'MESH:D008654', (159, 171))	('arginine depletion', 'MPA', (25, 43))	('lethal', 'Reg', (66, 72))	('auxotrophic cancers', 'Disease', (93, 112))	('ADI-PEG20', 'Var', (47, 56))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (139, 154))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (47, 56))	('prostate', 'Disease', (121, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (146, 154))	('arginine', 'Chemical', 'MESH:D001120', (84, 92))
238111	27735949	Indeed, clinical trials of ADI-PEG20 are underway in hepatocellular carcinoma, acute myeloid leukemia, non-small cell lung cancer, non-Hodgkin's lymphoma, breast carcinoma, melanoma and mesothelioma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast carcinoma', 'Disease', (155, 171))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (53, 77))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (103, 129))	('melanoma and mesothelioma', 'Disease', 'MESH:D008654', (173, 198))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (79, 101))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (79, 101))	('leukemia', 'Phenotype', 'HP:0001909', (93, 101))	('ADI-PEG20', 'Var', (27, 36))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 77))	('non-small cell lung cancer', 'Disease', (103, 129))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (27, 36))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (131, 153))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (85, 101))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('breast carcinoma', 'Disease', 'MESH:D001943', (155, 171))	('hepatocellular carcinoma', 'Disease', (53, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (131, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (135, 153))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (103, 129))	('acute myeloid leukemia', 'Disease', (79, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	("non-Hodgkin's lymphoma", 'Disease', (131, 153))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))	('breast carcinoma', 'Phenotype', 'HP:0003002', (155, 171))
238128	27735949	To examine the consequences of targeting this identified arginine auxotrophy in sarcoma, we measured cell numbers of the 15 sarcoma cell lines upon treating with a wide range of concentrations of ADI-PEG20 over a time course of 3 days.	('arginine', 'Chemical', 'MESH:D001120', (57, 65))	('sarcoma', 'Disease', (124, 131))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('ADI-PEG20', 'Var', (196, 205))	('sarcoma', 'Disease', (80, 87))	('arginine', 'MPA', (57, 65))	('15 sarcoma', 'Disease', (121, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('15 sarcoma', 'Disease', 'MESH:D012509', (121, 131))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (196, 205))
238131	27735949	Not surprisingly, ASS1 expression levels correlated with ADI-PEG20 IC50 values among our panel of sarcoma cell lines (R2=0.95, 95% CI: 0.89-0.99; P<0.001) (Figure 2c).	('ASS1', 'Gene', (18, 22))	('ASS1', 'Gene', '445', (18, 22))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (57, 66))	('sarcoma', 'Disease', (98, 105))	('expression levels', 'MPA', (23, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('ADI-PEG20', 'Var', (57, 66))
238135	27735949	Thus, unlike other cancer cell lines deficient in ASS1 expression where treatment with ADI-PEG20 is lethal, exploitation of arginine auxotrophy by ADI-PEG20 in sarcoma cell lines results in cytostasis instead.	('ADI-PEG20', 'Chemical', 'MESH:C512527', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('arginine auxotrophy', 'MPA', (124, 143))	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('ASS1', 'Gene', (50, 54))	('cancer', 'Disease', (19, 25))	('ASS1', 'Gene', '445', (50, 54))	('ADI-PEG20', 'Var', (147, 156))	('results in', 'Reg', (179, 189))	('sarcoma', 'Disease', (160, 167))	('arginine', 'Chemical', 'MESH:D001120', (124, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (87, 96))	('cytostasis', 'MPA', (190, 200))
238137	27735949	To determine which of these fates occurred in the case of sarcoma, we performed an in vivo xenograft tumor experiment using the SK-LMS-1 cell line and measured the effects of ADI-PEG20 exposure (see Materials and methods section) on tumor growth and ASS1 expression.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (233, 238))	('ADI-PEG20', 'Var', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('ASS1', 'Gene', (250, 254))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('ASS1', 'Gene', '445', (250, 254))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('sarcoma', 'Disease', (58, 65))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (128, 136))
238138	27735949	Although ADI-PEG20 significantly retarded tumor growth, a slow and small increase in tumor size was observed over time.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (42, 47))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (9, 18))	('retarded tumor', 'Disease', 'MESH:D009369', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('retarded tumor', 'Disease', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ADI-PEG20', 'Var', (9, 18))
238141	27735949	Hypermethylation of the transcription promoter is a common mechanism responsible for the loss of ASS1 expression in several cancers, and previous data suggests that this is indeed the mechanism behind ASS1 silencing in myofibrosarcomas.	('ASS1', 'Gene', (97, 101))	('silencing', 'NegReg', (206, 215))	('ASS1', 'Gene', (201, 205))	('ASS1', 'Gene', '445', (97, 101))	('ASS1', 'Gene', '445', (201, 205))	('expression', 'MPA', (102, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (227, 235))	('Hypermethylation', 'Var', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('myofibrosarcomas', 'Disease', (219, 235))	('myofibrosarcomas', 'Disease', 'None', (219, 235))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('loss', 'NegReg', (89, 93))
238143	27735949	We were unable to investigate whether the loss of ASS1 expression is also because of hypermethylation of the promoter in MNNG/HOS and SK-UT-1 cells, because both cell lines died after exposure to the combination of ADI-PEG20 and 5-aza-dC.	('ADI-PEG20', 'Var', (215, 224))	('ASS1', 'Gene', (50, 54))	('ASS1', 'Gene', '445', (50, 54))	('expression', 'MPA', (55, 65))	('SK-UT-1', 'CellLine', 'CVCL:0533', (134, 141))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (215, 224))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (229, 237))	('loss', 'NegReg', (42, 46))
238144	27735949	Together, these data suggest that treatment of sarcoma cells with ADI-PEG20 may induce a prolonged state of starvation before re-expression of ASS1.	('ADI-PEG20', 'Chemical', 'MESH:C512527', (66, 75))	('prolonged state of starvation', 'MPA', (89, 118))	('induce', 'Reg', (80, 86))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('ASS1', 'Gene', (143, 147))	('ADI-PEG20', 'Var', (66, 75))	('ASS1', 'Gene', '445', (143, 147))	('sarcoma', 'Disease', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
238145	27735949	To test this hypothesis, we analyzed markers of autophagy by immunoblotting of whole-cell lysates over 3 days of ADI-PEG20 treatment in the ASS1low sarcoma cell line SK-LMS1.	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('SK-LMS1', 'CellLine', 'CVCL:0628', (166, 173))	('ADI-PEG20', 'Var', (113, 122))	('sarcoma', 'Disease', (148, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('ASS1', 'Gene', (140, 144))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (113, 122))	('ASS1', 'Gene', '445', (140, 144))
238146	27735949	The results showed that, after a treatment with 1 mug/ml ADI-PEG20, there was an increase in autophagic flux, upon the addition of bafilomycin as compared with ADI-PEG20 treatment alone (Figure 4a).	('autophagic flux', 'CPA', (93, 108))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (160, 169))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (57, 66))	('bafilomycin', 'Chemical', '-', (131, 142))	('increase', 'PosReg', (81, 89))	('ADI-PEG20', 'Var', (57, 66))
238149	27735949	We observed a marked increase in the number of GFP-LC3 puncta, representing autophagosomes, in ADI-PEG20-treated cells relative to untreated cells.	('LC3', 'Gene', '84557', (51, 54))	('ADI-PEG20-treated', 'Var', (95, 112))	('LC3', 'Gene', (51, 54))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (95, 104))	('increase', 'PosReg', (21, 29))
238150	27735949	To verify autophagy induction, we combined ADI-PEG20 with chloroquine, which inhibits the formation of the autophagolysosome within the last steps of the autophagy process.	('chloroquine', 'Chemical', 'MESH:D002738', (58, 69))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (43, 52))	('inhibits', 'NegReg', (77, 85))	('ADI-PEG20', 'Var', (43, 52))
238151	27735949	SK-LMS-1 cells were treated with 1 mug/ml ADI-PEG20, 20 muM chloroquine or both.	('chloroquine', 'Chemical', 'MESH:D002738', (60, 71))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (42, 51))	('muM', 'Gene', '56925', (56, 59))	('ADI-PEG20', 'Var', (42, 51))	('muM', 'Gene', (56, 59))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (0, 8))
238154	27735949	Inhibition of autophagy by treatment with 50 muM Pepstatin A and 25 muM E64D also caused a significant increase in cell death when paired with ADI-PEG20 treatment (Figure 4e).	('autophagy', 'CPA', (14, 23))	('E64D', 'Var', (72, 76))	('E64D', 'Mutation', 'p.E64D', (72, 76))	('muM', 'Gene', (68, 71))	('Inhibition', 'NegReg', (0, 10))	('muM', 'Gene', '56925', (45, 48))	('muM', 'Gene', (45, 48))	('cell death', 'CPA', (115, 125))	('Pepstatin A', 'Chemical', 'MESH:C031375', (49, 60))	('muM', 'Gene', '56925', (68, 71))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (143, 152))
238157	27735949	Next, we investigated the mechanism of cell death induced through simultaneous starvation induction with ADI-PEG20 and chloroquine in two ASS1low sarcoma cell lines (SK-LMS-1 and MNNG/HOS).	('ASS1', 'Gene', (138, 142))	('chloroquine', 'Chemical', 'MESH:D002738', (119, 130))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (166, 174))	('ASS1', 'Gene', '445', (138, 142))	('ADI-PEG20', 'Var', (105, 114))	('sarcoma', 'Disease', (146, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (105, 114))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
238158	27735949	The cells were treated with 1 mug/ml ADI-PEG20, 20 muM of chloroquine or both.	('muM', 'Gene', '56925', (51, 54))	('chloroquine', 'Chemical', 'MESH:D002738', (58, 69))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (37, 46))	('muM', 'Gene', (51, 54))	('ADI-PEG20', 'Var', (37, 46))
238160	27735949	Although either ZVAD or necrostatin was capable of partial protection from cell death induced by ADI-PEG20 plus chloroquine treatment, necrostatin was more effective (Figure 5a), implicating necroptosis as the dominant form of cell death.	('necrostatin', 'Chemical', '-', (135, 146))	('cell death', 'CPA', (75, 85))	('chloroquine', 'Chemical', 'MESH:D002738', (112, 123))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (97, 106))	('ZVAD', 'Chemical', '-', (16, 20))	('necrostatin', 'Chemical', '-', (24, 35))	('ADI-PEG20', 'Var', (97, 106))
238161	27735949	Protection from ADI-PEG20 and chloroquine-induced cell death also resulted following shRNA-mediated knockdown of receptor-interacting protein 1 (RIP1) or RIP3, further suggesting necroptosis as the mechanism of cell death upon treatment with ADI-PEG20 and chloroquine (Figure 5b).	('knockdown', 'Var', (100, 109))	('RIP1', 'Gene', (145, 149))	('receptor-interacting protein 1', 'Gene', (113, 143))	('necroptosis', 'CPA', (179, 190))	('RIP3', 'Gene', '11035', (154, 158))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (242, 251))	('receptor-interacting protein 1', 'Gene', '8737', (113, 143))	('RIP1', 'Gene', '8737', (145, 149))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (16, 25))	('RIP3', 'Gene', (154, 158))	('cell', 'CPA', (50, 54))	('chloroquine', 'Chemical', 'MESH:D002738', (30, 41))	('chloroquine', 'Chemical', 'MESH:D002738', (256, 267))
238164	27735949	Although active caspase 8 can signal to downstream effector caspases to induce apoptosis, it can also cleave and functionally inactivate RIP1 and RIP3 kinases that are essential in signaling the initiation of necroptosis.	('cleave', 'Var', (102, 108))	('inactivate', 'NegReg', (126, 136))	('induce', 'PosReg', (72, 78))	('caspase 8', 'Gene', '841', (16, 25))	('apoptosis', 'CPA', (79, 88))	('RIP1', 'Gene', (137, 141))	('RIP3', 'Gene', '11035', (146, 150))	('RIP1', 'Gene', '8737', (137, 141))	('caspase 8', 'Gene', (16, 25))	('RIP3', 'Gene', (146, 150))
238165	27735949	As such, when caspase 8 is functionally inactive, because of decreased protein abundance, genetic mutation or pharmacological inhibition by ZVAD, RIP kinases maintain signal transduction ability, leading to the induction of necroptosis (Supplementary Figure S1).	('RIP', 'Gene', (146, 149))	('caspase 8', 'Gene', (14, 23))	('protein abundance', 'MPA', (71, 88))	('ZVAD', 'Chemical', '-', (140, 144))	('signal transduction ability', 'MPA', (167, 194))	('decreased', 'NegReg', (61, 70))	('caspase 8', 'Gene', '841', (14, 23))	('induction', 'Reg', (211, 220))	('genetic mutation', 'Var', (90, 106))	('necroptosis', 'Disease', (224, 235))	('RIP', 'Gene', '8737', (146, 149))
238166	27735949	Autophagy serves as a form of triage in which the cell chooses to utilize certain proteins for fuel, which it deems dispensable during starvation and we suspected that ADI-PEG20 would alter the complement of proteins in favor of necroptosis rather than apoptosis.	('complement of proteins', 'MPA', (194, 216))	('ADI-PEG20', 'Var', (168, 177))	('necroptosis', 'CPA', (229, 240))	('alter', 'Reg', (184, 189))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (168, 177))
238168	27735949	Immunoblots of lysates of cells treated with ADI-PEG20 alone showed that cleaved poly ADP ribose polymerase (PARP) and BCL2 remained constant (Supplementary Figure S2).	('BCL2', 'Gene', (119, 123))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (45, 54))	('PARP', 'Gene', '142', (109, 113))	('poly ADP ribose polymerase', 'Gene', '142', (81, 107))	('ADI-PEG20', 'Var', (45, 54))	('poly ADP ribose polymerase', 'Gene', (81, 107))	('BCL2', 'Gene', '596', (119, 123))	('PARP', 'Gene', (109, 113))
238170	27735949	The loss of cIAP1 primes cells for ripoptosome formation.	('primes', 'Reg', (18, 24))	('cIAP1', 'Gene', (12, 17))	('cIAP1', 'Gene', '329', (12, 17))	('ripoptosome formation', 'CPA', (35, 56))	('loss', 'Var', (4, 8))
238173	27735949	Analysis of protein levels at 24, 48 and 72 h of ADI-PEG20 and chloroquine treatment showed a significant decrease in cIAP1, full length and cleaved caspase 3, and full length and cleaved RIP1 (Figure 5c).	('cleaved', 'MPA', (180, 187))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (49, 58))	('caspase 3', 'Gene', (149, 158))	('decrease', 'NegReg', (106, 114))	('caspase 3', 'Gene', '836', (149, 158))	('RIP1', 'Gene', (188, 192))	('chloroquine', 'Chemical', 'MESH:D002738', (63, 74))	('cIAP1', 'Gene', '329', (118, 123))	('cIAP1', 'Gene', (118, 123))	('full', 'MPA', (125, 129))	('cleaved', 'MPA', (141, 148))	('ADI-PEG20', 'Var', (49, 58))	('RIP1', 'Gene', '8737', (188, 192))
238176	27735949	Interestingly, the protein levels seen in cells treated with the combination of ADI-PEG20 and chloroquine on day 3 were virtually identical to those present in cells treated with ADI-PEG20 alone (Supplementary Figure S2).	('ADI-PEG20', 'Chemical', 'MESH:C512527', (80, 89))	('protein levels', 'MPA', (19, 33))	('chloroquine', 'Chemical', 'MESH:D002738', (94, 105))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (179, 188))	('ADI-PEG20', 'Var', (80, 89))
238191	27735949	The above observations suggested that both ADI-PEG20 and chloroquine would be needed to produce an antitumor effect in vivo.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (43, 52))	('chloroquine', 'Chemical', 'MESH:D002738', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('ADI-PEG20', 'Var', (43, 52))
238195	27735949	After injection of the MNNG/HOS osteosarcoma cell line, mice were treated with PBS control, ADI-PEG20, chloroquine or a combination of the two for 24 days.	('ADI-PEG20', 'Var', (92, 101))	('HOS osteosarcoma', 'Disease', 'MESH:C535326', (28, 44))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (92, 101))	('chloroquine', 'Chemical', 'MESH:D002738', (103, 114))	('mice', 'Species', '10090', (56, 60))	('PBS', 'Chemical', 'MESH:D007854', (79, 82))	('osteosarcoma', 'Phenotype', 'HP:0002669', (32, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('HOS osteosarcoma', 'Disease', (28, 44))
238196	27735949	We found that, at doses effective for other tumors, single-agent chloroquine had no effect on sarcoma tumor growth, whereas the single-agent treatment with ADI-PEG20 delayed and reduced tumor growth.	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (156, 165))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('chloroquine', 'Chemical', 'MESH:D002738', (65, 76))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('sarcoma tumor', 'Disease', (94, 107))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (102, 107))	('sarcoma tumor', 'Disease', 'MESH:D012509', (94, 107))	('tumors', 'Disease', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('ADI-PEG20', 'Var', (156, 165))	('reduced', 'NegReg', (178, 185))
238204	27735949	Genetically, sarcomas frequently have mutations in p53 (50%), Rb (to a lesser extent) and occasional PI3K mutations (<1%), but none of the mutations identified in sarcoma (other than gastrointestinal stromal tumor (GIST) with cKIT and PDGF mutations) is either druggable or is high-frequency treatment targets.	('sarcomas', 'Disease', (13, 21))	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('sarcoma', 'Disease', (163, 170))	('gastrointestinal stromal tumor', 'Disease', (183, 213))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (183, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (183, 213))	('sarcoma', 'Disease', 'MESH:D012509', (13, 20))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	('mutations', 'Var', (38, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('sarcoma', 'Disease', (13, 20))	('PI3K', 'Gene', (101, 105))
238211	27735949	ADI-PEG20 treatment of prostate cancer is unique in that arginine starvation in these tumor cells causes chromatophagy, a form of autophagy in which cells start incorporating chromatin into autophagosomes, followed by cell death.	('arginine', 'Chemical', 'MESH:D001120', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('ADI-PEG20', 'Var', (0, 9))	('prostate cancer', 'Disease', (23, 38))	('chromatophagy', 'Disease', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (0, 9))	('prostate cancer', 'Disease', 'MESH:D011471', (23, 38))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (23, 38))
238232	27735949	Pepstatin A (used at 50 muM) and E64D (used at 25 muM) were obtained from Enzo Life Sciences (Farmingdale, NY, USA).	('E64D', 'Mutation', 'p.E64D', (33, 37))	('E64D', 'Var', (33, 37))	('muM', 'Gene', '56925', (24, 27))	('muM', 'Gene', (24, 27))	('muM', 'Gene', '56925', (50, 53))	('Pepstatin A', 'Chemical', 'MESH:C031375', (0, 11))	('muM', 'Gene', (50, 53))
238236	27735949	Mice were treated with PBS, ADI-PEG20, chloroquine or the combination of ADI-PEG20 and chloroquine.	('ADI-PEG20', 'Chemical', 'MESH:C512527', (73, 82))	('PBS', 'Chemical', 'MESH:D007854', (23, 26))	('ADI-PEG20', 'Var', (28, 37))	('ADI-PEG20', 'Var', (73, 82))	('chloroquine', 'Chemical', 'MESH:D002738', (87, 98))	('Mice', 'Species', '10090', (0, 4))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (28, 37))	('chloroquine', 'Chemical', 'MESH:D002738', (39, 50))
238244	27735949	For co-IP, SK-LMS-1 cells were treated with PBS, 1 mug/ml ADI-PEG20, 20 muM chloroquine, or both for 3 days.	('ADI-PEG20', 'Chemical', 'MESH:C512527', (58, 67))	('PBS', 'Chemical', 'MESH:D007854', (44, 47))	('muM', 'Gene', '56925', (72, 75))	('chloroquine', 'Chemical', 'MESH:D002738', (76, 87))	('ADI-PEG20', 'Var', (58, 67))	('muM', 'Gene', (72, 75))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (11, 19))
238246	27735949	The immunoprecipitates were subsequently immunoblotted with anti-RIP3 (Abcam), anti-RIP1 (Cell Signaling), anti-caspase 8 (Cell Signaling) and anti-actin (Sigma) as described above.	('anti-actin', 'Var', (143, 153))	('RIP1', 'Gene', (84, 88))	('RIP3', 'Gene', '11035', (65, 69))	('RIP1', 'Gene', '8737', (84, 88))	('caspase 8', 'Gene', '841', (112, 121))	('RIP3', 'Gene', (65, 69))	('caspase 8', 'Gene', (112, 121))
238417	23738139	In many breeds the effective population size is very small even in normal times but in some breeds, for example, the Bernese mountain dog and the leonberger, genetic variation has been further reduced by serious population declines during war or hard economic times.	('genetic variation', 'Var', (158, 175))	('reduced', 'NegReg', (193, 200))	('dog', 'Species', '9615', (134, 137))
238430	23738139	This observation also has important genetic implications, suggesting that some breeds may be like the rare human Li-Fraumeni families where a germ line mutation in a tumour suppressor gene (TP53) results in a hereditary predisposition to several types of cancer or they may resemble the situation in families with mutations in BRCA1 where the risk of developing breast and ovarian cancer is greater in relatives of affected people, rather than the cancer being transmitted as an autosomal dominant condition.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('ovarian cancer', 'Phenotype', 'HP:0100615', (373, 387))	('tumour', 'Disease', (166, 172))	('cancer', 'Disease', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (448, 454))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (448, 454))	('BRCA1', 'Gene', (327, 332))	('cancer', 'Disease', (381, 387))	('mutation', 'Var', (152, 160))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (362, 387))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('Li-Fraumeni', 'Disease', (113, 124))	('cancer', 'Disease', (448, 454))	('mutations', 'Var', (314, 323))	('human', 'Species', '9606', (107, 112))	('people', 'Species', '9606', (424, 430))	('TP53', 'Gene', (190, 194))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('results in', 'Reg', (196, 206))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (113, 124))
238437	23738139	Histiocytic sarcoma is the current term used to describe a spectrum of poorly differentiated, pleomorphic tumours shown to have an immunophenotype consistent with a myeloid dendritic antigen presenting cell origin: CD1+, CD4-, CD11c+, CD11d-, MHC II+, ICAM-1+, and Thy-1+-.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('Histiocytic sarcoma', 'Disease', (0, 19))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('ICAM-1', 'Gene', '403975', (252, 258))	('CD1+', 'Var', (215, 219))	('CD4', 'Gene', (221, 224))	('MHC II+', 'Var', (243, 250))	('pleomorphic tumours', 'Disease', 'MESH:D008228', (94, 113))	('myeloid dendritic', 'Disease', 'MESH:D007635', (165, 182))	('CD4', 'Gene', '403931', (221, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('myeloid dendritic', 'Disease', (165, 182))	('CD11d', 'Gene', '489930', (235, 240))	('ICAM-1', 'Gene', (252, 258))	('pleomorphic tumours', 'Disease', (94, 113))	('CD11d', 'Gene', (235, 240))	('CD11c+', 'Var', (227, 233))	('Histiocytic sarcoma', 'Disease', 'MESH:D054747', (0, 19))
238459	23738139	Almost all these recurrent CNAs were shared between the two breeds, suggesting that they are more associated with the cancer phenotype than with breed and a subset suggested involvement of known cancer-associated genes including deletions of the tumour suppressor genes CDKN2A/B, RB1, and PTEN.	('deletions', 'Var', (229, 238))	('cancer', 'Disease', (118, 124))	('RB1', 'Gene', '476915', (280, 283))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('CDKN2A/B', 'Gene', '100271861;481563', (270, 278))	('tumour', 'Disease', (246, 252))	('cancer', 'Disease', (195, 201))	('men', 'Species', '9606', (181, 184))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('involvement', 'Reg', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('RB1', 'Gene', (280, 283))	('CDKN2A/B', 'Gene', (270, 278))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (246, 252))	('associated', 'Reg', (98, 108))	('tumour', 'Disease', 'MESH:D009369', (246, 252))	('PTEN', 'Gene', (289, 293))
238461	23738139	Interestingly dysregulation of CDKN2 has also been associated with susceptibility to histiocytic sarcoma in Bernese mountain dogs by genome wide association study (GWAS).	('susceptibility', 'Reg', (67, 81))	('dysregulation', 'Var', (14, 27))	('associated', 'Reg', (51, 61))	('dogs', 'Species', '9615', (125, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (85, 104))	('CDKN2', 'Gene', (31, 36))	('histiocytic sarcoma', 'Disease', (85, 104))
238479	23738139	As is the case in many human and canine cancers, alterations in the function of the tumour suppressor genes RB and TP53 have been implicated in the pathogenesis of canine osteosarcoma.	('function', 'MPA', (68, 76))	('tumour', 'Disease', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('alterations', 'Var', (49, 60))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('canine', 'Species', '9615', (33, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('cancers', 'Disease', (40, 47))	('implicated', 'Reg', (130, 140))	('canine', 'Species', '9615', (164, 170))	('TP53', 'Gene', (115, 119))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('human', 'Species', '9606', (23, 28))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('osteosarcoma', 'Disease', (171, 183))
238490	23738139	Eleven loci (from 8 different chromosomes) showed a significant difference in the distribution of DNA copy number imbalances between tumours from golden retrievers compared with those from rottweilers; the most significant of these was the deletion of the WT1 gene which occurred in 48% of the rottweiler cases (14/29) but which was not observed in any of the 9 golden retrievers.	('WT1', 'Gene', (256, 259))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('WT1', 'Gene', '609253', (256, 259))	('imbalance', 'Phenotype', 'HP:0002172', (114, 123))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('deletion', 'Var', (240, 248))	('tumours', 'Disease', (133, 140))	('imbalances', 'Phenotype', 'HP:0002172', (114, 124))
238500	23738139	A small number of studies have examined the molecular genetic aspects of canine hemangiosarcoma with respect to growth regulation genes; mutations in the tumour suppressor gene TP53 have been reported and a further study suggested that alteration of the p16-cyclin D1-Rb pathway may be associated with the pathogenesis of canine hemangiosarcoma.	('associated', 'Reg', (286, 296))	('angiosarcoma', 'Phenotype', 'HP:0200058', (83, 95))	('cyclin D1', 'Gene', '449028', (258, 267))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('hemangiosarcoma', 'Disease', (329, 344))	('tumour', 'Disease', (154, 160))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (329, 344))	('canine', 'Species', '9615', (73, 79))	('TP53', 'Gene', (177, 181))	('hemangiosarcoma', 'Disease', (80, 95))	('cyclin D1', 'Gene', (258, 267))	('angiosarcoma', 'Phenotype', 'HP:0200058', (332, 344))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (80, 95))	('canine', 'Species', '9615', (322, 328))	('sarcoma', 'Phenotype', 'HP:0100242', (337, 344))	('mutations', 'Var', (137, 146))	('alteration', 'Var', (236, 246))
238509	23738139	firstly examined by immunohistochemistry the expression of CD31 (endothelial marker), PTEN, VEGF, p27 AKt, and p-AKT in sections from 12 haemangiosarcomas and 5 benign splenic haematomas and observed some abnormalities in PTEN expression in the tumours.	('p27', 'Gene', (98, 101))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('benign splenic haematomas', 'Disease', 'MESH:D013158', (161, 186))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('PTEN', 'Gene', (86, 90))	('haemangiosarcomas', 'Disease', (137, 154))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('haemangiosarcomas', 'Disease', 'None', (137, 154))	('expression', 'MPA', (227, 237))	('VEGF', 'Gene', (92, 96))	('tumours', 'Disease', (245, 252))	('p27', 'Gene', '403429', (98, 101))	('CD31', 'Gene', (59, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('angiosarcoma', 'Phenotype', 'HP:0200058', (141, 153))	('p-AKT', 'Var', (111, 116))	('benign splenic haematomas', 'Disease', (161, 186))
238510	23738139	Using cell lines established from some of these tumours the same group identified mutations of PTEN in the C-terminal domain that may affect the subcellular localisation and stability of the protein.	('tumours', 'Disease', (48, 55))	('stability of the protein', 'MPA', (174, 198))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('subcellular localisation', 'MPA', (145, 169))	('mutations', 'Var', (82, 91))	('affect', 'Reg', (134, 140))	('PTEN', 'Gene', (95, 99))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Disease', 'MESH:D009369', (48, 55))
238512	23738139	However the PTEN mutation alone does not fully explain the increased levels of VEGF and other angiogenesis promoting growth factors (platelet derived growth factor and basic fibroblast growth factor) thought to be elaborated by haemangiosarcoma cells, or the role of the inflammatory cells frequently associated with these tumours.	('tumours', 'Disease', 'MESH:D009369', (323, 330))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('tumours', 'Disease', (323, 330))	('haemangiosarcoma', 'Disease', (228, 244))	('basic fibroblast growth factor', 'Gene', '403857', (168, 198))	('mutation', 'Var', (17, 25))	('haemangiosarcoma', 'Disease', 'None', (228, 244))	('PTEN', 'Gene', (12, 16))	('tumour', 'Phenotype', 'HP:0002664', (323, 329))	('tumours', 'Phenotype', 'HP:0002664', (323, 330))	('basic fibroblast growth factor', 'Gene', (168, 198))	('increased', 'PosReg', (59, 68))	('angiosarcoma', 'Phenotype', 'HP:0200058', (232, 244))
238536	23738139	Alterations in the p53 tumour suppressor pathway have been identified in some canine MCTs but TP53 sequencing in a small number of cases did not reveal any mutations.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('p53', 'Gene', '403869', (19, 22))	('Alterations', 'Var', (0, 11))	('tumour', 'Disease', (23, 29))	('p53', 'Gene', (19, 22))	('canine', 'Species', '9615', (78, 84))	('MCTs', 'Disease', (85, 89))
238540	23738139	In 1996, London and others demonstrated expression of KIT on malignant mast cells derived from 4 spontaneous canine MCTs and subsequently reported internal tandem duplications in exon 11 of c-KIT in approximately 30 percent of canine MCTs.	('internal tandem duplications in exon', 'Var', (147, 183))	('canine', 'Species', '9615', (227, 233))	('canine', 'Species', '9615', (109, 115))	('c-KIT', 'Gene', (190, 195))
238541	23738139	Other studies have shown mutations in the juxtamembrane domain of c-KIT in dogs with MCTs, mainly within exon 11, with duplications, deletions and substitutions being described.	('mutations', 'Var', (25, 34))	('deletions', 'Var', (133, 142))	('duplications', 'Var', (119, 131))	('c-KIT', 'Gene', (66, 71))	('substitutions', 'Var', (147, 160))	('MCTs', 'Disease', (85, 89))	('dogs', 'Species', '9615', (75, 79))
238542	23738139	Several studies reported a significant association between mutation and higher grade of tumour.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('mutation', 'Var', (59, 67))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Disease', (88, 94))
238546	23738139	The presence of c-KIT mutations in only a proportion of mast cell tumours suggests that although mutations in this gene may be responsible for the development of some mast cell tumours, it is likely that mutational events in other genes are involved in the carcinogenesis of many mast cell tumours which are yet to be identified.	('mutations', 'Var', (97, 106))	('tumours', 'Phenotype', 'HP:0002664', (290, 297))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('involved', 'Reg', (241, 249))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('carcinogenesis of many mast cell tumours', 'Disease', 'MESH:D063646', (257, 297))	('mast cell tumour', 'Phenotype', 'HP:0100495', (280, 296))	('mast cell tumours', 'Disease', (167, 184))	('tumour', 'Phenotype', 'HP:0002664', (290, 296))	('mast cell tumours', 'Disease', 'MESH:D034801', (280, 297))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('mast cell tumours', 'Disease', (56, 73))	('carcinogenesis of many mast cell tumours', 'Disease', (257, 297))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('mast cell tumour', 'Phenotype', 'HP:0100495', (167, 183))	('mast cell tumours', 'Disease', 'MESH:D034801', (167, 184))	('mutations', 'Var', (22, 31))	('mast cell tumours', 'Disease', 'MESH:D034801', (56, 73))	('mast cell tumour', 'Phenotype', 'HP:0100495', (56, 72))	('responsible', 'Reg', (127, 138))	('men', 'Species', '9606', (154, 157))	('c-KIT', 'Gene', (16, 21))
238547	23738139	Tumour suppressor in lung cancer-1 (TSLC1) is a tumour-suppressor gene coding for an adhesion molecule that is involved in normal mast cell to mast cell, and mast cell to fibroblast interactions Loss of TSLC1 expression is associated with a poor prognosis in various human tumours, including non-small cell lung cancer, breast, prostate, oesophageal and gastric tumours and has been shown to correlate with grade in canine MCTs.	('tumours', 'Disease', 'MESH:D009369', (362, 369))	('associated', 'Reg', (223, 233))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (292, 318))	('Loss', 'Var', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Disease', (273, 280))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (362, 368))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('Tumour suppressor in lung cancer-1', 'Gene', (0, 34))	('canine', 'Species', '9615', (416, 422))	('tumour', 'Disease', 'MESH:D009369', (362, 368))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (296, 318))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumour', 'Disease', 'MESH:D009369', (273, 279))	('TSLC1', 'Gene', (203, 208))	('tumour', 'Disease', (273, 279))	('tumour', 'Disease', (362, 368))	('tumours', 'Phenotype', 'HP:0002664', (273, 280))	('tumours', 'Disease', 'MESH:D009369', (273, 280))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (292, 318))	('TSLC1', 'Gene', (36, 41))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('breast', 'Disease', (320, 326))	('Tumour suppressor in lung cancer-1', 'Gene', '23705', (0, 34))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('oesophageal and gastric tumours', 'Disease', 'MESH:D013274', (338, 369))	('human', 'Species', '9606', (267, 272))	('non-small cell lung cancer', 'Disease', (292, 318))	('tumours', 'Disease', (362, 369))	('TSLC1', 'Gene', '23705', (203, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('prostate', 'Disease', (328, 336))	('tumours', 'Phenotype', 'HP:0002664', (362, 369))	('TSLC1', 'Gene', '23705', (36, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (307, 318))
238548	23738139	In humans, mutations in the mismatch repair (MMR) genes give rise to Lynch syndrome, an inherited predisposition to early onset cancer, especially intestinal adenocarcinoma and skin cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('MMR', 'Gene', (45, 48))	('mutations', 'Var', (11, 20))	('especially intestinal adenocarcinoma', 'Disease', 'MESH:D007414', (136, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Lynch syndrome', 'Disease', (69, 83))	('skin cancer', 'Disease', 'MESH:D012878', (177, 188))	('cancer', 'Disease', (128, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('Lynch syndrome', 'Disease', 'MESH:D003123', (69, 83))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('humans', 'Species', '9606', (3, 9))	('cancer', 'Disease', (182, 188))	('give rise to', 'Reg', (56, 68))	('skin cancer', 'Phenotype', 'HP:0008069', (177, 188))	('skin cancer', 'Disease', (177, 188))	('especially intestinal adenocarcinoma', 'Disease', (136, 172))
238560	23738139	A distinct B-cell and T-cell prevalence of lymphoproliferative disease by breed was reported in North America; 1263 dogs representing 87 breeds, whose samples had been submitted for PARR analysis:clonal rearrangement of immunoglobulin heavy chain or T-cell receptor y chain:showed breed-specific susceptibility to develop B-cell or T-cell tumours.	('T-cell tumours', 'Disease', 'MESH:D009369', (332, 346))	('tumour', 'Phenotype', 'HP:0002664', (339, 345))	('dogs', 'Species', '9615', (116, 120))	('lymphoproliferative disease', 'Phenotype', 'HP:0005523', (43, 70))	('lymphoproliferative disease', 'Disease', 'MESH:D008232', (43, 70))	('tumours', 'Phenotype', 'HP:0002664', (339, 346))	('men', 'Species', '9606', (212, 215))	('develop', 'PosReg', (314, 321))	('clonal rearrangement', 'Var', (196, 216))	('T-cell tumours', 'Disease', (332, 346))	('B-cell', 'CPA', (322, 328))	('lymphoproliferative disease', 'Disease', (43, 70))
238565	23738139	Using CGH analysis on a subset of these tumours, the same study identified unique patterns of chromosomal gains and losses that segregated specifically with B-cell tumours and T-cell tumours (as previously identified by) indicating that consistent genetic abnormalities are associated with different tumour types and thus lending weight to the hypothesis that there is a heritable risk for development of canine lymphoma.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('lymphoma', 'Disease', (412, 420))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('lymphoma', 'Disease', 'MESH:D008223', (412, 420))	('chromosomal', 'Var', (94, 105))	('B-cell tumours and T-cell tumours', 'Disease', 'MESH:C538614', (157, 190))	('tumours', 'Disease', (183, 190))	('men', 'Species', '9606', (397, 400))	('tumours', 'Disease', (40, 47))	('canine', 'Species', '9615', (405, 411))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('tumours', 'Disease', 'MESH:D009369', (183, 190))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('development of canine', 'Phenotype', 'HP:0012738', (390, 411))	('tumours', 'Disease', (164, 171))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (412, 420))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (183, 189))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('tumour', 'Phenotype', 'HP:0002664', (300, 306))	('tumour', 'Disease', (40, 46))	('losses', 'NegReg', (116, 122))	('genetic abnormalities', 'Disease', 'MESH:D030342', (248, 269))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('tumour', 'Disease', 'MESH:D009369', (300, 306))	('genetic abnormalities', 'Disease', (248, 269))	('tumour', 'Disease', (300, 306))
238566	23738139	A deletion of chromosome 14 was exclusively seen in diffuse B-cell lymphoma and occurred in 7 out of 7 golden retrievers but only in 13% (4 of 31) of dogs from other breeds.	('dogs', 'Species', '9615', (150, 154))	('lymphoma', 'Phenotype', 'HP:0002665', (67, 75))	('cell lymphoma', 'Phenotype', 'HP:0012191', (62, 75))	('deletion', 'Var', (2, 10))	('seen', 'Reg', (44, 48))	('B-cell lymphoma', 'Disease', (60, 75))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (60, 75))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (60, 75))
238568	23738139	Interrogation of the recurrent CNAs identified revealed an extensive catalog of chromosomal regions and genes presenting with recurrent DNA copy number imbalance, within which are key genes previously associated with a range of human malignancies; copy number loss of CDNK2A/B occurred in 20/36 T-cell lymphoma cases and was more frequent in high grade than low grade cases.	('CDNK2A/B', 'Gene', (268, 276))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (295, 310))	('imbalance', 'Phenotype', 'HP:0002172', (152, 161))	('malignancies', 'Disease', 'MESH:D009369', (234, 246))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (295, 310))	('T-cell lymphoma', 'Disease', (295, 310))	('malignancies', 'Disease', (234, 246))	('cell lymphoma', 'Phenotype', 'HP:0012191', (297, 310))	('human', 'Species', '9606', (228, 233))	('lymphoma', 'Phenotype', 'HP:0002665', (302, 310))	('copy number loss', 'Var', (248, 264))
238569	23738139	The CNA associated most significantly with B cell lymphoma was a highly recurrent deletion of a discrete region on chromosome 26 (74/106 cases) which encompasses the canine immunoglobulin lambda locus.	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (43, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('cell lymphoma', 'Phenotype', 'HP:0012191', (45, 58))	('canine', 'Species', '9615', (166, 172))	('deletion', 'Var', (82, 90))	('lymphoma', 'Disease', (50, 58))
238571	23738139	Seven individual loci (on chromosomes 6, 12, 20, and 31) showed highly significant association with breed, each demonstrating an elevated incidence of copy number gain in boxers with T-cell lymphoma.	('T-cell lymphoma', 'Disease', (183, 198))	('cell lymphoma', 'Phenotype', 'HP:0012191', (185, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('association', 'Interaction', (83, 94))	('copy number gain', 'Var', (151, 167))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (183, 198))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (183, 198))
238583	23738139	Familial cases tend to be younger, to have a higher number of moles and to develop multiple primary tumours.	('tumours', 'Disease', (100, 107))	('Familial', 'Var', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('moles', 'Disease', (62, 67))	('moles', 'Phenotype', 'HP:0003764', (62, 67))	('develop', 'PosReg', (75, 82))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))
238585	23738139	Families with germline mutation in CDKN2A are also prone to pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('prone', 'Reg', (51, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('germline mutation', 'Var', (14, 31))	('CDKN2A', 'Gene', (35, 41))
238586	23738139	A number of pathways and genetic mutations have been identified in nonfamilial cutaneous melanoma; these include activating BRAF or NRAS mutations resulting in hyperactivation of the mitogen-activated protein kinase (MAPK) pathway and loss or mutation of PTEN, a negative regulator of the P13 K pathway.	('cutaneous melanoma', 'Disease', (79, 97))	('activating', 'PosReg', (113, 123))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('P13 K', 'Mutation', 'p.P13K', (289, 294))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('BRAF', 'Gene', '475526', (124, 128))	('mutations', 'Var', (137, 146))	('hyperactivation', 'PosReg', (160, 175))	('loss or mutation', 'NegReg', (235, 251))	('PTEN', 'Gene', (255, 259))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('NRAS', 'Gene', '403872', (132, 136))	('BRAF', 'Gene', (124, 128))	('NRAS', 'Gene', (132, 136))
238592	23738139	This study included both dermal and oral melanomas; 14 tumours were benign and 11 malignant but the abnormalities in p16 occurred with equal frequency in both benign and malignant tumours, suggesting that inactivation of this pathway is a critical step in the pathogenesis of melanoma.	('oral melanomas; 14 tumours', 'Disease', 'MESH:C563985', (36, 62))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('malignant tumours', 'Disease', 'MESH:D009369', (170, 187))	('melanoma', 'Disease', (276, 284))	('abnormalities', 'Var', (100, 113))	('p16', 'Gene', (117, 120))	('malignant tumours', 'Disease', (170, 187))	('melanoma', 'Disease', 'MESH:D008545', (276, 284))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('inactivation', 'Var', (205, 217))	('oral melanomas; 14 tumours', 'Disease', (36, 62))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
238594	23738139	More recently dysregulation of the Wnt/beta catenin signal pathway has been reported in 18 canine cutaneous melanomas, demonstrated by abnormal intracellular accumulation and increased expression of beta catenin.	('intracellular accumulation', 'MPA', (144, 170))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('cutaneous melanomas', 'Disease', (98, 117))	('expression', 'MPA', (185, 195))	('beta catenin', 'Gene', (39, 51))	('beta catenin', 'Gene', '477032', (199, 211))	('dysregulation', 'Var', (14, 27))	('canine', 'Species', '9615', (91, 97))	('beta catenin', 'Gene', (199, 211))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('increased', 'PosReg', (175, 184))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (98, 117))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (98, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('beta catenin', 'Gene', '477032', (39, 51))
238595	23738139	MicroRNA profiles have been examined in canine melanoma tissues and human and canine melanoma cell lines and microRNAs 145 and 205 have been identified as tumour suppressors in both canine and human melanoma cell lines.	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('human', 'Species', '9606', (68, 73))	('canine', 'Species', '9615', (40, 46))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('melanoma', 'Disease', (47, 55))	('microRNAs', 'Var', (109, 118))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('canine', 'Species', '9615', (182, 188))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('canine', 'Species', '9615', (78, 84))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (199, 207))	('human', 'Species', '9606', (193, 198))	('tumour', 'Disease', (155, 161))
238607	23738139	A proportion of human breast cancer is familial; women who have inherited mutations in the BRCA1 or BRCA2 (BRCA 1/2) genes have substantially increased risk of breast cancer but it is recognised that mutations in these genes only account for a small part, approximately 10%, of the total inherited effect.	('women', 'Species', '9606', (49, 54))	('BRCA2', 'Gene', (100, 105))	('BRCA1', 'Gene', (91, 96))	('BRCA 1/2', 'Gene', (107, 115))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('BRCA 1/2', 'Gene', '675;672', (107, 115))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('human', 'Species', '9606', (16, 21))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
238608	23738139	Furthermore BRCA1/2 mutation is rare in cases of sporadic breast cancer.	('BRCA1/2', 'Gene', '403437;474180', (12, 19))	('sporadic breast cancer', 'Disease', (49, 71))	('BRCA1/2', 'Gene', (12, 19))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (49, 71))	('mutation', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))
238614	23738139	A variable proportion of canine mammary tumours have been reported to contain mutations in TP53 and studies have shown an association between the level of COX-2 expression, malignant phenotype, and prognosis.	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('TP53', 'Gene', (91, 95))	('COX-2', 'Gene', (155, 160))	('association', 'Interaction', (122, 133))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumours', 'Disease', (40, 47))	('mutations', 'Var', (78, 87))	('canine', 'Species', '9615', (25, 31))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('COX-2', 'Gene', '804479', (155, 160))
238621	23738139	The same group also investigated the role of the dog leucocyte antigen (DLA) system as a genetic risk factor in the aetiology of canine mammary tumours in English springer spaniels, and by genotyping the polymorphic exon 2 of DLA class II loci, identified a significant association between a rare protective haplotype of MCH class II and the incidence of mammary tumours in this population of 363 Spaniels, 218 cases and 145 healthy controls.	('tumour', 'Phenotype', 'HP:0002664', (363, 369))	('dog', 'Species', '9615', (49, 52))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('haplotype', 'Var', (308, 317))	('DLA', 'Gene', '474862', (72, 75))	('DLA', 'Gene', (72, 75))	('tumours', 'Phenotype', 'HP:0002664', (363, 370))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('tumours', 'Disease', 'MESH:D009369', (363, 370))	('tumours', 'Disease', (363, 370))	('canine', 'Species', '9615', (129, 135))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('DLA', 'Gene', '474862', (226, 229))	('tumours', 'Disease', (144, 151))	('DLA', 'Gene', (226, 229))	('MCH class II', 'Gene', (321, 333))
238645	23738139	Recently a germline mutation in the mesenchymal-epithelial transition factor (MET) protooncogene was found in approximately 70% of rottweiler dogs, a breed predisposed to several types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('found', 'Reg', (101, 106))	('MET', 'Gene', (78, 81))	('dogs', 'Species', '9615', (142, 146))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('germline mutation', 'Var', (11, 28))
238646	23738139	This supports the concept that particular dog breeds may carry germline mutations that contribute to high rates of cancer in a manner similar to heritable, cancer-associated mutations in humans.	('contribute', 'Reg', (87, 97))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('humans', 'Species', '9606', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('germline mutations', 'Var', (63, 81))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('dog', 'Species', '9615', (42, 45))
238654	23738139	Pure-bred dogs allow the identification of rare variants in the whole canine population because they have been accidentally selected in a given dog breed, and for multifactorial diseases such as cancer, the impact of environmental exposure can be analysed against a reasonably homogenous genetic background.	('canine', 'Species', '9615', (70, 76))	('men', 'Species', '9606', (224, 227))	('dogs', 'Species', '9615', (10, 14))	('variants', 'Var', (48, 56))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('multifactorial diseases', 'Disease', 'MESH:D004194', (163, 186))	('dog', 'Species', '9615', (10, 13))	('dog', 'Species', '9615', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('multifactorial diseases', 'Disease', (163, 186))
238667	23226201	Cellular pathways that appear aberrantly regulated in response to the t(X;17)(p11;q25) translocation include the cell cycle and cell adhesion.	('Cellular pathways', 'Pathway', (0, 17))	('t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (70, 86))	('cell adhesion', 'CPA', (128, 141))	('cell cycle', 'CPA', (113, 123))	('t(X;17)(p11;q25', 'Var', (70, 85))
238684	23226201	The xenograft model of ASPS, established in immunocompromised mice, maintains characteristics consistent with the original ASPS tumor including tumor histology, expression of the ASPL-TFE3 type 1 fusion transcript and the ASPL-TFE3 type 1 fusion protein, as well as maintenance of the t(X;17)(p11;q25) translocation characteristic of ASPS.	('t(X', 'Var', (285, 288))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mice', 'Species', '10090', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (285, 301))	('original ASPS tumor', 'Disease', 'MESH:D018234', (114, 133))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('original ASPS tumor', 'Disease', (114, 133))
238742	23226201	The two expression ratios can now be expressed as a function of the fraction of tumor cells in the patient sample:This relationship finds that the two expression ratios <ri,k> and ri,k are identical only if fi is 1, i.e.	('<ri', 'Var', (169, 172))	('patient', 'Species', '9606', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))
238823	23226201	Apparently the cell cycle control imposed by TFE3 alone is diminished by its fusion transcript, however the genetic components of the cellular machinery needed for proliferation are responding to signals directing cellular mitosis and meiosis.	('mitosis', 'Disease', (223, 230))	('mitosis', 'Disease', 'None', (223, 230))	('meiosis', 'CPA', (235, 242))	('TFE3', 'Gene', (45, 49))	('cell cycle control', 'CPA', (15, 33))	('diminished', 'NegReg', (59, 69))	('fusion transcript', 'Var', (77, 94))
238825	23226201	The cellular processes affected by the non-reciprocal t(X;17) chromosomal translocation, that can be collectively linked to measures of gene expression derived independently from ASPS patient tissue and an ASPS cell, identify aberrant regulation of the cell-cycle and tissue stroma-related adhesion pathways as ASPS genetic signatures.	('regulation', 'MPA', (235, 245))	('aberrant', 'Var', (226, 234))	('patient', 'Species', '9606', (184, 191))	('tissue stroma-related adhesion pathways', 'Pathway', (268, 307))
238833	23226201	Recently CHK1 inhibitors have been proposed as cancer therapeutics on the basis of their ability to activate cell cycle checkpoints in p53 defective cancer cells.	('cancer', 'Disease', (149, 155))	('CHK1', 'Gene', '1111', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('activate', 'PosReg', (100, 108))	('cancer', 'Disease', (47, 53))	('cell cycle checkpoints', 'CPA', (109, 131))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('inhibitors', 'Var', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CHK1', 'Gene', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
238840	23226201	siRNA gene silencing demonstrated that chemotaxis requires activation of Pyk2, PI3K p85, and Lyn, as well as MAPK ERK.	('silencing', 'Var', (11, 20))	('Lyn', 'Gene', '4067', (93, 96))	('Pyk2', 'Gene', '2185', (73, 77))	('Pyk2', 'Gene', (73, 77))	('activation', 'PosReg', (59, 69))	('p85', 'Gene', '5296', (84, 87))	('p85', 'Gene', (84, 87))	('Lyn', 'Gene', (93, 96))
238841	23226201	MIP-1beta activation of CCR5 triggered translocation of Pyk2 and PI3K p85 from the cytoplasm to co-localize with Lyn, at the plasma membrane, with formation of a multi-molecular complex.	('translocation', 'MPA', (39, 52))	('p85', 'Gene', '5296', (70, 73))	('Lyn', 'Gene', (113, 116))	('CCR5', 'Gene', (24, 28))	('PI3K', 'Var', (65, 69))	('Lyn', 'Gene', '4067', (113, 116))	('p85', 'Gene', (70, 73))	('Pyk2', 'Gene', '2185', (56, 60))	('Pyk2', 'Gene', (56, 60))	('MIP-1beta', 'Gene', (0, 9))	('MIP-1beta', 'Gene', '6351', (0, 9))	('CCR5', 'Gene', '1234', (24, 28))
238846	23226201	Recently, beta chemokine CCL5 neutralization has been found to restrict cancer cell growth in colorectal cancer.	('CCL5', 'Gene', (25, 29))	('restrict', 'NegReg', (63, 71))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('cancer', 'Disease', (105, 111))	('CCL5', 'Gene', '6352', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('neutralization', 'Var', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
238858	23226201	Their antiproliferative and biochemical assays found sunitinib to markedly impair ASPS cell growth and switch off PDGFBR.	('PDGFBR', 'Gene', (114, 120))	('switch off', 'NegReg', (103, 113))	('sunitinib', 'Var', (53, 62))	('sunitinib', 'Chemical', 'MESH:D000077210', (53, 62))	('impair', 'NegReg', (75, 81))	('ASPS cell growth', 'CPA', (82, 98))
238944	33202305	Cellular reprogramming to rewire epigenetic alterations in human cancer.	('human', 'Species', '9606', (59, 64))	('epigenetic alterations', 'Var', (33, 55))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
238952	33202305	Genetic alterations of oncogenes and tumor suppressors are critical drivers of tumorigenesis.	('Genetic alterations', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (79, 84))	('oncogenes', 'Protein', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
238953	33202305	However, evidence now shows that epigenetic changes:both intrinsic and extrinsic to cells:may drive malignancy, supporting the possibility of cancer reversibility.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('malignancy', 'Disease', 'MESH:D009369', (100, 110))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('malignancy', 'Disease', (100, 110))	('drive', 'PosReg', (94, 99))	('epigenetic changes', 'Var', (33, 51))
238963	33202305	Yet, in rare examples, epigenetic alterations have been shown sufficient to initiate tumorigenesis prior to or without driver mutations.	('tumor', 'Disease', (85, 90))	('epigenetic alterations', 'Var', (23, 45))	('initiate', 'Reg', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
238964	33202305	Is rewiring such epigenetic alterations enough to control the cancerous phenotype?	('control', 'Reg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancerous', 'Disease', 'MESH:D009369', (62, 71))	('epigenetic alterations', 'Var', (17, 39))	('cancerous', 'Disease', (62, 71))
238996	33202305	These melanoma NT-ES cells retained a genetic alteration (trisomy 8 with 8qter deletion) from their parental melanoma, confirming the origin of the NT-ES line.	('trisomy 8', 'Var', (58, 67))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
238997	33202305	However, when melanoma-NT-ES cells were injected into a tetraploid blastocyst, the embryos were able to develop multiple functional tissues only up to E9.5, suggesting that the melanoma genome could not provide an organizational framework for late cell specification.	('melanoma', 'Disease', (14, 22))	('E9.5', 'Var', (151, 155))	('tetraploid blastocyst', 'Disease', (56, 77))	('tetraploid blastocyst', 'Disease', 'MESH:D057891', (56, 77))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
238999	33202305	Moreover, 33% of the chimeras developed rhabdomyosarcoma, the incidence of which is frequently correlated with a loss of the chromosome 8q region, suggesting a potential overlap between the pathways that operate in melanoma and rhabdomyosarcoma.	('chimeras', 'Var', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (40, 56))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('rhabdomyosarcoma', 'Disease', (40, 56))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (228, 244))	('rhabdomyosarcoma', 'Disease', (228, 244))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (40, 56))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (228, 244))	('melanoma and rhabdomyosarcoma', 'Disease', 'MESH:D012208', (215, 244))	('developed', 'PosReg', (30, 39))
239015	33202305	reprogrammed human melanoma cell lines harboring BRAFV600E or NRAS mutations with TetO-inducible OSK.	('NRAS', 'Gene', '4893', (62, 66))	('human', 'Species', '9606', (13, 18))	('BRAFV600E', 'Var', (49, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('NRAS', 'Gene', (62, 66))
239018	33202305	Cancer growth and survival can be impaired by the inactivation of a few oncogenic pathways.	('oncogenic pathways', 'Pathway', (72, 90))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('survival', 'CPA', (18, 26))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('impaired', 'NegReg', (34, 42))	('inactivation', 'Var', (50, 62))
239026	33202305	Nevertheless, in the presence of differentiation agents, such as retinoic acid and vitamin D3, both invasiveness and proliferation of PostiPC were significantly reduced, compared to the parental DLD-1 cell line.	('reduced', 'NegReg', (161, 168))	('proliferation', 'CPA', (117, 130))	('vitamin D3', 'Var', (83, 93))	('retinoic acid', 'Chemical', 'MESH:D014212', (65, 78))	('vitamin D3', 'Chemical', 'MESH:D002762', (83, 93))	('invasiveness', 'CPA', (100, 112))
239027	33202305	PostiPC cells acquired sensitivity to the anti-cancer drug 5-fluorodeoxyuridine to a higher degree than parental DLD-1 cells, showing that reprogramming of cancers could restore sensitivity to anti-cancer agents.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('PostiPC', 'Var', (0, 7))	('sensitivity', 'MPA', (23, 34))	('5-fluorodeoxyuridine', 'Chemical', 'MESH:D005467', (59, 79))	('cancers', 'Disease', (156, 163))	('cancer', 'Disease', (156, 162))	('sensitivity', 'MPA', (178, 189))	('cancer', 'Disease', (198, 204))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('restore', 'PosReg', (170, 177))
239028	33202305	Consistently, PostiPC showed reduced tumor formation compared to parental DLD-1 cells in an in vivo xenograft assay, indicating reduction of tumorigenicity via reprogramming.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('PostiPC', 'Var', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('reduction', 'NegReg', (128, 137))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('reduced', 'NegReg', (29, 36))	('tumor', 'Disease', (37, 42))
239035	33202305	Indeed, while parental sarcoma cell lines contained the active histone modification H3K4me3 in their MYC promoters, reprogrammed sarcoma cell lines had both active H3K4me3 and repressive H3K27me3 marks in their MYC promoter.	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('H3K4me3', 'Var', (84, 91))	('parental sarcoma', 'Disease', (14, 30))	('H3K4me3', 'Var', (164, 171))	('H3K27me3 marks', 'Var', (187, 201))	('sarcoma', 'Disease', (129, 136))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('parental sarcoma', 'Disease', 'MESH:D063129', (14, 30))	('sarcoma', 'Disease', (23, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
239036	33202305	Reprogrammed sarcoma cells that were differentiated to adipogenic and osteogenic lineages no longer contained the active mark H3K4me3 in the MYC promoter.	('H3K4me3', 'Var', (126, 133))	('sarcoma', 'Disease', (13, 20))	('sarcoma', 'Disease', 'MESH:D012509', (13, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))
239042	33202305	DNA hypermethylation is frequently found at non-classical oncogenes, such as polycomb repressor complex 2 (PRC2), TES, and CDKN1C in GBM.	('CDKN1C', 'Gene', '1028', (123, 129))	('CDKN1C', 'Gene', (123, 129))	('PRC2', 'Gene', (107, 111))	('hypermethylation', 'Var', (4, 20))
239049	33202305	These included promoter regions commonly associated with DNA hypermethylation in GBM, such as those of TES, CDKN1C, and many PRC2 target genes.	('CDKN1C', 'Gene', '1028', (108, 114))	('CDKN1C', 'Gene', (108, 114))	('hypermethylation', 'Var', (61, 77))	('GBM', 'Gene', (81, 84))
239057	33202305	Benign and early-stage tumors typically carry a small number of mutations, and thus, reprogramming barriers imposed by these genetic alterations may be lesser than those in advanced tumors.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutations', 'Var', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
239058	33202305	PNFs are benign Schwann cell (SC) tumors of the peripheral nerve sheath and mainly develop due to NF1 inactivation.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('inactivation', 'Var', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('NF1', 'Gene', (98, 101))	('NF1', 'Gene', '4763', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PNFs', 'Disease', (0, 4))
239059	33202305	generated iPSC lines from PNF primary cells with NF1 (-/-) alleles.	('alleles', 'Var', (59, 66))	('iPS', 'Disease', (10, 13))	('iPS', 'Disease', 'OMIM:613661', (10, 13))	('NF1', 'Gene', (49, 52))	('NF1', 'Gene', '4763', (49, 52))
239066	33202305	Therefore, this study showed that the deletion of NF1 did not cause abnormal phenotypes during differentiation of NC into other lineages but did alter the phenotypes during cell specification of NC into SC lineages.	('phenotypes', 'MPA', (155, 165))	('NF1', 'Gene', (50, 53))	('NF1', 'Gene', '4763', (50, 53))	('deletion', 'Var', (38, 46))	('cell specification', 'CPA', (173, 191))	('alter', 'Reg', (145, 150))
239068	33202305	While reset epigenetic changes persisted in the differentiated cells, the suppressed malignant phenotypes were selectively re-activated in the lineages corresponding to the primary cancers, but not in other lineages.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))	('epigenetic changes', 'Var', (12, 30))
239073	33202305	Through extensive genetic analysis, we confirmed that a line (designated "10-22" cells) was unambiguously derived from advanced PDAC cells because the cells harbored classical PDAC oncogenic mutations, such as mutations in the KRAS and TP53 genes, a heterozygous deletion of CDKN2A, homozygous deletions of SMAD4, as well as chromosomal rearrangements of the original tumor epithelial cells.	('SMAD4', 'Gene', (307, 312))	('CDKN2A', 'Gene', '1029', (275, 281))	('tumor', 'Disease', (368, 373))	('KRAS', 'Gene', (227, 231))	('mutations', 'Var', (210, 219))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('deletions', 'Var', (294, 303))	('deletion', 'Var', (263, 271))	('KRAS', 'Gene', '3845', (227, 231))	('PDAC', 'Chemical', '-', (128, 132))	('PDAC', 'Chemical', '-', (176, 180))	('SMAD4', 'Gene', '4089', (307, 312))	('TP53', 'Gene', (236, 240))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('TP53', 'Gene', '7157', (236, 240))	('CDKN2A', 'Gene', (275, 281))
239087	33202305	Thus, this study demonstrated that epigenetic reprogramming could decrease PDAC cells' aggressiveness and result in subsequent loss of in vivo tumorigenicity.	('tumor', 'Disease', (143, 148))	('aggressiveness', 'Disease', 'MESH:D001523', (87, 101))	('aggressiveness', 'Disease', (87, 101))	('epigenetic reprogramming', 'Var', (35, 59))	('aggressiveness', 'Phenotype', 'HP:0000718', (87, 101))	('loss', 'NegReg', (127, 131))	('decrease', 'NegReg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('PDAC', 'Chemical', '-', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
239097	33202305	One study showed that ectopic OCT4 competed with relatively unstable nucleosomes and subsequently established nucleosome-depleted regions in the regulatory regions of target genes in hypomethylated clones derived from the colon cancer line HCT 116.	('colon cancer', 'Phenotype', 'HP:0003003', (222, 234))	('ectopic', 'Var', (22, 29))	('colon cancer', 'Disease', 'MESH:D015179', (222, 234))	('colon cancer', 'Disease', (222, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('OCT4', 'Protein', (30, 34))
239099	33202305	In contrast, MYC is known to preferentially bind to active promoters and cooperatively enhance occupancy of OSK in both human and mouse.	('MYC', 'Var', (13, 16))	('human', 'Species', '9606', (120, 125))	('occupancy', 'MPA', (95, 104))	('preferentially', 'PosReg', (29, 43))	('bind', 'Interaction', (44, 48))	('enhance', 'PosReg', (87, 94))	('OSK', 'Protein', (108, 111))	('mouse', 'Species', '10090', (130, 135))
239103	33202305	In another study of bulk MEFs during reprogramming, OSK induced the redistribution of somatic TFs away from MEF enhancers to sites engaged by OSK elsewhere in the genome, which led to global destabilization of MEF enhancers.	('OSK', 'Var', (52, 55))	('MEFs', 'CellLine', 'CVCL:9115', (25, 29))	('MEF', 'Gene', '2000', (25, 28))	('MEF', 'Gene', (25, 28))	('MEF', 'Gene', '2000', (210, 213))	('destabilization', 'NegReg', (191, 206))	('MEF', 'Gene', (210, 213))	('global', 'MPA', (184, 190))	('MEF', 'Gene', (108, 111))	('MEF', 'Gene', '2000', (108, 111))	('redistribution', 'MPA', (68, 82))
239108	33202305	KLF4 is overexpressed in human PDAC, and ectopic KLF4 expression was sufficient to induce cells to undergo acinar ductal metaplasia (ADM) in the presence of mutant Kras in mice.	('mutant', 'Var', (157, 163))	('PDAC', 'Chemical', '-', (31, 35))	('induce', 'PosReg', (83, 89))	('human', 'Species', '9606', (25, 30))	('mice', 'Species', '10090', (172, 176))	('Kras', 'Gene', (164, 168))	('ectopic', 'Var', (41, 48))	('KLF4', 'Gene', (49, 53))	('Kras', 'Gene', '3845', (164, 168))	('acinar ductal metaplasia', 'CPA', (107, 131))
239118	33202305	Moreover, OSKM induction, along with Pdx1-Cre activation of Kras and p53 mutations, resulted in widespread PDAC development, suggesting that OSKM-mediated destabilization of somatic cell identity catalyzes irreversible cancer development.	('Kras', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('resulted in', 'Reg', (84, 95))	('widespread PDAC development', 'CPA', (96, 123))	('Kras', 'Gene', '3845', (60, 64))	('PDAC', 'Chemical', '-', (107, 111))	('Pdx1', 'Gene', '3651', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('Pdx1', 'Gene', (37, 41))	('cancer', 'Disease', (219, 225))	('mutations', 'Var', (73, 82))
239129	33202305	Hypomethylated R-DMRs were associated with hypermethylated C-DMRs, and, conversely, hypermethylated R-DMRs were associated with hypomethylated C-DMRs.	('R-DMRs', 'Chemical', '-', (100, 106))	('Hypomethylated', 'Var', (0, 14))	('C-DMRs', 'Chemical', '-', (143, 149))	('C-DMRs', 'Chemical', '-', (59, 65))	('hypermethylated', 'Var', (43, 58))	('R-DMRs', 'Chemical', '-', (15, 21))
239142	33202305	Common epigenetic factors can differentially elicit tumor formation or reprogramming to pluripotency.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('reprogramming', 'CPA', (71, 84))	('elicit', 'Reg', (45, 51))	('epigenetic factors', 'Var', (7, 25))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
239150	33202305	Not all cell types harboring the same mutations can develop cancer.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('develop', 'PosReg', (52, 59))	('cancer', 'Disease', (60, 66))	('mutations', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
239151	33202305	Likewise, transdifferentiation also results in decreased malignancy in a subset of tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('decreased malignancy', 'Disease', 'MESH:D009369', (47, 67))	('decreased malignancy', 'Disease', (47, 67))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('transdifferentiation', 'Var', (10, 30))
239152	33202305	For example, transdifferentiation of B lymphomas into macrophage-like cells impaired tumorigenicity in xenograft hosts.	('impaired', 'NegReg', (76, 84))	('tumor', 'Disease', (85, 90))	('B lymphomas', 'Disease', (37, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('transdifferentiation', 'Var', (13, 33))	('B lymphomas', 'Disease', 'MESH:D016393', (37, 48))	('B lymphomas', 'Phenotype', 'HP:0012191', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lymphomas', 'Phenotype', 'HP:0002665', (39, 48))
239157	33202305	Reversible epigenetic alterations can play a crucial role in the progression of cancers.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('epigenetic alterations', 'Var', (11, 33))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
239165	33202305	Therefore, cellular reprogramming of cancer cells could offer a useful tool to unveil cancer evolution driven by epigenetic alterations or aberrant transcriptional gene networks in the presence of mutations (Fig.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('aberrant', 'Var', (139, 147))	('cancer', 'Disease', (86, 92))
239170	33202305	We found that 90% of tumor epithelial cells did not harbor KRAS mutant alleles (unpublished data).	('KRAS', 'Gene', '3845', (59, 63))	('KRAS', 'Gene', (59, 63))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('mutant', 'Var', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
239172	33202305	We were only able to identify one iPS-like cell line harboring PDAC classical mutations after multiple attempts.	('PDAC', 'Chemical', '-', (63, 67))	('iPS', 'Disease', (34, 37))	('mutations', 'Var', (78, 87))	('PDAC', 'Gene', (63, 67))	('iPS', 'Disease', 'OMIM:613661', (34, 37))
239177	33202305	For example, for an initial quick screen of cancer clones, our study quantified mutant KRAS alleles by pyrosequencing and then confirmed the origin of iPSCs by comparative genome hybridization (CGH).	('KRAS', 'Gene', (87, 91))	('mutant', 'Var', (80, 86))	('KRAS', 'Gene', '3845', (87, 91))	('iPS', 'Disease', (151, 154))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('iPS', 'Disease', 'OMIM:613661', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
239178	33202305	Thus, if there is a set of specific mutations known to recur in a given cancer, pyrosequencing or ddPCR can be used to quickly screen colonies as well as to quantify the fraction of cancer cells in a primary tumor at low cost.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('tumor', 'Disease', (208, 213))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
239183	33202305	Even if all cancer cells in a given tumor have the same genetic alterations, not all cancer cells have the same epigenetic and metabolic changes.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('genetic alterations', 'Var', (56, 75))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', (36, 41))
239192	33202305	In contrast to most myeloid leukemia iPSC studies that documented complete removal of somatic identity in iPSCs, solid cancer iPSC studies show persisting epigenetic changes that prevent cells from being fully reprogrammed pluripotency.	('prevent', 'Reg', (179, 186))	('iPS', 'Disease', (37, 40))	('iPS', 'Disease', 'OMIM:613661', (37, 40))	('iPS', 'Disease', (106, 109))	('iPS', 'Disease', (126, 129))	('cancer iPS', 'Disease', 'MESH:D009369', (119, 129))	('leukemia', 'Phenotype', 'HP:0001909', (28, 36))	('myeloid leukemia iPSC', 'Disease', (20, 41))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (20, 36))	('iPS', 'Disease', 'OMIM:613661', (106, 109))	('cells', 'CPA', (187, 192))	('iPS', 'Disease', 'OMIM:613661', (126, 129))	('cancer iPS', 'Disease', (119, 129))	('epigenetic changes', 'Var', (155, 173))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('myeloid leukemia iPSC', 'Disease', 'MESH:D007951', (20, 41))
239194	33202305	Cells with certain mutations are resistant to reprogramming, and reactivation of the DNA repair machinery by reprogramming was shown to rescue chromosomal abnormalities in iPSCs in a cell-autonomous manner.	('chromosomal abnormalities in iPSCs', 'Disease', (143, 177))	('mutations', 'Var', (19, 28))	('reactivation', 'Var', (65, 77))	('rescue', 'PosReg', (136, 142))	('chromosomal abnormalities in iPSCs', 'Disease', 'MESH:D002869', (143, 177))
239210	32042878	IgG antibodies against desmoglein 1 were elevated at 280u (reference range <18), but none resulted against desmoglein 3, consistent with pemphigus foliaceus.	('desmoglein 3', 'Gene', (107, 119))	('IgG antibodies', 'Phenotype', 'HP:0003237', (0, 14))	('elevated', 'PosReg', (41, 49))	('desmoglein 3', 'Gene', '1830', (107, 119))	('desmoglein 1', 'Gene', (23, 35))	('280u', 'Var', (53, 57))	('desmoglein 1', 'Gene', '1828', (23, 35))	('IgG antibodies', 'MPA', (0, 14))
239297	30241159	Using a next-generation sequencing platform to test the same liver metastasis, the patient was noted to have a single-nucleotide variant in the EGFR gene and a somatic deletion in the TP53 gene.	('liver metastasis', 'Disease', 'MESH:D009362', (61, 77))	('liver metastasis', 'Disease', (61, 77))	('EGFR', 'Gene', (144, 148))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('single-nucleotide variant', 'Var', (111, 136))	('patient', 'Species', '9606', (83, 90))	('EGFR', 'Gene', '1956', (144, 148))	('deletion', 'Var', (168, 176))
239312	30241159	Molecularly, it is characterized by the ASPSCR1-TFE3 fusion gene, which is encoded by the unbalanced translocation der(17)t(X;17)(p11;q25).	('der(17)t(X;17)(p11', 'Var', (115, 133))	('TFE3', 'Gene', '7030', (48, 52))	('ASPS', 'Phenotype', 'HP:0012218', (40, 44))	('der(17)t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (115, 138))	('ASPSCR1', 'Gene', '79058', (40, 47))	('TFE3', 'Gene', (48, 52))	('ASPSCR1', 'Gene', (40, 47))
239321	30241159	Nivolumab, a humanized immunoglobulin G4 monoclonal antibody against programmed cell death (PD-1), reverses T-cell exhaustion induced by the ligation of PD-1 receptor to its ligands, PD-L1 and PD-L2.	('ligation', 'Var', (141, 149))	('human', 'Species', '9606', (13, 18))	('T-cell exhaustion', 'Phenotype', 'HP:0005435', (108, 125))	('T-cell exhaustion', 'CPA', (108, 125))	('PD-L2', 'Gene', (193, 198))	('PD-L2', 'Gene', '574057', (193, 198))	('PD-1', 'Gene', (153, 157))	('reverses', 'NegReg', (99, 107))
239324	30241159	Furthermore, combined checkpoint blockade has been shown to produce substantially higher antitumor response and/or longer progression-free survival in patients with advanced melanoma or NSCLC when compared with monotherapy.	('checkpoint', 'Protein', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('NSCLC', 'Disease', (186, 191))	('higher', 'PosReg', (82, 88))	('patients', 'Species', '9606', (151, 159))	('combined', 'Var', (13, 21))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Disease', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('progression-free survival', 'CPA', (122, 147))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
239340	30241159	As previously described with other translocation-associated sarcomas, the breakpoint where both genes bind could serve as a neoantigen.	('sarcomas', 'Disease', (60, 68))	('breakpoint', 'Var', (74, 84))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))
239361	25300797	Transcriptome sequencing was used to characterize the gene fusions and mutations in 11 human osteosarcomas.	('human', 'Species', '9606', (87, 92))	('osteosarcomas', 'Disease', (93, 106))	('osteosarcomas', 'Phenotype', 'HP:0002669', (93, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('mutations', 'Var', (71, 80))	('osteosarcomas', 'Disease', 'MESH:D012516', (93, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
239362	25300797	Nine of 11 samples were found to harbor genetic inactivating alterations in the TP53 pathway.	('genetic inactivating alterations', 'Var', (40, 72))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))
239368	25300797	Among solid tumors, sarcomas were the first cancer type associated with chromosomal translocations and gene fusions.	('chromosomal translocations', 'Var', (72, 98))	('solid tumors', 'Disease', (6, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcomas', 'Disease', (20, 28))	('cancer', 'Disease', (44, 50))	('gene fusions', 'Var', (103, 115))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('associated', 'Reg', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('solid tumors', 'Disease', 'MESH:D009369', (6, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
239371	25300797	However, no recurrent fusion has ever been found in human osteosarcoma, although osteosarcoma is known to exhibit frequent numerical and structural chromosomal aberrations, such as TP53 mutations and deletions, MDM2 amplification, CDKN2A deletion, and hemi- or homozygous loss of RB1.	('MDM2', 'Gene', (211, 215))	('TP53', 'Gene', (181, 185))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('MDM2', 'Gene', '4193', (211, 215))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))	('hemi-', 'Var', (252, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('amplification', 'Var', (216, 229))	('deletions', 'Var', (200, 209))	('TP53', 'Gene', '7157', (181, 185))	('loss', 'NegReg', (272, 276))	('osteosarcoma', 'Disease', (58, 70))	('CDKN2A', 'Gene', (231, 237))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))	('RB1', 'Gene', (280, 283))	('osteosarcoma', 'Disease', (81, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('mutations', 'Var', (186, 195))	('human', 'Species', '9606', (52, 57))	('CDKN2A', 'Gene', '1029', (231, 237))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (148, 171))	('deletion', 'Var', (238, 246))	('RB1', 'Gene', '5925', (280, 283))
239374	25300797	Two selectively rearranged genomic loci that gave rise to fusion genes in 5 of 11 tumors were detected.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('fusion', 'Var', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
239375	25300797	One hotspot in 17p associated with TP53-disrupting rearrangements, while the other hotspot in 12q associated with 12q amplification.	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('rearrangements', 'Var', (51, 65))
239385	25300797	Sample 6-2 harbored a fusion between TP53 and cyclinB1(CCNB1), while sample 1 had TP53 juxtaposed with the non-coding gene AC016582.2, whose biological function is unknown.	('TP53', 'Gene', (82, 86))	('CCNB1', 'Gene', '891', (55, 60))	('cyclinB1', 'Gene', (46, 54))	('cyclinB1', 'Gene', '891', (46, 54))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (37, 41))	('fusion', 'Var', (22, 28))	('CCNB1', 'Gene', (55, 60))
239388	25300797	The second hotspot, located in 12q, was rearranged in four osteosarcomas (samples 1, 8, 9, 10) and coincided with the genes MDM2 and CDK4 (Figure 1).	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('osteosarcomas', 'Disease', (59, 72))	('osteosarcoma', 'Phenotype', 'HP:0002669', (59, 71))	('osteosarcomas', 'Phenotype', 'HP:0002669', (59, 72))	('CDK4', 'Gene', (133, 137))	('rearranged', 'Var', (40, 50))	('osteosarcomas', 'Disease', 'MESH:D012516', (59, 72))	('CDK4', 'Gene', '1019', (133, 137))	('MDM2', 'Gene', '4193', (124, 128))	('MDM2', 'Gene', (124, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
239390	25300797	A strong localized gene dosage effect was observed in three of the four 12q-rearranged cases (samples 8, 9 and 10), suggesting that fusion genes in this locus often arise as a by-product of MDM2/CDK4 co-amplification (Figure 2B).	('MDM2', 'Gene', '4193', (190, 194))	('MDM2', 'Gene', (190, 194))	('fusion genes', 'Var', (132, 144))	('CDK4', 'Gene', (195, 199))	('CDK4', 'Gene', '1019', (195, 199))
239391	25300797	Many of the 12q fusion genes produced chimeric proteins or disrupted cancer-associated genes such as RUNX2, CCND3, and LRP1, indicating that some of the fusions may contribute to cancer progression independently of MDM2/CDK4 co-amplification.	('CCND3', 'Gene', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('contribute', 'Reg', (165, 175))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('CDK4', 'Gene', '1019', (220, 224))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('LRP1', 'Gene', (119, 123))	('CCND3', 'Gene', '896', (108, 113))	('fusions', 'Var', (153, 160))	('MDM2', 'Gene', (215, 219))	('LRP1', 'Gene', '4035', (119, 123))	('RUNX2', 'Gene', (101, 106))	('cancer', 'Disease', (69, 75))	('MDM2', 'Gene', '4193', (215, 219))	('RUNX2', 'Gene', '860', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('disrupted', 'NegReg', (59, 68))	('CDK4', 'Gene', (220, 224))	('produced', 'Reg', (29, 37))	('chimeric', 'Var', (38, 46))	('cancer', 'Disease', (179, 185))
239392	25300797	Based on the observed rearrangements in the TP53 and MDM2/CDK4 loci, we set out to analyze the p53 and RB1 pathways for further alterations.	('CDK4', 'Gene', '1019', (58, 62))	('MDM2', 'Gene', '4193', (53, 57))	('RB1', 'Gene', (103, 106))	('MDM2', 'Gene', (53, 57))	('analyze', 'Reg', (83, 90))	('RB1', 'Gene', '5925', (103, 106))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('TP53', 'Gene', '7157', (44, 48))	('rearrangements', 'Var', (22, 36))	('CDK4', 'Gene', (58, 62))	('TP53', 'Gene', (44, 48))
239393	25300797	In addition to the two TP53-rearranged samples (sample 1 and 6-2), we discovered a TP53 mutation with loss-of-heterozygosity in one sample (sample 3-1) (Figure 2C, Additional file 1: Figure S4), and TP53 deletions in two samples (samples 2 and 6-1) (Figure 2C, Additional file 1: Figure S5).	('TP53', 'Gene', '7157', (83, 87))	('mutation', 'Var', (88, 96))	('TP53', 'Gene', (23, 27))	('TP53', 'Gene', (199, 203))	('TP53', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (23, 27))	('deletions', 'Var', (204, 213))	('loss-of-heterozygosity', 'NegReg', (102, 124))	('TP53', 'Gene', '7157', (199, 203))
239397	25300797	Our mutation analysis revealed 522 non-synonymous variants, including mutations in genes IDH1, IDH2, SMARCB1, DNMT1, BRD7 and PIK3C3 (Figure 2C).	('BRD7', 'Gene', (117, 121))	('BRD7', 'Gene', '29117', (117, 121))	('PIK3C3', 'Gene', (126, 132))	('mutations', 'Var', (70, 79))	('DNMT1', 'Gene', (110, 115))	('SMARCB1', 'Gene', '6598', (101, 108))	('DNMT1', 'Gene', '1786', (110, 115))	('SMARCB1', 'Gene', (101, 108))	('IDH2', 'Gene', '3418', (95, 99))	('IDH2', 'Gene', (95, 99))	('IDH1', 'Gene', (89, 93))	('PIK3C3', 'Gene', '5289', (126, 132))	('IDH1', 'Gene', '3417', (89, 93))
239398	25300797	The IDH1 R132H mutation found in osteosarcoma sample 3-1 is a frequent event in low-grade brain tumors, central and periosteal chondromas, and central chondrosarcomas.	('IDH1', 'Gene', '3417', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('chondrosarcomas', 'Disease', (151, 166))	('R132H', 'Mutation', 'rs121913500', (9, 14))	('osteosarcoma', 'Phenotype', 'HP:0002669', (33, 45))	('brain tumors', 'Phenotype', 'HP:0030692', (90, 102))	('brain tumors', 'Disease', 'MESH:D001932', (90, 102))	('periosteal chondromas', 'Disease', (116, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('periosteal chondromas', 'Disease', 'MESH:D002812', (116, 137))	('brain tumors', 'Disease', (90, 102))	('central', 'Disease', (104, 111))	('R132H', 'Var', (9, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('IDH1', 'Gene', (4, 8))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (151, 165))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (151, 166))	('osteosarcoma', 'Disease', (33, 45))	('osteosarcoma', 'Disease', 'MESH:D012516', (33, 45))	('chondrosarcomas', 'Disease', 'MESH:D002813', (151, 166))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))
239399	25300797	Sample 3-1 also harbored a non-synonymous mutation in SMARCB1, a gene that has been associated with congenital risk of rhabdoid tumors and chondrosarcomas.	('chondrosarcomas', 'Disease', 'MESH:D002813', (139, 154))	('chondrosarcomas', 'Disease', (139, 154))	('associated with', 'Reg', (84, 99))	('rhabdoid tumors', 'Disease', (119, 134))	('SMARCB1', 'Gene', '6598', (54, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('non-synonymous mutation', 'Var', (27, 50))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (119, 134))	('SMARCB1', 'Gene', (54, 61))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (139, 154))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (139, 153))
239405	25300797	None of the 240 other sarcomas was positive for LRP1-SNRNP25 or KCNMB4-CCND3 fusions, nor for the four other fusion genes found in our analysis.	('KCNMB4', 'Gene', (64, 70))	('SNRNP25', 'Gene', (53, 60))	('sarcomas', 'Disease', (22, 30))	('CCND3', 'Gene', '896', (71, 76))	('fusions', 'Var', (77, 84))	('LRP1', 'Gene', (48, 52))	('CCND3', 'Gene', (71, 76))	('sarcomas', 'Disease', 'MESH:D012509', (22, 30))	('LRP1', 'Gene', '4035', (48, 52))	('SNRNP25', 'Gene', '79622', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('KCNMB4', 'Gene', '27345', (64, 70))
239406	25300797	In both LRP1-SNRNP25 positive tumors, the fusion juxtaposed exon 8 of LRP1 with exon 2 of SNRNP25 (Figure 3A) and resulted in increased expression of SNRNP25 under control of the LRP1 promoter (Figure 3D).	('LRP1', 'Gene', '4035', (179, 183))	('SNRNP25', 'Gene', '79622', (150, 157))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('expression', 'MPA', (136, 146))	('SNRNP25', 'Gene', (150, 157))	('fusion', 'Var', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Disease', (30, 36))	('SNRNP25', 'Gene', '79622', (13, 20))	('SNRNP25', 'Gene', (13, 20))	('LRP1', 'Gene', (8, 12))	('expression', 'Species', '29278', (136, 146))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('LRP1', 'Gene', '4035', (8, 12))	('SNRNP25', 'Gene', '79622', (90, 97))	('LRP1', 'Gene', (70, 74))	('SNRNP25', 'Gene', (90, 97))	('LRP1', 'Gene', '4035', (70, 74))	('increased', 'PosReg', (126, 135))	('LRP1', 'Gene', (179, 183))
239410	25300797	The FISH also revealed amplification of both LRP1 and SNRNP25, suggesting a complex genetic alteration of osteosarcoma.	('osteosarcoma', 'Disease', (106, 118))	('SNRNP25', 'Gene', (54, 61))	('LRP1', 'Gene', (45, 49))	('osteosarcoma', 'Disease', 'MESH:D012516', (106, 118))	('amplification', 'Var', (23, 36))	('LRP1', 'Gene', '4035', (45, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('SNRNP25', 'Gene', '79622', (54, 61))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
239417	25300797	To study any oncogenic contribution conferred by fusion genes in our cohort, we cloned the LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes into pcDNA3.1 expression vectors and validated the vectors by sequencing (Additional file 1: Figure S12A).	('CCND3', 'Gene', (115, 120))	('SNRNP25', 'Gene', '79622', (96, 103))	('LRP1', 'Gene', '4035', (91, 95))	('S12A', 'SUBSTITUTION', 'None', (234, 238))	('KCNMB4', 'Gene', '27345', (108, 114))	('SNRNP25', 'Gene', (96, 103))	('S12A', 'Var', (234, 238))	('KCNMB4', 'Gene', (108, 114))	('LRP1', 'Gene', (91, 95))	('CCND3', 'Gene', '896', (115, 120))	('expression vectors', 'Species', '29278', (148, 166))
239418	25300797	Transfection of the LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes into human osteosarcoma SAOS-2 cells resulted in detectable expression of fusion proteins (Additional file 1: Figure S12B).	('LRP1', 'Gene', (20, 24))	('expression', 'MPA', (123, 133))	('human', 'Species', '9606', (68, 73))	('SNRNP25', 'Gene', '79622', (25, 32))	('KCNMB4', 'Gene', '27345', (37, 43))	('CCND3', 'Gene', (44, 49))	('SNRNP25', 'Gene', (25, 32))	('LRP1', 'Gene', '4035', (20, 24))	('S12B', 'Var', (180, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('fusion', 'Interaction', (137, 143))	('KCNMB4', 'Gene', (37, 43))	('expression', 'Species', '29278', (123, 133))	('osteosarcoma', 'Disease', 'MESH:D012516', (74, 86))	('osteosarcoma', 'Disease', (74, 86))	('CCND3', 'Gene', '896', (44, 49))	('S12B', 'SUBSTITUTION', 'None', (180, 184))	('osteosarcoma', 'Phenotype', 'HP:0002669', (74, 86))	('SAOS-2', 'CellLine', 'CVCL:0548', (87, 93))
239423	25300797	However, both the LRP1-SNRNP25 and KCNMB4-CCND3 fusions significantly promoted cell migration of SAOS-2 cells in transwell assays (Figure 4A), and LRP1-SNRNP25 also promoted invasion significantly (Figure 4B).	('SAOS-2', 'CellLine', 'CVCL:0548', (97, 103))	('LRP1', 'Gene', (147, 151))	('fusions', 'Var', (48, 55))	('LRP1', 'Gene', (18, 22))	('cell migration', 'CPA', (79, 93))	('SNRNP25', 'Gene', (23, 30))	('KCNMB4', 'Gene', '27345', (35, 41))	('KCNMB4', 'Gene', (35, 41))	('LRP1', 'Gene', '4035', (147, 151))	('invasion', 'CPA', (174, 182))	('SNRNP25', 'Gene', '79622', (152, 159))	('promoted', 'PosReg', (165, 173))	('CCND3', 'Gene', '896', (42, 47))	('LRP1', 'Gene', '4035', (18, 22))	('promoted', 'PosReg', (70, 78))	('CCND3', 'Gene', (42, 47))	('SNRNP25', 'Gene', '79622', (23, 30))	('SNRNP25', 'Gene', (152, 159))
239429	25300797	Taken together, these data suggest that LRP1-SNRNP25 and KCNMB4-CCND3 fusions confer an oncogenic effect in human osteosarcoma by enhancing cancer cell motility.	('CCND3', 'Gene', '896', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('osteosarcoma', 'Disease', (114, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (114, 126))	('LRP1', 'Gene', (40, 44))	('LRP1', 'Gene', '4035', (40, 44))	('SNRNP25', 'Gene', '79622', (45, 52))	('oncogenic effect', 'MPA', (88, 104))	('cancer', 'Disease', (140, 146))	('KCNMB4', 'Gene', '27345', (57, 63))	('CCND3', 'Gene', (64, 69))	('SNRNP25', 'Gene', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('enhancing', 'PosReg', (130, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (114, 126))	('human', 'Species', '9606', (108, 113))	('KCNMB4', 'Gene', (57, 63))	('fusions', 'Var', (70, 77))
239430	25300797	Further investigation into the functional roles of KCNMB4-CCND3 and LRP1-SNRNP25 is necessary, particularly to investigate the mechanisms through which the fusion genes affect invasion/migration.	('LRP1', 'Gene', '4035', (68, 72))	('affect', 'Reg', (169, 175))	('KCNMB4', 'Gene', '27345', (51, 57))	('SNRNP25', 'Gene', '79622', (73, 80))	('KCNMB4', 'Gene', (51, 57))	('invasion/migration', 'CPA', (176, 194))	('CCND3', 'Gene', '896', (58, 63))	('CCND3', 'Gene', (58, 63))	('LRP1', 'Gene', (68, 72))	('SNRNP25', 'Gene', (73, 80))	('fusion', 'Var', (156, 162))
239438	25300797	Our preliminary data shows that the MMP-2, MMP-9, p-AKT, pERK, pMAPK, and JNK were increased significantly in transfected SAOS-2 tumor cells, while caspase-3 and Ki-67 did not change significantly (data not shown).	('tumor', 'Disease', (129, 134))	('increased', 'PosReg', (83, 92))	('SAOS-2', 'CellLine', 'CVCL:0548', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('MMP-2', 'Gene', '4313', (36, 41))	('caspase-3', 'Gene', '836', (148, 157))	('MMP-9', 'Gene', '4318', (43, 48))	('pMAPK', 'MPA', (63, 68))	('MMP-9', 'Gene', (43, 48))	('pERK', 'Gene', '9451', (57, 61))	('caspase-3', 'Gene', (148, 157))	('pERK', 'Gene', (57, 61))	('AKT', 'Gene', (52, 55))	('transfected', 'Var', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MMP-2', 'Gene', (36, 41))	('JNK', 'Gene', (74, 77))	('JNK', 'Gene', '5599', (74, 77))	('AKT', 'Gene', '207', (52, 55))
239443	25300797	This hypothesis is supported by the observation that all four LRP1-SNRNP25 and KCNMB4-CCND3 fusions had a transcript structure compatible with production of chimeric protein.	('SNRNP25', 'Gene', (67, 74))	('transcript structure', 'MPA', (106, 126))	('KCNMB4', 'Gene', (79, 85))	('LRP1', 'Gene', (62, 66))	('KCNMB4', 'Gene', '27345', (79, 85))	('fusions', 'Var', (92, 99))	('LRP1', 'Gene', '4035', (62, 66))	('SNRNP25', 'Gene', '79622', (67, 74))	('CCND3', 'Gene', '896', (86, 91))	('CCND3', 'Gene', (86, 91))
239444	25300797	Fusion genes that arise as a by-product of somatic copy number alterations but contribute an independent oncogenic effect have been observed in other cancers.	('Fusion', 'Var', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('copy number alterations', 'Var', (51, 74))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
239445	25300797	In glioblastoma, EGFR-SEPT14 and EGFR-PSPH fusions associated with EGFR amplification were recently observed to result in constitutive activation of EGFR signaling.	('activation', 'PosReg', (135, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('SEPT14', 'Gene', '346288', (22, 28))	('PSPH', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', '1956', (33, 37))	('glioblastoma', 'Disease', (3, 15))	('fusions', 'Var', (43, 50))	('SEPT14', 'Gene', (22, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('EGFR', 'Gene', (149, 153))	('PSPH', 'Gene', '5723', (38, 42))	('EGFR', 'Gene', (33, 37))	('EGFR', 'Gene', (67, 71))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
239448	25300797	Another limitation is that we did not identify the genomic breakpoints and protein products associated with KCNMB4-CCND3 and LRP1-SNRNP25 fusions in clinical samples.	('CCND3', 'Gene', (115, 120))	('SNRNP25', 'Gene', (130, 137))	('clinical samples', 'Species', '191496', (149, 165))	('KCNMB4', 'Gene', '27345', (108, 114))	('LRP1', 'Gene', (125, 129))	('KCNMB4', 'Gene', (108, 114))	('SNRNP25', 'Gene', '79622', (130, 137))	('LRP1', 'Gene', '4035', (125, 129))	('CCND3', 'Gene', '896', (115, 120))	('fusions', 'Var', (138, 145))
239452	25300797	The findings of our study support the view that the majority of osteosarcomas harbor alterations in the p53 pathway, including recurrent translocations disrupting the TP53 gene.	('p53', 'Gene', (104, 107))	('osteosarcomas', 'Disease', 'MESH:D012516', (64, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('p53', 'Gene', '7157', (104, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('alterations', 'Reg', (85, 96))	('TP53', 'Gene', '7157', (167, 171))	('osteosarcomas', 'Disease', (64, 77))	('translocations', 'Var', (137, 151))	('disrupting', 'NegReg', (152, 162))	('TP53', 'Gene', (167, 171))	('osteosarcomas', 'Phenotype', 'HP:0002669', (64, 77))	('osteosarcoma', 'Phenotype', 'HP:0002669', (64, 76))
239473	25300797	The detection of possible fusion proteins in osteosarcoma tissue lysate and FFPE tissue sections by western blotting and immunohistochemistry used anti-CCND3, anti-KCNMB4, anti-LRP-1 antibodies (ab28283, ab89703 and ab92544, ABCAM, Cambridge, MA) and anti-SNRNP25 antibody (H00079622-B01, Novus, Littleton, CO).	('H00079622-B01', 'Var', (274, 287))	('KCNMB4', 'Gene', '27345', (164, 170))	('CCND3', 'Gene', (152, 157))	('KCNMB4', 'Gene', (164, 170))	('SNRNP25', 'Gene', (256, 263))	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('osteosarcoma', 'Disease', (45, 57))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('LRP-1', 'Gene', (177, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('ab28283', 'Var', (195, 202))	('CCND3', 'Gene', '896', (152, 157))	('SNRNP25', 'Gene', '79622', (256, 263))	('LRP-1', 'Gene', '4035', (177, 182))
239516	24359263	During hospitalization a total body computerized tomography (CT) showed multiple nodular lesions in both lungs, minimal right pneumothorax, pathological soft tissue in the right maxillar sinus, and enlargement of supraclavear lymph nodes.	('multiple nodular lesions', 'Disease', 'MESH:D020518', (72, 96))	('supraclavear lymph nodes', 'CPA', (213, 237))	('pathological', 'Var', (140, 152))	('multiple nodular lesions', 'Disease', (72, 96))	('enlargement', 'PosReg', (198, 209))	('pneumothorax', 'Phenotype', 'HP:0002107', (126, 138))
239544	24359263	Quantitative evaluation of HHV8 DNA in the lungs, the Vater's papilla and the brain showed: 15872 copies/106 cells, 7789 copies/106 cells and 2316 copies/106 cells respectively.	('7789 copies/106', 'Var', (116, 131))	('15872 copies/106', 'Var', (92, 108))	('HHV8', 'Species', '37296', (27, 31))	('papilla', 'Disease', (62, 69))	('HHV8', 'Gene', (27, 31))	('papilla', 'Disease', 'MESH:D010211', (62, 69))
239599	22777357	Reprogrammed-sarcomas were also able to undergo Activin A (50ng/ml) Noggin (100ng/ml) directed differentiation into endoderm and ectoderm respectively (Figure A-E).	('sarcomas', 'Disease', (13, 21))	('ectoderm', 'CPA', (129, 137))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	('100ng/ml', 'Var', (76, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('endoderm', 'CPA', (116, 124))	('Noggin', 'Gene', '9241', (68, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('Noggin', 'Gene', (68, 74))
239629	22777357	In contrast, only rare CD235a(GPA) expressing cells can be observed at day 14, however at day 28 three distinct populations of cells can be identified: CD235a+/DAPI+ (green circle); CD235-/DAPI+ (blue circle); and CD235a+/DAPI- (yellow circle).	('DAPI', 'Chemical', 'MESH:C007293', (222, 226))	('CD235a', 'Gene', (214, 220))	('DAPI', 'Chemical', 'MESH:C007293', (189, 193))	('CD235a', 'Gene', (152, 158))	('DAPI', 'Chemical', 'MESH:C007293', (160, 164))	('CD235a', 'Gene', (23, 29))	('CD235a', 'Gene', '2993', (214, 220))	('CD235a', 'Gene', '2993', (152, 158))	('CD235a', 'Gene', '2993', (23, 29))	('CD235-/DAPI+', 'Var', (182, 194))
239632	22777357	Our results suggest that direct reprogramming can supersede the specific genetic and/or epigenetic changes that resulted in the lineage specific differentiation block and subsequent tumorigenesis.	('tumor', 'Disease', (182, 187))	('lineage specific differentiation block', 'CPA', (128, 166))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('epigenetic changes', 'Var', (88, 106))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
239635	22777357	We assessed the epigenetic status of the myc promoter in parental sarcomas and reprogrammed-sarcomas using chromatin immunoprecipitation to assess for active, H3K4triMe, and repressive, H3K27triMe marks.	('sarcomas', 'Disease', (92, 100))	('myc', 'Gene', (41, 44))	('H3K27triMe', 'Var', (186, 196))	('parental sarcomas', 'Disease', 'MESH:D063129', (57, 74))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('myc', 'Gene', '4609', (41, 44))	('H3K4triMe', 'Var', (159, 168))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('sarcomas', 'Disease', (66, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('parental sarcomas', 'Disease', (57, 74))
239636	22777357	We observed that in parental sarcoma cell lines the myc promoter is H3K4triMe modified - consistent with an active state; while in reprogrammed-sarcomas the myc promoter is H3K4triMe and H3K27triMe modified (Figure 4B) consistent with a bivalent state characteristic of many stem cell genes that exist in a 'poised' state that is amenable to being rapidly activated or repressed by removal of the appropriate modification.	('myc', 'Gene', (157, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (144, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('H3K27triMe', 'Var', (187, 197))	('sarcomas', 'Disease', (144, 152))	('parental sarcoma', 'Disease', (20, 36))	('myc', 'Gene', '4609', (157, 160))	('myc', 'Gene', (52, 55))	('parental sarcoma', 'Disease', 'MESH:D063129', (20, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('myc', 'Gene', '4609', (52, 55))	('sarcomas', 'Disease', 'MESH:D012509', (144, 152))
239647	22777357	However, given that 205 promoters were identified as hypomethylated and only 23 genes showed a definitive increase in gene expression, our data suggests that (as demonstrated for the myc promoter above) changes in DNA methylation are not sufficient to result in changes in gene expression for the majority of genes.	('gene expression', 'MPA', (273, 288))	('myc', 'Gene', (183, 186))	('changes', 'Reg', (262, 269))	('myc', 'Gene', '4609', (183, 186))	('changes', 'Var', (203, 210))
239651	22777357	As expected since the vast majority of genes were hypomethylated, all oncogenes and TSGs affected by DNA methylation were also hypomethylated as a result of reprogramming.	('oncogenes', 'Gene', (70, 79))	('methylation', 'Var', (105, 116))	('TSG', 'Gene', '57045', (84, 87))	('affected', 'Reg', (89, 97))	('TSG', 'Gene', (84, 87))	('hypomethylated', 'Var', (127, 141))
239653	22777357	However, in contrast to somatic reprogramming and tumorigenesis, which would have predicted that TSGs should have been silenced (via DNA hypermethylation); our observations that TSGs are also hypomethylated suggests that there may be significant differences in epigenetic control between reprogrammed cancer and somatic cells.	('TSG', 'Gene', (97, 100))	('TSG', 'Gene', '57045', (178, 181))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('cancer', 'Disease', (301, 307))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('TSG', 'Gene', '57045', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('TSG', 'Gene', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('hypomethylated', 'Var', (192, 206))	('tumor', 'Disease', (50, 55))
239665	22777357	To assess if this was similarly true for reprogrammed cancer cells, we performed gene expression analysis of our sarcoma and reprogrammed-sarcomas and compared them to known gene expression patterns for ESCs (GSE6561), mesenchymal stem cells (GSE6460), fibroblasts (GSE9865), reprogrammed fibroblasts (GSE9709), partially reprogrammed fibroblasts (GSE9865) and reprogrammed-sarcomas.	('GSE6561', 'Chemical', '-', (209, 216))	('sarcoma', 'Disease', (374, 381))	('sarcomas', 'Phenotype', 'HP:0100242', (374, 382))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('sarcomas', 'Disease', (374, 382))	('GSE9865', 'Chemical', '-', (266, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (374, 381))	('GSE6460', 'Chemical', '-', (243, 250))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('sarcoma', 'Disease', (138, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('cancer', 'Disease', (54, 60))	('sarcoma', 'Disease', (113, 120))	('sarcomas', 'Disease', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('GSE9865', 'Var', (348, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('GSE9865', 'Chemical', '-', (348, 355))	('sarcoma', 'Disease', 'MESH:D012509', (374, 381))	('sarcomas', 'Disease', 'MESH:D012509', (374, 382))
239684	22777357	To the best of our knowledge this is the first demonstration that bestowing aspects of pluripotentiality to human derived cancer cells results in their ability to achieve the terminally differentiated state both in an alternative lineage as well as the lineage in which they were originally blocked with a simultaneous abrogation of tumorigenicity.	('tumor', 'Disease', (333, 338))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('pluripotentiality', 'Var', (87, 104))	('human', 'Species', '9606', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('achieve', 'PosReg', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('terminally differentiated state', 'CPA', (175, 206))
239760	22777357	Chromatin immunoprecipitation (ChIP) was performed as previously described by us using EZ ChIP  Chromatin Immunoprecipitation Kit (Upstate; 17-371), and the following antibodies: Millipore: anti-trimethyl-histone H3(lys27); anti-trimethyl-histone H3(Lys4).	('anti-trimethyl-histone', 'Var', (190, 212))	('Lys4', 'Chemical', '-', (250, 254))	('anti-trimethyl-histone', 'Var', (224, 246))	('trimethyl-histone', 'Chemical', '-', (195, 212))	('trimethyl-histone', 'Chemical', '-', (229, 246))	('lys27', 'Chemical', '-', (216, 221))
239785	21152115	Dr. Harald zur Hausen of Germany won the Nobel Prize in 2008 for his discovery in 1983 that HPVs cause cervical cancer.	('HPVs', 'Var', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('HPV', 'Species', '10566', (92, 95))	('cause', 'Reg', (97, 102))	('cervical cancer', 'Disease', (103, 118))	('cervical cancer', 'Disease', 'MESH:D002583', (103, 118))
239787	21152115	High-risk or oncogenic HPVs are etiological agents of cervical cancer.	('cervical cancer', 'Disease', (54, 69))	('cervical cancer', 'Disease', 'MESH:D002583', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('oncogenic', 'Var', (13, 22))	('HPV', 'Species', '10566', (23, 26))
239792	21152115	The US Food and Drug Administration (FDA) in June 2006 approved Gardasil, the first cancer vaccine, for use in females 9-26 years of age to prevent cervical cancer, precancerous genital lesions, and genital warts caused by HPV6, HPV11, HPV16, and HPV18.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('HPV16', 'Species', '333760', (236, 241))	('precancerous genital lesions', 'Disease', 'MESH:D011230', (165, 193))	('HPV11', 'Species', '10580', (229, 234))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (168, 174))	('precancerous genital lesions', 'Disease', (165, 193))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('genital warts', 'Disease', (199, 212))	('prevent', 'PosReg', (140, 147))	('warts', 'Phenotype', 'HP:0200043', (207, 212))	('HPV18', 'Var', (247, 252))	('cervical cancer', 'Disease', 'MESH:D002583', (148, 163))	('HPV', 'Species', '10566', (247, 250))	('cervical cancer', 'Disease', (148, 163))	('cancer', 'Disease', (84, 90))	('HPV16', 'Gene', (236, 241))	('HPV6', 'Var', (223, 227))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('genital warts', 'Phenotype', 'HP:0032301', (199, 212))	('genital lesions', 'Phenotype', 'HP:0010787', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (157, 163))	('HPV11', 'Var', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('HPV', 'Species', '10566', (223, 226))	('HPV', 'Species', '10566', (236, 239))	('HPV', 'Species', '10566', (229, 232))
239794	21152115	EBV infects B lymphocytes, but does not replicate within the B cells; instead, it transforms them into lymphoblasts, which have an indefinite life span, rendering these cells immortal.	('transforms', 'Reg', (82, 92))	('EBV', 'Species', '10376', (0, 3))	('EBV', 'Var', (0, 3))
239802	21152115	For decades, SV40 which does not infect human has attracted the interest of many investigators in the field of cancer research because of its characteristic tumor antigens (T antigens) that can cause malignant cell transformation.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('SV40', 'Species', '1891767', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('SV40', 'Var', (13, 17))	('cancer', 'Disease', (111, 117))	('malignant cell transformation', 'CPA', (200, 229))	('cause', 'Reg', (194, 199))	('human', 'Species', '9606', (40, 45))
239806	21152115	The integrated MCV DNA encodes a mutant T antigen that prevents autoactivation of integrated virus replication.	('autoactivation', 'MPA', (64, 78))	('mutant', 'Var', (33, 39))	('prevents', 'NegReg', (55, 63))	('MCV', 'Species', '493803', (15, 18))
239810	21152115	Two viral oncogenes, E1A and E1B, have been identified as responsible for the adenovirus tumorigenicity and thus have served as useful tools for studying many important cellular processes in tumor biology.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('E1A', 'Var', (21, 24))	('E1B', 'Var', (29, 32))	('adenovirus', 'Species', '28285', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('adenovirus', 'Protein', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
239833	21152115	An E6 F47R mutant is defective for polyubiquitination and degradation of p53.	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('F47R', 'Mutation', 'p.F47R', (6, 10))	('polyubiquitination', 'Disease', 'None', (35, 53))	('E6 F47R', 'Var', (3, 10))	('defective', 'NegReg', (21, 30))	('polyubiquitination', 'Disease', (35, 53))	('degradation', 'MPA', (58, 69))
239837	21152115	In contrast, low-risk 11E6 has minimal binding affinity for E6AP and influences the degradation of p53 only weakly in vivo.	('E6AP', 'Gene', (60, 64))	('E6AP', 'Gene', '7337', (60, 64))	('11E6', 'Var', (22, 26))	('binding affinity', 'Interaction', (39, 55))	('influences', 'Reg', (69, 79))	('degradation', 'MPA', (84, 95))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('minimal', 'NegReg', (31, 38))
239839	21152115	Similar to E6 proteins encoded by other papillomaviruses, the 16E6 which has been extensively analyzed, contains four zinc-binding motifs (Cys-X-X-Cys) and forms two Cys/Cys fingers that bind zinc directly.	('papillomavirus', 'Disease', (40, 54))	('Cys', 'Chemical', 'MESH:D003545', (166, 169))	('16E6', 'Gene', (62, 66))	('Cys-X-X-Cys', 'Var', (139, 150))	('bind', 'Interaction', (187, 191))	('Cys', 'Chemical', 'MESH:D003545', (170, 173))	('Cys', 'Chemical', 'MESH:D003545', (139, 142))	('Cys', 'Chemical', 'MESH:D003545', (147, 150))	('X-X-Cys', 'Chemical', '-', (143, 150))	('papillomavirus', 'Disease', 'MESH:D030361', (40, 54))
239841	21152115	In addition to its effect on p53, 16E6 can interact with other transcription factors and coactivators, including p300/CBP, IRF-3, and c-Myc.	('c-Myc', 'Gene', (134, 139))	('p300', 'Gene', (113, 117))	('p300', 'Gene', '2033', (113, 117))	('CBP', 'Gene', (118, 121))	('IRF-3', 'Gene', '3661', (123, 128))	('p53', 'Gene', (29, 32))	('IRF-3', 'Gene', (123, 128))	('c-Myc', 'Gene', '4609', (134, 139))	('16E6', 'Var', (34, 38))	('CBP', 'Gene', '1387', (118, 121))	('p53', 'Gene', '7157', (29, 32))	('interact', 'Interaction', (43, 51))
239843	21152115	The multifunctional activity of 16E6 is not restricted to the nucleus, because it can act as a regulator of signal transduction through interacting with cytoplasmic E6BP (Erc55), E6TP, paxillin, TNFR1, protein tyrosine phosphatase H1, and PDZ proteins such as SAP97/hDlg and MAGI-1.	('protein tyrosine phosphatase H1', 'Gene', '5774', (202, 233))	('16E6', 'Var', (32, 36))	('E6BP', 'Gene', '5955', (165, 169))	('TNFR1', 'Gene', (195, 200))	('SAP97', 'Gene', (260, 265))	('Erc55', 'Gene', (171, 176))	('interacting', 'Interaction', (136, 147))	('Erc55', 'Gene', '5955', (171, 176))	('MAGI-1', 'Gene', '9223', (275, 281))	('hDlg', 'Gene', '1739', (266, 270))	('hDlg', 'Gene', (266, 270))	('SAP97', 'Gene', '1739', (260, 265))	('protein tyrosine phosphatase H1', 'Gene', (202, 233))	('TNFR1', 'Gene', '7132', (195, 200))	('E6BP', 'Gene', (165, 169))	('MAGI-1', 'Gene', (275, 281))
239848	21152115	In addition to its cellular transformation activities, oncogenic E7 also plays a role in the viral life cycle and affects many other cellular activities in HPV-infected cells.	('cellular transformation activities', 'CPA', (19, 53))	('HPV-infected', 'Disease', 'MESH:D030361', (156, 168))	('HPV-infected', 'Disease', (156, 168))	('oncogenic E7', 'Var', (55, 67))	('cellular activities', 'CPA', (133, 152))	('viral life cycle', 'CPA', (93, 109))	('affects', 'Reg', (114, 121))
239852	21152115	As both high-risk and low-risk HPV E7s interact with p300, PCAF, steroid receptor coactivator 1, and p600, these interactions do not appear to be sufficient to mediate the transformation function of HPV E7.	('HPV', 'Species', '10566', (199, 202))	('HPV', 'Species', '10566', (31, 34))	('p300', 'Gene', '2033', (53, 57))	('PCAF', 'Gene', (59, 63))	('interact', 'Interaction', (39, 47))	('p300', 'Gene', (53, 57))	('PCAF', 'Gene', '8850', (59, 63))	('p600', 'Var', (101, 105))
239853	21152115	The adenovirus genome encodes two viral oncogenes, E1A and E1B, positioned side-by-side in the left 11.2% of the genome.	('adenovirus', 'Species', '28285', (4, 14))	('E1B', 'Var', (59, 62))	('E1A', 'Var', (51, 54))
239857	21152115	Both E1A proteins (289R and 243R) are most abundant during early viral infection and display similar functions in the induction of cellular DNA synthesis, inactivation of pRB (equivalent to the HPV E7 oncoprotein), stimulation of cellular transformation, and promotion of apoptosis through protein-protein interactions.	('cellular DNA synthesis', 'MPA', (131, 153))	('inactivation', 'NegReg', (155, 167))	('pRB', 'Gene', (171, 174))	('viral infection', 'Disease', 'MESH:D001102', (65, 80))	('289R', 'Var', (19, 23))	('promotion', 'PosReg', (259, 268))	('viral infection', 'Disease', (65, 80))	('pRB', 'Gene', '5925', (171, 174))	('apoptosis', 'CPA', (272, 281))	('HPV', 'Species', '10566', (194, 197))	('cellular transformation', 'CPA', (230, 253))	('interactions', 'Interaction', (306, 318))	('protein-protein', 'Protein', (290, 305))	('stimulation', 'PosReg', (215, 226))
239858	21152115	E1A CR2 binds pRB and the related pocket proteins p107 and p130 with high affinity, and together with a lower-affinity binding region within CR1 displaces pRB proteins from E2F transcription factors, resulting in derepression of cell cycle genes.	('pRB', 'Gene', '5925', (155, 158))	('CR2', 'Species', '2498238', (4, 7))	('pRB', 'Gene', (155, 158))	('p107', 'Var', (50, 54))	('displaces', 'NegReg', (145, 154))	('pRB', 'Gene', (14, 17))	('E1A', 'Var', (0, 3))	('derepression', 'PosReg', (213, 225))	('cell cycle', 'CPA', (229, 239))	('pRB', 'Gene', '5925', (14, 17))
239862	21152115	The major roles of E1B-19K and E1B-55K in viral infection are suppression of host cell apoptosis and, in rodent cells, promotion of complete transformation in cooperation with E1A.	('viral infection', 'Disease', 'MESH:D001102', (42, 57))	('E1B-19K', 'Var', (19, 26))	('E1B-55K', 'Var', (31, 38))	('viral infection', 'Disease', (42, 57))	('complete transformation', 'CPA', (132, 155))	('host cell apoptosis', 'CPA', (77, 96))	('promotion', 'PosReg', (119, 128))
239863	21152115	Expression of E1A alone is not sufficient for efficiently transforming primary cells or inducing lung carcinogenesis in transgenic E1A mice, but E1B-19K and E1B-55K can individually cooperate with E1A to produce a fully transformed tumorigenic phenotype and to induce lung carcinogenesis in transgenic mice expressing both E1A and E1B transgenes.	('E1B-55K', 'Var', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('induce', 'PosReg', (261, 267))	('transgenic mice', 'Species', '10090', (291, 306))	('transgenic', 'Species', '10090', (291, 301))	('lung carcinogenesis', 'Disease', (268, 287))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('E1B-19K', 'Var', (145, 152))	('mice', 'Species', '10090', (135, 139))	('lung carcinogenesis', 'Disease', (97, 116))	('transgenic', 'Species', '10090', (120, 130))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (268, 287))	('mice', 'Species', '10090', (302, 306))	('tumor', 'Disease', (232, 237))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (97, 116))
239864	21152115	This is at least in part a consequence of (1) E1B-19K inhibition of the co-oligomerization of the Bcl-2 family proteins BAK and BAX, leading to blockade of caspase-mediated apoptosis, and (2) the interaction of E1B-55K with p53 for p53 degradation and thus the inhibition of p53 functions.	('blockade', 'NegReg', (144, 152))	('p53', 'Gene', '7157', (224, 227))	('p53', 'Gene', (232, 235))	('degradation', 'MPA', (236, 247))	('BAX', 'Gene', '581', (128, 131))	('BAX', 'Gene', (128, 131))	('BAK', 'Gene', (120, 123))	('inhibition', 'NegReg', (261, 271))	('p53', 'Gene', (224, 227))	('interaction', 'Interaction', (196, 207))	('BAK', 'Gene', '578', (120, 123))	('inhibition', 'NegReg', (54, 64))	('co-oligomerization', 'MPA', (72, 90))	('p53', 'Gene', '7157', (275, 278))	('caspase-mediated', 'CPA', (156, 172))	('functions', 'MPA', (279, 288))	('E1B-19K', 'Var', (46, 53))	('p53', 'Gene', (275, 278))	('p53', 'Gene', '7157', (232, 235))	('E1B-55K', 'Var', (211, 218))
239875	21152115	The MCC tumor-derived LT sequences harbor mutations prematurely truncating exon 2, which encodes the MCV LT ATPase/helicase.	('exon 2', 'Gene', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('helicase', 'Gene', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('MCV', 'Species', '493803', (101, 104))	('mutations', 'Var', (42, 51))	('helicase', 'Gene', '164045', (115, 123))
239885	21152115	EBV LMP1 is essential for the immortalization and transformation of human B cells, but its oncogenic activity can be downregulated by a truncated LMP1 (258 aa).	('truncated', 'Var', (136, 145))	('LMP1', 'Gene', (146, 150))	('258 aa', 'Var', (152, 158))	('human', 'Species', '9606', (68, 73))	('LMP1', 'Gene', '9260', (4, 8))	('downregulated', 'NegReg', (117, 130))	('oncogenic activity', 'CPA', (91, 109))	('EBV', 'Species', '10376', (0, 3))	('LMP1', 'Gene', (4, 8))	('LMP1', 'Gene', '9260', (146, 150))
239897	21152115	The translation initiation site of this second ORF is methionine-129 of full-length LMP1, and the ORF thus encodes an amino-terminally truncated form of the LMP1 protein.	('methionine', 'Chemical', 'MESH:D008715', (54, 64))	('LMP1', 'Gene', '9260', (84, 88))	('LMP1', 'Gene', (84, 88))	('LMP1', 'Gene', '9260', (157, 161))	('methionine-129', 'Var', (54, 68))	('LMP1', 'Gene', (157, 161))
239898	21152115	The truncated LMP1 (258 amino acids) consists of the fifth and sixth transmembrane domains and the cytoplasmic carboxy terminus of full-length LMP1.	('LMP1', 'Gene', '9260', (143, 147))	('258', 'Var', (20, 23))	('LMP1', 'Gene', '9260', (14, 18))	('LMP1', 'Gene', (143, 147))	('LMP1', 'Gene', (14, 18))
239899	21152115	Although the B95-8 cell line, an in vitro-immortalized lymphoblastoid cell line, was initially used to characterize truncated LMP1, a number of studies demonstrated that expression of truncated LMP1 was specifically upregulated during the lytic phase of viral replication.	('LMP1', 'Gene', '9260', (194, 198))	('LMP1', 'Gene', (194, 198))	('upregulated', 'PosReg', (216, 227))	('truncated', 'Var', (184, 193))	('LMP1', 'Gene', '9260', (126, 130))	('LMP1', 'Gene', (126, 130))	('expression', 'MPA', (170, 180))	('truncated', 'Var', (116, 125))
239900	21152115	Therefore, the truncated form of LMP1 is frequently referred to as lytic LMP1.	('LMP1', 'Gene', (73, 77))	('LMP1', 'Gene', '9260', (33, 37))	('LMP1', 'Gene', (33, 37))	('LMP1', 'Gene', '9260', (73, 77))	('truncated', 'Var', (15, 24))
239901	21152115	In contrast to full-length LMP1, truncated LMP1 does not transform rodent cells or alter the phenotypes of human B lymphocytes.	('human', 'Species', '9606', (107, 112))	('LMP1', 'Gene', '9260', (43, 47))	('LMP1', 'Gene', (43, 47))	('truncated', 'Var', (33, 42))	('LMP1', 'Gene', '9260', (27, 31))	('alter', 'Reg', (83, 88))	('LMP1', 'Gene', (27, 31))
239902	21152115	The biological activity of truncated LMP1 is its ability to negatively regulate LMP1 signaling pathways and LMP-1-mediated oncogenesis.	('LMP1', 'Gene', '9260', (80, 84))	('LMP-1', 'Gene', '9260', (108, 113))	('LMP1', 'Gene', (80, 84))	('regulate', 'Reg', (71, 79))	('oncogenesis', 'CPA', (123, 134))	('LMP-1', 'Gene', (108, 113))	('LMP1', 'Gene', '9260', (37, 41))	('truncated', 'Var', (27, 36))	('LMP1', 'Gene', (37, 41))	('negatively', 'NegReg', (60, 70))
239906	21152115	B cells with BARF1 expression exhibit increased levels of c-myc, CD23, and CD2.	('levels', 'MPA', (48, 54))	('CD2', 'Gene', (65, 68))	('BARF1', 'Gene', (13, 18))	('c-myc', 'Gene', '4609', (58, 63))	('c-myc', 'Gene', (58, 63))	('CD23', 'Gene', (65, 69))	('expression', 'Var', (19, 29))	('CD2', 'Gene', '914', (65, 68))	('CD2', 'Gene', (75, 78))	('CD23', 'Gene', '2208', (65, 69))	('increased', 'PosReg', (38, 47))	('CD2', 'Gene', '914', (75, 78))
239920	21152115	Mutations within this zinc finger affect Tax-mediated CREB transactivation as well as subcellular localization.	('subcellular localization', 'MPA', (86, 110))	('CREB', 'Gene', '1385', (54, 58))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (34, 40))	('CREB', 'Gene', (54, 58))
239921	21152115	Substitutions within the first leucine zipper affect Tax interactions with NF-kappaB and PP2A.	('Tax interactions', 'MPA', (53, 69))	('PP2A', 'Gene', '5524', (89, 93))	('NF-kappaB', 'Gene', (75, 84))	('affect', 'Reg', (46, 52))	('PP2A', 'Gene', (89, 93))	('Substitutions', 'Var', (0, 13))	('NF-kappaB', 'Gene', '4790', (75, 84))
239925	21152115	In HPV16, intron 1 and intron 2 of an E6E7 primary transcript each contain three alternative 3' splice sites which can be selected for RNA splicing in virus-infected cells, leading to the production of at least 14 species of mRNA transcripts with various coding potential.	('production', 'MPA', (188, 198))	('mRNA transcripts', 'MPA', (225, 241))	('HPV16', 'Species', '333760', (3, 8))	('E6E7', 'Var', (38, 42))
239926	21152115	Intron 1 of an HPV18 E6E7 primary transcript has a single 3' splice site.	('E6E7', 'Var', (21, 25))	('HPV18', 'Gene', (15, 20))	('HPV', 'Species', '10566', (15, 18))
239928	21152115	The cap-binding complex at the RNA 5' end was initially found to promotes the splicing of intron 1 of HPV16 E6E7 transcripts, but the enhanced intron 1 splicing by the cap-binding complex can be restrained by the distance of intron 1 from its RNA 5' cap.	('enhanced', 'PosReg', (134, 142))	('HPV16', 'Species', '333760', (102, 107))	('intron 1 splicing', 'MPA', (143, 160))	('HPV16', 'Gene', (102, 107))	('promotes', 'PosReg', (65, 73))	('E6E7', 'Var', (108, 112))	('splicing of intron 1', 'MPA', (78, 98))
239929	21152115	Under natural conditions, cellular epithelial growth factor (EGF) pathway regulates the intron 1 splicing of HPV16 E6E7 transcripts via Erk1/2 activation.	('E6E7', 'Var', (115, 119))	('intron 1 splicing', 'MPA', (88, 105))	('regulates', 'Reg', (74, 83))	('HPV16', 'Gene', (109, 114))	('EGF', 'Gene', (61, 64))	('HPV16', 'Species', '333760', (109, 114))	('EGF', 'Gene', '1950', (61, 64))
239932	21152115	Splicing of intron 1 in the HPV16 and HPV18 E6E7 pre-mRNAs is highly efficient, and the majority of the transcripts in cervical cancer tissues and cervical cancer-derived cell lines are E6*I, a spliced transcript without intron 1.	('HPV', 'Species', '10566', (28, 31))	('E6E7', 'Var', (44, 48))	('E6*I', 'Var', (186, 190))	('HPV', 'Species', '10566', (38, 41))	('cervical cancer', 'Disease', 'MESH:D002583', (119, 134))	('cervical cancer', 'Disease', (119, 134))	('cervical cancer', 'Disease', 'MESH:D002583', (147, 162))	('HPV16', 'Species', '333760', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cervical cancer', 'Disease', (147, 162))
239935	21152115	The suboptimal feature of E1A intron 1 makes it a minor intron, and its usage for RNA splicing occurs mainly late in infection.	('E1A', 'Var', (26, 29))	('infection', 'Disease', (117, 126))	('infection', 'Disease', 'MESH:D007239', (117, 126))
239949	21152115	While the 2.28-kb form is the main form produced early in infection, the proportion of the shorter spliced mRNAs increases over time, and the E1B-84R mRNA becomes predominant in the late phase.	('infection', 'Disease', (58, 67))	('E1B-84R', 'Var', (142, 149))	('infection', 'Disease', 'MESH:D007239', (58, 67))
239981	21152115	By systematically introduction of mutations in EBV's precursor miRNA transcripts to prevent their subsequent processing into mature viral miRNAs, a recent study shows that viral miRNAs from the BHRF1 locus inhibit apoptosis and favor cell cycle progression and proliferation during the early phase of infected human primary B cells.	('BHRF1', 'Gene', '3783706', (194, 199))	('apoptosis', 'CPA', (214, 223))	('cell cycle progression', 'CPA', (234, 256))	('miR', 'Gene', '220972', (178, 181))	('miR', 'Gene', (178, 181))	('proliferation', 'CPA', (261, 274))	('favor', 'PosReg', (228, 233))	('human', 'Species', '9606', (310, 315))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (138, 141))	('miR', 'Gene', (63, 66))	('EBV', 'Species', '10376', (47, 50))	('inhibit', 'NegReg', (206, 213))	('mutations', 'Var', (34, 43))	('BHRF1', 'Gene', (194, 199))
239985	21152115	More studies from recent reports indicate miR-K12-5, miR-K12-9 and miR-K12-10 repression of Bcl-2-associated transcription factor 1, an apoptosis-inducing factor, miR-K12-3 reduction of LRRC8D (leucine rich repeat containing 8 family, member D), a leucin-rich type III transmembrane protein involved in proliferation and activation of lymphocytes, NHP2L1 (non-histone chromosome protein 2-like 1), and a transcription factor NFIB, miR-K12-1 inhibition of p21 and NFkappaB inhibitor IkappaBalpha, miR-K12-4-3p suppression of GEMIN8, miR-K12-10a reduction of TWEAKR, miR-K12-1, -6, and -11 decrease of MAF (musculoaponeurotic fibrosarcoma oncogene homolog), K12-4-5p targeting retinoblastoma (Rb)-like protein 2 (Rbl2) and miR-K12-5 and -9*suppressing ORF50 mRNA.	('retinoblastoma', 'Phenotype', 'HP:0009919', (675, 689))	('GEMIN8', 'Gene', '54960', (524, 530))	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', '220972', (496, 499))	('musculoaponeurotic fibrosarcoma', 'Disease', 'MESH:D005354', (605, 636))	('sarcoma', 'Phenotype', 'HP:0100242', (629, 636))	('Rb', 'Phenotype', 'HP:0009919', (711, 713))	('NHP2L1', 'Gene', (348, 354))	('NHP2L1', 'Gene', '4809', (348, 354))	('miR', 'Gene', (163, 166))	('NFIB', 'Gene', '4781', (425, 429))	('miR', 'Gene', (67, 70))	('miR', 'Gene', '220972', (431, 434))	('K12-4-5p', 'Var', (656, 664))	('miR', 'Gene', (53, 56))	('miR', 'Gene', (496, 499))	('non-histone chromosome protein 2-like 1', 'Gene', (356, 395))	('Bcl-2-associated transcription factor 1', 'Gene', '9774', (92, 131))	('leucine rich repeat containing 8 family, member D', 'Gene', '55144', (194, 243))	('miR', 'Gene', '220972', (42, 45))	('retinoblastoma (Rb)-like protein 2', 'Gene', '5934', (675, 709))	('IkappaBalpha', 'Gene', (482, 494))	('musculoaponeurotic fibrosarcoma', 'Disease', (605, 636))	('LRRC8D', 'Gene', '55144', (186, 192))	('miR-K12-1, -6, and -11', 'Gene', '9149;79187;406904', (565, 587))	('miR', 'Gene', '220972', (565, 568))	('NFkappaB', 'Gene', '4790', (463, 471))	('miR', 'Gene', (431, 434))	('TWEAKR', 'Gene', '51330', (557, 563))	('miR', 'Gene', '220972', (532, 535))	('p21', 'Gene', '644914', (455, 458))	('miR', 'Gene', '220972', (67, 70))	('IkappaBalpha', 'Gene', '4792', (482, 494))	('MAF', 'Gene', (600, 603))	('TWEAKR', 'Gene', (557, 563))	('Rb', 'Phenotype', 'HP:0009919', (691, 693))	('Bcl-2-associated transcription factor 1', 'Gene', (92, 131))	('NFkappaB', 'Gene', (463, 471))	('miR', 'Gene', '220972', (721, 724))	('miR', 'Gene', (42, 45))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (624, 636))	('miR', 'Gene', (565, 568))	('Rbl2', 'Gene', (711, 715))	('suppressing', 'NegReg', (738, 749))	('non-histone chromosome protein 2-like 1', 'Gene', '4809', (356, 395))	('LRRC8D', 'Gene', (186, 192))	('MAF', 'Gene', '4094', (600, 603))	('ORF50', 'Gene', (750, 755))	('Rbl2', 'Gene', '5934', (711, 715))	('miR', 'Gene', (532, 535))	('miR', 'Gene', (721, 724))	('p21', 'Gene', (455, 458))	('NFIB', 'Gene', (425, 429))	('miR', 'Gene', '220972', (163, 166))	('GEMIN8', 'Gene', (524, 530))
239991	21152115	This observation was verified in a separate study showing that EBV LMP1 activates the miR-146a promoter but not a promoter with a mutation of the NF-kappaB response elements.	('activates', 'PosReg', (72, 81))	('EBV', 'Species', '10376', (63, 66))	('EBV', 'Var', (63, 66))	('miR-146a', 'Gene', '406938', (86, 94))	('LMP1', 'Gene', '9260', (67, 71))	('LMP1', 'Gene', (67, 71))	('NF-kappaB', 'Gene', '4790', (146, 155))	('miR-146a', 'Gene', (86, 94))	('NF-kappaB', 'Gene', (146, 155))
240007	21152115	Viral strategies for manipulating the expression of cellular genes to enhance viral persistence, viral latency, and survival of infected cells have provided numerous clues to the mechanisms of gene expression and their dysregulation during tumor development.	('tumor', 'Disease', (240, 245))	('enhance', 'PosReg', (70, 77))	('manipulating', 'Var', (21, 33))	('viral persistence', 'CPA', (78, 95))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
240012	21152115	In the case of an HPV16 or HPV18 E6E7 bicistronic transcript, retention of the first intron is needed to express E6, but splicing of this intron promotes E7 translation initiation to produce E7.	('HPV', 'Species', '10566', (27, 30))	('E6E7', 'Var', (33, 37))	('HPV', 'Species', '10566', (18, 21))	('E7 translation initiation', 'MPA', (154, 179))	('HPV18', 'Gene', (27, 32))	('HPV16', 'Species', '333760', (18, 23))	('HPV16', 'Var', (18, 23))	('promotes', 'PosReg', (145, 153))
240019	33946962	ATRX Alteration Contributes to Tumor Growth and Immune Escape in Pleomorphic Sarcomas There is still no efficient systemic treatment for pleomorphic sarcomas.	('ATRX', 'Gene', (0, 4))	('ATRX', 'Gene', '22589', (0, 4))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (137, 157))	('Tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('pleomorphic sarcomas', 'Disease', (137, 157))	('Sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('Immune Escape', 'CPA', (48, 61))	('Sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('Alteration', 'Var', (5, 15))	('Sarcomas', 'Disease', (77, 85))	('Tumor Growth', 'CPA', (31, 43))
240020	33946962	This phenotype is related to the inhibition of mast cell recruitment upon ATRX alteration, which could be targeted to adapt immunotherapy against pleomorphic sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('inhibition', 'NegReg', (33, 43))	('alteration', 'Var', (79, 89))	('pleomorphic sarcomas', 'Disease', (146, 166))	('mast', 'CPA', (47, 51))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (146, 166))	('ATRX', 'Gene', (74, 78))
240023	33946962	ATRX alteration is associated with the down-expression of genes linked to differentiation in leiomyosarcomas, and to immunity in an additional cohort of 60 poorly differentiated pleomorphic sarcomas.	('leiomyosarcomas', 'Disease', (93, 108))	('pleomorphic sarcomas', 'Disease', (178, 198))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('alteration', 'Var', (5, 15))	('ATRX', 'Gene', (0, 4))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (178, 198))	('sarcomas', 'Phenotype', 'HP:0100242', (190, 198))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (93, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (93, 108))	('down-expression', 'NegReg', (39, 54))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (93, 107))
240036	33946962	Mouse K7M2 tumor expression data are available on Gene Expression Omnibus (GEO) under accession GSE157953 and will be released on 09/01/2021 and available before by contacting the corresponding author.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('GSE157953', 'Var', (96, 105))	('tumor', 'Disease', (11, 16))	('Mouse', 'Species', '10090', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
240045	33946962	One triploid tumor developed in a male also presented a deletion of the gene, but with one copy left.	('deletion', 'Var', (56, 64))	('triploid tumor', 'Disease', 'MESH:D057885', (4, 18))	('triploid tumor', 'Disease', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
240067	33946962	By integrating point mutations and SV, ATRX is altered in 20 cases (29.8%; Figure 1A), with 8 point mutations (MS and NS; 40%), 7 FS (35%) and 5 SV (25%).	('altered', 'Reg', (47, 54))	('point', 'Disease', (94, 99))	('FS', 'Disease', 'MESH:D018223', (130, 132))	('point mutations', 'Var', (15, 30))
240069	33946962	At the mRNA level, mutated cases had a significantly lower ATRX expression than WT tumors (p = 0.000379; Figure 1C), and at the protein level, alterations led to a loss of nuclear protein (p < 0.0001; Figure 1C and Figure S2).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('WT tumors', 'Disease', 'MESH:C536751', (80, 89))	('mutated', 'Var', (19, 26))	('ATRX', 'Protein', (59, 63))	('nuclear protein', 'MPA', (172, 187))	('WT tumors', 'Disease', (80, 89))	('lower', 'NegReg', (53, 58))	('loss', 'NegReg', (164, 168))
240076	33946962	The association between enrichment of down-expressed genes linked to muscle system and of oLMS in ATRX altered tumors suggested that either ATRX alteration preferentially occurs in partially or undifferentiated cells, or that it may induce dedifferentiation.	('induce', 'Reg', (233, 239))	('altered tumors', 'Disease', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('down-expressed', 'NegReg', (38, 52))	('altered tumors', 'Disease', 'MESH:D004408', (103, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('LMS', 'Phenotype', 'HP:0100243', (91, 94))	('dedifferentiation', 'CPA', (240, 257))	('oLMS', 'Species', '221568', (90, 94))	('alteration', 'Var', (145, 155))
240081	33946962	Since this is particularly relevant as immunotherapies are currently not efficient in pleomorphic sarcomas, we functionally tested the hypothesis that ATRX alteration might modify the anti-tumor immune response.	('alteration', 'Var', (156, 166))	('tumor', 'Disease', (189, 194))	('modify', 'Reg', (173, 179))	('ATRX', 'Gene', (151, 155))	('pleomorphic sarcomas', 'Disease', (86, 106))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (86, 106))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tested', 'Reg', (124, 130))
240089	33946962	The involvement of ATRX alteration in the immune escape was tested by grafting K7M2 ATRXCT and ATRXKD cells in immunodeficient NSG mice and immunocompetent Balb/c mice (n = 15 for each group).	('immunodeficient NSG', 'Disease', (111, 130))	('K7M2', 'Var', (79, 83))	('immunodeficient NSG', 'Disease', 'MESH:D007153', (111, 130))	('mice', 'Species', '10090', (163, 167))	('mice', 'Species', '10090', (131, 135))
240090	33946962	Tumor-free survival in ATRXCT and ATRXKD models displayed no significant differences in immunodeficient NSG mice, whereas in immunocompetent Balb/c mice, there was 53.4% (8/13) of tumor induction with K7M2 ATRXCT versus 92.8% (13/14) with K7M2 ATRXKD.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('immunodeficient NSG', 'Disease', (88, 107))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('mice', 'Species', '10090', (108, 112))	('mice', 'Species', '10090', (148, 152))	('K7M2 ATRXCT', 'Var', (201, 212))	('immunodeficient NSG', 'Disease', 'MESH:D007153', (88, 107))
240091	33946962	Therefore, tumor-free survival was significantly poorer upon ATRX knock-down (p = 0.0097; Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('ATRX', 'Gene', (61, 65))	('tumor', 'Disease', (11, 16))	('poorer', 'NegReg', (49, 55))	('knock-down', 'Var', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
240094	33946962	Whereas, no consistent clusters arose with up-regulated genes upon ATRX knock-down (Figure S7B), one emerged in down-regulated genes, with 12 proteins out of 37 linked to mast cell pathways (including TPSB2 coding tryptase, a widely used mast cells marker) (Figure 6D).	('tryptase', 'Gene', (214, 222))	('tryptase', 'Gene', '100503895', (214, 222))	('TPSB2', 'Gene', (201, 206))	('knock-down', 'Var', (72, 82))	('up-regulated', 'PosReg', (43, 55))
240096	33946962	This significant difference prompted us to assess whether the proportion of infiltrating mast cells in human sarcomas is also related to ATRX alteration and the absence of ATRX from the nucleus.	('alteration', 'Var', (142, 152))	('ATRX', 'Gene', (137, 141))	('human', 'Species', '9606', (103, 108))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('related', 'Reg', (126, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcomas', 'Disease', (109, 117))
240100	33946962	This in-depth ATRX genetic analysis revealed that ATRX alteration likely affects a quarter of pleomorphic sarcomas, since it was found in 29.8% of LMS and 16.7% of poorly differentiated pleomorphic sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (94, 114))	('found', 'Reg', (129, 134))	('pleomorphic sarcomas', 'Disease', (94, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (198, 206))	('pleomorphic sarcomas', 'Disease', (186, 206))	('affects', 'Reg', (73, 80))	('alteration', 'Var', (55, 65))	('ATRX', 'Gene', (50, 54))	('LMS', 'Disease', (147, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (186, 206))	('LMS', 'Phenotype', 'HP:0100243', (147, 150))
240102	33946962	Three main factors link the two types of sarcomas in the present study: (i) In females, all alterations except in LMS48 can be interpreted as occurring on the active X, (ii) point mutations are more frequent (75% in LMS and 60% in the US) than structural variations (25% in LMS and 40% in the US), as previously observed; and (iii) the alterations lead preferentially to a frameshift, and thus, to a truncated protein in 66.7% of cases (20/30, 65% in LMS and 70% in the US), in agreement with previous descriptions in sarcomas.	('lead', 'Reg', (348, 352))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('LMS', 'Phenotype', 'HP:0100243', (216, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('sarcomas', 'Disease', (518, 526))	('point mutations', 'Var', (174, 189))	('sarcomas', 'Disease', 'MESH:D012509', (518, 526))	('LMS', 'Phenotype', 'HP:0100243', (114, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (518, 526))	('LMS', 'Phenotype', 'HP:0100243', (451, 454))	('protein', 'Protein', (410, 417))	('alterations', 'Var', (336, 347))	('LMS', 'Phenotype', 'HP:0100243', (274, 277))	('sarcoma', 'Phenotype', 'HP:0100242', (518, 525))	('truncated', 'MPA', (400, 409))	('frameshift', 'Var', (373, 383))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
240103	33946962	However, this association depends on the cohorts studied and was observed in only one cohort that mainly included missense mutations.	('died', 'Disease', 'MESH:D003643', (52, 56))	('died', 'Disease', (52, 56))	('missense mutations', 'Var', (114, 132))
240107	33946962	ATRX knock-down modifies tumor cell proliferation, as confirmed in vivo, where ATRX knock-down tumors grew three-fold faster than controls, and clonogenicity in sarcoma models.	('sarcoma', 'Disease', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('clonogenicity', 'CPA', (144, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('modifies', 'Reg', (16, 24))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('ATRX', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('faster', 'PosReg', (118, 124))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('grew', 'CPA', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('knock-down', 'Var', (84, 94))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))
240108	33946962	Interestingly, poorly differentiated pleomorphic sarcomas with ATRX alteration overexpressed genes related to metabolism, whose upregulation is a known hallmark of cancers and supports cell survival and proliferation.	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (37, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('hallmark of cancers', 'Disease', (152, 171))	('upregulation', 'PosReg', (128, 140))	('overexpressed', 'PosReg', (79, 92))	('alteration', 'Var', (68, 78))	('ATRX', 'Gene', (63, 67))	('hallmark of cancers', 'Disease', 'MESH:D009369', (152, 171))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('genes', 'Gene', (93, 98))	('pleomorphic sarcomas', 'Disease', (37, 57))
240109	33946962	In vivo experimentation revealed a new role of ATRX, as its alteration was associated with a poorer outcome exclusively in an immunocompetent murine host, and with down-expression of immune-related genes in poorly differentiated pleomorphic human sarcomas.	('ATRX', 'Gene', (47, 51))	('murine', 'Species', '10090', (142, 148))	('alteration', 'Var', (60, 70))	('sarcomas', 'Disease', (247, 255))	('human', 'Species', '9606', (241, 246))	('sarcomas', 'Disease', 'MESH:D012509', (247, 255))	('sarcomas', 'Phenotype', 'HP:0100242', (247, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (247, 254))	('down-expression', 'NegReg', (164, 179))
240123	33946962	Collectively, these results suggest that alterations of ATRX preferentially target its enzymatic functions rather than its protein-protein interactions, thus explaining why mutations in ATRX partner genes (i.e., DAXX, EZH2, SP100) are not frequent and not an alternative to ATRX alteration in sarcomas.	('SP100', 'Gene', (224, 229))	('DAXX', 'Gene', '13163', (212, 216))	('DAXX', 'Gene', (212, 216))	('sarcomas', 'Disease', 'MESH:D012509', (293, 301))	('sarcomas', 'Phenotype', 'HP:0100242', (293, 301))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('enzymatic functions', 'MPA', (87, 106))	('mutations', 'Var', (173, 182))	('sarcomas', 'Disease', (293, 301))	('EZH2', 'Gene', '14056', (218, 222))	('ATRX', 'Gene', (186, 190))	('SP100', 'Gene', '20684', (224, 229))	('alterations', 'Var', (41, 52))	('EZH2', 'Gene', (218, 222))
240124	33946962	We, thus, hypothesize that, by modifying its chromatin remodeling action, alterations of ATRX trigger a specific transcriptomic program that promotes attenuated mast cell recruitment, leading to the observed immune response in models and human tumors.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('modifying', 'Reg', (31, 40))	('human', 'Species', '9606', (238, 243))	('immune response', 'CPA', (208, 223))	('ATRX', 'Gene', (89, 93))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('alterations', 'Var', (74, 85))	('promotes', 'PosReg', (141, 149))	('mast cell', 'CPA', (161, 170))	('trigger', 'Reg', (94, 101))	('attenuated', 'NegReg', (150, 160))
240125	33946962	Our findings show that ATRX alterations are quite frequent in pleomorphic sarcomas (close to 25%) and mostly lead to the loss of ATRX.	('alterations', 'Var', (28, 39))	('loss', 'NegReg', (121, 125))	('frequent', 'Reg', (50, 58))	('pleomorphic sarcomas', 'Disease', (62, 82))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (62, 82))	('ATRX', 'MPA', (129, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('ATRX', 'Gene', (23, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
240126	33946962	In addition, we demonstrate that ATRX alterations are not only associated with ALT phenotype, but also with a lower differentiation in LMS and immune response regulation in poorly differentiated pleomorphic sarcomas, most probably through non-recruitment of mast cells.	('immune response regulation', 'MPA', (143, 169))	('pleomorphic sarcomas', 'Disease', (195, 215))	('associated', 'Reg', (63, 73))	('LMS', 'Disease', (135, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (207, 215))	('LMS', 'Phenotype', 'HP:0100243', (135, 138))	('lower', 'NegReg', (110, 115))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (195, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('alterations', 'Var', (38, 49))	('ATRX', 'Gene', (33, 37))	('ALT', 'Disease', (79, 82))
240143	32419365	While the term "immunogenic cell death" is not fully defined, activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can induce a type of death that mobilises the immune system against cancer.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('induce', 'Reg', (143, 149))	('activation', 'Var', (62, 72))	('receptor-interacting serine/threonine-protein kinase 1', 'Gene', '8737', (76, 130))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('RIPK1', 'Gene', (132, 137))	('mobilises', 'MPA', (171, 180))
240168	32419365	Although best known for their ability to regulate caspases, IAPs also influence TNF signalling via modulation of RIPK1 and activation of NF-kB (Gyrd-Hansen & Meier, 2010).	('caspases', 'Gene', (50, 58))	('RIPK1', 'Gene', (113, 118))	('IAP', 'Gene', '961', (60, 63))	('IAP', 'Gene', (60, 63))	('TNF signalling', 'MPA', (80, 94))	('activation', 'PosReg', (123, 133))	('caspases', 'Gene', '841;64044', (50, 58))	('influence', 'Reg', (70, 79))	('NF-kB', 'Protein', (137, 142))	('modulation', 'Var', (99, 109))
240171	32419365	Inhibiting cIAPs, therefore, unleashes the pro-death potential of RIPK1.	('pro-death potential', 'MPA', (43, 62))	('Inhibiting', 'Var', (0, 10))	('IAP', 'Gene', '961', (12, 15))	('IAP', 'Gene', (12, 15))	('RIPK1', 'Gene', (66, 71))	('unleashes', 'NegReg', (29, 38))
240178	32419365	Currently, there are at least four phase I or II trials recruiting patients with other indications to test LCL161 in combination with other drugs (NCT02098161, NCT02649673, NCT03111992 and NCT02890069).	('LCL161', 'Gene', (107, 113))	('NCT03111992', 'Var', (173, 184))	('patients', 'Species', '9606', (67, 75))	('NCT02098161', 'Var', (147, 158))	('LCL161', 'Chemical', 'MESH:C574246', (107, 113))	('NCT02890069', 'Var', (189, 200))	('NCT02649673', 'Var', (160, 171))
240179	32419365	The bivalent SM Birinapant has been advanced into several phase I or II trials as a single agent (NCT00993239, NCT01681368, NCT01486784 and NCT01681368) or in combination with gemcitabine (NCT01573780), 5-azacitidine (NCT02147873, NCT01828346) or other standard chemotherapeutics such as irinotecan or docetaxel (NCT01188499), carboplatin (NCT02756130), conatumumab (NCT01940172) and pembrolizumab (NCT02587962).	('NCT01940172', 'Var', (367, 378))	('NCT02147873', 'Var', (218, 229))	('NCT02756130', 'Var', (340, 351))	('NCT01573780', 'Var', (189, 200))	('SM', 'Chemical', '-', (13, 15))	('Birinapant', 'Chemical', 'MESH:C582429', (16, 26))	('NCT01188499', 'Var', (313, 324))	('NCT00993239', 'Var', (98, 109))
240201	32419365	Importantly, TNF/Mel/SM resulted in potent complex-II formation and caspase activation (Figs 1B-D and EV1A).	('caspase', 'Gene', '841;64044', (68, 75))	('TNF/Mel/SM', 'Var', (13, 23))	('Mel', 'Chemical', 'MESH:D008558', (17, 20))	('SM', 'Chemical', '-', (21, 23))	('complex-II', 'Interaction', (43, 53))	('caspase', 'Gene', (68, 75))	('activation', 'PosReg', (76, 86))
240203	32419365	Co-treatment with SM caused cell death that was dependent on the kinase activity of Ripk1 and Casp-8 at 24 h. This is evident as cell death was suppressed by genetic or pharmacological inhibition of Ripk1 or Casp-8 (Figs 1E, and EV1B and C).	('Ripk1', 'Gene', (199, 204))	('Casp-8', 'Gene', (208, 214))	('cell death', 'CPA', (129, 139))	('inhibition', 'Var', (185, 195))	('suppressed', 'NegReg', (144, 154))	('SM', 'Chemical', '-', (18, 20))
240206	32419365	Ectopic expression of BCL2 also suppressed Mel- or TNF/Mel-induced intrinsic apoptosis in HT1080 cells (Fig EV1E), corroborating that exposure to Mel triggers mitochondria-dependent apoptosis.	('intrinsic apoptosis', 'CPA', (67, 86))	('BCL2', 'Gene', (22, 26))	('Mel', 'Chemical', 'MESH:D008558', (55, 58))	('Ectopic expression', 'Var', (0, 18))	('TNF/Mel-induced', 'Gene', (51, 66))	('Mel', 'Chemical', 'MESH:D008558', (146, 149))	('Mel', 'Chemical', 'MESH:D008558', (43, 46))	('rat', 'Species', '10116', (122, 125))	('BCL2', 'Gene', '596', (22, 26))	('HT1080', 'CellLine', 'CVCL:0317', (90, 96))	('suppressed', 'NegReg', (32, 42))
240227	32419365	The delay in tumour growth of animals treated with TNF/Mel/SM translated into significantly prolonged survival when compared to the standard-of-care TNF/Mel (Fig 3B, median 24.5 vs. 18 days, P = 0.0063, log-rank test).	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('delay', 'NegReg', (4, 9))	('survival', 'CPA', (102, 110))	('Mel', 'Chemical', 'MESH:D008558', (55, 58))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('TNF/Mel/SM', 'Var', (51, 61))	('SM', 'Chemical', '-', (59, 61))	('tumour', 'Disease', (13, 19))	('Mel', 'Chemical', 'MESH:D008558', (153, 156))	('prolonged', 'PosReg', (92, 101))
240230	32419365	These analyses indicated that TNF/Mel/SM significantly increased tumour death compared to TNF/Mel alone (P = 0.0034, unpaired t-test) (Fig 3C), in keeping with augmented therapy in this therapeutic cohort.	('tumour death', 'Disease', (65, 77))	('Mel', 'Chemical', 'MESH:D008558', (34, 37))	('increased', 'PosReg', (55, 64))	('SM', 'Chemical', '-', (38, 40))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('Mel', 'Chemical', 'MESH:D008558', (94, 97))	('tumour death', 'Disease', 'MESH:D003643', (65, 77))	('TNF/Mel/SM', 'Var', (30, 40))
240241	32419365	An increase in locoregional toxicity was noted with TNF/Mel/SM when compared with TNF/Mel (Fig EV3F).	('SM', 'Chemical', '-', (60, 62))	('Mel', 'Chemical', 'MESH:D008558', (86, 89))	('TNF/Mel/SM', 'Var', (52, 62))	('Mel', 'Chemical', 'MESH:D008558', (56, 59))	('toxicity', 'Disease', 'MESH:D064420', (28, 36))	('toxicity', 'Disease', (28, 36))	('increase', 'PosReg', (3, 11))
240244	32419365	In contrast, TNF/Mel/SM resulted in all animals developing marked erythema and superficial desquamation, equating to grade III reactions.	('erythema', 'Disease', 'MESH:D004890', (66, 74))	('Mel', 'Chemical', 'MESH:D008558', (17, 20))	('TNF/Mel/SM', 'Var', (13, 23))	('erythema', 'Disease', (66, 74))	('SM', 'Chemical', '-', (21, 23))	('desquamation', 'Phenotype', 'HP:0040189', (91, 103))	('erythema', 'Phenotype', 'HP:0010783', (66, 74))
240254	32419365	Alongside these increases in immune effector cells, treatment with TNF/Mel/SM resulted in a significant reduction of CD3+CD4+Foxp3- T helper cells, with a corresponding increase in CD3+CD4+Foxp3+ regulatory T cells (T-regs) (Fig 4G and H).	('SM', 'Chemical', '-', (75, 77))	('Mel', 'Chemical', 'MESH:D008558', (71, 74))	('reduction', 'NegReg', (104, 113))	('increase', 'PosReg', (169, 177))	('T-reg', 'Chemical', '-', (216, 221))	('CD3+CD4+Foxp3+', 'MPA', (181, 195))	('TNF/Mel/SM', 'Var', (67, 77))	('CD3+CD4+Foxp3-', 'MPA', (117, 131))
240270	32419365	Addition of anti-CTLA-4 antibodies to ILP-TNF/Mel/SM led to a significant increase of T helper cells and also caused a reduction of intra-tumoural CD3+CD4+Foxp3+ regulatory T cells (Fig 5C and D).	('anti-CTLA-4', 'Gene', (12, 23))	('SM', 'Chemical', '-', (50, 52))	('T helper cells', 'CPA', (86, 100))	('anti-CTLA-4 antibodies', 'Var', (12, 34))	('increase', 'PosReg', (74, 82))	('antibodies', 'Var', (24, 34))	('intra-tumoural', 'Disease', (132, 146))	('increase of T helper cells', 'Phenotype', 'HP:0100828', (74, 100))	('Mel', 'Chemical', 'MESH:D008558', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('intra-tumoural', 'Disease', 'MESH:D009369', (132, 146))	('reduction', 'NegReg', (119, 128))
240271	32419365	On the other hand, treatment with anti-PD-1 antibodies caused a significant increase in active NK cells (Fig 5E).	('PD-1', 'Gene', '6622', (39, 43))	('PD-1', 'Gene', (39, 43))	('antibodies', 'Var', (44, 54))	('increase', 'PosReg', (76, 84))
240284	32419365	Consistent with the clinical finding, ILP-TNF/Mel had little effect on tumour growth at the challenge site in comparison to an untreated control (median 14 vs. 12 days, P = 0.3173, log-rank test) (Figs 6D and E, and EV6A and B).	('tumour', 'Disease', (71, 77))	('Mel', 'Chemical', 'MESH:D008558', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('ILP-TNF/Mel', 'Var', (38, 49))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
240286	32419365	Our data are consistent with the notion that treatment with ILP-TNF/Mel/SM drives anti-tumour immunity and is significantly more effective than the current standard-of-care treatment.	('drives', 'PosReg', (75, 81))	('tumour', 'Disease', (87, 93))	('ILP-TNF/Mel/SM', 'Var', (60, 74))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('SM', 'Chemical', '-', (72, 74))	('more', 'PosReg', (124, 128))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('Mel', 'Chemical', 'MESH:D008558', (68, 71))
240293	32419365	SM compounds that antagonise cIAP1/2 have received attention as potential cancer therapeutics because cIAP1/2 are overexpressed in many cancer types and their elimination from cancer cells often induces TNF-driven apoptosis (Vince et al, 2007; Bai et al, 2014; Fulda, 2015).	('cIAP1/2', 'Gene', (102, 109))	('cIAP1/2', 'Gene', '329;330', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('induces', 'Reg', (195, 202))	('elimination', 'Var', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('SM', 'Chemical', '-', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (136, 142))	('TNF-driven', 'MPA', (203, 213))	('cIAP1/2', 'Gene', (29, 36))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cIAP1/2', 'Gene', '329;330', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
240298	32419365	In line with this clinical assessment, we found that the enhanced necrotic area of ILP-TNF/Mel/SM-treated tumours correlated with improved long-term local disease control, when compared to standard-of-care ILP-TNF/Mel (in our neoadjuvant protocol).	('SM', 'Chemical', '-', (95, 97))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('ILP-TNF/Mel/SM-treated', 'Var', (83, 105))	('necrotic', 'Disease', (66, 74))	('Mel', 'Chemical', 'MESH:D008558', (214, 217))	('local disease control', 'CPA', (149, 170))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('tumours', 'Disease', (106, 113))	('necrotic', 'Disease', 'MESH:D009336', (66, 74))	('Mel', 'Chemical', 'MESH:D008558', (91, 94))	('enhanced', 'PosReg', (57, 65))	('improved', 'PosReg', (130, 138))
240304	32419365	This is because TNF can trigger cell death as well as NF-kappaB-dependent production and release of "danger signals" from dying cells that attract and stimulate immune cells.	('NF-kappaB', 'Gene', (54, 63))	('release', 'MPA', (89, 96))	('TNF', 'Var', (16, 19))	('stimulate', 'PosReg', (151, 160))	('NF-kappaB', 'Gene', '4790', (54, 63))	('cell', 'CPA', (32, 36))	('attract', 'PosReg', (139, 146))
240307	32419365	However, this was accompanied by an increase in the population of CD3+CD4+Foxp3+ T-reg cells with immunosuppressive activities.	('CD3+CD4+Foxp3+', 'Var', (66, 80))	('increase', 'PosReg', (36, 44))	('T-reg', 'Chemical', '-', (81, 86))
240308	32419365	Consistent with the notion that immune suppressive activities are present, we found that co-treatment with anti-CTLA-4 or anti-PD-1 antibodies significantly enhanced the survival benefit of ILP-TNF/Mel/SM.	('anti-CTLA-4', 'Gene', (107, 118))	('antibodies', 'Var', (132, 142))	('PD-1', 'Gene', (127, 131))	('enhanced', 'PosReg', (157, 165))	('SM', 'Chemical', '-', (202, 204))	('survival benefit', 'CPA', (170, 186))	('PD-1', 'Gene', '6622', (127, 131))	('anti-CTLA-4', 'Var', (107, 118))	('Mel', 'Chemical', 'MESH:D008558', (198, 201))
240365	32419365	Where applicable, anti-CTLA-4 or anti-PD-1 antibodies were delivered by intraperitoneal injection at doses of 500 and 200 mg, respectively, in three repeated doses at 48 h intervals.	('PD-1', 'Gene', '6622', (38, 42))	('PD-1', 'Gene', (38, 42))	('anti-CTLA-4', 'Var', (18, 29))
240439	30739231	In a recent case report of a giant panda (Ailuropoda melanoleuca) with ovarian cancer, histopathological studies revealed multiple lesions in the lungs, kidneys, perianal tissue and spleen at necropsy, that stained positive by immunohistochemistry for B7-H4, CA125, and HE4, as well as the presence of significantly high serum levels of the tumour antigen AFP.	('B7-H4', 'Var', (252, 257))	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('HE4', 'Gene', '10406', (270, 273))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))	('CA125', 'Gene', (259, 264))	('HE4', 'Gene', (270, 273))	('ovarian cancer', 'Disease', (71, 85))	('tumour', 'Phenotype', 'HP:0002664', (341, 347))	('giant panda', 'Species', '9646', (29, 40))	('Ailuropoda melanoleuca', 'Species', '9646', (42, 64))	('tumour', 'Disease', 'MESH:D009369', (341, 347))	('CA125', 'Gene', '94025', (259, 264))	('tumour', 'Disease', (341, 347))	('high', 'PosReg', (316, 320))
240468	30739231	As with metastatic breast cancer in humans, reduction and aberrant expression of BRCA1 in canine mammary tumours has been found to be significantly associated with malignant characteristics.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('canine', 'Species', '9615', (90, 96))	('BRCA1', 'Gene', (81, 86))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('aberrant expression', 'Var', (58, 77))	('tumours', 'Disease', (105, 112))	('humans', 'Species', '9606', (36, 42))	('malignant characteristics', 'CPA', (164, 189))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('associated', 'Reg', (148, 158))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('BRCA1', 'Gene', '672', (81, 86))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', (19, 32))
240469	30739231	Similarly, altered derlin-1 and stanniocalcin-1 expression levels are associated with the metastasis of human breast cancer cells and metastisizing canine mammary adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('stanniocalcin-1', 'Gene', (32, 47))	('expression levels', 'MPA', (48, 65))	('altered', 'Var', (11, 18))	('canine', 'Species', '9615', (148, 154))	('metastasis', 'CPA', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('breast cancer', 'Disease', (110, 123))	('stanniocalcin-1', 'Gene', '6781', (32, 47))	('associated', 'Reg', (70, 80))	('human', 'Species', '9606', (104, 109))	('adenocarcinomas', 'Disease', 'MESH:D000230', (163, 178))	('derlin-1', 'Gene', '79139', (19, 27))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('adenocarcinomas', 'Disease', (163, 178))	('derlin-1', 'Gene', (19, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
240479	30739231	In both species, the GISTs arise due to oncogenic mutations in the KIT tyrosine kinase, which also drives canine cutaneous mast cell tumours.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('cutaneous mast cell tumours', 'Disease', (113, 140))	('mutations', 'Var', (50, 59))	('KIT', 'Gene', (67, 70))	('mast cell tumour', 'Phenotype', 'HP:0100495', (123, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('canine', 'Species', '9615', (106, 112))	('cutaneous mast cell tumours', 'Disease', 'MESH:D034801', (113, 140))	('drives', 'PosReg', (99, 105))
240481	30739231	Although there are conflicting reports of the presence of BRAF, NRAS and c-KIT mutations in canine mucosal melanomas, possibly reflecting the complexity and heterogeneity of cancer seen in humans, a strong parallel between human and canine mucosal melanoma is frequent in activation of the RAS/MAPK and/or PI3K/AKT/mTOR signalling pathways with synergistic targeted inhibition of MEK and dual PI3K/mTOR inhibiting tumour growth of a canine melanoma cell line in nu/nu athymic mice.	('melanoma', 'Disease', (248, 256))	('mucosal melanoma', 'Disease', 'MESH:D008545', (240, 256))	('mTOR', 'Gene', '478232', (315, 319))	('canine', 'Species', '9615', (233, 239))	('activation', 'PosReg', (272, 282))	('melanoma', 'Disease', 'MESH:D008545', (440, 448))	('mutations', 'Var', (79, 88))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('human', 'Species', '9606', (223, 228))	('mucosal melanoma', 'Disease', (240, 256))	('cancer', 'Disease', (174, 180))	('NRAS', 'Gene', (64, 68))	('tumour', 'Phenotype', 'HP:0002664', (414, 420))	('mucosal melanomas', 'Disease', 'MESH:D008545', (99, 116))	('tumour', 'Disease', 'MESH:D009369', (414, 420))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('c-KIT', 'Gene', '403811', (73, 78))	('melanoma', 'Disease', 'MESH:D008545', (248, 256))	('tumour', 'Disease', (414, 420))	('humans', 'Species', '9606', (189, 195))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('RAS/MAPK and/or', 'Pathway', (290, 305))	('mTOR', 'Gene', (398, 402))	('mucosal melanomas', 'Disease', (99, 116))	('human', 'Species', '9606', (189, 194))	('BRAF', 'Gene', '475526', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (440, 448))	('melanoma', 'Disease', (440, 448))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('mTOR', 'Gene', '478232', (398, 402))	('melanoma', 'Disease', (107, 115))	('NRAS', 'Gene', '403872', (64, 68))	('mucosal melanoma', 'Disease', 'MESH:D008545', (99, 115))	('canine', 'Species', '9615', (92, 98))	('c-KIT', 'Gene', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('canine', 'Species', '9615', (433, 439))	('mTOR', 'Gene', (315, 319))	('inhibiting', 'NegReg', (403, 413))	('mice', 'Species', '10090', (476, 480))	('BRAF', 'Gene', (58, 62))	('MEK', 'Gene', (380, 383))
240500	30739231	A Phase II trial using L-MTP-PE in patients with osteosarcoma and synchronous or metachronous lung metastases concluded that there was evidence for a biological effect of L-MTP-PE on osteosarcoma lung metastases.	('L-MTP-PE', 'Chemical', 'MESH:C037144', (23, 31))	('osteosarcoma lung metastases', 'Disease', (183, 211))	('osteosarcoma and synchronous or metachronous lung metastases', 'Disease', 'MESH:D009362', (49, 109))	('osteosarcoma lung metastases', 'Disease', 'MESH:D009362', (183, 211))	('osteosarcoma', 'Phenotype', 'HP:0002669', (49, 61))	('L-MTP-PE', 'Var', (171, 179))	('osteosarcoma', 'Phenotype', 'HP:0002669', (183, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('patients', 'Species', '9606', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('L-MTP-PE', 'Chemical', 'MESH:C037144', (171, 179))
240501	30739231	A phase I dose escalation clinical trial in dogs with osteosarcoma found that ADXS31-164 (Listeria expressing a chimeric human HER2/neu fusion protein) administered in the setting of minimal residual disease could induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival.	('metastatic disease', 'CPA', (280, 298))	('HER2/neu-specific', 'Protein', (221, 238))	('reduce', 'NegReg', (256, 262))	('prolong', 'PosReg', (303, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('human', 'Species', '9606', (121, 126))	('ADXS31-164', 'Var', (78, 88))	('induce', 'PosReg', (214, 220))	('osteosarcoma', 'Disease', (54, 66))	('osteosarcoma', 'Phenotype', 'HP:0002669', (54, 66))	('overall survival', 'CPA', (311, 327))	('dogs', 'Species', '9615', (44, 48))	('osteosarcoma', 'Disease', 'MESH:D012516', (54, 66))
240516	28561686	Although mutations in the germline have classically been more associated with osteosarcoma, there is recent evidence germline alterations in patients with Ewing sarcoma also play a significant role in pathogenesis.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (155, 168))	('osteosarcoma', 'Disease', 'MESH:D012516', (78, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('associated', 'Reg', (62, 72))	('mutations', 'Var', (9, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('Ewing sarcoma', 'Disease', (155, 168))	('osteosarcoma', 'Disease', (78, 90))	('patients', 'Species', '9606', (141, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (78, 90))
240524	28561686	Ewing sarcoma (ES) is a small, round blue cell tumor characterized by oncogenic fusions between EWSR1 or, less often, FUS and genes of the ETS family (FLI1 being the most common; Table 1).	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('FLI1', 'Gene', (151, 155))	('FUS', 'Gene', (118, 121))	('fusions', 'Var', (80, 87))	('EWSR1', 'Gene', (96, 101))	('FUS', 'Gene', '2521', (118, 121))	('Ewing sarcoma', 'Disease', (0, 13))	('EWSR1', 'Gene', '2130', (96, 101))	('blue cell tumor', 'Disease', (37, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('blue cell tumor', 'Disease', 'MESH:D005935', (37, 52))	('FLI1', 'Gene', '2313', (151, 155))
240529	28561686	It is important to note that fusions involving EWSR1 and FUS are seen in a variety of other sarcomas, as well (Table 1).	('seen', 'Reg', (65, 69))	('EWSR1', 'Gene', '2130', (47, 52))	('sarcomas', 'Disease', (92, 100))	('fusions', 'Var', (29, 36))	('FUS', 'Gene', (57, 60))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('FUS', 'Gene', '2521', (57, 60))	('EWSR1', 'Gene', (47, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
240530	28561686	Thus, a fluorescent in situ hybridization result indicating a fusion involving EWSR1 is not pathognomonic for ES.	('EWSR1', 'Gene', (79, 84))	('EWSR1', 'Gene', '2130', (79, 84))	('fusion', 'Var', (62, 68))
240539	28561686	Further analysis of one of these candidate loci, EGR2, demonstrated cooperation between the susceptibility variant and microsatellite length that regulates a major driver of ES.	('EGR2', 'Gene', (49, 53))	('EGR2', 'Gene', '1959', (49, 53))	('variant', 'Var', (107, 114))	('regulates', 'Reg', (146, 155))
240540	28561686	Whole-genome or whole-exome sequencing has identified pathogenic or likely pathogenic germline mutations in 13.1% of 175 patients with ES.	('patients', 'Species', '9606', (121, 129))	('pathogenic', 'Reg', (75, 85))	('mutations', 'Var', (95, 104))	('pathogenic', 'Reg', (54, 64))
240541	28561686	Several of these mutations occurred in genes with a known susceptibility to sarcoma, such as TP53; however, several heterozygous carriers of mutations associated with recessive conditions, particularly Bloom syndrome and Fanconi anemia, were identified, suggesting that heterozygous mutation carriers of recessive DNA repair conditions may have increased ES susceptibility.	('Fanconi anemia', 'Phenotype', 'HP:0001994', (221, 235))	('Bloom syndrome', 'Disease', 'MESH:D001816', (202, 216))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('Fanconi anemia', 'Disease', (221, 235))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('sarcoma', 'Disease', (76, 83))	('Fanconi anemia', 'Disease', 'MESH:D005199', (221, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('anemia', 'Phenotype', 'HP:0001903', (229, 235))	('Bloom syndrome', 'Disease', (202, 216))	('mutations', 'Var', (17, 26))
240552	28561686	Consistent with this finding, silencing of EWSR1-FLI1 expression in ES cells blocks proliferation and places the cell in a dedifferentiated state that no longer clusters with Ewing tumors by gene expression profiling and principal component analysis and instead clusters with mesenchymal stem cells.	('blocks', 'NegReg', (77, 83))	('FLI1', 'Gene', (49, 53))	('FLI1', 'Gene', '2313', (49, 53))	('Ewing tumors', 'Disease', 'MESH:C563168', (175, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('Ewing tumors', 'Disease', (175, 187))	('proliferation', 'CPA', (84, 97))	('EWSR1', 'Gene', (43, 48))	('Ewing tumors', 'Phenotype', 'HP:0012254', (175, 187))	('silencing', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('EWSR1', 'Gene', '2130', (43, 48))
240564	28561686	This clinical study opened the door to the identification of two second-generation mithramycin analogs EC8042 and EC8105 as less toxic and more potent alternatives, and these continue to be further developed for the clinic.	('EC8042', 'CellLine', 'CVCL:5V07', (103, 109))	('EC8042', 'Var', (103, 109))	('EC8105', 'Var', (114, 120))	('mithramycin', 'Chemical', 'MESH:D008926', (83, 94))
240568	28561686	Subsequent to this study, it was shown that inhibition of LSD1 of the nucleosome remodeling and histone deacetylase complex with a small-molecule inhibitor HCI2509 both induced EWSR1-FLI1-repressed genes and repressed EWSR1-FLI1-induced genes and effectively reversed EWSR1-FLI1 activity on a genome-wide scale.	('LSD1', 'Gene', (58, 62))	('FLI1', 'Gene', (224, 228))	('LSD1', 'Gene', '23028', (58, 62))	('inhibition', 'Var', (44, 54))	('EWSR1', 'Gene', (268, 273))	('FLI1', 'Gene', '2313', (224, 228))	('FLI1', 'Gene', '2313', (183, 187))	('FLI1', 'Gene', (183, 187))	('induced', 'PosReg', (169, 176))	('EWSR1', 'Gene', '2130', (268, 273))	('EWSR1', 'Gene', (218, 223))	('HCI2509', 'Chemical', '-', (156, 163))	('FLI1', 'Gene', (274, 278))	('EWSR1', 'Gene', (177, 182))	('FLI1', 'Gene', '2313', (274, 278))	('EWSR1', 'Gene', '2130', (218, 223))	('EWSR1', 'Gene', '2130', (177, 182))
240587	28561686	Therefore, the Sarcoma Alliance for Research Through Collaboration phase II trial of IGF1R antibody R1507 was met with considerable enthusiasm, and 115 patients with ES accrued in just over 2 years.	('Sarcoma', 'Disease', (15, 22))	('Sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('R1507', 'Var', (100, 105))	('IGF1R', 'Gene', (85, 90))	('antibody R1507', 'Var', (91, 105))	('Sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('IGF1R', 'Gene', '3480', (85, 90))	('patients', 'Species', '9606', (152, 160))
240594	28561686	Among the most noteworthy findings was a highly important relationship that linked the EWSR1-FLI1 mutation with sensitivity to the PARPi olapirib.	('mutation', 'Var', (98, 106))	('EWSR1', 'Gene', (87, 92))	('FLI1', 'Gene', (93, 97))	('PARP', 'Gene', '142', (131, 135))	('olapirib', 'Chemical', '-', (137, 145))	('FLI1', 'Gene', '2313', (93, 97))	('EWSR1', 'Gene', '2130', (87, 92))	('PARP', 'Gene', (131, 135))
240597	28561686	However, combination of PARPi with other therapies, particularly irinotecan and temozolomide, has demonstrated noteworthy activity in preclinical models, and studies translating these combinations to patients are accruing (NCT01858168, NCT02392793, and NCT01286987).	('NCT01858168', 'Var', (223, 234))	('patients', 'Species', '9606', (200, 208))	('NCT02392793', 'Var', (236, 247))	('PARP', 'Gene', (24, 28))	('NCT01286987', 'Var', (253, 264))	('PARP', 'Gene', '142', (24, 28))	('temozolomide', 'Chemical', 'MESH:D000077204', (80, 92))	('irinotecan', 'Chemical', 'MESH:D000077146', (65, 75))	('activity', 'MPA', (122, 130))
240602	28561686	Close readers of the section above discussing ES biology for advancing care will note the extent to which the emphasis is on targeting either the EWSR1-FLI1 fusion directly or the downstream consequences of transcriptional activity of the EWSR1-FLI1 fusion.	('EWSR1', 'Gene', (146, 151))	('fusion', 'Var', (157, 163))	('FLI1', 'Gene', '2313', (152, 156))	('FLI1', 'Gene', (152, 156))	('EWSR1', 'Gene', (239, 244))	('FLI1', 'Gene', (245, 249))	('EWSR1', 'Gene', '2130', (146, 151))	('FLI1', 'Gene', '2313', (245, 249))	('EWSR1', 'Gene', '2130', (239, 244))
240604	28561686	Early studies suggest that at least the gene expression pattern of the Ewing-like sarcomas driven by alternative fusions such as CCNB3-BCOR and CIC-DUX4 is distinct from that seen in EWSR1-FLI1-positive ES.	('CCNB3', 'Gene', '85417', (129, 134))	('FLI1', 'Gene', '2313', (189, 193))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (71, 90))	('FLI1', 'Gene', (189, 193))	('BCOR', 'Gene', (135, 139))	('fusions', 'Var', (113, 120))	('Ewing-like sarcomas', 'Disease', (71, 90))	('CCNB3', 'Gene', (129, 134))	('DUX4', 'Gene', (148, 152))	('EWSR1', 'Gene', (183, 188))	('DUX4', 'Gene', '100288687', (148, 152))	('BCOR', 'Gene', '54880', (135, 139))	('EWSR1', 'Gene', '2130', (183, 188))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (71, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
240607	28561686	Notably, in the phase II trial of R1507 led by the Sarcoma Alliance for Research in Cancer, 65% of patients were older than 15 years, and 43% of patients had extraskeletal disease.	('patients', 'Species', '9606', (145, 153))	('Sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('had', 'Reg', (154, 157))	('R1507', 'Var', (34, 39))	('patients', 'Species', '9606', (99, 107))	('extraskeletal disease', 'Disease', (158, 179))	('Sarcoma', 'Disease', (51, 58))	('Sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))
240618	28561686	Osteosarcoma has been associated with cancer predisposition syndromes caused by highly penetrant germline mutations including Li-Fraumeni syndrome (LFS; TP53 mutations) and retinoblastoma (RB1 mutations) and has also been reported to occur in rare predisposition syndromes related to the DNA helicase (REQ4, WRN, and BLM mutations) and ribosomal protein pathways (RPS19, RPL5, RPL11, RPL35A, RPS24, RPS17, RPS7, RPS10, and RPS26 mutations).	('RPL11', 'Gene', (377, 382))	('DNA helicase', 'Pathway', (288, 300))	('RPL35A', 'Gene', '6165', (384, 390))	('RPS10', 'Gene', (412, 417))	('TP53', 'Gene', '7157', (153, 157))	('Osteosarcoma', 'Disease', (0, 12))	('WRN', 'Gene', (308, 311))	('WRN', 'Gene', '7486', (308, 311))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('retinoblastoma', 'Phenotype', 'HP:0009919', (173, 187))	('RPS26', 'Gene', (423, 428))	('RPL11', 'Gene', '6135', (377, 382))	('RB1', 'Gene', (189, 192))	('RPS17', 'Gene', (399, 404))	('RPS7', 'Gene', (406, 410))	('RPL35A', 'Gene', (384, 390))	('Li-Fraumeni syndrome', 'Disease', (126, 146))	('retinoblastoma', 'Disease', (173, 187))	('RPS24', 'Gene', '6229', (392, 397))	('cancer', 'Disease', (38, 44))	('RPL5', 'Gene', (371, 375))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (126, 146))	('mutations', 'Var', (158, 167))	('associated', 'Reg', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('BLM', 'Gene', (317, 320))	('caused', 'Reg', (70, 76))	('RB1', 'Gene', '5925', (189, 192))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('RPS10', 'Gene', '6204', (412, 417))	('BLM', 'Gene', '641', (317, 320))	('TP53', 'Gene', (153, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('RPL5', 'Gene', '6125', (371, 375))	('retinoblastoma', 'Disease', 'MESH:D012175', (173, 187))	('RPS17', 'Gene', '6218', (399, 404))	('RPS19', 'Gene', '6223', (364, 369))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('RPS26', 'Gene', '6231', (423, 428))	('RPS19', 'Gene', (364, 369))	('mutations', 'Var', (106, 115))	('RPS7', 'Gene', '6201', (406, 410))	('RPS24', 'Gene', (392, 397))	('ribosomal protein pathways', 'Pathway', (336, 362))
240619	28561686	In osteosarcoma, estimates indicate that as many as 10% of cases diagnosed before age 30 may be due to underlying TP53 germline mutations or rare variants; some have speculated that this rate may be even higher when osteosarcoma occurs in very young children younger than 5 years.	('osteosarcoma', 'Phenotype', 'HP:0002669', (216, 228))	('osteosarcoma', 'Disease', (216, 228))	('osteosarcoma', 'Disease', 'MESH:D012516', (216, 228))	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('germline mutations', 'Var', (119, 137))	('TP53', 'Gene', '7157', (114, 118))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('children', 'Species', '9606', (250, 258))	('variants', 'Var', (146, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('TP53', 'Gene', (114, 118))	('due', 'Reg', (96, 99))
240620	28561686	Although these underlying syndromes can be considered relatively rare in general in osteosarcoma, chromosomal aneuploidy remains a frequent finding in this pediatric tumor, suggesting that DNA repair defects leading to chromosomal instability may predispose individuals to development of osteosarcoma.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('predispose', 'Reg', (247, 257))	('chromosomal aneuploidy', 'Disease', (98, 120))	('chromosomal instability', 'Phenotype', 'HP:0040012', (219, 242))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (98, 120))	('chromosomal', 'MPA', (219, 230))	('defects', 'Var', (200, 207))	('tumor', 'Disease', (166, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('osteosarcoma', 'Disease', (84, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (288, 300))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))	('osteosarcoma', 'Disease', (288, 300))	('osteosarcoma', 'Disease', 'MESH:D012516', (288, 300))
240621	28561686	Single nucleotide polymorphisms can also be associated with many diseases including cancer.	('associated', 'Reg', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
240622	28561686	Genome-wide association studies have examined the role of single nucleotide polymorphisms in osteosarcoma with varying results, including the association of germline single nucleotide polymorphisms and risk for metastasis in osteosarcoma significance; all of this indicates the genetic causation of osteosarcoma is much greater than previously known.	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('single nucleotide polymorphisms', 'Var', (58, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('osteosarcoma', 'Disease', (299, 311))	('osteosarcoma', 'Phenotype', 'HP:0002669', (299, 311))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('single nucleotide polymorphisms', 'Var', (166, 197))	('osteosarcoma', 'Disease', (93, 105))	('association', 'Interaction', (142, 153))	('osteosarcoma', 'Disease', (225, 237))	('osteosarcoma', 'Disease', 'MESH:D012516', (93, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (299, 311))	('osteosarcoma', 'Phenotype', 'HP:0002669', (225, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('osteosarcoma', 'Disease', 'MESH:D012516', (225, 237))
240625	28561686	The most frequent somatic genomic alterations in osteosarcoma are TP53 and RB1 inactivation.	('osteosarcoma', 'Disease', (49, 61))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('inactivation', 'Var', (79, 91))	('osteosarcoma', 'Phenotype', 'HP:0002669', (49, 61))	('RB1', 'Gene', (75, 78))	('osteosarcoma', 'Disease', 'MESH:D012516', (49, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('RB1', 'Gene', '5925', (75, 78))
240627	28561686	TP53 alterations are most often structural variants (usually in intron 1), but mutations are also common.	('TP53', 'Gene', '7157', (0, 4))	('alterations', 'Var', (5, 16))	('TP53', 'Gene', (0, 4))
240628	28561686	On rare occasions, MDM2 amplification has been observed and reported to be more common in tumors from older patients with osteosarcoma.	('osteosarcoma', 'Disease', (122, 134))	('MDM2', 'Gene', '4193', (19, 23))	('osteosarcoma', 'Phenotype', 'HP:0002669', (122, 134))	('common', 'Reg', (80, 86))	('MDM2', 'Gene', (19, 23))	('osteosarcoma', 'Disease', 'MESH:D012516', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('amplification', 'Var', (24, 37))	('patients', 'Species', '9606', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
240629	28561686	RB1 is most often disrupted by deletion, and somatic mutations or structural variations occur only rarely.	('RB1', 'Gene', (0, 3))	('disrupted', 'Reg', (18, 27))	('deletion', 'Var', (31, 39))	('RB1', 'Gene', '5925', (0, 3))
240631	28561686	Copy number alterations and structural variants are the predominant mechanisms by which cancer gene protein function is altered, whereas point mutations and small insertions and deletions appear to be less common.	('structural variants', 'Var', (28, 47))	('altered', 'Reg', (120, 127))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('protein', 'Protein', (100, 107))	('Copy number alterations', 'Var', (0, 23))	('function', 'MPA', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
240636	28561686	MYC amplification has been correlated with poor outcome, a finding that needs to be confirmed in a large uniformly treated patient population and in a prospective trial.	('MYC', 'Gene', (0, 3))	('amplification', 'Var', (4, 17))	('patient', 'Species', '9606', (123, 130))	('MYC', 'Gene', '4609', (0, 3))
240641	28561686	Other cell cycle gene alterations in osteosarcoma include CDK4 amplification, which is interesting in that CDKN2A/B inhibits the CDK4-cyclin D (CCND1/2/3) complex.	('CDK4', 'Gene', '1019', (58, 62))	('CDKN2A/B', 'Gene', '1029;1030', (107, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('CCND1/2/3', 'Gene', '595;894;896', (144, 153))	('CDK4', 'Gene', (129, 133))	('CDKN2A/B', 'Gene', (107, 115))	('alterations', 'Reg', (22, 33))	('CDK4', 'Gene', '1019', (129, 133))	('osteosarcoma', 'Phenotype', 'HP:0002669', (37, 49))	('osteosarcoma', 'Disease', (37, 49))	('CCND1/2/3', 'Gene', (144, 153))	('CDK4', 'Gene', (58, 62))	('amplification', 'Var', (63, 76))	('inhibits', 'NegReg', (116, 124))	('osteosarcoma', 'Disease', 'MESH:D012516', (37, 49))
240642	28561686	Amplification of both CCNE1 and CCND3 have been reported in osteosarcomas.	('Amplification', 'Var', (0, 13))	('CCND3', 'Gene', '896', (32, 37))	('CCNE1', 'Gene', (22, 27))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('CCND3', 'Gene', (32, 37))	('reported', 'Reg', (48, 56))	('osteosarcomas', 'Phenotype', 'HP:0002669', (60, 73))	('osteosarcomas', 'Disease', (60, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('CCNE1', 'Gene', '898', (22, 27))	('osteosarcomas', 'Disease', 'MESH:D012516', (60, 73))
240663	28561686	Given the genomic mechanisms most common in osteosarcoma, copy number, and structural alterations, assays optimized to detect these types of variants are needed.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('copy number', 'Var', (58, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (44, 56))	('osteosarcoma', 'Disease', (44, 56))	('osteosarcoma', 'Disease', 'MESH:D012516', (44, 56))	('common', 'Reg', (34, 40))
240664	28561686	Although currently existing clinical sequencing tests do detect copy number alterations in many of the genes commonly affected in osteosarcoma, standards for calling thresholds predictive of therapy response are lacking.	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (130, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('copy number alterations', 'Var', (64, 87))	('osteosarcoma', 'Disease', (130, 142))
240667	28561686	The incidence of germline hereditary cancer predisposition mutations is estimated to be approximately 20% for the overall cancer patient population and at least 10% in pediatrics.	('hereditary cancer', 'Disease', (26, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('hereditary cancer', 'Disease', 'MESH:D009369', (26, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('patient', 'Species', '9606', (129, 136))
240669	28561686	Moreover, the combination of rare and specific childhood tumors with family history increases the risk for underlying germline mutations substantially (e.g., TP53 mutations associated with choroid plexus carcinoma or adrenocortical carcinoma).	('TP53', 'Gene', '7157', (158, 162))	('choroid plexus carcinoma', 'Disease', (189, 213))	('TP53', 'Gene', (158, 162))	('mutations', 'Var', (163, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (189, 213))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (217, 241))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (217, 241))	('childhood tumors', 'Disease', 'MESH:D009369', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (189, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('associated', 'Reg', (173, 183))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('adrenocortical carcinoma', 'Disease', (217, 241))	('childhood tumors', 'Disease', (47, 63))
240671	28561686	A recent study found that nearly half of (adult) patients with sarcoma have pathogenic monogenic and polygenic variation in known and novel cancer genes, and 5% had pathogenic mutations in genes associated with actionable management guidelines.	('monogenic', 'Var', (87, 96))	('mutations', 'Var', (176, 185))	('polygenic variation', 'Var', (101, 120))	('pathogenic', 'Reg', (76, 86))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
240676	28561686	In fact, a recent germline study for cancer predisposition genes in select pediatric cancer subtypes found that recorded family history in the medical record could not be used to predict risk for carrying a cancer predisposition gene mutation.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('mutation', 'Var', (234, 242))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
240677	28561686	Given the current limitations of its collection, family history cannot be the only factor in deciding to test pediatric patients with cancer, particularly those with bone sarcomas, for inherited cancer predisposition mutations; a striking family history should support genetic testing, but its absence does not rule against testing.	('bone sarcoma', 'Phenotype', 'HP:0002669', (166, 178))	('bone sarcomas', 'Disease', (166, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('bone sarcomas', 'Phenotype', 'HP:0002669', (166, 179))	('inherited cancer', 'Disease', 'MESH:D009386', (185, 201))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('genetic', 'Var', (269, 276))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('mutations', 'Var', (217, 226))	('inherited cancer', 'Disease', (185, 201))	('bone sarcomas', 'Disease', 'MESH:D001847', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
240682	28561686	Secondly, establishing a genetic causation through a newly identified cancer predisposition mutation then alerts other family members to a possible increased risk of malignancy.	('mutation', 'Var', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('malignancy', 'Disease', (166, 176))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))
240686	28561686	LFS is caused by germline mutations in TP53 and associated with breast cancer, brain tumors, adrenal tumors, leukemia, and sarcoma.	('associated', 'Reg', (48, 58))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('LFS', 'Disease', (0, 3))	('TP53', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('brain tumors', 'Disease', 'MESH:D001932', (79, 91))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('brain tumors', 'Phenotype', 'HP:0030692', (79, 91))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('adrenal tumors', 'Disease', 'MESH:D000310', (93, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('leukemia', 'Disease', (109, 117))	('leukemia', 'Disease', 'MESH:D007938', (109, 117))	('sarcoma', 'Disease', (123, 130))	('caused by', 'Reg', (7, 16))	('brain tumors', 'Disease', (79, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('adrenal tumors', 'Disease', (93, 107))	('germline mutations', 'Var', (17, 35))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
240690	28561686	Pediatric cancer occurs in 1:408 children before age 15 and 1:285 children before the age of 20, with an estimated genetic cause in 10% to 20%; this implies that a mutation in a known cancer predisposition gene potentially could be found in 1:1,500 to 1:3,000 of newborns screened for inherited genetic cancer predisposition, which is within the epidemiologic criteria already established for the newborn screening program.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', (303, 309))	('Pediatric cancer', 'Disease', 'MESH:D009369', (0, 16))	('children', 'Species', '9606', (66, 74))	('genetic cancer', 'Disease', (295, 309))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Pediatric cancer', 'Disease', (0, 16))	('mutation', 'Var', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('children', 'Species', '9606', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (10, 16))	('genetic cancer', 'Disease', 'MESH:D030342', (295, 309))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
240692	28561686	Until genetic testing for mutations in cancer predisposition genes becomes universal for all healthy children, we recommend the consideration of genetic testing for cancer risk genes in all children diagnosed with sarcoma.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('sarcoma', 'Disease', 'MESH:D012509', (214, 221))	('children', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('children', 'Species', '9606', (190, 198))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('sarcoma', 'Disease', (214, 221))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))
240694	28561686	Germline cancer risk mutations are commonly detected in patients with bone sarcomas, particularly osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('cancer', 'Disease', (9, 15))	('mutations', 'Var', (21, 30))	('patients', 'Species', '9606', (56, 64))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('bone sarcomas', 'Phenotype', 'HP:0002669', (70, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('detected', 'Reg', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('bone sarcomas', 'Disease', 'MESH:D001847', (70, 83))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('osteosarcoma', 'Disease', (98, 110))	('bone sarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('bone sarcomas', 'Disease', (70, 83))
240695	28561686	The implications of identifying germline cancer risk mutations are significant enough to warrant a consideration of referral of all patients with bone sarcoma, particularly those with osteosarcoma, to a cancer risk clinic.	('bone sarcoma', 'Phenotype', 'HP:0002669', (146, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('mutations', 'Var', (53, 62))	('bone sarcoma', 'Disease', (146, 158))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('osteosarcoma', 'Phenotype', 'HP:0002669', (184, 196))	('osteosarcoma', 'Disease', (184, 196))	('osteosarcoma', 'Disease', 'MESH:D012516', (184, 196))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('patients', 'Species', '9606', (132, 140))	('bone sarcoma', 'Disease', 'MESH:D001847', (146, 158))
240743	29515623	The observed alterations in catecholamine biosynthesis and the increases in levels of aromatic amino acids (phenylalanine and tryptophan) may cause neurotransmitter imbalances analogous to those previously exemplified by lowered levels of serotonin, dopamine, and norepinephrine in the AD brain (Storga et al.,; Matthews et al.,; Garcia-Alloza et al.,; Xu et al.,), again suggesting a potential link between tumor-brain and neurodegeneration.	('neurotransmitter imbalances', 'Phenotype', 'HP:0012535', (148, 175))	('neurodegeneration', 'Phenotype', 'HP:0002180', (424, 441))	('catecholamine biosynthesis', 'MPA', (28, 54))	('norepinephrine', 'Chemical', 'MESH:D009638', (264, 278))	('cause', 'Reg', (142, 147))	('serotonin', 'MPA', (239, 248))	('AD', 'Disease', 'MESH:D000544', (286, 288))	('dopamine', 'Chemical', 'MESH:D004298', (250, 258))	('tryptophan', 'Chemical', 'MESH:D014364', (126, 136))	('catecholamine', 'Chemical', 'MESH:D002395', (28, 41))	('levels', 'MPA', (229, 235))	('imbalances', 'Phenotype', 'HP:0002172', (165, 175))	('dopamine', 'MPA', (250, 258))	('neurotransmitter imbalances', 'MPA', (148, 175))	('levels', 'MPA', (76, 82))	('increases', 'PosReg', (63, 72))	('aromatic amino acids', 'Chemical', 'MESH:D024322', (86, 106))	('serotonin', 'Chemical', 'MESH:D012701', (239, 248))	('tumor-brain and neurodegeneration', 'Disease', 'MESH:D001932', (408, 441))	('Garcia-Alloza', 'Disease', (330, 343))	('tumor', 'Phenotype', 'HP:0002664', (408, 413))	('phenylalanine', 'Chemical', 'MESH:D010649', (108, 121))	('Garcia-Alloza', 'Disease', 'MESH:C536767', (330, 343))	('alterations', 'Var', (13, 24))	('AD', 'Disease', (286, 288))
240836	29066510	Then cells were incubated with the following antibodies in 1:50 dilution: FITC-conjuncted antibodies against human CD29, CD73, CD90, CD105 and CD166, and PE-conjuncted anti-human CD31, CD34, CD44, CD90, CD105 and CD166.	('CD166', 'Gene', '214', (143, 148))	('CD90', 'Gene', (197, 201))	('CD105', 'Var', (133, 138))	('CD34', 'Gene', (185, 189))	('CD44', 'Gene', '960', (191, 195))	('CD44', 'Gene', (191, 195))	('CD166', 'Gene', (213, 218))	('CD90', 'Gene', '7070', (197, 201))	('CD166', 'Gene', (143, 148))	('CD29', 'Gene', '3688', (115, 119))	('CD31', 'Gene', '5175', (179, 183))	('CD105', 'Var', (203, 208))	('CD34', 'Gene', '947', (185, 189))	('human', 'Species', '9606', (173, 178))	('CD90', 'Gene', (127, 131))	('CD29', 'Gene', (115, 119))	('human', 'Species', '9606', (109, 114))	('FITC', 'Chemical', 'MESH:D016650', (74, 78))	('CD73', 'Gene', '4907', (121, 125))	('CD31', 'Gene', (179, 183))	('CD90', 'Gene', '7070', (127, 131))	('CD73', 'Gene', (121, 125))	('CD166', 'Gene', '214', (213, 218))
240916	29066510	Over ninety-eight percent of uninfected PDLSCs were detected positive for mesenchyme markers CD29, CD44, CD73, CD90, CD105 and CD166 and only 1.4% and 9.5% cells expressed vascular endothelial marker CD34 or CD31, respectively (Fig.	('CD73', 'Gene', (105, 109))	('CD29', 'Gene', (93, 97))	('CD34', 'Gene', (200, 204))	('CD34', 'Gene', '947', (200, 204))	('CD105', 'Var', (117, 122))	('CD90', 'Gene', '7070', (111, 115))	('CD31', 'Gene', (208, 212))	('CD44', 'Gene', '960', (99, 103))	('CD90', 'Gene', (111, 115))	('CD31', 'Gene', '5175', (208, 212))	('CD44', 'Gene', (99, 103))	('CD29', 'Gene', '3688', (93, 97))	('CD73', 'Gene', '4907', (105, 109))	('CD166', 'Gene', (127, 132))	('CD166', 'Gene', '214', (127, 132))	('mesenchyme', 'CPA', (74, 84))
241026	29066510	It has been reported that KSHV can efficiently infect human MSCs of diverse origins.	('infect', 'Reg', (47, 53))	('KSHV', 'Species', '37296', (26, 30))	('KS', 'Phenotype', 'HP:0100726', (26, 28))	('human', 'Species', '9606', (54, 59))	('KSHV', 'Var', (26, 30))
241032	29066510	The current models for KS cell lineage include that (i) KSHV infects lymphatic endothelial cells (LEC) and drives them dedifferentiation towards blood endothelial cell (BEC) phenotype; (ii) KSHV infects BECs and drives them differentiation towards LEC phenotype; (iii) KSHV infects circulating endothelial progenitor cells and drives differentiation of these cells towards the LEC phenotype; (iv) KSHV infects LEC and drives EndMT.	('KS', 'Phenotype', 'HP:0100726', (23, 25))	('LEC', 'Gene', (248, 251))	('KSHV', 'Species', '37296', (190, 194))	('KSHV', 'Species', '37296', (56, 60))	('KSHV', 'Species', '37296', (397, 401))	('infects', 'Reg', (402, 409))	('KSHV', 'Species', '37296', (269, 273))	('infects', 'Reg', (274, 281))	('LEC', 'Gene', '6360', (410, 413))	('LEC', 'Gene', '6360', (377, 380))	('KS', 'Phenotype', 'HP:0100726', (56, 58))	('KS', 'Phenotype', 'HP:0100726', (190, 192))	('KS', 'Phenotype', 'HP:0100726', (397, 399))	('LEC', 'Gene', (410, 413))	('KSHV', 'Var', (397, 401))	('LEC', 'Gene', '6360', (98, 101))	('LEC', 'Gene', (377, 380))	('LEC', 'Gene', '6360', (248, 251))	('KS', 'Phenotype', 'HP:0100726', (269, 271))	('LEC', 'Gene', (98, 101))
241064	29099264	Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation.	('mammalian target of rapamycin', 'Gene', '2475', (67, 96))	('mammalian target of rapamycin', 'Gene', (67, 96))	('PI3K/mTOR', 'Gene', '5290;2475', (98, 107))	('increased', 'PosReg', (227, 236))	('phosphorylation', 'MPA', (237, 252))	('phosphatidylinositol-3-kinase', 'Gene', (37, 66))	('phosphatidylinositol-3-kinase', 'Gene', '5290', (37, 66))	('reduced', 'NegReg', (152, 159))	('motility', 'CPA', (187, 195))	('IGF1R', 'Gene', (295, 300))	('xenograft growth', 'CPA', (200, 216))	('UPS cell proliferation', 'CPA', (160, 182))	('increased phosphorylation of insulin-like growth factor', 'Phenotype', 'HP:0030269', (227, 282))	('IGF1R', 'Gene', '3480', (295, 300))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (256, 293))	('PI3K/mTOR', 'Gene', (98, 107))	('inhibiting', 'Var', (26, 36))	('insulin-like growth factor 1 receptor', 'Gene', (256, 293))
241076	29099264	The PI3K/mTOR pathway is frequently dysregulated in cancer through increased expression and/or activation of receptor tyrosine kinases, mutations in pathway components, or loss of negative pathway regulators, such as phosphatase and tensin homolog (PTEN).	('PI3K/mTOR', 'Gene', (4, 13))	('expression', 'MPA', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('loss', 'NegReg', (172, 176))	('dysregulated', 'Reg', (36, 48))	('PI3K/mTOR', 'Gene', '5290;2475', (4, 13))	('activation', 'PosReg', (95, 105))	('receptor', 'Protein', (109, 117))	('PTEN', 'Gene', (249, 253))	('increased', 'PosReg', (67, 76))	('mutations', 'Var', (136, 145))	('PTEN', 'Gene', '5728', (249, 253))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
241086	29099264	Previously, we found that a subset of UPS tumor samples expressed high levels of pAKT (S473), which corresponded to poor overall survival for those patients.	('patients', 'Species', '9606', (148, 156))	('S473', 'Var', (87, 91))	('poor', 'NegReg', (116, 120))	('AKT', 'Gene', '207', (82, 85))	('UPS tumor', 'Disease', 'MESH:D017118', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('AKT', 'Gene', (82, 85))	('UPS tumor', 'Disease', (38, 47))
241095	29099264	Interestingly, the RA-UPS cell line RIS-819.1 was more sensitive to BGT226 than the sporadic UPS-186 cell line.	('RA-UPS', 'Disease', (19, 25))	('BGT226', 'Var', (68, 74))	('RA-UPS', 'Disease', 'MESH:D001172', (19, 25))	('BGT226', 'Chemical', 'MESH:C570852', (68, 74))	('sensitive', 'MPA', (55, 64))
241099	29099264	Cell migration and invasion were reduced in a dose-dependent manner in both cell lines; however, these processes were not fully inhibited even at the highest dose of BGT226 (100 nM; Fig.	('BGT226', 'Gene', (166, 172))	('Cell migration', 'CPA', (0, 14))	('invasion', 'CPA', (19, 27))	('BGT226', 'Chemical', 'MESH:C570852', (166, 172))	('100 nM', 'Var', (174, 180))
241107	29099264	This finding is specific for pIGF1R and not for phosphorylated insulin receptor as there was no increase in the phosphorylated insulin receptor signal according to western blot analysis of whole cell lysates harvested from UPS-186 and RIS-819.1 cells treated with BGT226 for 2 or 96 hours (Supp Fig 1).	('insulin receptor', 'Gene', '3643', (127, 143))	('BGT226', 'Var', (264, 270))	('insulin receptor', 'Gene', (63, 79))	('BGT226', 'Chemical', 'MESH:C570852', (264, 270))	('IGF1R', 'Gene', (30, 35))	('insulin receptor', 'Gene', '3643', (63, 79))	('IGF1R', 'Gene', '3480', (30, 35))	('insulin receptor', 'Gene', (127, 143))
241109	29099264	Therefore, we selected the small molecule inhibitor AEW541 to block IGF1R activation following BGT226 treatment because AEW541 displays a higher affinity for IGF1R than insulin receptor in cellular assays.	('AEW541', 'Var', (120, 126))	('affinity', 'Interaction', (145, 153))	('AEW541', 'Chemical', '-', (120, 126))	('IGF1R', 'Gene', (158, 163))	('insulin receptor', 'Gene', (169, 185))	('BGT226', 'Gene', (95, 101))	('IGF1R', 'Gene', (68, 73))	('BGT226', 'Chemical', 'MESH:C570852', (95, 101))	('IGF1R', 'Gene', '3480', (68, 73))	('insulin receptor', 'Gene', '3643', (169, 185))	('IGF1R', 'Gene', '3480', (158, 163))	('AEW541', 'Chemical', '-', (52, 58))
241111	29099264	Western blot analysis results demonstrated that AEW541 reduced IGF1R activation at all concentrations, with the highest level of inhibition achieved at concentrations greater than 1 microM (Fig.	('reduced', 'NegReg', (55, 62))	('AEW541', 'Var', (48, 54))	('activation', 'MPA', (69, 79))	('IGF1R', 'Gene', (63, 68))	('reduced IGF1R', 'Phenotype', 'HP:0030269', (55, 68))	('AEW541', 'Chemical', '-', (48, 54))	('IGF1R', 'Gene', '3480', (63, 68))
241112	29099264	Although AEW541 downregulated pAKT in both cell lines, it did not strongly affect the activation status of S6K or 4EBP1, suggesting that IGF1R is not solely responsible for PI3K/mTOR pathway activation in UPS.	('AEW541', 'Chemical', '-', (9, 15))	('AKT', 'Gene', (31, 34))	('S6K', 'Gene', (107, 110))	('IGF1R', 'Gene', (137, 142))	('PI3K/mTOR', 'Gene', (173, 182))	('S6K', 'Gene', '6198', (107, 110))	('AEW541', 'Var', (9, 15))	('PI3K/mTOR', 'Gene', '5290;2475', (173, 182))	('IGF1R', 'Gene', '3480', (137, 142))	('AKT', 'Gene', '207', (31, 34))	('downregulated', 'NegReg', (16, 29))
241113	29099264	IGF1R can regulate cell growth and proliferation through PI3K/mTOR and/or mitogen-activated protein kinase pathway activation; accordingly, inhibition of the receptor via AEW541 elicited strong antiproliferative effects in the UPS cell lines (EC50 values: UPS-186, 4.39 microM; RIS-819.1, 4.96 microM) resulting from a significant increase of cells in G1 phase, a concomitant decrease of cells in S phase, and the induction of apoptosis in both cell lines (Fig.	('PI3K/mTOR', 'Gene', '5290;2475', (57, 66))	('apoptosis', 'CPA', (427, 436))	('antiproliferative effects', 'CPA', (194, 219))	('inhibition', 'Var', (140, 150))	('increase', 'PosReg', (331, 339))	('AEW541', 'Gene', (171, 177))	('UPS-186', 'Var', (256, 263))	('AEW541', 'Chemical', '-', (171, 177))	('IGF1R', 'Gene', (0, 5))	('PI3K/mTOR', 'Gene', (57, 66))	('cells in S phase', 'CPA', (388, 404))	('decrease', 'NegReg', (376, 384))	('IGF1R', 'Gene', '3480', (0, 5))	('cells in G1 phase', 'CPA', (343, 360))
241114	29099264	Recombinant IGF1 was used as an additional chemoattractant in these assays to assess the ability of AEW541 to prevent IGF1R activation and downstream signaling in the presence of ligand.	('IGF1', 'Gene', (118, 122))	('IGF1R', 'Gene', (118, 123))	('IGF1R', 'Gene', '3480', (118, 123))	('AEW541', 'Var', (100, 106))	('IGF1', 'Gene', '3479', (118, 122))	('activation', 'MPA', (124, 134))	('prevent', 'NegReg', (110, 117))	('IGF1', 'Gene', '3479', (12, 16))	('downstream signaling', 'MPA', (139, 159))	('AEW541', 'Chemical', '-', (100, 106))	('IGF1', 'Gene', (12, 16))
241115	29099264	As with BGT226 treatment, a larger proportion of apoptotic cells was detected in RIS-819.1 samples than in UPS-186 samples.	('RIS-819.1', 'Var', (81, 90))	('BGT226', 'Chemical', 'MESH:C570852', (8, 14))	('apoptotic cells', 'CPA', (49, 64))
241117	29099264	The sensitivity of RIS-819.1 cells to AEW541 was further reflected by the significant dose-dependent decline in both migration and invasion after treatment (Fig.	('invasion', 'CPA', (131, 139))	('migration', 'CPA', (117, 126))	('AEW541', 'Var', (38, 44))	('decline', 'NegReg', (101, 108))	('AEW541', 'Chemical', '-', (38, 44))
241118	29099264	In contrast, the only significant effects observed in UPS-186 cells were decreases in invasion with AEW541 concentrations greater than 2.5 microM.	('AEW541', 'Chemical', '-', (100, 106))	('invasion', 'CPA', (86, 94))	('decreases', 'NegReg', (73, 82))	('AEW541', 'Var', (100, 106))
241119	29099264	Taken together, these results demonstrate that AEW541 successfully attenuated IGF1R activation even in the presence of exogenous ligand and exerted antitumor effects in vitro in both cell lines.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('AEW541', 'Var', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('IGF1R', 'Gene', (78, 83))	('AEW541', 'Chemical', '-', (47, 53))	('IGF1R', 'Gene', '3480', (78, 83))	('tumor', 'Disease', (152, 157))	('attenuated', 'NegReg', (67, 77))	('activation', 'MPA', (84, 94))
241120	29099264	Although RIS-819.1 cells were more sensitive to drug treatment than UPS-186 cells, our data suggest that AEW541 could be used to prevent IGF1R activation following BGT226 treatment in both cell lines.	('AEW541', 'Var', (105, 111))	('BGT226', 'Chemical', 'MESH:C570852', (164, 170))	('prevent', 'NegReg', (129, 136))	('activation', 'MPA', (143, 153))	('AEW541', 'Chemical', '-', (105, 111))	('IGF1R', 'Gene', (137, 142))	('IGF1R', 'Gene', '3480', (137, 142))
241123	29099264	According to the combination index values, synergistic interactions occurred in 80% of the drug combinations in UPS-186 cells and in 60% of drug combinations in RIS-819.1 cells; however, the corresponding drug effects for most of the synergistic drug combinations were not substantial, with less than 50% cell death after treatment with AEW541 and BGT226 concentrations less than their EC50 values.	('AEW541', 'Chemical', '-', (337, 343))	('cell death', 'CPA', (305, 315))	('combinations', 'Var', (96, 108))	('BGT226', 'Chemical', 'MESH:C570852', (348, 354))
241124	29099264	Treatment with synergistic concentrations of AEW541 and BGT226 minimally affected cell-cycle distribution and apoptosis levels in UPS-186 and RIS-819.1 samples, further confirming the lack of antiproliferative effects (Supplementary Fig.	('cell-cycle distribution', 'CPA', (82, 105))	('AEW541', 'Var', (45, 51))	('BGT226', 'Chemical', 'MESH:C570852', (56, 62))	('AEW541', 'Chemical', '-', (45, 51))	('apoptosis levels', 'MPA', (110, 126))	('affected', 'Reg', (73, 81))	('BGT226', 'Gene', (56, 62))
241128	29099264	Mice treated daily with either BGT226 or AEW541 had tumor volumes comparable to those of the control group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BGT226', 'Chemical', 'MESH:C570852', (31, 37))	('tumor', 'Disease', (52, 57))	('AEW541', 'Var', (41, 47))	('BGT226', 'Var', (31, 37))	('Mice', 'Species', '10090', (0, 4))	('AEW541', 'Chemical', '-', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
241131	29099264	Immunohistochemical analysis revealed that AEW541 and BGT226 co-treatment moderately reduced cell proliferation as demonstrated by decreased Ki67 staining compared with vehicle or single-agent therapy but had little effect on apoptosis as determined by cleaved caspase 3 staining (Fig.	('AEW541', 'Chemical', '-', (43, 49))	('decreased', 'NegReg', (131, 140))	('cell proliferation', 'CPA', (93, 111))	('Ki67', 'Gene', '17345', (141, 145))	('BGT226', 'Gene', (54, 60))	('BGT226', 'Chemical', 'MESH:C570852', (54, 60))	('AEW541', 'Var', (43, 49))	('reduced', 'NegReg', (85, 92))	('Ki67', 'Gene', (141, 145))
241134	29099264	PI3K/mTOR signaling was more strongly inhibited by the combination treatment than by other treatments, as shown by the downregulation of pAKT, pS6RP, and p4EBP1; furthermore, AEW541 prevented BGT226-associated IGF1R activation in the combination group.	('AEW541', 'Var', (175, 181))	('BGT226', 'Chemical', 'MESH:C570852', (192, 198))	('IGF1R', 'Gene', '3480', (210, 215))	('PI3K/mTOR', 'Gene', '5290;2475', (0, 9))	('downregulation', 'NegReg', (119, 133))	('AKT', 'Gene', (138, 141))	('inhibited', 'NegReg', (38, 47))	('prevented', 'NegReg', (182, 191))	('AEW541', 'Chemical', '-', (175, 181))	('activation', 'PosReg', (216, 226))	('IGF1R', 'Gene', (210, 215))	('BGT226-associated', 'Gene', (192, 209))	('PI3K/mTOR', 'Gene', (0, 9))	('AKT', 'Gene', '207', (138, 141))
241135	29099264	Combination treatment did not significantly alter cell proliferation; however, the substantial antitumor effects of co-targeting PI3K, mTOR, and IGF1R in vivo suggested that combination treatment may affect other tumor-supporting processes such as cell migration and invasion.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (99, 104))	('affect', 'Reg', (200, 206))	('IGF1R', 'Gene', '3480', (145, 150))	('invasion', 'CPA', (267, 275))	('mTOR', 'Gene', '2475', (135, 139))	('mTOR', 'Gene', (135, 139))	('cell migration', 'CPA', (248, 262))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('PI3K', 'Var', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('IGF1R', 'Gene', (145, 150))
241139	29099264	It is surprising that BGT226-treated cells migrated and invaded as previous experiments demonstrated that inhibition of the PI3K/mTOR pathway sufficiently hindered UPS cell migration and invasion.	('hindered', 'NegReg', (155, 163))	('PI3K/mTOR', 'Gene', (124, 133))	('inhibition', 'Var', (106, 116))	('BGT226', 'Chemical', 'MESH:C570852', (22, 28))	('PI3K/mTOR', 'Gene', '5290;2475', (124, 133))	('UPS cell migration', 'CPA', (164, 182))	('invasion', 'CPA', (187, 195))
241143	29099264	In UPS-186 samples, co-treatment with AEW541 and BGT226 reduced cell migration and invasion by approximately 50% and 75%, respectively, compared with the control samples treated with DMSO + IGF1.	('BGT226', 'Gene', (49, 55))	('AEW541', 'Var', (38, 44))	('reduced', 'NegReg', (56, 63))	('BGT226', 'Chemical', 'MESH:C570852', (49, 55))	('IGF1', 'Gene', '3479', (190, 194))	('invasion', 'CPA', (83, 91))	('AEW541', 'Chemical', '-', (38, 44))	('DMSO', 'Chemical', 'MESH:D004121', (183, 187))	('cell migration', 'CPA', (64, 78))	('IGF1', 'Gene', (190, 194))
241145	29099264	Aberrant PI3K/mTOR signaling can facilitate the cytoplasmic sequestration of p27 through AKT-mediated phosphorylation at T157 and T198, which blocks the nuclear import of p27.	('p27', 'Gene', '1027', (77, 80))	('nuclear import', 'MPA', (153, 167))	('Aberrant', 'Var', (0, 8))	('p27', 'Gene', (171, 174))	('AKT', 'Gene', '207', (89, 92))	('facilitate', 'PosReg', (33, 43))	('PI3K/mTOR', 'Gene', '5290;2475', (9, 18))	('p27', 'Gene', '1027', (171, 174))	('T198', 'Var', (130, 134))	('PI3K/mTOR', 'Gene', (9, 18))	('blocks', 'NegReg', (142, 148))	('AKT', 'Gene', (89, 92))	('cytoplasmic sequestration', 'MPA', (48, 73))	('p27', 'Gene', (77, 80))
241148	29099264	BGT226 decreased cytoplasmic p27 levels, but nuclear p27 levels were not altered; AEW541 did not significantly affect cytoplasmic or nuclear p27 levels compared with control cells.	('p27', 'Gene', (53, 56))	('BGT226', 'Chemical', 'MESH:C570852', (0, 6))	('p27', 'Gene', '1027', (29, 32))	('AEW541', 'Var', (82, 88))	('p27', 'Gene', '1027', (53, 56))	('decreased', 'NegReg', (7, 16))	('p27', 'Gene', (141, 144))	('AEW541', 'Chemical', '-', (82, 88))	('p27', 'Gene', '1027', (141, 144))	('BGT226', 'Gene', (0, 6))	('p27', 'Gene', (29, 32))
241149	29099264	Combination treatment with AEW541 and BGT226, however, effectively reduced cytoplasmic p27 levels and simultaneously increased nuclear p27 levels.	('p27', 'Gene', '1027', (135, 138))	('increased', 'PosReg', (117, 126))	('AEW541', 'Var', (27, 33))	('reduced', 'NegReg', (67, 74))	('p27', 'Gene', (87, 90))	('AEW541', 'Chemical', '-', (27, 33))	('BGT226', 'Gene', (38, 44))	('p27', 'Gene', '1027', (87, 90))	('p27', 'Gene', (135, 138))	('BGT226', 'Chemical', 'MESH:C570852', (38, 44))
241155	29099264	To determine the potential downstream effect on RhoA, we used a colorimetric assay to evaluate RhoA activity in RIS-819.1 cells treated with BGT226 and AEW541 alone and in combination.	('RhoA', 'Gene', '387', (48, 52))	('BGT226', 'Chemical', 'MESH:C570852', (141, 147))	('AEW541', 'Chemical', '-', (152, 158))	('RhoA', 'Gene', '387', (95, 99))	('RhoA', 'Gene', (95, 99))	('AEW541', 'Var', (152, 158))	('RhoA', 'Gene', (48, 52))	('BGT226', 'Gene', (141, 147))
241159	29099264	Co-targeting PI3K, mTOR, and IGF1R reduced cytoplasmic p27 while simultaneously increasing nuclear p27 levels.	('PI3K', 'Var', (13, 17))	('IGF1R', 'Gene', (29, 34))	('p27', 'Gene', (99, 102))	('reduced', 'NegReg', (35, 42))	('IGF1R', 'Gene', '3480', (29, 34))	('p27', 'Gene', '1027', (99, 102))	('mTOR', 'Gene', '2475', (19, 23))	('mTOR', 'Gene', (19, 23))	('p27', 'Gene', (55, 58))	('p27', 'Gene', '1027', (55, 58))	('increasing', 'PosReg', (80, 90))
241162	29099264	We also found that BGT226 resulted in smaller xenografts in vivo; however, cell proliferation and apoptosis (measured by Ki67 and cleaved caspase 3 staining, respectively) were not altered in treated tumors.	('BGT226', 'Var', (19, 25))	('xenografts', 'CPA', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('Ki67', 'Gene', '17345', (121, 125))	('smaller', 'NegReg', (38, 45))	('BGT226', 'Chemical', 'MESH:C570852', (19, 25))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('Ki67', 'Gene', (121, 125))	('cell proliferation', 'CPA', (75, 93))
241170	29099264	Another report demonstrated that following phosphorylation by RSK1, a serine/threonine kinase downstream of PI3K/mTOR, cytoplasmic p27 promoted cell motility by inhibiting RhoA.	('p27', 'Gene', '1027', (131, 134))	('promoted', 'PosReg', (135, 143))	('RhoA', 'Gene', (172, 176))	('RSK1', 'Gene', '6195', (62, 66))	('PI3K/mTOR', 'Gene', (108, 117))	('RhoA', 'Gene', '387', (172, 176))	('cell motility', 'CPA', (144, 157))	('serine', 'Chemical', 'MESH:D012694', (70, 76))	('inhibiting', 'NegReg', (161, 171))	('cytoplasmic', 'Var', (119, 130))	('PI3K/mTOR', 'Gene', '5290;2475', (108, 117))	('p27', 'Gene', (131, 134))	('RSK1', 'Gene', (62, 66))
241171	29099264	Inhibition of RhoA blocks RhoA-dependent ROCK1 activation and prevents downstream actin remodeling through the ROCK1/LIMK/cofilin pathway, thus reducing cell motility.	('activation', 'MPA', (47, 57))	('cofilin', 'Gene', '1072', (122, 129))	('blocks', 'NegReg', (19, 25))	('reducing', 'NegReg', (144, 152))	('RhoA', 'Gene', '387', (14, 18))	('cofilin', 'Gene', (122, 129))	('prevents', 'NegReg', (62, 70))	('LIMK', 'Gene', '3984', (117, 121))	('RhoA', 'Gene', (26, 30))	('ROCK1', 'Gene', '6093', (111, 116))	('LIMK', 'Gene', (117, 121))	('Inhibition', 'Var', (0, 10))	('ROCK1', 'Gene', '6093', (41, 46))	('ROCK1', 'Gene', (41, 46))	('ROCK1', 'Gene', (111, 116))	('RhoA', 'Gene', (14, 18))	('RhoA', 'Gene', '387', (26, 30))	('cell motility', 'CPA', (153, 166))
241175	29099264	Although cytoplasmic p27 levels were significantly reduced after BGT226 treatment, cell motility was not inhibited (Fig 6A).	('reduced', 'NegReg', (51, 58))	('BGT226', 'Chemical', 'MESH:C570852', (65, 71))	('p27', 'Gene', (21, 24))	('p27', 'Gene', '1027', (21, 24))	('treatment', 'Var', (72, 81))	('BGT226', 'Gene', (65, 71))
241185	29099264	Additional in vivo survival studies could determine whether long-term co-treatment of UPS xenografts with BGT226 and AEW541 would improve survival times owing to disease stabilization and/or tumor regression or whether other compensatory mechanisms would arise.	('improve', 'PosReg', (130, 137))	('BGT226', 'Chemical', 'MESH:C570852', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('survival times', 'CPA', (138, 152))	('AEW541', 'Var', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('BGT226', 'Gene', (106, 112))	('AEW541', 'Chemical', '-', (117, 123))	('disease stabilization', 'CPA', (162, 183))
241187	29099264	Targeted blockade of IGF1R can induce adaptive responses to therapy, such as increased insulin receptor activation or dysregulated endocrine signaling, which could enhance oncogenic signaling and prove detrimental to patient outcome.	('enhance', 'PosReg', (164, 171))	('activation', 'PosReg', (104, 114))	('dysregulated endocrine signaling', 'MPA', (118, 150))	('patient', 'Species', '9606', (217, 224))	('insulin receptor', 'Gene', (87, 103))	('IGF1R', 'Gene', (21, 26))	('insulin receptor', 'Gene', '3643', (87, 103))	('increased', 'PosReg', (77, 86))	('Targeted blockade', 'Var', (0, 17))	('IGF1R', 'Gene', '3480', (21, 26))	('oncogenic signaling', 'CPA', (172, 191))
241200	29099264	Two of the tumors were associated with previous radiation (RIS-DL-620 and RIS-819.1) and the other three were sporadic.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('RIS-DL-620', 'Var', (59, 69))	('RIS-819.1', 'Var', (74, 83))	('associated', 'Reg', (23, 33))
241206	29099264	Immediately before administration, the NMP/BGT226 stock solution was diluted in PEG300 (10% NMP/BGT226 plus 90% PEG300).	('BGT226', 'Chemical', 'MESH:C570852', (96, 102))	('PEG300', 'Chemical', '-', (80, 86))	('PEG300', 'Chemical', '-', (112, 118))	('BGT226', 'Chemical', 'MESH:C570852', (43, 49))	('10% NMP/BGT226', 'Var', (88, 102))	('NMP/BGT226', 'Var', (92, 102))	('NMP', 'Chemical', '-', (39, 42))	('NMP', 'Chemical', '-', (92, 95))
241225	29018505	Therefore, the head and neck are fertile anatomic sites for the development of lymphoproliferative diseases, in which malignant neoplastic mutations occur in normal lymphoid tissue and give rise to a lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (200, 208))	('lymphoproliferative diseases', 'Disease', 'MESH:D008232', (79, 107))	('lymphoproliferative diseases', 'Disease', (79, 107))	('mutations', 'Var', (139, 148))	('give rise to', 'Reg', (185, 197))	('lymphoma', 'Disease', (200, 208))	('lymphoproliferative diseases', 'Phenotype', 'HP:0005523', (79, 107))
241306	25516617	Using chromatin immunoprecipitation (ChIP) assays, we showed that the KSHV genome acquires a uniquely distinct histone modification pattern of methylation (H3K4me3, H3K9me3, and H3K27me3) and acetylation (H3Ac) during de novo infection of human PBMCs.	('H3K4me3', 'Var', (156, 163))	('H3', 'Chemical', 'MESH:C012616', (205, 207))	('H3', 'Chemical', 'MESH:C012616', (156, 158))	('H3Ac', 'Chemical', '-', (205, 209))	('H3K27me3', 'Var', (178, 186))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('KSHV', 'Species', '37296', (70, 74))	('H3K9me3', 'Var', (165, 172))	('acetylation', 'MPA', (192, 203))	('H3', 'Chemical', 'MESH:C012616', (178, 180))	('human', 'Species', '9606', (239, 244))	('H3', 'Chemical', 'MESH:C012616', (165, 167))	('KSHV', 'Gene', (70, 74))	('methylation', 'MPA', (143, 154))
241333	25516617	Recently, we generated a recombinant KSHV with a deletion of the RBP-Jkappa site within the LANA promoter (LANAp).	('LANAp', 'Gene', (107, 112))	('LANA', 'Gene', '4961527', (107, 111))	('RBP-Jkappa', 'Gene', '3516', (65, 75))	('LANA', 'Gene', (92, 96))	('LANA', 'Gene', '4961527', (92, 96))	('RBP-Jkappa', 'Gene', (65, 75))	('LANAp', 'Gene', '4961527', (107, 112))	('KS', 'Phenotype', 'HP:0100726', (37, 39))	('deletion', 'Var', (49, 57))	('KSHV', 'Species', '37296', (37, 41))	('LANA', 'Gene', (107, 111))
241334	25516617	This virus showed that the RBP-Jkappa site was critical for the establishment of latent infection in primary cells, as mutation of this site resulted in increased lytic replication during infection of human peripheral blood mononuclear cells (PBMCs).	('RBP-Jkappa', 'Gene', (27, 37))	('mutation', 'Var', (119, 127))	('lytic replication', 'MPA', (163, 180))	('increased', 'PosReg', (153, 162))	('human', 'Species', '9606', (201, 206))	('RBP-Jkappa', 'Gene', '3516', (27, 37))
241338	25516617	A CpG island adjacent to a transcription initiation site is generally associated with repression or silencing of transcription, and hypermethylation of CpG islands is a common epigenetic alteration associated with cancer.	('silencing', 'NegReg', (100, 109))	('cancer', 'Disease', (214, 220))	('repression', 'MPA', (86, 96))	('hypermethylation', 'Var', (132, 148))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
241339	25516617	Typically, epigenetic changes on DNA and histones are important contributors to tumor progression.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('DNA', 'Protein', (33, 36))	('epigenetic changes', 'Var', (11, 29))	('histones', 'Protein', (41, 49))
241340	25516617	Epigenetic modifications are frequently found in KSHV-associated cancer.	('KSHV', 'Species', '37296', (49, 53))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('found', 'Reg', (40, 45))	('Epigenetic modifications', 'Var', (0, 24))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
241351	25516617	Here, we focused on the dynamic changes in KSHV gene expression and the epigenetic programming using activation markers H3K4me3 and H3Ac and repression markers H3K9me3 and H3K27me3 that occur during the first 7 days after infection of human PBMCs.	('H3K9me3', 'Var', (160, 167))	('KSHV', 'Species', '37296', (43, 47))	('H3', 'Chemical', 'MESH:C012616', (132, 134))	('KSHV gene', 'Gene', (43, 52))	('H3', 'Chemical', 'MESH:C012616', (172, 174))	('H3', 'Chemical', 'MESH:C012616', (160, 162))	('H3Ac', 'Chemical', '-', (132, 136))	('H3', 'Chemical', 'MESH:C012616', (120, 122))	('H3K4me3', 'Var', (120, 127))	('human', 'Species', '9606', (235, 240))	('KS', 'Phenotype', 'HP:0100726', (43, 45))	('H3Ac', 'Var', (132, 136))	('H3K27me3', 'Var', (172, 180))
241355	25516617	Previously, we have demonstrated that KSHV can successfully infect human PBMCs for up to 7 days.	('KS', 'Phenotype', 'HP:0100726', (38, 40))	('KSHV', 'Species', '37296', (38, 42))	('KSHV', 'Var', (38, 42))	('infect', 'Reg', (60, 66))	('to 7', 'Species', '1214577', (86, 90))	('human', 'Species', '9606', (67, 72))
241357	25516617	Chromatin immunoprecipitation (ChIP) assays for histone modifications were performed on those infected PBMCs using the antibodies against H3K4me3, H3K9me3, H3K27me3, and H3Ac (Fig.	('H3K27me3', 'Var', (156, 164))	('H3K9me3', 'Protein', (147, 154))	('H3', 'Chemical', 'MESH:C012616', (138, 140))	('H3K4me3', 'Protein', (138, 145))	('H3', 'Chemical', 'MESH:C012616', (156, 158))	('H3', 'Chemical', 'MESH:C012616', (170, 172))	('H3Ac', 'Chemical', '-', (170, 174))	('H3', 'Chemical', 'MESH:C012616', (147, 149))	('H3Ac', 'Protein', (170, 174))
241360	25516617	Significant modifications of trimethylated histone H3 lysine 4 (H3K4me3) and H3K27me3 were seen throughout the KSHV genome from 1 day to 7 days postinfection (p.i.)	('to 7', 'Species', '1214577', (134, 138))	('H3K27me3', 'Var', (77, 85))	('H3', 'Chemical', 'MESH:C012616', (77, 79))	('H3', 'Chemical', 'MESH:C012616', (64, 66))	('KSHV', 'Species', '37296', (111, 115))	('modifications', 'Reg', (12, 25))	('trimethylated histone', 'MPA', (29, 50))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('lysine 4', 'Chemical', '-', (54, 62))	('trimethylated histone', 'Chemical', '-', (29, 50))	('H3', 'Chemical', 'MESH:C012616', (51, 53))
241361	25516617	The viral genes associated with H3K4me3 modifications were localized at three major KSHV gene clusters (15 to 25 kb, 70 to 80 kb, and 105 to 120 kb).	('KSHV', 'Gene', (84, 88))	('H3K4me3 modifications', 'Var', (32, 53))	('H3', 'Chemical', 'MESH:C012616', (32, 34))	('KS', 'Phenotype', 'HP:0100726', (84, 86))	('KSHV', 'Species', '37296', (84, 88))
241370	25516617	These results are indicative of a different pattern of epigenetic modification across the KSHV genome during early primary PBMC infection from the patterns seen in BCBL1 and SLKp cells.	('KSHV', 'Species', '37296', (90, 94))	('epigenetic modification', 'Var', (55, 78))	('KSHV', 'Gene', (90, 94))	('KS', 'Phenotype', 'HP:0100726', (90, 92))
241371	25516617	This may reflect a pattern of epigenetic regulation of the KSHV genome which is unique for primary PBMC infection and could be important for latency establishment.	('KSHV', 'Gene', (59, 63))	('KSHV', 'Species', '37296', (59, 63))	('epigenetic regulation', 'Var', (30, 51))	('KS', 'Phenotype', 'HP:0100726', (59, 61))
241383	25516617	The results from the ChIP assays using various antibodies against histone modifications (H3K4me3, H3K9me3, H3K27me3, and H3Ac) showed that the KSHV genome is temporally modified with histone methylations and acetylation marks during primary infection of PBMCs.	('KS', 'Phenotype', 'HP:0100726', (143, 145))	('H3K4me3', 'Var', (89, 96))	('histone methylations', 'MPA', (183, 203))	('H3Ac', 'Chemical', '-', (121, 125))	('H3K9me3', 'Var', (98, 105))	('H3', 'Chemical', 'MESH:C012616', (89, 91))	('H3', 'Chemical', 'MESH:C012616', (98, 100))	('H3', 'Chemical', 'MESH:C012616', (121, 123))	('H3', 'Chemical', 'MESH:C012616', (107, 109))	('KSHV', 'Species', '37296', (143, 147))	('acetylation marks', 'MPA', (208, 225))	('H3K27me3', 'Var', (107, 115))
241387	25516617	Specifically, H3K9me3 and H3K27me3 established a stronger enrichment throughout the genome by 2 days p.i.	('H3', 'Chemical', 'MESH:C012616', (26, 28))	('H3K27me3', 'Var', (26, 34))	('stronger', 'PosReg', (49, 57))	('H3K9me3', 'Var', (14, 21))	('enrichment throughout the', 'MPA', (58, 83))	('H3', 'Chemical', 'MESH:C012616', (14, 16))
241389	25516617	for both H3K4me3 and H3K9me3 (Fig.	('H3', 'Chemical', 'MESH:C012616', (9, 11))	('H3K4me3', 'Protein', (9, 16))	('H3K9me3', 'Var', (21, 28))	('H3', 'Chemical', 'MESH:C012616', (21, 23))
241403	25516617	H3K4me3 modifications were associated with genomic regions which include genes involved in antiapoptosis (ORF16), DNA replication (ORF49, ORF56, ORF59, and ORF70), oncogenesis (K3), and virion particle assembly (ORF25, ORF29b, ORF45, ORF64, and ORF65) (Fig.	('antiapoptosis', 'Disease', (91, 104))	('ORF64', 'Gene', (234, 239))	('ORF65', 'Gene', '4961451', (245, 250))	('ORF7', 'Gene', '4961505', (156, 160))	('ORF45', 'Var', (227, 232))	('ORF59', 'Gene', (145, 150))	('ORF29b', 'Var', (219, 225))	('modifications', 'Var', (8, 21))	('associated', 'Reg', (27, 37))	('ORF49', 'Gene', (131, 136))	('H3', 'Chemical', 'MESH:C012616', (0, 2))	('ORF59', 'Gene', '4961492', (145, 150))	('ORF64', 'Gene', '4961441', (234, 239))	('ORF65', 'Gene', (245, 250))	('oncogenesis', 'Disease', (164, 175))	('ORF7', 'Gene', (156, 160))	('ORF49', 'Gene', '4961448', (131, 136))	('H3K4me3', 'Protein', (0, 7))
241404	25516617	H3K27me3 modifications on the KSHV genome during primary infection were widespread and efficiently occurred at many regions on the viral genome, including genes related to functions associated with antiapoptosis, DNA replication, oncogenesis, immunomodulation, regulation of transmembrane protein, and virion particle assembly (Fig.	('KSHV', 'Species', '37296', (30, 34))	('H3K27me3', 'Var', (0, 8))	('KS', 'Phenotype', 'HP:0100726', (30, 32))	('H3', 'Chemical', 'MESH:C012616', (0, 2))	('virion particle assembly', 'CPA', (302, 326))
241405	25516617	H3K9me3 modifications on the KSHV genome were linked to regulation of the transmembrane proteins (ORF4 and ORF7), virion structural proteins (ORF64 and ORF65), and proteins involved in the oncogenic process (K3 and K15) (Fig.	('regulation', 'MPA', (56, 66))	('ORF64', 'Gene', (142, 147))	('modifications', 'Var', (8, 21))	('H3', 'Chemical', 'MESH:C012616', (0, 2))	('KS', 'Phenotype', 'HP:0100726', (29, 31))	('KSHV', 'Species', '37296', (29, 33))	('linked', 'Reg', (46, 52))	('ORF65', 'Gene', (152, 157))	('ORF7', 'Gene', (107, 111))	('H3K9me3 modifications', 'Var', (0, 21))	('ORF65', 'Gene', '4961451', (152, 157))	('ORF64', 'Gene', '4961441', (142, 147))	('transmembrane', 'Protein', (74, 87))	('ORF7', 'Gene', '4961505', (107, 111))
241406	25516617	The H3Ac ChIP assay showed acetylation of a number of H3-associated regions across the KSHV genome, including regions encoding ORF11, K3, ORF18, ORF29a, ORF36, ORF42, ORF49, ORF59, ORF64, ORF68, and ORF69 (Fig.	('ORF64', 'Gene', (181, 186))	('ORF68', 'Gene', '4961470', (188, 193))	('KSHV', 'Species', '37296', (87, 91))	('ORF68', 'Gene', (188, 193))	('ORF11', 'Gene', (127, 132))	('H3', 'Chemical', 'MESH:C012616', (4, 6))	('ORF69', 'Gene', '4961444', (199, 204))	('ORF64', 'Gene', '4961441', (181, 186))	('H3-associated', 'Gene', (54, 67))	('ORF69', 'Gene', (199, 204))	('ORF36', 'Gene', (153, 158))	('ORF11', 'Gene', '4961439', (127, 132))	('acetylation', 'MPA', (27, 38))	('ORF42', 'Gene', (160, 165))	('ORF18', 'Gene', '4961499', (138, 143))	('ORF42', 'Gene', '4961440', (160, 165))	('ORF59', 'Gene', (174, 179))	('ORF49', 'Gene', (167, 172))	('H3Ac', 'Chemical', '-', (4, 8))	('ORF59', 'Gene', '4961492', (174, 179))	('ORF36', 'Gene', '4961434', (153, 158))	('H3', 'Chemical', 'MESH:C012616', (54, 56))	('ORF29a', 'Var', (145, 151))	('ORF18', 'Gene', (138, 143))	('KS', 'Phenotype', 'HP:0100726', (87, 89))	('ORF49', 'Gene', '4961448', (167, 172))
241409	25516617	The LANA-ChIP assay showed that LANA associated with viral DNA which carries lytic and latent ORFs, including K3, K7, K15, ORF18, ORF19, ORF25, ORF49, ORF64, ORF65, ORF68, ORF69, and ORF73.	('ORF18', 'Gene', (123, 128))	('ORF64', 'Gene', (151, 156))	('ORF65', 'Gene', '4961451', (158, 163))	('LANA', 'Gene', (4, 8))	('LANA', 'Gene', '4961527', (4, 8))	('ORF7', 'Gene', (183, 187))	('ORF19', 'Gene', '79783', (130, 135))	('ORF64', 'Gene', '4961441', (151, 156))	('ORF25', 'Var', (137, 142))	('LANA', 'Gene', (32, 36))	('ORF65', 'Gene', (158, 163))	('LANA', 'Gene', '4961527', (32, 36))	('ORF7', 'Gene', '4961505', (183, 187))	('ORF68', 'Gene', '4961470', (165, 170))	('ORF49', 'Gene', (144, 149))	('ORF19', 'Gene', (130, 135))	('ORF68', 'Gene', (165, 170))	('ORF69', 'Gene', '4961444', (172, 177))	('K15', 'Var', (118, 121))	('ORF49', 'Gene', '4961448', (144, 149))	('ORF69', 'Gene', (172, 177))	('ORF18', 'Gene', '4961499', (123, 128))
241412	25516617	The viral genes bound by RTA belonged to a group of transmembrane proteins (ORF4, ORF7, ORF22, ORF68), virion proteins (ORF29a, ORF32, ORF45, and ORF64), and capsid proteins (ORF62, ORF65, and ORF75) and also included genes involved in transcription regulation (ORF49 and ORF70) with some overlap for those also bound to LANA (Fig.	('ORF68', 'Gene', '4961470', (95, 100))	('ORF7', 'Gene', '4961505', (193, 197))	('LANA', 'Gene', (321, 325))	('ORF7', 'Gene', (82, 86))	('ORF68', 'Gene', (95, 100))	('ORF65', 'Gene', (182, 187))	('ORF64', 'Gene', (146, 151))	('ORF49', 'Gene', (262, 267))	('ORF32', 'Var', (128, 133))	('ORF7', 'Gene', (272, 276))	('ORF65', 'Gene', '4961451', (182, 187))	('ORF7', 'Gene', '4961505', (82, 86))	('LANA', 'Gene', '4961527', (321, 325))	('ORF22', 'Var', (88, 93))	('ORF7', 'Gene', '4961505', (272, 276))	('ORF7', 'Gene', (193, 197))	('ORF49', 'Gene', '4961448', (262, 267))	('ORF64', 'Gene', '4961441', (146, 151))
241413	25516617	The viral genomic regions bound by K8 were mostly associated with DNA replication (ORF59), transcription regulation (K8 and ORF49), virion proteins (ORF17, ORF27, ORF42, and ORF45), and oncogenesis (ORF34, ORF73, K3, K11.1, and K12) (Fig.	('ORF45', 'Var', (174, 179))	('ORF59', 'Gene', (83, 88))	('ORF59', 'Gene', '4961492', (83, 88))	('ORF49', 'Gene', '4961448', (124, 129))	('transcription regulation', 'MPA', (91, 115))	('ORF42', 'Gene', (163, 168))	('ORF7', 'Gene', (206, 210))	('ORF34', 'Gene', (199, 204))	('ORF49', 'Gene', (124, 129))	('K12', 'Gene', (228, 231))	('K12', 'Gene', '3859', (228, 231))	('ORF42', 'Gene', '4961440', (163, 168))	('DNA', 'MPA', (66, 69))	('ORF7', 'Gene', '4961505', (206, 210))	('associated', 'Reg', (50, 60))	('ORF34', 'Gene', '54954', (199, 204))	('K8', 'Var', (117, 119))	('oncogenesis', 'CPA', (186, 197))
241416	25516617	This is reminiscent of what was seen in the results of the H3K4me3, H3K9me3, H3K27me3, and H3Ac ChIP assays (Fig.	('H3K9me3', 'Var', (68, 75))	('H3', 'Chemical', 'MESH:C012616', (91, 93))	('H3K27me3', 'Var', (77, 85))	('H3', 'Chemical', 'MESH:C012616', (77, 79))	('H3K4me3', 'Var', (59, 66))	('H3', 'Chemical', 'MESH:C012616', (68, 70))	('H3Ac', 'Chemical', '-', (91, 95))	('H3', 'Chemical', 'MESH:C012616', (59, 61))
241433	25516617	the enriched signals for both the activation (H3K4me3) and repressive (H3K9me3) marks were sharply diminished, suggesting a role for ORF49 and lytic replication at 4 days p.i.	('H3K9me3', 'Var', (71, 78))	('ORF49', 'Gene', '4961448', (133, 138))	('enriched', 'MPA', (4, 12))	('lytic replication', 'CPA', (143, 160))	('H3', 'Chemical', 'MESH:C012616', (71, 73))	('diminished', 'NegReg', (99, 109))	('H3', 'Chemical', 'MESH:C012616', (46, 48))	('ORF49', 'Gene', (133, 138))	('H3K4me3', 'Var', (46, 53))
241441	25516617	In analyzing the data obtained from our ChIP assay focusing on the KSHV genes within the LuR which were associated with KSHV latent/lytic proteins (LANA/RTA/K8) as well as histone modification, we identified a number of virus-carried genes associated with epigenetic modifications in addition to the latent/lytic replication antigens during early primary infections (Table 1).	('LANA', 'Gene', '4961527', (148, 152))	('KS', 'Phenotype', 'HP:0100726', (67, 69))	('KSHV', 'Species', '37296', (67, 71))	('primary infections', 'Disease', (347, 365))	('KS', 'Phenotype', 'HP:0100726', (120, 122))	('KSHV', 'Species', '37296', (120, 124))	('LANA', 'Gene', (148, 152))	('epigenetic modifications', 'Var', (256, 280))	('primary infections', 'Disease', 'MESH:D009378', (347, 365))
241488	25516617	Surprisingly, antibodies against H3K4me3 and H3K27me3 simultaneously bound the ORF49 promoter from 1 day to 7 days p.i., suggesting that ORF49 may have a bivalent chromatin structure, which regulates ORF49 expression during primary infection.	('ORF49', 'Gene', '4961448', (200, 205))	('ORF49', 'Gene', (79, 84))	('H3', 'Chemical', 'MESH:C012616', (33, 35))	('ORF49', 'Gene', (137, 142))	('expression', 'MPA', (206, 216))	('bound', 'Reg', (69, 74))	('ORF49', 'Gene', (200, 205))	('H3K27me3', 'Var', (45, 53))	('ORF49', 'Gene', '4961448', (137, 142))	('ORF49', 'Gene', '4961448', (79, 84))	('to 7', 'Species', '1214577', (105, 109))	('H3', 'Chemical', 'MESH:C012616', (45, 47))	('regulates', 'Reg', (190, 199))
241500	25516617	Here, our investigation showed that histone modifications across the KSHV genome presented a unique pattern of histone modifications (H3K4me3, H3K9me3, H3K27me3, and H3Ac) during early infection of human PBMCs.	('H3K4me3', 'Var', (134, 141))	('H3', 'Chemical', 'MESH:C012616', (152, 154))	('KSHV', 'Species', '37296', (69, 73))	('H3', 'Chemical', 'MESH:C012616', (166, 168))	('H3Ac', 'Chemical', '-', (166, 170))	('H3K9me3', 'Var', (143, 150))	('H3', 'Chemical', 'MESH:C012616', (134, 136))	('KS', 'Phenotype', 'HP:0100726', (69, 71))	('human', 'Species', '9606', (198, 203))	('H3', 'Chemical', 'MESH:C012616', (143, 145))	('H3Ac', 'Var', (166, 170))	('H3K27me3', 'Var', (152, 160))
241511	25516617	However, recent studies showed that deletion of K3 does not restore MHC-I expression during lytic replication, suggesting that other KSHV antigens could be involved.	('expression', 'MPA', (74, 84))	('deletion', 'Var', (36, 44))	('MHC-I', 'Gene', (68, 73))	('KSHV', 'Species', '37296', (133, 137))	('KS', 'Phenotype', 'HP:0100726', (133, 135))
241537	25516617	Antibodies against H3K4me3 (Millipore 07-473), H3K9me3 (Millipore 07-442), H3K27me3 (Cell Signaling C36B11), and H3Ac (Millipore 06-599) were used for histone modifications.	('H3', 'Chemical', 'MESH:C012616', (75, 77))	('H3', 'Chemical', 'MESH:C012616', (19, 21))	('H3K27me3', 'Var', (75, 83))	('H3Ac', 'Chemical', '-', (113, 117))	('H3', 'Chemical', 'MESH:C012616', (113, 115))	('H3', 'Chemical', 'MESH:C012616', (47, 49))	('H3K4me3', 'Protein', (19, 26))
241550	25516617	pGEX-5X1-MBD2B and pET28a (+)-MBD3L1 were transfected into BL21 cells and expressed at 30 C overnight after induction.	('BL21', 'CellLine', 'CVCL:M639', (59, 63))	('pET28a', 'Var', (19, 25))	('MBD3L1', 'Gene', (30, 36))	('pGEX-5X1-MBD2B', 'Gene', (0, 14))	('MBD3L1', 'Gene', '85509', (30, 36))
241559	21183462	By combination of approaches: (i) in vitro and in cellulo splicing assays, (ii) footprinting assays and (iii) purification and analysis of reconstituted RNP complex, we define a small NRS element retaining splicing inhibitory property.	('RNP', 'Gene', (153, 156))	('RNP', 'Gene', '55599', (153, 156))	('splicing', 'MPA', (206, 214))	('small NRS', 'Var', (178, 187))
241576	21183462	Deletion of an internal 76-nt long segment (nucleotides 799-874) (NRS Delta76) had a limited effect on NRS activity.	('NRS activity', 'CPA', (103, 115))	('Delta76', 'Mutation', 'c.del76', (70, 77))	('Deletion', 'Var', (0, 8))
241582	21183462	Our earlier chemical and enzymatic probing of part of the NRS structure in collaboration with the Beemon group showed that the NRS-3' region, encompassing nucleotides from positions G910 to U926, forms an individual stem-loop structure and this was the basis for an NMR-3D structure analysis of this NRS fragment.	('U926', 'Var', (190, 194))	('G910', 'Var', (182, 186))	('U926', 'CellLine', 'CVCL:1027', (190, 194))	('NRS-3', 'Gene', (127, 132))
241593	21183462	Plasmids pRSVNeo-Int, pDelta76Neo-Int contain DNA sequences of the WT and Delta76 RSV NRSs from strain Prague C (PrC), respectively.	('pDelta76Neo-Int', 'Var', (22, 37))	('RSV', 'Species', '11886', (82, 85))	('Delta76', 'Mutation', 'c.del76', (23, 30))	('Delta76 RSV', 'Var', (74, 85))	('Delta76', 'Mutation', 'c.del76', (74, 81))	('RSV', 'Species', '11886', (10, 13))
241594	21183462	To get constructs containing WT and Delta76 NRS coding sequences under the control of a T7 RNA polymerase promoter, which are fused to a DNA sequence coding 3'-binding sites for the coat protein of phage MS2, the MS2 DNA sequences were excised from plasmid pADML-M3 by BamHI-HindIII digestions and were subcloned into plasmid pUC18 (pMS2 plasmid).	('MS2', 'Gene', (213, 216))	('MS2', 'Gene', '100271694', (204, 207))	('pMS2', 'Gene', '5395', (333, 337))	('MS2', 'Gene', (334, 337))	('pMS2', 'Gene', (333, 337))	('MS2', 'Gene', '100271694', (213, 216))	('Delta76', 'Var', (36, 43))	('Delta76', 'Mutation', 'c.del76', (36, 43))	('phage MS2', 'Species', '12022', (198, 207))	('MS2', 'Gene', (204, 207))	('MS2', 'Gene', '100271694', (334, 337))
241595	21183462	To obtain the control pT7MS2 plasmid, a T7 promoter was generated by annealing primers O-4672 and O-4673 and the resulting DNA was inserted between the BamHI and SacI sites located upstream of the MS2 DNA in plasmid pMS2.	('MS2', 'Gene', (25, 28))	('pMS2', 'Gene', (216, 220))	('MS2', 'Gene', '100271694', (197, 200))	('pMS2', 'Gene', '5395', (216, 220))	('MS2', 'Gene', (217, 220))	('O-4672', 'Var', (87, 93))	('MS2', 'Gene', (197, 200))	('MS2', 'Gene', '100271694', (25, 28))	('O-4673', 'Var', (98, 104))	('MS2', 'Gene', '100271694', (217, 220))
241596	21183462	To get pNRS-MS2 and pNRS Delta76-MS2 plasmids, the NRS WT and NRS Delta76 DNA fragments were PCR amplified with O-4666 (containing a T7 promoter sequence) and O-4667 and inserted into a BamHI/SacI digested pMS2 plasmid.	('Delta76', 'Var', (66, 73))	('MS2', 'Gene', '100271694', (207, 210))	('MS2', 'Gene', '100271694', (12, 15))	('pMS2', 'Gene', (206, 210))	('MS2', 'Gene', '100271694', (33, 36))	('pMS2', 'Gene', '5395', (206, 210))	('MS2', 'Gene', (207, 210))	('MS2', 'Gene', (12, 15))	('Delta76', 'Mutation', 'c.del76', (66, 73))	('MS2', 'Gene', (33, 36))	('Delta76', 'Mutation', 'c.del76', (25, 32))
241597	21183462	For in vitro splicing assays, plasmid pC2-NRS and its derivatives were produced by insertion of the NRS DNA sequences in the sense (pC2-NRS and derivatives) or antisense orientations (pC2-NRS Inv) into the intron of the earlier described C2 HIV construct built with HIV-1 BRU cDNA.	('pC2', 'Gene', (132, 135))	('pC2', 'Gene', (184, 187))	('antisense', 'Var', (160, 169))	('C2-NRS', 'Disease', (133, 139))	('C2 HIV construct', 'Disease', 'OMIM:217000', (238, 254))	('pC2', 'Gene', '3854', (132, 135))	('C2-NRS', 'Disease', 'OMIM:217000', (185, 191))	('pC2', 'Gene', '3854', (184, 187))	('insertion', 'Var', (83, 92))	('C2-NRS', 'Disease', (185, 191))	('C2 HIV construct', 'Disease', (238, 254))	('pC2', 'Gene', (38, 41))	('C2-NRS', 'Disease', 'OMIM:217000', (39, 45))	('HIV-1', 'Species', '11676', (266, 271))	('NRS', 'Gene', (100, 103))	('C2-NRS', 'Disease', (39, 45))	('pC2', 'Gene', '3854', (38, 41))	('C2-NRS', 'Disease', 'OMIM:217000', (133, 139))
241610	21183462	The GenBank accession number of RSV and related ASLV sequences used in the comparative secondary structure analysis are: L29198 (Schmidt Ruppin A), AF052428 (Schmidt Ruppin B), DQ365814 [ALV MQNCSU (A)], AY027920 (ALV ADOL-7501), AB303223 (ALV Stain Tym_S90), AF033810 (Fujinami Sarcoma Virus), V01170 (Y53 Sarcoma Virus).	('Sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('V01170', 'Var', (295, 301))	('Y53 Sarcoma Virus', 'Disease', 'MESH:D012509', (303, 320))	('RSV', 'Species', '11886', (32, 35))	('AB303223', 'Var', (230, 238))	('L29198', 'Var', (121, 127))	('AF052428', 'Var', (148, 156))	('Sarcoma', 'Phenotype', 'HP:0100242', (307, 314))	('AF033810', 'Var', (260, 268))	('Fujinami Sarcoma Virus', 'Species', '11885', (270, 292))	('DQ365814 [', 'Var', (177, 187))	('Y53 Sarcoma Virus', 'Disease', (303, 320))	('AY027920', 'Var', (204, 212))	('ASLV', 'Chemical', '-', (48, 52))
241615	21183462	MS2-tagged purified WT or variant NRS RNAs (250 pmol) were denatured, renatured and incubated with a 5-fold molar excess of purified MS2-MBP fusion protein at 4 C for 30 min.	('-fold molar', 'Phenotype', 'HP:0011093', (102, 113))	('NRS RNAs', 'Gene', (34, 42))	('MS2', 'Gene', (0, 3))	('MBP', 'Gene', '4155', (137, 140))	('variant', 'Var', (26, 33))	('MS2', 'Gene', '100271694', (133, 136))	('MBP', 'Gene', (137, 140))	('MS2', 'Gene', '100271694', (0, 3))	('MS2', 'Gene', (133, 136))
241623	21183462	Twenty fmol of purified pre-mRNA that contained the WT NRS sequence, its reverse sequence or variant NRS sequences inserted in the C2 HIV-1 pre-mRNA were incubated for 2 h at 30 C in a 22 microl standard reaction containing 8 microl of HeLa cell nuclear extract.	('HeLa', 'CellLine', 'CVCL:0030', (236, 240))	('HIV-1', 'Species', '11676', (134, 139))	('NRS', 'Gene', (101, 104))	('variant', 'Var', (93, 100))
241653	21183462	As the variant NRS Delta76 is functional, we hypothesized that its 2D structure should not be drastically modified.	('Delta76', 'Mutation', 'c.del76', (19, 26))	('NRS', 'Gene', (15, 18))	('Delta76', 'Var', (19, 26))
241654	21183462	The NRS Delta76 transcript contained the same additional sequences at the 5'- and 3'-extremities as the full length NRS transcript used above, and was analysed as the full length NRS.	('NRS', 'Gene', (4, 7))	('Delta76', 'Var', (8, 15))	('Delta76', 'Mutation', 'c.del76', (8, 15))
241661	21183462	As shown in Supplementary Figure S2, base substitutions are either located in single strands, or reinforce the stability of helix H2.	('stability', 'MPA', (111, 120))	('H2', 'Chemical', '-', (130, 132))	('reinforce', 'PosReg', (97, 106))	('base substitutions', 'Var', (37, 55))
241671	21183462	As expected, insertion of a non-related 266-nt long sequence in C2 RNA decreased the in vitro splicing efficiency by ~40% (C2-NRS Inv RNA compared with C2 RNA).	('C2-NRS', 'Disease', 'OMIM:217000', (123, 129))	('C2-NRS', 'Disease', (123, 129))	('in vitro splicing efficiency', 'MPA', (85, 113))	('insertion', 'Var', (13, 22))	('decreased', 'NegReg', (71, 80))
241673	21183462	As a positive control, we used the functional NRS Delta76 mutant and we produced four other variants (Figure 3A2).	('Delta76', 'Var', (50, 57))	('Delta76', 'Mutation', 'c.del76', (50, 57))	('NRS', 'Gene', (46, 49))
241678	21183462	As expected NRS Delta76 was as efficient in splicing inhibition as the NRS WT (Figure 3B1 lane 4 and B2).	('Delta76', 'Mutation', 'c.del76', (16, 23))	('Delta76', 'Var', (16, 23))	('splicing inhibition', 'MPA', (44, 63))	('NRS Delta76', 'Var', (12, 23))
241681	21183462	The same absence of inhibition was observed for NRS 26, showing that deletion of stem-loop SLS1 (position 717-747) has the same negative effect on NRS activity as deletion of stem-loop SLS4 (Figure 3B1 lane 7 and B2).	('NRS', 'CPA', (147, 150))	('SLS4', 'Chemical', '-', (185, 189))	('negative', 'NegReg', (128, 136))	('stem-loop SLS1', 'Gene', (81, 95))	('deletion', 'Var', (69, 77))
241683	21183462	Therefore, our data reveal that a very small truncated NRS variant containing only stem-loop structures SLS1 and SLS4 and helices H1 and H2 is sufficient to inhibit splicing in vitro.	('NRS', 'Gene', (55, 58))	('splicing', 'MPA', (165, 173))	('inhibit', 'NegReg', (157, 164))	('H2', 'Chemical', '-', (137, 139))	('variant', 'Var', (59, 66))	('SLS4', 'Chemical', '-', (113, 117))
241685	21183462	The WT, Delta76, 22, 24, 26 and 28 NRS variant RNAs, described above, were transcribed with three binding sites for the MS2 coat protein fused at their 3'-ends (Figure 4A).	('binding', 'Interaction', (98, 105))	('MS2', 'Gene', (120, 123))	('Delta76', 'Var', (8, 15))	('Delta76', 'Mutation', 'c.del76', (8, 15))	('MS2', 'Gene', '100271694', (120, 123))	('RNAs', 'Gene', (47, 51))
241690	21183462	As expected, only the deletion of the SLS4 sequence had a marked negative effect on U1 snRNA association (Figure 4B and C).	('U1 snRNA', 'Gene', (84, 92))	('SLS4', 'Gene', (38, 42))	('deletion', 'Var', (22, 30))	('negative', 'NegReg', (65, 73))	('SLS4', 'Chemical', '-', (38, 42))	('U1 snRNA', 'Gene', '26871', (84, 92))
241693	21183462	For a comparative analysis of SR and hnRNP H and A1 proteins in RNP complexes formed with the WT and variant NRSs, we turned to the western blot approach using specific antibodies (Figure 4D).	('RNP', 'Gene', (39, 42))	('variant', 'Var', (101, 108))	('hnRNP H', 'Gene', '3187', (37, 44))	('RNP', 'Gene', (64, 67))	('RNP', 'Gene', '55599', (64, 67))	('RNP', 'Gene', '55599', (39, 42))	('hnRNP H', 'Gene', (37, 44))
241712	21183462	Tests were performed three times on each of the NRS Delta76, 22 and 28 variants (Figure 5B and Supplementary Figure S5D).	('Delta76', 'Var', (52, 59))	('Delta76', 'Mutation', 'c.del76', (52, 59))	('Supplementary Figure S5D', 'Disease', 'MESH:D017034', (95, 119))	('Supplementary Figure S5D', 'Disease', (95, 119))
241726	21183462	Other ASLV NRSs can adopt this structure due to compensatory and semi-compensatory base substitutions in the stems and the location of several point mutations and insertion of nucleotide stretches in single-stranded segments.	('ASLV', 'Chemical', '-', (6, 10))	('base substitutions', 'Var', (83, 101))	('point mutations', 'Var', (143, 158))
241735	21183462	Sequences involved in helix H2 formation were previously proposed to bind SR proteins.	('SR protein', 'Gene', '10921', (74, 84))	('bind', 'Interaction', (69, 73))	('H2', 'Chemical', '-', (28, 30))	('Sequences', 'Var', (0, 9))	('SR protein', 'Gene', (74, 84))
241743	21183462	The NRS Delta76 variant was previously defined as the minimal functional NRS element.	('NRS', 'Gene', (4, 7))	('Delta76', 'Var', (8, 15))	('Delta76', 'Mutation', 'c.del76', (8, 15))
241744	21183462	Interestingly, although shorter in length than NRS Delta76, variant NRS 28, designed on the basis of the RNA 2D structure, inhibited in vitro splicing as efficiently as the NRS Delta76.	('Delta76', 'Mutation', 'c.del76', (51, 58))	('NRS 28', 'Gene', (68, 74))	('variant', 'Var', (60, 67))	('Delta76', 'Mutation', 'c.del76', (177, 184))	('inhibited', 'NegReg', (123, 132))
241751	21183462	Secondly, at higher concentration, by binding to sequences in helix H2 which are present in NRS Delta76 and 28 but are missing in NRS 22, protein 9G8 may have a supplementary stimulatory effect on NRS activity.	('Delta76', 'Var', (96, 103))	('helix H2', 'Protein', (62, 70))	('9G8', 'Gene', '6432', (146, 149))	('Delta76', 'Mutation', 'c.del76', (96, 103))	('binding', 'Interaction', (38, 45))	('9G8', 'Gene', (146, 149))	('H2', 'Chemical', '-', (68, 70))	('NRS', 'CPA', (197, 200))
241755	21183462	Our adaptation of the MS2 based RNP purification method to the purification of RNP complexes formed by WT or variant NRSs upon incubation in nuclear extract led to an unexpected result: binding of SR proteins to NRS is found to depend on both SLS1 and SLS4, while binding of U1 snRNP is strictly dependent on the presence of SLS4.	('SLS4', 'Chemical', '-', (252, 256))	('MS2', 'Gene', '100271694', (22, 25))	('SR protein', 'Gene', '10921', (197, 207))	('RNP', 'Gene', '55599', (32, 35))	('SLS4', 'Chemical', '-', (325, 329))	('variant', 'Var', (109, 116))	('RNP', 'Gene', (280, 283))	('RNP', 'Gene', '55599', (280, 283))	('RNP', 'Gene', (79, 82))	('depend', 'Reg', (228, 234))	('MS2', 'Gene', (22, 25))	('binding', 'Interaction', (186, 193))	('SR protein', 'Gene', (197, 207))	('RNP', 'Gene', '55599', (79, 82))	('RNP', 'Gene', (32, 35))
241758	21183462	Our finding of a strong negative effect of SLS4 deletion on SR protein binding is unexpected.	('SLS4', 'Chemical', '-', (43, 47))	('SLS4', 'Gene', (43, 47))	('SR protein', 'Gene', '10921', (60, 70))	('negative', 'NegReg', (24, 32))	('deletion', 'Var', (48, 56))	('SR protein', 'Gene', (60, 70))
241883	33714008	The presence of the disease-specific WWTR1 or TFE3 rearrangement was determined by FISH, and only cases carrying one of the two were entered.	('TFE3', 'Gene', (46, 50))	('WWTR1', 'Gene', (37, 42))	('WWTR1', 'Gene', '25937', (37, 42))	('disease-specific', 'Reg', (20, 36))	('rearrangement', 'Var', (51, 64))	('TFE3', 'Gene', '7030', (46, 50))
241901	33714008	We investigated symptoms and metastatic sites (included serosae), together with patients' age and sex, and molecular data (rearrangement of WWTR1 versus TFE3) as putative prognostic variables.	('TFE3', 'Gene', (153, 157))	('rearrangement', 'Var', (123, 136))	('patients', 'Species', '9606', (80, 88))	('TFE3', 'Gene', '7030', (153, 157))	('WWTR1', 'Gene', (140, 145))	('WWTR1', 'Gene', '25937', (140, 145))
241990	28836496	Cytogenetic studies revealed a 46 XY genotype.	('revealed', 'Reg', (20, 28))	('tic', 'Gene', '406', (8, 11))	('46 XY', 'Var', (31, 36))	('tic', 'Gene', (8, 11))
242004	28836496	Although the etiology is not completely understood, 46,XY GD results from failure of testicular development due to disruption of the underlying genetic pathways and several genes, including SRY (gene deletion or loss of function mutations; Yp11.3), NR5A1 (9q33) and DHH (homozygous or compound heterozygous mutations; 12q13.1) have been implicated.	('NR5A1', 'Gene', (249, 254))	('loss of function', 'NegReg', (212, 228))	('tic', 'Gene', '406', (88, 91))	('tic', 'Gene', (148, 151))	('mutations', 'Var', (229, 238))	('tic', 'Gene', (88, 91))	('failure', 'NegReg', (74, 81))	('GD', 'Phenotype', 'HP:0000133', (58, 60))	('GD', 'Disease', 'MESH:D005776', (58, 60))	('failure of testicular development', 'Phenotype', 'HP:0010469', (74, 107))	('DHH', 'Gene', (266, 269))	('SRY', 'Gene', (190, 193))	('tic', 'Gene', '406', (148, 151))
242005	28836496	In addition, patients with partial duplications of Xp (including the NR0B1 gene) and chromosome 9p deletions (involving the DMRT1 and DMRT2 genes) may also present with isolated 46,XY complete gonadal dysgenesis (CGD).	('GD', 'Phenotype', 'HP:0000133', (214, 216))	('NR0B1', 'Gene', (69, 74))	('DMRT1', 'Gene', (124, 129))	('patients', 'Species', '9606', (13, 21))	('XY complete gonadal dysgenesis', 'Phenotype', 'HP:0008668', (181, 211))	('gonadal dysgenesis', 'Disease', (193, 211))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (193, 211))	('present', 'Reg', (156, 163))	('partial duplications', 'Var', (27, 47))	('DMRT2', 'Gene', (134, 139))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (193, 211))	('GD', 'Disease', 'MESH:D005776', (214, 216))
242006	28836496	Rarely mutations in the CBX2 gene and also dublication of DAX1 gene have been  considered responsible for the development of 46, XY CGD.	('CGD.', 'Gene', '1536', (132, 136))	('GD', 'Phenotype', 'HP:0000133', (133, 135))	('CBX2', 'Gene', (24, 28))	('DAX1', 'Gene', (58, 62))	('responsible', 'Reg', (90, 101))	('CGD.', 'Gene', (132, 136))	('mutations', 'Var', (7, 16))
242030	28836496	The presence of isochromosome 12p, a specific marker of GCT and of chromosomal abnormalities in MT of non-GCT, strongly favor this hypothesis.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (67, 92))	('GCT', 'Phenotype', 'HP:0100728', (56, 59))	('isochromosome 12p', 'Var', (16, 33))	('chromosomal abnormalities', 'Disease', (67, 92))	('GCT', 'Phenotype', 'HP:0100728', (106, 109))
242196	30044058	Mammography-based screening for BC started in 1987 with high compliance.15 After approval from the Joint Ethics Committee of Helsinki University Hospital and from the Ministry of Health and Social Affairs, we searched the files of the FCR for patients diagnosed with an invasive breast carcinoma (ICD-O-314 morphology codes 801.0, 801.3, 802.0, 802.1-802.2, 803.2, 804.1, 807.0, 807.4, 808.2, 812.3, 814.0-814.1, 820.0, 820.1, 821.1, 824.0, 824.6, 824.9, 825.5, 831.0, 832.3, 840.1, 844.0, 848.0, 850.0-850.4, 851.0, 852.0, 852.2, 852.3, 852.4, 853.0, 854.0-854.1, 854.3, 855.0, 856.0, 857.2, 857.5 with behavior 3 and topography codes C50.0-C50.9) between 1953 and 2014 (n = 132 512; Figure 1).	('BC', 'Phenotype', 'HP:0003002', (32, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('invasive breast carcinoma', 'Disease', (270, 295))	('patients', 'Species', '9606', (243, 251))	('C50.0-C50.9', 'Var', (636, 647))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (270, 295))	('breast carcinoma', 'Phenotype', 'HP:0003002', (279, 295))
242288	29970461	In this study, we report that KSHV stimulates the RIG-I signaling pathway in a RNA polymerase (Pol) III-independent manner and subsequently induces type I interferon (IFN) responses.	('KSHV', 'Species', '37296', (30, 34))	('KSHV', 'Var', (30, 34))	('interferon (IFN)', 'Gene', '3439', (155, 171))	('at', 'Gene', '36849', (41, 43))	('at', 'Gene', '36849', (27, 29))	('poly', 'Chemical', '-', (83, 87))	('induces', 'Reg', (140, 147))	('at', 'Gene', '36849', (67, 69))	('interferon (IFN', 'Gene', (155, 170))	('KS', 'Phenotype', 'HP:0100726', (30, 32))
242290	29970461	By using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) approach, we identified multiple KSHV regions that give rise to RNA fragments binding to RIG-I, such as ORF810420-10496, Repeat region (LIR1)119059-119204, and ORF2543561-43650.	('LIR1', 'Gene', (237, 241))	('KSHV', 'Species', '37296', (134, 138))	('HITS-CLIP', 'Disease', (90, 99))	('ORF25', 'Gene', '4961452', (261, 266))	('binding', 'Interaction', (179, 186))	('RIG-I', 'Gene', (190, 195))	('ORF8', 'Gene', '4961501', (205, 209))	('119059-119204', 'Var', (242, 255))	('at', 'Gene', '36849', (83, 85))	('ORF8', 'Gene', (205, 209))	('LIR1', 'Gene', '10859', (237, 241))	('HITS-CLIP', 'Disease', 'None', (90, 99))	('at', 'Gene', '36849', (149, 151))	('ORF25', 'Gene', (261, 266))	('KS', 'Phenotype', 'HP:0100726', (134, 136))	('at', 'Gene', '36849', (47, 49))	('at', 'Gene', '36849', (226, 228))
242322	29970461	To determine the role of RNA Pol III in the KSHV-mediated RIG-I pathway, two different approaches were used: Pol III inhibition by a small molecule and Pol III depletion by small interfering RNA (siRNA) transfection.	('at', 'Gene', '36849', (65, 67))	('Pol III', 'Enzyme', (109, 116))	('at', 'Gene', '36849', (53, 55))	('KSHV', 'Species', '37296', (44, 48))	('depletion', 'NegReg', (160, 169))	('inhibition', 'NegReg', (117, 127))	('small interfering', 'Var', (173, 190))	('KS', 'Phenotype', 'HP:0100726', (44, 46))
242325	29970461	As expected, both doses of inhibitor ML-60218 inhibited IFN-beta induction in cells transfected with poly(dA-dT) (Fig.	('ML-60218', 'Chemical', '-', (37, 45))	('IFN-beta induction', 'MPA', (56, 74))	('poly', 'Chemical', '-', (101, 105))	('dA-dT', 'Chemical', '-', (106, 111))	('ML-60218', 'Var', (37, 45))	('inhibited', 'NegReg', (46, 55))
242329	29970461	In contrast, IFN-beta mRNA was not affected by the knockdown of POLR3A in KSHV-infected HEK293 cells (Fig.	('KSHV-infected', 'Disease', 'MESH:C537372', (74, 87))	('KSHV-infected', 'Disease', (74, 87))	('POLR3A', 'Gene', (64, 70))	('POLR3A', 'Gene', '11128', (64, 70))	('HEK293', 'CellLine', 'CVCL:0045', (88, 94))	('KS', 'Phenotype', 'HP:0100726', (74, 76))	('knockdown', 'Var', (51, 60))
242330	29970461	The siRNA-mediated knockdowns of Pol III and RIG-I were confirmed by both mRNA and protein expression using quantitative reverse transcription-PCR (qRT-PCR) and Western blotting, respectively (Fig.	('RIG-I', 'Gene', (45, 50))	('Pol', 'Enzyme', (33, 36))	('at', 'Gene', '36849', (14, 16))	('at', 'Gene', '36849', (115, 117))	('knockdowns', 'Var', (19, 29))
242333	29970461	Both qRT-PCR and Western blotting confirmed the siRNA-mediated knockdowns of Pol III and RIG-I at both mRNA and protein levels (Fig.	('Pol', 'Enzyme', (77, 80))	('at', 'Gene', '36849', (95, 97))	('at', 'Gene', '36849', (58, 60))	('knockdowns', 'Var', (63, 73))	('RIG-I', 'Gene', (89, 94))
242419	29970461	7A, compared to nontargeting control siRNA, IFN-beta induction was inhibited by RIG-I siRNA depletion but not by STING siRNA depletion, indicating that IFN-beta induction by ORF810420-10496 RNA was dependent on RIG-I.	('ORF8', 'Gene', '4961501', (174, 178))	('depletion', 'Var', (92, 101))	('inhibited', 'NegReg', (67, 76))	('ORF8', 'Gene', (174, 178))	('RIG-I', 'Gene', (80, 85))	('at', 'Gene', '36849', (141, 143))	('at', 'Gene', '36849', (149, 151))	('IFN-beta induction', 'MPA', (44, 62))
242446	29970461	These findings are consistent with the notion that double-stranded structures within viral RNAs function as primary activators of RIG-I during infection.	('infection', 'Disease', (143, 152))	('at', 'Gene', '36849', (121, 123))	('infection', 'Disease', 'MESH:D007239', (143, 152))	('double-stranded structures', 'Var', (51, 77))	('RIG-I', 'Gene', (130, 135))	('at', 'Gene', '36849', (48, 50))
242505	29970461	The small interfering RNA (siRNA) negative control (D-001810-10-05), siRNAs targeting human RIG-I (Ddx58) (L-012511-00-0005), and the two subunits of RNA polymerase (Pol) III (Polr3A and Polr3D) (L-019741-01-0005 and L-011594-00-005) were purchased from Dharmacon.	('L-011594-00-005', 'Var', (217, 232))	('Ddx58', 'Gene', (99, 104))	('Polr3D', 'Gene', '661', (187, 193))	('L-012511-00-0005', 'Var', (107, 123))	('human', 'Species', '9606', (86, 91))	('Polr3D', 'Gene', (187, 193))	('L-019741-01-0005', 'Var', (196, 212))	('Polr3A', 'Gene', (176, 182))	('at', 'Gene', '36849', (37, 39))	('Ddx58', 'Gene', '23586', (99, 104))	('Polr3A', 'Gene', '11128', (176, 182))	('poly', 'Chemical', '-', (154, 158))
242562	27826466	A 26-year-old HIV-positive (CD4 688 cells/mm3), female patient presented with a large unilateral leiomyosarcoma of the left buttock.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (97, 111))	('unilateral leiomyosarcoma', 'Disease', 'MESH:D007890', (86, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('unilateral leiomyosarcoma', 'Disease', (86, 111))	('CD4 688 cells/mm3', 'Var', (28, 45))	('patient', 'Species', '9606', (55, 62))
242601	26958471	FISH was positive for SYT (18q11.2) rearrangement (Fig.	('SYT', 'Gene', (22, 25))	('SYT', 'Gene', '6760', (22, 25))	('rearrangement', 'Var', (36, 49))
242645	32077199	Mutations of these genes account for approximately 30% of all cancers.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Disease', (62, 69))
242650	32077199	Within the last five years, we developed a potent chemically modified MIR143-3p that enabled us to elucidate the details of the KRAS signaling networks at play in colon and other cancer cells.	('MIR143-3p', 'Chemical', '-', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colon', 'Disease', 'MESH:D003110', (163, 168))	('MIR143-3p', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('colon', 'Disease', (163, 168))	('cancer', 'Disease', (179, 185))
242651	32077199	In this review, we will discuss the role of MIR143-3p in those RAS signaling networks that are related to various biological processes of cancer cells.	('MIR143-3p', 'Var', (44, 53))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('MIR143-3p', 'Chemical', '-', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
242657	32077199	MIR143-3p is one of the best known of the tumor suppressor miRNA.	('MIR143-3p', 'Var', (0, 9))	('tumor', 'Disease', (42, 47))	('MIR143-3p', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
242659	32077199	12  From previous studies, we learned that MIR143-3p functions as a tumor suppressor by modulating rat sarcoma (RAS) signaling networks, which are critical for cell proliferation, cell growth and apoptosis.	('tumor', 'Disease', (68, 73))	('MIR143-3p', 'Var', (43, 52))	('sarcoma', 'Disease', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('rat', 'Species', '10116', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('MIR143-3p', 'Chemical', '-', (43, 52))	('rat', 'Species', '10116', (172, 175))	('modulating', 'Reg', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))
242660	32077199	In this review, we discuss the roles of MIR143, mainly MIR143-3p, in RAS signaling networks in various cancers and its potential as a therapeutic agent.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('MIR143', 'Var', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MIR143-3p', 'Chemical', '-', (55, 64))	('MIR143-3p', 'Var', (55, 64))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
242663	32077199	14  MIR143-3p (the guide strand) and MIR143-5p (the passenger strand) are the two isoforms of MIR143, with MIR143-3p being a common isoform in normal tissues.	('MIR143', 'Gene', (94, 100))	('MIR143-3p', 'Chemical', '-', (107, 116))	('MIR143-3p', 'Var', (4, 13))	('MIR143-5p', 'Var', (37, 46))	('MIR143-5p', 'Chemical', '-', (37, 46))	('MIR143-3p', 'Var', (107, 116))	('MIR143-3p', 'Chemical', '-', (4, 13))
242669	32077199	Amplification and overexpression of RAS or upregulated stimulation from tyrosine kinase receptors such as EGFR and HER2 result in the continuous activation of RAS in cancer cells.	('activation', 'PosReg', (145, 155))	('HER2', 'Gene', (115, 119))	('Amplification', 'Var', (0, 13))	('upregulated', 'PosReg', (43, 54))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('HER2', 'Gene', '2064', (115, 119))	('EGFR', 'Gene', '24329', (106, 110))	('RAS', 'Protein', (159, 162))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('RAS', 'Protein', (36, 39))	('overexpression', 'PosReg', (18, 32))	('EGFR', 'Gene', (106, 110))
242670	32077199	19 ,  20  This dysregulation results in the stimulation of its effectors, MAPK/ERK, PI3K/AKT and RalGEF/RAL signaling pathways, which are the crucial pathways for tumorigenesis, cell proliferation, survival of cancer cells, differentiation and cell invasion.	('ERK', 'Gene', (79, 82))	('stimulation', 'PosReg', (44, 55))	('differentiation', 'CPA', (224, 239))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PI3K/AKT', 'Pathway', (84, 92))	('cell proliferation', 'CPA', (178, 196))	('rat', 'Species', '10116', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('ERK', 'Gene', '5594', (79, 82))	('tumor', 'Disease', (163, 168))	('RalGEF', 'Gene', (97, 103))	('dysregulation', 'Var', (15, 28))	('RalGEF', 'Gene', '29622', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))	('survival', 'CPA', (198, 206))
242673	32077199	23  Dysregulation of these RAS isoforms leads to the aberrant activation of downstream effector signaling pathways in various cancers, and their mutation rates found in human cancers differ among these isoforms.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Dysregulation', 'Var', (4, 17))	('rat', 'Species', '10116', (154, 157))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('downstream effector signaling pathways', 'Pathway', (76, 114))	('human', 'Species', '9606', (169, 174))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('activation', 'PosReg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
242675	32077199	24 ,  25  Mutations of these isoform genes are observed in approximately 30% of human cancers; and in those cancers, KRAS is the most frequently altered, accounting for 63%-85%, followed by 12%-25% for NRAS and 3%-12% for HRAS.	('altered', 'Reg', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('Mutations', 'Var', (10, 19))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('KRAS', 'Disease', (117, 121))	('cancers', 'Disease', (108, 115))
242680	32077199	36  For breast cancer, MIR30C and MIR200C target KRAS and exhibit anti-tumor effects.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('MIR200C', 'Gene', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('MIR30C', 'Var', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('target', 'Reg', (42, 48))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('KRAS', 'Protein', (49, 53))	('tumor', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))	('MIR200C', 'Gene', '100314049', (34, 41))
242684	32077199	39  Thus, MIR143-3p could be a major miRNA against RAS networks because of its contribution to the p53/MIR143/RAS cascade.	('MIR143-3p', 'Chemical', '-', (10, 19))	('p53', 'Gene', '301300', (99, 102))	('MIR143-3p', 'Var', (10, 19))	('p53', 'Gene', (99, 102))
242685	32077199	Regarding RAS signaling networks, MIR143-3p exerts its anti-tumor effects in various human cancers by targeting RAS and its effector signaling genes, such as AKT and ERK  12 ,  40 ,  41 ,  42  (Figure 2, Table 1).	('ERK', 'Gene', '5594', (166, 169))	('RAS', 'Gene', (112, 115))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('targeting', 'Reg', (102, 111))	('cancers', 'Disease', (91, 98))	('MIR143-3p', 'Var', (34, 43))	('ERK', 'Gene', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MIR143-3p', 'Chemical', '-', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (60, 65))	('human', 'Species', '9606', (85, 90))	('AKT', 'Gene', (158, 161))
242687	32077199	Therefore, the regulation of these pathways is a very important strategy for treating RAS-mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('RAS-mutant', 'Gene', (86, 96))	('RAS-mutant', 'Var', (86, 96))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rat', 'Species', '10116', (66, 69))
242689	32077199	Pancreatic cancer (PC) is very aggressive cancer with a poor prognosis, and, as mentioned above, a KRAS mutation is frequently observed in PC.	('aggressive cancer', 'Disease', 'MESH:D009369', (31, 48))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('aggressive cancer', 'Disease', (31, 48))	('PC', 'Phenotype', 'HP:0002894', (19, 21))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('observed', 'Reg', (127, 135))	('mutation', 'Var', (104, 112))	('KRAS', 'Gene', (99, 103))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))	('PC', 'Phenotype', 'HP:0002894', (139, 141))
242690	32077199	41 ,  43  The downregulation of MIR143-3p results in the activation of KRAS signaling networks, which implies an association between MIR143-3p and RAS in PC cells.	('MIR143-3p', 'Var', (133, 142))	('association', 'Interaction', (113, 124))	('activation', 'PosReg', (57, 67))	('MIR143-3p', 'Chemical', '-', (133, 142))	('PC', 'Phenotype', 'HP:0002894', (154, 156))	('MIR143-3p', 'Chemical', '-', (32, 41))	('KRAS signaling networks', 'Pathway', (71, 94))	('downregulation', 'NegReg', (14, 28))	('MIR143-3p', 'Gene', (32, 41))
242693	32077199	Hu et al also demonstrated the anti-tumor effect of MIR143-3p in a xenograft tumor model of PC cancer cells.	('MIR143-3p', 'Chemical', '-', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('PC', 'Phenotype', 'HP:0002894', (92, 94))	('cancer', 'Disease', (95, 101))	('MIR143-3p', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('rat', 'Species', '10116', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (36, 41))
242694	32077199	44  Kent et al 45  showed that a KRAS mutation in PC cells suppresses the expression levels of MIR143/145 through the inhibition of Ras-responsive element-binding protein (RREB1).	('RREB1', 'Gene', (172, 177))	('PC', 'Phenotype', 'HP:0002894', (50, 52))	('inhibition', 'NegReg', (118, 128))	('KRAS', 'Gene', (33, 37))	('RREB1', 'Gene', '306873', (172, 177))	('expression levels', 'MPA', (74, 91))	('mutation', 'Var', (38, 46))	('suppresses', 'NegReg', (59, 69))	('MIR143/145', 'Gene', (95, 105))
242696	32077199	46  The growth-suppressive effect of MIR143-3p in colorectal cancer cells by targeting KRAS was first reported in 2009.	('colorectal cancer', 'Disease', (50, 67))	('growth-suppressive effect', 'CPA', (8, 33))	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('MIR143-3p', 'Chemical', '-', (37, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('KRAS', 'Protein', (87, 91))	('MIR143-3p', 'Var', (37, 46))
242697	32077199	47  Chen et al 47  demonstrated that MIR143-3p inhibits colorectal cancer cell proliferation in vitro and in vivo by silencing KRAS expression.	('rat', 'Species', '10116', (86, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('rat', 'Species', '10116', (26, 29))	('MIR143-3p', 'Chemical', '-', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('KRAS expression', 'Protein', (127, 142))	('silencing', 'NegReg', (117, 126))	('MIR143-3p', 'Var', (37, 46))	('inhibits', 'NegReg', (47, 55))
242698	32077199	They validated the growth-suppressive function of MIR143-3p by silencing KRAS, which led to the stimulation of cell proliferation.	('KRAS', 'Gene', (73, 77))	('MIR143-3p', 'Chemical', '-', (50, 59))	('rat', 'Species', '10116', (123, 126))	('cell proliferation', 'CPA', (111, 129))	('stimulation', 'PosReg', (96, 107))	('growth-suppressive', 'CPA', (19, 37))	('silencing', 'Var', (63, 72))
242701	32077199	Pagliuca reported that overexpression of MIR143-3p and MIR145 reduces tumor growth both in vitro and in vivo and that the anti-tumor effect was mediated by profound inactivation of the MAPK/ERK signaling pathway.	('MIR143-3p', 'Chemical', '-', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('overexpression', 'PosReg', (23, 37))	('reduces', 'NegReg', (62, 69))	('inactivation', 'NegReg', (165, 177))	('ERK', 'Gene', '5594', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (127, 132))	('MIR145', 'Gene', '100314036', (55, 61))	('tumor', 'Disease', (70, 75))	('MIR143-3p', 'Var', (41, 50))	('ERK', 'Gene', (190, 193))	('MIR145', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Pagliuca', 'Chemical', '-', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
242702	32077199	49   MIR143 is also associated with the chemosensitivity of colon cancer cells.	('MIR143', 'Var', (5, 11))	('associated', 'Reg', (20, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (60, 72))	('colon cancer', 'Disease', 'MESH:D015179', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colon cancer', 'Disease', (60, 72))	('chemosensitivity', 'CPA', (40, 56))
242703	32077199	Fei et al 50  revealed that transfection with MIR143-3p increases the sensitivity to paclitaxel in a KRAS mutant cell line.	('MIR143-3p', 'Chemical', '-', (46, 55))	('increases', 'PosReg', (56, 65))	('MIR143-3p', 'Var', (46, 55))	('sensitivity to paclitaxel', 'MPA', (70, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (85, 95))
242704	32077199	We reported the synergistic effect of MIR143-3p with an epidermal growth factor receptor (EGFR) inhibitor, cetuximab, in KRAS mutant colon cancer cells; it was demonstrated that MIR143-3p systematically suppresses KRAS signaling networks, including MAPK/ERK and PI3K/AKT, and synergizes with cetuximab for growth inhibition both in vitro and in vivo.	('suppresses', 'NegReg', (203, 213))	('colon cancer', 'Disease', (133, 145))	('KRAS signaling networks', 'Pathway', (214, 237))	('epidermal growth factor receptor', 'Gene', (56, 88))	('rat', 'Species', '10116', (167, 170))	('MIR143-3p', 'Chemical', '-', (38, 47))	('cetuximab', 'Chemical', 'MESH:D000068818', (292, 301))	('EGFR', 'Gene', (90, 94))	('ERK', 'Gene', '5594', (254, 257))	('growth inhibition', 'CPA', (306, 323))	('EGFR', 'Gene', '24329', (90, 94))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('cetuximab', 'Chemical', 'MESH:D000068818', (107, 116))	('MIR143-3p', 'Chemical', '-', (178, 187))	('PI3K/AKT', 'Pathway', (262, 270))	('ERK', 'Gene', (254, 257))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('MIR143-3p', 'Var', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('epidermal growth factor receptor', 'Gene', '24329', (56, 88))
242705	32077199	42  In agreement, Gomes et al 51  reported that ectopic expression of MIR143-3p and MIR-145 increases the sensitivity to cetuximab in both KRAS wild-type and KRAS mutant colon cancer cells.	('colon cancer', 'Phenotype', 'HP:0003003', (170, 182))	('colon cancer', 'Disease', 'MESH:D015179', (170, 182))	('MIR143-3p', 'Chemical', '-', (70, 79))	('cetuximab', 'Chemical', 'MESH:D000068818', (121, 130))	('colon cancer', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('MIR143-3p', 'Var', (70, 79))	('sensitivity to cetuximab', 'MPA', (106, 130))	('MIR-145', 'Gene', (84, 91))	('increases', 'PosReg', (92, 101))	('MIR-145', 'Gene', '100314036', (84, 91))
242706	32077199	They demonstrated that MIR143-3p exhibits its anti-tumor effect through cetuximab-mediated antibody-dependent cellular cytotoxicity in colon cancer cells.	('cetuximab', 'Chemical', 'MESH:D000068818', (72, 81))	('cytotoxicity', 'Disease', (119, 131))	('rat', 'Species', '10116', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('colon cancer', 'Disease', (135, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (51, 56))	('cytotoxicity', 'Disease', 'MESH:D064420', (119, 131))	('MIR143-3p', 'Chemical', '-', (23, 32))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('MIR143-3p', 'Var', (23, 32))
242707	32077199	Recently, we found that the expression level of MIR143-3p is also downregulated in HER2-positive GC cells and that ectopic expression of MIR143 induced cell growth suppression in those cells.	('ectopic expression', 'Var', (115, 133))	('MIR143-3p', 'Chemical', '-', (48, 57))	('cell growth suppression', 'CPA', (152, 175))	('downregulated', 'NegReg', (66, 79))	('MIR143-3p', 'Var', (48, 57))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('MIR143', 'Gene', (137, 143))	('HER2', 'Gene', (83, 87))	('expression level', 'MPA', (28, 44))	('HER2', 'Gene', '2064', (83, 87))
242708	32077199	52  In that same study we demonstrated that MIR143-3p targets KRAS effector signaling genes such as KRAS, AKT and ERK, leading to suppression of GC cell growth, and clarified that MIR143-3p indirectly silences human epidermal growth factor receptor 2 (HER2), resulting in suppression of KRAS activation and its effector signaling pathways.	('GC cell growth', 'CPA', (145, 159))	('suppression', 'NegReg', (272, 283))	('epidermal growth factor receptor 2', 'Gene', '2064', (216, 250))	('rat', 'Species', '10116', (33, 36))	('HER2', 'Gene', (252, 256))	('human', 'Species', '9606', (210, 215))	('epidermal growth factor receptor 2', 'Gene', (216, 250))	('ERK', 'Gene', (114, 117))	('KRAS', 'Pathway', (287, 291))	('MIR143-3p', 'Chemical', '-', (180, 189))	('MIR143-3p', 'Var', (180, 189))	('suppression', 'NegReg', (130, 141))	('MIR143-3p', 'Chemical', '-', (44, 53))	('HER2', 'Gene', '2064', (252, 256))	('activation', 'PosReg', (292, 302))	('MIR143-3p', 'Var', (44, 53))	('GC', 'Phenotype', 'HP:0012126', (145, 147))	('silences', 'NegReg', (201, 209))	('ERK', 'Gene', '5594', (114, 117))
242710	32077199	46  Chen et al identified the suppressive effect of MIR143-3p in non-small cell lung cancer cell progression.	('MIR143-3p', 'Chemical', '-', (52, 61))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('suppressive effect', 'NegReg', (30, 48))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('MIR143-3p', 'Var', (52, 61))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
242711	32077199	They also demonstrated that MIR143 expression is modulated by TGF-beta and that MIR143-3p suppresses lung cancer progression through the silencing of KRAS.	('suppresses', 'NegReg', (90, 100))	('TGF-beta', 'Gene', (62, 70))	('TGF-beta', 'Gene', '24827', (62, 70))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('MIR143-3p', 'Chemical', '-', (80, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('silencing', 'NegReg', (137, 146))	('MIR143', 'Gene', (28, 34))	('MIR143-3p', 'Var', (80, 89))	('rat', 'Species', '10116', (17, 20))	('KRAS', 'Gene', (150, 154))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
242713	32077199	53  Dong and Hu demonstrated the cell growth suppression of exogenous MIR143 through the downregulation of the expression levels of EGFR, AKT and ERK1/2 and the phosphorylation of EGFR, AKT and ERK1/2 in NSCLC in vitro.	('EGFR', 'Gene', '24329', (180, 184))	('phosphorylation', 'MPA', (161, 176))	('ERK1/2', 'Gene', (146, 152))	('expression levels', 'MPA', (111, 128))	('ERK1/2', 'Gene', '50689;116590', (146, 152))	('exogenous', 'Var', (60, 69))	('NSCLC', 'Disease', 'MESH:D002289', (204, 209))	('rat', 'Species', '10116', (23, 26))	('cell growth', 'CPA', (33, 44))	('NSCLC', 'Disease', (204, 209))	('NSCLC', 'Phenotype', 'HP:0030358', (204, 209))	('suppression', 'NegReg', (45, 56))	('AKT', 'Gene', (138, 141))	('AKT', 'Gene', (186, 189))	('downregulation', 'NegReg', (89, 103))	('EGFR', 'Gene', (132, 136))	('EGFR', 'Gene', (180, 184))	('ERK1/2', 'Gene', (194, 200))	('ERK1/2', 'Gene', '50689;116590', (194, 200))	('EGFR', 'Gene', '24329', (132, 136))	('MIR143', 'Gene', (70, 76))
242715	32077199	53   We demonstrated that MIR143-3p silences KRAS and its effector molecules, such as AKT and ERK, in renal cell carcinoma and bladder cancer cells both in vitro and in vivo.	('ERK', 'Gene', (94, 97))	('rat', 'Species', '10116', (15, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('renal cell carcinoma', 'Disease', (102, 122))	('MIR143-3p', 'Chemical', '-', (26, 35))	('bladder cancer', 'Disease', 'MESH:D001749', (127, 141))	('bladder cancer', 'Disease', (127, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('AKT', 'Pathway', (86, 89))	('silences', 'NegReg', (36, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('KRAS', 'Gene', (45, 49))	('ERK', 'Gene', '5594', (94, 97))	('MIR143-3p', 'Var', (26, 35))
242717	32077199	54  Noguchi et al demonstrated the combination therapy with the ectopic expression of MIR143 and MIR145 showed the synergistic inhibition of bladder cancer cells through modulating PI3K/AKT and MAPK signaling pathways.	('MIR143', 'Gene', (86, 92))	('bladder cancer', 'Disease', (141, 155))	('MAPK signaling pathways', 'Pathway', (194, 217))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('MIR145', 'Gene', '100314036', (97, 103))	('ectopic expression', 'Var', (64, 82))	('rat', 'Species', '10116', (25, 28))	('modulating', 'Reg', (170, 180))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))	('MIR145', 'Gene', (97, 103))
242718	32077199	11  Recently, we discovered that MIR143-3p negatively regulated the KRAS/Musashi-2 cascade and, consequently, suppressed the cell growth in bladder cancer through downregulation of the KRAS protein expression level at the translational step.	('regulated', 'Reg', (54, 63))	('Musashi-2', 'Gene', '124540', (73, 82))	('cell growth', 'CPA', (125, 136))	('MIR143-3p', 'Chemical', '-', (33, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('MIR143-3p', 'Var', (33, 42))	('bladder cancer', 'Disease', (140, 154))	('bladder cancer', 'Disease', 'MESH:D001749', (140, 154))	('negatively', 'NegReg', (43, 53))	('suppressed', 'NegReg', (110, 120))	('downregulation', 'NegReg', (163, 177))	('Musashi-2', 'Gene', (73, 82))	('KRAS', 'Gene', (185, 189))
242720	32077199	Zhang et al 57  reported that MIR143-3p exhibits an anti-tumor effect on laryngeal squamous cell carcinoma, the most frequent cancer of the head and neck cancers, by targeting KRAS and its effector MAPK/ERK signaling pathway.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 106))	('head and neck cancers', 'Disease', 'MESH:D006258', (140, 161))	('ERK', 'Gene', (203, 206))	('KRAS', 'Protein', (176, 180))	('squamous cell carcinoma', 'Disease', (83, 106))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('MIR143-3p', 'Chemical', '-', (30, 39))	('tumor', 'Disease', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('MIR143-3p', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('targeting', 'Reg', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('head and neck cancers', 'Phenotype', 'HP:0012288', (140, 161))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ERK', 'Gene', '5594', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
242723	32077199	59  They found that MIR143-3p negatively regulated ERK5 expression, which led to the suppression of cervical cancer cell lines.	('suppression of cervical cancer', 'Disease', (85, 115))	('MIR143-3p', 'Var', (20, 29))	('suppression of cervical cancer', 'Disease', 'MESH:D002583', (85, 115))	('expression', 'MPA', (56, 66))	('ERK5', 'Gene', (51, 55))	('ERK5', 'Gene', '114509', (51, 55))	('MIR143-3p', 'Chemical', '-', (20, 29))	('negatively', 'NegReg', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
242732	32077199	64  Wang et al 65  demonstrated that the overexpression of MIR143 inhibits the tumor growth of glioma in vitro and in vivo through silencing NRAS.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('tumor', 'Disease', (79, 84))	('silencing', 'Var', (131, 140))	('inhibits', 'NegReg', (66, 74))	('rat', 'Species', '10116', (26, 29))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('glioma', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('overexpression', 'PosReg', (41, 55))	('MIR143', 'Gene', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('NRAS', 'Gene', (141, 145))
242733	32077199	In addition, they demonstrated that the restoration of MIR143 enhances the chemosensitivity to temozolomide, which is the standard initial drug for the treatment of glioma.	('MIR143', 'Gene', (55, 61))	('temozolomide', 'Chemical', 'MESH:D000077204', (95, 107))	('chemosensitivity to temozolomide', 'MPA', (75, 107))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('restoration', 'Var', (40, 51))	('rat', 'Species', '10116', (25, 28))	('enhances', 'PosReg', (62, 70))	('glioma', 'Disease', (165, 171))	('rat', 'Species', '10116', (45, 48))
242739	32077199	For instance, a PI3K inhibitor will cause the upregulation of HER2 or HER3, which induces the upregulation of the MAPK signaling pathway in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('HER3', 'Protein', (70, 74))	('HER2', 'Gene', '2064', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('upregulation', 'PosReg', (46, 58))	('upregulation', 'PosReg', (94, 106))	('PI3K inhibitor', 'Var', (16, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('MAPK signaling pathway', 'Pathway', (114, 136))	('HER2', 'Gene', (62, 66))
242740	32077199	69 ,  70  In addition, a MEK inhibitor will lead to the upregulation of the PI3K/AKT pathway in colorectal cancer.	('upregulation', 'PosReg', (56, 68))	('MEK', 'Gene', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('PI3K/AKT pathway', 'Pathway', (76, 92))	('colorectal cancer', 'Disease', (96, 113))	('inhibitor', 'Var', (29, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
242742	32077199	Numerous microRNA, such as MIRLET7 and MIR200C, have been reported in preclinical models to function as tumor suppressors in various types of cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', (104, 109))	('MIRLET7', 'Var', (27, 34))	('MIR200C', 'Gene', '100314049', (39, 46))	('MIR200C', 'Gene', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('cancer', 'Disease', (142, 148))
242744	32077199	Among the derivatives, CM-MIR143-3p, which is chemically modified only in the passenger strand (Figure 3), showed strikingly potent anti-proliferative activity.	('CM-MIR143-3p', 'Var', (23, 35))	('CM-MIR143-3p', 'Chemical', '-', (23, 35))	('rat', 'Species', '10116', (144, 147))	('anti-proliferative activity', 'CPA', (132, 159))
242745	32077199	The CM-MIR143-3p systemically inhibits the KRAS signaling networks, which include RAS-MAPK and PI3K-AKT effector signaling pathways, by silencing KRAS, SOS1, AKT and ERK both in vitro and in vivo in colon cancer cells.	('ERK', 'Gene', '5594', (166, 169))	('KRAS', 'Gene', (146, 150))	('SOS1', 'Gene', '313845', (152, 156))	('PI3K-AKT effector signaling pathways', 'Pathway', (95, 131))	('CM-MIR143-3p', 'Var', (4, 16))	('ERK', 'Gene', (166, 169))	('silencing', 'NegReg', (136, 145))	('RAS-MAPK', 'Pathway', (82, 90))	('AKT', 'Pathway', (158, 161))	('colon cancer', 'Disease', 'MESH:D015179', (199, 211))	('CM-MIR143-3p', 'Chemical', '-', (4, 16))	('colon cancer', 'Phenotype', 'HP:0003003', (199, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('colon cancer', 'Disease', (199, 211))	('KRAS signaling networks', 'Pathway', (43, 66))	('inhibits', 'NegReg', (30, 38))	('SOS1', 'Gene', (152, 156))
242746	32077199	42  In the same study, we further demonstrated the synergistic effect of an EGFR inhibitor and CM-MIR143-3p in KRAS mutant cells.	('EGFR', 'Gene', '24329', (76, 80))	('CM-MIR143-3p', 'Chemical', '-', (95, 107))	('synergistic', 'Interaction', (51, 62))	('EGFR', 'Gene', (76, 80))	('rat', 'Species', '10116', (41, 44))	('mutant', 'Var', (116, 122))
242747	32077199	51  In line with this result, Gomes et al 51  reported that MIR143 increases the sensitivity to cetuximab in both KRAS wild-type and KRAS mutant colon cancer cells.	('colon cancer', 'Disease', 'MESH:D015179', (145, 157))	('MIR143', 'Var', (60, 66))	('colon cancer', 'Disease', (145, 157))	('sensitivity to cetuximab', 'MPA', (81, 105))	('cetuximab', 'Chemical', 'MESH:D000068818', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutant', 'Var', (138, 144))	('increases', 'PosReg', (67, 76))	('colon cancer', 'Phenotype', 'HP:0003003', (145, 157))
242748	32077199	These results suggest the potential combinational therapy of MIR143 and EGFR inhibitors.	('EGFR', 'Gene', (72, 76))	('inhibitors', 'Var', (77, 87))	('EGFR', 'Gene', '24329', (72, 76))	('MIR143', 'Gene', (61, 67))
242749	32077199	Other than colorectal cancer, MIR143-3p displayed tumor suppressor effects on various types of cancers, such as PC, head and neck cancers, lung cancers and breast cancers.	('colorectal cancer', 'Disease', 'MESH:D015179', (11, 28))	('head and neck cancers', 'Disease', 'MESH:D006258', (116, 137))	('lung cancers', 'Disease', 'MESH:D008175', (139, 151))	('PC', 'Phenotype', 'HP:0002894', (112, 114))	('colorectal cancer', 'Disease', (11, 28))	('lung cancers', 'Disease', (139, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('breast cancers', 'Disease', 'MESH:D001943', (156, 170))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('breast cancers', 'Disease', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('lung cancers', 'Phenotype', 'HP:0100526', (139, 151))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancers', 'Disease', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('breast cancers', 'Phenotype', 'HP:0003002', (156, 170))	('MIR143-3p', 'Chemical', '-', (30, 39))	('cancers', 'Disease', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (50, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (11, 28))	('MIR143-3p', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('head and neck cancers', 'Phenotype', 'HP:0012288', (116, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancers', 'Disease', 'MESH:D009369', (144, 151))
242750	32077199	45 ,  53 ,  58 ,  62  Our group also found that CM-MIR143-3p exerts efficient suppression of KRAS networks in renal cell cancer  12  and bladder cancer  54  by systematically suppressing the KRAS networks, including PI3K/AKT and MAPK/ERK pathways.	('KRAS networks', 'Pathway', (191, 204))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('renal cell cancer', 'Disease', 'MESH:C538614', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('renal cell cancer', 'Disease', (110, 127))	('CM-MIR143-3p', 'Var', (48, 60))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('suppressing', 'NegReg', (175, 186))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('bladder cancer', 'Disease', (137, 151))	('PI3K/AKT', 'Pathway', (216, 224))	('ERK', 'Gene', '5594', (234, 237))	('ERK', 'Gene', (234, 237))	('suppression', 'NegReg', (78, 89))	('CM-MIR143-3p', 'Chemical', '-', (48, 60))	('renal cell cancer', 'Phenotype', 'HP:0005584', (110, 127))	('KRAS', 'Protein', (93, 97))
242751	32077199	Importantly, we demonstrated that the silencing of KRAS alone induces a "positive circuit" of KRAS expression; that is, the downregulation of KRAS is transient, finally leading to re-upregulation of KRAS expression, because KRAS is one of the target genes of each KRAS effector signaling pathway (Figure 2).	('KRAS', 'Gene', (142, 146))	('rat', 'Species', '10116', (23, 26))	('induces', 'Reg', (62, 69))	('silencing', 'Var', (38, 47))	('expression', 'MPA', (204, 214))	('downregulation', 'NegReg', (124, 138))	('KRAS', 'Gene', (51, 55))	('KRAS', 'Gene', (199, 203))
242755	32077199	73   In this review, we discussed the anti-cancer effects of MIR143-3p on different types of cancers, with suppression realized by targeting the genes related to RAS signaling networks.	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Disease', (43, 49))	('MIR143-3p', 'Chemical', '-', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('MIR143-3p', 'Var', (61, 70))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
242758	32077199	Given the critical effects of CM-MIR143-3p in suppressing the expression of both RAS and its effector signaling genes, we cannot help but speculate that CM-MIR143-3p efficiently functions as a therapeutic agent to impair the KRAS signaling networks.	('CM-MIR143-3p', 'Chemical', '-', (153, 165))	('expression', 'MPA', (62, 72))	('CM-MIR143-3p', 'Chemical', '-', (30, 42))	('CM-MIR143-3p', 'Var', (153, 165))	('impair', 'NegReg', (214, 220))	('RAS', 'Gene', (81, 84))	('KRAS signaling networks', 'Pathway', (225, 248))	('suppressing', 'NegReg', (46, 57))
242761	29263814	Using whole-genome sequencing, we identified a germline hemizygous deletion ablating CDKN2A-CDKN2B in a TP53 wild-type patient presenting with high-grade sarcoma, laryngeal squamous cell carcinoma and a family history suggestive of LFS.	('patient', 'Species', '9606', (119, 126))	('TP53', 'Gene', '7157', (104, 108))	('LFS', 'Disease', 'MESH:D016864', (232, 235))	('TP53', 'Gene', (104, 108))	('CDKN2B', 'Gene', (92, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('deletion', 'Var', (67, 75))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 196))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('ablating', 'NegReg', (76, 84))	('CDKN2B', 'Gene', '1030', (92, 98))	('LFS', 'Disease', (232, 235))	('laryngeal squamous cell carcinoma', 'Disease', (163, 196))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))
242762	29263814	Patient-derived cells demonstrated reduced basal gene and protein expression of the CDKN2A-encoded tumour suppressors p14ARF and p16INK4A with concomitant decrease in p21 and faster cell proliferation, implying potential deregulation of p53-mediated cell cycle control.	('CDKN2A-encoded', 'Gene', (84, 98))	('p14ARF', 'Gene', (118, 124))	('p53', 'Gene', '7157', (237, 240))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('reduced', 'NegReg', (35, 42))	('cell proliferation', 'CPA', (182, 200))	('tumour', 'Disease', (99, 105))	('p21', 'Gene', '1026', (167, 170))	('p14ARF', 'Gene', '1029', (118, 124))	('decrease', 'NegReg', (155, 163))	('p21', 'Gene', (167, 170))	('Patient', 'Species', '9606', (0, 7))	('p53', 'Gene', (237, 240))	('faster', 'PosReg', (175, 181))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('p16INK4A', 'Var', (129, 137))
242763	29263814	Review of 13 additional patients with pathogenic CDKN2A variants suggested associations of germline CDKN2A mutations with an expanded spectrum of non-melanoma familial cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (107, 116))	('non-melanoma familial cancers', 'Disease', 'OMIM:155600', (146, 175))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('variants', 'Var', (56, 64))	('CDKN2A', 'Gene', (100, 106))	('patients', 'Species', '9606', (24, 32))	('non-melanoma familial cancers', 'Disease', (146, 175))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('associations', 'Interaction', (75, 87))
242765	29263814	These findings highlight the potential contribution of germline CDKN2A deletions to cancer predisposition and the importance of interrogating the full extent of CDKN2A locus in clinical testing gene panels.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('deletions', 'Var', (71, 80))	('contribution', 'Reg', (39, 51))	('cancer', 'Disease', (84, 90))	('CDKN2A', 'Gene', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
242768	29263814	The majority of these patients have germline mutations in TP53, a known susceptibility gene associated with LFS/LFL.	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('germline mutations', 'Var', (36, 54))	('patients', 'Species', '9606', (22, 30))	('LFS', 'Disease', (108, 111))	('LFS', 'Disease', 'MESH:D016864', (108, 111))
242777	29263814	However, in this test, TP53 was part of a larger gene panel, which revealed a hemizygous deletion of all three p16INK4A exons of CDKN2A.	('CDKN2A', 'Gene', (129, 135))	('p16INK4A', 'Var', (111, 119))	('deletion', 'Var', (89, 97))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
242778	29263814	Given the absence of a personal or family history of melanoma, which might be expected in individuals with CDKN2A (specifically p16INK4A) mutations, we performed germline whole-genome sequencing (WGS) to further elucidate the basis for this patient's disease.	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('patient', 'Species', '9606', (241, 248))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('CDKN2A', 'Gene', (107, 113))	('mutations', 'Var', (138, 147))
242779	29263814	Copy-number analysis of the WGS data revealed a constitutional focal deletion on chromosome 9 of ~270 kb, resulting in a hemizygous loss of the entire CDKN2A-CDKN2B locus and partially truncating the flanking MTAP and CDKN2B-AS genes (Figure 1b).	('CDKN2B-AS', 'Gene', (218, 227))	('truncating', 'NegReg', (185, 195))	('CDKN2B-AS', 'Gene', '100048912', (218, 227))	('loss', 'NegReg', (132, 136))	('CDKN2B', 'Gene', (218, 224))	('CDKN2B', 'Gene', '1030', (218, 224))	('CDKN2B', 'Gene', (158, 164))	('MTAP', 'Gene', (209, 213))	('CDKN2B', 'Gene', '1030', (158, 164))	('deletion', 'Var', (69, 77))	('MTAP', 'Gene', '4507', (209, 213))
242781	29263814	Quantitative PCR (qPCR) validated the deletions in the patient's germline and tumour DNA, demonstrating a gene dosage ratio of 0.5 and 0.0, respectively, compared with healthy controls (Figure 1c).	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('deletions', 'Var', (38, 47))	('patient', 'Species', '9606', (55, 62))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
242783	29263814	Hemizygous loss of CDKN2A could affect dosage of two tumour suppressor proteins encoded by the gene, p14ARF and p16INK4A.	('p14ARF', 'Gene', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', (53, 59))	('CDKN2A', 'Gene', (19, 25))	('affect', 'Reg', (32, 38))	('p14ARF', 'Gene', '1029', (101, 107))	('dosage of', 'MPA', (39, 48))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('p16INK4A', 'Var', (112, 120))
242785	29263814	Reverse transcription qPCR analysis confirmed that basal gene expression of p14ARF and p16INK4A was 50% lower than in healthy controls (Figure 2a, P<0.001 and P<0.01, respectively).	('p16INK4A', 'Var', (87, 95))	('lower', 'NegReg', (104, 109))	('p14ARF', 'Gene', (76, 82))	('p14ARF', 'Gene', '1029', (76, 82))
242786	29263814	Immunoblot analysis of these two proteins in the patient LCLs did not show such a significant decrease; however, it should be noted that the p14ARF and p16INK4A levels in the LCLs of healthy controls were variable (Figure 2b).	('p14ARF', 'Gene', '1029', (141, 147))	('p16INK4A', 'Var', (152, 160))	('patient', 'Species', '9606', (49, 56))	('p14ARF', 'Gene', (141, 147))
242787	29263814	Nevertheless, immunohistochemical analysis of both MPNST and laryngeal SCC tumours were clearly null for p14ARF and p16INK4A (Figure 2c), consistent with the genomic loss observed by WGS (Figure 1b).	('p14ARF', 'Gene', (105, 111))	('laryngeal SCC tumours', 'Disease', 'MESH:D007822', (61, 82))	('MPNST', 'Phenotype', 'HP:0100697', (51, 56))	('laryngeal SCC tumour', 'Phenotype', 'HP:0012118', (61, 81))	('laryngeal SCC tumours', 'Disease', (61, 82))	('p14ARF', 'Gene', '1029', (105, 111))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('p16INK4A', 'Var', (116, 124))
242793	29263814	To our knowledge, this is the first report of a hemizygous CDKN2A-CDKN2B germline deletion in an LFS/LFL family, where the proband presented with MPNST-HNSCC without a personal or family history of melanoma.	('LFS', 'Disease', 'MESH:D016864', (97, 100))	('CDKN2B', 'Gene', '1030', (66, 72))	('MPNST-HNSCC', 'Disease', (146, 157))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('melanoma', 'Disease', (198, 206))	('deletion', 'Var', (82, 90))	('presented with', 'Reg', (131, 145))	('LFS', 'Disease', (97, 100))	('CDKN2B', 'Gene', (66, 72))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))	('MPNST', 'Phenotype', 'HP:0100697', (146, 151))
242794	29263814	The CDKN2A-CDKN2B locus encodes three tumour suppressor proteins:p14ARF, p16INK4A and p15INK4B:all involved in cell cycle via p53 and retinoblastoma pathways.	('p53', 'Gene', '7157', (126, 129))	('retinoblastoma', 'Phenotype', 'HP:0009919', (134, 148))	('p14ARF', 'Gene', '1029', (65, 71))	('p15INK4B', 'Gene', (86, 94))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('involved', 'Reg', (99, 107))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('p53', 'Gene', (126, 129))	('p16INK4A', 'Var', (73, 81))	('p14ARF', 'Gene', (65, 71))	('retinoblastoma', 'Disease', (134, 148))	('p15INK4B', 'Gene', '1030', (86, 94))	('retinoblastoma', 'Disease', 'MESH:D012175', (134, 148))	('tumour', 'Disease', (38, 44))	('CDKN2B', 'Gene', (11, 17))	('CDKN2B', 'Gene', '1030', (11, 17))
242795	29263814	p16INK4A and p15INK4B inhibit cyclin-dependent kinase (CDK)-mediated phosphorylation of retinoblastoma, thereby promoting G1 cell cycle arrest.	('p15INK4B', 'Gene', '1030', (13, 21))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (125, 142))	('p16INK4A', 'Var', (0, 8))	('inhibit', 'NegReg', (22, 29))	('G1 cell cycle arrest', 'CPA', (122, 142))	('retinoblastoma', 'Disease', 'MESH:D012175', (88, 102))	('retinoblastoma', 'Disease', (88, 102))	('p15INK4B', 'Gene', (13, 21))	('promoting', 'PosReg', (112, 121))	('retinoblastoma', 'Phenotype', 'HP:0009919', (88, 102))
242797	29263814	As p14ARF acts upstream of p53, it is conceivable that the germline hemizygous deletion of CDKN2A in our patient would phenocopy a hemizygous loss of TP53 in the impaired capacity for arresting cell proliferation.	('patient', 'Species', '9606', (105, 112))	('TP53', 'Gene', (150, 154))	('loss', 'NegReg', (142, 146))	('p53', 'Gene', '7157', (27, 30))	('CDKN2A', 'Gene', (91, 97))	('p14ARF', 'Gene', '1029', (3, 9))	('p14ARF', 'Gene', (3, 9))	('TP53', 'Gene', '7157', (150, 154))	('deletion', 'Var', (79, 87))	('p53', 'Gene', (27, 30))
242803	29263814	The complete genomic loss of the CDKN2A locus together with ablation of p14ARF and p16INK4A expression in both tumours (Figures 1b and 2c) is consistent with the observations in p14ARF-hemizygous mice, whereby loss of the residual wild-type ARF was observed to accompany tumour development.	('ARF', 'Disease', 'MESH:D058186', (75, 78))	('mice', 'Species', '10090', (196, 200))	('ablation', 'Var', (60, 68))	('ARF', 'Disease', 'MESH:D058186', (241, 244))	('p14ARF', 'Gene', '1029', (178, 184))	('CDKN2A', 'Gene', (33, 39))	('ARF', 'Disease', (181, 184))	('p14ARF', 'Gene', '1029', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('tumours', 'Disease', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('p14ARF', 'Gene', (178, 184))	('ARF', 'Disease', (75, 78))	('tumour', 'Disease', 'MESH:D009369', (271, 277))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (271, 277))	('ARF', 'Disease', (241, 244))	('tumour', 'Disease', (111, 117))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('tumours', 'Disease', 'MESH:D009369', (111, 118))	('p14ARF', 'Gene', (72, 78))	('p16INK4A', 'Gene', (83, 91))	('ARF', 'Disease', 'MESH:D058186', (181, 184))	('loss', 'NegReg', (21, 25))
242806	29263814	Presence of all three p53 pathway-associated proteins in the laryngeal SCC tumour suggests that tumorigenesis was probably less dependent on the p53 pathway and could potentially be more driven by deregulation in the retinoblastoma pathway associated with loss of p16INK4A.	('laryngeal SCC tumour', 'Disease', (61, 81))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('retinoblastoma', 'Phenotype', 'HP:0009919', (217, 231))	('p53', 'Gene', (22, 25))	('p16INK4A', 'Var', (264, 272))	('laryngeal SCC tumour', 'Phenotype', 'HP:0012118', (61, 81))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('p53', 'Gene', '7157', (22, 25))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('laryngeal SCC tumour', 'Disease', 'MESH:D007822', (61, 81))	('retinoblastoma', 'Disease', (217, 231))	('loss', 'Var', (256, 260))	('tumorigenesis', 'CPA', (96, 109))	('retinoblastoma', 'Disease', 'MESH:D012175', (217, 231))
242809	29263814	Germline mutations in CDKN2A are associated with familial melanoma and pancreatic cancer, and infrequently with neurofibroma, HNSCC and neural system tumours (astrocytoma and glioma).	('Germline mutations', 'Var', (0, 18))	('familial melanoma', 'Disease', 'OMIM:155600', (49, 66))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('astrocytoma and glioma', 'Disease', 'MESH:D005910', (159, 181))	('neurofibroma', 'Phenotype', 'HP:0001067', (112, 124))	('pancreatic cancer', 'Disease', (71, 88))	('neurofibroma', 'Disease', 'MESH:D009455', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('astrocytoma', 'Phenotype', 'HP:0009592', (159, 170))	('neural system tumour', 'Phenotype', 'HP:0004375', (136, 156))	('HNSCC', 'Disease', (126, 131))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('neural system tumours', 'Disease', 'MESH:C536149', (136, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('neurofibroma', 'Disease', (112, 124))	('HNSCC', 'Phenotype', 'HP:0012288', (126, 131))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('CDKN2A', 'Gene', (22, 28))	('neural system tumours', 'Disease', (136, 157))	('associated', 'Reg', (33, 43))	('familial melanoma', 'Disease', (49, 66))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
242810	29263814	To date, CDKN2A deletions have been reported in only a handful of kindreds displaying clustering of specific tumour spectrum, all of which feature melanoma: cutaneous malignant melanoma-neural system tumour, melanoma-HNSCC, melanoma-neurofibroma and malignant melanoma.	('neural system tumour', 'Phenotype', 'HP:0004375', (186, 206))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('neurofibroma', 'Phenotype', 'HP:0001067', (233, 245))	('malignant melanoma', 'Phenotype', 'HP:0002861', (250, 268))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('melanoma-neural system tumour', 'Disease', 'MESH:C536149', (177, 206))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('tumour', 'Disease', (109, 115))	('melanoma', 'Disease', (177, 185))	('malignant melanoma', 'Phenotype', 'HP:0002861', (167, 185))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Disease', 'MESH:D008545', (260, 268))	('malignant melanoma', 'Disease', 'MESH:D008545', (167, 185))	('CDKN2A', 'Gene', (9, 15))	('HNSCC', 'Phenotype', 'HP:0012288', (217, 222))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('tumour', 'Disease', (200, 206))	('malignant melanoma', 'Disease', (250, 268))	('melanoma-neural system tumour', 'Disease', (177, 206))	('melanoma-HNSCC, melanoma-neurofibroma', 'Disease', 'MESH:D008545', (208, 245))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (157, 185))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('melanoma', 'Disease', (260, 268))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('malignant melanoma', 'Disease', (167, 185))	('deletions', 'Var', (16, 25))	('SCC', 'Phenotype', 'HP:0002860', (219, 222))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('melanoma', 'Disease', (224, 232))	('malignant melanoma', 'Disease', 'MESH:D008545', (250, 268))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
242811	29263814	We reviewed the clinical records for a series of cancer patients who were found to be positive through gene panel testing for germline CDKN2A mutations to better understand the phenotypic and mutation spectrum.	('CDKN2A', 'Gene', (135, 141))	('mutations', 'Var', (142, 151))	('patients', 'Species', '9606', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
242812	29263814	In this series, there were a total of 29 cancers reported among the 14 patients from 12 unique families with germline CDKN2A mutations.	('CDKN2A', 'Gene', (118, 124))	('mutations', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('patients', 'Species', '9606', (71, 79))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
242819	29263814	highlighted a rare contiguous deletion in chromosome 9p21.3 obliterating ~25 genes including CDKN2A, CDKN2B and MTAP in a melanoma-prone family with additional tumour spectrum (neural system tumours, leukaemia, chondrosarcoma, pontomedullary PNET and cervical cancer), supporting our findings that genetic alterations involving CDKN2A could potentially underlie hereditary predisposition to cancers beyond melanoma.	('CDKN2A', 'Gene', (93, 99))	('neural system tumour', 'Phenotype', 'HP:0004375', (177, 197))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('melanoma', 'Phenotype', 'HP:0002861', (406, 414))	('melanoma', 'Disease', (406, 414))	('cancers', 'Phenotype', 'HP:0002664', (391, 398))	('cancer', 'Disease', (391, 397))	('cancers', 'Disease', (391, 398))	('cancer', 'Phenotype', 'HP:0002664', (391, 397))	('leukaemia', 'Disease', (200, 209))	('MTAP', 'Gene', (112, 116))	('CDKN2A', 'Gene', (328, 334))	('MTAP', 'Gene', '4507', (112, 116))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('p21', 'Gene', (54, 57))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('neural system tumours', 'Disease', 'MESH:C536149', (177, 198))	('additional tumour', 'Disease', 'MESH:D009369', (149, 166))	('CDKN2B', 'Gene', (101, 107))	('cancer', 'Disease', (260, 266))	('chondrosarcoma', 'Disease', 'MESH:D002813', (211, 225))	('deletion', 'Var', (30, 38))	('underlie', 'Reg', (353, 361))	('melanoma', 'Disease', 'MESH:D008545', (406, 414))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('chondrosarcoma', 'Disease', (211, 225))	('cancer', 'Disease', 'MESH:D009369', (391, 397))	('cancers', 'Disease', 'MESH:D009369', (391, 398))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('additional tumour', 'Disease', (149, 166))	('leukaemia', 'Disease', 'MESH:D007938', (200, 209))	('neural system tumours', 'Disease', (177, 198))	('CDKN2B', 'Gene', '1030', (101, 107))	('p21', 'Gene', '1026', (54, 57))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('genetic alterations', 'Var', (298, 317))	('melanoma', 'Disease', (122, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (211, 225))
242820	29263814	In our patient with hemizygous germline deletion of CDKN2A, it is prudent to extend melanoma screening given the increased risk of melanoma in families with CDKN2A alterations.	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('patient', 'Species', '9606', (7, 14))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('germline deletion', 'Var', (31, 48))	('CDKN2A', 'Gene', (52, 58))
242821	29263814	Recent reports revealed that loss of MTAP, a gene flanking and frequently co-deleted with CDKN2A, can render cancer cells sensitive to PRMT5 inhibition, thus opening up opportunities to exploit this vulnerability for treating tumours with MTAP-CDKN2A co-deletion.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('PRMT5', 'Gene', '10419', (135, 140))	('sensitive', 'MPA', (122, 131))	('cancer', 'Disease', (109, 115))	('MTAP', 'Gene', (239, 243))	('treating tumours', 'Disease', (217, 233))	('MTAP', 'Gene', (37, 41))	('loss', 'Var', (29, 33))	('treating tumours', 'Disease', 'MESH:D019553', (217, 233))	('MTAP', 'Gene', '4507', (239, 243))	('MTAP', 'Gene', '4507', (37, 41))	('PRMT5', 'Gene', (135, 140))
242822	29263814	For affected individuals with large deletions involving CDKN2A and MTAP, such as our patient and the family described by Baker et al., the possibility of targeting this PRMT5 dependence raises potential for therapeutic strategies.	('patient', 'Species', '9606', (85, 92))	('deletions', 'Var', (36, 45))	('PRMT5', 'Gene', (169, 174))	('PRMT5', 'Gene', '10419', (169, 174))	('MTAP', 'Gene', (67, 71))	('MTAP', 'Gene', '4507', (67, 71))	('CDKN2A', 'Gene', (56, 62))
242823	29263814	Currently, not all clinical testing panels include the entire CDKN2A locus (encompassing both p14ARF and p16INK4A genes).	('p16INK4A', 'Var', (105, 113))	('CDKN2A', 'Gene', (62, 68))	('p14ARF', 'Gene', '1029', (94, 100))	('p14ARF', 'Gene', (94, 100))
242824	29263814	Our study suggests the importance of interrogating the full extent of this locus as alterations to p14ARF may account for a small subset of germline TP53 wild-type LFS/LFL cases and should be included in clinical testing gene panels.	('p14ARF', 'Gene', (99, 105))	('LFS', 'Disease', (164, 167))	('TP53', 'Gene', '7157', (149, 153))	('LFS', 'Disease', 'MESH:D016864', (164, 167))	('p14ARF', 'Gene', '1029', (99, 105))	('TP53', 'Gene', (149, 153))	('alterations', 'Var', (84, 95))
242825	29263814	In summary, our study highlights the contribution of CDKN2A germline deletion to cancer predisposition in LFS/LFL patients and expands the non-melanoma phenotypic spectrum of cancers associated with germline CDKN2A mutations.	('LFS', 'Disease', (106, 109))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', (81, 87))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('LFS', 'Disease', 'MESH:D016864', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('CDKN2A', 'Gene', (208, 214))	('mutations', 'Var', (215, 224))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('deletion', 'Var', (69, 77))	('cancers', 'Disease', (175, 182))	('patients', 'Species', '9606', (114, 122))	('contribution', 'Reg', (37, 49))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('CDKN2A', 'Gene', (53, 59))	('cancers', 'Disease', 'MESH:D009369', (175, 182))
242851	28121946	Laboratory examination showed the following results: alanine aminotransferase, 482.1 U/L (0~40 U/L); aspartate aminotransferase, 345.6 U/L (13~35 U/L); total bilirubin, 184.2 mumol/L (3.4~17.1 mumol/L); direct bilirubin, 149.6 mumol/L (0~6.8 mumol/L); and CA-199 >1200 kU/L (<37 kU/L).	('bilirubin', 'Chemical', 'MESH:D001663', (158, 167))	('aspartate', 'MPA', (101, 110))	('bilirubin', 'Chemical', 'MESH:D001663', (210, 219))	('alanine aminotransferase', 'Enzyme', (53, 77))	('CA-199 >1200 kU/L', 'Var', (256, 273))	('direct bilirubin', 'MPA', (203, 219))	('CA-199', 'Chemical', '-', (256, 262))
242889	28121946	Kim et al detected point mutation at the second exon of codon 12 on KRAS gene.	('KRAS', 'Gene', (68, 72))	('point mutation', 'Var', (19, 33))	('KRAS', 'Gene', '3845', (68, 72))
242967	32192573	Immune therapies have demonstrated promising activity, including chimeric antigen receptor modified T cells and blinatumomab in relapsed/refractory pediatric B-ALL and dinutuximab in high-risk neuroblastoma and when combined with chemotherapy in recurrent/refractory neuroblastoma.	('blinatumomab', 'Disease', (112, 124))	('neuroblastoma', 'Disease', 'MESH:D009447', (193, 206))	('dinutuximab', 'Chemical', 'MESH:C112746', (168, 179))	('neuroblastoma', 'Disease', 'MESH:D009447', (267, 280))	('neuroblastoma', 'Disease', (193, 206))	('neuroblastoma', 'Disease', (267, 280))	('blinatumomab', 'Disease', 'None', (112, 124))	('neuroblastoma', 'Phenotype', 'HP:0003006', (267, 280))	('neuroblastoma', 'Phenotype', 'HP:0003006', (193, 206))	('relapsed/refractory pediatric B-ALL', 'Disease', (128, 163))	('chimeric', 'Var', (65, 73))
242969	32192573	ICIs have demonstrated impressive benefit in numerous advanced cancers in adults (reviewed in) and can induce tumor regression in children with solid tumors associated with germline mismatch repair deficiency.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('ICIs', 'Disease', 'None', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('children', 'Species', '9606', (130, 138))	('tumors', 'Disease', (150, 156))	('benefit', 'PosReg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('deficiency', 'Disease', 'MESH:D007153', (198, 208))	('cancers', 'Disease', (63, 70))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ICIs', 'Disease', (0, 4))	('deficiency', 'Disease', (198, 208))	('tumor', 'Disease', (150, 155))	('germline', 'Var', (173, 181))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
242970	32192573	Nivolumab, a humanized IgG4 monoclonal PD-1 blocking antibody, administered administered every 2 weeks (240 mg or approximately 3 mg/kg) or every 4 weeks (480 mg or approximately 6 mg/kg) is FDA approved in adults and children older than 12 years of age with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colon cancer and as second line therapy in adults with advanced melanoma, renal cell carcinoma, urothelial carcinoma, hepatocellular carcinoma, metastatic squamous cell non-small cell lung cancer, head and neck cancer, and small cell lung cancer, and relapsed or progressed classical Hodgkin lymphoma.	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (630, 646))	('colon cancer', 'Disease', 'MESH:D015179', (346, 358))	('carcinoma', 'Phenotype', 'HP:0030731', (431, 440))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (515, 541))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('children', 'Species', '9606', (218, 226))	('melanoma, renal cell carcinoma', 'Disease', 'MESH:C538614', (410, 440))	('carcinoma', 'Phenotype', 'HP:0030731', (453, 462))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (464, 488))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (519, 541))	('squamous cell non-small cell lung cancer', 'Disease', (501, 541))	('head and neck cancer', 'Phenotype', 'HP:0012288', (543, 563))	('relapsed', 'Disease', (597, 605))	('cancer', 'Phenotype', 'HP:0002664', (557, 563))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (442, 462))	('small cell lung cancer', 'Disease', 'MESH:D055752', (569, 591))	('colon cancer', 'Disease', (346, 358))	('small cell lung cancer', 'Disease', (569, 591))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (464, 488))	('lung cancer', 'Phenotype', 'HP:0100526', (580, 591))	('melanoma', 'Phenotype', 'HP:0002861', (410, 418))	('urothelial carcinoma', 'Disease', (442, 462))	('cancer', 'Phenotype', 'HP:0002664', (585, 591))	('lung cancer', 'Phenotype', 'HP:0100526', (530, 541))	('head and neck cancer', 'Disease', 'MESH:D006258', (543, 563))	('deficient', 'Var', (318, 327))	('PD-1', 'Gene', (39, 43))	('small cell lung cancer', 'Disease', 'MESH:D055752', (519, 541))	('hepatocellular carcinoma', 'Disease', (464, 488))	('PD-1', 'Gene', '5133', (39, 43))	('colon cancer', 'Phenotype', 'HP:0003003', (346, 358))	('Hodgkin lymphoma', 'Gene', (630, 646))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (479, 488))	('lymphoma', 'Phenotype', 'HP:0002665', (638, 646))	('squamous cell non-small cell lung cancer', 'Disease', 'MESH:D002289', (501, 541))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (420, 440))	('Hodgkin lymphoma', 'Gene', '3990', (630, 646))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (569, 591))	('cancer', 'Phenotype', 'HP:0002664', (535, 541))
243053	32192573	For Part A, the weight adjusted Clp was 0.18 +- 0.09 ml/h/kg for males, 0.16 +- 0.05 ml/h/kg for females, 0.20 +- 0.08 ml/h/kg for patients <12 years old at enrollment and 0.15 +- 0.06 ml/h/kg for patients >=12 years old.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (197, 205))	('0.16', 'Var', (72, 76))	('Clp', 'Gene', '810', (32, 35))	('0.20 +- 0.08', 'Var', (106, 118))	('Clp', 'Gene', (32, 35))
243096	32192573	Anti-PD1 monotherapy was previously reported to demonstrate a 41% ORR in a Phase II trial in PMBCL.	('Anti-PD1', 'Gene', (0, 8))	('PMBCL', 'Chemical', '-', (93, 98))	('monotherapy', 'Var', (9, 20))
243102	32192573	Given the current concept that response to PD-1/PD-L1 blockade in non-lymphoma tumors reflects reinvigoration of T cells recognizing neoantigens derived from tumor mutations, the absence of response may reflect the relatively low mutational burden in sporadic pediatric solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('PD-1/PD-L1 blockade in non-lymphoma tumors', 'Disease', 'MESH:D010300', (43, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', (276, 282))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (276, 281))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('PD-1/PD-L1 blockade in non-lymphoma tumors', 'Disease', (43, 85))	('mutations', 'Var', (164, 173))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('lymphoma', 'Phenotype', 'HP:0002665', (70, 78))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
243103	32192573	Our study did not assess tumor mutational burden limiting assessment of its impact in the pediatric tumors studied here although prior studies have demonstrated only ~5% of sporadic pediatric solid tumors are classified as "hypermutant", as defined by more than 10 mutations/mB, a minimum level that has been suggested to be associated with response to ICI.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations/mB', 'Var', (265, 277))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
243104	32192573	Of note, children with hypermutant tumors associated with germline mutations in mismatch repair genes show significant responses to PD-1 blockade, providing evidence that pediatric patients are capable of mounting PD-1 induced antitumor effects in the presence of adequate antigen to drive T cell responses.	('PD-1', 'Gene', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('PD-1', 'Gene', '5133', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('children', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (231, 236))	('PD-1', 'Gene', (132, 136))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('germline mutations', 'Var', (58, 76))	('patients', 'Species', '9606', (181, 189))	('PD-1', 'Gene', '5133', (132, 136))	('mismatch repair genes', 'Gene', (80, 101))
243105	32192573	Future studies are needed to determine whether selected cohorts of children with hypermutant sporadic solid tumors would demonstrate clinical benefit following PD-1 blockade.	('hypermutant', 'Var', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', (108, 114))	('children', 'Species', '9606', (67, 75))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('PD-1', 'Gene', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('PD-1', 'Gene', '5133', (160, 164))
243108	32192573	Future studies evaluating nivolumab, or other PD-1/PD-L1 blockers, alone or in combination with other immunomodulators, may be warranted in selected populations of patients with pediatric solid tumors whose tumors manifest higher mutational burden and/or other biomarkers that provide evidence for increased tumor immunogenicity.	('tumors whose tumors', 'Disease', 'MESH:D009369', (194, 213))	('nivolumab', 'Chemical', 'MESH:D000077594', (26, 35))	('PD-L1', 'Gene', '29126', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('patients', 'Species', '9606', (164, 172))	('tumors whose tumors', 'Disease', (194, 213))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('PD-1', 'Gene', (46, 50))	('tumor', 'Disease', (207, 212))	('PD-1', 'Gene', '5133', (46, 50))	('tumor', 'Disease', (308, 313))	('mutational', 'Var', (230, 240))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('PD-L1', 'Gene', (51, 56))
243121	31686910	Antibiotic therapy augments the efficacy of gemcitabine-containing regimens for advanced cancer: a retrospective study The addition of antibiotics reportedly augments the efficacy of gemcitabine (GEM) in tumor-bearing mice.	('GEM', 'Chemical', 'MESH:C056507', (196, 199))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('antibiotics', 'Var', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('augments', 'NegReg', (158, 166))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('efficacy', 'MPA', (171, 179))	('tumor', 'Disease', (204, 209))	('cancer', 'Disease', (89, 95))	('gemcitabine', 'Chemical', 'MESH:C056507', (183, 194))	('mice', 'Species', '10090', (218, 222))	('gemcitabine', 'Chemical', 'MESH:C056507', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
243158	31686910	In all cancer types, both the median PFS and the median OS of antibiotics-treated group were longer than these of antibiotics-untreated group.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('PFS', 'CPA', (37, 40))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('antibiotics-treated', 'Var', (62, 81))	('longer', 'PosReg', (93, 99))
243159	31686910	Especially, in pancreatic cancer, both the median PFS and the median OS of the antibiotics-treated group were significantly longer than those of the antibiotics-untreated group.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('pancreatic cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('antibiotics-treated', 'Var', (79, 98))	('longer', 'PosReg', (124, 130))	('PFS', 'MPA', (50, 53))
243173	31686910	In all cancer type in this study, there had been tendency that both the median PFS and the median OS in the antibiotics-treated group were longer than these of antibiotics-untreated group.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('antibiotics-treated', 'Var', (108, 127))	('longer', 'PosReg', (139, 145))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
243182	31686910	Alteration of gut microbiota by antibiotics influenced the efficacies and toxicities of irinotecan as irinotecan metabolism was affected by bacteria in mice gut Antibiotic treatment might change the gut microbiota in patients in the present study and might influence the metabolism of GEM by the bacteria in the gut similar to that in a previous report These changes might elevate the blood concentration of GEM, resulting in higher toxicities with GEM-containing regimen in the antibiotics-treated group.	('toxicities', 'Disease', (433, 443))	('elevate', 'PosReg', (373, 380))	('GEM', 'Chemical', 'MESH:C056507', (449, 452))	('GEM', 'Chemical', 'MESH:C056507', (408, 411))	('toxicities', 'Disease', 'MESH:D064420', (74, 84))	('change', 'Reg', (188, 194))	('higher', 'PosReg', (426, 432))	('toxicities', 'Disease', (74, 84))	('irinotecan', 'Chemical', 'MESH:C051890', (102, 112))	('metabolism', 'MPA', (271, 281))	('blood concentration of', 'MPA', (385, 407))	('gut microbiota', 'MPA', (199, 213))	('affected', 'Reg', (128, 136))	('mice', 'Species', '10090', (152, 156))	('patients', 'Species', '9606', (217, 225))	('changes', 'Var', (359, 366))	('GEM', 'Chemical', 'MESH:C056507', (285, 288))	('irinotecan', 'Chemical', 'MESH:C051890', (88, 98))	('toxicities', 'Disease', 'MESH:D064420', (433, 443))	('influence', 'Reg', (257, 266))
243197	31686910	It has been reported that the dysregulation of proteins participating in GEM metabolism pathway or the high expression of GEM efflux pump is the mechanisms responsible for GEM resistance.	('GEM efflux pump', 'Gene', (122, 137))	('high expression', 'MPA', (103, 118))	('dysregulation', 'Var', (30, 43))	('GEM', 'Chemical', 'MESH:C056507', (73, 76))	('GEM', 'Pathway', (73, 76))	('GEM', 'Chemical', 'MESH:C056507', (172, 175))	('GEM', 'Chemical', 'MESH:C056507', (122, 125))	('proteins', 'Protein', (47, 55))
243198	31686910	Moreover, it was also reported that BRCA1 associated protein 1 gene (BAP1) mutation is responsible for the sensitivity of GEM in patients with malignant mesothelioma.	('BAP1', 'Gene', '8314', (69, 73))	('BRCA1 associated protein 1', 'Gene', (36, 62))	('patients', 'Species', '9606', (129, 137))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (143, 165))	('BAP1', 'Gene', (69, 73))	('mutation', 'Var', (75, 83))	('BRCA1 associated protein 1', 'Gene', '8314', (36, 62))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (143, 165))	('GEM', 'Chemical', 'MESH:C056507', (122, 125))	('malignant mesothelioma', 'Disease', (143, 165))	('responsible', 'Reg', (87, 98))
243213	30614191	Much of the early success of ctDNA evaluation in adult malignancies focused on the identification of highly-recurrent hotspot mutations in oncogenes such as EGFR or KRAS, including polymerase chain reaction (PCR)-based assays that have gained regulatory approval in the United States and Europe.	('EGFR', 'Gene', (157, 161))	('hotspot', 'PosReg', (118, 125))	('KRAS', 'Gene', '3845', (165, 169))	('EGFR', 'Gene', '1956', (157, 161))	('malignancies', 'Disease', 'MESH:D009369', (55, 67))	('mutations', 'Var', (126, 135))	('malignancies', 'Disease', (55, 67))	('KRAS', 'Gene', (165, 169))
243214	30614191	Such recurrent single nucleotide variants (SNVs) are rare in pediatric malignancies.	('pediatric malignancies', 'Disease', (61, 83))	('single nucleotide variants', 'Var', (15, 41))	('pediatric malignancies', 'Disease', 'MESH:D063766', (61, 83))
243215	30614191	Instead, pediatric tumors are more commonly characterized by recurrent copy-number changes and translocations.	('pediatric tumors', 'Disease', 'MESH:D063766', (9, 25))	('pediatric tumors', 'Disease', (9, 25))	('characterized', 'Reg', (44, 57))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('copy-number changes', 'Var', (71, 90))	('translocations', 'Var', (95, 109))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
243225	30614191	Circulating tumor DNA can be detected and quantified by measuring the presence of somatic events, including SNVs, insertion/deletions (indels), copy-number changes, translocations, and methylation patterns that differentiate tumor DNA from cell-free DNA originating from normal cells.	('translocations', 'Var', (165, 179))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('insertion/deletions', 'Var', (114, 133))	('methylation', 'Var', (185, 196))	('copy-number changes', 'Var', (144, 163))	('tumor', 'Disease', (12, 17))
243228	30614191	In the late 1990s, it was shown that ctDNA microsatellites could be detected by PCR in patients with head and neck cancer.	('neck cancer', 'Disease', 'MESH:D006258', (110, 121))	('neck cancer', 'Disease', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('head and neck cancer', 'Phenotype', 'HP:0012288', (101, 121))	('microsatellites', 'Var', (43, 58))	('patients', 'Species', '9606', (87, 95))
243229	30614191	Since then, many studies have focused on using PCR to detect highly recurrent hotspot mutations in genes such as TP53, EGFR or BRAF (Fig.	('mutations', 'Var', (86, 95))	('BRAF', 'Gene', '673', (127, 131))	('BRAF', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (113, 117))	('EGFR', 'Gene', '1956', (119, 123))	('TP53', 'Gene', (113, 117))	('EGFR', 'Gene', (119, 123))
243230	30614191	PCR can also be adapted to the detection of structural variants which are more common in pediatric malignancies, such as copy-number alterations (i.e.	('pediatric malignancies', 'Disease', (89, 111))	('pediatric malignancies', 'Disease', 'MESH:D063766', (89, 111))	('copy-number alterations', 'Var', (121, 144))
243234	30614191	This mono-allelic fraction may not be an accurate estimate for the total abundance of ctDNA when the targeted region is affected by copy-number alterations, especially when the magnitude of those events is heterogeneous in the tumor (Table 1).	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('copy-number alterations', 'Var', (132, 155))	('tumor', 'Disease', (227, 232))
243235	30614191	For example, recurrent mutations in driver oncogenes, such as oncogenic EGFR mutations in patients with lung cancer, can be detected and monitored by NGS while also having the capacity to identify previously unknown or uncommon variants in this gene (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('EGFR', 'Gene', '1956', (72, 76))	('lung cancer', 'Disease', (104, 115))	('EGFR', 'Gene', (72, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('mutations', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('patients', 'Species', '9606', (90, 98))
243237	30614191	Next-generation sequencing can also be utilized to detect chromosomal copy-number alterations in ctDNA, a key feature of many pediatric malignancies (Fig.	('pediatric malignancies', 'Disease', 'MESH:D063766', (126, 148))	('pediatric malignancies', 'Disease', (126, 148))	('ctDNA', 'Disease', (97, 102))	('chromosomal copy-number alterations', 'Var', (58, 93))
243238	30614191	Economical shallow WGS, with a coverage of 0.1x and a turnaround time of 2 days, was first used to identify ctDNA in prostate cancer by detecting copy-number changes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('copy-number changes', 'Var', (146, 165))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('detecting', 'Reg', (136, 145))	('prostate cancer', 'Disease', (117, 132))
243243	30614191	High-throughput NGS can also be used for translocation detection in pediatric cancer.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pediatric cancer', 'Disease', 'MESH:D009369', (68, 84))	('pediatric cancer', 'Disease', (68, 84))	('translocation', 'Var', (41, 54))
243244	30614191	Translocations typically occur in introns that frequently span greater than 1,000 to 100,000 bases, with unique DNA break-points seen in each patient.	('patient', 'Species', '9606', (142, 149))	('Translocations', 'Var', (0, 14))	('occur', 'Reg', (25, 30))
243250	30614191	This approach efficiently identifies copy-number events in samples with a high fraction of tumor DNA (>= 3%) at a relatively low cost but is unable to identify specific base-pair substitutions, focal copy-number events, or translocations.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('copy-number', 'Var', (37, 48))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
243256	30614191	For example, studies have demonstrated the feasibility of detecting MYCN amplification in the peripheral blood of patients with neuroblastoma using real-time PCR with a sensitivity of 75-100% and specificity of 100%.	('neuroblastoma', 'Disease', 'MESH:D009447', (128, 141))	('neuroblastoma', 'Disease', (128, 141))	('amplification', 'Var', (73, 86))	('neuroblastoma', 'Phenotype', 'HP:0003006', (128, 141))	('patients', 'Species', '9606', (114, 122))	('MYCN', 'Gene', (68, 72))	('MYCN', 'Gene', '4613', (68, 72))
243258	30614191	Proof of concept studies found a correlation between plasma dPCR and tumor genomic analysis for detection of MYCN amplification, ALK amplification, and ALK hotspot mutations in neuroblastoma.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('amplification', 'Var', (114, 127))	('ALK', 'Gene', (129, 132))	('neuroblastoma', 'Disease', 'MESH:D009447', (177, 190))	('tumor', 'Disease', (69, 74))	('ALK', 'Gene', '238', (152, 155))	('neuroblastoma', 'Disease', (177, 190))	('ALK', 'Gene', '238', (129, 132))	('MYCN', 'Gene', (109, 113))	('neuroblastoma', 'Phenotype', 'HP:0003006', (177, 190))	('mutations', 'Var', (164, 173))	('ALK', 'Gene', (152, 155))	('MYCN', 'Gene', '4613', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
243259	30614191	NGS assays have also been utilized to detect variants associated with a worse outcome, including TP53 mutations and STAG2 loss in Ewing sarcoma, 8q gain in osteosarcoma, MYCN amplification in neuroblastoma, 1q gain in Wilms tumor, and PAX3 gene rearrangements in alveolar rhabdomyosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('TP53', 'Gene', '7157', (97, 101))	('gain', 'PosReg', (210, 214))	('Wilms tumor', 'Disease', 'MESH:D009396', (218, 229))	('rearrangements', 'Var', (245, 259))	('osteosarcoma', 'Disease', (156, 168))	('neuroblastoma', 'Disease', (192, 205))	('osteosarcoma', 'Disease', 'MESH:D012516', (156, 168))	('neuroblastoma', 'Phenotype', 'HP:0003006', (192, 205))	('Ewing sarcoma', 'Disease', (130, 143))	('PAX3', 'Gene', (235, 239))	('Wilms tumor', 'Phenotype', 'HP:0002667', (218, 229))	('alveolar rhabdomyosarcoma', 'Disease', (263, 288))	('mutations', 'Var', (102, 111))	('MYCN', 'Gene', (170, 174))	('neuroblastoma', 'Disease', 'MESH:D009447', (192, 205))	('loss', 'NegReg', (122, 126))	('STAG2', 'Gene', '10735', (116, 121))	('PAX3', 'Gene', '5077', (235, 239))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (272, 288))	('TP53', 'Gene', (97, 101))	('Wilms tumor', 'Disease', (218, 229))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (263, 288))	('STAG2', 'Gene', (116, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (156, 168))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (263, 288))	('variants', 'Var', (45, 53))	('gain', 'PosReg', (148, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (130, 143))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (130, 143))	('MYCN', 'Gene', '4613', (170, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))
243268	30614191	The authors demonstrated that MYCN levels remained elevated in patients with sub-total resections, but returned to baseline levels in patients with complete resections.	('MYCN', 'Gene', (30, 34))	('MYCN', 'Gene', '4613', (30, 34))	('sub-total resections', 'Var', (77, 97))	('patients', 'Species', '9606', (134, 142))	('elevated', 'PosReg', (51, 59))	('patients', 'Species', '9606', (63, 71))
243280	30614191	While the majority of copy-number alterations were present in primary, metastatic, and ctDNA samples, copy-number events that were specific for metastatic samples, such as NOTCH2, AKT2 and AKT3, were also observed in the plasma samples obtained at the time of relapse.	('AKT3', 'Gene', '10000', (189, 193))	('NOTCH2', 'Gene', (172, 178))	('AKT2', 'Gene', (180, 184))	('AKT2', 'Gene', '208', (180, 184))	('NOTCH2', 'Gene', '4853', (172, 178))	('copy-number', 'Var', (22, 33))	('AKT3', 'Gene', (189, 193))
243289	30614191	For example, NGS may be able to identify pathognomonic translocations in the plasma of patients with an undiagnosed tumor, however, clinical sequencing cannot currently be performed quickly enough for diagnostic purposes.	('translocations', 'Var', (55, 69))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
243303	30614191	As novel therapies become available for use in pediatric cancers, ctDNA may facilitate the identification of targetable mutations that direct the selection of specific agents and may also allow the detection of resistance mutations for patients undergoing targeted therapy.	('pediatric cancers', 'Disease', (47, 64))	('pediatric cancers', 'Disease', 'MESH:D009369', (47, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('patients', 'Species', '9606', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))
243307	30614191	ctDNA Circulating tumor DNA PCR Polymerase chain reaction SNVs Single nucleotide variants MRD minimal residual disease assays Indels insertion/deletions NGS next-generation sequencing dPCR digital PCR WGS whole-genome sequencing ULP-WGS ultra-low passage WGS	('insertion/deletions', 'Var', (133, 152))	('tumor', 'Disease', (18, 23))	('Indels', 'Var', (126, 132))	('MRD', 'Disease', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('MRD', 'Disease', 'None', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
243406	26034481	One pair of signals split apart due to rearrangement of the EWSR1 gene was detected (fig.	('EWSR1', 'Gene', '2130', (60, 65))	('EWSR1', 'Gene', (60, 65))	('rearrangement', 'Var', (39, 52))
243411	26034481	Histopathological tests of the resected tumor showed positivity for PDGFR (fig.	('PDGFR', 'Gene', '5159', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('PDGFR', 'Gene', (68, 73))	('positivity', 'Var', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
243421	26034481	In this case, one pair of signals split apart due to rearrangement of the EWSR1 gene was detected, suggesting the diagnosis of this tumor in ESFT.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('EWSR1', 'Gene', (74, 79))	('tumor', 'Disease', (132, 137))	('EWSR1', 'Gene', '2130', (74, 79))	('rearrangement', 'Var', (53, 66))
243438	24649216	Genetic profiling efforts have identified amplification, overexpression and mutation, while the molecular mechanisms of tumorigenesis driven by these genomic and genetic aberrations have yet to be fully elucidated yet.	('overexpression', 'PosReg', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('amplification', 'Var', (42, 55))	('mutation', 'Var', (76, 84))	('tumor', 'Disease', (120, 125))
243440	24649216	In conclusion, aberrations of cell cycle control would be a critical step in the development of uterine sarcoma.	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('aberrations', 'Var', (15, 26))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (96, 111))	('aberrations of cell cycle', 'Phenotype', 'HP:0011018', (15, 40))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))
243460	24649216	In general, amplification of c-myc correlates with distant metastases and is a factor of poor prognosis.	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('amplification', 'Var', (12, 25))	('c-myc', 'Gene', '4609', (29, 34))	('c-myc', 'Gene', (29, 34))	('metastases', 'Disease', (59, 69))
243465	24649216	Overexpression of specific genes, including transforming growth factor (TGF)-beta, retinoblastoma (Rb), p53, HER-2 (also known as ERBB2, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2), vascular endothelial growth factor (VEGF), estrogen receptor (ER), progesterone receptor (PR), cancer-testis-associated antigens (CATs), beta-catenin, B-cell CLL/lymphoma 2 (BCL-2), cyclooxygenase (COX)-2, p16INK4a (CDKN2A, cyclin-dependent kinase inhibitor 2A), phosphatase and tensin homolog (PTEN) and vimentin, has been detected in several cases (Table I).	('beta-catenin', 'Gene', (334, 346))	('cyclooxygenase (COX)-2', 'Gene', '807936', (379, 401))	('p53', 'Gene', '7157', (104, 107))	('Rb', 'Gene', '5925', (99, 101))	('cancer-testis-associated antigens (CATs)', 'Gene', '54478', (292, 332))	('beta-catenin', 'Gene', '1499', (334, 346))	('TGF', 'Gene', (72, 75))	('B-cell CLL/lymphoma', 'Phenotype', 'HP:0012191', (348, 367))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '101089220', (421, 457))	('lymphoma', 'Phenotype', 'HP:0002665', (359, 367))	('p53', 'Gene', (104, 107))	('vascular endothelial growth factor', 'Gene', '493845', (197, 231))	('vimentin', 'Gene', '101091951', (502, 510))	('Rb', 'Phenotype', 'HP:0009919', (99, 101))	('vimentin', 'Gene', (502, 510))	('TGF', 'Gene', '7040;7043', (72, 75))	('retinoblastoma', 'Phenotype', 'HP:0009919', (83, 97))	('p16INK4a', 'Var', (403, 411))	('cancer-testis-associated antigens (CATs', 'Gene', (292, 331))	('retinoblastoma', 'Disease', (83, 97))	('vascular endothelial growth factor', 'Gene', (197, 231))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (421, 457))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('estrogen receptor', 'Gene', (240, 257))	('ERBB2', 'Gene', '751824', (130, 135))	('B-cell CLL/lymphoma 2', 'Gene', (348, 369))	('estrogen receptor', 'Gene', '552888', (240, 257))	('erb', 'Gene', (139, 142))	('erb', 'Gene', '2100', (139, 142))	('leukemia', 'Phenotype', 'HP:0001909', (161, 169))	('erythroblastic leukemia viral', 'Disease', (146, 175))	('cyclooxygenase (COX)-2', 'Gene', (379, 401))	('ERBB2', 'Gene', (130, 135))	('B-cell CLL/lymphoma 2', 'Gene', '493934', (348, 369))	('b2 erythroblastic leukemia', 'Phenotype', 'HP:0004812', (143, 169))	('erythroblastic leukemia viral', 'Disease', 'MESH:D004915', (146, 175))	('retinoblastoma', 'Disease', 'MESH:D012175', (83, 97))
243480	24649216	Mutations of these genes have been identified as biomarkers against the treatment of certain carcinomas with small molecule inhibitors or monoclonal antibodies to the specific growth factor receptor.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('carcinomas', 'Disease', (93, 103))	('carcinomas', 'Disease', 'MESH:D002277', (93, 103))	('Mutations', 'Var', (0, 9))
243511	24649216	Loss of heterozygosity (LOH), amplification, overexpression and mutations may contribute to the risk of leiomyosarcoma development (Tables I and II).	('leiomyosarcoma development', 'Disease', (104, 130))	('Loss of heterozygosity', 'Var', (0, 22))	('amplification', 'Var', (30, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('mutations', 'Var', (64, 73))	('overexpression', 'PosReg', (45, 59))	('leiomyosarcoma development', 'Disease', 'MESH:D007890', (104, 130))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (104, 118))
243512	24649216	LOH on chromosome 10 occurred more frequently in leiomyosarcoma compared to leiomyoma and may contribute to sarcomagenesis.	('leiomyoma', 'Disease', (76, 85))	('sarcoma', 'Disease', (108, 115))	('sarcoma', 'Disease', (56, 63))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (49, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('LOH on chromosome', 'Var', (0, 17))	('leiomyoma', 'Disease', 'MESH:D007889', (76, 85))	('leiomyosarcoma', 'Disease', (49, 63))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (49, 63))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('contribute', 'Reg', (94, 104))
243515	24649216	Mutation of p53 was observed in 24% of leiomyosarcoma cases.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (39, 53))	('Mutation', 'Var', (0, 8))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (39, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('observed', 'Reg', (20, 28))	('leiomyosarcoma', 'Disease', (39, 53))
243533	24649216	Since BRCA1, a well-known tumor suppressor gene, plays a role in maintaining genomic stability, loss of BRCA1 function potentially is involved in the progression of leiomyosarcoma.	('BRCA1', 'Gene', (6, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('loss', 'Var', (96, 100))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (165, 179))	('BRCA1', 'Gene', '672', (104, 109))	('involved', 'Reg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('function', 'MPA', (110, 118))	('BRCA1', 'Gene', (104, 109))	('leiomyosarcoma', 'Disease', (165, 179))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (165, 179))	('tumor', 'Disease', (26, 31))	('BRCA1', 'Gene', '672', (6, 11))
243534	24649216	Frequent mutations of the MED12 gene were identified in 70% of leiomyosarcoma.	('identified', 'Reg', (42, 52))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (63, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('MED12', 'Gene', (26, 31))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (63, 77))	('mutations', 'Var', (9, 18))	('MED12', 'Gene', '9968', (26, 31))	('leiomyosarcoma', 'Disease', (63, 77))
243538	24649216	Mice with homozygous LMP2 deletion spontaneously developed uterine leiomyosarcoma.	('leiomyosarcoma', 'Disease', (67, 81))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (67, 81))	('LMP2', 'Gene', (21, 25))	('deletion', 'Var', (26, 34))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (67, 81))	('developed', 'Reg', (49, 58))	('Mice', 'Species', '10090', (0, 4))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
243563	24649216	Immunohistochemical study using a well-characterized panel of antibodies to p16, p53 and Ki-67 could pose a challenge, while it may be helpful in distinguishing STUMP from usual leiomyoma and leiomyosarcoma cases (Tables I and III).	('Ki-67', 'Gene', (89, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('leiomyoma and leiomyosarcoma', 'Disease', 'MESH:D007890', (178, 206))	('p16', 'Var', (76, 79))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))	('usual leiomyoma', 'Phenotype', 'HP:0007620', (172, 187))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (192, 206))
243567	24649216	A subset of STUMP characterized by strong, diffuse p16 positivity contains the morphological changes of coagulative tumor cell necrosis.	('coagulative tumor cell necrosis', 'Disease', (104, 135))	('p16 positivity', 'Var', (51, 65))	('positivity', 'Var', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('coagulative tumor cell necrosis', 'Disease', 'MESH:D025861', (104, 135))
243569	24649216	It may be possible to discern meaningful subsets of the STUMP patients with a malignant potential by using p16, p21 and p53 immunostaining.	('p53', 'Gene', '7157', (120, 123))	('p16', 'Var', (107, 110))	('p21', 'Gene', '1026', (112, 115))	('p53', 'Gene', (120, 123))	('patients', 'Species', '9606', (62, 70))	('p21', 'Gene', (112, 115))
243570	24649216	p16 is a cyclin-dependent kinase inhibitor (CDKI) that reduces cell cycle progression.	('p16', 'Var', (0, 3))	('CDKI', 'Gene', '1033', (44, 48))	('cyclin-dependent kinase inhibitor', 'Gene', (9, 42))	('CDKI', 'Gene', (44, 48))	('cell cycle progression', 'CPA', (63, 85))	('reduces', 'NegReg', (55, 62))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (9, 42))
243572	24649216	Although limited, p16, p21 and p53 may serve as useful markers in the assessment of problematic uterine smooth muscle tumors.	('p53', 'Gene', '7157', (31, 34))	('p53', 'Gene', (31, 34))	('p16', 'Var', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('muscle tumors', 'Disease', 'MESH:D009217', (111, 124))	('problematic uterine smooth muscle tumors', 'Phenotype', 'HP:0000131', (84, 124))	('muscle tumors', 'Disease', (111, 124))	('p21', 'Gene', '1026', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('p21', 'Gene', (23, 26))
243592	24649216	Recent genome-wide studies have identified complex chromosomal rearrangements as a sarcomagenic mechanism (Table I).	('complex chromosomal rearrangements', 'Var', (43, 77))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma', 'Disease', (83, 90))
243595	24649216	In addition, the 14-3-3 fusion oncogene rearrangements resulting from t(10;17) fusion transcripts were specific for undifferentiated endometrial stroma.	('endometrial stroma', 'Disease', (133, 151))	('t(10;17', 'Gene', (70, 77))	('endometrial stroma', 'Disease', 'MESH:D014591', (133, 151))	('fusion transcripts', 'Var', (79, 97))
243609	24649216	By contrast, adenosarcoma with sarcomatous overgrowth had a WT1 (+), Ki-67 (+) and p53 (+) immunophenotype.	('WT1', 'Gene', (60, 63))	('overgrowth', 'Phenotype', 'HP:0001548', (43, 53))	('sarcomatous overgrowth', 'Disease', 'MESH:D018316', (31, 53))	('p53', 'Gene', (83, 86))	('adenosarcoma', 'Disease', (13, 25))	('Ki-67', 'Var', (69, 74))	('adenosarcoma', 'Disease', 'MESH:D018195', (13, 25))	('p53', 'Gene', '7157', (83, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('sarcomatous overgrowth', 'Disease', (31, 53))	('WT1', 'Gene', '7490', (60, 63))
243614	24649216	In addition, HMGA1a transgenic mice developed aggressive uterine tumors resembling human uterine adenosarcoma.	('aggressive uterine tumors', 'Disease', 'MESH:D014594', (46, 71))	('aggressive uterine tumors', 'Disease', (46, 71))	('transgenic mice', 'Species', '10090', (20, 35))	('human', 'Species', '9606', (83, 88))	('uterine tumors', 'Phenotype', 'HP:0010784', (57, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('HMGA1a', 'Gene', (13, 19))	('transgenic', 'Var', (20, 30))	('adenosarcoma', 'Disease', (97, 109))	('adenosarcoma', 'Disease', 'MESH:D018195', (97, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
243626	24649216	In addition, p16 and p53 may have an oncogenic function due to the promotion of cell cycle regulation.	('promotion', 'PosReg', (67, 76))	('p53', 'Gene', (21, 24))	('p16', 'Var', (13, 16))	('p53', 'Gene', '7157', (21, 24))	('cell cycle regulation', 'CPA', (80, 101))
243627	24649216	These findings suggest that changes in the TGF-beta pathway as well as alterations in cell cycle regulation may be essential for the establishment and maintenance of the phenotypic characteristics of uterine carcinosarcoma.	('carcinosarcoma', 'Disease', (208, 222))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (200, 222))	('alterations', 'Reg', (71, 82))	('TGF-beta pathway', 'Pathway', (43, 59))	('carcinosarcoma', 'Disease', 'MESH:D002296', (208, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('changes', 'Var', (28, 35))	('cell', 'MPA', (86, 90))
243628	24649216	A diagnosis of uterine leiomyosarcoma is performed when 2/3 morphological criteria are met, such as coagulative tumor cell necrosis, diffuse cytological atypia, and mitotic index >10 MFs/10 HPFs.	('coagulative tumor cell necrosis', 'Disease', (100, 131))	('leiomyosarcoma', 'Disease', (23, 37))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (15, 37))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (23, 37))	('mitotic index', 'CPA', (165, 178))	('>10 MFs/10', 'Var', (179, 189))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (23, 37))	('coagulative tumor cell necrosis', 'Disease', 'MESH:D025861', (100, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
243630	24649216	Ki-67, p53, p16 and p21 were strongly expressed in leiomyosarcoma and a moderate expression of PTEN, FSCN1, ER, PR and MIB1 was also present (Tables I-III).	('MIB1', 'Gene', '57534', (119, 123))	('p21', 'Gene', (20, 23))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (51, 65))	('p21', 'Gene', '1026', (20, 23))	('p53', 'Gene', '7157', (7, 10))	('MIB1', 'Gene', (119, 123))	('FSCN1', 'Gene', (101, 106))	('p16', 'Var', (12, 15))	('PTEN', 'Gene', (95, 99))	('FSCN1', 'Gene', '6624', (101, 106))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (51, 65))	('leiomyosarcoma', 'Disease', (51, 65))	('p53', 'Gene', (7, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
243631	24649216	In experimental knockout models, the deficiency or germline mutation in the target genes such as LMP2 caused alterations in the expression of various genes associated with leiomyosarcomagenesis.	('germline mutation', 'Var', (51, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('deficiency', 'Disease', (37, 47))	('alterations', 'Reg', (109, 120))	('leiomyosarcomagenesis', 'Disease', 'None', (172, 193))	('leiomyosarcomagenesis', 'Disease', (172, 193))	('LMP2', 'Gene', (97, 101))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (172, 186))	('expression', 'MPA', (128, 138))	('deficiency', 'Disease', 'MESH:D007153', (37, 47))
243632	24649216	p16 and p53 pathway abnormalities were associated with cell cycle regulation.	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (8, 11))	('cell cycle regulation', 'CPA', (55, 76))	('associated', 'Reg', (39, 49))	('abnormalities', 'Var', (20, 33))
243636	24649216	Limited data are available regarding whether there was a significant difference in the expression and localization of p16, p21, p53 and Ki-67 between leiomyosarcoma and STUMP, as well as STUMP and usual leiomyoma (Tables I and III).	('Ki-67', 'Gene', (136, 141))	('usual leiomyoma', 'Phenotype', 'HP:0007620', (197, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('leiomyoma', 'Disease', 'MESH:D007889', (203, 212))	('leiomyosarcoma', 'Disease', (150, 164))	('p16', 'Var', (118, 121))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (150, 164))	('p21', 'Gene', '1026', (123, 126))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (150, 164))	('leiomyoma', 'Disease', (203, 212))	('p21', 'Gene', (123, 126))
243640	24649216	Chromosomal rearrangements that encode a tumor-specific chimeric oncogenic fusion protein appear to be critical events in the carcinogenesis of certain leukemias and solid carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('leukemias', 'Disease', (152, 161))	('tumor', 'Disease', (41, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('solid carcinomas', 'Disease', 'MESH:D018250', (166, 182))	('carcinogenesis', 'Disease', (126, 140))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('leukemias', 'Disease', 'MESH:D007938', (152, 161))	('solid carcinomas', 'Disease', (166, 182))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('leukemias', 'Phenotype', 'HP:0001909', (152, 161))	('Chromosomal rearrangements', 'Var', (0, 26))
243641	24649216	Previous genome-wide studies have identified complex chromosomal rearrangements in ESS, including JAZF1 (low-grade morphology) and 14-3-3 (YWHAE, undifferentiated morphology), as an oncogenic mechanism.	('JAZF1', 'Gene', (98, 103))	('ESS', 'Gene', (83, 86))	('YWHAE', 'Gene', '7531', (139, 144))	('JAZF1', 'Gene', '221895', (98, 103))	('chromosomal rearrangements', 'Var', (53, 79))	('YWHAE', 'Gene', (139, 144))
243644	24649216	Clinicopathological features including morphological criteria and clinical outcome appeared to correlate with immunohistochemical profiles, including Ki-67, p53, WT1 and CD10.	('Ki-67', 'Var', (150, 155))	('p53', 'Gene', '7157', (157, 160))	('CD10', 'Gene', (170, 174))	('CD10', 'Gene', '4311', (170, 174))	('WT1', 'Gene', '7490', (162, 165))	('WT1', 'Gene', (162, 165))	('p53', 'Gene', (157, 160))
243712	30388821	In Ferrari, overall response was 56% in patients receiving Dox or epirubicin+Ifo compared to 31% in patients treated with "other" chemotherapy as any line of treatment.	('Dox', 'Chemical', 'MESH:D004317', (59, 62))	('Dox', 'Var', (59, 62))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (100, 108))	('Ifo', 'Chemical', '-', (77, 80))	('epirubicin+Ifo', 'Var', (66, 80))	('epirubicin', 'Chemical', 'MESH:D015251', (66, 76))
243738	30388821	A retrospective review of advanced SS patients using RECIST found Dox + Ifo achieved responses at a higher rate compared to single agent doxorubicin or ifosfamide; however these results may have been confounded by the use of metastectomies.	('Dox', 'Var', (66, 69))	('ifosfamide', 'Chemical', 'MESH:D007069', (152, 162))	('doxorubicin', 'Chemical', 'MESH:D004317', (137, 148))	('advanced SS', 'Disease', (26, 37))	('Ifo', 'Chemical', '-', (72, 75))	('SS', 'Phenotype', 'HP:0012570', (35, 37))	('patients', 'Species', '9606', (38, 46))	('responses', 'MPA', (85, 94))	('Dox', 'Chemical', 'MESH:D004317', (66, 69))
243758	30388821	However, factors associated with receipt of adjuvant chemotherapy were age <30, primary extremity site, grade 3 histology, tumor size >5cm and positive surgical margins.	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('grade 3 histology', 'Var', (104, 121))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))
243762	30388821	Areas of future research cover a broad range of treatments including targeted therapies e.g., NY-ESO-1-directed therapies, tyrosine kinase inhibitors, Adoptive Cell therapies, epigenetics e.g., HDAC and EZH2 inhibitors, chromatin remodeling and metabolic pathways.	('chromatin', 'Pathway', (220, 229))	('EZH2', 'Gene', '2146', (203, 207))	('NY-ESO-1', 'Gene', '246100', (94, 102))	('NY-ESO-1', 'Gene', (94, 102))	('metabolic pathways', 'Pathway', (245, 263))	('EZH2', 'Gene', (203, 207))	('epigenetics', 'Var', (176, 187))
243829	21217773	Upon knockdown of EWS-FLI1, hsa-mir-145 expression dramatically increases in all Ewing's sarcoma cell lines tested.	('expression', 'MPA', (40, 50))	('knockdown', 'Var', (5, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (81, 96))	('hsa-mir-145', 'Gene', (28, 39))	('hsa-mir-145', 'Gene', '406937', (28, 39))	("Ewing's sarcoma", 'Disease', (81, 96))	('EWS-FLI1', 'Gene', '2130;2313', (18, 26))	('EWS-FLI1', 'Gene', (18, 26))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (81, 96))	('increases', 'PosReg', (64, 73))
243842	21217773	Consequently, factors that modulate EWS-FLI1 expression are predicted to affect tumor growth and differentiation by changing the expression of EWS-FLI1 signature genes.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('EWS-FLI1', 'Gene', (36, 44))	('factors', 'Var', (14, 21))	('expression', 'MPA', (129, 139))	('affect', 'Reg', (73, 79))	('EWS-FLI1', 'Gene', '2130;2313', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('differentiation', 'CPA', (97, 112))	('changing', 'Reg', (116, 124))	('tumor', 'Disease', (80, 85))	('EWS-FLI1', 'Gene', (143, 151))	('EWS-FLI1', 'Gene', '2130;2313', (143, 151))	('modulate', 'Var', (27, 35))
243843	21217773	So far, this has been demonstrated for hypoxia and for post-translational modifications of EWS-FLI1.	('hypoxia', 'Disease', 'MESH:D000860', (39, 46))	('EWS-FLI1', 'Gene', (91, 99))	('hypoxia', 'Disease', (39, 46))	('EWS-FLI1', 'Gene', '2130;2313', (91, 99))	('post-translational modifications', 'Var', (55, 87))
243848	21217773	In order to study the role of microRNAs in Ewing's sarcoma pathogenesis, we have performed a genome-wide screen for microRNAs that are affected by RNAi-mediated modulation of EWS-FLI1 in Ewing's sarcoma cell lines and differentially expressed between primary Ewing's sarcoma and MPC.	('modulation', 'Var', (161, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (187, 202))	('EWS-FLI1', 'Gene', (175, 183))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (259, 274))	("Ewing's sarcoma", 'Disease', (187, 202))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (43, 58))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (187, 202))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (259, 274))	('sarcoma', 'Phenotype', 'HP:0100242', (267, 274))	('EWS-FLI1', 'Gene', '2130;2313', (175, 183))	('affected', 'Reg', (135, 143))	("Ewing's sarcoma", 'Disease', (259, 274))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (43, 58))	("Ewing's sarcoma", 'Disease', (43, 58))
243873	21217773	Consistent with the hypothesis of positive feed-back regulation between the microRNA and EWS-FLI1 expression, high hsa-mir-145 was associated with low EWS-FLI1 protein in A673 and SK-N-MC, while low hsa-mir-145 was accompanied with the highest EWS-FLI1 protein expression in WE68 cells.	('EWS-FLI1', 'Gene', '2130;2313', (89, 97))	('EWS-FLI1', 'Gene', (89, 97))	('low', 'NegReg', (147, 150))	('EWS-FLI1', 'Gene', (151, 159))	('hsa-mir-145', 'Gene', (199, 210))	('SK-N-MC', 'CellLine', 'CVCL:0530', (180, 187))	('high', 'Var', (110, 114))	('hsa-mir-145', 'Gene', '406937', (115, 126))	('EWS-FLI1', 'Gene', '2130;2313', (151, 159))	('hsa-mir-145', 'Gene', '406937', (199, 210))	('protein', 'Protein', (160, 167))	('EWS-FLI1', 'Gene', (244, 252))	('hsa-mir-145', 'Gene', (115, 126))	('WE68', 'Chemical', '-', (275, 279))	('EWS-FLI1', 'Gene', '2130;2313', (244, 252))
243874	21217773	EWS-FLI1 has been identified as the major driver of Ewing's sarcoma proliferation, and antagonizing EWS-FLI1 expression with si-, sh-, antisense RNA or dominant negative constructs results in growth inhibition of Ewing's sarcoma cells in vitro and in vivo [for a recent review ].	("Ewing's sarcoma proliferation", 'Disease', 'MESH:C563168', (52, 81))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (213, 228))	('antisense', 'Var', (135, 144))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (52, 67))	('growth inhibition', 'CPA', (192, 209))	('EWS-FLI1', 'Gene', (0, 8))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (52, 67))	('antagonizing', 'Var', (87, 99))	('EWS-FLI1', 'Gene', (100, 108))	('si-', 'Var', (125, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (213, 228))	('EWS-FLI1', 'Gene', '2130;2313', (100, 108))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	("Ewing's sarcoma proliferation", 'Disease', (52, 81))	("Ewing's sarcoma", 'Disease', (213, 228))
243877	21217773	In this study, we identified hsa-mir-145 as a natural antagonist of EWS-FLI1, and, therefore, modulation of hsa-mir-145 appears to be an essential component of EWS-FLI1 mediated oncogenesis.	('hsa-mir-145', 'Gene', '406937', (108, 119))	('hsa-mir-145', 'Gene', (29, 40))	('hsa-mir-145', 'Gene', '406937', (29, 40))	('EWS-FLI1', 'Gene', (160, 168))	('modulation', 'Var', (94, 104))	('EWS-FLI1', 'Gene', '2130;2313', (160, 168))	('EWS-FLI1', 'Gene', (68, 76))	('EWS-FLI1', 'Gene', '2130;2313', (68, 76))	('hsa-mir-145', 'Gene', (108, 119))
243891	21217773	It has recently been demonstrated that primary hsa-mir-145 transcription and processing are activated by wildtype p53 activity.	('hsa-mir-145', 'Gene', (47, 58))	('p53', 'Gene', (114, 117))	('activated', 'PosReg', (92, 101))	('processing', 'MPA', (77, 87))	('hsa-mir-145', 'Gene', '406937', (47, 58))	('p53', 'Gene', '7157', (114, 117))	('transcription', 'MPA', (59, 72))	('wildtype', 'Var', (105, 113))
243892	21217773	Though we have previously reported that EWS-FLI1 reduces basal p53 levels via suppression of the NOTCH signaling pathway, providing a possible mechanism for hsa-mir-145 modulation in Ewing's sarcoma, the highest basal expression of mature hsa-mir-145 and lowest levels of EWS-FLI1 protein were observed in ESFT cell lines that express either a truncated (SK-N-MC) or no p53 at all (A673) and readily allowed for a further significant increase in hsa-mir-145 expression upon silencing of EWS-FLI1.	('hsa-mir-145', 'Gene', (446, 457))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('EWS-FLI1', 'Gene', '2130;2313', (40, 48))	('silencing', 'Var', (474, 483))	('p53', 'Gene', '7157', (63, 66))	('hsa-mir-145', 'Gene', (239, 250))	('reduces', 'NegReg', (49, 56))	('increase', 'PosReg', (434, 442))	('hsa-mir-145', 'Gene', '406937', (446, 457))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (183, 198))	('p53', 'Gene', (370, 373))	('p53', 'Gene', (63, 66))	('hsa-mir-145', 'Gene', '406937', (239, 250))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (183, 198))	('EWS-FLI1', 'Gene', (487, 495))	('hsa-mir-145', 'Gene', (157, 168))	('SK-N-MC', 'CellLine', 'CVCL:0530', (355, 362))	('expression', 'MPA', (458, 468))	('EWS-FLI1', 'Gene', (272, 280))	('p53', 'Gene', '7157', (370, 373))	('NOTCH signaling pathway', 'Pathway', (97, 120))	('EWS-FLI1', 'Gene', (40, 48))	('hsa-mir-145', 'Gene', '406937', (157, 168))	("Ewing's sarcoma", 'Disease', (183, 198))	('EWS-FLI1', 'Gene', '2130;2313', (487, 495))	('EWS-FLI1', 'Gene', '2130;2313', (272, 280))
243902	21217773	The inverse correlation between hsa-mir-145 RNA and EWS-FLI1 protein levels and its role in Ewing sarcoma cell growth suggest that subtle variations in the balance between these two molecules may impact tumor growth and progression.	('hsa-mir-145', 'Gene', '406937', (32, 43))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('EWS-FLI1', 'Gene', '2130;2313', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('impact', 'Reg', (196, 202))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('variations', 'Var', (138, 148))	('progression', 'CPA', (220, 231))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('inverse', 'NegReg', (4, 11))	('EWS-FLI1', 'Gene', (52, 60))	('hsa-mir-145', 'Gene', (32, 43))	('Ewing sarcoma', 'Disease', (92, 105))
244003	23318907	Among the various myxoid-predominant tumors, some possess MRI features that suggest a specific diagnosis, for example the presence of small linear or nodular foci of fat within a myxoid background is pathognomonic for myxoid liposarcoma at MRI, and has been reported to be evident in 42-95 % of cases.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (218, 236))	('liposarcoma', 'Phenotype', 'HP:0012034', (225, 236))	('myxoid liposarcoma', 'Disease', (218, 236))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('tumors', 'Disease', (37, 43))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (218, 236))	('presence', 'Var', (122, 130))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
244028	23318907	High-grade MFS has metastatic potential, while low-grade lesions are only locally aggressive; however, local recurrences can be higher grade than the original tumor, and low-grade MFS can gain metastatic potential at each recurrence.	('original tumor', 'Disease', (150, 164))	('metastatic potential', 'CPA', (193, 213))	('original tumor', 'Disease', 'MESH:D009369', (150, 164))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('low-grade MFS', 'Var', (170, 183))	('gain', 'PosReg', (188, 192))
244067	23727156	Inhibition of ER stress by siRNA knockdown of ATF6, IRE1, or PERK suppressed LC3 lipidation, a marker of autophagosome formation, during HCV infection.	('PERK', 'Gene', '9451', (61, 65))	('ATF6', 'Gene', '22926', (46, 50))	('knockdown', 'Var', (33, 42))	('HCV infection', 'Disease', (137, 150))	('HCV infection', 'Disease', 'MESH:D006526', (137, 150))	('PERK', 'Gene', (61, 65))	('suppressed', 'NegReg', (66, 76))	('ATF6', 'Gene', (46, 50))	('LC3', 'Gene', '84557', (77, 80))	('LC3', 'Gene', (77, 80))
244068	23727156	The UPR-autophagy pathway positively contributes to HCV replication since siRNA knockdown of Atg5 or CHOP in human hepatoma Huh7 cells inhibited early-stage synthesis of incoming HCV RNA.	('knockdown', 'Var', (80, 89))	('human', 'Species', '9606', (109, 114))	('CHOP', 'Gene', (101, 105))	('HCV', 'Species', '11103', (179, 182))	('hepatoma', 'Disease', (115, 123))	('hepatoma', 'Disease', 'MESH:D006528', (115, 123))	('HCV', 'Species', '11103', (52, 55))	('Atg5', 'Gene', (93, 97))	('Huh7', 'CellLine', 'CVCL:0336', (124, 128))	('early-stage synthesis', 'CPA', (145, 166))	('inhibited', 'NegReg', (135, 144))
244080	23727156	EBV can cause Burkitt's lymphoma, Hodgkin's lymphomas, B-cell post-transplant lymphoproliferative disorder, nasopharyngeal carcinoma, and gastric carcinoma.	('lymphoproliferative disorder', 'Disease', (78, 106))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (108, 132))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (14, 32))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (14, 32))	("Burkitt's lymphoma", 'Disease', (14, 32))	('cause', 'Reg', (8, 13))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('lymphomas', 'Phenotype', 'HP:0002665', (44, 53))	('nasopharyngeal carcinoma', 'Disease', (108, 132))	('lymphoproliferative disorder', 'Disease', 'MESH:D008232', (78, 106))	('gastric carcinoma', 'Disease', 'MESH:D013274', (138, 155))	("Hodgkin's lymphomas", 'Disease', 'MESH:D006689', (34, 53))	("Hodgkin's lymphomas", 'Phenotype', 'HP:0012189', (34, 53))	('gastric carcinoma', 'Disease', (138, 155))	('lymphoproliferative disorder', 'Phenotype', 'HP:0005523', (78, 106))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (138, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('EBV', 'Var', (0, 3))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (108, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	("Hodgkin's lymphomas", 'Disease', (34, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('EBV', 'Species', '10376', (0, 3))
244085	23727156	Cytoplasmic targeting of EBNA1 by a nuclear localization signal mutant resulted in increased epitope presentation due to EBNA1 becoming more accessible to the autophagy and MHC class II pathways.	('EBNA1', 'Gene', '17494214', (25, 30))	('EBNA1', 'Gene', (121, 126))	('increased', 'PosReg', (83, 92))	('EBNA1', 'Gene', '17494214', (121, 126))	('more', 'PosReg', (136, 140))	('EBNA1', 'Gene', (25, 30))	('epitope presentation', 'MPA', (93, 113))	('mutant', 'Var', (64, 70))
244111	23727156	Inhibition of Rab5 function by shRNA knockdown or Vps34 function by 3-Methyladenine treatment or shRNA knockdown impaired NS4B-induced autophagosome induction.	('NS4B', 'Gene', (122, 126))	('Rab5', 'Gene', '5868', (14, 18))	('Vps34', 'Gene', '5289', (50, 55))	('Rab5', 'Gene', (14, 18))	('shRNA', 'Gene', (97, 102))	('impaired', 'NegReg', (113, 121))	('NS4B', 'Gene', '951475', (122, 126))	('Vps34', 'Gene', (50, 55))	('3-Methyladenine', 'Chemical', 'MESH:C025946', (68, 83))	('knockdown', 'Var', (103, 112))
244116	23727156	Similar to HCV, HBV can also cause hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (35, 59))	('HCV', 'Species', '11103', (11, 14))	('hepatocellular carcinoma', 'Disease', (35, 59))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('HBV', 'Species', '10407', (16, 19))	('HBV', 'Var', (16, 19))	('cause', 'Reg', (29, 34))
244119	23727156	The role of autophagy during in vivo HBV infection was examined in HBV transgenic mice with a liver specific knockout of Atg5.	('HBV infection', 'Disease', (37, 50))	('HBV', 'Species', '10407', (37, 40))	('knockout', 'Var', (109, 117))	('HBV infection', 'Disease', 'MESH:D006509', (37, 50))	('Atg5', 'Gene', (121, 125))	('transgenic mice', 'Species', '10090', (71, 86))	('HBV', 'Species', '10407', (67, 70))
244121	23727156	Dysregulation of the autophagy pathway has been implicated in many human cancers.	('cancers', 'Disease', (73, 80))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('autophagy pathway', 'CPA', (21, 38))	('human', 'Species', '9606', (67, 72))	('implicated', 'Reg', (48, 58))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
244136	23727156	Further studies are necessary to determine the molecular basis of how mTOR inhibitors modulate viral infection and whether autophagy induction by mTOR inhibitors will have any anti-tumors effects on tumor virus associated cancers.	('modulate', 'Reg', (86, 94))	('viral infection', 'Disease', (95, 110))	('mTOR', 'Gene', (146, 150))	('mTOR', 'Gene', '2475', (70, 74))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('viral infection', 'Disease', 'MESH:D001102', (95, 110))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mTOR', 'Gene', '2475', (146, 150))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('inhibitors', 'Var', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Disease', (199, 204))	('tumors', 'Disease', (181, 187))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('autophagy', 'CPA', (123, 132))	('tumor', 'Disease', (181, 186))	('mTOR', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
244145	23727156	The KSHV viral FLIP derived peptides Tat-vFLIP-alpha2 and Tat-vFLIP-alpha4 contain autophagic death-inducing therapeutic activity by diminishing the ability of cellular FLIP or viral FLIP to bind Atg3, leading to robust autophagy induction and autophagic cell death of KSHV-induced tumor cells in vitro.	('KSHV', 'Species', '37296', (4, 8))	('autophagic cell death', 'CPA', (244, 265))	('bind', 'Interaction', (191, 195))	('Atg3', 'Gene', (196, 200))	('autophagic death-inducing', 'CPA', (83, 108))	('KS', 'Phenotype', 'HP:0100726', (4, 6))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('KSHV', 'Species', '37296', (269, 273))	('tumor', 'Disease', (282, 287))	('diminishing', 'NegReg', (133, 144))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('KS', 'Phenotype', 'HP:0100726', (269, 271))	('Atg3', 'Gene', '64422', (196, 200))	('Tat-vFLIP-alpha4', 'Var', (58, 74))	('cellular FLIP', 'CPA', (160, 173))	('autophagy induction', 'CPA', (220, 239))
244151	23727156	In addition to inducing autophagy in vitro and in vivo, the Tat-beclin 1 peptide was associated with clearance of small polyglutamine expansion protein aggregates.	('beclin 1', 'Gene', '8678', (64, 72))	('inducing', 'PosReg', (15, 23))	('beclin 1', 'Gene', (64, 72))	('polyglutamine', 'Chemical', 'MESH:C097188', (120, 133))	('small polyglutamine expansion', 'Var', (114, 143))	('clearance', 'MPA', (101, 110))	('autophagy', 'CPA', (24, 33))
244152	23727156	Since autophagy levels are decreased in hepatocellular carcinoma patients and mice with heterozygous disruption of beclin-1 exhibit a higher frequency of hepatocellular carcinoma, peptides specifically directed at increasing autophagy levels via Beclin-1 activity may serve as a therapeutic treatment of human cancers.	('cancers', 'Disease', 'MESH:D009369', (310, 317))	('increasing', 'PosReg', (214, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('decreased', 'NegReg', (27, 36))	('beclin-1', 'Gene', (115, 123))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (154, 178))	('hepatocellular carcinoma', 'Disease', (40, 64))	('autophagy levels', 'CPA', (6, 22))	('beclin-1', 'Gene', '56208', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (154, 178))	('disruption', 'Var', (101, 111))	('cancers', 'Phenotype', 'HP:0002664', (310, 317))	('cancers', 'Disease', (310, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('autophagy levels', 'CPA', (225, 241))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (40, 64))	('patients', 'Species', '9606', (65, 73))	('hepatocellular carcinoma', 'Disease', (154, 178))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (40, 64))	('human', 'Species', '9606', (304, 309))	('mice', 'Species', '10090', (78, 82))
244175	29682375	The bone marrow examination then showed 90% myeloblasts, with immunophenotype CD45dim/117+/13dim/33+/56-/2-/15-/14-/11b-/99+/HLA-DR-; CD34 positivity was detected for a subpopulation of 8% of blasts.	('CD34', 'Gene', (134, 138))	('CD45dim/117+/13dim/33+/56-/2-/15-/14-/11b-/99+/HLA-DR-', 'Var', (78, 132))	('CD34', 'Gene', '947', (134, 138))	('myeloblasts', 'CPA', (44, 55))
244224	29682375	It has been suggested that the CD56 cell surface expression together with the encoded fusion proteins in patients with the chromosomal abnormalities t(8:21) and inv(16) is associated with EM AML cell infiltration, although it is unknown whether these mechanisms are important for posttransplant EM relapse.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (123, 148))	('chromosomal abnormalities', 'Disease', (123, 148))	('AML', 'Disease', 'MESH:D015470', (191, 194))	('patients', 'Species', '9606', (105, 113))	('CD56', 'Gene', '4684', (31, 35))	('AML', 'Phenotype', 'HP:0004808', (191, 194))	('associated', 'Reg', (172, 182))	('AML', 'Disease', (191, 194))	('inv(16', 'Var', (161, 167))	('CD56', 'Gene', (31, 35))
244225	29682375	EM presentation has also been associated with other chromosomal abnormalities like trisomy of chromosomes 4, 8, and 11 as well as deletion of chromosomes 5q, 16q, and 20q.	('associated', 'Reg', (30, 40))	('chromosomal abnormalities', 'Disease', (52, 77))	('deletion', 'Var', (130, 138))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (52, 77))	('trisomy', 'Disease', (83, 90))
244227	29682375	Thirdly, some studies suggest that EM relapse is higher after allo-SCT compared to auto-SCT and that the incidence of MS relapse seems to be increased after DLI and in retransplanted patients.	('EM relapse', 'CPA', (35, 45))	('allo-SCT', 'Var', (62, 70))	('patients', 'Species', '9606', (183, 191))	('DLI', 'Disease', (157, 160))
244334	27716444	According to previous reports, non-metastatic AS who received R0 resections had much better survivals than those who received THx in the present study.	('better', 'PosReg', (85, 91))	('AS', 'Phenotype', 'HP:0200058', (46, 48))	('R0 resections', 'Var', (62, 75))	('THx', 'Chemical', 'MESH:D013974', (126, 129))	('non-metastatic AS', 'Var', (31, 48))	('survivals', 'CPA', (92, 101))
244393	20665663	In this report, we demonstrate that FLI sequences within EWS-FLI are responsible for interactions with Runx2.	('EWS', 'Gene', '14030', (57, 60))	('interactions', 'Interaction', (85, 97))	('Runx2', 'Gene', (103, 108))	('Runx2', 'Gene', '12393', (103, 108))	('EWS', 'Gene', (57, 60))	('sequences', 'Var', (40, 49))	('responsible', 'Reg', (69, 80))
244396	20665663	Disrupting interactions between Runx2 and EWS-FLI1 may promote differentiation of the tumor cell.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Runx2', 'Gene', '12393', (32, 37))	('tumor', 'Disease', (86, 91))	('interactions', 'Interaction', (11, 23))	('FLI1', 'Gene', (46, 50))	('Disrupting', 'Var', (0, 10))	('EWS', 'Gene', '14030', (42, 45))	('Runx2', 'Gene', (32, 37))	('promote', 'PosReg', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('FLI1', 'Gene', '14247', (46, 50))	('EWS', 'Gene', (42, 45))
244402	20665663	The chromosomal translocation t(11:22)(q24:q212) is the most common genetic mutation detected in Ewing's sarcomas and occurs in approximately 85% of cases.	("Ewing's sarcomas", 'Disease', (97, 113))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (97, 113))	('t(11:22)(q24:q212', 'Var', (30, 47))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (97, 112))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (97, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('t(11:22)(q24:q212)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 48))
244403	20665663	It fuses EWSR1 (Ewings sarcoma breakpoint region 1) to the Ets transcription factor gene FLI1 (Friend leukemia integration 1) and creates the cancer-specific fusion protein EWS-FLI.	('FLI1', 'Gene', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('Friend leukemia integration 1', 'Gene', '14247', (95, 124))	('Friend leukemia integration 1', 'Gene', (95, 124))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))	('EWS', 'Gene', '14030', (9, 12))	('Ewings sarcoma', 'Phenotype', 'HP:0012254', (16, 30))	('EWS', 'Gene', (9, 12))	('EWS', 'Gene', '14030', (173, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('Ewings sarcoma', 'Disease', 'MESH:C563168', (16, 30))	('cancer', 'Disease', (142, 148))	('EWS', 'Gene', (173, 176))	('EWSR1', 'Gene', '14030', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('EWSR1', 'Gene', (9, 14))	('fuses', 'Var', (3, 8))	('FLI1', 'Gene', '14247', (89, 93))	('Ewings sarcoma', 'Disease', (16, 30))
244404	20665663	Fusions between EWSR1 and other ETS family members, namely ERG, ETV1, ETV4 or FEV, are detected in the majority of the remaining 15% of Ewing's sarcomas.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (136, 151))	('Fusions', 'Var', (0, 7))	('sarcomas', 'Phenotype', 'HP:0100242', (144, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('ERG', 'Gene', (59, 62))	('detected', 'Reg', (87, 95))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (136, 152))	('EWSR1', 'Gene', '14030', (16, 21))	('ETV1', 'Gene', '14009', (64, 68))	('EWSR1', 'Gene', (16, 21))	('ETV4', 'Gene', (70, 74))	("Ewing's sarcomas", 'Disease', (136, 152))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (136, 152))	('ERG', 'Gene', '13876', (59, 62))	('ETV1', 'Gene', (64, 68))	('ETV4', 'Gene', '18612', (70, 74))
244445	20665663	These results suggested that interactions between the Ewing's sarcoma fusion protein, EWS-FLI, and Runx2 were mediated by amino acids derived from either EWSR1 or FLI1, or both proteins.	('EWSR1', 'Gene', (154, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('mediated by', 'Reg', (110, 121))	('amino acids', 'Var', (122, 133))	('EWS', 'Gene', '14030', (154, 157))	('Runx2', 'Gene', '12393', (99, 104))	('FLI1', 'Gene', (163, 167))	('EWS', 'Gene', '14030', (86, 89))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (54, 69))	('EWS', 'Gene', (154, 157))	('EWSR1', 'Gene', '14030', (154, 159))	("Ewing's sarcoma", 'Disease', (54, 69))	('Runx2', 'Gene', (99, 104))	('interactions', 'Interaction', (29, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (54, 69))	('EWS', 'Gene', (86, 89))	('FLI1', 'Gene', '14247', (163, 167))
244446	20665663	To identify the region of EWSR1 that binds Runx2, we tested several EWSR1 deletion constructs for their ability to bind the N-terminal half of Runx2 in the GST pulldown assays.	('EWSR1', 'Gene', '14030', (26, 31))	('tested', 'Reg', (53, 59))	('Runx2', 'Gene', '12393', (43, 48))	('Runx2', 'Gene', (143, 148))	('deletion', 'Var', (74, 82))	('bind', 'Interaction', (115, 119))	('Runx2', 'Gene', '12393', (143, 148))	('EWSR1', 'Gene', (26, 31))	('EWSR1', 'Gene', '14030', (68, 73))	('Runx2', 'Gene', (43, 48))	('EWSR1', 'Gene', (68, 73))
244471	20665663	As was observed in other laboratories, EWS-FLI expression altered the morphology of transfected cells (Fig 5B).	('morphology of transfected cells', 'CPA', (70, 101))	('EWS', 'Gene', '14030', (39, 42))	('expression', 'Var', (47, 57))	('EWS', 'Gene', (39, 42))	('altered', 'Reg', (58, 65))
244499	20665663	Using a set of EWSR1 deletions constructs, we found that the C-terminal region of EWSR1 was sufficient to bind Runx2, but the N-terminus of EWSR1 did not interact with Runx2.	('Runx2', 'Gene', (168, 173))	('Runx2', 'Gene', (111, 116))	('EWSR1', 'Gene', '14030', (15, 20))	('deletions', 'Var', (21, 30))	('EWSR1', 'Gene', (15, 20))	('Runx2', 'Gene', '12393', (168, 173))	('EWSR1', 'Gene', '14030', (82, 87))	('EWSR1', 'Gene', (82, 87))	('bind', 'Interaction', (106, 110))	('EWSR1', 'Gene', '14030', (140, 145))	('EWSR1', 'Gene', (140, 145))	('Runx2', 'Gene', '12393', (111, 116))
244500	20665663	These results negated our hypothesis that the repeated SYxQQS motif in the N-terminus TET proteins was responsible for the interactions with Runx2.	('interactions', 'Interaction', (123, 135))	('TET', 'Chemical', 'MESH:C010349', (86, 89))	('Runx2', 'Gene', (141, 146))	('Runx2', 'Gene', '12393', (141, 146))	('SYxQQS', 'Var', (55, 61))
244547	20930930	A frequent property of these tumors is the loss or inactivation of the tumor suppressor gene SMARCB1/INI1, which was unfortunately not investigated in the present case.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('INI1', 'Gene', '6598', (101, 105))	('inactivation', 'Var', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('loss', 'NegReg', (43, 47))	('tumors', 'Disease', (29, 35))	('tumor', 'Disease', (71, 76))	('INI1', 'Gene', (101, 105))
244550	20930930	But even an R0-resection still has a high risk of relapse due to tumor growth along the tendon sheets in up to 85% - therefore close ontological screenings are inalienable.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('R0-resection', 'Var', (12, 24))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))
244598	32711449	Based on multivariate logistic regression analysis, only SUVmax and HF were identified as independent risk factors for malignant tumors, and could be incorporated into the logistic regression predictive model.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('malignant tumors', 'Disease', (119, 135))	('malignant tumors', 'Disease', 'MESH:D009369', (119, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('SUVmax', 'Var', (57, 63))
244616	32711449	Additionally, multivariate logistic regression analysis identified SUVmax and HF as the only independent risk factors for malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('malignant tumors', 'Disease', (122, 138))	('malignant tumors', 'Disease', 'MESH:D009369', (122, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('SUVmax', 'Var', (67, 73))
244896	24885755	Further on, the observed improvement in relapse-free survival in EORTC 62771 was based mainly on fewer local relapses in the CHT group without a significant difference in the frequency of distant metastasis.	('local relapses', 'CPA', (103, 117))	('fewer', 'NegReg', (97, 102))	('relapse-free survival', 'CPA', (40, 61))	('EORTC', 'Chemical', '-', (65, 70))	('CHT', 'Gene', '60482', (125, 128))	('CHT', 'Gene', (125, 128))	('improvement', 'PosReg', (25, 36))	('EORTC 62771', 'Var', (65, 76))
244933	23036137	Other potential environmental carcinogens, such as herbicides, polyvinyl chloride, arsenicals, have been linked to sarcoma incidence.	('arsenicals', 'Chemical', 'MESH:D001152', (83, 93))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('arsenicals', 'Var', (83, 93))	('sarcoma', 'Disease', (115, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('polyvinyl chloride', 'Chemical', 'MESH:D011143', (63, 81))	('linked', 'Reg', (105, 111))	('polyvinyl chloride', 'Var', (63, 81))
244945	23036137	Moreover, in only about half of these cases has a genetic basis been identified, usually by serially assaying for likely causal genes (eg, mutations in BRCA1 or BRCA2 in families with lots of breast cancer).	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('mutations', 'Var', (139, 148))	('breast cancer', 'Disease', (192, 205))	('BRCA1', 'Gene', '672', (152, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('BRCA2', 'Gene', (161, 166))	('BRCA1', 'Gene', (152, 157))	('BRCA2', 'Gene', '675', (161, 166))
244948	23036137	In many cases, the mutations were identified in individuals who had no family or personal history of cancer, consistent with either a striking de novo mutation rate or differences in penetrance in this cohort.	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (19, 28))
244950	23036137	In some cases, the mutation may affect the choice of therapy for the primary cancer.	('mutation', 'Var', (19, 27))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('affect', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
244951	23036137	Clinicians may elect, for example, to avoid carcinogenic therapies in individuals carrying mutations in DNA repair genes.	('carcinogenic', 'Disease', 'MESH:D063646', (44, 56))	('DNA repair', 'Gene', (104, 114))	('mutations', 'Var', (91, 100))	('carcinogenic', 'Disease', (44, 56))
244955	23036137	Because each cancer seems to have its own spectrum of mutations, the study of sarcomas may shed interesting light on the biology of cancer in general, above that which will be had from sequencing more common cancer types through global enterprises such as the International Cancer Genome Consortium.	('cancer', 'Disease', (132, 138))	('sarcomas', 'Disease', (78, 86))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Cancer', 'Disease', (274, 280))	('Cancer', 'Phenotype', 'HP:0002664', (274, 280))	('mutations', 'Var', (54, 63))	('Cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
244957	23036137	will identify a significant proportion of individuals who carry mutations in new or known 'sarcoma genes'.	("'sarcoma", 'Disease', 'MESH:D012509', (90, 98))	("'sarcoma", 'Disease', (90, 98))	('mutations', 'Var', (64, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))
245042	31161474	In the initial proliferative phase, a lobulated intra-articular lesion is typical, with intermediate to slightly hyperintense signal on T1W and high signal on T2W (Fig.	('T1W', 'Var', (136, 139))	('intra-articular lesion', 'Disease', 'MESH:D057072', (48, 70))	('intra-articular lesion', 'Disease', (48, 70))
245205	28301537	However, it is rather difficult to implement wide surgical resection for dedifferentiated chondrosarcoma because of pathological fractures, lesion permeability, skip lesions and frequent secondary lung metastasis.	('lesion', 'Var', (140, 146))	('skip', 'Disease', (161, 165))	('pathological fractures', 'Phenotype', 'HP:0002756', (116, 138))	('chondrosarcoma', 'Disease', 'MESH:D002813', (90, 104))	('pathological fracture', 'Phenotype', 'HP:0002756', (116, 137))	('chondrosarcoma', 'Disease', (90, 104))	('fractures', 'Disease', 'MESH:D050723', (129, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('men', 'Species', '9606', (40, 43))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (90, 104))	('fractures', 'Disease', (129, 138))
245264	28301537	Patients with myofibroblastic sarcoma had been disease-free about 60 months until now, patient with malignant fibrous histiocytoma may be a shorter survival time (median 5 months) than patients with osteosarcoma(median 17 months)and patients with spindle cell sarcoma (median 8 months).	('malignant', 'Var', (100, 109))	('patient', 'Species', '9606', (185, 192))	('shorter', 'NegReg', (140, 147))	('osteosarcoma', 'Phenotype', 'HP:0002669', (199, 211))	('Patients', 'Species', '9606', (0, 8))	('patient', 'Species', '9606', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('myofibroblastic sarcoma', 'Disease', (14, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('patients', 'Species', '9606', (185, 193))	('myofibroblastic sarcoma', 'Disease', 'MESH:D012509', (14, 37))	('patients', 'Species', '9606', (233, 241))	('osteosarcoma', 'Disease', (199, 211))	('histiocytoma', 'Phenotype', 'HP:0012315', (118, 130))	('survival', 'MPA', (148, 156))	('patient', 'Species', '9606', (233, 240))	('osteosarcoma', 'Disease', 'MESH:D012516', (199, 211))	('spindle cell sarcoma', 'Disease', 'MESH:D012509', (247, 267))	('spindle cell sarcoma', 'Disease', (247, 267))
245297	28301537	In our series, one patients with myofibroblastic sarcoma had been disease-free about 60 months until now, patient with malignant fibrous histiocytoma may be a shorter survival time (median 5 months) than patients with osteosarcoma(median 17 months)and patients with spindle cell sarcoma (median 8 months).	('myofibroblastic sarcoma', 'Disease', 'MESH:D012509', (33, 56))	('patient', 'Species', '9606', (19, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('patient', 'Species', '9606', (106, 113))	('patients', 'Species', '9606', (204, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('patients', 'Species', '9606', (252, 260))	('histiocytoma', 'Phenotype', 'HP:0012315', (137, 149))	('survival', 'MPA', (167, 175))	('osteosarcoma', 'Disease', (218, 230))	('osteosarcoma', 'Disease', 'MESH:D012516', (218, 230))	('patient', 'Species', '9606', (252, 259))	('patients', 'Species', '9606', (19, 27))	('spindle cell sarcoma', 'Disease', 'MESH:D012509', (266, 286))	('spindle cell sarcoma', 'Disease', (266, 286))	('shorter', 'NegReg', (159, 166))	('malignant', 'Var', (119, 128))	('patient', 'Species', '9606', (204, 211))	('myofibroblastic sarcoma', 'Disease', (33, 56))	('osteosarcoma', 'Phenotype', 'HP:0002669', (218, 230))
245320	26481040	Long-term survival in low-grade endometrial stromal sarcoma with childbirth and multidisciplinary treatment: a case report Low-grade endometrial stromal sarcoma is very rare and difficult to diagnose in the early stage.	('Low-grade', 'Var', (123, 132))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (32, 59))	('endometrial stromal sarcoma', 'Disease', (133, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (133, 160))	('endometrial stromal sarcoma', 'Disease', (32, 59))
245458	22797074	Anti-sense knock-down of BCL2 was previously noted to sensitize synovial sarcoma cells to doxorubicin-induced apoptosis.	('sensitize', 'Reg', (54, 63))	('synovial sarcoma', 'Disease', (64, 80))	('BCL2', 'Gene', (25, 29))	('knock-down', 'Var', (11, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (64, 80))	('doxorubicin', 'Chemical', 'MESH:D004317', (90, 101))	('synovial sarcoma', 'Disease', 'MESH:D013584', (64, 80))
245465	22797074	We interrogated published and publicly available mouse synovial sarcoma expression profiles from the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo, profiles GSE6461 and GSE14469,) using D-chip software (www.dichip.org) with an alpha of 0.05 as the criterion for stringency (Fig.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (55, 71))	('synovial sarcoma', 'Disease', 'MESH:D013584', (55, 71))	('mouse', 'Species', '10090', (49, 54))	('synovial sarcoma', 'Disease', (55, 71))	('GSE6461', 'Var', (161, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('GSE14469', 'Var', (173, 181))	('GSE6461', 'Chemical', '-', (161, 168))
245467	22797074	Similar patterns were confirmed by comparing 29 human synovial sarcomas from GSE20196 to 5 human mesenchymal stem cell control samples from GSE26272 (Supplemental Figures 1B and C).	('synovial sarcomas', 'Disease', (54, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('GSE20196', 'Var', (77, 85))	('synovial sarcomas', 'Disease', 'MESH:D013584', (54, 71))	('Supplemental Figures 1B', 'Disease', (150, 173))	('human', 'Species', '9606', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (54, 70))	('Supplemental Figures 1B', 'Disease', 'MESH:C565748', (150, 173))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (54, 71))	('human', 'Species', '9606', (91, 96))
245488	22797074	In mouse synovial sarcoma cells, both Mcl1 and Bcl2a1a levels increased markedly upon knock-down of SS18-SSX2 using siRNA (Fig.	('synovial sarcoma', 'Disease', (9, 25))	('increased', 'PosReg', (62, 71))	('mouse', 'Species', '10090', (3, 8))	('Mcl1', 'MPA', (38, 42))	('SSX2', 'Gene', (105, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (9, 25))	('knock-down', 'Var', (86, 96))	('synovial sarcoma', 'Disease', 'MESH:D013584', (9, 25))	('Bcl2a1a', 'Gene', (47, 54))	('Bcl2a1a', 'Gene', '12044', (47, 54))	('SSX2', 'Gene', '6757', (105, 109))
245489	22797074	Similarly, knockdown of SS18-SSX2 in the human SYO1 cell line produced increased levels of both MCL1 and BCL2A1 (Fig.	('BCL2A1', 'MPA', (105, 111))	('SSX2', 'Gene', (29, 33))	('levels of', 'MPA', (81, 90))	('human', 'Species', '9606', (41, 46))	('SYO1', 'Gene', (47, 51))	('increased', 'PosReg', (71, 80))	('SYO1', 'Gene', '55027', (47, 51))	('MCL1', 'MPA', (96, 100))	('SSX2', 'Gene', '6757', (29, 33))	('knockdown', 'Var', (11, 20))
245499	22797074	In knock-down of either gene, response of the other was modest at best in SYO1 cells (Fig.	('SYO1', 'Gene', '55027', (74, 78))	('SYO1', 'Gene', (74, 78))	('knock-down', 'Var', (3, 13))
245581	33552992	However, compared with the PE group, the UPE group had a higher proportion of small-diameter lesions (<5 cm: 70.5% vs. 48.0%, P<0.001), lesions in superficial locations (55.8% vs. 38.0%, P=0.001), and adjuvant therapy administered (42.6% vs. 21.3%, P<0.001) and had different distributing trends for tumor grade (P=0.001) and AJCC stage (P=0.003).	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('lesions', 'Var', (136, 143))	('tumor', 'Disease', (300, 305))	('small-diameter lesions', 'CPA', (78, 100))	('AJCC', 'Disease', (326, 330))	('tumor', 'Disease', 'MESH:D009369', (300, 305))
245604	33552992	Based on our analysis, we found that UPE followed by R0 resection was associated with a better LRFS and 3-year LRFS rates than PE.	('LR', 'Chemical', '-', (111, 113))	('3-year LRFS rates', 'CPA', (104, 121))	('LR', 'Chemical', '-', (95, 97))	('R0 resection', 'Var', (53, 65))	('LRFS', 'CPA', (95, 99))	('better', 'PosReg', (88, 94))
245605	33552992	According to our univariable and multivariable analyses, UPE decreased the risk of local recurrence and was confirmed as an independent predictive factor of LR.	('decreased', 'NegReg', (61, 70))	('LR', 'Chemical', '-', (157, 159))	('UPE', 'Var', (57, 60))	('local recurrence', 'CPA', (83, 99))
245613	33552992	Our results also showed that the RG presented worse oncological outcomes, including DSS and MFS, and the presence of RTRS was a risk factor for DM.	('DM', 'Disease', 'MESH:D009223', (144, 146))	('presence', 'Var', (105, 113))	('MFS', 'Disease', (92, 95))	('DSS', 'Chemical', '-', (84, 87))	('DSS', 'Disease', (84, 87))
245663	33178932	In the tumors showing heterogeneous signal intensity, cystic areas within the tumor were avoided and at least three round ROIs (10-55 mm2) were placed on the ADC map corresponding to the areas of lowest ADC (on visual inspection).	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('heterogeneous signal intensity', 'Var', (22, 52))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
245682	33178932	Also differentiating hyperintense tumor from reactive peritumoral edema can sometimes be challenging.	('edema', 'Disease', 'MESH:D004487', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('edema', 'Phenotype', 'HP:0000969', (66, 71))	('hyperintense', 'Var', (21, 33))	('tumor', 'Disease', (34, 39))	('edema', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
245696	33178932	In the study by Eman et al, best cut-off criterion to differentiate benign and malignant tumors was ADC of <=0.67 with a sensitivity of 94%, specificity of 79% and accuracy of 87%.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('ADC of <=0.67', 'Var', (100, 113))	('malignant tumors', 'Disease', (79, 95))	('malignant tumors', 'Disease', 'MESH:D009369', (79, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
245774	31624760	Immunohistochemistry showed that the lesion was positive for SYT genome rearrangement, B-cell lymphoma-2 (Bcl-2), Vimentin, Pax-8, and CK7, and negative for smooth muscle actin (SMA), soluble protein-100, epithelial membrane antigen, CD99, and Pax-2.	('CD99', 'Gene', '4267', (234, 238))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (87, 102))	('B-cell lymphoma-2', 'Gene', (87, 104))	('SYT', 'Gene', '6760', (61, 64))	('Pax-8', 'Gene', (124, 129))	('Bcl-2', 'Gene', (106, 111))	('Pax-2', 'Gene', '5076', (244, 249))	('CK7', 'Gene', (135, 138))	('positive', 'Reg', (48, 56))	('Pax-8', 'Gene', '7849', (124, 129))	('rearrangement', 'Var', (72, 85))	('Vimentin', 'Gene', '7431', (114, 122))	('B-cell lymphoma-2', 'Gene', '596', (87, 104))	('Bcl-2', 'Gene', '596', (106, 111))	('lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('Vimentin', 'Gene', (114, 122))	('CD99', 'Gene', (234, 238))	('CK7', 'Gene', '3855', (135, 138))	('Pax-2', 'Gene', (244, 249))	('SYT', 'Gene', (61, 64))
245805	31624760	After 4 wk of chemotherapy with isocyclofosfamide combined with doxorubicin, the tumor volume was reduced to 50% of its original size, and no recurrence was found during 1 year of follow-up.	('doxorubicin', 'Chemical', 'MESH:D004317', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('reduced', 'NegReg', (98, 105))	('isocyclofosfamide', 'Var', (32, 49))	('tumor', 'Disease', (81, 86))	('isocyclofosfamide', 'Chemical', 'None', (32, 49))
245907	23356903	The negativity of CD34 in this case was one of the strong evidences against diagnosis of malignant PTs.	('negativity', 'Var', (4, 14))	('CD34', 'Gene', (18, 22))	('CD34', 'Gene', '947', (18, 22))
245933	23356903	It is interesting to know if gene mutation or amplification of EGFR would be detected in this case.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (63, 67))	('amplification', 'Var', (46, 59))
245948	21197471	Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins.	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('TP53', 'Gene', (102, 106))	('malignancies', 'Disease', (149, 161))	('human', 'Species', '9606', (143, 148))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('Cancers', 'Disease', (0, 7))	('tumour', 'Disease', (40, 46))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('malignancies', 'Disease', 'MESH:D009369', (149, 161))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('evade', 'NegReg', (19, 24))	('mutation', 'Var', (86, 94))	('mutated', 'Var', (188, 195))
245949	21197471	Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53.	('sarcomas', 'Disease', (119, 127))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('Ewing Sarcomas', 'Disease', 'MESH:C563168', (76, 90))	('TP53', 'Gene', (38, 42))	('Sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('observed', 'Reg', (57, 65))	('Ewing Sarcomas', 'Disease', (76, 90))	('Ewing Sarcomas', 'Phenotype', 'HP:0012254', (76, 90))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('genetic lesions', 'Var', (15, 30))	('Sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))
245953	21197471	The development of a malignant neoplasm generally requires attenuation of these p53 responses, and this can occur via mutation of the p53 protein.	('malignant neoplasm', 'Disease', 'MESH:D009369', (21, 39))	('neoplasm', 'Phenotype', 'HP:0002664', (31, 39))	('protein', 'Protein', (138, 145))	('attenuation', 'NegReg', (59, 70))	('mutation', 'Var', (118, 126))	('p53', 'Gene', (134, 137))	('malignant neoplasm', 'Disease', (21, 39))
245954	21197471	TP53 is the most frequently altered gene in cancer, with p53 mutations observed in approximately half of all tumours.	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('TP53', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('cancer', 'Disease', (44, 50))	('observed', 'Reg', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('mutations', 'Var', (61, 70))	('tumours', 'Disease', (109, 116))	('p53', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
245955	21197471	In contrast, TP53 mutations are infrequent in the Ewing Sarcoma Family of Tumours (ESFTs) with the majority of these sarcomas expressing a functional wild-type p53.	('TP53', 'Gene', (13, 17))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (50, 63))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('Ewing Sarcoma Family of Tumours', 'Disease', 'MESH:C563168', (50, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('Sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcomas', 'Disease', (117, 125))	('Tumours', 'Phenotype', 'HP:0002664', (74, 81))	('Ewing Sarcoma Family of Tumours', 'Disease', (50, 81))	('mutations', 'Var', (18, 27))
245959	21197471	A similar analysis of the available literature suggests that the majority of other sarcoma types are also associated with low frequencies of TP53 mutations, ranging from approximately 6% in well-differentiated/dedifferentiated liposarcomas to 23% in osteosarcomas (Table 2).	('osteosarcomas', 'Disease', 'MESH:D012516', (250, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('TP53', 'Gene', (141, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (231, 238))	('liposarcomas', 'Disease', 'MESH:D008080', (227, 239))	('osteosarcomas', 'Disease', (250, 263))	('liposarcoma', 'Phenotype', 'HP:0012034', (227, 238))	('liposarcomas', 'Phenotype', 'HP:0012034', (227, 239))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('osteosarcomas', 'Phenotype', 'HP:0002669', (250, 263))	('dedifferentiated liposarcomas', 'Phenotype', 'HP:0012034', (210, 239))	('sarcoma', 'Disease', (83, 90))	('osteosarcoma', 'Phenotype', 'HP:0002669', (250, 262))	('sarcoma', 'Disease', 'MESH:D012509', (255, 262))	('sarcoma', 'Disease', (255, 262))	('liposarcomas', 'Disease', (227, 239))	('sarcomas', 'Phenotype', 'HP:0100242', (255, 263))	('mutations', 'Var', (146, 155))	('sarcoma', 'Disease', 'MESH:D012509', (231, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (231, 239))	('sarcoma', 'Disease', (231, 238))
245961	21197471	Collectively, Ewing Sarcoma was associated with the lowest frequencies of TP53 mutation across all sarcoma types.	('Sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (14, 27))	('lowest', 'NegReg', (52, 58))	('mutation', 'Var', (79, 87))	('Ewing Sarcoma', 'Disease', (14, 27))	('sarcoma', 'Disease', (99, 106))	('TP53', 'Gene', (74, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (14, 27))
245962	21197471	The International Agency for Research on Cancer (IARC) has recently released recommendations for the detection of TP53 mutations, and advise direct sequencing of exons 4 to 10 of the TP53 gene.	('IARC', 'Disease', (49, 53))	('TP53', 'Gene', (183, 187))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TP53', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))	('IARC', 'Disease', 'None', (49, 53))
245964	21197471	Although mutant p53 is typically stabilized in cancer cells, and overexpression of p53 protein is predictive of TP53 mutation, this indirect approach cannot detect heterozygous truncating mutations of TP53.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('mutant', 'Var', (9, 15))	('cancer', 'Disease', (47, 53))	('overexpression', 'PosReg', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutation', 'Var', (117, 125))	('TP53', 'Gene', (112, 116))
245965	21197471	Nevertheless, frequencies of TP53 mutation reported by the studies in Tables 1 and 2 are consistent with publicly available sequencing data from the IARC TP53 database in which TP53 point mutations were observed in 373 out of 2145 (17.4%) tumours from bone or soft tissue origins.	('tumours', 'Phenotype', 'HP:0002664', (239, 246))	('IARC', 'Disease', 'None', (149, 153))	('point mutations', 'Var', (182, 197))	('mutation', 'Var', (34, 42))	('tumours', 'Disease', 'MESH:D009369', (239, 246))	('tumours', 'Disease', (239, 246))	('IARC', 'Disease', (149, 153))	('TP53', 'Gene', (29, 33))	('observed', 'Reg', (203, 211))	('TP53', 'Gene', (177, 181))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))
245969	21197471	One of the most common oncogenic defects observed involves amplification or overexpression of MDM2.	('MDM2', 'Gene', (94, 98))	('MDM2', 'Gene', '4193', (94, 98))	('amplification', 'Var', (59, 72))	('overexpression', 'PosReg', (76, 90))
245972	21197471	However, MDM2 amplification is a rare event in Ewing Sarcomas and is only observed in approximately 2% of ESFT cases (Table 3).	('MDM2', 'Gene', '4193', (9, 13))	('MDM2', 'Gene', (9, 13))	('Sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('Ewing Sarcomas', 'Disease', 'MESH:C563168', (47, 61))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (47, 60))	('Sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('Ewing Sarcomas', 'Disease', (47, 61))	('Ewing Sarcomas', 'Phenotype', 'HP:0012254', (47, 61))	('amplification', 'Var', (14, 27))
245974	21197471	Cancers can also attenuate p53 function through deletion of CDKN2A, the gene encoding p14ARF.	('p14ARF', 'Gene', '1029', (86, 92))	('Cancers', 'Disease', (0, 7))	('attenuate', 'NegReg', (17, 26))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('function', 'MPA', (31, 39))	('CDKN2A', 'Gene', (60, 66))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('p14ARF', 'Gene', (86, 92))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('CDKN2A', 'Gene', '1029', (60, 66))	('p53', 'Protein', (27, 30))	('deletion', 'Var', (48, 56))
245977	21197471	A summary of the available literature related to CDKN2A chromosomal alterations in ESFT cases revealed that either homozygous or hemizygous deletion of the CDKN2A locus are also relatively infrequent events, occurring in less than 20% of all cases (Table 3).	('CDKN2A', 'Gene', '1029', (49, 55))	('CDKN2A', 'Gene', (156, 162))	('CDKN2A', 'Gene', '1029', (156, 162))	('ESFT', 'Disease', (83, 87))	('deletion', 'Var', (140, 148))	('CDKN2A', 'Gene', (49, 55))
245978	21197471	CDKN2A alterations and TP53 mutations are mutually exclusive events in the majority of ESFT cases, suggesting that either genetic insult is sufficient to inactivate the p53 pathway in these cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('inactivate', 'NegReg', (154, 164))	('ESFT', 'Disease', (87, 91))	('p53 pathway', 'Pathway', (169, 180))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('CDKN2A', 'Gene', (0, 6))	('TP53', 'Gene', (23, 27))	('alterations', 'Var', (7, 18))	('CDKN2A', 'Gene', '1029', (0, 6))
245983	21197471	MDM4 amplification is a possible mechanism for functional inactivation of the p53 pathway in Ewing Sarcoma given the infrequent occurrences of MDM2 amplification, CDKN2A deletion, or TP53 mutation in these cancers.	('p53 pathway', 'Pathway', (78, 89))	('MDM4', 'Gene', '4194', (0, 4))	('CDKN2A', 'Gene', '1029', (163, 169))	('MDM4', 'Gene', (0, 4))	('inactivation', 'NegReg', (58, 70))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('Ewing Sarcoma', 'Disease', (93, 106))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('MDM2', 'Gene', (143, 147))	('TP53', 'Gene', (183, 187))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (93, 106))	('Sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('deletion', 'Var', (170, 178))	('MDM2', 'Gene', '4193', (143, 147))	('mutation', 'Var', (188, 196))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('CDKN2A', 'Gene', (163, 169))	('amplification', 'Var', (148, 161))
245985	21197471	The small proportion of ESFT cases with either MDM2 amplification or p14ARF deletion cannot collectively account for the ability of Ewing Sarcomas to develop in a cellular context with wild-type p53.	('deletion', 'Var', (76, 84))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (132, 145))	('MDM2', 'Gene', '4193', (47, 51))	('MDM2', 'Gene', (47, 51))	('p14ARF', 'Gene', '1029', (69, 75))	('Sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Ewing Sarcomas', 'Disease', 'MESH:C563168', (132, 146))	('Ewing Sarcomas', 'Disease', (132, 146))	('Sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('p14ARF', 'Gene', (69, 75))	('Ewing Sarcomas', 'Phenotype', 'HP:0012254', (132, 146))
245988	21197471	Abrogation of the p53 pathway through TP53 mutation is typically associated with enhanced tumour invasive and metastatic capabilities, and poorer patient survival rates.	('enhanced', 'PosReg', (81, 89))	('mutation', 'Var', (43, 51))	('p53 pathway', 'Pathway', (18, 29))	('TP53', 'Gene', (38, 42))	('tumour invasive', 'Disease', 'MESH:D009361', (90, 105))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour invasive', 'Disease', (90, 105))	('patient', 'Species', '9606', (146, 153))
245991	21197471	In order to test the functional intactness of these p53 signaling pathways in Ewing Sarcoma, Heinrich Kovar and colleagues investigated the response of several ESFT cell lines with varying p53 status to ectopic p53 expression.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('Ewing Sarcoma', 'Disease', (78, 91))	('p53', 'Protein', (211, 214))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('Sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('ectopic', 'Var', (203, 210))
245995	21197471	The frequent normal functioning of the p53 signaling pathway in ESFTs is also demonstrated by the observation that almost all Ewing Sarcoma cell lines have acquired either TP53 mutations or CDKN2A deletions, suggesting selective pressure for these genetic alterations to permit in vitro growth.	('deletions', 'Var', (197, 206))	('CDKN2A', 'Gene', '1029', (190, 196))	('Sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('TP53', 'Gene', (172, 176))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (126, 139))	('Ewing Sarcoma', 'Disease', (126, 139))	('mutations', 'Var', (177, 186))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (126, 139))	('CDKN2A', 'Gene', (190, 196))
245996	21197471	Similar observations have been made in the clinic, with p53 mutation and CDKN2A deletion defining a lethal subset of ESFTs associated with poor response to chemotherapy.	('ESFTs', 'Disease', (117, 122))	('deletion', 'Var', (80, 88))	('CDKN2A', 'Gene', '1029', (73, 79))	('p53', 'Gene', (56, 59))	('CDKN2A', 'Gene', (73, 79))
245998	21197471	ESFT patients with point mutation of TP53 are associated with a poor prognosis.	('TP53', 'Gene', (37, 41))	('patients', 'Species', '9606', (5, 13))	('point mutation', 'Var', (19, 33))
246000	21197471	This is not the case in Ewing Sarcoma, as TP53 mutations rarely occur, yet define a high-risk population of patients.	('TP53', 'Gene', (42, 46))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (24, 37))	('mutations', 'Var', (47, 56))	('Ewing Sarcoma', 'Disease', (24, 37))	('Sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (24, 37))	('patients', 'Species', '9606', (108, 116))
246001	21197471	TP53 mutations were identified in 8 of these 60 cases (13.3%), and all eight patients expressing mutant p53 ESFTs died within 21 months of diagnosis with a mean survival of 11 months, as compared to a mean survival of 99 months for patients with wild-type p53 ESFTs.	('patients', 'Species', '9606', (232, 240))	('patients', 'Species', '9606', (77, 85))	('p53', 'Gene', (104, 107))	('mutant', 'Var', (97, 103))
246003	21197471	The prognostic involvement of p53 mutation in Ewing Sarcoma was recently challenged by findings from a retrospective study involving 308 ESFT cases collected from 1971 to 2007.	('Ewing Sarcoma', 'Disease', (46, 59))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('Sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('mutation', 'Var', (34, 42))	('p53', 'Gene', (30, 33))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (46, 59))
246007	21197471	Gross chromosome rearrangements involving TP53 have been recently reported to influence the prognosis of Ewing Sarcoma.	('Gross chromosome rearrangements', 'Var', (0, 31))	('Ewing Sarcoma', 'Disease', (105, 118))	('influence', 'Reg', (78, 87))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('TP53', 'Gene', (42, 46))	('Sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (105, 118))
246008	21197471	Lopez-Guerrero and colleagues recently showed that alteration the TP53 locus alone was a prognostic marker for poor patient outcome.	('TP53', 'Gene', (66, 70))	('patient', 'Species', '9606', (116, 123))	('alteration', 'Var', (51, 61))
246011	21197471	Studies to date are consistent with the presence of TP53 point mutations in defining a high-risk population of ESFT patients.	('patients', 'Species', '9606', (116, 124))	('ESFT', 'Disease', (111, 115))	('TP53', 'Gene', (52, 56))	('point mutations', 'Var', (57, 72))
246014	21197471	The EWS-FLI1 translocation, t(11;22)(q24;12), is a chromosomal aberration specific to ESFTs and accounts for 85% of translocation events in Ewing Sarcoma.	('t(11;22)(q24;12', 'Var', (28, 43))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (51, 73))	('Sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (140, 153))	('Ewing Sarcoma', 'Disease', (140, 153))	('EWS-FLI1', 'Gene', (4, 12))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (140, 153))	('EWS-FLI1', 'Gene', '2130;2313', (4, 12))
246015	21197471	This reciprocal translocation generates fusion of the 5' segment of EWS on chromosome 22 with the 3' segment of FLI-1 on chromosome 11.	('fusion', 'Var', (40, 46))	('FLI-1', 'Gene', (112, 117))	('FLI-1', 'Gene', '2313', (112, 117))
246019	21197471	Two independent studies have shown that silencing of EWS-FLI1 expression in Ewing Sarcoma cell lines increases p53 activity, suggesting that the EWS-FLI1 fusion protein plays a role in the constitutive silencing of p53 tumour suppressor activity.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('EWS-FLI1', 'Gene', (145, 153))	('p53 activity', 'MPA', (111, 123))	('EWS-FLI1', 'Gene', '2130;2313', (145, 153))	('EWS-FLI1', 'Gene', (53, 61))	('increases', 'PosReg', (101, 110))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('EWS-FLI1', 'Gene', '2130;2313', (53, 61))	('tumour', 'Disease', (219, 225))	('Sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('silencing', 'Var', (40, 49))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (76, 89))	('Ewing Sarcoma', 'Disease', (76, 89))
246028	21197471	Reminiscent of Ewing Sarcoma, TP53 mutations are rare events in synovial sarcomas (Table 1), suggesting that these cancers rely on the ability of the SS18-SSX fusion protein to abrogate the p53 response, facilitating oncogenic transformation in the presence of a functional, wild-type p53.	('SS18', 'Gene', '6760', (150, 154))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('facilitating', 'PosReg', (204, 216))	('abrogate', 'NegReg', (177, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('SSX', 'Gene', (155, 158))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (64, 81))	('Ewing Sarcoma', 'Disease', (15, 28))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (15, 28))	('synovial sarcomas', 'Disease', (64, 81))	('p53', 'Pathway', (190, 193))	('Sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (15, 28))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('synovial sarcomas', 'Disease', 'MESH:D013584', (64, 81))	('oncogenic transformation', 'CPA', (217, 241))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (64, 80))	('SS18', 'Gene', (150, 154))	('SSX', 'Gene', '727837', (155, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (35, 44))
246033	21197471	Similar effects have been observed in mouse embryonic fibroblasts (MEFs) in which expression of EWS-FLI1 induced the p53-dependent growth arrest or apoptosis.	('mouse', 'Species', '10090', (38, 43))	('MEFs', 'CellLine', 'CVCL:9115', (67, 71))	('induced', 'Reg', (105, 112))	('growth arrest', 'Phenotype', 'HP:0001510', (131, 144))	('expression', 'Var', (82, 92))	('EWS-FLI1', 'Gene', (96, 104))	('apoptosis', 'CPA', (148, 157))	('growth arrest', 'Disease', (131, 144))	('EWS-FLI1', 'Gene', '2130;2313', (96, 104))	('growth arrest', 'Disease', 'MESH:D006323', (131, 144))
246034	21197471	This apoptotic or growth arrest response was considered to be p53-dependent, as MEFs null for p53, p19ARF, or p16 were unaffected in response to EWS-FLI1 expression.	('EWS-FLI1', 'Gene', (145, 153))	('p16', 'Gene', '1029', (110, 113))	('growth arrest', 'Phenotype', 'HP:0001510', (18, 31))	('MEFs', 'CellLine', 'CVCL:9115', (80, 84))	('EWS-FLI1', 'Gene', '2130;2313', (145, 153))	('p19ARF', 'Gene', (99, 105))	('p19ARF', 'Gene', '1029', (99, 105))	('p16', 'Gene', (110, 113))	('growth arrest', 'Disease', 'MESH:D006323', (18, 31))	('growth arrest', 'Disease', (18, 31))	('p53', 'Var', (94, 97))	('apoptotic', 'CPA', (5, 14))	('growth arrest response', 'Phenotype', 'HP:0031164', (18, 40))
246042	21197471	Conditional TP53 deletion in mouse MPCs led to the development osteosarcomas with a median tumour onset time of 50 weeks from birth.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('osteosarcomas', 'Disease', (63, 76))	('osteosarcomas', 'Phenotype', 'HP:0002669', (63, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (63, 75))	('tumour', 'Disease', (91, 97))	('osteosarcomas', 'Disease', 'MESH:D012516', (63, 76))	('led to', 'Reg', (40, 46))	('deletion', 'Var', (17, 25))	('mouse', 'Species', '10090', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('TP53', 'Gene', (12, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
246044	21197471	These data provide in vivo evidence to further support the cross-talk between p53 and EWS-FLI1 which is essential in primary MPCs for the development of Ewing Sarcomas.	('cross-talk', 'Var', (59, 69))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('Sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('EWS-FLI1', 'Gene', '2130;2313', (86, 94))	('Ewing Sarcomas', 'Disease', 'MESH:C563168', (153, 167))	('Sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('p53', 'Gene', (78, 81))	('Ewing Sarcomas', 'Disease', (153, 167))	('Ewing Sarcomas', 'Phenotype', 'HP:0012254', (153, 167))	('EWS-FLI1', 'Gene', (86, 94))
246047	21197471	A role of the IGF signaling pathway in the development of Ewing Sarcoma is evident through the finding that silencing of the EWS-FLI1 oncoprotein showed upregulation and activation of IGFBP genes.	('EWS-FLI1', 'Gene', (125, 133))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('silencing', 'Var', (108, 117))	('activation', 'PosReg', (170, 180))	('EWS-FLI1', 'Gene', '2130;2313', (125, 133))	('upregulation', 'PosReg', (153, 165))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (58, 71))	('Ewing Sarcoma', 'Disease', (58, 71))	('IGFBP', 'Gene', (184, 189))	('Sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('IGFBP', 'Gene', '3486', (184, 189))
246048	21197471	Ewing Sarcoma cell lines are highly sensitive to IGF1R inhibitors, especially in combination with conventional chemotherapy.	('Sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('IGF1R', 'Gene', '3480', (49, 54))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('Ewing Sarcoma', 'Disease', (0, 13))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('inhibitors', 'Var', (55, 65))	('IGF1R', 'Gene', (49, 54))
246054	21197471	Induction of IGF-BP3 gene expression by p53 enhanced secretion of an active form of IGF-BP3 capable of inhibiting IGF1R mitogenic signalling.	('IGF-BP3', 'Gene', (84, 91))	('secretion of an active', 'MPA', (53, 75))	('IGF-BP3', 'Gene', '3486', (84, 91))	('IGF1R', 'Gene', '3480', (114, 119))	('p53', 'Var', (40, 43))	('IGF-BP3', 'Gene', (13, 20))	('IGF-BP3', 'Gene', '3486', (13, 20))	('inhibiting', 'NegReg', (103, 113))	('IGF1R', 'Gene', (114, 119))	('enhanced', 'PosReg', (44, 52))
246057	21197471	Sequestration of MDM2 in the nucleus by high levels of mutant p53 may be a possible explanation for the high levels of IGF1R observed in some cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('high levels of IGF1R', 'Phenotype', 'HP:0030269', (104, 124))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Sequestration', 'MPA', (0, 13))	('IGF1R', 'Gene', (119, 124))	('mutant', 'Var', (55, 61))	('MDM2', 'Gene', (17, 21))	('MDM2', 'Gene', '4193', (17, 21))	('IGF1R', 'Gene', '3480', (119, 124))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('p53', 'Gene', (62, 65))
246064	21197471	Promising results from several preclinical studies have clearly demonstrated the therapeutic potential of Nutlin-3a in a variety of tumour types expressing wild-type p53, including liposarcoma, rhabdomyosarcoma, osteosarcoma, synovial sarcoma, neuroblastoma, retinoblastoma, and leukemia.	('osteosarcoma', 'Disease', (212, 224))	('wild-type p53', 'Var', (156, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('rhabdomyosarcoma', 'Disease', (194, 210))	('osteosarcoma', 'Disease', 'MESH:D012516', (212, 224))	('leukemia', 'Disease', 'MESH:D007938', (279, 287))	('leukemia', 'Disease', (279, 287))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('retinoblastoma', 'Phenotype', 'HP:0009919', (259, 273))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (226, 242))	('liposarcoma', 'Phenotype', 'HP:0012034', (181, 192))	('tumour', 'Disease', (132, 138))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (194, 210))	('retinoblastoma', 'Disease', (259, 273))	('liposarcoma', 'Disease', 'MESH:D008080', (181, 192))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (194, 210))	('neuroblastoma', 'Disease', (244, 257))	('neuroblastoma', 'Phenotype', 'HP:0003006', (244, 257))	('osteosarcoma', 'Phenotype', 'HP:0002669', (212, 224))	('neuroblastoma', 'Disease', 'MESH:D009447', (244, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('leukemia', 'Phenotype', 'HP:0001909', (279, 287))	('synovial sarcoma', 'Disease', (226, 242))	('liposarcoma', 'Disease', (181, 192))	('retinoblastoma', 'Disease', 'MESH:D012175', (259, 273))	('synovial sarcoma', 'Disease', 'MESH:D013584', (226, 242))
246075	21197471	MI-219 interacts with the p53 binding pocket of MDM2 with a higher affinity and selectivity than Nutlin-3a and hence attains a more potent stimulation of the p53 pathway.	('MI-219', 'Var', (0, 6))	('MI-219', 'Chemical', 'MESH:C574930', (0, 6))	('affinity', 'Interaction', (67, 75))	('MDM2', 'Gene', '4193', (48, 52))	('interacts', 'Interaction', (7, 16))	('MDM2', 'Gene', (48, 52))	('p53 pathway', 'Pathway', (158, 169))	('stimulation', 'PosReg', (139, 150))
246080	21197471	MDM2 antagonists have been demonstrated to elicit their most potent effects in cell lines where MDM2 is amplified or overexpressed.	('elicit', 'Reg', (43, 49))	('MDM2', 'Gene', '4193', (96, 100))	('antagonists', 'Var', (5, 16))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (96, 100))	('MDM2', 'Gene', (0, 4))
246083	21197471	Interestingly, Tenovin-6 was shown to repress the growth of cancer cells using in vitro and in vivo models through hyperacetylation of p53.	('hyperacetylation', 'Var', (115, 131))	('p53', 'Protein', (135, 138))	('repress', 'NegReg', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
246090	21197471	High doses of actinomycin D are associated with intercalation into the DNA and subsequent double-strand DNA breaks.	('double-strand DNA breaks', 'CPA', (90, 114))	('actinomycin', 'Gene', (14, 25))	('actinomycin D', 'Chemical', 'MESH:D003609', (14, 27))	('intercalation', 'Var', (48, 61))
246096	21197471	Ewing Sarcomas share the common genetic features including the universal presence of the EWS-ETS translocation and frequent retention of the wild-type p53 and its associated functional downstream pathways.	('Ewing Sarcomas', 'Disease', (0, 14))	('Sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing Sarcomas', 'Phenotype', 'HP:0012254', (0, 14))	('EWS-ETS', 'Gene', (89, 96))	('translocation', 'Var', (97, 110))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Sarcomas', 'Phenotype', 'HP:0100242', (6, 14))	('Ewing Sarcomas', 'Disease', 'MESH:C563168', (0, 14))
246100	21197471	In addition, complementation of these studies with direct TP53 sequencing of ESFT material would identify either patients with wild-type p53 tumours most likely to benefit from p53-based therapies or the less frequent "high risk" population of ESFTs containing point mutations in the TP53 gene.	('tumours', 'Disease', (141, 148))	('TP53', 'Gene', (284, 288))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('patients', 'Species', '9606', (113, 121))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('point mutations', 'Var', (261, 276))	('tumours', 'Disease', 'MESH:D009369', (141, 148))
246103	28541529	We show that the best performing published algorithms either find large numbers of fusions in negative control data or suffer from low sensitivity detecting known driving fusions in gold standard settings, such as EWSR1-FLI1.	('FLI1', 'Gene', (220, 224))	('FLI1', 'Gene', '2313', (220, 224))	('EWSR1', 'Gene', (214, 219))	('EWSR1', 'Gene', '2130', (214, 219))	('fusions', 'Var', (83, 90))
246107	28541529	Gene fusions are excellent tumor-specific biomarkers because they are very rarely present in healthy patients, and thus have the potential to be used for early diagnosis, as drug targets, and as neoantigens.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patients', 'Species', '9606', (101, 109))	('tumor', 'Disease', (27, 32))	('Gene fusions', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
246110	28541529	In leukemias, recurrent gene fusions and internal tandem duplications are among the most effective therapeutic targets.	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('leukemias', 'Disease', 'MESH:D007938', (3, 12))	('leukemias', 'Phenotype', 'HP:0001909', (3, 12))	('internal tandem duplications', 'Var', (41, 69))	('leukemias', 'Disease', (3, 12))
246111	28541529	For example, the discovery of oncogenic gene fusions, including BCR-ABL1 in chronic myelogenous leukemia (CML) and the FLT3 internal tandem duplication in acute myelogenous leukemia (AML), have provided critical insights into pathogenesis and led to important therapeutic advances.	('CML', 'Disease', 'MESH:D015464', (106, 109))	('acute myelogenous leukemia', 'Disease', (155, 181))	('CML', 'Disease', (106, 109))	('AML', 'Disease', 'MESH:D015470', (183, 186))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (161, 181))	('AML', 'Phenotype', 'HP:0004808', (183, 186))	('AML', 'Disease', (183, 186))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (155, 181))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (84, 104))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))	('CML', 'Phenotype', 'HP:0005506', (106, 109))	('myelogenous leukemia', 'Disease', (84, 104))	('BCR-ABL1', 'Gene', (64, 72))	('FLT3', 'Gene', (119, 123))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (161, 181))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('internal tandem duplication', 'Var', (124, 151))	('FLT3', 'Gene', '2322', (119, 123))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (76, 104))	('BCR-ABL1', 'Gene', '613;25', (64, 72))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (155, 181))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (84, 104))
246112	28541529	Recurrent gene fusions have also been identified in solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('solid tumors', 'Disease', 'MESH:D009369', (52, 64))	('gene fusions', 'Var', (10, 22))	('identified', 'Reg', (38, 48))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('solid tumors', 'Disease', (52, 64))
246113	28541529	Next generation sequencing focused on fusions involving known oncogenes, has enabled discovery of fusions in a variety of other cancers that can be targeted with existing drugs, such as FGFR, ALK and ROS family gene fusions.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('ALK', 'Gene', (192, 195))	('fusions', 'Var', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ROS', 'Chemical', '-', (200, 203))	('ALK', 'Gene', '238', (192, 195))
246122	28541529	Bona fide mutations or indels in the cancer genome compound this problem and further contribute to artifacts.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('indels', 'Var', (23, 29))	('contribute', 'Reg', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (10, 19))
246124	28541529	Raw fastq files generated from samples of three distinct normal breast epithelial organoids were downloaded on 3 February 2016 from SRA: SRR1027188, SRR1027189, SRR1027190.	('SRA', 'Gene', '10011', (132, 135))	('SRR1027190', 'Var', (161, 171))	('SRA', 'Gene', (132, 135))	('SRR1027189', 'Var', (149, 159))	('SRR1027188', 'Var', (137, 147))
246129	28541529	Six samples with EWS-FLI1 translocations from 2 different cell lines from were used in the analysis.	('FLI1', 'Gene', '2313', (21, 25))	('translocations', 'Var', (26, 40))	('EWS', 'Gene', '2130', (17, 20))	('EWS', 'Gene', (17, 20))	('FLI1', 'Gene', (21, 25))
246130	28541529	The EWS-FLI1 fusion was depleted in some samples by transfection with lentiviral shRNA shFLI1 and other samples were treated with a control shGFP which did not deplete the fusion.	('FLI1', 'Gene', (89, 93))	('FLI1', 'Gene', '2313', (89, 93))	('depleted', 'NegReg', (24, 32))	('FLI1', 'Gene', (8, 12))	('transfection', 'Var', (52, 64))	('FLI1', 'Gene', '2313', (8, 12))	('EWS', 'Gene', '2130', (4, 7))	('EWS', 'Gene', (4, 7))
246131	28541529	SRR1594020-SRR1594023 were obtained from Ewing sarcoma cell line SKMNC.	('SKMNC', 'CellLine', 'None', (65, 70))	('Ewing sarcoma', 'Disease', (41, 54))	('SRR1594020-SRR1594023', 'Var', (0, 21))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (41, 54))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (41, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
246132	28541529	SRR1594021 and SRR1594023 were treated with shFLI1 for 48 and 96 h, respectively.	('FLI1', 'Gene', (46, 50))	('SRR1594023', 'Var', (15, 25))	('FLI1', 'Gene', '2313', (46, 50))	('SRR1594021', 'Var', (0, 10))
246133	28541529	SRR1594024 and SRR1594025 were obtained from Ewing sarcoma cell line A673.	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('SRR1594025', 'Var', (15, 25))	('Ewing sarcoma', 'Disease', (45, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 58))
246143	28541529	The vast majority of validated gene fusions, including the BCR-ABL1 and EWS-FLI1 fusions discussed in this paper, occur at exon-exon boundaries.	('BCR-ABL1', 'Gene', '613;25', (59, 67))	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', (72, 75))	('FLI1', 'Gene', '2313', (76, 80))	('fusions', 'Var', (36, 43))	('fusions', 'Var', (81, 88))	('FLI1', 'Gene', (76, 80))	('occur', 'Reg', (114, 119))	('BCR-ABL1', 'Gene', (59, 67))
246158	28541529	NUP214-XKR3 was detected in all replicates and the BCR-ABL1 fusion was identified in all replicates except SRR192416 and SRR192417 by MACHETE, SOAPfuse and STAR-Fusion (Supplementary Tables S2-S5).	('NUP214', 'Gene', (0, 6))	('SRR192416', 'Var', (107, 116))	('BCR-ABL1', 'Gene', '613;25', (51, 59))	('NUP214', 'Gene', '8021', (0, 6))	('BCR-ABL1', 'Gene', (51, 59))	('SRR192417', 'Var', (121, 130))	('XKR3', 'Gene', (7, 11))	('STAR', 'Gene', '6770', (156, 160))	('XKR3', 'Gene', '150165', (7, 11))	('STAR', 'Gene', (156, 160))
246160	28541529	Both algorithms reported more fusions than in any of the other 10 replicates: 247 154 for STAR-Fusion and 57 46 for MACHETE.	('STAR', 'Gene', (90, 94))	('STAR', 'Gene', '6770', (90, 94))	('fusions', 'Var', (30, 37))
246164	28541529	We evaluated the sensitivity of MACHETE's detection of the documented alternative splicing between EWSR1 and FLI1 in the Ewing's sarcoma cell lines SKMNC and A673, as well as the detection of the reciprocal fusion event between FLI1 and EWSR1 in A673 (Figure 4B).	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (121, 136))	('alternative splicing', 'Var', (70, 90))	("Ewing's sarcoma", 'Disease', (121, 136))	('EWSR1', 'Gene', '2130', (99, 104))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (121, 136))	('SKMNC', 'CellLine', 'None', (148, 153))	('EWSR1', 'Gene', '2130', (237, 242))	('FLI1', 'Gene', (228, 232))	('FLI1', 'Gene', (109, 113))	('FLI1', 'Gene', '2313', (228, 232))	('FLI1', 'Gene', '2313', (109, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('EWSR1', 'Gene', (99, 104))	('EWSR1', 'Gene', (237, 242))
246171	28541529	The A673 sample is known to express the reciprocal FLI1-EWSR1 transcript.	('FLI1', 'Gene', (51, 55))	('FLI1', 'Gene', '2313', (51, 55))	('EWSR1', 'Gene', (56, 61))	('EWSR1', 'Gene', '2130', (56, 61))	('A673', 'Var', (4, 8))
246174	28541529	All algorithms were used to predict fusions in publicly available RNA-Seq data from the ovarian cancer cell line OVCAR3.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ovarian cancer', 'Disease', (88, 102))	('fusions', 'Var', (36, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (88, 102))
246175	28541529	We used RT-PCR on RNA we extracted in our own lab to validate the most abundant predicted fusions that passed MACHETE's statistical filters: two splice isoforms of a translocation giving rise to a fusion between the genes SPEN and NEU1, another translocation resulting in a fusion between NUP98 and the gene BEAN1, and a >2 Mb predicted duplication resulting in a fusion between the genes ITSN2 and OTOF.	('duplication', 'Var', (337, 348))	('SPEN', 'Gene', '23013', (222, 226))	('BEAN1', 'Gene', '146227', (308, 313))	('fusion', 'Interaction', (197, 203))	('NUP98', 'Gene', '4928', (289, 294))	('OTOF', 'Gene', '9381', (399, 403))	('NEU1', 'Gene', '4758', (231, 235))	('fusion', 'Interaction', (274, 280))	('NEU1', 'Gene', (231, 235))	('SPEN', 'Gene', (222, 226))	('ITSN2', 'Gene', (389, 394))	('fusion', 'Interaction', (364, 370))	('OTOF', 'Gene', (399, 403))	('BEAN1', 'Gene', (308, 313))	('ITSN2', 'Gene', '50618', (389, 394))	('NUP98', 'Gene', (289, 294))
246183	28541529	To our knowledge, this is the first report and validation of a NUP98 fusion in an ovarian cancer cell line.	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian cancer', 'Disease', 'MESH:D010051', (82, 96))	('NUP98', 'Gene', '4928', (63, 68))	('NUP98', 'Gene', (63, 68))	('ovarian cancer', 'Disease', (82, 96))	('fusion', 'Var', (69, 75))
246339	24048627	The combination of radiotherapy and tyrosine kinase inhibitors may cause excessive toxicity in these cases.	('toxicity', 'Disease', (83, 91))	('cause', 'Reg', (67, 72))	('tyrosine', 'Var', (36, 44))	('toxicity', 'Disease', 'MESH:D064420', (83, 91))
246441	32384440	The patient's respiratory rate was 23 breaths per minute, with severe hypoxemia, on arterial blood gas analysis (pH, 7.35; pCO2, 31 mm Hg; pO2, 39 mm Hg; bicarbonate, 17 mmol/L; base excess, 9.0; O2 saturation, 75.2%).	('O2', 'Chemical', 'MESH:D010100', (125, 127))	('bicarbonate', 'Chemical', 'MESH:D001639', (154, 165))	('pO2', 'Chemical', 'MESH:C093415', (139, 142))	('patient', 'Species', '9606', (4, 11))	('hypoxemia', 'Disease', 'MESH:D000860', (70, 79))	('pO2', 'Var', (139, 142))	('hypoxemia', 'Phenotype', 'HP:0012418', (70, 79))	('O2', 'Chemical', 'MESH:D010100', (140, 142))	('hypoxemia', 'Disease', (70, 79))	('O2', 'Chemical', 'MESH:D010100', (196, 198))
246491	31043173	The distribution rates of TFE3 positivity in nodular fasciitis, gastrointestinal stromal tumor, leiomyoma and scar tissue samples were 42.9, 40, 25 and 33%, respectively.	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (64, 94))	('leiomyoma', 'Disease', (96, 105))	('scar', 'Phenotype', 'HP:0100699', (110, 114))	('nodular fasciitis', 'Disease', (45, 62))	('leiomyoma', 'Disease', 'MESH:D007889', (96, 105))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (64, 94))	('TFE3', 'Gene', (26, 30))	('positivity', 'Var', (31, 41))	('nodular fasciitis', 'Disease', 'MESH:D020518', (45, 62))	('gastrointestinal stromal tumor', 'Disease', (64, 94))	('fasciitis', 'Phenotype', 'HP:0100537', (53, 62))	('TFE3', 'Gene', '7030', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
246499	31043173	DTF CTNNB1 mutations most frequently occur in exon 3 of this gene, which protect beta-catenin from degradation via adenomatous polyposis coli (APC) protein complex and thus enhance beta-catenin nuclear accumulation.	('mutations', 'Var', (11, 20))	('beta-catenin nuclear accumulation', 'MPA', (181, 214))	('APC', 'Phenotype', 'HP:0005227', (143, 146))	('APC', 'Disease', 'MESH:D011125', (143, 146))	('DTF CTNNB1', 'Gene', (0, 10))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (115, 141))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (115, 136))	('protect', 'PosReg', (73, 80))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (115, 141))	('enhance', 'PosReg', (173, 180))	('beta-catenin', 'Protein', (81, 93))	('degradation', 'MPA', (99, 110))	('APC', 'Disease', (143, 146))	('adenomatous polyposis coli', 'Disease', (115, 141))
246500	31043173	Transcription factor E3 (TFE3) plays important roles in autophagy, lysosomal biogenesis and cellular stress responses, and serves as an oncogene in many tumor types with rearrangement at Xp11.2, including renal cell carcinomas, alveolar soft tissue sarcomas and perivascular epithelioid cell neoplasms.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (205, 226))	('rearrangement', 'Var', (170, 183))	('epithelioid cell neoplasms', 'Disease', (275, 301))	('TFE3', 'Gene', (25, 29))	('TFE3', 'Gene', '7030', (25, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('tumor', 'Disease', (153, 158))	('alveolar soft tissue sarcomas', 'Disease', (228, 257))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (237, 257))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('alveolar soft tissue sarcomas', 'Phenotype', 'HP:0012218', (228, 257))	('alveolar soft tissue sarcomas', 'Disease', 'MESH:D012509', (228, 257))	('sarcomas', 'Phenotype', 'HP:0100242', (249, 257))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (205, 226))	('epithelioid cell neoplasms', 'Disease', 'MESH:D054973', (275, 301))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (205, 225))	('renal cell carcinomas', 'Disease', (205, 226))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('neoplasms', 'Phenotype', 'HP:0002664', (292, 301))
246539	31043173	These results suggest the absence of TFE3 gene rearrangement in DTP cases.	('TFE3', 'Gene', '7030', (37, 41))	('TFE3', 'Gene', (37, 41))	('rearrangement', 'Var', (47, 60))	('DTP', 'Disease', (64, 67))
246541	31043173	To date, trisomy 8, trisomy 20, APC, and beta-catenin mutations have been recognized for their contributions to the development of DTF.	('APC', 'Disease', (32, 35))	('mutations', 'Var', (54, 63))	('APC', 'Phenotype', 'HP:0005227', (32, 35))	('trisomy 8', 'Gene', (9, 18))	('DTF', 'Disease', (131, 134))	('APC', 'Disease', 'MESH:D011125', (32, 35))	('beta-catenin', 'Protein', (41, 53))	('trisomy 20', 'Gene', (20, 30))
246544	31043173	Wnt signaling plays pivotal roles in regulating tissue regeneration and cancer development, which can be activated by TFE3 expression.	('TFE3', 'Gene', (118, 122))	('tissue regeneration', 'CPA', (48, 67))	('activated', 'PosReg', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('expression', 'Var', (123, 133))	('TFE3', 'Gene', '7030', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
246548	31043173	Translocations of TFE3 gene can lead to a significant increase in its protein levels, and thus is associated with a certain type of cancer.	('protein levels', 'MPA', (70, 84))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Translocations', 'Var', (0, 14))	('TFE3', 'Gene', '7030', (18, 22))	('increase', 'PosReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('associated', 'Reg', (98, 108))	('TFE3', 'Gene', (18, 22))
246549	31043173	For instance, xp11.2 TFE3 translocation gene fusions occur in a subset of patients with renal cell carcinoma, especially children and young females, as revealed by both FISH analysis and positive IHC staining for TFE3.	('TFE3', 'Gene', '7030', (21, 25))	('children', 'Species', '9606', (121, 129))	('renal cell carcinoma', 'Disease', (88, 108))	('patients', 'Species', '9606', (74, 82))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (88, 108))	('TFE3', 'Gene', (21, 25))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (88, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('TFE3', 'Gene', (213, 217))	('translocation gene fusions', 'Var', (26, 52))	('occur', 'Reg', (53, 58))	('TFE3', 'Gene', '7030', (213, 217))
246550	31043173	Moreover, TFE3 gene fusions have been identified in patients with alveolar soft part sarcoma, epithelioid hemangioendothelioma and hepatic perivascular epithelioid cell tumors.	('TFE3', 'Gene', '7030', (10, 14))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (66, 92))	('identified', 'Reg', (38, 48))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (66, 92))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (94, 126))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (75, 92))	('epithelioid hemangioendothelioma and hepatic perivascular epithelioid cell tumors', 'Disease', 'MESH:D054973', (94, 175))	('TFE3', 'Gene', (10, 14))	('fusions', 'Var', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('patients', 'Species', '9606', (52, 60))	('alveolar soft part sarcoma', 'Disease', (66, 92))
246576	29387511	ES and PNET share the same cytogenetic alterations (t(11;22) (q24;Q12) which forms the EWSR1-FLI1 fusion product) as well as similar histopathological and immunohistochemical characteristics.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('EWSR1', 'Gene', (87, 92))	('FLI1', 'Gene', (93, 97))	('FLI1', 'Gene', '2313', (93, 97))	('EWSR1', 'Gene', '2130', (87, 92))	('t(11', 'Var', (52, 56))
246594	29387511	It is the characteristic translocations that disrupt the EWSR1 gene located at 22q12 which confirms the diagnosis and is found in 95%-100% of these cases.	('EWSR1', 'Gene', (57, 62))	('translocations', 'Var', (25, 39))	('EWSR1', 'Gene', '2130', (57, 62))
246599	29387511	There are no characteristic radiological signals; however, most lesions are encapsulated, hypoechoic on ultrasound, hypodense on CT, and iso-hypointense on T1, hyperintense on T2 on magnetic resonance imaging (MRI).	('hypoechoic', 'Disease', (90, 100))	('hypoechoic', 'Disease', 'None', (90, 100))	('hypodense', 'Var', (116, 125))	('iso-hypointense', 'Var', (137, 152))
246696	27296355	The fundamental pathogenetic mechanism involves dysregulated cytokine activity, which causes systemic inflammatory symptoms as well as lymphadenopathy.	('lymphadenopathy', 'Phenotype', 'HP:0002716', (135, 150))	('dysregulated', 'Var', (48, 60))	('dysregulated cytokine activity', 'Phenotype', 'HP:0031407', (48, 78))	('lymphadenopathy', 'Disease', (135, 150))	('causes', 'Reg', (86, 92))	('systemic inflammatory symptoms', 'Disease', (93, 123))	('lymphadenopathy', 'Disease', 'MESH:D008206', (135, 150))	('cytokine activity', 'MPA', (61, 78))
246722	27296355	In fact, recent molecular studies demonstrated clonality in the stromal cells in hyaline vascular Castleman disease, and suggested that genetic alteration in stromal cells including FDCs may be the underlying cause of the disease.	('vascular Castleman disease', 'Disease', (89, 115))	('vascular Castleman disease', 'Disease', 'MESH:C536362', (89, 115))	('genetic alteration', 'Var', (136, 154))
246765	27296355	Of note, in the vIL-6 transgenic mice, the production of endogenous IL-6 was also significantly upregulated; when the vIL-6 transgene was transferred onto an IL-6-deficient genetic background, the MCD-like phenotypes were abrogated, indicating that endogenous IL-6 is crucial in the pathogenesis of the disease.	('vIL-6', 'Gene', '4961449', (118, 123))	('vIL-6', 'Gene', '4961449', (16, 21))	('transgenic mice', 'Species', '10090', (22, 37))	('MCD', 'Gene', (197, 200))	('vIL-6', 'Gene', (118, 123))	('abrogated', 'NegReg', (222, 231))	('vIL-6', 'Gene', (16, 21))	('MCD', 'Gene', '4582', (197, 200))	('transferred', 'Var', (138, 149))
246809	27296355	Sporadic reports have shown cytogenetic abnormality or prevalent gene polymorphism that involves the IL-6 (presumed by the authors) or IL-6 receptor genes in iMCD patients, suggesting that germline aberration in genes involved in the regulation of innate immunity may play a role.	('IL-6', 'Gene', (101, 105))	('patients', 'Species', '9606', (163, 171))	('iMCD', 'Chemical', '-', (158, 162))	('polymorphism', 'Var', (70, 82))	('IL-6 receptor', 'Gene', (135, 148))
246825	27296355	Of note, the morphologic features of the plasma cell variant of CD can be seen in association with the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins and skin changes), which is a paraneoplastic syndrome due to an underlying monoclonal plasma cell neoplasm.	('endocrinopathy', 'Disease', 'MESH:C567425', (149, 163))	('polyneuropathy', 'Disease', 'MESH:D011115', (119, 133))	('organomegaly', 'Disease', (135, 147))	('polyneuropathy', 'Disease', (119, 133))	('polyneuropathy', 'Phenotype', 'HP:0001271', (119, 133))	('variant', 'Var', (53, 60))	('endocrinopathy', 'Disease', (149, 163))	('paraneoplastic syndrome', 'Disease', (206, 229))	('CD', 'Chemical', 'MESH:D002104', (64, 66))	('neoplasm', 'Disease', (274, 282))	('organomegaly', 'Disease', 'MESH:D016878', (135, 147))	('POEMS syndrome', 'Disease', (103, 117))	('POEMS syndrome', 'Disease', 'MESH:D016878', (103, 117))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (206, 229))	('neoplasm', 'Disease', 'MESH:D009369', (274, 282))	('skin changes', 'Phenotype', 'HP:0000951', (180, 192))	('neoplasm', 'Phenotype', 'HP:0002664', (274, 282))
246834	27296355	Thirdly, the associated viruses, including HIV, KSHV/HHV8 and even EBV can lead to various lymphoproliferative disorders either independent of or in association with MCD, which can greatly confound the differential diagnoses Since the first reports from Castleman and coworkers more than 60 years ago, our growing knowledge about the various conditions associated with name 'Castleman disease' has illustrated the paradigm of disease discovery.	('lead to', 'Reg', (75, 82))	('HHV8', 'Species', '37296', (53, 57))	('KSHV', 'Species', '37296', (48, 52))	('viruses', 'Var', (24, 31))	('lymphoproliferative disorders', 'Disease', (91, 120))	('MCD', 'Gene', (166, 169))	("'Castleman disease", 'Disease', (374, 392))	('KSHV/HHV8', 'Gene', (48, 57))	('MCD', 'Gene', '4582', (166, 169))	('lymphoproliferative disorders', 'Disease', 'MESH:D008232', (91, 120))	('HIV', 'Species', '12721', (43, 46))	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (91, 120))	("'Castleman disease", 'Disease', 'MESH:C536362', (374, 392))	('lymphoproliferative disorder', 'Phenotype', 'HP:0005523', (91, 119))
246849	27499916	Transcriptional deregulation by epigenetic mechanisms is an important event in the pathogenesis of cancer 1.	('Transcriptional', 'MPA', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('epigenetic', 'Var', (32, 42))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
246865	27499916	HR23b interacts with the xeroderma pigmentosum complementation group C (XPC) protein for the recognition of damaged DNA 15.	('xeroderma pigmentosum complementation group C', 'Gene', (25, 70))	('HR23b', 'Gene', '5887', (0, 5))	('damaged', 'Var', (108, 115))	('DNA', 'Gene', (116, 119))	('XPC', 'Gene', (72, 75))	('xeroderma pigmentosum complementation group C', 'Gene', '7508', (25, 70))	('HR23b', 'Gene', (0, 5))	('XPC', 'Gene', '7508', (72, 75))
246868	27499916	In addition, siRNA knock down of HR23b attenuated HDACi mediated proteasome inhibition and cell death induction 13.	('HDAC', 'Gene', (50, 54))	('cell death induction 13', 'CPA', (91, 114))	('HDAC', 'Gene', '9734', (50, 54))	('attenuated', 'NegReg', (39, 49))	('knock down', 'Var', (19, 29))	('HR23b', 'Gene', '5887', (33, 38))	('HR23b', 'Gene', (33, 38))
246870	27499916	Another study showed that the expression of HR23b is associated with disease stabilisation under HDACi therapy with belinostat in nonresectable hepatocellular carcinoma 19.	('HR23b', 'Gene', '5887', (44, 49))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (144, 168))	('HR23b', 'Gene', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('HDAC', 'Gene', (97, 101))	('HDAC', 'Gene', '9734', (97, 101))	('expression', 'Var', (30, 40))	('hepatocellular carcinoma 19', 'Disease', (144, 171))	('belinostat', 'Chemical', 'MESH:C487081', (116, 126))	('associated', 'Reg', (53, 63))	('hepatocellular carcinoma 19', 'Disease', 'MESH:D006528', (144, 171))
246871	27499916	A phase II trial with vorinostat in cutaneous T-cell lymphoma patients showed that those with high HR23b expression had a clinical response in 69% of cases suggesting a high predictive value of HR23b in these lymphomas 20.	('cutaneous T-cell lymphoma', 'Disease', 'MESH:D016410', (36, 61))	('HR23b', 'Gene', '5887', (194, 199))	('lymphoma', 'Phenotype', 'HP:0002665', (209, 217))	('expression', 'MPA', (105, 115))	('patients', 'Species', '9606', (62, 70))	('HR23b', 'Gene', (194, 199))	('HR23b', 'Gene', '5887', (99, 104))	('HR23b', 'Gene', (99, 104))	('lymphomas', 'Disease', 'MESH:D008223', (209, 218))	('high', 'Var', (94, 98))	('lymphomas', 'Phenotype', 'HP:0002665', (209, 218))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (46, 61))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (36, 61))	('vorinostat', 'Chemical', 'MESH:D000077337', (22, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('cell lymphoma', 'Phenotype', 'HP:0012191', (48, 61))	('lymphomas', 'Disease', (209, 218))	('cutaneous T-cell lymphoma', 'Disease', (36, 61))	('clinical', 'Species', '191496', (122, 130))
246878	27499916	The test cohort consisted of cell lines from (GIST: GIST-T1 with a KIT exon 11 mutation (p.V560_Y578del), GIST882 with a p.K642E mutation in KIT exon 13 and GIST48 with a p.V560D mutation in KIT exon 11 and an additional p.D820A mutation in KIT exon 17), well/dedifferentiated liposarcomas (WDLS/DDLS: T778, T449 and Fu-DDLS-1 24), myxoid liposarcoma (MLS: MLS1765 and MLS402), leiomyosarcoma (LMS: SK-LMS and SK-UT-1), synovial sarcoma (SS: HS-SY-II, 1273/99 and SW982), malignant peripheral nerve sheath tumours (MPNST: T265, STS26T and ST8814) and Ewing sarcomas (EWS: SK-N-MC and SK-ES-1).	('MLS', 'Phenotype', 'HP:0012268', (369, 372))	('p.V560_Y578del', 'Mutation', 'p.560,578del_Y', (89, 103))	('LMS', 'Phenotype', 'HP:0100243', (402, 405))	('liposarcomas', 'Phenotype', 'HP:0012034', (277, 289))	('sarcoma', 'Phenotype', 'HP:0100242', (557, 564))	('malignant peripheral nerve sheath tumours', 'Disease', 'MESH:D018319', (472, 513))	('MLS', 'Disease', 'MESH:C537466', (352, 355))	('liposarcoma', 'Phenotype', 'HP:0012034', (277, 288))	('MLS', 'Disease', (352, 355))	('liposarcoma', 'Phenotype', 'HP:0012034', (339, 350))	('tumour', 'Phenotype', 'HP:0002664', (506, 512))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))	('MLS', 'Disease', 'MESH:C537466', (369, 372))	('SK-N-MC', 'CellLine', 'CVCL:0530', (572, 579))	('p.D820A', 'Var', (221, 228))	('MLS', 'Disease', (369, 372))	('ST8814', 'CellLine', 'CVCL:8916', (539, 545))	('EWS', 'Phenotype', 'HP:0012254', (567, 570))	('sarcoma', 'Phenotype', 'HP:0100242', (429, 436))	('MLS', 'Phenotype', 'HP:0012268', (357, 360))	('STS', 'Phenotype', 'HP:0030448', (528, 531))	('leiomyosarcoma', 'Disease', (378, 392))	('p.D820A', 'Mutation', 'p.D820A', (221, 228))	('liposarcomas', 'Disease', (277, 289))	('SK-ES-1', 'CellLine', 'CVCL:0627', (584, 591))	('HS-SY-II', 'CellLine', 'CVCL:8719', (442, 450))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (551, 565))	('synovial sarcoma', 'Disease', (420, 436))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (332, 350))	('MLS', 'Phenotype', 'HP:0012268', (352, 355))	('MLS', 'Disease', 'MESH:C537466', (357, 360))	('MPNST', 'Phenotype', 'HP:0100697', (515, 520))	('Ewing sarcomas', 'Disease', (551, 565))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (551, 565))	('p.V560D', 'Mutation', 'rs121913521', (171, 178))	('p.V560D mutation', 'Var', (171, 187))	('MLS', 'Disease', (357, 360))	('STS26', 'CellLine', 'CVCL:8917', (528, 533))	('synovial sarcoma', 'Disease', 'MESH:D013584', (420, 436))	('SW982', 'CellLine', 'CVCL:1734', (464, 469))	('p.K642E mutation', 'Var', (121, 137))	('myxoid liposarcoma', 'Disease', (332, 350))	('sarcomas', 'Phenotype', 'HP:0100242', (281, 289))	('p.K642E', 'Mutation', 'rs121913512', (121, 128))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (332, 350))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (420, 436))	('sarcoma', 'Phenotype', 'HP:0100242', (385, 392))	('sarcoma', 'Phenotype', 'HP:0100242', (343, 350))	('liposarcomas', 'Disease', 'MESH:D008080', (277, 289))	('malignant peripheral nerve sheath tumours', 'Phenotype', 'HP:0100697', (472, 513))	('sarcomas', 'Phenotype', 'HP:0100242', (557, 565))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (378, 392))	('SK-UT-1', 'CellLine', 'CVCL:0533', (410, 417))	('tumours', 'Phenotype', 'HP:0002664', (506, 513))	('SS', 'Phenotype', 'HP:0012570', (438, 440))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (378, 392))	('LMS', 'Phenotype', 'HP:0100243', (394, 397))	('malignant peripheral nerve sheath tumours', 'Disease', (472, 513))
246903	27499916	Four of four cell lines with high HR23b expression were sensitive to vorinostat, whereas none of the four relatively low HR23b expressing lines were sensitive.	('high', 'Var', (29, 33))	('expression', 'MPA', (40, 50))	('sensitive to vorinostat', 'MPA', (56, 79))	('HR23b', 'Gene', '5887', (34, 39))	('HR23b', 'Gene', '5887', (121, 126))	('HR23b', 'Gene', (34, 39))	('vorinostat', 'Chemical', 'MESH:D000077337', (69, 79))	('HR23b', 'Gene', (121, 126))
246907	27499916	The overall expression level of HR23b comparing low, moderate and high HR23b expression was significantly associated with sensitivity to HDACi for vorinostat (p = 0.016) but not for belinostat, mocetinostat and entinostat (p = 0.125, p = 0.813 and p = 0.471, respectively; Fisher's exact tests).	('HR23b', 'Gene', (71, 76))	('HR23b', 'Gene', (32, 37))	('associated', 'Reg', (106, 116))	('vorinostat', 'Chemical', 'MESH:D000077337', (147, 157))	('HR23b', 'Gene', '5887', (71, 76))	('mocetinostat', 'Chemical', 'MESH:C523184', (194, 206))	('entinostat', 'Chemical', 'MESH:C118739', (211, 221))	('HDAC', 'Gene', (137, 141))	('high', 'Var', (66, 70))	('belinostat', 'Chemical', 'MESH:C487081', (182, 192))	('HR23b', 'Gene', '5887', (32, 37))	('HDAC', 'Gene', '9734', (137, 141))	('expression', 'MPA', (12, 22))
246914	27499916	Mocetinostat resulted in similar effects on apoptosis as belinostat.	('apoptosis', 'CPA', (44, 53))	('Mocetinostat', 'Chemical', 'MESH:C523184', (0, 12))	('Mocetinostat', 'Var', (0, 12))	('belinostat', 'Chemical', 'MESH:C487081', (57, 67))
246935	27499916	In particular, those with a KIT exon 11 mutation showed higher HR23b expression more frequently compared to KIT exon 9 mutated GIST in this particular location (p = 0.014, Fisher's exact test).	('mutation', 'Var', (40, 48))	('HR23b', 'Gene', '5887', (63, 68))	('KIT exon 11', 'Gene', (28, 39))	('HR23b', 'Gene', (63, 68))	('expression', 'MPA', (69, 79))	('higher', 'PosReg', (56, 62))
246961	27499916	showed that 58% of the patients with high HR23b expression achieved disease stabilisation under HDACi 19.	('HDAC', 'Gene', '9734', (96, 100))	('high', 'Var', (37, 41))	('patients', 'Species', '9606', (23, 31))	('disease stabilisation', 'CPA', (68, 89))	('HR23b', 'Gene', (42, 47))	('HR23b', 'Gene', '5887', (42, 47))	('HDAC', 'Gene', (96, 100))
246962	27499916	In a phase II clinical trial with vorinostat, 69% of CTCL patients received good clinical response with high HR23b expressing tumours 20.	('clinical', 'Species', '191496', (81, 89))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('CTCL', 'Phenotype', 'HP:0012192', (53, 57))	('clinical', 'Species', '191496', (14, 22))	('HR23b', 'Gene', (109, 114))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('high', 'Var', (104, 108))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('tumours', 'Disease', (126, 133))	('patients', 'Species', '9606', (58, 66))	('HR23b', 'Gene', '5887', (109, 114))	('vorinostat', 'Chemical', 'MESH:D000077337', (34, 44))
247005	21182764	Mutation carriers have a significantly greater risk of contralateral breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('contralateral breast cancers', 'Disease', (55, 83))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('Mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('contralateral breast cancers', 'Disease', 'MESH:D001943', (55, 83))
247030	21182764	The risk factors for breast carcinoma are age, early menarche, later menopause, nulliparity, later first pregnancy, medical history, family history with first-degree relatives with breast cancer, presence of the mutation BRCA1 and BRCA2, previous thoracic external radiotherapy, high breast density in mammography, use of hormones (high doses of estrogens and progesterone), alcoholism, and the Caucasian race.	('high breast density', 'Phenotype', 'HP:0010313', (279, 298))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('BRCA2', 'Gene', (231, 236))	('BRCA1', 'Gene', (221, 226))	('BRCA1', 'Gene', '672', (221, 226))	('breast cancer', 'Disease', (181, 194))	('breast carcinoma', 'Disease', (21, 37))	('alcoholism', 'Disease', (375, 385))	('breast carcinoma', 'Disease', 'MESH:D001943', (21, 37))	('BRCA2', 'Gene', '675', (231, 236))	('alcoholism', 'Disease', 'MESH:D000437', (375, 385))	('alcoholism', 'Phenotype', 'HP:0030955', (375, 385))	('later menopause', 'Phenotype', 'HP:0008209', (63, 78))	('breast carcinoma', 'Phenotype', 'HP:0003002', (21, 37))	('presence', 'Var', (196, 204))
247128	31516547	In patients with normal CD4 cell counts (> = 500/mul) at the time of initiating chemotherapy, there was a trend towards better survival.	('better', 'PosReg', (120, 126))	('CD4', 'Gene', (24, 27))	('CD4', 'Gene', '920', (24, 27))	('> = 500/mul', 'Var', (41, 52))	('patients', 'Species', '9606', (3, 11))	('survival', 'MPA', (127, 135))
247156	31462266	However, astroglia differentiated on human LN521 showed higher expression of several astroglia specific mRNAs and proteins such as GFAP, S100B, Angiopoietin-1, and EAAT1, compared to astroglia differentiated on murine L2020.	('EAAT1', 'Gene', (164, 169))	('GFAP', 'Gene', (131, 135))	('EAAT1', 'Gene', '6507', (164, 169))	('S100B', 'Gene', '6285', (137, 142))	('murine', 'Species', '10090', (211, 217))	('GFAP', 'Gene', '2670', (131, 135))	('expression', 'MPA', (63, 73))	('Angiopoietin-1', 'Gene', (144, 158))	('S100B', 'Gene', (137, 142))	('LN521', 'Var', (43, 48))	('human', 'Species', '9606', (37, 42))	('higher', 'PosReg', (56, 62))	('Angiopoietin-1', 'Gene', '284', (144, 158))
247182	31462266	NES cells were differentiated to astroglia in plates coated with poly-l-ornithine and murine L2020 (Sigma Aldrich, St. Louis, MO, USA) or LN521 (Biolaminin 521, BioLamina, Sundbyberg, Sweden) at 2 microg/ml.	('poly-l-ornithine', 'Chemical', 'MESH:C008973', (65, 81))	('LN521', 'Var', (138, 143))	('laminin', 'Gene', (148, 155))	('laminin', 'Gene', '38723', (148, 155))	('murine', 'Var', (86, 92))	('murine', 'Species', '10090', (86, 92))
247205	31462266	Immunostaining analysis showed that astroglia differentiated on LN521 and L2020 expressed glia markers, such as fatty acid binding protein 7 (FABP7) (Fig.	('FABP7', 'Gene', '2173', (142, 147))	('fatty acid binding protein 7', 'Gene', (112, 140))	('FABP7', 'Gene', (142, 147))	('expressed', 'Reg', (80, 89))	('L2020', 'Var', (74, 79))	('fatty acid binding protein 7', 'Gene', '2173', (112, 140))	('astroglia', 'CPA', (36, 45))	('LN521', 'Var', (64, 69))
247208	31462266	LN521 differentiated astroglia showed higher expression of glia fibrillary acid protein (GFAP), S100B, aldehyde dehydrogenase (ALDH1L1), glial derived neurotrophic factor (GDNF) and angiopoietin-1 (Ang-1) for all three lines.	('ALDH1L1', 'Gene', '10840', (127, 134))	('glia fibrillary acid protein', 'Gene', (59, 87))	('higher', 'PosReg', (38, 44))	('angiopoietin-1', 'Gene', '284', (182, 196))	('GDNF', 'Gene', (172, 176))	('glial derived neurotrophic factor', 'Gene', (137, 170))	('GDNF', 'Gene', '2668', (172, 176))	('glial derived neurotrophic factor', 'Gene', '2668', (137, 170))	('S100B', 'Gene', (96, 101))	('ALDH1L1', 'Gene', (127, 134))	('angiopoietin-1', 'Gene', (182, 196))	('Ang-1', 'Gene', (198, 203))	('Ang-1', 'Gene', '284', (198, 203))	('GFAP', 'Gene', (89, 93))	('glia fibrillary acid protein', 'Gene', '2670', (59, 87))	('GFAP', 'Gene', '2670', (89, 93))	('LN521', 'Var', (0, 5))	('S100B', 'Gene', '6285', (96, 101))	('expression', 'MPA', (45, 55))
247209	31462266	Additionally, the C1 and C9 lines showed higher expression of fatty acid binding protein 7 (FABP7) in astroglia differentiated on LN521 compared to L2020.	('expression', 'MPA', (48, 58))	('fatty acid binding protein 7', 'Gene', '2173', (62, 90))	('fatty acid binding protein 7', 'Gene', (62, 90))	('FABP7', 'Gene', '2173', (92, 97))	('higher', 'PosReg', (41, 47))	('C1 and C9', 'Gene', '735', (18, 27))	('FABP7', 'Gene', (92, 97))	('LN521', 'Var', (130, 135))
247213	31462266	mRNA levels of EAAT1 were higher in astroglia differentiated on LN521 compared to L2020 while no difference in EAAT2 mRNA expression was observed.	('higher', 'PosReg', (26, 32))	('EAAT2', 'Gene', (111, 116))	('EAAT1', 'Gene', (15, 20))	('EAAT2', 'Gene', '6506', (111, 116))	('EAAT1', 'Gene', '6507', (15, 20))	('LN521', 'Var', (64, 69))	('astroglia differentiated', 'CPA', (36, 60))	('mRNA levels', 'MPA', (0, 11))
247218	31462266	3c) was significantly higher in astroglia differentiated on LN521 (means +- standard deviations: C1 92.2 +- 1.4, C9 78.1 +- 6.0, AF 86.1 +- 2.4) than in astroglia differentiated on L2020 (means +- standard deviations: C1 64.4 +- 8.0, C9 63.3 +- 1.3, AF 69.6 +- 3.2).	('AF', 'Disease', 'MESH:D001281', (129, 131))	('higher', 'PosReg', (22, 28))	('astroglia', 'CPA', (32, 41))	('AF', 'Disease', 'MESH:D001281', (250, 252))	('LN521', 'Var', (60, 65))
247219	31462266	Similarly, EAAT1 mRNA was more highly expressed in astroglia differentiated on LN521 than on L2020, for all lines (Fig.	('LN521', 'Var', (79, 84))	('EAAT1', 'Gene', '6507', (11, 16))	('EAAT1', 'Gene', (11, 16))	('astroglia differentiated', 'CPA', (51, 75))	('highly', 'PosReg', (31, 37))
247220	31462266	To further understand these differences in glutamate uptake seen in astroglia differentiated on LN521 and L2020, mRNA levels of genes encoding proteins involved in the glutamate metabolism (Fig.	('LN521', 'Var', (96, 101))	('glutamate', 'Chemical', 'MESH:D018698', (168, 177))	('mRNA levels', 'MPA', (113, 124))	('L2020', 'Var', (106, 111))	('glutamate', 'Chemical', 'MESH:D018698', (43, 52))
247224	31462266	These results imply that differentiation on LN521 affects the glutamate metabolism as astroglia differentiated on LN521 showed higher expression of both glutamate importer EAAT1 and glutamine exporter SNAT3 across all the three lines.	('SNAT3', 'Gene', '10991', (201, 206))	('SNAT3', 'Gene', (201, 206))	('expression', 'MPA', (134, 144))	('EAAT1', 'Gene', (172, 177))	('EAAT1', 'Gene', '6507', (172, 177))	('LN521', 'Var', (114, 119))	('glutamate', 'Chemical', 'MESH:D018698', (62, 71))	('higher', 'PosReg', (127, 133))	('glutamate', 'Chemical', 'MESH:D018698', (153, 162))	('glutamate metabolism', 'MPA', (62, 82))	('glutamine', 'Chemical', 'MESH:D005973', (182, 191))
247226	31462266	Secretion of IL8 and IL6 were investigated to understand if the inflammatory state of the astroglia is different between differentiation on LN521 or L2020.	('IL6', 'Gene', '3569', (21, 24))	('L2020', 'Var', (149, 154))	('IL6', 'Gene', (21, 24))	('IL8', 'Gene', (13, 16))	('IL8', 'Gene', '3576', (13, 16))	('LN521', 'Var', (140, 145))
247230	31462266	Astroglia differentiated on LN521 secreted more S100B (Fig.	('S100B', 'Gene', (48, 53))	('S100B', 'Gene', '6285', (48, 53))	('LN521', 'Var', (28, 33))
247232	31462266	IL8 secretion was higher in C1 astroglia differentiated on LN521 than L2020, however, this difference was not seen in the other lines (Fig.	('LN521', 'Var', (59, 64))	('higher', 'PosReg', (18, 24))	('IL8', 'Gene', (0, 3))	('IL8', 'Gene', '3576', (0, 3))	('C1 astroglia', 'CPA', (28, 40))	('L2020', 'Var', (70, 75))
247233	31462266	No significant differences in media concentrations of APOE were observed between astroglia differentiated on LN521 and L2020 (Fig.	('APOE', 'Gene', (54, 58))	('APOE', 'Gene', '348', (54, 58))	('L2020', 'Var', (119, 124))	('LN521', 'Var', (109, 114))	('astroglia', 'CPA', (81, 90))
247234	31462266	Coculture with both LN521 astroglia and L2020 astroglia increased the paracellular tightness of r-iBECs as measured by TEER, compared to monocultured r-iBECs, for all lines (Fig.	('LN521', 'Var', (20, 25))	('tightness', 'Disease', (83, 92))	('increased', 'PosReg', (56, 65))	('L2020', 'Var', (40, 45))	('tightness', 'Disease', 'MESH:C536920', (83, 92))
247235	31462266	Passive permeability measured by fluorescein permeability was decreased in r-iBECs cocultured with both LN521 astroglia and L2020 astroglia compared to monoculture r-iBECs.	('L2020', 'Var', (124, 129))	('decreased', 'NegReg', (62, 71))	('Passive permeability', 'MPA', (0, 20))	('LN521', 'Var', (104, 109))	('fluorescein', 'Chemical', 'MESH:D019793', (33, 44))	('fluorescein permeability', 'MPA', (33, 57))
247236	31462266	Fluorescein permeability was lower in r-iBECs cocultured with L2020 astroglia compared to coculture with LN521 astroglia (Fig.	('lower', 'NegReg', (29, 34))	('Fluorescein permeability', 'MPA', (0, 24))	('Fluorescein', 'Chemical', 'MESH:D019793', (0, 11))	('L2020', 'Var', (62, 67))
247238	31462266	6c-k) showed higher expression of VE-cadherin in r-iBECs cocultured with LN521 astroglia lines compared to r-iBECs cocultured with L2020 astroglia lines (Fig.	('expression', 'MPA', (20, 30))	('LN521', 'Var', (73, 78))	('higher', 'PosReg', (13, 19))	('VE-cadherin', 'Gene', (34, 45))	('VE-cadherin', 'Gene', '1003', (34, 45))
247243	31462266	Astroglia differentiated on LN521 showed higher mRNA expression of known astroglia markers such as GFAP, GDNF, and S100B, across all three iPSC lines included in this study.	('LN521', 'Var', (28, 33))	('GDNF', 'Gene', (105, 109))	('GFAP', 'Gene', (99, 103))	('S100B', 'Gene', '6285', (115, 120))	('higher', 'PosReg', (41, 47))	('mRNA expression', 'MPA', (48, 63))	('GDNF', 'Gene', '2668', (105, 109))	('GFAP', 'Gene', '2670', (99, 103))	('S100B', 'Gene', (115, 120))
247246	31462266	The C1 line showed higher IL8 secretion when differentiated on LN521 compared to L2020 while no differences were identified in IL8 secretion in the other lines, and hence no uniform changes were observed in IL8 and IL6 secretion across the three cell lines.	('LN521', 'Var', (63, 68))	('IL8', 'Gene', (207, 210))	('IL8', 'Gene', '3576', (207, 210))	('higher', 'PosReg', (19, 25))	('IL8', 'Gene', (26, 29))	('IL8', 'Gene', '3576', (26, 29))	('IL8', 'Gene', (127, 130))	('IL8', 'Gene', '3576', (127, 130))	('IL6', 'Gene', '3569', (215, 218))	('IL6', 'Gene', (215, 218))
247250	31462266	Astroglia differentiated on LN521 have higher secretion of S100B and Ang-1 compared to astroglia differentiated on L2020.	('S100B', 'Gene', '6285', (59, 64))	('higher', 'PosReg', (39, 45))	('Ang-1', 'Gene', '284', (69, 74))	('S100B', 'Gene', (59, 64))	('Ang-1', 'Gene', (69, 74))	('secretion', 'MPA', (46, 55))	('LN521', 'Var', (28, 33))
247257	31462266	S100B secreted from astroglia in this study (recalculated to nM) were approximately 0.1 nM in L2020 cultures and 0.5 nM in LN521 cultures.	('S100B', 'Gene', (0, 5))	('L2020', 'Var', (94, 99))	('S100B', 'Gene', '6285', (0, 5))
247258	31462266	Astroglia cultured on LN521 have higher S100B mRNA expression and higher secretion of S100B suggesting that there is an increase in both S100B mRNA and S100B protein levels.	('higher', 'PosReg', (33, 39))	('S100B', 'Gene', '6285', (137, 142))	('S100B', 'Gene', (40, 45))	('increase', 'PosReg', (120, 128))	('S100B', 'Gene', '6285', (86, 91))	('S100B', 'Gene', '6285', (152, 157))	('S100B', 'Gene', (137, 142))	('higher', 'PosReg', (66, 72))	('S100B', 'Gene', (86, 91))	('LN521', 'Var', (22, 27))	('S100B', 'Gene', (152, 157))	('S100B', 'Gene', '6285', (40, 45))
247263	31462266	Astroglia cultures differentiated on LN521 were found to have higher expression of EAAT1 at both mRNA and protein levels, in all three investigated lines.	('EAAT1', 'Gene', (83, 88))	('EAAT1', 'Gene', '6507', (83, 88))	('expression', 'MPA', (69, 79))	('higher', 'PosReg', (62, 68))	('LN521', 'Var', (37, 42))
247270	31462266	Hence, the increase in EAAT1 expression seen in astroglia differentiated on LN521 could represent a more mature postnatal astroglia phenotype.	('increase', 'PosReg', (11, 19))	('EAAT1', 'Gene', '6507', (23, 28))	('LN521', 'Var', (76, 81))	('EAAT1', 'Gene', (23, 28))	('expression', 'MPA', (29, 39))
247274	31462266	Astroglia differentiated on both LN521 and L2020 create coculture BBB models with high TEER and low fluorescein permeability in the range of 1.5-3 x 10-6 cm/s, comparable to previously published hiPSC-derived BBB coculture models.	('fluorescein', 'Chemical', 'MESH:D019793', (100, 111))	('fluorescein permeability', 'MPA', (100, 124))	('TEER', 'MPA', (87, 91))	('LN521', 'Var', (33, 38))	('low', 'NegReg', (96, 99))	('L2020', 'Var', (43, 48))
247275	31462266	LN521 and L2020 astroglia promoted expression of BBB-specific proteins and transporters, and LN521 astroglia cocultures showed to improve the expression of VE-cadherin in r-iBECs.	('improve', 'PosReg', (130, 137))	('VE-cadherin', 'Gene', (156, 167))	('LN521', 'Var', (93, 98))	('promoted', 'PosReg', (26, 34))	('expression', 'MPA', (35, 45))	('transporters', 'MPA', (75, 87))	('VE-cadherin', 'Gene', '1003', (156, 167))	('expression', 'MPA', (142, 152))	('L2020', 'Var', (10, 15))	('BBB-specific proteins', 'Protein', (49, 70))
247282	31462266	Both the mRNA expression and the secretion of Ang-1 to the media were higher in LN521 astroglia compared to L2020 astroglia.	('Ang-1', 'Gene', (46, 51))	('Ang-1', 'Gene', '284', (46, 51))	('mRNA expression', 'MPA', (9, 24))	('LN521', 'Var', (80, 85))	('secretion of', 'MPA', (33, 45))	('higher', 'PosReg', (70, 76))
247283	31462266	We speculate that this could be the mechanism behind the increased expression of adherence junction protein VE-cadherin in r-iBECs cocultured with astroglia differentiated on LN521 compared to L2020.	('VE-cadherin', 'Gene', (108, 119))	('VE-cadherin', 'Gene', '1003', (108, 119))	('increased', 'PosReg', (57, 66))	('expression', 'MPA', (67, 77))	('LN521', 'Var', (175, 180))
247284	31462266	In addition, mRNA levels of GDNF were higher in astroglia differentiated on LN521, which could be another contributing factor to higher expression of VE-cadherin in r-iBECs cocultured with astroglia differentiated on LN521.	('GDNF', 'Gene', (28, 32))	('astroglia', 'CPA', (48, 57))	('LN521', 'Var', (76, 81))	('GDNF', 'Gene', '2668', (28, 32))	('VE-cadherin', 'Gene', (150, 161))	('higher', 'PosReg', (38, 44))	('mRNA levels', 'MPA', (13, 24))	('VE-cadherin', 'Gene', '1003', (150, 161))
247285	31462266	However, the GDNF concentration in the media was very low and differences between astroglia differentiated on LN521 and L2020 could therefore not be evaluated.	('L2020', 'Var', (120, 125))	('GDNF', 'Gene', '2668', (13, 17))	('GDNF', 'Gene', (13, 17))	('LN521', 'Var', (110, 115))
247288	31462266	r-iBECs in coculture with L2020 astroglia had lower fluorescein permeability than r-iBECs in coculture with LN521 astroglia.	('fluorescein', 'Chemical', 'MESH:D019793', (52, 63))	('lower', 'NegReg', (46, 51))	('L2020', 'Var', (26, 31))	('fluorescein permeability', 'MPA', (52, 76))
247294	31462266	P-gp through increased efflux of small lipophilic molecules and decreased caveolin1 by reduced transcytosis, both high P-gp and low caveolin1 are hallmarks of brain endothelium.	('high', 'Var', (114, 118))	('caveolin1', 'Gene', '857', (132, 141))	('caveolin1', 'Gene', '857', (74, 83))	('P-gp', 'Gene', '283871', (0, 4))	('P-gp', 'Gene', (119, 123))	('transcytosis', 'MPA', (95, 107))	('reduced', 'NegReg', (87, 94))	('P-gp', 'Gene', '283871', (119, 123))	('increased', 'PosReg', (13, 22))	('reduced transcytosis', 'Phenotype', 'HP:0025066', (87, 107))	('P-gp', 'Gene', (0, 4))	('efflux of small lipophilic molecules', 'MPA', (23, 59))	('low', 'NegReg', (128, 131))	('caveolin1', 'Gene', (132, 141))	('caveolin1', 'Gene', (74, 83))	('decreased', 'NegReg', (64, 73))
247296	31462266	In addition, our results suggest that astroglia differentiated on LN521 have a higher secretion of factors important for BBB formation in hiPSC-derived endothelial cells such as Ang-1.	('LN521', 'Var', (66, 71))	('Ang-1', 'Gene', '284', (178, 183))	('secretion of factors', 'MPA', (86, 106))	('Ang-1', 'Gene', (178, 183))	('higher', 'PosReg', (79, 85))	('astroglia', 'CPA', (38, 47))
247336	31310220	Orthologs of 8 KSHV genes (ORF11, K2, K4.2, K5, K6, K7, ORF49, and K12) are absent from CbGHV1.	('CbGHV1', 'Gene', (88, 94))	('K4.2', 'Gene', (38, 42))	('K12', 'Var', (67, 70))	('ORF49', 'Gene', (56, 61))	('KSHV', 'Species', '37296', (15, 19))	('ORF11', 'Gene', (27, 32))	('ORF11', 'Gene', '4961439', (27, 32))	('K4.2', 'Gene', '4961450', (38, 42))	('ORF49', 'Gene', '4961448', (56, 61))	('KSHV', 'Gene', (15, 19))
247339	31310220	Because ORF10 and ORF11 are related and may have arisen by duplication from an ancestral deoxyuridine triphosphatase gene, their functions may overlap.	('ORF11', 'Gene', (18, 23))	('duplication', 'Var', (59, 70))	('ORF10', 'Gene', (8, 13))	('ORF11', 'Gene', '4961439', (18, 23))
247594	25613038	5-year OS was 63% (95% CI 41-85%) for patients with positive IGF-1R/nuclear expression, and 73% (95% CI 61-85%; P = 0.05) in negative patients.	('positive', 'Var', (52, 60))	('IGF-1R', 'Gene', '3480', (61, 67))	('patients', 'Species', '9606', (134, 142))	('IGF-1R', 'Gene', (61, 67))	('patients', 'Species', '9606', (38, 46))	('positive IGF-1R', 'Phenotype', 'HP:0030269', (52, 67))
247645	25613038	The presence of SSX fusion transcripts was assessed on 46 frozen tissues by RT-PCR: 28 cases presented SSX1 variant, 18 had SSX2 variant.	('SSX2', 'Gene', (124, 128))	('SSX', 'Gene', '6757', (16, 19))	('variant', 'Var', (108, 115))	('SSX', 'Gene', (16, 19))	('SSX1', 'Gene', '6756', (103, 107))	('SSX2', 'Gene', '6757', (124, 128))	('SSX', 'Gene', '6757', (124, 127))	('SSX1', 'Gene', (103, 107))	('SSX', 'Gene', (103, 106))	('SSX', 'Gene', '6757', (103, 106))	('SSX', 'Gene', (124, 127))
247673	25613038	The implication of IGF/IGF-1R axis in SS development and management was discussed in a study demonstrating that SS18-SSX1 or SS18-SSX2 fusion genes up-regulate insulin-like growth factor-2 (IGF-2) through epigenetic mechanisms.	('SSX1', 'Gene', (117, 121))	('insulin-like growth factor-2', 'Gene', '3481', (160, 188))	('SSX2', 'Gene', '6757', (130, 134))	('SS18', 'Gene', (125, 129))	('insulin-like growth factor-2', 'Gene', (160, 188))	('IGF-1R', 'Gene', '3480', (23, 29))	('SSX2', 'Gene', (130, 134))	('IGF-1R', 'Gene', (23, 29))	('IGF-2', 'Gene', (190, 195))	('SS18', 'Gene', '6760', (125, 129))	('SS18', 'Gene', (112, 116))	('up-regulate', 'PosReg', (148, 159))	('SSX1', 'Gene', '6756', (117, 121))	('fusion genes', 'Var', (135, 147))	('IGF-2', 'Gene', '3481', (190, 195))	('SS18', 'Gene', '6760', (112, 116))
247675	25613038	In this study we demonstrated that a high percentage of SS presented positivity for IGF-1R, with nuclear and/or cytoplasmatic immunostaining in both monophasic and biphasic subtypes.	('IGF-1R', 'Gene', (84, 90))	('IGF-1R', 'Gene', '3480', (84, 90))	('positivity', 'Var', (69, 79))
247691	25613038	Altogether, these findings, should be analyzed in the context of older reported prognostic factors such as Ki67 and p53, and newer ones such as CINSARC.	('p53', 'Gene', '7157', (116, 119))	('Ki67', 'Var', (107, 111))	('p53', 'Gene', (116, 119))
247692	25613038	In a future scenario an high expression of Ki67, a mutated p53, a C2 CINSARC signature (increased genomic complexity), together with nuclear positivity for CXCR4 and IGF-1R expression, could represent novel tools to stratify SS patients for treatment.	('p53', 'Gene', (59, 62))	('Ki67', 'Var', (43, 47))	('p53', 'Gene', '7157', (59, 62))	('CXCR4', 'Gene', '7852', (156, 161))	('IGF-1R', 'Gene', '3480', (166, 172))	('IGF-1R', 'Gene', (166, 172))	('patients', 'Species', '9606', (228, 236))	('CXCR4', 'Gene', (156, 161))	('mutated', 'Var', (51, 58))
247725	22529590	Immunohistochemical staining revealed positivity for pancytokeratin in epithelial cells and spindle cells, and vimentin was positive for only the fibrous stroma [Figures 6-8].	('vimentin', 'Gene', '7431', (111, 119))	('positivity', 'Var', (38, 48))	('vimentin', 'Gene', (111, 119))	('pancytokeratin', 'Protein', (53, 67))	('fibrous stroma', 'Disease', 'MESH:D010411', (146, 160))	('fibrous stroma', 'Disease', (146, 160))
247738	22529590	Molecular studies of synovial sarcomas in other parts of the body reveal a characteristic translocation t(X;18)(p11.2;q11.2).	('t(X;18)(p11.2;q11.2', 'Var', (104, 123))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (104, 124))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (21, 38))	('synovial sarcomas', 'Disease', 'MESH:D013584', (21, 38))	('synovial sarcomas', 'Disease', (21, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (21, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))
247739	22529590	Bridge et al in 1988 in a cytogenetic analysis of a synovial sarcoma of the base of the tongue showed a reciprocal translocation involving chromosomes X and 18 t(X;18)(pl1.2;q11.2).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (52, 68))	('synovial sarcoma', 'Disease', 'MESH:D013584', (52, 68))	('t(X;18', 'Var', (160, 166))	('synovial sarcoma', 'Disease', (52, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
247803	32867125	Soft tissue sarcomas can be divided broadly into two genetic classes: (1) simple karyotype sarcomas associated with a recurrent mutation or translocation (e.g., synovial sarcoma, Ewing sarcoma) and (2) complex karyotype sarcomas with numerous chromosomal aberrations but a general lack of recurrent mutations (e.g., pleomorphic liposarcoma, leiomyosarcoma, MPNST).	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('Ewing sarcoma', 'Disease', (179, 192))	('Soft tissue sarcomas', 'Phenotype', 'HP:0030448', (0, 20))	('synovial sarcoma', 'Disease', (161, 177))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (316, 339))	('sarcomas', 'Disease', 'MESH:D012509', (220, 228))	('synovial sarcoma', 'Disease', 'MESH:D013584', (161, 177))	('sarcomas', 'Phenotype', 'HP:0100242', (220, 228))	('translocation', 'Var', (140, 153))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('sarcomas', 'Disease', (220, 228))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('MPNST', 'Phenotype', 'HP:0100697', (357, 362))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcomas', 'Disease', (12, 20))	('mutation', 'Var', (128, 136))	('sarcomas', 'Disease', (91, 99))	('numerous chromosomal aberrations', 'Phenotype', 'HP:0040012', (234, 266))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (161, 177))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (341, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (341, 355))	('associated', 'Reg', (100, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (179, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (179, 192))	('liposarcoma', 'Phenotype', 'HP:0012034', (328, 339))	('pleomorphic liposarcoma', 'Disease', (316, 339))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('leiomyosarcoma', 'Disease', (341, 355))
247871	32867125	MLPSs show a specific t(12;16)(q13;p11) with FUS-DDIT3 fusion gene in most cases (90-95%) and rarely t(12;22)(q13;q12) with EWSR1-DDIT3 fusion gene.	('FUS', 'Gene', '2521', (45, 48))	('MLPSs', 'Disease', (0, 5))	('EWSR1', 'Gene', (124, 129))	('MLPSs', 'Disease', 'None', (0, 5))	('DDIT3', 'Gene', '1649', (49, 54))	('t(12;16)(q13;p11', 'Var', (22, 38))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (22, 39))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (101, 118))	('DDIT3', 'Gene', (130, 135))	('MLPS', 'Phenotype', 'HP:0012268', (0, 4))	('EWSR1', 'Gene', '2130', (124, 129))	('DDIT3', 'Gene', '1649', (130, 135))	('FUS', 'Gene', (45, 48))	('DDIT3', 'Gene', (49, 54))
247926	32867125	In approximately 50-60% of IMTs, the tumors harbor rearrangement of the ALK gene at chromosome 2p23.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('ALK', 'Gene', (72, 75))	('ALK', 'Gene', '238', (72, 75))	('IMTs', 'Disease', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('rearrangement', 'Var', (51, 64))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
247991	32867125	Amplification of MDM2 can be detected in some of the high-grade EOSs.	('EOSs', 'Disease', 'None', (64, 68))	('Amplification', 'Var', (0, 13))	('EOSs', 'Disease', (64, 68))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))
248042	32867125	Deletion of the TSC2 gene on chromosome 16p and its consequent mTOR activation play a relevant role in the neoplastic process.	('neoplastic process', 'CPA', (107, 125))	('mTOR', 'Gene', (63, 67))	('neoplastic process', 'Phenotype', 'HP:0002664', (107, 125))	('activation', 'PosReg', (68, 78))	('TSC2', 'Gene', '7249', (16, 20))	('TSC2', 'Gene', (16, 20))	('mTOR', 'Gene', '2475', (63, 67))	('Deletion', 'Var', (0, 8))
248070	32867125	In pleomorphic RMS, the tumor cells are positive for desmin, myogenin, and MYOD1.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('myogenin', 'Gene', '4656', (61, 69))	('pleomorphic', 'Var', (3, 14))	('tumor', 'Disease', (24, 29))	('MYOD1', 'Protein', (75, 80))	('RMS', 'Phenotype', 'HP:0002859', (15, 18))	('desmin', 'Gene', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('myogenin', 'Gene', (61, 69))	('positive', 'Reg', (40, 48))	('desmin', 'Gene', '1674', (53, 59))
248084	32867125	Strong nuclear ERG immunoreactivity is specific for ES with EWSR1-ERG rearrangement.	('ERG', 'Gene', '2078', (66, 69))	('EWSR1', 'Gene', '2130', (60, 65))	('ERG', 'Gene', (66, 69))	('ERG', 'Gene', '2078', (15, 18))	('rearrangement', 'Var', (70, 83))	('ERG', 'Gene', (15, 18))	('EWSR1', 'Gene', (60, 65))	('ES', 'Phenotype', 'HP:0012254', (52, 54))
248090	32867125	Recently defined CIC-rearranged sarcomas and sarcomas with BCOR genetic alterations may occur in the retroperitoneum.	('BCOR', 'Gene', '54880', (59, 63))	('BCOR', 'Gene', (59, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('CIC-rearranged sarcoma', 'Disease', (17, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('CIC-rearranged sarcoma', 'Disease', 'MESH:D012509', (17, 39))	('genetic alterations', 'Var', (64, 83))	('sarcomas and sarcomas', 'Disease', 'MESH:D012509', (32, 53))
248092	32867125	Sarcomas with BCOR genetic alterations show solid sheets of uniform round to ovoid cells in a myxoid matrix and strong nuclear expression of BCOR and CCNB3.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('BCOR', 'Gene', '54880', (14, 18))	('CCNB3', 'Gene', '85417', (150, 155))	('BCOR', 'Gene', (141, 145))	('BCOR', 'Gene', '54880', (141, 145))	('genetic alterations', 'Var', (19, 38))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('CCNB3', 'Gene', (150, 155))	('BCOR', 'Gene', (14, 18))	('Sarcomas', 'Disease', (0, 8))
248108	32471472	On multivariate analysis, tumor size > 5 cm and non-initial radiation therapy were independent risk factors for OS in all patients, non-initial radiation therapy was an independent risk factor for EFS in all patients, and tumor size > 5 cm was an independent risk factor for OS in patients with events.	('patients', 'Species', '9606', (208, 216))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('non-initial radiation therapy', 'Var', (132, 161))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('patients', 'Species', '9606', (281, 289))	('patients', 'Species', '9606', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('EFS', 'Disease', (197, 200))
248155	32471472	Tumor size > 5 cm and non-initial RT were independent risk factors for OS in all patients, non-initial RT was an independent risk factor for EFS in all patients, and tumor size > 5 cm was an independent risk factor for OS in patients with events.	('non-initial', 'Var', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (225, 233))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('EFS', 'Disease', (141, 144))	('tumor', 'Disease', (166, 171))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (152, 160))
248180	32471472	But PAX-FOXO1 fusion gene status is absolutely a very important prognostic factor and is widely reported, not being able to analyze it could be a flaw of this study.	('FOXO1', 'Gene', (8, 13))	('FOXO1', 'Gene', '2308', (8, 13))	('fusion gene', 'Var', (14, 25))
248186	31380285	The Lethality of [Pazopanib + HDAC Inhibitors] Is Enhanced by Neratinib Sarcomas are a diverse set of malignancies.	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('Lethality', 'MPA', (4, 13))	('Neratinib', 'Chemical', 'MESH:C487932', (62, 71))	('Sarcomas', 'Disease', (72, 80))	('Sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('Neratinib', 'Var', (62, 71))	('malignancies', 'Disease', (102, 114))	('Enhanced', 'PosReg', (50, 58))	('Pazopanib', 'Chemical', 'MESH:C516667', (18, 27))	('Sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('HDAC', 'Gene', (30, 34))	('HDAC', 'Gene', '9734', (30, 34))
248195	31380285	Compared to other manipulations, knock down of eIF2alpha or over-expression of BCL-XL significantly reduced killing by the three-drug interaction.	('drug interaction', 'Phenotype', 'HP:0020172', (129, 145))	('eIF2alpha', 'Gene', '83939', (47, 56))	('killing', 'MPA', (108, 115))	('reduced', 'NegReg', (100, 107))	('knock down', 'Var', (33, 43))	('BCL-XL', 'Gene', (79, 85))	('eIF2alpha', 'Gene', (47, 56))	('over-expression', 'PosReg', (60, 75))	('BCL-XL', 'Gene', '598', (79, 85))
248203	31380285	This study identified an improvement of overall survival of ~2 months (10.7-12.5 months) in patients treated with pazopanib.	('pazopanib', 'Var', (114, 123))	('overall survival', 'MPA', (40, 56))	('patients', 'Species', '9606', (92, 100))	('pazopanib', 'Chemical', 'MESH:C516667', (114, 123))	('improvement', 'PosReg', (25, 36))
248213	31380285	Our most notable discovery was that not only did neratinib catalytically inhibit ERBB1/2/4, as it was designed to do, it also triggered the rapid internalization and subsequent proteolytic degradation of these receptors.	('triggered', 'Reg', (126, 135))	('neratinib', 'Var', (49, 58))	('internalization', 'MPA', (146, 161))	('proteolytic degradation', 'MPA', (177, 200))	('inhibit', 'NegReg', (73, 80))	('neratinib', 'Chemical', 'MESH:C487932', (49, 58))	('ERBB1/2/4', 'Pathway', (81, 90))
248217	31380285	We also discovered that not only did neratinib cause ERBB1/2/4 and c-MET degradation, it was also capable of causing plasma membrane-associated mutant RAS proteins to be internalized and degraded.	('proteins', 'Protein', (155, 163))	('neratinib', 'Chemical', 'MESH:C487932', (37, 46))	('cause', 'Reg', (47, 52))	('internalized', 'MPA', (170, 182))	('RAS proteins', 'Protein', (151, 163))	('degraded', 'MPA', (187, 195))	('c-MET', 'Gene', (67, 72))	('neratinib', 'Var', (37, 46))	('causing', 'Reg', (109, 116))	('ERBB1/2/4', 'MPA', (53, 62))	('mutant', 'Var', (144, 150))	('c-MET', 'Gene', '4233', (67, 72))
248218	31380285	The ability of neratinib to trigger all these events were enhanced by HDAC inhibitors, which was attributed to inactivation of chaperone proteins and a more intense prolonged autophagic digestive process.	('autophagic digestive process', 'CPA', (175, 203))	('inhibitors', 'Var', (75, 85))	('HDAC', 'Gene', (70, 74))	('chaperone proteins', 'Protein', (127, 145))	('enhanced', 'PosReg', (58, 66))	('HDAC', 'Gene', '9734', (70, 74))	('inactivation', 'NegReg', (111, 123))	('ability', 'MPA', (4, 11))	('neratinib', 'Chemical', 'MESH:C487932', (15, 24))
248219	31380285	Thus, in addition to inhibiting the primary evolution mechanism of compensatory survival signaling following [pazopanib + entinostat] exposure, neratinib could also attack other survival-related events such as RAS mutations.	('compensatory survival signaling', 'MPA', (67, 98))	('survival-related', 'CPA', (178, 194))	('inhibiting', 'NegReg', (21, 31))	('mutations', 'Var', (214, 223))	('neratinib', 'Chemical', 'MESH:C487932', (144, 153))	('RAS', 'Protein', (210, 213))	('attack', 'Reg', (165, 171))	('pazopanib', 'Chemical', 'MESH:C516667', (110, 119))	('entinostat', 'Chemical', 'MESH:C118739', (122, 132))
248227	31380285	Antibodies used: AIF (5318), BAX (5023), BAK (12105), BAD (9239), BIM (2933), BAK1 (12105), Beclin1 (3495), cathepsin B (31718), CD95 (8023), FADD (2782), eIF2alpha (5324), P-eIF2alpha S51 (3398), ULK-1 (8054), P-ULK-1 S757 (14202), P-AMPK S51 (2535), AMPKalpha (2532), P-ATM S1981 (13050), ATM (2873), ATG5 (12994), mTOR (2983), P-mTOR S2448 (5536), P-mTOR S2481 (2974), ATG13 (13468), MCL-1 (94296), BCL-XL (2764), P-AKT T308 (13038), P-ERK1/2 (5726), P-STAT3 Y705 (9145), P-p65 S536 (3033), p62 (23214), LAMP2 (49067) all from Cell Signaling Technology; P-ULK-1 S317 (3803a) from Abgent; P-ATG13 S318 (19127) from Novus Biologicals.	('Beclin1', 'Gene', (92, 99))	('eIF2alpha', 'Gene', '83939', (175, 184))	('AMPK', 'Gene', (235, 239))	('cathepsin B', 'Gene', (108, 119))	('AMPK', 'Gene', (252, 256))	('LAMP2', 'Gene', (507, 512))	('FADD', 'Gene', (142, 146))	('ULK-1', 'Gene', '8408', (213, 218))	('ATM', 'Gene', (272, 275))	('cathepsin B', 'Gene', '1508', (108, 119))	('P-p65 S536 (3033', 'Var', (475, 491))	('MCL-1', 'Gene', '4170', (387, 392))	('mTOR', 'Gene', '2475', (353, 357))	('ULK-1', 'Gene', (213, 218))	('ATG13', 'Gene', (372, 377))	('AKT', 'Gene', (419, 422))	('ULK-1', 'Gene', '8408', (197, 202))	('ATG5', 'Gene', (303, 307))	('ATG13', 'Gene', (593, 598))	('CD95', 'Gene', '355', (129, 133))	('ULK-1', 'Gene', (197, 202))	('MCL-1', 'Gene', (387, 392))	('AIF', 'Gene', '9131', (17, 20))	('ATM', 'Gene', '472', (291, 294))	('mTOR', 'Gene', (317, 321))	('BCL-XL', 'Gene', (402, 408))	('eIF2alpha', 'Gene', (155, 164))	('ULK-1', 'Gene', '8408', (559, 564))	('FADD', 'Gene', '8772', (142, 146))	('Beclin1', 'Gene', '8678', (92, 99))	('eIF2alpha', 'Gene', '83939', (155, 164))	('AKT', 'Gene', '207', (419, 422))	('LAMP2', 'Gene', '3920', (507, 512))	('mTOR', 'Gene', (332, 336))	('ULK-1', 'Gene', (559, 564))	('p62', 'Gene', '23636', (494, 497))	('AIF', 'Gene', (17, 20))	('AMPK', 'Gene', '5563', (235, 239))	('BAX', 'Gene', (29, 32))	('BAK1', 'Gene', '578', (78, 82))	('p62', 'Gene', (494, 497))	('ATM', 'Gene', '472', (272, 275))	('AMPK', 'Gene', '5563', (252, 256))	('STAT3', 'Gene', (456, 461))	('mTOR', 'Gene', '2475', (317, 321))	('CD95', 'Gene', (129, 133))	('BAX', 'Gene', '581', (29, 32))	('BAK1', 'Gene', (78, 82))	('ATG13', 'Gene', '9776', (372, 377))	('ATM', 'Gene', (291, 294))	('mTOR', 'Gene', '2475', (332, 336))	('mTOR', 'Gene', (353, 357))	('BCL-XL', 'Gene', '598', (402, 408))	('ATG13', 'Gene', '9776', (593, 598))	('STAT3', 'Gene', '6774', (456, 461))	('eIF2alpha', 'Gene', (175, 184))	('ATG5', 'Gene', '9474', (303, 307))
248228	31380285	The percentage knock down or over-expression of the specified proteins in HT1080 cells 24 h after transfection was: BAX, 83%; BAK, 86%; BID, 80%; BIM, 83%; NOXA, 84%; PUMA, 78%; ATM, 80%; AMPKalpha, 75%; ULK-1, 76%; mTOR, 83%; eIF2alpha, 85%; PERK, 90%; CD95, 81%; cathepsin B, 70%; BCL-XL, 79%; MCL-1, 84%; ATG5, 83%; Beclin1, 72%; AIF, 83%; ERBB1, 74%; ERBB2, 82%: ERBB3, 93%; ERBB4, 71%; CHOP, 83%; ATF4, 75%; ATF6, 79%; XBP-1, 76%; IRE1, 80%; dom.	('ERBB', 'Gene', (379, 383))	('ERBB', 'Gene', '1956;2064;2066', (367, 371))	('MCL-1', 'Gene', (296, 301))	('ERBB', 'Gene', '1956;2064;2066', (343, 347))	('knock down', 'Var', (15, 25))	('NOXA', 'Gene', (156, 160))	('CD95', 'Gene', (254, 258))	('PERK', 'Gene', (243, 247))	('over-expression', 'PosReg', (29, 44))	('mTOR', 'Gene', (216, 220))	('Beclin1', 'Gene', (319, 326))	('ULK-1', 'Gene', '8408', (204, 209))	('BID', 'Gene', (136, 139))	('cathepsin B', 'Gene', (265, 276))	('ERBB1', 'Gene', (343, 348))	('ERBB', 'Gene', (343, 347))	('ULK-1', 'Gene', (204, 209))	('ERBB', 'Gene', (367, 371))	('BID', 'Gene', '637', (136, 139))	('ATG5', 'Gene', '9474', (308, 312))	('mTOR', 'Gene', '2475', (216, 220))	('ATM', 'Gene', '472', (178, 181))	('cathepsin B', 'Gene', '1508', (265, 276))	('BCL-XL', 'Gene', (283, 289))	('ERBB2', 'Gene', (355, 360))	('PERK', 'Gene', '9451', (243, 247))	('AMPK', 'Gene', '5563', (188, 192))	('ERBB1', 'Gene', '1956', (343, 348))	('eIF2alpha', 'Gene', (227, 236))	('eIF2alpha', 'Gene', '83939', (227, 236))	('ERBB', 'Gene', '1956;2064;2066', (355, 359))	('ERBB2', 'Gene', '2064', (355, 360))	('ATG5', 'Gene', (308, 312))	('CD95', 'Gene', '355', (254, 258))	('ERBB', 'Gene', '1956;2064;2066', (379, 383))	('BAX', 'Gene', (116, 119))	('HT1080', 'CellLine', 'CVCL:0317', (74, 80))	('MCL-1', 'Gene', '4170', (296, 301))	('BAX', 'Gene', '581', (116, 119))	('BCL-XL', 'Gene', '598', (283, 289))	('AMPK', 'Gene', (188, 192))	('Beclin1', 'Gene', '8678', (319, 326))	('ATM', 'Gene', (178, 181))	('AIF', 'Gene', '9131', (333, 336))	('NOXA', 'Gene', '5366', (156, 160))	('AIF', 'Gene', (333, 336))	('ERBB', 'Gene', (355, 359))
248232	31380285	We used two validated siRNA tools to knock down K-RAS or N-RAS for antibody validation purposes; custom made NRAS-5 CCUGAGUACUGACCUAAGAdTdT and K-RAS Silencer s7940.	('knock', 'Var', (37, 42))	('K-RAS', 'Gene', (144, 149))	('K-RAS', 'Gene', '3845', (144, 149))	('K-RAS', 'Gene', '3845', (48, 53))	('K-RAS', 'Gene', (48, 53))	('NRAS', 'Gene', (109, 113))	('N-RAS', 'Gene', (57, 62))	('NRAS', 'Gene', '4893', (109, 113))	('N-RAS', 'Gene', '4893', (57, 62))
248233	31380285	Knock down of K-RAS or N-RAS reduced fluorescent staining by ~80%.	('K-RAS', 'Gene', '3845', (14, 19))	('N-RAS', 'Gene', (23, 28))	('K-RAS', 'Gene', (14, 19))	('N-RAS', 'Gene', '4893', (23, 28))	('reduced', 'NegReg', (29, 36))	('fluorescent staining', 'MPA', (37, 57))	('Knock down', 'Var', (0, 10))
248243	31380285	In sarcoma and renal carcinoma cells, pazopanib interacted in a greater than additive fashion with the HDAC inhibitors sodium valproate and AR42 to cause cell death (Figure 2).	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('interacted', 'Interaction', (48, 58))	('HDAC', 'Gene', '9734', (103, 107))	('sodium valproate', 'Chemical', 'MESH:D014635', (119, 135))	('renal carcinoma', 'Disease', (15, 30))	('cell death', 'CPA', (154, 164))	('pazopanib', 'Chemical', 'MESH:C516667', (38, 47))	('renal carcinoma', 'Disease', 'MESH:C538614', (15, 30))	('renal carcinoma', 'Phenotype', 'HP:0005584', (15, 30))	('sarcoma', 'Disease', 'MESH:D012509', (3, 10))	('pazopanib', 'Var', (38, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('sarcoma', 'Disease', (3, 10))	('AR42', 'Chemical', 'MESH:C524513', (140, 144))	('HDAC', 'Gene', (103, 107))
248246	31380285	Additional studies then determined the impact of [pazopanib + entinostat] exposure on cell signaling in sarcoma and ovarian carcinoma cells; pazopanib is FDA approved for the treatment of sarcoma and is compendium listed for the treatment of ovarian carcinoma.	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('sarcoma', 'Disease', (104, 111))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (242, 259))	('entinostat', 'Chemical', 'MESH:C118739', (62, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (242, 259))	('sarcoma', 'Disease', 'MESH:D012509', (188, 195))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (116, 133))	('ovarian carcinoma', 'Disease', (242, 259))	('pazopanib', 'Chemical', 'MESH:C516667', (141, 150))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (116, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('pazopanib', 'Chemical', 'MESH:C516667', (50, 59))	('sarcoma', 'Disease', (188, 195))	('ovarian carcinoma', 'Disease', (116, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('pazopanib', 'Var', (141, 150))
248252	31380285	Pazopanib caused a conformational change in the NH2-termini of chaperones such that epitopes were hidden from antibody detection and is where the chaperones bind and hydrolyze ATP as part of their function but did not alter antibody staining for the COOH termini.	('ATP', 'Chemical', 'MESH:D000255', (176, 179))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('hydrolyze', 'MPA', (166, 175))	('bind', 'Interaction', (157, 161))	('conformational', 'MPA', (19, 33))	('Pazopanib', 'Var', (0, 9))	('COOH', 'Chemical', 'MESH:D002255', (250, 254))
248253	31380285	In our present studies, pazopanib reduced the NH2-terminal IF staining intensity for GRP78, HSP90, and HSP70 but did not alter antibody staining levels directed at the COOH termini (Figure 6).	('HSP90', 'Gene', (92, 97))	('HSP90', 'Gene', '3320', (92, 97))	('HSP70', 'Gene', (103, 108))	('reduced', 'NegReg', (34, 41))	('pazopanib', 'Chemical', 'MESH:C516667', (24, 33))	('NH2-terminal IF', 'Protein', (46, 61))	('COOH', 'Chemical', 'MESH:D002255', (168, 172))	('HSP70', 'Gene', '3308', (103, 108))	('pazopanib', 'Var', (24, 33))	('GRP78', 'Gene', (85, 90))	('GRP78', 'Gene', '3309', (85, 90))
248255	31380285	Based on the receptor phosphorylation data in Figures 3-5, we next examined whether inhibitors of ERBB1/2/4 (neratinib) or of c-MET (crizotinib) could enhance the lethality of [pazopanib + entinostat].	('inhibitors', 'Var', (84, 94))	('ERBB1/2/4 (neratinib) or', 'Gene', '1956', (98, 122))	('entinostat', 'Chemical', 'MESH:C118739', (189, 199))	('c-MET', 'Gene', '4233', (126, 131))	('enhance', 'PosReg', (151, 158))	('ERBB1/2/4 (neratinib) or', 'Gene', (98, 122))	('crizotinib', 'Chemical', 'MESH:D000077547', (133, 143))	('lethality', 'CPA', (163, 172))	('c-MET', 'Gene', (126, 131))	('pazopanib', 'Chemical', 'MESH:C516667', (177, 186))
248280	31380285	Knock down of apoptosis inducing factor (AIF), i.e., necroptotic death, was significantly more protective than expression of dominant negative caspase 9.	('AIF', 'Gene', (41, 44))	('necroptotic death', 'CPA', (53, 70))	('apoptosis inducing factor', 'Gene', (14, 39))	('caspase 9', 'Gene', (143, 152))	('caspase 9', 'Gene', '842', (143, 152))	('AIF', 'Gene', '9131', (41, 44))	('Knock down', 'Var', (0, 10))	('apoptosis inducing factor', 'Gene', '9131', (14, 39))
248281	31380285	We then determined that knock down of YAP enhanced the lethality of neratinib, [pazopanib + entinostat] and the three-drug combination (Figure 13B).	('YAP', 'Gene', (38, 41))	('neratinib', 'Chemical', 'MESH:C487932', (68, 77))	('enhanced', 'PosReg', (42, 50))	('entinostat', 'Chemical', 'MESH:C118739', (92, 102))	('pazopanib', 'Chemical', 'MESH:C516667', (80, 89))	('YAP', 'Gene', '10413', (38, 41))	('lethality', 'MPA', (55, 64))	('knock down', 'Var', (24, 34))
248282	31380285	We have published that treatment of cells with either [pazopanib + HDAC inhibitor] or [neratinib + HDAC inhibitor] increases the levels of autophagosomes and autolysosomes in tumor cells, and that knock down of the autophagy regulatory proteins Beclin1 or ATG5 significantly suppressed autophagy and tumor cell killing.	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('autophagy', 'CPA', (286, 295))	('pazopanib', 'Chemical', 'MESH:C516667', (55, 64))	('increases', 'PosReg', (115, 124))	('HDAC', 'Gene', (67, 71))	('ATG5', 'Gene', '9474', (256, 260))	('HDAC', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('Beclin1', 'Gene', '8678', (245, 252))	('knock down', 'Var', (197, 207))	('ATG5', 'Gene', (256, 260))	('tumor', 'Disease', (175, 180))	('suppressed', 'NegReg', (275, 285))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('neratinib', 'Chemical', 'MESH:C487932', (87, 96))	('Beclin1', 'Gene', (245, 252))	('tumor', 'Disease', (300, 305))	('HDAC', 'Gene', '9734', (67, 71))	('HDAC', 'Gene', '9734', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
248283	31380285	More recently, we have shown that neratinib is capable of inducing LC3-associated phagocytosis (LAP), which requires expression of the protein Rubicon; knock down of Rubicon was significantly more protective than knock down of Beclin1 or ATG5 at preventing tumor cell killing (Figure 13B).	('Beclin1', 'Gene', '8678', (227, 234))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('LC3', 'Gene', (67, 70))	('inducing', 'Reg', (58, 66))	('Rubicon', 'Gene', '9711', (166, 173))	('knock down', 'Var', (152, 162))	('Rubicon', 'Gene', (166, 173))	('LC3', 'Gene', '84557', (67, 70))	('neratinib', 'Chemical', 'MESH:C487932', (34, 43))	('ATG5', 'Gene', '9474', (238, 242))	('Beclin1', 'Gene', (227, 234))	('Rubicon', 'Gene', (143, 150))	('ATG5', 'Gene', (238, 242))	('Rubicon', 'Gene', '9711', (143, 150))	('tumor', 'Disease', 'MESH:D009369', (257, 262))
248284	31380285	Knock down of Rubicon was significantly better at preventing tumor cell killing compared to knock down of Beclin1 (Figures 14A,B).	('Rubicon', 'Gene', (14, 21))	('Beclin1', 'Gene', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Beclin1', 'Gene', '8678', (106, 113))	('Knock down', 'Var', (0, 10))	('tumor', 'Disease', (61, 66))	('Rubicon', 'Gene', '9711', (14, 21))
248285	31380285	Knock down of eiF2alpha dampened the drug-induced inactivation of mTOR and further enhanced phosphorylation of YAP.	('mTOR', 'Gene', (66, 70))	('phosphorylation', 'MPA', (92, 107))	('mTOR', 'Gene', '2475', (66, 70))	('YAP', 'Gene', '10413', (111, 114))	('inactivation', 'MPA', (50, 62))	('enhanced', 'PosReg', (83, 91))	('YAP', 'Gene', (111, 114))	('eiF2alpha', 'Gene', '83939', (14, 23))	('eiF2alpha', 'Gene', (14, 23))	('dampened', 'NegReg', (24, 32))	('Knock down', 'Var', (0, 10))
248286	31380285	Knock down of eIF2alpha prevented drug exposure from reducing MCL-1 or BCL-XL expression.	('MCL-1', 'Gene', '4170', (62, 67))	('MCL-1', 'Gene', (62, 67))	('eIF2alpha', 'Gene', (14, 23))	('BCL-XL', 'Gene', '598', (71, 77))	('eIF2alpha', 'Gene', '83939', (14, 23))	('Knock down', 'Var', (0, 10))	('BCL-XL', 'Gene', (71, 77))
248287	31380285	Knock down of Rubicon prevented both mTOR inactivation and YAP phosphorylation but did not prevent MCL-1 and BCL-XL down-regulation.	('Rubicon', 'Gene', (14, 21))	('YAP', 'Gene', (59, 62))	('BCL-XL', 'Gene', '598', (109, 115))	('mTOR', 'Gene', (37, 41))	('mTOR', 'Gene', '2475', (37, 41))	('prevented', 'NegReg', (22, 31))	('MCL-1', 'Gene', (99, 104))	('Knock down', 'Var', (0, 10))	('YAP', 'Gene', '10413', (59, 62))	('MCL-1', 'Gene', '4170', (99, 104))	('Rubicon', 'Gene', '9711', (14, 21))	('BCL-XL', 'Gene', (109, 115))
248300	31380285	Both neratinib and crizotinib were capable of significantly enhancing [pazopanib + entinostat] lethality.	('neratinib', 'Chemical', 'MESH:C487932', (5, 14))	('enhancing', 'PosReg', (60, 69))	('entinostat', 'Chemical', 'MESH:C118739', (83, 93))	('crizotinib', 'Chemical', 'MESH:D000077547', (19, 29))	('[pazopanib + entinostat] lethality', 'MPA', (70, 104))	('crizotinib', 'Var', (19, 29))	('pazopanib', 'Chemical', 'MESH:C516667', (71, 80))
248305	31380285	Knock down of YAP enhanced the lethality of both the two-drug and three-drug combinations.	('YAP', 'Gene', (14, 17))	('enhanced', 'PosReg', (18, 26))	('lethality', 'MPA', (31, 40))	('Knock down', 'Var', (0, 10))	('YAP', 'Gene', '10413', (14, 17))
248312	31380285	Exposure of cells to [pazopanib + entinostat] reduced the phosphorylation of ULK-1 S757 that was associated with reduced mTORC1 and mTORC2 activities.	('S757', 'Var', (83, 87))	('mTORC2', 'Gene', '74343', (132, 138))	('mTORC2', 'Gene', (132, 138))	('phosphorylation', 'MPA', (58, 73))	('ULK-1', 'Gene', '8408', (77, 82))	('mTORC1', 'Gene', '382056', (121, 127))	('ULK-1', 'Gene', (77, 82))	('reduced', 'NegReg', (46, 53))	('reduced', 'NegReg', (113, 120))	('mTORC1', 'Gene', (121, 127))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))	('entinostat', 'Chemical', 'MESH:C118739', (34, 44))
248313	31380285	Both crizotinib and neratinib acted to cause further mTOR inactivation and further ULK-1 S757 dephosphorylation.	('ULK-1', 'Gene', (83, 88))	('crizotinib', 'Chemical', 'MESH:D000077547', (5, 15))	('neratinib', 'Chemical', 'MESH:C487932', (20, 29))	('mTOR', 'Gene', (53, 57))	('dephosphorylation', 'MPA', (94, 111))	('mTOR', 'Gene', '2475', (53, 57))	('ULK-1', 'Gene', '8408', (83, 88))	('S757', 'Var', (89, 93))
248318	31380285	We have previously published that treatment of cells with either [pazopanib + HDAC inhibitor] or [neratinib + HDAC inhibitor] increases the levels of autophagosomes and autolysosomes in tumor cells.	('increases', 'PosReg', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('neratinib', 'Chemical', 'MESH:C487932', (98, 107))	('HDAC', 'Gene', (110, 114))	('HDAC', 'Gene', '9734', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('levels of', 'MPA', (140, 149))	('autolysosomes', 'CPA', (169, 182))	('tumor', 'Disease', (186, 191))	('[pazopanib', 'Var', (65, 75))	('pazopanib', 'Chemical', 'MESH:C516667', (66, 75))	('HDAC', 'Gene', (78, 82))	('HDAC', 'Gene', '9734', (78, 82))
248319	31380285	More recently, we have shown that neratinib is capable of inducing LC3-associated phagocytosis, which requires the protein Rubicon.	('inducing', 'PosReg', (58, 66))	('LC3', 'Gene', '84557', (67, 70))	('neratinib', 'Chemical', 'MESH:C487932', (34, 43))	('Rubicon', 'Gene', (123, 130))	('LC3', 'Gene', (67, 70))	('Rubicon', 'Gene', '9711', (123, 130))	('neratinib', 'Var', (34, 43))
248320	31380285	And, compared to other autophagy-regulatory proteins whose expression we have manipulated, e.g., Beclin1, ATG5, knock down of Rubicon was significantly more protective.	('ATG5', 'Gene', (106, 110))	('Beclin1', 'Gene', '8678', (97, 104))	('knock down', 'Var', (112, 122))	('Beclin1', 'Gene', (97, 104))	('ATG5', 'Gene', '9474', (106, 110))	('protective', 'CPA', (157, 167))	('Rubicon', 'Gene', '9711', (126, 133))	('more', 'PosReg', (152, 156))	('Rubicon', 'Gene', (126, 133))
248321	31380285	In our sarcoma studies we also discovered that Rubicon knock down was significantly more protective against neratinib, [pazopanib + entinostat] and [pazopanib + entinostat + neratinib] when compared to Beclin1/ATG5.	('[pazopanib + entinostat', 'MPA', (119, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('Beclin1', 'Gene', (202, 209))	('knock down', 'Var', (55, 65))	('ATG5', 'Gene', (210, 214))	('pazopanib', 'Chemical', 'MESH:C516667', (120, 129))	('entinostat', 'Chemical', 'MESH:C118739', (132, 142))	('neratinib', 'Chemical', 'MESH:C487932', (174, 183))	('neratinib', 'MPA', (108, 117))	('sarcoma', 'Disease', 'MESH:D012509', (7, 14))	('Rubicon', 'Gene', (47, 54))	('pazopanib', 'Chemical', 'MESH:C516667', (149, 158))	('Beclin1', 'Gene', '8678', (202, 209))	('Rubicon', 'Gene', '9711', (47, 54))	('neratinib', 'Chemical', 'MESH:C487932', (108, 117))	('ATG5', 'Gene', '9474', (210, 214))	('entinostat', 'Chemical', 'MESH:C118739', (161, 171))	('sarcoma', 'Disease', (7, 14))
248323	31380285	For example, over-expression of Beclin1 can promote autophagy-dependent sarcoma growth and resistance to chemotherapy.	('sarcoma growth', 'Disease', (72, 86))	('promote', 'PosReg', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('Beclin1', 'Gene', '8678', (32, 39))	('resistance to chemotherapy', 'CPA', (91, 117))	('over-expression', 'Var', (13, 28))	('sarcoma growth', 'Disease', 'MESH:D006130', (72, 86))	('Beclin1', 'Gene', (32, 39))
248324	31380285	Combined inhibition of HDACs and BET bromodomains can facilitate myoblastoma/sarcoma cell differentiation, which requires phosphorylation, i.e., inactivation and cytoplasmic localization, of the Hippo Pathway effector YAP.	('HDAC', 'Gene', '9734', (23, 27))	('BET', 'Gene', '92737', (33, 36))	('YAP', 'Gene', '10413', (218, 221))	('BET', 'Gene', (33, 36))	('inactivation', 'Var', (145, 157))	('HDAC', 'Gene', (23, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('YAP', 'Gene', (218, 221))	('facilitate', 'PosReg', (54, 64))	('myoblastoma/sarcoma', 'Disease', (65, 84))	('inhibition', 'Var', (9, 19))	('myoblastoma/sarcoma', 'Disease', 'MESH:D009217', (65, 84))
248325	31380285	Furthermore, this differentiation process required increased signaling from unfolded protein response effectors, i.e., phosphorylation of eIF2alpha S51.	('signaling', 'MPA', (61, 70))	('phosphorylation', 'MPA', (119, 134))	('increased', 'PosReg', (51, 60))	('eIF2alpha', 'Gene', (138, 147))	('eIF2alpha', 'Gene', '83939', (138, 147))	('S51', 'Var', (148, 151))
248327	31380285	Knock down of YAP promoted LC3A/B conversion and expression of Beclin1 and ATG13, collectively arguing that autophagosome formation was being enhanced.	('LC3A/B', 'Gene', (27, 33))	('autophagosome formation', 'CPA', (108, 131))	('Beclin1', 'Gene', (63, 70))	('YAP', 'Gene', (14, 17))	('ATG13', 'Gene', (75, 80))	('expression', 'MPA', (49, 59))	('enhanced', 'PosReg', (142, 150))	('LC3A/B', 'Gene', '84557;81631', (27, 33))	('promoted', 'PosReg', (18, 26))	('ATG13', 'Gene', '9776', (75, 80))	('Knock down', 'Var', (0, 10))	('YAP', 'Gene', '10413', (14, 17))	('Beclin1', 'Gene', '8678', (63, 70))
248330	31380285	Knock down of eIF2alpha maintained MCL-1 and BCL-XL expression and blunted the drug-induced inactivation of mTOR but did not prevent YAP phosphorylation.	('mTOR', 'Gene', (108, 112))	('blunted', 'NegReg', (67, 74))	('eIF2alpha', 'Gene', (14, 23))	('MCL-1', 'Gene', (35, 40))	('drug-induced inactivation', 'MPA', (79, 104))	('mTOR', 'Gene', '2475', (108, 112))	('MCL-1', 'Gene', '4170', (35, 40))	('BCL-XL', 'Gene', '598', (45, 51))	('BCL-XL', 'Gene', (45, 51))	('eIF2alpha', 'Gene', '83939', (14, 23))	('maintained', 'PosReg', (24, 34))	('expression', 'MPA', (52, 62))	('YAP', 'Gene', '10413', (133, 136))	('Knock down', 'Var', (0, 10))	('YAP', 'Gene', (133, 136))
248331	31380285	Separately, knock down of Rubicon did not prevent the declines in MCL-1 and BCL-XL expression but did prevent the phosphorylation of YAP and the dephosphorylation of mTOR.	('BCL-XL', 'Gene', '598', (76, 82))	('MCL-1', 'Gene', '4170', (66, 71))	('MCL-1', 'Gene', (66, 71))	('mTOR', 'Gene', (166, 170))	('mTOR', 'Gene', '2475', (166, 170))	('YAP', 'Gene', '10413', (133, 136))	('dephosphorylation', 'MPA', (145, 162))	('prevent', 'NegReg', (102, 109))	('knock down', 'Var', (12, 22))	('Rubicon', 'Gene', '9711', (26, 33))	('Rubicon', 'Gene', (26, 33))	('BCL-XL', 'Gene', (76, 82))	('phosphorylation', 'MPA', (114, 129))	('YAP', 'Gene', (133, 136))
248343	29768143	Trametinib in Histiocytic Sarcoma with an Activating MAP2K1 (MEK1) Mutation A high prevalence of BRAF V600E mutations are detected in patients with Langerhans'-cell histiocytosis and Erdheim-Chester disease, which is a subset of non-Langerhans'-cell histiocytosis.	('Erdheim-Chester disease', 'Disease', 'MESH:D031249', (183, 206))	('Histiocytic Sarcoma', 'Disease', 'MESH:D054747', (14, 33))	('MEK1', 'Gene', '5604', (61, 65))	('patients', 'Species', '9606', (134, 142))	('Histiocytic Sarcoma', 'Disease', (14, 33))	('MAP2K1', 'Gene', '5604', (53, 59))	('Erdheim-Chester disease', 'Disease', (183, 206))	('MAP2K1', 'Gene', (53, 59))	('histiocytosis', 'Phenotype', 'HP:0100727', (250, 263))	('BRAF', 'Gene', (97, 101))	('Activating', 'PosReg', (42, 52))	('Mutation', 'Var', (67, 75))	('MEK1', 'Gene', (61, 65))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('V600E', 'Mutation', 'rs113488022', (102, 107))	("Langerhans'-cell histiocytosis", 'Disease', (148, 178))	('Sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('histiocytosis', 'Phenotype', 'HP:0100727', (165, 178))	('BRAF', 'Gene', '673', (97, 101))
248345	29768143	Oncogenic mutations in BRAF and mitogen-activated protein kinase (MAPK) are mutually exclusive and may be mechanisms by which the RAF-MEK-ERK pathway is activated in histiocytic neoplasms.	('neoplasms', 'Disease', (178, 187))	('MEK', 'Gene', (134, 137))	('ERK', 'Gene', (138, 141))	('RAF', 'Gene', '22882', (24, 27))	('activated', 'PosReg', (153, 162))	('BRAF', 'Gene', '673', (23, 27))	('RAF', 'Gene', (24, 27))	('MEK', 'Gene', '5609', (134, 137))	('MAPK', 'Gene', (66, 70))	('BRAF', 'Gene', (23, 27))	('neoplasms', 'Phenotype', 'HP:0002664', (178, 187))	('mutations', 'Var', (10, 19))	('ERK', 'Gene', '5594', (138, 141))	('RAF', 'Gene', (130, 133))	('neoplasms', 'Disease', 'MESH:D009369', (178, 187))	('RAF', 'Gene', '22882', (130, 133))
248349	29768143	We describe a patient who had histiocytic sarcoma with an activating mutation in MAP2K1 who had a complete clinical response and a response on imaging to trametinib, a MAPK kinase (MEK) 1 and 2 inhibitor A 62-year-old man with a history of untreated grade 1 or grade 2 follicular lymphoma (BCL2 rearranged) presented with a new onset of fatigue, persistent fever (temperature, 39 C), and night sweats.	('lymphoma', 'Phenotype', 'HP:0002665', (280, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('fatigue', 'Disease', 'MESH:D005221', (337, 344))	('man', 'Species', '9606', (218, 221))	('fever', 'Disease', 'MESH:D005334', (357, 362))	('follicular lymphoma', 'Disease', 'MESH:D008224', (269, 288))	('fever', 'Disease', (357, 362))	('BCL2', 'Gene', (290, 294))	('MAPK kinase (MEK) 1 and 2', 'Gene', '5604;5605', (168, 193))	('follicular lymphoma', 'Disease', (269, 288))	('fever', 'Phenotype', 'HP:0001945', (357, 362))	('histiocytic sarcoma', 'Disease', (30, 49))	('trametinib', 'Chemical', 'MESH:C560077', (154, 164))	('persistent fever', 'Phenotype', 'HP:0001954', (346, 362))	('fatigue', 'Disease', (337, 344))	('patient', 'Species', '9606', (14, 21))	('fatigue', 'Phenotype', 'HP:0012378', (337, 344))	('night sweats', 'Phenotype', 'HP:0030166', (388, 400))	('activating', 'PosReg', (58, 68))	('MAP2K1', 'Gene', '5604', (81, 87))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (30, 49))	('mutation', 'Var', (69, 77))	('sweats', 'Phenotype', 'HP:0000975', (394, 400))	('BCL2', 'Gene', '596', (290, 294))	('MAP2K1', 'Gene', (81, 87))
248354	29768143	The patient provided consent to undergo a next-generation sequencing test that revealed somatic mutations in BCL10, BCL2, CDKN1B, KIT, and MAP2K1-F53L.	('MAP2K1', 'Gene', '5604', (139, 145))	('BCL2', 'Gene', (116, 120))	('MAP2K1', 'Gene', (139, 145))	('BCL10', 'Gene', (109, 114))	('patient', 'Species', '9606', (4, 11))	('CDKN1B', 'Gene', '1027', (122, 128))	('F53L', 'Mutation', 'rs1057519728', (146, 150))	('BCL10', 'Gene', '8915', (109, 114))	('BCL2', 'Gene', '596', (116, 120))	('CDKN1B', 'Gene', (122, 128))	('KIT', 'Gene', (130, 133))	('mutations', 'Var', (96, 105))
248356	29768143	Substitution of leucine for phenylalanine in the negative regulatory domain of MAP2K1 results in a conformational shift that exposes the catalytic ATP-binding pocket and results in constitutive kinase activity.	('Substitution', 'Var', (0, 12))	('constitutive kinase activity', 'MPA', (181, 209))	('catalytic ATP-binding pocket', 'MPA', (137, 165))	('MAP2K1', 'Gene', (79, 85))	('phenylalanine', 'Chemical', 'MESH:D010649', (28, 41))	('leucine', 'Var', (16, 23))	('results in', 'Reg', (170, 180))	('ATP', 'Chemical', 'MESH:D000255', (147, 150))	('exposes', 'PosReg', (125, 132))	('leucine', 'Chemical', 'MESH:D007930', (16, 23))	('conformational shift', 'MPA', (99, 119))	('MAP2K1', 'Gene', '5604', (79, 85))
248359	29768143	These results are consistent with preclinical findings of MAP2K1 mutations as an alternative mechanism for activating the MAPK pathway in histiocytic neoplasms.	('MAP2K1', 'Gene', (58, 64))	('neoplasms', 'Phenotype', 'HP:0002664', (150, 159))	('activating', 'PosReg', (107, 117))	('neoplasms', 'Disease', 'MESH:D009369', (150, 159))	('MAP2K1', 'Gene', '5604', (58, 64))	('MAPK pathway', 'Pathway', (122, 134))	('neoplasms', 'Disease', (150, 159))	('mutations', 'Var', (65, 74))
248360	29768143	Like other types of non-Langerhans'-cell histiocytosis, histiocytic sarcoma (sporadic or transformed) may harbor mutations in the MAPK pathway, and tumor profiling may be helpful.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (56, 75))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (113, 122))	('histiocytic sarcoma', 'Disease', (56, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('MAPK pathway', 'Pathway', (130, 142))	('histiocytosis', 'Phenotype', 'HP:0100727', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
248361	29768143	Basket studies of MEK or ERK inhibitors in cancers harboring MAP2K1 mutations may be warranted.	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('MEK', 'Gene', (18, 21))	('MAP2K1', 'Gene', '5604', (61, 67))	('cancers', 'Disease', (43, 50))	('ERK', 'Gene', '5594', (25, 28))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('MEK', 'Gene', '5609', (18, 21))	('MAP2K1', 'Gene', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutations', 'Var', (68, 77))	('ERK', 'Gene', (25, 28))
248396	28649136	Despite these high viral titers, it is possible that EVs that carry viral proteins or nucleic acids could modulate host cells, for example by determining their permissiveness to infection.	('infection', 'Disease', (178, 187))	('infection', 'Disease', 'MESH:D007239', (178, 187))	('modulate', 'Reg', (106, 114))	('proteins', 'Protein', (74, 82))	('nucleic acids', 'Var', (86, 99))	('determining', 'Reg', (142, 153))
248425	28649136	Integrins and integrin-binding matrix proteins, many of which contain a signature motif of arginine, glycine, and aspartic acid (RGD), have an important role in virus entry and their potential role in the entry of EVs is also beginning to be understood .	('arginine', 'Chemical', 'MESH:D001120', (91, 99))	('virus entry', 'CPA', (161, 172))	('arginine', 'Var', (91, 99))	('glycine', 'Chemical', 'MESH:D005998', (101, 108))	('aspartic acid', 'Chemical', 'MESH:D001224', (114, 127))
248427	28649136	For example, the anti-integrin antibody Etaracizumab is in clinical trials as anti-angiogenesis agent in non-virus associated cancers, because blocking integrin signaling can induce cell death.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('blocking', 'Var', (143, 151))	('antibody Etaracizumab', 'Disease', (31, 52))	('cell death', 'CPA', (182, 192))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('antibody Etaracizumab', 'Disease', 'MESH:D007153', (31, 52))
248488	28649136	The delivery of LMP1 and EGFR and PI3CA through EVs induced growth stimulating signaling pathways in recipient cells, including the activation of the PI3kinase target, Akt1, and ERK1.	('PI3CA', 'Var', (34, 39))	('activation', 'PosReg', (132, 142))	('EGFR', 'Gene', (25, 29))	('Akt1', 'Gene', (168, 172))	('LMP1', 'Gene', '9260', (16, 20))	('ERK1', 'Gene', '5595', (178, 182))	('LMP1', 'Gene', (16, 20))	('Akt1', 'Gene', '207', (168, 172))	('ERK1', 'Gene', (178, 182))	('growth stimulating signaling pathways', 'Pathway', (60, 97))	('induced', 'Reg', (52, 59))	('EGFR', 'Gene', '1956', (25, 29))
248504	28649136	Analyses of the content of EVs from infected cells also indicated that KSHV EVs could affect cellular metabolism and that EVs from EBV infected cells could activate cellular signaling mediated by integrins, actin, interferon, and NF-kB through the transfer of critical regulatory proteins in these pathways.	('EVs', 'Var', (76, 79))	('transfer', 'Reg', (248, 256))	('affect', 'Reg', (86, 92))	('KSHV', 'Gene', (71, 75))	('infected', 'Var', (135, 143))	('integrins', 'Protein', (196, 205))	('EBV', 'Species', '10376', (131, 134))	('actin', 'Protein', (207, 212))	('cellular metabolism', 'MPA', (93, 112))	('NF-kB', 'Protein', (230, 235))	('activate', 'PosReg', (156, 164))	('cellular signaling', 'MPA', (165, 183))
248510	28649136	In addition to viral proteins and miRNAs, 5'pppEBER1, a small non-coding viral RNA, has also been found in EVs that are secreted from EBV infected cells.	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('EBV', 'Species', '10376', (134, 137))	("5'pppEBER1", 'Var', (42, 52))
248513	28649136	Modulating the content of EVs could be important for affecting the tumor environment by inducing cell growth, promoting angiogenesis, and inhibiting immune cell function, and also for potentiating metastasis.	('Modulating', 'Var', (0, 10))	('affecting', 'Reg', (53, 62))	('cell growth', 'CPA', (97, 108))	('potentiating', 'PosReg', (184, 196))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('promoting', 'PosReg', (110, 119))	('inducing', 'PosReg', (88, 96))	('metastasis', 'CPA', (197, 207))	('angiogenesis', 'CPA', (120, 132))	('inhibiting', 'NegReg', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('immune cell function', 'CPA', (149, 169))
248514	28649136	KSHV causes Kaposi's sarcoma and a variety of hyperplastic and neoplastic B cell disorders, such as primary effusion lymphoma (PEL).	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (12, 28))	('hyper', 'Disease', 'MESH:D053307', (46, 51))	('KSHV', 'Var', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('causes', 'Reg', (5, 11))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (12, 28))	("Kaposi's sarcoma", 'Disease', (12, 28))	('hyper', 'Disease', (46, 51))	('primary effusion lymphoma', 'Disease', (100, 125))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (100, 125))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (100, 125))	('PEL', 'Phenotype', 'HP:0030069', (127, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (117, 125))
248540	28649136	In this model, RNAs in EVs offer an evolutionary advantage for virus spread by priming neighboring cells for infection.	('infection', 'Disease', 'MESH:D007239', (109, 118))	('RNAs', 'Var', (15, 19))	('infection', 'Disease', (109, 118))
248547	28649136	HCMV replicates in a variety of cell types including endothelial cells that line the blood and lymphatic vasculature and can cause graft rejection in organ transplantation.	('graft rejection', 'CPA', (131, 146))	('cause', 'Reg', (125, 130))	('HCMV', 'Var', (0, 4))	('HCMV', 'Species', '10359', (0, 4))
248550	28649136	The cGAMP nucleotide triggers the recognition of foreign molecules via STING and also augments RIG-I and TLR signaling, leading to a strong interferon response.	('STING', 'Gene', '340061', (71, 76))	('RIG-I', 'Gene', '23586', (95, 100))	('STING', 'Gene', (71, 76))	('augments', 'NegReg', (86, 94))	('RIG-I', 'Gene', (95, 100))	('cGAMP', 'Var', (4, 9))	('recognition', 'MPA', (34, 45))	('interferon response', 'MPA', (140, 159))
248571	28649136	Approximately 20%-30% of all cancers are associated with viral infections and many features of cancer are also features of viral infection, such as dissemination (metastasis in cancer), uncontrolled DNA replication and metabolic perturbation (for example, glycolysis and nucleotide biogenesis).	('cancer', 'Disease', (177, 183))	('associated', 'Reg', (41, 51))	('uncontrolled', 'Var', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('viral infections', 'Disease', 'MESH:D001102', (57, 73))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (29, 35))	('viral infection', 'Disease', (123, 138))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('viral infections', 'Disease', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('viral infection', 'Disease', 'MESH:D001102', (123, 138))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('dissemination', 'Disease', (148, 161))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('glycolysis', 'Disease', (256, 266))	('cancers', 'Disease', (29, 36))	('viral infection', 'Disease', 'MESH:D001102', (57, 72))	('metabolic perturbation', 'CPA', (219, 241))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
248604	25609980	Most MRCs consistently show a reciprocal translocation t(12;16)(q13;p11.2), and less commonly, t(12;22)(q13;q12), leading to FUS-CHOP fusion and EWS-CHOP fusion, respectively.	('leading to', 'Reg', (114, 124))	('CHOP', 'Gene', (149, 153))	('EWS', 'Gene', (145, 148))	('FUS', 'Gene', '2521', (125, 128))	('FUS', 'Gene', (125, 128))	('MRC', 'Gene', '4345', (5, 8))	('CHOP', 'Gene', (129, 133))	('t(12', 'Var', (55, 59))	('MRC', 'Gene', (5, 8))	('EWS', 'Gene', '2130', (145, 148))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (95, 112))	('t(12;16)(q13;p11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (55, 74))	('CHOP', 'Gene', '1649', (149, 153))	('CHOP', 'Gene', '1649', (129, 133))
248606	25609980	There are 12 different kinds of FUS-CHOP fusion transcripts detected to date, and they can be mainly classified into three categories: specifically, type I (exons 7-2), type II (exons 5-2), and type III (exons 8-2).	('exons', 'Var', (178, 183))	('FUS', 'Gene', (32, 35))	('CHOP', 'Gene', (36, 40))	('FUS', 'Gene', '2521', (32, 35))	('CHOP', 'Gene', '1649', (36, 40))
248607	25609980	Besides, four types of EWS-CHOP have been described, including exons 7-2 (type 1), exons 10-2 (type 2), exons 13-2 (type 3), and exons 13-3 (type 4), among which type 1 fusion might have a more favorable course.	('exons 13-2', 'Var', (104, 114))	('exons 7-2', 'Var', (63, 72))	('CHOP', 'Gene', '1649', (27, 31))	('exons 13-3', 'Var', (129, 139))	('EWS', 'Gene', '2130', (23, 26))	('EWS', 'Gene', (23, 26))	('CHOP', 'Gene', (27, 31))	('exons 10-2', 'Var', (83, 93))
248612	25609980	MDM2 amplification results in an inhibited p53 activity with loss of function of this tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('loss of function', 'NegReg', (61, 77))	('amplification', 'Var', (5, 18))	('tumor', 'Disease', (86, 91))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('activity', 'MPA', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('inhibited', 'NegReg', (33, 42))
248627	25609980	Short hairpin RNA (shRNA)-based knockdown of YEATS4 in LPS cell lines resulted in better antiproliferative effects compared with MDM2.	('MDM2', 'Gene', '4193', (129, 133))	('LPS', 'Disease', (55, 58))	('MDM2', 'Gene', (129, 133))	('YEATS4', 'Gene', (45, 51))	('LPS', 'Disease', 'MESH:C536528', (55, 58))	('knockdown', 'Var', (32, 41))	('antiproliferative effects', 'CPA', (89, 114))	('YEATS4', 'Gene', '8089', (45, 51))
248631	25609980	In addition to the 12q13-15 amplicon, amplifications of 6q23 or 1p32, which are never seen in WD, have been detected in DD.	('DD', 'Chemical', 'MESH:C007792', (120, 122))	('1p32', 'Gene', (64, 68))	('amplifications', 'Var', (38, 52))	('WD', 'Disease', 'MESH:D006527', (94, 96))	('6q23', 'Gene', (56, 60))
248634	25609980	Amplification of 1p32 including the C-JUN oncogene is considered to inhibit PPAR-gamma via C/EBP-beta.	('C/EBP-beta', 'Gene', (91, 101))	('Amplification', 'Var', (0, 13))	('PPAR-gamma', 'Gene', (76, 86))	('C-JUN', 'Gene', (36, 41))	('inhibit', 'NegReg', (68, 75))	('PPAR-gamma', 'Gene', '5468', (76, 86))	('C/EBP-beta', 'Gene', '1051', (91, 101))	('C-JUN', 'Gene', '3725', (36, 41))
248636	25609980	Therefore, amplifications of ASK1 and JUN may explain the inhibition of adipocytic differentiation in DD, and also may be potential therapeutic targets.	('DD', 'Chemical', 'MESH:C007792', (102, 104))	('adipocytic differentiation', 'CPA', (72, 98))	('amplifications', 'Var', (11, 25))	('ASK1', 'Gene', '4217', (29, 33))	('inhibition', 'NegReg', (58, 68))	('ASK1', 'Gene', (29, 33))	('JUN', 'Protein', (38, 41))
248652	25609980	Goransson et al have shown that IL-6 is upregulated in human fibrosarcoma cells transfected with DDIT3-GFP or FUS-DDIT3-GFP and that IL-8 was downregulated after DDIT3 transfection and upregulated after transfection with FUS-DDIT3.	('IL-6', 'Gene', (32, 36))	('FUS', 'Gene', '2521', (110, 113))	('DDIT3-GFP', 'Var', (97, 106))	('FUS', 'Gene', (221, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('IL-8', 'Gene', '3576', (133, 137))	('fibrosarcoma', 'Disease', (61, 73))	('FUS', 'Gene', '2521', (221, 224))	('human', 'Species', '9606', (55, 60))	('IL-8', 'Gene', (133, 137))	('IL-6', 'Gene', '3569', (32, 36))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (61, 73))	('upregulated', 'PosReg', (185, 196))	('downregulated', 'NegReg', (142, 155))	('fibrosarcoma', 'Disease', 'MESH:D005354', (61, 73))	('upregulated', 'PosReg', (40, 51))	('FUS', 'Gene', (110, 113))
248656	25609980	PI3K mutations in the p110alpha catalytic subunit have been found to be very frequent in MRC tumors and associated with poor prognosis by Barretina et al in a study analyzing subtype-specific genomic alterations in 207 STS patients.	('MRC tumors', 'Disease', 'MESH:D009369', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('frequent', 'Reg', (77, 85))	('p110alpha', 'Gene', (22, 31))	('associated', 'Reg', (104, 114))	('p110alpha', 'Gene', '5290', (22, 31))	('PI3K mutations', 'Var', (0, 14))	('MRC tumors', 'Disease', (89, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (223, 231))
248658	25609980	Based on the results emerging from other cancer types, PI3K-mutated tumors are highly sensitive to Akt inhibition, and PI3K sequencing could thus be a potential therapeutic target.	('PI3K-mutated', 'Var', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('Akt', 'Pathway', (99, 102))
248678	25609980	Therefore, treatment with a PLK1 inhibitor potently induced G2-M growth arrest and apoptosis in LPS cells.	('LPS', 'Disease', (96, 99))	('growth arrest', 'Phenotype', 'HP:0001510', (65, 78))	('PLK1', 'Gene', '5347', (28, 32))	('LPS', 'Disease', 'MESH:C536528', (96, 99))	('inhibitor', 'Var', (33, 42))	('G2-M growth arrest', 'Disease', 'MESH:C566367', (60, 78))	('apoptosis', 'CPA', (83, 92))	('G2-M growth arrest', 'Disease', (60, 78))	('induced', 'Reg', (52, 59))	('PLK1', 'Gene', (28, 32))
248686	25609980	The downregulation of CALR by small-interfering RNA could induce adipogenesis in DD cells and reduce cell proliferation.	('DD', 'Chemical', 'MESH:C007792', (81, 83))	('induce', 'PosReg', (58, 64))	('CALR', 'Gene', (22, 26))	('cell proliferation', 'CPA', (101, 119))	('small-interfering', 'Var', (30, 47))	('downregulation', 'NegReg', (4, 18))	('reduce', 'NegReg', (94, 100))	('RNA', 'Gene', (48, 51))	('adipogenesis', 'MPA', (65, 77))
248699	25609980	MDM2 inhibitors activate p53 in both tumor and normal cells with wild-type p53; in other words, an intact p53 pathway is essential.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('p53', 'Gene', '7157', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('inhibitors', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('MDM2', 'Gene', (0, 4))	('MDM2', 'Gene', '4193', (0, 4))	('p53', 'Gene', (106, 109))	('activate', 'PosReg', (16, 24))
248700	25609980	Cells harboring mutated p53 have not been affected by Nutlin-3a.	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (24, 27))	('mutated', 'Var', (16, 23))
248701	25609980	Detailed analysis of aberrations in the p53 pathways may help in predicting tumor sensitivity and resistance to p53, activating therapy by MDM2 antagonists.	('MDM2', 'Gene', (139, 143))	('help', 'Reg', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('p53', 'Gene', (40, 43))	('MDM2', 'Gene', '4193', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (40, 43))	('p53', 'Gene', '7157', (112, 115))	('aberrations', 'Var', (21, 32))
248703	25609980	RG7112 (RO5045337) is a member of the Nutlin family and is the first MDM2 antagonist to be assessed clinically (Hoffmann-La Roche) (NCT01164033, NCT01143740, NCT00623870, and NCT00559533).	('NCT00559533', 'Var', (175, 186))	('RO5045337', 'Var', (8, 17))	('NCT00623870', 'Var', (158, 169))	('NCT01164033', 'Var', (132, 143))	('MDM2', 'Gene', '4193', (69, 73))	('NCT01143740', 'Var', (145, 156))	('MDM2', 'Gene', (69, 73))
248704	25609980	Preliminary clinical data indicate that RG7112 appears to be well tolerated in patients and shows initial evidence of clinical activity and a mechanism of action consistent with targeting of the MDM2-p53 interaction.	('MDM2', 'Gene', '4193', (195, 199))	('p53', 'Gene', (200, 203))	('MDM2', 'Gene', (195, 199))	('p53', 'Gene', '7157', (200, 203))	('patients', 'Species', '9606', (79, 87))	('RG7112', 'Var', (40, 46))
248706	25609980	MI-219, but not Nutlin-3, enhanced the auto ubiquitination and degradation of MDM2.	('enhanced', 'PosReg', (26, 34))	('degradation', 'MPA', (63, 74))	('MI-219', 'Var', (0, 6))	('MDM2', 'Gene', '4193', (78, 82))	('MDM2', 'Gene', (78, 82))	('MI-219', 'Chemical', 'MESH:C574930', (0, 6))	('auto ubiquitination', 'MPA', (39, 58))
248727	25609980	Similar to trabectidin, brostallicin (PNU-166196) is also a DNA minor-groove binder that alters the transcriptional regulation of FUS-DDIT3-induced genes.	('alters', 'Reg', (89, 95))	('brostallicin', 'Chemical', 'MESH:C455279', (24, 36))	('FUS', 'Gene', (130, 133))	('FUS', 'Gene', '2521', (130, 133))	('transcriptional regulation', 'MPA', (100, 126))	('PNU-166196', 'Var', (38, 48))
248731	25609980	Drugs developed to treat diseases caused by activated RTKs are generally divided into two groups: 1) small-molecule inhibitors of the ATP-binding site of the intracellular TKD, and 2) anti-RTK monoclonal antibodies directing destruction of RTK-expressing cells by the immune system or by interfering with the receptor activation.	('receptor', 'Protein', (309, 317))	('anti-RTK', 'Var', (184, 192))	('interfering', 'NegReg', (288, 299))	('ATP', 'Chemical', 'MESH:D000255', (134, 137))
248733	25609980	For example, imatinib mesylate constitutes the classic example of targeted therapy in mutation-activating c-Kit gastrointestinal stromal tumors (GISTs).	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('mutation-activating', 'Var', (86, 105))	('c-Kit', 'Gene', (106, 111))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (112, 143))	('c-Kit', 'Gene', '3815', (106, 111))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (13, 30))	('gastrointestinal stromal tumors', 'Disease', (112, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (112, 143))
248766	25609980	In a recent study evaluating the effects of NVP-BEZ235 in a panel of rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma cell lines (LPS was not included), Manara et al reported that NVP-BEZ235 effectively blocked the pathway and also showed promising efficacy with either doxorubicin and vincristine.	('doxorubicin', 'Chemical', 'MESH:D004317', (273, 284))	('BEZ235', 'Chemical', 'MESH:C531198', (48, 54))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (69, 85))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (105, 120))	('LPS', 'Disease', 'MESH:C536528', (133, 136))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (105, 120))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('NVP-BEZ235', 'Var', (183, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('vincristine', 'Chemical', 'MESH:D014750', (289, 300))	('BEZ235', 'Chemical', 'MESH:C531198', (187, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	("Ewing's sarcoma", 'Disease', (105, 120))	('rhabdomyosarcoma', 'Disease', (69, 85))	('pathway', 'Pathway', (218, 225))	('osteosarcoma', 'Disease', (87, 99))	('osteosarcoma', 'Disease', 'MESH:D012516', (87, 99))	('LPS', 'Disease', (133, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('blocked', 'NegReg', (206, 213))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (69, 85))
248816	21360650	In vivo PG11047 induced significant differences in EFS distribution compared to control in 5 of 32 (15.6%) of the evaluable solid tumor xenografts and in 0 of 7 (0%) of the evaluable ALL xenografts.	('EFS distribution', 'MPA', (51, 67))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('PG11047', 'Chemical', 'MESH:C415967', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('PG11047', 'Var', (8, 15))	('differences', 'Reg', (36, 47))
248831	21360650	PG11047 inhibits proliferation of a range of cancer cell lines, including breast cancer, prostate, non-small lung cell cancer, and small cell lung cancer cell lines.	('proliferation', 'CPA', (17, 30))	('non-small lung cell cancer', 'Disease', (99, 125))	('PG11047', 'Chemical', 'MESH:C415967', (0, 7))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (81, 87))	('prostate', 'Disease', (89, 97))	('PG11047', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('small lung cell cancer', 'Phenotype', 'HP:0030357', (103, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('non-small lung cell cancer', 'Disease', 'MESH:D002289', (99, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('small cell lung cancer', 'Disease', 'MESH:D055752', (131, 153))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('small cell lung cancer', 'Disease', (131, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('cancer', 'Disease', (45, 51))	('small lung', 'Phenotype', 'HP:0002089', (103, 113))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Disease', (74, 87))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('inhibits', 'NegReg', (8, 16))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (147, 153))	('non-small lung cell cancer', 'Phenotype', 'HP:0030358', (99, 125))
248833	21360650	The polyamine pathway is a downstream target for known oncogenes, and inhibition of polyamine synthesis can disrupt the action of those genes.	('polyamine pathway', 'Pathway', (4, 21))	('action', 'MPA', (120, 126))	('disrupt', 'NegReg', (108, 115))	('polyamine', 'Chemical', 'MESH:D011073', (4, 13))	('inhibition', 'Var', (70, 80))	('polyamine', 'Chemical', 'MESH:D011073', (84, 93))
248835	21360650	Furthermore, disabling ODC abolishes MYC-induced suppression of the CDK inhibitors p21(Cip1) and p27(Kip1), thereby impairing MYC's proliferative response.	('CDK inhibitors', 'Protein', (68, 82))	('suppression', 'MPA', (49, 60))	('MYC', 'Gene', '4609', (126, 129))	('Kip1', 'Gene', (101, 105))	('Kip1', 'Gene', '1027', (101, 105))	('MYC', 'Gene', '4609', (37, 40))	('Cip1', 'Gene', '1026', (87, 91))	('proliferative response', 'CPA', (132, 154))	('disabling', 'Var', (13, 22))	('impairing', 'NegReg', (116, 125))	('ODC', 'Gene', '4953', (23, 26))	('abolishes', 'NegReg', (27, 36))	('MYC', 'Gene', (126, 129))	('p21', 'Gene', (83, 86))	('ODC', 'Gene', (23, 26))	('p27', 'Gene', '3429', (97, 100))	('p27', 'Gene', (97, 100))	('p21', 'Gene', '644914', (83, 86))	('MYC', 'Gene', (37, 40))	('Cip1', 'Gene', (87, 91))
248838	21360650	Absolute IC50 values represent the concentration of PG11047 that reduces cell survival to 50% of the control value, while relative IC50 values represent the PG11047 concentration that reduces cell survival by 50% of the maximum PG11047 effect.	('PG11047', 'Chemical', 'MESH:C415967', (157, 164))	('cell survival', 'CPA', (192, 205))	('cell survival', 'CPA', (73, 86))	('reduces', 'NegReg', (65, 72))	('PG11047', 'Chemical', 'MESH:C415967', (52, 59))	('PG11047', 'Chemical', 'MESH:C415967', (228, 235))	('PG11047', 'Var', (52, 59))
189421	21360650	CB17SC scid-/- female mice (Taconic Farms, Germantown NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('osteosarcoma', 'Disease', (148, 160))	('glioma', 'Phenotype', 'HP:0009733', (269, 275))	('brain tumors', 'Phenotype', 'HP:0030692', (217, 229))	('osteosarcoma', 'Disease', 'MESH:D012516', (148, 160))	('mice', 'Species', '10090', (22, 26))	('non-glioblastoma brain tumors', 'Disease', 'MESH:D005909', (200, 229))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (162, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (162, 178))	('neuroblastoma', 'Disease', (181, 194))	('mice', 'Species', '10090', (250, 254))	('rhabdoid tumors', 'Disease', (114, 129))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (114, 129))	('neuroblastoma', 'Phenotype', 'HP:0003006', (181, 194))	('non-glioblastoma brain tumors', 'Disease', (200, 229))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('neuroblastoma', 'Disease', 'MESH:D009447', (181, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (148, 160))	('sarcomas', 'Disease', (131, 139))	('CB17SC', 'Var', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('glioma', 'Disease', (269, 275))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('glioma', 'Disease', 'MESH:D005910', (269, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('rhabdomyosarcoma', 'Disease', (162, 178))
248854	21360650	PG11047 induced significant differences in EFS distribution compared to control in 5 of 32 (15.6%) of the evaluable solid tumor xenografts and in 0 of 7 (0%) of the evaluable ALL xenografts.	('EFS distribution', 'MPA', (43, 59))	('PG11047', 'Chemical', 'MESH:C415967', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('PG11047', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('differences', 'Reg', (28, 39))	('tumor', 'Disease', (122, 127))
248861	21360650	The cytostatic pattern of response observed for the PPTP cell lines is consistent with that recently described for breast cancer, colon cancer, and lung cancer cell lines.	('PPTP', 'Chemical', 'MESH:C041869', (52, 56))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('PPTP', 'Var', (52, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('colon cancer', 'Disease', (130, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('breast cancer', 'Disease', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
248865	21360650	The in vivo antitumor activity observed for PG11047 against the PPTP childhood cancer models consisted of regression in a single ependymoma xenograft and tumor growth inhibition in selected other xenografts.	('ependymoma xenograft', 'Disease', 'MESH:D004806', (129, 149))	('PG11047', 'Var', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('ependymoma', 'Phenotype', 'HP:0002888', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('PPTP', 'Gene', (64, 68))	('PPTP', 'Chemical', 'MESH:C041869', (64, 68))	('tumor', 'Disease', (16, 21))	('ependymoma xenograft', 'Disease', (129, 149))	('PG11047', 'Chemical', 'MESH:C415967', (44, 51))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Disease', (154, 159))
248869	21360650	Because of this, further testing is required to define the effectiveness for PG11047 for this and other ependymoma xenografts.	('PG11047', 'Var', (77, 84))	('ependymoma xenografts', 'Disease', 'MESH:D004806', (104, 125))	('ependymoma xenografts', 'Disease', (104, 125))	('PG11047', 'Chemical', 'MESH:C415967', (77, 84))	('ependymoma', 'Phenotype', 'HP:0002888', (104, 114))
248878	21360650	PG11047 is under clinical evaluation in adults with cancer.	('PG11047', 'Chemical', 'MESH:C415967', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('PG11047', 'Var', (0, 7))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
248920	26366310	Tumor size >10 cm at presentation, mitotic rate >19 per 10 HPF, marginal or intralesional excision, and lack of adjuvant radiotherapy were found to be significant risk factors for progression of leiomyosarcomas located in the extremities.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sarcomas', 'Phenotype', 'HP:0100242', (202, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (195, 210))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (195, 210))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (195, 209))	('mitotic rate', 'CPA', (35, 47))	('leiomyosarcomas', 'Disease', (195, 210))	('>19', 'Var', (48, 51))
248938	26155311	In vivo photothermal therapy with a near-infrared (NIR) laser under the maximum permissible exposure (MPE) led to ablation of aggressive tumors containing GNS, but had no effect in the absence of GNS.	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('ablation', 'NegReg', (114, 122))	('GNS', 'Var', (155, 158))	('aggressive tumors', 'Disease', 'MESH:D001523', (126, 143))	('GNS', 'Chemical', '-', (196, 199))	('GNS', 'Chemical', '-', (155, 158))	('aggressive tumors', 'Disease', (126, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
248980	26155311	For the in vivo CT imaging and PTT studies, primary soft-tissue sarcomas were generated in the right hind leg of LSL-KrasG12D; p53FL/FL compound mutant mice between 6 and 10 weeks of age via intramuscular injection of an adenovirus expressing Cre recombinase (University of Iowa, Carver College of Medicine Viral Vector Core Facility).	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('p53', 'Gene', '22060', (127, 130))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (52, 71))	('mutant', 'Var', (145, 151))	('PTT', 'Chemical', '-', (31, 34))	('rat', 'Species', '10116', (82, 85))	('sarcomas', 'Disease', 'MESH:D012509', (64, 72))	('mice', 'Species', '10090', (152, 156))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (52, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcomas', 'Disease', (64, 72))	('p53', 'Gene', (127, 130))
249036	26155311	The 12-nm nanospheres have a plasmon peak at 520 nm while the GNS have peaks at 706 nm (60-nm GNS) or 945 nm (30-nm GNS).	('945 nm', 'Var', (102, 108))	('plasmon peak', 'MPA', (29, 41))	('GNS', 'Chemical', '-', (62, 65))	('GNS', 'Chemical', '-', (116, 119))	('GNS', 'Chemical', '-', (94, 97))
249104	26155311	The tumor temperature is much higher for mice with GNS injection than for mice with PBS injection.	('tumor', 'Disease', (4, 9))	('rat', 'Species', '10116', (15, 18))	('mice', 'Species', '10090', (41, 45))	('higher', 'PosReg', (30, 36))	('GNS injection', 'Var', (51, 64))	('PBS', 'Chemical', '-', (84, 87))	('GNS', 'Chemical', '-', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mice', 'Species', '10090', (74, 78))
249144	26155311	If we tune the GNS plasmon peak to lower wavelengths (~800 nm), we will be able to use a laser wavelength (808 nm), which will have much less water absorbance.	('808 nm', 'Var', (107, 113))	('GNS', 'Chemical', '-', (15, 18))	('water absorbance', 'MPA', (142, 158))	('water', 'Chemical', 'MESH:D014867', (142, 147))
249176	26155311	The lower liver uptake in this study might be due to dense PEGylation, which improves the ability of the GNS to evade phagocytosis.	('PEG', 'Chemical', 'MESH:D011092', (59, 62))	('lower', 'NegReg', (4, 9))	('improves', 'PosReg', (77, 85))	('GNS', 'Chemical', '-', (105, 108))	('PEGylation', 'Var', (59, 69))	('liver', 'MPA', (10, 15))
249201	25683183	CIC-DUX4 and CIC-FOXO4 fusions have been reported in soft tissue tumors, while BCOR-CCNB3 fusion with an X chromosomal inversion was described in both bone and soft tissue tumors.	('FOXO4', 'Gene', '4303', (17, 22))	('soft tissue tumors', 'Disease', 'MESH:D012983', (53, 71))	('fusions', 'Var', (23, 30))	('CIC', 'Gene', (13, 16))	('reported', 'Reg', (41, 49))	('BCOR', 'Gene', '54880', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('CCNB3', 'Gene', (84, 89))	('CIC', 'Gene', '23152', (0, 3))	('BCOR', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('DUX4', 'Gene', (4, 8))	('soft tissue tumors', 'Disease', (160, 178))	('CIC', 'Gene', '23152', (13, 16))	('FOXO4', 'Gene', (17, 22))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (160, 178))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('soft tissue tumors', 'Disease', (53, 71))	('DUX4', 'Gene', '100288687', (4, 8))	('soft tissue tumors', 'Disease', 'MESH:D012983', (160, 178))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (53, 71))	('CCNB3', 'Gene', '85417', (84, 89))	('CIC', 'Gene', (0, 3))
249202	25683183	CIC-DUX4 fusion can either harbor t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13), while t(4;19)(q35;q13.1) is reported more commonly.	('t(10;19)(q26.3;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (56, 75))	('DUX4', 'Gene', (4, 8))	('DUX4', 'Gene', '100288687', (4, 8))	('CIC', 'Gene', '23152', (0, 3))	('t(4;19)(q35;q13.1', 'Var', (34, 51))	('t(10;19)(q26.3;q13', 'Var', (56, 74))	('t(4;19)(q35;q13.1)', 'STRUCTURAL_ABNORMALITY', 'None', (34, 52))	('CIC', 'Gene', (0, 3))	('t(4;19)(q35;q13.1)', 'STRUCTURAL_ABNORMALITY', 'None', (83, 101))
249211	25683183	Upon conducting next-generation sequencing, unique mutations are being recognized: recurrent BCOR-CCNB3 fusion (in primitive bone and soft tissue sarcoma); CIC-FOXO4 fusion (in soft tissue sarcoma) Or CICDUX4 fusion as a result of either t(4;19) or t(10;19) translocations (in primitive soft tissue sarcoma).	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (177, 196))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (177, 196))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (287, 306))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (287, 306))	('t(10;19) translocations', 'Var', (249, 272))	('soft tissue sarcoma', 'Disease', (177, 196))	('primitive bone', 'Disease', (115, 129))	('soft tissue sarcoma', 'Disease', (287, 306))	('FOXO4', 'Gene', '4303', (160, 165))	('CCNB3', 'Gene', '85417', (98, 103))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (134, 153))	('CIC', 'Gene', (156, 159))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (134, 153))	('t(4;19', 'Var', (238, 244))	('soft tissue sarcoma', 'Disease', (134, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('CIC', 'Gene', (201, 204))	('BCOR', 'Gene', '54880', (93, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('CCNB3', 'Gene', (98, 103))	('fusion', 'Var', (104, 110))	('translocations', 'Var', (258, 272))	('CIC', 'Gene', '23152', (156, 159))	('BCOR', 'Gene', (93, 97))	('FOXO4', 'Gene', (160, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('fusion', 'Var', (166, 172))	('CIC', 'Gene', '23152', (201, 204))
249229	25683183	Recent studies have identified unique translocations and gene fusions in these unclassifiable highly aggressive undifferentiated small blue round cell sarcomas, which are considered to be of diagnostic value: CIC-DUX4 fusion transcript with either t(4;19) (q35;q13.1) translocation or t(10;19)(q26.3;q13) trans-location, and BCOR-CCNB3 fusion with an X chromosomal inversion, also CIC-FOXO4 fusions, all of which are EWSR1- and SYT-negative on FISH.	('EWSR1', 'Gene', '2130', (417, 422))	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('CIC', 'Gene', (381, 384))	('sarcomas', 'Disease', (151, 159))	('CCNB3', 'Gene', '85417', (330, 335))	('t(10;19)(q26.3;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (285, 304))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('DUX4', 'Gene', (213, 217))	('EWSR1', 'Gene', (417, 422))	('CIC', 'Gene', (209, 212))	('CIC', 'Gene', '23152', (381, 384))	('FOXO4', 'Gene', (385, 390))	('BCOR', 'Gene', '54880', (325, 329))	('CCNB3', 'Gene', (330, 335))	('DUX4', 'Gene', '100288687', (213, 217))	('BCOR', 'Gene', (325, 329))	('fusions', 'Var', (391, 398))	('FOXO4', 'Gene', '4303', (385, 390))	('CIC', 'Gene', '23152', (209, 212))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))
249251	20501846	Population-Based Estimate of the Contribution of TP53 Mutations to Subgroups of Early-Onset Breast Cancer: Australian Breast Cancer Family Study Although germline TP53 mutations have been identified in women with breast cancer from families meeting Li-Fraumeni criteria, their contribution to breast cancer per se is not well known, but is thought to be minimal.	('TP53', 'Gene', '7157', (49, 53))	('Breast Cancer', 'Disease', (92, 105))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('Breast Cancer', 'Phenotype', 'HP:0003002', (118, 131))	('Breast Cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (293, 306))	('mutations', 'Var', (168, 177))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Disease', (213, 226))	('TP53', 'Gene', (163, 167))	('breast cancer', 'Disease', (293, 306))	('breast cancer', 'Disease', 'MESH:D001943', (293, 306))	('TP53', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Breast Cancer', 'Disease', 'MESH:D001943', (118, 131))	('TP53', 'Gene', '7157', (163, 167))	('Breast Cancer', 'Disease', 'MESH:D001943', (92, 105))	('women', 'Species', '9606', (202, 207))	('Breast Cancer', 'Disease', (118, 131))
249252	20501846	We aimed to determine the prevalence of germline TP53 mutations in subgroups of early-onset breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
249257	20501846	Of the EO-FH group, three (7%) had a mutation: T13240G (a known intron 5 splicing mutation) in a 36-year-old from a classic Li-Fraumeni family; G12299A (exon 4 missense) in a 33-year-old from a Li-Fraumeni-like family; and 14058delG (exon 7 frame-shift) in a 39-year-old with a family cancer history that did not meet Li-Fraumeni criteria.	('14058delG', 'Var', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('G12299A', 'Mutation', 'g.12299G>A', (144, 151))	('T13240G', 'Var', (47, 54))	('14058delG', 'Mutation', 'c.14058delG', (223, 232))	('G12299A', 'Var', (144, 151))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('T13240G', 'Mutation', 'g.13240T>G', (47, 54))
249258	20501846	Germline TP53 mutations play a larger role in early-onset breast cancer than previously thought, and in this context, can be evident outside clinically defined Li-Fraumeni families.	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('mutations', 'Var', (14, 23))
249259	20501846	Based principally on studies of families with multiple cancers that accord with the Li-Fraumeni syndrome, a number of different cancers have been found to occur in people with a germline mutation in TP53, including breast cancer.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('TP53', 'Gene', '7157', (199, 203))	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('breast cancer', 'Disease', (215, 228))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('multiple cancers', 'Disease', 'MESH:D009369', (46, 62))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('Li-Fraumeni syndrome', 'Disease', (84, 104))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (84, 104))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('people', 'Species', '9606', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('TP53', 'Gene', (199, 203))	('multiple cancers', 'Disease', (46, 62))	('occur', 'Reg', (155, 160))	('germline mutation', 'Var', (178, 195))
249260	20501846	The breast cancers associated with germline TP53 mutations in the context of Li-Fraumeni families seem to occur at a very early age for that disease, the majority between 15 and 44 years.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mutations', 'Var', (49, 58))	('breast cancers', 'Phenotype', 'HP:0003002', (4, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancers', 'Disease', 'MESH:D001943', (4, 18))	('breast cancers', 'Disease', (4, 18))	('germline', 'Var', (35, 43))	('TP53', 'Gene', '7157', (44, 48))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('TP53', 'Gene', (44, 48))
249261	20501846	It is not controversial that women with early-onset breast cancer who have a family history consistent with Li-Fraumeni syndrome have a high probability of carrying a germline TP53 mutation.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (108, 128))	('germline', 'Var', (167, 175))	('women', 'Species', '9606', (29, 34))	('TP53', 'Gene', '7157', (176, 180))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('Li-Fraumeni syndrome', 'Disease', (108, 128))	('TP53', 'Gene', (176, 180))	('carrying', 'Reg', (156, 164))	('mutation', 'Var', (181, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))
249262	20501846	The contribution of TP53 germline mutations to breast cancer predisposition overall, however, has been thought to be minimal:much less than 1%.	('breast cancer', 'Disease', (47, 60))	('TP53', 'Gene', (20, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('germline mutations', 'Var', (25, 43))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TP53', 'Gene', '7157', (20, 24))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
249263	20501846	Follow-up of earlier reports suggests that germline TP53 mutations might be more frequent.	('germline', 'Var', (43, 51))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))
249264	20501846	Almost all of the previous studies that have screened for germline TP53 mutations have used convenience samples of subjects who met predetermined clinical criteria and have not focused on early-onset breast cancer unselected for family cancer history or on population-based samples of early-onset disease in multiple-case breast cancer families that do not meet the Li-Fraumeni syndrome criteria.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('Li-Fraumeni syndrome', 'Disease', (366, 386))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (366, 386))	('mutations', 'Var', (72, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (322, 335))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TP53', 'Gene', (67, 71))	('breast cancer', 'Disease', 'MESH:D001943', (322, 335))	('breast cancer', 'Disease', (322, 335))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (329, 335))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('TP53', 'Gene', '7157', (67, 71))	('breast cancer', 'Disease', (200, 213))
249265	20501846	Whereas mutations in BRCA1 or BRCA2 are thought to be most probable in the multiple-case families presenting to familial breast cancer services, population-based studies are finding that mutations in these genes are not as common as previously thought, even for multiple-case breast cancer families with early-onset disease, and a substantial proportion of carriers do not have a family history.	('BRCA1', 'Gene', '672', (21, 26))	('BRCA1', 'Gene', (21, 26))	('mutations', 'Var', (8, 17))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('familial breast cancer', 'Disease', 'MESH:D001943', (112, 134))	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BRCA2', 'Gene', (30, 35))	('familial breast cancer', 'Disease', (112, 134))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('breast cancer', 'Disease', (276, 289))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('BRCA2', 'Gene', '675', (30, 35))
249266	20501846	Other genetic alterations in CHEK2, ATM, BRIP1, and PALB2 might be responsible, but these mutations are rare in most populations and, on average, might not necessarily be associated with a high risk except perhaps in the context of a strong family history.	('ATM', 'Gene', (36, 39))	('BRIP1', 'Gene', (41, 46))	('mutations', 'Var', (90, 99))	('BRIP1', 'Gene', '83990', (41, 46))	('CHEK2', 'Gene', '11200', (29, 34))	('ATM', 'Gene', '472', (36, 39))	('CHEK2', 'Gene', (29, 34))	('PALB2', 'Gene', '79728', (52, 57))	('PALB2', 'Gene', (52, 57))	('associated', 'Reg', (171, 181))
249267	20501846	It is possible, therefore, that a clinically significant portion of early-onset breast cancer cases that are not caused by BRCA1, BRCA2, CHEK2, ATM, BRIP1, or PALB2 mutations is attributable to TP53 mutations, particularly if newer sequencing techniques are used.	('ATM', 'Gene', '472', (144, 147))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('mutations', 'Var', (199, 208))	('PALB2', 'Gene', '79728', (159, 164))	('BRCA2', 'Gene', '675', (130, 135))	('BRCA1', 'Gene', '672', (123, 128))	('BRCA1', 'Gene', (123, 128))	('TP53', 'Gene', (194, 198))	('ATM', 'Gene', (144, 147))	('mutations', 'Var', (165, 174))	('BRIP1', 'Gene', '83990', (149, 154))	('CHEK2', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CHEK2', 'Gene', '11200', (137, 142))	('BRIP1', 'Gene', (149, 154))	('BRCA2', 'Gene', (130, 135))	('TP53', 'Gene', '7157', (194, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('PALB2', 'Gene', (159, 164))
249268	20501846	To better elucidate the contribution of TP53 mutations to hereditary breast cancer, we have estimated the prevalence of TP53 mutations for two subgroups of a population-based sample of breast cancers: (a) cases with very early onset (<30 years) and (b) cases with early age of onset (30-39 years) and a strong family history of breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('TP53', 'Gene', '7157', (40, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('TP53', 'Gene', '7157', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('breast cancers', 'Disease', 'MESH:D001943', (185, 199))	('breast cancers', 'Disease', (185, 199))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (58, 82))	('breast cancers', 'Phenotype', 'HP:0003002', (185, 199))	('mutations', 'Var', (125, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (328, 341))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('TP53', 'Gene', (40, 44))	('breast cancer', 'Disease', 'MESH:D001943', (328, 341))	('TP53', 'Gene', (120, 124))	('hereditary breast cancer', 'Disease', (58, 82))	('breast cancer', 'Disease', (328, 341))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
249277	20501846	Of these, 82 women met the VEO criteria and 61 women met the EO-FH criteria, of whom 52 and 42, respectively, had sufficient DNA available for TP53 mutation testing.	('TP53', 'Gene', (143, 147))	('women', 'Species', '9606', (47, 52))	('women', 'Species', '9606', (13, 18))	('TP53', 'Gene', '7157', (143, 147))	('mutation', 'Var', (148, 156))
249278	20501846	For each case found to have a germline mutation in TP53, all of the relatives enrolled in the ABCFS from whom a blood sample was obtained were tested for the family-specific mutation.	('germline mutation', 'Var', (30, 47))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (51, 55))
249279	20501846	Table 1 shows that there was sufficient DNA for testing 52 of the VEO cases for TP53 mutations.	('mutations', 'Var', (85, 94))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))
249282	20501846	Therefore, of the 94 cases tested here for TP53 mutations, 22 (23%) were known to carry a breast cancer predisposing mutation in another gene (including 13 in BRCA1 and 6 in BRCA2).	('BRCA2', 'Gene', '675', (174, 179))	('TP53', 'Gene', '7157', (43, 47))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('BRCA2', 'Gene', (174, 179))	('BRCA1 and 6', 'Gene', '672', (159, 170))	('mutation', 'Var', (117, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
249291	20501846	First, the VNTR region, which is frequently variable for the number of repeats (we found between 6 and 10 copies of the repeated sequence AAAAT) and for two single-nucleotide polymorphisms (T8759C and 8913-8914insAAG), was amplified and sequenced using primers we had designed.	('T8759C', 'Var', (190, 196))	('T8759C', 'Mutation', 'g.8759T>C', (190, 196))	('8913-8914insAAG', 'Var', (201, 216))	('8913-8914insAAG', 'Mutation', 'c.8913_8914insAAG', (201, 216))
249295	20501846	Table 1 shows that, of the 52 tested cases in the VEO group, 2 (4%; 95% CI, 0.5-13%) had a TP53 mutation.	('TP53', 'Gene', '7157', (91, 95))	('TP53', 'Gene', (91, 95))	('mutation', 'Var', (96, 104))
249296	20501846	Of the 42 tested cases in the EO-FH group, 3 (7%; 95% CI, 1.5-20%) had a TP53 mutation.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('mutation', 'Var', (78, 86))
249297	20501846	The case carrier had the missense mutation G13203A (exon 6, codon R175H), which changes the arginine codon to that for histidine.	('G13203A', 'Var', (43, 50))	('changes', 'Reg', (80, 87))	('arginine', 'Chemical', 'MESH:D001120', (92, 100))	('G13203A', 'Mutation', 'rs28934578', (43, 50))	('arginine codon', 'MPA', (92, 106))	('histidine', 'Chemical', 'MESH:D006639', (119, 128))	('R175H', 'Mutation', 'rs28934578', (66, 71))
249305	20501846	The case carrier had a silent codon change of T125T in the last codon of exon 4 (G12299A) that has been shown to block the splicing excision of intron 4 from the TP53 transcript and thereby blocking TP53 synthesis by introduction of a stop codon.	('G12299A', 'Var', (81, 88))	('splicing excision', 'MPA', (123, 140))	('TP53', 'Gene', (199, 203))	('TP53', 'Gene', '7157', (162, 166))	('G12299A', 'Mutation', 'g.12299G>A', (81, 88))	('TP53', 'Gene', (162, 166))	('blocking', 'NegReg', (190, 198))	('block', 'NegReg', (113, 118))	('TP53', 'Gene', '7157', (199, 203))	('T125T', 'Var', (46, 51))
249312	20501846	This mutation (14058delG) lies in the region encoding the DNA binding region of TP53 and gives rise to a reading frameshift that changes codon 246 to a stop.	('14058delG', 'Mutation', 'c.14058delG', (15, 24))	('changes', 'Reg', (129, 136))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('14058delG', 'Var', (15, 24))	('codon 246', 'MPA', (137, 146))
249324	20501846	In this study, we used a population-based series of cases and applied extensive direct sequencing to estimate the contribution of germline TP53 mutations to two subgroups of early-onset breast cancer likely enriched for genetic causes, and found that 5 of 94 tested cases were carriers (5%; 95% CI, 2-12%).	('TP53', 'Gene', '7157', (139, 143))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('TP53', 'Gene', (139, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('mutations', 'Var', (144, 153))
249325	20501846	That is, germline mutations in TP53 might play a larger role in breast cancer than previously thought.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('germline mutations', 'Var', (9, 27))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('play', 'Reg', (42, 46))	('breast cancer', 'Disease', (64, 77))
249326	20501846	Our study also showed that, in the context of early-onset beast cancer, TP53 mutation carriers can be evident outside the traditional clinically defined Li-Fraumeni family syndrome.	('Li-Fraumeni family syndrome', 'Disease', 'MESH:D016864', (153, 180))	('TP53', 'Gene', '7157', (72, 76))	('mutation', 'Var', (77, 85))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('TP53', 'Gene', (72, 76))	('Li-Fraumeni family syndrome', 'Disease', (153, 180))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
249327	20501846	Few studies have tested for germline TP53 mutations in women with breast cancer outside the context of pedigrees meeting Li-Fraumeni criteria, and only one using population-based sampling.	('women', 'Species', '9606', (55, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tested', 'Reg', (17, 23))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
249330	20501846	Similarly, Gonzalez and colleagues tested for TP53 germline mutations in 525 women submitted for diagnostic testing without specifying the ascertainment criteria.	('TP53', 'Gene', '7157', (46, 50))	('women', 'Species', '9606', (77, 82))	('TP53', 'Gene', (46, 50))	('tested', 'Reg', (35, 41))	('germline mutations', 'Var', (51, 69))
249331	20501846	They found that 95% of mutation carriers who had family history recorded met either the CL-F syndrome or the LF-C criteria.	('CL-F syndrome', 'Disease', (88, 101))	('CL-F syndrome', 'Disease', 'OMIM:102510', (88, 101))	('LF-C', 'Disease', (109, 113))	('mutation', 'Var', (23, 31))
249333	20501846	On the other hand, and similar to our study, Lalloo and colleagues tested 100 women from the United Kingdom with very early onset breast cancer diagnosed at age 30 years or younger, unselected for family history, and found a TP53 mutation prevalence of 4% (95% CI, 1.1-10%).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('women', 'Species', '9606', (78, 83))	('TP53', 'Gene', '7157', (225, 229))	('mutation', 'Var', (230, 238))	('TP53', 'Gene', (225, 229))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
249336	20501846	The finding of TP53 mutation carriers outside of the definition of CL-F, LF-L, and LF-C syndrome might in part be due to more extensive TP53 mutation screening.	('CL-F', 'Gene', '9244', (67, 71))	('LF-C syndrome', 'Disease', (83, 96))	('mutation', 'Var', (20, 28))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('LF-C syndrome', 'Disease', 'MESH:C537418', (83, 96))	('TP53', 'Gene', '7157', (136, 140))	('CL-F', 'Gene', (67, 71))	('TP53', 'Gene', (136, 140))
249340	20501846	For each of the cases in our study with a germline TP53 mutation, four generations of pedigree information were available for review.	('mutation', 'Var', (56, 64))	('germline', 'Var', (42, 50))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (51, 55))
249341	20501846	Whereas our previous work had identified that 20% of these cases carried a disease-predisposing mutation in a known breast cancer susceptibility gene, we have now found that an additional 5% carried a pathogenic mutation in TP53.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('pathogenic', 'Reg', (201, 211))	('TP53', 'Gene', (224, 228))	('mutation', 'Var', (212, 220))	('mutation', 'Var', (96, 104))	('disease-predisposing', 'Reg', (75, 95))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('TP53', 'Gene', '7157', (224, 228))
249342	20501846	Therefore, almost as many cases in these targeted subgroups are caused by TP53 mutations as they are by mutations in BRCA2.	('BRCA2', 'Gene', (117, 122))	('BRCA2', 'Gene', '675', (117, 122))	('TP53', 'Gene', '7157', (74, 78))	('caused', 'Reg', (64, 70))	('TP53', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
249343	20501846	Yet, even within the EO-FH group, less than 30% could be attributed to known mutations in BRCA1, BRCA2, CHEK2, ATM, or TP53.	('BRCA2', 'Gene', (97, 102))	('ATM', 'Gene', (111, 114))	('BRCA1', 'Gene', '672', (90, 95))	('CHEK2', 'Gene', '11200', (104, 109))	('ATM', 'Gene', '472', (111, 114))	('BRCA2', 'Gene', '675', (97, 102))	('CHEK2', 'Gene', (104, 109))	('BRCA1', 'Gene', (90, 95))	('mutations', 'Var', (77, 86))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
249344	20501846	Thus, whereas TP53 might contribute to early-onset breast cancer more so than previously thought, a large proportion of early-onset breast cancer:even within multiple-case families:is due to genetic mutations in yet to be identified genes or mutations in known genes that current methods do not detect.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('due to', 'Reg', (184, 190))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('mutations', 'Var', (199, 208))	('breast cancer', 'Disease', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
249345	20501846	Our work and that of others suggest that TP53 mutation testing for subgroups of families with early-onset breast cancer might be warranted.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('mutation', 'Var', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
249356	31808966	This study shows that deregulated activity of GSK3beta in synovial sarcoma and fibrosarcoma is responsible for tumor cell proliferation through cyclin D1/CDK4-mediated cell cycle progression, and for tumor cell invasion via enhanced extracellular matrix degradation.	('enhanced', 'PosReg', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('GSK3beta', 'Protein', (46, 54))	('cyclin D1', 'Gene', (144, 153))	('synovial sarcoma', 'Disease', (58, 74))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (79, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (58, 74))	('tumor', 'Disease', (200, 205))	('cyclin D1', 'Gene', '595', (144, 153))	('CDK4', 'Gene', (154, 158))	('fibrosarcoma', 'Disease', 'MESH:D005354', (79, 91))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (58, 74))	('extracellular matrix degradation', 'CPA', (233, 265))	('tumor', 'Disease', (111, 116))	('fibrosarcoma', 'Disease', (79, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('CDK4', 'Gene', '1019', (154, 158))	('cell cycle progression', 'CPA', (168, 190))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('deregulated', 'Var', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('responsible', 'Reg', (95, 106))
249378	31808966	This is also the case with GSK3beta since we previously reported that AR-A014418 and SB-216763 inactivate GSK3beta in tumor cells within an hour of treatment.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('inactivate', 'NegReg', (95, 105))	('AR-A014418', 'Chemical', 'MESH:C479831', (70, 80))	('SB-216763', 'Var', (85, 94))	('SB-216763', 'Chemical', 'MESH:C417521', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('AR-A014418', 'Var', (70, 80))	('tumor', 'Disease', (118, 123))	('GSK3beta', 'Protein', (106, 114))
249380	31808966	Sarcoma and fibroblast cells were treated with DMSO or 25 micromol/L AR-A014418 for 24 hours.	('AR-A014418', 'Chemical', 'MESH:C479831', (69, 79))	('DMSO', 'Chemical', 'MESH:D004121', (47, 51))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('AR-A014418', 'Var', (69, 79))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
249386	31808966	Sarcoma cells were treated with DMSO or AR-A014418 (25 micromol/L) for 36 hours in serum-free medium.	('DMSO', 'Chemical', 'MESH:D004121', (32, 36))	('AR-A014418', 'Var', (40, 50))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('AR-A014418', 'Chemical', 'MESH:C479831', (40, 50))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
249400	31808966	All sarcoma cells showed higher levels of pGSK3betaY216 (active form) and lower levels of pGSK3betaS9 (inactive form) compared to NHDF fibroblast cells (Figure 1A).	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('sarcoma', 'Disease', (4, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('higher', 'PosReg', (25, 31))	('pGSK3betaY216', 'Var', (42, 55))	('lower', 'NegReg', (74, 79))
249401	31808966	Immunohistochemistry showed expression of GSK3beta with Y216 phosphorylation in primary synovial sarcoma and fibrosarcoma, but with less S9 phosphorylation (Figure S2).	('synovial sarcoma', 'Disease', (88, 104))	('fibrosarcoma', 'Disease', (109, 121))	('GSK3beta', 'Gene', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (88, 104))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (109, 121))	('fibrosarcoma', 'Disease', 'MESH:D005354', (109, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('synovial sarcoma', 'Disease', 'MESH:D013584', (88, 104))	('Y216 phosphorylation', 'Var', (56, 76))
249402	31808966	These findings are consistent with our previous observations in gastrointestinal cancer, glioblastoma and osteosarcoma25, 32, 36 and led us to hypothesize that sarcoma cells may depend on deregulated GSK3beta for their survival and proliferation.	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (64, 87))	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('deregulated', 'Var', (188, 199))	('glioblastoma and osteosarcoma25', 'Disease', 'MESH:D005909', (89, 120))	('gastrointestinal cancer', 'Disease', (64, 87))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (64, 87))	('sarcoma', 'Disease', (111, 118))	('GSK3beta', 'Protein', (200, 208))	('sarcoma', 'Disease', (160, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
249408	31808966	Viability of all sarcoma cells was reduced by treatment with AR-A014418 or SB-216763 in a dose- and time-dependent manner (Figure 1B).	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('AR-A014418', 'Var', (61, 71))	('Viability', 'CPA', (0, 9))	('SB-216763', 'Gene', (75, 84))	('reduced', 'NegReg', (35, 42))	('SB-216763', 'Chemical', 'MESH:C417521', (75, 84))	('sarcoma', 'Disease', 'MESH:D012509', (17, 24))	('AR-A014418', 'Chemical', 'MESH:C479831', (61, 71))	('sarcoma', 'Disease', (17, 24))
249409	31808966	The half-maximal inhibitory concentration (IC50) values at 96 hours after administration of AR-A014418 were 16.8, 20.1, 17.9, and 43.7 mumol/L for SYO-1, HS-SY-II, SW982 and HT1080 cells, respectively.	('SYO-1', 'Gene', (147, 152))	('HT1080', 'Gene', '8872', (174, 180))	('HT1080', 'Gene', (174, 180))	('SW982', 'CellLine', 'CVCL:1734', (164, 169))	('AR-A014418', 'Chemical', 'MESH:C479831', (92, 102))	('SYO-1', 'Gene', '55027', (147, 152))	('AR-A014418', 'Var', (92, 102))	('HS-SY-II', 'CellLine', 'CVCL:8719', (154, 162))
249411	31808966	These concentrations are within the range of pharmacological doses for each inhibitor.34, 35  AR-A014418 and SB-216763 are well established as highly specific against GSK3beta34, 35 and are widely used for studies on the biological functions of this enzyme.SR7,SR8 We previously demonstrated that both inhibitors attenuate the ability of GSK3beta to phosphorylate its substrate in tumor cells.36 ,SR4 The primary mechanism of action of these inhibitors is to compete with ATP for the ATP-binding domain in GSK3beta,34, 35 hence they are unlikely to directly influence the phosphorylation of S9 and Y216 residues in GSK3beta.	('Y216 residues', 'Var', (598, 611))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('SB-216763', 'Chemical', 'MESH:C417521', (109, 118))	('tumor', 'Disease', (381, 386))	('tumor', 'Disease', 'MESH:D009369', (381, 386))	('AR-A014418', 'Chemical', 'MESH:C479831', (94, 104))	('ATP', 'Chemical', 'MESH:D000255', (484, 487))	('ATP', 'Chemical', 'MESH:D000255', (472, 475))	('influence', 'Reg', (558, 567))
249413	31808966	As shown in Figure S4, treatment with AR-A014418 increased S9 phosphorylation but decreased Y216 phosphorylation of GSK3beta in the sarcoma cells.	('increased', 'PosReg', (49, 58))	('phosphorylation', 'MPA', (62, 77))	('sarcoma', 'Disease', (132, 139))	('AR-A014418', 'Var', (38, 48))	('Y216 phosphorylation', 'MPA', (92, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('GSK3beta', 'Protein', (116, 124))	('decreased', 'NegReg', (82, 91))	('AR-A014418', 'Chemical', 'MESH:C479831', (38, 48))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
249414	31808966	beta-catenin is a substrate of GSK3beta for phosphorylation and subsequent degradation by the ubiquitin-proteasomal system.SR5,SR6 It was located in the cytoplasm and nucleus of most synovial sarcoma cells, as well as the cytoplasm of fibrosarcoma cells and with scattered nuclear beta-catenin-positive cells (Figure S3), despite these cells having active GSK3beta (Figure 1A and Figure S4).	('GSK3beta', 'Enzyme', (356, 364))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (183, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('synovial sarcoma', 'Disease', 'MESH:D013584', (183, 199))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (235, 247))	('fibrosarcoma', 'Disease', 'MESH:D005354', (235, 247))	('SR6 It', 'Var', (127, 133))	('synovial sarcoma', 'Disease', (183, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('fibrosarcoma', 'Disease', (235, 247))	('system.SR5', 'Var', (116, 126))
249417	31808966	Similar effects were observed in the sarcoma cells following GSK3beta RNA interference (Figure 3 and Figure S6).	('GSK3beta RNA', 'Var', (61, 73))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('sarcoma', 'Disease', 'MESH:D012509', (37, 44))	('sarcoma', 'Disease', (37, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
249418	31808966	The biological effect of RNA interference depends on the efficiency of siRNA transfection and on the subsequent knockdown of the target molecule.	('N', 'Chemical', 'MESH:D009584', (26, 27))	('knockdown', 'Var', (112, 121))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('RNA interference', 'MPA', (25, 41))
249419	31808966	Therefore, we believe the pharmacological inhibitors more quickly and efficiently inhibit GSK3beta activity in cells, leading to a stronger biological effect on cells compared to treatment with GSK3beta-specific siRNA.	('stronger', 'PosReg', (131, 139))	('N', 'Chemical', 'MESH:D009584', (215, 216))	('inhibit', 'NegReg', (82, 89))	('GSK3beta', 'Enzyme', (90, 98))	('biological effect', 'MPA', (140, 157))	('inhibitors', 'Var', (42, 52))	('activity', 'MPA', (99, 107))
249421	31808966	Flow cytometry analysis revealed an increased G0/G1 fraction in all sarcoma cells treated with 25 micromol/L AR-A014418 for 24 hours, indicating the induction of G0/G1-phase cell cycle arrest (Figure 4A,B).	('AR-A014418', 'Var', (109, 119))	('G0/G1 fraction', 'CPA', (46, 60))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (174, 191))	('increased', 'PosReg', (36, 45))	('G0/G1-phase cell cycle arrest', 'CPA', (162, 191))	('sarcoma', 'Disease', (68, 75))	('AR-A014418', 'Chemical', 'MESH:C479831', (109, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
249427	31808966	Treatment with 25 micromol/L AR-A014418 for 48 hours significantly attenuated the invasive capacity of sarcoma cells (Figure 5A,B).	('sarcoma', 'Disease', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('AR-A014418', 'Chemical', 'MESH:C479831', (29, 39))	('attenuated', 'NegReg', (67, 77))	('AR-A014418', 'Var', (29, 39))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))
249430	31808966	Treatment of the sarcoma cells with 25 micromol/L AR-A014418 for 36 hours decreased the expression of these forms, as well as pro-MMP-2 secretion (Figure 5C).	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('MMP-2', 'Gene', (130, 135))	('AR-A014418', 'Var', (50, 60))	('sarcoma', 'Disease', 'MESH:D012509', (17, 24))	('MMP-2', 'Gene', '4313', (130, 135))	('AR-A014418', 'Chemical', 'MESH:C479831', (50, 60))	('decreased', 'NegReg', (74, 83))	('expression', 'MPA', (88, 98))	('sarcoma', 'Disease', (17, 24))
249437	31808966	Similar to the sarcoma cells in culture (Figure S4), immunohistochemistry showed that treatment of xenograft tumors with GSK3beta inhibitors enhanced S9 phosphorylation and reduced Y216 phosphorylation, but did not affect GSK3beta expression (Figure S7).	('GSK3beta', 'Gene', (121, 129))	('xenograft tumors', 'Disease', (99, 115))	('reduced', 'NegReg', (173, 180))	('inhibitors', 'Var', (130, 140))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcoma', 'Disease', (15, 22))	('xenograft tumors', 'Disease', 'MESH:D009369', (99, 115))	('Y216 phosphorylation', 'MPA', (181, 201))	('enhanced', 'PosReg', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('S9 phosphorylation', 'MPA', (150, 168))
249449	31808966	The highly proliferative and invasive nature of STS cells promotes their progression and results in incomplete surgical removal of the tumor and failure of chemotherapy.7 In the present study, inhibition of GSK3beta induced G0/G1-phase cell cycle arrest and decreased the expression of cyclin D1, CDK4 and CDK6.	('GSK3beta', 'Gene', (207, 215))	('inhibition', 'Var', (193, 203))	('cyclin D1', 'Gene', (286, 295))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('expression', 'MPA', (272, 282))	('decreased', 'NegReg', (258, 267))	('CDK4', 'Gene', (297, 301))	('tumor', 'Disease', (135, 140))	('G0/G1-phase cell cycle arrest', 'CPA', (224, 253))	('CDK4', 'Gene', '1019', (297, 301))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (236, 253))	('CDK6', 'Gene', (306, 310))	('CDK6', 'Gene', '1021', (306, 310))	('cyclin D1', 'Gene', '595', (286, 295))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
249450	31808966	This is responsible for the anti-proliferative effect of GSK3beta inhibitors on sarcoma cells, as we observed previously in gastrointestinal and pancreatic cancers.36, 47 It was reported that CDK4 and CDK6 are activated in a complex with cyclin D1 in various sarcoma types, including STSs, thus facilitating their progression.48 Therefore, our results suggest that synovial sarcoma and fibrosarcoma cells depend on deregulated GSK3beta for their survival and proliferation via cyclin D1 and CDK4/6-mediated cell cycle progression and evasion of apoptosis.	('sarcoma', 'Phenotype', 'HP:0100242', (391, 398))	('sarcoma', 'Disease', (374, 381))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('sarcoma', 'Disease', (80, 87))	('proliferation', 'CPA', (459, 472))	('gastrointestinal and pancreatic cancers', 'Disease', 'MESH:D005770', (124, 163))	('CDK4/6', 'Gene', (491, 497))	('cyclin D1', 'Gene', (477, 486))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('CDK4', 'Gene', '1019', (491, 495))	('sarcoma', 'Phenotype', 'HP:0100242', (374, 381))	('sarcoma', 'Disease', 'MESH:D012509', (259, 266))	('cyclin D1', 'Gene', (238, 247))	('CDK4', 'Gene', (192, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('deregulated', 'Var', (415, 426))	('sarcoma', 'Disease', (259, 266))	('cyclin D1', 'Gene', '595', (477, 486))	('synovial sarcoma', 'Disease', (365, 381))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (386, 398))	('cyclin D1', 'Gene', '595', (238, 247))	('GSK3beta', 'Gene', (427, 435))	('CDK4/6', 'Gene', '1019;1021', (491, 497))	('synovial sarcoma', 'Disease', 'MESH:D013584', (365, 381))	('sarcoma', 'Disease', 'MESH:D012509', (391, 398))	('evasion of apoptosis', 'CPA', (534, 554))	('CDK4', 'Gene', '1019', (192, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('CDK6', 'Gene', '1021', (201, 205))	('sarcoma', 'Disease', (391, 398))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (365, 381))	('fibrosarcoma', 'Disease', 'MESH:D005354', (386, 398))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('STSs', 'Phenotype', 'HP:0030448', (284, 288))	('sarcoma', 'Disease', 'MESH:D012509', (374, 381))	('fibrosarcoma', 'Disease', (386, 398))	('CDK6', 'Gene', (201, 205))	('CDK4', 'Gene', (491, 495))
249457	31808966	We also found that GSK3beta inhibition did not further increase nuclear accumulation of beta-catenin in the sarcoma cells and their xenograft tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('sarcoma', 'Disease', (108, 115))	('xenograft tumors', 'Disease', 'MESH:D009369', (132, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('inhibition', 'Var', (28, 38))	('nuclear accumulation', 'MPA', (64, 84))	('GSK3beta', 'Protein', (19, 27))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('xenograft tumors', 'Disease', (132, 148))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))
249458	31808966	Several previous studies reported activation of Wnt/beta-catenin signaling in synovial sarcoma and considered this to be a potential therapeutic target.SR28-SR35 However, none of these studies showed that inhibition of GSK3beta activates beta-catenin signaling in synovial sarcoma.	('GSK3beta', 'Protein', (219, 227))	('SR3', 'Gene', (157, 160))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (264, 280))	('synovial sarcoma', 'Disease', (78, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('synovial sarcoma', 'Disease', 'MESH:D013584', (264, 280))	('activates', 'PosReg', (228, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('synovial sarcoma', 'Disease', (264, 280))	('synovial sarcoma', 'Disease', 'MESH:D013584', (78, 94))	('SR3', 'Gene', '53349', (157, 160))	('beta-catenin signaling', 'MPA', (238, 260))	('inhibition', 'Var', (205, 215))
249462	31808966	Similar to the present study of synovial sarcoma and fibrosarcoma, we found higher GSK3beta expression and Y216 phosphorylation and lower S9 phosphorylation in CRC cell lines and primary tumors compared to non-neoplastic HEK293 cells and normal colorectal mucosa tissue, respectively.	('fibrosarcoma', 'Disease', (53, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('lower', 'NegReg', (132, 137))	('synovial sarcoma', 'Disease', (32, 48))	('synovial sarcoma', 'Disease', 'MESH:D013584', (32, 48))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('higher', 'PosReg', (76, 82))	('HEK293', 'CellLine', 'CVCL:0045', (221, 227))	('CRC', 'Disease', 'MESH:D015179', (160, 163))	('GSK3beta', 'Protein', (83, 91))	('CRC', 'Disease', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (32, 48))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (53, 65))	('tumors', 'Disease', (187, 193))	('CRC', 'Phenotype', 'HP:0003003', (160, 163))	('expression', 'MPA', (92, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('fibrosarcoma', 'Disease', 'MESH:D005354', (53, 65))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('Y216', 'Var', (107, 111))	('S9 phosphorylation', 'MPA', (138, 156))
249468	31808966	In conclusion, this study demonstrates that deregulated activity of GSK3beta in synovial sarcoma and fibrosarcoma is responsible for tumor cell proliferation via cyclin D1/CDK4-mediated cell cycle progression, and for tumor cell invasion via enhanced extracellular matrix degradation.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('deregulated', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (218, 223))	('CDK4', 'Gene', (172, 176))	('cell cycle progression', 'CPA', (186, 208))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('extracellular matrix degradation', 'CPA', (251, 283))	('GSK3beta', 'Protein', (68, 76))	('synovial sarcoma', 'Disease', (80, 96))	('CDK4', 'Gene', '1019', (172, 176))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (101, 113))	('synovial sarcoma', 'Disease', 'MESH:D013584', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (133, 138))	('enhanced', 'PosReg', (242, 250))	('fibrosarcoma', 'Disease', 'MESH:D005354', (101, 113))	('cyclin D1', 'Gene', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (80, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('fibrosarcoma', 'Disease', (101, 113))	('cyclin D1', 'Gene', '595', (162, 171))
249529	26972653	Because it is known that ablation of ovarian function by oophorectomy or radiation doses to the ovary > 5 Gy at an early age reduces the risk of breast cancer in women not receiving chest radiotherapy, we evaluated the influence of ovarian radiation on radiation-related breast cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('breast cancer', 'Disease', 'MESH:D001943', (271, 284))	('breast cancer', 'Phenotype', 'HP:0003002', (271, 284))	('ovarian radiation', 'Disease', 'MESH:D004194', (232, 249))	('breast cancer', 'Disease', (271, 284))	('reduces', 'NegReg', (125, 132))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('ovarian radiation', 'Disease', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ablation', 'Var', (25, 33))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('women', 'Species', '9606', (162, 167))
249669	26560505	FOXM1 interruption by siRNA decreased cell proliferation and increased chemosensitivity.	('cell proliferation', 'CPA', (38, 56))	('interruption', 'Var', (6, 18))	('decreased', 'NegReg', (28, 37))	('increased', 'PosReg', (61, 70))	('FOXM1', 'Gene', '2305', (0, 5))	('FOXM1', 'Gene', (0, 5))	('chemosensitivity', 'CPA', (71, 87))
34260	26560505	; GAPDH Hs99999905_m1.	('Hs99999905_m1', 'Var', (8, 21))	('GAPDH', 'Gene', '2597', (2, 7))	('GAPDH', 'Gene', (2, 7))
249712	26560505	The subsequent procedures were carried out according to the manufacturer's protocol and as described.26  After 24-h siRNA transfection, the transfected cells were seeded at 2000 cells per well in 96-well plates.	('transfection', 'Var', (122, 134))	('siRNA', 'Gene', (116, 121))	('man', 'Species', '9606', (60, 63))
249718	26560505	In addition, the serial sections immunostained with anti-Ki-67 showed that some immunoreactive cells for FOXM1 antibody are also reactive for Ki-67 (Fig.	('FOXM1', 'Gene', '2305', (105, 110))	('FOXM1', 'Gene', (105, 110))	('Ki-67', 'Var', (142, 147))
249720	26560505	In the univariate analysis of prognostic factors, the expression of FOXM1 was significantly associated with OS (P = 0.0142) (Fig.	('expression', 'Var', (54, 64))	('FOXM1', 'Gene', (68, 73))	('associated', 'Reg', (92, 102))	('FOXM1', 'Gene', '2305', (68, 73))
249722	26560505	The following clinicopathologic variables were also associated with poor prognosis in OS: large tumor size (more than 5 cm), tumor depth (deep origin), tumor necrosis, high mitotic activity (mitotic count >10/high power field) and high FNCLCC histological grade (I vs. II; II vs. III).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('high', 'Var', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor depth', 'Disease', 'MESH:D007222', (125, 136))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (152, 157))	('tumor necrosis', 'Disease', 'MESH:D009336', (152, 166))	('tumor', 'Disease', (125, 130))	('tumor depth', 'Disease', (125, 136))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor necrosis', 'Disease', (152, 166))
249738	26560505	Increased sensitivity for DOX at 10 ng/mL was observed in the TC616 cell line by FOXM1 interruption (Fig.	('interruption', 'Var', (87, 99))	('FOXM1', 'Gene', '2305', (81, 86))	('FOXM1', 'Gene', (81, 86))	('TC616', 'CellLine', 'CVCL:0825', (62, 67))	('DOX', 'Chemical', 'MESH:D004317', (26, 29))
249743	26560505	In the present study, FOXM1 expression was correlated with poor prognosis for OS among LMS patients in the univariate analysis.	('patients', 'Species', '9606', (91, 99))	('LMS', 'Phenotype', 'HP:0100243', (87, 90))	('FOXM1', 'Gene', '2305', (22, 27))	('FOXM1', 'Gene', (22, 27))	('expression', 'Var', (28, 38))
249745	26560505	Among the clinicopathologic factors, high FOXM1 expression was correlated with high mitotic activity, high MIB-1 labeling index, and high FNCLCC grade.	('high', 'Var', (37, 41))	('expression', 'MPA', (48, 58))	('MIB-1', 'Gene', (107, 112))	('FOXM1', 'Gene', (42, 47))	('high mitotic activity', 'CPA', (79, 100))	('FOXM1', 'Gene', '2305', (42, 47))	('MIB-1', 'Gene', '57534', (107, 112))
249752	26560505	Interruption of FOXM1, achieved by using siRNA, caused a reduction in cell proliferation.	('Interruption', 'Var', (0, 12))	('reduction', 'NegReg', (57, 66))	('FOXM1', 'Gene', '2305', (16, 21))	('cell proliferation', 'CPA', (70, 88))	('FOXM1', 'Gene', (16, 21))
249753	26560505	The interruption of FOXM1 decreases cell proliferation through an inhibition of cell-cycle progression in many cancer cell lines.18, 23 FOXM1 is one of a few genes shown to be upregulated during early cancer development, and the involvement of FOXM1 in the onset of tumorigenesis may be related mainly to its role in cell-cycle progression and proliferation.28, 29, 30, 31 FOXM1 interruption caused decreasing viability treated with DOX in TC616 cells.	('cancer', 'Disease', (201, 207))	('man', 'Species', '9606', (106, 109))	('DOX', 'Chemical', 'MESH:D004317', (433, 436))	('FOXM1', 'Gene', '2305', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', (111, 117))	('FOXM1', 'Gene', (20, 25))	('tumor', 'Disease', (266, 271))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('TC616', 'CellLine', 'CVCL:0825', (440, 445))	('FOXM1', 'Gene', '2305', (373, 378))	('FOXM1', 'Gene', '2305', (244, 249))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('decreasing', 'NegReg', (399, 409))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('FOXM1', 'Gene', '2305', (20, 25))	('FOXM1', 'Gene', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('viability', 'MPA', (410, 419))	('interruption', 'Var', (379, 391))	('FOXM1', 'Gene', (244, 249))	('FOXM1', 'Gene', (373, 378))
249759	26560505	Thiostrepton has the potential to be an agent for treating LMS with high FOXM1 expression, based on its ability to bind FOXM1 directly.	('LMS', 'Phenotype', 'HP:0100243', (59, 62))	('FOXM1', 'Gene', (73, 78))	('expression', 'MPA', (79, 89))	('high', 'Var', (68, 72))	('FOXM1', 'Gene', '2305', (73, 78))	('Thiostrepton', 'Chemical', 'MESH:D013883', (0, 12))	('bind', 'Interaction', (115, 119))	('FOXM1', 'Gene', (120, 125))	('FOXM1', 'Gene', '2305', (120, 125))	('LMS', 'Disease', (59, 62))
249771	27587590	For example, in cancer, the activity and clinical benefit of several agents mechanistically depend on specific mutations in genes that drive the cancer.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('activity', 'MPA', (28, 36))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('genes', 'Gene', (124, 129))
249909	25003594	The following International Classification for Childhood Cancer site recode extended ICD-0-3 histology codes were included: 8900-8902, 8910, 8912, 8920, 8921, 8960, 9180-9183, 9186, 9192, 9193, 9260 and 9500.	('9192', 'Var', (182, 186))	('9180-9183', 'Var', (165, 174))	('9193', 'Var', (188, 192))	('8920', 'Var', (147, 151))	('9260', 'Var', (194, 198))	('8960', 'Var', (159, 163))	('Childhood Cancer', 'Disease', (47, 63))	('Childhood Cancer', 'Disease', 'MESH:C536928', (47, 63))	('8921', 'Var', (153, 157))	('8910', 'Var', (135, 139))	('8900-8902', 'Var', (124, 133))	('8912', 'Var', (141, 145))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))
250212	24950227	The "Grep" Command But Not FusionMap, FusionFinder or ChimeraScan Captures the CIC-DUX4 Fusion Gene from Whole Transcriptome Sequencing Data on a Small Round Cell Tumor with t(4;19)(q35;q13) Whole transcriptome sequencing was used to study a small round cell tumor in which a t(4;19)(q35;q13) was part of the complex karyotype but where the initial reverse transcriptase PCR (RT-PCR) examination did not detect a CIC-DUX4 fusion transcript previously described as the crucial gene-level outcome of this specific translocation.	('CIC', 'Gene', '23152', (413, 416))	('CIC', 'Gene', (79, 82))	('DUX4', 'Gene', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('CIC', 'Gene', (413, 416))	('DUX4', 'Gene', (417, 421))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('DUX4', 'Gene', '100288687', (83, 87))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (276, 292))	('Tumor', 'Phenotype', 'HP:0002664', (163, 168))	('t(4;19)(q35;q13', 'Var', (276, 291))	('tumor', 'Disease', (259, 264))	('DUX4', 'Gene', '100288687', (417, 421))	('CIC', 'Gene', '23152', (79, 82))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (174, 190))
250219	24950227	The authors mentioned that a similar translocation had also been reported as part of complex karyotype in an embryonal rhabdomyosarcoma (RMS) cell line and as part of a three-way translocation t(4;19;12)(q35;q13.1;q13) in an undifferentiated/embryonal RMS and suggested that it might be a recurrent chromosomal aberration in malignant primitive mesenchymal stem cells.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (119, 135))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (299, 321))	('recurrent chromosomal aberration', 'Phenotype', 'HP:0040012', (289, 321))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('t(4;19;12)(q35', 'Var', (193, 207))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (109, 135))	('embryonal rhabdomyosarcoma', 'Disease', (109, 135))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (109, 135))
250220	24950227	Sommers et al described a subcutaneous primitive neuroectodermal tumor/Ewing sarcoma without EWSR1 rearrangement but with a complex karyotype containing a t(4;19)(q33~35;q13).	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (49, 70))	('Ewing sarcoma', 'Disease', (71, 84))	('EWSR1', 'Gene', (93, 98))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (39, 70))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (71, 84))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (49, 70))	('t(4;19)(q33~35;q13', 'Var', (155, 173))	('EWSR1', 'Gene', '2130', (93, 98))	('neuroectodermal tumor', 'Disease', (49, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
250221	24950227	Kawamura-Saito et al described two cases of Ewing-like sarcoma which had a t(4;19)(q35;q13) in their karyotypes.	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('t(4;19)(q35;q13', 'Var', (75, 90))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (75, 91))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (44, 62))	('Ewing-like sarcoma', 'Disease', (44, 62))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (44, 62))
250222	24950227	They also showed that the translocation resulted in fusion of the capicua transcriptional repressor CIC gene on 19q13, which codes for a high mobility group box transcription factor, with the double homeodomain DUX4 gene on 4q35.	('CIC', 'Gene', (100, 103))	('resulted in', 'Reg', (40, 51))	('fusion', 'Var', (52, 58))	('DUX4', 'Gene', (211, 215))	('CIC', 'Gene', '23152', (100, 103))	('DUX4', 'Gene', '100288687', (211, 215))
250226	24950227	So far, there are roughly 20 reported cases of sarcoma with the t(4;19)(q35;q13) and/or CIC-DUX4 fusion.	('CIC', 'Gene', '23152', (88, 91))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('t(4', 'Var', (64, 67))	('CIC', 'Gene', (88, 91))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (64, 80))	('sarcoma', 'Disease', (47, 54))	('DUX4', 'Gene', (92, 96))	('DUX4', 'Gene', '100288687', (92, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
250228	24950227	The current data suggest that the CIC-DUX4 fusion defines a subgroup of primitive round cell sarcomas, different from Ewing sarcoma, with distinctive histopathology and rapid disease progression.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (118, 131))	('DUX4', 'Gene', (38, 42))	('DUX4', 'Gene', '100288687', (38, 42))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcomas', 'Disease', (93, 101))	('CIC', 'Gene', '23152', (34, 37))	('fusion', 'Var', (43, 49))	('Ewing sarcoma', 'Disease', (118, 131))	('CIC', 'Gene', (34, 37))
250229	24950227	Recently, whole transcriptome sequencing (RNA-Seq, RNA sequencing) was shown to be an efficient tool in the detection of fusion genes in cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('fusion genes', 'Var', (121, 133))
250230	24950227	In short, extracted RNA from cancer cells is massively sequenced, and then the raw data are analyzed with one or more programs specifically dedicated to the task of detecting fusion transcripts such as ChimeraScan, FusionMap, and FusionFinder.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('ChimeraScan', 'Var', (202, 213))
250233	24950227	In the present study, we performed whole transcriptome sequencing to study a small round cell tumor in which t(4;19)(q35;q13) was part of a complex karyotype.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (109, 125))	('t(4;19)(q35;q13', 'Var', (109, 124))
250258	24950227	G-banding analysis yielded the diagnostic karyotype 46,XX,del(2)(q13q23),t(4;19)(q35;q13),ins(11;?)(q11;?	('46,XX,del(2)(q13q23),t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (52, 89))	('t(4;19)(q35;q13', 'Var', (73, 88))	('del(2)(q13q23', 'Var', (58, 71))
250268	24950227	Since fastq is a text-based format of the sequence data, we decided to use the "grep" command-line utility and search for sequences which contained part of the last exon of CIC (exon 20, nucleotides 4500-5473 in the sequence with accession number NM_015125 version 3).	('CIC', 'Gene', (173, 176))	('nucleotides 4500-5473', 'Var', (187, 208))	('exon', 'Var', (178, 182))	('CIC', 'Gene', '23152', (173, 176))
250272	24950227	The fusion had occurred between nt 4724 of CIC mRNA reference sequence NM_015125.3 and nt 771 of DUX4 mRNA reference sequence NM_033178.4.	('CIC', 'Gene', '23152', (43, 46))	('NM_015125.3', 'Var', (71, 82))	('DUX4', 'Gene', (97, 101))	('CIC', 'Gene', (43, 46))	('DUX4', 'Gene', '100288687', (97, 101))
250277	24950227	The small round cell tumor had the t(4;19)(q35;q13) translocation as part of its karyotype and in addition a split signal of the BAC RP11-556K23 (mapped on 19q13), which contains CIC, features that led us to nevertheless believe strongly that a CIC-DUX4 fusion must be present.	('CIC', 'Gene', '23152', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (35, 51))	('CIC', 'Gene', (245, 248))	('CIC', 'Gene', '23152', (179, 182))	('RP11', 'Gene', (133, 137))	('small', 'Disease', (4, 9))	('RP11', 'Gene', '26121', (133, 137))	('DUX4', 'Gene', (249, 253))	('DUX4', 'Gene', '100288687', (249, 253))	('t(4', 'Var', (35, 38))	('CIC', 'Gene', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
250283	24950227	The sequences obtained by "grep" were blasted against the human genomic plus transcript database (http://blast.ncbi.nlm.nih.gov/Blast.cgi) in order to identify possible chimeric fragments containing part of CIC and part of another gene.	('CIC', 'Gene', (207, 210))	('CIC', 'Gene', '23152', (207, 210))	('human', 'Species', '9606', (58, 63))	('chimeric', 'Var', (169, 177))
250286	24950227	The fusion occurred between nt 4724 of CIC mRNA reference sequence NM_015125.3 and nt 771 of DUX4 mRNA reference sequence NM_033178.4.	('occurred', 'Reg', (11, 19))	('NM_015125.3', 'Var', (67, 78))	('CIC', 'Gene', '23152', (39, 42))	('DUX4', 'Gene', (93, 97))	('DUX4', 'Gene', '100288687', (93, 97))	('CIC', 'Gene', (39, 42))
250287	24950227	CIC fusions have been reported at nt 4552, 4579, 4740, 4750 and for DUX4 at nt 1071, 1078, and 1145 of the reference sequence with accession number NM_033178.4.	('4579', 'Var', (43, 47))	('DUX4', 'Gene', '100288687', (68, 72))	('CIC', 'Gene', '23152', (0, 3))	('4740', 'Var', (49, 53))	('DUX4', 'Gene', (68, 72))	('CIC', 'Gene', (0, 3))	('4750', 'Var', (55, 59))
250297	24950227	In conclusion, our study showed that the three fusion-finder programs FusionMap, Fusion Finder, and ChimeraScan generated a plethora of fusion transcripts but not the biologically important and cancer-specific fusion gene, the CIC-DUX4 chimeric transcript.	('cancer', 'Disease', (194, 200))	('fusion transcripts', 'Var', (136, 154))	('CIC', 'Gene', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('DUX4', 'Gene', (231, 235))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('CIC', 'Gene', '23152', (227, 230))	('plethora', 'Phenotype', 'HP:0001050', (124, 132))	('DUX4', 'Gene', '100288687', (231, 235))
250343	23449111	Clusters of round, hyper- or hypo-fluorescent spots reflect RPE abnormalities.	('RPE abnormalities', 'Phenotype', 'HP:0007703', (60, 77))	('hyper-', 'MPA', (19, 25))	('RPE abnormalities', 'Disease', 'MESH:D000014', (60, 77))	('hypo-fluorescent', 'Var', (29, 45))	('RPE abnormalities', 'Disease', (60, 77))
250440	21138586	For example, while monoclonal antibodies (mAbs) are extraordinarily specific in their targeting, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness and the generation of antibodies against the therapeutic agent.	('acute anaphylaxis', 'Disease', (165, 182))	('rat', 'Species', '10116', (105, 108))	('rat', 'Species', '10116', (211, 214))	('serum sickness', 'Disease', (184, 198))	('mAbs', 'Var', (115, 119))	('anaphylaxis', 'Phenotype', 'HP:0100845', (171, 182))
250444	21138586	To assess whether inhibition of the Trks attenuates bone cancer pain, pain behaviors were analyzed in sham + vehicle and in tumor-bearing mice treated with early/acute ARRY-470, early/sustained ARRY-470, and late/acute ARRY-470.	('bone cancer pain', 'Disease', (52, 68))	('bone cancer pain', 'Phenotype', 'HP:0002653', (52, 68))	('pain', 'Disease', 'MESH:D010146', (70, 74))	('tumor', 'Disease', (124, 129))	('ARRY-470', 'Chemical', 'MESH:C000609083', (168, 176))	('bone cancer pain', 'Disease', 'MESH:D001859', (52, 68))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('pain', 'Disease', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('mice', 'Species', '10090', (138, 142))	('pain', 'Phenotype', 'HP:0012531', (64, 68))	('inhibition', 'Var', (18, 28))	('attenuates', 'NegReg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('pain', 'Disease', (70, 74))	('pain', 'Disease', 'MESH:D010146', (64, 68))	('ARRY-470', 'Chemical', 'MESH:C000609083', (219, 227))	('ARRY-470', 'Chemical', 'MESH:C000609083', (194, 202))	('pain', 'Phenotype', 'HP:0012531', (70, 74))
250453	21138586	Whereas all mice with GFP+ tumor cells growing in the periosteum showed significant sprouting of CGRP+ and NF200+ nerve fibers, approximately one half of these mice had 1-2 neuroma-like structures in the periosteum (Figure 4B, Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('neuroma', 'Disease', 'MESH:D009463', (173, 180))	('tumor', 'Disease', (27, 32))	('neuroma', 'Phenotype', 'HP:0030430', (173, 180))	('neuroma', 'Disease', (173, 180))	('NF200', 'Gene', (107, 112))	('sprouting', 'CPA', (84, 93))	('NF200', 'Gene', '380684', (107, 112))	('CGRP+', 'Protein', (97, 102))	('GFP+', 'Var', (22, 26))	('mice', 'Species', '10090', (160, 164))	('mice', 'Species', '10090', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
250459	21138586	Treatment of sarcoma-injected mice with ARRY-470 at days 6-20 post tumor injection resulted in no reduction in tumor growth (100 +- 0 of intramedullary space (Additional file 1 Figure S1B) and no significant change in bone resorption (2.6 +- 0.24; as compared to sarcoma + vehicle animals (2.8 +- 0.14) (Additional file 1 Figure S1E).	('mice', 'Species', '10090', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ARRY-470', 'Chemical', 'MESH:C000609083', (40, 48))	('sarcoma', 'Disease', 'MESH:D012509', (263, 270))	('bone resorption', 'Phenotype', 'HP:0002797', (218, 233))	('reduction', 'NegReg', (98, 107))	('tumor', 'Disease', (111, 116))	('sarcoma', 'Disease', (263, 270))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ARRY-470', 'Var', (40, 48))	('sarcoma', 'Disease', 'MESH:D012509', (13, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('tumor', 'Disease', (67, 72))	('bone resorption', 'CPA', (218, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('sarcoma', 'Disease', (13, 20))
250464	21138586	As the present results show that blockade of all three Trks reduces bone cancer pain, a key question is which neurotrophins and Trks are most likely the major contributors to the generation and maintenance of bone cancer pain.	('rat', 'Species', '10116', (183, 186))	('neurotrophin', 'Gene', (110, 122))	('blockade', 'Var', (33, 41))	('pain', 'Phenotype', 'HP:0012531', (80, 84))	('pain', 'Phenotype', 'HP:0012531', (221, 225))	('Trks reduces bone cancer pain', 'Disease', (55, 84))	('bone cancer pain', 'Disease', 'MESH:D001859', (68, 84))	('neurotrophin', 'Gene', '627', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bone cancer pain', 'Phenotype', 'HP:0002653', (68, 84))	('bone cancer pain', 'Disease', 'MESH:D001859', (209, 225))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('bone cancer pain', 'Disease', (209, 225))	('bone cancer pain', 'Phenotype', 'HP:0002653', (209, 225))	('Trks reduces bone cancer pain', 'Disease', 'MESH:D001859', (55, 84))
250474	21138586	Thus, while local injection of NT-3 has been reported to induce mild pain at the injection site, other reports suggest that NT-3 does not sensitize nociceptive primary afferent fibers and appears to be anti-nociceptive in some pain models such as complete Freund's adjuvant-induced skin inflammation.	('pain', 'Phenotype', 'HP:0012531', (227, 231))	('pain', 'Disease', 'MESH:D010146', (69, 73))	('pain', 'Disease', (69, 73))	('skin inflammation', 'Disease', (282, 299))	('anti-nociceptive', 'MPA', (202, 218))	('pain', 'Disease', 'MESH:D010146', (227, 231))	('pain', 'Disease', (227, 231))	('NT-3', 'Var', (124, 128))	('skin inflammation', 'Disease', 'MESH:D007249', (282, 299))	('skin inflammation', 'Phenotype', 'HP:0011123', (282, 299))	('NT-3', 'Gene', (31, 35))	("complete Freund's adjuvant-induced", 'Disease', (247, 281))	('pain', 'Phenotype', 'HP:0012531', (69, 73))
250478	21138586	Thus, since bone appears to lack the redundancy of the C-fiber non-peptidergic IB4/RET+ nerve fibers that are present in skin, blocking TrkA activation may be particularly efficacious in relieving bone pain vs. skin pain.	('skin pain', 'Disease', 'MESH:D010146', (211, 220))	('RET', 'Gene', '5979', (83, 86))	('skin pain', 'Disease', (211, 220))	('blocking', 'Var', (127, 135))	('bone pain', 'Disease', 'MESH:D010146', (197, 206))	('C-fiber', 'Species', '10185', (55, 62))	('RET', 'Gene', (83, 86))	('pain', 'Phenotype', 'HP:0012531', (216, 220))	('TrkA', 'Protein', (136, 140))	('pain', 'Phenotype', 'HP:0012531', (202, 206))	('bone pain', 'Disease', (197, 206))	('bone pain', 'Phenotype', 'HP:0002653', (197, 206))
250495	21138586	Previous studies have shown that inappropriate remodeling of sensory nerve fibers, whether through sprouting or neuroma-like formation, can give rise to hyperalgesia, allodynia, and spontaneous ectopic discharges that are perceived as highly painful in humans.	('allodynia', 'Phenotype', 'HP:0012533', (167, 176))	('hyperalgesia', 'Disease', 'MESH:D006930', (153, 165))	('hyperalgesia', 'Disease', (153, 165))	('allodynia', 'Disease', (167, 176))	('pain', 'Disease', (242, 246))	('give rise to', 'Reg', (140, 152))	('hyperalgesia', 'Phenotype', 'HP:0031005', (153, 165))	('pain', 'Phenotype', 'HP:0012531', (242, 246))	('allodynia', 'Disease', 'MESH:D006930', (167, 176))	('pain', 'Disease', 'MESH:D010146', (242, 246))	('neuroma', 'Phenotype', 'HP:0030430', (112, 119))	('humans', 'Species', '9606', (253, 259))	('neuroma', 'Disease', 'MESH:D009463', (112, 119))	('sprouting', 'CPA', (99, 108))	('remodeling', 'Var', (47, 57))	('neuroma', 'Disease', (112, 119))	('spontaneous ectopic discharges', 'MPA', (182, 212))
250641	22367140	Although depressed cellular immunity results in decreased total lymphocyte and CD4 counts, polyclonal B-cell activation produces increased circulating immune complexes with increased production of IgA, IgG, and IgE.	('IgE', 'Gene', '3497', (211, 214))	('IgE', 'Gene', (211, 214))	('CD4', 'Gene', (79, 82))	('IgA', 'MPA', (197, 200))	('cellular immunity', 'CPA', (19, 36))	('CD4', 'Gene', '920', (79, 82))	('increased', 'PosReg', (129, 138))	('decreased', 'NegReg', (48, 57))	('IgG', 'MPA', (202, 205))	('polyclonal', 'Var', (91, 101))	('increased production of IgA', 'Phenotype', 'HP:0003261', (173, 200))	('increased', 'PosReg', (173, 182))	('circulating immune complexes', 'MPA', (139, 167))	('circulating immune complexes', 'Phenotype', 'HP:0012224', (139, 167))	('production', 'MPA', (183, 193))
250688	33063945	NONE-STS of bone has favorable long-term survival similar to osteosarcoma.	('osteosarcoma', 'Disease', (61, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('NONE-STS', 'Var', (0, 8))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))
250726	33063945	Evaluation of 10-year DFS, OS, and SSS, respectively, by sarcoma histology (Figure 4A/B/C) identified MPNST as having the most favorable prognosis (DFS = 60.6%, [95%CI: 17.1-100%]; OS = 80.0%, [95%CI: 44.9-100%]; SSS = 80.0%, [95%CI: 44.9-100%]); albeit in a small group of only six patients.	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('patients', 'Species', '9606', (283, 291))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('FS', 'Disease', 'MESH:D018223', (149, 151))	('FS', 'Disease', 'MESH:D018223', (23, 25))	('4A/B', 'SUBSTITUTION', 'None', (83, 87))	('sarcoma', 'Disease', (57, 64))	('4A/B', 'Var', (83, 87))
250736	33063945	Consistent with other studies of soft-tissue and osteosarcoma, high degree of necrosis on final pathology 18 ,  19 ,  20  and receipt of chemotherapy 22 ,  23  were associated with improved survival; whereas axial tumor location 24  and high pathologic grade 1  were associated with worse outcomes on multivariate analyses.	('necrosis', 'Disease', 'MESH:D009336', (78, 86))	('osteosarcoma', 'Disease', (49, 61))	('improved', 'PosReg', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('osteosarcoma', 'Phenotype', 'HP:0002669', (49, 61))	('osteosarcoma', 'Disease', 'MESH:D012516', (49, 61))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('survival', 'MPA', (190, 198))	('high', 'Var', (63, 67))	('tumor', 'Disease', (214, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('necrosis', 'Disease', (78, 86))
250737	33063945	Our data further demonstrates favorable 5-year (70.7%) and 10-year (63.9%) SSS for the full cohort of 106 patients, with the notable finding of sarcoma-related death for UPS/MFH beyond 10 years (Appendix 1).	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('UPS/MFH', 'Var', (170, 177))	('sarcoma-related death', 'Disease', (144, 165))	('patients', 'Species', '9606', (106, 114))	('sarcoma-related death', 'Disease', 'MESH:D003643', (144, 165))
250786	33277516	The three STR kits Q11, MPX4, and PowerPlex ESX 17 included the same STR markers: D3S1358, FGA, D8S1179, D18S51, D21S11, TH01, VWA, SE33, D2S1338, D16S539, D19S433, and the gender-typing system Amelogenin.	('D21S11', 'Var', (113, 119))	('D2S1338', 'Var', (138, 145))	('D8S1179', 'Var', (96, 103))	('FGA', 'Gene', (91, 94))	('D19S433', 'Var', (156, 163))	('D16S539', 'Var', (147, 154))	('D3S1358', 'Var', (82, 89))	('D18S51', 'Var', (105, 111))	('FGA', 'Gene', '2243', (91, 94))
250819	33277516	High resolution HLA typing showed HLA-A*11:01,*24:02, HLA-B*15:01,*35:01 and HLA-C*03:03,*04:01 for HLA-class I as well as HLA-DRB1*01:01,*13:02 and HLA-DQB1*05:01,*06:04 for HLA-class II.	('HLA', 'Gene', (16, 19))	('HLA', 'Gene', '3119', (149, 152))	('HLA-DQB1', 'Gene', (149, 157))	('HLA', 'Gene', (175, 178))	('HLA', 'Gene', '3119', (54, 57))	('HLA', 'Gene', '3119', (77, 80))	('HLA', 'Gene', (149, 152))	('HLA', 'Gene', (77, 80))	('HLA', 'Gene', '3119', (100, 103))	('HLA', 'Gene', (54, 57))	('HLA-A', 'Gene', (34, 39))	('HLA-B', 'Gene', (54, 59))	('HLA', 'Gene', (100, 103))	('*35:01', 'Var', (66, 72))	('HLA', 'Gene', '3119', (123, 126))	('HLA-DQB1', 'Gene', '3119', (149, 157))	('HLA-DRB1', 'Gene', '3123', (123, 131))	('HLA', 'Gene', (123, 126))	('HLA-C', 'Gene', (77, 82))	('HLA-C', 'Gene', '3107', (77, 82))	('HLA', 'Gene', '3119', (34, 37))	('HLA-DRB1', 'Gene', (123, 131))	('HLA-A', 'Gene', '3105', (34, 39))	('HLA', 'Gene', '3119', (16, 19))	('HLA', 'Gene', (34, 37))	('HLA-B', 'Gene', '3106', (54, 59))	('HLA', 'Gene', '3119', (175, 178))
250821	33277516	In the frozen sections, the patient's IDCS were identified as MHCI- and MHCII-positive cells, co-expressing CD68, CD80 and showing partial expression of CD11c, CD86, CD205 and S100 protein (Table 1).	('CD205', 'Gene', '4065', (166, 171))	('CD80', 'Var', (114, 118))	('patient', 'Species', '9606', (28, 35))	('CD205', 'Gene', (166, 171))	('S100', 'Gene', (176, 180))	('CD86', 'Var', (160, 164))	('CD11c', 'Gene', '3687', (153, 158))	('CD11c', 'Gene', (153, 158))	('CD68', 'Var', (108, 112))	('S100', 'Gene', '6271', (176, 180))
250824	33277516	Immunophenotypic markers not expressed were CD1a, CD 1c, CD11c, CD14, CD21, CD23, CD86, CD123, CD207, Factor VII, Lysozyme, Clec10a, and Podoplanin (for pictures of some key stainings see Supplementary Fig.	('CD21', 'Var', (70, 74))	('CD207', 'Gene', (95, 100))	('CD11c', 'Gene', '3687', (57, 62))	('Lysozyme', 'Gene', '4069', (114, 122))	('CD 1c', 'Gene', (50, 55))	('CD11c', 'Gene', (57, 62))	('CD 1c', 'Gene', '911', (50, 55))	('CD123', 'Gene', '3563', (88, 93))	('Lysozyme', 'Gene', (114, 122))	('CD1a', 'Gene', (44, 48))	('Clec10a', 'Gene', '10462', (124, 131))	('CD207', 'Gene', '50489', (95, 100))	('Clec10a', 'Gene', (124, 131))	('CD1a', 'Gene', '909', (44, 48))	('CD86', 'Var', (82, 86))	('CD123', 'Gene', (88, 93))
250841	33277516	It revealed the following similarities: ish cgh enh(1p), dim(4q), enh(7), dim(8)(p12 pter), dim(13)(qter q31), enh(20), enh(22)(cen q12), enh(Y) (Fig.	('dim(8)(p12', 'Var', (74, 84))	('dim(13)(qter q31', 'Var', (92, 108))	('enh(1p', 'Gene', '10611', (48, 54))
250958	32805674	As for EpCAM transcript levels, protein expression was variable among the sarcoma cell lines: readily detectable in both ARMS cell lines (RH4 and RH30), weak (RH36 and TC32) or even absent (RD and CHP100) in either ERMS or Ewing Sarcoma cells (Fig.	('TC32', 'CellLine', 'CVCL:7151', (168, 172))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (223, 236))	('RMS', 'Phenotype', 'HP:0002859', (216, 219))	('RH4', 'Gene', (138, 141))	('EpCAM', 'Gene', '4072', (7, 12))	('RH4', 'Gene', '6007', (138, 141))	('RMS', 'Phenotype', 'HP:0002859', (122, 125))	('TC32', 'Var', (168, 172))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (223, 236))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('RH36', 'Var', (159, 163))	('Sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('RH30', 'Gene', (146, 150))	('RH30', 'Gene', '6007', (146, 150))	('Ewing Sarcoma', 'Disease', (223, 236))	('sarcoma', 'Disease', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('EpCAM', 'Gene', (7, 12))
250994	32805674	Deregulation of EMT-related genes in DSRCT tumors would explain their extreme inter-tumor heterogeneity, as their propensity to disseminate and resist to drug treatment.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Deregulation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (84, 89))	('EMT-related genes', 'Gene', (16, 33))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumor', 'Disease', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
251023	30950072	ABY-029 is retained longer within tumor tissue and achieves higher tumor-to-background ratios both in vivo and ex vivo than IRDye 700DX.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('IRDye 700DX', 'Chemical', '-', (124, 135))	('higher', 'PosReg', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ABY-029', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
251030	30950072	In addition, ABY-029 is not anticipated to cause any pharmacological response, given that no immunogenic side-effects were observed during toxicity testing using doses equivalent to one-thousand times the human microdose level.	('ABY-029', 'Var', (13, 20))	('toxicity', 'Disease', 'MESH:D064420', (139, 147))	('toxicity', 'Disease', (139, 147))	('human', 'Species', '9606', (205, 210))
251056	30950072	Prior to imaging, mice were administered 200 muL of a 1:1 solution of 4.98 muM ABY-029 and IRDye 700DX in PBS via intravascular tail vein injection.	('PBS via intravascular', 'Disease', 'MESH:D011535', (106, 127))	('mice', 'Species', '10090', (18, 22))	('PBS via intravascular', 'Disease', (106, 127))	('ABY-029', 'Var', (79, 86))	('IRDye 700DX', 'Chemical', '-', (91, 102))
251094	30950072	Additionally, significant differences to autofluorescence was also observed in SK-LMS-1, SW-982, and MES-SA at 8 and 24 hours, and SK-NEP-1 only at 8 hours (24-hour time point data was missing).	('differences', 'Reg', (26, 37))	('SK-LMS-1', 'Var', (79, 87))	('SW-982', 'CellLine', 'CVCL:1734', (89, 95))	('MES-SA', 'Chemical', '-', (101, 107))	('SK-NEP-1', 'Chemical', '-', (131, 139))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (79, 87))	('autofluorescence', 'MPA', (41, 57))
251109	30950072	ABY-029 in MES-SA tumors demonstrated a decrease in TBR as compared to muscle and skin and an increase when compared to fat.	('decrease', 'NegReg', (40, 48))	('increase', 'PosReg', (94, 102))	('ABY-029', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('TBR', 'MPA', (52, 55))	('MES-SA', 'Disease', (11, 17))	('TBR', 'Chemical', '-', (52, 55))	('MES-SA', 'Chemical', '-', (11, 17))
251115	30950072	The TBRs of VA-ES-BJ and MES-SA do not increase as substantially as the other tumor lines, likely due to both VA-ES-BJ and MES-SA having high levels of vascularity compared to the other tumor lines (Supplemental Data, Figure S1).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('BJ', 'CellLine', 'CVCL:6573', (116, 118))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MES-SA', 'Chemical', '-', (123, 129))	('BJ', 'CellLine', 'CVCL:6573', (18, 20))	('TBRs', 'Chemical', '-', (4, 8))	('VA-ES-BJ', 'Var', (110, 118))	('MES-SA', 'Chemical', '-', (25, 31))
251116	30950072	ABY-029 produced TBRs that were significantly greater than autofluorescence at 4 hours post-administration in all tumor lines, and negligible statistical differences between 4-, 8- and 24-hour timepoints.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ABY-029', 'Var', (0, 7))	('tumor', 'Disease', (114, 119))	('TBRs', 'MPA', (17, 21))	('TBRs', 'Chemical', '-', (17, 21))	('greater', 'PosReg', (46, 53))
251120	30950072	Therefore, not only does ABY-029 produce clinically relevant TBR values but more accurately represents viable tumor tissue.	('TBR values', 'MPA', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ABY-029', 'Var', (25, 32))	('TBR', 'Chemical', '-', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
251132	30950072	The effects of formalin fixation were more apparent in IRDye 700DX than in ABY-029, indicating that IRDye 800CW is the more stable fluorophore.	('IRDye', 'Chemical', '-', (55, 60))	('IRDye 700DX', 'Chemical', '-', (55, 66))	('IRDye 800CW', 'Var', (100, 111))	('formalin', 'Chemical', 'MESH:D005557', (15, 23))	('700DX', 'Var', (61, 66))	('IRDye', 'Chemical', '-', (100, 105))
251309	27701385	Patients with high expression of the gene profile had significantly higher cumulative incidence of death from sarcoma compared with patients with low expression.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('sarcoma', 'Disease', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('patients', 'Species', '9606', (132, 140))
251316	27701385	The modulation of the extracellular matrix is important to facilitate tumour cell migration and enhances sarcoma metastasis as shown by.	('modulation', 'Var', (4, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('facilitate', 'PosReg', (59, 69))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('enhances', 'PosReg', (96, 104))	('sarcoma metastasis', 'Disease', 'MESH:D009362', (105, 123))	('sarcoma metastasis', 'Disease', (105, 123))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))
251359	27774356	Genetically, ES is characterized by translocations involving the Ewing sarcoma breakpoint region 1 (EWSR1) 22q12 gene locus, with roughly 83% of cases demonstrating a t(11;22)(q24;q12) gene fusion resulting in an EWSR1-FLI1 gene product.	('t(11;22)(q24;q12', 'Var', (167, 183))	('FLI1', 'Gene', (219, 223))	('EWSR1', 'Gene', (100, 105))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (167, 184))	('FLI1', 'Gene', '2313', (219, 223))	('EWSR1', 'Gene', '2130', (213, 218))	('Ewing sarcoma breakpoint region 1', 'Gene', (65, 98))	('EWSR1', 'Gene', '2130', (100, 105))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (65, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('EWSR1', 'Gene', (213, 218))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))	('ES', 'Phenotype', 'HP:0012254', (13, 15))
251375	27774356	An immunohistochemical evaluation revealed tumor cells positive for CD99 and negative for cytokeratin, desmin, myogenin, terminal deoxynucleotidyl transferase (TdT), CD 45, CD3, and CD20, supporting a diagnosis of ES.	('CD 45', 'Gene', (166, 171))	('CD20', 'Gene', '54474', (182, 186))	('myogenin', 'Gene', '4656', (111, 119))	('desmin', 'Gene', '1674', (103, 109))	('TdT', 'Gene', (160, 163))	('tumor', 'Disease', (43, 48))	('negative', 'NegReg', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ES', 'Phenotype', 'HP:0012254', (214, 216))	('CD3', 'MPA', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('TdT', 'Gene', '1791', (160, 163))	('CD99', 'Var', (68, 72))	('myogenin', 'Gene', (111, 119))	('CD 45', 'Gene', '5788', (166, 171))	('desmin', 'Gene', (103, 109))	('terminal deoxynucleotidyl transferase', 'Gene', '1791', (121, 158))	('CD20', 'Gene', (182, 186))	('terminal deoxynucleotidyl transferase', 'Gene', (121, 158))
251376	27774356	FISH (fluorescence in situ hybridization) testing was positive for the EWSR1 gene locus rearrangement, further strengthening the diagnosis of ES.	('ES', 'Phenotype', 'HP:0012254', (142, 144))	('EWSR1', 'Gene', (71, 76))	('strengthening', 'PosReg', (111, 124))	('rearrangement', 'Var', (88, 101))	('EWSR1', 'Gene', '2130', (71, 76))
251394	27425618	Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc can derive from cells expressing Ng2/Cspg4.	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('deletion', 'Var', (88, 96))	('Trp53', 'Gene', (104, 109))	('tumor', 'Disease', (139, 144))	('desmoid tumor', 'Phenotype', 'HP:0100245', (131, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('desmoid tumors', 'Phenotype', 'HP:0100245', (131, 145))	('Apc', 'Gene', (170, 173))	('Apc', 'Gene', '11789', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('desmoid tumors', 'Disease', (131, 145))	('desmoid tumors', 'Disease', 'MESH:C535944', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('soft tissue sarcomas', 'Disease', (53, 73))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (53, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('tumor', 'Disease', (110, 115))	('mutation', 'Var', (158, 166))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (53, 73))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
251395	27425618	Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing beta-catenin in this same cell type caused desmoid tumors.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('desmoid tumors', 'Phenotype', 'HP:0100245', (204, 218))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('Trp53', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('desmoid tumors', 'Disease', (204, 218))	('sarcomas', 'Disease', (133, 141))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('desmoid tumors', 'Disease', 'MESH:C535944', (204, 218))	('resulted in', 'Reg', (59, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('Deletion', 'Var', (0, 8))	('human', 'Species', '9606', (127, 132))	('caused', 'Reg', (197, 203))	('soft tissue sarcomas', 'Disease', (84, 104))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))	('tumor', 'Disease', (212, 217))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('beta-catenin', 'MPA', (161, 173))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (84, 104))	('sarcomas', 'Disease', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('desmoid tumor', 'Phenotype', 'HP:0100245', (204, 217))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (84, 104))	('tumor', 'Disease', (22, 27))
251396	27425618	Comparing expression between Ng2/Cspg4 expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53, showed inhibition of beta-catenin signaling in the sarcomas.	('sarcomas', 'Disease', (78, 86))	('sarcomas', 'Disease', 'MESH:D012509', (173, 181))	('Trp53', 'Gene', (115, 120))	('beta-catenin signaling', 'MPA', (143, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (173, 181))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('inhibition', 'NegReg', (129, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcomas', 'Disease', (173, 181))	('deletion', 'Var', (103, 111))
251399	27425618	Here we used lineage tracing studies in mice to show that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor gene, can derive from Ng2/Cspg4 expressing pericytes.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('tumor', 'Disease', (124, 129))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (67, 87))	('soft tissue sarcomas', 'Disease', (67, 87))	('deletion', 'Var', (102, 110))	('Trp53', 'Gene', (118, 123))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (67, 87))	('mice', 'Species', '10090', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
251400	27425618	Benign mesenchymal desmoid tumors, driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('desmoid tumor', 'Phenotype', 'HP:0100245', (19, 32))	('Ng2/Cspg4', 'Gene', (97, 106))	('mutation', 'Var', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('desmoid tumors', 'Phenotype', 'HP:0100245', (19, 33))	('driven by', 'Reg', (35, 44))	('Benign mesenchymal desmoid tumors', 'Disease', (0, 33))	('Benign mesenchymal desmoid tumors', 'Disease', 'MESH:C535944', (0, 33))	('Apc', 'Gene', (59, 62))	('Apc', 'Gene', '11789', (59, 62))
251401	27425618	Driving mutations in Trp53 or beta-catenin in Ng2/Cspg4 expressing cells, resulted in sarcoma or desmoid tumor formation.	('sarcoma', 'Disease', (86, 93))	('Trp53', 'Gene', (21, 26))	('desmoid tumor', 'Disease', 'MESH:C535944', (97, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('resulted in', 'Reg', (74, 85))	('mutations', 'Var', (8, 17))	('desmoid tumor', 'Phenotype', 'HP:0100245', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('beta-catenin', 'Protein', (30, 42))	('sarcoma', 'Disease', 'MESH:D012509', (86, 93))	('desmoid tumor', 'Disease', (97, 110))
251402	27425618	Comparing the expression profiles from RNA sequencing between Ng2/Cspg4 expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53, showed inhibition of beta-catenin signaling in the sarcomas.	('inhibition', 'NegReg', (162, 172))	('sarcomas', 'Disease', 'MESH:D012509', (206, 214))	('sarcomas', 'Disease', 'MESH:D012509', (111, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (206, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('sarcomas', 'Disease', (206, 214))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('Trp53', 'Gene', (148, 153))	('Trp53', 'Gene', (101, 106))	('deletion', 'Var', (136, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('lacking', 'NegReg', (93, 100))	('sarcomas', 'Disease', (111, 119))	('beta-catenin signaling', 'MPA', (176, 198))
251405	27425618	Tumors are initiated by mutations in specific cell types.	('initiated by', 'Reg', (11, 23))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (24, 33))
251406	27425618	Since progenitor cell populations can survive over longer periods of time, they may be more likely to accumulate mutations that cause neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (134, 143))	('mutations', 'Var', (113, 122))	('neoplasia', 'Disease', (134, 143))	('neoplasia', 'Disease', 'MESH:D009369', (134, 143))
251412	27425618	Mutations in Apc or in beta-catenin itself are identified in almost all cases of this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('Mutations', 'Var', (0, 9))	('Apc', 'Gene', (13, 16))	('Apc', 'Gene', '11789', (13, 16))	('identified', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
251421	27425618	Lineage tracing studies in murine sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc, were used to investigate Ng2/Cspg4 expressing cells as a cell of origin for mesenchymal.	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('deletion', 'Var', (57, 65))	('Trp53', 'Gene', (73, 78))	('tumor', 'Disease', (108, 113))	('desmoid tumor', 'Phenotype', 'HP:0100245', (100, 113))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('desmoid tumors', 'Phenotype', 'HP:0100245', (100, 114))	('Apc', 'Gene', (139, 142))	('Apc', 'Gene', '11789', (139, 142))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('desmoid tumors', 'Disease', (100, 114))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutation', 'Var', (127, 135))	('desmoid tumors', 'Disease', 'MESH:C535944', (100, 114))	('murine', 'Species', '10090', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('sarcomas', 'Disease', 'MESH:D012509', (34, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (34, 42))	('sarcomas', 'Disease', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
251422	27425618	We also determined the ability of Trp53 deletion and/or stabilization of beta-catenin in Ng2/Cspg4 expressing cells to result in tumor formation.	('Trp53', 'Gene', (34, 39))	('deletion', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('result in', 'Reg', (119, 128))	('stabilization', 'MPA', (56, 69))	('tumor', 'Disease', (129, 134))	('beta-catenin', 'Protein', (73, 85))
251426	27425618	To study the origin of a benign tumor, we investigated desmoid tumors, which are benign locally invasive mesenchymal lesions driven by mutations activating beta-catenin mediated signaling.	('tumor', 'Disease', (63, 68))	('mutations', 'Var', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('desmoid tumors', 'Phenotype', 'HP:0100245', (55, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('desmoid tumor', 'Phenotype', 'HP:0100245', (55, 68))	('activating', 'PosReg', (145, 155))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('invasive mesenchymal lesions', 'Disease', 'MESH:C535700', (96, 124))	('desmoid tumors', 'Disease', 'MESH:C535944', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (32, 37))	('invasive mesenchymal lesions', 'Disease', (96, 124))	('desmoid tumors', 'Disease', (55, 69))
251427	27425618	The Apc1638N mouse harbors a mutation in Apc that results in the development of multiple desmoid tumors.	('mutation', 'Var', (29, 37))	('mouse', 'Species', '10090', (13, 18))	('desmoid tumors', 'Phenotype', 'HP:0100245', (89, 103))	('desmoid tumor', 'Phenotype', 'HP:0100245', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('multiple desmoid tumors', 'Disease', 'MESH:C535944', (80, 103))	('Apc', 'Gene', '11789', (4, 7))	('results in', 'Reg', (50, 60))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Apc', 'Gene', (41, 44))	('Apc', 'Gene', (4, 7))	('Apc', 'Gene', '11789', (41, 44))	('multiple desmoid tumors', 'Disease', (80, 103))
251429	27425618	To label Ng2/Cspg4 expressing cells, we crossed Ng2/Cspg4-CreER mice with Rosa26RlacZ mice.	('Rosa26', 'Gene', '14910', (74, 80))	('Ng2/Cspg4-CreER', 'Var', (48, 63))	('mice', 'Species', '10090', (86, 90))	('Rosa26', 'Gene', (74, 80))	('mice', 'Species', '10090', (64, 68))
251438	27425618	The Apc1638N mouse harbors a mutation in Apc that results in beta-catenin activation and the development of multiple desmoid tumors.	('mutation', 'Var', (29, 37))	('mouse', 'Species', '10090', (13, 18))	('desmoid tumors', 'Phenotype', 'HP:0100245', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('desmoid tumor', 'Phenotype', 'HP:0100245', (117, 130))	('Apc', 'Gene', '11789', (4, 7))	('beta-catenin', 'Protein', (61, 73))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('activation', 'PosReg', (74, 84))	('multiple desmoid tumors', 'Disease', 'MESH:C535944', (108, 131))	('Apc', 'Gene', (41, 44))	('Apc', 'Gene', (4, 7))	('Apc', 'Gene', '11789', (41, 44))	('multiple desmoid tumors', 'Disease', (108, 131))
251446	27425618	To determine whether mutations in Ng2/Cspg4 expressing cells could induce sarcomas, we crossed Ng2/Cspg4-Cre mice or Ng2/Cspg4-CreER mice with Trp53flox/flox mice to generate Ng2/Cspg4-Cre mediated Trp53 conditional knockout mice.	('sarcomas', 'Disease', (74, 82))	('mice', 'Species', '10090', (133, 137))	('mice', 'Species', '10090', (158, 162))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('induce', 'Reg', (67, 73))	('mice', 'Species', '10090', (225, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('mice', 'Species', '10090', (109, 113))	('Ng2/Cspg4', 'Gene', (34, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('mutations', 'Var', (21, 30))
251448	27425618	In Ng2/Cspg4-CreER;Trp53flox/flox mice treated with tamoxifen, 66 % developed bone sarcomas and 20 % developed soft tissue sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('mice', 'Species', '10090', (34, 38))	('bone sarcomas', 'Disease', 'MESH:D001847', (78, 91))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (111, 131))	('bone sarcomas', 'Disease', (78, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('soft tissue sarcomas', 'Disease', (111, 131))	('bone sarcomas', 'Phenotype', 'HP:0002669', (78, 91))	('tamoxifen', 'Chemical', 'MESH:D013629', (52, 61))	('Trp53flox/flox', 'Gene', (19, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('Ng2/Cspg4-CreER', 'Var', (3, 18))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (111, 131))
251454	27425618	2B), providing additional support to the concept that loss of Trp53 specifically in an Ng2/Cspg4 expressing cell predisposes to sarcoma formation.	('sarcoma', 'Disease', 'MESH:D012509', (128, 135))	('sarcoma', 'Disease', (128, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('predisposes', 'Reg', (113, 124))	('loss', 'Var', (54, 58))	('Trp53', 'Protein', (62, 67))
251464	27425618	We then investigated a mouse in which soft tissue sarcomas can be generated using an inducible KrasG12D mutation and Trp53 deletion driven by cre-recombinase.	('Trp53', 'Gene', (117, 122))	('soft tissue sarcomas', 'Disease', (38, 58))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (38, 58))	('deletion', 'Var', (123, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('mouse', 'Species', '10090', (23, 28))	('mutation', 'Var', (104, 112))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (38, 58))
251468	27425618	2K), resulting in tumors with histology identical to that seen in the soft tissue sarcomas generated by Trp53 deletion in the same cell types (Fig.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (70, 90))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (70, 90))	('Trp53', 'Gene', (104, 109))	('soft tissue sarcomas', 'Disease', (70, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('deletion', 'Var', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
251469	27425618	To determine if stabilizing beta-catenin mutations could induce desmoid tumors, we crossed Ng2/Cspg4-CreER mice with beta-catenin conditionally stabilized Ctnnb1ex3 mice.	('mutations', 'Var', (41, 50))	('desmoid tumors', 'Disease', 'MESH:C535944', (64, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mice', 'Species', '10090', (165, 169))	('desmoid tumors', 'Disease', (64, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mice', 'Species', '10090', (107, 111))	('induce', 'Reg', (57, 63))	('desmoid tumor', 'Phenotype', 'HP:0100245', (64, 77))	('desmoid tumors', 'Phenotype', 'HP:0100245', (64, 78))
251471	27425618	2M and N) A similar microarray platform as has been used in human tumors was used to compare mRNA from sarcomas that developed in Ng2/Cspg4-CreER;Trp53flox/flox with human tumors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('human', 'Species', '9606', (166, 171))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('sarcomas', 'Disease', (103, 111))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('Ng2/Cspg4-CreER', 'Var', (130, 145))	('human', 'Species', '9606', (60, 65))
251482	27425618	To determine the role of beta-catenin stabilization in sarcoma formation, we generated Ng2/Cspg4-Cre;Trp53flox/flox;;KrasG12D;Ctnnb1ex3 mice in which Ng2/Cspg4 expressing cells would harbor a mutation causing sarcomas, and also express a stabilized form of beta-catenin.	('harbor', 'Reg', (183, 189))	('mice', 'Species', '10090', (136, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('sarcomas', 'Phenotype', 'HP:0100242', (209, 217))	('sarcoma', 'Disease', (55, 62))	('sarcomas', 'Disease', (209, 217))	('mutation', 'Var', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcoma', 'Disease', 'MESH:D012509', (209, 216))	('causing', 'Reg', (201, 208))	('sarcoma', 'Disease', (209, 216))	('beta-catenin', 'Protein', (257, 269))	('sarcomas', 'Disease', 'MESH:D012509', (209, 217))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('stabilized', 'MPA', (238, 248))
251494	27425618	These data are consistent with the notion that beta-catenin transcriptional activity is lower in sarcomas than in the cells they arise from, and that stabilization of beta-catenin in sarcomas can suppress tumor growth.	('lower', 'NegReg', (88, 93))	('sarcomas', 'Disease', 'MESH:D012509', (183, 191))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('stabilization', 'Var', (150, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('beta-catenin', 'Protein', (167, 179))	('beta-catenin', 'Protein', (47, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('sarcomas', 'Disease', (183, 191))	('sarcomas', 'Disease', (97, 105))	('tumor', 'Disease', (205, 210))	('suppress', 'NegReg', (196, 204))	('transcriptional activity', 'MPA', (60, 84))
251504	27425618	While this possibility cannot be completely eliminated, the generation of sarcomas in Ng2/Cspg4-CreER mice following tamoxifen-inducible Cre suggests that the cell of origin of these mesenchymal tumors expresses Ng2/Cspg4 at tumor initiation.	('sarcomas', 'Disease', (74, 82))	('mice', 'Species', '10090', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('Ng2/Cspg4-CreER', 'Var', (86, 101))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (183, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('mesenchymal tumors', 'Disease', (183, 201))	('Ng2/Cspg4', 'Var', (212, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
251505	27425618	Mice with Trp53 mutations in Ng2/Cspg4 developed both osteogenic and soft tissue sarcomas a finding consistent with the notion that pericytes can differentiate into a variety of mesenchymal cell types.	('Trp53', 'Gene', (10, 15))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (69, 89))	('soft tissue sarcomas', 'Disease', (69, 89))	('osteogenic', 'CPA', (54, 64))	('mutations', 'Var', (16, 25))	('Ng2/Cspg4', 'Gene', (29, 38))	('Mice', 'Species', '10090', (0, 4))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (69, 89))	('developed', 'PosReg', (39, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
251506	27425618	The concept that a mesenchymal progenitor can form both bone and soft tissue sarcomas is in agreement with data from driving oncogenic mutations in MSCs, showing that the same mutation in MSCs can result in either bone or soft tissue sarcomas.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (65, 85))	('soft tissue sarcomas', 'Disease', (65, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('result in', 'Reg', (197, 206))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (222, 242))	('MSCs', 'Gene', (188, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (65, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('mutation', 'Var', (176, 184))	('soft tissue sarcomas', 'Disease', (222, 242))	('bone', 'Disease', (214, 218))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (222, 242))	('sarcomas', 'Phenotype', 'HP:0100242', (234, 242))
251507	27425618	Furthermore, we found that different mutations in the same cell type can cause different mesenchymal tumors.	('mesenchymal tumors', 'Disease', 'MESH:C535700', (89, 107))	('mesenchymal tumors', 'Disease', (89, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutations', 'Var', (37, 46))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('cause', 'Reg', (73, 78))
251508	27425618	Driving a stabilized form of beta-catenin in Ng2/Cspg4 expressing cells results in desmoid tumors, while Trp53 deletion causes sarcomas.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('desmoid tumors', 'Phenotype', 'HP:0100245', (83, 97))	('desmoid tumors', 'Disease', 'MESH:C535944', (83, 97))	('causes', 'Reg', (120, 126))	('sarcomas', 'Disease', (127, 135))	('desmoid tumor', 'Phenotype', 'HP:0100245', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Trp53', 'Gene', (105, 110))	('sarcomas', 'Disease', 'MESH:D012509', (127, 135))	('desmoid tumors', 'Disease', (83, 97))	('results in', 'Reg', (72, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('deletion', 'Var', (111, 119))
251516	27425618	Other mouse osteosarcoma models have been developed based on the conditional deletion or mutation of Trp53.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('conditional deletion', 'Var', (65, 85))	('mutation', 'Var', (89, 97))	('Trp53', 'Gene', (101, 106))	('osteosarcoma', 'Disease', (12, 24))	('osteosarcoma', 'Phenotype', 'HP:0002669', (12, 24))	('osteosarcoma', 'Disease', 'MESH:D012516', (12, 24))	('mouse', 'Species', '10090', (6, 11))
251517	27425618	However, driving deletion in a subset of cells and developing a sarcoma does not necessarily identify a specific cell of origin.	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('deletion', 'Var', (17, 25))	('sarcoma', 'Disease', (64, 71))
251519	27425618	Desmoid tumors are a clonal proliferation of mesenchymal cells driven by mutations in APC or CTNNB1 driving beta-catenin protein stabilization.	('APC', 'Gene', '11789', (86, 89))	('CTNNB1', 'Gene', '12387', (93, 99))	('APC', 'Gene', (86, 89))	('beta-catenin protein stabilization', 'MPA', (108, 142))	('Desmoid tumors', 'Phenotype', 'HP:0100245', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('CTNNB1', 'Gene', (93, 99))	('mutations', 'Var', (73, 82))	('Desmoid tumors', 'Disease', 'MESH:C535944', (0, 14))	('Desmoid tumors', 'Disease', (0, 14))
251520	27425618	Interestingly, while a subset of desmoid tumors were previously thought to be mutation negative when analyzed by traditional Sanger sequencing, deep sequencing found that most of these mutation negative tumors do indeed harbor mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('desmoid tumors', 'Disease', (33, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('desmoid tumors', 'Phenotype', 'HP:0100245', (33, 47))	('desmoid tumors', 'Disease', 'MESH:C535944', (33, 47))	('desmoid tumor', 'Phenotype', 'HP:0100245', (33, 46))	('negative', 'NegReg', (194, 202))	('harbor', 'Reg', (220, 226))	('mutations', 'Var', (227, 236))
251524	27425618	The finding that these tumors derive from perciytes is consistent with data showing a correlation between numbers of mesenchymal progenitors and numbers of desmoid tumors that from in Apc mutant mice.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mice', 'Species', '10090', (195, 199))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('desmoid tumors', 'Disease', (156, 170))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('Apc', 'Gene', (184, 187))	('Apc', 'Gene', '11789', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('desmoid tumor', 'Phenotype', 'HP:0100245', (156, 169))	('desmoid tumors', 'Phenotype', 'HP:0100245', (156, 170))	('desmoid tumors', 'Disease', 'MESH:C535944', (156, 170))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('mutant', 'Var', (188, 194))
251529	27425618	While our data cannot rule out this possibility, the finding that stabilization of beta-catenin in these cells results in desmoid tumors, suggests that high beta-catenin alone does not maintain the perciytes in a native undifferentiated state.	('desmoid tumors', 'Disease', 'MESH:C535944', (122, 136))	('results in', 'Reg', (111, 121))	('desmoid tumors', 'Disease', (122, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('stabilization', 'Var', (66, 79))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('desmoid tumors', 'Phenotype', 'HP:0100245', (122, 136))	('desmoid tumor', 'Phenotype', 'HP:0100245', (122, 135))
251535	27425618	We used Trp53 mutant mice, Apc1638N, Trp53flox/flox conditional, LSL-KrasG12D mice (Tuveson et al., 2004), Catnbex3 mice, Ng2/Cspg4-Cre and Ng2/Cspg4-CreER transgenic mice, and Rosa26RlacZ reporter mice as previously reported.	('mice', 'Species', '10090', (116, 120))	('Trp53flox/flox', 'Gene', (37, 51))	('Rosa26', 'Gene', '14910', (177, 183))	('mice', 'Species', '10090', (21, 25))	('mutant', 'Var', (14, 20))	('transgenic mice', 'Species', '10090', (156, 171))	('Rosa26', 'Gene', (177, 183))	('Trp53', 'Gene', (8, 13))	('Apc', 'Gene', '11789', (27, 30))	('Apc', 'Gene', (27, 30))	('mice', 'Species', '10090', (198, 202))	('mice', 'Species', '10090', (167, 171))	('mice', 'Species', '10090', (78, 82))
251537	27425618	Ng2/Cspg4-CreER;Trp53flox/flox mice, Ng2/Cspg-CreER;Trp53flox/- mice, Ng2/Cspg4-CreER;Trp53flox/+ mice, Ng2/Cspg4-CreER;Catnbex3 mice Ng2/Cspg4-Cre;Trp53flox/flox mice, Ng2/Cspg4-Cre;Trp53flox/- mice, and Ng2/Cspg4-Cre;Trp53flox/+ mice were generated by crossing the mice and used to determine if driving mutations in Ng2/Cspg4 expressing cells causes tumors.	('mice', 'Species', '10090', (195, 199))	('tumors', 'Disease', 'MESH:D009369', (352, 358))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('Ng2/Cspg4', 'Gene', (318, 327))	('mice', 'Species', '10090', (129, 133))	('mice', 'Species', '10090', (31, 35))	('mutations', 'Var', (305, 314))	('mice', 'Species', '10090', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('mice', 'Species', '10090', (231, 235))	('tumors', 'Disease', (352, 358))	('causes', 'Reg', (345, 351))	('mice', 'Species', '10090', (267, 271))	('mice', 'Species', '10090', (64, 68))	('mice', 'Species', '10090', (98, 102))
251565	25706482	Novel FUS-KLF17 and EWSR1-KLF17 Fusions in Myoepithelial Tumors Myoepithelial (ME) tumors of soft tissue and bone display a heterogeneous histologic spectrum and in about half of the cases harbor EWSR1 gene rearrangements.	('EWSR1', 'Gene', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Myoepithelial (ME) tumors', 'Disease', 'MESH:D009208', (64, 89))	('KLF17', 'Gene', '128209', (10, 15))	('EWSR1', 'Gene', '2130', (20, 25))	('KLF17', 'Gene', (26, 31))	('KLF17', 'Gene', '128209', (26, 31))	('EWSR1', 'Gene', '2130', (196, 201))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Fusions', 'Var', (32, 39))	('KLF17', 'Gene', (10, 15))	('Myoepithelial Tumors', 'Disease', 'MESH:D009208', (43, 63))	('FUS', 'Gene', (6, 9))	('EWSR1', 'Gene', (20, 25))	('FUS', 'Gene', '2521', (6, 9))	('Tumors', 'Phenotype', 'HP:0002664', (57, 63))	('Myoepithelial Tumors', 'Disease', (43, 63))
251572	25706482	Three additional cases with FUS-KLF17 fusions were identified and one KLF17 rearrangement (6.3%) was found among the 16 EWSR1-positive cases tested.	('FUS', 'Gene', '2521', (28, 31))	('EWSR1', 'Gene', '2130', (120, 125))	('KLF17', 'Gene', (32, 37))	('KLF17', 'Gene', '128209', (70, 75))	('KLF17', 'Gene', (70, 75))	('EWSR1', 'Gene', (120, 125))	('KLF17', 'Gene', '128209', (32, 37))	('FUS', 'Gene', (28, 31))	('fusions', 'Var', (38, 45))
251574	25706482	In conclusion, a small subset of ME tumors harbor FUS rearrangements, two thirds of them being associated with KLF17 fusion.	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('FUS', 'Gene', (50, 53))	('associated', 'Reg', (95, 105))	('FUS', 'Gene', '2521', (50, 53))	('ME', 'Chemical', '-', (33, 35))	('KLF17', 'Gene', '128209', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('KLF17', 'Gene', (111, 116))	('rearrangements', 'Var', (54, 68))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
251579	25706482	While pleomorphic adenomas of salivary gland frequently exhibit PLAG1 and HMGA2 abnormalities, PLAG1 rearrangements were mainly identified in a subset of cutaneous and superficial soft tissue ME tumors, often displaying ductal structures, consistent with benign mixed tumors.	('HMGA2', 'Gene', '8091', (74, 79))	('PLAG1', 'Gene', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('identified', 'Reg', (128, 138))	('PLAG1', 'Gene', '5324', (64, 69))	('PLAG1', 'Gene', '5324', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('ME', 'Chemical', '-', (192, 194))	('tumors', 'Disease', (195, 201))	('HMGA2', 'Gene', (74, 79))	('tumors', 'Disease', (268, 274))	('rearrangements', 'Var', (101, 115))	('adenomas', 'Disease', 'MESH:D000236', (18, 26))	('adenomas', 'Disease', (18, 26))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('PLAG1', 'Gene', (95, 100))
251581	25706482	A handful of early case reports described EWSR1 gene rearrangements, including t(1;22)(q23;q12) resulting in an EWSR1-PBX1 fusion and t(19;22)(q13;q12) involving an EWSR1-ZNF444 fusion.	('PBX1', 'Gene', (118, 122))	('t(19;22)(q13', 'Var', (134, 146))	('EWSR1', 'Gene', '2130', (42, 47))	('ZNF444', 'Gene', '55311', (171, 177))	('EWSR1', 'Gene', '2130', (165, 170))	('t(19;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (134, 151))	('PBX1', 'Gene', '5087', (118, 122))	('t(1;22)(q23;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (79, 95))	('EWSR1', 'Gene', (112, 117))	('ZNF444', 'Gene', (171, 177))	('EWSR1', 'Gene', (165, 170))	('EWSR1', 'Gene', '2130', (112, 117))	('EWSR1', 'Gene', (42, 47))
251582	25706482	A subsequent detailed molecular study of 66 ME tumors from soft tissue, bone, and lung revealed EWSR1 rearrangements occurred in 45% of cases, with different fusion partners including POU5F1, PBX1, and ZNF444.	('occurred', 'Reg', (117, 125))	('tumors', 'Disease', (47, 53))	('POU5F1', 'Gene', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('ZNF444', 'Gene', (202, 208))	('EWSR1', 'Gene', (96, 101))	('PBX1', 'Gene', (192, 196))	('ZNF444', 'Gene', '55311', (202, 208))	('EWSR1', 'Gene', '2130', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('PBX1', 'Gene', '5087', (192, 196))	('ME', 'Chemical', '-', (44, 46))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('rearrangements', 'Var', (102, 116))	('POU5F1', 'Gene', '5460', (184, 190))
251584	25706482	Five ME tumors with EWSR1-POU5F1 fusion shared a predominantly nested growth pattern with distinctive clear cell morphology.	('POU5F1', 'Gene', '5460', (26, 32))	('EWSR1', 'Gene', '2130', (20, 25))	('POU5F1', 'Gene', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('EWSR1', 'Gene', (20, 25))	('fusion', 'Var', (33, 39))	('ME', 'Chemical', '-', (5, 7))
251585	25706482	EWSR1-PBX1 translocations were found in 5 ME tumors associated with a bland sclerotic appearance and EWSR1-ZNF444 was identified in a pulmonary ME tumor.	('pulmonary ME tumor', 'Disease', (134, 152))	('EWSR1', 'Gene', (101, 106))	('ME', 'Chemical', '-', (42, 44))	('bland sclerotic', 'Disease', 'MESH:C538213', (70, 85))	('EWSR1', 'Gene', '2130', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('ZNF444', 'Gene', '55311', (107, 113))	('ME', 'Chemical', '-', (144, 146))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('bland sclerotic', 'Disease', (70, 85))	('tumors', 'Disease', (45, 51))	('PBX1', 'Gene', (6, 10))	('pulmonary ME tumor', 'Disease', 'MESH:D008175', (134, 152))	('EWSR1', 'Gene', '2130', (101, 106))	('EWSR1', 'Gene', (0, 5))	('found', 'Reg', (31, 36))	('PBX1', 'Gene', '5087', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('ZNF444', 'Gene', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('translocations', 'Var', (11, 25))
251586	25706482	More recently our group described novel EWSR1-PBX3 gene fusions in 3 cases of ME tumors, occurring with predilection in skeletal locations.	('fusions', 'Var', (56, 63))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('EWSR1', 'Gene', '2130', (40, 45))	('PBX3', 'Gene', '5090', (46, 50))	('EWSR1', 'Gene', (40, 45))	('PBX3', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ME', 'Chemical', '-', (78, 80))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
251588	25706482	Two more recent case reports described EWSR1-ATF1 and FUS-POU5F1 fusion transcripts in a pelvic ME tumor of 57 year-old woman and in a sacral lesion of a 54 year-old man, respectively.	('tumor', 'Disease', (99, 104))	('ATF1', 'Gene', (45, 49))	('EWSR1', 'Gene', '2130', (39, 44))	('ME', 'Chemical', '-', (96, 98))	('ATF1', 'Gene', '466', (45, 49))	('man', 'Species', '9606', (122, 125))	('FUS', 'Gene', (54, 57))	('woman', 'Species', '9606', (120, 125))	('FUS', 'Gene', '2521', (54, 57))	('EWSR1', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('fusion transcripts', 'Var', (65, 83))	('POU5F1', 'Gene', '5460', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('POU5F1', 'Gene', (58, 64))	('man', 'Species', '9606', (166, 169))
251591	25706482	We retrieved 66 cases of ME tumors lacking EWSR1 and PLAG1 gene rearrangements, 30 of which were included in our earlier study.	('PLAG1', 'Gene', '5324', (53, 58))	('ME', 'Chemical', '-', (25, 27))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('EWSR1', 'Gene', (43, 48))	('PLAG1', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('EWSR1', 'Gene', '2130', (43, 48))	('rearrangements', 'Var', (64, 78))
251636	25706482	Recently, a distinctive variant of cutaneous ME tumor, designated as syncytial myoepithelioma, was found to have a higher percentage (82%) of EWSR1 gene rearrangement.	('EWSR1', 'Gene', (142, 147))	('cutaneous ME tumor', 'Disease', (35, 53))	('syncytial myoepithelioma', 'Disease', 'MESH:D009208', (69, 93))	('EWSR1', 'Gene', '2130', (142, 147))	('gene rearrangement', 'Var', (148, 166))	('cutaneous ME tumor', 'Disease', 'MESH:D009369', (35, 53))	('syncytial myoepithelioma', 'Disease', (69, 93))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
251640	25706482	found 5 cutaneous and 3 soft tissue cases exhibiting PLAG1 rearrangement, which were associated with prominent ductal structures and PLAG1 immunoreactivity.	('PLAG1', 'Gene', '5324', (133, 138))	('PLAG1', 'Gene', '5324', (53, 58))	('rearrangement', 'Var', (59, 72))	('PLAG1', 'Gene', (53, 58))	('PLAG1', 'Gene', (133, 138))
251641	25706482	Conversely, a different study showed that cutaneous mixed tumors could also harbor EWSR1 abnormalities.	('harbor', 'Reg', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('EWSR1', 'Gene', (83, 88))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('EWSR1', 'Gene', '2130', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('abnormalities', 'Var', (89, 102))
251643	25706482	FUS rearrangement in ME tumors has only rarely been documented in literature.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('rearrangement', 'Var', (4, 17))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('FUS', 'Gene', (0, 3))	('FUS', 'Gene', '2521', (0, 3))	('ME', 'Chemical', '-', (21, 23))
251647	25706482	Cytogenetic analysis revealed a 46,XY,del(6)(p21),der(16)t(6;16)(p21;p11) karyotype.	('der(16)t(6;16)(p21;p11', 'Var', (50, 72))	('del(6)(p21', 'Var', (38, 48))	('46,XY,del(6)(p21),der(16)t(6;16)(p21;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (32, 73))	('revealed', 'Reg', (21, 29))
251671	25706482	In keeping with these results, the EWSR1-related fusions are more frequent events compared to FUS alterations in ME neoplasms.	('FUS', 'Gene', (94, 97))	('FUS', 'Gene', '2521', (94, 97))	('EWSR1', 'Gene', (35, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (116, 125))	('EWSR1', 'Gene', '2130', (35, 40))	('ME', 'Chemical', '-', (113, 115))	('neoplasms', 'Disease', 'MESH:D009369', (116, 125))	('fusions', 'Var', (49, 56))	('neoplasms', 'Disease', (116, 125))
251672	25706482	One possible explanation why FUS-KLF17 fusions outnumber EWSR1-KLF17 fusions in ME tumors is that both FUS and KLF17 have the same orientation (centromeric) and their fusion can be achieved by a simple balanced translocation.	('KLF17', 'Gene', (33, 38))	('KLF17', 'Gene', '128209', (63, 68))	('FUS', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('FUS', 'Gene', '2521', (103, 106))	('FUS', 'Gene', (29, 32))	('ME', 'Chemical', '-', (80, 82))	('tumors', 'Disease', (83, 89))	('fusions', 'Var', (39, 46))	('FUS', 'Gene', '2521', (29, 32))	('KLF17', 'Gene', '128209', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('KLF17', 'Gene', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('EWSR1', 'Gene', (57, 62))	('KLF17', 'Gene', '128209', (33, 38))	('KLF17', 'Gene', (111, 116))	('EWSR1', 'Gene', '2130', (57, 62))
251675	25706482	The most common fusion partner was KLF17 seen in 4 cases (67%), resulting in novel FUS-KLF17 fusions, which occurred mainly in the deep soft tissue of extremities in children.	('FUS', 'Gene', (83, 86))	('fusions', 'Var', (93, 100))	('FUS', 'Gene', '2521', (83, 86))	('children', 'Species', '9606', (166, 174))	('KLF17', 'Gene', '128209', (87, 92))	('KLF17', 'Gene', '128209', (35, 40))	('KLF17', 'Gene', (87, 92))	('KLF17', 'Gene', (35, 40))
251689	20527023	Our results confirm LOI in several tumors expressing high levels of IGF2, which may explain the observed paraneoplastic hypoglycemia.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IGF2', 'Gene', '3481', (68, 72))	('paraneoplastic hypoglycemia', 'Disease', 'MESH:D007003', (105, 132))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('hypoglycemia', 'Phenotype', 'HP:0001943', (120, 132))	('IGF2', 'Gene', (68, 72))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('high levels', 'Var', (53, 64))	('paraneoplastic hypoglycemia', 'Disease', (105, 132))
251729	20527023	Additionally, PCR and DNA sequencing for hot spots mutations were performed for PDGFRB exon 18 and ERBB2 exons 18-23, using standard procedures.	('mutations', 'Var', (51, 60))	('PDGFRB', 'Gene', '5159', (80, 86))	('ERBB2', 'Gene', (99, 104))	('ERBB2', 'Gene', '2064', (99, 104))	('PDGFRB', 'Gene', (80, 86))
251751	20527023	A DDR1 exon 13 N502S substitution was detected in one pleural SFT tumor, which has been previously reported in acute myeloid leukemia.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (111, 133))	('pleural SFT tumor', 'Disease', (54, 71))	('DDR1', 'Gene', '780', (2, 6))	('N502S', 'Var', (15, 20))	('DDR1', 'Gene', (2, 6))	('pleural SFT tumor', 'Disease', 'MESH:D010997', (54, 71))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (111, 133))	('N502S', 'Mutation', 'rs55787895', (15, 20))	('acute myeloid leukemia', 'Disease', (111, 133))
251753	20527023	Additionally, we tested all the 39 SFT samples for the presence of a putative mutation in the kinase domain of PDGFRB (Asp850Val), previously reported by Rossi et al.	('PDGFRB', 'Gene', '5159', (111, 117))	('PDGFRB', 'Gene', (111, 117))	('tested', 'Reg', (17, 23))	('Asp850Val', 'Var', (119, 128))	('Asp850Val', 'SUBSTITUTION', 'None', (119, 128))
251755	20527023	However none of our tumors showed mutations in this locus.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (34, 43))
251758	20527023	This result is in keeping with expression of both maternal and paternal IGF2 alleles and is consistent with IGF2 LOI.	('IGF2', 'Gene', (72, 76))	('IGF2', 'Gene', (108, 112))	('LOI', 'Var', (113, 116))	('IGF2', 'Gene', '3481', (108, 112))	('IGF2', 'Gene', '3481', (72, 76))
251786	20527023	Mutations in the FGFR1 have been previously described in the type I Pfeiffer craniosynostosis syndrome, which triggers FGF2 enhanced ligand binding.	('FGF2', 'Gene', (119, 123))	('craniosynostosis syndrome', 'Disease', 'MESH:D003398', (77, 102))	('craniosynostosis syndrome', 'Disease', (77, 102))	('FGFR1', 'Gene', (17, 22))	('enhanced', 'PosReg', (124, 132))	('Mutations', 'Var', (0, 9))	('craniosynostosis', 'Phenotype', 'HP:0001363', (77, 93))	('FGF2', 'Gene', '2247', (119, 123))	('FGFR1', 'Gene', '2260', (17, 22))	('ligand binding', 'Interaction', (133, 147))	('described', 'Reg', (44, 53))
251787	20527023	In cancer, overexpression of FGFR1 is triggered by different mechanisms of activation, including mutations (i.e.	('mutations', 'Var', (97, 106))	('FGFR1', 'Gene', '2260', (29, 34))	('activation', 'PosReg', (75, 85))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('overexpression', 'PosReg', (11, 25))	('FGFR1', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
251788	20527023	glioblastoma multiforme, melanoma), gene amplification (breast, oral cancer) or chromosomal translocation (leukemia).	('breast, oral cancer', 'Disease', 'MESH:D001943', (56, 75))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('glioblastoma multiforme', 'Disease', (0, 23))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('chromosomal translocation', 'Var', (80, 105))	('leukemia', 'Disease', (107, 115))	('gene amplification', 'Var', (36, 54))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Disease', (25, 33))
251797	20527023	Furthermore, mutations in DDR1, located in exon 13 N502S, have been identified recently in 3 patients with acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (107, 129))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (113, 129))	('patients', 'Species', '9606', (93, 101))	('N502S', 'Var', (51, 56))	('N502S', 'Mutation', 'rs55787895', (51, 56))	('DDR1', 'Gene', '780', (26, 30))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (107, 129))	('DDR1', 'Gene', (26, 30))	('acute myeloid leukemia', 'Disease', (107, 129))	('mutations', 'Var', (13, 22))	('identified', 'Reg', (68, 78))
251798	20527023	Despite the lack of DDR1 activating mutations in SFT, the significance of its upregulation in SFTs should be further investigated, due to its implications in fibroblast function and differentiation.	('activating', 'PosReg', (25, 35))	('mutations', 'Var', (36, 45))	('upregulation', 'PosReg', (78, 90))	('DDR1', 'Gene', '780', (20, 24))	('SFT', 'Gene', (49, 52))	('DDR1', 'Gene', (20, 24))
251799	20527023	In summary, our results further underscore the importance of the IGF2-INSR pathway in SFT oncogenesis and confirm that LOI contributes to high expression of IGF2.	('IGF2', 'Gene', (65, 69))	('expression', 'MPA', (143, 153))	('SFT oncogenesis', 'Disease', (86, 101))	('INSR', 'Gene', '3643', (70, 74))	('IGF2', 'Gene', '3481', (157, 161))	('IGF2', 'Gene', '3481', (65, 69))	('LOI', 'Var', (119, 122))	('INSR', 'Gene', (70, 74))	('IGF2', 'Gene', (157, 161))
251851	31178655	In the overall cohort, chemotherapy was associated with improved OS (HR 0.575, 95% CI 0.338-0.978, p < 0.041).	('chemotherapy', 'Var', (23, 35))	('OS', 'Chemical', '-', (65, 67))	('improved', 'PosReg', (56, 64))
251880	31178655	Furthermore, translocation status as a confirmatory diagnostic tool in the Ewing sarcoma family of tumor diagnosis is not available in the NCDB.	('tumor', 'Disease', (99, 104))	('translocation', 'Var', (13, 26))	('Ewing sarcoma', 'Disease', (75, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
251912	30254636	Both cDC2 and inflammatory DCs are equipped with a wide range of TLRs allowing them to become activated upon contact with various stimuli like polyI:C (TLR3), LPS (TLR4), and R848 (TLR8).	('polyI:C', 'Chemical', 'MESH:D011070', (143, 150))	('DC', 'Gene', '20299', (6, 8))	('R848', 'Var', (175, 179))	('TLR4', 'Gene', (164, 168))	('LPS', 'Disease', (159, 162))	('TLR8', 'Gene', (181, 185))	('TLR8', 'Gene', '51311', (181, 185))	('TLR3', 'Gene', (152, 156))	('LPS', 'Disease', 'MESH:C536528', (159, 162))	('cDC2', 'Gene', '983', (5, 9))	('TLR3', 'Gene', '7098', (152, 156))	('cDC2', 'Gene', (5, 9))	('TLR4', 'Gene', '7099', (164, 168))	('DC', 'Gene', '20299', (27, 29))
251979	30254636	Multigene constructs were generated that included both a TAA as well as one or more co-stimulatory genes such as CD80 (B7.1) or CD154 (CD40L) that could aid in the stimulation of DCs in situ and as such in the proper stimulation of TAA-specific CTLs.	('CD154', 'Gene', (128, 133))	('CD40L', 'Gene', '959', (135, 140))	('CD40L', 'Gene', (135, 140))	('B7.1', 'Gene', (119, 123))	('CD154', 'Gene', '959', (128, 133))	('aid', 'Reg', (153, 156))	('CD80', 'Var', (113, 117))	('B7.1', 'Gene', '941', (119, 123))	('DC', 'Gene', '20299', (179, 181))
251990	30254636	Also, several clinical-grade poxviral vaccination approaches such as PROSTVAC and ALVAC are regularly tested with the inclusion of a triad of immune enhancing co-stimulatory molecules, namely CD80 (B7.1), CD54 (intercellular adhesion molecule-1 or ICAM-1), and CD58 (leukocyte function-associated antigen- 3 or LFA3), collectively designated as TRICOM.	('intercellular adhesion molecule-1', 'Gene', '3383', (211, 244))	('ICAM-1', 'Gene', '3383', (248, 254))	('B7.1', 'Gene', (198, 202))	('CD58', 'Gene', '965', (261, 265))	('LFA3', 'Gene', '965', (311, 315))	('ICAM-1', 'Gene', (248, 254))	('intercellular adhesion molecule-1', 'Gene', (211, 244))	('B7.1', 'Gene', '941', (198, 202))	('CD80', 'Var', (192, 196))	('CD54', 'Gene', '3383', (205, 209))	('CD58', 'Gene', (261, 265))	('CD54', 'Gene', (205, 209))	('LFA3', 'Gene', (311, 315))
252002	30254636	Unexpectedly, tumors injected with ALVAC-B7.1 and ALVAC-IL-12 showed higher intratumoral levels of immunosuppressive cytokines like IL-10 and VEGF, and decreased intratumoral levels of pro-inflammatory cytokines IL-12 and IFN-gamma, when compared to tumors injected with saline.	('decreased', 'NegReg', (152, 161))	('IFN-gamma', 'Gene', '3458', (222, 231))	('IFN-gamma', 'Gene', (222, 231))	('tumor', 'Disease', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('B7.1', 'Gene', '941', (41, 45))	('higher', 'PosReg', (69, 75))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (81, 86))	('tumors', 'Disease', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('VEGF', 'Gene', '7422', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('IL-10', 'Gene', '3586', (132, 137))	('tumors', 'Disease', (250, 256))	('VEGF', 'Gene', (142, 146))	('tumor', 'Disease', (14, 19))	('IL-10', 'Gene', (132, 137))	('ALVAC-IL-12', 'Var', (50, 61))	('B7.1', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (250, 256))
252006	30254636	Also when ALVAC-CEA with CD80 was compared to its combination with the adjuvant GM-CSF, disease stabilization was seen in 26% compared to 37% of patients, who received the combination.	('patients', 'Species', '9606', (145, 153))	('disease stabilization', 'CPA', (88, 109))	('CEA', 'Gene', '1048', (16, 19))	('CEA', 'Gene', (16, 19))	('CD80', 'Var', (25, 29))
252036	30254636	On the other hand, when 13 NSCLC patients received sequential DNA and adenoviral vaccines coding for the lung tumor antigen L523S intramuscularly, this only resulted in L523S-specific sero-reactivity in one patient.	('patient', 'Species', '9606', (33, 40))	('patients', 'Species', '9606', (33, 41))	('NSCLC', 'Disease', (27, 32))	('lung tumor', 'Disease', (105, 115))	('lung tumor', 'Disease', 'MESH:D008175', (105, 115))	('sero-reactivity', 'MPA', (184, 199))	('L523S-specific', 'Var', (169, 183))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('lung tumor', 'Phenotype', 'HP:0100526', (105, 115))	('patient', 'Species', '9606', (207, 214))	('sero', 'Chemical', '-', (184, 188))	('L523S', 'Mutation', 'p.L523S', (124, 129))	('L523S', 'Mutation', 'p.L523S', (169, 174))
252066	30254636	So far, the first female patient with metastatic and recurrent synovial sarcoma, induced a robust NY-ESO-1-specific T cell response after three injections of LV305 with subsequent disease regression of 85% over 2.5 years.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (63, 79))	('synovial sarcoma', 'Disease', 'MESH:D013584', (63, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('LV305', 'Var', (158, 163))	('patient', 'Species', '9606', (25, 32))	('NY-ESO-1', 'Gene', '246100', (98, 106))	('LV305', 'Chemical', '-', (158, 163))	('synovial sarcoma', 'Disease', (63, 79))	('NY-ESO-1', 'Gene', (98, 106))
252068	30254636	G305 comprises a NY-ESO-1 recombinant protein and a TLR4 triggering glucopyranosyl lipid adjuvant stable emulsion (GLA-SE), with potential synergistic immunostimulatory and antineoplastic activities.	('TLR4', 'Gene', '7099', (52, 56))	('TLR4', 'Gene', (52, 56))	('glucopyranosyl lipid', 'Chemical', '-', (68, 88))	('G305', 'Var', (0, 4))	('NY-ESO-1', 'Gene', '246100', (17, 25))	('GLA', 'Chemical', 'MESH:D017965', (115, 118))	('NY-ESO-1', 'Gene', (17, 25))
252070	30254636	In general, CMB305 results in stronger and broader integrated responses than LV305 alone, underpinning the potential of heterologous prime-boost regimens.	('CMB305', 'Var', (12, 18))	('LV305', 'Chemical', '-', (77, 82))	('stronger', 'PosReg', (30, 38))
252075	30254636	Moreover, variants of the Sindbis virus have been preclinically explored for their differential abilities to target and activate DCs in vitro and in vivo.	('activate', 'PosReg', (120, 128))	('Sindbis virus', 'Species', '11034', (26, 39))	('variants', 'Var', (10, 18))	('DC', 'Gene', '20299', (129, 131))	('Sindbis', 'Gene', (26, 33))
252076	30254636	Importantly, human and mouse DCs were differentially infected by selected variants, suggesting differences in receptor expression between human and murine DCs.	('murine', 'Species', '10090', (148, 154))	('human', 'Species', '9606', (13, 18))	('differences', 'Reg', (95, 106))	('DC', 'Gene', '20299', (29, 31))	('human', 'Species', '9606', (138, 143))	('mouse', 'Species', '10090', (23, 28))	('variants', 'Var', (74, 82))	('DC', 'Gene', '20299', (155, 157))
252108	30254636	When an AAV vector containing the HPV16 E7 gene was used to infect mouse DCs, efficient gene transfer and DC activation was observed with upregulation of CD80 and CD83 next to T cell stimulation.	('upregulation', 'PosReg', (138, 150))	('DC', 'Gene', '20299', (73, 75))	('gene transfer', 'CPA', (88, 101))	('CD83', 'Gene', (163, 167))	('HPV16', 'Species', '333760', (34, 39))	('CD83', 'Gene', '12522', (163, 167))	('mouse', 'Species', '10090', (67, 72))	('DC', 'Gene', '20299', (106, 108))	('AAV', 'Species', '272636', (8, 11))	('CD80', 'Var', (154, 158))
252117	30254636	To further enhance the outcome of AAV immunization, a rational design of its capsid can be performed by site-directed mutagenesis of surface-exposed serine and threonine residues.	('enhance', 'PosReg', (11, 18))	('mutagenesis', 'Var', (118, 129))	('threonine', 'Chemical', 'MESH:D013912', (160, 169))	('serine', 'Chemical', 'MESH:D012694', (149, 155))	('AAV', 'Species', '272636', (34, 37))
252179	30254636	While in the field of nanovaccines, several combinations have been explored, the delivery of more than one antigen/adjuvant/genetic silencer (e.g., small interfering RNA against STAT3) is exactly what viral vectors could do.	('STAT3', 'Gene', '6774', (178, 183))	('genetic silencer', 'Disease', 'MESH:D030342', (124, 140))	('genetic silencer', 'Disease', (124, 140))	('small interfering', 'Var', (148, 165))	('nanovaccines', 'Chemical', '-', (22, 34))	('STAT3', 'Gene', (178, 183))
252305	26175585	Hypointense areas on T1- and T2-weighted images reflect the fibrous components of the tumor and are a potentially useful clue for an imaging diagnosis of the lesion.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('reflect', 'Reg', (48, 55))	('Hypointense areas', 'Var', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('fibrous', 'CPA', (60, 67))
252363	23323112	Immunoreactivity for CD99 has been reported in more than 50% of the myeloid sarcomas, which is in line with its not infrequent expression in hematopoietic tumors.	('hematopoietic tumors', 'Disease', (141, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('myeloid sarcomas', 'Disease', 'MESH:D023981', (68, 84))	('CD99', 'Gene', (21, 25))	('reported', 'Reg', (35, 43))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (141, 161))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (76, 84))	('Immunoreactivity', 'Var', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('myeloid sarcomas', 'Disease', (68, 84))	('CD99', 'Gene', '4267', (21, 25))
252367	23323112	In confusing cases showing negativity for a myeloid marker including MPO, a mutation analysis for PDGFR and c-kit, coupled with electron microscopic investigation, may be required.	('MPO', 'Gene', (69, 72))	('PDGFR', 'Gene', (98, 103))	('c-kit', 'Gene', '3815', (108, 113))	('c-kit', 'Gene', (108, 113))	('PDGFR', 'Gene', '5159', (98, 103))	('MPO', 'Gene', '4353', (69, 72))	('mutation', 'Var', (76, 84))
252422	30733995	For example, approximately 70% of sporadic osteosarcoma tumors contain acquired mutations in RB, the negative cell cycle regulator.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (43, 62))	('mutations', 'Var', (80, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('osteosarcoma tumors', 'Disease', (43, 62))	('osteosarcoma', 'Phenotype', 'HP:0002669', (43, 55))
252424	30733995	Inactivation of the CDKN2A gene:which codes for p14 and p16, 2 proteins involved in tumor suppression:also increases risk for osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('osteosarcoma', 'Disease', (126, 138))	('increases', 'Reg', (107, 116))	('p16', 'Gene', '1029', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('p14', 'Gene', (48, 51))	('CDKN2A', 'Gene', (20, 26))	('p14', 'Gene', '1029', (48, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('p16', 'Gene', (56, 59))	('CDKN2A', 'Gene', '1029', (20, 26))	('Inactivation', 'Var', (0, 12))
252426	30733995	With the former, p14 functions to inhibit degradation of p53 (the product of TP53) by sequestering the E3 ubiquitin ligase to the nucleolus, thereby preventing ubiquitin tagging of p53.	('preventing', 'NegReg', (149, 159))	('E3 ubiquitin ligase', 'Gene', (103, 122))	('p14', 'Var', (17, 20))	('ubiquitin tagging', 'MPA', (160, 177))	('E3 ubiquitin ligase', 'Gene', '158506', (103, 122))	('degradation', 'MPA', (42, 53))	('p53', 'Protein', (57, 60))	('inhibit', 'NegReg', (34, 41))	('sequestering', 'NegReg', (86, 98))	('p53', 'Protein', (181, 184))
252429	30733995	These regions are notable for encoding numerous tumor suppressors, explaining why such deletions may increase risk for osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('numerous tumor', 'Disease', 'MESH:D009369', (39, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('deletions', 'Var', (87, 96))	('numerous tumor', 'Disease', (39, 53))	('osteosarcoma', 'Disease', (119, 131))	('increase', 'Reg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
252545	25539263	Tumors with higher baseline blood flow (>= 50 mL/100 g/min) showed better histologic response to bevacizumab and radiation therapy compared with those with lower blood flow (< 50 mL/100 g/min) (67% vs 27%) (Table 3).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('bevacizumab', 'Chemical', 'MESH:D000068258', (97, 108))	('histologic response', 'CPA', (74, 93))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('>= 50 mL/100 g/min', 'Var', (40, 58))	('better', 'PosReg', (67, 73))
252641	31494268	R960-25) and anti-histone H4ac (pan-acetyl) (Catalog No.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('R960-25', 'Var', (0, 7))	('acetyl', 'Chemical', 'MESH:C011632', (36, 42))	('anti-histone', 'Var', (13, 25))
252664	31494268	s1846 and s1847); CCDC124 siRNAs (Catalog Nos.	('s1847)', 'Var', (10, 16))	('CCDC124', 'Gene', '115098', (18, 25))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('CCDC124', 'Gene', (18, 25))	('N', 'Chemical', 'MESH:D009584', (29, 30))
252668	31494268	s195034 and s195035); ING2 siRNAs (Catalog Nos.	('s195035)', 'Var', (12, 20))	('ING2', 'Gene', '3622', (22, 26))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('s195034', 'Chemical', 'None', (0, 7))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('ING2', 'Gene', (22, 26))
252669	31494268	s7431 and s7433); PARD3 siRNAs (Catalog No.	('PARD3', 'Gene', '56288', (18, 23))	('PARD3', 'Gene', (18, 23))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('s7433)', 'Var', (10, 16))	('N', 'Chemical', 'MESH:D009584', (27, 28))
252670	31494268	s32126 and s32128); RYBP siRNAs (Catalog Nos.	('RYBP', 'Gene', '23429', (20, 24))	('s32128)', 'Var', (11, 18))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('RYBP', 'Gene', (20, 24))
252671	31494268	s23812 and s23813); ZC3H15 siRNAs (Catalog Nos.	('N', 'Chemical', 'MESH:D009584', (43, 44))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('ZC3H15', 'Gene', '55854', (20, 26))	('s23813)', 'Var', (11, 18))	('ZC3H15', 'Gene', (20, 26))
252713	31494268	Using qPCR, we validated that the PLATO-BC method results in the Bio-Ub enrichment of several Ub-binding proteins, including ubiquitin C-terminal hydrolase 3 (UCHL3), epsin 3 (EPN3), signal transducing adaptor molecule 2 (STAM2), zinc finger AN1-type containing 6 (ZA20D3), and RNF115 ring finger protein 115 (ZNF364) (Figure 4C).	('ZNF364', 'Gene', (310, 316))	('ZNF364', 'Gene', '27246', (310, 316))	('ZA20D3', 'Gene', '54469', (265, 271))	('RNF115', 'Var', (278, 284))	('STAM2', 'Gene', '10254', (222, 227))	('N', 'Chemical', 'MESH:D009584', (243, 244))	('signal transducing adaptor molecule 2', 'Gene', (183, 220))	('PLATO', 'Chemical', 'MESH:C052444', (34, 39))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('UCHL3', 'Gene', '7347', (159, 164))	('STAM2', 'Gene', (222, 227))	('ZA20D3', 'Gene', (265, 271))	('epsin 3', 'Gene', (167, 174))	('epsin 3', 'Gene', '55040', (167, 174))	('N', 'Chemical', 'MESH:D009584', (311, 312))	('ubiquitin C-terminal hydrolase 3', 'Gene', '7347', (125, 157))	('N', 'Chemical', 'MESH:D009584', (279, 280))	('signal transducing adaptor molecule 2', 'Gene', '10254', (183, 220))	('EPN3', 'Gene', '55040', (176, 180))	('EPN3', 'Gene', (176, 180))	('ubiquitin C-terminal hydrolase 3', 'Gene', (125, 157))	('UCHL3', 'Gene', (159, 164))
252720	31494268	We cloned the RIOK3 ORF into the pcDNA-DEST40 vector, and co-transfected it into HEK293T cells, with the HA-tagged wild-type Ub (HA-Ub-wt), HA-Ub-K48, or HA-Ub-K63, in which all lysine residues of Ub were mutated to arginine except the K48 or K63, respectively.	('RIOK3', 'Gene', (14, 19))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('RIOK3', 'Gene', '8780', (14, 19))	('mutated', 'Var', (205, 212))	('arginine', 'Chemical', 'MESH:D001127', (216, 224))	('lysine', 'Chemical', 'MESH:C114808', (178, 184))	('arginine', 'MPA', (216, 224))
252736	31494268	We showed that knockdown of C19orf53 and PARD3 modestly increased ZIKV viral replication, which was comparable to the effect of IFITM3 knockdown (Figure 5C and D).	('C19orf53', 'Gene', (28, 36))	('PARD3', 'Gene', '56288', (41, 46))	('knockdown', 'Var', (15, 24))	('increased', 'PosReg', (56, 65))	('ZIKV', 'Gene', (66, 70))	('ZIKV', 'Species', '64320', (66, 70))	('C19orf53', 'Gene', '28974', (28, 36))	('PARD3', 'Gene', (41, 46))	('IFITM3', 'Gene', (128, 134))	('IFITM3', 'Gene', '10410', (128, 134))
252738	31494268	The NS1 mRNA of ZIKV increased when C19orf53 or PARD3 was knockdown in HFF-1 cells (Figure 5E).	('PARD3', 'Gene', (48, 53))	('increased', 'PosReg', (21, 30))	('PARD3', 'Gene', '56288', (48, 53))	('NS1', 'Gene', '5781', (4, 7))	('ZIKV', 'Species', '64320', (16, 20))	('C19orf53', 'Gene', (36, 44))	('N', 'Chemical', 'MESH:D009584', (4, 5))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('ZIKV', 'Gene', (16, 20))	('NS1', 'Gene', (4, 7))	('C19orf53', 'Gene', '28974', (36, 44))	('knockdown', 'Var', (58, 67))
252762	31494268	Nonetheless, other studies indeed show that JQ1 suppresses the EWSR1-FLI1-driven gene transcription in Ewing's sarcoma cells, and that the EWSR1-FLI1-bound chromatins correlate with H3K27 acetylation.	('FLI1', 'Gene', (69, 73))	('FLI1', 'Gene', '2313', (69, 73))	('acetylation', 'MPA', (188, 199))	('EWSR1', 'Gene', (139, 144))	('EWSR1', 'Gene', '2130', (63, 68))	('FLI1', 'Gene', (145, 149))	('JQ1', 'Var', (44, 47))	("Ewing's sarcoma", 'Disease', (103, 118))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('FLI1', 'Gene', '2313', (145, 149))	('suppresses', 'NegReg', (48, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (103, 118))	('EWSR1', 'Gene', '2130', (139, 144))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (103, 118))	('EWSR1', 'Gene', (63, 68))	('H3K27', 'Protein', (182, 187))	('acetyl', 'Chemical', 'MESH:C011632', (188, 194))
252768	31494268	We were able to use the alternative protein pull-down assay to confirm that RIOK3 binds to both free ubiquitin and polyubiquitin chains, preferentially K63-linked ones (Figure 4D and E).	('polyubiquitin chains', 'MPA', (115, 135))	('ubiquitin', 'Protein', (101, 110))	('RIOK3', 'Gene', (76, 81))	('K63-linked', 'Var', (152, 162))	('RIOK3', 'Gene', '8780', (76, 81))	('binds', 'Interaction', (82, 87))	('preferentially', 'PosReg', (137, 151))
252770	31494268	K63-linked ubiquitination is increasingly important in immune signaling, and many players, particularly in NF-kB and RIG-I pathways, are protein substrates of K63-linked ubiquitination that affects signaling transduction more than protein degradation.	('RIG-I', 'Gene', (117, 122))	('signaling transduction', 'MPA', (198, 220))	('affects', 'Reg', (190, 197))	('protein', 'MPA', (231, 238))	('RIG-I', 'Gene', '23586', (117, 122))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('K63-linked ubiquitination', 'Var', (159, 184))
252823	29216884	Positive surgical margins were associated with a higher risk of local recurrence (p = 0.02) and decreased OS (p = 0.04).	('decreased', 'NegReg', (96, 105))	('local recurrence', 'CPA', (64, 80))	('Positive', 'Var', (0, 8))	('OS', 'Chemical', '-', (106, 108))
252859	29216884	The following dose constraints and prescription details were used: 95% of prescription dose should cover 95% of PTV; Small bowel max point dose <54 Gy, V45 < 150 cm3, V55 < 1 cm3; Large bowel max point dose <60 Gy, V30 < 200 cm3, V35 < 150 cm3, V45 < 100 cm3; Stomach max point dose <54 Gy; Liver max point dose <50 Gy, mean < 20 Gy; Kidney V20 < 30% (combined kidney dose); Spinal cord Dmax <45 Gy.	('Small bowel', 'Disease', (117, 128))	('Liver', 'MPA', (291, 296))	('V45 < 100 cm3', 'Var', (245, 258))	('Large bowel', 'Phenotype', 'HP:0002037', (180, 191))	('Kidney', 'MPA', (334, 340))	('bowel', 'Disease', 'MESH:D015212', (123, 128))	('bowel', 'Disease', (123, 128))	('V45 < 150 cm3', 'Var', (152, 165))	('V35 < 150 cm3', 'Var', (230, 243))	('V55 < 1 cm3', 'Var', (167, 178))	('bowel', 'Disease', 'MESH:D015212', (186, 191))	('V30 < 200 cm3', 'Var', (215, 228))	('bowel', 'Disease', (186, 191))	('combined kidney', 'Phenotype', 'HP:0000085', (352, 367))	('PTV', 'Chemical', '-', (112, 115))	('Small bowel', 'Disease', 'MESH:D015212', (117, 128))
252887	29216884	R1 resection was significantly associated with OS on univariate cox analysis (p = 0.04) though this should be interpreted with caution given the small numbers in this study.	('cox', 'Gene', '1351', (64, 67))	('associated', 'Reg', (31, 41))	('cox', 'Gene', (64, 67))	('R1 resection', 'Var', (0, 12))	('OS', 'Chemical', '-', (47, 49))
252950	29216884	One of the largest multi-institutional retrospective series including over 1000 patients with RPS found that peri-operative administration of RT was statistically significantly associated with improved LC, and recent analysis of the NCDB and SEER databases revealed that peri-operative radiotherapy was associated with a significant increase in OS compared to patients who were treated with surgery alone.	('patients', 'Species', '9606', (80, 88))	('OS', 'Chemical', '-', (345, 347))	('improved', 'PosReg', (193, 201))	('RPS', 'Phenotype', 'HP:0006729', (94, 97))	('RPS', 'Disease', 'None', (94, 97))	('patients', 'Species', '9606', (360, 368))	('RPS', 'Disease', (94, 97))	('radiotherapy', 'Var', (286, 298))
252962	29113328	We also demonstrated that high glucose enhances susceptibility of various target cells to KSHV infection.	('KSHV infection', 'Disease', 'MESH:C537372', (90, 104))	('susceptibility', 'MPA', (48, 62))	('KSHV infection', 'Disease', (90, 104))	('enhances', 'PosReg', (39, 47))	('high glucose', 'Var', (26, 38))	('high glucose', 'Phenotype', 'HP:0003074', (26, 38))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))
252990	29113328	Consistent with the Western blot analysis, quantitative RT-PCR revealed that high glucose increased levels of ORF50 and ORF57 mRNAs, two viral lytic gene transcripts, in a dose-dependent manner (Figure 1B).	('levels', 'MPA', (100, 106))	('increased', 'PosReg', (90, 99))	('ORF57', 'Var', (120, 125))	('ORF50', 'Gene', (110, 115))	('glucose', 'Chemical', 'MESH:D005947', (82, 89))	('high glucose', 'Phenotype', 'HP:0003074', (77, 89))	('ORF50', 'Gene', '4961526', (110, 115))
253012	29113328	Here, we designated the previously identified AP1 site (-81 to -87) as the "AP1-(I)" element, and the newly identified AP1 site (-930 to -936) as the "AP1-(II)" element.	('AP1', 'Gene', (119, 122))	('AP1', 'Gene', '2353', (76, 79))	('AP1', 'Gene', '2353', (46, 49))	('AP1', 'Gene', (151, 154))	('"AP1', 'Gene', '2353', (75, 79))	('AP1', 'Gene', '2353', (119, 122))	('"AP1', 'Gene', (150, 154))	('"AP1', 'Gene', (75, 79))	('"AP1', 'Gene', '2353', (150, 154))	('AP1', 'Gene', '2353', (151, 154))	('-930 to -936', 'Var', (129, 141))	('AP1', 'Gene', (76, 79))	('AP1', 'Gene', (46, 49))
253015	29113328	Furthermore, point mutations at the AP1-(II) site in the ORF50 promoter substantially impaired the promoter activation by AP1 in BCBL1 and HKB5/B5 cells (Supplementary Figure 2).	('impaired', 'NegReg', (86, 94))	('AP1', 'Gene', '2353', (36, 39))	('point mutations', 'Var', (13, 28))	('AP1', 'Gene', (122, 125))	('promoter activation', 'MPA', (99, 118))	('ORF50', 'Gene', '4961526', (57, 62))	('ORF50', 'Gene', (57, 62))	('BCBL1', 'CellLine', 'CVCL:0165', (129, 134))	('AP1', 'Gene', '2353', (122, 125))	('AP1', 'Gene', (36, 39))
253018	29113328	To analyze whether the AP1-(I) or AP1-(II) element conferred the response to high glucose, the reporter plasmids encompassing 3 copies of wild-type or mutated AP1-(I) element or AP1-(II) element were transfected into BCBL1 cells.	('BCBL1', 'CellLine', 'CVCL:0165', (217, 222))	('AP1', 'Gene', '2353', (23, 26))	('AP1', 'Gene', (178, 181))	('AP1', 'Gene', (34, 37))	('AP1', 'Gene', (159, 162))	('response to high glucose', 'MPA', (65, 89))	('glucose', 'Chemical', 'MESH:D005947', (82, 89))	('AP1', 'Gene', '2353', (178, 181))	('AP1', 'Gene', '2353', (34, 37))	('high glucose', 'Phenotype', 'HP:0003074', (77, 89))	('AP1', 'Gene', '2353', (159, 162))	('AP1', 'Gene', (23, 26))	('mutated', 'Var', (151, 158))
253024	29113328	Western blot analysis revealed that high glucose did not alter c-Fos expression in cells; however, both total c-Jun and phosphorylated c-Jun levels were evidently increased by high glucose (Figure 5A).	('high glucose', 'Var', (176, 188))	('c-Jun', 'Gene', '3725', (135, 140))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('increased', 'PosReg', (163, 172))	('c-Jun', 'Gene', (110, 115))	('c-Jun', 'Gene', (135, 140))	('glucose', 'Chemical', 'MESH:D005947', (181, 188))	('high glucose', 'Phenotype', 'HP:0003074', (176, 188))	('c-Fos', 'Gene', (63, 68))	('high glucose', 'Phenotype', 'HP:0003074', (36, 48))	('c-Jun', 'Gene', '3725', (110, 115))	('c-Fos', 'Gene', '2353', (63, 68))
253027	29113328	Furthermore, treatment of BCBL1 cells with calphostin C (Cal-C; a PKC inhibitor), SP600125 (a JNK inhibitor) or a lentivirus-based vector expressing c-Jun shRNA, which decreased both total c-Jun and phosphorylated c-Jun levels, also led to reduced viral lytic protein expression (Figure 5C-5E).	('calphostin C', 'Chemical', 'MESH:C058819', (43, 55))	('reduced', 'NegReg', (240, 247))	('c-Jun', 'Gene', '3725', (214, 219))	('PKC', 'Gene', (66, 69))	('PKC', 'Gene', '112476', (66, 69))	('decreased', 'NegReg', (168, 177))	('c-Jun', 'Gene', (149, 154))	('c-Jun', 'Gene', '3725', (189, 194))	('JNK', 'Gene', '5599', (94, 97))	('SP600125', 'Chemical', 'MESH:C432165', (82, 90))	('c-Jun', 'Gene', (214, 219))	('SP600125', 'Var', (82, 90))	('viral lytic protein expression', 'MPA', (248, 278))	('BCBL1', 'CellLine', 'CVCL:0165', (26, 31))	('c-Jun', 'Gene', '3725', (149, 154))	('JNK', 'Gene', (94, 97))	('c-Jun', 'Gene', (189, 194))
253029	29113328	These results suggested that active AP1 protein complex caused by high glucose significantly contributes to the enhancement of KSHV reactivation.	('high glucose', 'Var', (66, 78))	('AP1', 'Gene', '2353', (36, 39))	('active', 'PosReg', (29, 35))	('high glucose', 'Phenotype', 'HP:0003074', (66, 78))	('glucose', 'Chemical', 'MESH:D005947', (71, 78))	('KSHV reactivation', 'MPA', (127, 144))	('KSHV', 'Species', '37296', (127, 131))	('enhancement', 'PosReg', (112, 123))	('AP1', 'Gene', (36, 39))
253034	29113328	Immunofluorescence analysis showed that TIME or 293T cells cultured in high glucose had a nearly 2.5-fold increase in viral infection compared to these cells cultured in normal glucose (Figure 6A and 6B).	('high', 'Var', (71, 75))	('glucose', 'Chemical', 'MESH:D005947', (177, 184))	('viral infection', 'Disease', 'MESH:D001102', (118, 133))	('293T', 'CellLine', 'CVCL:0063', (48, 52))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('increase', 'PosReg', (106, 114))	('high glucose', 'Phenotype', 'HP:0003074', (71, 83))	('viral infection', 'Disease', (118, 133))
253073	29113328	These findings implicate that high glucose may specifically affect KSHV-associated malignancies but not EBV-associated malignancies.	('glucose', 'Chemical', 'MESH:D005947', (35, 42))	('EBV', 'Species', '10376', (104, 107))	('malignancies', 'Disease', (119, 131))	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('high glucose', 'Phenotype', 'HP:0003074', (30, 42))	('KSHV', 'Species', '37296', (67, 71))	('high glucose', 'Var', (30, 42))	('affect', 'Reg', (60, 66))	('malignancies', 'Disease', (83, 95))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))
253098	29113328	Potential confounding risk factors for KS were identified as the following diagnoses: diabetes (ICD-9 code 250), HIV infection (HIV; ICD-9 codes 042-044 and V08), and operation of transplant (ICD-9 codes V420, V421, V426, V427 and V4283).	('V421', 'Var', (210, 214))	('V427', 'Var', (222, 226))	('HIV', 'Species', '12721', (128, 131))	('diabetes', 'Disease', (86, 94))	('V426', 'Var', (216, 220))	('HIV infection', 'Disease', 'MESH:D015658', (113, 126))	('diabetes', 'Disease', 'MESH:D003920', (86, 94))	('V420', 'Var', (204, 208))	('HIV', 'Species', '12721', (113, 116))	('V4283', 'Var', (231, 236))	('HIV infection', 'Disease', (113, 126))
253114	29113328	To generate ORF50 promoter deletion constructs, DNA fragments of the indicated size were amplified by PCR and cloned into pGL3-Basic (Promega).	('pGL3', 'Gene', '6391', (122, 126))	('ORF50', 'Gene', '4961526', (12, 17))	('ORF50', 'Gene', (12, 17))	('deletion', 'Var', (27, 35))	('pGL3', 'Gene', (122, 126))
253115	29113328	To construct the reporter plasmids that contain wild-type or mutated copies of AP1-binding sites, synthetic double-stranded oligonucleotides were cloned upstream of the adenovirus E4 promoter in pE4luc.	('AP1', 'Gene', (79, 82))	('oligonucleotides', 'Chemical', 'MESH:D009841', (124, 140))	('AP1', 'Gene', '2353', (79, 82))	('mutated', 'Var', (61, 68))
253130	29113328	After TIME cells and 293T cells were cultured for 4 days and 2 days, respectively, in normal or high glucose-containing media, cells were stained with antibodies specific to integrin alpha3 (sc-13545; Santa Cruz), beta1 (sc-18887; Santa Cruz), alphaVbeta3 (304402; BioLegend), alphaVbeta5 (MAB1961; Millipore), CD98/xCT (315602; BioLegend), and heparan sulfate (370255-1; AMIBIO).	('293T', 'CellLine', 'CVCL:0063', (21, 25))	('370255-1', 'Var', (362, 370))	('high glucose', 'Phenotype', 'HP:0003074', (96, 108))	('CD98', 'Gene', '6520', (311, 315))	('beta1', 'Gene', (214, 219))	('integrin alpha3', 'Gene', '3675', (174, 189))	('beta1', 'Gene', '146712', (214, 219))	('xCT', 'Gene', (316, 319))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('xCT', 'Gene', '23657', (316, 319))	('sc-13545;', 'Var', (191, 200))	('heparan sulfate', 'Chemical', 'MESH:D006497', (345, 360))	('integrin alpha3', 'Gene', (174, 189))	('sc-18887;', 'Var', (221, 230))	('CD98', 'Gene', (311, 315))
253133	28008375	Knockdown of EWSR1/FLI1 expression alters the transcriptome of Ewing sarcoma cells in vitro Ewing sarcoma breakpoint region 1 (EWSR1) fusion with Friend leukemia integration 1 transcription factor (FLI1) induced by a translocation of chromosome 11 with 22 contributes to Ewing sarcoma development.	('EWSR1', 'Gene', (127, 132))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (92, 125))	('FLI1', 'Gene', (198, 202))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('EWSR1', 'Gene', (13, 18))	('Ewing sarcoma', 'Disease', (271, 284))	('Friend leukemia integration 1 transcription factor', 'Gene', (146, 196))	('Friend leukemia integration 1 transcription factor', 'Gene', '2313', (146, 196))	('FLI1', 'Gene', '2313', (198, 202))	('alters', 'Reg', (35, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('EWSR1', 'Gene', '2130', (127, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('Ewing sarcoma', 'Disease', (63, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('FLI1', 'Gene', (19, 23))	('transcriptome', 'MPA', (46, 59))	('fusion', 'Var', (134, 140))	('EWSR1', 'Gene', '2130', (13, 18))	('Ewing sarcoma breakpoint region 1', 'Gene', (92, 125))	('FLI1', 'Gene', '2313', (19, 23))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (271, 284))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (271, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
253135	28008375	This study explored the potential critical gene targets of EWSR1/FLI1 knockdown in Ewing sarcoma cells on the gene expression profile based on online dataset, performed Limma algorithm for differentially expressed genes identification, constructed the transcriptional factor (TF)-gene regulatory network based on integrate transcriptional regulatory element database (TRED).	('knockdown', 'Var', (70, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('EWSR1/FLI1', 'Gene', (59, 69))	('Ewing sarcoma', 'Disease', (83, 96))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (83, 96))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (83, 96))
253136	28008375	The data showed up- and down-regulation of differentially expressed genes over time and peaked at 72 h after EWSR1/FLI1 knockdown in Ewing sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('EWSR1/FLI1', 'Gene', (109, 119))	('Ewing sarcoma', 'Disease', (133, 146))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (133, 146))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (133, 146))	('knockdown', 'Var', (120, 129))	('up-', 'PosReg', (16, 19))	('down-regulation', 'NegReg', (24, 39))	('differentially expressed genes', 'MPA', (43, 73))
253137	28008375	SMAD3 were up-regulated and FLI1, MYB, E2F1, ETS2, WT1 were down-regulated with more than half of their targets were down-regulated after EWSR1/FLI1 knockdown.	('MYB', 'Gene', (34, 37))	('up-regulated', 'PosReg', (11, 23))	('FLI1', 'Gene', (28, 32))	('SMAD3', 'Gene', (0, 5))	('down-regulated', 'NegReg', (60, 74))	('knockdown', 'Var', (149, 158))	('E2F1', 'Gene', '1869', (39, 43))	('WT1', 'Gene', '7490', (51, 54))	('down-regulated', 'NegReg', (117, 131))	('WT1', 'Gene', (51, 54))	('E2F1', 'Gene', (39, 43))	('ETS2', 'Gene', (45, 49))	('MYB', 'Gene', '4602', (34, 37))	('SMAD3', 'Gene', '4088', (0, 5))	('ETS2', 'Gene', '2114', (45, 49))
253139	28008375	These data demonstrated that knockdown of EWSR1/FLI1 expression led to transcriptome changes in Ewing sarcoma cells and that Ewing sarcoma development and progression caused by altered EWSR1/FLI1 expression may be associated with more complex transcriptome changes.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('EWSR1/FLI1', 'Gene', (185, 195))	('knockdown', 'Var', (29, 38))	('transcriptome changes', 'MPA', (71, 92))	('EWSR1/FLI1', 'Gene', (42, 52))	('altered', 'Var', (177, 184))	('progression', 'CPA', (155, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Ewing sarcoma', 'Disease', (96, 109))	('Ewing sarcoma', 'Disease', (125, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))
253147	28008375	However, to date, the precise molecular mechanisms about EWSR1/FLI1 fusion protein involving in Ewing sarcoma development remains to be defined; for example, how the EWSR1/FLI1 fusion protein interrupt normal cell cycle and why the EWSR1/FLI1 fusion protein only causes Ewing sarcoma or related tumors.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('tumors', 'Disease', (295, 301))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('normal cell cycle', 'CPA', (202, 219))	('Ewing sarcoma', 'Disease', (270, 283))	('interrupt', 'NegReg', (192, 201))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (270, 283))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (270, 283))	('Ewing sarcoma', 'Disease', (96, 109))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('EWSR1/FLI1', 'Gene', (166, 176))	('fusion', 'Var', (177, 183))	('causes', 'Reg', (263, 269))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))
253151	28008375	Thus, to better understand the transcriptional status affected by EWSR1/FLI1 protein in Ewing sarcoma, we first retrieved datasets from online database and then analyze the data of transcriptome changes in Ewing sarcoma cells at different periods of time points after knockdown of EWSR1/FLI1 and identifying the key TF and target genes.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (206, 219))	('EWSR1/FLI1', 'Gene', (281, 291))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('Ewing sarcoma', 'Disease', (206, 219))	('Ewing sarcoma', 'Disease', (88, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (206, 219))	('knockdown', 'Var', (268, 277))
253154	28008375	The raw data GSE27524 were obtained from HG-U133A_2 platform (Affymetrix Human Genome U133A 2.0 Array) and all the microarrays raw data (.CEL) from this project were included for this study, which contains 4 samples of 0 h, 3 samples of 18 h, 3 samples of 36 h, 2 samples of 54 h, 2 samples of 72 h, 2 samples of 96 h after EWSR1/FLI1 knockdown in A673 Ewing sarcoma cell line.	('Ewing sarcoma', 'Disease', (353, 366))	('knockdown', 'Var', (335, 344))	('EWSR1/FLI1', 'Gene', (324, 334))	('sarcoma', 'Phenotype', 'HP:0100242', (359, 366))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (353, 366))	('Human', 'Species', '9606', (73, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (353, 366))
253155	28008375	To identify DEGs in Ewing sarcoma after EWSR1/FLI1 knockdown, we utilized the limma algorithm package in R/Bioconductor to identify differentially expressed genes between two groups at a time.	('EWSR1/FLI1', 'Gene', (40, 50))	('Ewing sarcoma', 'Disease', (20, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (20, 33))	('knockdown', 'Var', (51, 60))
253158	28008375	In this study, we first identified DEGs in Ewing sarcoma after EWSR1/FLI1 knockdown by using the downloaded gene expression datasets GSE27524 from GEO Datasets of NCBI (http://www.ncbi.nlm.nih.gov/gds/).	('Ewing sarcoma', 'Disease', (43, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('knockdown', 'Var', (74, 83))	('EWSR1/FLI1', 'Gene', (63, 73))
253159	28008375	The datasets GSE27524 contained a cDNA microarray analysis of A673 in Ewing sarcoma cell line after inducible EWSR1/FLI1 knockdown with up to 96 h data.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('A673', 'Var', (62, 66))	('Ewing sarcoma', 'Disease', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (70, 83))
253160	28008375	We found that the changes of GO and KEGG terms showed almost the consistent trend with DEGs changes in each time point, that peaked in 72 h. We then focused on the DEGs that aberrantly expressed in all five groups to explore the biology function changes in Ewing sarcoma cells after EWSR1/FLI1 knockdown.	('Ewing sarcoma', 'Disease', (257, 270))	('knockdown', 'Var', (294, 303))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('EWSR1/FLI1', 'Gene', (283, 293))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (257, 270))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (257, 270))
253165	28008375	Translocation of chromosome 11 with 22 causes Ewing sarcoma breakpoint region 1 (EWSR1) fusion with Friend leukemia integration 1 transcription factor (FLI1) and in turn contributes to up to 95% of Ewing sarcoma.	('Ewing sarcoma breakpoint region 1', 'Gene', (46, 79))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (46, 79))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('Translocation', 'Var', (0, 13))	('Friend leukemia integration 1 transcription factor', 'Gene', (100, 150))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (46, 59))	('Friend leukemia integration 1 transcription factor', 'Gene', '2313', (100, 150))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (198, 211))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (198, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('FLI1', 'Gene', (152, 156))	('EWSR1', 'Gene', (81, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('Ewing sarcoma', 'Disease', (198, 211))	('contributes', 'Reg', (170, 181))	('fusion', 'Var', (88, 94))
253167	28008375	Thus, the current study explored the transcriptome changes after EWSR1/FLI1 knockdown in Ewing sarcoma cells.	('knockdown', 'Var', (76, 85))	('Ewing sarcoma', 'Disease', (89, 102))	('EWSR1/FLI1', 'Gene', (65, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))
253168	28008375	We utilized a combination of gene expression array data to perform the limma algorithm in R/Bioconductor to obtain DEGs and then DAVID annotation and transcriptional regulatory element database to identify transcriptome changes after EWSR1/FLI1 knockdown in Ewing sarcoma cells.	('knockdown', 'Var', (245, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('EWSR1/FLI1', 'Gene', (234, 244))	('Ewing sarcoma', 'Disease', (258, 271))	('transcriptome changes', 'MPA', (206, 227))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (258, 271))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (258, 271))
253175	28008375	Researches had showed that genes transcriptionally deregulated by EWSR1/FLI1 have the potential to contribute to malignant transformation, such as cell cycle regulators cyclinD1, indicated that EWSR1/FLI1 knockdown may partly inhibit the cell cycle progression of Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (270, 277))	('contribute', 'Reg', (99, 109))	('EWSR1/FLI1', 'Gene', (66, 76))	('knockdown', 'Var', (205, 214))	('cell cycle progression', 'CPA', (238, 260))	('Ewing sarcoma', 'Disease', (264, 277))	('inhibit', 'NegReg', (226, 233))	('malignant transformation', 'CPA', (113, 137))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (264, 277))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (264, 277))	('EWSR1/FLI1 knockdown', 'Var', (194, 214))
253177	28008375	These data indicate that EWSR1/FLI1 fusion protein alters cell cycle and upregulates purine and pyrimidine metabolism.	('upregulates', 'PosReg', (73, 84))	('cell cycle', 'CPA', (58, 68))	('purine', 'Chemical', 'MESH:C030985', (85, 91))	('EWSR1/FLI1', 'Gene', (25, 35))	('pyrimidine', 'Chemical', 'MESH:C030986', (96, 106))	('alters', 'Reg', (51, 57))	('fusion', 'Var', (36, 42))
253179	28008375	Furthermore, our current study also explored the transcriptome changes caused by EWSR1/FLI1 knockdown in Ewing sarcoma and found that there were nine transcription factors dysregulated in all of these five comparison groups compared to control after EWSR1/FLI1 knockdown.	('EWSR1/FLI1', 'Gene', (81, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('knockdown', 'Var', (92, 101))	('transcription factors', 'MPA', (150, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('dysregulated', 'Reg', (172, 184))	('Ewing sarcoma', 'Disease', (105, 118))
253180	28008375	As the only upregulated TF in this network, expression of SMAD3 and three of its targets were increased after EWSR1/FLI1 knockdown.	('knockdown', 'Var', (121, 130))	('expression', 'MPA', (44, 54))	('SMAD3', 'Gene', '4088', (58, 63))	('increased', 'PosReg', (94, 103))	('SMAD3', 'Gene', (58, 63))	('EWSR1/FLI1', 'Gene', (110, 120))	('upregulated', 'PosReg', (12, 23))
253181	28008375	For example, as an oncoprotein, MYB was downregulated and in turn regulated the most targets in this TF-gene network after EWSR1/FLI1 knockdown in Ewing sarcoma cells.	('EWSR1/FLI1', 'Gene', (123, 133))	('Ewing sarcoma', 'Disease', (147, 160))	('downregulated', 'NegReg', (40, 53))	('MYB', 'Gene', '4602', (32, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('MYB', 'Gene', (32, 35))	('knockdown', 'Var', (134, 143))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (147, 160))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (147, 160))	('regulated', 'Reg', (66, 75))
253185	28008375	In conclusion, the current study explored altered transcriptome after EWSR1/FLI1 knockdown in Ewing sarcoma cells and identified a dysregulated TF-gene regulatory network.	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('altered', 'Reg', (42, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('knockdown', 'Var', (81, 90))	('EWSR1/FLI1', 'Gene', (70, 80))	('Ewing sarcoma', 'Disease', (94, 107))	('transcriptome', 'MPA', (50, 63))	('TF-gene', 'Gene', (144, 151))
253211	23885287	Stains were performed with the following antibodies: CD31, CD34, CD20, CD3, CD15, and CD30.	('CD30', 'Gene', (86, 90))	('CD30', 'Gene', '943', (86, 90))	('CD31', 'Gene', (53, 57))	('CD3', 'Var', (71, 74))	('CD20', 'Gene', '54474', (65, 69))	('CD20', 'Gene', (65, 69))	('CD34', 'Gene', '947', (59, 63))	('CD31', 'Gene', '5175', (53, 57))	('CD34', 'Gene', (59, 63))	('CD15', 'Gene', '2526', (76, 80))	('CD15', 'Gene', (76, 80))
253366	31259909	Previous data showed that HLA-1 expression is epigenetically regulated, which is consistent with the observation of HLA-1 expression's cellular heterogeneity within the same tumor.	('tumor', 'Disease', (174, 179))	('epigenetically regulated', 'Var', (46, 70))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('expression', 'MPA', (32, 42))	('HLA-1', 'Gene', (26, 31))
253368	31259909	Mutations in HLA-1 genes may lead to the complete loss of HLA-1 on the cell surface in the whole tumor or to expressing nonfunctional mutated HLA-1.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('HLA-1', 'Gene', (13, 18))	('expressing nonfunctional mutated', 'MPA', (109, 141))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('loss', 'NegReg', (50, 54))	('HLA-1', 'Gene', (142, 147))	('HLA-1', 'Protein', (58, 63))	('tumor', 'Disease', (97, 102))	('Mutations', 'Var', (0, 9))
253376	31565186	Several pediatric cancer mouse models responded to single agent DC101-mediated VEGFR2 inhibition with tumor growth delay.	('pediatric cancer', 'Disease', 'MESH:D009369', (8, 24))	('tumor growth delay', 'Disease', 'MESH:D006130', (102, 120))	('mouse', 'Species', '10090', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor growth delay', 'Disease', (102, 120))	('VEGFR2', 'Gene', (79, 85))	('growth delay', 'Phenotype', 'HP:0001510', (108, 120))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('pediatric cancer', 'Disease', (8, 24))	('inhibition', 'NegReg', (86, 96))	('DC101-mediated', 'Var', (64, 78))
253384	31565186	Aberrant activation of VEGFR2 on endothelial cells by tumor cell-secreted VEGF-A drives angiogenesis, the development of new blood vessels from existing vessels.	('drives', 'PosReg', (81, 87))	('activation', 'PosReg', (9, 19))	('VEGFR2', 'Gene', (23, 29))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('angiogenesis', 'CPA', (88, 100))	('development of new blood vessels', 'CPA', (106, 138))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
253386	31565186	Inhibition of the VEGF pathway in cancer is thought to not only reduce the total number of vessels to support tumor growth, but also improve the function of vessels within the tumor, thereby more effectively delivering other anti-cancer therapeutics.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('reduce', 'NegReg', (64, 70))	('function', 'MPA', (145, 153))	('more', 'PosReg', (191, 195))	('improve', 'PosReg', (133, 140))	('tumor', 'Disease', (176, 181))	('VEGF', 'Gene', '7422', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('VEGF', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (110, 115))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
253404	31565186	Animals were treated with 20 mg/kg DC101 twice weekly for up to 4 weeks, either as a single agent or in combination with chemotherapies typically used for pediatric cancer patients.	('pediatric cancer', 'Disease', 'MESH:D009369', (155, 171))	('DC101', 'Var', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('pediatric cancer', 'Disease', (155, 171))	('patients', 'Species', '9606', (172, 180))
253411	31565186	Remarkably, this response was significantly enhanced with the addition of DC101 to gemcitabine/docetaxel (Figure 4A, top; Table 1).	('docetaxel', 'Chemical', 'MESH:C067311', (95, 104))	('DC101', 'Var', (74, 79))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('addition', 'Interaction', (62, 70))	('enhanced', 'PosReg', (44, 52))
253415	31565186	Combination treatment of DC101 and cyclophosphamide resulted in stable disease in animals bearing CTG-1458 tumors and DC101 also enhanced the anti-tumor activity of doxorubicin in the CTG-0926 PDX model.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (35, 51))	('enhanced', 'PosReg', (129, 137))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('DC101', 'Var', (118, 123))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('doxorubicin', 'Chemical', 'MESH:D004317', (165, 176))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
253417	31565186	Significant single agent activity of DC101 was observed in CTG-0994, which was not further enhanced with the addition of doxorubicin (Figure 5A).	('doxorubicin', 'Chemical', 'MESH:D004317', (121, 132))	('DC101', 'Gene', (37, 42))	('CTG-0994', 'Var', (59, 67))
253419	31565186	The combination of DC101 and doxorubicin was superior to either single agent in animals with CTG-0142 Ewing's sarcoma xenografts (Figure 5C).	("Ewing's sarcoma", 'Disease', (102, 117))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (102, 117))	('doxorubicin', 'Chemical', 'MESH:D004317', (29, 40))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (102, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('DC101', 'Var', (19, 24))
253426	31565186	Two additional osteosarcoma models demonstrated some reduction in tumor growth with DC101 monotherapy, but these responses were not statistically significant (Figure 5E and 5F).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('DC101', 'Gene', (84, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('tumor', 'Disease', (66, 71))	('monotherapy', 'Var', (90, 101))	('reduction', 'NegReg', (53, 62))	('osteosarcoma', 'Disease', (15, 27))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('osteosarcoma', 'Phenotype', 'HP:0002669', (15, 27))	('rat', 'Species', '10116', (42, 45))	('osteosarcoma', 'Disease', 'MESH:D012516', (15, 27))
253427	31565186	Combination treatment of DC101 and doxorubicin in these models did not significantly reduce tumor growth compared to vehicle and doxorubicin alone.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('reduce', 'NegReg', (85, 91))	('doxorubicin', 'Chemical', 'MESH:D004317', (129, 140))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))	('DC101', 'Var', (25, 30))
253428	31565186	A-204 malignant rhabdoid tumor, Y79 retinoblastoma, CTG-1072 hepatoblastoma, and CTG-1094 undifferentiated sarcoma models responded to DC101 and/or chemotherapy alone, but the combination did not improve response (Table 1).	('DC101', 'Var', (135, 140))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (90, 114))	('retinoblastoma', 'Phenotype', 'HP:0009919', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('undifferentiated sarcoma', 'Disease', (90, 114))	('hepatoblastoma', 'Disease', 'MESH:D018197', (61, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (6, 30))	('retinoblastoma', 'Disease', 'MESH:D012175', (36, 50))	('retinoblastoma', 'Disease', (36, 50))	('malignant rhabdoid tumor', 'Disease', (6, 30))	('hepatoblastoma', 'Disease', (61, 75))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (61, 75))
253432	31565186	DC101 monotherapy enhanced the duration of tumor growth delay following an initial response to doxorubicin in one model of each synovial sarcoma and Ewing's sarcoma.	('tumor growth delay', 'Disease', 'MESH:D006130', (43, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('doxorubicin', 'Chemical', 'MESH:D004317', (95, 106))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (128, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('monotherapy', 'Var', (6, 17))	('synovial sarcoma', 'Disease', 'MESH:D013584', (128, 144))	("Ewing's sarcoma", 'Disease', (149, 164))	('enhanced', 'PosReg', (18, 26))	('rat', 'Species', '10116', (33, 36))	('DC101', 'Gene', (0, 5))	('tumor growth delay', 'Disease', (43, 61))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (149, 164))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (149, 164))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('growth delay', 'Phenotype', 'HP:0001510', (49, 61))	('synovial sarcoma', 'Disease', (128, 144))
253433	31565186	We also observed that the concurrent administration of DC101 and chemotherapy improved the anti-tumor response compared to control and chemotherapy alone in mice bearing models of alveolar RMS, embryonal RMS, DSRCT, Ewing's sarcoma, neuroblastoma, and synovial sarcoma, but not osteosarcoma, hepatoblastoma, rhabdoid, or retinoblastoma.	('DC101', 'Var', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mice', 'Species', '10090', (157, 161))	('neuroblastoma', 'Phenotype', 'HP:0003006', (233, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('retinoblastoma', 'Disease', 'MESH:D012175', (321, 335))	('alveolar RMS', 'Disease', (180, 192))	('neuroblastoma', 'Disease', 'MESH:D009447', (233, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('alveolar RMS', 'Disease', 'MESH:D002282', (180, 192))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (292, 306))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (216, 231))	('osteosarcoma', 'Phenotype', 'HP:0002669', (278, 290))	('rhabdoid', 'Disease', (308, 316))	('sarcoma', 'Phenotype', 'HP:0100242', (283, 290))	('improved', 'PosReg', (78, 86))	('rat', 'Species', '10116', (45, 48))	('retinoblastoma', 'Phenotype', 'HP:0009919', (321, 335))	('synovial sarcoma', 'Disease', (252, 268))	('rhabdoid', 'Disease', 'MESH:D018335', (308, 316))	('tumor', 'Disease', (96, 101))	('synovial sarcoma', 'Disease', 'MESH:D013584', (252, 268))	('retinoblastoma', 'Disease', (321, 335))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	("Ewing's sarcoma", 'Disease', (216, 231))	('hepatoblastoma', 'Disease', (292, 306))	('osteosarcoma', 'Disease', (278, 290))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (216, 231))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (252, 268))	('osteosarcoma', 'Disease', 'MESH:D012516', (278, 290))	('hepatoblastoma', 'Disease', 'MESH:D018197', (292, 306))	('neuroblastoma', 'Disease', (233, 246))
253438	31565186	However, small molecule inhibitors may block multiple kinases, leading to off-target effects and associated toxicity and to date no VEGFR2 pathway inhibitor has been approved for pediatric indications.	('toxicity', 'Disease', (108, 116))	('toxicity', 'Disease', 'MESH:D064420', (108, 116))	('small', 'Var', (9, 14))	('off-target effects', 'MPA', (74, 92))
253440	31565186	We demonstrated that ramucirumab abrogated both VEGF-A- and pediatric cancer cell-driven endothelial cord formation in vitro; furthermore, treatment with DC101 improved response to chemotherapy in several xenograft mouse models representing a range of pediatric tumor types with high unmet need.	('response to chemotherapy', 'MPA', (169, 193))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('pediatric cancer', 'Disease', (60, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('abrogated', 'NegReg', (33, 42))	('DC101', 'Var', (154, 159))	('pediatric tumor', 'Disease', (252, 267))	('pediatric cancer', 'Disease', 'MESH:D009369', (60, 76))	('improved', 'PosReg', (160, 168))	('mouse', 'Species', '10090', (215, 220))	('rat', 'Species', '10116', (10, 13))	('pediatric tumor', 'Disease', 'MESH:D063766', (252, 267))
253443	31565186	This demonstrates the need for combination treatment of VEGFR2 pathway inhibition with a cytotoxic agent to hit both the tumor and the pathogenic tumor microenvironment.	('inhibition', 'Var', (71, 81))	('rat', 'Species', '10116', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (121, 126))	('VEGFR2', 'Gene', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
253445	31565186	Indeed, multiple pediatric tumor models met these criteria, including alveolar and embryonal RMS, DSRCT, Ewing's sarcoma, neuroblastoma, and synovial sarcoma and tumor regression was only observed when DC101 was combined with doxorubicin or another cytotoxic agent.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (141, 157))	('tumor', 'Disease', (162, 167))	('neuroblastoma', 'Disease', 'MESH:D009447', (122, 135))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (105, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('DSRCT', 'Disease', (98, 103))	('tumor', 'Disease', (27, 32))	('alveolar and embryonal RMS', 'Disease', 'MESH:D016301', (70, 96))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('DC101', 'Var', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('pediatric tumor', 'Disease', (17, 32))	('pediatric tumor', 'Disease', 'MESH:D063766', (17, 32))	("Ewing's sarcoma", 'Disease', (105, 120))	('synovial sarcoma', 'Disease', (141, 157))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (105, 120))	('synovial sarcoma', 'Disease', 'MESH:D013584', (141, 157))	('doxorubicin', 'Chemical', 'MESH:D004317', (226, 237))	('neuroblastoma', 'Disease', (122, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('neuroblastoma', 'Phenotype', 'HP:0003006', (122, 135))
253452	31565186	Our data demonstrate that VEGFR2 inhibition, either as monotherapy or in combination with chemotherapy, promotes anti-tumor responses in several pediatric cancer models and further supports clinical investigation of ramucirumab in combination with other therapies for pediatric cancer patients.	('VEGFR2', 'Gene', (26, 32))	('inhibition', 'Var', (33, 43))	('pediatric cancer', 'Disease', (145, 161))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('pediatric cancer', 'Disease', 'MESH:D009369', (268, 284))	('rat', 'Species', '10116', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('pediatric cancer', 'Disease', 'MESH:D009369', (145, 161))	('promotes', 'PosReg', (104, 112))	('tumor', 'Disease', (118, 123))	('patients', 'Species', '9606', (285, 293))	('pediatric cancer', 'Disease', (268, 284))
253457	31565186	The following antibodies were purchased from Cell Signaling Technology: VEGFR2 (cat#2479), VEGFR2 Y1175 (cat#2478), ERK1/2 (cat#4695), and ERK1/2 T202/Y204 (cat#4370).	('ERK1/2', 'Gene', '5595;5594', (116, 122))	('cat#4695', 'Var', (124, 132))	('ERK1/2', 'Gene', (139, 145))	('Y1175 (cat#2478', 'Var', (98, 113))	('ERK1/2', 'Gene', '5595;5594', (139, 145))	('T202/Y204', 'Var', (146, 155))	('ERK1/2', 'Gene', (116, 122))	('cat#2478', 'Var', (105, 113))
253488	30613825	Although approximately one third of sarcomas harbor specific translocations or mutations that may be amenable to targeted therapies, two thirds show a complex karyotype with multiple rearrangements, duplications, or deletions.	('deletions', 'Var', (216, 225))	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('duplications', 'Var', (199, 211))	('translocations', 'Var', (61, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('sarcomas', 'Disease', (36, 44))	('mutations', 'Var', (79, 88))
253640	28526720	The more tendencies toward improvement in response rate and PFS were observed in MRCL group than in the other groups (PFS in MRCL, vs. SS, p = .025; vs. other TRS, p = .049).	('improvement', 'PosReg', (27, 38))	('MRCL', 'Var', (125, 129))	('MRCL', 'Chemical', '-', (81, 85))	('response rate', 'CPA', (42, 55))	('MRCL', 'Chemical', '-', (125, 129))
253707	26573141	In addition, the promoters of ion channel genes are highly differentially methylated in Ewing sarcoma compared to non-malignant adult tissues.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('Ewing sarcoma', 'Disease', (88, 101))	('ion channel genes', 'Gene', (30, 47))	('methylated', 'Var', (74, 84))
253708	26573141	Ion channels regulate a variety of biological processes, including proliferation, and dysfunction of these channels contributes to tumor pathogenesis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('contributes', 'Reg', (116, 127))	('regulate', 'Reg', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('dysfunction', 'Var', (86, 97))	('tumor', 'Disease', (131, 136))	('proliferation', 'CPA', (67, 80))
253712	26573141	This study demonstrates that promoters of ion channels are aberrantly methylated in Ewing sarcoma and that epigenetic silencing of KCNA5 contributes to tumor cell proliferation, thus providing further evidence of the importance of ion channel dyregulation to tumorigenesis.	('Ewing sarcoma', 'Disease', (84, 97))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('KCNA5', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('contributes', 'Reg', (137, 148))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('epigenetic silencing', 'Var', (107, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('KCNA5', 'Gene', '3741', (131, 136))	('tumor', 'Disease', (259, 264))
253714	26573141	Cancer cells accomplish this by hijacking physiologic pathways and silencing or mutating tumor suppressor genes that control cell cycle progression.	('hijacking', 'Reg', (32, 41))	('silencing', 'NegReg', (67, 76))	('physiologic pathways', 'Pathway', (42, 62))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutating', 'Var', (80, 88))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
253720	26573141	In this way, more stable, and potentially irreversible, gene silencing is effected and cancer cells become locked in a stem cell-like state.	('gene', 'Var', (56, 60))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
253727	26573141	Our results reveal that, like other cancer, CpG islands in the promoters of differentiation-associated genes are targets of DNA methylation.	('CpG islands', 'Var', (44, 55))	('differentiation-associated genes', 'Gene', (76, 108))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
253728	26573141	In particular, these studies demonstrate that DNA hypermethylation contributes to epigenetic repression of the KCNA5 locus and that the resulting suppression of of the Kv1.5 ion channel supports cancer cell proliferation.	('KCNA5', 'Gene', (111, 116))	('Kv1.5', 'Gene', (168, 173))	('suppression', 'NegReg', (146, 157))	('cancer', 'Disease', (195, 201))	('Kv1.5', 'Gene', '3741', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('hypermethylation', 'Var', (50, 66))	('KCNA5', 'Gene', '3741', (111, 116))	('epigenetic repression', 'MPA', (82, 103))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
253732	26573141	All cell lines were cultured in standard cell culture media, supplemented with 10% FBS (Atlas Biologicals, Inc., F-500-A) at 37 C in 5% CO2.	('F-500-A', 'Var', (113, 120))	('FBS', 'Disease', (83, 86))	('CO2', 'Chemical', '-', (136, 139))	('FBS', 'Disease', 'MESH:D005198', (83, 86))
253743	26573141	Differential methylation was defined as a median difference in beta-value of at least 0.2 and a Bonferroni multiple test-corrected p-value of less than 0.05 between Ewing sarcoma and non-malignant adult tissues.	('Differential methylation', 'Var', (0, 24))	('Ewing sarcoma', 'Disease', (165, 178))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (165, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (165, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))
253748	26573141	DNA hypermethylation at the promoters of developmentally critical polycomb target genes has been observed in many adult tumors and is associated with transcriptional silencing of genes that direct cell differentiation ( and reviewed in).	('observed', 'Reg', (97, 105))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('silencing', 'NegReg', (166, 175))	('genes', 'Gene', (179, 184))	('adult tumors', 'Disease', 'MESH:C538052', (114, 126))	('transcriptional', 'MPA', (150, 165))	('adult tumors', 'Disease', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('hypermethylation', 'Var', (4, 20))
253749	26573141	Given the high level of polycomb protein expression that is evident in Ewing sarcoma, and the critical roles of these proteins in tumor pathogenesis, we hypothesized that abnormal DNA methylation of polycomb target genes might be a feature of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (243, 256))	('Ewing sarcoma', 'Disease', (71, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (243, 256))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('DNA', 'Var', (180, 183))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (243, 256))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('abnormal DNA methylation of polycomb target genes', 'Phenotype', 'HP:0003254', (171, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('tumor', 'Disease', (130, 135))
253757	26573141	In particular, numerous HOX genes were differentially methylated in Ewing sarcoma (Supplemental Table S1).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('Ewing sarcoma', 'Disease', (68, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('HOX genes', 'Gene', (24, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (68, 81))	('methylated', 'Var', (54, 64))	('differentially', 'Reg', (39, 53))
253761	26573141	Thus, in addition to the expected pattern of altered DNA methylation at developmental transcription factors, this analysis also identified ion regulatory genes as prime targets of differential methylation in Ewing sarcoma.	('methylation', 'Var', (193, 204))	('ion regulatory genes', 'Gene', (139, 159))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (208, 221))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (208, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('Ewing sarcoma', 'Disease', (208, 221))
253763	26573141	In particular, voltage-gated ion channels play critical roles in the maintenance of cellular homeostasis and specific deregulation of potassium ion channels has recently been broadly implicated in cancer pathogenesis.	('implicated', 'Reg', (183, 193))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('potassium', 'Chemical', 'MESH:D011188', (134, 143))	('cancer', 'Disease', (197, 203))	('deregulation', 'Var', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cellular homeostasis', 'MPA', (84, 104))
253766	26573141	Thus, deregulated expression of potassium ion channels is common in cancer but the mechanisms underlying their deregulation remain largely ill-defined.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('potassium', 'Chemical', 'MESH:D011188', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('deregulated', 'Var', (6, 17))	('expression', 'MPA', (18, 28))	('cancer', 'Disease', (68, 74))
253776	26573141	This analysis confirmed that the KCNA5 locus is methylated in Ewing sarcoma cell lines and tumors compared to both non-malignant fibroblasts and endothelial cells as well as bone marrow derived mesenchymal stem cells (MSC), a putative cell of Ewing sarcoma origin (Figure 2D).	('tumors', 'Disease', (91, 97))	('Ewing sarcoma', 'Disease', (243, 256))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('KCNA5', 'Gene', (33, 38))	('methylated', 'Var', (48, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (243, 256))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (243, 256))	('Ewing sarcoma', 'Disease', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('KCNA5', 'Gene', '3741', (33, 38))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (62, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (62, 75))
253779	26573141	This suggests that broader methylation of locus might be an adaptive response of cells to prolonged in vitro culture, or that Ewing sarcoma cells with more extensive DNA methylation of the KCNA5 gene are more amenable to generating a cell line (Figure 2D).	('Ewing sarcoma', 'Disease', (126, 139))	('KCNA5', 'Gene', '3741', (189, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (126, 139))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (126, 139))	('KCNA5', 'Gene', (189, 194))	('methylation', 'Var', (170, 181))
253781	26573141	In support of this, data from the MethHC database shows significant tumor-specific KCNA5 promoter DNA methylation in all of the 18 different tumor types analyzed (Supplemental Figure S1).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('methylation', 'Var', (102, 113))	('KCNA5', 'Gene', '3741', (83, 88))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('KCNA5', 'Gene', (83, 88))
253796	26573141	Together these data reveal that epigenetic silencing of the Kv1.5 channel, by DNA methylation of KCNA5, contributes to Ewing sarcoma cell proliferation and that this effect is mediated, at least in part, by the function of Kv1.5 as a negative regulator of cell-cycle progression (Figure 6).	('KCNA5', 'Gene', (97, 102))	('Kv1.5', 'Gene', (223, 228))	('Kv1.5', 'Gene', '3741', (60, 65))	('methylation', 'Var', (82, 93))	('Ewing sarcoma', 'Disease', (119, 132))	('Kv1.5', 'Gene', '3741', (223, 228))	('epigenetic silencing', 'Var', (32, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (119, 132))	('KCNA5', 'Gene', '3741', (97, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (119, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('Kv1.5', 'Gene', (60, 65))
253799	26573141	From these studies we discovered that, like other human cancers, CpG islands in the promoters of polycomb target genes are selectively methylated in Ewing sarcoma.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (149, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('methylated', 'Var', (135, 145))	('Ewing sarcoma', 'Disease', (149, 162))	('CpG islands', 'Var', (65, 76))	('human', 'Species', '9606', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
253801	26573141	More specifically, our studies identified potassium ion channels as frequent targets of aberrant DNA methylation in Ewing sarcoma and revealed that the promoter of KCNA5 is relatively hypermethylated in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('Ewing sarcoma', 'Disease', (116, 129))	('tumor', 'Disease', (203, 208))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('KCNA5', 'Gene', '3741', (164, 169))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('DNA', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('potassium', 'Chemical', 'MESH:D011188', (42, 51))	('aberrant', 'Var', (88, 96))	('KCNA5', 'Gene', (164, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
253802	26573141	In addition, interrogation of public databases showed that the KCNA5 locus is reproducibly hypermethylated, relative to adjacent normal tissues, in a wide variety of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('hypermethylated', 'Var', (91, 106))	('human', 'Species', '9606', (166, 171))	('KCNA5', 'Gene', '3741', (63, 68))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('KCNA5', 'Gene', (63, 68))
253805	26573141	Given that cell proliferation and survival are intimately linked to intracellular potassium ion levels, dysregulation of potassium channels can impact on the cancer phenotype.	('potassium', 'Chemical', 'MESH:D011188', (82, 91))	('impact', 'Reg', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('dysregulation', 'Var', (104, 117))	('potassium', 'Chemical', 'MESH:D011188', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
253806	26573141	Consistent with this, aberrant expression of ion channels is prevalent in cancer.	('aberrant expression', 'Var', (22, 41))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('prevalent', 'Reg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
253808	26573141	Thus, hijacking of potassium ion channel function by cancer cells has the potential to impact on cell proliferation, cell survival, migration, and differentiation.	('differentiation', 'CPA', (147, 162))	('potassium', 'Chemical', 'MESH:D011188', (19, 28))	('cancer', 'Disease', (53, 59))	('cell survival', 'CPA', (117, 130))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('migration', 'CPA', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('hijacking', 'Var', (6, 15))	('cell proliferation', 'CPA', (97, 115))	('impact', 'Reg', (87, 93))
253811	26573141	In myoblasts, high Kv1.5 expression leads to accumulation of cyclin-dependent kinase inhibitors and impairs cell-cycle progression at the G1 to S transition, suggesting the channel is a cell cycle checkpoint regulator and could function as a tumor suppressor gene.	('cyclin-dependent kinase inhibitors', 'MPA', (61, 95))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('accumulation', 'PosReg', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('high', 'Var', (14, 18))	('impairs', 'NegReg', (100, 107))	('cell-cycle progression at the G1 to S transition', 'CPA', (108, 156))	('tumor', 'Disease', (242, 247))	('Kv1.5', 'Gene', (19, 24))	('Kv1.5', 'Gene', '3741', (19, 24))
253814	26573141	Moreover, specific pharmacologic inhibition of Kv1.5 channel function partially restores proliferation in Ewing sarcoma cells that have been exposed to decitabine.	('proliferation', 'CPA', (89, 102))	('pharmacologic', 'Var', (19, 32))	('Kv1.5', 'Gene', '3741', (47, 52))	('Ewing sarcoma', 'Disease', (106, 119))	('restores', 'NegReg', (80, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('decitabine', 'Chemical', 'MESH:D000077209', (152, 162))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('Kv1.5', 'Gene', (47, 52))
253815	26573141	Thus, these studies together provide evidence that reactivation of silenced Kv1.5 channels can inhibit cancer proliferation, likely by permitting efflux of K+ ions and inhibiting G1 to S transition.	('Kv1.5', 'Gene', '3741', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('efflux of K+ ions', 'MPA', (146, 163))	('inhibit', 'NegReg', (95, 102))	('inhibiting', 'NegReg', (168, 178))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('Kv1.5', 'Gene', (76, 81))	('G1 to S transition', 'CPA', (179, 197))	('permitting', 'PosReg', (135, 145))	('silenced', 'Var', (67, 75))	('cancer', 'Disease', (103, 109))	('reactivation', 'Var', (51, 63))
253818	26573141	The contribution of ion channel deregulation to tumor pathogenesis remains a relatively unexplored area of investigation in cancer biology.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (48, 53))	('deregulation', 'Var', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
253819	26573141	We have now shown that the Kv1.5 channel is reproducibly targeted for epigenetic repression, by both polycomb proteins and by DNA methylation (this study), and that repression contributes to cancer cell survival and proliferation.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('polycomb proteins', 'Protein', (101, 118))	('Kv1.5', 'Gene', (27, 32))	('Kv1.5', 'Gene', '3741', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('contributes', 'Reg', (176, 187))	('epigenetic repression', 'Var', (70, 91))	('proliferation', 'CPA', (216, 229))
253820	26573141	These findings provide compelling evidence to support the designation of KCNA5 as a tumor suppressor gene in human cancers, and suggest that further studies into its mechanism of action as a cell cycle regulator will reveal how loss of Kv1.5 function supports the proliferative cancer phenotype.	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('KCNA5', 'Gene', (73, 78))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('Kv1.5', 'Gene', '3741', (236, 241))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('loss', 'Var', (228, 232))	('KCNA5', 'Gene', '3741', (73, 78))	('cancer', 'Disease', (278, 284))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('Kv1.5', 'Gene', (236, 241))
253835	24723789	Disease-specific mortality was defined as death from sarcoma (ICD-8; 170, 171, 192.49-99 and ICD-10; C40-C41, C47, C49) or death with known metastatic disease.	('C40', 'Gene', (101, 104))	('C40', 'Gene', '55571', (101, 104))	('C49', 'Var', (115, 118))	('sarcoma', 'Disease', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('C47', 'Var', (110, 113))
253836	24723789	Increasing age and tumor size, metastases at diagnosis, soft tissue involvement, high grade, and intralesional/marginal excision or no surgery was independently significantly associated with an increased overall mortality (Table 2).	('associated', 'Reg', (175, 185))	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('high', 'Var', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('soft tissue involvement', 'CPA', (56, 79))	('metastases', 'Disease', (31, 41))
253842	24466321	Tumor Vasculature-Targeted Recombinant Mutated Human TNF-alpha Enhanced the Antitumor Activity of Doxorubicin by Increasing Tumor Vessel Permeability in Mouse Xenograft Models Increasing evidence suggests that, when used in combination, tumor necrosis factor-alpha (TNF-alpha) synergizes with traditional chemotherapeutic drugs to exert a heightened antitumor effect.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (354, 359))	('TNF-alpha', 'Gene', '7124', (53, 62))	('tumor necrosis factor-alpha', 'Gene', '21926', (237, 264))	('TNF-alpha', 'Gene', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('Human', 'Species', '9606', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('TNF-alpha', 'Gene', '7124', (266, 275))	('Doxorubicin', 'Chemical', 'MESH:D004317', (98, 109))	('Tumor Vessel Permeability', 'MPA', (124, 149))	('Increasing', 'PosReg', (113, 123))	('TNF-alpha', 'Gene', (266, 275))	('Enhanced', 'PosReg', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('tumor', 'Disease', (80, 85))	('Tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (237, 242))	('tumor necrosis factor-alpha', 'Gene', (237, 264))	('Mouse', 'Species', '10090', (153, 158))	('Mutated', 'Var', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (237, 242))
253854	24466321	To overcome this limitation of toxicity, an effort has been made to create a TNF mutant by protein-engineering methods that retains the antitumor ability of TNF-alpha but exhibits decreased toxicity.	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('toxicity', 'Disease', 'MESH:D064420', (31, 39))	('toxicity', 'Disease', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('TNF', 'Gene', (77, 80))	('mutant', 'Var', (81, 87))	('toxicity', 'Disease', 'MESH:D064420', (190, 198))	('toxicity', 'Disease', (190, 198))	('tumor', 'Disease', (140, 145))
253855	24466321	One such TNF-alpha mutant, the recombinant mutated human TNF-alpha (rmhTNF-alpha), was generated by deleting the first seven amino acids at the N-terminus and replacing the Pro 8, Ser 9, and Asp 10 with Arg 8, Lys 9, and Arg 10, respectively, as well as Leu 157 with Phe 157 at the C-terminus.	('Arg', 'Chemical', 'MESH:D001120', (203, 206))	('Asp 10 with Arg', 'SUBSTITUTION', 'None', (191, 206))	('Lys', 'Chemical', 'MESH:D008239', (210, 213))	('Asp 10 with Arg', 'Var', (191, 206))	('Leu 157', 'Var', (254, 261))	('hTNF-alpha', 'Gene', (70, 80))	('Leu 157 with Phe', 'Mutation', 'p.L157F', (254, 270))	('human', 'Species', '9606', (51, 56))	('deleting', 'Var', (100, 108))	('Arg', 'Chemical', 'MESH:D001120', (221, 224))	('TNF-alpha', 'Gene', (57, 66))	('rmhTNF', 'Chemical', '-', (68, 74))	('hTNF-alpha', 'Gene', '7124', (70, 80))	('replacing', 'Reg', (159, 168))
253867	24466321	With the aim of further improving the potential clinical application of RGD-rmhTNF-alpha, we hypothesized that coupling the RGD-4C peptide to rmhTNF-alpha would selectively target it to tumor vessels in vivo, increase tumor vessel permeability, and promote the antitumor activity of chemotherapeutic agents within the tumor microenvironment.	('promote', 'PosReg', (249, 256))	('rmhTNF', 'Chemical', '-', (76, 82))	('tumor', 'Disease', (186, 191))	('hTNF-alpha', 'Gene', '7124', (78, 88))	('tumor', 'Disease', (218, 223))	('target', 'Reg', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('hTNF-alpha', 'Gene', (78, 88))	('increase tumor', 'Disease', (209, 223))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('increase tumor vessel permeability', 'Phenotype', 'HP:0030005', (209, 243))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('RGD-4C', 'Gene', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('hTNF-alpha', 'Gene', '7124', (144, 154))	('increase tumor', 'Disease', 'MESH:D009369', (209, 223))	('coupling', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('rmhTNF', 'Chemical', '-', (142, 148))	('hTNF-alpha', 'Gene', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))
253944	24466321	As expected, doxorubicin significantly inhibited tumor growth compared to the negative control (p<0.05).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('inhibited', 'NegReg', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('doxorubicin', 'Chemical', 'MESH:D004317', (13, 24))	('tumor', 'Disease', (49, 54))	('doxorubicin', 'Var', (13, 24))
254005	34040306	Patients with skip metastasis are more likely to have associated distant metastasis with lower survival rate.	('distant metastasis', 'CPA', (65, 83))	('skip metastasis', 'Var', (14, 29))	('lower', 'NegReg', (89, 94))	('Patients', 'Species', '9606', (0, 8))
254083	32873319	Recent findings have shown that the aberrant expression of IRGs occurs in early-stage tumors and can serve as prognostic biomarkers in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('IRGs', 'Chemical', '-', (59, 63))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('expression', 'MPA', (45, 55))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('aberrant', 'Var', (36, 44))	('cancers', 'Disease', (143, 150))	('IRGs', 'Gene', (59, 63))
254085	32873319	Univariate Cox regression analysis identified 57 and 33 DEIRGs to be significantly associated with OS and PFS, respectively (Additional file 2 and Additional file 3).	('IRGs', 'Chemical', '-', (58, 62))	('associated', 'Reg', (83, 93))	('DEIRGs', 'Var', (56, 62))	('PFS', 'Disease', (106, 109))
254126	32873319	IRG expression is connected to the immune infiltration level, key gene mutations, and chemosensitivity.	('IRG', 'Chemical', '-', (0, 3))	('mutations', 'Var', (71, 80))	('IRG', 'Gene', (0, 3))
254134	32873319	It has been estimated that Epstein-Barr virus infection is associated with approximately 200,000 malignancies each year, and EBS appears to dysregulate the expression of TCL1-family genes, leading to several typical lymphocyte cancers.	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('EBS', 'Chemical', '-', (125, 128))	('TCL1', 'Gene', '8115', (170, 174))	('TCL1', 'Gene', (170, 174))	('associated', 'Reg', (59, 69))	('Epstein-Barr virus infection', 'Disease', (27, 55))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('Epstein-Barr virus infection', 'Disease', 'MESH:D020031', (27, 55))	('expression', 'MPA', (156, 166))	('dysregulate', 'Var', (140, 151))	('leading to', 'Reg', (189, 199))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancers', 'Disease', (227, 234))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('malignancies', 'Disease', (97, 109))
254160	32873319	revealed a novel MTAP-RAF1 fusion in a 51-year-old sarcoma patient.	('sarcoma', 'Disease', (51, 58))	('RAF1', 'Gene', (22, 26))	('RAF1', 'Gene', '5894', (22, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('patient', 'Species', '9606', (59, 66))	('MTAP', 'Gene', (17, 21))	('fusion', 'Var', (27, 33))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('MTAP', 'Gene', '4507', (17, 21))
254162	32873319	Hence, the regulation of these IRGs may represent a significant breakthrough in tumor immunotherapy, as the immune system plays a crucial role in the occurrence and progression of cancer.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (80, 85))	('regulation', 'Var', (11, 21))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('IRGs', 'Chemical', '-', (31, 35))	('cancer', 'Disease', (180, 186))
254165	32873319	To date, numerous studies have developed signatures based on sequencing data to stratify sarcoma patients, including CINSARC, alternative splicing events, relapse-related genes, and lncRNA.	('CINSARC', 'Disease', (117, 124))	('alternative splicing events', 'Var', (126, 153))	('lncRNA', 'Disease', (182, 188))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('relapse-related', 'Disease', (155, 170))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('patients', 'Species', '9606', (97, 105))
254233	24812032	Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12).	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (21, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('t(11:22)(q24:q12)', 'STRUCTURAL_ABNORMALITY', 'None', (118, 135))	('EWS', 'Gene', '14030', (47, 50))	('t(11:22)(q24', 'Var', (118, 130))	('Ewing sarcomas', 'Disease', (21, 35))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (21, 35))	('EWS', 'Gene', (47, 50))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))
254246	24812032	The majority (85%) of Ewing sarcomas harbor the recurrent chromosomal translocation, t(11;22)(q24;q12).	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (48, 83))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (85, 102))	('t(11;22)(q24;q12', 'Var', (85, 101))	('Ewing sarcomas', 'Disease', (22, 36))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (22, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (22, 35))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (22, 36))
254247	24812032	This gene rearrangement creates a tumor-specific fusion protein, EWS/FLI, by joining the N-terminal transcriptional activation domain of the TET family protein, EWSR1, to the ETS DNA binding domain of transcription factor, FLI1.	('EWS', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('rearrangement', 'Var', (10, 23))	('EWS', 'Gene', '14030', (161, 164))	('EWS', 'Gene', '14030', (65, 68))	('EWS', 'Gene', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
254249	24812032	The remaining Ewing sarcomas express related fusions between FLI1 and different ETS family proteins (including ERG, ETV1, ETV4, FEV), or the alternate FUS-ERG fusion.	('Ewing sarcomas', 'Disease', 'MESH:C563168', (14, 28))	('ETS', 'Protein', (80, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (14, 28))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (14, 27))	('FLI1', 'Gene', (61, 65))	('fusions', 'Var', (45, 52))	('Ewing sarcomas', 'Disease', (14, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
254294	24812032	RUNX3 Sigma Mission shRNAs ("sh813": NM_004350.2-813s21c1 "sh1400": NM_004350.2-1400s21c1, "sh3300": NM_004350.2-3330s21c1) and a control non-target shRNA (shNT) were purchased from Sigma and transduced into A673 Ewing sarcoma cells with lentiviruses.	('sh3300": NM_004350.2-3330s21c1', 'Var', (92, 122))	('NM_004350.2-1400s21c1', 'Var', (68, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('Ewing sarcoma', 'Disease', (213, 226))	('sh1400": NM_004350.2-1400s21c1', 'Var', (59, 89))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (213, 226))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (213, 226))
254318	24812032	A series of RUNX3 C-terminal truncation mutants revealed that the N-terminus and the RUNT domain are sufficient for interactions with EWS/FLI (Figure 2B), similar to what was observed with the RUNX2/EWS/FLI interaction.	('EWS', 'Gene', (199, 202))	('interactions', 'Interaction', (116, 128))	('EWS', 'Gene', '14030', (134, 137))	('EWS', 'Gene', '14030', (199, 202))	('mutants', 'Var', (40, 47))	('RUNX2', 'Gene', '860', (193, 198))	('RUNX3', 'Gene', (12, 17))	('EWS', 'Gene', (134, 137))	('RUNX2', 'Gene', (193, 198))
254327	24812032	Compared to the shNT control, sh813 was the most efficient at reducing RUNX3 protein levels, but sh1400 and sh3300 also reduced RUNX3 expression (Figure 5A).	('RUNX3 expression', 'MPA', (128, 144))	('sh1400', 'Var', (97, 103))	('RUNX3 protein levels', 'MPA', (71, 91))	('reducing', 'NegReg', (62, 70))	('sh3300', 'Var', (108, 114))	('reduced', 'NegReg', (120, 127))	('expression', 'Species', '29278', (134, 144))
254331	24812032	The expression levels of three of the EWS/FLI target genes (NKX2-2, EPHB3, CDNK1 (p21)) were validated by qPCR using mRNA from the all three RUNX3 suppressed cells (sh813, sh1400 and sh3300) (Figures 5D-F).	('sh1400', 'Var', (172, 178))	('EWS', 'Gene', (38, 41))	('expression', 'Species', '29278', (4, 14))	('EPHB3', 'Gene', (68, 73))	('RUNX3', 'Gene', (141, 146))	('sh3300', 'Var', (183, 189))	('CDNK1', 'Gene', (75, 80))	('EWS', 'Gene', '14030', (38, 41))	('NKX2-2', 'Gene', (60, 66))	('sh813', 'Var', (165, 170))
254388	24517100	Intra- and peritumoral tubular areas of flow void on both T1WI and T2WI, representing rapid blood flow in distended vessels, were present in all cases (Figures 1 and 2).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('T2WI', 'Var', (67, 71))	('flow void', 'MPA', (40, 49))
254392	24517100	It is caused by a specific unbalanced translocation, der(17)t(X:17)(p11;p25), that results in the formation of an ASPL-TFE3 fusion gene.	('results in', 'Reg', (83, 93))	('der(17)t(X:17)(p11;p25', 'Var', (53, 75))	('ASPL', 'Gene', (114, 118))	('TFE3', 'Gene', (119, 123))	('caused by', 'Reg', (6, 15))	('TFE3', 'Gene', '7030', (119, 123))	('der(17)t(X:17)(p11;p25)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 76))	('ASPL', 'Gene', '79058', (114, 118))
254503	23493352	It may provide additional support for a diagnosis by identifying tumor-specific genetic signatures, help in prognostication and even in determining the best therapeutic options.	('tumor', 'Disease', (65, 70))	('help', 'Reg', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('genetic', 'Var', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
254529	22434719	After adjustment for demographic characteristics, low birthweight (<2500g) strongly increased risk for developing both rhabdoid sarcomas (OR=2.43, 95% CI 1.09, 5.41) and AT/RT (OR=2.99, 95% CI 1.31, 6.84).	('low birthweight', 'Phenotype', 'HP:0001518', (50, 65))	('AT', 'Disease', 'None', (170, 172))	('rhabdoid sarcomas', 'Disease', (119, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('low birthweight', 'Var', (50, 65))	('rhabdoid sarcomas', 'Disease', 'MESH:D018335', (119, 136))
254543	22434719	The loss or inactivation of the SMARCB1/hSNF5/INI tumor suppressor gene has been identified as the hallmark genetic defect in these tumors.	('INI tumor', 'Disease', 'MESH:D009369', (46, 55))	('SMARCB1', 'Gene', '6598', (32, 39))	('hSNF5', 'Gene', '6598', (40, 45))	('hallmark genetic defect', 'Disease', 'MESH:D030342', (99, 122))	('SMARCB1', 'Gene', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', (132, 138))	('INI tumor', 'Disease', (46, 55))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('hallmark genetic defect', 'Disease', (99, 122))	('hSNF5', 'Gene', (40, 45))	('inactivation', 'Var', (12, 24))	('loss', 'NegReg', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
254575	22434719	The increased risk of cancer among children with low birthweight persisted when looking at singleton births only.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('low birthweight', 'Var', (49, 64))	('cancer', 'Disease', (22, 28))	('low birthweight', 'Phenotype', 'HP:0001518', (49, 64))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('children', 'Species', '9606', (35, 43))
254658	30583594	The expression levels of FZD10 on the latter cell model (350,000 molecules/cell) is significantly higher than on SYO-1 cells (8000 molecules/cell), as determined by Scatchard plot analysis.	('expression levels', 'MPA', (4, 21))	('FZD10', 'Gene', (25, 30))	('FZD10', 'Gene', '11211', (25, 30))	('higher', 'PosReg', (98, 104))	('SYO-1', 'Gene', '55027', (113, 118))	('350,000', 'Var', (57, 64))	('SYO-1', 'Gene', (113, 118))
254667	30583594	The resulting radioactive complexes [111In]-2 and [90Y]-2 were evaluated in a first-in-human phase I study in patients with progressive advanced synovial sarcoma following a theranostic approach (Figure 1).	('[111In]-2', 'Var', (36, 45))	('human', 'Species', '9606', (87, 92))	('[90Y]-2', 'Var', (50, 57))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (145, 161))	('synovial sarcoma', 'Disease', 'MESH:D013584', (145, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('patients', 'Species', '9606', (110, 118))	('synovial sarcoma', 'Disease', (145, 161))
254675	30583594	A comparative study has demonstrated that the treatment of tumor-bearing mice with [211At]-2 (single doses of 25 and 50 microCi) suppresses the growth of SS xenografts more efficiently than the analogue beta-particle emitting antibody [90Y]-2 (50-microCi dose), without relevant toxicity.	('tumor', 'Disease', (59, 64))	('SS', 'Phenotype', 'HP:0012570', (154, 156))	('toxicity', 'Disease', 'MESH:D064420', (279, 287))	('mice', 'Species', '10090', (73, 77))	('toxicity', 'Disease', (279, 287))	('suppresses', 'NegReg', (129, 139))	('[211At]-2', 'Var', (83, 92))	('rat', 'Species', '10116', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('rat', 'Species', '10116', (31, 34))	('growth of', 'CPA', (144, 153))
254696	30583594	recently reported the two radioidinated ghrelin derivatives [131I]-5 and [131I]-6 (Figure 2).	('131I', 'Chemical', 'MESH:C000614965', (74, 78))	('131I', 'Chemical', 'MESH:C000614965', (61, 65))	('[131I]-5', 'Var', (60, 68))	('[131I]-6', 'Var', (73, 81))
254704	30583594	[K16-NODAGA(68Ga)]-4, NODAGA(68Ga)]-10 and [K16-NODAGA(68Ga)]-11 were selected because of their high potency towards GHSR-1a determined in vitro by inositol phosphate turnover assay (EC50 = 0.72, 1.91 and 1.41 nM, respectively), whereas [Nalpha-NODAGA(68Ga)]-12 was selected since no pharmacokinetic data of ghrelin inverse agonists was known to date.	('DAG', 'Chemical', '-', (50, 53))	('GHSR-1a', 'Gene', '208188', (117, 124))	('[K16-NODAGA(68Ga)]-11', 'Var', (43, 64))	('GHSR-1a', 'Gene', (117, 124))	('inositol phosphate', 'Chemical', 'MESH:D007295', (148, 166))	('DAG', 'Chemical', '-', (247, 250))	('DAG', 'Chemical', '-', (7, 10))	('NODAGA', 'Var', (22, 28))	('DAG', 'Chemical', '-', (24, 27))	('[K16-NODAGA(68Ga)]-4', 'Var', (0, 20))
254710	30583594	The binding affinity found for the metalated complex [DOTA(natGa)]-13 (IC50 = 9.1 nM) was of the same order of magnitude as for native ghrelin (IC50 = 8.1 nM).	('DOTA', 'Chemical', 'MESH:C071349', (54, 58))	('binding', 'Interaction', (4, 11))	('[DOTA', 'Var', (53, 58))
254715	30583594	performed a structure-activity study of ghrelin(1-8) in which they identified an analogue containing a fluorine-bearing aromatic prosthetic group (6-fluoro-2-naphthoic acid, PFPN), [PFPN]-14 (Figure 2) with subnanomolar binding affinity (IC50 = 0.11 nM).	('binding', 'Interaction', (220, 227))	('6-fluoro-2-naphthoic acid', 'Chemical', '-', (147, 172))	('[PFPN]-14', 'Var', (181, 190))	('PFPN', 'Chemical', '-', (174, 178))	('fluorine', 'Chemical', 'MESH:D005461', (103, 111))	('PFPN', 'Chemical', '-', (182, 186))
254717	30583594	The docking results agree with previous reported results, enhancing the importance of Glu124 at the N-terminal end as an anchor point for binding and its key role in the receptor activation.	('Glu124', 'Var', (86, 92))	('binding', 'Interaction', (138, 145))	('enhancing', 'PosReg', (58, 67))	('activation', 'PosReg', (179, 189))	('Glu124', 'Chemical', '-', (86, 92))
254722	30583594	[Flu]-15 is an agonist of GHSR-1a with in vitro binding affinity similar to that of the endogenous ghrelin (IC50 = 9.5 nM).	('Flu', 'Chemical', 'MESH:D019793', (1, 4))	('binding', 'Interaction', (48, 55))	('GHSR-1a', 'Gene', '208188', (26, 33))	('GHSR-1a', 'Gene', (26, 33))	('[Flu]-15', 'Var', (0, 8))
254740	30583594	The radiolabeled quinazoline derivatives [18F]-17, [11C]-18 and [11C]-19 have higher affinity for GHSR-1a (Ki = 16, 4, and 7 nM, respectively) than [11C]-16 (Ki = 22 nM).	('11C', 'Chemical', 'MESH:C000615233', (65, 68))	('[18F]-17', 'Var', (41, 49))	('18F', 'Chemical', 'MESH:C000615276', (42, 45))	('higher', 'PosReg', (78, 84))	('11C', 'Chemical', 'MESH:C000615233', (149, 152))	('11C', 'Chemical', 'MESH:C000615233', (52, 55))	('quinazoline', 'Chemical', 'MESH:D011799', (17, 28))	('[11C]-19', 'Var', (64, 72))	('GHSR-1a', 'Gene', '208188', (98, 105))	('affinity', 'Interaction', (85, 93))	('GHSR-1a', 'Gene', (98, 105))
254742	30583594	Instead, high levels of [18F]-17 were found in the small intestine, [11C]-18 in the liver, and [11C]-19 in the pancreas.	('pancreas', 'Disease', 'MESH:D010190', (111, 119))	('11C', 'Chemical', 'MESH:C000615233', (96, 99))	('11C', 'Chemical', 'MESH:C000615233', (69, 72))	('[18F]-17', 'Var', (24, 32))	('[11C]-19', 'Var', (95, 103))	('pancreas', 'Disease', (111, 119))	('18F', 'Chemical', 'MESH:C000615276', (25, 28))	('[11C]-18', 'Var', (68, 76))
254743	30583594	Competition assays by pretreatment with the high potent and selective GSHR-1a inhibitor YIL781 (Ki = 17 nM), demonstrated that [11C]-19 was an highly selective ligand for GSHR-1a in pancreas, which prompted the authors to claim its usefulness as a PET radiotracer for in vivo imaging of GHSR-1a in that organ.	('YIL781', 'Chemical', 'MESH:C524424', (88, 94))	('GSHR-1a', 'Gene', (171, 178))	('11C', 'Chemical', 'MESH:C000615233', (128, 131))	('pancreas', 'Disease', (182, 190))	('pancreas', 'Disease', 'MESH:D010190', (182, 190))	('rat', 'Species', '10116', (116, 119))	('GHSR-1a', 'Gene', '208188', (287, 294))	('GHSR-1a', 'Gene', (287, 294))	('[11C]-19', 'Var', (127, 135))
254745	30583594	Moreover, two lead derivatives with high binding affinities towards GHSR-1a were successfully 18F-labeled leading to the radioprobes [18F]-21 (IC50 = 20.6 nM) and [18F]-22 (IC50 = 9.3 nM; Figure 3).	('18F', 'Chemical', 'MESH:C000615276', (94, 97))	('binding', 'Interaction', (41, 48))	('GHSR-1a', 'Gene', '208188', (68, 75))	('18F', 'Chemical', 'MESH:C000615276', (164, 167))	('18F', 'Chemical', 'MESH:C000615276', (134, 137))	('[18F]-22', 'Var', (163, 171))	('[18F]-21', 'Var', (133, 141))	('GHSR-1a', 'Gene', (68, 75))
254747	30583594	Alteration in those functions may lead to various known pathophysiological conditions.	('lead to', 'Reg', (34, 41))	('rat', 'Species', '10116', (4, 7))	('Alteration', 'Var', (0, 10))
254770	30583594	The biodistribution profile of the radioiodinated analogues [125I]-37 and [125I]-38 was assessed in female ovariectomized athymic (NCr) nu/nu mice bearing GPER-expressing human endometrial Hec50 tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('endometrial', 'Disease', 'MESH:D014591', (177, 188))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('[125I]-38', 'Var', (74, 83))	('endometrial', 'Disease', (177, 188))	('125I', 'Chemical', 'MESH:C000614960', (61, 65))	('mice', 'Species', '10090', (142, 146))	('125I', 'Chemical', 'MESH:C000614960', (75, 79))	('[125I]-37', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('human', 'Species', '9606', (171, 176))
254774	30583594	The in vivo GPER-targeting properties of the radioactive complexes [99mTc]-39-[99mTc]-41 were assessed in mice bearing human endometrial and breast cancer cell xenografts.	('[99mTc]-39-[99mTc]-41', 'Var', (67, 88))	('mice', 'Species', '10090', (106, 110))	('endometrial', 'Disease', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('endometrial', 'Disease', 'MESH:D014591', (125, 136))	('breast cancer', 'Disease', (141, 154))	('GPER-targeting', 'CPA', (12, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('human', 'Species', '9606', (119, 124))
254779	30583594	The S1PR1-S1PR3 are expressed throughout the body, whereas S1PR4 is mostly found on immune cells, and S1PR5 in lymphocytes, natural killer cells, and oligodendrocytes.	('S1PR5', 'Gene', '53637', (102, 107))	('S1PR5', 'Gene', (102, 107))	('S1PR1-S1PR3', 'Var', (4, 15))
254795	30583594	The biodistribution of the 18F-labeled surrogates [18F]-49 and [18F]-50, obtained with very high radiochemical purity (>99%), was assessed in C57BL/6 wild type mice.	('[18F]-49', 'Var', (50, 58))	('[18F]-50', 'Var', (63, 71))	('mice', 'Species', '10090', (160, 164))	('18F', 'Chemical', 'MESH:C000615276', (64, 67))	('18F', 'Chemical', 'MESH:C000615276', (27, 30))	('18F', 'Chemical', 'MESH:C000615276', (51, 54))
254797	30583594	Following this pioneering work based on an S1PR agonist molecule (47), other authors also proposed fluorinated analogues of the S1PR antagonist W146 (51, Figure 6).. Those analogues presented in vitro potency (inhibition of the MAPK kinase pathway) comparable to the parent compound.	('S1PR', 'Gene', (128, 132))	('MAPK kinase pathway', 'Pathway', (228, 247))	('W146', 'Chemical', '-', (144, 148))	('analogues', 'Var', (172, 181))	('S1PR', 'Gene', '1901', (128, 132))	('S1PR', 'Gene', (43, 47))	('S1PR', 'Gene', '1901', (43, 47))
254801	30583594	Among the great variety of molecules explored, TZ3321 (52, Figure 7), a trifluoromethylphenyl-oxadiazol derived compound reported by Merck Serono, displays high binding potency for S1PR1 (IC50 = 2.13 nM), and high selectivity (IC50 > 1000 nM) for S1PR1 over S1PR2 and S1PR3.	('S1PR2', 'Gene', (258, 263))	('Serono', 'Chemical', '-', (139, 145))	('binding', 'Interaction', (161, 168))	('trifluoromethylphenyl-oxadiazol', 'Chemical', '-', (72, 103))	('TZ3321', 'Chemical', '-', (47, 53))	('S1PR2', 'Gene', '9294', (258, 263))	('S1PR1', 'Protein', (181, 186))	('TZ3321', 'Var', (47, 53))
254806	30583594	Brought together, the results allowed the authors to claim that [11C]-52 would be potentially useful for quantification of the S1PR1 expression as a biomarker of neointimal hyperplasia.	('S1PR1', 'Gene', (127, 132))	('11C', 'Chemical', 'MESH:C000615233', (65, 68))	('hyperplasia', 'Disease', (173, 184))	('[11C]-52', 'Var', (64, 72))	('hyperplasia', 'Disease', 'MESH:D006965', (173, 184))
254811	30583594	The results pointed to the conclusion that [11C]-52 could potentially be used as a PET radiotracer for monitoring early inflammatory response and the efficacy of antivascular inflammation therapy.	('vascular inflammation', 'Phenotype', 'HP:0002633', (166, 187))	('vascular inflammation', 'Disease', (166, 187))	('[11C]-52', 'Var', (43, 51))	('11C', 'Chemical', 'MESH:C000615233', (44, 47))	('vascular inflammation', 'Disease', 'MESH:D007249', (166, 187))
254816	30583594	One of the compounds of the oxadiazole family, 53 (Figure 7), emerged as the most promising due to its unprecedent potency (IC50 = 2.6 nM for S1PR1) and remarkable selectivity (>100-fold for S1PR1 versus S1PR2/S1PR3).	('S1PR2', 'Gene', '9294', (204, 209))	('oxadiazole', 'Chemical', 'MESH:D010069', (28, 38))	('S1PR2', 'Gene', (204, 209))	('S1PR1', 'Var', (191, 196))
254823	30583594	Based on these results, the authors claimed that [18F]-53 could be considered an S1PR1-specific PET tracer with high potential for in vivo imaging of this target, and allowing the quantitation of receptor expression in response to inflammation.	('[18F]-53', 'Var', (49, 57))	('inflammation', 'Disease', 'MESH:D007249', (231, 243))	('inflammation', 'Disease', (231, 243))	('18F', 'Chemical', 'MESH:C000615276', (50, 53))
254824	30583594	However, [18F]-53 was unable to penetrate the blood-brain barrier (BBB), which would preclude its use as a radiotracer for visualization of neuroinflammation in vivo.	('[18F]-53', 'Var', (9, 17))	('inflammation', 'Disease', 'MESH:D007249', (145, 157))	('inflammation', 'Disease', (145, 157))	('rat', 'Species', '10116', (37, 40))	('18F', 'Chemical', 'MESH:C000615276', (10, 13))
254831	30583594	Thus, [18F]-56 has the potential to be an efficient PET imaging tracer for visualization of S1PR1 expression in the brain.	('[18F]-56', 'Var', (6, 14))	('18F', 'Chemical', 'MESH:C000615276', (7, 10))	('S1PR1', 'Gene', (92, 97))
254890	29684152	The five-year overall survival of sarcoma patients in the discovery set was statistically significantly lower for high-chromatin entropy patients compared with low-chromatin entropy patients (27.6%, 95% confidence interval [CI] = 13.1 to 44.3, vs 57.5%, 95% CI = 49.1 to 65.1, of the patients survived for at least five years; hazard ratio [HR] = 2.13, 95% CI = 1.30 to 3.49).	('sarcoma', 'Disease', (34, 41))	('patients', 'Species', '9606', (284, 292))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('patients', 'Species', '9606', (137, 145))	('lower', 'NegReg', (104, 109))	('patients', 'Species', '9606', (182, 190))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('patients', 'Species', '9606', (42, 50))	('high-chromatin entropy', 'Var', (114, 136))
254896	29684152	The recurrence rate of ovarian cancer was statistically significantly higher for high-chromatin entropy patients compared with low-chromatin entropy patients (HR = 2.91, 95% CI = 1.74 to 4.88; 55.6%, 95% CI = 40.4% to 72.0%, vs 24.9%, 95% CI = 19.6% to 31.4%, of the patients relapsed within ten years) (Figure 2C).	('high-chromatin entropy', 'Var', (81, 103))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (267, 275))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ovarian cancer', 'Disease', (23, 37))	('patients', 'Species', '9606', (104, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('higher', 'PosReg', (70, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))
254897	29684152	Among patients classified as high risk by stage and grade, the time to recurrence was statistically significantly shorter for high-chromatin entropy patients compared with low-chromatin entropy patients (ten-year time to recurrence was 36.7%, 95% CI = 20.1% to 53.4%, vs 57.2%, 95% CI = 47.0% to 66.2%) (Figure 4B).	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (194, 202))	('high-chromatin entropy', 'Var', (126, 148))	('shorter', 'NegReg', (114, 121))	('patients', 'Species', '9606', (6, 14))
254911	29684152	Within the group of patients defined as low risk by curettage histology, high-chromatin entropy patients had a statistically significantly higher risk for cancer-specific death compared with low-chromatin entropy patients.	('death', 'Disease', 'MESH:D003643', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('death', 'Disease', (171, 176))	('higher', 'PosReg', (139, 145))	('patients', 'Species', '9606', (20, 28))	('high-chromatin entropy', 'Var', (73, 95))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
254923	29684152	The proportions of gynecological cancer patients classified as aneuploid are relatively large compared with the small subgroups of patients classified as high chromatin entropy.	('patients', 'Species', '9606', (131, 139))	('aneuploid', 'Var', (63, 72))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
254970	30149610	BCOR expression is a highly sensitive marker to identify HG-ESS with the YWHAE-NUTM2 fusion and BCOR internal tandem duplication (ITD), as well as a subset of BCOR-rearranged HG-ESS.	('BCOR', 'Gene', '54880', (0, 4))	('YWHAE', 'Gene', '7531', (73, 78))	('BCOR', 'Gene', '54880', (96, 100))	('BCOR', 'Gene', (159, 163))	('BCOR', 'Gene', '54880', (159, 163))	('YWHAE', 'Gene', (73, 78))	('internal tandem duplication', 'Var', (101, 128))	('BCOR', 'Gene', (96, 100))	('BCOR', 'Gene', (0, 4))
254971	30149610	ESS tumors are generally characterized by recurrent chromosomal translocations, both in LG-ESS and HG-ESS.	('chromosomal translocations', 'Var', (52, 78))	('ESS tumors', 'Disease', 'MESH:D009369', (0, 10))	('LG-ESS', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('ESS tumors', 'Disease', (0, 10))	('HG-ESS', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('LG-ESS', 'Chemical', '-', (88, 94))
254972	30149610	Table 2 shows a summary of the translocations described to date in ESS tumors.	('ESS tumors', 'Disease', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ESS tumors', 'Disease', 'MESH:D009369', (67, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('translocations', 'Var', (31, 45))
254984	30149610	While ESS-specific translocations aid in the correct diagnosis and can serve as a prognostic indicator, they also constitute ideal targets for (immuno)therapy.	('translocations', 'Var', (19, 33))	('aid', 'Gene', (34, 37))	('aid', 'Gene', '57379', (34, 37))
254985	30149610	Fusion proteins arising from chromosomal translocations represent potent tumor antigens because: (1) they are tumor-specific, (2) they are not expressed in normal tissues so there will not be peripheral tolerance towards them, (3) many of these breakpoints are shared by several patients, and (4) they are often required for tumorigenesis so they cannot downregulated in the tumors without loss of the malignant phenotype.	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('chromosomal translocations', 'Var', (29, 55))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (375, 380))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Disease', (73, 78))	('tumors', 'Disease', (375, 381))	('tumors', 'Disease', 'MESH:D009369', (375, 381))	('patients', 'Species', '9606', (279, 287))	('tumors', 'Phenotype', 'HP:0002664', (375, 381))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
254988	30149610	To our knowledge, nothing is known about the immunogenicity of fusion proteins arising from gene translocations in ESS tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('gene translocations', 'Var', (92, 111))	('ESS tumors', 'Disease', 'MESH:D009369', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ESS tumors', 'Disease', (115, 125))
254993	30149610	The BCR-ABL fusion region antigen is presented by several HLA alleles (HLA-DRB5*0101, DRB1*1501, B*3501, and B*3503).	('DRB1', 'Gene', (86, 90))	('HLA-DRB5', 'Gene', '3127', (71, 79))	('BCR-ABL', 'Gene', '25', (4, 11))	('B*3501', 'Var', (97, 103))	('HLA-DRB5', 'Gene', (71, 79))	('B*3503', 'Var', (109, 115))	('BCR-ABL', 'Gene', (4, 11))
254995	30149610	Furthermore, the authors showed that modification of the natural epitope from PAX-FKHR resulted in an increase affinity for HLA-B7 without loss of recognition by CTL for the wild-type epitope.	('modification', 'Var', (37, 49))	('HLA-B', 'Gene', (124, 129))	('HLA-B', 'Gene', '3106', (124, 129))	('FKHR', 'Gene', (82, 86))	('increase', 'PosReg', (102, 110))	('affinity', 'MPA', (111, 119))	('FKHR', 'Gene', '2308', (82, 86))
254998	30149610	However, the modification of anchor residues results in strong CTL activation, strong CTL killing across a range of ESFT types, and adoptive transfer of these CTLs increased survival of mice bearing Ewing sarcoma xenografts.	('survival', 'CPA', (174, 182))	('activation', 'PosReg', (67, 77))	('Ewing sarcoma', 'Disease', (199, 212))	('CTL', 'MPA', (63, 66))	('modification', 'Var', (13, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('mice', 'Species', '10090', (186, 190))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (199, 212))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (199, 212))	('CTL killing', 'CPA', (86, 97))	('increased', 'PosReg', (164, 173))
255003	30149610	reported two clinical trials on the vaccination of synovial sarcoma patients with peptides from the SYT-SSX fusion protein.	('synovial sarcoma', 'Disease', 'MESH:D013584', (51, 67))	('SSX', 'Gene', '727837', (104, 107))	('SYT', 'Gene', '6760', (100, 103))	('peptides', 'Var', (82, 90))	('patients', 'Species', '9606', (68, 76))	('SSX', 'Gene', (104, 107))	('synovial sarcoma', 'Disease', (51, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('SYT', 'Gene', (100, 103))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (51, 67))
255008	30149610	In the second study, vaccination of synovial sarcoma patients was performed with peptides spanning the SYT-SSX fusion, either using native peptides or peptides modified at an HLA-A24 anchor residue, both alone or mixed with incomplete Freund's adjuvant, and followed by IFNalpha.	('modified', 'Var', (160, 168))	('IFNalpha', 'Gene', '3439', (270, 278))	('IFNalpha', 'Gene', (270, 278))	('SYT', 'Gene', (103, 106))	('patients', 'Species', '9606', (53, 61))	('HLA-A', 'Gene', '3105', (175, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('SSX', 'Gene', '727837', (107, 110))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (36, 52))	('SYT', 'Gene', '6760', (103, 106))	('synovial sarcoma', 'Disease', 'MESH:D013584', (36, 52))	('HLA-A', 'Gene', (175, 180))	('SSX', 'Gene', (107, 110))	('synovial sarcoma', 'Disease', (36, 52))
255025	30149610	In addition, it should be evaluated whether binding of the translocation breakpoint peptides to HLA molecules can be enhanced by modifying the peptides at known anchor residues that are important for binding to the different HLA molecules without losing recognition of the endogenous epitope expressed by the tumor cells.	('tumor', 'Disease', (309, 314))	('enhanced', 'PosReg', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('binding', 'Interaction', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('modifying', 'Var', (129, 138))
255038	30149610	Recurrent translocations are a frequent phenomenon in both LG-ESS and HG-ESS that contribute to their tumorigenicity.	('translocations', 'Var', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('LG-ESS', 'Chemical', '-', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
255063	27843616	Demetri et al further showed that patients with an exon 9 mutation had a significantly worse median OS than the ones with exon 11 mutations (38 vs 66 months, p=0.001); this was also depicted by the absolute numbers of the patients being alive after 10 years (32 vs 262).	('OS', 'Chemical', '-', (100, 102))	('worse', 'NegReg', (87, 92))	('exon 9 mutation', 'Var', (51, 66))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (34, 42))	('median OS', 'MPA', (93, 102))
255068	27843616	PDGFR-alpha mutations in KIT wild-type GISTs have been first described in 2003.	('mutations', 'Var', (12, 21))	('PDGFR-alpha', 'Gene', (0, 11))	('PDGFR-alpha', 'Gene', '5156', (0, 11))
255069	27843616	It has been shown that PDGFR and KIT mutations were mutually exclusive, and that GIST cells with PDGFR-alpha mutation were no different with regard to signalling cascades and progression potential as the KIT-mutated cells.	('PDGFR', 'Gene', (23, 28))	('PDGFR', 'Gene', '5159', (97, 102))	('mutation', 'Var', (109, 117))	('PDGFR', 'Gene', '5159', (23, 28))	('KIT', 'Gene', (33, 36))	('PDGFR-alpha', 'Gene', (97, 108))	('PDGFR-alpha', 'Gene', '5156', (97, 108))	('PDGFR', 'Gene', (97, 102))
255074	27843616	This finding was in concordance with previous studies which tested the in vitro sensitivity of PDGFR-alpha mutated GIST cells to imatinib and this led to the development of D842V-specific inhibitors.	('D842V-specific', 'Var', (173, 187))	('PDGFR-alpha', 'Gene', (95, 106))	('imatinib', 'Chemical', 'MESH:D000068877', (129, 137))	('D842V', 'Mutation', 'rs121908585', (173, 178))	('PDGFR-alpha', 'Gene', '5156', (95, 106))
255077	27843616	Inherently resistant are mostly the cells with specific mutations (as the PDGFRA-D842V) or with activation of other signalling cascades (as the ones with BRAF/RAS mutations or insulin-like growth factor 1 receptor (IGF1-R) expression).	('IGF1-R', 'Gene', '3480', (215, 221))	('mutations', 'Var', (163, 172))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (176, 213))	('BRAF', 'Gene', '673', (154, 158))	('BRAF', 'Gene', (154, 158))	('insulin-like growth factor 1 receptor', 'Gene', (176, 213))	('D842V', 'Mutation', 'rs121908585', (81, 86))	('PDGFRA', 'Gene', '5156', (74, 80))	('IGF1-R', 'Gene', (215, 221))	('PDGFRA', 'Gene', (74, 80))
255078	27843616	The most common explanation for resistance development is the selection of clones with secondary KIT or PDGFRA mutations.	('mutations', 'Var', (111, 120))	('PDGFRA', 'Gene', '5156', (104, 110))	('PDGFRA', 'Gene', (104, 110))	('KIT', 'Gene', (97, 100))
255081	27843616	Interestingly, in this study, patients with exon 9 mutations had a better outcome than those with exon 11 mutations (TTP 19 vs only 5 months).	('exon 9 mutations', 'Var', (44, 60))	('patients', 'Species', '9606', (30, 38))	('mutations', 'Var', (51, 60))
255105	27843616	Patients with exon 11 mutations showed an overall response of 9%, but the 'clinical benefit rate' (CBR) at 16 weeks, which was the primary end point of the study, reached 50%.	('Patients', 'Species', '9606', (0, 8))	("'clinical benefit rate'", 'PosReg', (74, 97))	('mutations', 'Var', (22, 31))
255109	27843616	Nilotinib is another TKI with promising activity in imatinib-resistant GIST patients, and this is mostly due to its ability to inhibit in vitro certain mutations of KIT that are imatinib-resistant.	('patients', 'Species', '9606', (76, 84))	('imatinib', 'Chemical', 'MESH:D000068877', (52, 60))	('mutations', 'Var', (152, 161))	('Nilotinib', 'Chemical', 'MESH:C498826', (0, 9))	('inhibit', 'NegReg', (127, 134))	('activity', 'MPA', (40, 48))	('imatinib', 'Chemical', 'MESH:D000068877', (178, 186))	('KIT', 'Gene', (165, 168))
255115	27843616	Objective response was also higher with imatinib than with nilotinib.	('nilotinib', 'Chemical', 'MESH:C498826', (59, 68))	('imatinib', 'Var', (40, 48))	('Objective', 'MPA', (0, 9))	('higher', 'PosReg', (28, 34))	('imatinib', 'Chemical', 'MESH:D000068877', (40, 48))
255124	27843616	For PDGFR:a mutated GIST imatinib remains an acceptable option.	('imatinib', 'Chemical', 'MESH:D000068877', (25, 33))	('PDGFR:a', 'Gene', (4, 11))	('mutated', 'Var', (12, 19))	('PDGFR:a', 'Gene', '5156', (4, 11))
255174	27843616	Median PFS was significantly longer in the aldoxorubicin arm (8.4 vs 4.7 months, p=0.0002), and so was the overall RR (24% vs 5.3%).	('aldoxorubicin a', 'Chemical', '-', (43, 58))	('longer', 'PosReg', (29, 35))	('PFS', 'MPA', (7, 10))	('aldoxorubicin', 'Var', (43, 56))
255209	27843616	Immunotherapy constantly gains significance in the fight against cancer as treatment with antibodies against the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1) antigens, both expressed on the T-lymphocytes and serving as 'brakes' in our immune system, led to a significant increase in RR, PFS, and OS of melanoma patients (reviewed by Ascierto et al).	('PFS', 'Disease', (330, 333))	('OS of melanoma', 'Disease', (339, 353))	('patients', 'Species', '9606', (354, 362))	('melanoma', 'Phenotype', 'HP:0002861', (345, 353))	('PD-1', 'Gene', (195, 199))	('increase', 'PosReg', (314, 322))	('cytotoxic T-lymphocyte-associated protein-4', 'Gene', '1493', (113, 156))	('CTLA-4', 'Gene', '1493', (158, 164))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('OS of melanoma', 'Disease', 'MESH:C567932', (339, 353))	('CTLA-4', 'Gene', (158, 164))	('antibodies', 'Var', (90, 100))	('cytotoxic T-lymphocyte-associated protein-4', 'Gene', (113, 156))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
255301	21575861	Further, we identify alterations including overexpression or gene amplification of Wnt ligands and/or LRP5/6 co-receptors, epigenetic silencing of different cell surface Wnt antagonists in autocrine and mutations in adenomatous polyposis coli (APC) gene in two non-autocrine Wnt positive sarcoma cell lines.	('LRP5/6', 'Gene', '4041;4040', (102, 108))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (216, 242))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (216, 242))	('APC', 'Phenotype', 'HP:0005227', (244, 247))	('APC', 'Gene', (244, 247))	('overexpression', 'PosReg', (43, 57))	('sarcoma', 'Disease', 'MESH:D012509', (288, 295))	('adenomatous polyposis coli', 'Disease', (216, 242))	('gene', 'MPA', (61, 65))	('APC', 'Gene', '324', (244, 247))	('sarcoma', 'Disease', (288, 295))	('mutations', 'Var', (203, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('epigenetic silencing', 'Var', (123, 143))	('LRP5/6', 'Gene', (102, 108))
255307	21575861	Canonical Wnts activate a cell surface receptor complex consisting low-density lipoprotein receptor-related proteins (LRP) 5 and 6 and Frizzled (Fz) leading to inactivation of a beta-catenin degradation complex containing Adenomatous Polyposis Coli (APC), Axin and glycogen synthase kinase 3 (GSK3) beta, which otherwise targets beta-catenin for proteosomal degradation.	('beta-catenin', 'Gene', '1499', (178, 190))	('Axin', 'Gene', (256, 260))	('APC', 'Gene', '324', (250, 253))	('Adenomatous Polyposis Coli', 'Phenotype', 'HP:0005227', (222, 248))	('inactivation', 'MPA', (160, 172))	('glycogen synthase kinase 3 (GSK3) beta', 'Gene', '2932', (265, 303))	('beta-catenin', 'Gene', (178, 190))	('Axin', 'Gene', '8312', (256, 260))	('beta-catenin', 'Gene', (329, 341))	('APC', 'Phenotype', 'HP:0005227', (250, 253))	('APC', 'Gene', (250, 253))	('low-density', 'Var', (67, 78))	('beta-catenin', 'Gene', '1499', (329, 341))	('Adenomatous Polyposis Coli', 'Disease', (222, 248))	('Adenomatous Polyposis Coli', 'Disease', 'MESH:D011125', (222, 248))
255311	21575861	DKKs bind to LRP5/6 and inhibit Wnt canonical signaling.	('LRP5/6', 'Gene', '4041;4040', (13, 19))	('Wnt canonical signaling', 'Pathway', (32, 55))	('bind', 'Interaction', (5, 9))	('inhibit', 'NegReg', (24, 31))	('DKKs', 'Var', (0, 4))	('LRP5/6', 'Gene', (13, 19))
255314	21575861	Carcinomas that arise in these same tissues often exhibit aberrant Wnt pathway activation by mechanisms such as mutations of APC, CTNNB1 or AXIN and more recently through autocrine Wnt activation.	('AXIN', 'Gene', (140, 144))	('Carcinomas', 'Disease', (0, 10))	('AXIN', 'Gene', '8312', (140, 144))	('Carcinomas', 'Phenotype', 'HP:0030731', (0, 10))	('mutations', 'Var', (112, 121))	('CTNNB1', 'Gene', '1499', (130, 136))	('APC', 'Phenotype', 'HP:0005227', (125, 128))	('APC', 'Gene', (125, 128))	('activation', 'PosReg', (79, 89))	('Carcinomas', 'Disease', 'MESH:D002277', (0, 10))	('Wnt pathway', 'Pathway', (67, 78))	('APC', 'Gene', '324', (125, 128))	('CTNNB1', 'Gene', (130, 136))
255334	21575861	We then searched the Sanger Institute database on somatic mutations in cell lines and found that SK-UT-1 had been identified as having heterozygous APC mutations, consistent with our results of immunoblot analysis.	('APC', 'Gene', '324', (148, 151))	('mutations', 'Var', (152, 161))	('APC', 'Phenotype', 'HP:0005227', (148, 151))	('APC', 'Gene', (148, 151))	('SK-UT-1', 'Gene', (97, 104))
255335	21575861	We confirmed these mutations by sequence analysis (data not shown) and identified an insertion of "G" base at 4790_4791, resulting in an amino acid substitution of Alanine to Glycine and the generation of a premature stop codon in A2984 sarcoma line (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('Alanine', 'Chemical', 'MESH:D000409', (164, 171))	('substitution', 'Var', (148, 160))	('Alanine', 'MPA', (164, 171))	('Glycine', 'Chemical', 'MESH:D005998', (175, 182))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('sarcoma', 'Disease', (237, 244))	('premature stop codon', 'MPA', (207, 227))
255351	21575861	When the CDC25A reporter was co-transfected with a constitutively activated S33Y beta-catenin in HEK293T cells, we observed a dose dependent increase in reporter activity (Fig.	('HEK293T', 'CellLine', 'CVCL:0063', (97, 104))	('beta-catenin', 'Gene', '1499', (81, 93))	('S33Y', 'Var', (76, 80))	('reporter activity', 'MPA', (153, 170))	('increase', 'PosReg', (141, 149))	('S33Y', 'Mutation', 'rs121913400', (76, 80))	('beta-catenin', 'Gene', (81, 93))
255352	21575861	Moreover, the observed CDC25A promoter activity was inhibited when the putative TCFB sites (DeltaTCFB) in the CDC25A promoter were mutated (Fig.	('TCFB', 'Chemical', '-', (80, 84))	('CDC25A', 'Enzyme', (23, 29))	('TCFB', 'Chemical', '-', (97, 101))	('mutated', 'Var', (131, 138))	('DeltaTCFB', 'Chemical', '-', (92, 101))	('inhibited', 'NegReg', (52, 61))
255353	21575861	To address the biological significance of upregulated Wnt signaling in human sarcoma cells, we transduced tumor lines representing four distinct sarcoma subtypes exhibiting either autocrine Wnt activation or APC truncation mutations, with a constitutive dnTCF4 lentivirus.	('sarcoma', 'Disease', (145, 152))	('APC', 'Gene', '324', (208, 211))	('human', 'Species', '9606', (71, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('sarcoma', 'Disease', (77, 84))	('dnTCF4', 'Chemical', '-', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('APC', 'Phenotype', 'HP:0005227', (208, 211))	('APC', 'Gene', (208, 211))	('truncation mutations', 'Var', (212, 232))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('tumor', 'Disease', (106, 111))
255358	21575861	We also tested the effects of shRNA knockdown of either LRP5 or LRP6 in HOS and A204 sarcoma lines, which exhibited high levels of endogenous LRP5 and LRP6 proteins, respectively.	('tested', 'Reg', (8, 14))	('HOS', 'Disease', 'MESH:C535326', (72, 75))	('LRP5', 'Gene', '4041', (56, 60))	('LRP5', 'Gene', (142, 146))	('LRP5', 'Gene', (56, 60))	('LRP6', 'Gene', (151, 155))	('HOS', 'Disease', (72, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('knockdown', 'Var', (36, 45))	('sarcoma lines', 'Disease', 'MESH:D012509', (85, 98))	('LRP6', 'Gene', '4040', (64, 68))	('LRP5', 'Gene', '4041', (142, 146))	('sarcoma lines', 'Disease', (85, 98))	('LRP6', 'Gene', (64, 68))	('LRP6', 'Gene', '4040', (151, 155))
255360	21575861	In addition, the ectopic expression of a constitutively active beta-catenin rescued FRP-mediated inhibitory effects of Wnt downregulation on in vitro proliferation, further confirming the involvement of the canonical Wnt pathway (Fig.	('beta-catenin', 'Gene', (63, 75))	('inhibitory effects', 'MPA', (97, 115))	('downregulation', 'NegReg', (123, 137))	('ectopic', 'Var', (17, 24))	('beta-catenin', 'Gene', '1499', (63, 75))	('FRP', 'Gene', (84, 87))	('FRP', 'Gene', '2487', (84, 87))	('rescued', 'PosReg', (76, 83))
255370	21575861	Constitutive dnTCF4 expression significantly inhibited tumor formation (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('dnTCF4', 'Gene', (13, 19))	('expression', 'Var', (20, 30))	('tumor', 'Disease', (55, 60))	('dnTCF4', 'Chemical', '-', (13, 19))	('inhibited', 'NegReg', (45, 54))
255373	21575861	Ectopic CDC25A also rescued dnTCF4 mediated inhibition of cell proliferation with several additional Wnt activated sarcoma cell lines analyzed (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('sarcoma', 'Disease', (115, 122))	('cell proliferation', 'CPA', (58, 76))	('dnTCF4', 'Gene', (28, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('inhibition', 'NegReg', (44, 54))	('Ectopic', 'Var', (0, 7))	('rescued', 'NegReg', (20, 27))	('dnTCF4', 'Chemical', '-', (28, 34))	('CDC25A', 'Gene', (8, 14))
255391	21575861	When U-2 OS and HCT116 cells were co-transfected with the mutant (DeltaTCFB)-CDC25A reporter in the presence or absence of dnTCF4, its activity was further decreased in HCT116 but not in U-2 OS cells presumably due to reduced c-MYC transcriptional function specific to the carcinoma cells (Fig.	('mutant', 'Var', (58, 64))	('DeltaTCFB', 'Chemical', '-', (66, 75))	('HCT116', 'CellLine', 'CVCL:0291', (16, 22))	('U-2 OS', 'CellLine', 'CVCL:0042', (5, 11))	('activity', 'MPA', (135, 143))	('carcinoma', 'Disease', 'MESH:D002277', (273, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('DeltaTCFB)-CDC25A', 'Gene', (66, 83))	('decreased', 'NegReg', (156, 165))	('c-MYC', 'Protein', (226, 231))	('dnTCF4', 'Chemical', '-', (123, 129))	('reduced', 'NegReg', (218, 225))	('carcinoma', 'Disease', (273, 282))	('HCT116', 'CellLine', 'CVCL:0291', (169, 175))	('U-2 OS', 'CellLine', 'CVCL:0042', (187, 193))
255400	21575861	Frequent genetic aberrations observed in sarcomas include highly specific chromosomal translocations as in the case of Ewing's-, synovial- and alveolar rhabdomyosarcomas, while osteosarcomas, commonly exhibit Rb and p53 loss of function (reviewed in).	("Ewing's", 'Disease', 'MESH:C563168', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (143, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (152, 169))	('p53', 'Gene', (216, 219))	('osteosarcoma', 'Phenotype', 'HP:0002669', (177, 189))	('osteosarcomas', 'Disease', 'MESH:D012516', (177, 190))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (143, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('sarcomas', 'Disease', (182, 190))	('osteosarcomas', 'Disease', (177, 190))	('Ewing', 'Disease', (119, 124))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('synovial-', 'Disease', (129, 138))	('alveolar rhabdomyosarcomas', 'Disease', (143, 169))	('osteosarcomas', 'Phenotype', 'HP:0002669', (177, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcomas', 'Disease', (41, 49))	('sarcomas', 'Disease', (161, 169))	('loss of function', 'NegReg', (220, 236))	('chromosomal translocations', 'Var', (74, 100))	('p53', 'Gene', '7157', (216, 219))
255404	21575861	These findings argue that genetic alterations independent of Wnt activation may mask the ability to correlate Wnt activity with stemness in sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('mask', 'NegReg', (80, 84))	('stemness in sarcomas', 'Disease', 'MESH:D012509', (128, 148))	('genetic alterations', 'Var', (26, 45))	('stemness in sarcomas', 'Disease', (128, 148))
255409	21575861	beta-catenin mutations were absent in any of the Wnt activated sarcoma cell lines screened.	('sarcoma', 'Disease', (63, 70))	('beta-catenin', 'Gene', '1499', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('mutations', 'Var', (13, 22))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('beta-catenin', 'Gene', (0, 12))
255410	21575861	However, we identified APC truncation mutations in two sarcoma lines which lacked an autocrine activation mechanism.	('sarcoma lines', 'Disease', 'MESH:D012509', (55, 68))	('APC', 'Gene', '324', (23, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcoma lines', 'Disease', (55, 68))	('APC', 'Phenotype', 'HP:0005227', (23, 26))	('APC', 'Gene', (23, 26))	('truncation mutations', 'Var', (27, 47))
255411	21575861	Of note, A2984 and SK-UT-1, like representative Wnt autocrine sarcoma lines were growth inhibited in response to dnTCF4, which had no effects on non-Wnt activated sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcoma', 'Disease', (163, 170))	('sarcoma lines', 'Disease', (62, 75))	('sarcoma lines', 'Disease', 'MESH:D012509', (62, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('dnTCF4', 'Var', (113, 119))	('dnTCF4', 'Chemical', '-', (113, 119))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('growth', 'CPA', (81, 87))	('sarcoma', 'Disease', (62, 69))
255413	21575861	Further, Wnt autocrine activation contributes as importantly to the Wnt proliferative drive as an APC mutation, previously established as the initiating step in colon tumorigenesis.	('APC', 'Phenotype', 'HP:0005227', (98, 101))	('APC', 'Gene', (98, 101))	('Wnt proliferative drive', 'MPA', (68, 91))	('colon', 'Disease', (161, 166))	('mutation', 'Var', (102, 110))	('APC', 'Gene', '324', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('colon', 'Disease', 'MESH:D015179', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
255420	21575861	In fact, we found that oncogenic alterations of Rb, p53 or Ras pathways, observed in osteosarcomas, alone or in combination resulted in progressive inhibition of the ability of hMSCs to undergo osteogenic differentiation.	('osteosarcomas', 'Disease', (85, 98))	('osteosarcomas', 'Phenotype', 'HP:0002669', (85, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('osteosarcomas', 'Disease', 'MESH:D012516', (85, 98))	('inhibition', 'NegReg', (148, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('MSC', 'Gene', '9242', (178, 181))	('alterations', 'Var', (33, 44))	('Ras pathways', 'Pathway', (59, 71))	('MSC', 'Gene', (178, 181))
255423	21575861	In a mouse model generated by loss of function of WIF1, a Wnt antagonist, there was an increased incidence of radiation induced sarcomas, and these same authors identified epigenetic silencing of WIF1 in some human osteosarcomas associated with upregulation of Wnt signaling.	('human', 'Species', '9606', (209, 214))	('loss of function', 'NegReg', (30, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('WIF1', 'Gene', '24117', (50, 54))	('sarcomas', 'Disease', 'MESH:D012509', (220, 228))	('osteosarcoma', 'Phenotype', 'HP:0002669', (215, 227))	('sarcomas', 'Phenotype', 'HP:0100242', (220, 228))	('WIF1', 'Gene', (196, 200))	('sarcomas', 'Disease', (220, 228))	('mouse', 'Species', '10090', (5, 10))	('osteosarcomas', 'Disease', 'MESH:D012516', (215, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('epigenetic silencing', 'Var', (172, 192))	('WIF1', 'Gene', (50, 54))	('WIF1', 'Gene', '24117', (196, 200))	('osteosarcomas', 'Disease', (215, 228))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcomas', 'Disease', (128, 136))	('osteosarcomas', 'Phenotype', 'HP:0002669', (215, 228))
255430	21575861	Epigenetic silencing of Wnt antagonists including FRP1, FRP2, FRP4, FRP5, DKK1 and DKK2 was identified in some sarcoma lines as well.	('FRP2', 'Gene', (56, 60))	('FRP4', 'Gene', '6424', (62, 66))	('FRP1', 'Gene', (50, 54))	('FRP2', 'Gene', '6423', (56, 60))	('FRP', 'Gene', '2487', (56, 59))	('FRP', 'Gene', (50, 53))	('sarcoma lines', 'Disease', 'MESH:D012509', (111, 124))	('FRP1', 'Gene', '6422', (50, 54))	('DKK2', 'Gene', (83, 87))	('DKK2', 'Gene', '27123', (83, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('FRP', 'Gene', '2487', (68, 71))	('FRP', 'Gene', (62, 65))	('DKK1', 'Gene', (74, 78))	('DKK1', 'Gene', '22943', (74, 78))	('FRP', 'Gene', (56, 59))	('sarcoma lines', 'Disease', (111, 124))	('FRP', 'Gene', '2487', (50, 53))	('identified', 'Reg', (92, 102))	('Epigenetic silencing', 'Var', (0, 20))	('FRP4', 'Gene', (62, 66))	('FRP', 'Gene', (68, 71))	('FRP', 'Gene', '2487', (62, 65))
255488	33076385	Sections were then incubated with the following primary antibodies: anti-pS100 (#2666, RRID:AB_2335936, mouse monoclonal, clone 4C4.9 ready to use, Ventana Medical Systems, Tucson, AZ, USA), anti-pS100 (#2133, RRID:AB_2335920, rabbit polyclonal ready to use, Ventana Medical Systems, Tucson, AZ, USA), anti-SOX10 (#760-4968 rabbit monoclonal, clone SP267, ready to use, Ventana Medical Systems, Tucson, AZ, USA) anti-SOX10 (#BSB2581, rabbit monoclonal, clone EP268, ready to use, Bio SB, Santa Barbara, CA, USA), anti-TRPA1 (#ACC-037, RRID:AB_2040232, rabbit polyclonal, 1:100, Alomone Labs Ltd., Jerusalem, Israel) and anti-TRPA1 (#ab58844, RRID:AB_945957, rabbit polyclonal, 1:500, Abcam, Cambridge, UK) and anti-SNAIL+SLUG (#ab180714, RRID: AB 2728773, rabbit polyclonal, 1:500, Abcam Cambridge, UK).	('SOX10', 'Gene', (307, 312))	('SNAIL', 'Gene', (715, 720))	('SNAIL', 'Gene', '6615', (715, 720))	('SOX10', 'Gene', (417, 422))	('SOX10', 'Gene', '6663', (307, 312))	('SOX10', 'Gene', '6663', (417, 422))	('S100', 'Gene', '6271', (74, 78))	('S100', 'Gene', '6271', (197, 201))	('SLUG', 'Gene', '6591', (721, 725))	('anti-TRPA1', 'Gene', (620, 630))	('#ab58844', 'Var', (632, 640))	('SLUG', 'Gene', (721, 725))	('#ab180714', 'Var', (727, 736))	('S100', 'Gene', (74, 78))	('S100', 'Gene', (197, 201))
255602	29544549	NKX2.2 is considered the best ES marker with a sensitivity of 80% and a specificity of 84%, and so the positivity of CD99 and NKX2.2 is highly specific of ES.	('NKX2.2', 'Gene', '4821', (0, 6))	('ES', 'Chemical', 'MESH:D004540', (30, 32))	('CD99', 'Gene', '4267', (117, 121))	('NKX2.2', 'Gene', (126, 132))	('positivity', 'Var', (103, 113))	('NKX2.2', 'Gene', (0, 6))	('ES', 'Chemical', 'MESH:D004540', (155, 157))	('NKX2.2', 'Gene', '4821', (126, 132))	('CD99', 'Gene', (117, 121))
256057	29409495	PD-L1 and PD-L2 are both ligands of PD-1, and these interactions transduce co-inhibitory signals for T cell activation, suppress T cell function, which is called T cell exhaustion, and ultimately promote tumor evasion of the immune system.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('T cell', 'MPA', (129, 135))	('co-inhibitory', 'MPA', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('promote', 'PosReg', (196, 203))	('suppress', 'NegReg', (120, 128))	('tumor', 'Disease', (204, 209))	('interactions', 'Var', (52, 64))	('suppress T cell function', 'Phenotype', 'HP:0005435', (120, 144))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (162, 179))	('PD-1', 'Gene', (36, 40))	('PD-1', 'Gene', '5133', (36, 40))
256071	29409495	Among them, the SS1501 TMA included chronic synovitis (9 cases), giant cell tumor (14 cases), and synovial sarcoma (127 cases); the OS803 TMA included 27 cases of chondrosarcoma.	('SS1501', 'Var', (16, 22))	('chondrosarcoma', 'Disease', 'MESH:D002813', (163, 177))	('synovitis', 'Phenotype', 'HP:0100769', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('OS', 'Chemical', '-', (132, 134))	('synovitis', 'Disease', (44, 53))	('synovial sarcoma', 'Disease', (98, 114))	('chondrosarcoma', 'Disease', (163, 177))	('giant cell tumor', 'Disease', 'MESH:D005870', (65, 81))	('giant cell tumor', 'Phenotype', 'HP:0011847', (65, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('synovitis', 'Disease', 'MESH:D013585', (44, 53))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (98, 114))	('synovial sarcoma', 'Disease', 'MESH:D013584', (98, 114))	('SS1501', 'Mutation', 'SS1501', (16, 22))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (163, 177))	('giant cell tumor', 'Disease', (65, 81))
256085	29409495	The single-cell suspensions isolated from the mouse tumors were similarly examined for human lymphocyte infiltration by flow cytometry, and the fluorescent antibodies included APC-mouse CD45 (BioLegend, cat#103112), PE-human CD45, PerCP-human CD3, FITC-human CD4, and PE-human CD8a (cat#555483, 347344, 561005, and 340046; BD Pharmingen).	('561005', 'Var', (303, 309))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('human', 'Species', '9606', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('347344', 'Var', (295, 301))	('human', 'Species', '9606', (237, 242))	('CD8a', 'Gene', '925', (277, 281))	('human', 'Species', '9606', (87, 92))	('human', 'Species', '9606', (271, 276))	('tumors', 'Disease', (52, 58))	('mouse', 'Species', '10090', (46, 51))	('mouse', 'Species', '10090', (180, 185))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('340046', 'Var', (315, 321))	('human', 'Species', '9606', (253, 258))	('FITC', 'Chemical', 'MESH:D016650', (248, 252))	('CD8a', 'Gene', (277, 281))
256089	29409495	Antibodies for IHC against PD-L1 (M442) and PD-1 (M569) were purchased from Spring Bioscience.	('PD-1', 'Gene', (44, 48))	('M569', 'CellLine', 'CVCL:AC43', (50, 54))	('M442', 'Var', (34, 38))	('PD-1', 'Gene', '5133', (44, 48))
256133	29409495	Furthermore, we analyzed the survival curve of 62 osteosarcoma TMA patients, and high expression of PD-L1 significantly predicted a short OS time (P = 0.017).	('patients', 'Species', '9606', (67, 75))	('high', 'Var', (81, 85))	('short OS time', 'Disease', (132, 145))	('OS', 'Chemical', '-', (138, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('osteosarcoma TMA', 'Disease', 'MESH:D012516', (50, 66))	('osteosarcoma TMA', 'Disease', (50, 66))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('PD-L1', 'Gene', (100, 105))	('predicted', 'Reg', (120, 129))
256140	29409495	Considering the independent negative prognostic roles of PD-L1 and PD-1, we further divided the patients into three groups on the basis of PD-L1 and PD-1 expression to correlate the combined expression of PD-L1 and PD-1 with OS as follows: (I) positivity for both PD-L1 and PD-1 (n = 10), (II) positivity for either PD-L1 or PD-1 (n = 19), and (III) negativity for both PD-L1 and PD-1 (n = 33).	('positivity', 'Var', (294, 304))	('PD-1', 'Gene', (67, 71))	('PD-1', 'Gene', '5133', (274, 278))	('PD-1', 'Gene', '5133', (67, 71))	('PD-1', 'Gene', (325, 329))	('PD-1', 'Gene', '5133', (325, 329))	('PD-1', 'Gene', (380, 384))	('positivity', 'Var', (244, 254))	('PD-1', 'Gene', '5133', (380, 384))	('PD-L1', 'Gene', (264, 269))	('patients', 'Species', '9606', (96, 104))	('PD-1', 'Gene', (149, 153))	('OS', 'Chemical', '-', (225, 227))	('PD-L1', 'Gene', (316, 321))	('PD-1', 'Gene', '5133', (149, 153))	('PD-1', 'Gene', (215, 219))	('PD-1', 'Gene', (274, 278))	('PD-1', 'Gene', '5133', (215, 219))
256151	29409495	Figure 3b shows the heat map visualization of the top 100 differentially expressed genes between the PD-1 high-expression group and the PD-1 low-expression group (top 10 versus bottom 10 samples).	('PD-1', 'Gene', (136, 140))	('differentially', 'MPA', (58, 72))	('PD-1', 'Gene', '5133', (136, 140))	('PD-1', 'Gene', (101, 105))	('high-expression', 'Var', (106, 121))	('PD-1', 'Gene', '5133', (101, 105))
256172	29409495	These data reveal that nivolumab enhances tumor lymphocyte infiltration and the cytolytic activity of CD8 lymphocytes in lung metastases, which may be the mechanism by which nivolumab inhibits lung metastasis.	('lung metastases', 'Disease', 'MESH:D009362', (121, 136))	('cytolytic activity of', 'CPA', (80, 101))	('lung metastasis', 'CPA', (193, 208))	('tumor', 'Disease', (42, 47))	('CD8', 'Gene', (102, 105))	('nivolumab', 'Chemical', 'MESH:D000077594', (23, 32))	('enhances', 'PosReg', (33, 41))	('CD8', 'Gene', '925', (102, 105))	('nivolumab', 'Chemical', 'MESH:D000077594', (174, 183))	('inhibits', 'NegReg', (184, 192))	('nivolumab', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('lung metastases', 'Disease', (121, 136))
256175	29409495	Several studies have shown that inhibition of the PD-1 axis restores and enhances the immune response in vitro and in vivo.	('inhibition', 'Var', (32, 42))	('restores', 'PosReg', (60, 68))	('immune response', 'CPA', (86, 101))	('PD-1', 'Gene', (50, 54))	('PD-1', 'Gene', '5133', (50, 54))	('enhances', 'PosReg', (73, 81))
256190	29409495	As mentioned above, we detected high levels of PD-L1, PD-L2, and PD-1 expressions in GCT for the first time.	('PD-L1', 'Var', (47, 52))	('PD-L2', 'Gene', (54, 59))	('GCT', 'Gene', (85, 88))	('PD-1', 'Gene', (65, 69))	('PD-1', 'Gene', '5133', (65, 69))	('GCT', 'Gene', '25797', (85, 88))
256201	29409495	The PD-L1-associated poor prognosis may due to immune suppression, cisplatin resistance, and metastasis-related pathway activation, whereas PD-L2 may slow osteosarcoma progression by repressing DNA repair, stem cell-related pathways, and doxorubicin resistance.	('stem', 'CPA', (206, 210))	('PD-L2', 'Var', (140, 145))	('immune', 'MPA', (47, 53))	('repressing', 'PosReg', (183, 193))	('osteosarcoma', 'Phenotype', 'HP:0002669', (155, 167))	('slow', 'NegReg', (150, 154))	('metastasis-related pathway', 'Pathway', (93, 119))	('activation', 'PosReg', (120, 130))	('PD-L1-associated', 'Gene', (4, 20))	('osteosarcoma', 'Disease', (155, 167))	('osteosarcoma', 'Disease', 'MESH:D012516', (155, 167))	('cisplatin resistance', 'MPA', (67, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('doxorubicin resistance', 'MPA', (238, 260))	('DNA repair', 'MPA', (194, 204))	('doxorubicin', 'Chemical', 'MESH:D004317', (238, 249))
256211	29409495	One reason suggested by the authors was that the PD-1/PD-L1 axis mediated inherent functions in the tumor cells and that the PD-1/PD-L1 blockade may have affected the tumor cell-intrinsic signaling network and subsequently enhanced tumor growth or progression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('blockade', 'Var', (136, 144))	('tumor', 'Disease', (100, 105))	('PD-1', 'Gene', (49, 53))	('enhanced', 'PosReg', (223, 231))	('affected', 'Reg', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('PD-1', 'Gene', '5133', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('PD-1', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('PD-1', 'Gene', '5133', (125, 129))	('tumor', 'Disease', (232, 237))	('progression', 'CPA', (248, 259))	('tumor', 'Disease', (167, 172))
256399	26380804	An Ewing sarcoma breakpoint region 1 gene 22q12 rearrangement was proven by a two-color fluorescence in situ hybridization assay.	('rearrangement', 'Var', (48, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma breakpoint region 1', 'Gene', (3, 36))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (3, 36))
256431	26380804	However, recent advances of genetic investigation revealed that Ewing's sarcoma and pPNET showed the same chromosomal translocations as t(11;22)(q24;q12), and both were classified into the same category of ESFTs by the World Health Organization Classification in 2002.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (64, 79))	('t(11;22)(q24;q12', 'Var', (136, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('pPNET', 'Phenotype', 'HP:0030067', (84, 89))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (136, 153))	('pPNET', 'Gene', (84, 89))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (64, 79))	("Ewing's sarcoma", 'Disease', (64, 79))
256440	26380804	reported the radiographic characteristics of these tumors precisely, in which typical cases showed as isodense or hypodense on unenhanced CT, isointense on T1WI, and either isointense or hyperintense on T2WI as revealed by MRI.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('T1WI', 'MPA', (156, 160))	('isodense', 'MPA', (102, 110))	('hypodense', 'MPA', (114, 123))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('hyperintense', 'Var', (187, 199))	('isointense', 'Var', (142, 152))	('isointense', 'Var', (173, 183))
256444	26380804	reported that PNET showed a low level of SUV, and the detection sensitivity of FDG-PET was lower than that of helical CT.	('lower', 'NegReg', (91, 96))	('FDG', 'Chemical', 'MESH:D019788', (79, 82))	('detection sensitivity', 'MPA', (54, 75))	('FDG-PET', 'Var', (79, 86))
256453	26380804	Chromosomal translocations encoding transcription factors result in the production of chimeric proteins that are involved in tumorigenesis.	('production of chimeric proteins', 'MPA', (72, 103))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Chromosomal translocations', 'Var', (0, 26))	('tumor', 'Disease', (125, 130))	('result in', 'Reg', (58, 67))
256456	26380804	The interphase FISH method using Ewing sarcoma breakpoint region 1 (EWSR1) dual-color, break-apart probes is sensitive and specific for the detection of rearrangement of the EWS gene on chromosome 22q12, although the probes specifically identify t(22q12) but cannot specifically identify the translocation partners.	('Ewing sarcoma breakpoint region 1', 'Gene', (33, 66))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (33, 66))	('EWSR1', 'Gene', '2130', (68, 73))	('t(22q12', 'Var', (246, 253))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (33, 46))	('EWS', 'Gene', '2130', (174, 177))	('EWS', 'Gene', (68, 71))	('EWS', 'Gene', (174, 177))	('rearrangement', 'Var', (153, 166))	('EWS', 'Gene', '2130', (68, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('EWSR1', 'Gene', (68, 73))
256498	24282276	Inhibiting BMC differentiation into pericytes resulted in smaller tumor vessels with tiny lumens, decreased tumor blood vessel perfusion, and increased tumor cell apoptosis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('smaller', 'NegReg', (58, 65))	('Inhibiting', 'Var', (0, 10))	('increased', 'PosReg', (142, 151))	('tiny lumens', 'Phenotype', 'HP:0005486', (85, 96))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', (108, 113))	('decreased tumor', 'Disease', 'MESH:D009369', (98, 113))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('decreased tumor', 'Disease', (98, 113))
256499	24282276	Furthermore, we confirmed that disrupting the SDF-1alpha/CXCR4 axis decreased PDGF-B protein expression in the tumor microenvironment.	('decreased', 'NegReg', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('disrupting', 'Var', (31, 41))	('tumor', 'Disease', (111, 116))	('expression', 'MPA', (93, 103))	('PDGF-B', 'Gene', (78, 84))	('PDGF-B', 'Gene', '18591', (78, 84))
256500	24282276	We are first to demonstrate that SDF-1alpha modulates the expression of PDGF-B in the tumor microenvironment and that blocking this pathway affects the tumor vasculature.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('PDGF-B', 'Gene', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('modulates', 'Reg', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (86, 91))	('expression', 'MPA', (58, 68))	('PDGF-B', 'Gene', '18591', (72, 78))	('tumor', 'Disease', (152, 157))	('affects', 'Reg', (140, 147))	('blocking', 'Var', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
256538	24282276	There was a 79 % and 74 % decrease in desmin+ BM-derived pericytes and a 74 % and 73% decrease in NG2+ BM-derived pericytes in TC71 and A4573 tumors from AMD 3100 treated mice, respectively, compared to the tumors from PBS treated mice.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('desmin', 'Gene', (38, 44))	('desmin', 'Gene', '13346', (38, 44))	('TC71', 'Gene', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', (207, 213))	('decrease', 'NegReg', (86, 94))	('mice', 'Species', '10090', (171, 175))	('AMD', 'Disease', 'MESH:D006009', (154, 157))	('tumors', 'Disease', (142, 148))	('NG2', 'Gene', (98, 101))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('A4573', 'Var', (136, 141))	('NG2', 'Gene', '121021', (98, 101))	('AMD', 'Disease', (154, 157))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('mice', 'Species', '10090', (231, 235))	('decrease', 'NegReg', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))
256552	24282276	The total microvessel density was reduced by 50 % and 55 % in TC71 and A4573 tumors, respectively, compared with those from the PBS treated mice (Fig.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('reduced', 'NegReg', (34, 41))	('mice', 'Species', '10090', (140, 144))	('microvessel density', 'CPA', (10, 29))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TC71', 'Gene', (62, 66))	('A4573', 'Var', (71, 76))
256561	24282276	We previously demonstrated that vasculogenesis is essential for the expansion of Ewing's sarcoma tumor vasculature and that inhibiting this process, inhibits tumor growth.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	("Ewing's sarcoma tumor", 'Disease', (81, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	("Ewing's sarcoma tumor", 'Disease', 'MESH:C563168', (81, 102))	('inhibiting', 'Var', (124, 134))	('tumor', 'Disease', (97, 102))	('inhibits', 'NegReg', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (81, 96))
256565	24282276	We found that disrupting the SDF-1alpha/CXCR4 axis by blocking CXCR4 with the AMD 3100 antagonist downregulated PDGF-B protein expression, inhibited BM-derived pericyte differentiation, and decreased the total number of tumor vessel pericytes.	('downregulated', 'NegReg', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('expression', 'MPA', (127, 137))	('tumor', 'Disease', (220, 225))	('blocking CXCR4', 'MPA', (54, 68))	('AMD', 'Disease', 'MESH:D006009', (78, 81))	('disrupting', 'Var', (14, 24))	('PDGF-B', 'Gene', (112, 118))	('AMD', 'Disease', (78, 81))	('BM-derived pericyte differentiation', 'CPA', (149, 184))	('decreased', 'NegReg', (190, 199))	('PDGF-B', 'Gene', '18591', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('inhibited', 'NegReg', (139, 148))
256571	24282276	There was also decreased microvessel density and increased tumor cell apoptosis demonstrating that the tumor vascular integrity and blood flow had been compromised in response to blocking CXCR4 leading to tumor cell death.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', (103, 108))	('microvessel density', 'CPA', (25, 44))	('blocking', 'Var', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('decreased', 'NegReg', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
256575	24282276	The SDF-1alpha-treated tumors had a huge increase in the perivascular layer, even more than that seen in the wild type TC71 tumors.	('tumors', 'Disease', (23, 29))	('SDF-1alpha-treated', 'Var', (4, 22))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('perivascular layer', 'CPA', (57, 75))	('tumors', 'Disease', (124, 130))	('TC71 tumors', 'Disease', (119, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('TC71 tumors', 'Disease', 'MESH:D009369', (119, 130))	('increase', 'PosReg', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
256577	24282276	On the other hand, CXCR7 has been shown to be preferentially expressed by transformed cells and during embryonic development to confer cell growth and survival advantages, and to increase adhesiveness of cells.	('embryonic', 'Disease', (103, 112))	('CXCR7', 'Var', (19, 24))	('survival advantages', 'CPA', (151, 170))	('cell growth', 'CPA', (135, 146))	('embryonic', 'Disease', 'MESH:D009373', (103, 112))	('increase', 'PosReg', (179, 187))	('adhesiveness of cells', 'CPA', (188, 209))
256586	24282276	These data confirm a correlation between SDF-1alpha and the production of PDGF-B in the tumor microenvironment and suggest that SDF-1alpha induces BM-derived pericyte differentiation by upregulating PDGF-B.	('PDGF-B', 'Gene', '18591', (199, 205))	('BM-derived pericyte differentiation', 'CPA', (147, 182))	('PDGF-B', 'Gene', '18591', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('PDGF-B', 'Gene', (74, 80))	('induces', 'PosReg', (139, 146))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('upregulating', 'PosReg', (186, 198))	('PDGF-B', 'Gene', (199, 205))	('tumor', 'Disease', (88, 93))	('SDF-1alpha', 'Var', (128, 138))
256587	24282276	Pericytes appear sparse and detached from the vessel wall in tumors; however, targeting pericytes in addition to endothelial cells more efficiently reduces tumor vasculature than targeting one cell type alone.	('tumors', 'Disease', (61, 67))	('targeting', 'Var', (78, 87))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('reduces', 'NegReg', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))
256595	24282276	These findings are consistent with those of the current study and support the hypothesis that disrupting the SDF-1alpha/CXCR4 axis decreases PDGF-B expression in the tumor microenvironment, which in turn inhibits BM-derived pericyte differentiation and disrupts efficient tumor vasculature formation.	('disrupts', 'NegReg', (253, 261))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('BM-derived pericyte differentiation', 'CPA', (213, 248))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (272, 277))	('PDGF-B', 'Gene', '18591', (141, 147))	('tumor', 'Disease', (166, 171))	('decreases', 'NegReg', (131, 140))	('disrupting', 'Var', (94, 104))	('inhibits', 'NegReg', (204, 212))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('expression', 'MPA', (148, 158))	('PDGF-B', 'Gene', (141, 147))
256604	24282276	Our findings coincide with those of others showing that while targeting PDGF-B with the selective aptamer AX102 reduced tumor vascularity, it did not decrease tumor size.	('PDGF-B', 'Gene', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PDGF-B', 'Gene', '18591', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('reduced', 'NegReg', (112, 119))	('targeting', 'Var', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (120, 125))
256608	24282276	However, since vascular changes may induce hypoxia which could induce a survival response in the tumor microenvironment, future studies examining the effects of combination therapies on Ewing's sarcoma tumor vascular expansion and growth will be needed prior to translation to the clinic.	("Ewing's sarcoma tumor", 'Disease', (186, 207))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('vascular changes', 'Phenotype', 'HP:0002597', (15, 31))	('tumor', 'Disease', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('hypoxia', 'Disease', (43, 50))	('induce', 'Reg', (63, 69))	('hypoxia', 'Disease', 'MESH:D000860', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (97, 102))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (186, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('induce', 'Reg', (36, 42))	('vascular changes', 'Var', (15, 31))	("Ewing's sarcoma tumor", 'Disease', 'MESH:C563168', (186, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
256728	20442214	Current (ie, within 6 months) CD4 cell count was associated with incidence of Kaposi sarcoma among cART-treated men (rate ratios [RRs] = 18.91, 95% CI = 8.50 to 42.09, for CD4 level category <200 cells per cubic millimeter; RR = 3.55, 95% CI = 1.40 to 9.00, for 200-349 cells per cubic millimeter; and RR = 4.11, 95% CI = 1.74 to 9.70, for 350-499 cells per cubic millimeter; all compared with >=500 cells per cubic millimeter).	('to 9', 'Species', '1214577', (327, 331))	('CD4', 'Gene', (172, 175))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (78, 92))	('CD4', 'Gene', '920', (172, 175))	('to 9', 'Species', '1214577', (249, 253))	('Kaposi sarcoma', 'Disease', (78, 92))	('<200', 'Var', (191, 195))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (78, 92))	('CD4', 'Gene', (30, 33))	('men', 'Species', '9606', (112, 115))	('CD4', 'Gene', '920', (30, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
256736	20442214	Low CD4 cell count within 6 months of diagnosis (ie, current CD4 cell count) was associated with increased incidence of Kaposi sarcoma among cART-treated men.	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (120, 134))	('CD4', 'Gene', '920', (61, 64))	('CD4', 'Gene', (4, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('CD4', 'Gene', '920', (4, 7))	('Kaposi sarcoma', 'Disease', (120, 134))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (120, 134))	('men', 'Species', '9606', (154, 157))	('CD4', 'Gene', (61, 64))	('Low', 'Var', (0, 3))
256778	20442214	However, to ease the interpretation of the results, current CD4 cell count was categorized into four categories (<200, 200-349, 350-499, or >=500 cells per cubic millimeter).	('350-499', 'Var', (128, 135))	('CD4', 'Gene', (60, 63))	('CD4', 'Gene', '920', (60, 63))
256800	20442214	For simplicity, we report rates of Kaposi sarcoma by current CD4 cell level (<200, 200-349, 350-499, or >=500 cells per cubic millimeter) (Table 2).	('CD4', 'Gene', '920', (61, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('<200', 'Var', (77, 81))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (35, 49))	('350-499', 'Var', (92, 99))	('Kaposi sarcoma', 'Disease', (35, 49))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (35, 49))	('CD4', 'Gene', (61, 64))
256813	20442214	More specifically, current (ie, within 6 months) CD4 cell count was associated with crude incidence of Kaposi sarcoma among cART-treated men (RR = 18.91, 95% CI = 8.50 to 42.09, for CD4 level category <200 cells per cubic millimeter; RR = 3.55, 95% CI = 1.40 to 9.00, for 200-349 cells per cubic millimeter; and RR = 4.11, 95% CI = 1.74 to 9.70, for 350-499 cells per cubic millimeter; all compared with >=500 cells per cubic millimeter).	('CD4', 'Gene', (49, 52))	('CD4', 'Gene', '920', (182, 185))	('to 9', 'Species', '1214577', (259, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('CD4', 'Gene', '920', (49, 52))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (103, 117))	('<200', 'Var', (201, 205))	('Kaposi sarcoma', 'Disease', (103, 117))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (103, 117))	('CD4', 'Gene', (182, 185))	('men', 'Species', '9606', (137, 140))	('to 9', 'Species', '1214577', (337, 341))
256935	33526607	To improve on these encouraging results, clinical studies are now evaluating targeting different antigens (eg, receptor tyrosine kinase-like orphan receptor 2, CD133, GD-2, Muc1 and CD117) and the use of second-generation, third-generation and fourth-generation CARs (NCT03618381, NCT03356782, NCT01953900).	('CD117', 'Gene', '3815', (182, 187))	('NCT03356782', 'Var', (281, 292))	('CD117', 'Gene', (182, 187))	('receptor tyrosine kinase-like orphan receptor 2', 'Gene', (111, 158))	('CARs', 'Gene', '833', (262, 266))	('Muc1', 'Gene', (173, 177))	('Muc1', 'Gene', '4582', (173, 177))	('CD133', 'Gene', (160, 165))	('CD133', 'Gene', '8842', (160, 165))	('CARs', 'Gene', (262, 266))	('NCT03618381', 'Var', (268, 279))	('receptor tyrosine kinase-like orphan receptor 2', 'Gene', '4920', (111, 158))	('NCT01953900', 'Var', (294, 305))
256957	33526607	Another approach to DC-vaccination is to peptide-pulse DCs with a tumor antigen, forgoing the need for invasive surgical resection of tumor to isolate tumor lysates.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (66, 71))	('peptide-pulse DCs', 'Var', (41, 58))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (134, 139))
256958	33526607	One pilot study, including patients with advanced sarcoma that have progressed on standard-of-care chemotherapy and radiation (including synovial sarcoma, osteosarcoma and LPS), uses NY-ESO-1 peptide-pulsed DCs in combination with IL-2 and autologous lymphocytes tranduced with a NY-ESO-1-specific T-cell receptor, with or without CTLA-4 blockade (NCT02070406, NCT01697527).	('CTLA-4', 'Gene', '1493', (331, 337))	('synovial sarcoma', 'Disease', (137, 153))	('osteosarcoma', 'Disease', (155, 167))	('osteosarcoma', 'Disease', 'MESH:D012516', (155, 167))	('NY-ESO-1', 'Gene', (183, 191))	('NY-ESO-1', 'Gene', '246100', (280, 288))	('CTLA-4', 'Gene', (331, 337))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('synovial sarcoma', 'Disease', 'MESH:D013584', (137, 153))	('LPS', 'Disease', 'MESH:C536528', (172, 175))	('NY-ESO-1', 'Gene', '246100', (183, 191))	('patients', 'Species', '9606', (27, 35))	('IL-2', 'Gene', (231, 235))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (137, 153))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))	('NCT01697527', 'Var', (361, 372))	('NCT02070406', 'Var', (348, 359))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('osteosarcoma', 'Phenotype', 'HP:0002669', (155, 167))	('sarcoma', 'Disease', (146, 153))	('sarcoma', 'Disease', (50, 57))	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('IL-2', 'Gene', '3558', (231, 235))	('sarcoma', 'Disease', (160, 167))	('NY-ESO-1', 'Gene', (280, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('LPS', 'Disease', (172, 175))
256973	33526607	However, when evaluated as a therapeutic in a xenograft model, one dose of H-1PV did not lead to tumor regression or increased overall survival, although the lack of therapeutic effect could be attributed to insufficient dosing or owing to the use of immunodeficient mice in this study as OVs work, at least in part, by inducing antitumor immunity.	('tumor', 'Disease', (333, 338))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('inducing', 'PosReg', (320, 328))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('mice', 'Species', '10090', (267, 271))	('H-1PV', 'Var', (75, 80))
256974	33526607	Few have gained regulatory approval, such as the genetically engineered HSV-I Talimogene laherparepvec (T-VEC; Imlygic), which has specific virus attenuating mutations and encodes granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to promote anti-tumor immune responses.	('promote', 'PosReg', (250, 257))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (180, 228))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('GM-CSF', 'Gene', (230, 236))	('GM-CSF', 'Gene', '1437', (230, 236))	('tumor', 'Disease', (263, 268))	('mutations', 'Var', (158, 167))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (180, 228))
256986	33526607	Anti-tumor immunity can be promoted by antibodies targeting tumor antigens eliciting antibody-mediated or complement-mediated cytotoxicity.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cytotoxicity', 'Disease', (126, 138))	('promoted', 'PosReg', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (60, 65))	('cytotoxicity', 'Disease', 'MESH:D064420', (126, 138))	('antibodies', 'Var', (39, 49))
256989	33526607	GD2 is expressed in ~50% of osteosarcomas and STS', although with significant intratumoral heterogeneity, therefore, there is a potential of expanding the use of anti-GD2 for osteosarcoma, with clinical trials currently ongoing (NCT02502786, NCT02484443).	('STS', 'Phenotype', 'HP:0030448', (46, 49))	('tumor', 'Disease', (83, 88))	('osteosarcomas', 'Disease', (28, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('GD2', 'Chemical', '-', (167, 170))	('GD2', 'Chemical', '-', (0, 3))	('osteosarcoma', 'Phenotype', 'HP:0002669', (175, 187))	('osteosarcoma', 'Disease', (28, 40))	('osteosarcomas', 'Phenotype', 'HP:0002669', (28, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('osteosarcoma', 'Disease', (175, 187))	('osteosarcoma', 'Disease', 'MESH:D012516', (175, 187))	('anti-GD2', 'Var', (162, 170))	('osteosarcoma', 'Phenotype', 'HP:0002669', (28, 40))	('osteosarcomas', 'Disease', 'MESH:D012516', (28, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))
256995	33526607	The CD47-SIRPalpha pathway promotes tumor immune escape by inhibiting macrophage phagocytosis (do not eat me signal) and is an appealing target for immunotherapy as revealed by studies showing that: (1) an abundance of SIRPalpha in TAMs was associated with worse prognosis in patients with synovial sarcoma and myxofibrosarcoma; and (2) high expression of CD47 correlated with poor survival in osteosarcoma patients.	('patients', 'Species', '9606', (276, 284))	('SIRPalpha', 'Gene', (9, 18))	('macrophage phagocytosis', 'CPA', (70, 93))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (290, 306))	('tumor', 'Disease', (36, 41))	('CD47', 'Gene', (356, 360))	('osteosarcoma', 'Disease', (394, 406))	('osteosarcoma', 'Disease', 'MESH:D012516', (394, 406))	('promotes', 'PosReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SIRPalpha', 'Gene', '140885', (219, 228))	('inhibiting', 'NegReg', (59, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('synovial sarcoma and myxofibrosarcoma', 'Disease', 'MESH:D013584', (290, 327))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (315, 327))	('high', 'Var', (337, 341))	('SIRPalpha', 'Gene', '140885', (9, 18))	('SIRPalpha', 'Gene', (219, 228))	('patients', 'Species', '9606', (407, 415))	('osteosarcoma', 'Phenotype', 'HP:0002669', (394, 406))	('sarcoma', 'Phenotype', 'HP:0100242', (320, 327))	('sarcoma', 'Phenotype', 'HP:0100242', (399, 406))	('TAMs', 'Chemical', 'MESH:D013629', (232, 236))
257044	32476297	BRAF mutation and its inhibitors in sarcoma treatment The mitogen-activated protein kinase (MAPK) signaling pathway plays a significant role in mediating cellular physiological activities, such as proliferation, differentiation, apoptosis, and senescence.	('senescence', 'CPA', (244, 254))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('BRAF', 'Gene', '673', (0, 4))	('MAPK', 'Gene', '5594', (92, 96))	('sarcoma', 'Disease', (36, 43))	('BRAF', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('proliferation', 'CPA', (197, 210))	('differentiation', 'CPA', (212, 227))	('MAPK', 'Gene', (92, 96))	('mutation', 'Var', (5, 13))	('apoptosis', 'CPA', (229, 238))
257046	32476297	Regarding the BRAF mutation, approximately 95% of BRAF mutations belong to the BRAF V600E mutation, which can enhance the expression of the MAPK signaling pathway and is thus related to the occurrence and development of various malignant tumors and has been successfully identified as a therapeutic target.	('malignant tumors', 'Disease', (228, 244))	('expression', 'MPA', (122, 132))	('MAPK', 'Gene', (140, 144))	('BRAF', 'Gene', (50, 54))	('mutations', 'Var', (55, 64))	('V600E', 'Mutation', 'rs113488022', (84, 89))	('malignant tumors', 'Disease', 'MESH:D009369', (228, 244))	('enhance', 'PosReg', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('BRAF', 'Gene', '673', (14, 18))	('V600E', 'Var', (84, 89))	('BRAF', 'Gene', '673', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('related', 'Reg', (175, 182))	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', (79, 83))	('MAPK', 'Gene', '5594', (140, 144))	('BRAF', 'Gene', '673', (50, 54))
257048	32476297	Considering the successful use of BRAF inhibitors in melanoma, we provide a brief overview of the BRAF mutations, including their basic structures and activation mechanisms, and the new classification method for BRAF mutations.	('mutations', 'Var', (103, 112))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('BRAF', 'Gene', '673', (212, 216))	('BRAF', 'Gene', (98, 102))	('melanoma', 'Disease', (53, 61))	('BRAF', 'Gene', '673', (98, 102))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('BRAF', 'Gene', (212, 216))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))
257058	32476297	Abnormal activation of the MAPK pathway is partly caused by mutations in RAS and RAF, which changes the normal physiological activities of cells, promoting growth and differentiation and is related to the development of a variety of tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('RAF', 'Gene', (81, 84))	('activation', 'PosReg', (9, 19))	('related', 'Reg', (190, 197))	('tumors', 'Disease', (233, 239))	('MAPK', 'Gene', (27, 31))	('promoting', 'PosReg', (146, 155))	('growth', 'MPA', (156, 162))	('changes', 'Reg', (92, 99))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('RAS', 'Gene', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('RAF', 'Gene', '22882', (81, 84))	('mutations', 'Var', (60, 69))	('MAPK', 'Gene', '5594', (27, 31))
257059	32476297	For example, RAS mutation is associated with pancreatic cancer, lung cancer, and colorectal cancer, while RAF mutation can be detected in melanoma, thyroid cancer, and other malignant tumors.	('lung cancer', 'Disease', (64, 75))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('thyroid cancer', 'Disease', (148, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('RAF', 'Gene', (106, 109))	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('pancreatic cancer', 'Disease', (45, 62))	('colorectal cancer', 'Disease', (81, 98))	('mutation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('thyroid cancer', 'Disease', 'MESH:D013964', (148, 162))	('associated', 'Reg', (29, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('thyroid cancer', 'Phenotype', 'HP:0002890', (148, 162))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('RAS', 'Protein', (13, 16))	('malignant tumors', 'Disease', (174, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('malignant tumors', 'Disease', 'MESH:D009369', (174, 190))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('RAF', 'Gene', '22882', (106, 109))
257060	32476297	6  Concerning the RAF family, the BRAF mutation has attracted extensive attention due to its extensive mutation phenomenon in a variety of tumors and its higher mutation rate compared with ARAF and CRAF.	('RAF', 'Gene', '22882', (18, 21))	('RAF', 'Gene', (35, 38))	('CRAF', 'Gene', '5894', (198, 202))	('RAF', 'Gene', '22882', (199, 202))	('RAF', 'Gene', (18, 21))	('RAF', 'Gene', '22882', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('RAF', 'Gene', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('RAF', 'Gene', (190, 193))	('tumors', 'Disease', (139, 145))	('mutation', 'Var', (39, 47))	('RAF', 'Gene', '22882', (35, 38))	('BRAF', 'Gene', '673', (34, 38))	('ARAF', 'Gene', '369', (189, 193))	('CRAF', 'Gene', (198, 202))	('ARAF', 'Gene', (189, 193))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('BRAF', 'Gene', (34, 38))
257066	32476297	Since the BRAF mutation was identified in 2002, more than 50 mutations have been reported, and different tissues have different mutation frequencies 9 ,  10 (Figure 2).	('mutation', 'Var', (15, 23))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))
257067	32476297	Ninety-five percent of these mutations result from a kind of missense mutation in exon 15, that is, thymine mutates into adenosine at nucleotide 1799 (T > A), which contributes to changes in protein expression levels:valine (V) replaces glutamic acid (E) at amino acid 600.	('glutamic acid', 'MPA', (237, 250))	('changes', 'Reg', (180, 187))	('missense', 'Var', (61, 69))	('adenosine', 'Chemical', 'MESH:D000241', (121, 130))	('protein expression levels', 'MPA', (191, 216))	('1799 (T > A)', 'Mutation', 'rs113488022', (145, 157))	('mutations', 'Var', (29, 38))	('valine', 'Chemical', 'MESH:D014633', (217, 223))	('thymine', 'Chemical', 'MESH:D013941', (100, 107))	('glutamic acid', 'Chemical', 'MESH:D018698', (237, 250))
257069	32476297	11  BRAF V600E increases the activity of BRAF by 500 times, leading to an increase in MEK and ERK activity.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('ERK', 'Gene', (94, 97))	('MEK', 'Gene', (86, 89))	('V600E', 'Var', (9, 14))	('increase', 'PosReg', (74, 82))	('activity', 'MPA', (29, 37))	('MEK', 'Gene', '5609', (86, 89))	('BRAF', 'Gene', '673', (41, 45))	('increases', 'PosReg', (15, 24))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', (41, 45))	('BRAF', 'Gene', '673', (4, 8))	('ERK', 'Gene', '5594', (94, 97))
257071	32476297	5  The normal expression of BRAF requires dimerization, but the BRAF V600E mutation does not require dimerization and can also transmit signals; therefore, it can bypass the feedback inhibition caused by the ERK pathway.	('V600E', 'Var', (69, 74))	('BRAF', 'Gene', '673', (28, 32))	('BRAF', 'Gene', '673', (64, 68))	('ERK', 'Gene', '5594', (208, 211))	('ERK', 'Gene', (208, 211))	('BRAF', 'Gene', (64, 68))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('BRAF', 'Gene', (28, 32))
257080	32476297	There are two key sites on the AS, T599 and S602, and the phosphorylation of these two sites is necessary for BRAF activation.	('BRAF', 'Gene', (110, 114))	('BRAF', 'Gene', '673', (110, 114))	('T599', 'Var', (35, 39))	('S602', 'Var', (44, 48))
257083	32476297	In the BRAF inactive state, the DFG motif makes the AS orient toward the P-loop, which causes the G595-V600 of the AS and the G463-V470 of the P-loop to approach each other, forming a hydrophobic reaction, which maintains BRAF in an inactive state.	('BRAF', 'Gene', '673', (222, 226))	('DFG', 'Chemical', '-', (32, 35))	('G463-V470', 'Var', (126, 135))	('BRAF', 'Gene', (222, 226))	('BRAF', 'Gene', '673', (7, 11))	('BRAF', 'Gene', (7, 11))	('G595-V600', 'Var', (98, 107))
257084	32476297	1 ,  11 ,  12 ,  17  When combined with the RBD and CRD, RAS-GTP stimulates the phosphorylation of T599 and S602, hence disrupting the hydrophobic reaction, which causes the DFG to flip the AS again and activate BRAF 1 ,  12 ,  16 ,  18  (Figure 3B).	('CRD', 'Disease', (52, 55))	('disrupting', 'NegReg', (120, 130))	('flip', 'PosReg', (181, 185))	('S602', 'Var', (108, 112))	('CRD', 'Disease', 'OMIM:120970', (52, 55))	('hydrophobic reaction', 'MPA', (135, 155))	('phosphorylation', 'MPA', (80, 95))	('stimulates', 'PosReg', (65, 75))	('RAS-GTP', 'Chemical', '-', (57, 64))	('BRAF 1', 'Gene', (212, 218))	('BRAF 1', 'Gene', '673', (212, 218))	('T599', 'Var', (99, 103))	('DFG', 'Chemical', '-', (174, 177))
257085	32476297	Most BRAF mutations occur on the P-loop and the AS, such as the BRAF V600E mutation that occurs in the AS, and this mutation activates BRAF by destroying the hydrophobic reaction.	('activates', 'PosReg', (125, 134))	('BRAF', 'Gene', '673', (135, 139))	('V600E', 'Var', (69, 74))	('hydrophobic reaction', 'MPA', (158, 178))	('BRAF', 'Gene', '673', (5, 9))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (135, 139))	('BRAF', 'Gene', (5, 9))	('BRAF', 'Gene', (64, 68))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('destroying', 'NegReg', (143, 153))
257086	32476297	17 ,  19  In contrast, some mutations may weaken BRAF activity and even make BRAF completely inactive (such as BRAFD593V).	('inactive', 'MPA', (93, 101))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('weaken', 'NegReg', (42, 48))	('activity', 'MPA', (54, 62))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (49, 53))	('BRAF', 'Gene', (111, 115))	('mutations', 'Var', (28, 37))
257087	32476297	As early as 2004, BRAF mutations were classified into high, medium, and low activity mutations based on the level of BRAF mutation activity in vivo.	('activity', 'MPA', (76, 84))	('mutations', 'Var', (23, 32))	('BRAF', 'Gene', '673', (18, 22))	('BRAF', 'Gene', '673', (117, 121))	('BRAF', 'Gene', (18, 22))	('BRAF', 'Gene', (117, 121))
257088	32476297	17  Later, in 2017, a report further classified BRAF mutations into three types of mutations based on BRAF mutation activity, whether the mutation is dependent on RAS, whether the BRAF mutation is a monomer or a dimer, and the sensitivity to BRAF inhibitors 15 ,  20 ,  21  (Figure 4).	('BRAF', 'Gene', (180, 184))	('BRAF', 'Gene', '673', (242, 246))	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (242, 246))	('BRAF', 'Gene', (102, 106))	('mutations', 'Var', (53, 62))	('BRAF', 'Gene', '673', (180, 184))	('activity', 'MPA', (116, 124))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('mutation', 'Var', (107, 115))
257089	32476297	For patients with clinically different BRAF mutations, this classification of mutations will be of great significance for guiding treatments in the future.	('BRAF', 'Gene', '673', (39, 43))	('BRAF', 'Gene', (39, 43))	('mutations', 'Var', (44, 53))	('patients', 'Species', '9606', (4, 12))
257090	32476297	Class I mutant BRAF activity is elevated and typically includes the V600E, V600K, V600D, and V600R mutations, which are RAS-independent mutations that exist as monomers and are sensitive to BRAF inhibitors.	('activity', 'MPA', (20, 28))	('V600E', 'Var', (68, 73))	('BRAF', 'Gene', '673', (15, 19))	('elevated', 'PosReg', (32, 40))	('BRAF', 'Gene', (190, 194))	('BRAF', 'Gene', (15, 19))	('V600R', 'Var', (93, 98))	('V600K', 'Var', (75, 80))	('V600D', 'Var', (82, 87))	('V600E', 'Mutation', 'rs113488022', (68, 73))	('V600K', 'Mutation', 'rs121913227', (75, 80))	('V600D', 'Mutation', 'rs121913377', (82, 87))	('V600R', 'Mutation', 'rs121913227', (93, 98))	('BRAF', 'Gene', '673', (190, 194))
257091	32476297	15 ,  20  BRAF V600E destroys the hydrophobic reaction, thus activating BRAF.	('BRAF', 'Gene', (72, 76))	('hydrophobic reaction', 'MPA', (34, 54))	('V600E', 'Mutation', 'rs113488022', (15, 20))	('destroys', 'NegReg', (21, 29))	('BRAF', 'Gene', '673', (72, 76))	('V600E', 'Var', (15, 20))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('activating', 'PosReg', (61, 71))
257092	32476297	On the other hand, wild-type BRAF activation requires dimerization, but V600E can form a salt bridge with K507.	('BRAF', 'Gene', '673', (29, 33))	('form', 'Reg', (82, 86))	('BRAF', 'Gene', (29, 33))	('V600E', 'Var', (72, 77))	('K507', 'Var', (106, 110))	('K507', 'Chemical', '-', (106, 110))	('V600E', 'Mutation', 'rs113488022', (72, 77))
257093	32476297	This salt bridge mimics the conformational change during dimerization, so V600E can activate MEK in a monomeric state.	('V600E', 'Mutation', 'rs113488022', (74, 79))	('MEK', 'Gene', (93, 96))	('MEK', 'Gene', '5609', (93, 96))	('V600E', 'Var', (74, 79))	('activate', 'PosReg', (84, 92))
257094	32476297	15  Moreover, BRAF V600E is not affected by the inhibitory reaction between CR1 and CR3.	('V600E', 'Mutation', 'rs113488022', (19, 24))	('CR1', 'Gene', (76, 79))	('V600E', 'Var', (19, 24))	('BRAF', 'Gene', '673', (14, 18))	('CR3', 'Gene', '6998', (84, 87))	('CR1', 'Gene', '1378', (76, 79))	('BRAF', 'Gene', (14, 18))	('CR3', 'Gene', (84, 87))
257095	32476297	13  One typical class II BRAF mutation is K601E; BRAF activity is intermediate or elevated and is independent of RAS, similar to class I BRAF mutations.	('K601E', 'Var', (42, 47))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('elevated', 'PosReg', (82, 90))	('BRAF', 'Gene', '673', (25, 29))	('activity', 'MPA', (54, 62))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (25, 29))	('BRAF', 'Gene', (49, 53))	('K601E', 'Mutation', 'rs121913364', (42, 47))
257096	32476297	The difference between class I and class II BRAF mutations is that class II BRAF mutations exist in the form of dimers and are insensitive to BRAF inhibitors because current BRAF inhibitors, such as vemurafenib, are sensitive only to BRAF mutations in the monomeric form.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('BRAF', 'Gene', '673', (44, 48))	('mutations', 'Var', (49, 58))	('vemurafenib', 'Chemical', 'MESH:D000077484', (199, 210))	('BRAF', 'Gene', (44, 48))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', '673', (234, 238))	('BRAF', 'Gene', (174, 178))	('mutations', 'Var', (81, 90))	('BRAF', 'Gene', '673', (142, 146))	('BRAF', 'Gene', (234, 238))	('BRAF', 'Gene', (142, 146))
257097	32476297	For class II mutations, the efficacy of MEK inhibitors is better than that of BRAF inhibitors, but BRAF inhibitors combined with MEK inhibitors can provide additional efficacy.	('MEK', 'Gene', '5609', (40, 43))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', (78, 82))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('mutations', 'Var', (13, 22))	('MEK', 'Gene', (129, 132))	('MEK', 'Gene', (40, 43))	('MEK', 'Gene', '5609', (129, 132))
257098	32476297	15  Fortunately, a novel RAF inhibitor, BGB659, can inhibit BRAF dimers and monomers at the same concentration, which may bring new hope to patients with class II BRAF mutations.	('BRAF', 'Gene', (163, 167))	('inhibit', 'NegReg', (52, 59))	('RAF', 'Gene', (61, 64))	('BRAF', 'Gene', '673', (163, 167))	('RAF', 'Gene', '22882', (25, 28))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('RAF', 'Gene', (25, 28))	('BGB659', 'Chemical', '-', (40, 46))	('RAF', 'Gene', '22882', (164, 167))	('patients', 'Species', '9606', (140, 148))	('mutations', 'Var', (168, 177))	('RAF', 'Gene', '22882', (61, 64))	('RAF', 'Gene', (164, 167))	('BGB659', 'Gene', (40, 46))
257099	32476297	20  Class III mutations typically lead to G466V (impaired activity), D593V (completely inactive), etc, existing in the form of heterodimers, being dependent on RAS and having impaired or even kinase-dead activity.	('G466V', 'Var', (42, 47))	('D593V', 'Mutation', 'p.D593V', (69, 74))	('activity', 'MPA', (58, 66))	('D593V', 'Var', (69, 74))	('G466V', 'Mutation', 'rs121913351', (42, 47))	('lead', 'Reg', (34, 38))	('Class III', 'Gene', (4, 13))	('mutations', 'Var', (14, 23))
257100	32476297	11 ,  17 ,  21  Although this mutation reduces BRAF activity, it can activate MEK by activating CRAF.	('MEK', 'Gene', (78, 81))	('CRAF', 'Gene', (96, 100))	('MEK', 'Gene', '5609', (78, 81))	('CRAF', 'Gene', '5894', (96, 100))	('activate', 'PosReg', (69, 77))	('BRAF', 'Gene', (47, 51))	('mutation', 'Var', (30, 38))	('BRAF', 'Gene', '673', (47, 51))	('reduces', 'NegReg', (39, 46))
257101	32476297	Moreover, class III mutations often coexist with RAS mutations or NF1 deletions or mutations.	('mutations', 'Var', (83, 92))	('coexist', 'Reg', (36, 43))	('mutations', 'Var', (53, 62))	('NF1', 'Gene', (66, 69))	('NF1', 'Gene', '4763', (66, 69))	('deletions', 'Var', (70, 79))	('RAS', 'Disease', (49, 52))	('mutations', 'Var', (20, 29))
257103	32476297	In addition, in class III mutations, RAS may also be activated by upstream RTKs, so RTK inhibitors combined with MEK inhibitors may also be effective against such mutations.	('MEK', 'Gene', '5609', (113, 116))	('RAS', 'Protein', (37, 40))	('activated', 'PosReg', (53, 62))	('RTK', 'Gene', (75, 78))	('RTK', 'Gene', (84, 87))	('mutations', 'Var', (26, 35))	('RTK', 'Gene', '5979', (75, 78))	('RTK', 'Gene', '5979', (84, 87))	('MEK', 'Gene', (113, 116))
257104	32476297	21   The overall mutation rate of BRAF in malignant tumors is 7% but varies with the tumor type.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('mutation', 'Var', (17, 25))	('BRAF', 'Gene', '673', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('malignant tumors', 'Disease', (42, 58))	('malignant tumors', 'Disease', 'MESH:D009369', (42, 58))	('BRAF', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
257105	32476297	22 ,  23  It is estimated that the BRAF mutation occurs in almost all hairy cell leukemias, at least 50% of melanomas, 40% of thyroid cancers, 10% or less of colorectal cancers, and rarely in clear cell sarcomas (CCSs) and gastrointestinal stromal tumors (GISTs) 4 ,  22 ,  24 ,  25  (Figure 5A).	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('BRAF', 'Gene', (35, 39))	('melanomas', 'Disease', 'MESH:D008545', (108, 117))	('thyroid cancers', 'Disease', 'MESH:D013964', (126, 141))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (223, 254))	('colorectal cancers', 'Disease', (158, 176))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('thyroid cancer', 'Phenotype', 'HP:0002890', (126, 140))	('hairy cell leukemias', 'Disease', (70, 90))	('melanomas', 'Disease', (108, 117))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('mutation', 'Var', (40, 48))	('colorectal cancers', 'Disease', 'MESH:D015179', (158, 176))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('thyroid cancers', 'Disease', (126, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('hairy cell leukemias', 'Disease', 'MESH:D007943', (70, 90))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('leukemias', 'Phenotype', 'HP:0001909', (81, 90))	('clear cell sarcomas (CCSs) and gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (192, 254))	('BRAF', 'Gene', '673', (35, 39))	('GISTs', 'Phenotype', 'HP:0100723', (256, 261))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
257122	32476297	37 ,  38   The role of the BRAF mutation in sarcomas is controversial.	('sarcomas', 'Disease', (44, 52))	('BRAF', 'Gene', '673', (27, 31))	('sarcomas', 'Disease', 'MESH:D012509', (44, 52))	('BRAF', 'Gene', (27, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('mutation', 'Var', (32, 40))
257124	32476297	39  However, another report proposed that the BRAF mutation could lead to malignancy, not just a mutation.	('malignancy', 'Disease', (74, 84))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('malignancy', 'Disease', 'MESH:D009369', (74, 84))	('mutation', 'Var', (51, 59))	('lead to', 'Reg', (66, 73))
257127	32476297	These reports provide some references for the evaluation of BRAF mutations and gene sequencing in sarcoma to some extent, and future studies should focus on extensive, multispecimen research.	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcoma', 'Disease', (98, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('mutations', 'Var', (65, 74))
257129	32476297	Because some patients with a BRAF mutation in malignant tumors do not respond well to conventional chemotherapy, people are starting to focus on MAPK pathway target inhibition.	('BRAF', 'Gene', '673', (29, 33))	('malignant tumors', 'Disease', 'MESH:D009369', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BRAF', 'Gene', (29, 33))	('patients', 'Species', '9606', (13, 21))	('mutation', 'Var', (34, 42))	('MAPK', 'Gene', '5594', (145, 149))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('MAPK', 'Gene', (145, 149))	('people', 'Species', '9606', (113, 119))	('malignant tumors', 'Disease', (46, 62))
257130	32476297	4 ,  40  The application of BRAF inhibitors opens a new door for the treatment of patients with BRAF mutations (Table 1).	('BRAF', 'Gene', '673', (28, 32))	('mutations', 'Var', (101, 110))	('patients', 'Species', '9606', (82, 90))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('BRAF', 'Gene', (28, 32))
257137	32476297	6 ,  23  Therefore, sorafenib is mainly used for renal cell carcinoma and hepatocellular carcinoma, and its effect on melanoma mainly caused by a BRAF mutation is not good.	('sorafenib', 'Chemical', 'MESH:D000077157', (20, 29))	('BRAF', 'Gene', (146, 150))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (49, 69))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (49, 69))	('mutation', 'Var', (151, 159))	('caused by', 'Reg', (134, 143))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (74, 98))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('hepatocellular carcinoma', 'Disease', (74, 98))	('BRAF', 'Gene', '673', (146, 150))	('renal cell carcinoma', 'Disease', (49, 69))
257139	32476297	23  Given that BRAF accounts for 95% of all RAF mutations, it also restricts the use of sorafenib in melanoma.	('BRAF', 'Gene', '673', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('BRAF', 'Gene', (15, 19))	('melanoma', 'Disease', (101, 109))	('RAF', 'Gene', '22882', (16, 19))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('sorafenib', 'Chemical', 'MESH:D000077157', (88, 97))	('RAF', 'Gene', (16, 19))	('RAF', 'Gene', '22882', (44, 47))	('RAF', 'Gene', (44, 47))	('restricts', 'NegReg', (67, 76))	('mutations', 'Var', (48, 57))
257140	32476297	Vemurafenib (PLX4032) and its analogue PLX4720 can be highly selective in inhibiting BRAF V600E.	('inhibiting', 'NegReg', (74, 84))	('V600E', 'Mutation', 'rs113488022', (90, 95))	('PLX4032', 'Chemical', 'MESH:D000077484', (13, 20))	('BRAF', 'Gene', (85, 89))	('PLX4032', 'Var', (13, 20))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', '673', (85, 89))	('PLX4720', 'Chemical', 'MESH:C528407', (39, 46))
257143	32476297	Different from MEK inhibitors, which can inhibit both tumor cells and normal cells at the same time, vemurafenib inhibits only tumor cells with the BRAF V600E mutation.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MEK', 'Gene', '5609', (15, 18))	('V600E', 'Mutation', 'rs113488022', (153, 158))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('V600E', 'Var', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('vemurafenib', 'Chemical', 'MESH:D000077484', (101, 112))	('MEK', 'Gene', (15, 18))	('BRAF', 'Gene', '673', (148, 152))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('inhibits', 'NegReg', (113, 121))	('BRAF', 'Gene', (148, 152))
257145	32476297	40  In wild-type BRAF cells and in cells with RAS mutations treated with vemurafenib, the ERK pathway can be activated paradoxically.	('ERK', 'Gene', (90, 93))	('mutations', 'Var', (50, 59))	('BRAF', 'Gene', '673', (17, 21))	('vemurafenib', 'Chemical', 'MESH:D000077484', (73, 84))	('BRAF', 'Gene', (17, 21))	('RAS', 'Gene', (46, 49))	('ERK', 'Gene', '5594', (90, 93))
257146	32476297	2 ,  6 ,  7 ,  41  However, this phenomenon does not appear in BRAF V600E-mutant cells.	('V600E-mutant', 'Var', (68, 80))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (63, 67))	('V600E', 'Mutation', 'rs113488022', (68, 73))
257148	32476297	6  This also limits the extent of vemurafenib use, which requires the presence of BRAF mutations to be identified before the drug is administered.	('vemurafenib', 'Chemical', 'MESH:D000077484', (34, 45))	('mutations', 'Var', (87, 96))	('BRAF', 'Gene', (82, 86))	('BRAF', 'Gene', '673', (82, 86))
257152	32476297	41 ,  44  There have been reports about the efficacy of vemurafenib in thyroid cancer, hairy cell leukemia, and lung cancer with BRAF mutations.	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('lung cancer', 'Disease', (112, 123))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('thyroid cancer', 'Phenotype', 'HP:0002890', (71, 85))	('thyroid cancer', 'Disease', (71, 85))	('hairy cell leukemia', 'Disease', (87, 106))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (87, 106))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('vemurafenib', 'Chemical', 'MESH:D000077484', (56, 67))	('mutations', 'Var', (134, 143))	('thyroid cancer', 'Disease', 'MESH:D013964', (71, 85))
257155	32476297	7  Dabrafenib is 80 times more potent than vemurafenib, and studies have shown that dabrafenib also has effects on V600K and V600G mutations but not on K601E.	('vemurafenib', 'Chemical', 'MESH:D000077484', (43, 54))	('K601E', 'Mutation', 'rs121913364', (152, 157))	('dabrafenib', 'Chemical', 'MESH:C561627', (84, 94))	('V600G', 'Mutation', 'rs113488022', (125, 130))	('V600K', 'Var', (115, 120))	('effects', 'Reg', (104, 111))	('V600G', 'Var', (125, 130))	('V600K', 'Mutation', 'rs121913227', (115, 120))	('Dabrafenib', 'Chemical', 'MESH:C561627', (3, 13))
257158	32476297	45 ,  46 ,  47  On 27 June 2018, the combination of encorafenib and binimetinib (a kind of MEK inhibitor) was approved by the FDA to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('V600K', 'Var', (210, 215))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('encorafenib', 'Chemical', 'MESH:C000601108', (52, 63))	('patients', 'Species', '9606', (139, 147))	('V600E', 'Mutation', 'rs113488022', (201, 206))	('BRAF', 'Gene', '673', (196, 200))	('V600K', 'Mutation', 'rs121913227', (210, 215))	('binimetinib', 'Chemical', 'MESH:C581313', (68, 79))	('V600E', 'Var', (201, 206))	('BRAF', 'Gene', (196, 200))	('MEK', 'Gene', (91, 94))	('MEK', 'Gene', '5609', (91, 94))
257161	32476297	50 ,  51   A number of studies have reported that melanoma patients with the BRAF V600E mutation treated with BRAF inhibitors could achieve complete or partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST).	('BRAF', 'Gene', '673', (77, 81))	('V600E', 'Mutation', 'rs113488022', (82, 87))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('Tumors', 'Phenotype', 'HP:0002664', (224, 230))	('partial', 'NegReg', (152, 159))	('BRAF', 'Gene', (77, 81))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('V600E', 'Var', (82, 87))	('Tumors', 'Disease', (224, 230))	('patients', 'Species', '9606', (59, 67))	('Tumors', 'Disease', 'MESH:D009369', (224, 230))	('BRAF', 'Gene', '673', (110, 114))	('BRAF', 'Gene', (110, 114))
257162	32476297	However, to our knowledge, there are few clinical trials about the treatment of sarcoma patients with the BRAF V600E mutation treated with BRAF inhibitors, and most reports of sarcoma patients treated with BRAF inhibitors are case reports (Table 2).	('BRAF', 'Gene', (139, 143))	('BRAF', 'Gene', '673', (139, 143))	('patients', 'Species', '9606', (184, 192))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('sarcoma', 'Disease', (176, 183))	('V600E', 'Var', (111, 116))	('patients', 'Species', '9606', (88, 96))	('BRAF', 'Gene', '673', (106, 110))	('sarcoma', 'Disease', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('BRAF', 'Gene', '673', (206, 210))	('BRAF', 'Gene', (106, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('BRAF', 'Gene', (206, 210))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('V600E', 'Mutation', 'rs113488022', (111, 116))
257163	32476297	A study on nonmelanoma patients with a BRAF mutation treated with vemurafenib found that the response rates of non-small cell lung cancer and Erdheim-Chester disease or Langerhans cell histiocytosis with a BRAF mutation were 42% and 43%, respectively.	('vemurafenib', 'Chemical', 'MESH:D000077484', (66, 77))	('mutation', 'Var', (44, 52))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (115, 137))	('patients', 'Species', '9606', (23, 31))	('BRAF', 'Gene', '673', (206, 210))	('BRAF', 'Gene', (206, 210))	('BRAF', 'Gene', '673', (39, 43))	('Erdheim-Chester disease', 'Disease', 'MESH:D031249', (142, 165))	('BRAF', 'Gene', (39, 43))	('nonmelanoma', 'Disease', 'None', (11, 22))	('lung cancer', 'Disease', (126, 137))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('histiocytosis', 'Phenotype', 'HP:0100727', (185, 198))	('Erdheim-Chester disease', 'Disease', (142, 165))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('nonmelanoma', 'Disease', (11, 22))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (111, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Langerhans cell histiocytosis', 'Disease', (169, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('mutation', 'Var', (211, 219))
257166	32476297	52  In addition, the comforting effect of BRAF inhibitor was also observed in the treatment of Langerhans cell sarcoma and histiosarcoma with the BRAF V600E mutation.	('BRAF', 'Gene', '673', (42, 46))	('BRAF', 'Gene', (146, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('V600E', 'Var', (151, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('Langerhans cell sarcoma and histiosarcoma', 'Disease', 'MESH:D054752', (95, 136))	('BRAF', 'Gene', (42, 46))	('BRAF', 'Gene', '673', (146, 150))	('V600E', 'Mutation', 'rs113488022', (151, 156))
257169	32476297	After the inefficacy of dacarbazine, docetaxel, and radiotherapy, gene sequencing revealed the presence of the BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (116, 121))	('docetaxel', 'Chemical', 'MESH:D000077143', (37, 46))	('BRAF', 'Gene', '673', (111, 115))	('dacarbazine', 'Chemical', 'MESH:D003606', (24, 35))	('V600E', 'Var', (116, 121))	('BRAF', 'Gene', (111, 115))
257174	32476297	All of these studies have a common feature, that is, the BRAF mutation is present, and all of them have achieved various degrees of a response after the use of BRAF inhibitors.	('BRAF', 'Gene', '673', (160, 164))	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))
257175	32476297	This finding also provides insight into the prospect of the application of BRAF inhibitors in sarcomas and raises the possibility that as long as there are BRAF mutations in sarcomas, there is the possibility of using BRAF inhibitors.	('BRAF', 'Gene', (156, 160))	('BRAF', 'Gene', (218, 222))	('sarcomas', 'Disease', (174, 182))	('BRAF', 'Gene', '673', (218, 222))	('BRAF', 'Gene', '673', (75, 79))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('BRAF', 'Gene', (75, 79))	('mutations', 'Var', (161, 170))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('sarcomas', 'Disease', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('BRAF', 'Gene', '673', (156, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))
257182	32476297	42   A report found a second BRAF V600E mutation, BRAF V600E L514V, in a patient with a BRAF V600E-mutant left temporal lobe brain tumor who relapsed after treatment with dabrafenib.	('V600E', 'SUBSTITUTION', 'None', (34, 39))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('patient', 'Species', '9606', (73, 80))	('V600E', 'Var', (93, 98))	('V600E', 'Var', (55, 60))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('left temporal lobe brain tumor', 'Disease', (106, 136))	('left temporal lobe brain tumor', 'Disease', 'MESH:D004833', (106, 136))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('dabrafenib', 'Chemical', 'MESH:C561627', (171, 181))	('V600E', 'SUBSTITUTION', 'None', (93, 98))	('V600E', 'SUBSTITUTION', 'None', (55, 60))	('BRAF', 'Gene', '673', (50, 54))	('V600E', 'Var', (34, 39))	('brain tumor', 'Phenotype', 'HP:0030692', (125, 136))	('BRAF', 'Gene', (50, 54))	('L514V', 'Var', (61, 66))	('V600E', 'Mutation', 'rs113488022', (93, 98))	('L514V', 'SUBSTITUTION', 'None', (61, 66))	('V600E', 'Mutation', 'rs113488022', (55, 60))
257183	32476297	Moreover, this mutation was not detected before recurrence, suggesting that BRAF inhibitor resistance can be generated by a second mutation in BRAF.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('inhibitor resistance', 'MPA', (81, 101))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('mutation', 'Var', (131, 139))
257188	32476297	68  In addition, in RAS mutations, BRAF can bind to CRAF when BRAF is inhibited, thereby promoting the MAPK pathway.	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (35, 39))	('RAS', 'Gene', (20, 23))	('MAPK', 'Gene', '5594', (103, 107))	('CRAF', 'Gene', (52, 56))	('CRAF', 'Gene', '5894', (52, 56))	('bind', 'Interaction', (44, 48))	('MAPK', 'Gene', (103, 107))	('BRAF', 'Gene', (62, 66))	('mutations', 'Var', (24, 33))	('BRAF', 'Gene', '673', (35, 39))	('promoting', 'PosReg', (89, 98))
257193	32476297	2 ,  69  In addition to the BRAF V600E second mutation, some splice variants, and NRAS upregulation, BRAF amplification also likely plays a role in the resistance mechanism by the formation of dimers.	('dimers', 'MPA', (193, 199))	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', '673', (28, 32))	('V600E', 'Mutation', 'rs113488022', (33, 38))	('plays', 'Reg', (132, 137))	('V600E', 'Var', (33, 38))	('BRAF', 'Gene', '673', (101, 105))	('NRAS', 'Gene', (82, 86))	('BRAF', 'Gene', (28, 32))	('NRAS', 'Gene', '4893', (82, 86))	('upregulation', 'PosReg', (87, 99))
257196	32476297	2 ,  66 ,  71  The lack of NF1, which regulates RAS in a manner of negative feedback (Figure 6B), MEK1/2 mutation, and ERK mutation also confer resistance to BRAF inhibitors.	('mutation', 'Var', (105, 113))	('mutation', 'Var', (123, 131))	('RAS', 'Protein', (48, 51))	('ERK', 'Gene', '5594', (119, 122))	('BRAF', 'Gene', '673', (158, 162))	('ERK', 'Gene', (119, 122))	('resistance', 'MPA', (144, 154))	('NF1', 'Gene', (27, 30))	('BRAF', 'Gene', (158, 162))	('MEK1/2', 'Gene', '5604;5605', (98, 104))	('NF1', 'Gene', '4763', (27, 30))	('MEK1/2', 'Gene', (98, 104))	('confer', 'Reg', (137, 143))
257200	32476297	In this signaling pathway, the lack of PTEN, which inhibits AKT, or a mutation in AKT can cause resistance to BRAF inhibitors 63 ,  66 ,  75  (Figure 6C).	('PTEN', 'Gene', '5728', (39, 43))	('inhibits', 'NegReg', (51, 59))	('AKT', 'Gene', '207', (60, 63))	('AKT', 'Gene', '207', (82, 85))	('PTEN', 'Gene', (39, 43))	('BRAF', 'Gene', '673', (110, 114))	('cause', 'Reg', (90, 95))	('AKT', 'Gene', (60, 63))	('lack', 'Var', (31, 35))	('mutation', 'Var', (70, 78))	('BRAF', 'Gene', (110, 114))	('AKT', 'Gene', (82, 85))	('resistance', 'MPA', (96, 106))
257228	32476297	It is not difficult to see from the results of these clinical trials that in malignant melanoma, the combination of BRAF inhibitors and MEK inhibitors cannot only improve OS and PFS but also delay the recurrence and reduce the incidence of drug-related adverse reactions, especially the incidence of secondary skin tumors.	('MEK', 'Gene', (136, 139))	('skin tumors', 'Disease', 'MESH:D012878', (310, 321))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('skin tumors', 'Phenotype', 'HP:0008069', (310, 321))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('combination', 'Interaction', (101, 112))	('malignant melanoma', 'Disease', (77, 95))	('PFS', 'Disease', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('OS', 'Gene', '17451', (171, 173))	('improve', 'PosReg', (163, 170))	('recurrence', 'CPA', (201, 211))	('BRAF', 'Gene', '673', (116, 120))	('BRAF', 'Gene', (116, 120))	('malignant melanoma', 'Phenotype', 'HP:0002861', (77, 95))	('delay', 'NegReg', (191, 196))	('skin tumors', 'Disease', (310, 321))	('malignant melanoma', 'Disease', 'MESH:D008545', (77, 95))	('MEK', 'Gene', '5609', (136, 139))	('reduce', 'NegReg', (216, 222))	('drug-related adverse reactions', 'Phenotype', 'HP:0020172', (240, 270))	('inhibitors', 'Var', (121, 131))
257232	32476297	Most patients develop resistance within 3 years after receiving the combination of vemurafenib plus cobimetinib and dabrafenib plus trametinib, and some resistance mechanisms are the same as those of BRAF monotherapy, such as MEK mutation and BRAF amplification.	('BRAF', 'Gene', (200, 204))	('patients', 'Species', '9606', (5, 13))	('cobimetinib', 'Chemical', 'MESH:C574276', (100, 111))	('resistance', 'MPA', (22, 32))	('BRAF', 'Gene', '673', (243, 247))	('MEK', 'Gene', (226, 229))	('vemurafenib', 'Chemical', 'MESH:D000077484', (83, 94))	('MEK', 'Gene', '5609', (226, 229))	('BRAF', 'Gene', (243, 247))	('develop', 'Reg', (14, 21))	('dabrafenib', 'Chemical', 'MESH:C561627', (116, 126))	('trametinib', 'Chemical', 'MESH:C560077', (132, 142))	('BRAF', 'Gene', '673', (200, 204))	('amplification', 'Var', (248, 261))
257235	32476297	75  A study showed that simultaneous treatment with BRAF, EGFR, and MEK inhibitors can achieve satisfactory outcomes in colorectal cancer patients with BRAF V600E.	('EGFR', 'Gene', '1956', (58, 62))	('BRAF', 'Gene', (152, 156))	('colorectal cancer', 'Disease', (120, 137))	('MEK', 'Gene', '5609', (68, 71))	('EGFR', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('V600E', 'Mutation', 'rs113488022', (157, 162))	('BRAF', 'Gene', '673', (52, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('V600E', 'Var', (157, 162))	('BRAF', 'Gene', '673', (152, 156))	('BRAF', 'Gene', (52, 56))	('patients', 'Species', '9606', (138, 146))	('MEK', 'Gene', (68, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))
257239	32476297	Given the susceptibility of monotherapy to resistance, there have been exciting results obtained from combining BRAF inhibitors with other targeted inhibitors, such as MEK inhibitors.	('MEK', 'Gene', (168, 171))	('MEK', 'Gene', '5609', (168, 171))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('inhibitors', 'Var', (117, 127))
257249	28403900	A further analysis indicated suppression of USP39 arrested cell cycle progression at G2/M phase via p21 dependent way.	('p21', 'Gene', (100, 103))	('USP39', 'Gene', (44, 49))	('suppression', 'Var', (29, 40))	('cell cycle progression at G2/M phase', 'CPA', (59, 95))	('p21', 'Gene', '644914', (100, 103))	('USP39', 'Gene', '10713', (44, 49))	('arrested', 'NegReg', (50, 58))
257250	28403900	In addition, the results of Annexin V/7-AAD staining suggested the knockdown of USP39 could promote U2OS cell apoptosis through PARP cleavage.	('Annexin V', 'Gene', '308', (28, 37))	('PARP', 'Gene', '142', (128, 132))	('promote', 'PosReg', (92, 99))	('U2OS', 'CellLine', 'CVCL:0042', (100, 104))	('knockdown', 'Var', (67, 76))	('Annexin V', 'Gene', (28, 37))	('7-AAD', 'Chemical', 'MESH:C025942', (38, 43))	('USP39', 'Gene', '10713', (80, 85))	('PARP', 'Gene', (128, 132))	('USP39', 'Gene', (80, 85))	('U2OS cell apoptosis', 'CPA', (100, 119))
257260	28403900	Recently, scientists reported aberrant USP39 expression could inhibit breast cancer cell growth in vitro, however, little is known about how USP39 functions in human osteosarcoma and whether it can be used as an potential therapeutic target.	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('aberrant', 'Var', (30, 38))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('osteosarcoma', 'Phenotype', 'HP:0002669', (166, 178))	('USP39', 'Gene', '10713', (141, 146))	('osteosarcoma', 'Disease', (166, 178))	('expression', 'MPA', (45, 55))	('breast cancer', 'Disease', (70, 83))	('USP39', 'Gene', (141, 146))	('osteosarcoma', 'Disease', 'MESH:D012516', (166, 178))	('USP39', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('inhibit', 'NegReg', (62, 69))	('USP39', 'Gene', '10713', (39, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('human', 'Species', '9606', (160, 165))
257276	28403900	The Ct-value for each sample was calculated with the DeltaDeltaCt-method, and the results were expressed as 2-DeltaDeltaCT to analyze the fold change (tumor vs. normal): DeltaDeltaCT = (CT target gene - CT actin) normal-(CT target gene - CT actin) tumor.	('tumor', 'Disease', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('DeltaDeltaCT', 'Var', (170, 182))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
257281	28403900	The primary antibodies were rabbit anti-USP39 (1: 1000, 23865-1-AP, Proteintech), rabbit anti-PARP (1:1000, #9542, Cell Signaling), rabbit anti-Caspase-3 (1:500, 25546-1-AP, Proteintech), rabbit anti-CDK1 (1:1000,19532-1, Proteintech), rabbit anti-cyclin A2 (1:1000,18202-1-AP, Proteintech), rabbit anti-cyclin B1 (1:1000, #21540, SAB), rabbit anti-p21 (1:1000, #2947, cell signaling), and mouse anti-GAPDH (1:500,000, HRP-60004, Proteintech).	('rabbit', 'Species', '9986', (337, 343))	('PARP', 'Gene', '142', (94, 98))	('rabbit', 'Species', '9986', (132, 138))	('SAB', 'Gene', (331, 334))	('1:500', 'Var', (155, 160))	('mouse', 'Species', '10090', (390, 395))	('p21', 'Gene', (349, 352))	('PARP', 'Gene', (94, 98))	('Caspase-3', 'Gene', (144, 153))	('USP39', 'Gene', (40, 45))	('p21', 'Gene', '644914', (349, 352))	('cyclin B1', 'Gene', '891', (304, 313))	('cyclin B1', 'Gene', (304, 313))	('rabbit', 'Species', '9986', (82, 88))	('USP39', 'Gene', '10713', (40, 45))	('CDK1', 'Gene', '983', (200, 204))	('cyclin A2', 'Gene', (248, 257))	('CDK1', 'Gene', (200, 204))	('SAB', 'Gene', '9467', (331, 334))	('rabbit', 'Species', '9986', (292, 298))	('cyclin A2', 'Gene', '890', (248, 257))	('Caspase-3', 'Gene', '836', (144, 153))	('rabbit', 'Species', '9986', (236, 242))	('rabbit', 'Species', '9986', (188, 194))	('rabbit', 'Species', '9986', (28, 34))
257295	28403900	The results showed that U2OS had the highest expression level (Fig.	('U2OS', 'Var', (24, 28))	('expression level', 'MPA', (45, 61))	('U2OS', 'CellLine', 'CVCL:0042', (24, 28))
257302	28403900	3a, p < 0.001),which indicated that knockdown of USP39 had an obvious effect on suppressing cell viability.	('USP39', 'Gene', (49, 54))	('knockdown', 'Var', (36, 45))	('USP39', 'Gene', '10713', (49, 54))	('suppressing', 'NegReg', (80, 91))	('cell viability', 'CPA', (92, 106))
257305	28403900	Collectively, knockdown of USP39 could markedly suppress the proliferation and colony formation ability of osteosarcoma cells.	('suppress', 'NegReg', (48, 56))	('USP39', 'Gene', '10713', (27, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('USP39', 'Gene', (27, 32))	('osteosarcoma', 'Disease', (107, 119))	('colony formation ability', 'CPA', (79, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('knockdown', 'Var', (14, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
257306	28403900	To examine whether USP39 knockdown suppressed the growth of osteosarcoma cells through direct regulation of the cell cycle, the effect of USP39 repression on the cell cycle distribution was examined.	('osteosarcoma', 'Disease', 'MESH:D012516', (60, 72))	('USP39', 'Gene', (19, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('USP39', 'Gene', '10713', (138, 143))	('USP39', 'Gene', (138, 143))	('growth', 'CPA', (50, 56))	('suppressed', 'NegReg', (35, 45))	('osteosarcoma', 'Disease', (60, 72))	('USP39', 'Gene', '10713', (19, 24))	('cell cycle', 'CPA', (112, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('knockdown', 'Var', (25, 34))
257311	28403900	The mechanism by which USP39 knockdown arrested cell cycle might also affect the expression of negative and positive regulators of the cell cycle.	('affect', 'Reg', (70, 76))	('expression of', 'MPA', (81, 94))	('knockdown', 'Var', (29, 38))	('cell cycle', 'CPA', (48, 58))	('USP39', 'Gene', '10713', (23, 28))	('USP39', 'Gene', (23, 28))
257313	28403900	There is no significance difference in the protein expression of CDK1, however, the protein expression of cyclin A2 and p21 significantly increased in the USP39 silencing U2OS cells.	('increased', 'PosReg', (138, 147))	('U2OS', 'CellLine', 'CVCL:0042', (171, 175))	('p21', 'Gene', '644914', (120, 123))	('CDK1', 'Gene', (65, 69))	('USP39', 'Gene', (155, 160))	('cyclin A2', 'Gene', (106, 115))	('USP39', 'Gene', '10713', (155, 160))	('protein expression', 'MPA', (84, 102))	('CDK1', 'Gene', '983', (65, 69))	('silencing', 'Var', (161, 170))	('cyclin A2', 'Gene', '890', (106, 115))	('p21', 'Gene', (120, 123))
257314	28403900	On the basis of these results, we hypothesized that knockdown of USP39 mediated cell-cycle arrest might occur through a cyclin-dependent manner in U2OS cells.	('U2OS', 'CellLine', 'CVCL:0042', (147, 151))	('cell-cycle arrest', 'CPA', (80, 97))	('USP39', 'Gene', (65, 70))	('USP39', 'Gene', '10713', (65, 70))	('cyclin', 'Gene', '5111', (120, 126))	('cyclin', 'Gene', (120, 126))	('knockdown', 'Var', (52, 61))
257315	28403900	In order to demonstrate the effect of USP39 silencing on apoptosis of U2OS further, we performed flow cytometry using Annexin V and 7-aminoactinomycin D (7-AAD) as markers.	('USP39', 'Gene', '10713', (38, 43))	('USP39', 'Gene', (38, 43))	('7-AAD', 'Chemical', 'MESH:C025942', (154, 159))	('7-aminoactinomycin D', 'Chemical', 'MESH:C025942', (132, 152))	('U2OS', 'CellLine', 'CVCL:0042', (70, 74))	('Annexin V', 'Gene', '308', (118, 127))	('silencing', 'Var', (44, 53))	('Annexin V', 'Gene', (118, 127))
257316	28403900	5a, b, about 31.77 +- 0.34% cells had early apoptotic properties (Annexin V +/7-AAD-) after USP39 knockdown, which was dramatically higher than Con group (8.62 +- 0.19%) and shCon infected group (14.51 +- 0.52%).	('higher', 'PosReg', (132, 138))	('7-AAD', 'Chemical', 'MESH:C025942', (78, 83))	('Annexin V', 'Gene', '308', (66, 75))	('apoptotic properties', 'CPA', (44, 64))	('knockdown', 'Var', (98, 107))	('Annexin V', 'Gene', (66, 75))	('USP39', 'Gene', '10713', (92, 97))	('USP39', 'Gene', (92, 97))
257317	28403900	The percentages of late stage apoptotic cells (Annexin V +/7-AAD+) are also higher after USP39 knockdown (10.98 +- 0.28% in shUSP39-S1 infected group compared with 6.65 +- 0.04% in Con group and 5.69 +- 0.23% in shCon infected group).	('USP39', 'Gene', '10713', (89, 94))	('USP39', 'Gene', '10713', (126, 131))	('USP39', 'Gene', (89, 94))	('USP39', 'Gene', (126, 131))	('7-AAD', 'Chemical', 'MESH:C025942', (59, 64))	('knockdown', 'Var', (95, 104))	('shUSP39-S1', 'Gene', '5707', (124, 134))	('higher', 'PosReg', (76, 82))	('late stage apoptotic cells', 'CPA', (19, 45))	('Annexin V', 'Gene', '308', (47, 56))	('Annexin V', 'Gene', (47, 56))	('shUSP39-S1', 'Gene', (124, 134))
257318	28403900	These results suggested USP39 knockdown could promote U2OS cell apoptosis.	('promote', 'PosReg', (46, 53))	('U2OS cell apoptosis', 'CPA', (54, 73))	('USP39', 'Gene', '10713', (24, 29))	('USP39', 'Gene', (24, 29))	('knockdown', 'Var', (30, 39))	('U2OS', 'CellLine', 'CVCL:0042', (54, 58))
257320	28403900	A further analysis revealed that the cleavage caspase 3 and PARP were cleaved in the shUSP39 infected U2OS cells, indicating that the cleavage of PARP may be involved in shUSP39-mediated growth suppression in osteosarcoma cells.	('U2OS', 'CellLine', 'CVCL:0042', (102, 106))	('hUSP39', 'Gene', (86, 92))	('PARP', 'Gene', '142', (146, 150))	('osteosarcoma', 'Phenotype', 'HP:0002669', (209, 221))	('osteosarcoma', 'Disease', (209, 221))	('osteosarcoma', 'Disease', 'MESH:D012516', (209, 221))	('caspase 3', 'Gene', (46, 55))	('involved', 'Reg', (158, 166))	('PARP', 'Gene', '142', (60, 64))	('hUSP39', 'Gene', '10713', (171, 177))	('caspase 3', 'Gene', '836', (46, 55))	('PARP', 'Gene', (146, 150))	('cleavage', 'Var', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('growth suppression', 'CPA', (187, 205))	('hUSP39', 'Gene', '10713', (86, 92))	('hUSP39', 'Gene', (171, 177))	('PARP', 'Gene', (60, 64))
257323	28403900	Meanwhile, knockdown of USP39 could arrest cell cycle at G2/M via cyclin-dependent pathway and promoted apoptosis through PARP cleavage.	('USP39', 'Gene', '10713', (24, 29))	('promoted', 'PosReg', (95, 103))	('PARP', 'Gene', (122, 126))	('USP39', 'Gene', (24, 29))	('arrest', 'NegReg', (36, 42))	('PARP', 'Gene', '142', (122, 126))	('cyclin', 'Gene', '5111', (66, 72))	('cell cycle at G2/M', 'CPA', (43, 61))	('apoptosis', 'CPA', (104, 113))	('knockdown', 'Var', (11, 20))	('cyclin', 'Gene', (66, 72))
257324	28403900	Our research demonstrated that knockdown of USP39 had an effect on the cell cycle regulation, in which irreversible transition from one mitotic phase to the next by the complete deubiquitination of mitotic regulators plays an important role.	('USP39', 'Gene', (44, 49))	('effect', 'Reg', (57, 63))	('cell cycle regulation', 'MPA', (71, 92))	('deubiquitination', 'MPA', (178, 194))	('knockdown', 'Var', (31, 40))	('USP39', 'Gene', '10713', (44, 49))
257329	28403900	In our study, we have demonstrated that the expression of cyclin A2 and p21 increased which resulted in the arrest of cell cycle at G2/M phase after USP39 silencing, while the expression of CDK1 stayed the same.	('CDK1', 'Gene', '983', (190, 194))	('expression', 'MPA', (44, 54))	('silencing', 'Var', (155, 164))	('increased', 'PosReg', (76, 85))	('cyclin A2', 'Gene', '890', (58, 67))	('p21', 'Gene', (72, 75))	('USP39', 'Gene', (149, 154))	('cell cycle at G2/M phase', 'CPA', (118, 142))	('p21', 'Gene', '644914', (72, 75))	('USP39', 'Gene', '10713', (149, 154))	('cyclin A2', 'Gene', (58, 67))	('CDK1', 'Gene', (190, 194))	('arrest', 'CPA', (108, 114))
257333	28403900	Moreover, USP39 silencing could promote U2OS cell apoptosis by PARP cleavage, which were reliable indicators of apoptosis.	('PARP', 'Gene', '142', (63, 67))	('U2OS cell apoptosis', 'CPA', (40, 59))	('USP39', 'Gene', (10, 15))	('USP39', 'Gene', '10713', (10, 15))	('PARP', 'Gene', (63, 67))	('silencing', 'Var', (16, 25))	('U2OS', 'CellLine', 'CVCL:0042', (40, 44))	('promote', 'PosReg', (32, 39))
257334	28403900	In summary, our findings indicate that USP39 plays an important role in the cancer cell proliferation and cell cycle regulation in osteosarcoma, and depletion of it lead to retarded cell proliferation, triggered cell cycle arrest via p21-dependent way and promoted apoptosis through PARP cleavage.	('depletion', 'Var', (149, 158))	('promoted', 'PosReg', (256, 264))	('PARP', 'Gene', '142', (283, 287))	('USP39', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cell cycle arrest', 'CPA', (212, 229))	('PARP', 'Gene', (283, 287))	('osteosarcoma', 'Disease', (131, 143))	('retarded', 'Disease', (173, 181))	('osteosarcoma', 'Disease', 'MESH:D012516', (131, 143))	('USP39', 'Gene', '10713', (39, 44))	('retarded', 'Disease', 'MESH:D008607', (173, 181))	('cell proliferation', 'CPA', (182, 200))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (212, 229))	('apoptosis', 'CPA', (265, 274))	('cancer', 'Disease', (76, 82))	('p21', 'Gene', (234, 237))	('cell cycle regulation', 'CPA', (106, 127))	('p21', 'Gene', '644914', (234, 237))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('osteosarcoma', 'Phenotype', 'HP:0002669', (131, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('triggered', 'PosReg', (202, 211))
257427	31218087	Reverse transcription polymerase chain reaction (RT-PCR) on the gastric resection specimen was negative for EWS-FLI-1 types 1 and 2, EWS-ERG, and EWS-FEV translocations.	('FEV', 'Gene', '54738', (150, 153))	('ERG', 'Gene', (137, 140))	('EWS', 'Gene', '2130', (108, 111))	('EWS', 'Gene', (108, 111))	('EWS', 'Gene', '2130', (146, 149))	('EWS', 'Gene', (146, 149))	('FLI-1', 'Gene', (112, 117))	('FLI-1', 'Gene', '2313', (112, 117))	('EWS', 'Gene', '2130', (133, 136))	('EWS', 'Gene', (133, 136))	('translocations', 'Var', (154, 168))	('FEV', 'Gene', (150, 153))	('ERG', 'Gene', '2078', (137, 140))
257436	31218087	The most common chromosomal translocation is t(22;11)(q24;q12) that results in EWS-FLI-1 fusion, seen in 85-90% of the ESFT.	('EWS', 'Gene', '2130', (79, 82))	('EWS', 'Gene', (79, 82))	('FLI-1', 'Gene', (83, 88))	('results in', 'Reg', (68, 78))	('t(22;11)(q24;q12', 'Var', (45, 61))	('FLI-1', 'Gene', '2313', (83, 88))	('t(22;11)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (45, 62))
257438	31218087	As RT-PCR using commercial primers is limited to only the most prevalent EWSR1 fusion transcript, the rarer translocations associated with ESFT that could go undetected could be the likely explanation for our case being negative for the pathognomonic translocation.	('ESFT', 'Disease', (139, 143))	('EWSR1', 'Gene', (73, 78))	('EWSR1', 'Gene', '2130', (73, 78))	('fusion', 'Var', (79, 85))
257455	29998379	Our data support the view that the alteration of mitochondrial affinity for ADNs is one of the characteristic features of cancer cells.	('ADNs', 'Chemical', 'MESH:D000227', (76, 80))	('ADNs', 'Protein', (76, 80))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('rat', 'Species', '10116', (39, 42))	('mitochondrial affinity', 'MPA', (49, 71))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('alteration', 'Var', (35, 45))
257502	29998379	The coupling between mitochondrially bound HK(s) and the OXPHOS system in permeabilized cells was assayed by oxygraphy, through stimulation of mitochondrial respiration by locally generated ADP as described earlier (Eimre et al.	('ADP', 'Chemical', '-', (190, 193))	('rat', 'Species', '10116', (162, 165))	('rat', 'Species', '10116', (184, 187))	('stimulation', 'PosReg', (128, 139))	('ADP', 'Var', (190, 193))	('mitochondrial respiration', 'MPA', (143, 168))
257539	29998379	The mitochondrial respiration in all studied permeabilized cell types was activated with 2 mM ADP and the rate of O2 consumption was increased by about 3-4 times (Supplementary Fig.	('mitochondrial respiration', 'Enzyme', (4, 29))	('O2', 'Chemical', 'MESH:D010100', (114, 116))	('activated', 'PosReg', (74, 83))	('rat', 'Species', '10116', (23, 26))	('O2 consumption', 'MPA', (114, 128))	('ADP', 'Var', (94, 97))	('rat', 'Species', '10116', (106, 109))	('increased', 'PosReg', (133, 142))	('ADP', 'Chemical', '-', (94, 97))
257589	29998379	Titration experiments showed that the rates of maximal ADP-activated respiration (Vm) were lower in HL-1 cells compared to NB, as well as the Vm did not change during N2a cell differentiation.	('lower', 'NegReg', (91, 96))	('HL-1', 'Var', (100, 104))	('rat', 'Species', '10116', (74, 77))	('ADP', 'Chemical', '-', (55, 58))	('N2a', 'CellLine', 'CVCL:0470', (167, 170))	('rat', 'Species', '10116', (3, 6))	('rat', 'Species', '10116', (38, 41))
257646	29998379	These alterations could induce a decrease in the capacity of binding of some beta-tubulin isotypes to VDAC, and thereby loss of the cytoskeletal protein(s) role in the regulation of the mitochondrial VDAC channel permeability, which is characteristic for some oxidative muscle cells like CMs, m. soleus, and gastrocnemius red (Guzun et al.	('alterations', 'Var', (6, 17))	('decrease', 'NegReg', (33, 41))	('VDAC', 'Protein', (102, 106))	('mitochondrial VDAC channel permeability', 'MPA', (186, 225))	('beta-tubulin', 'Protein', (77, 89))	('loss', 'NegReg', (120, 124))	('rat', 'Species', '10116', (10, 13))	('binding', 'Interaction', (61, 68))
257664	29998379	The current study demonstrates that the presence of mitochondrially bound HK-2 can mediate the "Warburg" behavior of murine NB(s) and cardiac sarcoma cells.	('HK-2', 'Gene', (74, 78))	('HK-2', 'Gene', '15277', (74, 78))	('presence', 'Var', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('mediate', 'Reg', (83, 90))	('rat', 'Species', '10116', (25, 28))	('cardiac sarcoma', 'Disease', (134, 149))	('murine', 'Species', '10090', (117, 123))	('cardiac sarcoma', 'Phenotype', 'HP:0031350', (134, 149))	('cardiac sarcoma', 'Disease', 'MESH:D006331', (134, 149))
257667	29998379	The alternations in MOM permeability for adenine nucleotides seem to be a characteristic feature of malignant tumors and understanding of this regulation still requires further work.	('adenine nucleotides', 'Chemical', 'MESH:D000227', (41, 60))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('malignant tumors', 'Disease', (100, 116))	('MOM permeability for adenine nucleotides', 'MPA', (20, 60))	('alternations', 'Var', (4, 16))	('malignant tumors', 'Disease', 'MESH:D018198', (100, 116))
257727	26033451	Six of 8 mice lost muscle function after FGS with low-dose OBP-401.	('FGS', 'Gene', '227671', (41, 44))	('lost', 'NegReg', (14, 18))	('OBP', 'Gene', (59, 62))	('muscle function', 'CPA', (19, 34))	('FGS', 'Gene', (41, 44))	('low-dose', 'Var', (50, 58))	('mice', 'Species', '10090', (9, 13))	('OBP', 'Gene', '29991', (59, 62))
257755	26033451	Orthotopic STS tumors labeled with GFP by OBP-401 were observed with noninvasive fluorescence imaging (OV100) before FGS was performed.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('FGS', 'Gene', '227671', (117, 120))	('OBP', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('GFP', 'Var', (35, 38))	('FGS', 'Gene', (117, 120))	('STS', 'Phenotype', 'HP:0030448', (11, 14))	('OBP', 'Gene', '29991', (42, 45))	('tumors', 'Disease', (15, 21))
257780	26038756	To date, more than 95% of cervical cancers, 50%-90% of other anogenital cancers and 20%-30% of oropharyngeal cancers have been associated with persistent infection and genomic integration of high-risk HPVs.	('cervical cancers', 'Disease', (26, 42))	('cervical cancers', 'Disease', 'MESH:D002583', (26, 42))	('genomic integration', 'Var', (168, 187))	('infection', 'Disease', (154, 163))	('infection', 'Disease', 'MESH:D007239', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('associated', 'Reg', (127, 137))	('HPV', 'Species', '10566', (201, 204))	('oropharyngeal cancers', 'Disease', 'MESH:D009959', (95, 116))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rat', 'Species', '10116', (181, 184))	('anogenital cancers', 'Disease', 'MESH:D009369', (61, 79))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('oropharyngeal cancers', 'Disease', (95, 116))	('persistent infection', 'Phenotype', 'HP:0031035', (143, 163))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('anogenital cancers', 'Disease', (61, 79))
257781	26038756	Among the common high-risk HPVs (HPV16, 18, 31, 33, 45 and 58), HPV16 is the most prevalent genotype and is responsible for ~60% of cervical cancer cases worldwide.	('HPV16', 'Species', '333760', (33, 38))	('HPV', 'Species', '10566', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('prevalent', 'Reg', (82, 91))	('HPV16', 'Var', (64, 69))	('HPV16', 'Species', '333760', (64, 69))	('HPV', 'Species', '10566', (33, 36))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('responsible', 'Reg', (108, 119))	('cancer', 'Disease', (141, 147))	('HPV', 'Species', '10566', (64, 67))
257789	26038756	HPV16 E6 appears to be more potent than HPV18 E6 for p53 degradation.	('HPV1', 'Species', '12080', (0, 4))	('HPV16', 'Species', '333760', (0, 5))	('HPV16', 'Var', (0, 5))	('p53', 'Gene', '7157', (53, 56))	('p53', 'Gene', (53, 56))	('HPV1', 'Species', '12080', (40, 44))
257792	26038756	The F47 residue within the N-terminal hydrophobic interface of HPV16 E6 is essential, and mutation of this residue results in loss of the p53 degradation activity of E6.	('p53', 'Gene', (138, 141))	('p53', 'Gene', '7157', (138, 141))	('HPV16', 'Species', '333760', (63, 68))	('loss', 'NegReg', (126, 130))	('HPV16', 'Gene', (63, 68))	('mutation', 'Var', (90, 98))
257808	26038756	Although early transcripts of both low-risk and high-risk HPVs contain an intron with alternative splice sites overlapping the E1 or E2 coding regions, and both utilize an early polyadenylation signal downstream of the E5 coding region for RNA polyadenylation, a striking feature of the high-risk HPV E6E7 polycistronic transcript is its unique E6 intron structure and alternative RNA splicing in the E6 coding region.	('HPV', 'Gene', (297, 300))	('HPV', 'Species', '10566', (58, 61))	('E6E7', 'Var', (301, 305))	('HPV', 'Species', '10566', (297, 300))
257810	26038756	In the case of HPV16, alternative E6 intron splicing of the polycistronic E6E7 pre-mRNA leads to the production of seven RNA splicing isoforms, E6*I, E6*II, E6*III, E6*IV, E6*V, E6*VI and E6 E7 in addition to a full-length, unspliced E6 mRNA (Figure 1B).	('E6*V', 'Var', (172, 176))	('E6*II', 'Var', (150, 155))	('E6*VI', 'Var', (178, 183))	('E6*IV', 'Var', (165, 170))	('E6*III', 'Var', (157, 163))	('E6E7', 'Gene', (74, 78))	('E6 E7', 'Var', (188, 193))	('E6*I', 'Var', (144, 148))	('HPV16', 'Species', '333760', (15, 20))
257812	26038756	The splicing of intron 1 from HPV16 E6E7 pre-mRNA is highly efficient and depends on intron definition.	('splicing', 'MPA', (4, 12))	('E6E7', 'Var', (36, 40))	('HPV16', 'Species', '333760', (30, 35))	('HPV16', 'Gene', (30, 35))
257813	26038756	The majority of the spliced products in cervical cancer and its derived cell lines are E6*I, derived from splicing of the nucleotide (nt) 226 5' ss to the nt 409 3' ss.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('E6*I', 'Var', (87, 91))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
257815	26038756	HPV16 E6*I encodes a truncated E6*I protein with 43 aa residues, which is in general expressed at levels below the detection threshold.	('HPV16', 'Gene', (0, 5))	('HPV16', 'Species', '333760', (0, 5))	('E6*I', 'Var', (31, 35))	('E6*I', 'Var', (6, 10))
257816	26038756	Although the function of the HPV16 E6*I protein remains unknown, HPV18 E6*I appears to play a dominant negative role with regard to full-length E6 oncoprotein and to induce proteasomal degradation of PDZ proteins, including the tumor suppressor hDlg.	('PDZ proteins', 'Protein', (200, 212))	('HPV1', 'Species', '12080', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('HPV18', 'Gene', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('negative', 'NegReg', (103, 111))	('hDlg', 'Gene', '1739', (245, 249))	('E6*I', 'Var', (71, 75))	('hDlg', 'Gene', (245, 249))	('proteasomal degradation', 'MPA', (173, 196))	('HPV1', 'Species', '12080', (29, 33))	('tumor', 'Disease', (228, 233))	('induce', 'PosReg', (166, 172))	('HPV16', 'Species', '333760', (29, 34))
257817	26038756	Thus, E6*I splicing is not a viral strategy to produce a potent E6*I protein, but rather a strategy to create an E7 mRNA that can be translated into E7 oncoprotein.	('E6*I splicing', 'Var', (6, 19))	('rat', 'Species', '10116', (37, 40))	('E6*', 'Var', (64, 67))	('rat', 'Species', '10116', (82, 85))	('rat', 'Species', '10116', (93, 96))
257820	26038756	However, splicing that produces E6*I creates a premature stop codon immediately downstream of the splice junction and increases the distance between the E6*I ORF and the E7 ORF to >130 nts in both HPV16 and HPV18, a much better condition for scanning ribosomes to re-initiate E7 translation.	('E6*I', 'Var', (153, 157))	('HPV16', 'Species', '333760', (197, 202))	('E6*I', 'Var', (32, 36))	('splicing', 'Var', (9, 17))	('HPV1', 'Species', '12080', (207, 211))	('distance', 'MPA', (132, 140))	('premature stop codon', 'MPA', (47, 67))	('increases', 'PosReg', (118, 127))	('HPV1', 'Species', '12080', (197, 201))
257828	26038756	Established MCC cell lines contain integrated MCV DNA encoding a mutant T antigen that prevents replication of the integrated virus from being autoactivated.	('mutant', 'Var', (65, 71))	('rat', 'Species', '10116', (40, 43))	('replication', 'MPA', (96, 107))	('rat', 'Species', '10116', (120, 123))	('MCV', 'Species', '493803', (46, 49))
257842	26038756	This is because MCV sT functions differently from SV40 sT; MCV sT promotes eukaryotic translation initiation factor 4E-binding protein 1 hyperphosphorylation and cap-dependent translation in a PP2A-independent manner, whereas SV40 sT induces dephosphorylation of 4E-binding protein 1 in a PP2A-dependent manner and inhibits cap-dependent translation.	('inhibits', 'NegReg', (315, 323))	('PP2A', 'Gene', (289, 293))	('PP2A', 'Gene', (193, 197))	('SV40', 'Species', '1891767', (50, 54))	('PP2A', 'Gene', '5524', (289, 293))	('MCV', 'Species', '493803', (59, 62))	('SV40 sT', 'Var', (226, 233))	('cap-dependent translation', 'MPA', (162, 187))	('cap-dependent translation', 'MPA', (324, 349))	('SV40', 'Species', '1891767', (226, 230))	('PP2A', 'Gene', '5524', (193, 197))	('promotes', 'PosReg', (66, 74))	('dephosphorylation', 'MPA', (242, 259))	('MCV', 'Species', '493803', (16, 19))	('hyperphosphorylation', 'MPA', (137, 157))
257843	26038756	Moreover, MCV sT suppresses the activity of the E3 ubiqitin ligase SCFFbw7, which degrades MCV LT, and stabilizes MCV LT through its LT-stabilization domain; SV40 sT does not have an LT-stabilization domain.	('MCV LT', 'MPA', (91, 97))	('MCV', 'Species', '493803', (91, 94))	('MCV', 'Species', '493803', (10, 13))	('degrades', 'NegReg', (82, 90))	('activity', 'MPA', (32, 40))	('suppresses', 'NegReg', (17, 27))	('E3 ubiqitin ligase', 'Enzyme', (48, 66))	('SV40', 'Species', '1891767', (158, 162))	('MCV', 'Species', '493803', (114, 117))	('SCFFbw7', 'Gene', (67, 74))	('SV40', 'Var', (158, 162))	('LT-stabilization', 'MPA', (133, 149))
257844	26038756	Although inhibition of SCFFbw7 stabilizes MCV LT, introduction of mutations in the sT LT-stabilization domain decreases LT protein levels and eliminates synergism in MCV DNA replication and sT-induced cell transformation.	('mutations', 'Var', (66, 75))	('LT protein levels', 'MPA', (120, 137))	('MCV DNA replication', 'MPA', (166, 185))	('decreases', 'NegReg', (110, 119))	('MCV', 'Species', '493803', (42, 45))	('sT-induced cell transformation', 'CPA', (190, 220))	('MCV', 'Species', '493803', (166, 169))	('eliminates', 'NegReg', (142, 152))	('synergism', 'MPA', (153, 162))
257901	26038756	Tax inactivates the tumor suppressor p53 and its homologues p73alpha and beta, but activates canonical Wnt signaling in the presence of a Wnt pathway-associated protein, disheveled-associating protein with a high frequency of leucine residues (DAPLE).	('activates', 'PosReg', (83, 92))	('leucine', 'Chemical', 'MESH:D007930', (226, 233))	('canonical Wnt', 'MPA', (93, 106))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('DAPLE', 'Gene', (244, 249))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('DAPLE', 'Gene', '440193', (244, 249))	('leucine residues', 'Var', (226, 242))	('inactivates', 'NegReg', (4, 15))	('tumor', 'Disease', (20, 25))
257937	26038756	The LTd transcript can be spliced to the K12 ORF for polyadenylation to encode K12, or it can remain unspliced, in which case it is polyadenylated by using the same pA signal as the LTi RNA E to encode vCyclin and vFLIP.	('vCyclin', 'Gene', (202, 209))	('pA', 'Chemical', 'MESH:D011061', (165, 167))	('vFLIP', 'Gene', (214, 219))	('vCyclin', 'Gene', '4961471', (202, 209))	('K12', 'Var', (79, 82))	('vFLIP', 'Gene', '4961494', (214, 219))
257968	26038756	At least four of the HCV gene products, the viral core, NS3, NS4B and NS5A, exhibit transformation potential in tissue culture, and several oncogenic pathways can be altered by the expression of these HCV proteins, thus presumably contributing to HCC development.	('HCC', 'Gene', (247, 250))	('NS4B', 'Gene', (61, 65))	('oncogenic pathways', 'Pathway', (140, 158))	('altered', 'Reg', (166, 173))	('NS5A', 'Gene', (70, 74))	('transformation potential', 'CPA', (84, 108))	('HCV', 'Species', '11103', (201, 204))	('NS4B', 'Gene', '951475', (61, 65))	('expression', 'Var', (181, 191))	('contributing', 'Reg', (231, 243))	('HCC', 'Gene', '619501', (247, 250))	('HCC', 'Phenotype', 'HP:0001402', (247, 250))	('NS3', 'Gene', (56, 59))	('NS3', 'Gene', '3845', (56, 59))	('HCV', 'Species', '11103', (21, 24))
257977	26038756	In looking forward into the twenty-first century, understanding and manipulation of RNA splicing in the development and control of human cancers will definitely trigger another wave of discoveries in RNA biology.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('human', 'Species', '9606', (131, 136))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('manipulation', 'Var', (68, 80))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Disease', (137, 144))
257983	23588325	Dyskeratosis congenita (DC) is a multisystem disease characterized by chromosomal instability and caused by a variety of defined genetic mutations leading to dysfunctional telomere maintenance.	('caused by', 'Reg', (98, 107))	('multisystem disease', 'Disease', 'MESH:D004194', (33, 52))	('chromosomal instability', 'Phenotype', 'HP:0040012', (70, 93))	('mutations', 'Var', (137, 146))	('multisystem disease', 'Disease', (33, 52))	('Dyskeratosis congenita', 'Disease', 'MESH:D019871', (0, 22))	('Dyskeratosis congenita', 'Disease', (0, 22))
257984	23588325	Specifically, mutations in the gene DKC1 are associated with the severe X-linked DC phenotype previously known as the Hoyeraal-Hreidarsson syndrome.	('DKC1', 'Gene', (36, 40))	('severe X-linked DC phenotype', 'Disease', (65, 93))	('DKC1', 'Gene', '1736', (36, 40))	('associated', 'Reg', (45, 55))	('Hoyeraal-Hreidarsson syndrome', 'Disease', 'MESH:C536068', (118, 147))	('Hoyeraal-Hreidarsson syndrome', 'Disease', (118, 147))	('mutations', 'Var', (14, 23))
257986	23588325	These predispositions have often been attributed to tissue specific deficits in telomere function; however, because severely affected DC patients with DKC1 mutations often manifest with B and T cell immunodeficiency, it is possible that poor immune function and the resultant chronic inflammation that occurs in tissues such as the oral mucosa and lower GI tract in DC patients could contribute to DC cancer predisposition, as chronic inflammation in otherwise healthy individuals is known to increase the risk for GI cancer.	('immunodeficiency', 'Phenotype', 'HP:0002721', (199, 215))	('GI cancer', 'Disease', 'MESH:D009369', (515, 524))	('GI cancer', 'Phenotype', 'HP:0007378', (515, 524))	('cancer', 'Disease', (518, 524))	('inflammation', 'Disease', (284, 296))	('cancer', 'Disease', 'MESH:D009369', (401, 407))	('inflammation', 'Disease', (435, 447))	('T cell immunodeficiency', 'Disease', 'MESH:C536780', (192, 215))	('DKC1', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (518, 524))	('DKC1', 'Gene', '1736', (151, 155))	('deficit', 'Disease', (68, 75))	('contribute', 'Reg', (384, 394))	('poor immune function', 'Phenotype', 'HP:0002721', (237, 257))	('deficit', 'Disease', 'MESH:D009461', (68, 75))	('patients', 'Species', '9606', (369, 377))	('manifest', 'Reg', (172, 180))	('cancer', 'Disease', 'MESH:D009369', (518, 524))	('mutations', 'Var', (156, 165))	('cancer', 'Disease', (401, 407))	('patients', 'Species', '9606', (137, 145))	('GI cancer', 'Disease', (515, 524))	('cancer', 'Phenotype', 'HP:0002664', (401, 407))	('inflammation', 'Disease', 'MESH:D007249', (284, 296))	('inflammation', 'Disease', 'MESH:D007249', (435, 447))	('T cell immunodeficiency', 'Disease', (192, 215))
257989	23588325	He was formally diagnosed with dyskeratosis congenita at age 8, with genetic evaluation showing a known disease causing mutation in the DKC1 gene (29 C>T, causing an amino acid substitution P10L).	('29 C>T', 'Mutation', 'rs199422242', (147, 153))	('causing', 'Reg', (155, 162))	('P10L', 'Var', (190, 194))	('P10L', 'Mutation', 'rs199422242', (190, 194))	('dyskeratosis congenita', 'Disease', (31, 53))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (31, 53))	('DKC1', 'Gene', (136, 140))	('29 C>T', 'Var', (147, 153))	('DKC1', 'Gene', '1736', (136, 140))
258032	23588325	In the workup of this case, a diagnosis of Kaposi's sarcoma was considered, especially given the severity of our patient's inherent immunodeficiency caused by his DKC1 mutation, along with his prolonged immunosuppression with infliximab.	('DKC1', 'Gene', (163, 167))	('patient', 'Species', '9606', (113, 120))	('immunodeficiency', 'Phenotype', 'HP:0002721', (132, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('DKC1', 'Gene', '1736', (163, 167))	('immunodeficiency', 'Disease', 'MESH:D007153', (132, 148))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (43, 59))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (43, 59))	('immunodeficiency', 'Disease', (132, 148))	('mutation', 'Var', (168, 176))	("Kaposi's sarcoma", 'Disease', (43, 59))	('infliximab', 'Chemical', 'MESH:D000069285', (226, 236))
258046	23588325	These findings appear to parallel the development of idiopathic pulmonary fibrosis in older DC patients, and may arise from specific effects of telomerase deficiency in the liver itself.	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (64, 82))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (53, 82))	('patients', 'Species', '9606', (95, 103))	('deficiency', 'Var', (155, 165))	('idiopathic pulmonary fibrosis', 'Disease', (53, 82))
258071	30513863	However, in other studies, high expression of HIF-1alpha protein correlated with good prognosis, such as lung cancer, squamous cell carcinoma, or renal cell carcinoma.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('renal cell carcinoma', 'Disease', (146, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (146, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (146, 166))	('squamous cell carcinoma', 'Disease', (118, 141))	('HIF-1alpha', 'Gene', (46, 56))	('high', 'Var', (27, 31))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 141))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('protein', 'Protein', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('lung cancer', 'Disease', (105, 116))	('HIF-1alpha', 'Gene', '3091', (46, 56))
258083	30513863	The multiple-described relationship of HIF-1alpha and the epidermal growth factor-receptor (EGFR)/pAKT pathway also makes this link interesting for STS, because epidermal growth factor can initiate an intracellular signal transduction cascade involving the PI3K/AKT and MAPK signaling pathways.	('HIF-1alpha', 'Gene', '3091', (39, 49))	('MAPK signaling pathways', 'Pathway', (270, 293))	('epidermal growth factor-receptor', 'Gene', (58, 90))	('AKT', 'Gene', (262, 265))	('epidermal', 'Var', (161, 170))	('AKT', 'Gene', '207', (99, 102))	('HIF-1alpha', 'Gene', (39, 49))	('EGFR', 'Gene', '1956', (92, 96))	('AKT', 'Gene', (99, 102))	('EGFR', 'Gene', (92, 96))	('epidermal growth factor-receptor', 'Gene', '1956', (58, 90))	('AKT', 'Gene', '207', (262, 265))	('STS', 'Phenotype', 'HP:0030448', (148, 151))
258093	30513863	We found that a low level of HIF-1alpha mRNA is significantly associated with a 2.8-fold increased risk of tumor-related death in STS patients (p = 0.001) (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (134, 142))	('HIF-1alpha', 'Gene', (29, 39))	('STS', 'Phenotype', 'HP:0030448', (130, 133))	('low level', 'Var', (16, 25))	('HIF-1alpha', 'Gene', '3091', (29, 39))
258098	30513863	However, those patients with recurrence after the primary tumor resection had a 3.1-fold (univariate Cox's regression hazard analysis) increased risk of tumor-related death when the expression was less than 4.7 copies of HIF-1alpha mRNA per copy of HPRT mRNA in their primary tumors (p = 0.003).	('patients', 'Species', '9606', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('HPRT', 'Gene', (249, 253))	('primary tumor', 'Disease', (50, 63))	('HIF-1alpha', 'Gene', (221, 231))	('Cox', 'Gene', '1351', (101, 104))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Cox', 'Gene', (101, 104))	('HPRT', 'Gene', '3251', (249, 253))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('expression', 'MPA', (182, 192))	('primary tumors', 'Disease', (268, 282))	('tumor', 'Disease', (276, 281))	('primary tumor', 'Disease', 'MESH:D009369', (268, 281))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('less than 4.7', 'Var', (197, 210))	('HIF-1alpha', 'Gene', '3091', (221, 231))	('primary tumors', 'Disease', 'MESH:D009369', (268, 282))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('primary tumor', 'Disease', 'MESH:D009369', (50, 63))
258099	30513863	Patients with high HIF-1alpha mRNA expression had a recurrence after a mean of 19 months; whereas patients with a low HIF-1alpha mRNA expression had a recurrence after a mean of 14 months after the diagnosis of the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('HIF-1alpha', 'Gene', '3091', (19, 29))	('patients', 'Species', '9606', (98, 106))	('HIF-1alpha', 'Gene', (118, 128))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('primary tumor', 'Disease', (215, 228))	('HIF-1alpha', 'Gene', (19, 29))	('primary tumor', 'Disease', 'MESH:D009369', (215, 228))	('HIF-1alpha', 'Gene', '3091', (118, 128))
258114	30513863	The prognostic effect was further increased by combining both mRNAs of EGFR and HIF-1alpha in comparison to a low expression of a single marker.	('prognostic effect', 'MPA', (4, 21))	('HIF-1alpha', 'Gene', '3091', (80, 90))	('mRNAs', 'Var', (62, 67))	('HIF-1alpha', 'Gene', (80, 90))	('combining', 'Interaction', (47, 56))	('EGFR', 'Gene', '1956', (71, 75))	('increased', 'PosReg', (34, 43))	('EGFR', 'Gene', (71, 75))
258115	30513863	Furthermore, patients, who had a recurrence with primary tumors exhibiting low levels of HIF-1alpha mRNA have a poorer prognosis compared to patients with primary tumors exhibiting high levels of HIF-1alpha mRNA (data not shown).	('HIF-1alpha', 'Gene', (196, 206))	('primary tumors', 'Disease', (155, 169))	('primary tumors', 'Disease', (49, 63))	('HIF-1alpha', 'Gene', '3091', (89, 99))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('primary tumors', 'Disease', 'MESH:D009369', (155, 169))	('HIF-1alpha', 'Gene', '3091', (196, 206))	('primary tumors', 'Disease', 'MESH:D009369', (49, 63))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('HIF-1alpha', 'Gene', (89, 99))	('low levels', 'Var', (75, 85))	('patients', 'Species', '9606', (141, 149))
258142	30513863	In a univariate survival analysis for non-small cell lung cancer, a high EGFR mRNA expression was significantly associated with a prolonged progression-free survival.	('progression-free survival', 'CPA', (140, 165))	('prolonged', 'PosReg', (130, 139))	('EGFR', 'Gene', '1956', (73, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (38, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('high', 'Var', (68, 72))	('mRNA expression', 'MPA', (78, 93))	('EGFR', 'Gene', (73, 77))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (42, 64))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (38, 64))	('non-small cell lung cancer', 'Disease', (38, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
258149	30513863	showed that hypoxia and activation of HIF prolongs the activation and the half-life of the EGF-receptor, and epigenetic regulation of EGFR may also play a role.	('EGFR', 'Gene', (134, 138))	('epigenetic regulation', 'Var', (109, 130))	('EGF-receptor', 'Protein', (91, 103))	('activation', 'MPA', (55, 65))	('hypoxia', 'Disease', 'MESH:D000860', (12, 19))	('half-life', 'MPA', (74, 83))	('hypoxia', 'Disease', (12, 19))	('EGFR', 'Gene', '1956', (134, 138))	('prolongs', 'PosReg', (42, 50))
258189	28474974	Herein, we describe a T5-T6 epidural tumor in a 15-year-old girl in which many neoplastic cells had moderate and focally abundant cytoplasm, including plasmacytoid or rhabdoid cells, rather than the more common Ewing-like morphology described in the majority of such tumors.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('rhabdoid', 'Disease', 'MESH:D018335', (167, 175))	('girl', 'Species', '9606', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('T5-T6', 'Var', (22, 27))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('rhabdoid', 'Disease', (167, 175))	('tumor', 'Disease', (267, 272))	('tumors', 'Disease', (267, 273))	('tumors', 'Disease', 'MESH:D009369', (267, 273))
258190	28474974	The diagnosis was confirmed by fluorescent in situ hybridization after the tumor was found to be WT-I positive, and comprehensive genomic profiling demonstrated breakpoints in exon 20 and exon 1 of the CIC and DUX4 genes, respectively.	('CIC', 'Gene', (202, 205))	('DUX4', 'Gene', (210, 214))	('DUX4', 'Gene', '100288687', (210, 214))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('breakpoints in', 'Var', (161, 175))	('tumor', 'Disease', (75, 80))
258193	28474974	CIC-rearranged sarcomas are a group of EWSR1-negative primitive round- or spindle-cell sarcomas that most commonly harbor translocations between the human homologue of the Drosophila capicua (CIC) gene on chromosome 19q13 and the double-homeobox 4 (DUX4) gene on chromosome 4q35 or 10q26.3.	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('sarcomas', 'Disease', (87, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('Drosophila', 'Species', '7227', (172, 182))	('sarcomas', 'Disease', (15, 23))	('capicua', 'Gene', (183, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('EWSR1', 'Gene', '2130', (39, 44))	('harbor', 'Reg', (115, 121))	('CIC-rearranged sarcomas', 'Disease', (0, 23))	('human', 'Species', '9606', (149, 154))	('DUX4', 'Gene', (249, 253))	('CIC', 'Gene', (192, 195))	('CIC-rearranged sarcomas', 'Disease', 'MESH:D012509', (0, 23))	('EWSR1', 'Gene', (39, 44))	('translocations', 'Var', (122, 136))	('DUX4', 'Gene', '100288687', (249, 253))	('capicua', 'Gene', '53560', (183, 190))
258194	28474974	Occasional cases occurring in peripheral sites harbor variant translocation in which the CIC gene is fused with the forkhead box O4 (FOXO4) gene on chromosome Xq13.	('FOXO4', 'Gene', (133, 138))	('variant translocation', 'Var', (54, 75))	('CIC gene', 'Gene', (89, 97))	('FOXO4', 'Gene', '4303', (133, 138))	('forkhead box O4', 'Gene', '4303', (116, 131))	('forkhead box O4', 'Gene', (116, 131))
258196	28474974	recently reclassified a subset of central nervous system-primitive neuroectodermal tumors (CNS-PNETs) based on DNA methylation profiles; one of the four categories included the CNS Ewing sarcoma family of tumors with CIC alteration (CNS EFT-CIC), the majority of which harbored rearrangement of the CIC gene.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Ewing sarcoma family of tumors', 'Disease', (181, 211))	('Ewing sarcoma family of tumors', 'Disease', 'MESH:C563168', (181, 211))	('CIC', 'Gene', (299, 302))	('rearrangement', 'Var', (278, 291))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (67, 89))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (57, 89))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (181, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('neuroectodermal tumors', 'Disease', (67, 89))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (67, 89))
258212	28474974	RT-PCR and fluorescent in situ hybridization (FISH) performed on FFPE tissue at a reference center were negative for EWSR1 rearrangement, and FISH was negative for SYT and FUS rearrangements.	('EWSR1', 'Gene', (117, 122))	('rearrangement', 'Var', (123, 136))	('EWSR1', 'Gene', '2130', (117, 122))	('negative', 'NegReg', (104, 112))	('FUS', 'Gene', (172, 175))	('FUS', 'Gene', '2521', (172, 175))
258222	28474974	CGP was performed and found to be negative for targetable genomic alterations, but a CIC-DUX4 fusion transcript was demonstrated in which an in-frame fusion of exon 20 of the CIC gene at the S1564 break-point to exon 1 of the DUX4 gene at the G103 breakpoint (Figure 2(c)).	('DUX4', 'Gene', (89, 93))	('DUX4', 'Gene', (226, 230))	('DUX4', 'Gene', '100288687', (226, 230))	('S1564', 'Var', (191, 196))	('DUX4', 'Gene', '100288687', (89, 93))	('CIC', 'Gene', (175, 178))
258231	28474974	Due to morphologic and immunohistochemical overlap with Ewing sarcoma, CIC-rearranged tumors have been referred to as Ewing-like sarcoma; however, they lack the translocations involving EWSR1 gene on chromosome 22 or FUS gene fused to the ETS transcription factor family.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('CIC-rearranged tumors', 'Disease', 'MESH:D009369', (71, 92))	('EWSR1', 'Gene', (186, 191))	('CIC-rearranged tumors', 'Disease', (71, 92))	('Ewing-like sarcoma', 'Disease', (118, 136))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (118, 136))	('Ewing sarcoma', 'Disease', (56, 69))	('lack', 'NegReg', (152, 156))	('EWSR1', 'Gene', '2130', (186, 191))	('FUS', 'Gene', (217, 220))	('translocations', 'Var', (161, 175))	('FUS', 'Gene', '2521', (217, 220))
258233	28474974	reported that the karyo-typic translocation corresponded to fusion of the CIC and DUX4 genes.	('DUX4', 'Gene', (82, 86))	('fusion', 'Var', (60, 66))	('CIC', 'Gene', (74, 77))	('DUX4', 'Gene', '100288687', (82, 86))
258245	28474974	Two of three of the CNS EFT-CIC tumors analyzed with RNA sequencing demonstrated interchromosomal gene fusion between the CIC gene and the NUT midline carcinoma, family member 1 (NUTM1, located on chromosome 15q14).	('interchromosomal gene fusion', 'Var', (81, 109))	('NUTM1', 'Gene', '256646', (179, 184))	('NUTM1', 'Gene', (179, 184))	('EFT-CIC tumors', 'Disease', 'MESH:D009369', (24, 38))	('CIC gene', 'Gene', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('EFT-CIC tumors', 'Disease', (24, 38))	('NUT midline carcinoma, family member 1', 'Gene', '256646', (139, 177))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
258248	28474974	The third case harbored a frameshift deletion in CIC (exon6:c.902delC:p.S301fs).	('CIC', 'Gene', (49, 52))	('frameshift deletion', 'Var', (26, 45))	('p.S301fs', 'Mutation', 'p.S301fsX', (70, 78))	('exon6:c.902delC', 'Var', (54, 69))	('exon6:c.902delC', 'DELETION', 'None', (54, 69))
258249	28474974	Eight of nine tumors analyzed by a FISH breakapart probes demonstrated rearrangement of the CIC gene, including one of the cases that harbored the CIC-NUTM1 fusion.	('CIC gene', 'Gene', (92, 100))	('NUTM1', 'Gene', '256646', (151, 156))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('NUTM1', 'Gene', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('rearrangement', 'Var', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
258255	28474974	Instead DNA and RNA sequencing revealed in-frame tandem duplications of the BCL6 corepressor (BCOR) gene.	('BCOR', 'Gene', (94, 98))	('BCL6 corepressor', 'Gene', '54880', (76, 92))	('BCOR', 'Gene', '54880', (94, 98))	('in-frame tandem duplications', 'Var', (40, 68))	('BCL6 corepressor', 'Gene', (76, 92))
258256	28474974	The duplicated region in exon 15 of BCOR is reported to be similar to the BCOR internal tandem duplication described in a subset of clear-cell sarcomas of the kidney (CCSK), infantile undifferentiated round-cell sarcomas and primitive myxoid mesenchymal tumor of infancy.	('sarcomas', 'Phenotype', 'HP:0100242', (212, 220))	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcomas', 'Disease', (212, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('sarcomas', 'Disease', (143, 151))	('sarcomas of the kidney', 'Disease', (143, 165))	('BCOR', 'Gene', (36, 40))	('sarcomas', 'Disease', 'MESH:D012509', (143, 151))	('internal tandem duplication', 'Var', (79, 106))	('BCOR', 'Gene', (74, 78))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (235, 259))	('BCOR', 'Gene', '54880', (36, 40))	('BCOR', 'Gene', '54880', (74, 78))	('sarcomas', 'Disease', 'MESH:D012509', (212, 220))	('sarcomas of the kidney', 'Disease', 'MESH:D007674', (143, 165))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('myxoid mesenchymal tumor', 'Disease', (235, 259))
258304	28695109	In additional work, efforts to generate urothelial tumors in a mouse model harboring kRAS inducible activation, and loss of p53, resulted in STS development at the site of the suture.	('urothelial tumors', 'Disease', 'MESH:D001749', (40, 57))	('mouse', 'Species', '10090', (63, 68))	('p53', 'Gene', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('resulted in', 'Reg', (129, 140))	('urothelial tumors', 'Disease', (40, 57))	('STS development at the site of the suture', 'CPA', (141, 182))	('p53', 'Gene', '22060', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('kRAS', 'Gene', (85, 89))	('activation', 'PosReg', (100, 110))	('loss', 'Var', (116, 120))
258305	28695109	showed that muscle injury by cardiotoxin following specific P53 shutdown and kRAS activation in muscle PAX7+ cells cause accelerated sarcoma formation at the site of injury.	('kRAS activation', 'Gene', (77, 92))	('shutdown', 'Var', (64, 72))	('P53', 'Gene', (60, 63))	('P53', 'Gene', '7157', (60, 63))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('PAX7', 'Gene', (103, 107))	('muscle injury', 'Disease', 'MESH:D009135', (12, 25))	('sarcoma', 'Disease', (133, 140))	('accelerated', 'PosReg', (121, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('PAX7', 'Gene', '5081', (103, 107))	('muscle injury', 'Disease', (12, 25))
258357	25552390	A larger study of patients diagnosed 1978-1993 did show a negative prognostic effect of tumour volume >=100 ml in both localised and metastatic disease.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('>=100', 'Var', (102, 107))	('localised', 'Disease', (119, 128))	('negative', 'NegReg', (58, 66))	('metastatic disease', 'Disease', (133, 151))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (18, 26))
258410	25552390	For example, amplification of the MYCN gene in neuroblastic tumours is not associated with the clinico-radiologic disease stage.	('MYCN', 'Gene', (34, 38))	('neuroblastic tumours', 'Disease', 'MESH:D009369', (47, 67))	('MYCN', 'Gene', '4613', (34, 38))	('amplification', 'Var', (13, 26))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('neuroblastic tumours', 'Disease', (47, 67))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
258417	25552390	The more limited role for radiology is complemented by independent well-defined and proven risk factors (age, MYCN oncogene amplitude, chromosome 11q status, DNA ploidy, tumour histology and differentiation).	('chromosome 11q status', 'Var', (135, 156))	('DNA ploidy', 'Disease', (158, 168))	('tumour', 'Disease', (170, 176))	('MYCN', 'Gene', (110, 114))	('MYCN', 'Gene', '4613', (110, 114))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (170, 176))
258491	31114378	Univariate and multivariate Cox regression analyses were used to evaluate the potential prognostic factors including age, sex, grade of the tumor, initial response to pazopanib treatment, number of metastases, treatment line for pazopanib use and inflammation indexes, and changes before and after treatment: NLR, DNLR, LMR, PLR, DeltaNLR, DeltaDNLR, DeltaLMR, and DeltaPLR.	('metastases', 'Disease', (198, 208))	('DeltaLMR', 'Var', (351, 359))	('inflammation', 'Disease', 'MESH:D007249', (247, 259))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('metastases', 'Disease', 'MESH:D009362', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('inflammation', 'Disease', (247, 259))	('pazopanib', 'Chemical', 'MESH:C516667', (229, 238))	('pazopanib', 'Chemical', 'MESH:C516667', (167, 176))	('tumor', 'Disease', (140, 145))
258509	31114378	There was no difference in OS and PFS values according to the LMR cutoffs: 22.23 vs 7.93 months and 7.9 vs 7.2 months for LMR >3.6 and LMR <3.6, respectively.	('PFS', 'MPA', (34, 37))	('LMR >3.6', 'Var', (122, 130))	('OS', 'Chemical', '-', (27, 29))	('LMR', 'Var', (135, 138))
258538	31114378	On the other hand, Yi Que et al showed shorter OS and PFS in cases with high NLR and PLR in univariate analysis but shorter OS in cases with only high PLR in multivariate analysis.	('PFS', 'CPA', (54, 57))	('shorter', 'NegReg', (39, 46))	('OS', 'Chemical', '-', (124, 126))	('PLR', 'Var', (85, 88))	('OS', 'Chemical', '-', (47, 49))
258540	31114378	We found shorter OS and PFS in cases with DNLR >=3.1 and only shorter OS in cases with NLR >=4.8 and PLR >=195, but did not find difference in OS and PFS according to the LMR.	('OS', 'Chemical', '-', (70, 72))	('PFS', 'CPA', (24, 27))	('shorter', 'NegReg', (9, 16))	('OS', 'Chemical', '-', (17, 19))	('DNLR >=3.1', 'Var', (42, 52))	('OS', 'Chemical', '-', (143, 145))
258579	29719113	Like vinca alkaloids, eribulin is a microtubule destabilizing agent, but unlike all known MTAs, eribulin only inhibits microtubule growth while having no effect on microtubule shortening.	('eribulin', 'Chemical', 'MESH:C490954', (22, 30))	('inhibits', 'NegReg', (110, 118))	('microtubule growth', 'MPA', (119, 137))	('eribulin', 'Var', (96, 104))	('eribulin', 'Chemical', 'MESH:C490954', (96, 104))	('vinca alkaloids', 'Chemical', 'MESH:D014748', (5, 20))
258581	29719113	Eribulin is metabolized primarily by CYP3A4 and is a substrate for the P-glycoprotein (P-gp) drug efflux pump; however, it maintains full in vitro activity against cancer cells that are taxane-resistant due to beta-tubulin mutations.	('P-gp', 'Gene', '5243', (87, 91))	('CYP3A4', 'Gene', '1576', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('taxane', 'Chemical', 'MESH:C080625', (186, 192))	('P-glycoprotein', 'Gene', '5243', (71, 85))	('P-gp', 'Gene', (87, 91))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('P-glycoprotein', 'Gene', (71, 85))	('CYP3A4', 'Gene', (37, 43))	('beta-tubulin', 'Protein', (210, 222))	('mutations', 'Var', (223, 232))	('activity', 'MPA', (147, 155))
258595	29719113	Other eligibility criteria included adequate bone marrow function (peripheral absolute neutrophil count >= 1,000/mm3, platelets >= 100,000/mm3 (transfusion independent) and hemoglobin >= 8 g/dL); adequate renal function (age-adjusted normal serum creatinine or glomerular filtration rate >= 70 ml/min/1.73m2); adequate liver function (total bilirubin 1.5x institutional upper limit of normal for age, ALT <= 110 U/L AST <= 125 U/L and albumin >= 2 g/dL); and adequate cardiac function (shortening fraction >= 27% or ejection fraction >= 50% and QTc <= 480 msec).	('peripheral absolute neutrophil count', 'Phenotype', 'HP:0001875', (67, 103))	('renal function', 'CPA', (205, 219))	('cardiac function', 'CPA', (468, 484))	('AST', 'Gene', (416, 419))	('ejection fraction', 'MPA', (516, 533))	('adequate liver function', 'Phenotype', 'HP:0001410', (310, 333))	('adequate cardiac function', 'Phenotype', 'HP:0001635', (459, 484))	('AST', 'Gene', '26503', (416, 419))	('shortening', 'Var', (486, 496))	('liver', 'MPA', (319, 324))	('QTc', 'Chemical', '-', (545, 548))	('bone marrow function', 'CPA', (45, 65))
258677	29626752	Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor1 Desmoplastic Small Round Cell Tumor (DSRCT) is a rare sarcoma tumor of adolescence and young adulthood, which harbors a recurrent chromosomal translocation between the Ewing's sarcoma gene (EWSR1) and the Wilms' tumor suppressor gene (WT1).	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (227, 242))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (179, 214))	('Tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('EWSR1', 'Gene', '2130', (249, 254))	('Desmoplastic Small Round Cell Tumor', 'Disease', (22, 57))	('sarcoma tumor', 'Disease', (113, 126))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (264, 276))	("Ewing's sarcoma", 'Disease', (227, 242))	('EWSR1', 'Gene', (249, 254))	('sarcoma tumor', 'Disease', 'MESH:D012509', (113, 126))	('Desmoplastic Small', 'Disease', 'MESH:D058405', (22, 40))	('chromosomal', 'Var', (189, 200))	('WT1', 'Gene', (294, 297))	('Desmoplastic Small Round Cell Tumor', 'Disease', (59, 94))	('Tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Desmoplastic Small Round Cell Tumor', 'Disease', 'MESH:D058405', (22, 57))	("Wilms' tumor", 'Disease', 'MESH:D009396', (264, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	("Wilms' tumor", 'Disease', (264, 276))	('WT1', 'Gene', '7490', (294, 297))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Desmoplastic Small', 'Disease', 'MESH:D058405', (59, 77))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (227, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('Desmoplastic Small Round Cell Tumor', 'Disease', 'MESH:D058405', (59, 94))
258685	29626752	This disease that harbors a t(11;22) translocation involving a fusion of the EWSR1 gene on chromosome 22 with the WT1 gene on chromosome 11, occurs primarily in male young patients as between 12 and 28 years and presents a pervasive peritoneal primary tumor spreading with metastases to the liver, lung and lymph nodes.	('metastases to the liver', 'Disease', 'MESH:D009362', (273, 296))	('metastases to the liver', 'Disease', (273, 296))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('WT1', 'Gene', '7490', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('fusion', 'Var', (63, 69))	('WT1', 'Gene', (114, 117))	('EWSR1', 'Gene', (77, 82))	('patients', 'Species', '9606', (172, 180))	('tumor', 'Disease', (252, 257))	('EWSR1', 'Gene', '2130', (77, 82))
258698	29626752	A Synergistic anti-tumor effect was observed with the joined inhibition of Bcl-2 with ABT-263/ABT-199 and Mcl-1 with ONC201 (through Bag3/UspX inhibition) through the mitochondrial pathway of apoptosis involving caspase activation and PARP-cleavage.	('ABT', 'Chemical', 'MESH:C002502', (94, 97))	('Bag3', 'Gene', (133, 137))	('Bag3', 'Gene', '9531', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('inhibition', 'NegReg', (61, 71))	('Mcl-1 with ONC201', 'Gene', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Bcl-2', 'Gene', (75, 80))	('Bcl-2', 'Gene', '596', (75, 80))	('PARP', 'Gene', '1302', (235, 239))	('mitochondrial pathway of apoptosis', 'Pathway', (167, 201))	('tumor', 'Disease', (19, 24))	('ABT-263/ABT-199', 'Var', (86, 101))	('Mcl-1 with ONC201', 'Gene', '4170', (106, 123))	('ABT', 'Chemical', 'MESH:C002502', (86, 89))	('PARP', 'Gene', (235, 239))
258713	29626752	After washing with PBS, the cells were incubated overnight at 4 C with antibodies to DR5.	('antibodies', 'Var', (71, 81))	('DR5', 'Gene', (85, 88))	('PBS', 'Chemical', 'MESH:D007854', (19, 22))	('DR5', 'Gene', '8795', (85, 88))
258728	29626752	of ONC201 (50 or 100 mg/kg) or vehicle control on day 7, 14, 21, and 28 of tumor cells injections.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('50', 'Var', (11, 13))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('ONC201', 'Gene', (3, 9))
258748	29626752	This indicates that ONC201 treatment of DSRCT cells induces cytotoxicity via the intrinsic pathway of apoptosis.	('ONC201', 'Var', (20, 26))	('intrinsic pathway of apoptosis', 'Pathway', (81, 111))	('cytotoxicity', 'Disease', (60, 72))	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))
258769	29626752	In DSRCT we found that ONC201 did induce TRAIL and DR5 protein expression, and cell death through the extrinsic pathway of apoptosis (Figure 3).	('induce', 'PosReg', (34, 40))	('DR5', 'Gene', '8795', (51, 54))	('ONC201', 'Var', (23, 29))	('TRAIL', 'Gene', '8743', (41, 46))	('cell death', 'CPA', (79, 89))	('TRAIL', 'Gene', (41, 46))	('extrinsic pathway of apoptosis', 'Pathway', (102, 132))	('DR5', 'Gene', (51, 54))
259059	29343557	DICER1 and associated conditions: Identification of at-risk individuals and recommended surveillance strategies Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations.	('DICER1', 'Gene', (0, 6))	('DICER1', 'Gene', '23405', (0, 6))	('hereditary cancer', 'Disease', 'MESH:D009369', (156, 173))	('DICER1', 'Gene', (132, 138))	('DICER1', 'Gene', '23405', (132, 138))	('hereditary cancer', 'Disease', (156, 173))	('cause', 'Reg', (148, 153))	('variants', 'Var', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
259060	29343557	In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma and brain tumors including pineoblastoma and pituitary blastoma.	('nasal chondromesenchymal hamartoma', 'Disease', (327, 361))	('renal sarcoma', 'Phenotype', 'HP:0008663', (260, 273))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (53, 77))	('ovarian sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (88, 119))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (410, 436))	('nasal chondromesenchymal hamartoma', 'Disease', 'MESH:D006222', (327, 361))	('brain tumors', 'Disease', (441, 453))	('ovarian sex cord-stromal tumors', 'Disease', (88, 119))	('cystic nephroma', 'Disease', (243, 258))	('medulloepithelioma', 'Phenotype', 'HP:0030071', (376, 394))	('PPB', 'Phenotype', 'HP:0100528', (79, 82))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (142, 159))	('lung cysts', 'Disease', (231, 241))	('cystic nephroma', 'Disease', 'MESH:D018201', (243, 258))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('lung cysts', 'Phenotype', 'HP:0032445', (231, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (429, 436))	('develop', 'PosReg', (223, 230))	('renal sarcoma', 'Disease', (260, 273))	('genitourinary embryonal rhabdomyosarcoma', 'Disease', (396, 436))	('sex cord-stromal tumors', 'Phenotype', 'HP:0031918', (96, 119))	('genitourinary embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (396, 436))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('renal sarcoma', 'Disease', 'MESH:D007674', (260, 273))	('pineoblastoma', 'Phenotype', 'HP:0030408', (464, 477))	('Wilms tumor', 'Disease', 'MESH:D009396', (278, 289))	('tumors', 'Phenotype', 'HP:0002664', (447, 453))	('ciliary body medulloepithelioma', 'Disease', (363, 394))	('pineoblastoma', 'Disease', 'MESH:D010871', (464, 477))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (134, 159))	('Sertoli-Leydig cell tumor', 'Disease', (134, 159))	('pleuropulmonary blastoma', 'Disease', (53, 77))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (53, 77))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (134, 159))	('DICER1', 'Gene', '23405', (198, 204))	('pituitary blastoma', 'Disease', 'MESH:D018202', (482, 500))	('variants', 'Var', (205, 213))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('hamartoma', 'Phenotype', 'HP:0010566', (352, 361))	('Wilms tumor', 'Phenotype', 'HP:0002667', (278, 289))	('brain tumors', 'Disease', 'MESH:D001932', (441, 453))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('brain tumors', 'Phenotype', 'HP:0030692', (441, 453))	('tumor', 'Phenotype', 'HP:0002664', (447, 452))	('nodular hyperplasia', 'Disease', 'MESH:D020518', (291, 310))	('ovarian sex cord-stromal tumors', 'Disease', 'MESH:D018312', (88, 119))	('nodular hyperplasia', 'Disease', (291, 310))	('cancer', 'Disease', (36, 42))	('DICER1', 'Gene', (198, 204))	('hyperplasia of the thyroid', 'Phenotype', 'HP:0008249', (299, 325))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (420, 436))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('pineoblastoma', 'Disease', (464, 477))	('pituitary blastoma', 'Disease', (482, 500))	('Wilms tumor', 'Disease', (278, 289))
259078	29343557	In 2009, the Registry identified pathogenic germline DICER1 variants as the genetic basis of PPB.	('PPB', 'Disease', (93, 96))	('DICER1', 'Gene', (53, 59))	('DICER1', 'Gene', '23405', (53, 59))	('variants', 'Var', (60, 68))	('PPB', 'Phenotype', 'HP:0100528', (93, 96))
259082	29343557	Approaches to the diagnosis of DICER1-associated conditions and risk management recommendations for patients and family members with germline pathogenic variants in DICER1 are presented.	('DICER1', 'Gene', (31, 37))	('DICER1', 'Gene', '23405', (31, 37))	('DICER1', 'Gene', '23405', (165, 171))	('men', 'Species', '9606', (75, 78))	('patients', 'Species', '9606', (100, 108))	('men', 'Species', '9606', (85, 88))	('variants', 'Var', (153, 161))	('DICER1', 'Gene', (165, 171))
259083	29343557	Data from the International PPB and OTST Registries were collated to generate a dataset of 682 individuals from 652 families with pathogenic germline variants in DICER1 or clinical history of DICER1-associated conditions.	('variants', 'Var', (150, 158))	('DICER1', 'Gene', '23405', (192, 198))	('DICER1', 'Gene', (162, 168))	('DICER1', 'Gene', '23405', (162, 168))	('PPB', 'Phenotype', 'HP:0100528', (28, 31))	('DICER1', 'Gene', (192, 198))
259084	29343557	Although not all patients in the registries had germline DICER1 status available for review, the majority of individuals with PPB have germline mutations, and nearly all individuals with DICER1-associated conditions enrolled in the registries were individuals with PPB or ascertained on the basis of a first or second degree relative with PPB.	('PPB', 'Phenotype', 'HP:0100528', (339, 342))	('PPB', 'Phenotype', 'HP:0100528', (126, 129))	('DICER1', 'Gene', (187, 193))	('DICER1', 'Gene', '23405', (187, 193))	('DICER1', 'Gene', (57, 63))	('DICER1', 'Gene', '23405', (57, 63))	('patients', 'Species', '9606', (17, 25))	('PPB', 'Phenotype', 'HP:0100528', (265, 268))	('germline', 'Var', (135, 143))	('PPB', 'Gene', (126, 129))	('PPB', 'Disease', (265, 268))
259092	29343557	Over 70% of individuals with PPB have a germline loss-of-function mutation with a second, tumor specific missense mutation in the RNase IIIb domain.	('PPB', 'Phenotype', 'HP:0100528', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('PPB', 'Disease', (29, 32))	('loss-of-function', 'NegReg', (49, 65))	('mutation', 'Var', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
259093	29343557	The tumor-specific RNase IIIb missense mutations involve one of 5 "hotspot" codons, E1705, D1709, G1809, D1810 or E1813.	('tumor', 'Disease', (4, 9))	('D1709', 'Var', (91, 96))	('missense mutations', 'Var', (30, 48))	('RNase IIIb', 'Enzyme', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('E1813', 'Var', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('E1705', 'Var', (84, 89))	('D1810', 'Var', (105, 110))	('G1809', 'Var', (98, 103))
259094	29343557	Although most children with PPB have a germline loss-of-function mutation and a second tumor specific "hotspot" mutation, approximately 10% exhibit mosaicism.	('children', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('mosaicism', 'Var', (148, 157))	('loss-of-function', 'NegReg', (48, 64))	('PPB', 'Phenotype', 'HP:0100528', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('PPB', 'Disease', (28, 31))
259095	29343557	Individuals with mosaic "hotspot" mutations in the RNase IIIb domain may have tumor specific loss-of-function mutations and have earlier onset disease and a higher frequency of multisite disease.	('onset disease', 'Disease', (137, 150))	('mutations', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('RNase IIIb', 'Gene', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('multisite disease', 'Disease', (177, 194))	('loss-of-function', 'NegReg', (93, 109))	('onset disease', 'Disease', 'MESH:D000544', (137, 150))	('tumor', 'Disease', (78, 83))	('multisite disease', 'Disease', 'MESH:D004194', (177, 194))	('mutations', 'Var', (34, 43))
259097	29343557	Consider the two scenarios: a child with germline loss-of-function DICER1 mutations vs. a child with mosaicism for a missense mutation in one of the 5 hotspot amino acids.	('mutations', 'Var', (74, 83))	('child', 'Species', '9606', (30, 35))	('DICER1', 'Gene', (67, 73))	('DICER1', 'Gene', '23405', (67, 73))	('loss-of-function', 'NegReg', (50, 66))	('child', 'Species', '9606', (90, 95))
259100	29343557	In the second child, the second somatic mutation only needs to be a loss-of-function which may be hundreds of times more likely (chromosome loss, gene deletion, truncating mutations, etc).	('loss-of-function', 'NegReg', (68, 84))	('truncating mutations', 'Var', (161, 181))	('gene deletion', 'Var', (146, 159))	('chromosome', 'Var', (129, 139))	('child', 'Species', '9606', (14, 19))
259102	29343557	About 10-15% of individuals with DICER1 tumors appear to have biallelic mutations limited to tumor tissue, or low-level mosaicism for loss-of-function mutations.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('loss-of-function', 'NegReg', (134, 150))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (93, 98))	('DICER1', 'Gene', (33, 39))	('biallelic mutations', 'Var', (62, 81))	('DICER1', 'Gene', '23405', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumors', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
259103	29343557	To date, all the children with suspected tumor limited mutations have had single site disease and it is reasonable to consider that these children may not need intensive surveillance.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('children', 'Species', '9606', (138, 146))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', (41, 46))	('single site disease', 'Disease', (74, 93))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('children', 'Species', '9606', (17, 25))
259104	29343557	But without extensive sequencing of multiple tissue types and sites, it can be difficult to differentiate a child with tumor-limited DICER1 mutations from one with low-level mosaicism for a loss-of-function mutation.	('child', 'Species', '9606', (108, 113))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutations', 'Var', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('DICER1', 'Gene', (133, 139))	('DICER1', 'Gene', '23405', (133, 139))
259105	29343557	At a minimum, individuals with presumed biallelic somatic mutations should be aware of the risk for low-level mosaicism and individuals and their health care providers should be aware of the need to seek care expeditiously if signs or symptoms of DICER1-related conditions develop.	('biallelic', 'Var', (40, 49))	('DICER1', 'Gene', (247, 253))	('DICER1', 'Gene', '23405', (247, 253))
259106	29343557	Tumor-based or somatic testing for DICER1 mutations may be useful in a variety of clinical settings including diagnosing tumors which are challenging histologically, confirmation of biallelic somatic mutations, assessment for mosaicism and determining whether new findings represents a metastatic/recurrent or metachronous tumor.	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('men', 'Species', '9606', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('DICER1', 'Gene', (35, 41))	('metastatic/recurrent', 'CPA', (286, 306))	('tumor', 'Disease', (323, 328))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('DICER1', 'Gene', '23405', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
259108	29343557	Therefore, the children of individuals with a DICER1 pathogenic variant have a 50%, chance of inheriting the mutation.	('children', 'Species', '9606', (15, 23))	('DICER1', 'Gene', (46, 52))	('DICER1', 'Gene', '23405', (46, 52))	('variant', 'Var', (64, 71))
259109	29343557	An analysis of the prevalence of pathogenic germline DICER1 variation in the Exome Aggregation Consortium (excluding cases ascertained from The Cancer Genome Atlas) found that approximately 1:2,529 - 1:10,600 individuals in the general population carry a pathogenic or likely pathogenic DICER1 variant.	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('variation', 'Var', (60, 69))	('variant', 'Var', (294, 301))	('pathogenic', 'Reg', (276, 286))	('pathogenic', 'Reg', (33, 43))	('Cancer Genome Atlas', 'Disease', (144, 163))	('DICER1', 'Gene', (287, 293))	('DICER1', 'Gene', (53, 59))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (144, 163))	('DICER1', 'Gene', '23405', (53, 59))	('DICER1', 'Gene', '23405', (287, 293))	('pathogenic', 'Reg', (255, 265))
259117	29343557	Individuals at 50% risk of a germline pathogenic variant based on family history who do not pursue genetic testing should follow surveillance guidelines as if they have a DICER1 mutation unless/until genetic testing confirms that they did not inherit the familial mutation.	('variant', 'Var', (49, 56))	('DICER1', 'Gene', '23405', (171, 177))	('mutation', 'Var', (178, 186))	('DICER1', 'Gene', (171, 177))
259118	29343557	For individuals with pathogenic germline DICER1 variants, we recommend additional site-specific genetic testing of that variant for all first-degree relatives.	('DICER1', 'Gene', (41, 47))	('men', 'Species', '9606', (66, 69))	('DICER1', 'Gene', '23405', (41, 47))	('variants', 'Var', (48, 56))	('pathogenic', 'Reg', (21, 31))
259124	29343557	If no mutation is detected via DICER1 sequencing in a germline specimen (e.g., blood, saliva or skin fibroblasts), germline DICER1 deletion/duplication analyses should be performed, as some cases are due to copy-number variants.	('deletion/duplication', 'Var', (131, 151))	('DICER1', 'Gene', (31, 37))	('DICER1', 'Gene', '23405', (31, 37))	('due', 'Reg', (200, 203))	('copy-number variants', 'Var', (207, 227))	('DICER1', 'Gene', (124, 130))	('DICER1', 'Gene', '23405', (124, 130))	('men', 'Species', '9606', (68, 71))
259131	29343557	Testing of relatives is not generally indicated for individuals with biallelic somatic mutations in the absence of detectable pathogenic germline DICER1 variants, however, it should be noted that gonadal mosaicism may result in risk to offspring and therefore consideration could be given to offering children of individuals with possible mosaicism site specific testing in the rare event that their germline is involved.	('result', 'Reg', (218, 224))	('DICER1', 'Gene', (146, 152))	('risk', 'MPA', (228, 232))	('offspring', 'CPA', (236, 245))	('DICER1', 'Gene', '23405', (146, 152))	('children', 'Species', '9606', (301, 309))	('variants', 'Var', (153, 161))
259132	29343557	If testing is initiated due to a known familial DICER1 pathogenic variant, we recommend prioritization of predictive testing of first-degree relatives.	('variant', 'Var', (66, 73))	('men', 'Species', '9606', (83, 86))	('DICER1', 'Gene', (48, 54))	('DICER1', 'Gene', '23405', (48, 54))
259134	29343557	We recommend third trimester ultrasound (US) for women whose fetuses are at risk for a pathogenic germline DICER1 variant from either the maternal or paternal side to detect large lung cysts which might require early intervention after delivery.	('women', 'Species', '9606', (49, 54))	('large lung cysts', 'Phenotype', 'HP:0005948', (174, 190))	('variant', 'Var', (114, 121))	('DICER1', 'Gene', (107, 113))	('DICER1', 'Gene', '23405', (107, 113))	('men', 'Species', '9606', (51, 54))	('men', 'Species', '9606', (8, 11))	('lung cysts', 'Phenotype', 'HP:0032445', (180, 190))
259138	29343557	In discussions regarding prenatal testing, a thorough dialogue should include the relatively low penetrance of malignant conditions and high likelihood of a healthy child/adult (one without DICER1-associated conditions or minor findings) even if a DICER1 mutation is inherited.	('DICER1', 'Gene', (248, 254))	('DICER1', 'Gene', (190, 196))	('DICER1', 'Gene', '23405', (248, 254))	('mutation', 'Var', (255, 263))	('child', 'Species', '9606', (165, 170))	('DICER1', 'Gene', '23405', (190, 196))
259144	29343557	This neoplasm remains one of the pathognomonic manifestations of pathogenic germline DICER1 variants and one of the most important causes of DICER1-associated morbidity and mortality.	('DICER1', 'Gene', (141, 147))	('DICER1', 'Gene', '23405', (141, 147))	('neoplasm', 'Disease', (5, 13))	('neoplasm', 'Disease', 'MESH:D009369', (5, 13))	('neoplasm', 'Phenotype', 'HP:0002664', (5, 13))	('DICER1', 'Gene', (85, 91))	('DICER1', 'Gene', '23405', (85, 91))	('variants', 'Var', (92, 100))
259149	29343557	We recommend a chest x-ray (CXR) at birth for all children at risk of a pathogenic germline DICER1 variant to screen for any large pulmonary cysts.	('pulmonary cysts', 'Disease', (131, 146))	('men', 'Species', '9606', (8, 11))	('variant', 'Var', (99, 106))	('children', 'Species', '9606', (50, 58))	('large pulmonary cysts', 'Phenotype', 'HP:0005948', (125, 146))	('DICER1', 'Gene', (92, 98))	('DICER1', 'Gene', '23405', (92, 98))	('pulmonary cysts', 'Disease', 'MESH:D004445', (131, 146))	('pulmonary cysts', 'Phenotype', 'HP:0032445', (131, 146))	('pulmonary cyst', 'Phenotype', 'HP:0032445', (131, 145))
259151	29343557	In children who are found to be carriers of a pathogenic germline DICER1 variant, the first chest computed tomography (CT) should be obtained by 9 months of age, preferably between 3 and 6 months of age, since the incidence of Type II and III PPB increases after one year of age.	('children', 'Species', '9606', (3, 11))	('carriers', 'Reg', (32, 40))	('DICER1', 'Gene', (66, 72))	('pathogenic', 'Reg', (46, 56))	('DICER1', 'Gene', '23405', (66, 72))	('PPB', 'Phenotype', 'HP:0100528', (243, 246))	('variant', 'Var', (73, 80))
259152	29343557	In the absence of pulmonary cysts/PPB, most individuals with DICER1 mutations detected in early childhood will undergo only 2 chest CTs.	('pulmonary cyst', 'Phenotype', 'HP:0032445', (18, 32))	('pulmonary cysts', 'Disease', (18, 33))	('PPB', 'Phenotype', 'HP:0100528', (34, 37))	('pulmonary cysts', 'Phenotype', 'HP:0032445', (18, 33))	('pulmonary cysts', 'Disease', 'MESH:D004445', (18, 33))	('DICER1', 'Gene', (61, 67))	('DICER1', 'Gene', '23405', (61, 67))	('mutations', 'Var', (68, 77))	('child', 'Species', '9606', (96, 101))
259158	29343557	When a pulmonary cyst is identified in a young child with a pathogenic germline DICER1 variant or family history of a DICER1-associated condition, it should be assumed to be Type I PPB until proven otherwise.	('pulmonary cyst', 'Disease', (7, 21))	('DICER1', 'Gene', (80, 86))	('DICER1', 'Gene', '23405', (80, 86))	('DICER1', 'Gene', (118, 124))	('child', 'Species', '9606', (47, 52))	('pathogenic', 'Reg', (60, 70))	('DICER1', 'Gene', '23405', (118, 124))	('PPB', 'Phenotype', 'HP:0100528', (181, 184))	('pulmonary cyst', 'Phenotype', 'HP:0032445', (7, 21))	('variant', 'Var', (87, 94))
259162	29343557	Pulmonary cysts are often identified in adults with pathogenic germline DICER1 variants and are assumed to be Type Ir PPB.	('Pulmonary cysts', 'Phenotype', 'HP:0032445', (0, 15))	('Pulmonary cysts', 'Disease', (0, 15))	('PPB', 'Phenotype', 'HP:0100528', (118, 121))	('DICER1', 'Gene', (72, 78))	('DICER1', 'Gene', '23405', (72, 78))	('variants', 'Var', (79, 87))	('pathogenic', 'Reg', (52, 62))
259164	29343557	Further discussion of the management of pulmonary cysts among individuals including adolescents with pathogenic germline DICER1 variants is beyond the scope of this guideline but is available through the International PPB Registry's website (www.PPBregistry.org) or in the European Very Rare Tumor Group guidelines (www.raretumors-children.eu).	('pulmonary cysts', 'Disease', 'MESH:D004445', (40, 55))	('PPB', 'Phenotype', 'HP:0100528', (246, 249))	('DICER1', 'Gene', (121, 127))	('DICER1', 'Gene', '23405', (121, 127))	('Tumor', 'Phenotype', 'HP:0002664', (292, 297))	('PPB', 'Phenotype', 'HP:0100528', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('children', 'Species', '9606', (331, 339))	('men', 'Species', '9606', (32, 35))	('pulmonary cyst', 'Phenotype', 'HP:0032445', (40, 54))	('variants', 'Var', (128, 136))	('tumors', 'Disease', (324, 330))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('pulmonary cysts', 'Disease', (40, 55))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('pulmonary cysts', 'Phenotype', 'HP:0032445', (40, 55))
259166	29343557	A recent analysis showed 2/41 (5%) Wilms tumors are secondary to pathogenic germline DICER1 variants.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Wilms tumors', 'Disease', (35, 47))	('Wilms tumors', 'Phenotype', 'HP:0002667', (35, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('secondary', 'Reg', (52, 61))	('Wilms tumors', 'Disease', 'MESH:D009396', (35, 47))	('Wilms tumor', 'Phenotype', 'HP:0002667', (35, 46))	('DICER1', 'Gene', (85, 91))	('DICER1', 'Gene', '23405', (85, 91))	('variants', 'Var', (92, 100))
259171	29343557	As above, we expect that additional studies will clarify whether a normal US and/or resection of CN in early childhood predicts a lower likelihood of later renal malignancy.	('lower', 'NegReg', (130, 135))	('renal malignancy', 'Disease', 'MESH:D007674', (156, 172))	('child', 'Species', '9606', (109, 114))	('resection', 'Var', (84, 93))	('renal malignancy', 'Disease', (156, 172))	('renal malignancy', 'Phenotype', 'HP:0009726', (156, 172))
259172	29343557	Individuals with pathogenic germline DICER1 variants are at increased risk for Sertoli-Leydig cell tumor (SLCT) and gynandroblastoma.	('Sertoli-Leydig cell tumor', 'Disease', (79, 104))	('gynandroblastoma', 'Disease', (116, 132))	('DICER1', 'Gene', (37, 43))	('DICER1', 'Gene', '23405', (37, 43))	('gynandroblastoma', 'Disease', 'MESH:D018312', (116, 132))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (79, 104))	('SLCT', 'Phenotype', 'HP:0100619', (106, 110))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (79, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (87, 104))	('variants', 'Var', (44, 52))
259180	29343557	Thus far, data shows that individuals with germline DICER1 mutations have a lower risk of recurrence of the primary SLCT compared with those with biallelic tumor specific mutations, however, individuals with germline mutations may develop synchronous or metachronous contralateral tumors (see Table 4).	('DICER1', 'Gene', (52, 58))	('metachronous contralateral tumors', 'Disease', (254, 287))	('synchronous', 'CPA', (239, 250))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('metachronous contralateral tumors', 'Disease', 'MESH:D016609', (254, 287))	('DICER1', 'Gene', '23405', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('develop', 'PosReg', (231, 238))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('SLCT', 'Phenotype', 'HP:0100619', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', (281, 286))
259191	29343557	Follicular variant of papillary cancer and follicular thyroid cancer are the most common histologies seen in individuals with pathogenic germline DICER1 variants.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('papillary cancer', 'Disease', (22, 38))	('DICER1', 'Gene', (146, 152))	('follicular thyroid cancer', 'Disease', (43, 68))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (43, 68))	('papillary cancer', 'Disease', 'MESH:D000077273', (22, 38))	('thyroid cancer', 'Phenotype', 'HP:0002890', (54, 68))	('DICER1', 'Gene', '23405', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('variants', 'Var', (153, 161))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (43, 68))	('Follicular variant', 'Disease', (0, 18))
259192	29343557	To date, all thyroid tumors associated with pathogenic germline DICER1 variants have displayed indolent behavior, with disease usually confined to the thyroid gland.	('variants', 'Var', (71, 79))	('thyroid tumors', 'Disease', (13, 27))	('thyroid tumors', 'Disease', 'MESH:D013959', (13, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('DICER1', 'Gene', (64, 70))	('DICER1', 'Gene', '23405', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
259196	29343557	There are no prospective studies on the efficacy or timing of screening thyroid US in individuals with germline DICER1 pathogenic variants.	('DICER1', 'Gene', (112, 118))	('DICER1', 'Gene', '23405', (112, 118))	('variants', 'Var', (130, 138))
259201	29343557	Individuals with pathogenic germline DICER1 variants are at risk for ciliary body medulloepithelioma (CBME), and in an earlier report the PPB Registry noted four individuals, age 4, 6, 8 and 9 years, with CBME and pathogenic germline DICER1 variants.	('DICER1', 'Gene', (234, 240))	('DICER1', 'Gene', '23405', (234, 240))	('DICER1', 'Gene', (37, 43))	('DICER1', 'Gene', '23405', (37, 43))	('ciliary body medulloepithelioma', 'Disease', (69, 100))	('PPB', 'Phenotype', 'HP:0100528', (138, 141))	('variants', 'Var', (44, 52))	('medulloepithelioma', 'Phenotype', 'HP:0030071', (82, 100))
259202	29343557	There is an additional patient in the literature with somatic DICER1 variants, diagnosed at 18 years of age.	('variants', 'Var', (69, 77))	('DICER1', 'Gene', '23405', (62, 68))	('DICER1', 'Gene', (62, 68))	('patient', 'Species', '9606', (23, 30))
259207	29343557	Individuals with pathogenic germline DICER1 variants are at risk for developing benign nasal chondromesenchymal hamartoma (NCMH).	('DICER1', 'Gene', (37, 43))	('benign nasal chondromesenchymal hamartoma', 'Disease', 'MESH:D006222', (80, 121))	('DICER1', 'Gene', '23405', (37, 43))	('hamartoma', 'Phenotype', 'HP:0010566', (112, 121))	('benign nasal chondromesenchymal hamartoma', 'Disease', (80, 121))	('variants', 'Var', (44, 52))
259210	29343557	Thus, at this time, we recommend that individuals, caregivers and providers be aware of the potential for NCMH and that otolaryngologic evaluation be considered for persistent nasal or sinus symptoms in individuals of any age with pathogenic germline DICER1 variants.	('nasal', 'Disease', (176, 181))	('DICER1', 'Gene', (251, 257))	('DICER1', 'Gene', '23405', (251, 257))	('men', 'Species', '9606', (28, 31))	('variants', 'Var', (258, 266))	('sinus symptoms', 'Phenotype', 'HP:0000246', (185, 199))	('pathogenic', 'Reg', (231, 241))
259211	29343557	Primary tumors involving the central nervous system (CNS) have also been described among individuals with pathogenic germline DICER1 variants.	('DICER1', 'Gene', '23405', (126, 132))	('Primary tumors', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Primary tumors', 'Disease', 'MESH:D009369', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('DICER1', 'Gene', (126, 132))	('variants', 'Var', (133, 141))
259217	29343557	Eleven of 12 cases with germline or tumor material available for analysis demonstrated at least one germline or somatic DICER1 mutation.	('mutation', 'Var', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('DICER1', 'Gene', (120, 126))	('tumor', 'Disease', (36, 41))	('DICER1', 'Gene', '23405', (120, 126))
259218	29343557	Pineoblastomas may also be seen among individuals with pathogenic germline DICER1 variants.	('variants', 'Var', (82, 90))	('Pineoblastomas', 'Disease', (0, 14))	('Pineoblastomas', 'Disease', 'MESH:D010871', (0, 14))	('DICER1', 'Gene', (75, 81))	('DICER1', 'Gene', '23405', (75, 81))
259220	29343557	After the initial association of pineoblastoma with DICER1 mutations was described, in a subsequent series, 3 of 18 individuals without previously known genotypes were found to carry pathogenic germline DICER1 variants.	('DICER1', 'Gene', (52, 58))	('pathogenic', 'Reg', (183, 193))	('DICER1', 'Gene', '23405', (203, 209))	('variants', 'Var', (210, 218))	('DICER1', 'Gene', '23405', (52, 58))	('pineoblastoma', 'Disease', (33, 46))	('pineoblastoma', 'Phenotype', 'HP:0030408', (33, 46))	('mutations', 'Var', (59, 68))	('DICER1', 'Gene', (203, 209))	('pineoblastoma', 'Disease', 'MESH:D010871', (33, 46))
259222	29343557	Interestingly, 2 pituitary blastoma cases also involving LOH of the wildtype allele have been described, suggesting the possibility of a distinct mechanism of second-hit among these intracranial neoplasms.	('pituitary blastoma', 'Disease', (17, 35))	('LOH', 'Var', (57, 60))	('neoplasm', 'Phenotype', 'HP:0002664', (195, 203))	('intracranial neoplasms', 'Disease', 'MESH:D001932', (182, 204))	('neoplasms', 'Phenotype', 'HP:0002664', (195, 204))	('pituitary blastoma', 'Disease', 'MESH:D018202', (17, 35))	('intracranial neoplasms', 'Disease', (182, 204))
259223	29343557	In one study, 42% of 67 individuals with a pathogenic germline DICER1 variant were additionally found to be macrocephalic (occipital head circumference > 2 standard deviation) compared with 12% of 43 family controls.	('macrocephalic', 'Disease', (108, 121))	('DICER1', 'Gene', (63, 69))	('DICER1', 'Gene', '23405', (63, 69))	('pathogenic', 'Reg', (43, 53))	('macrocephalic', 'Disease', 'None', (108, 121))	('occipital head', 'Phenotype', 'HP:0000269', (123, 137))	('variant', 'Var', (70, 77))
259231	29343557	As knowledge of DICER1 and its clinical implications increases, facilitating larger studies of patients with pathogenic germline DICER1 variants, criteria for genetic testing and/or clinical diagnosis will continue to be refined.	('DICER1', 'Gene', '23405', (129, 135))	('variants', 'Var', (136, 144))	('patients', 'Species', '9606', (95, 103))	('DICER1', 'Gene', (16, 22))	('DICER1', 'Gene', '23405', (16, 22))	('DICER1', 'Gene', (129, 135))
259232	29343557	Similarly, the management guidelines for cancer/tumor screening and risk reduction in patients who have pathogenic germline DICER1 variants will continue to be updated (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (48, 53))	('DICER1', 'Gene', (124, 130))	('DICER1', 'Gene', '23405', (124, 130))	('variants', 'Var', (131, 139))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('men', 'Species', '9606', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('patients', 'Species', '9606', (86, 94))
259233	29343557	Most individuals with pathogenic germline DICER1 variants are healthy, or have only minor DICER1-associated conditions.	('DICER1', 'Gene', (90, 96))	('DICER1', 'Gene', '23405', (42, 48))	('variants', 'Var', (49, 57))	('pathogenic', 'Reg', (22, 32))	('DICER1', 'Gene', '23405', (90, 96))	('DICER1', 'Gene', (42, 48))
259234	29343557	The most severe manifestations of pathogenic germline DICER1 variants tend to present in early childhood with adulthood characterized by good health.	('child', 'Species', '9606', (95, 100))	('pathogenic', 'Reg', (34, 44))	('DICER1', 'Gene', (54, 60))	('DICER1', 'Gene', '23405', (54, 60))	('variants', 'Var', (61, 69))
259237	29343557	Given the overall good prognosis for most individuals with pathogenic germline DICER1 variants, the risks and potential benefits of lifelong screening must be carefully balanced.	('DICER1', 'Gene', '23405', (79, 85))	('pathogenic', 'Reg', (59, 69))	('DICER1', 'Gene', (79, 85))	('variants', 'Var', (86, 94))
259241	29343557	International collaboration is encouraged for all individuals with DICER1 pathogenic variants or DICER1-associated conditions to allow further revision of these guidelines and to help reduce the morbidity and mortality of individuals with pathogenic variants in DICER1.	('variants', 'Var', (85, 93))	('DICER1', 'Gene', (262, 268))	('DICER1', 'Gene', '23405', (262, 268))	('DICER1', 'Gene', (97, 103))	('DICER1', 'Gene', (67, 73))	('DICER1', 'Gene', '23405', (97, 103))	('DICER1', 'Gene', '23405', (67, 73))	('variants', 'Var', (250, 258))
259249	28300287	The average tumor RFP area in the first passage from RFP mice to non-colored mice was 20+-7%; in the second passage, 28+-11%; in the third passage was 27+-13%.	('mice', 'Species', '10090', (57, 61))	('mice', 'Species', '10090', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('RFP', 'Var', (53, 56))	('tumor', 'Disease', (12, 17))
259280	28300287	The average tumor RFP area in the first passage of RFP mice was 34 +- 22%; in the second passage was 34 +- 20%; and in the third passage was 36 +- 11%.	('RFP', 'Var', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('mice', 'Species', '10090', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
259281	28300287	The average tumor RFP area in the first passage from RFP mice to non-colored mice was 20+-7%; in the second passage was 28+-11%; and in the third passage was 27+-13%.	('mice', 'Species', '10090', (57, 61))	('mice', 'Species', '10090', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('RFP', 'Var', (53, 56))	('tumor', 'Disease', (12, 17))
259316	28178131	All 11 studies indicated high SUVmax, MTV, or/and TLG represented a worse prognosis than patients with low numerical value.	('MTV', 'Chemical', '-', (38, 41))	('TLG', 'Chemical', '-', (50, 53))	('TLG', 'Disease', (50, 53))	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (89, 97))	('SUVmax', 'MPA', (30, 36))	('MTV', 'MPA', (38, 41))
259324	28178131	PFS was better with low SUVmax patients in comparison with patients with high SUVmax (HR = 2.20, 95% CI: 1.47-3.30, I2 = 0%, P = 0.79) (Fig.	('PFS', 'CPA', (0, 3))	('patients', 'Species', '9606', (31, 39))	('low', 'Var', (20, 23))	('patients', 'Species', '9606', (59, 67))
259327	28178131	The pooled HR showed the significant survival advantage for low TLG over high TLG patients with sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('patients', 'Species', '9606', (82, 90))	('low', 'Var', (60, 63))	('TLG', 'Chemical', '-', (64, 67))	('TLG', 'Chemical', '-', (78, 81))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('sarcoma', 'Disease', (96, 103))
259345	28178131	According to the combined OR based on 1-, 3-, and 5-year OS and PFS, high SUVmax was associated with worse short- and long-term survival outcome and lesser survival benefit in patients with sarcoma.	('patients', 'Species', '9606', (176, 184))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('sarcoma', 'Disease', (190, 197))	('OS', 'Chemical', '-', (57, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('high', 'Var', (69, 73))	('SUVmax', 'MPA', (74, 80))
259367	24669185	One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing's sarcoma.	('sarcomas', 'Disease', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (171, 186))	('synovial sarcoma', 'Disease', (119, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (119, 135))	('synovial sarcoma', 'Disease', 'MESH:D013584', (119, 135))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (171, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('X:18 translocation', 'Var', (92, 110))	("Ewing's sarcoma", 'Disease', (171, 186))
259372	24669185	Gastrointestinal stromal tumor (GIST) is a malignant sarcoma felt to arise from the interstitial cell of Cajal and is characterized most commonly by activating mutations in c-kit, and less commonly in platelet-derived growth factor receptor alpha (PDGFRA).	('malignant sarcoma', 'Disease', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (160, 169))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (201, 246))	('PDGFRA', 'Gene', (248, 254))	('Gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (0, 30))	('PDGFRA', 'Gene', '5156', (248, 254))	('c-kit', 'Gene', (173, 178))	('activating', 'PosReg', (149, 159))	('platelet-derived growth factor receptor alpha', 'Gene', (201, 246))	('malignant sarcoma', 'Disease', 'MESH:D009369', (43, 60))	('Gastrointestinal stromal tumor', 'Disease', (0, 30))	('Gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (0, 30))	('c-kit', 'Gene', '3815', (173, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('GIST', 'Phenotype', 'HP:0100723', (32, 36))
259374	24669185	Interestingly, patients with complete responses, partial responses, and stable disease have similar rates of progression-free survival (PFS) compared with patients with stable disease using imatinib when using conventional response criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) with traditional computed tomography scanning.	('patients', 'Species', '9606', (15, 23))	('partial responses', 'Var', (49, 66))	('Solid Tumors', 'Disease', (281, 293))	('Solid Tumors', 'Disease', 'MESH:D009369', (281, 293))	('imatinib', 'Chemical', 'MESH:D000068877', (190, 198))	('patients', 'Species', '9606', (155, 163))	('Tumors', 'Phenotype', 'HP:0002664', (287, 293))
259376	24669185	The most common mutation site is at exon 11 and is usually sensitive to treatment with imatinib at 400 mg. Other mutations, such as exon 9, may benefit from higher doses of imatinib.	('exon 9', 'Var', (132, 138))	('imatinib', 'Chemical', 'MESH:D000068877', (87, 95))	('benefit', 'PosReg', (144, 151))	('imatinib', 'Chemical', 'MESH:D000068877', (173, 181))	('mutations', 'Var', (113, 122))
259377	24669185	A smaller percentage of GISTs have mutations in the platelet-derived growth factor receptor alpha, and these tumors may also be sensitive to imatinib.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (52, 97))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('platelet-derived growth factor receptor alpha', 'Gene', (52, 97))	('imatinib', 'Chemical', 'MESH:D000068877', (141, 149))	('sensitive to imatinib', 'MPA', (128, 149))	('GIST', 'Phenotype', 'HP:0100723', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('mutations', 'Var', (35, 44))
259408	24669185	The RFS rate was 98% in the imatinib group and 83% in the placebo group at 1 year, with a hazard ratio of 0.35 (one-sided P < 0.0001).	('imatinib', 'Var', (28, 36))	('imatinib', 'Chemical', 'MESH:D000068877', (28, 36))	('RFS', 'MPA', (4, 7))
259490	24669185	R1507 is a monoclonal antibody directed at IGF1R.	('IGF1R', 'Gene', '3480', (43, 48))	('IGF1R', 'Gene', (43, 48))	('R1507', 'Var', (0, 5))
259491	24669185	One hundred eleven patients with Ewing's sarcoma were treated with R1507 weekly at 9 mg/kg.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (33, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('patients', 'Species', '9606', (19, 27))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (33, 48))	("Ewing's sarcoma", 'Disease', (33, 48))	('R1507 weekly', 'Var', (67, 79))
259494	24669185	It has been evaluated in a Phase II trial of patients with metastatic Ewing's sarcoma or desmoplastic small cell tumors, which also contain fusions of the EWS gene.	('desmoplastic small cell tumors', 'Disease', (89, 119))	('desmoplastic small cell tumors', 'Disease', 'MESH:D058405', (89, 119))	('EWS', 'Gene', (155, 158))	('EWS', 'Gene', '2130', (155, 158))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (70, 85))	("Ewing's sarcoma", 'Disease', (70, 85))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (70, 85))	('patients', 'Species', '9606', (45, 53))	('fusions', 'Var', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
259517	24669185	PD0332991 is a CDK4 inhibitor.	('CDK4', 'Gene', '1019', (15, 19))	('CDK4', 'Gene', (15, 19))	('PD0332991', 'Var', (0, 9))	('PD0332991', 'Chemical', 'MESH:C500026', (0, 9))
259518	24669185	A recent Phase II trial using oral PD0332991 at 200 mg/day for 14 days in a 21-day cycle enrolled 29 patients, of whom 27 were evaluable for the primary endpoint of PFS higher than 40% at 12 weeks.	('PD0332991', 'Chemical', 'MESH:C500026', (35, 44))	('patients', 'Species', '9606', (101, 109))	('PFS', 'MPA', (165, 168))	('PD0332991', 'Var', (35, 44))
259520	24669185	GDC-0449 is an inhibitor of the hedgehog pathway.	('GDC-0449', 'Var', (0, 8))	('hedgehog pathway', 'Pathway', (32, 48))	('GDC-0449', 'Chemical', 'MESH:C538724', (0, 8))
259528	24669185	RAP and other therapeutics targeting mTOR are particularly active against malignancies driven by activated PI3K, Akt, or both, as well as by PTEN (phosphatase and tensin homologue deleted from chromosome 10) gene mutations as the tumor becomes dependent on this pathway for growth.	('tumor', 'Disease', (230, 235))	('Akt', 'Gene', '207', (113, 116))	('malignancies', 'Disease', (74, 86))	('Akt', 'Gene', (113, 116))	('mTOR', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('mTOR', 'Gene', '2475', (37, 41))	('mutations', 'Var', (213, 222))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('malignancies', 'Disease', 'MESH:D009369', (74, 86))
259533	24669185	By inhibiting mTOR, and therefore the translation of proteins that are essential for cell cycle traverse, cell growth, survival, and cell division, RAP and RAP analogs have antiproliferative and immunosuppressive effects.	('mTOR', 'Gene', '2475', (14, 18))	('analogs', 'Var', (160, 167))	('cell', 'CPA', (106, 110))	('immunosuppressive effects', 'CPA', (195, 220))	('inhibiting', 'NegReg', (3, 13))	('translation', 'MPA', (38, 49))	('antiproliferative', 'CPA', (173, 190))	('mTOR', 'Gene', (14, 18))
259550	24669185	Analysis of 51 cases of soft tissue sarcomas revealed mutations of the PTEN/MMAC1 gene in two cases (3.9%), both being leiomyosarcoma arising from the intraabdominal cavity.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('soft tissue sarcomas', 'Disease', (24, 44))	('leiomyosarcoma', 'Disease', (119, 133))	('mutations', 'Var', (54, 63))	('MMAC1', 'Gene', '5728', (76, 81))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (119, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (24, 44))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (24, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('MMAC1', 'Gene', (76, 81))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (119, 133))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (24, 44))
259569	24669185	AP23573 has favorable pharmaceutical and pharmacological characteristics, and early studies in human xenograft models have shown a potent inhibition of tumor growth with a five times a day oral administration schedule of AP23573.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('AP23573', 'Chemical', 'MESH:C515074', (0, 7))	('inhibition', 'NegReg', (138, 148))	('AP23573', 'Var', (221, 228))	('human', 'Species', '9606', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('AP23573', 'Chemical', 'MESH:C515074', (221, 228))	('AP23573', 'Var', (0, 7))
259585	24669185	The antitumor activity of AP23573 in this study is summarized in Table 1.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('AP23573', 'Var', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('AP23573', 'Chemical', 'MESH:C515074', (26, 33))
259595	24669185	The pre-specified endpoint of the study, the PFS was met with a statistically significant improvement in PFS (hazard ratio= 0.72; P>0,0001, stratified log-rank) and 52% gain in median PFS (22.4 weeks for ridaforolimus and 14.7 weeks for placebo).	('improvement', 'PosReg', (90, 101))	('gain', 'PosReg', (169, 173))	('ridaforolimus', 'Var', (204, 217))	('PFS', 'MPA', (105, 108))	('PFS', 'MPA', (184, 187))	('ridaforolimus', 'Chemical', 'MESH:C515074', (204, 217))
259598	24669185	The incidence of side effects was higher in the ridaforolimus arm, but there were no unexpected events and the overall safety profile was consistent with prior reported data with the same drug and other mTOR inhibitors.	('ridaforolimus', 'Chemical', 'MESH:C515074', (48, 61))	('ridaforolimus', 'Var', (48, 61))	('mTOR', 'Gene', (203, 207))	('mTOR', 'Gene', '2475', (203, 207))
259644	24669185	Disorders caused by mutation of the TSC1 or TSC2 genes usually result in overactivation of the mTOR pathway, as their gene products regulate negatively mTORC.	('TSC1', 'Gene', '7248', (36, 40))	('mTOR', 'Gene', (152, 156))	('TSC1', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (152, 156))	('mutation', 'Var', (20, 28))	('overactivation', 'PosReg', (73, 87))	('TSC2', 'Gene', '7249', (44, 48))	('result', 'Reg', (63, 69))	('mTOR', 'Gene', (95, 99))	('regulate', 'Reg', (132, 140))	('mTOR', 'Gene', '2475', (95, 99))	('TSC2', 'Gene', (44, 48))
259797	33706618	Some continuous variables were cast to categorical variables, such as age (>60years, <=60 years) and tumor size (<50 mm, 50-100 mm, >100 mm).	('50-100 mm', 'Var', (121, 130))	('age', 'Gene', '5973', (70, 73))	('<50 mm', 'Var', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('age', 'Gene', (70, 73))	('>100 mm', 'Var', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
259831	33706618	proposed that 70% of patients with high-grade STS will develop metastases, which was much higher than for low-grade STS.	('STS', 'Phenotype', 'HP:0030448', (46, 49))	('high-grade', 'Var', (35, 45))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('develop', 'PosReg', (55, 62))	('patients', 'Species', '9606', (21, 29))	('STS', 'Phenotype', 'HP:0030448', (116, 119))	('metastases', 'Disease', (63, 73))
259832	33706618	According to our nomograms for predicting lung, liver and bone metastasis, patients with high-grade STS suffered a higher risk of metastasis and thus a worse prognosis.	('metastasis', 'CPA', (130, 140))	('high-grade', 'Var', (89, 99))	('patients', 'Species', '9606', (75, 83))	('STS', 'Phenotype', 'HP:0030448', (100, 103))
259936	28216610	In a systemic review of the Cochrane database, liposomal anthracyclines were found to have superior response rate without an increase in toxic side effects.	('liposomal', 'Var', (47, 56))	('anthracyclines', 'Chemical', 'MESH:D018943', (57, 71))	('response', 'CPA', (100, 108))
259945	28086809	Fluorescence in situ hybridisation (FISH) showed a translocation involving the EWSR1 gene region.	('EWSR1', 'Gene', (79, 84))	('EWSR1', 'Gene', '2130', (79, 84))	('translocation', 'Var', (51, 64))
259966	28086809	A clear separation of red and green signals within a single cell was identified in most cells, which demonstrated the presence of the EWSR1 rearrangement (Fig.	('EWSR1', 'Gene', (134, 139))	('EWSR1', 'Gene', '2130', (134, 139))	('rearrangement', 'Var', (140, 153))
259990	28086809	Fortunately, molecular genetic characterisation of CCS has been shown to be specific for t(12;22) translocation, which has not yet been identified in melanoma.	('t(12', 'Gene', (89, 93))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('translocation', 'Var', (98, 111))
259991	28086809	Previous molecular studies showed that cutaneous melanoma has frequent BRAF mutations, but not in CCS.	('mutations', 'Var', (76, 85))	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', (71, 75))	('cutaneous melanoma', 'Disease', (39, 57))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (39, 57))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (39, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
259992	28086809	Therefore, we strengthened the diagnosis by using FISH analysis, which demonstrated an unequivocal EWSR1 gene rearrangement and lack of BRAF mutation.	('EWSR1', 'Gene', '2130', (99, 104))	('BRAF', 'Gene', '673', (136, 140))	('BRAF', 'Gene', (136, 140))	('rearrangement', 'Var', (110, 123))	('EWSR1', 'Gene', (99, 104))
260005	27297500	There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups.	('CDKN2A', 'Gene', (93, 99))	('translocation', 'Var', (63, 76))	('CDKN2A', 'Gene', '1029', (93, 99))	('EWSR1', 'Gene', (57, 62))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('mutation/loss', 'Var', (100, 113))	('EWSR1', 'Gene', '2130', (57, 62))
260006	27297500	After controlling for age, race, and primary site, EES was associated with superior EFS [hazard ratio = 0.69; 95% CI: 0.50-0.95; P = 0.02].	('EFS', 'Gene', '10278', (84, 87))	('EFS', 'Gene', (84, 87))	('EES', 'Chemical', '-', (51, 54))	('EES', 'Var', (51, 54))	('ES', 'Phenotype', 'HP:0012254', (52, 54))
260026	27297500	For both INT-0154 and AEWS0031, any tumor with any degree of bone involvement was considered a primary bone tumor.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('bone tumor', 'Disease', 'MESH:D001859', (103, 113))	('AEWS0031', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('bone tumor', 'Phenotype', 'HP:0010622', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('bone tumor', 'Disease', (103, 113))	('tumor', 'Disease', (36, 41))
260036	27297500	Information regarding tumor biology was also obtained where available and included type of EWSR1 translocation as determined in a prior study.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('translocation', 'Var', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('EWSR1', 'Gene', (91, 96))	('EWSR1', 'Gene', '2130', (91, 96))
260037	27297500	Presence or absence of a TP53 mutation or CDKN2A mutation/loss were assessed in a subset of patients included in a retrospective analysis.	('TP53', 'Gene', (25, 29))	('patients', 'Species', '9606', (92, 100))	('CDKN2A', 'Gene', (42, 48))	('CDKN2A', 'Gene', '1029', (42, 48))	('TP53', 'Gene', '7157', (25, 29))	('mutation/loss', 'Var', (49, 62))
260060	27297500	We also performed a sensitivity analysis of EFS focused exclusively on patients treated on AEWS0031 and observed a significantly decreased risk for event for patients with EES compared to skeletal ES [hazard ratio (HR) = 0.52; 95% CI 0.33-0.82; P = 0.005].	('EFS', 'Gene', '10278', (44, 47))	('patients', 'Species', '9606', (71, 79))	('EES', 'Chemical', '-', (172, 175))	('ES', 'Phenotype', 'HP:0012254', (173, 175))	('ES', 'Phenotype', 'HP:0012254', (197, 199))	('EFS', 'Gene', (44, 47))	('AEWS0031', 'Var', (91, 99))	('patients', 'Species', '9606', (158, 166))	('decreased', 'NegReg', (129, 138))
260067	27297500	These variables were also significant predictors of OS, though we also observed a trend in which patients with pelvic EES had superior OS (HR=0.18; 95% CI: 0.02-1.29; P=0.09; Table II).	('OS', 'Chemical', '-', (52, 54))	('pelvic', 'Var', (111, 117))	('OS', 'Chemical', '-', (135, 137))	('superior', 'PosReg', (126, 134))	('ES', 'Phenotype', 'HP:0012254', (119, 121))	('EES', 'Chemical', '-', (118, 121))	('patients', 'Species', '9606', (97, 105))
260072	27297500	Likewise, the frequency of TP53 mutation or CDKN2A mutation/loss did not differ between EES and skeletal Ewing sarcoma.	('TP53', 'Gene', '7157', (27, 31))	('skeletal Ewing sarcoma', 'Disease', (96, 118))	('TP53', 'Gene', (27, 31))	('EES', 'Chemical', '-', (88, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('CDKN2A', 'Gene', (44, 50))	('CDKN2A', 'Gene', '1029', (44, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('EES', 'Disease', (88, 91))	('mutation/loss', 'NegReg', (51, 64))	('ES', 'Phenotype', 'HP:0012254', (89, 91))	('mutation/loss', 'Var', (51, 64))	('skeletal Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 118))
260108	27297500	Recent literature has described a rare subset of highly aggressive EWSR1 translocation-negative sarcomas that have distinct genetic signatures and have been referred to as undifferentiated small round cell sarcomas or Ewing-like sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (206, 214))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('EWSR1', 'Gene', '2130', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (218, 237))	('sarcomas', 'Phenotype', 'HP:0100242', (206, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('translocation-negative', 'Var', (73, 95))	('sarcomas', 'Disease', (206, 214))	('sarcomas', 'Disease', (96, 104))	('Ewing-like sarcomas', 'Disease', (218, 237))	('sarcomas', 'Disease', 'MESH:D012509', (229, 237))	('EWSR1', 'Gene', (67, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (229, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('sarcomas', 'Disease', (229, 237))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (218, 237))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))
260110	27297500	While it is possible that our cohort included tumors harboring one of the mutations commonly seen in Ewing-like sarcomas such as CIC-DUX4 or BCOR-CCNB3, the potential impact on our study is minimal given the small proportion of translocation-negative tumors and the fact that these tumors were balanced between groups.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Ewing-like sarcomas', 'Disease', (101, 120))	('CCNB3', 'Gene', '85417', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('DUX4', 'Gene', (133, 137))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (101, 120))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('tumors', 'Disease', (46, 52))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (101, 120))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('DUX4', 'Gene', '100288687', (133, 137))	('CCNB3', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', (282, 288))	('BCOR', 'Gene', '54880', (141, 145))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('BCOR', 'Gene', (141, 145))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('mutations', 'Var', (74, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))
260208	34022875	There is little evidence of the efficacy of chemotherapy or hormonal therapy, even with estrogen receptor (ER) or progesterone receptor (PR) positivity, in treating MPT.	('progesterone receptor', 'Gene', (114, 135))	('progesterone receptor', 'Gene', '5241', (114, 135))	('positivity', 'Var', (141, 151))	('ER', 'Gene', '2099', (107, 109))	('estrogen receptor', 'Gene', (88, 105))	('MPT', 'Disease', (165, 168))	('estrogen receptor', 'Gene', '2099', (88, 105))	('PR', 'Gene', '5241', (137, 139))
260276	27074562	p53 down regulates FOXM1 and FOXM1 inhibition is also partly dependent on Rb and p21.	('FOXM1', 'Gene', (29, 34))	('FOXM1', 'Gene', (19, 24))	('Rb', 'Chemical', 'MESH:D012413', (74, 76))	('p53', 'Var', (0, 3))	('p21', 'Gene', (81, 84))	('p21', 'Gene', '644914', (81, 84))	('down regulates', 'NegReg', (4, 18))
260277	27074562	Abnormalities of p53 or Rb are frequent in sporadic sarcomas with bone or soft tissue sarcoma, accounting for 36% of index cancers in the high penetrance TP53 germline disorder, Li-Fraumeni syndrome.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('sporadic sarcomas', 'Disease', 'MESH:D012509', (43, 60))	('Abnormalities', 'Var', (0, 13))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (74, 93))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (74, 93))	('Rb', 'Chemical', 'MESH:D012413', (24, 26))	('soft tissue sarcoma', 'Disease', (74, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('frequent', 'Reg', (31, 39))	('Li-Fraumeni syndrome', 'Disease', (178, 198))	('TP53', 'Gene', (154, 158))	('sporadic sarcomas', 'Disease', (43, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (178, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('p53', 'Protein', (17, 20))	('TP53', 'Gene', '7157', (154, 158))
260280	27074562	In undifferentiated pleomorphic sarcoma, liposarcoma, and fibrosarcoma, dysregulation of the Hippo pathway increases expression of the effector co-transcriptional activator Yes-Associated Protein (YAP).	('increases', 'PosReg', (107, 116))	('Yes-Associated Protein', 'Gene', '10413', (173, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('YAP', 'Gene', (197, 200))	('undifferentiated pleomorphic sarcoma', 'Disease', (3, 39))	('fibrosarcoma', 'Disease', 'MESH:D005354', (58, 70))	('Yes-Associated Protein', 'Gene', (173, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('fibrosarcoma', 'Disease', (58, 70))	('liposarcoma', 'Disease', 'MESH:D008080', (41, 52))	('liposarcoma', 'Disease', (41, 52))	('YAP', 'Gene', '10413', (197, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('expression', 'MPA', (117, 127))	('dysregulation', 'Var', (72, 85))	('liposarcoma', 'Phenotype', 'HP:0012034', (41, 52))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (58, 70))	('Hippo pathway', 'Pathway', (93, 106))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (3, 39))
260284	27074562	Current systemic treatment of sarcoma is of limited efficacy and inhibiting FOXM1 represents a potential new strategy.	('FOXM1', 'Gene', (76, 81))	('inhibiting', 'Var', (65, 75))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('sarcoma', 'Disease', (30, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
260288	27074562	One candidate strategy is targeted inhibition of the mammalian transcription factor Forkhead Box M1 (FOXM1).	('Forkhead Box M1', 'Gene', '2305', (84, 99))	('FOXM1', 'Gene', (101, 106))	('mammalian', 'Species', '9606', (53, 62))	('Forkhead Box M1', 'Gene', (84, 99))	('inhibition', 'Var', (35, 45))
260289	27074562	In Drosophila melanogaster mutations of forkhead create ectopic head structures in the fruit fly embryos, hence the nomenclature.	('mutations', 'Var', (27, 36))	('ectopic', 'CPA', (56, 63))	('create', 'Reg', (49, 55))	('Drosophila melanogaster', 'Species', '7227', (3, 26))	('fruit fly', 'Species', '7227', (87, 96))	('forkhead', 'Gene', (40, 48))
260299	27074562	Early in the cell cycle at M/G1 transition almost all of the phosphate groups are removed from retinoblastoma protein (pRb) resulting in an unphosphorylated configuration.	('retinoblastoma', 'Gene', (95, 109))	('retinoblastoma', 'Phenotype', 'HP:0009919', (95, 109))	('phosphate', 'Chemical', 'MESH:D010710', (61, 70))	('pRb', 'Gene', (119, 122))	('M/G1', 'Var', (27, 31))	('M/G1', 'SUBSTITUTION', 'None', (27, 31))	('retinoblastoma', 'Gene', '5925', (95, 109))	('unphosphorylated configuration', 'MPA', (140, 170))	('phosphate groups', 'MPA', (61, 77))
260303	27074562	Children with hereditary retinoblastoma, a condition in which tumors arise from biallelic functional loss of RB1, have a 1,000 fold increased risk of osteosarcoma compared to the general population.	('osteosarcoma', 'Disease', (150, 162))	('RB1', 'Gene', '5925', (109, 112))	('hereditary retinoblastoma', 'Disease', (14, 39))	('Children', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('osteosarcoma', 'Phenotype', 'HP:0002669', (150, 162))	('osteosarcoma', 'Disease', 'MESH:D012516', (150, 162))	('tumors', 'Disease', (62, 68))	('loss', 'Var', (101, 105))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('retinoblastoma', 'Phenotype', 'HP:0009919', (25, 39))	('RB1', 'Gene', (109, 112))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (14, 39))
260304	27074562	Furthermore RB1 alterations are identified in 80% of primary sporadic osteosarcomas.	('RB1', 'Gene', (12, 15))	('alterations', 'Var', (16, 27))	('osteosarcomas', 'Disease', (70, 83))	('osteosarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('osteosarcomas', 'Phenotype', 'HP:0002669', (70, 83))	('RB1', 'Gene', '5925', (12, 15))	('identified', 'Reg', (32, 42))	('osteosarcomas', 'Disease', 'MESH:D012516', (70, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
260305	27074562	Amplification of CDK4 and loss of RB1, or CDKN2A loss are considered nearly universal in osteosarcoma with 20% of cases having either amplification of CDK4 or deletion of CDKN2A.	('osteosarcoma', 'Disease', (89, 101))	('loss', 'NegReg', (49, 53))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('RB1', 'Gene', '5925', (34, 37))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('CDKN2A', 'Gene', (171, 177))	('CDK4', 'Gene', (17, 21))	('amplification', 'Var', (134, 147))	('CDKN2A', 'Gene', (42, 48))	('loss', 'NegReg', (26, 30))	('CDK4', 'Gene', '1019', (17, 21))	('CDK4', 'Gene', '1019', (151, 155))	('CDK4', 'Gene', (151, 155))	('CDKN2A', 'Gene', '1029', (171, 177))	('deletion', 'Var', (159, 167))	('CDKN2A', 'Gene', '1029', (42, 48))	('RB1', 'Gene', (34, 37))
260308	27074562	Mice with osteoblast-restricted deletion of p53 and pRb develop short latency high-grade osteosarcoma.	('osteosarcoma', 'Disease', (89, 101))	('deletion', 'Var', (32, 40))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('pRb', 'Gene', (52, 55))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('p53', 'Gene', (44, 47))	('develop', 'Reg', (56, 63))	('Mice', 'Species', '10090', (0, 4))
260317	27074562	The highly penetrant cancer predisposition disorder Li-Fraumeni syndrome is associated with germline TP53 mutations.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('TP53', 'Gene', '7157', (101, 105))	('disorder Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (43, 72))	('associated', 'Reg', (76, 86))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('cancer', 'Disease', (21, 27))	('disorder Li-Fraumeni syndrome', 'Disease', (43, 72))
260319	27074562	TP53 mutations occur in 19% to 38% of sporadic osteosarcomas.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('osteosarcomas', 'Phenotype', 'HP:0002669', (47, 60))	('osteosarcomas', 'Disease', 'MESH:D012516', (47, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('mutations', 'Var', (5, 14))	('osteosarcomas', 'Disease', (47, 60))	('osteosarcoma', 'Phenotype', 'HP:0002669', (47, 59))
260322	27074562	A global gene expression analysis of different cancer types found FOXM1, E2F1, and MYBL2 are disproportionately upregulated in p53 mutant cancers.	('E2F1', 'Gene', (73, 77))	('FOXM1', 'Gene', (66, 71))	('cancer', 'Disease', (138, 144))	('MYBL2', 'Gene', '4605', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('mutant', 'Var', (131, 137))	('upregulated', 'PosReg', (112, 123))	('MYBL2', 'Gene', (83, 88))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('p53', 'Gene', (127, 130))	('E2F1', 'Gene', '1869', (73, 77))
260328	27074562	Microarray analysis of breast cancers demonstrates that FOXM1 regulates genes essential for chromosomal segregation and mitosis with loss of FOXM1 leading to mitotic spindle defects and mitotic catastrophe.	('FOXM1', 'Gene', (141, 146))	('mitotic spindle defects', 'CPA', (158, 181))	('mitotic catastrophe', 'CPA', (186, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('mitosis', 'Disease', (120, 127))	('breast cancers', 'Phenotype', 'HP:0003002', (23, 37))	('mitosis', 'Disease', 'None', (120, 127))	('breast cancers', 'Disease', 'MESH:D001943', (23, 37))	('leading to', 'Reg', (147, 157))	('breast cancers', 'Disease', (23, 37))	('loss', 'Var', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
260338	27074562	In malignant peripheral nerve sheath tumors, amplification of the CDK4 gene and increased levels of FOXM1 protein are significant independent predictors of poor survival.	('levels', 'MPA', (90, 96))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (3, 43))	('malignant peripheral nerve sheath tumors', 'Disease', (3, 43))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (3, 42))	('increased', 'PosReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (3, 43))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('CDK4', 'Gene', (66, 70))	('FOXM1', 'Gene', (100, 105))	('amplification', 'Var', (45, 58))	('CDK4', 'Gene', '1019', (66, 70))
260345	27074562	This postulate is partly substantiated by recent experimental evidence in which deregulated Hippo pathway signaling in soft-tissue sarcomas was found to promote FOXM1 expression and tumorigenesis in undifferentiated pleomorphic sarcoma, fibrosarcoma and liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (254, 265))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (119, 139))	('expression', 'MPA', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('FOXM1', 'Gene', (161, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('deregulated', 'Var', (80, 91))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (237, 249))	('promote', 'PosReg', (153, 160))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (199, 235))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('fibrosarcoma and liposarcoma', 'Disease', 'MESH:D005354', (237, 265))	('sarcomas', 'Disease', (131, 139))	('Hippo', 'Gene', (92, 97))	('undifferentiated pleomorphic sarcoma', 'Disease', (199, 235))	('tumor', 'Disease', (182, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
260349	27074562	This locus is amplified in several types of cancer with FOXM1 amplification among the most prevalent molecular aberration in non-Hodgkin's lymphoma.	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (125, 147))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (129, 147))	('prevalent', 'Reg', (91, 100))	("non-Hodgkin's lymphoma", 'Disease', (125, 147))	('amplification', 'Var', (62, 75))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (125, 147))	('FOXM1', 'Gene', (56, 61))
260353	27074562	Amplification of chromosomal region 12q13-15 is also found in well-differentiated liposarcomas within supernumerary ring and giant marker chromosomes.	('Amplification', 'Var', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('found', 'Reg', (53, 58))	('liposarcomas', 'Disease', 'MESH:D008080', (82, 94))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('liposarcomas', 'Phenotype', 'HP:0012034', (82, 94))	('liposarcomas', 'Disease', (82, 94))	('liposarcoma', 'Phenotype', 'HP:0012034', (82, 93))
260355	27074562	Translocations involving chromosome band12q13 occur in other soft tissue sarcomas subtypes.	('Translocations', 'Var', (0, 14))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (61, 80))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (61, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('occur', 'Reg', (46, 51))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (61, 81))	('soft tissue sarcomas', 'Disease', (61, 81))
260363	27074562	Direct binding to the FOXM1 promoter by E2F or c-Myc increases its expression by up regulating gene transcription.	('binding', 'Interaction', (7, 14))	('up regulating', 'PosReg', (81, 94))	('increases', 'PosReg', (53, 62))	('FOXM1', 'Gene', (22, 27))	('c-Myc', 'Gene', '4609', (47, 52))	('expression', 'MPA', (67, 77))	('c-Myc', 'Gene', (47, 52))	('E2F', 'Var', (40, 43))	('gene transcription', 'MPA', (95, 113))
260364	27074562	Mutation or inactivation of p53 frequently occurs in malignancies and may increase FOXM1 expression.	('p53', 'Gene', (28, 31))	('expression', 'MPA', (89, 99))	('malignancies', 'Disease', (53, 65))	('Mutation', 'Var', (0, 8))	('increase', 'PosReg', (74, 82))	('inactivation', 'Var', (12, 24))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('FOXM1', 'Gene', (83, 88))
260366	27074562	Li-Fraumeni syndrome, which arises from germline mutations in TP53, is informative.	('TP53', 'Gene', '7157', (62, 66))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('germline mutations', 'Var', (40, 58))	('TP53', 'Gene', (62, 66))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))
260367	27074562	Affected individuals are at markedly increased risk of developing the following six core malignancies: CNS tumors, breast cancer, acute leukemia, adrenocortical carcinoma, soft tissue and bone sarcomas.. Loss of function alterations in p53 typically leads to resistance to apoptosis because p53 stimulates pro-apoptotic gene expression including Noxa, Bad, Bax, DR4, Puma, Apaf1 and caspase-6.	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('resistance', 'MPA', (259, 269))	('pro-apoptotic', 'MPA', (306, 319))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (146, 170))	('acute leukemia', 'Disease', 'MESH:D015470', (130, 144))	('DR4', 'Gene', (362, 365))	('Loss of function', 'NegReg', (204, 220))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('stimulates', 'PosReg', (295, 305))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (146, 170))	('malignancies', 'Disease', (89, 101))	('Bax', 'Gene', (357, 360))	('acute leukemia', 'Phenotype', 'HP:0002488', (130, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('adrenocortical carcinoma', 'Disease', (146, 170))	('Bad', 'Disease', (352, 355))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Noxa', 'Disease', (346, 350))	('bone sarcomas', 'Disease', 'MESH:D001847', (188, 201))	('p53', 'Gene', (236, 239))	('tumors', 'Disease', (107, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('bone sarcomas', 'Disease', (188, 201))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('breast cancer', 'Disease', (115, 128))	('bone sarcomas', 'Phenotype', 'HP:0002669', (188, 201))	('Puma', 'Disease', (367, 371))	('soft tissue and bone sarcomas', 'Phenotype', 'HP:0030448', (172, 201))	('alterations', 'Var', (221, 232))	('Apaf1', 'Gene', (373, 378))	('caspase-6', 'Enzyme', (383, 392))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('acute leukemia', 'Disease', (130, 144))
260381	27074562	Bub1b knockdown suppresses in-vivo tumor growth with regression of established tumors affected by post-mitotic endoreduplication checkpoint mitotic catastrophe.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('suppresses', 'NegReg', (16, 26))	('tumor', 'Disease', (79, 84))	('Bub1b', 'Gene', '701', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('knockdown', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('Bub1b', 'Gene', (0, 5))
260384	27074562	Interestingly, patients with mosaic variegated aneuploidy syndrome, a rare disorder with has biallelic or heterozygous mutations of the Bub1B gene, have constitutional aneuploidy and a predisposition to early childhood cancer including rhabdomyosarcoma, leukemia and Wilm's tumor.	('patients', 'Species', '9606', (15, 23))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (236, 252))	('leukemia', 'Phenotype', 'HP:0001909', (254, 262))	('aneuploidy syndrome', 'Disease', (47, 66))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('a rare disorder', 'Disease', 'MESH:D035583', (68, 83))	('aneuploidy syndrome', 'Disease', 'MESH:D000782', (47, 66))	('constitutional aneuploidy', 'Disease', (153, 178))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (236, 252))	('leukemia', 'Disease', 'MESH:D007938', (254, 262))	('leukemia', 'Disease', (254, 262))	('a rare disorder', 'Disease', (68, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('constitutional aneuploidy', 'Disease', 'MESH:D000782', (153, 178))	('biallelic', 'Var', (93, 102))	("Wilm's tumor", 'Disease', (267, 279))	("Wilm's tumor", 'Disease', 'MESH:D009396', (267, 279))	('Bub1B', 'Gene', '701', (136, 141))	('cancer', 'Disease', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('Bub1B', 'Gene', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('rhabdomyosarcoma', 'Disease', (236, 252))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (267, 279))
260385	27074562	Targeting FOXM1 may prove a useful future therapeutic strategy in rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (66, 82))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (66, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('FOXM1', 'Gene', (10, 15))	('Targeting', 'Var', (0, 9))	('rhabdomyosarcoma', 'Disease', (66, 82))
260402	27074562	In a systematic evaluation of Ewing sarcoma cell lines, human samples and xenograft models siRNA mediated inhibition of SOX2 induces apoptosis and G1/S phase arrest.	('Ewing sarcoma', 'Disease', (30, 43))	('SOX2', 'Gene', (120, 124))	('apoptosis', 'CPA', (133, 142))	('G1/S phase arrest', 'CPA', (147, 164))	('inhibition', 'Var', (106, 116))	('human', 'Species', '9606', (56, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (30, 43))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (30, 43))	('induces', 'Reg', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('SOX2', 'Gene', '6657', (120, 124))
260411	27074562	The characteristic t (X: 18)(p11.2; q11.2) translocation of synovial sarcoma fuses the SS18 gene on chromosome 18 to one of three homologous genes, SSX1, SSX2 or SSX4, which cluster on the X chromosome.	('p11', 'Gene', (29, 32))	('SSX1', 'Gene', (148, 152))	('SSX2', 'Gene', '6757', (154, 158))	('synovial sarcoma', 'Disease', (60, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('fuses', 'Var', (77, 82))	('SS18', 'Gene', '6760', (87, 91))	('SSX1', 'Gene', '6756', (148, 152))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (60, 76))	('synovial sarcoma', 'Disease', 'MESH:D013584', (60, 76))	('translocation', 'Var', (43, 56))	('SSX4', 'Gene', '6759', (162, 166))	('p11', 'Gene', '118460', (29, 32))	('SS18', 'Gene', (87, 91))	('SSX2', 'Gene', (154, 158))	('SSX4', 'Gene', (162, 166))
260419	27074562	However, inferring its effect on upregulating pluripotency genes and in particular activation of SOX2 in other tumors raises an important question: Does inhibition of FOXM1 vicariously targets SOX2 in synovial sarcoma?	('synovial sarcoma', 'Phenotype', 'HP:0012570', (201, 217))	('SOX2', 'Gene', '6657', (97, 101))	('SOX2', 'Gene', '6657', (193, 197))	('SOX2', 'Gene', (97, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('SOX2', 'Gene', (193, 197))	('synovial sarcoma', 'Disease', 'MESH:D013584', (201, 217))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('FOXM1', 'Gene', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('synovial sarcoma', 'Disease', (201, 217))	('inhibition', 'Var', (153, 163))	('pluripotency', 'MPA', (46, 58))	('upregulating', 'PosReg', (33, 45))
260433	27074562	FOXM1 expression is repressed during retinoic acid induced differentiation of early stage P19 EC cells and FOXM1 knockdown in EC cells causes spontaneous differentiation to mesodermal derivatives such as adipose tissue or muscle.	('FOXM1', 'Gene', (107, 112))	('retinoic acid', 'Chemical', 'MESH:D014212', (37, 50))	('EC', 'Phenotype', 'HP:0002898', (94, 96))	('spontaneous differentiation', 'CPA', (142, 169))	('EC', 'Phenotype', 'HP:0002898', (126, 128))	('knockdown', 'Var', (113, 122))	('causes', 'Reg', (135, 141))
260465	27074562	Genetic loss of beta-catenin prevents synovial sarcoma formation.	('prevents', 'NegReg', (29, 37))	('synovial sarcoma', 'Disease', 'MESH:D013584', (38, 54))	('beta-catenin', 'Gene', (16, 28))	('synovial sarcoma', 'Disease', (38, 54))	('Genetic loss', 'Var', (0, 12))	('beta-catenin', 'Gene', '1499', (16, 28))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (38, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
260466	27074562	Aberrant hedgehog signaling occurs in basal cell carcinoma, medulloblastoma, and chondrosarcoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (60, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('medulloblastoma', 'Disease', 'MESH:D008527', (60, 75))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (38, 58))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (38, 58))	('basal cell carcinoma', 'Disease', (38, 58))	('Aberrant', 'Var', (0, 8))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (81, 95))	('hedgehog signaling', 'Pathway', (9, 27))	('medulloblastoma', 'Disease', (60, 75))	('chondrosarcoma', 'Disease', (81, 95))	('chondrosarcoma', 'Disease', 'MESH:D002813', (81, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
260474	27074562	Using information from The Cancer Genome Atlas Project, aberrant Hippo pathway signaling has been causally implicated in greater than 25% of sarcomas.	('Hippo pathway signaling', 'Pathway', (65, 88))	('sarcomas', 'Disease', 'MESH:D012509', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('Cancer', 'Disease', (27, 33))	('aberrant', 'Var', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('sarcomas', 'Disease', (141, 149))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('implicated', 'Reg', (107, 117))
260477	27074562	Inhibiting YAP decreases proliferation of sarcoma cells.	('sarcoma', 'Disease', (42, 49))	('YAP', 'Gene', (11, 14))	('Inhibiting', 'Var', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('decreases', 'NegReg', (15, 24))	('YAP', 'Gene', '10413', (11, 14))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))
260480	27074562	In a specific tumor type, dysregulation of Hippo signaling arises from a translocation fusion oncogene involving another FOX family member, FOXO1 in rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', (149, 165))	('Hippo signaling', 'MPA', (43, 58))	('dysregulation', 'Var', (26, 39))	('tumor', 'Disease', (14, 19))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (149, 165))	('FOXO1', 'Gene', (140, 145))	('FOXO1', 'Gene', '2308', (140, 145))	('translocation', 'Var', (73, 86))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (149, 165))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('arises from', 'Reg', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
260487	27074562	These include RNA interference, thiazole antibiotics and proteasome inhibitors, the appreciation that standard anticancer drugs such as cisplatin suppress FOXM1, and targeting FOXM1 interaction with other proteins using a synthetic ARF related peptide or nucleophosmin.	('FOXM1', 'Gene', (155, 160))	('cancer', 'Disease', (115, 121))	('ARF', 'Disease', 'MESH:D058186', (232, 235))	('interaction', 'Interaction', (182, 193))	('nucleophosmin', 'Gene', (255, 268))	('suppress', 'NegReg', (146, 154))	('ARF', 'Disease', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('RNA interference', 'MPA', (14, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('thiazole', 'Chemical', 'MESH:D013844', (32, 40))	('targeting', 'Var', (166, 175))	('nucleophosmin', 'Gene', '4869', (255, 268))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('FOXM1', 'Gene', (176, 181))
260488	27074562	In a selected specific, targeting FOXM1 retards p53-null sarcoma and lymphoma.	('retards', 'Disease', (40, 47))	('sarcoma and lymphoma', 'Disease', 'MESH:D012509', (57, 77))	('targeting', 'Var', (24, 33))	('retards', 'Disease', 'MESH:D008607', (40, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('FOXM1', 'Gene', (34, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
260489	27074562	Preclinical studies that ablate FOXM1 by RNA interference have demonstrated decreased cellular proliferation in numerous types of cancer including osteosarcoma.	('osteosarcoma', 'Disease', (147, 159))	('cellular proliferation', 'CPA', (86, 108))	('ablate', 'Var', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (147, 159))	('osteosarcoma', 'Disease', 'MESH:D012516', (147, 159))	('cancer', 'Disease', (130, 136))	('FOXM1', 'Gene', (32, 37))	('decreased', 'NegReg', (76, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('RNA interference', 'MPA', (41, 57))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
260490	27074562	Knockdown of FOXM1 causes increased cellular senescence of mAKT1 expressing osteosarcoma cells and deletion of FOXM1 can diminish cancer cell invasion, migration and angiogenesis.	('cellular senescence', 'CPA', (36, 55))	('FOXM1', 'Gene', (111, 116))	('diminish', 'NegReg', (121, 129))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('FOXM1', 'Gene', (13, 18))	('increased', 'PosReg', (26, 35))	('deletion', 'Var', (99, 107))	('osteosarcoma', 'Disease', (76, 88))	('osteosarcoma', 'Disease', 'MESH:D012516', (76, 88))	('mAKT1', 'Gene', '11651', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('mAKT1', 'Gene', (59, 64))
260504	27074562	Both nucleophosmin and FOXM1 tend to co-localize in the nucleolus of cancer cells and RNAi- mediated nucleophosmin knockdown in cancer cells decreases levels of FOXM1.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('levels', 'MPA', (151, 157))	('nucleophosmin', 'Gene', '4869', (101, 114))	('FOXM1', 'MPA', (161, 166))	('knockdown', 'Var', (115, 124))	('nucleophosmin', 'Gene', '4869', (5, 18))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('decreases', 'NegReg', (141, 150))	('nucleophosmin', 'Gene', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('nucleophosmin', 'Gene', (5, 18))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', (128, 134))
260518	27074562	In pediatric B-acute lymphoblastic leukemia FOXM1 is overexpressed and in cell lines inhibition of FOXM1 with thiostrepton enhanced cytotoxicity to commonly used chemotherapeutic agents (dexamethasone, asparaginase, daunorubicin, vincristine and Ara-C).	('enhanced', 'PosReg', (123, 131))	('Ara-C', 'Chemical', 'MESH:D003561', (246, 251))	('lymphoblastic leukemia', 'Disease', (21, 43))	('cytotoxicity', 'Disease', 'MESH:D064420', (132, 144))	('inhibition', 'Var', (85, 95))	('leukemia', 'Phenotype', 'HP:0001909', (35, 43))	('FOXM1', 'Gene', (44, 49))	('vincristine', 'Chemical', 'MESH:D014750', (230, 241))	('daunorubicin', 'Chemical', 'MESH:D003630', (216, 228))	('FOXM1', 'Gene', (99, 104))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (15, 43))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (21, 43))	('thiostrepton', 'Chemical', 'MESH:D013883', (110, 122))	('cytotoxicity', 'Disease', (132, 144))	('dexamethasone', 'Chemical', 'MESH:D003907', (187, 200))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (21, 43))
260527	27074562	Inhibition of MDM2 by nutlins in liposarcoma activates the p53 pathway with decreased cellular proliferation in MDM2-amplified liposarcoma.	('p53 pathway', 'Pathway', (59, 70))	('cellular proliferation', 'CPA', (86, 108))	('activates', 'PosReg', (45, 54))	('liposarcoma', 'Disease', (33, 44))	('MDM2', 'Gene', '4193', (112, 116))	('MDM2', 'Gene', (112, 116))	('liposarcoma', 'Disease', (127, 138))	('liposarcoma', 'Disease', 'MESH:D008080', (33, 44))	('decreased', 'NegReg', (76, 85))	('MDM2', 'Gene', '4193', (14, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('liposarcoma', 'Phenotype', 'HP:0012034', (33, 44))	('Inhibition', 'Var', (0, 10))	('MDM2', 'Gene', (14, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (127, 138))	('liposarcoma', 'Disease', 'MESH:D008080', (127, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
260528	27074562	In one proof of principle study of 20 patients with well differentiated or dedifferentiated liposarcoma (18 TP53 wild-type, 2 TP53 missense mutant) treated with the nutlin RG7112, one patient had a complete response with fourteen patients experiencing stable disease.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('TP53', 'Gene', (126, 130))	('liposarcoma', 'Disease', (92, 103))	('well differentiated', 'Disease', (52, 71))	('TP53', 'Gene', (108, 112))	('TP53', 'Gene', '7157', (108, 112))	('patient', 'Species', '9606', (230, 237))	('missense mutant', 'Var', (131, 146))	('patients', 'Species', '9606', (230, 238))	('liposarcoma', 'Disease', 'MESH:D008080', (92, 103))	('patient', 'Species', '9606', (38, 45))	('liposarcoma', 'Phenotype', 'HP:0012034', (92, 103))	('patients', 'Species', '9606', (38, 46))	('TP53', 'Gene', '7157', (126, 130))	('patient', 'Species', '9606', (184, 191))
260535	27074562	The central role of FOXM1 in the cell cycle, and it's recurring theme of importance in stem cell preferentially activated developmental pathways suggests that targeting FOXM1 is a potential advance in treating sarcoma.	('sarcoma', 'Disease', (210, 217))	('FOXM1', 'Gene', (169, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('targeting', 'Var', (159, 168))
260536	27074562	This review infers that certain sarcoma subtypes such as Ewing sarcoma and osteosarcoma may be particularly 'druggable' using FOXM1 inhibition.	('osteosarcoma', 'Disease', (75, 87))	('Ewing sarcoma', 'Disease', (57, 70))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Disease', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcoma', 'Disease', (80, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('FOXM1', 'Gene', (126, 131))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('inhibition', 'Var', (132, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))
260551	25273374	Among the Et family members, Et-743 and Et-729 show the most potent antitumor activity on several carcinoma cell types (Table 1).	('Et-729', 'Var', (40, 46))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('tumor', 'Disease', (72, 77))	('carcinoma', 'Disease', 'MESH:D002277', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Et-729', 'Chemical', 'MESH:C100350', (40, 46))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('Et-743', 'Chemical', 'MESH:D000077606', (29, 35))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('carcinoma', 'Disease', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Et-743', 'Var', (29, 35))
260553	25273374	Et-743 has an effect on cell proliferation against a wide range of cancer subtypes at low concentration.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('cancer', 'Disease', (67, 73))	('effect', 'Reg', (14, 20))	('n', 'Chemical', 'MESH:D009584', (12, 13))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('Et-743', 'Chemical', 'MESH:D000077606', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Et-743', 'Var', (0, 6))	('cell proliferation against', 'CPA', (24, 50))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (69, 70))
260554	25273374	illustrated that a continuous exposure of the tumor to Et-743 resulted in a significant improvement of the antitumor activity in vitro (Table 2).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (46, 51))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('tumor', 'Disease', (111, 116))	('Et-743', 'Chemical', 'MESH:D000077606', (55, 61))	('improvement', 'PosReg', (88, 99))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('Et-743', 'Var', (55, 61))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (108, 109))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
260556	25273374	At micromolar concentration, Et-743 was found to inhibit a number of DNA-binding proteins, including NF-Y, TATA binding protein, E2F, and SRF/TCF.	('TATA binding protein', 'Protein', (107, 127))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('TCF', 'Gene', '3172', (142, 145))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('Et-743', 'Var', (29, 35))	('DNA-binding proteins', 'Protein', (69, 89))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('Et-743', 'Chemical', 'MESH:D000077606', (29, 35))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('TCF', 'Gene', (142, 145))	('SRF', 'Gene', '6722', (138, 141))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('SRF', 'Gene', (138, 141))	('NF-Y', 'Gene', (101, 105))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('inhibit', 'NegReg', (49, 56))
260561	25273374	Since NF-Y interacts with several essential genes involving DNA metabolism and cell-cycle regulators, the inhibition of this protein can cause a delay in S-phase progression and accumulation of cells in G2/M phase, which is in agreement with the observation of Simoens and coworkers.	('n', 'Chemical', 'MESH:D009584', (12, 13))	('n', 'Chemical', 'MESH:D009584', (266, 267))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('cells in G2/M phase', 'CPA', (194, 213))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('n', 'Chemical', 'MESH:D009584', (201, 202))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('S-phase progression', 'CPA', (154, 173))	('n', 'Chemical', 'MESH:D009584', (256, 257))	('inhibition', 'Var', (106, 116))	('delay', 'NegReg', (145, 150))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('interacts', 'Reg', (11, 20))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('accumulation', 'PosReg', (178, 190))	('n', 'Chemical', 'MESH:D009584', (270, 271))	('n', 'Chemical', 'MESH:D009584', (189, 190))	('NF-Y', 'Gene', (6, 10))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('n', 'Chemical', 'MESH:D009584', (234, 235))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('n', 'Chemical', 'MESH:D009584', (225, 226))	('n', 'Chemical', 'MESH:D009584', (131, 132))
260562	25273374	The inhibition of transcription factor NF-Y, however, still occurs at high concentration of Et-743, three times higher than the pharmacological concentration when pre-incubating NF-Y with Et-743.	('n', 'Chemical', 'MESH:D009584', (156, 157))	('Et-743', 'Var', (92, 98))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('n', 'Chemical', 'MESH:D009584', (161, 162))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('Et-743', 'Chemical', 'MESH:D000077606', (92, 98))	('Et-743', 'Chemical', 'MESH:D000077606', (188, 194))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('inhibition', 'NegReg', (4, 14))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (146, 147))
260566	25273374	Possibly, at its pharmacological concentration, Et-743 interferes with the binding of NF-Y to other co-activators, such as PCAF, which in turn regulates the expression of several critical genes.	('interferes', 'NegReg', (55, 65))	('Et-743', 'Chemical', 'MESH:D000077606', (48, 54))	('binding', 'Interaction', (75, 82))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('PCAF', 'Gene', (123, 127))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('PCAF', 'Gene', '8850', (123, 127))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('n', 'Chemical', 'MESH:D009584', (166, 167))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (190, 191))	('Et-743', 'Var', (48, 54))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('NF-Y', 'Gene', (86, 90))	('expression', 'MPA', (157, 167))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('regulates', 'Reg', (143, 152))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('N', 'Chemical', 'MESH:D009584', (86, 87))
260576	25273374	Possibly, the protein-DNA complex increases the sequence selectivity of Et-743.	('N', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('Et-743', 'Chemical', 'MESH:D000077606', (72, 78))	('Et-743', 'Var', (72, 78))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('sequence selectivity', 'MPA', (48, 68))	('increases', 'PosReg', (34, 43))
260581	25273374	DNA adducts formed with Et-743 was found to block gene expressions by causing RNA polymerase II arrest during transcription and competing with certain transcription factors, such as Sp1, for the binding site on DNA.	('causing', 'Reg', (70, 77))	('Et-743', 'Chemical', 'MESH:D000077606', (24, 30))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('arrest during transcription', 'MPA', (96, 123))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('RNA', 'MPA', (78, 81))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('block', 'NegReg', (44, 49))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (163, 164))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('Et-743', 'Var', (24, 30))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('n', 'Chemical', 'MESH:D009584', (197, 198))	('gene expressions', 'MPA', (50, 66))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (107, 108))
260589	25273374	An Et-743-induced adduct traps the XPG-DNA complex, generating irreversible SSBs, which are transformed into double-strand breaks (DSBs) during transcription.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (156, 157))	('Et-743', 'Chemical', 'MESH:D000077606', (3, 9))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('XPG', 'Gene', '2073', (35, 38))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('DSBs', 'Chemical', '-', (131, 135))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('XPG', 'Gene', (35, 38))	('adduct', 'Var', (18, 24))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('SSBs', 'Chemical', 'MESH:C016118', (76, 80))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('SSBs', 'MPA', (76, 80))
260590	25273374	Homologous recombination (HR) repair can recognize and repair the DSBs induced by Et-743; hence cells lacking HR repair (common in human tumors) are significantly more sensitive to Et-743.	('DSBs', 'Chemical', '-', (66, 70))	('tumors', 'Disease', (137, 143))	('Et-743', 'Chemical', 'MESH:D000077606', (82, 88))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('DSBs', 'Var', (66, 70))	('sensitive', 'MPA', (168, 177))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('Et-743', 'Chemical', 'MESH:D000077606', (181, 187))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('Et-743', 'Var', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('human', 'Species', '9606', (131, 136))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('n', 'Chemical', 'MESH:D009584', (170, 171))
260591	25273374	on the less complicated bacterial nuclease UvrABC system demonstrated that the incision event induced by Et-743-DNA adduct is more efficient at the less favored sequence 5'-AGT.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('Et-743', 'Chemical', 'MESH:D000077606', (105, 111))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('Et-743-DNA', 'Var', (105, 115))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('n', 'Chemical', 'MESH:D009584', (166, 167))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('incision', 'MPA', (79, 87))	('n', 'Chemical', 'MESH:D009584', (80, 81))
260592	25273374	Based on this result, they proposed a different mechanism of how Et-743 induces apoptosis (Figure 4).	('n', 'Chemical', 'MESH:D009584', (53, 54))	('Et-743', 'Var', (65, 71))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('Et-743', 'Chemical', 'MESH:D000077606', (65, 71))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('apoptosis', 'CPA', (80, 89))	('n', 'Chemical', 'MESH:D009584', (73, 74))
260593	25273374	The UvrA protein of the UvrABC machinery recognizes the Et-743-DNA lesion and initiates the repair mechanism by forming a dimer with another UvrA protein, then a heterotrimer UvrA2B.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('dimer', 'MPA', (122, 127))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('Et-743', 'Chemical', 'MESH:D000077606', (56, 62))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('Et-743-DNA', 'Var', (56, 66))
260596	25273374	Et-743 can also dissociate from the bubble before the incision happens depending on the stability of the Et-743-DNA adduct, which also leads to cell survival.	('cell survival', 'CPA', (144, 157))	('Et-743', 'Chemical', 'MESH:D000077606', (105, 111))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('Et-743-DNA', 'Var', (105, 115))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('Et-743', 'Chemical', 'MESH:D000077606', (0, 6))	('leads to', 'Reg', (135, 143))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('n', 'Chemical', 'MESH:D009584', (9, 10))
260638	25273374	Subsequent transamination of Et-597 may happen to provide Et-596 (27), which will incorporate the dioxymethylene to yield Et-594 (28).	('n', 'Chemical', 'MESH:D009584', (19, 20))	('Et-594', 'Chemical', '-', (122, 128))	('Et-596', 'Chemical', '-', (58, 64))	('dioxymethylene', 'Chemical', '-', (98, 112))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('Et-594', 'Var', (122, 128))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('Et-597', 'Chemical', '-', (29, 35))	('Et-596', 'Var', (58, 64))
260689	25273374	After switching from the TBDPS ether to the acetate, simultaneous cleavage of the Boc group and the MOM ether gave the aminophenol, which was readily cyclized to afford 75.	('Boc', 'Gene', '91653', (82, 85))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('Boc', 'Gene', (82, 85))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('TBDPS', 'Chemical', '-', (25, 30))	('gave', 'Reg', (110, 114))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('cleavage', 'Var', (66, 74))	('MOM ether', 'Chemical', '-', (100, 109))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('ether', 'Chemical', 'MESH:D004986', (31, 36))	('aminophenol', 'Chemical', 'MESH:D000627', (119, 130))	('ether', 'Chemical', 'MESH:D004986', (104, 109))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('acetate', 'Chemical', 'MESH:D000085', (44, 51))
260715	25273374	Upon treatment of 95 and 96 with AcOH in CH2Cl2 and CF3CH2OH, the desired tetrahydroisoquinoline formation reaction proceeded to give 97 as a single isomer.	('tetrahydroisoquinoline formation', 'MPA', (74, 106))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (12, 13))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('CF3CH2OH', 'Var', (52, 60))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('tetrahydroisoquinoline', 'Chemical', 'MESH:C014843', (74, 96))	('CH2Cl2', 'Chemical', 'MESH:D008752', (41, 47))	('AcOH', 'Chemical', 'MESH:D019342', (33, 37))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('CF3CH2OH', 'Chemical', 'MESH:D014270', (52, 60))
260821	25983693	However, the appearance of point mutations can hinder the treatment of patients with these new molecules, raising costs and the need to development new analogs that target the novel mutations.	('patients', 'Species', '9606', (71, 79))	('hinder', 'NegReg', (47, 53))	('point mutations', 'Var', (27, 42))
260829	25983693	The main drawback in target therapy is the mutation of the target, and in this specific case, the mutation of the imatinib binding site, which makes 20-40% of patients resistant to imatinib therapy.	('mutation', 'Var', (98, 106))	('imatinib', 'Chemical', 'MESH:D000068877', (114, 122))	('mutation', 'Var', (43, 51))	('imatinib', 'Chemical', 'MESH:D000068877', (181, 189))	('patients', 'Species', '9606', (159, 167))
260830	25983693	As the use of imatinib grew, case reports on imatinib resistant CML began to appear, indicating that the majority of resistant phenotypes are associated with point mutations in the BCR-ABL kinase domain.	('imatinib', 'Chemical', 'MESH:D000068877', (14, 22))	('imatinib', 'Chemical', 'MESH:D000068877', (45, 53))	('CML', 'Disease', 'MESH:D015464', (64, 67))	('CML', 'Phenotype', 'HP:0005506', (64, 67))	('point mutations', 'Var', (158, 173))	('BCR-ABL', 'Gene', '25', (181, 188))	('CML', 'Disease', (64, 67))	('associated', 'Reg', (142, 152))	('BCR-ABL', 'Gene', (181, 188))
260831	25983693	A number of studies have identified critical point mutations in the kinase domain of the BCR-ABL protein.	('BCR-ABL', 'Gene', (89, 96))	('mutations', 'Var', (51, 60))	('BCR-ABL', 'Gene', '25', (89, 96))
260832	25983693	These mutations reduce the affinity of the imatinib with its target, and may be accompanied by the amplification of the BCR-ABL gene.	('reduce', 'NegReg', (16, 22))	('amplification', 'PosReg', (99, 112))	('imatinib', 'Chemical', 'MESH:D000068877', (43, 51))	('BCR-ABL', 'Gene', (120, 127))	('BCR-ABL', 'Gene', '25', (120, 127))	('affinity', 'Interaction', (27, 35))	('mutations', 'Var', (6, 15))
260836	25983693	These tumor cells present a successive acquisition of mutations, and it was discovered that the identity of the component mutations present in a compound mutation reflects the type of drugs to which the patient was exposed previously.	('mutation', 'Var', (154, 162))	('patient', 'Species', '9606', (203, 210))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
260837	25983693	The most frequent BCR-ABL mutation is T315I, which is known to cause resistance to most of the available TK inhibitors.	('BCR-ABL', 'Gene', '25', (18, 25))	('BCR-ABL', 'Gene', (18, 25))	('T315I', 'Var', (38, 43))	('T315I', 'Mutation', 'rs121913459', (38, 43))
260838	25983693	The substitution of a threonine by an isoleucine impairs the formation of a hydrogen bond with the TKI, thus preventing the binding of the drug.	('formation of a hydrogen bond', 'MPA', (61, 89))	('isoleucine', 'Chemical', 'MESH:D007532', (38, 48))	('impairs', 'NegReg', (49, 56))	('binding', 'Interaction', (124, 131))	('substitution', 'Var', (4, 16))	('preventing', 'NegReg', (109, 119))	('threonine', 'Chemical', 'MESH:D013912', (22, 31))	('hydrogen', 'Chemical', 'MESH:D006859', (76, 84))	('TKI', 'Protein', (99, 102))
260839	25983693	Recent studies have shown that only the third generation TKI (ponatinib) is able to inhibit BCR-ABL with the T315I mutation.	('T315I', 'Var', (109, 114))	('T315I', 'Mutation', 'rs121913459', (109, 114))	('BCR-ABL', 'Gene', '25', (92, 99))	('inhibit', 'NegReg', (84, 91))	('BCR-ABL', 'Gene', (92, 99))	('ponatinib', 'Chemical', 'MESH:C545373', (62, 71))
260858	25983693	The capacity of tumors and viruses generate and select viable mutants will be proportional to their mutation and replication rates.	('tumors', 'Disease', (16, 22))	('mutants', 'Var', (62, 69))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
260862	25983693	These mutation rates are reflected in the rapid emergence of resistance to therapy in tumor cells and viruses, and it has even been suggested that this characteristic could be exploited therapeutically through lethal mutagenesis (Mutational catastrophe).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('mutation', 'Var', (6, 14))	('resistance to therapy', 'MPA', (61, 82))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('lethal mutagenesis', 'Var', (210, 228))
260864	25983693	In this case, if a viral sequence has a mutation rate around six orders of magnitude higher than the same sequence in a normal human cell, during the proliferation of the tumor, the retroviral homologs will be mutating at a much higher rate than a normal cell, but below the catastrophe threshold.	('mutating', 'Var', (210, 218))	('human', 'Species', '9606', (127, 132))	('mutation', 'MPA', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
260865	25983693	As discussed by, sequences in tumors that are highly homologous to those of retroviruses are typical of drug resistance, and will contain point mutations that confer resistance on the tumors containing them.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('resistance', 'MPA', (166, 176))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Disease', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('point mutations', 'Var', (138, 153))
260872	25983693	The IRAK1 mutation has been found in Primary effusion lymphoma (PEL), a disease that develops in HIV-positive patients, in association with viral infections.	('Primary effusion lymphoma', 'Disease', (37, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (54, 62))	('patients', 'Species', '9606', (110, 118))	('mutation', 'Var', (10, 18))	('viral infections', 'Disease', (140, 156))	('viral infections', 'Disease', 'MESH:D001102', (140, 156))	('PEL', 'Phenotype', 'HP:0030069', (64, 67))	('found', 'Reg', (28, 33))	('IRAK1', 'Gene', '3654', (4, 9))	('Primary effusion lymphoma', 'Disease', 'MESH:D054685', (37, 62))	('IRAK1', 'Gene', (4, 9))	('HIV-positive', 'Disease', (97, 109))	('HIV-positive', 'Disease', 'MESH:D015658', (97, 109))	('Primary effusion lymphoma', 'Phenotype', 'HP:0030069', (37, 62))
260873	25983693	Only additional data will confirm whether IRAK1 presents point mutations under pressure from its inhibitors.	('IRAK1', 'Gene', (42, 47))	('IRAK1', 'Gene', '3654', (42, 47))	('point mutations', 'Var', (57, 72))
260874	25983693	But exactly which amino acid may be substituted in a given position (such as T315I in the case of BCR-ABL), and its importance for the outcome of a chemotherapy procedure, is related to selection of which particular mutation will confer advantage.	('T315I', 'Mutation', 'rs121913459', (77, 82))	('BCR-ABL', 'Gene', '25', (98, 105))	('BCR-ABL', 'Gene', (98, 105))	('T315I', 'Var', (77, 82))
260882	25983693	Most of the targets for drug development are molecules involved in tumor progression, exactly because these sequences maintain their function under high mutation rates.	('function', 'MPA', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('mutation', 'Var', (153, 161))
260893	22795729	Anthracycline exposure was associated with sarcoma risk (OR = 3.5, 95% CI = 1.6-7.7) adjusting for radiation dose, other chemotherapy, and primary cancer.	('Anthracycline', 'Var', (0, 13))	('Anthracycline', 'Chemical', 'MESH:D018943', (0, 13))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('associated with', 'Reg', (27, 42))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
260895	22795729	Of the risk factors evaluated, radiation exposure was the most important for secondary sarcoma development in childhood cancer survivors; anthracycline chemotherapy exposure was also associated with increased risk.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('anthracycline', 'Chemical', 'MESH:D018943', (138, 151))	('anthracycline', 'Var', (138, 151))	('secondary sarcoma', 'Disease', (77, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('secondary sarcoma', 'Disease', 'MESH:D012509', (77, 94))	('childhood cancer', 'Disease', 'MESH:C536928', (110, 126))	('childhood cancer', 'Disease', (110, 126))
260926	22795729	The model EOR = beta1D, corresponds to a straight-line dose-response relation, and beta1 equals the slope (EOR/Gy).	('beta1', 'Gene', '10678', (83, 88))	('beta1', 'Gene', (16, 21))	('beta1', 'Gene', '10678', (16, 21))	('EOR', 'Var', (10, 13))	('beta1', 'Gene', (83, 88))
260941	22795729	Radiation therapy exposure was associated with a significantly increased risk for the secondary sarcoma development (OR = 4.1, 95% CI: 1.8 - 9.5) after adjustment for primary cancer diagnosis, anthracycline exposure, and use of other chemotherapeutic agents.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('secondary sarcoma', 'Disease', 'MESH:D012509', (86, 103))	('Radiation therapy', 'Var', (0, 17))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('anthracycline', 'Chemical', 'MESH:D018943', (193, 206))	('secondary sarcoma', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
260946	22795729	Exposure to anthracyline therapy was associated with an increased risk of sarcoma, adjusting for radiation dose, primary cancer diagnosis, and other chemotherapy (OR 3.5, 95% CI: 1.6-7.7).	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('anthracyline', 'Chemical', '-', (12, 24))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('sarcoma', 'Disease', (74, 81))	('anthracyline therapy', 'Var', (12, 32))	('cancer', 'Disease', (121, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
260970	22795729	After controlling for radiation dose, we found that anthracycline exposure is associated with an increased risk of secondary sarcomas.	('anthracycline', 'Chemical', 'MESH:D018943', (52, 65))	('secondary sarcomas', 'Disease', (115, 133))	('anthracycline', 'Var', (52, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('secondary sarcomas', 'Disease', 'MESH:D012509', (115, 133))
260971	22795729	Our findings are consistent with early laboratory-based studies suggesting that anthracyclines are tumorigenic in vivo and in vitro.	('tumor', 'Disease', (99, 104))	('anthracyclines', 'Var', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('anthracyclines', 'Chemical', 'MESH:D018943', (80, 94))
260974	22795729	Our data suggest that it may be that anthracyclines, rather than alkylators, are associated with secondary sarcomas.	('secondary sarcomas', 'Disease', 'MESH:D012509', (97, 115))	('anthracyclines', 'Chemical', 'MESH:D018943', (37, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('anthracyclines', 'Var', (37, 51))	('secondary sarcomas', 'Disease', (97, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('associated', 'Reg', (81, 91))
261062	22661203	Ridaforolimus (AP23573, MK-8669, formerly deforolimus) is an inhibitor of mammalian target of rapamycin (mTOR), an integral component of the phosphatidyl 3-kinase (P13K)/AKT signaling pathway.	('deforolimus', 'Disease', 'None', (42, 53))	('mammalian target of rapamycin', 'Gene', '2475', (74, 103))	('mammalian target of rapamycin', 'Gene', (74, 103))	('AKT', 'Gene', '207', (170, 173))	('Ridaforolimus', 'Chemical', 'MESH:C515074', (0, 13))	('AP23573', 'Var', (15, 22))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('AKT', 'Gene', (170, 173))	('P13K', 'Mutation', 'p.P13K', (164, 168))	('AP23573', 'Chemical', 'MESH:C515074', (15, 22))	('MK-8669', 'Chemical', 'MESH:C515074', (24, 31))	('deforolimus', 'Disease', (42, 53))
261063	22661203	Deregulation of the PI3K/AKT pathway is frequently observed in a variety of malignancies.	('AKT', 'Gene', (25, 28))	('malignancies', 'Disease', (76, 88))	('Deregulation', 'Var', (0, 12))	('AKT', 'Gene', '207', (25, 28))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))
261073	22661203	A total of 711 patients were randomised, and the median PFS increased from 17.7 weeks in the ridaforolimus arm compared with 14.6 weeks in the placebo arm (P < 0.001); no difference in overall survival was observed.	('patients', 'Species', '9606', (15, 23))	('ridaforolimus', 'Var', (93, 106))	('PFS', 'MPA', (56, 59))	('ridaforolimus', 'Chemical', 'MESH:C515074', (93, 106))	('increased', 'PosReg', (60, 69))
261076	22661203	Inhibition of RANKL by denosumab in giant cell tumours of bone was expected to inhibit bone destruction and giant cells.	('inhibit', 'NegReg', (79, 86))	('tumours of bone', 'Phenotype', 'HP:0010622', (47, 62))	('denosumab', 'Gene', (23, 32))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('giant cell tumours', 'Disease', (36, 54))	('giant cell tumours', 'Disease', 'MESH:D018286', (36, 54))	('giant cell tumour', 'Phenotype', 'HP:0011847', (36, 53))	('Inhibition', 'Var', (0, 10))	('RANKL', 'Gene', (14, 19))	('RANKL', 'Gene', '8600', (14, 19))	('giant cell tumours of bone', 'Phenotype', 'HP:0011847', (36, 62))	('denosumab', 'Chemical', 'MESH:D000069448', (23, 32))	('bone destruction', 'Phenotype', 'HP:0002797', (87, 103))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
261086	22661203	International guidelines were adapted to incorporate 3 years of adjuvant imatinib as the gold standard, except for known imatinib resistant mutations, such as PDGFR D842V mutated GIST.	('PDGFR', 'Gene', (159, 164))	('imatinib', 'Chemical', 'MESH:D000068877', (73, 81))	('PDGFR', 'Gene', '5159', (159, 164))	('imatinib', 'Chemical', 'MESH:D000068877', (121, 129))	('D842V', 'Mutation', 'p.D842V', (165, 170))	('GIST', 'Phenotype', 'HP:0100723', (179, 183))	('D842V mutated', 'Var', (165, 178))
261088	22661203	The proposed mechanism of action is as follows: this benign, but sometimes recurrent and then invalidating tumour, overexpresses colony stimulating factor 1 (CSF1) that may result from a t(1 ;2) translocation.	('result from', 'Reg', (173, 184))	('t(1 ;2) translocation', 'Var', (187, 208))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('colony stimulating factor 1', 'Gene', (129, 156))	('CSF1', 'Gene', '1435', (158, 162))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('CSF1', 'Gene', (158, 162))	('colony stimulating factor 1', 'Gene', '1435', (129, 156))	('overexpresses', 'PosReg', (115, 128))	('tumour', 'Disease', (107, 113))
261103	22661203	Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma that is frequently characterized by an activated platelet derived growth factor receptor beta (PDGFR-B) as a result of a translocation between chromosome 17 and 22.	('Dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (0, 31))	('activated', 'PosReg', (98, 107))	('Dermatofibrosarcoma protuberans', 'Disease', (0, 31))	('dermal sarcoma', 'Disease', (44, 58))	('platelet derived growth factor receptor beta', 'Gene', (108, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('translocation', 'Var', (180, 193))	('dermal sarcoma', 'Disease', 'MESH:D012509', (44, 58))	('PDGFR-B', 'Gene', '5159', (154, 161))	('platelet derived growth factor receptor beta', 'Gene', '5159', (108, 152))	('PDGFR-B', 'Gene', (154, 161))
261114	22661203	published about 115 patients who received the monoclonal IGF-1R antibody R1507 either at doses of 9 mg/kg intravenously once a week or 27 mg/kg intravenously every three weeks.	('patients', 'Species', '9606', (20, 28))	('IGF-1R', 'Gene', (57, 63))	('R1507', 'Var', (73, 78))	('IGF-1R', 'Gene', '3480', (57, 63))
261123	22661203	Results of IGF-1R combination studies are promising and studies with (dual) tyrosine kinase inhibitors are urgently awaited.	('combination', 'Var', (18, 29))	('IGF-1R', 'Gene', (11, 17))	('IGF-1R', 'Gene', '3480', (11, 17))
261125	22661203	Approximately half of IMTs carry rearrangements of the anaplastic lymphoma kinase (ALK) locus on chromosome 2p23, causing aberrant ALK expression.	('anaplastic lymphoma kinase', 'Gene', (55, 81))	('ALK', 'Gene', '238', (83, 86))	('ALK', 'Gene', '238', (131, 134))	('causing', 'Reg', (114, 121))	('rearrangements', 'Var', (33, 47))	('anaplastic lymphoma kinase', 'Gene', '238', (55, 81))	('expression', 'MPA', (135, 145))	('ALK', 'Gene', (83, 86))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (55, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (66, 74))	('ALK', 'Gene', (131, 134))
261135	22661203	In eight patients immunohistochemical staining demonstrated 100 % TFE3 positivity and 75 % MET positivity with a strong association between TFE3 expression and MET positivity with correlation coefficient of 0.808 (P = 0.02).	('patients', 'Species', '9606', (9, 17))	('TFE3', 'Gene', '7030', (66, 70))	('TFE3', 'Gene', (140, 144))	('TFE3', 'Gene', (66, 70))	('positivity', 'Var', (71, 81))	('TFE3', 'Gene', '7030', (140, 144))
261207	29218216	In a study by Chiang et al., an assessment of the frequency of genetic rearrangements of endometrial stromal tumors demonstrated that four extrauterine ESSs had gene combinations of rearrangements in JAZF1-SUZ12andJAZF1-PHF1 and EPC1-PHF1 and PHF1-JAZF1, which were mutually exclusive in individual patients.	('PHF1', 'Gene', (220, 224))	('patients', 'Species', '9606', (299, 307))	('PHF1', 'Gene', (243, 247))	('JAZF1', 'Gene', '221895', (248, 253))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('PHF1', 'Gene', (234, 238))	('rearrangements', 'Var', (182, 196))	('JAZF1', 'Gene', '221895', (200, 205))	('andJAZF1', 'Gene', '221895', (211, 219))	('PHF1', 'Gene', '5252', (220, 224))	('JAZF1', 'Gene', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('andJAZF1', 'Gene', (211, 219))	('EPC1', 'Gene', '80314', (229, 233))	('JAZF1', 'Gene', (200, 205))	('endometrial stromal tumors', 'Disease', (89, 115))	('EPC1', 'Gene', (229, 233))	('PHF1', 'Gene', '5252', (243, 247))	('PHF1', 'Gene', '5252', (234, 238))	('JAZF1', 'Gene', '221895', (214, 219))	('ESSs', 'Gene', (152, 156))	('JAZF1', 'Gene', (214, 219))	('endometrial stromal tumors', 'Disease', 'MESH:D036821', (89, 115))	('ESSs', 'Gene', '54539', (152, 156))
261217	25713799	As a consequence, the majority of patients with high-grade RLS will develop locally recurrent disease following surgery, and this constitutes the cause of death in most patients.	('high-grade', 'Var', (48, 58))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (34, 42))	('death', 'Disease', 'MESH:D003643', (155, 160))	('death', 'Disease', (155, 160))	('develop', 'PosReg', (68, 75))	('locally', 'Disease', (76, 83))
261290	25713799	Co-amplification of MDM2 and CDK4 is a common feature in well-differentiated liposarcoma and is thought to be the initiating "driving" factor in fat tumorigenesis, resulting in proliferation through combined effects upon p53 (by inactivating TP53) and the cell cycle (by RB1 phosphorylation), respectively.	('combined', 'Interaction', (199, 207))	('CDK4', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('RB1', 'Gene', '5925', (271, 274))	('effects', 'Reg', (208, 215))	('liposarcoma', 'Phenotype', 'HP:0012034', (77, 88))	('MDM2', 'Gene', (20, 24))	('cell cycle', 'CPA', (256, 266))	('inactivating', 'NegReg', (229, 241))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('p53', 'Gene', '7157', (221, 224))	('liposarcoma', 'Disease', 'MESH:D008080', (77, 88))	('RB', 'Phenotype', 'HP:0009919', (271, 273))	('TP53', 'Gene', (242, 246))	('Co-amplification', 'Var', (0, 16))	('p53', 'Gene', (221, 224))	('RB1', 'Gene', (271, 274))	('liposarcoma', 'Disease', (77, 88))	('tumor', 'Disease', (149, 154))	('TP53', 'Gene', '7157', (242, 246))	('proliferation', 'CPA', (177, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
261292	25713799	P53 mutations are rarely seen in well-differentiated and dedifferentiated liposarcomas, but are commonly in pleomorphic liposarcomas.	('P53', 'Gene', (0, 3))	('liposarcomas', 'Disease', (120, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('liposarcomas', 'Disease', 'MESH:D008080', (74, 86))	('dedifferentiated liposarcoma', 'Disease', (57, 85))	('P53', 'Gene', '7157', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (108, 132))	('liposarcomas', 'Phenotype', 'HP:0012034', (74, 86))	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (57, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('liposarcoma', 'Phenotype', 'HP:0012034', (74, 85))	('liposarcomas', 'Disease', 'MESH:D008080', (120, 132))	('mutations', 'Var', (4, 13))	('well-differentiated', 'Disease', (33, 52))	('liposarcomas', 'Disease', (74, 86))	('liposarcomas', 'Phenotype', 'HP:0012034', (120, 132))	('pleomorphic liposarcomas', 'Disease', (108, 132))	('dedifferentiated liposarcomas', 'Phenotype', 'HP:0012034', (57, 86))	('liposarcoma', 'Phenotype', 'HP:0012034', (120, 131))
261293	25713799	showed 16.7% of pleomorphic liposarcoma cases had mutations in p53.	('liposarcoma', 'Phenotype', 'HP:0012034', (28, 39))	('p53', 'Gene', '7157', (63, 66))	('p53', 'Gene', (63, 66))	('mutations', 'Var', (50, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('pleomorphic liposarcoma', 'Disease', (16, 39))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (16, 39))
261294	25713799	Similarly, high p53 mutations rates (approximately 60%) were observed in pleomorphic liposarcoma by Ghadimi et al..	('pleomorphic liposarcoma', 'Disease', (73, 96))	('p53', 'Gene', (16, 19))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('p53', 'Gene', '7157', (16, 19))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (73, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('mutations', 'Var', (20, 29))
261305	25713799	Several recent studies have reported that most sarcomas diagnosed as poorly differentiated sarcomas and arising in the RP are, in fact, dedifferentiated liposarcomas and can now be diagnosed as such on the basis of MDM2 amplification even in challenging cases of a non-lipogenic undifferentiated sarcoma without an atypical adipocytic component.	('dedifferentiated liposarcomas', 'Phenotype', 'HP:0012034', (136, 165))	('liposarcomas', 'Disease', (153, 165))	('sarcomas', 'Disease', 'MESH:D012509', (157, 165))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcomas', 'Disease', (47, 55))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (279, 303))	('sarcomas', 'Disease', (157, 165))	('undifferentiated sarcoma', 'Disease', (279, 303))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('dedifferentiated liposarcoma', 'Disease', (136, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcomas', 'Disease', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('MDM2', 'Gene', (215, 219))	('liposarcomas', 'Disease', 'MESH:D008080', (153, 165))	('liposarcoma', 'Phenotype', 'HP:0012034', (153, 164))	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (136, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('liposarcomas', 'Phenotype', 'HP:0012034', (153, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (296, 303))	('amplification', 'Var', (220, 233))
261309	25713799	described consistent amplification of the fibroblast growth factor receptor substrate 2 gene (FRS2) in dedifferentiated (and well-differentiated) liposarcoma.	('FRS2', 'Gene', '10818', (94, 98))	('fibroblast growth factor receptor substrate 2', 'Gene', (42, 87))	('liposarcoma', 'Disease', 'MESH:D008080', (146, 157))	('FRS2', 'Gene', (94, 98))	('liposarcoma', 'Phenotype', 'HP:0012034', (146, 157))	('fibroblast growth factor receptor substrate 2', 'Gene', '10818', (42, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('amplification', 'Var', (21, 34))	('liposarcoma', 'Disease', (146, 157))
261320	25713799	Chromosomal imbalances additionally to the 12q13-q15 amplicon, including amplifications in 1p32 (including JUN), 1q21-q24, and/or 6q23 (including the ASK1 or MAP3K5 gene), have been reported to be more frequent in dedifferentiated liposarcoma than in well-differentiated liposarcoma.	('MAP3K5', 'Gene', '4217', (158, 164))	('liposarcoma', 'Disease', 'MESH:D008080', (231, 242))	('amplifications', 'Var', (73, 87))	('MAP3K5', 'Gene', (158, 164))	('6q23', 'Var', (130, 134))	('1p32', 'Gene', (91, 95))	('liposarcoma', 'Disease', (271, 282))	('imbalances', 'Phenotype', 'HP:0002172', (12, 22))	('liposarcoma', 'Disease', (231, 242))	('ASK1', 'Gene', '4217', (150, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('dedifferentiated liposarcoma', 'Disease', (214, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('liposarcoma', 'Phenotype', 'HP:0012034', (271, 282))	('1q21-q24', 'Var', (113, 121))	('ASK1', 'Gene', (150, 154))	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (214, 242))	('liposarcoma', 'Phenotype', 'HP:0012034', (231, 242))	('frequent', 'Reg', (202, 210))	('liposarcoma', 'Disease', 'MESH:D008080', (271, 282))
261335	25713799	On the other hand, although all liposarcomas share the amplification of 12q13-15, resulting in overexpression of MDM2 and CDK4, the molecular biology of the disease is heterogeneous, and likely to be differing between limb and retroperitoneal disease locations, given the fact that recent molecular studies highlighted major ontogenetic differences between normal subcutaneous and visceral (including retroperitoneal) fat tissue.	('amplification', 'Var', (55, 68))	('liposarcomas', 'Disease', 'MESH:D008080', (32, 44))	('MDM2', 'Gene', (113, 117))	('liposarcomas', 'Disease', (32, 44))	('overexpression', 'PosReg', (95, 109))	('retroperitoneal disease', 'Disease', (227, 250))	('liposarcoma', 'Phenotype', 'HP:0012034', (32, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('CDK4', 'Gene', (122, 126))	('retroperitoneal disease', 'Disease', 'MESH:D012186', (227, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('liposarcomas', 'Phenotype', 'HP:0012034', (32, 44))
261339	25713799	Second, macroscopically incomplete, piecemeal resection, or tumor rupture are associated with a dismal outcome and should not be attempted unless for symptomatic reasons.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor rupture', 'Disease', (60, 73))	('macroscopically', 'Var', (8, 23))	('tumor rupture', 'Disease', 'MESH:D012421', (60, 73))
261461	25276327	The most commonly used chemotherapy regimens for MCD with cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) or cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP).	('cyclophosphamide', 'Var', (130, 146))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (58, 74))	('CHOP', 'Gene', (190, 194))	('dexamethasone', 'Chemical', 'MESH:D003907', (106, 119))	('MCD', 'Disease', 'MESH:D012514', (49, 52))	('doxorubicin', 'Chemical', 'MESH:D004317', (89, 100))	('doxorubicin', 'Chemical', 'MESH:D004317', (161, 172))	('MCD', 'Disease', (49, 52))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (130, 146))	('vincristine', 'Chemical', 'MESH:D014750', (76, 87))	('CVAD', 'Chemical', '-', (121, 125))	('CHOP', 'Gene', '1649', (190, 194))	('vincristine', 'Chemical', 'MESH:D014750', (148, 159))	('prednisone', 'Chemical', 'MESH:D011241', (178, 188))
261490	24146786	The presence of JAZF1-JJAZ1 markedly inhibited apoptosis and induced proliferation rates.	('induced', 'PosReg', (61, 68))	('JAZF1', 'Gene', (16, 21))	('inhibited', 'NegReg', (37, 46))	('apoptosis', 'CPA', (47, 56))	('proliferation rates', 'CPA', (69, 88))	('JAZF1', 'Gene', '221895', (16, 21))	('JJAZ1', 'Gene', '23512', (22, 27))	('JJAZ1', 'Gene', (22, 27))	('presence', 'Var', (4, 12))
261491	24146786	Subsequently, rearrangements of JAZF1, SUZ12, PHF1 and EPC1 have been reported in endometrial stromal nodules (ESNs), ESS, and rarely in UES.	('ESS', 'Disease', (118, 121))	('PHF1', 'Gene', '5252', (46, 50))	('JAZF1', 'Gene', (32, 37))	('UES', 'Chemical', '-', (137, 140))	('reported', 'Reg', (70, 78))	('rearrangements', 'Var', (14, 28))	('JAZF1', 'Gene', '221895', (32, 37))	('EPC1', 'Gene', '80314', (55, 59))	('SUZ12', 'Gene', '23512', (39, 44))	('EPC1', 'Gene', (55, 59))	('PHF1', 'Gene', (46, 50))	('SUZ12', 'Gene', (39, 44))	('endometrial stromal nodules', 'Disease', (82, 109))
261495	24146786	While WHO2003 ESS-LG tumors in general have a good prognosis and behave in a relatively indolent manner, late recurrences and distal metastases do occasionally occur.	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('ESS-LG', 'Chemical', '-', (14, 20))	('metastases', 'Disease', (133, 143))	('WHO2003', 'Var', (6, 13))	('metastases', 'Disease', 'MESH:D009362', (133, 143))
261501	24146786	To further study this hypothesis, we have investigated WHO2003 defined ESS-LG with reasonably long term follow-up (median: 53, range: 24-83) to identify features that are independently prognostic.	('ESS-LG', 'Disease', (71, 77))	('WHO2003', 'Var', (55, 62))	('ESS-LG', 'Chemical', '-', (71, 77))
261534	24146786	The advantage of these criteria compared to mitosis counts and the fact that the classification is well reproducible and strongly prognostic makes clear that the WHO2003 classification can be an improvement.	('WHO2003', 'Var', (162, 169))	('mitosis', 'Disease', (44, 51))	('mitosis', 'Disease', 'None', (44, 51))
261563	24146786	In conclusion, in FIGO2009, WHO2003 defined ESS-LG, elevated levels of proliferation as measured by MAI, PPH3 and Ki-67 seem predictive of tumors that will recur.	('ESS-LG', 'Disease', (44, 50))	('ESS-LG', 'Chemical', '-', (44, 50))	('PPH3', 'Chemical', '-', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('levels', 'MPA', (61, 67))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('WHO2003', 'Var', (28, 35))	('Ki-67', 'Chemical', '-', (114, 119))	('elevated', 'PosReg', (52, 60))
261565	21624110	The small-molecule MDM2 antagonist Nutlin-3a activates the p53 pathway and efficiently induces apoptosis in tumours with amplified MDM2 gene and overexpression of MDM2 protein.	('p53 pathway', 'Pathway', (59, 70))	('tumours', 'Disease', (108, 115))	('MDM2', 'Gene', (131, 135))	('activates', 'PosReg', (45, 54))	('amplified', 'Var', (121, 130))	('apoptosis', 'CPA', (95, 104))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (35, 44))	('induces', 'Reg', (87, 94))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))
261569	21624110	Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type TP53 and amplified MDM2, or with Methotrexate in both MDM2 normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose.	('TP53', 'Gene', '7157', (103, 107))	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('sarcoma', 'Disease', (183, 190))	('TP53', 'Gene', (103, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('MDM2', 'Gene', (122, 126))	('reduction', 'NegReg', (230, 239))	('Doxorubicin', 'Chemical', 'MESH:D004317', (34, 45))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (50, 59))	('Methotrexate', 'Chemical', 'MESH:D008727', (136, 148))	('cytotoxic drug dose', 'MPA', (243, 262))	('amplified', 'Var', (112, 121))
261570	21624110	Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated TP53, but inhibited the effect of Methotrexate.	('Methotrexate', 'Chemical', 'MESH:D008727', (166, 178))	('Cisplatin', 'MPA', (95, 104))	('mutated', 'Var', (124, 131))	('effect', 'MPA', (50, 56))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('potentiate', 'PosReg', (35, 45))	('Cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (15, 24))	('inhibited', 'NegReg', (142, 151))	('Doxorubicin', 'Chemical', 'MESH:D004317', (79, 90))
261573	21624110	However, aberrations of this pathway are probably even more wide-spread, as tumours retaining wild-type p53 (TP53Wt) might have defects in other parts of the pathway.	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('defects', 'NegReg', (128, 135))	('tumours', 'Disease', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (109, 113))	('aberrations', 'Var', (9, 20))	('TP53', 'Gene', (109, 113))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
261574	21624110	In sarcomas, malignant tumours resembling mesenchymal tissue, amplification of MDM2 (murine double minute 2) is relatively common (20%) in tumours having TP53Wt, resulting in disabled p53 function because overexpressed MDM2 protein binds to and inactivates p53.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('protein', 'Protein', (224, 231))	('p53', 'Protein', (184, 187))	('inactivates', 'NegReg', (245, 256))	('tumours', 'Disease', (139, 146))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('murine', 'Species', '10090', (85, 91))	('malignant tumours', 'Disease', 'MESH:D009369', (13, 30))	('malignant tumours', 'Disease', (13, 30))	('disabled', 'NegReg', (175, 183))	('function', 'MPA', (188, 196))	('TP53', 'Gene', (154, 158))	('overexpressed', 'PosReg', (205, 218))	('tumours', 'Disease', (23, 30))	('p53', 'Protein', (257, 260))	('MDM2', 'Gene', (79, 83))	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('sarcomas', 'Disease', (3, 11))	('amplification', 'Var', (62, 75))	('TP53', 'Gene', '7157', (154, 158))	('binds to', 'Interaction', (232, 240))
261575	21624110	Remaining tumours may have other aberrations in their p53 pathway, either p53 mutations (TP53Mut, 11-31% depending on subtype), or other changes in the downstream pathway that do not affect the level of MDM2 (MDM2Wt/TP53Wt, 11-88% depending on subtype).	('tumours', 'Disease', (10, 17))	('TP53', 'Gene', (216, 220))	('TP53', 'Gene', '7157', (89, 93))	('MDM2Wt', 'Gene', (209, 215))	('TP53', 'Gene', (89, 93))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('changes', 'Reg', (137, 144))	('mutations', 'Var', (78, 87))	('p53', 'Gene', (74, 77))	('MDM2Wt', 'Gene', '4193', (209, 215))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('p53 pathway', 'Pathway', (54, 65))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('TP53', 'Gene', '7157', (216, 220))
261593	21624110	Our studies show significant potentiation and/or reduction of effective dose of cytotoxic drugs by Nutlin, in both wild-type and mutated TP53 tumours, suggesting that clinical combination studies in sarcoma are warranted.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('potentiation', 'PosReg', (29, 41))	('tumours', 'Disease', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('reduction', 'NegReg', (49, 58))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('mutated', 'Var', (129, 136))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('TP53', 'Gene', '7157', (137, 141))	('effective dose of cytotoxic drugs', 'MPA', (62, 95))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('sarcoma', 'Disease', (199, 206))	('TP53', 'Gene', (137, 141))
261595	21624110	Two cell lines had MDM2Ampl and three had MDM2Wt(Table 1).	('MDM2Wt', 'Gene', '4193', (42, 48))	('MDM2Ampl', 'Var', (19, 27))	('MDM2Wt', 'Gene', (42, 48))
261599	21624110	The total protein coding region of TP53 (exon 2 to 11) was amplified in five distinct fragments by using flanking intronic primers with M13 tails, generating products of 837, 464, 887, 300 and 275 base pairs respectively.	('464', 'Var', (175, 178))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('887', 'Var', (180, 183))
261603	21624110	Briefly, in a 96-well plate (Becton Dickinson), cells were seeded in 100 mul/well at appropriate cell densities; 500 cells per well for OSA, 1 500 for T778, 10 000 for RMS13, 2 000 for U2OS and 8 000 for SaOS-2.	('RMS13', 'Var', (168, 173))	('U2OS', 'CellLine', 'CVCL:0042', (185, 189))	('T778', 'Var', (151, 155))
261610	21624110	Furthermore we evaluated how much each drug dose in a synergistic combination could be reduced at a given effect level compared with the doses for each drug alone, the so-called dose-reduction index (DRI): Notably, non-synergistic combinations could also result in reduced drug doses (DRI > 1) as illustrated by the example: if drug A and drug B each inhibit 50% and if (0.5A+ 0.5B) also inhibits 50% and both drugs have no overlapping toxicity toward the host, DRI >= 1 may still be beneficial.	('inhibit', 'NegReg', (351, 358))	('reduced', 'NegReg', (265, 272))	('toxicity', 'Disease', 'MESH:D064420', (436, 444))	('toxicity', 'Disease', (436, 444))	('inhibits', 'NegReg', (388, 396))	('reduced drug doses', 'Phenotype', 'HP:0020171', (265, 283))	('non-synergistic', 'Var', (215, 230))	('combinations', 'Var', (231, 243))	('drug doses', 'MPA', (273, 283))
261618	21624110	RMS13, previously described as TP53Wt, did not respond to Nutlin-3a, and was found to have a transversion in codon 280, exon 8, changing the amino acid from arginine to serine in the resulting protein.	('arginine', 'Chemical', 'MESH:D001120', (157, 165))	('RMS13', 'Var', (0, 5))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (58, 67))	('serine', 'Chemical', 'MESH:D012694', (169, 175))	('changing', 'Reg', (128, 136))	('amino acid from arginine to serine', 'MPA', (141, 175))
261619	21624110	Protein analysis uncovered high levels of probably dysfunctional p53 protein and constitutively high p21 and PUMA (see below).	('p53 protein', 'Protein', (65, 76))	('p21', 'Gene', (101, 104))	('dysfunctional', 'Var', (51, 64))	('p21', 'Gene', '644914', (101, 104))
261620	21624110	This is consistent with a report that the Rh30 cell line, established independently from a xenograft from the same patient, also had this mutation and illustrates the usefulness of Nutlin as a probe for p53 status.	('patient', 'Species', '9606', (115, 122))	('had', 'Reg', (129, 132))	('mutation', 'Var', (138, 146))
261631	21624110	Figure 2 shows an Fa-CI plot illustrating the effects of Nutlin-3a and Doxorubicin in a 1:1 fixed drug ratio combination and demonstrates synergism at Fa > 0.5 for T778 whereas on average the other two cell lines display less than additive effects.	('Doxorubicin', 'Chemical', 'MESH:D004317', (71, 82))	('synergism', 'MPA', (138, 147))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (57, 66))	('T778', 'Var', (164, 168))
261634	21624110	Methotrexate on the other hand showed more than additive effect when combined with Nutlin-3a for T778 and U2OS, MDM2Ampl and MDM2Wt, respectively.	('U2OS', 'CellLine', 'CVCL:0042', (106, 110))	('MDM2Wt', 'Gene', (125, 131))	('U2OS', 'Var', (106, 110))	('T778', 'Var', (97, 101))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (83, 92))	('MDM2Ampl', 'Var', (112, 120))	('Methotrexate', 'Chemical', 'MESH:D008727', (0, 12))	('MDM2Wt', 'Gene', '4193', (125, 131))
261637	21624110	In addition, in cell lines being MDM2Ampl or MDM2Wt, T778 and U2OS respectively, we found that reduced dose of Methotrexate would suffice when combined with Nutlin-3a.	('Methotrexate', 'Chemical', 'MESH:D008727', (111, 123))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (157, 166))	('U2OS', 'CellLine', 'CVCL:0042', (62, 66))	('MDM2Wt', 'Gene', (45, 51))	('MDM2Ampl', 'Var', (33, 41))	('MDM2Wt', 'Gene', '4193', (45, 51))
261654	21624110	Although TP53 mutations are not so frequent in sarcomas, the pathway may also be inactivated by amplification of the MDM2 gene which is observed almost exclusively in tumours where TP53 is wild-type.	('amplification', 'Var', (96, 109))	('sarcomas', 'Disease', (47, 55))	('TP53', 'Gene', (181, 185))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('tumours', 'Disease', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('MDM2', 'Gene', (117, 121))	('inactivated', 'NegReg', (81, 92))	('TP53', 'Gene', '7157', (181, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
261656	21624110	If tumours contain defects of the p53 pathway that are upstream of p53 or suppress p53 levels, activation of p53 could bypass the defect and, provided the right signals are present, either induce apoptosis directly or sensitize the cells to induction of apoptosis by traditional therapy.	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('sensitize', 'Reg', (218, 227))	('induce', 'Reg', (189, 195))	('suppress', 'NegReg', (74, 82))	('apoptosis', 'CPA', (196, 205))	('defects', 'Var', (19, 26))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('p53 pathway', 'Pathway', (34, 45))	('p53 levels', 'MPA', (83, 93))
261660	21624110	Although it has been shown that Nutlin alone is very efficacious in MDM2Ampl sarcoma cell lines in vitro and in vivo , the effects of combinations with standard therapeutics in sarcomas is still unknown.	('sarcomas', 'Disease', (177, 185))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('sarcoma', 'Disease', (177, 184))	('MDM2Ampl', 'Var', (68, 76))	('sarcomas', 'Disease', 'MESH:D012509', (177, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('sarcoma', 'Disease', (77, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (177, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
261669	21624110	Neither Doxorubicin nor Cisplatin showed consistent differences in effect in relation to MDM2 amplification or TP53 mutation, but the TP53 mutated cell line (RMS13) was more sensitive to all three genotoxic agents tested than the TP53 null cell line (SaOS-2).	('Doxorubicin', 'Chemical', 'MESH:D004317', (8, 19))	('TP53', 'Gene', (134, 138))	('TP53', 'Gene', '7157', (111, 115))	('TP53', 'Gene', (230, 234))	('mutated', 'Var', (139, 146))	('TP53', 'Gene', (111, 115))	('sensitive', 'MPA', (174, 183))	('TP53', 'Gene', '7157', (134, 138))	('Cisplatin', 'Chemical', 'MESH:D002945', (24, 33))	('more', 'PosReg', (169, 173))	('TP53', 'Gene', '7157', (230, 234))
261677	21624110	It was reported that when cells with dysfunctional TP53 were exposed to high concentrations of Nutlin (e.g.	('dysfunctional', 'Var', (37, 50))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (51, 55))
261679	21624110	Nutlin combined with Cisplatin or Doxorubicin has also previously been reported to induce apoptosis much more efficiently than either drug alone in cells with dysfunctional TP53, most likely due to E2F1-mediated up-regulation of p73 activity.	('E2F1', 'Gene', '1869', (198, 202))	('p73', 'Gene', '7161', (229, 232))	('E2F1', 'Gene', (198, 202))	('induce', 'PosReg', (83, 89))	('p73', 'Gene', (229, 232))	('Doxorubicin', 'Chemical', 'MESH:D004317', (34, 45))	('Cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('TP53', 'Gene', '7157', (173, 177))	('up-regulation', 'PosReg', (212, 225))	('TP53', 'Gene', (173, 177))	('apoptosis', 'CPA', (90, 99))	('dysfunctional', 'Var', (159, 172))
261688	21624110	Our in vitro data suggest that MDM2 antagonists could offer effective therapy for sarcoma either as single agent or in combination with prevailing chemotherapy, and may significantly reduce the genotoxic burden with the same or better antitumour effect.	('genotoxic burden', 'CPA', (194, 210))	('tumour', 'Disease', 'MESH:D009369', (239, 245))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('tumour', 'Disease', (239, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('antagonists', 'Var', (36, 47))	('sarcoma', 'Disease', (82, 89))	('MDM2', 'Gene', (31, 35))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('reduce', 'NegReg', (183, 189))
261699	33674598	Aberrant phase separation has been postulated as the cause of certain cancers.	('cause', 'Reg', (53, 58))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
261728	33674598	As control experiments, mCherry alone, mCherry-EWSLCD, or the DNA-binding mutant of EWS-FLI1 (GFP-EWS-FLI1(R2L2)) cannot form any puncta on DNA (Fig.	('EWS-FLI1', 'Gene', (84, 92))	('EWS-FLI1', 'Gene', (98, 106))	('EWS-FLI1', 'Gene', '2130;2313', (84, 92))	('EWS', 'Gene', '2130', (98, 101))	('EWS', 'Gene', '2130', (84, 87))	('EWS', 'Gene', (84, 87))	('EWS', 'Gene', (98, 101))	('EWS-FLI1', 'Gene', '2130;2313', (98, 106))	('EWS', 'Gene', '2130', (47, 50))	('EWS', 'Gene', (47, 50))	('mutant', 'Var', (74, 80))
261756	33674598	These results confirmed that Pol II CTDN26-mCherry can be specifically recruited into the FUS-Gal4 condensates under lower concentrations.	('Gal4', 'Gene', (94, 98))	('FUS', 'Gene', '2521', (90, 93))	('Gal4', 'Gene', '3960', (94, 98))	('CTDN26-mCherry', 'Var', (36, 50))	('FUS', 'Gene', (90, 93))
261766	33674598	We noticed that the transcription efficiency of the MS2 labeling method was higher than UTP-Fluor647 labeling method (Supplementary Fig.	('MS2', 'Var', (52, 55))	('MS2', 'Species', '2710868', (52, 55))	('transcription efficiency', 'MPA', (20, 44))	('higher', 'PosReg', (76, 82))	('UTP-Fluor647', 'Chemical', '-', (88, 100))
261770	33674598	6a), we questioned if we fused T7 RNAP and Pol II CTDN26 together, whether this fusion complex can be recruited into FUS-Gal4 or EWS-FLI1 condensates, and then the fusion T7 RNAP inside the condensates might activate gene transcriptions on DNA nearby inside the condensates.	('FUS', 'Gene', (117, 120))	('FUS', 'Gene', '2521', (117, 120))	('gene transcriptions', 'MPA', (217, 236))	('EWS-FLI1', 'Gene', (129, 137))	('Gal4', 'Gene', '3960', (121, 125))	('EWS-FLI1', 'Gene', '2130;2313', (129, 137))	('fusion T7 RNAP', 'Var', (164, 178))	('activate', 'PosReg', (208, 216))	('CTDN26', 'Gene', (50, 56))	('Gal4', 'Gene', (121, 125))
261772	33674598	As expected, enriched Fluor647 signals representing nascent RNA transcripts were detected within FUS-Gal4 condensates (white arrows in Fig.	('FUS', 'Gene', (97, 100))	('Fluor647', 'Chemical', '-', (22, 30))	('FUS', 'Gene', '2521', (97, 100))	('Fluor647', 'Var', (22, 30))	('Gal4', 'Gene', '3960', (101, 105))	('Gal4', 'Gene', (101, 105))
261776	33674598	The result showed that there were few detectable Fluor647 signals (0.11, N = 442), suggesting that free UTP-Fluor647 barely binds to DNA and the FUS-Gal4 condensates.	('FUS', 'Gene', '2521', (145, 148))	('Gal4', 'Gene', (149, 153))	('UTP-Fluor647', 'Var', (104, 116))	('binds', 'Interaction', (124, 129))	('Fluor647', 'Chemical', '-', (49, 57))	('UTP-Fluor647', 'Chemical', '-', (104, 116))	('Fluor647', 'Chemical', '-', (108, 116))	('Gal4', 'Gene', '3960', (149, 153))	('FUS', 'Gene', (145, 148))
261786	33674598	Lessnick and coworkers also found that maximal EWS-FLI1-mediated gene expression was associated with 20-26x GGAA-microsatellite-length polymorphisms.	('20-26x', 'Var', (101, 107))	('expression', 'MPA', (70, 80))	('EWS-FLI1', 'Gene', '2130;2313', (47, 55))	('EWS-FLI1', 'Gene', (47, 55))
261787	33674598	For EWS-FLI1, we found that when the length of GGAA-microsatellites increased, elevated relative luciferase activity was also observed (Fig.	('luciferase', 'Enzyme', (97, 107))	('activity', 'MPA', (108, 116))	('GGAA-microsatellites', 'Gene', (47, 67))	('EWS-FLI1', 'Gene', (4, 12))	('elevated', 'PosReg', (79, 87))	('length', 'Var', (37, 43))	('EWS-FLI1', 'Gene', '2130;2313', (4, 12))
261792	33674598	Furthermore, we conducted a bioinformatics analysis of chromatin immunoprecipitation sequencing (ChIP-seq) data (NCBI, GEO: GSE99959) to characterize the promoter-like EWS-FLI1-bound microsatellites in Ewing sarcoma cell line A673.	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('microsatellites', 'Var', (183, 198))	('Ewing sarcoma', 'Disease', (202, 215))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (202, 215))	('EWS-FLI1', 'Gene', (168, 176))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (202, 215))	('EWS-FLI1', 'Gene', '2130;2313', (168, 176))
261824	33674598	Lessnick and coworkers have also shown that consecutive motifs are more highly bound by EWS-FLI1 by ChIP-seq data analyses, and even a change of a single base pair can generate a new string of consecutive motifs.	('highly', 'PosReg', (72, 78))	('EWS-FLI1', 'Gene', (88, 96))	('bound', 'Interaction', (79, 84))	('EWS-FLI1', 'Gene', '2130;2313', (88, 96))	('change', 'Var', (135, 141))
261845	33674598	The GFP molecule fused in all constructs in this work was the superfolder GFP (sfGFP), which contained a single mutation (A206K) and can avoid the weak dimerization of GFP.	('A206K', 'Mutation', 'p.A206K', (122, 127))	('weak dimerization', 'MPA', (147, 164))	('A206K', 'Var', (122, 127))
261863	33674598	E6921) with EWS-FLI1 cDNA, FUS-ERG cDNA, or FUS-Gal4 cDNA.	('ERG', 'Gene', '2078', (31, 34))	('E6921', 'Var', (0, 5))	('EWS-FLI1', 'Gene', '2130;2313', (12, 20))	('FUS', 'Gene', '2521', (27, 30))	('Gal4', 'Gene', '3960', (48, 52))	('ERG', 'Gene', (31, 34))	('FUS', 'Gene', (44, 47))	('FUS', 'Gene', '2521', (44, 47))	('FUS', 'Gene', (27, 30))	('Gal4', 'Gene', (48, 52))	('EWS-FLI1', 'Gene', (12, 20))
261868	33674598	The mixed samples with different molar ratios and a different number of Gal4DBD binding sites were visualized by a Nikon inverted microscope (Ti-Eclipse) with a 90x oil objective and a camera (HAMAMATSU ORCA-Flash4.0 V3 Digital CMOS camera C13440-20CU, Yihan Lin Lab at Peking University), and the output was a 2D image file (Supplementary Fig.	('Gal4DBD', 'Gene', (72, 79))	('C13440-20CU', 'Var', (240, 251))	('Gal4DBD', 'Gene', '3960', (72, 79))	('different molar', 'Phenotype', 'HP:0011054', (23, 38))
261871	33674598	Differential gene expression following EWS-FLI1 knockdown was determined using the R package DESeq2 with the Benjamini-Hochberg corrected q value cutoff of 0.05.	('EWS-FLI1', 'Gene', (39, 47))	('EWS-FLI1', 'Gene', '2130;2313', (39, 47))	('knockdown', 'Var', (48, 57))
261896	33674598	C418B, for RNA transcripts labeling), and T7 RNAP (~0.4 unit) or CTDN26-T7 RNAP.	('C418B', 'SUBSTITUTION', 'None', (0, 5))	('C418B', 'Var', (0, 5))	('CTDN26-T7', 'Var', (65, 74))
261899	33674598	MP5105) followed the instructions provided by Lucigen and let the phage plaques grow bigger on top agar plates.	('grow', 'PosReg', (80, 84))	('agar', 'Chemical', 'MESH:D000362', (99, 103))	('phage', 'Gene', (66, 71))	('MP5105', 'Var', (0, 6))
261911	27798235	p120 binding masks the motif, stabilizing the cadherin at cell junctions.	('p120', 'Var', (0, 4))	('cadherin', 'Gene', (46, 54))	('cadherin', 'Gene', '999;1000;1003', (46, 54))	('stabilizing', 'PosReg', (30, 41))
261917	27798235	However, K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, and p120 protects VE-cadherin from K5.	('cadherin', 'Gene', (124, 132))	('VE-cadherin', 'Gene', '1003', (121, 132))	('cadherin', 'Gene', '999;1000;1003', (93, 101))	('p120', 'Var', (107, 111))	('cadherin', 'Gene', '999;1000;1003', (124, 132))	('displacement', 'MPA', (63, 75))	('cadherin', 'Gene', '999;1000;1003', (23, 31))	('cadherin', 'Gene', (23, 31))	('VE-cadherin', 'Gene', (20, 31))	('VE-cadherin', 'Gene', (121, 132))	('VE-cadherin', 'Gene', '1003', (20, 31))	('cadherin', 'Gene', (93, 101))
261918	27798235	Thus multiple context-dependent signals drive VE-cadherin endocytosis, but p120 binding to the cadherin juxtamembrane domain acts as a master regulator guarding cadherin stability.	('VE-cadherin', 'Gene', (46, 57))	('cadherin', 'Gene', (95, 103))	('cadherin', 'Gene', '999;1000;1003', (95, 103))	('VE-cadherin', 'Gene', '1003', (46, 57))	('cadherin', 'Gene', '999;1000;1003', (49, 57))	('cadherin', 'Gene', '999;1000;1003', (161, 169))	('cadherin', 'Gene', (161, 169))	('p120 binding', 'Var', (75, 87))	('cadherin', 'Gene', (49, 57))
261920	27798235	Because disruption of endothelial adhesion contributes to a wide variety of diseases, especially through excessive inflammation and facilitation of cancer metastasis, elucidating the basic cellular processes that determine the balance of endothelial adhesion is an important goal.	('disruption', 'Var', (8, 18))	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('contributes', 'Reg', (43, 54))	('inflammation', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer metastasis', 'Disease', (148, 165))	('cancer metastasis', 'Disease', 'MESH:D009362', (148, 165))	('diseases', 'Disease', (76, 84))
261924	27798235	The juxtamembrane domain of VE-cadherin binds to p120-catenin (p120), which stabilizes cadherins at the adherens junction.	('VE-cadherin', 'Gene', (28, 39))	('p120-catenin', 'Gene', '1500', (49, 61))	('VE-cadherin', 'Gene', '1003', (28, 39))	('cadherin', 'Gene', (31, 39))	('p120-catenin', 'Gene', (49, 61))	('cadherin', 'Gene', '999;1000;1003', (31, 39))	('binds', 'Interaction', (40, 45))	('cadherin', 'Gene', (87, 95))	('stabilizes', 'PosReg', (76, 86))	('cadherin', 'Gene', '999;1000;1003', (87, 95))	('p120', 'Var', (63, 67))
261925	27798235	In the absence of p120 binding, cadherins are rapidly endocytosed and degraded.	('cadherin', 'Gene', '999;1000;1003', (32, 40))	('cadherin', 'Gene', (32, 40))	('degraded', 'NegReg', (70, 78))	('endocytosed', 'MPA', (54, 65))	('p120', 'Var', (18, 22))
261926	27798235	Thus p120 binding to cadherins can function as a regulator of adherens junction stability.	('adherens junction stability', 'CPA', (62, 89))	('binding', 'Interaction', (10, 17))	('p120', 'Var', (5, 9))	('cadherin', 'Gene', '999;1000;1003', (21, 29))	('cadherin', 'Gene', (21, 29))
261928	27798235	p120 binding physically masks the endocytic signal, blocking its function and stabilizing the cadherin.	('p120 binding', 'Var', (0, 12))	('masks', 'NegReg', (24, 29))	('endocytic signal', 'MPA', (34, 50))	('cadherin', 'Gene', '999;1000;1003', (94, 102))	('cadherin', 'Gene', (94, 102))	('blocking', 'NegReg', (52, 60))	('function', 'MPA', (65, 73))	('stabilizing', 'Reg', (78, 89))
261929	27798235	Endothelial-specific deletion of p120 in mice results in hemorrhaging, vascular patterning defects, and embryonic lethality, underscoring the importance of p120 for maintenance of vessel stability.	('p120', 'Gene', (33, 37))	('mice', 'Species', '10090', (41, 45))	('vascular patterning defects', 'CPA', (71, 98))	('deletion', 'Var', (21, 29))	('hemorrhaging', 'Disease', (57, 69))	('embryonic lethality', 'Disease', 'MESH:D020964', (104, 123))	('embryonic lethality', 'Disease', (104, 123))	('hemorrhaging', 'Disease', 'MESH:D006470', (57, 69))
261930	27798235	However, p120-modulation of VE-cadherin endocytosis allows a level of constitutive internalization of the cadherin.	('VE-cadherin', 'Gene', (28, 39))	('VE-cadherin', 'Gene', '1003', (28, 39))	('constitutive internalization', 'MPA', (70, 98))	('p120-modulation', 'Var', (9, 24))	('cadherin', 'Gene', (106, 114))	('cadherin', 'Gene', (31, 39))	('cadherin', 'Gene', '999;1000;1003', (106, 114))	('cadherin', 'Gene', '999;1000;1003', (31, 39))
261931	27798235	Constitutive VE-cadherin endocytosis confers plasticity to endothelial cell-cell junctions, and expression of a VE-cadherin mutant resistant to constitutive endocytosis inhibits collective migration of endothelial cells.	('mutant', 'Var', (124, 130))	('plasticity', 'MPA', (45, 55))	('collective migration of endothelial cells', 'CPA', (178, 219))	('VE-cadherin', 'Gene', (112, 123))	('inhibits', 'NegReg', (169, 177))	('VE-cadherin', 'Gene', '1003', (112, 123))	('VE-cadherin', 'Gene', '1003', (13, 24))	('VE-cadherin', 'Gene', (13, 24))
261933	27798235	If p120-modulated constitutive endocytosis of VE-cadherin is responsible for balancing stability and flexibility of endothelial adhesion, what causes the disruption of this mechanism in diseases associated with inappropriate loss of endothelial adhesion?	('VE-cadherin', 'Gene', (46, 57))	('inappropriate loss', 'Disease', 'MESH:D007177', (211, 229))	('VE-cadherin', 'Gene', '1003', (46, 57))	('p120-modulated', 'Var', (3, 17))	('inappropriate loss', 'Disease', (211, 229))
261941	27798235	K5 targets VE-cadherin for ubiquitination, displaces p120 from the VE-cadherin juxtamembrane domain, and induces VE-cadherin endocytosis.	('induces', 'Reg', (105, 112))	('VE-cadherin', 'Gene', '1003', (11, 22))	('VE-cadherin', 'Gene', (67, 78))	('ubiquitination', 'MPA', (27, 41))	('p120', 'Var', (53, 57))	('VE-cadherin', 'Gene', (113, 124))	('VE-cadherin', 'Gene', '1003', (67, 78))	('VE-cadherin', 'Gene', (11, 22))	('displaces', 'NegReg', (43, 52))	('VE-cadherin', 'Gene', '1003', (113, 124))
261942	27798235	Furthermore, we identify two membrane-proximal lysines within the p120-binding site as the specific VE-cadherin residues targeted by K5 and demonstrate that p120 binding can protect VE-cadherin from K5-induced down-regulation.	('VE-cadherin', 'Gene', '1003', (182, 193))	('VE-cadherin', 'Gene', '1003', (100, 111))	('binding', 'Interaction', (162, 169))	('VE-cadherin', 'Gene', (182, 193))	('p120', 'Var', (157, 161))	('lysines', 'Chemical', 'MESH:D008239', (47, 54))	('down-regulation', 'NegReg', (210, 225))	('VE-cadherin', 'Gene', (100, 111))
261943	27798235	Of interest, a VE-cadherin mutant resistant to constitutive endocytosis is still susceptible to down-regulation by K5.	('VE-cadherin', 'Gene', '1003', (15, 26))	('down-regulation', 'NegReg', (96, 111))	('VE-cadherin', 'Gene', (15, 26))	('mutant', 'Var', (27, 33))
261944	27798235	Thus, even though different endocytic signals drive constitutive and K5-induced VE-cadherin internalization, p120 maintains a key role as the guardian of VE-cadherin stability through protection of the cadherin juxtamembrane domain.	('cadherin', 'Gene', '999;1000;1003', (83, 91))	('VE-cadherin', 'Gene', '1003', (80, 91))	('p120', 'Var', (109, 113))	('VE-cadherin', 'Gene', '1003', (154, 165))	('cadherin', 'Gene', '999;1000;1003', (157, 165))	('cadherin', 'Gene', (157, 165))	('VE-cadherin', 'Gene', (154, 165))	('cadherin', 'Gene', '999;1000;1003', (202, 210))	('cadherin', 'Gene', (202, 210))	('cadherin', 'Gene', (83, 91))	('VE-cadherin', 'Gene', (80, 91))
261947	27798235	In agreement with previous reports, expression of K5 caused a sharp reduction in VE-cadherin protein levels (Figure 1A).	('VE-cadherin', 'Gene', '1003', (81, 92))	('VE-cadherin', 'Gene', (81, 92))	('expression', 'Var', (36, 46))	('reduction', 'NegReg', (68, 77))
261950	27798235	Expression of K5 in keratinocytes failed to decrease levels of epithelial cadherin (E-cadherin; Supplemental Figure S1B), also indicating that K5-mediated down-regulation of VE-cadherin is a specific process rather than the result of nonspecific targeting of cell surface proteins.	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('epithelial cadherin', 'Gene', '999', (63, 82))	('E-cadherin', 'Gene', (175, 185))	('E-cadherin', 'Gene', '999', (175, 185))	('VE-cadherin', 'Gene', (174, 185))	('epithelial cadherin', 'Gene', (63, 82))	('VE-cadherin', 'Gene', '1003', (174, 185))	('down-regulation', 'NegReg', (155, 170))	('K5-mediated', 'Var', (143, 154))
261951	27798235	K5-mediated down-regulation of VE-cadherin in endothelial cells was also evident by immunofluorescence (Figure 1B).	('down-regulation', 'NegReg', (12, 27))	('VE-cadherin', 'Gene', (31, 42))	('VE-cadherin', 'Gene', '1003', (31, 42))	('K5-mediated', 'Var', (0, 11))
261952	27798235	Furthermore, even though K5 did not cause a significant reduction in total protein levels of beta-catenin or p120, K5 expression did displace both catenins from cell-cell junctions (Figure 1B).	('displace', 'NegReg', (133, 141))	('beta-catenin', 'Gene', (93, 105))	('beta-catenin', 'Gene', '1499', (93, 105))	('K5 expression', 'Var', (115, 128))	('catenins', 'Protein', (147, 155))
261955	27798235	After transient expression in COS cells, we detected coprecipitation of the K5 mutant with VE-cadherin, indicating that these proteins form a biochemical complex (Figure 1C).	('VE-cadherin', 'Gene', (91, 102))	('mutant', 'Var', (79, 85))	('VE-cadherin', 'Gene', '1003', (91, 102))
261957	27798235	In addition, we found that K5-mediated down-regulation of VE-cadherin is associated with ubiquitination of the cadherin.	('ubiquitination', 'MPA', (89, 103))	('cadherin', 'Gene', '999;1000;1003', (111, 119))	('cadherin', 'Gene', (111, 119))	('K5-mediated', 'Var', (27, 38))	('down-regulation', 'NegReg', (39, 54))	('cadherin', 'Gene', '999;1000;1003', (61, 69))	('cadherin', 'Gene', (61, 69))	('VE-cadherin', 'Gene', (58, 69))	('VE-cadherin', 'Gene', '1003', (58, 69))
261958	27798235	Prolonged treatment of endothelial cells with MG-132 to broadly disrupt the ubiquitin-proteasome system blocked the ability of K5 to remove VE-cadherin and p120 from cell-cell junctions (Supplemental Figure S2A).	('p120', 'Var', (156, 160))	('MG-132', 'Chemical', 'MESH:C072553', (46, 52))	('ability', 'MPA', (116, 123))	('remove', 'NegReg', (133, 139))	('VE-cadherin', 'Gene', '1003', (140, 151))	('VE-cadherin', 'Gene', (140, 151))	('blocked', 'NegReg', (104, 111))
261959	27798235	Furthermore, the K5 mutant lacking ubiquitin ligase activity failed to down-regulate VE-cadherin stably expressed in a CHO cell line (Supplemental Figure S2B).	('K5 mutant', 'Var', (17, 26))	('lacking', 'NegReg', (27, 34))	('VE-cadherin', 'Gene', (85, 96))	('VE-cadherin', 'Gene', '1003', (85, 96))	('a CHO', 'CellLine', 'CVCL:0213', (117, 122))	('down-regulate', 'NegReg', (71, 84))
261963	27798235	Either K5 targets VE-cadherin directly or K5-mediated ubiquitination of another adherens junction component, such as p120, leads to the subsequent down-regulation of VE-cadherin.	('VE-cadherin', 'Gene', (18, 29))	('VE-cadherin', 'Gene', '1003', (18, 29))	('K5-mediated', 'Var', (42, 53))	('VE-cadherin', 'Gene', (166, 177))	('VE-cadherin', 'Gene', '1003', (166, 177))	('down-regulation', 'NegReg', (147, 162))	('ubiquitination', 'MPA', (54, 68))
261972	27798235	Given their thin profile, we were unable to determine the subcellular localization of VE-cadherin or p120 in cells lining the vascular spaces.	('p120', 'Var', (101, 105))	('VE-cadherin', 'Gene', '1003', (86, 97))	('VE-cadherin', 'Gene', (86, 97))
261973	27798235	However, the endothelial-derived spindle cells expressed both VE-cadherin and p120 and were large enough to distinguish junctional from cytoplasmic staining patterns (Figure 3, C and D).	('VE-cadherin', 'Gene', (62, 73))	('p120', 'Var', (78, 82))	('VE-cadherin', 'Gene', '1003', (62, 73))
261975	27798235	Because VE-cadherin undergoes rapid endocytosis and degradation in the absence of p120 binding, disruption of p120 in Kaposi sarcoma lesions suggests that down-regulation of VE-cadherin in the lesions may result from increased internalization of the cadherin.	('VE-cadherin', 'Gene', (8, 19))	('internalization', 'MPA', (227, 242))	('VE-cadherin', 'Gene', (174, 185))	('Kaposi sarcoma lesions', 'Disease', (118, 140))	('cadherin', 'Gene', '999;1000;1003', (250, 258))	('Kaposi sarcoma lesions', 'Disease', 'MESH:D012514', (118, 140))	('cadherin', 'Gene', '999;1000;1003', (11, 19))	('down-regulation', 'NegReg', (155, 170))	('increased', 'PosReg', (217, 226))	('degradation', 'MPA', (52, 63))	('VE-cadherin', 'Gene', '1003', (8, 19))	('cadherin', 'Gene', '999;1000;1003', (177, 185))	('cadherin', 'Gene', (250, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('VE-cadherin', 'Gene', '1003', (174, 185))	('cadherin', 'Gene', (11, 19))	('p120', 'Var', (110, 114))	('cadherin', 'Gene', (177, 185))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (118, 132))	('disruption', 'Var', (96, 106))
261976	27798235	In fact, we found that expression of K5 in endothelial cells significantly increased VE-cadherin endocytosis (Figure 4A).	('VE-cadherin', 'Gene', (85, 96))	('increased', 'PosReg', (75, 84))	('VE-cadherin', 'Gene', '1003', (85, 96))	('expression', 'Var', (23, 33))
261980	27798235	This constitutive endocytic motif is anchored by three acidic amino acids within the core p120-binding region (DEE646-648; Figure 5A), and mutation of these residues results in a cadherin variant that is resistant to constitutive endocytosis.	('mutation', 'Var', (139, 147))	('results in', 'Reg', (166, 176))	('variant', 'Var', (188, 195))	('cadherin', 'Gene', '999;1000;1003', (179, 187))	('cadherin', 'Gene', (179, 187))
261982	27798235	Surprisingly, the constitutive endocytosis-defective VE-cadherin mutant was not resistant to down-regulation by K5 (Figure 5B), indicating that K5-mediated ubiquitination of the cadherin is sufficient to drive cadherin endocytosis, even in the absence of the constitutive endocytic signal.	('K5-mediated', 'Var', (144, 155))	('cadherin', 'Gene', '999;1000;1003', (56, 64))	('cadherin', 'Gene', (56, 64))	('VE-cadherin', 'Gene', (53, 64))	('cadherin', 'Gene', '999;1000;1003', (178, 186))	('cadherin', 'Gene', (178, 186))	('VE-cadherin', 'Gene', '1003', (53, 64))	('drive', 'PosReg', (204, 209))	('cadherin', 'Gene', '999;1000;1003', (210, 218))	('cadherin', 'Gene', (210, 218))	('ubiquitination', 'MPA', (156, 170))
261983	27798235	A control VE-cadherin mutant that does not bind p120 but undergoes constitutive endocytosis (GGG649-651) was also susceptible to K5-induced down-regulation (Figure 5B).	('VE-cadherin', 'Gene', '1003', (10, 21))	('down-regulation', 'NegReg', (140, 155))	('GGG649-651', 'Var', (93, 103))	('constitutive endocytosis', 'MPA', (67, 91))	('VE-cadherin', 'Gene', (10, 21))
261985	27798235	In particular, two membrane-proximal lysines, K626 and K633, are potential target residues for K5-mediated ubiquitination (Figure 5A).	('K633', 'Var', (55, 59))	('K5-mediated ubiquitination', 'MPA', (95, 121))	('lysines', 'Chemical', 'MESH:D008239', (37, 44))	('K626', 'Chemical', '-', (46, 50))	('K633', 'Chemical', '-', (55, 59))	('K626', 'Var', (46, 50))
261987	27798235	Unlike the constitutive endocytosis-resistant VE-cadherin mutant, the K626R, K633R mutant was resistant to down-regulation by K5 (Figures 5C and S3).	('K633R', 'Var', (77, 82))	('VE-cadherin', 'Gene', (46, 57))	('VE-cadherin', 'Gene', '1003', (46, 57))	('K626R', 'SUBSTITUTION', 'None', (70, 75))	('K633R', 'SUBSTITUTION', 'None', (77, 82))	('K626R', 'Var', (70, 75))
261988	27798235	The K626R, K633R mutant also failed to undergo K5-induced internalization (Figure 5D).	('K633R', 'SUBSTITUTION', 'None', (11, 16))	('K626R', 'SUBSTITUTION', 'None', (4, 9))	('K5-induced internalization', 'MPA', (47, 73))	('K626R', 'Var', (4, 9))	('K633R', 'Var', (11, 16))	('failed', 'NegReg', (29, 35))
261990	27798235	Binding of p120 to the VE-cadherin juxtamembrane domain modulates cadherin endocytosis by masking the constitutive endocytic signal.	('p120', 'Var', (11, 15))	('cadherin', 'Gene', (66, 74))	('cadherin', 'Gene', '999;1000;1003', (66, 74))	('masking', 'NegReg', (90, 97))	('modulates', 'Reg', (56, 65))	('constitutive endocytic signal', 'MPA', (102, 131))	('VE-cadherin', 'Gene', (23, 34))	('cadherin', 'Gene', '999;1000;1003', (26, 34))	('cadherin', 'Gene', (26, 34))	('VE-cadherin', 'Gene', '1003', (23, 34))
261991	27798235	Therefore we asked whether p120 might similarly regulate K5-induced VE-cadherin endocytosis.	('p120', 'Var', (27, 31))	('VE-cadherin', 'Gene', '1003', (68, 79))	('regulate', 'Reg', (48, 56))	('VE-cadherin', 'Gene', (68, 79))
261992	27798235	In particular, we tested whether K5-induced VE-cadherin endocytosis was associated with separation of p120 from the cadherin cytoplasmic tail and, conversely, whether p120 could protect VE-cadherin from down-regulation by K5.	('VE-cadherin', 'Gene', (186, 197))	('cadherin', 'Gene', '999;1000;1003', (116, 124))	('cadherin', 'Gene', (116, 124))	('cadherin', 'Gene', '999;1000;1003', (47, 55))	('cadherin', 'Gene', (47, 55))	('VE-cadherin', 'Gene', '1003', (186, 197))	('VE-cadherin', 'Gene', (44, 55))	('p120', 'Var', (167, 171))	('VE-cadherin', 'Gene', '1003', (44, 55))	('down-regulation', 'NegReg', (203, 218))	('cadherin', 'Gene', '999;1000;1003', (189, 197))	('cadherin', 'Gene', (189, 197))	('tested', 'Reg', (18, 24))
261994	27798235	However, VE-cadherin that is not bound to p120 is rapidly internalized and degraded, so the size of any p120-unbound cadherin pool is likely quite small.	('internalized', 'MPA', (58, 70))	('cadherin', 'Gene', '999;1000;1003', (12, 20))	('cadherin', 'Gene', (12, 20))	('VE-cadherin', 'Gene', (9, 20))	('VE-cadherin', 'Gene', '1003', (9, 20))	('p120', 'Var', (42, 46))	('cadherin', 'Gene', '999;1000;1003', (117, 125))	('cadherin', 'Gene', (117, 125))
261997	27798235	Of interest, most of the VE-cadherin-containing vesicles did not contain p120, indicating that in the process of K5-induced VE-cadherin endocytosis, p120 is displaced from the cadherin (Figure 6C).	('VE-cadherin', 'Gene', (124, 135))	('cadherin', 'Gene', (176, 184))	('cadherin', 'Gene', '999;1000;1003', (176, 184))	('VE-cadherin', 'Gene', '1003', (124, 135))	('p120', 'Var', (149, 153))	('VE-cadherin', 'Gene', '1003', (25, 36))	('cadherin', 'Gene', '999;1000;1003', (127, 135))	('cadherin', 'Gene', (127, 135))	('VE-cadherin', 'Gene', (25, 36))	('cadherin', 'Gene', '999;1000;1003', (28, 36))	('cadherin', 'Gene', (28, 36))
261998	27798235	Because K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, we also tested whether p120 could protect VE-cadherin from down-regulation by K5.	('VE-cadherin', 'Gene', (19, 30))	('cadherin', 'Gene', '999;1000;1003', (22, 30))	('cadherin', 'Gene', (22, 30))	('cadherin', 'Gene', (92, 100))	('VE-cadherin', 'Gene', (144, 155))	('cadherin', 'Gene', '999;1000;1003', (92, 100))	('cadherin', 'Gene', '999;1000;1003', (147, 155))	('cadherin', 'Gene', (147, 155))	('VE-cadherin', 'Gene', '1003', (19, 30))	('VE-cadherin', 'Gene', '1003', (144, 155))	('down-regulation', 'NegReg', (161, 176))	('tested', 'Reg', (110, 116))	('p120', 'Var', (125, 129))
261999	27798235	Indeed, increased expression of p120 in endothelial cells limited the reduction of VE-cadherin protein levels induced by K5 expression (Figure 7, A and B).	('reduction', 'NegReg', (70, 79))	('VE-cadherin', 'Gene', '1003', (83, 94))	('p120', 'Var', (32, 36))	('increased', 'PosReg', (8, 17))	('reduction of VE-cadherin protein levels', 'Phenotype', 'HP:0040209', (70, 109))	('VE-cadherin', 'Gene', (83, 94))	('limited', 'NegReg', (58, 65))
262001	27798235	In contrast to wild-type VE-cadherin, p120 failed to prevent down-regulation of the DEE mutant in response to K5 expression (Figure 7C).	('VE-cadherin', 'Gene', (25, 36))	('down-regulation', 'NegReg', (61, 76))	('VE-cadherin', 'Gene', '1003', (25, 36))	('p120', 'Var', (38, 42))
262002	27798235	Together these results suggest that p120 binding to VE-cadherin directly controls K5-induced down-regulation of VE-cadherin.	('down-regulation', 'NegReg', (93, 108))	('VE-cadherin', 'Gene', (52, 63))	('p120', 'Var', (36, 40))	('VE-cadherin', 'Gene', '1003', (52, 63))	('binding', 'Interaction', (41, 48))	('VE-cadherin', 'Gene', (112, 123))	('VE-cadherin', 'Gene', '1003', (112, 123))
262003	27798235	Thus, even though constitutive- and K5-induced VE-cadherin endocytosis are driven by distinct internalization signals, p120 functions as a common modulator of both mechanisms (Figure 8).	('p120', 'Var', (119, 123))	('VE-cadherin', 'Gene', (47, 58))	('VE-cadherin', 'Gene', '1003', (47, 58))	('internalization', 'MPA', (94, 109))
262007	27798235	However, p120 maintains a key role modulating VE-cadherin endocytosis by protecting against both the constitutive and K5-mediated endocytic signals (Figure 7).	('p120', 'Var', (9, 13))	('VE-cadherin', 'Gene', (46, 57))	('K5-mediated endocytic signals', 'MPA', (118, 147))	('VE-cadherin', 'Gene', '1003', (46, 57))	('modulating', 'Reg', (35, 45))	('constitutive', 'MPA', (101, 113))
262008	27798235	The p120 binding site in the cadherin juxtamembrane domain can be divided into a region mediating tight binding and a region mediating more dynamic interactions.	('cadherin', 'Gene', '999;1000;1003', (29, 37))	('p120 binding', 'Var', (4, 16))	('cadherin', 'Gene', (29, 37))	('binding', 'Interaction', (104, 111))
262009	27798235	Because the VE-cadherin lysines targeted by K5 lie within the dynamic p120-binding region, our results support a model in which p120 and K5 compete for access to the VE-cadherin juxtamembrane domain.	('p120', 'Var', (128, 132))	('lysines', 'Chemical', 'MESH:D008239', (24, 31))	('VE-cadherin', 'Gene', (12, 23))	('VE-cadherin', 'Gene', (166, 177))	('VE-cadherin', 'Gene', '1003', (12, 23))	('VE-cadherin', 'Gene', '1003', (166, 177))
262010	27798235	Thus p120 protects VE-cadherin from down-regulation by K5, and K5-induced ubiquitination of VE-cadherin displaces p120 (Figure 8).	('ubiquitination', 'MPA', (74, 88))	('VE-cadherin', 'Gene', (19, 30))	('p120', 'Var', (5, 9))	('displaces', 'NegReg', (104, 113))	('down-regulation', 'NegReg', (36, 51))	('VE-cadherin', 'Gene', (92, 103))	('VE-cadherin', 'Gene', '1003', (19, 30))	('VE-cadherin', 'Gene', '1003', (92, 103))	('p120', 'MPA', (114, 118))
262011	27798235	These findings indicate that a variety of signals may trigger VE-cadherin endocytosis both in the context of normal physiology and in disease states, but p120 binding to the cadherin juxtamembrane domain serves as a common control point guarding cadherin stability.	('p120 binding', 'Var', (154, 166))	('trigger', 'Reg', (54, 61))	('cadherin', 'Gene', '999;1000;1003', (246, 254))	('cadherin', 'Gene', (246, 254))	('cadherin', 'Gene', '999;1000;1003', (174, 182))	('cadherin', 'Gene', (174, 182))	('cadherin', 'Gene', '999;1000;1003', (65, 73))	('cadherin', 'Gene', (65, 73))	('VE-cadherin', 'Gene', (62, 73))	('VE-cadherin', 'Gene', '1003', (62, 73))
262012	27798235	Because p120 binding to classical cadherins both in the endothelium and in other tissues is an important regulator of adherens junction dynamics, understanding other processes that may displace p120 from cadherins remains an important area for research.	('cadherin', 'Gene', '999;1000;1003', (204, 212))	('cadherin', 'Gene', (204, 212))	('p120', 'Var', (8, 12))	('p120', 'Var', (194, 198))	('cadherin', 'Gene', '999;1000;1003', (34, 42))	('cadherin', 'Gene', (34, 42))
262021	27798235	This raises the possibility that p120 binding may compete with phosphorylation and Hakai-mediated ubiquitination of the cadherin.	('p120', 'Var', (33, 37))	('ubiquitination', 'MPA', (98, 112))	('Hakai', 'Gene', '79872', (83, 88))	('phosphorylation', 'MPA', (63, 78))	('cadherin', 'Gene', '999;1000;1003', (120, 128))	('cadherin', 'Gene', (120, 128))	('Hakai', 'Gene', (83, 88))
262022	27798235	Although this hypothesis has not been tested, it would, if correct, represent another instance of p120 modulation of a cadherin endocytic mechanism.	('p120 modulation', 'Var', (98, 113))	('cadherin', 'Gene', '999;1000;1003', (119, 127))	('cadherin', 'Gene', (119, 127))
262023	27798235	One study supporting this possibility used mitochondria-targeting assays to demonstrate that E-cadherin ubiquitination and p120 recruitment were mutually exclusive.	('p120 recruitment', 'Var', (123, 139))	('E-cadherin', 'Gene', (93, 103))	('E-cadherin', 'Gene', '999', (93, 103))	('ubiquitination', 'MPA', (104, 118))
262025	27798235	Instead, Hakai-mediated ubiquitination may target E-cadherin that has already entered the endocytic pathway for lysosomal degradation rather than recycling back to the cell surface, a mechanism dependent on Hrs and Src.	('lysosomal degradation', 'MPA', (112, 133))	('Hakai', 'Gene', (9, 14))	('E-cadherin', 'Gene', (50, 60))	('E-cadherin', 'Gene', '999', (50, 60))	('ubiquitination', 'Var', (24, 38))	('Src', 'Gene', '6714', (215, 218))	('Hakai', 'Gene', '79872', (9, 14))	('Src', 'Gene', (215, 218))
262033	27798235	As with many viral pathomechanisms, K5-induced down-regulation of VE-cadherin may result from the hijacking of existing cellular machinery.	('K5-induced', 'Var', (36, 46))	('down-regulation', 'NegReg', (47, 62))	('VE-cadherin', 'Gene', '1003', (66, 77))	('VE-cadherin', 'Gene', (66, 77))
262039	27798235	Additional HHV-8 virulence factors could also explain why expression of K5 in cultured endothelial cells did not decrease p120 protein levels (Figure 1), whereas p120 staining in Kaposi sarcoma lesion biopsies was substantially decreased (Figure 3B).	('p120', 'Var', (162, 166))	('HHV-8', 'Species', '37296', (11, 16))	('decrease', 'NegReg', (113, 121))	('Kaposi sarcoma lesion', 'Disease', 'MESH:D012514', (179, 200))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (179, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('Kaposi sarcoma lesion', 'Disease', (179, 200))	('decreased', 'NegReg', (228, 237))	('p120 protein levels', 'MPA', (122, 141))
262040	27798235	In addition to regulating cadherin stability, p120 also affects cytoskeletal dynamics through regulation of Rho GTPases.	('cytoskeletal dynamics', 'MPA', (64, 85))	('p120', 'Var', (46, 50))	('regulation', 'Reg', (94, 104))	('cadherin', 'Gene', '999;1000;1003', (26, 34))	('cadherin', 'Gene', (26, 34))	('Rho GTPases', 'Protein', (108, 119))	('regulating', 'Reg', (15, 25))	('affects', 'Reg', (56, 63))
262041	27798235	This function is separable from p120 modulation of cadherin endocytosis, but recruitment of p120 to cell borders can influence the spreading of individual cells on an adhesive substrate.	('cadherin', 'Gene', (51, 59))	('p120', 'Var', (92, 96))	('influence', 'Reg', (117, 126))	('cadherin', 'Gene', '999;1000;1003', (51, 59))
262042	27798235	Our results indicate that p120 binding to the cadherin juxtamembrane domain modulates VE-cadherin endocytosis driven by two very different signals.	('VE-cadherin', 'Gene', '1003', (86, 97))	('cadherin', 'Gene', '999;1000;1003', (46, 54))	('cadherin', 'Gene', (46, 54))	('modulates', 'Reg', (76, 85))	('cadherin', 'Gene', '999;1000;1003', (89, 97))	('cadherin', 'Gene', (89, 97))	('p120 binding', 'Var', (26, 38))	('VE-cadherin', 'Gene', (86, 97))
262043	27798235	p120 regulates both the constitutive endocytosis and recycling of VE-cadherin, which establishes junctional plasticity necessary for collective migration of endothelial cells, and the K5-induced ubiquitination, endocytosis, and down-regulation of VE-cadherin associated with the endothelial-derived tumor Kaposi sarcoma.	('regulates', 'Reg', (5, 14))	('VE-cadherin', 'Gene', '1003', (66, 77))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (305, 319))	('tumor Kaposi sarcoma', 'Disease', 'MESH:D012514', (299, 319))	('down-regulation', 'NegReg', (228, 243))	('tumor Kaposi sarcoma', 'Disease', (299, 319))	('recycling', 'MPA', (53, 62))	('VE-cadherin', 'Gene', (247, 258))	('endocytosis', 'MPA', (211, 222))	('K5-induced ubiquitination', 'MPA', (184, 209))	('constitutive endocytosis', 'MPA', (24, 48))	('VE-cadherin', 'Gene', (66, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (312, 319))	('p120', 'Var', (0, 4))	('VE-cadherin', 'Gene', '1003', (247, 258))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))
262047	27798235	These studies suggest that a variety of different endocytic signals drive cadherin internalization and promote junctional plasticity in different contexts, whereas p120 functions as the master regulator stabilizing the cadherin and guarding junctional stability.	('cadherin', 'Gene', '999;1000;1003', (74, 82))	('cadherin', 'Gene', (74, 82))	('internalization', 'MPA', (83, 98))	('promote', 'PosReg', (103, 110))	('p120', 'Var', (164, 168))	('cadherin', 'Gene', (219, 227))	('cadherin', 'Gene', '999;1000;1003', (219, 227))	('junctional plasticity', 'CPA', (111, 132))
262048	27798235	For example, p120 is displaced from the cadherin by K5-mediated ubiquitination (Figure 6), whereas overexpression of p120 protects the cadherin from K5-mediated down-regulation (Figure 7).	('p120', 'Var', (117, 121))	('cadherin', 'Gene', '999;1000;1003', (135, 143))	('cadherin', 'Gene', (135, 143))	('cadherin', 'Gene', '999;1000;1003', (40, 48))	('cadherin', 'Gene', (40, 48))	('p120', 'Var', (13, 17))	('down-regulation', 'NegReg', (161, 176))
262049	27798235	These two observations suggest that p120 and K5 compete for cadherin binding or that p120 modulates the ligase activity of K5, among other possibilities.	('p120', 'Var', (36, 40))	('ligase', 'Enzyme', (104, 110))	('activity', 'MPA', (111, 119))	('cadherin', 'Gene', '999;1000;1003', (60, 68))	('cadherin', 'Gene', (60, 68))	('binding', 'Interaction', (69, 76))	('modulates', 'Reg', (90, 99))	('p120', 'Var', (85, 89))
262058	27798235	The ligase-dead K5 mutant (C30A, C32A, H40A, C43A), described previously, was created by site-directed mutagenesis.	('C32A', 'SUBSTITUTION', 'None', (33, 37))	('C43A', 'Var', (45, 49))	('C30A', 'SUBSTITUTION', 'None', (27, 31))	('C43A', 'SUBSTITUTION', 'None', (45, 49))	('H40A', 'Var', (39, 43))	('C32A', 'Var', (33, 37))	('C30A', 'Var', (27, 31))	('H40A', 'SUBSTITUTION', 'None', (39, 43))
262062	27798235	The K5-resistant mutant (K626R, K633R), constitutive endocytosis-resistant mutant (DEE646-648AAA), and p120-binding control mutant (GGG649-651AAA) were created by site-directed mutagenesis (primers described in Supplemental Table S1).	('K633R', 'SUBSTITUTION', 'None', (32, 37))	('K626R', 'SUBSTITUTION', 'None', (25, 30))	('K633R', 'Var', (32, 37))	('K626R', 'Var', (25, 30))
262065	27798235	The MARCH-2 mutant contains C64S and C67S point mutations.	('C67S', 'Var', (37, 41))	('C67S', 'SUBSTITUTION', 'None', (37, 41))	('MARCH-2', 'Gene', '51257', (4, 11))	('MARCH-2', 'Gene', (4, 11))	('C64S', 'SUBSTITUTION', 'None', (28, 32))	('C64S', 'Var', (28, 32))
262144	26883654	BMD of the lumbar spine (L1-L4) and of the proximal femur (total femur, femoral neck) of the nonoperated side was assessed by dual-energy x-ray absorptiometry (DEXA) (Hologic DiscoveryTM A, Hologic ExplorerTM; Hologic Inc, Bedford, MA, USA) (S/N 45313; Lunar  Prodigy; GE Medical Systems, Munich, Germany).	('S/N 45313', 'Var', (242, 251))	('BMD', 'Disease', 'MESH:D020388', (0, 3))	('S/N 45313', 'SUBSTITUTION', 'None', (242, 251))	('BMD', 'Disease', (0, 3))
262240	23710400	S-100 is a very specific marker for IDCS, but malignant melanoma and malignant peripheral nerve sheath tumors are also positive for S-100.	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (69, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('malignant melanoma', 'Phenotype', 'HP:0002861', (46, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (69, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('S-100', 'Chemical', '-', (132, 137))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (69, 108))	('malignant melanoma', 'Disease', 'MESH:D008545', (46, 64))	('malignant peripheral nerve sheath tumors', 'Disease', (69, 109))	('S-100', 'Chemical', '-', (0, 5))	('IDCS', 'Disease', (36, 40))	('S-100', 'Var', (132, 137))	('malignant melanoma', 'Disease', (46, 64))
262279	21747606	Immunohistochemical studies of primary renal SS cases have consistently shown positivity for Bcl2, CD99/Mic2, CD56, Vimentin and focal positivity for EMA.	('Vimentin', 'Gene', '7431', (116, 124))	('Mic2', 'Gene', '4267', (104, 108))	('positivity', 'Var', (78, 88))	('EMA', 'Gene', '4582', (150, 153))	('CD56', 'Gene', '4684', (110, 114))	('CD99', 'Gene', (99, 103))	('Mic2', 'Gene', (104, 108))	('Bcl2', 'Gene', (93, 97))	('primary renal SS', 'Phenotype', 'HP:0030409', (31, 47))	('CD56', 'Gene', (110, 114))	('SS', 'Phenotype', 'HP:0012570', (45, 47))	('Vimentin', 'Gene', (116, 124))	('CD99', 'Gene', '4267', (99, 103))	('primary renal SS', 'Disease', (31, 47))	('EMA', 'Gene', (150, 153))	('Bcl2', 'Gene', '596', (93, 97))
262285	21747606	Hemangiopericytoma differs from renal SS by its CD34 positivity and CK negativity.	('SS', 'Phenotype', 'HP:0012570', (38, 40))	('CD34', 'Gene', (48, 52))	('positivity', 'Var', (53, 63))	('CD34', 'Gene', '947', (48, 52))	('Hemangiopericytoma', 'Disease', (0, 18))
262305	33669730	The most commonly found is the chimeric protein EWSR1-FLI1 t(11;22)(q24;q12), which is detected in almost 90% of the cases, while EWSR1-ERG t(21;22)(q22;q12) accounts for only 10% of the cases.	('ERG', 'Gene', '2078', (136, 139))	('t(11;22)(q24;q12', 'Var', (59, 75))	('ERG', 'Gene', (136, 139))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (59, 76))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (140, 157))	('found', 'Reg', (18, 23))
262382	33669730	The primary antibodies used were anti-Collagen type I (AB 34710, Abcam, Cambridge, UK), anti-Collagen type IV (AB 6586, Abcam), anti-Fibronectin (AB2413, Abcam), anti-Laminin (MAB19562, Millipore), anti-Vimentin (V6389, Sigma, Saint Louis, MO, USA) and anti-Ki67 (AB16667, Abcam).	('V6389', 'Var', (213, 218))	('Fibronectin', 'Gene', '2335', (133, 144))	('Vimentin', 'Gene', '7431', (203, 211))	('Fibronectin', 'Gene', (133, 144))	('anti-Ki67', 'Var', (253, 262))	('Vimentin', 'Gene', (203, 211))
262415	33669730	In addition, we detected the EWSR1-FLI1 target gene DAX1, strongly expressed in ES-12, ES-16 and ES-11 compared to ES-2 and ES-6 (Figure 2b; uncropped and unadjusted agarose gel image relative to Figure 2A are shown in Figure S4).	('ES-6', 'Gene', '109581', (124, 128))	('agarose', 'Chemical', 'MESH:D012685', (166, 173))	('ES-16', 'Chemical', '-', (87, 92))	('ES-12', 'Gene', '109604', (80, 85))	('ES-6', 'Gene', (124, 128))	('ES-12', 'Gene', (80, 85))	('DAX1', 'Gene', '190', (52, 56))	('ES-11', 'Chemical', '-', (97, 102))	('DAX1', 'Gene', (52, 56))	('ES-16', 'Var', (87, 92))	('ES-11', 'Var', (97, 102))
262424	33669730	For non-encapsulated spheroids, we observed a reduction in metabolic activity upon SN-38 exposure but not upon docetaxel challenge (Figure S3c-e).	('reduction', 'NegReg', (46, 55))	('docetaxel', 'Chemical', 'MESH:D000077143', (111, 120))	('metabolic activity', 'MPA', (59, 77))	('SN-38', 'Var', (83, 88))	('spheroids', 'Chemical', '-', (21, 30))	('SN-38', 'Chemical', 'MESH:D000077146', (83, 88))
262448	33669730	Interestingly, ES-11 showed a reduced growth in vivo compared to ES-6.	('ES-11', 'Var', (15, 20))	('ES-6', 'Gene', (65, 69))	('growth', 'MPA', (38, 44))	('reduced', 'NegReg', (30, 37))	('ES-11', 'Chemical', '-', (15, 20))	('ES-6', 'Gene', '109581', (65, 69))
262461	33669730	For instance, fibronectin is secreted by many ES cell lines such as A4537, 6647, TC106 and 5838 and we detected it also in 2D cultures, indicating that our cultures shared this characteristic with established ES cell lines.	('A4537', 'Var', (68, 73))	('fibronectin', 'Gene', '2335', (14, 25))	('fibronectin', 'Gene', (14, 25))
262466	33669730	Strikingly, tumour relapse was much more enhanced in irinotecan-treated ES-2 mice (derived at diagnosis) than in ES-6 PDX (derived from late-relapse sample), in line with the trend we observed in encapsulated ES spheroids.	('mice', 'Species', '10090', (77, 81))	('irinotecan', 'Chemical', 'MESH:D000077146', (53, 63))	('ES-2', 'Var', (72, 76))	('tumour', 'Disease', (12, 18))	('enhanced', 'PosReg', (41, 49))	('ES-6', 'Gene', '109581', (113, 117))	('ES spheroids', 'Chemical', '-', (209, 221))	('ES-6', 'Gene', (113, 117))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
262489	33125840	All six patients with POLE-mutated tumors, including one with stage IV SWI/SNF-deficient tumor were alive with no evidence of disease.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('POLE-mutated', 'Var', (22, 34))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('SNF-deficient tumor', 'Disease', 'MESH:D009369', (75, 94))	('SNF-deficient tumor', 'Disease', (75, 94))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('patients', 'Species', '9606', (8, 16))
262497	33125840	In the case of DDEC, the inactivating mutation and consequent protein loss was only observed in the undifferentiated carcinoma and not in the corresponding clonally related differentiated endometrioid carcinoma component [2, 3].	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (188, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('loss', 'NegReg', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('undifferentiated carcinoma', 'Disease', (100, 126))	('endometrioid carcinoma', 'Disease', (188, 210))	('inactivating mutation', 'Var', (25, 46))	('protein', 'MPA', (62, 69))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (100, 126))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (188, 210))
262498	33125840	While additional functional studies are needed to confirm a causal relationship between core SWI/SNF protein inactivation and the development of DDEC/UEC, there are several examples linking core SWI/SNF protein inactivation and the development of histologically and immunophenotypically undifferentiated malignancy.	('core SWI/SNF', 'Gene', (190, 202))	('undifferentiated malignancy', 'Disease', 'MESH:D008228', (287, 314))	('inactivation', 'NegReg', (211, 223))	('undifferentiated malignancy', 'Disease', (287, 314))	('DDEC/UEC', 'Disease', (145, 153))	('inactivation', 'Var', (109, 121))
262499	33125840	These include SMARCB1 (protein also known as INI1) inactivation in malignant rhabdoid tumor, atypical rhabdoid/teratoid tumor, epithelioid sarcoma and undifferentiated sinonasal carcinoma, and SMARCA4 (protein also known as BRG1) inactivation in small cell carcinoma hypercalcemic-type of the ovary, SMARCA4-deficient uterine sarcoma/malignant rhabdoid tumor of the uterus, rhabdoid undifferentiated lung carcinoma and gastrointestinal tract carcinoma [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26].	('SMARCB1', 'Gene', (14, 21))	('small cell carcinoma hypercalcemic-type of the ovary', 'Disease', 'MESH:D010051', (246, 298))	('gastrointestinal tract carcinoma', 'Phenotype', 'HP:0002672', (419, 451))	('carcinoma', 'Phenotype', 'HP:0030731', (405, 414))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (334, 358))	('malignant rhabdoid tumor', 'Disease', (334, 358))	('rhabdoid', 'Disease', (374, 382))	('sarcoma', 'Phenotype', 'HP:0100242', (326, 333))	('teratoid tumor', 'Disease', 'MESH:D013724', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('BRG1', 'Gene', '6597', (224, 228))	('teratoid tumor', 'Phenotype', 'HP:0009792', (111, 125))	('inactivation', 'Var', (51, 63))	('SMARCA4', 'Gene', (300, 307))	('rhabdoid', 'Disease', (102, 110))	('BRG1', 'Gene', (224, 228))	('rhabdoid', 'Disease', 'MESH:D018335', (374, 382))	('SMARCA4', 'Gene', '6597', (193, 200))	('rhabdoid', 'Disease', 'MESH:D018335', (344, 352))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('rhabdoid', 'Disease', 'MESH:D018335', (102, 110))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (318, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (442, 451))	('rhabdoid undifferentiated lung carcinoma and gastrointestinal tract carcinoma', 'Disease', 'MESH:D012142', (374, 451))	('rhabdoid', 'Disease', (77, 85))	('sarcoma', 'Disease', (139, 146))	('SMARCA4-deficient uterine sarcoma/malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (300, 358))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (67, 91))	('rhabdoid', 'Disease', (344, 352))	('tumor of the uterus', 'Phenotype', 'HP:0010784', (353, 372))	('inactivation', 'Var', (230, 242))	('malignant rhabdoid tumor', 'Disease', (67, 91))	('sarcoma', 'Disease', (326, 333))	('deficient uterine', 'Phenotype', 'HP:0000013', (308, 325))	('rhabdoid', 'Disease', 'MESH:D018335', (77, 85))	('teratoid tumor', 'Disease', (111, 125))	('SMARCA4', 'Gene', '6597', (300, 307))	('undifferentiated sinonasal carcinoma', 'Disease', (151, 187))	('INI1', 'Gene', (45, 49))	('INI1', 'Gene', '6598', (45, 49))	('undifferentiated sinonasal carcinoma', 'Disease', 'MESH:C537344', (151, 187))	('sarcoma', 'Disease', 'MESH:D012509', (326, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('SMARCA4', 'Gene', (193, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (246, 266))	('SMARCB1', 'Gene', '6598', (14, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
262523	33125840	Two SWI/SNF-deficient DDEC/UEC harbored POLE exonuclease domain mutation (both POLE V411L hotspot) - a SMARCB1-deficient DDEC (FIGO IA) and an ARID1A/1B-deficient DDEC (FIGO IVB).	('SMARCB1', 'Gene', (103, 110))	('mutation', 'Var', (64, 72))	('1B-deficient DDEC', 'Disease', 'MESH:C536016', (150, 167))	('SWI/SNF-deficient DDEC', 'Disease', (4, 26))	('ARID1A/1B', 'Gene', (143, 152))	('SNF-deficient DDEC/UEC', 'Disease', (8, 30))	('ARID1A/1B', 'Gene', '8289;57492', (143, 152))	('1B-deficient DDEC', 'Disease', (150, 167))	('SNF-deficient DDEC/UEC', 'Disease', 'MESH:D007153', (8, 30))	('SWI/SNF-deficient DDEC', 'Disease', 'MESH:D007153', (4, 26))	('SMARCB1', 'Gene', '6598', (103, 110))	('V411L', 'Mutation', 'rs1196350669', (84, 89))
262525	33125840	Three SWI/SNF-intact DDEC harbored POLE mutations (two P286R and one V411L) (all with stage I disease - pT1 and N0) and one SWI/SNF-intact UEC harbored a POLE mutation (P286R) (FIGO IVB with mesenteric tumor metastasis).	('P286R', 'Mutation', 'p.P286R', (55, 60))	('tumor metastasis', 'Disease', 'MESH:D009362', (202, 218))	('tumor metastasis', 'Disease', (202, 218))	('P286R', 'Mutation', 'p.P286R', (169, 174))	('V411L', 'Mutation', 'rs1196350669', (69, 74))	('P286R', 'Var', (55, 60))	('P286R', 'Var', (169, 174))	('V411L', 'Var', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
262528	33125840	Two the 4 SWI/SNF-intact tumors with POLE mutation were MMR-deficient, with one showing isolated PMS2 loss and the other showing isolated MSH6 loss.	('MMR-deficient', 'Disease', 'MESH:C536928', (56, 69))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('MSH6', 'Gene', (138, 142))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PMS2', 'Gene', (97, 101))	('MSH6', 'Gene', '2956', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('mutation', 'Var', (42, 50))	('loss', 'NegReg', (143, 147))	('MMR-deficient', 'Disease', (56, 69))	('loss', 'NegReg', (102, 106))	('PMS2', 'Gene', '5395', (97, 101))
262536	33125840	Nearly all of the patients (30 of 31) with stage III and IV SWI/SNF-deficient tumors died from their disease, except for one patient with stage IV ARID1A/1B-deficient tumor that also harbored a POLE V411L mutation.	('1B-deficient tumor', 'Disease', 'MESH:C536016', (154, 172))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('V411L', 'Mutation', 'rs1196350669', (199, 204))	('ARID1A/1B', 'Gene', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SNF-deficient tumors died', 'Disease', (64, 89))	('ARID1A/1B', 'Gene', '8289;57492', (147, 156))	('patient', 'Species', '9606', (18, 25))	('1B-deficient tumor', 'Disease', (154, 172))	('V411L', 'Var', (199, 204))	('patient', 'Species', '9606', (125, 132))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('SNF-deficient tumors died', 'Disease', 'MESH:D003643', (64, 89))
262561	33125840	The majority of DDEC/UEC harbor inactivating mutations involving core components of SWI/SNF complex with SMARCA4 and ARID1A/ARID1B being most commonly inactivated, resulting in absent expression of corresponding proteins in the undifferentiated tumor.	('SMARCA4', 'Gene', '6597', (105, 112))	('DDEC/UEC', 'Disease', (16, 24))	('ARID1B', 'Gene', (124, 130))	('ARID1A', 'Gene', '8289', (117, 123))	('absent', 'NegReg', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('ARID1A', 'Gene', (117, 123))	('undifferentiated tumor', 'Disease', (228, 250))	('inactivating mutations', 'Var', (32, 54))	('expression', 'MPA', (184, 194))	('undifferentiated tumor', 'Disease', 'MESH:D002277', (228, 250))	('proteins', 'Protein', (212, 220))	('ARID1B', 'Gene', '57492', (124, 130))	('SMARCA4', 'Gene', (105, 112))
262576	33125840	We however believe that these additional mechanism(s), if present, would only be involved in rare cases of DDEC/UEC, based on our prior studies that genetically screened 43 DDEC for mutations in all SWI/SNF complex proteins (implicated in human cancer development) which identified only genomic inactivation of SMARCA4, ARID1B, and SMARCB1 as recurrent events [2, 11].	('SMARCA4', 'Gene', '6597', (311, 318))	('ARID1B', 'Gene', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('inactivation', 'Var', (295, 307))	('cancer', 'Disease', (245, 251))	('SMARCB1', 'Gene', '6598', (332, 339))	('SMARCB1', 'Gene', (332, 339))	('ARID1B', 'Gene', '57492', (320, 326))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('SMARCA4', 'Gene', (311, 318))	('mutations', 'Var', (182, 191))	('human', 'Species', '9606', (239, 244))
262615	32993530	A novel mutation of the MEN1 gene in a patient with multiple endocrine neoplasia type 1 and recurrent fibromyxoid sarcoma - a case report Multiple endocrine neoplasia type 1 (MEN1) syndrome is usually accompanied by endocrine tumors, but non-endocrine tumors can occur as well.	('MEN1', 'Gene', '4221', (175, 179))	('MEN1', 'Gene', '4221', (24, 28))	('fibromyxoid sarcoma', 'Disease', (102, 121))	('endocrine tumors', 'Disease', 'MESH:D009377', (216, 232))	('endocrine tumors', 'Disease', (216, 232))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (147, 166))	('MEN1', 'Gene', (175, 179))	('MEN1', 'Gene', (24, 28))	('Multiple endocrine neoplasia type 1 (MEN1) syndrome', 'Disease', 'MESH:D018761', (138, 189))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('mutation', 'Var', (8, 16))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('patient', 'Species', '9606', (39, 46))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (102, 121))	('neoplasia', 'Phenotype', 'HP:0002664', (71, 80))	('neoplasia', 'Phenotype', 'HP:0002664', (157, 166))	('endocrine tumors', 'Disease', 'MESH:D009377', (242, 258))	('endocrine tumors', 'Disease', (242, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (61, 80))	('multiple endocrine neoplasia type 1', 'Gene', (52, 87))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (52, 87))
262628	32993530	Germline or somatic, mostly inactivating mutations of the coding region of the MEN1 gene on the chromosome 11q13 result in a loss of a functional tumor-suppressor protein called menin.	('inactivating mutations', 'Var', (28, 50))	('loss', 'NegReg', (125, 129))	('MEN1', 'Gene', '4221', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('MEN1', 'Gene', (79, 83))	('tumor', 'Disease', (146, 151))	('menin', 'Gene', '4221', (178, 183))	('menin', 'Gene', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
262629	32993530	Its precise role is still under investigation, but it appears to have multiple roles in gene transcription and its dysfunction could lead to unregulated cell division and consequential tumor growth in susceptible tissues.	('tumor', 'Disease', (185, 190))	('lead to', 'Reg', (133, 140))	('unregulated', 'MPA', (141, 152))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('dysfunction', 'Var', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
262632	32993530	Furthermore, the MEN1 gene mutations have not been formerly reported in sarcomas but only occasionally in a benign smooth muscle tumors and lipomas.	('mutations', 'Var', (27, 36))	('muscle tumors', 'Disease', (122, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('lipomas', 'Phenotype', 'HP:0012032', (140, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('benign smooth muscle tumors', 'Phenotype', 'HP:0031460', (108, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('lipomas', 'Disease', 'MESH:D008067', (140, 147))	('sarcomas', 'Disease', (72, 80))	('lipomas', 'Disease', (140, 147))	('MEN1', 'Gene', (17, 21))	('MEN1', 'Gene', '4221', (17, 21))	('muscle tumors', 'Disease', 'MESH:D009217', (122, 135))
262654	32993530	Ultimately, our patient affirmed genetic testing and turned out to be a carrier of a novel mutation variant of the MEN1 gene.	('MEN1', 'Gene', '4221', (115, 119))	('mutation variant', 'Var', (91, 107))	('patient', 'Species', '9606', (16, 23))	('MEN1', 'Gene', (115, 119))
262656	32993530	Analysis of the MEN1 gene coding region revealed a heterozygous mutation (variant c.812_820del, p.Gly271_Leu273del) in the exon 5.	('c.812_820del', 'Mutation', 'c.812_820del', (82, 94))	('p.Gly271_Leu273del', 'Mutation', 'p.271_,273delL', (96, 114))	('MEN1', 'Gene', (16, 20))	('MEN1', 'Gene', '4221', (16, 20))	('p.Gly271_Leu273del', 'Var', (96, 114))
262657	32993530	Pathogenicity of identified mutation was verified in reference databases for mutations related to MEN1 syndrome (http://www.umd.be/MEN1/).	('MEN1', 'Gene', '4221', (131, 135))	('mutation', 'Var', (28, 36))	('MEN1', 'Gene', (131, 135))	('MEN1', 'Gene', (98, 102))	('MEN1', 'Gene', '4221', (98, 102))
262658	32993530	To date, more than 1300 mutations have been detected in the MEN1 gene region.	('mutations', 'Var', (24, 33))	('MEN1', 'Gene', (60, 64))	('MEN1', 'Gene', '4221', (60, 64))
262659	32993530	Our patient is a carrier of a novel mutation of the MEN1 gene that has not been previously described in the literature.	('patient', 'Species', '9606', (4, 11))	('MEN1', 'Gene', (52, 56))	('MEN1', 'Gene', '4221', (52, 56))	('mutation', 'Var', (36, 44))
262666	32993530	There are some reports on rare MEN1 gene mutations, however, in patients with the undifferentiated sarcoma.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (64, 72))	('MEN1', 'Gene', (31, 35))	('MEN1', 'Gene', '4221', (31, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (82, 106))	('undifferentiated sarcoma', 'Disease', (82, 106))
262668	32993530	One must be aware of the fact that there is generally no obvious genotype-phenotype correlation of specific mutations with the associated tumor varieties even among family members who carry the same mutation.	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('mutations', 'Var', (108, 117))	('tumor', 'Disease', (138, 143))
262669	32993530	Moreover, this case of a novel MEN1 gene mutation and atypical tumor such as fibromyxoid sarcoma raises the question if there will ever be a genotype-phenotype correlation as in other MEN syndromes.	('fibromyxoid sarcoma', 'Disease', (77, 96))	('tumor', 'Disease', (63, 68))	('MEN1', 'Gene', (31, 35))	('MEN1', 'Gene', '4221', (31, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('MEN', 'Species', '9606', (31, 34))	('mutation', 'Var', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MEN', 'Species', '9606', (184, 187))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (77, 96))
262704	32184294	Eribulin is also reported to have less neurotoxicity in preclinical models and patients, and no peripheral neuropathy was observed in the phase I trial in children, suggesting eribulin may have advantages over vincristine with respect to long-term toxicity.	('advantages', 'PosReg', (194, 204))	('Eribulin', 'Chemical', 'MESH:C490954', (0, 8))	('neurotoxicity', 'Disease', 'MESH:D020258', (39, 52))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (96, 117))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (96, 117))	('vincristine', 'Chemical', 'MESH:D014750', (210, 221))	('peripheral neuropathy', 'Disease', (96, 117))	('toxicity', 'Disease', 'MESH:D064420', (248, 256))	('eribulin', 'Var', (176, 184))	('neurotoxicity', 'Disease', (39, 52))	('toxicity', 'Disease', (248, 256))	('patients', 'Species', '9606', (79, 87))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('eribulin', 'Chemical', 'MESH:C490954', (176, 184))	('toxicity', 'Disease', (44, 52))	('children', 'Species', '9606', (155, 163))
262735	32184294	Proteins were transferred to Immobilon-FL PVDF membranes (MilliporeSigma) and probed with antibodies for cleaved PARP (Cell Signaling #5625), phospho-S139-H2A.X (#9718), TP53 (#48818), CDKN1A/p21 (#2947), MDM2 (#86934), PUMA/BBC3 (#12450) phospho-S345-Chk1 (#2348), Chk1 (#2360), phospho-T68-Chk2 (#2197), Chk2 (#3440), full length/cleaved caspase 3 (#9668), cleaved caspase 3 (#9664), phospho-S10-histone H3 (#53348), histone H3 (#4499), GAPDH (#2118) or RRM2B/p53R2 (Invitrogen #PA5-19970).	('caspase 3', 'Gene', '12367', (340, 349))	('phospho', 'Chemical', '-', (239, 246))	('MDM2', 'Gene', '17246', (205, 209))	('histone H3', 'Protein', (419, 429))	('Chk1', 'Gene', (266, 270))	('Chk2', 'Gene', (306, 310))	('PARP', 'Gene', '11545', (113, 117))	('GAPDH', 'Gene', (439, 444))	('Chk1', 'Gene', (252, 256))	('RRM2B', 'Gene', '382985', (456, 461))	('#9664', 'Var', (378, 383))	('p53R2', 'Gene', '382985', (462, 467))	('phospho', 'Chemical', '-', (142, 149))	('#3440', 'Var', (312, 317))	('BBC3', 'Gene', '170770', (225, 229))	('Chk1', 'Gene', '12649', (266, 270))	('CDKN1A', 'Gene', (185, 191))	('RRM2B', 'Gene', (456, 461))	('caspase 3', 'Gene', (340, 349))	('GAPDH', 'Gene', '14433', (439, 444))	('PARP', 'Gene', (113, 117))	('Chk1', 'Gene', '12649', (252, 256))	('caspase 3', 'Gene', '12367', (367, 376))	('PUMA', 'Gene', '170770', (220, 224))	('p21', 'Gene', '12575', (192, 195))	('Chk2', 'Gene', '50883', (292, 296))	('phospho', 'Chemical', '-', (386, 393))	('BBC3', 'Gene', (225, 229))	('H2A.X', 'Gene', (155, 160))	('H3', 'Chemical', 'MESH:C012616', (406, 408))	('PUMA', 'Gene', (220, 224))	('p53R2', 'Gene', (462, 467))	('MDM2', 'Gene', (205, 209))	('CDKN1A', 'Gene', '12575', (185, 191))	('#53348', 'Var', (410, 416))	('H2A.X', 'Gene', '15270', (155, 160))	('phospho', 'Chemical', '-', (280, 287))	('H3', 'Chemical', 'MESH:C012616', (427, 429))	('#2118', 'Var', (446, 451))	('Chk2', 'Gene', '50883', (306, 310))	('caspase 3', 'Gene', (367, 376))	('#4499', 'Var', (431, 436))	('Chk2', 'Gene', (292, 296))	('p21', 'Gene', (192, 195))
262747	32184294	Primary antibodies were 53BP1 (Cell Signaling #4937), phospho-S10-H3 (#53348), or gamma-H2A.X (Abcam #ab26350).	('gamma-H2A.X', 'Gene', (82, 93))	('53BP1', 'Gene', (24, 29))	('gamma-H2A.X', 'Gene', '15270', (82, 93))	('53BP1', 'Gene', '27223', (24, 29))	('phospho-S10-H3', 'Chemical', '-', (54, 68))	('#53348', 'Var', (70, 76))
262788	32184294	S1A), although at 24h the induction of gamma-H2A.X appeared to be greater in combination-treated tumors than in those from irinotecan-treated mice.	('gamma-H2A.X', 'Gene', '15270', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('irinotecan', 'Chemical', 'MESH:D000077146', (123, 133))	('mice', 'Species', '10090', (142, 146))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('combination-treated', 'Var', (77, 96))	('gamma-H2A.X', 'Gene', (39, 50))
262813	32184294	The effect of combination treatment was additive in terms of increased expression compared to single agent treatments for TP53INIP1, RRM2B, CDKN1A and MDM2 (Supplementary Table S7).	('expression', 'MPA', (71, 81))	('RRM2B', 'Gene', '382985', (133, 138))	('CDKN1A', 'Gene', (140, 146))	('MDM2', 'Gene', (151, 155))	('CDKN1A', 'Gene', '12575', (140, 146))	('increased', 'PosReg', (61, 70))	('TP53INIP1', 'Var', (122, 131))	('RRM2B', 'Gene', (133, 138))	('MDM2', 'Gene', '17246', (151, 155))
262814	32184294	Two exceptions were BBC3, which at 144h was similar to the irinotecan sample, and TP53AIP1, which was greater than the sum of the expression in tumors treated with single agents.	('tumors', 'Disease', (144, 150))	('BBC3', 'Gene', '170770', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TP53AIP1', 'Var', (82, 90))	('irinotecan', 'Chemical', 'MESH:D000077146', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('BBC3', 'Gene', (20, 24))
262848	32184294	There was a trend towards increased CD34+ cells in tumors from combination-treated mice compared to control mice, although this was not statistically significant (Figs.	('CD34', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mice', 'Species', '10090', (108, 112))	('combination-treated', 'Var', (63, 82))	('tumors', 'Disease', (51, 57))	('CD34', 'Gene', '12490', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('mice', 'Species', '10090', (83, 87))	('increased', 'PosReg', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
262863	32184294	Potentially, substitution of eribulin for vincristine could reduce peripheral neuropathy in patients, hence improve patient quality of life.	('peripheral neuropathy', 'Disease', 'MESH:D010523', (67, 88))	('patient', 'Species', '9606', (92, 99))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (67, 88))	('peripheral neuropathy', 'Disease', (67, 88))	('patient', 'Species', '9606', (116, 123))	('reduce', 'NegReg', (60, 66))	('patients', 'Species', '9606', (92, 100))	('substitution', 'Var', (13, 25))	('vincristine', 'Chemical', 'MESH:D014750', (42, 53))	('improve', 'PosReg', (108, 115))	('eribulin', 'Chemical', 'MESH:C490954', (29, 37))
262868	32184294	For 4 models, where the EFS was far greater for the eribulin combination compared to the vincristine combination (EFSEI:EFSVI >1.5) each of these models isTP53 wild type, whereas 4 of 5 xenograft models where the combinations had similar activity have mutant TP53, the exception being RBD1 in which TP53 genotype has not been determined.	('eribulin', 'Chemical', 'MESH:C490954', (52, 60))	('mutant', 'Var', (252, 258))	('vincristine', 'Chemical', 'MESH:D014750', (89, 100))	('TP53', 'Gene', (259, 263))
262873	32184294	In contrast, eribulin did not induce TP53AIP1 and only slightly reduced Sestrins 1/2.	('Sestrins 1/2', 'Gene', '140742;230784', (72, 84))	('eribulin', 'Chemical', 'MESH:C490954', (13, 21))	('Sestrins 1/2', 'Gene', (72, 84))	('reduced', 'NegReg', (64, 71))	('TP53AIP1', 'Var', (37, 45))
262882	32184294	These results strongly implicate the role of TP53 in mediating the response to eribulin-irinotecan therapy, and support the model proposed whereby inhibition of microtubule dynamics leads to accumulation of nuclear TP53 under conditions of DNA damage.	('implicate', 'Reg', (23, 32))	('irinotecan', 'Chemical', 'MESH:D000077146', (88, 98))	('microtubule', 'MPA', (161, 172))	('eribulin', 'Chemical', 'MESH:C490954', (79, 87))	('inhibition', 'Var', (147, 157))	('nuclear', 'MPA', (207, 214))	('accumulation', 'PosReg', (191, 203))	('TP53', 'Protein', (215, 219))
262893	32184294	Several lines of evidence indicate that the combination activates the TP53 pathway and increases nuclear TP53; further, in tumors for which eribulin-irinotecan had greater activity than vincristine-irinotecan, tumors were wild type for TP53.	('activates', 'PosReg', (56, 65))	('eribulin-irinotecan', 'Var', (140, 159))	('activity', 'MPA', (172, 180))	('tumors', 'Disease', (123, 129))	('increases', 'PosReg', (87, 96))	('irinotecan', 'Chemical', 'MESH:D000077146', (198, 208))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('TP53 pathway', 'Pathway', (70, 82))	('eribulin', 'Chemical', 'MESH:C490954', (140, 148))	('tumors', 'Disease', (210, 216))	('vincristine-irinotecan', 'Chemical', '-', (186, 208))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('nuclear TP53', 'MPA', (97, 109))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('irinotecan', 'Chemical', 'MESH:D000077146', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
262904	30947707	We analyzed the mRNA-seq data to compare cancer/normal gene expression level, identify biological processes and molecular pathways that are associated with the pathogenesis of FISS, and identify multimegabase genomic regions of potential somatic copy number alteration (SCNA) in FISS.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('FISS', 'Disease', (279, 283))	('FISS', 'Disease', (176, 180))	('copy number alteration', 'Var', (246, 268))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
262917	30947707	In the context of feline sarcoma, somatic copy number alterations (SCNAs) have been studied genome-wide, revealing recurrent copy number gains and losses, but it is unknown to what extent these alterations correlate with elevated or reduced tumor transcript abundances, though such changes would be expected based on current understanding of cancer biology.	('reduced', 'NegReg', (233, 240))	('sarcoma', 'Disease', (25, 32))	('elevated', 'PosReg', (221, 229))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('tumor', 'Disease', (241, 246))	('cancer', 'Disease', (342, 348))	('alterations', 'Var', (194, 205))	('sarcoma', 'Disease', 'MESH:D012509', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('gains', 'PosReg', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('losses', 'NegReg', (147, 153))	('copy number', 'Var', (125, 136))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
262956	30947707	A mixture of microarray and mRNA-seq transcriptome datasets derived from human soft-tissue sarcoma and normal skeletal muscle were obtained from NCBI GEO via accession numbers GSE54734, GSE6481, GSE2719, GSE2361, GSE2719, GSE7905, and GSE2193.	('GSE2361', 'Chemical', '-', (204, 211))	('GSE2719', 'Var', (213, 220))	('GSE6481', 'Var', (186, 193))	('GSE7905', 'Chemical', '-', (222, 229))	('soft-tissue sarcoma', 'Disease', (79, 98))	('GSE7905', 'Var', (222, 229))	('GSE2719', 'Var', (195, 202))	('GSE2361', 'Var', (204, 211))	('human', 'Species', '9606', (73, 78))	('GSE2719', 'Chemical', '-', (213, 220))	('GSE2719', 'Chemical', '-', (195, 202))	('GSE6481', 'Chemical', '-', (186, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('GSE2193', 'Var', (235, 242))	('GSE54734', 'Var', (176, 184))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (79, 98))	('GSE2193', 'Chemical', '-', (235, 242))
263000	30947707	Of these regions, the region (50-60 Mbp on chromosome Fc-D3) that was the most downregulated transcriptionally in our study was previously reported to have a recurrent somatic deletion in FISS.	('deletion', 'Var', (176, 184))	('Mbp', 'Gene', (36, 39))	('Fc-D3', 'Gene', (54, 59))	('Mbp', 'Gene', '4155', (36, 39))	('Fc-D3', 'Gene', '100380874', (54, 59))
263003	30947707	The 50-60 Mbp region of Fc-D3 coincides with a previously reported recurrent chromosomal deletion in FISS and in non-injection-site-associated feline sarcoma; its human syntenic region spans 20.9-80.3 Mbp on Hs-18 (Hs-18q23), which is recurrently deleted in human soft-tissue sarcoma (q < 0.02 based on analysis of SCNA data from ref.	('Mbp', 'Gene', (10, 13))	('Mbp', 'Gene', '4155', (10, 13))	('Fc-D3', 'Gene', '100380874', (24, 29))	('human', 'Species', '9606', (258, 263))	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('Mbp', 'Gene', (201, 204))	('sarcoma', 'Disease', 'MESH:D012509', (276, 283))	('Mbp', 'Gene', '4155', (201, 204))	('soft-tissue sarcoma', 'Disease', (264, 283))	('sarcoma', 'Disease', (276, 283))	('human', 'Species', '9606', (163, 168))	('deletion', 'Var', (89, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('sarcoma', 'Disease', (150, 157))	('Fc-D3', 'Gene', (24, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (264, 283))
263019	30947707	>Because the compound GSK-1059615 (an inhibitor of phosphoinositide 3-kinases (PI3K) and mammalian target of rapamycin (mTOR)) had the strongest enrichment in the in silico screen (Fig.	('phosphoinositide 3-kinases', 'Gene', '5294', (51, 77))	('GSK', 'Chemical', '-', (22, 25))	('phosphoinositide 3-kinases', 'Gene', (51, 77))	('mammalian target of rapamycin (mTOR)', 'Gene', (89, 125))	('GSK-1059615', 'Var', (22, 33))	('mammalian target of rapamycin (mTOR))', 'Gene', '2475', (89, 126))
263020	30947707	We found that 48 h incubation with GSK-1059615 potently inhibited growth of FISS-derived cells in vitro, with an IC50 of 4.6 muM (Fig.	('inhibited', 'NegReg', (56, 65))	('GSK-1059615', 'Var', (35, 46))	('growth of FISS-derived cells in vitro', 'CPA', (66, 103))	('GSK', 'Chemical', '-', (35, 38))
263054	30947707	Human soft tissue sarcoma is known to have many recurrent SCNAs, including deletions and amplifications, that range from focal to broad in scale.	('soft tissue sarcoma', 'Disease', (6, 25))	('Human', 'Species', '9606', (0, 5))	('deletions', 'Var', (75, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (6, 25))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (6, 25))	('recurrent SCNAs', 'Phenotype', 'HP:0100776', (48, 63))
263056	30947707	By our mRNA-seq-based method, we found one putative SCNA (a probable deletion on Fc-D3) that overlapped with a recurrent SCNA detected in a previous DNA-based analysis of feline sarcoma.	('Fc-D3', 'Gene', '100380874', (81, 86))	('Fc-D3', 'Gene', (81, 86))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('deletion', 'Var', (69, 77))	('sarcoma', 'Disease', (178, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
263057	30947707	However, our finding does bolster the likely functional significance of the recurrent Fc-D3 deletion in FISS.	('FISS', 'Disease', (104, 108))	('Fc-D3', 'Gene', '100380874', (86, 91))	('deletion', 'Var', (92, 100))	('Fc-D3', 'Gene', (86, 91))
263064	30947707	Of the fifteen drugs and drug targets that were identified through the screen of drug-to-cell-line databases using the sets of genes that are coherently upregulated or downregulated in sarcoma (across studies in three species), the compound GSK-1059615 is particularly interesting.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('GSK-1059615', 'Var', (241, 252))	('downregulated', 'NegReg', (168, 181))	('upregulated', 'PosReg', (153, 164))	('sarcoma', 'Disease', 'MESH:D012509', (185, 192))	('GSK', 'Chemical', '-', (241, 244))	('sarcoma', 'Disease', (185, 192))
263065	30947707	GSK-1059615 inhibits PI3K and mTOR and it has been investigated as a potential antineoplastic in humans.	('humans', 'Species', '9606', (97, 103))	('GSK-1059615', 'Var', (0, 11))	('inhibits', 'NegReg', (12, 20))	('mTOR', 'Gene', (30, 34))	('PI3K', 'Pathway', (21, 25))	('mTOR', 'Gene', '2475', (30, 34))	('GSK', 'Chemical', '-', (0, 3))
263066	30947707	7) that GSK-1059615 potently inhibits growth of FISS-derived cells suggests that dual PI3K and mTOR targeting is worthy of further study as a potential therapeutic approach for FISS.	('GSK', 'Chemical', '-', (8, 11))	('GSK-1059615', 'Var', (8, 19))	('inhibits', 'NegReg', (29, 37))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('growth of FISS-derived cells', 'CPA', (38, 66))
263070	30947707	Also intriguing is the identification of the drugs AS601245, a Janus N-terminal kinase inhibitor, and rosiglitazone, a PPARgamma selective agonist, as their co-administration to colon cancer cells has been reported to synergistically reduce cell migration.	('colon cancer', 'Phenotype', 'HP:0003003', (178, 190))	('cell migration', 'CPA', (241, 255))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('colon cancer', 'Disease', 'MESH:D015179', (178, 190))	('PPARgamma', 'Gene', (119, 128))	('reduce', 'NegReg', (234, 240))	('AS601245', 'Chemical', 'MESH:C489138', (51, 59))	('colon cancer', 'Disease', (178, 190))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (102, 115))	('PPARgamma', 'Gene', '5468', (119, 128))	('AS601245', 'Var', (51, 59))
263096	30034819	Moreover, the V-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation has been reported in the setting of LCH, histiocytic sarcoma, disseminated JXG, ECD and even follicular dendritic cell sarcoma.	('follicular dendritic cell sarcoma', 'Disease', (176, 209))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', (14, 60))	('ECD', 'Disease', 'MESH:C574275', (163, 166))	('ECD', 'Disease', (163, 166))	('follicular dendritic cell sarcoma', 'Disease', 'MESH:D054740', (176, 209))	('sarcoma', 'Disease', 'MESH:D012509', (202, 209))	('V600E', 'Mutation', 'rs113488022', (68, 73))	('BRAF', 'Gene', (62, 66))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('sarcoma', 'Disease', (202, 209))	('sarcoma', 'Disease', (27, 34))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('sarcoma', 'Disease', (136, 143))	('disseminated JXG', 'Disease', (145, 161))	('V600E', 'Var', (68, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('reported', 'Reg', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('LCH', 'Disease', (119, 122))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (14, 60))
263112	30034819	The BRAF V600E mutation, which has been detected in patients with LCH, has been also identified in patients with ECD, but not in patients with other N-LCHs.	('LCH', 'Disease', (66, 69))	('ECD', 'Disease', (113, 116))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('N-LCHs', 'Chemical', '-', (149, 155))	('patients', 'Species', '9606', (129, 137))	('V600E', 'Var', (9, 14))	('patients', 'Species', '9606', (99, 107))	('BRAF', 'Gene', (4, 8))	('ECD', 'Disease', 'MESH:C574275', (113, 116))	('patients', 'Species', '9606', (52, 60))
263113	30034819	Positivity for CD1a and S100 raises clinical suspicion for LCH, while a lipid-laden histiocytic foamy infiltrate that immunochemically does not express CD1a and S100 guides the diagnosis for ECD (Fig.	('LCH', 'Disease', (59, 62))	('CD1a', 'Gene', (152, 156))	('CD1a', 'Gene', (15, 19))	('S100', 'Gene', (24, 28))	('S100', 'Gene', (161, 165))	('lipid-laden histiocytic foamy', 'Phenotype', 'HP:0003651', (72, 101))	('S100', 'Gene', '6271', (161, 165))	('CD1a', 'Gene', '909', (152, 156))	('lipid', 'Chemical', 'MESH:D008055', (72, 77))	('S100', 'Gene', '6271', (24, 28))	('CD1a', 'Gene', '909', (15, 19))	('Positivity', 'Var', (0, 10))	('ECD', 'Disease', 'MESH:C574275', (191, 194))	('ECD', 'Disease', (191, 194))
263157	30034819	After the discovery of BRAF V600E mutation in histiocytes in a significant proportion of ECD patients, the BRAF inhibitor vemurafenib has been used in the treatment of ECD patients who harboured the specific mutation, and exhibited promising results with a rather impressive efficacy.	('ECD', 'Disease', 'MESH:C574275', (168, 171))	('ECD', 'Disease', (89, 92))	('vemurafenib', 'Chemical', 'MESH:D000077484', (122, 133))	('ECD', 'Disease', (168, 171))	('V600E', 'Var', (28, 33))	('BRAF', 'Gene', (23, 27))	('patients', 'Species', '9606', (172, 180))	('V600E', 'Mutation', 'rs113488022', (28, 33))	('patients', 'Species', '9606', (93, 101))	('ECD', 'Disease', 'MESH:C574275', (89, 92))
263274	29390282	As for the genetic characteristics of solitary fibrous tumors, NAB2-STAT6 gene fusions and subsequent enhanced expression of Stat6 have been reported.	('NAB2', 'Gene', (63, 67))	('STAT6', 'Gene', '6778', (68, 73))	('enhanced', 'PosReg', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Stat6', 'Gene', (125, 130))	('solitary fibrous tumors', 'Disease', (38, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('expression', 'MPA', (111, 121))	('Stat6', 'Gene', '6778', (125, 130))	('NAB2', 'Gene', '4665', (63, 67))	('gene fusions', 'Var', (74, 86))	('STAT6', 'Gene', (68, 73))	('solitary fibrous tumors', 'Disease', 'MESH:D054364', (38, 61))
263354	30313107	Pathological stage was T1bN1M0 stage IIB according to the TNM Classification of Malignant Tumors-7th edition.	('Malignant Tumors-7th edition', 'Disease', 'MESH:D018198', (80, 108))	('Malignant Tumors-7th edition', 'Disease', (80, 108))	('Tumors', 'Phenotype', 'HP:0002664', (90, 96))	('T1bN1M0 stage', 'Var', (23, 36))
263404	30313107	Analysis of the expression pattern of p53 mutation revealed a common mutational pattern in both carcinoma and sarcoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (96, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('mutation', 'Var', (42, 50))
263433	28160567	This study describes targeting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD synthesis, by FK866 in EwS cells.	('FK866', 'Var', (125, 130))	('EwS', 'Gene', (134, 137))	('FK866', 'Chemical', 'MESH:C480543', (125, 130))	('nicotinamide phosphoribosyltransferase', 'Gene', (31, 69))	('NAD', 'Chemical', 'MESH:D009243', (107, 110))	('NAMPT', 'Gene', (71, 76))	('NAMPT', 'Gene', '10135', (71, 76))	('nicotinamide phosphoribosyltransferase', 'Gene', '10135', (31, 69))	('EwS', 'Phenotype', 'HP:0012254', (134, 137))	('EwS', 'Gene', '2130', (134, 137))
263435	28160567	Using conditional EWS-FLI1 knockdown by doxycycline-inducible shRNA revealed that EWS-FLI1 depletion significantly reduces the sensitivity of EwS cells to NAMPT inhibition.	('NAMPT', 'Gene', (155, 160))	('NAMPT', 'Gene', '10135', (155, 160))	('sensitivity', 'MPA', (127, 138))	('EwS', 'Gene', '2130', (142, 145))	('EwS', 'Phenotype', 'HP:0012254', (142, 145))	('depletion', 'Var', (91, 100))	('EWS-FLI1', 'Gene', (82, 90))	('doxycycline', 'Chemical', 'MESH:D004318', (40, 51))	('reduces', 'NegReg', (115, 122))	('EWS-FLI1', 'Gene', '2130;2313', (82, 90))	('EwS', 'Gene', (142, 145))	('EWS-FLI1', 'Gene', (18, 26))	('EWS-FLI1', 'Gene', '2130;2313', (18, 26))
263452	28160567	EWS-FLI1 expression was described as sensitizer to PARP inhibition, and targeting PARP1 by immobilizing it on DNA double strand breaks has been proposed as a treatment strategy for EwS.	('PARP', 'Gene', (82, 86))	('PARP', 'Gene', (51, 55))	('EwS', 'Gene', (181, 184))	('EWS-FLI1', 'Gene', (0, 8))	('PARP1', 'Gene', (82, 87))	('PARP', 'Gene', '142', (82, 86))	('PARP1', 'Gene', '142', (82, 87))	('targeting', 'Var', (72, 81))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('EwS', 'Phenotype', 'HP:0012254', (181, 184))	('PARP', 'Gene', '142', (51, 55))	('EwS', 'Gene', '2130', (181, 184))
263459	28160567	FK866 has been evaluated as anticancer agent in several hematologic malignancies, solid tumors and cancer cell lines.	('hematologic malignancies', 'Disease', 'MESH:D019337', (56, 80))	('solid tumors', 'Disease', (82, 94))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('hematologic malignancies', 'Disease', (56, 80))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('solid tumors', 'Disease', 'MESH:D009369', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('FK866', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('FK866', 'Chemical', 'MESH:C480543', (0, 5))
263462	28160567	We demonstrate that expression of EWS-FLI1 increases the susceptibility to FK866-induced NAD depletion, apoptosis, and glycolytic stress.	('FK866-induced', 'Gene', (75, 88))	('susceptibility to', 'MPA', (57, 74))	('glycolytic stress', 'MPA', (119, 136))	('expression', 'Var', (20, 30))	('EWS-FLI1', 'Gene', (34, 42))	('increases', 'PosReg', (43, 52))	('FK866', 'Chemical', 'MESH:C480543', (75, 80))	('NAD', 'Chemical', 'MESH:D009243', (89, 92))	('apoptosis', 'CPA', (104, 113))	('EWS-FLI1', 'Gene', '2130;2313', (34, 42))
263463	28160567	These findings suggest that inhibiting NAMPT-mediated NAD salvage might represent a novel approach to attenuate EwS cell proliferation by blocking the engine of the disease.	('EwS', 'Gene', (112, 115))	('inhibiting', 'Var', (28, 38))	('blocking', 'NegReg', (138, 146))	('engine of', 'MPA', (151, 160))	('NAMPT', 'Gene', (39, 44))	('NAMPT', 'Gene', '10135', (39, 44))	('EwS', 'Phenotype', 'HP:0012254', (112, 115))	('EwS', 'Gene', '2130', (112, 115))	('NAD', 'Chemical', 'MESH:D009243', (54, 57))
263466	28160567	Furthermore, we found that NAMPT inhibition by FK866 acted specifically via reducing NAMPT activity in A673sh cells and had no effect on EWS-FLI1 protein levels (Figure 1A & 1C).	('EWS-FLI1', 'Gene', (137, 145))	('FK866', 'Var', (47, 52))	('FK866', 'Chemical', 'MESH:C480543', (47, 52))	('reducing', 'NegReg', (76, 84))	('NAMPT', 'Gene', (85, 90))	('EWS-FLI1', 'Gene', '2130;2313', (137, 145))	('NAMPT', 'Gene', '10135', (85, 90))	('NAMPT', 'Gene', '10135', (27, 32))	('NAMPT', 'Gene', (27, 32))
263467	28160567	Under both conditions, EFH and EFL, NAMPT activity was significantly and similarly reduced after treatment with FK866 as indicated by a dramatic loss of NAD in A673sh cells at 24 h and almost no detectable NAD after 48 h inhibitor treatment (Figure 1B).	('NAD', 'Chemical', 'MESH:D009243', (153, 156))	('NAD', 'Chemical', 'MESH:D009243', (206, 209))	('NAD', 'MPA', (153, 156))	('reduced', 'NegReg', (83, 90))	('loss', 'NegReg', (145, 149))	('FK866', 'Var', (112, 117))	('NAMPT', 'Gene', (36, 41))	('NAMPT', 'Gene', '10135', (36, 41))	('FK866', 'Chemical', 'MESH:C480543', (112, 117))	('EFH', 'Chemical', '-', (23, 26))
263468	28160567	Following NAD depletion, ATP levels declined in a delayed manner (Figure 1D) which may be the consequence of cellular energy stress and ensuing cell death in response to FK866 as was previously reported for hepatocarcinoma cells.	('NAD', 'Chemical', 'MESH:D009243', (10, 13))	('hepatocarcinoma', 'Disease', (207, 222))	('hepatocarcinoma', 'Disease', 'None', (207, 222))	('FK866', 'Var', (170, 175))	('FK866', 'Chemical', 'MESH:C480543', (170, 175))	('ATP', 'Chemical', 'MESH:D000255', (25, 28))	('ATP levels', 'MPA', (25, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))
263472	28160567	Maintenance of higher ATP levels in FK866 treated EFL versus EFH cells suggests diminished vulnerability to NAMPT inhibition possibly due to EWS-FLI1 knockdown-induced cell cycle arrest.	('EWS-FLI1', 'Gene', (141, 149))	('arrest', 'Disease', 'MESH:D006323', (179, 185))	('EFH', 'Chemical', '-', (61, 64))	('NAMPT', 'Gene', (108, 113))	('NAMPT', 'Gene', '10135', (108, 113))	('higher', 'PosReg', (15, 21))	('EWS-FLI1', 'Gene', '2130;2313', (141, 149))	('cell cycle', 'CPA', (168, 178))	('arrest', 'Disease', (179, 185))	('vulnerability', 'MPA', (91, 104))	('FK866', 'Var', (36, 41))	('FK866', 'Chemical', 'MESH:C480543', (36, 41))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (168, 185))	('ATP levels', 'MPA', (22, 32))	('ATP', 'Chemical', 'MESH:D000255', (22, 25))
263476	28160567	The effect of FK866 on NAD abundance in A673sh cells could be largely restored by adding NA or NMN (Figure 2A-2B).	('FK866', 'Chemical', 'MESH:C480543', (14, 19))	('NMN', 'Chemical', 'MESH:D009537', (95, 98))	('NAD abundance', 'MPA', (23, 36))	('NAD', 'Chemical', 'MESH:D009243', (23, 26))	('FK866', 'Var', (14, 19))
263485	28160567	To better understand how NAMPT inhibition leads to changes in EwS cell metabolism, we evaluated mitochondrial respiration and glycolysis in A673sh (EFH and EFL) and TC32 cells in the presence and absence of FK866 (24 h or 48 h) as well as with and without addition of NA.	('NAMPT', 'Gene', (25, 30))	('EwS', 'Gene', (62, 65))	('FK866', 'Var', (207, 212))	('mitochondrial respiration', 'MPA', (96, 121))	('glycolysis', 'MPA', (126, 136))	('FK866', 'Chemical', 'MESH:C480543', (207, 212))	('changes', 'Reg', (51, 58))	('EFH', 'Chemical', '-', (148, 151))	('A673sh', 'Var', (140, 146))	('EwS', 'Phenotype', 'HP:0012254', (62, 65))	('EwS', 'Gene', '2130', (62, 65))	('NAMPT', 'Gene', '10135', (25, 30))
263491	28160567	Thus, it is unlikely that doxycycline treatment had any influence on our results other than reducing EWS-FLI1 levels through shRNA mediated knockdown.	('knockdown', 'Var', (140, 149))	('EWS-FLI1', 'Gene', '2130;2313', (101, 109))	('EWS-FLI1', 'Gene', (101, 109))	('doxycycline', 'Chemical', 'MESH:D004318', (26, 37))
263495	28160567	At a time when EFH-FK866 treated cells showed diminished GR and GC compared to EFH-DMSO control treated cells, EFL cells still maintained indistinguishably high GR and GC under FK866 treatment (Figure 3C).	('EFH', 'Chemical', '-', (79, 82))	('FK866', 'Var', (177, 182))	('FK866', 'Chemical', 'MESH:C480543', (19, 24))	('FK866', 'Chemical', 'MESH:C480543', (177, 182))	('EFH', 'Chemical', '-', (15, 18))	('DMSO', 'Chemical', 'MESH:D004121', (83, 87))	('diminished', 'NegReg', (46, 56))
263496	28160567	During 48 h NAMPT inhibition (Figure 3D), EWS-FLI1 silencing did not exert a rescue effect on glycolysis anymore and for both high and low EWS-FLI1 expression, FK866 application resulted in a loss of GR as well as GC (Figure 3D).	('low', 'NegReg', (135, 138))	('glycolysis', 'MPA', (94, 104))	('silencing', 'Var', (51, 60))	('EWS-FLI1', 'Gene', '2130;2313', (42, 50))	('NAMPT', 'Gene', '10135', (12, 17))	('EWS-FLI1', 'Gene', (139, 147))	('NAMPT', 'Gene', (12, 17))	('EWS-FLI1', 'Gene', '2130;2313', (139, 147))	('FK866', 'Chemical', 'MESH:C480543', (160, 165))	('EWS-FLI1', 'Gene', (42, 50))	('loss', 'NegReg', (192, 196))
263503	28160567	We demonstrate that also in EwS cells, FK866 treatment leads to mitochondrial dysfunction (Figure 3), DNA synthesis blockade (Supplementary Figure 2A), and cell death (Figure 4A and Supplementary Figure 2B).	('mitochondrial dysfunction', 'Disease', (64, 89))	('EwS', 'Gene', '2130', (28, 31))	('DNA synthesis', 'MPA', (102, 115))	('EwS', 'Gene', (28, 31))	('FK866', 'Chemical', 'MESH:C480543', (39, 44))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (64, 89))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (64, 89))	('FK866 treatment', 'Var', (39, 54))	('treatment', 'Var', (45, 54))	('blockade', 'NegReg', (116, 124))	('EwS', 'Phenotype', 'HP:0012254', (28, 31))	('cell death', 'CPA', (156, 166))
263504	28160567	EdU incorporation assays in A673sh and SK-N-MC cells treated with 5 nM FK866 for 72 h completely abolished S-phase, indicating strong cell cycle inhibition (Supplementary Figure 2A).	('cell cycle', 'CPA', (134, 144))	('S-phase', 'CPA', (107, 114))	('FK866', 'Var', (71, 76))	('abolished', 'NegReg', (97, 106))	('FK866', 'Chemical', 'MESH:C480543', (71, 76))	('SK-N-MC', 'CellLine', 'CVCL:0530', (39, 46))
263506	28160567	However, in contrast to Etoposide, a classical apoptosis inducer in EwS, FK866 treatment did not result in PARP1 cleavage, excluding a caspase-driven cell death mechanism (Supplementary Figure 2C).	('PARP1', 'Gene', '142', (107, 112))	('Etoposide', 'Chemical', 'MESH:D005047', (24, 33))	('FK866', 'Var', (73, 78))	('PARP1', 'Gene', (107, 112))	('EwS', 'Gene', (68, 71))	('cleavage', 'MPA', (113, 121))	('FK866', 'Chemical', 'MESH:C480543', (73, 78))	('EwS', 'Phenotype', 'HP:0012254', (68, 71))	('EwS', 'Gene', '2130', (68, 71))
263507	28160567	In A673sh, we observed a significant increase of 2.4 +- 0.44 fold in AnnexinV-positive/DAPI-negative cells already after 48 h of FK866 treatment under EFH conditions versus only 1.63 +- 0.29 fold in EFL cells.	('EFH', 'Chemical', '-', (151, 154))	('DAPI', 'Chemical', 'MESH:C007293', (87, 91))	('FK866', 'Var', (129, 134))	('FK866', 'Chemical', 'MESH:C480543', (129, 134))	('A673sh', 'Var', (3, 9))	('increase', 'PosReg', (37, 45))
263509	28160567	NA supplementation (25 muM) reduced the proportion of dead cells to basal levels which, at 72 h, was slightly higher in EFL than in EFH cells.	('EFH', 'Chemical', '-', (132, 135))	('higher', 'PosReg', (110, 116))	('muM', 'Gene', '56925', (23, 26))	('EFL', 'Var', (120, 123))	('muM', 'Gene', (23, 26))
263510	28160567	In TC32 cells, FK866 treatment (5 nM) for 72 h induced an increase in AnnexinV-positive/DAPI-negative cells of 14.3 +- 2.8 fold, which was fully rescued by the addition of NA.	('increase', 'PosReg', (58, 66))	('FK866', 'Var', (15, 20))	('AnnexinV-positive/DAPI-negative cells', 'MPA', (70, 107))	('FK866', 'Chemical', 'MESH:C480543', (15, 20))	('DAPI', 'Chemical', 'MESH:C007293', (88, 92))
263511	28160567	To validate these results, cell viability under monolayer growth conditions was assessed in response to increasing doses of FK866 in A673sh under EFH and EFL conditions and a total of seven EwS cell lines harboring different gene rearrangements, such as EWS-FLI1 exon 7/6 fusion (A673, TC32, SK-N-MC, TC252), EWS-FLI1 exon 9/4 fusion (STA-ET-2.2), and EWS-ERG fusion (STA-ET-11, RM-82), summarized in (Supplementary Table 1 and Figure 5A).	('ERG', 'Gene', (356, 359))	('EWS', 'Gene', (352, 355))	('A673sh', 'Var', (133, 139))	('EWS-FLI1', 'Gene', '2130;2313', (254, 262))	('STA-ET-11', 'Chemical', '-', (368, 377))	('EWS-FLI1', 'Gene', '2130;2313', (309, 317))	('ERG', 'Gene', '2078', (356, 359))	('SK-N-MC', 'CellLine', 'CVCL:0530', (292, 299))	('RM-82', 'Chemical', '-', (379, 384))	('EwS', 'Phenotype', 'HP:0012254', (190, 193))	('EwS', 'Gene', (190, 193))	('EWS', 'Gene', (309, 312))	('EWS', 'Gene', (254, 257))	('STA-ET-2', 'Chemical', '-', (335, 343))	('EWS', 'Gene', '2130', (352, 355))	('TC252', 'CellLine', 'CVCL:S866', (301, 306))	('FK866', 'Chemical', 'MESH:C480543', (124, 129))	('EwS', 'Gene', '2130', (190, 193))	('EFH', 'Chemical', '-', (146, 149))	('EWS-FLI1', 'Gene', (309, 317))	('EWS-FLI1', 'Gene', (254, 262))	('EWS', 'Gene', '2130', (309, 312))	('EWS', 'Gene', '2130', (254, 257))
263513	28160567	Intriguingly, despite comparable NAMPT protein levels (Figure 5C), the IC50 of the A673sh clone shifted from 1.06 in EFH to 2.65 nM in EFL conditions, as a consequence of significantly elevated viability values of EFL compared to EFH cells for each individual inhibitor concentration tested (Figure 5A).	('EFH', 'Chemical', '-', (230, 233))	('viability', 'MPA', (194, 203))	('EFH', 'Chemical', '-', (117, 120))	('NAMPT', 'Gene', (33, 38))	('NAMPT', 'Gene', '10135', (33, 38))	('elevated', 'PosReg', (185, 193))	('A673sh', 'Var', (83, 89))
263514	28160567	Generally, EwS cells showed a striking sensitivity to FK866 with IC50 values in the sub-nanomolar range (mean 0.51+-0.31 nM), while IC50 values in the tested non-EwS cell lines were significantly higher (mean 2.55+-1.52 nM) (p= 0.006).	('EwS', 'Phenotype', 'HP:0012254', (162, 165))	('EwS', 'Gene', (11, 14))	('IC50', 'MPA', (65, 69))	('EwS', 'Gene', '2130', (162, 165))	('FK866', 'Var', (54, 59))	('EwS', 'Gene', (162, 165))	('FK866', 'Chemical', 'MESH:C480543', (54, 59))	('EwS', 'Phenotype', 'HP:0012254', (11, 14))	('EwS', 'Gene', '2130', (11, 14))
263516	28160567	FK866 toxicity not only affected EwS cells under monolayer but also under anchorage-independent growth conditions, a hallmark of oncogenic transformation.	('toxicity', 'Disease', 'MESH:D064420', (6, 14))	('toxicity', 'Disease', (6, 14))	('EwS', 'Phenotype', 'HP:0012254', (33, 36))	('EwS', 'Gene', '2130', (33, 36))	('FK866', 'Var', (0, 5))	('affected', 'Reg', (24, 32))	('FK866', 'Chemical', 'MESH:C480543', (0, 5))	('EwS', 'Gene', (33, 36))
263521	28160567	Aberrant cellular metabolism in cancer development has gained tremendous interest over the years and is discussed as a promising target in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cellular metabolism', 'MPA', (9, 28))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (139, 145))
263528	28160567	By using a doxycycline-inducible EWS-FLI1 knockdown approach, we found that NAMPT inhibition in the absence of the oncogene maintained functional glycolysis for a longer time period than in presence of EWS-FLI1.	('doxycycline', 'Chemical', 'MESH:D004318', (11, 22))	('NAMPT', 'Gene', '10135', (76, 81))	('functional glycolysis', 'MPA', (135, 156))	('NAMPT', 'Gene', (76, 81))	('EWS-FLI1', 'Gene', (33, 41))	('EWS-FLI1', 'Gene', '2130;2313', (33, 41))	('EWS-FLI1', 'Gene', (202, 210))	('EWS-FLI1', 'Gene', '2130;2313', (202, 210))	('absence', 'Var', (100, 107))
263530	28160567	A comprehensive study of NAMPT inhibition in various tumor cell types in vitro and in vivo impressively demonstrated FK866-induced blockade of glycolysis, serine biosynthesis, tricarboxylic acid (TCA) cycle, and alterations in the pentose phosphate pathway.	('FK866', 'Chemical', 'MESH:C480543', (117, 122))	('FK866-induced', 'Var', (117, 130))	('NAMPT', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TCA', 'Chemical', 'MESH:D014233', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('blockade', 'NegReg', (131, 139))	('glycolysis', 'MPA', (143, 153))	('serine', 'Chemical', 'MESH:D012694', (155, 161))	('pentose phosphate', 'Chemical', 'MESH:D010428', (231, 248))	('tumor', 'Disease', (53, 58))	('alterations', 'Reg', (212, 223))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (176, 194))	('pentose phosphate pathway', 'Pathway', (231, 256))	('serine biosynthesis', 'MPA', (155, 174))	('NAMPT', 'Gene', '10135', (25, 30))
263534	28160567	The mechanism of cell death induced by FK866 in EwS cells was not in the scope of this study and requires further investigations.	('EwS', 'Gene', '2130', (48, 51))	('FK866', 'Var', (39, 44))	('EwS', 'Gene', (48, 51))	('FK866', 'Chemical', 'MESH:C480543', (39, 44))	('EwS', 'Phenotype', 'HP:0012254', (48, 51))
263536	28160567	Absence of PARP1 cleavage excludes classical apoptosis for FK866 induced loss of EwS viability.	('PARP1', 'Gene', '142', (11, 16))	('PARP1', 'Gene', (11, 16))	('EwS', 'Phenotype', 'HP:0012254', (81, 84))	('FK866', 'Var', (59, 64))	('loss of EwS viability', 'Disease', 'MESH:C563168', (73, 94))	('FK866', 'Chemical', 'MESH:C480543', (59, 64))	('loss of EwS viability', 'Disease', (73, 94))
263541	28160567	We have previously shown that high SIRT1 positivity in EwS is associated primarily with metastases and is also present in primary EwS tumors and cell lines.	('SIRT1', 'Gene', (35, 40))	('EwS', 'Phenotype', 'HP:0012254', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('EwS', 'Gene', (130, 133))	('metastases', 'Disease', (88, 98))	('EwS', 'Gene', '2130', (55, 58))	('positivity', 'Var', (41, 51))	('associated', 'Reg', (62, 72))	('EwS', 'Gene', (55, 58))	('primary EwS tumors', 'Disease', (122, 140))	('high', 'Var', (30, 34))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('SIRT1', 'Gene', '23411', (35, 40))	('EwS', 'Phenotype', 'HP:0012254', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('primary EwS tumors', 'Disease', 'MESH:C563168', (122, 140))	('EwS', 'Gene', '2130', (130, 133))
263547	28160567	This finding may at least partially be explained by EWS-FLI1 knockdown-induced growth inhibition.	('knockdown-induced', 'Var', (61, 78))	('growth', 'CPA', (79, 85))	('EWS-FLI1', 'Gene', (52, 60))	('EWS-FLI1', 'Gene', '2130;2313', (52, 60))
263549	28160567	As discussed recently at the 2nd European Ewing Sarcoma Research Summit, stochastic variations in EWS-FLI1 expression may translate into differential metastatic behavior, since EFL cells were demonstrated to have drastically increased migratory and metastatic potential.	('translate into', 'Reg', (122, 136))	('Sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('EWS-FLI1', 'Gene', (98, 106))	('increased', 'PosReg', (225, 234))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (42, 55))	('variations', 'Var', (84, 94))	('EWS-FLI1', 'Gene', '2130;2313', (98, 106))	('Ewing Sarcoma', 'Disease', (42, 55))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (42, 55))
263550	28160567	Whether variations in metabolic activity as described here for EWS-FLI1 knockdown may contribute to EwS progression remains to be investigated.	('EwS', 'Phenotype', 'HP:0012254', (100, 103))	('EwS', 'Gene', (100, 103))	('EWS-FLI1', 'Gene', (63, 71))	('metabolic activity', 'MPA', (22, 40))	('contribute', 'Reg', (86, 96))	('knockdown', 'Var', (72, 81))	('EwS', 'Gene', '2130', (100, 103))	('EWS-FLI1', 'Gene', '2130;2313', (63, 71))
263554	28160567	This was confirmed for several hematologic and solid tumor models, where NAMPT inhibitors FK866 and CHS828 showed potent anticancer activity.	('FK866', 'Var', (90, 95))	('NAMPT', 'Gene', (73, 78))	('NAMPT', 'Gene', '10135', (73, 78))	('solid tumor', 'Disease', (47, 58))	('FK866', 'Chemical', 'MESH:C480543', (90, 95))	('solid tumor', 'Disease', 'MESH:D009369', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CHS828', 'Chemical', 'MESH:C401312', (100, 106))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
263557	28160567	In addition, low bioavailability for FK866 in vivo and rapid intravenous clearance prohibited sufficient drug delivery, which also highlights the need for second generation NAMPT inhibitors with increased efficacy, and some promising candidates are already on the horizon.	('sufficient drug delivery', 'MPA', (94, 118))	('NAMPT', 'Gene', '10135', (173, 178))	('low', 'NegReg', (13, 16))	('FK866', 'Var', (37, 42))	('bioavailability', 'MPA', (17, 32))	('NAMPT', 'Gene', (173, 178))	('FK866', 'Chemical', 'MESH:C480543', (37, 42))	('prohibited', 'NegReg', (83, 93))
263578	28160567	For the inducible EWS-FLI1 knockdown via shRNA, doxycycline treatment (1mug/mL) was started 24 h prior to drug treatment and the cells were kept in doxycycline until processing.	('doxycycline', 'Chemical', 'MESH:D004318', (48, 59))	('knockdown', 'Var', (27, 36))	('doxycycline', 'Chemical', 'MESH:D004318', (148, 159))	('EWS-FLI1', 'Gene', (18, 26))	('EWS-FLI1', 'Gene', '2130;2313', (18, 26))
263596	28160567	Antibodies used were FLI1 from MyBiosource (#300723, San Diego, CA, USA), GAPDH by Ambion (#4300, Thermo Fisher Scientifc, Waltham, MA, USA), NAMPT from Santa Cruz Biotechnology (#130058, Santa Cruz, CA, USA), and Vinculin from Sigma (#V4505, Darmstadt, Germany).	('FLI1', 'Gene', '2313', (21, 25))	('NAMPT', 'Gene', (142, 147))	('#300723', 'Var', (44, 51))	('GAPDH', 'Gene', '2597', (74, 79))	('GAPDH', 'Gene', (74, 79))	('Vinculin', 'Gene', (214, 222))	('#130058', 'Var', (179, 186))	('Vinculin', 'Gene', '7414', (214, 222))	('FLI1', 'Gene', (21, 25))	('NAMPT', 'Gene', '10135', (142, 147))
263607	23899007	In both animal models, inhibition of Rho, ROCK or MLC resulted in greatly decreased cell invasiveness in vitro, while inhibition of extracellular proteases using a broad spectrum inhibitor did not have a significant effect.	('Rho', 'Gene', (37, 40))	('MLC', 'Gene', '396067', (50, 53))	('cell invasiveness in vitro', 'CPA', (84, 110))	('inhibition', 'Var', (23, 33))	('MLC', 'Gene', (50, 53))	('decreased', 'NegReg', (74, 83))
263608	23899007	The inhibition of both Rho activity and MLC phosphorylation by dominant negative mutants led to a decreased capability of chicken sarcoma cells to metastasize.	('Rho', 'Protein', (23, 26))	('chicken sarcoma', 'Phenotype', 'HP:0031350', (122, 137))	('MLC', 'Gene', '396067', (40, 43))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('MLC', 'Gene', (40, 43))	('chicken', 'Species', '9031', (122, 129))	('sarcoma', 'Disease', (130, 137))	('negative', 'NegReg', (72, 80))	('mutants', 'Var', (81, 88))	('decreased', 'NegReg', (98, 107))	('inhibition', 'NegReg', (4, 14))	('activity', 'MPA', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
263628	23899007	To elucidate the role of individual components of Rho/ROCK/MLC signaling in the amoeboid invasiveness of sarcoma cells, cell lines were prepared to stably express either GFP-tagged dnRhoA (A3dnRho; inactivating mutation T19N) or GFP-tagged non-phosphorylable (dominant negative) MLC (A3dnMLC; mutations T18A, S19A) in A3 cells.	('RhoA', 'Gene', (183, 187))	('MLC', 'Gene', '396067', (288, 291))	('RhoA', 'Gene', '395442', (183, 187))	('T18A', 'Mutation', 'c.18T>A', (303, 307))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('MLC', 'Gene', (288, 291))	('MLC', 'Gene', (279, 282))	('mutations T18A', 'Var', (293, 307))	('amoeboid invasiveness of sarcoma', 'Disease', (80, 112))	('amoeboid invasiveness of sarcoma', 'Disease', 'MESH:D012509', (80, 112))	('S19A', 'Mutation', 'p.S19A', (309, 313))	('MLC', 'Gene', '396067', (59, 62))	('MLC', 'Gene', '396067', (279, 282))	('T19N', 'Mutation', 'p.T19N', (220, 224))	('S19A', 'Var', (309, 313))	('MLC', 'Gene', (59, 62))	('T18A', 'Var', (303, 307))
263644	23899007	Both PR9692 and PR9692-E9 cells give rise to rapidly growing sarcomas.	('rapidly growing', 'CPA', (45, 60))	('sarcomas', 'Disease', (61, 69))	('PR9692', 'Var', (5, 11))	('sarcomas', 'Disease', 'MESH:D012509', (61, 69))	('PR9692-E9 cells', 'Var', (16, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
263646	23899007	Microarray analysis comparing metastatic PR9692 cells to non-metastatic PR9692-E9 have revealed an almost 80 fold increased expression of myl9 (myosin regulatory light chain 2, mlc2) mRNA in PR9692 cells, suggestive of the potentially increased actomyosin contractility of PR9692 cells.	('myl9', 'Gene', '396215', (138, 142))	('mlc2', 'Gene', (177, 181))	('mlc2', 'Gene', '396215', (177, 181))	('myosin', 'Gene', (249, 255))	('myosin', 'Gene', '396469', (249, 255))	('myosin', 'Gene', (144, 150))	('myosin', 'Gene', '396469', (144, 150))	('increased', 'PosReg', (114, 123))	('increased actomyosin contractility', 'Phenotype', 'HP:0002486', (235, 269))	('increased', 'PosReg', (235, 244))	('myl9', 'Gene', (138, 142))	('expression', 'MPA', (124, 134))	('PR9692', 'Var', (191, 197))
263647	23899007	An analysis of morphology in 3D collagen revealed that PR9692 cells adopt a rounded morphology in a 3D environment (Figure 4C, Additional file 1: Figure S1).	('adopt', 'Reg', (68, 73))	('rounded morphology', 'CPA', (76, 94))	('S', 'Chemical', 'MESH:D013455', (153, 154))	('collagen', 'Gene', (32, 40))	('PR9692', 'Var', (55, 61))	('collagen', 'Gene', '396340', (32, 40))
263648	23899007	The analyses revealed that PR9692 cells produce smaller amount of both MT1-MMP (MMP14) and MMP-2 than PR9692-E9 cells (Figure 3B and C).	('MMP14', 'Gene', '426253', (80, 85))	('MMP-2', 'Gene', '386583', (91, 96))	('PR9692', 'Var', (27, 33))	('smaller', 'NegReg', (48, 55))	('MMP-2', 'Gene', (91, 96))	('MMP14', 'Gene', (80, 85))
263649	23899007	The addition of ROCK inhibitor to PR9692 cells greatly inhibited their invasiveness, even below the invasive capacity of PR9692-E9 (Figures 3A and 4B), and induced an effective amoeboid-mesenchymal transition (Figure 4C, Additional file 1: Figure S1).	('S', 'Chemical', 'MESH:D013455', (247, 248))	('induced', 'Reg', (156, 163))	('PR9692', 'Var', (34, 40))	('amoeboid-mesenchymal transition', 'CPA', (177, 208))	('invasiveness', 'CPA', (71, 83))	('inhibited', 'NegReg', (55, 64))
263651	23899007	To inhibit RhoA and MLC signaling in PR9692 cells, replication-defective viruses encoding dominant negative RhoA (dnRho; inactivating mutation T19N) or non-phosphorylable MLC (dnMLC; mutations T18A, S19A) were used to infect PR9692 cells.	('RhoA', 'Gene', '395442', (108, 112))	('S19A', 'Mutation', 'p.S19A', (199, 203))	('RhoA', 'Gene', (108, 112))	('mutations T18A', 'Var', (183, 197))	('MLC', 'Gene', (178, 181))	('MLC', 'Gene', (20, 23))	('T19N', 'Mutation', 'p.T19N', (143, 147))	('MLC', 'Gene', (171, 174))	('T18A', 'Var', (193, 197))	('RhoA', 'Gene', '395442', (11, 15))	('replication-defective viruses', 'Species', '353207', (51, 80))	('T19N', 'Var', (143, 147))	('T18A', 'Mutation', 'c.18T>A', (193, 197))	('inhibit', 'NegReg', (3, 10))	('S19A', 'Var', (199, 203))	('RhoA', 'Gene', (11, 15))	('MLC', 'Gene', '396067', (178, 181))	('MLC', 'Gene', '396067', (171, 174))	('MLC', 'Gene', '396067', (20, 23))
263674	23899007	Next we compared the metastatic potential of PR9692-E9, PR9692-E9-mock and PR9692-E9-caRhoA cells.	('RhoA', 'Gene', '395442', (87, 91))	('metastatic potential', 'CPA', (21, 41))	('RhoA', 'Gene', (87, 91))	('PR9692-E9', 'Var', (45, 54))
263675	23899007	Lungs of animals injected with PR9692-E9, PR9692-E9-mock or PR9692-E9-caRhoA cells were inspected for the presence of metastases 28, 35 and 45 days post-injection.	('RhoA', 'Gene', '395442', (72, 76))	('RhoA', 'Gene', (72, 76))	('metastases', 'Disease', (118, 128))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('PR9692-E9', 'Var', (31, 40))
263683	23899007	Similarly, Y-27632 was shown to inhibit the tumor growth and intrahepatic metastasis of hepatocellular carcinoma.	('Y-27632', 'Var', (11, 18))	('inhibit', 'NegReg', (32, 39))	('Y-27632', 'Chemical', 'MESH:C108830', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (88, 112))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('intrahepatic metastasis of hepatocellular carcinoma', 'Disease', 'MESH:D009362', (61, 112))	('tumor', 'Disease', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('S', 'Chemical', 'MESH:D013455', (0, 1))
263684	23899007	observed that DIAPH3 silencing in human carcinoma cells resulted in microtubule destabilization, a rounded morphology, and enhanced MYPT1 phosphorylation associated with increased invasive capability and metastatic potential in mice.	('enhanced', 'PosReg', (123, 131))	('human', 'Species', '9606', (34, 39))	('MYPT1', 'Gene', '4659', (132, 137))	('microtubule', 'MPA', (68, 79))	('invasive capability', 'CPA', (180, 199))	('carcinoma', 'Disease', 'MESH:D002277', (40, 49))	('DIAPH3', 'Gene', '81624', (14, 20))	('increased', 'PosReg', (170, 179))	('metastatic potential', 'CPA', (204, 224))	('destabilization', 'NegReg', (80, 95))	('MYPT1', 'Gene', (132, 137))	('DIAPH3', 'Gene', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinoma', 'Disease', (40, 49))	('mice', 'Species', '10090', (228, 232))	('silencing', 'Var', (21, 30))	('rounded morphology', 'CPA', (99, 117))
263701	23899007	The A3dnRhoA and A3dnMLC cell lines were prepared to stably express either a GFP-fused dominant negative RhoA (mutations F25N, T19N) from pEGFP-dnRhoA or a non-phosphorylable (dominant negative) GFP-fused MLC (mutations T18A, S19A) by selection in G418 at 400 mug/ml and subsequent FACS sorting of GFP-positive cells (FACSVantage SE, BD Biosciences).	('mutations F25N', 'Var', (111, 125))	('MLC', 'Gene', (205, 208))	('mutations T18A', 'Var', (210, 224))	('S', 'Chemical', 'MESH:D013455', (285, 286))	('RhoA', 'Gene', (8, 12))	('MLC', 'Gene', (21, 24))	('T18A', 'Var', (220, 224))	('S', 'Chemical', 'MESH:D013455', (226, 227))	('RhoA', 'Gene', '395442', (146, 150))	('S', 'Chemical', 'MESH:D013455', (330, 331))	('T18A', 'Mutation', 'c.18T>A', (220, 224))	('RhoA', 'Gene', '395442', (105, 109))	('S', 'Chemical', 'MESH:D013455', (321, 322))	('T19N', 'Mutation', 'p.T19N', (127, 131))	('MLC', 'Gene', '396067', (205, 208))	('RhoA', 'Gene', (146, 150))	('RhoA', 'Gene', (105, 109))	('G418', 'Chemical', 'MESH:C010680', (248, 252))	('S19A', 'Mutation', 'p.S19A', (226, 230))	('MLC', 'Gene', '396067', (21, 24))	('RhoA', 'Gene', '395442', (8, 12))	('F25N', 'Mutation', 'p.F25N', (121, 125))
263708	23899007	SFCV-GFP-caRhoA was constructed based on pEGFP-caRhoA (bearing RhoA with mutations F25N, G14V) similarly to SFCV-GFP-dnRhoA.	('RhoA', 'Gene', (49, 53))	('RhoA', 'Gene', (63, 67))	('RhoA', 'Gene', (11, 15))	('mutations F25N', 'Var', (73, 87))	('RhoA', 'Gene', '395442', (11, 15))	('S', 'Chemical', 'MESH:D013455', (108, 109))	('F25N', 'Mutation', 'p.F25N', (83, 87))	('G14V', 'Mutation', 'p.G14V', (89, 93))	('G14V', 'Var', (89, 93))	('RhoA', 'Gene', '395442', (119, 123))	('RhoA', 'Gene', (119, 123))	('RhoA', 'Gene', '395442', (49, 53))	('RhoA', 'Gene', '395442', (63, 67))	('S', 'Chemical', 'MESH:D013455', (0, 1))
263749	21052502	Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12).	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (27, 42))	('Sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (56, 71))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor of bone', 'Phenotype', 'HP:0010622', (105, 118))	("Ewing's sarcoma", 'Disease', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('t(11;22)(q24;q12', 'Var', (186, 202))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (56, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('tumor', 'Disease', (105, 110))	("Ewing's Sarcoma", 'Disease', (27, 42))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (186, 203))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (27, 42))
263751	21052502	It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis.	('mutations', 'Var', (58, 67))	('FLI', 'Gene', (32, 35))	('modulate', 'Reg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('cell cycle', 'CPA', (100, 110))	('tumor', 'Disease', (125, 130))	('facilitate', 'PosReg', (114, 124))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (71, 86))	('FLI', 'Gene', '2314', (32, 35))	("Ewing's sarcoma", 'Disease', (71, 86))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (71, 86))
263752	21052502	This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered.	("Ewing's sarcoma", 'Disease', (99, 114))	('cell cycle', 'CPA', (85, 95))	('deregulation', 'Var', (65, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (99, 114))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (99, 114))
263779	21052502	In addition, expression of EWS/FLI in primary murine fibroblasts results in cell death whereas immortalized human fibroblasts undergo a p53-dependent growth arrest with concomitant downregulation of several cell cycle regulators.	('p53', 'Gene', '7157', (136, 139))	('murine', 'Species', '10090', (46, 52))	('downregulation', 'NegReg', (181, 195))	('growth arrest', 'Disease', (150, 163))	('FLI', 'Gene', '2314', (31, 34))	('expression', 'Var', (13, 23))	('FLI', 'Gene', (31, 34))	('human', 'Species', '9606', (108, 113))	('cell death', 'CPA', (76, 86))	('growth arrest', 'Disease', 'MESH:D006323', (150, 163))	('growth arrest', 'Phenotype', 'HP:0001510', (150, 163))	('results in', 'Reg', (65, 75))	('p53', 'Gene', (136, 139))
263790	21052502	Cyclin-dependent kinases, or CDKs, are the master regulators of the cell cycle, and it is defects in their function that often lead to inappropriate cell growth.	('defects', 'Var', (90, 97))	('Cyclin', 'Gene', '5111', (0, 6))	('lead to', 'Reg', (127, 134))	('CDKs', 'Gene', '983;1017;1019;1021', (29, 33))	('function', 'MPA', (107, 115))	('inappropriate cell growth', 'CPA', (135, 160))	('Cyclin', 'Gene', (0, 6))	('CDKs', 'Gene', (29, 33))
263797	21052502	Multiple levels exist within the G1 phase to ensure that cells harboring mutations or other detrimental aberrations are not allowed to enter S phase.	('detrimental aberrations', 'Disease', 'MESH:D002869', (92, 115))	('detrimental aberrations', 'Disease', (92, 115))	('mutations', 'Var', (73, 82))
263803	21052502	There are three different D-type cyclins (i.e., cyclins D1, D2, and D3) and two different E-type cyclins (i.e., cyclins E1 and E2), all of which exhibit different tissue-specific patterns of expression.	('cyclins', 'Gene', (33, 40))	('cyclins', 'Gene', '81669', (33, 40))	('cyclins', 'Gene', (112, 119))	('cyclins', 'Gene', '81669', (112, 119))	('cyclins', 'Gene', (48, 55))	('cyclins', 'Gene', '81669', (48, 55))	('cyclins', 'Gene', (97, 104))	('cyclins', 'Gene', '81669', (97, 104))	('D3', 'Var', (68, 70))
263808	21052502	Surprisingly, mutations targeting RB itself are extremely rare in primary Ewing's tumors, as are mutations involving CDK4 gene amplification and/or overexpression of cyclin D1.	('CDK4', 'Gene', '1019', (117, 121))	('cyclin D1', 'Gene', '595', (166, 175))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (74, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('cyclin D1', 'Gene', (166, 175))	("primary Ewing's tumor", 'Disease', 'MESH:C563168', (66, 87))	("Ewing's tumors", 'Disease', (74, 88))	("primary Ewing's tumor", 'Disease', (66, 87))	('RB', 'Chemical', 'MESH:D012413', (34, 36))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	("Ewing's tumors", 'Disease', 'MESH:C563168', (74, 88))	('CDK4', 'Gene', (117, 121))	('mutations', 'Var', (14, 23))	("Ewing's tumor", 'Phenotype', 'HP:0012254', (74, 87))
263821	21052502	Consequently, the presence of INK4 CKIs results in the inability of CDK4/6 to phosphorylate RB, thus inhibiting progression in the G1 phase of the cell cycle.	('presence', 'Var', (18, 26))	('INK4', 'Gene', '1029', (30, 34))	('INK4', 'Gene', (30, 34))	('inability', 'NegReg', (55, 64))	('RB', 'Chemical', 'MESH:D012413', (92, 94))	('CKI', 'Gene', '1119', (35, 38))	('CKI', 'Gene', (35, 38))	('progression in the G1 phase of the cell cycle', 'CPA', (112, 157))	('inhibiting', 'NegReg', (101, 111))
263822	21052502	The most frequent genetic aberration associated with Ewing's sarcoma involves deletion of the CDKN2A locus, which results in functional loss of the p16 gene.	('CDKN2A', 'Gene', '1029', (94, 100))	('p16', 'Gene', '1029', (148, 151))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (53, 68))	('deletion', 'Var', (78, 86))	('functional', 'MPA', (125, 135))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (53, 68))	("Ewing's sarcoma", 'Disease', (53, 68))	('loss', 'NegReg', (136, 140))	('p16', 'Gene', (148, 151))	('CDKN2A', 'Gene', (94, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
263823	21052502	Interestingly, the gene encoding p15 (CDKN2B) maps to the same chromosomal region as CDKN2A, and so deletions present in cancer cells involving CDKN2A often also affect CDKN2B, resulting in functional loss of both p16 and p15.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CDKN2B', 'Gene', '1030', (169, 175))	('CDKN2A', 'Gene', '1029', (85, 91))	('deletions', 'Var', (100, 109))	('CDKN2B', 'Gene', (38, 44))	('p15', 'Gene', (33, 36))	('loss', 'NegReg', (201, 205))	('CDKN2A', 'Gene', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CDKN2B', 'Gene', '1030', (38, 44))	('p15', 'Gene', (222, 225))	('p15', 'Gene', '1030', (33, 36))	('affect', 'Reg', (162, 168))	('CDKN2A', 'Gene', '1029', (144, 150))	('p16', 'Gene', (214, 217))	('p15', 'Gene', '1030', (222, 225))	('CDKN2B', 'Gene', (169, 175))	('CDKN2A', 'Gene', (85, 91))	('p16', 'Gene', '1029', (214, 217))	('cancer', 'Disease', (121, 127))
263824	21052502	Approximately 10-30% of all primary Ewing's tumors exhibit either homozygous or hemizygous deletion of the CDKN2A gene and sometimes also deletion of the CDKN2B gene.	("Ewing's tumor", 'Phenotype', 'HP:0012254', (36, 49))	('CDKN2A', 'Gene', '1029', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('deletion', 'Var', (91, 99))	("primary Ewing's tumor", 'Disease', 'MESH:C563168', (28, 49))	("Ewing's tumors", 'Disease', (36, 50))	("primary Ewing's tumor", 'Disease', (28, 49))	('CDKN2B', 'Gene', (154, 160))	('CDKN2B', 'Gene', '1030', (154, 160))	("Ewing's tumors", 'Disease', 'MESH:C563168', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CDKN2A', 'Gene', (107, 113))	('deletion', 'Var', (138, 146))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (36, 50))
263827	21052502	Deletions of the CDKN2A locus as well as hypermethylation of the gene promoter both appear to contribute to this type of mutation with the latter being almost nonexistent in primary tumor samples.	('tumor', 'Disease', (182, 187))	('CDKN2A', 'Gene', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('CDKN2A', 'Gene', '1029', (17, 23))	('Deletions', 'Var', (0, 9))	('contribute', 'Reg', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
263828	21052502	It is not entirely understood why such a discrepancy exists, but the fact that deletion of CDKN2A is the most prevalent mutation associated with Ewing's sarcoma suggests an important role for the alteration in at least a subset of Ewing's sarcoma.	('prevalent', 'Reg', (110, 119))	('associated', 'Reg', (129, 139))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (145, 160))	('CDKN2A', 'Gene', (91, 97))	("Ewing's sarcoma", 'Disease', (145, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (145, 160))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (231, 246))	('CDKN2A', 'Gene', '1029', (91, 97))	("Ewing's sarcoma", 'Disease', (231, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (231, 246))	('deletion', 'Var', (79, 87))
263836	21052502	Interestingly, no studies to date have identified mutations or alterations involving cyclin A2 or CDK2 that could contribute to the process of Ewing's sarcoma oncogenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	("Ewing's sarcoma oncogenesis", 'Disease', (143, 170))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (143, 158))	('alterations', 'Var', (63, 74))	("Ewing's sarcoma oncogenesis", 'Disease', 'MESH:C563168', (143, 170))	('CDK2', 'Gene', '1017', (98, 102))	('cyclin A2', 'Gene', (85, 94))	('cyclin A2', 'Gene', '890', (85, 94))	('CDK2', 'Gene', (98, 102))	('contribute', 'Reg', (114, 124))
263839	21052502	Absence of such regulation can result in oncogenesis via any number of mechanisms, including the deletion of a single gene, parts of or whole chromosomes, and even aberrant chromosomal fusions, as is seen with Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (210, 225))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (210, 225))	('oncogenesis', 'CPA', (41, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('Absence', 'NegReg', (0, 7))	('result in', 'Reg', (31, 40))	('deletion', 'Var', (97, 105))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (210, 225))
263852	21052502	Lack of regulation during mitosis can lead to oncogenesis as checkpoints normally present in the cell that act to prevent aberrant exit, and re-entry may cause cells with missing/damaged DNA to continue to proliferate.	('missing/damaged', 'Var', (171, 186))	('mitosis', 'Disease', (26, 33))	('cause', 'Reg', (154, 159))	('oncogenesis', 'Disease', (46, 57))	('mitosis', 'Disease', 'None', (26, 33))	('lead to', 'Reg', (38, 45))
263853	21052502	Recently it has been suggested that wild-type EWS plays an important role in mitotic spindle formation and that the presence of EWS/FLI interferes with this function by acting in a dominant-negative fashion.	('mitotic spindle formation', 'CPA', (77, 102))	('presence', 'Var', (116, 124))	('FLI', 'Gene', '2314', (132, 135))	('FLI', 'Gene', (132, 135))	('interferes', 'NegReg', (136, 146))
263858	21052502	In conjunction with the CDK4/6 inhibitor p16INK4A, mutations of the TP53 gene are the most recurrent genetic alterations associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (51, 60))	('associated', 'Reg', (121, 131))	('p16INK4A', 'Gene', (41, 49))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('TP53', 'Gene', '7157', (68, 72))	('p16INK4A', 'Gene', '1029', (41, 49))	('TP53', 'Gene', (68, 72))
263872	21052502	Although more than half of all primary patient-derived Ewing's sarcoma cell lines possess direct p53 loss-of-function mutations, only about 5-20% of Ewing's tumors exhibit similar genetic defects.	('genetic defects', 'Disease', (180, 195))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (55, 70))	('patient', 'Species', '9606', (39, 46))	('p53', 'Gene', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('mutations', 'Var', (118, 127))	('p53', 'Gene', '7157', (97, 100))	("Ewing's tumors", 'Disease', 'MESH:C563168', (149, 163))	("Ewing's sarcoma", 'Disease', (55, 70))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (55, 70))	('loss-of-function', 'NegReg', (101, 117))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (149, 163))	("Ewing's tumor", 'Phenotype', 'HP:0012254', (149, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('genetic defects', 'Disease', 'MESH:D030342', (180, 195))	("Ewing's tumors", 'Disease', (149, 163))
263873	21052502	Yet, many of these studies have shown that patients harboring p53 mutations not only have a significantly poorer outcome with respect to both disease-free and overall survival but also have a higher probability of relapse.	('mutations', 'Var', (66, 75))	('poorer', 'NegReg', (106, 112))	('patients', 'Species', '9606', (43, 51))	('relapse', 'CPA', (214, 221))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
263874	21052502	Mutations in MDM2 seem to be extremely rare in Ewing's tumors.	("Ewing's tumor", 'Phenotype', 'HP:0012254', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	("Ewing's tumors", 'Disease', (47, 61))	('MDM2', 'Gene', '4193', (13, 17))	('MDM2', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('Mutations', 'Var', (0, 9))	("Ewing's tumors", 'Disease', 'MESH:C563168', (47, 61))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (47, 61))
263875	21052502	However, since a large percentage of Ewing's tumors exhibit deletion of the CDKN2A locus, it is likely that they also harbor deletions in p14ARF.	('CDKN2A', 'Gene', '1029', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	("Ewing's tumors", 'Disease', (37, 51))	('p14ARF', 'Gene', '1029', (138, 144))	('deletion', 'Var', (60, 68))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	("Ewing's tumors", 'Disease', 'MESH:C563168', (37, 51))	('p14ARF', 'Gene', (138, 144))	('deletions', 'Var', (125, 134))	('CDKN2A', 'Gene', (76, 82))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (37, 51))	("Ewing's tumor", 'Phenotype', 'HP:0012254', (37, 50))
263876	21052502	Consequently, targeted disruption of TP53 may not be as important for the pathogenesis of Ewing's sarcoma as is general inhibition of the p53 pathway.	('p53', 'Gene', (138, 141))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (90, 105))	('disruption', 'Var', (23, 33))	('p53', 'Gene', '7157', (138, 141))	("Ewing's sarcoma", 'Disease', (90, 105))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (90, 105))	('TP53', 'Gene', '7157', (37, 41))	('targeted disruption', 'Var', (14, 33))	('TP53', 'Gene', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
263878	21052502	One important example of this is the discrepancy seen with respect to p53 loss-of-function mutations.	('p53', 'Gene', '7157', (70, 73))	('mutations', 'Var', (91, 100))	('loss-of-function', 'NegReg', (74, 90))	('p53', 'Gene', (70, 73))
263880	21052502	In addition, ectopic expression of the fusion protein in various primary cell lines, including human foreskin fibroblasts, has been shown to cause p53-mediated growth arrest.	('human', 'Species', '9606', (95, 100))	('growth arrest', 'Disease', 'MESH:D006323', (160, 173))	('growth arrest', 'Disease', (160, 173))	('cause', 'Reg', (141, 146))	('growth arrest', 'Phenotype', 'HP:0001510', (160, 173))	('p53', 'Gene', '7157', (147, 150))	('ectopic expression', 'Var', (13, 31))	('p53', 'Gene', (147, 150))
263882	21052502	Thus, it is likely that primary tumors expressing wild-type p53 harbor other genetic abnormalities yet to be identified that impinge on other aspects of the p53 pathway.	('wild-type', 'Var', (50, 59))	('genetic abnormalities', 'Disease', 'MESH:D030342', (77, 98))	('p53', 'Gene', '7157', (157, 160))	('genetic abnormalities', 'Disease', (77, 98))	('p53', 'Gene', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('p53', 'Gene', '7157', (60, 63))	('tumors', 'Disease', (32, 38))	('p53', 'Gene', (157, 160))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
263902	21052502	Consequently, it is possible that genetic alterations targeting these CIP/KIP family members could act as a mechanism for EWS/FLI-mediated transformation in the development of Ewing's sarcoma.	('CIP', 'Gene', (70, 73))	('FLI', 'Gene', '2314', (126, 129))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (176, 191))	('FLI', 'Gene', (126, 129))	("Ewing's sarcoma", 'Disease', (176, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('act', 'Reg', (99, 102))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (176, 191))	('genetic alterations', 'Var', (34, 53))	('CIP', 'Gene', '90523', (70, 73))
263913	21052502	Nonetheless, this conclusion is somewhat controversial, as experiments demonstrating this relationship are found only to exist under conditions where loss of EWS/FLI expression inhibits cell growth, raising the question of whether this result is limited to particular experimental conditions or is specific to the disease process.	('cell growth', 'CPA', (186, 197))	('FLI', 'Gene', '2314', (162, 165))	('inhibits', 'NegReg', (177, 185))	('loss', 'Var', (150, 154))	('FLI', 'Gene', (162, 165))
263914	21052502	Interestingly, it has also been shown that EWS/FLI expression increases the levels of ID2, or inhibitor of DNA binding 2.	('FLI', 'Gene', '2314', (47, 50))	('increases', 'PosReg', (62, 71))	('FLI', 'Gene', (47, 50))	('levels of', 'MPA', (76, 85))	('ID2, or inhibitor of DNA binding 2', 'Gene', '3398', (86, 120))	('expression', 'Var', (51, 61))
263919	21052502	Patients exhibiting a higher Ki67 positivity tended to have a better chemotherapeutic response, as measured by the amount of tumor necrosis following initial treatment.	('tumor necrosis', 'Disease', 'MESH:D009336', (125, 139))	('positivity', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('better', 'PosReg', (62, 68))	('tumor necrosis', 'Disease', (125, 139))	('Patients', 'Species', '9606', (0, 8))	('chemotherapeutic response', 'CPA', (69, 94))	('Ki67 positivity', 'Var', (29, 44))
263924	21052502	The most common genetic alteration associated with Ewing's tumors involves deletion of CDKN2A, which encodes the p16 and p14 proteins.	('p16', 'Gene', (113, 116))	("Ewing's tumors", 'Disease', 'MESH:C563168', (51, 65))	('CDKN2A', 'Gene', '1029', (87, 93))	('deletion', 'Var', (75, 83))	('p14', 'Gene', (121, 124))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (51, 65))	('p16', 'Gene', '1029', (113, 116))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('p14', 'Gene', '1029', (121, 124))	("Ewing's tumor", 'Phenotype', 'HP:0012254', (51, 64))	("Ewing's tumors", 'Disease', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('CDKN2A', 'Gene', (87, 93))
263925	21052502	Yet, only about one-third of all tumors actually possess such mutations.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('mutations', 'Var', (62, 71))
263926	21052502	In addition, the second most frequent aberration identified to be associated with Ewing's sarcoma involves mutation of TP53.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (82, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('associated', 'Reg', (66, 76))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (82, 97))	('TP53', 'Gene', '7157', (119, 123))	('mutation', 'Var', (107, 115))	('TP53', 'Gene', (119, 123))	("Ewing's sarcoma", 'Disease', (82, 97))
263927	21052502	Again, however, less than one-fourth of all Ewing's tumors actually possess a mutant form of p53.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	("Ewing's tumor", 'Phenotype', 'HP:0012254', (44, 57))	('p53', 'Gene', '7157', (93, 96))	('p53', 'Gene', (93, 96))	("Ewing's tumors", 'Disease', (44, 58))	("Ewing's tumors", 'Disease', 'MESH:C563168', (44, 58))	('mutant', 'Var', (78, 84))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (44, 58))
263931	21052502	Although no individual mutation has been identified to explain how the cell cycle is deregulated in Ewing's sarcoma, most tumors contain genetic alterations that specifically affect the activity of cyclin-dependent kinase inhibitors.	('tumors', 'Disease', (122, 128))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (100, 115))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('cyclin', 'Gene', (198, 204))	("Ewing's sarcoma", 'Disease', (100, 115))	('activity', 'MPA', (186, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (100, 115))	('deregulated', 'Reg', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('genetic alterations', 'Var', (137, 156))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('affect', 'Reg', (175, 181))	('cyclin', 'Gene', '5111', (198, 204))
263932	21052502	For instance, mutations in CDKN2A and CDKN2B result in functional loss of p16 and p15, respectively.	('p16', 'Gene', (74, 77))	('loss', 'NegReg', (66, 70))	('p15', 'Gene', (82, 85))	('p15', 'Gene', '1030', (82, 85))	('CDKN2B', 'Gene', '1030', (38, 44))	('p16', 'Gene', '1029', (74, 77))	('CDKN2A', 'Gene', (27, 33))	('CDKN2A', 'Gene', '1029', (27, 33))	('CDKN2B', 'Gene', (38, 44))	('mutations', 'Var', (14, 23))
263933	21052502	In addition, deactivating mutations in p14ARF (often resulting from deletions in CDKN2A) and p53 as well as amplification of MDM2 all lead to functional loss of p21.	('p21', 'Gene', (161, 164))	('deletions', 'Var', (68, 77))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('loss', 'NegReg', (153, 157))	('CDKN2A', 'Gene', (81, 87))	('deactivating mutations', 'Var', (13, 35))	('p14ARF', 'Gene', '1029', (39, 45))	('CDKN2A', 'Gene', '1029', (81, 87))	('p21', 'Gene', '1026', (161, 164))	('MDM2', 'Gene', '4193', (125, 129))	('resulting from', 'Reg', (53, 67))	('MDM2', 'Gene', (125, 129))	('p14ARF', 'Gene', (39, 45))
263934	21052502	Those mutations affecting positive cell cycle regulators such as cyclins and CDKs occur much less frequently and often have only been identified in in vitro experiments using patient-derived cell lines.	('CDKs', 'Gene', (77, 81))	('patient', 'Species', '9606', (175, 182))	('cyclins', 'Gene', (65, 72))	('cyclins', 'Gene', '81669', (65, 72))	('CDKs', 'Gene', '983;1017;1019;1021', (77, 81))	('mutations', 'Var', (6, 15))
263935	21052502	Consequently, it is possible that underlying Ewing's sarcoma development is the inactivation of CKIs, a common mechanism by which the cell cycle is deregulated.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (45, 60))	("Ewing's sarcoma", 'Disease', (45, 60))	('CKI', 'Gene', '1119', (96, 99))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (45, 60))	('CKI', 'Gene', (96, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('inactivation', 'Var', (80, 92))
263938	21052502	However, it is important to point out that EWS/FLI must have some effect on the cell cycle since previous experiments have shown that mutations in specific regulators (such as p53) are often required to create a permissive environment for EWS/FLI expression.	('create', 'Reg', (203, 209))	('FLI', 'Gene', '2314', (47, 50))	('FLI', 'Gene', (243, 246))	('p53', 'Gene', (176, 179))	('FLI', 'Gene', (47, 50))	('p53', 'Gene', '7157', (176, 179))	('permissive environment', 'MPA', (212, 234))	('mutations', 'Var', (134, 143))	('FLI', 'Gene', '2314', (243, 246))
263939	21052502	In addition, some type of mutation affecting cell cycle regulation is present in a large percentage of primary Ewing's tumors analyzed, suggesting that EWS/FLI activity does trigger cell cycle inhibitory pathways and that these pathways must be bypassed prior to tumor development.	("Ewing's tumors", 'Disease', 'MESH:C563168', (111, 125))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('mutation', 'Var', (26, 34))	("primary Ewing's tumor", 'Disease', (103, 124))	("primary Ewing's tumor", 'Disease', 'MESH:C563168', (103, 124))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (111, 125))	('trigger', 'Reg', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('cell cycle inhibitory pathways', 'Pathway', (182, 212))	('tumor', 'Disease', (263, 268))	('FLI', 'Gene', '2314', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	("Ewing's tumor", 'Phenotype', 'HP:0012254', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	("Ewing's tumors", 'Disease', (111, 125))	('FLI', 'Gene', (156, 159))
263950	33190360	Inhibition of lysosomal enzymes maintained intracellular talaporfin levels.	('Inhibition', 'Var', (0, 10))	('talaporfin', 'Chemical', 'MESH:C053434', (57, 67))	('lysosomal enzymes', 'Enzyme', (14, 31))	('intracellular talaporfin levels', 'MPA', (43, 74))
263951	33190360	Inhibition of K-Ras signaling reduced talaporfin uptake in carcinoma and sarcoma cell lines.	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (59, 80))	('talaporfin uptake', 'MPA', (38, 55))	('K-Ras', 'Gene', '3845', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('talaporfin', 'Chemical', 'MESH:C053434', (38, 48))	('reduced', 'NegReg', (30, 37))	('Inhibition', 'Var', (0, 10))	('K-Ras', 'Gene', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
264009	33190360	Uptake was greatly reduced in MFH03 after incubation on ice.	('MFH03', 'Var', (30, 35))	('reduced', 'NegReg', (19, 26))	('MFH03', 'Chemical', '-', (30, 35))
264011	33190360	Moreover, the uptake of talaporfin was significantly reduced by culturing with 2-DG and NaN3, which inhibit intracellular ATP synthesis.	('intracellular ATP synthesis', 'MPA', (108, 135))	('2-DG', 'Chemical', 'MESH:D003847', (79, 83))	('ATP', 'Chemical', 'MESH:D000255', (122, 125))	('reduced', 'NegReg', (53, 60))	('talaporfin', 'Chemical', 'MESH:C053434', (24, 34))	('NaN3', 'Chemical', 'MESH:D019810', (88, 92))	('NaN3', 'Var', (88, 92))	('inhibit', 'NegReg', (100, 107))	('uptake', 'MPA', (14, 20))
264023	33190360	We analyzed MFH03 after treatment with the lysosomal degradation inhibitors chloroquine (CQ) or NH4Cl, which suppressed lysosomal enzyme activity by increasing the internal pH of endosomes.	('internal pH of endosomes', 'MPA', (164, 188))	('suppressed', 'NegReg', (109, 119))	('NH4Cl', 'Var', (96, 101))	('MFH03', 'Chemical', '-', (12, 17))	('chloroquine', 'Chemical', 'MESH:D002738', (76, 87))	('NH4Cl', 'Chemical', '-', (96, 101))	('lysosomal', 'Enzyme', (120, 129))	('CQ', 'Chemical', 'MESH:D002738', (89, 91))	('increasing', 'PosReg', (149, 159))
264024	33190360	15  Results showed that after culture with CQ or NH4Cl for 48 hours, the decrease in fluorescence intensity of talaporfin was significantly inhibited (Figure 4A, B).	('fluorescence intensity', 'MPA', (85, 107))	('NH4Cl', 'Var', (49, 54))	('inhibited', 'NegReg', (140, 149))	('CQ', 'Chemical', 'MESH:D002738', (43, 45))	('decrease', 'NegReg', (73, 81))	('talaporfin', 'Chemical', 'MESH:C053434', (111, 121))	('NH4Cl', 'Chemical', '-', (49, 54))
264028	33190360	16 ,  17 ,  18  Therefore, we evaluated the changes in talaporfin uptake by the inhibition of the Ras signaling pathway in K-Ras mutant cancer cells, the lung cancer cell line A549, and the pancreatic cancer cell line MIA PaCa2 with K-Ras mutation.	('inhibition', 'NegReg', (80, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('cancer', 'Disease', (201, 207))	('A549', 'CellLine', 'CVCL:0023', (176, 180))	('K-Ras', 'Gene', (123, 128))	('cancer', 'Disease', (136, 142))	('K-Ras', 'Gene', (233, 238))	('pancreatic cancer', 'Disease', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('talaporfin', 'Chemical', 'MESH:C053434', (55, 65))	('mutant', 'Var', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('lung cancer', 'Disease', (154, 165))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (190, 207))	('Ras signaling pathway', 'Pathway', (98, 119))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('K-Ras', 'Gene', '3845', (123, 128))	('K-Ras', 'Gene', '3845', (233, 238))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('MIA PaCa2', 'CellLine', 'CVCL:0428', (218, 227))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('pancreatic cancer', 'Disease', 'MESH:D010190', (190, 207))
264031	33190360	Results showed that all inhibitors reduced talaporfin uptake in A549 and MIA PaCa2 cells (Figure 5A-H).	('talaporfin', 'Chemical', 'MESH:C053434', (43, 53))	('reduced', 'NegReg', (35, 42))	('inhibitors', 'Var', (24, 34))	('MIA PaCa2', 'CellLine', 'CVCL:0428', (73, 82))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('talaporfin uptake', 'MPA', (43, 60))
264032	33190360	In HDFa cells without K-Ras mutation, the inhibitory effects were slightly limited compared with A549 and MIA PaCa2 cells (Figure 5I-L).	('HDFa', 'Disease', (3, 7))	('K-Ras', 'Gene', (22, 27))	('MIA PaCa2', 'CellLine', 'CVCL:0428', (106, 115))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('mutation', 'Var', (28, 36))	('HDFa', 'Disease', 'None', (3, 7))	('K-Ras', 'Gene', '3845', (22, 27))
264064	33190360	21  Mutant forms of p53 and Ras might also harness endocytosis in cancer cells.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('harness endocytosis', 'Disease', (43, 62))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('harness endocytosis', 'Disease', 'MESH:D006938', (43, 62))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('Mutant', 'Var', (4, 10))	('cancer', 'Disease', (66, 72))
264066	33190360	Moreover, in cancer cell lines with K-Ras mutations, the uptake of talaporfin was suppressed by PI3K and MAPK inhibitors.	('uptake of', 'MPA', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('K-Ras', 'Gene', '3845', (36, 41))	('K-Ras', 'Gene', (36, 41))	('suppressed', 'NegReg', (82, 92))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('mutations', 'Var', (42, 51))	('talaporfin', 'Chemical', 'MESH:C053434', (67, 77))
264067	33190360	This might indicate that the mutation of K-Ras promotes the uptake of talaporfin.	('mutation', 'Var', (29, 37))	('uptake of', 'MPA', (60, 69))	('promotes', 'PosReg', (47, 55))	('K-Ras', 'Gene', '3845', (41, 46))	('talaporfin', 'Chemical', 'MESH:C053434', (70, 80))	('K-Ras', 'Gene', (41, 46))
264068	33190360	16  Roy et al showed that K-Ras mutations regulate caveolae-dependent endocytosis in human colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('K-Ras', 'Gene', '3845', (26, 31))	('K-Ras', 'Gene', (26, 31))	('colon cancer', 'Disease', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('caveolae-dependent endocytosis', 'MPA', (51, 81))	('mutations', 'Var', (32, 41))	('regulate', 'Reg', (42, 50))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('human', 'Species', '9606', (85, 90))
264069	33190360	It has also been reported that mutation of K-Ras enhances the glycolytic pathway by a glucose transporter.	('K-Ras', 'Gene', '3845', (43, 48))	('glycolytic pathway', 'Pathway', (62, 80))	('K-Ras', 'Gene', (43, 48))	('mutation', 'Var', (31, 39))	('enhances', 'PosReg', (49, 57))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))
264070	33190360	18 ,  22  These studies suggest that the promotion of talaporfin uptake via mutated K-Ras activation is mediated by the high amount of intracellular ATP.	('promotion', 'PosReg', (41, 50))	('activation', 'PosReg', (90, 100))	('K-Ras', 'Gene', (84, 89))	('talaporfin', 'Chemical', 'MESH:C053434', (54, 64))	('mutated', 'Var', (76, 83))	('talaporfin uptake', 'MPA', (54, 71))	('ATP', 'Chemical', 'MESH:D000255', (149, 152))	('K-Ras', 'Gene', '3845', (84, 89))
264072	33190360	However, the amount of ATP was maintained by PI3K and MAPK inhibitors in cancer cell lines.	('ATP', 'Chemical', 'MESH:D000255', (23, 26))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('PI3K', 'Var', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MAPK', 'Gene', (54, 58))
264074	33190360	Cell death after PDT could induce anti-tumor immune responses by activation of immune cells, cytokine release, CD8+ T cell infiltration, and the formation of immunological memory, 3 ,  4  which suggests possible benefits of combination therapy using PDT and immunotherapy.	('immune cells', 'CPA', (79, 91))	('PDT', 'Var', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('induce', 'PosReg', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cytokine', 'CPA', (93, 101))	('tumor', 'Disease', (39, 44))	('CD8', 'Gene', (111, 114))	('activation', 'PosReg', (65, 75))	('CD8', 'Gene', '925', (111, 114))
264099	32095555	Compared to the total number of patients treated with CBCT-guidance over the study period, the overall rate of IGRT-related variances and re-planning was 6.2% and 1.4% respectively.	('patients', 'Species', '9606', (32, 40))	('variances', 'Var', (124, 133))	('IGRT-related', 'Gene', (111, 123))
264113	32095555	Head-and-neck: The majority of head-and-neck variances (60%) were non-tumor related ('normal tissue motion' being the most common sub-category), and these were re-planned at a rate of 3%.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('head-and-neck', 'Disease', (31, 44))	('variances', 'Var', (45, 54))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
264115	32095555	Upper GI: The majority of upper GI variances (79%) were non-tumor related ('normal tissue motion' being the most common sub-category), and these were re-planned at a rate of 24%.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('variances', 'Var', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('upper', 'Gene', (26, 31))	('tumor', 'Disease', (60, 65))
264117	32095555	GU: The majority of GU variances (78%) were non-tumor related ('bladder/rectum filling' being the most common sub-category), and these were re-planned at a rate of 14%.	('variances', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
264158	30568973	Bronchoscopy revealed rifampin-resistant miliary TB, and she was started on isoniazid, levofloxacin, amikacin, ethambutol, and pyrazinamide.	('ethambutol', 'Chemical', 'MESH:D004977', (111, 121))	('amikacin', 'Chemical', 'MESH:D000583', (101, 109))	('pyrazinamide', 'Chemical', 'MESH:D011718', (127, 139))	('isoniazid', 'Chemical', 'MESH:D007538', (76, 85))	('miliary TB', 'Disease', (41, 51))	('levofloxacin', 'Chemical', 'MESH:D064704', (87, 99))	('rifampin', 'Chemical', 'MESH:D012293', (22, 30))	('rifampin-resistant', 'Var', (22, 40))	('TB', 'Chemical', 'MESH:D013725', (49, 51))
264245	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', (32, 50))	('motile spermatozoa', 'Disease', 'MESH:D000072660', (32, 50))	('x400', 'Var', (85, 89))
264257	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))
264287	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))
264296	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))
264392	21316601	Studies of mouse and man implicate a number of causative mutations in eRMS that include p53, Shh/Ptch1/Sufu, Ras and Rb1.	('Sufu', 'Gene', '51684', (103, 107))	('mouse', 'Species', '10090', (11, 16))	('eRMS', 'Gene', (70, 74))	('man', 'Species', '9606', (21, 24))	('p53', 'Gene', (88, 91))	('Sufu', 'Gene', (103, 107))	('mutations', 'Var', (57, 66))
264400	21316601	To generate mouse models of embryonal rhabdomyosarcoma, lineage-specific homozygous deletion of p53 with or without concurrent heterozygous Patched1 (Ptch1) deletion was achieved by interbreeding Ptch1 or p53 conditional lines with the myogenic Cre mouse lines MCre, Myf5Cre, Pax7CreER, or Myf6Cre.	('Patched1', 'Gene', (140, 148))	('p53', 'Gene', (96, 99))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (28, 54))	('Myf5', 'Gene', (267, 271))	('deletion', 'Var', (84, 92))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (38, 54))	('Patched1', 'Gene', '19206', (140, 148))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (28, 54))	('mouse', 'Species', '10090', (12, 17))	('mouse', 'Species', '10090', (249, 254))	('embryonal rhabdomyosarcoma', 'Disease', (28, 54))	('Myf6', 'Gene', (290, 294))	('Myf5', 'Gene', '17877', (267, 271))	('Myf6', 'Gene', '17878', (290, 294))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
264415	21316601	For mice harboring only Cre-driven p53 deletions, tumors were soft tissue sarcomas except that half of Myf5Cre-p53 tumors were osteosarcoma arising from the ribs (Figure 1E).	('p53', 'Gene', (35, 38))	('Myf5', 'Gene', '17877', (103, 107))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('osteosarcoma', 'Phenotype', 'HP:0002669', (127, 139))	('mice', 'Species', '10090', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (62, 81))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('tumors', 'Disease', (115, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('Myf5', 'Gene', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('osteosarcoma', 'Disease', (127, 139))	('sarcomas', 'Disease', (74, 82))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (62, 82))	('deletions', 'Var', (39, 48))	('osteosarcoma', 'Disease', 'MESH:D012516', (127, 139))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
264417	21316601	Ptch1+/-;p53-/- mice of all Cre lineages had a tendency to develop tumors at a higher frequency than did p53-/- mice, although this trend did not reach statistical significance (Figure 1B).	('develop', 'PosReg', (59, 66))	('Ptch1+/-;p53-/-', 'Var', (0, 15))	('mice', 'Species', '10090', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('p53-/-', 'Var', (9, 15))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mice', 'Species', '10090', (112, 116))
264418	21316601	All Ptch1+/-;p53-/- tumors were soft tissue tumors except for osteosarcoma.	('Ptch1+/-;p53-/-', 'Var', (4, 19))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('soft tissue tumors', 'Disease', (32, 50))	('p53-/-', 'Var', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('osteosarcoma', 'Phenotype', 'HP:0002669', (62, 74))	('osteosarcoma', 'Disease', (62, 74))	('soft tissue tumors', 'Disease', 'MESH:D012983', (32, 50))	('osteosarcoma', 'Disease', 'MESH:D012516', (62, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (32, 50))
264422	21316601	Myf6Cre-p53-/- gave rise to the highest percentage of eRMS (100%) in the context of p53 deletion only (Figure 1E), and MCre was the second highest with 31% and 42% of the tumors diagnosed as eRMS in p53-/- and Ptch1+/-;p53-/-, respectively (Figure 1E).	('Ptch1+/-;p53-/-', 'Var', (210, 225))	('Myf6', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('p53-/-', 'Var', (199, 205))	('deletion', 'Var', (88, 96))	('Myf6', 'Gene', '17878', (0, 4))	('eRMS', 'Disease', (191, 195))	('eRMS', 'Disease', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
264423	21316601	eRMS developed in 13% of Pax7CreER-Ptch1+/-;p53-/- mice but in none of Pax7CreER-p53-/- mice, most tumors of which were diagnosed as UPS (Figure 1E).	('p53-/-', 'Var', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('mice', 'Species', '10090', (88, 92))	('eRMS', 'Disease', (0, 4))	('Pax7CreER-Ptch1+/-;p53-/-', 'Var', (25, 50))	('tumors', 'Disease', (99, 105))
264427	21316601	None of these genes was upregulated in the tumors from the original lineage compared to other groups of tumors (for example, Myf6 is not over-expressed in soft tissue tumors from Myf6Cre-Ptch1+/-;p53-/- or Myf6Cre-p53-/- mice compared to tumors of other mouse lines).	('soft tissue tumors', 'Disease', (155, 173))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Myf6', 'Gene', '17878', (179, 183))	('mouse', 'Species', '10090', (254, 259))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (155, 173))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', (238, 244))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('soft tissue tumors', 'Disease', 'MESH:D012983', (155, 173))	('Myf6', 'Gene', (179, 183))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('Myf6', 'Gene', (206, 210))	('Myf6', 'Gene', '17878', (206, 210))	('p53-/-', 'Var', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('Myf6', 'Gene', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('mice', 'Species', '10090', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Myf6', 'Gene', '17878', (125, 129))	('tumors', 'Disease', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
264431	21316601	High frequency of retinoblastoma (Rb1) gene mutation has been reported in a subset of human rhabdomyosarcoma.	('mutation', 'Var', (44, 52))	('rhabdomyosarcoma', 'Disease', (92, 108))	('reported', 'Reg', (62, 70))	('human', 'Species', '9606', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('retinoblastoma', 'Gene', (18, 32))	('retinoblastoma', 'Gene', '5925', (18, 32))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (92, 108))	('Rb1', 'Gene', (34, 37))	('retinoblastoma', 'Phenotype', 'HP:0009919', (18, 32))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (92, 108))
264433	21316601	Loss of Rb1 in the Myf5 or hypaxial Pax3 lineages (Myf5Cre and MCre, respectively) led to embryonic lethality, which is consistent with a previous report.	('Rb1', 'Gene', (8, 11))	('Myf5', 'Gene', (19, 23))	('Myf5', 'Gene', '17877', (51, 55))	('Pax3', 'Gene', '18505', (36, 40))	('Pax3', 'Gene', (36, 40))	('embryonic lethality', 'Disease', 'MESH:D020964', (90, 109))	('embryonic lethality', 'Disease', (90, 109))	('Myf5', 'Gene', (51, 55))	('Myf5', 'Gene', '17877', (19, 23))	('Loss', 'Var', (0, 4))
264434	21316601	When Rb1 was inactivated in Myf6 or Pax7 lineage using Myf6Cre or Pax7CreER mice, mice were born in normal Mendelian ratios and developed normally throughout adolescence and early adulthood.	('mice', 'Species', '10090', (82, 86))	('Myf6', 'Gene', (55, 59))	('Myf6', 'Gene', (28, 32))	('inactivated', 'Var', (13, 24))	('Rb1', 'Gene', (5, 8))	('Myf6', 'Gene', '17878', (55, 59))	('Myf6', 'Gene', '17878', (28, 32))	('mice', 'Species', '10090', (76, 80))
264438	21316601	Myogenin and Desmin-positive tumor cells were far less frequent than Ptch1+/-;p53-/ - or p53-/- tumors with intact Rb1 (from any Cre driver).	('less', 'NegReg', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('Rb1', 'Protein', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Desmin', 'Gene', '13346', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', (29, 34))	('Myogenin', 'Gene', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Myogenin', 'Gene', '17928', (0, 8))	('Ptch1+/-', 'Var', (69, 77))	('Desmin', 'Gene', (13, 19))
264441	21316601	Unsupervised global gene expression analysis demonstrated a strong difference between tumors with intact versus deleted Rb1 (Figure S1F).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Rb1', 'Gene', (120, 123))	('difference', 'Reg', (67, 77))	('deleted', 'Var', (112, 119))
264444	21316601	Tumor cells from Myf6Cre-p53-/-, Pax7CreER-p53-/-, Myf6Cre-Ptch1+/-;p53-/-, Pax7CreER-Ptch1+/-;p53-/-, Myf6Cre-p53-/-;Rb1-/-, Pax7CreER-p53-/-;Rb1-/-, and Myf6Cre-Pax3P3F/P3F; p53-/- mice were cultured under myogenic differentiation condition for 5 days.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Myf6', 'Gene', '17878', (17, 21))	('p53-/-', 'Var', (68, 74))	('Myf6', 'Gene', (51, 55))	('Pax3', 'Gene', (163, 167))	('Myf6', 'Gene', (103, 107))	('Pax3', 'Gene', '18505', (163, 167))	('Pax7CreER-Ptch1+/-', 'Var', (76, 94))	('Myf6', 'Gene', '17878', (51, 55))	('Myf6', 'Gene', (155, 159))	('mice', 'Species', '10090', (183, 187))	('Myf6', 'Gene', '17878', (103, 107))	('Myf6', 'Gene', '17878', (155, 159))	('Pax7CreER-p53-/-', 'Var', (126, 142))	('Myf6', 'Gene', (17, 21))
264448	21316601	Myf6Cre-p53-/- and Pax7CreER-p53-/- cells showed similar percentages of Ki67 positivity (Figure 5D).	('Myf6', 'Gene', (0, 4))	('Myf6', 'Gene', '17878', (0, 4))	('Pax7CreER-p53-/-', 'Var', (19, 35))	('Ki67', 'Gene', '17345', (72, 76))	('positivity', 'Reg', (77, 87))	('Ki67', 'Gene', (72, 76))
264449	21316601	On the other hand, Myf6Cre-p53-/-;Rb1-/- and Pax7CreER-p53-/-;Rb1-/- tumor cells also showed Ki67 positivity similar to each other but significantly higher than tumors with intact Rb1.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Ki67', 'Gene', (93, 97))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('Ki67', 'Gene', '17345', (93, 97))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('Myf6', 'Gene', '17878', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Myf6', 'Gene', (19, 23))	('Pax7CreER-p53-/-;Rb1-/-', 'Var', (45, 68))	('higher', 'PosReg', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (161, 166))
264450	21316601	The difference in cell growth rates between tumors with and without Rb1 deletion was accentuated under low serum conditions (Figure 5E,F).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cell growth rates', 'CPA', (18, 35))	('Rb1', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('deletion', 'Var', (72, 80))
264452	21316601	The results also suggest that loss of Rb1 can increase tumor cell proliferation and reduce myogenic differentiation.	('reduce', 'NegReg', (84, 90))	('myogenic differentiation', 'CPA', (91, 115))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('increase', 'PosReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('Rb1', 'Gene', (38, 41))	('loss', 'Var', (30, 34))
264455	21316601	Having compared the myodifferentiation capacity of eRMS by cell of origin relative to aRMS, we next explored in more detail the observation that Pax7CreER-Ptch1+/-;p53-/- tumors were often morphologically similar but showed varying degrees of phenotypic differentiation leading to the pathological diagnosis of either eRMS or UPS.	('UPS', 'Disease', (326, 329))	('Pax7CreER-Ptch1+/-;p53-/-', 'Var', (145, 170))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('leading to', 'Reg', (270, 280))	('eRMS', 'Disease', (318, 322))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
264456	21316601	To this end, we examined markers of myodifferentiation among Ptch1+/-;p53-/- or p53-/- mouse tumors from any cell of origin, correlating cohorts of tumors diagnosed by the pathologists as eRMS or undifferentiated spindle cell sarcoma (i.e., UPS), based upon histological features with Myogenin or Desmin staining.	('Myogenin', 'Gene', (285, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('Myogenin', 'Gene', '17928', (285, 293))	('Desmin', 'Gene', '13346', (297, 303))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mouse', 'Species', '10090', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('Ptch1+/-', 'Var', (61, 69))	('Desmin', 'Gene', (297, 303))	('eRMS', 'Disease', (188, 192))	('sarcoma', 'Disease', 'MESH:D012509', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('sarcoma', 'Disease', (226, 233))
264464	21316601	This profile, however, classified 7 out of 10 spindle cell variant eRMS as classical eRMS, and predicted 4 out of 6 spindle cell rhabdomyosarcoma as eRMS.	('rhabdomyosarcoma', 'Disease', (129, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (129, 145))	('variant', 'Var', (59, 66))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (129, 145))	('spindle cell', 'Disease', (46, 58))
264492	21316601	Based upon expression patterns in mouse tumors, other investigators have similarly postulated a (neural crest) cell of origin for double mutant NF1 and p53 associated rhabdomyosarcoma.	('mouse', 'Species', '10090', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('NF1', 'Gene', '18015', (144, 147))	('p53', 'Gene', (152, 155))	('double mutant', 'Var', (130, 143))	('rhabdomyosarcoma', 'Disease', (167, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (167, 183))	('associated', 'Reg', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('NF1', 'Gene', (144, 147))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (167, 183))	('tumors', 'Disease', (40, 46))
264503	21316601	Many pathways lead to eRMS, but the most well known pathway is the germline disruption of p53 in Li-Fraumeni syndrome (LFS).	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (97, 117))	('p53', 'Gene', (90, 93))	('lead', 'Reg', (14, 18))	('Li-Fraumeni syndrome', 'Disease', (97, 117))	('eRMS', 'Disease', (22, 26))	('disruption', 'Var', (76, 86))
264519	21316601	We were struck by the contrast between the 10% of human tumors that expressed all 4 mutant signatures versus the 28% tumors that only coveted a p53 off signature.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (56, 62))	('mutant', 'Var', (84, 90))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('human', 'Species', '9606', (50, 55))
264521	21316601	Early studies suggested that Rb1 abnormalities rarely occur in eRMS or aRMS, but a recent study reports that Rb1 allelic imbalance occurred in 13 of 27 eRMS tested (but much less frequently than in aRMS).	('imbalance', 'Phenotype', 'HP:0002172', (121, 130))	('allelic', 'Var', (113, 120))	('Rb1 abnormalities', 'Disease', (29, 46))	('occurred', 'Reg', (131, 139))	('Rb1 abnormalities', 'Disease', 'MESH:D012175', (29, 46))	('Rb1', 'Gene', (109, 112))
264524	21316601	However, among patients with hereditary Rb1 mutations, rhabdomyosarcomas reported to have occurred were more often categorized as RMS "Not Otherwise Specified (NOS)" than eRMS (note that NOS may imply inadequate tissue rather than diagnostic uncertainty).	('patients', 'Species', '9606', (15, 23))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (55, 72))	('Rb1', 'Gene', (40, 43))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (55, 71))	('mutations', 'Var', (44, 53))	('rhabdomyosarcomas', 'Disease', (55, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (55, 72))
264561	21331153	Early studies demonstrated that peripheral blood mononuclear cells taken from patients following treatment with liposomal MTP demonstrated increased tumor cell killing in vitro compared with baseline samples.	('liposomal MTP', 'Var', (112, 125))	('MTP', 'Var', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('increased', 'PosReg', (139, 148))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('MTP', 'Chemical', 'MESH:C037144', (122, 125))	('tumor', 'Disease', (149, 154))
264566	21331153	Analysis of this study has been complicated; the first analysis published in 2005 showed a trend towards improved outcomes for the MTP-containing arm that was not statistically significance.	('improved', 'PosReg', (105, 113))	('outcomes', 'MPA', (114, 122))	('MTP-containing', 'Var', (131, 145))	('MTP', 'Chemical', 'MESH:C037144', (131, 134))
264587	21331153	Potential targets for immunotherapy have been divided into five categories: mutated, shared tumor specific, differentiation antigens, overexpressed antigens, and viral antigens.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mutated', 'Var', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
264588	21331153	"Mutated" antigens involve a mutation in the cancer not present in normal tissues, thus making the target inherently specific.	('mutation', 'Var', (29, 37))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
264607	21331153	Since the class I HLA type A*02.01 is relatively common, expressed by about half of the Caucasian population, targeting A*02.01 associated epitopes in pilot immunotherapy trials for sarcoma is a reasonable approach.	('A*02.01', 'Var', (120, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcoma', 'Disease', (182, 189))	('sarcoma', 'Disease', 'MESH:D012509', (182, 189))
264643	21331153	Improved survival was seen in the group of patients receiving vaccination compared with those undergoing leukapheresis but not receiving vaccination.	('survival', 'MPA', (9, 17))	('patients', 'Species', '9606', (43, 51))	('Improved', 'PosReg', (0, 8))	('vaccination', 'Var', (62, 73))
264656	21331153	The same group has produced interesting in vitro data showing that while CTL generated to the wild-type peptide killed tumor relatively poorly (the peptide used for the vaccine), a one amino acid substituted K9I peptide (also an A*2402 associated epitope) produced CTL which killed tumor far more effectively.	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('K9I', 'Var', (208, 211))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('poorly', 'NegReg', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
264683	32758199	A 27-year-old woman underwent extensive resection of the primary tumor and partial lung resection after chemotherapy for left femoral synovial sarcoma and multiple lung metastases 4 years prior.	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('femoral synovial sarcoma', 'Disease', 'MESH:D013584', (126, 150))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('femoral synovial sarcoma', 'Disease', (126, 150))	('A 27', 'Gene', '28912', (0, 4))	('woman', 'Species', '9606', (14, 19))	('A 27', 'Gene', (0, 4))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (134, 150))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('lung metastases', 'Disease', (164, 179))	('lung metastases', 'Disease', 'MESH:D009362', (164, 179))	('partial', 'Var', (75, 82))
264744	32758199	Recently, the molecular mechanism underlying translocation-related sarcoma has been elucidated, and biological target treatments are being developed.	('translocation-related', 'Var', (45, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('sarcoma', 'Disease', (67, 74))
264946	29121995	CIC rearrangements have been reported in soft tissue tumors.	('soft tissue tumors', 'Phenotype', 'HP:0031459', (41, 59))	('rearrangements', 'Var', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('reported', 'Reg', (29, 37))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
264985	28959166	Furthermore, platinum amounts in tumours after compound 2 or cisplatin electrochemotherapy were approximately 2-fold higher compared to the drug treatment only, and the same increase of platinum bound to DNA was observed.	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('cisplatin', 'Var', (61, 70))	('platinum amounts', 'MPA', (13, 29))	('platinum', 'Chemical', 'MESH:D010984', (186, 194))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumours', 'Disease', (33, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('increase', 'PosReg', (174, 182))	('platinum', 'Chemical', 'MESH:D010984', (13, 21))	('higher', 'PosReg', (117, 123))
264989	28959166	Among these mechanisms, the inactivation of cisplatin via thiol-containing molecules, such as glutathione and metallothionein, increased the repair of cisplatin-DNA adducts, enhanced tolerance to cisplatin-DNA adducts, resulting in the failure of apoptotic pathways and reduction of platinum accumulation through decreased drug uptake or increased drug efflux.	('repair', 'MPA', (141, 147))	('enhanced', 'PosReg', (174, 182))	('failure', 'NegReg', (236, 243))	('inactivation', 'Var', (28, 40))	('increased', 'PosReg', (338, 347))	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('tolerance', 'MPA', (183, 192))	('glutathione', 'Chemical', 'MESH:D005978', (94, 105))	('platinum accumulation', 'MPA', (283, 304))	('drug efflux', 'MPA', (348, 359))	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('decreased', 'NegReg', (313, 322))	('apoptotic pathways', 'Pathway', (247, 265))	('drug uptake', 'MPA', (323, 334))	('reduction', 'NegReg', (270, 279))	('platinum', 'Chemical', 'MESH:D010984', (283, 291))	('thiol', 'Chemical', 'MESH:D013438', (58, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('increased', 'PosReg', (127, 136))
264997	28959166	Electroporation increases the cytotoxicity up to 80-fold in cisplatin-sensitive and cisplatin-resistant tumour models, in vitro and in vivo.	('cytotoxicity', 'Disease', (30, 42))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('Electroporation', 'Var', (0, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('increases', 'PosReg', (16, 25))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('cytotoxicity', 'Disease', 'MESH:D064420', (30, 42))	('tumour', 'Disease', (104, 110))
265049	28959166	Similar to in vitro data, growth of tumours with variable intrinsic sensitivity to cisplatin (sensitive, moderately sensitive and resistant) after compound 2 electrochemotherapy was less delayed (up to 9.7 days) compared to cisplatin electrochemotherapy.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('electrochemotherapy', 'Var', (158, 177))	('delayed', 'NegReg', (187, 194))	('to 9', 'Species', '1214577', (199, 203))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('growth of tumours', 'Disease', 'MESH:D006130', (26, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (224, 233))	('growth of tumours', 'Disease', (26, 43))
265063	28959166	The most potentiated cytotoxic effect of cisplatin electrochemotherapy was observed in cisplatin-resistant TBLCl2Pt cells, resulting in a 77-fold decrease in IC50 value, as previously demonstrated (79-fold).	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('decrease', 'NegReg', (146, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('TBLCl2Pt', 'Chemical', '-', (107, 115))	('IC50 value', 'MPA', (158, 168))	('cisplatin-resistant', 'Var', (87, 106))
265067	28959166	Since electroporation of cells with cisplatin renders cisplatin-resistant TBLCl2Pt cells to equal level of sensitivity as cisplatin-sensitive cells, and IC50 values were statistically non-significant, consistent with the data obtained in a previous study.	('cisplatin-resistant', 'Var', (54, 73))	('TBLCl2Pt', 'Chemical', '-', (74, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('TBLCl2Pt', 'Gene', (74, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('electroporation', 'Var', (6, 21))
265097	28959166	Notably, cisplatin or compound 2 alone did not delay growth of cisplatin-resistant TBLCl2Pt tumours, but electroporation potentiated antitumour effectiveness of either of the drugs used, resulting in prolonged tumour 2.2-fold and 1.6-fold growth delay, respectively (Table 2, Figure 2).	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('growth delay', 'Phenotype', 'HP:0001510', (239, 251))	('tumour', 'Disease', (92, 98))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('potentiated', 'PosReg', (121, 132))	('delay growth', 'Phenotype', 'HP:0001510', (47, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('growth delay', 'CPA', (239, 251))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Disease', (210, 216))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('electroporation', 'Var', (105, 120))	('tumour', 'Disease', (137, 143))	('TBLCl2Pt', 'Chemical', '-', (83, 91))	('tumours', 'Disease', (92, 99))	('prolonged', 'PosReg', (200, 209))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
265101	28959166	However, significant antitumour effectiveness was only obtained with KP1339 electrochemotherapy in SA-1 tumours, while electrochemotherapy with KP418 has no significant effect on tumour growth delay in SA-1 and in B16F1 melanoma tumours.	('melanoma tumours', 'Disease', (220, 236))	('tumour', 'Disease', 'MESH:D009369', (229, 235))	('tumour', 'Disease', (229, 235))	('SA-1', 'Gene', (99, 103))	('tumour growth delay', 'Disease', 'MESH:D006130', (179, 198))	('tumour growth delay', 'Disease', (179, 198))	('tumours', 'Disease', (104, 111))	('SA-1', 'Gene', '20842', (202, 206))	('KP1339', 'Chemical', 'MESH:C551585', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('tumours', 'Disease', 'MESH:D009369', (104, 111))	('tumour', 'Disease', (179, 185))	('SA-1', 'Gene', '20842', (99, 103))	('tumours', 'Disease', (229, 236))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('KP418', 'Chemical', 'MESH:C521720', (144, 149))	('KP1339', 'Var', (69, 75))	('tumour', 'Disease', (25, 31))	('growth delay', 'Phenotype', 'HP:0001510', (186, 198))	('tumour', 'Disease', (104, 110))	('melanoma tumours', 'Disease', 'MESH:D008545', (220, 236))	('tumours', 'Phenotype', 'HP:0002664', (229, 236))	('tumours', 'Disease', 'MESH:D009369', (229, 236))	('SA-1', 'Gene', (202, 206))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))
265102	28959166	Although, the type of administration of KP1339 was different (intravenously), at equimolar doses, its antitumour effectiveness was comparable to the effect of compound 2.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('KP1339', 'Var', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumour', 'Disease', (106, 112))	('KP1339', 'Chemical', 'MESH:C551585', (40, 46))
265130	28959166	Indeed, in tumours treated with electrochemotherapy compared to the drug administration only, approximately 2-fold higher platinum binding to DNA was achieved, correlated with pronounced antitumour effectiveness (Figure 3).	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('tumour', 'Disease', (191, 197))	('higher', 'PosReg', (115, 121))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('platinum', 'CPA', (122, 130))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('platinum', 'Chemical', 'MESH:D010984', (122, 130))	('electrochemotherapy', 'Var', (32, 51))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumour', 'Disease', (11, 17))	('tumours', 'Disease', (11, 18))
265148	28959166	Electroporation increased compound 2 cytotoxicity up to 6-fold in vitro and antitumour effectiveness up to 3-fold in vivo, but it had less evident effects compared to cisplatin.	('tumour', 'Disease', (80, 86))	('cytotoxicity', 'Disease', (37, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('increased', 'PosReg', (16, 25))	('Electroporation', 'Var', (0, 15))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('compound', 'Gene', (26, 34))
265149	28959166	The underlying mechanism of antitumour effectiveness of electrochemotherapy could be increased drug uptake, and an approximately 2 times higher amount of platinum in the tumours was reflected to the same extent in higher amount of Pt bound on its target of action to the DNA.	('higher', 'PosReg', (214, 220))	('bound', 'Interaction', (234, 239))	('tumours', 'Disease', 'MESH:D009369', (170, 177))	('tumour', 'Disease', (170, 176))	('tumours', 'Disease', (170, 177))	('drug uptake', 'CPA', (95, 106))	('tumour', 'Disease', (32, 38))	('higher', 'PosReg', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('increased', 'PosReg', (85, 94))	('electrochemotherapy', 'Var', (56, 75))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('platinum', 'Chemical', 'MESH:D010984', (154, 162))	('Pt', 'Chemical', 'MESH:D010984', (231, 233))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('tumours', 'Phenotype', 'HP:0002664', (170, 177))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
265215	28438212	Expression of several cytokeratin and especially CK 34betaE12, CK 5/6 and p63 favors sarcomatoid carcinoma.	('CK 5/6', 'Gene', (63, 69))	('CK 5/6', 'Gene', '3852', (63, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('p63', 'Gene', '8626', (74, 77))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (85, 106))	('sarcomatoid carcinoma', 'Disease', (85, 106))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (85, 106))	('CK 34betaE12', 'Var', (49, 61))	('p63', 'Gene', (74, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
265240	27102149	Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1).	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('fibroblast growth factor receptor 2', 'Gene', '14183', (435, 470))	('FGFR2', 'Gene', (472, 477))	('ARID1A', 'Gene', (400, 406))	('rat', 'Species', '10116', (286, 289))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('isocitrate dehydrogenase', 'Gene', '3417', (280, 304))	('BRCA1-Associated', 'Gene', (312, 328))	('sarcoma viral', 'Disease', 'MESH:D001102', (193, 206))	('ROS1', 'Chemical', '-', (505, 509))	('raf', 'Gene', (182, 185))	('sarcoma viral', 'Disease', (193, 206))	('murine', 'Species', '10090', (186, 192))	('fibroblast growth factor receptor 2', 'Gene', (435, 470))	('BAP1', 'Gene', (340, 344))	('mutations', 'Var', (267, 276))	('mutations', 'Var', (61, 70))	('epidermal growth factor receptor', 'Gene', '24329', (88, 120))	('isocitrate dehydrogenase', 'Gene', (280, 304))	('sarcoma viral', 'Disease', 'MESH:D001102', (141, 154))	('rat', 'Species', '10116', (137, 140))	('tumor', 'Disease', (235, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('raf', 'Gene', '22882', (182, 185))	('sarcoma viral', 'Disease', (141, 154))	('epidermal growth factor receptor', 'Gene', (88, 120))
265259	27102149	With the advent of whole genome sequencing, mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53) were unraveled.	('raf', 'Gene', (151, 154))	('EGFR', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('sarcoma viral', 'Disease', 'MESH:D001102', (162, 175))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('sarcoma viral', 'Disease', 'MESH:D001102', (110, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('tumor', 'Disease', (204, 209))	('mutations', 'Var', (44, 53))	('rat', 'Species', '10116', (106, 109))	('sarcoma viral', 'Disease', (162, 175))	('sarcoma viral', 'Disease', (110, 123))	('epidermal growth factor receptor', 'Gene', (57, 89))	('raf', 'Gene', '22882', (151, 154))	('murine', 'Species', '10090', (155, 161))	('epidermal growth factor receptor', 'Gene', '24329', (57, 89))
265260	27102149	More recently, novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor (FGFR2) and ROS proto-oncogene 1 (ROS1) were revealed.	('FGFR2', 'Gene', (224, 229))	('ROS1', 'Gene', (257, 261))	('isocitrate dehydrogenase', 'Gene', '3417', (34, 58))	('IDH', 'Gene', (60, 63))	('BAP1', 'Gene', (94, 98))	('isocitrate dehydrogenase', 'Gene', (34, 58))	('ROS1', 'Chemical', '-', (257, 261))	('mutations', 'Var', (21, 30))
265268	27102149	Well established genomic alterations include overexpression of EGFR (5%-27%), vascular endothelial growth factor (VEGF) and its receptor (VEGFR) (55%-60%), human epidermal growth factor receptor 2 (HER2)/erb-b2 receptor tyrosine kinase 2 (ERBB2) (0%-20%), and MET proto-oncogene (MET) (7%-21%), mutations in BRAF (5%) and loss of function mutation in TP53 (3%-45%).	('ERBB2', 'Gene', (239, 244))	('vascular endothelial growth factor', 'Gene', '7422', (78, 112))	('epidermal growth factor receptor 2', 'Gene', (162, 196))	('VEGF', 'Gene', '7422', (138, 142))	('mutations', 'Var', (295, 304))	('overexpression', 'PosReg', (45, 59))	('erb-b2 receptor tyrosine kinase 2', 'Gene', '2064', (204, 237))	('vascular endothelial growth factor', 'Gene', (78, 112))	('VEGF', 'Gene', (138, 142))	('ERBB2', 'Gene', '2064', (239, 244))	('erb-b2 receptor tyrosine kinase 2', 'Gene', (204, 237))	('BRAF', 'Gene', (308, 312))	('VEGFR', 'Gene', '3791', (138, 143))	('VEGFR', 'Gene', (138, 143))	('VEGF', 'Gene', '7422', (114, 118))	('VEGF', 'Gene', (114, 118))	('rat', 'Species', '10116', (29, 32))	('TP53', 'Gene', (351, 355))	('epidermal growth factor receptor 2', 'Gene', '2064', (162, 196))	('human', 'Species', '9606', (156, 161))	('loss of function', 'NegReg', (322, 338))
265274	27102149	Other novel genetic signatures include IDH mutations (16%-36%), FGFR (5%-50%) and ROS1 fusions (9%).	('FGFR', 'Gene', (64, 68))	('ROS1', 'Gene', (82, 86))	('mutations', 'Var', (43, 52))	('ROS1', 'Chemical', '-', (82, 86))	('IDH', 'Gene', (39, 42))
265277	27102149	The common genetic alterations in ICC include TP53 (30%), KRAS (24%), ARID1A (20%), IDH1 (18%) and MCL1 (16%), whereas for extrahepatic CCA, common aberrations include TP53 (45%), KRAS (40%), ERBB2 (20%), SMAD4 (25%), F-box/WD repeat-containing protein 7 (FBXW7) (15%) and CDKN2A (15%).	('TP53', 'Var', (168, 172))	('CDKN2A', 'Gene', (273, 279))	('SMAD4', 'Gene', (205, 210))	('TP53', 'Var', (46, 50))	('FBXW7', 'Gene', (256, 261))	('MCL1', 'Gene', '4170', (99, 103))	('rat', 'Species', '10116', (152, 155))	('rat', 'Species', '10116', (23, 26))	('IDH1', 'Gene', (84, 88))	('MCL1', 'Gene', (99, 103))	('ERBB2', 'Gene', '2064', (192, 197))	('CDKN2A', 'Gene', '1029', (273, 279))	('F-box/WD repeat-containing protein 7', 'Gene', '55294', (218, 254))	('ERBB2', 'Gene', (192, 197))	('IDH1', 'Gene', '3417', (84, 88))	('SMAD4', 'Gene', '4089', (205, 210))	('FBXW7', 'Gene', '55294', (256, 261))	('F-box/WD repeat-containing protein 7', 'Gene', (218, 254))
265278	27102149	Furthermore, there were significant differences with regards to the prognostic significance of the above molecular markers, with TP53, KRAS and MTOR alterations predicting a worse prognosis in ICC, and BAP1, PBRM1 and chromatin modulating genes linked to a worse survival in ECC.	('BAP1', 'Gene', (202, 206))	('alterations', 'Var', (149, 160))	('ICC', 'Disease', (193, 196))	('PBRM1', 'Gene', '55193', (208, 213))	('rat', 'Species', '10116', (153, 156))	('KRAS', 'Gene', (135, 139))	('MTOR', 'Gene', '2475', (144, 148))	('MTOR', 'Gene', (144, 148))	('predicting', 'Reg', (161, 171))	('TP53', 'Gene', (129, 133))	('PBRM1', 'Gene', (208, 213))
265279	27102149	A subsequent meta-analysis of 4,458 patients with the study of 102 individual markers revealed that genetic alterations of HER2 and TP53 were more common in ECC, and BCL-2, EGFR, SMAD4, p16 and VEGF-A were more frequent in ICC.	('common', 'Reg', (147, 153))	('genetic alterations', 'Var', (100, 119))	('SMAD4', 'Gene', '4089', (179, 184))	('patients', 'Species', '9606', (36, 44))	('p16', 'Gene', '1029', (186, 189))	('TP53', 'Gene', (132, 136))	('SMAD4', 'Gene', (179, 184))	('BCL-2', 'Gene', '596', (166, 171))	('rat', 'Species', '10116', (112, 115))	('ECC', 'Disease', (157, 160))	('VEGF-A', 'Gene', '7422', (194, 200))	('VEGF-A', 'Gene', (194, 200))	('HER2', 'Protein', (123, 127))	('BCL-2', 'Gene', (166, 171))	('p16', 'Gene', (186, 189))
265286	27102149	Despite the strong rationale of targeting EGFR in BTCs and early interesting results with single arm phase II trials suggesting the benefits of EGFR inhibitors either as single agents or in combination with chemotherapy (Table 2), four completed randomized studies have failed to confirm the benefits of targeting EGFR in advanced BTCs.	('EGFR', 'Gene', (144, 148))	('inhibitors', 'Var', (149, 159))	('rat', 'Species', '10116', (19, 22))
265294	27102149	Additional biomarker-driven trials will provide further insight as most of the studies were conducted in patients who were unselected for KRAS mutation status or other signatures implicated in predicting response to EGFR therapy.	('patients', 'Species', '9606', (105, 113))	('KRAS', 'Gene', (138, 142))	('mutation', 'Var', (143, 151))
265302	27102149	Of the 124 patients enrolled (62 in each arm), the addition of cediranib improved the response rate (44% in the cediranib arm and 19% in the placebo arm, P = 0.004) but did not improve the median PFS (8.0 months in cediranib arm and 7.4 months in placebo arm, HR 0.93, P = 0.72) or OS (14.1 months in cediranib arm and 11.9 months in placebo arm, HR 0.86, P = 0.44).	('cediranib', 'Var', (112, 121))	('OS', 'Chemical', '-', (282, 284))	('rat', 'Species', '10116', (95, 98))	('PFS', 'MPA', (196, 199))	('improved', 'PosReg', (73, 81))	('cediranib', 'Chemical', 'MESH:C500926', (301, 310))	('cediranib', 'Chemical', 'MESH:C500926', (215, 224))	('cediranib', 'Chemical', 'MESH:C500926', (112, 121))	('patients', 'Species', '9606', (11, 19))	('cediranib', 'Chemical', 'MESH:C500926', (63, 72))	('response', 'MPA', (86, 94))
265310	27102149	Recent discoveries include IDH1/2 mutations, FGFR2 and ROS1 fusions, and mutations in chromatin remodeling genes for example ARID1A and BAP1.	('BAP1', 'Gene', (136, 140))	('ROS1', 'Chemical', '-', (55, 59))	('FGFR2', 'Gene', (45, 50))	('fusions', 'Var', (60, 67))	('ROS1', 'Gene', (55, 59))	('mutations', 'Var', (73, 82))	('ARID1A', 'Gene', (125, 131))	('IDH1/2', 'Gene', (27, 33))	('mutations', 'Var', (34, 43))
265312	27102149	IDH1 and 2 alterations exist in several tumors including gliomas and more recently identified in BTCs through high throughput molecular profiling.	('alterations', 'Var', (11, 22))	('rat', 'Species', '10116', (15, 18))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('IDH1 and 2', 'Gene', '3417;3418', (0, 10))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
265314	27102149	IDH mutations enhance the conversion of alpha-ketoglutarate to 2-hydroxyglutarate (2-HG), an oncometabolite that inhibits alpha-ketoglutarate-dependent enzymes responsible for DNA methylation, epigenetic regulation and call signaling.	('IDH', 'Gene', (0, 3))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (63, 81))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (40, 59))	('alpha-ketoglutarate-dependent enzymes', 'Enzyme', (122, 159))	('2-HG', 'Chemical', 'MESH:C019417', (83, 87))	('enhance', 'PosReg', (14, 21))	('conversion', 'MPA', (26, 36))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (122, 141))	('mutations', 'Var', (4, 13))	('inhibits', 'NegReg', (113, 121))
265316	27102149	In a cohort of 326 patients with resected ICC, IDH mutation was associated with longer time to recurrence and OS.	('IDH', 'Gene', (47, 50))	('mutation', 'Var', (51, 59))	('OS', 'Chemical', '-', (110, 112))	('patients', 'Species', '9606', (19, 27))
265317	27102149	In addition, the authors observed enhanced p53 and DNA hypermethylation among patients with IDH mutations.	('enhanced', 'PosReg', (34, 42))	('patients', 'Species', '9606', (78, 86))	('p53', 'Protein', (43, 46))	('DNA hypermethylation', 'MPA', (51, 71))	('IDH', 'Gene', (92, 95))	('mutations', 'Var', (96, 105))
265321	27102149	found that a selective R132H-IDH1 inhibitor (AGI-5198) impeded the growth of IDH-mutant glioma cells.	('IDH-mutant', 'Var', (77, 87))	('IDH1', 'Gene', (29, 33))	('glioma', 'Disease', (88, 94))	('IDH1', 'Gene', '3417', (29, 33))	('growth', 'CPA', (67, 73))	('impeded', 'NegReg', (55, 62))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('R132H', 'Mutation', 'rs121913500', (23, 28))	('AGI-5198', 'Chemical', 'MESH:C581156', (45, 53))
265322	27102149	showed that AGI-6780 selectively inhibits the leukemic cells harboring mutant IDH2/R140Q.	('IDH2', 'Gene', (78, 82))	('AGI-6780', 'Chemical', 'MESH:C581155', (12, 20))	('leukemic', 'Disease', 'MESH:D007938', (46, 54))	('IDH2', 'Gene', '3418', (78, 82))	('mutant', 'Var', (71, 77))	('R140Q', 'Mutation', 'rs121913502', (83, 88))	('inhibits', 'NegReg', (33, 41))	('leukemic', 'Disease', (46, 54))
265328	27102149	Whole exome sequencing and fluorescence in situ hybridization (FISH) have identified FGFR2 alterations primarily in 6%-50% of ICC and 0-5% of ECC.	('rat', 'Species', '10116', (95, 98))	('alterations', 'Var', (91, 102))	('ICC', 'Disease', (126, 129))	('ECC', 'Disease', (142, 145))	('FGFR2', 'Gene', (85, 90))
265329	27102149	analyzed 75 CCA patients with next generation sequencing, and found that genetic alterations in the FGFR pathway occurred in 13% of intrahepatic CCA and 5% of extrahepatic CCA, and that these alterations were associated with improved survival.	('FGFR pathway', 'Pathway', (100, 112))	('genetic alterations', 'Var', (73, 92))	('intrahepatic', 'Disease', (132, 144))	('patients', 'Species', '9606', (16, 24))	('rat', 'Species', '10116', (85, 88))	('rat', 'Species', '10116', (39, 42))	('occurred', 'Reg', (113, 121))	('improved', 'PosReg', (225, 233))	('rat', 'Species', '10116', (196, 199))
265333	27102149	observed FGFR2 fusions (FGFR2-AHCYL1 or FGFR2-BICC1) in 13.6% of ICC (9/66 ICC), and that inhibition of FGFR2 impeded activation of MAPK pathway, which is responsible for uncontrolled tumor growth.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('BICC1', 'Gene', '80114', (46, 51))	('FGFR2', 'Gene', (104, 109))	('fusions', 'Var', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('AHCYL1', 'Gene', (30, 36))	('FGFR2', 'Gene', (9, 14))	('BICC1', 'Gene', (46, 51))	('MAPK', 'Gene', '5595;5594;5595', (132, 136))	('tumor', 'Disease', (184, 189))	('MAPK', 'Gene', (132, 136))	('AHCYL1', 'Gene', '10768', (30, 36))	('inhibition', 'Var', (90, 100))	('impeded', 'NegReg', (110, 117))	('ICC', 'Disease', (65, 68))
265334	27102149	Another study evaluated 152 CCA and 4 intraductal papillary biliary neoplasm of the bile duct with FISH, and reported FGFR2 translocation in 12/96 (13%) of ICC, with a female predominance.	('biliary neoplasm', 'Phenotype', 'HP:0100574', (60, 76))	('ICC', 'Disease', (156, 159))	('translocation', 'Var', (124, 137))	('intraductal papillary biliary neoplasm', 'Disease', (38, 76))	('FGFR2', 'Gene', (118, 123))	('intraductal papillary biliary neoplasm', 'Disease', 'MESH:D000077779', (38, 76))	('neoplasm', 'Phenotype', 'HP:0002664', (68, 76))	('CCA', 'Disease', (28, 31))
265335	27102149	Those who harbored FGFR2 translocations had improved cancer-specific survival (123 vs. 37 months) and superior DFS (125 months vs. 26 months).	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('DFS', 'CPA', (111, 114))	('superior', 'PosReg', (102, 110))	('FGFR2', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('improved', 'PosReg', (44, 52))	('translocations', 'Var', (25, 39))
265336	27102149	Furthermore, cholangiocarcinoma harboring FGFR2 translocation and concomitant KRAS mutation are only rarely reported.	('cholangiocarcinoma', 'Disease', (13, 31))	('FGFR2', 'Gene', (42, 47))	('translocation', 'Var', (48, 61))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (13, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))
265337	27102149	In a study comprising of 109 ICC, 40 ECC and 11 gallbladder cases, novel FGFR2 gene fusions (FGFR2-KCTD1 and FGFR2-TXLNA) and a new variation of FGFR2-BICC (Type 2) were reported.	('BICC', 'Gene', (151, 155))	('KCTD1', 'Gene', '284252', (99, 104))	('fusions', 'Var', (84, 91))	('BICC', 'Gene', '80114', (151, 155))	('TXLNA', 'Gene', (115, 120))	('FGFR2', 'Gene', (73, 78))	('TXLNA', 'Gene', '200081', (115, 120))	('KCTD1', 'Gene', (99, 104))
265338	27102149	Using NIH3T3 clones that express either wild-type or kinase-inactive mutant forms of FGFR2-KCTD1 or FGFR2-TXLNA, the Nakamura et al.	('KCTD1', 'Gene', '284252', (91, 96))	('mutant', 'Var', (69, 75))	('NIH3T3', 'CellLine', 'CVCL:0594', (6, 12))	('TXLNA', 'Gene', '200081', (106, 111))	('TXLNA', 'Gene', (106, 111))	('KCTD1', 'Gene', (91, 96))
265339	27102149	showed that wild-type FGFR fusions, and not the mutant forms induce tumor growth in vivo via ligand-independent autophosphorylation and activation of the MAPK signaling pathway.	('tumor', 'Disease', (68, 73))	('FGFR', 'Gene', (22, 26))	('induce', 'PosReg', (61, 67))	('MAPK', 'Gene', (154, 158))	('MAPK', 'Gene', '5595;5594;5595', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('activation', 'PosReg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('fusions', 'Var', (27, 34))
265340	27102149	In addition, there was marked inhibition of FGFR autophosphorylation and cell proliferation by the FGFR inhibitors (BGJ398 and PD173474).	('PD173474', 'Var', (127, 135))	('FGFR', 'Gene', (99, 103))	('FGFR', 'Protein', (44, 48))	('rat', 'Species', '10116', (85, 88))	('PD173474', 'Chemical', '-', (127, 135))	('inhibition', 'NegReg', (30, 40))	('autophosphorylation', 'MPA', (49, 68))	('cell proliferation', 'CPA', (73, 91))	('BGJ398', 'Chemical', 'MESH:C568950', (116, 122))	('BGJ398', 'Gene', (116, 122))
265341	27102149	In a genome-wide and whole transcriptome sequencing on 6 ICC samples with FGFR2 translocations in 3/6 (50%) patients, two out of three patients responded to FGFR2 inhibitors.	('translocations', 'Var', (80, 94))	('patients', 'Species', '9606', (135, 143))	('FGFR2', 'Gene', (74, 79))	('patients', 'Species', '9606', (108, 116))	('responded', 'MPA', (144, 153))
265343	27102149	Another patient with FGFR2-TACC3 fusion who previously achieved a partial response with pazopanib, and subsequently received ponatinib attained stable disease.	('TACC3', 'Gene', '10460', (27, 32))	('TACC3', 'Gene', (27, 32))	('patient', 'Species', '9606', (8, 15))	('pazopanib', 'Chemical', 'MESH:C516667', (88, 97))	('fusion', 'Var', (33, 39))	('ponatinib', 'Chemical', 'MESH:C545373', (125, 134))
265344	27102149	These encouraging results suggest that FGFR2 has the potential to be an actionable molecular target, and that patients who harbor these alterations may benefit from tyrosine-kinase directed therapies.	('tyrosine', 'Chemical', 'MESH:D014443', (165, 173))	('tyrosine-kinase directed', 'MPA', (165, 189))	('benefit', 'PosReg', (152, 159))	('alterations', 'Var', (136, 147))	('FGFR2', 'Gene', (39, 44))	('rat', 'Species', '10116', (140, 143))	('patients', 'Species', '9606', (110, 118))
265345	27102149	An ongoing phase 2 study of BGJ398 (a selective pan-FGFR inhibitor) in patients with advanced or metastatic CCA with FGFR genetic alterations reported promising efficacy (Javle MM et al, 2016 Gastrointestinal Cancer Symposium, J Clin Oncol 34, 2016 (suppl 4S; abstr 335)) The overall RR was 22% (8/36 evaluable patients) and DCR was 75% (27/26 patients).	('BGJ398', 'Chemical', 'MESH:C568950', (28, 34))	('Gastrointestinal Cancer', 'Disease', (192, 215))	('DCR', 'Chemical', '-', (325, 328))	('patients', 'Species', '9606', (71, 79))	('Gastrointestinal Cancer', 'Phenotype', 'HP:0007378', (192, 215))	('BGJ398', 'Gene', (28, 34))	('Cancer', 'Phenotype', 'HP:0002664', (209, 215))	('patients', 'Species', '9606', (311, 319))	('FGFR', 'Gene', (117, 121))	('rat', 'Species', '10116', (134, 137))	('Gastrointestinal Cancer', 'Disease', 'MESH:D004067', (192, 215))	('genetic alterations', 'Var', (122, 141))	('patients', 'Species', '9606', (344, 352))
265353	27102149	A phase II study demonstrated that pembrolizumab led to high RR in colorectal cancer patients with genetic defects in mismatch repair (MMR).	('pembrolizumab', 'Chemical', 'MESH:C582435', (35, 48))	('genetic defects', 'Disease', 'MESH:D030342', (99, 114))	('genetic defects', 'Disease', (99, 114))	('mismatch', 'Var', (118, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('patients', 'Species', '9606', (85, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rat', 'Species', '10116', (24, 27))	('high', 'PosReg', (56, 60))	('colorectal cancer', 'Disease', (67, 84))
265365	27102149	These fusions further activate downstream effectors such as STAT3 and AKT.	('AKT', 'Gene', '207', (70, 73))	('STAT3', 'Gene', '6774', (60, 65))	('AKT', 'Gene', (70, 73))	('STAT3', 'Gene', (60, 65))	('fusions', 'Var', (6, 13))	('activate', 'PosReg', (22, 30))
265366	27102149	The FIG-ROS fusion driver gene has been shown to accelerate tumor growth in an orthotopic allograft mouse model, and that inactivation of the gene portends an antitumor effect.	('inactivation', 'Var', (122, 134))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('mouse', 'Species', '10090', (100, 105))	('raf', 'Gene', '22882', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('ROS', 'Chemical', '-', (8, 11))	('accelerate', 'PosReg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (163, 168))	('raf', 'Gene', (95, 98))	('tumor', 'Disease', (60, 65))	('rat', 'Species', '10116', (55, 58))	('FIG-ROS', 'Gene', (4, 11))
265367	27102149	Notably, TAE684 (an ALK inhibitor) has been shown to inhibit ROS kinase activity, with consequent cell inhibition and cell death in BaF3 cells expressing this fusion protein.	('ROS', 'Protein', (61, 64))	('inhibit', 'NegReg', (53, 60))	('BaF3', 'CellLine', 'CVCL:0161', (132, 136))	('TAE684', 'Var', (9, 15))	('activity', 'MPA', (72, 80))	('cell inhibition', 'CPA', (98, 113))	('TAE684', 'Chemical', 'MESH:C516714', (9, 15))	('cell death', 'CPA', (118, 128))	('ROS', 'Chemical', '-', (61, 64))
265368	27102149	Given the success of crizotinib in attaining an impressive response rate of 48% in ROS1- rearranged non-small cell lung cancer, similar studies in CCA are warranted to evaluate the potential benefit of targeted therapy in patients with ROS fusions.	('non-small cell lung cancer', 'Disease', (100, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('ROS1', 'Chemical', '-', (83, 87))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (104, 126))	('ROS', 'Chemical', '-', (83, 86))	('ROS1- rearranged', 'Var', (83, 99))	('patients', 'Species', '9606', (222, 230))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (100, 126))	('crizotinib', 'Chemical', 'MESH:D000077547', (21, 31))	('rat', 'Species', '10116', (68, 71))	('CCA', 'Disease', (147, 150))	('ROS', 'Chemical', '-', (236, 239))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (100, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
265369	27102149	A phase II trial of crizotinib in patients with ALK, MET or ROS1 alterations is underway (NCT02034981).	('alterations', 'Var', (65, 76))	('ROS1', 'Chemical', '-', (60, 64))	('crizotinib', 'Chemical', 'MESH:D000077547', (20, 30))	('ALK', 'Gene', (48, 51))	('patients', 'Species', '9606', (34, 42))	('rat', 'Species', '10116', (69, 72))	('ROS1', 'Gene', (60, 64))	('MET', 'Gene', (53, 56))
265370	27102149	Constitutive activation of the EGFR, HER2, MET and Insulin growth factor (IGF) receptor or disruption of the PTEN and SMAD4 triggers the downstream activation of PI3K/PTEN/AKT/mTOR signaling pathway.	('PI3', 'Gene', (162, 165))	('SMAD4', 'Gene', (118, 123))	('disruption', 'Var', (91, 101))	('EGFR', 'Protein', (31, 35))	('AKT', 'Gene', (172, 175))	('mTOR', 'Gene', '2475', (176, 180))	('mTOR', 'Gene', (176, 180))	('PTEN', 'Gene', (109, 113))	('activation', 'PosReg', (13, 23))	('HER2', 'Protein', (37, 41))	('PTEN', 'Gene', (167, 171))	('SMAD4', 'Gene', '4089', (118, 123))	('AKT', 'Gene', '207', (172, 175))	('PTEN', 'Gene', '5728', (167, 171))	('PTEN', 'Gene', '5728', (109, 113))	('PI3', 'Gene', '5266', (162, 165))	('MET', 'Protein', (43, 46))
265371	27102149	Dysregulation of this pathway subsequently stimulates cell proliferation, angiogenesis and survival.	('survival', 'CPA', (91, 99))	('cell proliferation', 'CPA', (54, 72))	('Dysregulation', 'Var', (0, 13))	('angiogenesis', 'CPA', (74, 86))	('rat', 'Species', '10116', (66, 69))	('stimulates', 'PosReg', (43, 53))
265373	27102149	The incidence of PIK3CA (a subunit of PI3K) hotspot mutations in CCA ranges from 5% to 34%.	('mutations', 'Var', (52, 61))	('PI3', 'Gene', (38, 41))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('PI3', 'Gene', '5266', (38, 41))	('CCA', 'Disease', (65, 68))
265375	27102149	Dual inhibition of AKT and MTOR with MK-2206 and everolimus (RAD001) has been shown to enhance anti-proliferative effects in CCA.	('everolimus', 'Chemical', 'MESH:D000068338', (49, 59))	('CCA', 'Disease', (125, 128))	('MTOR', 'Gene', '2475', (27, 31))	('anti-proliferative effects', 'CPA', (95, 121))	('AKT', 'Gene', '207', (19, 22))	('enhance', 'PosReg', (87, 94))	('MK-2206', 'Chemical', 'MESH:C548887', (37, 44))	('MTOR', 'Gene', (27, 31))	('AKT', 'Gene', (19, 22))	('MK-2206', 'Var', (37, 44))	('rat', 'Species', '10116', (107, 110))
265385	27102149	Gain of function mutations in KRAS constitutes one of the most frequent mutations in CCA, with the most frequent alteration in codon 12.	('rat', 'Species', '10116', (117, 120))	('CCA', 'Disease', (85, 88))	('KRAS', 'Gene', (30, 34))	('mutations', 'Var', (17, 26))	('Gain of function', 'PosReg', (0, 16))
265388	27102149	In this study, no BRAF V600E mutations were found.	('V600E', 'Mutation', 'rs113488022', (23, 28))	('BRAF', 'Gene', (18, 22))	('V600E', 'Var', (23, 28))
265391	27102149	The most common BRAF gene mutation found in human cancers is V600E, and exists in up to 22% of CCA in one report.	('human', 'Species', '9606', (44, 49))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('CCA', 'Disease', (95, 98))	('cancers', 'Disease', (50, 57))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('BRAF gene', 'Gene', (16, 25))	('V600E', 'Var', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
265392	27102149	In a recent phase II "basket" study of vemurafenib in BRAF V600 mutated non-melanoma cancers, one patient with CCA achieved a durable PR of more than one year.	('patient', 'Species', '9606', (98, 105))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('non-melanoma cancers', 'Disease', (72, 92))	('BRAF V600 mutated', 'Var', (54, 71))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('vemurafenib', 'Chemical', 'MESH:D000077484', (39, 50))	('non-melanoma cancers', 'Disease', 'MESH:D008545', (72, 92))
265400	27102149	Aberrant Notch signaling was first described in acute T-cell lymphoblastic leukemia, and subsequently in CCA.	('Aberrant', 'Var', (0, 8))	('CCA', 'Disease', (105, 108))	('acute T-cell lymphoblastic leukemia', 'Disease', 'MESH:D054218', (48, 83))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (61, 83))	('Notch signaling', 'MPA', (9, 24))	('acute T-cell lymphoblastic leukemia', 'Disease', (48, 83))	('leukemia', 'Phenotype', 'HP:0001909', (75, 83))
265401	27102149	Notch-mediated conversion of hepatocytes into biliary lineage has been shown to promote intrahepatic CCA formation and progression in a mouse model of ICC.	('intrahepatic CCA', 'Disease', (88, 104))	('promote', 'PosReg', (80, 87))	('progression', 'CPA', (119, 130))	('Notch-mediated conversion', 'Var', (0, 25))	('mouse', 'Species', '10090', (136, 141))
265409	27102149	The abrogation of PRKAR1A gene expression has been linked to significant cell inhibition and apoptosis of CC cells via suppression of the JAK/STAT, MAPK, PI3K/AKT and WNT/beta-catenin pathway signaling.	('AKT', 'Gene', '207', (159, 162))	('cell inhibition', 'CPA', (73, 88))	('PI3', 'Gene', '5266', (154, 157))	('beta-catenin', 'Gene', '1499', (171, 183))	('PRKAR1A', 'Gene', '5573', (18, 25))	('AKT', 'Gene', (159, 162))	('PRKAR1A', 'Gene', (18, 25))	('JAK/STAT', 'Pathway', (138, 146))	('MAPK', 'Gene', (148, 152))	('PI3', 'Gene', (154, 157))	('expression', 'MPA', (31, 41))	('MAPK', 'Gene', '5595;5594;5595', (148, 152))	('beta-catenin', 'Gene', (171, 183))	('suppression', 'NegReg', (119, 130))	('apoptosis', 'CPA', (93, 102))	('abrogation', 'Var', (4, 14))
265411	27102149	Aberrant genetic alterations of the Wingless-type MMTV integration site family (Wnt)/beta-catenin signaling cascade has been implicated in tumorigenesis in several studies.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('beta-catenin', 'Gene', '1499', (85, 97))	('rat', 'Species', '10116', (60, 63))	('MMTV', 'Species', '11757', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('rat', 'Species', '10116', (21, 24))	('Aberrant genetic alterations', 'Var', (0, 28))	('beta-catenin', 'Gene', (85, 97))	('implicated', 'Reg', (125, 135))
265419	27102149	Given the promising early evidence of efficacy signal with IDH and FGFR2 inhibitors in early phase trials, additional studies should focus on novel strategies targeting IDH mutations and FGFR2 fusions.	('FGFR2', 'Gene', (67, 72))	('inhibitors', 'Var', (73, 83))	('FGFR2', 'Gene', (187, 192))	('rat', 'Species', '10116', (150, 153))
265432	27816050	A handle of studies have reported that lncRNAs were crucial players in cancer biology, especially contributed to aberrant expression of gene products involved in the progress of numerous of human tumors.	('expression', 'MPA', (122, 132))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('cancer', 'Disease', (71, 77))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('human', 'Species', '9606', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('aberrant', 'Var', (113, 121))
265436	27816050	It has been reported that knockdown of EWSAT1 decreases soft agar colony growth of Ewing sarcoma cell lines, which indicated that EWSAT1 exerted an essential role on the occurrence, development and progression of malignant tumors.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('EWSAT1', 'Gene', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('EWSAT1', 'Gene', (130, 136))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('decreases soft agar colony growth of Ewing sarcoma', 'Disease', 'MESH:C563168', (46, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('malignant tumors', 'Disease', (213, 229))	('knockdown', 'Var', (26, 35))	('malignant tumors', 'Disease', 'MESH:D018198', (213, 229))	('EWSAT1', 'Gene', '283673', (39, 45))	('EWSAT1', 'Gene', '283673', (130, 136))	('decreases soft agar colony growth of Ewing sarcoma', 'Disease', (46, 96))
265440	27816050	We identified EWSAT1 harbors two conserved miR-326/330-5p clusters's cognate sites as the results of overlap for miRDB (http://mirdb.org/cgi-bin/custom_predict/customDetail.cgi) and PITA software (http://132.77.150.113/pubs/mir07/mir07_ prediction.html), and then we made an assumption that EWSAT1 might function as a competing endogenous RNA (ceRNA) for miR-326/330-5p clusters.	('EWSAT1', 'Gene', (14, 20))	('330-5p', 'Chemical', '-', (51, 57))	('EWSAT1', 'Gene', (291, 297))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('EWSAT1', 'Gene', '283673', (14, 20))	('miR-326/330-5p clusters', 'Var', (355, 378))	('330-5p', 'Chemical', '-', (363, 369))	('EWSAT1', 'Gene', '283673', (291, 297))
265441	27816050	Then, we searched microRNA.org, TargetScan, and PicTar for underlying targets of miR-326/330-5p that owned oncogenic characteristics, and found cyclin D1, a known oncogene, was an underlying target of miR-326/330-5p clusters.	('330-5p', 'Chemical', '-', (89, 95))	('330-5p', 'Chemical', '-', (209, 215))	('miR-326/330-5p', 'Var', (81, 95))	('cyclin D1', 'Gene', '595', (144, 153))	('cyclin D1', 'Gene', (144, 153))
265442	27816050	Collectively, we identified EWSAT1 might be a crucial oncogenic regulator involved in NPC progression via functioning as a ceRNA for miR-326/330-5p clusters, and in return initiating cyclin D1 pathway.	('NPC', 'Gene', '4864', (86, 89))	('cyclin D1', 'Gene', '595', (183, 192))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('EWSAT1', 'Gene', '283673', (28, 34))	('cyclin D1', 'Gene', (183, 192))	('330-5p', 'Chemical', '-', (141, 147))	('miR-326/330-5p clusters', 'Var', (133, 156))	('initiating', 'PosReg', (172, 182))	('EWSAT1', 'Gene', (28, 34))	('NPC', 'Gene', (86, 89))
265448	27816050	Moreover, Kaplan-Meier analysis indicated that high EWSAT1 expression was related to a poorer OS (log-rank test, P =0.0014, Fig.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('EWSAT1', 'Gene', '283673', (52, 58))	('high', 'Var', (47, 51))	('expression', 'MPA', (59, 69))	('EWSAT1', 'Gene', (52, 58))	('si', 'Chemical', 'MESH:D012825', (65, 67))
265449	27816050	These results demonstrated that high EWSAT1 expression was related to poor prognosis, and over-expression of EWSAT1 might be essential in NPC progression.	('EWSAT1', 'Gene', '283673', (109, 115))	('high', 'Var', (32, 36))	('NPC', 'Gene', (138, 141))	('expression', 'MPA', (44, 54))	('si', 'Chemical', 'MESH:D012825', (149, 151))	('EWSAT1', 'Gene', (37, 43))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('over-expression', 'PosReg', (90, 105))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('EWSAT1', 'Gene', (109, 115))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('NPC', 'Gene', '4864', (138, 141))	('EWSAT1', 'Gene', '283673', (37, 43))
265452	27816050	Firstly, we established NPC cell lines (CNE-1 and SUNE-1) with EWSAT1 stable over-expression or transient knockdown (Using RNAi).	('CNE-1', 'CellLine', 'CVCL:6888', (40, 45))	('SUNE-1', 'CellLine', 'CVCL:6946', (50, 56))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('NPC', 'Gene', (24, 27))	('NPC', 'Gene', '4864', (24, 27))	('EWSAT1', 'Gene', '283673', (63, 69))	('knockdown', 'Var', (106, 115))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('over-expression', 'PosReg', (77, 92))	('EWSAT1', 'Gene', (63, 69))	('si', 'Chemical', 'MESH:D012825', (100, 102))
265453	27816050	And then, trypan blue staining, colony formation as well as CCK8 assay were conducted to explore the role of EWSAT1 on NPC cell growth, and results demonstrated silence of EWSAT1 induced a reduction in the cell growth of CNE-1 and SUNE-1 cells than that of in their blank counterparts (Fig.	('cell growth', 'CPA', (206, 217))	('EWSAT1', 'Gene', '283673', (109, 115))	('SUNE-1', 'CellLine', 'CVCL:6946', (231, 237))	('CNE-1', 'CPA', (221, 226))	('EWSAT1', 'Gene', '283673', (172, 178))	('EWSAT1', 'Gene', (109, 115))	('CNE-1', 'CellLine', 'CVCL:6888', (221, 226))	('NPC', 'Gene', (119, 122))	('EWSAT1', 'Gene', (172, 178))	('reduction', 'NegReg', (189, 198))	('NPC', 'Gene', '4864', (119, 122))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('trypan blue', 'Chemical', 'MESH:D014343', (10, 21))	('silence', 'Var', (161, 168))
265458	27816050	In miRDB, miRNAs with target score>=50 were selected, and in PITA, miRNAs with target score target score DeltaDeltaG<=-10 kcal/mol were selected, then intersection was conducted in the selected miRNAs in miRDB and PITA, and miR-326 and miR-330-5p were got as the candidate miRNAs (Table S1-2).	('miR-330', 'Gene', (236, 243))	('miR-326', 'Var', (224, 231))	('miR-330', 'Gene', '442902', (236, 243))	('330-5p', 'Chemical', '-', (240, 246))
265459	27816050	To further verify whether miR-326/330-5p were enrichment in EWSAT1, we applied a pull-down assay by a biotin-labeled specific EWSAT1 probe.	('EWSAT1', 'Gene', '283673', (126, 132))	('330-5p', 'Chemical', '-', (34, 40))	('EWSAT1', 'Gene', '283673', (60, 66))	('biotin', 'Chemical', 'MESH:D001710', (102, 108))	('EWSAT1', 'Gene', (126, 132))	('EWSAT1', 'Gene', (60, 66))	('miR-326/330-5p', 'Var', (26, 40))
265461	27816050	Results revealed that miR-326/330-5p were much richer in precipitate of EWSAT1 probe than that of in NC probe (Fig.	('330-5p', 'Chemical', '-', (30, 36))	('EWSAT1', 'Gene', '283673', (72, 78))	('precipitate', 'MPA', (57, 68))	('miR-326/330-5p', 'Var', (22, 36))	('EWSAT1', 'Gene', (72, 78))
265462	27816050	These results reveal that miR-326/330-5p directly bind to EWSAT1 at the recognitive sites.	('330-5p', 'Chemical', '-', (34, 40))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('bind', 'Interaction', (50, 54))	('EWSAT1', 'Gene', '283673', (58, 64))	('EWSAT1', 'Gene', (58, 64))	('miR-326/330-5p', 'Var', (26, 40))
265463	27816050	Moreover, up-regulated miR-326/330-5p in CNE-1 and SUNE-1 cells, which stably over-expressed EWSAT1, significantly reversed the favorable roles of EWSAT1 on cell growth in NPC cells (Fig.	('EWSAT1', 'Gene', (93, 99))	('over-expressed', 'PosReg', (78, 92))	('NPC', 'Gene', '4864', (172, 175))	('330-5p', 'Chemical', '-', (31, 37))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('EWSAT1', 'Gene', '283673', (147, 153))	('CNE-1', 'CellLine', 'CVCL:6888', (41, 46))	('EWSAT1', 'Gene', '283673', (93, 99))	('cell growth', 'CPA', (157, 168))	('miR-326/330-5p', 'Var', (23, 37))	('EWSAT1', 'Gene', (147, 153))	('SUNE-1', 'CellLine', 'CVCL:6946', (51, 57))	('NPC', 'Gene', (172, 175))	('up-regulated', 'PosReg', (10, 22))
265464	27816050	These data indicated that EWSAT1 facilitated cell growth through binding miR-326/330-5p on NPC cells.	('EWSAT1', 'Gene', '283673', (26, 32))	('facilitated', 'PosReg', (33, 44))	('EWSAT1', 'Gene', (26, 32))	('binding', 'Interaction', (65, 72))	('NPC', 'Gene', (91, 94))	('miR-326/330-5p', 'Var', (73, 87))	('NPC', 'Gene', '4864', (91, 94))	('330-5p', 'Chemical', '-', (81, 87))	('cell growth', 'CPA', (45, 56))
265465	27816050	Having verified EWSAT1 was a target of miR-326/330-5p, the mechanism of miR-326/330-5p in EWSAT1-induced inhibition on NPC cells was still unknown.	('EWSAT1', 'Gene', (16, 22))	('330-5p', 'Chemical', '-', (80, 86))	('miR-326/330-5p', 'Var', (72, 86))	('EWSAT1', 'Gene', '283673', (90, 96))	('miR-326/330-5p', 'Var', (39, 53))	('NPC', 'Gene', (119, 122))	('330-5p', 'Chemical', '-', (47, 53))	('EWSAT1', 'Gene', (90, 96))	('NPC', 'Gene', '4864', (119, 122))	('EWSAT1', 'Gene', '283673', (16, 22))
265466	27816050	Both miR-326 and miR-330-5p repressed cell growth in NPC cell lines, while over-expressed EWSAT1 in miR-326 or miR-330-5p treated cells, significantly reversed the growth-inhibitory role of miR-326/330-5p in CNE-1 and SUNE-1 cells (Fig.	('EWSAT1', 'Gene', '283673', (90, 96))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('330-5p', 'Chemical', '-', (198, 204))	('over-expressed', 'PosReg', (75, 89))	('miR-330', 'Gene', (111, 118))	('miR-330', 'Gene', '442902', (111, 118))	('cell growth', 'CPA', (38, 49))	('NPC', 'Gene', (53, 56))	('EWSAT1', 'Gene', (90, 96))	('SUNE-1', 'CellLine', 'CVCL:6946', (218, 224))	('330-5p', 'Chemical', '-', (21, 27))	('330-5p', 'Chemical', '-', (115, 121))	('miR-326', 'Var', (5, 12))	('NPC', 'Gene', '4864', (53, 56))	('CNE-1', 'CellLine', 'CVCL:6888', (208, 213))	('growth-inhibitory', 'CPA', (164, 181))	('reversed', 'NegReg', (151, 159))	('miR-330', 'Gene', '442902', (17, 24))	('miR-330', 'Gene', (17, 24))
265467	27816050	These results confirmed that miR-326/330-5p made sense in EWSAT1-induced inhibitory roles on NPC cells.	('NPC', 'Gene', (93, 96))	('inhibitory roles', 'MPA', (73, 89))	('EWSAT1', 'Gene', '283673', (58, 64))	('NPC', 'Gene', '4864', (93, 96))	('miR-326/330-5p', 'Var', (29, 43))	('330-5p', 'Chemical', '-', (37, 43))	('EWSAT1', 'Gene', (58, 64))
265469	27816050	To explore the function of miR-326/330-5p on NPC, we screen Targetscan, miRanda, PicTar to select potential predicted targets of miR-326/330-5p.	('NPC', 'Gene', (45, 48))	('330-5p', 'Chemical', '-', (137, 143))	('miR-326/330-5p', 'Var', (129, 143))	('NPC', 'Gene', '4864', (45, 48))	('330-5p', 'Chemical', '-', (35, 41))
265471	27816050	These revealed that cyclin D1 could be a direct target of miR-326/330-5p in NPC.	('miR-326/330-5p', 'Var', (58, 72))	('NPC', 'Gene', (76, 79))	('330-5p', 'Chemical', '-', (66, 72))	('NPC', 'Gene', '4864', (76, 79))	('cyclin D1', 'Gene', '595', (20, 29))	('cyclin D1', 'Gene', (20, 29))
265472	27816050	Next, we used luciferase reporter assays to verify whether cyclin D1 expression are really regulated by miR-326/330-5p, and results demonstrate that miR-326/330-5p inhibits luciferase activity in CNE-1 cells and SUNE-1 cells at the reporter plasmid with a WT cyclin D1 3'-UTR, but no significant inhibition was observed at the reporter plasmid with a mutant cyclin D1 3'-UTR (Fig.	('330-5p', 'Chemical', '-', (157, 163))	('cyclin D1', 'Gene', '595', (358, 367))	('inhibits', 'NegReg', (164, 172))	('luciferase', 'Enzyme', (173, 183))	('cyclin D1', 'Gene', '595', (259, 268))	('cyclin D1', 'Gene', (358, 367))	('cyclin D1', 'Gene', (259, 268))	('activity', 'MPA', (184, 192))	('si', 'Chemical', 'MESH:D012825', (284, 286))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('CNE-1', 'CellLine', 'CVCL:6888', (196, 201))	('SUNE-1', 'CellLine', 'CVCL:6946', (212, 218))	('miR-326/330-5p', 'Var', (149, 163))	('cyclin D1', 'Gene', '595', (59, 68))	('330-5p', 'Chemical', '-', (112, 118))	('cyclin D1', 'Gene', (59, 68))
265473	27816050	We next investigated the mechanism of miR-326/330-5p on NPC cell growth.	('NPC', 'Gene', '4864', (56, 59))	('330-5p', 'Chemical', '-', (46, 52))	('miR-326/330-5p', 'Var', (38, 52))	('NPC', 'Gene', (56, 59))
265474	27816050	Results of Trypan blue staining demonstrated both miR-326/330-5p and si-CCND1 treatment decreased cell growth of CNE-1 and SUNE-1 cells in comparison to that of in their blank counterparts (Fig.	('330-5p', 'Chemical', '-', (58, 64))	('CNE-1', 'CellLine', 'CVCL:6888', (113, 118))	('SUNE-1', 'CellLine', 'CVCL:6946', (123, 129))	('si-CCND1', 'Gene', (69, 77))	('cell growth', 'CPA', (98, 109))	('decreased', 'NegReg', (88, 97))	('miR-326/330-5p', 'Var', (50, 64))	('si', 'Chemical', 'MESH:D012825', (69, 71))
265475	27816050	4D), However, when treated CNE-1 and SUNE-1 cells with EWSAT1 plus si-CCND1, the favorable role of EWSAT1 on cell growth was inhibited by cyclin D1 knockdown, and the negative effect of si-CCND1 was alleviated by EWSAT1 over-expression (Fig.	('cyclin D1', 'Gene', (138, 147))	('EWSAT1', 'Gene', '283673', (213, 219))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('over-expression', 'PosReg', (220, 235))	('EWSAT1', 'Gene', (99, 105))	('SUNE-1', 'CellLine', 'CVCL:6946', (37, 43))	('si', 'Chemical', 'MESH:D012825', (231, 233))	('cell growth', 'CPA', (109, 120))	('EWSAT1', 'Gene', (213, 219))	('CNE-1', 'CellLine', 'CVCL:6888', (27, 32))	('EWSAT1', 'Gene', '283673', (55, 61))	('EWSAT1', 'Gene', '283673', (99, 105))	('si-CCND1', 'Var', (186, 194))	('inhibited', 'NegReg', (125, 134))	('si', 'Chemical', 'MESH:D012825', (186, 188))	('cyclin D1', 'Gene', '595', (138, 147))	('si-CCND1', 'Var', (67, 75))	('EWSAT1', 'Gene', (55, 61))
265476	27816050	Additionally, we next investigated the effect of EWSAT1 and miR-326/330-5p on the protein expression of cyclin D1.	('cyclin D1', 'Gene', '595', (104, 113))	('miR-326/330-5p', 'Var', (60, 74))	('cyclin D1', 'Gene', (104, 113))	('EWSAT1', 'Gene', '283673', (49, 55))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('investigated', 'Reg', (22, 34))	('330-5p', 'Chemical', '-', (68, 74))	('EWSAT1', 'Gene', (49, 55))
265477	27816050	Results revealed that both miR-326/330-5p and si-CCND1 treatment inhibited protein expression of cyclin D1, while EWSAT1 treatment significantly increased protein expression of cyclin D1 in CNE-1 and SUNE-1 cells (Fig.	('cyclin D1', 'Gene', (97, 106))	('si', 'Chemical', 'MESH:D012825', (169, 171))	('cyclin D1', 'Gene', (177, 186))	('protein expression', 'MPA', (155, 173))	('EWSAT1', 'Gene', '283673', (114, 120))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('cyclin D1', 'Gene', '595', (97, 106))	('protein expression', 'MPA', (75, 93))	('cyclin D1', 'Gene', '595', (177, 186))	('inhibited', 'NegReg', (65, 74))	('EWSAT1', 'Gene', (114, 120))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('increased', 'PosReg', (145, 154))	('SUNE-1', 'CellLine', 'CVCL:6946', (200, 206))	('si', 'Chemical', 'MESH:D012825', (131, 133))	('330-5p', 'Chemical', '-', (35, 41))	('miR-326/330-5p', 'Var', (27, 41))	('CNE-1', 'CellLine', 'CVCL:6888', (190, 195))	('si-CCND1', 'Var', (46, 54))
265478	27816050	However, when treated CNE-1 and SUNE-1 cells with EWSAT1 plus si-CCND1, the favorable role of EWSAT1 on protein expression of cyclin D1 was inhibited by cyclin D1 knockdown, and the negative effect of si-CCND1 was alleviated by EWSAT1 over-expression (Fig.	('EWSAT1', 'Gene', (228, 234))	('si', 'Chemical', 'MESH:D012825', (201, 203))	('cyclin D1', 'Gene', (153, 162))	('inhibited', 'NegReg', (140, 149))	('si-CCND1', 'Var', (62, 70))	('EWSAT1', 'Gene', '283673', (50, 56))	('CNE-1', 'CellLine', 'CVCL:6888', (22, 27))	('over-expression', 'PosReg', (235, 250))	('cyclin D1', 'Gene', '595', (153, 162))	('knockdown', 'Var', (163, 172))	('si', 'Chemical', 'MESH:D012825', (246, 248))	('si-CCND1', 'Var', (201, 209))	('cyclin D1', 'Gene', (126, 135))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('EWSAT1', 'Gene', (50, 56))	('protein expression', 'MPA', (104, 122))	('EWSAT1', 'Gene', '283673', (94, 100))	('cyclin D1', 'Gene', '595', (126, 135))	('EWSAT1', 'Gene', '283673', (228, 234))	('SUNE-1', 'CellLine', 'CVCL:6946', (32, 38))	('EWSAT1', 'Gene', (94, 100))
265481	27816050	Marques et al reported EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis.	('EWSAT1', 'Gene', '283673', (23, 29))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('Ewing sarcoma oncogenesis', 'Disease', (67, 92))	('EWSAT1', 'Gene', (23, 29))	('facilitates', 'PosReg', (55, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('gene repression', 'Var', (39, 54))	('Ewing sarcoma oncogenesis', 'Disease', 'MESH:C563168', (67, 92))
265485	27816050	EWSAT1 was revealed as a direct target of miR-326/330-5p clusters, and there was an interactive suppression between them.	('interactive', 'Interaction', (84, 95))	('EWSAT1', 'Gene', '283673', (0, 6))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('330-5p', 'Chemical', '-', (50, 56))	('miR-326/330-5p clusters', 'Var', (42, 65))	('EWSAT1', 'Gene', (0, 6))
265499	27816050	Recent studies indicated miR-326/330-5p showed tumor suppressive role on lung cancer, breast cancer, malignant melanoma, colorectal cancer, and glioblastoma, while their role on NPC had not been investigated.	('miR-326/330-5p', 'Var', (25, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('colorectal cancer', 'Disease', (121, 138))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('breast cancer', 'Disease', (86, 99))	('NPC', 'Gene', (178, 181))	('malignant melanoma', 'Disease', (101, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('NPC', 'Gene', '4864', (178, 181))	('tumor', 'Disease', (47, 52))	('glioblastoma', 'Disease', (144, 156))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('330-5p', 'Chemical', '-', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('malignant melanoma', 'Phenotype', 'HP:0002861', (101, 119))	('lung cancer', 'Disease', (73, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('malignant melanoma', 'Disease', 'MESH:D008545', (101, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
265500	27816050	In our present study, miR-326/330-5p inhibited growth in NPC cell lines.	('inhibited', 'NegReg', (37, 46))	('growth in', 'CPA', (47, 56))	('NPC', 'Gene', (57, 60))	('330-5p', 'Chemical', '-', (30, 36))	('NPC', 'Gene', '4864', (57, 60))	('miR-326/330-5p', 'Var', (22, 36))
265501	27816050	More-over, biotin-avidin pull-down system demonstrated EWSAT1 could pull down miR-326/330-5p.	('pull', 'Reg', (68, 72))	('miR-326/330-5p', 'Var', (78, 92))	('biotin', 'Chemical', 'MESH:D001710', (11, 17))	('330-5p', 'Chemical', '-', (86, 92))	('EWSAT1', 'Gene', '283673', (55, 61))	('EWSAT1', 'Gene', (55, 61))
265503	27816050	Having shown the critical role of miR-326/330-5p on suppressing NPC progression, we searched for the potential gene effectors involved in its function.	('330-5p', 'Chemical', '-', (42, 48))	('miR-326/330-5p', 'Var', (34, 48))	('suppressing', 'NegReg', (52, 63))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('NPC', 'Gene', (64, 67))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('NPC', 'Gene', '4864', (64, 67))
265507	27816050	But among all of the predicted target genes for miR-326/330-5p clusters, we found that cyclin D1 acted as a crucial effector of miR-326/330-5p.	('cyclin D1', 'Gene', (87, 96))	('330-5p', 'Chemical', '-', (56, 62))	('miR-326/330-5p', 'Var', (128, 142))	('cyclin D1', 'Gene', '595', (87, 96))	('330-5p', 'Chemical', '-', (136, 142))
265508	27816050	Aberrant cyclin D1 expression has been associated to several types of cancers.	('expression', 'MPA', (19, 29))	('Aberrant', 'Var', (0, 8))	('cyclin D1', 'Gene', '595', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cyclin D1', 'Gene', (9, 18))	('associated', 'Reg', (39, 49))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('cancers', 'Disease', (70, 77))
265509	27816050	Using bio-informatics, we verified cyclin D1 as a direct target of miR-326/330-5p, and luciferase reporter assays confirmed that miR-326/330-5p targeted cyclin D1 mRNA at its 3'-UTR.	('330-5p', 'Chemical', '-', (137, 143))	('cyclin D1', 'Gene', (35, 44))	('targeted', 'Reg', (144, 152))	('miR-326/330-5p', 'Var', (129, 143))	('cyclin D1', 'Gene', '595', (153, 162))	('mRNA', 'MPA', (163, 167))	('cyclin D1', 'Gene', (153, 162))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('330-5p', 'Chemical', '-', (75, 81))	('cyclin D1', 'Gene', '595', (35, 44))
265510	27816050	Moreover, our results also demonstrated miR-326/330-5p clusters exerted its tumor suppressive role on NPC through targeting cyclin D1.	('330-5p', 'Chemical', '-', (48, 54))	('cyclin D1', 'Gene', '595', (124, 133))	('miR-326/330-5p clusters', 'Var', (40, 63))	('cyclin D1', 'Gene', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('NPC', 'Gene', (102, 105))	('NPC', 'Gene', '4864', (102, 105))	('targeting', 'Reg', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
265511	27816050	Interesting, we found that when treated CNE-1 and SUNE-1 cells with EWSAT1 plus si-CCND1, the negative effect of si-CCND1 was alleviated by EWSAT1 over-expression.	('CNE-1', 'CellLine', 'CVCL:6888', (40, 45))	('si-CCND1', 'Var', (113, 121))	('SUNE-1', 'CellLine', 'CVCL:6946', (50, 56))	('EWSAT1', 'Gene', '283673', (140, 146))	('EWSAT1', 'Gene', '283673', (68, 74))	('EWSAT1', 'Gene', (140, 146))	('EWSAT1', 'Gene', (68, 74))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('si-CCND1', 'Var', (80, 88))	('si', 'Chemical', 'MESH:D012825', (80, 82))
265513	27816050	Those effects could be partially attributed to EWSAT1 functioning as a ceRNA for miR-326/330-3p.	('EWSAT1', 'Gene', '283673', (47, 53))	('EWSAT1', 'Gene', (47, 53))	('miR-326/330-3p', 'Var', (81, 95))
265515	27816050	In conclusion, our data reveal that high-expressed EWSAT1 is an oncogenic lncRNA that facilitates the oncogenisis and progression of NPC through miR-326/330-5p-cyclin D1 axis.	('cyclin D1', 'Gene', '595', (160, 169))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('cyclin D1', 'Gene', (160, 169))	('facilitates', 'PosReg', (86, 97))	('EWSAT1', 'Gene', '283673', (51, 57))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('NPC', 'Gene', (133, 136))	('high-expressed', 'Var', (36, 50))	('330-5p', 'Chemical', '-', (153, 159))	('si', 'Chemical', 'MESH:D012825', (125, 127))	('EWSAT1', 'Gene', (51, 57))	('NPC', 'Gene', '4864', (133, 136))	('progression', 'CPA', (118, 129))	('oncogenisis', 'CPA', (102, 113))
265530	27816050	The cells were washed with 1x PBS (pH7.4) and then transiently transfected with 100 nM NC or pcDNA3.1-CT-GFP-EWSAT1, si-EWSAT1, miR-326, miR-330-5p, or si-CCND1, using Lipofectamine  2000 (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions.	('EWSAT1', 'Gene', '283673', (109, 115))	('EWSAT1', 'Gene', '283673', (120, 126))	('si', 'Chemical', 'MESH:D012825', (152, 154))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('PBS', 'Chemical', 'MESH:D007854', (30, 33))	('330-5p', 'Chemical', '-', (141, 147))	('miR-326', 'Var', (128, 135))	('EWSAT1', 'Gene', (109, 115))	('EWSAT1', 'Gene', (120, 126))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('miR-330', 'Gene', '442902', (137, 144))	('Lipofectamine  2000', 'Chemical', 'MESH:C086724', (168, 187))	('miR-330', 'Gene', (137, 144))	('si-CCND1', 'Var', (152, 160))	('si', 'Chemical', 'MESH:D012825', (55, 57))
265544	27816050	Oligonucleotides containing the wild-type (WT) or mutant (MT) puptative miR-330-5p or miR-326 binding sites of the 3'-untranslated regions (3'-UTR) of the CCND1 mRNA were ligated into the pMIR-REPORT luciferase reporter plasmid vector (see in http://www.addgene.org/browse/sequence_vdb/3582/), respectively.	('miR-330', 'Gene', (72, 79))	('miR-330', 'Gene', '442902', (72, 79))	('330-5p', 'Chemical', '-', (76, 82))	('mutant', 'Var', (50, 56))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('miR-326', 'Gene', (86, 93))	('CCND1', 'Gene', (155, 160))
265551	27816050	The CNE-1 and SUNE-1 cells were seeded in 24-well culture plates at a density of 3 x 105 cells per well, and the cells were then transfected with Vector, miR-326, miR-330-5p, pcDNA3.1-CT-GFP-EWSAT1, miR-326 plus pcDNA3.1-CT-GFP-EWSAT1, or miR-330-5p plus pcDNA3.1-CT-GFP-EWSAT1.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('miR-326', 'Var', (199, 206))	('EWSAT1', 'Gene', (191, 197))	('EWSAT1', 'Gene', (228, 234))	('CNE-1', 'CellLine', 'CVCL:6888', (4, 9))	('miR-330', 'Gene', (163, 170))	('EWSAT1', 'Gene', '283673', (271, 277))	('miR-330', 'Gene', '442902', (163, 170))	('330-5p', 'Chemical', '-', (167, 173))	('miR-330', 'Gene', '442902', (239, 246))	('EWSAT1', 'Gene', (271, 277))	('miR-326', 'Var', (154, 161))	('SUNE-1', 'CellLine', 'CVCL:6946', (14, 20))	('miR-330', 'Gene', (239, 246))	('EWSAT1', 'Gene', '283673', (228, 234))	('EWSAT1', 'Gene', '283673', (191, 197))	('330-5p', 'Chemical', '-', (243, 249))
265565	27671553	In this report, we show that silencing of EWS-FLI1 with either siRNA or small-molecule EWS-FLI1 inhibitors suppressed the expression of ENT1, ENT2, and TK1 and thus decreased 18F-FLT PET activity.	('decreased', 'NegReg', (165, 174))	('EWS-FLI1', 'Gene', '2130;2313', (42, 50))	('expression', 'MPA', (122, 132))	('EWS-FLI1', 'Gene', '2130;2313', (87, 95))	('18F-FLT PET activity', 'CPA', (175, 195))	('silencing', 'Var', (29, 38))	('ENT1', 'Gene', '2030', (136, 140))	('ENT2', 'Gene', '3177', (142, 146))	('suppressed', 'NegReg', (107, 117))	('ENT2', 'Gene', (142, 146))	('TK1', 'Gene', (152, 155))	('EWS-FLI1', 'Gene', (42, 50))	('TK1', 'Gene', '7083', (152, 155))	('EWS-FLI1', 'Gene', (87, 95))	('ENT1', 'Gene', (136, 140))
265570	27671553	Silencing of EWS-FLI1 has been shown to limit anchorage-independent growth, to put the cell in a more dedifferentiated state, and to limit the ability of the cells to continue to proliferate.	('anchorage-independent growth', 'CPA', (46, 74))	('put', 'Reg', (79, 82))	('EWS-FLI1', 'Gene', (13, 21))	('EWS-FLI1', 'Gene', '2130;2313', (13, 21))	('Silencing', 'Var', (0, 9))	('limit', 'NegReg', (133, 138))	('limit', 'NegReg', (40, 45))
265583	27671553	We found limited suppression of the majority of these targets, except for three proteins responsible for 18F-FLT activity, all of which were significantly suppressed with silencing of EWS-FLI1 (see arrows, Fig.	('EWS-FLI1', 'Gene', '2130;2313', (184, 192))	('suppressed', 'NegReg', (155, 165))	('silencing', 'Var', (171, 180))	('EWS-FLI1', 'Gene', (184, 192))
265588	27671553	It is not incorporated into newly synthesized DNA and is less prone to catabolism due to the replacement of the hydroxyl group at the 3' position with the fluorine tag.	('fluorine', 'Chemical', 'MESH:D005461', (155, 163))	('replacement', 'Var', (93, 104))	('catabolism', 'MPA', (71, 81))
265594	27671553	One study established the importance of context for the activity of the tracer, showing that it is most sensitive in the setting of high nucleoside transporter expression, high TK1, and an agent that induced cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (208, 225))	('nucleoside', 'Chemical', 'MESH:D009705', (137, 147))	('TK1', 'Gene', (177, 180))	('TK1', 'Gene', '7083', (177, 180))	('high', 'Var', (172, 176))	('high nucleoside transporter expression', 'MPA', (132, 170))
265595	27671553	We confirmed that silencing of EWS-FLI1 repressed the mRNA expression of ENT1, ENT2, and TK1 in four Ewing sarcoma cell lines (Fig.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('silencing', 'Var', (18, 27))	('mRNA expression', 'MPA', (54, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('ENT1', 'Gene', (73, 77))	('ENT2', 'Gene', '3177', (79, 83))	('TK1', 'Gene', '7083', (89, 92))	('ENT2', 'Gene', (79, 83))	('EWS-FLI1', 'Gene', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('ENT1', 'Gene', '2030', (73, 77))	('Ewing sarcoma', 'Disease', (101, 114))	('EWS-FLI1', 'Gene', '2130;2313', (31, 39))	('TK1', 'Gene', (89, 92))
265603	27671553	In addition, we showed that the second-generation mithramycin analogs EC-8042 and EC-8105 also suppressed expression of those three molecules in a highly significant manner (Fig.	('suppressed', 'NegReg', (95, 105))	('expression', 'MPA', (106, 116))	('EC-8042', 'Var', (70, 77))	('EC-8042', 'Chemical', 'MESH:C576677', (70, 77))	('EC-8105', 'Var', (82, 89))	('EC-8105', 'Chemical', '-', (82, 89))	('mithramycin', 'Chemical', 'MESH:D008926', (50, 61))
265608	27671553	18F-FLT activity was markedly suppressed with silencing of EWS-FLI1 by siRNA, but not when a non-targeting siRNA (control) was used (Fig.	('18F-FLT activity', 'CPA', (0, 16))	('suppressed', 'NegReg', (30, 40))	('silencing', 'Var', (46, 55))	('EWS-FLI1', 'Gene', (59, 67))	('EWS-FLI1', 'Gene', '2130;2313', (59, 67))
265615	27671553	Additionally, treatment of TC32 cells with 50 nM MMA, 50 nM EC8042 and 15 nM EC8105 for the same duration utilized above caused no significant suppression of 18F-FDG activity (Fig.	('EC8042', 'Var', (60, 66))	('18F-FDG', 'CPA', (158, 165))	('TC32', 'CellLine', 'CVCL:7151', (27, 31))	('18F-FDG', 'Chemical', '-', (158, 165))	('EC', 'Chemical', '-', (77, 79))	('EC', 'Chemical', '-', (60, 62))	('suppression', 'NegReg', (143, 154))	('MMA', 'Chemical', '-', (49, 52))
265621	27671553	Silencing of EWS-FLI1 with siRNA caused a marked arrest of TC32 cells in G1, from 40.8% (SEM +/- 3.0) to 60.8 (SEM +/- 3.1) (Fig.	('TC32', 'CellLine', 'CVCL:7151', (59, 63))	('arrest', 'NegReg', (49, 55))	('EWS-FLI1', 'Gene', (13, 21))	('EWS-FLI1', 'Gene', '2130;2313', (13, 21))	('Silencing', 'Var', (0, 9))
265622	27671553	This G1 arrest was phenocopied with mithramycin and EC-8042 in particular (Fig.	('EC-8042', 'Var', (52, 59))	('G1 arrest', 'Disease', (5, 14))	('EC-8042', 'Chemical', 'MESH:C576677', (52, 59))	('mithramycin', 'Chemical', 'MESH:D008926', (36, 47))
265623	27671553	In contrast, EC-8105 did not cause a G1 arrest and instead increased the percentage of cells in S-phase from 17.4 (SEM +/- 1.7) to 25.8 (SEM +/- 3).	('SEM +/- 1', 'Gene', '7979', (115, 124))	('SEM +/- 1', 'Gene', (115, 124))	('EC-8105', 'Var', (13, 20))	('increased', 'PosReg', (59, 68))	('EC-8105', 'Chemical', '-', (13, 20))
265626	27671553	These results show that in Ewing sarcoma cells, blockade of EWS-FLI1 leads to an inability of cells to take up and retain 18F-FLT and this effect is the major determinant of activity in this cell type in the setting of EWS-FLI1 directed therapy.	('EWS-FLI1', 'Gene', (60, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (27, 40))	('Ewing sarcoma', 'Disease', (27, 40))	('blockade', 'Var', (48, 56))	('EWS-FLI1', 'Gene', (219, 227))	('EWS-FLI1', 'Gene', '2130;2313', (60, 68))	('inability', 'NegReg', (81, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (27, 40))	('EWS-FLI1', 'Gene', '2130;2313', (219, 227))
265632	27671553	Again, marked suppression of 18F-FLT activity was observed in vivo (particularly at 24 h) and was most prominent with EC-8042, consistent with an EWS-FLI1-specific effect (Fig.	('EWS-FLI1', 'Gene', '2130;2313', (146, 154))	('suppression', 'NegReg', (14, 25))	('18F-FLT', 'CPA', (29, 36))	('EC-8042', 'Chemical', 'MESH:C576677', (118, 125))	('EC-8042', 'Var', (118, 125))	('EWS-FLI1', 'Gene', (146, 154))
265636	27671553	Interestingly, EC-8042 showed the greatest degree of suppression of 18F-FLT activity and the most marked changes in staining, which correlates with the most profound response to treatment that we recently reported.	('EC-8042', 'Chemical', 'MESH:C576677', (15, 22))	('EC-8042', 'Var', (15, 22))	('activity', 'MPA', (76, 84))	('changes', 'Reg', (105, 112))	('18F-FLT', 'Protein', (68, 75))	('staining', 'MPA', (116, 124))	('suppression', 'NegReg', (53, 64))
265642	27671553	We show that silencing of EWS-FLI1 leads to a loss in expression of TK1, ENT2 and ENT1.	('expression', 'MPA', (54, 64))	('TK1', 'Gene', (68, 71))	('TK1', 'Gene', '7083', (68, 71))	('loss', 'NegReg', (46, 50))	('ENT1', 'Gene', '2030', (82, 86))	('ENT2', 'Gene', '3177', (73, 77))	('EWS-FLI1', 'Gene', (26, 34))	('ENT2', 'Gene', (73, 77))	('EWS-FLI1', 'Gene', '2130;2313', (26, 34))	('ENT1', 'Gene', (82, 86))	('silencing', 'Var', (13, 22))
265710	27512409	H. pylori infection is consistently associated with gastric carcinoma and all nasopharyngeal carcinoma (NPC) cases are associated with EBV infection, while T-cell leukemia is rare in HTLV-1 negative subjects.	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (78, 102))	('carcinoma', 'Disease', (60, 69))	('H. pylori', 'Species', '210', (0, 9))	('NPC', 'Gene', '4864', (104, 107))	('EBV infection', 'Disease', 'MESH:D020031', (135, 148))	('associated', 'Reg', (119, 129))	('carcinoma', 'Disease', 'MESH:D002277', (60, 69))	('EBV infection', 'Disease', (135, 148))	('infection', 'Var', (10, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('T-cell leukemia', 'Disease', (156, 171))	('carcinoma', 'Disease', (93, 102))	('gastric carcinoma', 'Disease', 'MESH:D013274', (52, 69))	('leukemia', 'Phenotype', 'HP:0001909', (163, 171))	('gastric carcinoma', 'Disease', (52, 69))	('associated', 'Reg', (36, 46))	('T-cell leukemia', 'Disease', 'MESH:D015458', (156, 171))	('NPC', 'Gene', (104, 107))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (52, 69))	('H. pylori infection', 'Phenotype', 'HP:0005202', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('HTLV-1', 'Species', '11908', (183, 189))	('carcinoma', 'Disease', 'MESH:D002277', (93, 102))
265762	27512409	Mirroring the global situation, HPV16 is the most prevalent type among diagnosed cancer cases in NA countries (59 %), followed by HPV-18 (8.6-17 %).	('HPV16', 'Species', '333760', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('prevalent', 'Reg', (50, 59))	('HPV16', 'Var', (32, 37))	('cancer', 'Disease', (81, 87))	('HPV', 'Species', '10566', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('HPV', 'Species', '10566', (130, 133))
265852	27512409	There is a close association between T-cell Leukemia and the presence of antibodies to HTLV-I.	('HTLV-I', 'Species', '11908', (87, 93))	('HTLV-I', 'Gene', (87, 93))	('T-cell Leukemia', 'Disease', (37, 52))	('T-cell Leukemia', 'Disease', 'MESH:D015458', (37, 52))	('Leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('antibodies', 'Var', (73, 83))	('presence', 'Reg', (61, 69))
265938	23801904	The combined metabolic and morphological information of FDG-PET/CT imaging allows a high diagnostic accuracy for the detection of OS; FDG-PET/CT is significantly more accurate than FDG-PET alone and improves staging and restaging in patients with OS.	('FDG-PET/CT', 'Var', (134, 144))	('FDG', 'Chemical', 'MESH:D019788', (181, 184))	('restaging', 'CPA', (220, 229))	('FDG', 'Chemical', 'MESH:D019788', (56, 59))	('OS', 'Phenotype', 'HP:0002669', (130, 132))	('improves', 'PosReg', (199, 207))	('OS', 'Phenotype', 'HP:0002669', (247, 249))	('patients', 'Species', '9606', (233, 241))	('more', 'PosReg', (162, 166))	('FDG', 'Chemical', 'MESH:D019788', (134, 137))	('staging', 'CPA', (208, 215))
265976	23285056	Furthermore, in all protocols the signals of the transduced Atto488-BSA were predominantly punctual consistent with an endosomal localisation.	('punctual', 'MPA', (91, 99))	('Atto488-BSA', 'Var', (60, 71))	('Atto488', 'Chemical', '-', (60, 67))
266034	23285056	The transduction efficiency tests show striking differences in the amount of transduced Atto488-BSA into the cells and cytotoxicity although the percentage of transduced cells is comparable in the experiments using different transduction reagents.	('Atto488', 'Chemical', '-', (88, 95))	('cytotoxicity', 'Disease', 'MESH:D064420', (119, 131))	('Atto488-BSA', 'Var', (88, 99))	('cytotoxicity', 'Disease', (119, 131))
266048	23285056	To test whether the internalised proteins are still active after transduction and PCI treatment the 119 kDa subunit of beta-galactosidase was transduced into sarcoma cells using the Chariot transduction reagent followed by PCI treatment.	('sarcoma', 'Disease', 'MESH:D012509', (158, 165))	('beta-galactosidase', 'Gene', '2720', (119, 137))	('sarcoma', 'Disease', (158, 165))	('beta-galactosidase', 'Gene', (119, 137))	('transduced', 'Var', (142, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
266050	23285056	beta-galactosidase activity was clearly detectable in transduced and PCI treated cell whereas not transduced, PCI treated cells revealed undetectable beta-galactosidase activity (Figure S7).	('transduced', 'Var', (54, 64))	('beta-galactosidase', 'Gene', '2720', (150, 168))	('beta-galactosidase', 'Gene', '2720', (0, 18))	('beta-galactosidase', 'Gene', (150, 168))	('activity', 'MPA', (169, 177))	('activity', 'MPA', (19, 27))	('undetectable beta-galactosidase activity', 'Phenotype', 'HP:0008166', (137, 177))	('beta-galactosidase', 'Gene', (0, 18))	('detectable', 'Reg', (40, 50))
266176	24921409	(2002) observed higher association rates of EdMV to CD46 and a higher cell entry efficiency compared to CD150, respectively.	('association', 'Interaction', (23, 34))	('EdMV', 'Var', (44, 48))	('CD46', 'Gene', (52, 56))	('cell entry efficiency', 'CPA', (70, 91))	('CD150', 'Gene', '6504', (104, 109))	('higher', 'PosReg', (63, 69))	('CD150', 'Gene', (104, 109))	('EdMV', 'Chemical', '-', (44, 48))
266183	24921409	(2001), EdMV replicated selectively in human myeloma cell lines in vitro, displaying syncytial formations and eventual lysis of tumor cells.	('lysis', 'CPA', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('myeloma', 'Disease', 'MESH:D009101', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('EdMV', 'Chemical', '-', (8, 12))	('tumor', 'Disease', (128, 133))	('myeloma', 'Disease', (45, 52))	('human', 'Species', '9606', (39, 44))	('EdMV', 'Var', (8, 12))	('syncytial formations', 'CPA', (85, 105))
266202	24921409	In xenotransplantation studies, Caco-2 adenocarcinomas with a volume of 150-200 mm3 revealed a growth arrest after a single intratumoral injection of the Schwarz MV strain (1.5 x 107 TCID50; tissue culture infective dose 50).	('1.5', 'Var', (173, 176))	('adenocarcinomas', 'Disease', (39, 54))	('growth arrest', 'Disease', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('growth arrest', 'Disease', 'MESH:D006323', (95, 108))	('MV strain', 'Species', '11234', (162, 171))	('Caco-2', 'CellLine', 'CVCL:0025', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('growth arrest', 'Phenotype', 'HP:0001510', (95, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('tumor', 'Disease', (129, 134))	('adenocarcinomas', 'Disease', 'MESH:D000230', (39, 54))
266216	24921409	To further enhance tumor cell specificity and the efficacy of infection, numerous modifications to the measles virus have been performed and led to the development and investigation of selectivity- and efficacy-enhanced, engineered MV strains.	('measles virus', 'Species', '11234', (103, 116))	('enhance', 'PosReg', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('modifications', 'Var', (82, 95))	('tumor', 'Disease', (19, 24))	('MV strain', 'Species', '11234', (232, 241))
266226	24921409	EdMV efficiently entered cells through tumorselective CD38, epidermal growth factor receptor (EGFR) or EGFR mutant vIII (EGFRvIII) in vitro and in vivo by lacking CD46 and SLAM specificity.	('vIII', 'Gene', (115, 119))	('EGFR', 'Gene', '1956', (103, 107))	('vIII', 'Gene', '1351', (125, 129))	('lacking', 'NegReg', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (121, 125))	('vIII', 'Gene', '1351', (115, 119))	('CD38', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('epidermal growth factor receptor', 'Gene', (60, 92))	('epidermal growth factor receptor', 'Gene', '1956', (60, 92))	('CD46', 'Protein', (163, 167))	('EGFR', 'Gene', (103, 107))	('EdMV', 'Chemical', '-', (0, 4))	('vIII', 'Gene', (125, 129))	('EGFR', 'Gene', '1956', (121, 125))	('mutant', 'Var', (108, 114))	('EGFR', 'Gene', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
266227	24921409	Commonly used genetic modifications target cell tropism, as exemplarily shown with a myeloma specific MV.	('cell tropism', 'MPA', (43, 55))	('target', 'Reg', (36, 42))	('myeloma', 'Disease', (85, 92))	('genetic modifications', 'Var', (14, 35))	('myeloma', 'Disease', 'MESH:D009101', (85, 92))	('MV', 'Species', '11234', (102, 104))
266230	24921409	In vitro experiments using Chinese hamster ovary cells (CHO) expressing CD38 revealed an enhanced susceptibility to the modified MV in contrast to the non-modified MV vaccine strain.	('MV', 'Species', '11234', (164, 166))	('enhanced', 'PosReg', (89, 97))	('Chinese hamster', 'Species', '10029', (27, 42))	('CD38', 'Gene', (72, 76))	('modified', 'Var', (120, 128))	('CHO', 'CellLine', 'CVCL:0213', (56, 59))	('susceptibility', 'MPA', (98, 112))	('MV', 'Species', '11234', (129, 131))
266237	24921409	A CD20-expressing HT1080 cell xenograft model in immunocompromised mice revealed a diminished progression of tumor growth after systemic administration of the anti-CD20-displaying measles virus (MVHalphaCD20), whereas this growth retardation was less pronounced in control groups, treated with non-modified MV.	('growth retardation', 'Phenotype', 'HP:0001510', (223, 241))	('anti-CD20-displaying', 'Var', (159, 179))	('measles virus', 'Species', '11234', (180, 193))	('growth retardation', 'Disease', 'MESH:D006130', (223, 241))	('growth retardation', 'Disease', (223, 241))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MV', 'Species', '11234', (307, 309))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('diminished', 'NegReg', (83, 93))	('MV', 'Species', '11234', (195, 197))	('mice', 'Species', '10090', (67, 71))	('tumor', 'Disease', (109, 114))	('HT1080', 'CellLine', 'CVCL:0317', (18, 24))
266261	24921409	Interestingly, an additional insertion of the IFN-beta gene into MV-NIS resulted in an accumulated immune cell infiltration and decreased vascular density in a mesothelioma xenotransplantation model.	('vascular density', 'CPA', (138, 154))	('insertion', 'Var', (29, 38))	('IFN', 'Gene', (46, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (160, 172))	('NIS', 'Chemical', 'MESH:D009532', (68, 71))	('accumulated', 'PosReg', (87, 98))	('immune cell infiltration', 'CPA', (99, 123))	('MV', 'Species', '11234', (65, 67))	('decreased', 'NegReg', (128, 137))	('mesothelioma', 'Disease', (160, 172))	('IFN', 'Gene', '3439', (46, 49))
266262	24921409	New approaches for melanoma therapy combine measles virus targeted against melanoma-associated antigen (high molecular weight melanoma-associated antigen HMWMAA) and an insertion of the FCU1 gene (MV-FCU-1-alpha-HMWMAA).	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('combine measles', 'Phenotype', 'HP:0020088', (36, 51))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('MV', 'Species', '11234', (197, 199))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('FCU1', 'Gene', (186, 190))	('measles virus', 'Species', '11234', (44, 57))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('insertion', 'Var', (169, 178))
266273	24921409	In murine models for B-cell lymphomas and colon adenocarcinoma, treatment with a MV vaccine strain displaying an insertion of the granulocyte-macrophage colony-stimulating factor (GM-CSF) resulted in a retarded tumor progression and an increased median overall survival time.	('colon adenocarcinoma', 'Disease', (42, 62))	('insertion', 'Var', (113, 122))	('retarded tumor', 'Disease', (202, 216))	('increased', 'PosReg', (236, 245))	('GM-CSF', 'Gene', (180, 186))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (21, 36))	('lymphomas', 'Phenotype', 'HP:0002665', (28, 37))	('GM-CSF', 'Gene', '1437', (180, 186))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (42, 62))	('retarded tumor', 'Disease', 'MESH:D009369', (202, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (21, 37))	('murine', 'Species', '10090', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('B-cell lymphomas', 'Disease', (21, 37))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (21, 37))	('cell lymphoma', 'Phenotype', 'HP:0012191', (23, 36))	('lymphoma', 'Phenotype', 'HP:0002665', (28, 36))	('MV', 'Species', '11234', (81, 83))
266276	24921409	Another approach to increase MV activity was achieved by modifications to avoid antiviral counter-actions of the immune system.	('MV', 'Species', '11234', (29, 31))	('modifications', 'Var', (57, 70))	('MV activity', 'MPA', (29, 40))	('increase MV', 'Phenotype', 'HP:0005518', (20, 31))	('increase', 'PosReg', (20, 28))
266280	24921409	Compared to the parental MV the modified MV-eGFP-Pwt shows markedly reduced capacity to induce IFN.	('modified', 'Var', (32, 40))	('IFN', 'Gene', (95, 98))	('MV', 'Species', '11234', (41, 43))	('MV', 'Species', '11234', (25, 27))	('reduced', 'NegReg', (68, 75))	('IFN', 'Gene', '3439', (95, 98))
266301	24921409	Intraperitoneal administration of MV-CEA is used in patients with recurrent ovarian cancer and leads to a dose-dependent stabilization of the disease in all patients of the higher dose levels (107 to 109 TCID50) compared to only 5 of 12 patients treated in the lower dose range (103 to 106 TCID50).	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (66, 90))	('ovarian cancer', 'Disease', (76, 90))	('stabilization', 'PosReg', (121, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('patients', 'Species', '9606', (157, 165))	('CEA', 'Gene', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('107 to 109 TCID50', 'Var', (193, 210))	('ovarian cancer', 'Disease', 'MESH:D010051', (76, 90))	('CEA', 'Gene', '5670', (37, 40))	('patients', 'Species', '9606', (237, 245))	('MV', 'Species', '11234', (34, 36))	('patients', 'Species', '9606', (52, 60))
266309	24921409	Whereas the attenuation of measles virus vaccine strains can be attributed to genetic modifications in almost every viral protein affecting host cell tropism and the ability to inhibit cellular antiviral defense mechanisms, the basis of attenuation of the CDV vaccine strains is largely unknown.	('cellular antiviral defense mechanisms', 'MPA', (185, 222))	('measles virus', 'Species', '11234', (27, 40))	('modifications', 'Var', (86, 99))	('genetic modifications', 'Var', (78, 99))	('inhibit', 'NegReg', (177, 184))	('CDV', 'Species', '11232', (256, 259))
266310	24921409	(2011) reported that the modifications of the CDV matrix protein could be one factor influencing the virulence by affecting particle composition and envelope protein distribution in polarized epithelial cells.	('virulence', 'MPA', (101, 110))	('modifications', 'Var', (25, 38))	('affecting', 'Reg', (114, 123))	('CDV', 'Species', '11232', (46, 49))	('particle composition', 'MPA', (124, 144))	('influencing', 'Reg', (85, 96))	('envelope protein distribution', 'MPA', (149, 178))
266324	24921409	The lesser aggressive phenotype is assumed due to respective findings in human medicine where tumors with a normal or high RECK expression are often associated with a better prognosis, whereas tumors lacking a RECK expression or displaying low amounts of this protein are commonly related to a poorer prognosis.	('high', 'Var', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('RECK', 'Protein', (123, 127))	('human', 'Species', '9606', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('better', 'PosReg', (167, 173))
266325	24921409	This review highlights recent findings and provides new insights into different strategies in tumor treatment using morbilliviruses with special emphasis of virus modifications to enhance tumor cell sensitivity, therapeutic efficacy, and to reduce pathogen associated adverse side effects.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('modifications', 'Var', (163, 176))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('enhance', 'PosReg', (180, 187))
266328	24921409	In vitro, many different modifications of the MV were performed in order to improve tumor cell specificity and achieve an enhanced anti-cancer immune response or to regulate the tumor microenvironment, namely vascularization.	('tumor', 'Disease', (178, 183))	('enhanced', 'PosReg', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('modifications', 'Var', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', (136, 142))	('regulate', 'Reg', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('MV', 'Species', '11234', (46, 48))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('improve', 'PosReg', (76, 83))
266385	20419128	Comprising more than 50 histological subtypes, soft tissue sarcoma (STS) can be classified into two major groups: those with specific genetic alterations (translocations or point mutations) and relatively simple karyotypes, and those with complex, unbalanced aneuploid karyotypes.	('rat', 'Species', '10116', (146, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (47, 66))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (47, 66))	('point mutations', 'Var', (173, 188))	('soft tissue sarcoma', 'Disease', (47, 66))
266386	20419128	Enhanced understanding of the molecular aberrations driving the inception and progression of several STS subtypes belonging to the first group (e.g., c-Kit mutations in gastrointestinal stromal tumors [GIST] or the 17;22 translocation leading to PDGF-B over-expression in dermatofibrosarcoma protuberans; [DFSP]), has resulted in clinical applications of effective targeted therapies (e.g.	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (272, 303))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (169, 200))	('c-Kit', 'Gene', (150, 155))	('mutations', 'Var', (156, 165))	('gastrointestinal stromal tumors', 'Disease', (169, 200))	('PDGF-B', 'Gene', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('rat', 'Species', '10116', (44, 47))	('c-Kit', 'Gene', '3815', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (169, 200))	('dermatofibrosarcoma protuberans', 'Disease', (272, 303))	('PDGF-B', 'Gene', '5155', (246, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (284, 291))	('over-expression', 'PosReg', (253, 268))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (279, 291))
266396	20419128	Recent studies have shown that WFA suppresses human breast and prostate cancer cells' growth in vitro and in vivo by inducing marked apoptosis.	('growth', 'CPA', (86, 92))	('apoptosis', 'CPA', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('WFA', 'Chemical', 'MESH:C009684', (31, 34))	('WFA', 'Var', (31, 34))	('inducing', 'Reg', (117, 125))	('human', 'Species', '9606', (46, 51))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (52, 78))	('suppresses', 'NegReg', (35, 45))
266403	20419128	Furthermore, WFA-modified vimentin was found to elicit significant proapoptotic and antiangiogenic effects, whereas vimentin knockdown resulted in decreased WFA sensitivity.	('knockdown', 'Var', (125, 134))	('WFA', 'Chemical', 'MESH:C009684', (13, 16))	('antiangiogenic', 'CPA', (84, 98))	('proapoptotic', 'MPA', (67, 79))	('WFA sensitivity', 'MPA', (157, 172))	('WFA', 'Chemical', 'MESH:C009684', (157, 160))	('decreased', 'NegReg', (147, 156))	('elicit', 'PosReg', (48, 54))	('vimentin', 'Protein', (26, 34))	('vimentin', 'Gene', (116, 124))
266451	20419128	Anti-vimentin SMARTpool siRNA elicited a substantial decrease in vimentin expression in SKLMS1 cells (WB; Figure 3B).	('expression', 'MPA', (74, 84))	('Anti-vimentin', 'Var', (0, 13))	('decrease', 'NegReg', (53, 61))	('SKLMS1', 'CellLine', 'CVCL:0628', (88, 94))	('vimentin', 'Protein', (65, 73))
266452	20419128	Vimentin knockdown per se did not induce significant apoptosis in STS cells, as compared to mock or non-targeting siRNA transfection.	('Vimentin', 'Gene', '7431', (0, 8))	('knockdown', 'Var', (9, 18))	('Vimentin', 'Gene', (0, 8))
266454	20419128	However, vimentin knockdown substantially blocked WFA-induced apoptosis.	('vimentin', 'Protein', (9, 17))	('knockdown', 'Var', (18, 27))	('WFA', 'Chemical', 'MESH:C009684', (50, 53))	('blocked', 'NegReg', (42, 49))
266458	20419128	After knockdown, vimentin was forcefully re-expressed in the cells (WB, Figure 3C); cells were treated with WFA or DMSO as control and subjected to Annexin V/FACS analysis.	('Annexin V', 'Gene', '308', (148, 157))	('Annexin V', 'Gene', (148, 157))	('WFA', 'Chemical', 'MESH:C009684', (108, 111))	('knockdown', 'Var', (6, 15))	('DMSO', 'Chemical', 'MESH:D004121', (115, 119))
266460	20419128	Re-expression of vimentin restored SKLMS1 sensitivity to WFA (Figure 3C).	('WFA', 'Chemical', 'MESH:C009684', (57, 60))	('restored', 'PosReg', (26, 34))	('SKLMS1 sensitivity', 'MPA', (35, 53))	('Re-expression', 'Var', (0, 13))	('SKLMS1', 'CellLine', 'CVCL:0628', (35, 41))	('vimentin', 'Protein', (17, 25))
266461	20419128	However, as shown in Figure 2, WFA induces more significant pro-apoptotic effects in STS cells as compared to normal mesenchymal cells (i.e.	('WFA', 'Var', (31, 34))	('pro-apoptotic effects', 'MPA', (60, 81))	('WFA', 'Chemical', 'MESH:C009684', (31, 34))
266469	20419128	Next, after vimentin knockdown using morpholino oligos, SKLMS1 cells were transfected to express either wild-type vimentin or vimentin mutated at caspase cleavage sites (D85N and D259N).	('D259N', 'Mutation', 'p.D259N', (179, 184))	('vimentin', 'Gene', (126, 134))	('D85N', 'Var', (170, 174))	('D259N', 'Var', (179, 184))	('SKLMS1', 'CellLine', 'CVCL:0628', (56, 62))	('mutated', 'Var', (135, 142))	('D85N', 'Mutation', 'rs749097460', (170, 174))	('morpholino oligos', 'Chemical', 'MESH:D060172', (37, 54))
266471	20419128	However, we observed a significant decrease in WFA-induced apoptosis in cells expressing the mutated vimentin, and we noticed a dramatic decrease in both vimentin degradation and caspase-3 activation (Figure 4C).	('caspase-3', 'Gene', '836', (179, 188))	('mutated', 'Var', (93, 100))	('decrease', 'NegReg', (137, 145))	('WFA', 'Chemical', 'MESH:C009684', (47, 50))	('vimentin', 'Protein', (101, 109))	('decrease', 'NegReg', (35, 43))	('caspase-3', 'Gene', (179, 188))	('vimentin degradation', 'MPA', (154, 174))	('activation', 'PosReg', (189, 199))
266482	20419128	Vimentin knockdown abrogated WFA-induced pAKT inhibition, NF-kappaB protein decrease and activity blockade, and increased levels of protein ubiquitination (Figure 5B).	('WFA', 'Chemical', 'MESH:C009684', (29, 32))	('Vimentin', 'Gene', '7431', (0, 8))	('knockdown', 'Var', (9, 18))	('levels of protein ubiquitination', 'MPA', (122, 154))	('AKT', 'Gene', (42, 45))	('NF-kappaB', 'Gene', '4790', (58, 67))	('abrogated', 'NegReg', (19, 28))	('activity blockade', 'MPA', (89, 106))	('increased', 'PosReg', (112, 121))	('NF-kappaB', 'Gene', (58, 67))	('decrease', 'NegReg', (76, 84))	('AKT', 'Gene', '207', (42, 45))	('Vimentin', 'Gene', (0, 8))
266493	20419128	As anticipated, STS-CM enhanced endothelial cell migration and invasion.	('rat', 'Species', '10116', (52, 55))	('enhanced', 'PosReg', (23, 31))	('STS-CM', 'Var', (16, 22))	('invasion', 'CPA', (63, 71))	('endothelial cell migration', 'CPA', (32, 58))
266494	20419128	More important, WFA abrogated migration and invasion of endothelial cells cultured in STS-CM, but not that of those grown in regular medium (Figure 6D).	('WFA', 'Chemical', 'MESH:C009684', (16, 19))	('WFA', 'Var', (16, 19))	('abrogated', 'NegReg', (20, 29))	('rat', 'Species', '10116', (33, 36))
266500	20419128	These results suggest that WFA potentially abrogates cell growth, inhibits migration and invasion, and induces apoptosis in proliferating endothelial cells within the STS microenvironment.	('rat', 'Species', '10116', (131, 134))	('cell growth', 'CPA', (53, 64))	('inhibits', 'NegReg', (66, 74))	('WFA', 'Chemical', 'MESH:C009684', (27, 30))	('WFA', 'Var', (27, 30))	('invasion', 'CPA', (89, 97))	('rat', 'Species', '10116', (78, 81))	('abrogates', 'NegReg', (43, 52))	('induces', 'Reg', (103, 110))	('apoptosis', 'CPA', (111, 120))
266550	20419128	Similarly, phosphorylated, disassembled vimentin has been demonstrated to enhance the recycling of integrins subjected to endocytosis to the plasma membrane during cell migration.	('integrins', 'Protein', (99, 108))	('rat', 'Species', '10116', (65, 68))	('phosphorylated', 'Var', (11, 25))	('vimentin', 'Protein', (40, 48))	('rat', 'Species', '10116', (172, 175))	('recycling of', 'MPA', (86, 98))	('enhance', 'PosReg', (74, 81))
266554	20419128	Recently vimentin knockdown was reported to inhibit vimentin-expressing epithelial cell migration and adhesion.	('knockdown', 'Var', (18, 27))	('rat', 'Species', '10116', (91, 94))	('vimentin', 'Protein', (9, 17))	('inhibit', 'NegReg', (44, 51))	('adhesion', 'CPA', (102, 110))	('vimentin-expressing', 'Protein', (52, 71))
266562	20419128	The potential utility of vimentin as an anti-cancer molecular therapeutic target is highlighted by recent findings suggesting marked proapoptotic effects induced by vimentin cleavage.	('cleavage', 'Var', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('proapoptotic effects', 'MPA', (133, 153))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('vimentin', 'Protein', (165, 173))
266563	20419128	Vimentin undergoes rapid caspase-induced proteolysis (at caspase cleavage sites: Asp85, Asp259, and Asp429; upon diverse proapoptotic stimuli, including ionizing radiation, Fas, TRAIL, TNFalpha, and tamoxifen administration.	('TNFalpha', 'Gene', (185, 193))	('Vimentin', 'Gene', '7431', (0, 8))	('Asp259', 'Chemical', '-', (88, 94))	('caspase-induced proteolysis', 'MPA', (25, 52))	('TRAIL', 'Gene', (178, 183))	('tamoxifen', 'Chemical', 'MESH:D013629', (199, 208))	('TNFalpha', 'Gene', '7124', (185, 193))	('Asp85', 'Chemical', '-', (81, 86))	('Asp429', 'Chemical', '-', (100, 106))	('Asp429', 'Var', (100, 106))	('rat', 'Species', '10116', (217, 220))	('TRAIL', 'Gene', '8743', (178, 183))	('Fas', 'Chemical', 'MESH:C038178', (173, 176))	('Vimentin', 'Gene', (0, 8))
266568	20419128	Furthermore, vimentin knockdown, as well as inhibition of vimentin degradation (using either caspase inhibition or overexpression of caspase-resistant vimentin), abrogated WFA-induced apoptosis.	('abrogated', 'NegReg', (162, 171))	('WFA', 'Chemical', 'MESH:C009684', (172, 175))	('degradation', 'MPA', (67, 78))	('knockdown', 'Var', (22, 31))	('vimentin', 'Protein', (13, 21))	('inhibition', 'NegReg', (44, 54))	('WFA-induced apoptosis', 'CPA', (172, 193))	('vimentin', 'Protein', (58, 66))
266570	20419128	On one hand, vimentin's inherent properties elicit protumorigenic, prometastatic effects; on the other hand, its cleavage strongly incites proapoptotic signals.	('prometastatic effects', 'CPA', (67, 88))	('proapoptotic signals', 'MPA', (139, 159))	('elicit', 'Reg', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('vimentin', 'Protein', (13, 21))	('incites', 'Reg', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('cleavage', 'Var', (113, 121))
266578	20419128	Furthermore, these effects were independent of p53 mutational status; three of the cell lines tested (SKLMS1, STS26T, and PLS1) harbor mutated p53, whereas HT1080 exhibits wild type p53.	('SKLMS1', 'CellLine', 'CVCL:0628', (102, 108))	('HT1080', 'Gene', (156, 162))	('p53', 'Gene', '7157', (143, 146))	('p53', 'Gene', '7157', (182, 185))	('PLS1', 'Gene', (122, 126))	('mutated', 'Var', (135, 142))	('STS26T', 'CellLine', 'CVCL:8917', (110, 116))	('PLS1', 'Gene', '5357', (122, 126))	('HT1080', 'Gene', '8872', (156, 162))	('p53', 'Gene', (182, 185))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('p53', 'Gene', (143, 146))
266579	20419128	This finding is important because p53 mutations are very common in STS, and p53-mutated STS are more therapeutically resistant.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('mutations', 'Var', (38, 47))
266652	20419128	Five of the most vascularized areas within a tumor ("hot spots") identified based on CD31 positivity were chosen at low magnification and vessels were counted in a representative high-power (x400) field in each of these areas.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('CD31', 'Gene', (85, 89))	('positivity', 'Var', (90, 100))	('CD31', 'Gene', '5175', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
266658	32532104	In the Tp53C273X/C273X rat model we therefore aimed to characterize specific gene expression pattern of angiosarcomas with a loss of TP53 function.	('loss', 'NegReg', (125, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('C273X', 'Mutation', 'p.C273X', (17, 22))	('angiosarcoma', 'Phenotype', 'HP:0200058', (104, 116))	('rat', 'Species', '10116', (23, 26))	('Tp53C273X/C273X', 'Var', (7, 22))	('function', 'MPA', (138, 146))	('C273X', 'Mutation', 'p.C273X', (11, 16))	('angiosarcomas', 'Disease', (104, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('angiosarcomas', 'Disease', 'MESH:D006394', (104, 117))	('TP53', 'Gene', (133, 137))	('angiosarcomas', 'Phenotype', 'HP:0200058', (104, 117))
266677	32532104	TP53 is the most frequently altered gene in cancers, with TP53 mutations observed in approximately half of all tumors and more cases exhibiting epigenetic deregulation of TP53.	('mutations', 'Var', (63, 72))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TP53', 'Gene', (58, 62))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('observed', 'Reg', (73, 81))
266678	32532104	Inactivation of p53 plays a critical role in sarcomagenesis.	('sarcomagenesis', 'Disease', 'None', (45, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('p53', 'Gene', (16, 19))	('sarcomagenesis', 'Disease', (45, 59))	('Inactivation', 'Var', (0, 12))
266679	32532104	It was shown that new germline mutations of the TP53 gene, although rare among patients with sporadic STS, are, however, reported in patients with family history of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('germline mutations', 'Var', (22, 40))	('patients', 'Species', '9606', (133, 141))	('TP53', 'Gene', (48, 52))	('reported', 'Reg', (121, 129))	('patients', 'Species', '9606', (79, 87))	('sarcoma', 'Disease', 'MESH:D012509', (165, 172))	('sarcoma', 'Disease', (165, 172))
266680	32532104	A high rate of point mutations in TP53 is reported not only in childhood sarcomas and families with the Li-Fraumeni syndrome, but also in adult-onset sarcomas, including leiomyosarcoma, osteosarcoma, and undifferentiated pleomorphic sarcomas.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (170, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('rat', 'Species', '10116', (7, 10))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))	('sarcomas', 'Disease', (150, 158))	('osteosarcoma', 'Disease', (186, 198))	('leiomyosarcoma', 'Disease', (170, 184))	('osteosarcoma', 'Disease', 'MESH:D012516', (186, 198))	('TP53', 'Gene', (34, 38))	('point mutations', 'Var', (15, 30))	('sarcomas', 'Disease', 'MESH:D012509', (233, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('sarcomas', 'Phenotype', 'HP:0100242', (233, 241))	('Li-Fraumeni syndrome', 'Disease', (104, 124))	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (204, 241))	('undifferentiated pleomorphic sarcomas', 'Disease', (204, 241))	('sarcomas', 'Disease', (233, 241))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('sarcomas', 'Disease', (73, 81))	('osteosarcoma', 'Phenotype', 'HP:0002669', (186, 198))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (170, 184))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (104, 124))
266681	32532104	It has also been described that alterations of TP53 in rhabdomyosarcoma include a complete deletion of both TP53 alleles, complete deletions of one allele with or without point mutation of the other allele, and absence of detectable transcript (mRNA).	('deletion', 'Var', (91, 99))	('TP53', 'Gene', (108, 112))	('TP53', 'Gene', (47, 51))	('rat', 'Species', '10116', (36, 39))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (55, 71))	('alterations', 'Var', (32, 43))	('deletions', 'Var', (131, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (55, 71))	('absence', 'NegReg', (211, 218))	('rhabdomyosarcoma', 'Disease', (55, 71))
266682	32532104	On the other hand, osteosarcomas are characterized with homozygous deletions of TP53, lack of TP53 RNA expression or aberrant expression of p53 protein.	('osteosarcomas', 'Disease', 'MESH:D012516', (19, 32))	('deletions', 'Var', (67, 76))	('protein', 'Protein', (144, 151))	('expression', 'MPA', (126, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('aberrant', 'Var', (117, 125))	('TP53', 'Gene', (80, 84))	('lack', 'NegReg', (86, 90))	('osteosarcomas', 'Disease', (19, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('osteosarcomas', 'Phenotype', 'HP:0002669', (19, 32))
266683	32532104	The most recent genomic analysis has confirmed that, in angiosarcoma, the most common alterations are denoted as TP53 mutation, TP53 c.217-c.1178 missense substitution, and TP53 missense (besides MYC amplification, and KDR mutation).	('MYC', 'Gene', (196, 199))	('KDR', 'Gene', (219, 222))	('angiosarcoma', 'Disease', (56, 68))	('TP53', 'Gene', (128, 132))	('c.217-c.1178 missense substitution', 'Var', (133, 167))	('angiosarcoma', 'Phenotype', 'HP:0200058', (56, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('TP53', 'Gene', (173, 177))	('angiosarcoma', 'Disease', 'MESH:D006394', (56, 68))	('TP53', 'Gene', (113, 117))	('MYC', 'Gene', '24577', (196, 199))	('KDR', 'Gene', '25589', (219, 222))	('rat', 'Species', '10116', (90, 93))
266684	32532104	All these data confirm that TP53 functional inactivation by either dominant or recessive manner plays a significant role in human sarcomatogenesis including angiosarcoma development.	('sarcomatogenesis', 'Disease', (130, 146))	('angiosarcoma', 'Phenotype', 'HP:0200058', (157, 169))	('TP53', 'Gene', (28, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('angiosarcoma', 'Disease', 'MESH:D006394', (157, 169))	('human', 'Species', '9606', (124, 129))	('angiosarcoma', 'Disease', (157, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('sarcomatogenesis', 'Disease', 'None', (130, 146))	('functional inactivation', 'Var', (33, 56))
266685	32532104	We used Wistar strain Tp53 knockout rats (p53 TGEM  Rat; TP53-deficient Wistar rat) Tp53C273X/C273X colony as a sarcoma development model.	('C273X', 'Mutation', 'p.C273X', (88, 93))	('Tp53C273X/C273X', 'Var', (84, 99))	('rat', 'Species', '10116', (36, 39))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('Rat', 'Species', '10116', (52, 55))	('C273X', 'Mutation', 'p.C273X', (94, 99))	('sarcoma', 'Disease', (112, 119))	('rat', 'Species', '10116', (79, 82))	('rats', 'Species', '10116', (36, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
266688	32532104	In fact, complete absence of functional p53 protein in homozygous mutant animals was demonstrated already in embryonic fibroblasts.	('mutant', 'Var', (66, 72))	('rat', 'Species', '10116', (92, 95))	('protein', 'Protein', (44, 51))	('absence', 'NegReg', (18, 25))	('p53 protein', 'Protein', (40, 51))
266690	32532104	Surprisingly, it was shown that tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation in comparison to the tumors that develop in heterozygous Tp53C273X/WT animals.	('aneuploidy', 'Disease', 'MESH:D000782', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('aneuploidy', 'Disease', (81, 91))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('Tp53C273X/WT', 'Var', (198, 210))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
266693	32532104	As it was previously shown in a mouse model, p53+/- animals are susceptible to oncogenesis and tumor development:due to a reduction in p53 dosage in cells.	('p53+/-', 'Var', (45, 51))	('p53', 'Protein', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('reduction', 'NegReg', (122, 131))	('mouse', 'Species', '10090', (32, 37))	('oncogenesis', 'CPA', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
266694	32532104	All these data suggest that tumor development in Tp53+/- and Tp53-/- organisms can be driven by different mechanisms.	('Tp53-/-', 'Var', (61, 68))	('tumor', 'Disease', (28, 33))	('Tp53+/-', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
266697	32532104	A high frequency (52%) of short deletions is observed in the mutation pattern of radiation-induced sarcomas ; Tp53+/C273X rats were recently used as model in the study on such tumors.	('C273X', 'Mutation', 'p.C273X', (116, 121))	('short deletions', 'Var', (26, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('rats', 'Species', '10116', (122, 126))	('sarcomas', 'Disease', (99, 107))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcomas', 'Disease', 'MESH:D012509', (99, 107))
266710	32532104	The most extreme differences in gene expression (FC > 10 and FDR < 0.025, marked in red in Figure 4a-c) were observed between wild-type (Tp53+/+) normal tissue and angiosarcoma tissue in Tp53-/- rats.	('angiosarcoma', 'Phenotype', 'HP:0200058', (164, 176))	('rats', 'Species', '10116', (195, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('Tp53-/-', 'Var', (187, 194))	('angiosarcoma', 'Disease', 'MESH:D006394', (164, 176))	('angiosarcoma', 'Disease', (164, 176))
266733	32532104	Those classes are: topoisomerase inhibitor (enrichment score -97.84), HDAC inhibitor (-95.95), CDK inhibitor (-94.38), DNA synthesis inhibitors (-92.69), JAK inhibitors (-92.60) and HIF activators (-91.06) (Table S7).	('DNA synthesis', 'MPA', (119, 132))	('CDK', 'MPA', (95, 98))	('-92.60', 'Var', (170, 176))	('DA', 'Chemical', 'MESH:C025953', (71, 73))	('-92.69', 'Var', (145, 151))
266735	32532104	Ingenuity Pathway Analysis (IPA) revealed differences in expression of genes involved in P53 signaling between wild-type and Tp53 knockout rats.	('expression', 'MPA', (57, 67))	('P53', 'Gene', (89, 92))	('P53', 'Gene', '24842', (89, 92))	('Tp53', 'Gene', (125, 129))	('knockout', 'Var', (130, 138))	('differences', 'Reg', (42, 53))	('rats', 'Species', '10116', (139, 143))
266738	32532104	In the sarcoma group, the activity of some of these genes seemed to be restored despite the presence of mutated Tp53.	('presence', 'Reg', (92, 100))	('Tp53', 'Gene', (112, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('mutated', 'Var', (104, 111))	('sarcoma', 'Disease', (7, 14))	('sarcoma', 'Disease', 'MESH:D012509', (7, 14))	('activity', 'MPA', (26, 34))	('restored', 'PosReg', (71, 79))
266749	32532104	The incidence of osteosarcomas is 57% and 36% in F344-Tp53 homozygous and heterozygous animals, respectively.	('osteosarcomas', 'Disease', (17, 30))	('F344-Tp53', 'Var', (49, 58))	('osteosarcomas', 'Phenotype', 'HP:0002669', (17, 30))	('osteosarcomas', 'Disease', 'MESH:D012516', (17, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))
266753	32532104	A homozygous null rat:Tp53Delta11/Delta11:with a complete loss of p53 protein has a shortened disease-free lifespan due to early onset of cancers.	('rat', 'Species', '10116', (18, 21))	('disease-free lifespan', 'CPA', (94, 115))	('protein', 'Protein', (70, 77))	('loss', 'NegReg', (58, 62))	('Tp53Delta11/Delta11', 'Var', (22, 41))	('Delta11', 'Mutation', 'c.del11', (34, 41))	('p53 protein', 'Protein', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('Delta11', 'Mutation', 'c.del11', (26, 33))	('shortened', 'NegReg', (84, 93))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
266754	32532104	The tumor spectrum in these null mutant rats includes both sarcomas and carcinomas, with a predominance of nervous system tumors.	('tumor', 'Disease', (4, 9))	('nervous system tumors', 'Phenotype', 'HP:0004375', (107, 128))	('nervous system tumors', 'Disease', (107, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('rats', 'Species', '10116', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutant', 'Var', (33, 39))	('sarcomas and carcinomas', 'Disease', 'MESH:D012509', (59, 82))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (122, 127))	('nervous system tumors', 'Disease', 'MESH:D009423', (107, 128))
266755	32532104	The Tp53Delta11/+ rats experience a later onset of tumorigenesis and develop skin and endocrine cancers in addition to the cancer types recognized in the null homozygote.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('endocrine cancers', 'Disease', (86, 103))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (51, 56))	('Tp53Delta11/+', 'Var', (4, 17))	('develop', 'PosReg', (69, 76))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('rats', 'Species', '10116', (18, 22))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('endocrine cancers', 'Disease', 'MESH:D004701', (86, 103))	('cancer', 'Disease', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
266763	32532104	Wistar background homozygous mutant Tp53C273X/C273X rats predominantly develop sarcomas with an onset at four months of age and with a high frequency of pulmonary metastases.	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('C273X', 'Mutation', 'p.C273X', (40, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Disease', (79, 87))	('rats', 'Species', '10116', (52, 56))	('develop', 'PosReg', (71, 78))	('C273X', 'Mutation', 'p.C273X', (46, 51))	('pulmonary metastases', 'Disease', 'MESH:D009362', (153, 173))	('pulmonary metastases', 'Disease', (153, 173))	('Tp53C273X/C273X', 'Var', (36, 51))
266766	32532104	Tp53C273X/+ rats predominantly develop osteosarcomas, therefore this model may be generally used for soft tissue and bone sarcoma research and should be referred in appropriate papers, including imaging/PET-oriented manuals.	('osteosarcomas', 'Disease', 'MESH:D012516', (39, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (39, 51))	('soft tissue and bone sarcoma', 'Phenotype', 'HP:0030448', (101, 129))	('Tp53C273X/+', 'Var', (0, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('bone sarcoma', 'Disease', (117, 129))	('develop', 'Reg', (31, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('osteosarcomas', 'Disease', (39, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('rats', 'Species', '10116', (12, 16))	('bone sarcoma', 'Disease', 'MESH:D012509', (117, 129))	('bone sarcoma', 'Phenotype', 'HP:0002669', (117, 129))	('osteosarcomas', 'Phenotype', 'HP:0002669', (39, 52))
266767	32532104	In the TGEM Rat model the introduced DNA mutation finally truncates the protein at the DNA binding domain, eliminating functionally essential domains including the nuclear localization domain and the homo-oligomerization domain of the translated protein, which results in rapid degradation of residual non-functional peptide.	('truncates', 'NegReg', (58, 67))	('nuclear localization domain', 'MPA', (164, 191))	('degradation', 'MPA', (278, 289))	('protein', 'Protein', (72, 79))	('eliminating', 'NegReg', (107, 118))	('residual non-functional peptide', 'MPA', (293, 324))	('homo-oligomerization domain', 'MPA', (200, 227))	('mutation', 'Var', (41, 49))	('Rat', 'Species', '10116', (12, 15))	('DNA', 'Gene', (37, 40))	('functionally essential domains', 'MPA', (119, 149))
266772	32532104	Simultaneously, angiosarcoma genome analyses revealed mutations and amplifications of VEGF, MDM2, TP53, CDKN2A, KRAS and MYC.	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('MDM2', 'Gene', (92, 96))	('VEGF', 'Gene', (86, 90))	('MYC', 'Gene', (121, 124))	('mutations', 'Var', (54, 63))	('angiosarcoma', 'Disease', (16, 28))	('MYC', 'Gene', '24577', (121, 124))	('VEGF', 'Gene', '83785', (86, 90))	('MDM2', 'Gene', '314856', (92, 96))	('angiosarcoma', 'Disease', 'MESH:D006394', (16, 28))	('revealed', 'Reg', (45, 53))	('angiosarcoma', 'Phenotype', 'HP:0200058', (16, 28))	('KRAS', 'Gene', '24525', (112, 116))	('CDKN2A', 'Gene', '25163', (104, 110))	('KRAS', 'Gene', (112, 116))	('CDKN2A', 'Gene', (104, 110))	('amplifications', 'MPA', (68, 82))	('TP53', 'Gene', (98, 102))
266773	32532104	TP53 was reported as mutated in 35% of the lesions and CDKN2A lost in 26%.	('TP53', 'Gene', (0, 4))	('lost', 'NegReg', (62, 66))	('CDKN2A', 'Gene', '25163', (55, 61))	('mutated', 'Var', (21, 28))	('CDKN2A', 'Gene', (55, 61))
266776	32532104	In our study, the most upregulated genes included Rho GTPase Activating Protein 42 (Arhgap42), mitochondrial Propionyl-CoA Carboxylase Subunit Alpha (Pcca), LOC294154 (similar to chromosome 6 open reading frame 106 isoform a) with ubiquitin binding activity, Spindle and kinetochore-associated protein 3 (Ska3) and Solute Carrier Family 16, Member 3 (Monocarboxylic Acid Transporter 4:Slc16a3).	('Pcca', 'Gene', (150, 154))	('Spindle and kinetochore-associated protein 3', 'Gene', '361047', (259, 303))	('Rho GTPase Activating Protein 42', 'Gene', (50, 82))	('upregulated', 'PosReg', (23, 34))	('Propionyl-CoA Carboxylase Subunit Alpha', 'Gene', (109, 148))	('Ska3', 'Gene', '361047', (305, 309))	('Arhgap42', 'Gene', '500943', (84, 92))	('Rho GTPase Activating Protein 42', 'Gene', '500943', (50, 82))	('Slc16a3', 'Gene', (385, 392))	('Slc16a3', 'Gene', '80878', (385, 392))	('Ska3', 'Gene', (305, 309))	('Pcca', 'Gene', '687008', (150, 154))	('LOC294154', 'Var', (157, 166))	('Arhgap42', 'Gene', (84, 92))	('Propionyl-CoA Carboxylase Subunit Alpha', 'Gene', '687008', (109, 148))	('Solute Carrier Family 16, Member 3 (Monocarboxylic Acid Transporter 4', 'Gene', '80878', (315, 384))
266787	32532104	Genotypes of the rats were determined using simple allele-discriminating PCR (initial denaturation 94  C for 6 min, 35 cycles of 94  C for 20 s, 52  C for 20 s, 72  C for 20 s, final elongation 72  C for 7 min) with two primer sets: (1) Tp53 wild-type reverse primer (5'-GTCTCTCCCAGGACAGGTA-3'), and Tp53 common forward primer (5'-GAAGACTCCAGGTAGGAAGC-3') or (2) Tp53 mutant reverse primer (5'-GTCTCTCCCAGGACAGGTT -3') and Tp53 common forward primer.	('rats', 'Species', '10116', (17, 21))	('mutant', 'Var', (368, 374))	('rat', 'Species', '10116', (92, 95))	('rat', 'Species', '10116', (17, 20))	('Tp53', 'Gene', (363, 367))
266793	32532104	The groups were the following: (1) Ko with sarcoma already developed (referred to as Sarcoma in figures and tables), (2) with total knockout of the Tp53 (Ko), (3) with heterozygous knockout of the Tp53 (Het), (4) healthy controls (Healthy).	('Sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('Sarcoma', 'Disease', (85, 92))	('Tp53', 'Gene', (148, 152))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('Tp53', 'Gene', (197, 201))	('Sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('knockout', 'Var', (132, 140))
266826	32532104	In conclusion, the Tp53C273X/C273X rat model can be used for studying sarcoma biology, in particular angiosarcoma and osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcoma', 'Disease', (70, 77))	('Tp53C273X/C273X', 'Var', (19, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('osteosarcoma', 'Phenotype', 'HP:0002669', (118, 130))	('angiosarcoma', 'Phenotype', 'HP:0200058', (101, 113))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('C273X', 'Mutation', 'p.C273X', (29, 34))	('rat', 'Species', '10116', (35, 38))	('angiosarcoma and osteosarcoma', 'Disease', 'MESH:D006394', (101, 130))	('sarcoma', 'Disease', (106, 113))	('sarcoma', 'Disease', (123, 130))	('C273X', 'Mutation', 'p.C273X', (23, 28))
266892	28031902	A. Molecular diagnosis consistent with HLH: pathologic mutations of PRF1, UNC13D, Munc188-2, Rab27a, STX11, SH2D1A or BIRC4 or B.	('PRF1', 'Gene', (68, 72))	('Rab27a', 'Gene', '5873', (93, 99))	('mutations', 'Var', (55, 64))	('SH2D1A', 'Gene', '4068', (108, 114))	('SH2D1A', 'Gene', (108, 114))	('STX11', 'Gene', (101, 106))	('UNC13D', 'Gene', '201294', (74, 80))	('Rab27a', 'Gene', (93, 99))	('BIRC4', 'Gene', (118, 123))	('STX11', 'Gene', '8676', (101, 106))	('Munc188-2', 'Gene', (82, 91))	('BIRC4', 'Gene', '331', (118, 123))	('PRF1', 'Gene', '5551', (68, 72))	('UNC13D', 'Gene', (74, 80))
266952	25915910	In univariate analysis, the factors significantly associated with local recurrence were histologic type, location, tumor size, number of contiguous organs resected, R1 vs R0 resection, and vascular resection.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('local', 'Disease', (66, 71))	('R1 vs R0 resection', 'Var', (165, 183))	('tumor', 'Disease', (115, 120))	('vascular resection', 'Var', (189, 207))	('associated', 'Reg', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
266975	25915910	However, we found that patients with high-grade leiomyosarcoma have a disease-specific survival almost identical to those with dedifferentiated liposarcoma, but have a much lower local recurrence rate and a higher distant recurrence rate.	('distant recurrence rate', 'CPA', (214, 237))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (48, 62))	('local recurrence rate', 'CPA', (179, 200))	('patients', 'Species', '9606', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('liposarcoma', 'Disease', (144, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('high-grade', 'Var', (37, 47))	('liposarcoma', 'Disease', 'MESH:D008080', (144, 155))	('leiomyosarcoma', 'Disease', (48, 62))	('lower', 'NegReg', (173, 178))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (48, 62))	('liposarcoma', 'Phenotype', 'HP:0012034', (144, 155))	('higher', 'PosReg', (207, 213))
267004	25915910	We have also found that copy number alterations in well-differentiated and dedifferentiated liposarcoma are predictive of outcome.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('liposarcoma', 'Disease', (92, 103))	('liposarcoma', 'Disease', 'MESH:D008080', (92, 103))	('copy number alterations', 'Var', (24, 47))	('well-differentiated', 'Disease', (51, 70))	('liposarcoma', 'Phenotype', 'HP:0012034', (92, 103))
267005	25915910	After profiling tumor samples using Agilent 244K comparative genomic hybridization arrays, we identified 9 regions of copy number alteration as recurrent in dedifferentiated liposarcoma but not well-differentiated liposarcoma.	('liposarcoma', 'Disease', (214, 225))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('liposarcoma', 'Disease', (174, 185))	('liposarcoma', 'Disease', 'MESH:D008080', (214, 225))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('liposarcoma', 'Disease', 'MESH:D008080', (174, 185))	('copy number alteration', 'Var', (118, 140))	('liposarcoma', 'Phenotype', 'HP:0012034', (214, 225))	('tumor', 'Disease', (16, 21))	('liposarcoma', 'Phenotype', 'HP:0012034', (174, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
267006	25915910	Among patients with primary retroperitoneal dedifferentiated liposarcoma, loss of 19q13 was associated with poor recurrence-free survival (HR, 2.9; P=0.01) and with poor disease-specific survival (HR, 7.4; P=0.002).	('recurrence-free survival', 'CPA', (113, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('loss', 'Var', (74, 78))	('primary retroperitoneal dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (20, 72))	('poor', 'NegReg', (165, 169))	('patients', 'Species', '9606', (6, 14))	('liposarcoma', 'Phenotype', 'HP:0012034', (61, 72))	('disease-specific survival', 'CPA', (170, 195))	('19q13', 'Gene', (82, 87))	('poor', 'NegReg', (108, 112))
267007	25915910	This chromosome region includes the CEBP gene, and copy number loss of 19q correlated with downregulation of CEBP mRNA expression.	('CEBP', 'Gene', (36, 40))	('downregulation', 'NegReg', (91, 105))	('CEBP', 'Gene', '1050', (36, 40))	('CEBP', 'Gene', (109, 113))	('CEBP', 'Gene', '1050', (109, 113))	('copy number loss', 'Var', (51, 67))
267011	25915910	These results suggest that primary retroperitoneal dedifferentiated liposarcoma patients harboring CEBP promoter methylation are at high risk of recurrence.	('patients', 'Species', '9606', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('methylation', 'Var', (113, 124))	('CEBP', 'Gene', (99, 103))	('CEBP', 'Gene', '1050', (99, 103))	('liposarcoma', 'Phenotype', 'HP:0012034', (68, 79))	('primary retroperitoneal dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (27, 79))
267073	30254937	The power morcellation is associated with an increased risk of recurrence, shorten time to recurrence, and a marked increased risk of peritoneal recurrence when compared to uLMS removed by nonpower morcellation or en bloc removal in the first surgery.	('uLMS', 'Phenotype', 'HP:0002891', (173, 177))	('power morcellation', 'Var', (4, 22))	('peritoneal recurrence', 'Disease', (134, 155))	('LMS', 'Disease', (174, 177))	('LMS', 'Disease', 'MESH:C535903', (174, 177))
267096	30254937	The power morcellation yields a significant risk of recurrence, potential for intra-abdominal tumor spread, and upstaging after re-exploration.	('upstaging', 'CPA', (112, 121))	('intra-abdominal tumor', 'Disease', 'None', (78, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('power morcellation', 'Var', (4, 22))	('intra-abdominal tumor', 'Disease', (78, 99))	('recurrence', 'CPA', (52, 62))
267128	29770138	Although increasing number of studies are demonstrating CTA re-expression in cancer, their functional role in oncogenesis is largely unexplored.	('re-expression', 'Var', (60, 73))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (77, 83))	('CTA', 'Protein', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
267180	29770138	Further, in colorectal cancer, the presence of NY-ESO-1 antibodies has been recently correlated with several prognostic clinicopathological parameters including depth of tumor invasion, clinical stage, lymph node, and distant metastasis.	('presence', 'Var', (35, 43))	('colorectal cancer', 'Disease', (12, 29))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('distant metastasis', 'CPA', (218, 236))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('NY-ESO-1', 'Gene', '1485', (47, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('tumor', 'Disease', (170, 175))	('lymph node', 'CPA', (202, 212))	('correlated', 'Reg', (85, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('NY-ESO-1', 'Gene', (47, 55))
267201	29770138	Other modifications to the acellular vaccine approach currently in clinical trial are the use of a bacterial vector for NY-ESO-1 vaccine delivery (NCT01967758, Table 1); and combinatorial treatment of NY-ESO-1 vaccination with the mTOR inhibitor Sirolimus (NCT01536054, NCT02833506, Table 1) or with the demethylating agent Decitabine (NCT02750995, Table 1).	('Sirolimus', 'Chemical', 'MESH:D020123', (246, 255))	('NCT02833506', 'Var', (270, 281))	('NY-ESO-1', 'Gene', (201, 209))	('NY-ESO-1', 'Gene', '1485', (120, 128))	('mTOR', 'Gene', '2475', (231, 235))	('mTOR', 'Gene', (231, 235))	('Decitabine', 'Chemical', 'MESH:D000077209', (324, 334))	('NY-ESO-1', 'Gene', '1485', (201, 209))	('NY-ESO-1', 'Gene', (120, 128))	('NCT01536054', 'Var', (257, 268))
267203	29770138	The safety and efficacy of NY-ESO-1-pulsed DCs is currently under study in various clinical trials (Table 1), either alone (NCT02692976, NCT01883518, NCT02334735, NCT02224599) or in combination with a NY-ESO-1 protein vaccine and TLR4 agonist (NCT02387125).	('NY-ESO-1', 'Gene', (27, 35))	('TLR4', 'Gene', (230, 234))	('TLR4', 'Gene', '7099', (230, 234))	('NY-ESO-1', 'Gene', '1485', (201, 209))	('NY-ESO-1', 'Gene', (201, 209))	('NCT01883518', 'Var', (137, 148))	('NY-ESO-1', 'Gene', '1485', (27, 35))	('NCT02224599', 'Var', (163, 174))	('NCT02334735', 'Var', (150, 161))	('NCT02692976', 'Var', (124, 135))
267215	29770138	In a first cohort, approximately half of patients with metastatic melanoma or synovial cell sarcoma who received NY-ESO-1 transduced CD8+ T cells and IL-2 showed a clinical response.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('NY-ESO-1', 'Gene', '1485', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('synovial cell sarcoma', 'Phenotype', 'HP:0012570', (78, 99))	('transduced', 'Var', (122, 132))	('CD8', 'Gene', (133, 136))	('CD8', 'Gene', '925', (133, 136))	('synovial cell sarcoma', 'Disease', (78, 99))	('patients', 'Species', '9606', (41, 49))	('synovial cell sarcoma', 'Disease', 'MESH:D013584', (78, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('NY-ESO-1', 'Gene', (113, 121))
267222	29770138	While some current trials, summarized in Table 2, study NY-ESO-1 specific or multi-TAA TCR-transduced T cells in a range of advanced solid tumors (NCT03047811, NCT02457650, NCT02869217, NCT02366546), others focus on subgroups of patients with esophageal cancer (NCT01795976), breast cancer (NCT03093350), pancreatic cancer (NCT03192462), rhabdomyosarcoma (NCT02239861), hepatocellular carcinoma (NCT03175705), synovial sarcoma (NCT03250325), or hematological cancers (NCT02494167, NCT02291848).	('patients', 'Species', '9606', (229, 237))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (305, 322))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (338, 354))	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (410, 426))	('esophageal cancer', 'Disease', (243, 260))	('breast cancer', 'Disease', (276, 289))	('NCT03192462', 'Var', (324, 335))	('NY-ESO-1', 'Gene', '1485', (56, 64))	('hematological cancers', 'Disease', (445, 466))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (370, 394))	('carcinoma', 'Phenotype', 'HP:0030731', (385, 394))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('NY-ESO-1', 'Gene', (56, 64))	('solid tumors', 'Disease', 'MESH:D009369', (133, 145))	('hematological cancers', 'Disease', 'MESH:D009369', (445, 466))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('NCT02494167', 'Var', (468, 479))	('NCT03047811', 'Var', (147, 158))	('NCT01795976', 'Var', (262, 273))	('pancreatic cancer', 'Disease', 'MESH:D010190', (305, 322))	('esophageal cancer', 'Disease', 'MESH:D004938', (243, 260))	('NCT03093350', 'Var', (291, 302))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (370, 394))	('cancers', 'Phenotype', 'HP:0002664', (459, 466))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('sarcoma', 'Phenotype', 'HP:0100242', (347, 354))	('sarcoma', 'Phenotype', 'HP:0100242', (419, 426))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('NCT03250325', 'Var', (428, 439))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('rhabdomyosarcoma', 'Disease', (338, 354))	('pancreatic cancer', 'Disease', (305, 322))	('NCT02239861', 'Var', (356, 367))	('hepatocellular carcinoma', 'Disease', (370, 394))	('synovial sarcoma', 'Disease', (410, 426))	('NCT03175705', 'Var', (396, 407))	('synovial sarcoma', 'Disease', 'MESH:D013584', (410, 426))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('solid tumors', 'Disease', (133, 145))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (338, 354))
267225	29770138	Similarly, adoptive transfer of affinity-enhanced NY-ESO-1 transduced T cells is under evaluation (Table 2) in metastatic melanoma (NCT01350401), ovarian cancer (NCT01567891), synovial sarcoma (NCT01343043), myxoid/round cell liposarcoma (NCT02992743) and non-small cell lung cancer (NCT03029273, NCT02588612), and in a patient cohort with a variety of advanced solid cancers (NCT03159585).	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (256, 282))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('liposarcoma', 'Disease', (226, 237))	('NCT02992743', 'Var', (239, 250))	('synovial sarcoma', 'Disease', (176, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (146, 160))	('NCT03029273', 'Var', (284, 295))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (208, 237))	('NCT02588612', 'Var', (297, 308))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (271, 282))	('synovial sarcoma', 'Disease', 'MESH:D013584', (176, 192))	('non-small cell lung cancer', 'Disease', (256, 282))	('advanced solid cancers', 'Disease', 'MESH:D006223', (353, 375))	('liposarcoma', 'Phenotype', 'HP:0012034', (226, 237))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('ovarian cancer', 'Disease', (146, 160))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (176, 192))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('ovarian cancer', 'Phenotype', 'HP:0100615', (146, 160))	('liposarcoma', 'Disease', 'MESH:D008080', (226, 237))	('NY-ESO-1', 'Gene', '1485', (50, 58))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (256, 282))	('advanced solid cancers', 'Disease', (353, 375))	('NCT01343043', 'Var', (194, 205))	('NCT01350401', 'Var', (132, 143))	('patient', 'Species', '9606', (320, 327))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (260, 282))	('NY-ESO-1', 'Gene', (50, 58))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('NCT01567891', 'Var', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancers', 'Phenotype', 'HP:0002664', (368, 375))
267226	29770138	Furthermore, the safety, feasibility, and efficacy of NY-ESO-1 or multi TAA transduced T cell therapy in combination with other modalities is currently under review, including combination with treatment with the demethylating agent Decitabine (NCT03017131, NCT01333046, Table 3), NY-ESO-1157-165-pulsed DCs (NCT01697527, Table 3), transduced peripheral blood stem cells (NCT03240861, Table 3), or dominant-negative transforming growth factor-beta receptor II transduced TILs (NCT02650986, Table 3).	('NY-ESO-1', 'Gene', '1485', (54, 62))	('NY-ESO-1', 'Gene', '1485', (280, 288))	('NY-ESO-1', 'Gene', (54, 62))	('NY-ESO-1', 'Gene', (280, 288))	('NCT03240861', 'Var', (371, 382))	('NCT03017131', 'Var', (244, 255))	('Decitabine', 'Chemical', 'MESH:D000077209', (232, 242))
267228	29770138	For example, a case study demonstrated that treatment with HLA-DP4-restricted NY-ESO-1 transduced CD4+ T cells can induce complete regression of a refractory metastatic melanoma, with a durable response ongoing at 22 months.	('CD4', 'Gene', '920', (98, 101))	('NY-ESO-1', 'Gene', '1485', (78, 86))	('HLA-DP', 'Gene', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('HLA-DP', 'Gene', '3115', (59, 65))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('transduced', 'Var', (87, 97))	('NY-ESO-1', 'Gene', (78, 86))	('CD4', 'Gene', (98, 101))	('regression', 'NegReg', (131, 141))
267249	29770138	Therefore, a pilot phase I trial has been designed to determine the safety and efficacy of combining CTLA-4 blockade with NY-ESO-1 adoptive T cell therapy and NY-ESO-1 vaccination in patients with locally advanced or metastatic malignancies (NCT02070406, Table 3).	('metastatic', 'CPA', (217, 227))	('NY-ESO-1', 'Gene', (159, 167))	('malignancies', 'Disease', (228, 240))	('NY-ESO-1', 'Gene', '1485', (122, 130))	('locally advanced', 'Disease', (197, 213))	('NY-ESO-1', 'Gene', '1485', (159, 167))	('CTLA-4', 'Gene', (101, 107))	('blockade', 'Var', (108, 116))	('malignancies', 'Disease', 'MESH:D009369', (228, 240))	('NY-ESO-1', 'Gene', (122, 130))	('patients', 'Species', '9606', (183, 191))
267250	29770138	Similarly to CTLA-4 inhibition, inhibition of the immune checkpoint molecule PD-1 induces a NY-ESO-1 specific CD8+ cytotoxic immune response.	('induces', 'Reg', (82, 89))	('inhibition', 'Var', (32, 42))	('NY-ESO-1', 'Gene', '1485', (92, 100))	('CD8', 'Gene', (110, 113))	('NY-ESO-1', 'Gene', (92, 100))	('CD8', 'Gene', '925', (110, 113))	('PD-1', 'Gene', (77, 81))
267252	29770138	In vitro blockade of both PD-1 and Tim-3 increased cytotoxic cell proliferation and cytokine secretion of NY-ESO-1157-165 CD8+ T cells.	('PD-1', 'Gene', (26, 30))	('increased', 'PosReg', (41, 50))	('Tim-3', 'Gene', (35, 40))	('cytokine secretion', 'MPA', (84, 102))	('NY-ESO-1', 'Gene', '1485', (106, 114))	('CD8', 'Gene', (122, 125))	('cytotoxic cell proliferation', 'CPA', (51, 79))	('Tim-3', 'Gene', '84868', (35, 40))	('CD8', 'Gene', '925', (122, 125))	('NY-ESO-1', 'Gene', (106, 114))	('blockade', 'Var', (9, 17))
267258	29770138	In this study, NY-ESO-1 transduced T cells could infiltrate tumors and reduce tumor growth by 50%; however, the cells could not reduce tumor burden and showed upregulation of PD-1, Tim-3, and LAG-3.	('reduce', 'NegReg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (60, 65))	('Tim-3', 'Gene', (181, 186))	('NY-ESO-1', 'Gene', '1485', (15, 23))	('transduced', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('NY-ESO-1', 'Gene', (15, 23))	('LAG-3', 'Gene', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('Tim-3', 'Gene', '84868', (181, 186))	('PD-1', 'Gene', (175, 179))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumors', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('LAG-3', 'Gene', '3902', (192, 197))	('upregulation', 'PosReg', (159, 171))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
267259	29770138	PD-1 blockade in addition to injection of transduced T cells reduced the tumor burden with an additional 35%.	('blockade', 'Var', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PD-1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('T cells reduced', 'Phenotype', 'HP:0005403', (53, 68))	('tumor', 'Disease', (73, 78))	('reduced', 'NegReg', (61, 68))
267260	29770138	Ongoing clinical trials are exploring the safety of combining NY-ESO-1 peptide vaccination with Nivolumab (NCT01176461, Table 3), or with both Nivolumab and Ipilimumab (NCT01176474, Table 3).	('NY-ESO-1', 'Gene', (62, 70))	('Nivolumab', 'Chemical', 'MESH:D000077594', (143, 152))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (157, 167))	('Nivolumab', 'Chemical', 'MESH:D000077594', (96, 105))	('NY-ESO-1', 'Gene', '1485', (62, 70))	('NCT01176461', 'Var', (107, 118))
267268	29770138	Since then, several preclinical studies have shown that demethylation not only increases expression of NY-ESO-1 specifically in tumor cells, but also induces specific CD8+ immune responses and tumor cell cytotoxicity; and when used in combination with NY-ESO-1 immunotherapy it reduced the tumor burden and prolonged the survival in several mouse models.	('CD8', 'Gene', '925', (167, 170))	('mouse', 'Species', '10090', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('NY-ESO-1', 'Gene', '1485', (103, 111))	('demethylation', 'Var', (56, 69))	('tumor', 'Disease', (290, 295))	('expression', 'MPA', (89, 99))	('NY-ESO-1', 'Gene', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('prolonged', 'PosReg', (307, 316))	('tumor', 'Disease', (193, 198))	('survival', 'CPA', (321, 329))	('increases', 'PosReg', (79, 88))	('CD8', 'Gene', (167, 170))	('reduced', 'NegReg', (278, 285))	('NY-ESO-1', 'Gene', '1485', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', (128, 133))	('NY-ESO-1', 'Gene', (252, 260))	('cytotoxicity', 'Disease', (204, 216))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cytotoxicity', 'Disease', 'MESH:D064420', (204, 216))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('induces', 'Reg', (150, 157))
267269	29770138	These experimental findings suggest that epigenetic modulation may enhance or even enable NY-ESO-1 adoptive immunotherapy in poorly immunogenic tumor types.	('enable', 'PosReg', (83, 89))	('immunogenic tumor', 'Disease', 'MESH:D009369', (132, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('NY-ESO-1', 'Gene', (90, 98))	('enhance', 'PosReg', (67, 74))	('immunogenic tumor', 'Disease', (132, 149))	('NY-ESO-1', 'Gene', '1485', (90, 98))	('epigenetic modulation', 'Var', (41, 62))
267390	31632884	These techniques included depression with expiration, T6-10 anterior-superior NAGs and T6-10 anterior-superior with side bending SNAGs.	('T6-10', 'Var', (87, 92))	('depression', 'Disease', 'MESH:D003866', (26, 36))	('T6-10', 'Var', (54, 59))	('depression', 'Phenotype', 'HP:0000716', (26, 36))	('depression', 'Disease', (26, 36))
267476	30915039	Orf50/RTA auto-activates its own promoter and transactivates the expression of several downstream lytic genes such as K5, K8, K2, K12, ORF6, ORF57, ORF74, K9, ORF59, vIL6, PAN-RNA, vIRF1, K1, and ORF65, either through an RTA-responsive element (RRE) or via other viral regulatory genes.	('vIL6', 'Gene', '4961449', (166, 170))	('ORF74', 'Var', (148, 153))	('ORF59', 'Var', (159, 164))	('transactivates', 'Reg', (46, 60))	('ORF65', 'Gene', (196, 201))	('auto-activates', 'PosReg', (10, 24))	('ORF6', 'Gene', (135, 139))	('expression', 'MPA', (65, 75))	('PAN', 'Gene', (172, 175))	('promoter', 'MPA', (33, 41))	('Orf50', 'Gene', '4961526', (0, 5))	('ORF57', 'Gene', (141, 146))	('PAN', 'Gene', '51816', (172, 175))	('vIL6', 'Gene', (166, 170))	('Orf50', 'Gene', (0, 5))	('K12', 'Gene', (130, 133))	('K12', 'Gene', '3859', (130, 133))
267512	30915039	VEGF-A, VEGF-C (angiogenic molecules), GRO (cytokine with inflammatory and growth-regulatory properties), RANTES, and SDF-1 were alleviated upon blocking COX-2.	('RANTES', 'Gene', (106, 112))	('VEGF-A', 'Gene', '7422', (0, 6))	('VEGF-A', 'Gene', (0, 6))	('VEGF-C', 'Gene', (8, 14))	('RANTES', 'Gene', '6352', (106, 112))	('COX-2', 'Gene', (154, 159))	('SDF-1', 'Gene', '6387', (118, 123))	('alleviated', 'NegReg', (129, 139))	('blocking', 'Var', (145, 153))	('COX-2', 'Gene', '5743', (154, 159))	('VEGF-C', 'Gene', '7424', (8, 14))	('SDF-1', 'Gene', (118, 123))
267515	30915039	KSHV-induced COX-2 enhanced the levels of these molecules and promoted endothelial cell tube formation, while this effect was reversed upon blocking COX-2 using chemical inhibitors.	('levels of these molecules', 'MPA', (32, 57))	('KSHV', 'Species', '37296', (0, 4))	('endothelial cell tube formation', 'CPA', (71, 102))	('COX-2', 'Gene', (149, 154))	('COX-2', 'Gene', '5743', (149, 154))	('COX-2', 'Gene', (13, 18))	('KSHV-induced', 'Var', (0, 12))	('promoted', 'PosReg', (62, 70))	('COX-2', 'Gene', '5743', (13, 18))	('enhanced', 'PosReg', (19, 27))
267533	30915039	PI3K, PKC, FAK, MEK, P38, and JNK inhibition strongly reduced COX-2 promoter activity and its gene expression.	('COX-2', 'Gene', (62, 67))	('PKC', 'Gene', (6, 9))	('P38', 'Gene', (21, 24))	('PKC', 'Gene', '112476', (6, 9))	('inhibition', 'Var', (34, 44))	('COX-2', 'Gene', '5743', (62, 67))	('JNK', 'Gene', (30, 33))	('PI3', 'Gene', '5266', (0, 3))	('FAK', 'Gene', (11, 14))	('reduced', 'NegReg', (54, 61))	('MEK', 'Gene', (16, 19))	('FAK', 'Gene', '5747', (11, 14))	('gene expression', 'MPA', (94, 109))	('JNK', 'Gene', '5599', (30, 33))	('P38', 'Gene', '5594', (21, 24))	('MEK', 'Gene', '5609', (16, 19))	('PI3', 'Gene', (0, 3))
267541	30915039	Blocking COX-2 with celecoxib or NS398 [N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide] decreased activation of signaling molecules including NFKB (reduced nuclear translocation of p65), FAK, Src, AKT, ERK, P-38, RSK, and Rac1-GTPase, and thereby decreased vFLIP-mediated protection of HMVECs from anoikis.	('celecoxib', 'Chemical', 'MESH:D000068579', (20, 29))	('COX-2', 'Gene', '5743', (9, 14))	('P-38', 'Gene', (213, 217))	('FAK', 'Gene', (193, 196))	('P-38', 'Gene', '5594', (213, 217))	('Src', 'Gene', (198, 201))	('Rac1', 'Gene', (228, 232))	('p65', 'Gene', '5970', (187, 190))	('ERK', 'Gene', '5594', (208, 211))	('nuclear translocation', 'MPA', (162, 183))	('decreased', 'NegReg', (253, 262))	('AKT', 'Gene', '207', (203, 206))	('NFKB', 'Gene', (148, 152))	('FAK', 'Gene', '5747', (193, 196))	('Src', 'Gene', '6714', (198, 201))	('activation', 'PosReg', (104, 114))	('AKT', 'Gene', (203, 206))	('ERK', 'Gene', (208, 211))	('decreased', 'NegReg', (94, 103))	('signaling', 'MPA', (118, 127))	('vFLIP', 'Gene', '4961494', (263, 268))	('Rac1', 'Gene', '5879', (228, 232))	('vFLIP', 'Gene', (263, 268))	('N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide', 'Chemical', 'MESH:C080955', (40, 92))	('COX-2', 'Gene', (9, 14))	('RSK', 'Gene', (219, 222))	('NS398', 'Chemical', 'MESH:C080955', (33, 38))	('NS398', 'Var', (33, 38))	('RSK', 'Gene', '6196', (219, 222))	('p65', 'Gene', (187, 190))
267550	30915039	Exogenous PGE2 supplementation could reverse this inhibitory effect of indomethacin and NS-398.	('supplementation', 'Var', (15, 30))	('PGE2', 'Chemical', 'MESH:D015232', (10, 14))	('NS-398', 'Chemical', 'MESH:C080955', (88, 94))	('PGE2', 'Gene', (10, 14))	('indomethacin', 'Chemical', 'MESH:D007213', (71, 83))
267585	30915039	Blocking EP1 in TIVE-LTC cells reduced KSHV latency protein LANA1 while blocking EP4 downregulated COX-2 gene expression and PGE2 levels suggesting that KSHV utilizes EP receptors to maintain latency and COX-2/PGE2 levels.	('PGE2 levels', 'MPA', (125, 136))	('EP1', 'Gene', (9, 12))	('downregulated', 'NegReg', (85, 98))	('reduced', 'NegReg', (31, 38))	('EP4', 'Gene', '5734', (81, 84))	('COX-2', 'Gene', (204, 209))	('PGE2', 'Chemical', 'MESH:D015232', (210, 214))	('EP4', 'Gene', (81, 84))	('COX-2', 'Gene', '5743', (204, 209))	('PGE2', 'Chemical', 'MESH:D015232', (125, 129))	('EP1', 'Gene', '5731', (9, 12))	('COX-2', 'Gene', (99, 104))	('KSHV', 'Species', '37296', (39, 43))	('KSHV', 'Species', '37296', (153, 157))	('blocking', 'Var', (72, 80))	('COX-2', 'Gene', '5743', (99, 104))
267591	30915039	KSHV induced PGE2 induced Ca2+ levels, which sequentially enhanced signaling via EP1 receptor.	('EP1', 'Gene', (81, 84))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('PGE2', 'Chemical', 'MESH:D015232', (13, 17))	('enhanced', 'PosReg', (58, 66))	('PGE2', 'Gene', (13, 17))	('EP1', 'Gene', '5731', (81, 84))	('Ca2+ levels', 'MPA', (26, 37))	('Ca2+', 'Chemical', 'MESH:D000069285', (26, 30))	('signaling', 'MPA', (67, 76))
267597	30915039	A combination of COX-2 inhibitor celecoxib, EP1 antagonist SC-51322, and EP4 antagonist GW 627368X induced apoptosis and promoted expression of tumor suppressors such as ATM, FHIT, HIC1, MCL1, NCAM1, RASSF1, TIMP2, TIMP3, and TP53 in PEL cells.	('expression', 'MPA', (130, 140))	('ATM', 'Gene', (170, 173))	('EP1', 'Gene', (44, 47))	('SC-51322', 'Chemical', '-', (59, 67))	('SC-51322', 'Var', (59, 67))	('FHIT', 'Gene', '2272', (175, 179))	('MCL1', 'Gene', '4170', (187, 191))	('EP4', 'Gene', '5734', (73, 76))	('TP53', 'Gene', (226, 230))	('EP4', 'Gene', (73, 76))	('COX-2', 'Gene', '5743', (17, 22))	('GW 627368X', 'Chemical', 'MESH:C515270', (88, 98))	('TIMP2', 'Gene', '7077', (208, 213))	('NCAM1', 'Gene', (193, 198))	('apoptosis', 'CPA', (107, 116))	('celecoxib', 'Chemical', 'MESH:D000068579', (33, 42))	('tumor', 'Disease', (144, 149))	('HIC1', 'Gene', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('TIMP3', 'Gene', (215, 220))	('TIMP3', 'Gene', '7078', (215, 220))	('ATM', 'Gene', '472', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('induced', 'PosReg', (99, 106))	('RASSF1', 'Gene', '11186', (200, 206))	('EP1', 'Gene', '5731', (44, 47))	('TP53', 'Gene', '7157', (226, 230))	('RASSF1', 'Gene', (200, 206))	('HIC1', 'Gene', '3090', (181, 185))	('FHIT', 'Gene', (175, 179))	('NCAM1', 'Gene', '4684', (193, 198))	('TIMP2', 'Gene', (208, 213))	('promoted', 'PosReg', (121, 129))	('MCL1', 'Gene', (187, 191))	('COX-2', 'Gene', (17, 22))
267608	30915039	Targeting of 5LO/LTB4 provides a new avenue of treatment against KSHV associated malignancies.	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('KSHV', 'Species', '37296', (65, 69))	('malignancies', 'Disease', (81, 93))	('5LO/LTB4', 'Var', (13, 21))	('LTB4', 'Chemical', 'MESH:D007975', (17, 21))
267616	30915039	Similar upregulation of 5LO pathway enzymes was seen in KSHV infected BCBL-1 than KSHV negative BJAB cells.	('upregulation', 'PosReg', (8, 20))	('KSHV infected', 'Var', (56, 69))	('BJAB', 'CellLine', 'CVCL:5711', (96, 100))	('KSHV', 'Species', '37296', (56, 60))	('5LO pathway enzymes', 'Enzyme', (24, 43))	('KSHV', 'Species', '37296', (82, 86))
267624	30915039	Treating BCBL-1 cells with NF-kappaB inhibitor Bay11-7082 has shown to drastically reduce the levels of 5LO (Figure 4).	('Bay11-7082', 'Chemical', 'MESH:C434003', (47, 57))	('Bay11-7082', 'Var', (47, 57))	('NF-kappaB', 'Gene', '4790', (27, 36))	('NF-kappaB', 'Gene', (27, 36))	('levels of 5LO', 'MPA', (94, 107))	('reduce', 'NegReg', (83, 89))
267629	30915039	MK866 is an orally active anticancer drug that blocks binding of 5LO to the membrane by specifically interacting with the membrane-bound activating protein FLAP, which is necessary for cellular LT biosynthesis.	('blocks', 'NegReg', (47, 53))	('interacting', 'Interaction', (101, 112))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('MK866', 'Chemical', '-', (0, 5))	('MK866', 'Var', (0, 5))	('binding', 'Interaction', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
267639	30915039	Silencing 5LO reversed lipogenesis by lowering FASN promoter activity and its expression.	('5LO', 'Gene', (10, 13))	('expression', 'MPA', (78, 88))	('lipogenesis', 'MPA', (23, 34))	('FASN', 'Gene', '2194', (47, 51))	('lowering', 'NegReg', (38, 46))	('Silencing', 'Var', (0, 9))	('FASN', 'Gene', (47, 51))
267673	30915039	Knocking down ALXR/FPR in Osteosarcoma U2OS cells using CRISPR/CAS9 technology affected lipoxin signaling as high levels of NFKB, AKT, ERK1/2, and inflammatory proteins (COX-2, 5LO) were still persistent in lipoxin treated cells.	('Osteosarcoma', 'Disease', (26, 38))	('AKT', 'Gene', '207', (130, 133))	('Osteosarcoma', 'Disease', 'MESH:D012516', (26, 38))	('affected', 'Reg', (79, 87))	('lipoxin signaling', 'MPA', (88, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('ERK1/2', 'Gene', (135, 141))	('ERK1/2', 'Gene', '5595;5594', (135, 141))	('lipoxin', 'Chemical', 'MESH:D044045', (207, 214))	('ALXR', 'Gene', (14, 18))	('U2OS', 'CellLine', 'CVCL:0042', (39, 43))	('lipoxin', 'Chemical', 'MESH:D044045', (88, 95))	('FPR', 'Gene', '2357', (19, 22))	('COX-2', 'Gene', (170, 175))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('AKT', 'Gene', (130, 133))	('COX-2', 'Gene', '5743', (170, 175))	('FPR', 'Gene', (19, 22))	('ALXR', 'Gene', '2358', (14, 18))	('Knocking', 'Var', (0, 8))
267688	30915039	Studies so far have shown that KSHV alters the lipid mediators of the arachidonic acid pathway for its own advantage.	('alters', 'Reg', (36, 42))	('KSHV', 'Species', '37296', (31, 35))	('arachidonic acid', 'Chemical', 'MESH:D016718', (70, 86))	('KSHV', 'Var', (31, 35))	('lipid mediators', 'MPA', (47, 62))	('lipid', 'Chemical', 'MESH:D008055', (47, 52))
267738	30170102	For dosimetry comparison between IMRT and AP WLI the different cardiac volumes (V) receiving percentage (%) of prescribed RT doses (V95, V83, V67, V50) were estimated.	('V83', 'Var', (137, 140))	('V67', 'Chemical', 'MESH:C088036', (142, 145))	('V95', 'Var', (132, 135))	('V67', 'Var', (142, 145))	('V50', 'Var', (147, 150))
267743	30170102	Using the AP WLI plan and IMRT plans the following dose-volume histograms (DVHs) were calculated:V100, 105, V110 for lungs; V95, V83, V67, V50 for the atria and ventricles, myocardium, coronary arteries, stomach, liver, kidneys and thyroid; and V5, V10 isodose lines.	('V100', 'Var', (97, 101))	('V67', 'Var', (134, 137))	('V95', 'Var', (124, 127))	('V50', 'Var', (139, 142))	('V110', 'Var', (108, 112))	('V67', 'Chemical', 'MESH:C088036', (134, 137))	('V83', 'Var', (129, 132))
267754	30170102	Assuming that for each structure, four statistical tests would be done, one each at V95, V83, V67 and V50 with 20 patients, there would be an 80% power to detect a difference of 100% with Standard AP WLI versus 93% with IMRT assuming a standard deviation of 8 (as seen for the whole heart), a one-tailed test and a Bonferroni correction for 4 statistical tests so that each test was done at p<0.0125.	('V67', 'Chemical', 'MESH:C088036', (94, 97))	('V67', 'Var', (94, 97))	('V50', 'Var', (102, 105))	('patients', 'Species', '9606', (114, 122))	('V83', 'Var', (89, 92))
267767	30170102	The dosimetry data shown in table 1 and figures 1 and 5, show that compared to standard AP WLI, CS IMRT resulted in significantly lower radiation dose exposure to the mean whole heart, left and right ventricles and left ventricular myocardium for V95, V83, V67 and V50.	('V50', 'Var', (265, 268))	('V95', 'Var', (247, 250))	('lower', 'NegReg', (130, 135))	('radiation dose exposure', 'MPA', (136, 159))	('ventricular myocardium', 'Disease', (220, 242))	('V67', 'Var', (257, 260))	('V83', 'Var', (252, 255))	('ventricular myocardium', 'Disease', 'MESH:D056830', (220, 242))	('V67', 'Chemical', 'MESH:C088036', (257, 260))
267768	30170102	For the coronary arteries, whole lung CS IMRT also resulted in significantly lower doses for V95, V83 and V67.	('V83', 'Var', (98, 101))	('lower', 'NegReg', (77, 82))	('V67', 'Var', (106, 109))	('doses for V95', 'MPA', (83, 96))	('V67', 'Chemical', 'MESH:C088036', (106, 109))
267792	30170102	Anthracycline doses >= 250mg/m2 and cardiac doses >= 15Gy were associated with complications.The Institute Gustave Roussy report showed that the 20 year incidence of CHF was 18% after heart dose >3.7Gy and 9% after lower doses.	('CHF', 'Disease', 'MESH:D006333', (166, 169))	('Anthracycline', 'Chemical', 'MESH:D018943', (0, 13))	('heart dose >3.7Gy', 'Var', (184, 201))	('CHF', 'Disease', (166, 169))
267796	30170102	In a recent review of the epidemiology and pathophysiology of cardiovascular disease in childhood Cancer survivors, the known risk factors for cardiomyopathy/congestive heart failure were anthracyclines >=250mg/m2 when administered alone or anthracyclines >=100mg/m2 when administered in combination with >=15Gy chest RT.	('cardiovascular disease', 'Disease', (62, 84))	('>=250mg/m2', 'Var', (203, 213))	('childhood Cancer', 'Disease', 'MESH:D009369', (88, 104))	('congestive heart failure', 'Phenotype', 'HP:0001635', (158, 182))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (62, 84))	('cardiomyopathy', 'Disease', (143, 157))	('congestive heart failure', 'Disease', 'MESH:D006333', (158, 182))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('congestive heart failure', 'Disease', (158, 182))	('cardiovascular disease', 'Disease', 'MESH:D002318', (62, 84))	('anthracyclines', 'Chemical', 'MESH:D018943', (188, 202))	('childhood Cancer', 'Disease', (88, 104))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (143, 157))	('anthracyclines', 'Chemical', 'MESH:D018943', (241, 255))	('cardiomyopathy', 'Disease', 'MESH:D009202', (143, 157))	('>=100mg/m2', 'Var', (256, 266))
267806	24993903	Malignant Round Cell Tumor of Bone with EWSR1-NFATC2 Gene Fusion Gene rearrangements involving the Ewing sarcoma breakpoint region 1 ('EWSR1) gene are seen in a broad range of sarcomas and some non-mesenchymal neoplasms.	('NFATC2', 'Gene', '4773', (46, 52))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (99, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (198, 219))	('rearrangements', 'Var', (70, 84))	('Tumor of Bone', 'Phenotype', 'HP:0010622', (21, 34))	('EWSR1', 'Gene', '2130', (135, 140))	('neoplasms', 'Phenotype', 'HP:0002664', (210, 219))	('Round Cell Tumor of Bone', 'Phenotype', 'HP:0011847', (10, 34))	('EWSR1', 'Gene', '2130', (40, 45))	('Tumor', 'Phenotype', 'HP:0002664', (21, 26))	('NFATC2', 'Gene', (46, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('mesenchymal neoplasms', 'Disease', (198, 219))	('seen', 'Reg', (151, 155))	('sarcomas', 'Disease', 'MESH:D012509', (176, 184))	('EWSR1', 'Gene', (135, 140))	('Ewing sarcoma breakpoint region 1', 'Gene', (99, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (99, 112))	('EWSR1', 'Gene', (40, 45))	('Malignant Round Cell Tumor of Bone', 'Disease', (0, 34))	('sarcomas', 'Disease', (176, 184))
267808	24993903	More recently, EWSR1 gene fusion to non-ETS family members, including the nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene has been reported in a histological variant of Ewing sarcoma.	('fusion', 'Var', (26, 32))	('reported', 'Reg', (171, 179))	('NFATC2', 'Gene', (149, 155))	('Ewing sarcoma', 'Disease', (209, 222))	('EWSR1', 'Gene', (15, 20))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (209, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (209, 222))	('NFATC2', 'Gene', '4773', (149, 155))	('EWSR1', 'Gene', '2130', (15, 20))	('nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2', 'Gene', '4773', (74, 147))
267809	24993903	Here we report a malignant round cell tumor of bone with an EWSR1-NFATC2 fusion gene.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor of bone', 'Phenotype', 'HP:0010622', (38, 51))	('fusion gene', 'Var', (73, 84))	('NFATC2', 'Gene', (66, 72))	('EWSR1', 'Gene', '2130', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('EWSR1', 'Gene', (60, 65))	('NFATC2', 'Gene', '4773', (66, 72))	('round cell tumor of bone', 'Phenotype', 'HP:0011847', (27, 51))
267810	24993903	This report builds upon the unusual morphological and clinical presentation of bone neoplasms containing an EWSR1-NFATC2 fusion gene.	('bone neoplasms', 'Disease', 'MESH:D001859', (79, 93))	('neoplasms', 'Phenotype', 'HP:0002664', (84, 93))	('bone neoplasms', 'Disease', (79, 93))	('EWSR1', 'Gene', (108, 113))	('NFATC2', 'Gene', (114, 120))	('EWSR1', 'Gene', '2130', (108, 113))	('bone neoplasms', 'Phenotype', 'HP:0010622', (79, 93))	('NFATC2', 'Gene', '4773', (114, 120))	('fusion gene', 'Var', (121, 132))
267813	24993903	In 85 to 90% of cases the translocation is t(11;22)(q24;q12) resulting in EWSR1-FLI1 fusion gene.	('t(11;22)(q24;q12', 'Var', (43, 59))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (43, 60))	('EWSR1', 'Gene', '2130', (74, 79))	('EWSR1', 'Gene', (74, 79))
267816	24993903	These translocations result in the fusion of the N-terminal transactivation domain of EWSR1 with the C-terminal DNA-binding domain of the ETS family member generating a potent and oncogenic transcription factor.	('result in', 'Reg', (21, 30))	('EWSR1', 'Gene', (86, 91))	('fusion', 'Var', (35, 41))	('EWSR1', 'Gene', '2130', (86, 91))
267818	24993903	The EWSR1-FLI1 fusion promotes numerous oncogenic properties, including cell proliferation, transformation, in vivo tumor growth, and chemoresistance in experimental models and is considered a therapeutic target.	('fusion', 'Var', (15, 21))	('promotes', 'PosReg', (22, 30))	('tumor', 'Disease', (116, 121))	('EWSR1', 'Gene', '2130', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('chemoresistance', 'CPA', (134, 149))	('cell proliferation', 'CPA', (72, 90))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('transformation', 'CPA', (92, 106))	('EWSR1', 'Gene', (4, 9))
267819	24993903	More recently, rare cases of Ewing sarcoma-like tumors with fusions between EWSR1 and non-ETS family members have been described.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (29, 42))	('fusions', 'Var', (60, 67))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('EWSR1', 'Gene', (76, 81))	('Ewing sarcoma-like tumors', 'Disease', (29, 54))	('EWSR1', 'Gene', '2130', (76, 81))	('Ewing sarcoma-like tumors', 'Disease', 'MESH:C563168', (29, 54))
267821	24993903	The rearrangement of the EWSR1 gene is not specific to the Ewing sarcoma family of tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('EWSR1', 'Gene', (25, 30))	('rearrangement', 'Var', (4, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('tumors', 'Disease', (83, 89))	('Ewing sarcoma', 'Disease', (59, 72))	('EWSR1', 'Gene', '2130', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))
267823	24993903	In addition to mesenchymal tumors, EWSR1 gene fusions have also been described in hyalinizing clear cell carcinoma of salivary gland, and in rare cases of mesothelioma and mucoepidermoid carcinoma of salivary gland.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('carcinoma of salivary gland', 'Disease', 'MESH:D012468', (187, 214))	('described', 'Reg', (69, 78))	('carcinoma of salivary gland', 'Disease', 'MESH:D012468', (105, 132))	('carcinoma of salivary gland', 'Disease', (187, 214))	('EWSR1', 'Gene', (35, 40))	('fusions', 'Var', (46, 53))	('carcinoma of salivary gland', 'Disease', (105, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('carcinoma of salivary gland', 'Phenotype', 'HP:0100684', (187, 214))	('EWSR1', 'Gene', '2130', (35, 40))	('mesothelioma and mucoepidermoid carcinoma of salivary gland', 'Disease', 'MESH:D018277', (155, 214))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (15, 33))	('carcinoma of salivary gland', 'Phenotype', 'HP:0100684', (105, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mesenchymal tumors', 'Disease', (15, 33))
267824	24993903	Here we report an aggressive tumor of bone with focal small round cell features in a young male adult characterized by the amplification of the EWSR1-NFATC2 fusion gene.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('EWSR1', 'Gene', '2130', (144, 149))	('NFATC2', 'Gene', '4773', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor of bone', 'Phenotype', 'HP:0010622', (29, 42))	('tumor', 'Disease', (29, 34))	('amplification', 'Var', (123, 136))	('NFATC2', 'Gene', (150, 156))	('EWSR1', 'Gene', (144, 149))
267826	24993903	The case described in this report builds upon prior cases and expands the morphological spectrum of tumors described to contain amplification of this gene fusion.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('amplification', 'Var', (128, 141))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))
267844	24993903	The EWSR1-NFATC2 fusion was investigated by a dual-color FISH assay with Spectrum Green-labeled BAC clones RP11-367E7 and RP11-480L23 corresponding to the EWSR1-5' region and Spectrum Red-labeled BAC clones RP11-2L23 and RP11-73P15 corresponding to the NFATC2-3' region (Empire Genomics, Buffalo, NY).	('RP11-73P15', 'Var', (221, 231))	('NFATC2', 'Gene', (10, 16))	('EWSR1', 'Gene', '2130', (4, 9))	('EWSR1', 'Gene', (155, 160))	('NFATC2', 'Gene', '4773', (253, 259))	('Spectrum Green', 'Chemical', '-', (73, 87))	('RP11-367E7', 'Var', (107, 117))	('RP11-480L23', 'Var', (122, 133))	('EWSR1', 'Gene', '2130', (155, 160))	('NFATC2', 'Gene', '4773', (10, 16))	('NFATC2', 'Gene', (253, 259))	('EWSR1', 'Gene', (4, 9))
267863	24993903	To further characterize the fusion, RT-PCR was performed for the EWSR1-NFATC2 fusion transcript, and detected the predicted 573 base pair fragment (Figure 4D).	('NFATC2', 'Gene', '4773', (71, 77))	('EWSR1', 'Gene', (65, 70))	('EWSR1', 'Gene', '2130', (65, 70))	('NFATC2', 'Gene', (71, 77))	('573 base pair', 'Var', (124, 137))
267869	24993903	The presence of EWSR1-NFATC2 fusion, focal small round cell morphology and CD99 immunopositivity in the reoccurrence favor an Ewing-like sarcoma.	('EWSR1', 'Gene', '2130', (16, 21))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (126, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('NFATC2', 'Gene', '4773', (22, 28))	('CD99', 'Gene', (75, 79))	('EWSR1', 'Gene', (16, 21))	('NFATC2', 'Gene', (22, 28))	('Ewing-like sarcoma', 'Disease', (126, 144))	('fusion', 'Var', (29, 35))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (126, 144))	('CD99', 'Gene', '4267', (75, 79))
267877	24993903	Moreover, EWSR1 gene fusions, such as EWSR1-CREB3L1, have been described in small cell osteosarcomas.	('described', 'Reg', (63, 72))	('EWSR1', 'Gene', (10, 15))	('osteosarcomas', 'Disease', (87, 100))	('EWSR1', 'Gene', '2130', (10, 15))	('EWSR1', 'Gene', '2130', (38, 43))	('CREB3L1', 'Gene', '90993', (44, 51))	('CREB3L1', 'Gene', (44, 51))	('osteosarcomas', 'Phenotype', 'HP:0002669', (87, 100))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('osteosarcomas', 'Disease', 'MESH:D012516', (87, 100))	('fusions', 'Var', (21, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('EWSR1', 'Gene', (38, 43))
267879	24993903	Molecular detection of tumor-specific translocations has been widely used as a reliable diagnostic tool in soft tissue sarcomas and is beginning to be more commonly applied to bone tumors.	('sarcomas', 'Disease', (119, 127))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (107, 127))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('bone tumors', 'Disease', (176, 187))	('bone tumors', 'Disease', 'MESH:D001859', (176, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('tumor', 'Disease', (23, 28))	('bone tumors', 'Phenotype', 'HP:0010622', (176, 187))	('translocations', 'Var', (38, 52))
267880	24993903	However, the diagnostic implication of any molecular finding needs to be interpreted with morphologic, radiological, and clinical correlation as translocations with the same gene fusion are increasingly being discovered in different tumors with distinct morphology and clinical presentation.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('translocations', 'Var', (145, 159))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', (233, 239))	('discovered', 'Reg', (209, 219))
267882	24993903	The amplification of the EWSR1-NFATC2 fusion gene present in our case has been described in a series of Ewing sarcoma-like tumors as well as a myoepithelioma-like sarcoma of bone.	('NFATC2', 'Gene', (31, 37))	('Ewing sarcoma-like tumors', 'Disease', (104, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('EWSR1', 'Gene', (25, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('EWSR1', 'Gene', '2130', (25, 30))	('myoepithelioma-like sarcoma', 'Disease', 'MESH:D009208', (143, 170))	('Ewing sarcoma-like tumors', 'Disease', 'MESH:C563168', (104, 129))	('NFATC2', 'Gene', '4773', (31, 37))	('myoepithelioma-like sarcoma', 'Disease', (143, 170))	('amplification', 'Var', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('described', 'Reg', (79, 88))
267883	24993903	Our case shares similarities with Ewing sarcoma-like tumors previously described, being present in a patient older than 18 years of age, showing CD99 positivity (only on the reoccurrence) and unusual morphology with atypical cells and occasional prominent nucleoli (primarily in the reoccurrence).	('positivity', 'Var', (150, 160))	('Ewing sarcoma-like tumors', 'Disease', (34, 59))	('Ewing sarcoma-like tumors', 'Disease', 'MESH:C563168', (34, 59))	('CD99', 'Gene', '4267', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (34, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('CD99', 'Gene', (145, 149))	('patient', 'Species', '9606', (101, 108))
267929	30121442	Histopathological characterization is important because dedifferentiation confers the tumor with metastatic capability and increased risk of local recurrence following inadequate resection margins.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('dedifferentiation', 'Var', (56, 73))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('metastatic capability', 'CPA', (97, 118))
268006	25437539	Most EWS tumors have a translocation involving the EWS gene on chromosome 22 and the FLI gene on chromosome 11.	('EWS', 'Gene', (51, 54))	('FLI', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('translocation', 'Var', (23, 36))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('FLI', 'Gene', '2314', (85, 88))
268020	25437539	An analysis of the Cancer Cell Line Encyclopedia indicates that EWS behaves as an outlier and shows high levels of both PARP1 and SLNF11 compared to other cancers, including osteosarcoma (OS), another form of bone cancer.	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('Cancer', 'Disease', (19, 25))	('osteosarcoma', 'Phenotype', 'HP:0002669', (174, 186))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('osteosarcoma', 'Disease', 'MESH:D012516', (174, 186))	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('PARP1', 'Gene', (120, 125))	('PARP1', 'Gene', '142', (120, 125))	('bone cancer', 'Disease', 'MESH:D001859', (209, 220))	('bone cancer', 'Disease', (209, 220))	('SLNF11', 'Var', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', (155, 162))	('osteosarcoma', 'Disease', (174, 186))
268021	25437539	Since high levels of SLFN11 expression can increase sensitivity to DNA-damaging agents, we reasoned that EWS might be deficient in DNA-damage repair.	('high levels', 'Var', (6, 17))	('sensitivity to DNA-damaging agents', 'MPA', (52, 86))	('SLFN11', 'Gene', '91607', (21, 27))	('increase', 'PosReg', (43, 51))	('SLFN11', 'Gene', (21, 27))
268026	25437539	At 10-muM olaparib and 1- or 10-muM BMN-673, the basal level of DNA damage after 12 hours of exposure to the PARPi was elevated in ES-8, especially for BMN-673 (Figure 1D-G).	('muM', 'Gene', '56925', (6, 9))	('PARP', 'Gene', '142', (109, 113))	('muM', 'Gene', (6, 9))	('elevated', 'PosReg', (119, 127))	('olaparib', 'Chemical', 'MESH:C531550', (10, 18))	('BMN-673', 'Chemical', 'MESH:C586365', (36, 43))	('muM', 'Gene', '56925', (32, 35))	('BMN-673', 'Chemical', 'MESH:C586365', (152, 159))	('BMN-673', 'Var', (152, 159))	('BMN-673', 'Var', (36, 43))	('muM', 'Gene', (32, 35))	('PARP', 'Gene', (109, 113))
268037	25437539	To determine whether sensitivity to PARPis depends on the expression of PARP1, we knocked down PARP1 protein in ES-8 cells with an siRNA (Figure 2F-J).	('PARP1', 'Gene', '142', (72, 77))	('PARP1', 'Gene', (72, 77))	('PARP', 'Gene', (95, 99))	('PARP', 'Gene', '142', (36, 40))	('PARP', 'Gene', '142', (72, 76))	('knocked', 'Var', (82, 89))	('protein', 'Protein', (101, 108))	('PARP', 'Gene', (72, 76))	('PARP', 'Gene', '142', (95, 99))	('PARP1', 'Gene', '142', (95, 100))	('PARP', 'Gene', (36, 40))	('PARP1', 'Gene', (95, 100))
268038	25437539	For each drug, PARPi sensitivity was reduced when PARP1 expression was knocked down relative to a control siRNA, consistent with the PARP trapping mechanism.	('PARP', 'Gene', (133, 137))	('knocked', 'Var', (71, 78))	('PARP', 'Gene', '142', (50, 54))	('PARP', 'Gene', '142', (15, 19))	('PARP1', 'Gene', '142', (50, 55))	('expression', 'MPA', (56, 66))	('PARP', 'Gene', '142', (133, 137))	('PARP1', 'Gene', (50, 55))	('reduced', 'NegReg', (37, 44))	('PARP', 'Gene', (50, 54))	('PARP', 'Gene', (15, 19))
268044	25437539	We also tested 2 PET tracers (F18-deoxyglucose and C11-methionine); C11-methionine provided superior sensitivity and signal-to-noise for the orthotopic EWS xenografts (Figure 3J-M and data not shown).	('F18-deoxyglucose', 'Chemical', '-', (30, 46))	('C11-methionine', 'Chemical', 'MESH:C086242', (51, 65))	('C11-methionine', 'Var', (68, 82))	('signal-to-noise', 'MPA', (117, 132))	('C11-methionine', 'Chemical', 'MESH:C086242', (68, 82))
268051	25437539	A total of 7 drug pairs were examined (3 PARPi + SN-38, 3 PARPi + TMZ, and SN-38 + TMZ) in four EWS cell lines.	('PARP', 'Gene', '142', (58, 62))	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('SN-38', 'Chemical', 'MESH:D000077146', (49, 54))	('SN-38 + TMZ', 'Var', (75, 86))	('PARP', 'Gene', (41, 45))	('SN-38', 'Chemical', 'MESH:D000077146', (75, 80))	('PARP', 'Gene', (58, 62))	('PARP', 'Gene', '142', (41, 45))	('TMZ', 'Chemical', 'MESH:D000077204', (66, 69))
268052	25437539	In every EWS cell line tested, the fitted kappa value indicated additivity or synergy for all PARPi + SN-38 or TMZ combinations.	('additivity', 'Interaction', (64, 74))	('PARP', 'Gene', '142', (94, 98))	('synergy', 'MPA', (78, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (111, 114))	('SN-38', 'Chemical', 'MESH:D000077146', (102, 107))	('combinations', 'Var', (115, 127))	('PARP', 'Gene', (94, 98))
268083	25437539	The ES-6 cells were similar to ES-1 in their poor engraftment efficiency and slow growth but the tumors showed response to olaparib+IRN+TMZ(50%) and BMN-673(80%)+IRN+TMZ(50%) (Figure S5).	('olaparib', 'Chemical', 'MESH:C531550', (123, 131))	('BMN-673', 'Chemical', 'MESH:C586365', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ES-1', 'Gene', '8209', (31, 35))	('BMN-673', 'Var', (149, 156))	('ES-1', 'Gene', (31, 35))	('tumors', 'Disease', (97, 103))	('slow growth', 'Phenotype', 'HP:0001510', (77, 88))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('response', 'MPA', (111, 119))
268088	25437539	Our in vitro RSM predicted that BMN-673+IRN or BMN-673+TMZ would be significantly cytotoxic, olaparib+IRN may be more efficacious than olaparib+TMZ, and that veliparib-combination chemotherapy would probably not achieve significant in vivo efficacy at the dose and schedule used for these experiments.	('IRN', 'Chemical', 'MESH:D000077146', (40, 43))	('IRN', 'Chemical', 'MESH:D000077146', (102, 105))	('BMN-673', 'Chemical', 'MESH:C586365', (32, 39))	('BMN-673+IRN', 'Var', (32, 43))	('veliparib', 'Chemical', 'MESH:C521013', (158, 167))	('olaparib', 'Chemical', 'MESH:C531550', (93, 101))	('olaparib', 'Chemical', 'MESH:C531550', (135, 143))	('cytotoxic', 'CPA', (82, 91))	('BMN-673', 'Chemical', 'MESH:C586365', (47, 54))	('BMN-673+TMZ', 'Var', (47, 58))
268095	25437539	As predicted by the RSM, of the groups that received combinations of PARPis with TMZ, only those that received BMN-673+TMZ(50%) had significantly improved overall survival (p=0.0004, Fig.	('PARP', 'Gene', '142', (69, 73))	('overall survival', 'CPA', (155, 171))	('improved', 'PosReg', (146, 154))	('TMZ', 'Chemical', 'MESH:D000077204', (81, 84))	('PARP', 'Gene', (69, 73))	('TMZ', 'Chemical', 'MESH:D000077204', (119, 122))	('combinations', 'Var', (53, 65))
268096	25437539	The groups that received PARPi+IRN tolerated the combinations well; responses were significantly better in the olaparib+IRN or BMN-673+IRN groups than in the veliparib+IRN or TMZ+IRN groups (p=0.0001, Figure 5C).	('IRN', 'Chemical', 'MESH:D000077146', (135, 138))	('PARP', 'Gene', (25, 29))	('IRN', 'Chemical', 'MESH:D000077146', (120, 123))	('veliparib', 'Chemical', 'MESH:C521013', (158, 167))	('IRN', 'Chemical', 'MESH:D000077146', (168, 171))	('olaparib', 'Chemical', 'MESH:C531550', (111, 119))	('IRN', 'Chemical', 'MESH:D000077146', (31, 34))	('better', 'PosReg', (97, 103))	('IRN', 'Chemical', 'MESH:D000077146', (179, 182))	('TMZ', 'Chemical', 'MESH:D000077204', (175, 178))	('BMN-673', 'Chemical', 'MESH:C586365', (127, 134))	('BMN-673+IRN', 'Var', (127, 138))	('PARP', 'Gene', '142', (25, 29))	('responses', 'MPA', (68, 77))
268125	25437539	The majority of EWS cell lines have TP53 mutations so it is difficult to compare the sensitivity of wild type and TP53-deficient EWS cell lines to PARPis and DNA-damaging agents.	('mutations', 'Var', (41, 50))	('PARP', 'Gene', (147, 151))	('TP53', 'Gene', (36, 40))	('TP53', 'Gene', '7157', (114, 118))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (114, 118))	('PARP', 'Gene', '142', (147, 151))
268129	25437539	In a separate whole-genome sequencing study, 17% of EWS tumors had inactivating somatic mutations in STAG2, a component of the cohesin complex.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('STAG2', 'Gene', (101, 106))	('STAG2', 'Gene', '10735', (101, 106))	('inactivating', 'Var', (67, 79))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
268135	25437539	Specifically, BMN-673 may be more active as a single agent because it remains bound to PARP1 longer than does olaparib or veliparib, resulting in more persistent PARP-DNA adducts.	('BMN-673', 'Chemical', 'MESH:C586365', (14, 21))	('PARP', 'Gene', '142', (162, 166))	('PARP1', 'Gene', (87, 92))	('veliparib', 'Chemical', 'MESH:C521013', (122, 131))	('BMN-673', 'Var', (14, 21))	('PARP', 'Gene', (87, 91))	('olaparib', 'Chemical', 'MESH:C531550', (110, 118))	('PARP', 'Gene', (162, 166))	('PARP', 'Gene', '142', (87, 91))	('PARP1', 'Gene', '142', (87, 92))
268168	25437539	Cells were harvested 48 h post transfection and lysed for Western analysis to confirm knockdown of PARP1.	('PARP1', 'Gene', (99, 104))	('knockdown', 'Var', (86, 95))	('PARP1', 'Gene', '142', (99, 104))
268187	21959309	Claudin-5 is also required in cardiovascular development, and monoallelic loss of a chromosome 22 segment including claudin-5 locus causes velocardio-facial syndrome, including cardiac malformations.	('claudin-5', 'Gene', (116, 125))	('cardiac malformations', 'Disease', (177, 198))	('cardiac malformations', 'Phenotype', 'HP:0001627', (177, 198))	('monoallelic loss', 'Var', (62, 78))	('cardiac malformations', 'Disease', 'MESH:D006331', (177, 198))	('velocardio-facial syndrome', 'Disease', 'MESH:D005148', (139, 165))	('Claudin-5', 'Gene', '7122', (0, 9))	('causes', 'Reg', (132, 138))	('velocardio-facial syndrome', 'Disease', (139, 165))	('Claudin-5', 'Gene', (0, 9))
268217	21959309	A great majority of epithelioid hemangioendotheliomas showed positivity in tumor cells, but this varied from one region to another, with both membrane and cytoplasmic staining (Fig.	('epithelioid hemangioendotheliomas', 'Disease', 'MESH:D018323', (20, 53))	('epithelioid hemangioendotheliomas', 'Disease', (20, 53))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('epithelioid hemangioendotheliomas', 'Phenotype', 'HP:0032060', (20, 53))	('positivity', 'Var', (61, 71))	('tumor', 'Disease', (75, 80))
268225	21959309	Slides from selected blocks containing angiosarcomas and hemangioendothelioma variants showed practically identical results with the mouse monoclonal antibody to claudin-5.	('hemangioendothelioma', 'Disease', (57, 77))	('angiosarcomas', 'Disease', 'MESH:D006394', (39, 52))	('angiosarcomas', 'Phenotype', 'HP:0200058', (39, 52))	('variants', 'Var', (78, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('angiosarcoma', 'Phenotype', 'HP:0200058', (39, 51))	('angiosarcomas', 'Disease', (39, 52))	('hemangioendothelioma', 'Disease', 'MESH:D006390', (57, 77))
268266	21959309	The potential keratin 18, and to some degree keratin 8 and 7, immunoreactivity in angiosarcoma can be a further pitfall in the differential diagnosis between angiosarcoma and carcinoma.	('keratin 18', 'Gene', '3875', (14, 24))	('angiosarcoma and carcinoma', 'Disease', 'MESH:D006394', (158, 184))	('angiosarcoma', 'Phenotype', 'HP:0200058', (158, 170))	('angiosarcoma', 'Disease', 'MESH:D006394', (82, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('keratin 18', 'Gene', (14, 24))	('keratin 8', 'Gene', '3856', (45, 54))	('angiosarcoma', 'Disease', (82, 94))	('keratin 8', 'Gene', (45, 54))	('angiosarcoma', 'Disease', 'MESH:D006394', (158, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('immunoreactivity', 'Var', (62, 78))	('angiosarcoma', 'Phenotype', 'HP:0200058', (82, 94))	('angiosarcoma', 'Disease', (158, 170))
268280	32310940	The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy.	('aggressive malignancy', 'Disease', (243, 264))	('aggressive malignancy', 'Disease', 'MESH:D009369', (243, 264))	('loss', 'NegReg', (169, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('undifferentiated embryonal sarcoma', 'Disease', (25, 59))	('Undifferentiated embryonal sarcoma of the liver', 'Disease', 'MESH:D002277', (174, 221))	('TP53', 'Gene', '7157', (152, 156))	('mutation', 'Var', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('TP53', 'Gene', (152, 156))	('Undifferentiated embryonal sarcoma of the liver', 'Disease', (174, 221))	('undifferentiated embryonal sarcoma', 'Disease', 'MESH:D002277', (25, 59))
268283	32310940	Congruent with prior reports, we identified structural variants in chr19q13 in 10 of 13 evaluable tumors.	('chr19q13', 'Gene', (67, 75))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('structural variants', 'Var', (44, 63))
268286	32310940	Concurrent TP53 mutation or copy number loss was identified in all evaluable tumors with evidence of C19MC overexpression.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mutation', 'Var', (16, 24))	('C19MC', 'Chemical', '-', (101, 106))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('copy number loss', 'Var', (28, 44))
268287	32310940	We find that C19MC miRNAs exhibit significant negative correlation to TP53 regulatory miRNAs and K-Ras regulatory miRNAs.	('C19MC', 'Var', (13, 18))	('TP53', 'Gene', '7157', (70, 74))	('TP53', 'Gene', (70, 74))	('correlation', 'Interaction', (55, 66))	('K-Ras', 'Gene', '3845', (97, 102))	('negative', 'NegReg', (46, 54))	('K-Ras', 'Gene', (97, 102))	('C19MC', 'Chemical', '-', (13, 18))
268288	32310940	In summary, utilizing a combination of next-generation sequencing and high-density arrays we identify the combination of C19MC hyperexpression via chromosomal structural event with TP53 mutation or loss as highly recurrent genomic features of UESL.	('TP53', 'Gene', (181, 185))	('C19MC', 'Chemical', '-', (121, 126))	('loss', 'NegReg', (198, 202))	('UESL', 'Disease', (243, 247))	('TP53', 'Gene', '7157', (181, 185))	('mutation', 'Var', (186, 194))
268290	32310940	We find that UESL tumors harbor aberrant transcriptional start sites within C19MC region that is driven by structural rearrangement, leading to extreme overexpression of C19MC miRNAs.	('overexpression', 'PosReg', (152, 166))	('UESL tumors', 'Disease', (13, 24))	('C19MC', 'Chemical', '-', (170, 175))	('C19MC', 'Chemical', '-', (76, 81))	('UESL tumors', 'Disease', 'MESH:D009369', (13, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('C19MC', 'Var', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
268291	32310940	We further find that C19MC miRNAs negatively correlate with TP53 and K-Ras regulatory miRNAs.	('C19MC', 'Chemical', '-', (21, 26))	('C19MC', 'Var', (21, 26))	('K-Ras', 'Gene', '3845', (69, 74))	('TP53', 'Gene', '7157', (60, 64))	('negatively', 'NegReg', (34, 44))	('TP53', 'Gene', (60, 64))	('K-Ras', 'Gene', (69, 74))
268292	32310940	UESL also harbors highly recurrent TP53 mutation or copy number loss.	('mutation', 'Var', (40, 48))	('copy number loss', 'Var', (52, 68))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))
268300	32310940	Supporting the hypothesis that these two tumors are related, conventional cytogenetic studies as well as targeted sequencing approaches have identified recurrent chromosomal alterations affecting a noncoding region on chr19q13.4 in several cases of UESL as well as recurrently in mesenchymal hamartoma.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('hamartoma', 'Phenotype', 'HP:0010566', (292, 301))	('mesenchymal hamartoma', 'Disease', 'MESH:D006222', (280, 301))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('mesenchymal hamartoma', 'Disease', (280, 301))	('chromosomal alterations', 'Var', (162, 185))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('UESL', 'Disease', (249, 253))	('affecting', 'Reg', (186, 195))
268302	32310940	Given the noncoding nature and lack of an obvious oncogene in the vicinity of 19q13.4, disruption of a regulatory region of either a neighboring gene or of the nearby chromosomal 19 microRNA cluster (C19MC) have been hypothesized as a catalyst for tumorigenesis.	('tumor', 'Disease', (248, 253))	('C19MC', 'Chemical', '-', (200, 205))	('cluster', 'Species', '100569', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('disruption', 'Var', (87, 97))
268304	32310940	C19MC has been implicated in various tumors including but not limited to embryonal tumors with multilayered rosettes (a pediatric tumor type affecting central nervous system), breast cancer, hepatocellular carcinoma, parathyroid tumors, infantile hemangioma, testicular germ cell tumors, and thyroid adenomas.	('C19MC', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('infantile hemangioma', 'Disease', (237, 257))	('hepatocellular carcinoma', 'Disease', (191, 215))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('hemangioma', 'Phenotype', 'HP:0001028', (247, 257))	('parathyroid tumors', 'Disease', 'MESH:D010282', (217, 235))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('C19MC', 'Chemical', '-', (0, 5))	('germ cell tumors', 'Phenotype', 'HP:0100728', (270, 286))	('parathyroid tumors', 'Disease', (217, 235))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumors', 'Disease', 'MESH:D009369', (280, 286))	('infantile hemangioma', 'Disease', 'MESH:C535860', (237, 257))	('embryonal tumors', 'Phenotype', 'HP:0002898', (73, 89))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('embryonal tumors', 'Disease', (73, 89))	('embryonal tumors', 'Disease', 'MESH:D009373', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumor', 'Disease', (280, 285))	('tumors', 'Disease', (229, 235))	('thyroid adenomas', 'Disease', (292, 308))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('implicated', 'Reg', (15, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('thyroid adenomas', 'Disease', 'MESH:D013964', (292, 308))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (191, 215))	('tumor', 'Disease', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('thyroid adenomas', 'Phenotype', 'HP:0000854', (292, 308))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('tumor type affecting central nervous system', 'Phenotype', 'HP:0100006', (130, 173))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumors', 'Disease', (83, 89))	('tumor', 'Disease', (37, 42))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (191, 215))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumors', 'Disease', (280, 286))	('breast cancer', 'Disease', (176, 189))	('rosettes', 'Phenotype', 'HP:0031925', (108, 116))
268307	32310940	In the placenta, C19MC plays a pivotal role in trophoblast differentiation and migration as well as in providing resistance to viral infection.	('viral infection', 'Disease', 'MESH:D001102', (127, 142))	('migration', 'CPA', (79, 88))	('C19MC', 'Var', (17, 22))	('viral infection', 'Disease', (127, 142))	('trophoblast differentiation', 'CPA', (47, 74))	('C19MC', 'Chemical', '-', (17, 22))
268309	32310940	We find that UESL display a highly aneuploid genome with recurrent structural alterations of chr19q13 that are uniformly associated with aberrantly high levels of transcriptional activity of the chromosome 19 microRNA cluster.	('aneuploid', 'Disease', 'MESH:D000782', (35, 44))	('associated', 'Reg', (121, 131))	('cluster', 'Species', '100569', (218, 225))	('structural alterations', 'Var', (67, 89))	('chr19q13', 'Gene', (93, 101))	('aneuploid', 'Disease', (35, 44))
268310	32310940	In addition we find that TP53 mutation or loss is present in all samples that also display C19MC changes.	('C19MC', 'Var', (91, 96))	('TP53', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('C19MC', 'Chemical', '-', (91, 96))	('TP53', 'Gene', '7157', (25, 29))	('loss', 'NegReg', (42, 46))
268314	32310940	From SNP array analysis, all 13 analyzed tumors displayed substantial degrees of aneuploidy typified by areas of complex genomic rearrangements suggestive of chromoanagenesis events such as chromothripsis (a phenomenon where multiple double stranded DNA breaks occur in a limited number of chromosomal segments followed by random reassembly leads to high frequency structural variants in isolated genomic regions) or chromoplexy (chromosomal restructuring phenomenon characterized by chained inter- and intra- chromosomal translations with frequent deletions at the breakpoints) (Figs 1 and S1 Fig).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('aneuploidy', 'Disease', 'MESH:D000782', (81, 91))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('chromothripsis', 'Disease', (190, 204))	('deletions', 'Var', (549, 558))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('multiple double stranded DNA breaks', 'Phenotype', 'HP:0040012', (225, 260))	('aneuploidy', 'Disease', (81, 91))	('chromothripsis', 'Disease', 'MESH:D000072837', (190, 204))	('structural variants', 'MPA', (365, 384))
268316	32310940	In 10 of the 13 tumors with chromosomal complexity, there was clear evidence of a copy number change point in 19q34.42, suggestive of unbalanced structural alterations and concordant with previous reports of recurrent chromosomal breaks in this region.	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (218, 236))	('point', 'Var', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('recurrent chromosomal breaks', 'Phenotype', 'HP:0040012', (208, 236))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('copy number change point', 'Var', (82, 106))
268317	32310940	Notably, the C19MC region had increased copy number in multiple samples (Fig 1C and 1E and S1 Fig).	('increased', 'PosReg', (30, 39))	('C19MC', 'Var', (13, 18))	('C19MC', 'Chemical', '-', (13, 18))	('copy number', 'MPA', (40, 51))
268318	32310940	Given the evidence of recurrent structural alterations in the vicinity of the chromosome 19 microRNA cluster as well as evidence in another tumor type that translocations to this area can lead to significant C19MC overexpression, we manually inspected mapped whole transcriptome sequencing in this region.	('overexpression', 'PosReg', (214, 228))	('cluster', 'Species', '100569', (101, 108))	('lead to', 'Reg', (188, 195))	('C19MC', 'Chemical', '-', (208, 213))	('C19MC', 'MPA', (208, 213))	('translocations', 'Var', (156, 170))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('alterations', 'Var', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
268321	32310940	All samples (10 of 10) with copy number change points in 19q13.42 displayed this C19MC transcriptional activity starting at or near the position of the predicted region of copy number transition.	('C19MC', 'Chemical', '-', (81, 86))	('C19MC transcriptional activity', 'MPA', (81, 111))	('copy number change points', 'Var', (28, 53))
268322	32310940	Notably, C19MC transcriptional activity had an abrupt, sample specific start site, suggestive of aberrant expression due to chromosomal structural event disrupting the natural transcriptional start site (Fig 2A).	('C19MC', 'Var', (9, 14))	('expression', 'MPA', (106, 116))	('C19MC', 'Chemical', '-', (9, 14))	('disrupting', 'NegReg', (153, 163))
268323	32310940	Previous reports have shown recurrent fusions involving the C19MC locus in several cases of UESL.	('UESL', 'Disease', (92, 96))	('C19MC', 'Gene', (60, 65))	('C19MC', 'Chemical', '-', (60, 65))	('fusions', 'Var', (38, 45))
268324	32310940	It is possible that the aberrant transcriptional activities within C19MC observed (Fig 2A) could be driven by chromosomal structural rearrangements.	('C19MC', 'Chemical', '-', (67, 72))	('C19MC', 'Var', (67, 72))	('transcriptional activities', 'MPA', (33, 59))
268328	32310940	Sanger sequencing of the product confirmed a fusion between ZIM2/PEG3 and C19MC, Chr19:54,178,123::Chr19:57,345,748 (Hg19 genome build) (Fig 2D).	('ZIM2', 'Gene', '23619', (60, 64))	('ZIM2', 'Gene', (60, 64))	('C19MC', 'Chemical', '-', (74, 79))	('PEG3', 'Gene', '5178', (65, 69))	('C19MC', 'Var', (74, 79))	('PEG3', 'Gene', (65, 69))
268329	32310940	Strikingly, the fusion point co-ordinate Chr19:54,178,123 is at the aberrant transcription start site of PATWXD sample (Fig 2A) suggesting that the fusion with PEG3/ZIM2 likely drives the aberrant transcription of C19MC in this sample.	('PEG3', 'Gene', (160, 164))	('C19MC', 'Gene', (214, 219))	('ZIM2', 'Gene', '23619', (165, 169))	('C19MC', 'Chemical', '-', (214, 219))	('ZIM2', 'Gene', (165, 169))	('fusion', 'Var', (148, 154))	('PEG3', 'Gene', '5178', (160, 164))	('transcription', 'MPA', (197, 210))
268336	32310940	Eight miRNAs (miR-518a, miR-518c, miR-518f, miR-520f, miR-520g, miR-519a, miR-512, and miR-519d) had dominant expression of 3p over 5p, thirteen miRNAs (miR-520d, miR-519e, miR-525, miR-519b, miR-515, miR-522, miR-519c, miR-520a, miR-524, miR-518e, miR-526b, miR-516b, and miR-516a) had dominant expression of 5p over 3p, and three miRNAs (miR-523, miR-518d, and miR-520c) had nearly equal amount of 5p and 3p mature miRNAs (Fig 3B).	('miR-520a', 'Gene', '574467', (220, 228))	('miR-519c', 'Gene', '574466', (210, 218))	('miR-520d', 'Gene', '574482', (153, 161))	('miR-524', 'Gene', (230, 237))	('miR-518c', 'Gene', (24, 32))	('miR-518f', 'Gene', (34, 42))	('miR-520c', 'Gene', (363, 371))	('miR-520f', 'Gene', (44, 52))	('3p', 'Chemical', '-', (318, 320))	('miR-520d', 'Gene', (153, 161))	('miR-520g', 'Gene', (54, 62))	('miR-525', 'Gene', (173, 180))	('miR-516b', 'Var', (259, 267))	('miR-519a', 'Var', (64, 72))	('miR-520c', 'Gene', '574476', (363, 371))	('miR-518d', 'Gene', '574489', (349, 357))	('miR-519d', 'Gene', '574480', (87, 95))	('miR-519d', 'Gene', (87, 95))	('miR-516a', 'Var', (273, 281))	('miR-512', 'Var', (74, 81))	('miR-526b', 'Gene', '574468', (249, 257))	('miR-518e', 'Gene', (239, 247))	('miR-524', 'Gene', '574478', (230, 237))	('3p', 'Chemical', '-', (124, 126))	('miR-523', 'Gene', (340, 347))	('miR-525', 'Gene', '574470', (173, 180))	('miR-520g', 'Gene', '574484', (54, 62))	('miR-519c', 'Gene', (210, 218))	('miR-526b', 'Gene', (249, 257))	('miR-515', 'Var', (192, 199))	('miR-520a', 'Gene', (220, 228))	('miR-520f', 'Gene', '574464', (44, 52))	('miR-519b', 'Gene', '574469', (182, 190))	('miR-519e', 'Gene', (163, 171))	('miR-522', 'Gene', (201, 208))	('miR-523', 'Gene', '574471', (340, 347))	('miR-518d', 'Gene', (349, 357))	('miR-522', 'Gene', '574495', (201, 208))	('3p', 'Chemical', '-', (407, 409))	('miR-518c', 'Gene', '574477', (24, 32))	('miR-518e', 'Gene', '574487', (239, 247))	('miR-519e', 'Gene', '574463', (163, 171))	('miR-519b', 'Gene', (182, 190))	('miR-518f', 'Gene', '574472', (34, 42))
268337	32310940	Notably, miR-526b, miR-516b, and miR-516a had >100 fold expression of 5p over 3p suggesting that these 5p super dominant miRNAs might sponge corresponding 3p miRNAs.	('miR-516a', 'Var', (33, 41))	('miR-526b', 'Gene', '574468', (9, 17))	('3p', 'Chemical', '-', (155, 157))	('miR-516b', 'Var', (19, 27))	('miR-526b', 'Gene', (9, 17))	('3p', 'Chemical', '-', (78, 80))
268338	32310940	Therefore, not only hyper-expression of C19MC miRNAs but also the relative stability of 3p versus 5p mature forms also might contribute to UESL.	('hyper-expression', 'Var', (20, 36))	('UESL', 'Disease', (139, 143))	('C19MC', 'Chemical', '-', (40, 45))	('contribute', 'Reg', (125, 135))	('3p', 'Chemical', '-', (88, 90))	('C19MC', 'Var', (40, 45))
268340	32310940	In UESL, the majority of the C19MC microRNAs (set-1) formed a tightly correlated expression pattern, suggesting shared expressional regulation of the majority of the cluster (Fig 4A and S1 Table).	('C19MC', 'Var', (29, 34))	('expressional', 'MPA', (119, 131))	('C19MC', 'Chemical', '-', (29, 34))	('cluster (Fig', 'Species', '100569', (166, 178))
268341	32310940	Notably, this tightly correlated cluster of C19MC miRNAs were strongly negatively correlated to a second cluster of TP53-regulatory miRNAs of potential oncologic importance (Fig 4A and S1 Table).	('C19MC', 'Var', (44, 49))	('TP53', 'Gene', (116, 120))	('cluster', 'Species', '100569', (105, 112))	('negatively', 'NegReg', (71, 81))	('cluster', 'Species', '100569', (33, 40))	('C19MC', 'Chemical', '-', (44, 49))	('TP53', 'Gene', '7157', (116, 120))
268343	32310940	Additionally, a smaller subset of C19MC miRNAs (Set-2) formed a distinct correlatively co-expressed cluster, which was negatively correlated to a separate large set of TP53 and KRAS-regulatory miRNAs (Set-2) (Fig 4A and S1 Table).	('C19MC', 'Chemical', '-', (34, 39))	('cluster', 'Species', '100569', (100, 107))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('C19MC', 'Var', (34, 39))	('KRAS', 'Gene', (177, 181))	('KRAS', 'Gene', '3845', (177, 181))
268345	32310940	In summary, C19MC microRNAs are substantially overexpressed in UESL and exhibit a strong negative correlation to K-Ras and TP53 regulatory miRNAs.	('negative', 'NegReg', (89, 97))	('K-Ras', 'Gene', '3845', (113, 118))	('K-Ras', 'Gene', (113, 118))	('overexpressed', 'PosReg', (46, 59))	('C19MC', 'Chemical', '-', (12, 17))	('TP53', 'Gene', '7157', (123, 127))	('C19MC', 'Var', (12, 17))	('TP53', 'Gene', (123, 127))
268346	32310940	From the paired whole exome sequencing cohort (n = 7), we observed a median of 39 somatic coding mutations per sample (range: 21-77), placing UES on the low end of the mutational burden spectrum across cancer types, similar to other pediatric malignancies.	('mutations', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('malignancies', 'Disease', (243, 255))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('malignancies', 'Disease', 'MESH:D009369', (243, 255))
268348	32310940	To further evaluate the spectrum of TP53 alteration in UESL, we additionally evaluated tumor-only sequencing for TP53 mutation and evaluated for copy number loss of TP53 from SNP array data.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TP53', 'Gene', (165, 169))	('tumor', 'Disease', (87, 92))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', '7157', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutation', 'Var', (118, 126))	('TP53', 'Gene', (36, 40))	('TP53', 'Gene', (113, 117))	('TP53', 'Gene', '7157', (165, 169))
268349	32310940	In total, 12 of 13 patients (92.3%) with both mutational and CNV data harbored either TP53 mutation or copy number loss (Fig 4B).	('mutation', 'Var', (91, 99))	('patients', 'Species', '9606', (19, 27))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('harbored', 'Reg', (70, 78))	('copy number loss', 'Var', (103, 119))
268350	32310940	One additional sample lacked TP53 mutation by exome sequencing but did not have SNP array data for which to evaluate copy number loss.	('TP53', 'Gene', '7157', (29, 33))	('lacked', 'NegReg', (22, 28))	('TP53', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))
268352	32310940	Notably all tumors with documented C19MC overexpression that were evaluable for both mutation and CNV also harbored TP53 mutation or loss (12 of 12).	('TP53', 'Gene', (116, 120))	('C19MC', 'Chemical', '-', (35, 40))	('loss', 'NegReg', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutation', 'Var', (121, 129))	('tumors', 'Disease', (12, 18))	('TP53', 'Gene', '7157', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
268353	32310940	From the matched sequencing cohort, we noted several additional possibly pathogenic somatic mutations including singleton mutations in 3 different JAK-STAT pathway genes, though none other than TP53 that were recurrent at the gene level (S2 Table).	('pathogenic', 'Reg', (73, 83))	('mutations', 'Var', (92, 101))	('TP53', 'Gene', '7157', (194, 198))	('mutations', 'Var', (122, 131))	('TP53', 'Gene', (194, 198))	('JAK-STAT pathway', 'Pathway', (147, 163))
268354	32310940	Given recent reports of an association of DICER1 syndrome with mesenchymal hamartoma of the liver, we specifically analyzed somatic and germline sequencing data for evidence inactivating mutation in DICER1 but found none in our cohort.	('DICER1', 'Gene', (199, 205))	('DICER1', 'Gene', '23405', (199, 205))	('mesenchymal hamartoma of the liver', 'Disease', (63, 97))	('DICER1', 'Gene', '23405', (42, 48))	('inactivating mutation', 'Var', (174, 195))	('association', 'Interaction', (27, 38))	('hamartoma', 'Phenotype', 'HP:0010566', (75, 84))	('mesenchymal hamartoma of the liver', 'Disease', 'MESH:D006222', (63, 97))	('DICER1', 'Gene', (42, 48))
268357	32310940	Considering the well-established role of C19MC in placental physiology regulating trophoblast differentiation and antiviral response, our results suggest a causal role of C19MC in the expressional perturbations noted.	('C19MC', 'Chemical', '-', (171, 176))	('trophoblast', 'CPA', (82, 93))	('C19MC', 'Chemical', '-', (41, 46))	('C19MC', 'Var', (171, 176))
268359	32310940	We find that UESL are characterized by marked aneuploidy, recurrent structural variants near the start site of C19MC leading to pronounced C19MC overexpression, and highly recurrent TP53 mutation or copy number loss.	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('C19MC', 'Chemical', '-', (111, 116))	('variants', 'Var', (79, 87))	('C19MC', 'MPA', (139, 144))	('aneuploidy', 'Disease', (46, 56))	('C19MC', 'Chemical', '-', (139, 144))	('mutation', 'Var', (187, 195))	('copy number loss', 'Var', (199, 215))	('overexpression', 'PosReg', (145, 159))	('aneuploidy', 'Disease', 'MESH:D000782', (46, 56))
268360	32310940	We further confirm the C19MC fusion event in one of the tumors, which can potentially replace the putative C19MC transcriptional regulatory region with PEG3/ZIM2 gene, explaining the markedly aberrant transcriptional activity of C19MC in this sample is likely driven by PEG3/ZIM2 promoter.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PEG3', 'Gene', (152, 156))	('PEG3', 'Gene', (270, 274))	('ZIM2', 'Gene', '23619', (157, 161))	('C19MC', 'Chemical', '-', (107, 112))	('PEG3', 'Gene', '5178', (152, 156))	('C19MC', 'Var', (229, 234))	('C19MC', 'Chemical', '-', (229, 234))	('ZIM2', 'Gene', '23619', (275, 279))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('C19MC', 'Chemical', '-', (23, 28))	('transcriptional activity', 'MPA', (201, 225))	('ZIM2', 'Gene', (157, 161))	('ZIM2', 'Gene', (275, 279))	('PEG3', 'Gene', '5178', (270, 274))
268362	32310940	Previously reports have documented recurrent chromosomal translocations in the C19MC locus in mesenchymal hamartoma of the liver as well as in several cases of UESL.	('C19MC', 'Chemical', '-', (79, 84))	('UESL', 'Disease', (160, 164))	('mesenchymal hamartoma of the liver', 'Disease', 'MESH:D006222', (94, 128))	('mesenchymal hamartoma of the liver', 'Disease', (94, 128))	('C19MC', 'Gene', (79, 84))	('hamartoma', 'Phenotype', 'HP:0010566', (106, 115))	('chromosomal translocations', 'Var', (45, 71))
268363	32310940	These prior reports of UESL, however, did not identify that the functional consequence of these fusion events is to lead to extreme overexpression of C19MC.	('C19MC', 'Var', (150, 155))	('overexpression', 'PosReg', (132, 146))	('C19MC', 'Chemical', '-', (150, 155))
268365	32310940	Furthermore, we find it striking that all UESL tumors in our study that demonstrated C19MC overexpression also had evidence of TP53 mutation or copy number loss.	('mutation', 'Var', (132, 140))	('UESL tumors', 'Disease', (42, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('copy number loss', 'Var', (144, 160))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('C19MC', 'Chemical', '-', (85, 90))	('UESL tumors', 'Disease', 'MESH:D009369', (42, 53))
268366	32310940	Given the clinical evidence that some UESL arise from MHL, and that both UESL and MHL share C19MC structural variations, we hypothesize a multistep model for UESL genomic development: C19MC translocation could be the first event leading to a benign tumor, and in some cases TP53 mutation/loss occurs to lead malignant transformation to UESL (S2 Fig).	('benign tumor', 'Disease', (242, 254))	('benign tumor', 'Disease', 'MESH:D009369', (242, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('C19MC', 'Chemical', '-', (184, 189))	('C19MC translocation', 'Var', (184, 203))	('leading to', 'Reg', (229, 239))	('TP53', 'Gene', '7157', (274, 278))	('C19MC', 'Chemical', '-', (92, 97))	('UESL', 'Disease', (336, 340))	('TP53', 'Gene', (274, 278))	('mutation/loss', 'Var', (279, 292))
268367	32310940	Notably, both TP53 alteration and C19MC overexpression may influence common downstream pathways, including K-Ras activation.	('C19MC', 'Chemical', '-', (34, 39))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('C19MC', 'Var', (34, 39))	('overexpression', 'PosReg', (40, 54))	('activation', 'PosReg', (113, 123))	('influence', 'Reg', (59, 68))	('K-Ras', 'Gene', '3845', (107, 112))	('K-Ras', 'Gene', (107, 112))
268368	32310940	Our UESL miRNA-seq results with C19MC miRNAs negatively correlating to TP53 and K-Ras regulatory miRNAs support this hypothesis.	('K-Ras', 'Gene', (80, 85))	('TP53', 'Gene', '7157', (71, 75))	('C19MC', 'Chemical', '-', (32, 37))	('K-Ras', 'Gene', '3845', (80, 85))	('C19MC', 'Var', (32, 37))	('TP53', 'Gene', (71, 75))
268369	32310940	Further studies, such as confirming C19MC overexpression but lack of TP53 mutation in MHL, and further understanding of the direct influence of C19MC miRNAs on p53 and K-ras function would be necessary to confirm our proposed model.	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('C19MC', 'Chemical', '-', (36, 41))	('K-ras', 'Gene', (168, 173))	('K-ras', 'Gene', '3845', (168, 173))	('lack', 'NegReg', (61, 65))	('C19MC', 'Chemical', '-', (144, 149))
268370	32310940	Previous reports have implicated C19MC as driver of cell proliferation in several tumor types both benign and malignant.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('C19MC', 'Chemical', '-', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('C19MC', 'Var', (33, 38))
268371	32310940	Most analogous to our current findings, embryonal tumors with multilayer rosettes (ETMR) are now known to be characterized by C19MC fusion leading to extreme C19MC overexpression.	('C19MC fusion', 'Var', (126, 138))	('embryonal tumors', 'Phenotype', 'HP:0002898', (40, 56))	('overexpression', 'PosReg', (164, 178))	('embryonal tumors', 'Disease', (40, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('C19MC', 'MPA', (158, 163))	('C19MC', 'Chemical', '-', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('C19MC', 'Chemical', '-', (158, 163))	('embryonal tumors', 'Disease', 'MESH:D009373', (40, 56))	('rosettes', 'Phenotype', 'HP:0031925', (73, 81))
268372	32310940	Unlike ETMR, where C19MC fusion is consistently with the same gene partner, TTYH1, in UESL C19MC fusions have been described with a variety of partners, including the novel PEG3/ZIM2-C19MC fusion described in this study.	('TTYH1', 'Gene', (76, 81))	('C19MC fusions', 'Var', (91, 104))	('TTYH1', 'Gene', '57348', (76, 81))	('PEG3', 'Gene', (173, 177))	('ZIM2', 'Gene', '23619', (178, 182))	('C19MC', 'Chemical', '-', (183, 188))	('C19MC', 'Chemical', '-', (19, 24))	('C19MC', 'Chemical', '-', (91, 96))	('ZIM2', 'Gene', (178, 182))	('PEG3', 'Gene', '5178', (173, 177))
268376	32310940	Our data on C19MC miRNA negative correlation to KRAS- and TP53-regulatory miRNAs supports this notion.	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (48, 52))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('negative', 'NegReg', (24, 32))	('C19MC', 'Chemical', '-', (12, 17))	('C19MC', 'Var', (12, 17))
268391	32310940	DNA/RNA were extracted from qualifying tumor samples (fresh frozen/FFPE) and matched blood using either AllPrep DNA/RNA Mini Kit (Qiagen #80204) or AllPrep DNA/RNA FFPE Kit (Qiagen #80234) or miRNeasy FFPE Kit (Qiagen #217504) or miRNeasy Mini Kit (Qiagen #217004).	('Kit', 'Gene', (206, 209))	('Kit', 'Gene', (169, 172))	('Kit', 'Gene', (244, 247))	('Kit', 'Gene', '3815', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Kit', 'Gene', '3815', (244, 247))	('Kit', 'Gene', (125, 128))	('Qiagen', 'Var', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Kit', 'Gene', '3815', (169, 172))	('Kit', 'Gene', '3815', (125, 128))	('Qiagen', 'Var', (130, 136))	('Qiagen #80234', 'Var', (174, 187))	('tumor', 'Disease', (39, 44))	('Qiagen', 'Var', (249, 255))
268394	32310940	The Genome Analysis Toolkit was used for insertion/deletion realignment, quality score recalibration, and identification of single nucleotide and insertion/deletion variants.	('kit', 'Gene', (24, 27))	('kit', 'Gene', '3815', (24, 27))	('insertion/deletion', 'Var', (146, 164))
268395	32310940	We additionally utilized annotation by curated databases including COSMIC and the Cancer Gene Census to manually review variants for functional consequence and known status as an oncogene/tumor suppressor gene.	('tumor', 'Disease', (188, 193))	('variants', 'Var', (120, 128))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
268396	32310940	We defined putatively pathogenic mutations as those that are hotspot missense mutations or those that are truncating mutations (stopgain, splice site, frameshift) in a characterized tumor suppressor gene.	('tumor', 'Disease', (182, 187))	('pathogenic', 'Reg', (22, 32))	('mutations', 'Var', (33, 42))	('missense mutations', 'Var', (69, 87))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('frameshift', 'Var', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
268400	32310940	For a candidate fusion in tumor from patient ID: PATWXD, primers were designed to span the predicted breakpoint.	('patient', 'Species', '9606', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('fusion', 'Var', (16, 22))
268423	30871572	Both patients with SS18-SSX1 fusion transcript detected in peripheral blood had the SS18 rearrangement confirmed by FISH in their tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('rearrangement', 'Var', (89, 102))	('patients', 'Species', '9606', (5, 13))	('SSX1', 'Gene', '6756', (24, 28))	('SS18', 'Gene', (19, 23))	('SS18', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SSX1', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('SS18', 'Gene', '6760', (19, 23))	('SS18', 'Gene', '6760', (84, 88))
268431	30871572	We have recently demonstrated that simultaneous detection of copy number changes and point mutations in ctDNA increased the number of molecular markers that can be monitored in plasma and may be clinically useful in leiomyosarcoma.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (216, 230))	('ctDNA', 'Gene', (104, 109))	('point mutations', 'Var', (85, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('increased', 'PosReg', (110, 119))	('copy number changes', 'Var', (61, 80))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (216, 230))	('detection', 'Reg', (48, 57))	('leiomyosarcoma', 'Disease', (216, 230))
268483	29056712	Among the most recurrent aberrations were deletions of the CDKN2A/B and MTAP loci on dog chromosome 11q16 (CFA11q16), and the RB1 tumor suppressor gene on CFA22q11.	('MTAP', 'Gene', (72, 76))	('CDKN2A/B', 'Gene', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('dog', 'Species', '9615', (85, 88))	('deletions', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CDKN2A/B', 'Gene', '100271861;481563', (59, 67))	('RB1', 'Gene', '476915', (126, 129))	('tumor', 'Disease', (130, 135))	('RB1', 'Gene', (126, 129))	('MTAP', 'Gene', '474729', (72, 76))
268487	29056712	The first utilized microarray-based techniques to compare transcriptional profiles of localized HM and non-neoplastic splenic control tissue, finding significant tumor-associated deregulation of canonical pathways including cell cycle regulation, DNA replication, and DNA mismatch repair.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('DNA replication', 'CPA', (247, 262))	('tumor', 'Disease', (162, 167))	('cell cycle regulation', 'CPA', (224, 245))	('deregulation', 'Reg', (179, 191))	('canonical pathways', 'Pathway', (195, 213))	('DNA mismatch repair', 'Var', (268, 287))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
268514	29056712	Activating somatic mutations of BRAF, most commonly via substitution of valine for glutamic acid at codon 600 (BRAF V600E), have been shown to result in constitutive activation of the MAPK pathway in several human cancers, including malignant melanomas and thyroid tumors.	('Activating', 'PosReg', (0, 10))	('BRAF', 'Gene', (32, 36))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('thyroid tumors', 'Disease', 'MESH:D013959', (257, 271))	('V600E', 'Mutation', 'rs113488022', (116, 121))	('human', 'Species', '9606', (208, 213))	('valine for glutamic acid at codon 600', 'Mutation', 'rs113488022', (72, 109))	('MAPK pathway', 'Pathway', (184, 196))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('V600E', 'Var', (116, 121))	('malignant melanomas', 'Disease', 'MESH:D008545', (233, 252))	('malignant melanomas', 'Disease', (233, 252))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('thyroid tumors', 'Disease', (257, 271))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('activation', 'PosReg', (166, 176))	('malignant melanomas', 'Phenotype', 'HP:0002861', (233, 252))	('substitution', 'Var', (56, 68))
268515	29056712	The presence of the BRAF V600E mutation as an initiator of tumorigenesis confers an effective therapeutic target via selective inhibition of the MAPK pathway.	('tumor', 'Disease', (59, 64))	('V600E', 'Var', (25, 30))	('MAPK pathway', 'Pathway', (145, 157))	('inhibition', 'NegReg', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('V600E', 'Mutation', 'rs113488022', (25, 30))	('BRAF', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
268557	28404969	The significant difference suggested that the predicted radiosensitive patients strongly benefited from radiotherapy compared with non-radiotherapy.	('patients', 'Species', '9606', (71, 79))	('benefited', 'PosReg', (89, 98))	('radiotherapy', 'Var', (104, 116))
268558	28404969	Figure 1(b) shows significant differences between nonradiosensitive patients under radiotherapy and non-radiotherapy, suggesting that radiotherapy not only did not benefit, but worsen the survival for nonradiosensitive patients.	('worsen', 'NegReg', (177, 183))	('survival', 'MPA', (188, 196))	('patients', 'Species', '9606', (68, 76))	('radiotherapy', 'Var', (134, 146))	('patients', 'Species', '9606', (219, 227))
268698	27364557	Mutations in the Wnt/beta-catenin pathway are rare in Ewing sarcoma but the Wnt pathway modulator LGR5 is often highly expressed, suggesting a potential role for the axis in tumor pathogenesis.	('tumor', 'Disease', (174, 179))	('LGR5', 'Gene', (98, 102))	('LGR5', 'Gene', '8549', (98, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (54, 67))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (54, 67))	('Wnt/beta-catenin pathway', 'Pathway', (17, 41))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Ewing sarcoma', 'Disease', (54, 67))
268708	27364557	The two most common translocations are t(11;22)q(24;12), which encodes the EWS/FLI1 fusion protein in about 85% of cases, and t(21;22)(q22;q12), which encodes EWS/ERG in 5-10% of cases.	('EWS/FLI1', 'Gene', (75, 83))	('ERG', 'Gene', '2078', (163, 166))	('ERG', 'Gene', (163, 166))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (126, 143))	('t(21;22)(q22', 'Var', (126, 138))
268716	27364557	The transcriptional targets of Wnt/beta-catenin/TCF signaling are context- and cell type-dependent and their modulation can alter numerous cellular functions including proliferation, patterning, migration, and self-renewal.	('proliferation', 'CPA', (168, 181))	('TCF', 'Gene', (48, 51))	('TCF', 'Gene', '3172', (48, 51))	('patterning', 'CPA', (183, 193))	('cellular functions', 'CPA', (139, 157))	('alter', 'Reg', (124, 129))	('self-renewal', 'CPA', (210, 222))	('modulation', 'Var', (109, 119))	('migration', 'CPA', (195, 204))
268717	27364557	In epithelial tumors, particularly colorectal cancer, inactivating mutations in genes encoding destruction complex proteins or activating mutations in beta-catenin itself commonly deregulate the Wnt/beta-catenin signaling pathway.	('epithelial tumors', 'Disease', 'MESH:D002277', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (35, 52))	('beta-catenin', 'Gene', (151, 163))	('colorectal cancer', 'Phenotype', 'HP:0003003', (35, 52))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('epithelial tumors', 'Disease', (3, 20))	('colorectal cancer', 'Disease', (35, 52))	('deregulate', 'Reg', (180, 190))	('inactivating mutations', 'Var', (54, 76))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Wnt/beta-catenin signaling pathway', 'Pathway', (195, 229))	('mutations', 'Var', (138, 147))
268718	27364557	Recent studies have also highlighted the possible significance of defects in the Wnt/beta-catenin pathway in some sarcomas, however recurrent mutations have not been described in Ewing sarcoma.	('defects', 'Var', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('Wnt/beta-catenin pathway', 'Pathway', (81, 105))	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('Ewing sarcoma', 'Disease', (179, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', (114, 122))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (179, 192))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (179, 192))
268762	27364557	These data corroborate our in vitro studies and lend support for the hypothesis that Ewing sarcoma cells that express high levels of LGR5 are more responsive to ligand-dependent activation of Wnt/beta-catenin signaling.	('Ewing sarcoma', 'Disease', (85, 98))	('LGR5', 'Gene', (133, 137))	('LGR5', 'Gene', '8549', (133, 137))	('high levels', 'Var', (118, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('more', 'PosReg', (142, 146))	('responsive to', 'MPA', (147, 160))
268770	27364557	In this clinically homogeneous patient population, high expression of LEF1 was significantly associated with worse event free (Fig.	('patient', 'Species', '9606', (31, 38))	('event free', 'MPA', (115, 125))	('LEF1', 'Gene', '51176', (70, 74))	('high expression', 'Var', (51, 66))	('LEF1', 'Gene', (70, 74))
268781	27364557	Together these data provide compelling evidence that activation of Wnt/beta-catenin antagonizes the transcriptional function of EWS/ETS fusions in Ewing sarcoma.	('transcriptional function', 'MPA', (100, 124))	('Ewing sarcoma', 'Disease', (147, 160))	('activation', 'PosReg', (53, 63))	('fusions', 'Var', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('EWS/ETS', 'Gene', (128, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (147, 160))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (147, 160))	('antagonizes', 'NegReg', (84, 95))
268802	27364557	Subcutaneous tumor formation was also abrogated in A673 cells following TNC knockdown (Fig.	('Subcutaneous tumor', 'Disease', (0, 18))	('knockdown', 'Var', (76, 85))	('Subcutaneous tumor', 'Phenotype', 'HP:0001482', (0, 18))	('TNC', 'Gene', (72, 75))	('abrogated', 'NegReg', (38, 47))	('Subcutaneous tumor', 'Disease', 'MESH:D013352', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
268804	27364557	We speculate that the effect of knockdown on subcutaneous engraftment was more pronounced in A673 than TC32 cells due to fact that the absolute levels of TNC expression in A673 cells were lower than in TC32 cells, both at baseline and following knockdown (Fig.	('A673', 'Var', (172, 176))	('TC32', 'CellLine', 'CVCL:7151', (103, 107))	('lower', 'NegReg', (188, 193))	('TNC', 'Protein', (154, 157))	('TC32', 'CellLine', 'CVCL:7151', (202, 206))
268810	27364557	In keeping with the microenvironment being the source of Wnt/beta-catenin activation in these tumors, recurrent somatic mutations in the pathway are rare and Wnt and RSPO ligands are highly expressed in developing bone, the predominant site of Ewing tumors in pediatric and young adult patients.	('RSPO', 'Gene', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('patients', 'Species', '9606', (286, 294))	('Ewing tumors', 'Disease', 'MESH:C563168', (244, 256))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('Ewing tumors', 'Phenotype', 'HP:0012254', (244, 256))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mutations', 'Var', (120, 129))	('RSPO', 'Gene', '284654', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('Ewing tumors', 'Disease', (244, 256))
268812	27364557	In particular, we have shown that the extracellular matrix encoding gene, TNC, respectively, is induced by Wnt/beta-catenin activation in Ewing sarcoma and that high-level TNC promotes cell migration, tumorigenicity and lung engraftment.	('lung engraftment', 'CPA', (220, 236))	('cell migration', 'CPA', (185, 199))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (138, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('TNC', 'Var', (172, 175))	('Ewing sarcoma', 'Disease', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('promotes', 'PosReg', (176, 184))	('tumor', 'Disease', (201, 206))	('TNC', 'Gene', (74, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (138, 151))
268814	27364557	As an example, reversible plasticity of tumor cells between proliferative and migratory states, such as occurs in epithelial to mesenchymal transitions, has been linked to metastasis and epigenetic plasticity of chromatin states promotes emergence of drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (251, 266))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('linked', 'Reg', (162, 168))	('promotes', 'PosReg', (229, 237))	('epigenetic plasticity', 'Var', (187, 208))	('emergence', 'MPA', (238, 247))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('metastasis', 'CPA', (172, 182))
268817	27364557	Expression of the Wnt-potentiating ligand, LGR5, was found to be heterogeneous on a cell-to-cell basis and we have previously shown that the presence of LGR5 directly impacts on the Wnt response when RSPO ligands are present.	('LGR5', 'Gene', '8549', (43, 47))	('RSPO', 'Gene', (200, 204))	('presence', 'Var', (141, 149))	('LGR5', 'Gene', (43, 47))	('LGR5', 'Gene', '8549', (153, 157))	('impacts', 'Reg', (167, 174))	('RSPO', 'Gene', '284654', (200, 204))	('Wnt', 'MPA', (182, 185))	('LGR5', 'Gene', (153, 157))
268868	24244164	When comparing the effects of commercially available p38 inhibitors with compounds in the VICHEM library, we noted that p38 inhibitors SB202190, SB203580, VX745, SKF86002, SB220025, and a derivative of SB220025 (VI18802) differed in their ability to block KSHV reactivation, as shown by their effect on the expression of KSHV envelope glycoprotein K8.1 ( figure 1B ), although their ability to inhibit the phosphorylation of MK2, a p38 target, seemed comparable ( figure 1B ).	('MK2', 'Gene', (425, 428))	('VI18802', 'Chemical', '-', (212, 219))	('p38', 'Gene', '1432', (120, 123))	('SB220025', 'Chemical', 'MESH:C110631', (202, 210))	('p38', 'Gene', (53, 56))	('VX745', 'Var', (155, 160))	('KSHV', 'Disease', (256, 260))	('SB220025', 'Chemical', 'MESH:C110631', (172, 180))	('p38', 'Gene', (432, 435))	('K8.1 ( figure 1B', 'Gene', '4961469', (348, 364))	('phosphorylation', 'MPA', (406, 421))	('SKF86002', 'Var', (162, 170))	('inhibit', 'NegReg', (394, 401))	('SB203580', 'Chemical', 'MESH:C093642', (145, 153))	('MK2', 'Gene', '9261', (425, 428))	('p38', 'Gene', '1432', (53, 56))	('p38', 'Gene', '1432', (432, 435))	('SB202190', 'Var', (135, 143))	('p38', 'Gene', (120, 123))	('SB220025', 'Var', (172, 180))	('SB203580', 'Var', (145, 153))	('HE', 'Chemical', '-', (93, 95))	('expression', 'MPA', (307, 317))
268869	24244164	Of these compounds, SB220025 was the most potent with regard to inhibiting K8.1 expression ( figure 1B ) or virus production (not shown).	('K8.1', 'Protein', (75, 79))	('inhibiting', 'NegReg', (64, 74))	('SB220025', 'Var', (20, 28))	('SB220025', 'Chemical', 'MESH:C110631', (20, 28))	('expression', 'MPA', (80, 90))	('virus production', 'CPA', (108, 124))
268871	24244164	We then determined which other cellular kinases are inhibited by SB220025 and its derivative VI18802.	('cellular kinases', 'Enzyme', (31, 47))	('VI18802', 'Chemical', '-', (93, 100))	('SB220025', 'Chemical', 'MESH:C110631', (65, 73))	('inhibited', 'NegReg', (52, 61))	('SB220025', 'Var', (65, 73))
268872	24244164	Compound SKF86002, although a strong inhibitor of lytic reactivation, was not included in this comparison, as it reduced the levels of total MK2 ( figure 1B ).	('reduced', 'NegReg', (113, 120))	('SKF86002', 'Var', (9, 17))	('MK2 ( figure 1B', 'Gene', '9261', (141, 156))	('levels', 'MPA', (125, 131))
268873	24244164	The list of cellular kinases inhibited by SB220025 and VI18802 is shown in a table presented in figure S1B, which also includes previously published data on compounds SB203580, SB202190 and VX745.	('inhibited', 'NegReg', (29, 38))	('VI18802', 'Var', (55, 62))	('SB203580', 'Chemical', 'MESH:C093642', (167, 175))	('SB203580', 'Var', (167, 175))	('cellular kinases', 'Enzyme', (12, 28))	('SB220025', 'Chemical', 'MESH:C110631', (42, 50))	('VI18802', 'Chemical', '-', (55, 62))	('SB220025', 'Var', (42, 50))	('SB202190', 'Var', (177, 185))
268877	24244164	As shown in  figure 2 , silencing of MAP4K4 in these cells significantly reduced production of infectious viral progeny by more than 60% ( figure 2A ), as well as the expression of immediate-early (RTA), early (KbZIP, ORF45) and late (K8.1) lytic proteins ( figure 2B ).	('MAP4K4', 'Gene', '9448', (37, 43))	('MAP4K4', 'Gene', (37, 43))	('reduced', 'NegReg', (73, 80))	('late', 'Protein', (229, 233))	('production of infectious viral progeny', 'MPA', (81, 119))	('ORF45', 'Gene', '4961474', (218, 223))	('expression', 'MPA', (167, 177))	('silencing', 'Var', (24, 33))	('ORF45', 'Gene', (218, 223))
268879	24244164	In contrast to other lytic KSHV proteins, the expression of the viral homologue of IL-6, vIL-6, was slightly increased by MAP4K4 knockdown ( figure 2B ).	('IL-6', 'Gene', (90, 94))	('IL-6', 'Gene', '3569', (83, 87))	('increased', 'PosReg', (109, 118))	('IL-6', 'Gene', '3569', (90, 94))	('MAP4K4', 'Gene', '9448', (122, 128))	('MAP4K4', 'Gene', (122, 128))	('vIL-6', 'Gene', '4961449', (89, 94))	('knockdown', 'Var', (129, 138))	('IL-6', 'Gene', (83, 87))	('expression', 'MPA', (46, 56))	('vIL-6', 'Gene', (89, 94))
268881	24244164	Consistently with the observed decrease in virus production and lytic protein expression, MAP4K4 depletion also reduced KSHV genome replication ( figure 2C ), similarly to foscarnet, an inhibitor of KSHV DNA polymerase.	('MAP4K4', 'Gene', (90, 96))	('KSHV', 'Gene', (120, 124))	('decrease', 'NegReg', (31, 39))	('virus production', 'MPA', (43, 59))	('foscarnet', 'Chemical', 'MESH:D017245', (172, 181))	('MAP4K4', 'Gene', '9448', (90, 96))	('lytic protein expression', 'MPA', (64, 88))	('reduced', 'NegReg', (112, 119))	('depletion', 'Var', (97, 106))
268883	24244164	To control whether MAP4K4 knockdown affects transduction or expression of baculovirus RTA, we evaluated the levels of RTA mRNA transcripts before and after MAP4K4 depletion in cells not infected with KSHV that had been treated with baculovirus RTA alone or in combination with Na-butyrate.	('MAP4K4', 'Gene', '9448', (156, 162))	('depletion', 'Var', (163, 172))	('MAP4K4', 'Gene', (156, 162))	('MAP4K4', 'Gene', '9448', (19, 25))	('MAP4K4', 'Gene', (19, 25))	('transduction', 'MPA', (44, 56))	('Na-butyrate', 'Chemical', '-', (277, 288))
268889	24244164	As we observed that MAP4K4 supports the KSHV lytic cycle ( figure 2 ) and since it had been reported to be a promigratory kinase, we investigated if its silencing might affect the ability of KSHV-infected endothelial cells to invade matrigel.	('KSHV-infected', 'Disease', (191, 204))	('rat', 'Species', '10116', (115, 118))	('MAP4K4', 'Gene', '9448', (20, 26))	('affect', 'Reg', (169, 175))	('KSHV-infected', 'Disease', 'MESH:C537372', (191, 204))	('silencing', 'Var', (153, 162))	('KSHV lytic cycle', 'CPA', (40, 56))	('MAP4K4', 'Gene', (20, 26))	('invade matrigel', 'CPA', (226, 241))
268894	24244164	We were able to identify 54 cellular genes that showed at least a 1.5-fold decrease in their expression levels after MAP4K4 knockdown in HuAR2T rKSHV.219 undergoing viral reactivation as compared to control siRNA treated, reactivated HuAR2T rKSHV.219 cells in at least two out of three independent experiments ( figure 4A ).	('knockdown', 'Var', (124, 133))	('decrease', 'NegReg', (75, 83))	('expression levels', 'MPA', (93, 110))	('KSHV.219', 'CellLine', 'CVCL:G580', (242, 250))	('MAP4K4', 'Gene', '9448', (117, 123))	('KSHV.219', 'CellLine', 'CVCL:G580', (145, 153))	('MAP4K4', 'Gene', (117, 123))
268898	24244164	As shown in  figure 4B-C , COX-2 mRNA and protein expression is upregulated following induction of the viral lytic cycle and can be reduced by silencing MAP4K4.	('MAP4K4', 'Gene', '9448', (153, 159))	('COX-2', 'Gene', '5743', (27, 32))	('MAP4K4', 'Gene', (153, 159))	('COX-2', 'Gene', (27, 32))	('upregulated', 'PosReg', (64, 75))	('reduced', 'NegReg', (132, 139))	('silencing', 'Var', (143, 152))
268899	24244164	Likewise, we could show that the expression of both MMP-7 and MMP-13 mRNAs increased after the induction of the lytic cycle and was significantly reduced after MAP4K4 depletion ( figure 4B ).	('MAP4K4', 'Gene', '9448', (160, 166))	('MMP-13', 'Gene', (62, 68))	('MAP4K4', 'Gene', (160, 166))	('depletion', 'Var', (167, 176))	('reduced', 'NegReg', (146, 153))	('MMP-7', 'Gene', (52, 57))	('expression', 'MPA', (33, 43))	('MMP-7', 'Gene', '4316', (52, 57))	('increased', 'PosReg', (75, 84))	('MMP-13', 'Gene', '4322', (62, 68))
268907	24244164	We noted that silencing of MAP4K4 led to a reduced expression of the early KSHV protein KbZIP ( figure 5B ) and its mRNA transcript, as well as K8.1 mRNA expression ( figure 5D ), whereas silencing of MMP-7 and MMP-13 had no effect on the protein and mRNA levels of KbZIP ( figure 5B, 5D ) or mRNA levels of K8.1 ( figure 5D ).	('KbZIP', 'Gene', (88, 93))	('silencing', 'Var', (14, 23))	('mRNA levels', 'MPA', (251, 262))	('K8.1 mRNA expression', 'MPA', (144, 164))	('MMP-7', 'Gene', (201, 206))	('MMP-7', 'Gene', '4316', (201, 206))	('mRNA transcript', 'MPA', (116, 131))	('protein', 'MPA', (239, 246))	('MAP4K4', 'Gene', '9448', (27, 33))	('expression', 'MPA', (51, 61))	('MMP-13', 'Gene', '4322', (211, 217))	('MMP-13', 'Gene', (211, 217))	('K8.1 ( figure 5D', 'Gene', '4961469', (308, 324))	('reduced', 'NegReg', (43, 50))	('MAP4K4', 'Gene', (27, 33))
268909	24244164	As shown in  figure 4 , silencing of MAP4K4 reduces the expression of PTGS2, encoding cyclooxygenase 2 (COX-2).	('MAP4K4', 'Gene', '9448', (37, 43))	('COX-2', 'Gene', (104, 109))	('MAP4K4', 'Gene', (37, 43))	('COX-2', 'Gene', '5743', (104, 109))	('PTGS2', 'Gene', (70, 75))	('cyclooxygenase 2', 'Gene', '5743', (86, 102))	('PTGS2', 'Gene', '5743', (70, 75))	('expression', 'MPA', (56, 66))	('cyclooxygenase 2', 'Gene', (86, 102))	('reduces', 'NegReg', (44, 51))	('silencing', 'Var', (24, 33))
268914	24244164	Interestingly, both MAP4K4 and COX-2 silencing inhibited KSHV lytic reactivation ( figure 6B ).	('KSHV lytic reactivation', 'CPA', (57, 80))	('inhibited', 'NegReg', (47, 56))	('COX-2', 'Gene', '5743', (31, 36))	('MAP4K4', 'Gene', '9448', (20, 26))	('silencing', 'Var', (37, 46))	('MAP4K4', 'Gene', (20, 26))	('COX-2', 'Gene', (31, 36))
268920	24244164	On day 5 after infection, KSHV-infected HUVECs showed a markedly increased invasiveness compared to uninfected cells, and this increased invasiveness depended on the expression of MAP4K4, since silencing of MAP4K4 with siRNA reduced their invasiveness to background levels ( figure 7A-B ).	('increased', 'PosReg', (65, 74))	('MAP4K4', 'Gene', (207, 213))	('KSHV-infected', 'Disease', (26, 39))	('silencing', 'Var', (194, 203))	('invasiveness', 'MPA', (239, 251))	('reduced', 'NegReg', (225, 232))	('KSHV-infected', 'Disease', 'MESH:C537372', (26, 39))	('invasiveness', 'CPA', (75, 87))	('MAP4K4', 'Gene', '9448', (180, 186))	('MAP4K4', 'Gene', '9448', (207, 213))	('MAP4K4', 'Gene', (180, 186))
268921	24244164	Similar to KSHV-infected HuAR2T cells, expression of COX-2 increased after infection of HUVECs with KSHV and silencing of MAP4K4 by siRNA reduced COX-2 levels in KSHV-infected primary endothelial cells ( figure 7C ).	('COX-2', 'Gene', (146, 151))	('KSHV-infected', 'Disease', (162, 175))	('KSHV-infected', 'Disease', 'MESH:C537372', (162, 175))	('KSHV-infected', 'Disease', 'MESH:C537372', (11, 24))	('MAP4K4', 'Gene', '9448', (122, 128))	('reduced', 'NegReg', (138, 145))	('COX-2', 'Gene', '5743', (146, 151))	('MAP4K4', 'Gene', (122, 128))	('COX-2', 'Gene', (53, 58))	('increased', 'PosReg', (59, 68))	('COX-2', 'Gene', '5743', (53, 58))	('silencing', 'Var', (109, 118))	('expression', 'MPA', (39, 49))	('KSHV-infected', 'Disease', (11, 24))
268923	24244164	Moreover, KSHV lytic protein expression was inhibited after MAP4K4 depletion in primary cells, similarly to what we had found in immortalized endothelial cells ( figure 7D ).	('depletion', 'Var', (67, 76))	('inhibited', 'NegReg', (44, 53))	('MAP4K4', 'Gene', '9448', (60, 66))	('MAP4K4', 'Gene', (60, 66))	('KSHV lytic protein', 'Protein', (10, 28))	('expression', 'MPA', (29, 39))
268940	24244164	By blocking, among others, the p38 cascade, SB220025 inhibits the production of IL-1beta and TNF-alpha, and belongs to the CSAID class of cytokine biosynthesis inhibitors.	('p38', 'Gene', (31, 34))	('TNF-alpha', 'Gene', '7124', (93, 102))	('SB220025', 'Chemical', 'MESH:C110631', (44, 52))	('IL-1beta', 'Gene', '3553', (80, 88))	('SB220025', 'Var', (44, 52))	('CSAID', 'Chemical', '-', (123, 128))	('TNF-alpha', 'Gene', (93, 102))	('p38', 'Gene', '1432', (31, 34))	('inhibits', 'NegReg', (53, 61))	('IL-1beta', 'Gene', (80, 88))	('blocking', 'NegReg', (3, 11))
268943	24244164	Interestingly, we identified several JNK isoforms and their putative upstream activators MAP4K4 (NCK interacting kinase (NIK) or haematopoietic/germinal centre kinase (HGK)), MINK (Misshapen/NIK related kinase), and TNIK (TRAF2 and NCK interacting kinase) as targets of SB220025 (figure S1B).	('MINK', 'Species', '9666', (175, 179))	('NIK', 'Gene', (191, 194))	('SB220025', 'Chemical', 'MESH:C110631', (270, 278))	('SB220025', 'Var', (270, 278))	('MAP4K4', 'Gene', '9448', (89, 95))	('JNK', 'Gene', (37, 40))	('NIK', 'Gene', '9448', (217, 220))	('NIK', 'Gene', '9448', (121, 124))	('MAP4K4', 'Gene', (89, 95))	('HGK', 'Gene', (168, 171))	('JNK', 'Gene', '5599', (37, 40))	('NIK', 'Gene', '9448', (191, 194))	('NIK', 'Gene', (217, 220))	('HGK', 'Gene', '9448', (168, 171))	('NIK', 'Gene', (121, 124))
268946	24244164	While siRNA-mediated knockdown of TNIK and MINK did not affect KSHV reactivation (data not shown), MAP4K4 silencing reduced KSHV virus production ( figure 2A ), lytic protein expression ( figure 2B ), and KSHV replication ( figure 2C ) in immortalized, as well as primary endothelial cells ( figure 7D ).	('lytic', 'MPA', (161, 166))	('MINK', 'Species', '9666', (43, 47))	('MAP4K4', 'Gene', '9448', (99, 105))	('NIK', 'Gene', '9448', (35, 38))	('KSHV replication', 'CPA', (205, 221))	('MAP4K4', 'Gene', (99, 105))	('KSHV virus', 'Gene', (124, 134))	('silencing', 'Var', (106, 115))	('NIK', 'Gene', (35, 38))	('reduced', 'NegReg', (116, 123))
268953	24244164	Similarly, silencing of MAP4K4 reduced the increased invasiveness of KSHV-infected primary umbilical vein endothelial cells ( figure 7A-C ).	('silencing', 'Var', (11, 20))	('reduced', 'NegReg', (31, 38))	('invasiveness of KSHV-infected', 'Disease', (53, 82))	('MAP4K4', 'Gene', '9448', (24, 30))	('invasiveness of KSHV-infected', 'Disease', 'MESH:C537372', (53, 82))	('MAP4K4', 'Gene', (24, 30))
268956	24244164	Among cellular genes known to affect migration/invasion, we found PTGS2, encoding COX-2, to be downregulated after MAP4K4 knockdown ( figure 4A ).	('MAP4K4', 'Gene', (115, 121))	('downregulated', 'NegReg', (95, 108))	('rat', 'Species', '10116', (40, 43))	('COX-2', 'Gene', (82, 87))	('PTGS2', 'Gene', (66, 71))	('knockdown', 'Var', (122, 131))	('PTGS2', 'Gene', '5743', (66, 71))	('MAP4K4', 'Gene', '9448', (115, 121))	('COX-2', 'Gene', '5743', (82, 87))
268961	24244164	COX-2 inhibitors are known to also block human cytomegalovirus replication, as PGE2 enhances, for instance, CMV promoter activation.	('human cytomegalovirus', 'Species', '10359', (41, 62))	('enhances', 'PosReg', (84, 92))	('block', 'NegReg', (35, 40))	('PGE2', 'Chemical', 'MESH:D015232', (79, 83))	('PGE2', 'Gene', (79, 83))	('CMV promoter activation', 'MPA', (108, 131))	('inhibitors', 'Var', (6, 16))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))
268963	24244164	Of note, MAP4K4 expression levels after COX-2 depletion and its chemical inhibition were slightly reduced ( figure 6B, 6D-E ).	('MAP4K4', 'Gene', (9, 15))	('depletion', 'Var', (46, 55))	('COX-2', 'Gene', (40, 45))	('expression levels', 'MPA', (16, 33))	('COX-2', 'Gene', '5743', (40, 45))	('reduced', 'NegReg', (98, 105))	('MAP4K4', 'Gene', '9448', (9, 15))
268967	24244164	We could also show that, similarly to MAP4K4 knockdown, COX-2 silencing or chemical inhibition significantly reduces the invasiveness of KSHV-infected endothelial cells ( figure 6A, 6C ).	('silencing', 'Var', (62, 71))	('COX-2', 'Gene', '5743', (56, 61))	('invasiveness of KSHV-infected', 'Disease', 'MESH:C537372', (121, 150))	('MAP4K4', 'Gene', '9448', (38, 44))	('chemical inhibition', 'Var', (75, 94))	('MAP4K4', 'Gene', (38, 44))	('invasiveness of KSHV-infected', 'Disease', (121, 150))	('reduces', 'NegReg', (109, 116))	('COX-2', 'Gene', (56, 61))
268974	24244164	Given the reported role of MAP4K4 as an upstream activator of JNK, and the role of JNK in KSHV reactivation, we also explored if silencing of MAP4K4 in KSHV-infected endothelial cells would alter the levels of JNK 1/2/3 phosphorylation, using phospho-specific antibodies in Western blot analysis.	('JNK 1', 'Gene', (210, 215))	('JNK 1', 'Gene', '5599', (210, 215))	('levels', 'MPA', (200, 206))	('MAP4K4', 'Gene', (142, 148))	('KSHV-infected', 'Disease', 'MESH:C537372', (152, 165))	('JNK', 'Gene', '5599', (210, 213))	('JNK', 'Gene', '5599', (83, 86))	('JNK', 'Gene', (83, 86))	('silencing', 'Var', (129, 138))	('JNK', 'Gene', '5599', (62, 65))	('MAP4K4', 'Gene', '9448', (27, 33))	('JNK', 'Gene', (62, 65))	('alter', 'Reg', (190, 195))	('MAP4K4', 'Gene', '9448', (142, 148))	('JNK', 'Gene', (210, 213))	('MAP4K4', 'Gene', (27, 33))	('KSHV-infected', 'Disease', (152, 165))
268988	24244164	The following siRNAs (siGENOME SMARTpool) were obtained from Dharmacon, Thermo Scientific: Control (Non-targeting siRNA Pool #2, D-001206-14-20), MAP4K4 (M-003971-02-0005), MMP-7 (M-003782-01-0005), MMP-13 (M-005955-01-0005).	('MMP-13', 'Gene', (199, 205))	('MMP-7', 'Gene', '4316', (173, 178))	('MAP4K4', 'Gene', (146, 152))	('M-003782-01-0005', 'Var', (180, 196))	('M-003971-02-0005', 'Var', (154, 170))	('MAP4K4', 'Gene', '9448', (146, 152))	('MMP-7', 'Gene', (173, 178))	('MMP-13', 'Gene', '4322', (199, 205))
269001	24244164	Data were filtered according to the following criteria: 1) More than 1.5 fold downregulation in lytically induced HuAR2T rKSHV.219 cells after MAP4K4 knockdown compared to control siRNA treated induced cells (each of three experiments).	('KSHV.219', 'CellLine', 'CVCL:G580', (122, 130))	('downregulation', 'NegReg', (78, 92))	('MAP4K4', 'Gene', '9448', (143, 149))	('knockdown', 'Var', (150, 159))	('MAP4K4', 'Gene', (143, 149))
269005	24244164	The following TaqMan gene expression assays (Applied Biosystems: #4331182) were used: Hs00153133_m1 (PTGS2/COX-2), Hs99999908_m1 (GUSB), Hs01042796_m1 (MMP-7), Hs00233992_m1 (MMP-13), Hs02758991_g1 (GAPDH); primer-probe sets for RTA, KbZIP, K8.1.	('COX-2', 'Gene', (107, 112))	('GAPDH', 'Gene', (199, 204))	('Hs99999908_m1', 'Var', (115, 128))	('COX-2', 'Gene', '5743', (107, 112))	('GUSB', 'Gene', (130, 134))	('GUSB', 'Gene', '2990', (130, 134))	('MMP-7', 'Gene', '4316', (152, 157))	('Hs02758991_g1', 'Var', (184, 197))	('Hs00153133_m1', 'Var', (86, 99))	('PTGS2', 'Gene', '5743', (101, 106))	('PTGS2', 'Gene', (101, 106))	('Hs01042796_m1', 'Var', (137, 150))	('MMP-13', 'Gene', '4322', (175, 181))	('Hs00233992_m1', 'Var', (160, 173))	('MMP-7', 'Gene', (152, 157))	('MMP-13', 'Gene', (175, 181))	('GAPDH', 'Gene', '2597', (199, 204))
269028	24244164	VI18802 is a phenoxypyrimidine targeting p38alpha.	('p38alpha', 'Gene', (41, 49))	('VI18802', 'Chemical', '-', (0, 7))	('VI18802', 'Var', (0, 7))	('p38alpha', 'Gene', '1432', (41, 49))	('phenoxypyrimidine', 'Chemical', '-', (13, 30))
269042	24244164	Akt (P31749), b-Raf (P15056), CD34 (P28906), CDC2L1 (A4VCI5), c-Jun (P05412), COX-1 (P23219), COX-2 (P35354), CSNK1A1L (Q8N752), CSNK1D (P48730), CSNK1E (P49674), ERK1 (P27361), IFN-alpha (P01562), IL-1beta (P01584), IL-2 (P60568), IL-6 (P05231), JNK1 (P45983), JNK3 (P53779), KSHV K15 (Q9QR69), KSHV K8.1 (D2XQF0), KSHV KbZIP (E5LBX3), KSHV LANA (J9QT20), KSHV ORF45 (F5HDE4), KSHV RTA (F5HCV3), KSHV v-Cyclin (Q77Q36), KSHV v-FLIP (Q76RF1), KSHV vGPCR (Q98146), KSHV vIL-6 (Q98823), MAP4K4 (O95819), MEK1 (Q02750), MINK (Q8N4C8), MK2 (P49137), MMP-1 (P03956), MMP-13 (P45452), MMP-19 (Q99542), MMP-2 (P08253), MMP-3 (P08254), MMP-7 (P09237), MMP-9 (P14780), NF-kappaB (Q04206), Notch (P46531), p38alpha (Q16539), PI3K (P42336), Pim-1 (P11309), Pim-3 (Q86V86), PKA (P17612), PKCdelta (Q05655), RBP-Jkappa (Q06330), STK36 (Q9NRP7), TLR7/8 (D1CS68), TNF-alpha (P01375), TNFR alpha (P19438), TNIK (Q9UKE5).	('JNK', 'Gene', '5599', (247, 250))	('ERK', 'Gene', (163, 166))	('IL-1beta', 'Gene', (198, 206))	('P14780', 'Var', (651, 657))	('MMP-2', 'Gene', (596, 601))	('K15', 'Gene', '4961473', (282, 285))	('MMP-13', 'Gene', '4322', (562, 568))	('NIK', 'Gene', '9448', (891, 894))	('ORF45', 'Gene', (362, 367))	('MMP-1', 'Gene', '4312', (562, 567))	('K15', 'Gene', (282, 285))	('JNK', 'Gene', (262, 265))	('MMP-1', 'Gene', '4312', (579, 584))	('COX-2', 'Gene', (94, 99))	('IL-2', 'Gene', (217, 221))	('JNK', 'Gene', '5599', (262, 265))	('MMP-1', 'Gene', '4312', (546, 551))	('MAP4K4', 'Gene', '9448', (485, 491))	('CD34', 'Gene', '947', (30, 34))	('MMP-7', 'Gene', (628, 633))	('c-Jun', 'Gene', '3725', (62, 67))	('Pim-3', 'Gene', '415116', (746, 751))	('Pim-1', 'Gene', '5292', (730, 735))	('MINK', 'Species', '9666', (517, 521))	('p38alpha', 'Gene', (696, 704))	('Pim-3', 'Gene', (746, 751))	('MK2', 'Gene', (532, 535))	('IL-6', 'Gene', '3569', (470, 474))	('vIL-6', 'Gene', '4961449', (469, 474))	('c-Jun', 'Gene', (62, 67))	('MMP-13', 'Gene', (562, 568))	('P46531', 'Var', (687, 693))	('MMP-1', 'Gene', (562, 567))	('MMP-1', 'Gene', (579, 584))	('COX-2', 'Gene', '5743', (94, 99))	('LANA', 'Gene', (342, 346))	('p38alpha', 'Gene', '1432', (696, 704))	('LANA', 'Gene', '4961527', (342, 346))	('IL-6', 'Gene', '3569', (232, 236))	('MMP-9', 'Gene', (644, 649))	('MEK', 'Gene', '5609', (502, 505))	('MMP-1', 'Gene', (546, 551))	('IL-6', 'Gene', (470, 474))	('MMP-7', 'Gene', '4316', (628, 633))	('MAP4K4', 'Gene', (485, 491))	('MMP-9', 'Gene', '4318', (644, 649))	('v-Cyclin', 'Gene', (402, 410))	('ERK', 'Gene', '5594', (163, 166))	('MMP-3', 'Gene', (612, 617))	('Pim-1', 'Gene', (730, 735))	('Q04206', 'Var', (671, 677))	('IL-2', 'Gene', '3558', (217, 221))	('IL-1beta', 'Gene', '3553', (198, 206))	('NIK', 'Gene', (891, 894))	('MMP-2', 'Gene', '4313', (596, 601))	('v-Cyclin', 'Gene', '4961471', (402, 410))	('TNF-alpha', 'Gene', '7124', (849, 858))	('IL-6', 'Gene', (232, 236))	('CD34', 'Gene', (30, 34))	('MEK', 'Gene', (502, 505))	('vIL-6', 'Gene', (469, 474))	('MK2', 'Gene', '9261', (532, 535))	('JNK', 'Gene', (247, 250))	('ORF45', 'Gene', '4961474', (362, 367))	('TNF-alpha', 'Gene', (849, 858))	('MMP-3', 'Gene', '4314', (612, 617))
269157	22898682	These analyses have demonstrated a relationship between changes in SUV and favorable histologic response to chemotherapy in osteosarcoma and Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (141, 156))	('SUV', 'Gene', (67, 70))	('osteosarcoma', 'Disease', (124, 136))	("Ewing's sarcoma", 'Disease', (141, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (141, 156))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('changes', 'Var', (56, 63))
269197	22879388	These tumors frequently share expression of the EWS-FLI-1 translocation, which is central to tumor survival but not present in healthy cells.	('translocation', 'Var', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Disease', (93, 98))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('EWS-FLI-1', 'Gene', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
269198	22879388	Computer prediction analysis of peptide binding, HLA-A2.1 stabilization assays, and induction of Cytotoxic T-Lymphocytes (CTL) in immunized HLA-A2.1 transgenic mice were used to assess the immunogenicity of native and modified peptides derived from the fusion region of EWS-FLI-1 type 1.	('transgenic mice', 'Species', '10090', (149, 164))	('Cytotoxic', 'Disease', (97, 106))	('modified', 'Var', (218, 226))	('Cytotoxic', 'Disease', 'MESH:D064420', (97, 106))
269201	22879388	In contrast, peptides with modified anchor residues induced potent CTL killing of Ewing Sarcoma cells presenting endogenous (native) peptides.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (82, 95))	('Ewing Sarcoma', 'Disease', (82, 95))	('CTL killing', 'CPA', (67, 78))	('modified', 'Var', (27, 35))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('Sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
269202	22879388	The adoptive transfer of CTL specific for the modified peptide YLNPSVDSV resulted in enhanced survival of mice with established Ewing Sarcoma xenografts.	('mice', 'Species', '10090', (106, 110))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('enhanced', 'PosReg', (85, 93))	('YLNPSVDSV', 'Var', (63, 72))	('YLNPSVDSV', 'Chemical', '-', (63, 72))	('Sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('survival', 'CPA', (94, 102))	('Ewing Sarcoma', 'Disease', (128, 141))
269204	22879388	Stimulation of human Peripheral Blood Mononuclear Cells with YLNPSVDSV peptide resulted in potent CTL-killing.	('YLNPSVDSV', 'Chemical', '-', (61, 70))	('CTL-killing', 'CPA', (98, 109))	('YLNPSVDSV', 'Var', (61, 70))	('human', 'Species', '9606', (15, 20))
269205	22879388	These data show that YLNPSVDSV peptide is a promising antigen for ESFT immunotherapy and warrants further clinical development.	('YLNPSVDSV', 'Var', (21, 30))	('YLNPSVDSV', 'Chemical', '-', (21, 30))	('ESFT', 'Disease', (66, 70))
269208	22879388	Ewing Sarcoma, and the historically named Primitive Neuroectodermal Tumor (pPNET), Biphenotypic Sarcoma and Askin's tumor, all share recurrent translocations that involve fusion of the EWS gene (22q-12) to genes encoding ETS transcription factors, of which, fusion to the FLI-1 gene occurs in about 90% of cases.	('fusion', 'Var', (171, 177))	('FLI-1', 'Gene', (272, 277))	('Sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	("Askin's tumor", 'Disease', (108, 121))	('Neuroectodermal Tumor', 'Phenotype', 'HP:0030061', (52, 73))	('Neuroectodermal Tumor', 'Disease', (52, 73))	('Ewing Sarcoma', 'Disease', (0, 13))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Neuroectodermal Tumor', 'Disease', 'MESH:D017599', (52, 73))	('EWS', 'Gene', (185, 188))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('Biphenotypic Sarcoma', 'Disease', (83, 103))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Biphenotypic Sarcoma', 'Disease', 'MESH:D015456', (83, 103))	('translocations', 'Var', (143, 157))	('Sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Primitive Neuroectodermal Tumor', 'Phenotype', 'HP:0030065', (42, 73))	('Tumor', 'Phenotype', 'HP:0002664', (68, 73))	("Askin's tumor", 'Disease', 'MESH:C563168', (108, 121))
269217	22879388	The modification of key binding residues, in contrast, results in potent CTL activation, strong CTL killing across a range of ESFT types and increased survival of mice with established Ewing Sarcoma xenografts.	('increased', 'PosReg', (141, 150))	('activation', 'PosReg', (77, 87))	('survival', 'CPA', (151, 159))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (185, 198))	('CTL', 'MPA', (73, 76))	('Sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('modification', 'Var', (4, 16))	('mice', 'Species', '10090', (163, 167))	('Ewing Sarcoma', 'Disease', (185, 198))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (185, 198))	('CTL killing', 'CPA', (96, 107))
269247	22879388	However, appropriately modified tumor peptides can often prime the immune response to act against native tumor peptides incapable of inducing an immune response on their own.	('immune response', 'MPA', (67, 82))	('modified', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('act against', 'MPA', (86, 97))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (105, 110))	('prime', 'PosReg', (57, 62))
269248	22879388	As expected, the predicted binding affinities of peptides modified in this manner increased substantially both SYFPEITHI and BIMAS scores following the substitution of residues at positions 1, 2, 6, and/or 9 with Tyrosine (Y), Leucine (L), Isoleucine (I) and/or Valine (V: see Table 2).	('substitution', 'Var', (152, 164))	('Leucine', 'Chemical', 'MESH:D007930', (227, 234))	('Isoleucine', 'Chemical', 'MESH:D007532', (240, 250))	('binding', 'Interaction', (27, 34))	('Valine', 'Chemical', 'MESH:D014633', (262, 268))	('increased', 'PosReg', (82, 91))	('Tyrosine', 'Chemical', 'MESH:D014443', (213, 221))	('Tyrosine', 'Var', (213, 221))
269251	22879388	As shown in Figure 1 (A-C), most of the modified peptides, but not all, displayed a stronger binding capacity than the corresponding native peptides from which they were derived.	('A-C', 'Disease', 'MESH:C537418', (22, 25))	('stronger', 'PosReg', (84, 92))	('modified', 'Var', (40, 48))	('A-C', 'Disease', (22, 25))	('binding', 'Interaction', (93, 100))
269252	22879388	We also sought to determine whether modified peptides would show an improved capacity to stabilize MHC molecules on the live cell surface, as the ability of peptide/MHC complexes to remain on the cell surface is critical to the initiation of T-cell activation.	('modified', 'Var', (36, 44))	('MHC', 'Gene', '3107', (165, 168))	('MHC', 'Gene', (99, 102))	('MHC', 'Gene', '3107', (99, 102))	('MHC', 'Gene', (165, 168))
269254	22879388	Unlike the native peptide sequences SYGQQNPSY (#1) and SSYGQQNPS (#9) from which they were derived, each of the modified peptides (#4, #6, #8, and #11, #12, and #13 respectively) showed improved stabilization of cell surface MHC (Fig.	('MHC', 'Gene', (225, 228))	('modified', 'Var', (112, 120))	('stabilization', 'MPA', (195, 208))	('improved', 'PosReg', (186, 194))	('MHC', 'Gene', '3107', (225, 228))
269255	22879388	The native sequence QQNPSYDSV (#14) was found to stabilize cell surface MHC molecules at a high concentration (50microg/ml), but not at low concentrations <10microg/ml (Fig.	('MHC', 'Gene', (72, 75))	('stabilize cell surface', 'MPA', (49, 71))	('MHC', 'Gene', '3107', (72, 75))	('QQNPSYDSV', 'Var', (20, 29))
269259	22879388	These data show that modifying native EWS-FLI-1 Type 1 junction peptides can result in better retention of peptide/MHC complexes on the cell surface.	('retention', 'MPA', (94, 103))	('modifying', 'Var', (21, 30))	('MHC', 'Gene', (115, 118))	('EWS-FLI-1', 'Gene', (38, 47))	('MHC', 'Gene', '3107', (115, 118))	('better', 'PosReg', (87, 93))
269260	22879388	A critical question when modifying tumor peptides to induce CTL activation is whether or not CTL raised against the modified peptide will recognize and kill tumor cells expressing the native peptide.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('modified', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
269261	22879388	We conducted CTL assays using purified CD8 T-cells derived from HLA-A2.1/Kb mice immunized with native or modified peptides.	('mice', 'Species', '10090', (76, 80))	('modified', 'Var', (106, 114))	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))
269265	22879388	The strongest CTL activity was displayed by modified peptides QINPSVDSV (#21) and YLNPSVDSV (#24) which both displayed over 40% killing.	('YLNPSVDSV', 'Var', (82, 91))	('CTL', 'CPA', (14, 17))	('YLNPSVDSV', 'Chemical', '-', (82, 91))
269267	22879388	Collectively, these data show that the CTL-inducing capacity of native EWS-FLI-1 Type 1 junction peptides presented on HLA-A2.1 is low, but modification of key MHC-binding anchor residues can result in the activation of CTL clones capable of recognizing and killing unmodified tumor cells expressing native EWS-FLI-1 Type 1 junction peptides.	('tumor', 'Disease', (277, 282))	('CTL clones', 'CPA', (220, 230))	('modification', 'Var', (140, 152))	('MHC', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('MHC', 'Gene', '3107', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('killing', 'CPA', (258, 265))	('activation', 'PosReg', (206, 216))
269272	22879388	On days 5 and 12 post-tumor challenge, we adoptively transferred CD8 T-cells derived from HLA-A2.1/Kb mice immunized with YLNPSVDSV (#24) or irrelevant control peptide (Flu: GILGFVFTL).	('mice', 'Species', '10090', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('YLNPSVDSV', 'Chemical', '-', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CD8', 'Gene', (65, 68))	('CD8', 'Gene', '925', (65, 68))	('YLNPSVDSV (#24', 'Var', (122, 136))	('tumor', 'Disease', (22, 27))
269274	22879388	Treatment of the xenografts with T-cells specific for YLNPSVDSV significantly increased mouse survival time when compared with untreated mice or mice receiving T-cells recognizing an irrelevant peptide (Flu: GILGFVFTL) (Fig.	('mice', 'Species', '10090', (137, 141))	('increased', 'PosReg', (78, 87))	('mouse', 'Species', '10090', (88, 93))	('mice', 'Species', '10090', (145, 149))	('YLNPSVDSV', 'Var', (54, 63))	('YLNPSVDSV', 'Chemical', '-', (54, 63))	('mouse survival time', 'CPA', (88, 107))
269279	22879388	The results indicate that the adoptive transfer of YLNPSVDSV-specific CTL, but not irrelevant control CTL, into mice with established Ewing Sarcoma xenografts results in enhanced survival.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (134, 147))	('YLNPSVDSV-specific', 'Var', (51, 69))	('survival', 'CPA', (179, 187))	('Ewing Sarcoma', 'Disease', (134, 147))	('enhanced', 'PosReg', (170, 178))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (134, 147))	('YLNPSVDSV', 'Chemical', '-', (51, 60))	('Sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('mice', 'Species', '10090', (112, 116))
269284	22879388	We conducted CTL assays using purified CD8 T-cells derived from HLA-A2.1/Kb mice immunized with native (QQNPSYDSV #14) or modified (YLNPSVDSV #24) peptides.	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('YLNPSVDSV #24', 'Var', (132, 145))	('mice', 'Species', '10090', (76, 80))	('QQNPSYDSV', 'Var', (104, 113))	('YLNPSVDSV', 'Chemical', '-', (132, 141))
269286	22879388	Furthermore, YLNPSVDSV-specific CTL (#24) showed significantly improved killing against 7 out of these 8 lines when compared with QQNPSYDSV-specific CTL (#14).	('killing', 'CPA', (72, 79))	('YLNPSVDSV', 'Chemical', '-', (13, 22))	('improved', 'PosReg', (63, 71))	('YLNPSVDSV-specific', 'Var', (13, 31))
269288	22879388	These data also underline the improved cytotoxic capacity of CTL raised using a modified (YLNPSVDSV #24) EWS-FLI-1 Type 1 peptide in comparison to CTL raised using the native (QQNPSYDSV #14) peptide.	('improved', 'PosReg', (30, 38))	('cytotoxic capacity', 'CPA', (39, 57))	('YLNPSVDSV', 'Chemical', '-', (90, 99))	('modified (YLNPSVDSV #24', 'Var', (80, 103))
269291	22879388	Pre-characterized PBMC from 3 different HLA-A2.1+ donors with known recall responses Influenza A peptides were stimulated with native (QQNPSYDSV #14), modified (YLNPSVDSV #24), or positive control (GILGFVFTL; Flu) peptide.	('YLNPSVDSV #24', 'Var', (161, 174))	('QQNPSYDSV #14', 'Var', (135, 148))	('YLNPSVDSV', 'Chemical', '-', (161, 170))
269294	22879388	After 4 weeks of peptide stimulation, however, the level of CD8 T-cells specific for YLNPSVDSV peptide expanded to between 2.57% and 2.86%.	('CD8', 'Gene', '925', (60, 63))	('YLNPSVDSV', 'Var', (85, 94))	('YLNPSVDSV', 'Chemical', '-', (85, 94))	('CD8', 'Gene', (60, 63))
269296	22879388	As shown in Figure 3C, for each of the 3 donors tested YLNPSVDSV-specific CTL displayed substantially improved killing of TC-71 Ewing sarcoma cells compared to QQNPSYDSV-specific CTL.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('YLNPSVDSV-specific', 'Var', (55, 73))	('Ewing sarcoma', 'Disease', (128, 141))	('YLNPSVDSV', 'Chemical', '-', (55, 64))	('TC-71', 'Chemical', '-', (122, 127))	('improved', 'PosReg', (102, 110))	('killing', 'CPA', (111, 118))
269308	22879388	Importantly, CTL raised using modified peptides were able to recognize and kill tumor cells endogenously expressing native EWS-FLI-1 Type 1 peptides.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (80, 85))	('modified', 'Var', (30, 38))
269309	22879388	CTL induced with modified peptide (YLNPSVDSV) and recognizing EWS-FLI-1 Type 1 were adoptively transferred into immune compromised mice bearing established TC-71 xenografts.	('modified', 'Var', (17, 25))	('TC-71', 'Chemical', '-', (156, 161))	('mice', 'Species', '10090', (131, 135))	('YLNPSVDSV', 'Chemical', '-', (35, 44))	('YLNPSVDSV', 'Var', (35, 44))
269316	22879388	The successful activation of CD8 T-cells from healthy human PBMC using the modified YLNPSVDSV peptide indicates that CD8 T-cell clones capable of recognizing this sequence exist and are not depleted during selection in the thymus.	('YLNPSVDSV', 'Chemical', '-', (84, 93))	('CD8', 'Gene', '925', (29, 32))	('modified', 'Var', (75, 83))	('CD8', 'Gene', (117, 120))	('CD8', 'Gene', '925', (117, 120))	('human', 'Species', '9606', (54, 59))	('CD8', 'Gene', (29, 32))
269317	22879388	Furthermore, YLNPSVDSV-specific CTL can be readily activated by peptide to result in the potent killing of cells bearing the EWS-FLI-1 Type 1 translocation.	('EWS-FLI-1', 'Gene', (125, 134))	('YLNPSVDSV', 'Chemical', '-', (13, 22))	('YLNPSVDSV-specific', 'Var', (13, 31))
269319	22879388	In addition, immunogenic MHC Class II-restricted peptides spanning the EWS-FLI-1 breakpoint region merit further investigation for their capacity to induce tumor-specific helper T-cell responses, as ultimately a multi-pronged approach is likely to yield the most effective antitumor immunity.	('MHC', 'Gene', '3107', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('EWS-FLI-1', 'Gene', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('peptides', 'Var', (49, 57))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (277, 282))	('MHC', 'Gene', (25, 28))
269324	22879388	However, CTL that recognize a modified EWS-FLI-1 peptide, YLNPSVDSV, potently kill several different ESFT tumor types.	('ESFT', 'Disease', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('YLNPSVDSV', 'Var', (58, 67))	('YLNPSVDSV', 'Chemical', '-', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('kill', 'NegReg', (78, 82))	('tumor', 'Disease', (106, 111))
269439	32629971	The ultimate goal of pharmacogenetics and pharmacogenomics (two terms that are frequently used interchangeably) is to define genomic variations, which may provide useful information to improve drug efficacy and reduce the risk of chemotherapy-related toxicities.	('variations', 'Var', (133, 143))	('reduce', 'NegReg', (211, 217))	('improve drug efficacy', 'Phenotype', 'HP:0020173', (185, 206))	('improve', 'PosReg', (185, 192))	('toxicities', 'Disease', 'MESH:D064420', (251, 261))	('drug', 'MPA', (193, 197))	('toxicities', 'Disease', (251, 261))
269441	32629971	The majority of studies, which have been performed so far in HGOS, have evaluated single nucleotide polymorphisms (SNPs) in several candidate genes of possible relevance for the biology, drug response, detoxification and susceptibility to treatment-related toxicities, in order to indicate biomarkers which may provide the bases for planning tailored treatments aimed to increase therapeutic benefits and limit adverse events.	('increase', 'PosReg', (371, 379))	('single nucleotide polymorphisms', 'Var', (82, 113))	('toxicities', 'Disease', 'MESH:D064420', (257, 267))	('toxicities', 'Disease', (257, 267))
269447	32629971	The first international genome-wide association study (GWAS) using a high-throughput approach including 941 samples and 3291 controls identified SNPs in the glutamate metabotropic receptor 4 (GRM4) gene and in a gene desert at chromosome 2p25.2 which were found to be associated with risk to develop HGOS.	('glutamate metabotropic receptor 4', 'Gene', '2914', (157, 190))	('SNPs', 'Var', (145, 149))	('associated', 'Reg', (268, 278))	('HGOS', 'Disease', (300, 304))	('GRM4', 'Gene', (192, 196))	('glutamate metabotropic receptor 4', 'Gene', (157, 190))	('GRM4', 'Gene', '2914', (192, 196))
269448	32629971	The risk association between GRM4 rs11906953 and HGOS was subsequently confirmed in two studies carried out in Chinese populations.	('rs11906953', 'Var', (34, 44))	('HGOS', 'Disease', (49, 53))	('GRM4', 'Gene', (29, 33))	('GRM4', 'Gene', '2914', (29, 33))	('rs11906953', 'Mutation', 'rs11906953', (34, 44))
269452	32629971	The first, performing WGS or WES on 1120 pediatric cancer patients (39 HGOS), identified TP53, APC, breast related cancer antigen 2 (BRCA2), neurofibromin 1 (NF1), PMS1 homolog 2, mismatch repair system component (PMS2), RB transcriptional corepressor 1 (RB1) and RUNX family transcription factor 1 (RUNX1) to be affected by mutations in more than three cases.	('RUNX1', 'Gene', (300, 305))	('APC', 'Disease', (95, 98))	('RUNX1', 'Gene', '861', (300, 305))	('RB1', 'Gene', '5925', (255, 258))	('NF1', 'Gene', (158, 161))	('RB transcriptional corepressor 1', 'Gene', '5925', (221, 253))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('neurofibromin 1', 'Gene', (141, 156))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('BRCA2', 'Gene', (133, 138))	('mutations', 'Var', (325, 334))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('PMS1', 'Gene', (164, 168))	('PMS2', 'Gene', '5395', (214, 218))	('PMS1', 'Gene', '5378', (164, 168))	('RUNX family transcription factor 1', 'Gene', (264, 298))	('patients', 'Species', '9606', (58, 66))	('BRCA2', 'Gene', '675', (133, 138))	('RB1', 'Gene', (255, 258))	('cancer', 'Disease', (115, 121))	('TP53', 'Gene', (89, 93))	('RB transcriptional corepressor 1', 'Gene', (221, 253))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('NF1', 'Gene', '4763', (158, 161))	('PMS2', 'Gene', (214, 218))	('breast related cancer antigen 2', 'Gene', '675', (100, 131))	('breast related cancer antigen 2', 'Gene', (100, 131))	('cancer', 'Disease', (51, 57))	('APC', 'Disease', 'MESH:D011125', (95, 98))	('neurofibromin 1', 'Gene', '4763', (141, 156))
269453	32629971	The second, reporting WES data on germline DNA samples from 1162 prevalently adult sarcoma patients (124 HGOS) found that 55% of patients had an excess of pathogenic germline variants in the 72 pan-sarcoma genes, such as TP53, BRCA2, ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and ERCC2.	('BRCA2', 'Gene', '675', (227, 232))	('sarcoma', 'Disease', 'MESH:D012509', (198, 205))	('ataxia telangiectasia mutated', 'Gene', '472', (234, 263))	('sarcoma', 'Disease', (198, 205))	('telangiectasia', 'Phenotype', 'HP:0001009', (278, 292))	('patients', 'Species', '9606', (91, 99))	('ATR', 'Gene', '545', (311, 314))	('pathogenic', 'CPA', (155, 165))	('ataxia', 'Phenotype', 'HP:0001251', (234, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('ataxia telangiectasia and Rad3 related', 'Gene', '545', (271, 309))	('variants', 'Var', (175, 183))	('ATM', 'Gene', '472', (265, 268))	('sarcoma', 'Disease', (83, 90))	('patients', 'Species', '9606', (129, 137))	('ataxia', 'Phenotype', 'HP:0001251', (271, 277))	('ataxia telangiectasia mutated', 'Gene', (234, 263))	('BRCA2', 'Gene', (227, 232))	('ATR', 'Gene', (311, 314))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('TP53', 'Gene', (221, 225))	('ATM', 'Gene', (265, 268))	('ERCC2', 'Gene', (321, 326))	('telangiectasia', 'Phenotype', 'HP:0001009', (241, 255))
269458	32629971	A significantly higher P/LP variant burden in the 238 high-interest cancer-susceptibility genes was found in the HGOS cases compared to the in-house controls restricted to European ancestry.	('higher', 'PosReg', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('variant burden', 'Var', (28, 42))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('P/LP', 'Var', (23, 27))	('cancer', 'Disease', (68, 74))	('HGOS', 'Disease', (113, 117))
269459	32629971	A P/LP variant was identified in 28% of the cases, of which nearly three-quarters mapped to an autosomal dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene.	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('autosomal dominant gene', 'Disease', (95, 118))	('mapped', 'Reg', (82, 88))	('P/LP', 'Var', (2, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('osteosarcoma-associated cancer predisposition syndrome', 'Disease', 'MESH:D009369', (130, 184))
269460	32629971	Higher than expected frequencies of P/LP variants were found in genes previously linked to osteosarcoma, e.g., cyclin dependent kinase inhibitor 2A (CDKN2A), menin 1 (MEN1), Von Hippel-Lindau (VHL) tumor suppressor, protection of telomeres 1 (POT1), APC, mutS homolog 2 (MSH2), ATRX chromatin remodeler (ATRX) and TP53.	('CDKN2A', 'Gene', '1029', (149, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('MSH2', 'Gene', '4436', (271, 275))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('linked', 'Reg', (81, 87))	('osteosarcoma', 'Disease', (91, 103))	('mutS homolog 2', 'Gene', '4436', (255, 269))	('osteosarcoma', 'Disease', 'MESH:D012516', (91, 103))	('variants', 'Var', (41, 49))	('ATRX', 'Gene', '546', (278, 282))	('POT1', 'Gene', '25913', (243, 247))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (111, 147))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (174, 203))	('TP53', 'Gene', (314, 318))	('ATRX', 'Gene', (304, 308))	('APC', 'Disease', 'MESH:D011125', (250, 253))	('cyclin dependent kinase inhibitor 2A', 'Gene', (111, 147))	('protection of telomeres 1', 'Gene', '25913', (216, 241))	('APC', 'Disease', (250, 253))	('ATRX', 'Gene', '546', (304, 308))	('POT1', 'Gene', (243, 247))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('CDKN2A', 'Gene', (149, 155))	('protection of telomeres 1', 'Gene', (216, 241))	('MSH2', 'Gene', (271, 275))	('ATRX', 'Gene', (278, 282))	('mutS homolog 2', 'Gene', (255, 269))
269463	32629971	Polymorphisms of the GST family (GSTP1 rs1695, GSTT1 and GSTM1 null allele, and GSTM3 rs1799735 were analyzed in a meta-analysis including 24 case-control studies with a total of 2405 HGOS cases and 3293 controls.	('rs1695', 'Var', (39, 45))	('GSTM3', 'Gene', (80, 85))	('GST', 'Gene', '373156', (57, 60))	('GST', 'Gene', '373156', (47, 50))	('GST', 'Gene', '373156', (21, 24))	('GST', 'Gene', (47, 50))	('GSTM3', 'Gene', '2947', (80, 85))	('rs1695', 'Mutation', 'rs1695', (39, 45))	('GST', 'Gene', (80, 83))	('rs1799735', 'Mutation', 'rs1799735', (86, 95))	('GST', 'Gene', (33, 36))	('GST', 'Gene', '373156', (80, 83))	('GST', 'Gene', (57, 60))	('rs1799735', 'Var', (86, 95))	('GST', 'Gene', '373156', (33, 36))	('GST', 'Gene', (21, 24))
269465	32629971	The two most frequently studied variants of MDM2, rs1690916 and rs2279744, for which inconclusive data were reported regarding a possible association with risk to develop HGOS were considered in a meta-analysis including six populations with a total of 246 HGOS patients and 1760 controls (rs2279744) and 433 HGOS patients and 1959 controls (rs2279744).	('HGOS', 'Disease', (257, 261))	('rs1690916', 'Var', (50, 59))	('patients', 'Species', '9606', (314, 322))	('rs1690916', 'Mutation', 'rs1690916', (50, 59))	('MDM2', 'Gene', (44, 48))	('rs2279744', 'Mutation', 'rs2279744', (342, 351))	('rs2279744', 'Mutation', 'rs2279744', (64, 73))	('rs2279744', 'Mutation', 'rs2279744', (290, 299))	('patients', 'Species', '9606', (262, 270))	('HGOS', 'Disease', (171, 175))	('rs2279744', 'Var', (64, 73))	('rs2279744', 'Var', (290, 299))
269466	32629971	A more comprehensive approach was used in a one meta-analysis considering 32 case-control studies with a total of 6924 HGOS patients and 8412 controls, and 24 SNPs in 14 genes.	('SNPs', 'Var', (159, 163))	('patients', 'Species', '9606', (124, 132))	('HGOS', 'Disease', (119, 123))
269467	32629971	Nine risk alleles (CTLA-4 rs231775; protein kinase CGMP-dependent 1, PRCKG rs454006; RecQ like helicase 5, RECQL5 rs820196; TNF-a rs1800629; TP53 rs1042522; XRCC3 rs861539; VEGF rs699947 and VEGF rs3025039) with an average pooled OR = 2.082 (CI 1.59-3.26; p < 0.003) and three protective alleles (interleukin 8, IL-8 rs4073; MDM2 rs1690916; and VEGF rs2010963) with OR = 0.61 (0.51-0.72, p < 0.038) were identified.	('rs231775', 'Mutation', 'rs231775', (26, 34))	('rs454006', 'Mutation', 'rs454006', (75, 83))	('interleukin 8', 'Gene', (297, 310))	('RecQ like helicase 5', 'Gene', '9400', (85, 105))	('rs1800629', 'Var', (130, 139))	('VEGF', 'Gene', (173, 177))	('VEGF', 'Gene', '7422', (345, 349))	('rs4073', 'Var', (317, 323))	('RECQL5', 'Gene', (107, 113))	('rs1690916', 'Mutation', 'rs1690916', (330, 339))	('TNF-a', 'Gene', '7124', (124, 129))	('rs1042522', 'Mutation', 'rs1042522', (146, 155))	('VEGF', 'Gene', (345, 349))	('rs3025039', 'Mutation', 'rs3025039', (196, 205))	('rs1800629', 'Mutation', 'rs1800629', (130, 139))	('VEGF', 'Gene', '7422', (191, 195))	('rs2010963', 'Mutation', 'rs2010963', (350, 359))	('rs699947', 'Mutation', 'rs699947', (178, 186))	('VEGF', 'Gene', (191, 195))	('rs231775', 'Var', (26, 34))	('TNF-a', 'Gene', (124, 129))	('rs820196', 'Mutation', 'rs820196', (114, 122))	('rs4073', 'Mutation', 'rs4073', (317, 323))	('rs861539', 'Mutation', 'rs861539', (163, 171))	('protein kinase CGMP-dependent', 'Enzyme', (36, 65))	('interleukin 8', 'Gene', '3576', (297, 310))	('RECQL5', 'Gene', '9400', (107, 113))	('RecQ like helicase 5', 'Gene', (85, 105))	('VEGF', 'Gene', '7422', (173, 177))	('MDM2', 'Var', (325, 329))
269469	32629971	The significance of mutations and genetic abnormalities of the TP53 gene for bone and soft tissue sarcoma pathogenesis and progression has been supported by several studies, which have proven the high frequency and variability of TP53 mutations in HGOS.	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', (230, 234))	('mutations', 'Var', (235, 244))	('genetic abnormalities', 'Disease', 'MESH:D030342', (34, 55))	('genetic abnormalities', 'Disease', (34, 55))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (86, 105))	('sarcoma', 'Disease', (98, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
269471	32629971	This fact has strengthened the interest for TP53 and its pathway as possible therapeutic targets, especially for tumors that, like HGOS, frequently present alterations of this gene.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('alterations', 'Var', (156, 167))	('HGOS', 'Disease', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
269472	32629971	MDM4 amplification has been revealed in 35% HGOS and it has been associated to poor prognosis in HGOS, soft tissue sarcomas, and other cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (103, 123))	('MDM4', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('cancers', 'Disease', (135, 142))	('HGOS', 'Disease', (97, 101))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('HGOS', 'Disease', (44, 48))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (103, 122))	('sarcomas', 'Disease', (115, 123))
269475	32629971	Although TP53 and MDM2 SNPs have been extensively reported as risk factors for HGOS, much fewer information is available about their impact on clinical outcomes of HGOS patients.	('HGOS', 'Disease', (79, 83))	('MDM2 SNPs', 'Var', (18, 27))	('patients', 'Species', '9606', (169, 177))	('TP53', 'Var', (9, 13))
269477	32629971	The TP53 rs1042522 Arg72Pro polymorphism (Pro/Pro versus wild-type Arg/Arg genotype) was reported to be associated with increased risk of relapse and to have an adverse prognostic value for event-free and overall survival in HGOS patients.	('rs1042522', 'Mutation', 'rs1042522', (9, 18))	('TP53', 'Gene', (4, 8))	('Arg72Pro', 'Var', (19, 27))	('Arg', 'Chemical', 'MESH:D001120', (67, 70))	('associated', 'Reg', (104, 114))	('HGOS', 'Disease', (225, 229))	('patients', 'Species', '9606', (230, 238))	('Arg', 'Chemical', 'MESH:D001120', (71, 74))	('Arg', 'Chemical', 'MESH:D001120', (19, 22))	('Arg72Pro', 'SUBSTITUTION', 'None', (19, 27))	('Pro', 'Chemical', 'MESH:D011392', (42, 45))	('relapse', 'CPA', (138, 145))	('Pro', 'Chemical', 'MESH:D011392', (24, 27))	('Pro', 'Chemical', 'MESH:D011392', (46, 49))
269478	32629971	In a series of 210 HGOS Chinese patients, the GG genotype of the TP53 rs1042522 polymorphism was found to be associated with a shorter survival time compared with patients carrying the CC genotype.	('shorter', 'NegReg', (127, 134))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (32, 40))	('TP53', 'Gene', (65, 69))	('rs1042522', 'Var', (70, 79))	('survival time', 'CPA', (135, 148))	('rs1042522', 'Mutation', 'rs1042522', (70, 79))
269479	32629971	The variant status of TP53_IVS2+38G/C rs1642785 polymorphism was reported to be associated with better event-free survival in a group of 126 HGOS.	('rs1642785', 'DBSNP_MENTION', 'None', (38, 47))	('event-free survival', 'CPA', (103, 122))	('better', 'PosReg', (96, 102))	('rs1642785', 'Var', (38, 47))
269480	32629971	Concerning MDM2, a meta-analysis indicated that polymorphisms affecting this gene are related to HGOS risk, but do not seem to have effects on patients' survival, even if further studies are needed to confirm the last assumption.	('HGOS', 'Disease', (97, 101))	('patients', 'Species', '9606', (143, 151))	('polymorphisms', 'Var', (48, 61))	('related', 'Reg', (86, 93))	('MDM2', 'Gene', (11, 15))
269481	32629971	Consequently, it is not surprising that polymorphisms of genes belonging to DNA repair pathways have proved to be associated with drug response, survival and toxicity in different tumors.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('polymorphisms', 'Var', (40, 53))	('drug response', 'CPA', (130, 143))	('toxicity', 'Disease', 'MESH:D064420', (158, 166))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('toxicity', 'Disease', (158, 166))	('tumors', 'Disease', (180, 186))	('associated', 'Reg', (114, 124))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('survival', 'CPA', (145, 153))
269482	32629971	The CC genotype of the ERCC1 rs11615 polymorphism was found to be associated with good response to cisplatin-based chemotherapy and better overall survival when compared to TT genotype.	('rs11615', 'Mutation', 'rs11615', (29, 36))	('overall', 'MPA', (139, 146))	('ERCC1', 'Gene', (23, 28))	('better', 'PosReg', (132, 138))	('rs11615', 'Var', (29, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))
269483	32629971	Patients carrying the C allele of the ERCC1 rs3212986 polymorphism were described to have better event-free survival.	('rs3212986', 'Mutation', 'rs3212986', (44, 53))	('ERCC1', 'Gene', (38, 43))	('rs3212986', 'Var', (44, 53))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (90, 96))	('event-free survival', 'CPA', (97, 116))
269484	32629971	Association with poor response to chemotherapy was reported for the AC/CC genotype of the ERCC1 rs2298881 polymorphism, but another study provided partially opposite findings indicating that the AC/AA genotype associated with poor chemotherapy responsiveness.	('ERCC1', 'Gene', (90, 95))	('rs2298881 polymorphism', 'Var', (96, 118))	('polymorphism', 'Var', (106, 118))	('rs2298881', 'Mutation', 'rs2298881', (96, 105))
269485	32629971	Concerning the ERCC2 rs13181 polymorphism, the TT genotype was found to be associated with better treatment response and event-free survival compared to GT/GG genotype, but there were also studies reporting the correlation with a better event-free survival for the GG compared to TT genotype or for the GG compared to AA genotype.	('rs13181', 'Mutation', 'rs13181', (21, 28))	('ERCC2', 'Gene', (15, 20))	('rs13181', 'Var', (21, 28))	('better', 'PosReg', (230, 236))
269486	32629971	An association with better event-free survival was reported for the GA/AA genotypes of ERCC2 rs1799793 polymorphism compared to GG genotype and for patients with at least one polymorphic allele (GA/AA).	('GA/AA', 'Disease', (68, 73))	('patients', 'Species', '9606', (148, 156))	('better', 'PosReg', (20, 26))	('ERCC2', 'Gene', (87, 92))	('polymorphism', 'Var', (103, 115))	('rs1799793 polymorphism', 'Var', (93, 115))	('event-free survival', 'CPA', (27, 46))	('rs1799793', 'Mutation', 'rs1799793', (93, 102))
269487	32629971	Better response to cisplatin-based chemotherapy and overall survival was described for the TT genotype of the ERCC5 rs2296147 and rs1047768 polymorphisms.	('ERCC5', 'Gene', (110, 115))	('rs2296147', 'Mutation', 'rs2296147', (116, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('rs1047768', 'Var', (130, 139))	('rs1047768', 'Mutation', 'rs1047768', (130, 139))	('rs2296147', 'Var', (116, 125))
269488	32629971	The TT genotype and T allele of the nucleotide excision repair homolog (MMS19) rs29001322 polymorphism resulted to be associated with better response to cisplatin-based chemotherapy and increased overall survival.	('better', 'PosReg', (134, 140))	('response', 'MPA', (141, 149))	('rs29001322 polymorphism', 'Var', (79, 102))	('MMS19', 'Gene', (72, 77))	('increased', 'PosReg', (186, 195))	('rs29001322', 'Mutation', 'rs29001322', (79, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('polymorphism', 'Var', (90, 102))	('overall survival', 'CPA', (196, 212))
269489	32629971	An association with worse outcome was found for patients carrying the C allele of the MSH2 rs4638843 polymorphism.	('rs4638843', 'Var', (91, 100))	('MSH2', 'Gene', (86, 90))	('MSH2', 'Gene', '4436', (86, 90))	('patients', 'Species', '9606', (48, 56))	('rs4638843', 'Mutation', 'rs4638843', (91, 100))
269490	32629971	The nibrin (NBN) rs1805794+rs709816+rs1063054 CGA haplotype was found to be associated with shorter event-free survival compared with CAA haplotype.	('rs1063054', 'Mutation', 'rs1063054', (36, 45))	('rs709816', 'Mutation', 'rs709816', (27, 35))	('rs1805794+rs709816+rs1063054', 'Var', (17, 45))	('NBN', 'Gene', '4683', (12, 15))	('NBN', 'Gene', (12, 15))	('nibrin', 'Gene', '4683', (4, 10))	('nibrin', 'Gene', (4, 10))	('rs1805794', 'Mutation', 'rs1805794', (17, 26))	('shorter', 'NegReg', (92, 99))	('event-free', 'MPA', (100, 110))
269491	32629971	Patients carrying the AC/CC genotypes of xeroderma pigmentosum complementation group C (XPC) rs2228001 polymorphism showed higher response rates to pre-operative chemotherapy.	('rs2228001 polymorphism', 'Var', (93, 115))	('polymorphism', 'Var', (103, 115))	('higher', 'PosReg', (123, 129))	('XPC', 'Gene', (88, 91))	('rs2228001', 'Mutation', 'rs2228001', (93, 102))	('xeroderma pigmentosum complementation group C', 'Gene', '7508', (41, 86))	('response', 'MPA', (130, 138))	('Patients', 'Species', '9606', (0, 8))	('XPC', 'Gene', '7508', (88, 91))	('xeroderma pigmentosum complementation group C', 'Gene', (41, 86))
269493	32629971	Two of these studies confirmed that HGOS patients carrying the C allele of ERCC1 rs11615 polymorphism showed better response to chemotherapy in both Caucasian and Chinese populations.	('patients', 'Species', '9606', (41, 49))	('rs11615', 'Mutation', 'rs11615', (81, 88))	('response to chemotherapy', 'CPA', (116, 140))	('C allele', 'Var', (63, 71))	('rs11615 polymorphism', 'Var', (81, 101))	('ERCC1', 'Gene', (75, 80))	('better', 'PosReg', (109, 115))
269495	32629971	The third meta-analysis indicated that the AA genotype of ERCC2 rs13181 polymorphism was associated with a better survival rate compared to the GG genotype in both Chinese and Caucasian HGOS patients.	('rs13181', 'Mutation', 'rs13181', (64, 71))	('ERCC2', 'Gene', (58, 63))	('patients', 'Species', '9606', (191, 199))	('better', 'PosReg', (107, 113))	('polymorphism', 'Var', (72, 84))	('rs13181 polymorphism', 'Var', (64, 84))	('survival rate', 'CPA', (114, 127))
269497	32629971	It is therefore easily understandable that DMEs can significantly influence the tumor responsiveness to chemotherapy, as well as the susceptibility of normal tissues to treatment-related toxicities.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('toxicities', 'Disease', (187, 197))	('tumor', 'Disease', (80, 85))	('influence', 'Reg', (66, 75))	('toxicities', 'Disease', 'MESH:D064420', (187, 197))	('DMEs', 'Var', (43, 47))
269499	32629971	For example, gene variations resulting in a DME function impairment can decrease the therapeutic activity of pharmacologically inactive prodrugs, which require bioactivation to become effective, but also be associated with a lower induction of toxicity in normal cells.	('toxicity', 'Disease', 'MESH:D064420', (244, 252))	('toxicity', 'Disease', (244, 252))	('gene variations', 'Var', (13, 28))	('impairment', 'NegReg', (57, 67))	('decrease', 'NegReg', (72, 80))
269500	32629971	On the other hand, regarding DMEs involved in drug detoxification, gene alterations associated with an impaired enzyme activity can determine an increased therapeutic effectiveness, but also a higher risk for collateral toxicity.	('gene alterations', 'Var', (67, 83))	('toxicity', 'Disease', 'MESH:D064420', (220, 228))	('toxicity', 'Disease', (220, 228))	('increased', 'PosReg', (145, 154))	('therapeutic effectiveness', 'MPA', (155, 180))
269502	32629971	Different polymorphisms of the GSTP1 gene have been reported to be associated with a variable enzyme ability to metabolize anticancer agents and, for some of them, evidence of a possible clinical impact in HGOS has been reported, even if findings were sometimes contradictory or, at least, not completely concordant.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HGOS', 'Disease', (206, 210))	('polymorphisms', 'Var', (10, 23))	('impact', 'Reg', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('GSTP1', 'Gene', (31, 36))	('cancer', 'Disease', (127, 133))
269503	32629971	This is the case for studies that analyzed the GSTP1 rs1695 polymorphism, which have provided discordant indications.	('rs1695', 'Var', (53, 59))	('rs1695', 'Mutation', 'rs1695', (53, 59))	('GSTP1', 'Gene', (47, 52))
269504	32629971	The GSTP1 rs1695 AG + GG genotypes have mostly been reported to be associated with poor histological response and worse survival in HGOS patients treated with neo-adjuvant chemotherapy, but a large Chinese study showed that the GG genotype was related to good response to chemotherapy.	('GSTP1', 'Gene', (4, 9))	('rs1695', 'Mutation', 'rs1695', (10, 16))	('rs1695 AG', 'Var', (10, 19))	('patients', 'Species', '9606', (137, 145))
269505	32629971	The GSTM1 null allele was reported to be associated with an increased relapse rate in non-metastatic patients, and with poor survival in metastatic patients.	('null', 'Var', (10, 14))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (148, 156))	('relapse rate', 'CPA', (70, 82))	('GSTM1', 'Gene', (4, 9))
269506	32629971	The non-null allele of GSTT1 was correlated with poor survival in metastatic patients.	('patients', 'Species', '9606', (77, 85))	('GSTT1', 'Gene', (23, 28))	('non-null', 'Var', (4, 12))	('poor', 'NegReg', (49, 53))
269508	32629971	The GSTM3*B allele of rs1799735 was reported to be associated with the presence of metastases at diagnosis, whereas the GSTM3*A allele rs1799735 emerged to be correlated with worse survival in patients presenting metastasis at clinical onset.	('patients', 'Species', '9606', (193, 201))	('rs1799735', 'Var', (22, 31))	('metastases', 'Disease', (83, 93))	('rs1799735', 'Mutation', 'rs1799735', (135, 144))	('metastases', 'Disease', 'MESH:D009362', (83, 93))	('GSTM3', 'Gene', (120, 125))	('associated', 'Reg', (51, 61))	('GSTM3', 'Gene', (4, 9))	('GSTM3', 'Gene', '2947', (120, 125))	('rs1799735', 'Mutation', 'rs1799735', (22, 31))	('GSTM3', 'Gene', '2947', (4, 9))	('rs1799735', 'Var', (135, 144))
269510	32629971	In a study performed on tumor tissue from 66 HGOS patients, the GSTP1 rs1138272 variant genotype proved to be associated with both shorter event-free and overall survival, whereas no association with survival was revealed for deletions of either GSTM1 or GSTT1.	('overall survival', 'CPA', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('GSTP1', 'Gene', (64, 69))	('patients', 'Species', '9606', (50, 58))	('rs1138272', 'Mutation', 'rs1138272', (70, 79))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('GSTM1', 'Gene', (246, 251))	('shorter', 'NegReg', (131, 138))	('GSTT1', 'Gene', (255, 260))	('event-free', 'CPA', (139, 149))	('rs1138272', 'Var', (70, 79))
269511	32629971	Meta-analyses about GST polymorphisms in HGOS provided apparently contradictory results.	('HGOS', 'Gene', (41, 45))	('GST', 'Gene', (20, 23))	('GST', 'Gene', '373156', (20, 23))	('polymorphisms', 'Var', (24, 37))
269512	32629971	One of these studies revealed significant associations between the AA genotype of GSTP1 rs1695 polymorphism and good tumor response, progression-free and overall survival.	('overall survival', 'CPA', (154, 170))	('GSTP1', 'Gene', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('rs1695', 'Mutation', 'rs1695', (88, 94))	('progression-free', 'CPA', (133, 149))	('tumor', 'Disease', (117, 122))	('polymorphism', 'Var', (95, 107))	('rs1695 polymorphism', 'Var', (88, 107))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
269514	32629971	A third meta-analysis performed on 681 Chinese Han patients, did not find any association between GSTM1 and GSTT1 polymorphisms and chemosensitivity.	('GSTT1', 'Gene', (108, 113))	('GSTM1', 'Gene', (98, 103))	('patients', 'Species', '9606', (51, 59))	('polymorphisms', 'Var', (114, 127))
269517	32629971	Since these enzymes show a relevant genetic variability, CYPs polymorphic variants can lead to differences in treatment response and susceptibility to chemotherapy-associated toxicities.	('toxicities', 'Disease', 'MESH:D064420', (175, 185))	('CYP', 'Gene', (57, 60))	('polymorphic variants', 'Var', (62, 82))	('lead to differences', 'Reg', (87, 106))	('CYP', 'Gene', '4051', (57, 60))	('toxicities', 'Disease', (175, 185))	('treatment response', 'CPA', (110, 128))
269518	32629971	The reported evidence with the most relevant clinical impact in HGOS concerns the CYP3A4 rs4646437 polymorphism.	('CYP3A4', 'Gene', (82, 88))	('rs4646437', 'Mutation', 'rs4646437', (89, 98))	('CYP3A4', 'Gene', '1576', (82, 88))	('HGOS', 'Disease', (64, 68))	('rs4646437', 'Var', (89, 98))
269519	32629971	The variant allele of CYP3A4 rs4646437 was shown to be associated with better treatment response and survival in HGOS patients treated with standard neoadjuvant chemotherapy protocols, most probably due to the reduced CYP3A4-mediated drug inactivation.	('better', 'PosReg', (71, 77))	('CYP3A4', 'Gene', '1576', (218, 224))	('reduced', 'NegReg', (210, 217))	('CYP3A4', 'Gene', '1576', (22, 28))	('treatment response', 'CPA', (78, 96))	('rs4646437', 'Var', (29, 38))	('survival', 'CPA', (101, 109))	('CYP3A4', 'Gene', (218, 224))	('patients', 'Species', '9606', (118, 126))	('CYP3A4', 'Gene', (22, 28))	('rs4646437', 'Mutation', 'rs4646437', (29, 38))
269520	32629971	The variant genotype of the CYP2B6*6 (rs3745274 and rs2279343) polymorphism was found to be associated with a worse event-free survival, probably because of a decreased enzyme expression and a consequent decreased ifosfamide activation.	('rs3745274', 'Mutation', 'rs3745274', (38, 47))	('rs2279343', 'Var', (52, 61))	('ifosfamide', 'Chemical', 'MESH:D007069', (214, 224))	('worse', 'NegReg', (110, 115))	('decreased', 'NegReg', (159, 168))	('decreased', 'NegReg', (204, 213))	('ifosfamide activation', 'MPA', (214, 235))	('rs2279343', 'Mutation', 'rs2279343', (52, 61))	('CYP2B6', 'Gene', '1555', (28, 34))	('rs3745274', 'Var', (38, 47))	('CYP2B6', 'Gene', (28, 34))	('enzyme expression', 'MPA', (169, 186))
269521	32629971	The TT genotype of the ABCB1 rs1128503 polymorphism was related to good chemotherapy response and better survival in three studies, but some discrepant observations were reported in other two analyses; The CT/TT genotypes of the ABCC2 rs717620 polymorphism were shown to be associated with a poor response to pre-operative chemotherapy, whereas the AA/GA genotypes of the ABCC2 rs2273697 polymorphism correlated with worse event-free survival; The variant status of the ABCC2_1249A/G (rs2273697) polymorphism was reported to be associated with worse event-free survival; Association with poor response to first-line chemotherapy and worse survival was described for the TT genotype and T allele of the ABCC3 rs4148416 polymorphism; Worse survival was found to be associated with the G allele of the ABCC5 rs939338 polymorphism.	('rs4148416', 'Mutation', 'rs4148416', (708, 717))	('ABCC5', 'Gene', (799, 804))	('rs2273697', 'Mutation', 'rs2273697', (485, 494))	('rs4148416', 'Var', (708, 717))	('ABCC5', 'Gene', '10057', (799, 804))	('rs939338', 'Mutation', 'rs939338', (805, 813))	('rs1128503', 'Mutation', 'rs1128503', (29, 38))	('1249A/G', 'Mutation', 'rs2273697', (476, 483))	('rs939338', 'Var', (805, 813))	('rs717620', 'Mutation', 'rs717620', (235, 243))	('rs2273697', 'Mutation', 'rs2273697', (378, 387))
269524	32629971	Gene polymorphisms that have reported to be significantly associated with therapy response and /or survival in HGOS can be summarized as follows: A meta-analysis confirmed the association of ABCB1 rs1128503 (TT genotype) with good response and of ABCC3 rs418416 (T allele) with poor response to chemotherapy in Caucasian populations.	('ABCB1', 'Gene', (191, 196))	('ABCC3', 'Gene', (247, 252))	('rs1128503', 'Mutation', 'rs1128503', (197, 206))	('rs1128503', 'Var', (197, 206))	('rs418416', 'Mutation', 'rs418416', (253, 261))	('rs418416', 'Var', (253, 261))
269529	32629971	The GG genotype of the rs1053129 polymorphism of the dihydrofolate reductase (DHFR) gene, the main target of MTX, was reported to be associated with a higher probability to develop metastasis during follow-up.	('DHFR', 'Gene', (78, 82))	('MTX', 'Chemical', 'MESH:D008727', (109, 112))	('DHFR', 'Gene', '1719', (78, 82))	('develop', 'PosReg', (173, 180))	('rs1053129', 'Mutation', 'rs1053129', (23, 32))	('rs1053129', 'Var', (23, 32))
269530	32629971	The rs1051266 polymorphism of the solute carrier family 19 folate transporter member 1 (SLC19A1) gene (also known as reduced folate carrier, RFC or reduced folate carrier 1, RFC1), a MTX membrane transporter, was reported to be associated with clinical outcome, showing that patients bearing the allele G had better survival and lower predisposition to develop metastases.	('reduced folate carrier', 'Phenotype', 'HP:0100507', (148, 170))	('folate', 'Chemical', 'MESH:D005492', (156, 162))	('patients', 'Species', '9606', (275, 283))	('SLC19A1', 'Gene', (88, 95))	('RFC1', 'Gene', '5981', (174, 178))	('folate', 'Chemical', 'MESH:D005492', (59, 65))	('rs1051266', 'Var', (4, 13))	('SLC19A1', 'Gene', '6573', (88, 95))	('solute carrier family 19 folate transporter member 1', 'Gene', '6573', (34, 86))	('associated', 'Reg', (228, 238))	('survival', 'CPA', (316, 324))	('RFC1', 'Gene', (174, 178))	('rs1051266', 'Mutation', 'rs1051266', (4, 13))	('reduced folate carrier', 'Phenotype', 'HP:0100507', (117, 139))	('MTX', 'Chemical', 'MESH:D008727', (183, 186))	('metastases', 'Disease', 'MESH:D009362', (361, 371))	('better', 'PosReg', (309, 315))	('folate', 'Chemical', 'MESH:D005492', (125, 131))	('metastases', 'Disease', (361, 371))
269531	32629971	The AG/AA genotype of the rs2236225 polymorphism of the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 (MTHFD1) gene, a folate cycle enzyme which is involved in de novo purine synthesis, was found to be associated with good histological response after preoperative chemotherapy.	('folate', 'Chemical', 'MESH:D005492', (133, 139))	('MTHFD1', 'Gene', '4522', (117, 123))	('rs2236225', 'Var', (26, 35))	('rs2236225', 'Mutation', 'rs2236225', (26, 35))	('MTHFD1', 'Gene', (117, 123))	('purine', 'Chemical', 'MESH:C030985', (182, 188))	('folate', 'Chemical', 'MESH:D005492', (75, 81))
269532	32629971	The TT genotype of the rs11545078 polymorphism of the gamma-glutamyl hydrolase (GGH) gene, an enzyme which catalyzes the hydrolysis of folylpoly-gamma-glutamates and anti-folylpoly-gamma-glutamates influencing the overall effectiveness of MTX, was found to be associated with poor survival.	('GGH', 'Gene', (80, 83))	('polymorphism', 'Var', (34, 46))	('folylpoly-gamma-glutamates', 'Chemical', 'MESH:C000591491', (135, 161))	('poor', 'NegReg', (276, 280))	('folylpoly-gamma-glutamates', 'Chemical', 'MESH:C000591491', (171, 197))	('MTX', 'Chemical', 'MESH:D008727', (239, 242))	('rs11545078', 'Mutation', 'rs11545078', (23, 33))	('gamma-glutamyl hydrolase', 'Gene', '8836', (54, 78))	('GGH', 'Gene', '8836', (80, 83))	('gamma-glutamyl hydrolase', 'Gene', (54, 78))	('associated', 'Reg', (260, 270))	('rs11545078 polymorphism', 'Var', (23, 46))
269534	32629971	Patients with at least one polymorphic allele of SLCO1B1 rs4149056 and rs11045879 polymorphisms exhibited longer event-free survival compared to patients with two wild-type alleles.	('event-free survival', 'CPA', (113, 132))	('SLCO1B1', 'Gene', (49, 56))	('patients', 'Species', '9606', (145, 153))	('longer', 'PosReg', (106, 112))	('rs11045879', 'Mutation', 'rs11045879', (71, 81))	('rs4149056', 'Mutation', 'rs4149056', (57, 66))	('Patients', 'Species', '9606', (0, 8))	('SLCO1B1', 'Gene', '10599', (49, 56))	('rs4149056', 'Var', (57, 66))	('rs11045879', 'Var', (71, 81))
269537	32629971	Mainly candidate gene and pathway driven approaches have revealed some recurrent associations between gene variations and collateral toxicities in HGOS patients.	('toxicities', 'Disease', 'MESH:D064420', (133, 143))	('variations', 'Var', (107, 117))	('toxicities', 'Disease', (133, 143))	('patients', 'Species', '9606', (152, 160))	('HGOS', 'Disease', (147, 151))
269539	32629971	Since the possible functional role of most of these genetic variants is not yet clear and can be different in normal and tumor cells, further functional studies are needed to elucidate their biological consequences in association with cell death, drug detoxification and transport in both normal and tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (300, 305))	('tumor', 'Disease', (121, 126))	('variants', 'Var', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
269542	32629971	The 5,10-methylene tetrahydrofolate reductase (MTHFR) rs1801133 polymorphism leads to a C to T substitution at nucleotide position 677, with the result of a substitution of valine for alanine in the functional enzyme and a decreased enzymatic activity.	('rs1801133', 'Gene', (54, 63))	('decreased', 'NegReg', (223, 232))	('valine', 'Chemical', 'MESH:D014633', (173, 179))	('rs1801133', 'Mutation', 'rs1801133', (54, 63))	('substitution', 'Var', (95, 107))	('substitution', 'Var', (157, 169))	('MTHFR) rs1801133', 'Gene', (47, 63))	('C to T substitution at nucleotide position 677', 'Mutation', 'rs1801133', (88, 134))	('alanine', 'Chemical', 'MESH:D000409', (184, 191))	('5,10-methylene tetrahydrofolate reductase', 'Gene', '4524', (4, 45))	('valine', 'Protein', (173, 179))	('enzymatic activity', 'MPA', (233, 251))	('leads to', 'Reg', (77, 85))
269544	32629971	In a recent study, the variant T allele of this polymorphism was reported to correlate with higher degrees of hematologic toxicities in 59 Han Chinese patients with HGOS.	('hematologic toxicities', 'Disease', (110, 132))	('variant', 'Var', (23, 30))	('patients', 'Species', '9606', (151, 159))	('hematologic toxicities', 'Disease', 'MESH:D006402', (110, 132))
269545	32629971	A second polymorphism of the MTHFR gene, rs1801131, leads to an A to C substitution at nucleotide 1289 and also to reduced enzyme activity.	('MTHFR', 'Gene', (29, 34))	('reduced', 'NegReg', (115, 122))	('substitution', 'Var', (71, 83))	('rs1801131', 'Mutation', 'rs1801131', (41, 50))	('enzyme activity', 'MPA', (123, 138))	('A to C', 'MPA', (64, 70))	('rs1801131', 'Var', (41, 50))	('A to C substitution at nucleotide 1289', 'Mutation', 'c.1289A>C', (64, 102))
269547	32629971	AG/GG genotypes of a third gene polymorphism belonging to the folate pathway, the MTHFD1 rs2236225, were reported to be associated with anemia.	('associated', 'Reg', (120, 130))	('rs2236225', 'Var', (89, 98))	('MTHFD1', 'Gene', (82, 88))	('rs2236225', 'Mutation', 'rs2236225', (89, 98))	('anemia', 'Disease', (136, 142))	('folate', 'Chemical', 'MESH:D005492', (62, 68))	('anemia', 'Disease', 'MESH:D000740', (136, 142))	('MTHFD1', 'Gene', '4522', (82, 88))	('anemia', 'Phenotype', 'HP:0001903', (136, 142))
269548	32629971	Among the ABC transporter gene family, three polymorphisms of the ABCC2 gene, rs717620 (GG), rs17222723 (AT/TT) and rs 2273697 (AA + GA) have been reported to be associated with hematological toxicities.	('ABC', 'Gene', (10, 13))	('ABC', 'Gene', (66, 69))	('hematological toxicities', 'Disease', 'MESH:D006402', (178, 202))	('ABC', 'Gene', '10058', (10, 13))	('ABC', 'Gene', '10058', (66, 69))	('AT', 'Disease', 'None', (105, 107))	('associated', 'Reg', (162, 172))	('rs 2273697', 'Var', (116, 126))	('rs17222723', 'Mutation', 'rs17222723', (93, 103))	('hematological toxicities', 'Disease', (178, 202))	('rs717620', 'Mutation', 'rs717620', (78, 86))	('rs 2273697', 'Mutation', 'rs 2273697', (116, 126))
269549	32629971	The AC/AA genotypes of ERCC1 rs3212986 and the AG/GG genotypes of GSTP1 rs1695 were reported to be associated with leukopenia in one study.	('rs3212986', 'Var', (29, 38))	('leukopenia', 'Disease', (115, 125))	('leukopenia', 'Disease', 'MESH:D007970', (115, 125))	('GSTP1', 'Gene', (66, 71))	('rs1695', 'Var', (72, 78))	('ERCC1', 'Gene', (23, 28))	('rs3212986', 'Mutation', 'rs3212986', (29, 38))	('rs1695', 'Mutation', 'rs1695', (72, 78))	('leukopenia', 'Phenotype', 'HP:0001882', (115, 125))	('associated', 'Reg', (99, 109))
269550	32629971	Another polymorphism of the NER pathway, the AA/AG genotype of ERCC2 rs1799793, was reported in association with thrombocytopenia.	('NER pathway', 'Pathway', (28, 39))	('ERCC2', 'Gene', (63, 68))	('thrombocytopenia', 'Disease', 'MESH:D013921', (113, 129))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (113, 129))	('rs1799793', 'Mutation', 'rs1799793', (69, 78))	('rs1799793', 'Var', (69, 78))	('association', 'Reg', (96, 107))	('thrombocytopenia', 'Disease', (113, 129))
269551	32629971	The MTHFR rs1801133 polymorphism has been reported by different groups to be associated with liver toxicity.	('polymorphism', 'Var', (20, 32))	('rs1801133 polymorphism', 'Var', (10, 32))	('liver toxicity', 'Disease', (93, 107))	('MTHFR', 'Gene', (4, 9))	('liver toxicity', 'Disease', 'MESH:D056486', (93, 107))	('rs1801133', 'Mutation', 'rs1801133', (10, 19))	('associated', 'Reg', (77, 87))
269552	32629971	One study carried out in patients after high-dose MTX-therapy found a significant association between the T allele and liver toxicity in 49 patients with HGOS.	('MTX', 'Chemical', 'MESH:D008727', (50, 53))	('T allele', 'Var', (106, 114))	('patients', 'Species', '9606', (25, 33))	('liver toxicity', 'Disease', 'MESH:D056486', (119, 133))	('patients', 'Species', '9606', (140, 148))	('liver toxicity', 'Disease', (119, 133))
269553	32629971	This association, however, was not confirmed in the subsequent meta-analysis, including seven studies with a total of 1044 patients (148 with HGOS), whereas a recent study on 59 Han Chinese patients with HGOS found the variant T allele of MTHFR rs1801133 being associated with higher degrees of liver toxicity.	('MTHFR', 'Gene', (239, 244))	('rs1801133', 'Var', (245, 254))	('rs1801133', 'Mutation', 'rs1801133', (245, 254))	('patients', 'Species', '9606', (190, 198))	('associated with', 'Reg', (261, 276))	('patients', 'Species', '9606', (123, 131))	('variant', 'Var', (219, 226))	('liver toxicity', 'Disease', 'MESH:D056486', (295, 309))	('liver toxicity', 'Disease', (295, 309))
269555	32629971	The CC genotype of MTHFR rs1801133 was associated with a higher degree of liver toxicity.	('rs1801133', 'Mutation', 'rs1801133', (25, 34))	('MTHFR', 'Gene', (19, 24))	('liver toxicity', 'Disease', (74, 88))	('rs1801133', 'Var', (25, 34))	('liver toxicity', 'Disease', 'MESH:D056486', (74, 88))
269557	32629971	A very small descriptive study of 18 patients, including seven with HGOS who had developed severe clinical or liver toxicity measured by elevated alanine transaminase (ALT) levels revealed that rare alleles of MTHFR rs1801133 and thymidylate synthase (TS) rs34743033 were more frequent in HGOS patients compared to the normal population.	('TS', 'Gene', '7298', (252, 254))	('HGOS', 'Disease', (289, 293))	('rs34743033', 'Mutation', 'rs34743033', (256, 266))	('liver toxicity', 'Disease', 'MESH:D056486', (110, 124))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (294, 302))	('rs34743033', 'Var', (256, 266))	('liver toxicity', 'Disease', (110, 124))	('frequent', 'Reg', (277, 285))	('alanine', 'Chemical', 'MESH:D000409', (146, 153))	('rs1801133', 'Var', (216, 225))	('elevated alanine transaminase', 'Phenotype', 'HP:0031964', (137, 166))	('elevated alanine', 'Phenotype', 'HP:0003348', (137, 153))	('thymidylate synthase', 'Gene', (230, 250))	('rs1801133', 'Mutation', 'rs1801133', (216, 225))	('MTHFR', 'Gene', (210, 215))	('thymidylate synthase', 'Gene', '7298', (230, 250))
269559	32629971	Among the ABC transporter genes, two polymorphisms of the ABCC2 gene, rs717620 (GG) and rs2273697 (GG), and ABCB1 rs1128503 (TC + TT) have been reported to be associated with liver toxicity.	('rs2273697', 'Var', (88, 97))	('ABC', 'Gene', (10, 13))	('rs717620', 'Var', (70, 78))	('ABC', 'Gene', '10058', (58, 61))	('ABC', 'Gene', (108, 111))	('rs717620', 'Mutation', 'rs717620', (70, 78))	('ABC', 'Gene', '10058', (10, 13))	('rs1128503', 'Mutation', 'rs1128503', (114, 123))	('associated', 'Reg', (159, 169))	('rs1128503', 'Var', (114, 123))	('TC', 'Chemical', 'MESH:D013667', (125, 127))	('ABC', 'Gene', '10058', (108, 111))	('rs2273697', 'Mutation', 'rs2273697', (88, 97))	('liver toxicity', 'Disease', 'MESH:D056486', (175, 189))	('liver toxicity', 'Disease', (175, 189))	('ABC', 'Gene', (58, 61))
269561	32629971	Mueller and co-workers described one patient who was homozygous for the variant of MTHFR rs1801133 (TT) but wild-type for MTHFR rs1801131 (AA).	('patient', 'Species', '9606', (37, 44))	('rs1801133', 'Var', (89, 98))	('rs1801133', 'Mutation', 'rs1801133', (89, 98))	('MTHFR', 'Gene', (83, 88))	('rs1801131', 'Mutation', 'rs1801131', (128, 137))	('variant', 'Var', (72, 79))
269562	32629971	They concluded that the association between MTHFR rs1801133 TT and severe MTX-related toxicity could be explained by disturbances in the folate status and by prolonged MTX exposure due to delayed MTX clearance.	('folate', 'Chemical', 'MESH:D005492', (137, 143))	('folate status', 'MPA', (137, 150))	('rs1801133', 'Mutation', 'rs1801133', (50, 59))	('MTHFR', 'Gene', (44, 49))	('MTX', 'Chemical', 'MESH:D008727', (74, 77))	('MTX', 'Chemical', 'MESH:D008727', (168, 171))	('toxicity', 'Disease', 'MESH:D064420', (86, 94))	('MTX', 'Chemical', 'MESH:D008727', (196, 199))	('toxicity', 'Disease', (86, 94))	('rs1801133', 'Var', (50, 59))
269563	32629971	One study reported that patients with the variant genotypes GA/AA of SLC19A1 rs1051266 had significantly lower MTX plasma levels at 48 and 72 h, whereas the GG genotype was associated with higher plasma levels and nephrotoxicity.	('lower', 'NegReg', (105, 110))	('MTX', 'Chemical', 'MESH:D008727', (111, 114))	('SLC19A1', 'Gene', '6573', (69, 76))	('rs1051266', 'Var', (77, 86))	('nephrotoxicity', 'Disease', (214, 228))	('SLC19A1', 'Gene', (69, 76))	('nephrotoxicity', 'Disease', 'MESH:D007674', (214, 228))	('patients', 'Species', '9606', (24, 32))	('rs1051266', 'Mutation', 'rs1051266', (77, 86))	('plasma levels', 'MPA', (196, 209))
269564	32629971	Similar evidence was reported in 50 HGOS patients carrying the variant allele of MTHFR rs1801133 (CT/TT) and of ERCC2 rs13181 (AC/CC).	('rs1801133', 'Mutation', 'rs1801133', (87, 96))	('rs13181', 'Var', (118, 125))	('MTHFR', 'Gene', (81, 86))	('patients', 'Species', '9606', (41, 49))	('rs13181', 'Mutation', 'rs13181', (118, 125))	('ERCC2', 'Gene', (112, 117))	('rs1801133', 'Var', (87, 96))
269567	32629971	First, evidence was provided by a candidate gene study in 50 patients with HGOS that the GSTP1 rs1695 variant allele was associated with cardiotoxicity, but this result was not confirmed by others.	('rs1695', 'Var', (95, 101))	('cardiotoxicity', 'Disease', 'MESH:D066126', (137, 151))	('GSTP1', 'Gene', (89, 94))	('cardiotoxicity', 'Disease', (137, 151))	('associated', 'Reg', (121, 131))	('patients', 'Species', '9606', (61, 69))	('rs1695', 'Mutation', 'rs1695', (95, 101))
269570	32629971	The variant GG genotype of the CBR3 rs1056892, which influences the synthesis of these metabolites, was associated with cardiomyopathy in patients who received low-to-moderate-dose but not in patients who received high-dose anthracyclines.	('cardiomyopathy', 'Disease', (120, 134))	('rs1056892', 'Mutation', 'rs1056892', (36, 45))	('CBR3', 'Gene', '874', (31, 35))	('patients', 'Species', '9606', (192, 200))	('CBR3', 'Gene', (31, 35))	('associated with', 'Reg', (104, 119))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (120, 134))	('synthesis of these metabolites', 'MPA', (68, 98))	('cardiomyopathy', 'Disease', 'MESH:D009202', (120, 134))	('rs1056892', 'Var', (36, 45))	('anthracyclines', 'Chemical', 'MESH:D018943', (224, 238))	('patients', 'Species', '9606', (138, 146))
269572	32629971	They identified a strong association between the variant G allele of solute carrier family 28 member 3 (SLC28A3) rs7853758 and ACT which was confirmed in a subsequent study by the same authors.	('solute carrier family 28 member 3', 'Gene', (69, 102))	('SLC28A3', 'Gene', (104, 111))	('rs7853758', 'Var', (113, 122))	('rs7853758', 'Mutation', 'rs7853758', (113, 122))	('SLC28A3', 'Gene', '64078', (104, 111))	('ACT', 'Disease', (127, 130))	('solute carrier family 28 member 3', 'Gene', '64078', (69, 102))
269573	32629971	In addition, associations between ACT and a second variant of SLC28A3, rs885004, and the variant rs17863783 in UDP glucuronosyltransferase 1 A6 (UGT1A6) were confirmed in this replication study including 16 patients with HGOS of the total cohort of 202 pediatric cancer patients.	('UGT1A6', 'Gene', (145, 151))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('patients', 'Species', '9606', (270, 278))	('cancer', 'Disease', (263, 269))	('rs17863783', 'Var', (97, 107))	('UDP glucuronosyltransferase 1 A6', 'Gene', '54578', (111, 143))	('SLC28A3', 'Gene', (62, 69))	('UDP glucuronosyltransferase 1 A6', 'Gene', (111, 143))	('rs17863783', 'Mutation', 'rs17863783', (97, 107))	('SLC28A3', 'Gene', '64078', (62, 69))	('rs885004', 'Mutation', 'rs885004', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('rs885004', 'Var', (71, 79))	('associations', 'Interaction', (13, 25))	('UGT1A6', 'Gene', '54578', (145, 151))
269574	32629971	In another large study including pediatric patients with bone tumors, using a cardiovascular SNP array to profile common SNPs in 2100 genes considered relevant to de novo cardiovascular disease, the AA genotype of rs2232228 in the hyaluronan synthase 3 (HAS3) gene conferred an increased risk for cardiomyopathy compared to the AA genotype.	('bone tumor', 'Phenotype', 'HP:0010622', (57, 67))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (171, 193))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patients', 'Species', '9606', (43, 51))	('cardiovascular disease', 'Disease', 'MESH:D002318', (171, 193))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (297, 311))	('bone tumors', 'Phenotype', 'HP:0010622', (57, 68))	('hyaluronan synthase 3', 'Gene', '3038', (231, 252))	('cardiomyopathy', 'Disease', 'MESH:D009202', (297, 311))	('bone tumors', 'Disease', (57, 68))	('rs2232228', 'Var', (214, 223))	('HAS3', 'Gene', (254, 258))	('hyaluronan synthase 3', 'Gene', (231, 252))	('rs2232228', 'Mutation', 'rs2232228', (214, 223))	('cardiovascular disease', 'Disease', (171, 193))	('bone tumors', 'Disease', 'MESH:D001859', (57, 68))	('cardiomyopathy', 'Disease', (297, 311))
269576	32629971	In order to identify new variants and to improve their previously reported genotype-guided risk prediction model, Visscher and co-workers genotyped two cohorts of pediatric cancer patients for 4578 SNPs in absorption, distribution, metabolism, excretion (ADME) and toxicity genes.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('variants', 'Var', (25, 33))	('SNPs', 'Var', (198, 202))	('cancer', 'Disease', (173, 179))	('toxicity', 'Disease', 'MESH:D064420', (265, 273))	('toxicity', 'Disease', (265, 273))	('metabolism', 'MPA', (232, 242))	('excretion', 'MPA', (244, 253))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('distribution', 'MPA', (218, 230))	('patients', 'Species', '9606', (180, 188))
269577	32629971	Two novel SNPs, rs4982753 in solute carrier family 22 member 17 (SLC22A17) and rs4149178 in solute carrier family 22 member 7 (SLC22A7), were identified to be significantly associated with ACT.	('rs4149178', 'Var', (79, 88))	('solute carrier family 22 member 17', 'Gene', '51310', (29, 63))	('ACT', 'Disease', (189, 192))	('SLC22A7', 'Gene', (127, 134))	('SLC22A17', 'Gene', '51310', (65, 73))	('SLC22A17', 'Gene', (65, 73))	('rs4982753', 'Var', (16, 25))	('rs4149178', 'Mutation', 'rs4149178', (79, 88))	('rs4982753', 'Mutation', 'rs4982753', (16, 25))	('solute carrier family 22 member 17', 'Gene', (29, 63))	('solute carrier family 22 member 7', 'Gene', '10864', (92, 125))	('associated', 'Reg', (173, 183))	('solute carrier family 22 member 7', 'Gene', (92, 125))	('SLC22A7', 'Gene', '10864', (127, 134))
269578	32629971	The same group performed a GWAS study in which they identified the new non-synonymous variant rs2229774 in the retinoic acid receptor gamma (RARG) gene to be associated with ACT in childhood cancer.	('RARG', 'Gene', '5916', (141, 145))	('retinoic acid receptor gamma', 'Gene', '5916', (111, 139))	('cancer', 'Disease', (191, 197))	('rs2229774', 'Mutation', 'rs2229774', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('associated', 'Reg', (158, 168))	('retinoic acid receptor gamma', 'Gene', (111, 139))	('RARG', 'Gene', (141, 145))	('rs2229774', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ACT', 'Disease', (174, 177))
269580	32629971	They state that RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT.	('SLC28A3', 'Gene', '64078', (32, 39))	('association', 'Interaction', (147, 158))	('RARG', 'Gene', '5916', (16, 20))	('UGT1A6', 'Gene', '54578', (54, 60))	('rs7853758', 'Var', (40, 49))	('rs2229774', 'Var', (21, 30))	('UGT1A6', 'Gene', (54, 60))	('rs17863783', 'Mutation', 'rs17863783', (61, 71))	('rs17863783', 'Var', (61, 71))	('rs7853758', 'Mutation', 'rs7853758', (40, 49))	('rs2229774', 'Mutation', 'rs2229774', (21, 30))	('SLC28A3', 'Gene', (32, 39))	('ACT', 'Disease', (164, 167))	('RARG', 'Gene', (16, 20))
269581	32629971	A recent study carried out on 167 anthracycline-exposed childhood cancer survivors (75 cases and 92 matched controls with different diagnosis including 40 with bone tumors) reported that patients who had the GSTM1 null genotype had a significantly higher risk to develop cardiomyopathy.	('cardiomyopathy', 'Disease', 'MESH:D009202', (271, 285))	('patients', 'Species', '9606', (187, 195))	('bone tumor', 'Phenotype', 'HP:0010622', (160, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('GSTM1', 'Gene', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cardiomyopathy', 'Disease', (271, 285))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (271, 285))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('bone tumors', 'Disease', (160, 171))	('null', 'Var', (214, 218))	('bone tumors', 'Phenotype', 'HP:0010622', (160, 171))	('develop', 'PosReg', (263, 270))	('anthracycline', 'Chemical', 'MESH:D018943', (34, 47))	('bone tumors', 'Disease', 'MESH:D001859', (160, 171))	('cancer', 'Disease', (66, 72))
269586	32629971	Since many of them reported protective effect of gene variants which were not verified in replicate studies, Figure 2 shows only those polymorphisms that were found to be significantly associated with ototoxicity.	('associated', 'Reg', (185, 195))	('ototoxicity', 'Disease', 'MESH:D006311', (201, 212))	('variants', 'Var', (54, 62))	('polymorphisms', 'Var', (135, 148))	('ototoxicity', 'Disease', (201, 212))
269587	32629971	In a subgroup of 32 HGOS patients, the CC genotype of XPC rs2228001 was associated with ototoxicity.	('ototoxicity', 'Disease', (88, 99))	('rs2228001', 'Mutation', 'rs2228001', (58, 67))	('associated with', 'Reg', (72, 87))	('rs2228001', 'Var', (58, 67))	('XPC', 'Gene', (54, 57))	('patients', 'Species', '9606', (25, 33))	('XPC', 'Gene', '7508', (54, 57))	('ototoxicity', 'Disease', 'MESH:D006311', (88, 99))
269588	32629971	The variant allele A of the LDL receptor related protein 2 (LRP2) rs2075252 was reported in association with ototoxicity in a series of 38 patients with HGOS, but no evidence of this association was found in the study by Ross and co-workers.	('LRP2', 'Gene', (60, 64))	('ototoxicity', 'Disease', (109, 120))	('LDL receptor related protein 2', 'Gene', '4036', (28, 58))	('ototoxicity', 'Disease', 'MESH:D006311', (109, 120))	('patients', 'Species', '9606', (139, 147))	('rs2075252', 'Var', (66, 75))	('LRP2', 'Gene', '4036', (60, 64))	('association', 'Reg', (92, 103))	('HGOS', 'Disease', (153, 157))	('LDL receptor related protein 2', 'Gene', (28, 58))	('rs2075252', 'Mutation', 'rs2075252', (66, 75))
269589	32629971	Another candidate-gene study reported that the variant T allele of the solute carrier family 22 member 2 (SLC22A2) rs316019 was associated with hearing loss in 41 patients with HGOS.	('hearing loss', 'Disease', 'MESH:D034381', (144, 156))	('solute carrier family 22 member 2', 'Gene', '6582', (71, 104))	('patients', 'Species', '9606', (163, 171))	('SLC22A2', 'Gene', '6582', (106, 113))	('SLC22A2', 'Gene', (106, 113))	('rs316019', 'Mutation', 'rs316019', (115, 123))	('hearing loss', 'Phenotype', 'HP:0000365', (144, 156))	('rs316019', 'Var', (115, 123))	('associated with', 'Reg', (128, 143))	('hearing loss', 'Disease', (144, 156))	('solute carrier family 22 member 2', 'Gene', (71, 104))
269590	32629971	Variants of thiopurine S-methyltransferase TPMT (rs12201199, rs180046 and rs1142345) and catechol O-methyltransferase (COMT) (rs4646316 and rs9332377) were reported to be associated with ototoxicity after treatment with cisplatin in different cancers, including HGOS.	('rs12201199', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('associated with', 'Reg', (171, 186))	('rs9332377', 'Var', (140, 149))	('rs1142345', 'Var', (74, 83))	('ototoxicity', 'Disease', 'MESH:D006311', (187, 198))	('rs9332377', 'Mutation', 'rs9332377', (140, 149))	('TPMT', 'Gene', '7172', (43, 47))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('COMT', 'Gene', '1312', (119, 123))	('catechol O-methyltransferase', 'Gene', (89, 117))	('ototoxicity', 'Disease', (187, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('COMT', 'Gene', (119, 123))	('rs4646316', 'Var', (126, 135))	('thiopurine', 'Chemical', '-', (12, 22))	('rs4646316', 'Mutation', 'rs4646316', (126, 135))	('rs180046', 'Var', (61, 69))	('HGOS', 'Disease', (262, 266))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('catechol O-methyltransferase', 'Gene', '1312', (89, 117))	('rs1142345', 'Mutation', 'rs1142345', (74, 83))	('cancers', 'Disease', (243, 250))	('TPMT', 'Gene', (43, 47))	('rs180046', 'Mutation', 'rs180046', (61, 69))	('rs12201199', 'Mutation', 'rs12201199', (49, 59))
269591	32629971	In the only study of exclusively patients with HGOS (n = 139), no associations between these variants and increased risk of ototoxicity were reported.	('patients', 'Species', '9606', (33, 41))	('associations', 'Interaction', (66, 78))	('variants', 'Var', (93, 101))	('ototoxicity', 'Disease', 'MESH:D006311', (124, 135))	('ototoxicity', 'Disease', (124, 135))
269592	32629971	However, the meta-analysis including a total of 664 patients revealed that the COMT rs4646361 was the only one that remained significant but associated with less risk (OR = 1.52) as predicted in the other studies (OR = 2.52).	('COMT', 'Gene', '1312', (79, 83))	('rs4646361', 'Var', (84, 93))	('rs4646361', 'Mutation', 'rs4646361', (84, 93))	('COMT', 'Gene', (79, 83))	('less', 'NegReg', (157, 161))	('patients', 'Species', '9606', (52, 60))
269593	32629971	Although initially promising, variants in the COMT and TPMT genes do not seem to play major roles as risk factors to develop cisplatin-induced ototoxicity and therefore stronger markers for clinical decision making are warranted.	('variants', 'Var', (30, 38))	('ototoxicity', 'Disease', 'MESH:D006311', (143, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('TPMT', 'Gene', (55, 59))	('ototoxicity', 'Disease', (143, 154))	('COMT', 'Gene', '1312', (46, 50))	('TPMT', 'Gene', '7172', (55, 59))	('COMT', 'Gene', (46, 50))
269594	32629971	However, pharmacogenetic testing for the TPMT alleles *2 (rs1800462), *3A (rs1800460 and rs1142345), *3B (rs1800460) or *3C (rs1142345) is recommended by the Canadian Pharmacogenomics Network for Drug Safety in pediatric cancer patients when prescribing cisplatin (PharmGKB ID PA166170751).	('cisplatin', 'Chemical', 'MESH:D002945', (254, 263))	('TPMT', 'Gene', (41, 45))	('rs1142345', 'Var', (125, 134))	('rs1800462', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('rs1142345', 'Mutation', 'rs1142345', (125, 134))	('rs1800462', 'Mutation', 'rs1800462', (58, 67))	('patients', 'Species', '9606', (228, 236))	('TPMT', 'Gene', '7172', (41, 45))	('rs1800460', 'Mutation', 'rs1800460', (75, 84))	('rs1800460', 'Mutation', 'rs1800460', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('rs1142345', 'Var', (89, 98))	('rs1800460', 'Var', (75, 84))	('rs1800460', 'Var', (106, 115))	('rs1142345', 'Mutation', 'rs1142345', (89, 98))
269595	32629971	The acylphosphatase 2 (ACYP2) rs1872328 was reported first in children with brain tumors and was then confirmed in patients with HGOS.	('acylphosphatase 2', 'Gene', '98', (4, 21))	('children', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (115, 123))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('rs1872328', 'Mutation', 'rs1872328', (30, 39))	('brain tumors', 'Disease', (76, 88))	('brain tumors', 'Phenotype', 'HP:0030692', (76, 88))	('ACYP2', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('acylphosphatase 2', 'Gene', (4, 21))	('rs1872328', 'Var', (30, 39))	('brain tumors', 'Disease', 'MESH:D001932', (76, 88))	('ACYP2', 'Gene', '98', (23, 28))
269596	32629971	Protective effects were reported for the GSTM3* rs1799735 allele in a group with normal hearing and for the G alleles of Otos rs77124181 (c.-192-182C>G) and rs2291767 (c.-192-22A>G).	('GSTM3', 'Gene', '2947', (41, 46))	('rs2291767 (c.-192-22A>G', 'Var', (157, 180))	('rs77124181 (c.-192-182C>G', 'Var', (126, 151))	('c.-192-182C>G', 'Var', (138, 151))	('rs77124181', 'Mutation', 'rs77124181', (126, 136))	('c.-192-182C>G', 'Mutation', 'rs77124181', (138, 151))	('Pro', 'Chemical', 'MESH:D011392', (0, 3))	('rs1799735', 'Mutation', 'rs1799735', (48, 57))	('GSTM3', 'Gene', (41, 46))	('normal hearing', 'Phenotype', 'HP:0000365', (81, 95))	('c.-192-22A>G', 'Mutation', 'rs2291767', (168, 180))	('rs2291767', 'Mutation', 'rs2291767', (157, 166))
269597	32629971	In addition to the toxicities that can result also in the long-term insufficiencies described above, several polymorphisms have been reported in association with less severe but frequent toxicities influencing the quality of life during chemotherapy treatment.	('polymorphisms', 'Var', (109, 122))	('insufficiencies', 'Disease', 'MESH:D000309', (68, 83))	('toxicities', 'Disease', 'MESH:D064420', (19, 29))	('toxicities', 'Disease', (187, 197))	('insufficiencies', 'Disease', (68, 83))	('toxicities', 'Disease', (19, 29))	('toxicities', 'Disease', 'MESH:D064420', (187, 197))
269598	32629971	In a study on tumor tissue obtained from 66 HGOS patients, the CC genotype of XRCC3 rs 861539 was associated with nausea.	('associated with', 'Reg', (98, 113))	('tumor', 'Disease', (14, 19))	('rs 861539', 'Var', (84, 93))	('XRCC3', 'Gene', (78, 83))	('nausea', 'Phenotype', 'HP:0002018', (114, 120))	('nausea', 'Disease', (114, 120))	('nausea', 'Disease', 'MESH:D009325', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
269599	32629971	The same study reported the GA/AA genotype of ERCC2 rs1799793 to be associated with nausea and gastrointestinal toxicity.	('associated', 'Reg', (68, 78))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (95, 120))	('ERCC2', 'Gene', (46, 51))	('rs1799793', 'Mutation', 'rs1799793', (52, 61))	('nausea', 'Disease', (84, 90))	('gastrointestinal toxicity', 'Disease', (95, 120))	('nausea', 'Phenotype', 'HP:0002018', (84, 90))	('rs1799793', 'Var', (52, 61))	('nausea', 'Disease', 'MESH:D009325', (84, 90))
269600	32629971	Similar evidence was reported for the CC/CT genotypes of XRCC3 rs861539 being associated with nausea and vomiting, as was reported also for the GG genotype of ABCC2 rs3740066.	('rs861539', 'Mutation', 'rs861539', (63, 71))	('associated', 'Reg', (78, 88))	('rs3740066', 'Mutation', 'rs3740066', (165, 174))	('vomiting', 'Disease', (105, 113))	('rs3740066', 'Var', (165, 174))	('vomiting', 'Disease', 'MESH:D014839', (105, 113))	('XRCC3', 'Gene', (57, 62))	('nausea', 'Phenotype', 'HP:0002018', (94, 100))	('nausea', 'Disease', (94, 100))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (94, 113))	('rs861539', 'Var', (63, 71))	('nausea', 'Disease', 'MESH:D009325', (94, 100))	('vomiting', 'Phenotype', 'HP:0002013', (105, 113))
269601	32629971	The following polymorphisms were reported in association with mucositis: the T allele of DHFR rs1650723 and the CT genotype of ABCG2 rs2231135, the TT genotype of ERCC1 rs1615 and CT/CC genotypes of ABCB1 rs1045642 after MTX treatment, and the GG genotype of SLC19A1 rs1051266.	('mucositis', 'Disease', 'MESH:D052016', (62, 71))	('rs1045642', 'Var', (205, 214))	('MTX', 'Chemical', 'MESH:D008727', (221, 224))	('rs1045642', 'Mutation', 'rs1045642', (205, 214))	('ERCC1', 'Gene', (163, 168))	('rs2231135', 'Var', (133, 142))	('rs1051266', 'Var', (267, 276))	('mucositis', 'Disease', (62, 71))	('ABCB1', 'Gene', (199, 204))	('DHFR', 'Gene', (89, 93))	('rs1615', 'Mutation', 'rs1615', (169, 175))	('rs1051266', 'Mutation', 'rs1051266', (267, 276))	('rs2231135', 'Mutation', 'rs2231135', (133, 142))	('rs1650723', 'Var', (94, 103))	('DHFR', 'Gene', '1719', (89, 93))	('SLC19A1', 'Gene', (259, 266))	('rs1615', 'Var', (169, 175))	('ABCG2', 'Gene', (127, 132))	('ABCG2', 'Gene', '9429', (127, 132))	('SLC19A1', 'Gene', '6573', (259, 266))	('rs1650723', 'Mutation', 'rs1650723', (94, 103))
269602	32629971	Two studies reported polymorphisms in association with fever: the AC/AA genotypes of ERCC1 rs3212986 and the T allele of MTHFR rs1801133.	('rs3212986', 'Mutation', 'rs3212986', (91, 100))	('rs3212986', 'Var', (91, 100))	('rs1801133', 'Mutation', 'rs1801133', (127, 136))	('rs1801133', 'Var', (127, 136))	('fever', 'Disease', 'MESH:D005334', (55, 60))	('fever', 'Disease', (55, 60))	('ERCC1', 'Gene', (85, 90))	('fever', 'Phenotype', 'HP:0001945', (55, 60))
269605	32629971	The CG+GG genotype of the hsa-miR-124a rs531564 polymorphism proved to be associated with a decreased risk for HGOS development and a higher five-year survival rate compared to CC genotype.	('rs531564', 'Var', (39, 47))	('hsa-miR-124a', 'Gene', (26, 38))	('higher', 'PosReg', (134, 140))	('rs531564', 'Mutation', 'rs531564', (39, 47))	('decreased', 'NegReg', (92, 101))	('HGOS development', 'CPA', (111, 127))
269606	32629971	Multiple lines of evidence suggest that the profile of isomiRs is cell- and tissue-specific, and, therefore, can be used as a biomarker for many diseases, including cancers.	('isomiRs', 'Var', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Disease', (165, 172))
269619	32629971	This dataset was expanded by the non-overlapping dataset of 33 samples obtained from 31 patients with the aim to identify recurrent copy number (CN) alterations in druggable and clinically actionable cancer genes.	('alterations', 'Var', (149, 160))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('copy number', 'Var', (132, 143))	('cancer', 'Disease', (200, 206))
269621	32629971	Recurrent deletions, structural variations (SV) and somatic nucleotide variants (SNV) were found most frequently in the tumor suppressor genes TP53 (74%), RB1 (64%) and phosphatase and tensin homolog (PTEN; 56%).	('TP53', 'Gene', (143, 147))	('RB1', 'Gene', (155, 158))	('PTEN', 'Gene', (201, 205))	('RB1', 'Gene', '5925', (155, 158))	('PTEN', 'Gene', '5728', (201, 205))	('structural variations', 'Var', (21, 42))	('deletions', 'Var', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
269631	32629971	A total of 281 variants were significantly associated with tumor necrosis.	('tumor necrosis', 'Disease', (59, 73))	('associated', 'Reg', (43, 53))	('variants', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor necrosis', 'Disease', 'MESH:D009336', (59, 73))
269654	32629971	NGS techniques are expected to generate new findings and indicate genetic alterations, which may be of help to better delineate the genes and biochemical pathways important for HGOS growth, progression, clinical behavior and, most of all, biomarkers that may predict which therapy will have the highest probability to obtain the major benefits with minimal risk of toxicity in genetically-stratified subgroups of patients.	('toxicity', 'Disease', (365, 373))	('patients', 'Species', '9606', (413, 421))	('toxicity', 'Disease', 'MESH:D064420', (365, 373))	('alterations', 'Var', (74, 85))
269661	32629971	This study applied the strategy of comprehensive genomic profiling to sequence both DNA and RNA from sarcoma tumor samples, with the aim to identify known and novel alterations that may drive oncogenicity and potentially impact on physicians' treatment decision-making.	('impact', 'Reg', (221, 227))	('sarcoma tumor', 'Disease', 'MESH:D012509', (101, 114))	('sarcoma tumor', 'Disease', (101, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('treatment decision-making', 'CPA', (243, 268))	('oncogenicity', 'CPA', (192, 204))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('alterations', 'Var', (165, 176))	('drive', 'PosReg', (186, 191))
269666	32629971	However, there are at least two major items that must be taken into consideration for a possible clinical translation of the provided evidence:  Targeting non-coding RNAs can be performed by using small interfering RNAs, antisense oligonucleotides, ribozymes, or aptamers, as well as by using clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) methodologies.	('small', 'Var', (197, 202))	('RNAs', 'Protein', (215, 219))	('oligonucleotides', 'Chemical', 'MESH:D009841', (231, 247))	('antisense', 'Var', (221, 230))
269670	32629971	This possibility has a relevant clinical impact because it has been observed that higher numbers of somatic mutations are correlated with a better clinical response to monoclonal antibodies which block immune checkpoint molecules such as the CTLA-4, programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1).	('block', 'NegReg', (196, 201))	('better', 'PosReg', (140, 146))	('programmed cell death-1', 'Gene', (250, 273))	('mutations', 'Var', (108, 117))	('PD-L1', 'Gene', '29126', (313, 318))	('programmed death-ligand 1', 'Gene', (286, 311))	('PD-1', 'Gene', (275, 279))	('programmed death-ligand 1', 'Gene', '29126', (286, 311))	('programmed cell death-1', 'Gene', '5133', (250, 273))	('PD-1', 'Gene', '5133', (275, 279))	('PD-L1', 'Gene', (313, 318))
269673	32629971	A strategy that may speed up the identification of tumor-related biomarkers can also consist in paired sequencing of blood and tumor cells from the same patient, enabling the identification of the mutations and genetic alterations that are specifically acquired in the malignant cells but also those present at germline level.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (197, 206))	('genetic alterations', 'Var', (211, 230))	('patient', 'Species', '9606', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
269677	32629971	The number of mutations or genetic alterations that can be considered as tumor drivers has significantly increased in the last decade thanks to the development of new techniques, as well as through the data generated by large international sequencing studies, such as the Cancer Genome Atlas or the International Cancer Genome Consortium projects.	('Cancer', 'Phenotype', 'HP:0002664', (313, 319))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Cancer', 'Phenotype', 'HP:0002664', (272, 278))	('Cancer', 'Disease', (272, 278))	('Cancer', 'Disease', (313, 319))	('tumor', 'Disease', (73, 78))	('Cancer', 'Disease', 'MESH:D009369', (272, 278))	('Cancer', 'Disease', 'MESH:D009369', (313, 319))	('genetic alterations', 'Var', (27, 46))	('mutations', 'Var', (14, 23))
269787	28439237	In their review, divide the genetic changes found in sarcomas into three groups: sarcomas with specific translocations (Ewing sarcoma, aneurysmal bone cyst), tumors with gene mutations or amplifications (chondrosarcoma, fibrous dysplasia, Chordoma), and sarcomas with genetic instability.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('sarcomas', 'Disease', 'MESH:D012509', (254, 262))	('sarcomas', 'Disease', (81, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (254, 262))	('aneurysmal bone cyst', 'Disease', 'MESH:D017824', (135, 155))	('sarcomas', 'Disease', (254, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (120, 133))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (120, 133))	('aneurysmal bone cyst', 'Disease', (135, 155))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (158, 164))	('translocations', 'Var', (104, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('chondrosarcoma', 'Disease', (204, 218))	('chondrosarcoma', 'Disease', 'MESH:D002813', (204, 218))	('Chordoma', 'Gene', (239, 247))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('fibrous dysplasia', 'Disease', (220, 237))	('sarcomas', 'Disease', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('Ewing sarcoma', 'Disease', (120, 133))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('Chordoma', 'Phenotype', 'HP:0010762', (239, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('fibrous dysplasia', 'Disease', 'MESH:D005357', (220, 237))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (204, 218))	('bone cyst', 'Phenotype', 'HP:0012062', (146, 155))	('gene mutations', 'Var', (170, 184))	('Chordoma', 'Gene', '121775', (239, 247))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('aneurysmal bone cyst', 'Phenotype', 'HP:0012063', (135, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
269828	28439237	The block of Fgf2 factor could modulate the progression of osteosarcoma.	('block', 'Var', (4, 9))	('osteosarcoma', 'Phenotype', 'HP:0002669', (59, 71))	('osteosarcoma', 'Disease', (59, 71))	('osteosarcoma', 'Disease', 'MESH:D012516', (59, 71))	('Fgf2', 'Gene', (13, 17))	('modulate', 'Reg', (31, 39))	('Fgf2', 'Gene', '2247', (13, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
269840	28439237	Using immunofluorescence, high levels of nestin expression were associated with poorer clinical outcomes.	('high', 'Var', (26, 30))	('expression', 'MPA', (48, 58))	('nestin', 'Gene', (41, 47))	('nestin', 'Gene', '10763', (41, 47))
269855	28439237	found that Y1 and VEGF/CXCR4 seem to intervene in the pathogenesis of the malignant phenotype of osteosarcoma by acting on cell invasiveness and metastasis growth, because the deletion of the gene produces a lower involvement of the cells by the tumor and a lower spread.	('deletion', 'Var', (176, 184))	('metastasis growth', 'Disease', 'MESH:D009362', (145, 162))	('CXCR4', 'Gene', '7852', (23, 28))	('metastasis growth', 'Disease', (145, 162))	('CXCR4', 'Gene', (23, 28))	('lower', 'NegReg', (258, 263))	('cell invasiveness', 'CPA', (123, 140))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('VEGF', 'Gene', '7422', (18, 22))	('spread', 'CPA', (264, 270))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('osteosarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('osteosarcoma', 'Disease', (97, 109))	('osteosarcoma', 'Disease', 'MESH:D012516', (97, 109))	('tumor', 'Disease', (246, 251))	('lower', 'NegReg', (208, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('VEGF', 'Gene', (18, 22))
269857	28439237	analyzed the c-kit gene in patients affected by osteosarcoma; the author notes that gene alteration of the protein is a prognostic marker of the tumor; moreover, exons 11 and 17 can't be considered for the treatment of cancer through reduction of c-kit tyrosine kinase activity.	('c-kit', 'Gene', '3815', (13, 18))	('c-kit', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('c-kit', 'Gene', '3815', (247, 252))	('c-kit', 'Gene', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('exons 11', 'Var', (162, 170))	('osteosarcoma', 'Disease', (48, 60))	('tumor', 'Disease', (145, 150))	('patients', 'Species', '9606', (27, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (48, 60))	('reduction', 'NegReg', (234, 243))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('cancer', 'Disease', (219, 225))
269858	28439237	observed, through a molecular analysis of cell line OS1, a genome instability after mutations that affect the function of the transcription factor Runx2.	('Runx2', 'Gene', '860', (147, 152))	('Runx2', 'Gene', (147, 152))	('genome instability', 'MPA', (59, 77))	('function', 'MPA', (110, 118))	('mutations', 'Var', (84, 93))	('OS1', 'Gene', (52, 55))	('OS1', 'Gene', '2487', (52, 55))
269868	28439237	report an association study of common single-nucleotide polymorphisms (SNPs) across 8q24 to explore the role this region may play in osteosarcoma risk.	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('single-nucleotide polymorphisms', 'Var', (38, 69))	('osteosarcoma', 'Disease', (133, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))
269870	28439237	The study suggested that several SNPs in 8q24 may be associated with osteosarcoma, but the susceptibility observed was modest.	('SNPs', 'Var', (33, 37))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('osteosarcoma', 'Disease', (69, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (69, 81))	('associated', 'Reg', (53, 63))	('8q24', 'Gene', (41, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
269877	28439237	evaluated the role of ATO and the degree of expression of the Fas protein of human osteosarcoma cells (Saos-2 cell line); the author affirms that ATO reduces cell proliferation according to the dose and time and increased the expression of the Fas protein, although other mechanisms are interested in this process.	('cell proliferation', 'CPA', (158, 176))	('Saos-2', 'CellLine', 'CVCL:0548', (103, 109))	('ATO', 'Var', (146, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('expression', 'MPA', (226, 236))	('osteosarcoma', 'Phenotype', 'HP:0002669', (83, 95))	('osteosarcoma', 'Disease', (83, 95))	('osteosarcoma', 'Disease', 'MESH:D012516', (83, 95))	('ATO', 'Chemical', 'MESH:D000077237', (146, 149))	('increased', 'PosReg', (212, 221))	('reduces', 'NegReg', (150, 157))	('Fas protein', 'Protein', (244, 255))	('ATO', 'Chemical', 'MESH:D000077237', (22, 25))	('human', 'Species', '9606', (77, 82))
269878	28439237	, assert that the + 49G/A polymorphism of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a molecule that decreases the immune response mediated by T-cells, promotes the development of osteosarcoma.	('cytotoxic T-lymphocyte antigen-4', 'Gene', (42, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('immune response', 'MPA', (115, 130))	('49G/A', 'SUBSTITUTION', 'None', (20, 25))	('CTLA-4', 'Gene', (76, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (180, 192))	('49G/A', 'Var', (20, 25))	('osteosarcoma', 'Disease', (180, 192))	('osteosarcoma', 'Phenotype', 'HP:0002669', (180, 192))	('promotes', 'PosReg', (152, 160))	('CTLA-4', 'Gene', '1493', (76, 82))	('cytotoxic T-lymphocyte antigen-4', 'Gene', '1493', (42, 74))
269882	28439237	The restoration of this marker may provide therapeutic benefits in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('restoration', 'Var', (4, 15))	('osteosarcoma', 'Disease', (67, 79))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
269891	28439237	After the successful construction of a recombinant plasmid of hArgBP2 gene, they identified the expression of GFP-hArgBP2 fusion mainly localized in the cytoplasm and perinucleus of MG-63 cells.	('fusion', 'Var', (122, 128))	('MG-63', 'CellLine', 'CVCL:0426', (182, 187))	('hArgBP2', 'Gene', (62, 69))	('hArgBP2', 'Gene', '8470', (62, 69))	('hArgBP2', 'Gene', (114, 121))	('hArgBP2', 'Gene', '8470', (114, 121))
269897	28439237	Genetic alterations of glutathione S-transferase supergene family can change the body's defense mechanisms to carcinogens, increasing the risk of cancer and pharmacoresistance.	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Disease', (146, 152))	('glutathione S-transferase', 'Gene', (23, 48))	('glutathione S-transferase', 'Gene', '373156', (23, 48))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('increasing', 'PosReg', (123, 133))	('change', 'Reg', (70, 76))	('defense mechanisms to carcinogens', 'MPA', (88, 121))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
269899	28439237	They concluded that GST polymorphisms may have a role in treatment response and osteosarcoma progression.	('role', 'Reg', (49, 53))	('treatment response', 'CPA', (57, 75))	('polymorphisms', 'Var', (24, 37))	('osteosarcoma', 'Disease', (80, 92))	('GS', 'Disease', 'MESH:D011125', (20, 22))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
269900	28439237	Ewing's sarcoma is one of the few solid tumors for which the underlying molecular genetic abnormality has been described: rearrangement of the EWS gene on chromosome 22q12 with an ETS gene family member.	("Ewing's sarcoma", 'Disease', (0, 15))	('rearrangement', 'Var', (122, 135))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('genetic abnormality', 'Disease', 'MESH:D030342', (82, 101))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('genetic abnormality', 'Disease', (82, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('EWS', 'Gene', '2130', (143, 146))	('EWS', 'Gene', (143, 146))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('tumors', 'Disease', (40, 46))
269901	28439237	These translocations define Ewing's sarcoma family tumors (ESFT) and provide a valuable tool for their accurate and unequivocal diagnosis.	('ES', 'Phenotype', 'HP:0012254', (59, 61))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	("Ewing's sarcoma family tumors", 'Disease', (28, 57))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (28, 43))	("Ewing's sarcoma family tumors", 'Disease', 'MESH:C563168', (28, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('translocations', 'Var', (6, 20))
269903	28439237	Ewing's sarcomas is a particular type of bone tumor due to translocations of genes with formation of EWS-ETS fusion proteins, in particular EWS-FLI, a transcription factor more involved in the neoplasm.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('neoplasm', 'Disease', (193, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('FLI', 'Gene', (144, 147))	('bone tumor', 'Disease', 'MESH:D001859', (41, 51))	('FLI', 'Gene', '2314', (144, 147))	('EWS', 'Gene', '2130', (101, 104))	('neoplasm', 'Phenotype', 'HP:0002664', (193, 201))	('EWS', 'Gene', '2130', (140, 143))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (0, 16))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (0, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('EWS', 'Gene', (101, 104))	('bone tumor', 'Phenotype', 'HP:0010622', (41, 51))	('neoplasm', 'Disease', 'MESH:D009369', (193, 201))	('bone tumor', 'Disease', (41, 51))	("Ewing's sarcomas", 'Disease', (0, 16))	('EWS', 'Gene', (140, 143))	('translocations', 'Var', (59, 73))
269913	28439237	investigated EWS-FLI1-bound DNA sequences in two Ewing cell lines and showed that the transcription factor preferentially binds two types of sequences including consensus ETS motifs and microsatellite sequences.	('preferentially', 'PosReg', (107, 121))	('binds', 'Interaction', (122, 127))	('microsatellite sequences', 'Var', (186, 210))	('EWS', 'Gene', '2130', (13, 16))	('EWS', 'Gene', (13, 16))	('FLI1', 'Gene', (17, 21))	('FLI1', 'Gene', '2313', (17, 21))
269914	28439237	Importantly, in vivo EWS-FLI1-bound microsatellites are significantly associated with EWS-FLI1-driven gene activation.	('FLI1', 'Gene', (25, 29))	('FLI1', 'Gene', '2313', (25, 29))	('FLI1', 'Gene', '2313', (90, 94))	('FLI1', 'Gene', (90, 94))	('associated', 'Reg', (70, 80))	('microsatellites', 'Var', (36, 51))	('EWS', 'Gene', '2130', (21, 24))	('EWS', 'Gene', (21, 24))	('EWS', 'Gene', '2130', (86, 89))	('EWS', 'Gene', (86, 89))
269919	28439237	studied CD99 expression associated with EWS/FLI1 translocations in order to define the clinical and prognostic results of bone tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('translocations', 'Var', (49, 63))	('associated', 'Reg', (24, 34))	('bone tumor', 'Disease', (122, 132))	('bone tumor', 'Phenotype', 'HP:0010622', (122, 132))	('EWS', 'Gene', '2130', (40, 43))	('EWS', 'Gene', (40, 43))	('CD99', 'Gene', '4267', (8, 12))	('bone tumor', 'Disease', 'MESH:D001859', (122, 132))	('FLI1', 'Gene', '2313', (44, 48))	('FLI1', 'Gene', (44, 48))	('CD99', 'Gene', (8, 12))
269925	28439237	ESAP1 reduces the transcriptional activity of EWS-FLI1 and also disrupts cell cycle kinetics in Ewing tumor cells (Figure 2).	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('disrupts', 'NegReg', (64, 72))	('Ewing tumor', 'Phenotype', 'HP:0012254', (96, 107))	('reduces', 'NegReg', (6, 13))	('transcriptional activity', 'MPA', (18, 42))	('ESAP1', 'Var', (0, 5))	('EWS', 'Gene', '2130', (46, 49))	('EWS', 'Gene', (46, 49))	('FLI1', 'Gene', '2313', (50, 54))	('FLI1', 'Gene', (50, 54))	('Ewing tumor', 'Disease', (96, 107))	('cell cycle kinetics', 'CPA', (73, 92))	('Ewing tumor', 'Disease', 'MESH:C563168', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
269935	28439237	An interesting study by the University of Texas group suggested that modulation of receptor activator NF-kappa B (RANKL) by vascular endothelial growth factor-165 (VEGF165) can result in the activation of osteoclastic cells in Ewing's tumor, through RANKL gene expression, and lead to the destruction bone.	('osteoclastic cells', 'CPA', (205, 223))	('NF-kappa B', 'Gene', (102, 112))	("Ewing's tumor", 'Disease', 'MESH:C563168', (227, 240))	('modulation', 'Var', (69, 79))	('VEGF', 'Gene', '7422', (164, 168))	('activation', 'PosReg', (191, 201))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('lead to', 'Reg', (277, 284))	('destruction bone', 'Phenotype', 'HP:0002797', (289, 305))	('destruction bone', 'CPA', (289, 305))	("Ewing's tumor", 'Disease', (227, 240))	('NF-kappa B', 'Gene', '4790', (102, 112))	('RANKL gene expression', 'Gene', (250, 271))	('vascular endothelial growth factor', 'Gene', (124, 158))	("Ewing's tumor", 'Phenotype', 'HP:0012254', (227, 240))	('VEGF', 'Gene', (164, 168))	('vascular endothelial growth factor', 'Gene', '7422', (124, 158))
269971	28439237	The author found deletions of loci at the level of CDKN2A, EXT1, and EXT2 genes, who are interested in the development of the disease.	('CDKN2A', 'Gene', '1029', (51, 57))	('deletions', 'Var', (17, 26))	('EXT2', 'Gene', (69, 73))	('EXT1', 'Gene', (59, 63))	('EXT2', 'Gene', '2132', (69, 73))	('CDKN2A', 'Gene', (51, 57))	('EXT1', 'Gene', '2131', (59, 63))
269974	28439237	According to the ESMO/EUROBONET Working Group, the overexpression of p53 protein, 17p1 alterations, and TP53 mutations in high-grade chondrosarcomas suggest that the p53 mutation is a late event involved in tumor progression.	('TP53', 'Gene', '7157', (104, 108))	('protein', 'Protein', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('ES', 'Phenotype', 'HP:0012254', (17, 19))	('mutation', 'Var', (170, 178))	('chondrosarcomas', 'Disease', (133, 148))	('p53', 'Gene', '7157', (166, 169))	('high-grade', 'Disease', (122, 132))	('overexpression', 'PosReg', (51, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('p53', 'Gene', '7157', (69, 72))	('TP53', 'Gene', (104, 108))	('p53', 'Gene', (166, 169))	('mutations', 'Var', (109, 118))	('tumor', 'Disease', (207, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('p53', 'Gene', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (133, 147))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (133, 148))	('chondrosarcomas', 'Disease', 'MESH:D002813', (133, 148))
269975	28439237	Amplification of 12q13 and loss of 9p21 are genetic aberrations found in conventional chondrosarcomas.	('loss', 'Var', (27, 31))	('9p21', 'Gene', (35, 39))	('Amplification of 12q13', 'Var', (0, 22))	('chondrosarcomas', 'Disease', 'MESH:D002813', (86, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('chondrosarcomas', 'Disease', (86, 101))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (86, 100))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (86, 101))
269986	28439237	identified somatic heterozygous isocitratedehydrogenase 1 (IDH1) hot spots (R132C and R132H) or IDH2 (R172S) as mutations present in cartilaginous tumors but not in other mesenchymal tumors.	('IDH2', 'Gene', '3418', (96, 100))	('R172S', 'Mutation', 'rs1057519736', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mesenchymal tumors', 'Disease', (171, 189))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('R132H', 'Var', (86, 91))	('R132H', 'Mutation', 'p.R132H', (86, 91))	('R132C', 'Mutation', 'p.R132C', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (133, 153))	('R132C', 'Var', (76, 81))	('cartilaginous tumors', 'Disease', (133, 153))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('IDH2', 'Gene', (96, 100))	('IDH1', 'Gene', (59, 63))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (171, 189))
269990	28439237	Authors found improved survival in peripheral dedifferentiated chondrosarcomas with PAI-1 expression.	('chondrosarcomas', 'Phenotype', 'HP:0006765', (63, 78))	('improved', 'PosReg', (14, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('PAI-1', 'Gene', '5054', (84, 89))	('chondrosarcomas', 'Disease', 'MESH:D002813', (63, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('chondrosarcomas', 'Disease', (63, 78))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (63, 77))	('PAI-1', 'Gene', (84, 89))	('expression', 'Var', (90, 100))
269998	28439237	Thus, both hypoxia and dysregulated expression of a developmental pathway are causes of increased VEGF expression in chondrosarcoma.	('chondrosarcoma', 'Disease', (117, 131))	('chondrosarcoma', 'Disease', 'MESH:D002813', (117, 131))	('VEGF', 'Gene', '7422', (98, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('expression', 'MPA', (103, 113))	('increased', 'PosReg', (88, 97))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (117, 131))	('hypoxia', 'Disease', (11, 18))	('dysregulated', 'Var', (23, 35))	('hypoxia', 'Disease', 'MESH:D000860', (11, 18))	('VEGF', 'Gene', (98, 102))	('increased VEGF expression', 'Phenotype', 'HP:0030269', (88, 113))
270009	28439237	evaluated the role of aromatase and estrogen receptor alpha in bone tumor proliferation; the authors suggest that the presence of both markers in tumor cells in patients with chondrosarcoma indicates a higher risk of cell proliferation.	('cell proliferation', 'CPA', (217, 235))	('estrogen receptor alpha', 'Gene', '2099', (36, 59))	('tumor', 'Disease', (146, 151))	('bone tumor', 'Phenotype', 'HP:0010622', (63, 73))	('bone tumor', 'Disease', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', (68, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('presence', 'Var', (118, 126))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (175, 189))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('aromatase', 'Gene', '1588', (22, 31))	('bone tumor', 'Disease', 'MESH:D001859', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('estrogen receptor alpha', 'Gene', (36, 59))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('aromatase', 'Gene', (22, 31))	('chondrosarcoma', 'Disease', 'MESH:D002813', (175, 189))	('chondrosarcoma', 'Disease', (175, 189))
270019	28439237	The authors observed that a high COX-2 expression adversely affects patient survival and a positive correlation between CD34 and COX-2 expression, which confirms the relationship between COX-2 and angiogenesis, suggesting a possible role for this marker in patient prognosis.	('affects', 'Reg', (60, 67))	('adversely', 'NegReg', (50, 59))	('patient', 'Species', '9606', (68, 75))	('COX-2', 'Gene', (33, 38))	('correlation', 'Interaction', (100, 111))	('COX-2', 'Gene', (187, 192))	('COX-2', 'Gene', (129, 134))	('COX-2', 'Gene', '5743', (187, 192))	('CD34', 'Gene', (120, 124))	('patient', 'Species', '9606', (257, 264))	('COX-2', 'Gene', '5743', (33, 38))	('CD34', 'Gene', '947', (120, 124))	('COX-2', 'Gene', '5743', (129, 134))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))	('patient survival', 'CPA', (68, 84))
270043	26709919	We show in vitro that CNI-1493 decreases M2-stimulated Ewing Sarcoma tumor cell invasion and extravasation, offering a functional mechanism through which CNI-1493 attenuates metastasis.	('Ewing Sarcoma tumor', 'Disease', (55, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CNI-1493', 'Chemical', 'MESH:C097256', (154, 162))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (55, 68))	('decreases', 'NegReg', (31, 40))	('extravasation', 'CPA', (93, 106))	('CNI-1493', 'Var', (22, 30))	('attenuates', 'NegReg', (163, 173))	('CNI-1493', 'Var', (154, 162))	('Ewing Sarcoma tumor', 'Disease', 'MESH:C563168', (55, 74))	('Sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('CNI-1493', 'Chemical', 'MESH:C097256', (22, 30))	('metastasis', 'CPA', (174, 184))
270064	26709919	In this study, we find that CNI-1493 markedly decreases the incidence of invasive metastasis and tumor burden in a mouse model of Ewing Sarcoma, and that it suppresses M2 macrophage-stimulated tumor cell invasion and extravasation in vitro.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (130, 143))	('Ewing Sarcoma', 'Disease', (130, 143))	('CNI-1493', 'Chemical', 'MESH:C097256', (28, 36))	('extravasation', 'CPA', (217, 230))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mouse', 'Species', '10090', (115, 120))	('invasive metastasis', 'Disease', 'MESH:D009362', (73, 92))	('tumor', 'Disease', (97, 102))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (130, 143))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('suppresses', 'NegReg', (157, 167))	('decreases', 'NegReg', (46, 55))	('CNI-1493', 'Var', (28, 36))	('Sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('tumor', 'Disease', (193, 198))	('invasive metastasis', 'Disease', (73, 92))
270123	26709919	We first asked whether human primary M1 and M2 macrophages derived from blood monocytes altered invasion of Ewing Sarcoma cells through a basement membrane extract using three-dimensional invasion assays, and whether CNI-1493 altered that process (Fig 1A).	('altered', 'Reg', (226, 233))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('CNI-1493', 'Chemical', 'MESH:C097256', (217, 225))	('Sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('invasion', 'CPA', (96, 104))	('human', 'Species', '9606', (23, 28))	('altered', 'Reg', (88, 95))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('CNI-1493', 'Var', (217, 225))	('Ewing Sarcoma', 'Disease', (108, 121))
270126	26709919	CNI-1493 had no effect on invasion by SK-NEP-1 cells alone or when co-cultured with M1 macrophages, indicating that CNI-1493 was not having a direct effect on tumor cells or a generalized effect on all macrophages.	('CNI-1493', 'Chemical', 'MESH:C097256', (0, 8))	('SK-NEP-1', 'CellLine', 'CVCL:0631', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('CNI-1493', 'Var', (116, 124))	('tumor', 'Disease', (159, 164))	('CNI-1493', 'Chemical', 'MESH:C097256', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
270127	26709919	To assure that these results were not unique to SK-NEP-1 cells, stimulation of Ewing Sarcoma tumor cell invasion by M2 macrophages and decrease in M2-induced tumor cell invasion by CNI-1493 treatment was confirmed in three additional cell lines, CHLA-10, CHLA-32 and TC-71 (Fig 2) Gene microarray analysis of macrophages treated with CNI-1493 demonstrates that the gene expression pattern of M1 and M2 cells does not change (Fig 1B), indicating that CNI-1493 is not simply inducing a switch in macrophage phenotypes, conferring the properties of M1 macrophages on previously polarized M2 macrophages.	('tumor', 'Disease', (158, 163))	('CNI-1493', 'Chemical', 'MESH:C097256', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CNI-1493', 'Chemical', 'MESH:C097256', (450, 458))	('CNI-1493', 'Chemical', 'MESH:C097256', (334, 342))	('SK-NEP-1', 'CellLine', 'CVCL:0631', (48, 56))	('tumor', 'Disease', (93, 98))	('CHLA-10', 'CellLine', 'CVCL:6583', (246, 253))	('Ewing Sarcoma tumor', 'Disease', 'MESH:C563168', (79, 98))	('CNI-1493', 'Var', (450, 458))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('Ewing Sarcoma tumor', 'Disease', (79, 98))	('CHLA-32', 'CellLine', 'CVCL:M151', (255, 262))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
270136	26709919	This may indicate that protease inhibition is not the means through which CNI-1493 decreases M2-induced tumor cell invasion.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CNI-1493', 'Var', (74, 82))	('decreases', 'NegReg', (83, 92))	('tumor', 'Disease', (104, 109))	('CNI-1493', 'Chemical', 'MESH:C097256', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
270138	26709919	With the in vitro data showing that CNI-1493 inhibits tumor cell invasion through extracellular matrix, we utilized a well-established murine model of Ewing Sarcoma to examine CNI-1493's potential anti-metastatic properties in vivo.	('CNI-1493', 'Var', (36, 44))	('inhibits', 'NegReg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (151, 164))	('CNI-1493', 'Chemical', 'MESH:C097256', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CNI-1493', 'Chemical', 'MESH:C097256', (36, 44))	('Ewing Sarcoma', 'Disease', (151, 164))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (151, 164))	('Sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('murine', 'Species', '10090', (135, 141))
270142	26709919	Only four of 19 mice with primary tumor (21.1%) demonstrated any pulmonary metastases in the CNI-1493 treatment group, compared to 11 of 21 control animals (52.4%, p = 0.05).	('pulmonary metastases', 'Disease', 'MESH:D009362', (65, 85))	('CNI-1493', 'Chemical', 'MESH:C097256', (93, 101))	('pulmonary metastases', 'Disease', (65, 85))	('primary tumor', 'Disease', 'MESH:D009369', (26, 39))	('primary tumor', 'Disease', (26, 39))	('mice', 'Species', '10090', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('CNI-1493', 'Var', (93, 101))
270151	26709919	Primary tumor mass was modestly but significantly decreased in CNI-1493-treated mice versus control mice, with a mean mass of 3.9 +- 3.3 g versus 6.1+-3.9g, respectively (p<0.05, Fig 5C).	('Primary tumor', 'Disease', (0, 13))	('CNI-1493', 'Chemical', 'MESH:C097256', (63, 71))	('Primary tumor', 'Disease', 'MESH:D009369', (0, 13))	('mice', 'Species', '10090', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('decreased', 'NegReg', (50, 59))	('mice', 'Species', '10090', (80, 84))	('CNI-1493-treated', 'Var', (63, 79))
270169	26709919	Inhibitory effects of CNI-1493 on intravasation at the primary site cannot be ruled out, but if egress from the primary site were the principal mechanism of action of CNI-1493, drug treatment would have resulted in fewer metastases with similar extents of invasion.	('CNI-1493', 'Chemical', 'MESH:C097256', (167, 175))	('metastases', 'Disease', (221, 231))	('CNI-1493', 'Var', (167, 175))	('fewer', 'NegReg', (215, 220))	('metastases', 'Disease', 'MESH:D009362', (221, 231))	('CNI-1493', 'Chemical', 'MESH:C097256', (22, 30))
270170	26709919	However, we observed intravascular metastases with noninvasive morphologies in CNI-1493-treated mice, strongly suggesting that the primary effect of CNI-1493 consists of inhibiting extravasation.	('intravascular metastases', 'Disease', (21, 45))	('CNI-1493', 'Chemical', 'MESH:C097256', (79, 87))	('CNI-1493', 'Var', (149, 157))	('extravasation', 'MPA', (181, 194))	('mice', 'Species', '10090', (96, 100))	('CNI-1493', 'Chemical', 'MESH:C097256', (149, 157))	('intravascular metastases', 'Disease', 'MESH:D009362', (21, 45))	('inhibiting', 'NegReg', (170, 180))
270175	26709919	Our findings show that CNI-1493 decreases tumor cell invasion by acting through macrophages and not directly on tumor cells, as these results were not seen in the absence of macrophages.	('tumor', 'Disease', (42, 47))	('decreases tumor', 'Disease', (32, 47))	('CNI-1493', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CNI-1493', 'Chemical', 'MESH:C097256', (23, 31))	('tumor', 'Disease', (112, 117))	('decreases tumor', 'Disease', 'MESH:D009369', (32, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
270179	26709919	Other possible mechanisms through which CNI-1493 could decrease tumor cell invasion and extravasation include inhibiting M2-induced tumor cell migration, disrupting tumor cell-macrophage communication, modifying actin cytoskeleton dynamics, and altering interactions with other stromal components of the tumor microenvironment and the endothelium.	('disrupting tumor', 'Disease', 'MESH:D019958', (154, 170))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (304, 309))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('modifying', 'Reg', (202, 211))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('CNI-1493', 'Var', (40, 48))	('disrupting tumor', 'Disease', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('interactions', 'Interaction', (254, 266))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', (64, 69))	('actin cytoskeleton dynamics', 'MPA', (212, 239))	('decrease', 'NegReg', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('inhibiting', 'NegReg', (110, 120))	('altering', 'Reg', (245, 253))	('M2-induced', 'MPA', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CNI-1493', 'Chemical', 'MESH:C097256', (40, 48))	('extravasation', 'CPA', (88, 101))
270189	26709919	Since few other models of this disease exist, a resection model is a needed tool to better understand how CNI-1493 may affect the course of Ewing Sarcoma.	('CNI-1493', 'Chemical', 'MESH:C097256', (106, 114))	('Sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (140, 153))	('Ewing Sarcoma', 'Disease', (140, 153))	('CNI-1493', 'Var', (106, 114))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (140, 153))	('affect', 'Reg', (119, 125))	('course', 'MPA', (130, 136))
270203	24836648	RESULTS: L-PDT significantly decreased tumor but not lung IFP compared to controls (no L-PDT) without affecting TBF.	('decreased tumor', 'Disease', 'MESH:D009369', (29, 44))	('L-PDT', 'Var', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('decreased tumor', 'Disease', (29, 44))	('TBF', 'Chemical', '-', (112, 115))	('lung IFP', 'MPA', (53, 61))
270205	24836648	DISCUSSION: L-PDT specifically enhanced convection in blood vessels of tumor but not of normal lung tissue, which was associated with a significant improvement of Liporubicin distribution in tumors compared to controls.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('enhanced', 'PosReg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('improvement', 'PosReg', (148, 159))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('convection in blood vessels', 'MPA', (40, 67))	('blood vessels of tumor', 'Phenotype', 'HP:0100742', (54, 76))	('Liporubicin', 'Chemical', '-', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('L-PDT', 'Var', (12, 17))	('tumors', 'Disease', (191, 197))	('tumor', 'Disease', (71, 76))	('Liporubicin distribution', 'MPA', (163, 187))
270213	24836648	However, the precise mechanism by which L-PDT improves drug transport through the tumor vasculature remains unknown.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('L-PDT', 'Var', (40, 45))	('tumor', 'Disease', (82, 87))	('improves', 'PosReg', (46, 54))
270220	24836648	In the present study, we hypothesized that L-PDT caused a transient improvement in the function of tumor vasculature in a somewhat similar way to "vascular normalization."	('tumor', 'Disease', (99, 104))	('improvement', 'PosReg', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('L-PDT', 'Var', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
270226	24836648	IFP was measured in tumor and normal lung in 10 and 8 animals, respectively, before and during 1 hour following L-PDT.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('L-PDT', 'Var', (112, 117))	('tumor', 'Disease', (20, 25))
270227	24836648	In a separate set of five animals, TBF was measured in tumors before and during 1 hour following L-PDT.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('TBF', 'Chemical', '-', (35, 38))	('L-PDT', 'Var', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
270265	24836648	L-PDT caused a persistent decrease in tumors but not lung IFP (Figure 1A) that was significantly lower than the pre-L-PDT values up to 30 minutes following light delivery.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('decrease', 'NegReg', (26, 34))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('lower', 'NegReg', (97, 102))	('L-PDT', 'Var', (0, 5))
270266	24836648	Between 30 and 60 minutes following L-PDT, tumor IFP was lower than the pre-L-PDT values, but this difference was not significant.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('L-PDT', 'Var', (36, 41))	('tumor', 'Disease', (43, 48))	('lower', 'NegReg', (57, 62))
270271	24836648	L-PDT caused a brief decrease in TBF to 352 +- 46 PU in the immediate post-L-PDT period.	('L-PDT', 'Var', (0, 5))	('TBF', 'MPA', (33, 36))	('decrease', 'NegReg', (21, 29))	('TBF', 'Chemical', '-', (33, 36))
270277	24836648	In tumors pretreated by L-PDT, however, the doxorubicin signal was increased and more homogenous throughout the tumor interstitium (Figure 3A).	('doxorubicin signal', 'MPA', (44, 62))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', (3, 8))	('L-PDT', 'Var', (24, 29))	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('tumors', 'Disease', (3, 9))	('homogenous', 'MPA', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('more', 'PosReg', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('increased', 'PosReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
270278	24836648	Signal quantification showed that L-PDT significantly enhanced the penetration depth of doxorubicin from the tumor vessels compared to IV alone (P < .05).	('L-PDT', 'Var', (34, 39))	('doxorubicin', 'Chemical', 'MESH:D004317', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('penetration depth', 'CPA', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('enhanced', 'PosReg', (54, 62))	('tumor', 'Disease', (109, 114))
270279	24836648	In addition, the total count of pixels within the first 105 mum around tumor vessels was significantly higher in the L-PDT compared to the IV-alone group.	('L-PDT', 'Var', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('higher', 'PosReg', (103, 109))	('tumor', 'Disease', (71, 76))
270281	24836648	Photodynamic therapy was shown to induce a variety of effects ranging from transient changes in the tumor vasculature to direct tumor cytotoxic effects.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Photodynamic therapy', 'Var', (0, 20))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
270283	24836648	These studies have shown that L-PDT of the tumor vasculature could significantly enhance the distribution of drugs administered subsequently without affecting its distribution in normal tissue.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('distribution of drugs administered', 'MPA', (93, 127))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('L-PDT', 'Var', (30, 35))	('tumor', 'Disease', (43, 48))	('enhance', 'PosReg', (81, 88))
270284	24836648	In prostate cancer, vascular-targeted PDT was shown to enhance effective permeability of tumor vessels.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('PDT', 'Var', (38, 41))	('effective', 'CPA', (63, 72))	('enhance', 'PosReg', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
270288	24836648	In this study, we found that L-PDT decreased tumor but not lung IFP and had no effect on TBF (Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('decreased tumor', 'Disease', (35, 50))	('L-PDT', 'Var', (29, 34))	('TBF', 'Chemical', '-', (89, 92))	('decreased tumor', 'Disease', 'MESH:D009369', (35, 50))
270290	24836648	If we consider the IFP changes induced by L-PDT and postulate that the constant TBF, following L-PDT, suggests a stable intravascular hydrostatic pressure, the application of the Starling equation in our model predicts that L-PDT enhanced drug convection between the intravascular and extravascular spaces (Figure 4B).	('enhanced', 'PosReg', (230, 238))	('L-PDT', 'Var', (224, 229))	('Starling', 'Species', '9172', (179, 187))	('TBF', 'Chemical', '-', (80, 83))
270292	24836648	Instead, our data seem to suggest that L-PDT decreases tumor vessel permeability, which reduces tumor IFP while keeping intravascular hydrostatic pressure stable and leaving normal tissues unaffected (Figure 4B).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('intravascular hydrostatic pressure', 'MPA', (120, 154))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (55, 60))	('decreases tumor', 'Disease', 'MESH:D009369', (45, 60))	('L-PDT', 'Var', (39, 44))	('decreases tumor', 'Disease', (45, 60))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('reduces', 'NegReg', (88, 95))
270295	24836648	In other words, L-PDT-treated tumor vessels had more convection and kept a certain degree of permeability that favored liporubicin extravasation and distribution.	('L-PDT-treated', 'Var', (16, 29))	('liporubicin extravasation', 'MPA', (119, 144))	('liporubicin', 'Chemical', '-', (119, 130))	('favored', 'PosReg', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('distribution', 'MPA', (149, 161))	('convection', 'MPA', (53, 63))	('more', 'PosReg', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('permeability', 'MPA', (93, 105))	('tumor', 'Disease', (30, 35))
270300	24836648	Here, we find that L-PDT administered with the drug/light conditions used has a specific effect on the tumor vasculature while leaving normal vessels unaffected.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('L-PDT', 'Var', (19, 24))	('effect', 'Reg', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
270301	24836648	Previous studies have already suggested that the mechanism for drug distribution enhancement by L-PDT is different in normal and tumor tissues.	('L-PDT', 'Var', (96, 101))	('drug distribution', 'MPA', (63, 80))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('enhancement', 'PosReg', (81, 92))	('tumor', 'Disease', (129, 134))
270316	24836648	It is mandatory to further determine how L-PDT affects the tumor and normal vasculatures for longer periods of time and how this affects subsequent administrations of chemotherapy.	('L-PDT', 'Var', (41, 46))	('tumor', 'Disease', (59, 64))	('affects', 'Reg', (129, 136))	('affects', 'Reg', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
270322	24836648	In conclusion, Visudyne-mediated L-PDT has the potential to selectively enhance Liporubicin distribution in tumors in a model of sarcoma metastasis to the lung by reducing tumor IFP.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Liporubicin distribution', 'MPA', (80, 104))	('enhance', 'PosReg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (172, 177))	('sarcoma metastasis to the lung', 'Disease', (129, 159))	('tumor', 'Disease', (108, 113))	('Liporubicin', 'Chemical', '-', (80, 91))	('L-PDT', 'Var', (33, 38))	('Visudyne', 'Chemical', 'MESH:D000077362', (15, 23))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('reducing', 'NegReg', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('sarcoma metastasis to the lung', 'Disease', 'MESH:D009362', (129, 159))
270323	24836648	The enhancement of convection in tumors by L-PDT is a novel and attractive concept that opens new perspectives for the management of superficially spreading tumors.	('enhancement', 'PosReg', (4, 15))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('L-PDT', 'Var', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', (33, 39))	('convection in', 'MPA', (19, 32))
270327	33488087	An evaluation was undertaken to assess whether the introduction of the DMDT has improved the pathway, the primary endpoint being a reduction in time to definitive diagnosis (TTDD).	('pathway', 'Pathway', (93, 100))	('reduction', 'NegReg', (131, 140))	('DMDT', 'Var', (71, 75))	('time to definitive diagnosis', 'MPA', (144, 172))	('DMDT', 'Chemical', '-', (71, 75))	('improved', 'PosReg', (80, 88))	('TTDD', 'Chemical', '-', (174, 178))
270328	33488087	The introduction of the DMDT has led to a reduction in TTDD (7 days).	('DMDT', 'Chemical', '-', (24, 28))	('DMDT', 'Var', (24, 28))	('reduction', 'NegReg', (42, 51))	('TTDD', 'Chemical', '-', (55, 59))
270361	33488087	The aim of this evaluation is to assess whether the DMDT has improved the patient pathway, with the primary endpoints being a reduction in time to first management decision and a reduction in time to definitive diagnosis (TTDD).	('improved', 'PosReg', (61, 69))	('patient', 'Species', '9606', (74, 81))	('time to definitive diagnosis', 'MPA', (192, 220))	('time to first management decision', 'MPA', (139, 172))	('DMDT', 'Var', (52, 56))	('TTDD', 'Chemical', '-', (222, 226))	('patient pathway', 'Pathway', (74, 89))	('reduction', 'NegReg', (126, 135))	('reduction', 'NegReg', (179, 188))	('DMDT', 'Chemical', '-', (52, 56))
270384	33488087	Our study has shown that the introduction of the DMDT has reduced our time to make a first management decision by 6 total days and our time to definitive diagnosis by 7 total days.	('DMDT', 'Chemical', '-', (49, 53))	('DMDT', 'Var', (49, 53))	('reduced', 'NegReg', (58, 65))
270388	33488087	We have also demonstrated an increase in the scheduling of multiple diagnostic techniques at the point of triage as a result of the introduction of the DMDT (11% in 2018 compared to 1% in 2015) with a subsequent reduction in the scheduling of each of the single diagnostic services (biopsy only 21% in 2015-3% in 2018, clinic only 18% in 2015-13% in 2018 and scan only 7% in 2015-1.5% in 2018) highlighting our "one-stop shop" approach and hence, the increased efficiency of our service.	('DMDT', 'Chemical', '-', (152, 156))	('scheduling', 'MPA', (229, 239))	('increase', 'PosReg', (29, 37))	('reduction', 'NegReg', (212, 221))	('DMDT', 'Var', (152, 156))	('scheduling', 'MPA', (45, 55))
270453	32110934	Inhibition of MMP2 and MMP9 affects OS tumor growth and metastasis formation.	('MMP9', 'Gene', '4318', (23, 27))	('OS', 'Phenotype', 'HP:0002669', (36, 38))	('MMP2', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('OS tumor', 'Disease', (36, 44))	('MMP2', 'Gene', '4313', (14, 18))	('Inhibition', 'Var', (0, 10))	('MMP9', 'Gene', (23, 27))	('metastasis formation', 'CPA', (56, 76))	('OS tumor', 'Disease', 'MESH:C567932', (36, 44))
270481	32110934	Indeed, any perturbation of SHH expression/function during these early steps of embryonic development leads to severe alterations of the skeleton development with reduction in the size or absence of certain elements of the craniofacial, axial or appendicular skeletons.	('SHH', 'Gene', (28, 31))	('reduction', 'NegReg', (163, 172))	('perturbation', 'Var', (12, 24))	('absence', 'NegReg', (188, 195))	('alterations', 'Reg', (118, 129))	('expression/function', 'MPA', (32, 51))	('skeleton development', 'CPA', (137, 157))	('size', 'CPA', (180, 184))	('SHH', 'Gene', '6469', (28, 31))
270482	32110934	Such alterations of SHH, whatever their causes, are often lethal before birth as they are also associated with the defective formation of important none-skeletal organs.	('SHH', 'Gene', '6469', (20, 23))	('alterations', 'Var', (5, 16))	('associated', 'Reg', (95, 105))	('SHH', 'Gene', (20, 23))
270489	32110934	Any perturbations in the SHH expression level or pattern during the bud and pallet stages of limb morphogenesis, whatever their genetic or environmental origins, lead to a large spectrum of limb dysmorphic features ranging from the absence of most of the autopod to polydactylism.	('SHH', 'Gene', (25, 28))	('limb dysmorphic', 'Disease', 'MESH:D017880', (190, 205))	('SHH', 'Gene', '6469', (25, 28))	('perturbations', 'Var', (4, 17))	('polydactylism', 'Disease', (266, 279))	('limb dysmorphic', 'Disease', (190, 205))	('lead to', 'Reg', (162, 169))
270493	32110934	In cases of SHH expression disruptions in the notochord, the axial skeleton formation is always severely affected with presence of caudal dysgenesis, cyclopia and rib absence.	('affected', 'Reg', (105, 113))	('rib absence', 'CPA', (163, 174))	('caudal dysgenesis', 'Disease', (131, 148))	('axial skeleton formation', 'CPA', (61, 85))	('rib absence', 'Phenotype', 'HP:0000921', (163, 174))	('cyclopia', 'Disease', (150, 158))	('disruptions', 'Var', (27, 38))	('SHH', 'Gene', (12, 15))	('cyclopia', 'Phenotype', 'HP:0009914', (150, 158))	('SHH', 'Gene', '6469', (12, 15))
270496	32110934	Defects in SHH expression in the enamel knocks lead to severe alterations of the size and the shape of the teeth and to disruptions of the polarity and organization of the ameloblast and odontoblast layers.	('shape of the teeth', 'Phenotype', 'HP:0006482', (94, 112))	('SHH', 'Gene', (11, 14))	('Defects', 'Var', (0, 7))	('disruptions', 'Reg', (120, 131))	('SHH', 'Gene', '6469', (11, 14))	('alterations', 'Reg', (62, 73))
270501	32110934	Mutations in some of the genes involved in the SHH cascade, such as SMO, Ptch or Sufu, have been associated with the development of cancers.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('Sufu', 'Gene', (81, 85))	('Ptch', 'Gene', (73, 77))	('SMO', 'Disease', (68, 71))	('Ptch', 'Gene', '5727', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('SHH', 'Gene', '6469', (47, 50))	('Mutations', 'Var', (0, 9))	('associated with', 'Reg', (97, 112))	('SHH', 'Gene', (47, 50))	('Sufu', 'Gene', '51684', (81, 85))
270502	32110934	For example, mutations of Ptch were originally described in Gorlin syndrome, a rare hereditary disease with an autosomal dominant transmission, characterized by the association of multiple basal cell carcinoma, medulloblastoma and rhabdomyosarcoma.	('basal cell carcinoma', 'Disease', (189, 209))	('medulloblastoma', 'Phenotype', 'HP:0002885', (211, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('hereditary disease', 'Disease', (84, 102))	('Gorlin syndrome', 'Disease', (60, 75))	('medulloblastoma and rhabdomyosarcoma', 'Disease', 'MESH:D008527', (211, 247))	('hereditary disease', 'Disease', 'MESH:D030342', (84, 102))	('described', 'Reg', (47, 56))	('Ptch', 'Gene', '5727', (26, 30))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (231, 247))	('mutations', 'Var', (13, 22))	('Ptch', 'Gene', (26, 30))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (189, 209))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (189, 209))
270503	32110934	Sporadic mutations of SHH have been described in basal cell carcinoma, medulloblastoma and in breast carcinoma cell lines.	('medulloblastoma', 'Phenotype', 'HP:0002885', (71, 86))	('SHH', 'Gene', '6469', (22, 25))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (49, 69))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (49, 69))	('basal cell carcinoma', 'Disease', (49, 69))	('breast carcinoma', 'Phenotype', 'HP:0003002', (94, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('mutations', 'Var', (9, 18))	('medulloblastoma', 'Disease', (71, 86))	('SHH', 'Gene', (22, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('described', 'Reg', (36, 45))	('breast carcinoma', 'Disease', 'MESH:D001943', (94, 110))	('breast carcinoma', 'Disease', (94, 110))	('medulloblastoma', 'Disease', 'MESH:D008527', (71, 86))
270504	32110934	The SHH pathway can be also activated without mutations of the genes involved in the SHH cascade, mainly through a paracrine effect of SHH and, thus, on the canonical cascade.	('SHH', 'Gene', (4, 7))	('SHH', 'Gene', '6469', (135, 138))	('mutations', 'Var', (46, 55))	('SHH', 'Gene', '6469', (85, 88))	('activated', 'PosReg', (28, 37))	('SHH', 'Gene', (135, 138))	('SHH', 'Gene', '6469', (4, 7))	('SHH', 'Gene', (85, 88))
270517	32110934	showed, in an immunohistochemistry study on a tissue-microarray of 58 OS samples, that overall survival was shortened in patients with high Gli2 expression and that, during the 5 years of follow-up, living patients significantly expressed lower Gli2 compared to patients who died.	('high', 'Var', (135, 139))	('OS', 'Phenotype', 'HP:0002669', (70, 72))	('Gli2', 'Gene', '2736', (140, 144))	('Gli2', 'Gene', (140, 144))	('expression', 'MPA', (145, 155))	('shortened', 'NegReg', (108, 117))	('patients', 'Species', '9606', (206, 214))	('died', 'Disease', 'MESH:D003643', (275, 279))	('Gli2', 'Gene', '2736', (245, 249))	('died', 'Disease', (275, 279))	('patients', 'Species', '9606', (262, 270))	('lower', 'NegReg', (239, 244))	('patients', 'Species', '9606', (121, 129))	('Gli2', 'Gene', (245, 249))
270521	32110934	Moreover, inhibition of SMO by cyclopamine, a specific inhibitor of SMO, or by genetic invalidation of SMO, prevented cell proliferation in vitro and tumor growth in vivo.	('genetic invalidation', 'Var', (79, 99))	('inhibition', 'NegReg', (10, 20))	('SMO', 'Gene', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('prevented', 'NegReg', (108, 117))	('cyclopamine', 'Chemical', 'MESH:C000541', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cell proliferation', 'CPA', (118, 136))	('tumor', 'Disease', (150, 155))
270523	32110934	In SaOS2 and 143B OS cell lines, inhibition of Gli2 prevented OS proliferation in vitro, through inhibition of cell cycle proteins cyclin D1, pRb and SKP2.	('inhibition', 'Var', (33, 43))	('pRb', 'Gene', '5925', (142, 145))	('pRb', 'Gene', (142, 145))	('Gli2', 'Gene', (47, 51))	('cyclin D1', 'Gene', (131, 140))	('B OS', 'CellLine', 'CVCL:1E41', (16, 20))	('SaOS2', 'CellLine', 'CVCL:0548', (3, 8))	('SKP2', 'Gene', '6502', (150, 154))	('inhibition', 'NegReg', (97, 107))	('OS', 'Phenotype', 'HP:0002669', (5, 7))	('prevented', 'NegReg', (52, 61))	('OS proliferation in vitro', 'CPA', (62, 87))	('OS', 'Phenotype', 'HP:0002669', (62, 64))	('SKP2', 'Gene', (150, 154))	('cell', 'MPA', (111, 115))	('Gli2', 'Gene', '2736', (47, 51))	('OS', 'Phenotype', 'HP:0002669', (18, 20))	('cyclin D1', 'Gene', '595', (131, 140))
270525	32110934	In addition, invalidation of Gli2 in KHOS and U2OS cell lines has been shown to induce a decrease in OS proliferation both in 2D and 3D cultures and to promote OS cell sensitivity to chemotherapies doxorubicin and methotrexate.	('Gli2', 'Gene', (29, 33))	('OS', 'Phenotype', 'HP:0002669', (101, 103))	('doxorubicin', 'Chemical', 'MESH:D004317', (198, 209))	('OS', 'Phenotype', 'HP:0002669', (39, 41))	('OS proliferation', 'CPA', (101, 117))	('OS', 'Phenotype', 'HP:0002669', (160, 162))	('decrease', 'NegReg', (89, 97))	('invalidation', 'Var', (13, 25))	('U2OS', 'CellLine', 'CVCL:0042', (46, 50))	('methotrexate', 'Chemical', 'MESH:D008727', (214, 226))	('OS', 'Phenotype', 'HP:0002669', (48, 50))	('Gli2', 'Gene', '2736', (29, 33))	('promote', 'PosReg', (152, 159))
270528	32110934	In a 143B-induced xenograft model, targeting of Gli2 by genetic invalidation in tumor cells inhibited tumor growth and provided a significant survival benefit.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('inhibited', 'NegReg', (92, 101))	('genetic invalidation', 'Var', (56, 76))	('survival benefit', 'CPA', (142, 158))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Gli2', 'Gene', '2736', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (80, 85))	('Gli2', 'Gene', (48, 52))	('targeting', 'Var', (35, 44))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
270530	32110934	treated mice orally with IPI-926, a semi-synthetic analog of cyclopamin and small-molecule inhibitor of SMO, and showed a specific inhibition of ligand-dependent HH pathway and a significant decrease in tumor weight and volume.	('IPI-926', 'Chemical', 'MESH:C541444', (25, 32))	('tumor', 'Disease', (203, 208))	('HH', 'Disease', 'MESH:D006432', (162, 164))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('decrease', 'NegReg', (191, 199))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('mice', 'Species', '10090', (8, 12))	('IPI-926', 'Var', (25, 32))	('inhibition', 'NegReg', (131, 141))
270534	32110934	In OS cell lines, ATO promotes apoptotic cell death and, importantly, induces the accumulation of DNA damage.	('ATO', 'Var', (18, 21))	('promotes', 'PosReg', (22, 30))	('accumulation', 'MPA', (82, 94))	('DNA damage', 'MPA', (98, 108))	('induces', 'Reg', (70, 77))	('OS', 'Phenotype', 'HP:0002669', (3, 5))	('ATO', 'Chemical', 'MESH:D000077237', (18, 21))	('death', 'Disease', 'MESH:D003643', (46, 51))	('death', 'Disease', (46, 51))
270539	32110934	Importantly, this radioprotection was alleviated by SHH antibody neutralization or Gli1 invalidation.	('Gli1', 'Gene', (83, 87))	('invalidation', 'Var', (88, 100))	('alleviated', 'NegReg', (38, 48))	('Gli1', 'Gene', '2735', (83, 87))	('SHH', 'Gene', (52, 55))	('neutralization', 'Var', (65, 79))	('SHH', 'Gene', '6469', (52, 55))
270540	32110934	Very recently, activation of SHH signaling was found to be involved in the resistance of OS cells to ionizing radiations as radio-resistant OS MG63 cells expressed increased level of SHH, SMO, Ptch1 proteins and increased nuclear localization of Gli1 compared to radiosensitive cells, whereas silencing of SHH rendered the radio-resistant cells more radiosensitive.	('SMO', 'MPA', (188, 191))	('SHH', 'Gene', '6469', (29, 32))	('OS MG63', 'CellLine', 'CVCL:0426', (140, 147))	('Ptch1', 'Gene', '5727', (193, 198))	('Ptch1', 'Gene', (193, 198))	('OS', 'Phenotype', 'HP:0002669', (89, 91))	('silencing', 'Var', (293, 302))	('SHH', 'Gene', (306, 309))	('SHH', 'Gene', (183, 186))	('OS', 'Phenotype', 'HP:0002669', (140, 142))	('SHH', 'Gene', (29, 32))	('Gli1', 'Gene', (246, 250))	('nuclear localization', 'MPA', (222, 242))	('increased', 'PosReg', (212, 221))	('SHH', 'Gene', '6469', (183, 186))	('SHH', 'Gene', '6469', (306, 309))	('Gli1', 'Gene', '2735', (246, 250))	('increased', 'PosReg', (164, 173))
270550	32110934	Gli1 was identified as a direct transcriptional target of EWS-FL1 through an HH ligand-independent mechanism and appears essential in EWS-Fli1-induced tumorigenic signaling as its direct inhibition by si/sh-RNA or by chemical small-molecule inhibitor NCS75503 impaired proliferation and clonogenicity of ES cells.	('si/sh-RNA', 'Var', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('inhibition', 'NegReg', (187, 197))	('Gli1', 'Gene', '2735', (0, 4))	('proliferation', 'CPA', (269, 282))	('tumor', 'Disease', (151, 156))	('HH', 'Disease', 'MESH:D006432', (77, 79))	('Gli1', 'Gene', (0, 4))	('impaired', 'NegReg', (260, 268))	('clonogenicity of ES cells', 'CPA', (287, 312))	('Fli1', 'Gene', '2313', (138, 142))	('EWS', 'Gene', (58, 61))	('EWS', 'Gene', '2130', (134, 137))	('EWS', 'Gene', (134, 137))	('ES', 'Phenotype', 'HP:0012254', (304, 306))	('EWS', 'Gene', '2130', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('Fli1', 'Gene', (138, 142))
270558	32110934	Several synthetic SMO inhibitors with a higher efficiency were then developed and tested in various cancer preclinical models and in phase I, II or III clinical trials, such as GDC-0449 (Vismodegib/Erivedge), LDE225 (Erismodegib/Sonidegib/Odomzo), IPI-926 (Saridegib), BMS-833923/XL139, PF-04449913 (Glasdegib), LY2940680 (Taladegib) or IPI-926 (Vismodegib/Erivedge).	('IPI-926', 'Chemical', 'MESH:C541444', (248, 255))	('IPI-926', 'Var', (337, 344))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('IPI-926', 'Chemical', 'MESH:C541444', (337, 344))	('LDE225', 'Var', (209, 215))	('LY2940680', 'Var', (312, 321))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('PF-04449913', 'Var', (287, 298))
270594	31533332	Given their key role in the regulation of transcription and translation, deregulation of their expression and/or function has been associated with several diseases, including cancer.	('function', 'MPA', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('deregulation', 'Var', (73, 85))	('associated', 'Reg', (131, 141))	('diseases', 'Disease', (155, 163))	('expression', 'MPA', (95, 105))
270596	31533332	Indeed, the dysregulated miRNAs may act as either tumor suppressors or oncogenes in cancer by increasing proliferation, angiogenesis, invasion, and metastasis and by inhibiting apoptosis.	('apoptosis', 'CPA', (177, 186))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('metastasis', 'CPA', (148, 158))	('dysregulated', 'Var', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('miR', 'Gene', (25, 28))	('proliferation', 'CPA', (105, 118))	('angiogenesis', 'CPA', (120, 132))	('invasion', 'CPA', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('miR', 'Gene', '22877', (25, 28))	('inhibiting', 'NegReg', (166, 176))	('tumor', 'Disease', (50, 55))	('increasing', 'PosReg', (94, 104))
270598	31533332	ESCRT-I/ESCRT-II trigger involution of the limiting membrane into the MVB lumen, and ESCRT-III forms a spiral-shaped structure that constricts the budding neck, inducing ATPase VPS4 activation and membrane scission.	('VPS4', 'Gene', (177, 181))	('membrane scission', 'CPA', (197, 214))	('VPS4', 'Gene', '27183', (177, 181))	('ESCRT-III', 'Var', (85, 94))	('activation', 'PosReg', (182, 192))	('inducing', 'PosReg', (161, 169))
270601	31533332	Although the underlying mechanisms remain unknown, it has been described that miRNAs can be sorted into exosomes by four possible paths: a) the neuronal sphingomyelinase 2 (nSMase)-dependent pathway: overexpression of nSMase2 increases the number of miRNAs embodied in exosomes while its inhibition reduces the number of exosomal miRNAs; b) the miRNA motif and sumoylated heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent pathway: hnRNPA2B1 recognizes the GGAG motif in 3' UTR of miRNA sequences, determining its packaging into exosomes; c) the 3' end of the miRNA sequence-dependent pathway: 3' ends of uridylated endogenous miRNAs are mainly presented in exosomes derived from B cells or urine, whereas the 3' ends of adenylated endogenous miRNAs are especially presented in B cells; and d) the miRNA-induced silencing complex (miRISC)-related pathway: the knockout of argonaute protein 2 (AGO2) could decrease the types and abundance of preferentially exported miRNAs in exosomes isolated from HEK293T cells.	('miR', 'Gene', (490, 493))	('AGO2', 'Gene', (902, 906))	('miR', 'Gene', (569, 572))	('nSMase', 'Gene', '6610', (173, 179))	('miR', 'Gene', (974, 977))	('miR', 'Gene', (78, 81))	('miR', 'Gene', '22877', (636, 639))	('miR', 'Gene', (807, 810))	('miR', 'Gene', (330, 333))	('knockout', 'Var', (869, 877))	('argonaute protein 2', 'Gene', '27161', (881, 900))	('miR', 'Gene', '22877', (752, 755))	('hnRNPA2B1', 'Gene', (441, 450))	('miR', 'Gene', (250, 253))	('neuronal sphingomyelinase 2', 'Gene', (144, 171))	('nSMase', 'Gene', '6610', (218, 224))	('miR', 'Gene', '22877', (840, 843))	('nSMase2', 'Gene', '55512', (218, 225))	('miR', 'Gene', '22877', (490, 493))	('miR', 'Gene', '22877', (78, 81))	('miR', 'Gene', '22877', (569, 572))	('nSMase', 'Gene', (173, 179))	('miR', 'Gene', '22877', (974, 977))	('miR', 'Gene', '22877', (807, 810))	('hnRNP', 'Gene', '3183', (441, 446))	('miR', 'Gene', '22877', (330, 333))	('miR', 'Gene', (345, 348))	('hnRNPA2B1', 'Gene', '3181', (441, 450))	('miR', 'Gene', '22877', (250, 253))	('hnRNP', 'Gene', '3183', (414, 419))	('hnRNP', 'Gene', (441, 446))	('decrease', 'NegReg', (914, 922))	('argonaute protein 2', 'Gene', (881, 900))	('nSMase', 'Gene', (218, 224))	('AGO2', 'Gene', '27161', (902, 906))	('miR', 'Gene', (636, 639))	('neuronal sphingomyelinase 2', 'Gene', '6610', (144, 171))	('hnRNP', 'Gene', (414, 419))	('miR', 'Gene', '22877', (345, 348))	('miR', 'Gene', (752, 755))	('nSMase2', 'Gene', (218, 225))	('miR', 'Gene', (840, 843))
270608	31533332	Exosomal miR-17-92 cluster regulates gene expression during angiogenesis in leukemia; in colon rectal cancer (CRC), exosomal miR-1246 promotes human umbilical vascular endothelial cell (HUVEC) proliferation, migration, and tube formation, thus activating the Smad 1/5/8 pathway; and in breast cancer, miR-122 carried in exosomes mediates high levels of angiogenesis to sustain tumor growth and to facilitate metastasis.	('promotes', 'PosReg', (134, 142))	('miR-17-92', 'Gene', '407975', (9, 18))	('CRC', 'Disease', 'MESH:D015179', (110, 113))	('breast cancer', 'Disease', 'MESH:D001943', (286, 299))	('breast cancer', 'Disease', (286, 299))	('Smad 1/5', 'Gene', (259, 267))	('Smad 1/5', 'Gene', '4086;4090', (259, 267))	('tube formation', 'CPA', (223, 237))	('tumor', 'Disease', (377, 382))	('rectal cancer', 'Phenotype', 'HP:0100743', (95, 108))	('miR-122', 'Gene', '406906', (301, 308))	('regulates', 'Reg', (27, 36))	('colon rectal cancer', 'Disease', (89, 108))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('miR-1246', 'Gene', '100302142', (125, 133))	('human', 'Species', '9606', (143, 148))	('gene expression', 'MPA', (37, 52))	('facilitate', 'PosReg', (397, 407))	('activating', 'PosReg', (244, 254))	('miR-122', 'Gene', (301, 308))	('miR-17-92', 'Gene', (9, 18))	('exosomal', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('colon rectal cancer', 'Disease', 'MESH:D015179', (89, 108))	('metastasis', 'CPA', (408, 418))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('CRC', 'Disease', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('human umbilical vascular endothelial cell', 'CPA', (143, 184))	('migration', 'CPA', (208, 217))	('leukemia', 'Disease', (76, 84))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (286, 299))	('miR-1246', 'Gene', (125, 133))
270634	31533332	In turn, monocytes produce interleukin (IL)-6, which leads to STAT3 activation and consequent secretion of miR-155 within exosomes that are internalized by NB cells.	('STAT3', 'Gene', (62, 67))	('miR-155', 'Var', (107, 114))	('activation', 'PosReg', (68, 78))	('interleukin (IL)-6', 'Gene', (27, 45))	('interleukin (IL)-6', 'Gene', '3569', (27, 45))	('secretion', 'MPA', (94, 103))	('STAT3', 'Gene', '6774', (62, 67))	('NB', 'Disease', 'MESH:D009447', (156, 158))
270651	31533332	Deregulation of miRNA-34 has been described to have a role in the promotion of several tumors such as lung, skin, breast, urinary bladder, and kidney and may be considered as a diagnostic and prognostic biomarker in HB.	('promotion', 'PosReg', (66, 75))	('skin', 'Disease', (108, 112))	('urinary bladder', 'Disease', (122, 137))	('lung', 'Disease', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Deregulation', 'Var', (0, 12))	('kidney', 'Disease', (143, 149))	('miR', 'Gene', '22877', (16, 19))	('HB', 'Disease', 'MESH:D018197', (216, 218))	('breast', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('miR', 'Gene', (16, 19))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
270680	31533332	In OS tissues, dysregulation of miR-25-3p expression is correlated with poor prognosis, and previous works showed both oncogenic and tumor-suppressor functions depending on the cellular context.	('miR', 'Gene', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('miR', 'Gene', '22877', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('dysregulation', 'Var', (15, 28))
270688	31533332	This tumor is characterized by balanced chromosomal translocations t(11;22)(q24;q12), which results in the production of EWS-FLI1 oncoprotein.	('EWS', 'Gene', '2130', (121, 124))	('EWS', 'Gene', (121, 124))	('results in', 'Reg', (92, 102))	('FLI1', 'Gene', '2313', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('FLI1', 'Gene', (125, 129))	('production', 'MPA', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('t(11;22)(q24;q12', 'Var', (67, 83))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (67, 84))
270694	31533332	Indeed, deficiency of CD99 increased miR-34a and decreased Notch 1 and Notch 3 levels.	('Notch 3', 'Gene', (71, 78))	('CD99', 'Gene', (22, 26))	('increased', 'PosReg', (27, 36))	('miR-34a', 'Gene', '407040', (37, 44))	('Notch 1', 'Gene', '4851', (59, 66))	('decreased', 'NegReg', (49, 58))	('miR-34a', 'Gene', (37, 44))	('CD99', 'Gene', '4267', (22, 26))	('deficiency', 'Var', (8, 18))	('Notch 1', 'Gene', (59, 66))	('Notch 3', 'Gene', '4854', (71, 78))
270695	31533332	Moreover, exosomes isolated from CD99-silenced EWS cells were able to influence the recipient wild-type EWS cells by mimicking CD99 silencing and by inducing neural differentiation.	('EWS', 'Gene', '2130', (104, 107))	('EWS', 'Gene', (104, 107))	('silencing', 'Var', (132, 141))	('CD99', 'Gene', (127, 131))	('inducing', 'Reg', (149, 157))	('CD99', 'Gene', '4267', (33, 37))	('neural differentiation', 'CPA', (158, 180))	('EWS', 'Gene', '2130', (47, 50))	('EWS', 'Gene', (47, 50))	('CD99', 'Gene', '4267', (127, 131))	('CD99', 'Gene', (33, 37))
270732	31533332	This malignancy is associated with a typical chromosomal translocation, t(11;22) (p13;q12), involving a fusion between the EWSR1 and WT1 gene, which leads to production of chimeric protein with transcriptional regulatory activity.	('EWSR1', 'Gene', (123, 128))	('production of chimeric protein', 'MPA', (158, 188))	('malignancy', 'Disease', (5, 15))	('p13', 'Gene', '440926', (82, 85))	('WT1', 'Gene', (133, 136))	('EWSR1', 'Gene', '2130', (123, 128))	('fusion', 'Var', (104, 110))	('transcriptional regulatory activity', 'MPA', (194, 229))	('malignancy', 'Disease', 'MESH:D009369', (5, 15))	('leads to', 'Reg', (149, 157))	('WT1', 'Gene', '7490', (133, 136))	('p13', 'Gene', (82, 85))
270763	31533332	Most recent works describe a high number of modulated miRNAs in AML also based on high-risk of disease, treatment resistance, and patient survival, suggesting miRNAs as potential biomarkers in pediatric leukemias.	('pediatric leukemias', 'Disease', 'MESH:D063766', (193, 212))	('patient', 'Species', '9606', (130, 137))	('miR', 'Gene', (54, 57))	('leukemia', 'Phenotype', 'HP:0001909', (203, 211))	('miR', 'Gene', '22877', (54, 57))	('pediatric leukemias', 'Disease', (193, 212))	('AML', 'Disease', 'MESH:D015470', (64, 67))	('modulated', 'Var', (44, 53))	('leukemias', 'Phenotype', 'HP:0001909', (203, 212))	('miR', 'Gene', (159, 162))	('AML', 'Disease', (64, 67))	('miR', 'Gene', '22877', (159, 162))
270768	31533332	Among these, miR-155, miR-375, miR-150, miR-92a, miR-210, miR-29, miR-223, miR-202-3p, miR-21, miR-146a, miR-148, and mi-135b were specifically reported.	('miR', 'Gene', (13, 16))	('miR', 'Gene', '22877', (95, 98))	('miR', 'Gene', '22877', (40, 43))	('miR-21', 'Gene', (87, 93))	('miR-223', 'Gene', '407008', (66, 73))	('miR', 'Gene', '22877', (31, 34))	('miR', 'Gene', '22877', (87, 90))	('miR', 'Gene', (75, 78))	('miR-375', 'Gene', '494324', (22, 29))	('miR', 'Gene', '22877', (22, 25))	('miR', 'Gene', (66, 69))	('miR', 'Gene', (58, 61))	('miR-92', 'Gene', '407047', (40, 46))	('miR-375', 'Gene', (22, 29))	('miR', 'Gene', '22877', (13, 16))	('miR-210', 'Gene', '406992', (49, 56))	('miR-21', 'Gene', '406991', (49, 55))	('miR', 'Gene', (105, 108))	('miR', 'Gene', '22877', (75, 78))	('miR-92', 'Gene', (40, 46))	('miR', 'Gene', (49, 52))	('miR', 'Gene', '22877', (58, 61))	('miR-210', 'Gene', (49, 56))	('miR', 'Gene', '22877', (66, 69))	('mi-135b', 'Var', (118, 125))	('miR-21', 'Gene', '406991', (87, 93))	('miR', 'Gene', (95, 98))	('miR', 'Gene', (40, 43))	('miR-223', 'Gene', (66, 73))	('miR', 'Gene', '22877', (105, 108))	('miR-21', 'Gene', (49, 55))	('miR', 'Gene', (31, 34))	('miR', 'Gene', (87, 90))	('miR', 'Gene', '22877', (49, 52))	('miR', 'Gene', (22, 25))
270779	31533332	Aberrant miRNA expression has been found in different lymphomas; some of these are known for their pathological role.	('Aberrant', 'Var', (0, 8))	('lymphoma', 'Phenotype', 'HP:0002665', (54, 62))	('lymphomas', 'Disease', 'MESH:D008223', (54, 63))	('lymphomas', 'Disease', (54, 63))	('miR', 'Gene', '22877', (9, 12))	('lymphomas', 'Phenotype', 'HP:0002665', (54, 63))	('miR', 'Gene', (9, 12))	('found', 'Reg', (35, 40))
270784	31533332	suggested a role of miR-146a in the pathogenesis of DLBCL because of its higher level of expression in blood samples of patients than healthy donors.	('miR-146a', 'Var', (20, 28))	('level of expression', 'MPA', (80, 99))	('patients', 'Species', '9606', (120, 128))	('DLBCL', 'Disease', (52, 57))	('higher', 'PosReg', (73, 79))
270791	31533332	The emerging involvement of miRNA deregulation in the cancer pathogenesis has opened promising opportunities for their clinical application in tumor diagnosis, outcome prediction, and therapy.	('tumor', 'Disease', (143, 148))	('deregulation', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('involvement', 'Reg', (13, 24))	('miR', 'Gene', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('miR', 'Gene', '22877', (28, 31))
270861	27721200	According to the study, tumors >5 cm and high-grade tumors had the highest risk for recurrence, and the histologic subtype associated with the greatest recurrence rate was an undifferentiated pleomorphic sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('high-grade', 'Var', (41, 51))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (192, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('pleomorphic sarcoma', 'Disease', (192, 211))
270878	25437654	Reverse transcription polymerase chain reaction from a formalin-fixed, paraffin-embedded biopsy specimen revealed a FUS-CREB3L2 gene fusion (exon6/int/exon5), leading to the diagnosis of LGFMS.	('LGFMS', 'Disease', (187, 192))	('CREB3L2', 'Gene', (120, 127))	('exon6/int/exon5', 'Var', (141, 156))	('FUS', 'Gene', (116, 119))	('CREB3L2', 'Gene', '64764', (120, 127))	('FUS', 'Gene', '2521', (116, 119))	('paraffin', 'Chemical', 'MESH:D010232', (71, 79))	('formalin', 'Chemical', 'MESH:D005557', (55, 63))
270894	25437654	Reverse transcription polymerase chain reaction (RT-PCR) from a formalin-fixed, paraffin-embedded (FFPE) biopsy specimen revealed FUS-CREB3L2 gene fusion (exon6/int/exon5), leading to the diagnosis of LGFMS.	('LGFMS', 'Disease', (201, 206))	('exon6/int/exon5', 'Var', (155, 170))	('CREB3L2', 'Gene', '64764', (134, 141))	('formalin', 'Chemical', 'MESH:D005557', (64, 72))	('paraffin', 'Chemical', 'MESH:D010232', (80, 88))	('FUS', 'Gene', (130, 133))	('FUS', 'Gene', '2521', (130, 133))	('CREB3L2', 'Gene', (134, 141))
270913	25437654	Genomic DNA-based long PCR revealed a gene fusion between the part of intron 6 of FUS and part of exon 5 of CREB3L2.	('gene fusion', 'Var', (38, 49))	('CREB3L2', 'Gene', (108, 115))	('FUS', 'Gene', (82, 85))	('FUS', 'Gene', '2521', (82, 85))	('CREB3L2', 'Gene', '64764', (108, 115))
270915	25437654	Thus, the fusion gene in this case was exon6/int6/exon5 of the FUS-CREB3L2.	('CREB3L2', 'Gene', '64764', (67, 74))	('CREB3L2', 'Gene', (67, 74))	('FUS', 'Gene', (63, 66))	('exon6/int6/exon5', 'Var', (39, 55))	('FUS', 'Gene', '2521', (63, 66))
270930	25437654	Recently, LGFMS was shown to be associated with gene fusions involving CREB3-family genes, which encode members of the basic leucine zipper family of transcription factors.	('gene fusions', 'Var', (48, 60))	('CREB3', 'Gene', (71, 76))	('CREB3', 'Gene', '10488', (71, 76))	('associated', 'Reg', (32, 42))	('LGFMS', 'Gene', (10, 15))
270933	25437654	The present case harbored an exon6/exon5 type FUS-CREB3L2 fusion gene.	('FUS', 'Gene', (46, 49))	('CREB3L2', 'Gene', '64764', (50, 57))	('exon6/exon5 type', 'Var', (29, 45))	('FUS', 'Gene', '2521', (46, 49))	('CREB3L2', 'Gene', (50, 57))
270940	25437654	This work was supported in part by a Grant-in-Aid for General Scientific Research from the  (#26670286 to Tsuyoshi Saito, and #25861342 to Yoshiyuki Suehara), Tokyo, Japan.	('#25861342', 'Var', (126, 135))	('Aid', 'Gene', '57379', (46, 49))	('Aid', 'Gene', (46, 49))	('#26670286', 'Var', (93, 102))
270952	24489895	Furthermore, our isolation of bone marrow-derived cell populations containing a cell type that, when infected with KSHV, renders a tumorigenic KS-like spindle cell, should facilitate systematic identification of KS progenitor cells.	('KS', 'Phenotype', 'HP:0100726', (143, 145))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('KS', 'Phenotype', 'HP:0100726', (212, 214))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('KSHV', 'Species', '37296', (115, 119))	('tumor', 'Disease', (131, 136))	('KS', 'Phenotype', 'HP:0100726', (115, 117))	('infected', 'Var', (101, 109))	('KSHV', 'Gene', (115, 119))
270976	24489895	First, we evaluated whether a recombinant infectious KSHV, rKSHV.219, could replace BAC36 in exactly the same cellular environment to yield tumorigenic cells and whether, in these cells, rKSHV.219 could complete a full replicative cycle.	('rKSHV.219', 'Var', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('replicative cycle', 'CPA', (219, 236))	('KSHV', 'Species', '37296', (53, 57))	('KSHV', 'Species', '37296', (188, 192))	('KSHV', 'Species', '37296', (60, 64))	('KS', 'Phenotype', 'HP:0100726', (53, 55))	('KS', 'Phenotype', 'HP:0100726', (188, 190))	('KS', 'Phenotype', 'HP:0100726', (60, 62))	('tumor', 'Disease', (140, 145))
270993	24489895	Like the mECK36, the mECKnull.rK formed significantly more colonies at 6 weeks than the control and the mECKnull cells (Figure 2A, B) suggesting that the presence of the viral genome conferred a transformed phenotype.	('more', 'PosReg', (54, 58))	('mEC', 'Gene', (9, 12))	('mEC', 'Gene', '56838', (9, 12))	('conferred', 'Reg', (183, 192))	('colonies', 'CPA', (59, 67))	('mEC', 'Gene', '56838', (104, 107))	('transformed phenotype', 'CPA', (195, 216))	('mEC', 'Gene', (21, 24))	('mEC', 'Gene', '56838', (21, 24))	('mEC', 'Gene', (104, 107))	('presence', 'Var', (154, 162))
271048	24489895	Although BAC36 transfection into mEC resulted in a cell population capable of forming KS-like lesions in immunocompromised mice, accompanied by increased lytic gene expression, we were able to neither identify nor recover BAC36 generated virus particles in cell culture, tumor sections or explanted materials.	('mice', 'Species', '10090', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('BAC36', 'Gene', (9, 14))	('rat', 'Species', '10116', (232, 235))	('mEC', 'Gene', (33, 36))	('mEC', 'Gene', '56838', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor', 'Disease', (271, 276))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('lytic gene', 'Gene', (154, 164))	('KS-like lesions', 'Disease', (86, 101))	('increased', 'PosReg', (144, 153))	('transfection', 'Var', (15, 27))
271052	24489895	Regarding the BAC36 system, there are both reports showing the ability to recover BAC36 virions from human cells as well as reports depicting genetic modifications of BAC36 that could compromise its ability to faithfully reproduce KSHV lytic replicative abilities.	('human', 'Species', '9606', (101, 106))	('KSHV', 'Species', '37296', (231, 235))	('BAC36', 'Gene', (82, 87))	('BAC36', 'Gene', (167, 172))	('KS', 'Phenotype', 'HP:0100726', (231, 233))	('genetic modifications', 'Var', (142, 163))
271078	24489895	However, sought to determine if we could recreate a murine KSHV tumorigenesis model from primary cells and de novo infection with the rKSHV.219.	('KSHV', 'Species', '37296', (59, 63))	('tumor', 'Disease', (64, 69))	('KS', 'Phenotype', 'HP:0100726', (59, 61))	('rKSHV.219', 'Var', (134, 143))	('KS', 'Phenotype', 'HP:0100726', (135, 137))	('KSHV', 'Species', '37296', (135, 139))	('infection', 'Disease', (115, 124))	('infection', 'Disease', 'MESH:D007239', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('murine', 'Species', '10090', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
271090	24489895	Importantly, both explanations point to the presence of a KS-like spindle cell progenitor among the bone marrow population that was targeted both by BAC36 transfection and rKSHV.219 infection.	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('infection', 'Disease', (182, 191))	('infection', 'Disease', 'MESH:D007239', (182, 191))	('KS', 'Phenotype', 'HP:0100726', (173, 175))	('transfection', 'Var', (155, 167))	('KSHV', 'Species', '37296', (173, 177))
271133	24489895	GEO accession numbers are as follows: Aortic Endothelial cells (AEC: GSM686077, GSM686078), Bone marrow derived mesenchymal stem cells (BM_MSC: GSM757750), N-Cadherin expressing endothelial cells (EC_NCadh: GSM859433, GSM859434), VE-Cadherin expressing endothelial cells (EC_VECadh: GSM859435, GSM859436), VE+N-Cadherin expressing endothelial cells (EC_VE+NCadh: GSM859437, GSM859438), total bone marrow (BM: GSM821069, GSM821070, GSM821071), undifferentiated embryonic stem cells (undiffESC: GSM839393, GSM839394, GSM839395), fetal liver erythroblasts (FLE: GSM842148, GSM842149, GSM842150), bone marrow-derived macrophages (BM_Macro: GSM787745, GSM787746, GSM787747), peripheral macrophages (Macro: GSM466436, GSM466437, GSM466438), hematopoietic stem cells (HSC: GSM862182, GSM862184), leukemia stem cells (LSC: GSM862186, GSM862188), glomerular endothelial cells (GEC: GSM532931, GSM532932, GSM532933) and subcutaneous tissue (SubQ: GSM905121, GSM905122, GSM905123).	('leukemia', 'Disease', 'MESH:D007938', (789, 797))	('leukemia', 'Disease', (789, 797))	('GSM532933', 'Var', (895, 904))	('EC', 'Gene', '56838', (197, 199))	('EC', 'Gene', '56838', (276, 278))	('N-Cadherin', 'Gene', (309, 319))	('N-Cadherin', 'Gene', '1000', (309, 319))	('GSM905123', 'Var', (959, 968))	('GSM905122', 'Var', (948, 957))	('EC', 'Gene', '56838', (272, 274))	('EC', 'Gene', '56838', (869, 871))	('VE-Cadherin', 'Gene', '1003', (230, 241))	('leukemia', 'Phenotype', 'HP:0001909', (789, 797))	('EC', 'Gene', '56838', (350, 352))	('VE-Cadherin', 'Gene', (230, 241))	('EC', 'Gene', '56838', (65, 67))	('N-Cadherin', 'Gene', (156, 166))	('GSM532932', 'Var', (884, 893))	('N-Cadherin', 'Gene', '1000', (156, 166))
271150	32169218	Genetic inhibition of RA production in tumor cells or pharmacologic inhibition of RA signaling within TME increases stimulatory monocyte-derived cells, enhances T cell-dependent anti-tumor immunity, and synergizes with immune checkpoint blockade.	('enhances', 'PosReg', (152, 160))	('stimulatory monocyte-derived cells', 'MPA', (116, 150))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('inhibition', 'Var', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', (39, 44))	('increases', 'PosReg', (106, 115))	('inhibition', 'Var', (8, 18))	('RA', 'Chemical', 'MESH:D014212', (22, 24))	('RA', 'Chemical', 'MESH:D014212', (82, 84))
271180	32169218	Sarcomas have over 60 subtypes, but based on their underlying genetic aberrations can be broadly divided into: (1) translocations generating fusion oncogenes, (2) mutations in tumor suppressors or oncogenes, and (3) genomic instability without a consistent mutation.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutations', 'Var', (163, 172))	('translocations', 'Var', (115, 129))	('tumor', 'Disease', (176, 181))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('Sarcomas', 'Disease', (0, 8))
271181	32169218	We utilize a representative mouse model for each of these genetic categories: synovial sarcoma (SS) (driven by SYT-SSX fusion oncogene), undifferentiated pleomorphic sarcoma (UPS) (driven by loss of p53 and activation of KRAS), and fibrosarcoma (FS) (syngeneic transplant of sarcoma cell lines derived from methylcolanthrene induced murine fibrosarcomas).	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('p53', 'Gene', '22059', (199, 202))	('KRAS', 'Gene', '16653', (221, 225))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Disease', (166, 173))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (232, 244))	('murine', 'Species', '10090', (333, 339))	('SYT', 'Gene', '268996', (111, 114))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (137, 173))	('sarcoma', 'Disease', 'MESH:D012509', (275, 282))	('sarcoma', 'Disease', (275, 282))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('fibrosarcoma', 'Disease', 'MESH:D005354', (232, 244))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (340, 352))	('fibrosarcomas', 'Disease', 'MESH:D005354', (340, 353))	('undifferentiated pleomorphic sarcoma', 'Disease', (137, 173))	('sarcoma', 'Disease', 'MESH:D012509', (345, 352))	('p53', 'Gene', (199, 202))	('fibrosarcoma', 'Disease', (232, 244))	('synovial sarcoma', 'Disease', (78, 94))	('mouse', 'Species', '10090', (28, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('SYT', 'Gene', (111, 114))	('sarcoma', 'Disease', (345, 352))	('methylcolanthrene', 'Chemical', '-', (307, 324))	('sarcomas', 'Phenotype', 'HP:0100242', (345, 353))	('fibrosarcoma', 'Disease', 'MESH:D005354', (340, 352))	('synovial sarcoma', 'Disease', 'MESH:D013584', (78, 94))	('fibrosarcomas', 'Disease', (340, 353))	('fibrosarcoma', 'Disease', (340, 352))	('KRAS', 'Gene', (221, 225))	('loss', 'Var', (191, 195))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (345, 352))	('sarcoma', 'Disease', (237, 244))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
271235	32169218	Consistent with our observations above, DC differentiation was suppressed in the presence of SNU398.	('DC', 'Gene', '13179', (40, 42))	('SNU398', 'Var', (93, 99))	('suppressed', 'NegReg', (63, 73))	('SNU398', 'Chemical', '-', (93, 99))
271257	32169218	Deletion of Raldh3 resulted in compensatory increase in Raldh1 expression (Figure S4A).	('Raldh1', 'Gene', '11668', (56, 62))	('expression', 'MPA', (63, 73))	('Raldh3', 'Gene', '56847', (12, 18))	('increase', 'PosReg', (44, 52))	('Raldh1', 'Gene', (56, 62))	('Raldh3', 'Gene', (12, 18))	('Deletion', 'Var', (0, 8))
271260	32169218	Notably, a significantly higher fraction of F4/80+ TAMs in DKO tumors were CD11c+ MHCII+ and expressed higher levels of activation markers CD40, CD86, and tumor necrosis factor alpha (TNF-alpha) (Figures 4C, S4F, and S4G).	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('DKO tumors', 'Disease', (59, 69))	('DKO tumors', 'Disease', 'MESH:D009369', (59, 69))	('levels', 'MPA', (110, 116))	('CD11c', 'Gene', '16411', (75, 80))	('F4/80+ TAMs', 'Var', (44, 55))	('tumor necrosis factor alpha', 'Gene', (155, 182))	('TAMs', 'Chemical', '-', (51, 55))	('high', 'Gene', '104137', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('TNF-alpha', 'Gene', (184, 193))	('CD4', 'Gene', (139, 142))	('high', 'Gene', (25, 29))	('CD11c', 'Gene', (75, 80))	('TNF-alpha', 'Gene', '21926', (184, 193))	('high', 'Gene', '104137', (103, 107))	('tumor necrosis factor alpha', 'Gene', '21926', (155, 182))	('MHCII', 'Gene', (82, 87))	('CD86', 'MPA', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CD4', 'Gene', '12504', (139, 142))	('high', 'Gene', (103, 107))	('MHCII', 'Gene', '111364', (82, 87))
271275	32169218	Depletion of either CD4+ or CD8+ T cells allowed for rapid growth of DKO tumors in vivo, demonstrating a role of T cells (Figure 5E).	('CD4', 'Gene', (20, 23))	('DKO tumors', 'Disease', (69, 79))	('CD8+', 'Var', (28, 32))	('DKO tumors', 'Disease', 'MESH:D009369', (69, 79))	('CD4', 'Gene', '12504', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('growth', 'MPA', (59, 65))
271287	32169218	Strikingly, intratumoral BMS493 robustly synergized with systemic alphaPD1 therapy in FS (Figures 6D and S6A).	('tumor', 'Disease', (17, 22))	('BMS493', 'Var', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BMS493', 'Chemical', 'MESH:C542472', (25, 31))
271288	32169218	Of interest, Raldh1 and Raldh3 were significantly upregulated in tumors treated with BMS493, suggesting a potential resistance mechanism whereby tumors upregulate RA production in response to RA signaling blockade (Figure S6B).	('Raldh3', 'Gene', (24, 30))	('upregulate', 'PosReg', (152, 162))	('tumors', 'Disease', (65, 71))	('BMS493', 'Chemical', 'MESH:C542472', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('RA production', 'MPA', (163, 176))	('Raldh1', 'Gene', (13, 19))	('RA', 'Chemical', 'MESH:D014212', (163, 165))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('upregulated', 'PosReg', (50, 61))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('Raldh3', 'Gene', '56847', (24, 30))	('Raldh1', 'Gene', '11668', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RA', 'Chemical', 'MESH:D014212', (192, 194))	('BMS493', 'Var', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))
271294	32169218	Similar to transplantation-based models, BMS493 increased stimulatory myeloid cells and T cells within both types of tumors (Figures 6G, 6H, S6F, and S6G).	('increased', 'PosReg', (48, 57))	('BMS493', 'Chemical', 'MESH:C542472', (41, 47))	('S6F', 'Mutation', 'p.S6F', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('T cells', 'CPA', (88, 95))	('tumors', 'Disease', (117, 123))	('BMS493', 'Var', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('S6G', 'Mutation', 'rs1229353893', (150, 153))	('stimulatory myeloid cells', 'CPA', (58, 83))
271295	32169218	Thus far, we show that reducing RA in TME promotes monocyte differentiation into immunostimulatory APCs and enhances anti-tumor T cell responses.	('APC', 'Disease', 'MESH:D011125', (99, 102))	('RA', 'Chemical', 'MESH:D014212', (32, 34))	('monocyte differentiation', 'CPA', (51, 75))	('APC', 'Disease', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('reducing RA', 'Var', (23, 34))	('enhances', 'PosReg', (108, 116))	('tumor', 'Disease', (122, 127))
271296	32169218	To further examine the link between these two observations, we devised a monocyte-transplant experiment whereby bone marrow monocytes from LysMCre: Rosa26tdT mice were treated ex vivo with DMSO (control) or BMS493 (irreversible RAR blockade), washed, and transplanted into syngeneic FS tumors.	('LysM', 'Gene', '17105', (139, 143))	('BMS493', 'Var', (207, 213))	('FS tumors', 'Disease', 'MESH:D018223', (283, 292))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('mice', 'Species', '10090', (158, 162))	('RAR', 'Gene', '19401', (228, 231))	('FS tumors', 'Disease', (283, 292))	('BMS493', 'Chemical', 'MESH:C542472', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('RAR', 'Gene', (228, 231))	('Rosa26tdT', 'Chemical', '-', (148, 157))	('DMSO', 'Chemical', 'MESH:D004121', (189, 193))	('LysM', 'Gene', (139, 143))
271299	32169218	Concomitantly, tumors transplanted with BMS493-treated monocytes grew at a significantly slower rate and displayed an immunostimulatory TME with evidence of activated APCs and T cells (Figures 6J and 6K).	('grew', 'CPA', (65, 69))	('immunostimulatory TME', 'MPA', (118, 139))	('T cells', 'CPA', (176, 183))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('BMS493-treated', 'Var', (40, 54))	('APC', 'Disease', 'MESH:D011125', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('slower', 'NegReg', (89, 95))	('APC', 'Disease', (167, 170))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('BMS493', 'Chemical', 'MESH:C542472', (40, 46))	('tumors', 'Disease', (15, 21))
271350	32169218	LysMCre mice were obtained from Jackson Laboratories and bred to 1) Rosa26LSL-tdT 2) Irf4flox or 3) Rosa26Cas9-eGFP mice.	('mice', 'Species', '10090', (116, 120))	('tdT', 'Gene', '21673', (78, 81))	('LysM', 'Gene', (0, 4))	('LysM', 'Gene', '17105', (0, 4))	('Rosa26Cas9-eGFP', 'Var', (100, 115))	('mice', 'Species', '10090', (8, 12))	('tdT', 'Gene', (78, 81))
271379	32169218	Single cell suspensions generated from mouse tumors were incubated for 4 hours at 37 C with PMA (50ng/mL; Sigma), Ionomycin (750ng/mL; Sigma) and GolgiStop (5ug/mL; BD).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('PMA', 'Chemical', '-', (92, 95))	('750ng/mL', 'Var', (125, 133))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Ionomycin', 'Chemical', 'MESH:D015759', (114, 123))	('mouse', 'Species', '10090', (39, 44))
271395	32169218	Normal donor human monocytes (obtained the Human Immunology Core at the University of Pennsylvania were cultured with GM-CSF (50ng/mL) & IL-4 (50ng/mL), or M-CSF (50ng/mL).	('human', 'Species', '9606', (13, 18))	('Pen', 'Gene', '30052', (86, 89))	('50ng/mL', 'Var', (126, 133))	('IL-4', 'Var', (137, 141))	('Pen', 'Gene', (86, 89))	('Human', 'Species', '9606', (43, 48))
271412	32169218	Arg1 (Mm00475988_m1), Hprt (Mm03024075_m1), Tnfa (Mm00443258_m1), Il1b (Mm00434228_m1), Cd40 (Mm00441891_m1), Cd80 (Mm00441891_m1), Cd86 (Mm00444543_m1), Raldh1 (Mm00657317_m1), Raldh2 (Mm00501306_m1), Raldh3 (Mm00474049_m1), Irf4 (Mm00516431_m1), Zbtb46 (Mm00511327_m1), Raldh1 (Hs00946916_m1), Raldh2 (Hs00180254_m1), Raldh3 (Hs00167476_m1), Irf4 (Hs01056533_m1), Zbtb46 (Hs01008168_m1), Hprt (Cat #4333768).	('Raldh2', 'Gene', '19378', (178, 184))	('Arg1', 'Gene', '11846', (0, 4))	('Cat', 'Gene', '12359', (396, 399))	('Raldh2', 'Gene', '19378', (296, 302))	('Zbtb46', 'Gene', (248, 254))	('Hs00180254_m1', 'Var', (304, 317))	('Hs00946916_m1', 'Var', (280, 293))	('Mm00511327_m1', 'Var', (256, 269))	('Il1b', 'Gene', (66, 70))	('Hs01056533_m1', 'Var', (350, 363))	('Mm00516431_m1', 'Var', (232, 245))	('Hprt', 'Gene', '15452', (390, 394))	('Hprt', 'Gene', (390, 394))	('Mm00444543_m1', 'Var', (138, 151))	('Tnfa', 'Gene', (44, 48))	('Raldh2', 'Gene', (178, 184))	('Il1b', 'Gene', '16176', (66, 70))	('Mm00474049_m1', 'Var', (210, 223))	('Arg1', 'Gene', (0, 4))	('Zbtb46', 'Gene', '72147', (366, 372))	('Raldh2', 'Gene', (296, 302))	('Raldh3', 'Gene', '56847', (202, 208))	('Mm00434228_m1', 'Var', (72, 85))	('Zbtb46', 'Gene', '72147', (248, 254))	('Raldh1', 'Gene', (154, 160))	('Raldh3', 'Gene', '56847', (320, 326))	('Raldh1', 'Gene', (272, 278))	('Tnfa', 'Gene', '21926', (44, 48))	('Hs01008168_m1', 'Var', (374, 387))	('Mm00657317_m1', 'Var', (162, 175))	('Cat', 'Gene', (396, 399))	('Mm00501306_m1', 'Var', (186, 199))	('Raldh3', 'Gene', (202, 208))	('Hprt', 'Gene', '15452', (22, 26))	('Hprt', 'Gene', (22, 26))	('Raldh3', 'Gene', (320, 326))	('Hs00167476_m1', 'Var', (328, 341))	('Raldh1', 'Gene', '11668', (154, 160))	('Raldh1', 'Gene', '11668', (272, 278))	('Zbtb46', 'Gene', (366, 372))
271440	24848257	Signaling of PD1 on T cells via PD-L1 (B7-H1) or PD-L2 (B7-DC) inhibits T cell receptor-mediated activation by recruitment of the SHP2 phosphatase.	('B7-DC', 'Gene', '58205', (56, 61))	('B7-DC', 'Gene', (56, 61))	('recruitment', 'MPA', (111, 122))	('PD-L1', 'Var', (32, 37))	('inhibits', 'NegReg', (63, 71))	('PD-L2', 'Var', (49, 54))	('SHP2', 'Gene', '19247', (130, 134))	('SHP2', 'Gene', (130, 134))
271443	24848257	Early evidence for a role for the PD1/PD-L1 axis in tumor immune escape comes from clinical trials of anti-PD1 and PD-L1 monoclonal antibody (mAb) therapy involving more than 500 patients with advanced cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (52, 57))	('anti-PD1', 'Var', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('PD-L1', 'Gene', (115, 120))
271445	24848257	Thus, although PD1 signaling on T cells is one important mechanism used by tumors to escape antitumor immune responses, interruption of this axis alone induces meaningful antitumor effects in only a minority of cases, suggesting that other mechanisms also contribute to immune evasion.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('interruption', 'Var', (120, 132))	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('contribute', 'Reg', (256, 266))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', (75, 80))	('immune evasion', 'MPA', (270, 284))
271451	24848257	We find that MDSC-mediated suppression of antitumor immunity is a local phenomena limited to the tumor bed because inhibition of MDSC trafficking to the tumor enhances the potency of PD1 checkpoint blockade.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (46, 51))	('PD1 checkpoint blockade', 'MPA', (183, 206))	('potency', 'MPA', (172, 179))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('inhibition', 'Var', (115, 125))	('enhances', 'PosReg', (159, 167))	('MDSC', 'Gene', (129, 133))	('suppression', 'NegReg', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
271456	24848257	1C, left panel), leading us to postulate that tumor-induced PD1 signaling on T cells contributes to immune escape in M3-9-M RMS.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RMS', 'Phenotype', 'HP:0002859', (124, 127))	('M3-9-M RMS', 'Var', (117, 127))	('tumor', 'Disease', (46, 51))	('immune escape', 'MPA', (100, 113))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
271462	24848257	Although delayed treatment did not lead to tumor regression, M3-9-M-bearing mice treated with delayed anti-PD1 demonstrated significantly more interferon-gamma-positive (IFN-gamma+) and tumor necrosis factor-alpha-positive (TNF-alpha+) CD8+ T cells in the spleen (Fig.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('CD8', 'Gene', '925', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('anti-PD1', 'Var', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('CD8', 'Gene', (236, 239))	('tumor', 'Disease', (186, 191))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('more', 'PosReg', (138, 142))	('IFN-gamma+) and tumor necrosis factor-alpha', 'Gene', '15978;21926', (170, 213))	('TNF-alpha+', 'Gene', (224, 234))	('tumor', 'Disease', (43, 48))	('TNF-alpha+', 'Gene', '21926', (224, 234))
271465	24848257	The antitumor effects observed were absolutely dependent on host T cells because administration of anti-PD1 to RAG-/- mice lacking T cells resulted in no difference in tumor growth (fig.	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('anti-PD1', 'Var', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mice', 'Species', '10090', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
271469	24848257	2A), and we found that a substantial component of the antitumor effects observed was due to the capacity for PD1 blockade to augment immunity toward HY-associated antigens.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('blockade', 'Var', (113, 121))	('PD1', 'Protein', (109, 112))	('augment', 'PosReg', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('immunity toward HY-associated antigens', 'MPA', (133, 171))
271470	24848257	In addition, splenic T cells taken from M3-9-M tumor-bearing mice demonstrated low levels of immune reactivity to immunodominant class I- and class II-restricted HY antigens, which was substantially increased after treatment with anti-PD1 (Fig.	('immune reactivity', 'MPA', (93, 110))	('mice', 'Species', '10090', (61, 65))	('anti-PD1', 'Var', (230, 238))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('increased', 'PosReg', (199, 208))	('tumor', 'Disease', (47, 52))
271471	24848257	This effect is not due to a nonspecific enhancement of T cell responsiveness in anti-PD1-treated mice because tumor-free mice and mice bearing 76-9 tumors, which do not express HY, did not show significant increases in HY-specific IFN-gamma production after anti-PD1 therapy (Fig.	('mice', 'Species', '10090', (130, 134))	('IFN-gamma', 'Gene', '15978', (231, 240))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('IFN-gamma', 'Gene', (231, 240))	('mice', 'Species', '10090', (97, 101))	('mice', 'Species', '10090', (121, 125))	('anti-PD1', 'Var', (258, 266))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
271473	24848257	Together, these data identify PD1 signaling in T cells as one mechanism used by RMS to evade immune responses, and illustrate that the efficacy of anti-PD1 treatment is significantly reduced with increasing tumor burden, raising the prospect that other mechanisms of immune escape contribute to tumor growth in this model.	('anti-PD1', 'Var', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('reduced', 'NegReg', (183, 190))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (207, 212))	('RMS', 'Phenotype', 'HP:0002859', (80, 83))	('tumor', 'Disease', (295, 300))
271492	24848257	To do this, we sorted CD11b+Ly6Ghi cells from the tumors of M3-9-M-bearing animals and measured inhibition of T cell proliferation after addition of nor-NOHA (Nw-hydroxy-nor-arginine) (arginase inhibitor) or l-NMMA (l-NG-monomethyl-arginine-citrate) (iNOS inhibitor).	('l-NMMA', 'Chemical', 'MESH:C417052', (208, 214))	('nor-NOHA', 'Chemical', 'MESH:C473306', (149, 157))	('l-NMMA', 'Var', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('Nw-hydroxy-nor-arginine', 'Chemical', 'MESH:D001127', (159, 182))	('l-NG-monomethyl-arginine-citrate', 'Chemical', 'MESH:C102006', (216, 248))	('Ly6G', 'Gene', '546644', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('inhibition', 'NegReg', (96, 106))	('T cell proliferation', 'CPA', (110, 130))	('Ly6G', 'Gene', (28, 32))
271493	24848257	Both inhibitors significantly reduced CD4+ and CD8+ T cell suppression, though inhibition of arginase-1 (nor-NOHA) led to a larger decrease in suppressive potential (Fig.	('CD4', 'Gene', (38, 41))	('CD8', 'Gene', (47, 50))	('arginase-1', 'Protein', (93, 103))	('nor-NOHA', 'Chemical', 'MESH:C473306', (105, 113))	('CD8', 'Gene', '925', (47, 50))	('CD4', 'Gene', '12504', (38, 41))	('inhibition', 'Var', (79, 89))	('reduced', 'NegReg', (30, 37))	('decrease', 'NegReg', (131, 139))	('suppressive potential', 'MPA', (143, 164))
271500	24848257	We tested whether RMS tumors produce and secrete ligands for CXCR2 and found that both M3-9-M and 76-9 RMS expressed message for CXCL1 and CXCL2 (Fig.	('M3-9-M', 'Var', (87, 93))	('RMS tumors', 'Disease', (18, 28))	('CXCL2', 'MPA', (139, 144))	('RMS', 'Phenotype', 'HP:0002859', (18, 21))	('RMS tumors', 'Disease', 'MESH:D009369', (18, 28))	('RMS', 'Phenotype', 'HP:0002859', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
271513	24848257	S7C) animals with CXCR2-/- marrow showed significant increases in percentage and absolute numbers of CD11b+Ly6Ghi cells compared to wild-type mice with the same tumors, presumably as a result of diminishing trafficking into other tissues.	('Ly6G', 'Gene', (107, 111))	('diminishing', 'NegReg', (195, 206))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('mice', 'Species', '10090', (142, 146))	('Ly6G', 'Gene', '546644', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('increases', 'PosReg', (53, 62))	('CXCR2-/- marrow', 'Var', (18, 33))
271516	24848257	We observed a modest decrease in M3-9-M and 76-9 tumor growth rate in recipients of CXCR2-/- marrow compared to recipients of wild-type marrow (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('76-9', 'MPA', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('decrease', 'NegReg', (21, 29))	('CXCR2-/- marrow', 'Var', (84, 99))	('M3-9-M', 'MPA', (33, 39))	('tumor', 'Disease', (49, 54))
271518	24848257	We did not observe significant reductions in angiogenesis between tumors with CXCR2-/- MDSCs compared with controls, which led us to conclude that the diminished tumor growth observed was not primarily due to antiangiogenic effects (fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (162, 167))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('CXCR2-/- MDSCs', 'Var', (78, 92))	('diminished', 'NegReg', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
271527	24848257	To explore whether supranormal CXCL8 levels correlated with diminished overall survival in this population, an actuarial analysis was performed.	('diminished', 'NegReg', (60, 70))	('CXCL8', 'Gene', '3576', (31, 36))	('CXCL8', 'Gene', (31, 36))	('supranormal', 'Var', (19, 30))	('overall survival', 'MPA', (71, 87))
271534	24848257	In contrast, mice reconstituted with CXCR2-/- hematopoietic cells and then treated with anti-PD1 experienced significant reductions in tumor growth (Fig.	('anti-PD1', 'Var', (88, 96))	('mice', 'Species', '10090', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('reductions', 'NegReg', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
271535	24848257	Kaplan-Meier survival analysis in M3-9-M-bearing mice shows a modest but significant difference in median survival between wild type and wild type + anti-PD1 (median survival of 42.5 days versus 53 days, respectively), whereas mice with CXCR2-/- marrow experienced a much larger increase in median survival after anti-PD1 therapy (P < 0.001; median survival of 57 days versus undefined) (Fig.	('median', 'MPA', (291, 297))	('anti-PD1', 'Var', (149, 157))	('mice', 'Species', '10090', (227, 231))	('mice', 'Species', '10090', (49, 53))
271537	24848257	Consistent with our results demonstrating that anti-PD1 mediates its effects in this model by augmenting T cell-mediated antitumor immunity, we observed increases in tumor-infiltrating CD8+ T cells after anti-PD1 therapy (Fig.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('augmenting', 'PosReg', (94, 104))	('anti-PD1', 'Var', (47, 55))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (125, 130))	('increases', 'PosReg', (153, 162))	('CD8', 'Gene', (185, 188))	('CD8', 'Gene', '925', (185, 188))	('anti-PD1', 'Var', (204, 212))
271540	24848257	7D), which resulted in an increased IFN-g concentration within the serum of CXCR2-/- mice that were treated with anti-PD1 (Fig.	('mice', 'Species', '10090', (85, 89))	('anti-PD1', 'Var', (113, 121))	('IFN-g', 'Gene', '15978', (36, 41))	('increased', 'PosReg', (26, 35))	('IFN-g', 'Gene', (36, 41))
271547	24848257	8D) on day 15 demonstrated that anti-CXCR2 induced significant reductions in CD11b+Ly6Ghi cells when compared to nontreated controls.	('reductions', 'NegReg', (63, 73))	('Ly6G', 'Gene', (83, 87))	('anti-CXCR2', 'Var', (32, 42))	('Ly6G', 'Gene', '546644', (83, 87))
271549	24848257	We conclude that anti-CXCR2 likely diminishes tumor bed-associated GrMDSCs by modulating tumor trafficking rather than by inducing depletion.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('anti-CXCR2', 'Var', (17, 27))	('tumor', 'Disease', (46, 51))	('diminishes', 'NegReg', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('modulating', 'Reg', (78, 88))
271553	24848257	Antibodies that block CTLA4 signaling prolong survival in patients with metastatic malignant melanoma, and antibodies that block PD1 signaling or PD-L1 binding to PD1 mediate objective antitumor responses in patients with melanoma, non-small cell lung cancer, and renal cell carcinoma.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (232, 258))	('Antibodies', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('survival', 'CPA', (46, 54))	('CTLA4', 'Gene', '1493', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (264, 284))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('non-small cell lung cancer', 'Disease', (232, 258))	('malignant melanoma', 'Disease', (83, 101))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('PD1', 'MPA', (129, 132))	('renal cell carcinoma', 'Disease', (264, 284))	('CTLA4', 'Gene', (22, 27))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (264, 284))	('binding', 'Interaction', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('patients', 'Species', '9606', (58, 66))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (232, 258))	('prolong', 'PosReg', (38, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('tumor', 'Disease', (189, 194))	('patients', 'Species', '9606', (208, 216))	('malignant melanoma', 'Phenotype', 'HP:0002861', (83, 101))	('malignant melanoma', 'Disease', 'MESH:D008545', (83, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (236, 258))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
271557	24848257	Tumor development is completely inhibited when animals are treated with anti-PD1 at the time of tumor inoculation, but anti-PD1 has only weak effects on established tumors, regardless of whether they are immunogenic, as is the case with M3-9-M, which expresses a minor histocompatibility antigen.	('anti-PD1', 'Var', (119, 127))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inhibited', 'NegReg', (32, 41))	('tumors', 'Disease', (165, 171))	('Tumor development', 'CPA', (0, 17))	('tumor inoculation', 'Disease', 'MESH:D002372', (96, 113))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor inoculation', 'Disease', (96, 113))
271559	24848257	Expansion of MDSCs is a major mechanism used by cancers to escape immune surveillance.	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('MDSCs', 'Gene', (13, 18))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('Expansion', 'Var', (0, 9))
271582	24848257	In murine hepatocellular carcinoma, a direct correlation between increases in hepatic CXCL1 and MDSC frequency was observed, and splenic MDSC accumulation was significantly reduced with anti-CXCL1 therapy.	('hepatic CXCL1', 'MPA', (78, 91))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (10, 34))	('anti-CXCL1', 'Var', (186, 196))	('hepatocellular carcinoma', 'Disease', (10, 34))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (10, 34))	('increases', 'PosReg', (65, 74))	('reduced', 'NegReg', (173, 180))	('splenic MDSC accumulation', 'Disease', (129, 154))	('MDSC frequency', 'MPA', (96, 110))	('murine', 'Species', '10090', (3, 9))	('splenic MDSC accumulation', 'Disease', 'MESH:D013158', (129, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
271584	24848257	recently showed that deletion of CXCR2 in a mouse model of colitis-associated tumorigenesis reduced the number of GrMDSCs within the tumor, which had a marked effect on T cell function.	('colitis', 'Disease', (59, 66))	('colitis', 'Disease', 'MESH:D003092', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('GrMDSCs within the tumor', 'Disease', 'MESH:D009369', (114, 138))	('colitis', 'Phenotype', 'HP:0002583', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('deletion', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (133, 138))	('reduced', 'NegReg', (92, 99))	('tumor', 'Disease', (78, 83))	('CXCR2', 'Gene', (33, 38))	('mouse', 'Species', '10090', (44, 49))	('GrMDSCs within the tumor', 'Disease', (114, 138))
271605	24848257	Others have sought to modulate the suppressive capabilities of MDSCs using pharmacological inhibitors such as l-NMMA (a specific iNOS inhibitor), which led to a reversal of T cell dysfunction; however l-NMMA is toxic in humans and associated with myocardial depression and significantly increased mortality.	('myocardial depression', 'Disease', 'MESH:D003866', (247, 268))	('depression', 'Phenotype', 'HP:0000716', (258, 268))	('l-NMMA', 'Var', (201, 207))	('humans', 'Species', '9606', (220, 226))	('mortality', 'Disease', (297, 306))	('T cell dysfunction', 'Phenotype', 'HP:0005435', (173, 191))	('increased', 'PosReg', (287, 296))	('T cell dysfunction', 'Disease', (173, 191))	('associated with', 'Reg', (231, 246))	('l-NMMA', 'Chemical', 'MESH:C417052', (110, 116))	('myocardial depression', 'Disease', (247, 268))	('T cell dysfunction', 'Disease', 'MESH:D004194', (173, 191))	('l-NMMA', 'Chemical', 'MESH:C417052', (201, 207))
271718	31231465	Recent studies have focused on epigenetic misregulation in Ewing sarcoma development and potential new oncotargets for treatment.	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('Ewing sarcoma', 'Disease', (59, 72))	('epigenetic misregulation', 'Var', (31, 55))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))
271723	31231465	Genetic depletion (shRNA) of LSD2 significantly impaired oncogenic transformation with only a modest impact on proliferation.	('impaired', 'NegReg', (48, 56))	('oncogenic transformation', 'CPA', (57, 81))	('LSD2', 'Gene', '221656', (29, 33))	('Genetic depletion', 'Var', (0, 17))	('LSD2', 'Gene', (29, 33))
271725	31231465	Gene set enrichment analysis showed that SP-2509 does not impact LSD2 targeted genes.	('LSD2', 'Gene', (65, 69))	('LSD2', 'Gene', '221656', (65, 69))	('SP-2509', 'Chemical', 'MESH:C000594309', (41, 48))	('SP-2509', 'Var', (41, 48))
271729	31231465	85% of all translocations in Ewing sarcoma consist of the reciprocal chromosomal translocation (11;22) (q24;q12), which encodes EWS/FLI, the distinguishing oncogenic driver required for Ewing sarcomagenesis.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (186, 199))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (29, 42))	('EWS', 'Gene', '2130', (128, 131))	('EWS', 'Gene', (128, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (29, 42))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (186, 199))	('Ewing sarcomagenesis', 'Phenotype', 'HP:0012254', (186, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('Ewing sarcomagenesis', 'Disease', (186, 206))	('FLI', 'Gene', '2314', (132, 135))	('FLI', 'Gene', (132, 135))	('Ewing sarcoma', 'Disease', (29, 42))	('Ewing sarcomagenesis', 'Disease', 'MESH:C563168', (186, 206))	('translocations', 'Var', (11, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
271738	31231465	The critical role of LSD1 in epigenetic regulation has encouraged the development of several targeted small molecule agents including GSK2879552, INCB059872, IMG-7289, and ORY-2001.	('GSK2879552', 'Var', (134, 144))	('LSD1', 'Gene', '23028', (21, 25))	('LSD1', 'Gene', (21, 25))
271741	31231465	Genetic depletion (shRNA) of LSD2 significantly reduced the efficacy of SP-2509 only in Ewing sarcoma cells highly sensitive to the drug, implying that LSD2 influences SP-2509 cytotoxicity.	('LSD2', 'Gene', '221656', (152, 156))	('influences', 'Reg', (157, 167))	('cytotoxicity', 'Disease', 'MESH:D064420', (176, 188))	('LSD2', 'Gene', '221656', (29, 33))	('efficacy', 'MPA', (60, 68))	('reduced', 'NegReg', (48, 55))	('SP-2509', 'Chemical', 'MESH:C000594309', (168, 175))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('SP-2509', 'Chemical', 'MESH:C000594309', (72, 79))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('Genetic depletion', 'Var', (0, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('LSD2', 'Gene', (152, 156))	('cytotoxicity', 'Disease', (176, 188))	('Ewing sarcoma', 'Disease', (88, 101))	('LSD2', 'Gene', (29, 33))
271742	31231465	These data suggest that SP-2509 affects both LSD1 and LSD2.	('affects', 'Reg', (32, 39))	('LSD1', 'Gene', '23028', (45, 49))	('SP-2509', 'Chemical', 'MESH:C000594309', (24, 31))	('LSD2', 'Gene', '221656', (54, 58))	('LSD2', 'Gene', (54, 58))	('LSD1', 'Gene', (45, 49))	('SP-2509', 'Var', (24, 31))
271762	31231465	We utilized RNA sequencing and pathway analysis to characterize genes regulated by LSD2, and used gene set enrichment analysis to study how drug treatment with SP-2509 impacts LSD2 gene regulation.	('LSD2', 'Gene', '221656', (176, 180))	('SP-2509', 'Var', (160, 167))	('gene regulation', 'MPA', (181, 196))	('LSD2', 'Gene', (83, 87))	('impacts', 'Reg', (168, 175))	('LSD2', 'Gene', (176, 180))	('SP-2509', 'Chemical', 'MESH:C000594309', (160, 167))	('LSD2', 'Gene', '221656', (83, 87))
271763	31231465	We hypothesized that LSD2 is an epigenetic enzyme critical for cell proliferation and oncogenic transformation of Ewing sarcoma cells, and predicted that SP-2509 inhibits not only LSD1, but also LSD2.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('SP-2509', 'Chemical', 'MESH:C000594309', (154, 161))	('LSD2', 'Gene', (195, 199))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (114, 127))	('LSD2', 'Gene', (21, 25))	('LSD1', 'Gene', (180, 184))	('inhibits', 'NegReg', (162, 170))	('SP-2509', 'Var', (154, 161))	('LSD1', 'Gene', '23028', (180, 184))	('LSD2', 'Gene', '221656', (21, 25))	('Ewing sarcoma', 'Disease', (114, 127))	('LSD2', 'Gene', '221656', (195, 199))
271774	31231465	LSD1 mRNA expression was not significantly affected by LSD2 knockdown in the two cell lines (<25% change) (Figure 2C-2D).	('LSD1', 'Gene', '23028', (0, 4))	('mRNA expression', 'MPA', (5, 20))	('LSD2', 'Gene', (55, 59))	('knockdown', 'Var', (60, 69))	('LSD1', 'Gene', (0, 4))	('LSD2', 'Gene', '221656', (55, 59))
271778	31231465	LSD1 protein expression was minimally impacted by endogenous knockdown of LSD2 in the two cell lines (<25 % change) (Figure 3C-3F).	('LSD1', 'Gene', '23028', (0, 4))	('knockdown', 'Var', (61, 70))	('LSD2', 'Gene', '221656', (74, 78))	('protein', 'Protein', (5, 12))	('LSD1', 'Gene', (0, 4))	('LSD2', 'Gene', (74, 78))
271779	31231465	To elucidate whether LSD2 is required for Ewing sarcoma cell proliferation, live cell IncuCyte imaging of cells following LSD2 knockdown was performed.	('LSD2', 'Gene', (122, 126))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (42, 55))	('LSD2', 'Gene', (21, 25))	('Ewing sarcoma', 'Disease', (42, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('LSD2', 'Gene', '221656', (122, 126))	('LSD2', 'Gene', '221656', (21, 25))	('knockdown', 'Var', (127, 136))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (42, 55))
271783	31231465	The reason for the discrepancy between the data for the two shRNA is unclear but may be because of the following: 1) a specific fold decrease in LSD2 knockdown may be required to significantly impact proliferation; 2) the two shRNAs target the 3'UTR region of LSD2 at different locations and may have different off target effects; 3) they may impact various LSD2 isoforms differently, which may affect proliferation.	('impact', 'Reg', (193, 199))	('LSD2', 'Gene', (260, 264))	('proliferation', 'MPA', (402, 415))	('decrease', 'NegReg', (133, 141))	('LSD2', 'Gene', '221656', (358, 362))	('LSD2', 'Gene', '221656', (145, 149))	('proliferation', 'CPA', (200, 213))	('impact', 'Reg', (343, 349))	('knockdown', 'Var', (150, 159))	('LSD2', 'Gene', (358, 362))	('LSD2', 'Gene', '221656', (260, 264))	('LSD2', 'Gene', (145, 149))	('affect', 'Reg', (395, 401))
271785	31231465	Our results suggest that knockdown of LSD2 with iLSD2-3a did modestly impact proliferation, while knockdown with the second hairpin did not.	('LSD2', 'Gene', '221656', (49, 53))	('LSD2', 'Gene', (49, 53))	('LSD2', 'Gene', (38, 42))	('LSD2', 'Gene', '221656', (38, 42))	('impact', 'Reg', (70, 76))	('knockdown', 'Var', (25, 34))	('proliferation', 'CPA', (77, 90))
271786	31231465	Following successful knockdown of LSD2, we assessed whether depletion of LSD2 has any impact on oncogenic transformation using soft agar assays to measure anchorage-independent growth.	('LSD2', 'Gene', '221656', (73, 77))	('LSD2', 'Gene', (34, 38))	('oncogenic transformation', 'CPA', (96, 120))	('LSD2', 'Gene', (73, 77))	('agar', 'Chemical', 'MESH:D000362', (132, 136))	('depletion', 'MPA', (60, 69))	('knockdown', 'Var', (21, 30))	('LSD2', 'Gene', '221656', (34, 38))
271787	31231465	A significant 5.5- and 4.3-fold reduction in A673 colony number was noted after knockdown using iLSD2-3a and -7a, respectively, as compared to iLuc control (Figure 5A-5B).	('knockdown', 'Var', (80, 89))	('LSD2', 'Gene', '221656', (97, 101))	('A673 colony number', 'CPA', (45, 63))	('reduction', 'NegReg', (32, 41))	('LSD2', 'Gene', (97, 101))
271788	31231465	Similarly, for TC32 cells, a 5.8- and 7.5-fold reduction in TC32 colony number was noted after knockdown with iLSD2-3a and -7a, respectively (Figure 5C-5D).	('TC32 colony number', 'CPA', (60, 78))	('LSD2', 'Gene', '221656', (111, 115))	('reduction', 'NegReg', (47, 56))	('TC32', 'CellLine', 'CVCL:7151', (15, 19))	('TC32', 'CellLine', 'CVCL:7151', (60, 64))	('knockdown', 'Var', (95, 104))	('LSD2', 'Gene', (111, 115))
271792	31231465	For clarity, genes upregulated by knockdown of LSD2 will be referred to as "LSD2-downregulated" and genes downregulated after LSD2 knockdown will be referred to as "LSD2-upregulated".	('LSD2', 'Gene', (47, 51))	('upregulated', 'PosReg', (19, 30))	('LSD2', 'Gene', '221656', (76, 80))	('downregulated', 'NegReg', (106, 119))	('LSD2', 'Gene', (126, 130))	('LSD2', 'Gene', (165, 169))	('LSD2', 'Gene', '221656', (47, 51))	('LSD2', 'Gene', '221656', (165, 169))	('LSD2', 'Gene', (76, 80))	('knockdown', 'Var', (34, 43))	('LSD2', 'Gene', '221656', (126, 130))
271793	31231465	Using a significance cut off of >=1.5 fold change, knockdown of endogenous LSD2 with iLSD2-3a identified 624 LSD2-downregulated genes and 1051 LSD2-upregulated genes (Figure 6A-6B).	('LSD2', 'Gene', (143, 147))	('LSD2', 'Gene', '221656', (86, 90))	('LSD2', 'Gene', (75, 79))	('LSD2', 'Gene', '221656', (109, 113))	('LSD2', 'Gene', '221656', (75, 79))	('LSD2', 'Gene', (86, 90))	('LSD2', 'Gene', '221656', (143, 147))	('LSD2', 'Gene', (109, 113))	('knockdown', 'Var', (51, 60))
271809	31231465	The small molecule SP-2509 has been shown to globally disrupt EWS/FLI-mediated gene regulation via inhibition of LSD1 function.	('SP-2509', 'Var', (19, 26))	('FLI', 'Gene', '2314', (66, 69))	('inhibition', 'NegReg', (99, 109))	('LSD1', 'Gene', (113, 117))	('function', 'MPA', (118, 126))	('FLI', 'Gene', (66, 69))	('disrupt', 'NegReg', (54, 61))	('SP-2509', 'Chemical', 'MESH:C000594309', (19, 26))	('EWS', 'Gene', '2130', (62, 65))	('EWS', 'Gene', (62, 65))	('LSD1', 'Gene', '23028', (113, 117))
271810	31231465	Additionally, LSD2 expression impacts SP-2509 drug cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))	('impacts', 'Reg', (30, 37))	('expression', 'Var', (19, 29))	('SP-2509', 'Chemical', 'MESH:C000594309', (38, 45))	('LSD2', 'Gene', (14, 18))	('cytotoxicity', 'Disease', (51, 63))	('LSD2', 'Gene', '221656', (14, 18))
271814	31231465	In contrast, these data suggested that SP-2509 does not interfere with LSD2 activity at these targets, as drug treatment with SP-2509 does not inhibit LSD2-activated genes.	('LSD2', 'Gene', (151, 155))	('SP-2509', 'Chemical', 'MESH:C000594309', (126, 133))	('LSD2', 'Gene', '221656', (71, 75))	('SP-2509', 'Var', (126, 133))	('LSD2', 'Gene', '221656', (151, 155))	('SP-2509', 'Chemical', 'MESH:C000594309', (39, 46))	('LSD2', 'Gene', (71, 75))
271818	31231465	However, while induction of LSD2 mRNA was previously shown to correlate with sensitivity to SP-2509, SP-2509 does not significantly impact LSD2's role as a transcriptional regulator in Ewing sarcoma.	('LSD2', 'Gene', '221656', (28, 32))	('SP-2509', 'Chemical', 'MESH:C000594309', (92, 99))	('LSD2', 'Gene', '221656', (139, 143))	('SP-2509', 'Var', (101, 108))	('LSD2', 'Gene', (28, 32))	('Ewing sarcoma', 'Disease', (185, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('SP-2509', 'Chemical', 'MESH:C000594309', (101, 108))	('LSD2', 'Gene', (139, 143))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (185, 198))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (185, 198))
271819	31231465	Understanding the epigenetic misregulation of Ewing sarcoma is crucial for the development of novel therapies.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (46, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('epigenetic misregulation', 'Var', (18, 42))	('Ewing sarcoma', 'Disease', (46, 59))
271822	31231465	We previously showed that reversible LSD1 inhibition with SP-2509 leads to the induction of apoptosis and disruption of the EWS/FLI transcriptional signature.	('EWS', 'Gene', '2130', (124, 127))	('EWS', 'Gene', (124, 127))	('apoptosis', 'CPA', (92, 101))	('SP-2509', 'Chemical', 'MESH:C000594309', (58, 65))	('inhibition', 'NegReg', (42, 52))	('FLI', 'Gene', '2314', (128, 131))	('LSD1', 'Gene', (37, 41))	('SP-2509', 'Var', (58, 65))	('LSD1', 'Gene', '23028', (37, 41))	('FLI', 'Gene', (128, 131))	('disruption', 'NegReg', (106, 116))
271823	31231465	Furthermore, we also showed that LSD1 inhibition with SP-2509 decreases Ewing sarcoma cell viability through the engagement of the endoplasmic reticulum stress response.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('SP-2509', 'Var', (54, 61))	('decreases Ewing sarcoma', 'Disease', 'MESH:C563168', (62, 85))	('LSD1', 'Gene', (33, 37))	('LSD1', 'Gene', '23028', (33, 37))	('inhibition', 'NegReg', (38, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('decreases Ewing sarcoma', 'Disease', (62, 85))	('SP-2509', 'Chemical', 'MESH:C000594309', (54, 61))
271824	31231465	Interestingly, knockdown of LSD2 expression led to decreased SP-2509 cytotoxicity in A673 cells, suggesting that the drug may impact LSD2 expression and/or function.	('LSD2', 'Gene', '221656', (28, 32))	('SP-2509', 'Chemical', 'MESH:C000594309', (61, 68))	('cytotoxicity', 'Disease', 'MESH:D064420', (69, 81))	('knockdown', 'Var', (15, 24))	('function', 'MPA', (156, 164))	('LSD2', 'Gene', (28, 32))	('decreased', 'NegReg', (51, 60))	('impact', 'Reg', (126, 132))	('LSD2', 'Gene', '221656', (133, 137))	('expression', 'MPA', (138, 148))	('cytotoxicity', 'Disease', (69, 81))	('LSD2', 'Gene', (133, 137))
271826	31231465	Based on the previous research, we hypothesized that SP-2509 inhibits LSD1 and LSD2 and that LSD2 mediates SP-2509 drug toxicity.	('drug toxicity', 'Disease', 'MESH:D064420', (115, 128))	('SP-2509', 'Var', (107, 114))	('LSD2', 'Gene', '221656', (93, 97))	('SP-2509', 'Var', (53, 60))	('LSD1', 'Gene', (70, 74))	('LSD1', 'Gene', '23028', (70, 74))	('LSD2', 'Gene', (79, 83))	('LSD2', 'Gene', (93, 97))	('SP-2509', 'Chemical', 'MESH:C000594309', (107, 114))	('LSD2', 'Gene', '221656', (79, 83))	('drug toxicity', 'Disease', (115, 128))	('SP-2509', 'Chemical', 'MESH:C000594309', (53, 60))	('inhibits', 'NegReg', (61, 69))
271827	31231465	Surprisingly however, our RNA seq and GSEA results implied that SP-2509 does not significantly impact the function of LSD2 as a transcriptional regulator in Ewing sarcoma.	('GSEA', 'Chemical', '-', (38, 42))	('SP-2509', 'Chemical', 'MESH:C000594309', (64, 71))	('Ewing sarcoma', 'Disease', (157, 170))	('LSD2', 'Gene', '221656', (118, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (157, 170))	('SP-2509', 'Var', (64, 71))	('LSD2', 'Gene', (118, 122))
271830	31231465	Thus, we concluded that SP-2509 does not inhibit LSD2 function, suggesting that LSD2 regulates a unique cohort of genes independent of LSD1 and that SP-2509 displays specificity for LSD1.	('SP-2509', 'Var', (149, 156))	('LSD1', 'Gene', (182, 186))	('LSD2', 'Gene', '221656', (80, 84))	('LSD1', 'Gene', '23028', (182, 186))	('regulates', 'Reg', (85, 94))	('LSD2', 'Gene', (49, 53))	('LSD1', 'Gene', (135, 139))	('SP-2509', 'Chemical', 'MESH:C000594309', (24, 31))	('LSD1', 'Gene', '23028', (135, 139))	('SP-2509', 'Chemical', 'MESH:C000594309', (149, 156))	('LSD2', 'Gene', (80, 84))	('LSD2', 'Gene', '221656', (49, 53))
271842	31231465	Thus, knockdown of LSD2 may lead to metabolic inhibition, which in turn impacts the oncogenic capacity of the Ewing sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (110, 123))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (110, 123))	('LSD2', 'Gene', '221656', (19, 23))	('impacts', 'Reg', (72, 79))	('knockdown', 'Var', (6, 15))	('LSD2', 'Gene', (19, 23))	('Ewing sarcoma', 'Disease', (110, 123))	('lead to', 'Reg', (28, 35))	('metabolic inhibition', 'CPA', (36, 56))
271845	31231465	Significantly decreased anchorage-independent growth in soft agar was noted after the knockdown of endogenous LSD2 expression using both hairpins (Figure 5A-5D).	('knockdown', 'Var', (86, 95))	('anchorage-independent growth in soft agar', 'CPA', (24, 65))	('decreased', 'NegReg', (14, 23))	('agar', 'Chemical', 'MESH:D000362', (61, 65))	('LSD2', 'Gene', (110, 114))	('LSD2', 'Gene', '221656', (110, 114))
271849	31231465	Understanding mechanisms of epigenetic misregulation in Ewing sarcoma is important for our ability to further understand the basic biology of this aggressive malignancy.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('malignancy', 'Disease', (158, 168))	('epigenetic misregulation', 'Var', (28, 52))	('Ewing sarcoma', 'Disease', (56, 69))	('malignancy', 'Disease', 'MESH:D009369', (158, 168))
271861	31231465	Soft agar assays were utilized to examine the anchorage-independent growth capacity of A673 and TC32 cells following LSD2 knockdown as previously described, but modified by seeding 7500 to 12500 cells into duplicate 6cm plates.	('anchorage-independent growth capacity', 'CPA', (46, 83))	('TC32', 'CellLine', 'CVCL:7151', (96, 100))	('knockdown', 'Var', (122, 131))	('LSD2', 'Gene', (117, 121))	('agar', 'Chemical', 'MESH:D000362', (5, 9))	('LSD2', 'Gene', '221656', (117, 121))
271862	31231465	The proliferative capacity of A673 and TC32 cells following LSD2 knockdown was assessed through IncuCyte (Essen) live cell imaging.	('proliferative capacity', 'CPA', (4, 26))	('LSD2', 'Gene', '221656', (60, 64))	('TC32', 'CellLine', 'CVCL:7151', (39, 43))	('knockdown', 'Var', (65, 74))	('LSD2', 'Gene', (60, 64))
271891	27560552	Tumour cell cultures were set up under sterile conditions within 1 h of surgical resection by simple mechanical tissue dissociation using RPMI-1640 culture medium supplemented with penicillin (100 U ml-1), streptomycin (100 mug ml-1), amphotericin B (5 mug ml-1), foetal calf serum (20% v v-1) and D-glucose (0.4% v v-1).	('v-1', 'Gene', '28299', (289, 292))	('amphotericin B', 'Chemical', 'MESH:D000666', (235, 249))	('penicillin', 'Chemical', 'MESH:D010406', (181, 191))	('streptomycin', 'Chemical', 'MESH:D013307', (206, 218))	('calf', 'Species', '9913', (271, 275))	('v-1', 'Gene', (316, 319))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('RPMI-1640', 'Chemical', '-', (138, 147))	('100', 'Var', (220, 223))	('D-glucose', 'Chemical', 'MESH:D005947', (298, 307))	('v-1', 'Gene', (289, 292))	('v-1', 'Gene', '28299', (316, 319))
271898	27560552	Alleles for 10 human loci including THO1, D21S11, D5S818, D13S317, D7S820, D16S539, CSFIPO, AMEL, vWA and TPOX were assessed and compared with large cell line STR profile databases using the standard match threshold of 80%.	('THO1', 'Gene', '9984', (36, 40))	('D16S539', 'Var', (75, 82))	('D5S818', 'Var', (50, 56))	('THO1', 'Gene', (36, 40))	('D21S11', 'Var', (42, 48))	('D13S317', 'Var', (58, 65))	('human', 'Species', '9606', (15, 20))	('D7S820', 'Var', (67, 73))
271912	27560552	Short tandem repeat profiling of the morphologic variants in both tumours showed identical profiles that reassuringly were significantly distinct from those of all the other cell lines in our laboratory and the examined databases (Table 3).	('variants', 'Var', (49, 57))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))
271932	27560552	Short tandem repeat profiling, which is the current recommended standard for cell line identification, not only reliably confirmed identical profiles for the morphologic variants in Shef-LMS 01 and Shef-MFS 01, but established unique genomic identities for all the primary tumour cell lines reported in this study (Table 3).	('tumour', 'Disease', 'MESH:D009369', (273, 279))	('Shef-LMS 01', 'Gene', (182, 193))	('tumour', 'Disease', (273, 279))	('variants', 'Var', (170, 178))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('Shef-MFS 01', 'Gene', (198, 209))
271957	27560552	Further, FISH analysis performed on the diagnostic tissue sample for MDM2 copy number (data not shown) was concordant with the array CGH results.	('copy number', 'Var', (74, 85))	('CGH', 'Gene', (133, 136))	('CGH', 'Gene', '3342', (133, 136))	('MDM2', 'Gene', '4193', (69, 73))	('MDM2', 'Gene', (69, 73))
271967	27654937	There have been some notable successes, for example, tyrosine kinase inhibitors in BCR-ABL1 positive chronic myeloid leukemia (CML).	('myeloid leukemia', 'Disease', 'MESH:D007951', (109, 125))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (109, 125))	('CML', 'Disease', 'MESH:D015464', (127, 130))	('BCR-ABL1', 'Gene', '613;25', (83, 91))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('CML', 'Disease', (127, 130))	('myeloid leukemia', 'Disease', (109, 125))	('BCR-ABL1', 'Gene', (83, 91))	('tyrosine', 'Var', (53, 61))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (101, 125))
272001	27654937	by the median IC50 or PC1) would risk removing a drug-specific signal and thus over-correcting the results and furthermore would not be generalizable to other studies.	('IC50', 'Var', (14, 18))	('PC1', 'Gene', (22, 25))	('PC1', 'Gene', '5122', (22, 25))	('drug-specific signal', 'MPA', (49, 69))	('removing', 'NegReg', (38, 46))
272006	27654937	Also among the top associations, an improved P value was observed for PLX-4720 and BRAF mutation.	('mutation', 'Var', (88, 96))	('BRAF', 'Gene', (83, 87))	('associations', 'Interaction', (19, 31))	('BRAF', 'Gene', '673', (83, 87))	('PLX-4720', 'Gene', (70, 78))
272011	27654937	These results reveal that inactivating mutations may be equally important in prediction of PD-0332991 resistance.	('PD-0332991', 'Gene', (91, 101))	('inactivating mutations', 'Var', (26, 48))	('PD-0332991', 'Chemical', 'MESH:C500026', (91, 101))
272013	27654937	EWS-FLI1 translocations are characteristic of Ewing's sarcoma and this putative biomarker was subsequently shown to be an effective predictor in mouse xenograft.	('translocations', 'Var', (9, 23))	('mouse', 'Species', '10090', (145, 150))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (46, 61))	('EWS-FLI1', 'Gene', (0, 8))	("Ewing's sarcoma", 'Disease', (46, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (46, 61))
272016	27654937	Using a conventional approach, we also found the association of PARP inhibitors in EWS-FLI1 mutation to be among the most significant in these data (P = 2.6 x 10-9, P = 1.9 x 10-8; FDR = 1.15 x 10-6, FDR = 7.35 x 10-6 for rucaparib (AG-014699) and olaparib (AZD-2281), respectively; Fig.	('PARP', 'Gene', (64, 68))	('mutation', 'Var', (92, 100))	('rucaparib', 'Chemical', 'MESH:C531549', (222, 231))	('AZD', 'Chemical', '-', (258, 261))	('olaparib', 'Chemical', 'MESH:C531550', (248, 256))	('PARP', 'Gene', '142', (64, 68))	('association', 'Interaction', (49, 60))	('EWS-FLI1', 'Gene', (83, 91))
272022	27654937	4a) following correction for GLDS, namely BRAF mutation and AZ628 and NOTCH1 mutation and ATRA.	('BRAF', 'Gene', '673', (42, 46))	('NOTCH1', 'Gene', (70, 76))	('mutation', 'Var', (77, 85))	('AZ628', 'Var', (60, 65))	('NOTCH1', 'Gene', '4851', (70, 76))	('BRAF', 'Gene', (42, 46))
272027	27654937	When conditioning on GLDS a new significant association appears between MK-2206 and PIK3CA mutation (FDR = 5.1 x 10-4), a result that is supported by recent phase II clinical studies.	('PIK3CA', 'Gene', '5290', (84, 90))	('MK-2206', 'Chemical', 'MESH:C548887', (72, 79))	('mutation', 'Var', (91, 99))	('MK-2206', 'Gene', (72, 79))	('PIK3CA', 'Gene', (84, 90))
272032	27654937	This is sometimes employed in analysis of large panels of cell lines; however, in any analysis of these or any data obtained from a diverse set of cancers, tissue of origin (or cancer type) will often be highly confounded (and sometimes perfectly confounded) with certain mutations; extreme examples include BCR-ABL1 in CML and EWS-FLI1 in Ewing's sarcoma, where almost all samples will harbor these aberrations (and other cancer types will not).	('mutations', 'Var', (272, 281))	('cancer', 'Disease', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('BCR-ABL1', 'Gene', '613;25', (308, 316))	('cancer', 'Disease', (423, 429))	("Ewing's sarcoma", 'Disease', (340, 355))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('sarcoma', 'Phenotype', 'HP:0100242', (348, 355))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('EWS-FLI1', 'Gene', (328, 336))	('cancers', 'Disease', (147, 154))	('cancer', 'Disease', 'MESH:D009369', (423, 429))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (340, 355))	('CML', 'Disease', 'MESH:D015464', (320, 323))	('BCR-ABL1', 'Gene', (308, 316))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancer', 'Disease', (147, 153))	('CML', 'Disease', (320, 323))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (340, 355))
272039	27654937	Controlling for the expression of these genes is somewhat more conservative, as the number of significant associations between drugs and cancer gene mutations drops to 30.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('mutations', 'Var', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (137, 143))
272043	27654937	We showed that the expression of various genes, processes, and mutations were associated with GLDS, many of which are also related to clinical MDR; in future it may be possible to derive a model from such a set of mutations and/or expression estimates, which may be useful as an in vivo pan-cancer prognostic indicator.	('mutations', 'Var', (63, 72))	('associated', 'Reg', (78, 88))	('GLDS', 'Disease', (94, 98))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
272138	25743327	For example, a high rate of TP53 mutation has been reported in RAS compared with sporadic lesions.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('RAS', 'Disease', (63, 66))
272147	25126005	Detection of MDM2 amplification may supplement histopathology and aid to distinguish liposarcoma from other soft tissue neoplasia.	('liposarcoma', 'Disease', (85, 96))	('MDM2', 'Gene', (13, 17))	('neoplasia', 'Disease', (120, 129))	('neoplasia', 'Phenotype', 'HP:0002664', (120, 129))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('liposarcoma', 'Disease', 'MESH:D008080', (85, 96))	('soft tissue neoplasia', 'Phenotype', 'HP:0031459', (108, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('amplification', 'Var', (18, 31))	('neoplasia', 'Disease', 'MESH:D009369', (120, 129))
272155	25126005	Amplification of MDM2 is characteristic for well differentiated and dedifferentiated liposarcomas.	('Amplification', 'Var', (0, 13))	('liposarcomas', 'Disease', 'MESH:D008080', (85, 97))	('MDM2', 'Gene', (17, 21))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('liposarcomas', 'Phenotype', 'HP:0012034', (85, 97))	('well differentiated', 'Disease', (44, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('liposarcomas', 'Disease', (85, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
272203	25126005	Physiologically CDK4 is itself activated by D cyclines during G1 progression and inhibited by p16 (INK4a).	('INK4a', 'Gene', '1029', (99, 104))	('p16', 'Gene', '1029', (94, 97))	('INK4a', 'Gene', (99, 104))	('D cyclines', 'Chemical', '-', (44, 54))	('inhibited', 'NegReg', (81, 90))	('CDK4', 'Gene', (16, 20))	('D cyclines', 'Var', (44, 54))	('CDK4', 'Gene', '1019', (16, 20))	('p16', 'Gene', (94, 97))	('activated', 'PosReg', (31, 40))
272204	25126005	Conversely p53 point mutations are rarely found in ALT and DDLPS.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('point mutations', 'Var', (15, 30))
272207	25126005	Spindle cell lipoma are reported to frequently have chromosome 12 polysomy  while ALT and DDLPS close to always show MDM2 amplifications.	('chromosome 12 polysomy', 'Var', (52, 74))	('polysomy', 'Var', (66, 74))	('lipoma', 'Disease', 'MESH:D008067', (13, 19))	('lipoma', 'Disease', (13, 19))	('lipoma', 'Phenotype', 'HP:0012032', (13, 19))
272210	25126005	A recent study could demonstrate that peripheral undifferentiated sarcomas with MDM2 amplification correspond to DDLPS, even if a well-differentiated component was not present .	('MDM2', 'Gene', (80, 84))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('amplification', 'Var', (85, 98))	('sarcomas', 'Disease', (66, 74))	('DDLPS', 'Disease', (113, 118))
272211	25126005	Overall, few non-liposarcomatous tumours are known to have increased MDM2 gene copy numbers.	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('non-liposarcomatous tumours', 'Disease', (13, 40))	('liposarcoma', 'Phenotype', 'HP:0012034', (17, 28))	('copy numbers', 'Var', (79, 91))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('MDM2', 'Gene', (69, 73))	('non-liposarcomatous tumours', 'Disease', 'MESH:D009369', (13, 40))
272212	25126005	Most notably low grade osteosarcoma arising on the surface of bone may feature 12q14 amplifications  while extraosseous osteosarcoma are complex genomic sarcoma without recurrent MDM2 amplifications.	('extraosseous osteosarcoma', 'Disease', 'MESH:D012516', (107, 132))	('osteosarcoma', 'Phenotype', 'HP:0002669', (120, 132))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('sarcoma', 'Disease', (125, 132))	('osteosarcoma', 'Phenotype', 'HP:0002669', (23, 35))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))	('amplifications', 'Var', (85, 99))	('sarcoma', 'Disease', (28, 35))	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('sarcoma', 'Disease', (153, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('osteosarcoma', 'Disease', (120, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (120, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('12q14', 'Gene', (79, 84))	('extraosseous osteosarcoma', 'Disease', (107, 132))	('osteosarcoma', 'Disease', (23, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (23, 35))
272219	25126005	Low grade Osteosarcoma (OS) may also harbour amplified MDM2.	('Osteosarcoma', 'Disease', 'MESH:D012516', (10, 22))	('amplified', 'Var', (45, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (10, 22))	('OS', 'Phenotype', 'HP:0002669', (24, 26))	('MDM2', 'Gene', (55, 59))	('Osteosarcoma', 'Disease', (10, 22))
272227	25126005	The recurrent MDM2 amplification might be a key to targeted therapy of DDLPS: Experimental MDM2-inhibitors have been successfully employed in vitro to reactivate p53 and mediate apoptosis .	('p53', 'Gene', (162, 165))	('reactivate', 'Var', (151, 161))	('p53', 'Gene', '7157', (162, 165))	('apoptosis', 'CPA', (178, 187))	('mediate', 'Reg', (170, 177))
272235	25126005	Detection of MDM2 and CDK4 amplification and coexpression by FISH and IHC has a high specificity and may support classification of challenging cases.	('MDM2', 'Gene', (13, 17))	('CDK4', 'Gene', (22, 26))	('CDK4', 'Gene', '1019', (22, 26))	('support', 'Reg', (105, 112))	('amplification', 'Var', (27, 40))
272258	24937829	In face of this atypical aspect for lipoma hypothesis, we forwarded the material to pathology, where immature neoplasia was observed, with round cell proliferation with large cytoplasm and nuclei with dense chromatin forming mantles, compatible with malignant neoplasia of round cells, requiring immunohistochemistry for differentiation, a technique that revealed CD99 + strong and diffuse, desmin + in isolated foci, EMA + in several foci, multiple enolase + foci, vimentin +, Ki67 + in 10% of neoplastic cells and S100 protein + in multiple foci, where the diagnosis of Ewing sarcoma of soft parts was completed, with moderate level of proliferation (Figures 3, 4 and 5).	('neoplasia', 'Disease', 'MESH:D009369', (260, 269))	('neoplasia', 'Disease', (110, 119))	('malignant neoplasia', 'Disease', (250, 269))	('neoplasia', 'Disease', 'MESH:D009369', (110, 119))	('neoplasia', 'Disease', (260, 269))	('vimentin', 'Gene', '7431', (466, 474))	('malignant neoplasia', 'Disease', 'MESH:D009369', (250, 269))	('lipoma', 'Phenotype', 'HP:0012032', (36, 42))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (572, 585))	('neoplasia', 'Phenotype', 'HP:0002664', (110, 119))	('vimentin', 'Gene', (466, 474))	('sarcoma', 'Phenotype', 'HP:0100242', (578, 585))	('CD99 +', 'Var', (364, 370))	('neoplasia', 'Phenotype', 'HP:0002664', (260, 269))	('Ewing sarcoma of soft parts', 'Disease', (572, 599))	('Ewing sarcoma of soft parts', 'Disease', 'MESH:C563168', (572, 599))
272309	30239117	Polarization-sensitive OCT, a variant of OCT that is sensitive to the birefringent optical properties of tissues, such as highly ordered collagen or muscle fibres, has been shown to differentiate between human breast tumours and normal fibrous breast stroma.	('differentiate', 'Reg', (182, 195))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('fibrous breast stroma', 'Disease', (236, 257))	('tumours', 'Phenotype', 'HP:0002664', (217, 224))	('breast tumours', 'Disease', (210, 224))	('Polarization-sensitive', 'Var', (0, 22))	('human', 'Species', '9606', (204, 209))	('fibrous breast stroma', 'Disease', 'MESH:D001943', (236, 257))	('breast tumours', 'Disease', 'MESH:D001943', (210, 224))
272340	30098215	In particular, four microRNAs encoded in the 14q32 locus (miR-127-5p, miR-369-3p, miR-544a, and miR-655-3p) were associated with an OM phenotype in clinical metastasis samples.	('miR-127-5p', 'Gene', '100302123', (58, 68))	('miR-544a', 'Gene', '664613', (82, 90))	('associated with', 'Reg', (113, 128))	('miR-655-3p', 'Var', (96, 106))	('miR-369-3p', 'Gene', '442914', (70, 80))	('miR-544a', 'Gene', (82, 90))	('miR-369-3p', 'Gene', (70, 80))	('OM phenotype', 'Disease', (132, 144))	('miR-127-5p', 'Gene', (58, 68))
272379	30098215	Moreover, the mean interval from the date of the initial diagnosis of prostate cancer to the time of diagnosis of bone metastases was 4.9 years (range 0.7-10.5) in the group with <5 lesions, compared with 3.3 years (range 0.5-10.7) in the group with >5 lesions (p = 0.02).	('prostate cancer', 'Disease', 'MESH:D011471', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('<5 lesions', 'Var', (179, 189))	('bone metastases', 'Disease', 'MESH:D009362', (114, 129))	('bone metastases', 'Disease', (114, 129))	('prostate cancer', 'Disease', (70, 85))
272397	30174970	The case reports patient CAGF, female, 49 years old, homeless in Sao Paulo, crack addict for ten years, and smoker 70 years/pack of cigarettes, G10P10, without breast cancer in her family history.	('patient', 'Species', '9606', (17, 24))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('crack addict', 'Phenotype', 'HP:0030858', (76, 88))	('G10P10', 'Var', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
272442	27601937	In our search for responsible autophagic regulatory genes upstream of mammalian target of rapamycin (mTOR), we now discovered that, in contrast to MES-SA cells, a TP53-637C>T nonsense mutation located in the transactivating domain of the oncogenic suppressor p53 causes loss of its protein and consequently reduced PUMA induction in ESS-1 cells.	('TP53-637C>T', 'Var', (163, 174))	('PUMA', 'Gene', '27113', (315, 319))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', '2475', (101, 105))	('reduced', 'NegReg', (307, 314))	('loss', 'NegReg', (270, 274))	('ESS-1', 'Gene', '7046', (333, 338))	('protein', 'Protein', (282, 289))	('p53', 'Gene', (259, 262))	('mammalian target of rapamycin', 'Gene', '2475', (70, 99))	('PUMA', 'Gene', (315, 319))	('MES-SA', 'CellLine', 'CVCL:1404', (147, 153))	('mammalian target of rapamycin', 'Gene', (70, 99))	('ESS-1', 'Gene', (333, 338))
272450	27601937	Counteracting the effects of HDACs by inhibition of HDAC activity therefore induces chromatin relaxation which leads to altered expression of only few but important genes involved in the regulation of many disbalanced tumor cell processes as cell cycle arrest, differentiation, and apoptosis.	('altered', 'Reg', (120, 127))	('chromatin', 'MPA', (84, 93))	('HDAC', 'Gene', (52, 56))	('differentiation', 'CPA', (261, 276))	('HDAC', 'Gene', '9734', (52, 56))	('apoptosis', 'CPA', (282, 291))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (242, 259))	('HDAC', 'Gene', (29, 33))	('expression', 'Species', '29278', (128, 138))	('inhibition', 'Var', (38, 48))	('HDAC', 'Gene', '9734', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cell cycle arrest', 'CPA', (242, 259))	('expression', 'MPA', (128, 138))	('tumor', 'Disease', (218, 223))	('induces', 'Reg', (76, 83))
272458	27601937	mTOR inactivation by SAHA thus rescues ULK1 activation and thereby induces autophagy.	('rescues', 'PosReg', (31, 38))	('mTOR', 'Gene', '2475', (0, 4))	('ULK1', 'Gene', (39, 43))	('SAHA', 'Chemical', 'MESH:D000077337', (21, 25))	('ULK1', 'Gene', '8408', (39, 43))	('inactivation', 'Var', (5, 17))	('induces', 'Reg', (67, 74))	('autophagy', 'CPA', (75, 84))	('mTOR', 'Gene', (0, 4))	('activation', 'MPA', (44, 54))
272465	27601937	Our group verified that SAHA exerts cytotoxicity on uterine sarcoma cells and significantly prevented tumor cell proliferation by increasing expression of the cell cycle kinase p21WAF1 and decreasing expression of HDAC2 and 7 in vitro.	('expression', 'Species', '29278', (141, 151))	('expression', 'MPA', (200, 210))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('decreasing', 'NegReg', (189, 199))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (52, 67))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('sarcoma', 'Disease', (60, 67))	('HDAC', 'Gene', '9734', (214, 218))	('prevented', 'NegReg', (92, 101))	('increasing', 'PosReg', (130, 140))	('expression', 'Species', '29278', (200, 210))	('HDAC', 'Gene', (214, 218))	('expression', 'MPA', (141, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('tumor', 'Disease', (102, 107))	('cytotoxicity', 'Disease', (36, 48))	('p21WAF1', 'Var', (177, 184))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('SAHA', 'Chemical', 'MESH:D000077337', (24, 28))
272488	27601937	The presence or absence of the TP53 mutation was confirmed by more than tenfold re-sequencing of further ESS-1 subclones or the corresponding control region in MES-SA cells, respectively.	('ESS-1', 'Gene', '7046', (105, 110))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('MES-SA', 'CellLine', 'CVCL:1404', (160, 166))	('ESS-1', 'Gene', (105, 110))	('mutation', 'Var', (36, 44))
272502	27601937	Following antibodies and concentrations/dilutions were used: rabbit anti-PUMA (1 mug/ml)/1:1000; rabbit anti-cleaved CASP-9 (1 mug/ml)/1:1000; rabbit anti Cleaved poly-ADP-ribose polymerase-1 (PARP-1)/1:1000 (Cell Signaling; Frankfurt, Germany); purified mouse anti-human p53 (0.5 mg/ml)/1:100 (clone DO-7; BD Pharmingen; Schwechat, Austria); mouse anti-p21WAF1 (0.5 mug/ml)/1:2000 (Zymed; San Francisco, CA, USA); polyclonal rabbit anti-human phospho-mTOR (Ser2448) and mTOR Antibody (#2972) Antibody (Cell signaling; Frankfurt, Germany).	('mouse', 'Species', '10090', (255, 260))	('human', 'Species', '9606', (438, 443))	('poly-ADP-ribose polymerase-1', 'Gene', (163, 191))	('PUMA', 'Gene', (73, 77))	('mTOR', 'Gene', (471, 475))	('CASP-9', 'Gene', (117, 123))	('PARP-1', 'Gene', '142', (193, 199))	('Ser2448', 'Var', (458, 465))	('mTOR', 'Gene', '2475', (471, 475))	('rabbit', 'Species', '9986', (97, 103))	('CASP-9', 'Gene', '842', (117, 123))	('mTOR', 'Gene', (452, 456))	('rabbit', 'Species', '9986', (143, 149))	('PUMA', 'Gene', '27113', (73, 77))	('PARP-1', 'Gene', (193, 199))	('poly-ADP-ribose polymerase-1', 'Gene', '142', (163, 191))	('rabbit', 'Species', '9986', (61, 67))	('mTOR', 'Gene', '2475', (452, 456))	('rabbit', 'Species', '9986', (426, 432))	('human', 'Species', '9606', (266, 271))	('mouse', 'Species', '10090', (343, 348))
272507	27601937	Originating from TP53-WT, a control vector containing the 637C>T mutation was constructed (TP53-637C>T) by using the QuikChange II Site-Directed Mutagenesis Kit (Agilent Technologies; CA, USA).	('TP53-637C>T', 'Var', (91, 102))	('637C>T', 'Mutation', 'rs397516436', (58, 64))	('TP53-WT', 'Gene', (17, 24))	('637C>T', 'Mutation', 'rs397516436', (96, 102))	('TP53-WT', 'Gene', '7157', (17, 24))
272509	27601937	TP53-WT or TP53-637C>T were transiently transfected using Lipofectamine 2000 transfection reagent (Life Tech; Vienna, Austria) with a DNA (mug) to Lipofectamine (mul) ratio of 1:2.5.	('TP53-WT', 'Gene', '7157', (0, 7))	('Lipofectamine', 'Chemical', 'MESH:C086724', (147, 160))	('TP53-637C>T', 'Var', (11, 22))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (58, 76))	('Lipofectamine', 'Chemical', 'MESH:C086724', (58, 71))	('TP53-WT', 'Gene', (0, 7))
272510	27601937	MES-SA cells were transiently transfected with 50 or 100 nM SignalSilence p53 si-RNA I or 100 nM non-targeted control si-RNA (Cell Signaling) using Lipofectamine 2000 transfection reagent.	('p53 si-RNA', 'Var', (74, 84))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (148, 166))	('MES-SA', 'CellLine', 'CVCL:1404', (0, 6))	('SignalSilence', 'Var', (60, 73))
272512	27601937	5 x 104 cells per well were seeded in 24-well borosilicate glass plates (Asahi Glass Co., Tokyo, Japan) and incubated at 5 % CO2 and 37  C. After 24 h, transfection of cells containing TP53-WT or TP53-637C>T plasmids was performed as described above and treatment of non-transfected control cells was initiated.	('TP53-WT', 'Gene', (185, 192))	('TP53-WT', 'Gene', '7157', (185, 192))	('CO2', 'Chemical', '-', (125, 128))	('borosilicate', 'Chemical', '-', (46, 58))	('TP53-637C>T', 'Var', (196, 207))
272533	27601937	Thereby, in ESS-1 cell derived genomic DNA, a homozygous 637C>T transition in exon 6 of TP53 was revealed that was not present in MES-SA cells.	('637C>T', 'Mutation', 'rs397516436', (57, 63))	('ESS-1', 'Gene', '7046', (12, 17))	('MES-SA', 'CellLine', 'CVCL:1404', (130, 136))	('TP53', 'Gene', '7157', (88, 92))	('ESS-1', 'Gene', (12, 17))	('637C>T', 'Var', (57, 63))	('TP53', 'Gene', (88, 92))
272534	27601937	At the protein level, the R213X non-sense mutation is located at the N-terminal region of the DNA binding domain (DBD) of p53 as depicted in Fig.	('R213X', 'Var', (26, 31))	('R213X', 'Mutation', 'rs397516436', (26, 31))	('p53', 'Gene', (122, 125))
272535	27601937	This finding implicated that apoptosis resistance or induction of autophagy is related to p53-deficiency due to the TP53-637C>T mutation in ESS-1 cells.	('apoptosis resistance', 'CPA', (29, 49))	('ESS-1', 'Gene', (140, 145))	('autophagy', 'CPA', (66, 75))	('ESS-1', 'Gene', '7046', (140, 145))	('TP53-637C>T', 'Var', (116, 127))	('p53-deficiency', 'Disease', (90, 104))	('p53-deficiency', 'Disease', 'MESH:D007153', (90, 104))
272546	27601937	Subsequently, we tested whether the restoration of p53 also resulted in activation of apoptotic executioner caspases, in combination with LDH measurements, to assess the amount of apoptosis and cell-mediated cytotoxicity (Fig.	('activation', 'PosReg', (72, 82))	('p53', 'Gene', (51, 54))	('cytotoxicity', 'Disease', (208, 220))	('caspases', 'Gene', '841;842', (108, 116))	('restoration', 'Var', (36, 47))	('cytotoxicity', 'Disease', 'MESH:D064420', (208, 220))	('caspases', 'Gene', (108, 116))
272553	27601937	Nevertheless, at the investigated time-point, the levels of SAHA and TRAIL treated control cells were not yet reached (~28 % of lysis control), but were higher than that of cells supplied individually with SAHA-, TRAIL-, TP53-WT- or SAHA and TP53-637C>T (~6 to 9 % of lysis control).	('TRAIL', 'Gene', '8743', (213, 218))	('TP53-637C>T', 'Var', (242, 253))	('TRAIL', 'Gene', '8743', (69, 74))	('SAHA', 'Chemical', 'MESH:D000077337', (60, 64))	('TRAIL', 'Gene', (213, 218))	('TRAIL', 'Gene', (69, 74))	('TP53-WT', 'Gene', (221, 228))	('TP53-WT', 'Gene', '7157', (221, 228))	('SAHA', 'Chemical', 'MESH:D000077337', (206, 210))	('SAHA', 'Chemical', 'MESH:D000077337', (233, 237))	('to 9', 'Species', '1214577', (258, 262))
272563	27601937	Next, we additionally employed MDC and PI staining to quantify and depict TP53 transfected ESS-1 cells regarding autophagosome formation and cytotoxicity (Fig.	('MDC', 'Chemical', 'MESH:C008542', (31, 34))	('cytotoxicity', 'Disease', 'MESH:D064420', (141, 153))	('ESS-1', 'Gene', '7046', (91, 96))	('transfected', 'Var', (79, 90))	('TP53', 'Gene', '7157', (74, 78))	('autophagosome formation', 'CPA', (113, 136))	('TP53', 'Gene', (74, 78))	('cytotoxicity', 'Disease', (141, 153))	('ESS-1', 'Gene', (91, 96))
272571	27601937	Transient transfection of MES-SA cells with p53 si-RNA demonstrated partially reduced p53 expression which was not present in untreated or control si-RNA transfected cells.	('MES-SA', 'CellLine', 'CVCL:1404', (26, 32))	('si-RNA', 'Var', (48, 54))	('expression', 'Species', '29278', (90, 100))	('p53', 'Gene', (44, 47))	('expression', 'MPA', (90, 100))	('reduced', 'NegReg', (78, 85))	('p53', 'Gene', (86, 89))
272576	27601937	Therefore, upon TP53 reconstitution and administration of 3 microM SAHA, several TP53 mutant and SAHA-responsive cell lines, which have been previously reported to undergo autophagy, were screened for their mode of cell death.	('SAHA', 'Chemical', 'MESH:D000077337', (97, 101))	('mutant', 'Var', (86, 92))	('SAHA', 'Chemical', 'MESH:D000077337', (67, 71))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
272581	27601937	Furthermore, equal (HeLa cells) or slightly higher LDH levels ranging from 11 to 97 % were detected when TP53-WT was additionally transfected in comparison to only SAHA-treated tumor cells after 24 h (Fig.	('higher', 'PosReg', (44, 50))	('LDH levels', 'MPA', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('to 9', 'Species', '1214577', (78, 82))	('TP53-WT', 'Gene', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('transfected', 'Var', (130, 141))	('SAHA', 'Chemical', 'MESH:D000077337', (164, 168))	('TP53-WT', 'Gene', '7157', (105, 112))	('HeLa', 'CellLine', 'CVCL:0030', (20, 24))	('tumor', 'Disease', (177, 182))
272590	27601937	We detected a homozygous 637C>T transition in exon 6 of the TP53 gene in the ESS-1 cell line which results in the formation of a premature stop codon.	('637C>T', 'Var', (25, 31))	('ESS-1', 'Gene', '7046', (77, 82))	('TP53', 'Gene', '7157', (60, 64))	('637C>T', 'Mutation', 'rs397516436', (25, 31))	('TP53', 'Gene', (60, 64))	('ESS-1', 'Gene', (77, 82))
272594	27601937	The R213X non-sense mutation, which is not present in MES-SA cells, is located at the N-terminus of the DNA binding domain (DBD) of p53 and leads to a truncated protein that is missing the last ~180 of 393 amino acids.	('R213X', 'Mutation', 'rs397516436', (4, 9))	('leads to', 'Reg', (140, 148))	('R213X', 'Var', (4, 9))	('truncated', 'MPA', (151, 160))	('MES-SA', 'CellLine', 'CVCL:1404', (54, 60))
272595	27601937	Although we used a monoclonal human-specific p53 antibody (clone DO-7) that recognizes an epitope between amino acids 1-45 of wildtype as well as mutant forms of p53, we were not able to detect the presumptive truncated p53 protein in our experiments.	('human', 'Species', '9606', (30, 35))	('mutant', 'Var', (146, 152))	('p53', 'Gene', (162, 165))
272596	27601937	In support of our finding, also ovarian cancer patients possessing the R213X mutation exhibited null type mutations that could not be detected by immunohistochemical staining for unknown reasons.	('R213X', 'Var', (71, 76))	('exhibited', 'Reg', (86, 95))	('also ovarian cancer', 'Disease', (27, 46))	('also ovarian cancer', 'Disease', 'MESH:D010051', (27, 46))	('patients', 'Species', '9606', (47, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('R213X', 'Mutation', 'rs397516436', (71, 76))
272598	27601937	The identified homozygous p53 mutation thus clearly explains apoptosis resistance in ESS-1 cells as in the case of complete p53-deficiency, no physical interactions or transcriptional activities can take place at all.	('mutation', 'Var', (30, 38))	('apoptosis resistance', 'CPA', (61, 81))	('explains', 'Reg', (52, 60))	('p53', 'Gene', (26, 29))	('ESS-1', 'Gene', '7046', (85, 90))	('p53-deficiency', 'Disease', (124, 138))	('p53-deficiency', 'Disease', 'MESH:D007153', (124, 138))	('ESS-1', 'Gene', (85, 90))
272599	27601937	Alternatively, in case of undetectable p53 protein, it was previously reported that the R213X mutation disrupted the efficiency of p53 transactivation by its inability to bind consensus binding sequences of p53 in the regulatory region of the p21WAF gene.	('efficiency', 'MPA', (117, 127))	('p53', 'Protein', (131, 134))	('inability', 'NegReg', (158, 167))	('binding', 'Interaction', (186, 193))	('disrupted', 'NegReg', (103, 112))	('bind', 'Interaction', (171, 175))	('R213X', 'Var', (88, 93))	('R213X', 'Mutation', 'rs397516436', (88, 93))
272607	27601937	Accordingly, a study demonstrated that complexes constituted by acetylated p53 as well as acetylated histones and coactivators were held responsible for HDACi-induced apoptosis in HepG2 cells.	('HepG2', 'CellLine', 'CVCL:0027', (180, 185))	('acetylated', 'Var', (64, 74))	('responsible', 'Reg', (137, 148))	('HDAC', 'Gene', (153, 157))	('p53', 'Protein', (75, 78))	('HDAC', 'Gene', '9734', (153, 157))	('complexes', 'Interaction', (39, 48))
272609	27601937	Taken together, we conclude that in ESS-1 and MES-SA cells and at least in a subset of tumor cell lines in general, p53 could be essential in mediating SAHA-induced apoptosis, while absence or degradation of p53 in the cytoplasmic compartment could lead to activation of a SAHA-mediated autophagic pathway.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('lead to', 'Reg', (249, 256))	('degradation', 'MPA', (193, 204))	('SAHA', 'Chemical', 'MESH:D000077337', (273, 277))	('ESS-1', 'Gene', '7046', (36, 41))	('tumor', 'Disease', (87, 92))	('MES-SA', 'CellLine', 'CVCL:1404', (46, 52))	('absence', 'Var', (182, 189))	('p53', 'Gene', (208, 211))	('SAHA-mediated autophagic pathway', 'Pathway', (273, 305))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ESS-1', 'Gene', (36, 41))	('activation', 'PosReg', (257, 267))	('SAHA', 'Chemical', 'MESH:D000077337', (152, 156))
272611	27601937	Thus, mutant p53 re-activation using a well-tolerated small molecule inhibitor or inhibitors of MDM2-mediated proteasomal degradation might help to restore p53-dependent apoptosis and tumor suppression.	('mutant', 'Var', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('MDM2', 'Gene', '4193', (96, 100))	('MDM2', 'Gene', (96, 100))	('tumor', 'Disease', (184, 189))	('re-activation', 'PosReg', (17, 30))	('restore', 'PosReg', (148, 155))	('p53', 'Gene', (13, 16))
272612	27601937	As nonsense TP53 mutations of which the 637C>T mutant is found most often are even more common in human tumors than TP53 missense mutations (listed in the UMD TP53 muatation database; http://p53.free.fr), their restoration by drugs will be of significance but require different approaches.	('TP53', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('637C>T', 'Mutation', 'rs397516436', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('common', 'Reg', (88, 94))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', '7157', (12, 16))	('tumors', 'Disease', (104, 110))	('TP53', 'Gene', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('TP53', 'Gene', '7157', (116, 120))	('human', 'Species', '9606', (98, 103))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
272614	27601937	gentamicin and G418), can achieve read-through of the 637C>T transition leading to expression of full-length p53, however due to their toxicity further screening for less toxic compounds is necessary.	('G418', 'Var', (15, 19))	('637C>T', 'Mutation', 'rs397516436', (54, 60))	('expression', 'Species', '29278', (83, 93))	('expression', 'MPA', (83, 93))	('toxicity', 'Disease', 'MESH:D064420', (135, 143))	('toxicity', 'Disease', (135, 143))	('G418', 'Chemical', 'MESH:C010680', (15, 19))	('637C>T', 'Var', (54, 60))	('gentamicin', 'Chemical', 'MESH:D005839', (0, 10))
272616	27601937	In addition, in a subset of tumor cells where inhibition of autophagy causes non-apoptotic cell death, the therapeutic potential of autophagy targeting in combination with SAHA therapy could be employed.	('tumor', 'Disease', (28, 33))	('inhibition', 'Var', (46, 56))	('non-apoptotic cell death', 'CPA', (77, 101))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('SAHA', 'Chemical', 'MESH:D000077337', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('autophagy', 'CPA', (60, 69))
272640	23161774	The NF1 syndrome is caused by alterations in the NF1 gene, mapping to the long arm of chromosome 17, which encodes the tumor suppressor protein neurofibromin.	('NF1 syndrome', 'Disease', 'MESH:C537392', (4, 16))	('tumor', 'Disease', (119, 124))	('neurofibromin', 'Gene', (144, 157))	('NF1 syndrome', 'Disease', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('alterations', 'Var', (30, 41))	('NF1', 'Gene', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('NF1', 'Gene', '4763', (4, 7))	('caused by', 'Reg', (20, 29))	('neurofibromin', 'Gene', '4763', (144, 157))	('NF1', 'Gene', (49, 52))	('NF1', 'Gene', '4763', (49, 52))
272642	23161774	Biallelic mutations of the NF1 gene are found in a significant portion of all MPNSTs, and among patients with NF1, one of the alleles is altered in the germline.	('NF1', 'Gene', (110, 113))	('Biallelic mutations', 'Var', (0, 19))	('NF1', 'Gene', '4763', (110, 113))	('MPNSTs', 'Disease', (78, 84))	('found', 'Reg', (40, 45))	('NF1', 'Gene', (27, 30))	('patients', 'Species', '9606', (96, 104))	('NF1', 'Gene', '4763', (27, 30))
272665	23161774	For DFS, a slightly lower survival percentage was observed among NF1 patients, although not significantly different (P = .42) (Fig.	('lower', 'NegReg', (20, 25))	('patients', 'Species', '9606', (69, 77))	('survival', 'MPA', (26, 34))	('DFS', 'Var', (4, 7))	('NF1', 'Gene', (65, 68))	('NF1', 'Gene', '4763', (65, 68))
272710	23161774	TP53 mutations are frequent in many cancer types, and some small studies report mutations in up to 70% of NF1-associated MPNSTs; others claim that TP53 mutations are mainly found in non-NF1 MPNSTs, while we and others have reported that TP53 mutations are rare in MPNST.	('TP53', 'Gene', '7157', (237, 241))	('TP53', 'Gene', (147, 151))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('mutations', 'Var', (80, 89))	('NF1', 'Gene', (186, 189))	('TP53', 'Gene', (237, 241))	('cancer', 'Disease', (36, 42))	('NF1', 'Gene', '4763', (186, 189))	('NF1', 'Gene', (106, 109))	('NF1', 'Gene', '4763', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('TP53', 'Gene', '7157', (147, 151))
272715	23161774	This finding is as expected because NF1 carries a germline mutation of the NF1 gene, which is believed to be an initiating factor for development of both neurofibromas and MPNSTs.	('NF1', 'Gene', (36, 39))	('germline mutation', 'Var', (50, 67))	('NF1', 'Gene', '4763', (36, 39))	('NF1', 'Gene', (75, 78))	('NF1', 'Gene', '4763', (75, 78))	('neurofibromas', 'Disease', (154, 167))	('neurofibromas', 'Phenotype', 'HP:0001067', (154, 167))	('neurofibromas', 'Disease', 'MESH:D009455', (154, 167))
272716	23161774	However, since the same NF1 mutations are found in sporadic tumors, this cannot alone explain any difference in outcome.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (28, 37))	('sporadic tumors', 'Disease', 'MESH:D009369', (51, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('NF1', 'Gene', (24, 27))	('sporadic tumors', 'Disease', (51, 66))	('NF1', 'Gene', '4763', (24, 27))
272753	33066583	This increase within the cell processes requires firm attachment to matrix through integrin alphavbeta3 binding, as disruption of these adhesion sites prevented Ca2+ influxes.	('Ca2+ influxes', 'MPA', (161, 174))	('integrin alphavbeta3', 'Gene', '3685', (83, 103))	('disruption', 'Var', (116, 126))	('prevented', 'NegReg', (151, 160))	('binding', 'Interaction', (104, 111))	('integrin alphavbeta3', 'Gene', (83, 103))	('Ca2+', 'Chemical', 'MESH:D000069285', (161, 165))
272755	33066583	Upon mechanical loading, changes within the cell membrane cause the organisation and recruitment of integrins, and focal adhesion complex proteins, such as focal adhesion kinase (FAK) and the Ras homologue (Rho) guanosine triphosphatase (GTPase), as well as binding of alpha-actinin to the cytoskeleton, and release of beta-catenin from adherens junctions.	('beta-catenin', 'Gene', (319, 331))	('beta-catenin', 'Gene', '1499', (319, 331))	('alpha-actinin', 'Gene', '87', (269, 282))	('release', 'MPA', (308, 315))	('binding', 'Interaction', (258, 265))	('alpha-actinin', 'Gene', (269, 282))	('focal adhesion kinase', 'Gene', '5747', (156, 177))	('recruitment', 'MPA', (85, 96))	('FAK', 'Gene', (179, 182))	('FAK', 'Gene', '5747', (179, 182))	('changes', 'Var', (25, 32))	('focal adhesion kinase', 'Gene', (156, 177))
272759	33066583	Similarly, integrin alpha v beta 1 engagement has been shown to increase Src and Jun N-terminal kinase (JNK) signalling and beta-catenin nuclear localisation, respectively, as well as ALP and OCN mRNA expression.	('integrin alpha v beta 1', 'Protein', (11, 34))	('JNK', 'Gene', '5599', (104, 107))	('Jun N-terminal kinase', 'Gene', (81, 102))	('OCN', 'Gene', (192, 195))	('engagement', 'Var', (35, 45))	('ALP', 'Gene', (184, 187))	('nuclear localisation', 'MPA', (137, 157))	('beta-catenin', 'Gene', (124, 136))	('beta-catenin', 'Gene', '1499', (124, 136))	('increase', 'PosReg', (64, 72))	('ALP', 'Gene', '250', (184, 187))	('Jun N-terminal kinase', 'Gene', '5599', (81, 102))	('Src', 'Gene', (73, 76))	('Src', 'Gene', '6714', (73, 76))	('OCN', 'Gene', '632', (192, 195))	('JNK', 'Gene', (104, 107))
272784	33066583	Studies in epithelial malignancies demonstrate that mechanotransduction can promote cancer cell proliferation, plasticity, chemoresistance, migratory, and metastatic properties and stemness.	('malignancies', 'Disease', 'MESH:D009369', (22, 34))	('promote', 'PosReg', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('rat', 'Species', '10116', (103, 106))	('cancer', 'Disease', (84, 90))	('malignancies', 'Disease', (22, 34))	('metastatic properties', 'CPA', (155, 176))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (11, 34))	('stemness', 'CPA', (181, 189))	('plasticity', 'CPA', (111, 121))	('migratory', 'CPA', (140, 149))	('chemoresistance', 'CPA', (123, 138))	('mechanotransduction', 'Var', (52, 71))	('rat', 'Species', '10116', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rat', 'Species', '10116', (42, 45))
272806	33066583	When human OSA or osteoblasts were encapsulated in hydrogels with tunable stiffness and ECM adhesion ligand density, normal osteoblasts were more responsive to ECM adhesion ligand density changes to promote osteogenesis, while OSA cells were more responsive to stiffness changes.	('osteogenesis', 'Disease', (207, 219))	('osteogenesis', 'Disease', 'MESH:D010013', (207, 219))	('OSA', 'Phenotype', 'HP:0002669', (227, 230))	('changes', 'Var', (188, 195))	('promote', 'PosReg', (199, 206))	('human', 'Species', '9606', (5, 10))	('OSA', 'Phenotype', 'HP:0002669', (11, 14))
272810	33066583	Alternative splicing within the fibronectin repeat domain of tenascin-C permits the interaction with various growth factor receptors and proteins.	('fibronectin', 'Gene', '2335', (32, 43))	('tenascin-C', 'Gene', (61, 71))	('fibronectin', 'Gene', (32, 43))	('tenascin-C', 'Gene', '3371', (61, 71))	('Alternative splicing', 'Var', (0, 20))	('proteins', 'Protein', (137, 145))	('interaction', 'Interaction', (84, 95))
272815	33066583	RNA analyses that compared paired non-tumour and tumour samples from human OSA patients, as well as paired primary and metastatic human and mouse OSA cell lines, indicate that ECM components are upregulated in tumour and metastatic variants.	('mouse', 'Species', '10090', (140, 145))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('variants', 'Var', (232, 240))	('human', 'Species', '9606', (69, 74))	('upregulated', 'PosReg', (195, 206))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('OSA', 'Phenotype', 'HP:0002669', (146, 149))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('human', 'Species', '9606', (130, 135))	('patients', 'Species', '9606', (79, 87))	('OSA', 'Phenotype', 'HP:0002669', (75, 78))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', (38, 44))	('tumour', 'Disease', (210, 216))	('tumour', 'Disease', (49, 55))
272824	33066583	Further research is necessary to determine whether the same applies to OSA, and how these changes in ECM modulating enzymes can impact the mechanical microenvironment and mechanosignalling in this and other sarcomas.	('impact', 'Reg', (128, 134))	('mechanical microenvironment', 'CPA', (139, 166))	('sarcomas', 'Disease', 'MESH:D012509', (207, 215))	('mechanosignalling', 'CPA', (171, 188))	('sarcomas', 'Phenotype', 'HP:0100242', (207, 215))	('changes', 'Var', (90, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('OSA', 'Phenotype', 'HP:0002669', (71, 74))	('sarcomas', 'Disease', (207, 215))	('OSA', 'Disease', (71, 74))
272837	33066583	The role of TAZ/YAP is similar in canine OSA, as depletion of TAZ or YAP in canine OSA cell lines significantly decreases cell migration and viability, and depletion of YAP enhances sensitivity to doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (197, 208))	('depletion', 'Var', (156, 165))	('canine', 'Species', '9615', (76, 82))	('enhances', 'PosReg', (173, 181))	('depletion', 'MPA', (49, 58))	('OSA', 'Phenotype', 'HP:0002669', (41, 44))	('OSA', 'Phenotype', 'HP:0002669', (83, 86))	('viability', 'CPA', (141, 150))	('canine', 'Species', '9615', (34, 40))	('rat', 'Species', '10116', (130, 133))	('sensitivity to doxorubicin', 'MPA', (182, 208))	('TAZ/YAP', 'Gene', (12, 19))	('cell migration', 'CPA', (122, 136))	('TAZ/YAP', 'Gene', '10413', (12, 19))	('decreases', 'NegReg', (112, 121))
272843	33066583	Inhibition of actin polymerisation by cytochalasin D led to a decrease in nuclear YAP levels in MG63 human OSA cells.	('actin', 'Protein', (14, 19))	('MG63', 'CellLine', 'CVCL:0426', (96, 100))	('Inhibition', 'NegReg', (0, 10))	('OSA', 'Phenotype', 'HP:0002669', (107, 110))	('human', 'Species', '9606', (101, 106))	('decrease', 'NegReg', (62, 70))	('nuclear YAP levels', 'MPA', (74, 92))	('cytochalasin', 'Var', (38, 50))
272844	33066583	Similarly, ROCK inhibition through siRNA or ROCK2 inhibitor SR3677, leads to a decrease in nuclear and overall YAP levels, and downstream target genes, cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), and cyclin D1 (CCND1).	('cyclin D1', 'Gene', (241, 250))	('SR3677', 'Var', (60, 66))	('inhibition', 'NegReg', (16, 26))	('ROCK2', 'Gene', '9475', (44, 49))	('cyclin D1', 'Gene', '595', (241, 250))	('nuclear and', 'MPA', (91, 102))	('CYR61', 'Gene', (189, 194))	('YAP levels', 'MPA', (111, 121))	('cysteine-rich angiogenic inducer 61', 'Gene', '3491', (152, 187))	('CTGF', 'Gene', '1490', (230, 234))	('ROCK2', 'Gene', (44, 49))	('cysteine-rich angiogenic inducer 61', 'Gene', (152, 187))	('CCND1', 'Gene', '595', (252, 257))	('CTGF', 'Gene', (230, 234))	('SR3677', 'Chemical', '-', (60, 66))	('decrease', 'NegReg', (79, 87))	('CCND1', 'Gene', (252, 257))	('connective tissue growth factor', 'Gene', '1490', (197, 228))	('connective tissue growth factor', 'Gene', (197, 228))	('CYR61', 'Gene', '3491', (189, 194))
272846	33066583	Analysis of the tumour tissue isolated from mice injected with ROCK-depleted tumour cells demonstrated a decrease in total YAP immunolabeling, suggesting that modulation of YAP by ROCK might impact tumour growth and metastasis in OSA.	('rat', 'Species', '10116', (97, 100))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('OSA', 'Disease', (230, 233))	('tumour growth', 'Disease', (198, 211))	('mice', 'Species', '10090', (44, 48))	('decrease', 'NegReg', (105, 113))	('impact', 'Reg', (191, 197))	('modulation', 'Var', (159, 169))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('metastasis', 'CPA', (216, 226))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (198, 204))	('tumour growth', 'Disease', 'MESH:D006130', (198, 211))	('OSA', 'Phenotype', 'HP:0002669', (230, 233))	('tumour', 'Disease', (16, 22))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
272885	33066583	Pazopanib decreases the nuclear localisation of TAZ/YAP through enhancing its proteasome-mediated degradation.	('decreases', 'NegReg', (10, 19))	('enhancing', 'PosReg', (64, 73))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('nuclear localisation', 'MPA', (24, 44))	('TAZ/YAP', 'Gene', '10413', (48, 55))	('proteasome-mediated degradation', 'MPA', (78, 109))	('TAZ/YAP', 'Gene', (48, 55))	('Pazopanib', 'Var', (0, 9))
272891	33066583	Simvastatin in particular has been shown to inhibit cell growth and cell cycle progression, while increasing apoptosis in human OSA cell lines.	('human', 'Species', '9606', (122, 127))	('cell cycle progression', 'CPA', (68, 90))	('cell growth', 'CPA', (52, 63))	('increasing', 'PosReg', (98, 108))	('inhibit', 'NegReg', (44, 51))	('apoptosis', 'CPA', (109, 118))	('Simvastatin', 'Chemical', 'MESH:D019821', (0, 11))	('OSA', 'Phenotype', 'HP:0002669', (128, 131))	('Simvastatin', 'Var', (0, 11))
272900	33066583	siRNA-mediated depletion of MRTF-A leads to a significant decrease in the levels of focal adhesion-associated proteins, namely, paxillin, vinculin, zyxin and in the activation of FAK.	('depletion', 'Var', (15, 24))	('paxillin', 'Gene', '5829', (128, 136))	('levels of focal adhesion-associated proteins', 'MPA', (74, 118))	('MRTF-A', 'Gene', '57591', (28, 34))	('zyxin', 'Gene', '7791', (148, 153))	('paxillin', 'Gene', (128, 136))	('vinculin', 'Gene', '7414', (138, 146))	('decrease', 'NegReg', (58, 66))	('vinculin', 'Gene', (138, 146))	('FAK', 'Gene', (179, 182))	('FAK', 'Gene', '5747', (179, 182))	('zyxin', 'Gene', (148, 153))	('MRTF-A', 'Gene', (28, 34))
272915	33066583	Treatment of MG63 cells with CCG-203971 decreased the nuclear and total protein levels of MRTF-A, vimentin, snail, fibronectin and MMP9 in a stiff environment.	('fibronectin', 'Gene', '2335', (115, 126))	('MRTF-A', 'Gene', (90, 96))	('MG63', 'CellLine', 'CVCL:0426', (13, 17))	('CCG-203971', 'Var', (29, 39))	('CCG-203971', 'Chemical', 'MESH:C000589288', (29, 39))	('snail', 'Gene', (108, 113))	('MRTF-A', 'Gene', '57591', (90, 96))	('fibronectin', 'Gene', (115, 126))	('MMP9', 'Gene', (131, 135))	('vimentin', 'Gene', (98, 106))	('snail', 'Gene', '6615', (108, 113))	('MMP9', 'Gene', '4318', (131, 135))	('vimentin', 'Gene', '7431', (98, 106))	('decreased', 'NegReg', (40, 49))
272919	33066583	To become active, phosphatidylinositol 4,5-bisphosphate (PIP2) or S100P proteins binds to the FERM domain, allowing for its dissociation.	('phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (18, 55))	('ER', 'Gene', '2069', (95, 97))	('S100P', 'Var', (66, 71))	('PIP2', 'Chemical', 'MESH:D019269', (57, 61))	('binds', 'Interaction', (81, 86))	('S100P', 'SUBSTITUTION', 'None', (66, 71))	('dissociation', 'MPA', (124, 136))
272922	33066583	A highly metastatic variant of murine OSA cells is enriched for ezrin and in vivo mouse models demonstrated that ezrin promotes a survival effect upon cancer cell's arrival to the lung, possibly through the activation of MAPK signalling.	('promotes', 'PosReg', (119, 127))	('mouse', 'Species', '10090', (82, 87))	('OSA', 'Phenotype', 'HP:0002669', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('survival effect', 'CPA', (130, 145))	('cancer', 'Disease', (151, 157))	('rat', 'Species', '10116', (102, 105))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('murine', 'Species', '10090', (31, 37))	('ezrin', 'Var', (113, 118))
272923	33066583	Furthermore, both phosphodefective (T567A) and phosphomimetic (T567D) ezrin mutants are unable to form metastases in the lung, even 100 days post tail vein injection.	('T567D', 'Mutation', 'p.T567D', (63, 68))	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('T567D', 'Var', (63, 68))	('unable', 'NegReg', (88, 94))	('mutants', 'Var', (76, 83))	('ezrin', 'Gene', (70, 75))	('T567A', 'Mutation', 'c.567T>A', (36, 41))	('metastases', 'Disease', (103, 113))	('T567A', 'Var', (36, 41))
272928	33066583	Along these lines, fibroblasts transfected with various ezrin mutants found that the phosphomimetic mutant had more spread tubulin fibres, and increased vimentin and actin fibre length.	('increased', 'PosReg', (143, 152))	('mutant', 'Var', (100, 106))	('spread tubulin fibres', 'CPA', (116, 137))	('vimentin', 'Gene', '7431', (153, 161))	('vimentin', 'Gene', (153, 161))	('more', 'PosReg', (111, 115))
272933	33066583	Alternatively, the T567-phosphorylated form of ezrin can suppress Hippo signalling, as seen in hepatocellular carcinoma.	('Hippo signalling', 'MPA', (66, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('suppress', 'NegReg', (57, 65))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('hepatocellular carcinoma', 'Disease', (95, 119))	('T567-phosphorylated', 'Var', (19, 38))
272937	33066583	In vitro assays found that these compounds work by directly binding to ezrin to inhibit phosphorylation; although NSC305787 can inhibit PKC kinase activity at higher doses, this is not the case for NSC668394.	('phosphorylation', 'MPA', (88, 103))	('PKC', 'Gene', (136, 139))	('PKC', 'Gene', '112476', (136, 139))	('inhibit', 'NegReg', (128, 135))	('inhibit', 'NegReg', (80, 87))	('NSC305787', 'Chemical', 'MESH:C570896', (114, 123))	('NSC305787', 'Var', (114, 123))	('binding', 'Interaction', (60, 67))
272938	33066583	The invasion capacity of murine OSA cells expressing high levels of ezrin was blunted by treatment with either compound in vitro, which also significantly decreased metastatic growth in ex vivo lung cultures, with NSC305787 showing slightly greater anti-metastatic effects compared to control.	('invasion capacity', 'CPA', (4, 21))	('blunted', 'NegReg', (78, 85))	('OSA', 'Phenotype', 'HP:0002669', (32, 35))	('decreased', 'NegReg', (155, 164))	('NSC305787', 'Chemical', 'MESH:C570896', (214, 223))	('NSC305787', 'Var', (214, 223))	('murine', 'Species', '10090', (25, 31))	('metastatic growth', 'CPA', (165, 182))
272939	33066583	Lastly, in vivo tail vein injection of OSA cells followed by treatment with either inhibitor demonstrated that NSC305787 prolongs survival compared to the vehicle control.	('prolongs', 'PosReg', (121, 129))	('survival', 'CPA', (130, 138))	('NSC305787', 'Chemical', 'MESH:C570896', (111, 120))	('NSC305787', 'Var', (111, 120))	('OSA', 'Phenotype', 'HP:0002669', (39, 42))	('rat', 'Species', '10116', (100, 103))
272940	33066583	Further studies performed using transgenic models of OSA (Osx-Cre+ p53fl/fl pRBfl/fl) exhibited similar results, as the incidence of lung metastasis was significantly reduced with NSC305787 treatment, a compound that also reached the more favourable plasma concentrations as compared to NSC668394.	('lung metastasis', 'CPA', (133, 148))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('NSC305787', 'Var', (180, 189))	('NSC305787', 'Chemical', 'MESH:C570896', (180, 189))	('OSA', 'Phenotype', 'HP:0002669', (53, 56))	('rat', 'Species', '10116', (264, 267))	('reduced', 'NegReg', (167, 174))
272942	33066583	Several candidate compounds that were found in this screen (MMV667492, MMV020549, MMV666069, MMV665877) decreased cancer cell motility in vitro and substantially decreased lung metastatic growth in an ex vivo lung culture compared to NSC305787.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('MMV667492', 'Var', (60, 69))	('NSC305787', 'Chemical', 'MESH:C570896', (234, 243))	('MMV665877', 'Var', (93, 102))	('MMV666069', 'Var', (82, 91))	('decreased', 'NegReg', (104, 113))	('decreased', 'NegReg', (162, 171))	('lung metastatic growth in an ex vivo lung culture', 'CPA', (172, 221))	('decreased lung', 'Phenotype', 'HP:0002089', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('MMV020549', 'Var', (71, 80))	('cancer', 'Disease', (114, 120))
272947	33066583	Fanelli and colleagues (2020) recently found that two compounds, NSC130813 (NERI02; F06) and triptolide, which inhibit DNA repair through binding of DNA repair proteins, enhance sensitivity to cisplatin in U2OS and Saos2 cells.	('inhibit', 'NegReg', (111, 118))	('ER', 'Gene', '2069', (77, 79))	('U2OS', 'CellLine', 'CVCL:0042', (206, 210))	('DNA repair', 'MPA', (119, 129))	('binding', 'Interaction', (138, 145))	('enhance', 'PosReg', (170, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('NSC130813', 'Var', (65, 74))	('triptolide', 'Chemical', 'MESH:C001899', (93, 103))	('sensitivity to cisplatin', 'MPA', (178, 202))
272965	33066583	The karyotype of OSA is notoriously complex; genomic analysis of OSA tumours from both human and canine samples show multiple copy number variations and structural variants of certain genes.	('OSA', 'Phenotype', 'HP:0002669', (17, 20))	('tumours', 'Disease', (69, 76))	('canine', 'Species', '9615', (97, 103))	('structural variants', 'Var', (153, 172))	('OSA', 'Phenotype', 'HP:0002669', (65, 68))	('human', 'Species', '9606', (87, 92))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
272967	33066583	It is imperative that we use a strategic approach to understand how certain mutations can attenuate or potentiate mechanosignalling.	('mechanosignalling', 'CPA', (114, 131))	('mutations', 'Var', (76, 85))	('rat', 'Species', '10116', (33, 36))	('attenuate', 'NegReg', (90, 99))	('potentiate', 'PosReg', (103, 113))	('rat', 'Species', '10116', (10, 13))
272972	33066583	Given this relationship between IGF1R and mechanical stimulus, further research will be needed to understand how, and if, somatic mutations in IGF1R could potentiate the FAK signalling cascade.	('FAK', 'Gene', (170, 173))	('IGF1R', 'Gene', (32, 37))	('FAK', 'Gene', '5747', (170, 173))	('IGF1R', 'Gene', '3480', (32, 37))	('IGF1R', 'Gene', (143, 148))	('mutations', 'Var', (130, 139))	('potentiate', 'PosReg', (155, 165))	('IGF1R', 'Gene', '3480', (143, 148))
272974	33066583	This really raises the which came first, the chicken-or-the-egg question: do genomic aberrations potentiate mechanosignalling or are genomic aberrations the result of mechanical forces in the environment?	('mechanosignalling', 'CPA', (108, 125))	('chicken', 'Species', '9031', (45, 52))	('rat', 'Species', '10116', (89, 92))	('aberrations', 'Var', (85, 96))	('rat', 'Species', '10116', (145, 148))	('potentiate', 'PosReg', (97, 107))
272982	30125801	It represents a candidate for targeted therapy, e.g., by truncated tissue factor (tTF)-NGR, binding to CD13, and causing tumor vascular thrombosis.	('binding', 'Interaction', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor vascular thrombosis', 'Disease', 'MESH:D013927', (121, 146))	('tissue factor', 'Gene', '2152', (67, 80))	('TF', 'Gene', '2152', (83, 85))	('tumor vascular thrombosis', 'Disease', (121, 146))	('CD13', 'Gene', '290', (103, 107))	('truncated', 'Var', (57, 66))	('CD13', 'Gene', (103, 107))	('causing', 'Reg', (113, 120))	('tissue factor', 'Gene', (67, 80))
273017	30125801	The presence of CD13 on STS tumor cells or in the tumor vasculature had significant prognostic impact in univariate analysis for relapse-free survival (RFS) and overall survival (OS), where higher expression levels of CD13 indicated a better prognosis.	('expression levels', 'MPA', (197, 214))	('tumor', 'Disease', (28, 33))	('CD13', 'Gene', '290', (218, 222))	('CD13', 'Gene', (218, 222))	('CD13', 'Gene', '290', (16, 20))	('CD13', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('presence', 'Var', (4, 12))	('relapse-free', 'Disease', (129, 141))	('tumor', 'Disease', (50, 55))	('higher', 'PosReg', (190, 196))
273044	30125801	Subsequently, sections were incubated over night at 4 C with a CD13 antibody (SP187, Cell Marque; dilution 1:300) and a CD31 antibody (JC70A, DAKO, dilution 1:200) followed by a 60-minute incubation with a Cy3-labeled goat anti-rabbit-IgG antibody (#111-165-003, Dianova; dilution 1:200) and an FITC-labeled goat anti-mouse-IgG (#554001, BD Pharmingen; dilution 1:500).	('goat', 'Species', '9925', (218, 222))	('goat', 'Species', '9925', (308, 312))	('rabbit', 'Species', '9986', (228, 234))	('mouse', 'Species', '10090', (318, 323))	('CD31', 'Gene', (120, 124))	('IgG antibody', 'Phenotype', 'HP:0003237', (235, 247))	('CD13', 'Gene', '290', (63, 67))	('FITC', 'Chemical', 'MESH:D016650', (295, 299))	('CD13', 'Gene', (63, 67))	('Cy3', 'Chemical', '-', (206, 209))	('CD31', 'Gene', '5175', (120, 124))	('#554001', 'Var', (329, 336))
273078	30125801	Multivariate Cox proportional hazard models with patient age, tumor stage, and tumor site (extremity versus nonextremity) as additional clinical prognostic factors showed that the independent impact of CD13 positivity on prognosis in tumor cells and in vascular/perivascular zones is significant (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (62, 67))	('CD13', 'Gene', '290', (202, 206))	('patient', 'Species', '9606', (49, 56))	('CD13', 'Gene', (202, 206))	('perivascular zones', 'Phenotype', 'HP:0012520', (262, 280))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('positivity', 'Var', (207, 217))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
273115	30125801	The observation that antiangiogenic therapy can decrease delivery of cytotoxic drugs into tumors also argues in this direction.	('antiangiogenic', 'Var', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('delivery of cytotoxic drugs into', 'MPA', (57, 89))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('decrease', 'NegReg', (48, 56))
273123	30125801	As a CD13-negative STS xenograft model was not available, we refer to our published data on small cell lung cancer, which showed that tumors with CD13 positivity only in the tumor vascular cells but CD13 negative on the tumor cells can also be effectively treated with tTF-NGR.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (220, 225))	('positivity', 'Var', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumors', 'Disease', (134, 140))	('CD13', 'Gene', (5, 9))	('small cell lung cancer', 'Disease', 'MESH:D055752', (92, 114))	('CD13', 'Gene', '290', (199, 203))	('CD13', 'Gene', (146, 150))	('small cell lung cancer', 'Disease', (92, 114))	('TF', 'Gene', '2152', (270, 272))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (174, 179))	('CD13', 'Gene', '290', (5, 9))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (92, 114))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('CD13', 'Gene', (199, 203))	('CD13', 'Gene', '290', (146, 150))
273155	22314185	Activated VEGFR2-signaling, sometimes by KDR gene mutations found in juvenile capillary hemangiomas and angiosarcomas, is believed to be pathogenetically important.	('KDR', 'Gene', (41, 44))	('hemangioma', 'Phenotype', 'HP:0001028', (88, 98))	('VEGFR2', 'Gene', '3791', (10, 16))	('mutations', 'Var', (50, 59))	('angiosarcoma', 'Phenotype', 'HP:0200058', (104, 116))	('juvenile capillary hemangiomas', 'Disease', (69, 99))	('VEGFR2', 'Gene', (10, 16))	('juvenile capillary hemangiomas', 'Disease', 'MESH:D018324', (69, 99))	('KDR', 'Gene', '3791', (41, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('hemangiomas', 'Phenotype', 'HP:0001028', (88, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('hemangiomas and angiosarcomas', 'Disease', 'MESH:D006394', (88, 117))	('capillary hemangiomas', 'Phenotype', 'HP:0005306', (78, 99))	('angiosarcomas', 'Phenotype', 'HP:0200058', (104, 117))
273296	21559197	Biopsies from the ulcer base are more likely to demonstrate characteristic CMV inclusions, which are usually seen in stromal and endothelial cells, as compared to HSV infection, which manifests in squamous cells.	('ulcer', 'Disease', 'MESH:D014456', (18, 23))	('ulcer', 'Disease', (18, 23))	('inclusions', 'Var', (79, 89))	('HSV infection', 'Disease', 'MESH:C536395', (163, 176))	('CMV', 'Disease', (75, 78))	('HSV infection', 'Disease', (163, 176))
273330	21559197	MAI leads to an exudative enteropathy and altered secretion of inflammatory mediators (e.g., interleukin-1).	('MAI', 'Var', (0, 3))	('enteropathy', 'Phenotype', 'HP:0002242', (26, 37))	('altered', 'Reg', (42, 49))	('secretion of inflammatory mediators', 'MPA', (50, 85))	('enteropathy', 'Disease', 'MESH:C538273', (26, 37))	('MAI', 'Species', '55883', (0, 3))	('enteropathy', 'Disease', (26, 37))
273337	21559197	As in gastric infection (see above), CMV causes intestinal inflammation, erosion, and ulceration, with characteristic CMV inclusions in stromal and endothelial cells.	('gastric infection', 'Disease', (6, 23))	('inclusions', 'Var', (122, 132))	('ulcer', 'Disease', 'MESH:D014456', (86, 91))	('ulcer', 'Disease', (86, 91))	('intestinal inflammation', 'Disease', 'MESH:D007249', (48, 71))	('causes', 'Reg', (41, 47))	('gastric infection', 'Disease', 'MESH:D013274', (6, 23))	('intestinal inflammation', 'Disease', (48, 71))	('erosion', 'Disease', (73, 80))	('CMV', 'Var', (37, 40))
273408	32048619	Fifty one cases of undifferentiated round cell sarcomas, including 32 cases, tested for BCOR-CCNB3 and CIC-DUX4 fusions, by reverse transcription polymerase chain reaction technique and 44 tumours, for CCNB3 immunostaining, were analyzed.	('undifferentiated', 'Disease', (19, 35))	('CIC', 'Gene', (103, 106))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('BCOR-CCNB3', 'Gene', '54880;85417', (88, 98))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcomas', 'Disease', (47, 55))	('CCNB3', 'Gene', (93, 98))	('tested', 'Reg', (77, 83))	('CCNB3', 'Gene', '85417', (202, 207))	('CIC', 'Gene', '23152', (103, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('DUX4', 'Gene', (107, 111))	('CCNB3', 'Gene', (202, 207))	('tumours', 'Disease', (189, 196))	('fusions', 'Var', (112, 119))	('BCOR-CCNB3', 'Gene', (88, 98))	('DUX4', 'Gene', '100288687', (107, 111))	('CCNB3', 'Gene', '85417', (93, 98))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('tumours', 'Disease', 'MESH:D009369', (189, 196))
273410	32048619	Five of 32 (15.6%) tested cases were positive for BCOR-CCNB3 fusion and seven (21.8%) for CIC-DUX4 fusions.	('fusion', 'Var', (61, 67))	('CIC', 'Gene', (90, 93))	('DUX4', 'Gene', (94, 98))	('DUX4', 'Gene', '100288687', (94, 98))	('BCOR-CCNB3', 'Gene', (50, 60))	('CIC', 'Gene', '23152', (90, 93))	('positive', 'Reg', (37, 45))	('BCOR-CCNB3', 'Gene', '54880;85417', (50, 60))
273422	32048619	Ewing sarcoma is characterized by recurrent translocations between EWSR1 (Ewing sarcoma RNA binding protein 1) and ETS (E26 transformation-specific) family of transcription factors.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', '2130', (67, 72))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (74, 87))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (74, 87))	('Ewing sarcoma', 'Disease', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('EWSR1', 'Gene', (67, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('translocations', 'Var', (44, 58))	('Ewing sarcoma', 'Disease', (74, 87))
273428	32048619	Some studies have shown certain small round cell sarcomas, displaying EWSR1 rearrangement and fusion with non-ETS fusion genes, such as PATZ1, POU5F, NFATc2 or SP3.	('PATZ1', 'Gene', (136, 141))	('SP3', 'Gene', '6670', (160, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('NFATc2', 'Gene', '4773', (150, 156))	('EWSR1', 'Gene', (70, 75))	('PATZ1', 'Gene', '23598', (136, 141))	('sarcomas', 'Disease', (49, 57))	('EWSR1', 'Gene', '2130', (70, 75))	('SP3', 'Gene', (160, 163))	('rearrangement', 'Var', (76, 89))	('fusion', 'Interaction', (94, 100))	('NFATc2', 'Gene', (150, 156))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))
273429	32048619	CIC (capicua homolog)-DUX4 (double homeobox 4) is a relatively newly identified gene fusion, resulting from either t(4; 19)(q35; q13)or t(10; 19)(q26; q13) translocations.	('CIC', 'Gene', (0, 3))	('DUX4', 'Gene', '100288687', (22, 26))	('capicua homolog', 'Gene', (5, 20))	('double homeobox 4', 'Gene', (28, 45))	('CIC', 'Gene', '23152', (0, 3))	('t(4; 19)(q35; q13', 'Var', (115, 132))	('capicua homolog', 'Gene', '23152', (5, 20))	('DUX4', 'Gene', (22, 26))	('double homeobox 4', 'Gene', '100288687', (28, 45))
273430	32048619	Pierron et al identified recurrent gene fusions of BCOR (encoding Bcl-6 interacting corepressor) and CCNB3 (cyclin B3), leading to BCOR-CCNB3 fusions in certain unclassifiable small round cell sarcomas, occurring in adolescents and young adults.	('fusions', 'Var', (142, 149))	('BCOR', 'Gene', (131, 135))	('cyclin B3', 'Gene', (108, 117))	('Bcl-6 interacting corepressor', 'Gene', (66, 95))	('CCNB3', 'Gene', (101, 106))	('Bcl-6 interacting corepressor', 'Gene', '54880', (66, 95))	('CCNB3', 'Gene', '85417', (136, 141))	('sarcomas', 'Disease', 'MESH:D012509', (193, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('BCOR-CCNB3', 'Gene', (131, 141))	('sarcomas', 'Disease', (193, 201))	('BCOR', 'Gene', '54880', (51, 55))	('cyclin B3', 'Gene', '85417', (108, 117))	('fusions', 'Var', (40, 47))	('BCOR', 'Gene', '54880', (131, 135))	('CCNB3', 'Gene', (136, 141))	('BCOR-CCNB3', 'Gene', '54880;85417', (131, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('BCOR', 'Gene', (51, 55))	('CCNB3', 'Gene', '85417', (101, 106))
273451	32048619	Paraffin blocks of all 51 cases were available for reverse transcription polymerase chain reaction (RT-PCR), for testing CIC-DUX4 and BCOR-CCNB3 gene fusions.	('BCOR-CCNB3', 'Gene', '54880;85417', (134, 144))	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('CIC', 'Gene', (121, 124))	('fusions', 'Var', (150, 157))	('DUX4', 'Gene', (125, 129))	('DUX4', 'Gene', '100288687', (125, 129))	('CIC', 'Gene', '23152', (121, 124))	('BCOR-CCNB3', 'Gene', (134, 144))
273476	32048619	Three cases positive for BCOR-CCNB3 fusion and a single case positive for the CIC-DUX4 fusion on further testing for sequencing displayed positive results.	('DUX4', 'Gene', (82, 86))	('DUX4', 'Gene', '100288687', (82, 86))	('BCOR-CCNB3', 'Gene', (25, 35))	('CIC', 'Gene', '23152', (78, 81))	('BCOR-CCNB3', 'Gene', '54880;85417', (25, 35))	('CIC', 'Gene', (78, 81))	('fusion', 'Var', (36, 42))
273479	32048619	Among the five cases harbouring BCOR-CCNB3 fusions, there were four males and a single female patient (M:F=4:1), with age ranging from 6 to 29 yr (average=26; median=25 yr).	('fusions', 'Var', (43, 50))	('BCOR-CCNB3', 'Gene', (32, 42))	('BCOR-CCNB3', 'Gene', '54880;85417', (32, 42))	('patient', 'Species', '9606', (94, 101))
273480	32048619	Among the seven cases harbouring CIC-DUX4 fusions, there were five female and two male patients, with age ranging from 8 to 53 yr (average=31.5, median=25 yr).	('DUX4', 'Gene', '100288687', (37, 41))	('CIC', 'Gene', '23152', (33, 36))	('CIC', 'Gene', (33, 36))	('DUX4', 'Gene', (37, 41))	('fusions', 'Var', (42, 49))	('patients', 'Species', '9606', (87, 95))
273500	32048619	Diffuse immunostaining for CCNB3 was also observed in another four cases, negative for BCOR-CCNB3 fusions, a single case of CIC-DUX4-positive sarcoma and three cases, wherein gene fusions could not be tested.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('CIC', 'Gene', (124, 127))	('sarcoma', 'Disease', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('fusions', 'Var', (98, 105))	('CCNB3', 'Gene', (92, 97))	('DUX4', 'Gene', (128, 132))	('BCOR-CCNB3', 'Gene', (87, 97))	('CCNB3', 'Gene', '85417', (27, 32))	('DUX4', 'Gene', '100288687', (128, 132))	('BCOR-CCNB3', 'Gene', '54880;85417', (87, 97))	('CCNB3', 'Gene', '85417', (92, 97))	('CIC', 'Gene', '23152', (124, 127))	('CCNB3', 'Gene', (27, 32))
273533	32048619	Subsequently, various investigators identified BCOR-CCNB3 fusions in 1.4-13 per cent, in different studies.	('fusions', 'Var', (58, 65))	('BCOR-CCNB3', 'Gene', (47, 57))	('BCOR-CCNB3', 'Gene', '54880;85417', (47, 57))
273534	32048619	Machado et al observed CIC-DUX4 fusions in six and BCOR-CCNB3 fusions in five cases, respectively, of 200 undifferentiated sarcomas, with an overall frequency of 5.5 per cent of these transcripts.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('undifferentiated sarcomas', 'Disease', (106, 131))	('fusions', 'Var', (32, 39))	('DUX4', 'Gene', (27, 31))	('DUX4', 'Gene', '100288687', (27, 31))	('BCOR-CCNB3', 'Gene', (51, 61))	('CIC', 'Gene', '23152', (23, 26))	('CIC', 'Gene', (23, 26))	('fusions', 'Var', (62, 69))	('BCOR-CCNB3', 'Gene', '54880;85417', (51, 61))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (106, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))
273560	32048619	EWSR1 rearrangement and/or specific fusion transcripts for ESFTs were negative in 40 cases, of the present study.	('rearrangement', 'Var', (6, 19))	('EWSR1', 'Gene', '2130', (0, 5))	('negative', 'NegReg', (70, 78))	('ESFTs', 'Gene', (59, 64))	('EWSR1', 'Gene', (0, 5))
273563	32048619	While WT1 immunostaining was observed in 70 per cent cases of our study, lack of EWSR1 rearrangement in nine cases and polyphenotypic differentiation in four cases helped in ruling out a DSRCT.	('EWSR1', 'Gene', '2130', (81, 86))	('WT1', 'Gene', '7490', (6, 9))	('rearrangement', 'Var', (87, 100))	('WT1', 'Gene', (6, 9))	('EWSR1', 'Gene', (81, 86))	('lack', 'Var', (73, 77))	('DSRCT', 'Disease', (187, 192))
273619	21996728	Deregulation of normal differentiation driven by SYT-SSX is therefore believed to be the basis for multipotent stem cell transformation that leads to cancer development.	('SS', 'Phenotype', 'HP:0012570', (53, 55))	('SSX', 'Gene', (53, 56))	('Deregulation', 'Var', (0, 12))	('normal differentiation', 'CPA', (16, 38))	('SSX', 'Gene', '6757', (53, 56))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('leads to', 'Reg', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
273621	21996728	It will also be interesting to investigate if SYT-SSX expression results in the acquisition of additional features that influence tumor progression and behavior.	('SSX', 'Gene', '6757', (50, 53))	('SSX', 'Gene', (50, 53))	('expression', 'Var', (54, 64))	('influence', 'Reg', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('results in', 'Reg', (65, 75))	('SS', 'Phenotype', 'HP:0012570', (50, 52))
273623	21996728	Expression of SYT-SSX2 results in the activation of a pro-neural program, while altering normal differentiation, in both murine myoblasts and human bone marrow-derived mesenchymal stem cells (BMMSCs).	('normal differentiation', 'MPA', (89, 111))	('SSX2', 'Gene', (18, 22))	('Expression', 'Var', (0, 10))	('human', 'Species', '9606', (142, 147))	('altering', 'Reg', (80, 88))	('murine', 'Species', '10090', (121, 127))	('SSX2', 'Gene', '6757', (18, 22))	('activation', 'PosReg', (38, 48))	('SS', 'Phenotype', 'HP:0012570', (18, 20))	('pro-neural program', 'CPA', (54, 72))
273628	21996728	The present studies provide an important insight into the primary events that unfold upon SYT-SSX expression in the undifferentiated stem cell from which the cancer is thought to arise.	('SSX', 'Gene', (94, 97))	('expression', 'Var', (98, 108))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('SS', 'Phenotype', 'HP:0012570', (94, 96))	('SSX', 'Gene', '6757', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
273629	21996728	SYT-SSX expression is sufficient to drive tumorigenesis, and previous studies showed that SYT-SSX fusions might alter the differentiation potential of SS cells.	('SSX', 'Gene', (94, 97))	('tumor', 'Disease', (42, 47))	('alter', 'Reg', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('differentiation potential', 'CPA', (122, 147))	('fusions', 'Var', (98, 105))	('SS', 'Phenotype', 'HP:0012570', (151, 153))	('SSX', 'Gene', '6757', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('SSX', 'Gene', (4, 7))	('SS', 'Phenotype', 'HP:0012570', (4, 6))	('SS', 'Phenotype', 'HP:0012570', (94, 96))	('SSX', 'Gene', '6757', (94, 97))
273631	21996728	Additionally, in a transgenic SS model, SYT-SSX2 expression in muscle progenitors formed tumors that recapitulated the human disease, further indicating that myoblasts are a relevant model system.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('SS', 'Phenotype', 'HP:0012570', (44, 46))	('SS', 'Phenotype', 'HP:0012570', (30, 32))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('SSX2', 'Gene', (44, 48))	('expression', 'Var', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('SSX2', 'Gene', '6757', (44, 48))	('human', 'Species', '9606', (119, 124))
273660	21996728	To determine whether the ability of SYT-SSX2 to target chromatin is required for the observed effects, we tested SXdel3, an SYT-SSX2 mutant with a 20-residue deletion in its SSX-targeting module (Figure 1e, diagram).	('SS', 'Phenotype', 'HP:0012570', (40, 42))	('SSX', 'Gene', '6757', (128, 131))	('SSX', 'Gene', '6757', (40, 43))	('SSX2', 'Gene', (40, 44))	('SS', 'Phenotype', 'HP:0012570', (174, 176))	('SSX', 'Gene', (40, 43))	('SSX', 'Gene', '6757', (174, 177))	('SSX', 'Gene', (174, 177))	('SSX2', 'Gene', '6757', (128, 132))	('deletion', 'Var', (158, 166))	('SS', 'Phenotype', 'HP:0012570', (128, 130))	('mutant', 'Var', (133, 139))	('SSX2', 'Gene', '6757', (40, 44))	('SSX', 'Gene', (128, 131))	('SSX2', 'Gene', (128, 132))
273661	21996728	SXdel3 is unable to colocalize with Polycomb and antagonize its Bmi1 component in U2OS cells.	('SXdel3', 'Var', (0, 6))	('Bmi1', 'Gene', '648', (64, 68))	('antagonize', 'NegReg', (49, 59))	('Bmi1', 'Gene', (64, 68))	('U2OS', 'CellLine', 'CVCL:0042', (82, 86))
273671	21996728	A full characterization of the gene expression profiles initiated by SYT-SSX2 in BMMSCs identified approximately 750 significantly upregulated and more than 500 significantly downregulated genes when compared with vector-transduced BMMSCs (all microarray and ChIP-Seq data have been deposited in the Gene Expression Omnibus (; available at http://www.ncbi.nlm.nih.gov/geo/) and can be obtained through accession numbers GSE26562 (C2C12 microarray), GSE26563 (BMMSC microarray) and GSE26564 (C2C12 ChIPSeq)).	('SSX2', 'Gene', (73, 77))	('GSE26564', 'Var', (481, 489))	('SSX2', 'Gene', '6757', (73, 77))	('GSE26563', 'Var', (449, 457))	('SS', 'Phenotype', 'HP:0012570', (73, 75))	('upregulated', 'PosReg', (131, 142))
273684	21996728	We started by inhibiting FGFR activity with PD173074, a small molecule with high selectivity for the FGFR kinase.	('PD173074', 'Var', (44, 52))	('PD173074', 'Chemical', 'MESH:C115711', (44, 52))	('FGFR', 'Protein', (25, 29))	('inhibiting', 'NegReg', (14, 24))	('activity', 'MPA', (30, 38))
273685	21996728	A 2-day treatment with PD173074 led to a marked diminution of NEF signal in SYT-SSX2-expressing BMMSCs (Figure 3a, left histogram), reflecting the dependence of the neural marker on active FGFR.	('PD173074', 'Chemical', 'MESH:C115711', (23, 31))	('NEF signal', 'MPA', (62, 72))	('SSX2', 'Gene', (80, 84))	('PD173074', 'Var', (23, 31))	('SSX2', 'Gene', '6757', (80, 84))	('SS', 'Phenotype', 'HP:0012570', (80, 82))	('diminution', 'NegReg', (48, 58))
273686	21996728	More specifically, infection of SYT-SSX2-expressing BMMSCs with two FGFR2-specific short-hairpin RNA (shRNA) vectors (833 and 703; Figure 3a, middle panel) showed significant growth retardation when compared with a non-targeting vector (2910; Figure 3a, right histogram, dark gray bars).	('growth retardation', 'Disease', 'MESH:D006130', (175, 193))	('SSX2', 'Gene', (36, 40))	('growth retardation', 'Disease', (175, 193))	('833', 'Var', (118, 121))	('FGFR2', 'Gene', '2263', (68, 73))	('SS', 'Phenotype', 'HP:0012570', (36, 38))	('growth retardation', 'Phenotype', 'HP:0001510', (175, 193))	('FGFR2', 'Gene', (68, 73))	('SSX2', 'Gene', '6757', (36, 40))
273687	21996728	Apart from growth inhibition, FGFR2 depletion caused a specific attenuation of the NEF signal in the SYT-SSX2-expressing BMMSCs cells (more pronounced with 703; Figure 3a, right histogram, light-gray bars).	('SS', 'Phenotype', 'HP:0012570', (105, 107))	('NEF signal', 'MPA', (83, 93))	('SSX2', 'Gene', (105, 109))	('depletion', 'Var', (36, 45))	('attenuation', 'NegReg', (64, 75))	('FGFR2', 'Gene', (30, 35))	('FGFR2', 'Gene', '2263', (30, 35))	('SSX2', 'Gene', '6757', (105, 109))
273690	21996728	We observed that approximately 15% of the SYO-1 cell population contained NEF, and PD173074 caused a graded disappearance of NEF-positive SYO-1 cells and an incremental inhibition of their growth (Figure 3b, left and middle panels).	('SYO-1', 'Gene', '55027', (138, 143))	('inhibition', 'NegReg', (169, 179))	('SYO-1', 'Gene', (42, 47))	('SYO-1', 'Gene', '55027', (42, 47))	('SYO-1', 'Gene', (138, 143))	('PD173074', 'Var', (83, 91))	('PD173074', 'Chemical', 'MESH:C115711', (83, 91))	('growth', 'MPA', (189, 195))	('disappearance', 'NegReg', (108, 121))
273691	21996728	As in the SYT-SSX2-expressing BMMSCs, FGFR2 depletion with the 833 and 703 shRNAs also led to a marked decrease in the number of NEF-positive SYO-1 cells as well as a delay in their growth (Figure 3b, right panel).	('delay', 'NegReg', (167, 172))	('growth', 'CPA', (182, 188))	('FGFR2', 'Gene', '2263', (38, 43))	('SYO-1', 'Gene', '55027', (142, 147))	('depletion', 'Var', (44, 53))	('SYO-1', 'Gene', (142, 147))	('833', 'Var', (63, 66))	('SSX2', 'Gene', '6757', (14, 18))	('SS', 'Phenotype', 'HP:0012570', (14, 16))	('SSX2', 'Gene', (14, 18))	('decrease', 'NegReg', (103, 111))	('FGFR2', 'Gene', (38, 43))
273700	21996728	Furthermore, knockdown of SYT-SSX in SS cells led to a loss of neuronal features (the present study and).	('SS', 'Phenotype', 'HP:0012570', (37, 39))	('loss', 'NegReg', (55, 59))	('SS', 'Phenotype', 'HP:0012570', (30, 32))	('loss of neuronal features', 'Phenotype', 'HP:0002529', (55, 80))	('SSX', 'Gene', '6757', (30, 33))	('SSX', 'Gene', (30, 33))	('neuronal features', 'CPA', (63, 80))	('knockdown', 'Var', (13, 22))
273708	21996728	Imposing a lineage commitment on stem/progenitor cells appears to be a recurrent feature of sarcoma-associated translocations.	('translocations', 'Var', (111, 125))	('lineage commitment', 'CPA', (11, 29))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('sarcoma', 'Disease', (92, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
273712	21996728	Regardless, the dominant effect on cellular identity is thought to be a part of oncogenesis initiation by sarcoma-associated translocations and a necessary step toward malignant transformation.	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('translocations', 'Var', (125, 139))	('sarcoma', 'Disease', (106, 113))
273716	21996728	Additionally, expression of SYT-SSX2 in committed myogenic progenitor cells resulted in tumor formation in mice suggesting that the cell-of-origin could be a more differentiated entity.	('expression', 'Var', (14, 24))	('SS', 'Phenotype', 'HP:0012570', (32, 34))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('SSX2', 'Gene', (32, 36))	('mice', 'Species', '10090', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('resulted in', 'Reg', (76, 87))	('tumor', 'Disease', (88, 93))	('SSX2', 'Gene', '6757', (32, 36))
273811	32274663	showed that FDG-PET/CT had higher diagnostic accuracy than PET or CT alone in detecting tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('FDG', 'Chemical', 'MESH:D019788', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('FDG-PET/CT', 'Var', (12, 22))
273934	31850204	Surgical treatment should be interdisciplinary in cases where primary instability is inevitable, or resection extent may lead to secondary fracture.	('secondary', 'Disease', (129, 138))	('secondary fracture', 'Phenotype', 'HP:0002757', (129, 147))	('resection extent', 'Var', (100, 116))	('fracture', 'Disease', 'MESH:D050723', (139, 147))	('fracture', 'Disease', (139, 147))	('lead to', 'Reg', (121, 128))
274097	24957555	extremity localised primary tumour, high grade histology, no detectable metastasis at primary diagnosis and age below 40 years.	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('high', 'Var', (36, 40))	('tumour', 'Disease', (28, 34))
274104	24957555	We have also extracted data from spindle cell non-osteosarcomas arising from bone tissue (SCS) in the gross material, code M881, M883 and M889, and data from more unspecific bone tumours, code M880 and M882 in order to capture OS cases wrongly classified among these ICD-codes.	('M882', 'Var', (202, 206))	('M883', 'Var', (129, 133))	('osteosarcomas arising from bone tissue', 'Phenotype', 'HP:0010622', (50, 88))	('bone tumour', 'Phenotype', 'HP:0010622', (174, 185))	('bone tumours', 'Disease', (174, 186))	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('osteosarcomas', 'Disease', (50, 63))	('bone tumours', 'Disease', 'MESH:D001859', (174, 186))	('OS', 'Phenotype', 'HP:0002669', (227, 229))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('osteosarcomas', 'Phenotype', 'HP:0002669', (50, 63))	('M889', 'Var', (138, 142))	('osteosarcomas', 'Disease', 'MESH:D012516', (50, 63))
274183	25705534	We present the case of a 32-year-old case with EWS-PNETs of the lung that presented with chest pain to the pulmonology clinic, determined to have pulmonary nodules, and diagnosed with surgical removal of the nodule.	('PNET', 'Phenotype', 'HP:0030065', (51, 55))	('chest pain', 'Disease', 'MESH:D002637', (89, 99))	('EWS-PNETs', 'Var', (47, 56))	('chest pain', 'Disease', (89, 99))	('pain', 'Phenotype', 'HP:0012531', (95, 99))	('chest pain', 'Phenotype', 'HP:0100749', (89, 99))	('EWS', 'Phenotype', 'HP:0012254', (47, 50))	('PNETs', 'Phenotype', 'HP:0030065', (51, 56))	('pulmonary nodules', 'Disease', (146, 163))
274322	33734413	Of the GISTs, none carried c-kit or PDGFRA mutations, 13 tumors (65.0%) were located in the jejunum or ileum, and 6 tumors (30.0%) were located in the duodenum.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('GISTs', 'Phenotype', 'HP:0100723', (7, 12))	('c-kit', 'Gene', '3815', (27, 32))	('c-kit', 'Gene', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PDGFRA', 'Gene', '5156', (36, 42))	('PDGFRA', 'Gene', (36, 42))	('tumors', 'Disease', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
274350	33734413	Inactivating mutations in NF1 is associated with downstream activation of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling, and uncontrolled cellular growth, differentiation, and survival, which is associated with the disease origin of NF1, including NF1-associated neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (340, 348))	('uncontrolled cellular growth', 'CPA', (202, 230))	('NF1', 'Gene', (325, 328))	('NF1', 'Gene', '4763', (310, 313))	('activation', 'PosReg', (60, 70))	('neoplasms', 'Disease', 'MESH:D009369', (340, 349))	('survival', 'CPA', (253, 261))	('NF1', 'Gene', (310, 313))	('Inactivating mutations', 'Var', (0, 22))	('differentiation', 'CPA', (232, 247))	('protein kinase B', 'Gene', '2185', (138, 154))	('mechanistic target of rapamycin', 'Gene', (155, 186))	('mechanistic target of rapamycin', 'Gene', '2475', (155, 186))	('mitogen-activated', 'MPA', (74, 91))	('neoplasms', 'Disease', (340, 349))	('protein kinase B', 'Gene', (138, 154))	('NF1', 'Gene', '4763', (26, 29))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', '4763', (325, 328))	('neoplasms', 'Phenotype', 'HP:0002664', (340, 349))
274359	33734413	A 2000 review found that NF1-associated LGGs undergo malignant transformation more frequently than comparable sporadic LGGs; thus, malignant transformation of NF1-associated LGGs may be associated with the increased prevalence and younger age of diagnosis for HGG among patients with NF1 in our study compared with the general population.	('NF1', 'Gene', '4763', (159, 162))	('patients', 'Species', '9606', (270, 278))	('malignant transformation', 'Var', (131, 155))	('NF1', 'Gene', (284, 287))	('HGG', 'Disease', (260, 263))	('NF1', 'Gene', '4763', (284, 287))	('NF1', 'Gene', (25, 28))	('NF1', 'Gene', '4763', (25, 28))	('NF1', 'Gene', (159, 162))
274421	29539283	After the introduction of zidovudine and didanosine, the incidence of these tumors began to decrease.	('didanosine', 'Chemical', 'MESH:D016049', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('zidovudine', 'Chemical', 'MESH:D015215', (26, 36))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('didanosine', 'Var', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
274497	29539283	The presence of HIV also increases the risk of classic Hodgkin's lymphoma, which is not AIDS-defining.	('AIDS', 'Disease', (88, 92))	('AIDS', 'Disease', 'MESH:D000163', (88, 92))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (55, 73))	('HIV', 'Species', '12721', (16, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (65, 73))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (55, 73))	('presence', 'Var', (4, 12))	("Hodgkin's lymphoma", 'Disease', (55, 73))
274513	29539283	However, in patients with advanced AIDS in whom a biopsy is not possible, the combination of an FDG-avid CNS lesion and an elevated EBV viral load in the CSF has a high positive predictive value and can be used to justify therapy.	('patients', 'Species', '9606', (12, 20))	('EBV', 'Disease', (132, 135))	('FDG', 'Chemical', 'MESH:D019788', (96, 99))	('AIDS', 'Disease', 'MESH:D000163', (35, 39))	('CNS', 'Disease', (105, 108))	('AIDS', 'Disease', (35, 39))	('EBV', 'Disease', 'MESH:D020031', (132, 135))	('lesion', 'Var', (109, 115))
274535	29539283	In addition, HIV increases the risk of several other cancers, including squamous-cell skin cancer, Merkel-cell carcinoma, the myelodysplastic syndrome, polycythemia vera, and (especially in sub-Saharan Africa) squamous-cell carcinoma of the conjunctiva.	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (126, 150))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('squamous-cell carcinoma', 'Disease', (210, 233))	('Merkel-cell carcinoma', 'Disease', 'MESH:D015266', (99, 120))	('squamous-cell skin cancer', 'Disease', 'MESH:D018307', (72, 97))	('polycythemia', 'Phenotype', 'HP:0001901', (152, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('squamous-cell carcinoma', 'Disease', 'MESH:D002294', (210, 233))	('HIV', 'Species', '12721', (13, 16))	('polycythemia vera', 'Disease', (152, 169))	('Merkel-cell carcinoma', 'Disease', (99, 120))	('squamous-cell skin cancer', 'Disease', (72, 97))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('myelodysplastic syndrome', 'Disease', (126, 150))	('cancers', 'Disease', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('HIV', 'Var', (13, 16))	('skin cancer', 'Phenotype', 'HP:0008069', (86, 97))	('polycythemia vera', 'Disease', 'MESH:D011087', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (126, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
274639	28403880	Surprisingly, we found that the global health status/QoL in the TM-ILP group was not significantly different from the general population or from patients with amputation, but it was higher than that of patients with cancer in general.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('patients', 'Species', '9606', (202, 210))	('TM-ILP', 'Var', (64, 70))	('higher', 'PosReg', (182, 188))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))
274662	28403880	By definition, TM-ILP itself cannot be considered a curative treatment; however, the combination of TM-ILP followed by resection of the residual tumor can establish local tumor control and, thus, limb salvage in more than 80% of cases.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (145, 150))	('limb salvage', 'CPA', (196, 208))	('tumor', 'Disease', (171, 176))	('TM-ILP', 'Var', (100, 106))
274666	28403880	Six weeks after TM-ILP, the response of the tumor to ILP was assessed using MRI, and the remaining tumor was removed with close margins (usually 1-2 mm safety margin) in a limb-sparing and function-preserving resection.	('tumor', 'Disease', (99, 104))	('TM-ILP', 'Var', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (44, 49))
274734	28403880	Nonetheless, we identified a difference in QoL specifically between patients with TM-ILP and the EORTC's all cancer patients group: patients after TM-ILP showed significantly higher scores on the global health status/QoL scale.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('higher', 'PosReg', (175, 181))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Disease', (109, 115))	('patients', 'Species', '9606', (68, 76))	('global health status/QoL scale', 'MPA', (196, 226))	('TM-ILP', 'Var', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('patients', 'Species', '9606', (132, 140))
274737	28403880	To the contrary, our data indicate that the overall QoL of patients after TM-ILP seemed less affected than cancer patients in general.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('less', 'NegReg', (88, 92))	('TM-ILP', 'Var', (74, 80))	('patients', 'Species', '9606', (59, 67))	('QoL', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Disease', (107, 113))
274756	27378829	Systemic inhibition of Notch signaling reduced muscle atrophy.	('muscle atrophy', 'Disease', 'MESH:D009133', (47, 61))	('muscle atrophy', 'Phenotype', 'HP:0003202', (47, 61))	('reduced', 'NegReg', (39, 46))	('Notch signaling', 'Gene', (23, 38))	('muscle atrophy', 'Disease', (47, 61))	('inhibition', 'Var', (9, 19))	('S', 'Chemical', 'MESH:D013455', (0, 1))
274782	27378829	K7M2 has high metastatic potential and has previously been shown to feature increased Notch signaling when compared with nonmetastatic osteosarcoma cells.	('metastatic potential', 'CPA', (14, 34))	('K7M2', 'Var', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('increased', 'PosReg', (76, 85))	('osteosarcoma', 'Disease', (135, 147))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('osteosarcoma', 'Disease', 'MESH:D012516', (135, 147))	('Notch signaling', 'MPA', (86, 101))
274792	27378829	K7M2 and K12 are related murine osteosarcoma cell populations with differing metastatic potentials: K7M2 is highly metastatic to the lung but K12 is virtually nonmetastatic.	('K7M2', 'Var', (100, 104))	('osteosarcoma', 'Disease', (32, 44))	('osteosarcoma', 'Phenotype', 'HP:0002669', (32, 44))	('osteosarcoma', 'Disease', 'MESH:D012516', (32, 44))	('murine', 'Species', '10090', (25, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
274842	27378829	While the effect of Notch inhibition on cancer development has been extensively studied, its effect in CAC has not been addressed.	('CAC', 'Disease', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('inhibition', 'NegReg', (26, 36))	('cancer', 'Disease', (40, 46))	('Notch', 'Var', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CAC', 'Phenotype', 'HP:0004326', (103, 106))
274845	27378829	Results showed that the size of the primary osteosarcoma tumors was not significantly decreased by Notch inhibition (Figure 4(a)).	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (44, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Notch inhibition', 'Var', (99, 115))	('osteosarcoma tumors', 'Disease', (44, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('osteosarcoma', 'Phenotype', 'HP:0002669', (44, 56))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))
274849	27378829	Compared with the control MDSCs (MDSC/MDSC or MDSC/K12), MDSCs cocultured with K7M2 (MDSC/K7M2) developed reduced myogenic potential, as demonstrated by the decreased immunostaining of myosin heavy chain (MHC)+ myotubes (Figures 5(b) and 5(c)).	('myogenic potential', 'CPA', (114, 132))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('K7M2', 'Var', (79, 83))	('MDSC/K12', 'Gene', (46, 54))	('immunostaining', 'MPA', (167, 181))	('MDSC/K12', 'Gene', '268482', (46, 54))	('S', 'Chemical', 'MESH:D013455', (59, 60))	('S', 'Chemical', 'MESH:D013455', (40, 41))	('decreased', 'NegReg', (157, 166))	('reduced', 'NegReg', (106, 113))	('S', 'Chemical', 'MESH:D013455', (28, 29))	('S', 'Chemical', 'MESH:D013455', (48, 49))
274853	27378829	This observation suggests that Notch inhibition could rescue the myogenic potential of MDSCs repressed by coculture with K7M2 cells.	('rescue', 'PosReg', (54, 60))	('Notch inhibition', 'Var', (31, 47))	('S', 'Chemical', 'MESH:D013455', (89, 90))	('myogenic potential', 'CPA', (65, 83))
274854	27378829	Here, we directly compared the expression levels of Notch pathway genes between K7M2 cells and MDSCs and found they were greater in K7M2 cells (Figures 5(d) and 5(e)).	('S', 'Chemical', 'MESH:D013455', (97, 98))	('Notch pathway genes', 'Gene', (52, 71))	('K7M2', 'Var', (132, 136))	('expression levels', 'MPA', (31, 48))	('greater', 'PosReg', (121, 128))
274860	27378829	Additionally, the expression of Notch signaling genes in MDSCs was found to be upregulated by K7M2 exosome treatment, in contrast to MSDCs treated with exosomes isolated from MDSCs (MDSC exosomes) (Figures 6(b) and 6(c)).	('S', 'Chemical', 'MESH:D013455', (184, 185))	('S', 'Chemical', 'MESH:D013455', (177, 178))	('K7M2 exosome', 'Var', (94, 106))	('expression', 'MPA', (18, 28))	('S', 'Chemical', 'MESH:D013455', (134, 135))	('Notch signaling genes', 'Gene', (32, 53))	('upregulated', 'PosReg', (79, 90))	('S', 'Chemical', 'MESH:D013455', (59, 60))
274875	27378829	This current result also reveals the coactivation of proinflammatory signaling and Notch signaling in both the K7M2-induced osteosarcoma tumor and the atrophic muscles of tumor-bearing mice (Figure 3).	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('osteosarcoma tumor', 'Disease', 'MESH:D012516', (124, 142))	('proinflammatory signaling', 'MPA', (53, 78))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('mice', 'Species', '10090', (185, 189))	('atrophic muscle', 'Phenotype', 'HP:0003202', (151, 166))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('atrophic muscles of tumor', 'Disease', 'MESH:D020966', (151, 176))	('K7M2-induced', 'Var', (111, 123))	('osteosarcoma tumor', 'Disease', (124, 142))	('atrophic muscles', 'Phenotype', 'HP:0003202', (151, 167))	('Notch signaling', 'MPA', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('atrophic muscles of tumor', 'Disease', (151, 176))
274886	27378829	Therefore, we suggest that exosomes from K7M2 cells may contain miRNAs, Notch ligands (e.g., DLLs or Jagged), or both, allowing transfer of the Notch-activating signal from tumor to muscle.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('K7M2', 'Var', (41, 45))	('Notch-activating signal', 'MPA', (144, 167))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('transfer', 'MPA', (128, 136))
274888	27378829	Notch inhibitors, including gamma-secretase inhibitors, have been extensively studied in clinical trials in patients with solid tumors; MK-0752, a potent inhibitor of gamma-secretase, has been utilized in clinical trials to study its effect on Notch inhibition and cancer development.	('solid tumors', 'Disease', (122, 134))	('MK-0752', 'Var', (136, 143))	('MK-0752', 'Chemical', 'MESH:C554093', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('solid tumors', 'Disease', 'MESH:D009369', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('patients', 'Species', '9606', (108, 116))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))
274889	27378829	Our current study illustrated that although systemic MK-0752 treatment of tumor-carrying mice at a lower dosage may not efficiently repress the gross development of osteosarcoma, it could still improve the histology of atrophic muscle.	('improve', 'PosReg', (194, 201))	('MK-0752', 'Var', (53, 60))	('osteosarcoma', 'Disease', (165, 177))	('MK-0752', 'Chemical', 'MESH:C554093', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('osteosarcoma', 'Phenotype', 'HP:0002669', (165, 177))	('atrophic muscle', 'Phenotype', 'HP:0003202', (219, 234))	('mice', 'Species', '10090', (89, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('atrophic muscle', 'Disease', 'MESH:D020966', (219, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('tumor', 'Disease', (74, 79))	('atrophic muscle', 'Disease', (219, 234))
275004	23431249	The IGF1R gene was sequenced in 47 ES tumor samples and 8 ES cell lines; only one tumor sample showed a nonsynonymous mutation, R1353H, in a region with low functional impact.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ES', 'Phenotype', 'HP:0012254', (35, 37))	('R1353H', 'Mutation', 'rs149470389', (128, 134))	('IGF1R', 'Gene', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('R1353H', 'Var', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('ES tumor', 'Disease', 'MESH:C563168', (35, 43))	('ES tumor', 'Disease', (35, 43))	('IGF1R', 'Gene', '3480', (4, 9))	('tumor', 'Disease', (82, 87))	('ES', 'Phenotype', 'HP:0012254', (58, 60))
275035	23431249	Total and phosphorylated proteins were assessed using separate multiplex assays for the IGF-1R signaling pathway according to the manufacturer's instructions: Akt Phospho 7-Plex Panel (LHO0001) and Akt Total 7-Plex Panel (LHO0002, Life Technologies, Carlsbad, CA).	('Akt', 'Gene', (159, 162))	('Akt', 'Gene', '207', (198, 201))	('IGF-1R signaling pathway', 'Pathway', (88, 112))	('LHO0001', 'Var', (185, 192))	('LHO0002', 'Var', (222, 229))	('Akt', 'Gene', (198, 201))	('Akt', 'Gene', '207', (159, 162))
275048	23431249	NWTb3 cells showed a mean fluorescence of 1127.32, comparatively greater than the mean fluorescence of TC71 , RDES , SKES , MHH-ES-1 , A4573 , and TC32  cells (Figure 2).	('TC71', 'CellLine', 'CVCL:2213', (103, 107))	('greater', 'PosReg', (65, 72))	('fluorescence', 'MPA', (26, 38))	('ES', 'Phenotype', 'HP:0012254', (128, 130))	('1127.32', 'Var', (42, 49))	('ES', 'Phenotype', 'HP:0012254', (112, 114))	('ES', 'Phenotype', 'HP:0012254', (119, 121))	('TC32', 'CellLine', 'CVCL:7151', (147, 151))
275053	23431249	Differences in IGF-1R total protein levels among ALDH-sorted ES cell populations were not statistically significant, though ALDH-high SKES cells tended to express slightly less IGF-1R than ALDH-low or unsorted cells, while ALDH-high TC71 cells expressed slightly more IGF-1R than respective ALDH-low or unsorted populations (Figure 5(a)).	('ALDH-high', 'Var', (124, 133))	('less', 'NegReg', (172, 176))	('IGF-1R', 'MPA', (177, 183))	('ES', 'Phenotype', 'HP:0012254', (136, 138))	('ES', 'Phenotype', 'HP:0012254', (61, 63))	('TC71', 'CellLine', 'CVCL:2213', (233, 237))
275061	23431249	Of these 55 total DNAs, only one sample, an ES tumor sample, showed a nonsynonymous mutation, R1353H, encoded in exon 21, the last exon.	('ES tumor', 'Disease', 'MESH:C563168', (44, 52))	('ES tumor', 'Disease', (44, 52))	('R1353H', 'Mutation', 'rs149470389', (94, 100))	('R1353H', 'Var', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ES', 'Phenotype', 'HP:0012254', (44, 46))
275077	23431249	Mutations in IGF-1R have not yet been identified in sarcoma in the published literature.	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('sarcoma', 'Disease', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('Mutations', 'Var', (0, 9))	('IGF-1R', 'Gene', (13, 19))
275078	23431249	A limited set of tumors analyzed for IGF-1R mutations are described in the Sanger COSMIC database, and mutations were identified in 13 of 1486 tumor samples (0.9%) within 7 of 18 tumor types.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (143, 148))	('tumors', 'Disease', (17, 23))	('IGF-1R', 'Gene', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (179, 184))
275080	23431249	Importantly, a recent study of the IGF-1R system as a prognostic indicator in Ewing sarcoma reported that, contrary to prior assumptions, high expression of IGF-1 and IGF-1R predicted higher rates of event-free and overall survival, suggesting that the patients most in need of targeted therapies may not be in the subset of patients who will respond to IGF-1R treatment.	('patients', 'Species', '9606', (325, 333))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('IGF-1', 'Gene', (157, 162))	('patients', 'Species', '9606', (253, 261))	('IGF-1R', 'Gene', (167, 173))	('overall survival', 'CPA', (215, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('higher', 'PosReg', (184, 190))	('high', 'Var', (138, 142))	('Ewing sarcoma', 'Disease', (78, 91))
275081	23431249	The promise of IGF-1R inhibition as a treatment for Ewing sarcoma garnered remarkable enthusiasm over the course of the past two decades.	('inhibition', 'Var', (22, 32))	('IGF-1R', 'Gene', (15, 21))	('Ewing sarcoma garnered', 'Disease', (52, 74))	('Ewing sarcoma garnered', 'Disease', 'MESH:C563168', (52, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
275085	23431249	Successful inhibition of tumor growth was subsequently demonstrated in ES xenograft models with dominant negative receptors, antisense knockdown, and small molecules targeting IGF-1R.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('IGF-1R', 'Gene', (176, 182))	('antisense knockdown', 'Var', (125, 144))	('knockdown', 'Var', (135, 144))	('tumor', 'Disease', (25, 30))	('ES', 'Phenotype', 'HP:0012254', (71, 73))	('inhibition', 'NegReg', (11, 21))	('negative', 'NegReg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
275086	23431249	It is important to note that in the antisense and dominant negative IGF-1R experiments, tumor cell expression of IGF-1R was impaired at the time of injection, thus preventing robust establishment of tumors, and in the alphaIR3 and small molecule studies, treatment also began before tumors were well established.	('impaired', 'NegReg', (124, 132))	('tumors', 'Disease', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('IGF-1R', 'Gene', (113, 119))	('preventing', 'NegReg', (164, 174))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('negative', 'NegReg', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('antisense', 'Var', (36, 45))	('tumors', 'Disease', (283, 289))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('IR', 'Gene', '3643', (223, 225))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (283, 288))	('IGF-1R', 'Gene', (68, 74))
275092	23431249	Currently, phase I/II or phase II trials of three humanized monoclonal antibodies have been conducted in Ewing sarcoma: R1507 (Roche, Basel, Switzerland), figitumumab (CP-751871; Pfizer, New London, CT), and cixutumumab (IMC-A12; ImClone systems, Branchburg, NJ).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('figitumumab', 'Chemical', 'MESH:C525021', (155, 166))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('cixutumumab', 'Chemical', 'MESH:C557414', (208, 219))	('CP-751871;', 'Var', (168, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('human', 'Species', '9606', (50, 55))	('Ewing sarcoma', 'Disease', (105, 118))
275097	23431249	Indeed, high IGFBP3, low IGF-1, and high IGFBP-3/IGF-1 ratios were associated with better overall survival in a retrospective study of patients with ES.	('high', 'Var', (8, 12))	('patients', 'Species', '9606', (135, 143))	('IGFBP-3', 'Gene', (41, 48))	('ES', 'Phenotype', 'HP:0012254', (149, 151))	('low', 'NegReg', (21, 24))	('IGFBP3', 'Gene', '3486', (13, 19))	('high IGFBP', 'Phenotype', 'HP:0030269', (8, 18))	('low IGF', 'Phenotype', 'HP:0002850', (21, 28))	('better', 'PosReg', (83, 89))	('IGFBP-3', 'Gene', '3486', (41, 48))	('high IGFBP', 'Phenotype', 'HP:0030269', (36, 46))	('IGF-1', 'Gene', (25, 30))	('IGFBP3', 'Gene', (13, 19))	('overall survival', 'MPA', (90, 106))
275101	23431249	Anti-IGF-1R therapy clearly provides therapeutic benefit for a select group of patients, and identifying predictive markers of this effect would be an extraordinary advance toward individualizing treatment.	('Anti-IGF-1R', 'Var', (0, 11))	('therapeutic benefit', 'MPA', (37, 56))	('patients', 'Species', '9606', (79, 87))
275104	23431249	In the figitumumab trial, intermediate pretreatment IGF-1 levels were associated with higher overall survival, with patients in the second and third quartiles of baseline IGF-1 levels showing longer median survival probabilities by several months when compared to those in the highest and lowest quartiles.	('intermediate', 'Var', (26, 38))	('overall survival', 'MPA', (93, 109))	('figitumumab', 'Chemical', 'MESH:C525021', (7, 18))	('longer', 'PosReg', (192, 198))	('patients', 'Species', '9606', (116, 124))	('IGF-1', 'Gene', (171, 176))	('higher', 'PosReg', (86, 92))	('IGF-1', 'Gene', (52, 57))
275107	23431249	Studies have shown potential positive interactions of IGF-1R inhibitors with the c-Kit inhibitor imatinib and the Her2 inhibitor trastuzumab.	('trastuzumab', 'Chemical', 'MESH:D000068878', (129, 140))	('Her2', 'Gene', (114, 118))	('inhibitors', 'Var', (61, 71))	('imatinib', 'Chemical', 'MESH:D000068877', (97, 105))	('c-Kit', 'Gene', (81, 86))	('interactions', 'Interaction', (38, 50))	('c-Kit', 'Gene', '3815', (81, 86))	('Her2', 'Gene', '2064', (114, 118))	('IGF-1R', 'Gene', (54, 60))
275118	23431249	However, despite the numerous potential candidates for combination therapy with anti-IGF-1R antibodies, it is necessary to take into account the mixed results of preclinical and clinical studies as well as the modest biological evidence underlying IGF-1R as a target for Ewing sarcoma therapy.	('Ewing sarcoma', 'Disease', (271, 284))	('anti-IGF-1R', 'Gene', (80, 91))	('clinical', 'Species', '191496', (178, 186))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (271, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (271, 284))	('anti-IGF-1R', 'Var', (80, 91))	('clinical', 'Species', '191496', (165, 173))
275143	22020872	[18F]FLT-MP is a very poor substrate for thymidylate kinase, the second kinase in the thymidine salvage pathway, and very little FLT becomes incorporated into the DNA.	('thymidine', 'Chemical', 'MESH:D013936', (86, 95))	('FLT', 'Chemical', '-', (129, 132))	('[18F]', 'Var', (0, 5))	('FLT', 'Chemical', '-', (5, 8))	('thymidylate kinase', 'Gene', (41, 59))	('thymidylate kinase', 'Gene', '1841', (41, 59))
275226	22020872	These observations suggest that measurements of [18F]FLT tumor uptake after neoadjuvant chemotherapy and/or radiation therapy are unlikely to improve treatment response assessment as compared with [18F]FDG-PET.	('[18F]FLT', 'Var', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('FLT', 'Chemical', '-', (53, 56))	('tumor', 'Disease', (57, 62))	('FDG', 'Chemical', '-', (202, 205))
275253	22020872	Animal experimental studies have shown that [18F]FLT tumor uptake decreases rapidly in response to a variety of therapeutic interventions, and some have reported earlier response predictions with [18F]FLT than with [18F]FDG.	('FLT', 'Chemical', '-', (49, 52))	('decreases', 'NegReg', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('FLT', 'Chemical', '-', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('[18F]FLT', 'Var', (196, 204))	('tumor', 'Disease', (53, 58))	('FDG', 'Chemical', '-', (220, 223))
275294	22020872	In summary, in patients with high-grade soft tissue sarcoma, [18F]FLT PET/CT imaging does not reliably predict histopathological response to neoadjuvant therapy, and [18F]FLT uptake is unrelated to TK1 and Ki-67 expression.	('TK1', 'Gene', '7083', (198, 201))	('patients', 'Species', '9606', (15, 23))	('[18F]FLT', 'Var', (166, 174))	('FLT', 'Chemical', '-', (66, 69))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (40, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (40, 59))	('soft tissue sarcoma', 'Disease', (40, 59))	('FLT', 'Chemical', '-', (171, 174))	('TK1', 'Gene', (198, 201))
275296	22020872	Moreover, the reasons for the uncoupling between [18F]FLT retention and TK1 and Ki-67 activity in sarcoma warrants further studies.	('[18F]', 'Var', (49, 54))	('TK1', 'Gene', (72, 75))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcoma', 'Disease', (98, 105))	('FLT', 'Chemical', '-', (54, 57))	('TK1', 'Gene', '7083', (72, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
275304	31304084	Molecular targeted drugs such as epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), however, have remarkably improved the clinical course for non-small cell lung cancer (NSCLC) patients with EGFR mutations.	('patients', 'Species', '9606', (201, 209))	('epidermal growth factor receptor', 'Gene', '1956', (33, 65))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (170, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('NSCLC', 'Disease', (194, 199))	('EGFR', 'Gene', (67, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (166, 192))	('EGFR', 'Gene', '1956', (215, 219))	('EGFR', 'Gene', (215, 219))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('epidermal growth factor receptor', 'Gene', (33, 65))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (166, 192))	('improved', 'PosReg', (133, 141))	('clinical', 'MPA', (146, 154))	('EGFR', 'Gene', '1956', (67, 71))	('mutations', 'Var', (220, 229))	('non-small cell lung cancer', 'Disease', (166, 192))
275310	31304084	In 2008, a 60-year-old Japanese man was first diagnosed with cT2N0M1 stage IV adenocarcinoma of the lung and multiple metastases including the brain and the 12th thoracic vertebra (Th12) (Fig.	('adenocarcinoma of the lung', 'Disease', (78, 104))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (78, 104))	('12th thoracic vertebra', 'Disease', 'MESH:D013896', (157, 179))	('metastases', 'Disease', (118, 128))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('12th thoracic vertebra', 'Phenotype', 'HP:0011940', (157, 179))	('12th thoracic vertebra', 'Disease', (157, 179))	('cT2N0M1', 'Var', (61, 68))	('man', 'Species', '9606', (32, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
275313	31304084	After the disease progression of lung lesion was detected in computed tomography (CT) in 2014, a lung rebiopsy revealed an activating EGFR mutation (exon 19 deletion) without a secondary mutation (T790M) in exon 20.	('activating', 'PosReg', (123, 133))	('EGFR', 'Gene', (134, 138))	('T790M', 'Mutation', 'rs121434569', (197, 202))	('lung lesion', 'Disease', 'MESH:D008171', (33, 44))	('lung lesion', 'Disease', (33, 44))	('exon', 'Var', (149, 153))	('EGFR', 'Gene', '1956', (134, 138))
275316	31304084	In 2017, the disease progression of lung lesion was further developed in CT, and a liquid biopsy showed a secondary mutation (T790M) in exon 20 of EGFR.	('EGFR', 'Gene', (147, 151))	('lung lesion', 'Disease', 'MESH:D008171', (36, 47))	('lung lesion', 'Disease', (36, 47))	('T790M', 'Mutation', 'rs121434569', (126, 131))	('T790M', 'Var', (126, 131))	('EGFR', 'Gene', '1956', (147, 151))
275337	31304084	The resulting genomic instability could cause second malignancies including RIS.	('cause', 'Reg', (40, 45))	('malignancies', 'Disease', (53, 65))	('RIS', 'Disease', (76, 79))	('RIS', 'Chemical', '-', (76, 79))	('genomic instability', 'Var', (14, 33))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))
275344	31304084	Epithelial-to-mesenchymal transition (EMT) including sarcomatous transformation of metastatic lung adenocarcinoma has been reported as a cause of acquired resistance to EGFR-TKIs; namely, the original genetic phenotype such as activating EGFR mutations is retained, despite EMT.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('EGFR', 'Gene', '1956', (169, 173))	('activating', 'PosReg', (227, 237))	('mutations', 'Var', (243, 252))	('EGFR', 'Gene', '1956', (238, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('EGFR', 'Gene', (238, 242))	('Epithelial-to-mesenchymal transition', 'CPA', (0, 36))	('EGFR', 'Gene', (169, 173))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (53, 79))	('sarcomatous transformation of metastatic lung adenocarcinoma', 'Disease', 'MESH:D018316', (53, 113))
275345	31304084	In the present case, however, the genetic examination of the sarcoma revealed no mutations in EGFR, indicating that the detected sarcoma is not correlated with the primary lung cancer.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('EGFR', 'Gene', '1956', (94, 98))	('primary lung cancer', 'Disease', (164, 183))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('EGFR', 'Gene', (94, 98))	('primary lung cancer', 'Disease', 'MESH:D008175', (164, 183))	('mutations', 'Var', (81, 90))	('sarcoma', 'Disease', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('sarcoma', 'Disease', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
275420	26499785	Histopathological findings for the 71 patients who were referred to us after an unplanned excision and who had complete presentation status showed that 16.7 % had complete tumor resection (R0 resection status), 69.8 % had microscopic incomplete resection (R1 resection status), and 13.5 % had macroscopic incomplete resection (R2 resection status).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('microscopic', 'Var', (222, 233))	('patients', 'Species', '9606', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
275429	26499785	On the other hand, revisional surgery that excised the residual tumor led to a real improvement in resection status in half of the cases (n = 35, 49.3 %; R0-R0-1 n = 6, R1-R0-1 n = 22, R2-R0-1 n = 6, and R2-R1-1 n = 1).	('tumor', 'Disease', (64, 69))	('resection', 'MPA', (99, 108))	('R2-R0-1', 'Var', (185, 192))	('R0-R0-1', 'Var', (154, 161))	('improvement', 'PosReg', (84, 95))	('R1-R0-1', 'Var', (169, 176))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('R2-R1-1', 'Var', (204, 211))
275555	32290418	Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility Ewing sarcoma is an aggressive pediatric cancer of enigmatic cellular origins typically resulting from a single translocation event t (11; 22) (q24; q12).	('Ewing Sarcoma Developmental', 'Disease', (18, 45))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (139, 152))	('Ewing Sarcoma Developmental', 'Disease', 'MESH:C563168', (18, 45))	('FLI1', 'Gene', '2313', (119, 123))	('EWSR1', 'Gene', '2130', (113, 118))	('Sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('t (11; 22) (q24; q12', 'Var', (271, 291))	('resulting from', 'Reg', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (139, 152))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (18, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('FLI1', 'Gene', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Ewing sarcoma', 'Disease', (139, 152))	('EWSR1', 'Gene', (113, 118))	('cancer', 'Disease', (180, 186))
275559	32290418	Ewing sarcoma is an aggressive cancer of the bone and soft tissues resulting from the fusion of Ewing sarcoma RNA Binding Protein 1 (EWSR1) to Friend leukemia integration 1 transcription factor (FLI1) (85%) or E-twenty-six-related (ETS-related) gene (ERG) (15%).	('ERG', 'Gene', (251, 254))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('ERG', 'Gene', '2078', (251, 254))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('cancer of the bone', 'Phenotype', 'HP:0010622', (31, 49))	('resulting from', 'Reg', (67, 81))	('cancer', 'Disease', (31, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('FLI1', 'Gene', (195, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Disease', (96, 109))	('Friend leukemia integration 1 transcription factor', 'Gene', (143, 193))	('Friend leukemia integration 1 transcription factor', 'Gene', '2313', (143, 193))	('fusion', 'Var', (86, 92))	('EWSR1', 'Gene', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (31, 37))
275562	32290418	However, ectopic EWSR1-FLI1 expression is toxic or unstable in most primary cell types and, to date, no successful model of Ewing sarcomagenesis has been established.	('ectopic', 'Var', (9, 16))	('Ewing sarcomagenesis', 'Disease', (124, 144))	('Ewing sarcomagenesis', 'Disease', 'MESH:C563168', (124, 144))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (124, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('EWSR1-FLI1', 'Gene', (17, 27))	('Ewing sarcomagenesis', 'Phenotype', 'HP:0012254', (124, 144))
275579	32290418	It was previously reported that ectopic EWSR1-FLI1 expression induces neuroectodermal marker expression in MSCs and that EWSR1-FLI1 knockdown in Ewing sarcoma cells promotes mesenchymal marker expression.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (145, 158))	('induces', 'PosReg', (62, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (145, 158))	('neuroectodermal marker expression', 'MPA', (70, 103))	('promotes', 'PosReg', (165, 173))	('EWSR1-FLI1', 'Gene', (40, 50))	('MSCs', 'Disease', (107, 111))	('Ewing sarcoma', 'Disease', (145, 158))	('ectopic', 'Var', (32, 39))	('EWSR1-FLI1', 'Gene', (121, 131))	('mesenchymal marker expression', 'CPA', (174, 203))
275581	32290418	Studies which involved depleting EWSR1-FLI1 were analyzed for corresponding changes in PHATE_1 position (Figure S5).	('PHATE', 'Chemical', '-', (87, 92))	('depleting', 'Var', (23, 32))	('EWSR1-FLI1', 'Gene', (33, 43))
275582	32290418	It was found in each case that EWSR1-FLI1 knock-down drove cells higher on PHATE_1 towards the mesodermal branch and away from the pluripotency/neuroectodermal lineage branches.	('EWSR1-FLI1', 'Gene', (31, 41))	('knock-down', 'Var', (42, 52))	('pluripotency', 'Disease', (131, 143))	('PHATE_1', 'Gene', (75, 82))	('PHATE', 'Chemical', '-', (75, 80))	('pluripotency', 'Disease', 'None', (131, 143))
275584	32290418	This revealed the genes which drive samples higher on PHATE_1 and vice versa (Figure 3C).	('higher', 'PosReg', (44, 50))	('PHATE', 'Chemical', '-', (54, 59))	('PHATE_1', 'Var', (54, 61))
275591	32290418	In agreement with this finding, we found that LSD1-inhibiting interventions like SP2509 treatment and LSD1 knock-down pushed Ewing sarcoma higher on PHATE_1 (Figure S6B-D).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('PHATE', 'Chemical', '-', (149, 154))	('LSD1', 'Gene', (46, 50))	('knock-down', 'Var', (107, 117))	('LSD1', 'Gene', '23028', (46, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Ewing sarcoma', 'Disease', (125, 138))	('LSD1', 'Gene', (102, 106))	('higher', 'PosReg', (139, 145))	('LSD1', 'Gene', '23028', (102, 106))
275593	32290418	Furthermore, recent literature indicates that EWSR1-FLI1 antagonizes TEA domain transcription factor 1 (TEAD1) transcriptional programs.	('TEA domain transcription factor 1', 'Gene', (69, 102))	('EWSR1-FLI1', 'Var', (46, 56))	('antagonizes', 'NegReg', (57, 68))	('TEAD1', 'Gene', '7003', (104, 109))	('TEAD1', 'Gene', (104, 109))	('TEA domain transcription factor 1', 'Gene', '7003', (69, 102))
275600	32290418	In the above results, we found that EWSR1-FLI1 pushes Ewing sarcoma cells along a developmental trajectory between pluripotent/neuroectodermal and mesodermal cell states.	('EWSR1-FLI1', 'Var', (36, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (54, 67))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (54, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('Ewing sarcoma', 'Disease', (54, 67))
275617	32290418	If our first assertion is correct, then it follows that PHATE_1-low (pluripotent/neuroectodermal) tissues would show significantly higher accumulation of R-loops compared to PHATE_1-high (mesodermal) tissues.	('PHATE', 'Chemical', '-', (56, 61))	('PHATE_1-low', 'Var', (56, 67))	('PHATE', 'Chemical', '-', (174, 179))	('R-loops', 'MPA', (154, 161))	('higher accumulation', 'PosReg', (131, 150))
275618	32290418	This analysis revealed that there are significantly more R-loops in PHATE_1-low cell types (iPSCs, NSCs, and hESCs) compared to a PHATE_1-high cell type (MSCs).	('PHATE_1-low', 'Var', (68, 79))	('hESCs', 'Disease', (109, 114))	('PHATE', 'Chemical', '-', (130, 135))	('R-loops', 'MPA', (57, 64))	('NSCs', 'Disease', (99, 103))	('more', 'PosReg', (52, 56))	('PHATE', 'Chemical', '-', (68, 73))
275621	32290418	However, we had not identified any downstream effectors that might be key to processing R-loops and maintaining genome stability in these tumors.	('R-loops', 'Var', (88, 95))	('genome', 'MPA', (112, 118))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
275624	32290418	Compared to IMR90, a fibroblast and PHATE_1-high cell type, we observed dramatic increase in the post-translationally modified (activated/ mono-ubiquitinated) forms of FANCD2 and FANCI protein in Ewing sarcoma cells (black triangles, Figure 7A) and a marked increase in cell death with knockdown of multiple Fanconi anemia genes (Figure 7B).	('knockdown', 'Var', (286, 295))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('cell death', 'CPA', (270, 280))	('anemia', 'Phenotype', 'HP:0001903', (316, 322))	('IMR90', 'CellLine', 'CVCL:0347', (12, 17))	('Ewing sarcoma', 'Disease', (196, 209))	('Fanconi anemia', 'Disease', (308, 322))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (308, 322))	('PHATE', 'Chemical', '-', (36, 41))	('post-translationally modified', 'MPA', (97, 126))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (196, 209))	('increase', 'PosReg', (81, 89))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (196, 209))	('Fanconi anemia', 'Disease', 'MESH:D005199', (308, 322))	('FANCD2', 'Gene', (168, 174))
275628	32290418	Furthermore, the chemical inhibition of FEN1 resulted in severe toxicity in Ewing sarcoma, but not in IMR90 (Figure 7D).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('IMR90', 'CellLine', 'CVCL:0347', (102, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('Ewing sarcoma', 'Disease', (76, 89))	('chemical inhibition', 'Var', (17, 36))	('toxicity', 'Disease', 'MESH:D064420', (64, 72))	('FEN1', 'Gene', (40, 44))	('toxicity', 'Disease', (64, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (76, 89))
275639	32290418	This led us to hypothesize that EWSR1-FLI1 reactivates developmental gene programs in normal tissue types as part of Ewing sarcomagenesis.	('Ewing sarcomagenesis', 'Phenotype', 'HP:0012254', (117, 137))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (117, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('EWSR1-FLI1', 'Var', (32, 42))	('reactivates', 'Reg', (43, 54))	('Ewing sarcomagenesis', 'Disease', (117, 137))	('Ewing sarcomagenesis', 'Disease', 'MESH:C563168', (117, 137))	('developmental gene', 'Gene', (55, 73))
275646	32290418	Multiple studies have demonstrated that ectopic EWSR1-FLI1 expression leads to the expression of neuroectodermal markers in MSCs and that EWSR1-FLI1 depletion in Ewing sarcoma cells leads to increased mesenchymal gene expression patterns.	('ectopic', 'Var', (40, 47))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (162, 175))	('EWSR1-FLI1', 'Gene', (138, 148))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (162, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('leads to', 'Reg', (70, 78))	('increased', 'PosReg', (191, 200))	('mesenchymal gene', 'CPA', (201, 217))	('Ewing sarcoma', 'Disease', (162, 175))	('expression', 'MPA', (83, 93))	('depletion', 'NegReg', (149, 158))	('EWSR1-FLI1', 'Gene', (48, 58))
275651	32290418	These results indicate the degree to which EWSR1-FLI1 hijacks normal developmental trajectories and also indicates that many of the classical Ewing sarcoma gene sets may be, in fact, markers of cell lineage rather than bona fide markers of Ewing sarcoma.	('EWSR1-FLI1', 'Var', (43, 53))	('Ewing sarcoma', 'Disease', (240, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Ewing sarcoma', 'Disease', (142, 155))	('hijacks', 'PosReg', (54, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (240, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (240, 253))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (142, 155))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (142, 155))
275652	32290418	Previous reports demonstrated that inhibition of LSD1 interferes with the EWSR1-FLI1 transcriptomic program.	('LSD1', 'Gene', '23028', (49, 53))	('EWSR1-FLI1', 'Gene', (74, 84))	('inhibition', 'Var', (35, 45))	('interferes', 'NegReg', (54, 64))	('LSD1', 'Gene', (49, 53))
275654	32290418	Furthermore, previous studies have described an antagonistic relationship between TEAD1 and EWSR1-FLI1 in which EWSR1-FLI1 prevents the transcription of TEAD1 target genes, preventing ECM sensing.	('EWSR1-FLI1', 'Var', (112, 122))	('transcription', 'MPA', (136, 149))	('TEAD1', 'Gene', (82, 87))	('prevents', 'NegReg', (123, 131))	('preventing', 'NegReg', (173, 183))	('TEAD1', 'Gene', '7003', (153, 158))	('TEAD1', 'Gene', (153, 158))	('ECM sensing', 'MPA', (184, 195))	('TEAD1', 'Gene', '7003', (82, 87))
275656	32290418	This finding implies that the antagonism between EWSR1-FLI1 and TEAD1 is bi-directional and that Ewing sarcoma cells can be induced to undergo further transformation in basal conditions through TEAD1 knock down.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (97, 110))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (97, 110))	('TEAD1', 'Gene', (64, 69))	('knock down', 'Var', (200, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('TEAD1', 'Gene', '7003', (194, 199))	('Ewing sarcoma', 'Disease', (97, 110))	('TEAD1', 'Gene', (194, 199))	('TEAD1', 'Gene', '7003', (64, 69))
275669	32290418	Given the permissivity for EWSR1-FLI1 in PHATE_1-low tissues, we further hypothesized that they would display high R-loop levels and share Ewing sarcoma's predicted dependency upon R-loop and replication-stress-mitigating factors.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (139, 152))	('PHATE', 'Chemical', '-', (41, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (139, 152))	('EWSR1-FLI1', 'Var', (27, 37))	('Ewing sarcoma', 'Disease', (139, 152))	('high', 'PosReg', (110, 114))	('R-loop levels', 'MPA', (115, 128))
275671	32290418	Furthermore, reanalysis of public DRIP sequencing data revealed that PHATE_1-low tissue types display significantly higher R-loop accumulation compared to PHATE_1-high tissues (Figure 6) and higher expression of Fanconi Anemia and flap endonuclease genes compared to all other tissue types except for Ewing sarcoma and HSCs (Figure 8).	('higher', 'PosReg', (191, 197))	('PHATE', 'Chemical', '-', (155, 160))	('Fanconi Anemia', 'Disease', (212, 226))	('higher', 'PosReg', (116, 122))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (301, 314))	('Fanconi Anemia', 'Disease', 'MESH:D005199', (212, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (307, 314))	('Ewing sarcoma and HSCs', 'Disease', 'MESH:C563168', (301, 323))	('Anemia', 'Phenotype', 'HP:0001903', (220, 226))	('flap endonuclease genes', 'Gene', (231, 254))	('expression', 'MPA', (198, 208))	('PHATE_1-low', 'Var', (69, 80))	('R-loop accumulation', 'MPA', (123, 142))	('Fanconi Anemia', 'Phenotype', 'HP:0001994', (212, 226))	('PHATE', 'Chemical', '-', (69, 74))
275697	32290418	Additionally, the custom collection of "Ewing sarcoma gene sets" was curated in a three-step process: (1) Five new gene sets were defined from recent literature: "Riggi 2014 activated by EWSR1-FLI1" and "Riggi 2014 repressed by EWSR1-FLI1" were defined from Riggi et al.	('Riggi', 'Gene', (163, 168))	('Ewing sarcoma', 'Disease', (40, 53))	('activated', 'PosReg', (174, 183))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (40, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('EWSR1-FLI1', 'Var', (187, 197))
275699	32290418	2020 from independent component analysis of single cell RNA-Sequencing data in a Ewing sarcoma cell line with an inducible knockdown of EWSR1-FLI1, representing gene expression profiles specific to Ewing sarcoma cells with high or low expression of EWSR1-FLI1 respectively.	('Ewing sarcoma', 'Disease', (81, 94))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (198, 211))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (198, 211))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('EWSR1-FLI1', 'Gene', (136, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('knockdown', 'Var', (123, 132))	('Ewing sarcoma', 'Disease', (198, 211))
275702	32290418	"Torchia targets of EWSR1-FLI1 fusion up", "Torchia targets of EWSR1-FLI1 fusion top 20 up", "Torchia targets of EWSR1-FLI1 fusion down", and "Torchia targets of EWSR1-FLI1 fusion top 20 down" were conducted in a mouse model of leukemia, which was deemed unsuitable because of the need for a normal tissue background and the divergent genetic background of mice from humans.	('leukemia', 'Disease', 'MESH:D007938', (228, 236))	('mouse', 'Species', '10090', (213, 218))	('humans', 'Species', '9606', (367, 373))	('fusion', 'Var', (31, 37))	('EWSR1-FLI1', 'Gene', (20, 30))	('leukemia', 'Phenotype', 'HP:0001909', (228, 236))	('mice', 'Species', '10090', (357, 361))	('leukemia', 'Disease', (228, 236))
275704	32290418	The "EWSR1-FLI1 transcriptome" was defined as the "Ewing sarcoma gene sets" which comes from studies that observe changes in gene expression after ectopic expression of EWSR1-FLI1 in non-Ewing tissues or after knock-down of EWSR1-FLI1 in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('EWSR1-FLI1', 'Gene', (224, 234))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (238, 251))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (238, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('EWSR1-FLI1', 'Gene', (169, 179))	('knock-down', 'Var', (210, 220))	('Ewing sarcoma', 'Disease', (51, 64))	('gene expression', 'MPA', (125, 140))	('Ewing sarcoma', 'Disease', (238, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('changes', 'Reg', (114, 121))
275723	32290418	The t test was one-tailed in the case of EWS-FLI1 knock-down experiments, and two-tailed in the case of other interventions.	('knock-down experiments', 'Var', (50, 72))	('EWS', 'Gene', '2130', (41, 44))	('EWS', 'Gene', (41, 44))
275777	31857985	Hallmark translocation of ES involving the fusion of the ES gene on chromosome 22 with the friend leukaemia virus integration site 1 (FLI1) gene on chromosome 11 shows the characteristic translocation t(11;22) (q24;q12) which is present in 85% and > 90% of PNETs/ES and extraosseous ES, respectively (Fig.5) (6).	('FLI1', 'Gene', (134, 138))	('PNET', 'Phenotype', 'HP:0030065', (257, 261))	('friend leukaemia virus integration site 1', 'Gene', (91, 132))	('ES', 'Phenotype', 'HP:0012254', (263, 265))	('ES', 'Phenotype', 'HP:0012254', (57, 59))	('ES', 'Phenotype', 'HP:0012254', (283, 285))	('friend leukaemia virus integration site 1', 'Gene', '2313', (91, 132))	('ES', 'Phenotype', 'HP:0012254', (26, 28))	('t(11;22) (q24;q12', 'Var', (201, 218))	('FLI1', 'Gene', '2313', (134, 138))
275783	31857985	The MRI features included reactive sclerosis pattern with hypointense to isointense on T1W1 and hypointense to hyperintense on T2W2.	('hypointense', 'Var', (96, 107))	('sclerosis', 'Disease', (35, 44))	('hypointense', 'Var', (58, 69))	('sclerosis', 'Disease', 'MESH:D012598', (35, 44))
275803	30518396	Associations of clock genes polymorphisms with soft tissue sarcoma susceptibility and prognosis Dysfunction of the circadian clock and polymorphisms of some circadian genes have been linked to cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('sarcoma', 'Disease', (59, 66))	('Associations', 'Interaction', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('cancer', 'Disease', (193, 199))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (47, 66))	('linked', 'Reg', (183, 189))	('polymorphisms', 'Var', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('polymorphisms', 'Var', (135, 148))
275804	30518396	We investigated the relationship between circadian genes germline variation and susceptibility or prognosis of patients with soft tissue sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('germline', 'Var', (57, 65))	('soft tissue sarcoma', 'Disease', (125, 144))	('investigated', 'Reg', (3, 15))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (125, 144))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (125, 144))	('patients', 'Species', '9606', (111, 119))
275805	30518396	We considered the 14 single nucleotide polymorphisms (SNPs) of 6 core circadian genes that have a minor allele frequency > 5% and that are known to be associated with cancer risk or prognosis.	('single nucleotide polymorphisms', 'Var', (21, 52))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('associated', 'Reg', (151, 161))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
275807	30518396	Associations between the selected clock genes polymorphisms and sarcoma susceptibility or prognosis were tested assuming 3 models of inheritance: additive, recessive and dominant.	('Associations', 'Interaction', (0, 12))	('tested', 'Reg', (105, 111))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Disease', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('polymorphisms', 'Var', (46, 59))
275811	30518396	The present analysis suggested that carriers of the minor allele of the CLOCK polymorphism rs1801260 (C) or of PER2 rs934945 (T) had a reduced predisposition to sarcoma (26% and 35% respectively with the additive model) and liposarcoma (33% and 41% respectively).	('rs1801260', 'Var', (91, 100))	('sarcoma', 'Disease', (161, 168))	('sarcoma', 'Disease', 'MESH:D012509', (228, 235))	('rs934945', 'Var', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('PER2', 'Gene', (111, 115))	('sarcoma', 'Disease', (228, 235))	('rs1801260', 'Mutation', 'rs1801260', (91, 100))	('liposarcoma', 'Disease', (224, 235))	('PER2', 'Gene', '8864', (111, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('reduced', 'NegReg', (135, 142))	('rs934945', 'Mutation', 'rs934945', (116, 124))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('liposarcoma', 'Phenotype', 'HP:0012034', (224, 235))	('liposarcoma', 'Disease', 'MESH:D008080', (224, 235))
275812	30518396	The minor allele (A) of NPAS2 rs895520 was associated with an increased predisposition to sarcoma of 33% and leiomyosarcoma of 44%.	('PAS', 'Chemical', 'MESH:D011478', (25, 28))	('sarcoma', 'Disease', (90, 97))	('leiomyosarcoma', 'Disease', (109, 123))	('sarcoma', 'Disease', (116, 123))	('NPAS2', 'Gene', (24, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (109, 123))	('rs895520', 'Mutation', 'rs895520', (30, 38))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (109, 123))	('rs895520', 'Var', (30, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
275814	30518396	PER1 rs3027178 was associated with a reduced predisposition only in liposarcoma subgroup (32%).	('rs3027178', 'Var', (5, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('liposarcoma', 'Disease', (68, 79))	('PER1', 'Gene', (0, 4))	('liposarcoma', 'Disease', 'MESH:D008080', (68, 79))	('liposarcoma', 'Phenotype', 'HP:0012034', (68, 79))	('reduced', 'NegReg', (37, 44))	('rs3027178', 'Mutation', 'rs3027178', (5, 14))
275815	30518396	rs7602358 located upstream PER2 was significantly associated with liposarcoma survival (HR: 1.98; 95% CI 1.02-3.85; P = 0.04).	('associated with', 'Reg', (50, 65))	('PER2', 'Gene', '8864', (27, 31))	('rs7602358', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('liposarcoma', 'Disease', (66, 77))	('liposarcoma', 'Disease', 'MESH:D008080', (66, 77))	('rs7602358', 'Mutation', 'rs7602358', (0, 9))	('PER2', 'Gene', (27, 31))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))
275816	30518396	Germline genetic variation in the circadian pathway was associated with the risk of developing soft tissue sarcoma (P = 0.035).	('Germline genetic variation', 'Var', (0, 26))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (95, 114))	('associated', 'Reg', (56, 66))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (95, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('circadian pathway', 'Pathway', (34, 51))	('soft tissue sarcoma', 'Disease', (95, 114))
275817	30518396	Genetic variation of circadian genes appears to play a role in the determinism of patient susceptibility and prognosis.	('role', 'Reg', (55, 59))	('Genetic variation', 'Var', (0, 17))	('patient', 'Species', '9606', (82, 89))	('circadian genes', 'Gene', (21, 36))	('play', 'Reg', (48, 52))
275823	30518396	Zhu and Colleagues studied a structural variant in the circadian gene PER3, which was detected to be significantly associated with increased risk of breast cancer in young women.	('PER3', 'Gene', '8863', (70, 74))	('associated', 'Reg', (115, 125))	('breast cancer', 'Disease', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('PER3', 'Gene', (70, 74))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('women', 'Species', '9606', (172, 177))	('structural variant', 'Var', (29, 47))
275824	30518396	Subsequently, in a growing number of molecular epidemiological studies, germline variations in clock genes have been associated by several Authors with different type of cancer susceptibility and in some cases with the prognosis of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (170, 176))	('associated', 'Reg', (117, 127))	('cancer', 'Disease', (232, 238))	('patients', 'Species', '9606', (239, 247))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('clock genes', 'Gene', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('germline', 'Var', (72, 80))	('variations', 'Var', (81, 91))
275825	30518396	Recently the discovery rate of susceptibility loci is being greatly accelerated by genome-wide association studies (GWASs) which can test up to one million single nucleotide polymorphisms (SNPs) in thousands of subjects at a time, nevertheless associations between clock genes variations and sarcoma susceptibility has not been explored yet.	('sarcoma', 'Disease', (292, 299))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('sarcoma', 'Disease', 'MESH:D012509', (292, 299))	('variations', 'Var', (277, 287))
275826	30518396	Given the potential role of circadian genes in tumorigenesis, it has been hypothesized that genetic variations in these genes could be associated with an individual's susceptibility also with sarcoma.	('genetic variations', 'Var', (92, 110))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('associated', 'Reg', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('sarcoma', 'Disease', (192, 199))	('tumor', 'Disease', (47, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
275828	30518396	We conducted a retrospective study to test the hypothesis that genetic variation (in terms of candidate single nucleotide polymorphisms, SNPs) of the circadian pathway might be associated to the susceptibility and the prognosis of patients affected with sarcoma.	('genetic variation', 'Var', (63, 80))	('sarcoma', 'Disease', (254, 261))	('patients', 'Species', '9606', (231, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('circadian pathway', 'Pathway', (150, 167))	('sarcoma', 'Disease', 'MESH:D012509', (254, 261))	('associated', 'Reg', (177, 187))
275836	30518396	They are the following: rs1801260, rs3736544, rs3749474.	('rs1801260', 'Var', (24, 33))	('rs3749474', 'Mutation', 'rs3749474', (46, 55))	('rs1801260', 'Mutation', 'rs1801260', (24, 33))	('rs3749474', 'Var', (46, 55))	('rs3736544', 'Mutation', 'rs3736544', (35, 44))	('rs3736544', 'Var', (35, 44))
275839	30518396	In order to enrich our analysis, rs3809125 (3'-UTR) and rs7302060 were added based on literature (see Table 2).	('rs3809125', 'Var', (33, 42))	('rs7302060', 'Mutation', 'rs7302060', (56, 65))	('rs7302060', 'Var', (56, 65))	('rs3809125', 'Mutation', 'rs3809125', (33, 42))
275842	30518396	NPAS2 rs895520, PER2 rs7602358, RORA rs339972, and rs10519097 had a statistically significant association with cancer risk.	('rs10519097', 'Mutation', 'rs10519097', (51, 61))	('NPAS2', 'Gene', (0, 5))	('RORA', 'Gene', (32, 36))	('rs7602358', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs10519097', 'Var', (51, 61))	('RORA', 'Gene', '6095', (32, 36))	('rs895520', 'Mutation', 'rs895520', (6, 14))	('PER2', 'Gene', (16, 20))	('rs339972', 'Var', (37, 45))	('PAS', 'Chemical', 'MESH:D011478', (1, 4))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('rs7602358', 'Mutation', 'rs7602358', (21, 30))	('rs895520', 'Var', (6, 14))	('PER2', 'Gene', '8864', (16, 20))	('rs339972', 'Mutation', 'rs339972', (37, 45))
275844	30518396	PER1 rs3027178 and PER2 rs934945 were selected based on literature.	('rs934945', 'Mutation', 'rs934945', (24, 32))	('rs3027178', 'Var', (5, 14))	('PER2', 'Gene', (19, 23))	('rs934945', 'Var', (24, 32))	('PER2', 'Gene', '8864', (19, 23))	('rs3027178', 'Mutation', 'rs3027178', (5, 14))
275857	30518396	A total of 14 preselected SNPs in 6 circadian clock genes were successfully genotyped, and no departures from Hardy-Weinberg equilibrium were observed neither among the controls nor among the patients, as reported in Additional file 1: Table S1 (P > 0.05).	('circadian clock genes', 'Gene', (36, 57))	('SNPs', 'Var', (26, 30))	('patients', 'Species', '9606', (192, 200))
275865	30518396	rs1801260 is located on 3'-UTR region of CLOCK.	('rs1801260', 'Mutation', 'rs1801260', (0, 9))	('rs1801260', 'Var', (0, 9))	('CLOCK.', 'Gene', (41, 47))	('CLOCK.', 'Gene', '9575', (41, 47))
275873	30518396	rs895520 is located on an intron of NPAS2 locus.	('PAS', 'Chemical', 'MESH:D011478', (37, 40))	('rs895520', 'Mutation', 'rs895520', (0, 8))	('rs895520', 'Var', (0, 8))	('NPAS2', 'Gene', (36, 41))
275874	30518396	The present analysis suggested that the minor allele (A) was associated with an increased predisposition to sarcoma of 33% under an additive (per allele OR 1.33; 95% CI 1.02-1.73; P = 0.03) and a recessive (OR 1.70; 95% CI 1.08-2.68; P = 0.02) model.	('minor', 'Var', (40, 45))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Disease', (108, 115))
275880	30518396	PER2 dysfunction can also impair p53-mediated apoptosis and consequently result in genomic instability and the accumulation of damaged cells.	('PER2', 'Gene', '8864', (0, 4))	('genomic instability', 'CPA', (83, 102))	('accumulation', 'PosReg', (111, 123))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('PER2', 'Gene', (0, 4))	('impair', 'NegReg', (26, 32))	('dysfunction', 'Var', (5, 16))	('result in', 'Reg', (73, 82))
275882	30518396	rs934945 (C>T) is located on the last exon of PER2 locus and has a missense functional effect, leading to the substitution Glycine-Glutamic Acid.	('rs934945 (C>T', 'Var', (0, 13))	('Glutamic Acid', 'Chemical', 'MESH:D018698', (131, 144))	('Glycine', 'Chemical', 'MESH:D005998', (123, 130))	('PER2', 'Gene', (46, 50))	('PER2', 'Gene', '8864', (46, 50))	('Glycine-Glutamic Acid', 'MPA', (123, 144))	('rs934945', 'Mutation', 'rs934945', (0, 8))
275885	30518396	Moreover, in liposarcoma subgroup PER1 rs3027178, a genetic variant with a synonymous functional effect, was associated with a reduced predisposition (per allele OR 0.68; 95% CI 0.47-0.98; P = 0.04).	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('rs3027178', 'Mutation', 'rs3027178', (39, 48))	('rs3027178', 'Var', (39, 48))	('liposarcoma', 'Disease', (13, 24))	('predisposition', 'MPA', (135, 149))	('liposarcoma', 'Phenotype', 'HP:0012034', (13, 24))	('liposarcoma', 'Disease', 'MESH:D008080', (13, 24))	('reduced', 'NegReg', (127, 134))
275889	30518396	rs339972 C allele was associated with a decreased predisposition to develop sarcoma assuming an additive (per allele OR 0.71;95% CI 0.53-0.96; P = 0.02) or a dominant (OR 0.64; 95% CI 0.44-0.93; P = 0.02) genetic model.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('rs339972', 'Mutation', 'rs339972', (0, 8))	('rs339972 C', 'Var', (0, 10))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('decreased', 'NegReg', (40, 49))
275892	30518396	rs7602358 located upstream PER2 was significantly associated with liposarcoma survival (HR 1.98; 95% CI 1.02-3.85; P = 0.04) employing an additive genetic model.	('associated with', 'Reg', (50, 65))	('PER2', 'Gene', '8864', (27, 31))	('rs7602358', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('liposarcoma', 'Disease', (66, 77))	('liposarcoma', 'Disease', 'MESH:D008080', (66, 77))	('rs7602358', 'Mutation', 'rs7602358', (0, 9))	('PER2', 'Gene', (27, 31))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))
275893	30518396	We found a significant association between circadian pathway variation and risk of developing this tumour (circadian pathway P value 0.035).	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('circadian pathway', 'Pathway', (43, 60))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('variation', 'Var', (61, 70))
275898	30518396	Our results argue in favor of this hypothesis, in fact 4 of the 13 analyzed genetic variant were statistically significantly associated with the predisposition to sarcoma employing an additive model of inheritance.	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('sarcoma', 'Disease', (163, 170))	('variant', 'Var', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('associated', 'Reg', (125, 135))
275899	30518396	They are: CLOCK rs1801260, NPAS2 rs895520, PER2 rs934945, and RORA rs339972.	('rs895520', 'Mutation', 'rs895520', (33, 41))	('RORA', 'Gene', '6095', (62, 66))	('rs934945', 'Mutation', 'rs934945', (48, 56))	('NPAS2', 'Gene', (27, 32))	('rs1801260', 'Mutation', 'rs1801260', (16, 25))	('PAS', 'Chemical', 'MESH:D011478', (28, 31))	('rs934945', 'Var', (48, 56))	('PER2', 'Gene', (43, 47))	('rs895520', 'Var', (33, 41))	('PER2', 'Gene', '8864', (43, 47))	('rs339972', 'Mutation', 'rs339972', (67, 75))	('RORA', 'Gene', (62, 66))
275900	30518396	In our previous meta-analysis on sarcoma genetic variations we highlighted the interesting fact that the susceptibility, defined as odds ratio, statistically significantly associated with single variants ranged between higher values (mean approximately 1.70) than those usually observed for other malignancies such as breast, colorectal, and gastric carcinomas, which generally include odds ratios between 1.10 and 1.30.	('variants', 'Var', (195, 203))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('gastric carcinomas', 'Disease', 'MESH:D013274', (342, 360))	('malignancies', 'Disease', (297, 309))	('colorectal', 'Disease', (326, 336))	('variations', 'Var', (49, 59))	('gastric carcinomas', 'Disease', (342, 360))	('breast', 'Disease', (318, 324))	('sarcoma', 'Disease', (33, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (350, 359))	('carcinomas', 'Phenotype', 'HP:0030731', (350, 360))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('malignancies', 'Disease', 'MESH:D009369', (297, 309))
275908	30518396	Our findings in the present study showed that carriers of the C allele of rs1801260 had a reduced predisposition to sarcoma (26%).	('reduced', 'NegReg', (90, 97))	('rs1801260', 'Mutation', 'rs1801260', (74, 83))	('sarcoma', 'Disease', (116, 123))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('rs1801260', 'Var', (74, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
275910	30518396	who evaluated the association between clock genes polymorphisms and prognosis in patients with colorectal cancer, the presence of T allele and the TT genotype of rs1801260 SNP were related to decreased overall survival and unfavorable prognosis.	('decreased', 'NegReg', (192, 201))	('colorectal cancer', 'Disease', (95, 112))	('presence', 'Var', (118, 126))	('patients', 'Species', '9606', (81, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('rs1801260 SNP', 'Var', (162, 175))	('overall survival', 'CPA', (202, 218))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('rs1801260', 'Mutation', 'rs1801260', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
275911	30518396	In gastric cancer our group suggested that rs1801260 C allele affect patient survival only if combined with the major allele of CLOCK rs3749474.	('rs1801260 C', 'Var', (43, 54))	('affect', 'Reg', (62, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('patient survival', 'CPA', (69, 85))	('rs1801260', 'Mutation', 'rs1801260', (43, 52))	('patient', 'Species', '9606', (69, 76))	('gastric cancer', 'Disease', (3, 17))	('rs3749474', 'Mutation', 'rs3749474', (134, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
275914	30518396	NPAS2 rs895520 is located on an intron of NPAS2 locus.	('NPAS2', 'Gene', (0, 5))	('NPAS2', 'Gene', (42, 47))	('rs895520', 'Mutation', 'rs895520', (6, 14))	('PAS', 'Chemical', 'MESH:D011478', (1, 4))	('PAS', 'Chemical', 'MESH:D011478', (43, 46))	('rs895520', 'Var', (6, 14))
275916	30518396	This result is also congruent with findings from a NCI genome-wide association study on prostate cancer (CGEMS project), released in 2006 and not included in our meta-analysis, that showed some significant associations between variants in circadian genes and prostate cancer susceptibility.	('prostate cancer', 'Disease', (88, 103))	('prostate cancer', 'Disease', (259, 274))	('variants', 'Var', (227, 235))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('circadian genes', 'Gene', (239, 254))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (259, 274))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (259, 274))
275919	30518396	NPAS2 rs895521 was associated with P <= 0.01.	('NPAS2', 'Gene', (0, 5))	('PAS', 'Chemical', 'MESH:D011478', (1, 4))	('rs895521', 'Mutation', 'rs895521', (6, 14))	('rs895521', 'Var', (6, 14))
275920	30518396	The present analysis suggested that the minor allele (A) was associated with an increased predisposition to sarcoma of 33%.	('minor', 'Var', (40, 45))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Disease', (108, 115))
275921	30518396	PER2 rs934945 has a missense functional effect causing glycine to glutamic acid substitution in PER2 protein and is probably related to a decreased PER2 activity.	('rs934945', 'Var', (5, 13))	('glutamic acid', 'Chemical', 'MESH:D018698', (66, 79))	('PER2', 'Gene', (148, 152))	('PER2', 'Gene', '8864', (0, 4))	('glycine to glutamic acid substitution', 'MPA', (55, 92))	('PER2', 'Gene', '8864', (96, 100))	('decreased', 'NegReg', (138, 147))	('glycine', 'Chemical', 'MESH:D005998', (55, 62))	('PER2', 'Gene', '8864', (148, 152))	('protein', 'Protein', (101, 108))	('rs934945', 'Mutation', 'rs934945', (5, 13))	('activity', 'MPA', (153, 161))	('PER2', 'Gene', (0, 4))	('causing', 'Reg', (47, 54))	('PER2', 'Gene', (96, 100))
275922	30518396	Dai and Colleagues suggested that individuals carrying both the CLOCK rs3805151 (not considered in our study) CC and PER2 TT genotype had an increased breast cancer risk (OR 2.28; 95% CI 1.22-4.26).	('PER2', 'Gene', (117, 121))	('rs3805151', 'Var', (70, 79))	('PER2', 'Gene', '8864', (117, 121))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('rs3805151', 'Mutation', 'rs3805151', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
275925	30518396	RORA rs339972 is located on an intron of RORA locus.	('rs339972', 'Var', (5, 13))	('RORA', 'Gene', (41, 45))	('RORA', 'Gene', (0, 4))	('rs339972', 'Mutation', 'rs339972', (5, 13))	('RORA', 'Gene', '6095', (41, 45))	('RORA', 'Gene', '6095', (0, 4))
275928	30518396	In the current study rs339972 C allele was associated with a decreased predisposition to develop sarcoma (per allele OR 0.71; 95% CI 0.53-0.96; P = 0.02).	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('rs339972', 'Mutation', 'rs339972', (21, 29))	('sarcoma', 'Disease', (97, 104))	('rs339972 C', 'Var', (21, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('decreased', 'NegReg', (61, 70))
275930	30518396	Employing an additive model of inheritance CLOCK rs1801260 and PER2 rs934945 were statistically significantly associated with liposarcoma, while NPAS2 rs895520 and RORA rs339972 were statistically significantly associated with leiomyosarcoma.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (227, 241))	('PER2', 'Gene', '8864', (63, 67))	('rs895520', 'Mutation', 'rs895520', (151, 159))	('RORA', 'Gene', (164, 168))	('rs339972', 'Mutation', 'rs339972', (169, 177))	('liposarcoma', 'Phenotype', 'HP:0012034', (126, 137))	('associated', 'Reg', (110, 120))	('rs1801260', 'Var', (49, 58))	('leiomyosarcoma', 'Disease', (227, 241))	('RORA', 'Gene', '6095', (164, 168))	('liposarcoma', 'Disease', 'MESH:D008080', (126, 137))	('rs1801260', 'Mutation', 'rs1801260', (49, 58))	('rs934945', 'Var', (68, 76))	('NPAS2', 'Gene', (145, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('associated', 'Reg', (211, 221))	('rs934945', 'Mutation', 'rs934945', (68, 76))	('rs895520', 'Var', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('PAS', 'Chemical', 'MESH:D011478', (146, 149))	('liposarcoma', 'Disease', (126, 137))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (227, 241))	('PER2', 'Gene', (63, 67))
275931	30518396	Moreover, PER1 rs3027178 was found to be associated only with liposarcoma susceptibility.	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('associated', 'Reg', (41, 51))	('rs3027178', 'Mutation', 'rs3027178', (15, 24))	('liposarcoma', 'Disease', (62, 73))	('PER1', 'Gene', (10, 14))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))	('liposarcoma', 'Disease', 'MESH:D008080', (62, 73))	('rs3027178', 'Var', (15, 24))
275937	30518396	Recently, CLOCK and PER2 polymorphisms have been linked to obesity and the metabolic syndrome.	('obesity', 'Phenotype', 'HP:0001513', (59, 66))	('PER2', 'Gene', '8864', (20, 24))	('linked', 'Reg', (49, 55))	('CLOCK', 'Gene', (10, 15))	('polymorphisms', 'Var', (25, 38))	('obesity and the metabolic syndrome', 'Disease', 'MESH:D009765', (59, 93))	('PER2', 'Gene', (20, 24))
275939	30518396	Genetic variation in the circadian system has been associated with tumor aggressiveness or patient survival in hepatocellular carcinoma, melanoma as well as prostate, colorectal, gastric and breast cancer.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (111, 135))	('associated with', 'Reg', (51, 66))	('colorectal', 'Disease', (167, 177))	('tumor aggressiveness', 'Disease', (67, 87))	('gastric and breast cancer', 'Disease', 'MESH:D013274', (179, 204))	('Genetic variation', 'Var', (0, 17))	('prostate', 'Disease', (157, 165))	('hepatocellular carcinoma', 'Disease', (111, 135))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (67, 87))	('aggressiveness', 'Phenotype', 'HP:0000718', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patient', 'Species', '9606', (91, 98))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (111, 135))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('patient survival', 'CPA', (91, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
275941	30518396	In particular, rs7602358 located upstream PER2, was significantly associated with liposarcoma prognosis.	('PER2', 'Gene', (42, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('liposarcoma', 'Disease', (82, 93))	('associated with', 'Reg', (66, 81))	('PER2', 'Gene', '8864', (42, 46))	('rs7602358', 'Mutation', 'rs7602358', (15, 24))	('rs7602358', 'Var', (15, 24))	('liposarcoma', 'Phenotype', 'HP:0012034', (82, 93))	('liposarcoma', 'Disease', 'MESH:D008080', (82, 93))
275942	30518396	rs7602358 was previously considered by four research groups evaluating the associations with prostate cancer, breast cancer, and glioma risk.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('prostate cancer', 'Disease', (93, 108))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs7602358', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('glioma', 'Disease', (129, 135))	('rs7602358', 'Mutation', 'rs7602358', (0, 9))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
275943	30518396	Zhu and Colleagues found a difference in risk association of rs7602358 with prostate cancer between less aggressive and more aggressive prostate cancer subgroup, leading to suppose a role of PER2 in malignant cells aggressiveness.	('aggressiveness', 'Disease', (215, 229))	('PER2', 'Gene', (191, 195))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (125, 151))	('aggressive prostate cancer', 'Disease', (125, 151))	('aggressiveness', 'Phenotype', 'HP:0000718', (215, 229))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PER2', 'Gene', '8864', (191, 195))	('rs7602358', 'Mutation', 'rs7602358', (61, 70))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('prostate cancer', 'Disease', (76, 91))	('aggressiveness', 'Disease', 'MESH:D001523', (215, 229))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('rs7602358', 'Var', (61, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))
275944	30518396	We used a gene- and pathway-based approach to investigate the overall effect of circadian clock gene germline variations on soft tissue sarcoma risk.	('soft tissue sarcoma', 'Disease', (124, 143))	('variations', 'Var', (110, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (124, 143))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (124, 143))
275945	30518396	Our results suggest that genetic variation in the circadian rhythm pathway as a whole is related to soft tissue sarcoma susceptibility.	('genetic variation', 'Var', (25, 42))	('circadian rhythm pathway', 'Pathway', (50, 74))	('soft tissue sarcoma', 'Disease', (100, 119))	('related', 'Reg', (89, 96))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (100, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (100, 119))
275948	30518396	To the best of our knowledge, this is the first study investigating the associations of germline circadian clock genes polymorphisms in relation to risk or prognosis of soft tissue sarcoma.	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (169, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('associations', 'Interaction', (72, 84))	('polymorphisms', 'Var', (119, 132))	('soft tissue sarcoma', 'Disease', (169, 188))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (169, 188))
275953	30518396	In conclusion, the present work represents the first article on association between genetic variation of clock-related genes and soft tissue sarcoma susceptibility or prognosis.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (129, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('genetic variation', 'Var', (84, 101))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (129, 148))	('soft tissue sarcoma', 'Disease', (129, 148))	('association', 'Interaction', (64, 75))
276110	29098019	En bloc resection was demonstrated to be associated with a decrease in OS rate in a recent pooled data analysis of 377 patients.	('patients', 'Species', '9606', (119, 127))	('resection', 'Var', (8, 17))	('OS', 'Chemical', '-', (71, 73))	('decrease', 'NegReg', (59, 67))	('OS rate', 'MPA', (71, 78))
276199	25685180	In univariable analyses, male sex, increased age at clinic entry, low or missing CD4+ lymphocyte nadir, low time-varying CD4+ lymphocyte count, increased log10 HIV RNA, and cumulative follow-up time with log10 HIV RNA >= 5.0 were all associated with increased risk of ADC among patients at INI.	('increased', 'PosReg', (35, 44))	('ADC', 'Gene', (268, 271))	('INI', 'Gene', (290, 293))	('CD4', 'Gene', (121, 124))	('log10', 'Var', (154, 159))	('INI', 'Gene', '84844', (290, 293))	('CD4', 'Gene', '920', (121, 124))	('ADC', 'Gene', '113451', (268, 271))	('CD4', 'Gene', (81, 84))	('CD4+ lymphocyte nadir', 'Phenotype', 'HP:0005407', (81, 102))	('patients', 'Species', '9606', (278, 286))	('CD4', 'Gene', '920', (81, 84))	('increased', 'PosReg', (144, 153))
276200	25685180	In multivariable models, male sex and low CD4+ lymphocyte count remained statistically associated with increased risk of ADC at both sites.	('ADC', 'Gene', (121, 124))	('CD4', 'Gene', (42, 45))	('CD4', 'Gene', '920', (42, 45))	('ADC', 'Gene', '113451', (121, 124))	('low', 'Var', (38, 41))
276202	25685180	Cumulative follow-up time with log10 HIV RNA >= 5.0 was no longer associated with ADC risk when included in a model adjusting for CD4+ lymphocyte count.	('ADC', 'Gene', '113451', (82, 85))	('CD4', 'Gene', '920', (130, 133))	('ADC', 'Gene', (82, 85))	('log10', 'Var', (31, 36))	('CD4', 'Gene', (130, 133))
276207	25685180	Age, low CD4+ lymphocyte nadir, and history of malignancy prior to clinic entry were associated with increased risk of NADC at VCCC in univariable analyses.	('NADC', 'Chemical', '-', (119, 123))	('CD4+ lymphocyte nadir', 'Phenotype', 'HP:0005407', (9, 30))	('low', 'Var', (5, 8))	('NADC', 'Disease', (119, 123))	('CD4', 'Gene', (9, 12))	('CD4', 'Gene', '920', (9, 12))	('malignancy', 'Disease', 'MESH:D009369', (47, 57))	('malignancy', 'Disease', (47, 57))
276252	25685180	By doing so, cancers without a known association with HIV or other infections (such as breast and prostate cancer) may have limited our ability to detect risk differences conferred by immunodeficiency, HIV-1 RNA, or co-infection by hepatitis viruses.	('HIV-1', 'Species', '11676', (202, 207))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('co-infection by hepatitis viruses', 'Disease', (216, 249))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('HIV or other infections', 'Disease', 'MESH:D015658', (54, 77))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('HIV-1 RNA', 'Var', (202, 211))	('immunodeficiency', 'Phenotype', 'HP:0002721', (184, 200))	('immunodeficiency', 'Disease', 'MESH:D007153', (184, 200))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (87, 113))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('hepatitis', 'Phenotype', 'HP:0012115', (232, 241))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('immunodeficiency', 'Disease', (184, 200))	('cancers', 'Disease', (13, 20))	('co-infection by hepatitis viruses', 'Disease', 'MESH:D060085', (216, 249))	('HIV or other infections', 'Disease', (54, 77))
276296	25287160	NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and non-malignant skeletal pain.	('NGF', 'Gene', (183, 186))	('attenuates', 'NegReg', (188, 198))	('bone destruction', 'Phenotype', 'HP:0002797', (70, 86))	('NGF', 'Gene', '18049', (183, 186))	('NGF', 'Gene', (0, 3))	('bone cancer', 'Disease', 'MESH:D001859', (35, 46))	('increases', 'PosReg', (91, 100))	('bone cancer', 'Disease', (35, 46))	('pain', 'Phenotype', 'HP:0012531', (241, 245))	('NGF', 'Gene', '18049', (0, 3))	('attenuates', 'NegReg', (59, 69))	('humans', 'Species', '9606', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('malignant skeletal pain', 'Disease', (222, 245))	('malignant skeletal pain', 'Disease', 'MESH:D010146', (222, 245))	('skeletal pain', 'Phenotype', 'HP:0002653', (232, 245))	('blockade', 'Var', (150, 158))	('limb use', 'CPA', (101, 109))	('bone destruction', 'CPA', (70, 86))
276299	25287160	Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma.	('bone sarcoma', 'Disease', 'MESH:D001847', (130, 142))	('weight loss', 'Disease', 'MESH:D015431', (105, 116))	('head and neck cancer', 'Phenotype', 'HP:0012288', (53, 73))	('weight loss', 'Phenotype', 'HP:0001824', (105, 116))	('bone sarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('reduced', 'NegReg', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('weight loss', 'Disease', (105, 116))	('NGF', 'Gene', (93, 96))	('osteoarthritis', 'Disease', 'MESH:D010003', (34, 48))	('reduced weight', 'Phenotype', 'HP:0004325', (97, 111))	('neck cancer', 'Phenotype', 'HP:0012288', (62, 73))	('blockade', 'Var', (81, 89))	('bone sarcoma', 'Disease', (130, 142))	('mice', 'Species', '10090', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('osteoarthritis', 'Phenotype', 'HP:0002758', (34, 48))	('osteoarthritis', 'Disease', (34, 48))	('neck cancer', 'Disease', 'MESH:D006258', (62, 73))	('neck cancer', 'Disease', (62, 73))
276301	25287160	Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight.	('tumor', 'Disease', (68, 73))	('blockade', 'Var', (29, 37))	('delay', 'NegReg', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('bone fracture', 'Disease', 'MESH:D050723', (166, 179))	('bone fracture', 'Disease', (166, 179))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('use', 'MPA', (129, 132))	('tumor metastasis to bone', 'Phenotype', 'HP:0010622', (68, 92))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('integrity', 'MPA', (115, 124))	('NGF', 'Gene', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('maintain', 'Reg', (185, 193))	('body weight', 'CPA', (194, 205))	('bone fracture', 'Phenotype', 'HP:0020110', (166, 179))
276306	25287160	Maintenance of the functional status of patients with CMB requires proactive management as CMB can cause excruciating bone pain, pathologic fractures, spinal cord and nerve compression syndromes, weight loss, derangements of calcium and phosphate homeostasis and decline in the ability to load and use tumor-bearing bones cannot be viewed individually but rather as interactive events ultimately contributing to increased morbidity, mortality, and diminished quality of life.	('derangements', 'MPA', (209, 221))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('weight loss', 'Disease', (196, 207))	('fractures', 'Disease', (140, 149))	('decline', 'NegReg', (263, 270))	('fractures', 'Disease', 'MESH:D050723', (140, 149))	('calcium', 'Chemical', 'MESH:D002118', (225, 232))	('pathologic fractures', 'Phenotype', 'HP:0002756', (129, 149))	('pathologic', 'Disease', (129, 139))	('rat', 'Species', '10116', (356, 359))	('phosphate', 'Chemical', 'MESH:D010710', (237, 246))	('nerve compression', 'Phenotype', 'HP:0003406', (167, 184))	('tumor', 'Disease', (302, 307))	('ability', 'MPA', (278, 285))	('CMB', 'Var', (91, 94))	('weight loss', 'Disease', 'MESH:D015431', (196, 207))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('CMB', 'Phenotype', 'HP:0010622', (54, 57))	('patients', 'Species', '9606', (40, 48))	('bone pain', 'Disease', 'MESH:D010146', (118, 127))	('cause', 'Reg', (99, 104))	('weight loss', 'Phenotype', 'HP:0001824', (196, 207))	('pain', 'Phenotype', 'HP:0012531', (123, 127))	('bone pain', 'Disease', (118, 127))	('bone pain', 'Phenotype', 'HP:0002653', (118, 127))	('CMB', 'Phenotype', 'HP:0010622', (91, 94))
276308	25287160	A therapy showing promise in blocking pain induced by CMB and non-malignant skeletal pain is inhibition of nerve growth factor (NGF) and its primary receptor, tyrosine kinase receptor type 1 (TrkA).	('pain', 'Disease', 'MESH:D010146', (38, 42))	('CMB', 'Phenotype', 'HP:0010622', (54, 57))	('pain', 'Disease', (38, 42))	('malignant skeletal pain', 'Disease', 'MESH:D010146', (66, 89))	('pain', 'Disease', (85, 89))	('CMB', 'Disease', (54, 57))	('TrkA', 'Gene', (192, 196))	('NGF', 'Gene', (128, 131))	('pain', 'Phenotype', 'HP:0012531', (85, 89))	('skeletal pain', 'Phenotype', 'HP:0002653', (76, 89))	('pain', 'Disease', 'MESH:D010146', (85, 89))	('pain', 'Phenotype', 'HP:0012531', (38, 42))	('malignant skeletal pain', 'Disease', (66, 89))	('inhibition', 'Var', (93, 103))
276309	25287160	In breast, sarcoma, and prostate mouse models of CMB, anti-NGF significantly attenuates bone cancer pain.	('pain', 'Phenotype', 'HP:0012531', (100, 104))	('sarcoma', 'Disease', (11, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('bone cancer pain', 'Disease', 'MESH:D001859', (88, 104))	('anti-NGF', 'Var', (54, 62))	('bone cancer pain', 'Disease', (88, 104))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CMB', 'Phenotype', 'HP:0010622', (49, 52))	('bone cancer pain', 'Phenotype', 'HP:0002653', (88, 104))	('sarcoma', 'Disease', 'MESH:D012509', (11, 18))	('mouse', 'Species', '10090', (33, 38))	('attenuates', 'NegReg', (77, 87))
276310	25287160	Additionally, in humans, anti-NGF attenuates moderate-to-severe skeletal pain due to osteoarthritis or low back pain.	('attenuates', 'NegReg', (34, 44))	('moderate-to-severe', 'Disease', (45, 63))	('skeletal pain', 'Disease', (64, 77))	('skeletal pain', 'Phenotype', 'HP:0002653', (64, 77))	('osteoarthritis', 'Disease', 'MESH:D010003', (85, 99))	('skeletal pain', 'Disease', 'MESH:D010146', (64, 77))	('pain', 'Phenotype', 'HP:0012531', (73, 77))	('back pain', 'Phenotype', 'HP:0003418', (107, 116))	('osteoarthritis', 'Phenotype', 'HP:0002758', (85, 99))	('pain', 'Phenotype', 'HP:0012531', (112, 116))	('osteoarthritis', 'Disease', (85, 99))	('humans', 'Species', '9606', (17, 23))	('anti-NGF', 'Var', (25, 33))	('low back pain', 'Phenotype', 'HP:0003419', (103, 116))	('rat', 'Species', '10116', (49, 52))	('low back pain', 'Disease', 'MESH:D017116', (103, 116))	('low back pain', 'Disease', (103, 116))
276311	25287160	While animal and human studies suggest that blockade of NGF/TrkA effectively alleviates malignant and non-malignant skeletal pain, most efforts at developing novel therapies to block or sequester NGF or TrkA were not initially developed to treat skeletal pain but rather to block/attenuate tumor growth and metastasis.	('blockade', 'Var', (44, 52))	('alleviates', 'NegReg', (77, 87))	('skeletal pain', 'Disease', 'MESH:D010146', (116, 129))	('TrkA', 'Gene', (203, 207))	('pain', 'Phenotype', 'HP:0012531', (255, 259))	('skeletal pain', 'Phenotype', 'HP:0002653', (116, 129))	('human', 'Species', '9606', (17, 22))	('NGF', 'Gene', (196, 199))	('malignant skeletal pain', 'Disease', (106, 129))	('malignant skeletal pain', 'Disease', 'MESH:D010146', (106, 129))	('skeletal pain', 'Disease', (246, 259))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('attenuate tumor', 'Disease', 'MESH:C538265', (280, 295))	('pain', 'Phenotype', 'HP:0012531', (125, 129))	('NGF/TrkA', 'Gene', (56, 64))	('skeletal pain', 'Disease', 'MESH:D010146', (246, 259))	('rat', 'Species', '10116', (264, 267))	('skeletal pain', 'Phenotype', 'HP:0002653', (246, 259))	('attenuate tumor', 'Disease', (280, 295))
276313	25287160	Moreover, in vivo studies show that anti-NGF inhibits ethylnitrosourea-induced carcinogenesis in mice and rats, and either anti-NGF or siRNA against NGF inhibits breast cancer tumor growth and metastasis in a mouse xenograft model.	('rats', 'Species', '10116', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast cancer tumor', 'Disease', (162, 181))	('anti-NGF', 'Var', (36, 44))	('metastasis in a mouse xenograft model', 'CPA', (193, 230))	('inhibits', 'NegReg', (45, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('anti-NGF', 'Var', (123, 131))	('mice', 'Species', '10090', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('carcinogenesis', 'Disease', (79, 93))	('inhibits', 'NegReg', (153, 161))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (162, 181))	('ethylnitrosourea', 'Chemical', 'MESH:D005038', (54, 70))	('mouse', 'Species', '10090', (209, 214))	('breast cancer tumor', 'Disease', 'MESH:D001943', (162, 181))
276319	25287160	All procedures adhered to the guidelines of the Committee for Research and Ethical Issues of the International Association for the Study of Pain and were approved by the Institutional Animal Care and Use Committee at the University of Arizona (Tucson, AZ).Experiments were initiated with 90 mice, out of which a total of 85 mice were included for data analyses:naive (n=8); sham surgery (n=13); NCTC 2472 (femur-injected) + vehicle (n=36); NCTC 2472 (femur injected) + anti-NGF (n=24); NCTC 2472 + vehicle (muscle-injected) (n=4).	('mice', 'Species', '10090', (291, 295))	('Pain', 'Phenotype', 'HP:0012531', (140, 144))	('NCTC 2472', 'Var', (440, 449))	('Pain', 'Disease', 'MESH:D010146', (140, 144))	('mice', 'Species', '10090', (324, 328))	('Pain', 'Disease', (140, 144))
276323	25287160	In vitro and in vivo tumor cell characteristics of GFP-transfected NCTC 2472 cells (growth rate, bone resorption rate, induction of bone cancer-related pain), were temporally, behaviorally, and physically identical to that of non-transfected NCTC 2472 cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('GFP-transfected', 'Var', (51, 66))	('bone resorption', 'Phenotype', 'HP:0002797', (97, 112))	('bone resorption rate', 'CPA', (97, 117))	('bone cancer', 'Disease', (132, 143))	('tumor', 'Disease', (21, 26))	('rat', 'Species', '10116', (91, 94))	('pain', 'Phenotype', 'HP:0012531', (152, 156))	('rat', 'Species', '10116', (113, 116))	('pain', 'Disease', 'MESH:D010146', (152, 156))	('NCTC 2472', 'Gene', (67, 76))	('pain', 'Disease', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('growth rate', 'CPA', (84, 95))	('bone cancer', 'Disease', 'MESH:D001859', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
276348	25287160	Post-surgical pain in NCTC 2472-injected mice was similar to that experienced by sham mice, peaking at Day 3 post-surgery and significantly lessened by Day 5 post-surgery.	('pain', 'Disease', 'MESH:D010146', (14, 18))	('pain', 'Disease', (14, 18))	('mice', 'Species', '10090', (41, 45))	('mice', 'Species', '10090', (86, 90))	('lessened', 'NegReg', (140, 148))	('NCTC 2472-injected', 'Var', (22, 40))	('pain', 'Phenotype', 'HP:0012531', (14, 18))
276358	25287160	4A shows representative radiographs of the proximal aspects of mouse femurs of vehicle- and anti-NGF-treated mice at Day 28 post-NCTC 2472 cell injection, and the attenuating effect of anti-NGF on disease progression is striking.	('anti-NGF', 'Var', (185, 193))	('mouse', 'Species', '10090', (63, 68))	('mice', 'Species', '10090', (109, 113))	('attenuating', 'NegReg', (163, 174))
276360	25287160	Mean bone scores for anti-NGF-treated mice at Days 21 and 28 were 4.0+-0.5 and 5.7+-0.4, respectively.	('mice', 'Species', '10090', (38, 42))	('bone scores', 'CPA', (5, 16))	('anti-NGF-treated', 'Var', (21, 37))
276362	25287160	The importance of the attenuating effect of anti-NGF on bone destruction in terms of overall functionality was demonstrated by the fact that at Day 28 post-NCTC 2472 injection, the percent of anti-NGF-treated mice with evidence of fracture was half that of vehicle-treated mice (Fig.	('mice', 'Species', '10090', (209, 213))	('bone destruction', 'Phenotype', 'HP:0002797', (56, 72))	('rat', 'Species', '10116', (118, 121))	('anti-NGF-treated', 'Var', (192, 208))	('fracture', 'Disease', 'MESH:D050723', (231, 239))	('fracture', 'Disease', (231, 239))	('bone destruction', 'CPA', (56, 72))	('mice', 'Species', '10090', (273, 277))
276364	25287160	Our data show that at Day 28 post-cancer cell injection, when there was significant disease progression and bone destruction, mice treated with anti-NGF therapy had only lost ~2% of their baseline weight, whereas vehicle-treated mice had lost ~6% of their baseline weight (Fig.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('baseline', 'MPA', (188, 196))	('mice', 'Species', '10090', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('lost', 'NegReg', (170, 174))	('bone destruction', 'Phenotype', 'HP:0002797', (108, 124))	('mice', 'Species', '10090', (229, 233))	('anti-NGF', 'Var', (144, 152))
276373	25287160	In anti-NGF-treated mice with similar bone scores, were associated with mean spontaneous nocifensive behaviors of 129.2+-15.5 and 91.6+-26.1 sec, respectively.	('mice', 'Species', '10090', (20, 24))	('anti-NGF-treated', 'Var', (3, 19))	('spontaneous nocifensive behaviors', 'CPA', (77, 110))
276374	25287160	Taken together, these data demonstrated that anti-NGF treatment reduced pain in mid-stage bone cancer disease by approximately 40-60%.	('reduced pain', 'Phenotype', 'HP:0007328', (64, 76))	('pain', 'Phenotype', 'HP:0012531', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('pain', 'Disease', 'MESH:D010146', (72, 76))	('pain', 'Disease', (72, 76))	('bone cancer disease', 'Disease', 'MESH:D001859', (90, 109))	('reduced', 'NegReg', (64, 71))	('rat', 'Species', '10116', (34, 37))	('bone cancer disease', 'Disease', (90, 109))	('anti-NGF', 'Var', (45, 53))
276377	25287160	Taken together, these data show that anti-NGF treatment reduced the time spent in spontaneous nocifensive behavior in mice suffering with late stage bone cancer disease by approximately 70%.	('time spent in spontaneous nocifensive behavior', 'MPA', (68, 114))	('late stage bone cancer disease', 'Disease', 'MESH:D001859', (138, 168))	('anti-NGF', 'Var', (37, 45))	('reduced', 'NegReg', (56, 63))	('late stage bone cancer disease', 'Disease', (138, 168))	('mice', 'Species', '10090', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
276378	25287160	The efficacy of anti-NGF in reducing bone pain in both early and late stage bone cancer disease was also revealed by analysis of spontaneous nocifensive behavior exhibited by vehicle- and anti-NGF-treated mice with respect to time (day) following cancer-cell injection (Fig.	('late stage bone cancer disease', 'Disease', 'MESH:D001859', (65, 95))	('bone pain', 'Phenotype', 'HP:0002653', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('reducing', 'NegReg', (28, 36))	('anti-NGF', 'Var', (16, 24))	('cancer', 'Disease', (247, 253))	('late stage bone cancer disease', 'Disease', (65, 95))	('bone pain', 'Disease', 'MESH:D010146', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('mice', 'Species', '10090', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bone pain', 'Disease', (37, 46))	('pain', 'Phenotype', 'HP:0012531', (42, 46))
276381	25287160	In contrast, anti-NGF-treated mice had a mean spontaneous nocifensive behavior of 28.5+-6.8 sec, illustrating that cancer-induced bone pain had been reduced six-fold.	('cancer', 'Disease', (115, 121))	('mice', 'Species', '10090', (30, 34))	('rat', 'Species', '10116', (103, 106))	('bone pain', 'Phenotype', 'HP:0002653', (130, 139))	('pain', 'Phenotype', 'HP:0012531', (135, 139))	('spontaneous nocifensive behavior', 'MPA', (46, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('anti-NGF-treated', 'Var', (13, 29))	('bone pain', 'Disease', 'MESH:D010146', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('bone pain', 'Disease', (130, 139))
276383	25287160	However, at these same time points, anti-NGF-treated mice had significantly reduced mean spontaneous nocifensive behaviors of 114.8+-14.8 and 102.9+-24.3 sec, respectively.	('reduced', 'NegReg', (76, 83))	('mice', 'Species', '10090', (53, 57))	('anti-NGF-treated', 'Var', (36, 52))	('spontaneous nocifensive behaviors', 'CPA', (89, 122))
276384	25287160	Taken together, these data show that at Days 21 and 28, when mice had severe to extreme bone destruction, anti-NGF treatment resulted in mice spending approximately 30-40% of the total 300-second assessment period in spontaneous nocifensive behavior as opposed to approximately 80% as in the case of vehicle-treated mice.	('mice', 'Species', '10090', (61, 65))	('bone destruction', 'Phenotype', 'HP:0002797', (88, 104))	('spontaneous nocifensive behavior', 'MPA', (217, 249))	('mice', 'Species', '10090', (316, 320))	('anti-NGF', 'Var', (106, 114))	('mice', 'Species', '10090', (137, 141))
276388	25287160	In contrast, anti-NGF treatment reduced bone cancer-induced pain enough that the animal was capable of preserving the ability of the tumor-bearing hind limb to bear weight.	('bone cancer', 'Disease', 'MESH:D001859', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('reduced', 'NegReg', (32, 39))	('bone cancer', 'Disease', (40, 51))	('pain', 'Phenotype', 'HP:0012531', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('anti-NGF', 'Var', (13, 21))	('pain', 'Disease', 'MESH:D010146', (60, 64))	('tumor', 'Disease', (133, 138))	('pain', 'Disease', (60, 64))
276390	25287160	Assessment of mouse limb use in an open field, comparable to assessment of gait, posture and the spontaneous use of the affected limb in humans, demonstrated that anti-NGF treatment prevented limb use impairment.	('mouse', 'Species', '10090', (14, 19))	('anti-NGF', 'Var', (163, 171))	('rat', 'Species', '10116', (152, 155))	('prevented', 'NegReg', (182, 191))	('limb use impairment', 'CPA', (192, 211))	('humans', 'Species', '9606', (137, 143))
276393	25287160	In the present study, we used a mouse model of sarcoma-induced bone cancer and showed that early treatment with anti-NGF reduced tumor-induced bone destruction, delayed time-to-fracture, and increased the use of the tumor-bearing limb.	('tumor', 'Disease', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('reduced', 'NegReg', (121, 128))	('sarcoma-induced bone cancer', 'Disease', 'MESH:D001859', (47, 74))	('increased', 'PosReg', (191, 200))	('anti-NGF', 'Var', (112, 120))	('fracture', 'Disease', 'MESH:D050723', (177, 185))	('sarcoma-induced bone cancer', 'Disease', (47, 74))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('mouse', 'Species', '10090', (32, 37))	('bone destruction', 'Phenotype', 'HP:0002797', (143, 159))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('fracture', 'Disease', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
276394	25287160	Additionally, as suggested in previous studies in animal models of osteoarthritis and head/neck cancer, early blockade of NGF also reduced weight loss in animals with bone cancer.	('reduced weight', 'Phenotype', 'HP:0004325', (131, 145))	('weight loss', 'Phenotype', 'HP:0001824', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('bone cancer', 'Disease', 'MESH:D001859', (167, 178))	('head/neck cancer', 'Disease', (86, 102))	('osteoarthritis', 'Phenotype', 'HP:0002758', (67, 81))	('bone cancer', 'Disease', (167, 178))	('osteoarthritis', 'Disease', (67, 81))	('reduced', 'NegReg', (131, 138))	('weight loss', 'Disease', 'MESH:D015431', (139, 150))	('blockade', 'Var', (110, 118))	('NGF', 'Gene', (122, 125))	('osteoarthritis', 'Disease', 'MESH:D010003', (67, 81))	('head/neck cancer', 'Disease', 'MESH:D006258', (86, 102))	('neck cancer', 'Phenotype', 'HP:0012288', (91, 102))	('weight loss', 'Disease', (139, 150))
276395	25287160	In terms of the extent and time course of pain relief, blockade of NGF reduced bone cancer pain by 40-70% depending on the pain measure being assessed, and this analgesic effect was maintained even in animals with late stage disease.	('bone cancer pain', 'Phenotype', 'HP:0002653', (79, 95))	('NGF', 'Gene', (67, 70))	('pain', 'Disease', 'MESH:D010146', (42, 46))	('pain', 'Disease', (42, 46))	('pain', 'Phenotype', 'HP:0012531', (42, 46))	('pain', 'Phenotype', 'HP:0012531', (123, 127))	('reduced', 'NegReg', (71, 78))	('bone cancer pain', 'Disease', 'MESH:D001859', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('blockade', 'Var', (55, 63))	('pain', 'Phenotype', 'HP:0012531', (91, 95))	('pain', 'Disease', 'MESH:D010146', (123, 127))	('pain', 'Disease', (123, 127))	('pain', 'Disease', 'MESH:D010146', (91, 95))	('pain', 'Disease', (91, 95))	('bone cancer pain', 'Disease', (79, 95))
276396	25287160	In the current study, NGF blockade delayed bone cancer disease progression; measured by time-to-fracture, tumor-induced bone destruction, and tumor-bearing limb use.	('NGF', 'Gene', (22, 25))	('fracture', 'Disease', 'MESH:D050723', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('fracture', 'Disease', (96, 104))	('bone cancer disease', 'Disease', 'MESH:D001859', (43, 62))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', (142, 147))	('delayed', 'NegReg', (35, 42))	('bone cancer disease', 'Disease', (43, 62))	('blockade', 'Var', (26, 34))	('bone destruction', 'Phenotype', 'HP:0002797', (120, 136))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', (106, 111))
276397	25287160	Previous studies in human clinical trials in patients with moderate-to-severe osteoarthritis pain showed that anti-NGF attenuated this pain by 40-50%.	('pain', 'Phenotype', 'HP:0012531', (93, 97))	('human', 'Species', '9606', (20, 25))	('osteoarthritis pain', 'Disease', 'MESH:D010003', (78, 97))	('pain', 'Phenotype', 'HP:0012531', (135, 139))	('pain', 'Disease', 'MESH:D010146', (135, 139))	('pain', 'Disease', 'MESH:D010146', (93, 97))	('pain', 'Disease', (135, 139))	('pain', 'Disease', (93, 97))	('patients', 'Species', '9606', (45, 53))	('osteoarthritis', 'Phenotype', 'HP:0002758', (78, 92))	('osteoarthritis pain', 'Disease', (78, 97))	('rat', 'Species', '10116', (63, 66))	('attenuated', 'NegReg', (119, 129))	('anti-NGF', 'Var', (110, 118))
276399	25287160	Whether this earlier-than-expected joint replacement was caused by overuse of the arthritic joints due to the robust pain relief provided by anti-NGF, or was a direct effect of blocking NGF on the maintenance and formation of adult bone remains unknown.	('overuse', 'PosReg', (67, 74))	('pain', 'Phenotype', 'HP:0012531', (117, 121))	('anti-NGF', 'Var', (141, 149))	('pain', 'Disease', 'MESH:D010146', (117, 121))	('pain', 'Disease', (117, 121))	('arthritic joints', 'Disease', 'MESH:D015535', (82, 98))	('arthritic joints', 'Disease', (82, 98))	('joint replacement', 'Disease', (35, 52))
276401	25287160	A second major finding of the present study is that anti-NGF in this model of sarcoma-induced bone cancer reduced weight loss at late stage time points.	('anti-NGF', 'Var', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('weight loss', 'Disease', 'MESH:D015431', (114, 125))	('sarcoma-induced bone cancer', 'Disease', 'MESH:D001859', (78, 105))	('reduced weight', 'Phenotype', 'HP:0004325', (106, 120))	('sarcoma-induced bone cancer', 'Disease', (78, 105))	('weight loss', 'Disease', (114, 125))	('weight loss', 'Phenotype', 'HP:0001824', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('reduced', 'NegReg', (106, 113))
276402	25287160	This anti-NGF inhibition of weight loss confirms and extends what was previously reported in a rat model of Freund's induced osteoarthritis, and a mouse model of head/neck cancer, where anti-NGF markedly reduced weight loss.	('weight loss', 'Disease', (212, 223))	('anti-NGF', 'Var', (5, 13))	('weight loss', 'Disease', 'MESH:D015431', (28, 39))	('rat', 'Species', '10116', (95, 98))	('osteoarthritis', 'Disease', 'MESH:D010003', (125, 139))	('weight loss', 'Phenotype', 'HP:0001824', (28, 39))	('anti-NGF', 'Var', (186, 194))	('weight loss', 'Disease', (28, 39))	('inhibition', 'NegReg', (14, 24))	('osteoarthritis', 'Phenotype', 'HP:0002758', (125, 139))	('osteoarthritis', 'Disease', (125, 139))	('neck cancer', 'Phenotype', 'HP:0012288', (167, 178))	('weight loss', 'Disease', 'MESH:D015431', (212, 223))	('reduced weight', 'Phenotype', 'HP:0004325', (204, 218))	('head/neck cancer', 'Disease', 'MESH:D006258', (162, 178))	('mouse', 'Species', '10090', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('weight loss', 'Phenotype', 'HP:0001824', (212, 223))	('reduced', 'NegReg', (204, 211))	('head/neck cancer', 'Disease', (162, 178))
276404	25287160	Anti-NGF may indirectly affect weight loss by impacting the circulating levels of variety of cytokines (e.g., TNF-alpha, IL-6 and leptin) proposed to be involved in the regulation of body mass and cachexia.	('weight loss', 'Disease', 'MESH:D015431', (31, 42))	('TNF-alpha', 'Gene', '21926', (110, 119))	('cachexia', 'Disease', 'MESH:D002100', (197, 205))	('Anti-NGF', 'Var', (0, 8))	('circulating levels of', 'MPA', (60, 81))	('weight loss', 'Disease', (31, 42))	('cachexia', 'Disease', (197, 205))	('weight loss', 'Phenotype', 'HP:0001824', (31, 42))	('TNF-alpha', 'Gene', (110, 119))	('affect', 'Reg', (24, 30))	('leptin', 'MPA', (130, 136))	('cachexia', 'Phenotype', 'HP:0004326', (197, 205))	('IL-6', 'Gene', (121, 125))	('IL-6', 'Gene', '16193', (121, 125))	('impacting', 'Reg', (46, 55))
276412	25287160	However, the present data suggests that if anti-NGF can reduce tumor-induced bone destruction, time-to-fracture, weight loss, and CMB pain, and also maintain the functional status of patients, then early rather than late administration of anti-NGF following the initial diagnosis of CMB appears warranted.	('maintain', 'Reg', (149, 157))	('CMB', 'Phenotype', 'HP:0010622', (283, 286))	('bone destruction', 'Phenotype', 'HP:0002797', (77, 93))	('weight loss', 'Disease', 'MESH:D015431', (113, 124))	('CMB pain', 'Disease', (130, 138))	('weight loss', 'Phenotype', 'HP:0001824', (113, 124))	('CMB', 'Phenotype', 'HP:0010622', (130, 133))	('anti-NGF', 'Var', (43, 51))	('rat', 'Species', '10116', (229, 232))	('fracture', 'Disease', (103, 111))	('functional status', 'MPA', (162, 179))	('tumor', 'Disease', (63, 68))	('weight loss', 'Disease', (113, 124))	('rat', 'Species', '10116', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CMB pain', 'Disease', 'MESH:D010146', (130, 138))	('pain', 'Phenotype', 'HP:0012531', (134, 138))	('patients', 'Species', '9606', (183, 191))	('fracture', 'Disease', 'MESH:D050723', (103, 111))	('reduce', 'NegReg', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
276415	25287160	In contrast, blockade of NGF or TrkA has remarkable efficacy in attenuating skeletal pain, and a total of 11,000 patients that received anti-NGF for non-metastatic skeletal pain had relatively few side effects.	('skeletal pain', 'Disease', 'MESH:D010146', (76, 89))	('TrkA', 'Gene', (32, 36))	('patients', 'Species', '9606', (113, 121))	('pain', 'Phenotype', 'HP:0012531', (173, 177))	('attenuating', 'NegReg', (64, 75))	('skeletal pain', 'Phenotype', 'HP:0002653', (164, 177))	('skeletal pain', 'Disease', (164, 177))	('anti-NGF', 'Var', (136, 144))	('non-metastatic', 'Disease', (149, 163))	('NGF', 'Gene', (25, 28))	('skeletal pain', 'Disease', 'MESH:D010146', (164, 177))	('skeletal pain', 'Phenotype', 'HP:0002653', (76, 89))	('pain', 'Phenotype', 'HP:0012531', (85, 89))	('skeletal pain', 'Disease', (76, 89))
276428	25287160	Injection of too high a concentration of NCTC 2472 cells would induce significant tumor burden and bone destruction within a few days post-surgery and preclude differentiation between the pain caused by the arthrotomy from that of cancer-induced changes in bone remodeling.	('NCTC 2472 cells', 'Var', (41, 56))	('bone destruction', 'CPA', (99, 115))	('preclude', 'NegReg', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('induce', 'Reg', (63, 69))	('pain', 'Disease', 'MESH:D010146', (188, 192))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('bone destruction', 'Phenotype', 'HP:0002797', (99, 115))	('pain', 'Phenotype', 'HP:0012531', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Disease', (82, 87))	('pain', 'Disease', (188, 192))	('rat', 'Species', '10116', (31, 34))
276431	25287160	These previous studies and the current study show anti-NGF effectively attenuates bone pain in all three mouse models of bone cancer pain.	('bone cancer pain', 'Phenotype', 'HP:0002653', (121, 137))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bone pain', 'Phenotype', 'HP:0002653', (82, 91))	('bone cancer pain', 'Disease', (121, 137))	('anti-NGF', 'Var', (50, 58))	('mouse', 'Species', '10090', (105, 110))	('pain', 'Phenotype', 'HP:0012531', (133, 137))	('bone pain', 'Disease', 'MESH:D010146', (82, 91))	('bone cancer pain', 'Disease', 'MESH:D001859', (121, 137))	('attenuates', 'NegReg', (71, 81))	('bone pain', 'Disease', (82, 91))	('pain', 'Phenotype', 'HP:0012531', (87, 91))
276436	25287160	Blockade of NGF reduced bone cancer pain by 40-70% depending on the pain measure being assessed, and this analgesic effect was maintained even in animals with late stage disease.	('NGF', 'Gene', (12, 15))	('Blockade', 'Var', (0, 8))	('pain', 'Phenotype', 'HP:0012531', (36, 40))	('pain', 'Phenotype', 'HP:0012531', (68, 72))	('reduced', 'NegReg', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('pain', 'Disease', 'MESH:D010146', (36, 40))	('pain', 'Disease', (36, 40))	('pain', 'Disease', 'MESH:D010146', (68, 72))	('pain', 'Disease', (68, 72))	('bone cancer pain', 'Disease', 'MESH:D001859', (24, 40))	('bone cancer pain', 'Disease', (24, 40))	('bone cancer pain', 'Phenotype', 'HP:0002653', (24, 40))
276455	23198197	A 43-year-old patient was sent from another institution presenting an adnexal mass and elevated tumor markers: cancer antigen 125 (CA 125)-5232 IU/mL; CA 19.9-468 IU/mL; CA 15.3-910 IU/mL IU/mL, CEA-6.9 ng/mL; alpha-fetoprotein 1.9 ng/mL.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('CA 125', 'Gene', (131, 137))	('CA 125', 'Gene', '94025', (131, 137))	('alpha-fetoprotein', 'MPA', (210, 227))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('patient', 'Species', '9606', (14, 21))	('CA 19.9-468 IU/mL', 'Var', (151, 168))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('elevated tumor', 'Disease', (87, 101))	('elevated tumor', 'Disease', 'MESH:D009369', (87, 101))
276501	23198197	Early tumor stage, low myometrial invasion, and low mitotic count were shown as prognostic factors associated with a lengthened overall survival.	('lengthened', 'PosReg', (117, 127))	('overall', 'MPA', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('low', 'Var', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
276545	32907549	In this study, we showed that the combination therapy of THP + IFO + VP-16 was effective for patients with soft tissue sarcomas, with an overall response rate of 36%, which was relatively higher than the response rate found with ADR + IFO combination and other combinations.	('sarcomas', 'Disease', (119, 127))	('IFO', 'Chemical', 'MESH:D007069', (63, 66))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (107, 127))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (107, 126))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('IFO', 'Chemical', 'MESH:D007069', (235, 238))	('patients', 'Species', '9606', (93, 101))	('THP', 'Chemical', 'MESH:C027260', (57, 60))	('THP', 'Var', (57, 60))
276607	31363027	Consistent with this possibility, we have previously demonstrated that an MHV68 mutant deficient in all 14 pre-miRNAs is attenuated for latency establishment in vivo.	('MHV68', 'Species', '1440122', (74, 79))	('attenuated', 'NegReg', (121, 131))	('mutant', 'Var', (80, 86))	('MHV68', 'Gene', (74, 79))	('rat', 'Species', '10116', (60, 63))	('deficient', 'NegReg', (87, 96))	('latency establishment', 'CPA', (136, 157))
276609	31363027	Using a panel of MHV68 TMER mutants, we determined that TMER5-encoded MHV68 miR-7 is required for efficient establishment of MHV68 latency in vivo and sought to determine the target that mediates this requirement.	('MHV68', 'Gene', (70, 75))	('mutants', 'Var', (28, 35))	('MHV68', 'Gene', (125, 130))	('MHV68', 'Species', '1440122', (17, 22))	('MHV68', 'Species', '1440122', (125, 130))	('MHV68', 'Gene', (17, 22))	('MHV68', 'Species', '1440122', (70, 75))
276613	31363027	Moreover, miR-7-5p repression of EWSR1 specifically promoted latent infection of germinal center B cells, suggesting that EWSR1 repression may be a key regulatory step for gammaherpesvirus-driven B cell differentiation.	('miR-7-5p repression', 'Var', (10, 29))	('EWSR1', 'Gene', '14030', (122, 127))	('latent infection of germinal center B cells', 'CPA', (61, 104))	('EWSR1', 'Gene', '14030', (33, 38))	('EWSR1', 'Gene', (33, 38))	('miR-7-5p', 'Chemical', '-', (10, 18))	('infection of germinal center', 'Phenotype', 'HP:0002849', (68, 96))	('EWSR1', 'Gene', (122, 127))	('promoted', 'PosReg', (52, 60))
276623	31363027	Although the mean titer of MHV68.DeltamiR7.12 (250 PFU) at 4 dpi was slightly reduced compared to the WT virus titer (420 PFU), this difference was not significant, indicating that any delay in mutant virus replication was minimal in vivo.	('MHV68.DeltamiR7.12', 'Var', (27, 45))	('titer', 'MPA', (18, 23))	('reduced', 'NegReg', (78, 85))	('MHV68', 'Species', '1440122', (27, 32))
276628	31363027	To define whether the critical function of TMER5-derived miRNAs in latency was mediated by miRNAs derived from pre-miR-7 or pre-miR-12, we generated two other mutant viruses, MHV68.DeltamiR7 and MHV68.DeltamiR12, which carry deletions of single pre-miR-7 or pre-miR-12 stem-loops, respectively (Fig.	('pre-miR-12', 'Gene', (258, 268))	('MHV68', 'Species', '1440122', (175, 180))	('MHV68', 'Species', '1440122', (195, 200))	('rat', 'Species', '10116', (143, 146))	('miR-12', 'Chemical', '-', (262, 268))	('miR-12', 'Chemical', '-', (128, 134))	('deletions', 'Var', (225, 234))
276633	31363027	Conversely, the ability of MHV68.DeltamiR12 to establish latency (1 in 270) was similar to that of wild-type virus (1 in 380), demonstrating that miRNAs derived from miR-12 are completely dispensable for latent infection.	('miR-12', 'Chemical', '-', (166, 172))	('MHV68', 'Species', '1440122', (27, 32))	('MHV68.DeltamiR12', 'Var', (27, 43))	('rat', 'Species', '10116', (134, 137))	('miR-12', 'Gene', (166, 172))
276636	31363027	Within this study, we identified 10 and 15 targets of miR-7-5p and miR-7-3p, respectively (Table S4).	('miR-7-3p', 'Var', (67, 75))	('miR-7-5p', 'Var', (54, 62))	('miR-7-3p', 'Chemical', '-', (67, 75))	('miR-7-5p', 'Chemical', '-', (54, 62))
276637	31363027	To focus these additional studies, we selected the top four most prevalent targets for each miRNA for molecular validation: miR-7-5p targets RGS16 (regulator of G-protein signaling 16), EWSR1, ARHGEF18 (rho/rac guanine nucleotide exchange factor 18), and BIRC5 (baculoviral IAP repeat containing 5), whereas miR-7-3p targets TMEM38B (transmembrane protein 38B), LARS2 (leucyl-tRNA synthetase 2 mitochondrial), RNF138 (ring finger protein 138), and ANAPC7 (anaphase promoting complex subunit 7).	('RNF138', 'Gene', (410, 416))	('TMEM38B', 'Gene', (325, 332))	('EWSR1', 'Gene', (186, 191))	('EWSR1', 'Gene', '14030', (186, 191))	('LARS2', 'Gene', (362, 367))	('baculoviral IAP repeat', 'Disease', 'MESH:D000647', (262, 284))	('ANAPC7', 'Gene', (448, 454))	('baculoviral IAP repeat', 'Disease', (262, 284))	('RGS16', 'Var', (141, 146))	('miR-7-3p', 'Chemical', '-', (308, 316))	('miR-7-5p', 'Chemical', '-', (124, 132))
276640	31363027	Endogenous EWSR1 and ARHGEF18 transcripts were significantly reduced (61 and 40% reductions, respectively) in the presence of miR-7-5p, whereas the expression of BIRC5 transcript was not affected.	('EWSR1', 'Gene', '14030', (11, 16))	('EWSR1', 'Gene', (11, 16))	('miR-7-5p', 'Var', (126, 134))	('reductions', 'NegReg', (81, 91))	('miR-7-5p', 'Chemical', '-', (126, 134))	('ARHGEF18', 'Gene', (21, 29))	('transcripts', 'MPA', (30, 41))	('reduced', 'NegReg', (61, 68))
276641	31363027	Unexpectedly, RGS16 expression was increased 145% in the presence of miR-7-5p, suggesting that miR-7-5p may stabilize rather than repress this host transcript.	('increased', 'PosReg', (35, 44))	('expression', 'MPA', (20, 30))	('miR-7-5p', 'Chemical', '-', (95, 103))	('rat', 'Species', '10116', (118, 121))	('miR-7-5p', 'Chemical', '-', (69, 77))	('miR-7-5p', 'Var', (95, 103))	('RGS16', 'Gene', (14, 19))
276643	31363027	Thus, of the top miRNA-mRNA target interactions tested, miR-7-5p binding to EWSR1 resulted in the highest degree of target repression.	('target repression', 'MPA', (116, 133))	('binding', 'Interaction', (65, 72))	('EWSR1', 'Gene', '14030', (76, 81))	('EWSR1', 'Gene', (76, 81))	('miR-7-5p', 'Var', (56, 64))	('miR-7-5p', 'Chemical', '-', (56, 64))
276646	31363027	Interestingly, as opposed to miRNA binding interactions which frequently occur within the 3' untranslated region (3'UTR) of the target transcript, miR-7-5p bound to the coding sequence of EWSR1.	('EWSR1', 'Gene', '14030', (188, 193))	('miR-7-5p', 'Var', (147, 155))	('miR-7-5p', 'Chemical', '-', (147, 155))	('bound', 'Interaction', (156, 161))	('EWSR1', 'Gene', (188, 193))
276647	31363027	Supporting our observations of strong EWSR1 repression by miR-7-5p, this interaction displayed a high degree of complementarity throughout, including 6 of 7 nt within the seed sequence (nt 2 to 8) of the miRNA.	('EWSR1', 'Gene', '14030', (38, 43))	('repression', 'NegReg', (44, 54))	('miR-7-5p', 'Var', (58, 66))	('miR-7-5p', 'Chemical', '-', (58, 66))	('EWSR1', 'Gene', (38, 43))
276649	31363027	3A) mediated by this miRNA, miR-7-5p also resulted in a striking repression of both luciferase target transcripts carrying the EWSR1 miRNA binding sequence (Fig.	('EWSR1', 'Gene', '14030', (127, 132))	('EWSR1', 'Gene', (127, 132))	('luciferase', 'Enzyme', (84, 94))	('miR-7-5p', 'Var', (28, 36))	('repression', 'NegReg', (65, 75))	('miR-7-5p', 'Chemical', '-', (28, 36))
276652	31363027	To determine whether EWSR1 is specifically repressed in latently infected B cells in vivo, we infected mice with MHV68.H2bYFP, an enhanced yellow fluorescent protein (eYFP)-marked recombinant MHV68 that is phenotypically wild type.	('EWSR1', 'Gene', '14030', (21, 26))	('EWSR1', 'Gene', (21, 26))	('mice', 'Species', '10090', (103, 107))	('MHV68', 'Species', '1440122', (113, 118))	('MHV68', 'Species', '1440122', (192, 197))	('MHV68.H2bYFP', 'Var', (113, 125))
276654	31363027	Compared to YFP- noninfected B cells, the level of EWSR1 transcript was significantly decreased in YFP+ latently infected B cells.	('EWSR1', 'Gene', '14030', (51, 56))	('EWSR1', 'Gene', (51, 56))	('level', 'MPA', (42, 47))	('decreased', 'NegReg', (86, 95))	('YFP+', 'Var', (99, 103))
276655	31363027	In contrast, the expression of control BIRC5 transcript, which was not altered by miR-7-5p in vitro (Fig.	('miR-7-5p', 'Chemical', '-', (82, 90))	('miR-7-5p', 'Var', (82, 90))	('BIRC5', 'Gene', (39, 44))
276657	31363027	Together, these data demonstrated that EWSR1 is strongly repressed by miR-7-5p both in vitro and in vivo.	('EWSR1', 'Gene', '14030', (39, 44))	('EWSR1', 'Gene', (39, 44))	('miR-7-5p', 'Var', (70, 78))	('rat', 'Species', '10116', (28, 31))	('miR-7-5p', 'Chemical', '-', (70, 78))
276662	31363027	Thus, we speculated that direct replacement of the MHV68 pre-miR-7 stem-loop with a sequence-specific shRNA directed against EWSR1 should generate a functional and highly specific anti-EWSR1 siRNA.	('EWSR1', 'Gene', '14030', (185, 190))	('MHV68', 'Gene', (51, 56))	('EWSR1', 'Gene', '14030', (125, 130))	('EWSR1', 'Gene', (125, 130))	('EWSR1', 'Gene', (185, 190))	('replacement', 'Var', (32, 43))	('MHV68', 'Species', '1440122', (51, 56))	('rat', 'Species', '10116', (142, 145))
276663	31363027	To test this possibility, we first designed four EWSR1-specific small interfering RNAs (siRNAs) (EW-siR-1, -2, -3, and -4), and four control siRNAs with scrambled sequences (SC-siR-1, -2, -3, and -4) (Fig.	('EWSR1', 'Gene', (49, 54))	('EW-siR-1', 'Var', (97, 105))	('small interfering', 'Reg', (64, 81))	('EWSR1', 'Gene', '14030', (49, 54))
276681	31363027	Based on these results, we incorporated the anti-EWSR1 shRNAs or scrambled shRNAs into the MHV68 genome in place of the pre-miR-7 and pre-miR-12 stem-loops to generate the recombinant viruses MHV68.EW.shR and MHV68.SC.shR, respectively (Fig.	('rat', 'Species', '10116', (163, 166))	('EWSR1', 'Gene', '14030', (49, 54))	('EWSR1', 'Gene', (49, 54))	('MHV68', 'Species', '1440122', (91, 96))	('MHV68', 'Species', '1440122', (209, 214))	('MHV68.EW.shR', 'Var', (192, 204))	('MHV68', 'Species', '1440122', (192, 197))	('rat', 'Species', '10116', (34, 37))	('miR-12', 'Chemical', '-', (138, 144))	('MHV68.SC.shR', 'Var', (209, 221))
276685	31363027	To determine whether recombinant virus expressing anti-EWSR1 shRNAs specifically repressed EWSR1 transcript in latently infected B cells in vivo, we infected mice with wild-type MHV68, MHV68.EW.shR, or MHV68.SC.shR for 16 days and quantified EWSR1 expression in infected B cells.	('MHV68.SC.shR', 'Var', (202, 214))	('mice', 'Species', '10090', (158, 162))	('EWSR1', 'Gene', '14030', (55, 60))	('EWSR1', 'Gene', (55, 60))	('EWSR1', 'Gene', '14030', (242, 247))	('MHV68', 'Species', '1440122', (185, 190))	('EWSR1', 'Gene', (242, 247))	('MHV68', 'Species', '1440122', (178, 183))	('EWSR1', 'Gene', '14030', (91, 96))	('EWSR1', 'Gene', (91, 96))	('MHV68', 'Species', '1440122', (202, 207))
276689	31363027	Notably, B cells infected with mutant virus carrying control scrambled shRNAs in place of pre-miRNA stem-loops displayed increased levels of EWSR1 transcript, providing additional evidence that TMER5-derived miRNAs suppress EWSR1 in vivo.	('mutant', 'Var', (31, 37))	('levels', 'MPA', (131, 137))	('EWSR1', 'Gene', '14030', (224, 229))	('EWSR1', 'Gene', (224, 229))	('EWSR1', 'Gene', (141, 146))	('increased', 'PosReg', (121, 130))	('EWSR1', 'Gene', '14030', (141, 146))	('suppress', 'NegReg', (215, 223))
276690	31363027	In contrast, the level of EWSR1 in B cells infected with mutant virus carrying anti-EWSR1 shRNAs was reduced to a level below that of wild-type virus, demonstrating effective shRNA-mediated repression of EWSR1 in vivo.	('EWSR1', 'Gene', '14030', (204, 209))	('EWSR1', 'Gene', (84, 89))	('EWSR1', 'Gene', (204, 209))	('EWSR1', 'Gene', '14030', (84, 89))	('mutant', 'Var', (57, 63))	('reduced', 'NegReg', (101, 108))	('EWSR1', 'Gene', (26, 31))	('rat', 'Species', '10116', (158, 161))	('EWSR1', 'Gene', '14030', (26, 31))
276693	31363027	As expected, the weights of spleens from mice infected with wild-type virus (137 mg) were significantly more than those of mock-infected mice (88 mg) (Fig.	('weights', 'CPA', (17, 24))	('mice', 'Species', '10090', (41, 45))	('more', 'PosReg', (104, 108))	('137 mg', 'Var', (77, 83))	('mock-infected', 'Disease', 'MESH:D007239', (123, 136))	('mock-infected', 'Disease', (123, 136))	('mice', 'Species', '10090', (137, 141))
276698	31363027	This finding was in contrast to the slight delay in lytic replication observed with viruses deficient in pre-miR-7 and pre-miR-12 (Fig.	('pre-miR-12', 'Var', (119, 129))	('lytic replication', 'MPA', (52, 69))	('miR-12', 'Chemical', '-', (123, 129))	('viruses deficient', 'Disease', (84, 101))	('viruses deficient', 'Disease', 'MESH:D006482', (84, 101))
276707	31363027	Together, these data suggested that miR-7-5p may directly contribute to the virus-mediated differentiation of naive B cells into germinal center B cells.	('contribute', 'Reg', (58, 68))	('miR-7-5p', 'Chemical', '-', (36, 44))	('miR-7-5p', 'Var', (36, 44))
276708	31363027	Consistent with this possibility, incorporation of anti-EWSR1 shRNAs into the miR-7-5p-deficient virus fully restored both naive B cell (9% WT versus 8% EW.shR) and germinal center B cell (79% WT versus 83% EW.shR) infection to levels equivalent to that of wild-type virus.	('EWSR1', 'Gene', '14030', (56, 61))	('EWSR1', 'Gene', (56, 61))	('germinal center B cell', 'CPA', (165, 187))	('miR-7-5p', 'Chemical', '-', (78, 86))	('rat', 'Species', '10116', (41, 44))	('restored', 'PosReg', (109, 117))	('incorporation', 'Var', (34, 47))
276713	31363027	Through in vitro validation of qCLASH-identified targets, we defined EWSR1 as a likely important host mRNA target of the pre-miR-7-derived miRNAs mghv-miR-M1-7-5p or mghv-miR-M1-7-3p.	('EWSR1', 'Gene', '14030', (69, 74))	('EWSR1', 'Gene', (69, 74))	('mghv-miR-M1-7-3p', 'Var', (166, 182))	('5p', 'Chemical', '-', (160, 162))	('mghv', 'Chemical', '-', (146, 150))	('mghv-miR-M1-7-5p', 'Var', (146, 162))	('mghv', 'Chemical', '-', (166, 170))
276714	31363027	Subsequently, through the use of recombinant viruses expressing scrambled or target-specific shRNAs in place of TMER5-encoded miRNAs, we demonstrated that in vivo repression of EWSR1 completely restored the attenuation of MHV68 TMER5 mutant viruses.	('mutant', 'Var', (234, 240))	('repression', 'Var', (163, 173))	('MHV68', 'Species', '1440122', (222, 227))	('attenuation', 'MPA', (207, 218))	('MHV68', 'Gene', (222, 227))	('EWSR1', 'Gene', '14030', (177, 182))	('EWSR1', 'Gene', (177, 182))	('restored', 'PosReg', (194, 202))	('rat', 'Species', '10116', (144, 147))
276719	31363027	Based on previous reports demonstrating effective processing of heterologous miRNAs from the MHV68 TMERs and functional expression and processing of shRNAs placed downstream of tRNAs, we speculated that direct replacement of an MHV68 pre-miRNA stem-loop with an shRNA would generate a functional and highly specific siRNA directed against the target transcript of interest.	('generate', 'PosReg', (274, 282))	('MHV68', 'Gene', (93, 98))	('replacement', 'Var', (210, 221))	('MHV68', 'Species', '1440122', (228, 233))	('MHV68', 'Gene', (228, 233))	('rat', 'Species', '10116', (33, 36))	('siRNA directed against', 'MPA', (316, 338))	('MHV68', 'Species', '1440122', (93, 98))	('rat', 'Species', '10116', (278, 281))
276720	31363027	Indeed, substitution of the TMER5-encoded pre-miRNA stem-loops with shRNAs directed against EWSR1, the most highly repressed target of a TMER5-encoded miRNA, fully restored attenuation of the TMER5 pre-miRNA mutant virus.	('restored', 'PosReg', (164, 172))	('attenuation', 'MPA', (173, 184))	('EWSR1', 'Gene', '14030', (92, 97))	('EWSR1', 'Gene', (92, 97))	('substitution', 'Var', (8, 20))
276723	31363027	In that scenario, fusion of the N-terminal transcription-activating domain of EWSR1 to the C-terminal DNA-binding domain of the transcription factor FLI-1 (Friend Leukemia Integration 1) generates an oncogenic transcriptional activator, EWS/FLI-1, that drives cell growth, proliferation, and transformation.	('transformation', 'CPA', (292, 306))	('drives', 'PosReg', (253, 259))	('EWS', 'Gene', '14030', (78, 81))	('Leukemia', 'Phenotype', 'HP:0001909', (163, 171))	('rat', 'Species', '10116', (177, 180))	('rat', 'Species', '10116', (191, 194))	('Friend Leukemia', 'Disease', 'MESH:D007938', (156, 171))	('EWS', 'Gene', '14030', (237, 240))	('rat', 'Species', '10116', (280, 283))	('cell growth', 'CPA', (260, 271))	('EWSR1', 'Gene', '14030', (78, 83))	('EWSR1', 'Gene', (78, 83))	('fusion', 'Var', (18, 24))	('EWS', 'Gene', (78, 81))	('EWS', 'Gene', (237, 240))	('Friend Leukemia', 'Disease', (156, 171))
276744	31363027	Wild-type bacterial artificial chromosome (BAC)-derived MHV68, parental wild-type marker virus MHV68.ORF73betala, a recombinant virus that expresses beta-lactamase as a fusion to mLANA, and MHV68.DeltamiR7.12, a recombinant virus that is deficient in the expression of the pre-miR-7 and pre-miR-12 double step-loops, have been previously described.	('MHV68', 'Species', '1440122', (190, 195))	('mLANA', 'Gene', (179, 184))	('miR-12', 'Chemical', '-', (291, 297))	('mLANA', 'Gene', '77836', (179, 184))	('MHV68.DeltamiR7.12', 'Var', (190, 208))	('MHV68', 'Species', '1440122', (95, 100))	('MHV68', 'Species', '1440122', (56, 61))
276747	31363027	Subsequently, the Kan selection marker was removed after induction of I-SceI-mediated recombination by 1% arabinose, leaving behind the desired mutations.	('arabinose', 'Chemical', 'MESH:D001089', (106, 115))	('mutations', 'Var', (144, 153))	('leaving behind', 'Reg', (117, 131))
276775	31363027	For luciferase assays, the murine EWSR1 coding region (nt 303 to 848 or nt 1000 to 1539) was cloned into the PmeI site of the pmirGLO dual-luciferase miRNA target expression vector (Promega, E1330), and the resulting recombinant plasmids were verified by Sanger sequencing.	('EWSR1', 'Gene', (34, 39))	('nt 1000 to 1539', 'Var', (72, 87))	('EWSR1', 'Gene', '14030', (34, 39))	('murine', 'Species', '10090', (27, 33))
276801	31363027	with 104 PFU of MHV68.EW.shR or MHV68.SC.shR, or with wild-type control virus.	('MHV68.EW.shR', 'Var', (16, 28))	('MHV68', 'Species', '1440122', (32, 37))	('MHV68', 'Species', '1440122', (16, 21))	('MHV68.SC.shR', 'Var', (32, 44))
276809	29226910	Recently, however, next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumour neoantigens, which are highly desirable immunogens because they arise from somatic mutations of the tumour and are therefore tumour specific.	('tumour', 'Disease', 'MESH:D009369', (250, 256))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', (118, 124))	('tumour', 'Disease', (250, 256))	('tumour', 'Disease', (225, 231))	('mutations', 'Var', (208, 217))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('tumour', 'Disease', 'MESH:D009369', (118, 124))
276838	29226910	Tumour heterogeneity between and within tumours is also a major challenge to the development of cancer immunotherapy; a crucial factor in this regard is the clonal evolution of tumour cells arising from selective pressure, which leads some mutant clones to expand, whereas it leads others to become extinct.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumour', 'Disease', (177, 183))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('mutant', 'Var', (240, 246))	('tumours', 'Disease', (40, 47))	('tumour', 'Disease', (40, 46))	('expand', 'PosReg', (257, 263))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', (96, 102))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
276858	29226910	Tumour neoantigens are generated as products of somatic mutations, and hence they are not only exquisitely tumour specific but also highly immunogenic on the basis of lack of central tolerance.	('mutations', 'Var', (56, 65))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Disease', (107, 113))
276864	29226910	A comparatively higher burden of mutated predicted immunogenic epitopes was associated with improved patient survival in a study that assessed 515 tumours with 6 different histologies from TCGA.	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('mutated', 'Var', (33, 40))	('patient survival', 'CPA', (101, 117))	('tumours', 'Disease', 'MESH:D009369', (147, 154))	('tumours', 'Disease', (147, 154))	('patient', 'Species', '9606', (101, 108))	('improved', 'PosReg', (92, 100))
276865	29226910	Consistent with these findings, analysis of whole-exome sequencing of 619 colorectal cancers showed that high neoantigen load is associated with increased numbers of TILs and improved survival.	('colorectal cancers', 'Disease', 'MESH:D015179', (74, 92))	('high', 'Var', (105, 109))	('colorectal cancers', 'Disease', (74, 92))	('TILs', 'Disease', (166, 170))	('neoantigen', 'Protein', (110, 120))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('increased', 'PosReg', (145, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('survival', 'CPA', (184, 192))	('improved', 'PosReg', (175, 183))
276867	29226910	In addition, associations between mutational load and clinical response to CPB have been shown in patients with melanoma, non-small-cell lung cancer (NSCLC) and colorectal cancer.	('non-small-cell lung cancer', 'Disease', (122, 148))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('colorectal cancer', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('CPB', 'Chemical', '-', (75, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('melanoma', 'Disease', (112, 120))	('associations', 'Interaction', (13, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('NSCLC', 'Disease', (150, 155))	('mutational load', 'Var', (34, 49))
276870	29226910	Furthermore, CD4+ and CD8+ TILs that mediate tumour regression upon adoptive transfer in patients with solid tumours have been characterized to have specificity for neo-antigens.	('CD4+', 'Var', (13, 17))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('solid tumours', 'Disease', (103, 116))	('tumour regression', 'Disease', 'MESH:D009365', (45, 62))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('neo-antigens', 'Protein', (165, 177))	('patients', 'Species', '9606', (89, 97))	('tumour regression', 'Disease', (45, 62))	('solid tumours', 'Disease', 'MESH:D009369', (103, 116))	('CD8', 'Gene', (22, 25))	('CD8', 'Gene', '925', (22, 25))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
276872	29226910	Third, animal experiments and human studies have directly shown that neoantigen-specific T cells are cytolytic for tumour cells that present mutated peptides, and they can contribute to complete or partial tumour regression.	('human', 'Species', '9606', (30, 35))	('mutated', 'Var', (141, 148))	('tumour regression', 'Disease', (206, 223))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumour regression', 'Disease', 'MESH:D009365', (206, 223))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('peptides', 'Chemical', 'MESH:D010455', (149, 157))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (206, 212))	('tumour', 'Disease', (115, 121))
276911	29226910	The built-in adjuvant function of single-stranded RNA through Toll-like receptor 7 (TLR7) and TLR8 stimulation (together with the relative ease of encoding multiple vaccine epitopes on the same RNA molecule) suggests its superiority as a cancer vaccine formulation.	('stimulation', 'PosReg', (99, 110))	('single-stranded', 'Var', (34, 49))	('TLR7', 'Gene', (84, 88))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('TLR7', 'Gene', '51284', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('Toll-like receptor 7', 'Gene', '51284', (62, 82))	('TLR8', 'Gene', (94, 98))	('TLR8', 'Gene', '51311', (94, 98))	('Toll-like receptor 7', 'Gene', (62, 82))
276913	29226910	Poly-ICLC was shown to induce similar innate immune signalling pathways to the highly immunogenic yellow fever vaccine, and it markedly increased the immunogenicity of a peptide vaccine in patients with ovarian cancer.	('Poly-ICLC', 'Var', (0, 9))	('fever', 'Disease', 'MESH:D005334', (105, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (203, 217))	('immunogenicity', 'MPA', (150, 164))	('fever', 'Disease', (105, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (203, 217))	('induce', 'Reg', (23, 29))	('fever', 'Phenotype', 'HP:0001945', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('increased', 'PosReg', (136, 145))	('patients', 'Species', '9606', (189, 197))	('ovarian cancer', 'Disease', (203, 217))	('innate immune signalling pathways', 'Pathway', (38, 71))
276942	29226910	Comprehensive mutational analysis is carried out through whole-exome sequencing and neoepitopes encoded by somatic mutations in the tumour are selected that have the highest probability of being presented by the individual's MHC molecules on the basis of affinity predictions.	('mutations', 'Var', (115, 124))	('tumour', 'Disease', (132, 138))	('MHC', 'Gene', (225, 228))	('MHC', 'Gene', '3107', (225, 228))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))
276944	29226910	Matched RNA-seq is used to confirm with high confidence the mutations that are likely to be expressed by tumour cells.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (60, 69))	('tumour', 'Disease', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
276959	29226910	In the majority of cases, neoantigen-specific T cells could discriminate mutated antigens from wild-type antigens in vitro; in some patients, these T cells recognized autologous tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('mutated', 'Var', (73, 80))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('tumour', 'Disease', (178, 184))	('patients', 'Species', '9606', (132, 140))
276977	29226910	Although the number and quality of tumour neo-antigens required for the generation of an effective antitumour immune response are not known, identification of neoepitopes that have the greatest probability of generating effective immunity is important, particularly for tumours in which the number of mutations encoding such neoantigens is limiting (tumours with low mutation rates).	('mutations', 'Var', (301, 310))	('tumours', 'Disease', (270, 277))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('tumours', 'Disease', (350, 357))	('tumour', 'Phenotype', 'HP:0002664', (350, 356))	('tumour', 'Disease', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (270, 277))	('tumours', 'Disease', 'MESH:D009369', (270, 277))	('tumour', 'Disease', 'MESH:D009369', (350, 356))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', (350, 356))	('tumours', 'Phenotype', 'HP:0002664', (350, 357))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('tumours', 'Disease', 'MESH:D009369', (350, 357))	('tumour', 'Disease', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('tumour', 'Disease', 'MESH:D009369', (270, 276))	('tumour', 'Disease', (270, 276))
276987	29226910	It can be anticipated that future improvement in prediction algorithms to identify neoantigens arising from gene fusions, splice variants and errors in translation will increase the number of targetable neoantigens, which is particularly important for tumours with lower mutation load.	('tumours', 'Disease', 'MESH:D009369', (252, 259))	('errors', 'Var', (142, 148))	('tumours', 'Disease', (252, 259))	('increase', 'PosReg', (169, 177))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('tumours', 'Phenotype', 'HP:0002664', (252, 259))
277005	29226910	Antigens arising from mutation of the tumour genome that causes tumour cells to express specific proteins that are not expressed on normal cells.	('mutation', 'Var', (22, 30))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('tumour', 'Disease', (64, 70))	('express specific proteins', 'MPA', (80, 105))	('tumour', 'Disease', (38, 44))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
277007	29226910	Cancer cells within the same tumour tissue can have distinct phenotypical and functional profiles as a consequence of genetic changes, environmental differences and reversible changes in cell properties.	('tumour', 'Disease', (29, 35))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('changes', 'Var', (126, 133))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('changes', 'Reg', (176, 183))
277031	29226910	A notable example is a study carried out in patients with metastatic ovarian cancer using NY-ESO-1 long peptides, which provided compelling evidence for the superiority of the TLR3 agonist poly-ICLC compared with incomplete Freund's adjuvant or placebo, as it led to markedly stronger antibody and T cell responses.	('ovarian cancer', 'Disease', (69, 83))	('poly-ICLC', 'Var', (189, 198))	('patients', 'Species', '9606', (44, 52))	('NY-ESO-1', 'Gene', '246100', (90, 98))	('NY-ESO-1', 'Gene', (90, 98))	('peptides', 'Chemical', 'MESH:D010455', (104, 112))	('TLR3', 'Gene', (176, 180))	('TLR3', 'Gene', '7098', (176, 180))	('poly-ICLC', 'Chemical', '-', (189, 198))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))	('T cell responses', 'CPA', (298, 314))	('stronger', 'PosReg', (276, 284))
277034	29226910	Somatic tumour mutations can be categorized as passenger or driver mutations; passenger mutations represent the majority of mutations and have no effect on the fitness of the cell, whereas driver mutations typically make up only a small proportion of mutations per cell (~5-20%) and provide a selective advantage to the malignant clone.	('tumour', 'Disease', (8, 14))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('tumour', 'Disease', 'MESH:D009369', (8, 14))	('mutations', 'Var', (124, 133))
277035	29226910	Neoantigens arising from clonal mutations are attractive immunological targets as they are expressed on all cells within the cancer cell population.	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))
277036	29226910	Neoantigens arising from subclonal mutations are expressed on only that subclone, and hence targeting them at best eliminates a fraction of the tumour cells within that population.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', (144, 150))	('eliminates', 'NegReg', (115, 125))	('mutations', 'Var', (35, 44))
277042	29226910	Finally, personalized neoantigen vaccines do carry the advantage that they have the potential to be re-formulated in a versatile manner for the same individual should new mutations and corresponding neoantigens be identified in a relapsing tumour.	('mutations', 'Var', (171, 180))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('tumour', 'Disease', (240, 246))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))
277047	27545889	Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d-/- mice experienced a higher incidence of tumors and exacerbated viral infections compared to WT animals.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (157, 163))	('higher', 'PosReg', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('exacerbated viral infections', 'Phenotype', 'HP:0004429', (168, 196))	('il17d-/-', 'Var', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mice', 'Species', '10090', (118, 122))	('viral infections', 'Disease', 'MESH:D001102', (180, 196))	('exacerbated', 'PosReg', (168, 179))	('viral infections', 'Disease', (180, 196))
277048	27545889	Moreover, activating Nrf2 to induce IL-17D in established tumors led to natural killer cell-dependent tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('IL-17D', 'Gene', (36, 42))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Nrf2', 'Gene', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('activating', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('induce', 'PosReg', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
277064	27545889	The induction of IL-17D is required for effective cancer surveillance and antiviral responses, as mice deficient in IL-17D had increased formation of MCA-induced tumors and exacerbated pathology when infected with vaccinia virus (VV) or murine cytomegalovirus (MCMV).	('vaccinia virus', 'Disease', 'MESH:D014615', (214, 228))	('cancer', 'Disease', (50, 56))	('IL-17D', 'Gene', (116, 122))	('vaccinia virus', 'Disease', (214, 228))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pathology', 'CPA', (185, 194))	('MCA-induced', 'CPA', (150, 161))	('mice', 'Species', '10090', (98, 102))	('formation', 'CPA', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('MCA', 'Chemical', 'MESH:D008748', (150, 153))	('exacerbated', 'PosReg', (173, 184))	('MCMV', 'Species', '10366', (261, 265))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('murine cytomegalovirus', 'Species', '10366', (237, 259))	('deficient', 'Var', (103, 112))	('tumors', 'Disease', (162, 168))	('increased', 'PosReg', (127, 136))
277068	27545889	To test this, we treated murine embryonic fibroblasts (MEFs) and the 3-methylcholanthrene (MCA)-induced sarcoma cell line F244 with H2O2, a known activator of Nrf2 (Fig.	('sarcoma', 'Disease', (104, 111))	('H2O2', 'Var', (132, 136))	('H2O2', 'Chemical', 'MESH:D006861', (132, 136))	('MCA', 'Chemical', 'MESH:D008748', (91, 94))	('3-methylcholanthrene', 'Chemical', 'MESH:D008748', (69, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('MEFs', 'CellLine', 'CVCL:9115', (55, 59))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('murine', 'Species', '10090', (25, 31))
277089	27545889	Mice treated topically with tBHQ had increased transcript and protein levels of il17d and Nrf2, respectively, commensurate with those observed following infection by scarification (Fig.	('il17d', 'Gene', (80, 85))	('tBHQ', 'Chemical', 'MESH:C018855', (28, 32))	('scar', 'Phenotype', 'HP:0100699', (166, 170))	('tBHQ', 'Var', (28, 32))	('increased', 'PosReg', (37, 46))	('Mice', 'Species', '10090', (0, 4))	('infection', 'Disease', (153, 162))	('Nrf2', 'Gene', (90, 94))	('infection', 'Disease', 'MESH:D007239', (153, 162))
277095	27545889	Despite demonstrating a largely normal immune system at baseline, strikingly, il17d-/- mice were significantly more susceptible to the development of primary tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('primary tumors', 'Disease', 'MESH:D009369', (150, 164))	('mice', 'Species', '10090', (87, 91))	('susceptible', 'Reg', (116, 127))	('il17d-/-', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('primary tumors', 'Disease', (150, 164))
277096	27545889	At a 25mug dose of MCA, approximately twice the number of il17d-/- mice compared to WT mice developed primary tumors.	('il17d-/-', 'Var', (58, 66))	('mice', 'Species', '10090', (67, 71))	('primary tumors', 'Disease', 'MESH:D009369', (102, 116))	('MCA', 'Chemical', 'MESH:D008748', (19, 22))	('mice', 'Species', '10090', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('developed', 'PosReg', (92, 101))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('primary tumors', 'Disease', (102, 116))
277100	27545889	Following infection of WT and il17d-/- animals, we observed an exacerbation of the VV scar in il17d-/- animals compared to WT animals at two doses (Fig.	('il17d-/-', 'Var', (94, 102))	('infection', 'Disease', (10, 19))	('infection', 'Disease', 'MESH:D007239', (10, 19))	('scar', 'Phenotype', 'HP:0100699', (86, 90))	('exacerbation', 'PosReg', (63, 75))	('VV scar', 'CPA', (83, 90))
277106	27545889	4A), we hypothesized that activating Nrf2 in vivo would induce IL-17D in established tumors, which in turn would initiate protective immunosurveillance.	('Nrf2', 'Gene', (37, 41))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('induce', 'PosReg', (56, 62))	('initiate', 'Reg', (113, 121))	('IL-17D', 'Protein', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('activating', 'Var', (26, 36))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
277108	27545889	We found that treatment with tBHQ delayed tumor growth in WT mice bearing F244 or B16 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('F244', 'Var', (74, 78))	('tumor', 'Disease', (42, 47))	('mice', 'Species', '10090', (61, 65))	('tBHQ', 'Gene', (29, 33))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (86, 92))	('delayed', 'NegReg', (34, 41))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tBHQ', 'Chemical', 'MESH:C018855', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
277109	27545889	Moreover, tBHQ led to the in vivo induction of both hmox1 and il17d in tumors derived from both transplanted cell lines (Fig.	('hmox1', 'Gene', (52, 57))	('il17d', 'Gene', (62, 67))	('induction', 'PosReg', (34, 43))	('tBHQ', 'Chemical', 'MESH:C018855', (10, 14))	('tBHQ', 'Var', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
277115	27545889	Based on established definitions for tumor growth phenotypes, we classified F38K1 as a progressor tumor (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('F38K1', 'Var', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (98, 103))
277118	27545889	S5C) mice transplanted with F38K1 failed to delay tumor growth.	('delay tumor', 'Disease', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('delay tumor', 'Disease', 'MESH:D009369', (44, 55))	('F38K1', 'Var', (28, 33))	('mice', 'Species', '10090', (5, 9))
277120	27545889	To analyze the requirement of tumor-derived Nrf2 during tBHQ-induced tumor rejection, we generated independent sarcoma and melanoma cell lines bearing a stable knockdown of nrf2 via shRNA (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('nrf2', 'Gene', (173, 177))	('knockdown', 'Var', (160, 169))	('tumor', 'Disease', (69, 74))	('sarcoma', 'Disease', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('tBHQ', 'Chemical', 'MESH:C018855', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (30, 35))
277124	27545889	Moreover, the tBHQ-mediated induction of il17d (and hmox1) was abolished in vivo when nrf2 was knocked down (Fig.	('tBHQ', 'Chemical', 'MESH:C018855', (14, 18))	('nrf2', 'Gene', (86, 90))	('knocked down', 'Var', (95, 107))
277126	27545889	It should be noted that silencing nrf2 in these progressor tumors actually caused them to display growth delay compared to the parental cells (Fig.	('growth delay', 'Phenotype', 'HP:0001510', (98, 110))	('growth delay', 'CPA', (98, 110))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('nrf2', 'Gene', (34, 38))	('silencing', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors actually', 'Disease', (59, 74))	('tumors actually', 'Disease', 'MESH:D009369', (59, 74))
277133	27545889	Our TIL analysis revealed an increase in the percentage and total number of infiltrating NK cells when tumors were treated with tBHQ (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('increase', 'PosReg', (29, 37))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('tBHQ', 'Var', (128, 132))	('tBHQ', 'Chemical', 'MESH:C018855', (128, 132))
277143	27545889	In this study, we have demonstrated an obligate role for IL-17D in effective tumor surveillance, optimal antiviral responses, and cancer immune therapy via Nrf2 agonists.	('IL-17D', 'Gene', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('antiviral', 'MPA', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('agonists', 'Var', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (77, 82))	('Nrf2', 'Gene', (156, 160))
277148	27545889	A tumor suppressor role for Nrf2 is supported by previous studies showing that mice genetically deficient in Nrf2 are more susceptible to a wide range of carcinogen-induced cancers (see review).	('Nrf2', 'Gene', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('susceptible', 'Reg', (123, 134))	('mice', 'Species', '10090', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', (2, 7))	('deficient', 'Var', (96, 105))	('carcinogen-induced cancers', 'Disease', 'MESH:D009369', (154, 180))	('carcinogen-induced cancers', 'Disease', (154, 180))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
277152	27545889	Importantly, cancer immunoediting and tumor elimination have been extensively documented in mouse models of MCA-induced sarcomas, and it was recently shown that MCA can acutely induce Nrf2 and its target genes in liver after 24 hours.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer immunoediting', 'Disease', (13, 33))	('sarcomas', 'Disease', (120, 128))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('MCA', 'Var', (161, 164))	('mouse', 'Species', '10090', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('MCA', 'Chemical', 'MESH:D008748', (161, 164))	('cancer immunoediting', 'Disease', 'MESH:D009369', (13, 33))	('induce', 'PosReg', (177, 183))	('MCA', 'Chemical', 'MESH:D008748', (108, 111))	('Nrf2', 'Gene', (184, 188))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
277164	27545889	We have implicated that Nrf2 agonists, some of which are currently in clinical trials, would be highly efficacious inducers of cancer immunosurveillance and immune therapy by acutely inducing IL-17D.	('cancer immunosurveillance', 'Disease', (127, 152))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('inducing', 'PosReg', (183, 191))	('inducers', 'PosReg', (115, 123))	('agonists', 'Var', (29, 37))	('Nrf2', 'Gene', (24, 28))	('cancer immunosurveillance', 'Disease', 'MESH:D009369', (127, 152))	('IL-17D', 'MPA', (192, 198))
277172	27545889	On the other hand, a pro-tumor role for IL-17A was shown in breast cancer whereby neutralizing IL-17A with antibodies reduced chemokine expression, and thereby breast cancer cell migration and metastasis.	('breast cancer', 'Disease', (60, 73))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('neutralizing', 'Var', (82, 94))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('tumor', 'Disease', (25, 30))	('reduced', 'NegReg', (118, 125))	('metastasis', 'CPA', (193, 203))	('IL-17A', 'Gene', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('chemokine expression', 'MPA', (126, 146))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
277183	27545889	Moreover, oncogenic alleles have been shown to induce Nrf2, and mutations in KEAP1 can be detected in cancer cells, leading to constitutive Nrf2 activation.	('activation', 'PosReg', (145, 155))	('induce', 'PosReg', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('KEAP1', 'Gene', (77, 82))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Nrf2', 'Protein', (54, 58))	('mutations', 'Var', (64, 73))	('constitutive', 'MPA', (127, 139))
277194	27545889	Nrf2 was activated in cell lines in vitro with either tert-butylhydroquinone (Spectrum) or H2O2 (Fisher).	('Nrf2', 'Gene', (0, 4))	('H2O2', 'Var', (91, 95))	('H2O2', 'Chemical', 'MESH:D006861', (91, 95))	('tert-butylhydroquinone', 'Chemical', 'MESH:C018855', (54, 76))
277200	27545889	Cells were grown in the presence of 10-40 mug/ml puromycin, and nrf2 knockdown was confirmed with qPCR.	('nrf2', 'Gene', (64, 68))	('knockdown', 'Var', (69, 78))	('puromycin', 'Chemical', 'MESH:D011691', (49, 58))
277249	24348858	Metastasis is a multistep process that begins when a primary tumor acquires mutations and becomes invasive.	('mutations', 'Var', (76, 85))	('Metastasis', 'Disease', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
277253	24348858	The sarcoma 180 mouse cell line is derived from a sarcoma that was carried in Swiss Webster mice and has been described to grow in multiple inbred mouse strains due to beta2-microglobulin deficiency, major histocompatibility complex (MHC) class I destabilization and a lack of recognition by host cytotoxic T lymphocytes.	('destabilization', 'NegReg', (247, 262))	('mouse', 'Species', '10090', (147, 152))	('sarcoma', 'Disease', (4, 11))	('beta2-microglobulin', 'Gene', (168, 187))	('deficiency', 'Var', (188, 198))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('sarcoma', 'Disease', (50, 57))	('beta2-microglobulin', 'Gene', '12010', (168, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('mouse', 'Species', '10090', (16, 21))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('mice', 'Species', '10090', (92, 96))
277290	24348858	The AST, ALT and BUN levels in the Juemingzi groups were lower than those in the control group and the mice from the 200-mg/kg b.w.	('ALT', 'Gene', (9, 12))	('AST', 'Gene', '235504', (4, 7))	('AST', 'Gene', (4, 7))	('ALT', 'Gene', '76282', (9, 12))	('mice', 'Species', '10090', (103, 107))	('Juemingzi', 'Var', (35, 44))	('lower', 'NegReg', (57, 62))
277293	24348858	The serum TNF-alpha and IL-1beta levels of the mice in the Juemingzi-treated groups were significantly higher than those in the control group (Fig.	('higher', 'PosReg', (103, 109))	('TNF-alpha', 'Gene', (10, 19))	('IL-1beta', 'Gene', '16176', (24, 32))	('Juemingzi-treated', 'Var', (59, 76))	('IL-1beta', 'Gene', (24, 32))	('TNF-alpha', 'Gene', '21926', (10, 19))	('mice', 'Species', '10090', (47, 51))
277315	24348858	The results from the present study have demonstrated that Juemingzi is able to decrease sarcoma 180 tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('decrease sarcoma 180 tumors', 'Disease', 'MESH:D012510', (79, 106))	('decrease sarcoma 180 tumors', 'Disease', (79, 106))	('Juemingzi', 'Var', (58, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
277319	30986130	Remodeling the cancer epigenome: mutations in the SWI/SNF complex offer new therapeutic opportunities Cancer genome sequencing studies have discovered mutations in members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex in nearly 25% of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('Cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('men', 'Species', '9606', (201, 204))	('mutations', 'Var', (33, 42))	('SWI/SNF', 'Gene', (211, 218))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cancers', 'Disease', (272, 279))	('Cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('SWI/SNF', 'Gene', (50, 57))	('mutations', 'Var', (151, 160))	('cancer', 'Disease', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancers', 'Disease', 'MESH:D009369', (272, 279))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (272, 278))	('Sucrose', 'Chemical', 'MESH:D013395', (186, 193))	('human', 'Species', '9606', (266, 271))
277321	30986130	The unexpected finding of frequent mutations in the complex has fueled studies to identify the mechanisms that drive tumor development and the accompanying therapeutic vulnerabilities.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('men', 'Species', '9606', (130, 133))	('mutations', 'Var', (35, 44))
277322	30986130	In the review, we focus upon the potential roles different SWI/SNF subunit mutations play in human oncogenesis, their common and unique mechanisms of transformation and the potential for translating these mechanisms into targeted therapies for SWI/SNF-mutant tumors.	('human', 'Species', '9606', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('tumors', 'Disease', (259, 265))	('mutations', 'Var', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('SWI/SNF subunit', 'Gene', (59, 74))
277323	30986130	We currently have limited insights into how mutations in different SWI/SNF subunits drive the development of human tumors.	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('men', 'Species', '9606', (101, 104))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (44, 53))	('SWI/SNF', 'Gene', (67, 74))	('drive', 'Reg', (84, 89))
277324	30986130	In addition, therapeutic options for SWI/SNF-mutant cancers have mainly evolved from high-throughput screens of cell lines with mutations in different subunits.	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('SWI/SNF-mutant', 'Var', (37, 51))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('SWI/SNF-mutant', 'Gene', (37, 51))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
277326	30986130	Numerous studies over the past 40 years have given considerable insights into how mutations in classic oncogenes and tumor suppressor genes (TSGs), such as TP53, RAS, CDKN2A and PIK3CA, drive tumor development.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (192, 197))	('PIK3CA', 'Gene', (178, 184))	('tumor', 'Disease', (117, 122))	('CDKN2A', 'Gene', (167, 173))	('men', 'Species', '9606', (205, 208))	('TP53', 'Gene', (156, 160))	('RAS', 'Gene', (162, 165))	('mutations', 'Var', (82, 91))	('PIK3CA', 'Gene', '5290', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('drive', 'PosReg', (186, 191))
277327	30986130	Importantly, recent reports from large-scale cancer genome landscape studies such as the Cancer Genome Atlas (TCGA) and others firmly established the frequent occurrence of these pathogenic mutations across a broad range of human cancers.	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Cancer', 'Disease', (89, 95))	('mutations', 'Var', (190, 199))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Cancer', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (224, 229))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancers', 'Disease', (230, 237))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', (45, 51))
277329	30986130	However, one unexpected finding from these studies was pathogenic mutations in components of the SWI/SNF (Mating Type Switching/Sucrose Non-Fermentable) chromatin remodeling complex in nearly 25% of all cancers, a rate that approaches the frequency of TP53 mutations.	('mutations', 'Var', (66, 75))	('SWI/SNF', 'Gene', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('Sucrose', 'Chemical', 'MESH:D013395', (128, 135))	('men', 'Species', '9606', (143, 146))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
277334	30986130	Compared to the large number of reports detailing the mechanisms by which classic oncogenes/TSGs drive tumorigenesis, only a limited number of mechanistic studies have explored the actions of SWI/SNF mutations in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('human', 'Species', '9606', (213, 218))	('tumors', 'Disease', (219, 225))	('mutations', 'Var', (200, 209))	('tumor', 'Disease', (219, 224))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Disease', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('SWI/SNF', 'Gene', (192, 199))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
277335	30986130	For example, in contrast to tumors with mutations in classic oncogenes/TSGs, many SWI/SNF-mutant tumors are genomically simple, possessing only the mutation in a single SWI/SNF subunit.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (28, 34))	('SWI/SNF-mutant', 'Var', (82, 96))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('SWI/SNF-mutant', 'Gene', (82, 96))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
277336	30986130	The fact that mutations across members of the SWI/SNF complex appear at one of the highest rates across all human tumors emphasizes the need to accelerate the pace of research in this field to reach the same level of knowledge achieved for other cancer mutations.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('SWI/SNF', 'Gene', (46, 53))	('highest', 'Reg', (83, 90))	('human', 'Species', '9606', (108, 113))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('mutations', 'Var', (14, 23))
277338	30986130	This review will focus upon emerging mechanisms that account for the development of SWI/SNF-mutant tumors and the potential for targeting them for treatment options.	('SWI/SNF-mutant', 'Var', (84, 98))	('SWI/SNF-mutant', 'Gene', (84, 98))	('men', 'Species', '9606', (76, 79))	('men', 'Species', '9606', (152, 155))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
277339	30986130	We will not cover the range of tumors that possess SWI/SNF subunit mutations or their genetics because of other recent reviews on these topics.	('SWI/SNF subunit', 'Gene', (51, 66))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', (31, 37))	('mutations', 'Var', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (31, 37))
277340	30986130	The first clue linking SWI/SNF complexes to cancer arose from studies identifying biallelic inactivation of SMARCB1 in nearly all rhabdoid tumors, aggressive poorly differentiated pediatric solid tumors.	('SMARCB1', 'Gene', (108, 115))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('rhabdoid tumors', 'Disease', (130, 145))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (130, 145))	('tumors', 'Disease', (196, 202))	('cancer', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('biallelic inactivation', 'Var', (82, 104))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
277341	30986130	Since these seminal reports, the list of other human malignancies showing genetic loss of SMARCB1 has greatly expanded, including epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumors, extraskeletal myxoid chondrosarcoma, myoepithelial carcinoma, renal medullary carcinoma, and poorly differentiated chordoma.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('renal medullary carcinoma', 'Disease', 'MESH:D018276', (267, 292))	('sarcoma', 'Disease', (142, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('SMARCB1', 'Gene', (90, 97))	('genetic loss', 'Var', (74, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('chordoma', 'Phenotype', 'HP:0010762', (320, 328))	('sarcoma', 'Disease', 'MESH:D012509', (233, 240))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('sarcoma', 'Disease', (233, 240))	('human', 'Species', '9606', (47, 52))	('chordoma', 'Disease', (320, 328))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (242, 265))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (163, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (219, 240))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('myoepithelial carcinoma', 'Disease', (242, 265))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (163, 203))	('malignancies', 'Disease', (53, 65))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (226, 240))	('myxoid chondrosarcoma', 'Disease', (219, 240))	('chordoma', 'Disease', 'MESH:D002817', (320, 328))	('renal medullary carcinoma', 'Disease', (267, 292))	('malignant peripheral nerve sheath tumors', 'Disease', (163, 203))
277342	30986130	Building upon these findings, recent next generation sequencing studies have revealed that mutations in genes encoding other SWI/SNF subunits occur broadly in cancer.	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('occur', 'Reg', (142, 147))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
277343	30986130	For example, SMARCA4 (BRG1), encoding a catalytic ATPase and a core subunit of SWI/SNF complexes, is recurrently mutated in lung cancer, medulloblastoma, pancreatic cancer, and small cell carcinoma of the ovary hypercalcemic type (SCCOHT).	('SMARCA4', 'Gene', '6597', (13, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('BRG1', 'Gene', (22, 26))	('small cell carcinoma of the ovary hypercalcemic', 'Disease', 'MESH:D010051', (177, 224))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', (124, 135))	('SMARCA4', 'Gene', (13, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('mutated', 'Var', (113, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (177, 197))	('pancreatic cancer', 'Disease', (154, 171))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('medulloblastoma', 'Disease', 'MESH:D008527', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('small cell carcinoma of the ovary hypercalcemic', 'Disease', (177, 224))	('medulloblastoma', 'Phenotype', 'HP:0002885', (137, 152))	('medulloblastoma', 'Disease', (137, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('BRG1', 'Gene', '6597', (22, 26))
277344	30986130	Inactivating mutations of ARID1A occur in 45% of ovarian clear cell carcinomas, 30% of endometrioid carcinomas, 27% of gastric cancers, 18% of bladder cancers, and approximately 10% of colorectal, pancreatic and liver cancers.	('liver cancer', 'Phenotype', 'HP:0002896', (212, 224))	('pancreatic and liver cancers', 'Disease', 'MESH:D006528', (197, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (87, 110))	('occur', 'Reg', (33, 38))	('ARID1A', 'Gene', (26, 32))	('colorectal', 'Disease', 'MESH:D015179', (185, 195))	('Inactivating mutations', 'Var', (0, 22))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (87, 110))	('ARID1A', 'Gene', '8289', (26, 32))	('bladder cancers', 'Phenotype', 'HP:0009725', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('gastric cancers', 'Disease', (119, 134))	('gastric cancers', 'Disease', 'MESH:D013274', (119, 134))	('gastric cancers', 'Phenotype', 'HP:0012126', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ovarian clear cell carcinomas', 'Disease', (49, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('liver cancers', 'Phenotype', 'HP:0002896', (212, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('bladder cancers', 'Disease', 'MESH:D001749', (143, 158))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (49, 78))	('endometrioid carcinomas', 'Disease', (87, 110))	('colorectal', 'Disease', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('bladder cancers', 'Disease', (143, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
277345	30986130	Finally, inactivating mutations of PBRM1 are present in 40% of kidney cancers and 8% of pancreatic cancers.	('pancreatic cancers', 'Disease', 'MESH:D010190', (88, 106))	('pancreatic cancers', 'Disease', (88, 106))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('present', 'Reg', (45, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (88, 105))	('inactivating mutations', 'Var', (9, 31))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('kidney cancers', 'Disease', 'MESH:D007680', (63, 77))	('kidney cancers', 'Disease', (63, 77))	('kidney cancers', 'Phenotype', 'HP:0009726', (63, 77))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (88, 106))	('PBRM1', 'Gene', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('PBRM1', 'Gene', '55193', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
277346	30986130	Representative examples of tumors with significant frequencies of mutations in these SWI/SNF subunits are shown in Table 1.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('SWI/SNF', 'Gene', (85, 92))
277347	30986130	The first studies characterizing SMARCB1 loss in rhabdoid tumors showed a complete loss of protein, associated with either nonsense mutations or partial to complete gene deletions.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('protein', 'MPA', (91, 98))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('SMARCB1', 'Gene', (33, 40))	('nonsense mutations', 'Var', (123, 141))	('rhabdoid tumors', 'Disease', (49, 64))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (49, 64))	('partial to complete gene deletions', 'Var', (145, 179))	('loss', 'NegReg', (41, 45))	('loss', 'NegReg', (83, 87))
277348	30986130	Similarly, the preponderance of SMARCA4 mutations in SCCOHTs results in loss of function.	('mutations', 'Var', (40, 49))	('SMARCA4', 'Gene', (32, 39))	('SMARCA4', 'Gene', '6597', (32, 39))	('loss', 'NegReg', (72, 76))
277349	30986130	This paradigm has held true for other SWI/SNF subunits- the vast majority of mutations/deletions lead to a lack of protein in tumors.	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('mutations/deletions', 'Var', (77, 96))	('lack', 'NegReg', (107, 111))	('protein', 'Protein', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
277350	30986130	However, TCGA data also demonstrate focal amplification, over-expression and/or somatic, potentially activating missense mutations in many SWI/SNF subunits including known tumor suppressors SMARCA4 and SMARCB1.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('missense mutations', 'Var', (112, 130))	('tumor', 'Disease', (172, 177))	('over-expression', 'PosReg', (57, 72))	('SWI/SNF', 'Gene', (139, 146))	('SMARCA4', 'Gene', (190, 197))	('activating', 'PosReg', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('SMARCA4', 'Gene', '6597', (190, 197))
277351	30986130	For example, approximately 5% of medulloblastomas, a pediatric brain tumor, possess missense mutations in SMARCA4, clustered within the SNF2 and Helicase domains.	('brain tumor', 'Phenotype', 'HP:0030692', (63, 74))	('SNF2', 'Gene', '6595', (136, 140))	('SMARCA4', 'Gene', (106, 113))	('medulloblastomas', 'Disease', (33, 49))	('SMARCA4', 'Gene', '6597', (106, 113))	('medulloblastoma', 'Phenotype', 'HP:0002885', (33, 48))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('brain tumor', 'Disease', 'MESH:D001932', (63, 74))	('brain tumor', 'Disease', (63, 74))	('medulloblastomas', 'Disease', 'MESH:D008527', (33, 49))	('SNF2', 'Gene', (136, 140))	('missense mutations', 'Var', (84, 102))
277352	30986130	Of note, some of the same missense mutations found in human tumors, such as C-terminal K364del and R377H in SMARCB1 and R885H and L921F in SMARCA4, occur in the rare neurodevelopmental disorder, Coffin-Siris syndrome.	('SMARCB1', 'Gene', (108, 115))	('C-terminal K364del', 'Var', (76, 94))	('R885H', 'Var', (120, 125))	('R377H', 'Mutation', 'rs387906812', (99, 104))	('K364del', 'Mutation', 'p.364delK', (87, 94))	('R885H', 'Mutation', 'rs1064794284', (120, 125))	('SMARCA4', 'Gene', '6597', (139, 146))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('occur', 'Reg', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('neurodevelopmental disorder', 'Disease', 'MESH:D002658', (166, 193))	('R377H', 'Var', (99, 104))	('human', 'Species', '9606', (54, 59))	('L921F', 'Mutation', 'rs281875228', (130, 135))	('tumors', 'Disease', (60, 66))	('neurodevelopmental disorder', 'Disease', (166, 193))	('Coffin-Siris syndrome', 'Disease', (195, 216))	('neurodevelopmental disorder', 'Phenotype', 'HP:0012759', (166, 193))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (195, 216))	('L921F', 'Var', (130, 135))	('SMARCA4', 'Gene', (139, 146))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
277353	30986130	Whether these subunit genes with missense mutations produce altered proteins that can impact normal SWI/SNF complex functions and how they might contribute to tumor development remain unknown.	('men', 'Species', '9606', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('contribute', 'Reg', (145, 155))	('SWI/SNF', 'Protein', (100, 107))	('impact', 'Reg', (86, 92))	('proteins', 'Protein', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('missense mutations', 'Var', (33, 51))
277354	30986130	A recent report did demonstrate that some SMARCA4 missense mutations found in human tumors had aberrant activities when assessed in mouse embryo fibroblasts.	('missense mutations', 'Var', (50, 68))	('activities', 'MPA', (104, 114))	('SMARCA4', 'Gene', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('SMARCA4', 'Gene', '6597', (42, 49))	('mouse', 'Species', '10090', (132, 137))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('human', 'Species', '9606', (78, 83))
277356	30986130	Multiple studies strongly support the notion that SWI/SNF loss of function mutations serve as drivers in multiple human tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('loss of function', 'NegReg', (58, 74))	('human', 'Species', '9606', (114, 119))	('SWI/SNF', 'Gene', (50, 57))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
277357	30986130	For example, re-expression of SMARCB1 in rhabdoid tumor cell lines or SMARCA4 in SCCOHT cell lines leads to growth arrest followed by replicative senescence.	('replicative senescence', 'CPA', (134, 156))	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('SMARCA4', 'Gene', (70, 77))	('growth arrest', 'Phenotype', 'HP:0001510', (108, 121))	('SMARCA4', 'Gene', '6597', (70, 77))	('SMARCB1', 'Gene', (30, 37))	('arrest', 'Disease', (115, 121))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('re-expression', 'Var', (13, 26))	('rhabdoid tumor', 'Disease', (41, 55))
277360	30986130	Inactivation of Arid1a in GEMMs contributes to the development of cancers of the colon, liver and ovary.	('liver', 'Disease', (88, 93))	('Arid1a', 'Gene', '8289', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Arid1a', 'Gene', (16, 22))	('cancers of the colon', 'Disease', (66, 86))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers of the colon', 'Disease', 'MESH:D015179', (66, 86))	('men', 'Species', '9606', (58, 61))	('Inactivation', 'Var', (0, 12))	('ovary', 'Disease', (98, 103))
277361	30986130	In addition, deletion of Smarca4 in GEMMs results in breast and uterine cancers.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('deletion', 'Var', (13, 21))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('results in', 'Reg', (42, 52))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('Smarca4', 'Gene', (25, 32))	('uterine cancers', 'Phenotype', 'HP:0010784', (64, 79))
277362	30986130	Germline mutations in SWI/SNF subunits can also lead to familial cancers similar to other well-characterized TSGs such as TP53 and RB1.	('Germline mutations', 'Var', (0, 18))	('familial cancers', 'Disease', (56, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('SWI/SNF', 'Gene', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('lead to', 'Reg', (48, 55))	('familial cancers', 'Disease', 'MESH:D009369', (56, 72))
277364	30986130	Many of the pediatric/young adult cancers with a SWI/SNF subunit mutation represent some of the most aggressive tumors with little to no long-term survival.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('aggressive tumors', 'Disease', 'MESH:D001523', (101, 118))	('SWI/SNF subunit', 'Gene', (49, 64))	('aggressive tumors', 'Disease', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutation', 'Var', (65, 73))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
277365	30986130	In adult malignancies, loss of a single SWI/SNF subunit can result in more aggressive tumor progression with decreased survival.	('decreased', 'NegReg', (109, 118))	('survival', 'CPA', (119, 127))	('malignancies', 'Disease', (9, 21))	('aggressive tumor', 'Disease', 'MESH:D001523', (75, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('aggressive tumor', 'Disease', (75, 91))	('malignancies', 'Disease', 'MESH:D009369', (9, 21))	('SWI/SNF', 'Gene', (40, 47))	('loss', 'Var', (23, 27))	('subunit', 'Protein', (48, 55))
277366	30986130	Inactivation of SWI/SNF subunits in GEMMs also often leads to highly aggressive tumors.	('aggressive tumors', 'Disease', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('SWI/SNF', 'Gene', (16, 23))	('aggressive tumors', 'Disease', 'MESH:D001523', (69, 86))	('leads to', 'Reg', (53, 61))	('Inactivation', 'Var', (0, 12))
277367	30986130	Therefore, the mutations in SWI/SNF subunits found in human cancers significantly impact the course of tumor development.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('tumor', 'Disease', (103, 108))	('mutations', 'Var', (15, 24))	('SWI/SNF', 'Gene', (28, 35))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('impact', 'Reg', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('men', 'Species', '9606', (116, 119))	('human', 'Species', '9606', (54, 59))
277370	30986130	While these studies raise important questions about how cellular context determines the role of aberrant SWI/SNF complex activities in human tumor development, their relevance as therapeutic targets remain unclear.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('aberrant', 'Var', (96, 104))	('tumor', 'Disease', (141, 146))	('human', 'Species', '9606', (135, 140))	('men', 'Species', '9606', (154, 157))	('SWI/SNF', 'Gene', (105, 112))
277372	30986130	Mutations in SMARCA4 occur more frequently than its sibling ATPase (SMARCA2/BRM) and generally do not appear in a particular tumor type.	('SMARCA4', 'Gene', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('SMARCA2', 'Gene', (68, 75))	('SMARCA2', 'Gene', '6595', (68, 75))	('BRM', 'Gene', '6595', (76, 79))	('SMARCA4', 'Gene', '6597', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('Mutations', 'Var', (0, 9))	('BRM', 'Gene', (76, 79))
277373	30986130	Mutations in SMARCA4 can be categorized as: a driver event with a simple genetic background a defining characteristic in all tumors, but with a more complex genetic background or not a driver mutation, but adding to the genetic burden and acting as a tumor progression event in the tumor.	('SMARCA4', 'Gene', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('SMARCA4', 'Gene', '6597', (13, 20))	('tumor', 'Disease', (282, 287))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
277374	30986130	Cancers with putative SMARCA4 driver mutations show nearly 100% of tumors with SMARCA4 protein loss, few chromosomal copy number aberrations, and rare mutations in other cancer driver genes.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('SMARCA4', 'Gene', (22, 29))	('cancer', 'Disease', (170, 176))	('Cancers', 'Disease', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('protein', 'Protein', (87, 94))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('SMARCA4', 'Gene', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (37, 46))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('SMARCA4', 'Gene', '6597', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('loss', 'NegReg', (95, 99))	('tumors', 'Disease', (67, 73))	('SMARCA4', 'Gene', '6597', (22, 29))
277376	30986130	SCCOHT, a rare and aggressive form of ovarian cancer found in young women, have mutational loss (germline or somatic) of SMARCA4, epigenetic silencing of SMARCA2, and rarely any other genetic abnormalities.	('epigenetic silencing', 'Var', (130, 150))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('aggressive form of ovarian cancer', 'Disease', 'MESH:D001523', (19, 52))	('mutational', 'Var', (80, 90))	('SMARCA2', 'Gene', (154, 161))	('SMARCA2', 'Gene', '6595', (154, 161))	('SMARCA4', 'Gene', (121, 128))	('women', 'Species', '9606', (68, 73))	('SMARCA4', 'Gene', '6597', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('genetic abnormalities', 'Disease', 'MESH:D030342', (184, 205))	('genetic abnormalities', 'Disease', (184, 205))	('aggressive form of ovarian cancer', 'Disease', (19, 52))
277377	30986130	Rhabdoid tumor predisposition syndrome 2 (RTPS2) defines patients with rhabdoid tumors possessing SMARCA4 mutations rather than the hallmark SMARCB1 loss.	('Rhabdoid tumor', 'Disease', (0, 14))	('SMARCA4', 'Gene', '6597', (98, 105))	('rhabdoid tumors', 'Disease', (71, 86))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (71, 86))	('patients', 'Species', '9606', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (106, 115))	('SMARCA4', 'Gene', (98, 105))	('Rhabdoid tumor', 'Disease', 'MESH:D018335', (0, 14))
277379	30986130	The SMARCA4 mutations in RTPS2 were mostly germline, occurred in children less than 12 months old and often associated with a poorer prognosis.	('children', 'Species', '9606', (65, 73))	('RTPS2', 'Gene', (25, 30))	('mutations', 'Var', (12, 21))	('SMARCA4', 'Gene', (4, 11))	('occurred', 'Reg', (53, 61))	('SMARCA4', 'Gene', '6597', (4, 11))	('associated with', 'Reg', (108, 123))
277382	30986130	In addition to SMARCA4 loss in all cases, SMARCA4-DTS tumors have a more complex genetic background with mutations most commonly in TP53 and occasionally alterations in other driver genes such as CDKN2A, KRAS and MYC.	('SMARCA4', 'Gene', '6597', (15, 22))	('SMARCA4', 'Gene', (42, 49))	('MYC', 'Gene', '4609', (213, 216))	('TP53', 'Gene', (132, 136))	('KRAS', 'Gene', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('SMARCA4', 'Gene', '6597', (42, 49))	('CDKN2A', 'Gene', (196, 202))	('mutations', 'Var', (105, 114))	('KRAS', 'Gene', '3845', (204, 208))	('SMARCA4', 'Gene', (15, 22))	('SMARCA4-DTS tumors', 'Disease', 'MESH:D009369', (42, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('MYC', 'Gene', (213, 216))	('SMARCA4-DTS tumors', 'Disease', (42, 60))
277385	30986130	SMARCA4 mutations are also found in genetically-complex tumors presumably adding to their genetic burden.	('SMARCA4', 'Gene', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SMARCA4', 'Gene', '6597', (0, 7))	('mutations', 'Var', (8, 17))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
277386	30986130	These mutations, while not found in all cases, can act as progression events in adult cancers and usually correlate with poorer prognosis, as observed with non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (156, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('non-small cell lung cancer', 'Disease', (156, 182))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (160, 182))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (156, 182))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('mutations', 'Var', (6, 15))
277387	30986130	Interestingly, SMARCA4 mutations and protein loss have also been observed in poorly differentiated tumors, potentially associated with dedifferentiation, another progression event.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('SMARCA4', 'Gene', '6597', (15, 22))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('SMARCA4', 'Gene', (15, 22))	('poorly', 'Disease', (77, 83))	('dedifferentiation', 'Disease', (135, 152))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('observed', 'Reg', (65, 73))	('loss', 'NegReg', (45, 49))	('protein', 'Protein', (37, 44))	('associated', 'Reg', (119, 129))
277389	30986130	In stark contrast to SMARCA4, mutations in SMARCA2 seldom occur across any tumor type.	('SMARCA4', 'Gene', (21, 28))	('SMARCA2', 'Gene', (43, 50))	('SMARCA2', 'Gene', '6595', (43, 50))	('SMARCA4', 'Gene', '6597', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
277390	30986130	Only a few cancers to date have been described with SMARCA2 mutations or deletions in addition to other mutational burdens, including adenoid cystic carcinoma, non-melanoma skin cancer, hepatocellular carcinoma and head and neck squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('adenoid cystic carcinoma', 'Disease', (134, 158))	('mutations', 'Var', (60, 69))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (186, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (229, 252))	('deletions', 'Var', (73, 82))	('SMARCA2', 'Gene', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('SMARCA2', 'Gene', '6595', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (215, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (186, 210))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (160, 184))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (215, 252))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (134, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('hepatocellular carcinoma', 'Disease', (186, 210))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('skin cancer', 'Phenotype', 'HP:0008069', (173, 184))	('cancers', 'Disease', (11, 18))	('non-melanoma skin cancer', 'Disease', (160, 184))
277391	30986130	Although not frequently mutated, loss of SMARCA2 expression occurs across numerous tumor types and cancer cell lines through epigenetic silencing.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('loss', 'NegReg', (33, 37))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('expression', 'MPA', (49, 59))	('SMARCA2', 'Gene', (41, 48))	('cancer', 'Disease', (99, 105))	('SMARCA2', 'Gene', '6595', (41, 48))	('epigenetic silencing', 'Var', (125, 145))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
277392	30986130	The exact mechanism of the epigenetic silencing varies, but can arise through promoter methylation, promoter polymorphisms or HDAC/EZH2-driven mechanisms.	('epigenetic silencing', 'Var', (27, 47))	('arise', 'Reg', (64, 69))	('EZH2', 'Gene', (131, 135))	('EZH2', 'Gene', '2146', (131, 135))	('HDAC', 'Gene', (126, 130))	('HDAC', 'Gene', '9734', (126, 130))
277400	30986130	Mutations in SMARCB1 have previously been identified in 95% of pediatric rhabdoid tumors (RT), poorly differentiated and clinically aggressive tumors that arise primarily in the kidney and central nervous system.	('identified', 'Reg', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('aggressive tumors', 'Disease', (132, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SMARCB1', 'Gene', (13, 20))	('aggressive tumors', 'Disease', 'MESH:D001523', (132, 149))	('rhabdoid tumors', 'Disease', (73, 88))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (73, 88))
277401	30986130	They are now defined by biallelic alterations in the SMARCB1 tumor suppressor gene located at chromosome 22q11.2, making loss of expression of SMARCB1 protein a diagnostic hallmark of this cancer.	('protein', 'Protein', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('biallelic', 'Var', (24, 33))	('loss of', 'NegReg', (121, 128))	('SMARCB1', 'Gene', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('SMARCB1', 'Gene', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Disease', (61, 66))	('cancer', 'Disease', (189, 195))
277402	30986130	Beyond the common SMARCB1 mutation, these tumors appear genetically simple and uniform, bearing no other recurrent driver mutations with primarily diploid genomes.	('SMARCB1', 'Gene', (18, 25))	('mutation', 'Var', (26, 34))	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
277403	30986130	SMARCB1 mutations also drive development of other aggressive tumors in children and young adults- epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumors, extraskeletal myxoid chondrosarcoma, myoepithelial carcinoma, renal medullary carcinoma, and poorly differentiated chordoma.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('renal medullary carcinoma', 'Disease', 'MESH:D018276', (235, 260))	('sarcoma', 'Disease', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('chordoma', 'Phenotype', 'HP:0010762', (288, 296))	('chordoma', 'Disease', (288, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('mutations', 'Var', (8, 17))	('aggressive tumors', 'Disease', (50, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('drive', 'Reg', (23, 28))	('sarcoma', 'Disease', 'MESH:D012509', (201, 208))	('aggressive tumors', 'Disease', 'MESH:D001523', (50, 67))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (131, 171))	('sarcoma', 'Disease', (201, 208))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (210, 233))	('children', 'Species', '9606', (71, 79))	('chordoma', 'Disease', 'MESH:D002817', (288, 296))	('SMARCB1', 'Gene', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (131, 171))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (187, 208))	('men', 'Species', '9606', (36, 39))	('renal medullary carcinoma', 'Disease', (235, 260))	('malignant peripheral nerve sheath tumors', 'Disease', (131, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('myoepithelial carcinoma', 'Disease', (210, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('myxoid chondrosarcoma', 'Disease', (187, 208))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (194, 208))
277410	30986130	A comprehensive investigation into how loss of SMARCB1 function drives ES tumorigenesis remains elusive.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('SMARCB1', 'Gene', (47, 54))	('tumor', 'Disease', (74, 79))	('loss', 'Var', (39, 43))
277411	30986130	(2014), do corroborate two previous studies suggesting the leading mechanism for SMARCB1 loss of function is biallelic deletion in 22q11 encompassing the SMARCB1 tumor suppressor gene locus.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('loss of function', 'NegReg', (89, 105))	('tumor', 'Disease', (162, 167))	('SMARCB1', 'Gene', (81, 88))	('biallelic deletion in', 'Var', (109, 130))	('22q11', 'Gene', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
277413	30986130	A mutation of the SMARCB1 gene has been implicated in the development of schwannomatosis in both sporadic and familial cases.	('mutation', 'Var', (2, 10))	('SMARCB1', 'Gene', (18, 25))	('men', 'Species', '9606', (65, 68))	('schwannomatosis', 'Disease', (73, 88))	('schwannomatosis', 'Disease', 'MESH:C536641', (73, 88))	('implicated', 'Reg', (40, 50))
277414	30986130	SMARCB1 mutations have been found in 45% of familial probands and 9% of sporadic patients.	('patients', 'Species', '9606', (81, 89))	('SMARCB1', 'Gene', (0, 7))	('found', 'Reg', (28, 33))	('mutations', 'Var', (8, 17))
277415	30986130	The comparison with germline SMARCB1 mutations in patients with RT indicates that nontruncating mutations occur more significantly in schwannomatosis than in RTs (p < 0.0001).	('occur', 'Reg', (106, 111))	('patients', 'Species', '9606', (50, 58))	('schwannomatosis', 'Disease', 'MESH:C536641', (134, 149))	('SMARCB1', 'Gene', (29, 36))	('mutations', 'Var', (37, 46))	('schwannomatosis', 'Disease', (134, 149))	('nontruncating', 'MPA', (82, 95))
277416	30986130	Whereas SMARCB1 mutations alone seemingly account for RT development, a substantial heterogeneity of mutations schwannomatosis exists even for familial disease.	('familial disease', 'Disease', 'MESH:D003141', (143, 159))	('SMARCB1', 'Gene', (8, 15))	('mutations', 'Var', (16, 25))	('schwannomatosis', 'Disease', (111, 126))	('schwannomatosis', 'Disease', 'MESH:C536641', (111, 126))	('men', 'Species', '9606', (64, 67))	('familial disease', 'Disease', (143, 159))
277417	30986130	Schwannomas often possess mutations in the NF2 tumor suppressor, located near the SMARCB1 locus on chromosome 22 and in the LZTR1 gene.	('NF2', 'Gene', '4771', (43, 46))	('Schwannomas', 'Phenotype', 'HP:0100008', (0, 11))	('LZTR1', 'Gene', '8216', (124, 129))	('Schwannomas', 'Disease', (0, 11))	('Schwannomas', 'Disease', 'MESH:D009442', (0, 11))	('LZTR1', 'Gene', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('NF2', 'Gene', (43, 46))	('tumor', 'Disease', (47, 52))
277418	30986130	(2014), the most common SMARCB1 mutation in schwannomas is found within the 3'UTR- c.*82C>T.	('schwannomas', 'Disease', 'MESH:D009442', (44, 55))	('c.*82C>T', 'Mutation', 'rs878854600', (83, 91))	('schwannomas', 'Disease', (44, 55))	('schwannomas', 'Phenotype', 'HP:0100008', (44, 55))	('mutation', 'Var', (32, 40))	('SMARCB1', 'Gene', (24, 31))
277419	30986130	How this alteration contributes to the development of schwannomatosis remains unknown, but could act by regulating gene expression through alternative splicing within the UTR.	('expression', 'MPA', (120, 130))	('alternative splicing', 'Var', (139, 159))	('contributes', 'Reg', (20, 31))	('men', 'Species', '9606', (46, 49))	('schwannomatosis', 'Disease', (54, 69))	('schwannomatosis', 'Disease', 'MESH:C536641', (54, 69))	('regulating', 'Reg', (104, 114))
277420	30986130	(2015) also reported that SMARCB1 mutations in schwannomatosis target an unidentified N-terminal winged helix DNA binding domain also present in BAF45a/PHF10 subunit of the SWI/SNF complex.	('BAF45a', 'Gene', '55274', (145, 151))	('schwannomatosis', 'Disease', 'MESH:C536641', (47, 62))	('SMARCB1', 'Gene', (26, 33))	('BAF45a', 'Gene', (145, 151))	('PHF10', 'Gene', '55274', (152, 157))	('PHF10', 'Gene', (152, 157))	('mutations', 'Var', (34, 43))	('schwannomatosis', 'Disease', (47, 62))
277427	30986130	Mutations in ARID1A can also affect regulation of normal development, whereas its absence resulted in poor differentiation of stem cells.	('ARID1A', 'Gene', '8289', (13, 19))	('absence', 'NegReg', (82, 89))	('affect', 'Reg', (29, 35))	('ARID1A', 'Gene', (13, 19))	('poor', 'NegReg', (102, 106))	('Mutations', 'Var', (0, 9))	('men', 'Species', '9606', (64, 67))	('regulation of normal', 'MPA', (36, 56))
277428	30986130	ARID1A mutations appear in many types of cancers, ranging from nearly 50% in ovarian clear cell carcinoma (OCCC) to 2.5% in breast cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('appear', 'Reg', (17, 23))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (77, 105))	('ARID1A', 'Gene', '8289', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('ARID1A', 'Gene', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('breast cancer', 'Disease', (124, 137))	('cancers', 'Disease', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('ovarian clear cell carcinoma', 'Disease', (77, 105))	('mutations', 'Var', (7, 16))
277429	30986130	Other cancers with significant frequencies of ARID1A mutations include gastric, endometrial, lung, medulloblastoma, hepatocellular carcinoma and pancreas.	('endometrial', 'Disease', 'MESH:D014591', (80, 91))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (116, 140))	('endometrial', 'Disease', (80, 91))	('gastric', 'Disease', (71, 78))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (116, 140))	('medulloblastoma', 'Disease', 'MESH:D008527', (99, 114))	('medulloblastoma', 'Phenotype', 'HP:0002885', (99, 114))	('lung', 'Disease', (93, 97))	('medulloblastoma', 'Disease', (99, 114))	('mutations', 'Var', (53, 62))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('pancreas', 'Disease', (145, 153))	('cancers', 'Disease', (6, 13))	('ARID1A', 'Gene', (46, 52))	('hepatocellular carcinoma', 'Disease', (116, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ARID1A', 'Gene', '8289', (46, 52))
277430	30986130	In general, most tumors possess truncating mutations of ARID1A although some tumors contain missense mutations.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('truncating', 'MPA', (32, 42))	('ARID1A', 'Gene', '8289', (56, 62))	('ARID1A', 'Gene', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('missense mutations', 'Var', (92, 110))
277432	30986130	One mechanism comes from ovarian cancer studies using a GEMM with ARID1A knockdown and PI3K mutations by Kim et al.	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('ARID1A', 'Gene', '8289', (66, 72))	('mutations', 'Var', (92, 101))	('ARID1A', 'Gene', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('ovarian cancer', 'Disease', 'MESH:D010051', (25, 39))	('PI3K mutations', 'Var', (87, 101))	('ovarian cancer', 'Disease', (25, 39))	('knockdown', 'Var', (73, 82))
277433	30986130	They found that these mutations resulted in the loss of recruitment of an HDAC complex and promotion of an inflammation response.	('loss', 'NegReg', (48, 52))	('men', 'Species', '9606', (63, 66))	('inflammation', 'Disease', (107, 119))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))	('recruitment', 'MPA', (56, 67))	('HDAC', 'Gene', (74, 78))	('HDAC', 'Gene', '9734', (74, 78))	('mutations', 'Var', (22, 31))	('promotion', 'PosReg', (91, 100))
277434	30986130	The group demonstrated that the loss of ARID1A impairs recruitment of the Sin3A-HDAC complex while the PI3K mutations increased NF-kB signaling.	('recruitment', 'MPA', (55, 66))	('ARID1A', 'Gene', (40, 46))	('men', 'Species', '9606', (62, 65))	('mutations', 'Var', (108, 117))	('PI3K', 'Var', (103, 107))	('HDAC', 'Gene', (80, 84))	('impairs', 'NegReg', (47, 54))	('increased', 'PosReg', (118, 127))	('HDAC', 'Gene', '9734', (80, 84))	('loss', 'Var', (32, 36))	('NF-kB signaling', 'MPA', (128, 143))	('ARID1A', 'Gene', '8289', (40, 46))
277435	30986130	ARID1A loss has also been linked individually to either HDAC repression and PI3K pathway mutations.	('loss', 'NegReg', (7, 11))	('HDAC', 'Gene', (56, 60))	('ARID1A', 'Gene', '8289', (0, 6))	('PI3K pathway', 'Pathway', (76, 88))	('HDAC', 'Gene', '9734', (56, 60))	('ARID1A', 'Gene', (0, 6))	('mutations', 'Var', (89, 98))
277436	30986130	showed that ARID1A inactivation along with activation of PI3K/AKT pathway upregulated inflammatory pathways resulting in tissue damage and subsequent carcinogenesis.	('AKT', 'Gene', (62, 65))	('upregulated', 'PosReg', (74, 85))	('inflammatory pathways', 'Pathway', (86, 107))	('carcinogenesis', 'CPA', (150, 164))	('activation', 'PosReg', (43, 53))	('AKT', 'Gene', '207', (62, 65))	('ARID1A', 'Gene', '8289', (12, 18))	('inactivation', 'Var', (19, 31))	('ARID1A', 'Gene', (12, 18))	('tissue damage', 'CPA', (121, 134))
277437	30986130	Using a novel GEMM, the investigators found that ARID1A inactivation alone was not sufficient for tumor development, but required concurrent activation of PIK3CA.	('PIK3CA', 'Gene', '5290', (155, 161))	('men', 'Species', '9606', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('inactivation', 'Var', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PIK3CA', 'Gene', (155, 161))	('ARID1A', 'Gene', '8289', (49, 55))	('ARID1A', 'Gene', (49, 55))	('tumor', 'Disease', (98, 103))	('activation', 'PosReg', (141, 151))
277438	30986130	They also showed that inactivation of ARID1A and activation of PIK3CA led to an overproduction of IL-6, an inflammatory factor, that drove tumor growth.	('inactivation', 'Var', (22, 34))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('ARID1A', 'Gene', '8289', (38, 44))	('ARID1A', 'Gene', (38, 44))	('IL-6', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('PIK3CA', 'Gene', (63, 69))	('overproduction', 'MPA', (80, 94))	('PIK3CA', 'Gene', '5290', (63, 69))	('IL-6', 'Gene', '3569', (98, 102))	('activation', 'PosReg', (49, 59))
277440	30986130	implicates a dependence upon histone deacetylase 6 (HDAC6) activity for mutant ARID1A-driven tumor development.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutant', 'Var', (72, 78))	('tumor', 'Disease', (93, 98))	('histone deacetylase 6', 'Gene', '10013', (29, 50))	('HDAC6', 'Gene', '10013', (52, 57))	('HDAC6', 'Gene', (52, 57))	('ARID1A', 'Gene', '8289', (79, 85))	('ARID1A', 'Gene', (79, 85))	('histone deacetylase 6', 'Gene', (29, 50))	('men', 'Species', '9606', (106, 109))
277441	30986130	In both cellular and animal models, they found that inactivation of HDAC6 resulted in a reduction in the size of only mutant ARID1A-driven tumors.	('HDAC6', 'Gene', '10013', (68, 73))	('HDAC6', 'Gene', (68, 73))	('reduction', 'NegReg', (88, 97))	('size', 'MPA', (105, 109))	('ARID1A', 'Gene', '8289', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ARID1A', 'Gene', (125, 131))	('inactivation', 'Var', (52, 64))	('mutant', 'Var', (118, 124))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
277443	30986130	They further showed that HDAC6 inhibition promoted TP53 mediated apoptosis through HDAC6-catalyzed deacetylation of TP53 Lys120 resulting in its inactivation.	('Lys120', 'Chemical', '-', (121, 127))	('TP53', 'Gene', (116, 120))	('inactivation', 'MPA', (145, 157))	('Lys120', 'Var', (121, 127))	('HDAC6', 'Gene', '10013', (83, 88))	('TP53', 'Protein', (51, 55))	('HDAC6', 'Gene', '10013', (25, 30))	('HDAC6', 'Gene', (83, 88))	('HDAC6', 'Gene', (25, 30))	('promoted', 'PosReg', (42, 50))	('deacetylation', 'MPA', (99, 112))
277444	30986130	Thus, loss of ARID1A increases HDAC6 expression and inhibits TP53-driven apoptosis implicating HDAC6 inactivation as a potential target for therapeutic intervention.	('increases', 'PosReg', (21, 30))	('HDAC6', 'Gene', '10013', (95, 100))	('loss', 'Var', (6, 10))	('HDAC6', 'Gene', (95, 100))	('TP53-driven apoptosis', 'CPA', (61, 82))	('ARID1A', 'Gene', '8289', (14, 20))	('HDAC6', 'Gene', '10013', (31, 36))	('inhibits', 'NegReg', (52, 60))	('ARID1A', 'Gene', (14, 20))	('HDAC6', 'Gene', (31, 36))	('expression', 'MPA', (37, 47))
277445	30986130	PBRM1 is the second most commonly mutated gene in clear cell renal cell carcinoma, with mutations occurring in 29-41% of tumors and frequently co-occurring with VHL mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('PBRM1', 'Gene', (0, 5))	('mutations', 'Var', (88, 97))	('clear cell renal cell carcinoma', 'Disease', (50, 81))	('PBRM1', 'Gene', '55193', (0, 5))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (50, 81))	('VHL', 'Gene', (161, 164))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (50, 81))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (61, 81))	('VHL', 'Gene', '7428', (161, 164))
277446	30986130	GEMMs demonstrated that PBRM1 loss in ccRCC is secondary to VHL loss, and the combined disruption of these genes resulted in multifocal tumors.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('resulted in', 'Reg', (113, 124))	('multifocal tumors', 'Disease', (125, 142))	('PBRM1', 'Gene', (24, 29))	('multifocal tumors', 'Disease', 'None', (125, 142))	('ccRCC', 'Disease', (38, 43))	('PBRM1', 'Gene', '55193', (24, 29))	('VHL loss', 'Disease', 'MESH:D006623', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('loss', 'NegReg', (30, 34))	('disruption', 'Var', (87, 97))	('VHL loss', 'Disease', (60, 68))
277448	30986130	Mutations in ARID2 are found in a wide spectrum of tumor types including hepatocellular carcinoma and melanoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (73, 97))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('hepatocellular carcinoma', 'Disease', (73, 97))	('found', 'Reg', (23, 28))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (73, 97))	('tumor', 'Disease', (51, 56))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('melanoma', 'Disease', (102, 110))	('Mutations', 'Var', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('ARID2', 'Gene', (13, 18))
277449	30986130	In addition, ARID2 mutations are found at lower levels in some cancers, such as stomach adenocarcinoma (8%) and non-small cell lung cancer (4%), that did not reach significance in reported studies.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (112, 138))	('stomach adenocarcinoma', 'Disease', (80, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('mutations', 'Var', (19, 28))	('non-small cell lung cancer', 'Disease', (112, 138))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (112, 138))	('cancers', 'Disease', (63, 70))	('ARID2', 'Gene', (13, 18))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
277450	30986130	Nevertheless, cancers with moderate mutation rates in ARID2 may also rely on disruption of the PBAF complex.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ARID2', 'Gene', (54, 59))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('mutation', 'Var', (36, 44))
277454	30986130	Mutations in other SWI/SNF subunits occur less frequently in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('human', 'Species', '9606', (61, 66))	('SWI/SNF', 'Gene', (19, 26))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
277455	30986130	Examples include SMARCE1 mutations in spinal meningiomas, BCL7B/C in gastric cancer and SMARCC2 mutations in gastric and colorectal cancers.	('spinal meningiomas', 'Phenotype', 'HP:0100010', (38, 56))	('BCL7B/C', 'Gene', (58, 65))	('colorectal cancers', 'Disease', 'MESH:D015179', (121, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('meningiomas', 'Phenotype', 'HP:0002858', (45, 56))	('spinal meningiomas', 'Disease', 'MESH:D008577', (38, 56))	('SMARCC2', 'Gene', (88, 95))	('mutations', 'Var', (96, 105))	('mutations', 'Var', (25, 34))	('gastric cancer', 'Disease', (69, 83))	('SMARCC2', 'Gene', '6601', (88, 95))	('colorectal cancers', 'Disease', (121, 139))	('spinal meningiomas', 'Disease', (38, 56))	('SMARCE1', 'Gene', '6605', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gastric', 'Disease', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('SMARCE1', 'Gene', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BCL7B/C', 'Gene', '9275', (58, 65))
277456	30986130	However, one of the most intriguing mutations involving SWI/SNF subunits are the fusion oncogenes possessing the SS18 subunit found in synovial sarcomas.	('synovial sarcomas', 'Disease', 'MESH:D013584', (135, 152))	('synovial sarcomas', 'Disease', (135, 152))	('sarcomas', 'Phenotype', 'HP:0100242', (144, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('SS18', 'Gene', (113, 117))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (135, 151))	('mutations', 'Var', (36, 45))	('SWI/SNF', 'Gene', (56, 63))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (135, 152))	('SS18', 'Gene', '6760', (113, 117))
277465	30986130	Some of these studies have further implicated these changes as drivers of altered differentiation in SWI/SNF mutant cancers.	('SWI/SNF', 'Gene', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('mutant', 'Var', (109, 115))	('cancers', 'Disease', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
277468	30986130	Loss of the SMARCB1 subunit led to upregulation of the PRC2 catalytic methyltransferase subunit, EZH2, resulting in an increase in H3K27me3 marks.	('upregulation', 'PosReg', (35, 47))	('SMARCB1', 'Gene', (12, 19))	('EZH2', 'Gene', '2146', (97, 101))	('increase', 'PosReg', (119, 127))	('EZH2', 'Gene', (97, 101))	('H3K27me3', 'Protein', (131, 139))	('Loss', 'Var', (0, 4))
277469	30986130	This antagonistic relationship led to uncovering the therapeutic vulnerability in SWI/SNF-mutant cancers to EZH2 inhibitors in.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('SWI/SNF-mutant', 'Var', (82, 96))	('EZH2', 'Gene', (108, 112))	('EZH2', 'Gene', '2146', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SWI/SNF-mutant', 'Gene', (82, 96))
277471	30986130	The chromatin independent interactions of SWI/SNF and PRC1 also depend on the ATPase activity of SMARCA4 because point mutations inactivating the its activity disrupt these interactions.	('interactions', 'Interaction', (26, 38))	('depend', 'Reg', (64, 70))	('point mutations', 'Var', (113, 128))	('inactivating', 'NegReg', (129, 141))	('disrupt', 'NegReg', (159, 166))	('chromatin independent', 'MPA', (4, 25))	('SMARCA4', 'Gene', (97, 104))	('SMARCA4', 'Gene', '6597', (97, 104))	('interactions', 'Interaction', (173, 185))	('PRC1', 'Gene', (54, 58))	('ATPase activity', 'MPA', (78, 93))	('activity', 'MPA', (150, 158))
277479	30986130	These results suggest loss of SMARCB1 works in tandem with other SWI/SNF core subunits to drive tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('SMARCB1', 'Gene', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('drive', 'PosReg', (90, 95))	('loss', 'Var', (22, 26))
277480	30986130	Importantly, they also show that many of the subunit mutations found in human cancers alter the normal assembly of SWI/SNF complexes resulting in aberrant forms.	('SWI/SNF complexes', 'Protein', (115, 132))	('aberrant forms', 'MPA', (146, 160))	('human', 'Species', '9606', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('mutations', 'Var', (53, 62))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('assembly', 'MPA', (103, 111))	('cancers', 'Disease', (78, 85))	('alter', 'Reg', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
277481	30986130	Another recent report demonstrated that inhibition of BRD9, a SWI/SNF subunit that can appear in abnormal complexes induced by mutations in other subunits, can reactive epigenetically-silenced genes in tumors.	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('epigenetically-silenced genes', 'MPA', (169, 198))	('tumors', 'Disease', (202, 208))	('BRD9', 'Gene', '65980', (54, 58))	('inhibition', 'NegReg', (40, 50))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('BRD9', 'Gene', (54, 58))	('mutations', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
277483	30986130	Overall, these findings emphasize the critical need for further studies on the composition and activities of the SWI/SNF complex in cancers drive by mutations in different subunits, especially for identifying novel avenues for therapeutic interventions.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('mutations', 'Var', (149, 158))	('drive by', 'Reg', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
277485	30986130	This report provided a logical mechanism for how loss of SMARCB1 in tumors could fuel tumor development through increased expression of CMYC, a known oncogene.	('tumor', 'Disease', (68, 73))	('fuel', 'PosReg', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('expression', 'MPA', (122, 132))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('loss', 'Var', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (86, 91))	('CMYC', 'Gene', '4609', (136, 140))	('CMYC', 'Gene', (136, 140))	('SMARCB1', 'Gene', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('increased', 'PosReg', (112, 121))	('men', 'Species', '9606', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
277487	30986130	However, the role of several key oncogenic pathways to the SWI/SNF-mutant driven tumorigenesis appear clear.	('SWI/SNF-mutant', 'Gene', (59, 73))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('SWI/SNF-mutant', 'Var', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
277489	30986130	Nearly half of human cancers possess a TP53 mutation and anti-cancer drugs often initiate TP53 activation to force cancer cell death.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutation', 'Var', (44, 52))	('human', 'Species', '9606', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('death', 'Disease', 'MESH:D003643', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('TP53', 'Gene', (90, 94))	('death', 'Disease', (127, 132))	('cancer', 'Disease', (62, 68))	('cancers', 'Disease', (21, 28))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('TP53', 'Gene', (39, 43))
277491	30986130	Inactivating mutations of SMARCB1 and SMARCA4 inhibited the cell growth suppression and apoptosis controlled by TP53.	('apoptosis', 'CPA', (88, 97))	('SMARCA4', 'Gene', (38, 45))	('Inactivating mutations', 'Var', (0, 22))	('SMARCA4', 'Gene', '6597', (38, 45))	('SMARCB1', 'Gene', (26, 33))	('cell growth suppression', 'CPA', (60, 83))	('inhibited', 'NegReg', (46, 55))
277493	30986130	They also found that TP53 could not exert its anti-cancer functions without direct interaction with the SWI/SNF complex and suggested that CDKN1A (p21) was the protein most dependent upon this interaction.	('p21', 'Gene', (147, 150))	('CDKN1A', 'Gene', '1026', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('p21', 'Gene', '1026', (147, 150))	('TP53', 'Var', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('CDKN1A', 'Gene', (139, 145))
277495	30986130	They found that mutant TP53 interacts with the SWI/SNF complex to regulate the VEGFR2 promoter through chromatin remodeling.	('VEGFR2', 'Gene', '3791', (79, 85))	('promoter', 'MPA', (86, 94))	('VEGFR2', 'Gene', (79, 85))	('mutant', 'Var', (16, 22))	('TP53', 'Gene', (23, 27))	('regulate', 'Reg', (66, 74))
277498	30986130	Whether the recent efforts to therapeutically target TP53 in human cancers will extend to the treatment of SWI/SNF-mutant tumors remains an exciting possibility.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('SWI/SNF-mutant', 'Gene', (107, 121))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('men', 'Species', '9606', (99, 102))	('SWI/SNF-mutant', 'Var', (107, 121))	('human', 'Species', '9606', (61, 66))
277501	30986130	Upon re-expression of SMARCA4, the RB growth arrest pathway was restored.	('restored', 'PosReg', (64, 72))	('re-expression', 'Var', (5, 18))	('RB growth arrest', 'Disease', 'MESH:D006323', (35, 51))	('RB growth arrest', 'Disease', (35, 51))	('SMARCA4', 'Gene', (22, 29))	('growth arrest', 'Phenotype', 'HP:0001510', (38, 51))	('SMARCA4', 'Gene', '6597', (22, 29))
277502	30986130	Of interest, re-expression of either SMARCA2 or SMARCA4 could restore RB meditated cell cycle arrest, suggesting that each ATPase subunit could compensate for one other in mediating RB pathways.	('SMARCA2', 'Gene', (37, 44))	('SMARCA2', 'Gene', '6595', (37, 44))	('restore', 'PosReg', (62, 69))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('SMARCA4', 'Gene', (48, 55))	('arrest', 'Disease', (94, 100))	('SMARCA4', 'Gene', '6597', (48, 55))	('RB', 'Chemical', 'MESH:D012413', (182, 184))	('RB', 'Chemical', 'MESH:D012413', (70, 72))	('re-expression', 'Var', (13, 26))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))
277507	30986130	Furthermore, inactivation of CDKN2A or RB1 did not accelerate tumor formation in a SMARCB1-conditional mouse model, despite aberrant upregulation of genes regulated by the target of RB pathway regulation- the E2F transcription factor.	('CDKN2A', 'Gene', (29, 35))	('RB', 'Chemical', 'MESH:D012413', (39, 41))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inactivation', 'Var', (13, 25))	('mouse', 'Species', '10090', (103, 108))	('tumor', 'Disease', (62, 67))	('upregulation', 'PosReg', (133, 145))	('RB', 'Chemical', 'MESH:D012413', (182, 184))	('RB1', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
277514	30986130	Evidence for clinical activity of approved or investigational agents in SWI/SNF-mutant tumors is limited with no drugs approved specifically for treatment of SWI/SNF-mutant cancers.	('SWI/SNF-mutant', 'Gene', (72, 86))	('men', 'Species', '9606', (150, 153))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancers', 'Disease', (173, 180))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('SWI/SNF-mutant', 'Var', (72, 86))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
277517	30986130	Targeted drug development in SWI/SNF-mutant cancers has focused on synthetic lethal relationships with loss of SWI/SNF subunits because no gene replacement strategies have yet proven clinically effective in cancer (Table 2).	('men', 'Species', '9606', (151, 154))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Disease', (207, 213))	('SWI/SNF-mutant', 'Gene', (29, 43))	('cancer', 'Disease', (44, 50))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('SWI/SNF', 'Gene', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('men', 'Species', '9606', (21, 24))	('SWI/SNF-mutant', 'Var', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
277518	30986130	For example, elucidation of antagonism between the SWI/SNF complex and PRC2 that regulates transcriptional silencing through H3K27 methylation has identified the PRC2 catalytic subunit, EZH2, as synthetic lethal with SMARCB1 loss.	('H3K27', 'Protein', (125, 130))	('loss', 'NegReg', (225, 229))	('EZH2', 'Gene', (186, 190))	('transcriptional silencing', 'MPA', (91, 116))	('EZH2', 'Gene', '2146', (186, 190))	('SMARCB1', 'Gene', (217, 224))	('methylation', 'Var', (131, 142))
277519	30986130	Thus, EZH2, a promising therapeutic target in rhabdoid tumors and other SWI/SNF-mutant cancers, is currently in numerous clinical trials.	('SWI/SNF-mutant', 'Gene', (72, 86))	('cancers', 'Disease', (87, 94))	('EZH2', 'Gene', '2146', (6, 10))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (46, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('EZH2', 'Gene', (6, 10))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('SWI/SNF-mutant', 'Var', (72, 86))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('rhabdoid tumors', 'Disease', (46, 61))
277525	30986130	The phase II Pediatric MATCH trial (NCT0321366) is investigating how well tazemetostat works in patients with metastatic, recurrent or non-responsive solid tumors, non-hodgkin lymphoma, or histiocytic disorders that have EZH2, SMARCB1, or SMARCA4 gene mutations.	('recurrent', 'Disease', (122, 131))	('histiocytic disorders', 'Disease', (189, 210))	('SMARCA4', 'Gene', (239, 246))	('lymphoma', 'Phenotype', 'HP:0002665', (176, 184))	('non-hodgkin lymphoma', 'Disease', (164, 184))	('SMARCB1', 'Gene', (227, 234))	('non-hodgkin lymphoma', 'Disease', 'MESH:D008228', (164, 184))	('hodgkin lymphoma', 'Phenotype', 'HP:0012189', (168, 184))	('tazemetostat', 'Chemical', 'MESH:C000593333', (74, 86))	('EZH2', 'Gene', '2146', (221, 225))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('EZH2', 'Gene', (221, 225))	('histiocytic disorders', 'Disease', 'MESH:D015620', (189, 210))	('metastatic', 'Disease', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutations', 'Var', (252, 261))	('patients', 'Species', '9606', (96, 104))	('tumors', 'Disease', (156, 162))	('SMARCA4', 'Gene', '6597', (239, 246))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('non-hodgkin lymphoma', 'Phenotype', 'HP:0012539', (164, 184))
277531	30986130	These studies have led to identification of SWI/SNF-mutation-dependent sensitivities to RTK inhibitors such as ponatinib and NVP-BGJ398 that likely result from altered activity of mutant SWI/SNF complexes at RTK promoters.	('activity', 'MPA', (168, 176))	('SWI/SNF', 'Protein', (187, 194))	('SWI/SNF-mutation-dependent', 'Gene', (44, 70))	('complexes', 'Protein', (195, 204))	('RTK', 'Gene', '5979', (88, 91))	('RTK', 'Gene', (208, 211))	('mutant', 'Var', (180, 186))	('altered', 'Reg', (160, 167))	('RTK', 'Gene', (88, 91))	('NVP-BGJ398', 'Chemical', 'MESH:C568950', (125, 135))	('RTK', 'Gene', '5979', (208, 211))	('sensitivities', 'Reg', (71, 84))	('ponatinib', 'Chemical', 'MESH:C545373', (111, 120))
277538	30986130	Despite these emerging lines of preclinical and clinical inquiry into SWI/SNF-mutation dependent therapeutic vulnerabilities, whether SWI/SNF-mutant cancers may share these vulnerabilities and how they depend on mutant SWI/SNF subunit and/or tissue type remain underexplored questions.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('SWI/SNF-mutant', 'Var', (134, 148))	('SWI/SNF-mutation', 'Gene', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('SWI/SNF-mutant', 'Gene', (134, 148))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
277539	30986130	Key differences also exist between adult and pediatric SWI/SNF-mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('SWI/SNF-mutant', 'Gene', (55, 69))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('SWI/SNF-mutant', 'Var', (55, 69))
277540	30986130	For example, SMARCA2 may comprise a therapeutic target in SMARCA4-mutant adult lung cancers, but most pediatric rhabdoid tumors and SCCOHTs lack SMARCA2 expression through epigenetic silencing.	('lack', 'NegReg', (140, 144))	('SMARCA2', 'Gene', (13, 20))	('SMARCA2', 'Gene', '6595', (13, 20))	('expression', 'MPA', (153, 163))	('SMARCA4', 'Gene', '6597', (58, 65))	('SMARCA2', 'Gene', (145, 152))	('SMARCA2', 'Gene', '6595', (145, 152))	('lung cancers', 'Disease', 'MESH:D008175', (79, 91))	('lung cancers', 'Disease', (79, 91))	('epigenetic silencing', 'Var', (172, 192))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (79, 91))	('SMARCA4', 'Gene', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('rhabdoid tumors', 'Disease', (112, 127))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (112, 127))
277541	30986130	The finding of frequent mutations of subunits of the SWI/SNF chromatin remodeling complex by the TCGA and other tumor sequencing projects across a broad range of cancers has sparked renewed interest in targeting the epigenome with new treatment options.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('men', 'Species', '9606', (240, 243))	('cancers', 'Disease', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('SWI/SNF', 'Gene', (53, 60))	('tumor', 'Disease', (112, 117))	('mutations', 'Var', (24, 33))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
277542	30986130	Because many of these mutations result in loss of function, efforts at identifying therapeutic vulnerabilities have suffered the same hurdles encountered for tumor suppressor genes such as BRCA1, RB1 or TP53.	('tumor', 'Disease', (158, 163))	('BRCA1', 'Gene', (189, 194))	('TP53', 'Gene', (203, 207))	('BRCA1', 'Gene', '672', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('RB1', 'Gene', (196, 199))	('function', 'MPA', (50, 58))	('loss', 'NegReg', (42, 46))
277543	30986130	While recent studies have implicated the underlying mechanisms by which mutant SWI/SNF subunits can drive tumorigenesis, this knowledge has translated into limited novel treatment options.	('mutant', 'Var', (72, 78))	('SWI/SNF', 'Gene', (79, 86))	('drive', 'Reg', (100, 105))	('subunits', 'Protein', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('men', 'Species', '9606', (175, 178))	('tumor', 'Disease', (106, 111))
277544	30986130	The only options that have led to drugs in clinical trials for these cancers have come from characterizing downstream signaling pathways altered by these mutations or through synthetic lethality screens of tumor cell lines.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (154, 163))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('altered', 'Reg', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cancers', 'Disease', (69, 76))
277545	30986130	Therefore, accelerating the pace of research for understanding how mutations in SWI/SNF subunits drive development of nearly 25% of human cancers should become a high priority.	('men', 'Species', '9606', (110, 113))	('mutations', 'Var', (67, 76))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('SWI/SNF', 'Gene', (80, 87))	('human', 'Species', '9606', (132, 137))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
277549	30986130	Another concern from the screening studies relates to the focus of each screen on one type of SWI/SNF-mutant tumor.	('SWI/SNF-mutant', 'Gene', (94, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('SWI/SNF-mutant', 'Var', (94, 108))	('tumor', 'Disease', (109, 114))
277551	30986130	Once EZH2 inhibitors became available, multiple groups subsequently assessed its effects on tumors with mutations in different SWI/SNF subunits.	('SWI/SNF', 'Gene', (127, 134))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('EZH2', 'Gene', '2146', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('EZH2', 'Gene', (5, 9))
277553	30986130	These efficacy studies continue to expand as cell lines become available from tumors with newly-discovered mutations in SWI/SNF subunits.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumors', 'Disease', (78, 84))	('SWI/SNF', 'Gene', (120, 127))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
277554	30986130	While this scheme works, it does not appear like the most efficient manner to find new treatment avenues for SWI/SNF-mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SWI/SNF-mutant', 'Var', (109, 123))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('SWI/SNF-mutant', 'Gene', (109, 123))	('men', 'Species', '9606', (92, 95))
277555	30986130	We advocate for a more unified approach to the study of SWI/SNF-mutant cancers that looks for the common mechanisms that drive tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('SWI/SNF-mutant', 'Gene', (56, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('tumor', 'Disease', (127, 132))	('cancers', 'Disease', (71, 78))	('SWI/SNF-mutant', 'Var', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
277556	30986130	We believe this approach will lead to novel insights into the roles of mutations in epigenetic regulators in human tumor development and to the identification of new targets for therapeutic intervention for aggressive cancers that often possess mutations in SWI/SNF subunits.	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SWI/SNF', 'Gene', (258, 265))	('mutations', 'Var', (245, 254))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('men', 'Species', '9606', (128, 131))	('tumor', 'Disease', (115, 120))	('aggressive cancers', 'Disease', (207, 225))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('aggressive cancers', 'Disease', 'MESH:D009369', (207, 225))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
277563	30986130	As discussed in the review, missense mutations appear at "hotspots" in SMARCA4 and SMARCB1 in SCCOHTs and rhabdoid tumors, respectively.	('SMARCB1', 'Gene', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SMARCA4', 'Gene', '6597', (71, 78))	('rhabdoid tumors', 'Disease', (106, 121))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (106, 121))	('missense mutations', 'Var', (28, 46))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('SMARCA4', 'Gene', (71, 78))	('SCCOHTs', 'Disease', (94, 101))
277564	30986130	Missense mutations also occur at specific sites in some of the other subunits including SMARCA2, ARID1B and SMARCC1.	('occur', 'Reg', (24, 29))	('SMARCA2', 'Gene', (88, 95))	('SMARCA2', 'Gene', '6595', (88, 95))	('ARID1B', 'Gene', (97, 103))	('SMARCC1', 'Gene', (108, 115))	('ARID1B', 'Gene', '57492', (97, 103))	('SMARCC1', 'Gene', '6599', (108, 115))	('Missense mutations', 'Var', (0, 18))
277565	30986130	Of import, many of the same missense mutations appear to drive the development of several human developmental disorders.	('developmental disorders', 'Disease', 'MESH:D002658', (96, 119))	('drive', 'PosReg', (57, 62))	('men', 'Species', '9606', (103, 106))	('human', 'Species', '9606', (90, 95))	('missense mutations', 'Var', (28, 46))	('men', 'Species', '9606', (74, 77))	('developmental disorders', 'Disease', (96, 119))
277566	30986130	Considering that the SS18-SSX and EWS-FLI1 fusion proteins imbue the SWI/SNF complex with de novo oncogenic features, these missense mutations could exert similar effects.	('EWS', 'Gene', (34, 37))	('FLI1', 'Gene', '2313', (38, 42))	('FLI1', 'Gene', (38, 42))	('SSX', 'Gene', '6757', (26, 29))	('SS18', 'Gene', '6760', (21, 25))	('SSX', 'Gene', (26, 29))	('missense', 'Var', (124, 132))	('SS18', 'Gene', (21, 25))	('EWS', 'Gene', '2130', (34, 37))
277567	30986130	Therapeutic vulnerabilities may also arise in tumors with missense mutations that do appear in those with loss of function, similar to differences seen between TP53 deletions versus missense mutations upon tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (206, 211))	('deletions', 'Var', (165, 174))	('tumor', 'Disease', (46, 51))	('missense mutations', 'Var', (182, 200))	('missense mutations', 'Var', (58, 76))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('TP53', 'Gene', (160, 164))	('tumors', 'Disease', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
277568	30986130	Further characterization of these SWI/SNF missense mutations may also prove efficacious for adult malignancies which often have missense mutations in SWI/SNF subunits rather than loss of protein expression.	('SWI/SNF', 'Gene', (34, 41))	('malignancies', 'Disease', (98, 110))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('missense mutations', 'Var', (42, 60))	('missense mutations', 'Var', (128, 146))	('SWI/SNF', 'Gene', (150, 157))
277569	30986130	Studies that identify common mechanisms of tumor development among different epigenetic regulators such as the SWI/SNF complex, histone modification and substitutions and DNA methyltransferases will yield new drugs for more effective treatments of a broad range of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('men', 'Species', '9606', (56, 59))	('human', 'Species', '9606', (265, 270))	('substitutions', 'Var', (153, 166))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancers', 'Disease', 'MESH:D009369', (271, 278))	('men', 'Species', '9606', (239, 242))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('tumor', 'Disease', (43, 48))	('cancers', 'Disease', (271, 278))
277570	30986130	With the further development of CRISPR technologies, treatments for SWI/SNF-mutant tumors will appear that disrupt the key enhancers and/or super enhancers required for tumor development.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('men', 'Species', '9606', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (83, 88))	('SWI/SNF-mutant', 'Var', (68, 82))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('disrupt', 'NegReg', (107, 114))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', (169, 174))	('SWI/SNF-mutant', 'Gene', (68, 82))	('men', 'Species', '9606', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('men', 'Species', '9606', (58, 61))
277571	30986130	The completion of clinical trials for targeting of epigenetic vulnerabilities in SWI/SNF-mutant tumors such as EZH2, HDACs and BRD9 will establish the efficacy of these treatment approaches.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('HDAC', 'Gene', (117, 121))	('SWI/SNF-mutant', 'Var', (81, 95))	('HDAC', 'Gene', '9734', (117, 121))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('BRD9', 'Gene', '65980', (127, 131))	('EZH2', 'Gene', '2146', (111, 115))	('epigenetic vulnerabilities', 'MPA', (51, 77))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('SWI/SNF-mutant', 'Gene', (81, 95))	('EZH2', 'Gene', (111, 115))	('BRD9', 'Gene', (127, 131))	('men', 'Species', '9606', (174, 177))
277572	30986130	Mutations in subunits of the SWI/SNF complex appear in nearly 25% of all human cancers.	('cancers', 'Disease', (79, 86))	('appear', 'Reg', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('human', 'Species', '9606', (73, 78))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('SWI/SNF', 'Gene', (29, 36))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
277574	30986130	Importantly, some of these tumors possess only a mutation in one SWI/SNF subunit along with little evidence of genomic instability.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('SWI/SNF', 'Gene', (65, 72))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('mutation', 'Var', (49, 57))
277577	30986130	Because of this central role in controlling chromatin organization, mutations in the complex can disrupt the regulation of many cellular processes such as proliferation, programmed cell death and differentiation as well as normal development.	('death', 'Disease', 'MESH:D003643', (186, 191))	('disrupt', 'NegReg', (97, 104))	('normal development', 'CPA', (223, 241))	('regulation', 'MPA', (109, 119))	('mutations', 'Var', (68, 77))	('death', 'Disease', (186, 191))	('differentiation', 'CPA', (196, 211))	('men', 'Species', '9606', (237, 240))
277578	30986130	Because of its broad regulatory roles, studies have identified multiple mechanisms underlying the development of SWI/SNF-mutant tumors including changes in enhancer and super-enhancer sites, altered interactions with key histone modifications, aberrant regulation of the RB and TP53 tumor suppressor pathways and changes in interactions with non-coding RNAs.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('men', 'Species', '9606', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('altered', 'Reg', (191, 198))	('tumors', 'Disease', (128, 134))	('histone', 'Protein', (221, 228))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('SWI/SNF-mutant', 'Gene', (113, 127))	('regulation', 'Reg', (253, 263))	('interactions', 'Interaction', (199, 211))	('SWI/SNF-mutant', 'Var', (113, 127))	('RB', 'Chemical', 'MESH:D012413', (271, 273))	('tumor', 'Disease', (128, 133))	('changes', 'Reg', (145, 152))	('changes', 'Reg', (313, 320))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (283, 288))	('interactions', 'Interaction', (324, 336))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
277591	30326929	Based on our findings, we can conclude that detection of the chimeric SS18-SSX fusion gene after surgical excision and/or chemotherapy/radiotherapy is a rare circumstance and hence in itself is not sufficient for monitoring the tumor recurrence.	('SSX', 'Gene', '6757', (75, 78))	('SSX', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('chimeric', 'Var', (61, 69))	('SS18', 'Gene', '6760', (70, 74))	('tumor', 'Disease', (228, 233))	('SS18', 'Gene', (70, 74))
277595	30326929	The characteristic and specific translocation t(X;18((p11.2q11.2)) of human SS causes the fusion of the SS18 (also known as SYT) gene on chromosome 18 to SSX1, SSX2 or, rarely, SSX4 on chromosome X at Xp11.2, and contributes to the formation of SS18-SSX fusion transcripts, regardless of histologic subtype.	('SSX', 'Gene', '6757', (250, 253))	('SYT', 'Gene', '6760', (124, 127))	('SSX', 'Gene', '6757', (154, 157))	('SS18', 'Gene', (104, 108))	('SSX', 'Gene', '6757', (177, 180))	('SSX', 'Gene', (250, 253))	('SSX', 'Gene', (154, 157))	('fusion', 'Var', (90, 96))	('causes', 'Reg', (79, 85))	('SSX', 'Gene', (177, 180))	('SSX', 'Gene', '6757', (160, 163))	('SSX1', 'Gene', '6756', (154, 158))	('SS18', 'Gene', (245, 249))	('SS18', 'Gene', '6760', (104, 108))	('human', 'Species', '9606', (70, 75))	('SSX1', 'Gene', (154, 158))	('SYT', 'Gene', (124, 127))	('SSX', 'Gene', (160, 163))	('SSX2', 'Gene', (160, 164))	('SSX4', 'Gene', (177, 181))	('SS18', 'Gene', '6760', (245, 249))	('SSX2', 'Gene', '6757', (160, 164))	('SSX4', 'Gene', '6759', (177, 181))
277597	30326929	The presence of the SS18-SSX fusion transcripts facilitates the specific and sensitive diagnosis of SS using either conventional RT-PCR, qRT-PCR or dual color FISH as diagnostic tools in fresh tumors or paraffin-embedded tissues.	('SS18', 'Gene', (20, 24))	('paraffin', 'Chemical', 'MESH:D010232', (203, 211))	('SS18', 'Gene', '6760', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('SSX', 'Gene', '6757', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('facilitates', 'PosReg', (48, 59))	('SSX', 'Gene', (25, 28))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('presence', 'Var', (4, 12))
277615	30326929	Until PCR measurements were taken, the reverse transcribed cDNA samples were stored at -20  C. To demonstrate the SS18-SSX1 or SS18-SSX2 fusion genes, nested PCR and droplet digital PCR (ddPCR) were accomplished.	('SSX2', 'Gene', (132, 136))	('SS18', 'Gene', '6760', (127, 131))	('SSX1', 'Gene', '6756', (119, 123))	('fusion', 'Var', (137, 143))	('SS18', 'Gene', (114, 118))	('SSX1', 'Gene', (119, 123))	('SS18', 'Gene', (127, 131))	('SSX2', 'Gene', '6757', (132, 136))	('SS18', 'Gene', '6760', (114, 118))
277621	30326929	ddPCR was accomplished using the SS18-SSX1-positive FAM (Hs03024820_ft) and the SS18-SSX2-positive FAM (Hs03024398_ft) Taqman assays (Applied Biosystems) and the QX200 ddPCR system (Bio-Rad Laboratories, Hercules, CA, USA) according to the manufacturer's protocol.	('SS18', 'Gene', (80, 84))	('SSX2', 'Gene', '6757', (85, 89))	('SS18', 'Gene', (33, 37))	('Rad', 'Gene', '6236', (186, 189))	('SSX1', 'Gene', '6756', (38, 42))	('Hs03024820_ft', 'Var', (57, 70))	('Rad', 'Gene', (186, 189))	('SSX2', 'Gene', (85, 89))	('SS18', 'Gene', '6760', (80, 84))	('SSX1', 'Gene', (38, 42))	('Hs03024398_ft', 'Var', (104, 117))	('SS18', 'Gene', '6760', (33, 37))
277651	30326929	They could only detect the SS18-SSX2 fusion gene transcripts in the positive control 1273/99 cell line, but not in the liquid biopsies of the investigated patients.	('SSX2', 'Gene', (32, 36))	('SS18', 'Gene', '6760', (27, 31))	('SS18', 'Gene', (27, 31))	('patients', 'Species', '9606', (155, 163))	('fusion', 'Var', (37, 43))	('SSX2', 'Gene', '6757', (32, 36))
277660	30326929	MiR-92b-3p seemed to be significantly higher in SS patients compared to healthy individuals and correlated with tumor dynamics in animal experiments.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (51, 59))	('higher', 'PosReg', (38, 44))	('tumor', 'Disease', (112, 117))	('MiR-92b-3p', 'Var', (0, 10))
277669	29650946	Flow cytometry showed 86% immature myeloid cells with the t(15;17) translocation, and molecular analysis showed expression of the PML/RARalpha fusion protein, which confirmed the diagnosis of APL.	('APL', 'Disease', 'MESH:D015473', (192, 195))	('RARalpha', 'Gene', (134, 142))	('PML', 'Gene', '5371', (130, 133))	('RARalpha', 'Gene', '5914', (134, 142))	('PML', 'Gene', (130, 133))	('translocation', 'Var', (67, 80))	('APL', 'Disease', (192, 195))	('expression', 'MPA', (112, 122))
277675	29650946	Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia that is characterized by a translocation between chromosomes 15 and 17 t(15;17)(q22;q21) and fusion between the PML gene and the retinoic acid receptor alpha gene, RARalpha.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (57, 73))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (51, 73))	('PML', 'Gene', (186, 189))	('t(15;17)(q22;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (145, 162))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (51, 73))	('Acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (0, 28))	('RARalpha', 'Gene', '5914', (238, 246))	('APL', 'Disease', (30, 33))	('Acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (0, 28))	('PML', 'Gene', '5371', (186, 189))	('fusion', 'Var', (167, 173))	('Acute promyelocytic leukemia', 'Disease', (0, 28))	('leukemia', 'Phenotype', 'HP:0001909', (20, 28))	('RARalpha', 'Gene', (238, 246))	('retinoic acid receptor alpha', 'Gene', (203, 231))	('acute myeloid leukemia', 'Disease', (51, 73))	('leukemia', 'Phenotype', 'HP:0001909', (65, 73))	('APL', 'Disease', 'MESH:D015473', (30, 33))	('retinoic acid receptor alpha', 'Gene', '5914', (203, 231))
277684	29650946	The cytogenetic and molecular findings showed translocation between chromosomes 15 and 17 t(15;17)(q22;q21) and fusion between the PML gene and the retinoic acid receptor alpha gene, RARalpha, confirming the diagnosis of APL.	('RARalpha', 'Gene', '5914', (183, 191))	('PML', 'Gene', (131, 134))	('retinoic acid receptor alpha', 'Gene', '5914', (148, 176))	('t(15;17)(q22;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (90, 107))	('RARalpha', 'Gene', (183, 191))	('translocation', 'Var', (46, 59))	('APL', 'Disease', (221, 224))	('APL', 'Disease', 'MESH:D015473', (221, 224))	('PML', 'Gene', '5371', (131, 134))	('t(15', 'Gene', (90, 94))	('retinoic acid receptor alpha', 'Gene', (148, 176))	('fusion', 'Var', (112, 118))
277690	29650946	Cytogenetic analysis showed t(15;17) (q22q21) in 40% of the metaphase preparations analyzed, and polymerase chain reaction (PCR) for the PML-RARalpha gene showed residual disease, compatible with relapse of APL.	('RARalpha', 'Gene', '5914', (141, 149))	('PML', 'Gene', '5371', (137, 140))	('PML', 'Gene', (137, 140))	('APL', 'Disease', (207, 210))	('t(15;17) (q22q21', 'Var', (28, 44))	('RARalpha', 'Gene', (141, 149))	('APL', 'Disease', 'MESH:D015473', (207, 210))
277700	29650946	The factors associated with extramedullary relapse include age less than 45 years, elevated white blood cell (WBC) count >10.109/L, and the presence of the bcr3 isoform of PML-RARalpha.	('bcr3', 'Gene', '644165', (156, 160))	('PML', 'Gene', '5371', (172, 175))	('RARalpha', 'Gene', (176, 184))	('PML', 'Gene', (172, 175))	('elevated white blood cell', 'Phenotype', 'HP:0001974', (83, 108))	('presence', 'Var', (140, 148))	('extramedullary relapse', 'Disease', (28, 50))	('bcr3', 'Gene', (156, 160))	('RARalpha', 'Gene', '5914', (176, 184))
277739	29098360	Immunohistochemical labelling for the hypoxia marker HIF-1alpha in clinically derived osteosarcoma tumour samples correlates with pathologic stage, and tumours from patients with medium to strong HIF-1alpha expression had decreases in both overall survival and disease-free survival.	('HIF-1alpha', 'Gene', (196, 206))	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('osteosarcoma tumour', 'Disease', 'MESH:D012516', (86, 105))	('tumours', 'Disease', (152, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('osteosarcoma tumour', 'Disease', (86, 105))	('medium', 'Var', (179, 185))	('clinical', 'Species', '191496', (67, 75))	('hypoxia', 'Disease', 'MESH:D000860', (38, 45))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('patients', 'Species', '9606', (165, 173))	('disease-free survival', 'CPA', (261, 282))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('hypoxia', 'Disease', (38, 45))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('decreases', 'NegReg', (222, 231))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('overall survival', 'CPA', (240, 256))
277769	29098360	Finally, in a mouse model of chondrosarcoma, siRNA inhibition of CXCR4 decreased overall tumour volume and incidence of metastases to the lungs.	('mouse', 'Species', '10090', (14, 19))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('metastases', 'Disease', (120, 130))	('chondrosarcoma', 'Disease', 'MESH:D002813', (29, 43))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (29, 43))	('chondrosarcoma', 'Disease', (29, 43))	('inhibition', 'Var', (51, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('metastases', 'Disease', 'MESH:D009362', (120, 130))	('decreased', 'NegReg', (71, 80))
277770	29098360	Overall, expression of CXCR4 is a poor prognostic indicator that is associated with an increase in many of the processes that are associated with cancer progression including cell migration and metastasis.	('expression', 'Var', (9, 19))	('CXCR4', 'Var', (23, 28))	('cancer', 'Disease', (146, 152))	('processes', 'CPA', (111, 120))	('increase', 'PosReg', (87, 95))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('metastasis', 'CPA', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cell migration', 'CPA', (175, 189))
277774	29098360	The presence of CXCR4 has also been shown to correlate with metastatic disease in prostate cancer, where xenograft tumours that over expressed CXCR4 grafted into immunodeficient NOD/SCID mice exhibited increased growth, vessel density and metastasis.	('xenograft tumours', 'Disease', 'MESH:D009369', (105, 122))	('CXCR4', 'Var', (143, 148))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('metastatic disease', 'Disease', (60, 78))	('metastasis', 'CPA', (239, 249))	('mice', 'Species', '10090', (187, 191))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('SCID', 'Gene', '19090', (182, 186))	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('SCID', 'Phenotype', 'HP:0004430', (182, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))	('immunodeficient NOD', 'Disease', (162, 181))	('prostate cancer', 'Disease', (82, 97))	('xenograft tumours', 'Disease', (105, 122))	('SCID', 'Gene', (182, 186))	('increased', 'PosReg', (202, 211))	('immunodeficient NOD', 'Disease', 'MESH:D020191', (162, 181))	('presence', 'Var', (4, 12))	('vessel density', 'CPA', (220, 234))	('growth', 'CPA', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
277775	29098360	As in primary bone tumours, expression of CXCR4 causes cancer progression, and, in the case of breast or prostate cancer, may increase the risk of metastasis to bone.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('breast or prostate cancer', 'Disease', 'MESH:D011471', (95, 120))	('breast or prostate cancer', 'Disease', (95, 120))	('CXCR4', 'Var', (42, 47))	('metastasis to bone', 'CPA', (147, 165))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('expression', 'Var', (28, 38))	('bone tumours', 'Disease', 'MESH:D001859', (14, 26))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('increase', 'PosReg', (126, 134))	('bone tumours', 'Disease', (14, 26))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', (114, 120))
277796	29098360	AQ4N becomes AQ4 after activation in hypoxic conditions whereupon it non-covalently binds to DNA to facilitate anti-tumour activity and selectively inhibits the activity of the DNA separation enzyme topoisomerase II.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('hypoxic conditions', 'Disease', 'MESH:D009135', (37, 55))	('facilitate', 'PosReg', (100, 110))	('tumour', 'Disease', (116, 122))	('AQ4N', 'Var', (0, 4))	('inhibits', 'NegReg', (148, 156))	('binds', 'Interaction', (84, 89))	('AQ4', 'Chemical', '-', (13, 16))	('AQ4N', 'Chemical', 'MESH:C094428', (0, 4))	('hypoxic conditions', 'Disease', (37, 55))	('DNA separation enzyme topoisomerase II', 'Enzyme', (177, 215))	('AQ4', 'Chemical', '-', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('activity', 'MPA', (161, 169))
277797	29098360	Mice injected with LNCaP prostate tumour cells and treated with AQ4N in conjunction with the anti-androgenic drug bicalutamide exhibited delayed tumour growth which was significantly greater than bicalutamide alone.	('tumour', 'Disease', (145, 151))	('prostate tumour', 'Disease', (25, 40))	('delayed', 'NegReg', (137, 144))	('LNCaP', 'CellLine', 'CVCL:0395', (19, 24))	('prostate tumour', 'Phenotype', 'HP:0100787', (25, 40))	('AQ4N', 'Var', (64, 68))	('AQ4N', 'Chemical', 'MESH:C094428', (64, 68))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('greater', 'PosReg', (183, 190))	('tumour', 'Disease', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('bicalutamide', 'Chemical', 'MESH:C053541', (196, 208))	('Mice', 'Species', '10090', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('prostate tumour', 'Disease', 'MESH:D011471', (25, 40))	('bicalutamide', 'Chemical', 'MESH:C053541', (114, 126))
277798	29098360	AQ4N has been delivered to human breast tumours as part of a phase I clinical trial and shown promise.	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('clinical', 'Species', '191496', (69, 77))	('breast tumours', 'Disease', 'MESH:D001943', (33, 47))	('human', 'Species', '9606', (27, 32))	('AQ4N', 'Var', (0, 4))	('AQ4N', 'Chemical', 'MESH:C094428', (0, 4))	('breast tumours', 'Disease', (33, 47))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
277806	29098360	Other phase III clinical trials of TH-302 in pancreatic cancer found no significant increase in 1-year survival rate with TH-302 and although there was a small yet significant increase in progression-free survival this study did not reach primary overall survival endpoints.	('pancreatic cancer', 'Disease', (45, 62))	('TH-302', 'Chemical', 'MESH:C552526', (35, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('TH-302', 'Var', (122, 128))	('1-year survival', 'MPA', (96, 111))	('clinical', 'Species', '191496', (16, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('TH-302', 'Chemical', 'MESH:C552526', (122, 128))
277811	29098360	Furthermore, TH-302 triggers cell cycle arrest and apoptosis in multiple myeloma cells under hypoxic conditions, while in vivo treatment of the 5T33MM mouse model of multiple myeloma with TH-302 triggered apoptosis of multiple myeloma cells within the bone microenvironment.	('multiple myeloma', 'Disease', 'MESH:D009101', (166, 182))	('triggers', 'Reg', (20, 28))	('TH-302', 'Var', (13, 19))	('apoptosis', 'CPA', (205, 214))	('mouse', 'Species', '10090', (151, 156))	('multiple myeloma cells', 'Disease', (218, 240))	('multiple myeloma cells', 'Disease', 'MESH:D009101', (218, 240))	('multiple myeloma', 'Disease', (166, 182))	('arrest', 'Disease', 'MESH:D006323', (40, 46))	('hypoxic conditions', 'Disease', 'MESH:D009135', (93, 111))	('multiple myeloma', 'Phenotype', 'HP:0006775', (218, 234))	('TH-302', 'Chemical', 'MESH:C552526', (188, 194))	('TH-302', 'Chemical', 'MESH:C552526', (13, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (218, 234))	('multiple myeloma', 'Phenotype', 'HP:0006775', (64, 80))	('apoptosis', 'CPA', (51, 60))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (29, 46))	('multiple myeloma', 'Phenotype', 'HP:0006775', (166, 182))	('multiple myeloma cells', 'Disease', (64, 86))	('multiple myeloma cells', 'Disease', 'MESH:D009101', (64, 86))	('hypoxic conditions', 'Disease', (93, 111))	('multiple myeloma', 'Disease', 'MESH:D009101', (64, 80))	('arrest', 'Disease', (40, 46))
277816	29098360	The fact these two separate studies both investigating the effect of TH-302 upon mice injected with PC-3 prostate cancer cells can show such different results strongly suggests that the working requirements for TH-302 may be specific not only to the type of cancer under investigation, but also to the specific combination of other chemotherapeutic agents used, the strain of mouse model and other holistic considerations.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('TH-302', 'Chemical', 'MESH:C552526', (69, 75))	('mice', 'Species', '10090', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('prostate cancer', 'Disease', (105, 120))	('mouse', 'Species', '10090', (376, 381))	('TH-302', 'Chemical', 'MESH:C552526', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('TH-302', 'Var', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('cancer', 'Disease', (258, 264))	('PC-3', 'CellLine', 'CVCL:0035', (100, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('cancer', 'Disease', (114, 120))
277846	29098360	Under healthy conditions HIF-1alpha inhibits c-Myc activity, but in MM deregulated c-Myc becomes oncogenic and facilitates HIF-1alpha induced VEGF production and secretion to increase angiogenesis.	('deregulated', 'Var', (71, 82))	('angiogenesis', 'CPA', (184, 196))	('c-Myc', 'Gene', (83, 88))	('c-Myc', 'Gene', (45, 50))	('oncogenic', 'MPA', (97, 106))	('increase', 'PosReg', (175, 183))	('secretion', 'MPA', (162, 171))	('facilitates', 'PosReg', (111, 122))	('VEGF production', 'MPA', (142, 157))	('c-Myc', 'Gene', '4609', (83, 88))	('c-Myc', 'Gene', '4609', (45, 50))
277864	29098360	HIF-1alpha knockdown or TGF-beta blockade has also been shown to reduce bone metastasis and increase survival in mice implanted orthotopically with human MDA-MB-231 breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('bone metastasis', 'Disease', 'MESH:D009362', (72, 87))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (154, 164))	('TGF-beta', 'Gene', (24, 32))	('blockade', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('bone metastasis', 'Disease', (72, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('human', 'Species', '9606', (148, 153))	('increase', 'PosReg', (92, 100))	('reduce', 'NegReg', (65, 71))	('survival', 'CPA', (101, 109))	('mice', 'Species', '10090', (113, 117))	('knockdown', 'Var', (11, 20))	('HIF-1alpha', 'Gene', (0, 10))
277877	29098360	We previously showed that patients with high LOX expressing ER- tumours exhibit significantly worse distant metastasis-free survival and poorer overall survival than low LOX expressing ER- counterparts.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('poorer', 'NegReg', (137, 143))	('overall', 'MPA', (144, 151))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('patients', 'Species', '9606', (26, 34))	('worse', 'NegReg', (94, 99))	('distant metastasis-free survival', 'CPA', (100, 132))	('ER-', 'Var', (60, 63))	('high LOX expressing ER-', 'Var', (40, 63))
277885	29098360	A lack of lesion formation in mice injected with conditioned media from 4T1 cells with shRNA knockdown for LOX confirmed a role for the enzyme.	('knockdown', 'Var', (93, 102))	('mice', 'Species', '10090', (30, 34))	('shRNA', 'Gene', (87, 92))
277954	28693790	Before "omic" analysis, the TAp73alpha-induced by doxycycline and noninduced human osteosarcoma cell Saos-2 (p53 null) were successfully cultured.	('TAp73alpha-induced', 'Var', (28, 46))	('TAp73alpha', 'Chemical', '-', (28, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (83, 95))	('doxycycline', 'Chemical', 'MESH:D004318', (50, 61))	('osteosarcoma', 'Disease', (83, 95))	('osteosarcoma', 'Disease', 'MESH:D012516', (83, 95))	('p53', 'Gene', '7157', (109, 112))	('p53', 'Gene', (109, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('human', 'Species', '9606', (77, 82))
277955	28693790	Through proteomics analysis, differential phosphorylations present in the noninduced controls but absent in TAp73alpha-induced cells were affirmed to be dependent on mTOR activation, and TAp73alpha was thought to induce activation of specific phosphatases upstream of the mTOR signaling pathway.	('mTOR', 'Gene', (272, 276))	('mTOR', 'Gene', '2475', (272, 276))	('mTOR', 'Gene', (166, 170))	('phosphatases', 'Enzyme', (243, 255))	('mTOR', 'Gene', '2475', (166, 170))	('TAp73alpha', 'Chemical', '-', (108, 118))	('TAp73alpha', 'Chemical', '-', (187, 197))	('TAp73alpha', 'Var', (187, 197))	('activation', 'PosReg', (220, 230))	('phosphorylations', 'MPA', (42, 58))
277957	28693790	In glycolysis related group, the level of phosphoenolpyruvate (PEP) and lactoyl-glutathione were significantly higher in TAp73alpha-induced cells when compared with that of the noninduced cells.	('TAp73alpha-induced', 'Var', (121, 139))	('lactoyl-glutathione', 'MPA', (72, 91))	('TAp73alpha', 'Chemical', '-', (121, 131))	('level of phosphoenolpyruvate', 'MPA', (33, 61))	('phosphoenolpyruvate', 'Chemical', 'MESH:D010728', (42, 61))	('lactoyl-glutathione', 'Chemical', 'MESH:C013585', (72, 91))	('higher', 'PosReg', (111, 117))	('PEP', 'Chemical', 'MESH:D010728', (63, 66))
277960	28693790	In the pentose phosphate pathway related group, 6-phosphogluconolactone (6PGL), NADPH and NADP+ were significantly raised in TAp73alpha-induced cells when compared with that of noninduced cells.	('raised', 'PosReg', (115, 121))	('6-phosphogluconolactone', 'Chemical', 'MESH:C114004', (48, 71))	('TAp73alpha-induced', 'Var', (125, 143))	('NADP+', 'MPA', (90, 95))	('pentose', 'Pathway', (7, 14))	('pentose phosphate', 'Chemical', 'MESH:D010428', (7, 24))	('TAp73alpha', 'Chemical', '-', (125, 135))	('NADPH', 'Chemical', 'MESH:D009249', (80, 85))	('NADP+', 'Chemical', 'MESH:D009249', (90, 95))	('NADPH', 'Gene', (80, 85))	('6-phosphogluconolactone', 'MPA', (48, 71))
277962	28693790	In the purine metabolism related group, adenosine was increased significantly and adenine was decreased significantly in TAp73alpha-induced cells when compared with that of noninduced cells.	('TAp73alpha-induced', 'Var', (121, 139))	('adenosine', 'MPA', (40, 49))	('TAp73alpha', 'Chemical', '-', (121, 131))	('increased', 'PosReg', (54, 63))	('decreased', 'NegReg', (94, 103))	('adenosine', 'Chemical', 'MESH:D000241', (40, 49))	('adenine', 'Chemical', 'MESH:D000225', (82, 89))	('adenine', 'MPA', (82, 89))	('purine', 'Chemical', 'MESH:C030985', (7, 13))
277964	28693790	In the PI3K/Akt/mTOR signaling pathway related group, PIP2 was at a significantly higher level in TAp73alpha-induced cells when compared with that of noninduced cells.	('higher level', 'PosReg', (82, 94))	('Akt', 'Gene', '207', (12, 15))	('Akt', 'Gene', (12, 15))	('mTOR', 'Gene', '2475', (16, 20))	('PIP2', 'Chemical', 'MESH:D019269', (54, 58))	('TAp73alpha-induced', 'Var', (98, 116))	('mTOR', 'Gene', (16, 20))	('TAp73alpha', 'Chemical', '-', (98, 108))
277965	28693790	Furthermore, through lipidomics analysis, the expression of TAp73alpha might influence lipid biosynthesis and lipid oxidation to a certain extent in the absence of external stimuli.	('TAp73alpha', 'Var', (60, 70))	('expression', 'Var', (46, 56))	('influence', 'Reg', (77, 86))	('lipid biosynthesis', 'MPA', (87, 105))	('lipid oxidation', 'MPA', (110, 125))	('lipid', 'Chemical', 'MESH:D008055', (21, 26))	('lipid', 'Chemical', 'MESH:D008055', (87, 92))	('lipid', 'Chemical', 'MESH:D008055', (110, 115))	('TAp73alpha', 'Chemical', '-', (60, 70))
277973	28693790	Meanwhile, the analysis demonstrated that TAp73 modulated amino acid metabolism, and glutaminolysis affected aspartate, alanine, valine, leucine and isoleucine through GLS-2 regulation.	('valine', 'MPA', (129, 135))	('alanine', 'MPA', (120, 127))	('affected', 'Reg', (100, 108))	('modulated', 'Reg', (48, 57))	('alanine', 'Chemical', 'MESH:D000409', (120, 127))	('TAp73', 'Chemical', '-', (42, 47))	('isoleucine', 'MPA', (149, 159))	('GLS-2', 'Gene', '27165', (168, 173))	('leucine', 'Chemical', 'MESH:D007930', (137, 144))	('GLS-2', 'Gene', (168, 173))	('leucine', 'MPA', (137, 144))	('aspartate', 'Chemical', 'MESH:D001224', (109, 118))	('isoleucine', 'Chemical', 'MESH:D007532', (149, 159))	('valine', 'Chemical', 'MESH:D014633', (129, 135))	('leucine', 'Chemical', 'MESH:D007930', (152, 159))	('TAp73', 'Var', (42, 47))	('glutaminolysis', 'MPA', (85, 99))	('amino acid metabolism', 'MPA', (58, 79))	('aspartate', 'MPA', (109, 118))
278014	28693790	The nucleotide base signatures could be affected by CDDP, whereas mildly increased by DOX and decreased by MTX.	('increased', 'PosReg', (73, 82))	('affected', 'Reg', (40, 48))	('MTX', 'Chemical', 'MESH:D008727', (107, 110))	('nucleotide base signatures', 'MPA', (4, 30))	('DOX', 'Chemical', 'MESH:D004317', (86, 89))	('CDDP', 'Chemical', 'MESH:D002945', (52, 56))	('decreased', 'NegReg', (94, 103))	('CDDP', 'Var', (52, 56))
278015	28693790	Regarding other compounds, CDDP and DOX, but not MTX, could decreased m- and s-inositols; and acetate(s), creatine, and gluthathione could be mildly increased by CDDP and decreased by DOX and MTX.	('decreased', 'NegReg', (171, 180))	('decreased', 'NegReg', (60, 69))	('creatine', 'MPA', (106, 114))	('m- and s-inositols', 'Chemical', '-', (70, 88))	('gluthathione', 'Chemical', '-', (120, 132))	('gluthathione', 'MPA', (120, 132))	('increased', 'PosReg', (149, 158))	('CDDP', 'Chemical', 'MESH:D002945', (162, 166))	('m- and s-inositols', 'MPA', (70, 88))	('MTX', 'Chemical', 'MESH:D008727', (192, 195))	('acetate', 'Chemical', 'MESH:D000085', (94, 101))	('CDDP', 'Var', (162, 166))	('DOX', 'Chemical', 'MESH:D004317', (36, 39))	('DOX', 'Chemical', 'MESH:D004317', (184, 187))	('creatine', 'Chemical', 'MESH:D003401', (106, 114))	('MTX', 'Chemical', 'MESH:D008727', (49, 52))	('CDDP', 'Chemical', 'MESH:D002945', (27, 31))
278017	28693790	Although mTORC1 pathway is highly expressed in clinical osteosarcoma patients, inhibition of mTORC1 may not be enough to induce significant cell death of human osteosarcoma MG-63 cells.	('mTORC1', 'Gene', (9, 15))	('mTORC1', 'Gene', (93, 99))	('human', 'Species', '9606', (154, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('patients', 'Species', '9606', (69, 77))	('osteosarcoma', 'Disease', (56, 68))	('inhibition', 'Var', (79, 89))	('mTORC1', 'Gene', '382056', (9, 15))	('mTORC1', 'Gene', '382056', (93, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (160, 172))	('MG-63', 'CellLine', 'CVCL:0426', (173, 178))	('osteosarcoma', 'Disease', 'MESH:D012516', (56, 68))	('osteosarcoma', 'Disease', (160, 172))	('osteosarcoma', 'Disease', 'MESH:D012516', (160, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
278019	28693790	The mTORC1 in osteosarcoma cells was silenced by mTORC1 inhibitor rapamycin and Raptor silencing.	('silencing', 'Var', (87, 96))	('osteosarcoma', 'Disease', (14, 26))	('silenced', 'NegReg', (37, 45))	('mTORC1', 'Gene', '382056', (4, 10))	('mTORC1', 'Gene', '382056', (49, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (14, 26))	('osteosarcoma', 'Disease', 'MESH:D012516', (14, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('mTORC1', 'Gene', (4, 10))	('mTORC1', 'Gene', (49, 55))
278021	28693790	Inhibition of mTORC1 led to reduced amino acid metabolites including serine and glycine in osteosarcoma cells.	('mTORC1', 'Gene', (14, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('reduced', 'NegReg', (28, 35))	('amino acid metabolites', 'MPA', (36, 58))	('mTORC1', 'Gene', '382056', (14, 20))	('serine', 'Chemical', 'MESH:D012694', (69, 75))	('Inhibition', 'Var', (0, 10))	('serine', 'MPA', (69, 75))	('glycine', 'Chemical', 'MESH:D005998', (80, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('osteosarcoma', 'Disease', (91, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (91, 103))
278058	28693790	Eight significantly differential metabolites, including carbamoyl phosphate, CMP, ribose-phosphate, cytosine, cyclic-AMP, DL-Pipecolic acid, Ng,NG-dimethyl-L-arginine and nicotinamide were selected.	('NG-dimethyl-L-arginine', 'Chemical', '-', (144, 166))	('nicotinamide', 'Chemical', 'MESH:D009536', (171, 183))	('DL-Pipecolic acid', 'MPA', (122, 139))	('cyclic-AMP', 'Chemical', 'MESH:D000242', (110, 120))	('cytosine', 'MPA', (100, 108))	('cyclic-AMP', 'MPA', (110, 120))	('ribose-phosphate', 'Chemical', 'MESH:C031626', (82, 98))	('CMP', 'Chemical', 'MESH:D003568', (77, 80))	('carbamoyl phosphate', 'MPA', (56, 75))	('carbamoyl phosphate', 'Chemical', 'MESH:D002221', (56, 75))	('CMP', 'MPA', (77, 80))	('cytosine', 'Chemical', 'MESH:D003596', (100, 108))	('DL-Pipecolic acid', 'Chemical', 'MESH:C031345', (122, 139))	('ribose-phosphate', 'MPA', (82, 98))	('NG-dimethyl-L-arginine', 'Var', (144, 166))
278063	28693790	Based on the metabolomics study in brain cancer, 2-hydroxyglutarate (2-HG) was found as an oncometabolite was verified to be generated by mutant isocitrate dehydrogenase (IDH).	('IDH', 'Gene', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('IDH', 'Gene', '3417', (171, 174))	('brain cancer', 'Disease', 'MESH:D001932', (35, 47))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (49, 67))	('mutant', 'Var', (138, 144))	('2-HG', 'Chemical', 'MESH:C019417', (69, 73))	('isocitrate', 'Chemical', 'MESH:C034219', (145, 155))	('brain cancer', 'Phenotype', 'HP:0030692', (35, 47))	('brain cancer', 'Disease', (35, 47))
278064	28693790	Mutations of IDH, which is an essential enzyme for cellular respiration in the TCA cycle, have been implicated in tumorigenesis, cell maintenance, and proliferation of several diverse tumors, such as acute myeloid leukemia, angioimmunoblastic lymphomas, and glioma.	('glioma', 'Disease', 'MESH:D005910', (258, 264))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (200, 222))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (206, 222))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('leukemia', 'Phenotype', 'HP:0001909', (214, 222))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (200, 222))	('lymphomas', 'Phenotype', 'HP:0002665', (243, 252))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (184, 189))	('Mutations', 'Var', (0, 9))	('angioimmunoblastic lymphomas', 'Disease', (224, 252))	('IDH', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('TCA', 'Chemical', 'MESH:D014233', (79, 82))	('acute myeloid leukemia', 'Disease', (200, 222))	('IDH', 'Gene', '3417', (13, 16))	('angioimmunoblastic lymphomas', 'Disease', 'MESH:D007119', (224, 252))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', (184, 190))	('glioma', 'Disease', (258, 264))	('implicated', 'Reg', (100, 110))
278068	28693790	In our study, highly IDH1/2 mutations (61%) were detected in high grade chondrosarcoma withthe majority (86%) of mutations being present on the IDH1 gene.	('detected', 'Reg', (49, 57))	('chondrosarcoma withthe', 'Disease', (72, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('IDH1/2', 'Gene', '3417;3418', (21, 27))	('chondrosarcoma withthe', 'Disease', 'MESH:D002813', (72, 94))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (72, 86))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', (144, 148))	('IDH1/2', 'Gene', (21, 27))	('mutations', 'Var', (28, 37))	('IDH1', 'Gene', '3417', (144, 148))	('IDH1', 'Gene', '3417', (21, 25))
278069	28693790	The IDH1/2 mutations could be a potential diagnostic biomarker for dedifferentiated chondrosarcoma.	('mutations', 'Var', (11, 20))	('IDH1/2', 'Gene', '3417;3418', (4, 10))	('chondrosarcoma', 'Disease', 'MESH:D002813', (84, 98))	('chondrosarcoma', 'Disease', (84, 98))	('IDH1/2', 'Gene', (4, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (84, 98))
278070	28693790	Future metabolomics studies will help us to further investigate the functional roles of IDH1/2 mutations in chondrosarcoma.	('IDH1/2', 'Gene', (88, 94))	('chondrosarcoma', 'Disease', (108, 122))	('chondrosarcoma', 'Disease', 'MESH:D002813', (108, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('mutations', 'Var', (95, 104))	('IDH1/2', 'Gene', '3417;3418', (88, 94))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (108, 122))
278083	26429873	All three LG-ESSs exhibited either one of JAZF1-SUZ12, JAZF1-PHF1 and MEAF6-PHF1 fusions, whereas the two UUSs did not.	('PHF1', 'Gene', (61, 65))	('MEAF6', 'Gene', (70, 75))	('SUZ12', 'Gene', '23512', (48, 53))	('exhibited', 'Reg', (18, 27))	('JAZF1', 'Gene', '221895', (55, 60))	('PHF1', 'Gene', '5252', (61, 65))	('ESSs', 'Gene', '54539', (13, 17))	('SUZ12', 'Gene', (48, 53))	('fusions', 'Var', (81, 88))	('PHF1', 'Gene', (76, 80))	('JAZF1', 'Gene', (42, 47))	('PHF1', 'Gene', '5252', (76, 80))	('JAZF1', 'Gene', (55, 60))	('MEAF6', 'Gene', '64769', (70, 75))	('JAZF1', 'Gene', '221895', (42, 47))	('ESSs', 'Gene', (13, 17))
278086	26429873	We found 81 non-silent mutations (35 from LG-ESSs and 46 from UUSs) that included 15 putative cancer genes catalogued in cancer-related databases, including PPARG and IRF4 mutations.	('mutations', 'Var', (172, 181))	('ESSs', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ESSs', 'Gene', '54539', (45, 49))	('PPARG', 'Gene', '5468', (157, 162))	('PPARG', 'Gene', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('IRF4', 'Gene', '3662', (167, 171))	('IRF4', 'Gene', (167, 171))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
278089	26429873	HG-ESS is defined as an ESS with t(10;17)(q22;p13) rearrangement leading to YWHAE-FAM22 gene fusion, while UUS is a 'wastebasket category' that does not harbor any specific chromosomal translocation.	('YWHAE', 'Gene', '7531', (76, 81))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (33, 50))	('YWHAE', 'Gene', (76, 81))	('rearrangement', 'Var', (51, 64))	('HG-ESS', 'Disease', (0, 6))
278096	26429873	To address whether the mutations found in our study could be causally implicated in ESS development, we queried the cancer Gene Census, the CHASM analysis and the pan-cancer databases.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (167, 173))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('implicated', 'Reg', (70, 80))	('ESS development', 'Disease', (84, 99))
278099	26429873	Of note, all the UUSs harbored CNA loss on 16q, where tumor suppressor genes CYLD and CDH1 reside.	('CYLD', 'Gene', '1540', (77, 81))	('CDH1', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CDH1', 'Gene', '999', (86, 90))	('CNA loss', 'Var', (31, 39))	('tumor', 'Disease', (54, 59))	('CYLD', 'Gene', (77, 81))
278104	26429873	All of the copy number losses except RB1 were heterozygous deletion while RB1 loss was homozygous deletion (Figure 2).	('losses', 'NegReg', (23, 29))	('copy number', 'Var', (11, 22))	('loss', 'NegReg', (78, 82))	('RB1', 'Gene', (74, 77))	('RB1', 'Gene', (37, 40))	('RB1', 'Gene', '5925', (37, 40))	('RB1', 'Gene', '5925', (74, 77))
278109	26429873	A total of 81 non-silent point mutations and indels (median: 10, range: 6-36) were identified in the five ESSs (Supplementary Table S3).	('ESSs', 'Gene', '54539', (106, 110))	('ESSs', 'Gene', (106, 110))	('indels', 'Var', (45, 51))
278114	26429873	Together, we detected 15 putative cancer-related genes with somatic mutations that could be causally implicated in ESS development (Figure 3C).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('implicated', 'Reg', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('mutations', 'Var', (68, 77))	('ESS development', 'Disease', (115, 130))
278116	26429873	Sanger validation of the mutations including four putative cancer-related genes (SRGAP3, PPARG, DCC and ZFP36L2) is illustrated in Supplementary Figure S2.	('DCC', 'Gene', '1630', (96, 99))	('mutations', 'Var', (25, 34))	('ZFP36L2', 'Gene', '678', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ZFP36L2', 'Gene', (104, 111))	('SRGAP3', 'Gene', (81, 87))	('PPARG', 'Gene', '5468', (89, 94))	('PPARG', 'Gene', (89, 94))	('DCC', 'Gene', (96, 99))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('SRGAP3', 'Gene', '9901', (81, 87))
278122	26429873	Together, this study identified that ESSs harbored not only ESS-specific fusions but also somatic mutations and CNAs encompassing driver genes.	('ESSs', 'Gene', '54539', (37, 41))	('fusions', 'Var', (73, 80))	('ESSs', 'Gene', (37, 41))
278123	26429873	Our findings suggest a possibility that gene fusions alone may not fully develop ESSs as identified in other tumors.	('ESSs', 'Gene', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('ESSs', 'Gene', '54539', (81, 85))	('gene fusions', 'Var', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
278126	26429873	Loss of CDH1 results in dysfunction of cell-cell adhesion, allowing for abnormal cell-cell interaction such as epithelial-mesenchymal transition (EMT).	('dysfunction', 'MPA', (24, 35))	('CDH1', 'Gene', (8, 12))	('epithelial-mesenchymal transition', 'CPA', (111, 144))	('CDH1', 'Gene', '999', (8, 12))	('Loss', 'Var', (0, 4))	('cell-cell adhesion', 'CPA', (39, 57))	('allowing', 'Reg', (59, 67))
278132	26429873	In spite of the earlier report on positive TP53 mutations in ESSs, we did not identify any TP53 point mutations in the ESSs by WES.	('ESSs', 'Gene', (61, 65))	('TP53', 'Gene', (91, 95))	('TP53', 'Gene', '7157', (43, 47))	('ESSs', 'Gene', '54539', (119, 123))	('ESSs', 'Gene', '54539', (61, 65))	('ESSs', 'Gene', (119, 123))	('TP53', 'Gene', '7157', (91, 95))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
278134	26429873	Together, these data indicate that TP53 inactivation in ESSs may result from point mutation or deletion and suggest a possibility that haploinsufficiency of TP53 might inactivate its tumor suppressor roles.	('TP53', 'Gene', (157, 161))	('deletion', 'Var', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('haploinsufficiency', 'Disease', (135, 153))	('TP53', 'Gene', '7157', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('ESSs', 'Gene', (56, 60))	('TP53', 'Gene', (35, 39))	('inactivate', 'NegReg', (168, 178))	('ESSs', 'Gene', '54539', (56, 60))	('inactivation', 'NegReg', (40, 52))	('result', 'Reg', (65, 71))	('tumor', 'Disease', (183, 188))	('haploinsufficiency', 'Disease', 'MESH:D058495', (135, 153))	('point mutation', 'Var', (77, 91))	('TP53', 'Gene', '7157', (157, 161))
278140	26429873	As expected, we were able to find JAZF1-SUZ12, JAZF1-PHF1 and MEAF6-PHF fusions in each of the three LG-ESSs.	('SUZ12', 'Gene', (40, 45))	('PHF1', 'Gene', '5252', (53, 57))	('JAZF1', 'Gene', (47, 52))	('ESSs', 'Gene', (104, 108))	('JAZF1', 'Gene', (34, 39))	('ESSs', 'Gene', '54539', (104, 108))	('JAZF1', 'Gene', '221895', (47, 52))	('SUZ12', 'Gene', '23512', (40, 45))	('fusions', 'Var', (72, 79))	('PHF1', 'Gene', (53, 57))	('MEAF6', 'Gene', (62, 67))	('MEAF6', 'Gene', '64769', (62, 67))	('JAZF1', 'Gene', '221895', (34, 39))
278142	26429873	We found PPARG and IRF4 mutations in the ESSs.	('PPARG', 'Gene', '5468', (9, 14))	('ESSs', 'Gene', (41, 45))	('PPARG', 'Gene', (9, 14))	('ESSs', 'Gene', '54539', (41, 45))	('IRF4', 'Gene', '3662', (19, 23))	('IRF4', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
278146	26429873	A chromosomal translocation involving IRF4 and the IgH locus, t(6;14)(p25;q32) is considered a cause of multiple myeloma.	('t(6;14)(p25;q32)', 'STRUCTURAL_ABNORMALITY', 'None', (62, 78))	('multiple myeloma', 'Phenotype', 'HP:0006775', (104, 120))	('multiple myeloma', 'Disease', 'MESH:D009101', (104, 120))	('cause', 'Reg', (95, 100))	('multiple myeloma', 'Disease', (104, 120))	('t(6;14)(p25;q32', 'Var', (62, 77))	('IgH', 'Gene', (51, 54))	('IgH', 'Gene', '3492', (51, 54))	('IRF4', 'Gene', '3662', (38, 42))	('IRF4', 'Gene', (38, 42))
278148	26429873	Together, these data suggest a possible rationale that PPARG and IRF4 mutations might be involved in ESS development.	('IRF4', 'Gene', '3662', (65, 69))	('mutations', 'Var', (70, 79))	('IRF4', 'Gene', (65, 69))	('PPARG', 'Gene', (55, 60))	('involved', 'Reg', (89, 97))	('ESS development', 'Disease', (101, 116))	('PPARG', 'Gene', '5468', (55, 60))
278152	26429873	Further investigation with larger sample size across diverse ethnic groups would reveal additional information, e.g., discovery of potential additional driver mutations in ESSs and additional novel fusions in LG-ESSs and HG-ESSs.	('ESSs', 'Gene', (212, 216))	('ESSs', 'Gene', (224, 228))	('ESSs', 'Gene', (172, 176))	('mutations', 'Var', (159, 168))	('ESSs', 'Gene', '54539', (212, 216))	('ESSs', 'Gene', '54539', (224, 228))	('fusions', 'Interaction', (198, 205))	('ESSs', 'Gene', '54539', (172, 176))
278162	26429873	Then, we used the CHASM analysis program with 'uterus' option for cancer tissue type (FDR < 0.3) in order to identify the putative cancer-related mutations.	('cancer', 'Disease', (131, 137))	('mutations', 'Var', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (66, 72))
278190	25184919	Therefore, the association of the clinical data with the histological picture and negativity for HHV-8 favor the diagnosis of acroangiodermatitis.	('acroangiodermatitis', 'Disease', (126, 145))	('HHV-8', 'Species', '37296', (97, 102))	('negativity', 'Var', (82, 92))	('HHV-8', 'Gene', (97, 102))	('acroangiodermatitis', 'Disease', 'None', (126, 145))
278202	25184919	However, negativity for HHV-8, acral location, histological picture of the lesion are features that indicate this diagnosis.	('HHV-8', 'Species', '37296', (24, 29))	('HHV-8', 'Gene', (24, 29))	('negativity', 'Var', (9, 19))
278214	25165661	Immunotyping with CD34 showed positivity in the endothelial cells but negativity in the surrounding parenchyma, which ruled out Kaposi's sarcoma and was consistent with the diagnosis of pseudo-Kaposi's sarcoma [Figure 3].	("pseudo-Kaposi's sarcoma", 'Disease', 'MESH:D012514', (186, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('positivity', 'Var', (30, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (128, 144))	("Kaposi's sarcoma", 'Disease', (128, 144))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (193, 209))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (193, 209))	('CD34', 'Gene', '947', (18, 22))	("pseudo-Kaposi's sarcoma", 'Disease', (186, 209))	('CD34', 'Gene', (18, 22))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (128, 144))
278228	25165661	Erythromycin appears to have anti-inflammatory effect and has been shown to inhibit the chemotaxis of leukocytes, monocytes, and eosinophils.	('inhibit', 'NegReg', (76, 83))	('Erythromycin', 'Chemical', 'MESH:D004917', (0, 12))	('anti-inflammatory effect', 'CPA', (29, 53))	('Erythromycin', 'Var', (0, 12))	('chemotaxis of leukocytes', 'CPA', (88, 112))
278234	22415797	The other issue to be addressed is how to best combine IGF-1R inhibitors with other therapeutic approaches.	('IGF-1R', 'Gene', (55, 61))	('IGF-1R', 'Gene', '3480', (55, 61))	('inhibitors', 'Var', (62, 72))
278240	22415797	Similarly, mammalian target of rapamycin (m-TOR) inhibitors can activate PI3K-Akt pathway via loss of negative feedback on IRS-1 (insulin receptor substrate:1), an effect that can be suppressed by IGF-1R blockade.	('IRS-1', 'Gene', (123, 128))	('insulin receptor substrate:1', 'Gene', '3667', (130, 158))	('IGF-1R', 'Gene', '3480', (197, 203))	('insulin receptor substrate:1', 'Gene', (130, 158))	('loss', 'NegReg', (94, 98))	('Akt', 'Gene', '207', (78, 81))	('IGF-1R', 'Gene', (197, 203))	('negative feedback', 'MPA', (102, 119))	('TOR', 'Gene', (44, 47))	('TOR', 'Gene', '6097', (44, 47))	('mammalian target of rapamycin', 'Gene', '2475', (11, 40))	('mammalian target of rapamycin', 'Gene', (11, 40))	('Akt', 'Gene', (78, 81))	('inhibitors', 'Var', (49, 59))	('IRS-1', 'Gene', '3667', (123, 128))	('activate', 'PosReg', (64, 72))
278249	22415797	The main event following IGF-1R phosphorylation is the stimulation of phophoinositol 3-kinase (PI3K)-Akt signaling pathway, leading to cell survival.	('Akt', 'Gene', '207', (101, 104))	('phosphorylation', 'Var', (32, 47))	('Akt', 'Gene', (101, 104))	('cell survival', 'CPA', (135, 148))	('stimulation', 'PosReg', (55, 66))	('IGF-1R', 'Gene', '3480', (25, 31))	('IGF-1R', 'Gene', (25, 31))
278253	22415797	Low levels of IGF-1R copy number gain were also shown in lung cancer, pancreatic adenocarcinoma and colon cancer.	('IGF-1R', 'Gene', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Low levels of IGF', 'Phenotype', 'HP:0002850', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('pancreatic adenocarcinoma and colon cancer', 'Disease', 'MESH:D010190', (70, 112))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('copy number', 'Var', (21, 32))	('gain', 'PosReg', (33, 37))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (70, 95))	('IGF-1R', 'Gene', '3480', (14, 20))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
278263	22415797	Hyperglycemia was more frequently observed with tyrosine kinase inhibitors.	('Hyperglycemia', 'Disease', 'MESH:D006943', (0, 13))	('observed', 'Reg', (34, 42))	('Hyperglycemia', 'Disease', (0, 13))	('tyrosine', 'Var', (48, 56))	('Hyperglycemia', 'Phenotype', 'HP:0003074', (0, 13))
278267	22415797	Grade 3 thrombocytopenia was considered a DLT with 20 mg/kg of AMG-479 and lymphocyte count decrease occurred in 7 % of the patients treated with CP-751, 871.	('lymphocyte', 'MPA', (75, 85))	('AMG', 'Gene', '265', (63, 66))	('thrombocytopenia', 'Disease', 'MESH:D013921', (8, 24))	('decrease', 'NegReg', (92, 100))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (8, 24))	('CP-751', 'Chemical', '-', (146, 152))	('CP-751', 'Var', (146, 152))	('thrombocytopenia', 'Disease', (8, 24))	('patients', 'Species', '9606', (124, 132))	('lymphocyte count decrease', 'Phenotype', 'HP:0001888', (75, 100))	('AMG', 'Gene', (63, 66))
278273	22415797	As an example IGF-1R gene copy number gain (3 % amplification and 24 % high polysomy) had surprisingly positive prognostic value.	('gain', 'PosReg', (38, 42))	('IGF-1R', 'Gene', (14, 20))	('copy number', 'Var', (26, 37))	('amplification', 'MPA', (48, 61))	('IGF-1R', 'Gene', '3480', (14, 20))
278275	22415797	The predictive value of IGF-1R copy number gain needs further investigation.	('copy number', 'Var', (31, 42))	('gain', 'PosReg', (43, 47))	('IGF-1R', 'Gene', '3480', (24, 30))	('IGF-1R', 'Gene', (24, 30))
278290	22415797	IGF-1R axis alteration were described in many sarcoma subtypes.	('alteration', 'Var', (12, 22))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (46, 62))	('sarcoma subtypes', 'Disease', (46, 62))	('IGF-1R', 'Gene', '3480', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('IGF-1R', 'Gene', (0, 6))	('described', 'Reg', (28, 37))
278293	22415797	In desmoplastic small round cell tumors (DSRCT) EWS-WT1 translocation induces a threefold over-expression of IGF-1R.	('CT', 'Chemical', 'MESH:D002251', (44, 46))	('EWS-WT1', 'Gene', '7490', (48, 55))	('desmoplastic small round cell tumors', 'Disease', (3, 39))	('over-expression', 'PosReg', (90, 105))	('IGF-1R', 'Gene', '3480', (109, 115))	('translocation', 'Var', (56, 69))	('IGF-1R', 'Gene', (109, 115))	('EWS-WT1', 'Gene', (48, 55))	('desmoplastic small round cell tumors', 'Disease', 'MESH:D058405', (3, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))
278294	22415797	Gastrointestinal stromal tumors (GISTs) lacking of KIT and PDGFRalpha mutations presented significantly higher prevalence of IGF-1R amplification compared to mutated ones.	('lacking', 'NegReg', (40, 47))	('IGF-1R', 'Gene', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (70, 79))	('KIT', 'Gene', (51, 54))	('PDGFRalpha', 'Gene', '5156', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('Gastrointestinal stromal tumors', 'Disease', (0, 31))	('PDGFRalpha', 'Gene', (59, 69))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('GISTs', 'Phenotype', 'HP:0100723', (33, 38))	('higher', 'PosReg', (104, 110))	('IGF-1R', 'Gene', '3480', (125, 131))	('amplification', 'MPA', (132, 145))
278295	22415797	High IGF-1 and IGF-2 expression levels were associated to a highly malignant phenotype and negative prognostic value in wild type and mutant GISTs.	('High IGF-1', 'Phenotype', 'HP:0030269', (0, 10))	('IGF-1', 'Gene', '3479', (5, 10))	('expression levels', 'MPA', (21, 38))	('IGF-1', 'Gene', (5, 10))	('GISTs', 'Phenotype', 'HP:0100723', (141, 146))	('IGF-2', 'Gene', (15, 20))	('IGF-2', 'Gene', '3481', (15, 20))	('mutant', 'Var', (134, 140))
278299	22415797	The results of two phase II trials were recently published, evaluating the efficacy and safety of R1507 (robatumumab, a fully human IgG1 mAb to IGF-1R) in recurrent and refractory Ewing's sarcomas and AMG 479 (fully human mAb to IGF-1R) in recurrent refractory Ewing's family of tumors and desmoplastic small round cell tumors (DSRT).	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('human', 'Species', '9606', (216, 221))	('desmoplastic small round cell tumors', 'Disease', 'MESH:D058405', (290, 326))	('AMG', 'Gene', '265', (201, 204))	('IGF-1R', 'Gene', '3480', (144, 150))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (180, 196))	('IGF-1R', 'Gene', (144, 150))	('R1507', 'Var', (98, 103))	("Ewing's family of tumors", 'Disease', (261, 285))	('sarcomas', 'Phenotype', 'HP:0100242', (188, 196))	('desmoplastic small round cell tumors', 'Disease', (290, 326))	("Ewing's sarcomas", 'Disease', (180, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('human', 'Species', '9606', (126, 131))	('robatumumab', 'Chemical', 'MESH:C573312', (105, 116))	('IGF-1R', 'Gene', '3480', (229, 235))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('IGF-1R', 'Gene', (229, 235))	("Ewing's family of tumors", 'Disease', 'MESH:C563168', (261, 285))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('AMG', 'Gene', (201, 204))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (180, 195))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (180, 196))
278300	22415797	In the SARC 001 study 111 Ewing's sarcoma patients were treated with R1507, administered intravenously at 9 mg/kg weekly.	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('R1507', 'Var', (69, 74))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (26, 41))	("Ewing's sarcoma", 'Disease', (26, 41))	('patients', 'Species', '9606', (42, 50))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (26, 41))
278324	22415797	Reciprocal inhibition of ERS1 or IGF-1R transcript levels was produced by siRNA knockdown of one or the other of these targets.	('IGF-1R', 'Gene', '3480', (33, 39))	('knockdown', 'Var', (80, 89))	('IGF-1R', 'Gene', (33, 39))	('transcript levels', 'MPA', (40, 57))	('ERS1', 'Gene', (25, 29))
278325	22415797	Furthermore it was shown in vitro and in vivo synergism of dual targeting of these pathways by fulvestrant or tamoxifen combined with h10H5, an IGF-1R monoclonal antibody.	('IGF-1R', 'Gene', '3480', (144, 150))	('h10H5', 'Var', (134, 139))	('IGF-1R', 'Gene', (144, 150))	('fulvestrant', 'Chemical', 'MESH:D000077267', (95, 106))	('tamoxifen', 'Chemical', 'MESH:D013629', (110, 119))	('h10H5', 'Chemical', '-', (134, 139))
278329	22415797	HER2 heterodimerisation with other members of HER family is a well-known phenomenon.	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('heterodimerisation', 'Var', (5, 23))
278331	22415797	Another mechanism contributing to trastuzumab resistance is p27kip down-regulation and this was stimulated by IGF-1 in some preclinical models.	('IGF-1', 'Gene', (110, 115))	('trastuzumab', 'Chemical', 'MESH:D000068878', (34, 45))	('down-regulation', 'NegReg', (67, 82))	('p27kip', 'Var', (60, 66))	('IGF-1', 'Gene', '3479', (110, 115))
278335	22415797	Additional phase II trials are evaluating the IGF-1R inhibitors associated to endocrine treatment or HER2 inhibitors in advanced breast cancer tumors (Table 2).	('inhibitors', 'Var', (53, 63))	('breast cancer tumors', 'Disease', 'MESH:D001943', (129, 149))	('HER2', 'Gene', (101, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('IGF-1R', 'Gene', '3480', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HER2', 'Gene', '2064', (101, 105))	('IGF-1R', 'Gene', (46, 52))	('breast cancer tumors', 'Disease', (129, 149))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
278348	22415797	This was related to several genetic alterations such as loss of imprinting or loss of heterozygosity of the 11p15 gene locus.	('p15', 'Gene', '1030', (110, 113))	('p15', 'Gene', (110, 113))	('loss', 'NegReg', (56, 60))	('loss', 'Var', (78, 82))
278359	22415797	(Table 3) Aberrant expression of IGF-1R is detected in many cancers.	('IGF-1R', 'Gene', '3480', (33, 39))	('expression', 'MPA', (19, 29))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('IGF-1R', 'Gene', (33, 39))	('cancers', 'Disease', (60, 67))	('Aberrant', 'Var', (10, 18))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('detected', 'Reg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
278365	22415797	(Figure 2) To give an example: sarcoma cell lines resistant to BMS 536924 (small molecule IGF-1R tyrosine kinase inhibitor) expressed high levels of IGFBP-3 and IGFBP-6 whereas the sensitive ones showed high expression level of IGF-1 and IGF-2.	('IGF-1', 'Gene', '3479', (90, 95))	('sarcoma', 'Disease', (31, 38))	('IGFBP-3', 'Gene', '3486', (149, 156))	('IGFBP-6', 'Gene', '3489', (161, 168))	('IGF-1', 'Gene', '3479', (228, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('IGF-1', 'Gene', (228, 233))	('IGFBP-3', 'Gene', (149, 156))	('IGF-2', 'Gene', (238, 243))	('IGFBP-6', 'Gene', (161, 168))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))	('IGF-2', 'Gene', '3481', (238, 243))	('IGF-1R', 'Gene', '3480', (90, 96))	('IGF-1R', 'Gene', (90, 96))	('BMS 536924', 'Var', (63, 73))	('IGF-1', 'Gene', (90, 95))
278372	22415797	On the other hand IGF-1R gene copy number gain was identified in some tumor types, such as wild-type GIST, breast cancer and NSCLC.	('IGF-1R', 'Gene', '3480', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('gain', 'PosReg', (42, 46))	('gene copy number', 'Var', (25, 41))	('IGF-1R', 'Gene', (18, 24))	('NSCLC', 'Disease', (125, 130))	('tumor', 'Disease', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
278374	22415797	IGF-1R phosphorylation leads to the activation of multiple signaling pathways.	('activation', 'PosReg', (36, 46))	('multiple signaling pathways', 'Pathway', (50, 77))	('IGF-1R', 'Gene', '3480', (0, 6))	('phosphorylation', 'Var', (7, 22))	('IGF-1R', 'Gene', (0, 6))
278380	22415797	Parallel inhibition of a second growth factor receptor such as EGFR or HER2 or a concomitant downstream signaling blockade such as m-TOR or PI3K could considerably enhance antitumor activity.	('inhibition', 'NegReg', (9, 19))	('enhance', 'PosReg', (164, 171))	('EGFR', 'Gene', '1956', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PI3K', 'Var', (140, 144))	('EGFR', 'Gene', (63, 67))	('HER2', 'Gene', (71, 75))	('tumor', 'Disease', (176, 181))	('HER2', 'Gene', '2064', (71, 75))	('TOR', 'Gene', '6097', (133, 136))	('TOR', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
278386	22643847	Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation.	('epigenetic events', 'Var', (12, 29))	('neoplastic transformation', 'Disease', 'MESH:D002471', (163, 188))	('Genetic', 'Var', (0, 7))	('differentiation', 'CPA', (91, 106))	('neoplastic transformation', 'Disease', (163, 188))	('normal development', 'CPA', (69, 87))
278394	22643847	Although a theoretically attractive option, differentiation therapy has historically been greatly hampered by both our practical lack of understanding of the biology of normal differentiation pathways as well as by our theoretical inability to envision a methodology that could restore or supersede a tumor's immutable genetic level mutations which result in the lineage specific block to differentiation and subsequent tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (420, 425))	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Disease', (420, 425))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Disease', (301, 306))	('mutations', 'Var', (333, 342))
278409	22643847	Models such as those proposed by Pierce and colleagues have been historically minimized in favor of the more common notions of solid tumorigenesis which hypothesize that mutations occurring in "normal" tissue results in gradual dedifferentiation to cancer cells harboring features of normal tissue reflecting varying degrees of differentiation - a feature invariably linked to cancer aggressiveness.	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('dedifferentiation', 'CPA', (228, 245))	('cancer aggressiveness', 'Disease', (377, 398))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Disease', (249, 255))	('solid tumor', 'Disease', (127, 138))	('solid tumor', 'Disease', 'MESH:D009369', (127, 138))	('aggressiveness', 'Phenotype', 'HP:0000718', (384, 398))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (377, 398))	('cancer', 'Disease', (377, 383))	('cancer', 'Disease', 'MESH:D009369', (377, 383))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
278428	22643847	Sakimura and colleagues observed that intraperitoneal administration of depsipeptide to chondrosarcomas xenografted in nude mice resulted in down-regulated the synthesis of glycosaminoglycans and an elevation of alkaline phosphatase activity; both consistent with chondrosarcoma differentiation.	('alkaline phosphatase activity', 'MPA', (212, 241))	('chondrosarcomas', 'Disease', (88, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('depsipeptide', 'Chemical', 'MESH:D047630', (72, 84))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (264, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (88, 102))	('depsipeptide', 'Var', (72, 84))	('down-regulated', 'NegReg', (141, 155))	('nude mice', 'Species', '10090', (119, 128))	('glycosaminoglycans', 'Chemical', 'MESH:D006025', (173, 191))	('elevation', 'PosReg', (199, 208))	('chondrosarcomas', 'Disease', 'MESH:D002813', (88, 103))	('chondrosarcoma', 'Disease', 'MESH:D002813', (264, 278))	('chondrosarcoma', 'Disease', (264, 278))	('synthesis of glycosaminoglycans', 'MPA', (160, 191))	('chondrosarcoma', 'Disease', 'MESH:D002813', (88, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('chondrosarcoma', 'Disease', (88, 102))
278437	22643847	Levels of the cyclin-dependent kinase inhibitors (CDKIs) p18, p21 and p27 were shown to be increased in all treated RMS cell lines but no CDK4 inhibition or hypophosphorylation of the Rb protein suggesting that ATRA-induced differentiation was not sufficient to induce cell cycle arrest in RMS cells.	('ATRA', 'Chemical', 'MESH:D014212', (211, 215))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (269, 286))	('p27', 'Gene', '3429', (70, 73))	('p27', 'Gene', (70, 73))	('increased', 'PosReg', (91, 100))	('p21', 'Var', (62, 65))	('p18', 'Var', (57, 60))	('CDK4', 'Gene', '1019', (138, 142))	('CDK4', 'Gene', (138, 142))
278446	22643847	Development of knockout mouse models of PPARgamma have revealed its importance in the development of adipose, placental and cardiac tissue as the null-PPARgamma phenotype is embryonic lethal.	('mouse', 'Species', '10090', (24, 29))	('null-PPARgamma', 'Var', (146, 160))	('PPARgamma', 'Gene', (40, 49))
278451	22643847	The combination of TGZ with the RXR agonist, ATRA, had a synergistic effect in irreversibly inhibiting MCF7 growth, reduction of BCL2 expression, and apoptosis of cells.	('MCF7', 'CellLine', 'CVCL:0031', (103, 107))	('BCL2', 'Gene', (129, 133))	('TGZ', 'Var', (19, 22))	('RXR', 'Gene', '6256', (32, 35))	('apoptosis of cells', 'CPA', (150, 168))	('TGZ', 'Chemical', 'MESH:D000077288', (19, 22))	('RXR', 'Gene', (32, 35))	('ATRA', 'Chemical', 'MESH:D014212', (45, 49))	('reduction', 'NegReg', (116, 125))	('BCL2', 'Gene', '596', (129, 133))	('MCF7', 'Gene', (103, 107))	('combination', 'Interaction', (4, 15))	('inhibiting', 'NegReg', (92, 102))
278459	22643847	Forni and colleagues evaluated the effects of trabectedin treatment in myxoid liposarcoma cell lines and found that trabectedin induces the dissociation of TLS-CHOP from target promoter sequences based on a series of chromatin immunoprecipitation experiments.	('trabectedin', 'Var', (116, 127))	('CHOP', 'Gene', (160, 164))	('TLS', 'Gene', (156, 159))	('myxoid liposarcoma cell lines', 'Disease', (71, 100))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (71, 89))	('trabectedin', 'Chemical', 'MESH:D000077606', (46, 57))	('TLS', 'Gene', '2521', (156, 159))	('liposarcoma', 'Phenotype', 'HP:0012034', (78, 89))	('dissociation', 'MPA', (140, 152))	('trabectedin', 'Chemical', 'MESH:D000077606', (116, 127))	('induces', 'Reg', (128, 135))	('CHOP', 'Gene', '1649', (160, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('myxoid liposarcoma cell lines', 'Disease', 'MESH:D018208', (71, 100))
278483	22643847	Our recent work identified that this patient had one specific sub-type of TLS-CHOP (type II) and that this was also the only patient who possessed a mutated form of p53.	('p53', 'Gene', (165, 168))	('CHOP', 'Gene', '1649', (78, 82))	('p53', 'Gene', '7157', (165, 168))	('patient', 'Species', '9606', (37, 44))	('mutated', 'Var', (149, 156))	('CHOP', 'Gene', (78, 82))	('TLS', 'Gene', (74, 77))	('TLS', 'Gene', '2521', (74, 77))	('patient', 'Species', '9606', (125, 132))
278506	22374462	Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, GD2-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres.	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('patient', 'Species', '9606', (81, 88))	('chimeric', 'Var', (10, 18))	('GD2-specific cytolytic responses', 'MPA', (105, 137))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (167, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (167, 180))	('tumour cells', 'Disease', (192, 204))	('tumour cells', 'Disease', 'MESH:C538614', (192, 204))	('gene-modified', 'Var', (28, 41))	('Ewing sarcoma', 'Disease', (167, 180))
278518	22374462	In high-risk neuroblastoma, a highly GD2-expressing malignancy, immunotherapy with a chimeric GD2-specific antibody combined with GM-CSF and IL-2 significantly improved event-free survival.	('neuroblastoma', 'Phenotype', 'HP:0003006', (13, 26))	('GM-CSF', 'Gene', '1437', (130, 136))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('malignancy', 'Disease', (52, 62))	('IL-2', 'Gene', (141, 145))	('IL-2', 'Gene', '3558', (141, 145))	('chimeric', 'Var', (85, 93))	('event-free survival', 'CPA', (169, 188))	('neuroblastoma', 'Disease', 'MESH:D009447', (13, 26))	('improved', 'PosReg', (160, 168))	('neuroblastoma', 'Disease', (13, 26))	('GM-CSF', 'Gene', (130, 136))
278523	22374462	The identity of all cancer cell lines was confirmed by short tandem repeat profiling (Supplementary Figure S1).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('short tandem repeat', 'Var', (55, 74))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))
278543	22374462	T cells were analysed using mAbs against CD3, CD8, CD4, and CD56 (BD Pharmingen).	('CD56', 'Gene', (60, 64))	('CD8', 'Gene', '925', (46, 49))	('CD4', 'Gene', (51, 54))	('CD4', 'Gene', '920', (51, 54))	('CD56', 'Gene', '4684', (60, 64))	('CD8', 'Gene', (46, 49))	('CD3', 'Var', (41, 44))
278564	22374462	G2a in all Ewing sarcoma cell lines (Figure 1A).	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('G2a', 'Var', (0, 3))	('Ewing sarcoma', 'Disease', (11, 24))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (11, 24))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (11, 24))
278584	22374462	ELISpot analysis of a wider range of cell lines revealed significant increases of IFN-gamma-producing cells in cocultures with both GD2int (TC-71) and GD2low (VH-64, A4573, Cado-ES-1, WE-68) Ewing sarcoma cell lines (Figure 3B).	('increases', 'PosReg', (69, 78))	('TC-71', 'CellLine', 'CVCL:2213', (140, 145))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (191, 204))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (191, 204))	('GD2low', 'Var', (151, 157))	('IFN-gamma', 'Gene', '3458', (82, 91))	('IFN-gamma', 'Gene', (82, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('Cado-ES-1', 'Chemical', '-', (173, 182))	('GD2int', 'Var', (132, 138))	('Ewing sarcoma', 'Disease', (191, 204))
278589	22374462	Translation of these findings into novel, GD2-based treatment strategies relies on the sensitivity of primary Ewing sarcoma cells to GD2 targeting and on the capacity of T cells obtained from sarcoma patients to mediate antitumour responses.	('targeting', 'Var', (137, 146))	('patients', 'Species', '9606', (200, 208))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (110, 123))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (110, 123))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('tumour', 'Disease', (224, 230))	('sarcoma', 'Disease', (116, 123))	('sarcoma', 'Disease', (192, 199))	('Ewing sarcoma', 'Disease', (110, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('GD2', 'Gene', (133, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
278629	22374462	A potential explanation is that differentiation-inducing agents present within the serum-containing culture medium may affect GD2 expression via transcriptional and/or epigenetic regulation of enzymes involved in ganglioside metabolism.	('GD2', 'Gene', (126, 129))	('expression', 'MPA', (130, 140))	('transcriptional', 'MPA', (145, 160))	('ganglioside', 'Chemical', 'MESH:D005732', (213, 224))	('affect', 'Reg', (119, 125))	('epigenetic regulation', 'Var', (168, 189))
278773	32859662	In 2015, trabectedin was also approved in the USA based on a pivotal phase III trial, which demonstrated that trabectedin had a significantly longer PFS compared with dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after failure of prior chemotherapy.	('trabectedin', 'Chemical', 'MESH:D000077606', (110, 121))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (220, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('liposarcoma', 'Phenotype', 'HP:0012034', (205, 216))	('liposarcoma', 'Disease', 'MESH:D008080', (205, 216))	('trabectedin', 'Chemical', 'MESH:D000077606', (9, 20))	('dacarbazine', 'Chemical', 'MESH:D003606', (167, 178))	('trabectedin', 'Var', (110, 121))	('PFS', 'MPA', (149, 152))	('patients', 'Species', '9606', (182, 190))	('longer', 'PosReg', (142, 148))	('leiomyosarcoma', 'Disease', (220, 234))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (220, 234))	('liposarcoma', 'Disease', (205, 216))
278872	32555637	These studies provide insight into how KSHV induces KS tumor formation.	('KS tumor', 'Disease', 'MESH:D009369', (52, 60))	('KS tumor', 'Disease', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('KSHV', 'Species', '37296', (39, 43))	('KSHV', 'Var', (39, 43))	('induces', 'Reg', (44, 51))
278876	32555637	Despite being necessary for KS and PEL formation, the mechanisms by which KSHV induces tumor formation in human cells are poorly understood.	('human', 'Species', '9606', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('KSHV', 'Species', '37296', (74, 78))	('KSHV', 'Var', (74, 78))
278878	32555637	Shortening of the telomeres eventually leads to activation of the DNA damage response and the tumor suppressor proteins p53 and Rb.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('p53', 'Gene', '7157', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('Shortening', 'Var', (0, 10))	('activation', 'PosReg', (48, 58))	('p53', 'Gene', (120, 123))	('DNA damage response', 'Pathway', (66, 85))
278943	32555637	In addition, KSHV does not increase telomerase activity in either BECs or LECs during early passage (Fig 4A).	('KSHV', 'Var', (13, 17))	('telomerase', 'Gene', (36, 46))	('LEC', 'Gene', (74, 77))	('KSHV', 'Species', '37296', (13, 17))	('LEC', 'Gene', '6360', (74, 77))	('telomerase', 'Gene', 'None', (36, 46))
278958	32555637	The cells infected with the DeltamiR or the DeltavFLIP viral mutants maintained the normal cell phenotype at late passage while cells infected with a virus lacking vCyclin or a double deletion of vCyclin and vFLIP became flattened and spread out, indicative of senescence (Fig 5A).	('vCyclin', 'Gene', (164, 171))	('spread out', 'CPA', (235, 245))	('vCyclin', 'Gene', (196, 203))	('infected', 'Disease', 'MESH:D007239', (134, 142))	('infected', 'Disease', 'MESH:D007239', (10, 18))	('vCyclin', 'Gene', '4961471', (164, 171))	('infected', 'Disease', (134, 142))	('vCyclin', 'Gene', '4961471', (196, 203))	('infected', 'Disease', (10, 18))	('vFLIP', 'Gene', '4961494', (49, 54))	('double deletion', 'Var', (177, 192))	('lacking', 'NegReg', (156, 163))	('vFLIP', 'Gene', (49, 54))	('mutants', 'Var', (61, 68))	('vFLIP', 'Gene', '4961494', (208, 213))	('vFLIP', 'Gene', (208, 213))
278960	32555637	Fewer than 40% of the LECs infected with either the DeltamiR or the DeltavFLIP viral mutants stained positive for beta-galactosidase activity, indicating that these genes are not required for LECs to bypass senescence (Fig 5B).	('infected', 'Disease', 'MESH:D007239', (27, 35))	('LEC', 'Gene', (192, 195))	('beta-galactosidase', 'Gene', (114, 132))	('LEC', 'Gene', '6360', (192, 195))	('infected', 'Disease', (27, 35))	('LEC', 'Gene', (22, 25))	('LEC', 'Gene', '6360', (22, 25))	('mutants', 'Var', (85, 92))	('vFLIP', 'Gene', '4961494', (73, 78))	('vFLIP', 'Gene', (73, 78))	('beta-galactosidase', 'Gene', '2720', (114, 132))
278990	32555637	STAT3 signaling has been shown to repress p53 expression and activity, thus dysregulation of this pathway may play an important role in regulating cell proliferation and senescence.	('p53', 'Gene', (42, 45))	('repress', 'NegReg', (34, 41))	('p53', 'Gene', '7157', (42, 45))	('cell proliferation', 'CPA', (147, 165))	('senescence', 'CPA', (170, 180))	('STAT3', 'Gene', '6774', (0, 5))	('dysregulation', 'Var', (76, 89))	('play', 'Reg', (110, 114))	('activity', 'MPA', (61, 69))	('STAT3', 'Gene', (0, 5))	('expression', 'MPA', (46, 56))	('rat', 'Species', '10116', (159, 162))
279069	31100962	This was confirmed by CVA21 infecting and causing lysis in each of these cell lines at a multiplicity of infection (MOI) of 1.	('lysis', 'MPA', (50, 55))	('causing', 'Reg', (42, 49))	('CVA21', 'Species', '12069', (22, 27))	('CVA21', 'Var', (22, 27))
279076	31100962	Despite higher Sk-Mel-28 susceptibility to CVA21, Sk-Mel-28 and ME4405 share similar virus replication kinetics.	('ME4405', 'Chemical', '-', (64, 70))	('susceptibility', 'MPA', (25, 39))	('CVA21', 'Species', '12069', (43, 48))	('ME4405', 'Var', (64, 70))	('higher', 'PosReg', (8, 14))
279077	31100962	NOD-SCID mice with melanoma xenografts cleared tumours by day 21 post-infection when given 103 TCID50 CVA21 (TCID:Tissue culture Infective Dose) and remained tumour-free until the end of the trial at day 35.	('tumour-free', 'Disease', 'MESH:D000072662', (158, 169))	('TCID50 CVA21', 'Var', (95, 107))	('melanoma xenografts cleared tumours', 'Disease', 'MESH:D008545', (19, 54))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour-free', 'Disease', (158, 169))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('CVA21', 'Species', '12069', (102, 107))	('SCID', 'Disease', 'MESH:D053632', (4, 8))	('SCID', 'Disease', (4, 8))	('SCID', 'Phenotype', 'HP:0004430', (4, 8))	('melanoma xenografts cleared tumours', 'Disease', (19, 54))	('mice', 'Species', '10090', (9, 13))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
279086	31100962	Bone progenitor cells incubated with CVA21 showed some nonsignificant decrease when compared to phosphate buffered saline (PBS) controls.	('CVA21', 'Species', '12069', (37, 42))	('PBS', 'Disease', 'MESH:D011535', (123, 126))	('phosphate buffered saline', 'Chemical', '-', (96, 121))	('CVA21', 'Var', (37, 42))	('PBS', 'Disease', (123, 126))	('decrease', 'NegReg', (70, 78))
279089	31100962	An MOI of 100 induced extensive lytic destruction in all of the breast cancer cell lines and none of the controls.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('MOI of 100', 'Var', (3, 13))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))	('lytic destruction', 'CPA', (32, 49))
279105	31100962	In a vaccination assay, C56BL/6 mice pretreated with CVA21-lysed MB49-ICAM-1 bladder cancer cells were effectively protected from later challenge with the same cells injected into the opposite flank, compared to 50% of control mice challenged with uninfected lysate.	('CVA21', 'Species', '12069', (53, 58))	('MB49-ICAM-1 bladder cancer', 'Disease', 'MESH:D001749', (65, 91))	('MB', 'Phenotype', 'HP:0002885', (65, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('mice', 'Species', '10090', (227, 231))	('CVA21-lysed', 'Var', (53, 64))	('mice', 'Species', '10090', (32, 36))	('C56BL/6', 'Gene', '12274', (24, 31))	('C56BL/6', 'Gene', (24, 31))	('MB49-ICAM-1 bladder cancer', 'Disease', (65, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
279113	31100962	This was confirmed in vivo where SCID mice with KAS6/1 multiple myeloma xenografts were treated with CVA21 RNA, with CVA21 virions and RNase treated CVA21 RNA as controls.	('SCID', 'Disease', 'MESH:D053632', (33, 37))	('multiple myeloma', 'Disease', 'MESH:D009101', (55, 71))	('SCID', 'Disease', (33, 37))	('CVA21', 'Species', '12069', (149, 154))	('mice', 'Species', '10090', (38, 42))	('multiple myeloma', 'Phenotype', 'HP:0006775', (55, 71))	('SCID', 'Phenotype', 'HP:0004430', (33, 37))	('multiple myeloma', 'Disease', (55, 71))	('myeloma xenografts', 'Disease', (64, 82))	('CVA21 RNA', 'Var', (101, 110))	('myeloma xenografts', 'Disease', 'MESH:D009101', (64, 82))	('CVA21', 'Species', '12069', (117, 122))	('CVA21', 'Species', '12069', (101, 106))
279124	31100962	In a Phase I/II clinical trial on systemic treatment of resistant malignancies (STORM), the enrolled patients with late-stage cancer were grouped into three CAVATAK dose cohorts, low (n = 3, 108 TCID50), medium (n = 3, 3 x 108 TCID50) and high (n = ~80, 109 TCID50).	('late-stage cancer', 'Disease', (115, 132))	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('n = 3', 'Var', (212, 217))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('malignancies', 'Disease', (66, 78))	('n = 3', 'Var', (184, 189))	('late-stage cancer', 'Disease', 'MESH:D009369', (115, 132))
279137	31100962	Of 28 enteroviral strains tested against 12 human cancer cell lines and a bone marrow stroma control cell line, Coxsackievirus strains B2 Ohio-1 (CVB2 Ohio-1), B3 Nancy (CVB3 Nancy) and B4 JBV (CVB4 JBV) stood out as causing cell death in A549 and LK-87 lung cancer cells with no toxicity in controls.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('human', 'Species', '9606', (44, 49))	('cancer', 'Disease', (50, 56))	('CVB3', 'Species', '12072', (170, 174))	('lung cancer', 'Disease', (254, 265))	('bone marrow stroma', 'Disease', 'MESH:D001855', (74, 92))	('A549', 'CellLine', 'CVCL:0023', (239, 243))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cell death', 'CPA', (225, 235))	('bone marrow stroma', 'Disease', (74, 92))	('B3 Nancy', 'Var', (160, 168))	('cancer', 'Disease', (259, 265))	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('causing', 'Reg', (217, 224))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('toxicity', 'Disease', 'MESH:D064420', (280, 288))	('B4 JBV', 'Var', (186, 192))	('CVB2', 'Species', '82639', (146, 150))	('CVB4', 'Species', '12073', (194, 198))	('toxicity', 'Disease', (280, 288))
279138	31100962	In a second screen against nine non-small cell lung cancer cell lines (NSCLC), CVB3 Nancy induced cytolysis in all.	('cytolysis', 'MPA', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('CVB3', 'Species', '12072', (79, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('Nancy', 'Var', (84, 89))	('SCLC', 'Phenotype', 'HP:0030357', (72, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (36, 58))	('cell lung cancer', 'Disease', (42, 58))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (32, 58))	('CVB3', 'Gene', (79, 83))	('NSCLC', 'Disease', (71, 76))	('cell lung cancer', 'Disease', 'MESH:D008175', (42, 58))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
279139	31100962	Infectivity against these cells was directly proportional to the sum of CAR and DAF expression and could be abrogated by siRNA knockdown of CAR.	('CAR', 'Gene', '1525', (140, 143))	('CAR', 'Gene', (140, 143))	('CAR', 'Gene', '1525', (72, 75))	('CAR', 'Gene', (72, 75))	('knockdown', 'Var', (127, 136))	('DAF', 'Gene', '1604', (80, 83))	('DAF', 'Gene', (80, 83))
279150	31100962	Despite showing similar viral titres in treated tumours, mice treated with CVB 31-1-93 died by day six post-infection, and four out of six mice treated with CVB3 Nancy died by day eight.	('mice', 'Species', '10090', (57, 61))	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('CVB3', 'Species', '12072', (157, 161))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('mice', 'Species', '10090', (139, 143))	('CVB 31-1-93', 'Var', (75, 86))	('tumours', 'Disease', 'MESH:D009369', (48, 55))
279155	31100962	When infected by CVB3 2035A at an MOI of 10, there was extensive lytic destruction of all three cell lines and high titres of viral progeny produced after 48 h. Mouse studies showed single infusions of CVB3 2035A could suppress Ishikawa and HEC-1-B tumours significantly, but not HEC-1-A tumours.	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('tumours', 'Phenotype', 'HP:0002664', (288, 295))	('Ishikawa', 'CPA', (228, 236))	('EC', 'Phenotype', 'HP:0012114', (281, 283))	('HEC-1-A tumours', 'Disease', (280, 295))	('HEC-1-A tumours', 'Disease', 'MESH:D009369', (280, 295))	('HEC-1-B tumours', 'Disease', 'MESH:D006509', (241, 256))	('CVB3 2035A', 'Var', (202, 212))	('EC', 'Phenotype', 'HP:0012114', (242, 244))	('h. Mouse', 'Species', '10090', (158, 166))	('CVB3', 'Species', '12072', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (288, 294))	('HEC-1-B tumours', 'Disease', (241, 256))	('CVB3', 'Species', '12072', (202, 206))	('suppress', 'NegReg', (219, 227))	('tumours', 'Phenotype', 'HP:0002664', (249, 256))
279176	31100962	In mice bearing HT1080 sarcoma xenografts, three doses of 106 TCID50 LAPV were sufficient to control tumour growth by 40% and induced cancer cells apoptosis, as shown by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay.	('induced', 'PosReg', (126, 133))	('HT1080', 'CellLine', 'CVCL:0317', (16, 22))	('tumour', 'Disease', (101, 107))	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('TCID50 LAPV', 'Var', (62, 73))	('cancer', 'Disease', (134, 140))	('dUTP', 'Chemical', 'MESH:C027078', (208, 212))	('mice', 'Species', '10090', (3, 7))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('control', 'PosReg', (93, 100))	('sarcoma', 'Disease', (23, 30))	('PV', 'Species', '138950', (71, 73))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
279182	31100962	The PV mutant A133Gmono-cre illustrates another strategy to neuro-attenuate oncolytic PV.	('PV', 'Species', '138950', (4, 6))	('PV', 'Species', '138950', (86, 88))	('mutant A133Gmono-cre', 'Var', (7, 27))	('A133G', 'Mutation', 'rs1260838986', (14, 19))	('A133Gmono-cre', 'Var', (14, 27))
279184	31100962	The rationale for the relocation to the specific spacer site in the 5' UTR was that base substitutions in this region attenuated the wild-type PV but were not genomically stable.	('PV', 'Species', '138950', (143, 145))	('base substitutions', 'Var', (84, 102))	('attenuated', 'NegReg', (118, 128))	('wild-type PV', 'MPA', (133, 145))
279185	31100962	In vitro and in vivo adapted mono-CRE PV isolates accumulated mutations allowing increased replication in neuro-2a neuroblastoma cells.	('PV', 'Species', '138950', (38, 40))	('replication', 'MPA', (91, 102))	('neuro-2a neuroblastoma', 'Disease', 'MESH:D009447', (106, 128))	('neuro-2a neuroblastoma', 'Disease', (106, 128))	('neuroblastoma', 'Phenotype', 'HP:0003006', (115, 128))	('increased', 'PosReg', (81, 90))	('mutations', 'Var', (62, 71))
279186	31100962	One mutation, A133G, was present in both cases, and so A133Gmono-CRE PV was isolated and used in further studies.	('A133G', 'Var', (14, 19))	('PV', 'Species', '138950', (69, 71))	('A133G', 'Mutation', 'rs1260838986', (14, 19))	('A133G', 'Mutation', 'rs1260838986', (55, 60))	('A133Gmono-CRE', 'Var', (55, 68))
279187	31100962	Along with pre-exposure to mono-CRE PV, four intratumoural injections of A133Gmono-CRE PV into neuro-2a xenograft tumours were sufficient to clear tumours in 82% of mice, and also effectively vaccinate against re-challenge with neuro-2a cells.	('tumours', 'Disease', (114, 121))	('mice', 'Species', '10090', (165, 169))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('neuro-2a xenograft tumours', 'Disease', 'MESH:C536203', (95, 121))	('tumours', 'Disease', 'MESH:D009369', (147, 154))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('A133Gmono-CRE', 'Var', (73, 86))	('neuro-2a xenograft tumours', 'Disease', (95, 121))	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('vaccinate', 'Reg', (192, 201))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('A133G', 'Mutation', 'rs1260838986', (73, 78))	('tumour', 'Disease', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumour', 'Disease', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('PV', 'Species', '138950', (87, 89))	('tumours', 'Disease', (147, 154))	('PV', 'Species', '138950', (36, 38))
279193	31100962	PVSRIPO neuro-attenuation is also partly due to the presence of double-stranded RNA binding protein 76 (DRBP76).	('DRBP76', 'Gene', '3609', (104, 110))	('PVS', 'Disease', (0, 3))	('presence', 'Var', (52, 60))	('DRBP76', 'Gene', (104, 110))	('PVS', 'Disease', 'MESH:D018458', (0, 3))
279207	31100962	Athymic mice bearing U87MGDeltaEGFR glioblastoma multiforme tumours were challenged with either a low dose of (107 PFU) or high dose (109 PFU) PVSRIPO.	('PVS', 'Disease', (143, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('glioblastoma multiforme tumours', 'Disease', (36, 67))	('U87MGDeltaEGFR', 'Var', (21, 35))	('PVS', 'Disease', 'MESH:D018458', (143, 146))	('glioblastoma multiforme tumours', 'Disease', 'MESH:D005909', (36, 67))	('U87MG', 'CellLine', 'CVCL:0022', (21, 26))	('109 PFU', 'Var', (134, 141))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('mice', 'Species', '10090', (8, 12))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
279211	31100962	Athymic mice with bilateral HTB-15 astrocytoma tumours treated with 108 TCID50 PVSRIPO in both tumours showed an average of a 45% decrease in tumour mass by day 10, nearly clearing the xenografts by day 28.	('tumour', 'Disease', (142, 148))	('astrocytoma', 'Phenotype', 'HP:0009592', (35, 46))	('PVS', 'Disease', 'MESH:D018458', (79, 82))	('bilateral HTB-15 astrocytoma tumours', 'Disease', 'MESH:D001254', (18, 54))	('tumours', 'Disease', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('decrease', 'NegReg', (130, 138))	('PVS', 'Disease', (79, 82))	('tumours', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('bilateral HTB-15 astrocytoma tumours', 'Disease', (18, 54))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('tumour', 'Disease', (47, 53))	('tumour', 'Disease', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('mice', 'Species', '10090', (8, 12))	('TCID50', 'Var', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
279220	31100962	PVSRIPO has been shown to infect human THP1 macrophages, but unlike many of the cancer cells studied, PVSRIPO infection of macrophages is sublethal and serves to induce expression of major histocompatibility complex class II and costimulatory molecules and further leads to (interferon-beta) IFN-beta, (interleukin-12) IL-12 and (tumor necrosis factor- alpha)TNF-alpha production.	('IFN-beta', 'Gene', '3456', (292, 300))	('human', 'Species', '9606', (33, 38))	('expression', 'MPA', (169, 179))	('induce', 'PosReg', (162, 168))	('tumor necrosis factor- alpha', 'Gene', '7124', (330, 358))	('PVS', 'Disease', 'MESH:D018458', (0, 3))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PVS', 'Disease', 'MESH:D018458', (102, 105))	('tumor necrosis factor- alpha', 'Gene', (330, 358))	('interferon-beta', 'Gene', '3456', (275, 290))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('PVS', 'Disease', (0, 3))	('TNF-alpha', 'Gene', '7124', (359, 368))	('TNF-alpha', 'Gene', (359, 368))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('IFN-beta', 'Gene', (292, 300))	('interferon-beta', 'Gene', (275, 290))	('PVS', 'Disease', (102, 105))	('leads to', 'Reg', (265, 273))	('THP1', 'Gene', '2736', (39, 43))	('THP1', 'Gene', (39, 43))	('infection', 'Var', (110, 119))
279236	31100962	Several echoviruses have been evaluated for selective tropism towards different cancers, including EV7, EV1, EV5, EV12, EV15, EV17, EV26 and EV29.	('EV29', 'Var', (141, 145))	('EV17', 'Var', (126, 130))	('EV26', 'Chemical', '-', (132, 136))	('EV12', 'Chemical', '-', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('EV17', 'Chemical', '-', (126, 130))	('cancers', 'Disease', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('EV15', 'Chemical', '-', (120, 124))	('EV26', 'Var', (132, 136))	('EV15', 'Var', (120, 124))	('EV12', 'Var', (114, 118))	('EV29', 'Chemical', '-', (141, 145))	('EV5', 'Chemical', '-', (109, 112))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
279266	31100962	Consistent with this finding, EV1 was shown to cause cytolysis in a panel of eight ovarian cancer cell lines and ovarian cell spheroids with high expression of alpha2beta1.	('cytolysis', 'MPA', (53, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('EV1', 'Var', (30, 33))	('ovarian cancer', 'Disease', (83, 97))	('alpha2beta1', 'Protein', (160, 171))
279269	31100962	While several prostate cancer cell lines as well as healthy prostate cell lines were also shown to express alpha2beta1, EV1 selectively destroyed the cancer cell lines.	('EV1', 'Var', (120, 123))	('destroyed', 'NegReg', (136, 145))	('prostate cancer', 'Disease', 'MESH:D011471', (14, 29))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('cancer', 'Disease', (150, 156))	('prostate cancer', 'Disease', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('alpha2beta1', 'Protein', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
279277	31100962	At seven days post-infection, treatment with EV1 resulted in a dose-dependent decrease in tumour volume as measured by change in flux with the low dose (103 TCID50) responsible for a 47.38% reduction, the medium dose (105 TCID50) for a 68.5% reduction and a 71.5% reduction in the high dose (107 TCID50) cohort.	('reduction', 'NegReg', (190, 199))	('decrease', 'NegReg', (78, 86))	('EV1', 'Var', (45, 48))	('tumour volume', 'Disease', (90, 103))	('103 TCID50', 'Var', (153, 163))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('flux', 'MPA', (129, 133))	('tumour volume', 'Disease', 'MESH:D009369', (90, 103))
279283	31100962	Finally, the broader oncolytic ability of Echoviruses was tested in a study with viruses including EV12, EV15, EV17, EV26, and EV29 against a selection of six colorectal cell lines.	('EV26', 'Chemical', '-', (117, 121))	('EV29', 'Chemical', '-', (127, 131))	('EV15', 'Chemical', '-', (105, 109))	('EV15', 'Var', (105, 109))	('EV26', 'Var', (117, 121))	('EV17', 'Var', (111, 115))	('EV12', 'Chemical', '-', (99, 103))	('EV17', 'Chemical', '-', (111, 115))	('Echovirus', 'Species', '33758', (42, 51))	('EV29', 'Var', (127, 131))	('EV12', 'Var', (99, 103))
279284	31100962	EV12 attached and caused CPE in five out of six cell lines, with productive replication in four cell lines.	('EV12', 'Var', (0, 4))	('EV12', 'Chemical', '-', (0, 4))	('caused', 'Reg', (18, 24))	('CPE', 'Disease', (25, 28))
279302	31100962	Finally, rabbits injected with F-647a immortalised rabbit T-cells that developed rabbit adult T-cell-like leukaemia showed increased survival when given BEV MZ-468, with treatment animals surviving up to four months until the end of the trial, comparative to control animals which died by day 11.	('increased', 'PosReg', (123, 132))	('rabbit', 'Species', '9986', (51, 57))	('F-647a', 'Var', (31, 37))	('rabbit', 'Species', '9986', (9, 15))	('leukaemia', 'Disease', 'MESH:D007938', (106, 115))	('rabbit', 'Species', '9986', (81, 87))	('leukaemia', 'Disease', (106, 115))	('T-cell-like leukaemia', 'Phenotype', 'HP:0005517', (94, 115))	('rabbits', 'Species', '9986', (9, 16))
279304	31100962	The selective oncolytic activity of SVV was implied to be receptor-mediated, as transfection of resistant cells with SVV genomic RNA resulted in productive infection.	('SVV', 'Species', '390157', (117, 120))	('productive infection', 'CPA', (145, 165))	('SVV', 'Species', '390157', (36, 39))	('resulted in', 'Reg', (133, 144))	('transfection', 'Var', (80, 92))	('SVV', 'Gene', (117, 120))
279307	31100962	Moreover, ANTXR1 knockout mutations protected SVV-susceptible cells in vitro and in mice models, conclusively showing that the cellular receptor for SVV is ANTXR1.	('SVV', 'Species', '390157', (46, 49))	('mutations', 'Var', (26, 35))	('ANTXR1', 'Gene', (10, 16))	('SVV', 'Species', '390157', (149, 152))	('mice', 'Species', '10090', (84, 88))
279316	31100962	Similarly, when athymic mice with Y79 retinoblastoma xenograft tumours were treated with 108, 1011 or 1014 vp/kg SVV, six of eight, seven of seven and five of seven mice, respectively, cleared the tumours.	('tumours', 'Disease', (63, 70))	('1014 vp/kg', 'Var', (102, 112))	('mice', 'Species', '10090', (165, 169))	('tumours', 'Disease', (197, 204))	('mice', 'Species', '10090', (24, 28))	('tumours', 'Disease', 'MESH:D009369', (197, 204))	('108', 'Var', (89, 92))	('retinoblastoma', 'Phenotype', 'HP:0009919', (38, 52))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('Y79 retinoblastoma xenograft tumours', 'Disease', 'MESH:D012175', (34, 70))	('SVV', 'Species', '390157', (113, 116))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('Y79 retinoblastoma xenograft tumours', 'Disease', (34, 70))	('tumours', 'Phenotype', 'HP:0002664', (197, 204))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
279319	31100962	These findings were consistent with in vivo trials of immuno-deficient mice challenged with intraocular Y79 xenografts, where 19 of 20 tumours were successfully treated by a single injection of 1013 vp/kg SVV.	('mice', 'Species', '10090', (71, 75))	('SVV', 'Species', '390157', (205, 208))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', (135, 142))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('1013 vp/kg', 'Var', (194, 204))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
279333	31100962	While classic primary cultures were completely refractory, variant cultures were highly sensitive to SVV infection with EC50 (effective viral concentrations to cause lysis in 50% of cells) values of 1.6 x 10-3 vp/cell, 3.1 x 10-4 vp/cell and 3.9 x 10-3 vp/cell, respectively.	('EC', 'Phenotype', 'HP:0012114', (120, 122))	('SVV infection', 'Disease', (101, 114))	('SVV infection', 'Disease', 'MESH:D007239', (101, 114))	('variant', 'Var', (59, 66))
279335	31100962	Furthermore, mouse models challenged with classical SCLC xenografts were completely resistant to SVV, while the variant transplants were significantly suppressed for the duration of the trial.	('mouse', 'Species', '10090', (13, 18))	('SCLC', 'Gene', '7864', (52, 56))	('SCLC', 'Phenotype', 'HP:0030357', (52, 56))	('SCLC', 'Gene', (52, 56))	('variant', 'Var', (112, 119))	('SVV', 'Species', '390157', (97, 100))
279336	31100962	Investigations into SVV treatment dose showed that mice bearing LX36 tumours had similar responses of tumour suppression when treated with 109 to 1011 vp/kg SVV, and two out of six mice completely cleared tumours when treated with 1014 vp/kg SVV.	('tumour suppression', 'Disease', (102, 120))	('tumours', 'Disease', (69, 76))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('mice', 'Species', '10090', (181, 185))	('tumours', 'Disease', 'MESH:D009369', (205, 212))	('tumour suppression', 'Disease', 'OMIM:146850', (102, 120))	('tumours', 'Disease', (205, 212))	('mice', 'Species', '10090', (51, 55))	('SVV', 'Species', '390157', (242, 245))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('SVV', 'Species', '390157', (20, 23))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('SVV', 'Species', '390157', (157, 160))	('tumours', 'Disease', 'MESH:D009369', (69, 76))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('LX36', 'Var', (64, 68))
279356	31100962	In part A of the trial, 13 patients were injected with 109, 1010 or 1011 vp/kg NTX-010, and in part B, patients were given oral (days 1 to 14) and intravenous (days 1 and 8) cyclophosphamide, in combination with two doses of 1011 vp/kg NTX-010.	('NTX-010', 'Chemical', '-', (79, 86))	('NTX-010', 'Gene', (79, 86))	('patients', 'Species', '9606', (27, 35))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (174, 190))	('NTX-010', 'Chemical', '-', (236, 243))	('109', 'Var', (55, 58))	('patients', 'Species', '9606', (103, 111))
279370	31100962	Despite attenuation, TMEV-OVA has been shown to generate increased levels of OVA-specific cytotoxic T-lymphocytes (CTLs) in vivo, increasing survival time and delaying tumour outgrowth in mice with established OVA-expressing B16 melanoma.	('mice', 'Species', '10090', (188, 192))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('tumour outgrowth', 'Disease', 'MESH:D009369', (168, 184))	('melanoma', 'Disease', (229, 237))	('TMEV', 'Species', '12124', (21, 25))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('increasing', 'PosReg', (130, 140))	('TMEV-OVA', 'Var', (21, 29))	('levels', 'MPA', (67, 73))	('melanoma', 'Disease', 'MESH:D008545', (229, 237))	('tumour outgrowth', 'Phenotype', 'HP:0001548', (168, 184))	('delaying', 'NegReg', (159, 167))	('tumour outgrowth', 'Disease', (168, 184))	('increased', 'PosReg', (57, 66))	('survival time', 'CPA', (141, 154))
279374	31100962	To confirm that the immunisation process can work for weakly immunogenic tumour antigen, TMEV expressing p66 was infected into a mouse breast cancer model, and three out of ten treated mice cleared tumours.	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('immunogenic tumour', 'Disease', (61, 79))	('p66', 'Var', (105, 108))	('tumours', 'Disease', 'MESH:D009369', (198, 205))	('TMEV', 'Species', '12124', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mice', 'Species', '10090', (185, 189))	('tumours', 'Disease', (198, 205))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('mouse', 'Species', '10090', (129, 134))	('breast cancer', 'Disease', (135, 148))	('immunogenic tumour', 'Disease', 'MESH:D009369', (61, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
279386	31100962	In vivo, GD7-KS1 significantly delayed B16 tumour outgrowth and increased survival when compared to DA strain and vehicle controls.	('survival', 'CPA', (74, 82))	('tumour outgrowth', 'Phenotype', 'HP:0001548', (43, 59))	('tumour outgrowth', 'Disease', (43, 59))	('delayed', 'NegReg', (31, 38))	('tumour outgrowth', 'Disease', 'MESH:D009369', (43, 59))	('increased', 'PosReg', (64, 73))	('GD7-KS1', 'Var', (9, 16))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))
279398	31100962	Indeed, inhibition of NFkappaB signalling reduced CCRCC susceptibility to EMCV by promoting apoptosis.	('reduced', 'NegReg', (42, 49))	('apoptosis', 'CPA', (92, 101))	('EMCV', 'Species', '12104', (74, 78))	('promoting', 'PosReg', (82, 91))	('inhibition', 'Var', (8, 18))	('CCRCC', 'Phenotype', 'HP:0006770', (50, 55))	('CCRCC', 'Disease', (50, 55))	('NFkappaB', 'Protein', (22, 30))
279408	31100962	BALB/c mice bearing MPC-11 tumours were treated with either a single intravenous (IV) injection of 107 TCID50 vMC24 or intratumoural (IT) injection of 106 TCID50 vMC24.	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('mice', 'Species', '10090', (7, 11))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('MPC-11 tumours', 'Disease', 'MESH:C567449', (20, 34))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('vMC24', 'Chemical', '-', (162, 167))	('tumour', 'Disease', (27, 33))	('vMC24', 'Chemical', '-', (110, 115))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('TCID50 vMC24', 'Var', (103, 115))	('MPC-11 tumours', 'Disease', (20, 34))	('tumour', 'Disease', (124, 130))
279413	31100962	Multiple vMC24 variants with complementary micro-RNA sequences (miRT viruses) were generated.	('vMC24', 'Gene', (9, 14))	('variants', 'Var', (15, 23))	('vMC24', 'Chemical', '-', (9, 14))
279414	31100962	The miRT viruses had combinations of miR125b (expressed in brain tissue), miR124 (expressed in neurons), miR133 and miR208a (enriched in cardiomyoctyes).	('cardiomyoctyes', 'Disease', 'None', (137, 151))	('miR133', 'Var', (105, 111))	('miR124', 'Var', (74, 80))	('miR208a', 'Var', (116, 123))	('cardiomyoctyes', 'Disease', (137, 151))	('miR125b', 'Var', (37, 44))
279416	31100962	vMC24-NC had two miR124 sequences in the 5' UTR, and one miR133b and one miR208a in the 3' UTR.	('miR133b', 'Gene', (57, 64))	('miR133b', 'Gene', '723817', (57, 64))	('vMC24', 'Chemical', '-', (0, 5))	('miR124', 'Var', (17, 23))
279417	31100962	In vivo experiments with mice bearing MPC-11 tumours showed that four of ten mice treated with vMC24-NC cleared tumours and two delayed tumour growth, with no negative side-effects.	('vMC24-NC', 'Var', (95, 103))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', (45, 51))	('MPC-11 tumours', 'Disease', (38, 52))	('mice', 'Species', '10090', (77, 81))	('vMC24', 'Chemical', '-', (95, 100))	('tumours', 'Disease', (112, 119))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('mice', 'Species', '10090', (25, 29))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (112, 118))	('MPC-11 tumours', 'Disease', 'MESH:C567449', (38, 52))	('tumour', 'Disease', (136, 142))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('tumours', 'Disease', (45, 52))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (45, 52))
279418	31100962	The mice treated with vMC24 had a rapid tumour regression, but seven out of ten developed paralysis.	('paralysis', 'Phenotype', 'HP:0003470', (90, 99))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('mice', 'Species', '10090', (4, 8))	('paralysis', 'Disease', 'MESH:D010243', (90, 99))	('tumour', 'Disease', (40, 46))	('vMC24', 'Var', (22, 27))	('paralysis', 'Disease', (90, 99))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('vMC24', 'Chemical', '-', (22, 27))
279419	31100962	Furthermore, vMC24-NC was also shown to eliminate tumours in a dose-dependent manner while remaining genetically stable in vivo.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('vMC24', 'Chemical', '-', (13, 18))	('tumours', 'Disease', (50, 57))	('vMC24-NC', 'Var', (13, 21))	('eliminate', 'NegReg', (40, 49))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
279442	28557016	LMS accounts for 15%-30% of RP sarcomas, and patients with RP LMS have a significant risk of distant metastasis (>50%) but a lower risk of local recurrence than patients with other RP sarcomas, particularly in comparison to RP liposarcomas which have a predominantly local pattern of recurrence.	('liposarcomas', 'Disease', (227, 239))	('RP sarcomas', 'Disease', (28, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('liposarcomas', 'Disease', 'MESH:D008080', (227, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (231, 238))	('sarcomas', 'Phenotype', 'HP:0100242', (231, 239))	('patients', 'Species', '9606', (161, 169))	('RP LMS', 'Var', (59, 65))	('RP sarcomas', 'Disease', 'MESH:C538365', (181, 192))	('patients', 'Species', '9606', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('liposarcomas', 'Phenotype', 'HP:0012034', (227, 239))	('sarcomas', 'Phenotype', 'HP:0100242', (184, 192))	('RP sarcomas', 'Disease', 'MESH:C538365', (28, 39))	('RP sarcomas', 'Disease', (181, 192))	('distant metastasis', 'CPA', (93, 111))	('liposarcoma', 'Phenotype', 'HP:0012034', (227, 238))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
279566	28284028	Indicative of the role latent genes have in KSHV tumorigenesis, expression of the latency locus in B-cells in C57BL/6 mice led to a significant increase of lymphomas and hyperplasia in mice.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mice', 'Species', '10090', (185, 189))	('tumor', 'Disease', (49, 54))	('KSHV', 'Species', '37296', (44, 48))	('expression', 'Var', (64, 74))	('lymphomas', 'Phenotype', 'HP:0002665', (156, 165))	('mice', 'Species', '10090', (118, 122))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))	('increase of lymphomas and hyperplasia', 'Disease', 'MESH:D006965', (144, 181))	('KS', 'Phenotype', 'HP:0100726', (44, 46))
279585	28284028	The activation of mTORC1 promotes protein synthesis by activating several translation initiation factors.	('translation initiation factors', 'MPA', (74, 104))	('mTORC1', 'Gene', (18, 24))	('promotes', 'PosReg', (25, 33))	('activation', 'Var', (4, 14))	('activating', 'PosReg', (55, 65))	('mTORC1', 'Gene', '382056', (18, 24))	('protein synthesis', 'MPA', (34, 51))
279590	28284028	In non-viral cancers many genes within the PI3K/Akt/mTOR pathway are mutated to prevent the shutdown of this pathway, while in viral cancers oncogenic viral proteins activate this pathway at the protein level.	('mTOR', 'Gene', (52, 56))	('Akt', 'Gene', (48, 51))	('mTOR', 'Gene', '2475', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('non-viral cancers', 'Disease', (3, 20))	('mutated', 'Var', (69, 76))	('shutdown', 'MPA', (92, 100))	('non-viral cancers', 'Disease', 'MESH:D016751', (3, 20))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('viral cancers oncogenic viral proteins', 'Disease', (127, 165))	('viral cancers oncogenic viral proteins', 'Disease', 'MESH:D001102', (127, 165))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('Akt', 'Gene', '207', (48, 51))	('prevent', 'NegReg', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
279598	28284028	ERK1/2 achieves this by activating the p90 S6 kinase (RSK) leading to the phosphorylation of S6 and eIF4B, or by promoting the activation of the transcription factor activator protein 1 (AP-1).	('phosphorylation', 'MPA', (74, 89))	('AP-1', 'Gene', (187, 191))	('activator protein 1', 'Gene', '3725', (166, 185))	('ERK1/2', 'Gene', (0, 6))	('ERK1/2', 'Gene', '5595;5594', (0, 6))	('activating', 'PosReg', (24, 34))	('activator protein 1', 'Gene', (166, 185))	('RSK', 'Gene', '6196', (54, 57))	('eIF4B', 'Gene', '1975', (100, 105))	('AP-1', 'Gene', '3725', (187, 191))	('activation', 'PosReg', (127, 137))	('RSK', 'Gene', (54, 57))	('eIF4B', 'Gene', (100, 105))	('promoting', 'PosReg', (113, 122))	('p90', 'Var', (39, 42))
279604	28284028	Cross-inhibition can also occur within the two pathways as Akt can phosphorylate inactivating residues on Raf.	('Akt', 'Gene', (59, 62))	('Raf', 'Gene', '22882', (106, 109))	('Raf', 'Gene', (106, 109))	('Akt', 'Gene', '207', (59, 62))	('inactivating', 'Var', (81, 93))
279608	28284028	Low doses of NVP-BEZ235, a dual inhibitor that targets both PI3K and mTOR resulted in apoptosis in PEL cells.	('mTOR', 'Gene', (69, 73))	('BEZ235', 'Chemical', 'MESH:C531198', (17, 23))	('PEL', 'Phenotype', 'HP:0030069', (99, 102))	('NVP-BEZ235', 'Var', (13, 23))	('mTOR', 'Gene', '2475', (69, 73))
279614	28284028	While there is less clinical work performed showing the efficacy of MAPK/ERK inhibitors in treating KSHV diseases, the use of MAPK inhibitors in vitro attenuates de novo infection of endothelial cells and proper reactivation from latency in PEL cells.	('MAPK', 'Gene', '5595;5594;5595', (68, 72))	('ERK', 'Gene', '5594', (73, 76))	('PEL', 'Phenotype', 'HP:0030069', (241, 244))	('attenuates', 'NegReg', (151, 161))	('ERK', 'Gene', (73, 76))	('reactivation', 'CPA', (212, 224))	('de novo infection', 'CPA', (162, 179))	('MAPK', 'Gene', (126, 130))	('MAPK', 'Gene', '5595;5594;5595', (126, 130))	('KS', 'Phenotype', 'HP:0100726', (100, 102))	('KSHV diseases', 'Disease', 'MESH:C537372', (100, 113))	('inhibitors', 'Var', (131, 141))	('KSHV diseases', 'Disease', (100, 113))	('MAPK', 'Gene', (68, 72))
279624	28284028	Cells infected with a mutant KSHV virus lacking K1 had attenuated activation of Akt following reactivation.	('lacking', 'NegReg', (40, 47))	('Akt', 'Gene', '207', (80, 83))	('attenuated', 'NegReg', (55, 65))	('activation', 'MPA', (66, 76))	('Akt', 'Gene', (80, 83))	('KS', 'Phenotype', 'HP:0100726', (29, 31))	('KSHV', 'Species', '37296', (29, 33))	('mutant', 'Var', (22, 28))	('KSHV', 'Gene', (29, 33))
279625	28284028	Moreover, it was recently shown that K1 also enhances survival of KSHV infected cells through AMPK.	('KS', 'Phenotype', 'HP:0100726', (66, 68))	('KSHV', 'Species', '37296', (66, 70))	('AMPK', 'Var', (94, 98))	('enhances', 'PosReg', (45, 53))	('survival', 'CPA', (54, 62))
279629	28284028	K15 activates the MAPK/ERK pathway, but through MEK1/2 in a TNF receptor-associated factor 2 (TRAF-2) dependent manner.	('MEK1/2', 'Gene', (48, 54))	('TRAF-2', 'Gene', '7186', (94, 100))	('TNF receptor-associated factor 2', 'Gene', '7186', (60, 92))	('K15', 'Var', (0, 3))	('MAPK', 'Gene', (18, 22))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'Gene', (23, 26))	('TRAF-2', 'Gene', (94, 100))	('MAPK', 'Gene', '5595;5594;5595', (18, 22))	('activates', 'PosReg', (4, 13))	('TNF receptor-associated factor 2', 'Gene', (60, 92))	('MEK1/2', 'Gene', '5604;5605', (48, 54))
279637	28284028	Knockdown of vGPCR also severely attenuated tumor growth and secretion of VEGF in a mouse model where endothelial cells transfected with a bacterial artificial chromosome encoding KSHV were injected into nude mice.	('nude mice', 'Species', '10090', (204, 213))	('Knockdown', 'Var', (0, 9))	('KS', 'Phenotype', 'HP:0100726', (180, 182))	('KSHV', 'Species', '37296', (180, 184))	('vGPCR', 'Gene', '4961465', (13, 18))	('attenuated tumor', 'Disease', (33, 49))	('attenuated tumor', 'Disease', 'MESH:C538265', (33, 49))	('mouse', 'Species', '10090', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('secretion of VEGF', 'MPA', (61, 78))	('vGPCR', 'Gene', (13, 18))
279652	28284028	Overexpression of vPK in cells augmented anchorage-independent growth, angiogenesis, and cell proliferation as well.	('cell proliferation', 'CPA', (89, 107))	('augmented', 'PosReg', (31, 40))	('angiogenesis', 'CPA', (71, 83))	('anchorage-independent growth', 'CPA', (41, 69))	('vPK', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))	('men', 'Species', '9606', (34, 37))
279667	28284028	Suggestive of ORF45's role in mediating protein synthesis, expression of ORF45 promotes the association of cellular and viral mRNAs with higher 5' UTR complexity to polysomes.	('ORF45', 'Gene', '4961474', (14, 19))	('higher', 'PosReg', (137, 143))	('ORF45', 'Gene', (14, 19))	('promotes', 'PosReg', (79, 87))	('ORF45', 'Gene', '4961474', (73, 78))	('ORF45', 'Gene', (73, 78))	('cellular', 'Protein', (107, 115))	('expression', 'Var', (59, 69))	('association', 'Interaction', (92, 103))
279670	28284028	Inhibition of these pathways by biochemical means or drug treatment often attenuates viral replication and/or induces cell death in KSHV-infected cells.	('men', 'Species', '9606', (63, 66))	('KSHV-infected', 'Disease', (132, 145))	('KSHV-infected', 'Disease', 'MESH:C537372', (132, 145))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('Inhibition', 'Var', (0, 10))	('induces', 'Reg', (110, 117))	('cell death', 'CPA', (118, 128))	('attenuates', 'NegReg', (74, 84))	('viral replication', 'CPA', (85, 102))
279687	33047515	Epigenomic alterations Heritable change that does not affect the DNA sequence but results in a change in gene expression.	('gene expression', 'MPA', (105, 120))	('change', 'Reg', (95, 101))	('Epigenomic alterations', 'Var', (0, 22))	('rat', 'Species', '10116', (15, 18))
279689	33047515	Genomic alterations Permanent modifications in the DNA sequence including somatic mutations, copy-number variations (CNVs), and gene fusions.	('copy-number variations', 'Var', (93, 115))	('modifications', 'Reg', (30, 43))	('gene fusions', 'Var', (128, 140))	('rat', 'Species', '10116', (12, 15))
279718	33047515	The expression of these factors in sarcomas is oncogene-driven and triggered by a combination of mutational and epigenetic events or by developmental programs (Rodriguez et al, 2012; Xiao et al, 2013).	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('triggered by', 'Reg', (67, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('mutational', 'Var', (97, 107))	('sarcomas', 'Disease', (35, 43))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))
279751	33047515	Finally, the detection of low CD3+ or CD4+ TILs was significantly correlated with better overall survival by a univariate analysis (D'Angelo et al, 2015).	('CD4', 'Gene', (38, 41))	('better', 'PosReg', (82, 88))	('CD4', 'Gene', '920', (38, 41))	('CD3+', 'Var', (30, 34))	('low CD3+', 'Var', (26, 34))	('overall survival', 'CPA', (89, 105))
279758	33047515	Whether this holds true for translocation-driven sarcomas, such as alveolar rhabdomyosarcoma (ARMS), EwS, myxoid LPS, and SS, which display rather "silent" genomes, remains to be determined.	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (67, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('translocation-driven', 'Var', (28, 48))	('EwS', 'Phenotype', 'HP:0012254', (101, 104))	('sarcomas', 'Disease', (49, 57))	('EwS', 'Gene', '2130', (101, 104))	('ARMS', 'Phenotype', 'HP:0006779', (94, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (76, 92))	('alveolar rhabdomyosarcoma', 'Disease', (67, 92))	('LPS', 'Disease', (113, 116))	('EwS', 'Gene', (101, 104))	('LPS', 'Disease', 'MESH:C536528', (113, 116))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (67, 92))	('rat', 'Species', '10116', (140, 143))	('LPS', 'Phenotype', 'HP:0012034', (113, 116))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))
279760	33047515	Although the adaptation of tumor cells to in vitro cell culture is accompanied by additional genetic mutations, these rather low-passaged CHS cell lines retained the most relevant mutations of the patient's founder clone (Rey et al, 2019).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patient', 'Species', '9606', (197, 204))	('mutations', 'Var', (101, 110))	('mutations', 'Var', (180, 189))	('rat', 'Species', '10116', (118, 121))	('tumor', 'Disease', (27, 32))	('CHS', 'Phenotype', 'HP:0006765', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CHS', 'Disease', (138, 141))	('CHS', 'Disease', 'MESH:D002609', (138, 141))
279775	33047515	More recent models include deletion of Tp53, Rb, Prx-1, or Prkar1a; overexpression of Sonic Hedgehog signaling components; or targeting Apc and Twist, and lead to the formation of metastatic OS (Jacques et al, 2018).	('Sonic Hedgehog', 'Gene', '6469', (86, 100))	('OS', 'Phenotype', 'HP:0002669', (191, 193))	('Tp53', 'Gene', '7157', (39, 43))	('Prx-1', 'Gene', (49, 54))	('Twist', 'Gene', '7291', (144, 149))	('Apc', 'Gene', '324', (136, 139))	('Prx-1', 'Gene', '5052', (49, 54))	('Sonic Hedgehog', 'Gene', (86, 100))	('Twist', 'Gene', (144, 149))	('deletion', 'Var', (27, 35))	('overexpression', 'PosReg', (68, 82))	('metastatic OS', 'CPA', (180, 193))	('Prkar1a', 'Gene', '5573', (59, 66))	('lead to', 'Reg', (155, 162))	('Apc', 'Gene', (136, 139))	('Tp53', 'Gene', (39, 43))	('Prkar1a', 'Gene', (59, 66))
279777	33047515	For example, the conditional Pax3-Fkhr knock-in allele is associated with the development of ARMS with a frequency that can be increased by the loss of function of Ink4a/ARF and Tp53 (Keller et al, 2004).	('Ink4a/ARF', 'Gene', (164, 173))	('associated with', 'Reg', (58, 73))	('Pax3', 'Gene', '5077', (29, 33))	('loss of function', 'NegReg', (144, 160))	('Tp53', 'Gene', (178, 182))	('ARMS', 'Phenotype', 'HP:0006779', (93, 97))	('Pax3', 'Gene', (29, 33))	('Fkhr', 'Gene', (34, 38))	('Tp53', 'Gene', '7157', (178, 182))	('Fkhr', 'Gene', '2308', (34, 38))	('knock-in', 'Var', (39, 47))	('Ink4a/ARF', 'Gene', '1029', (164, 173))
279778	33047515	The latter model has also helped to demonstrate that Hedgehog signaling drives aberrant expression of myogenic specification factors, which may induce ERMS from non-myogenic endothelial progenitors (Drummond et al, 2018).	('induce', 'PosReg', (144, 150))	('aberrant', 'Var', (79, 87))	('ERMS', 'Disease', (151, 155))	('rat', 'Species', '10116', (43, 46))	('myogenic specification factors', 'Gene', (102, 132))	('expression', 'MPA', (88, 98))	('ERMS', 'Phenotype', 'HP:0006743', (151, 155))
279799	33047515	In fact, 90% of GISTs harbor driver mutations in the KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor alpha (PDGFRA), which can be targeted by tyrosine kinase inhibitors (TKIs).	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (107, 152))	('receptor tyrosine kinase', 'Gene', (72, 96))	('mutations', 'Var', (36, 45))	('platelet-derived growth factor receptor alpha', 'Gene', (107, 152))	('receptor tyrosine kinase', 'Gene', '5979', (72, 96))	('KIT', 'Gene', (98, 101))	('PDGFRA', 'Gene', (154, 160))	('GISTs', 'Phenotype', 'HP:0100723', (16, 21))	('PDGFRA', 'Gene', '5156', (154, 160))
279805	33047515	In addition, resistance to conventional TKIs (e.g., imatinib) is associated with secondary mutations of KIT or PDGFRA in GIST (see section "Resistance to targeted therapies").	('KIT', 'Gene', (104, 107))	('imatinib', 'Chemical', 'MESH:D000068877', (52, 60))	('PDGFRA', 'Gene', '5156', (111, 117))	('PDGFRA', 'Gene', (111, 117))	('associated', 'Reg', (65, 75))	('mutations', 'Var', (91, 100))
279807	33047515	The Asp842Val (D842V) mutation of PDGFRA was identified as the primary driver mutation in 5-6% of GISTs, which are refractory to all currently approved TKIs (Corless et al, 2005).	('GISTs', 'Phenotype', 'HP:0100723', (98, 103))	('D842V', 'Mutation', 'rs121908585', (15, 20))	('Asp842Val', 'SUBSTITUTION', 'None', (4, 13))	('Asp842Val', 'Var', (4, 13))	('PDGFRA', 'Gene', '5156', (34, 40))	('PDGFRA', 'Gene', (34, 40))
279808	33047515	The D842V mutation is located in the exon 18 encoding the PDGFRA activation loop and modifies the protein conformation to a "constitutive" active form.	('PDGFRA', 'Gene', (58, 64))	('D842V', 'Var', (4, 9))	('PDGFRA', 'Gene', '5156', (58, 64))	('modifies', 'Reg', (85, 93))	('D842V', 'Mutation', 'rs121908585', (4, 9))	('protein', 'Protein', (98, 105))
279811	33047515	Ripretinib:an inhibitor of all known KIT and PDGFRA mutations:forces the switching of the mutated receptors to assume the "off" position.	('mutations', 'Var', (52, 61))	('PDGFRA', 'Gene', (45, 51))	('PDGFRA', 'Gene', '5156', (45, 51))	('KIT', 'Gene', (37, 40))	('switching', 'MPA', (73, 82))	('Ripretinib', 'Chemical', '-', (0, 10))
279813	33047515	Similarly, the classification of BRAF mutations, the knowledge about dysregulated signaling pathways and dysregulated circuitries related to these mutations, and the function of BRAF in sarcoma led to the development of new therapeutic options to overcome resistance to conventional chemotherapy.	('BRAF', 'Gene', (178, 182))	('BRAF', 'Gene', '673', (33, 37))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('BRAF', 'Gene', (33, 37))	('sarcoma', 'Disease', (186, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('BRAF', 'Gene', '673', (178, 182))	('mutations', 'Var', (38, 47))
279814	33047515	For instance, the BRAF V600E mutation was recently identified as a potential therapeutic target in a small subset of SS (Watanabe et al, 2020).	('V600E', 'Mutation', 'rs113488022', (23, 28))	('BRAF', 'Gene', (18, 22))	('V600E', 'Var', (23, 28))	('BRAF', 'Gene', '673', (18, 22))
279815	33047515	It is interesting to note that resistance to BRAF mutation inhibitors may be overcome by combining BRAF inhibitors with EGFR, PI3K, mTOR, MEK, RTK, HGF, and MET inhibitors, leading to the targeting of the MAPK and PI3K-AKT-mTOR signaling pathways (Liu et al, 2020).	('mTOR', 'Gene', '2475', (132, 136))	('inhibitors', 'Var', (104, 114))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('MEK', 'Gene', '5609', (138, 141))	('mTOR', 'Gene', (223, 227))	('EGFR', 'Gene', (120, 124))	('AKT', 'Gene', (219, 222))	('MET', 'Gene', (157, 160))	('MEK', 'Gene', (138, 141))	('HGF', 'Gene', '3082', (148, 151))	('mTOR', 'Gene', '2475', (223, 227))	('mTOR', 'Gene', (132, 136))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('HGF', 'Gene', (148, 151))	('EGFR', 'Gene', '1956', (120, 124))	('AKT', 'Gene', '207', (219, 222))	('MET', 'Gene', '79811', (157, 160))
279818	33047515	The inhibition of haspin reduced cancer cell proliferation and regulated the immune system by increasing the frequency of interferon gamma (IFNgamma)-producing CD8+ T cells and reducing the number of Tregs in vivo (Melms et al, 2019).	('rat', 'Species', '10116', (52, 55))	('CD8', 'Gene', '925', (160, 163))	('reduced', 'NegReg', (25, 32))	('haspin', 'Gene', '83903', (18, 24))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('increasing', 'PosReg', (94, 104))	('inhibition', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('haspin', 'Gene', (18, 24))	('Tregs', 'CPA', (200, 205))	('regulated', 'Reg', (63, 72))	('reducing', 'NegReg', (177, 185))	('CD8', 'Gene', (160, 163))
279832	33047515	In particular, GIST commonly shows activating mutations in the receptor tyrosine kinases KIT and PDGFRA.	('receptor tyrosine kinase', 'Gene', (63, 87))	('mutations', 'Var', (46, 55))	('receptor tyrosine kinase', 'Gene', '5979', (63, 87))	('activating', 'PosReg', (35, 45))	('PDGFRA', 'Gene', (97, 103))	('KIT', 'Gene', (89, 92))	('PDGFRA', 'Gene', '5156', (97, 103))
279833	33047515	While physiological KIT or PDGFRalpha signaling are involved in cell differentiation and survival, activating mutations in both genes results in constitutive ligand-independent receptor activation, leading to GIST tumorigenesis.	('PDGFRalpha', 'Gene', '5156', (27, 37))	('mutations', 'Var', (110, 119))	('constitutive ligand-independent receptor', 'MPA', (145, 185))	('activation', 'PosReg', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('PDGFRalpha', 'Gene', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (214, 219))
279835	33047515	The resistance toward TKIs in GIST is mainly related to secondary mutations of KIT (Li & Raut, 2019; Napolitano & Vincenzi, 2019), but can also be triggered by PDGFRA mutations (Lim et al, 2008; Kalfusova et al, 2019).	('mutations', 'Var', (66, 75))	('Lim', 'Gene', '10611', (178, 181))	('Lim', 'Gene', (178, 181))	('resistance', 'MPA', (4, 14))	('PDGFRA', 'Gene', (160, 166))	('triggered', 'Gene', (147, 156))	('related', 'Reg', (45, 52))	('PDGFRA', 'Gene', '5156', (160, 166))	('KIT', 'Gene', (79, 82))
279839	33047515	Similarly, in another SS cell line, the presence of an NRAS mutation sustained ERK activation and caused resistance to pazopanib treatment (Lanzi et al, 2019).	('resistance to pazopanib treatment', 'MPA', (105, 138))	('ERK', 'Gene', (79, 82))	('mutation', 'Var', (60, 68))	('NRAS', 'Gene', '4893', (55, 59))	('pazopanib', 'Chemical', 'MESH:C516667', (119, 128))	('presence', 'Var', (40, 48))	('ERK', 'Gene', '5594', (79, 82))	('NRAS', 'Gene', (55, 59))	('caused', 'Reg', (98, 104))	('activation', 'PosReg', (83, 93))
279841	33047515	Phosphoproteomic profiling of pazopanib-resistant cells identified the inhibition of HSP90 as a therapeutic route to overcome resistance (Vyse et al, 2018).	('pazopanib', 'Chemical', 'MESH:C516667', (30, 39))	('HSP90', 'Gene', (85, 90))	('inhibition', 'Var', (71, 81))	('HSP90', 'Gene', '3320', (85, 90))
279863	33047515	Here, the authors showed that common sarcomas (except for SS) are characterized by a high number of copy-number variations (CNVs) and recurrent point mutations in relatively few genes, such as TP53, ATRX, and RB1.	('RB1', 'Gene', '5925', (209, 212))	('point mutations', 'Var', (144, 159))	('ATRX', 'Gene', (199, 203))	('TP53', 'Gene', '7157', (193, 197))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('TP53', 'Gene', (193, 197))	('RB1', 'Gene', (209, 212))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('ATRX', 'Gene', '546', (199, 203))	('copy-number variations', 'Var', (100, 122))	('sarcomas', 'Disease', (37, 45))
279864	33047515	Importantly, specific genomic and transcriptomic alterations also define molecular subtypes, which are associated with patient outcome (Cancer Genome Atlas Research Network, 2017).	('patient', 'Species', '9606', (119, 126))	('alterations', 'Var', (49, 60))	('Cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Cancer', 'Disease', (136, 142))	('Cancer', 'Disease', 'MESH:D009369', (136, 142))	('rat', 'Species', '10116', (53, 56))
279865	33047515	Other studies have identified whole-genome duplication as a cause of the structural complexity of UPS (Steele et al, 2019), and CDKN2A alterations as a predictor of worse overall survival across sarcoma subtypes (Bui et al, 2019).	('UPS', 'Disease', (98, 101))	('sarcoma', 'Disease', (195, 202))	('cause', 'Reg', (60, 65))	('CDKN2A', 'Gene', '1029', (128, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('rat', 'Species', '10116', (139, 142))	('alterations', 'Var', (135, 146))	('UPS', 'Disease', 'MESH:D017118', (98, 101))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('CDKN2A', 'Gene', (128, 134))
279869	33047515	It is noteworthy that ATRX has been shown to be required for response to CDK4 inhibitors in LPS, providing a potential biomarker for upcoming clinical trials (Kovatcheva et al, 2015; Cancer Genome Atlas Research Network, 2017).	('ATRX', 'Gene', (22, 26))	('Cancer', 'Disease', 'MESH:D009369', (183, 189))	('LPS', 'Disease', 'MESH:C536528', (92, 95))	('CDK4', 'Gene', '1019', (73, 77))	('inhibitors', 'Var', (78, 88))	('ATRX', 'Gene', '546', (22, 26))	('LPS', 'Phenotype', 'HP:0012034', (92, 95))	('LPS', 'Disease', (92, 95))	('Cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Cancer', 'Disease', (183, 189))	('CDK4', 'Gene', (73, 77))
279872	33047515	Exome sequencing has revealed a combination of single-base substitutions, loss of heterozygosity events, and/or large-scale genome instability involving 14 driver genes (ATM, ATRX, BAP1, BRCA2, FANCA, MDC1, MUTYH, NUMA1, PTEN, RB1, RECQL4, RET, TP53, and WRN) and many additional genes that define a "BRCAness" signature in > 80% of OS (Kovac et al, 2015).	('MDC1', 'Gene', '9656', (201, 205))	('RECQL4', 'Gene', '9401', (232, 238))	('RET', 'Gene', '5979', (240, 243))	('ATM', 'Gene', (170, 173))	('FANCA', 'Gene', (194, 199))	('PTEN', 'Gene', '5728', (221, 225))	('BRCA2', 'Gene', '675', (187, 192))	('RECQL4', 'Gene', (232, 238))	('BAP1', 'Gene', '8314', (181, 185))	('MUTYH', 'Gene', (207, 212))	('TP53', 'Gene', '7157', (245, 249))	('NUMA1', 'Gene', (214, 219))	('NUMA1', 'Gene', '4926', (214, 219))	('RET', 'Gene', (240, 243))	('MUTYH', 'Gene', '4595', (207, 212))	('RB1', 'Gene', (227, 230))	('BAP1', 'Gene', (181, 185))	('ATM', 'Gene', '472', (170, 173))	('WRN', 'Gene', (255, 258))	('WRN', 'Gene', '7486', (255, 258))	('FANCA', 'Gene', '2175', (194, 199))	('MDC1', 'Gene', (201, 205))	('ATRX', 'Gene', (175, 179))	('PTEN', 'Gene', (221, 225))	('BRCA2', 'Gene', (187, 192))	('single-base', 'Var', (47, 58))	('RB1', 'Gene', '5925', (227, 230))	('OS', 'Phenotype', 'HP:0002669', (333, 335))	('ATRX', 'Gene', '546', (175, 179))	('TP53', 'Gene', (245, 249))	('BRCAness', 'Disease', (301, 309))	('BRCAness', 'Disease', 'None', (301, 309))
279873	33047515	In fact, OS is characterized by a very complex altered genomic landscape explained by chromothripsis-generating driver mutations and multiple genomic rearrangements (Behjati et al, 2017).	('rat', 'Species', '10116', (105, 108))	('chromothripsis', 'Disease', (86, 100))	('OS', 'Phenotype', 'HP:0002669', (9, 11))	('chromothripsis', 'Disease', 'MESH:D000072837', (86, 100))	('mutations', 'Var', (119, 128))
279874	33047515	However, in some cases, OS tumorigenesis is associated with germline alterations in TP53, RB1, and RECQL1/2/3 predisposing patients to the accumulation of high numbers of somatic mutations (Smida et al, 2017; Baumhoer et al, 2019; Sayles et al, 2019).	('associated', 'Reg', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('RB1', 'Gene', (90, 93))	('RECQL1/2/3', 'Gene', (99, 109))	('alterations', 'Var', (69, 80))	('OS tumor', 'Disease', (24, 32))	('patients', 'Species', '9606', (123, 131))	('TP53', 'Gene', '7157', (84, 88))	('RB1', 'Gene', '5925', (90, 93))	('OS tumor', 'Disease', 'MESH:C567932', (24, 32))	('RECQL1/2/3', 'Gene', '5965;7486', (99, 109))	('OS', 'Phenotype', 'HP:0002669', (24, 26))	('TP53', 'Gene', (84, 88))	('rat', 'Species', '10116', (73, 76))
279878	33047515	In contrast to OS and most sarcomas of adulthood, translocation-driven pediatric sarcomas, such as EwS, SS, or fusion-positive ARMS, exhibit much lower rates of single-nucleotide variants and CNVs, and, instead, appear to be driven by marked epigenetic and transcriptomic perturbations induced by the fusion oncoproteins (Shern et al, 2014; Tirode et al, 2014; Cancer Genome Atlas Research Network, 2017).	('sarcomas', 'Disease', (81, 89))	('rat', 'Species', '10116', (152, 155))	('OS', 'Phenotype', 'HP:0002669', (15, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('lower', 'NegReg', (146, 151))	('Cancer', 'Disease', (361, 367))	('EwS', 'Gene', '2130', (99, 102))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('Cancer', 'Disease', 'MESH:D009369', (361, 367))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcomas', 'Disease', (27, 35))	('single-nucleotide variants', 'Var', (161, 187))	('EwS', 'Phenotype', 'HP:0012254', (99, 102))	('ARMS', 'Phenotype', 'HP:0006779', (127, 131))	('EwS', 'Gene', (99, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('Cancer', 'Phenotype', 'HP:0002664', (361, 367))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
279882	33047515	Importantly, variability at this MYBL2-associated GGAA-microsatellite is inherited via the germline and linked to intertumoral variation in MYBL2 expression (Musa et al, 2019).	('MYBL2', 'Gene', (140, 145))	('tumor', 'Disease', (119, 124))	('linked', 'Reg', (104, 110))	('variability', 'Var', (13, 24))	('MYBL2', 'Gene', '4605', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('MYBL2', 'Gene', '4605', (140, 145))	('MYBL2', 'Gene', (33, 38))	('expression', 'MPA', (146, 156))
279883	33047515	As MYBL2 is phosphorylated and activated by CDK2 (Musa et al, 2017), high MYBL2 expression sensitizes EwS cells to CDK2 inhibition, indicating the potential for using MYBL2 as a biomarker in anti-CDK2 therapy (Musa et al, 2019).	('CDK2', 'Gene', '1017', (115, 119))	('EwS', 'Gene', (102, 105))	('CDK2', 'Gene', '1017', (44, 48))	('MYBL2', 'Gene', (3, 8))	('sensitizes', 'Reg', (91, 101))	('MYBL2', 'Gene', '4605', (74, 79))	('CDK2', 'Gene', '1017', (196, 200))	('CDK2', 'Gene', (115, 119))	('EwS', 'Phenotype', 'HP:0012254', (102, 105))	('MYBL2', 'Gene', '4605', (167, 172))	('high', 'Var', (69, 73))	('MYBL2', 'Gene', (74, 79))	('MYBL2', 'Gene', (167, 172))	('EwS', 'Gene', '2130', (102, 105))	('CDK2', 'Gene', (44, 48))	('MYBL2', 'Gene', '4605', (3, 8))	('CDK2', 'Gene', (196, 200))
279888	33047515	Mutations in chromatin remodeler components have recently been recognized as oncogenic drivers in adult and pediatric sarcomas (Nacev et al, 2019).	('sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcomas', 'Disease', (118, 126))	('Mutations', 'Var', (0, 9))
279889	33047515	Recurrent somatic missense mutations in histone H3 at lysine 36 impair the mesenchymal differentiation program and promote the initiation of UPS (Fang et al, 2016; Lu et al, 2016).	('promote', 'PosReg', (115, 122))	('histone H3', 'Protein', (40, 50))	('initiation', 'CPA', (127, 137))	('UPS', 'Disease', (141, 144))	('mesenchymal differentiation program', 'CPA', (75, 110))	('lysine', 'Chemical', 'MESH:D008239', (54, 60))	('missense mutations', 'Var', (18, 36))	('UPS', 'Disease', 'MESH:D017118', (141, 144))	('impair', 'NegReg', (64, 70))
279890	33047515	K36M mutations in H3F3B have also been detected in most chondroblastomas (Behjati et al, 2013).	('chondroblastomas', 'Disease', 'MESH:D002804', (56, 72))	('chondroblastomas', 'Disease', (56, 72))	('H3F3B', 'Gene', '3021', (18, 23))	('H3F3B', 'Gene', (18, 23))	('K36M', 'Mutation', 'p.K36M', (0, 4))	('detected', 'Reg', (39, 47))	('K36M mutations', 'Var', (0, 14))
279891	33047515	The detection of histone mutations could help in therapeutic choices as recently evidenced by an instructive case of a patient diagnosed with a histiocytic neoplasm harboring a histone H3K36I mutation.	('patient', 'Species', '9606', (119, 126))	('histone', 'Protein', (177, 184))	('neoplasm', 'Disease', (156, 164))	('neoplasm', 'Phenotype', 'HP:0002664', (156, 164))	('H3K36I mutation', 'Var', (185, 200))	('help', 'Reg', (41, 45))	('neoplasm', 'Disease', 'MESH:D009369', (156, 164))
279893	33047515	Similarly, mutations in chromatin remodeling genes, including ATRX, DOT1L, and H3F3A, have been identified in 14 UPS cases highlighting the potential involvement of deregulated chromatin remodeling pathways in tumorigenesis (Ali et al, 2019).	('mutations', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('H3F3A', 'Gene', '3020', (79, 84))	('identified', 'Reg', (96, 106))	('tumor', 'Disease', (210, 215))	('DOT1L', 'Gene', (68, 73))	('ATRX', 'Gene', (62, 66))	('UPS', 'Disease', 'MESH:D017118', (113, 116))	('H3F3A', 'Gene', (79, 84))	('DOT1L', 'Gene', '84444', (68, 73))	('chromatin remodeling pathways', 'Pathway', (177, 206))	('ATRX', 'Gene', '546', (62, 66))	('UPS', 'Disease', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
279894	33047515	Epigenetic alterations and signatures have also been extensively explored in EwS.	('Epigenetic alterations', 'Var', (0, 22))	('rat', 'Species', '10116', (15, 18))	('EwS', 'Phenotype', 'HP:0012254', (77, 80))	('EwS', 'Gene', '2130', (77, 80))	('EwS', 'Gene', (77, 80))
279900	33047515	Deregulation of epigenetic programs also plays key roles in other sarcoma subtypes, such as SS, an STS that often occurs in young adults.	('sarcoma', 'Disease', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Deregulation', 'Var', (0, 12))	('epigenetic', 'Protein', (16, 26))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('roles', 'Reg', (51, 56))
279901	33047515	The defining genetic event present in all histological variants of SS is the translocation of the SS18 gene on chromosome 18q11 to an SSX gene (mainly SSX1 or SSX2) located on chrXp11 (Clark et al, 1994).	('SSX2', 'Gene', (159, 163))	('SSX1', 'Gene', '6756', (151, 155))	('variants', 'Var', (55, 63))	('SSX', 'Gene', '6757', (159, 162))	('SSX', 'Gene', '6757', (134, 137))	('SSX', 'Gene', '6757', (151, 154))	('SS18', 'Gene', (98, 102))	('SSX1', 'Gene', (151, 155))	('SSX', 'Gene', (151, 154))	('SSX', 'Gene', (134, 137))	('SSX2', 'Gene', '6757', (159, 163))	('SSX', 'Gene', (159, 162))	('translocation', 'Var', (77, 90))	('SS18', 'Gene', '6760', (98, 102))
279906	33047515	Apart from their roles in sarcomagenesis, specific epigenetic alterations can be used to improve bone sarcoma and STS classification, diagnosis, and patient stratification (Fig 1; Koelsche et al, 2018a; Weidema et al, 2020).	('bone sarcoma', 'Disease', 'MESH:D012509', (97, 109))	('improve', 'PosReg', (89, 96))	('bone sarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('sarcomagenesis', 'Disease', (26, 40))	('rat', 'Species', '10116', (159, 162))	('bone sarcoma', 'Disease', (97, 109))	('patient', 'Species', '9606', (149, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('rat', 'Species', '10116', (66, 69))	('sarcomagenesis', 'Disease', 'None', (26, 40))	('epigenetic alterations', 'Var', (51, 73))
279910	33047515	Methylation profiling also provides evidence for defining novel entities, such as the recently described primary intracranial sarcoma subtype with highly recurrent DICER1 mutations (Koelsche et al, 2018b).	('intracranial sarcoma', 'Disease', (113, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('DICER1', 'Gene', '23405', (164, 170))	('intracranial sarcoma', 'Disease', 'MESH:D012509', (113, 133))	('mutations', 'Var', (171, 180))	('DICER1', 'Gene', (164, 170))
279951	33047515	Circulating EV-associated transforming growth factor beta (TGF-beta) levels were elevated in OS patients compared with healthy individuals (Baglio et al, 2017), and circulating vesicular miR-25-3p and miR-92a-3p were elevated in LPS patients (Casadei et al, 2017).	('TGF-beta', 'Gene', (59, 67))	('vesicular', 'Species', '11276', (177, 186))	('OS', 'Phenotype', 'HP:0002669', (93, 95))	('LPS', 'Disease', (229, 232))	('miR-92a-3p', 'Var', (201, 211))	('elevated', 'PosReg', (81, 89))	('TGF-beta', 'Gene', '7039', (59, 67))	('LPS', 'Phenotype', 'HP:0012034', (229, 232))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (233, 241))	('elevated', 'PosReg', (217, 225))	('LPS', 'Disease', 'MESH:C536528', (229, 232))
279952	33047515	Moreover, miR-25-3p and miR-92a-3p modulated macrophages in the local TME, which in turn released IL-6, increasing the proliferation, migration, and invasion of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('miR-25-3p', 'Var', (10, 19))	('IL-6', 'Gene', (98, 102))	('rat', 'Species', '10116', (126, 129))	('proliferation', 'CPA', (119, 132))	('IL-6', 'Gene', '3569', (98, 102))	('rat', 'Species', '10116', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('migration', 'CPA', (134, 143))	('cancer', 'Disease', (161, 167))	('increasing', 'PosReg', (104, 114))	('miR-92a-3p', 'Var', (24, 34))	('modulated', 'Reg', (35, 44))	('invasion', 'CPA', (149, 157))
279956	33047515	Promising data were also obtained for SS, where serum miR-92b-3p constituted a robust marker for discriminating patients with SS from other STS patients and was elevated in EVs compared with AGO2-positive fractions (Uotani et al, 2017).	('AGO2', 'Gene', '27161', (191, 195))	('miR-92b-3p', 'Var', (54, 64))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (144, 152))	('elevated', 'PosReg', (161, 169))	('AGO2', 'Gene', (191, 195))
279963	33047515	The response to chemotherapy can be monitored by the identification of dysregulated levels of miRNAs (miR-124, miR-133a, miR-135b, miR-148a, miR-199a-3p, miR-27a, miR-385, and miR-9) and mRNAs (ANNEXIN2, CDC5L, CDKN1B, CIP4, MTAP, PEDF, SMAD2, and WWOX) in EVs isolated from the serum of OS patients with a poor chemotherapeutic response when compared with good responders (Xu et al, 2017).	('miR-27a', 'Gene', '407018', (154, 161))	('PEDF', 'Gene', '5176', (231, 235))	('MTAP', 'Gene', (225, 229))	('MTAP', 'Gene', '4507', (225, 229))	('CDKN1B', 'Gene', (211, 217))	('miR-124', 'Var', (102, 109))	('patients', 'Species', '9606', (291, 299))	('miR-27a', 'Gene', (154, 161))	('miR-148a', 'Gene', '406940', (131, 139))	('WWOX', 'Gene', '51741', (248, 252))	('miR-148a', 'Gene', (131, 139))	('CIP4', 'Gene', (219, 223))	('CIP4', 'Gene', '9322', (219, 223))	('miR-199a-3p', 'Gene', (141, 152))	('miR-135b', 'Gene', '442891', (121, 129))	('SMAD2', 'Gene', '4087', (237, 242))	('CDKN1B', 'Gene', '1027', (211, 217))	('ANNEXIN2', 'Gene', (194, 202))	('OS', 'Phenotype', 'HP:0002669', (288, 290))	('miR-199a-3p', 'Gene', '406977', (141, 152))	('ANNEXIN2', 'Gene', '302', (194, 202))	('miR-133a', 'Var', (111, 119))	('CDC5L', 'Gene', (204, 209))	('miR-135b', 'Gene', (121, 129))	('SMAD2', 'Gene', (237, 242))	('CDC5L', 'Gene', '988', (204, 209))	('PEDF', 'Gene', (231, 235))	('WWOX', 'Gene', (248, 252))
279983	33047515	In patients affected by GIST, mutations of KIT and PDGFRA were detected, and the amount of mutant cfDNA correlated with clinical progression (Maier et al, 2013).	('PDGFRA', 'Gene', '5156', (51, 57))	('PDGFRA', 'Gene', (51, 57))	('KIT', 'Gene', (43, 46))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (30, 39))
279984	33047515	Interestingly, the usefulness of cfDNA analysis was demonstrated to identify TKI-resistant mutations (Yoo et al, 2014).	('mutations', 'Var', (91, 100))	('TKI-resistant', 'Disease', (77, 90))	('rat', 'Species', '10116', (59, 62))
279985	33047515	In a series of CHSs, ctDNA levels detected by mutated IDH1 correlated with tumor grade and prognosis (Gutteridge et al, 2017).	('IDH1', 'Gene', (54, 58))	('CHSs', 'Disease', (15, 19))	('mutated', 'Var', (46, 53))	('prognosis', 'CPA', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CHS', 'Phenotype', 'HP:0006765', (15, 18))	('IDH1', 'Gene', '3417', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ctDNA levels', 'MPA', (21, 33))	('CHSs', 'Disease', 'None', (15, 19))	('tumor', 'Disease', (75, 80))	('correlated', 'Reg', (59, 69))
279986	33047515	Patient-specific somatic alterations in cfDNA were observed in OS (Barris et al, 2018) and were associated with inferior outcomes in EwS and OS patients (Shulman et al, 2018).	('alterations', 'Var', (25, 36))	('OS', 'Phenotype', 'HP:0002669', (63, 65))	('rat', 'Species', '10116', (29, 32))	('patients', 'Species', '9606', (144, 152))	('OS', 'Phenotype', 'HP:0002669', (141, 143))	('EwS', 'Phenotype', 'HP:0012254', (133, 136))	('EwS', 'Gene', '2130', (133, 136))	('cfDNA', 'Gene', (40, 45))	('Patient', 'Species', '9606', (0, 7))	('EwS', 'Gene', (133, 136))
279988	33047515	Indeed, copy numbers of cell-free EWSR1-ETS fusion sequences correlate with patients' risk factors such as tumor volume, pelvic tumor, and metastatic status, and most EwS patients show a fast reduction of cfDNA levels during treatment, while recurrence of increasing cfDNA levels indicates relapse (Krumbholz et al, 2016).	('copy', 'Var', (8, 12))	('tumor', 'Disease', (107, 112))	('EWSR1', 'Gene', '2130', (34, 39))	('cfDNA levels', 'MPA', (205, 217))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('EwS', 'Phenotype', 'HP:0012254', (167, 170))	('pelvic tumor', 'Disease', 'MESH:D010386', (121, 133))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('EwS', 'Gene', (167, 170))	('patients', 'Species', '9606', (171, 179))	('EWSR1', 'Gene', (34, 39))	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('pelvic tumor', 'Disease', (121, 133))	('tumor', 'Disease', (128, 133))	('EwS', 'Gene', '2130', (167, 170))	('reduction', 'NegReg', (192, 201))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('pelvic tumor', 'Phenotype', 'HP:0031501', (121, 133))
279994	33047515	Several recent studies have identified therapeutically targetable mutations in sarcoma patients and have used this knowledge to guide treatment (Groisberg et al, 2017).	('mutations', 'Var', (66, 75))	('sarcoma', 'Disease', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('patients', 'Species', '9606', (87, 95))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
280038	33047515	For example, Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter-driven modified oncolytic Adenovirus, was tested in a phase I clinical trial to assess its clinical safety in patients with advanced solid tumors (Nemunaitis et al, 2010).	('Telomelysin', 'Var', (13, 24))	('hTERT', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('patients', 'Species', '9606', (194, 202))	('human', 'Species', '9606', (28, 33))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('Adenovirus', 'Species', '10508', (110, 120))	('hTERT', 'Gene', '7015', (68, 73))
280042	33047515	HSV1716 was safe in the pediatric population, with minimal toxicities reported; however, no clinical responses were observed in this phase I trial (Streby et al, 2017).	('toxicities', 'Disease', 'MESH:D064420', (59, 69))	('toxicities', 'Disease', (59, 69))	('HSV1716', 'Var', (0, 7))
280054	33047515	Delta-24-RGD is a replication-competent Adenovirus that harbors a 24-bp deletion in the E1A region (responsible for binding Rb protein) that triggers tumor selectivity.	('Adenovirus', 'Species', '10508', (40, 50))	('binding', 'Interaction', (116, 123))	('triggers', 'Reg', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('Rb protein', 'Protein', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('deletion', 'Var', (72, 80))
280056	33047515	VCN-01 is an oncolytic Adenovirus where the E1A gene also contains deletions in the pRb binding site, thus rendering its selective replication in Rb-deficient tumor cells (Rodriguez-Garcia et al, 2015).	('Rb-deficient tumor', 'Disease', 'MESH:D009369', (146, 164))	('Rodriguez-Garcia', 'Disease', 'MESH:C538183', (172, 188))	('Adenovirus', 'Species', '10508', (23, 33))	('E1A', 'Gene', (44, 47))	('deletions', 'Var', (67, 76))	('Rodriguez-Garcia', 'Disease', (172, 188))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Rb-deficient tumor', 'Disease', (146, 164))	('binding', 'Interaction', (88, 95))	('pRb', 'Gene', (84, 87))	('selective replication', 'MPA', (121, 142))	('rendering', 'Reg', (107, 116))
280065	33047515	Epigenetic profiles emerge as useful tools to improve diagnostic accuracy in sarcomas and to discover or better delineate new sarcoma subtypes.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('sarcoma', 'Disease', (77, 84))	('Epigenetic profiles', 'Var', (0, 19))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('sarcoma', 'Disease', (126, 133))	('improve', 'PosReg', (46, 53))
280066	33047515	In addition, epigenetic events occurring during sarcomagenesis have been identified as new, promising opportunities for treating sarcomas.	('sarcomagenesis', 'Disease', 'None', (48, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('epigenetic events', 'Var', (13, 30))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('sarcomagenesis', 'Disease', (48, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcomas', 'Disease', (129, 137))
280184	32131863	Furthermore, in small round cell tumor, patients often had genetic and molecular alterations, which were also associated with survival and hard to get related data.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('genetic', 'Var', (59, 66))	('associated', 'Reg', (110, 120))	('tumor', 'Disease', (33, 38))
280283	26284114	Inhibition of the Notch pathway using a gamma-secretase inhibitor significantly reduced tumour growth and self-renewal in both tumour types, suggesting possible novel therapeutic options to reduce tumour recurrence for patients with these high-grade sarcomas.	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('tumour', 'Disease', (197, 203))	('Notch pathway', 'Pathway', (18, 31))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (219, 227))	('tumour growth', 'Disease', 'MESH:D006130', (88, 101))	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('self-renewal', 'CPA', (106, 118))	('reduced', 'NegReg', (80, 87))	('sarcomas', 'Disease', 'MESH:D012509', (250, 258))	('Inhibition', 'Var', (0, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (250, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('sarcomas', 'Disease', (250, 258))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('tumour growth', 'Disease', (88, 101))	('tumour', 'Disease', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
280295	25093581	Clinical and Biochemical Function of Polymorphic NR0B1 GGAA-Microsatellites in Ewing Sarcoma: A Report from the Children's Oncology Group The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood.	('Polymorphic', 'Var', (37, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (163, 176))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (163, 176))	('NR0B1', 'Gene', (49, 54))	('Oncology', 'Phenotype', 'HP:0002664', (123, 131))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (79, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('Ewing Sarcoma', 'Disease', (79, 92))	('NR0B1', 'Gene', '190', (49, 54))	('Ewing sarcoma', 'Disease', (163, 176))	('Sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('Children', 'Species', '9606', (112, 120))
280303	25093581	Ewing sarcoma is a prototypical chromosomal translocation-associated malignancy, in which virtually all cases harbor a balanced somatic translocation fusing the EWSR1 gene (EWS) to a member of the (E- twenty six) ETS-family of transcription factors, most commonly FLI1 (FLI).	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('FLI', 'Gene', '2313', (264, 267))	('FLI', 'Gene', (270, 273))	('FLI1', 'Gene', (264, 268))	('EWS', 'Gene', (173, 176))	('EWSR1', 'Gene', '2130', (161, 166))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('malignancy', 'Disease', 'MESH:D009369', (69, 79))	('FLI1', 'Gene', '2313', (264, 268))	('Ewing sarcoma', 'Disease', (0, 13))	('malignancy', 'Disease', (69, 79))	('FLI', 'Gene', '2313', (270, 273))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('FLI', 'Gene', (264, 267))	('EWSR1', 'Gene', (161, 166))	('fusing', 'Var', (150, 156))
280305	25093581	The EWS/FLI chimera product is a potent oncogenic transcription factor, characterized by fusion of a transcriptional-regulatory domain of EWS to the DNA binding domain of FLI.	('FLI', 'Gene', '2313', (8, 11))	('EWS', 'Gene', (138, 141))	('fusion', 'Var', (89, 95))	('FLI', 'Gene', (171, 174))	('FLI', 'Gene', '2313', (171, 174))	('FLI', 'Gene', (8, 11))
280310	25093581	These findings collectively demonstrate an unprecedented link between microsatellite DNA and transcriptional dysregulation in Ewing sarcoma.	('Ewing sarcoma', 'Disease', (126, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('transcriptional dysregulation', 'MPA', (93, 122))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (126, 139))	('microsatellite DNA', 'Var', (70, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (126, 139))
280317	25093581	It remains unclear how the substantially larger spectrum of GGAA-microsatellite polymorphisms, observed in human populations influences EWS/FLI-mediated transcriptional activity.	('GGAA-microsatellite', 'Gene', (60, 79))	('human', 'Species', '9606', (107, 112))	('FLI', 'Gene', (140, 143))	('influences', 'Reg', (125, 135))	('polymorphisms', 'Var', (80, 93))	('FLI', 'Gene', '2313', (140, 143))
280376	25093581	These data demonstrate that the distribution of polymorphic NR0B1 GGAA-microsatellite haplotypes in tumor samples were markedly different than white European populations, which is compelling given the higher incidence of Ewing sarcoma in white non-Hispanic patients of European descent.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (221, 234))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (221, 234))	('tumor', 'Disease', (100, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('polymorphic', 'Var', (48, 59))	('different', 'Reg', (128, 137))	('patients', 'Species', '9606', (257, 265))	('NR0B1', 'Gene', (60, 65))	('Ewing sarcoma', 'Disease', (221, 234))
280388	25093581	The human-derived sequences contained varying combinations of single-base insertions and contiguous GGAA sequences, thus complicating the interpretation of these data (see Figure 2B).	('single-base insertions', 'Var', (62, 84))	('human', 'Species', '9606', (4, 9))	('GGAA', 'Gene', (100, 104))	('complicating', 'Reg', (121, 133))
280398	25093581	To investigate if GGAA-microsatellite polymorphisms influenced NR0B1 gene expression in Ewing sarcoma tumors, we quantified normalized NR0B1 expression using microarray data from 31 Ewing sarcoma samples from which both PCR sequencing data and RNA were available.	('Ewing sarcoma tumors', 'Disease', (88, 108))	('expression', 'MPA', (74, 84))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (88, 108))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Disease', (182, 195))	('polymorphisms', 'Var', (38, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('influenced', 'Reg', (52, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('NR0B1', 'Gene', (63, 68))
280415	25093581	Transcriptional dysregulation via microsatellite DNA in Ewing sarcoma represents a fascinating and novel property of the EWS/FLI chimera.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('Transcriptional', 'MPA', (0, 15))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('FLI', 'Gene', '2313', (125, 128))	('microsatellite DNA', 'Var', (34, 52))	('Ewing sarcoma', 'Disease', (56, 69))	('FLI', 'Gene', (125, 128))	('dysregulation', 'Var', (16, 29))
280426	25093581	A potential explanation for the bimodal biochemical expression patterns observed in this study is that the stoichiometric occupancy of EWS/FLI and associated co-factors is most optimal across microsatellites containing 21-25 or 55-60 GGAA motifs.	('microsatellites', 'Var', (192, 207))	('FLI', 'Gene', (139, 142))	('FLI', 'Gene', '2313', (139, 142))
280427	25093581	Guanine-rich DNA sequences can predispose to the formation of non-B-form DNA structures and G-quadruplexes, which may influence EWS/FLI and associated co-factor occupancy.	('Guanine-rich', 'Var', (0, 12))	('FLI', 'Gene', '2313', (132, 135))	('G-quadruplexes', 'Var', (92, 106))	('non-B-form DNA structures', 'Protein', (62, 87))	('Guanine', 'Chemical', 'MESH:D006147', (0, 7))	('FLI', 'Gene', (132, 135))	('influence', 'Reg', (118, 127))
280435	25093581	Compared to white European controls, a strong enrichment for NR0B1 microsatellite haplotypes containing either 21-25 or 56-50 GGAA motifs and a bias against smaller alleles containing 17-20 GGAA motifs was observed in patient samples.	('NR0B1', 'Gene', (61, 66))	('patient', 'Species', '9606', (218, 225))	('21-25', 'Var', (111, 116))
280438	25093581	The luciferase assays and qRT-PCR data from human-derived cell lines clearly show that the most common GGAA-microsatellite allele observed in tumors also facilitates maximal EWS/FLI-mediated gene expression.	('human', 'Species', '9606', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FLI', 'Gene', (178, 181))	('allele', 'Var', (123, 129))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('FLI', 'Gene', '2313', (178, 181))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('GGAA-microsatellite', 'Gene', (103, 122))	('facilitates', 'PosReg', (154, 165))
280439	25093581	The results from these experiments are further supported by patterns of NR0B1 gene expression observed in tumor microarray data, wherein tumors harboring small GGAA microsatellites (<20 GGAA repeats, Figure 5D) are those that have the lowest levels of NR0B1 gene expression.	('tumors', 'Disease', (137, 143))	('microsatellites', 'Var', (165, 180))	('tumor', 'Disease', (137, 142))	('NR0B1', 'Gene', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (106, 111))
280448	25093581	Additionally, ectopic EWS/FLI expression in murine-derived NIH3T3 cells does not upregulate Nr0b1, further supporting observation that GGAA-microsatellites are necessary for regulation of Nr0b1 in Ewing sarcoma.	('Ewing sarcoma', 'Disease', (197, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('FLI', 'Gene', (26, 29))	('Nr0b1', 'Gene', '11614', (92, 97))	('Nr0b1', 'Gene', (92, 97))	('NIH3T3', 'CellLine', 'CVCL:0594', (59, 65))	('FLI', 'Gene', '2313', (26, 29))	('murine', 'Species', '10090', (44, 50))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (197, 210))	('Nr0b1', 'Gene', '11614', (188, 193))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (197, 210))	('ectopic', 'Var', (14, 21))	('Nr0b1', 'Gene', (188, 193))
280455	25093581	Based on our biochemical data, a greater diversity of GGAA motifs at important microsatellite loci may actually negatively impact EWS/FLI-mediated gene expression, which appears optimal over a narrow range of GGAA motifs.	('motifs', 'Var', (59, 65))	('FLI', 'Gene', (134, 137))	('FLI', 'Gene', '2313', (134, 137))	('negatively impact', 'NegReg', (112, 129))
280456	25093581	Additional work will be needed to discern the relative contributions of microsatellite polymorphisms and SNPs in the susceptibility to Ewing sarcoma development.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (135, 148))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (135, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('Ewing sarcoma', 'Disease', (135, 148))	('microsatellite polymorphisms', 'Var', (72, 100))
280464	25093581	At the NR0B1 locus, these polymorphisms do not influence clinical outcomes, favoring a model in which these GGAA polymorphisms may contribute to the elusive permissive cellular and genetic environment necessary for EWS/FLI-mediated transformation.	('polymorphisms', 'Var', (113, 126))	('GGAA', 'Gene', (108, 112))	('FLI', 'Gene', (219, 222))	('contribute', 'Reg', (131, 141))	('FLI', 'Gene', '2313', (219, 222))
280659	30093970	Modulating the expression of a discrete pool of cancer-specific RNA transcripts may hold unique therapeutic potential as a precision anti-cancer medicine.	('Modulating', 'Var', (0, 10))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('RNA', 'Gene', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('expression', 'MPA', (15, 25))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
280667	30093970	A 96-well plate cytotoxicity assay, based on the MTT Proliferation assay, was then developed to compare the ability of antisense oligomers targeting these genes to suppress EFT cell growth at levels comparable to a conventional chemotherapeutic agent, like etoposide.	('etoposide', 'Chemical', 'MESH:D005047', (257, 266))	('mers', 'Species', '1335626', (134, 138))	('cytotoxicity', 'Disease', 'MESH:D064420', (16, 28))	('MTT', 'Chemical', 'MESH:C070243', (49, 52))	('antisense', 'Var', (119, 128))	('EFT cell growth', 'CPA', (173, 188))	('cytotoxicity', 'Disease', (16, 28))	('suppress', 'NegReg', (164, 172))
280723	30093970	Morpholino combinations that included oligomers targeting PHDGH-1 and either XAGE1 or CYP4F22-3 showed the most consistent synergistic effects across both EFT cell lines.	('oligomers', 'Var', (38, 47))	('mers', 'Species', '1335626', (43, 47))	('XAGE1', 'Gene', (77, 82))	('CYP4F22', 'Gene', (86, 93))	('Morpholino', 'Chemical', 'MESH:D060172', (0, 10))	('XAGE1', 'Gene', '653220', (77, 82))	('PHDGH-1', 'Gene', (58, 65))	('CYP4F22', 'Gene', '126410', (86, 93))
280725	30093970	Our group has hypothesized that for diseases like cancer, there is a disease specific-transcriptome that promotes tumor survival that is essentially exclusive to the patient's healthy transcriptome, and that the cancer-specific pool of transcripts can be safely targeted by antisense therapeutic intervention with no off-target effects in normal tissues.	('promotes', 'PosReg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('antisense', 'Var', (274, 283))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('patient', 'Species', '9606', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
280735	30093970	A list of 12 genes containing k-mers over-represented in EFT cells at ratios exceeding 10,000:1 compared to normal tissues were down-selected as putative candidates for antisense therapy, and a final list of 6 gene targets was selected based on their putative relevance to EFT pathology or known mechanism of action in cancer.	('k-mers', 'Var', (30, 36))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('mers', 'Species', '1335626', (32, 36))	('over-represented', 'PosReg', (37, 53))	('down-selected', 'NegReg', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))
280749	30093970	While P53 status could partially explain the difference in sensitivity between EFT cell lines, recent studies suggest that variations in p16/p14 gene status may account for greater variability in drug sensitivity.	('variations', 'Var', (123, 133))	('p16', 'Gene', (137, 140))	('p14', 'Gene', (141, 144))	('P53', 'Gene', (6, 9))	('drug sensitivity', 'Phenotype', 'HP:0020174', (196, 212))	('p14', 'Gene', '1029', (141, 144))	('drug sensitivity', 'MPA', (196, 212))	('P53', 'Gene', '7157', (6, 9))	('p16', 'Gene', '1029', (137, 140))
280752	30093970	These observations hint that multidrug resistance is more likely to occur in EFT cells harboring defects in p16/p14 proteins, rather than cells that have simply lost P53, which is a common artifact of drug resistant forms of EFT.	('P53', 'Gene', '7157', (166, 169))	('occur', 'Reg', (68, 73))	('p16', 'Gene', '1029', (108, 111))	('defects', 'Var', (97, 104))	('p14', 'Gene', '1029', (112, 115))	('multidrug resistance', 'MPA', (29, 49))	('p16', 'Gene', (108, 111))	('P53', 'Gene', (166, 169))	('p14', 'Gene', (112, 115))
280753	30093970	While oncogene status appears to dictate tumor-specific sensitivity to both conventional and gene-directed therapeutic agents, we acknowledge that cell-specific variability in antisense oligonucleotide uptake may also contribute to differences in EFT sensitivity observed.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('EFT', 'MPA', (247, 250))	('tumor', 'Disease', (41, 46))	('contribute', 'Reg', (218, 228))	('dictate', 'Reg', (33, 40))	('oligonucleotide', 'Chemical', 'MESH:D009841', (186, 201))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('antisense', 'Var', (176, 185))
280772	30093970	via dysregulation of pRB/p53 and apoptotic pathways) made them a reasonable, contrasting cell line for this pilot study.	('p53', 'Gene', '7157', (25, 28))	('p53', 'Gene', (25, 28))	('pRB', 'Gene', (21, 24))	('dysregulation', 'Var', (4, 17))	('apoptotic pathways', 'Pathway', (33, 51))	('pRB', 'Gene', '5925', (21, 24))
280782	30093970	Our analysis also appears to link the dysregulation of RNA processing genes RBM11 and FBL to EWS for the first time.	('EWS', 'Gene', '2130', (93, 96))	('EWS', 'Gene', (93, 96))	('RBM11', 'Gene', (76, 81))	('FBL', 'Gene', (86, 89))	('dysregulation', 'Var', (38, 51))	('RBM11', 'Gene', '54033', (76, 81))	('FBL', 'Gene', '2091', (86, 89))	('EWS', 'Phenotype', 'HP:0012254', (93, 96))
280783	30093970	This harmonizes well with observations that tumors utilize alternative splicing to promote proteome diversity and oncogenic splice variant expression to promote growth, evade immune surveillance, and support tumor cell survival.	('tumors', 'Disease', (44, 50))	('immune surveillance', 'CPA', (175, 194))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('support', 'PosReg', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('growth', 'MPA', (161, 167))	('evade', 'NegReg', (169, 174))	('proteome diversity', 'Protein', (91, 109))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (208, 213))	('promote', 'PosReg', (83, 90))	('promote', 'PosReg', (153, 160))	('alternative splicing', 'Var', (59, 79))	('tumor', 'Disease', (44, 49))
280785	30093970	The CCND1 gene, which is directly regulated by the EWS-FLI-1 transcription factor, encodes two alternative transcripts of cyclin D1; the common cyclin D1a isoform and a truncated cyclin D1b variant that promotes cellular transformation and prostate cancer progression.	('EWS', 'Gene', (51, 54))	('cyclin D1', 'Gene', '595', (122, 131))	('cellular transformation', 'CPA', (212, 235))	('cyclin D1', 'Gene', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('EWS', 'Phenotype', 'HP:0012254', (51, 54))	('FLI-1', 'Gene', '2313', (55, 60))	('prostate cancer', 'Disease', 'MESH:D011471', (240, 255))	('prostate cancer', 'Phenotype', 'HP:0012125', (240, 255))	('promotes', 'PosReg', (203, 211))	('cyclin D1', 'Gene', '595', (144, 153))	('prostate cancer', 'Disease', (240, 255))	('EWS', 'Gene', '2130', (51, 54))	('FLI-1', 'Gene', (55, 60))	('variant', 'Var', (190, 197))	('cyclin D1', 'Gene', (179, 188))	('CCND1', 'Gene', '595', (4, 9))	('CCND1', 'Gene', (4, 9))	('cyclin D1', 'Gene', '595', (179, 188))	('cyclin D1', 'Gene', (122, 131))
280796	30093970	Our study also associates the dysregulation of the phase II drug-metabolizing gene, UDP glycosyltransferase 3A2 (UGT3A2) to EWS for the first time.	('EWS', 'Phenotype', 'HP:0012254', (124, 127))	('EWS', 'Gene', '2130', (124, 127))	('EWS', 'Gene', (124, 127))	('dysregulation', 'Var', (30, 43))	('UGT3A2', 'Gene', '167127', (113, 119))	('UGT3A2', 'Gene', (113, 119))	('UDP glycosyltransferase 3A2', 'Gene', '167127', (84, 111))	('UDP glycosyltransferase 3A2', 'Gene', (84, 111))
280797	30093970	Dysregulation of UGT family pathways was also previously reported in castration-resistant forms of prostate cancer.	('UGT family pathways', 'Pathway', (17, 36))	('Dysregulation', 'Var', (0, 13))	('prostate cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('reported', 'Reg', (57, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
280803	30093970	We detected an over-represented k-mer in four splice variants of the IGFBP-2 gene (see Supplementary Figure 1), however our approach did not discriminate if the same k-mer was found in all splice variations of the gene.	('over-represented', 'PosReg', (15, 31))	('IGFBP-2', 'Gene', (69, 76))	('k-mer', 'Var', (32, 37))	('IGFBP-2', 'Gene', '3485', (69, 76))
280821	30093970	Using the down selection strategy highlighted in Table 2, we identified 6 lead gene targets for antisense drug development, each with an anticipated independent mechanisms of action against EWS tumors.	('EWS', 'Phenotype', 'HP:0012254', (190, 193))	('EWS', 'Gene', '2130', (190, 193))	('EWS', 'Gene', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('antisense', 'Var', (96, 105))	('tumors', 'Disease', (194, 200))
280824	30093970	The k-mer abundance for this dataset, representing 26 different tissues from 95 individuals, with between 6 and 26 samples per tissue, was compared to a cancer-specific RNA-Seq dataset comprised of three Ewing's Sarcoma RNA-Seq samples (Cell lines/SRA archive accessions: A673/SRR2541170, TC-32/SRR2541171, TTC-466/SRR2541172) available in the ArrayExpress database under accession number: E-GEOD-73610.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('Sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('SRA', 'Gene', (248, 251))	("Ewing's Sarcoma", 'Disease', (204, 219))	('cancer', 'Disease', (153, 159))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (204, 219))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (204, 219))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TC-32', 'CellLine', 'CVCL:7151', (289, 294))	('SRA', 'Gene', '10307', (248, 251))	('A673/SRR2541170', 'Var', (272, 287))	('TTC-466/SRR2541172', 'Var', (307, 325))
280829	30093970	For example, if k-mer A had abundances in Ewing's samples of 28341, 349248, and 54922, and abundances in normal cerebral cortex samples of 34115, 1551, 16368, 54135, 167743, and 2376, the abundance ratio for this k-mer between these tissues was 28341/167743 = 0.16.	('1551', 'Var', (146, 150))	('349248', 'Var', (68, 74))	('16368', 'Var', (152, 157))	("Ewing's", 'Disease', 'MESH:C563168', (42, 49))	('54135', 'Var', (159, 164))	('54922', 'Var', (80, 85))	('34115', 'Var', (139, 144))	('Ewing', 'Disease', (42, 47))	('167743', 'Var', (166, 172))
280935	24349741	Identification of the characteristic t (11;22)(q24;q12) or EWSR1-FLI1 fusion transcript or defined variant translocation can be invaluable in confirming this diagnostic entity.	('EWSR1', 'Gene', (59, 64))	('FLI1', 'Gene', '2313', (65, 69))	('FLI1', 'Gene', (65, 69))	('EWSR1', 'Gene', '2130', (59, 64))	('t (11;22)(q24;q12', 'Var', (37, 54))	('fusion', 'Var', (70, 76))	('variant translocation', 'Var', (99, 120))
280940	24349741	Distinguishing from SCCNET or SNUC is possible with identification of the 2;13 and 1;13 translocations or respective PAX3-FOXO1 and PAX7-FOXO1 fusion transcripts.	('SCC', 'Gene', (20, 23))	('SCC', 'Phenotype', 'HP:0002860', (20, 23))	('FOXO1', 'Gene', (122, 127))	('PAX7', 'Gene', '5081', (132, 136))	('FOXO1', 'Gene', '2308', (122, 127))	('FOXO1', 'Gene', '2308', (137, 142))	('fusion transcripts', 'Var', (143, 161))	('SCC', 'Gene', '6317', (20, 23))	('FOXO1', 'Gene', (137, 142))	('PAX7', 'Gene', (132, 136))	('PAX3', 'Gene', '5077', (117, 121))	('PAX3', 'Gene', (117, 121))
280948	24349741	Demonstration of the EBV virus (EBV-encoded early RNAs) by in situ hybridization in addition to a NK-cell immunophenotype (CD3-, CD56+, perforin and granzyme B+) confirmed the diagnosis.	('EBV', 'Species', '10376', (32, 35))	('CD56', 'Gene', '4684', (129, 133))	('EBV', 'Species', '10376', (21, 24))	('CD3-', 'Var', (123, 127))	('CD56', 'Gene', (129, 133))
280949	24349741	Immunophenotypically, DLBL has positive findings for B-lineage markers (CD20+, CD79+, CD3-, CD56).	('CD56', 'Gene', (92, 96))	('CD3-', 'Var', (86, 90))	('CD20', 'Gene', '54474', (72, 76))	('B-lineage markers', 'CPA', (53, 70))	('CD79+', 'Var', (79, 84))	('CD56', 'Gene', '4684', (92, 96))	('CD20', 'Gene', (72, 76))
280987	24349741	Because most of the IHC studies use antibodies that detect all P63 isoforms (TAp63alpha, TAp63beta, TAp63gamma, DeltaNp63alpha, DeltaNp63beta, DeltaNp63gamma) .	('TAp63beta', 'Var', (89, 98))	('TAp63gamma', 'Var', (100, 110))	('P63', 'Gene', '8626', (63, 66))	('DeltaNp63alpha', 'Var', (112, 126))	('DeltaNp63beta', 'Var', (128, 141))	('DeltaNp63gamma', 'Var', (143, 157))	('P63', 'Gene', (63, 66))
280997	24349741	The application of molecular analysis of the EWS-FLI1 fusion transcript was suggestive of Ewing sarcomas and PNET confirmation.	('EWS', 'Gene', (45, 48))	('fusion', 'Var', (54, 60))	('PNET confirmation', 'Disease', (109, 126))	('Ewing sarcomas', 'Disease', (90, 104))	('FLI1', 'Gene', (49, 53))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (90, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('FLI1', 'Gene', '2313', (49, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (90, 104))	('EWS', 'Gene', '2130', (45, 48))
281009	24349741	This neoplasm, uniquely characterized by rearrangements of the NUT or 15q14 gene (q14;p13.1).	('rearrangements', 'Var', (41, 55))	('NUT', 'Gene', '256646', (63, 66))	('men', 'Species', '9606', (50, 53))	('NUT', 'Gene', (63, 66))	('neoplasm', 'Disease', (5, 13))	('neoplasm', 'Disease', 'MESH:D009369', (5, 13))	('neoplasm', 'Phenotype', 'HP:0002664', (5, 13))
281031	21138865	Knock-down of EWSR1-FLI1 in Ewing sarcoma cell lines allows differentiation towards bone, cartilage and adipocyte lineage, suggesting that the tumor-initiating translocation event originally occurs in an MSC.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('FLI1', 'Gene', (20, 24))	('cartilage', 'Disease', (90, 99))	('tumor', 'Disease', (143, 148))	('FLI1', 'Gene', '2313', (20, 24))	('cartilage', 'Disease', 'MESH:D002357', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('Knock-down', 'Var', (0, 10))	('Ewing sarcoma', 'Disease', (28, 41))	('EWSR1', 'Gene', '2130', (14, 19))	('differentiation', 'CPA', (60, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (28, 41))	('EWSR1', 'Gene', (14, 19))
281054	21138865	For fat differentiation, 0.5mM isobutylmethylxanthine (IBMX) which raises cAMP levels, 50uM indomethacin which here acts as a PPARgamma agonist, and 500nM dexamethasone were used.	('indomethacin', 'Chemical', 'MESH:D007213', (92, 104))	('raises', 'PosReg', (67, 73))	('cAMP', 'Chemical', '-', (74, 78))	('IBMX', 'Chemical', 'MESH:D015056', (55, 59))	('50uM', 'Var', (87, 91))	('dexamethasone', 'Chemical', 'MESH:D003907', (155, 168))	('PPARgamma', 'Gene', (126, 135))	('isobutylmethylxanthine', 'Chemical', 'MESH:D015056', (31, 53))	('PPARgamma', 'Gene', '5468', (126, 135))	('cAMP levels', 'MPA', (74, 85))
281084	21138865	The detection was performed with secondary antibody Blocker, Blocker D, Streptavidin-HRP D (Ventana Medical Systems), followed by incubation with Tyramide-Alexa Fluor 488, 568 or 647 (Invitrogen catalog number T20922, T20914, T20916).	('Alexa Fluor 488', 'Chemical', '-', (155, 170))	('T20914', 'Var', (218, 224))	('T20916', 'Var', (226, 232))	('Tyramide', 'Chemical', '-', (146, 154))	('T20922', 'Var', (210, 216))
281088	21138865	However, a liposarcoma cell line DDLS8817 demonstrated fat, bone and cartilage trilineage differentiation potential characteristic of MSCs and expressed MSC surface markers, CD73, CD105, CD44 and CD90 (Supplemental data, Figure S1).	('CD73', 'Gene', '4907', (174, 178))	('liposarcoma', 'Phenotype', 'HP:0012034', (11, 22))	('cartilage', 'Disease', (69, 78))	('CD44', 'Gene', (187, 191))	('DDLS8817', 'CellLine', 'CVCL:M814', (33, 41))	('cartilage', 'Disease', 'MESH:D002357', (69, 78))	('CD105', 'Var', (180, 185))	('MSCs', 'Disease', (134, 138))	('CD73', 'Gene', (174, 178))	('fat', 'CPA', (55, 58))	('liposarcoma', 'Disease', (11, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('CD90', 'Gene', '7070', (196, 200))	('CD44', 'Gene', '960', (187, 191))	('liposarcoma', 'Disease', 'MESH:D008080', (11, 22))	('CD90', 'Gene', (196, 200))
281089	21138865	When injected into mice, DDLS8817 cells formed tumors indistinguishable from the dedifferentiated component of dedifferentiated liposarcoma (data not shown).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('liposarcoma', 'Phenotype', 'HP:0012034', (128, 139))	('liposarcoma', 'Disease', 'MESH:D008080', (128, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('DDLS8817', 'CellLine', 'CVCL:M814', (25, 33))	('DDLS8817', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('liposarcoma', 'Disease', (128, 139))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mice', 'Species', '10090', (19, 23))
281094	21138865	We found (Supplemental data, Table S1) that MSC markers CD73, CD105, CD90 and CD44 were expressed in a fraction of tumor cells averaging about 50% across a variety of sarcoma types.	('CD90', 'Gene', '7070', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CD105', 'Var', (62, 67))	('CD90', 'Gene', (69, 73))	('CD44', 'Gene', (78, 82))	('CD73', 'Gene', '4907', (56, 60))	('tumor', 'Disease', (115, 120))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('CD73', 'Gene', (56, 60))	('sarcoma', 'Disease', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('CD44', 'Gene', '960', (78, 82))
281104	21138865	Translocations involving SYT are present in over 95% of synovial sarcomas.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (56, 72))	('Translocations', 'Var', (0, 14))	('SYT', 'Gene', '6760', (25, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (56, 73))	('SYT', 'Gene', (25, 28))	('synovial sarcomas', 'Disease', (56, 73))	('synovial sarcomas', 'Disease', 'MESH:D013584', (56, 73))
281105	21138865	Similarly, MDM2 amplification has recently been shown to be a diagnostic marker of liposarcoma.	('liposarcoma', 'Disease', 'MESH:D008080', (83, 94))	('liposarcoma', 'Phenotype', 'HP:0012034', (83, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('amplification', 'Var', (16, 29))	('MDM2', 'Gene', '4193', (11, 15))	('liposarcoma', 'Disease', (83, 94))	('MDM2', 'Gene', (11, 15))
281138	21138865	After 7 days of coculture we observed a marked increase in sarcoma cell number when grown in the presence of SDBMSCs as compared to sarcoma cells grown alone (Figure 5A).	('sarcoma', 'Disease', (59, 66))	('increase in sarcoma cell number', 'Disease', 'MESH:D012509', (47, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcoma', 'Disease', (132, 139))	('increase in sarcoma cell number', 'Disease', (47, 78))	('SDBMSCs', 'Var', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
281142	21138865	In contrast, in the presence of Beas2B human epithelial cells, sarcoma cells remained in coloni-like foci similar to sarcoma cells grown alone.	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Disease', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('human', 'Species', '9606', (39, 44))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('Beas2B', 'Var', (32, 38))
281176	21138865	Some surgical sarcoma samples we analyzed did not yield any MSC cultures, such as 334, 904, 355, 394 (Table 1).	('sarcoma', 'Disease', (14, 21))	('355', 'Var', (92, 95))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))
281185	21138865	Potential therapeutic strategies to target pericytes in sarcoma may involve antibodies against CD105, which we show to be largely restricted to sarcoma vasculature, and endosialin which is expressed on tumor pericytes and malignant cells.	('sarcoma', 'Disease', (144, 151))	('sarcoma vasculature', 'Disease', 'MESH:C565633', (144, 163))	('CD105', 'Gene', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('tumor', 'Disease', (202, 207))	('sarcoma', 'Disease', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('antibodies', 'Var', (76, 86))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('endosialin', 'Gene', (169, 179))	('sarcoma vasculature', 'Disease', (144, 163))	('endosialin', 'Gene', '57124', (169, 179))
281271	21412072	Notably, single-marker expression was present in 38% of liposarcoma (n=26) and 13% of rhabdomyosarcoma (n=15).	('single-marker expression', 'Var', (9, 33))	('liposarcoma', 'Phenotype', 'HP:0012034', (56, 67))	('liposarcoma', 'Disease', 'MESH:D008080', (56, 67))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (86, 102))	('present', 'Reg', (38, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('rhabdomyosarcoma', 'Disease', (86, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('liposarcoma', 'Disease', (56, 67))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (86, 102))
281275	21412072	A much larger proportion (37%, 21/57) of cases showed positivity for at least 1 Group 1 markers, similar to the relatively high incidence of staining with a single marker seen in other non-LMS sarcomas.	('LMS', 'Phenotype', 'HP:0100243', (189, 192))	('sarcomas', 'Disease', 'MESH:D012509', (193, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('sarcomas', 'Disease', (193, 201))	('positivity', 'Var', (54, 64))
281296	21412072	The loss of PRDM16 promotes differentiation of brown fat precursors into skeletal muscle and results in elevated expression of genes involved in smooth, cardiac, and skeletal muscle (including ACTG2, MYLK, CFL2, SLMAP, and CASQ2).	('SLMAP', 'Gene', (212, 217))	('expression', 'MPA', (113, 123))	('promotes', 'PosReg', (19, 27))	('MYLK', 'Gene', (200, 204))	('ACTG2', 'Gene', '72', (193, 198))	('differentiation', 'CPA', (28, 43))	('PRDM16', 'Gene', (12, 18))	('CASQ2', 'Gene', '845', (223, 228))	('CFL2', 'Gene', '1073', (206, 210))	('MYLK', 'Gene', '4638', (200, 204))	('ACTG2', 'Gene', (193, 198))	('PRDM16', 'Gene', '63976', (12, 18))	('SLMAP', 'Gene', '7871', (212, 217))	('CASQ2', 'Gene', (223, 228))	('elevated', 'PosReg', (104, 112))	('CFL2', 'Gene', (206, 210))	('loss', 'Var', (4, 8))
281307	29499066	Although ORF20 did not have a global effect on translation, ORF20 enhanced RIG-I induced expression of endogenous OASL in an IRF3-dependent but IFNAR-independent manner.	('expression of endogenous OASL', 'MPA', (89, 118))	('p', 'Chemical', 'MESH:D010758', (154, 155))	('RIG-I', 'Gene', '23586', (75, 80))	('s', 'Chemical', 'MESH:D013455', (51, 52))	('s', 'Chemical', 'MESH:D013455', (94, 95))	('IFNAR', 'Gene', (144, 149))	('IRF3', 'Gene', (125, 129))	('ORF20', 'Var', (60, 65))	('IRF3', 'Gene', '3661', (125, 129))	('enhanced', 'PosReg', (66, 74))	('s', 'Chemical', 'MESH:D013455', (112, 113))	('RIG-I', 'Gene', (75, 80))	('IFNAR', 'Gene', '3454', (144, 149))	('p', 'Chemical', 'MESH:D010758', (132, 133))	('s', 'Chemical', 'MESH:D013455', (95, 96))	('p', 'Chemical', 'MESH:D010758', (91, 92))	('expression', 'Species', '29278', (89, 99))
281311	29499066	During infection with a KSHV ORF20stop mutant, however, OASL-dependent enhancement of infectivity was lost.	('s', 'Chemical', 'MESH:D013455', (100, 101))	('p', 'Chemical', 'MESH:D010758', (63, 64))	('KSHV', 'Species', '37296', (24, 28))	('lost', 'NegReg', (102, 106))	('s', 'Chemical', 'MESH:D013455', (104, 105))	('ORF20stop', 'Var', (29, 38))	('KSHV', 'Gene', (24, 28))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('s', 'Chemical', 'MESH:D013455', (34, 35))	('infectivity', 'MPA', (86, 97))
281312	29499066	Our data have characterized the interaction of ORF20 with OASL and suggest ORF20 usurps the function of OASL to benefit KSHV infection.	('s', 'Chemical', 'MESH:D013455', (86, 87))	('ORF20', 'Var', (75, 80))	('s', 'Chemical', 'MESH:D013455', (72, 73))	('KSHV infection', 'Disease', 'MESH:C537372', (120, 134))	('s', 'Chemical', 'MESH:D013455', (67, 68))	('s', 'Chemical', 'MESH:D013455', (82, 83))	('KSHV infection', 'Disease', (120, 134))	('benefit', 'PosReg', (112, 119))	('usurps', 'NegReg', (81, 87))	('function', 'MPA', (92, 100))
281330	29499066	The sequences for ORF20FL (AAC57101.1) and ORF20B (ABD28871.1), both of which start with a methionine, were submitted to Genbank as part of the genomic annotations for the minor and predominant (M and P) strains of KSHV, respectively, despite the presence of the sequences encoding ORF20FL and ORF20B in both genomes.	('p', 'Chemical', 'MESH:D010758', (182, 183))	('s', 'Chemical', 'MESH:D013455', (162, 163))	('s', 'Chemical', 'MESH:D013455', (108, 109))	('s', 'Chemical', 'MESH:D013455', (250, 251))	('s', 'Chemical', 'MESH:D013455', (12, 13))	('s', 'Chemical', 'MESH:D013455', (130, 131))	('methionine', 'Chemical', 'MESH:D008715', (91, 101))	('s', 'Chemical', 'MESH:D013455', (210, 211))	('s', 'Chemical', 'MESH:D013455', (263, 264))	('p', 'Chemical', 'MESH:D010758', (132, 133))	('ORF20FL', 'Var', (282, 289))	('s', 'Chemical', 'MESH:D013455', (271, 272))	('s', 'Chemical', 'MESH:D013455', (223, 224))	('ORF20FL', 'Gene', (18, 25))	('s', 'Chemical', 'MESH:D013455', (78, 79))	('p', 'Chemical', 'MESH:D010758', (247, 248))	('s', 'Chemical', 'MESH:D013455', (237, 238))	('p', 'Chemical', 'MESH:D010758', (224, 225))	('s', 'Chemical', 'MESH:D013455', (204, 205))	('KSHV', 'Species', '37296', (215, 219))	('ORF20B', 'Var', (294, 300))	('p', 'Chemical', 'MESH:D010758', (238, 239))	('s', 'Chemical', 'MESH:D013455', (315, 316))	('s', 'Chemical', 'MESH:D013455', (4, 5))
281333	29499066	Transiently expressed HSV-1 UL24, KSHV ORF20WT, HCMV UL76, and MHV68 ORF20 have been reported to affect the mitotic cdc2/cyclinB complex, thereby inducing cell cycle arrest and apoptosis.	('HSV-1', 'Gene', (22, 27))	('p', 'Chemical', 'MESH:D010758', (14, 15))	('inducing', 'PosReg', (146, 154))	('s', 'Chemical', 'MESH:D013455', (170, 171))	('p', 'Chemical', 'MESH:D010758', (180, 181))	('arrest', 'Disease', (166, 172))	('mitotic', 'MPA', (108, 115))	('s', 'Chemical', 'MESH:D013455', (185, 186))	('s', 'Chemical', 'MESH:D013455', (18, 19))	('UL76', 'Gene', (53, 57))	('cdc2', 'Gene', '983', (116, 120))	('p', 'Chemical', 'MESH:D010758', (132, 133))	('s', 'Chemical', 'MESH:D013455', (17, 18))	('UL76', 'Gene', '3293831', (53, 57))	('p', 'Chemical', 'MESH:D010758', (178, 179))	('MHV68 ORF20', 'Var', (63, 74))	('s', 'Chemical', 'MESH:D013455', (183, 184))	('arrest', 'Disease', 'MESH:D006323', (166, 172))	('MHV68', 'Species', '1440122', (63, 68))	('apoptosis', 'CPA', (177, 186))	('KSHV', 'Species', '37296', (34, 38))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('cdc2', 'Gene', (116, 120))	('affect', 'Reg', (97, 103))	('HSV-1', 'Species', '10298', (22, 27))	('KSHV ORF20WT', 'Var', (34, 46))	('UL24', 'Gene', (28, 32))	('UL24', 'Gene', '24271468', (28, 32))	('s', 'Chemical', 'MESH:D013455', (4, 5))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (155, 172))
281334	29499066	However, studies with MHV68 WT and ORF20 mutant viruses found no effect on the cell cycle.	('cell cycle', 'CPA', (79, 89))	('MHV68', 'Species', '1440122', (22, 27))	('ORF20', 'Gene', (35, 40))	('s', 'Chemical', 'MESH:D013455', (52, 53))	('mutant', 'Var', (41, 47))	('MHV68', 'Gene', (22, 27))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('s', 'Chemical', 'MESH:D013455', (15, 16))	('s', 'Chemical', 'MESH:D013455', (54, 55))
281372	29499066	A plasmid construct encoding genomic ORF20WT, equipped with a C-terminal myc epitope tag, can potentially express ORF20FL, ORF20A, and ORF20B (Fig 1B), but we only observed two distinct bands upon immunoblotting cell lysates with an anti-myc antibody (Fig 1C).	('p', 'Chemical', 'MESH:D010758', (94, 95))	('s', 'Chemical', 'MESH:D013455', (5, 6))	('p', 'Chemical', 'MESH:D010758', (108, 109))	('s', 'Chemical', 'MESH:D013455', (112, 113))	('myc', 'Gene', '4609', (73, 76))	('myc', 'Gene', '4609', (238, 241))	('p', 'Chemical', 'MESH:D010758', (82, 83))	('ORF20FL', 'Var', (114, 121))	('ORF20A', 'Var', (123, 129))	('s', 'Chemical', 'MESH:D013455', (111, 112))	('s', 'Chemical', 'MESH:D013455', (223, 224))	('s', 'Chemical', 'MESH:D013455', (166, 167))	('s', 'Chemical', 'MESH:D013455', (190, 191))	('myc', 'Gene', (73, 76))	('myc', 'Gene', (238, 241))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('p', 'Chemical', 'MESH:D010758', (193, 194))	('p', 'Chemical', 'MESH:D010758', (2, 3))	('p', 'Chemical', 'MESH:D010758', (50, 51))	('ORF20B', 'Var', (135, 141))	('s', 'Chemical', 'MESH:D013455', (219, 220))	('s', 'Chemical', 'MESH:D013455', (179, 180))	('p', 'Chemical', 'MESH:D010758', (78, 79))	('s', 'Chemical', 'MESH:D013455', (13, 14))
281374	29499066	We found that the two bands observed upon expression of ORF20WT correspond to ORF20FL and ORF20B (Fig 1C).	('p', 'Chemical', 'MESH:D010758', (38, 39))	('expression', 'Species', '29278', (42, 52))	('ORF20WT', 'Var', (56, 63))	('s', 'Chemical', 'MESH:D013455', (69, 70))	('ORF20FL', 'Var', (78, 85))	('p', 'Chemical', 'MESH:D010758', (70, 71))	('s', 'Chemical', 'MESH:D013455', (30, 31))	('s', 'Chemical', 'MESH:D013455', (47, 48))	('s', 'Chemical', 'MESH:D013455', (26, 27))	('p', 'Chemical', 'MESH:D010758', (44, 45))	('s', 'Chemical', 'MESH:D013455', (48, 49))	('ORF20B', 'Var', (90, 96))
281378	29499066	We determined the subcellular localization of ORF20WT as well as the individual ORF20 isoforms ORF20FL, ORF20A, and ORF20B in HeLa cells by immunofluorescence (IF) and confocal microscopy.	('s', 'Chemical', 'MESH:D013455', (18, 19))	('s', 'Chemical', 'MESH:D013455', (63, 64))	('p', 'Chemical', 'MESH:D010758', (185, 186))	('ORF20FL', 'Var', (95, 102))	('s', 'Chemical', 'MESH:D013455', (87, 88))	('s', 'Chemical', 'MESH:D013455', (93, 94))	('ORF20A', 'Var', (104, 110))	('s', 'Chemical', 'MESH:D013455', (135, 136))	('s', 'Chemical', 'MESH:D013455', (55, 56))	('s', 'Chemical', 'MESH:D013455', (152, 153))	('ORF20B', 'Var', (116, 122))	('HeLa', 'CellLine', 'CVCL:0030', (126, 130))	('s', 'Chemical', 'MESH:D013455', (182, 183))
281385	29499066	HeLa S3 cells were metabolically labeled with stable heavy or light isotopes of arginine and lysine, then transfected with myc-tagged ORF20WT or LacZ as a control.	('HeLa S3', 'CellLine', 'CVCL:0058', (0, 7))	('lysine', 'Chemical', 'MESH:D008239', (93, 99))	('s', 'Chemical', 'MESH:D013455', (69, 70))	('myc', 'Gene', '4609', (123, 126))	('s', 'Chemical', 'MESH:D013455', (110, 111))	('s', 'Chemical', 'MESH:D013455', (12, 13))	('ORF20WT', 'Var', (134, 141))	('p', 'Chemical', 'MESH:D010758', (73, 74))	('s', 'Chemical', 'MESH:D013455', (46, 47))	('s', 'Chemical', 'MESH:D013455', (75, 76))	('s', 'Chemical', 'MESH:D013455', (95, 96))	('myc', 'Gene', (123, 126))	('arginine', 'Chemical', 'MESH:D001120', (80, 88))	('s', 'Chemical', 'MESH:D013455', (151, 152))
281399	29499066	Endogenous OASL was specifically expressed in RIG-I N transfected 293T cells, but not in the absence of RIG-I N transfection or in 293T OASL-/- cells.	('RIG-I', 'Gene', (104, 109))	('RIG-I', 'Gene', (46, 51))	('s', 'Chemical', 'MESH:D013455', (148, 149))	('s', 'Chemical', 'MESH:D013455', (75, 76))	('s', 'Chemical', 'MESH:D013455', (18, 19))	('s', 'Chemical', 'MESH:D013455', (58, 59))	('p', 'Chemical', 'MESH:D010758', (21, 22))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('293T', 'CellLine', 'CVCL:0063', (131, 135))	('293T', 'CellLine', 'CVCL:0063', (66, 70))	('p', 'Chemical', 'MESH:D010758', (35, 36))	('s', 'Chemical', 'MESH:D013455', (39, 40))	('s', 'Chemical', 'MESH:D013455', (95, 96))	('transfected', 'Var', (54, 65))	('RIG-I', 'Gene', '23586', (104, 109))	('RIG-I', 'Gene', '23586', (46, 51))	('s', 'Chemical', 'MESH:D013455', (38, 39))	('s', 'Chemical', 'MESH:D013455', (116, 117))	('s', 'Chemical', 'MESH:D013455', (20, 21))
281407	29499066	We found that OASL co-immunoprecipitated with all ORF20 isoforms (FL, A, and B) individually as well as with ORF20WT, but not with the LacZ control.	('s', 'Chemical', 'MESH:D013455', (63, 64))	('p', 'Chemical', 'MESH:D010758', (28, 29))	('s', 'Chemical', 'MESH:D013455', (94, 95))	('ORF20WT', 'Var', (109, 116))	('s', 'Chemical', 'MESH:D013455', (57, 58))	('s', 'Chemical', 'MESH:D013455', (102, 103))	('ORF20', 'Gene', (50, 55))	('p', 'Chemical', 'MESH:D010758', (33, 34))
281411	29499066	Thus, to analyze localization, we transfected HeLa S3 cells with either myc-tagged ORF20WT or V5-tagged OASL, or co-transfected them with both plasmids.	('s', 'Chemical', 'MESH:D013455', (38, 39))	('s', 'Chemical', 'MESH:D013455', (58, 59))	('ORF20WT', 'Var', (83, 90))	('s', 'Chemical', 'MESH:D013455', (146, 147))	('p', 'Chemical', 'MESH:D010758', (143, 144))	('myc', 'Gene', (72, 75))	('s', 'Chemical', 'MESH:D013455', (150, 151))	('s', 'Chemical', 'MESH:D013455', (120, 121))	('myc', 'Gene', '4609', (72, 75))	('HeLa S3', 'CellLine', 'CVCL:0058', (46, 53))	('s', 'Chemical', 'MESH:D013455', (3, 4))
281427	29499066	In parallel, we co-transfected 293T cells with ORF20WT and RIG-I N to induce expression of endogenous OASL.	('expression', 'Species', '29278', (77, 87))	('expression', 'MPA', (77, 87))	('s', 'Chemical', 'MESH:D013455', (83, 84))	('s', 'Chemical', 'MESH:D013455', (100, 101))	('p', 'Chemical', 'MESH:D010758', (3, 4))	('p', 'Chemical', 'MESH:D010758', (79, 80))	('293T', 'CellLine', 'CVCL:0063', (31, 35))	('RIG-I', 'Gene', '23586', (59, 64))	('induce', 'PosReg', (70, 76))	('s', 'Chemical', 'MESH:D013455', (23, 24))	('s', 'Chemical', 'MESH:D013455', (82, 83))	('ORF20WT', 'Var', (47, 54))	('s', 'Chemical', 'MESH:D013455', (40, 41))	('endogenous', 'MPA', (91, 101))	('RIG-I', 'Gene', (59, 64))
281429	29499066	In ORF20WT expressing cells with nuclear translocation of IRF3, ORF20WT localized to the nuclei and nucleoli (S1D Fig), similar to what we saw in HeLa cells, where endogenous OASL was detected even in the absence of RIG-I N (Fig 3C).	('ORF20WT', 'Var', (3, 10))	('HeLa', 'CellLine', 'CVCL:0030', (146, 150))	('p', 'Chemical', 'MESH:D010758', (13, 14))	('s', 'Chemical', 'MESH:D013455', (45, 46))	('IRF3', 'Gene', (58, 62))	('IRF3', 'Gene', '3661', (58, 62))	('s', 'Chemical', 'MESH:D013455', (155, 156))	('s', 'Chemical', 'MESH:D013455', (139, 140))	('s', 'Chemical', 'MESH:D013455', (26, 27))	('s', 'Chemical', 'MESH:D013455', (207, 208))	('s', 'Chemical', 'MESH:D013455', (16, 17))	('RIG-I', 'Gene', '23586', (216, 221))	('s', 'Chemical', 'MESH:D013455', (173, 174))	('s', 'Chemical', 'MESH:D013455', (120, 121))	('RIG-I', 'Gene', (216, 221))	('ORF20WT', 'Var', (64, 71))	('s', 'Chemical', 'MESH:D013455', (17, 18))	('s', 'Chemical', 'MESH:D013455', (182, 183))
281447	29499066	We verified expression of all homologs by immunoblotting, and found that UL24, M76, and ORF20B were of similar sizes, while UL76 and MHV68 ORF20 were more similar to the size of ORF20WT (Fig 5B and 5C).	('UL76', 'Gene', (124, 128))	('s', 'Chemical', 'MESH:D013455', (18, 19))	('s', 'Chemical', 'MESH:D013455', (111, 112))	('s', 'Chemical', 'MESH:D013455', (103, 104))	('MHV68', 'Species', '1440122', (133, 138))	('ORF20B', 'Var', (88, 94))	('s', 'Chemical', 'MESH:D013455', (155, 156))	('s', 'Chemical', 'MESH:D013455', (170, 171))	('M76', 'Var', (79, 82))	('s', 'Chemical', 'MESH:D013455', (115, 116))	('MHV68', 'Var', (133, 138))	('UL24', 'Gene', (73, 77))	('UL24', 'Gene', '24271468', (73, 77))	('s', 'Chemical', 'MESH:D013455', (37, 38))	('expression', 'Species', '29278', (12, 22))	('UL76', 'Gene', '3293831', (124, 128))	('s', 'Chemical', 'MESH:D013455', (17, 18))
281449	29499066	To determine whether OASL interacted with UL24 family members, we co-transfected 293T cells with V5-tagged OASL and myc-tagged KSHV ORF20FL, MCMV M76, HCMV UL76, or HSV-1 UL24, or LacZ-myc as a control.	('myc', 'Gene', '4609', (116, 119))	('UL24', 'Gene', (42, 46))	('UL24', 'Gene', '24271468', (42, 46))	('s', 'Chemical', 'MESH:D013455', (60, 61))	('myc', 'Gene', (116, 119))	('s', 'Chemical', 'MESH:D013455', (90, 91))	('UL76', 'Gene', (156, 160))	('myc', 'Gene', '4609', (185, 188))	('UL76', 'Gene', '3293831', (156, 160))	('myc', 'Gene', (185, 188))	('s', 'Chemical', 'MESH:D013455', (190, 191))	('s', 'Chemical', 'MESH:D013455', (73, 74))	('MCMV', 'Species', '10366', (141, 145))	('HSV-1', 'Species', '10298', (165, 170))	('293T', 'CellLine', 'CVCL:0063', (81, 85))	('UL24', 'Gene', (171, 175))	('UL24', 'Gene', '24271468', (171, 175))	('MCMV M76', 'Var', (141, 149))	('KSHV', 'Species', '37296', (127, 131))
281450	29499066	OASL co-immunoprecipitated strongly with KSHV ORF20FL and MCMV M76.	('s', 'Chemical', 'MESH:D013455', (27, 28))	('p', 'Chemical', 'MESH:D010758', (14, 15))	('MCMV', 'Species', '10366', (58, 62))	('KSHV', 'Species', '37296', (41, 45))	('KSHV', 'Gene', (41, 45))	('p', 'Chemical', 'MESH:D010758', (19, 20))	('MCMV', 'Var', (58, 62))	('ORF20FL', 'Var', (46, 53))
281454	29499066	We next analyzed the interaction of ORF20 with a variety of V5-tagged OASL mutants to determine if specific OASL domains or functions are required for the interaction to occur.	('OASL', 'Gene', (70, 74))	('interaction', 'Interaction', (21, 32))	('s', 'Chemical', 'MESH:D013455', (132, 133))	('mutants', 'Var', (75, 82))	('ORF20', 'Gene', (36, 41))	('s', 'Chemical', 'MESH:D013455', (81, 82))	('s', 'Chemical', 'MESH:D013455', (99, 100))	('s', 'Chemical', 'MESH:D013455', (119, 120))
281455	29499066	The mutants included DeltaUBL, lacking the ubiquitin-like domain of OASL; P-loop mutants V67G and N72K with reduced nucleic acid binding; three RNA binding mutants, R45E/K66E/R196E/K200E (RKRK), K63E, and K66E; and three catalytic triad mutants, E81A, E83A, and T152A, based on homology with the catalytic site of the OAS family enzymes (Fig 6A).	('V67G', 'Mutation', 'p.V67G', (89, 93))	('s', 'Chemical', 'MESH:D013455', (162, 163))	('s', 'Chemical', 'MESH:D013455', (306, 307))	('s', 'Chemical', 'MESH:D013455', (243, 244))	('OAS', 'Gene', '64093', (318, 321))	('s', 'Chemical', 'MESH:D013455', (10, 11))	('ubiquitin-like domain', 'MPA', (43, 64))	('R196E', 'SUBSTITUTION', 'None', (175, 180))	('K63E', 'Var', (195, 199))	('K66E', 'Mutation', 'p.K66E', (170, 174))	('R196E', 'Var', (175, 180))	('V67G', 'Var', (89, 93))	('K63E', 'Mutation', 'p.K63E', (195, 199))	('K200E', 'SUBSTITUTION', 'None', (181, 186))	('s', 'Chemical', 'MESH:D013455', (335, 336))	('OAS', 'Gene', (68, 71))	('s', 'Chemical', 'MESH:D013455', (271, 272))	('R45E', 'Var', (165, 169))	('s', 'Chemical', 'MESH:D013455', (87, 88))	('N72K', 'Var', (98, 102))	('T152A', 'Mutation', 'rs767930531', (262, 267))	('K66E', 'Var', (205, 209))	('E83A', 'Var', (252, 256))	('DeltaUBL', 'Gene', (21, 29))	('OAS', 'Gene', '64093', (68, 71))	('N72K', 'Mutation', 'p.N72K', (98, 102))	('E81A', 'Mutation', 'p.E81A', (246, 250))	('E83A', 'Mutation', 'p.E83A', (252, 256))	('reduced', 'NegReg', (108, 115))	('p', 'Chemical', 'MESH:D010758', (79, 80))	('lacking', 'NegReg', (31, 38))	('K66E', 'Mutation', 'p.K66E', (205, 209))	('K200E', 'Var', (181, 186))	('nucleic acid binding', 'MPA', (116, 136))	('OAS', 'Gene', (318, 321))	('R45E', 'SUBSTITUTION', 'None', (165, 169))
281457	29499066	We co-transfected myc-tagged ORF20WT with V5-tagged OAS1, WT OASL, or the various OASL mutants and verified their expression in input lysates (Fig 6B).	('s', 'Chemical', 'MESH:D013455', (140, 141))	('s', 'Chemical', 'MESH:D013455', (93, 94))	('myc', 'Gene', (18, 21))	('s', 'Chemical', 'MESH:D013455', (80, 81))	('mutants', 'Var', (87, 94))	('p', 'Chemical', 'MESH:D010758', (116, 117))	('OAS1', 'Gene', '4938', (52, 56))	('expression', 'Species', '29278', (114, 124))	('s', 'Chemical', 'MESH:D013455', (136, 137))	('s', 'Chemical', 'MESH:D013455', (120, 121))	('myc', 'Gene', '4609', (18, 21))	('s', 'Chemical', 'MESH:D013455', (10, 11))	('s', 'Chemical', 'MESH:D013455', (119, 120))	('p', 'Chemical', 'MESH:D010758', (130, 131))	('OAS1', 'Gene', (52, 56))
281459	29499066	We then performed an anti-myc immunoprecipitation and found that WT OASL and all OASL mutants co-immunoprecipitated with ORF20WT, but not with the negative control LacZ (Fig 6B).	('mutants', 'Var', (86, 93))	('myc', 'Gene', '4609', (26, 29))	('ORF20WT', 'Var', (121, 128))	('p', 'Chemical', 'MESH:D010758', (41, 42))	('p', 'Chemical', 'MESH:D010758', (103, 104))	('OASL', 'Gene', (81, 85))	('s', 'Chemical', 'MESH:D013455', (92, 93))	('p', 'Chemical', 'MESH:D010758', (108, 109))	('p', 'Chemical', 'MESH:D010758', (8, 9))	('p', 'Chemical', 'MESH:D010758', (36, 37))	('myc', 'Gene', (26, 29))
281463	29499066	Based on secondary structure and nuclear and nucleolar localization sequence predictions (Fig 6C), we created three ORF20B deletion mutants: ORF20B 1-235, 1-220, and 1-186 (Fig 6C).	('s', 'Chemical', 'MESH:D013455', (138, 139))	('s', 'Chemical', 'MESH:D013455', (87, 88))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('ORF20B', 'Gene', (116, 122))	('deletion', 'Var', (123, 131))	('s', 'Chemical', 'MESH:D013455', (19, 20))	('1-220', 'Var', (155, 160))	('s', 'Chemical', 'MESH:D013455', (2, 3))	('s', 'Chemical', 'MESH:D013455', (68, 69))	('1-235', 'Var', (148, 153))	('p', 'Chemical', 'MESH:D010758', (77, 78))
281464	29499066	We co-transfected the myc-tagged ORF20 isoforms WT, FL, A, or B, ORF20B deletion mutants, or LacZ as a control with V5-tagged OASL.	('myc', 'Gene', '4609', (22, 25))	('s', 'Chemical', 'MESH:D013455', (87, 88))	('myc', 'Gene', (22, 25))	('s', 'Chemical', 'MESH:D013455', (99, 100))	('s', 'Chemical', 'MESH:D013455', (46, 47))	('s', 'Chemical', 'MESH:D013455', (40, 41))	('s', 'Chemical', 'MESH:D013455', (10, 11))	('deletion mutants', 'Var', (72, 88))	('ORF20B', 'Gene', (65, 71))
281465	29499066	OASL and all ORF20 isoforms and truncation mutants were expressed in input lysates as expected (Fig 6D).	('p', 'Chemical', 'MESH:D010758', (58, 59))	('s', 'Chemical', 'MESH:D013455', (49, 50))	('truncation mutants', 'Var', (32, 50))	('s', 'Chemical', 'MESH:D013455', (20, 21))	('s', 'Chemical', 'MESH:D013455', (84, 85))	('s', 'Chemical', 'MESH:D013455', (77, 78))	('s', 'Chemical', 'MESH:D013455', (81, 82))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('s', 'Chemical', 'MESH:D013455', (61, 62))	('s', 'Chemical', 'MESH:D013455', (26, 27))	('ORF20', 'Gene', (13, 18))	('p', 'Chemical', 'MESH:D010758', (71, 72))	('s', 'Chemical', 'MESH:D013455', (62, 63))
281466	29499066	We then performed an anti-myc immunoprecipitation and found that OASL co-immunoprecipitated with all ORF20B deletion mutants, suggesting that the first 186 amino acids of ORF20B are important for the interaction with OASL (Fig 6D).	('myc', 'Gene', '4609', (26, 29))	('s', 'Chemical', 'MESH:D013455', (149, 150))	('s', 'Chemical', 'MESH:D013455', (166, 167))	('p', 'Chemical', 'MESH:D010758', (79, 80))	('mutants', 'Var', (117, 124))	('p', 'Chemical', 'MESH:D010758', (41, 42))	('ORF20B', 'Gene', (101, 107))	('s', 'Chemical', 'MESH:D013455', (131, 132))	('interaction', 'Interaction', (200, 211))	('s', 'Chemical', 'MESH:D013455', (126, 127))	('p', 'Chemical', 'MESH:D010758', (8, 9))	('p', 'Chemical', 'MESH:D010758', (84, 85))	('p', 'Chemical', 'MESH:D010758', (184, 185))	('p', 'Chemical', 'MESH:D010758', (36, 37))	('myc', 'Gene', (26, 29))	('deletion mutants', 'Var', (108, 124))	('s', 'Chemical', 'MESH:D013455', (123, 124))
281467	29499066	We then verified the subcellular localization of all ORF20B deletion mutants and found that all mutants localized to the nuclei and nucleoli (S5 Fig).	('s', 'Chemical', 'MESH:D013455', (21, 22))	('localized', 'Reg', (104, 113))	('deletion', 'Var', (60, 68))	('ORF20B', 'Gene', (53, 59))	('s', 'Chemical', 'MESH:D013455', (102, 103))	('s', 'Chemical', 'MESH:D013455', (75, 76))
281478	29499066	We performed sucrose gradient fractionation of ribosomes from cells expressing ORF20WT, OASL, or both ORF20WT and OASL together.	('s', 'Chemical', 'MESH:D013455', (18, 19))	('s', 'Chemical', 'MESH:D013455', (66, 67))	('sucrose', 'Chemical', 'MESH:D013395', (13, 20))	('s', 'Chemical', 'MESH:D013455', (51, 52))	('p', 'Chemical', 'MESH:D010758', (3, 4))	('ORF20WT', 'Var', (79, 86))	('s', 'Chemical', 'MESH:D013455', (55, 56))	('s', 'Chemical', 'MESH:D013455', (73, 74))	('p', 'Chemical', 'MESH:D010758', (70, 71))	('s', 'Chemical', 'MESH:D013455', (74, 75))	('s', 'Chemical', 'MESH:D013455', (13, 14))	('ORF20WT', 'Var', (102, 109))
281485	29499066	In summary, the co-sedimentation of ORF20WT and OASL with the 40S and 60S ribosomal subunits verifies our identification of 40S and 60S ribosomal subunit proteins as specific interaction partners of ORF20WT and OASL.	('interaction', 'Interaction', (175, 186))	('p', 'Chemical', 'MESH:D010758', (154, 155))	('ORF20WT', 'Var', (199, 206))	('s', 'Chemical', 'MESH:D013455', (100, 101))	('s', 'Chemical', 'MESH:D013455', (146, 147))	('s', 'Chemical', 'MESH:D013455', (166, 167))	('s', 'Chemical', 'MESH:D013455', (194, 195))	('s', 'Chemical', 'MESH:D013455', (19, 20))	('s', 'Chemical', 'MESH:D013455', (78, 79))	('s', 'Chemical', 'MESH:D013455', (84, 85))	('p', 'Chemical', 'MESH:D010758', (187, 188))	('s', 'Chemical', 'MESH:D013455', (91, 92))	('s', 'Chemical', 'MESH:D013455', (161, 162))	('s', 'Chemical', 'MESH:D013455', (140, 141))	('s', 'Chemical', 'MESH:D013455', (164, 165))	('s', 'Chemical', 'MESH:D013455', (3, 4))	('p', 'Chemical', 'MESH:D010758', (167, 168))
281486	29499066	Furthermore, the association of ORF20WT and OASL with polysomes suggests that these proteins may affect protein translation.	('s', 'Chemical', 'MESH:D013455', (18, 19))	('s', 'Chemical', 'MESH:D013455', (58, 59))	('association', 'Interaction', (17, 28))	('s', 'Chemical', 'MESH:D013455', (69, 70))	('affect', 'Reg', (97, 103))	('p', 'Chemical', 'MESH:D010758', (104, 105))	('ORF20WT', 'Var', (32, 39))	('s', 'Chemical', 'MESH:D013455', (19, 20))	('p', 'Chemical', 'MESH:D010758', (84, 85))	('s', 'Chemical', 'MESH:D013455', (116, 117))	('s', 'Chemical', 'MESH:D013455', (71, 72))	('protein translation', 'MPA', (104, 123))	('s', 'Chemical', 'MESH:D013455', (91, 92))	('s', 'Chemical', 'MESH:D013455', (64, 65))	('s', 'Chemical', 'MESH:D013455', (81, 82))	('p', 'Chemical', 'MESH:D010758', (54, 55))	('s', 'Chemical', 'MESH:D013455', (62, 63))
281487	29499066	To analyze whether ORF20WT and OASL have global effects on cellular translation, we utilized a puromycin incorporation assay.	('s', 'Chemical', 'MESH:D013455', (54, 55))	('s', 'Chemical', 'MESH:D013455', (121, 122))	('effects', 'Reg', (48, 55))	('s', 'Chemical', 'MESH:D013455', (72, 73))	('s', 'Chemical', 'MESH:D013455', (120, 121))	('cellular translation', 'MPA', (59, 79))	('p', 'Chemical', 'MESH:D010758', (110, 111))	('ORF20WT', 'Var', (19, 26))	('puromycin', 'Chemical', 'MESH:D011691', (95, 104))	('p', 'Chemical', 'MESH:D010758', (95, 96))
281488	29499066	293T cells were transfected with EV, ORF20WT, ORF20FL, or ORF20B, and either EV as a control or RIG-I N to induce expression of endogenous OASL.	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('RIG-I', 'Gene', (96, 101))	('EV', 'Chemical', '-', (33, 35))	('EV', 'Chemical', '-', (77, 79))	('s', 'Chemical', 'MESH:D013455', (119, 120))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('induce', 'PosReg', (107, 113))	('s', 'Chemical', 'MESH:D013455', (120, 121))	('expression', 'Species', '29278', (114, 124))	('RIG-I', 'Gene', '23586', (96, 101))	('s', 'Chemical', 'MESH:D013455', (81, 82))	('expression', 'MPA', (114, 124))	('ORF20WT', 'Var', (37, 44))	('ORF20B', 'Var', (58, 64))	('s', 'Chemical', 'MESH:D013455', (137, 138))	('s', 'Chemical', 'MESH:D013455', (20, 21))	('ORF20FL', 'Var', (46, 53))
281494	29499066	Interestingly, the amount of OASL protein was slightly increased when ORF20 forms were present (Fig 9A).	('p', 'Chemical', 'MESH:D010758', (34, 35))	('s', 'Chemical', 'MESH:D013455', (90, 91))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('s', 'Chemical', 'MESH:D013455', (80, 81))	('increased', 'PosReg', (55, 64))	('OASL protein', 'Protein', (29, 41))	('ORF20 forms', 'Var', (70, 81))	('s', 'Chemical', 'MESH:D013455', (46, 47))	('s', 'Chemical', 'MESH:D013455', (44, 45))	('amount', 'MPA', (19, 25))	('s', 'Chemical', 'MESH:D013455', (61, 62))	('s', 'Chemical', 'MESH:D013455', (6, 7))
281497	29499066	In addition, we observed a further significant increase in OASL mRNA levels when ORF20WT and RIG-I N were expressed (Fig 9B).	('s', 'Chemical', 'MESH:D013455', (18, 19))	('s', 'Chemical', 'MESH:D013455', (111, 112))	('RIG-I', 'Gene', (93, 98))	('s', 'Chemical', 'MESH:D013455', (35, 36))	('s', 'Chemical', 'MESH:D013455', (74, 75))	('s', 'Chemical', 'MESH:D013455', (53, 54))	('p', 'Chemical', 'MESH:D010758', (108, 109))	('s', 'Chemical', 'MESH:D013455', (112, 113))	('ORF20WT', 'Var', (81, 88))	('RIG-I', 'Gene', '23586', (93, 98))	('increase', 'PosReg', (47, 55))	('OASL mRNA levels', 'MPA', (59, 75))
281499	29499066	Unlike for ORF20WT, compared to EV with RIG-I N, we observed no upregulation of OASL mRNA levels in cells co-expressing RIG-I N and either ORF59, K8.1, ORF27, or RTA (S6A Fig).	('OASL mRNA levels', 'MPA', (80, 96))	('s', 'Chemical', 'MESH:D013455', (115, 116))	('RIG-I', 'Gene', (40, 45))	('upregulation', 'PosReg', (64, 76))	('ORF59', 'Var', (139, 144))	('ORF27', 'Var', (152, 157))	('K8.1', 'Gene', (146, 150))	('s', 'Chemical', 'MESH:D013455', (114, 115))	('EV', 'Chemical', '-', (32, 34))	('s', 'Chemical', 'MESH:D013455', (104, 105))	('K8.1', 'Gene', '3887', (146, 150))	('RIG-I', 'Gene', '23586', (120, 125))	('s', 'Chemical', 'MESH:D013455', (95, 96))	('RIG-I', 'Gene', '23586', (40, 45))	('p', 'Chemical', 'MESH:D010758', (111, 112))	('p', 'Chemical', 'MESH:D010758', (65, 66))	('p', 'Chemical', 'MESH:D010758', (23, 24))	('RIG-I', 'Gene', (120, 125))	('s', 'Chemical', 'MESH:D013455', (54, 55))
281501	29499066	Next, we determined whether ORF20 also enhanced OASL expression when endogenous RIG-I was stimulated.	('s', 'Chemical', 'MESH:D013455', (58, 59))	('s', 'Chemical', 'MESH:D013455', (90, 91))	('RIG-I', 'Gene', (80, 85))	('s', 'Chemical', 'MESH:D013455', (88, 89))	('s', 'Chemical', 'MESH:D013455', (36, 37))	('s', 'Chemical', 'MESH:D013455', (78, 79))	('expression', 'Species', '29278', (53, 63))	('OASL expression', 'MPA', (48, 63))	('ORF20', 'Var', (28, 33))	('RIG-I', 'Gene', '23586', (80, 85))	('s', 'Chemical', 'MESH:D013455', (59, 60))	('enhanced', 'PosReg', (39, 47))
281503	29499066	We found that OASL mRNA levels were significantly upregulated upon 5'pppRNA stimulation, and as with RIG-I N (Fig 9B), OASL mRNA levels were significantly increased in the presence of ORF20WT (Fig 9C).	('s', 'Chemical', 'MESH:D013455', (76, 77))	("5'pppRNA stimulation", 'MPA', (67, 87))	('p', 'Chemical', 'MESH:D010758', (70, 71))	('s', 'Chemical', 'MESH:D013455', (36, 37))	('s', 'Chemical', 'MESH:D013455', (161, 162))	('OASL mRNA levels', 'MPA', (14, 30))	('p', 'Chemical', 'MESH:D010758', (172, 173))	('increased', 'PosReg', (155, 164))	('RIG-I', 'Gene', (101, 106))	('ORF20WT', 'Var', (184, 191))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('s', 'Chemical', 'MESH:D013455', (175, 176))	('upregulated', 'PosReg', (50, 61))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('s', 'Chemical', 'MESH:D013455', (134, 135))	('p', 'Chemical', 'MESH:D010758', (63, 64))	('s', 'Chemical', 'MESH:D013455', (141, 142))	('s', 'Chemical', 'MESH:D013455', (94, 95))	('s', 'Chemical', 'MESH:D013455', (29, 30))	('OASL mRNA levels', 'MPA', (119, 135))	('RIG-I', 'Gene', '23586', (101, 106))	('p', 'Chemical', 'MESH:D010758', (71, 72))
281505	29499066	To do so, we used siRNA to knockdown IRF3, IFNAR, or STAT1 expression, then transfected cells with combinations of empty vector, ORF20WT, and/or RIG-I N. In control siRNA-transfected cells, we observed upregulation of OASL in the presence of ORF20WT and RIG-I N (Fig 9D), as shown previously (Fig 9B).	('s', 'Chemical', 'MESH:D013455', (275, 276))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('s', 'Chemical', 'MESH:D013455', (273, 274))	('s', 'Chemical', 'MESH:D013455', (187, 188))	('OASL', 'MPA', (218, 222))	('p', 'Chemical', 'MESH:D010758', (61, 62))	('s', 'Chemical', 'MESH:D013455', (233, 234))	('IRF3', 'Gene', '3661', (37, 41))	('s', 'Chemical', 'MESH:D013455', (18, 19))	('p', 'Chemical', 'MESH:D010758', (203, 204))	('s', 'Chemical', 'MESH:D013455', (175, 176))	('RIG-I', 'Gene', '23586', (145, 150))	('s', 'Chemical', 'MESH:D013455', (288, 289))	('p', 'Chemical', 'MESH:D010758', (281, 282))	('IFNAR', 'Gene', (43, 48))	('s', 'Chemical', 'MESH:D013455', (65, 66))	('s', 'Chemical', 'MESH:D013455', (80, 81))	('expression', 'Species', '29278', (59, 69))	('IFNAR', 'Gene', '3454', (43, 48))	('STAT1', 'Gene', (53, 58))	('RIG-I', 'Gene', '23586', (254, 259))	('s', 'Chemical', 'MESH:D013455', (64, 65))	('s', 'Chemical', 'MESH:D013455', (165, 166))	('upregulation', 'PosReg', (202, 214))	('s', 'Chemical', 'MESH:D013455', (14, 15))	('s', 'Chemical', 'MESH:D013455', (6, 7))	('p', 'Chemical', 'MESH:D010758', (230, 231))	('RIG-I', 'Gene', (145, 150))	('ORF20WT', 'Var', (242, 249))	('s', 'Chemical', 'MESH:D013455', (110, 111))	('s', 'Chemical', 'MESH:D013455', (92, 93))	('IRF3', 'Gene', (37, 41))	('STAT1', 'Gene', '6772', (53, 58))	('RIG-I', 'Gene', (254, 259))	('s', 'Chemical', 'MESH:D013455', (195, 196))
281507	29499066	Next, we analyzed the effect of IFNAR and STAT1 knockdown on the ability of ORF20WT to upregulate OASL mRNA levels and found that neither IFNAR nor STAT1 knockdown affected upregulation of OASL mRNA levels (Fig 9D), although expression of both was efficiently inhibited (S6C and S6D Fig, respectively).	('p', 'Chemical', 'MESH:D010758', (174, 175))	('STAT1', 'Gene', (42, 47))	('IFNAR', 'Gene', '3454', (32, 37))	('s', 'Chemical', 'MESH:D013455', (290, 291))	('p', 'Chemical', 'MESH:D010758', (291, 292))	('OASL mRNA levels', 'MPA', (189, 205))	('STAT1', 'Gene', '6772', (42, 47))	('p', 'Chemical', 'MESH:D010758', (227, 228))	('IFNAR', 'Gene', (138, 143))	('s', 'Chemical', 'MESH:D013455', (231, 232))	('knockdown', 'Var', (154, 163))	('s', 'Chemical', 'MESH:D013455', (113, 114))	('IFNAR', 'Gene', '3454', (138, 143))	('s', 'Chemical', 'MESH:D013455', (230, 231))	('upregulation', 'PosReg', (173, 185))	('STAT1', 'Gene', (148, 153))	('s', 'Chemical', 'MESH:D013455', (246, 247))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('OASL mRNA levels', 'MPA', (98, 114))	('expression', 'Species', '29278', (225, 235))	('s', 'Chemical', 'MESH:D013455', (204, 205))	('STAT1', 'Gene', '6772', (148, 153))	('IFNAR', 'Gene', (32, 37))
281508	29499066	In summary, these results suggest that although ORF20 does not globally affect translation, it affects expression of endogenous OASL at both the mRNA and protein levels, and ORF20-mediated upregulation of OASL mRNA expression is IRF3- but not IFNAR-dependent.	('s', 'Chemical', 'MESH:D013455', (227, 228))	('s', 'Chemical', 'MESH:D013455', (83, 84))	('s', 'Chemical', 'MESH:D013455', (220, 221))	('s', 'Chemical', 'MESH:D013455', (108, 109))	('ORF20-mediated', 'Gene', (174, 188))	('s', 'Chemical', 'MESH:D013455', (109, 110))	('OASL mRNA expression', 'MPA', (205, 225))	('s', 'Chemical', 'MESH:D013455', (3, 4))	('p', 'Chemical', 'MESH:D010758', (251, 252))	('expression', 'MPA', (103, 113))	('s', 'Chemical', 'MESH:D013455', (57, 58))	('s', 'Chemical', 'MESH:D013455', (167, 168))	('s', 'Chemical', 'MESH:D013455', (26, 27))	('s', 'Chemical', 'MESH:D013455', (24, 25))	('upregulation', 'PosReg', (189, 201))	('p', 'Chemical', 'MESH:D010758', (154, 155))	('p', 'Chemical', 'MESH:D010758', (217, 218))	('IFNAR', 'Gene', (243, 248))	('s', 'Chemical', 'MESH:D013455', (221, 222))	('s', 'Chemical', 'MESH:D013455', (15, 16))	('IRF3', 'Gene', (229, 233))	('IFNAR', 'Gene', '3454', (243, 248))	('ORF20', 'Var', (48, 53))	('s', 'Chemical', 'MESH:D013455', (126, 127))	('p', 'Chemical', 'MESH:D010758', (105, 106))	('expression', 'Species', '29278', (103, 113))	('s', 'Chemical', 'MESH:D013455', (31, 32))	('affects', 'Reg', (95, 102))	('s', 'Chemical', 'MESH:D013455', (101, 102))	('p', 'Chemical', 'MESH:D010758', (190, 191))	('IRF3', 'Gene', '3661', (229, 233))	('expression', 'Species', '29278', (215, 225))	('s', 'Chemical', 'MESH:D013455', (20, 21))
281511	29499066	OASL co-immunoprecipitated with RIG-I in both the presence and absence of ORF20WT (S7A Fig).	('RIG-I', 'Gene', '23586', (32, 37))	('s', 'Chemical', 'MESH:D013455', (65, 66))	('p', 'Chemical', 'MESH:D010758', (14, 15))	('s', 'Chemical', 'MESH:D013455', (53, 54))	('RIG-I', 'Gene', (32, 37))	('ORF20WT', 'Var', (74, 81))	('p', 'Chemical', 'MESH:D010758', (50, 51))	('p', 'Chemical', 'MESH:D010758', (19, 20))
281512	29499066	ORF20WT did not interact with RIG-I in the absence of OASL, but did co-immunoprecipitate with RIG-I in the presence of OASL, suggesting the detected interaction was due to OASL binding both RIG-I and ORF20WT (S7A Fig).	('RIG-I', 'Gene', '23586', (190, 195))	('s', 'Chemical', 'MESH:D013455', (45, 46))	('RIG-I', 'Gene', (94, 99))	('s', 'Chemical', 'MESH:D013455', (163, 164))	('p', 'Chemical', 'MESH:D010758', (107, 108))	('RIG-I', 'Gene', (190, 195))	('RIG-I', 'Gene', '23586', (30, 35))	('interaction', 'Interaction', (149, 160))	('s', 'Chemical', 'MESH:D013455', (125, 126))	('s', 'Chemical', 'MESH:D013455', (110, 111))	('RIG-I', 'Gene', '23586', (94, 99))	('ORF20WT', 'Var', (200, 207))	('RIG-I', 'Gene', (30, 35))	('s', 'Chemical', 'MESH:D013455', (130, 131))	('binding', 'Interaction', (177, 184))	('p', 'Chemical', 'MESH:D010758', (82, 83))	('p', 'Chemical', 'MESH:D010758', (77, 78))
281513	29499066	Our analysis of the subcellular localization of RIG-I, OASL, and ORF20WT in HeLa S3 cells showed that RIG-I was located in the cytoplasm, as expected, OASL was in the cytoplasm and nucleoli, and ORF20WT in the nuclei and nucleoli (S7B Fig) as shown previously (Fig 3E and 3F, Fig 4, S1 Fig).	('p', 'Chemical', 'MESH:D010758', (143, 144))	('s', 'Chemical', 'MESH:D013455', (139, 140))	('RIG-I', 'Gene', (102, 107))	('s', 'Chemical', 'MESH:D013455', (243, 244))	('p', 'Chemical', 'MESH:D010758', (171, 172))	('s', 'Chemical', 'MESH:D013455', (241, 242))	('s', 'Chemical', 'MESH:D013455', (11, 12))	('s', 'Chemical', 'MESH:D013455', (90, 91))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('p', 'Chemical', 'MESH:D010758', (131, 132))	('s', 'Chemical', 'MESH:D013455', (88, 89))	('p', 'Chemical', 'MESH:D010758', (249, 250))	('s', 'Chemical', 'MESH:D013455', (256, 257))	('RIG-I', 'Gene', '23586', (48, 53))	('s', 'Chemical', 'MESH:D013455', (134, 135))	('s', 'Chemical', 'MESH:D013455', (158, 159))	('s', 'Chemical', 'MESH:D013455', (174, 175))	('RIG-I', 'Gene', '23586', (102, 107))	('s', 'Chemical', 'MESH:D013455', (110, 111))	('HeLa S3', 'CellLine', 'CVCL:0058', (76, 83))	('RIG-I', 'Gene', (48, 53))	('s', 'Chemical', 'MESH:D013455', (20, 21))	('ORF20WT', 'Var', (195, 202))
281515	29499066	Co-expression of ORF20WT and RIG-I did not alter their subcellular localization, nor did they co-localize (S7B Fig).	('RIG-I', 'Gene', '23586', (29, 34))	('expression', 'Species', '29278', (3, 13))	('s', 'Chemical', 'MESH:D013455', (55, 56))	('RIG-I', 'Gene', (29, 34))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('s', 'Chemical', 'MESH:D013455', (8, 9))	('ORF20WT', 'Var', (17, 24))
281516	29499066	When RIG-I, OASL, and ORF20WT were co-expressed, neither their individual subcellular localization, nor the co-localization between ORF20WT and OASL in the nucleoli, nor the co-localization between RIG-I and OASL in the cytoplasm, was affected (S7C Fig).	('s', 'Chemical', 'MESH:D013455', (227, 228))	('RIG-I', 'Gene', '23586', (5, 10))	('RIG-I', 'Gene', '23586', (198, 203))	('ORF20WT', 'Var', (132, 139))	('p', 'Chemical', 'MESH:D010758', (224, 225))	('RIG-I', 'Gene', (5, 10))	('s', 'Chemical', 'MESH:D013455', (74, 75))	('RIG-I', 'Gene', (198, 203))	('s', 'Chemical', 'MESH:D013455', (43, 44))	('s', 'Chemical', 'MESH:D013455', (44, 45))	('s', 'Chemical', 'MESH:D013455', (233, 234))	('p', 'Chemical', 'MESH:D010758', (40, 41))
281517	29499066	Co-localization between ORF20WT and RIG-I was also not observed in the presence of OASL (S7C Fig).	('ORF20WT', 'Var', (24, 31))	('RIG-I', 'Gene', '23586', (36, 41))	('s', 'Chemical', 'MESH:D013455', (74, 75))	('s', 'Chemical', 'MESH:D013455', (57, 58))	('RIG-I', 'Gene', (36, 41))	('s', 'Chemical', 'MESH:D013455', (44, 45))	('p', 'Chemical', 'MESH:D010758', (71, 72))	('s', 'Chemical', 'MESH:D013455', (48, 49))
281539	29499066	We infected 293T OASL-/- cells reconstituted with either EV or hOASL with KSHVLYT ORF20stop.	('s', 'Chemical', 'MESH:D013455', (87, 88))	('EV', 'Chemical', '-', (57, 59))	('hOASL', 'Gene', '8638', (63, 68))	('s', 'Chemical', 'MESH:D013455', (29, 30))	('p', 'Chemical', 'MESH:D010758', (90, 91))	('s', 'Chemical', 'MESH:D013455', (36, 37))	('KSHVLYT', 'Var', (74, 81))	('ORF20stop', 'Var', (82, 91))	('KSHV', 'Species', '37296', (74, 78))	('hOASL', 'Gene', (63, 68))	('293T', 'CellLine', 'CVCL:0063', (12, 16))
281553	29499066	We characterized the conserved interaction of ORF20 isoforms and homologs with OASL, and we used a variety of mutants to further characterize the interaction of ORF20 with OASL.	('mutants', 'Var', (110, 117))	('s', 'Chemical', 'MESH:D013455', (93, 94))	('interaction', 'Interaction', (31, 42))	('s', 'Chemical', 'MESH:D013455', (72, 73))	('s', 'Chemical', 'MESH:D013455', (53, 54))	('interaction', 'Interaction', (146, 157))	('s', 'Chemical', 'MESH:D013455', (116, 117))	('s', 'Chemical', 'MESH:D013455', (24, 25))	('s', 'Chemical', 'MESH:D013455', (59, 60))
281558	29499066	In this study, we have characterized the three protein isoforms of KSHV ORF20WT: ORF20FL, ORF20A, and ORF20B.	('KSHV', 'Gene', (67, 71))	('ORF20FL', 'Var', (81, 88))	('s', 'Chemical', 'MESH:D013455', (56, 57))	('ORF20A', 'Var', (90, 96))	('s', 'Chemical', 'MESH:D013455', (8, 9))	('s', 'Chemical', 'MESH:D013455', (6, 7))	('ORF20B', 'Var', (102, 108))	('KSHV', 'Species', '37296', (67, 71))	('s', 'Chemical', 'MESH:D013455', (62, 63))	('p', 'Chemical', 'MESH:D010758', (47, 48))
281574	29499066	We characterized the interaction of ORF20WT with a variety of OASL mutants and found that the interaction occurred independently of RNA-binding and the ubiquitin-like domain of OASL.	('p', 'Chemical', 'MESH:D010758', (119, 120))	('interaction', 'Interaction', (21, 32))	('s', 'Chemical', 'MESH:D013455', (73, 74))	('mutants', 'Var', (67, 74))	('OASL', 'Gene', (62, 66))
281575	29499066	Whether nucleolar localization of OASL is exclusively required for its interaction with ORF20WT is still unclear, as the expression of the OASLDeltaUBL mutant was low and thus nucleolar localization may have been obscured.	('s', 'Chemical', 'MESH:D013455', (174, 175))	('s', 'Chemical', 'MESH:D013455', (127, 128))	('s', 'Chemical', 'MESH:D013455', (97, 98))	('expression', 'Species', '29278', (121, 131))	('s', 'Chemical', 'MESH:D013455', (69, 70))	('s', 'Chemical', 'MESH:D013455', (115, 116))	('expression', 'MPA', (121, 131))	('low', 'NegReg', (163, 166))	('s', 'Chemical', 'MESH:D013455', (215, 216))	('mutant', 'Var', (152, 158))	('OASLDeltaUBL', 'Gene', (139, 151))	('s', 'Chemical', 'MESH:D013455', (161, 162))	('s', 'Chemical', 'MESH:D013455', (47, 48))	('s', 'Chemical', 'MESH:D013455', (126, 127))	('s', 'Chemical', 'MESH:D013455', (40, 41))	('s', 'Chemical', 'MESH:D013455', (99, 100))
281578	29499066	We now show that OASL mRNA expression is increased in latently infected HuARLT2-rKSHV.219 cells compared to uninfected cells, and OASL mRNA expression is further increased upon reactivation with concomitant ORF20 mRNA expression.	('KSHV.219', 'CellLine', 'CVCL:G580', (81, 89))	('s', 'Chemical', 'MESH:D013455', (146, 147))	('p', 'Chemical', 'MESH:D010758', (29, 30))	('p', 'Chemical', 'MESH:D010758', (173, 174))	('s', 'Chemical', 'MESH:D013455', (123, 124))	('expression', 'Species', '29278', (140, 150))	('increased', 'PosReg', (162, 171))	('s', 'Chemical', 'MESH:D013455', (145, 146))	('p', 'Chemical', 'MESH:D010758', (220, 221))	('s', 'Chemical', 'MESH:D013455', (33, 34))	('expression', 'Species', '29278', (218, 228))	('s', 'Chemical', 'MESH:D013455', (168, 169))	('p', 'Chemical', 'MESH:D010758', (99, 100))	('s', 'Chemical', 'MESH:D013455', (223, 224))	('s', 'Chemical', 'MESH:D013455', (224, 225))	('expression', 'Species', '29278', (27, 37))	('s', 'Chemical', 'MESH:D013455', (152, 153))	('s', 'Chemical', 'MESH:D013455', (39, 40))	('s', 'Chemical', 'MESH:D013455', (32, 33))	('s', 'Chemical', 'MESH:D013455', (47, 48))	('OASL mRNA expression', 'MPA', (130, 150))	('OASL mRNA expression', 'MPA', (17, 37))	('s', 'Chemical', 'MESH:D013455', (7, 8))	('increased', 'PosReg', (41, 50))	('ORF20', 'Var', (207, 212))	('p', 'Chemical', 'MESH:D010758', (142, 143))	('s', 'Chemical', 'MESH:D013455', (94, 95))
281582	29499066	When we infected OASL-reconstituted cells with MHV68-GFP or KSHVLYT, we found that the number of infected cells was significantly increased compared to EV-transfected cells.	('MHV68-GFP', 'Var', (47, 56))	('s', 'Chemical', 'MESH:D013455', (27, 28))	('s', 'Chemical', 'MESH:D013455', (40, 41))	('MHV68', 'Species', '1440122', (47, 52))	('p', 'Chemical', 'MESH:D010758', (143, 144))	('EV', 'Chemical', '-', (152, 154))	('s', 'Chemical', 'MESH:D013455', (159, 160))	('s', 'Chemical', 'MESH:D013455', (114, 115))	('s', 'Chemical', 'MESH:D013455', (110, 111))	('s', 'Chemical', 'MESH:D013455', (116, 117))	('s', 'Chemical', 'MESH:D013455', (136, 137))	('increased', 'PosReg', (130, 139))	('KSHV', 'Species', '37296', (60, 64))	('s', 'Chemical', 'MESH:D013455', (171, 172))
281583	29499066	When we infected hOASL-reconstituted 293T OASL-/- cells with KSHVLYT ORF20stop, we did not observe enhancement of infection.	('KSHVLYT ORF20stop', 'Var', (61, 78))	('ORF20stop', 'Var', (69, 78))	('s', 'Chemical', 'MESH:D013455', (93, 94))	('p', 'Chemical', 'MESH:D010758', (77, 78))	('hOASL', 'Gene', '8638', (17, 22))	('s', 'Chemical', 'MESH:D013455', (74, 75))	('hOASL', 'Gene', (17, 22))	('293T', 'CellLine', 'CVCL:0063', (37, 41))	('s', 'Chemical', 'MESH:D013455', (54, 55))	('KSHV', 'Species', '37296', (61, 65))	('s', 'Chemical', 'MESH:D013455', (28, 29))
281595	29499066	Both proteins sedimented with 40S and 60S ribosomal subunits when expressed individually and in combination with each other, further validating the protein interactions we identified by q-AP-MS. Interestingly, we found that when ORF20 and OASL were co-expressed, both proteins associated with polysomes.	('s', 'Chemical', 'MESH:D013455', (258, 259))	('polysomes', 'MPA', (293, 302))	('proteins', 'Protein', (268, 276))	('p', 'Chemical', 'MESH:D010758', (268, 269))	('s', 'Chemical', 'MESH:D013455', (52, 53))	('s', 'Chemical', 'MESH:D013455', (275, 276))	('s', 'Chemical', 'MESH:D013455', (297, 298))	('s', 'Chemical', 'MESH:D013455', (12, 13))	('p', 'Chemical', 'MESH:D010758', (293, 294))	('s', 'Chemical', 'MESH:D013455', (257, 258))	('s', 'Chemical', 'MESH:D013455', (201, 202))	('p', 'Chemical', 'MESH:D010758', (148, 149))	('s', 'Chemical', 'MESH:D013455', (167, 168))	('p', 'Chemical', 'MESH:D010758', (5, 6))	('q-AP', 'Chemical', '-', (186, 190))	('p', 'Chemical', 'MESH:D010758', (68, 69))	('s', 'Chemical', 'MESH:D013455', (278, 279))	('s', 'Chemical', 'MESH:D013455', (279, 280))	('s', 'Chemical', 'MESH:D013455', (72, 73))	('s', 'Chemical', 'MESH:D013455', (71, 72))	('s', 'Chemical', 'MESH:D013455', (301, 302))	('s', 'Chemical', 'MESH:D013455', (14, 15))	('ORF20', 'Var', (229, 234))	('p', 'Chemical', 'MESH:D010758', (254, 255))	('associated', 'Interaction', (277, 287))	('s', 'Chemical', 'MESH:D013455', (46, 47))	('s', 'Chemical', 'MESH:D013455', (59, 60))
281611	29499066	By manipulating the incorporation of specific ribosomal proteins, a virus could promote translation of desirable mRNAs.	('translation of', 'MPA', (88, 102))	('ribosomal proteins', 'Protein', (46, 64))	('s', 'Chemical', 'MESH:D013455', (63, 64))	('s', 'Chemical', 'MESH:D013455', (117, 118))	('p', 'Chemical', 'MESH:D010758', (38, 39))	('p', 'Chemical', 'MESH:D010758', (25, 26))	('p', 'Chemical', 'MESH:D010758', (7, 8))	('s', 'Chemical', 'MESH:D013455', (72, 73))	('p', 'Chemical', 'MESH:D010758', (56, 57))	('s', 'Chemical', 'MESH:D013455', (50, 51))	('s', 'Chemical', 'MESH:D013455', (92, 93))	('p', 'Chemical', 'MESH:D010758', (80, 81))	('s', 'Chemical', 'MESH:D013455', (37, 38))	('s', 'Chemical', 'MESH:D013455', (105, 106))	('manipulating', 'Var', (3, 15))	('promote', 'PosReg', (80, 87))
281623	29499066	Antibodies against fibrillarin (# 2639), IRF3 (# 4302 for immunoblotting), STAT1 (# 9172), and the anti-myc tag mouse monoclonal 9B11 (# 2276) were from Cell Signaling.	('# 9172', 'Var', (82, 88))	('STAT1', 'Gene', '6772', (75, 80))	('# 2639', 'Var', (32, 38))	('myc', 'Gene', (104, 107))	('IRF3', 'Gene', '3661', (41, 45))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('s', 'Chemical', 'MESH:D013455', (115, 116))	('s', 'Chemical', 'MESH:D013455', (16, 17))	('# 2276', 'Var', (135, 141))	('# 4302', 'Var', (47, 53))	('myc', 'Gene', '4609', (104, 107))	('STAT1', 'Gene', (75, 80))	('mouse', 'Species', '10090', (112, 117))	('IRF3', 'Gene', (41, 45))
281624	29499066	Rabbit anti-c-myc (# C3956), mouse anti-tubulin (# T6199-200UL), and mouse anti-beta-actin (#A5441) antibodies were purchased from Sigma-Aldrich.	('s', 'Chemical', 'MESH:D013455', (72, 73))	('mouse', 'Species', '10090', (69, 74))	('# T6199-200UL', 'Var', (49, 62))	('s', 'Chemical', 'MESH:D013455', (32, 33))	('c-myc', 'Gene', (12, 17))	('mouse', 'Species', '10090', (29, 34))	('c-myc', 'Gene', '4609', (12, 17))	('s', 'Chemical', 'MESH:D013455', (109, 110))	('# C3956', 'Var', (19, 26))	('s', 'Chemical', 'MESH:D013455', (122, 123))	('p', 'Chemical', 'MESH:D010758', (116, 117))	('Rabbit', 'Species', '9986', (0, 6))
281626	29499066	Anti-V5 antibodies were purchased from Invitrogen (# R960-25) and Biolegend (# 680601).	('p', 'Chemical', 'MESH:D010758', (24, 25))	('# 680601', 'Var', (77, 85))	('s', 'Chemical', 'MESH:D013455', (30, 31))	('# R960-25', 'Var', (51, 60))	('s', 'Chemical', 'MESH:D013455', (17, 18))
281635	29499066	ORF20FLgA and ORF20FLB potentially express ORF20FL and ORF20A or ORF20FL and ORF20B, respectively, from their genomic start codons.	('s', 'Chemical', 'MESH:D013455', (41, 42))	('s', 'Chemical', 'MESH:D013455', (87, 88))	('ORF20A', 'Var', (55, 61))	('ORF20FL', 'Var', (43, 50))	('s', 'Chemical', 'MESH:D013455', (118, 119))	('ORF20B', 'Var', (77, 83))	('ORF20FL', 'Var', (65, 72))	('express', 'Reg', (35, 42))	('ORF20FLgA', 'Var', (0, 9))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('p', 'Chemical', 'MESH:D010758', (23, 24))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('s', 'Chemical', 'MESH:D013455', (129, 130))	('s', 'Chemical', 'MESH:D013455', (40, 41))
281643	29499066	pcDNA3.1 human OASL-V5 WT (OASL-V5 or hOASL) and mutants have been previously described.	('mutants', 'Var', (49, 56))	('s', 'Chemical', 'MESH:D013455', (80, 81))	('s', 'Chemical', 'MESH:D013455', (55, 56))	('hOASL', 'Gene', '8638', (38, 43))	('s', 'Chemical', 'MESH:D013455', (74, 75))	('human', 'Species', '9606', (9, 14))	('p', 'Chemical', 'MESH:D010758', (67, 68))	('hOASL', 'Gene', (38, 43))	('pcDNA3.1', 'Gene', (0, 8))	('p', 'Chemical', 'MESH:D010758', (0, 1))
281651	29499066	We mutated the ORF20FL GAG codon for E69 into the stop codon TAG to stop translation of ORF20FL, ORF20A, and ORF20B without altering the ORF21 promoter.	('E69', 'Var', (37, 40))	('ORF20FL', 'Var', (88, 95))	('p', 'Chemical', 'MESH:D010758', (143, 144))	('s', 'Chemical', 'MESH:D013455', (50, 51))	('ORF20B', 'Var', (109, 115))	('s', 'Chemical', 'MESH:D013455', (68, 69))	('s', 'Chemical', 'MESH:D013455', (77, 78))	('p', 'Chemical', 'MESH:D010758', (53, 54))	('p', 'Chemical', 'MESH:D010758', (71, 72))	('mutated', 'Var', (3, 10))
281652	29499066	KSHVLYT-BAC mutant clones were fully sequenced to confirm successful mutagenesis and to exclude additional undesired mutations in the viral genome.	('s', 'Chemical', 'MESH:D013455', (63, 64))	('s', 'Chemical', 'MESH:D013455', (58, 59))	('s', 'Chemical', 'MESH:D013455', (111, 112))	('KSHV', 'Species', '37296', (0, 4))	('mutagenesis', 'Var', (69, 80))	('s', 'Chemical', 'MESH:D013455', (125, 126))	('mutant', 'Var', (12, 18))	('s', 'Chemical', 'MESH:D013455', (37, 38))	('s', 'Chemical', 'MESH:D013455', (77, 78))	('s', 'Chemical', 'MESH:D013455', (64, 65))	('KSHVLYT-BAC', 'Gene', (0, 11))	('s', 'Chemical', 'MESH:D013455', (24, 25))	('s', 'Chemical', 'MESH:D013455', (79, 80))
281654	29499066	For reconstitution of KSHVLYT wildtype or ORF20stop, BAC DNA was transfected into hTERT RPE-1 cells using Polyfect (Qiagen), propagated in the same cells, and concentrated by centrifugation for 4 h at 15,000 xg at 4 C. Viral stock titers were determined using the median tissue culture infective dose (TCID50) method on M2-10B4 cells and hTERT-RPE1 cells for MHV68 and KSHVLYT, respectively, as previously described.	('p', 'Chemical', 'MESH:D010758', (381, 382))	('p', 'Chemical', 'MESH:D010758', (395, 396))	('s', 'Chemical', 'MESH:D013455', (402, 403))	('s', 'Chemical', 'MESH:D013455', (69, 70))	('s', 'Chemical', 'MESH:D013455', (225, 226))	('s', 'Chemical', 'MESH:D013455', (393, 394))	('p', 'Chemical', 'MESH:D010758', (125, 126))	('s', 'Chemical', 'MESH:D013455', (273, 274))	('s', 'Chemical', 'MESH:D013455', (98, 99))	('s', 'Chemical', 'MESH:D013455', (274, 275))	('s', 'Chemical', 'MESH:D013455', (353, 354))	('s', 'Chemical', 'MESH:D013455', (298, 299))	('s', 'Chemical', 'MESH:D013455', (408, 409))	('hTERT-RPE1', 'Gene', '7015', (338, 348))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('hTERT-RPE1', 'Gene', (338, 348))	('MHV68', 'Species', '1440122', (359, 364))	('p', 'Chemical', 'MESH:D010758', (36, 37))	('KSHV', 'Species', '37296', (22, 26))	('s', 'Chemical', 'MESH:D013455', (255, 256))	('s', 'Chemical', 'MESH:D013455', (63, 64))	('ORF20stop', 'Var', (42, 51))	('s', 'Chemical', 'MESH:D013455', (152, 153))	('s', 'Chemical', 'MESH:D013455', (332, 333))	('KSHV', 'Species', '37296', (369, 373))	('hTERT RPE-1', 'CellLine', 'CVCL:4388', (82, 93))	('s', 'Chemical', 'MESH:D013455', (47, 48))	('p', 'Chemical', 'MESH:D010758', (50, 51))	('s', 'Chemical', 'MESH:D013455', (380, 381))	('s', 'Chemical', 'MESH:D013455', (143, 144))	('s', 'Chemical', 'MESH:D013455', (101, 102))	('p', 'Chemical', 'MESH:D010758', (128, 129))	('s', 'Chemical', 'MESH:D013455', (236, 237))
281687	29499066	HeLa S3 cells were metabolically labeled for 10 days in lysine- and arginine-free DMEM (Pierce) supplemented with dialyzed fetal bovine serum (Pierce), p/s (Invitrogen), 2 mM glutamine (Invitrogen), and either 0.22 mM 13C6 15N2 L-lysine-2HCl and 0.1385 mM 13C6 L-arginine-HCl (Pierce) for heavy-labeled cells or the corresponding unlabeled amino acids (Pierce) for light-labeled cells.	('arginine', 'Chemical', 'MESH:D001120', (68, 76))	('s', 'Chemical', 'MESH:D013455', (307, 308))	('s', 'Chemical', 'MESH:D013455', (321, 322))	('s', 'Chemical', 'MESH:D013455', (12, 13))	('p', 'Chemical', 'MESH:D010758', (322, 323))	('s', 'Chemical', 'MESH:D013455', (154, 155))	('DMEM', 'Chemical', '-', (82, 86))	('HCl', 'Chemical', '-', (272, 275))	('s', 'Chemical', 'MESH:D013455', (58, 59))	('HCl', 'Chemical', '-', (238, 241))	('s', 'Chemical', 'MESH:D013455', (51, 52))	('HeLa S3', 'CellLine', 'CVCL:0058', (0, 7))	('bovine', 'Species', '9913', (129, 135))	('s', 'Chemical', 'MESH:D013455', (383, 384))	('s', 'Chemical', 'MESH:D013455', (232, 233))	('glutamine', 'Chemical', 'MESH:D005973', (175, 184))	('s', 'Chemical', 'MESH:D013455', (136, 137))	('p', 'Chemical', 'MESH:D010758', (98, 99))	('s', 'Chemical', 'MESH:D013455', (350, 351))	('arginine', 'Chemical', 'MESH:D001120', (263, 271))	('p', 'Chemical', 'MESH:D010758', (99, 100))	('s', 'Chemical', 'MESH:D013455', (96, 97))	('0.22 mM 13C6 15N2', 'Var', (210, 227))	('lysine', 'Chemical', 'MESH:D008239', (56, 62))	('p', 'Chemical', 'MESH:D010758', (152, 153))	('lysine', 'Chemical', 'MESH:D008239', (230, 236))	('0.1385 mM 13C6', 'Var', (246, 260))
281690	29499066	For the forward experiment, heavy labeled HeLa S3 cells were transfected with ORF20WT or OASL-myc, while light labeled HeLa S3 cells were transfected with LacZ-myc.	('s', 'Chemical', 'MESH:D013455', (54, 55))	('s', 'Chemical', 'MESH:D013455', (142, 143))	('s', 'Chemical', 'MESH:D013455', (65, 66))	('p', 'Chemical', 'MESH:D010758', (18, 19))	('myc', 'Gene', (94, 97))	('s', 'Chemical', 'MESH:D013455', (131, 132))	('HeLa S3', 'CellLine', 'CVCL:0058', (42, 49))	('myc', 'Gene', (160, 163))	('ORF20WT', 'Var', (78, 85))	('myc', 'Gene', '4609', (94, 97))	('HeLa S3', 'CellLine', 'CVCL:0058', (119, 126))	('myc', 'Gene', '4609', (160, 163))
281706	29499066	293T cells were transfected with either ORF20WT, OASL-myc, or both combined.	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('myc', 'Gene', '4609', (54, 57))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('myc', 'Gene', (54, 57))	('ORF20WT', 'Var', (40, 47))	('s', 'Chemical', 'MESH:D013455', (20, 21))
281711	29499066	293T cells were transfected with pcDNA4/myc-His B (EV), ORF20WT, ORF20FL, or ORF20B, and a small amount of either pcDNA3.1(+) (EV, control) or RIG-I N to induce expression of endogenous OASL.	('EV', 'Chemical', '-', (51, 53))	('induce', 'PosReg', (154, 160))	('ORF20B', 'Var', (77, 83))	('s', 'Chemical', 'MESH:D013455', (91, 92))	('RIG-I', 'Gene', (143, 148))	('expression', 'MPA', (161, 171))	('s', 'Chemical', 'MESH:D013455', (184, 185))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('p', 'Chemical', 'MESH:D010758', (163, 164))	('EV', 'Chemical', '-', (127, 129))	('s', 'Chemical', 'MESH:D013455', (167, 168))	('myc', 'Gene', '4609', (40, 43))	('ORF20WT', 'Var', (56, 63))	('s', 'Chemical', 'MESH:D013455', (166, 167))	('ORF20FL', 'Var', (65, 72))	('p', 'Chemical', 'MESH:D010758', (114, 115))	('p', 'Chemical', 'MESH:D010758', (33, 34))	('myc', 'Gene', (40, 43))	('expression', 'Species', '29278', (161, 171))	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('s', 'Chemical', 'MESH:D013455', (46, 47))	('RIG-I', 'Gene', '23586', (143, 148))	('s', 'Chemical', 'MESH:D013455', (20, 21))
281723	29499066	All siRNAs were purchased from Dharmacon/GE Life Sciences: ON-TARGETplus non-targeting pool (D-001810-10-20, control siRNA), ON-TARGETplus human IRF3 SMARTpool siRNA (L-006875-00-0010), ON-TARGETplus human STAT1 SMARTpool siRNA (L-003543-00-0005), and ON-TARGETplus human IFNAR1 SMARTpool siRNA (L-020209-00-0005).	('p', 'Chemical', 'MESH:D010758', (134, 135))	('p', 'Chemical', 'MESH:D010758', (261, 262))	('human', 'Species', '9606', (200, 205))	('L-003543-00-0005', 'Var', (229, 245))	('p', 'Chemical', 'MESH:D010758', (284, 285))	('p', 'Chemical', 'MESH:D010758', (195, 196))	('s', 'Chemical', 'MESH:D013455', (264, 265))	('s', 'Chemical', 'MESH:D013455', (289, 290))	('L-006875-00-0010', 'Var', (167, 183))	('s', 'Chemical', 'MESH:D013455', (9, 10))	('IRF3', 'Gene', (145, 149))	('p', 'Chemical', 'MESH:D010758', (155, 156))	('s', 'Chemical', 'MESH:D013455', (137, 138))	('p', 'Chemical', 'MESH:D010758', (68, 69))	('s', 'Chemical', 'MESH:D013455', (56, 57))	('L-020209-00-0005', 'Var', (296, 312))	('STAT1', 'Gene', (206, 211))	('p', 'Chemical', 'MESH:D010758', (217, 218))	('s', 'Chemical', 'MESH:D013455', (198, 199))	('s', 'Chemical', 'MESH:D013455', (160, 161))	('s', 'Chemical', 'MESH:D013455', (71, 72))	('s', 'Chemical', 'MESH:D013455', (222, 223))	('IRF3', 'Gene', '3661', (145, 149))	('IFNAR1', 'Gene', (272, 278))	('D-001810-10-20', 'Var', (93, 107))	('s', 'Chemical', 'MESH:D013455', (117, 118))	('IFNAR1', 'Gene', '3454', (272, 278))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('STAT1', 'Gene', '6772', (206, 211))	('s', 'Chemical', 'MESH:D013455', (22, 23))	('human', 'Species', '9606', (139, 144))	('p', 'Chemical', 'MESH:D010758', (16, 17))	('s', 'Chemical', 'MESH:D013455', (4, 5))	('human', 'Species', '9606', (266, 271))
281729	29499066	2 days later cells were co-transfected with pcDNA4/myc-His B (EV) or ORF20WT, and either pcDNA3.1(+) (EV) or RIG-I N. 24 h later, RNA was prepared and q-RT-PCR was performed for OASL, GAPDH, and either IRF3, STAT1, or IFNAR as appropriate.	('s', 'Chemical', 'MESH:D013455', (162, 163))	('s', 'Chemical', 'MESH:D013455', (225, 226))	('GAPDH', 'Gene', '2597', (184, 189))	('RIG-I', 'Gene', '23586', (109, 114))	('STAT1', 'Gene', (208, 213))	('p', 'Chemical', 'MESH:D010758', (141, 142))	('s', 'Chemical', 'MESH:D013455', (5, 6))	('myc', 'Gene', '4609', (51, 54))	('p', 'Chemical', 'MESH:D010758', (228, 229))	('IRF3', 'Gene', '3661', (202, 206))	('p', 'Chemical', 'MESH:D010758', (164, 165))	('myc', 'Gene', (51, 54))	('p', 'Chemical', 'MESH:D010758', (138, 139))	('GAPDH', 'Gene', (184, 189))	('s', 'Chemical', 'MESH:D013455', (57, 58))	('RIG-I', 'Gene', (109, 114))	('s', 'Chemical', 'MESH:D013455', (136, 137))	('STAT1', 'Gene', '6772', (208, 213))	('EV', 'Chemical', '-', (62, 64))	('IFNAR', 'Gene', (218, 223))	('s', 'Chemical', 'MESH:D013455', (17, 18))	('p', 'Chemical', 'MESH:D010758', (44, 45))	('IFNAR', 'Gene', '3454', (218, 223))	('EV', 'Chemical', '-', (102, 104))	('p', 'Chemical', 'MESH:D010758', (232, 233))	('p', 'Chemical', 'MESH:D010758', (89, 90))	('ORF20WT', 'Var', (69, 76))	('s', 'Chemical', 'MESH:D013455', (31, 32))	('p', 'Chemical', 'MESH:D010758', (229, 230))	('IRF3', 'Gene', (202, 206))
281734	29499066	The next day, 16 h, 20 h, or 24 h post infection for VSV-GFP, MHV68-GFP, or KSHVLYT, respectively, cells were detached using trypsin, fixed for 30 minutes with 4% PFA, and the number of green cells was determined by flow cytometry on an LSRII instrument.	('p', 'Chemical', 'MESH:D010758', (34, 35))	('s', 'Chemical', 'MESH:D013455', (103, 104))	('s', 'Chemical', 'MESH:D013455', (87, 88))	('s', 'Chemical', 'MESH:D013455', (200, 201))	('s', 'Chemical', 'MESH:D013455', (245, 246))	('s', 'Chemical', 'MESH:D013455', (36, 37))	('MHV68-GFP', 'Var', (62, 71))	('s', 'Chemical', 'MESH:D013455', (153, 154))	('p', 'Chemical', 'MESH:D010758', (128, 129))	('KSHV', 'Species', '37296', (76, 80))	('PFA', 'Chemical', 'MESH:D017245', (163, 166))	('MHV68', 'Species', '1440122', (62, 67))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('s', 'Chemical', 'MESH:D013455', (120, 121))	('s', 'Chemical', 'MESH:D013455', (129, 130))	('VSV-GFP', 'Var', (53, 60))	('s', 'Chemical', 'MESH:D013455', (196, 197))
281764	27144561	Although deregulated BCL2 expression is critical for apoptosis, which is a key step in tumorigenesis, it is not clear the mechanism underlying the stability of the BCL2 protein.	('deregulated', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('BCL2', 'Gene', (21, 25))	('BCL2', 'Gene', (164, 168))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('BCL2', 'Gene', '596', (21, 25))	('BCL2', 'Gene', '596', (164, 168))
281766	27144561	In this context, while the role of aberrantly expressed miRNAs is well established for other types of cancer, few studies exist for ES.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('aberrantly expressed', 'Var', (35, 55))
281772	27144561	As a consequence, their abnormal expression, caused by chromosomal alterations, might contribute to develop cancer and/or its progression.	('chromosomal alterations', 'Var', (55, 78))	('abnormal', 'Reg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('expression', 'MPA', (33, 43))	('contribute', 'Reg', (86, 96))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
281812	27144561	To note, our study suggests that certain aberrantly expressed miRNAs all target the BCL-2 family genes in ES patients.	('target', 'Reg', (73, 79))	('patients', 'Species', '9606', (109, 117))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('BCL-2', 'Gene', '596', (84, 89))	('aberrantly expressed', 'Var', (41, 61))	('BCL-2', 'Gene', (84, 89))
281813	27144561	As shown in Figure 4, we identified the BCL-2 gene as being a specific target of miR-21, miR-181a, miR-181b, miR-29a, miR-29b, miR-497, miR-195, let-7a, miR-34a and miR-1915 (Figure 4 and Table 4).	('miR', 'Gene', (109, 112))	('miR', 'Gene', '220972', (99, 102))	('miR-497', 'Gene', (127, 134))	('miR-29b', 'Gene', '407024', (118, 125))	('miR-497', 'Gene', '574456', (127, 134))	('miR', 'Gene', (165, 168))	('miR-195', 'Gene', '406971', (136, 143))	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (99, 102))	('miR', 'Gene', '220972', (89, 92))	('miR-34a', 'Gene', (153, 160))	('miR-21', 'Gene', '406991', (81, 87))	('miR-1915', 'Gene', (165, 173))	('BCL-2', 'Gene', '596', (40, 45))	('miR-29b', 'Gene', (118, 125))	('miR-195', 'Gene', (136, 143))	('miR-34a', 'Gene', '407040', (153, 160))	('miR', 'Gene', '220972', (153, 156))	('let-7a', 'Var', (145, 151))	('BCL-2', 'Gene', (40, 45))	('miR', 'Gene', (81, 84))	('miR', 'Gene', (89, 92))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', '220972', (118, 121))	('miR-29a', 'Gene', (109, 116))	('miR-29a', 'Gene', '407021', (109, 116))	('miR-21', 'Gene', (81, 87))	('miR-1915', 'Gene', '100302129', (165, 173))	('miR', 'Gene', '220972', (109, 112))	('miR', 'Gene', (153, 156))	('miR', 'Gene', (127, 130))	('miR', 'Gene', (136, 139))	('miR', 'Gene', '220972', (165, 168))	('miR', 'Gene', (118, 121))
281815	27144561	Using the microarray approach we identified 58 differentially expressed miRNAs, including miR-21, miR-30b, miR-27a, miR-106b, miR-181a/b, miR-130a, let-7e, let-7b, let-7f, let-7g, let-7a and miR-34a, all of them up-regulated.	('miR-130a', 'Gene', '406919', (138, 146))	('miR-130a', 'Gene', (138, 146))	('let-7e', 'Gene', '406887', (148, 154))	('miR', 'Gene', (126, 129))	('miR', 'Gene', '220972', (116, 119))	('miR-27a', 'Gene', '407018', (107, 114))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', '220972', (107, 110))	('up-regulated', 'PosReg', (212, 224))	('miR-21', 'Gene', '406991', (90, 96))	('let-7b', 'Gene', (156, 162))	('miR', 'Gene', '220972', (98, 101))	('miR-106b', 'Gene', '406900', (116, 124))	('miR', 'Gene', (116, 119))	('miR', 'Gene', (138, 141))	('miR-30b', 'Gene', '407030', (98, 105))	('miR', 'Gene', (90, 93))	('miR-30b', 'Gene', (98, 105))	('miR', 'Gene', (107, 110))	('miR-106b', 'Gene', (116, 124))	('miR', 'Gene', '220972', (191, 194))	('miR-27a', 'Gene', (107, 114))	('miR', 'Gene', (98, 101))	('miR-34a', 'Gene', (191, 198))	('miR-21', 'Gene', (90, 96))	('let-7g', 'Gene', '406890', (172, 178))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (191, 194))	('let-7f', 'Var', (164, 170))	('miR', 'Gene', '220972', (126, 129))	('miR-34a', 'Gene', '407040', (191, 198))	('let-7g', 'Gene', (172, 178))	('let-7e', 'Gene', (148, 154))	('let-7b', 'Gene', '406884', (156, 162))	('miR', 'Gene', (72, 75))	('let-7a', 'Var', (180, 186))
281826	27144561	In a different study, depletion or down-regulation of miR-21 by a specific antisense oligonucleotide, has been demonstrated to result in decreased cell proliferation, inhibited cell-cycle progression and increased cell apoptosis.	('cell-cycle progression', 'CPA', (177, 199))	('oligonucleotide', 'Chemical', 'MESH:D009841', (85, 100))	('inhibited', 'NegReg', (167, 176))	('cell apoptosis', 'CPA', (214, 228))	('depletion', 'Var', (22, 31))	('cell proliferation', 'CPA', (147, 165))	('increased', 'PosReg', (204, 213))	('miR-21', 'Gene', '406991', (54, 60))	('decreased', 'NegReg', (137, 146))	('miR-21', 'Gene', (54, 60))	('down-regulation', 'NegReg', (35, 50))
281829	27144561	Aberrantly regulated miR-181a and miR-181b have been correlated with cancer progression and poor survival in cervical cancer, ovarian cancer and breast cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('miR', 'Gene', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (152, 158))	('cervical cancer', 'Disease', 'MESH:D002583', (109, 124))	('cervical cancer', 'Disease', (109, 124))	('cancer', 'Disease', (134, 140))	('miR', 'Gene', '220972', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('Aberrantly regulated', 'Var', (0, 20))	('cancer', 'Disease', (118, 124))	('ovarian cancer', 'Disease', 'MESH:D010051', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('miR', 'Gene', (34, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('correlated', 'Reg', (53, 63))	('miR', 'Gene', '220972', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('ovarian cancer', 'Disease', (126, 140))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Disease', (145, 158))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
281856	27144561	Although this finding does not imply that genes for miRNAs clusters are associated with genomic alterations, those located in the regions involved in chromosomal translocations might be aberrantly expressed in translocation-caused Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (231, 244))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (231, 244))	('translocation-caused', 'Var', (210, 230))	('Ewing sarcoma', 'Disease', (231, 244))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))
281860	27144561	They observed that the inhibition of HIF-1alpha decreased the miR-210 expression and autophagy and that the silencing of miR-210 up-regulated BCL-2 expression.	('silencing', 'Var', (108, 117))	('miR-210', 'Gene', (121, 128))	('miR-210', 'Gene', '406992', (121, 128))	('BCL-2', 'Gene', '596', (142, 147))	('inhibition', 'NegReg', (23, 33))	('decreased', 'NegReg', (48, 57))	('HIF-1alpha', 'Gene', (37, 47))	('expression', 'MPA', (70, 80))	('up-regulated', 'PosReg', (129, 141))	('BCL-2', 'Gene', (142, 147))	('miR-210', 'Gene', (62, 69))	('expression', 'MPA', (148, 158))	('miR-210', 'Gene', '406992', (62, 69))	('autophagy', 'CPA', (85, 94))	('HIF-1alpha', 'Gene', '3091', (37, 47))
281875	27144561	recently demonstrated that miR-1275 was downregulated during Glioma stem-like cell differentiation, together with the upregulation of its target, CLDN11, via PRC2-H3K27me3.	('Glioma', 'Phenotype', 'HP:0009733', (61, 67))	('CLDN11', 'Gene', (146, 152))	('upregulation', 'PosReg', (118, 130))	('downregulated', 'NegReg', (40, 53))	('miR-1275', 'Gene', '100302123', (27, 35))	('miR-1275', 'Gene', (27, 35))	('CLDN11', 'Gene', '5010', (146, 152))	('PRC2-H3K27me3', 'Var', (158, 171))	('Glioma stem-like cell differentiation', 'CPA', (61, 98))
281876	27144561	Several studies have highlighted the essential contribution of PRC2-H3K27me3 to the repression of developmental regulator genes that enable successful cell fate reassignment.	('developmental regulator genes', 'Gene', (98, 127))	('PRC2-H3K27me3', 'Var', (63, 76))	('men', 'Species', '9606', (169, 172))	('men', 'Species', '9606', (105, 108))
281880	27144561	Although several groups have already identified and characterized deregulated miRNAs expression in ES using different approaches, a limiting factor has been the scarce availability of patient tissue's samples for research given the low incidence of the tumor (approximately one case per million in the general population).	('miR', 'Gene', '220972', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('miR', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('deregulated', 'Var', (66, 77))	('tumor', 'Disease', (253, 258))	('patient', 'Species', '9606', (184, 191))
281907	27144561	Briefly, microarray processing in the a-Hyb was performed as follows: incubation in Pre-Hyb Solution (Miltenyi Biotec) for 5 min at 42  C, hybridization with the labelled RNAs for 960 min at 42  C, washing with Wash Buffer I (Miltenyi Biotec) for 1 min at 10  C (2 cycles) and with Wash Buffer II (Miltenyi Biotec) for 1 min at 10  C (2 cycles).	('RNAs', 'Protein', (171, 175))	('Biotec', 'Chemical', '-', (111, 117))	('Biotec', 'Chemical', '-', (307, 313))	('Wash Buffer II', 'Disease', (282, 296))	('Biotec', 'Chemical', '-', (235, 241))	('hybridization', 'Var', (139, 152))	('Wash Buffer II', 'Disease', 'MESH:C537730', (282, 296))
281927	27144561	Target Gene prediction of deregulated miRNAs; Table S5.	('deregulated', 'Var', (26, 37))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))
281928	27144561	Summary of chromosomal loci of deregulated miRNAs in Ewing's Sarcoma tissue; Table S6.	('miR', 'Gene', '220972', (43, 46))	("Ewing's Sarcoma", 'Disease', (53, 68))	('miR', 'Gene', (43, 46))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (53, 68))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (53, 68))	('deregulated', 'Var', (31, 42))	('Sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
281954	32204400	Mechanistically, epi-1 increased intracellular calcium levels, which stimulated reactive oxygen species (ROS) production and calpain activity, subsequently causing mitochondrial damage and cell death.	('stimulated', 'PosReg', (69, 79))	('ROS', 'Chemical', 'MESH:D017382', (105, 108))	('calpain', 'Protein', (125, 132))	('mitochondrial damage', 'Disease', (164, 184))	('epi-1', 'Chemical', '-', (17, 22))	('increased intracellular calcium', 'Phenotype', 'HP:0003575', (23, 54))	('epi-1', 'Var', (17, 22))	('causing', 'Reg', (156, 163))	('mitochondrial damage', 'Disease', 'MESH:D028361', (164, 184))	('calcium', 'Chemical', 'MESH:D002118', (47, 54))	('increased', 'PosReg', (23, 32))	('activity', 'MPA', (133, 141))	('intracellular calcium levels', 'MPA', (33, 61))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (80, 103))
281961	32204400	To determine whether the alpha-helical structure is essential for epi-1-mediated cytotoxicity in synovial sarcoma cells, SW982 cells were treated with epi-1 or scr-epi-1 (scrambled epi-1; has the same charge as epi-1, but its secondary structure is an imperfect alpha-helix).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('SW982', 'CellLine', 'CVCL:1734', (121, 126))	('cytotoxicity', 'Disease', (81, 93))	('epi-1', 'Chemical', '-', (151, 156))	('epi-1', 'Chemical', '-', (66, 71))	('synovial sarcoma', 'Disease', 'MESH:D013584', (97, 113))	('epi-1', 'Var', (151, 156))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (97, 113))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('epi-1', 'Chemical', '-', (181, 186))	('epi-1', 'Chemical', '-', (211, 216))	('scr-epi-1', 'Var', (160, 169))	('epi-1', 'Chemical', '-', (164, 169))	('synovial sarcoma', 'Disease', (97, 113))
281966	32204400	Activation of caspase-3 was induced by stau but not epi-1 (Figure 2A,B).	('stau', 'Chemical', 'MESH:D019311', (39, 43))	('caspase-3', 'Gene', '836', (14, 23))	('epi-1', 'Chemical', '-', (52, 57))	('caspase-3', 'Gene', (14, 23))	('stau', 'Var', (39, 43))
281967	32204400	Consistently, epi-1 did not induce activation of caspase-3 at any tested time point (Figure 2D).	('caspase-3', 'Gene', (49, 58))	('epi-1', 'Var', (14, 19))	('epi-1', 'Chemical', '-', (14, 19))	('caspase-3', 'Gene', '836', (49, 58))
281971	32204400	Epi-1-treated cells also exhibited propidium iodide incorporation, while stau-treated cells did not (Figure 2F).	('Epi-1', 'Chemical', '-', (0, 5))	('Epi-1-treated', 'Var', (0, 13))	('stau', 'Chemical', 'MESH:D019311', (73, 77))	('propidium iodide incorporation', 'MPA', (35, 65))	('propidium iodide', 'Chemical', 'MESH:D011419', (35, 51))
281976	32204400	Calpain activity was also quickly induced within 15 min (Figure 3D), and suppression of calpain activity by PD151746 inhibited epi-1-mediated cytotoxicity (Figure 3E).	('calpain activity', 'MPA', (88, 104))	('epi-1', 'Chemical', '-', (127, 132))	('cytotoxicity', 'Disease', 'MESH:D064420', (142, 154))	('suppression', 'NegReg', (73, 84))	('PD151746', 'Var', (108, 116))	('epi-1-mediated', 'MPA', (127, 141))	('Calpain activity', 'MPA', (0, 16))	('inhibited', 'NegReg', (117, 126))	('cytotoxicity', 'Disease', (142, 154))	('PD151746', 'Chemical', 'MESH:C117345', (108, 116))
281979	32204400	We found that epi-1-triggered mitochondrial hyperpolarization occurs within 30 min and is sustained to 3 h (Figure 4A-C).	('epi-1-triggered', 'Var', (14, 29))	('mitochondrial hyperpolarization', 'MPA', (30, 61))	('epi-1', 'Chemical', '-', (14, 19))
281980	32204400	Both BAPTA (Figure 4D,E) and PD151746 (Figure 4F,G) suppressed epi-1-induced mitochondrial hyperpolarization, suggesting that calcium induction of calpain is required for epi-1 to cause mitochondrial hyperpolarization.	('PD151746', 'Chemical', 'MESH:C117345', (29, 37))	('epi-1', 'Chemical', '-', (63, 68))	('mitochondrial hyperpolarization', 'MPA', (77, 108))	('BAPTA', 'Chemical', 'MESH:C025603', (5, 10))	('PD151746', 'Var', (29, 37))	('suppressed', 'NegReg', (52, 62))	('calcium', 'Chemical', 'MESH:D002118', (126, 133))	('epi-1', 'Chemical', '-', (171, 176))	('epi-1-induced', 'Gene', (63, 76))
281984	32204400	The levels of catalase (Figure 5C,D), SOD1 (Figure 5C,E), and SOD2 (Figure 5C,E) were all decreased by epi-1.	('levels', 'MPA', (4, 10))	('epi-1', 'Chemical', '-', (103, 108))	('catalase', 'Gene', (14, 22))	('SOD2', 'Gene', (62, 66))	('epi-1', 'Var', (103, 108))	('catalase', 'Gene', '847', (14, 22))	('decreased', 'NegReg', (90, 99))	('SOD2', 'Gene', '6648', (62, 66))	('SOD1', 'Gene', (38, 42))	('SOD1', 'Gene', '6647', (38, 42))
281995	32204400	H&E histological analysis demonstrated that epi-1-treated tumors also exhibited a reduced number of nuclei compared to saline-treated tumors (Figure 7D).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('that', 'Var', (39, 43))	('epi-1', 'Chemical', '-', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
281996	32204400	Furthermore, the number of karyolytic cells, a hallmark of necrosis, was significantly increased in the epi-1-treated samples (indicated by red arrows in Figure 7D).	('necrosis', 'Disease', (59, 67))	('increased', 'PosReg', (87, 96))	('epi-1-treated', 'Var', (104, 117))	('epi-1', 'Chemical', '-', (104, 109))	('necrosis', 'Disease', 'MESH:D009336', (59, 67))
282002	32204400	Because alpha2beta1 integrin plays an essential role in promoting migration and invasion in human osteosarcoma cell lines, the migration and invasion activities of cancer cells might be especially susceptible to epi-1 treatment and its induction of calpain activation.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('invasion', 'CPA', (80, 88))	('alpha2beta1 integrin', 'Protein', (8, 28))	('invasion activities', 'CPA', (141, 160))	('epi-1', 'Var', (212, 217))	('migration', 'CPA', (66, 75))	('promoting', 'PosReg', (56, 65))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('activation', 'PosReg', (257, 267))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('calpain', 'Protein', (249, 256))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('human', 'Species', '9606', (92, 97))	('osteosarcoma', 'Disease', (98, 110))	('migration', 'CPA', (127, 136))	('epi-1', 'Chemical', '-', (212, 217))
282009	32204400	Additionally, epi-1 induces synovial sarcoma cell death by necrosis.	('necrosis', 'Disease', (59, 67))	('epi-1', 'Chemical', '-', (14, 19))	('epi-1', 'Var', (14, 19))	('synovial sarcoma cell death', 'Disease', 'MESH:D013584', (28, 55))	('synovial sarcoma cell death', 'Disease', (28, 55))	('necrosis', 'Disease', 'MESH:D009336', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (28, 44))
282011	32204400	Furthermore, release of cyclophilin A is stimulated by epi-1-induced necrosis, and cyclophilin A-mediated macrophage differentiation, migration, and proliferation may contribute to tumor suppression.	('tumor', 'Disease', (181, 186))	('necrosis', 'Disease', (69, 77))	('epi-1', 'Chemical', '-', (55, 60))	('contribute', 'Reg', (167, 177))	('necrosis', 'Disease', 'MESH:D009336', (69, 77))	('proliferation', 'CPA', (149, 162))	('migration', 'CPA', (134, 143))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('stimulated', 'PosReg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('release of cyclophilin A', 'MPA', (13, 37))	('cyclophilin', 'Var', (83, 94))
282013	32204400	For example, epi-1 induces lytic cell death in fibrosarcoma, but it triggers cells death through apoptosis in U937 human leukemia cells.	('cells death', 'CPA', (77, 88))	('fibrosarcoma', 'Disease', (47, 59))	('epi-1', 'Var', (13, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('U937', 'CellLine', 'CVCL:0007', (110, 114))	('leukemia', 'Disease', (121, 129))	('triggers', 'Reg', (68, 76))	('leukemia', 'Disease', 'MESH:D007938', (121, 129))	('human', 'Species', '9606', (115, 120))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (47, 59))	('fibrosarcoma', 'Disease', 'MESH:D005354', (47, 59))	('epi-1', 'Chemical', '-', (13, 18))	('apoptosis', 'CPA', (97, 106))
282015	32204400	Thus, epi-1 may initiate cell death through different pathways in a cell-type-dependent manner, and it may be especially useful as an anticancer agent in synovial sarcoma.	('synovial sarcoma', 'Disease', 'MESH:D013584', (154, 170))	('cancer', 'Disease', (138, 144))	('epi-1', 'Var', (6, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('synovial sarcoma', 'Disease', (154, 170))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cell death', 'CPA', (25, 35))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (154, 170))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('epi-1', 'Chemical', '-', (6, 11))
282020	32204400	Propidium iodide (PI), 2',7'-dichlordihydrofluorescein diacetate (DCF-DA), Trolox, TEMPOL, MitoTEMPO, BAPTA (BA), U0126, PD151746, Necrostatin-1 (Nec-1), staurosporine (stau), and DMSO were purchased from Sigma (Merck KGaA, Darmstadt, Germany).	("2',7'-dichlordihydrofluorescein diacetate", 'Chemical', '-', (23, 64))	('Propidium iodide', 'Chemical', 'MESH:D011419', (0, 16))	('TEMPOL', 'Chemical', 'MESH:C001803', (83, 89))	('PD151746', 'Chemical', 'MESH:C117345', (121, 129))	('BA', 'Chemical', 'MESH:C025603', (109, 111))	('MitoTEMPO', 'Chemical', 'MESH:C555916', (91, 100))	('BA', 'Chemical', 'MESH:C025603', (102, 104))	('Necrostatin-1', 'Chemical', 'MESH:C507699', (131, 144))	('DMSO', 'Chemical', 'MESH:D004121', (180, 184))	('PD151746', 'Var', (121, 129))	('U0126', 'Chemical', 'MESH:C113580', (114, 119))	('staurosporine', 'Chemical', 'MESH:D019311', (154, 167))	('Nec-1', 'Chemical', 'MESH:C507699', (146, 151))	('U0126', 'Var', (114, 119))	('DCF-DA', 'Chemical', '-', (66, 72))	('stau', 'Chemical', 'MESH:D019311', (154, 158))	('Trolox', 'Chemical', 'MESH:C010643', (75, 81))	('stau', 'Chemical', 'MESH:D019311', (169, 173))	('BAPTA', 'Chemical', 'MESH:C025603', (102, 107))
282052	32204400	Furthermore, the mechanism underlying epi-1 toxicity involves increased intracellular calcium and subsequent calpain activation.	('increased', 'PosReg', (62, 71))	('epi-1', 'Chemical', '-', (38, 43))	('epi-1', 'Var', (38, 43))	('intracellular calcium', 'MPA', (72, 93))	('calpain', 'Protein', (109, 116))	('increased intracellular calcium', 'Phenotype', 'HP:0003575', (62, 93))	('calcium', 'Chemical', 'MESH:D002118', (86, 93))	('activation', 'PosReg', (117, 127))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('toxicity', 'Disease', (44, 52))
282053	32204400	Importantly, activation of calpain is required for epi-1-mediated mitochondrial dysfunction and cell death.	('epi-1', 'Chemical', '-', (51, 56))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (66, 91))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (66, 91))	('mitochondrial dysfunction', 'Disease', (66, 91))	('epi-1-mediated', 'Var', (51, 65))
282060	31238957	Concordantly, depletion of FUS elevates the occupancy of AFF4 and Cdk9 on the viral promoter and activates HIV gene transcription.	('transcription', 'MPA', (116, 129))	('occupancy', 'MPA', (44, 53))	('Cdk9', 'Gene', (66, 70))	('HIV gene', 'Gene', (107, 115))	('AFF4', 'Gene', (57, 61))	('activates', 'PosReg', (97, 106))	('elevates', 'PosReg', (31, 39))	('FUS', 'Chemical', '-', (27, 30))	('AFF4', 'Gene', '27125', (57, 61))	('HIV', 'Species', '12721', (107, 110))	('depletion', 'Var', (14, 23))	('Cdk9', 'Gene', '1025', (66, 70))
282062	31238957	In HIV infected cells, knockout of FUS delays the gradual entry of HIV into latency, and similarly promotes viral activation in a T cell latency model that is treated with JQ1.	('viral activation', 'MPA', (108, 124))	('gradual entry of HIV into latency', 'MPA', (50, 83))	('knockout', 'Var', (23, 31))	('FUS', 'Chemical', '-', (35, 38))	('promotes', 'PosReg', (99, 107))	('HIV infected', 'Disease', (3, 15))	('HIV infected', 'Disease', 'MESH:D015658', (3, 15))	('HIV', 'Species', '12721', (67, 70))	('delays', 'NegReg', (39, 45))	('FUS', 'Gene', (35, 38))	('HIV', 'Species', '12721', (3, 6))
282063	31238957	Finally, effects of FUS on HIV gene transcription are also exhibited genome wide, where FUS mainly occupies gene promoters at transcription starting sites, while its knockdown leads to an increase in AFF4 and Cdk9 occupancy on gene promoters of FUS affected genes.	('knockdown', 'Var', (166, 175))	('FUS', 'Chemical', '-', (20, 23))	('FUS', 'Gene', (88, 91))	('Cdk9', 'Gene', '1025', (209, 213))	('FUS', 'Chemical', '-', (245, 248))	('AFF4', 'Gene', '27125', (200, 204))	('increase', 'PosReg', (188, 196))	('FUS', 'Chemical', '-', (88, 91))	('Cdk9', 'Gene', (209, 213))	('AFF4', 'Gene', (200, 204))	('occupancy', 'MPA', (214, 223))	('HIV', 'Species', '12721', (27, 30))
282069	31238957	In P-TEFb, the Cdk9 kinase phosphorylates NELF and DSIF and antagonizes their inhibitory effects.	('NELF', 'Gene', (42, 46))	('Cdk9', 'Gene', '1025', (15, 19))	('Cdk9', 'Gene', (15, 19))	('inhibitory effects', 'MPA', (78, 96))	('antagonizes', 'NegReg', (60, 71))	('P-TEFb', 'Var', (3, 9))
282077	31238957	Like other proteins of the FET family (FUS, EWSR1 and TAF15; Ewing's sarcoma (EWS) and TAF15 (TATA-binding protein-associated factor), mutations in fused in sarcoma (FUS) are directly linked with protein aggregation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia patients.	('EWSR1', 'Gene', '2130', (44, 49))	('TAF15', 'Gene', '8148', (87, 92))	('linked', 'Reg', (184, 190))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (219, 248))	('frontotemporal dementia', 'Disease', (259, 282))	("Ewing's sarcoma", 'Disease', (61, 76))	('EWS', 'Gene', '2130', (78, 81))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('sarcoma', 'Disease', (157, 164))	('sarcoma', 'Disease', (69, 76))	('TAF15', 'Gene', (54, 59))	('patients', 'Species', '9606', (283, 291))	('sclerosis', 'Disease', (239, 248))	('mutations', 'Var', (135, 144))	('EWS', 'Gene', '2130', (44, 47))	('TAF15', 'Gene', '8148', (54, 59))	('ALS', 'Gene', (250, 253))	('EWSR1', 'Gene', (44, 49))	('dementia', 'Phenotype', 'HP:0000726', (274, 282))	('sclerosis', 'Disease', 'MESH:D012598', (239, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('frontotemporal dementia', 'Phenotype', 'HP:0002145', (259, 282))	('ALS', 'Gene', '6647', (250, 253))	('EWS', 'Gene', (78, 81))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (61, 76))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (61, 76))	('FUS', 'Chemical', '-', (166, 169))	('EWS', 'Gene', (44, 47))	('TAF15', 'Gene', (87, 92))	('FUS', 'Chemical', '-', (39, 42))	('protein aggregation', 'MPA', (196, 215))
282082	31238957	Knockdown (KD) of FUS promotes a small increase in RNAPII traveling ratios at FUS-bound genes.	('FUS', 'Chemical', '-', (78, 81))	('Knockdown', 'Var', (0, 9))	('FUS', 'Chemical', '-', (18, 21))	('increase', 'PosReg', (39, 47))	('RNAPII traveling ratios', 'MPA', (51, 74))
282085	31238957	Finally, loss of FUS also leads to accumulation of a phosphorylated Ser2 of the CTD of RNAPII near TSSs of genes that are enriched with FUS.	('FUS', 'Chemical', '-', (17, 20))	('FUS', 'Chemical', '-', (136, 139))	('accumulation', 'PosReg', (35, 47))	('loss', 'Var', (9, 13))	('phosphorylated', 'MPA', (53, 67))	('FUS', 'Gene', (17, 20))	('Ser2', 'Gene', (68, 72))	('Ser2', 'Gene', '3714', (68, 72))
282091	31238957	Importantly, knockout of FUS delayed the progressive entry of HIV into a latency state in infected T cells.	('FUS', 'Chemical', '-', (25, 28))	('knockout', 'Var', (13, 21))	('FUS', 'Gene', (25, 28))	('HIV', 'Species', '12721', (62, 65))	('delayed', 'NegReg', (29, 36))
282092	31238957	In another T cell latency model, depletion of FUS expression also enhanced the activation effects of the BET bromodomain inhibitor JQ1.	('depletion', 'Var', (33, 42))	('activation', 'MPA', (79, 89))	('enhanced', 'PosReg', (66, 74))	('FUS expression', 'Protein', (46, 60))	('FUS', 'Chemical', '-', (46, 49))
282095	31238957	Finally, effects of FUS in modulating the transcription from the HIV promoter were also exhibited genome-wide, as elevated occupancy levels of AFF4 and Cdk9 were detected around gene promoters that were upregulated following knockdown of FUS expression.	('Cdk9', 'Gene', '1025', (152, 156))	('HIV', 'Species', '12721', (65, 68))	('FUS', 'Chemical', '-', (20, 23))	('Cdk9', 'Gene', (152, 156))	('knockdown', 'Var', (225, 234))	('modulating', 'Reg', (27, 37))	('transcription', 'MPA', (42, 55))	('AFF4', 'Gene', (143, 147))	('AFF4', 'Gene', '27125', (143, 147))	('FUS', 'Chemical', '-', (238, 241))	('upregulated', 'PosReg', (203, 214))	('elevated', 'PosReg', (114, 122))	('occupancy levels', 'MPA', (123, 139))	('FUS', 'Gene', (238, 241))
282106	31238957	Flag-FUS and full length HA-AFF4 or its truncated proteins including HA-AFF4 (1-850) (1-650), (1-400), (1-300) were over-expressed in cells, and cell lysates were subjected to IP with HA-antibody, followed by western blotting with anti-Flag antibody (Fig.	('Flag-FUS', 'Chemical', '-', (0, 8))	('AFF4', 'Gene', '27125', (72, 76))	('1-650', 'Var', (86, 91))	('1-300', 'Var', (104, 109))	('AFF4', 'Gene', (28, 32))	('AFF4', 'Gene', '27125', (28, 32))	('1-400', 'Var', (95, 100))	('AFF4', 'Gene', (72, 76))
282123	31238957	In addition, we also generated J-LTR-Luc cells that stably expressed a Flag-FUS mutant that does not bind RNA, as it consists of arginine to serine mutations in RGG1 2 and 3 of FUS (J-LTR-Luc-FUS SGG4).	('mutations', 'Var', (148, 157))	('arginine', 'Chemical', 'MESH:D001120', (129, 137))	('RGG1 2', 'Gene', (161, 167))	('FUS', 'Chemical', '-', (76, 79))	('FUS', 'Chemical', '-', (177, 180))	('serine', 'Chemical', 'MESH:D012694', (141, 147))	('Flag-FUS', 'Chemical', '-', (71, 79))	('FUS', 'Chemical', '-', (192, 195))
282125	31238957	Expression of the SGG4 FUS mutant in J-LTR-Luc cells, did not repressed HIV-mediated luciferase activity and transcription levels returned to those displayed by the wild type J-LTR-Luc control cells (black bars versus white bars), implying that the RNA binding of FUS is required for the ability of FUS to repress HIV transcription.	('mutant', 'Var', (27, 33))	('FUS', 'Chemical', '-', (299, 302))	('FUS', 'Chemical', '-', (264, 267))	('HIV', 'Species', '12721', (72, 75))	('HIV', 'Species', '12721', (314, 317))	('FUS', 'Chemical', '-', (23, 26))	('SGG4 FUS', 'Gene', (18, 26))
282132	31238957	No inhibition of HIV transcription was observed upon ectopic expression of the FUS-SGG4 mutant (Fig.	('FUS', 'Chemical', '-', (79, 82))	('HIV', 'Species', '12721', (17, 20))	('mutant', 'Var', (88, 94))	('FUS-SGG4', 'Gene', (79, 87))
282144	31238957	Upon FUS KO, Tat transactivation was also increased, reaching similar levels as in the control cells that expressed the scramble sgRNA.	('increased', 'PosReg', (42, 51))	('FUS KO', 'Var', (5, 11))	('FUS', 'Chemical', '-', (5, 8))	('Tat', 'Gene', '6898', (13, 16))	('Tat', 'Gene', (13, 16))
282161	31238957	Finally, a Tat mutant that does not bind TAR (Tat 1-48) demonstrated that it cannot compete with FUS on association with TAR RNA (Additional file 1: Figure S2B).	('Tat', 'Gene', (11, 14))	('Tat', 'Gene', '6898', (46, 49))	('FUS', 'Chemical', '-', (97, 100))	('Tat', 'Gene', (46, 49))	('mutant', 'Var', (15, 21))	('Tat', 'Gene', '6898', (11, 14))
282166	31238957	Our results showed that TAR deletion lowered the levels of FUS occupancy on the HIV promoter relatively to FUS levels when (Fig.	('lowered', 'NegReg', (37, 44))	('levels', 'MPA', (49, 55))	('FUS', 'Chemical', '-', (59, 62))	('HIV', 'Species', '12721', (80, 83))	('FUS', 'Chemical', '-', (107, 110))	('FUS occupancy on', 'MPA', (59, 75))	('deletion', 'Var', (28, 36))	('TAR', 'Gene', (24, 27))
282174	31238957	Our analysis demonstrated that in J-LTR-Luc-FUS KO cells, upon FUS KO, Cdk9 occupancy on the HIV promoter was elevated, relative to that in control J-LTR-Luc cells.	('HIV', 'Species', '12721', (93, 96))	('FUS', 'Chemical', '-', (63, 66))	('Cdk9', 'Gene', '1025', (71, 75))	('occupancy', 'MPA', (76, 85))	('Cdk9', 'Gene', (71, 75))	('FUS', 'Chemical', '-', (44, 47))	('elevated', 'PosReg', (110, 118))	('FUS KO', 'Var', (63, 69))
282176	31238957	Our results indicate that FUS limits the occupancy of AFF4 and P-TEFb on the HIV promoter (Fig.	('AFF4', 'Gene', '27125', (54, 58))	('AFF4', 'Gene', (54, 58))	('P-TEFb', 'Var', (63, 69))	('occupancy', 'MPA', (41, 50))	('HIV', 'Species', '12721', (77, 80))	('FUS', 'Chemical', '-', (26, 29))
282181	31238957	Significantly, J-LTR-Luc-FUS KO cells exhibited a delay in their entry into viral latency, compared with control J-LTR-Luc cells.	('delay', 'NegReg', (50, 55))	('J-LTR-Luc-FUS', 'Var', (15, 28))	('entry', 'MPA', (65, 70))	('FUS', 'Chemical', '-', (25, 28))
282187	31238957	These cells express an attenuated form of Tat (H13L) that activates in cis the expression of an integrated d2GFP reporter inserted in place of the nef gene and is regulated under the control of the viral LTR promoter.	('activates', 'PosReg', (58, 67))	('Tat', 'Gene', '6898', (42, 45))	('expression', 'MPA', (79, 89))	('d2GFP', 'Gene', (107, 112))	('Tat', 'Gene', (42, 45))	('H13L', 'SUBSTITUTION', 'None', (47, 51))	('H13L', 'Var', (47, 51))
282194	31238957	We demonstrated that while 2D10 cells that were not treated with JQ1 displayed undetectable levels of HIV mRNA, the combination of FUS KD and treatment with JQ1 led to an increase in HIV Gag and Rev mRNA levels, relative to control cells that expressed FUS (Fig.	('Gag', 'Gene', '17276', (187, 190))	('HIV', 'Species', '12721', (102, 105))	('Rev', 'Gene', (195, 198))	('HIV mRNA', 'MPA', (102, 110))	('Rev', 'Gene', '19714', (195, 198))	('JQ1', 'Gene', (157, 160))	('HIV', 'Species', '12721', (183, 186))	('FUS', 'Chemical', '-', (131, 134))	('treatment', 'Var', (142, 151))	('FUS KD', 'Var', (131, 137))	('FUS', 'Chemical', '-', (253, 256))	('increase', 'PosReg', (171, 179))	('Gag', 'Gene', (187, 190))
282197	31238957	The formation of these liquid membrane-less condensates is mediated through the N-terminal low complexity (LC) region of FUS, which exhibits a disordered structure and contains multiple repeats of a S/GYS/G motifs.	('disordered', 'Disease', 'MESH:D030342', (143, 153))	('disordered', 'Disease', (143, 153))	('S/GYS/G motifs', 'Var', (199, 213))	('FUS', 'Chemical', '-', (121, 124))
282199	31238957	With time, or as a result of specific mutations, FUS liquid droplets convert to an aggregated state, which is reminiscent of the pathological state seen in ALS patients.	('patients', 'Species', '9606', (160, 168))	('ALS', 'Gene', '6647', (156, 159))	('FUS', 'Chemical', '-', (49, 52))	('ALS', 'Gene', (156, 159))	('aggregated', 'MPA', (83, 93))	('mutations', 'Var', (38, 47))	('FUS liquid droplets', 'MPA', (49, 68))
282215	31238957	We focused our analysis on FUS affected loci (in FUS KO cells), and combined these datasets with the ChIP-seq analysis describing the occupancy of SEC and P-TEFb (AFF4 and Cdk9).	('AFF4', 'Gene', (163, 167))	('Cdk9', 'Gene', (172, 176))	('FUS', 'Chemical', '-', (27, 30))	('P-TEFb', 'Var', (155, 161))	('FUS', 'Chemical', '-', (49, 52))	('AFF4', 'Gene', '27125', (163, 167))	('Cdk9', 'Gene', '1025', (172, 176))	('FUS', 'Disease', (27, 30))
282218	31238957	As previous reports suggested that FUS associates with RNAPII-CTD and P-TEFb, we tested the effects of FUS KO on the assembly of the elongation complex:P-TEFb/SEC, RNAPII in J-LTR-Luc-FUS KO (Additional file 1: Figure S4), and compared it to that of J-LTR-Luc wild-type cells.	('P-TEFb/SEC', 'Var', (152, 162))	('tested', 'Reg', (81, 87))	('FUS', 'Chemical', '-', (35, 38))	('FUS', 'Chemical', '-', (103, 106))	('FUS', 'Chemical', '-', (184, 187))
282226	31238957	Elucidating the role of SEC/P-TEFb in controlling HIV gene transcription is also of a high clinical significance, as transcription repression of the integrated provirus, mainly in resting CD4+ infected cells, results in the establishment and maintenance of the latent viral reservoir that is highly stable and refractory to anti-retroviral therapy.	('transcription', 'Var', (117, 130))	('repression', 'NegReg', (131, 141))	('HIV', 'Species', '12721', (50, 53))	('results in', 'Reg', (209, 219))
282231	31238957	Upon ectopic expression, FUS inhibits Tat-independent HIV gene transcription.	('FUS', 'Chemical', '-', (25, 28))	('Tat', 'Gene', '6898', (38, 41))	('Tat', 'Gene', (38, 41))	('ectopic expression', 'Var', (5, 23))	('HIV', 'Species', '12721', (54, 57))	('inhibits', 'NegReg', (29, 37))
282240	31238957	Our experiments that demonstrate that a FUS mutant that cannot bind RNA (FUS-SGG4) has no inhibitory effects on HIV transcription (Fig.	('FUS', 'Chemical', '-', (73, 76))	('HIV transcription', 'MPA', (112, 129))	('HIV', 'Species', '12721', (112, 115))	('FUS', 'Chemical', '-', (40, 43))	('mutant', 'Var', (44, 50))
282242	31238957	Moreover, we show that association of the FUS-SGG4 mutant with TAR RNA is reduced relative to the wild type FUS (Additional file 1: Figure S2).	('FUS-SGG4', 'Gene', (42, 50))	('association', 'Interaction', (23, 34))	('TAR RNA', 'Disease', (63, 70))	('FUS', 'Chemical', '-', (42, 45))	('mutant', 'Var', (51, 57))	('FUS', 'Chemical', '-', (108, 111))	('reduced', 'NegReg', (74, 81))
282253	31238957	Moreover, FUS globally affects SEC and P-TEFb occupancy, and in genes that are affected due to FUS knockdown, this occupancy is elevated relative to genes that are not-affected due to FUS depletion (Fig.	('FUS', 'Chemical', '-', (10, 13))	('affects', 'Reg', (23, 30))	('SEC', 'MPA', (31, 34))	('FUS', 'Var', (95, 98))	('P-TEFb occupancy', 'Disease', (39, 55))	('FUS', 'Chemical', '-', (184, 187))	('knockdown', 'Var', (99, 108))	('FUS', 'Chemical', '-', (95, 98))	('elevated', 'PosReg', (128, 136))	('P-TEFb occupancy', 'Disease', 'MESH:D009784', (39, 55))
282254	31238957	Nevertheless, FUS knockout does not affect the assembly of the transcription machinery, and we show that it can associate with the CTD of RNAPII both at its Ser5 or Ser2 forms, implying a role of FUS both at initiation or elongation of transcription (Additional file 1: Figure S4).	('FUS', 'Chemical', '-', (196, 199))	('Ser2', 'Gene', (165, 169))	('FUS', 'Chemical', '-', (14, 17))	('knockout', 'Var', (18, 26))	('Ser5', 'Chemical', '-', (157, 161))	('Ser2', 'Gene', '3714', (165, 169))
282256	31238957	One current approach to successfully eradicate the latent reservoir is to reactivate HIV gene expression in latently infected cells, and eliminate the active virus by HAART.	('HIV gene', 'Gene', (85, 93))	('reactivate', 'Var', (74, 84))	('eliminate', 'NegReg', (137, 146))	('HIV', 'Species', '12721', (85, 88))	('active virus', 'MPA', (151, 163))
282260	31238957	Importantly, we also demonstrate that FUS depletion enhances the reactivation of latent infected cells that is exhibited following treatment of cells with JQ1 (Fig.	('depletion', 'Var', (42, 51))	('reactivation', 'MPA', (65, 77))	('enhances', 'PosReg', (52, 60))	('FUS', 'Chemical', '-', (38, 41))
282266	31238957	These effects of FUS find their way in modulation of HIV latency, as in T cell latency models, we show that knockout of FUS delays the establishment of viral latency and enhances HIV gene activation upon treatment with JQ1.	('FUS', 'Chemical', '-', (17, 20))	('FUS', 'Chemical', '-', (120, 123))	('HIV', 'Species', '12721', (179, 182))	('activation', 'MPA', (188, 198))	('enhances', 'PosReg', (170, 178))	('delays', 'NegReg', (124, 130))	('HIV', 'Species', '12721', (53, 56))	('FUS', 'Gene', (120, 123))	('establishment', 'MPA', (135, 148))	('viral latency', 'MPA', (152, 165))	('knockout', 'Var', (108, 116))	('HIV gene', 'Gene', (179, 187))
282363	30185195	Primary histiocytic sarcoma of the central nervous system: a case report with platelet derived growth factor receptor mutation and PD-L1/PD-L2 expression and literature review Histiocytic sarcoma (HS) is an aggressive malignant neoplasm.	('sarcoma of the central nervous system', 'Disease', 'MESH:D002493', (20, 57))	('sarcoma of the central nervous system', 'Disease', (20, 57))	('Histiocytic sarcoma', 'Disease', (176, 195))	('Histiocytic sarcoma', 'Disease', 'MESH:D054747', (176, 195))	('PD-L1', 'Gene', '29126', (131, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('malignant neoplasm', 'Disease', (218, 236))	('mutation', 'Var', (118, 126))	('malignant neoplasm', 'Disease', 'MESH:D009369', (218, 236))	('neoplasm', 'Phenotype', 'HP:0002664', (228, 236))	('PD-L2', 'Gene', (137, 142))	('PD-L2', 'Gene', '80380', (137, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('PD-L1', 'Gene', (131, 136))
282404	30185195	Genomic sequencing of her tumor showed a novel mutation in the platelet-derived growth factor receptor A (p.V608I) and therefore, she was started on Dasatinib, a tyrosine kinase inhibitor (TKI) with known CNS penetration.	('tyrosine kinase', 'Gene', (162, 177))	('p.V608I', 'Var', (106, 113))	('Dasatinib', 'Chemical', 'MESH:D000069439', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('p.V608I', 'Mutation', 'p.V608I', (106, 113))	('tyrosine kinase', 'Gene', '7294', (162, 177))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
282416	30185195	The other important aspect of this case is that we were able to obtain adequate amount of tissue from surgical resection of the brain tumor and performed genomic sequencing revealing a novel PDGFR mutation which is highly targetable with TKI's.	('brain tumor', 'Phenotype', 'HP:0030692', (128, 139))	('PDGFR', 'Gene', (191, 196))	('PDGFR', 'Gene', '5159', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('brain tumor', 'Disease', (128, 139))	('brain tumor', 'Disease', 'MESH:D001932', (128, 139))	('mutation', 'Var', (197, 205))
282433	30185195	The genomic sequencing of the tumor tissue showed a novel PDGFR mutation, which could be targeted with TKI's.	('mutation', 'Var', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PDGFR', 'Gene', (58, 63))	('PDGFR', 'Gene', '5159', (58, 63))	('tumor', 'Disease', (30, 35))
282489	29437879	Mixed-background, mixed-gender LSL-KrasG12D;p53FL/FL (KP) mice with conditional mutations in oncogenic K-ras and both alleles of p53 (Figure 1b) were injected into the gastrocnemius muscle with an adenovirus expressing Cre recombinase as previously described.	('p53', 'Gene', '22060', (44, 47))	('p53', 'Gene', '22060', (129, 132))	('mutations', 'Var', (80, 89))	('mice', 'Species', '10090', (58, 62))	('p53', 'Gene', (44, 47))	('G12D', 'Mutation', 'rs121913529', (39, 43))	('p53', 'Gene', (129, 132))	('K-ras', 'Gene', (103, 108))	('K-ras', 'Gene', '16653', (103, 108))
282519	29437879	Therefore, to calculate RBE in the autochthonous sarcoma model, we sought to determine which of the three single doses of X-ray treatments (20 Gy, 25 Gy, and 30 Gy) induced a similar growth delay as a single fraction of 10 Gy carbon ion radiotherapy.	('carbon', 'Chemical', 'MESH:D002244', (226, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('20 Gy', 'Var', (140, 145))	('growth delay', 'Phenotype', 'HP:0001510', (183, 195))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('growth', 'MPA', (183, 189))	('sarcoma', 'Disease', (49, 56))
282542	29437879	Following treatment, a dose response relationship was observed in which tumors receiving CIT or higher dose X-rays exhibited slower regrowth than those treated with lower doses of X-ray radiation (Figure 3a).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('regrowth', 'CPA', (132, 140))	('CIT', 'Var', (89, 92))	('rays', 'Species', '255564', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('slower', 'NegReg', (125, 131))
282559	29437879	Phospho-histone H3 staining at tumor endpoint (Figure 5c-d) similarly revealed a higher mitotic fraction in tumors treated with 10 Gy carbon compared to 30 Gy X-rays (p<0.01).	('rays', 'Species', '255564', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('higher', 'PosReg', (81, 87))	('mitotic fraction', 'CPA', (88, 104))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('carbon', 'Chemical', 'MESH:D002244', (134, 140))	('10 Gy carbon', 'Var', (128, 140))
282561	29437879	In contrast to the increased proliferation and mitotic fraction in carbon ion treated tumors at study endpoint, histologic examination 24-48 hours after treatment showed significantly less staining with phospho-histone H3 in tumors treated with 10 Gy carbon compared to 30 Gy X-rays.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('10 Gy carbon', 'Var', (245, 257))	('less', 'NegReg', (184, 188))	('tumors', 'Disease', (225, 231))	('carbon', 'Chemical', 'MESH:D002244', (251, 257))	('rat', 'Species', '10116', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('rays', 'Species', '255564', (278, 282))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('carbon', 'Chemical', 'MESH:D002244', (67, 73))	('staining with phospho-histone', 'MPA', (189, 218))
282565	29437879	Because CIT may improve activation of the immune system following treatment, we also stained tumors for CD3 to quantify tumor-associated T-cells.	('immune', 'CPA', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('activation', 'MPA', (24, 34))	('CD3', 'Gene', (104, 107))	('tumor', 'Disease', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('CD3', 'Gene', '12501', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (93, 99))	('improve', 'PosReg', (16, 23))	('CIT', 'Var', (8, 11))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
282566	29437879	Remarkably, 24 to 48 hours after radiation, sarcomas treated with carbon ions had increased numbers of CD3+ T-cells compared to sarcomas treated with isoeffective X-rays (Figure 5g-h).	('increased numbers of CD3+ T-cells', 'Phenotype', 'HP:0045080', (82, 115))	('rays', 'Species', '255564', (165, 169))	('carbon ions', 'Var', (66, 77))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('carbon', 'Chemical', 'MESH:D002244', (66, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomas', 'Disease', (128, 136))	('CD3', 'Gene', (103, 106))	('sarcomas', 'Disease', 'MESH:D012509', (44, 52))	('increased', 'PosReg', (82, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('CD3', 'Gene', '12501', (103, 106))	('sarcomas', 'Disease', (44, 52))
282567	29437879	Thus, while isoeffective treatments resulted in similar tumor cell death at 1-2 days, their effect on the tumor stroma at this time differed with CIT eliciting larger T-cell infiltrate.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('T-cell', 'CPA', (167, 173))	('rat', 'Species', '10116', (180, 183))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CIT', 'Var', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (106, 111))
282569	29437879	While these transplant models are helpful tools that facilitate investigating the treatment response of cancers with a wide range of oncogenic mutations, they do not recapitulate a native tumor-stromal interaction.	('tumor', 'Disease', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('mutations', 'Var', (143, 152))
282598	29437879	Recently, two groups reported that micronuclei, which form after irradiated cells proceed through mitosis with damaged DNA, stimulate the innate immune system via interferon-stimulated gene expression .	('innate immune system', 'MPA', (138, 158))	('mitosis', 'Disease', (98, 105))	('mitosis', 'Disease', 'None', (98, 105))	('micronuclei', 'Var', (35, 46))	('stimulate', 'PosReg', (124, 133))
282624	28552607	The development of this default tumor type caused by p53 loss can be overridden by various oncogenic signals: RAS reprograms p53_KO BMSCs into undifferentiated sarcoma, AKT enhances osteoblastic OS, while cFOS promotes chondroblastic OS formation.	('AKT', 'Gene', '11651', (169, 172))	('OS', 'Phenotype', 'HP:0002669', (195, 197))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('promotes', 'PosReg', (210, 218))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (143, 167))	('OS', 'Phenotype', 'HP:0002669', (234, 236))	('BMSC', 'Chemical', '-', (132, 136))	('undifferentiated sarcoma', 'Disease', (143, 167))	('osteoblastic OS', 'Disease', (182, 197))	('AKT', 'Gene', (169, 172))	('p53_KO', 'Var', (125, 131))	('loss', 'NegReg', (57, 61))	('default tumor type', 'Disease', 'MESH:D009369', (24, 42))	('osteoblastic OS', 'Disease', 'MESH:C567932', (182, 197))	('default tumor type', 'Disease', (24, 42))	('enhances', 'PosReg', (173, 181))	('OS', 'Phenotype', 'HP:0002669', (207, 209))	('p53', 'Gene', (53, 56))	('chondroblastic OS formation', 'CPA', (219, 246))
282641	28552607	Around 25% of mice with heterozygous deletion of trp53 (also called p53) develop OS after a long latency, suggesting that a second genetic or epigenetic event is required for the full development of OS.	('trp53', 'Gene', '22059', (49, 54))	('deletion', 'Var', (37, 45))	('mice', 'Species', '10090', (14, 18))	('OS', 'Phenotype', 'HP:0002669', (81, 83))	('OS', 'Phenotype', 'HP:0002669', (199, 201))	('trp53', 'Gene', (49, 54))	('develop', 'Reg', (73, 80))
282642	28552607	A recent genome-wide sequencing study of human OS showed that almost all the human OS have point mutations, deletions, amplifications, and/or translocations in the TP53 gene or the genes encoding other components (e.g., HDM2) in the p53 signaling pathway, demonstrating the importance of p53 loss in osteosarcomagenesis.	('point mutations', 'Var', (91, 106))	('amplifications', 'Var', (119, 133))	('loss', 'NegReg', (292, 296))	('HDM2', 'Gene', '4193', (220, 224))	('translocations', 'Var', (142, 156))	('HDM2', 'Gene', (220, 224))	('rat', 'Species', '10116', (263, 266))	('human', 'Species', '9606', (41, 46))	('p53', 'Gene', (288, 291))	('osteosarcoma', 'Phenotype', 'HP:0002669', (300, 312))	('TP53 gene', 'Gene', (164, 173))	('OS', 'Phenotype', 'HP:0002669', (47, 49))	('osteosarcomagenesis', 'Disease', 'None', (300, 319))	('deletions', 'Var', (108, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))	('OS', 'Phenotype', 'HP:0002669', (83, 85))	('osteosarcomagenesis', 'Disease', (300, 319))	('human', 'Species', '9606', (77, 82))
282643	28552607	In human OS and patient-derived OS cell lines, TP53 deletions and point mutations are common.	('human', 'Species', '9606', (3, 8))	('OS', 'Phenotype', 'HP:0002669', (9, 11))	('OS', 'Phenotype', 'HP:0002669', (32, 34))	('point mutations', 'Var', (66, 81))	('deletions', 'Var', (52, 61))	('patient', 'Species', '9606', (16, 23))	('TP53', 'Gene', (47, 51))
282651	28552607	We find that the default tumor type arising from p53_KO BMSCs is osteoblastic OS, and that oncogenic signals can override this default lineage choice.	('BMSC', 'Chemical', '-', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('osteoblastic OS', 'Disease', (65, 80))	('osteoblastic OS', 'Disease', 'MESH:C567932', (65, 80))	('OS', 'Phenotype', 'HP:0002669', (78, 80))	('default tumor type', 'Disease', 'MESH:D009369', (17, 35))	('p53_KO BMSCs', 'Var', (49, 61))	('default tumor type', 'Disease', (17, 35))
282656	28552607	These p53_KO BMSCs are immortalized and multipotent with the ability of differentiating into three lineages: osteocytes, chondrocytes, and adipocytes.	('BMSC', 'Chemical', '-', (13, 17))	('p53_KO', 'Var', (6, 12))	('chondrocytes', 'CPA', (121, 133))	('differentiating', 'Reg', (72, 87))	('osteocytes', 'CPA', (109, 119))
282658	28552607	Five out of nine mice transplanted with p53_KO BMSCs generated tumors with an average latency (time between transplantation and tumor harvesting) of 44 days; the other four mice did not develop tumors within a 4-month period (Table S1).	('p53_KO BMSCs', 'Var', (40, 52))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('rat', 'Species', '10116', (57, 60))	('tumor', 'Disease', (194, 199))	('mice', 'Species', '10090', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('BMSC', 'Chemical', '-', (47, 51))	('tumors', 'Disease', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Disease', (63, 68))	('mice', 'Species', '10090', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (128, 133))	('tumors', 'Disease', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (194, 200))
282660	28552607	This finding is consistent with our previous in vitro observation showing that p53_KO BMSCs are predisposed to osteoblastic differentiation.	('osteoblastic differentiation', 'Disease', 'MESH:D012734', (111, 139))	('osteoblastic differentiation', 'Disease', (111, 139))	('p53_KO', 'Var', (79, 85))	('BMSC', 'Chemical', '-', (86, 90))
282661	28552607	Thus, the default subtype of OS formed from p53_KO BMSCs is osteoblastic OS.	('OS', 'Phenotype', 'HP:0002669', (73, 75))	('OS', 'Phenotype', 'HP:0002669', (29, 31))	('p53_KO', 'Var', (44, 50))	('BMSC', 'Chemical', '-', (51, 55))	('osteoblastic OS', 'Disease', 'MESH:C567932', (60, 75))	('osteoblastic OS', 'Disease', (60, 75))
282665	28552607	We transduced p53_KO BMSCs using murine retroviruses expressing Akt2, cFos, k-Ras (Kirsten Ras) (V12), or h-Ras (Harvey Ras) (V12).	('Kirsten Ras', 'Gene', '16653', (83, 94))	('k-Ras', 'Gene', '16653', (76, 81))	('k-Ras', 'Gene', (76, 81))	('murine', 'Species', '10090', (33, 39))	('Akt2', 'Gene', (64, 68))	('h-Ras', 'Gene', '15461', (106, 111))	('Harvey Ras', 'Gene', '15461', (113, 123))	('Harvey Ras', 'Gene', (113, 123))	('h-Ras', 'Gene', (106, 111))	('BMSC', 'Chemical', '-', (21, 25))	('Kirsten Ras', 'Gene', (83, 94))	('Akt2', 'Gene', '11652', (64, 68))	('cFos', 'Var', (70, 74))
282666	28552607	About 20% of p53_KO BMSCs generated colonies (Figure S1A).	('p53_KO', 'Var', (13, 19))	('BMSC', 'Chemical', '-', (20, 24))	('rat', 'Species', '10116', (30, 33))	('colonies', 'CPA', (36, 44))
282669	28552607	Nonetheless, oncogenes, such as cFos, k-Ras (V12), and Akt2, can greatly enhance the transformation of p53_KO BMSCs.	('enhance', 'PosReg', (73, 80))	('BMSC', 'Chemical', '-', (110, 114))	('k-Ras', 'Gene', (38, 43))	('transformation', 'CPA', (85, 99))	('Akt2', 'Gene', (55, 59))	('k-Ras', 'Gene', '16653', (38, 43))	('p53_KO BMSCs', 'Var', (103, 115))	('Akt2', 'Gene', '11652', (55, 59))
282671	28552607	Tumor formation frequency was 100% for p53_KO BMSCs transduced with each of the oncogenes, and tumor formation latency was decreased by oncogenes (Table S1).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BMSC', 'Chemical', '-', (46, 50))	('oncogenes', 'Var', (136, 145))	('decreased', 'NegReg', (123, 132))	('Tumor formation frequency', 'CPA', (0, 25))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('transduced', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p53_KO BMSCs transduced', 'Var', (39, 62))	('tumor', 'Disease', (95, 100))
282679	28552607	Similar to the results from intramuscular injection, k-RAS (V12) induced undifferentiated sarcoma while cFOS transformed these cells into chondroblastic OS.	('OS', 'Phenotype', 'HP:0002669', (153, 155))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (73, 97))	('undifferentiated sarcoma', 'Disease', (73, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('cFOS', 'Var', (104, 108))	('OS', 'Phenotype', 'HP:0002669', (106, 108))	('k-RAS', 'Var', (53, 58))
282681	28552607	Therefore, the injection sites do not appear to affect the tumor types, at least for k-RAS (V12)- and cFOS-driven tumors originating from p53_KO BMSCs.	('BMSC', 'Chemical', '-', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('OS', 'Phenotype', 'HP:0002669', (104, 106))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('p53_KO', 'Var', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
282682	28552607	In summary, different oncogenes transform p53_KO BMSCs into different types of sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Disease', (79, 87))	('BMSC', 'Chemical', '-', (49, 53))	('p53_KO BMSCs', 'Var', (42, 54))
282688	28552607	These results indicate that a single cFOS-transformed p53_KO BMSC is multipotent and has the capacity to generate tumors with features of chondroblastic OS.	('OS', 'Phenotype', 'HP:0002669', (153, 155))	('generate', 'PosReg', (105, 113))	('chondroblastic OS', 'Disease', (138, 155))	('OS', 'Phenotype', 'HP:0002669', (39, 41))	('p53_KO', 'Var', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('BMSC', 'Chemical', '-', (61, 65))	('rat', 'Species', '10116', (109, 112))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
282701	28552607	All the control cells (p53_KO BMSCs + cFos + shLuc) formed chondroblastic OS while Sox9 knockdown cells (p53_KO BMSCs + cFos + shSox9) had decreased cartilage formation (Figures 6C and 6D).	('p53_KO BMSCs + cFos', 'Var', (105, 124))	('BMSC', 'Chemical', '-', (112, 116))	('decreased cartilage', 'Disease', (139, 158))	('OS', 'Phenotype', 'HP:0002669', (74, 76))	('BMSC', 'Chemical', '-', (30, 34))	('chondroblastic OS', 'CPA', (59, 76))	('decreased cartilage', 'Disease', 'MESH:C535916', (139, 158))
282705	28552607	These results together demonstrate that Sox9, by itself, has no capacity to transform p53_KO BMSCs.	('p53_KO', 'Var', (86, 92))	('BMSC', 'Chemical', '-', (93, 97))	('transform', 'Reg', (76, 85))	('rat', 'Species', '10116', (30, 33))
282714	28552607	In the in vivo studies, the p53 gene was conditionally deleted using Prx1-driven Cre recombinase.	('deleted', 'Var', (55, 62))	('Prx1', 'Gene', '18933', (69, 73))	('p53 gene', 'Gene', (28, 36))	('Prx1', 'Gene', (69, 73))
282719	28552607	In addition, our models use p53_KO MSCs derived from mouse bone marrow, and therefore are more relevant to osteosarcomagenesis than MSCs isolated from other tissues.	('osteosarcomagenesis', 'Disease', (107, 126))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('p53_KO', 'Var', (28, 34))	('mouse', 'Species', '10090', (53, 58))	('osteosarcomagenesis', 'Disease', 'None', (107, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
282724	28552607	Similar to the observations in mouse models, we observed a role of cFOS in inducing chondrogenesis using BMSCs as a cellular model.	('cFOS', 'Var', (67, 71))	('BMSC', 'Chemical', '-', (105, 109))	('chondrogenesis', 'CPA', (84, 98))	('mouse', 'Species', '10090', (31, 36))	('inducing', 'Reg', (75, 83))	('OS', 'Phenotype', 'HP:0002669', (69, 71))
282727	28552607	The dual roles of cFOS in OS are reminiscent of the dual roles of p53 in BMSCs, in which p53 not only prevents tumorigenesis but also affects the lineage choice of these cells.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('affects', 'Reg', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('OS', 'Phenotype', 'HP:0002669', (26, 28))	('p53', 'Var', (89, 92))	('lineage choice of these cells', 'CPA', (146, 175))	('prevents', 'NegReg', (102, 110))	('tumor', 'Disease', (111, 116))	('OS', 'Phenotype', 'HP:0002669', (20, 22))	('BMSC', 'Chemical', '-', (73, 77))
282737	28552607	Using single clones of p53_KO BMSCs, our study supports an alternative explanation: p53_KO BMSCs are multipotent in the generation of different types of sarcomas and oncogenic signals dictate the tumor types.	('p53_KO', 'Var', (84, 90))	('rat', 'Species', '10116', (124, 127))	('tumor', 'Disease', (196, 201))	('sarcomas', 'Disease', 'MESH:D012509', (153, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('BMSC', 'Chemical', '-', (91, 95))	('BMSC', 'Chemical', '-', (30, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('sarcomas', 'Disease', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
282738	28552607	Although the default tumor type generated from p53_KO BMSCs is osteoblastic OS, oncogenic signals can override this default program and direct these cells to develop into various lineage tumors.	('default tumor type', 'Disease', (13, 31))	('develop', 'CPA', (158, 165))	('osteoblastic OS', 'Disease', 'MESH:C567932', (63, 78))	('osteoblastic OS', 'Disease', (63, 78))	('rat', 'Species', '10116', (36, 39))	('BMSC', 'Chemical', '-', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('direct', 'Reg', (136, 142))	('p53_KO BMSCs', 'Var', (47, 59))	('default tumor type', 'Disease', 'MESH:D009369', (13, 31))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('OS', 'Phenotype', 'HP:0002669', (76, 78))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
282742	28552607	In particular, the AKT pathway was aberrantly upregulated in OS through PTEN (Phosphatase and tensin homolog) deletions or PI3K mutations.	('PTEN', 'Gene', '19211', (72, 76))	('PTEN', 'Gene', (72, 76))	('OS', 'Phenotype', 'HP:0002669', (61, 63))	('AKT', 'Gene', '11651', (19, 22))	('PI3K mutations', 'Var', (123, 137))	('AKT', 'Gene', (19, 22))	('deletions', 'Var', (110, 119))	('upregulated', 'PosReg', (46, 57))
282746	28552607	Since both k-RAS and h-RAS reprogram p53_KO BMSCs into undifferentiated sarcomas, our results are consistent with the relative infrequency of Ras mutations in human osteoblastic OS.	('osteoblastic OS', 'Disease', 'MESH:C567932', (165, 180))	('mutations', 'Var', (146, 155))	('undifferentiated sarcoma', 'Disease', (55, 79))	('osteoblastic OS', 'Disease', (165, 180))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('BMSC', 'Chemical', '-', (44, 48))	('human', 'Species', '9606', (159, 164))	('OS', 'Phenotype', 'HP:0002669', (178, 180))	('sarcomas', 'Disease', (72, 80))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (55, 79))
282749	28552607	All of these mouse models use a tissue- or cell-type-specific Cre recombinase to conditionally delete p53 and/or RB1.	('mouse', 'Species', '10090', (13, 18))	('RB1', 'Gene', '19645', (113, 116))	('RB1', 'Gene', (113, 116))	('delete', 'Var', (95, 101))	('p53', 'Gene', (102, 105))
282753	28552607	p53+/+ and p53-/- mice were described previously and housed in the mouse facility of the National Cancer Institute.	('p53+/+', 'Var', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (98, 104))	('mice', 'Species', '10090', (18, 22))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('mouse', 'Species', '10090', (67, 72))
282785	28552607	The sequences of shRNAs for knocking down mouse Sox9 were: shSox9(m)_#1: 5'-CCG GGC GAC GTC ATC TCC AAC ATT GCT CGA GCA ATG TTG GAG ATG ACG TCG CTT TTT-3'; shSox9(m)_#3: 5'-CCG GAG ACT CAC ATC TCT CCT AAT GCT CGA GCA TTA GGA GAG ATG TGA GTC TTT TTT-3'.	('CGA', 'Gene', '12652', (209, 212))	('mouse', 'Species', '10090', (42, 47))	('knocking', 'Var', (28, 36))	('CGA', 'Gene', (209, 212))	('CGA', 'Gene', (112, 115))	('CGA', 'Gene', '12652', (112, 115))
282941	32138705	ASRs were 1.9 for complex genomic and 1.3 for recurrent translocation sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('complex genomic', 'Var', (18, 33))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))
282971	32138705	Besides, endometrial stromal sarcoma NOS (89303), low grade endometrial stromal sarcoma (89313) and stromal sarcoma (89353) not described in the WHO 2013 have been also included.	('89303', 'Var', (42, 47))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (9, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (60, 87))	('stromal sarcoma', 'Disease', 'MESH:D046152', (21, 36))	('endometrial stromal sarcoma NOS', 'Disease', 'MESH:D018203', (9, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('stromal sarcoma', 'Disease', 'MESH:D046152', (72, 87))	('89353', 'Var', (117, 122))	('89313', 'Var', (89, 94))	('stromal sarcoma', 'Disease', 'MESH:D046152', (100, 115))	('stromal sarcoma', 'Disease', (100, 115))	('endometrial stromal sarcoma', 'Disease', (60, 87))	('endometrial stromal sarcoma NOS', 'Disease', (9, 40))
282974	32138705	Two main distinct genetic groups were defined: (i) sarcomas defined with simple genetics based on recurrent translocations (e.g.	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('translocations', 'Var', (108, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Disease', (51, 59))
282975	32138705	Ewing sarcoma, myxoid liposarcoma), activating or inactivating mutations (e.g epithelioid sarcoma, gastrointestinal stromal tumor), MDM2 amplification (e.g.	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (99, 129))	('liposarcoma', 'Phenotype', 'HP:0012034', (22, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('epithelioid sarcoma', 'Disease', (78, 97))	('MDM2', 'Gene', '4193', (132, 136))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (99, 129))	('amplification', 'Var', (137, 150))	('gastrointestinal stromal tumor', 'Disease', (99, 129))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (15, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('myxoid liposarcoma', 'Disease', (15, 33))	('Ewing sarcoma', 'Disease', (0, 13))	('activating', 'PosReg', (36, 46))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (15, 33))	('inactivating', 'NegReg', (50, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (78, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('MDM2', 'Gene', (132, 136))
282998	32138705	According to the genomic profile, the incidence increased steadily with age, except for tumors harboring recurrent translocations and MDM2 amplification among women (see Additional File 3).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('amplification', 'Var', (139, 152))	('translocations', 'Var', (115, 129))	('MDM2', 'Gene', '4193', (134, 138))	('MDM2', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('women', 'Species', '9606', (159, 164))
283100	30524904	The HLA-I expression on these tumors could be visualized by minimally one of the HLA-I antibodies, but did not reach the level of HLA-I that was observed on the endothelial cells in the same slide (Figure 3a-b).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('HLA-I', 'Gene', (81, 86))	('HLA-I', 'Protein', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('antibodies', 'Var', (87, 97))
283109	30524904	In these 2 tumors (SS24 and SS53), the ducts demonstrated strongly elevated HLA-I expression compared to the spindle cell compartments in between the ducts (Figure 4e).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('HLA-I', 'Protein', (76, 81))	('SS53', 'Var', (28, 32))	('SS', 'Phenotype', 'HP:0012570', (19, 21))	('elevated', 'PosReg', (67, 75))	('expression', 'MPA', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('SS', 'Phenotype', 'HP:0012570', (28, 30))
283128	30524904	In addition, PRAME was homogeneously expressed in 85% of all patients investigated, making it less likely for this tumor to develop PRAME negative escape variants in reaction to PRAME-specific TCR-gene therapy when compared to similar approaches targeting other tumor associated antigens, e.g.	('PRAME', 'Gene', (13, 18))	('PRAME', 'Gene', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('variants', 'Var', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('TCR', 'Gene', (193, 196))	('tumor', 'Disease', (262, 267))	('tumor', 'Disease', (115, 120))	('patients', 'Species', '9606', (61, 69))	('PRAME', 'Gene', '23532', (132, 137))	('PRAME', 'Gene', (132, 137))	('TCR', 'Gene', '6962', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('PRAME', 'Gene', '23532', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('PRAME', 'Gene', '23532', (178, 183))
283134	30524904	Our expression array data indicate that EWSR1-NFATc2 translocation positive Ewing sarcomas might also be a suitable candidate for PRAME-TCR gene therapy, since 100% of tumors tested are PRAME positive, and high levels of T cell infiltration were already described by Szuhai et.	('tumors', 'Disease', (168, 174))	('TCR', 'Gene', '6962', (136, 139))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (76, 90))	('translocation', 'Var', (53, 66))	('Ewing sarcomas', 'Disease', (76, 90))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (76, 90))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('NFATc2', 'Gene', (46, 52))	('TCR', 'Gene', (136, 139))	('high levels of T cell', 'Phenotype', 'HP:0100828', (206, 227))	('EWSR1', 'Gene', '2130', (40, 45))	('PRAME', 'Gene', '23532', (186, 191))	('PRAME', 'Gene', (186, 191))	('PRAME', 'Gene', '23532', (130, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('PRAME', 'Gene', (130, 135))	('NFATc2', 'Gene', '4773', (46, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('EWSR1', 'Gene', (40, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
283153	30524904	mRNA expression data from Ewing sarcomas, synovial sarcoma, osteosarcomas, BCOR-CCNB3 translocation sarcomas and EWSR1-NFATc2 translocation positive Ewing sarcomas were downloaded from the Gene Expression Omnibus (GSE20196, GSE2109, GSE14827, GSE2110, GSE34620, GSE12102, GSE34800 and GSE60740).	('GSE20196', 'Var', (214, 222))	('Ewing sarcomas', 'Disease', (149, 163))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (149, 163))	('CCNB3', 'Gene', (80, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('GSE12102', 'Var', (262, 270))	('GSE60740', 'Var', (285, 293))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('BCOR', 'Gene', (75, 79))	('synovial sarcoma', 'Disease', (42, 58))	('NFATc2', 'Gene', (119, 125))	('osteosarcomas', 'Phenotype', 'HP:0002669', (60, 73))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))	('sarcomas', 'Disease', 'MESH:D012509', (155, 163))	('synovial sarcoma', 'Disease', 'MESH:D013584', (42, 58))	('GSE2110', 'Chemical', '-', (243, 250))	('EWSR1', 'Gene', '2130', (113, 118))	('sarcomas', 'Disease', (100, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcomas', 'Disease', (155, 163))	('GSE2110', 'Var', (243, 250))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (26, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (42, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('NFATc2', 'Gene', '4773', (119, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('GSE2109', 'Chemical', '-', (224, 231))	('Ewing sarcomas', 'Disease', (26, 40))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (26, 40))	('CCNB3', 'Gene', '85417', (80, 85))	('GSE34620', 'Var', (252, 260))	('EWSR1', 'Gene', (113, 118))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('osteosarcomas', 'Disease', 'MESH:D012516', (60, 73))	('GSE2109', 'Var', (224, 231))	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('sarcomas', 'Disease', (65, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (149, 163))	('GSE14827', 'Var', (233, 241))	('sarcomas', 'Disease', (32, 40))	('osteosarcomas', 'Disease', (60, 73))	('GSE34800', 'Var', (272, 280))	('BCOR', 'Gene', '54880', (75, 79))
283158	30524904	All tumors were confirmed to be SS based on histology and genetic testing for (X;18) rearrangements in routine diagnostics.	('SS', 'Phenotype', 'HP:0012570', (32, 34))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('rearrangements', 'Var', (85, 99))
283247	29607435	Other anomalies that have been demonstrated are rearrangements of the YWHAE gene on chromosome 17 and the FAM22 gene on chromosome 10, dysregulation of epidermal growth factor and overproduction of the C-kit protein.	('C-kit', 'Gene', '3815', (202, 207))	('rearrangements', 'Var', (48, 62))	('overproduction', 'PosReg', (180, 194))	('epidermal growth factor', 'Gene', (152, 175))	('YWHAE', 'Gene', (70, 75))	('dysregulation', 'Var', (135, 148))	('C-kit', 'Gene', (202, 207))	('epidermal growth factor', 'Gene', '1950', (152, 175))	('YWHAE', 'Gene', '7531', (70, 75))	('FAM22', 'Gene', (106, 111))
283301	28626593	Although S100 negative cells have been described in previous case reports, a review of cases suggests that a large proportion of tumours will show S100 positivity in more than 50% of the neoplastic cells.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('S100', 'Gene', '6271', (9, 13))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('S100', 'Gene', (147, 151))	('S100', 'Gene', '6271', (147, 151))	('tumours', 'Disease', (129, 136))	('positivity', 'Var', (152, 162))	('S100', 'Gene', (9, 13))
283308	27458533	Deregulation of the FGF/FGFR signaling pathway has been associated with multiple development syndromes and cancers, and thus therapeutic strategies targeting FGFs and FGFR in human cancer are currently being explored.	('FGF', 'Gene', (158, 161))	('FGF', 'Gene', (167, 170))	('associated', 'Reg', (56, 66))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (158, 161))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('FGF', 'Gene', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (24, 27))	('human', 'Species', '9606', (175, 180))	('FGF', 'Gene', (20, 23))	('cancer', 'Disease', (181, 187))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (20, 23))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rat', 'Species', '10116', (139, 142))	('syndromes and cancers', 'Disease', 'MESH:D009369', (93, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
283354	27458533	The activation of FGFRs brings the intracellular kinases into close proximity, enabling them to transphosphorylate each other.	('activation', 'Var', (4, 14))	('enabling', 'Reg', (79, 87))	('transphosphorylate', 'MPA', (96, 114))	('FGF', 'Gene', (18, 21))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (18, 21))
283364	27458533	However, a study on the expression of cell surface receptors revealed low expression of FGFR-2 and FGFR-3 across ten OS cell lines (OS229, OS232, OS231, OS238, OS242, OS252, OS290, OS293, OS308, and OS311) .	('OS290', 'Var', (174, 179))	('OS308', 'Var', (188, 193))	('FGFR-3', 'Gene', (99, 105))	('OS238', 'Var', (153, 158))	('OS', 'Phenotype', 'HP:0002669', (139, 141))	('expression', 'MPA', (74, 84))	('OS', 'Phenotype', 'HP:0002669', (132, 134))	('OS231', 'Var', (146, 151))	('OS293', 'CellLine', 'CVCL:0045', (181, 186))	('OS229', 'CellLine', 'CVCL:D748', (132, 137))	('FGFR-2', 'Gene', '2263', (88, 94))	('OS', 'Phenotype', 'HP:0002669', (153, 155))	('OS', 'Phenotype', 'HP:0002669', (146, 148))	('OS311', 'Var', (199, 204))	('OS242', 'Var', (160, 165))	('FGFR-2', 'Gene', (88, 94))	('low', 'NegReg', (70, 73))	('OS293', 'Var', (181, 186))	('OS252', 'Var', (167, 172))	('OS232', 'Var', (139, 144))	('OS', 'Phenotype', 'HP:0002669', (117, 119))	('FGFR-3', 'Gene', '2261', (99, 105))
283365	27458533	In addition, amplification of FGFR-1 is disproportionately observed in the rare histological variants of OS.	('OS', 'Phenotype', 'HP:0002669', (105, 107))	('FGFR-1', 'Gene', (30, 36))	('amplification', 'Var', (13, 26))	('FGFR-1', 'Gene', '2260', (30, 36))	('observed', 'Reg', (59, 67))
283366	27458533	The amplification of FGFR-1 was observed in 18.5% of patients who showed a poor response to chemotherapy, and no FGFR-1 gene amplification was detected in the patients who responded well to therapy .	('FGFR-1', 'Gene', '2260', (21, 27))	('patients', 'Species', '9606', (53, 61))	('FGFR-1', 'Gene', (113, 119))	('amplification', 'Var', (4, 17))	('FGFR-1', 'Gene', '2260', (113, 119))	('patients', 'Species', '9606', (159, 167))	('FGFR-1', 'Gene', (21, 27))
283368	27458533	High expression of FGF2 and its receptor 3 FGFR3 was an adverse prognostic factor.	('FGFR3', 'Gene', (43, 48))	('High expression', 'Var', (0, 15))	('FGF2', 'Gene', (19, 23))	('FGFR3', 'Gene', '2261', (43, 48))
283372	27458533	FGFs and FGFRs are thought to be negative regulators of chondrocytic growth, such as achondroplasia and related chondrodysplasias, which are caused by constitutively active mutations in FGFR3 .	('caused by', 'Reg', (141, 150))	('FGF', 'Gene', (186, 189))	('achondroplasia', 'Disease', (85, 99))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (9, 12))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (186, 189))	('mutations', 'Var', (173, 182))	('FGF', 'Gene', (0, 3))	('FGFR3', 'Gene', '2261', (186, 191))	('achondroplasia', 'Disease', 'MESH:D000130', (85, 99))	('chondrodysplasias', 'Disease', 'MESH:D010009', (112, 129))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (0, 3))	('chondrodysplasias', 'Disease', (112, 129))	('FGFR3', 'Gene', (186, 191))	('FGF', 'Gene', (9, 12))
283379	27458533	Recently, several FGFR4 tyrosine kinase domain mutations were found in 7.5% primary human RMS tumors, and the mutants K535 and E550 showed autophosphorylation of the receptor.	('FGFR4', 'Gene', (18, 23))	('RMS tumors', 'Disease', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('RMS tumors', 'Disease', 'MESH:D009369', (90, 100))	('E550', 'Var', (127, 131))	('K535', 'Var', (118, 122))	('RMS', 'Phenotype', 'HP:0002859', (90, 93))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (84, 89))	('autophosphorylation', 'MPA', (139, 158))	('found', 'Reg', (62, 67))
283384	27458533	Inhibiting FGFR signaling might represent an important strategy to enhance the efficacy of current RMS treatments.	('RMS', 'Phenotype', 'HP:0002859', (99, 102))	('Inhibiting', 'Var', (0, 10))	('FGF', 'Gene', (11, 14))	('rat', 'Species', '10116', (57, 60))	('enhance', 'PosReg', (67, 74))	('RMS', 'Disease', (99, 102))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (11, 14))
283387	27458533	Several studies showed the amplification of FRS2 gene as well as the overexpression of FRS2 protein in liposarcoma, and the FGFR/FRS2 signaling was activated in about 75% of FRS2-positive high-grade liposarcomas.	('liposarcoma', 'Phenotype', 'HP:0012034', (199, 210))	('liposarcoma', 'Phenotype', 'HP:0012034', (103, 114))	('FRS2', 'Gene', '10818', (174, 178))	('FRS2', 'Gene', (129, 133))	('liposarcomas', 'Disease', (199, 211))	('liposarcoma', 'Disease', 'MESH:D008080', (199, 210))	('overexpression', 'PosReg', (69, 83))	('FRS2', 'Gene', '10818', (44, 48))	('liposarcoma', 'Disease', 'MESH:D008080', (103, 114))	('amplification', 'Var', (27, 40))	('FGF', 'Gene', (124, 127))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (124, 127))	('FRS2', 'Gene', '10818', (129, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('FRS2', 'Gene', (87, 91))	('liposarcoma', 'Disease', (199, 210))	('liposarcomas', 'Disease', 'MESH:D008080', (199, 211))	('liposarcoma', 'Disease', (103, 114))	('protein', 'Protein', (92, 99))	('FRS2', 'Gene', (174, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('liposarcomas', 'Phenotype', 'HP:0012034', (199, 211))	('FRS2', 'Gene', '10818', (87, 91))	('FRS2', 'Gene', (44, 48))	('activated', 'PosReg', (148, 157))
283389	27458533	Importantly, use of the FGFR selective inhibitor NVP-BGJ-398 can significantly inhibit the growth of two cell lines and suppressed the FGFR signal transduction.	('inhibit', 'NegReg', (79, 86))	('FGF', 'Gene', (135, 138))	('NVP-BGJ-398', 'Var', (49, 60))	('suppressed', 'NegReg', (120, 130))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (135, 138))	('growth of two cell lines', 'CPA', (91, 115))	('FGF', 'Gene', (24, 27))	('NVP-BGJ-398', 'Chemical', 'MESH:C568950', (49, 60))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (24, 27))
283392	27458533	In vitro, inhibition of FGFR showed effects on proliferation and cell migration and induced apoptosis, which indicated that the FGFR might be a therapy target for myxoid liposarcoma .	('induced', 'Reg', (84, 91))	('apoptosis', 'CPA', (92, 101))	('myxoid liposarcoma', 'Disease', (163, 181))	('cell migration', 'CPA', (65, 79))	('rat', 'Species', '10116', (54, 57))	('liposarcoma', 'Phenotype', 'HP:0012034', (170, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('effects', 'Reg', (36, 43))	('FGF', 'Gene', (24, 27))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (163, 181))	('FGF', 'Gene', (128, 131))	('inhibition', 'Var', (10, 20))	('proliferation', 'CPA', (47, 60))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (163, 181))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (24, 27))	('rat', 'Species', '10116', (73, 76))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (128, 131))
283396	27458533	While FGFR inhibitors induced significant growth inhibition in vitro and in vivo was only associated with a downregulation of phosphorylated ERK1/2 and an ERK kinase inhibitor showed growth inhibitory effects for synovial sarcoma .	('synovial sarcoma', 'Phenotype', 'HP:0012570', (213, 229))	('synovial sarcoma', 'Disease', 'MESH:D013584', (213, 229))	('ERK1/2', 'Gene', (141, 147))	('ERK', 'Gene', (141, 144))	('ERK', 'Gene', (155, 158))	('ERK', 'Gene', '5594', (155, 158))	('ERK1/2', 'Gene', '5595;5594', (141, 147))	('FGF', 'Gene', (6, 9))	('growth', 'MPA', (42, 48))	('inhibitors', 'Var', (11, 21))	('synovial sarcoma', 'Disease', (213, 229))	('downregulation', 'NegReg', (108, 122))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (6, 9))	('ERK', 'Gene', '5594', (141, 144))	('phosphorylated', 'MPA', (126, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
283406	27458533	A phase 1 clinical trial of BAY1187982, an anti-FGFR2 antibody, in subjects with advanced solid tumors known to express FGFR2 has been conducted (http://ClinicalTrials.gov, NCT02368951).	('BAY1187982', 'Chemical', 'MESH:C000621819', (28, 38))	('FGFR2', 'Gene', (48, 53))	('FGFR2', 'Gene', '2263', (48, 53))	('solid tumors', 'Disease', 'MESH:D009369', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('FGFR2', 'Gene', '2263', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('BAY1187982', 'Var', (28, 38))	('solid tumors', 'Disease', (90, 102))	('FGFR2', 'Gene', (120, 125))
283407	27458533	BGJ398 will be tested in phase 2 clinical trials in patients with advanced cholangiocarcinoma with FGFR2 gene fusions or other FGFR genetic alterations (http://ClinicalTrials.gov, NCT02150967).	('fusions', 'Var', (110, 117))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('genetic alterations', 'Var', (132, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('FGF', 'Gene', (99, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('FGF', 'Gene', (127, 130))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (99, 102))	('FGFR2', 'Gene', '2263', (99, 104))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (127, 130))	('rat', 'Species', '10116', (144, 147))	('cholangiocarcinoma', 'Disease', (75, 93))	('FGFR2', 'Gene', (99, 104))	('patients', 'Species', '9606', (52, 60))
283410	27458533	Aberrations in FGFR signaling are involved in the pathophysiology of several malignancies and disorders.	('FGF', 'Gene', (15, 18))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (15, 18))	('involved', 'Reg', (34, 42))	('rat', 'Species', '10116', (4, 7))	('Aberrations', 'Var', (0, 11))	('malignancies and disorders', 'Disease', 'MESH:D009369', (77, 103))
283411	27458533	FGFR inhibitors such as small-molecule FGFR inhibitors could be of potential use for targeted therapy in sarcomas.	('FGF', 'Gene', (39, 42))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (39, 42))	('small-molecule', 'Var', (24, 38))	('FGF', 'Gene', (0, 3))	('sarcomas', 'Disease', 'MESH:D012509', (105, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (0, 3))	('sarcomas', 'Disease', (105, 113))
283418	27458533	In a recent study, ponatinib (AP24534) was determined as the most potent FGFR4 inhibitor because it was shown to inhibit the growth of RMS cells expressing wild-type or mutated FGFR4 by increasing apoptosis.	('apoptosis', 'CPA', (197, 206))	('ponatinib', 'Chemical', 'MESH:C545373', (19, 28))	('mutated', 'Var', (169, 176))	('FGFR4', 'Gene', (177, 182))	('inhibit', 'NegReg', (113, 120))	('AP24534', 'Chemical', 'MESH:C545373', (30, 37))	('growth', 'MPA', (125, 131))	('RMS', 'Phenotype', 'HP:0002859', (135, 138))	('increasing', 'PosReg', (186, 196))
283419	27458533	Similar results were observed in a RMS mouse model expressing mutated FGFR4.	('mouse', 'Species', '10090', (39, 44))	('FGFR4', 'Gene', (70, 75))	('RMS', 'Phenotype', 'HP:0002859', (35, 38))	('mutated', 'Var', (62, 69))
283423	27458533	The genetic alterations of FGF/FGFR are involved in sarcomas such as OS, chondrosarcoma, RMS, liposarcomas, and synovial sarcoma.	('genetic alterations', 'Var', (4, 23))	('liposarcomas', 'Disease', 'MESH:D008080', (94, 106))	('liposarcoma', 'Phenotype', 'HP:0012034', (94, 105))	('rat', 'Species', '10116', (16, 19))	('chondrosarcoma', 'Disease', (73, 87))	('chondrosarcoma', 'Disease', 'MESH:D002813', (73, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('FGF', 'Gene', (31, 34))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (31, 34))	('involved', 'Reg', (40, 48))	('OS', 'Phenotype', 'HP:0002669', (69, 71))	('liposarcomas', 'Phenotype', 'HP:0012034', (94, 106))	('synovial sarcoma', 'Disease', (112, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('synovial sarcoma', 'Disease', 'MESH:D013584', (112, 128))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (73, 87))	('RMS', 'Phenotype', 'HP:0002859', (89, 92))	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('liposarcomas', 'Disease', (94, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('FGF', 'Gene', (27, 30))	('sarcomas', 'Disease', (52, 60))	('sarcomas', 'Disease', 'MESH:D012509', (98, 106))	('FGF', 'Gene', '2246;25317;2258;2247;14173;54250;2248;2251;2252;2253;2254;2255;2256;2257;2258;8822;8823;80903;8822;8817;14172;9965;26281;26291;27006;8074', (27, 30))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (112, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('sarcomas', 'Disease', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('RMS', 'Disease', (89, 92))
283426	27458533	81372872 and 81402215), funds from the University Cancer Foundation via the Sister Institution Network Fund (SINF) at the Tianjin Medical University Cancer Institute & Hospital (TMUCIH), Fudan University Shanghai Cancer Center (FUSCC), and University of Texas MD Anderson Cancer Center (UT MDACC).	('Cancer', 'Disease', 'MESH:D009369', (213, 219))	('Cancer', 'Phenotype', 'HP:0002664', (272, 278))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Cancer', 'Disease', (272, 278))	('Texas MD Anderson Cancer', 'Disease', 'MESH:C535460', (254, 278))	('81372872', 'Var', (0, 8))	('Cancer', 'Disease', (50, 56))	('Shanghai Cancer', 'Disease', (204, 219))	('Cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Shanghai Cancer', 'Disease', 'MESH:D009369', (204, 219))	('Cancer', 'Disease', 'MESH:D009369', (272, 278))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('81402215', 'Var', (13, 21))	('SINF', 'Disease', (109, 113))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (213, 219))	('Texas MD Anderson Cancer', 'Disease', (254, 278))	('SINF', 'Disease', 'None', (109, 113))	('Cancer', 'Disease', (149, 155))
283455	26194680	GTV agreement for both cases was almost perfect; CTV agreement was substantial for RPS1 and almost perfect for RPS2.	('GTV', 'Chemical', '-', (0, 3))	('RPS2', 'Gene', (111, 115))	('RPS2', 'Gene', '6187', (111, 115))	('RPS1', 'Var', (83, 87))
283459	26194680	Of note, the contour variability as demonstrated by the standard deviations was greater for all RPS1 target volumes than for RPS2 target volumes.	('RPS2', 'Gene', (125, 129))	('contour', 'MPA', (13, 20))	('RPS2', 'Gene', '6187', (125, 129))	('RPS1', 'Var', (96, 100))
283461	26194680	Agreement sensitivity and specificity values are provided in Tables 2-4 and show that in all cases, the specificity values were greater than sensitivity values, and sensitivity was higher for all RPS1 target volumes compared with RPS2 target volumes.	('RPS1', 'Var', (196, 200))	('sensitivity', 'MPA', (165, 176))	('RPS2', 'Gene', (230, 234))	('RPS2', 'Gene', '6187', (230, 234))	('higher', 'PosReg', (181, 187))	('specificity values', 'MPA', (104, 122))
283468	26194680	The degree of contour variability as represented by standard deviations of the volumes were larger for RPS1 than for RPS2 for both the GTV and the CTV structures (15.9% vs 3.7% and 17.3% vs 10.2%, respectively.)	('RPS2', 'Gene', (117, 121))	('RPS2', 'Gene', '6187', (117, 121))	('GTV', 'Chemical', '-', (135, 138))	('RPS1', 'Var', (103, 107))
283473	26194680	Similarly, the contour sensitivity values (true positive rates) for RPS1 were lower than those for RPS2 for both the GTV and CTV structures.	('RPS2', 'Gene', (99, 103))	('RPS2', 'Gene', '6187', (99, 103))	('contour sensitivity values', 'MPA', (15, 41))	('GTV', 'Chemical', '-', (117, 120))	('lower', 'NegReg', (78, 83))	('RPS1', 'Var', (68, 72))
283491	24345474	Recently, soft tissue sarcomas have increasingly been classified on the basis of underlying genetic alterations; however, the role of aberrant DNA methylation in these tumors is not well understood and, consequently, the usefulness of methylation-based classification is unclear.	('aberrant', 'Var', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('soft tissue sarcomas', 'Disease', (10, 30))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (10, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (10, 30))
283494	24345474	Compared with non-neoplastic fat, NNAT showed DNA hypomethylation and inverse gene expression in myxoid liposarcomas, and DNA hypermethylation and inverse gene expression in dedifferentiated and pleomorphic liposarcomas.	('liposarcoma', 'Phenotype', 'HP:0012034', (104, 115))	('liposarcomas', 'Phenotype', 'HP:0012034', (207, 219))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (97, 115))	('liposarcoma', 'Phenotype', 'HP:0012034', (207, 218))	('myxoid liposarcomas', 'Disease', (97, 116))	('NNAT', 'Gene', (34, 38))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (97, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (97, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (211, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('pleomorphic liposarcomas', 'Disease', (195, 219))	('liposarcomas', 'Phenotype', 'HP:0012034', (104, 116))	('NNAT', 'Gene', '4826', (34, 38))	('hypermethylation', 'Var', (126, 142))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (195, 219))
283498	24345474	The role of aberrant DNA methylation in the development of human malignancies is well established and has been shown to contribute to the pathogenesis of cancer.	('human', 'Species', '9606', (59, 64))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('contribute', 'Reg', (120, 130))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('malignancies', 'Disease', (65, 77))	('aberrant', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DNA', 'Protein', (21, 24))
283500	24345474	Hypermethylation has been assumed as a silencing mechanism for tumor suppressor genes, developmental programs and imprinting, and as crucial for maintaining cell differentiation and fate.	('tumor', 'Disease', (63, 68))	('Hypermethylation', 'Var', (0, 16))	('silencing', 'NegReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cell differentiation', 'CPA', (157, 177))
283510	24345474	According to this, sarcomas can be classified into two main groups: (a) sarcomas with specific genetic alterations on a background of relatively few chromosomal changes and (b) sarcomas with no specific genetic alterations on a complex background of numerous chromosomal changes.	('sarcomas', 'Disease', (177, 185))	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('alterations', 'Var', (103, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('numerous chromosomal changes', 'Phenotype', 'HP:0040012', (250, 278))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('sarcomas', 'Disease', 'MESH:D012509', (177, 185))	('genetic alterations', 'Var', (95, 114))	('sarcomas', 'Disease', 'MESH:D012509', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('sarcomas', 'Disease', (72, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (177, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('sarcomas', 'Disease', (19, 27))
283512	24345474	For example, SSs and MLSs are characterized by subtype-specific translocations, gastrointestinal stromal tumors (GISTs) carry KIT gene mutations, well-differentiated liposarcomas (WDLSs) and DDLSs show amplifications of the MDM2 gene, and extrarenal rhabdoid tumors have a high incidence of homozygous deletions of the SMARCB1 gene.	('GISTs', 'Phenotype', 'HP:0100723', (113, 118))	('liposarcoma', 'Phenotype', 'HP:0012034', (166, 177))	('MLS', 'Gene', (21, 24))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (80, 111))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (80, 111))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('KIT gene', 'Gene', (126, 134))	('carry', 'Reg', (120, 125))	('liposarcomas', 'Disease', (166, 178))	('rhabdoid tumors', 'Disease', (250, 265))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (250, 265))	('mutations', 'Var', (135, 144))	('SMARCB1', 'Gene', '6598', (319, 326))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('MDM2', 'Gene', (224, 228))	('SMARCB1', 'Gene', (319, 326))	('SSs', 'Disease', (13, 16))	('SSs', 'Phenotype', 'HP:0012570', (13, 16))	('gastrointestinal stromal tumors', 'Disease', (80, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('MDM2', 'Gene', '4193', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('liposarcomas', 'Disease', 'MESH:D008080', (166, 178))	('MLS', 'Gene', '3052', (21, 24))	('MLSs', 'Phenotype', 'HP:0012268', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('liposarcomas', 'Phenotype', 'HP:0012034', (166, 178))
283520	24345474	While previous studies have profiled DNA methylation in soft tissue sarcomas, they have either been limited to specific sarcoma subtypes or genes with corresponding CpG islands or sites.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (56, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (56, 76))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (120, 136))	('methylation', 'Var', (41, 52))	('profiled', 'Reg', (28, 36))	('soft tissue sarcomas', 'Disease', (56, 76))	('sarcoma subtypes', 'Disease', (120, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
283521	24345474	Genome-wide DNA methylation studies suggest there are distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas and they have revealed genes that are potential targets of epigenetic inactivation in Ewing's sarcoma.	('alveolar rhabdomyosarcomas', 'Disease', (115, 141))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (115, 141))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (115, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (228, 243))	("Ewing's sarcoma", 'Disease', (228, 243))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (228, 243))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (124, 141))	('epigenetic inactivation', 'Var', (201, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
283523	24345474	While epigenetic abnormalities have been extensively characterized in STSs, their influence on mRNA expression in a large cohort of primary, high-grade sarcoma samples has not been described in a genome-wide study so far.	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('mRNA expression', 'MPA', (95, 110))	('STSs', 'Phenotype', 'HP:0030448', (70, 74))	('sarcoma', 'Disease', (152, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('epigenetic abnormalities', 'Var', (6, 30))
283526	24345474	We integrated our methylation data with mRNA expression data to identify diagnostically relevant DNA methylation changes between different sarcoma subtypes and functional relevant genes including potential tumor-suppressor candidates.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (139, 155))	('sarcoma subtypes', 'Disease', (139, 155))	('changes', 'Reg', (113, 120))	('tumor', 'Disease', (206, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('methylation', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
283529	24345474	This M-value-based binarization translates to mean beta values (over all samples including primary tumors, non-neoplastic fat cells and cell lines) of 0.14 (SD 0.11) and 0.64 (SD 0.13) for hypo- and hypermethylation, respectively.	('hypermethylation', 'Var', (199, 215))	('hypo-', 'Var', (189, 194))	('primary tumors', 'Disease', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('primary tumors', 'Disease', 'MESH:D009369', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
283563	24345474	This suggests that aberrant DNA methylation might have functional consequences in approximately 25% of the genes showing differential DNA methylation for the seven sarcoma clusters.	('aberrant', 'Var', (19, 27))	('sarcoma clusters', 'Disease', 'MESH:D003027', (164, 180))	('sarcoma clusters', 'Disease', (164, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
283588	24345474	As mentioned above, this CpG site had a positive correlation between methylation and gene expression for the whole sarcoma collection.	('positive', 'PosReg', (40, 48))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('gene expression', 'MPA', (85, 100))	('sarcoma', 'Disease', (115, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('methylation', 'Var', (69, 80))
283591	24345474	NNAT, CD36 and ELF5 were hypomethylated and ALDH1A3 and EFEMP1 were hypermethylated in MLS samples.	('hypomethylated', 'Var', (25, 39))	('ALDH1A3', 'Gene', (44, 51))	('MLS', 'Gene', '3052', (87, 90))	('CD36', 'Species', '42374', (6, 10))	('NNAT', 'Gene', (0, 4))	('ALDH1A3', 'Gene', '220', (44, 51))	('EFEMP1', 'Gene', '2202', (56, 62))	('EFEMP1', 'Gene', (56, 62))	('CD36', 'Gene', (6, 10))	('ELF5', 'Gene', (15, 19))	('NNAT', 'Gene', '4826', (0, 4))	('MLS', 'Gene', (87, 90))	('hypermethylated', 'PosReg', (68, 83))
283619	24345474	Furthermore, the CpG site cg22298088 in the promoter region of NNAT had the highest importance for classification of MLS in the whole sarcoma collection (Figures 4 and 6; Table 2).	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('NNAT', 'Gene', (63, 67))	('MLS', 'Gene', '3052', (117, 120))	('sarcoma', 'Disease', (134, 141))	('MLS', 'Gene', (117, 120))	('cg22298088', 'Var', (26, 36))	('cg22298088', 'Chemical', '-', (26, 36))	('NNAT', 'Gene', '4826', (63, 67))
283625	24345474	On the other hand, the average DNA methylation frequency in MLS was about 45% lower compared to the six non-neoplastic fat samples and was accompanied by a higher NNAT expression (Figure 8e,f).	('higher', 'PosReg', (156, 162))	('MLS', 'Gene', '3052', (60, 63))	('MLS', 'Gene', (60, 63))	('NNAT', 'Gene', '4826', (163, 167))	('DNA', 'MPA', (31, 34))	('methylation', 'Var', (35, 46))	('NNAT', 'Gene', (163, 167))	('lower', 'NegReg', (78, 83))
283631	24345474	Several studies have shown that changes in DNA methylation for a growing number of genes play an essential role in cancer development, emphasizing the crucial role of these epigenetic changes for future diagnosis, prognosis and prediction of response to therapies.	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('changes', 'Var', (32, 39))
283632	24345474	Previous studies of epigenetic alterations in soft tissue sarcomas either focused on specific candidate genes or particular sarcoma subtypes.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (46, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('particular sarcoma subtypes', 'Disease', (113, 140))	('particular sarcoma subtypes', 'Disease', 'MESH:D012509', (113, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (46, 66))	('soft tissue sarcomas', 'Disease', (46, 66))	('epigenetic alterations', 'Var', (20, 42))	('focused', 'Reg', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
283642	24345474	This CpG site was hypermethylated exclusively in samples of sarcoma cluster 7, which comprised all SS samples and one MPNST sample.	('sarcoma cluster', 'Disease', 'MESH:D003027', (60, 75))	('sarcoma cluster', 'Disease', (60, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('hypermethylated', 'Var', (18, 33))
283654	24345474	The CDKN2A locus on chromosome 9p21 is frequently mutated or deleted in a variety of carcinomas as well as in soft tissue sarcomas.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (110, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('soft tissue sarcomas', 'Disease', (110, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('CDKN2A', 'Gene', '1029', (4, 10))	('carcinomas', 'Disease', 'MESH:D002277', (85, 95))	('CDKN2A', 'Gene', (4, 10))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (110, 130))	('deleted', 'Var', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('carcinomas', 'Disease', (85, 95))
283655	24345474	However, hypermethylation of the promoter region of CDKN2A seems to have only a limited effect on gene inactivation.	('hypermethylation', 'Var', (9, 25))	('CDKN2A', 'Gene', '1029', (52, 58))	('CDKN2A', 'Gene', (52, 58))
283662	24345474	ZNF217 is a marker of poor prognosis in breast cancer, COL14A1 is a candidate tumor-suppressor gene frequently methylated in renal cell carcinomas and the transcription factor DMRT2 is downregulated in clear-cell renal-cell carcinomas.	('ZNF217', 'Gene', (0, 6))	('ZNF217', 'Gene', '7764', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('renal cell carcinomas', 'Disease', (125, 146))	('downregulated', 'NegReg', (185, 198))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('methylated', 'Var', (111, 121))	('renal-cell carcinomas', 'Phenotype', 'HP:0005584', (213, 234))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (125, 146))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('DMRT2', 'Gene', '10655', (176, 181))	('breast cancer', 'Disease', (40, 53))	('DMRT2', 'Gene', (176, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('clear-cell renal-cell carcinomas', 'Disease', 'MESH:C538614', (202, 234))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('clear-cell renal-cell carcinomas', 'Disease', (202, 234))	('COL14A1', 'Gene', (55, 62))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('COL14A1', 'Gene', '7373', (55, 62))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (125, 146))	('clear-cell renal-cell carcinomas', 'Phenotype', 'HP:0006770', (202, 234))
283665	24345474	This indicates that sarcoma cell lines are useful for molecular and epigenetic studies, especially for hypermethylated genes (for example, ALDH1A3) but are only of limited use for hypomethylated genes.	('ALDH1A3', 'Gene', (139, 146))	('hypermethylated', 'Var', (103, 118))	('sarcoma', 'Disease', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('ALDH1A3', 'Gene', '220', (139, 146))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))
283691	24345474	It was hypothesized that reactivation of maternal NNAT would lead to an overall downregulation of BLCAP.	('BLCAP', 'Gene', (98, 103))	('NNAT', 'Gene', '4826', (50, 54))	('BLCAP', 'Gene', '10904', (98, 103))	('NNAT', 'Gene', (50, 54))	('reactivation', 'Var', (25, 37))	('downregulation', 'NegReg', (80, 94))
283693	24345474	In the context of our findings, it is of interest that NNAT was previously reported to be upregulated in MLS compared to normal fat and that ectopic expression of NNAT in pre-adipocytes stimulated differentiation into mature adipocytes by induction of adipogenic transcription factors.	('NNAT', 'Gene', '4826', (55, 59))	('stimulated', 'PosReg', (186, 196))	('MLS', 'Gene', '3052', (105, 108))	('MLS', 'Gene', (105, 108))	('NNAT', 'Gene', '4826', (163, 167))	('NNAT', 'Gene', (55, 59))	('differentiation', 'CPA', (197, 212))	('upregulated', 'PosReg', (90, 101))	('NNAT', 'Gene', (163, 167))	('ectopic expression', 'Var', (141, 159))
283695	24345474	On the other hand, we observed DNA hypermethylation and complete downregulation of NNAT in two further liposarcoma subtypes, namely DDLS and PLS, indicating hampered or complete disruption of normal adipogenesis in these subtypes.	('hypermethylation', 'Var', (35, 51))	('liposarcoma subtype', 'Disease', 'MESH:D008080', (103, 122))	('NNAT', 'Gene', '4826', (83, 87))	('PLS', 'Disease', (141, 144))	('normal adipogenesis', 'MPA', (192, 211))	('liposarcoma subtype', 'Disease', (103, 122))	('sarcoma subtypes', 'Disease', (107, 123))	('liposarcoma', 'Phenotype', 'HP:0012034', (103, 114))	('NNAT', 'Gene', (83, 87))	('PLS', 'Disease', 'MESH:D010214', (141, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('downregulation', 'NegReg', (65, 79))	('disruption', 'NegReg', (178, 188))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (107, 123))
283696	24345474	In MLS, demethylation and reactivation of the maternal NNAT allele may have occurred.	('NNAT', 'Gene', '4826', (55, 59))	('demethylation', 'Var', (8, 21))	('NNAT', 'Gene', (55, 59))	('MLS', 'Gene', '3052', (3, 6))	('MLS', 'Gene', (3, 6))
283699	24345474	The subclassification of liposarcomas has important prognostic significance: patients with pleomorphic and dedifferentiated liposarcomas have an unfavorable prognosis compared to patients with MLS or WDLS.	('liposarcomas', 'Disease', (124, 136))	('liposarcoma', 'Phenotype', 'HP:0012034', (25, 36))	('MLS', 'Gene', (193, 196))	('liposarcoma', 'Phenotype', 'HP:0012034', (124, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('patients', 'Species', '9606', (77, 85))	('liposarcomas', 'Disease', 'MESH:D008080', (25, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('patients', 'Species', '9606', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('liposarcomas', 'Phenotype', 'HP:0012034', (124, 136))	('liposarcomas', 'Phenotype', 'HP:0012034', (25, 37))	('pleomorphic', 'Var', (91, 102))	('liposarcomas', 'Disease', 'MESH:D008080', (124, 136))	('liposarcomas', 'Disease', (25, 37))	('MLS', 'Gene', '3052', (193, 196))
283700	24345474	However, in contrast to our data identifying NNAT as a putative tumor suppressor in MLS, it was recently shown that high NNAT expression correlates with decreased survival of patients with glioblastoma, and that silencing of NNAT through miR-708 promotes cell migration and metastasis formation in breast cancer.	('MLS', 'Gene', '3052', (84, 87))	('metastasis formation', 'CPA', (274, 294))	('promotes', 'PosReg', (246, 254))	('NNAT', 'Gene', '4826', (121, 125))	('glioblastoma', 'Disease', (189, 201))	('decreased', 'NegReg', (153, 162))	('silencing', 'Var', (212, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('MLS', 'Gene', (84, 87))	('NNAT', 'Gene', (45, 49))	('miR-708', 'Gene', (238, 245))	('NNAT', 'Gene', '4826', (45, 49))	('expression', 'MPA', (126, 136))	('cell migration', 'CPA', (255, 269))	('breast cancer', 'Phenotype', 'HP:0003002', (298, 311))	('survival', 'CPA', (163, 171))	('NNAT', 'Gene', (225, 229))	('tumor', 'Disease', (64, 69))	('miR-708', 'Gene', '100126333', (238, 245))	('breast cancer', 'Disease', 'MESH:D001943', (298, 311))	('breast cancer', 'Disease', (298, 311))	('high', 'PosReg', (116, 120))	('NNAT', 'Gene', '4826', (225, 229))	('patients', 'Species', '9606', (175, 183))	('NNAT', 'Gene', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (189, 201))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
283702	24345474	In summary, our DNA methylation and gene expression approach for a collection of 80 primary, high-grade soft tissue sarcomas and 14 sarcoma cell lines, accomplished four aims: (1) the identification of diagnostically relevant DNA methylation differences between different sarcoma subtypes, (2) the identification of new subtype-specific and functionally relevant candidate genes that showed correlation between DNA methylation and gene expression, (3) the identification of DNA methylation patterns in sarcoma cell lines, which could be used in the future for the functional validation of candidate genes that show gene expression changes influenced by DNA methylation and (4) the identification of new and functionally relevant DNA methylation differences between liposarcomas and non-neoplastic fat tissue with NNAT as a new potential tumor-suppressor gene for MLS.	('MLS', 'Gene', (863, 866))	('soft tissue sarcomas', 'Disease', (104, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (502, 509))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (104, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (769, 776))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))	('neoplastic fat tissue', 'Phenotype', 'HP:0200013', (786, 807))	('sarcomas', 'Phenotype', 'HP:0100242', (769, 777))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (104, 124))	('tumor', 'Disease', (837, 842))	('sarcoma', 'Disease', (132, 139))	('liposarcomas', 'Disease', 'MESH:D008080', (765, 777))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('differences', 'Reg', (745, 756))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (272, 288))	('sarcoma', 'Disease', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (837, 842))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma subtypes', 'Disease', (272, 288))	('NNAT', 'Gene', (813, 817))	('DNA', 'Gene', (729, 732))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('liposarcomas', 'Phenotype', 'HP:0012034', (765, 777))	('NNAT', 'Gene', '4826', (813, 817))	('sarcoma', 'Disease', 'MESH:D012509', (272, 279))	('MLS', 'Gene', '3052', (863, 866))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('sarcoma', 'Disease', 'MESH:D012509', (502, 509))	('liposarcoma', 'Phenotype', 'HP:0012034', (765, 776))	('tumor', 'Phenotype', 'HP:0002664', (837, 842))	('sarcoma', 'Disease', (272, 279))	('methylation', 'Var', (733, 744))	('sarcoma', 'Disease', (502, 509))	('sarcoma', 'Disease', 'MESH:D012509', (769, 776))	('sarcoma', 'Disease', (769, 776))	('liposarcomas', 'Disease', (765, 777))
283746	33188621	The Duchenne muscular dystrophy gene and cancer Mutation of the Duchenne muscular dystrophy (DMD) gene causes Duchenne and Becker muscular dystrophy, degenerative neuromuscular disorders that primarily affect voluntary muscles.	('muscular dystrophy', 'Phenotype', 'HP:0003560', (130, 148))	('Duchenne muscular dystrophy', 'Disease', (4, 31))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (13, 31))	('Duchenne and Becker muscular dystrophy', 'Disease', 'MESH:D020388', (110, 148))	('Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (4, 31))	('degenerative neuromuscular disorders', 'Disease', 'MESH:D009468', (150, 186))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (73, 91))	('degenerative neuromuscular disorders', 'Disease', (150, 186))	('causes', 'Reg', (103, 109))	('Mutation', 'Var', (48, 56))	('cancer', 'Disease', (41, 47))	('Duchenne muscular dystrophy', 'Disease', (64, 91))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (64, 91))
283747	33188621	However, increasing evidence implicates DMD in the development of all major cancer types.	('DMD', 'Var', (40, 43))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
283757	33188621	The loss of dystrophin, through out-of-frame DMD gene mutation, in Duchenne patients is responsible for severe muscle degeneration and premature death.	('mutation', 'Var', (54, 62))	('muscle degeneration', 'Disease', 'MESH:D009135', (111, 130))	('Duchenne', 'Disease', (67, 75))	('patients', 'Species', '9606', (76, 84))	('dystrophin', 'Gene', (12, 22))	('premature death', 'Disease', 'MESH:D003643', (135, 150))	('muscle degeneration', 'Phenotype', 'HP:0003202', (111, 130))	('Duchenne', 'Disease', 'MESH:D020388', (67, 75))	('DMD gene', 'Gene', (45, 53))	('premature death', 'Disease', (135, 150))	('loss', 'NegReg', (4, 8))	('out-of-frame', 'NegReg', (32, 44))	('muscle degeneration', 'Disease', (111, 130))
283761	33188621	Dp71 and Dp40 additionally lack the rod domain and part of the WW domain (Fig.	('lack', 'NegReg', (27, 31))	('Dp40', 'Var', (9, 13))	('Dp71', 'Gene', (0, 4))	('rod domain', 'MPA', (36, 46))	('Dp71', 'Gene', '13405', (0, 4))
283763	33188621	These have been organised into groups, with the most common being Dp71d group isoforms that contain exon 78 and Dp71f group isoforms that do not contain exon 78.	('Dp71', 'Gene', '13405', (112, 116))	('Dp71', 'Gene', (112, 116))	('Dp71', 'Gene', (66, 70))	('exon 78', 'Var', (100, 107))	('Dp71', 'Gene', '13405', (66, 70))
283769	33188621	A common basis may underlie the frequent occurrence of CFS/DMD rearrangements in germ cells of DMD patients and similar alterations found in cancer cells.	('rat', 'Species', '10116', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CFS/DMD', 'Gene', (55, 62))	('rearrangements', 'Var', (63, 77))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
283774	33188621	Here, we comprehensively review the overlooked, but accumulating evidence supporting a role for the DMD gene and its variants in neoplastic disease.	('neoplastic disease', 'Disease', (129, 147))	('variants', 'Var', (117, 125))	('neoplastic disease', 'Phenotype', 'HP:0002664', (129, 147))	('DMD gene', 'Gene', (100, 108))	('neoplastic disease', 'Disease', 'MESH:D009386', (129, 147))
283788	33188621	Dystrophin complexes with dystroglycan and loss of dystrophin is known to affect the level and localisation of other DAPC components.	('level', 'MPA', (85, 90))	('dystrophin', 'Protein', (51, 61))	('dystroglycan', 'Gene', '1605', (26, 38))	('Dystrophin', 'Gene', '1756', (0, 10))	('complexes', 'Interaction', (11, 20))	('affect', 'Reg', (74, 80))	('dystroglycan', 'Gene', (26, 38))	('localisation', 'MPA', (95, 107))	('loss', 'Var', (43, 47))	('Dystrophin', 'Gene', (0, 10))
283791	33188621	They also found that mdx ERMS tumours showed altered expression patterns and mutations of known equivalent to human RMS-associated genes such as TP53 and mouse double minute 2 ortholog (MDM2), a negative regulator of p53.	('MDM2', 'Gene', (186, 190))	('altered', 'Reg', (45, 52))	('ERMS tumours', 'Disease', (25, 37))	('ERMS tumours', 'Disease', 'MESH:D009369', (25, 37))	('mouse', 'Species', '10090', (154, 159))	('expression patterns', 'MPA', (53, 72))	('p53', 'Gene', (217, 220))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('TP53', 'Gene', '7157', (145, 149))	('MDM2', 'Gene', '17246', (186, 190))	('TP53', 'Gene', (145, 149))	('human', 'Species', '9606', (110, 115))	('mutations', 'Var', (77, 86))	('p53', 'Gene', '22060', (217, 220))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
283796	33188621	However, the age of onset and incidence was strongly strain-dependent, with the C57BL/10 background of mdx mice being the most tumour-susceptible.	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('mice', 'Species', '10090', (107, 111))	('C57BL/10', 'Var', (80, 88))	('tumour', 'Disease', (127, 133))
283798	33188621	Another independent study reported RMS in > 90% of dystrophin and dysferlin double mutant mice.	('RMS', 'MPA', (35, 38))	('mice', 'Species', '10090', (90, 94))	('dysferlin', 'Gene', '26903', (66, 75))	('dystrophin', 'Gene', (51, 61))	('dysferlin', 'Gene', (66, 75))	('double mutant', 'Var', (76, 89))
283800	33188621	Interestingly, such genetic lesions are present before sarcoma development in aged mdx mice and, importantly, DMD patient skeletal muscle tissues also display gross genomic instability.	('genetic lesions', 'Var', (20, 35))	('sarcoma', 'Disease', (55, 62))	('mice', 'Species', '10090', (87, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('lesions', 'Var', (28, 35))	('patient', 'Species', '9606', (114, 121))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))
283801	33188621	suggested that the adipocyte and connective tissue proliferation characteristics of DMD may create the required molecular context for sarcoma development from multipotent mesenchymal or muscle-derived stem cells.	('connective tissue proliferation', 'Phenotype', 'HP:0100898', (33, 64))	('DMD', 'Var', (84, 87))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('rat', 'Species', '10116', (58, 61))	('sarcoma', 'Disease', (134, 141))	('adipocyte', 'CPA', (19, 28))
283805	33188621	cemented Dp427 as a tumour suppressor in myogenic tumours, where intragenic deletion of the DMD gene is a frequent mechanism by which they progress to high-grade lethal sarcomas.	('Dp427', 'Gene', '13405', (9, 14))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Disease', (20, 26))	('high-grade lethal', 'CPA', (151, 168))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('Dp427', 'Gene', (9, 14))	('myogenic tumours', 'Disease', 'MESH:D009369', (41, 57))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('DMD', 'Gene', (92, 95))	('progress', 'Reg', (139, 147))	('deletion', 'Var', (76, 84))	('sarcomas', 'Disease', 'MESH:D012509', (169, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('sarcomas', 'Disease', (169, 177))	('myogenic tumours', 'Disease', (41, 57))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
283807	33188621	found intragenic DMD deletions in 63% of high-grade myogenic cancers, including gastrointestinal stromal tumour (GIST), leiomyosarcoma (LMS) and RMS.	('leiomyosarcoma', 'Disease', (120, 134))	('RMS', 'Disease', (145, 148))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (120, 134))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('deletions', 'Var', (21, 30))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('gastrointestinal stromal tumour', 'Disease', (80, 111))	('gastrointestinal stromal tumour', 'Disease', 'MESH:D046152', (80, 111))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (80, 111))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (120, 134))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('GIST', 'Phenotype', 'HP:0100723', (113, 117))	('LMS', 'Phenotype', 'HP:0100243', (136, 139))
283809	33188621	Further exploration using multiplex ligation-dependent probe amplification (MLPA)-based copy number assessment for each exon revealed DMD deletions in 43% of high-grade myogenic cancers.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('DMD deletions', 'Var', (134, 147))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Disease', (178, 185))	('rat', 'Species', '10116', (13, 16))
283810	33188621	As a result, all the deletions abolish Dp427 expression, which was absent or weakly present in 96% of metastatic GIST, 62% of metastatic LMS and 100% of metastatic RMS.	('abolish', 'NegReg', (31, 38))	('Dp427', 'Gene', '13405', (39, 44))	('deletions', 'Var', (21, 30))	('expression', 'MPA', (45, 55))	('Dp427', 'Gene', (39, 44))	('LMS', 'Phenotype', 'HP:0100243', (137, 140))	('GIST', 'Phenotype', 'HP:0100723', (113, 117))
283814	33188621	Re-expressing Dp427 using a miniDMD construct lacking exons 17-48 inhibited migration, invasion and invadopodia formation in multiple myogenic sarcoma subtypes, lending support to the hypothesis that depletion of Dp427 promotes the metastatic potential of myogenic tumours.	('invadopodia formation', 'CPA', (100, 121))	('tumours', 'Phenotype', 'HP:0002664', (265, 272))	('rat', 'Species', '10116', (79, 82))	('myogenic tumours', 'Disease', 'MESH:D009369', (256, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('promotes', 'PosReg', (219, 227))	('inhibited', 'NegReg', (66, 75))	('Dp427', 'Gene', '13405', (213, 218))	('myogenic', 'Disease', (134, 142))	('depletion', 'Var', (200, 209))	('Dp427', 'Gene', '13405', (14, 19))	('migration', 'CPA', (76, 85))	('invasion', 'CPA', (87, 95))	('Dp427', 'Gene', (213, 218))	('Dp427', 'Gene', (14, 19))	('myogenic tumours', 'Disease', (256, 272))	('sarcoma', 'Disease', 'MESH:D012509', (143, 150))	('sarcoma', 'Disease', (143, 150))
283816	33188621	The authors suggested that DMD inactivation may be a driving event in myogenic cancer development and a target for therapeutic attack.	('cancer', 'Disease', (79, 85))	('DMD inactivation', 'Var', (27, 43))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
283818	33188621	GISTs largely result from constitutively activating mutations in KIT or PDGFRA receptor tyrosine kinases.	('mutations', 'Var', (52, 61))	('KIT', 'Gene', (65, 68))	('activating', 'PosReg', (41, 51))	('PDGFRA', 'Gene', '5156', (72, 78))	('PDGFRA', 'Gene', (72, 78))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('result', 'Reg', (14, 20))	('KIT', 'Gene', '3815', (65, 68))
283819	33188621	Mutations disrupting the regulation of the cell cycle may serve as subsequent drivers of tumour progression, resulting in low-risk and high-risk GIST classifications.	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('Mutations', 'Var', (0, 9))	('disrupting', 'NegReg', (10, 20))	('regulation', 'MPA', (25, 35))	('GIST', 'Phenotype', 'HP:0100723', (145, 149))
283820	33188621	DMD inactivation adds a final step to a model for metastatic spread of myogenic cancers.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('DMD inactivation', 'Var', (0, 16))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
283821	33188621	In this study DMD deletions were only found in KIT/PDGFRA mutant GISTs (31% vs. 0% in wild-type), supporting the idea of DMD inactivation as a late event in metastatic progression.	('mutant', 'Var', (58, 64))	('PDGFRA', 'Gene', '5156', (51, 57))	('PDGFRA', 'Gene', (51, 57))	('GIST', 'Phenotype', 'HP:0100723', (65, 69))	('KIT', 'Gene', '3815', (47, 50))	('KIT', 'Gene', (47, 50))
283822	33188621	analysed 318 sarcomas using array CGH and confirmed the occurrence of DMD deletions in 16.5% of all types examined, 16.5% in sarcomas with complex genomic profiles (including LMS), 21.6% in synovial sarcomas and 14.2% in GISTs.	('sarcomas', 'Phenotype', 'HP:0100242', (199, 207))	('sarcomas', 'Disease', (199, 207))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('sarcomas', 'Disease', (13, 21))	('deletions', 'Var', (74, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('sarcomas', 'Disease', 'MESH:D012509', (125, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcomas', 'Disease', (125, 133))	('DMD deletions', 'Var', (70, 83))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (190, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('synovial sarcomas', 'Disease', (190, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('LMS', 'Phenotype', 'HP:0100243', (175, 178))	('synovial sarcomas', 'Disease', 'MESH:D013584', (190, 207))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (190, 206))	('sarcomas', 'Disease', 'MESH:D012509', (199, 207))	('GIST', 'Phenotype', 'HP:0100723', (221, 225))
283823	33188621	In line with previous work, these deletions appeared to be restricted to the 5' region of DMD and to affect the expression of the full-length Dp427 gene product.	('Dp427', 'Gene', '13405', (142, 147))	('Dp427', 'Gene', (142, 147))	('deletions', 'Var', (34, 43))	('affect', 'Reg', (101, 107))	('expression', 'MPA', (112, 122))
283825	33188621	Conversely, the authors found that neither Dp427 nor Dp71 expression levels were prognostic for metastatic progression, suggesting a central role for Dp427 deletion in this process.	('Dp71', 'Gene', (53, 57))	('metastatic progression', 'CPA', (96, 118))	('Dp71', 'Gene', '13405', (53, 57))	('Dp427', 'Gene', '13405', (43, 48))	('Dp427', 'Gene', '13405', (150, 155))	('Dp427', 'Gene', (43, 48))	('Dp427', 'Gene', (150, 155))	('deletion', 'Var', (156, 164))
283829	33188621	Inhibition of Dp71 likely induces cell cycle arrest, which may explain the requirement of Dp71 for tumour progression.	('Dp71', 'Gene', '13405', (90, 94))	('induces', 'Reg', (26, 33))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('arrest', 'Disease', (45, 51))	('tumour', 'Disease', (99, 105))	('Dp71', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (34, 51))	('Dp71', 'Gene', '13405', (14, 18))	('Dp71', 'Gene', (90, 94))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
283831	33188621	Inactivation of tumour suppressor genes through homozygous deletion is common in cancer.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('homozygous deletion', 'Var', (48, 67))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Inactivation', 'Var', (0, 12))
283832	33188621	Intron retention is another common mechanism by which tumour suppressor genes may be inactivated.	('Intron retention', 'Var', (0, 16))	('tumour', 'Disease', (54, 60))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
283837	33188621	who nonetheless suggested that post-transcriptional DMD modifications should be considered as secondary alterations in cancer.	('rat', 'Species', '10116', (108, 111))	('post-transcriptional DMD modifications', 'Var', (31, 69))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
283839	33188621	In the case of DMD inactivation in sarcomas, metastatic progression may be determined by the ratio of Dp427 to Dp71, a suggestion that warrants further investigation.	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('sarcomas', 'Disease', (35, 43))	('metastatic progression', 'CPA', (45, 67))	('DMD inactivation', 'Var', (15, 31))	('Dp427', 'Gene', '13405', (102, 107))	('Dp71', 'Gene', '13405', (111, 115))	('rat', 'Species', '10116', (93, 96))	('Dp427', 'Gene', (102, 107))	('Dp71', 'Gene', (111, 115))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))
283841	33188621	investigated DMD expression levels and genetic alterations in non-myogenic tumours in pairwise comparisons to normal tissues.	('myogenic tumours', 'Disease', (66, 82))	('genetic', 'Var', (39, 46))	('myogenic tumours', 'Disease', 'MESH:D009369', (66, 82))	('DMD expression levels', 'MPA', (13, 34))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('rat', 'Species', '10116', (51, 54))
283843	33188621	The RNAseq data showed that the median frequency of DMD alterations in non-myogenic tumours (3.4%) was higher than that in other common tumour suppressor genes, such as BRCA1 (1.6%), BRCA2 (2.8%) and PTEN (3%).	('tumour', 'Disease', (84, 90))	('DMD alterations', 'Var', (52, 67))	('BRCA2', 'Gene', (183, 188))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('PTEN', 'Gene', '5728', (200, 204))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('PTEN', 'Gene', (200, 204))	('tumour', 'Disease', (136, 142))	('rat', 'Species', '10116', (60, 63))	('myogenic tumours', 'Disease', 'MESH:D009369', (75, 91))	('BRCA1', 'Gene', '672', (169, 174))	('BRCA2', 'Gene', '675', (183, 188))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('myogenic tumours', 'Disease', (75, 91))	('BRCA1', 'Gene', (169, 174))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
283847	33188621	performed whole exome sequencing (WES), whole genome sequencing (WGS) and SNP array analysis on 14 olfactory neuroblastoma patient samples and found that somatic DMD deletions occurred in 86% of the tumours.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('patient', 'Species', '9606', (123, 130))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('olfactory neuroblastoma', 'Disease', (99, 122))	('olfactory neuroblastoma', 'Disease', 'MESH:D018304', (99, 122))	('DMD deletions', 'Var', (162, 175))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumours', 'Disease', (199, 206))	('neuroblastoma', 'Phenotype', 'HP:0003006', (109, 122))
283848	33188621	In line with DMD deletions in STS, in olfactory neuroblastoma these are concentrated in the 5' end of the gene and all but one are predicted to preserve Dp71 expression.	('Dp71', 'Gene', '13405', (153, 157))	('neuroblastoma', 'Phenotype', 'HP:0003006', (48, 61))	('expression', 'MPA', (158, 168))	('STS', 'Phenotype', 'HP:0030448', (30, 33))	('deletions', 'Var', (17, 26))	('olfactory neuroblastoma', 'Disease', (38, 61))	('rat', 'Species', '10116', (79, 82))	('olfactory neuroblastoma', 'Disease', 'MESH:D018304', (38, 61))	('Dp71', 'Gene', (153, 157))
283851	33188621	Of the 55 patients with progressive/high grade tumours evaluated, 17 (32%) either exhibited deletions in the DMD gene or silenced expression.	('silenced', 'NegReg', (121, 129))	('expression', 'MPA', (130, 140))	('DMD gene', 'Gene', (109, 117))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('exhibited', 'Reg', (82, 91))	('tumours', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('patients', 'Species', '9606', (10, 18))	('deletions', 'Var', (92, 101))
283854	33188621	Western blotting and immunohistochemistry on patient tissues harbouring DMD deletions confirmed a loss or reduction of Dp427 protein expression, and electron microscopy revealed a reduced density of cytoskeleton filaments in tumour cells.	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', (225, 231))	('reduced', 'NegReg', (180, 187))	('reduction', 'NegReg', (106, 115))	('density', 'MPA', (188, 195))	('patient', 'Species', '9606', (45, 52))	('loss', 'NegReg', (98, 102))	('Dp427', 'Gene', '13405', (119, 124))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('Dp427', 'Gene', (119, 124))	('deletions', 'Var', (76, 85))
283855	33188621	Interestingly, compared to DMD wild-type, patients with DMD alterations showed significantly shorter progression-free (1.6 years vs. 2.6 years, p = 0.038) and overall survival (5.1 years vs. median not reached, p = 0.006) times.	('overall survival', 'CPA', (159, 175))	('rat', 'Species', '10116', (64, 67))	('shorter', 'NegReg', (93, 100))	('alterations', 'Var', (60, 71))	('progression-free', 'CPA', (101, 117))	('patients', 'Species', '9606', (42, 50))
283856	33188621	DMD alterations were also found to be significantly more common in progressive/high grade meningiomas than in grade I and II non-progressive meningiomas.	('meningiomas', 'Disease', 'MESH:D008577', (90, 101))	('meningioma', 'Phenotype', 'HP:0002858', (90, 100))	('meningiomas', 'Disease', 'MESH:D008577', (141, 152))	('rat', 'Species', '10116', (8, 11))	('meningioma', 'Phenotype', 'HP:0002858', (141, 151))	('meningiomas', 'Phenotype', 'HP:0002858', (141, 152))	('common', 'Reg', (57, 63))	('meningiomas', 'Phenotype', 'HP:0002858', (90, 101))	('DMD', 'Var', (0, 3))	('meningiomas', 'Disease', (90, 101))	('meningiomas', 'Disease', (141, 152))
283857	33188621	This suggests that DMD inactivation may be associated with high grade malignancy in meningioma.	('high', 'Disease', (59, 63))	('malignancy', 'Disease', 'MESH:D009369', (70, 80))	('meningioma', 'Phenotype', 'HP:0002858', (84, 94))	('malignancy', 'Disease', (70, 80))	('meningioma', 'Disease', 'MESH:D008577', (84, 94))	('DMD inactivation', 'Var', (19, 35))	('associated', 'Reg', (43, 53))	('meningioma', 'Disease', (84, 94))
283860	33188621	Of 12 samples harbouring DMD mutations, 11 had alterations in both copies of the neurofibromin 2 (NF2) gene, the most commonly mutated gene in meningioma, which encodes the tumour suppressor protein merlin.	('tumour', 'Disease', (173, 179))	('neurofibromin 2', 'Gene', '4771', (81, 96))	('NF2', 'Gene', '4771', (98, 101))	('merlin', 'Gene', (199, 205))	('mutations', 'Var', (29, 38))	('neurofibromin 2', 'Gene', (81, 96))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('meningioma', 'Disease', (143, 153))	('alterations', 'Reg', (47, 58))	('meningioma', 'Phenotype', 'HP:0002858', (143, 153))	('merlin', 'Gene', '4771', (199, 205))	('meningioma', 'Disease', 'MESH:D008577', (143, 153))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('NF2', 'Gene', (98, 101))	('rat', 'Species', '10116', (51, 54))
283861	33188621	Expression analysis of methylation subgroups showed that DMD expression was higher in subgroups with NF2 mutations compared to NF2 wild-type cases.	('NF2', 'Gene', (127, 130))	('NF2', 'Gene', '4771', (127, 130))	('higher', 'PosReg', (76, 82))	('NF2', 'Gene', (101, 104))	('mutations', 'Var', (105, 114))	('DMD expression', 'MPA', (57, 71))	('NF2', 'Gene', '4771', (101, 104))
283862	33188621	DMD was also found to be one of the most highly upregulated genes in NF2 mutant samples.	('NF2', 'Gene', (69, 72))	('mutant', 'Var', (73, 79))	('NF2', 'Gene', '4771', (69, 72))	('upregulated', 'PosReg', (48, 59))
283866	33188621	A complex picture of DMD, and likely DAPC, disruption within nervous system tumours is apparent since alterations in the dystrophin-associated protein alpha-dystroglycan have also been reported in human gliomas.	('disruption within nervous system tumours', 'Disease', 'MESH:D009423', (43, 83))	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('dystroglycan', 'Gene', '1605', (157, 169))	('alterations', 'Var', (102, 113))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('disruption within nervous system tumours', 'Disease', (43, 83))	('rat', 'Species', '10116', (106, 109))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('dystroglycan', 'Gene', (157, 169))	('human', 'Species', '9606', (197, 202))	('gliomas', 'Disease', (203, 210))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
283879	33188621	This indicates that altered DMD gene products in the brain can disrupt nervous system function regardless of cancer.	('disrupt', 'Reg', (63, 70))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('nervous system', 'CPA', (71, 85))	('cancer', 'Disease', (109, 115))	('altered DMD', 'Var', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('DMD', 'Var', (28, 31))	('disrupt nervous system', 'Phenotype', 'HP:0000707', (63, 85))
283882	33188621	The central location of both of these mutations in the dystrophin gene suggests that Dp71 is unaffected and that the individuals are not expected to display severe intellectual disability based on our knowledge of the genotype to phenotype ratio in DMD.	('Dp71', 'Gene', (85, 89))	('severe intellectual disability', 'Phenotype', 'HP:0010864', (157, 187))	('Dp71', 'Gene', '13405', (85, 89))	('mutations', 'Var', (38, 47))	('dystrophin', 'Gene', (55, 65))	('intellectual disability', 'Phenotype', 'HP:0001249', (164, 187))	('rat', 'Species', '10116', (240, 243))
283884	33188621	Downregulation of DMD has first been implicated in the pathogenesis of malignant melanoma by Korner et al.. Digital karyotyping and multiplex PCR analysis of cell lines derived from established metastatic melanomas revealed DMD deletions in the M1 (in-frame deletion of exons 3-29), RPMI-7951 (in-frame deletion of exons 17-30) and WM-793 (out-of-frame deletion of exons 42-43) cell lines.	('melanomas', 'Disease', (205, 214))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanomas', 'Phenotype', 'HP:0002861', (205, 214))	('melanomas', 'Disease', 'MESH:D008545', (205, 214))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('malignant melanoma', 'Phenotype', 'HP:0002861', (71, 89))	('malignant melanoma', 'Disease', 'MESH:D008545', (71, 89))	('deletions', 'Var', (228, 237))	('DMD', 'Var', (224, 227))	('malignant melanoma', 'Disease', (71, 89))
283885	33188621	These deletions are outside the major hotspot region of exons 45-53 for DMD mutations in Duchenne muscular dystrophy patients and appear to be tumour-specific mutational events.	('mutations', 'Var', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('tumour', 'Disease', (143, 149))	('Duchenne muscular dystrophy', 'Disease', (89, 116))	('patients', 'Species', '9606', (117, 125))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (98, 116))	('Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (89, 116))
283886	33188621	DMD expression analysis of full-length Dp427 variants in non-cancerous primary melanocytes from three different donors revealed high expression levels of Dp427m.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Dp427', 'Gene', '13405', (39, 44))	('variants', 'Var', (45, 53))	('cancer', 'Disease', (61, 67))	('Dp427', 'Gene', '13405', (154, 159))	('Dp427', 'Gene', (39, 44))	('expression levels', 'MPA', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Dp427', 'Gene', (154, 159))
283889	33188621	Additionally, the same melanocytes also expressed Dp71 and Dp116.	('Dp116', 'Var', (59, 64))	('Dp71', 'Gene', '13405', (50, 54))	('Dp71', 'Gene', (50, 54))
283893	33188621	The sequencing results revealed five known polymorphisms and six new variants including D214N (MM-232 cell line) located within the actin-binding domain and G3189E (WM1205LU cell line) located within the C-terminal ZZ domain.	('G3189E', 'Var', (157, 163))	('D214N', 'Mutation', 'rs876657781', (88, 93))	('WM1205LU', 'CellLine', 'CVCL:5239', (165, 173))	('MM-232', 'CellLine', 'CVCL:G581', (95, 101))	('D214N', 'Var', (88, 93))	('G3189E', 'Mutation', 'p.G3189E', (157, 163))
283894	33188621	These variants are considered to be melanoma-specific since no new variants were found in cell lines expressing Dp427m that may affect dystrophin function.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('variants', 'Var', (6, 14))	('affect', 'Reg', (128, 134))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('Dp427', 'Gene', '13405', (112, 117))	('dystrophin function', 'MPA', (135, 154))	('Dp427', 'Gene', (112, 117))
283899	33188621	Lymphomas and lymphocytic leukaemia's have both been linked to aberrant DMD gene expression.	('linked', 'Reg', (53, 59))	('Lymphomas', 'Phenotype', 'HP:0002665', (0, 9))	('aberrant', 'Var', (63, 71))	('Lymphomas and lymphocytic leukaemia', 'Disease', 'MESH:D015451', (0, 35))
283900	33188621	showed, using microarray-based analyses (with a DMD probe set that detects all DMD transcripts) that DMD is downregulated 8-fold in primary Hodgkin's lymphoma (HL, nodular sclerosing subtype) tumour tissues compared to germinal centre B cells.	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (140, 158))	('HL', 'CellLine', 'CVCL:2492', (160, 162))	('DMD', 'Var', (101, 104))	("Hodgkin's lymphoma", 'Disease', (140, 158))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (150, 158))	('tumour', 'Disease', (192, 198))	('downregulated', 'NegReg', (108, 121))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (140, 158))
283906	33188621	One case report of DMD concomitant with acute lymphoblastic leukaemia has so far been published (Table 1) and several independent studies using microarray-based gene expression profiling have highlighted the diagnostic potential for DMD in B-cell chronic lymphocytic leukaemia (B-CLL).	('acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006721', (40, 69))	('B-cell chronic lymphocytic leukaemia', 'Disease', (240, 276))	('chronic lymphocytic leukaemia', 'Phenotype', 'HP:0005550', (247, 276))	('acute lymphoblastic leukaemia', 'Disease', 'MESH:D054198', (40, 69))	('DMD', 'Var', (233, 236))	('B-cell chronic lymphocytic leukaemia', 'Disease', 'MESH:D015448', (240, 276))	('acute lymphoblastic leukaemia', 'Disease', (40, 69))
283907	33188621	further reported that high DMD expression across 134 B-CLL patients was associated with a shorter lymphocyte doubling time and was predictive of a poor patient survival (median overall survival for patients with high DMD expression was 90.1 months vs. median not reached for patients with low DMD expression).	('high DMD expression', 'Var', (22, 41))	('patient', 'Species', '9606', (198, 205))	('patients', 'Species', '9606', (198, 206))	('shorter', 'NegReg', (90, 97))	('patient', 'Species', '9606', (59, 66))	('patient', 'Species', '9606', (275, 282))	('poor', 'NegReg', (147, 151))	('patient survival', 'CPA', (152, 168))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (275, 283))	('patient', 'Species', '9606', (152, 159))	('lymphocyte doubling time', 'CPA', (98, 122))
283927	33188621	In line with this finding, Kaplan-Meier analysis of patients after surgical resection revealed that those with a high Dp71 expression exhibited a significantly favourable overall survival time compared to those with a low Dp71 expression (56.56% vs. 30.8% 5-year survival rate, respectively; p < 0.001) providing evidence that Dp71 may act as a tumour suppressor in gastric adenocarcinoma.	('Dp71', 'Gene', (118, 122))	('high', 'Var', (113, 117))	('tumour', 'Disease', (345, 351))	('Dp71', 'Gene', '13405', (327, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('rat', 'Species', '10116', (272, 275))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (366, 388))	('Dp71', 'Gene', '13405', (118, 122))	('Dp71', 'Gene', (222, 226))	('gastric adenocarcinoma', 'Disease', (366, 388))	('Dp71', 'Gene', '13405', (222, 226))	('tumour', 'Phenotype', 'HP:0002664', (345, 351))	('tumour', 'Disease', 'MESH:D009369', (345, 351))	('Dp71', 'Gene', (327, 331))	('favourable', 'PosReg', (160, 170))	('patients', 'Species', '9606', (52, 60))
283932	33188621	Combination analyses revealed a consistent association in males and showed that the DMD SNP rs5927056 is associated with a reduced risk of NPC (odds ratio: 0.85, p = 9.44 x 10- 5).	('rat', 'Species', '10116', (149, 152))	('rs5927056', 'Var', (92, 101))	('NPC', 'Phenotype', 'HP:0100630', (139, 142))	('NPC', 'Disease', (139, 142))	('rs5927056', 'Mutation', 'rs5927056', (92, 101))	('reduced', 'NegReg', (123, 130))
283933	33188621	Additionally, NPC risk association with X chromosome SNPs was found to be decreased by 8.3% after excluding rs5927056, suggesting a strong effect of this locus on NPC susceptibility.	('rs5927056', 'Var', (108, 117))	('NPC', 'Phenotype', 'HP:0100630', (14, 17))	('NPC', 'Phenotype', 'HP:0100630', (163, 166))	('X chromosome SNPs', 'Var', (40, 57))	('NPC', 'Disease', (14, 17))	('rs5927056', 'Mutation', 'rs5927056', (108, 117))	('decreased', 'NegReg', (74, 83))
283939	33188621	Interestingly, in sporadic breast cancer, the median frequency of DMD alterations (3.95%) was higher than those of BRCA1 (1.95%) and BRCA2 (3.4%).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('sporadic breast cancer', 'Disease', (18, 40))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (18, 40))	('BRCA1', 'Gene', '672', (115, 120))	('BRCA2', 'Gene', (133, 138))	('rat', 'Species', '10116', (74, 77))	('BRCA1', 'Gene', (115, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('DMD alterations', 'Var', (66, 81))	('BRCA2', 'Gene', '675', (133, 138))
283940	33188621	Additional survival analyses revealed that in breast and uterine cancer, patients with DMD alterations exhibited significantly poorer survival rates compared to wild-type patients.	('DMD alterations', 'Var', (87, 102))	('poorer', 'NegReg', (127, 133))	('rat', 'Species', '10116', (95, 98))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('survival rates', 'CPA', (134, 148))	('breast', 'Disease', (46, 52))	('rat', 'Species', '10116', (143, 146))	('uterine cancer', 'Phenotype', 'HP:0010784', (57, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
283942	33188621	For some carcinomas, the DMD gene and/or its protein products appear to be tumour suppressive, whereas in others they appear to be oncogenic.	('tumour suppressive', 'Disease', 'MESH:D009369', (75, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('carcinomas', 'Disease', 'MESH:D009369', (9, 19))	('carcinomas', 'Phenotype', 'HP:0030731', (9, 19))	('tumour suppressive', 'Disease', (75, 93))	('carcinomas', 'Disease', (9, 19))	('DMD gene', 'Var', (25, 33))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
283948	33188621	Firstly, the incidence and risk of cancer for DMD patients is unknown, in particular whether germline DMD inactivation may predispose to sarcoma.	('inactivation', 'Var', (106, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('predispose', 'Reg', (123, 133))	('cancer', 'Disease', (35, 41))	('sarcoma', 'Disease', (137, 144))
283954	33188621	The frequency of DMD gene alterations (i.e., mutations and copy number alterations) varies across cancers (Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (45, 54))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('rat', 'Species', '10116', (75, 78))	('copy number alterations', 'Var', (59, 82))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('rat', 'Species', '10116', (30, 33))	('cancers', 'Disease', (98, 105))
283955	33188621	In some cases, there is clear evidence of recurrent mutations that abrogate the expression of DMD gene products (i.e., Dp427 in STS) and/or specific functional domains such as the N-terminal actin-binding domain as seen in meningioma.	('mutations', 'Var', (52, 61))	('meningioma', 'Disease', 'MESH:D008577', (223, 233))	('meningioma', 'Phenotype', 'HP:0002858', (223, 233))	('abrogate', 'NegReg', (67, 75))	('meningioma', 'Disease', (223, 233))	('Dp427', 'Gene', '13405', (119, 124))	('expression', 'MPA', (80, 90))	('Dp427', 'Gene', (119, 124))	('STS', 'Phenotype', 'HP:0030448', (128, 131))
283956	33188621	Disrupted or altered gene expression through non-mutational mechanisms may also be relevant for disease development (i.e., virus-induced alterations in gene expression programmes or epigenetic modifications).	('epigenetic modifications', 'Var', (182, 206))	('gene expression', 'MPA', (21, 36))	('alterations', 'Reg', (137, 148))	('rat', 'Species', '10116', (141, 144))	('gene expression programmes', 'MPA', (152, 178))	('altered', 'Reg', (13, 20))
283961	33188621	The tumour context may be important with gene variants acting as either oncogenes or tumour suppressors depending on the specific tumour microenvironment.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', (85, 91))	('tumour', 'Disease', (130, 136))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('variants', 'Var', (46, 54))	('tumour', 'Disease', (4, 10))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
283962	33188621	To our knowledge a role for DMD in intra-tumour heterogeneity has not been examined, and more work is required to ascertain the mechanisms by which DMD dysregulation alters cancer cell functions.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('DMD', 'Var', (148, 151))	('intra-tumour', 'Disease', (35, 47))	('cancer', 'Disease', (173, 179))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('dysregulation', 'Var', (152, 165))	('intra-tumour', 'Disease', 'MESH:D009369', (35, 47))	('alters', 'Reg', (166, 172))
283963	33188621	Also, several cellular pathways implicated in cancer development are disrupted in DMD.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('disrupted', 'Reg', (69, 78))	('DMD', 'Var', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cellular pathways', 'Pathway', (14, 31))
284026	33633500	A genetic mutation within the gene TP53 that encodes p53, a protein involved in regulation of the cell cycle, has been identified in dogs with histiocytic sarcoma, resulting in speculation that this mutation could affect p53 function and may be involved in the pathogenesis of canine histiocytic sarcoma.	('histiocytic sarcoma', 'Disease', (143, 162))	('p53', 'Gene', '403869', (221, 224))	('mutation', 'Var', (10, 18))	('histiocytic sarcoma', 'Disease', (284, 303))	('involved', 'Reg', (245, 253))	('dogs', 'Species', '9615', (133, 137))	('p53', 'Gene', '403869', (53, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('mutation', 'Var', (199, 207))	('p53', 'Gene', (221, 224))	('TP53', 'Gene', (35, 39))	('canine', 'Species', '9615', (277, 283))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (143, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (296, 303))	('TP53', 'Gene', '403869', (35, 39))	('affect', 'Reg', (214, 220))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (284, 303))	('p53', 'Gene', (53, 56))	('function', 'MPA', (225, 233))
284027	33633500	However, associations between specific genetic mutations and histiocytic sarcomas have not yet been investigated in reptiles.	('histiocytic sarcomas', 'Disease', (61, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('mutations', 'Var', (47, 56))	('histiocytic sarcomas', 'Disease', 'MESH:D054747', (61, 81))
284029	33633500	Histiocytic cell lineage can be characterised using IHC by immunoreactivity to vimentin, CD18 and Iba1 and concurrent negative immunoreactivity to cytokeratin, CD3, CD20, CD79a.	('vimentin', 'Gene', (79, 87))	('Iba1', 'Gene', (98, 102))	('CD79a', 'Var', (171, 176))	('CD18', 'Protein', (89, 93))	('immunoreactivity', 'MPA', (127, 143))	('negative', 'NegReg', (118, 126))	('vimentin', 'Gene', '7431', (79, 87))
284030	33633500	Confirmation of the cellular origin of anaplastic sarcomas can be attempted by IHC, however the anaplastic nature of the neoplasms may result in aberrant marker expression, hindering interpretation of immunohistochemical results.	('result in', 'Reg', (135, 144))	('anaplastic sarcoma', 'Disease', (39, 57))	('neoplasms', 'Disease', 'MESH:D009369', (121, 130))	('neoplasms', 'Disease', (121, 130))	('sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('neoplasm', 'Phenotype', 'HP:0002664', (121, 129))	('anaplastic sarcoma', 'Disease', 'MESH:D012509', (39, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('aberrant', 'Var', (145, 153))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))	('sarcomas', 'Disease', (50, 58))
284060	31807262	The criteria used to classify this tumor as a phyllodes tumor were stromal overgrowth, nuclear pleomorphism, high mitotic rate in stromal cells, infiltrative border in surrounding breast tissue, benign breast epithelium, and pericanalicular pattern of stromal growth.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('overgrowth', 'Phenotype', 'HP:0001548', (75, 85))	('high', 'Var', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (35, 40))	('stromal overgrowth', 'CPA', (67, 85))	('phyllodes tumor', 'Disease', 'MESH:D003557', (46, 61))	('nuclear pleomorphism', 'CPA', (87, 107))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('phyllodes tumor', 'Disease', (46, 61))
284134	31486610	Given its excellent activity against a variety of gram-negative bacilli, colistin was later reconsidered for the treatment of systemic infections due to the rising number of infections caused by MDR gram-negative bacteria in recent years.	('activity', 'MPA', (20, 28))	('systemic infections', 'Disease', 'MESH:D019578', (126, 145))	('infections', 'Disease', (135, 145))	('systemic infections', 'Disease', (126, 145))	('infections', 'Disease', 'MESH:D007239', (174, 184))	('colistin', 'Chemical', 'MESH:D003091', (73, 81))	('MDR', 'Var', (195, 198))	('rising number of infections', 'Phenotype', 'HP:0002719', (157, 184))	('infections', 'Disease', 'MESH:D007239', (135, 145))	('infections', 'Disease', (174, 184))
284159	29755686	However, mutations are obviously not the only molecular alterations that drive tumor development.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', (79, 84))
284231	29755686	Therapy in PT8 and PT9 was administered based on RNA overexpression of the therapeutic target despite the identification of genetic alterations on DNA level (deletion mutations in CDKN2A/B and PTEN).	('CDKN2A/B', 'Gene', '1029;1030', (180, 188))	('PTEN', 'Gene', (193, 197))	('PTEN', 'Gene', '5728', (193, 197))	('CDKN2A/B', 'Gene', (180, 188))	('deletion mutations', 'Var', (158, 176))
284246	29755686	However, G1 AEs were significantly less in patients receiving targeted therapy (Chi square P=0.009).	('less', 'NegReg', (35, 39))	('targeted therapy', 'Var', (62, 78))	('patients', 'Species', '9606', (43, 51))	('G1 AEs', 'MPA', (9, 15))	('AEs', 'Chemical', '-', (12, 15))
284250	29755686	OS was significantly longer in patients receiving targeted therapy as evaluated both by a log-rank (Mantel-Haenszel/ Mantel-Cox) (P=0.0014) and the Gehan-Breslow-Wilcoxon test (P=0.0025) with a hazard ratio (HR) of 0.1435 and a 95% confidence interval (CI) ranging from 0.044 to 0.471.	('targeted therapy', 'Var', (50, 66))	('longer', 'PosReg', (21, 27))	('Cox', 'Gene', '1351', (124, 127))	('Cox', 'Gene', (124, 127))	('patients', 'Species', '9606', (31, 39))
284275	29755686	It is noteworthy that of the 100 patients with refractory pediatric cancer enrolled in the multicenter individualized cancer therapy (icat) study, potential actionable alterations were found only in 31% with copy number alterations and deleterious mutations most commonly identified.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('copy number alterations', 'Var', (208, 231))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
284278	29755686	Our results suggest that patients receiving targeted therapies based on expression analysis of their tumors may have a significantly higher OS and PFS than those who did not.	('PFS', 'CPA', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('higher', 'PosReg', (133, 139))	('patients', 'Species', '9606', (25, 33))	('FS', 'Phenotype', 'HP:0100244', (148, 150))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('targeted therapies', 'Var', (44, 62))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
284289	29755686	It has been shown that matching targeted therapy to a documented molecular aberration in each patient results in a significantly higher response rate and longer PFS in adults with advanced cancer when compared to unmatched therapy choices.	('PFS', 'MPA', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('higher', 'PosReg', (129, 135))	('targeted therapy', 'Var', (32, 48))	('response', 'MPA', (136, 144))	('FS', 'Phenotype', 'HP:0100244', (162, 164))	('patient', 'Species', '9606', (94, 101))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
284294	29755686	While previous trials provided variable efficacy data of molecularly guided therapy using mutation analysis and copy number alterations in patients with advanced cancer, our study provides evidence supporting the possible efficacy of transcriptome-based targeted therapy in patients with refractory pediatric sarcoma, which warrants further investigation of this methodology in a larger population of pediatric patients.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('patients', 'Species', '9606', (139, 147))	('pediatric sarcoma', 'Disease', (299, 316))	('cancer', 'Disease', (162, 168))	('patients', 'Species', '9606', (274, 282))	('alterations', 'Var', (124, 135))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (299, 316))	('sarcoma', 'Phenotype', 'HP:0100242', (309, 316))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('patients', 'Species', '9606', (411, 419))	('copy number alterations', 'Var', (112, 135))	('mutation', 'Var', (90, 98))
284322	29755686	Overall survival (OS) was defined as the time from enrollment to the time of death or last follow up and was compared using the Kaplan-Meier estimator in two similar patient groups: patients who received targeted therapies and patients who did not.	('death', 'Disease', 'MESH:D003643', (77, 82))	('death', 'Disease', (77, 82))	('patient', 'Species', '9606', (182, 189))	('targeted therapies', 'Var', (204, 222))	('patient', 'Species', '9606', (227, 234))	('patients', 'Species', '9606', (182, 190))	('patient', 'Species', '9606', (166, 173))	('patients', 'Species', '9606', (227, 235))
284358	27559251	in their study showed that music could reduce anxiety, pain, and improve mood and quality of life.	('reduce', 'NegReg', (39, 45))	('anxiety', 'Disease', 'MESH:D001008', (46, 53))	('pain', 'Disease', 'MESH:D010146', (55, 59))	('pain', 'Disease', (55, 59))	('anxiety', 'Disease', (46, 53))	('improve', 'PosReg', (65, 72))	('anxiety', 'Phenotype', 'HP:0000739', (46, 53))	('quality of life', 'CPA', (82, 97))	('pain', 'Phenotype', 'HP:0012531', (55, 59))	('music', 'Var', (27, 32))
284377	27559251	RFA, cryoablation, high frequency focused ultrasound, image-guided percutaneous cementing and microwaves are proven to be effective in reducing pain and increasing bone strength.	('pain', 'Disease', 'MESH:D010146', (144, 148))	('pain', 'Disease', (144, 148))	('cryoablation', 'Var', (5, 17))	('bone strength', 'CPA', (164, 177))	('pain', 'Phenotype', 'HP:0012531', (144, 148))	('reducing', 'NegReg', (135, 143))	('increasing', 'PosReg', (153, 163))
284401	27559251	In aggressive bone and soft issue tumors, discrepancy between the rate of growth and the vascular supply of the feeding vessel frequently give rise to foul smelling fungating tumor mass.	('tumor', 'Disease', (175, 180))	('tumors', 'Disease', (34, 40))	('tumor', 'Disease', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('give rise to', 'Reg', (138, 150))	('discrepancy', 'Var', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('foul smelling', 'MPA', (151, 164))
284482	23528889	Nanomolar melatonin decreases the proliferation of ovarian CHO cells slightly (12%).	('proliferation', 'CPA', (34, 47))	('ovarian CHO', 'Disease', 'MESH:D010051', (51, 62))	('decreases', 'NegReg', (20, 29))	('Nanomolar', 'Var', (0, 9))	('ovarian CHO', 'Disease', (51, 62))	('rat', 'Species', '10116', (41, 44))	('melatonin', 'Chemical', 'MESH:D008550', (10, 19))
284498	23528889	Activated caspase 8 then cleaves executioner caspases (3, 6 and 7), which will act on their substrates, giving place to the morphological and biochemical features of apoptosis, or activates other proteins that allow crosstalk with the intrinsic pathway of apoptosis.	('caspases', 'Gene', '841;842', (45, 53))	('rat', 'Species', '10116', (97, 100))	('activates', 'PosReg', (180, 189))	('caspase 8', 'Gene', (10, 19))	('cleaves', 'Var', (25, 32))	('giving place', 'Reg', (104, 116))	('caspases', 'Gene', (45, 53))	('intrinsic pathway of apoptosis', 'Pathway', (235, 265))	('proteins', 'Protein', (196, 204))	('caspase 8', 'Gene', '841', (10, 19))
284499	23528889	The intrinsic pathway of apoptosis relies on the disruption and permeabilization of the mitochondrial outer membrane (MOMP), which is followed by cytochrome c release and activation of the apoptosome.	('permeabilization', 'MPA', (64, 80))	('cytochrome c', 'Gene', (146, 158))	('activation', 'PosReg', (171, 181))	('cytochrome c', 'Gene', '54205', (146, 158))	('disruption', 'Var', (49, 59))	('apoptosis', 'Disease', (25, 34))
284520	23528889	These data strongly support that both the intrinsic and extrinsic pathways of apoptosis are activated by millimolar concentrations of melatonin in hematological cancer cells.	('millimolar', 'Var', (105, 115))	('extrinsic pathways of', 'Pathway', (56, 77))	('apoptosis', 'CPA', (78, 87))	('activated', 'PosReg', (92, 101))	('intrinsic', 'Pathway', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('hematological cancer', 'Phenotype', 'HP:0004377', (147, 167))	('melatonin', 'Chemical', 'MESH:D008550', (134, 143))	('hematological cancer', 'Disease', 'MESH:D009369', (147, 167))	('rat', 'Species', '10116', (123, 126))	('hematological cancer', 'Disease', (147, 167))
284523	23528889	A cytotoxic effect by millimolar concentrations of melatonin was also found in Ewing's sarcoma cells, although not in other types of sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (79, 94))	('sarcoma', 'Disease', (87, 94))	("Ewing's sarcoma", 'Disease', (79, 94))	('rat', 'Species', '10116', (40, 43))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (79, 94))	('cytotoxic', 'CPA', (2, 11))	('melatonin', 'Chemical', 'MESH:D008550', (51, 60))	('millimolar concentrations', 'Var', (22, 47))	('sarcoma', 'Disease', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
284549	23528889	Opposite to what was expected, researchers found that there is an early increase in oxidative stress in those cancer cells, where melatonin induces apoptosis, besides the late increase of intracellular oxidants associated to apoptosis itself.	('increase', 'PosReg', (72, 80))	('cancer', 'Disease', (110, 116))	('induces', 'Reg', (140, 147))	('melatonin', 'Chemical', 'MESH:D008550', (130, 139))	('increase in oxidative stress', 'Phenotype', 'HP:0025464', (72, 100))	('oxidative stress', 'MPA', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('melatonin', 'Var', (130, 139))	('apoptosis', 'CPA', (148, 157))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
284566	23528889	Oxidative modification of such a complex can collapse the mitochondrial membrane potential and trigger the translocation of Bax and Bad pro-apoptotic proteins and the release of cytochrome c to the cytosol.	('cytochrome c', 'Gene', '54205', (178, 190))	('Bax', 'Gene', '581', (124, 127))	('Oxidative', 'Var', (0, 9))	('trigger', 'Reg', (95, 102))	('collapse', 'NegReg', (45, 53))	('translocation', 'MPA', (107, 120))	('cytochrome c', 'Gene', (178, 190))	('mitochondrial membrane potential', 'MPA', (58, 90))	('Bax', 'Gene', (124, 127))
284568	23528889	ROS can also activate the ASK/JNK signaling pathway and drive cells to apoptosis.	('activate', 'PosReg', (13, 21))	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('JNK', 'Gene', (30, 33))	('JNK', 'Gene', '5599', (30, 33))	('drive', 'PosReg', (56, 61))
284579	23528889	Inhibitors of these kinases prevented melatonin-induced cell death.	('prevented', 'NegReg', (28, 37))	('Inhibitors', 'Var', (0, 10))	('melatonin', 'Chemical', 'MESH:D008550', (38, 47))
284707	21731691	For the DH and JH regions, DH3 and JH4 were used most frequently in the sarcoma cells, which is consistent with the findings in epithelial cancer cells.	('epithelial cancer', 'Disease', 'MESH:D000077216', (128, 145))	('epithelial cancer', 'Disease', (128, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('sarcoma cells', 'Disease', (72, 85))	('sarcoma cells', 'Disease', 'MESH:D012509', (72, 85))	('DH3', 'Var', (27, 30))	('epithelial cancer', 'Phenotype', 'HP:0031492', (128, 145))
284711	21731691	Deletion of this sequence from the mouse germline resulted in a 5-fold to 10-fold decrease in RAG expression and a partial block at the pro-B to pre-B transition.	('block', 'NegReg', (123, 128))	('decrease', 'NegReg', (82, 90))	('pro-B', 'MPA', (136, 141))	('RAG expression', 'MPA', (94, 108))	('mouse', 'Species', '10090', (35, 40))	('Deletion', 'Var', (0, 8))
284762	27047932	In melanomas with a brisk tumor-infiltrating lymphocyte response, single labeling with Ki-67 may lead to overestimation of the proliferative index due to the high density of mitotically active inflammatory cells (fig.	('mitotically', 'CPA', (174, 185))	('Ki-67', 'Var', (87, 92))	('overestimation', 'PosReg', (105, 119))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('melanomas', 'Disease', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('Ki-67', 'Chemical', '-', (87, 92))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanomas', 'Phenotype', 'HP:0002861', (3, 12))	('tumor', 'Disease', (26, 31))	('melanomas', 'Disease', 'MESH:D008545', (3, 12))	('proliferative', 'MPA', (127, 140))
284784	27047932	Recent studies demonstrate that IHC is a practical and easy method to detect the genetic mutational status of BRAF V600E (fig.	('V600E', 'Mutation', 'rs113488022', (115, 120))	('BRAF', 'Gene', (110, 114))	('V600E', 'Var', (115, 120))
284787	27047932	Genetic mutations in v-raf murine sarcoma viral oncogene homolog B (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) are present in approximately 50 and 20% of melanomas, respectively, and result in constitutive activation of MAPK pathways.	('AS', 'Phenotype', 'HP:0200058', (93, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (21, 66))	('activation', 'PosReg', (221, 231))	('melanomas', 'Disease', 'MESH:D008545', (169, 178))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanomas', 'Phenotype', 'HP:0002861', (169, 178))	('AS', 'Phenotype', 'HP:0200058', (122, 124))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', (21, 66))	('mutations', 'Var', (8, 17))	('neuroblastoma', 'Phenotype', 'HP:0003006', (78, 91))	('neuroblastoma RAS viral', 'Disease', (78, 101))	('melanomas', 'Disease', (169, 178))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (78, 101))	('MAPK pathways', 'Pathway', (235, 248))
284790	27047932	Recent studies have shown that IHC for BRAF V600E and NRAS Q16R has excellent specificity that is highly concordant with molecular testing (e.g.	('Q16R', 'Mutation', 'rs779896859', (59, 63))	('V600E', 'Mutation', 'rs113488022', (44, 49))	('BRAF V600E', 'Var', (39, 49))	('AS', 'Phenotype', 'HP:0200058', (56, 58))	('NRAS Q16R', 'Var', (54, 63))
284791	27047932	Other point mutations of BRAF (V600K, V600Q, and V600R) or NRAS (Q61K, Q61L, Q61H) melanomas do not stain positively with BRAF VE1 and NRAS Q61R antibodies, respectively.	('V600Q', 'Var', (38, 43))	('V600R', 'Var', (49, 54))	('AS', 'Phenotype', 'HP:0200058', (61, 63))	('V600K', 'Mutation', 'rs121913227', (31, 36))	('melanomas', 'Disease', (83, 92))	('Q61H', 'Var', (77, 81))	('V600R', 'Mutation', 'rs121913227', (49, 54))	('Q61K', 'Mutation', 'rs121913254', (65, 69))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('V600K', 'Var', (31, 36))	('Q61H', 'Mutation', 'rs121913255', (77, 81))	('Q61L', 'Mutation', 'rs11554290', (71, 75))	('AS', 'Phenotype', 'HP:0200058', (137, 139))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('V600Q', 'Mutation', 'p.V600Q', (38, 43))	('Q61L', 'Var', (71, 75))	('Q61R', 'Mutation', 'rs11554290', (140, 144))	('NRAS', 'Gene', (59, 63))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))
284792	27047932	In addition, studies indicate that germline mutation of BRAC1-associated protein (BAP-1) is associated with multiple cutaneous Spitzoid melanocytic neoplasms, as well as frequent somatic mutations in uveal melanoma.	('multiple cutaneous Spitzoid melanocytic neoplasms', 'Disease', (108, 157))	('BAP-1', 'Gene', '8314', (82, 87))	('uveal melanoma', 'Disease', (200, 214))	('uveal melanoma', 'Disease', 'MESH:C536494', (200, 214))	('multiple cutaneous Spitzoid melanocytic neoplasms', 'Disease', 'MESH:D009508', (108, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (200, 214))	('germline mutation', 'Var', (35, 52))	('BAP-1', 'Gene', (82, 87))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('neoplasms', 'Phenotype', 'HP:0002664', (148, 157))	('associated', 'Reg', (92, 102))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (136, 157))
284793	27047932	The loss of BAP-1 in BAP-1 mutant melanocytic lesions can be detected by IHC.	('BAP-1', 'Gene', (21, 26))	('BAP-1', 'Gene', '8314', (12, 17))	('mutant', 'Var', (27, 33))	('BAP-1', 'Gene', (12, 17))	('melanocytic lesions', 'Disease', (34, 53))	('BAP-1', 'Gene', '8314', (21, 26))	('melanocytic lesions', 'Disease', 'MESH:D009508', (34, 53))	('loss', 'NegReg', (4, 8))
284794	27047932	In addition to genomic mutations, recent data demonstrate that epigenetic alterations play important roles in melanoma pathogenesis.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('roles', 'Reg', (101, 106))	('epigenetic alterations', 'Var', (63, 85))
284898	27047932	Molecular analysis to confirm the presence of an EWS-FLI-1 fusion or the associated t(11;22)(q24;q12) translocation is more definitive, although a number of histologically distinct tumors are now known to be associated with this translocation, and not all Ewing's sarcoma/PNET are positive.	('EWS', 'Gene', '2130', (49, 52))	('EWS', 'Gene', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('PNET', 'Phenotype', 'HP:0030065', (272, 276))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('FLI-1', 'Gene', '2313', (53, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (256, 271))	('FLI-1', 'Gene', (53, 58))	('fusion', 'Var', (59, 65))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (256, 271))	("Ewing's sarcoma", 'Disease', (256, 271))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (84, 101))
284983	23055934	Of the early SRV-2 associated lymphomas that occurred in pig-tailed macaques, two were classified as lymphoblastic (T76321, T80120), one as immunoblastic (T76088) and the remaining two as anaplastic large cell lymphomas with Reed-Sternberg-like cells (T81497, T81228) (Table 1).	('lymphomas', 'Disease', (210, 219))	('immunoblastic', 'Disease', 'MESH:D016400', (140, 153))	('lymphomas', 'Disease', 'MESH:D008223', (30, 39))	('lymphoblastic', 'Disease', (101, 114))	('lymphomas', 'Phenotype', 'HP:0002665', (30, 39))	('T76321', 'Var', (116, 122))	('lymphomas', 'Disease', 'MESH:D008223', (210, 219))	('T81497', 'Var', (252, 258))	('T80120', 'Var', (124, 130))	('lymphomas', 'Disease', (30, 39))	('SRV-2', 'Gene', (13, 18))	('immunoblastic', 'Disease', (140, 153))	('pig-tailed macaques', 'Species', '9545', (57, 76))	('lymphomas', 'Phenotype', 'HP:0002665', (210, 219))	('anaplastic large cell lymphomas', 'Phenotype', 'HP:0012193', (188, 219))	('cell lymphoma', 'Phenotype', 'HP:0012191', (205, 218))	('lymphoma', 'Phenotype', 'HP:0002665', (30, 38))	('lymphoma', 'Phenotype', 'HP:0002665', (210, 218))	('SRV-2', 'Species', '39068', (13, 18))	('T81228', 'Var', (260, 266))
284984	23055934	The lymphomas from pig-tailed, rhesus and cynomolgus macaques experimentally infected with immunodeficiency viruses were classified as lymphoblastic (99091), immunoblastic (A01110, A01112, and L758), centroblastic (02206), and follicular large cell (93034).	('lymphoblastic', 'Disease', (135, 148))	('immunodeficiency viruses', 'Disease', (91, 115))	('lymphomas', 'Disease', 'MESH:D008223', (4, 13))	('lymphomas', 'Phenotype', 'HP:0002665', (4, 13))	('L758', 'Var', (193, 197))	('immunodeficiency', 'Phenotype', 'HP:0002721', (91, 107))	('immunoblastic', 'Disease', (158, 171))	('A01112', 'Var', (181, 187))	('pig', 'Species', '9823', (19, 22))	('93034', 'Var', (250, 255))	('A01110', 'Var', (173, 179))	('immunodeficiency viruses', 'Disease', 'MESH:D007153', (91, 115))	('lymphomas', 'Disease', (4, 13))	('follicular large', 'Phenotype', 'HP:0002729', (227, 243))	('cynomolgus macaque', 'Species', '9541', (42, 60))	('lymphoma', 'Phenotype', 'HP:0002665', (4, 12))	('99091', 'Var', (150, 155))	('02206', 'Var', (215, 220))	('immunoblastic', 'Disease', 'MESH:D016400', (158, 171))
284985	23055934	The other lymphomas from macaques 92170, 95017, A08044 and A07762 were not classified.	('lymphomas', 'Disease', 'MESH:D008223', (10, 19))	('A08044', 'Var', (48, 54))	('lymphomas', 'Phenotype', 'HP:0002665', (10, 19))	('95017', 'Var', (41, 46))	('A07762', 'Var', (59, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (10, 18))	('lymphomas', 'Disease', (10, 19))
284997	23055934	In T76321, lymphoblastic lymphomas were observed in spleen, liver, kidney, pancreas, lymph nodes, lung, adrenal gland, urinary bladder, salivary gland and bone marrow.	('pancreas', 'Disease', (75, 83))	('observed', 'Reg', (40, 48))	('pancreas', 'Disease', 'MESH:D010190', (75, 83))	('lymphoblastic lymphomas', 'Disease', (11, 34))	('T76321', 'Var', (3, 9))	('lymphomas', 'Phenotype', 'HP:0002665', (25, 34))	('lymphoma', 'Phenotype', 'HP:0002665', (25, 33))	('lymphoblastic lymphomas', 'Disease', 'MESH:D054198', (11, 34))
285002	23055934	T76088 was diagnosed with multifocal lymphoma in lymph nodes and multiple visceral organs and tissues, including spleen, liver, kidney and lung.	('lymphoma', 'Phenotype', 'HP:0002665', (37, 45))	('spleen', 'Disease', (113, 119))	('multifocal lymphoma', 'Disease', (26, 45))	('multifocal lymphoma', 'Disease', 'None', (26, 45))	('T76088', 'Var', (0, 6))	('lung', 'Disease', (139, 143))	('liver', 'Disease', (121, 126))	('kidney', 'Disease', (128, 134))
285006	23055934	The CD3 staining of T76321 and T76088 was representative of that observed in the other three SRV-2 associated lymphomas.	('SRV-2', 'Species', '39068', (93, 98))	('lymphomas', 'Disease', (110, 119))	('lymphomas', 'Disease', 'MESH:D008223', (110, 119))	('T76321', 'Var', (20, 26))	('T76088', 'Var', (31, 37))	('lymphomas', 'Phenotype', 'HP:0002665', (110, 119))	('SRV-2', 'Gene', (93, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (110, 118))
285016	23055934	Similar CD20 staining was observed in the 02206 and A01110 lymphomas, while the A07762 lymphoma showed variable CD20 expression.	('CD20', 'Gene', (112, 116))	('CD20', 'Gene', '931', (112, 116))	('lymphomas', 'Phenotype', 'HP:0002665', (59, 68))	('02206', 'Var', (42, 47))	('lymphoma', 'Disease', (87, 95))	('lymphoma', 'Disease', (59, 67))	('lymphoma', 'Disease', 'MESH:D008223', (59, 67))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('lymphomas', 'Disease', 'MESH:D008223', (59, 68))	('lymphoma', 'Disease', 'MESH:D008223', (87, 95))	('CD20', 'Gene', '931', (8, 12))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('lymphomas', 'Disease', (59, 68))	('A01110', 'Var', (52, 58))	('CD20', 'Gene', (8, 12))
285026	23055934	Figure 5A shows a section of a tumor (T) from A01112 located adjacent to normal colonic mucosa (N) where small aggregates of normal small, dense B-lymphocytes, positive for CD20 were present (Figure 5A, red circle and Figure 5B).	('CD20', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('colonic mucosa', 'Disease', 'MESH:D015179', (80, 94))	('colonic mucosa', 'Disease', (80, 94))	('tumor', 'Disease', (31, 36))	('A01112', 'Var', (46, 52))	('CD20', 'Gene', '931', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
285036	23055934	The other two lymphomas from A01112 and 93034 were negative for IgM expression (Table 1).	('lymphomas', 'Disease', 'MESH:D008223', (14, 23))	('A01112', 'Var', (29, 35))	('lymphomas', 'Phenotype', 'HP:0002665', (14, 23))	('negative', 'NegReg', (51, 59))	('lymphoma', 'Phenotype', 'HP:0002665', (14, 22))	('lymphomas', 'Disease', (14, 23))	('IgM', 'Protein', (64, 67))
285060	23055934	The 93034 lymphoma had the second highest RV2 viral load of nearly 300 viral genome copies per cell, showing a strong correlation between expression of the gB late lytic marker and high viral load.	('93034', 'Var', (4, 9))	('lymphoma', 'Disease', (10, 18))	('lymphoma', 'Disease', 'MESH:D008223', (10, 18))	('lymphoma', 'Phenotype', 'HP:0002665', (10, 18))	('RV2', 'Gene', (42, 45))	('gB', 'Chemical', '-', (156, 158))
285063	23055934	Very strong anti-gB staining was observed in the A01112 lymph node lymphoma with staining associated with essentially every blastoid tumor cell (Figure 7D, insert).	('blastoid tumor', 'Disease', (124, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (67, 75))	('gB', 'Chemical', '-', (17, 19))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('lymph node lymphoma', 'Disease', (56, 75))	('blastoid tumor', 'Disease', 'MESH:D009369', (124, 138))	('lymph node lymphoma', 'Disease', 'MESH:D000072717', (56, 75))	('anti-gB', 'Protein', (12, 19))	('A01112', 'Var', (49, 55))
285078	23055934	The A07762 lymphoma, which had nine LCV copies/cell, was negative for EBNA-2 staining in multiple tumor sections (data not shown).	('EBNA-2', 'Gene', '17494192', (70, 76))	('A07762', 'Var', (4, 10))	('lymphoma', 'Disease', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('multiple tumor', 'Disease', (89, 103))	('multiple tumor', 'Disease', 'MESH:D009369', (89, 103))	('EBNA-2', 'Gene', (70, 76))	('lymphoma', 'Disease', 'MESH:D008223', (11, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))
285079	23055934	Similarly, A01110 lymphoma, which had 0.6 LCV copies/cell, was also negative for EBNA-2 staining (data not shown).	('EBNA-2', 'Gene', (81, 87))	('lymphoma', 'Disease', (18, 26))	('lymphoma', 'Disease', 'MESH:D008223', (18, 26))	('EBNA-2', 'Gene', '17494192', (81, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (18, 26))	('A01110', 'Var', (11, 17))
285080	23055934	However, the A08044 lymphoma with four LCV copies/cell stained strongly for EBNA-2 (Figure 4D), and this staining overlapped that of CD20 (compare Figure 4A and D).	('strongly', 'PosReg', (63, 71))	('CD20', 'Gene', (133, 137))	('EBNA-2', 'Gene', '17494192', (76, 82))	('lymphoma', 'Disease', (20, 28))	('stained', 'Reg', (55, 62))	('lymphoma', 'Disease', 'MESH:D008223', (20, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (20, 28))	('EBNA-2', 'Gene', (76, 82))	('A08044', 'Var', (13, 19))	('CD20', 'Gene', '931', (133, 137))
285109	23055934	Of the five lymphomas in the LCV-High group of lymphomas in our study, only three (A07762, A08044 and A01110) had tissue blocks for immunohistochemical localization studies.	('lymphoma', 'Phenotype', 'HP:0002665', (12, 20))	('lymphomas', 'Disease', (12, 21))	('A07762', 'Var', (83, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('A08044', 'Var', (91, 97))	('lymphomas', 'Disease', 'MESH:D008223', (12, 21))	('lymphomas', 'Disease', (47, 56))	('A01110', 'Var', (102, 108))	('lymphomas', 'Disease', 'MESH:D008223', (47, 56))	('lymphomas', 'Phenotype', 'HP:0002665', (12, 21))	('lymphomas', 'Phenotype', 'HP:0002665', (47, 56))
285110	23055934	Using a monoclonal antibody to the EBV EBNA-2 latency-associated protein, we observed strong staining in the A08044 lymphoma in the nuclei of the vast majority of the blastoid tumor cells.	('EBNA-2', 'Gene', (39, 45))	('EBV', 'Species', '10376', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('lymphoma', 'Disease', (116, 124))	('blastoid tumor', 'Disease', 'MESH:D009369', (167, 181))	('lymphoma', 'Disease', 'MESH:D008223', (116, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (116, 124))	('blastoid tumor', 'Disease', (167, 181))	('EBNA-2', 'Gene', '17494192', (39, 45))	('A08044', 'Var', (109, 115))	('staining', 'MPA', (93, 101))
285113	23055934	Phenotype analysis revealed that two of the LCV-high lymphomas, A01110 and A08044, stained strongly for the B-cell marker CD20, confirming previous correlations between CD20 expression and EBV-associated lymphomas.	('EBV', 'Species', '10376', (189, 192))	('CD20', 'Gene', (122, 126))	('CD20', 'Gene', '931', (122, 126))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('stained', 'Reg', (83, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (204, 212))	('lymphomas', 'Disease', (204, 213))	('lymphomas', 'Disease', 'MESH:D008223', (204, 213))	('lymphomas', 'Disease', (53, 62))	('LCV-high lymphoma', 'Disease', (44, 61))	('lymphomas', 'Phenotype', 'HP:0002665', (204, 213))	('A08044', 'Var', (75, 81))	('lymphomas', 'Disease', 'MESH:D008223', (53, 62))	('CD20', 'Gene', (169, 173))	('LCV-high lymphoma', 'Disease', 'MESH:D008228', (44, 61))	('lymphomas', 'Phenotype', 'HP:0002665', (53, 62))	('CD20', 'Gene', '931', (169, 173))
285114	23055934	A08044 was also tested for expression of the B-cell antigen, BLA.36 and heterogenous staining was detected within the tumor sample (Table 1).	('A08044', 'Var', (0, 6))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))
285128	23055934	Similar to the lytic replication of RRV detected in vitro in the previous study, the RV2-infected tumor cells in the lymphoma lesions in the present study expressed the ORF59 DNA polymerase processivity factor, an early marker of lytic replication, and the virion gB, a late marker of lytic replication.	('RV2-infected tumor', 'Disease', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('lymphoma lesions', 'Disease', (117, 133))	('RV2-infected tumor', 'Disease', 'MESH:D009369', (85, 103))	('gB', 'Chemical', '-', (264, 266))	('lymphoma', 'Phenotype', 'HP:0002665', (117, 125))	('lymphoma lesions', 'Disease', 'MESH:D008223', (117, 133))	('RRV', 'Species', '154334', (36, 39))	('ORF59 DNA', 'Var', (169, 178))
285164	23055934	Furthermore, whereas macaque LCV, like the human gammaherpesviruses EBV and KSHV, are latent in the proliferating tumor cells, the RV2 rhadinoviruses express both early and late stage replication markers and show high viral loads consistent with ongoing virus replication.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('KS', 'Phenotype', 'HP:0100726', (76, 78))	('tumor', 'Disease', (114, 119))	('KSHV', 'Species', '37296', (76, 80))	('EBV', 'Species', '10376', (68, 71))	('viral loads', 'MPA', (218, 229))	('RV2', 'Var', (131, 134))	('human', 'Species', '9606', (43, 48))
285193	22550415	These reports suggest that the fusion proteins particularly affect the cell growth, cell proliferation, TP53 pathway, and chromatin remodeling mechanisms, contributing to SS oncogenesis.	('TP53 pathway', 'Pathway', (104, 116))	('contributing', 'Reg', (155, 167))	('cell proliferation', 'CPA', (84, 102))	('SS', 'Phenotype', 'HP:0012570', (171, 173))	('cell growth', 'CPA', (71, 82))	('fusion', 'Var', (31, 37))	('SS oncogenesis', 'Disease', (171, 185))	('oncogenesis', 'Disease', (174, 185))	('affect', 'Reg', (60, 66))	('rat', 'Species', '10116', (96, 99))	('chromatin remodeling mechanisms', 'CPA', (122, 153))
285219	22550415	Furthermore, SS18 affects the expression of genes important for placental development, such as peroxisome proliferator-activated receptor-binding protein (PPARB).	('PPARB', 'Gene', '5469', (155, 160))	('expression', 'MPA', (30, 40))	('SS', 'Phenotype', 'HP:0012570', (13, 15))	('PPARB', 'Gene', (155, 160))	('SS18', 'Var', (13, 17))	('peroxisome proliferator-activated receptor-binding protein', 'Gene', '5469', (95, 153))	('affects', 'Reg', (18, 25))
285232	22550415	In addition, rare cases of SS18-SSX4 chimeric variants in SS have been described, but these have been characterized by high breakpoint variability, with a possible functional unpredictability as a consequence..	('SS', 'Phenotype', 'HP:0012570', (32, 34))	('SSX4', 'Gene', (32, 36))	('SS', 'Phenotype', 'HP:0012570', (27, 29))	('chimeric variants', 'Var', (37, 54))	('SS', 'Phenotype', 'HP:0012570', (58, 60))	('SSX4', 'Gene', '6759', (32, 36))
285242	22550415	The authors described tumor development in mice that resembled human SS with regard to histological appearance, immunohistochemistry, transcriptional profile, and SS18-SSX2 fusion gene expression in tumor cells.	('tumor', 'Disease', (199, 204))	('mice', 'Species', '10090', (43, 47))	('human', 'Species', '9606', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('fusion gene', 'Var', (173, 184))	('SS18-SSX2', 'Gene', (163, 172))	('SS', 'Phenotype', 'HP:0012570', (168, 170))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', (22, 27))	('SS', 'Phenotype', 'HP:0012570', (163, 165))	('SS', 'Phenotype', 'HP:0012570', (69, 71))
285249	22550415	A study conducted by Xie and colleagues focused on the influence of the SS18-SSX1 and SS18-SSX2 fusion proteins on tumor-relevant and growth-regulatory proteins, including cyclins A/D1/E, cyclin-dependent kinases (CDKs), p27, and BCL-2 (a proto-oncogene).	('SS', 'Phenotype', 'HP:0012570', (77, 79))	('SS', 'Phenotype', 'HP:0012570', (91, 93))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('A/D1', 'Var', (180, 184))	('SS', 'Phenotype', 'HP:0012570', (86, 88))	('SS', 'Phenotype', 'HP:0012570', (72, 74))	('A/D1', 'SUBSTITUTION', 'None', (180, 184))	('p27', 'Gene', '3429', (221, 224))	('p27', 'Gene', (221, 224))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
285251	22550415	They suggested that the SS18-SSX2 protein interferes with the ubiquitin-dependent degradation pathway, which results in the upregulation of cyclin D1.	('upregulation', 'PosReg', (124, 136))	('interferes', 'NegReg', (42, 52))	('ubiquitin-dependent', 'Pathway', (62, 81))	('SS', 'Phenotype', 'HP:0012570', (24, 26))	('cyclin D1', 'Gene', '595', (140, 149))	('SS18-SSX2', 'Var', (24, 33))	('cyclin D1', 'Gene', (140, 149))	('SS', 'Phenotype', 'HP:0012570', (29, 31))
285256	22550415	The misregulation of beta-catenin-mediated signaling leads to the development of numerous human malignancies.	('misregulation', 'Var', (4, 17))	('beta-catenin', 'Gene', '1499', (21, 33))	('numerous human malignancies', 'Disease', 'MESH:D009369', (81, 108))	('numerous human malignancies', 'Disease', (81, 108))	('beta-catenin', 'Gene', (21, 33))	('leads to', 'Reg', (53, 61))
285257	22550415	demonstrated that SS18-SSX2 stimulates beta-catenin signaling in a P300-dependent manner.	('SS', 'Phenotype', 'HP:0012570', (23, 25))	('P300', 'Gene', (67, 71))	('stimulates', 'PosReg', (28, 38))	('rat', 'Species', '10116', (7, 10))	('beta-catenin', 'Gene', (39, 51))	('SS', 'Phenotype', 'HP:0012570', (18, 20))	('SS18-SSX2', 'Var', (18, 27))	('beta-catenin', 'Gene', '1499', (39, 51))	('P300', 'Gene', '2033', (67, 71))
285260	22550415	These findings suggest that SS18-SSX2 triggers tumor development partially through the beta-catenin signaling but it should be further investigated whether SS18-SSX1 has the same effect.	('SS', 'Phenotype', 'HP:0012570', (156, 158))	('beta-catenin', 'Gene', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('beta-catenin', 'Gene', '1499', (87, 99))	('SS', 'Phenotype', 'HP:0012570', (161, 163))	('SS', 'Phenotype', 'HP:0012570', (28, 30))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('triggers', 'Reg', (38, 46))	('SS18-SSX2', 'Var', (28, 37))	('tumor', 'Disease', (47, 52))	('SS', 'Phenotype', 'HP:0012570', (33, 35))
285268	22550415	This experiment has been conducted only in one SS cell line carrying SS18-SSX2 transcript, but two other studies of D'Arcy and coworkers demonstrated that TP53 is affected in cell lines expressing both SS18-SSX1 and SS18-SSX2.	('SS', 'Phenotype', 'HP:0012570', (207, 209))	('TP53', 'MPA', (155, 159))	('SS', 'Phenotype', 'HP:0012570', (74, 76))	('rat', 'Species', '10116', (144, 147))	('SS', 'Phenotype', 'HP:0012570', (47, 49))	('SS18-SSX2', 'Var', (216, 225))	('SS', 'Phenotype', 'HP:0012570', (202, 204))	('SS', 'Phenotype', 'HP:0012570', (69, 71))	('affected', 'Reg', (163, 171))	('SS18-SSX1', 'Var', (202, 211))
285269	22550415	Firstly, they demonstrated that SS18-SSX1 promotes TP53 ubiquitination and degradation by a mechanism involving the HDM2 (Mdm2 p53 binding protein homolog in mouse).	('HDM2', 'Gene', '4193', (116, 120))	('HDM2', 'Gene', (116, 120))	('mouse', 'Species', '10090', (158, 163))	('Mdm2', 'Gene', '17246', (122, 126))	('SS', 'Phenotype', 'HP:0012570', (37, 39))	('SS', 'Phenotype', 'HP:0012570', (32, 34))	('Mdm2', 'Gene', (122, 126))	('SS18-SSX1', 'Var', (32, 41))	('promotes', 'PosReg', (42, 50))	('TP53 ubiquitination', 'MPA', (51, 70))	('degradation', 'MPA', (75, 86))	('p53', 'Gene', '22059', (127, 130))	('rat', 'Species', '10116', (21, 24))	('p53', 'Gene', (127, 130))
285272	22550415	Another observation was that SS18-SSX1 attenuates the TP53 response and changes the expression levels of several TP53-regulated genes, such as BBC3 (BCL2 binding component 3) and PMAIP1 (phorbol-12-myristate-13-acetate-induced protein 1), but it does not affect the expression level of the p21WAF1/CIP1 (also known as CDKN1A-cyclin-dependent kinase inhibitor 1A).	('p21WAF1/CIP1', 'Gene', '1026', (290, 302))	('phorbol-12-myristate-13-acetate', 'Chemical', 'MESH:D013755', (187, 218))	('PMAIP1', 'Gene', '5366', (179, 185))	('BCL2 binding component 3', 'Gene', '27113', (149, 173))	('p21WAF1/CIP1', 'Gene', (290, 302))	('SS18-SSX1', 'Var', (29, 38))	('TP53-regulated genes', 'Gene', (113, 133))	('TP53 response', 'MPA', (54, 67))	('BCL2 binding component 3', 'Gene', (149, 173))	('BBC3', 'Gene', '27113', (143, 147))	('SS', 'Phenotype', 'HP:0012570', (34, 36))	('expression levels', 'MPA', (84, 101))	('attenuates', 'NegReg', (39, 49))	('BBC3', 'Gene', (143, 147))	('changes', 'Reg', (72, 79))	('PMAIP1', 'Gene', (179, 185))	('SS', 'Phenotype', 'HP:0012570', (29, 31))
285289	22550415	The authors demonstrated also that the knockdown of SS18-SSX2 results in a strong upregulation of COM1 expression, which reduces in vitro cell growth and colony formation of SYO-1 cell line.	('colony formation of SYO-1 cell line', 'CPA', (154, 189))	('SS', 'Phenotype', 'HP:0012570', (57, 59))	('SS18-SSX2', 'Gene', (52, 61))	('expression', 'MPA', (103, 113))	('knockdown', 'Var', (39, 48))	('in vitro cell growth', 'CPA', (129, 149))	('COM1', 'Gene', (98, 102))	('COM1', 'Gene', '26471', (98, 102))	('rat', 'Species', '10116', (19, 22))	('SS', 'Phenotype', 'HP:0012570', (52, 54))	('reduces', 'NegReg', (121, 128))	('upregulation', 'PosReg', (82, 94))	('SYO-1', 'CellLine', 'CVCL:7146', (174, 179))
285290	22550415	Additionally, the restoration of COM1 expression induced apoptosis in this cell line.	('COM1', 'Gene', '26471', (33, 37))	('COM1', 'Gene', (33, 37))	('restoration', 'Var', (18, 29))	('expression', 'MPA', (38, 48))	('rat', 'Species', '10116', (23, 26))
285292	22550415	performed RNA interference experiments targeting the 19-nucleotide sequence of SS18-SSX2 mRNA in SYO-1 cells, demonstrating that downregulation of the fusion gene inhibits cell proliferation and diminishes the protein levels of ERK1, ERK2, p-ERK, and cyclin D1.	('p-ERK', 'Gene', '9451', (240, 245))	('p-ERK', 'Gene', (240, 245))	('rat', 'Species', '10116', (184, 187))	('ERK2', 'Gene', (234, 238))	('diminishes', 'NegReg', (195, 205))	('downregulation', 'Var', (129, 143))	('ERK1', 'Gene', (228, 232))	('SS', 'Phenotype', 'HP:0012570', (79, 81))	('SYO-1', 'CellLine', 'CVCL:7146', (97, 102))	('ERK1', 'Gene', '5595', (228, 232))	('rat', 'Species', '10116', (117, 120))	('SS', 'Phenotype', 'HP:0012570', (84, 86))	('inhibits', 'NegReg', (163, 171))	('cyclin D1', 'Gene', (251, 260))	('protein levels', 'MPA', (210, 224))	('cell proliferation', 'CPA', (172, 190))	('19-nucleotide', 'Chemical', '-', (53, 66))	('cyclin D1', 'Gene', '595', (251, 260))	('ERK2', 'Gene', '5594', (234, 238))
285303	22550415	Ito and colleagues observed that SS18 and SS18-SSX1 proteins (but not SS18-SSX2 protein) can bind mSIN3A proteins, which are a part of the histone deacetylase complex (HDAC).	('bind', 'Interaction', (93, 97))	('mSIN3A', 'Gene', '20466', (98, 104))	('SS18', 'Var', (33, 37))	('SS', 'Phenotype', 'HP:0012570', (47, 49))	('SS', 'Phenotype', 'HP:0012570', (42, 44))	('SS', 'Phenotype', 'HP:0012570', (33, 35))	('SS', 'Phenotype', 'HP:0012570', (70, 72))	('mSIN3A', 'Gene', (98, 104))	('SS', 'Phenotype', 'HP:0012570', (75, 77))
285325	22550415	Such strategy is reasonable especially in the light of recent findings made by Erkizan and coworkers who identified a small molecule inhibitor of EWS-FLI1 fusion transcript interaction with RNA helicase A (RHA), which is important in the oncogenesis of Ewing's sarcoma family tumors (ESFTs).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (253, 268))	('FLI1', 'Gene', '2313', (150, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('RHA', 'Gene', (206, 209))	('EWS', 'Gene', (146, 149))	('EWS', 'Gene', '2130', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('interaction', 'Interaction', (173, 184))	("Ewing's sarcoma family tumors", 'Disease', 'MESH:C563168', (253, 282))	('RHA', 'Gene', '1660', (206, 209))	('RNA helicase A', 'Gene', (190, 204))	("Ewing's sarcoma family tumors", 'Disease', (253, 282))	('rat', 'Species', '10116', (7, 10))	('fusion', 'Var', (155, 161))	('RNA helicase A', 'Gene', '1660', (190, 204))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('FLI1', 'Gene', (150, 154))
285331	22550415	Another study published by Kemp and colleagues demonstrated that pharmacological inhibition of polycomb repressor complex-2 (PRC-2) is a successful therapeutic strategy in malignant pleural mesothelioma.	('rat', 'Species', '10116', (162, 165))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (172, 202))	('rat', 'Species', '10116', (54, 57))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (182, 202))	('PRC-2', 'Gene', (125, 130))	('malignant pleural mesothelioma', 'Disease', (172, 202))	('pharmacological inhibition', 'Var', (65, 91))
285340	22550415	Furthermore, there are two phase II clinical trials in progress including SS patients, which examine the treatment with HDAC inhibitors (NCT01112384 and NCT01136499).	('NCT01112384', 'Var', (137, 148))	('SS', 'Phenotype', 'HP:0012570', (74, 76))	('patients', 'Species', '9606', (77, 85))	('NCT01136499', 'Var', (153, 164))
285347	22550415	As far as pathways involving cell growth, cell proliferation, TP53, and chromatin remodeling are concerned, it has been shown that both the SS18-SSX1 and SS18-SSX2 fusion proteins may interfere with them, but often through distinct molecular interactions.	('SS18-SSX2', 'Gene', (154, 163))	('SS18-SSX1', 'Gene', (140, 149))	('SS', 'Phenotype', 'HP:0012570', (145, 147))	('SS', 'Phenotype', 'HP:0012570', (154, 156))	('SS', 'Phenotype', 'HP:0012570', (140, 142))	('fusion', 'Var', (164, 170))	('rat', 'Species', '10116', (54, 57))	('interactions', 'Interaction', (242, 254))	('interfere', 'NegReg', (184, 193))	('SS', 'Phenotype', 'HP:0012570', (159, 161))
285362	32176331	Answers frequently portray cancer as mutant cells gone rogue with rapid, uncontrolled, and even zombie-like growth.	('portray', 'Reg', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutant', 'Var', (37, 43))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
285377	32176331	Their tumor ecosystems exhibit spatial and temporal fluctuations in blood-borne nutrients, oxygen, growth factors, immune cells, and hormones.19, 20, 21 Even when considering 2 genetically identical cancer cells, differences between these cells in proximity to nutrients may promote different transcription rates of growth factors.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('growth', 'Protein', (316, 322))	('transcription rates', 'MPA', (293, 312))	('promote', 'PosReg', (275, 282))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('oxygen', 'Chemical', 'MESH:D010100', (91, 97))	('cancer', 'Disease', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('differences', 'Var', (213, 224))
285385	32176331	Mutations suggest directional selection for promoting the progressive evolution of cancer.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('promoting', 'PosReg', (44, 53))
285482	31789976	These included the SHH subtype of medulloblastoma and diffuse large B-cell lymphoma (DLBCL), where high HK2 expression correlated with poor prognosis.	('medulloblastoma', 'Disease', 'MESH:D008527', (34, 49))	('HK2', 'Gene', '3099', (104, 107))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (68, 83))	('medulloblastoma', 'Phenotype', 'HP:0002885', (34, 49))	('SHH', 'Gene', '6469', (19, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('high', 'Var', (99, 103))	('medulloblastoma', 'Disease', (34, 49))	('expression', 'MPA', (108, 118))	('SHH', 'Gene', (19, 22))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (68, 83))	('HK2', 'Gene', (104, 107))	('B-cell lymphoma', 'Disease', (68, 83))
285485	31789976	High LDHA expression has been linked to poor prognoses in neuroblastoma, where it correlated with MYCN-amplification, and in medulloblastoma, where it was associated with two of the genetically-defined subtypes, including the aggressive group 3 subtype which portends a very poor prognosis.	('MYCN', 'Gene', '4613', (98, 102))	('neuroblastoma', 'Phenotype', 'HP:0003006', (58, 71))	('High', 'Var', (0, 4))	('associated', 'Reg', (155, 165))	('LDHA', 'Gene', '3939', (5, 9))	('medulloblastoma', 'Disease', 'MESH:D008527', (125, 140))	('correlated', 'Reg', (82, 92))	('LDHA', 'Gene', (5, 9))	('neuroblastoma', 'Disease', 'MESH:D009447', (58, 71))	('medulloblastoma', 'Phenotype', 'HP:0002885', (125, 140))	('MYCN', 'Gene', (98, 102))	('neuroblastoma', 'Disease', (58, 71))	('medulloblastoma', 'Disease', (125, 140))
285493	31789976	In medulloblastoma, genetic depletion of HK2 abrogated the aggressive phenotype of these cells in vivo; in osteosarcoma, genetic depletion of HK2 induced apoptosis in some, but not all preclinical models.	('abrogated', 'NegReg', (45, 54))	('HK2', 'Gene', '3099', (142, 145))	('medulloblastoma', 'Disease', 'MESH:D008527', (3, 18))	('genetic depletion', 'Var', (121, 138))	('medulloblastoma', 'Phenotype', 'HP:0002885', (3, 18))	('apoptosis', 'CPA', (154, 163))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('genetic', 'Var', (20, 27))	('osteosarcoma', 'Disease', (107, 119))	('medulloblastoma', 'Disease', (3, 18))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('HK2', 'Gene', (41, 44))	('HK2', 'Gene', '3099', (41, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('HK2', 'Gene', (142, 145))
285494	31789976	Genetic depletion of LDHA was effective in inhibiting the growth of preclinical models of neuroblastoma and Ewing sarcoma, which was also sensitive to pharmacological targeting of LDH.	('inhibiting', 'NegReg', (43, 53))	('LDHA', 'Gene', (21, 25))	('neuroblastoma', 'Disease', (90, 103))	('LDHA', 'Gene', '3939', (21, 25))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('neuroblastoma', 'Phenotype', 'HP:0003006', (90, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('Genetic depletion', 'Var', (0, 17))	('growth', 'MPA', (58, 64))	('Ewing sarcoma', 'Disease', (108, 121))	('neuroblastoma', 'Disease', 'MESH:D009447', (90, 103))
285497	31789976	In models of pediatric AML, resistance to adriamycin was associated with increased glycolysis and HK2 expression in patient samples.	('glycolysis', 'MPA', (83, 93))	('increased', 'PosReg', (73, 82))	('resistance', 'Var', (28, 38))	('expression', 'MPA', (102, 112))	('patient', 'Species', '9606', (116, 123))	('AML', 'Disease', 'MESH:D015470', (23, 26))	('HK2', 'Gene', (98, 101))	('HK2', 'Gene', '3099', (98, 101))	('AML', 'Phenotype', 'HP:0004808', (23, 26))	('AML', 'Disease', (23, 26))	('adriamycin', 'Chemical', 'MESH:D004317', (42, 52))
285500	31789976	In pediatric ALL models, resistance to glucocorticoid agents could be mitigated by the addition of 2-DG, and in Ewing sarcoma cell lines, the addition of 2-DG to standard chemotherapy drugs enhanced their antiproliferative effect.	('Ewing sarcoma', 'Disease', (112, 125))	('ALL', 'Phenotype', 'HP:0006721', (13, 16))	('antiproliferative effect', 'CPA', (205, 229))	('2-DG', 'Chemical', 'MESH:D003847', (99, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (112, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('2-DG', 'Var', (154, 158))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (112, 125))	('2-DG', 'Chemical', 'MESH:D003847', (154, 158))	('enhanced', 'PosReg', (190, 198))
285507	31789976	Metformin treatment was associated with cancer cell growth inhibition in preclinical models of several pediatric solid tumors, including Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, HGG and osteosarcoma, in which antitumor effects against primary tumor cells and microenvironmental factors were reported.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('tumor', 'Disease', (220, 225))	('Metformin', 'Var', (0, 9))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('HGG', 'Disease', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (250, 255))	('Ewing sarcoma', 'Disease', (137, 150))	('rhabdomyosarcoma', 'Disease', (152, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('tumors', 'Disease', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('cancer', 'Disease', (40, 46))	('osteosarcoma', 'Disease', (193, 205))	('osteosarcoma', 'Disease', 'MESH:D012516', (193, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (152, 168))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (152, 168))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (119, 124))	('neuroblastoma', 'Disease', (170, 183))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('neuroblastoma', 'Phenotype', 'HP:0003006', (170, 183))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (137, 150))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('osteosarcoma', 'Phenotype', 'HP:0002669', (193, 205))	('neuroblastoma', 'Disease', 'MESH:D009447', (170, 183))
285513	31789976	Functionally, inhibition of PDK1, which permits more entry of pyruvate into the TCA cycle, resulted in decreased cell growth in models of AML and retinoblastoma, where it also sensitized cells to the effects of chemotherapy.	('entry', 'MPA', (53, 58))	('AML', 'Phenotype', 'HP:0004808', (138, 141))	('AML', 'Disease', (138, 141))	('retinoblastoma', 'Disease', 'MESH:D012175', (146, 160))	('retinoblastoma', 'Disease', (146, 160))	('retinoblastoma', 'Phenotype', 'HP:0009919', (146, 160))	('decreased', 'NegReg', (103, 112))	('pyruvate', 'Chemical', 'MESH:D019289', (62, 70))	('cell growth', 'CPA', (113, 124))	('PDK1', 'Gene', '5163', (28, 32))	('PDK1', 'Gene', (28, 32))	('AML', 'Disease', 'MESH:D015470', (138, 141))	('TCA', 'Chemical', 'MESH:D014233', (80, 83))	('inhibition', 'Var', (14, 24))
285514	31789976	Inhibition of OXPHOS also improved responses to chemotherapy in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (64, 76))	('OXPHOS', 'Enzyme', (14, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('responses to chemotherapy', 'MPA', (35, 60))	('Inhibition', 'Var', (0, 10))	('osteosarcoma', 'Disease', (64, 76))	('improved', 'PosReg', (26, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (64, 76))
285528	31789976	In Ewing sarcoma tumors, high glutamine synthetase expression correlated with worse survival.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('Ewing sarcoma tumors', 'Disease', (3, 23))	('high glutamine', 'Phenotype', 'HP:0003217', (25, 39))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (3, 23))	('high', 'Var', (25, 29))	('expression', 'MPA', (51, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('glutamine synthetase', 'Gene', (30, 50))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('glutamine synthetase', 'Gene', '2752', (30, 50))
285531	31789976	In medulloblastoma, dietary glutamine restriction increased survival in a mouse xenograft model and synergized with cisplatin treatment.	('survival', 'CPA', (60, 68))	('dietary', 'Var', (20, 27))	('medulloblastoma', 'Disease', 'MESH:D008527', (3, 18))	('medulloblastoma', 'Phenotype', 'HP:0002885', (3, 18))	('increased', 'PosReg', (50, 59))	('medulloblastoma', 'Disease', (3, 18))	('mouse', 'Species', '10090', (74, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('glutamine', 'Chemical', 'MESH:D005973', (28, 37))
285536	31789976	In rhabdomyosarcoma and Ewing sarcoma, inhibition of glutamine synthetase with methionine sulfoximine selectively abolished the ability of glutamine-deprived cells to proliferate.	('glutamine synthetase', 'Gene', '2752', (53, 73))	('inhibition', 'Var', (39, 49))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (3, 19))	('glutamine', 'Chemical', 'MESH:D005973', (139, 148))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (24, 37))	('glutamine', 'Chemical', 'MESH:D005973', (53, 62))	('rhabdomyosarcoma and Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('abolished', 'NegReg', (114, 123))	('methionine sulfoximine', 'Chemical', 'MESH:D008717', (79, 101))	('glutamine synthetase', 'Gene', (53, 73))	('proliferate', 'CPA', (167, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
285538	31789976	Pharmacological and genetic inhibition of glutamine synthetase significantly reduced Ewing sarcoma orthotopic xenograft tumor growth.	('Ewing sarcoma', 'Disease', (85, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('glutamine synthetase', 'Gene', (42, 62))	('genetic inhibition', 'Var', (20, 38))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('reduced', 'NegReg', (77, 84))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('glutamine synthetase', 'Gene', '2752', (42, 62))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
285541	31789976	Overexpression of enzymes in these pathways has been linked to more aggressive cancer phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('linked', 'Reg', (53, 59))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
285547	31789976	Preclinical studies targeting serine-glycine-one-carbon metabolism have shown promise as a potential therapeutic strategy for pediatric malignancies and indicate that perturbation of these pathways impacts multiple other metabolic processes in pediatric cancer models.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('metabolic processes', 'MPA', (221, 240))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('malignancies', 'Disease', (136, 148))	('impacts', 'Reg', (198, 205))	('carbon', 'Chemical', 'MESH:D002244', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('perturbation', 'Var', (167, 179))	('cancer', 'Disease', (254, 260))	('serine-glycine-one-carbon metabolism', 'MPA', (30, 66))	('glycine', 'Chemical', 'MESH:D005998', (37, 44))	('serine', 'Chemical', 'MESH:D012694', (30, 36))
285548	31789976	In AML models, knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD2), which is essential for mitochondrial one-carbon folate metabolism, decreased cell growth in culture and prolonged survival in murine models.	('MTHFD2', 'Gene', (69, 75))	('cell growth in culture', 'CPA', (155, 177))	('murine', 'Species', '10090', (204, 210))	('knockdown', 'Var', (15, 24))	('survival', 'CPA', (192, 200))	('prolonged', 'PosReg', (182, 191))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('decreased', 'NegReg', (145, 154))	('MTHFD2', 'Gene', '17768', (69, 75))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('tetrahydrofolate', 'Chemical', 'MESH:C030371', (37, 53))	('carbon folate', 'Chemical', '-', (119, 132))	('AML', 'Disease', (3, 6))
285549	31789976	Mechanistically, loss of MTHFD2 increased glycine dependence and depleted TCA cycle intermediates in these models.	('MTHFD2', 'Gene', (25, 31))	('glycine', 'Chemical', 'MESH:D005998', (42, 49))	('TCA cycle intermediates', 'MPA', (74, 97))	('depleted', 'NegReg', (65, 73))	('MTHFD2', 'Gene', '17768', (25, 31))	('glycine dependence', 'MPA', (42, 60))	('increased', 'PosReg', (32, 41))	('loss', 'Var', (17, 21))	('TCA', 'Chemical', 'MESH:D014233', (74, 77))
285550	31789976	In MYCN-amplified neuroblastoma cell lines, GLDC knockdown inhibited cellular proliferation and tumorigenicity by disrupting glycolysis, the TCA cycle, lipid synthesis, and purine metabolism.	('neuroblastoma', 'Disease', (18, 31))	('neuroblastoma', 'Phenotype', 'HP:0003006', (18, 31))	('purine', 'Chemical', 'MESH:C030985', (173, 179))	('GLDC', 'Gene', '2731', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MYCN', 'Gene', '4613', (3, 7))	('inhibited', 'NegReg', (59, 68))	('TCA cycle', 'MPA', (141, 150))	('neuroblastoma', 'Disease', 'MESH:D009447', (18, 31))	('glycolysis', 'MPA', (125, 135))	('lipid', 'Chemical', 'MESH:D008055', (152, 157))	('cellular proliferation', 'CPA', (69, 91))	('MYCN', 'Gene', (3, 7))	('tumor', 'Disease', (96, 101))	('purine metabolism', 'MPA', (173, 190))	('TCA', 'Chemical', 'MESH:D014233', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('lipid synthesis', 'MPA', (152, 167))	('GLDC', 'Gene', (44, 48))	('knockdown', 'Var', (49, 58))	('disrupting', 'NegReg', (114, 124))
285552	31789976	Similarly, in several studies using Ewing sarcoma models, both pharmacological and genetic inhibition of PHGDH decreased proliferation and induced apoptosis in cell lines and xenografts through induction of ROS and DNA damage.	('induced', 'Reg', (139, 146))	('inhibition', 'Var', (91, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('ROS', 'MPA', (207, 210))	('proliferation', 'CPA', (121, 134))	('PHGDH', 'Gene', (105, 110))	('decreased', 'NegReg', (111, 120))	('DNA damage', 'MPA', (215, 225))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (36, 49))	('PHGDH', 'Gene', '26227', (105, 110))	('induction', 'Reg', (194, 203))	('ROS', 'Chemical', 'MESH:D017382', (207, 210))	('apoptosis', 'CPA', (147, 156))	('Ewing sarcoma', 'Disease', (36, 49))
285557	31789976	Consequently, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) resulted in growth arrest in ASS1-deficient models of osteosarcoma, Ewing sarcoma, synovial sarcoma, and alveolar soft part sarcoma.	('synovial sarcoma', 'Disease', 'MESH:D013584', (172, 188))	('sarcoma', 'Disease', 'MESH:D012509', (181, 188))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (203, 220))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (194, 220))	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('sarcoma', 'Disease', (181, 188))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (172, 188))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('sarcoma', 'Disease', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('sarcoma', 'Disease', (148, 155))	('ASS1', 'Gene', (118, 122))	('ASS1', 'Gene', '445', (118, 122))	('arginine', 'Chemical', 'MESH:D001120', (58, 66))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (157, 170))	('pegylated', 'Var', (48, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('growth arrest', 'Phenotype', 'HP:0001510', (101, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('growth arrest', 'Disease', 'MESH:D006323', (101, 114))	('osteosarcoma', 'Disease', (143, 155))	('osteosarcoma', 'Disease', 'MESH:D012516', (143, 155))	('Ewing sarcoma', 'Disease', (157, 170))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (78, 87))	('arginine', 'Chemical', 'MESH:D001120', (14, 22))	('sarcoma', 'Disease', 'MESH:D012509', (213, 220))	('synovial sarcoma', 'Disease', (172, 188))	('growth arrest', 'Disease', (101, 114))	('sarcoma', 'Disease', (213, 220))
285559	31789976	In preclinical models of osteosarcoma, Ewing sarcoma, synovial sarcoma, and rhabdomyosarcoma, efficacy was noted using ADI-PEG20 plus gemcitabine and docetaxel, and this combination is currently being evaluated in a phase II trial (NCT03449901) for patients with soft tissue sarcoma, including adolescents.	('rhabdomyosarcoma', 'Disease', (76, 92))	('osteosarcoma', 'Phenotype', 'HP:0002669', (25, 37))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('sarcoma', 'Disease', (30, 37))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('sarcoma', 'Disease', (85, 92))	('sarcoma', 'Disease', 'MESH:D012509', (275, 282))	('sarcoma', 'Disease', (275, 282))	('sarcoma', 'Disease', (45, 52))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (76, 92))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (263, 282))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (39, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (76, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('docetaxel', 'Chemical', 'MESH:D000077143', (150, 159))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('synovial sarcoma', 'Disease', (54, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('osteosarcoma', 'Disease', (25, 37))	('osteosarcoma', 'Disease', 'MESH:D012516', (25, 37))	('patients', 'Species', '9606', (249, 257))	('synovial sarcoma', 'Disease', 'MESH:D013584', (54, 70))	('Ewing sarcoma', 'Disease', (39, 52))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (54, 70))	('ADI-PEG20', 'Var', (119, 128))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (119, 128))
285588	31789976	These include reports of metabolic phenotypes that differ from untransformed cells due to the influence of a particular oncogenic driver such as EWS-FLI1, RAS, or MYC, mutations of metabolic enzymes, or factors based on tissue of origin, or microenvironmental conditions, as well as alterations in specific pathways such as lipid synthesis and maintenance of antioxidant homeostasis.	('lipid synthesis', 'MPA', (324, 339))	('EWS', 'Gene', '2130', (145, 148))	('EWS', 'Gene', (145, 148))	('RAS', 'Gene', (155, 158))	('alterations', 'Reg', (283, 294))	('MYC', 'Gene', (163, 166))	('FLI1', 'Gene', (149, 153))	('FLI1', 'Gene', '2313', (149, 153))	('lipid', 'Chemical', 'MESH:D008055', (324, 329))	('influence', 'Reg', (94, 103))	('mutations', 'Var', (168, 177))
285595	29660202	In 2017, The Cancer Genome Atlas (TCGA) Research Network's work on u-LMS has confirmed mutations and deletions in RB1,TP53 and PTEN.	('RB1', 'Gene', (114, 117))	('Cancer Genome Atlas', 'Disease', (13, 32))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (13, 32))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('RB1', 'Gene', '5925', (114, 117))	('PTEN', 'Gene', (127, 131))	('deletions', 'Var', (101, 110))	('PTEN', 'Gene', '5728', (127, 131))	('mutations', 'Var', (87, 96))
285598	29660202	TP53 and ATRX mutations can be important mechanisms in the pathogenesis of u-LMS and are correlated with a poor prognosis.	('ATRX', 'Gene', '546', (9, 13))	('u-LMS', 'Disease', (75, 80))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (0, 4))	('mechanisms', 'Reg', (41, 51))	('ATRX', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
285599	29660202	In an update based on the 2014 WHO classification, low-grade ESS is often associated with gene rearrangement bringing about the JAZF 1-SUZ12 (formerly JAZF1-JJAZ1) fusion gene, whereas high-grade ESS is associated with the YWHAE-NUTM fusion gene.	('low-grade ESS', 'Disease', (51, 64))	('JAZF 1', 'Gene', (128, 134))	('JAZF1', 'Gene', '221895', (151, 156))	('JAZF 1', 'Gene', '221895', (128, 134))	('YWHAE', 'Gene', (223, 228))	('SUZ12', 'Gene', '23512', (135, 140))	('gene rearrangement', 'Var', (90, 108))	('JAZF1', 'Gene', (151, 156))	('SUZ12', 'Gene', (135, 140))	('fusion gene', 'Var', (164, 175))	('JJAZ1', 'Gene', '23512', (157, 162))	('JJAZ1', 'Gene', (157, 162))	('YWHAE', 'Gene', '7531', (223, 228))	('associated', 'Reg', (74, 84))
285600	29660202	Low-grade ESS with JAZF1 rearrangement may correlate with metastasis.	('JAZF1', 'Gene', (19, 24))	('correlate', 'Reg', (43, 52))	('rearrangement', 'Var', (25, 38))	('JAZF1', 'Gene', '221895', (19, 24))	('ESS', 'Disease', (10, 13))	('metastasis', 'CPA', (58, 68))
285614	29660202	The other, which accounts for two-thirds of STS, has a complicated karyotype, with instability of many genes and mutation of the TP53 gene that encodes p53 in many cases;4 u-LMS is considered to belong to the latter group.	('TP53', 'Gene', '7157', (129, 133))	('TP53', 'Gene', (129, 133))	('mutation', 'Var', (113, 121))
285633	29660202	Genetic deficiency of 10 q means inactivation of tumor suppressor gene PTEN, leading to activation of the PI3K/AKT pathway and the downstream mTOR pathway.	('PI3K/AKT pathway', 'Pathway', (106, 122))	('mTOR', 'Gene', (142, 146))	('activation', 'PosReg', (88, 98))	('tumor suppressor', 'Gene', '7248', (49, 65))	('mTOR', 'Gene', '2475', (142, 146))	('Genetic deficiency', 'Disease', 'MESH:D030342', (0, 18))	('PI3', 'Species', '1196084', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PTEN', 'Gene', (71, 75))	('tumor suppressor', 'Gene', (49, 65))	('PTEN', 'Gene', '5728', (71, 75))	('Genetic deficiency', 'Disease', (0, 18))	('inactivation', 'Var', (33, 45))
285634	29660202	Hernando et al reported abnormalities of the PI3K-AKT signaling pathway in many LMS.	('PI3K-AKT signaling pathway', 'Pathway', (45, 71))	('PI3', 'Species', '1196084', (45, 48))	('LMS', 'Disease', (80, 83))	('abnormalities', 'Var', (24, 37))
285641	29660202	It has also been reported that an abnormality in this pathway is an obvious factor related to poor prognosis.17  Many studies have shown that the frequencies of TP53 mutation in uterine leiomyoma (u-LM), smooth muscle tumor of uncertain malignant potential (STUMP) and u-LMS are 0%, 6%-29% and 24%-30%, respectively.	('muscle tumor', 'Disease', 'MESH:D009217', (211, 223))	('TP53', 'Gene', (161, 165))	('muscle tumor', 'Disease', (211, 223))	('leiomyoma', 'Disease', (186, 195))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (178, 195))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('leiomyoma', 'Disease', 'MESH:D007889', (186, 195))	('TP53', 'Gene', '7157', (161, 165))	('mutation', 'Var', (166, 174))
285642	29660202	It has also been reported that the frequencies of PTEN mutation are 5%, 33% and 42%-58%, respectively.21 However, u-LMS has shown a lower frequency of TP53 mutation, higher expression of MDM2, and a higher TP53/MDM2 ratio than the other sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (237, 245))	('higher', 'PosReg', (166, 172))	('TP53', 'Gene', '7157', (206, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('TP53', 'Gene', (206, 210))	('sarcomas', 'Phenotype', 'HP:0100242', (237, 245))	('TP53', 'Gene', (151, 155))	('expression', 'MPA', (173, 183))	('higher', 'PosReg', (199, 205))	('PTEN', 'Gene', (50, 54))	('sarcomas', 'Disease', (237, 245))	('PTEN', 'Gene', '5728', (50, 54))	('u-LMS', 'Disease', (114, 119))	('MDM2', 'Protein', (187, 191))	('lower', 'NegReg', (132, 137))	('TP53', 'Gene', '7157', (151, 155))	('mutation', 'Var', (156, 164))
285648	29660202	Makinen et al observed a mutation in MED12 that resides on the long arm of the X chromosome (Xq13.1.)	('MED12', 'Gene', (37, 42))	('mutation', 'Var', (25, 33))	('MED12', 'Gene', '9968', (37, 42))
285649	29660202	MED12 is known to be involved in p53 and Wnt/beta-catenin pathways.26 Interestingly, in vitro study of u-LM has shown that the u-LM cells with MED12 mutation grow poorly in culture and cannot be maintained through passage.27  In 2012, the same research group demonstrated that, albeit at low frequencies, MED12 mutations are observed in u-LMS, as well as u-LM, while no mutations were found in other sarcomas or in gastrointestinal stromal tumors (GIST), suggesting that a subgroup of u-LMS may develop from an LM precursor.	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (415, 446))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (415, 446))	('mutations', 'Var', (311, 320))	('MED12', 'Gene', '9968', (0, 5))	('MED12', 'Gene', (305, 310))	('MED12', 'Gene', '9968', (143, 148))	('beta-catenin', 'Gene', (45, 57))	('gastrointestinal stromal tumors', 'Disease', (415, 446))	('beta-catenin', 'Gene', '1499', (45, 57))	('sarcomas', 'Disease', 'MESH:D012509', (400, 408))	('MED12', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (440, 446))	('u-LMS', 'Disease', (337, 342))	('sarcomas', 'Phenotype', 'HP:0100242', (400, 408))	('sarcomas', 'Disease', (400, 408))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('MED12', 'Gene', '9968', (305, 310))	('MED12', 'Gene', (143, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (400, 407))
285651	29660202	They postulated that MED12 could be a tumor suppressor gene, and that MED12 protein expression inhibits LMS oncogenesis.29 Schwetye et al compared the frequencies of MED12 gene mutations among normal myometrium adjacent to LM, pelvic LM and extrauterine LM.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('MED12', 'Gene', '9968', (166, 171))	('mutations', 'Var', (177, 186))	('MED12', 'Gene', (21, 26))	('MED12', 'Gene', (166, 171))	('tumor suppressor', 'Gene', (38, 54))	('MED12', 'Gene', (70, 75))	('MED12', 'Gene', '9968', (21, 26))	('MED12', 'Gene', '9968', (70, 75))	('tumor suppressor', 'Gene', '7248', (38, 54))
285652	29660202	MED12 mutations were detected in 54% of u-LM, 15% of cases in myometrium adjacent to LM, and 0% of extrauterine LM.	('MED12', 'Gene', (0, 5))	('MED12', 'Gene', '9968', (0, 5))	('u-LM', 'Disease', (40, 44))	('detected', 'Reg', (21, 29))	('mutations', 'Var', (6, 15))
285653	29660202	Moreover, MED12 mutations were also detected in 30% of u-LMS compared with 4% of extrauterine LMS, suggesting that smooth muscle tumors in pelvic/retroperitoneal sites are subject to the same mutational changes as those of uterine myometrium.30 Recently, Zhang et al showed the frequencies of MED12, TP53 or PTEN mutations in LM, mitotically active LM, cellular LM, atypical LM, STUMP and u-LMS.	('MED12', 'Gene', (293, 298))	('mitotically active LM', 'Disease', (330, 351))	('muscle tumors', 'Disease', (122, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('MED12', 'Gene', '9968', (293, 298))	('TP53', 'Gene', '7157', (300, 304))	('TP53', 'Gene', (300, 304))	('MED12', 'Gene', (10, 15))	('PTEN', 'Gene', (308, 312))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('u-LMS', 'Disease', (389, 394))	('atypical LM', 'Disease', (366, 377))	('PTEN', 'Gene', '5728', (308, 312))	('STUMP', 'Disease', (379, 384))	('MED12', 'Gene', '9968', (10, 15))	('cellular LM', 'Disease', (353, 364))	('mutations', 'Var', (313, 322))	('muscle tumors', 'Disease', 'MESH:D009217', (122, 135))
285654	29660202	STUMP and atypical LM were more similar to LMS, with high frequencies of TP53 and PTEN mutations and low frequencies of MED12 mutation.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('MED12', 'Gene', (120, 125))	('MED12', 'Gene', '9968', (120, 125))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))	('mutations', 'Var', (87, 96))
285657	29660202	Because u-LM is related to familial hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome, heterozygous germ-line mutations in fumarate hydratase (FH), which is a tumor suppressor and encodes fumarase of the tricarboxylic acid cycle, has been reported to be related to the development of u-LM.32 Recent studies have shown that a kind of u-LMS can be derived from the precursor lesion of u-LM based on the examination of 3 driver genes, MED12, HMGA 2 and FH.33  Based on several studies, MED12 mutation is also observed in u-LMS, while it is more frequent in u-LM than in u-LMS.	('familial hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome', 'Disease', 'MESH:C535516', (27, 100))	('MED12', 'Gene', (498, 503))	('mutation', 'Var', (504, 512))	('tumor suppressor', 'Gene', (174, 190))	('HMGA 2', 'Gene', '8091', (454, 460))	('renal cell cancer', 'Phenotype', 'HP:0005584', (66, 83))	('fumarase', 'Gene', (203, 211))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('u-LMS', 'Disease', (533, 538))	('HMGA 2', 'Gene', (454, 460))	('MED12', 'Gene', (447, 452))	('FH', 'Gene', '2271', (465, 467))	('tumor suppressor', 'Gene', '7248', (174, 190))	('fumarate hydratase', 'Gene', (138, 156))	('MED12', 'Gene', '9968', (498, 503))	('fumarase', 'Gene', '2271', (203, 211))	('observed', 'Reg', (521, 529))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('fumarate hydratase', 'Gene', '2271', (138, 156))	('MED12', 'Gene', '9968', (447, 452))	('FH', 'Gene', '2271', (158, 160))
285658	29660202	MED12 mutations are rarely observed in other sarcomas or in GIST, as well as extrauterine LMS,29, 30 suggesting that MED12 can be a useful biomarker to diagnose uterine-derived LMS, although it is difficult to distinguish between u-LM and u-LMS only by examination of MED12 mutation.	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('MED12', 'Gene', '9968', (117, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcomas', 'Disease', (45, 53))	('MED12', 'Gene', (0, 5))	('MED12', 'Gene', (117, 122))	('uterine-derived LMS', 'Disease', (161, 180))	('MED12', 'Gene', (268, 273))	('MED12', 'Gene', '9968', (0, 5))	('mutations', 'Var', (6, 15))	('MED12', 'Gene', '9968', (268, 273))
285664	29660202	TP53 and ATRX mutations can be important mechanisms in the pathogenesis of u-LMS and are correlated with a poor prognosis.39  The Cancer Genome Atlas indicated that high miR-181b was more common in u-LMS and was an independent predictor of recurrence-free survival in a multivariate model, including tumor size.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('TP53', 'Gene', '7157', (0, 4))	('ATRX', 'Gene', '546', (9, 13))	('TP53', 'Gene', (0, 4))	('Cancer Genome Atlas', 'Disease', (130, 149))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (300, 305))	('high miR-181b', 'Var', (165, 178))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (130, 149))	('common', 'Reg', (188, 194))	('miR-181b', 'Var', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('ATRX', 'Gene', (9, 13))	('u-LMS', 'Disease', (198, 203))
285669	29660202	In contrast, in LMS as a whole, aberrant PI3K-AKT-mTOR signaling may be crucial, given recurrent deletion/mutation of PTEN.	('PI3', 'Species', '1196084', (41, 44))	('mTOR', 'Gene', (50, 54))	('PTEN', 'Gene', '5728', (118, 122))	('mTOR', 'Gene', '2475', (50, 54))	('PTEN', 'Gene', (118, 122))	('deletion/mutation', 'Var', (97, 114))
285675	29660202	Based on 2014 WHO classification, LG-ESS is often associated with gene rearrangement bringing about the JAZF 1-SUZ12 (formerly JAZF1-JJAZ1) fusion gene, whereas HG-ESS is associated with the YWHAE-NUTM fusion gene.	('JAZF1', 'Gene', '221895', (127, 132))	('fusion', 'Var', (140, 146))	('JAZF 1', 'Gene', '221895', (104, 110))	('gene rearrangement', 'Var', (66, 84))	('LG-ESS', 'Chemical', '-', (34, 40))	('YWHAE', 'Gene', '7531', (191, 196))	('JAZF1', 'Gene', (127, 132))	('SUZ12', 'Gene', (111, 116))	('JJAZ1', 'Gene', '23512', (133, 138))	('SUZ12', 'Gene', '23512', (111, 116))	('JJAZ1', 'Gene', (133, 138))	('associated', 'Reg', (50, 60))	('LG-ESS', 'Disease', (34, 40))	('YWHAE', 'Gene', (191, 196))	('JAZF 1', 'Gene', (104, 110))
285676	29660202	LG-ESS with JAZF1 rearrangement may correlate with metastasis.	('metastasis', 'CPA', (51, 61))	('JAZF1', 'Gene', (12, 17))	('correlate', 'Reg', (36, 45))	('rearrangement', 'Var', (18, 31))	('JAZF1', 'Gene', '221895', (12, 17))	('LG-ESS', 'Chemical', '-', (0, 6))
285678	29660202	However, LG-ESS is characterized by late recurrences even in patients with stage I disease, suggesting the need for long-term follow-up.2 In an in vitro study, Quan et al47 found that the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA) combined with inhibition of PI3K (LY294002, LY) and mammalian target of rapamycin (mTOR) led to the strongest growth inhibition and slowest growth recovery in an ESS cell line.	('LY294002', 'Var', (292, 300))	('slowest', 'NegReg', (390, 397))	('mTOR', 'Gene', (341, 345))	('mTOR', 'Gene', '2475', (341, 345))	('SAHA', 'Chemical', 'MESH:D000077337', (252, 256))	('patients', 'Species', '9606', (61, 69))	('Quan', 'Species', '1196084', (160, 164))	('PI3', 'Species', '1196084', (286, 289))	('slowest growth', 'Phenotype', 'HP:0001510', (390, 404))	('growth recovery', 'CPA', (398, 413))	('growth inhibition', 'CPA', (368, 385))	('LG-ESS', 'Chemical', '-', (9, 15))	('mammalian target of rapamycin', 'Gene', '2475', (310, 339))	('mammalian target of rapamycin', 'Gene', (310, 339))	('suberanilohydroxamic acid', 'Chemical', 'MESH:D000077337', (225, 250))
285680	29660202	Based on the growing evidence, LG-ESS is classified into 3 categories based on molecular genetic abnormalities: translocation t(7;17) (p15;q21); 6p21-rearrangements; and X;22 or 17-rearrangements.	('LG-ESS', 'Disease', (31, 37))	('genetic abnormalities', 'Disease', 'MESH:D030342', (89, 110))	('X;22 or 17-rearrangements', 'Var', (170, 195))	('p21', 'Gene', '1026', (146, 149))	('p21', 'Gene', (146, 149))	('genetic abnormalities', 'Disease', (89, 110))	('LG-ESS', 'Chemical', '-', (31, 37))	('p15', 'Gene', (135, 138))	('p15', 'Gene', '1030', (135, 138))
285685	29660202	In an update based on 2014 WHO classification, LG-ESS is often associated with gene rearrangement bringing about the JAZF 1-SUZ12 fusion gene, whereas HG-ESS is associated with the YWHAE-NUTM fusion gene, suggesting that LG-ESS and HG-ESS are independent units.46 Clinically, HG-ESS shows more malignant potential than LG-ESS.	('malignant potential', 'CPA', (294, 313))	('LG-ESS', 'Chemical', '-', (221, 227))	('YWHAE', 'Gene', (181, 186))	('LG-ESS', 'Chemical', '-', (47, 53))	('JAZF 1', 'Gene', '221895', (117, 123))	('LG-ESS', 'Chemical', '-', (319, 325))	('gene rearrangement', 'Var', (79, 97))	('HG-ESS', 'Disease', (276, 282))	('associated', 'Reg', (63, 73))	('SUZ12', 'Gene', '23512', (124, 129))	('SUZ12', 'Gene', (124, 129))	('YWHAE', 'Gene', '7531', (181, 186))	('JAZF 1', 'Gene', (117, 123))
285856	24416489	For DMFS, tumor size less than 6 cm, WHO performance score 0, superficial tumors, stage II or less, histological grade 2 or less, and radical surgery were favorable factors (Supplementary Table 1).	('superficial', 'Disease', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('DMFS', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (10, 15))	('DMFS', 'Chemical', '-', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('men', 'Species', '9606', (180, 183))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
285860	24416489	For DMFS, tumor size, tumor depth, histological grade, and radical surgery were significant (Supplementary Table 3).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('DMFS', 'Var', (4, 8))	('tumor', 'Disease', (10, 15))	('DMFS', 'Chemical', '-', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('men', 'Species', '9606', (99, 102))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
285974	20349325	No increase in tumors or tissue proliferation was observed following N-ethyl N-nitrosourea exposure or following tail wounding and subsequent tissue regeneration compared to controls.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('N-ethyl N-nitrosourea', 'Var', (69, 90))	('N-ethyl N-nitrosourea', 'Chemical', 'MESH:D005038', (69, 90))	('tissue proliferation', 'CPA', (25, 45))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
285992	20349325	Plasmids pKH3orfA, which expresses WDSV rv-cyclin (OrfA) with an N-terminal HA tag from a CMV promoter, and pcDNA3.1orfA have been previously characterized.	('WDSV', 'Species', '39720', (35, 39))	('cyclin', 'Gene', (43, 49))	('WDSV', 'Var', (35, 39))	('cyclin', 'Gene', '18538', (43, 49))
286024	20349325	One-month-old rv-cyclin transgenic, GFP transgenic, or control zebrafish was treated with 3.0 mM ENU at 25 C for 1 h every 3 days, for a total of three treatments.	('ENU', 'Chemical', 'MESH:D005038', (97, 100))	('zebrafish', 'Species', '7955', (63, 72))	('transgenic', 'Species', '10090', (40, 50))	('cyclin', 'Gene', '18538', (17, 23))	('cyclin', 'Gene', (17, 23))	('transgenic', 'Species', '10090', (24, 34))	('transgenic', 'Var', (24, 34))
286040	20349325	Over a 4-day period, there appeared to be a slight increase in lethality in embryos expressing rv-cyclin (12% day 1; 16% day 4) from the CMVtk promoter; however, lethality was not statistically higher in embryos injected with CMVtk rv-cyclin compared to embryos injected with control constructs at any time point (Fisher's exact test) (Fig.	('cyclin', 'Gene', '18538', (235, 241))	('cyclin', 'Gene', (235, 241))	('cyclin', 'Gene', '18538', (98, 104))	('lethality', 'MPA', (63, 72))	('cyclin', 'Gene', (98, 104))	('CMVtk', 'Var', (226, 231))
286064	20349325	Rv-cyclin protein was detected in CMVtk rv-cyclin transgenic zebrafish by immunohistochemistry of transverse sections of caudal tail region.	('CMVtk', 'Var', (34, 39))	('cyclin', 'Gene', '18538', (43, 49))	('cyclin', 'Gene', (43, 49))	('caudal tail', 'Phenotype', 'HP:0002825', (121, 132))	('transgenic', 'Species', '10090', (50, 60))	('cyclin', 'Gene', '18538', (3, 9))	('cyclin', 'Gene', (3, 9))	('zebrafish', 'Species', '7955', (61, 70))
286065	20349325	In rv-cyclin transgenic zebrafish, protein levels were highest in muscle and surface epithelium of the skin (Fig.	('zebrafish', 'Species', '7955', (24, 33))	('transgenic', 'Var', (13, 23))	('highest', 'PosReg', (55, 62))	('transgenic', 'Species', '10090', (13, 23))	('cyclin', 'Gene', '18538', (6, 12))	('cyclin', 'Gene', (6, 12))	('protein levels', 'MPA', (35, 49))
286077	20349325	Skin-specific expression of WDSV rv-cyclin in a transgenic mouse model has been demonstrated to induce hyperplasia in response to wound healing.	('mouse', 'Species', '10090', (59, 64))	('hyperplasia', 'Disease', (103, 114))	('induce', 'Reg', (96, 102))	('cyclin', 'Gene', '18538', (36, 42))	('cyclin', 'Gene', (36, 42))	('response to wound healing', 'CPA', (118, 143))	('WDSV', 'Var', (28, 32))	('WDSV', 'Species', '39720', (28, 32))	('hyperplasia', 'Disease', 'MESH:D006965', (103, 114))	('transgenic', 'Species', '10090', (48, 58))
286103	20349325	In tumor-prone zebrafish mutants, cancer incidence is close to 30%.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutants', 'Var', (25, 32))	('tumor', 'Disease', (3, 8))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('zebrafish', 'Species', '7955', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
286104	20349325	Lastly, it is possible that genome duplication before the teleost radiation may provide a degree of redundancy in tumor suppressor loci that make zebrafish more resistant to cancer.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('zebrafish', 'Species', '7955', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('genome duplication', 'Var', (28, 46))	('cancer', 'Disease', (174, 180))	('tumor', 'Disease', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('resistant', 'CPA', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('more', 'PosReg', (156, 160))
286105	20349325	Although the causal role of WDSV in dermal sarcoma development has not been conclusively established, there is substantial evidence that rv-cyclin interacts with host proteins involved in cell cycle progression and transcription, the dysregulation of which may be involved in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('dermal sarcoma', 'Disease', (36, 50))	('cyclin', 'Gene', (140, 146))	('dysregulation', 'Var', (234, 247))	('dermal sarcoma', 'Disease', 'MESH:D012509', (36, 50))	('tumor', 'Disease', (276, 281))	('cyclin', 'Gene', '18538', (140, 146))	('involved', 'Reg', (264, 272))	('WDSV', 'Species', '39720', (28, 32))	('interacts', 'Interaction', (147, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
286124	22328909	Molecular analyses have revealed a variety of genetic alterations in osteosarcoma, including inactivation of p53 and retinoblastoma (Rb) tumor suppressor genes and overexpression of oncogenes such as MDM2.	('MDM2', 'Gene', (200, 204))	('tumor', 'Disease', (137, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('osteosarcoma', 'Disease', (69, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('inactivation', 'Var', (93, 105))	('retinoblastoma', 'Phenotype', 'HP:0009919', (117, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('overexpression', 'PosReg', (164, 178))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('p53 and retinoblastoma (Rb)', 'Gene', '7157;5925', (109, 136))	('p53 and retinoblastoma (Rb', 'Gene', (109, 135))	('MDM2', 'Gene', '4193', (200, 204))
286125	22328909	For example, alterations of the RB1 gene have been shown in up to 70% of reported cases, and loss of heterozygosity for RB1 has been shown to be a marker of poor prognosis.	('RB1', 'Gene', '5925', (120, 123))	('RB1', 'Gene', (32, 35))	('loss of heterozygosity', 'Var', (93, 115))	('RB1', 'Gene', '5925', (32, 35))	('alterations', 'Var', (13, 24))	('RB1', 'Gene', (120, 123))
286127	22328909	Osteosarcoma is the second most common malignancy associated with Li-Fraumeni syndrome characterized by p53 mutations at chromosome 17p13 and the development of numerous and varied cancers.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (66, 86))	('p53', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('p53', 'Gene', '7157', (104, 107))	('Li-Fraumeni syndrome', 'Disease', (66, 86))	('malignancy', 'Disease', 'MESH:D009369', (39, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('Osteosarcoma', 'Disease', (0, 12))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('malignancy', 'Disease', (39, 49))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))	('mutations at', 'Var', (108, 120))
286174	22328909	Altered mTOR signaling has been demonstrated in various malignancies and has been linked to a worse prognosis in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('mTOR', 'Gene', '2475', (8, 12))	('Altered', 'Var', (0, 7))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('mTOR', 'Gene', (8, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('linked', 'Reg', (82, 88))	('osteosarcoma', 'Disease', (113, 125))	('malignancies', 'Disease', (56, 68))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))
286176	22328909	In fact, in one phase II trial, partial response or stability was demonstrated in 30% of patients treated with AP23573, an analogue of rapamycin.	('rapamycin', 'Chemical', 'MESH:D020123', (135, 144))	('AP23573', 'Var', (111, 118))	('stability', 'MPA', (52, 61))	('patients', 'Species', '9606', (89, 97))	('AP23573', 'Chemical', 'MESH:C515074', (111, 118))
286183	22328909	Thus dysregulation of IGF-1 and its receptor might be involved in osteosarcomagenesis.	('dysregulation', 'Var', (5, 18))	('IGF-1', 'Gene', '3479', (22, 27))	('IGF-1', 'Gene', (22, 27))	('osteosarcomagenesis', 'Disease', 'None', (66, 85))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('osteosarcomagenesis', 'Disease', (66, 85))	('involved', 'Reg', (54, 62))
286191	22328909	MTP-PE is believed to activate macrophages and monocytes against nearby tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('MTP-PE', 'Var', (0, 6))	('macrophages', 'CPA', (31, 42))	('tumor', 'Disease', (72, 77))	('MTP-PE', 'Chemical', 'MESH:C037144', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('activate', 'PosReg', (22, 30))
286192	22328909	MTP-PE has been shown to have a positive impact on survival when given in combination with standard chemotherapy in non-metastatic patients.	('patients', 'Species', '9606', (131, 139))	('survival', 'CPA', (51, 59))	('MTP-PE', 'Var', (0, 6))	('MTP-PE', 'Chemical', 'MESH:C037144', (0, 6))
286216	22328909	p53 and RB alterations appear to be more correlated with high grade chondrosarcomas with approximately 96% having involvement of one or the other.	('p53', 'Gene', (0, 3))	('alterations', 'Var', (11, 22))	('p53', 'Gene', '7157', (0, 3))	('chondrosarcomas', 'Disease', 'MESH:D002813', (68, 83))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (68, 82))	('chondrosarcomas', 'Disease', (68, 83))	('RB', 'Disease', 'MESH:D012175', (8, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (68, 83))	('correlated', 'Reg', (41, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
286217	22328909	In support of this, amplifications of 12q13 and loss of 9p21 both associated with p53 pathways, are seen consistently in chondrosarcoma Loss of INK4, which inhibits the cell cycle by causing arrest at G1, has also been associated with increasing histologic grade.	('loss', 'Var', (48, 52))	('INK4', 'Gene', '1029', (144, 148))	('INK4', 'Gene', (144, 148))	('amplifications', 'Var', (20, 34))	('associated', 'Reg', (66, 76))	('causing', 'Reg', (183, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('inhibits', 'NegReg', (156, 164))	('arrest at G1', 'CPA', (191, 203))	('chondrosarcoma Loss', 'Disease', (121, 140))	('cell cycle', 'CPA', (169, 179))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('chondrosarcoma Loss', 'Disease', 'MESH:D002813', (121, 140))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (121, 135))
286218	22328909	CDK4 has also been implicated as a driver of chondrosarcomagenesis and its knockdown by short hairpin RNAs have resulted in decreased colony formation in culture.	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('chondrosarcomagenesis', 'Disease', 'None', (45, 66))	('decreased', 'NegReg', (124, 133))	('knockdown', 'Var', (75, 84))	('chondrosarcomagenesis', 'Disease', (45, 66))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (45, 59))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))	('colony formation in culture', 'CPA', (134, 161))
286219	22328909	Some have suggested an epigenetic component to the pathogenesis of chondrosarcoma.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (67, 81))	('chondrosarcoma', 'Disease', 'MESH:D002813', (67, 81))	('epigenetic', 'Var', (23, 33))	('chondrosarcoma', 'Disease', (67, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
286273	22328909	However, CD99 is not specific to Ewing's sarcoma and is seen in various other malignancies such as lymphomas, leukemias and rhabdomyosarcoma.	('lymphomas', 'Phenotype', 'HP:0002665', (99, 108))	('CD99', 'Var', (9, 13))	('leukemias', 'Phenotype', 'HP:0001909', (110, 119))	('lymphomas', 'Disease', 'MESH:D008223', (99, 108))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (33, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('malignancies', 'Disease', (78, 90))	('seen', 'Reg', (56, 60))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (124, 140))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (33, 48))	('leukemias and rhabdomyosarcoma', 'Disease', 'MESH:D012208', (110, 140))	('lymphomas', 'Disease', (99, 108))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	("Ewing's sarcoma", 'Disease', (33, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
286280	22328909	More recently, using a tetracycline-inducible EWS-FLI1 expression system in a rhabdomyosarcoma cell line, it has been shown that the presence of EWS/FLI induces the expression of genes normally associated with neural crest development.	('FLI', 'Gene', (50, 53))	('rhabdomyosarcoma', 'Disease', (78, 94))	('expression', 'MPA', (165, 175))	('induces', 'PosReg', (153, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('FLI1', 'Gene', '2313', (50, 54))	('FLI', 'Gene', '2314', (149, 152))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (78, 94))	('FLI1', 'Gene', (50, 54))	('FLI', 'Gene', (149, 152))	('presence', 'Var', (133, 141))	('tetracycline', 'Chemical', 'MESH:D013752', (23, 35))	('FLI', 'Gene', '2314', (50, 53))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (78, 94))
286317	22328909	Further, it has been shown that administration of EWS/FLI-1 antisense oligonucleotides and rapamycin induced apotosis of Ewings cells in culture.	('oligonucleotides', 'Chemical', 'MESH:D009841', (70, 86))	('apotosis of Ewings', 'Disease', (109, 127))	('rapamycin', 'Chemical', 'MESH:D020123', (91, 100))	('FLI-1', 'Gene', '2313', (54, 59))	('FLI-1', 'Gene', (54, 59))	('apotosis of Ewings', 'Disease', 'MESH:C563168', (109, 127))	('antisense oligonucleotides', 'Var', (60, 86))
286330	22328909	Rocchi et al, in knockdown experiments using Ewing's sarcoma cell lines, demonstrated that knockdown of CD99 resulted in decreased cell growth as well as smaller tumors with fewer metastases in a mouse model.	('smaller', 'NegReg', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (45, 60))	('cell growth', 'CPA', (131, 142))	('mouse', 'Species', '10090', (196, 201))	("Ewing's sarcoma", 'Disease', (45, 60))	('metastases', 'Disease', 'MESH:D009362', (180, 190))	('CD99', 'Gene', (104, 108))	('knockdown', 'Var', (91, 100))	('decreased', 'NegReg', (121, 130))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (45, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('metastases', 'Disease', (180, 190))
286339	32559641	MDM2 amplification and fusion gene ss18-ssx in a poorly differentiated synovial sarcoma: A rare but puzzling conjunction The detection of specific alterations by genetic analyses has been included in the diagnostic criterions of the World Health Organization's classification of soft tissues tumors since 2013.	('ssx', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumors', 'Disease', (292, 298))	('synovial sarcoma', 'Disease', (71, 87))	('amplification', 'Var', (5, 18))	('ssx', 'Gene', '6757', (40, 43))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('ss18', 'Gene', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('MDM2', 'Gene', '4193', (0, 4))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (71, 87))	('synovial sarcoma', 'Disease', 'MESH:D013584', (71, 87))	('MDM2', 'Gene', (0, 4))	('ss18', 'Gene', '6760', (35, 39))
286340	32559641	The presence of a SS18 rearrangement is pathognomonic of synovial sarcoma (SS).	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('synovial sarcoma', 'Disease', (57, 73))	('rearrangement', 'Var', (23, 36))	('SS18', 'Gene', '6760', (18, 22))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (57, 73))	('synovial sarcoma', 'Disease', 'MESH:D013584', (57, 73))	('presence', 'Var', (4, 12))	('SS18', 'Gene', (18, 22))
286341	32559641	MDM2 amplification is strongly correlated to well-differentiated or dedifferentiated liposarcoma (DDLPS) in the context of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('liposarcoma', 'Disease', (85, 96))	('amplification', 'Var', (5, 18))	('correlated to', 'Reg', (31, 44))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('MDM2', 'Gene', '4193', (0, 4))	('liposarcoma', 'Disease', 'MESH:D008080', (85, 96))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('sarcoma', 'Disease', (89, 96))	('MDM2', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('sarcoma', 'Disease', (123, 130))
286342	32559641	We identified one case of poorly differentiated sarcoma harboring both SS18-SSX2 fusion and MDM2 amplification.	('SS18', 'Gene', '6760', (71, 75))	('fusion', 'Var', (81, 87))	('MDM2', 'Gene', '4193', (92, 96))	('SSX2', 'Gene', (76, 80))	('MDM2', 'Gene', (92, 96))	('sarcoma', 'Disease', (48, 55))	('SS18', 'Gene', (71, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('SSX2', 'Gene', '6757', (76, 80))	('sarcoma', 'Disease', 'MESH:D012509', (48, 55))
286343	32559641	The review of the literature showed high discrepancies, concerning the incidence of MDM2 amplification in SS: from 1.4% up to 40%.	('MDM2', 'Gene', (84, 88))	('SS', 'Disease', (106, 108))	('MDM2', 'Gene', '4193', (84, 88))	('amplification', 'Var', (89, 102))
286345	32559641	We performed a retrospective and prospective study in 96 sarcomas, (56 SS and 40 DDLPS), using FISH and/or array-CGH to detect MDM2 amplification and SS18 rearrangement.	('SS18', 'Gene', '6760', (150, 154))	('amplification', 'Var', (132, 145))	('MDM2', 'Gene', '4193', (127, 131))	('MDM2', 'Gene', (127, 131))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('SS18', 'Gene', (150, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcomas', 'Disease', (57, 65))
286347	32559641	We concluded that MDM2 amplification in SS is a very rare event.	('MDM2', 'Gene', (18, 22))	('amplification', 'Var', (23, 36))	('MDM2', 'Gene', '4193', (18, 22))
286349	32559641	If the detection of MDM2 amplification is performed first in a poorly differentiated sarcoma, that may lead to not search other anomalies such as SS18 rearrangement and therefore to an erroneous diagnosis.	('SS18', 'Gene', (146, 150))	('rearrangement', 'Var', (151, 164))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('MDM2', 'Gene', '4193', (20, 24))	('SS18', 'Gene', '6760', (146, 150))	('MDM2', 'Gene', (20, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcoma', 'Disease', (85, 92))	('amplification', 'Var', (25, 38))
286353	32559641	Conversely, Next Generation Sequencing (NGS) studies have increased the number of fusion genes related to a same tumor entity.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('fusion', 'Var', (82, 88))
286357	32559641	It results from the t(X;18)(p11;q11) that fuses SS18 either with SSX1 or with SSX2.	('SS18', 'Gene', (48, 52))	('SSX2', 'Gene', (78, 82))	('SS18', 'Gene', '6760', (48, 52))	('SSX1', 'Gene', '6756', (65, 69))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (20, 36))	('SSX1', 'Gene', (65, 69))	('fuses', 'Var', (42, 47))	('SSX2', 'Gene', '6757', (78, 82))
286364	32559641	Though it can be observed occasionally in STS, such as intimal sarcoma or paraosteal osteosarcoma, MDM2 amplification is strongly related to atypical lipomatous tumors (ALT), well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS).	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('lipomatous tumors', 'Disease', 'MESH:D008080', (150, 167))	('liposarcoma', 'Phenotype', 'HP:0012034', (236, 247))	('liposarcoma', 'Disease', (195, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('related', 'Reg', (130, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('MDM2', 'Gene', (99, 103))	('liposarcoma', 'Disease', 'MESH:D008080', (236, 247))	('lipomatous tumors', 'Disease', (150, 167))	('liposarcoma', 'Phenotype', 'HP:0012034', (195, 206))	('lipomatous tumors', 'Phenotype', 'HP:0012031', (150, 167))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))	('sarcoma', 'Disease', (90, 97))	('MDM2', 'Gene', '4193', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('sarcoma', 'Disease', 'MESH:D012509', (240, 247))	('liposarcoma', 'Disease', 'MESH:D008080', (195, 206))	('liposarcoma', 'Disease', (236, 247))	('amplification', 'Var', (104, 117))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('sarcoma', 'Disease', (240, 247))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('sarcoma', 'Disease', (199, 206))
286365	32559641	Whether the amplification of MDM2 is a recurrent or an exceptional feature of SS, has to be clearly and definitively established because of such a potential impact in molecular diagnosis.	('MDM2', 'Gene', '4193', (29, 33))	('amplification', 'Var', (12, 25))	('MDM2', 'Gene', (29, 33))
286377	32559641	Molecular analyses showed the presence of both SS18-SSX2 fusion and MDM2 amplification.	('SSX2', 'Gene', (52, 56))	('MDM2', 'Gene', '4193', (68, 72))	('MDM2', 'Gene', (68, 72))	('SSX2', 'Gene', '6757', (52, 56))	('SS18', 'Gene', (47, 51))	('SS18', 'Gene', '6760', (47, 51))	('amplification', 'Var', (73, 86))
286385	32559641	The SS18 rearrangement involved SSX1 in 26 cases, SSX2 in 15 cases and SSX4 in one case, respectively.	('SSX1', 'Gene', (32, 36))	('SSX4', 'Gene', '6759', (71, 75))	('SS18', 'Gene', '6760', (4, 8))	('SSX4', 'Gene', (71, 75))	('SSX2', 'Gene', (50, 54))	('SSX1', 'Gene', '6756', (32, 36))	('rearrangement', 'Var', (9, 22))	('SS18', 'Gene', (4, 8))	('involved', 'Reg', (23, 31))	('SSX2', 'Gene', '6757', (50, 54))
286398	32559641	Deletion was defined by a log2 ratio Cy5/Cy3 < - 0.4 and gains by a log2 ratio Cy3/Cy5 > 0.4.	('Cy5/Cy3 < - 0.4', 'Var', (37, 52))	('Cy5', 'Chemical', '-', (37, 40))	('gains', 'PosReg', (57, 62))	('Cy3', 'Chemical', '-', (41, 44))	('Cy3', 'Chemical', '-', (79, 82))	('Cy5', 'Chemical', '-', (83, 86))
286402	32559641	Labeling of tumor DNA by Cy5 and of reference DNA by Cy3 was followed by purification and co-hybridization in equal quantity on a genome-wide oligonucleotide-based microarray Sureprint G3 Human CGH 180 k (average resolution 13 kb) (Agilent, Santa Clara, CA).	('Human', 'Species', '9606', (188, 193))	('Cy3', 'Chemical', '-', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CGH 180 k', 'Var', (194, 203))	('oligonucleotide', 'Chemical', 'MESH:D009841', (142, 157))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Cy5', 'Chemical', '-', (25, 28))	('tumor', 'Disease', (12, 17))
286404	32559641	Gene amplification was defined by a log2 ratio Cy5/Cy3 > 1.1 and gain was defined by a log2 ratio Cy5/Cy3 between 0.2 and 1.1.	('gain', 'PosReg', (65, 69))	('Cy5/Cy3', 'Var', (47, 54))	('Cy3', 'Chemical', '-', (102, 105))	('Cy5', 'Chemical', '-', (47, 50))	('Cy5', 'Chemical', '-', (98, 101))	('Cy3', 'Chemical', '-', (51, 54))
286417	32559641	Moreover expression of SMARCB1 and H3K27me3 was conserved.	('H3K27me3', 'Var', (35, 43))	('SMARCB1', 'Gene', '6598', (23, 30))	('SMARCB1', 'Gene', (23, 30))
286427	32559641	The exploration analysis using four of five fusion-finder tools detected the same overexpressed fusion (Tools-Split/Span reads: TopHat fusion-292/5; Defuse-385/183; StarFusion-52/5; Fusion Catcher-27/434).	('fusion-292/5', 'Var', (135, 147))	('Defuse-385/183', 'Var', (149, 163))	('Star', 'Gene', '6770', (165, 169))	('Star', 'Gene', (165, 169))
286436	32559641	We concluded that the alteration surrounding SS18 was secondary to breakages generated by 18q amplification and was not related to an oncogenic SS18-SSX fusion gene.	('SS18', 'Gene', '6760', (45, 49))	('SS18', 'Gene', '6760', (144, 148))	('breakages', 'Var', (67, 76))	('18q amplification', 'Var', (90, 107))	('SS18', 'Gene', (144, 148))	('SS18', 'Gene', (45, 49))	('SSX', 'Gene', '6757', (149, 152))	('SSX', 'Gene', (149, 152))
286440	32559641	The clinical consequence of these mutations in the background of the SS18-SSX fusion is not clearly established yet.	('SSX', 'Gene', '6757', (74, 77))	('SSX', 'Gene', (74, 77))	('SS18', 'Gene', '6760', (69, 73))	('mutations', 'Var', (34, 43))	('SS18', 'Gene', (69, 73))
286442	32559641	Recent data showed that tumors harboring both fusion genes and genomic instability undergo an aggressive outcome.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('undergo', 'Reg', (83, 90))	('genomic instability', 'Var', (63, 82))	('fusion genes', 'Var', (46, 58))
286443	32559641	Genomic amplification is a remarkable genomic feature that can be a diagnostic marker when recurrent in a tumor type or a marker of instability and aggressiveness.	('Genomic amplification', 'Var', (0, 21))	('aggressiveness', 'Phenotype', 'HP:0000718', (148, 162))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('aggressiveness', 'Disease', 'MESH:D001523', (148, 162))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('aggressiveness', 'Disease', (148, 162))	('tumor', 'Disease', (106, 111))
286445	32559641	The frequency of this association of two alterations - i.e SS18 fusion and MDM2 amplification- individually known to be representative of a specific entity has to be determined.	('SS18', 'Gene', '6760', (59, 63))	('MDM2', 'Gene', '4193', (75, 79))	('MDM2', 'Gene', (75, 79))	('amplification-', 'Var', (80, 94))	('SS18', 'Gene', (59, 63))
286448	32559641	Indeed, the conjunction of SS18 rearrangement and MDM2 amplification raises diagnostic issues with consequences on decision-making and treatment strategies.	('MDM2', 'Gene', (50, 54))	('consequences', 'Reg', (99, 111))	('SS18', 'Gene', '6760', (27, 31))	('SS18', 'Gene', (27, 31))	('rearrangement', 'Var', (32, 45))	('MDM2', 'Gene', '4193', (50, 54))
286449	32559641	Notably, the finding of MDM2 amplification in a soft tissue tumor is never meaningless and deserves peculiar attention.	('amplification', 'Var', (29, 42))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MDM2', 'Gene', '4193', (24, 28))	('MDM2', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (48, 65))	('tumor', 'Disease', (60, 65))
286450	32559641	For instance, amplification and expression of MDM2 has been detected also in malignant peripheral nerve sheath tumor (MPNST), a tumor that can be hard to distinguish from both DDLPS and SS Makise et al.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('malignant peripheral nerve sheath tumor', 'Disease', (77, 116))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (77, 116))	('amplification', 'Var', (14, 27))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('detected', 'Reg', (60, 68))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (77, 116))	('tumor', 'Disease', (128, 133))	('expression', 'MPA', (32, 42))	('MDM2', 'Gene', '4193', (46, 50))	('MDM2', 'Gene', (46, 50))
286452	32559641	Indeed, PRC2 alteration leading to H3K27me3 deficiency has been reported as the molecular hallmark of MPNST.	('MPNST', 'Disease', (102, 107))	('alteration', 'Var', (13, 23))	('PRC2', 'Gene', (8, 12))	('deficiency', 'Disease', (44, 54))	('deficiency', 'Disease', 'MESH:D007153', (44, 54))
286459	32559641	In contrast to SS18-SSX fusion that has been described as fully specific of SS, MDM2 amplification has been reported in a variety of STS other than WDLPS/DDLPS and even in tumors other than STS.	('MDM2', 'Gene', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('WDLPS/DDLPS', 'Disease', (148, 159))	('tumors', 'Disease', (172, 178))	('SS18', 'Gene', (15, 19))	('reported', 'Reg', (108, 116))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('SSX', 'Gene', '6757', (20, 23))	('amplification', 'Var', (85, 98))	('SSX', 'Gene', (20, 23))	('SS18', 'Gene', '6760', (15, 19))	('MDM2', 'Gene', '4193', (80, 84))
286468	32559641	Since in routine practice multiple molecular analyses are not usually performed, the detection of MDM2 amplification is often done in priority in the context of a poorly differentiated sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('MDM2', 'Gene', '4193', (98, 102))	('MDM2', 'Gene', (98, 102))	('sarcoma', 'Disease', 'MESH:D012509', (185, 192))	('amplification', 'Var', (103, 116))	('sarcoma', 'Disease', (185, 192))
286475	32559641	Our study is, to the best of our knowledge, the only one to investigate specifically both SS18 rearrangements in DDLPS and MDM2 amplification in molecularly confirmed SS in a large series of patients.	('SS18', 'Gene', (90, 94))	('rearrangements', 'Var', (95, 109))	('patients', 'Species', '9606', (191, 199))	('MDM2', 'Gene', '4193', (123, 127))	('MDM2', 'Gene', (123, 127))	('SS18', 'Gene', '6760', (90, 94))
286627	30922296	Nonetheless, we documented a statistically significant increased risk of cancer in patients receiving haemodialysis, and an excess risk of borderline statistical significance in the remaining patients.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('haemodialysis', 'Var', (102, 115))	('patients', 'Species', '9606', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (83, 91))
286664	28484076	Numbers of AH1-specific CD8+ T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8+ T cells contributed to tumor eradication.	('increased', 'PosReg', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('AH1-specific', 'Gene', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('F8-TNF', 'Var', (85, 91))	('tumor', 'Disease', (169, 174))	('doxorubicin', 'Chemical', 'MESH:D004317', (97, 108))
286686	28484076	In particular, a strong activity in mouse models of sarcoma has been observed for TNF fusions to the F8 or the L19 antibody, specific to the alternatively-spliced EDA and EDB domains of fibronectin, respectively.	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('activity', 'MPA', (24, 32))	('EDA', 'Gene', '13607', (163, 166))	('sarcoma', 'Disease', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('EDA', 'Gene', (163, 166))	('fusions', 'Var', (86, 93))	('TNF', 'Gene', (82, 85))	('mouse', 'Species', '10090', (36, 41))
286689	28484076	Similarly, potent therapeutic activity in sarcoma has been reported for L19-TNF in combination with melphalan.	('sarcoma', 'Disease', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('L19-TNF', 'Var', (72, 79))	('therapeutic activity', 'MPA', (18, 38))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('melphalan', 'Chemical', 'MESH:D008558', (100, 109))
286690	28484076	The fully-human version of L19-TNF has been shown to be clinically active in isolated limb perfusion procedures and for the intralesional administration to patients with stage III melanoma.	('patients', 'Species', '9606', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('human', 'Species', '9606', (10, 15))	('rat', 'Species', '10116', (146, 149))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('L19-TNF', 'Var', (27, 34))	('active', 'MPA', (67, 73))	('isolated limb perfusion procedures', 'CPA', (77, 111))
286720	28484076	For immunofluorescence staining with H2-Ld tetramers, freshly frozen tissue sections were generated from F8-TNF/doxorubicin treated and saline treated mouse spleens from day 18 of the therapy, from tumors 48 h after the first injection and from spleens of healthy BALB/c mice.	('rat', 'Species', '10116', (94, 97))	('mice', 'Species', '10090', (271, 275))	('mouse', 'Species', '10090', (151, 156))	('saline', 'Chemical', 'MESH:D012965', (136, 142))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('mers', 'Species', '1335626', (48, 52))	('H2', 'Chemical', '-', (37, 39))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('F8-TNF/doxorubicin', 'Var', (105, 123))
286732	28484076	We used a hard-filtering strategy with the following criteria: DP>20, FS<30, QD>2.	('FS<30', 'Var', (70, 75))	('rat', 'Species', '10116', (27, 30))	('DP>20', 'Var', (63, 68))
286768	28484076	Exome sequencing of WEHI-164 was performed in order to identify mutations in protein coding regions of the DNA of the tumor cell line.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (118, 123))
286780	28484076	Tetramer analysis was performed with recombinant H-2Ld molecules loaded with AH1 (SPSYV-YHQF) or with p29 (YPNVNIHNF), an irrelevant peptide serving as negative control.	('AH1', 'Var', (77, 80))	('p29', 'Gene', '68592', (102, 105))	('p29', 'Gene', (102, 105))	('H-2Ld', 'Gene', (49, 54))
286783	28484076	Flow cytometry analysis revealed an expansion of AH1-specific CD8+ T cells in F8-TNF/doxorubicin treated mice compared to saline treated mice.	('doxorubicin', 'Chemical', 'MESH:D004317', (85, 96))	('AH1-specific', 'Gene', (49, 61))	('expansion', 'PosReg', (36, 45))	('mice', 'Species', '10090', (105, 109))	('mice', 'Species', '10090', (137, 141))	('saline', 'Chemical', 'MESH:D012965', (122, 128))	('F8-TNF/doxorubicin', 'Var', (78, 96))
286791	28484076	In order to learn about the dynamics of the T cell receptor (TCR) sequences as a result of the therapy intervention, CD8+ T cells were purified from spleens of mice treated with F8-TNF/doxorubicin or saline, 18 days after the start of therapy.	('T cell receptor', 'Gene', (44, 59))	('T cell receptor', 'Gene', '328483', (44, 59))	('F8-TNF/doxorubicin', 'Var', (178, 196))	('saline', 'Chemical', 'MESH:D012965', (200, 206))	('doxorubicin', 'Chemical', 'MESH:D004317', (185, 196))	('TCR', 'Gene', (61, 64))	('mice', 'Species', '10090', (160, 164))	('TCR', 'Gene', '328483', (61, 64))
286793	28484076	In total, 41200 +- 2571 and 46007 +- 25379 unique TCR-beta sequences were determined in the two study groups.	('46007 +- 25379', 'Var', (28, 42))	('TCR', 'Gene', '328483', (50, 53))	('TCR', 'Gene', (50, 53))
286794	28484076	The average number of productive TCR-beta sequence reads was 262318 +- 36756 for the treatment group and 1012046 +- 198544 for the saline treated group samples.	('262318 +- 36756', 'Var', (61, 76))	('TCR', 'Gene', (33, 36))	('saline', 'Chemical', 'MESH:D012965', (131, 137))	('TCR', 'Gene', '328483', (33, 36))	('1012046 +- 198544', 'Var', (105, 122))
286795	28484076	A significant increase in sequence diversity was observed for lymphocytes from the F8-TNF/doxorubicin group, as evidenced by using the Gini coefficient (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (90, 101))	('F8-TNF/doxorubicin', 'Var', (83, 101))	('sequence diversity', 'MPA', (26, 44))	('increase', 'PosReg', (14, 22))
286801	28484076	Anthracyclines are commonly used for the first-line treatment of metastatic soft-tissue sarcomas in humans, but are rarely associated with objective responses and lead to median progression-free survival of approximately 4 months.	('sarcomas', 'Disease', (88, 96))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (76, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (76, 96))	('Anthracyclines', 'Var', (0, 14))	('humans', 'Species', '9606', (100, 106))
286806	28484076	It is often assumed that immune rejection of solid tumors relies on the recognition of mutated peptides presented on MHC class I by CD8+ T cells.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutated', 'Var', (87, 94))	('solid tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('peptides', 'Chemical', 'MESH:D010455', (95, 103))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))
286811	28484076	Flow cytometry analysis and the staining of spleen sections revealed a specific detection of SPSYVYHQF by CD8+ T cells, which had increased in number after cancer cure, while being largely undetectable before pharmacological intervention and in suitable negative controls.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('SPSYVYHQF', 'Disease', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CD8+', 'Var', (106, 110))
286817	28484076	As for self-peptides, thymic presentation of these retroviral products leads to immunological tolerance due to deletion of the respective TCR or BCR specificities.	('TCR', 'Gene', (138, 141))	('BCR', 'Gene', (145, 148))	('TCR', 'Gene', '328483', (138, 141))	('peptides', 'Chemical', 'MESH:D010455', (12, 20))	('immunological tolerance', 'CPA', (80, 103))	('deletion', 'Var', (111, 119))	('leads to', 'Reg', (71, 79))
286827	28484076	Encouraged by promising results in exploratory clinical trials in sarcoma patients, L19-TNF (a fully human fusion protein specific to the EDB domain of fibronectin) in combination with doxorubicin is about to enter Phase III clinical trials as a first-line treatment for different subtypes of soft-tissue sarcomas.	('sarcoma', 'Disease', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Disease', (305, 313))	('sarcoma', 'Disease', 'MESH:D012509', (305, 312))	('patients', 'Species', '9606', (74, 82))	('rat', 'Species', '10116', (40, 43))	('human', 'Species', '9606', (101, 106))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (293, 312))	('sarcoma', 'Disease', (305, 312))	('doxorubicin', 'Chemical', 'MESH:D004317', (185, 196))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('L19-TNF', 'Var', (84, 91))	('sarcomas', 'Disease', 'MESH:D012509', (305, 313))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))	('sarcomas', 'Phenotype', 'HP:0100242', (305, 313))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (293, 313))
286832	27548722	Silencing or stable inhibition of furin delayed tumor growth in Rh30 and RD xenografts in vivo, and was correlated with lower microvessel density.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('lower', 'NegReg', (120, 125))	('microvessel density', 'CPA', (126, 145))	('tumor', 'Disease', (48, 53))	('furin', 'Gene', (34, 39))	('Rh30', 'Gene', '6007', (64, 68))	('inhibition', 'NegReg', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Silencing', 'Var', (0, 9))	('delayed', 'NegReg', (40, 47))	('Rh30', 'Gene', (64, 68))
286833	27548722	Reduced furin activity also decreased migration and invasion abilities in vitro, and inhibition of furin in RMS cells diminished processing of IGF1R, VEGF-C, PDGF-B and MT1-MMP, leading to lower levels of mature proteins.	('VEGF-C', 'Gene', '7424', (150, 156))	('RMS', 'Phenotype', 'HP:0002859', (108, 111))	('PDGF-B', 'Gene', (158, 164))	('MT1-MMP', 'Gene', (169, 176))	('PDGF-B', 'Gene', '5155', (158, 164))	('processing', 'MPA', (129, 139))	('MT1-MMP', 'Gene', '4323', (169, 176))	('IGF1R', 'Gene', '3480', (143, 148))	('furin', 'Gene', (99, 104))	('activity', 'MPA', (14, 22))	('IGF1R', 'Gene', (143, 148))	('furin', 'Protein', (8, 13))	('diminished', 'NegReg', (118, 128))	('decreased', 'NegReg', (28, 37))	('lower', 'NegReg', (189, 194))	('levels of mature proteins', 'MPA', (195, 220))	('inhibition', 'Var', (85, 95))	('rat', 'Species', '10116', (41, 44))	('VEGF-C', 'Gene', (150, 156))
286836	27548722	They are usually cleaved at the general consensus motif R/K-Xn-R/K , where n = 0, 2, 4 or 6 and X rarely Cys or Pro.	('R/K-Xn-R/K', 'Var', (56, 66))	('Cys', 'Var', (105, 108))	('Cys', 'Chemical', 'MESH:D003545', (105, 108))
286838	27548722	Consequently, deregulated activity of PCs has been associated with pathological conditions like Alzheimer's disease, endocrinopathies or cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (96, 115))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (96, 115))	("Alzheimer's disease", 'Disease', (96, 115))	('PCs', 'Gene', (38, 41))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('associated', 'Reg', (51, 61))	('deregulated', 'Var', (14, 25))	('endocrinopathies', 'Disease', (117, 133))	('cancer', 'Disease', (137, 143))	('endocrinopathies', 'Disease', 'MESH:C567425', (117, 133))
286843	27548722	In a previous study, we identified cell surface furin as potential receptor for peptides that specifically homed to rhabdomyosarcoma (RMS) cells in vitro and in vivo.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (116, 132))	('RMS', 'Phenotype', 'HP:0002859', (134, 137))	('peptides', 'Var', (80, 88))	('homed', 'MPA', (107, 112))	('rhabdomyosarcoma', 'Disease', (116, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (116, 132))
286878	27548722	qRT-PCR detection of furin, alpha1-PDX and the house keeping gene GAPDH was performed with assay-on-demand Hs00965485_g1, Hs01097800_m1 or Hs99999905_m1, respectively (Applied Biosystems, Basel, Switzerland), and normalized to GAPDH.	('GAPDH', 'Gene', '2597', (227, 232))	('GAPDH', 'Gene', '2597', (66, 71))	('GAPDH', 'Gene', (227, 232))	('GAPDH', 'Gene', (66, 71))	('Hs01097800_m1', 'Var', (122, 135))	('Hs00965485_g1', 'Var', (107, 120))	('Hs99999905_m1', 'Var', (139, 152))
286920	27548722	Moreover, furin silencing and inhibition led to delayed tumor onset rather than to a complete tumor growth inhibition, hinting at a role of furin in early steps of tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (164, 169))	('furin', 'Protein', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('inhibition', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (56, 61))	('silencing', 'NegReg', (16, 25))	('tumor', 'Disease', (94, 99))	('rat', 'Species', '10116', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
286932	27548722	In contrast, inhibition of furin activity through expression of pdx or decreased expression by silencing of furin resulted in delayed wound closure for both Rh30 and RD cells.	('Rh30', 'Gene', (157, 161))	('pdx', 'Gene', (64, 67))	('delayed wound closure', 'Phenotype', 'HP:0000270', (126, 147))	('wound closure', 'CPA', (134, 147))	('delayed', 'NegReg', (126, 133))	('furin', 'Gene', (108, 113))	('activity', 'MPA', (33, 41))	('Rh30', 'Gene', '6007', (157, 161))	('silencing', 'Var', (95, 104))	('furin', 'Enzyme', (27, 32))	('inhibition', 'NegReg', (13, 23))	('decreased', 'NegReg', (71, 80))	('expression', 'MPA', (81, 91))
286947	27548722	Conversely, a decrease of furin activity, either by expression of the inhibitor pdx or by silencing of furin, led to an accumulation of IGF1Rbeta precursor and lower levels of mature IGF1Rbeta (Fig 5B).	('IGF1R', 'Gene', (183, 188))	('accumulation', 'PosReg', (120, 132))	('silencing', 'Var', (90, 99))	('furin', 'Gene', (103, 108))	('IGF1R', 'Gene', '3480', (183, 188))	('IGF1R', 'Gene', (136, 141))	('activity', 'MPA', (32, 40))	('IGF1R', 'Gene', '3480', (136, 141))	('decrease', 'NegReg', (14, 22))	('pdx', 'Gene', (80, 83))	('furin', 'Protein', (26, 31))	('lower', 'NegReg', (160, 165))
286949	27548722	As expected, silencing of furin severely impaired maturation of IGF1Rbeta, leading to a decrease in mature form and accumulation of IGF1Rbeta proform.	('accumulation', 'PosReg', (116, 128))	('decrease', 'NegReg', (88, 96))	('IGF1R', 'Gene', (132, 137))	('IGF1R', 'Gene', '3480', (132, 137))	('mature', 'MPA', (100, 106))	('rat', 'Species', '10116', (54, 57))	('IGF1R', 'Gene', (64, 69))	('maturation', 'MPA', (50, 60))	('impaired', 'NegReg', (41, 49))	('IGF1R', 'Gene', '3480', (64, 69))	('furin', 'Protein', (26, 31))	('silencing', 'Var', (13, 22))
286951	27548722	In contrast, silencing of furin and subsequent loss of IGF1Rbeta maturation mostly prevented stimulation of Akt phosphorylation, indicating an inability of RMS cells to trigger IGF signaling in the absence of furin activity (Fig 5C).	('IGF1R', 'Gene', '3480', (55, 60))	('Akt', 'Gene', (108, 111))	('prevented', 'NegReg', (83, 92))	('stimulation', 'MPA', (93, 104))	('loss', 'NegReg', (47, 51))	('Akt', 'Gene', '207', (108, 111))	('RMS', 'Phenotype', 'HP:0002859', (156, 159))	('IGF1R', 'Gene', (55, 60))	('furin', 'Protein', (26, 31))	('rat', 'Species', '10116', (69, 72))	('silencing', 'Var', (13, 22))
286957	27548722	We observed delayed RMS tumor growth upon engraftment of mice with Rh30 and RD cells with reduced furin activity, achieved either by silencing or by expression of the pan-PC inhibitor alpha1-PDX/pdx.	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('reduced', 'NegReg', (90, 97))	('activity', 'MPA', (104, 112))	('Rh30', 'Gene', '6007', (67, 71))	('RMS tumor', 'Disease', (20, 29))	('RMS', 'Phenotype', 'HP:0002859', (20, 23))	('silencing', 'Var', (133, 142))	('furin', 'Protein', (98, 103))	('delayed', 'NegReg', (12, 19))	('RMS tumor', 'Disease', 'MESH:D009369', (20, 29))	('Rh30', 'Gene', (67, 71))
286959	27548722	Similarly, furin inhibition in carcinoma cells diminishes PDGF-A and IGF1R processing and abolishes stimulation of related signaling pathway.	('stimulation', 'MPA', (100, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('furin', 'Protein', (11, 16))	('PDGF-A', 'Gene', (58, 64))	('carcinoma', 'Disease', 'MESH:D002277', (31, 40))	('carcinoma', 'Disease', (31, 40))	('inhibition', 'Var', (17, 27))	('related signaling pathway', 'Pathway', (115, 140))	('IGF1R', 'Gene', (69, 74))	('diminishes', 'NegReg', (47, 57))	('PDGF-A', 'Gene', '5154', (58, 64))	('abolishes', 'NegReg', (90, 99))	('IGF1R', 'Gene', '3480', (69, 74))
286974	27548722	Similar to our studies, others showed that inhibition of furin decreases cell motility, migration and invasiveness of breast cancer, lung adenocarcinoma, fibrosarcoma and osteosarcoma cells in vitro and proposed furin inhibition for prevention of metastasis.	('inhibition', 'Var', (43, 53))	('invasiveness of breast cancer', 'Disease', 'MESH:D001943', (102, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('fibrosarcoma', 'Disease', 'MESH:D005354', (154, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('osteosarcoma', 'Disease', (171, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('fibrosarcoma', 'Disease', (154, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('invasiveness of breast cancer', 'Disease', (102, 131))	('rat', 'Species', '10116', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cell motility', 'CPA', (73, 86))	('furin', 'Gene', (57, 62))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('decreases', 'NegReg', (63, 72))	('migration', 'CPA', (88, 97))	('lung adenocarcinoma', 'Disease', (133, 152))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (154, 166))
286982	27446218	However, correlation coefficients between GEMusicA-processed expression data between EFT and ESC decreased whereas correlation coefficients between EFT and EC as well as between EFT and MSC increased after knockdown of EWSR1-FLI1.	('EWSR1', 'Gene', (219, 224))	('EWSR1', 'Gene', '2130', (219, 224))	('increased', 'PosReg', (190, 199))	('decreased', 'NegReg', (97, 106))	('FLI1', 'Gene', (225, 229))	('correlation coefficients', 'MPA', (9, 33))	('correlation coefficients', 'MPA', (115, 139))	('FLI1', 'Gene', '2313', (225, 229))	('knockdown', 'Var', (206, 215))
286994	27446218	The following data sets were used: GSE1824, GSE1825, GSE7007, GSE2248, GSE2361, GSM139881-GSM139883 and GSM139888-GSM139893 from GSE6029, GSM86779, GSM86781 and GSM867783 form GSE3788, GSE2638, GSE2639, and GSM1529859-GSM1529861 from GSE62600.	('GSM867783', 'Var', (161, 170))	('GSE7007', 'Chemical', '-', (53, 60))	('GSM139888-GSM139893', 'Var', (104, 123))
287002	27446218	The neuroblastoma cell lines CHP-126 and SiMa are cell lines with a MYCN (v-myc avian myelocytomatosis viral oncogene, neuroblastoma derived) amplification whereas SH-SY5Y cells have no MYCN amplification.	('neuroblastoma', 'Phenotype', 'HP:0003006', (4, 17))	('myelocytomatosis viral', 'Disease', (86, 108))	('neuroblastoma cell lines CHP-126', 'Disease', 'MESH:D009447', (4, 36))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (164, 171))	('myelocytomatosis viral', 'Disease', 'MESH:D001102', (86, 108))	('MYCN', 'Gene', '4613', (68, 72))	('neuroblastoma', 'Disease', 'MESH:D009447', (119, 132))	('MYCN', 'Gene', (186, 190))	('MYCN', 'Gene', '4613', (186, 190))	('neuroblastoma', 'Disease', (119, 132))	('neuroblastoma', 'Disease', 'MESH:D009447', (4, 17))	('neuroblastoma', 'Phenotype', 'HP:0003006', (119, 132))	('neuroblastoma', 'Disease', (4, 17))	('amplification', 'Var', (142, 155))	('MYCN', 'Gene', (68, 72))	('neuroblastoma cell lines CHP-126', 'Disease', (4, 36))
287008	27446218	The EFT cell line data set from GSE7007 contains data from EFT cell lines after knockdown of EWSR1-FLI1.	('FLI1', 'Gene', '2313', (99, 103))	('knockdown', 'Var', (80, 89))	('GSE7007', 'Chemical', '-', (32, 39))	('EWSR1', 'Gene', (93, 98))	('EWSR1', 'Gene', '2130', (93, 98))	('FLI1', 'Gene', (99, 103))
287010	27446218	We compared the correlation coefficients between different non-EFT samples and EFT cell lines with and without knockdown of EWSR1-FLI1 (Figure 6).	('knockdown', 'Var', (111, 120))	('EWSR1', 'Gene', (124, 129))	('FLI1', 'Gene', (130, 134))	('EWSR1', 'Gene', '2130', (124, 129))	('FLI1', 'Gene', '2313', (130, 134))
287011	27446218	Interestingly, the correlation coefficients for ESC, NSC, HSC, or NB decreased after knockdown of EWSR1-FLI1 (p < 0.01) whereas the correlation coefficients for MSC or endothelial cells increased after knockdown of EWSR1-FLI1 (p < 0.00001).	('FLI1', 'Gene', (104, 108))	('EWSR1', 'Gene', '2130', (98, 103))	('FLI1', 'Gene', '2313', (104, 108))	('decreased', 'NegReg', (69, 78))	('ESC', 'Disease', (48, 51))	('FLI1', 'Gene', '2313', (221, 225))	('NSC', 'Disease', (53, 56))	('FLI1', 'Gene', (221, 225))	('NB', 'Phenotype', 'HP:0003006', (66, 68))	('EWSR1', 'Gene', (215, 220))	('knockdown', 'Var', (85, 94))	('EWSR1', 'Gene', (98, 103))	('HSC', 'Disease', (58, 61))	('correlation', 'MPA', (19, 30))	('EWSR1', 'Gene', '2130', (215, 220))
287018	27446218	In this regard it is interesting to note that A673 cells have been initially established as rhabdomyosarcoma cells whereas SK-N-MC cells were established as neuroblastoma cell line, suggesting that the histological phenotype of EFT can vary extensively.	('SK-N-MC', 'CellLine', 'CVCL:0530', (123, 130))	('rhabdomyosarcoma', 'Disease', (92, 108))	('neuroblastoma', 'Disease', 'MESH:D009447', (157, 170))	('A673', 'Var', (46, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (92, 108))	('neuroblastoma', 'Disease', (157, 170))	('neuroblastoma', 'Phenotype', 'HP:0003006', (157, 170))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (92, 108))
287019	27446218	Evidence for the classification of both cell lines as EFT comes from the detection of EWSR1-FLI1 fusions.	('EWSR1', 'Gene', (86, 91))	('fusions', 'Var', (97, 104))	('FLI1', 'Gene', (92, 96))	('EWSR1', 'Gene', '2130', (86, 91))	('FLI1', 'Gene', '2313', (92, 96))
287037	26905812	The Wnt family of secreted proteins fulfills key evolutionarily conserved functions in normal development and adult tissue maintenance and its deregulation by alteration of expression or mutation of its key components including beta-catenin, adenomateous polyposis coli (APC) and AXIN, is associated with development and progression of diverse cancer types.	('cancer', 'Disease', (344, 350))	('adenomateous polyposis coli', 'Disease', (242, 269))	('deregulation', 'PosReg', (143, 155))	('adenomateous polyposis coli', 'Phenotype', 'HP:0005227', (242, 269))	('APC', 'Disease', 'MESH:D011125', (271, 274))	('AXIN', 'Gene', '12005', (280, 284))	('AXIN', 'Gene', (280, 284))	('APC', 'Disease', (271, 274))	('beta-catenin', 'Protein', (228, 240))	('adenomateous polyposis coli', 'Disease', 'MESH:D011125', (242, 269))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('associated', 'Reg', (289, 299))	('expression', 'MPA', (173, 183))	('mutation', 'Var', (187, 195))	('alteration', 'Var', (159, 169))	('cancer', 'Disease', 'MESH:D009369', (344, 350))
287039	26905812	Studies on the MYF5-CRE SS18/SSX2 transgenic model of SS found that SS18-SSX2 aberrantly activates Wnt/beta-catenin signaling and that genetic deletion of beta-catenin blocks tumor formation.	('tumor', 'Disease', (175, 180))	('MYF5', 'Gene', '17877', (15, 19))	('SSX', 'Gene', '727837', (73, 76))	('SSX', 'Gene', (29, 32))	('blocks', 'NegReg', (168, 174))	('SSX', 'Gene', '727837', (29, 32))	('activates', 'PosReg', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('genetic deletion', 'Var', (135, 151))	('Wnt/beta-catenin signaling', 'MPA', (99, 125))	('MYF5', 'Gene', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('SSX', 'Gene', (73, 76))
287042	26905812	Despite elevated expression of several Wnt target genes, particularly AXIN2, nuclear localization of ss-catenin is seen in only 30-60% of SS and genetic screens revealed low incidence of beta-catenin, APC, AXIN1 and AXIN2 mutations.	('elevated', 'PosReg', (8, 16))	('beta-catenin', 'Protein', (187, 199))	('AXIN2', 'Gene', (216, 221))	('low incidence of beta-catenin', 'Phenotype', 'HP:0040209', (170, 199))	('APC', 'Disease', 'MESH:D011125', (201, 204))	('AXIN1', 'Gene', (206, 211))	('expression', 'MPA', (17, 27))	('AXIN2', 'Gene', (70, 75))	('mutations', 'Var', (222, 231))	('AXIN1', 'Gene', '12005', (206, 211))	('APC', 'Disease', (201, 204))
287067	26905812	C3H10T1/2wt and C3H10T1/2pLIVc cells as well as STOpLIVc and STOSS18-SSX-V5 containing the reporter plasmid displayed no significant increase in luciferase activity compared to their PGL3 containing counterparts.	('C3H10T1/2', 'CellLine', 'CVCL:0190', (16, 25))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (0, 9))	('activity', 'MPA', (156, 164))	('C3H10T1/2pLIVc', 'Var', (16, 30))	('C3H10T1/2wt', 'Var', (0, 11))	('increase', 'PosReg', (133, 141))	('SSX', 'Gene', (69, 72))	('SSX', 'Gene', '727837', (69, 72))	('luciferase', 'Enzyme', (145, 155))
287069	26905812	We next compared transcriptome changes in C3H10T1/2SS18-SSX1-V5 and C3H10T1/2pLIVc cells on Affymetrix arrays and analyzed >2 fold differentially expressed probesets (Tables S1 and S2).	('SSX1', 'Gene', (56, 60))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (68, 77))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (42, 51))	('SSX1', 'Gene', '6756', (56, 60))	('C3H10T1/2pLIVc', 'Var', (68, 82))
287077	26905812	To determine whether the beta-catenin -TCF/LEF complex is implicated in AXIN2 induction by SS18-SSX1, we expressed a dominant negative (DeltaN) mouse LEF-1 mutant, which lacks the beta-catenin binding domain but retains intact DNA binding activity, in C3H10T1/2pLIVc and C3H10T1/2SS18-SSX1-V5 cells.	('DNA binding', 'Interaction', (227, 238))	('mouse', 'Species', '10090', (144, 149))	('SSX1', 'Gene', '6756', (96, 100))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (252, 261))	('SSX1', 'Gene', '6756', (285, 289))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (271, 280))	('activity', 'MPA', (239, 247))	('mutant', 'Var', (156, 162))	('SSX1', 'Gene', (96, 100))	('SSX1', 'Gene', (285, 289))	('LEF-1', 'Gene', '16842', (150, 155))	('LEF-1', 'Gene', (150, 155))
287079	26905812	A <10% decrease in AXIN2 mRNA levels was observed in the presence of DeltaN LEF-1 in C3H10T1/2SS18-SSX1-V5 cells (Fig.	('SSX1', 'Gene', '6756', (99, 103))	('LEF-1', 'Gene', '16842', (76, 81))	('SSX1', 'Gene', (99, 103))	('DeltaN', 'Var', (69, 75))	('LEF-1', 'Gene', (76, 81))	('decrease', 'NegReg', (7, 15))	('AXIN2 mRNA levels', 'MPA', (19, 36))
287083	26905812	AXIN2 message was induced roughly 700 fold by Wnt3a in C3H10T1/2pLIVc cells and the induction was strongly blunted by DeltaN LEF-1 (Fig.	('blunted', 'NegReg', (107, 114))	('AXIN2', 'Gene', (0, 5))	('LEF-1', 'Gene', '16842', (125, 130))	('LEF-1', 'Gene', (125, 130))	('Wnt3a', 'Gene', '22416', (46, 51))	('DeltaN', 'Var', (118, 124))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (55, 64))	('Wnt3a', 'Gene', (46, 51))
287087	26905812	In primary SS11 and SS12 cells, DeltaN LEF-1 not only failed to repress but tended to enhance AXIN2 expression (Fig.	('enhance', 'PosReg', (86, 93))	('DeltaN', 'Var', (32, 38))	('expression', 'MPA', (100, 110))	('LEF-1', 'Gene', '16842', (39, 44))	('LEF-1', 'Gene', (39, 44))	('AXIN2', 'Protein', (94, 99))
287092	26905812	The number of foci increased comparably in the nuclei of Wnt3a stimulated C3H10T1/2 and C3H10T1/2SS18-SSX1-V5 cells (Fig.	('C3H10T1/2', 'Var', (74, 83))	('Wnt3a', 'Gene', (57, 62))	('SSX1', 'Gene', '6756', (102, 106))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (88, 97))	('SSX1', 'Gene', (102, 106))	('Wnt3a', 'Gene', '22416', (57, 62))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (74, 83))
287098	26905812	Together with luciferase-based assay results that showed no effect of DeltaN LEF-1 on SS18-SSX-dependent AXIN2 expression (Fig.	('SSX', 'Gene', (91, 94))	('DeltaN', 'Var', (70, 76))	('SSX', 'Gene', '727837', (91, 94))	('LEF-1', 'Gene', '16842', (77, 82))	('LEF-1', 'Gene', (77, 82))
287116	26905812	In the absence of exogenous stimuli, changes in LEF-1 expression levels did not affect AXIN2 expression significantly (Fig.	('LEF-1', 'Gene', '16842', (48, 53))	('LEF-1', 'Gene', (48, 53))	('changes', 'Var', (37, 44))	('AXIN2', 'Gene', (87, 92))	('expression', 'MPA', (93, 103))
287118	26905812	By contrast, TCF3 depletion caused mild AXIN2 repression, below statistical significance.	('TCF3', 'Gene', '21423', (13, 17))	('depletion', 'Var', (18, 27))	('AXIN2', 'Protein', (40, 45))	('TCF3', 'Gene', (13, 17))
287136	26905812	Anti-V5 and anti-HDAC1 antibodies generated a high number of nuclear foci in all of the cells expressing SS18-SSX-V5, consistent with robust association between the fusion protein and HDAC.	('SSX', 'Gene', '727837', (110, 113))	('HDAC1', 'Gene', '433759', (17, 22))	('Anti-V5', 'Var', (0, 7))	('HDAC1', 'Gene', (17, 22))	('nuclear foci', 'CPA', (61, 73))	('SSX', 'Gene', (110, 113))
287156	26905812	In the presence of SS18-SSX, TCF3/4 enrichment occurred primarily at the region upstream of the first ATG close to the T2 TCF/LEF binding site (-274 to -182), whereas HDAC enrichment was also observed downstream, within the region containing the T6 TCF/LEF binding site (+1554 +1936).	('TCF3/4', 'Gene', '21423;21413', (29, 35))	('+1554 +1936', 'Var', (271, 282))	('SSX', 'Gene', '727837', (24, 27))	('-274 to -182', 'Var', (144, 156))	('SSX', 'Gene', (24, 27))	('TCF3/4', 'Gene', (29, 35))
287160	26905812	Wnt3a stimulation of C3H10T1/2pLIVc (0.1 muM for 16 h) did not result in significant dissociation of HDAC from LEF-1(not shown) whereas it increased association between LEF-1 and beta-catenin, as discussed earlier (Fig.	('Wnt3a', 'Gene', '22416', (0, 5))	('Wnt3a', 'Gene', (0, 5))	('LEF-1', 'Gene', '16842', (111, 116))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (21, 30))	('increased', 'PosReg', (139, 148))	('association', 'Interaction', (149, 160))	('LEF-1', 'Gene', '16842', (169, 174))	('LEF-1', 'Gene', (111, 116))	('LEF-1', 'Gene', (169, 174))	('beta-catenin', 'Protein', (179, 191))	('C3H10T1/2pLIVc', 'Var', (21, 35))
287166	26905812	As enhancement of beta-catenin translocation to the nucleus occurs in NIH3T3 and STO cells (Fig.	('NIH3T3', 'Var', (70, 76))	('NIH3T3', 'CellLine', 'CVCL:0594', (70, 76))	('beta-catenin', 'Protein', (18, 30))	('enhancement', 'PosReg', (3, 14))
287169	26905812	Accordingly, GSK3beta-dependent phosphorylation of beta-catenin on Thr41, Ser33 and Ser37, which precedes proteosomal degradation, was increased in the presence of SS18-SSX1 (Fig.	('SSX1', 'Gene', (169, 173))	('Ser37', 'Var', (84, 89))	('GSK3beta', 'Gene', '56637', (13, 21))	('Thr41', 'Chemical', '-', (67, 72))	('increased', 'PosReg', (135, 144))	('GSK3beta', 'Gene', (13, 21))	('Ser37', 'Chemical', '-', (84, 89))	('SSX1', 'Gene', '6756', (169, 173))	('beta-catenin', 'Protein', (51, 63))	('phosphorylation', 'MPA', (32, 47))	('Ser33', 'Chemical', '-', (74, 79))
287189	26905812	PLAs using anti-V5 and anti-LEF-1 antibodies showed 30% reduction in the number of SS18-SSX/LEF-1 interactions, upon TSA treatment (Figs 7E and S8), suggesting their dependence on intact HDAC availability and supporting ternary complex formation.	('interactions', 'Interaction', (98, 110))	('LEF-1', 'Gene', '16842', (28, 33))	('LEF-1', 'Gene', (28, 33))	('SSX', 'Gene', (88, 91))	('TSA', 'Chemical', 'MESH:C012589', (117, 120))	('SSX', 'Gene', '727837', (88, 91))	('anti-V5', 'Var', (11, 18))	('LEF-1', 'Gene', '16842', (92, 97))	('LEF-1', 'Gene', (92, 97))	('reduction', 'NegReg', (56, 65))
287195	26905812	Although these findings do not exclude the possible contribution of histone acetylases (HATs), they support the notion that HDAC activity at the AXIN2 promoter is reduced upon SS18-SSX expression.	('SSX', 'Gene', '727837', (181, 184))	('reduced', 'NegReg', (163, 170))	('expression', 'Var', (185, 195))	('SSX', 'Gene', (181, 184))	('HDAC activity', 'MPA', (124, 137))
287220	26905812	The increased SS18-SSX-HDAC interaction upon LEF-1 depletion suggests that SS18-SSX-HDAC association may precede ternary complex formation.	('LEF-1', 'Gene', '16842', (45, 50))	('SSX', 'Gene', (80, 83))	('SSX', 'Gene', '727837', (80, 83))	('SSX', 'Gene', (19, 22))	('LEF-1', 'Gene', (45, 50))	('SSX', 'Gene', '727837', (19, 22))	('depletion', 'Var', (51, 60))	('increased', 'PosReg', (4, 13))
287228	26905812	Antibodies used for western blot, immunoprecipitation, immunofluorescence or proximity ligation assay (PLA) were: mouse anti-V5epitope (Invitrogen Carlsbad, CA), rabbit polyclonal anti-V5 tag (Abcam, Cambridge UK), monoclonal anti-HA (Covance Research Product Inc Geneva Switzerland), mouse anti-Xpress (Invitrogen), mouse anti-tubulin (Calbiochem), rabbit anti-alpha/beta tubulin (Cell Signaling), mouse anti-actin clone AC-40 (SIGMA), anti-TCF4 and anti-LEF-1 (Santa Cruz Biotechnology inc. Germany), rabbit anti-TCF4 (C48H11, Cell Signaling), anti-TCF3 + 4 [6F12-3], anti-Histone H3AcK9, anti-HDAC1 Ab7028, anti-HDAC1 Ab46985 and anti-TLE-1 (Abcam, Cambridge UK), anti-TLE1,2,3,4 (Cell Signaling), mouse anti-beta-catenin (BD), beta-catenin antibody sampler kit (Cell Signaling, Beverly MA).	('LEF-1', 'Gene', '16842', (456, 461))	('rabbit', 'Species', '9986', (503, 509))	('mouse', 'Species', '10090', (317, 322))	('TCF3', 'Gene', (551, 555))	('TCF4', 'Gene', '21413', (442, 446))	('HDAC1', 'Gene', '433759', (596, 601))	('TCF4', 'Gene', (515, 519))	('rabbit', 'Species', '9986', (162, 168))	('mouse', 'Species', '10090', (285, 290))	('TLE-1', 'Gene', '21885', (638, 643))	('rabbit', 'Species', '9986', (350, 356))	('anti-Histone', 'Var', (570, 582))	('TLE1', 'Gene', (672, 676))	('TLE-1', 'Gene', (638, 643))	('HDAC1', 'Gene', (615, 620))	('TCF4', 'Gene', (442, 446))	('TLE1', 'Gene', '21885', (672, 676))	('TCF3', 'Gene', '21423', (551, 555))	('mouse', 'Species', '10090', (701, 706))	('TCF4', 'Gene', '21413', (515, 519))	('HDAC1', 'Gene', '433759', (615, 620))	('LEF-1', 'Gene', (456, 461))	('mouse', 'Species', '10090', (114, 119))	('mouse', 'Species', '10090', (399, 404))	('HDAC1', 'Gene', (596, 601))
287237	26905812	The mouse Axin-2 promoter sequence cloned into the pGL3 basic vector, p043 mTcf-4 B and pcDNA3.1/nV5-beta catenin were obtained from Adgene, SS18 and SS18-SSX mutants and HA-tagged mouse LEF-1 were constructed as described in supplemental methods.	('mouse', 'Species', '10090', (4, 9))	('mTcf-4 B', 'Gene', (75, 83))	('SSX', 'Gene', '727837', (155, 158))	('mutants', 'Var', (159, 166))	('LEF-1', 'Gene', '16842', (187, 192))	('LEF-1', 'Gene', (187, 192))	('mouse', 'Species', '10090', (181, 186))	('SSX', 'Gene', (155, 158))	('mTcf-4 B', 'Gene', '21416', (75, 83))	('Axin-2', 'Gene', (10, 16))	('Axin-2', 'Gene', '12006', (10, 16))
287239	26905812	Expression of SS18-SSX1-V5, SS18-SSX1-HA, SS18-V5, SS18-1-412-V5, XP-SS18-SSX-161-491, LEF-1-HA was achieved using the self inactivating lentiviral Gene Transfer and Expression system pLIVc which produces a floxed proviral genome (Detailed information on pLIVc is available on demand).	('SS18-1-412-V5', 'Var', (51, 64))	('SSX1', 'Gene', (33, 37))	('SSX', 'Gene', (33, 36))	('SSX1', 'Gene', (19, 23))	('LEF-1', 'Gene', '16842', (87, 92))	('SSX1', 'Gene', '6756', (33, 37))	('SSX', 'Gene', (74, 77))	('SSX', 'Gene', (19, 22))	('LEF-1', 'Gene', (87, 92))	('SSX', 'Gene', '727837', (74, 77))	('SSX', 'Gene', '727837', (33, 36))	('SS18-V5', 'Var', (42, 49))	('SSX', 'Gene', '727837', (19, 22))	('SSX1', 'Gene', '6756', (19, 23))
287241	26905812	siRNAs used were s13510 and s13512 for SS18 (life technology), sc-35805 for mouse LEF1, sc-43526 for mouse TCF4 (Santa Cruz biotechnology), a pool of Mm-Tcf2a, 1,2,3,4 (QUIAGEN) for TCF3 and esiRNA MU-04762-1 (SIGMA)for beta-catenin.	('TCF3', 'Gene', '21423', (182, 186))	('LEF1', 'Gene', '16842', (82, 86))	('TCF3', 'Gene', (182, 186))	('LEF1', 'Gene', (82, 86))	('mouse', 'Species', '10090', (76, 81))	('TCF4', 'Gene', (107, 111))	('mouse', 'Species', '10090', (101, 106))	('TCF4', 'Gene', '21413', (107, 111))	('s13512', 'Var', (28, 34))
287275	25075796	Translocation-related sarcomas represent about a quarter of sarcoma cases.	('sarcomas', 'Disease', (22, 30))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('sarcoma', 'Disease', (60, 67))	('sarcomas', 'Disease', 'MESH:D012509', (22, 30))	('sarcoma', 'Disease', (22, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('Translocation-related', 'Var', (0, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))
287294	25075796	Multifocality discouraged metastasectomy and therefore the patient continued chemotherapy for three additional cycles, with persistence of grade 2 nausea.	('Multifocality', 'Var', (0, 13))	('nausea', 'Phenotype', 'HP:0002018', (147, 153))	('patient', 'Species', '9606', (59, 66))	('nausea', 'Disease', (147, 153))	('nausea', 'Disease', 'MESH:D009325', (147, 153))	('metastasectomy', 'CPA', (26, 40))	('discouraged', 'NegReg', (14, 25))
287473	29248197	PIK3CA mutation upregulates NF-kappaB, leading to induction of EMT and IL-6 dependent STAT3 activation, and elevation of IL-6 transcription occurs due to the mutated PIK3CA gene.	('EMT', 'CPA', (63, 66))	('PIK3CA', 'Gene', (166, 172))	('STAT3', 'Gene', (86, 91))	('PIK3CA', 'Gene', '5290', (166, 172))	('IL-6', 'Gene', (71, 75))	('IL-6', 'Gene', '3569', (121, 125))	('upregulates', 'PosReg', (16, 27))	('NF-kappaB', 'Gene', '4790', (28, 37))	('PIK3CA', 'Gene', (0, 6))	('NF-kappaB', 'Gene', (28, 37))	('IL-6', 'Gene', '3569', (71, 75))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))	('mutated', 'Var', (158, 165))	('induction', 'PosReg', (50, 59))	('IL-6', 'Gene', (121, 125))	('elevation', 'PosReg', (108, 117))	('STAT3', 'Gene', '6774', (86, 91))
287474	29248197	Because increased IL-6 is associated with increased risk of VTE via induction of pro-coagulant factors, it may be speculated that PIK3CA mutation in uterine carcinosarcoma induces the IL-6 elevation that causes thromboembolic events.	('carcinosarcoma', 'Disease', (157, 171))	('thromboembolic', 'Disease', 'MESH:D013923', (211, 225))	('VTE', 'Disease', 'MESH:D054556', (60, 63))	('PIK3CA', 'Gene', (130, 136))	('carcinosarcoma', 'Disease', 'MESH:D002296', (157, 171))	('mutation', 'Var', (137, 145))	('thromboembolic', 'Disease', (211, 225))	('induces', 'Reg', (172, 179))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (149, 171))	('causes', 'Reg', (204, 210))	('VTE', 'Disease', (60, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('IL-6', 'Gene', '3569', (18, 22))	('IL-6', 'Gene', '3569', (184, 188))	('thromboembolic events', 'Phenotype', 'HP:0001907', (211, 232))	('IL-6', 'Gene', (18, 22))	('IL-6', 'Gene', (184, 188))	('PIK3CA', 'Gene', '5290', (130, 136))	('-6 elevation', 'Phenotype', 'HP:0030783', (186, 198))	('elevation', 'PosReg', (189, 198))	('increased', 'PosReg', (8, 17))
287506	30862685	Ectopic E-cadherin expression acts to downregulate phosphorylated CREB (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth.	('TBX2', 'Gene', '6909', (110, 114))	('E-cadherin', 'Protein', (8, 18))	('phosphorylated', 'MPA', (51, 65))	('TBX2', 'Gene', (110, 114))	('pen', 'Gene', '27344', (141, 144))	('inhibit', 'NegReg', (119, 126))	('downregulate', 'NegReg', (38, 50))	('Ectopic', 'Var', (0, 7))	('pen', 'Gene', (141, 144))
287507	30862685	RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on p-CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells.	('restores', 'PosReg', (90, 98))	('TBX2', 'Gene', (27, 31))	('TBX2', 'Gene', '6909', (27, 31))	('sarcoma', 'Disease', (146, 153))	('pen', 'Gene', '27344', (128, 131))	('p-CREB levels', 'MPA', (72, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('knockdown', 'Var', (14, 23))	('pen', 'Gene', (128, 131))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
287519	30862685	In addition, loss-of-function germline mutations in E-cadherin predispose individuals to familial gastric cancer, early onset colorectal cancer, and hereditary lobular breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('hereditary lobular breast cancer', 'Disease', 'MESH:D001943', (149, 181))	('familial gastric cancer', 'Disease', (89, 112))	('loss-of-function', 'NegReg', (13, 29))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (160, 181))	('colorectal cancer', 'Disease', (126, 143))	('familial gastric cancer', 'Disease', 'MESH:D013274', (89, 112))	('germline mutations', 'Var', (30, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('E-cadherin', 'Gene', (52, 62))	('hereditary lobular breast cancer', 'Disease', (149, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
287523	30862685	Though not a generalized phenomenon, in some carcinomas E-cadherin is sufficient to induce a more epithelial-like phenotype; however, our study demonstrates E-cadherin expression is not sufficient to alter epithelial plasticity biomarkers, migration, or invasion.	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('carcinomas', 'Disease', (45, 55))	('E-cadherin', 'Var', (157, 167))	('carcinomas', 'Disease', 'MESH:D002277', (45, 55))	('migration', 'CPA', (240, 249))	('alter', 'Reg', (200, 205))	('epithelial plasticity biomarkers', 'CPA', (206, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
287524	30862685	E-cadherin expression did, however, significantly inhibit both anchorage-independent growth and spheroid growth in sarcoma cells.	('spheroid growth', 'CPA', (96, 111))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('pen', 'Gene', (77, 80))	('sarcoma', 'Disease', (115, 122))	('inhibit', 'NegReg', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('pen', 'Gene', '27344', (77, 80))	('expression', 'Var', (11, 21))	('E-cadherin', 'Protein', (0, 10))
287528	30862685	TBX2 knockdown led to reductions in total and phospho-CREB and phenocopied E-cadherin-mediated inhibition of anchorage-independent growth.	('TBX2', 'Gene', '6909', (0, 4))	('TBX2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('reductions', 'NegReg', (22, 32))	('inhibition', 'NegReg', (95, 105))	('pen', 'Gene', (123, 126))	('pen', 'Gene', '27344', (123, 126))
287555	30862685	E-cadherinhigh patients had improved metastasis-free survival (Figure 1A) and overall survival compared to E-cadherinlow patients (Figure 1B).	('patients', 'Species', '9606', (15, 23))	('E-cadherinhigh', 'Var', (0, 14))	('improved', 'PosReg', (28, 36))	('overall survival', 'CPA', (78, 94))	('patients', 'Species', '9606', (121, 129))	('metastasis-free survival', 'CPA', (37, 61))
287556	30862685	Likewise, soft tissue sarcoma (STS) patients from The Cancer Genome Atlas with higher E-cadherin mRNA trended toward better overall survival than patients with lower E-cadherin (Figure 1C) while patients with higher E-cadherin protein had significantly improved overall survival compared to patients with lower E-cadherin protein levels (Figure 1D).	('overall survival', 'MPA', (124, 140))	('STS', 'Disease', (31, 34))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (10, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('E-cadherin mRNA', 'Var', (86, 101))	('patients', 'Species', '9606', (36, 44))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('overall', 'MPA', (262, 269))	('soft tissue sarcoma', 'Disease', (10, 29))	('STS', 'Disease', 'MESH:D012509', (31, 34))	('STS', 'Phenotype', 'HP:0030448', (31, 34))	('better', 'PosReg', (117, 123))	('patients', 'Species', '9606', (291, 299))	('patients', 'Species', '9606', (195, 203))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (10, 29))	('higher', 'PosReg', (79, 85))	('improved', 'PosReg', (253, 261))	('patients', 'Species', '9606', (146, 154))
287559	30862685	Given the important role of E-cadherin as a mediator of the epithelial phenotype, we hypothesized that E-cadherin may promote an MET-like phenotype in sarcomas, including suppression of migration and invasion pathways.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('invasion', 'CPA', (200, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcomas', 'Disease', (151, 159))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('E-cadherin', 'Var', (103, 113))	('MET-like phenotype', 'MPA', (129, 147))	('promote', 'PosReg', (118, 125))	('suppression', 'NegReg', (171, 182))
287565	30862685	Using empirical probably density functions, we calculated EMT scores for E-cadherinhigh vs. E-cadherinlow expressing osteosarcomas.	('osteosarcomas', 'Disease', (117, 130))	('osteosarcoma', 'Phenotype', 'HP:0002669', (117, 129))	('osteosarcomas', 'Phenotype', 'HP:0002669', (117, 130))	('E-cadherinhigh', 'Var', (73, 87))	('osteosarcomas', 'Disease', 'MESH:D012516', (117, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
287566	30862685	The scoring metric was strongly mesenchymal for all sarcomas analyzed, regardless of E-cadherin status, suggesting that E-cadherin was not capable of lineage reprogramming toward an epithelial-like state in sarcomas (Figure 2E).	('E-cadherin', 'Var', (120, 130))	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('sarcomas', 'Disease', 'MESH:D012509', (207, 215))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (207, 215))	('sarcomas', 'Disease', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('sarcomas', 'Disease', (207, 215))
287567	30862685	Together, using both computational and experimental approaches, our results suggest that E-cadherin overexpression need not be sufficient to induce MET in sarcomas, and that E-cadherin acts independently of migration/invasion programs to inhibit sarcoma aggressiveness.	('inhibit', 'NegReg', (238, 245))	('sarcoma aggressiveness', 'Disease', (246, 268))	('sarcomas', 'Disease', 'MESH:D012509', (155, 163))	('pen', 'Gene', (194, 197))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('E-cadherin', 'Var', (174, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcomas', 'Disease', (155, 163))	('pen', 'Gene', '27344', (194, 197))	('sarcoma aggressiveness', 'Disease', 'MESH:D001523', (246, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('aggressiveness', 'Phenotype', 'HP:0000718', (254, 268))	('E-cadherin', 'Protein', (89, 99))
287569	30862685	Given the role of E-cadherin as a cell adhesion molecule, we posited that E-cadherin may alter the anchorage-independent growth phenotype of sarcoma cells.	('sarcoma', 'Disease', (141, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('pen', 'Gene', (113, 116))	('alter', 'Reg', (89, 94))	('pen', 'Gene', '27344', (113, 116))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))	('E-cadherin', 'Var', (74, 84))
287579	30862685	Consistent with this, we also observed lower levels of phospho- and total CREB in Abrams canine osteosarcoma cells expressing E-cadherin as compared to cells expressing an empty vector lacking E-cadherin (Figure 4D).	('levels', 'MPA', (45, 51))	('E-cadherin', 'Var', (126, 136))	('Abrams canine osteosarcoma', 'Disease', (82, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (96, 108))	('phospho-', 'MPA', (55, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('Abrams canine osteosarcoma', 'Disease', 'MESH:D012516', (82, 108))	('Abrams canine', 'Phenotype', 'HP:0012738', (82, 95))	('CREB', 'Protein', (74, 78))	('lower', 'NegReg', (39, 44))
287583	30862685	During our analysis of MET biomarkers and phenotypes in E-cadherin expressing cells, we noted that groups of E-cadherin+ 143B cells lost cell surface N-cadherin expression (Supplementary Figure 4A).	('lost', 'NegReg', (132, 136))	('N-cadherin', 'Gene', '1000', (150, 160))	('N-cadherin', 'Gene', (150, 160))	('E-cadherin+', 'Var', (109, 120))
287589	30862685	Likewise, N-cadherin knockdown did not alter levels of p-CREB protein, as determined by p-CREB ELISAs and western blotting (Supplementary Figure 4F, G).	('knockdown', 'Var', (21, 30))	('N-cadherin', 'Gene', '1000', (10, 20))	('N-cadherin', 'Gene', (10, 20))
287595	30862685	Similarly, U2OS cells ectopically expressing E-cadherin (Supplementary Figure 1E) had significantly lower levels of TBX2 mRNA (Figure 5B).	('U2OS', 'CellLine', 'CVCL:0042', (11, 15))	('lower', 'NegReg', (100, 105))	('E-cadherin', 'Var', (45, 55))	('TBX2', 'Gene', '6909', (116, 120))	('TBX2', 'Gene', (116, 120))
287596	30862685	To further delineate the directionality of the E-cadherin/CREB/TBX2 signaling network, we performed siRNA-mediated CREB knockdown and measured TBX2 mRNA levels.	('TBX2', 'Gene', (143, 147))	('TBX2', 'Gene', '6909', (63, 67))	('TBX2', 'Gene', (63, 67))	('knockdown', 'Var', (120, 129))	('TBX2', 'Gene', '6909', (143, 147))
287597	30862685	Interestingly, CREB knockdown had no effect on TBX2 expression (Figure 5C, Supplementary Figure 3B), suggesting that CREB is downstream or independent of TBX2 in this gene regulatory network.	('TBX2', 'Gene', (47, 51))	('TBX2', 'Gene', (154, 158))	('TBX2', 'Gene', '6909', (47, 51))	('pen', 'Gene', (143, 146))	('knockdown', 'Var', (20, 29))	('pen', 'Gene', '27344', (143, 146))	('TBX2', 'Gene', '6909', (154, 158))
287598	30862685	Consistent with these data, TBX2 knockdown (Figure 5D) led to significant reductions in CREB mRNA (Figure 5E) and protein (Figure 5F).	('TBX2', 'Gene', '6909', (28, 32))	('knockdown', 'Var', (33, 42))	('reductions', 'NegReg', (74, 84))	('TBX2', 'Gene', (28, 32))	('CREB mRNA', 'MPA', (88, 97))
287602	30862685	Our model predicted that TBX2 knockdown would restrict anchorage-independent growth in a similar way as that by E-cadherin overexpression (Figure 6B).	('TBX2', 'Gene', '6909', (25, 29))	('pen', 'Gene', '27344', (69, 72))	('TBX2', 'Gene', (25, 29))	('restrict', 'NegReg', (46, 54))	('knockdown', 'Var', (30, 39))	('pen', 'Gene', (69, 72))
287603	30862685	To test this prediction, we used two independent siRNA to TBX2 to knockdown expression and measured anchorage independent growth.	('TBX2', 'Gene', '6909', (58, 62))	('pen', 'Gene', '27344', (114, 117))	('TBX2', 'Gene', (58, 62))	('expression', 'MPA', (76, 86))	('pen', 'Gene', (41, 44))	('knockdown', 'Var', (66, 75))	('pen', 'Gene', '27344', (41, 44))	('pen', 'Gene', (114, 117))
287604	30862685	Consistent with our prediction, TBX2 knockdown using two independent siRNAs significantly abrogated colony growth in 143B cells (Figure 6C).	('abrogated', 'NegReg', (90, 99))	('knockdown', 'Var', (37, 46))	('pen', 'Gene', (61, 64))	('TBX2', 'Gene', '6909', (32, 36))	('pen', 'Gene', '27344', (61, 64))	('TBX2', 'Gene', (32, 36))	('colony growth in 143B cells', 'CPA', (100, 127))
287605	30862685	Further, the model predicted that knockdown of TBX2 under ectopic expression of E-cadherin accentuates sensitivity to anchorage independence (Figure 6B).	('TBX2', 'Gene', (47, 51))	('pen', 'Gene', (132, 135))	('pen', 'Gene', '27344', (132, 135))	('TBX2', 'Gene', '6909', (47, 51))	('knockdown', 'Var', (34, 43))	('accentuates', 'PosReg', (91, 102))
287606	30862685	However, TBX2 knockdown had no effect on spheroid formation, when E-cadherin was overexpressed in U2OS cells (Figure 6D).	('spheroid formation', 'CPA', (41, 59))	('TBX2', 'Gene', '6909', (9, 13))	('TBX2', 'Gene', (9, 13))	('knockdown', 'Var', (14, 23))	('U2OS', 'CellLine', 'CVCL:0042', (98, 102))
287610	30862685	Therefore, to determine if similar regulatory networks between TBX2 and E-cadherin exist in sarcomas, we knocked down TBX2 with two independent siRNAs in U2OS cells and measured E-cadherin mRNA and protein levels.	('sarcomas', 'Disease', (92, 100))	('U2OS', 'CellLine', 'CVCL:0042', (154, 158))	('TBX2', 'Gene', '6909', (63, 67))	('knocked', 'Var', (105, 112))	('measured', 'Reg', (169, 177))	('TBX2', 'Gene', (63, 67))	('TBX2', 'Gene', '6909', (118, 122))	('pen', 'Gene', (136, 139))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('TBX2', 'Gene', (118, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('pen', 'Gene', '27344', (136, 139))
287611	30862685	TBX2 knockdown led to a modest, albeit significant, two- to four-fold upregulation of E-cadherin mRNA levels (Figure 6E).	('TBX2', 'Gene', '6909', (0, 4))	('upregulation', 'PosReg', (70, 82))	('TBX2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('E-cadherin mRNA levels', 'MPA', (86, 108))
287612	30862685	The relative lack of E-cadherin re-activation upon TBX2 knockdown led us to hypothesize that sarcoma cells had alterations in the promoter of E-cadherin that prevented robust increases in expression upon TBX2 downregulation.	('TBX2', 'Gene', '6909', (51, 55))	('expression', 'MPA', (188, 198))	('TBX2', 'Gene', (51, 55))	('downregulation', 'NegReg', (209, 223))	('sarcoma', 'Disease', (93, 100))	('alterations', 'Var', (111, 122))	('TBX2', 'Gene', '6909', (204, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('TBX2', 'Gene', (204, 208))	('increases', 'PosReg', (175, 184))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
287618	30862685	The revised model predicted that, consistent with our experimental results, the effect of TBX2 knockdown on anchorage-independent growth in the context of E-cadherin overexpression was reduced (Supplementary Figure 5).	('TBX2', 'Gene', '6909', (90, 94))	('overexpression', 'PosReg', (166, 180))	('TBX2', 'Gene', (90, 94))	('knockdown', 'Var', (95, 104))	('pen', 'Gene', (122, 125))	('pen', 'Gene', '27344', (122, 125))	('reduced', 'NegReg', (185, 192))
287637	30862685	While E-cadherin inhibits anchorage-independent growth through a signaling axis, the role of E-cadherin in suppressing spheroid growth is mediated, at least in part, through its mechanical activity of increasing cell-cell adhesion and cellular aggregation (Figure 7).	('inhibits', 'NegReg', (17, 25))	('increasing', 'PosReg', (201, 211))	('cell-cell adhesion', 'CPA', (212, 230))	('pen', 'Gene', (40, 43))	('cellular aggregation', 'CPA', (235, 255))	('pen', 'Gene', '27344', (40, 43))	('spheroid growth', 'CPA', (119, 134))	('E-cadherin', 'Var', (93, 103))	('suppressing', 'NegReg', (107, 118))
287638	30862685	This observation is consistent with previous reports in which knock down of E-cadherin led to less cell-cell adhesion and lower multicellular aggregation in colorectal cancer cells.	('lower', 'NegReg', (122, 127))	('knock down', 'Var', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('less', 'NegReg', (94, 98))	('E-cadherin', 'Protein', (76, 86))	('colorectal cancer', 'Disease', (157, 174))	('multicellular aggregation', 'Disease', 'MESH:D001791', (128, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('multicellular aggregation', 'Disease', (128, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))	('cell-cell adhesion', 'CPA', (99, 117))
287640	30862685	Yet, despite the fact that E-cadherin did not change migration or invasion in sarcomas, E-cadherin may still inhibit invasiveness of some tumors not by maintaining an epithelial state, but by increasing cell-cell adhesion.	('invasiveness', 'CPA', (117, 129))	('sarcomas', 'Disease', (78, 86))	('cell-cell adhesion', 'CPA', (203, 221))	('increasing', 'PosReg', (192, 202))	('inhibit', 'NegReg', (109, 116))	('tumors', 'Disease', (138, 144))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('E-cadherin', 'Var', (88, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
287648	30862685	Indeed, multiple reports in carcinomas suggest that treatment with epigenetic modifiers, including histone deacetylases inhibitors, can upregulate E-cadherin.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('carcinomas', 'Disease', (28, 38))	('carcinomas', 'Disease', 'MESH:D002277', (28, 38))	('epigenetic', 'Var', (67, 77))	('upregulate', 'PosReg', (136, 146))	('histone deacetylases', 'Protein', (99, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('E-cadherin', 'Protein', (147, 157))
287649	30862685	Consistent with this hypothesis, when anchorage-dependent and anchorage-independent subpopulations of osteosarcoma cells are compared, the anchorage-independent subpopulations are significantly more susceptible to epigenetic modifying therapies.	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('pen', 'Gene', (76, 79))	('osteosarcoma', 'Disease', 'MESH:D012516', (102, 114))	('pen', 'Gene', (50, 53))	('pen', 'Gene', (153, 156))	('epigenetic modifying', 'Var', (214, 234))	('pen', 'Gene', '27344', (76, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('pen', 'Gene', '27344', (153, 156))	('pen', 'Gene', '27344', (50, 53))	('susceptible', 'Reg', (199, 210))	('osteosarcoma', 'Disease', (102, 114))
287692	26325017	The kinetic enhancement of tissue during and after injection of Gd-DTPA was obtained using a 3D T1-weighted fast spoiled-gradient (SPGR) echo sequence (TR, 4-5 ms; echo time [TE], 1-2 seconds; slice thickness, 5 mm; FA, 25 ; FOV, 32cm; temporal resolution (Deltat) of 6.5 ms) and consisted of 10-12 images in the sagittal plane.	('Gd-DTPA', 'Chemical', 'MESH:D019786', (64, 71))	('enhancement', 'PosReg', (12, 23))	('Gd-DTPA', 'Var', (64, 71))
287728	26325017	Radiotherapy is known to cause necrosis and fibrosis of tumor and surrounding adjacent normal tissue, which can result in what appears as worsening of disease on imaging.	('result', 'Reg', (112, 118))	('fibrosis of tumor', 'Disease', (44, 61))	('necrosis', 'Disease', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('necrosis', 'Disease', 'MESH:D009336', (31, 39))	('Radiotherapy', 'Var', (0, 12))	('fibrosis of tumor', 'Disease', 'MESH:D005355', (44, 61))	('worsening', 'MPA', (138, 147))
287808	27100297	Univariate analysis revealed that survival was significantly influenced by SUVmax, age, stage, tumor size, and initial tumor location.	('tumor', 'Disease', (119, 124))	('influenced', 'Reg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SUVmax', 'Var', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('survival', 'MPA', (34, 42))	('tumor', 'Disease', (95, 100))
287855	23456762	Cytologic atypia, in the form of nuclear enlargement, variation in nuclear shape, and prominent hyperchromasia, was considered significant if it could be discernible at low power magnification (10x objective).	('nuclear shape', 'CPA', (67, 80))	('hyperchromasia', 'Disease', 'None', (96, 110))	('enlargement', 'PosReg', (41, 52))	('hyperchromasia', 'Disease', (96, 110))	('nuclear', 'CPA', (33, 40))	('variation', 'Var', (54, 63))
287873	23456762	Fewer patients from EIO had high-grade tumors (76% vs. 91%) or locoregional metastasis (14% vs. 28%) compared to the MSKCC or BWH/DFCI subsets.	('locoregional metastasis', 'CPA', (63, 86))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (6, 14))	('EIO', 'Var', (20, 23))	('tumors', 'Disease', (39, 45))
287920	23457041	After measuring TF expression and TG activity, users can choose cut-offs c1 ~ c4 to define (i) high-TF expression ('ETF > c1'), (ii) low-TF expression ('ETF < c2'), (iii) high-TG activity ('ATG > c3') and (iv) low-TG activity ('ATG < c4'), denoted by TF+, TF-, TG+ and TG-, respectively.	('TG', 'Chemical', '-', (176, 178))	('high-TG activity', 'MPA', (171, 187))	('TG', 'Chemical', '-', (269, 271))	('TG', 'Chemical', '-', (191, 193))	('TG', 'Chemical', '-', (214, 216))	("'ETF", 'Var', (152, 156))	('low-TG activity', 'MPA', (210, 225))	("'ETF", 'Var', (115, 119))	('TG', 'Chemical', '-', (229, 231))	('TG', 'Chemical', '-', (34, 36))	('TG', 'Chemical', '-', (261, 263))
287922	23457041	ChIP-PED can then search for biological contexts associated with four regulatory patterns: (i) TF+TG+, (ii) TF+TG-, (iii) TF-TG+ and (iv) TF-TG-.	('TG', 'Chemical', '-', (141, 143))	('TF-TG+', 'Var', (122, 128))	('TG', 'Chemical', '-', (125, 127))	('TG', 'Chemical', '-', (111, 113))	('TG', 'Chemical', '-', (98, 100))	('TF+TG-', 'Var', (108, 114))	('TF+TG+', 'Disease', (95, 101))
287932	23457041	As this observation holds for multiple mouse and human TFs from different microarray platforms (GPL1261 and GPL96), our results suggest that biological variability in the publicly available Affymetrix microarray data is stronger than the laboratory or batch effects.	('GPL1261', 'Var', (96, 103))	('human', 'Species', '9606', (49, 54))	('mouse', 'Species', '10090', (39, 44))	('GPL96', 'Var', (108, 113))
287964	23457041	To examine STAT1 functional activity in hepatitis C-infected PBMCs in more detail, we searched for all contexts in GSE7123 and also found healthy PBMCs along with the predicted hepatitis C-infected PBMCs.	('GSE7123', 'Chemical', '-', (115, 122))	('hepatitis C-infected', 'Disease', 'MESH:D006526', (177, 197))	('hepatitis C-infected', 'Disease', 'MESH:D006526', (40, 60))	('GSE7123', 'Var', (115, 122))	('hepatitis', 'Phenotype', 'HP:0012115', (177, 186))	('hepatitis C-infected', 'Disease', (177, 197))	('hepatitis', 'Phenotype', 'HP:0012115', (40, 49))	('hepatitis C-infected', 'Disease', (40, 60))
287973	23457041	Knocking down of MYC using shMYC in TC71 and MHH-ES Ewing sarcoma cell lines resulted in a substantially slower proliferation rate and tumorigenicity when compared with control cells (Fig.	('MYC', 'Gene', (17, 20))	('slower', 'NegReg', (105, 111))	('Knocking down', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumorigenicity', 'CPA', (135, 149))	('TC71', 'CellLine', 'CVCL:2213', (36, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('MHH-ES Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 65))	('MHH-ES Ewing sarcoma', 'Disease', (45, 65))	('shMYC', 'Gene', (27, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
287974	23457041	Furthermore, xenograft of control and shMYC TC71 Ewing sarcoma cells into immunodeficient mice (NOD/SCID/IL-2gamma null) resulted in a significant decrease in volume and weight for the MYC knockdown tumors after 6 weeks of growth (Fig.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('MYC', 'Gene', (185, 188))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('TC71', 'Gene', (44, 48))	('decrease', 'NegReg', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('SCID', 'Disease', (100, 104))	('mice', 'Species', '10090', (90, 94))	('TC71', 'CellLine', 'CVCL:2213', (44, 48))	('SCID', 'Disease', 'MESH:D053632', (100, 104))	('Ewing sarcoma', 'Disease', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('knockdown', 'Var', (189, 198))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))
287983	23457041	In this respect, the default cut-offs that define high- or low-TF expression or TG activity should be primarily used for initial exploration or first-pass automatic hypothesis screening, rather than as strict optimal cut-offs that apply to all TFs.	('low-TF', 'NegReg', (59, 65))	('activity', 'MPA', (83, 91))	('TG', 'Chemical', '-', (80, 82))	('high-', 'Var', (50, 55))
288000	23421389	However, STSs involving the hip or the thigh have been associated with a particularly high risk of thromboembolism.	('thromboembolism', 'Disease', (99, 114))	('STSs', 'Phenotype', 'HP:0030448', (9, 13))	('thromboembolism', 'Disease', 'MESH:D013923', (99, 114))	('thromboembolism', 'Phenotype', 'HP:0001907', (99, 114))	('STSs', 'Var', (9, 13))
288090	23251062	Variable non-specific positivity was reported for CD23, CD68, Ki-FDC1p, Ki-M4p and S-100.	('CD68', 'Gene', (56, 60))	('CD23', 'Gene', '2208', (50, 54))	('CD68', 'Gene', '968', (56, 60))	('S-100', 'Gene', (83, 88))	('CD23', 'Gene', (50, 54))	('Ki-M4p', 'Var', (72, 78))
288175	20398380	Although, there was no evident difference between patients with medicare and without medicare in hospitalization, it is noticeable that the diagnosing and treatment cost for patients with medicare was significantly lower than those without medicare (Figure 5C, Table 7).	('patients', 'Species', '9606', (50, 58))	('medicare', 'Var', (188, 196))	('patients', 'Species', '9606', (174, 182))	('men', 'Species', '9606', (160, 163))	('lower', 'NegReg', (215, 220))
288267	33578857	Concerning the histopathological results, the treatment with POH/beta-CD at a dose of 50 mg/kg promoted approximately 60% inhibition of tumor growth in a sarcoma S180-induced mice model and the reduction of nuclear immunoexpression of the Ki67 antigen compared to the control group.	('mice', 'Species', '10090', (175, 179))	('POH/beta-CD', 'Var', (61, 72))	('Ki67', 'Gene', '17345', (239, 243))	('Ki67', 'Gene', (239, 243))	('reduction', 'NegReg', (194, 203))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('inhibition', 'NegReg', (122, 132))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('POH', 'Chemical', 'MESH:C032208', (61, 64))	('sarcoma', 'Disease', (154, 161))	('nuclear immunoexpression', 'MPA', (207, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('tumor', 'Disease', (136, 141))
288271	33578857	The conjugation of POH with temozolomide was shown to block the induction of the pro-angiogenic process, thus demonstrating to be a potential inhibitor of tumor progression and recurrence in glioma stem cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('POH', 'Gene', (19, 22))	('conjugation', 'Var', (4, 15))	('glioma', 'Disease', (191, 197))	('temozolomide', 'Chemical', 'MESH:D000077204', (28, 40))	('tumor', 'Disease', (155, 160))	('POH', 'Chemical', 'MESH:C032208', (19, 22))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('block', 'NegReg', (54, 59))	('pro-angiogenic process', 'CPA', (81, 103))
288336	33578857	The DSC curves of the raw materials (POH and beta-CD) compared to those obtained by the analyses of the complexes (CO, PM and MA) confirm that the best interaction between the POH and beta-CD was obtained with CO methodology; the POH reduction of the melting endotherm (73.14 to 127.40  C, -29.41 J/g) was more significant compared to other methodologies (PM and MA).	('CO', 'Chemical', '-', (210, 212))	('POH', 'Chemical', 'MESH:C032208', (176, 179))	('CO', 'Chemical', '-', (115, 117))	('POH', 'Var', (230, 233))	('DS', 'Chemical', 'MESH:D003903', (4, 6))	('interaction', 'Interaction', (152, 163))	('reduction', 'NegReg', (234, 243))	('POH', 'Chemical', 'MESH:C032208', (37, 40))	('73.14 to 127.40  C', 'Var', (270, 288))	('POH', 'Chemical', 'MESH:C032208', (230, 233))
288410	33578857	In our work, nuclear immunoexpression of the Ki67 antigen was reduced in the groups treated with 5-FU and POH/beta-CD (50 mg/Kg) compared to the group treated with the vehicle.	('nuclear immunoexpression', 'MPA', (13, 37))	('Ki67', 'Gene', '17345', (45, 49))	('POH/beta-CD', 'Var', (106, 117))	('5-FU', 'Var', (97, 101))	('Ki67', 'Gene', (45, 49))	('5-FU', 'Chemical', 'MESH:D005472', (97, 101))	('POH', 'Chemical', 'MESH:C032208', (106, 109))	('reduced', 'NegReg', (62, 69))
288422	33578857	A.A.R., R.S.S., L.N.A., R.G.A., M.M.P., C.B., M.C.	('M.M.P.', 'Var', (32, 38))	('C.B', 'Gene', '13030', (40, 43))	('C.B', 'Gene', (40, 43))	('R.G.A.', 'Var', (24, 30))
288473	30472815	However, the first case in our report exhibits no evidence of epithelial differentiation, further supported by total IHC negativity for CK, low molecular weight CK, and high molecular weight CK, which is in contrast with previous reports about metaplastic carcinoma with melanocytic differentiation.	('metaplastic carcinoma', 'Disease', (244, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('low', 'Var', (140, 143))	('metaplastic carcinoma', 'Disease', 'MESH:D002277', (244, 265))	('high molecular', 'Var', (169, 183))
288474	30472815	One difficulty in the differential diagnosis of our first case was the interpretation of S100 protein positivity with HMB-45 negativity by IHC.	('S100', 'Gene', '6285', (89, 93))	('S100', 'Gene', (89, 93))	('positivity', 'Var', (102, 112))
288475	30472815	There have been reports of S100 protein positivity in some metaplastic carcinoma and basal-type breast cancers.	('metaplastic carcinoma', 'Disease', (59, 80))	('S100', 'Gene', '6285', (27, 31))	('breast cancers', 'Phenotype', 'HP:0003002', (96, 110))	('basal-type breast cancers', 'Disease', (85, 110))	('S100', 'Gene', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('metaplastic carcinoma', 'Disease', 'MESH:D002277', (59, 80))	('basal-type breast cancers', 'Disease', 'MESH:D001943', (85, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('positivity', 'Var', (40, 50))
288480	30472815	There have been efforts to find the ideal biomarker for differentiating these two entities, and some recent studies have suggested that the presence of BRAF mutation favors the diagnosis of melanoma over clear cell sarcoma.	('BRAF', 'Gene', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('clear cell sarcoma', 'Disease', (204, 222))	('favors', 'PosReg', (166, 172))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (204, 222))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('mutation', 'Var', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('presence', 'Var', (140, 148))	('BRAF', 'Gene', '673', (152, 156))
288488	30472815	Furthermore, the BRAF V600E mutation was also confirmed in case 1 by real-time polymerase chain reaction using the peptide nucleic acid clamping method.	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('V600E', 'Var', (22, 27))
288489	30472815	To date, only two other cases of PNCMB have been tested for BRAF mutation, and one case reported by Rassouli and Voutsadakis had a BRAF V600E mutation.	('BRAF', 'Gene', (131, 135))	('V600E mutation', 'Var', (136, 150))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('V600E', 'Mutation', 'rs113488022', (136, 141))	('mutation', 'Var', (65, 73))	('PNCMB', 'Chemical', '-', (33, 38))	('BRAF', 'Gene', '673', (131, 135))
288490	30472815	Our first case is the second reported case of PNCMB with BRAF mutation.	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('PNCMB', 'Disease', (46, 51))	('PNCMB', 'Chemical', '-', (46, 51))	('mutation', 'Var', (62, 70))
288492	30472815	Case 1 presented here and the previously reported BRAF mutant PMMB case have some additional features in common: both are solitary amelanotic tumors confined to the breast parenchyma, show positivity for S100 protein by IHC, have no evidence of primary melanoma except the breast on systemic workup studies, and were diagnosed at an early stage without nodal involvement.	('solitary amelanotic tumors', 'Disease', 'MESH:D018328', (122, 148))	('breast parenchyma', 'Disease', 'MESH:D010195', (165, 182))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('BRAF', 'Gene', (50, 54))	('solitary amelanotic tumors', 'Disease', (122, 148))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('melanoma', 'Disease', (253, 261))	('mutant', 'Var', (55, 61))	('melanoma', 'Disease', 'MESH:D008545', (253, 261))	('PMMB', 'Chemical', '-', (62, 66))	('PMMB', 'Gene', (62, 66))	('S100', 'Gene', '6285', (204, 208))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('S100', 'Gene', (204, 208))	('BRAF', 'Gene', '673', (50, 54))	('breast parenchyma', 'Disease', (165, 182))
288493	30472815	The presence of BRAF mutation in PMMB cases suggests that PMMB may have similar pathogenesis with typical malignant melanoma, and that PMMB may also be eligible for targeted therapy such as BRAF inhibitors.	('PMMB', 'Chemical', '-', (33, 37))	('malignant melanoma', 'Disease', (106, 124))	('BRAF', 'Gene', (190, 194))	('PMMB', 'Gene', (33, 37))	('BRAF', 'Gene', (16, 20))	('PMMB', 'Disease', (58, 62))	('BRAF', 'Gene', '673', (16, 20))	('malignant melanoma', 'Phenotype', 'HP:0002861', (106, 124))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('mutation', 'Var', (21, 29))	('PMMB', 'Chemical', '-', (58, 62))	('malignant melanoma', 'Disease', 'MESH:D008545', (106, 124))	('BRAF', 'Gene', '673', (190, 194))	('PMMB', 'Chemical', '-', (135, 139))
288654	28494349	We have previously developed UPS (MSC-5H-GFP, MSC-5H-O, T-5H-GFP#1 and T-5H-O cell lines) and FUS-CHOP-expressing MRCLS models (MSC-5H-FC and T-5H-FC#1 cell lines) using hBMSCs sequentially mutated with up to six oncogenic events (see Table S1 and Supplemental information for a description of these cell lines).	('MSC', 'Gene', (46, 49))	('mutated', 'Var', (190, 197))	('MSC', 'Gene', (172, 175))	('T-5H', 'Chemical', '-', (142, 146))	('T-5H', 'Chemical', '-', (56, 60))	('T-5H', 'Chemical', '-', (71, 75))	('5H', 'Chemical', '-', (132, 134))	('MSC', 'Gene', '17681', (34, 37))	('MSC', 'Gene', '17681', (128, 131))	('5H', 'Chemical', '-', (58, 60))	('T-5H-O', 'Chemical', '-', (71, 77))	('5H', 'Chemical', '-', (50, 52))	('MSC', 'Gene', (34, 37))	('MRCLS', 'Phenotype', 'HP:0012268', (114, 119))	('5H', 'Chemical', '-', (144, 146))	('MSC', 'Gene', (128, 131))	('MSC', 'Gene', '17681', (46, 49))	('5H', 'Chemical', '-', (73, 75))	('MSC', 'Gene', '17681', (172, 175))	('5H', 'Chemical', '-', (38, 40))
288660	28494349	Both MSC-5H-FC (Figure 1C) and T-5H-FC#1 cells (Figure S1A) treated with 0.5 nM trabectedin showed a slow transition through the S-phase followed by G2 arrest, meanwhile cells treated with a higher concentration (2 nM) showed a more stringent S-phase block and a consistent increment in the Sub-G1 apoptotic population at latter times.	('trabectedin', 'Chemical', 'MESH:D000077606', (80, 91))	('increment', 'PosReg', (274, 283))	('Sub-G1 apoptotic population', 'CPA', (291, 318))	('MSC', 'Gene', '17681', (5, 8))	('MSC', 'Gene', (5, 8))	('arrest', 'Disease', 'MESH:D006323', (152, 158))	('S-phase', 'CPA', (243, 250))	('5H', 'Chemical', '-', (33, 35))	('5H', 'Chemical', '-', (9, 11))	('arrest', 'Disease', (152, 158))	('0.5 nM', 'Var', (73, 79))	('T-5H', 'Chemical', '-', (31, 35))
288711	28494349	In other types of tumors it has been described that trabectedin is able to induce apoptosis and G2/M cell cycle arrest and to reduce tumorsphere growth in CSC subpopulations derived from prostate cancer cell lines.	('reduce', 'NegReg', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumorsphere growth', 'Disease', (133, 151))	('tumors', 'Disease', (18, 24))	('arrest', 'Disease', 'MESH:D006323', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumorsphere growth', 'Disease', 'MESH:D006130', (133, 151))	('trabectedin', 'Chemical', 'MESH:D000077606', (52, 63))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('apoptosis', 'CPA', (82, 91))	('tumors', 'Disease', (133, 139))	('arrest', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (101, 118))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (187, 202))	('trabectedin', 'Var', (52, 63))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (187, 202))	('induce', 'PosReg', (75, 81))	('prostate cancer', 'Disease', (187, 202))
288712	28494349	We also demonstrate that, unlike what we previously reported for doxorubicin, trabectedin represses the expression of multiple genes and pathways involved in the development and maintenance of the CSC phenotype.	('represses', 'NegReg', (90, 99))	('trabectedin', 'Chemical', 'MESH:D000077606', (78, 89))	('expression', 'MPA', (104, 114))	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))	('trabectedin', 'Var', (78, 89))
288767	28205183	Immunohistochemically, the tumor cells were positive for D2-40, BCL-2, CD99, and p53; they were negative for TTF-1, WT1, calretinin, cytokeratin (CK)5/6, CK7, CK20, HBME-1, CEA, and CD34.	('WT1', 'Gene', (116, 119))	('p53', 'Gene', (81, 84))	('CK7', 'Gene', '3855', (154, 157))	('CD34', 'Gene', '947', (182, 186))	('calretinin', 'Gene', (121, 131))	('WT1', 'Gene', '7490', (116, 119))	('tumor', 'Disease', (27, 32))	('HBME-1', 'CellLine', 'CVCL:U718', (165, 171))	('CK20', 'Gene', (159, 163))	('D2-40', 'Var', (57, 62))	('TTF-1', 'Gene', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CD99', 'Gene', (71, 75))	('BCL-2', 'Gene', '596', (64, 69))	('BCL-2', 'Gene', (64, 69))	('CK20', 'Gene', '54474', (159, 163))	('calretinin', 'Gene', '794', (121, 131))	('CD99', 'Gene', '4267', (71, 75))	('CD34', 'Gene', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CK7', 'Gene', (154, 157))	('p53', 'Gene', '7157', (81, 84))	('TTF-1', 'Gene', '7270', (109, 114))
288799	28205183	The chromosomal translocation t(X;18)(p11.2;q11.2) has been found in more than 90% of synovial sarcomas, regardless of histologic subtype.	('t(X;18)(p11.2;q11.2', 'Var', (30, 49))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (86, 103))	('found', 'Reg', (60, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (86, 102))	('synovial sarcomas', 'Disease', 'MESH:D013584', (86, 103))	('synovial sarcomas', 'Disease', (86, 103))
288859	28352674	Furthermore, because cytogenetic abnormalities are detected in approximately 55% of MS cases, the identification of an AML-associated abnormality (i.e., trisomy 8, t[8;21][q22;q22] or inv[p13.1q22]/t[16;16][p13.1;q22]) may be useful in obtaining an accurate diagnosis.	('inv[p13.1q22]/t[16;16][p13.1;q22]', 'Var', (184, 217))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('trisomy 8', 'Var', (153, 162))	('AML', 'Phenotype', 'HP:0004808', (119, 122))	('AML', 'Disease', (119, 122))	('t[8;21][q22;q22]', 'Var', (164, 180))
288875	27595033	Patient underwent exploratory laparotomy, resection of large retroperitoneal tumor (weight 5621 gm) en block with small intestine (Figure 3), and primary small bowel to small bowel anastomosis.	('retroperitoneal tumor', 'Disease', (61, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('small bowel to small bowel anastomosis', 'Disease', 'MESH:D015212', (154, 192))	('small bowel to small bowel anastomosis', 'Disease', (154, 192))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('weight 5621 gm', 'Var', (84, 98))	('tumor', 'Disease', (77, 82))	('retroperitoneal tumor', 'Disease', 'MESH:D012186', (61, 82))
288881	31088504	miRNA deregulation targets specific pathways in leiomyosarcoma development: an in silico analysis MicroRNA (miRNA) mediate post-transcriptional gene repression and are involved in a variety of human diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('deregulation', 'Var', (6, 18))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (48, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('involved', 'Reg', (168, 176))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('leiomyosarcoma', 'Disease', (48, 62))	('cancer', 'Disease', (219, 225))	('post-transcriptional gene repression', 'MPA', (123, 159))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (48, 62))	('human', 'Species', '9606', (193, 198))
288885	31088504	We first employed the Sarcoma microRNA Expression Database, a repository that describes the patterns of over 1000 miRNA expression in various human sarcoma types, to identify differentially expressed miRNA comparing leiomyosarcoma and smooth muscle samples.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (216, 230))	('sarcoma', 'Disease', (223, 230))	('Sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('Sarcoma', 'Disease', (22, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('sarcoma', 'Disease', (148, 155))	('miRNA', 'Var', (200, 205))	('human', 'Species', '9606', (142, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (216, 230))	('leiomyosarcoma', 'Disease', (216, 230))	('sarcoma', 'Disease', 'MESH:D012509', (223, 230))
288926	31088504	Our results support this hypothesis and suggest that evading this form of control could contribute to leiomyosarcoma development.	('evading', 'Var', (53, 60))	('contribute', 'Reg', (88, 98))	('leiomyosarcoma', 'Disease', (102, 116))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (102, 116))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (102, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))
288935	31088504	In a different study, the same research group suggested that activation of DR1 induces osteosarcoma cell apoptosis via changes to the MAPK pathway.	('MAPK', 'Gene', (134, 138))	('MAPK', 'Gene', '5595;5594;5595', (134, 138))	('changes', 'Reg', (119, 126))	('induces', 'PosReg', (79, 86))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('osteosarcoma', 'Disease', (87, 99))	('DR1', 'Gene', (75, 78))	('osteosarcoma', 'Disease', 'MESH:D012516', (87, 99))	('DR1', 'Gene', '1810', (75, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('activation', 'Var', (61, 71))
288941	31088504	Numerous studies have reported dysregulated potassium channel expression in human cancer.	('dysregulated', 'Var', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('human', 'Species', '9606', (76, 81))
288945	31088504	As regards the target genes we have identified as potentially targeted by miRNA specifically deregulated in leiomyosarcoma, we could not validate our results in silico due to the lack of publicly available data on leiomyosarcoma.	('leiomyosarcoma', 'Disease', (214, 228))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (108, 122))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (214, 228))	('deregulated', 'Reg', (93, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (214, 228))	('miRNA', 'Var', (74, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (108, 122))	('leiomyosarcoma', 'Disease', (108, 122))
288950	31088504	Overall our results suggest that there are pathways particularly targeted by miRNA altered expression which are already been linked to other malignancies, but are worth to be studied in leiomyosarcoma such as RNA pol III and tRNA functions and dopamine neurotransmission pathway.	('expression', 'MPA', (91, 101))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (186, 200))	('dopamine', 'Chemical', 'MESH:D004298', (244, 252))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (186, 200))	('miRNA altered', 'Var', (77, 90))	('leiomyosarcoma', 'Disease', (186, 200))	('malignancies', 'Disease', 'MESH:D009369', (141, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('tRNA', 'Gene', '4563', (225, 229))	('malignancies', 'Disease', (141, 153))	('tRNA', 'Gene', (225, 229))
288973	30519452	It is characterized by t(9;22)(q22;q12), fusing EWSR1 to NRA3 (genes formerly termed CHN, TEC, or NOR1) .	('EWSR1', 'Gene', (48, 53))	('fusing', 'Var', (41, 47))	('NOR1', 'Gene', (98, 102))	('TEC', 'Gene', '7006', (90, 93))	('t(9;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (23, 39))	('CHN', 'Gene', '8013', (85, 88))	('EWSR1', 'Gene', '2130', (48, 53))	('TEC', 'Gene', (90, 93))	('NRA3', 'Gene', (57, 61))	('CHN', 'Gene', (85, 88))	('NOR1', 'Gene', '8013', (98, 102))
288984	30519452	Biallelic inactivation of the exostosin glycosyltransferase  ( EXT1 or EXT2) genes is observed in the majority of both sporadic and hereditary osteochondroma cases , .	('hereditary osteochondroma', 'Disease', (132, 157))	('observed', 'Reg', (86, 94))	('EXT2', 'Gene', (71, 75))	('EXT1', 'Gene', '2131', (63, 67))	('osteochondroma', 'Phenotype', 'HP:0030431', (143, 157))	('EXT2', 'Gene', '2132', (71, 75))	('Biallelic inactivation', 'Var', (0, 22))	('EXT1', 'Gene', (63, 67))	('hereditary osteochondroma', 'Disease', 'MESH:D015831', (132, 157))
288988	30519452	The EXT-negative cells in osteochondroma create an extracellular mutation-promoting environment, whereupon neighboring EXT-positive cells acquire late-stage mutations that cause malignant transformation into CS.	('osteochondroma', 'Phenotype', 'HP:0030431', (26, 40))	('mutations', 'Var', (157, 166))	('osteochondroma', 'Disease', 'MESH:D015831', (26, 40))	('cause', 'Reg', (172, 177))	('malignant transformation', 'CPA', (178, 202))	('osteochondroma', 'Disease', (26, 40))	('CS', 'Phenotype', 'HP:0006765', (208, 210))
288990	30519452	Mutations in the isocitrate dehydrogenase ( IDH) 1 and 2 genes are present in 85% of hereditary enchondromatosis-associated disorders, Ollier disease (enchondromatosis only), and Maffuci syndrome (enchondromatosis and hemangiomas) and 50% of solitary enchondromas .	('Maffuci syndrome', 'Disease', (179, 195))	('enchondromatosis', 'Disease', 'MESH:D004687', (96, 112))	('enchondromatosis', 'Disease', (151, 167))	('enchondroma', 'Phenotype', 'HP:0030038', (151, 162))	('hemangiomas', 'Phenotype', 'HP:0001028', (218, 229))	('enchondromatosis', 'Disease', (197, 213))	('enchondroma', 'Phenotype', 'HP:0030038', (197, 208))	('hereditary enchondromatosis-associated disorders', 'Disease', 'MESH:D004687', (85, 133))	('enchondromas', 'Disease', 'MESH:D002812', (251, 263))	('enchondromatosis', 'Disease', 'MESH:D004687', (151, 167))	('hereditary enchondromatosis-associated disorders', 'Disease', (85, 133))	('Mutations', 'Var', (0, 9))	('enchondroma', 'Phenotype', 'HP:0030038', (251, 262))	('enchondromatosis', 'Disease', 'MESH:D004687', (197, 213))	('isocitrate dehydrogenase ( IDH) 1 and 2', 'Gene', '3417;3418', (17, 56))	('present', 'Reg', (67, 74))	('enchondromatosis-', 'Phenotype', 'HP:0030038', (96, 113))	('enchondromas', 'Disease', (251, 263))	('Maffuci syndrome', 'Disease', 'MESH:D013577', (179, 195))	('enchondromatosis', 'Disease', (96, 112))	('Ollier disease', 'Disease', 'MESH:D004687', (135, 149))	('enchondromatosis and hemangiomas', 'Disease', 'MESH:D004687', (197, 229))	('enchondroma', 'Phenotype', 'HP:0030038', (96, 107))	('Ollier disease', 'Disease', (135, 149))	('Ollier disease', 'Phenotype', 'HP:0500045', (135, 149))	('enchondromas', 'Phenotype', 'HP:0030038', (251, 263))
288992	30519452	IDH mutations are present in 52-59% of central CS and 57% of dedifferentiated CS .	('central CS', 'Disease', (39, 49))	('IDH', 'Gene', (0, 3))	('CS', 'Phenotype', 'HP:0006765', (78, 80))	('IDH', 'Gene', '3417', (0, 3))	('CS', 'Phenotype', 'HP:0006765', (47, 49))	('mutations', 'Var', (4, 13))
288993	30519452	The presence of IDH mutations in benign enchondromas and malignant CS supports the notion that IDH mutations are an early event, and these cartilaginous neoplasms represent a spectrum of malignant potential.	('CS', 'Phenotype', 'HP:0006765', (67, 69))	('enchondroma', 'Phenotype', 'HP:0030038', (40, 51))	('neoplasms', 'Phenotype', 'HP:0002664', (153, 162))	('enchondromas', 'Disease', 'MESH:D002812', (40, 52))	('cartilaginous neoplasms', 'Disease', (139, 162))	('benign', 'Disease', (33, 39))	('IDH', 'Gene', (16, 19))	('cartilaginous neoplasms', 'Disease', 'MESH:D015831', (139, 162))	('enchondromas', 'Disease', (40, 52))	('enchondromas', 'Phenotype', 'HP:0030038', (40, 52))	('IDH', 'Gene', '3417', (16, 19))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))	('mutations', 'Var', (20, 29))
288994	30519452	IDH mutations are found in gliomas, acute myeloid leukemia (AML), and cholangiocarcinomas .	('cholangiocarcinomas', 'Disease', (70, 89))	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('IDH', 'Gene', (0, 3))	('AML', 'Disease', 'MESH:D015470', (60, 63))	('acute myeloid leukemia', 'Disease', (36, 58))	('found', 'Reg', (18, 23))	('IDH', 'Gene', '3417', (0, 3))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (70, 89))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (36, 58))	('AML', 'Phenotype', 'HP:0004808', (60, 63))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (42, 58))	('AML', 'Disease', (60, 63))	('mutations', 'Var', (4, 13))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('gliomas', 'Disease', (27, 34))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (36, 58))
288996	30519452	Mutant IDH (m IDH) loses the ability to convert isocitrate to alpha-KG and gains a new function that leads to the accumulation of delta-2-hydroxyglutarate (D2HG).	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', (14, 17))	('ability', 'MPA', (29, 36))	('delta-2-hydroxyglutarate', 'MPA', (130, 154))	('IDH', 'Gene', '3417', (7, 10))	('isocitrate', 'Chemical', 'MESH:C034219', (48, 58))	('IDH', 'Gene', '3417', (14, 17))	('gains', 'PosReg', (75, 80))	('convert isocitrate to alpha-KG', 'MPA', (40, 70))	('accumulation', 'PosReg', (114, 126))	('loses', 'NegReg', (19, 24))	('Mutant', 'Var', (0, 6))	('alpha-KG', 'Chemical', 'MESH:D007656', (62, 70))	('delta-2-hydroxyglutarate', 'Chemical', '-', (130, 154))
288997	30519452	D2HG is considered an oncometabolite owing to its inhibition of alpha-KG-dependent dioxygenases involved in DNA and histone demethylation, which leads to a hypermethylated state of DNA and histones .	('DNA', 'Protein', (181, 184))	('alpha-KG', 'Chemical', 'MESH:D007656', (64, 72))	('inhibition', 'NegReg', (50, 60))	('histones', 'Protein', (189, 197))	('histone', 'Protein', (116, 123))	('leads to', 'Reg', (145, 153))	('alpha-KG-dependent dioxygenases', 'Enzyme', (64, 95))	('hypermethylated state', 'MPA', (156, 177))	('D2HG', 'Var', (0, 4))
288999	30519452	Inhibition of oncogenic m IDH1/2 represents an opportunity for therapeutic intervention.	('IDH1/2', 'Gene', (26, 32))	('IDH1/2', 'Gene', '3417;3418', (26, 32))	('Inhibition', 'Var', (0, 10))
289004	30519452	Likewise, IDH305 (Novartis), FT-2102 (Forma Therapeutics), and BAY1436032 (Bayer) are in early phase clinical testing.	('IDH', 'Gene', (10, 13))	('BAY1436032', 'Var', (63, 73))	('clinical', 'Species', '191496', (101, 109))	('IDH', 'Gene', '3417', (10, 13))
289005	30519452	m IDH inhibition is a promising therapeutic approach in advanced CS.	('IDH', 'Gene', (2, 5))	('CS', 'Phenotype', 'HP:0006765', (65, 67))	('inhibition', 'Var', (6, 16))	('IDH', 'Gene', '3417', (2, 5))	('advanced CS', 'Disease', (56, 67))
289007	30519452	In addition to confirming IDH1/2 mutations in 59% of the cases, the investigators identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions, and rearrangements identified in 37% of cases.	('cartilage collagen', 'Gene', (122, 140))	('deletions', 'Var', (171, 180))	('cartilage collagen', 'Gene', '1280', (122, 140))	('IDH1/2', 'Gene', (26, 32))	('mutations', 'Var', (33, 42))	('rearrangements', 'Var', (186, 200))	('insertions', 'Var', (159, 169))	('COL2A1', 'Gene', '1280', (146, 152))	('COL2A1', 'Gene', (146, 152))	('IDH1/2', 'Gene', '3417;3418', (26, 32))
289009	30519452	Disruption of the collagen maturation process through production of aberrant pro-collagen alpha-chain is the likely result.	('collagen maturation process', 'CPA', (18, 45))	('aberrant pro-collagen alpha-chain', 'Phenotype', 'HP:0008271', (68, 101))	('aberrant', 'Var', (68, 76))	('pro-collagen alpha-chain', 'Protein', (77, 101))	('rat', 'Species', '10116', (31, 34))
289010	30519452	The investigators hypothesized that COL2A1 mutations might bring about fundamental perturbation of matrix deposition and signaling that contributes to oncogenesis through abrogation of normal differentiation programs in CS.	('matrix', 'CPA', (99, 105))	('oncogenesis', 'CPA', (151, 162))	('mutations', 'Var', (43, 52))	('CS', 'Phenotype', 'HP:0006765', (220, 222))	('COL2A1', 'Gene', '1280', (36, 42))	('abrogation', 'NegReg', (171, 181))	('COL2A1', 'Gene', (36, 42))	('contributes', 'Reg', (136, 147))
289022	30519452	Perturbations to tumor suppressor pathways are common in CS.	('CS', 'Phenotype', 'HP:0006765', (57, 59))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('Perturbations', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
289029	30519452	Likewise, alterations in the TP53 gene occur in 20-50% of conventional and dedifferentiated CS , .	('TP53', 'Gene', (29, 33))	('alterations', 'Var', (10, 21))	('rat', 'Species', '10116', (14, 17))	('CS', 'Phenotype', 'HP:0006765', (92, 94))
289036	30519452	Loss of PTEN function has been implicated in many human cancers; however, PTEN mutations are rare in CS despite evidence of active Akt signaling , .	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('CS', 'Phenotype', 'HP:0006765', (101, 103))	('Akt', 'Gene', (131, 134))	('PTEN', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('PTEN', 'Gene', '5728', (8, 12))	('PTEN', 'Gene', (74, 78))	('Akt', 'Gene', '207', (131, 134))	('PTEN', 'Gene', '5728', (74, 78))	('human', 'Species', '9606', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('mutations', 'Var', (79, 88))
289049	30519452	In contrast, miR-181a is considered a CS oncogene, as it is overexpressed in high-grade CS, is upregulated by hypoxia, and increases vascular endothelial growth factor (VEGF) expression by targeting regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling .	('vascular endothelial growth factor', 'Gene', '7422', (133, 167))	('CXC chemokine receptor 4', 'Gene', (268, 292))	('CXCR4', 'Gene', '7852', (294, 299))	('targeting', 'NegReg', (189, 198))	('RGS16', 'Gene', (236, 241))	('CXCR4', 'Gene', (294, 299))	('vascular endothelial growth factor', 'Gene', (133, 167))	('increases', 'PosReg', (123, 132))	('expression', 'MPA', (175, 185))	('CS', 'Phenotype', 'HP:0006765', (38, 40))	('CS', 'Phenotype', 'HP:0006765', (88, 90))	('CXC chemokine receptor 4', 'Gene', '7852', (268, 292))	('RGS16', 'Gene', '6004', (236, 241))	('hypoxia', 'Disease', (110, 117))	('VEGF', 'Gene', '7422', (169, 173))	('VEGF', 'Gene', (169, 173))	('regulator of G-protein signaling 16', 'Gene', (199, 234))	('hypoxia', 'Disease', 'MESH:D000860', (110, 117))	('increases vascular endothelial growth factor', 'Phenotype', 'HP:0031052', (123, 167))	('upregulated', 'PosReg', (95, 106))	('miR-181a', 'Var', (13, 21))	('regulator of G-protein signaling 16', 'Gene', '6004', (199, 234))
289052	30519452	Similarly, hypermethylation of the promoter region of the tumor suppressor RUNX3 transcription factor leads to reduced gene expression, increased proliferation, and reduced apoptosis in CS cells in vitro .	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('apoptosis', 'CPA', (173, 182))	('gene expression', 'MPA', (119, 134))	('hypermethylation', 'Var', (11, 27))	('proliferation', 'CPA', (146, 159))	('rat', 'Species', '10116', (153, 156))	('reduced', 'NegReg', (111, 118))	('CS', 'Phenotype', 'HP:0006765', (186, 188))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('RUNX3', 'Gene', '864', (75, 80))	('increased', 'PosReg', (136, 145))	('RUNX3', 'Gene', (75, 80))	('reduced', 'NegReg', (165, 172))
289053	30519452	Expression of RUNX3 correlates with improved CS clinical outcomes, further underlying the importance of DNA methylation in CS .	('RUNX3', 'Gene', (14, 19))	('RUNX3', 'Gene', '864', (14, 19))	('clinical', 'Species', '191496', (48, 56))	('Expression', 'Var', (0, 10))	('CS', 'Phenotype', 'HP:0006765', (123, 125))	('improved', 'PosReg', (36, 44))	('CS', 'Phenotype', 'HP:0006765', (45, 47))
289054	30519452	Naturally, the postulated mechanism is mutant IDH-induced accumulation of D2HG leading to inhibition of the demethylase TET methylcytosine dioxygenase proteins.	('inhibition', 'NegReg', (90, 100))	('D2HG', 'Gene', (74, 78))	('accumulation', 'PosReg', (58, 70))	('IDH', 'Gene', (46, 49))	('demethylase', 'Enzyme', (108, 119))	('IDH', 'Gene', '3417', (46, 49))	('mutant', 'Var', (39, 45))
289055	30519452	This analysis of 92 central and 45 peripheral CS tumors showed that although the CS were strongly positive for the H3K4me3, H3K9me3, and H3K27me3 histone modifications, neither these modifications nor the variable levels of 5-hydroxymethylcytosine and 5-methylcytosine correlated with IDH1/2 mutation status.	('positive', 'Reg', (98, 106))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (224, 247))	('CS', 'Phenotype', 'HP:0006765', (46, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('CS', 'Phenotype', 'HP:0006765', (81, 83))	('H3K4me3', 'Protein', (115, 122))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('H3K27me3', 'Var', (137, 145))	('IDH1/2', 'Gene', '3417;3418', (285, 291))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (252, 268))	('tumors', 'Disease', (49, 55))	('H3K9me3', 'Var', (124, 131))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('IDH1/2', 'Gene', (285, 291))
289232	33190044	Silencing TGF-beta expression in MSCs can revert the EMT-promoting effect, subsequently accompanied by the anti-proliferative and pro-apoptotic effect of MSCs on A549 lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('TGF-beta', 'Gene', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('MSC', 'Gene', '9242', (33, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('TGF-beta', 'Gene', '7039', (10, 18))	('MSC', 'Gene', '9242', (154, 157))	('A549', 'CellLine', 'CVCL:0023', (162, 166))	('rat', 'Species', '10116', (119, 122))	('MSC', 'Gene', (33, 36))	('MSC', 'Gene', (154, 157))	('EMT-promoting effect', 'CPA', (53, 73))	('revert', 'NegReg', (42, 48))	('anti-proliferative', 'CPA', (107, 125))	('Silencing', 'Var', (0, 9))
289306	33190044	More recently, a novel suicide gene, namely, iCasp9, has been proposed and MSCs co-expressing iCasp9 and TRAIL successfully target an aggressive sarcoma type.	('aggressive sarcoma', 'Disease', 'MESH:D012509', (134, 152))	('MSC', 'Gene', '9242', (75, 78))	('iCasp9', 'Var', (94, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('aggressive sarcoma', 'Disease', (134, 152))	('MSC', 'Gene', (75, 78))	('target', 'Reg', (124, 130))
289347	33190044	However, it is important to be aware whether gene-modified MSCs may be detrimental to MSC-based therapies.	('gene-modified', 'Var', (45, 58))	('MSC', 'Gene', '9242', (86, 89))	('MSC', 'Gene', '9242', (59, 62))	('MSC', 'Gene', (86, 89))	('MSC', 'Gene', (59, 62))
289466	29491601	Bcl-2 alteration may also participate in the pathogenesis of this neoplasm.	('neoplasm', 'Disease', (66, 74))	('participate', 'Reg', (26, 37))	('neoplasm', 'Disease', 'MESH:D009369', (66, 74))	('neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('alteration', 'Var', (6, 16))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))
289506	27602777	The median hemoglobin level, platelet and leukocyte counts were 10.6 g/dl (range: 8-14), 309 G/L (range 30-486) and 9.3 G/L (range 2.8-15), respectively.	('309 G/L', 'SUBSTITUTION', 'None', (89, 96))	('309 G/L', 'Var', (89, 96))	('hemoglobin level', 'MPA', (11, 27))
289525	27602777	The KIT D816V mutation was detected in 3 of 14 (21%) patients tested.	('D816V', 'Var', (8, 13))	('patients', 'Species', '9606', (53, 61))	('D816V', 'Mutation', 'rs121913507', (8, 13))	('KIT', 'Gene', (4, 7))
289526	27602777	Of the remaining 11 patients without KIT D816V mutations, 7 patients (50%) had wild-type KIT (KIT WT), whereas the other 4 patients (29%) had mutations detected in exon 17 (Asp 822 Lys, n = 1; Leu 799 Phe, n = 1), exon 11 (Val 560 Gly, n = 1) and exon 8 (Del D419, n = 1).	('Leu 799 Phe', 'Mutation', 'p.L799F', (193, 204))	('Asp 822 Lys', 'Mutation', 'p.D822K', (173, 184))	('Del D419', 'Var', (255, 263))	('Val 560 Gly', 'Var', (223, 234))	('D816V', 'Var', (41, 46))	('Asp 822 Lys', 'Var', (173, 184))	('D816V', 'Mutation', 'rs121913507', (41, 46))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (60, 68))	('Val 560 Gly', 'Mutation', 'rs121913521', (223, 234))	('patients', 'Species', '9606', (20, 28))
289529	27602777	A recent study from CEREMAST reported on the patterns of FDG-PET/CT in systemic mastocytosis.	('mastocytosis', 'Phenotype', 'HP:0100495', (80, 92))	('systemic mastocytosis', 'Disease', (71, 92))	('FDG-PET/CT', 'Var', (57, 67))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (71, 92))
289545	27602777	Of the patients tested for KIT mutations, death occurred in 2 of 3 patients in the subgroup with the KIT D816V mutation and in 5 of 11 patients without any KIT mutations.	('D816V', 'Mutation', 'rs121913507', (105, 110))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (67, 75))	('D816V mutation', 'Var', (105, 119))	('KIT', 'Gene', (101, 104))	('death', 'Disease', 'MESH:D003643', (42, 47))	('death', 'Disease', (42, 47))	('patients', 'Species', '9606', (7, 15))
289555	27602777	The KIT D816V mutant found in adult human mastocytosis causes constitutive activation of the KIT kinase.	('activation', 'PosReg', (75, 85))	('constitutive', 'MPA', (62, 74))	('mastocytosis', 'Disease', 'MESH:D008415', (42, 54))	('mastocytosis', 'Disease', (42, 54))	('D816V', 'Var', (8, 13))	('human', 'Species', '9606', (36, 41))	('D816V', 'Mutation', 'rs121913507', (8, 13))	('KIT kinase', 'Enzyme', (93, 103))	('KIT', 'Gene', (4, 7))	('mastocytosis', 'Phenotype', 'HP:0100495', (42, 54))
289556	27602777	Particularly, the KIT D816V mutation confers resistance to the majority of TKI drugs.	('D816V', 'Var', (22, 27))	('D816V', 'Mutation', 'rs121913507', (22, 27))	('resistance', 'MPA', (45, 55))	('KIT', 'Gene', (18, 21))
289557	27602777	In October 2006, the U.S. Food & Drug Administration gave approval for the use of imatinib in adult patients either with ASM lacking the D816V KIT mutation or with an unknown KIT mutation status at a dose of 400 mg daily.	('ASM', 'Gene', '283120', (121, 124))	('ASM', 'Gene', (121, 124))	('D816V', 'Mutation', 'rs121913507', (137, 142))	('the D816V', 'Var', (133, 142))	('patients', 'Species', '9606', (100, 108))	('imatinib', 'Chemical', 'MESH:D000068877', (82, 90))
289561	27602777	Dasatinib has demonstrated significant inhibitory activity at sub-micromolar concentrations in vitro against both KIT WT and the KIT D816V mutation, as well as against juxtamembrane domain mutants of KIT.	('KIT', 'Gene', (129, 132))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('D816V', 'Var', (133, 138))	('D816V', 'Mutation', 'rs121913507', (133, 138))	('inhibitory activity', 'MPA', (39, 58))
289576	27602777	The following data from each article were extracted by 2 independent authors (JM, SGL): patient demographics (e.g., age, sex, geographic origin when available, personal or familial history of mastocytosis, age at disease onset), disease characteristics (e.g., date of diagnosis, time from the start of symptoms to diagnosis, organ involvement, cutaneous lesions, localization of the sarcoma, mast cell activation symptoms (MCAS)), biological characteristics (e.g., blood cell counts, serum tryptase level, MC phenotype, KIT mutations), histopathology, cytology and disease and patient outcome.	('sarcoma', 'Disease', 'MESH:D012509', (383, 390))	('patient', 'Species', '9606', (88, 95))	('cutaneous lesions', 'Disease', (344, 361))	('mastocytosis', 'Disease', 'MESH:D008415', (192, 204))	('sarcoma', 'Disease', (383, 390))	('mastocytosis', 'Disease', (192, 204))	('KIT', 'Gene', (520, 523))	('patient', 'Species', '9606', (577, 584))	('sarcoma', 'Phenotype', 'HP:0100242', (383, 390))	('cutaneous lesions', 'Disease', 'MESH:D051437', (344, 361))	('mastocytosis', 'Phenotype', 'HP:0100495', (192, 204))	('mutations', 'Var', (524, 533))	('mast cell activation symptoms', 'Disease', (392, 421))	('serum tryptase level', 'MPA', (484, 504))
289581	27602777	Wild-type or KIT D816V mutations are frequent, and complete gene sequencing is needed.	('KIT', 'Gene', (13, 16))	('D816V', 'Var', (17, 22))	('D816V', 'Mutation', 'rs121913507', (17, 22))
289840	27197945	The top 100 most variant cancer genes were used in unsupervised clustering to generate heat maps using CIMminer.	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('variant', 'Var', (17, 24))
289875	27197945	Similarly, deletions of the region in chromosome 26 containing the PTEN gene have been observed in 40.7% of canine histiocytic sarcomas and 30% of canine osteosarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (159, 167))	('canine', 'Species', '9615', (108, 114))	('osteosarcomas', 'Phenotype', 'HP:0002669', (154, 167))	('sarcomas', 'Disease', (127, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('osteosarcoma', 'Phenotype', 'HP:0002669', (154, 166))	('osteosarcomas', 'Disease', 'MESH:D012516', (154, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('sarcomas', 'Disease', (159, 167))	('deletions', 'Var', (11, 20))	('PTEN', 'Gene', (67, 71))	('sarcomas', 'Disease', 'MESH:D012509', (127, 135))	('canine', 'Species', '9615', (147, 153))	('PTEN', 'Gene', '403832', (67, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('observed', 'Reg', (87, 95))	('osteosarcomas', 'Disease', (154, 167))
289909	27197945	Sequencing would be an invaluable tool in identifying potential mutations and/or deletions in oncogenes and tumour suppressors across the entire genome.	('tumour', 'Disease', (108, 114))	('oncogenes', 'Gene', (94, 103))	('deletions', 'Var', (81, 90))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (64, 73))	('tumour', 'Disease', 'MESH:D009369', (108, 114))
289910	27197945	Array-CGH would allow investigation of alterations in copy number of genes and their role in canine cancer progression.	('copy number', 'Var', (54, 65))	('canine', 'Species', '9615', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
289934	29100385	A key element that allows cancer development is the deregulation of histone acetylation as well as the mutation and/or aberrant expression of HDACs.	('aberrant', 'Var', (119, 127))	('deregulation', 'MPA', (52, 64))	('HDAC', 'Gene', (142, 146))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('HDAC', 'Gene', '9734', (142, 146))	('histone acetylation', 'MPA', (68, 87))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('expression', 'MPA', (128, 138))	('mutation', 'Var', (103, 111))
289937	29100385	Interestingly, inhibition of HDAC activity by small molecules has been shown to provide a therapeutic benefit to patients with diverse diseases including malignancies.	('inhibition', 'NegReg', (15, 25))	('malignancies', 'Disease', 'MESH:D009369', (154, 166))	('patients', 'Species', '9606', (113, 121))	('HDAC', 'Gene', (29, 33))	('HDAC', 'Gene', '9734', (29, 33))	('small molecules', 'Var', (46, 61))	('malignancies', 'Disease', (154, 166))
289945	29100385	After treatment with the respective IC50 and IC75 concentrations of SAHA, LBH-589, and PXD101 for 48 h, whole cell lysates were extracted from the cells and prepared for western blot analysis.	('PXD101', 'Var', (87, 93))	('LBH', 'Gene', (74, 77))	('SAHA', 'Chemical', 'MESH:D000077337', (68, 72))	('LBH', 'Gene', '81606', (74, 77))
289952	29100385	Consistent with the inhibition of G1-to-S phase progression we found decreased cyclin D1 expression and decreased phosphorylation of CDK4 and CDK2 in SW-982 cells in response to SAHA, LBH-589, and PXD101.	('cyclin D1', 'Gene', (79, 88))	('LBH', 'Gene', '81606', (184, 187))	('expression', 'MPA', (89, 99))	('PXD101', 'Var', (197, 203))	('decreased', 'NegReg', (69, 78))	('CDK4', 'Gene', (133, 137))	('decreased', 'NegReg', (104, 113))	('CDK2', 'Gene', (142, 146))	('SW-982', 'CellLine', 'CVCL:1734', (150, 156))	('CDK4', 'Gene', '1019', (133, 137))	('SAHA', 'Chemical', 'MESH:D000077337', (178, 182))	('phosphorylation', 'MPA', (114, 129))	('LBH', 'Gene', (184, 187))	('CDK2', 'Gene', '1017', (142, 146))	('cyclin D1', 'Gene', '595', (79, 88))
289954	29100385	In SW-1353, treatment with LBH-582 and PXD101 led to diminished phosphorylation of CDK4, although only small changes in cell cycle distribution were observed.	('CDK4', 'Gene', '1019', (83, 87))	('diminished', 'NegReg', (53, 63))	('phosphorylation', 'MPA', (64, 79))	('LBH', 'Gene', (27, 30))	('PXD101', 'Var', (39, 45))	('LBH', 'Gene', '81606', (27, 30))	('SW-1353', 'CellLine', 'CVCL:0543', (3, 10))	('CDK4', 'Gene', (83, 87))
289961	29100385	Interestingly, we found no up-regulation but a slight down-regulation of p53 in SW-982 cells expressing wild-type p53, although phosphorylated histone variant H2AX, a biomarker for DNA double strand breaks (DBS), was elevated in response to all three HDAC inhibitors used (Figure 5).	('SW-982', 'CellLine', 'CVCL:1734', (80, 86))	('p53', 'Gene', (114, 117))	('H2AX', 'Gene', '3014', (159, 163))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('H2AX', 'Gene', (159, 163))	('p53', 'Gene', '7157', (114, 117))	('down-regulation', 'NegReg', (54, 69))	('DBS', 'Chemical', '-', (207, 210))	('HDAC', 'Gene', (251, 255))	('variant', 'Var', (151, 158))	('elevated', 'PosReg', (217, 225))	('HDAC', 'Gene', '9734', (251, 255))
289968	29100385	In SW-982 cells, caspase 3/7 activity was increased in response to SAHA, PXD101, LBH-589 treatment after 24 and 48 hours (p < 0.05) up to 23%.	('increased', 'PosReg', (42, 51))	('LBH', 'Gene', '81606', (81, 84))	('caspase 3', 'Gene', '836', (17, 26))	('PXD101', 'Var', (73, 79))	('SAHA', 'Chemical', 'MESH:D000077337', (67, 71))	('activity', 'MPA', (29, 37))	('LBH', 'Gene', (81, 84))	('SW-982', 'CellLine', 'CVCL:1734', (3, 9))	('caspase 3', 'Gene', (17, 26))
289977	29100385	Whereas in SW-982 cells no synergistic effect could be observed (Figure 7A), in SW1353 cells the combination of doxorubicin with all three HDACi resulted in a significant reduction of cell growth compared to doxorubicin treatment alone (Figure 7B).	('SW1353', 'Var', (80, 86))	('combination', 'Interaction', (97, 108))	('SW1353', 'CellLine', 'CVCL:0543', (80, 86))	('cell growth', 'CPA', (184, 195))	('doxorubicin', 'Chemical', 'MESH:D004317', (208, 219))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('HDAC', 'Gene', (139, 143))	('reduction', 'NegReg', (171, 180))	('HDAC', 'Gene', '9734', (139, 143))	('SW-982', 'CellLine', 'CVCL:1734', (11, 17))
289981	29100385	SAHA and PXD101 have been shown to suppress growth of various tumor cells in vitro at low micromolar concentrations.	('PXD101', 'Var', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('SAHA', 'Chemical', 'MESH:D000077337', (0, 4))	('suppress', 'NegReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
290002	29100385	Consistent with the inhibition of G1-to-S phase progression, we found decreased cyclin D1 expression and decreased phosphorylation of CDK4 and CDK2 in synovial sarcoma cells in response to SAHA, LBH-589, and PXD101.	('PXD101', 'Var', (208, 214))	('synovial sarcoma cells', 'Disease', (151, 173))	('LBH', 'Gene', (195, 198))	('cyclin D1', 'Gene', (80, 89))	('decreased', 'NegReg', (70, 79))	('CDK2', 'Gene', '1017', (143, 147))	('LBH', 'Gene', '81606', (195, 198))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (151, 167))	('expression', 'MPA', (90, 100))	('SAHA', 'Chemical', 'MESH:D000077337', (189, 193))	('CDK4', 'Gene', '1019', (134, 138))	('CDK4', 'Gene', (134, 138))	('cyclin D1', 'Gene', '595', (80, 89))	('phosphorylation', 'MPA', (115, 130))	('synovial sarcoma cells', 'Disease', 'MESH:D013584', (151, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('decreased', 'NegReg', (105, 114))	('CDK2', 'Gene', (143, 147))
290013	29100385	In endometrial cancers SAHA was demonstrated to increase p21 expression at simultaneous reduction of p53 and cyclin D level as seen here by SAHA, LBH-589, and PXD101 in synovial sarcoma cells and by SAHA in chondrosarcoma cells.	('SAHA', 'Chemical', 'MESH:D000077337', (23, 27))	('LBH', 'Gene', (146, 149))	('chondrosarcoma', 'Disease', (207, 221))	('chondrosarcoma', 'Disease', 'MESH:D002813', (207, 221))	('p21', 'Gene', (57, 60))	('endometrial cancers SAHA', 'Disease', (3, 27))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (169, 185))	('cyclin', 'Gene', '5111', (109, 115))	('p21', 'Gene', '644914', (57, 60))	('SAHA', 'Chemical', 'MESH:D000077337', (140, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('LBH', 'Gene', '81606', (146, 149))	('PXD101', 'Var', (159, 165))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (207, 221))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('reduction', 'NegReg', (88, 97))	('cyclin', 'Gene', (109, 115))	('p53', 'Gene', '7157', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('synovial sarcoma cells', 'Disease', 'MESH:D013584', (169, 191))	('synovial sarcoma cells', 'Disease', (169, 191))	('p53', 'Gene', (101, 104))	('SAHA', 'Chemical', 'MESH:D000077337', (199, 203))	('endometrial cancers SAHA', 'Disease', 'MESH:D016889', (3, 27))	('increase', 'PosReg', (48, 56))
290044	29100385	The FITC-conjugated monoclonal cleaved caspase-3 (Asp175) antibody (Cell Signaling Technology, Danvers, MA) detects endogenous levels of the large fragment (17/19 kDa) of activated caspase-3 resulting from cleavage adjacent to aspartic acid175.	('17/19 kDa', 'Var', (157, 166))	('caspase-3', 'Gene', '836', (181, 190))	('cleavage', 'Var', (206, 214))	('caspase-3', 'Gene', (39, 48))	('aspartic acid175', 'Chemical', '-', (227, 243))	('Asp175', 'Chemical', '-', (50, 56))	('caspase-3', 'Gene', (181, 190))	('FITC', 'Chemical', 'MESH:D016650', (4, 8))	('caspase-3', 'Gene', '836', (39, 48))
290067	28511645	We have found that a selective c-MET inhibitor suppresses the growth of Yamato-SS cells, but fails to suppress the growth of SYO-1 or HS-SY-II cells.	('growth', 'CPA', (62, 68))	('SYO-1', 'Gene', '55027', (125, 130))	('SYO-1', 'Gene', (125, 130))	('c-MET', 'Protein', (31, 36))	('suppresses', 'NegReg', (47, 57))	('Yamato', 'Chemical', '-', (72, 78))	('SS', 'Phenotype', 'HP:0012570', (79, 81))	('Yamato-SS cells', 'CPA', (72, 87))	('inhibitor', 'Var', (37, 46))	('HS-SY-II', 'CellLine', 'CVCL:8719', (134, 142))
290089	28511645	Antibodies against PDGFRalpha (#7074), p-PDGFRalpha (Tyr754; #2992, Tyr849; #3170, Tyr1018; #4547), c-MET (#8198), p-MET (Tyr1234/1235; #3077), AKT (#4691), p-AKT (Ser473; #4060), ERK (#4695), p-ERK (Thr202/Tyr204; #4370), PARP (#9542) and beta-actin (#4970) were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('Tyr1018', 'Chemical', '-', (83, 90))	('AKT', 'Gene', (144, 147))	('ERK', 'Gene', (180, 183))	('Tyr754', 'Chemical', '-', (53, 59))	('AKT', 'Gene', '207', (159, 162))	('ERK', 'Gene', (195, 198))	('Ser473; #4060', 'Var', (164, 177))	('#9542', 'Var', (229, 234))	('#4970', 'Var', (252, 257))	('AKT', 'Gene', '207', (144, 147))	('Tyr754; #2992', 'Var', (53, 66))	('Tyr1018; #4547', 'Var', (83, 97))	('#4691', 'Var', (149, 154))	('PARP', 'Gene', '142', (223, 227))	('#7074', 'Var', (31, 36))	('ERK', 'Gene', '5594', (180, 183))	('AKT', 'Gene', (159, 162))	('PARP', 'Gene', (223, 227))	('ERK', 'Gene', '5594', (195, 198))	('Tyr849', 'Chemical', '-', (68, 74))	('#4695', 'Var', (185, 190))
290090	28511645	An antibody against p-PDGFRalpha (Tyr762; AF21141) was purchased from R&D systems (Minneapolis, MN, USA).	('Tyr762;', 'Var', (34, 41))	('Tyr762', 'Chemical', '-', (34, 40))	('p-PDGFRalpha', 'Gene', (20, 32))	('MN', 'CellLine', 'CVCL:U508', (96, 98))
290120	28511645	Silencing of c-MET expression significantly inhibited the growth of Yamato-SS cells but had little effect on the viability of the SYO-1 or HS-SY-II cells (Fig.	('growth', 'CPA', (58, 64))	('inhibited', 'NegReg', (44, 53))	('Yamato', 'Chemical', '-', (68, 74))	('SS', 'Phenotype', 'HP:0012570', (75, 77))	('Yamato-SS cells', 'CPA', (68, 83))	('SYO-1', 'Gene', '55027', (130, 135))	('HS-SY-II', 'CellLine', 'CVCL:8719', (139, 147))	('Silencing', 'Var', (0, 9))	('SYO-1', 'Gene', (130, 135))	('c-MET', 'Protein', (13, 18))
290121	28511645	By contrast, knockdown of PDGFRalpha expression markedly abrogated the proliferation of SYO-1 and HS-SY-II cells, but not that of Yamato-SS cells (Fig.	('Yamato', 'Chemical', '-', (130, 136))	('SYO-1', 'Gene', '55027', (88, 93))	('SS', 'Phenotype', 'HP:0012570', (137, 139))	('abrogated', 'NegReg', (57, 66))	('SYO-1', 'Gene', (88, 93))	('proliferation', 'CPA', (71, 84))	('HS-SY-II', 'CellLine', 'CVCL:8719', (98, 106))	('HS-SY-II', 'CPA', (98, 106))	('knockdown', 'Var', (13, 22))	('PDGFRalpha', 'Gene', (26, 36))
290128	28511645	TAS-115 increased the percentage of cells in the G0/G1-phase and decreased the percentage of cells in the S-phase in the Yamato-SS, SYO-1 and HS-SY-II cells in a dose-dependent manner (Fig.	('G0/G1-phase', 'CPA', (49, 60))	('decreased', 'NegReg', (65, 74))	('HS-SY-II', 'CellLine', 'CVCL:8719', (142, 150))	('SYO-1', 'Gene', '55027', (132, 137))	('TAS-115', 'Var', (0, 7))	('Yamato', 'Chemical', '-', (121, 127))	('increased', 'PosReg', (8, 17))	('SYO-1', 'Gene', (132, 137))	('TAS-115', 'Chemical', 'MESH:C000590217', (0, 7))	('SS', 'Phenotype', 'HP:0012570', (128, 130))
290131	28511645	TAS-115 also caused slight apoptosis in the Yamato-SS cells, but not in the SYO-1 or HS-SY-II cells.	('HS-SY-II', 'CellLine', 'CVCL:8719', (85, 93))	('SYO-1', 'Gene', '55027', (76, 81))	('Yamato', 'Chemical', '-', (44, 50))	('SYO-1', 'Gene', (76, 81))	('TAS-115', 'Var', (0, 7))	('TAS-115', 'Chemical', 'MESH:C000590217', (0, 7))	('SS', 'Phenotype', 'HP:0012570', (51, 53))
290135	28511645	Among them, the PDGFRalpha residue Tyr849, which is located inside tyrosine kinase domain II, is critical for activation of the kinase.	('Tyr849', 'Chemical', '-', (35, 41))	('tyrosine', 'Chemical', 'MESH:D014443', (67, 75))	('activation', 'PosReg', (110, 120))	('Tyr849', 'Var', (35, 41))
290137	28511645	TAS-115 at concentrations as low as 1-10 muM remarkably inhibited the phosphorylation of PDGFRalpha on Tyr849, as well as its downstream effectors AKT and ERK 1/2, in the SYO-1 and HS-SY-II cells (Fig.	('PDGFRalpha', 'Gene', (89, 99))	('Tyr849', 'Var', (103, 109))	('Tyr849', 'Chemical', '-', (103, 109))	('HS-SY-II', 'CellLine', 'CVCL:8719', (181, 189))	('muM', 'Gene', '56925', (41, 44))	('muM', 'Gene', (41, 44))	('phosphorylation', 'MPA', (70, 85))	('SYO-1', 'Gene', (171, 176))	('SYO-1', 'Gene', '55027', (171, 176))	('AKT', 'Gene', '207', (147, 150))	('TAS-115', 'Chemical', 'MESH:C000590217', (0, 7))	('ERK 1/2', 'Gene', '5595;5594', (155, 162))	('inhibited', 'NegReg', (56, 65))	('ERK 1/2', 'Gene', (155, 162))	('AKT', 'Gene', (147, 150))
290143	28511645	In SYO-1 and HS-SY-II cells, rhPDGF-BB treatment enhanced the phosphorylation of PDGFRalpha at Tyr754, Tyr762, Tyr849, Tyr1018, as well as the phosphorylation of downstream effectors, AKT and ERK 1/2.	('Tyr849', 'Var', (111, 117))	('enhanced', 'PosReg', (49, 57))	('HS-SY-II', 'CellLine', 'CVCL:8719', (13, 21))	('Tyr849', 'Chemical', '-', (111, 117))	('AKT', 'Gene', '207', (184, 187))	('Tyr762', 'Var', (103, 109))	('phosphorylation', 'MPA', (62, 77))	('phosphorylation', 'MPA', (143, 158))	('ERK 1/2', 'Gene', (192, 199))	('Tyr1018', 'Chemical', '-', (119, 126))	('SYO-1', 'Gene', '55027', (3, 8))	('Tyr762', 'Chemical', '-', (103, 109))	('SYO-1', 'Gene', (3, 8))	('PDGFRalpha', 'Gene', (81, 91))	('rhPDGF-BB', 'Gene', (29, 38))	('Tyr754', 'Var', (95, 101))	('Tyr1018', 'Var', (119, 126))	('ERK 1/2', 'Gene', '5595;5594', (192, 199))	('AKT', 'Gene', (184, 187))	('Tyr754', 'Chemical', '-', (95, 101))
290148	28511645	Both TAS-115 and pazopanib blocked the phosphorylation of PDGFRalpha at Tyr754, Tyr762, Tyr849, Tyr1018, as well as the phosphorylation of downstream effectors in SYO-1 xenograft tumours (Fig.	('Tyr1018', 'Chemical', '-', (96, 103))	('phosphorylation', 'MPA', (39, 54))	('PDGFRalpha', 'Gene', (58, 68))	('Tyr762', 'Chemical', '-', (80, 86))	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('phosphorylation', 'MPA', (120, 135))	('pazopanib', 'Chemical', 'MESH:C516667', (17, 26))	('Tyr754', 'Chemical', '-', (72, 78))	('Tyr849', 'Var', (88, 94))	('Tyr762', 'Var', (80, 86))	('SYO-1 xenograft tumours', 'Disease', 'MESH:D009369', (163, 186))	('Tyr849', 'Chemical', '-', (88, 94))	('Tyr754', 'Var', (72, 78))	('TAS-115', 'Chemical', 'MESH:C000590217', (5, 12))	('Tyr1018', 'Var', (96, 103))	('SYO-1 xenograft tumours', 'Disease', (163, 186))	('blocked', 'NegReg', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))
290170	28511645	Aberrant activation of HGF/c-MET signalling by mutation, autocrine or paracrine HGF stimulation, or overexpression has been implicated in the oncogenesis of large number of cancers.	('HGF', 'Gene', '3082', (80, 83))	('activation', 'PosReg', (9, 19))	('implicated', 'Reg', (124, 134))	('HGF', 'Gene', (23, 26))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Disease', (173, 180))	('mutation', 'Var', (47, 55))	('HGF', 'Gene', '3082', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('HGF', 'Gene', (80, 83))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
290171	28511645	Additionally, upregulation or mutational activation of PDGF ligand or PDGFR expression has also been reported in many types of malignancies.	('PDGFR', 'Gene', (70, 75))	('PDGF', 'Protein', (55, 59))	('PDGFR', 'Gene', '5159', (70, 75))	('malignancies', 'Disease', 'MESH:D009369', (127, 139))	('malignancies', 'Disease', (127, 139))	('mutational', 'Var', (30, 40))	('upregulation', 'PosReg', (14, 26))
290173	28511645	Likewise, we noted that 36% of SS specimens expressed both HGF and c-MET, which resulted in a significantly worse clinical course in SS patients.	('clinical', 'Species', '191496', (114, 122))	('resulted', 'Reg', (80, 88))	('SS', 'Phenotype', 'HP:0012570', (133, 135))	('HGF', 'Gene', (59, 62))	('patients', 'Species', '9606', (136, 144))	('c-MET', 'Var', (67, 72))	('SS', 'Phenotype', 'HP:0012570', (31, 33))	('HGF', 'Gene', '3082', (59, 62))
290176	28511645	Silencing of c-MET or PDGFRalpha expression revealed that the proliferation of the Yamato-SS cells sustained the high dependency upon c-MET signalling and that the viability of the SYO-1 or HS-SY-II cells was primarily driven by PDGFRalpha pathway.	('PDGFRalpha pathway', 'Pathway', (229, 247))	('high dependency upon c-MET signalling', 'MPA', (113, 150))	('Silencing', 'Var', (0, 9))	('HS-SY-II', 'CellLine', 'CVCL:8719', (190, 198))	('Yamato', 'Chemical', '-', (83, 89))	('SYO-1', 'Gene', '55027', (181, 186))	('SS', 'Phenotype', 'HP:0012570', (90, 92))	('PDGFRalpha', 'Gene', (22, 32))	('SYO-1', 'Gene', (181, 186))
290203	28511645	In some translocation-related sarcomas, fusion genes are assumed to contribute to the upregulation of RTK cascades.	('upregulation', 'PosReg', (86, 98))	('sarcomas', 'Disease', (30, 38))	('RTK cascades', 'Pathway', (102, 114))	('sarcomas', 'Disease', 'MESH:D012509', (30, 38))	('fusion genes', 'Var', (40, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
290207	28511645	By sharp contrast, our parallel study showed that SS18-SSX silencing did not elicit the downregulation or inactivation of either c-MET or PDGFRalpha.	('downregulation', 'NegReg', (88, 102))	('SS18', 'Gene', (50, 54))	('PDGFRalpha', 'Protein', (138, 148))	('SS18', 'Gene', '6760', (50, 54))	('SSX', 'Gene', '6757', (55, 58))	('c-MET', 'Protein', (129, 134))	('SS', 'Phenotype', 'HP:0012570', (55, 57))	('SSX', 'Gene', (55, 58))	('silencing', 'Var', (59, 68))	('inactivation', 'NegReg', (106, 118))	('SS', 'Phenotype', 'HP:0012570', (50, 52))
290222	28511645	By inhibiting c-MET or PDGFRalpha signalling, TAS-115 achieves significant therapeutic effects in both c-MET-dependent and PDGFRalpha-dependent SS cells in vitro and in vivo.	('c-MET', 'Protein', (14, 19))	('c-MET-dependent', 'Var', (103, 118))	('inhibiting', 'NegReg', (3, 13))	('TAS-115', 'Gene', (46, 53))	('TAS-115', 'Chemical', 'MESH:C000590217', (46, 53))	('SS', 'Phenotype', 'HP:0012570', (144, 146))	('PDGFRalpha-dependent', 'Gene', (123, 143))	('PDGFRalpha', 'Protein', (23, 33))
290274	25729528	On multivariate analysis of these factors, along with the factors significantly associated with comorbidity (age, FNCLCC grade, synovial sarcoma and initial tumor size), the presence of comorbidity was significantly associated with poor DSS after adjustment for initial presentation (Table 3).	('tumor', 'Disease', (157, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (128, 144))	('DSS', 'Chemical', '-', (237, 240))	('associated', 'Reg', (216, 226))	('synovial sarcoma', 'Disease', 'MESH:D013584', (128, 144))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('poor DSS', 'Disease', (232, 240))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('presence', 'Var', (174, 182))	('synovial sarcoma', 'Disease', (128, 144))
290296	25729528	Many explanations for the prognostic or confounding effects of comorbidity have been proposed; suggestions include that comorbidity might affect treatment selection; might increase the likelihood of experiencing treatment-related adverse effects in addition to exacerbations of the comorbidity; might decrease the likelihood of completing prescribed treatments, resulting in lower rates of disease control; and might limit life expectancy itself, independent of the underlying malignancy.	('increase', 'PosReg', (172, 180))	('decrease', 'NegReg', (301, 309))	('comorbidity', 'Var', (120, 131))	('malignancy', 'Disease', 'MESH:D009369', (477, 487))	('affect', 'Reg', (138, 144))	('life expectancy', 'CPA', (423, 438))	('exacerbations', 'PosReg', (261, 274))	('malignancy', 'Disease', (477, 487))	('lower', 'NegReg', (375, 380))	('limit', 'NegReg', (417, 422))	('treatment selection', 'CPA', (145, 164))	('disease control', 'CPA', (390, 405))
290477	29416174	Ifosfamide and cyclophosphamide can also lead to long term fertility complications including azoospermia in male patients.	('azoospermia', 'Phenotype', 'HP:0000027', (93, 104))	('patients', 'Species', '9606', (113, 121))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (15, 31))	('azoospermia', 'Disease', 'MESH:D053713', (93, 104))	('lead to', 'Reg', (41, 48))	('cyclophosphamide', 'Var', (15, 31))	('azoospermia', 'Disease', (93, 104))	('fertility complications', 'Phenotype', 'HP:0000144', (59, 82))	('Ifosfamide', 'Chemical', 'MESH:D007069', (0, 10))
290506	25963410	Multiple oncogenic mutations related to targeted therapy in nasopharyngeal carcinoma An increasing number of targeted drugs have been tested for the treatment of nasopharyngeal carcinoma (NPC).	('NPC', 'Gene', '4864', (188, 191))	('carcinoma', 'Disease', 'MESH:D002277', (177, 186))	('mutations', 'Var', (19, 28))	('carcinoma', 'Disease', 'MESH:D002277', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (162, 186))	('men', 'Species', '9606', (154, 157))	('NPC', 'Gene', (188, 191))	('carcinoma', 'Disease', (177, 186))	('NPC', 'Phenotype', 'HP:0100630', (188, 191))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (60, 84))	('carcinoma', 'Disease', (75, 84))
290507	25963410	This study aimed to detect targeted therapy-related oncogenic mutations in NPC and to determine which targeted therapy might be potentially effective in treating NPC.	('NPC', 'Gene', (162, 165))	('NPC', 'Phenotype', 'HP:0100630', (162, 165))	('NPC', 'Gene', (75, 78))	('NPC', 'Phenotype', 'HP:0100630', (75, 78))	('NPC', 'Gene', '4864', (162, 165))	('NPC', 'Gene', '4864', (75, 78))	('mutations', 'Var', (62, 71))
290509	25963410	Among 70 patients, 12 (17.1%) had mutations in 5 oncogenes: 7 (10.0%) had v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutation, 2 (2.8%) had epidermal growth factor receptor (EGFR) mutation, 1 (1.4%) had phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, 1 (1.4%) had Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and 1 (1.4%) had simultaneous EGFR and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations.	('sarcoma viral', 'Disease', 'MESH:D001102', (105, 118))	('sarcoma viral', 'Disease', (105, 118))	('mutations', 'Var', (485, 494))	('v-Raf murine sarcoma viral oncogene homolog B1', 'Gene', (431, 477))	('epidermal growth factor receptor', 'Gene', (165, 197))	('sarcoma viral', 'Disease', 'MESH:D001102', (344, 357))	('epidermal growth factor receptor', 'Gene', '1956', (165, 197))	('rat', 'Species', '10116', (340, 343))	('sarcoma viral', 'Disease', (344, 357))	('sarcoma', 'Phenotype', 'HP:0100242', (444, 451))	('mutation', 'Var', (309, 317))	('sarcoma viral', 'Disease', 'MESH:D001102', (444, 457))	('v-Raf murine sarcoma viral oncogene homolog B1', 'Gene', '114486', (431, 477))	('mutation', 'Var', (142, 150))	('PIK3CA', 'Gene', (301, 307))	('mutation', 'Var', (205, 213))	('patients', 'Species', '9606', (9, 17))	('BRAF', 'Gene', (479, 483))	('sarcoma', 'Phenotype', 'HP:0100242', (344, 351))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (228, 248))	('mutations', 'Var', (34, 43))
290525	25963410	Additionally, the monoclonal antibody against VEGF had anti-angiogenic effects.	('VEGF', 'Gene', '7422', (46, 50))	('monoclonal antibody', 'Var', (18, 37))	('anti-angiogenic effects', 'CPA', (55, 78))	('VEGF', 'Gene', (46, 50))
290529	25963410	Here, we aimed to evaluate the prevalence of targeted therapy-related oncogenic mutations in NPC using the SNaPshot assay and to identify potentially effective targets in NPC.	('NPC', 'Gene', '4864', (171, 174))	('NPC', 'Phenotype', 'HP:0100630', (93, 96))	('mutations', 'Var', (80, 89))	('NPC', 'Gene', (93, 96))	('NPC', 'Gene', '4864', (93, 96))	('NPC', 'Phenotype', 'HP:0100630', (171, 174))	('NPC', 'Gene', (171, 174))
290532	25963410	All of these factors are common hotspots for mutations in cancer.	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))
290548	25963410	Among the 70 patients, 12 (17.1%) had mutations in 5 oncogenes: 7 (10.0%) had KIT (M541L) mutation, 2 (2.8%) had EGFR (T790M) mutation, 1 (1.4%) had PIK3CA (H1047R) mutation, 1 (1.4%) had KRAS (G13D) mutation, and 1 (1.4%) had simultaneous EGFR and BRAF (V600E) mutations (Figures 1 and 2).	('H1047R', 'Mutation', 'rs121913279', (157, 163))	('M541L', 'Mutation', 'rs3822214', (83, 88))	('KIT (M541L) mutation', 'Var', (78, 98))	('patients', 'Species', '9606', (13, 21))	('T790M', 'Mutation', 'rs121434569', (119, 124))	('G13D', 'Mutation', 'rs112445441', (194, 198))	('mutations', 'Var', (38, 47))	('V600E', 'Mutation', 'rs113488022', (255, 260))
290550	25963410	In this study, with the rapid detection method, we found that KIT mutation was the most frequent in NPC followed by EGFR mutation, whereas PI3KCA, KRAS, and BRAF mutations were less frequent, which was consistent with the results of a previous study.	('NPC', 'Gene', '4864', (100, 103))	('frequent', 'Reg', (88, 96))	('mutation', 'Var', (66, 74))	('NPC', 'Phenotype', 'HP:0100630', (100, 103))	('EGFR', 'Gene', (116, 120))	('KIT', 'Gene', (62, 65))	('NPC', 'Gene', (100, 103))
290551	25963410	Although another retrospective study showed that NPC patients who had recurrence or developed metastases had high mutation frequencies due to the relatively short follow-up duration, our study did not find the same result.	('metastases', 'Disease', (94, 104))	('NPC', 'Gene', (49, 52))	('patients', 'Species', '9606', (53, 61))	('mutation frequencies', 'Var', (114, 134))	('NPC', 'Gene', '4864', (49, 52))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('rat', 'Species', '10116', (175, 178))	('NPC', 'Phenotype', 'HP:0100630', (49, 52))
290555	25963410	It is well known that the KIT oncogene inhibitor imatinib has been widely used in clinical practice and has been approved for use in melanoma, gastrointestinal stromal tumor (GIST), and chronic myelogenous leukemia (CML) patients with KIT mutations.	('patients', 'Species', '9606', (221, 229))	('CML', 'Disease', 'MESH:D015464', (216, 219))	('leukemia', 'Phenotype', 'HP:0001909', (206, 214))	('mutations', 'Var', (239, 248))	('KIT', 'Gene', (235, 238))	('CML', 'Disease', (216, 219))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('chronic myelogenous leukemia', 'Disease', (186, 214))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (186, 214))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (143, 173))	('CML', 'Phenotype', 'HP:0005506', (216, 219))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (194, 214))	('imatinib', 'Chemical', 'MESH:D000068877', (49, 57))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (143, 173))	('GIST', 'Phenotype', 'HP:0100723', (175, 179))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (186, 214))	('gastrointestinal stromal tumor', 'Disease', (143, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
290556	25963410	In our study, a KIT mutation in exon 10 (M541L), which is different than the functional mutations in exon 9 and exon 11, occurred in 10% of NPC patients.	('occurred', 'Reg', (121, 129))	('M541L', 'Mutation', 'rs3822214', (41, 46))	('M541L', 'Var', (41, 46))	('patients', 'Species', '9606', (144, 152))	('NPC', 'Phenotype', 'HP:0100630', (140, 143))	('NPC', 'Gene', (140, 143))	('NPC', 'Gene', '4864', (140, 143))
290557	25963410	However, the KIT (M541L) mutation was considered a gene polymorphism in CML.	('CML', 'Disease', (72, 75))	('M541L', 'Mutation', 'rs3822214', (18, 23))	('CML', 'Disease', 'MESH:D015464', (72, 75))	('CML', 'Phenotype', 'HP:0005506', (72, 75))	('KIT (M541L', 'Var', (13, 23))
290564	25963410	However, EGFR mutations are reported to have an extremely low prevalence (0-1%) in NPC.	('NPC', 'Gene', (83, 86))	('NPC', 'Gene', '4864', (83, 86))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('NPC', 'Phenotype', 'HP:0100630', (83, 86))
290565	25963410	In our study, EGFR mutations were detected in 3 (4.3%) patients, all of whom had the T790M mutation in exon 20.	('detected', 'Reg', (34, 42))	('EGFR', 'Gene', (14, 18))	('T790M', 'Mutation', 'rs121434569', (85, 90))	('mutations', 'Var', (19, 28))	('T790M', 'Var', (85, 90))	('patients', 'Species', '9606', (55, 63))
290567	25963410	This result could be explained by the low EGFR mutation rate in NPC.	('rat', 'Species', '10116', (56, 59))	('mutation', 'Var', (47, 55))	('EGFR', 'Gene', (42, 46))	('NPC', 'Gene', (64, 67))	('NPC', 'Phenotype', 'HP:0100630', (64, 67))	('NPC', 'Gene', '4864', (64, 67))
290568	25963410	In addition, patients with the T790M mutation showed primary resistance to gefitinib.	('T790M', 'Var', (31, 36))	('patients', 'Species', '9606', (13, 21))	('resistance', 'MPA', (61, 71))	('gefitinib', 'Chemical', 'MESH:D000077156', (75, 84))	('T790M', 'Mutation', 'rs121434569', (31, 36))
290576	25963410	The treatment of NPC cells with the PI3K inhibitor LY294002 led to the inhibition of AKT activation.	('LY294002', 'Chemical', 'MESH:C085911', (51, 59))	('LY294002', 'Var', (51, 59))	('AKT', 'Gene', '207', (85, 88))	('men', 'Species', '9606', (9, 12))	('inhibition', 'NegReg', (71, 81))	('activation', 'PosReg', (89, 99))	('AKT', 'Gene', (85, 88))	('NPC', 'Gene', (17, 20))	('NPC', 'Phenotype', 'HP:0100630', (17, 20))	('NPC', 'Gene', '4864', (17, 20))
290580	25963410	Previous studies detected no KRAS mutations in NPC specimens or cell lines.	('KRAS', 'Gene', (29, 33))	('men', 'Species', '9606', (56, 59))	('NPC', 'Phenotype', 'HP:0100630', (47, 50))	('NPC', 'Gene', (47, 50))	('mutations', 'Var', (34, 43))	('NPC', 'Gene', '4864', (47, 50))
290582	25963410	Mutations of the Ras signaling pathway might lead to cetuximab resistance in NPC.	('NPC', 'Phenotype', 'HP:0100630', (77, 80))	('cetuximab resistance', 'MPA', (53, 73))	('NPC', 'Gene', (77, 80))	('lead to', 'Reg', (45, 52))	('Mutations', 'Var', (0, 9))	('cetuximab', 'Chemical', 'MESH:D000068818', (53, 62))	('NPC', 'Gene', '4864', (77, 80))	('Ras signaling pathway', 'Pathway', (17, 38))
290584	25963410	BRAF mutations were more common in melanoma, and a BRAF inhibitor has been approved for the treatment of melanoma.	('common', 'Reg', (25, 31))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('men', 'Species', '9606', (97, 100))	('mutations', 'Var', (5, 14))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
290589	25963410	In our study, we found that 10% of patients with NPC had KIT mutations that were not at the commonly mutated sites.	('NPC', 'Gene', (49, 52))	('NPC', 'Gene', '4864', (49, 52))	('mutations', 'Var', (61, 70))	('patients', 'Species', '9606', (35, 43))	('KIT', 'Gene', (57, 60))	('NPC', 'Phenotype', 'HP:0100630', (49, 52))
290624	29995228	This proved a challenge as the patient was currently on aspirin and prasugrel therapy, and withdrawal of the ADP receptor antagonist (P2Y12) would put the patient at high risk of acute stent thrombosis.	('P2Y12', 'Gene', '64805', (134, 139))	('patient', 'Species', '9606', (155, 162))	('thrombosis', 'Disease', (191, 201))	('P2Y12', 'Gene', (134, 139))	('patient', 'Species', '9606', (31, 38))	('aspirin', 'Chemical', 'MESH:D001241', (56, 63))	('thrombosis', 'Disease', 'MESH:D013927', (191, 201))	('withdrawal', 'Var', (91, 101))	('prasugrel', 'Chemical', 'MESH:D000068799', (68, 77))
290649	30116519	Retrospective audit of 957 consecutive 18F-FDG PET-CT scans compared to CT and MRI in 493 patients with different histological subtypes of bone and soft tissue sarcoma The use of 18F-FDG PET-CT (PET-CT) is widespread in many cancer types compared to sarcoma.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (148, 167))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('sarcoma', 'Disease', 'MESH:D012509', (250, 257))	('cancer', 'Disease', (225, 231))	('FDG', 'Chemical', 'MESH:D019788', (183, 186))	('sarcoma', 'Disease', (160, 167))	('sarcoma', 'Disease', (250, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('FDG', 'Chemical', 'MESH:D019788', (43, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('patients', 'Species', '9606', (90, 98))	('18F-FDG', 'Var', (179, 186))
290651	30116519	Firstly, the correlation between sarcoma sub-type and grade with 18FDG SUVmax, secondly, the practical uses of PET-CT in the clinical setting of staging (during initial diagnosis), restaging (new baseline prior to definitive intervention) and treatment response.	('SUVmax', 'Gene', (71, 77))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('18FDG', 'Var', (65, 70))	('sarcoma', 'Disease', (33, 40))	('18FDG', 'Chemical', 'MESH:D019788', (65, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))
290653	30116519	High-grade (II/III) bone and soft tissue sarcoma correlated with high SUVmax, especially undifferentiated pleomorphic sarcoma, leiomyosarcoma, translocation induced sarcomas (Ewing, synovial, alveolar rhabdomyosarcoma), de-differentiated liposarcoma and osteosarcoma.	('liposarcoma', 'Disease', 'MESH:D008080', (238, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcoma', 'Disease', (118, 125))	('leiomyosarcoma', 'Disease', (127, 141))	('alveolar rhabdomyosarcoma', 'Disease', (192, 217))	('sarcoma', 'Disease', 'MESH:D012509', (165, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcomas', 'Disease', 'MESH:D012509', (165, 173))	('sarcoma', 'Disease', (165, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('sarcoma', 'Disease', 'MESH:D012509', (242, 249))	('osteosarcoma', 'Phenotype', 'HP:0002669', (254, 266))	('synovial', 'Disease', (182, 190))	('sarcoma', 'Disease', 'MESH:D012509', (259, 266))	('sarcomas', 'Disease', (165, 173))	('sarcoma', 'Disease', (242, 249))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (106, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (201, 217))	('undifferentiated', 'Disease', (89, 105))	('Ewing', 'Disease', (175, 180))	('sarcoma', 'Disease', (259, 266))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (192, 217))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (29, 48))	('liposarcoma', 'Disease', (238, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('sarcoma', 'Disease', (210, 217))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (192, 217))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (127, 141))	('Ewing', 'Disease', 'MESH:C563168', (175, 180))	('pleomorphic sarcoma', 'Disease', (106, 125))	('sarcoma', 'Disease', (41, 48))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (127, 141))	('translocation', 'Var', (143, 156))	('osteosarcoma', 'Disease', (254, 266))	('osteosarcoma', 'Disease', 'MESH:D012516', (254, 266))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('liposarcoma', 'Phenotype', 'HP:0012034', (238, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('high', 'Var', (65, 69))	('sarcoma', 'Disease', (134, 141))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
290667	30116519	The maximum standardized uptake value (SUVmax) of 18FDG into higher-grade sarcoma appears to correlate with mitotic count and grade in some reported series, and potentially with overall prognosis.	('18FDG', 'Var', (50, 55))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('18FDG', 'Chemical', 'MESH:D019788', (50, 55))	('standardized uptake', 'MPA', (12, 31))	('sarcoma', 'Disease', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
290686	30116519	The differences in sarcoma disease distribution between the 18FDG PET-CT and conventional MRI/CT scans were documented if scans were performed within 4 weeks of each other, otherwise any differences were not reported for the purpose of this evaluation.	('18FDG', 'Var', (60, 65))	('18FDG', 'Chemical', 'MESH:D019788', (60, 65))	('sarcoma disease', 'Disease', 'MESH:D012509', (19, 34))	('sarcoma disease', 'Disease', (19, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))
290711	30116519	Overall, given the prevalence of sarcoma sub-types in this bone and soft tissue sarcoma series, and compared to conventional MRI/CT, PET-CT appeared to have a greater sensitivity (96% vs 54%), positive predictive value (96%) and negative predictive value (99%), even though these sensitivity and specificity values were not prospectively evaluated.	('PET-CT', 'Var', (133, 139))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (68, 87))	('sarcoma', 'Disease', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcoma', 'Disease', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))
290729	30116519	What we have not been able to fully assess in all circumstances, is to prospectively prove that direct and important changes to subsequent clinical management of patients ensued as a result of the PET-CT results, and the PET-CT results alone.	('patients', 'Species', '9606', (162, 170))	('results', 'Var', (204, 211))	('changes', 'Reg', (117, 124))	('PET-CT results', 'Var', (197, 211))
290740	30116519	In summary, PET-CT in high-grade sarcoma offers the prospect additional benefit in routine staging of high-grade sarcoma at baseline, and specific staging situations during relapse and treatment.	('high-grade', 'Disease', (22, 32))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', (113, 120))	('sarcoma', 'Disease', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('PET-CT', 'Var', (12, 18))
291048	30936721	In addition, this study included studies of anthracycline-based combinations, which might be anticipated to yield a higher ORR than anthracycline monotherapy.	('combinations', 'Var', (64, 76))	('anthracycline', 'Chemical', 'MESH:D018943', (44, 57))	('anthracycline', 'Chemical', 'MESH:D018943', (132, 145))	('anthracycline-based', 'Var', (44, 63))
291072	30936721	A meta-analysis favored CIV to decrease cardiotoxicity.	('cardiotoxicity', 'Disease', (40, 54))	('CIV', 'Chemical', '-', (24, 27))	('decrease', 'NegReg', (31, 39))	('CIV', 'Var', (24, 27))	('cardiotoxicity', 'Disease', 'MESH:D066126', (40, 54))
291092	30936721	After binding, BR96 is internalized into endocytic lysosomes.	('BR96', 'Chemical', '-', (15, 19))	('BR96', 'Var', (15, 19))	('binding', 'Interaction', (6, 13))
291093	30936721	ALDOX-conjugated BR96 demonstrated a 50-fold improvement in the 50% Inhibitory Concentration (IC50) in vitro vs a non-binding control mAb in the L2987 lung carcinoma model.	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('rat', 'Species', '10116', (29, 32))	('ALDOX', 'Chemical', 'MESH:C575867', (0, 5))	('lung carcinoma', 'Disease', 'MESH:D008175', (151, 165))	('BR96', 'Chemical', '-', (17, 21))	('BR96', 'Var', (17, 21))	('lung carcinoma', 'Disease', (151, 165))	('rat', 'Species', '10116', (86, 89))	('improvement', 'PosReg', (45, 56))
291095	30936721	Significant activity, including long-term (>1 year) cures in mice, was obtained after administration of the BR96-DOX conjugate in human lung, colon, and breast carcinoma xenografts.	('BR96', 'Chemical', '-', (108, 112))	('rat', 'Species', '10116', (94, 97))	('mice', 'Species', '10090', (61, 65))	('breast carcinoma', 'Phenotype', 'HP:0003002', (153, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('activity', 'MPA', (12, 20))	('BR96-DOX', 'Var', (108, 116))	('breast carcinoma xenografts', 'Disease', (153, 180))	('DOX', 'Chemical', 'MESH:D004317', (113, 116))	('breast carcinoma xenografts', 'Disease', 'MESH:D001943', (153, 180))	('human', 'Species', '9606', (130, 135))
291096	30936721	Neither optimized doses of DOX, BR96 alone, mixtures of DOX with unconjugated BR96, nor ALDOX conjugates of control mAb yielded significant antitumor activity.	('DOX', 'Chemical', 'MESH:D004317', (27, 30))	('tumor', 'Disease', (144, 149))	('ALDOX', 'Chemical', 'MESH:C575867', (88, 93))	('BR96', 'Chemical', '-', (32, 36))	('DOX', 'Chemical', 'MESH:D004317', (90, 93))	('BR96', 'Var', (32, 36))	('BR96', 'Chemical', '-', (78, 82))	('DOX', 'Chemical', 'MESH:D004317', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
291159	30936721	Mitochondrial DNA deletions were present in both DOX- and ALDOX-treated rats, although to a lesser extent in the latter.	('DOX', 'Chemical', 'MESH:D004317', (49, 52))	('Mitochondrial DNA', 'Gene', (0, 17))	('rats', 'Species', '10116', (72, 76))	('deletions', 'Var', (18, 27))	('ALDOX', 'Chemical', 'MESH:C575867', (58, 63))	('DOX', 'Chemical', 'MESH:D004317', (60, 63))
291266	30936721	PFS, the primary endpoint, was not significantly improved (ALDOX: mPFS 4.11 months, 95% CI 2.79-5.06 months; control: mPFS 2.96 months, 95% CI 2.56-4.17 months; HR =0.81, 95% CI 0.64-1.03, P=0.087).	('ALDOX', 'Chemical', 'MESH:C575867', (59, 64))	('PFS', 'Disease', (0, 3))	('mPFS', 'Var', (66, 70))
291267	30936721	For L-sarcomas, PFS was improved (ALDOX: mPFS 5.32 months, 95% CI 3.45-7.16 months; control: mPFS 2.96 months, 95% CI 2.10-4.37 months; HR =0.62, 95% CI 0.44-0.88, P=0.007).	('L-sarcomas', 'Disease', 'MESH:D012509', (4, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('L-sarcomas', 'Disease', (4, 14))	('improved', 'PosReg', (24, 32))	('mPFS', 'Var', (41, 45))	('ALDOX', 'Chemical', 'MESH:C575867', (34, 39))	('PFS', 'MPA', (16, 19))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))
291352	30936721	Selection of dosing for such a trial is important, although the Phase III dosing of ALDOX (350 mg/m2 =260 mg/m2 DE) is probably reasonable, given its prior use suggesting lower cardiotoxicity than conventional doses of DOX (75 mg/m2 DE) and evidence of activity in the STS setting from the Phase II trial.	('cardiotoxicity', 'Disease', (177, 191))	('ALDOX', 'Chemical', 'MESH:C575867', (84, 89))	('DOX', 'Chemical', 'MESH:D004317', (219, 222))	('DOX', 'Chemical', 'MESH:D004317', (86, 89))	('cardiotoxicity', 'Disease', 'MESH:D066126', (177, 191))	('350 mg/m2', 'Var', (91, 100))	('lower', 'NegReg', (171, 176))
291401	30519175	The patient was diagnosed with pT1aN0M0 disease and was treated with adjuvant chemotherapy according to the COG AEWS1031 protocol.	('EWS', 'Phenotype', 'HP:0012254', (113, 116))	('patient', 'Species', '9606', (4, 11))	('pT1aN0M0', 'Var', (31, 39))	('EWS', 'Gene', '2130', (113, 116))	('EWS', 'Gene', (113, 116))
291410	30519175	Furthermore, in rhabdomyosarcoma, hedgehog signaling in endothelial progenitors leads to transformation exclusively in the head and neck (which is associated with a good prognosis) and not at other locations (associated with poorer prognoses), thus making it likely that the cell of origin differs at different sites, similar to what may be observed in EWS.	('rhabdomyosarcoma', 'Disease', (16, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (16, 32))	('transformation', 'MPA', (89, 103))	('leads to', 'Reg', (80, 88))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (16, 32))	('EWS', 'Gene', '2130', (353, 356))	('EWS', 'Gene', (353, 356))	('EWS', 'Phenotype', 'HP:0012254', (353, 356))	('hedgehog', 'Var', (34, 42))
291434	29219111	Bone marrow examination showed 22% blasts, which were strongly myeloperoxidase positive (Figure 2a) and were also CD34+ (Figure 2b) confirming the diagnosis of acute myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (174, 182))	('CD34+', 'Var', (114, 119))	('acute myeloid leukemia', 'Disease', (160, 182))	('myeloperoxidase', 'Enzyme', (63, 78))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (160, 182))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (160, 182))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (166, 182))
291435	29219111	Conventional cytogenetics revealed t(5:12) and trisomy 21 (Figure 2c); the acute myeloid leukemia molecular panel (FLT3, CEBPA, NPM1, C-kit, and BCR-ABL) was negative.	('ABL', 'Gene', '25', (149, 152))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('acute myeloid leukemia', 'Disease', (75, 97))	('ABL', 'Gene', (149, 152))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (81, 97))	('revealed', 'Reg', (26, 34))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (75, 97))	('trisomy 21', 'Var', (47, 57))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (75, 97))
291513	20865011	In this Review we describe the epidemiology of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years.	('KSHV', 'Var', (122, 126))	('induce', 'Reg', (131, 137))	('KS', 'Phenotype', 'HP:0100726', (47, 49))	('KS', 'Phenotype', 'HP:0100726', (138, 140))	('KSHV', 'Species', '37296', (54, 58))	('KSHV', 'Species', '37296', (122, 126))	('KS', 'Phenotype', 'HP:0100726', (54, 56))	('KS', 'Phenotype', 'HP:0100726', (122, 124))
291549	20865011	Classic KS risk is associated with diplotypes of interleukin-8 receptor-beta (IL8RB), IL-13 (Ref.)	('IL8RB', 'Gene', '3579', (78, 83))	('interleukin-8 receptor-beta', 'Gene', (49, 76))	('IL-13', 'Gene', (86, 91))	('diplotypes', 'Var', (35, 45))	('IL8RB', 'Gene', (78, 83))	('IL-13', 'Gene', '3596', (86, 91))	('KS', 'Phenotype', 'HP:0100726', (8, 10))	('interleukin-8 receptor-beta', 'Gene', '3579', (49, 76))	('Classic KS', 'Disease', (0, 10))
291552	20865011	These data suggest that common host genetic variants, in addition to environmental factors, timing and possibly routes of infection, all contribute to the oncogenic outcome of KSHV infection.	('KSHV infection', 'Disease', 'MESH:C537372', (176, 190))	('KS', 'Phenotype', 'HP:0100726', (176, 178))	('KSHV infection', 'Disease', (176, 190))	('men', 'Species', '9606', (76, 79))	('contribute', 'Reg', (137, 147))	('variants', 'Var', (44, 52))
291560	20865011	The observation that KSHV infection of blood vessel endothelial cells in vitro induces lymphatic endothelial markers, and infection of lymphatic cells leads to reprogramming towards blood vessel cells, adds to the complexity.	('leads to', 'Reg', (151, 159))	('KS', 'Phenotype', 'HP:0100726', (21, 23))	('reprogramming towards blood vessel cells', 'CPA', (160, 200))	('lymphatic endothelial markers', 'MPA', (87, 116))	('infection', 'Var', (122, 131))	('induces', 'PosReg', (79, 86))	('KSHV infection', 'Disease', 'MESH:C537372', (21, 35))	('KSHV infection', 'Disease', (21, 35))
291561	20865011	We suspect that KSHV infects circulating endothelial precursor cells, driving them towards a lymphatic lineage.	('driving', 'Reg', (70, 77))	('KS', 'Phenotype', 'HP:0100726', (16, 18))	('infects', 'Reg', (21, 28))	('KSHV', 'Species', '37296', (16, 20))	('KSHV', 'Var', (16, 20))
291574	20865011	Supporting the idea that KS is only truly neoplastic in advanced stages is the observation that cellular oncogenic alterations, such as p53 and KRAS mutations or BCL-2 overexpression, as well as gene copy number changes, occur only in late-stage advanced disease.	('KRAS', 'Gene', '3845', (144, 148))	('mutations', 'Var', (149, 158))	('KS', 'Phenotype', 'HP:0100726', (25, 27))	('p53', 'Gene', '7157', (136, 139))	('BCL-2', 'Gene', '596', (162, 167))	('BCL-2', 'Gene', (162, 167))	('overexpression', 'PosReg', (168, 182))	('KRAS', 'Gene', (144, 148))	('p53', 'Gene', (136, 139))
291597	20865011	The mechanisms by which KSHV perturbs normal immune responses and evades host immunity, are reviewed elsewhere.	('evades', 'NegReg', (66, 72))	('KSHV', 'Species', '37296', (24, 28))	('KSHV', 'Var', (24, 28))	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('normal immune responses', 'CPA', (38, 61))	('perturbs', 'Reg', (29, 37))	('host immunity', 'CPA', (73, 86))
291601	20865011	In addition, LANA has been shown to deregulate Wnt signalling by nuclear trapping of glycogen synthase kinase 3beta (GSK3beta), thereby stabilizing beta-catenin, and to inhibit anti-proliferative transforming growth factor-beta (TGFbeta) signalling by epigenetic suppression of TGFbeta receptors.	('GSK3beta', 'Gene', (117, 125))	('TGFbeta', 'Gene', (229, 236))	('inhibit', 'NegReg', (169, 176))	('TGFbeta', 'Gene', '7040', (278, 285))	('epigenetic suppression', 'Var', (252, 274))	('deregulate', 'PosReg', (36, 46))	('beta-catenin', 'Gene', (148, 160))	('nuclear trapping', 'MPA', (65, 81))	('LANA', 'Gene', (13, 17))	('glycogen synthase kinase 3beta', 'Gene', (85, 115))	('GSK3beta', 'Gene', '2932', (117, 125))	('beta-catenin', 'Gene', '1499', (148, 160))	('glycogen synthase kinase 3beta', 'Gene', '2932', (85, 115))	('LANA', 'Gene', '4961527', (13, 17))	('TGFbeta', 'Gene', '7040', (229, 236))	('TGFbeta', 'Gene', (278, 285))	('Wnt signalling', 'MPA', (47, 61))
291610	20865011	A large number of cytokines, including chemokines implicated in KS pathogenesis, are induced in endothelial cells by vFLIP activation of NF-kappaB.	('KS', 'Phenotype', 'HP:0100726', (64, 66))	('NF-kappaB', 'Gene', '4790', (137, 146))	('NF-kappaB', 'Gene', (137, 146))	('activation', 'PosReg', (123, 133))	('vFLIP', 'Var', (117, 122))
291612	20865011	Interestingly, vFLIP also suppresses autophagy, an important pro-oncogenic activity, by preventing ATG3 from binding and processing LC3 (Ref.).	('ATG3', 'Gene', (99, 103))	('vFLIP', 'Var', (15, 20))	('preventing', 'NegReg', (88, 98))	('ATG3', 'Gene', '64422', (99, 103))	('suppresses', 'NegReg', (26, 36))	('LC3', 'Gene', '84557', (132, 135))	('LC3', 'Gene', (132, 135))	('autophagy', 'CPA', (37, 46))	('processing', 'MPA', (121, 131))	('binding', 'Interaction', (109, 116))
291616	20865011	As several cytokine mRNAs have ARE elements, kaposin B expression results in an increase in the production of pro-inflammatory cytokines.	('kaposin B', 'Gene', (45, 54))	('men', 'Species', '9606', (38, 41))	('increase', 'PosReg', (80, 88))	('production of pro-inflammatory cytokines', 'MPA', (96, 136))	('expression', 'Var', (55, 65))
291631	20865011	KSHV also induces cellular miRNAs.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('induces', 'Reg', (10, 17))	('cellular miRNAs', 'CPA', (18, 33))
291636	20865011	Mice expressing transgenic vGCPR develop angiogenic lesions that resemble KS, as vGPCR is only expressed in a proportion of cells, and these cells drive VEGF-mediated angiogenesis using paracrine mechanisms.	('vGPCR', 'Gene', '4961465', (81, 86))	('vGCPR', 'Gene', (27, 32))	('transgenic', 'Species', '10090', (16, 26))	('drive', 'Reg', (147, 152))	('angiogenic lesions', 'CPA', (41, 59))	('transgenic', 'Var', (16, 26))	('Mice', 'Species', '10090', (0, 4))	('vGPCR', 'Gene', (81, 86))	('KS', 'Phenotype', 'HP:0100726', (74, 76))
291656	20865011	The gp130-binding IL-6R modulated vIL-6 virokine is angiogenic and might induce spindle cell proliferation and survival.	('IL-6R', 'Gene', '3570', (18, 23))	('vIL-6', 'Gene', (34, 39))	('IL-6R', 'Gene', (18, 23))	('vIL-6', 'Gene', '4961449', (34, 39))	('spindle cell proliferation', 'CPA', (80, 106))	('survival', 'CPA', (111, 119))	('modulated', 'Var', (24, 33))	('induce', 'PosReg', (73, 79))	('angiogenic', 'CPA', (52, 62))
291661	20865011	vIRF3 activates VEGF secretion by stabilizing HIF1alpha.	('HIF1alpha', 'Gene', '3091', (46, 55))	('stabilizing', 'Var', (34, 45))	('vIRF3', 'Gene', (0, 5))	('RF', 'Phenotype', 'HP:0005200', (2, 4))	('VEGF secretion', 'MPA', (16, 30))	('HIF1alpha', 'Gene', (46, 55))	('activates', 'PosReg', (6, 15))
291666	20865011	Like K1, the SH2 and SH3 domain-containing K15 also flanks the terminal repeat region of the KSHV episome (Box 1), activates the NF-kappaB and MAPK pathways and induces the expression of several inflammatory and angiogenic genes.	('K15', 'Var', (43, 46))	('MAPK pathways', 'Pathway', (143, 156))	('activates', 'PosReg', (115, 124))	('induces', 'PosReg', (161, 168))	('NF-kappaB', 'Gene', (129, 138))	('KSHV', 'Species', '37296', (93, 97))	('KS', 'Phenotype', 'HP:0100726', (93, 95))	('expression', 'MPA', (173, 183))	('NF-kappaB', 'Gene', '4790', (129, 138))
291677	20865011	Underscoring its dependence on HIV infection and immunosuppression, HAART has reduced the incidence of AIDS-KS, and can induce AIDS-KS regression.	('AIDS-KS', 'Disease', 'MESH:D000163', (127, 134))	('HIV infection', 'Disease', (31, 44))	('HAART', 'Var', (68, 73))	('KS', 'Phenotype', 'HP:0100726', (108, 110))	('AIDS-KS', 'Disease', 'MESH:D000163', (103, 110))	('AIDS-KS', 'Disease', (127, 134))	('HIV infection', 'Disease', 'MESH:D015658', (31, 44))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('AIDS-KS', 'Disease', (103, 110))	('reduced', 'NegReg', (78, 85))
291699	27298923	Extra skeletal Soft Tissue Ewing's Sarcoma with Variant Translocation of Chromosome t (4; 22) (q35; q12)-A Case Report Ewing's sarcomas is a rare primitive neuroectodermal tumour (PNET) which has an annual incidence of 2.9 /million population in USA 1Jeffery Toretsky et al (2008) They are very uncommon in African and Asian population.	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (119, 135))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (27, 42))	('Sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('primitive neuroectodermal tumour', 'Phenotype', 'HP:0030065', (146, 178))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (119, 134))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (27, 42))	('PNET', 'Phenotype', 'HP:0030065', (180, 184))	("Ewing's sarcomas", 'Disease', (119, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('neuroectodermal tumour', 'Disease', 'MESH:D017599', (156, 178))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (119, 135))	('Variant Translocation', 'Var', (48, 69))	('neuroectodermal tumour', 'Phenotype', 'HP:0030061', (156, 178))	("Ewing's Sarcoma", 'Disease', (27, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('neuroectodermal tumour', 'Disease', (156, 178))
291724	27298923	The common genetic alteration in ES is a translocation between the EWS gene on chromosome 22 and various genes of the ETS family of transcription factors.	('ES', 'Phenotype', 'HP:0012254', (33, 35))	('EWS', 'Gene', '2130', (67, 70))	('EWS', 'Gene', (67, 70))	('translocation', 'Var', (41, 54))
291726	27298923	Previously only one case of complex translocation was identified in a dysmorphic 15- year-old girl, t (4; 11; 22) (q21; q24; q12).	('dysmorphic', 'Disease', (70, 80))	('girl', 'Species', '9606', (94, 98))	('t (4; 11; 22) (q21; q24; q12', 'Var', (100, 128))	('dysmorphic', 'Disease', 'None', (70, 80))
291732	27298923	Apart from various prognostic factors recently it has been reported that the type of EWS/Flil fusion transcript is prognostically relevant, as patients with the type l EWS/Flil fusion transcript appear to have increased disease-free survival over that of patients with other fusion transcript types 6.	('Flil', 'Gene', (89, 93))	('Flil', 'Gene', '2314', (89, 93))	('increased', 'PosReg', (210, 219))	('disease-free survival', 'CPA', (220, 241))	('Flil', 'Gene', (172, 176))	('Flil', 'Gene', '2314', (172, 176))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (255, 263))	('EWS', 'Gene', '2130', (85, 88))	('EWS', 'Gene', (85, 88))	('EWS', 'Gene', '2130', (168, 171))	('EWS', 'Gene', (168, 171))	('fusion transcript', 'Var', (177, 194))
291735	27298923	Karyotype and insitu hybridization helps to detect the type of chromosomal translocation which can predict the overall prognosis of the tumor.	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('chromosomal translocation', 'Var', (63, 88))	('predict', 'Reg', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
291742	22013118	A Novel Combination Immunotherapy for Cancer by IL-13Ralpha2-Targeted DNA Vaccine and Immunotoxin in Murine Tumor Models Optimum efficacy of therapeutic cancer vaccines may require combinations that generate effective antitumor immune responses, as well as overcome immune evasion and tolerance mechanisms mediated by progressing tumor.	('immune evasion', 'MPA', (266, 280))	('cancer', 'Disease', (153, 159))	('combinations', 'Var', (181, 193))	('IL-13Ralpha2', 'Gene', '16165', (48, 60))	('tumor', 'Disease', (330, 335))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Cancer', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('Murine', 'Species', '10090', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('Tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Disease', (222, 227))	('rat', 'Species', '10116', (203, 206))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('IL-13Ralpha2', 'Gene', (48, 60))	('Cancer', 'Disease', (38, 44))
291744	22013118	A targeted cytotoxin composed of IL-13 and mutated Pseudomonas exotoxin induced specific killing of IL-13Ra2+ tumor cells.	('IL-13Ra2', 'Gene', (100, 108))	('IL-13Ra2', 'Gene', '16165', (100, 108))	('IL-13', 'Gene', (100, 105))	('IL-13', 'Gene', '16163', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('killing', 'CPA', (89, 96))	('Pseudomonas exotoxin', 'Gene', (51, 71))	('IL-13', 'Gene', (33, 38))	('IL-13', 'Gene', '16163', (33, 38))	('mutated', 'Var', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
291755	22013118	For example, cancer vaccines are being combined with other immunotherapy, with standard cancer drugs, targeted small-molecule drugs, and local and systemic radiation of tumors, or laser therapy.	('radiation of tumors', 'Disease', 'MESH:D004194', (156, 175))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('small-molecule', 'Var', (111, 125))	('radiation of tumors', 'Disease', (156, 175))
291765	22013118	Indeed, we showed that immunization with a DNA vaccine encoding IL-13Ralpha2 chain inhibited IL-13Ralpha2-expressing D5 murine melanoma tumor growth in both prophylactic and therapeutic models.	('murine', 'Species', '10090', (120, 126))	('melanoma tumor', 'Disease', (127, 141))	('inhibited', 'NegReg', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('IL-13Ralpha2', 'Var', (64, 76))	('melanoma tumor', 'Disease', 'MESH:D008545', (127, 141))
291785	22013118	Anti-CD4 (GK1.5) and anti-CD8 (2.43) Abs were grown as ascites, purified on protein G columns, and titered for in vivo efficacy.	('anti-CD8', 'Var', (21, 29))	('GK1.5', 'Gene', (10, 15))	('ascites', 'Disease', (55, 62))	('GK1.5', 'Gene', '16607', (10, 15))	('ascites', 'Disease', 'MESH:D001201', (55, 62))	('ascites', 'Phenotype', 'HP:0001541', (55, 62))
291794	22013118	Animals were injected with excipient (0.2% human serum albumin in PBS) or IL13-PE (50 or 250 microg/ kg) once a day on every third day intratumorally (30 ml using a Hamilton microinjection syringe).	('rat', 'Species', '10116', (138, 141))	('0.2', 'Var', (38, 41))	('PBS', 'Chemical', 'MESH:D007854', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('IL13', 'Gene', '16163', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('IL13', 'Gene', (74, 78))	('human', 'Species', '9606', (43, 48))	('tumor', 'Disease', (140, 145))
291800	22013118	with 0.25 mg anti-CD4 Ab (GK1.5) and/or anti-CD8 Ab (2.43) on days -2, -1, +5, +11, +17, and +23 relative to the tumor implantation.	('tumor', 'Disease', (113, 118))	('GK1.5', 'Gene', '16607', (26, 31))	('anti-CD4', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('GK1.5', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('anti-CD8', 'Var', (40, 48))
291830	22013118	In contrast, the tumor growth in mice treated with IL13-PE and IL-13Ralpha2 DNA vaccine continued to be reduced during the treatment.	('IL-13Ralpha2', 'Var', (63, 75))	('IL13', 'Gene', (51, 55))	('tumor', 'Disease', (17, 22))	('reduced', 'NegReg', (104, 111))	('IL13', 'Gene', '16163', (51, 55))	('mice', 'Species', '10090', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
291834	22013118	A significantly prolonged OST was observed in the combination-therapy group (65 d), which was >2-fold that of the control group.	('combination-therapy', 'Var', (50, 69))	('prolonged', 'PosReg', (16, 25))	('OST', 'CPA', (26, 29))	('OST', 'Chemical', '-', (26, 29))
291837	22013118	These results indicated that combination therapy with IL13-PE and IL-13Ralpha2 DNA vaccination could be effective in significantly reducing tumor burden and prolonging survival in 4T1 and MCA304 tumor-bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('mice', 'Species', '10090', (209, 213))	('MCA304 tumor', 'Disease', (188, 200))	('tumor', 'Disease', (195, 200))	('IL-13Ralpha2', 'Var', (66, 78))	('MCA304 tumor', 'Disease', 'MESH:D009369', (188, 200))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('survival', 'CPA', (168, 176))	('reducing', 'NegReg', (131, 139))	('IL13', 'Gene', '16163', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('IL13', 'Gene', (54, 58))	('prolonging', 'PosReg', (157, 167))	('tumor', 'Disease', (140, 145))
291867	22013118	These results suggested that combination therapy with IL13-PE and IL-13Ralpha2 DNA vaccine induced regression of 4T1 and MCA304 tumors and involved infiltration of CD4+ and CD8+ T cells and production of proinflammatory chemokines in tumors.	('MCA304 tumors', 'Disease', (121, 134))	('MCA304 tumors', 'Disease', 'MESH:D009369', (121, 134))	('IL-13Ralpha2', 'Var', (66, 78))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('rat', 'Species', '10116', (154, 157))	('regression', 'NegReg', (99, 109))	('tumors', 'Disease', (234, 240))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CD4+', 'MPA', (164, 168))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('IL13', 'Gene', '16163', (54, 58))	('IL13', 'Gene', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('4T1', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
291876	22013118	MCA304 tumor volume in RAG-2 knockout mice (1861 +- 197 mm3) was similar to that in C57BL/6 mice without combination therapy (1820 +- 287 mm3) at day 27.	('RAG-2', 'Gene', (23, 28))	('knockout', 'Var', (29, 37))	('mice', 'Species', '10090', (38, 42))	('MCA304 tumor', 'Disease', 'MESH:D009369', (0, 12))	('MCA304 tumor', 'Disease', (0, 12))	('RAG-2', 'Gene', '19374', (23, 28))	('mice', 'Species', '10090', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
291888	22013118	It was reported that CD4+CD25+Foxp3+ Tregs contribute to the immune suppression that occurs in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', (95, 101))	('CD4+CD25+Foxp3+', 'Var', (21, 36))	('immune suppression', 'CPA', (61, 79))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
291891	22013118	Gating on CD3+ CD4+ cells and analyzing for the expression of CD25 and Foxp3, we found that the percentage of CD4+CD25+Foxp3+ cells in the splenocytes of tumor-free mice was relatively low (7.5%).	('CD4+CD25+Foxp3+', 'Var', (110, 125))	('mice', 'Species', '10090', (165, 169))	('CD3', 'Gene', (10, 13))	('CD3', 'Gene', '12503', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
291911	22013118	These results suggested that, in addition to the generation of an IL-13Ralpha2-specific immune response, combination therapy decreased immunosuppressive MDSCs in spleen and tumor, which could further enhance the efficacy of combination therapy.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('immunosuppressive MDSCs', 'MPA', (135, 158))	('decreased', 'NegReg', (125, 134))	('rat', 'Species', '10116', (53, 56))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('combination', 'Var', (105, 116))	('enhance', 'PosReg', (200, 207))
291915	22013118	The therapeutic effect mediated by the IL13-PE and IL-13Ralpha2 DNA vaccine combination correlated with tumor infiltration of CD4+ and CD8+ T cells and was abrogated when these cells were depleted, indicating that these cells may have played a role in the regression of tumors through CTL activation in the periphery and cellular infiltration into tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('tumors', 'Phenotype', 'HP:0002664', (348, 354))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('IL13', 'Gene', '16163', (39, 43))	('IL13', 'Gene', (39, 43))	('tumors', 'Disease', (270, 276))	('IL-13Ralpha2', 'Var', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('tumors', 'Disease', (348, 354))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('tumor', 'Disease', (104, 109))	('rat', 'Species', '10116', (116, 119))	('tumors', 'Disease', 'MESH:D009369', (348, 354))	('tumor', 'Disease', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('CTL', 'CPA', (285, 288))	('cellular infiltration', 'CPA', (321, 342))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('rat', 'Species', '10116', (336, 339))	('tumor', 'Disease', (348, 353))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))
291921	22013118	We have shown previously that tumor cells that express IL-13Ralpha2 are killed by immunotoxin IL13-PE, and these dying tumor cells release Ags and/or apoptotic bodies, which then induce adaptive immunity.	('IL-13Ralpha2', 'Var', (55, 67))	('tumor', 'Disease', (119, 124))	('induce', 'Reg', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('adaptive immunity', 'CPA', (186, 203))	('IL13', 'Gene', '16163', (94, 98))	('IL13', 'Gene', (94, 98))	('Ags', 'MPA', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (30, 35))
291937	22013118	Indeed, in this study we found that combination therapy with IL13-PE and IL-13Ralpha2 DNA vaccine dramatically decreased MDSCs in both splenocytes and tumor compared with the control group.	('IL13', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('MDSCs', 'MPA', (121, 126))	('decreased', 'NegReg', (111, 120))	('tumor', 'Disease', (151, 156))	('IL-13Ralpha2', 'Var', (73, 85))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('IL13', 'Gene', '16163', (61, 65))
291947	23441188	Genomic EWS-FLI1 Fusion Sequences in Ewing Sarcoma Resemble Breakpoint Characteristics of Immature Lymphoid Malignancies Chromosomal translocations between the EWS gene and members of the ETS gene family are characteristic molecular features of the Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('EWS', 'Gene', (8, 11))	('Ewing Sarcoma', 'Disease', (37, 50))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('EWS', 'Gene', '2130', (8, 11))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (249, 262))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (249, 262))	('EWS', 'Gene', '2130', (160, 163))	('EWS', 'Gene', (160, 163))	('Lymphoid Malignancies', 'Disease', (99, 120))	('Lymphoid Malignancies', 'Phenotype', 'HP:0002665', (99, 120))	('FLI1', 'Gene', '2313', (12, 16))	('Chromosomal translocations', 'Var', (121, 147))	('FLI1', 'Gene', (12, 16))	('Lymphoid Malignancies', 'Disease', 'MESH:D008223', (99, 120))	('Sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('Ewing sarcoma', 'Disease', (249, 262))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (37, 50))
291948	23441188	The most common translocation t(11;22)(q24;q12) fuses the EWS gene to FLI1, and is present in 85-90% of Ewing sarcomas.	('Ewing sarcomas', 'Disease', (104, 118))	('t(11;22)(q24;q12', 'Var', (30, 46))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (104, 118))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 47))	('FLI1', 'Gene', '2313', (70, 74))	('FLI1', 'Gene', (70, 74))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (104, 118))	('EWS', 'Gene', (58, 61))	('EWS', 'Gene', '2130', (58, 61))
291951	23441188	The occurrence of small deletions and duplications at the genomic junction is characteristic of involvement of the non-homologous end-joining (NHEJ) repair system, similar to findings at chromosomal breakpoints in pediatric leukemia and lymphoma.	('chromosomal breakpoint', 'Phenotype', 'HP:0040012', (187, 209))	('leukemia', 'Phenotype', 'HP:0001909', (224, 232))	('duplications', 'Var', (38, 50))	('pediatric leukemia and lymphoma', 'Disease', 'MESH:D063766', (214, 245))	('lymphoma', 'Phenotype', 'HP:0002665', (237, 245))	('involvement', 'Reg', (96, 107))
291952	23441188	Reciprocal balanced chromosomal translocations are recurrent and specific somatic aberrations in a wide variety of tumors, and are particularly associated with hematological malignancies.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('hematological malignancies', 'Disease', 'MESH:D019337', (160, 186))	('associated', 'Reg', (144, 154))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('hematological malignancies', 'Phenotype', 'HP:0004377', (160, 186))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('Reciprocal', 'Var', (0, 10))	('hematological malignancies', 'Disease', (160, 186))
291954	23441188	In multiple myeloma, incorrect class switch recombination by activation-induced deaminase (AID) during secondary antibody diversification induces translocations within the immunoglobulin switch regions.	('multiple myeloma', 'Disease', (3, 19))	('activation-induced deaminase', 'Gene', '57379', (61, 89))	('incorrect class switch recombination', 'Phenotype', 'HP:0002959', (21, 57))	('activation-induced deaminase', 'Gene', (61, 89))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))	('AID', 'Gene', (91, 94))	('induces', 'Reg', (138, 145))	('incorrect', 'Var', (21, 30))	('AID', 'Gene', '57379', (91, 94))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('translocations', 'MPA', (146, 160))
291957	23441188	Far fewer breakpoint DNA sequences have been deciphered from solid tumors to allow comparative analyses, although there is increasing evidence of recurrent chromosomal translocations in non-hematological tumors of both mesenchymal and epithelial origin.	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('chromosomal translocations', 'Var', (156, 182))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
291961	23441188	The most common translocation found in ES is t(11;22)(q24;q12), which fuses the EWS gene with the FLI1 gene.	('EWS', 'Gene', (80, 83))	('t(11;22)(q24;q12', 'Var', (45, 61))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (45, 62))	('EWS', 'Gene', '2130', (80, 83))	('FLI1', 'Gene', (98, 102))	('FLI1', 'Gene', '2313', (98, 102))
291963	23441188	In 10% of cases, the EWS gene is fused to the ERG gene resulting in the t(21;22)(q22;q12) translocation.	('t(21;22)(q22;q12', 'Var', (72, 88))	('EWS', 'Gene', '2130', (21, 24))	('ERG', 'Gene', (46, 49))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (72, 89))	('EWS', 'Gene', (21, 24))
291990	23441188	The lower detection rate of the reciprocal FLI1-EWS fusion site is in line with results from other recurrent chromosomal translocations and is attributable to large deletions or complex rearrangements on der11.	('EWS', 'Gene', (48, 51))	('EWS', 'Gene', '2130', (48, 51))	('der11', 'Gene', (204, 209))	('deletions', 'Var', (165, 174))	('FLI1', 'Gene', (43, 47))	('FLI1', 'Gene', '2313', (43, 47))
291992	23441188	Kernel density analysis confirmed this observation and showed a statistically significant overrepresentation of breakpoints within the cluster region at the 5'-region of the ESW-BCR (Figure 2B).	('breakpoints', 'Var', (112, 123))	('overrepresentation', 'PosReg', (90, 108))	('BCR', 'Gene', '613', (178, 181))	('BCR', 'Gene', (178, 181))
291998	23441188	In 34/49 (69%) samples, genomic breakpoints within the FLI1 gene resulted in an EWS-FLI1 fusion transcript of EWS exons 1-7 fused to FLI1 exons 6-9, representing Ewing sarcoma type 1.	('EWS-FLI1', 'Gene', (80, 88))	('EWS', 'Gene', (110, 113))	('FLI1', 'Gene', '2313', (84, 88))	('EWS', 'Gene', '2130', (110, 113))	('FLI1', 'Gene', (55, 59))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (162, 175))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (162, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('FLI1', 'Gene', '2313', (55, 59))	('EWS', 'Gene', (80, 83))	('EWS-FLI1', 'Gene', '2130;2313', (80, 88))	('EWS', 'Gene', '2130', (80, 83))	('Ewing sarcoma', 'Disease', (162, 175))	('FLI1', 'Gene', (84, 88))	('resulted in', 'Reg', (65, 76))	('FLI1', 'Gene', (133, 137))	('FLI1', 'Gene', '2313', (133, 137))	('genomic breakpoints', 'Var', (24, 43))
292008	23441188	Immature leukemia cells in particular show predominantly sequence-independent breakage with small microhomologies or deletions at the fusion sites.	('breakage', 'Var', (78, 86))	('leukemia', 'Phenotype', 'HP:0001909', (9, 17))	('leukemia', 'Disease', 'MESH:D007938', (9, 17))	('deletions', 'Var', (117, 126))	('leukemia', 'Disease', (9, 17))
292009	23441188	Chromosomal fusion of the EWS gene to one member of the ETS family of transcription factors is the genetic hallmark of ES-.	('Chromosomal fusion', 'Var', (0, 18))	('ES-', 'Disease', (119, 122))	('EWS', 'Gene', (26, 29))	('EWS', 'Gene', '2130', (26, 29))
292010	23441188	Detection of the chromosomal translocation by FISH, or amplification of the resulting fusion transcripts by RT-PCR, has become a well-established diagnostic component for molecular confirmation of histopathological tumor classification.	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('chromosomal translocation', 'Var', (17, 42))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))
292013	23441188	The chemical stability of DNA facilitates storage and transport of patient material, and in contrast to RT-PCR methods, enables the detection of fusion genes independent of their gene expression.	('fusion genes', 'Var', (145, 157))	('facilitates', 'PosReg', (30, 41))	('patient', 'Species', '9606', (67, 74))
292015	23441188	Fusion of EWS to one of its partner genes is an early event in tumorigenesis and an essential oncogenic factor for maintaining the malignant transformation of ES-.	('tumor', 'Disease', (63, 68))	('Fusion', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('EWS', 'Gene', '2130', (10, 13))	('EWS', 'Gene', (10, 13))
292030	23441188	This subtype of leukemia cells shows small microhomologies or non-template insertions, as well as small deletions and duplications at the chromosomal breakpoint regions, indicating that NHEJ repair is involved in breakpoint initiation.	('leukemia', 'Disease', 'MESH:D007938', (16, 24))	('leukemia', 'Disease', (16, 24))	('chromosomal breakpoint', 'Phenotype', 'HP:0040012', (138, 160))	('deletions', 'Var', (104, 113))	('duplications', 'Var', (118, 130))	('leukemia', 'Phenotype', 'HP:0001909', (16, 24))
292031	23441188	This observation of reciprocal balanced translocations with an NHEJ repair signature indicates molecular genetic similarities to mesenchymal tumors.	('mesenchymal tumors', 'Disease', 'MESH:C535700', (129, 147))	('mesenchymal tumors', 'Disease', (129, 147))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('balanced translocations', 'Var', (31, 54))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('NHEJ repair', 'Gene', (63, 74))
292034	20362353	The arylstibonic acid compound NSC13746 disrupts B-ZIP binding to DNA in living cells The inhibition of DNA binding of basic leucine zipper (B-ZIP) transcription factors is a clinically relevant molecular target.	('ZIP', 'Gene', '1613', (143, 146))	('arylstibonic acid', 'Chemical', '-', (4, 21))	('DNA', 'Protein', (66, 69))	('ZIP', 'Gene', '1613', (51, 54))	('ZIP', 'Gene', (143, 146))	('ZIP', 'Gene', (51, 54))	('NSC13746', 'Var', (31, 39))	('leucine', 'Chemical', 'MESH:D007930', (125, 132))	('NSC13746', 'Chemical', 'MESH:C551445', (31, 39))	('disrupts', 'NegReg', (40, 48))
292041	20362353	Additionally, the arylstibonic acid compound was cytostatic in clear cell sarcoma cells, which express a chimera between the B-ZIP domain of ATF-1 and N-terminal activation domain of EWS but not in K562 cells that express a non-B-ZIP containing chimeric protein BCR-ABL.	('K562', 'CellLine', 'CVCL:0004', (198, 202))	('ZIP', 'Gene', '1613', (230, 233))	('ZIP', 'Gene', '1613', (127, 130))	('ZIP', 'Gene', (127, 130))	('ATF-1', 'Gene', (141, 146))	('chimera', 'Var', (105, 112))	('ZIP', 'Gene', (230, 233))	('ATF-1', 'Gene', '466', (141, 146))	('BCR-ABL', 'Gene', '25', (262, 269))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (63, 81))	('arylstibonic acid', 'Chemical', '-', (18, 35))	('clear cell sarcoma', 'Disease', (63, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('BCR-ABL', 'Gene', (262, 269))
292048	20362353	In addition, upstream oncogenic mutations in serine-threonine kinase cascades can phosphorylate downstream nuclear B-ZIP transcription factors resulting in their chronic activation which makes them potential drug targets even though they themselves are not mutated.	('activation', 'PosReg', (170, 180))	('serine-threonine', 'Enzyme', (45, 61))	('ZIP', 'Gene', '1613', (117, 120))	('serine', 'Chemical', 'MESH:D012694', (45, 51))	('ZIP', 'Gene', (117, 120))	('mutations', 'Var', (32, 41))
292055	20362353	A-Fos expression in mammalian cells reduces Ha-ras-mediated cellular transformation whereas A-Fos expression in mouse epidermis converts papillomas to benign sebaceous adenomas and prevents conversion into carcinomas.	('converts', 'Reg', (128, 136))	('expression', 'Species', '29278', (6, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('expression', 'Species', '29278', (98, 108))	('carcinomas', 'Disease', (206, 216))	('mouse', 'Species', '10090', (112, 117))	('papilloma', 'Phenotype', 'HP:0012740', (137, 146))	('sebaceous adenomas', 'Phenotype', 'HP:0009720', (158, 176))	('papillomas', 'Phenotype', 'HP:0012740', (137, 147))	('Ha-ras-mediated cellular transformation', 'MPA', (44, 83))	('adenomas', 'Disease', (168, 176))	('reduces', 'NegReg', (36, 43))	('adenomas', 'Disease', 'MESH:D000236', (168, 176))	('A-Fos', 'Var', (92, 97))	('mammalian', 'Species', '9606', (20, 29))	('papillomas', 'Disease', 'MESH:D010212', (137, 147))	('papillomas', 'Disease', (137, 147))	('carcinomas', 'Disease', 'MESH:D009369', (206, 216))
292056	20362353	These results suggest that inhibiting B-ZIP DNA binding is a clinically relevant molecular target.	('inhibiting', 'Var', (27, 37))	('ZIP', 'Gene', (40, 43))	('ZIP', 'Gene', '1613', (40, 43))
292061	20362353	B-ZIP recoveries in NIH-3T3 cells were faster in a dose-dependent manner in the presence of either NSC13746 or A-ZIPs, suggesting that they inhibit B-ZIP DNA binding in live cells.	('ZIP', 'Gene', (113, 116))	('ZIP', 'Gene', '1613', (2, 5))	('NIH-3T3', 'CellLine', 'CVCL:0594', (20, 27))	('inhibit', 'NegReg', (140, 147))	('NSC13746', 'Chemical', 'MESH:C551445', (99, 107))	('NSC13746', 'Var', (99, 107))	('ZIP', 'Gene', (2, 5))	('faster', 'PosReg', (39, 45))	('ZIP', 'Gene', '1613', (150, 153))	('ZIP', 'Gene', '1613', (113, 116))	('ZIP', 'Gene', (150, 153))
292063	20362353	NSC13746 was non-toxic in the cells we examined except for a clear cell sarcoma that expresses the chimeric protein EWS-ATF1 where ATF1 is a B-ZIP domain.	('ZIP', 'Gene', '1613', (143, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('ZIP', 'Gene', (143, 146))	('clear cell sarcoma', 'Disease', (61, 79))	('EWS-ATF1', 'Gene', (116, 124))	('NSC13746', 'Var', (0, 8))	('NSC13746', 'Chemical', 'MESH:C551445', (0, 8))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (61, 79))
292064	20362353	The arylstibonic acids NSC13746, NSC13778 and NSC13748 that contain the antimony element were obtained from the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD (Fig.	('Cancer', 'Disease', 'MESH:D009369', (194, 200))	('NSC13746', 'Chemical', 'MESH:C551445', (23, 31))	('NSC13748', 'Var', (46, 54))	('NSC13748', 'Chemical', '-', (46, 54))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Cancer', 'Disease', (194, 200))	('arylstibonic acids', 'Chemical', '-', (4, 22))
292100	20362353	A chimera between VBP, a B-ZIP domain and GFP (GFP-VBP) had a recovery time after photobleaching of approximately 2 s (Fig.	('ZIP', 'Gene', (27, 30))	('recovery', 'MPA', (62, 70))	('chimera', 'Var', (2, 9))	('ZIP', 'Gene', '1613', (27, 30))
292105	20362353	NSC13746 caused a dose dependent increase in GFP-VBP nuclear recovery after FRAP (Fig.	('nuclear recovery', 'MPA', (53, 69))	('increase', 'PosReg', (33, 41))	('NSC13746', 'Var', (0, 8))	('NSC13746', 'Chemical', 'MESH:C551445', (0, 8))	('GFP-VBP', 'Gene', (45, 52))
292106	20362353	The nuclear recovery measured by FRAP of a structurally unrelated nuclear transcription factor, GFP labeled glucocorticoid receptor (GFP-GR), was unaffected after incubation with the highest concentration (100 muM) of two active compounds (NSC13746, NSC13778), demonstrating the specificity of NSC13746 in increasing the recovery of the GFP-VBP chimeric protein.	('increasing', 'PosReg', (306, 316))	('NSC13746', 'Var', (294, 302))	('NSC13746', 'Chemical', 'MESH:C551445', (294, 302))	('NSC13746', 'Chemical', 'MESH:C551445', (240, 248))
292107	20362353	To investigate whether the increase in GFP-VBP recovery in the presence of NSC13746 represents inhibition of DNA binding, cells were co-transfected with GFP-VBP and mCherry-A-VBP, a dominant negative protein that preferentially binds to VBP and blocks DNA binding.	('NSC13746', 'Var', (75, 83))	('NSC13746', 'Chemical', 'MESH:C551445', (75, 83))	('DNA binding', 'Interaction', (252, 263))	('binds', 'Interaction', (228, 233))	('GFP-VBP', 'MPA', (39, 46))	('mCh', 'Gene', (165, 168))	('mCh', 'Gene', '104242', (165, 168))	('increase', 'PosReg', (27, 35))	('preferentially', 'PosReg', (213, 227))	('blocks', 'NegReg', (245, 251))
292113	20362353	These experiments suggest that the dose- dependent increase in GFP-VBP recovery by NSC13746 is due to the inhibition of VBP DNA binding in living cells.	('increase', 'PosReg', (51, 59))	('GFP-VBP recovery', 'MPA', (63, 79))	('NSC13746', 'Var', (83, 91))	('VBP', 'Protein', (120, 123))	('inhibition', 'NegReg', (106, 116))	('NSC13746', 'Chemical', 'MESH:C551445', (83, 91))
292114	20362353	To gain insight into the structural reasons for the increased recovery of VBP in the presence of NSC13746 after FRAP, we measured the recovery of GFP-VBP domain mutants by FRAP (Fig.	('GFP-VBP', 'Gene', (146, 153))	('NSC13746', 'Chemical', 'MESH:C551445', (97, 105))	('NSC13746', 'Gene', (97, 105))	('domain mutants', 'Var', (154, 168))
292116	20362353	A deletion mutant of the VBP basic region that has been shown to inhibit DNA binding (16) (GFP-VBP-LZ) had an even faster recovery.	('inhibit', 'NegReg', (65, 72))	('VBP', 'Gene', (25, 28))	('deletion mutant', 'Var', (2, 17))	('LZ', 'Chemical', '-', (99, 101))
292117	20362353	The slower recovery of GFP-VBP in the presence of either NSC13746 or A-VBP compared to GFP-VBP-LZ may be due to residual GFP-VBP DNA binding.	('NSC13746', 'Var', (57, 65))	('NSC13746', 'Chemical', 'MESH:C551445', (57, 65))	('slower', 'NegReg', (4, 10))	('recovery', 'MPA', (11, 19))	('LZ', 'Chemical', '-', (95, 97))	('binding', 'Interaction', (133, 140))
292119	20362353	A GFP-VBP mutant containing two proline residues in the leucine zipper should structurally prevent dimerization and allow measurement of the recovery of a monomer.	('prevent', 'NegReg', (91, 98))	('mutant', 'Var', (10, 16))	('recovery of a monomer', 'MPA', (141, 162))	('GFP-VBP', 'Gene', (2, 9))	('dimerization', 'MPA', (99, 111))	('leucine', 'Chemical', 'MESH:D007930', (56, 63))	('proline', 'Chemical', 'MESH:D011392', (32, 39))
292122	20362353	Taken together, these data suggest that NSC13746 increases the recovery of GFP-VBP by inhibiting DNA binding.	('NSC13746', 'Var', (40, 48))	('GFP-VBP', 'Gene', (75, 82))	('NSC13746', 'Chemical', 'MESH:C551445', (40, 48))	('increases', 'PosReg', (49, 58))	('DNA binding', 'Interaction', (97, 108))	('inhibiting', 'NegReg', (86, 96))	('recovery', 'MPA', (63, 71))
292123	20362353	After demonstrating reasonable structural evidence using A-ZIP and leucine zipper mutants that FRAP could measure the ability of NSC13746 to inhibit B-ZIP DNA binding, we used Chromatin Immunoprecipitation (ChIP) as a more direct means to support this claim.	('ZIP', 'Gene', '1613', (59, 62))	('ZIP', 'Gene', (151, 154))	('NSC13746', 'Chemical', 'MESH:C551445', (129, 137))	('ZIP', 'Gene', (59, 62))	('NSC13746', 'Gene', (129, 137))	('leucine', 'Chemical', 'MESH:D007930', (67, 74))	('mutants', 'Var', (82, 89))	('inhibit', 'NegReg', (141, 148))	('ZIP', 'Gene', '1613', (151, 154))
292125	20362353	Cells treated with NSC13746 showed a 30% reduction in CREB DNA binding compared to mock treated cells, while cells treated with NSC13748 were unaffected (Fig.	('NSC13746', 'Chemical', 'MESH:C551445', (19, 27))	('NSC13748', 'Chemical', '-', (128, 136))	('NSC13746', 'Var', (19, 27))	('CREB', 'Gene', (54, 58))	('CREB', 'Gene', '12912', (54, 58))	('reduction', 'NegReg', (41, 50))
292126	20362353	These results, along with analyses by FRAP, suggest that NSC13746 binds to the B-ZIP to inhibit DNA binding.	('DNA binding', 'Interaction', (96, 107))	('NSC13746', 'Var', (57, 65))	('NSC13746', 'Chemical', 'MESH:C551445', (57, 65))	('inhibit', 'NegReg', (88, 95))	('ZIP', 'Gene', '1613', (81, 84))	('ZIP', 'Gene', (81, 84))
292128	20362353	NSC13746 increases the recovery of different B-ZIP domains.	('ZIP', 'Gene', (47, 50))	('recovery', 'MPA', (23, 31))	('NSC13746', 'Var', (0, 8))	('increases', 'PosReg', (9, 18))	('NSC13746', 'Chemical', 'MESH:C551445', (0, 8))	('ZIP', 'Gene', '1613', (47, 50))
292129	20362353	After observing a dose-dependent increase in recovery of GFP-VBP by NSC13746 (Fig.	('NSC13746', 'Chemical', 'MESH:C551445', (68, 76))	('NSC13746', 'Var', (68, 76))	('increase', 'PosReg', (33, 41))	('GFP-VBP', 'MPA', (57, 64))	('recovery', 'MPA', (45, 53))
292130	20362353	2B), we investigated whether NSC13746 increased the recovery of additional B-ZIP domains.	('NSC13746', 'Var', (29, 37))	('NSC13746', 'Chemical', 'MESH:C551445', (29, 37))	('ZIP', 'Gene', '1613', (77, 80))	('ZIP', 'Gene', (77, 80))	('recovery', 'MPA', (52, 60))	('increased', 'PosReg', (38, 47))
292131	20362353	A FRAP analysis showed that the interaction of NSC13746 with GFP-CREB or GFP-C/EBPbeta also caused an increase in the recovery of these B-ZIP domains (Fig.	('CREB', 'Gene', '12912', (65, 69))	('ZIP', 'Gene', '1613', (138, 141))	('C/EBPbeta', 'Gene', '12606', (77, 86))	('CREB', 'Gene', (65, 69))	('C/EBPbeta', 'Gene', (77, 86))	('ZIP', 'Gene', (138, 141))	('NSC13746', 'Chemical', 'MESH:C551445', (47, 55))	('NSC13746', 'Var', (47, 55))	('increase', 'PosReg', (102, 110))	('interaction', 'Interaction', (32, 43))	('recovery', 'MPA', (118, 126))
292132	20362353	These results indicate that NSC13746 is promiscuous and can inhibit the DNA binding of different B-ZIP domains in vivo.	('ZIP', 'Gene', (99, 102))	('inhibit', 'NegReg', (60, 67))	('DNA binding', 'Interaction', (72, 83))	('NSC13746', 'Var', (28, 36))	('ZIP', 'Gene', '1613', (99, 102))	('NSC13746', 'Chemical', 'MESH:C551445', (28, 36))
292153	20362353	Because NSC13746 promiscuously disrupts the DNA binding of all B-ZIP domains examined in living cells (Figs.	('NSC13746', 'Chemical', 'MESH:C551445', (8, 16))	('ZIP', 'Gene', '1613', (65, 68))	('disrupts', 'NegReg', (31, 39))	('ZIP', 'Gene', (65, 68))	('DNA binding', 'Interaction', (44, 55))	('NSC13746', 'Var', (8, 16))
292155	20362353	To investigate the potential for NSC13746 to inhibit the growth of cells, we used a cell line whose viability is dependent on a B-ZIP domain.	('NSC13746', 'Chemical', 'MESH:C551445', (33, 41))	('NSC13746', 'Var', (33, 41))	('ZIP', 'Gene', (130, 133))	('ZIP', 'Gene', '1613', (130, 133))
292156	20362353	Several human cancers contain chimeric proteins containing a B-ZIP domain.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('ZIP', 'Gene', '1613', (63, 66))	('ZIP', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('chimeric', 'Var', (30, 38))	('human', 'Species', '9606', (8, 13))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
292162	20362353	A 96-h incubation with increasing concentrations of NSC13746 caused up to 25% decrease in cell growth, whereas the inactive antimony compound (NSC13748) did not affect cell growth (Fig.	('NSC13748', 'Chemical', '-', (143, 151))	('NSC13746', 'Chemical', 'MESH:C551445', (52, 60))	('decrease', 'NegReg', (78, 86))	('cell growth', 'CPA', (90, 101))	('NSC13746', 'Var', (52, 60))
292163	20362353	The K562 leukemia cells containing a non-B-ZIP oncogenic gene fusion, BCR/abl, were not affected by active (NSC13746) or inactive drug (NSC13748), suggesting that the inhibition of cell growth in EWS-ATF1 cells is caused by specific targeting of the B-ZIP domain by NSC13746.	('ZIP', 'Gene', '1613', (43, 46))	('ZIP', 'Gene', (43, 46))	('NSC13746', 'Var', (266, 274))	('NSC13748', 'Chemical', '-', (136, 144))	('NSC13746', 'Chemical', 'MESH:C551445', (266, 274))	('K562', 'CellLine', 'CVCL:0004', (4, 8))	('inhibition', 'NegReg', (167, 177))	('NSC13746', 'Chemical', 'MESH:C551445', (108, 116))	('ZIP', 'Gene', '1613', (252, 255))	('leukemia', 'Phenotype', 'HP:0001909', (9, 17))	('leukemia', 'Disease', 'MESH:D007938', (9, 17))	('cell growth', 'CPA', (181, 192))	('leukemia', 'Disease', (9, 17))	('ZIP', 'Gene', (252, 255))
292169	20362353	In the present study, we evaluated the effects of NSC13746, a water soluble analogue of NSC13778, on B-ZIP mobility and localization in living cells and compared these findings to well-characterized dominant negatives that selectively inhibit B-ZIP DNA binding.	('NSC13746', 'Var', (50, 58))	('NSC13746', 'Chemical', 'MESH:C551445', (50, 58))	('ZIP', 'Gene', '1613', (103, 106))	('inhibit', 'NegReg', (235, 242))	('ZIP', 'Gene', '1613', (245, 248))	('ZIP', 'Gene', (103, 106))	('ZIP', 'Gene', (245, 248))	('water', 'Chemical', 'MESH:D014867', (62, 67))	('localization', 'MPA', (120, 132))
292170	20362353	A FRAP analysis showed that NSC13746 caused a dose-dependent increase in the recovery of GFP-VBP, as well as GFP-CREB and GFP-C/EBPbeta.	('CREB', 'Gene', (113, 117))	('C/EBPbeta', 'Gene', (126, 135))	('C/EBPbeta', 'Gene', '12606', (126, 135))	('recovery', 'MPA', (77, 85))	('CREB', 'Gene', '12912', (113, 117))	('increase', 'PosReg', (61, 69))	('NSC13746', 'Var', (28, 36))	('GFP-VBP', 'MPA', (89, 96))	('NSC13746', 'Chemical', 'MESH:C551445', (28, 36))
292171	20362353	This increase in recovery of different B-ZIP domains by NSC13746 is caused by inhibition of DNA binding, since dominant negative A-ZIPs which have been shown to specifically interact with B-ZIP domains to inhibit DNA binding caused similar increases in B-ZIP recovery by FRAP.	('NSC13746', 'Var', (56, 64))	('ZIP', 'Gene', '1613', (255, 258))	('ZIP', 'Gene', '1613', (41, 44))	('inhibit', 'NegReg', (205, 212))	('ZIP', 'Gene', (255, 258))	('ZIP', 'Gene', (41, 44))	('increase', 'PosReg', (5, 13))	('ZIP', 'Gene', '1613', (131, 134))	('ZIP', 'Gene', '1613', (190, 193))	('DNA', 'Protein', (213, 216))	('ZIP', 'Gene', (131, 134))	('ZIP', 'Gene', (190, 193))	('NSC13746', 'Chemical', 'MESH:C551445', (56, 64))	('increases', 'PosReg', (240, 249))
292172	20362353	In addition, NSC13746 inhibits B-ZIP DNA binding as directly measured by ChIP.	('NSC13746', 'Chemical', 'MESH:C551445', (13, 21))	('NSC13746', 'Var', (13, 21))	('ZIP', 'Gene', '1613', (33, 36))	('inhibits', 'NegReg', (22, 30))	('ZIP', 'Gene', (33, 36))
292173	20362353	Deleting the basic region from GFP-VBP caused even faster recovery of the B-ZIP protein, highlighting the importance of the basic region for the decreased recovery of the B-ZIP domain and providing further support that the increased recovery of the B-ZIP domains in the present of NSC13746 or A-ZIPs is a consequence of the inhibition of DNA binding.	('increased', 'PosReg', (223, 232))	('ZIP', 'Gene', (295, 298))	('ZIP', 'Gene', (251, 254))	('ZIP', 'Gene', '1613', (173, 176))	('ZIP', 'Gene', '1613', (76, 79))	('DNA binding', 'Interaction', (338, 349))	('NSC13746', 'Chemical', 'MESH:C551445', (281, 289))	('NSC13746', 'Var', (281, 289))	('ZIP', 'Gene', (173, 176))	('ZIP', 'Gene', (76, 79))	('recovery', 'MPA', (155, 163))	('recovery', 'MPA', (233, 241))	('Deleting', 'Var', (0, 8))	('ZIP', 'Gene', '1613', (295, 298))	('ZIP', 'Gene', '1613', (251, 254))
292174	20362353	Together these results demonstrate that both the A-ZIPs and NSC13746 exerted in vivo effects on DNA binding that were comparable to their previously measured in vitro properties.	('NSC13746', 'Chemical', 'MESH:C551445', (60, 68))	('ZIP', 'Gene', '1613', (51, 54))	('DNA binding', 'Interaction', (96, 107))	('NSC13746', 'Var', (60, 68))	('ZIP', 'Gene', (51, 54))
292176	20362353	We found that NSC13746 caused a partial cytoplasmic localization of all B-ZIP domains but not the GR domain.	('partial cytoplasmic localization', 'MPA', (32, 64))	('ZIP', 'Gene', '1613', (74, 77))	('NSC13746', 'Var', (14, 22))	('ZIP', 'Gene', (74, 77))	('NSC13746', 'Chemical', 'MESH:C551445', (14, 22))
292187	20362353	NSC13746 is a promiscuous compound that inhibits the B-ZIP DNA binding of many B-ZIP proteins.	('ZIP', 'Gene', '1613', (55, 58))	('ZIP', 'Gene', (55, 58))	('NSC13746', 'Var', (0, 8))	('inhibits', 'NegReg', (40, 48))	('NSC13746', 'Chemical', 'MESH:C551445', (0, 8))	('ZIP', 'Gene', '1613', (81, 84))	('ZIP', 'Gene', (81, 84))
292193	20362353	However, following a two-stage chemical carcinogenesis protocol, A-CEBP expression prevents skin papilloma formation or causes existing papillomas to regress.	('carcinogenesis', 'Disease', 'MESH:D063646', (40, 54))	('papillomas', 'Phenotype', 'HP:0012740', (136, 146))	('A-CEBP expression', 'Var', (65, 82))	('causes', 'Reg', (120, 126))	('carcinogenesis', 'Disease', (40, 54))	('expression', 'Species', '29278', (72, 82))	('skin papilloma', 'Disease', 'MESH:D010212', (92, 106))	('papilloma', 'Phenotype', 'HP:0012740', (136, 145))	('papillomas', 'Disease', 'MESH:D010212', (136, 146))	('papillomas', 'Disease', (136, 146))	('prevents', 'NegReg', (83, 91))	('skin papilloma', 'Disease', (92, 106))	('papilloma', 'Phenotype', 'HP:0012740', (97, 106))
292194	20362353	Child- hood cancers can be formed by translocation events leading to gene fusions.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('Child', 'Species', '9606', (0, 5))	('cancers', 'Disease', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('translocation', 'Var', (37, 50))	('gene', 'MPA', (69, 73))
292210	31703704	Disease status of the patients who answered the questionnaires could have been an influence of QoL and we could show reduced scores in the group of disease-free patients with neoadjuvant RCT, but not for the patients with recurrence or metastasis, so it is very hard to discriminate whether radiation therapy could really have an impact or not.	('patients', 'Species', '9606', (208, 216))	('reduced', 'NegReg', (117, 124))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (161, 169))	('neoadjuvant', 'Var', (175, 186))	('scores', 'MPA', (125, 131))
292343	31355033	When it is difficult to diagnose definitely even with hematoxylin and eosin staining and immunohistochemical analysis, molecular genetic or cytogenetic testing for USP6 genetic rearrangements can be helpful to confirm the diagnosis.	('hematoxylin', 'Chemical', 'MESH:D006416', (54, 65))	('eosin', 'Chemical', 'MESH:D004801', (70, 75))	('genetic rearrangements', 'Var', (169, 191))	('USP6', 'Gene', (164, 168))
292377	30545340	Particularly, pazopanib acts as a novel TKI and plays a key role in a broad spectrum of tumour types (13/40, 32.5%) during these trials.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('pazopanib', 'Chemical', 'MESH:C516667', (14, 23))	('pazopanib', 'Var', (14, 23))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))
292380	30545340	In particular, anlotinib (NCT02449343, NCT01878448) and apatinib (NCT0312846, NC03064243, NCT03104335, NCT02711007, NCT03163381) are two typical representatives of multi-RTK inhibitors and VEGFR inhibitors that were developed in China.	('NCT01878448', 'Var', (39, 50))	('NC03064243', 'Var', (78, 88))	('apatinib', 'Chemical', 'MESH:C553458', (56, 64))	('VEGFR', 'Gene', '3791', (189, 194))	('anlotinib', 'Chemical', 'MESH:C000625192', (15, 24))	('NCT03104335', 'Var', (90, 101))	('VEGFR', 'Gene', (189, 194))	('NCT0312846', 'Var', (66, 76))	('NCT02449343', 'Var', (26, 37))
292382	30545340	Among them, 11 trials focused on the PD1 antibody (NCT0321745, NCT0312376, NCT3013127, NCT03056001, NCT3138061, NCT3069378, NCT02888665, NCT02691026, NCT02406781, NCT2301039, NCT03282344).	('NCT3138061', 'Var', (100, 110))	('NCT3069378', 'Var', (112, 122))	('NCT02691026', 'Var', (137, 148))	('NCT0321745', 'Var', (51, 61))	('NCT03056001', 'Var', (87, 98))	('PD1', 'Gene', '5133', (37, 40))	('NCT03282344', 'Var', (175, 186))	('PD1', 'Gene', (37, 40))	('NCT02406781', 'Var', (150, 161))	('NCT2301039', 'Var', (163, 173))	('NCT3013127', 'Var', (75, 85))	('NCT02888665', 'Var', (124, 135))
292383	30545340	Four trials evaluated anti-PD-L1 therapy (NCT03141684, NCT03074318, NCT03233698, NCT02609984), and two trials used the PD1 antibody combined with the CTLA-4 antibody as treatment (NCT02982486, NCT02428192).	('CTLA-4', 'Gene', '1493', (150, 156))	('NCT03074318', 'Var', (55, 66))	('PD1', 'Gene', '5133', (119, 122))	('NCT03141684', 'Var', (42, 53))	('NCT02982486', 'Var', (180, 191))	('NCT03233698', 'Var', (68, 79))	('NCT02609984', 'Var', (81, 92))	('CTLA-4', 'Gene', (150, 156))	('PD1', 'Gene', (119, 122))	('PD-L1', 'Gene', (27, 32))	('PD-L1', 'Gene', '29126', (27, 32))
292400	30545340	After the production of imatinib, other promising TKIs have been utilized in clinical trials and released to the market, including sunitinib (NCT00400569, NCT00474994), sorafenib (NCT00238121, NCT00245102, NCT00217620) and pazopanib (NCT00753688).	('NCT00400569', 'Var', (142, 153))	('NCT00245102', 'Var', (193, 204))	('sunitinib', 'Chemical', 'MESH:D000077210', (131, 140))	('pazopanib', 'Chemical', 'MESH:C516667', (223, 232))	('sorafenib', 'Chemical', 'MESH:D000077157', (169, 178))	('NCT00217620', 'Var', (206, 217))	('NCT00753688', 'Var', (234, 245))	('NCT00238121', 'Var', (180, 191))	('imatinib', 'Chemical', 'MESH:D000068877', (24, 32))
292403	30545340	The results showed that the median progression-free survival was 4.6 months for the pazopanib group compared with 1.6 months for the placebo group, which indicated that pazopanib is a promising treatment option for patients with STS.	('patients', 'Species', '9606', (215, 223))	('pazopanib', 'Var', (84, 93))	('STS', 'Disease', (229, 232))	('pazopanib', 'Chemical', 'MESH:C516667', (169, 178))	('pazopanib', 'Chemical', 'MESH:C516667', (84, 93))
292407	30545340	Recently, a growing number of phase II/III clinical trials of apatinib, which is a new type of VEGFR inhibitor for sarcomas, have also been initiated in China (NCT0312846, NC03064243, NCT03104335, NCT02711007, NCT03163381).	('NCT03163381', 'Var', (210, 221))	('apatinib', 'Chemical', 'MESH:C553458', (62, 70))	('VEGFR', 'Gene', '3791', (95, 100))	('NCT0312846', 'Var', (160, 170))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('VEGFR', 'Gene', (95, 100))	('NCT02711007', 'Var', (197, 208))	('NC03064243', 'Var', (172, 182))	('sarcomas', 'Disease', (115, 123))	('NCT03104335', 'Var', (184, 195))
292408	30545340	In addition, clinical trials focusing on other promising VEGFR inhibitors, such as cabozantinib (NCT01755195, NCT01979393), and tivozanib (NCT01782313), are ongoing and recruiting patients.	('NCT01755195', 'Var', (97, 108))	('cabozantinib', 'Chemical', 'MESH:C558660', (83, 95))	('VEGFR', 'Gene', (57, 62))	('NCT01782313', 'Var', (139, 150))	('tivozanib', 'Chemical', 'MESH:C553176', (128, 137))	('NCT01979393', 'Var', (110, 121))	('patients', 'Species', '9606', (180, 188))	('VEGFR', 'Gene', '3791', (57, 62))
292416	30545340	A blockade of the PD-1/PD-L1 axis results in a profound tumour response that could occur as early as 8-12 weeks.	('blockade', 'Var', (2, 10))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (18, 28))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('PD-1/PD-L1', 'Disease', (18, 28))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))
292419	30545340	Given its mechanism and clinical benefit in melanoma, trials involving dual blockade with PD-1/PD-L1 and cytotoxic T-lymphocyte-associated protein 4 inhibitors in sarcoma are ongoing (NCT02428192, NCT02982486).	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('NCT02428192', 'Var', (184, 195))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (105, 148))	('sarcoma', 'Disease', (163, 170))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (105, 148))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (90, 100))	('PD-1/PD-L1', 'Disease', (90, 100))
292420	30545340	Talimogene laherparepvec (T-VEC) combined with pembrolizumab demonstrated acceptable safety and promising anti-tumor activity across a range of sarcoma histologies with 4 patients maintain PR (NCT03069378).	('sarcoma', 'Disease', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (171, 179))	('tumor', 'Disease', (111, 116))	('PR (NCT03069378', 'Var', (189, 204))	('pembrolizumab', 'Chemical', 'MESH:C582435', (47, 60))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))
292424	30545340	For example, blockade of mTOR combined with nivolumab is being tested for antitumour activity in sarcoma (NCT03190174).	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('blockade', 'Var', (13, 21))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('nivolumab', 'Chemical', 'MESH:D000077594', (44, 53))	('tumour', 'Disease', (78, 84))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('mTOR', 'Gene', '2475', (25, 29))	('mTOR', 'Gene', (25, 29))
292430	30319719	 EWSR1 Rearrangement and CD99 Expression as Diagnostic Biomarkers for Ewing/PNET Sarcomas in a Moroccan Population Ewing sarcoma/primitive neuroectodermal tumor (Ewing/PNET sarcomas or EPS) are a group of round cell tumors.	('CD99', 'Gene', (25, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (129, 160))	('Ewing/PNET sarcomas', 'Disease', 'MESH:C563168', (162, 181))	('EWSR1', 'Gene', '2130', (1, 6))	('cell tumors', 'Disease', (211, 222))	('EPS', 'Disease', 'MESH:D001480', (185, 188))	('Ewing sarcoma', 'Disease', (115, 128))	('CD99', 'Gene', '4267', (25, 29))	('cell tumors', 'Disease', 'MESH:D005935', (211, 222))	('Sarcomas', 'Phenotype', 'HP:0100242', (81, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (173, 181))	('Ewing/PNET Sarcomas', 'Disease', (70, 89))	('Ewing/PNET sarcomas', 'Disease', (162, 181))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Ewing/PNET Sarcomas', 'Disease', 'MESH:C563168', (70, 89))	('EWSR1', 'Gene', (1, 6))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (139, 160))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Rearrangement', 'Var', (7, 20))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (115, 128))	('EPS', 'Disease', (185, 188))	('neuroectodermal tumor', 'Disease', (139, 160))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (115, 128))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (139, 160))
292434	30319719	We investigated the diagnostic value of combined CD99 immunostaining and EWSR1 t(22q12) alteration using a dual-color, break-apart rearrangement probe in forty-one formalin-fixed paraffin-embedded (FFPE) tissue samples from pediatric and adult patients diagnosed with EPS.	('paraffin', 'Chemical', 'MESH:D010232', (179, 187))	('CD99', 'Gene', '4267', (49, 53))	('EWSR1', 'Gene', (73, 78))	('CD99', 'Gene', (49, 53))	('EPS', 'Disease', (268, 271))	('EWSR1', 'Gene', '2130', (73, 78))	('patients', 'Species', '9606', (244, 252))	('formalin', 'Chemical', 'MESH:D005557', (164, 172))	('alteration', 'Var', (88, 98))	('EPS', 'Disease', 'MESH:D001480', (268, 271))
292436	30319719	In addition, CD99 positivity was found to correlate with EWSR1 rearrangement (p < 0.05).	('CD99', 'Gene', (13, 17))	('positivity', 'Var', (18, 28))	('EWSR1', 'Gene', (57, 62))	('CD99', 'Gene', '4267', (13, 17))	('EWSR1', 'Gene', '2130', (57, 62))
292448	30319719	Importantly, these tumors show frequent and specific rearrangement of the Ewing sarcoma breakpoint region 1 (EWSR1) gene located on chromosome 22.	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('EWSR1', 'Gene', '2130', (109, 114))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (74, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('EWSR1', 'Gene', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('Ewing sarcoma', 'Disease', (74, 87))	('rearrangement', 'Var', (53, 66))
292449	30319719	Translocations between EWSR1 and Friend leukemia integration 1 transcription factor (FLI1) (85%, t(11;22)(q24;q12)) and between EWSR1 and ETS transcription factor (ERG) (10%, t(21;22)(q22;q12)) are key differential cytogenetic alterations in EPS.	('EPS', 'Disease', 'MESH:D001480', (242, 245))	('Translocations', 'Var', (0, 14))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (175, 192))	('t(11;22)(q24', 'Var', (97, 109))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (97, 114))	('EWSR1', 'Gene', (128, 133))	('EWSR1', 'Gene', (23, 28))	('EPS', 'Disease', (242, 245))	('ETS', 'Chemical', '-', (138, 141))	('Friend leukemia', 'Disease', (33, 48))	('EWSR1', 'Gene', '2130', (23, 28))	('EWSR1', 'Gene', '2130', (128, 133))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))	('FLI1', 'Gene', (85, 89))	('Friend leukemia', 'Disease', 'MESH:D007938', (33, 48))
292451	30319719	Specific FISH with break-apart probe targeting translocations on FFPE sections is commonly used in combination with CD99 immunostaining for diagnosis of these tumors.	('CD99', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('translocations', 'Var', (47, 61))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('CD99', 'Gene', '4267', (116, 120))
292452	30319719	Here, we report the results of a study evaluating the sensitivity and specificity of FISH-based EWSR1 rearrangement, as well its correlation with CD99 positivity, for enhanced diagnosis of EPS in a large Moroccan cohort.	('rearrangement', 'Var', (102, 115))	('enhanced', 'PosReg', (167, 175))	('EWSR1', 'Gene', (96, 101))	('EPS', 'Disease', (189, 192))	('CD99', 'Gene', '4267', (146, 150))	('EWSR1', 'Gene', '2130', (96, 101))	('CD99', 'Gene', (146, 150))	('EPS', 'Disease', 'MESH:D001480', (189, 192))
292467	30319719	A chi2 test was used to correlate CD99 positivity with the presence of EWSR1 rearrangement.	('CD99', 'Gene', '4267', (34, 38))	('rearrangement', 'Var', (77, 90))	('CD99', 'Gene', (34, 38))	('EWSR1', 'Gene', (71, 76))	('EWSR1', 'Gene', '2130', (71, 76))
292472	30319719	92.7% of the cases (38/41) showed a positivity for CD99 antibody, including 29 cases with strong, diffuse, and characteristic membranous staining (Figure 1(b)).	('CD99', 'Gene', '4267', (51, 55))	('positivity', 'Var', (36, 46))	('CD99', 'Gene', (51, 55))
292474	30319719	The FISH analysis showed a rearrangement of the EWSR1 gene locus in 48.8% of the cases (20/41) (Figure 1(c)).	('EWSR1', 'Gene', (48, 53))	('EWSR1', 'Gene', '2130', (48, 53))	('rearrangement', 'Var', (27, 40))
292479	30319719	Furthermore, we found a strong correlation between the diffuse positivity >= 50% of CD99 and the presence of EWSR1 rearrangement (p < 0.05) (Table 3).	('EWSR1', 'Gene', '2130', (109, 114))	('presence', 'Var', (97, 105))	('rearrangement', 'Var', (115, 128))	('CD99', 'Gene', '4267', (84, 88))	('EWSR1', 'Gene', (109, 114))	('CD99', 'Gene', (84, 88))
292485	30319719	We have performed a comprehensive investigation of combined CD99 immunostaining and EWSR1 rearrangement as diagnostic biomarkers to increase their sensitivities and specificities in a large cohort of Moroccan EPS patients.	('CD99', 'Gene', (60, 64))	('increase', 'PosReg', (132, 140))	('EPS', 'Disease', 'MESH:D001480', (209, 212))	('EWSR1', 'Gene', (84, 89))	('sensitivities', 'MPA', (147, 160))	('CD99', 'Gene', '4267', (60, 64))	('rearrangement', 'Var', (90, 103))	('patients', 'Species', '9606', (213, 221))	('EPS', 'Disease', (209, 212))	('EWSR1', 'Gene', '2130', (84, 89))
292487	30319719	The dual-color, break-apart FISH technique is used in several pathology laboratories to identify the rearrangement of the EWSR1 gene with a potential added value in the diagnosis of EPS.	('EWSR1', 'Gene', '2130', (122, 127))	('rearrangement', 'Var', (101, 114))	('EPS', 'Disease', 'MESH:D001480', (182, 185))	('value', 'Reg', (156, 161))	('EWSR1', 'Gene', (122, 127))	('EPS', 'Disease', (182, 185))
292490	30319719	Tumors containing <50% of CD99 positive cells had low probability to be rearranged as demonstrated by the chi2 test (p < 0.005).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD99', 'Gene', (26, 30))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CD99', 'Gene', '4267', (26, 30))	('rearranged', 'Var', (72, 82))
292493	30319719	It was suggested that a combination of CD99 and FLI1 may increase the accuracy of IHC.	('CD99', 'Gene', (39, 43))	('FLI1', 'Gene', (48, 52))	('combination', 'Var', (24, 35))	('increase', 'PosReg', (57, 65))	('CD99', 'Gene', '4267', (39, 43))	('IHC', 'Disease', (82, 85))	('accuracy', 'MPA', (70, 78))
292498	30319719	Our study showed that EWSR1 rearrangement and CD99 expression are potential biomarkers for diagnosis of EPS, and more advanced investigation to study their correlations with prognosis, survival, and therapy response are awaited.	('EWSR1', 'Gene', '2130', (22, 27))	('rearrangement', 'Var', (28, 41))	('EPS', 'Disease', (104, 107))	('EWSR1', 'Gene', (22, 27))	('CD99', 'Gene', '4267', (46, 50))	('EPS', 'Disease', 'MESH:D001480', (104, 107))	('CD99', 'Gene', (46, 50))
292499	30319719	In order to correctly diagnose EPS, laboratory testing should include both histopathology and CD99 immunostaining, as well as molecular analysis using a dual-color, break-apart rearrangement probe in order to better characterize this entity by identifying the EWSR1 rearrangement.	('EWSR1', 'Gene', '2130', (260, 265))	('EPS', 'Disease', (31, 34))	('CD99', 'Gene', '4267', (94, 98))	('CD99', 'Gene', (94, 98))	('EPS', 'Disease', 'MESH:D001480', (31, 34))	('rearrangement', 'Var', (266, 279))	('EWSR1', 'Gene', (260, 265))
292507	30050324	Pazopanib showed higher incidence of all-grade nausea, diarrhea and hypertension compared with sorafenib and sunitinib.	('nausea', 'Disease', (47, 53))	('hypertension', 'Disease', 'MESH:D006973', (68, 80))	('nausea', 'Disease', 'MESH:D009325', (47, 53))	('sorafenib', 'Chemical', 'MESH:D000077157', (95, 104))	('hypertension', 'Disease', (68, 80))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('diarrhea', 'Phenotype', 'HP:0002014', (55, 63))	('hypertension', 'Phenotype', 'HP:0000822', (68, 80))	('diarrhea', 'Disease', 'MESH:D003967', (55, 63))	('diarrhea', 'Disease', (55, 63))	('sunitinib', 'Chemical', 'MESH:D000077210', (109, 118))	('Pazopanib', 'Var', (0, 9))	('nausea', 'Phenotype', 'HP:0002018', (47, 53))
292510	30050324	Moreover, the frequency of grade >=3 mucositis was significantly higher in the sunitinib group compared with the pazopanib or sorafenib group (7.6% vs. 1.3%, OR 6.448, 95% CI 1.499-27.731, P=0.013).	('sunitinib', 'Chemical', 'MESH:D000077210', (79, 88))	('pazopanib', 'Chemical', 'MESH:C516667', (113, 122))	('sunitinib', 'Var', (79, 88))	('mucositis', 'Disease', (37, 46))	('higher', 'PosReg', (65, 71))	('sorafenib', 'Chemical', 'MESH:D000077157', (126, 135))	('mucositis', 'Disease', 'MESH:D052016', (37, 46))
292515	30050324	Based on the clinical trials, pazopanib was determined to be well tolerated in metastatic or advanced STS and demonstrated antitumor activity in non-liposarcoma.	('non-liposarcoma', 'Disease', (145, 160))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('pazopanib', 'Chemical', 'MESH:C516667', (30, 39))	('liposarcoma', 'Phenotype', 'HP:0012034', (149, 160))	('tumor', 'Disease', (127, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('pazopanib', 'Var', (30, 39))	('metastatic', 'Disease', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('non-liposarcoma', 'Disease', 'MESH:D008080', (145, 160))
292520	30050324	Based on preclinical data, the level of tumor growth inhibition for pazopanib was similar to that for sorafenib.	('pazopanib', 'Chemical', 'MESH:C516667', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('pazopanib', 'Var', (68, 77))	('sorafenib', 'Chemical', 'MESH:D000077157', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
292540	30050324	The incidence of all-grade nausea was highest with pazopanib (47.2%) followed by sunitinib (24.2%) and sorafenib (7.6%).	('sorafenib', 'Chemical', 'MESH:D000077157', (103, 112))	('nausea', 'Phenotype', 'HP:0002018', (27, 33))	('nausea', 'Disease', (27, 33))	('nausea', 'Disease', 'MESH:D009325', (27, 33))	('pazopanib', 'Chemical', 'MESH:C516667', (51, 60))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))	('pazopanib', 'Var', (51, 60))
292543	30050324	The incidence of all-grade hypertension was highest with pazopanib (40.9%) followed by sunitinib (18.2%) and sorafenib (9.3%).	('hypertension', 'Disease', 'MESH:D006973', (27, 39))	('sunitinib', 'Chemical', 'MESH:D000077210', (87, 96))	('pazopanib', 'Var', (57, 66))	('hypertension', 'Disease', (27, 39))	('hypertension', 'Phenotype', 'HP:0000822', (27, 39))	('sorafenib', 'Chemical', 'MESH:D000077157', (109, 118))	('pazopanib', 'Chemical', 'MESH:C516667', (57, 66))
292548	30050324	Similarly, the frequency of all-grade diarrhea was significantly greater in patients treated with pazopanib than in those treated with sorafenib (43.2% vs. 23.5%, OR 2.470, 95% CI 1.808-3.375, P<0.001).	('pazopanib', 'Chemical', 'MESH:C516667', (98, 107))	('patients', 'Species', '9606', (76, 84))	('pazopanib', 'Var', (98, 107))	('diarrhea', 'Phenotype', 'HP:0002014', (38, 46))	('diarrhea', 'Disease', 'MESH:D003967', (38, 46))	('sorafenib', 'Chemical', 'MESH:D000077157', (135, 144))	('diarrhea', 'Disease', (38, 46))
292550	30050324	All-grade vomiting was significantly more common for pazopanib compared with sorafenib (27.4% vs. 5.4%, OR 6.183, 95% CI 3.324-11.501, P<0.001).	('pazopanib', 'Var', (53, 62))	('vomiting', 'Phenotype', 'HP:0002013', (10, 18))	('vomiting', 'Disease', (10, 18))	('sorafenib', 'Chemical', 'MESH:D000077157', (77, 86))	('-grade vomiting', 'Phenotype', 'HP:0002572', (3, 18))	('vomiting', 'Disease', 'MESH:D014839', (10, 18))	('pazopanib', 'Chemical', 'MESH:C516667', (53, 62))
292556	30050324	For all-grade leukopenia, patients in the pazopanib group also experienced significantly higher frequency than patients in the sorafenib group (42.3% vs. 10.4%, OR 6.293, 95% CI 3.352-11.814, P<0.001) and sunitinib group (42.3% vs. 14.3%, OR 4.390, 95% CI 0.947-20.347, P=0.048), whereas there was no significant difference between sunitinib and sorafenib (14.3% vs. 10.4%, OR 1.433, 95% CI 0.292-7.026, P=0.649; Figure 2G).	('leukopenia', 'Disease', (14, 24))	('pazopanib', 'Chemical', 'MESH:C516667', (42, 51))	('leukopenia', 'Disease', 'MESH:D007970', (14, 24))	('patients', 'Species', '9606', (26, 34))	('higher', 'PosReg', (89, 95))	('sunitinib', 'Chemical', 'MESH:D000077210', (332, 341))	('sunitinib', 'Chemical', 'MESH:D000077210', (205, 214))	('sorafenib', 'Chemical', 'MESH:D000077157', (346, 355))	('pazopanib', 'Var', (42, 51))	('leukopenia', 'Phenotype', 'HP:0001882', (14, 24))	('sorafenib', 'Chemical', 'MESH:D000077157', (127, 136))	('patients', 'Species', '9606', (111, 119))
292558	30050324	Another common adverse effect, elevated all-grade ALT, was more common for pazopanib compared with sorafenib (24.7% vs. 7.7%, OR 3.907, 95% CI 2.159-7.069, P<0.001) and sunitinib vs. sorafenib (21.2% vs. 7.7%, OR 3.200, 95% CI 1.354-7.566, P=0.010).	('pazopanib', 'Chemical', 'MESH:C516667', (75, 84))	('all-grade ALT', 'MPA', (40, 53))	('pazopanib', 'Var', (75, 84))	('sunitinib', 'Chemical', 'MESH:D000077210', (169, 178))	('sorafenib', 'Chemical', 'MESH:D000077157', (183, 192))	('elevated', 'PosReg', (31, 39))	('sorafenib', 'Chemical', 'MESH:D000077157', (99, 108))
292563	30050324	Grade >=3 fatigue was significantly more common for pazopanib compared with sorafenib (11.0% vs. 6.5%, OR 1.778, 95% CI 1.046-3.022, P=0.037) and sunitinib (11.0% vs. 1.5%, OR 8.053, 95% CI 1.089-59.555, P=0.012).	('sorafenib', 'Chemical', 'MESH:D000077157', (76, 85))	('sunitinib', 'Chemical', 'MESH:D000077210', (146, 155))	('fatigue', 'Disease', (10, 17))	('fatigue', 'Phenotype', 'HP:0012378', (10, 17))	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('pazopanib', 'Var', (52, 61))	('fatigue', 'Disease', 'MESH:D005221', (10, 17))
292569	30050324	Another common adverse effect, grade >=3 rash, was less common for pazopanib compared with sorafenib (0.4% vs. 8.3%, OR 0.047, 95% CI 0.006-0.346, P<0.001).	('pazopanib', 'Var', (67, 76))	('rash', 'Disease', 'MESH:D005076', (41, 45))	('rash', 'Phenotype', 'HP:0000988', (41, 45))	('sorafenib', 'Chemical', 'MESH:D000077157', (91, 100))	('rash', 'Disease', (41, 45))	('pazopanib', 'Chemical', 'MESH:C516667', (67, 76))
292587	30050324	Moreover, the frequency of grade >=3 mucositis was significantly higher in the sunitinib group compared with the pazopanib or sorafenib groups.	('sunitinib', 'Chemical', 'MESH:D000077210', (79, 88))	('pazopanib', 'Chemical', 'MESH:C516667', (113, 122))	('sunitinib', 'Var', (79, 88))	('mucositis', 'Disease', (37, 46))	('higher', 'PosReg', (65, 71))	('sorafenib', 'Chemical', 'MESH:D000077157', (126, 135))	('mucositis', 'Disease', 'MESH:D052016', (37, 46))
292652	29805376	Trabectedin also interacts with DNA repair mechanisms, making cells with homologous recombination repair (HRR) deficiencies, such as BRCA1 and BRCA2 mutations, more sensitive to trabectedin.	('BRCA2', 'Gene', '675', (143, 148))	('more', 'PosReg', (160, 164))	('mutations', 'Var', (149, 158))	('deficiencies', 'Var', (111, 123))	('sensitive', 'MPA', (165, 174))	('BRCA1', 'Gene', '672', (133, 138))	('BRCA2', 'Gene', (143, 148))	('trabectedin', 'Chemical', 'MESH:D000077606', (178, 189))	('BRCA1', 'Gene', (133, 138))
292658	29805376	For pazopanib, median PFS was 4.6 months (95% CI 3.7-4.8) compared with 1.6 months (0.9-1.8) for placebo (p < 0 0001) and overall survival was 12.5 months (10.6-14.8) versus 10.7 months (8.7-12.8) with placebo (p = 0.25).	('pazopanib', 'Chemical', 'MESH:C516667', (4, 13))	('PFS', 'MPA', (22, 25))	('pazopanib', 'Var', (4, 13))
292675	29746587	Silencing of HIF1alpha rescued the hypoxia associated phenotype of KSHV positive cells.	('rescued', 'PosReg', (23, 30))	('HIF1alpha', 'Gene', (13, 22))	('hypoxia', 'Disease', 'MESH:D000860', (35, 42))	('KSHV', 'Species', '37296', (67, 71))	('hypoxia', 'Disease', (35, 42))	('Silencing', 'Var', (0, 9))
292692	29746587	Metabolite profiling of KSHV infected cells suggest a wide difference between metabolite pools of KSHV infected cells when compared to control cells, including those which are common to anabolic pathways of most cancer cells.	('KSHV', 'Species', '37296', (24, 28))	('KSHV', 'Gene', (98, 102))	('metabolite pools', 'MPA', (78, 94))	('infected', 'Var', (103, 111))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('KSHV', 'Species', '37296', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
292700	29746587	Hypoxia on the other hand plays an important role in KSHV reactivation biology where HIF1alpha facilitates KSHV-encoded RTA-mediated reactivation by binding with LANA and up-regulating RTA expression.	('LANA', 'Gene', '4961527', (162, 166))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('HIF1alpha', 'Var', (85, 94))	('Hypoxia', 'Disease', (0, 7))	('RTA-mediated reactivation', 'MPA', (120, 145))	('KSHV', 'Species', '37296', (107, 111))	('LANA', 'Gene', (162, 166))	('binding', 'Interaction', (149, 156))	('up-regulating', 'PosReg', (171, 184))	('RTA expression', 'MPA', (185, 199))	('KSHV', 'Species', '37296', (53, 57))	('KSHV-encoded', 'Gene', (107, 119))	('facilitates', 'PosReg', (95, 106))
292734	29746587	A time dependent enhancement in the glucose uptake was observed for BJAB-KSHV cells when compared to BJAB cells growing in normoxic condition.	('BJAB', 'CellLine', 'CVCL:5711', (68, 72))	('BJAB-KSHV', 'Var', (68, 77))	('BJAB-KSHV', 'CellLine', 'CVCL:5711', (68, 77))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('BJAB', 'CellLine', 'CVCL:5711', (101, 105))	('enhancement', 'PosReg', (17, 28))	('glucose uptake', 'CPA', (36, 50))
292736	29746587	To rule out the possibility of an effect of puromycin pretreatment on glucose uptake, glucose consumption was also measured in cells growing either in the presence of puromycin, or its absence for 48 hours.	('puromycin', 'Var', (167, 176))	('glucose consumption', 'MPA', (86, 105))	('puromycin', 'Chemical', 'MESH:D011691', (44, 53))	('puromycin', 'Chemical', 'MESH:D011691', (167, 176))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))	('glucose', 'Chemical', 'MESH:D005947', (70, 77))
292761	29746587	Similarly, RTA was shown to be up-regulated by RT-PCR in CoCl2 and 1% O2, as expected (Fig 2B & 2C).	('CoCl2', 'Chemical', 'MESH:C018021', (57, 62))	('O2', 'Chemical', 'MESH:D010100', (70, 72))	('up-regulated', 'PosReg', (31, 43))	('RT-PCR', 'Var', (47, 53))	('RTA', 'Gene', (11, 14))
292777	29746587	Next, we wanted to determine if HIF1alpha knockdown in KSHV-positive cells can rescue the hypoxia associated expression of KSHV-encoded genes.	('rescue', 'PosReg', (79, 85))	('KSHV', 'Species', '37296', (55, 59))	('KSHV-encoded genes', 'Gene', (123, 141))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('hypoxia', 'Disease', (90, 97))	('KSHV', 'Species', '37296', (123, 127))	('knockdown', 'Var', (42, 51))
292838	29746587	The KSHV-bacmid clone containing vGPCR-Frame shift knock out mutant (KSHV-vGPCR-FS-KO) or vGPCR-Frame shift mutant reversed (KSHV-vGPCR-FS-R) KSHV were transfected into HEK293T cells to generate stable lines.	('vGPCR', 'Gene', '4961465', (74, 79))	('KSHV', 'Species', '37296', (4, 8))	('KSHV', 'Species', '37296', (69, 73))	('KSHV', 'Species', '37296', (142, 146))	('vGPCR', 'Gene', '4961465', (130, 135))	('vGPCR', 'Gene', (90, 95))	('vGPCR', 'Gene', '4961465', (33, 38))	('KSHV', 'Species', '37296', (125, 129))	('mutant', 'Var', (108, 114))	('vGPCR', 'Gene', (74, 79))	('vGPCR', 'Gene', (33, 38))	('vGPCR', 'Gene', (130, 135))	('vGPCR', 'Gene', '4961465', (90, 95))	('HEK293T', 'CellLine', 'CVCL:0063', (169, 176))
292841	29746587	KSHV reactivation of the vGPCR-Frame shift mutant or revertant was induced by treatment with TPA and Butyric acid followed by standard virus purification.	('KSHV', 'Species', '37296', (0, 4))	('Butyric acid', 'Chemical', 'MESH:D020148', (101, 113))	('vGPCR', 'Gene', (25, 30))	('TPA', 'Chemical', 'MESH:D013755', (93, 96))	('mutant', 'Var', (43, 49))	('vGPCR', 'Gene', '4961465', (25, 30))
292842	29746587	As expected, the vGPCR-Frame shift mutant showed a substantial decrease in lytic replication with significantly less yield in genome copies.	('vGPCR', 'Gene', (17, 22))	('lytic replication', 'CPA', (75, 92))	('mutant', 'Var', (35, 41))	('less', 'NegReg', (112, 116))	('decrease', 'NegReg', (63, 71))	('vGPCR', 'Gene', '4961465', (17, 22))	('genome copies', 'MPA', (126, 139))
292843	29746587	To determine if vGPCR was a critical factor for the observed metabolic changes in hypoxia, PBMCs were infected with the vGPCR knockout and revertant KSHV virus and cells were subjected to hypoxic induction by treating with CoCl2.	('vGPCR', 'Gene', '4961465', (16, 21))	('hypoxia', 'Disease', (82, 89))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('vGPCR', 'Gene', '4961465', (120, 125))	('knockout', 'Var', (126, 134))	('KSHV', 'Species', '37296', (149, 153))	('CoCl2', 'Chemical', 'MESH:C018021', (223, 228))	('vGPCR', 'Gene', (16, 21))	('vGPCR', 'Gene', (120, 125))
292849	29746587	The PBMCs infected with the vGPCR kockout KSHV showed a significantly lower glucose uptake compared to the revertant (Wild type) KSHV infected cells (Fig 9E).	('vGPCR', 'Gene', (28, 33))	('KSHV', 'Species', '37296', (42, 46))	('kockout', 'Var', (34, 41))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('lower', 'NegReg', (70, 75))	('vGPCR', 'Gene', '4961465', (28, 33))	('KSHV', 'Species', '37296', (129, 133))	('glucose uptake', 'MPA', (76, 90))
292895	29746587	This study also provided information on the differences due to hypoxia induced due to low oxygen compared to CoCl2, especially in terms of cell survival and growth.	('growth', 'CPA', (157, 163))	('CoCl2', 'Chemical', 'MESH:C018021', (109, 114))	('oxygen', 'Chemical', 'MESH:D010100', (90, 96))	('hypoxia', 'Disease', 'MESH:D000860', (63, 70))	('hypoxia', 'Disease', (63, 70))	('low', 'Var', (86, 89))
293068	28588856	Single-nucleotide polymorphism array is a novel method that can be used to define tumor genome and be used as a guidance to choose the proper treatment regimen.	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Single-nucleotide', 'Var', (0, 17))
293087	28588856	The analysis of rs2032582 (SNP) in tandem repeats of ABCB1 gene was carried out using allele-specific polymerase chain reaction.	('rs2032582', 'Mutation', 'rs2032582', (16, 25))	('rs2032582', 'Var', (16, 25))	('ABCB1', 'Gene', (53, 58))	('ABCB1', 'Gene', '5243', (53, 58))
293182	25206203	7), focal positivity for synaptophysin and negativity for desmin and diagnosis came compatible with ES or primitive neuroectodermal tumor (PNET).	('synaptophysin', 'Gene', '6855', (25, 38))	('desmin', 'Gene', (58, 64))	('negativity', 'Var', (43, 53))	('ES', 'Phenotype', 'HP:0012254', (100, 102))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (116, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PNET', 'Phenotype', 'HP:0030065', (139, 143))	('neuroectodermal tumor', 'Disease', (116, 137))	('desmin', 'Gene', '1674', (58, 64))	('synaptophysin', 'Gene', (25, 38))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (106, 137))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (116, 137))
293185	25206203	ES is related to the PNET, sharing a common karyotype translocation t(11;12)(q24;q12) in approximately 90% of these tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('PNET', 'Phenotype', 'HP:0030065', (21, 25))	('t(11;12)(q24;q12', 'Var', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('t(11;12)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (68, 85))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
293217	25206203	Poor prognostic factors are patients below 10 years of age, pelvic lesions, presence of metastasis, presence of systemic symptoms, large tumor volume, high mitotic rate, filigree pattern in histopathological sections and poor response to chemotherapy.	('high mitotic rate', 'CPA', (151, 168))	('tumor', 'Disease', (137, 142))	('pelvic lesions', 'Disease', (60, 74))	('metastasis', 'CPA', (88, 98))	('filigree', 'Var', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('patients', 'Species', '9606', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
293231	22719951	The use of small molecules that restore p53 activity, such as CP-31398 or Nutlin-3a, in association with TNF-alpha, potentiated the cell death of respectively TP53Mut and TP53Wt/MDM2Ampl.	('TNF-alpha', 'Gene', (105, 114))	('TP53', 'Gene', (171, 175))	('CP-31398', 'Var', (62, 70))	('p53', 'Gene', (40, 43))	('CP-31398', 'Chemical', 'MESH:C402665', (62, 70))	('activity', 'MPA', (44, 52))	('TP53', 'Gene', (159, 163))	('TP53', 'Gene', '7157', (159, 163))	('MDM2', 'Gene', (178, 182))	('potentiated', 'PosReg', (116, 127))	('p53', 'Gene', '7157', (40, 43))	('MDM2', 'Gene', '4193', (178, 182))	('TNF-alpha', 'Gene', '7124', (105, 114))	('cell death', 'CPA', (132, 142))	('TP53', 'Gene', '7157', (171, 175))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (74, 83))
293232	22719951	In particular, CP-31398 was able to induce p53 as well as some of its apoptotic target genes in TP53Mut cells.	('TP53', 'Gene', (96, 100))	('CP-31398', 'Var', (15, 23))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('CP-31398', 'Chemical', 'MESH:C402665', (15, 23))	('induce', 'PosReg', (36, 42))	('TP53', 'Gene', '7157', (96, 100))
293254	22719951	Importantly, TP53 mutations or inactivations were found to correlate with a poorer outcome in sarcoma patients.	('TP53', 'Gene', (13, 17))	('inactivations', 'Var', (31, 44))	('sarcoma', 'Disease', (94, 101))	('patients', 'Species', '9606', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('TP53', 'Gene', '7157', (13, 17))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('mutations', 'Var', (18, 27))
293256	22719951	The recent emergence of small molecules restoring the wild-type conformation of mutant p53 protein, as well as blocking the MDM2-p53 interaction, is likely to become a promising anti-tumour strategy.	('interaction', 'Interaction', (133, 144))	('tumour', 'Disease', (183, 189))	('mutant', 'Var', (80, 86))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('blocking', 'NegReg', (111, 119))	('restoring', 'PosReg', (40, 49))	('protein', 'Protein', (91, 98))	('p53', 'Gene', (129, 132))	('MDM2', 'Gene', '4193', (124, 128))	('p53', 'Gene', '7157', (129, 132))	('MDM2', 'Gene', (124, 128))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('conformation', 'MPA', (64, 76))
293257	22719951	In this context, the conformational changes observed in the case of missense mutation of p53 are reversible at least to some extent.	('p53', 'Gene', '7157', (89, 92))	('p53', 'Gene', (89, 92))	('missense mutation', 'Var', (68, 85))
293258	22719951	Thus, CP-31398, a styrylquinazoline, can rescue some mutant p53 to a wild-type conformation and therefore increase the steady-state wild-type p53 to high levels equivalent to those observed following DNA damage.	('rescue', 'PosReg', (41, 47))	('CP-31398', 'Var', (6, 14))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('CP-31398', 'Chemical', 'MESH:C402665', (6, 14))	('p53', 'Gene', (60, 63))	('mutant', 'Var', (53, 59))	('p53', 'Gene', '7157', (60, 63))	('increase', 'PosReg', (106, 114))	('styrylquinazoline', 'Chemical', 'MESH:C501448', (18, 35))
293275	22719951	The excitation wavelengths were 488 nm for Alexa 488, 543 nm for the TUNEL positive nuclei revealed by the Cell Death Detection Kit, and 633 nm for TO-PRO3.	('Alexa 488', 'Chemical', '-', (43, 52))	('633 nm', 'Var', (137, 143))	('PRO3', 'Gene', (151, 155))	('PRO3', 'Gene', '5831', (151, 155))
293305	22719951	In MFH100 and MFH152 cells, TP53 had respectively a homozygous 524 G>A (R175H) and 503 A>C (H168P) missense mutation (TP53Mut).	('R175H', 'Mutation', 'rs28934578', (72, 77))	('503 A>C', 'Mutation', 'c.503A>C', (83, 90))	('TP53', 'Gene', '7157', (28, 32))	('524 G>A', 'Var', (63, 70))	('MFH', 'Gene', (3, 6))	('503 A>C (H168P', 'Var', (83, 97))	('TP53', 'Gene', (28, 32))	('MFH', 'Gene', (14, 17))	('524 G>A', 'Mutation', 'rs28934578', (63, 70))	('TP53', 'Gene', '7157', (118, 122))	('H168P', 'Mutation', 'p.H168P', (92, 97))	('TP53', 'Gene', (118, 122))	('MFH', 'Gene', '27086', (3, 6))	('MFH', 'Gene', '27086', (14, 17))
293306	22719951	In MFH95 and LMS148 cells, a TP53 deletion was observed since no amplification of TP53 exons 2 to 11 could be obtained (TP53Null).	('TP53', 'Gene', (82, 86))	('MFH', 'Gene', (3, 6))	('LMS148', 'CellLine', 'CVCL:M822', (13, 19))	('TP53', 'Gene', '7157', (29, 33))	('deletion', 'Var', (34, 42))	('TP53', 'Gene', (29, 33))	('MFH', 'Gene', '27086', (3, 6))	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
293314	22719951	In order to confirm the role of p53 in TNF-alpha-induced apoptosis of STS, we first knocked down p53 in the TP53Wt/MDM2Wt TNF-alpha sensitive HT1080 cell line by stable transfection of a vector encoding a short hairpin RNA (shRNA) targeting p53 (shRNA-p53) or luciferase mRNA as a control (shRNA-luc) (Fig.	('TP53', 'Gene', (108, 112))	('p53', 'Gene', '7157', (97, 100))	('p53', 'Gene', '7157', (32, 35))	('MDM2', 'Gene', (115, 119))	('STS', 'Phenotype', 'HP:0030448', (70, 73))	('p53', 'Gene', (97, 100))	('HT1080', 'Gene', (142, 148))	('HT1080', 'Gene', '8872', (142, 148))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (252, 255))	('MDM2', 'Gene', '4193', (115, 119))	('TNF-alpha', 'Gene', '7124', (122, 131))	('TNF-alpha', 'Gene', (122, 131))	('TP53', 'Gene', '7157', (108, 112))	('knocked', 'Var', (84, 91))	('p53', 'Gene', (252, 255))	('p53', 'Gene', '7157', (241, 244))	('TNF-alpha', 'Gene', '7124', (39, 48))	('TNF-alpha', 'Gene', (39, 48))	('p53', 'Gene', (241, 244))
293315	22719951	Silencing of p53 resulted in the abrogation of TNF-alpha-induced apoptosis (29% and 36% apoptosis respectively in non-transfected and control cells versus 3% in shRNA-p53 cells, p<0.05) (Fig.	('abrogation', 'NegReg', (33, 43))	('p53', 'Gene', '7157', (167, 170))	('apoptosis', 'CPA', (65, 74))	('TNF-alpha', 'Gene', '7124', (47, 56))	('p53', 'Gene', (13, 16))	('p53', 'Gene', (167, 170))	('Silencing', 'Var', (0, 9))	('TNF-alpha', 'Gene', (47, 56))	('p53', 'Gene', '7157', (13, 16))
293316	22719951	Moreover, the inhibition of TNF-alpha-induced apoptosis in shRNA-p53 transfected cells was not due to the decrease of TNF-R1 expression (data not shown).	('apoptosis', 'CPA', (46, 55))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('TNF', 'Gene', (28, 31))	('transfected', 'Var', (69, 80))	('TNF-alpha', 'Gene', (28, 37))	('expression', 'Species', '29278', (125, 135))	('TNF', 'Gene', (118, 121))	('TNF', 'Gene', '7124', (28, 31))	('expression', 'MPA', (125, 135))	('TNF', 'Gene', '7124', (118, 121))	('TNF-alpha', 'Gene', '7124', (28, 37))
293324	22719951	The small molecule CP-31398 was reported to stabilize the wild-type-associated epitope (mAb1620) of the p53 DNA-binding domain, thus conferring a wild-type conformation to mutant p53 and rescuing p53 functions.	('mutant', 'Var', (172, 178))	('p53', 'Gene', (104, 107))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('p53', 'Gene', '7157', (104, 107))	('functions', 'MPA', (200, 209))	('conformation', 'MPA', (156, 168))	('CP-31398', 'Chemical', 'MESH:C402665', (19, 27))	('CP-31398', 'Var', (19, 27))	('rescuing', 'PosReg', (187, 195))	('p53', 'Gene', '7157', (196, 199))	('p53', 'Gene', (196, 199))	('conferring', 'Reg', (133, 143))
293325	22719951	Therefore, we asked whether sarcoma cell lines treatment with CP-31398 would enhance p53 protein expression and its transcriptional activity.	('transcriptional activity', 'MPA', (116, 140))	('sarcoma', 'Disease', (28, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('CP-31398', 'Var', (62, 70))	('CP-31398', 'Chemical', 'MESH:C402665', (62, 70))	('p53', 'Gene', '7157', (85, 88))	('expression', 'Species', '29278', (97, 107))	('p53', 'Gene', (85, 88))	('enhance', 'PosReg', (77, 84))	('protein', 'Protein', (89, 96))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))
293327	22719951	Furthermore, CP-31398 treatment increased expression of the p53 targets p21 and BAX.	('expression', 'Species', '29278', (42, 52))	('expression', 'MPA', (42, 52))	('p21', 'Gene', (72, 75))	('p53', 'Gene', (60, 63))	('p21', 'Gene', '644914', (72, 75))	('increased', 'PosReg', (32, 41))	('p53', 'Gene', '7157', (60, 63))	('BAX', 'Gene', (80, 83))	('CP-31398', 'Var', (13, 21))	('BAX', 'Gene', '581', (80, 83))	('CP-31398', 'Chemical', 'MESH:C402665', (13, 21))
293329	22719951	In order to investigate whether CP-31398 can restore the sensitivity of TP53Mut cell lines to TNF-alpha-induced cell death, we incubated MFH152 and MFH100 cells with 50 ng/ml TNF-alpha and/or CP-31398 (Fig.	('CP-31398', 'Chemical', 'MESH:C402665', (192, 200))	('TNF-alpha', 'Gene', (175, 184))	('MFH', 'Gene', '27086', (148, 151))	('TNF-alpha', 'Gene', '7124', (94, 103))	('TP53', 'Gene', '7157', (72, 76))	('TP53', 'Gene', (72, 76))	('MFH', 'Gene', (148, 151))	('TNF-alpha', 'Gene', (94, 103))	('MFH', 'Gene', '27086', (137, 140))	('CP-31398', 'Chemical', 'MESH:C402665', (32, 40))	('TNF-alpha', 'Gene', '7124', (175, 184))	('CP-31398', 'Var', (192, 200))	('MFH', 'Gene', (137, 140))
293330	22719951	Results show that CP-31398 alone had a slight apoptotic effect.	('CP-31398', 'Chemical', 'MESH:C402665', (18, 26))	('CP-31398', 'Var', (18, 26))	('apoptotic effect', 'CPA', (46, 62))
293331	22719951	However, CP-31398 pre-treatment followed by 72 h TNF-alpha had a synergistic effect on apoptosis induction in both TP53Mut cell lines (28% and 43% respectively for MFH152 and MFH100).	('MFH', 'Gene', (175, 178))	('MFH', 'Gene', (164, 167))	('TNF-alpha', 'Gene', '7124', (49, 58))	('TP53', 'Gene', '7157', (115, 119))	('CP-31398', 'Var', (9, 17))	('TNF-alpha', 'Gene', (49, 58))	('TP53', 'Gene', (115, 119))	('apoptosis', 'CPA', (87, 96))	('CP-31398', 'Chemical', 'MESH:C402665', (9, 17))	('MFH', 'Gene', '27086', (175, 178))	('MFH', 'Gene', '27086', (164, 167))
293361	22719951	Accumulating evidence indicates that p53 dysregulation is very common in STS and that p53 mutations correlate with increased resistance to current therapeutic strategies.	('STS', 'Phenotype', 'HP:0030448', (73, 76))	('mutations', 'Var', (90, 99))	('p53', 'Gene', '7157', (86, 89))	('increased', 'PosReg', (115, 124))	('dysregulation', 'Var', (41, 54))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('p53', 'Gene', (86, 89))
293363	22719951	We demonstrated that STS tumour resistance to TNF-alpha-induced-cell death was also associated with p53 inactivation (by point mutation or MDM2 amplification).	('MDM2', 'Gene', (139, 143))	('inactivation', 'NegReg', (104, 116))	('TNF-alpha', 'Gene', '7124', (46, 55))	('point mutation', 'Var', (121, 135))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('p53', 'Gene', '7157', (100, 103))	('TNF-alpha', 'Gene', (46, 55))	('associated', 'Reg', (84, 94))	('STS', 'Phenotype', 'HP:0030448', (21, 24))	('tumour', 'Disease', (25, 31))	('MDM2', 'Gene', '4193', (139, 143))	('p53', 'Gene', (100, 103))
293368	22719951	It is well known that the conformation of the DNA-binding domain of p53 is flexible and that conformational changes in mutant p53 are reversible.	('p53', 'Gene', '7157', (126, 129))	('p53', 'Gene', '7157', (68, 71))	('p53', 'Gene', (68, 71))	('mutant', 'Var', (119, 125))	('p53', 'Gene', (126, 129))
293369	22719951	Thus, restoration of p53 wild-type function to the highly accumulated mutant p53 in tumour cells may possibly result in a considerable therapeutic response.	('tumour', 'Disease', (84, 90))	('mutant', 'Var', (70, 76))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('therapeutic response', 'CPA', (135, 155))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('p53', 'Gene', (21, 24))	('result in', 'Reg', (110, 119))
293370	22719951	In this regard, we investigated the effect of CP-31398, a small molecule known to rescue p53 functions.	('p53', 'Gene', '7157', (89, 92))	('p53', 'Gene', (89, 92))	('CP-31398', 'Var', (46, 54))	('CP-31398', 'Chemical', 'MESH:C402665', (46, 54))
293372	22719951	An improvement of TNF-alpha killing efficiency can thus be obtained when used in association with p53 re-activating agents in the context of p53 mutation.	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('TNF-alpha', 'Gene', '7124', (18, 27))	('TNF-alpha', 'Gene', (18, 27))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))	('improvement', 'PosReg', (3, 14))	('mutation', 'Var', (145, 153))
293375	22719951	Consequently, it potently stabilizes and activates wild-type, but not mutant p53 protein in tumour cells in contrast to chemotherapeutics whose mechanism of action, at least in part, relies on genotoxic activation of p53.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('p53', 'Gene', (217, 220))	('p53', 'Gene', '7157', (217, 220))	('tumour', 'Disease', (92, 98))	('mutant', 'Var', (70, 76))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('protein', 'Protein', (81, 88))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('stabilizes', 'MPA', (26, 36))	('activates', 'PosReg', (41, 50))
293379	22719951	It has been reported that in p53-mutated cell lines, NF-kappaB was induced at higher levels following TNF-alpha treatment and that TNF-alpha-induced apoptosis in these cells was modulated by mutated p53 as well as by the NF-kappaB induction.	('TNF-alpha', 'Gene', (102, 111))	('apoptosis', 'CPA', (149, 158))	('NF-kappaB', 'Gene', (221, 230))	('p53', 'Gene', (199, 202))	('NF-kappaB', 'Gene', '4790', (53, 62))	('NF-kappaB', 'Gene', (53, 62))	('p53', 'Gene', '7157', (199, 202))	('TNF-alpha', 'Gene', '7124', (131, 140))	('higher', 'PosReg', (78, 84))	('mutated', 'Var', (191, 198))	('TNF-alpha', 'Gene', (131, 140))	('p53', 'Gene', (29, 32))	('modulated', 'Reg', (178, 187))	('induced', 'PosReg', (67, 74))	('p53', 'Gene', '7157', (29, 32))	('NF-kappaB', 'Gene', '4790', (221, 230))	('TNF-alpha', 'Gene', '7124', (102, 111))
293385	22719951	Indeed, this may have important implications since the use of both CP-31398 and Nutlin-3a, which act on various pathways, may be useful in overcoming drug resistance and thus could result in a more efficient therapeutic response.	('drug resistance', 'MPA', (150, 165))	('CP-31398', 'Chemical', 'MESH:C402665', (67, 75))	('Nutlin-3a', 'Gene', (80, 89))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (80, 89))	('result in', 'Reg', (181, 190))	('CP-31398', 'Var', (67, 75))	('therapeutic response', 'CPA', (208, 228))	('more', 'PosReg', (193, 197))	('overcoming', 'NegReg', (139, 149))	('drug resistance', 'Phenotype', 'HP:0020174', (150, 165))
293386	22719951	In conclusion, our data indicate that activating p53 with CP-31398 or Nutlin-3a, in respectively TP53Mut and TP53Wt/MDM2Ampl cell lines, restores sensitivity to TNF-alpha.	('TNF-alpha', 'Gene', (161, 170))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('TP53', 'Gene', '7157', (97, 101))	('activating', 'PosReg', (38, 48))	('CP-31398', 'Var', (58, 66))	('MDM2', 'Gene', '4193', (116, 120))	('MDM2', 'Gene', (116, 120))	('restores', 'PosReg', (137, 145))	('CP-31398', 'Chemical', 'MESH:C402665', (58, 66))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (70, 79))	('TP53', 'Gene', (97, 101))	('TP53', 'Gene', '7157', (109, 113))	('TP53', 'Gene', (109, 113))	('TNF-alpha', 'Gene', '7124', (161, 170))
293388	22719951	These findings thus provide a new strategy for treating highly refractory STS, in which p53 is frequently mutated or inactivated.	('inactivated', 'NegReg', (117, 128))	('STS', 'Phenotype', 'HP:0030448', (74, 77))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('mutated', 'Var', (106, 113))
293482	27888003	However, in mammalian cells, it has been verified that the delivery of long dsRNAs is closely related to the activation of the interferon (IFN) pathway, which is part of the defence mechanism against viral infection.	('long dsRNAs', 'Var', (71, 82))	('mammalian', 'Species', '9606', (12, 21))	('viral infection', 'Disease', 'MESH:D001102', (200, 215))	('activation', 'PosReg', (109, 119))	('viral infection', 'Disease', (200, 215))
293497	27888003	They discovered that several miRNAs such as hsa-miR-205-5p, hsa-miR-203 and hsa-miR-30c-2-3p targeting runt-related transcription factor 2 (Runx2), and hsa-miR- 320a targeting beta-catenin, exhibited substantially different targeting gene-expression levels between DEX and PTH treatment.	('targeting gene-expression levels', 'MPA', (224, 256))	('hsa-miR- 320a', 'Gene', (152, 165))	('PTH', 'Gene', (273, 276))	('hsa-miR- 320a', 'Gene', '407037', (152, 165))	('hsa-miR-205', 'Gene', '406988', (44, 55))	('beta-catenin', 'Gene', (176, 188))	('runt-related transcription factor 2', 'Gene', (103, 138))	('DEX', 'Chemical', 'MESH:D003907', (265, 268))	('PTH', 'Gene', '5741', (273, 276))	('beta-catenin', 'Gene', '1499', (176, 188))	('hsa-miR-205', 'Gene', (44, 55))	('hsa-miR-203', 'Gene', (60, 71))	('hsa-miR-203', 'Gene', '406986', (60, 71))	('runt-related transcription factor 2', 'Gene', '860', (103, 138))	('hsa-miR-30c-2-3p', 'Var', (76, 92))	('Runx2', 'Gene', '860', (140, 145))	('Runx2', 'Gene', (140, 145))
293500	27888003	Additionally, mmu-miR-705 and mmu-miR-3077-5p were also observed to be negative regulators of osteoblast differentiation by targeting HOXA10.	('HOXA10', 'Gene', '3206', (134, 140))	('mmu-miR-705', 'Gene', (14, 25))	('HOXA10', 'Gene', (134, 140))	('osteoblast differentiation', 'CPA', (94, 120))	('targeting', 'Reg', (124, 133))	('mmu-miR-705', 'Gene', '735267', (14, 25))	('mmu-miR-3077-5p', 'Var', (30, 45))
293505	27888003	They indicated that endothelial hsa-miR-31-5p, which is secreted within senescent cell-derived microvesicles, is taken up by mesenchymal stem cells, in which it suppresses osteogenic differentiation by knocking down Frizzled-3.	('Frizzled-3', 'Gene', (216, 226))	('31-5p', 'Chemical', '-', (40, 45))	('knocking', 'Var', (202, 210))	('hsa-miR-31', 'Gene', (32, 42))	('osteogenic differentiation', 'CPA', (172, 198))	('Frizzled-3', 'Gene', '7976', (216, 226))	('suppresses', 'NegReg', (161, 171))	('hsa-miR-31', 'Gene', '407035', (32, 42))
293512	27888003	LRP5 is a single-pass transmembrane protein, and absence of or variation of in LRP5 has been shown to result in decreased bone mass and osteoporosis.	('LRP5', 'Gene', (79, 83))	('osteoporosis', 'Disease', (136, 148))	('bone mass', 'MPA', (122, 131))	('osteoporosis', 'Phenotype', 'HP:0000939', (136, 148))	('variation', 'Var', (63, 72))	('absence', 'NegReg', (49, 56))	('LRP5', 'Gene', '4041', (0, 4))	('LRP5', 'Gene', (0, 4))	('LRP5', 'Gene', '4041', (79, 83))	('decreased', 'NegReg', (112, 121))	('osteoporosis', 'Disease', 'MESH:D010024', (136, 148))
293527	27888003	To understand whether other effective paracrine pathways exist in the interaction between the two cell types, Li and colleagues conducted miRNA-mediated osteoclast-directed osteoblastic bone formation in ovariectomized (OVX) mice, indicating that inhibition of osteoclast-derived exosomal mmu-miR-214-3p induced significantly suppressed osteoclastogenesis.	('suppressed', 'NegReg', (326, 336))	('osteoclastogenesis', 'CPA', (337, 355))	('mice', 'Species', '10090', (225, 229))	('osteoblastic bone', 'Disease', 'MESH:D001859', (173, 190))	('mmu-miR-214-3p', 'Var', (289, 303))	('osteoblastic bone', 'Disease', (173, 190))
293528	27888003	Additionally, mmu-miR-214-3p also negatively controlled osteogenic differentiation by targeting Osterix and activating transcription factor 4 (ATF4), promoting osteoclastogenesis via the PI3K/Akt pathway by targeting phosphatase and tensin homologue (PTEN).	('Osterix', 'Gene', (96, 103))	('Akt', 'Gene', '207', (192, 195))	('ATF4', 'Gene', (143, 147))	('promoting', 'PosReg', (150, 159))	('ATF4', 'Gene', '468', (143, 147))	('negatively', 'NegReg', (34, 44))	('Osterix', 'Gene', '121340', (96, 103))	('activating transcription factor 4', 'Gene', '468', (108, 141))	('activating transcription factor 4', 'Gene', (108, 141))	('osteogenic differentiation', 'CPA', (56, 82))	('Akt', 'Gene', (192, 195))	('osteoclastogenesis', 'CPA', (160, 178))	('targeting', 'Reg', (86, 95))	('phosphatase and tensin homologue', 'Gene', '5728', (217, 249))	('mmu-miR-214-3p', 'Var', (14, 28))	('PTEN', 'Gene', (251, 255))	('PTEN', 'Gene', '5728', (251, 255))	('targeting', 'Reg', (207, 216))
293536	27888003	As the most common degenerative bone disease in elderly women, postmenopausal osteoporosis is caused by a remodelling imbalance between bone formation and bone resorption due to oestrogen deficiency.	('caused by', 'Reg', (94, 103))	('women', 'Species', '9606', (56, 61))	('degenerative bone disease', 'Disease', 'MESH:D001847', (19, 44))	('osteoporosis', 'Phenotype', 'HP:0000939', (78, 90))	('deficiency', 'Var', (188, 198))	('oestrogen', 'Protein', (178, 187))	('degenerative bone disease', 'Disease', (19, 44))	('imbalance', 'Phenotype', 'HP:0002172', (118, 127))	('osteoporosis', 'Disease', 'MESH:D010024', (78, 90))	('bone resorption', 'Phenotype', 'HP:0002797', (155, 170))	('osteoporosis', 'Disease', (78, 90))	('postmenopausal osteoporosis', 'Phenotype', 'HP:0008209', (63, 90))
293539	27888003	observed that mmu-miR-29a-3p protected rats from GC-induced bone loss and fragility by regulating Wnt and its inhibitor Dkk-1, making miR-29a-3p a potential candidate for alleviating GCOP.	('rats', 'Species', '10116', (39, 43))	('Dkk-1', 'Gene', '293897', (120, 125))	('Dkk-1', 'Gene', (120, 125))	('GCOP', 'Disease', (183, 187))	('Wnt', 'Gene', (98, 101))	('bone loss', 'Disease', 'MESH:D001859', (60, 69))	('miR-29a-3p', 'Var', (134, 144))	('GC-induced', 'Disease', (49, 59))	('fragility', 'CPA', (74, 83))	('Wnt', 'Gene', '114487', (98, 101))	('bone loss', 'Phenotype', 'HP:0002797', (60, 69))	('bone loss', 'Disease', (60, 69))
293540	27888003	The inhibition of histone deacetylase (HDAC) 4 with miR-29a-3p restored the acetylation state of beta-catenin and Runx2, ameliorating the harmful effects of glucocorticoids on osteoblastic mineralization.	('miR-29a-3p', 'Var', (52, 62))	('acetylation state', 'MPA', (76, 93))	('histone deacetylase (HDAC) 4', 'Gene', (18, 46))	('ameliorating', 'PosReg', (121, 133))	('beta-catenin', 'Gene', (97, 109))	('restored', 'PosReg', (63, 71))	('Runx2', 'Gene', '860', (114, 119))	('Runx2', 'Gene', (114, 119))	('rat', 'Species', '10116', (127, 130))	('beta-catenin', 'Gene', '1499', (97, 109))	('histone deacetylase (HDAC) 4', 'Gene', '9759', (18, 46))	('osteoblastic mineralization', 'CPA', (176, 203))	('inhibition', 'NegReg', (4, 14))
293543	27888003	In addition, hsa-miR-442a could down-regulate certain gene expression levels related to osteoclastogenesis inhibition, including cluster of differentiation 226 (CD226), phosphoprotein associated with glycosphingo-lipid microdomains 1 (PAG-1), insulin-like growth factor 1 (IGF-1) and transducer of ERBB2 (TOB-2), making hsa-miR-442a another possible biomarker underlying post-menopausal osteoporosis.	('osteoporosis', 'Disease', (387, 399))	('insulin-like growth factor 1', 'Gene', '3479', (243, 271))	('osteoporosis', 'Phenotype', 'HP:0000939', (387, 399))	('PAG-1', 'Gene', (235, 240))	('osteoporosis', 'Disease', 'MESH:D010024', (387, 399))	('IGF-1', 'Gene', (273, 278))	('gene expression levels', 'MPA', (54, 76))	('PAG-1', 'Gene', '55824', (235, 240))	('insulin-like growth factor 1', 'Gene', (243, 271))	('hsa-miR-442a', 'Var', (13, 25))	('IGF-1', 'Gene', '3479', (273, 278))	('transducer of ERBB2', 'Gene', '10766', (284, 303))	('CD226', 'Gene', (161, 166))	('phosphoprotein associated with glycosphingo-lipid microdomains 1', 'Gene', '55824', (169, 233))	('TOB-2', 'Gene', (305, 310))	('transducer of ERBB2', 'Gene', (284, 303))	('TOB-2', 'Gene', '10766', (305, 310))	('osteoclastogenesis', 'Disease', (88, 106))	('down-regulate', 'NegReg', (32, 45))
293544	27888003	Furthermore, hsa-miR-194-5p was identified as a potential biomarker of postmenopausal osteoporosis according to Meng et al.	('postmenopausal osteoporosis', 'Phenotype', 'HP:0008209', (71, 98))	('osteoporosis', 'Disease', 'MESH:D010024', (86, 98))	('osteoporosis', 'Disease', (86, 98))	('hsa-miR-194-5p', 'Var', (13, 27))	('osteoporosis', 'Phenotype', 'HP:0000939', (86, 98))
293553	27888003	reported that mmu-miR-140-3p and mmu-miR-214-3p impeded sponges via constructed Cre/loxP-based hybrid baculovirus vectors, demonstrating improved bone formation and mitigated excessive bone resorption in an osteoporotic bone defect rat model, thus paving a new avenue to the treatment of osteoporotic bone defects through combination of osteogenic factors and functional miRNAs.	('bone resorption', 'CPA', (185, 200))	('osteoporotic bone defect', 'Disease', 'MESH:D058866', (288, 312))	('mmu-miR-214-3p', 'Var', (33, 47))	('rat', 'Species', '10116', (232, 235))	('excessive bone', 'Phenotype', 'HP:0100774', (175, 189))	('bone formation', 'CPA', (146, 160))	('osteoporotic bone defects', 'Disease', (288, 313))	('bone resorption', 'Phenotype', 'HP:0002797', (185, 200))	('rat', 'Species', '10116', (130, 133))	('osteoporotic bone defect', 'Disease', (207, 231))	('osteoporotic bone defect', 'Disease', 'MESH:D058866', (207, 231))	('mitigated', 'NegReg', (165, 174))	('improved', 'PosReg', (137, 145))	('osteoporotic bone defects', 'Disease', 'MESH:D058866', (288, 313))
293554	27888003	In addition, Krzeszinski and colleagues found that mmu-miR-34a-5p knockout and heterozygous mice exhibited elevated bone resorption and reduced bone mass by targeting transforming growth factor-beta-induced factor 2 (Tgif2), indicating that miR-34a-5p was a critical osteoclast suppressor and a potential therapeutic strategy to combat osteoporosis, and could exert both anti-catabolic and anabolic effects compared to current drugs that are solely anti-catabolic.	('mmu-miR-34a', 'Gene', (51, 62))	('transforming growth factor-beta', 'Gene', (167, 198))	('reduced', 'NegReg', (136, 143))	('mice', 'Species', '10090', (92, 96))	('elevated', 'PosReg', (107, 115))	('miR-34a-5p', 'Chemical', '-', (55, 65))	('anti-catabolic', 'MPA', (371, 385))	('mmu-miR-34a', 'Gene', '723848', (51, 62))	('bone resorption', 'Phenotype', 'HP:0002797', (116, 131))	('miR-34a-5p', 'Var', (241, 251))	('Tgif2', 'Gene', (217, 222))	('bone resorption', 'CPA', (116, 131))	('osteoporosis', 'Disease', (336, 348))	('targeting', 'Var', (157, 166))	('osteoporosis', 'Phenotype', 'HP:0000939', (336, 348))	('anabolic', 'MPA', (390, 398))	('transforming growth factor-beta', 'Gene', '7124', (167, 198))	('miR-34a-5p', 'Chemical', '-', (241, 251))	('osteoporosis', 'Disease', 'MESH:D010024', (336, 348))	('rat', 'Species', '10116', (319, 322))	('bone mass', 'CPA', (144, 153))
293560	27888003	In addition, this group also reported that mmu-miR-705 and mmu-miR-3077-5p could mediate the shift of BMSC cell lineages into adipocytes in osteoporosis by targeting HOXA10 and Runx2, respectively.	('osteoporosis', 'Disease', 'MESH:D010024', (140, 152))	('HOXA10', 'Gene', (166, 172))	('mmu-miR-3077-5p', 'Var', (59, 74))	('osteoporosis', 'Disease', (140, 152))	('HOXA10', 'Gene', '3206', (166, 172))	('mmu-miR-705', 'Gene', '735267', (43, 54))	('osteoporosis', 'Phenotype', 'HP:0000939', (140, 152))	('Runx2', 'Gene', (177, 182))	('mmu-miR-705', 'Gene', (43, 54))	('Runx2', 'Gene', '860', (177, 182))	('targeting', 'Reg', (156, 165))
293574	27888003	reported BMSC sheets incorporating with non-viral oligonucleotide anti-mmu-miR-138-5p by a vitamin C-induced method, which displayed significantly improved bone regeneration in vivo by activating the ERK1/2 pathway via targeting Runx2.	('bone regeneration', 'CPA', (156, 173))	('activating', 'PosReg', (185, 195))	('ERK1/2', 'Gene', (200, 206))	('ERK1/2', 'Gene', '5595;5594', (200, 206))	('Runx2', 'Gene', '860', (229, 234))	('Runx2', 'Gene', (229, 234))	('anti-mmu-miR-138-5p', 'Var', (66, 85))	('rat', 'Species', '10116', (167, 170))	('oligonucleotide', 'Chemical', 'MESH:D009841', (50, 65))	('rat', 'Species', '10116', (28, 31))	('vitamin C', 'Chemical', 'MESH:D001205', (91, 100))	('improved', 'PosReg', (147, 155))
293575	27888003	It was verified that the miR-29 family could negatively regulate the extracellular matrix (ECM) production during the early stage of osteogenesis, and inhibition of the miR-29 family could promote ECM synthesis in osteoblastogenesis.	('negatively', 'NegReg', (45, 55))	('osteogenesis', 'Disease', (133, 145))	('osteogenesis', 'Disease', 'MESH:D010013', (133, 145))	('osteoblastogenesis', 'Disease', (214, 232))	('miR-29', 'Gene', (25, 31))	('regulate', 'MPA', (56, 64))	('inhibition', 'Var', (151, 161))	('promote', 'PosReg', (189, 196))	('ECM synthesis', 'MPA', (197, 210))	('miR-29', 'Gene', (169, 175))	('osteoblastogenesis', 'Disease', 'None', (214, 232))
293582	27888003	They also systematically evaluated the roles of mmu-miR-31-5p-modified adipose tissue-originated stem cells (ASCs) both in vitro and in vivo, indicating that knockdown of miR-31-5p by lentivirus (antisense) in ASCs exhibited dramatically improved repair of CSDs by targeting Runx2 and SATB2.	('miR-31', 'Gene', (52, 58))	('miR-31', 'Gene', '100314232', (52, 58))	('31-5p', 'Chemical', '-', (175, 180))	('SATB2', 'Gene', '23314', (285, 290))	('Runx2', 'Gene', '860', (275, 280))	('Runx2', 'Gene', (275, 280))	('improved', 'PosReg', (238, 246))	('31-5p', 'Chemical', '-', (56, 61))	('CSDs', 'Disease', 'None', (257, 261))	('miR-31', 'Gene', '100314232', (171, 177))	('repair of', 'CPA', (247, 256))	('knockdown', 'Var', (158, 167))	('CS', 'Phenotype', 'HP:0006765', (257, 259))	('targeting', 'Reg', (265, 274))	('CSDs', 'Disease', (257, 261))	('miR-31', 'Gene', (171, 177))	('SATB2', 'Gene', (285, 290))
293591	27888003	The development of cancer can be attributed to the dysregulation of miRNA expression to a certain extent, making miRNA-targeted interventions a promising approach for the diagnosis, as well as the treatment, of different malignancies.	('malignancies', 'Disease', (221, 233))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))	('dysregulation', 'Var', (51, 64))	('miRNA expression', 'Protein', (68, 84))
293596	27888003	found that the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of OS cells were effectively prevented by overexpression of hsa-miR-204-5p directly targeting Sirtuin 1 (Sirt 1).	('OS', 'Phenotype', 'HP:0002669', (97, 99))	('prevented', 'NegReg', (123, 132))	('Sirtuin 1', 'Gene', (188, 197))	('rat', 'Species', '10116', (22, 25))	('Sirt 1', 'Gene', (199, 205))	('Sirt 1', 'Gene', '23411', (199, 205))	('overexpression', 'PosReg', (136, 150))	('invasion', 'CPA', (41, 49))	('rat', 'Species', '10116', (33, 36))	('Sirtuin 1', 'Gene', '23411', (188, 197))	('migration', 'CPA', (30, 39))	('hsa-miR-204-5p', 'Var', (154, 168))	('epithelial-mesenchymal transition', 'CPA', (54, 87))
293622	27888003	Aberrant activation of Ras and Wnt signallings were critical events during the development of PC bone metastasis.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('Ras', 'Pathway', (23, 26))	('PC', 'Phenotype', 'HP:0012125', (94, 96))	('Wnt', 'Gene', (31, 34))	('Wnt', 'Gene', '114487', (31, 34))
293623	27888003	hsa-miR-34a-5p was reported to restrain the bone metastasis of Ras-activated PC via the Wnt signalling pathway by targeting transcription factor 7 (TCF7).	('TCF7', 'Gene', (148, 152))	('restrain', 'NegReg', (31, 39))	('TCF7', 'Gene', '6932', (148, 152))	('bone metastasis', 'CPA', (44, 59))	('Ras-activated PC', 'Disease', (63, 79))	('Wnt', 'Gene', (88, 91))	('transcription factor 7', 'Gene', (124, 146))	('Wnt', 'Gene', '114487', (88, 91))	('targeting', 'Reg', (114, 123))	('transcription factor 7', 'Gene', '6932', (124, 146))	('miR-34a-5p', 'Chemical', '-', (4, 14))	('hsa-miR-34a-5p', 'Var', (0, 14))	('PC', 'Phenotype', 'HP:0012125', (77, 79))
293632	27888003	reported that hsa-miR-139-5p promoted the inhibition of chondrocyte proliferation and migration in human chondrocyte CHON-001 cells by suppressing insulin-like growth factor 1 receptor (IGF1R) and eukaryotic translation initiation factor 4 gamma 2 (EIF4G2), both of which play pivotal roles in facilitating the translation initiation and proliferation of cancer cells.	('IGF1R', 'Gene', (186, 191))	('CHON-001', 'CellLine', 'CVCL:C462', (117, 125))	('eukaryotic translation initiation factor 4 gamma 2', 'Gene', '1982', (197, 247))	('chondrocyte proliferation', 'CPA', (56, 81))	('EIF4G2', 'Gene', (249, 255))	('insulin-like growth factor 1 receptor', 'Gene', (147, 184))	('cancer', 'Disease', (355, 361))	('promoted', 'PosReg', (29, 37))	('rat', 'Species', '10116', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('eukaryotic translation initiation factor 4 gamma 2', 'Gene', (197, 247))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (147, 184))	('rat', 'Species', '10116', (345, 348))	('IGF1R', 'Gene', '3480', (186, 191))	('EIF4G2', 'Gene', '1982', (249, 255))	('rat', 'Species', '10116', (89, 92))	('hsa-miR-139-5p', 'Var', (14, 28))	('cancer', 'Disease', 'MESH:D009369', (355, 361))	('human', 'Species', '9606', (99, 104))	('suppressing', 'NegReg', (135, 146))
293634	27888003	In addition, Smad3 was also a target of hsa-miR-16-5p, which might contribute to the deterioration of OA.	('Smad3', 'Gene', '4088', (13, 18))	('rat', 'Species', '10116', (92, 95))	('Smad3', 'Gene', (13, 18))	('hsa-miR-16-5p', 'Var', (40, 53))	('OA', 'Phenotype', 'HP:0002758', (102, 104))	('contribute', 'Reg', (67, 77))
293639	27888003	Similarly, hsa-miR-142-3p and mmu-miR-210-5p could suppress inflammation and chondrocyte apoptosis in OA via the NF-kappaB pathway by targeting HMGB-1 and death receptor 6 (DR6), respectively.	('DR6', 'Gene', '27242', (173, 176))	('suppress', 'NegReg', (51, 59))	('NF-kappaB', 'Gene', '4790', (113, 122))	('targeting', 'Reg', (134, 143))	('mmu-miR-210-5p', 'Var', (30, 44))	('DR6', 'Gene', (173, 176))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('hsa-miR-142-3p', 'Var', (11, 25))	('death receptor 6', 'Gene', '27242', (155, 171))	('HMGB-1', 'Gene', '3146', (144, 150))	('NF-kappaB', 'Gene', (113, 122))	('inflammation', 'Disease', (60, 72))	('HMGB-1', 'Gene', (144, 150))	('OA', 'Phenotype', 'HP:0002758', (102, 104))	('death receptor 6', 'Gene', (155, 171))
293641	27888003	FGF2-induced ADAMTS expression inhibited the transcription of hsa-miR-105-5p by targeting Runx2, thus accelerating the progression of OA.	('rat', 'Species', '10116', (108, 111))	('FGF2', 'Gene', (0, 4))	('transcription', 'MPA', (45, 58))	('Runx2', 'Gene', (90, 95))	('ADAMTS', 'Gene', (13, 19))	('accelerating', 'PosReg', (102, 114))	('Runx2', 'Gene', '860', (90, 95))	('OA', 'Phenotype', 'HP:0002758', (134, 136))	('inhibited', 'NegReg', (31, 40))	('targeting', 'Var', (80, 89))	('FGF2', 'Gene', '2247', (0, 4))
293644	27888003	Thus, inhibition of hsa-miR-365a-3p might be an effective therapy for the prevention and treatment of traumatic OA.	('traumatic OA', 'Disease', (102, 114))	('miR-365', 'Chemical', '-', (24, 31))	('hsa-miR-365a-3p', 'Protein', (20, 35))	('OA', 'Phenotype', 'HP:0002758', (112, 114))	('inhibition', 'Var', (6, 16))	('traumatic OA', 'Disease', 'MESH:D010003', (102, 114))
293646	27888003	Silencing of gene expression in a sequence-specific manner at post-transcriptional levels can be achieved by small-interfering RNAs (siRNAs), which were initially proposed by Fire and colleagues in 1998 and were developed rapidly to treat musculoskeletal disorders over the last two decades.	('small-interfering', 'Var', (109, 126))	('musculoskeletal disorders', 'Disease', (239, 264))	('Silencing', 'NegReg', (0, 9))	('skeletal disorders', 'Phenotype', 'HP:0000924', (246, 264))	('musculoskeletal disorders', 'Disease', 'MESH:D009140', (239, 264))
293690	27888003	However, the effect of local inhibition of Noggin expression by targeting siRNA transfection in vivo was not as dramatic as expected from the in vitro findings, which may due to the inadequate dose of Noggin-targeted siRNA and/or insufficient efficacy of the delivery system for siRNA into cells.	('siRNA', 'Gene', (74, 79))	('Noggin', 'Gene', '9241', (201, 207))	('Noggin', 'Gene', '9241', (43, 49))	('Noggin', 'Gene', (201, 207))	('Noggin', 'Gene', (43, 49))	('transfection', 'Var', (80, 92))
293692	27888003	In addition to the investigations of the potent application of siRNAs to combat bone defects and resorption, siRNAs could be also efficient and anticipated tools to restrain tumour development and metastasis to the skeletal system.	('metastasis to the skeletal system', 'CPA', (197, 230))	('restrain', 'NegReg', (165, 173))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('bone defects', 'Disease', 'MESH:D001847', (80, 92))	('tumour', 'Disease', (174, 180))	('siRNAs', 'Var', (109, 115))	('bone defects', 'Disease', (80, 92))
293695	27888003	Silencing of VEGF via siRNAs was confirmed to suppress osteosarcoma angiogenesis and to promote tumour cell apoptosis via activation of phosphoinositide 3-kinase (PI3K) and the protein kinase B (AKT) signalling pathway in SaOS-2 cells.	('activation', 'PosReg', (122, 132))	('Silencing', 'Var', (0, 9))	('promote', 'PosReg', (88, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('AKT', 'Gene', (195, 198))	('siRNAs', 'Gene', (22, 28))	('phosphoinositide 3-kinase', 'Gene', '5293', (136, 161))	('suppress', 'NegReg', (46, 54))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('SaOS-2', 'CellLine', 'CVCL:0548', (222, 228))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('OS', 'Phenotype', 'HP:0002669', (224, 226))	('protein kinase B', 'Gene', '2185', (177, 193))	('tumour', 'Disease', (96, 102))	('phosphoinositide 3-kinase', 'Gene', (136, 161))	('osteosarcoma', 'Disease', (55, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('protein kinase B', 'Gene', (177, 193))	('AKT', 'Gene', '207', (195, 198))
293698	27888003	siRNA-mediated silencing of TCTP displayed obviously promoted apoptosis of the Saos-2 and U2OS cell lines, together with inhibited development of xenografts in nude mice.	('promoted', 'PosReg', (53, 61))	('nude mice', 'Species', '10090', (160, 169))	('OS', 'Phenotype', 'HP:0002669', (92, 94))	('silencing', 'Var', (15, 24))	('U2OS', 'CellLine', 'CVCL:0042', (90, 94))	('apoptosis', 'CPA', (62, 71))	('TCTP', 'Gene', (28, 32))	('inhibited', 'NegReg', (121, 130))	('development of xenografts in nude mice', 'CPA', (131, 169))	('TCTP', 'Gene', '7178', (28, 32))
293712	27888003	observed that CD147 expression affected the recurrence rate of GCTB after a clinicopathological analysis of 80 cases and CD147 knockdown by siRNA revealed dramatically inhibited proliferation, migration and invasion of GCTB cells in vitro.	('CD147', 'Gene', (121, 126))	('rat', 'Species', '10116', (55, 58))	('proliferation', 'CPA', (178, 191))	('affected', 'Reg', (31, 39))	('CD147', 'Gene', '682', (14, 19))	('migration', 'CPA', (193, 202))	('inhibited', 'NegReg', (168, 177))	('CD147', 'Gene', '682', (121, 126))	('CD147', 'Gene', (14, 19))	('rat', 'Species', '10116', (196, 199))	('knockdown', 'Var', (127, 136))	('rat', 'Species', '10116', (185, 188))	('invasion', 'CPA', (207, 215))
293713	27888003	Lau and colleagues found that p63 was an important factor facilitating GCT tumourigenesis via suppression of p53 by binding to the CDC2 and CDC25C p53-REs, and knockdown of p63 by siRNA manifested greatly decreased proliferation and promoted the apopotsis of GCT stromal cells.	('proliferation', 'CPA', (215, 228))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('binding', 'Interaction', (116, 123))	('suppression', 'NegReg', (94, 105))	('CDC2', 'Gene', (140, 144))	('CDC25C', 'Gene', (140, 146))	('CDC2', 'Gene', '983', (140, 144))	('tumour', 'Disease', (75, 81))	('rat', 'Species', '10116', (222, 225))	('CDC2', 'Gene', '983', (131, 135))	('p53', 'Gene', '7157', (109, 112))	('p63', 'Gene', (173, 176))	('CDC2', 'Gene', (131, 135))	('CDC25C', 'Gene', '995', (140, 146))	('p63', 'Gene', (30, 33))	('GCT', 'Disease', (71, 74))	('p63', 'Gene', '8626', (173, 176))	('apopotsis of GCT stromal cells', 'CPA', (246, 276))	('knockdown', 'Var', (160, 169))	('p63', 'Gene', '8626', (30, 33))	('p53', 'Gene', (109, 112))	('decreased', 'NegReg', (205, 214))	('p53', 'Gene', '7157', (147, 150))	('promoted', 'PosReg', (233, 241))	('p53', 'Gene', (147, 150))
293714	27888003	Bertrand and colleagues described that silencing of EWS/FLI-1 (one of the critical oncogenes in Ewing sarcoma) by siRNAs delivered by hydrogenated cationic nanodiamonds (ND-H) had enhanced the cytotoxic impact of vincristine on Ewing sarcoma (ES) cells.	('FLI-1', 'Gene', '2313', (56, 61))	('cytotoxic impact', 'CPA', (193, 209))	('EWS', 'Gene', (52, 55))	('vincristine', 'Chemical', 'MESH:D014750', (213, 224))	('hydrogen', 'Chemical', 'MESH:D006859', (134, 142))	('silencing', 'Var', (39, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('FLI-1', 'Gene', (56, 61))	('ND-H', 'Gene', (170, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (228, 241))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (228, 241))	('EWS', 'Gene', '2130', (52, 55))	('Ewing sarcoma', 'Disease', (96, 109))	('enhanced', 'PosReg', (180, 188))	('ND-H', 'Gene', '169792', (170, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('ES', 'Phenotype', 'HP:0012254', (243, 245))	('Ewing sarcoma', 'Disease', (228, 241))
293720	27888003	Huang and colleagues reported that silencing of phosphatidylinositol 3-kinase cb (PI3Kcb) alleviated BCP by increasing glial excitability.	('glial excitability', 'CPA', (119, 137))	('BCP', 'Chemical', '-', (101, 104))	('silencing', 'Var', (35, 44))	('alleviated', 'NegReg', (90, 100))	('BCP', 'Disease', (101, 104))	('PI3Kcb', 'Gene', (82, 88))	('increasing', 'PosReg', (108, 118))
293723	27888003	Based on this discovery, Xu and colleagues observed that siRNA-mediated PDGF knockdown effectively relieved BCP by blocking the AKT/ERK signalling pathway.	('ERK', 'Gene', '5594', (132, 135))	('BCP', 'Chemical', '-', (108, 111))	('ERK', 'Gene', (132, 135))	('blocking', 'NegReg', (115, 123))	('knockdown', 'Var', (77, 86))	('AKT', 'Gene', (128, 131))	('PDGF', 'Gene', (72, 76))	('AKT', 'Gene', '207', (128, 131))	('relieved', 'NegReg', (99, 107))	('BCP', 'Disease', (108, 111))
293734	27888003	Moreover, they determined that up-regulation of VEGF expression in chondrocytes derived from femoral head osteonecrosis in pigs was mediated partially by HIF-1alpha, and silencing of HIF-1alpha by siRNA transfection led to obviously decreased VEGF expression.	('up-regulation', 'PosReg', (31, 44))	('VEGF', 'Gene', (48, 52))	('femoral head osteonecrosis', 'Disease', 'MESH:D000070603', (93, 119))	('silencing', 'Var', (170, 179))	('femoral head osteonecrosis', 'Disease', (93, 119))	('decreased', 'NegReg', (233, 242))	('pigs', 'Species', '9823', (123, 127))	('osteonecrosis', 'Phenotype', 'HP:0010885', (106, 119))	('VEGF expression', 'MPA', (243, 258))
293736	27888003	Li and colleagues further reported that blockage of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) by siRNA inhibited adipogenesis and enhanced osteogenesis in BMSCs, thus providing a novel avenue for impeding the development of SAON.	('impeding', 'NegReg', (216, 224))	('PPAR-gamma', 'Gene', '5468', (102, 112))	('enhanced', 'PosReg', (150, 158))	('blockage', 'Var', (40, 48))	('siRNA', 'Gene', (117, 122))	('peroxisome proliferator-activated receptor-gamma', 'Gene', (52, 100))	('inhibited', 'NegReg', (123, 132))	('SAON', 'Chemical', '-', (244, 248))	('adipogenesis', 'MPA', (133, 145))	('peroxisome proliferator-activated receptor-gamma', 'Gene', '5468', (52, 100))	('osteogenesis', 'Disease', (159, 171))	('osteogenesis', 'Disease', 'MESH:D010013', (159, 171))	('PPAR-gamma', 'Gene', (102, 112))
293737	27888003	PPAR-gamma is a specific transcriptional factor correlated with adipogenesis, and knockout of PPAR-gamma in BMSCs led to increased osteoblastogenesis.	('osteoblastogenesis', 'Disease', 'None', (131, 149))	('PPAR-gamma', 'Gene', (0, 10))	('increased', 'PosReg', (121, 130))	('osteoblastogenesis', 'Disease', (131, 149))	('PPAR-gamma', 'Gene', (94, 104))	('knockout', 'Var', (82, 90))	('PPAR-gamma', 'Gene', '5468', (0, 10))	('PPAR-gamma', 'Gene', '5468', (94, 104))
293740	27888003	Akagi and colleagues demonstrated that intra-articular injection of MMP-13 siRNA in the early stage of a surgically-induced murine OA model showed delayed cartilage degradation.	('MMP-13', 'Var', (68, 74))	('siRNA', 'Gene', (75, 80))	('cartilage degradation', 'CPA', (155, 176))	('OA', 'Phenotype', 'HP:0002758', (131, 133))	('murine', 'Species', '10090', (124, 130))	('rat', 'Species', '10116', (28, 31))
293745	27888003	observed that the gene blockage of collagen type I alpha 1 (COL1A1) and high temperature requirement factor A1 (HtrA1) via siRNA induced an distinctly enhanced differentiation index of chondrocytes cultured with BMP-2 under hypoxic conditions, thus offering the potential opportunity to explore novel ACI-based treatment in the future.	('HtrA1', 'Gene', (112, 117))	('enhanced', 'PosReg', (151, 159))	('high temperature requirement factor A1', 'Gene', (72, 110))	('differentiation index', 'CPA', (160, 181))	('BMP-2', 'Gene', '650', (212, 217))	('collagen type I alpha 1', 'Gene', '1277', (35, 58))	('gene blockage', 'Var', (18, 31))	('COL1A1', 'Gene', '1277', (60, 66))	('COL1A1', 'Gene', (60, 66))	('collagen type I alpha 1', 'Gene', (35, 58))	('BMP-2', 'Gene', (212, 217))	('high temperature requirement factor A1', 'Gene', '5654', (72, 110))	('ACI', 'Chemical', '-', (301, 304))	('HtrA1', 'Gene', '5654', (112, 117))
293747	27888003	siRNA-mediated blockage of ADAMTS-5 demonstrated protective effects on cartilage degradation.	('blockage', 'Var', (15, 23))	('ADAMTS-5', 'Gene', '11096', (27, 35))	('rat', 'Species', '10116', (43, 46))	('cartilage degradation', 'CPA', (71, 92))	('ADAMTS-5', 'Gene', (27, 35))
293784	27888003	Incorporation of miRNA-or siRNA-loaded particles inside injectable biodegradable matrices might be highly favorable in localizing the delivery of miRNAs or siRNAs to the sites of bone defects, osteoporosis or tumour, thus, maximizing the therapeutic effect.	('osteoporosis', 'Phenotype', 'HP:0000939', (193, 205))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('bone defects', 'Disease', (179, 191))	('maximizing', 'PosReg', (223, 233))	('miRNAs', 'Var', (146, 152))	('osteoporosis or tumour', 'Disease', 'MESH:D010024', (193, 215))	('osteoporosis or tumour', 'Disease', (193, 215))	('therapeutic effect', 'CPA', (238, 256))	('rat', 'Species', '10116', (7, 10))	('bone defects', 'Disease', 'MESH:D001847', (179, 191))	('localizing', 'MPA', (119, 129))
293805	32158531	Interestingly, the PNPLA2 gene is deleted in 45% of DDLPS samples analyzed under TCGA project, and the deletion is associated with significantly lower PNPLA2 expression level.	('PNPLA2 gene', 'Gene', (19, 30))	('DD', 'Chemical', 'MESH:C007792', (52, 54))	('lower', 'NegReg', (145, 150))	('PNPLA2 expression level', 'MPA', (151, 174))	('deletion', 'Var', (103, 111))
293808	32158531	In respect to the pathogenesis of the disease, our results give a new insight into possible molecular mechanisms involved and support the recent observation that deletion of PNPLA2 is a novel factor in liposarcoma progression.	('deletion', 'Var', (162, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('factor', 'Reg', (192, 198))	('PNPLA2', 'Gene', (174, 180))	('liposarcoma', 'Disease', (202, 213))	('liposarcoma', 'Disease', 'MESH:D008080', (202, 213))	('liposarcoma', 'Phenotype', 'HP:0012034', (202, 213))
293816	32158531	DDLPS is reported to metastasize at a rate between 13 and 47%, and metastases are fatal, therefore DDLPS gives a sixfold higher risk of death compared to WDLPS.	('DDLPS', 'Var', (99, 104))	('death', 'Disease', 'MESH:D003643', (136, 141))	('DD', 'Chemical', 'MESH:C007792', (99, 101))	('death', 'Disease', (136, 141))	('metastases', 'Disease', (67, 77))	('WD', 'Disease', 'MESH:D006527', (154, 156))	('DD', 'Chemical', 'MESH:C007792', (0, 2))	('metastases', 'Disease', 'MESH:D009362', (67, 77))
293909	32158531	Strikingly, the deletion of the 11p15.5 region was detected only in DDLPS specimens, but not in the WDLPS specimens.	('DD', 'Chemical', 'MESH:C007792', (68, 70))	('deletion', 'Var', (16, 24))	('11p15.5', 'Gene', (32, 39))	('WD', 'Disease', 'MESH:D006527', (100, 102))	('DDLPS', 'Disease', (68, 73))
293911	32158531	It seems likely that PNPLA2 loss precedes the loss of the WD phenotype, and that the deletion of PNPLA2 may be an important event in the transition of WDLPS towards DDLPS.	('PNPLA2', 'Gene', (97, 103))	('DD', 'Chemical', 'MESH:C007792', (165, 167))	('WD', 'Disease', 'MESH:D006527', (58, 60))	('WD', 'Disease', 'MESH:D006527', (151, 153))	('PNPLA2', 'Gene', (21, 27))	('deletion', 'Var', (85, 93))	('loss', 'NegReg', (28, 32))
293913	32158531	In another study by Lyu et al., knock-out of PLIN1 in mice caused down-regulation of adipogenic pathways despite the near normal level of PPARgamma.	('down-regulation', 'NegReg', (66, 81))	('knock-out', 'Var', (32, 41))	('mice', 'Species', '10090', (54, 58))	('adipogenic pathways', 'Pathway', (85, 104))	('PLIN1', 'Gene', (45, 50))
294010	28403214	Eleven patients (73%) had a predominance of CTCs with CD45-/ (CK/beta-cat)-/VIM+ phenotype 17 cells/ml (patient specimen range per mL: 29-31,418 cells; mean: 5,739 cells; median: 1,576 cells) as shown in Fig 3A.	('beta-cat', 'Gene', '1499', (65, 73))	('patient', 'Species', '9606', (7, 14))	('CD45-/', 'Var', (54, 60))	('beta-cat', 'Gene', (65, 73))	('patient', 'Species', '9606', (104, 111))	('patients', 'Species', '9606', (7, 15))
294012	28403214	A large number of cells exhibiting alternative phenotypes CD45-/(CK/beta-catenin)+/VIM- and CD45-/(CK/beta-catenin)+/VIM+ were seen in the other 4 patients; the patient with embryonal cell sarcoma (ES) had the highest levels of those cell sub-populations.	('ES', 'Chemical', '-', (198, 200))	('beta-catenin', 'Gene', '1499', (102, 114))	('CD45-/', 'Var', (92, 98))	('patient', 'Species', '9606', (147, 154))	('patient', 'Species', '9606', (161, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('patients', 'Species', '9606', (147, 155))	('embryonal cell sarcoma', 'Disease', (174, 196))	('embryonal cell sarcoma', 'Disease', 'MESH:D012509', (174, 196))	('beta-catenin', 'Gene', (68, 80))	('beta-catenin', 'Gene', (102, 114))	('beta-catenin', 'Gene', '1499', (68, 80))
294014	28403214	Interestingly, cells with phenotypes CD45-/(CK/ beta-cat)-/VIM+ and CD45-/(CK/beta-cat)+/VIM+ exhibit very distinct morphologies, as can be seen in the representative micrographs from a patient with soft tissue neoplasm (STN) and a patient with ES, respectively (Fig 3C).	('beta-cat', 'Gene', '1499', (48, 56))	('soft tissue neoplasm', 'Disease', 'MESH:D012983', (199, 219))	('beta-cat', 'Gene', (78, 86))	('soft tissue neoplasm', 'Disease', (199, 219))	('CD45-/', 'Var', (37, 43))	('ES', 'Chemical', '-', (245, 247))	('soft tissue neoplasm', 'Phenotype', 'HP:0031459', (199, 219))	('beta-cat', 'Gene', (48, 56))	('beta-cat', 'Gene', '1499', (78, 86))	('neoplasm', 'Phenotype', 'HP:0002664', (211, 219))	('patient', 'Species', '9606', (232, 239))	('patient', 'Species', '9606', (186, 193))	('STN', 'Phenotype', 'HP:0031459', (221, 224))
294028	28403214	ASPS was selected for validation studies because its characteristic hallmark TFE3 genetic rearrangement allows for unambiguous identification of tumor cells enriched from blood samples with the ApoStream  device.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TFE3', 'Gene', (77, 81))	('genetic rearrangement', 'Var', (82, 103))	('tumor', 'Disease', (145, 150))	('ASPS', 'Phenotype', 'HP:0012218', (0, 4))	('TFE3', 'Gene', '7030', (77, 81))
294037	28403214	Surprisingly, in the sarcoma patient population tested at baseline, we found evidence of a co-occurring epithelial phenotype in 4 of 15 patients, as evidenced by the presence of a CD45-/(CK/beta-cat)+/VIM- population.	('patient', 'Species', '9606', (29, 36))	('patient', 'Species', '9606', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('beta-cat', 'Gene', '1499', (190, 198))	('patients', 'Species', '9606', (136, 144))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('sarcoma', 'Disease', (21, 28))	('CD45-/', 'Var', (180, 186))	('beta-cat', 'Gene', (190, 198))
294207	33670681	The inflammation markers of the blood improved a few days after the surgery (Figure 3); the patient's postoperative CRP level, white blood cell count, and neutrophil count were 0.305 mg/dL, 2.83 x 103/microL, and 57.9%, respectively.	('patient', 'Species', '9606', (92, 99))	('0.305 mg/dL', 'Var', (177, 188))	('CRP', 'Gene', (116, 119))	('inflammation', 'Disease', 'MESH:D007249', (4, 16))	('CRP', 'Gene', '1401', (116, 119))	('inflammation', 'Disease', (4, 16))
294268	29977133	posit that "many clinicians do not initiate chemotherapy with ifosfamide monotherapy" at least in part because ifosfamide is associated with increased risks of toxicities at high doses (with high doses recommended after failure of first-line chemotherapy).	('toxicities', 'Disease', 'MESH:D064420', (160, 170))	('toxicities', 'Disease', (160, 170))	('ifosfamide', 'Var', (111, 121))
294297	28541635	The following inclusion criteria were applied: 1) patient age <=50 years; 2) diagnosis of a primary tumor with malignant behavior located at the uterus (International Classification of Diseases for Oncology, 3rd Edition [ICD-O-3]/World Health Organization [WHO] 2008 site-specific codes C540-549, 559); 3) active follow-up (diagnosis not obtained from autopsy or death certificate); and 4) histologically confirmed sarcoma limited to the uterus (FIGO stage I disease).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('death', 'Disease', 'MESH:D003643', (363, 368))	('sarcoma', 'Disease', (415, 422))	('death', 'Disease', (363, 368))	('C540-549', 'Var', (287, 295))	('Oncology', 'Phenotype', 'HP:0002664', (198, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (415, 422))	('primary tumor', 'Disease', (92, 105))	('sarcoma', 'Disease', 'MESH:D012509', (415, 422))	('C540-549', 'CellLine', 'CVCL:0023', (287, 295))	('primary tumor', 'Disease', 'MESH:D009369', (92, 105))	('patient', 'Species', '9606', (50, 57))	('sarcoma limited to the uterus', 'Phenotype', 'HP:0010784', (415, 444))
294322	28541635	According to the histopathology report, LND was performed in 29.4% of the patients; higher rates of LND were noted for women with AS (50.6%) and LG-ESS (29.0%) compared to LMS (25.3%) (p<0.001).	('patients', 'Species', '9606', (74, 82))	('women', 'Species', '9606', (119, 124))	('LG-ESS', 'Var', (145, 151))	('higher', 'PosReg', (84, 90))
294441	28220751	Most likely, false-negative margins or inadvertent tumor contamination of the wound during resection were the underlying causes leading to the consequences and the outcome observed in this case, which is depicted in Figure 4.	('false-negative', 'Var', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('inadvertent tumor', 'Disease', (39, 56))	('inadvertent tumor', 'Disease', 'MESH:D009369', (39, 56))
294609	23678263	The direct involvement of valves or significant obstruction of cardiac chambers, which interrupts blood flow, often causes congestive heart failure or arrhythmias.	('causes', 'Reg', (116, 122))	('heart failure', 'Phenotype', 'HP:0001635', (134, 147))	('congestive heart failure', 'Phenotype', 'HP:0001635', (123, 147))	('congestive heart failure', 'Disease', 'MESH:D006333', (123, 147))	('obstruction', 'Var', (48, 59))	('arrhythmias', 'Phenotype', 'HP:0011675', (151, 162))	('congestive heart failure', 'Disease', (123, 147))	('arrhythmia', 'Phenotype', 'HP:0011675', (151, 161))	('arrhythmias', 'Disease', 'MESH:D001145', (151, 162))	('interrupts', 'NegReg', (87, 97))	('blood flow', 'MPA', (98, 108))	('arrhythmias', 'Disease', (151, 162))	('involvement', 'Reg', (11, 22))
294717	29491688	SYT (GenBank accession number NC_000018) is normally expressed in human tissues, whereas SSX expression is limited to normal testis and thyroid, and some variants are found in human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (182, 194))	('variants', 'Var', (154, 162))	('SS', 'Phenotype', 'HP:0012570', (89, 91))	('SSX', 'Gene', '6757', (89, 92))	('human', 'Species', '9606', (66, 71))	('SSX', 'Gene', (89, 92))	('malignancies', 'Disease', (182, 194))	('human', 'Species', '9606', (176, 181))	('SYT', 'Gene', '6857', (0, 3))	('SYT', 'Gene', (0, 3))
294718	29491688	The SSX family reportedly comprises nine highly homologous synovial sarcoma X genes (SSX1-9); however, SSX1 or SSX2 (GenBank accession number (SSX1) or NC_000023) account for > 90% of t (X;18) translocations and SSX4 is involved in few cases.	('SSX', 'Gene', (111, 114))	('SSX2', 'Gene', (111, 115))	('SSX', 'Gene', (85, 88))	('SSX4', 'Gene', (212, 216))	('SSX', 'Gene', '6757', (4, 7))	('SS', 'Phenotype', 'HP:0012570', (103, 105))	('SSX', 'Gene', (212, 215))	('SSX2', 'Gene', '6757', (111, 115))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (59, 75))	('SSX1', 'Gene', '6756', (85, 89))	('SSX4', 'Gene', '6759', (212, 216))	('SS', 'Phenotype', 'HP:0012570', (143, 145))	('SSX1', 'Gene', (85, 89))	('SSX', 'Gene', (4, 7))	('SS', 'Phenotype', 'HP:0012570', (111, 113))	('SS', 'Phenotype', 'HP:0012570', (85, 87))	('SSX', 'Gene', '6757', (143, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('SSX', 'Gene', '6757', (103, 106))	('SSX1-9', 'Gene', '6756;6757;10214;6759;6758;280657;280658;280659;280660', (85, 91))	('SSX1', 'Gene', '6756', (143, 147))	('SSX', 'Gene', '6757', (111, 114))	('t (X', 'Var', (184, 188))	('SSX1', 'Gene', '6756', (103, 107))	('SSX', 'Gene', '6757', (85, 88))	('SSX1', 'Gene', (143, 147))	('SSX', 'Gene', (143, 146))	('SSX', 'Gene', '6757', (212, 215))	('synovial sarcoma', 'Disease', (59, 75))	('SS', 'Phenotype', 'HP:0012570', (4, 6))	('SSX1', 'Gene', (103, 107))	('SSX', 'Gene', (103, 106))	('SSX1-9', 'Gene', (85, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (59, 75))
294737	29491688	A PCR product of > 100 base pairs was obtained in tumor tissues only (Figure 1B), and direct sequencing of this PCR product confirmed the fusion between exon 10 of the SYT gene and exon 6 of the SSX2 gene (Figure 1A and C).	('SS', 'Phenotype', 'HP:0012570', (195, 197))	('SSX2', 'Gene', '6757', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('SYT', 'Gene', '6857', (168, 171))	('fusion', 'Var', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SSX2', 'Gene', (195, 199))	('SYT', 'Gene', (168, 171))	('tumor', 'Disease', (50, 55))
294751	29491688	Many alterations, such as microsatellite alteration, DNA methylation, and some mutations, in cancer cells have been recently detected in circulating cfDNA.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('DNA', 'MPA', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('microsatellite alteration', 'Var', (26, 51))	('mutations', 'Var', (79, 88))
294758	29491688	Numerous gene alterations have been recently identified using advanced technologies such as next-generation sequencing, and fusion genes have been reported to contribute to tumorgenesis .	('alterations', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('contribute', 'Reg', (159, 169))
294759	29491688	For example, recurrent fusions of R-spondin family members RSPO2 and RSPO3, which occur in 10% of colon tumors, have been reported to be involved in the activation of Wnt signaling pathway.	('involved', 'Reg', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Wnt signaling pathway', 'Pathway', (167, 188))	('activation', 'PosReg', (153, 163))	('RSPO3', 'Gene', (69, 74))	('RSPO3', 'Gene', '84870', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('fusions', 'Var', (23, 30))	('RSPO2', 'Gene', '340419', (59, 64))	('colon tumors', 'Phenotype', 'HP:0100273', (98, 110))	('colon tumors', 'Disease', 'MESH:D015179', (98, 110))	('colon tumors', 'Disease', (98, 110))	('RSPO2', 'Gene', (59, 64))
294760	29491688	NCOA2, a negative growth regulator repressing Wnt signaling pathway, was reported to be disrupted by recurrent fusion with LACTB2 in colorectal cancer.	('LACTB2', 'Gene', '51110', (123, 129))	('colorectal cancer', 'Disease', (133, 150))	('NCOA2', 'Gene', '10499', (0, 5))	('disrupted', 'NegReg', (88, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('NCOA2', 'Gene', (0, 5))	('fusion', 'Var', (111, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('LACTB2', 'Gene', (123, 129))
294767	29491688	In the future, this method may be useful for translocation-derived diseases such as SS or for other cancers which contain translocations.	('SS', 'Phenotype', 'HP:0012570', (84, 86))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('translocations', 'Var', (122, 136))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
294810	25821397	When comparing the univariate results (Table 2), Hispanic ethnicity was a significant factor only during the 1997-2003 time period, during which time Hispanic patients had improved overall survival over non-Hispanic patients (P = 0.0004).	('improved', 'PosReg', (172, 180))	('patients', 'Species', '9606', (216, 224))	('Hispanic', 'Var', (150, 158))	('patients', 'Species', '9606', (159, 167))	('overall survival', 'MPA', (181, 197))
294842	23614996	Infection with KSHV has been shown to lead to the development of Kaposi sarcoma (KS) as well as multicentric Castleman's disease and primary effusion lymphomas.	('lymphomas', 'Phenotype', 'HP:0002665', (150, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (65, 79))	("Castleman's disease", 'Disease', 'MESH:C536362', (109, 128))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (65, 79))	('KSHV', 'Species', '37296', (15, 19))	('Kaposi sarcoma', 'Disease', (65, 79))	('lead to', 'Reg', (38, 45))	('men', 'Species', '9606', (57, 60))	('Infection', 'Var', (0, 9))	('primary effusion lymphomas', 'Disease', (133, 159))	('primary effusion lymphomas', 'Disease', 'MESH:D054685', (133, 159))	("Castleman's disease", 'Disease', (109, 128))	('KSHV', 'Gene', (15, 19))
294879	23614996	Log-binomial regression was used to estimate the relative risk of KSHV on VL suppression (<400 vs. >=400) by 6- and 12-months on treatment respectively.	('<400', 'Var', (90, 94))	('KSHV', 'Species', '37296', (66, 70))	('VL suppression', 'MPA', (74, 88))	('men', 'Species', '9606', (134, 137))
294897	23614996	The KSHV+ group presented with a somewhat higher median CD4 cell count (90 vs.78 cells/mm3) than their KSHV-counterparts.	('KSHV', 'Species', '37296', (4, 8))	('KSHV', 'Species', '37296', (103, 107))	('CD4', 'Gene', (56, 59))	('higher', 'PosReg', (42, 48))	('CD4', 'Gene', '920', (56, 59))	('KSHV+', 'Var', (4, 9))
294900	23614996	Those reactive to both K8.1 and Orf73 were more likely to have a detectable KSHV viral load (n=15, 20%) when compared to those reactive to lytic K8.1 (n=2, 3%) or latent Orf73 (n=2, 8%) alone.	('Orf73', 'Gene', (32, 37))	('KSHV', 'Species', '37296', (76, 80))	('Orf73', 'Gene', '4961527', (170, 175))	('Orf73', 'Gene', '4961527', (32, 37))	('K8.1', 'Var', (23, 27))	('KSHV', 'Gene', (76, 80))	('Orf73', 'Gene', (170, 175))
294914	23614996	When we restricted the analysis to the KSHV positive group, those with antibodies to Orf73 only demonstrated the best virologic response of all the groups - 100% (25/25) of this group achieved suppression of HIV viral load to <400 copies/mL by 6- and 12-months on treatment.	('antibodies', 'Var', (71, 81))	('men', 'Species', '9606', (269, 272))	('HIV viral load', 'MPA', (208, 222))	('suppression', 'NegReg', (193, 204))	('Orf73', 'Gene', (85, 90))	('KSHV', 'Species', '37296', (39, 43))	('Orf73', 'Gene', '4961527', (85, 90))
294933	23614996	Other in vitro work also suggested that KSHV increased HIV-1 replication in acutely infected cells but also induced reactivation of HIV-1 replication in chronically infected cells.	('replication', 'MPA', (61, 72))	('HIV-1', 'Species', '11676', (55, 60))	('increased', 'PosReg', (45, 54))	('HIV-1', 'Gene', (55, 60))	('HIV-1', 'Species', '11676', (132, 137))	('KSHV', 'Species', '37296', (40, 44))	('reactivation', 'MPA', (116, 128))	('replication', 'MPA', (138, 149))	('KSHV', 'Var', (40, 44))
295054	23346404	On the other hand, the addition of ZVAD-FMK inhibited the expressed capase-3 to almost the same level as in the case of the control.	('capase-3', 'Enzyme', (68, 76))	('inhibited', 'NegReg', (44, 53))	('ZVAD-FMK', 'Var', (35, 43))	('ZVAD-FMK', 'Chemical', 'MESH:C096713', (35, 43))
295060	23346404	The fluorescence intensity of the cells treated with ESA-FITC increased significantly, as compared to the control cells (treated with PBS only).	('increased', 'PosReg', (62, 71))	('fluorescence intensity', 'MPA', (4, 26))	('PBS', 'Chemical', '-', (134, 137))	('ESA-FITC', 'Var', (53, 61))	('ESA-FITC', 'Chemical', '-', (53, 61))
295079	23346404	Furthermore, the fluorescence intensity of the cells treated with EPV containing FITC was found to be almost equal to the fluorescence intensity of the cells that were treated with EV containing FITC.	('FITC', 'Var', (81, 85))	('fluorescence intensity', 'MPA', (17, 39))	('FITC', 'Chemical', 'MESH:D016650', (195, 199))	('FITC', 'Chemical', 'MESH:D016650', (81, 85))
295080	23346404	Therefore, PEGylation did not hinder the binding of ESA to the sugar chains on the surface of the cells.	('sugar', 'Chemical', 'MESH:D000073893', (63, 68))	('ESA', 'Chemical', '-', (52, 55))	('binding', 'Interaction', (41, 48))	('PEG', 'Chemical', '-', (11, 14))	('PEGylation', 'Var', (11, 21))
295131	22550426	Using RT-PCR to detect specific tumor-associated fusion transcripts, otherwise occult tumor cells are found in blood or bone marrow in 20-30% of Ewing sarcoma patients, and their presence is associated with inferior outcomes.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (145, 158))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (145, 158))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('fusion transcripts', 'Var', (49, 67))	('Ewing sarcoma', 'Disease', (145, 158))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('patients', 'Species', '9606', (159, 167))
295145	22550426	Tumors not containing FLI1 translocations usually have other partners for EWS, including ERG, ETV1, E1AF, and FEV.	('ERG', 'Gene', (89, 92))	('E1AF', 'Gene', '2118', (100, 104))	('translocations', 'Var', (27, 41))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('EWS', 'Gene', '2130', (74, 77))	('EWS', 'Gene', (74, 77))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ETV1', 'Gene', (94, 98))	('ERG', 'Gene', '2078', (89, 92))	('FLI1', 'Gene', (22, 26))	('FEV', 'Disease', (110, 113))	('FLI1', 'Gene', '2313', (22, 26))	('ETV1', 'Gene', '2115', (94, 98))	('E1AF', 'Gene', (100, 104))
295165	22550426	Variations on this enrichment approach have been described previously and can increase the confidence at which low numbers of tumor cells can be identified.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Variations', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
295175	22550426	In fact, in this study high CD56 expression in CD99+/CD90+ cells was determined to be an independent prognostic marker with an 11-fold risk of relapse.	('CD56', 'Gene', '4684', (28, 32))	('CD99', 'Gene', (47, 51))	('high', 'Var', (23, 27))	('CD56', 'Gene', (28, 32))	('CD90', 'Gene', '7070', (53, 57))	('CD99', 'Gene', '4267', (47, 51))	('CD90', 'Gene', (53, 57))
295178	22550426	Another potential method to assess MRD is the use of a FISH break-apart probe to identify translocations involving the EWS gene.	('EWS', 'Gene', (119, 122))	('EWS', 'Gene', '2130', (119, 122))	('translocations', 'Var', (90, 104))
295189	22550426	In those patients, the percentage of cells reported with possible EWSR1 rearrangement ranged from 0.2% to 7% (median 2.5%) of 200-500 tested mononuclear cells.	('patients', 'Species', '9606', (9, 17))	('EWSR1', 'Gene', (66, 71))	('to 7', 'Species', '1214577', (103, 107))	('rearrangement', 'Var', (72, 85))	('EWSR1', 'Gene', '2130', (66, 71))
295191	22550426	The reason for this false negative remains unclear, as FISH readily showed the characteristic EWSR1 break apart in the primary bone tumor, as well in a subsequent bone marrow sample done after induction chemotherapy, in which a low level of residual tumor cells was identified despite conventional morphology showing bone marrow remission.	('break', 'Var', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('EWSR1', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('break apart', 'Phenotype', 'HP:0001061', (100, 111))	('bone tumor', 'Disease', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('bone tumor', 'Phenotype', 'HP:0010622', (127, 137))	('tumor', 'Disease', (132, 137))	('EWSR1', 'Gene', '2130', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('bone tumor', 'Disease', 'MESH:D001859', (127, 137))	('tumor', 'Disease', (250, 255))
295207	22550426	For FISH, changes in the EWS gene during decondensation of DNA can cause an occasional cell to appear as if there may be a true rearrangement, as discussed earlier and noted in Figure 2.	('cause', 'Reg', (67, 72))	('changes', 'Var', (10, 17))	('EWS', 'Gene', '2130', (25, 28))	('EWS', 'Gene', (25, 28))
295219	22550426	ES appears particularly well suited for MRD detection due to tumor-specific translocations that facilitate RT-PCR and FISH detection as well as expression of tumor-specific cell surface proteins like CD99 that facilitate detection by flow cytometry.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('tumor', 'Disease', (158, 163))	('facilitate', 'PosReg', (96, 106))	('translocations', 'Var', (76, 90))	('RT-PCR', 'Disease', (107, 113))	('CD99', 'Gene', '4267', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CD99', 'Gene', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (61, 66))
295222	31665941	The landscape of tyrosine kinase inhibitors in sarcomas: looking beyond pazopanib Introduction: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the dysregulation of fundamental cellular processes including proliferation, migration, and apoptosis.	('sarcomas', 'Disease', (47, 55))	('migration', 'CPA', (330, 339))	('implicated', 'Reg', (211, 221))	('aberrations', 'Var', (171, 182))	('pazopanib', 'Chemical', 'MESH:C516667', (72, 81))	('oncogenesis', 'Disease', (233, 244))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('proliferation', 'CPA', (315, 328))	('apoptosis', 'CPA', (345, 354))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
295231	31665941	GIST is the most common subtype of STS and is characterized (in 85-90% of patients) by activating mutations in the receptor tyrosine kinases (RTKs) KIT and platelet-derived growth factor receptor (PDGFR).	('KIT', 'Gene', '3815', (148, 151))	('platelet-derived growth factor receptor', 'Gene', (156, 195))	('KIT', 'Gene', (148, 151))	('patients', 'Species', '9606', (74, 82))	('PDGFR', 'Gene', (197, 202))	('PDGFR', 'Gene', '5159', (197, 202))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('mutations', 'Var', (98, 107))	('activating', 'PosReg', (87, 97))	('RTKs', 'Gene', (142, 146))	('platelet-derived growth factor receptor', 'Gene', '5159', (156, 195))	('STS', 'Phenotype', 'HP:0030448', (35, 38))
295233	31665941	For instance, ripretinib, a switch control type II inhibitor of KIT, and avapritinib, a potent type I KIT/PDGFRalpha inhibitor, are both currently undergoing phase III trials in the third/fourth line-setting and may further improve the outcomes of patients with advanced GIST (NCT03353753, NCT03465722).	('NCT03465722', 'Var', (290, 301))	('NCT03353753', 'Var', (277, 288))	('PDGFRalpha', 'Gene', (106, 116))	('KIT', 'Gene', '3815', (64, 67))	('KIT', 'Gene', '3815', (102, 105))	('GIST', 'Phenotype', 'HP:0100723', (271, 275))	('improve', 'PosReg', (224, 231))	('ripretinib', 'Chemical', '-', (14, 24))	('KIT', 'Gene', (64, 67))	('KIT', 'Gene', (102, 105))	('patients', 'Species', '9606', (248, 256))	('avapritinib', 'Chemical', '-', (73, 84))	('PDGFRalpha', 'Gene', '5156', (106, 116))
295237	31665941	The approval of pazopanib in STS was based on data from the double-blind, placebo-controlled, randomized, PALETTE phase III trial (NCT00753688) that found a significant improvement in progression-free survival (PFS) in patients with non-adipocytic STS treated with pazopanib compared to placebo alone, after the failure of first- or further-line chemotherapy.	('improvement', 'PosReg', (169, 180))	('STS', 'Phenotype', 'HP:0030448', (29, 32))	('progression-free', 'MPA', (184, 200))	('pazopanib', 'Chemical', 'MESH:C516667', (265, 274))	('patients', 'Species', '9606', (219, 227))	('pazopanib', 'Var', (265, 274))	('pazopanib', 'Chemical', 'MESH:C516667', (16, 25))	('STS', 'Phenotype', 'HP:0030448', (248, 251))
295250	31665941	Furthermore, treatment of xenograft models with these TKIs commonly led to a decrease in tumor perfusion, extravasation, vascular permeability, and/or formation of metastases, thereby highlighting their antimetastatic properties.	('TKIs', 'Var', (54, 58))	('extravasation', 'MPA', (106, 119))	('metastases', 'Disease', 'MESH:D009362', (164, 174))	('decrease', 'NegReg', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('metastases', 'Disease', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('vascular permeability', 'MPA', (121, 142))
295259	31665941	This inhibitor has been shown to inhibit cell proliferation and growth in in vitro and in vivo preclinical models harboring fusion NTRK oncogenes with concurrent blockade of AKT, signal transducer and activator of transcription 3 (STAT3), and/or extracellular signal-regulated kinases (ERK) downstream signaling pathways.	('ERK', 'Gene', '5594', (286, 289))	('NTRK', 'Gene', (131, 135))	('ERK', 'Gene', (286, 289))	('STAT3', 'Gene', '6774', (231, 236))	('extracellular signal-regulated kinases', 'Gene', '5594', (246, 284))	('inhibit', 'NegReg', (33, 40))	('cell proliferation', 'CPA', (41, 59))	('STAT3', 'Gene', (231, 236))	('blockade', 'NegReg', (162, 170))	('AKT', 'Gene', '207', (174, 177))	('fusion', 'Var', (124, 130))	('signal transducer and activator of transcription 3', 'Gene', '6774', (179, 229))	('growth', 'CPA', (64, 70))	('AKT', 'Gene', (174, 177))	('extracellular signal-regulated kinases', 'Gene', (246, 284))
295271	31665941	Imatinib has also shown antitumor effect in preclinical models of DFSP and giant-cell fibroblastoma, which are rare, recurrent, and infiltrative tumors of the dermis classically characterized by a COL1A1/PDGFB translocation.	('tumor', 'Disease', (28, 33))	('DFSP', 'Disease', (66, 70))	('COL1A1', 'Gene', '1277', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('PDGFB', 'Gene', '5155', (204, 209))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('COL1A1', 'Gene', (197, 203))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('giant-cell fibroblastoma', 'Disease', 'MESH:D018223', (75, 99))	('PDGFB', 'Gene', (204, 209))	('translocation', 'Var', (210, 223))	('tumors of the dermis', 'Phenotype', 'HP:0008069', (145, 165))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('DFSP', 'Disease', 'MESH:D018223', (66, 70))	('giant-cell fibroblastoma', 'Disease', (75, 99))
295280	31665941	DTs are a rare and locally invasive soft tissue tumor characterized by catenin beta-1 (CTNNB1) or adenomatous polyposis coli (APC) mutations.	('mutations', 'Var', (131, 140))	('tumor', 'Disease', (48, 53))	('DTs', 'Disease', (0, 3))	('CTNNB1', 'Gene', '1499', (87, 93))	('catenin beta-1', 'Gene', (71, 85))	('APC', 'Phenotype', 'HP:0005227', (126, 129))	('APC', 'Disease', 'MESH:D011125', (126, 129))	('APC', 'Disease', (126, 129))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (36, 53))	('adenomatous polyposis coli', 'Gene', '324', (98, 124))	('DT', 'Phenotype', 'HP:0100245', (0, 2))	('adenomatous polyposis coli', 'Gene', (98, 124))	('catenin beta-1', 'Gene', '1499', (71, 85))	('CTNNB1', 'Gene', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (98, 124))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
295291	31665941	PDGFB rearrangement was confirmed in the EORTC trial by fluorescence in-situ hybridization (FISH) analysis and in the SWOG trial by reverse transcription-polymerase chain reaction (RT-PCR).	('PDGFB', 'Gene', (0, 5))	('rearrangement', 'Var', (6, 19))	('PDGFB', 'Gene', '5155', (0, 5))
295302	31665941	In addition, small interfering RNA (siRNA)-knockdown of PDGFRalpha was found to phenocopy the antiproliferative effects of sunitinib and decrease cell viability in MRT cells.	('sunitinib', 'Chemical', 'MESH:D000077210', (123, 132))	('PDGFRalpha', 'Gene', '5156', (56, 66))	('decrease', 'NegReg', (137, 145))	('PDGFRalpha', 'Gene', (56, 66))	('cell viability in MRT cells', 'CPA', (146, 173))	('antiproliferative effects', 'MPA', (94, 119))	('small', 'Var', (13, 18))
295401	31665941	Later studies have shown cediranib to possess antiproliferative effects in cell line models of MRT, SS, and LMS.	('cediranib', 'Chemical', 'MESH:C500926', (25, 34))	('LMS', 'Disease', (108, 111))	('LMS', 'Phenotype', 'HP:0100243', (108, 111))	('cediranib', 'Var', (25, 34))	('SS', 'Phenotype', 'HP:0012570', (100, 102))	('MRT', 'Disease', (95, 98))	('antiproliferative effects', 'MPA', (46, 71))
295415	31665941	The primary end-point of this trial was the median percentage change in sum of target lesion diameters from baseline to week 24, or progression if sooner, and the results showed a significant decrease in tumor size in patients on cediranib compared to the placebo group (-8.3% vs +13.4%, p = 0.0010).	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('decrease', 'NegReg', (192, 200))	('cediranib', 'Var', (230, 239))	('patients', 'Species', '9606', (218, 226))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('cediranib', 'Chemical', 'MESH:C500926', (230, 239))
295436	31665941	Utilizing RNA interference (RNAi), the authors showed that only the combined knockdown of FGFR1, FGFR2, and PDGFRalpha was able to phenocopy nintedanib treatment.	('nintedanib', 'Chemical', 'MESH:C530716', (141, 151))	('PDGFRalpha', 'Gene', '5156', (108, 118))	('FGFR2', 'Gene', (97, 102))	('FGFR2', 'Gene', '2263', (97, 102))	('knockdown', 'Var', (77, 86))	('PDGFRalpha', 'Gene', (108, 118))	('FGFR1', 'Gene', (90, 95))	('FGFR1', 'Gene', '2260', (90, 95))
295442	31665941	RNAi-mediated knockdown of GINS1 was able to phenocopy the antiproliferative effects of anlotinib in SS cell lines, thereby confirming that the targeting of GINS1 by anlotinib was essential in achieving its antitumor effect.	('anlotinib', 'Chemical', 'MESH:C000625192', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('GINS1', 'Gene', '9837', (157, 162))	('GINS1', 'Gene', (157, 162))	('anlotinib', 'Chemical', 'MESH:C000625192', (88, 97))	('GINS1', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('antiproliferative effects', 'CPA', (59, 84))	('knockdown', 'Var', (14, 23))	('GINS1', 'Gene', '9837', (27, 32))	('SS', 'Phenotype', 'HP:0012570', (101, 103))
295456	31665941	In the LPS and MPNST cell lines assessed, sitravatinib displayed greater antiproliferative effects compared to pazopanib, crizotinib, and imatinib, with an associated increased reduction in RTK and AKT phosphorylation both in vitro and in vivo.	('MPNST', 'Phenotype', 'HP:0100697', (15, 20))	('LPS', 'Disease', 'MESH:C536528', (7, 10))	('imatinib', 'Chemical', 'MESH:D000068877', (138, 146))	('reduction', 'NegReg', (177, 186))	('crizotinib', 'Chemical', 'MESH:D000077547', (122, 132))	('AKT', 'Gene', '207', (198, 201))	('RTK', 'Protein', (190, 193))	('pazopanib', 'Chemical', 'MESH:C516667', (111, 120))	('sitravatinib', 'Var', (42, 54))	('sitravatinib', 'Chemical', 'MESH:C000611865', (42, 54))	('LPS', 'Phenotype', 'HP:0012034', (7, 10))	('LPS', 'Disease', (7, 10))	('AKT', 'Gene', (198, 201))	('antiproliferative effects', 'CPA', (73, 98))
295457	31665941	To determine if the antiproliferative effects observed in cells were due to the inhibition of RTKs by sitravatinib, the authors utilized siRNA-mediated knockdown of PDGFRbeta, MET, IGF1R, and KIT to phenocopy sitravatinib's effects.	('knockdown', 'Var', (152, 161))	('KIT', 'Gene', '3815', (192, 195))	('PDGFRbeta', 'Gene', '5156', (165, 174))	('antiproliferative', 'MPA', (20, 37))	('IGF1R', 'Gene', (181, 186))	('sitravatinib', 'Chemical', 'MESH:C000611865', (102, 114))	('KIT', 'Gene', (192, 195))	('sitravatinib', 'Chemical', 'MESH:C000611865', (209, 221))	('IGF1R', 'Gene', '3480', (181, 186))	('PDGFRbeta', 'Gene', (165, 174))
295458	31665941	The antiproliferative effect induced by silencing multiple RTKs simultaneously was comparable to those observed with sitravatinib, thereby confirming the correlation between inhibition of these RTKs and the significant reduction in tumor cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('silencing', 'Var', (40, 49))	('reduction', 'NegReg', (219, 228))	('tumor', 'Disease', (232, 237))	('antiproliferative effect', 'CPA', (4, 28))	('sitravatinib', 'Chemical', 'MESH:C000611865', (117, 129))
295467	31665941	Utilizing a 119 anticancer inhibitor screen, crizotinib was found to be the only TKI that resulted in significant suppression of cellular growth in patient-derived CIC-DUX4 fusion-positive small round cell tumor primary cells.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('crizotinib', 'Var', (45, 55))	('tumor', 'Disease', (206, 211))	('DUX4', 'Gene', (168, 172))	('suppression', 'NegReg', (114, 125))	('DUX4', 'Gene', '100288687', (168, 172))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('patient', 'Species', '9606', (148, 155))	('cellular growth', 'MPA', (129, 144))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('crizotinib', 'Chemical', 'MESH:D000077547', (45, 55))
295480	31665941	Approximately 50% of IMTs are known to harbor ALK gene rearrangements, predominantly translocations with variable fusion partners, resulting in the overexpression of chimeric ALK protein.	('overexpression', 'PosReg', (148, 162))	('ALK', 'Gene', (175, 178))	('ALK', 'Gene', '238', (46, 49))	('rearrangements', 'Var', (55, 69))	('chimeric', 'MPA', (166, 174))	('ALK', 'Gene', (46, 49))	('ALK', 'Gene', '238', (175, 178))
295482	31665941	The presence of ALK gene rearrangement was determined centrally using immunohistochemistry and FISH techniques and deemed positive if greater than 15% of cells demonstrated confirmed gene rearrangements on FISH analysis or positive staining for ALK on immunohistochemistry.	('ALK', 'Gene', '238', (16, 19))	('ALK', 'Gene', '238', (245, 248))	('gene rearrangements', 'Var', (183, 202))	('ALK', 'Gene', (16, 19))	('ALK', 'Gene', (245, 248))
295483	31665941	In the cases which harbored the ALK fusion, 6 of 12 (50%) patients achieved an objective response to crizotinib, compared to only 1 of 7 (14.3%) patients with unaltered ALK.	('patients', 'Species', '9606', (145, 153))	('ALK', 'Gene', (32, 35))	('crizotinib', 'Chemical', 'MESH:D000077547', (101, 111))	('ALK', 'Gene', '238', (169, 172))	('ALK', 'Gene', '238', (32, 35))	('patients', 'Species', '9606', (58, 66))	('ALK', 'Gene', (169, 172))	('fusion', 'Var', (36, 42))
295485	31665941	With an objective response observed in half of IMT patients with a proven rearrangement of ALK, the CREATE trial supports the use of crizotinib in this clinical setting.	('ALK', 'Gene', (91, 94))	('crizotinib', 'Chemical', 'MESH:D000077547', (133, 143))	('ALK', 'Gene', '238', (91, 94))	('patients', 'Species', '9606', (51, 59))	('rearrangement', 'Var', (74, 87))
295486	31665941	CCS is a sarcoma affecting tendons and aponeuroses and is characterized by a chromosomal translocation resulting in the generation of a EWSR1-ATF1 fusion gene and subsequent aberrant overexpression of MET.	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('EWSR1', 'Gene', '2130', (136, 141))	('ATF1', 'Gene', (142, 146))	('ATF1', 'Gene', '466', (142, 146))	('sarcoma', 'Disease', (9, 16))	('CCS', 'Disease', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('EWSR1', 'Gene', (136, 141))	('fusion gene', 'Var', (147, 158))	('MET', 'MPA', (201, 204))	('overexpression', 'PosReg', (183, 197))
295492	31665941	The CREATE trial is an example of a biomarker-driven basket trial, leveraging on the demonstrated biological activity of crizotinib in preclinical work and applying that to sarcoma subtypes with known genetic alterations resulting in the upregulation of ALK and/or MET.	('ALK', 'Gene', '238', (254, 257))	('upregulation', 'PosReg', (238, 250))	('sarcoma', 'Disease', (173, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('ALK', 'Gene', (254, 257))	('MET', 'MPA', (265, 268))	('crizotinib', 'Chemical', 'MESH:D000077547', (121, 131))	('alterations', 'Var', (209, 220))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))
295497	31665941	Within these models, dasatinib was also found to induce apoptosis and cell cycle arrest, with concomitant inhibition of cellular migration and invasiveness.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('dasatinib', 'Chemical', 'MESH:D000069439', (21, 30))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('induce', 'PosReg', (49, 55))	('dasatinib', 'Var', (21, 30))	('invasiveness', 'CPA', (143, 155))	('apoptosis', 'CPA', (56, 65))	('inhibition', 'NegReg', (106, 116))	('arrest', 'Disease', (81, 87))	('cellular migration', 'CPA', (120, 138))
295514	31665941	The approval was based on the findings of a clinical development program which included patients of any age and any tumor type and encompassed three clinical study protocols (NCT02122913, NCT02637687, and NCT02576431).	('patients', 'Species', '9606', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('NCT02122913', 'Var', (175, 186))	('tumor', 'Disease', (116, 121))
295521	31665941	The impressive overall response rate supports the use of larotrectinib in patients with sarcomas harboring NTRK alterations.	('sarcomas', 'Disease', (88, 96))	('larotrectinib', 'Chemical', 'MESH:C000609083', (57, 70))	('patients', 'Species', '9606', (74, 82))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('alterations', 'Var', (112, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
295537	31665941	This metabolic variation will therefore result in certain patients being under- or overdosed, when using a standard dosing regimen, leading to a lack of clinical efficacy or increased toxicity and adverse effects, respectively.	('patients', 'Species', '9606', (58, 66))	('lack', 'NegReg', (145, 149))	('clinical efficacy', 'MPA', (153, 170))	('toxicity', 'Disease', 'MESH:D064420', (184, 192))	('toxicity', 'Disease', (184, 192))	('variation', 'Var', (15, 24))	('increased', 'PosReg', (174, 183))
295541	31665941	Therefore, patients with increased or decreased levels of CYP activity or those harboring CYP polymorphisms will result in substantial differences in TKI plasma concentrations.	('CYP', 'Gene', '4051', (90, 93))	('differences', 'Reg', (135, 146))	('decreased', 'NegReg', (38, 47))	('TKI plasma concentrations', 'MPA', (150, 175))	('CYP', 'Gene', (58, 61))	('CYP', 'Gene', '4051', (58, 61))	('patients', 'Species', '9606', (11, 19))	('CYP', 'Gene', (90, 93))	('polymorphisms', 'Var', (94, 107))
295546	31665941	Several studies have highlighted how maintaining the patient plasma concentration of a TKI above a trough plasma concentration (Cmin) threshold through inter-patient and time-point specific dosage variation, whilst also maintaining a concentration below one that would result in toxicity/adverse effects, has resulted in increased molecular responses and PFS in GIST, RCC, and chronic myeloid leukemia patients.	('chronic myeloid leukemia', 'Disease', (377, 401))	('toxicity', 'Disease', (279, 287))	('GIST', 'Disease', (362, 366))	('GIST', 'Phenotype', 'HP:0100723', (362, 366))	('molecular responses', 'CPA', (331, 350))	('variation', 'Var', (197, 206))	('RCC', 'Phenotype', 'HP:0005584', (368, 371))	('RCC', 'Disease', (368, 371))	('patient', 'Species', '9606', (158, 165))	('increased', 'PosReg', (321, 330))	('patients', 'Species', '9606', (402, 410))	('patient', 'Species', '9606', (53, 60))	('RCC', 'Disease', 'MESH:C538614', (368, 371))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (377, 401))	('patient', 'Species', '9606', (402, 409))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (377, 401))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (385, 401))	('leukemia', 'Phenotype', 'HP:0001909', (393, 401))	('toxicity', 'Disease', 'MESH:D064420', (279, 287))	('PFS', 'CPA', (355, 358))
295716	27073487	An Olympus BX-50 microscope (Olympus Corp., Tokyo, Japan) with DP-20 digital camera (Olympus Corp.) was used to capture images at a magnification of x100 and magnification, x400 (vimentin immunostaining).	('vimentin', 'Gene', (179, 187))	('vimentin', 'Gene', '7431', (179, 187))	('x400', 'Var', (173, 177))
295717	27073487	Immunohistochemistry revealed positivity for vimentin; and negativity for CK, desmin, S-100 and CD117 (Fig.	('negativity', 'NegReg', (59, 69))	('vimentin', 'Gene', (45, 53))	('positivity', 'Var', (30, 40))	('S-100', 'Gene', '6271', (86, 91))	('desmin', 'Gene', '1674', (78, 84))	('CD117', 'Gene', '3815', (96, 101))	('CD117', 'Gene', (96, 101))	('S-100', 'Gene', (86, 91))	('vimentin', 'Gene', '7431', (45, 53))	('desmin', 'Gene', (78, 84))
295736	27073487	Damage to these structures may cause severe post-operative complications such as hemorrhaging and fatalities.	('Damage', 'Var', (0, 6))	('hemorrhaging', 'Disease', (81, 93))	('fatalities', 'Disease', (98, 108))	('cause', 'Reg', (31, 36))	('hemorrhaging', 'Disease', 'MESH:D006470', (81, 93))
295755	27073487	The present study provides evidence that neo-adjuvant chemotherapy for those high grading or unresectable retroperitoneal tumor may lead to the possibility to perform complete resection or an improvement in prognostic outcome.	('prognostic', 'MPA', (207, 217))	('improvement', 'Reg', (192, 203))	('high grading', 'Var', (77, 89))	('retroperitoneal tumor', 'Disease', (106, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('retroperitoneal tumor', 'Disease', 'MESH:D012186', (106, 127))
295837	25663853	Synovial sarcoma is characterized by a specific t(X;18)(p11.2;q11.2) chromosomal translocation.	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (48, 68))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('t(X;18)(p11.2', 'Var', (48, 61))	('sarcoma', 'Disease', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))
295859	25663853	A number of mutations at this location are believed to represent basic mechanisms involved in the development of sarcomas.	('sarcomas', 'Disease', (113, 121))	('mutations', 'Var', (12, 21))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
295860	25663853	The MED12 gene mutation occurs in uterine leiomyomas, but can also occur in pelvic and retroperitoneal LMSs.	('mutation', 'Var', (15, 23))	('leiomyomas', 'Disease', (42, 52))	('occurs', 'Reg', (24, 30))	('MED12', 'Gene', (4, 9))	('MED12', 'Gene', '9968', (4, 9))	('leiomyomas', 'Disease', 'MESH:D007889', (42, 52))	('LMSs', 'Phenotype', 'HP:0100243', (103, 107))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (34, 52))	('occur', 'Reg', (67, 72))
295862	25663853	In addition, 4q31 and 18q22 deletions were associated with a susceptibility for metastasis, and 1p33-p32.3 duplications were correlated with increased survival rates.	('metastasis', 'CPA', (80, 90))	('p32', 'Gene', (101, 104))	('p32', 'Gene', '3622', (101, 104))	('increased', 'PosReg', (141, 150))	('4q31', 'Var', (13, 17))	('survival rates', 'CPA', (151, 165))
295863	25663853	The duplications at 1q21.3 were identified to be an independent prognostic marker for shorter survival times in patients with LMS, which suggested that genes located in this region may be involved in the aggressiveness of LMS.	('aggressiveness', 'Phenotype', 'HP:0000718', (204, 218))	('involved', 'Reg', (188, 196))	('shorter', 'NegReg', (86, 93))	('survival times', 'CPA', (94, 108))	('patients', 'Species', '9606', (112, 120))	('aggressiveness', 'Disease', 'MESH:D001523', (204, 218))	('duplications', 'Var', (4, 16))	('LMS', 'Disease', (126, 129))	('aggressiveness', 'Disease', (204, 218))
295865	25663853	The FH gene mutation exhibits familial inheritance, which may explain the occurrence of soft-tissue sarcomas at a young age in homozygous individuals.	('FH', 'Gene', '2271', (4, 6))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (88, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Disease', (100, 108))	('mutation', 'Var', (12, 20))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
295866	25663853	At present, limited data exists concerning the association between LMS and the FH gene mutation.	('LMS', 'Disease', (67, 70))	('mutation', 'Var', (87, 95))	('FH', 'Gene', '2271', (79, 81))
295878	25663853	Previous studies, which have analyzed the overexpression of p16 and p53 genes, MED12 gene mutations, c-Myc expression, 4q31 and 18q22 deletions and FH mutations suggest that sarcomas possess a more complex molecular and genetic basis than is currently known or understood.	('p16', 'Gene', (60, 63))	('mutations', 'Var', (90, 99))	('deletions', 'Var', (134, 143))	('sarcomas', 'Disease', (174, 182))	('c-Myc', 'Gene', '4609', (101, 106))	('MED12', 'Gene', (79, 84))	('c-Myc', 'Gene', (101, 106))	('p16', 'Gene', '1029', (60, 63))	('FH', 'Gene', '2271', (148, 150))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('MED12', 'Gene', '9968', (79, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))
295897	22104361	Although fewer than 200 cases have been described in the literature, identification of a characteristic chromosomal translocation [t(11;22)(p13;q12)] and fusion protein (EWSR1-WT1) has facilitated the definitive diagnosis of DSRCT.	('[t(11;22)(p13;q12)]', 'Var', (130, 149))	('EWSR1', 'Gene', (170, 175))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (131, 148))	('WT1', 'Gene', '7490', (176, 179))	('EWSR1', 'Gene', '2130', (170, 175))	('WT1', 'Gene', (176, 179))	('DSRCT', 'Disease', (225, 230))	('facilitated', 'PosReg', (185, 196))
295950	22104361	The mean V30 Gy for the vertebral bodies and the pelvic bones were 67.8% and 77.3% lower respectively for the IMRT plans compared to the 3D conventional plans (Fig 3B, 3C) Seven of the eight patients received simultaneous radiosensitizing chemotherapy (Table 1).	('V30', 'Var', (9, 12))	('patients', 'Species', '9606', (191, 199))	('lower', 'NegReg', (83, 88))
295980	22104361	Although the recent discovery of a unique disease-specific translocation involving the fusion of the Wilms tumor gene product WT1 and the Ewing's sarcoma gene product EWS has facilitated diagnosis, outcomes after treatment unfortunately remain poor.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Wilms tumor', 'Disease', (101, 112))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (138, 153))	('WT1', 'Gene', '7490', (126, 129))	('Wilms tumor', 'Phenotype', 'HP:0002667', (101, 112))	('WT1', 'Gene', (126, 129))	("Ewing's sarcoma", 'Disease', (138, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (138, 153))	('EWS', 'Gene', '2130', (167, 170))	('EWS', 'Gene', (167, 170))	('fusion', 'Var', (87, 93))	('Wilms tumor', 'Disease', 'MESH:D009396', (101, 112))
296047	22067331	Common Prox1-expression in angiosarcoma may reflect lymphatic endothelial phenotype in these tumors.	('angiosarcoma', 'Phenotype', 'HP:0200058', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Common', 'Var', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Prox1', 'Gene', (7, 12))	('angiosarcoma', 'Disease', 'MESH:D006394', (27, 39))	('Prox1', 'Gene', '5629', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('angiosarcoma', 'Disease', (27, 39))
296165	22067331	Two studies indicate that Prox1 may be a tumor suppressor protein specifically lost in breast cancer and cholangiocarcinoma progression by genetic or epigenetic mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Prox1', 'Gene', (26, 31))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (105, 123))	('tumor', 'Disease', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('lost', 'NegReg', (79, 83))	('Prox1', 'Gene', '5629', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (105, 123))	('epigenetic', 'Var', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cholangiocarcinoma', 'Disease', (105, 123))
296210	33644515	If present, hypoechoic areas within the mass can indicate tumor necrosis or areas of hemorrhage.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('hemorrhage', 'Disease', 'MESH:D006470', (85, 95))	('tumor necrosis', 'Disease', (58, 72))	('hypoechoic areas', 'Var', (12, 28))	('hemorrhage', 'Disease', (85, 95))	('tumor necrosis', 'Disease', 'MESH:D009336', (58, 72))
296302	33012142	However, their conclusion from the articles they studied was that LDRT decreased pain in 13%-90% of patients in the short term, while a long-term analgesic effect was observed in 44%-87% of patients.	('decreased pain', 'Phenotype', 'HP:0007328', (71, 85))	('decreased pain', 'Disease', (71, 85))	('patients', 'Species', '9606', (190, 198))	('pain', 'Phenotype', 'HP:0012531', (81, 85))	('patients', 'Species', '9606', (100, 108))	('LDRT', 'Var', (66, 70))	('decreased pain', 'Disease', 'MESH:D010146', (71, 85))
296336	33012142	noted no post-radiation sarcoma in patients receiving less than 48 Gy compared to an absolute risk of 130 cases per 10,000 person-years of patients who had received 60 Gy or more.	('less', 'Var', (54, 58))	('patients', 'Species', '9606', (139, 147))	('sarcoma', 'Disease', (24, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('patients', 'Species', '9606', (35, 43))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))
296404	30548868	On the one hand, NOD activation can prevent, inhibit, or block carcinogenesis by controlling epithelial cell regeneration while, on the other hand, it can promote carcinogenesis via the production of pro-inflammatory cytokines that contribute to chronic inflammation.21, 68 Furthermore, increased cancer risk is also associated with the presence of polymorphisms in genes CARD4 and CARD15.21 These polymorphisms can produce altered NODs with disrupted cytokine-producing profiles and therefore pose an increased risk, causing inflammation and cancer.	('inflammation', 'Disease', (254, 266))	('CARD4', 'Gene', '107607', (372, 377))	('cancer', 'Phenotype', 'HP:0002664', (543, 549))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('polymorphisms', 'Var', (398, 411))	('N', 'Chemical', 'MESH:D009584', (432, 433))	('block carcinogenesis', 'Disease', 'MESH:D063646', (57, 77))	('cancer', 'Disease', 'MESH:D009369', (543, 549))	('CARD15', 'Gene', '257632', (382, 388))	('inflammation', 'Disease', 'MESH:D007249', (526, 538))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('causing', 'Reg', (518, 525))	('inflammation', 'Disease', 'MESH:D007249', (254, 266))	('disrupted cytokine-producing profiles', 'MPA', (442, 479))	('CARD15', 'Gene', (382, 388))	('cancer', 'Disease', (297, 303))	('rat', 'Species', '10116', (115, 118))	('inflammation', 'Disease', (526, 538))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('block carcinogenesis', 'Disease', (57, 77))	('CARD4', 'Gene', (372, 377))	('cancer', 'Disease', (543, 549))
296409	30548868	Such enhancement of anticancer immunity has been investigated in the context of NOD2 agonists which, mainly, activate monocytes and macrophages85 although stimulation of NK cells86, 87 and DCs88, 89, 90 has also been reported.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (24, 30))	('enhancement', 'PosReg', (5, 16))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('activate', 'PosReg', (109, 117))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('DCs88', 'Var', (189, 194))	('N', 'Chemical', 'MESH:D009584', (80, 81))
296420	30548868	Among 21 synthetic analogs tested, only six compounds, namely FK-156 (3), FK-565 (4), FR-46758 (5), FR-48217 (6), FR-46091 (7), and FR-47920 (8) showed promising tumor growth inhibition (20%-50%).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('FR-48217', 'Var', (100, 108))	('FR-48217', 'Chemical', 'MESH:C047918', (100, 108))	('tumor', 'Disease', (162, 167))	('FR-47920', 'Var', (132, 140))	('FR-47920', 'Chemical', 'MESH:C023456', (132, 140))	('FK-565', 'Chemical', 'MESH:C039537', (74, 80))	('FR-46091', 'Var', (114, 122))	('FK-565', 'Var', (74, 80))	('FK-156', 'Var', (62, 68))	('FR-46758', 'Var', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('FR-46758', 'Chemical', 'MESH:C023456', (86, 94))
296426	30548868	Specifically, reduced M109 lung metastasis formation was observed when high doses of 4 (1-10 mg/kg) were administered prophylactically 2 to 4 days before the inoculation of M109 tumor cells in an experimental metastasis model.	('reduced', 'NegReg', (14, 21))	('tumor', 'Disease', (178, 183))	('M109', 'Var', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
296436	30548868	According to the type of modifications in MDP, NOD2 agonists possessing anticancer activities can be classified into four groups namely, lipophilic derivatives, hydrophilic derivatives, conjugates, and desmuramylpeptides.	('MDP', 'Chemical', 'MESH:C041058', (42, 45))	('modifications', 'Var', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
296468	30548868	This effect may be the consequence of the ability of 11 to augment the production of several cytokines by the monocytes including colony-stimulating factors (CSFs), IL-1, and IL-6, which have central roles in the regulation of hematopoiesis.136 Similar results, in terms of increased hematopoiesis, were also obtained in immunosuppressed mice in which multiple injections of 11 (100 microg/dose) effectively restored the white blood cell count, mainly due to an increase in neutrophil counts.137 In both studies (healthy cynomolgus monkeys and mice), the increase in white blood count may be attributable to the augmenting effect of 11 on the production of CSFs, followed by the proliferation and differentiation of stem cells in bone marrow.136, 137 Due to the success in animal studies, 11 was entered into clinical trials in which it demonstrated a restorative effect on leukopenia in cancer patients.138, 139 In 1991, 11 (trade name Nopia) was put in the market in Japan for treating cancer patients with leukopenia induced by chemotherapy or radiotherapy.134, 135 Besides its important role in stimulating hematopoiesis and immune functions, 11 also elicits antitumor immunity against tumors and metastases in vivo.88, 140, 141 Yoo et al141 investigated the antimetastatic effect of 11 in three highly metastatic cancers in mice, namely B16-BL6 melanoma, colon 26-M3.1 carcinoma, and L5178Y-ML25 T lymphoma.	('mice', 'Species', '10090', (338, 342))	('cancers', 'Phenotype', 'HP:0002664', (1318, 1325))	('metastases', 'Disease', (1201, 1211))	('tumor', 'Phenotype', 'HP:0002664', (1190, 1195))	('cancer', 'Disease', (1318, 1324))	('cancers', 'Disease', (1318, 1325))	('hematopoiesis', 'Disease', 'MESH:C536227', (227, 240))	('leukopenia', 'Disease', 'MESH:D007970', (1009, 1019))	('tumor', 'Phenotype', 'HP:0002664', (1167, 1172))	('tumors', 'Disease', (1190, 1196))	('cancer', 'Phenotype', 'HP:0002664', (1318, 1324))	('melanoma', 'Phenotype', 'HP:0002861', (1350, 1358))	('melanoma', 'Disease', (1350, 1358))	('L5178Y-ML25', 'Var', (1389, 1400))	('cancer', 'Disease', (888, 894))	('hematopoiesis', 'Disease', (227, 240))	('leukopenia', 'Phenotype', 'HP:0001882', (1009, 1019))	('mice', 'Species', '10090', (1329, 1333))	('T lymphoma', 'Phenotype', 'HP:0012190', (1401, 1411))	('rat', 'Species', '10116', (857, 860))	('patients', 'Species', '9606', (895, 903))	('cancer', 'Disease', 'MESH:D009369', (988, 994))	('cancer', 'Phenotype', 'HP:0002664', (888, 894))	('mice', 'Species', '10090', (544, 548))	('leukopenia', 'Disease', (1009, 1019))	('tumors', 'Disease', 'MESH:D009369', (1190, 1196))	('leukopenia', 'Disease', 'MESH:D007970', (874, 884))	('antimetastatic effect', 'MPA', (1263, 1284))	('lymphoma', 'Phenotype', 'HP:0002665', (1403, 1411))	('leukopenia', 'Phenotype', 'HP:0001882', (874, 884))	('cancer', 'Disease', 'MESH:D009369', (1318, 1324))	('rat', 'Species', '10116', (844, 847))	('T lymphoma', 'Disease', 'MESH:D016399', (1401, 1411))	('patients', 'Species', '9606', (995, 1003))	('cancers', 'Disease', 'MESH:D009369', (1318, 1325))	('increase in white blood count', 'Phenotype', 'HP:0001974', (555, 584))	('tumor', 'Disease', (1190, 1195))	('leukopenia', 'Disease', (874, 884))	('hematopoiesis', 'Disease', 'MESH:C536227', (284, 297))	('tumor', 'Disease', (1167, 1172))	('cancer', 'Disease', 'MESH:D009369', (888, 894))	('hematopoiesis', 'Disease', 'MESH:C536227', (1111, 1124))	('melanoma', 'Disease', 'MESH:D008545', (1350, 1358))	('colon 26-M3.1 carcinoma', 'Disease', (1360, 1383))	('tumor', 'Disease', 'MESH:D009369', (1190, 1195))	('cynomolgus monkeys', 'Species', '9541', (521, 539))	('T lymphoma', 'Disease', (1401, 1411))	('cancer', 'Phenotype', 'HP:0002664', (988, 994))	('N', 'Chemical', 'MESH:D009584', (937, 938))	('cancer', 'Disease', (988, 994))	('colon 26-M3.1 carcinoma', 'Disease', 'MESH:D015179', (1360, 1383))	('rat', 'Species', '10116', (686, 689))	('hematopoiesis', 'Disease', (1111, 1124))	('hematopoiesis', 'Disease', (284, 297))	('tumor', 'Disease', 'MESH:D009369', (1167, 1172))	('carcinoma', 'Phenotype', 'HP:0030731', (1374, 1383))	('metastases', 'Disease', 'MESH:D009362', (1201, 1211))	('tumors', 'Phenotype', 'HP:0002664', (1190, 1196))
296469	30548868	A single subcutaneous injection of 11 (100 microg) given 2 or 4 days before tumor cell inoculation caused a significant reduction of lung metastasis of B16-BL6 melanoma (60%) and colon 26-M3.1 carcinoma (25%-40%) as well as liver metastasis of L5178Y-ML25 T lymphoma (65%-70%).	('T lymphoma', 'Disease', (256, 266))	('T lymphoma', 'Disease', 'MESH:D016399', (256, 266))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('colon 26-M3.1 carcinoma', 'Disease', (179, 202))	('liver metastasis', 'Disease', 'MESH:D009362', (224, 240))	('tumor', 'Disease', (76, 81))	('liver metastasis', 'Disease', (224, 240))	('colon 26-M3.1 carcinoma', 'Disease', 'MESH:D015179', (179, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('reduction of lung metastasis of B16-BL6 melanoma', 'Disease', 'MESH:D008546', (120, 168))	('T lymphoma', 'Phenotype', 'HP:0012190', (256, 266))	('lymphoma', 'Phenotype', 'HP:0002665', (258, 266))	('L5178Y-ML25', 'Var', (244, 255))	('reduction of lung metastasis of B16-BL6 melanoma', 'Disease', (120, 168))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
296484	30548868	In contrast, multiple injections of 18 (0.4 mg) in PBS or treatment with squalene (or squalene) vehicle oil alone were less effective in terms of tumor regression resulting in only 2 or even 0 to 1 tumor-free animals out of 7, respectively.151 It is worth noting that despite squalene (or squalane) vehicle oil alone showed no significant antitumor activity in that tumor model, several squalene-based oil-in-water emulsion such as FM59 have been recognized as efficient adjuvants and are already used in various vaccines.84 Moreover, two injections of 18 (400 microg/dose) also restored the depressed allogeneic cell-mediated cytotoxicity of spleen cells in 3LL-bearing mice when administered intraperitoneally, intravenously, or intratumorally.152  Conjugation of MDP to GDP led to the formation of lipophilic MDP-GDP (19) which was recognized as a very potent immunostimulant, especially when incorporated into liposomes.	('squalene', 'Chemical', 'MESH:D013185', (86, 94))	('squalane', 'Chemical', 'MESH:C019556', (289, 297))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('mice', 'Species', '10090', (671, 675))	('cytotoxicity', 'Disease', (627, 639))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('cytotoxicity', 'Disease', 'MESH:D064420', (627, 639))	('tumor', 'Phenotype', 'HP:0002664', (736, 741))	('MDP', 'Chemical', 'MESH:C041058', (812, 815))	('MDP', 'Chemical', 'MESH:C041058', (766, 769))	('rat', 'Species', '10116', (903, 906))	('tumor', 'Disease', (343, 348))	('tumor', 'Disease', (366, 371))	('squalene', 'Chemical', 'MESH:D013185', (73, 81))	('GDP', 'Chemical', 'MESH:D006153', (816, 819))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('rat', 'Species', '10116', (734, 737))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('MDP-GDP', 'Chemical', 'MESH:C043932', (812, 819))	('tumor', 'Disease', (198, 203))	('squalene', 'Chemical', 'MESH:D013185', (276, 284))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (736, 741))	('GDP', 'Chemical', 'MESH:D006153', (773, 776))	('squalene', 'Chemical', 'MESH:D013185', (387, 395))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('lipophilic', 'Var', (801, 811))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (736, 741))
296490	30548868	The similar antimetastatic effect was observed when B16-BL6 tumor-bearing mice were treated with liposomes containing 19 or two other MDP-GDP derivatives, namely GDP derivative of murabutide (hydrophilic, apyrogenic MDP derivative with immunoadjuvant and antitumor activity) and MDP(d,d) (MDP derivative completely devoid of immunoadjuvant activity).154 Mice with lung metastases received five intravenous injections of liposomal 19, murabutide-GDP, or MDP(d,d)-GDP resulting in 53%, 36%, and 71% fewer number of lung metastases than control mice, respectively.	('MDP', 'Chemical', 'MESH:C041058', (134, 137))	('lung metastases', 'Disease', 'MESH:D009362', (364, 379))	('lung metastases', 'Disease', 'MESH:D009362', (513, 528))	('murabutide-GDP', 'Chemical', 'MESH:C033575', (434, 448))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('murabutide-GDP', 'Var', (434, 448))	('fewer', 'NegReg', (497, 502))	('GDP', 'Chemical', 'MESH:D006153', (445, 448))	('tumor', 'Disease', (60, 65))	('lung metastases', 'Disease', (364, 379))	('MDP-GDP', 'Chemical', 'MESH:C043932', (134, 141))	('lung metastases', 'Disease', (513, 528))	('tumor', 'Disease', (259, 264))	('MDP', 'Chemical', 'MESH:C041058', (289, 292))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('mice', 'Species', '10090', (74, 78))	('Mice', 'Species', '10090', (354, 358))	('mice', 'Species', '10090', (542, 546))	('MDP', 'Chemical', 'MESH:C041058', (216, 219))	('MDP', 'Chemical', 'MESH:C041058', (279, 282))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MDP', 'Chemical', 'MESH:C041058', (453, 456))	('GDP', 'Chemical', 'MESH:D006153', (138, 141))	('GDP', 'Chemical', 'MESH:D006153', (162, 165))	('GDP', 'Chemical', 'MESH:D006153', (462, 465))	('MDP(d,d)-GDP', 'Chemical', 'MESH:C043932', (453, 465))
296494	30548868	In addition to enhancing the cytotoxic potential of alveolar macrophages, 19 incorporated into liposomes also showed promising results in stimulating the tumoricidal activity of macrophages in liver.155, 156, 157, 158 To achieve optimal delivery to the liver, 19 was incorporated into liposomes composed of (i) DSPC and PS (7:0.3 molar ratio)153, 155, 157, 158 or (ii) DSPC and dimyristoylphosphatidylglycerol (DMPG) (10:1 molar ratio).156 Philips et al158 demonstrated that liposomal 19 was 16-fold more effective than liposomal MDP or 2400-fold more effective than free MDP in inducing Kupffer cell cytotoxic activity in vitro.	('liposomal 19', 'Var', (475, 487))	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (274, 277))	('MDP', 'Chemical', 'MESH:C041058', (530, 533))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('dimyristoylphosphatidylglycerol', 'Chemical', 'MESH:C002773', (378, 409))	('PC', 'Phenotype', 'HP:0002894', (313, 315))	('rat', 'Species', '10116', (336, 339))	('PC', 'Phenotype', 'HP:0002894', (371, 373))	('rat', 'Species', '10116', (429, 432))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('rat', 'Species', '10116', (464, 467))	('MDP', 'Chemical', 'MESH:C041058', (572, 575))	('Kupffer cell cytotoxic activity', 'CPA', (588, 619))	('inducing', 'Reg', (579, 587))	('DMPG', 'Chemical', 'MESH:C002773', (411, 415))	('tumor', 'Disease', (154, 159))
296495	30548868	Moreover, Kupffer cells were also activated after administration of a single intravenous injection of liposomal 19 (0.1-1 microg/dose) into healthy mice.158 More importantly, prophylactic or therapeutic treatment with liposomal 19 (0.1-1 microg/dose), but not free MDP or control liposomes, resulted in a significant reduction in the number of metastasis in B16-F10 melanoma-bearing mice.	('liposomal 19', 'Var', (218, 230))	('MDP', 'Chemical', 'MESH:C041058', (265, 268))	('mice', 'Species', '10090', (148, 152))	('mice', 'Species', '10090', (383, 387))	('melanoma', 'Phenotype', 'HP:0002861', (366, 374))	('rat', 'Species', '10116', (58, 61))	('melanoma', 'Disease', (366, 374))	('reduction', 'NegReg', (317, 326))	('melanoma', 'Disease', 'MESH:D008545', (366, 374))
296496	30548868	Specifically, prophylactic or therapeutic treatment led to a 70% to 90% reduction of liver tumor burden.155 Similar results were obtained by Brodt et al157 who demonstrated that multiple intravenous injections of liposomal 19 (2 microg/dose) administered either as a therapeutic or prophylactic/therapeutic treatment was equally effective in diminishing the number of hepatic metastases in H-59 lung carcinoma-bearing mice.	('reduction of liver tumor', 'Disease', 'MESH:D017093', (72, 96))	('hepatic metastases', 'Disease', 'MESH:D009362', (368, 386))	('H-59 lung carcinoma-bearing', 'Disease', (390, 417))	('carcinoma', 'Phenotype', 'HP:0030731', (400, 409))	('liver tumor', 'Phenotype', 'HP:0002896', (85, 96))	('H-59 lung carcinoma-bearing', 'Disease', 'MESH:C565698', (390, 417))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('liposomal', 'Var', (213, 222))	('reduction of liver tumor', 'Disease', (72, 96))	('rat', 'Species', '10116', (167, 170))	('hepatic metastases', 'Disease', (368, 386))	('diminishing', 'NegReg', (342, 353))	('to 9', 'Species', '1214577', (65, 69))	('mice', 'Species', '10090', (418, 422))
296518	30548868	The conjugation of MDP-l-Ala to cholesterol, an essential structural component of animal cell membranes, resulted in a new lipophilic MDP derivative MDP-l-Ala-3-O-cholesterol (23; Figure 6) which showed promising macrophage-mediated cytotoxicity in vitro when incorporated into liposomes.	('MDP', 'Chemical', 'MESH:C041058', (134, 137))	('cytotoxicity', 'Disease', 'MESH:D064420', (233, 245))	('cholesterol', 'Chemical', 'MESH:D002784', (32, 43))	('MDP', 'Chemical', 'MESH:C041058', (149, 152))	('MDP-l-Ala', 'Chemical', 'MESH:C035295', (149, 158))	('rat', 'Species', '10116', (267, 270))	('cytotoxicity', 'Disease', (233, 245))	('MDP-l-Ala-3-O-cholesterol', 'Var', (149, 174))	('MDP-l-Ala', 'Chemical', 'MESH:C035295', (19, 28))	('MDP-l-Ala-3-O-cholesterol', 'Chemical', 'MESH:C047489', (149, 174))	('MDP', 'Chemical', 'MESH:C041058', (19, 22))	('cholesterol', 'Chemical', 'MESH:D002784', (163, 174))
296521	30548868	Comparison of relative activities of MDP, liposomal MDP and liposomal 23 in stimulating rat macrophage-mediated cytotoxicity revealed that liposomal MDP and liposomal 23 were 880- and 7400-fold more effective than free MDP, respectively.164 Results confirmed that encapsulation of MDP into liposomes indeed enhances macrophage-mediated cytotoxicity when compared with that of free MDP.	('MDP', 'Chemical', 'MESH:C041058', (219, 222))	('encapsulation', 'Var', (264, 277))	('MDP', 'Chemical', 'MESH:C041058', (281, 284))	('MDP', 'Chemical', 'MESH:C041058', (381, 384))	('cytotoxicity', 'Disease', (112, 124))	('MDP', 'Chemical', 'MESH:C041058', (149, 152))	('cytotoxicity', 'Disease', (336, 348))	('rat', 'Species', '10116', (88, 91))	('MDP', 'Chemical', 'MESH:C041058', (52, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (336, 348))	('MDP', 'Chemical', 'MESH:C041058', (37, 40))	('enhances', 'PosReg', (307, 315))
296522	30548868	However, the retention of hydrosoluble MDP in liposomes is still poor resulting in loss of 90% of MDP.164 Conjugation to cholesterol improved the lipophilic character of 23 and facilitated its incorporation into phospholipid bilayers resulting in stable 23-containing liposomes with greatly improved macrophage-activating properties as free or liposomal MDP.	('23-containing liposomes', 'MPA', (254, 277))	('lipophilic character', 'MPA', (146, 166))	('facilitated', 'PosReg', (177, 188))	('rat', 'Species', '10116', (200, 203))	('MDP', 'Chemical', 'MESH:C041058', (354, 357))	('macrophage-activating properties', 'CPA', (300, 332))	('improved', 'PosReg', (291, 299))	('Conjugation', 'Var', (106, 117))	('cholesterol', 'Chemical', 'MESH:D002784', (121, 132))	('improved', 'PosReg', (133, 141))	('MDP', 'Chemical', 'MESH:C041058', (39, 42))	('MDP', 'Chemical', 'MESH:C041058', (98, 101))	('incorporation', 'MPA', (193, 206))
296528	30548868	Attempts have also been made to improve the anticancer activity of MDP by binding it to various protein carriers, namely neoglycoproteins,168 antibodies,169 maleylated bovine serum albumin (MBSA),170 and gelatin,171 as well as to the nonproteinaceous carrier polyguanylic acid (MDP-PolyG).172 Roche et al168 demonstrated that conjugation of MDP to neoglycoproteins enhanced the tumoricidal activity of macrophages, both in vitro and in vivo, thereby protecting the mice against metastatic growth.	('tumor', 'Disease', (378, 383))	('polyguanylic acid', 'Chemical', 'MESH:D011068', (259, 276))	('MDP', 'Chemical', 'MESH:C041058', (67, 70))	('cancer', 'Disease', (48, 54))	('MDP-PolyG', 'Chemical', 'MESH:C041058', (278, 287))	('mice', 'Species', '10090', (465, 469))	('tumor', 'Disease', 'MESH:D009369', (378, 383))	('serum albumin', 'Gene', (175, 188))	('bovine', 'Species', '9913', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('rat', 'Species', '10116', (315, 318))	('serum albumin', 'Gene', '11657', (175, 188))	('enhanced', 'PosReg', (365, 373))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('conjugation', 'Var', (326, 337))	('protecting', 'Reg', (450, 460))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('metastatic growth', 'CPA', (478, 495))	('MDP', 'Chemical', 'MESH:C041058', (278, 281))	('MDP', 'Chemical', 'MESH:C041058', (341, 344))
296530	30548868	Moreover, 3LL cells coated with MDP-6B6-IgM were even more efficient in activating macrophages.	('MDP-6B6', 'Chemical', 'MESH:C041058', (32, 39))	('activating macrophages', 'MPA', (72, 94))	('MDP-6B6-IgM', 'Var', (32, 43))
296537	30548868	MDP conjugated to MBSA or to polyguanylic acid (PolyG) was internalized by macrophages through scavenger receptor-mediated endocytosis, which resulted in a 50- or 20-fold higher cytotoxic activity against tumor cells, in comparison to that elicited by free MDP.	('MDP', 'Chemical', 'MESH:C041058', (257, 260))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('MDP', 'Chemical', 'MESH:C041058', (0, 3))	('higher', 'PosReg', (171, 177))	('polyguanylic acid', 'Chemical', 'MESH:D011068', (29, 46))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('scavenger receptor-mediated endocytosis', 'MPA', (95, 134))	('polyguanylic acid', 'Var', (29, 46))	('PolyG', 'Chemical', 'MESH:D011068', (48, 53))
296544	30548868	Although compound 31 by itself demonstrated growth inhibitory effect against a panel of human cell lines with IC50 in the nM concentration range (1.3-320 nM, 72 hours treatment), the tumor growth inhibition was not as efficient as that of PTX alone (0.3-280 nM, 72 hours treatment).	('IC50', 'Var', (110, 114))	('rat', 'Species', '10116', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('growth inhibitory', 'MPA', (44, 61))	('human', 'Species', '9606', (88, 93))	('rat', 'Species', '10116', (38, 41))	('PTX', 'Chemical', 'MESH:C051905', (239, 242))
296555	30548868	Namely, MDSCs can increase production of MMP9 (involved in tumor angiogenesis promotion) or enhance tumor cell invasion and migration through the TGFbeta pathway.	('MMP9', 'Gene', (41, 45))	('increase', 'PosReg', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('production', 'MPA', (27, 37))	('TGFbeta pathway', 'Pathway', (146, 161))	('MMP9', 'Gene', '17395', (41, 45))	('rat', 'Species', '10116', (127, 130))	('MDSCs', 'Var', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('enhance', 'PosReg', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
296558	30548868	Besides its anticancer activity, TNF-alpha is also involved in the development of the tissue architecture necessary for tumor growth and metastatic dissemination, as well as in the induction of other cytokines, angiogenic factors, and MMPs, thus leading to the increased growth and survival of tumor cells.179 Although 32 exerts its antimetastatic activity through modulation of TME, there is still a lot unknown about the exact mechanism of this modulation.	('MMPs', 'Gene', (235, 239))	('tumor', 'Disease', (294, 299))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('modulation', 'Var', (365, 375))	('cancer', 'Disease', (16, 22))	('MMPs', 'Gene', '17394;17395;17384', (235, 239))	('antimetastatic activity', 'CPA', (333, 356))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TME', 'Gene', (379, 382))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', (120, 125))
296574	30548868	Replacement of d-isoGln with a d-Gln-n-butyl-ester residue in the peptide part of MDP afforded murabutide (34), another hydrophilic MDP derivative, that has similar adjuvant activity but lacks the pyrogenicity and toxicity of MDP.189, 190, 191, 192 Besides its adjuvant activity, 34 has also been shown to activate the immune system to fight cancer.	('MDP', 'Chemical', 'MESH:C041058', (226, 229))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('cancer', 'Disease', (342, 348))	('toxicity of MDP', 'Disease', 'MESH:D064420', (214, 229))	('toxicity of MDP', 'Disease', (214, 229))	('immune system', 'CPA', (319, 332))	('activate', 'PosReg', (306, 314))	('MDP', 'Chemical', 'MESH:C041058', (132, 135))	('MDP', 'Chemical', 'MESH:C041058', (82, 85))	('Replacement', 'Var', (0, 11))	('d-Gln-n-butyl-ester', 'Chemical', 'MESH:C033575', (31, 50))	('d-isoGln', 'Chemical', 'MESH:C012442', (15, 23))
296594	30548868	The most significant tumor growth delay was seen when mice with established SA-1 tumors received 2.5 microg of 36 (five injections in 5 consecutive days) and 5 x 105 U of TNFNv3 (three injections given every second day), and was prolonged to 9.2 days when compared to untreated controls and 3.2 days when compared to TNFNv3 (5 x 105 U/dose) treated mice.	('tumors', 'Disease', (81, 87))	('TNFNv3', 'Gene', (171, 177))	('tumor', 'Disease', (21, 26))	('N', 'Chemical', 'MESH:D009584', (172, 173))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('delay', 'NegReg', (34, 39))	('N', 'Chemical', 'MESH:D009584', (320, 321))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('N', 'Chemical', 'MESH:D009584', (318, 319))	('to 9', 'Species', '1214577', (239, 243))	('growth delay', 'Phenotype', 'HP:0001510', (27, 39))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mice', 'Species', '10090', (349, 353))	('5 x 105 U', 'Var', (158, 167))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mice', 'Species', '10090', (54, 58))
296599	30548868	Also, based on the observation that desmuramylpeptides can potentiate the antitumor activity of cytokines, it might be interesting to also test them in combination with other chemotherapeutics at low doses, potentially resulting in fewer side effects.	('desmuramylpeptides', 'Var', (36, 54))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('potentiate', 'PosReg', (59, 69))	('tumor', 'Disease', (78, 83))
296603	30548868	Besides substitutions in the peptide portion, modifications can also be introduced into the carbohydrate moiety of MDP.	('substitutions', 'Var', (8, 21))	('modifications', 'Var', (46, 59))	('carbohydrate', 'Chemical', 'MESH:D002241', (92, 104))	('MDP', 'Chemical', 'MESH:C041058', (115, 118))
296608	30548868	Several compounds have so far been synthesized, among which DY-16-43 (37; Figure 10), 38, MDC-405 (39) and salutaxel (40) exhibit the most effective anticancer activity.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('MDC', 'Gene', '20299', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('MDC', 'Gene', (90, 93))	('DY-16-43', 'Var', (60, 68))
296686	27162541	Furthermore, FOXM1 inhibition improved the chemosensitivity to docetaxel in vitro.	('docetaxel', 'Chemical', 'MESH:D000077143', (63, 72))	('inhibition', 'Var', (19, 29))	('chemosensitivity to docetaxel', 'MPA', (43, 72))	('FOXM1', 'Gene', (13, 18))	('FOXM1', 'Gene', '2305', (13, 18))	('improved', 'PosReg', (30, 38))
296687	27162541	Conclusions: FOXM1 inhibition may be a potential therapeutic option for angiosarcoma.	('angiosarcoma', 'Disease', (72, 84))	('inhibition', 'Var', (19, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('angiosarcoma', 'Phenotype', 'HP:0200058', (72, 84))	('FOXM1', 'Gene', (13, 18))	('FOXM1', 'Gene', '2305', (13, 18))	('angiosarcoma', 'Disease', 'MESH:D006394', (72, 84))
296697	27162541	Overexpression of FOXM1 is a poor prognostic factor in many of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('Overexpression', 'Var', (0, 14))	('FOXM1', 'Gene', (18, 23))	('FOXM1', 'Gene', '2305', (18, 23))
34260	27162541	; GAPDH Hs99999905_m1.	('Hs99999905_m1', 'Var', (8, 21))	('GAPDH', 'Gene', '2597', (2, 7))	('GAPDH', 'Gene', (2, 7))
296758	27162541	Among these factors, advanced TNM stage was significantly correlated with high FOXM1 expression (P = 0.041).	('expression', 'MPA', (85, 95))	('high', 'Var', (74, 78))	('TNM', 'Gene', (30, 33))	('TNM', 'Gene', '10178', (30, 33))	('FOXM1', 'Gene', (79, 84))	('FOXM1', 'Gene', '2305', (79, 84))
296759	27162541	Patients with angiosarcoma and high FOXM1 expression had a significantly shorter DSS (5-year survival, 23.5% vs. 47.1%; P = 0.013; Fig.	('angiosarcoma', 'Disease', (14, 26))	('DSS', 'Gene', (81, 84))	('angiosarcoma', 'Phenotype', 'HP:0200058', (14, 26))	('DSS', 'Gene', '5376', (81, 84))	('FOXM1', 'Gene', (36, 41))	('shorter', 'NegReg', (73, 80))	('Patients', 'Species', '9606', (0, 8))	('FOXM1', 'Gene', '2305', (36, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('high', 'Var', (31, 35))	('angiosarcoma', 'Disease', 'MESH:D006394', (14, 26))
296761	27162541	Among the patients with non-advanced anigosarcoma, FOXM1 positivity was significantly correlated to the shorter DSS and EFS (P=0.049 and P=0.014, respectively; Supplemental Fig.	('FOXM1', 'Gene', '2305', (51, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('shorter', 'NegReg', (104, 111))	('anigosarcoma', 'Disease', (37, 49))	('DSS', 'Gene', (112, 115))	('DSS', 'Gene', '5376', (112, 115))	('anigosarcoma', 'Disease', 'None', (37, 49))	('EFS', 'MPA', (120, 123))	('patients', 'Species', '9606', (10, 18))	('positivity', 'Var', (57, 67))	('FOXM1', 'Gene', (51, 56))
296775	27162541	The cells treated with both thiostrepton and docetaxel demonstrated significantly lower cell viability compared to those treated with DMSO or thiostrepton alone (P < 0.01 and P < 0.0001, respectively).	('thiostrepton', 'Var', (28, 40))	('docetaxel', 'Chemical', 'MESH:D000077143', (45, 54))	('DMSO', 'Chemical', 'MESH:D004121', (134, 138))	('cell viability', 'CPA', (88, 102))	('thiostrepton', 'Chemical', 'MESH:D013883', (28, 40))	('thiostrepton', 'Chemical', 'MESH:D013883', (142, 154))	('lower', 'NegReg', (82, 87))
296780	27162541	High FOXM1 expression was also an independent adverse prognostic factor of DSS and EFS in Cox multivariate analyses.	('High', 'Var', (0, 4))	('DSS', 'Gene', (75, 78))	('FOXM1', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('DSS', 'Gene', '5376', (75, 78))	('FOXM1', 'Gene', '2305', (5, 10))	('EFS', 'Disease', (83, 86))	('Cox', 'Gene', '1351', (90, 93))	('Cox', 'Gene', (90, 93))
296781	27162541	In the subgroup analyses on patients with non-advanced angiosarcoma, FOXM1 positivity was significantly correlated to the shorter DSS and EFS.	('FOXM1', 'Gene', (69, 74))	('correlated', 'Reg', (104, 114))	('EFS', 'Disease', (138, 141))	('angiosarcoma', 'Phenotype', 'HP:0200058', (55, 67))	('DSS', 'Gene', (130, 133))	('DSS', 'Gene', '5376', (130, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('angiosarcoma', 'Disease', 'MESH:D006394', (55, 67))	('patients', 'Species', '9606', (28, 36))	('positivity', 'Var', (75, 85))	('angiosarcoma', 'Disease', (55, 67))	('FOXM1', 'Gene', '2305', (69, 74))
296789	27162541	FOXM1 has been shown to be a target of Yes-associated protein (YAP), a downstream effector of the Hippo pathway, in some sacromas, and deregulation of the Hippo pathway has been shown to promote FOXM1 expression and tumorigenesis.	('promote', 'PosReg', (187, 194))	('FOXM1', 'Gene', (195, 200))	('tumor', 'Disease', (216, 221))	('sacromas', 'Disease', (121, 129))	('YAP', 'Gene', (63, 66))	('deregulation', 'Var', (135, 147))	('YAP', 'Gene', '10413', (63, 66))	('FOXM1', 'Gene', '2305', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('FOXM1', 'Gene', '2305', (195, 200))	('FOXM1', 'Gene', (0, 5))	('expression', 'MPA', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Yes-associated protein', 'Gene', '10413', (39, 61))	('Hippo pathway', 'Pathway', (155, 168))	('Yes-associated protein', 'Gene', (39, 61))	('sacromas', 'Disease', 'None', (121, 129))
296812	21052545	Recently, insulin-like-growth-factor-1-receptor (IGF1R) antibodies have been shown to have a modest single-agent activity in EWS.	('EWS', 'Phenotype', 'HP:0012254', (125, 128))	('insulin-like-growth-factor-1-receptor', 'Gene', '3480', (10, 47))	('insulin-like-growth-factor-1-receptor', 'Gene', (10, 47))	('antibodies', 'Var', (56, 66))	('IGF1R', 'Gene', (49, 54))
296825	21052545	Insulin-like growth factor 1 receptor (IGF1R) inhibitors have demonstrated significant activity in EWS, renewing hope for patients with this disease.	('Insulin-like growth factor 1 receptor', 'Gene', (0, 37))	('inhibitors', 'Var', (46, 56))	('IGF1R', 'Gene', (39, 44))	('Insulin-like growth factor 1 receptor', 'Gene', '3480', (0, 37))	('activity', 'MPA', (87, 95))	('EWS', 'Phenotype', 'HP:0012254', (99, 102))	('patients', 'Species', '9606', (122, 130))	('EWS', 'Disease', (99, 102))
296826	21052545	However, most EWS patients whose disease responds to IGF1R inhibitors develop resistance to the therapy and disease relapse or recurrence within several months.	('IGF1R', 'Gene', (53, 58))	('develop', 'Reg', (70, 77))	('inhibitors', 'Var', (59, 69))	('resistance to', 'MPA', (78, 91))	('patients', 'Species', '9606', (18, 26))	('EWS', 'Phenotype', 'HP:0012254', (14, 17))
296830	21052545	EWS characteristically possesses a unique translocation that results from the fusion of the N-terminal of the EWS gene (EWS) on chromosome 22 to the C-terminal of an erythroblastosis virus-transforming sequence-1 (ETS) fusion partner.	('EWS', 'Phenotype', 'HP:0012254', (110, 113))	('EWS', 'Gene', (110, 113))	('fusion', 'Var', (78, 84))	('results from', 'Reg', (61, 73))	('erythroblastosis', 'Disease', (166, 182))	('EWS', 'Phenotype', 'HP:0012254', (0, 3))	('EWS', 'Phenotype', 'HP:0012254', (120, 123))	('erythroblastosis', 'Disease', 'MESH:D004899', (166, 182))
296833	21052545	Although different exon-intron combinations are possible, the two most common fusions are either EWS exon 7 to FLI-1 exon 6 (type 1; 51% of EWS patients) or EWS exon 7 to FLI1 exon 5 (type 2; 27% of patients).	('EWS', 'Phenotype', 'HP:0012254', (97, 100))	('FLI-1', 'Gene', '2313', (111, 116))	('FLI-1', 'Gene', (111, 116))	('patients', 'Species', '9606', (144, 152))	('EWS', 'Phenotype', 'HP:0012254', (157, 160))	('patients', 'Species', '9606', (199, 207))	('EWS', 'Phenotype', 'HP:0012254', (140, 143))	('EWS exon 7', 'Var', (157, 167))
296836	21052545	Reduction of EWS-FLI1 expression in cell lines and nude mouse models by nanoparticle-delivered oligodeoxynucleotides, antisense RNA, and siRNA is associated with anti-EWS activity.	('antisense', 'Var', (118, 127))	('mouse', 'Species', '10090', (56, 61))	('EWS-FLI1', 'Gene', (13, 21))	('EWS', 'Phenotype', 'HP:0012254', (13, 16))	('Reduction', 'NegReg', (0, 9))	('EWS', 'Phenotype', 'HP:0012254', (167, 170))	('expression', 'MPA', (22, 32))
296838	21052545	Recently, surface plasmon resonance screening revealed that YK-4-279, a lead compound with potent anti-EWS activity, blocked RNA helicase A binding to EWS-FLI1, induced apoptosis in EWS cell lines, and reduced growth in EWS xenografts.	('reduced', 'NegReg', (202, 209))	('apoptosis', 'CPA', (169, 178))	('EWS', 'Phenotype', 'HP:0012254', (103, 106))	('YK-4-279', 'Var', (60, 68))	('induced', 'PosReg', (161, 168))	('binding', 'Interaction', (140, 147))	('RNA helicase A', 'Gene', (125, 139))	('EWS-FLI1', 'Gene', (151, 159))	('EWS', 'Phenotype', 'HP:0012254', (182, 185))	('EWS', 'Phenotype', 'HP:0012254', (220, 223))	('growth in EWS xenografts', 'CPA', (210, 234))	('EWS', 'Phenotype', 'HP:0012254', (151, 154))	('RNA helicase A', 'Gene', '1660', (125, 139))	('blocked', 'NegReg', (117, 124))
296846	21052545	Other studies of some of these antibodies have been completed, and studies of R1507, CP-751,871 (figitumumab), and AMG-479 have been published.	('R1507', 'Var', (78, 83))	('AMG', 'Gene', (115, 118))	('AMG', 'Gene', '265', (115, 118))
296856	21052545	Other grade 1 or 2 toxicities such as lymphopenia and thrombocytopenia are also commonly observed when anti-IGF1R antibodies are used and are increased when anti-IGF1R antibodies are used in combination with mTOR inhibitors.	('toxicities', 'Disease', 'MESH:D064420', (19, 29))	('anti-IGF1R antibodies', 'Var', (103, 124))	('thrombocytopenia', 'Disease', 'MESH:D013921', (54, 70))	('lymphopenia', 'Disease', (38, 49))	('mTOR', 'Gene', (208, 212))	('mTOR', 'Gene', '2475', (208, 212))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (54, 70))	('toxicities', 'Disease', (19, 29))	('lymphopenia', 'Phenotype', 'HP:0001888', (38, 49))	('thrombocytopenia', 'Disease', (54, 70))	('antibodies', 'Var', (114, 124))	('lymphopenia', 'Disease', 'MESH:D008231', (38, 49))
296858	21052545	A favorable safety profile of anti-IGF1R antibodies and modest activity has been seen in EWS patients.	('abl', 'Gene', '25', (7, 10))	('abl', 'Gene', (7, 10))	('EWS', 'Phenotype', 'HP:0012254', (89, 92))	('EWS', 'Disease', (89, 92))	('patients', 'Species', '9606', (93, 101))	('anti-IGF1R', 'Gene', (30, 40))	('anti-IGF1R', 'Var', (30, 40))
296867	21052545	In addition, an inactivated insulin receptor gene is associated with normal growth in mice, but mutations or deletions of the insulin receptor gene in humans with Donohue syndrome have been associated with abnormal growth, resulting in short stature.	('deletions', 'Var', (109, 118))	('short stature', 'Phenotype', 'HP:0004322', (236, 249))	('abnormal growth', 'MPA', (206, 221))	('mice', 'Species', '10090', (86, 90))	('associated', 'Reg', (190, 200))	('short stature', 'Disease', (236, 249))	('humans', 'Species', '9606', (151, 157))	('mutations', 'Var', (96, 105))	('abnormal growth', 'Phenotype', 'HP:0001507', (206, 221))
296889	21052545	The initial results of a Pediatric Preclinical Testing Program investigation of MLN8237, an Aurora kinase A inhibitor, showed promise for EWS.	('EWS', 'Phenotype', 'HP:0012254', (138, 141))	('MLN8237', 'Var', (80, 87))	('Aurora kinase A', 'Gene', '6790', (92, 107))	('EWS', 'Disease', (138, 141))	('Aurora kinase A', 'Gene', (92, 107))
296897	21052545	Is chromosomal translocation the initial event in sarcomagenesis in EWS?	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('chromosomal translocation', 'Var', (3, 28))	('sarcoma', 'Disease', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('EWS', 'Phenotype', 'HP:0012254', (68, 71))
296920	33884777	We demonstrate that the ICL is able to ablate cancer cells at very low-power levels that can be clinically implemented but that this effect does not appear to be specific to C1619 when compared to normal fibroblasts.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('ablate', 'NegReg', (39, 45))	('C1619', 'CellLine', 'CVCL:9G75', (174, 179))	('C1619', 'Var', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
296979	33884777	For example, in patient samples S10099 and MS1543, the tumor tissues exhibit higher absorption than neighboring healthy tissues, only for the amide A band.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('MS1543', 'Var', (43, 49))	('absorption', 'MPA', (84, 94))	('higher', 'PosReg', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('S10099', 'Var', (32, 38))	('patient', 'Species', '9606', (16, 23))	('amide', 'Chemical', 'MESH:D000577', (142, 147))
296982	33884777	For patient sample S10097, tumor tissue exhibits higher absorption in the amide A band than the amide B band, while for patient samples MS1722, MS1932, and MS1689, absorption in the amide B band is higher than in the amide A band.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('absorption', 'MPA', (56, 66))	('amide', 'Chemical', 'MESH:D000577', (182, 187))	('amide', 'Chemical', 'MESH:D000577', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('amide', 'Chemical', 'MESH:D000577', (74, 79))	('amide A band', 'MPA', (74, 86))	('patient', 'Species', '9606', (120, 127))	('patient', 'Species', '9606', (4, 11))	('MS1932', 'Var', (144, 150))	('S10097', 'Var', (19, 25))	('MS1722', 'Var', (136, 142))	('amide', 'Chemical', 'MESH:D000577', (217, 222))	('absorption', 'MPA', (164, 174))	('higher', 'PosReg', (198, 204))	('higher', 'PosReg', (49, 55))	('MS1689', 'Var', (156, 162))
297004	32630642	In various type of malignancies, new treatments, such as molecular targeted drugs and immunotherapies, have shown superior clinical outcomes compared to those of standard treatments.	('molecular targeted', 'Var', (57, 75))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('malignancies', 'Disease', (19, 31))
297011	32630642	Chromosomal translocations of t(2;13)(q35;q14) or t(1;13)(q36;q14) are detected in most patients with ARMS.	('t(2;13)(q35;q14', 'Var', (30, 45))	('t(1;13)(q36;q14', 'Var', (50, 65))	('patients', 'Species', '9606', (88, 96))	('RMS', 'Phenotype', 'HP:0002859', (103, 106))	('t(1;13)(q36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (50, 66))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 46))
297014	32630642	Previous studies have reported that PAX-FOXO1 fusion proteins have oncogenic potential and function as dominant oncogenes in promoting tumorigenesis in fusion-positive RMS.	('fusion-positive', 'Var', (152, 167))	('FOXO1', 'Gene', (40, 45))	('FOXO1', 'Gene', '2308', (40, 45))	('RMS', 'Phenotype', 'HP:0002859', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('promoting', 'PosReg', (125, 134))	('tumor', 'Disease', (135, 140))	('oncogenic potential', 'CPA', (67, 86))	('fusion', 'Var', (46, 52))	('RMS', 'Disease', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
297016	32630642	reported that positivity for PAX3-FOXO1 or PAX7-FOXO1 significantly correlated with worse event-free survival (EFS) and overall survival (OS).	('PAX7', 'Gene', (43, 47))	('PAX3', 'Gene', '5077', (29, 33))	('PAX3', 'Gene', (29, 33))	('FOXO1', 'Gene', '2308', (34, 39))	('FOXO1', 'Gene', (48, 53))	('FOXO1', 'Gene', (34, 39))	('event-free survival', 'CPA', (90, 109))	('positivity', 'Var', (14, 24))	('FOXO1', 'Gene', '2308', (48, 53))	('PAX7', 'Gene', '5081', (43, 47))	('worse', 'NegReg', (84, 89))	('overall survival', 'CPA', (120, 136))
297017	32630642	Based on these reports, PAX-FOXO1 may be considered a strong potential therapeutic target and biomarker predicting prognosis in RMS patients with PAX-FOXO1 translocation.	('FOXO1', 'Gene', (150, 155))	('FOXO1', 'Gene', '2308', (150, 155))	('translocation', 'Var', (156, 169))	('RMS', 'Disease', (128, 131))	('FOXO1', 'Gene', (28, 33))	('FOXO1', 'Gene', '2308', (28, 33))	('RMS', 'Phenotype', 'HP:0002859', (128, 131))	('patients', 'Species', '9606', (132, 140))
297093	32630642	In basic studies, cixutumumab, a human monoclonal antibody against IGF-1R, showed antitumor activity in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('IGF-1R', 'Gene', '3480', (67, 73))	('cixutumumab', 'Chemical', 'MESH:C557414', (18, 29))	('IGF-1R', 'Gene', (67, 73))	('tumor', 'Disease', (86, 91))	('human', 'Species', '9606', (33, 38))	('cixutumumab', 'Var', (18, 29))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
297099	32630642	In another phase 2 study on combination treatment with cixutumumab and temsirolimus in 43 patients with recurrent or refractory sarcoma, an objective response was not observed.	('sarcoma', 'Disease', 'MESH:D012509', (128, 135))	('sarcoma', 'Disease', (128, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('cixutumumab', 'Var', (55, 66))	('temsirolimus', 'Chemical', 'MESH:C401859', (71, 83))	('patients', 'Species', '9606', (90, 98))	('cixutumumab', 'Chemical', 'MESH:C557414', (55, 66))
297131	32630642	Multivariate analysis revealed a significant association between PD-L1 expression and poor OS.	('poor OS', 'Disease', (86, 93))	('PD-L1', 'Gene', '29126', (65, 70))	('expression', 'Var', (71, 81))	('PD-L1', 'Gene', (65, 70))
297177	32630642	In the study, RAS knockout in ERMS xenograft models resulted in tumor regression and myogenic differentiation, and recombinant oncolytic myxoma virus targeting RAS significantly reduced tumor growth and improved OS in a xenograft model of ERMS.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('myxoma virus', 'Species', '10273', (137, 149))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('improved', 'PosReg', (203, 211))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('ERMS', 'Disease', (239, 243))	('RMS', 'Phenotype', 'HP:0002859', (31, 34))	('RMS', 'Phenotype', 'HP:0002859', (240, 243))	('myogenic differentiation', 'CPA', (85, 109))	('tumor', 'Disease', (186, 191))	('RAS', 'Gene', (160, 163))	('OS in', 'CPA', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('knockout', 'Var', (18, 26))	('reduced', 'NegReg', (178, 185))	('oncolytic myxoma', 'Phenotype', 'HP:0031461', (127, 143))
297193	32630642	reported that RMS patients with the PAX-FOXO1 fusion protein had a lower tumor mutational burden (TMB) than those without the fusion protein, and that high TMB was significantly associated with worse local control, DFS, and OS.	('DFS', 'Disease', (215, 218))	('FOXO1', 'Gene', (40, 45))	('local control', 'CPA', (200, 213))	('FOXO1', 'Gene', '2308', (40, 45))	('RMS', 'Disease', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('RMS', 'Phenotype', 'HP:0002859', (14, 17))	('tumor', 'Disease', (73, 78))	('TMB', 'Chemical', '-', (156, 159))	('patients', 'Species', '9606', (18, 26))	('fusion protein', 'Var', (46, 60))	('lower', 'NegReg', (67, 72))	('TMB', 'Chemical', '-', (98, 101))
297371	32158266	However, increasing evidence shows that the combination of PD-1 inhibitors and chemotherapy is efficacious and safe for many types of malignancies, including STS.	('malignancies', 'Disease', 'MESH:D009369', (134, 146))	('STS', 'Disease', 'MESH:D012509', (158, 161))	('PD-1', 'Gene', (59, 63))	('PD-1', 'Gene', '5133', (59, 63))	('inhibitors', 'Var', (64, 74))	('malignancies', 'Disease', (134, 146))	('STS', 'Phenotype', 'HP:0030448', (158, 161))	('STS', 'Disease', (158, 161))
297456	32158266	However, immune-related thyroid disorders appear to be more common in patients treated with camrelizumab than in those treated with pembrolizumab, in line with other studies using camrelizumab.	('patients', 'Species', '9606', (70, 78))	('thyroid disorders', 'Disease', (24, 41))	('thyroid disorders', 'Phenotype', 'HP:0000820', (24, 41))	('camrelizumab', 'Chemical', '-', (180, 192))	('pembrolizumab', 'Chemical', 'MESH:C582435', (132, 145))	('thyroid disorders', 'Disease', 'MESH:D013959', (24, 41))	('camrelizumab', 'Chemical', '-', (92, 104))	('camrelizumab', 'Var', (92, 104))	('common', 'Reg', (60, 66))
297480	31662915	Workup at the transplant center showed parvovirus and EBV positivity as well as worsening cytopenias.	('positivity', 'Var', (58, 68))	('cytopenias', 'Disease', 'MESH:D006402', (90, 100))	('cytopenias', 'Disease', (90, 100))	('EBV', 'Protein', (54, 57))	('parvovirus', 'Protein', (39, 49))
297483	31662915	This mass was biopsied, and the final pathology report indicated myeloid sarcoma (CD45+, CD34+, CD1117+, and MPO+).	('CD45', 'Gene', '5788', (82, 86))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (65, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('myeloid sarcoma', 'Disease', (65, 80))	('CD45', 'Gene', (82, 86))	('CD34', 'Gene', (89, 93))	('CD34', 'Gene', '947', (89, 93))	('CD1117+', 'Var', (96, 103))	('CD1117', 'Chemical', 'MESH:C492532', (96, 102))
297571	31624714	Surgeons may achieve insufficient resection margins during chest wall sarcoma resection owing to insufficient adherence to surgical principles, low-grade chest wall sarcomas, or a tumor location near vital structures.	('low-grade', 'Var', (144, 153))	('chest wall sarcoma', 'Disease', 'MESH:D002637', (59, 77))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Disease', (165, 173))	('tumor', 'Disease', (180, 185))	('insufficient', 'NegReg', (97, 109))	('chest wall sarcoma', 'Disease', (154, 172))	('chest wall sarcoma', 'Disease', 'MESH:D002637', (154, 172))	('sarcomas', 'Disease', 'MESH:D012509', (165, 173))	('chest wall sarcoma', 'Disease', (59, 77))
297595	30410809	FISH for SYT gene rearrangement (Figure 10) was performed and was negative, ruling out a synovial sarcoma.	('synovial sarcoma', 'Disease', (89, 105))	('SYT', 'Gene', (9, 12))	('rearrangement', 'Var', (18, 31))	('SYT', 'Gene', '6760', (9, 12))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (89, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('synovial sarcoma', 'Disease', 'MESH:D013584', (89, 105))
297609	30410809	At the genetic level, the majority of CCSKs have internal tandem duplications (ITDs) of the BCOR gene, whereas a minority has the YWHAE-NUTM2 or YWHAE-FAM22 gene fusion, and a third category comprises CCSKs with double negativity for BCOR ITDs, YWHAE-NUTM2, and YWHAE-FAM22 fusion.	('YWHAE', 'Gene', (130, 135))	('internal tandem duplications', 'Var', (49, 77))	('YWHAE', 'Gene', '7531', (145, 150))	('BCOR', 'Gene', '54880', (234, 238))	('CCSKs', 'Chemical', '-', (38, 43))	('YWHAE', 'Gene', '7531', (245, 250))	('YWHAE', 'Gene', (262, 267))	('YWHAE', 'Gene', '7531', (130, 135))	('CCSK', 'Phenotype', 'HP:0006770', (38, 42))	('BCOR', 'Gene', (92, 96))	('YWHAE', 'Gene', (145, 150))	('YWHAE', 'Gene', '7531', (262, 267))	('BCOR', 'Gene', '54880', (92, 96))	('YWHAE', 'Gene', (245, 250))	('CCSK', 'Phenotype', 'HP:0006770', (201, 205))	('CCSKs', 'Chemical', '-', (201, 206))	('BCOR', 'Gene', (234, 238))
297610	30410809	reported 2 primary renal sarcomas demonstrating BCOR-CCNB3 gene fusions with histologic overlap with CCSK and positive immunoreactivity for BCOR, cyclin D1, TLE1, and SATB2 in the neoplastic cells.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('SATB2', 'Gene', (167, 172))	('BCOR', 'Gene', '54880', (48, 52))	('CCNB3', 'Gene', (53, 58))	('SATB2', 'Gene', '23314', (167, 172))	('TLE1', 'Gene', (157, 161))	('CCSK', 'Phenotype', 'HP:0006770', (101, 105))	('BCOR', 'Gene', (48, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('renal sarcomas', 'Phenotype', 'HP:0008663', (19, 33))	('cyclin D1', 'Gene', (146, 155))	('BCOR', 'Gene', '54880', (140, 144))	('primary renal sarcomas', 'Disease', 'MESH:D007674', (11, 33))	('primary renal sarcomas', 'Disease', (11, 33))	('TLE1', 'Gene', '7088', (157, 161))	('fusions', 'Var', (64, 71))	('CCSK', 'Chemical', '-', (101, 105))	('BCOR', 'Gene', (140, 144))	('cyclin D1', 'Gene', '595', (146, 155))	('CCNB3', 'Gene', '85417', (53, 58))
297619	30410809	Given all that, we are uncertain of the mechanism behind the TLE1 immunopositivity in our CCSK case; however, we postulate that the presence of the YWHAE-FAM22 rearrangement, identical to that in endometrial stromal sarcoma, in a minority of CCSK cases or the recent demonstration of BCOR-CCNB3 gene fusions in rare cases of CCSK may play a role in this finding.	('CCSK', 'Phenotype', 'HP:0006770', (242, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('CCSK', 'Chemical', '-', (325, 329))	('TLE1', 'Gene', '7088', (61, 65))	('CCNB3', 'Gene', (289, 294))	('CCSK', 'Phenotype', 'HP:0006770', (325, 329))	('endometrial stromal sarcoma', 'Disease', (196, 223))	('BCOR', 'Gene', (284, 288))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (196, 223))	('YWHAE', 'Gene', (148, 153))	('CCSK', 'Phenotype', 'HP:0006770', (90, 94))	('TLE1', 'Gene', (61, 65))	('BCOR', 'Gene', '54880', (284, 288))	('CCSK', 'Chemical', '-', (90, 94))	('CCNB3', 'Gene', '85417', (289, 294))	('CCSK', 'Chemical', '-', (242, 246))	('rearrangement', 'Var', (160, 173))	('YWHAE', 'Gene', '7531', (148, 153))
297623	28292439	Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7 and KRAS, similar to endometrioid and serous uterine carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('carcinomas', 'Disease', 'MESH:D002277', (121, 131))	('mutations', 'Var', (9, 18))	('TP53', 'Gene', '7157', (33, 37))	('PIK3CA', 'Gene', (45, 51))	('PTEN', 'Gene', '5728', (39, 43))	('PPP2R1A', 'Gene', '5518', (53, 60))	('FBXW7', 'Gene', (62, 67))	('carcinomas', 'Disease', (121, 131))	('KRAS', 'Gene', '3845', (72, 76))	('PPP2R1A', 'Gene', (53, 60))	('endometrioid', 'Disease', (89, 101))	('PIK3CA', 'Gene', '5290', (45, 51))	('TP53', 'Gene', (33, 37))	('serous uterine carcinomas', 'Phenotype', 'HP:0012887', (106, 131))	('KRAS', 'Gene', (72, 76))	('FBXW7', 'Gene', '55294', (62, 67))	('PTEN', 'Gene', (39, 43))	('tri', 'Chemical', '-', (95, 98))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (113, 131))
297624	28292439	Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters.	('tri', 'Chemical', '-', (135, 138))	('epithelial-to-mesenchymal', 'CPA', (45, 70))	('epigenetic alterations', 'Var', (149, 171))
297632	28292439	Heterologous differentiation is a prognostic feature associated with a higher risk of tumor recurrence, particularly when present in early-stage disease.	('Heterologous', 'Var', (0, 12))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
297637	28292439	Prior work that included 13 non-hypermutated UCS tumors found a high frequency of TP53 mutations and lower frequencies of FBXW7, PIK3CA and PPP2R1A mutations.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('FBXW7', 'Gene', '55294', (122, 127))	('PPP2R1A', 'Gene', '5518', (140, 147))	('PIK3CA', 'Gene', (129, 135))	('UCS', 'Phenotype', 'HP:0002891', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('FBXW7', 'Gene', (122, 127))	('mutations', 'Var', (87, 96))	('PIK3CA', 'Gene', '5290', (129, 135))	('UCS tumors', 'Disease', 'MESH:D009369', (45, 55))	('UCS tumors', 'Disease', (45, 55))	('PPP2R1A', 'Gene', (140, 147))
297638	28292439	Many of the mutations in chromatin-remodeling genes were found in hypermutated UCS samples or in carcinosarcoma tumors of ovarian origin.	('tumors of ovarian origin', 'Phenotype', 'HP:0100615', (112, 136))	('carcinosarcoma tumors of ovarian', 'Disease', 'MESH:D002296', (97, 129))	('carcinosarcoma tumors of ovarian', 'Disease', (97, 129))	('UCS', 'Phenotype', 'HP:0002891', (79, 82))	('chromatin-remodeling genes', 'Gene', (25, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('mutations', 'Var', (12, 21))	('found', 'Reg', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
297639	28292439	A recent publication of 24 non-hypermutated UCS tumor-normal exomes found lower frequencies of TP53 and FBXW7 mutations.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('mutations', 'Var', (110, 119))	('FBXW7', 'Gene', '55294', (104, 109))	('UCS', 'Phenotype', 'HP:0002891', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('TP53', 'Gene', '7157', (95, 99))	('FBXW7', 'Gene', (104, 109))	('TP53', 'Gene', (95, 99))
297646	28292439	From this set of mutations, we selected 492 sites for independent hybrid-capture validation, representing 161 genes from lists of significantly mutated genes in this study (below and Supplemental Experimental Procedures) as well as The Cancer Genome Atlas (TCGA) endometrioid endometrial cancer (UCEC) study.	('Cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tri', 'Chemical', '-', (269, 272))	('Cancer Genome Atlas', 'Disease', (236, 255))	('tri', 'Chemical', '-', (282, 285))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (236, 255))	('endometrial cancer', 'Disease', (276, 294))	('endometrial cancer', 'Phenotype', 'HP:0012114', (276, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('mutations', 'Var', (17, 26))	('endometrial cancer', 'Disease', 'MESH:D016889', (276, 294))
297648	28292439	Analysis of mutational signatures also identified an APOBEC signature with C>T and TC>AA/T substitutions in a single tumor that had elevated expression of several APOBEC3 genes (Figure S1B).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('elevated', 'PosReg', (132, 140))	('tumor', 'Disease', (117, 122))	('APOBEC3 genes', 'Gene', (163, 176))	('expression', 'MPA', (141, 151))	('substitutions', 'Var', (91, 104))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('C>T', 'Var', (75, 78))	('TC>AA/T substitutions', 'Var', (83, 104))
297649	28292439	Combined analysis using multiple versions of MutSig identified 14 significantly recurring mutations, many of which were also recurrent mutations in uterine endometrial cancer (Figure 1B and Table S3).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (90, 99))	('endometrial cancer', 'Disease', (156, 174))	('endometrial cancer', 'Phenotype', 'HP:0012114', (156, 174))	('endometrial cancer', 'Disease', 'MESH:D016889', (156, 174))
297650	28292439	Most prominent were TP53 mutations, which were found in all but five tumors (91%).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('TP53', 'Gene', '7157', (20, 24))
297651	28292439	Approximately half of the UCS tumors had mutations in one or more of the PI3-kinase pathway genes:PIK3CA (35%), PTEN (19%) or PIK3R1 (11%).	('mutations', 'Var', (41, 50))	('UCS tumors', 'Disease', 'MESH:D009369', (26, 36))	('PIK3R1', 'Gene', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('PIK3CA', 'Gene', (98, 104))	('UCS tumors', 'Disease', (26, 36))	('PIK3CA', 'Gene', '5290', (98, 104))	('PI3-kinase pathway', 'Pathway', (73, 91))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PTEN', 'Gene', (112, 116))	('UCS', 'Phenotype', 'HP:0002891', (26, 29))	('PTEN', 'Gene', '5728', (112, 116))	('PIK3R1', 'Gene', '5295', (126, 132))
297652	28292439	However, unlike previous studies of endometrial tumors where PTEN and TP53 mutations tended to be mutually exclusive and confined to one of the two common histologic subtypes (endometrioid or serous), eight (73%) of 11 tumors with PTEN mutations also had a TP53 mutation.	('tumors', 'Disease', (48, 54))	('TP53', 'Gene', (70, 74))	('PTEN', 'Gene', (61, 65))	('endometrial tumors', 'Disease', 'MESH:D016889', (36, 54))	('TP53', 'Gene', (257, 261))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('endometrial tumors', 'Disease', (36, 54))	('PTEN', 'Gene', '5728', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('TP53', 'Gene', '7157', (70, 74))	('PTEN', 'Gene', (231, 235))	('mutations', 'Var', (236, 245))	('TP53', 'Gene', '7157', (257, 261))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tri', 'Chemical', '-', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('PTEN', 'Gene', '5728', (231, 235))	('tri', 'Chemical', '-', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
297654	28292439	Genes that were significantly mutated in UCS but not in endometrial carcinomas include the tumor suppressor RB1 (11%) and the splicing factor U2AF1 (4%), which was twice mutated at a hotspot (p.S34F) also found in lung adenocarcinoma and acute myeloid leukemia tumors.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (214, 233))	('p.S34F', 'Var', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (56, 78))	('tumor', 'Disease', (91, 96))	('RB1', 'Gene', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (56, 78))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (244, 260))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (238, 260))	('leukemia', 'Phenotype', 'HP:0001909', (252, 260))	('U2AF1', 'Gene', (142, 147))	('lung adenocarcinoma', 'Disease', (214, 233))	('RB1', 'Gene', '5925', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('endometrial carcinomas', 'Disease', (56, 78))	('UCS', 'Phenotype', 'HP:0002891', (41, 44))	('acute myeloid leukemia tumors', 'Disease', 'MESH:D015470', (238, 267))	('U2AF1', 'Gene', '7307', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('tumor', 'Disease', (261, 266))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (214, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (56, 77))	('p.S34F', 'Mutation', 'rs371769427', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('acute myeloid leukemia tumors', 'Disease', (238, 267))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
297657	28292439	The PIK3CA hotspots p.E545K and p.H1047R are the two most commonly reported mutated PIK3CA sites in this study and in cancer overall (COSMIC v78), both leading to a constitutively active enzyme.	('PIK3CA', 'Gene', '5290', (84, 90))	('constitutively active enzyme', 'MPA', (165, 193))	('cancer', 'Disease', (118, 124))	('leading to', 'Reg', (152, 162))	('p.H1047R', 'Mutation', 'rs121913279', (32, 40))	('p.E545K', 'Var', (20, 27))	('PIK3CA', 'Gene', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('p.E545K', 'Mutation', 'rs104886003', (20, 27))	('p.H1047R', 'Var', (32, 40))	('PIK3CA', 'Gene', (84, 90))	('PIK3CA', 'Gene', '5290', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
297658	28292439	PTEN and ARHGAP35 mutations were more common in the few tumors without identified TP53 mutations.	('TP53', 'Gene', (82, 86))	('ARHGAP35', 'Gene', '2909', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ARHGAP35', 'Gene', (9, 17))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('TP53', 'Gene', '7157', (82, 86))	('PTEN', 'Gene', (0, 4))	('common', 'Reg', (38, 44))	('PTEN', 'Gene', '5728', (0, 4))	('mutations', 'Var', (18, 27))
297661	28292439	The APOBEC signature was characterized by C>T/G at TCW (W=A/T), the POLE signature had a predominance of C>A at TCT and C>T at TCG, the microsatellite instability (MSI) signature had a significant enrichment of one-base indels, and the spontaneous deamination signature was dominated by C>T at CpG di-nucleotides.	('MSI', 'Disease', 'None', (164, 167))	('C>T', 'Var', (120, 123))	('C>T/G', 'Var', (42, 47))	('C>A', 'Var', (105, 108))	('MSI', 'Disease', (164, 167))	('di-nucleotides', 'Chemical', 'MESH:D015226', (298, 312))
297668	28292439	Recurring focal deletions contained the tumor suppressors PTPRD (9q23) and RB1 (13q12.2).	('deletions', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('PTPRD', 'Gene', (58, 63))	('RB1', 'Gene', (75, 78))	('RB1', 'Gene', '5925', (75, 78))	('tumor', 'Disease', (40, 45))
297670	28292439	These alterations included somatic mutations in PIK3CA, PIK3R1 and PTEN, in addition to homozygous deletions of PTEN and NF1.	('NF1', 'Gene', '4763', (121, 124))	('deletions', 'Var', (99, 108))	('PIK3CA', 'Gene', (48, 54))	('PIK3R1', 'Gene', '5295', (56, 62))	('PIK3R1', 'Gene', (56, 62))	('mutations', 'Var', (35, 44))	('PTEN', 'Gene', (67, 71))	('PTEN', 'Gene', (112, 116))	('PIK3CA', 'Gene', '5290', (48, 54))	('PTEN', 'Gene', '5728', (67, 71))	('PTEN', 'Gene', '5728', (112, 116))	('NF1', 'Gene', (121, 124))
297671	28292439	Alterations were also identified in AKT/mTOR targets in 32% of patients, including frequent mutations in FBXW7, AKT2 and STK11.	('FBXW7', 'Gene', (105, 110))	('AKT', 'Gene', '207', (36, 39))	('mTOR', 'Gene', (40, 44))	('mutations', 'Var', (92, 101))	('AKT', 'Gene', '207', (112, 115))	('mTOR', 'Gene', '2475', (40, 44))	('AKT', 'Gene', (36, 39))	('STK11', 'Gene', (121, 126))	('AKT2', 'Gene', (112, 116))	('AKT2', 'Gene', '208', (112, 116))	('patients', 'Species', '9606', (63, 71))	('FBXW7', 'Gene', '55294', (105, 110))	('AKT', 'Gene', (112, 115))	('STK11', 'Gene', '6794', (121, 126))
297673	28292439	Recurrent hotspot mutations were seen in PIK3CA and PPP2R1A (Figure 2B).	('PIK3CA', 'Gene', (41, 47))	('PPP2R1A', 'Gene', (52, 59))	('PPP2R1A', 'Gene', '5518', (52, 59))	('hotspot', 'PosReg', (10, 17))	('PIK3CA', 'Gene', '5290', (41, 47))	('mutations', 'Var', (18, 27))
297674	28292439	Potentially clinically relevant alterations in cell cycle genes were found in 22.8% of patients, including somatic mutations in CCND1, CDKN2B; high-level amplification of CCNE1; and homozygous deletion of CDKN2A and CDKN2B.	('CDKN2B', 'Gene', '1030', (216, 222))	('mutations', 'Var', (115, 124))	('CCND1', 'Gene', (128, 133))	('CDKN2A', 'Gene', (205, 211))	('CCNE1', 'Gene', (171, 176))	('alterations', 'Reg', (32, 43))	('CCNE1', 'Gene', '898', (171, 176))	('CDKN2B', 'Gene', '1030', (135, 141))	('homozygous deletion', 'Var', (182, 201))	('CDKN2A', 'Gene', '1029', (205, 211))	('CCND1', 'Gene', '595', (128, 133))	('cell cycle genes', 'Gene', (47, 63))	('CDKN2B', 'Gene', (216, 222))	('patients', 'Species', '9606', (87, 95))	('CDKN2B', 'Gene', (135, 141))
297675	28292439	Potentially actionable alterations were also found in multiple cases for somatic mutations in ERBB2, ERBB3, BRCA2, and homozygous deletion of ATM.	('BRCA2', 'Gene', (108, 113))	('ATM', 'Gene', '472', (142, 145))	('BRCA2', 'Gene', '675', (108, 113))	('ERBB2', 'Gene', (94, 99))	('ERBB3', 'Gene', (101, 106))	('ERBB3', 'Gene', '2065', (101, 106))	('mutations', 'Var', (81, 90))	('ERBB2', 'Gene', '2064', (94, 99))	('ATM', 'Gene', (142, 145))
297676	28292439	Mutations in chromatin remodeling genes including ARID1A and CHD4 were common and are becoming potentially actionable (Figure 2B).	('CHD4', 'Gene', '1108', (61, 65))	('Mutations', 'Var', (0, 9))	('CHD4', 'Gene', (61, 65))	('ARID1A', 'Gene', '8289', (50, 56))	('ARID1A', 'Gene', (50, 56))
297677	28292439	Single cases with FGFR2 and SMARCA4 mutations and an in-frame fusion with ALK were identified.	('ALK', 'Gene', (74, 77))	('FGFR2', 'Gene', (18, 23))	('FGFR2', 'Gene', '2263', (18, 23))	('SMARCA4', 'Gene', (28, 35))	('mutations', 'Var', (36, 45))	('SMARCA4', 'Gene', '6597', (28, 35))	('ALK', 'Gene', '238', (74, 77))
297679	28292439	Seventy-three percent of all mutations (Figure 3B) and 82% of those in significantly mutated genes (Figure 3C) were found to be clonal, which is similar to the frequencies seen in most other solid tumor types.	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (197, 202))
297680	28292439	The high clonal proportion of UCS mutations is consistent with mutations from bladder urothelial carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, skin cutaneous melanoma, and stomach adenocarcinoma.	('lung adenocarcinoma', 'Disease', (108, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 182))	('UCS', 'Phenotype', 'HP:0002891', (30, 33))	('skin cutaneous melanoma', 'Disease', (159, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 157))	('lung squamous cell carcinoma', 'Disease', (129, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('stomach adenocarcinoma', 'Disease', (188, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))	('bladder urothelial carcinoma', 'Disease', (78, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (164, 182))	('UCS', 'Gene', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (78, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (188, 210))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (129, 157))	('mutations', 'Var', (34, 43))
297709	28292439	One group of tumors from the DNA methylation clustering exhibited a hypermethylation pattern similar to that of endometrioid UCEC, whereas the others were much more similar to the serous subtype (Figure S5B).	('endometrioid UCEC', 'Disease', (112, 129))	('methylation', 'Var', (33, 44))	('exhibited', 'Reg', (56, 65))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('S5B', 'Gene', '5711', (203, 206))	('hypermethylation', 'MPA', (68, 84))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tri', 'Chemical', '-', (118, 121))	('S5B', 'Gene', (203, 206))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
297712	28292439	This subset of tumors had frequent PTEN mutations, which were almost exclusive to the endometrioid subtype of UCEC, suggesting an independent molecular mechanism underlying the development of this histologic subtype.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('PTEN', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('PTEN', 'Gene', '5728', (35, 39))	('mutations', 'Var', (40, 49))	('tri', 'Chemical', '-', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
297713	28292439	Tumors with PTEN mutations had frequent amplification of chromosome 8p (p = 0.001, Fisher's exact test), whereas chromosome 8q was amplified in most tumors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('amplification', 'MPA', (40, 53))	('chromosome 8p', 'Protein', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('PTEN', 'Gene', (12, 16))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', (149, 155))	('PTEN', 'Gene', '5728', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (17, 26))
297716	28292439	The mismatch repair gene MLH1 was epigenetically silenced in two tumors that were independently identified by PCR as having high microsatellite instability (Figure S5A).	('high microsatellite instability', 'MPA', (124, 155))	('epigenetically', 'Var', (34, 48))	('MLH1', 'Gene', '4292', (25, 29))	('MLH1', 'Gene', (25, 29))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
297719	28292439	This contrasts with serous ovarian tumors, in which 12% have epigenetic silencing and 3% have BRCA1 somatic mutations.	('epigenetic silencing', 'Var', (61, 81))	('ovarian tumors', 'Phenotype', 'HP:0100615', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('serous ovarian tumors', 'Phenotype', 'HP:0012887', (20, 41))	('BRCA1', 'Gene', '672', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('serous ovarian tumors', 'Disease', 'MESH:D010051', (20, 41))	('BRCA1', 'Gene', (94, 99))	('serous ovarian tumors', 'Disease', (20, 41))
297730	28292439	However, UCS showed higher activity of the cell cycle and DNA damage response pathways than either the gynecologic carcinomas or sarcomas, with elevated levels of Cyclin E1 and FOXM1 (cell cycle pathway), and phospho-CHK2, MRE11, RAD50 and RAD51 (DNA damage response pathway), delineating additional future targets for therapy (Figure 7B).	('RAD51', 'Gene', (240, 245))	('cell cycle', 'Pathway', (43, 53))	('RAD50', 'Gene', (230, 235))	('higher', 'PosReg', (20, 26))	('carcinomas', 'Disease', (115, 125))	('DNA damage response pathways', 'Pathway', (58, 86))	('Cyclin E1', 'MPA', (163, 172))	('FOXM1', 'Gene', (177, 182))	('elevated', 'PosReg', (144, 152))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('elevated levels of Cyclin', 'Phenotype', 'HP:0003236', (144, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('activity', 'MPA', (27, 35))	('sarcomas', 'Disease', (129, 137))	('phospho-CHK2', 'Var', (209, 221))	('MRE11', 'Gene', (223, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('carcinomas', 'Disease', 'MESH:D002277', (115, 125))	('levels', 'MPA', (153, 159))	('UCS', 'Phenotype', 'HP:0002891', (9, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
297735	28292439	Additionally, more than three-quarters of the cases also had mutation in FBXW7, amplification of CCNE1 or RB1 loss, suggesting deregulated cell cycle function.	('loss', 'NegReg', (110, 114))	('RB1', 'Gene', '5925', (106, 109))	('mutation', 'Var', (61, 69))	('deregulated', 'PosReg', (127, 138))	('FBXW7', 'Gene', '55294', (73, 78))	('cell cycle function', 'CPA', (139, 158))	('CCNE1', 'Gene', '898', (97, 102))	('CCNE1', 'Gene', (97, 102))	('RB1', 'Gene', (106, 109))	('FBXW7', 'Gene', (73, 78))
297738	28292439	A number of reports indicate that inactivation of chromatin remodeling genes such as ARID1A and CHD4 results in susceptibility to various targeted therapies including PARP and EZH2 inhibition.	('PARP', 'Gene', (167, 171))	('ARID1A', 'Gene', (85, 91))	('susceptibility', 'Reg', (112, 126))	('inactivation', 'Var', (34, 46))	('CHD4', 'Gene', '1108', (96, 100))	('EZH2', 'Gene', '2146', (176, 180))	('PARP', 'Gene', '142', (167, 171))	('EZH2', 'Gene', (176, 180))	('CHD4', 'Gene', (96, 100))	('ARID1A', 'Gene', '8289', (85, 91))
297740	28292439	PI3K inhibition has been successful in advanced endometrial cancers with responses seen in patients with pathway alterations despite some limitations due to tolerability.	('PI3K', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('patients', 'Species', '9606', (91, 99))	('endometrial cancer', 'Phenotype', 'HP:0012114', (48, 66))	('endometrial cancers', 'Disease', 'MESH:D016889', (48, 67))	('endometrial cancers', 'Disease', (48, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
297742	28292439	A minority of UCS tumors has molecular features consistent with an endometrioid subtype, including PTEN and KRAS mutations and corresponding gene expression profiles.	('KRAS', 'Gene', (108, 112))	('UCS', 'Phenotype', 'HP:0002891', (14, 17))	('tri', 'Chemical', '-', (73, 76))	('KRAS', 'Gene', '3845', (108, 112))	('endometrioid', 'Disease', (67, 79))	('UCS tumors', 'Disease', 'MESH:D009369', (14, 24))	('mutations', 'Var', (113, 122))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('PTEN', 'Gene', (99, 103))	('PTEN', 'Gene', '5728', (99, 103))	('UCS tumors', 'Disease', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
297749	28292439	In addition, molecular features including DNA methylation, copy number and gene expression recapitulate the endometrial versus serous dichotomy observed in endometrial carcinomas, which was in line with a previous report studying genetic mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('tri', 'Chemical', '-', (114, 117))	('endometrial carcinomas', 'Disease', (156, 178))	('endometrial versus serous dichotomy', 'Disease', (108, 143))	('tri', 'Chemical', '-', (162, 165))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (156, 178))	('copy number', 'Var', (59, 70))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (156, 178))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))
297753	28292439	In comparison to prior work where many of the mutations in chromatin-remodeling genes, including CHD4 and ARID1A, were found in hypermutated UCS samples or in carcinosarcoma tumors of ovarian origin, the present study identifies these mutations in more than one-third of non-hypermutated UCS samples.	('CHD4', 'Gene', (97, 101))	('carcinosarcoma tumors of ovarian', 'Disease', 'MESH:D002296', (159, 191))	('tumors of ovarian origin', 'Phenotype', 'HP:0100615', (174, 198))	('UCS', 'Phenotype', 'HP:0002891', (141, 144))	('mutations', 'Var', (46, 55))	('ARID1A', 'Gene', '8289', (106, 112))	('ARID1A', 'Gene', (106, 112))	('UCS', 'Phenotype', 'HP:0002891', (288, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('found', 'Reg', (119, 124))	('CHD4', 'Gene', '1108', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('carcinosarcoma tumors of ovarian', 'Disease', (159, 191))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
297765	28292439	Each candidate mutation site was assessed in the matched RNA-seq tumor data to identify candidate mutations with independent confirmation from RNA.	('mutations', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
297766	28292439	35.6% of the candidate mutations occurred at expressed sites in the RNA-seq with sufficient coverage for >90% power to detect the mutation observed in the tumor DNA.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))
297777	28292439	We identify multiple somatic mutations and copy number alterations that offer expanded therapeutic options including potential use of PARP, EZH2, cell cycle and PI3K pathway inhibitors.	('copy number alterations', 'Var', (43, 66))	('EZH2', 'Gene', '2146', (140, 144))	('PARP', 'Gene', (134, 138))	('EZH2', 'Gene', (140, 144))	('PI3K pathway', 'Pathway', (161, 173))	('PARP', 'Gene', '142', (134, 138))
297779	28292439	Uterine carcinosarcomas (UCS) have frequent TP53 mutations UCS demonstrate a strong and varied degree of epithelial-mesenchymal transition MicroRNA expression in UCS is under epigenetic control Multiple alterations are present in UCS in genes that are therapeutic targets	('UCS', 'Phenotype', 'HP:0002891', (59, 62))	('UCS', 'Phenotype', 'HP:0002891', (25, 28))	('carcinosarcomas', 'Disease', (8, 23))	('mutations', 'Var', (49, 58))	('UCS', 'Phenotype', 'HP:0002891', (162, 165))	('TP53', 'Gene', '7157', (44, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('UCS', 'Phenotype', 'HP:0002891', (230, 233))	('TP53', 'Gene', (44, 48))	('carcinosarcomas', 'Disease', 'MESH:D002296', (8, 23))
297810	25540867	Tumor cell PD-L1 positivity and intra-tumoral PD-1 lymphocytes were found to be independent prognostic factors of overall survival (OS) and event free survival.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('intra-tumoral PD-1', 'Disease', 'MESH:D010300', (32, 50))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('overall survival', 'MPA', (114, 130))	('positivity', 'Var', (17, 27))	('PD-L1', 'Gene', (11, 16))	('intra-tumoral PD-1', 'Disease', (32, 50))
297814	25540867	We also sought to evaluate the prevalence of macrophages and TIL subsets including CD3+, CD4+, CD8+ and FOXP3+.	('FOXP3+', 'Var', (104, 110))	('CD8', 'Gene', '925', (95, 98))	('CD3', 'Gene', (83, 86))	('CD3', 'Gene', '12501', (83, 86))	('CD8', 'Gene', (95, 98))
297842	25540867	(Figure 2) As a dichotomous variable, CD3+, CD8+, and CD4+ expression was defined as "low density" if the percentage of cells was <5% and "high density" if the percentage of cells was >= 5%.	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('CD3', 'Gene', (38, 41))	('CD3', 'Gene', '12501', (38, 41))	('CD4+', 'Var', (54, 58))
297856	25540867	Tumors with GIST histology were more likely to have >1% FOXP3+ infiltration compared to other histologies, p=0.053.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('GIST', 'Phenotype', 'HP:0100723', (12, 16))	('GIST', 'Var', (12, 16))	('Tumors', 'Disease', (0, 6))	('FOXP3+ infiltration', 'MPA', (56, 75))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
297857	25540867	Deep tumors were more likely to be associated with high FOXP3+ (32/33, 97%) compared to superficial tumors (0), p=0.028.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Deep tumors', 'Disease', 'MESH:D057887', (0, 11))	('tumors', 'Disease', (100, 106))	('Deep tumors', 'Disease', (0, 11))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('high FOXP3+', 'Var', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
297866	25540867	Positive lymphocytic PD-L1 expression was significantly associated with high CD8+ p= 0.018.	('CD8', 'Gene', (77, 80))	('CD8', 'Gene', '925', (77, 80))	('high', 'Var', (72, 76))
297875	25540867	In addition, most of the high density FOXP3+ tumors were GIST histology.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GIST', 'Phenotype', 'HP:0100723', (57, 61))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('FOXP3+', 'Var', (38, 44))
297886	25540867	It has since been demonstrated in multiple tumor types that lack of PD-L1 expression does not preclude a response to PD-1 blockade, with overall response rates ranging from 10-15%.	('lack', 'Var', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PD-L1', 'Gene', (68, 73))	('PD-1', 'Gene', (117, 121))	('PD-1', 'Gene', '5133', (117, 121))	('tumor', 'Disease', (43, 48))
297893	25540867	did identify PD-L1 and PD-1 positivity as independent prognostic indicators of overall survival.	('positivity', 'Var', (28, 38))	('PD-1', 'Gene', (23, 27))	('PD-L1', 'Gene', (13, 18))	('PD-1', 'Gene', '5133', (23, 27))
297957	27134709	Patch stage of Kaposi's sarcoma can be differentiated from well-differentiated angiosarcoma not only by the clinical history and progression but also by positivity for HHV-8 and showing nil to minimal endothelial cell atypia.	('angiosarcoma', 'Disease', (79, 91))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (15, 31))	('angiosarcoma', 'Phenotype', 'HP:0200058', (79, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (15, 31))	("Kaposi's sarcoma", 'Disease', (15, 31))	('HHV-8', 'Gene', (168, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('angiosarcoma', 'Disease', 'MESH:D006394', (79, 91))	('positivity', 'Var', (153, 163))	('HHV-8', 'Species', '37296', (168, 173))
297967	22937311	Of those, disease manifestations in the ovary or the stomach have been reported particularly in patients with eosinophilic differentiation (M4eo) and inversion 16.	('ovary', 'Disease', (40, 45))	('eosinophilic', 'Disease', (110, 122))	('ovary', 'Disease', 'MESH:D010051', (40, 45))	('eosinophilic', 'Disease', 'MESH:D004802', (110, 122))	('inversion 16', 'Var', (150, 162))	('patients', 'Species', '9606', (96, 104))
297969	22937311	In the case of the 51-year old proposita, the diagnosis of an AML M4eo was confirmed morphologically and cytogenetically by the characteristic inversion (16) (p13q22) in 12/2003.	('AML', 'Disease', (62, 65))	('16) (p13q22', 'Var', (154, 165))	('AML', 'Phenotype', 'HP:0004808', (62, 65))	('AML', 'Disease', 'MESH:D015470', (62, 65))
298018	21254746	Radical surgical procedure was imposed by: 1) the tumour's large dimension, 2) shoulder girdle muscle invasion, 3) close contact and invasion of axilla vascular and nervous bundle and 4) histopathological form-low-grade sarcoma-more aggressive and a higher rate of metastases.	('sarcoma', 'Disease', (220, 227))	('metastases', 'Disease', (265, 275))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('form-low-grade', 'Var', (205, 219))	('tumour', 'Disease', (50, 56))	('metastases', 'Disease', 'MESH:D009362', (265, 275))	('shoulder girdle', 'Phenotype', 'HP:0003547', (79, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('axilla vascular', 'Disease', (145, 160))	('shoulder girdle muscle invasion', 'CPA', (79, 110))	('sarcoma', 'Disease', 'MESH:D012509', (220, 227))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('shoulder girdle muscle', 'Phenotype', 'HP:0003547', (79, 101))	('axilla vascular', 'Disease', 'MESH:D000783', (145, 160))
298053	20513245	Pathology revealed a T3N0M0 (AJCC 2002) parotid myxofibrosarcoma of low histological grade.	('parotid myxofibrosarcoma', 'Disease', (40, 64))	('T3N0M0', 'Var', (21, 27))	('parotid myxofibrosarcoma', 'Phenotype', 'HP:0031523', (40, 64))	('parotid myxofibrosarcoma', 'Disease', 'MESH:D010309', (40, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
298084	29416163	There was no higher risk of tibia fracture in patients with partial tibial resection.	('tibia fracture', 'Disease', (28, 42))	('patients', 'Species', '9606', (46, 54))	('partial tibial resection', 'Var', (60, 84))	('tibia fracture', 'Disease', 'MESH:D050723', (28, 42))
298170	28542597	Eight microRNAs (143, 153, 184, 193b, 195, 203, 206 and 223) were selected for evaluation as EWS/Fli1-repressed and underexpressed in Ewing Sarcoma cells, and reported to be growth suppressive in other pediatric or/and adult cancers.	('Fli1', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('EWS', 'Gene', '2130', (93, 96))	('EWS', 'Gene', (93, 96))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (134, 147))	('cancers', 'Disease', (225, 232))	('Ewing Sarcoma', 'Disease', (134, 147))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (134, 147))	('143', 'Var', (17, 20))	('Fli1', 'Gene', '2313', (97, 101))	('Sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
298173	28542597	In subsequent analyses, we found that stable overexpression of miR-193b also inhibits anchorage-independent growth in both A673 and SK-ES-1 cells.	('miR-193b', 'Var', (63, 71))	('anchorage-independent growth', 'CPA', (86, 114))	('overexpression', 'PosReg', (45, 59))	('inhibits', 'NegReg', (77, 85))	('SK-ES-1', 'CellLine', 'CVCL:0627', (132, 139))
298174	28542597	We further show that miR-193b negatively regulates expression of the ErbB4 oncogene in A673 and SK-ES-1 cells, and that depletion of ErbB4 is itself inhibitory to anchorage-independent growth in the same cell lines.	('ErbB4', 'Gene', (133, 138))	('ErbB4', 'Gene', (69, 74))	('ErbB4', 'Gene', '2066', (69, 74))	('regulates', 'Reg', (41, 50))	('expression', 'MPA', (51, 61))	('depletion', 'MPA', (120, 129))	('negatively', 'NegReg', (30, 40))	('SK-ES-1', 'CellLine', 'CVCL:0627', (96, 103))	('ErbB4', 'Gene', '2066', (133, 138))	('miR-193b', 'Var', (21, 29))
298180	28542597	In cancer, miRs function as context-dependent tumor suppressors or oncogenes, capable, through their molecular function as regulators of gene expression, of modifying all aspects of tumorigenesis, including tumor cell proliferation, apoptosis, invasion/metastasis, stem-like properties and angiogenesis.	('stem-like properties', 'CPA', (265, 285))	('invasion/metastasis', 'CPA', (244, 263))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('miRs', 'Var', (11, 15))	('angiogenesis', 'CPA', (290, 302))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('cancer', 'Disease', (3, 9))	('apoptosis', 'CPA', (233, 242))	('modifying', 'Reg', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
298182	28542597	Seeking to identify new EWS/Ets-driven oncogenic pathways with targeting potential in Ewing Sarcoma, our laboratory previously performed global miR profiling upon silencing of the EWS/Fli1 oncoprotein.	('Fli1', 'Gene', '2313', (184, 188))	('EWS', 'Gene', '2130', (24, 27))	('EWS', 'Gene', (24, 27))	('EWS', 'Gene', '2130', (180, 183))	('Fli1', 'Gene', (184, 188))	('silencing', 'Var', (163, 172))	('EWS', 'Gene', (180, 183))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (86, 99))	('Sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('Ewing Sarcoma', 'Disease', (86, 99))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (86, 99))
298184	28542597	In follow-up functional studies, we validated oncogenesis-modifying roles for several individual EWS/Fli1-regulated miRs or/and miR clusters in Ewing Sarcoma.	('Fli1', 'Gene', (101, 105))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (144, 157))	('EWS', 'Gene', (97, 100))	('EWS', 'Gene', '2130', (97, 100))	('Ewing Sarcoma', 'Disease', (144, 157))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (144, 157))	('Sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('miRs', 'Var', (116, 120))	('Fli1', 'Gene', '2313', (101, 105))
298191	28542597	ShRNAs 1 and 2 for ErbB4 correspond to TRCN0000001411 and TRCN0000379973, respectively.	('ErbB4', 'Gene', (19, 24))	('TRCN0000379973', 'Var', (58, 72))	('TRCN0000001411', 'Var', (39, 53))	('ErbB4', 'Gene', '2066', (19, 24))
298201	28542597	For 3'UTR activity assays, Ewing Sarcoma cells were transiently cotransfected using Lipofectamine 2000 with a psiCHECK-2 reporter construct containing the wild-type ErbB4 3'UTR miR-193b site or the mutated site (introduced via standard cloning techniques followed by sequence verification), and miR-193b mimic, non-targeting negative control mimic, or no nucleic acid (Mock group).	('ErbB4', 'Gene', (165, 170))	('miR-193b mimic', 'Var', (295, 309))	('ErbB4', 'Gene', '2066', (165, 170))	('Sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (27, 40))	('Ewing Sarcoma', 'Disease', (27, 40))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (27, 40))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (84, 102))
298208	28542597	From this group, we selected miRs that met two or more of the following three criteria: 1) miRs shown to have predominantly or exclusively anti-oncogenic effects in other cancers; 2) miRs with target profiles relevant to Ewing Sarcoma oncogenesis; and 3) miRs expressed at relatively low levels in Ewing Sarcoma cells (and thus potentially more amenable to replacement).	('Ewing Sarcoma oncogenesis', 'Disease', 'MESH:C563168', (221, 246))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (221, 234))	('miRs', 'Var', (183, 187))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (298, 311))	('Sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('Ewing Sarcoma', 'Disease', (298, 311))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (298, 311))	('Sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('Ewing Sarcoma oncogenesis', 'Disease', (221, 246))	('cancers', 'Disease', (171, 178))	('anti-oncogenic', 'MPA', (139, 153))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (221, 234))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
298211	28542597	In the MTT assay, miR-193b and miR-206 consistently inhibited the growth of both A673 and SK-ES-1 cells, while in the clonogenic assay, miR-193b and miR-223 showed the most potent inhibition of colony formation in both cell lines.	('miR-193b', 'Var', (18, 26))	('growth', 'CPA', (66, 72))	('colony formation', 'CPA', (194, 210))	('MTT', 'Chemical', 'MESH:C070243', (7, 10))	('miR-206', 'Gene', (31, 38))	('miR-223', 'Gene', (149, 156))	('miR-206', 'Gene', '406989', (31, 38))	('inhibited', 'NegReg', (52, 61))	('miR-223', 'Gene', '407008', (149, 156))	('miR-193b', 'Var', (136, 144))	('SK-ES-1', 'CellLine', 'CVCL:0627', (90, 97))
298221	28542597	These analyses revealed robust negative regulation of ErbB4 protein expression by miR-193b in both A673 and SK-ES-1 cells (Fig 4).	('expression', 'MPA', (68, 78))	('negative regulation', 'NegReg', (31, 50))	('miR-193b', 'Var', (82, 90))	('SK-ES-1', 'CellLine', 'CVCL:0627', (108, 115))	('ErbB4', 'Gene', (54, 59))	('ErbB4', 'Gene', '2066', (54, 59))
298223	28542597	To determine if this site is responsive to regulation by miR-193b in Ewing Sarcoma cells, we examined its activity in a 3'UTR reporter system.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (69, 82))	('Sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('miR-193b', 'Var', (57, 65))	('Ewing Sarcoma', 'Disease', (69, 82))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (69, 82))
298224	28542597	As shown in Fig 5B, in both A673 and SK-ES-1 cells, the wild-type ErbB4 3'UTR site, but not the mutated site, caused robust downregulation of reporter activity in the presence of miR-193b, but not the non-targeting negative miR control.	('miR-193b', 'Var', (179, 187))	('reporter activity', 'MPA', (142, 159))	('ErbB4', 'Gene', (66, 71))	('SK-ES-1', 'CellLine', 'CVCL:0627', (37, 44))	('ErbB4', 'Gene', '2066', (66, 71))	('downregulation', 'NegReg', (124, 138))
298225	28542597	Thus, miR-193b likely regulates ErbB4 expression levels through direct action on the proximal 3'UTR.	('miR-193b', 'Var', (6, 14))	('expression levels', 'MPA', (38, 55))	('regulates', 'Reg', (22, 31))	('ErbB4', 'Gene', (32, 37))	('ErbB4', 'Gene', '2066', (32, 37))
298229	28542597	Our studies identify miR-193b as a new growth-suppressive microRNA in Ewing Sarcoma, and provide evidence in support of ErbB4 as a mediator of this growth inhibition.	('ErbB4', 'Gene', (120, 125))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('ErbB4', 'Gene', '2066', (120, 125))	('Sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (70, 83))	('growth-suppressive', 'PosReg', (39, 57))	('Ewing Sarcoma', 'Disease', (70, 83))	('miR-193b', 'Var', (21, 29))
298235	28542597	Tumor suppressive action for miR-193b has also been shown in acute leukemia, both lymphoid and myeloid types.	('leukemia', 'Disease', (67, 75))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-193b', 'Var', (29, 37))	('acute leukemia', 'Phenotype', 'HP:0002488', (61, 75))	('Tumor suppressive', 'NegReg', (0, 17))	('leukemia', 'Phenotype', 'HP:0001909', (67, 75))	('leukemia', 'Disease', 'MESH:D007938', (67, 75))
298243	28542597	In closing, our studies identify miR-193b as a new growth-suppressive miR in Ewing Sarcoma, and ErbB4 as a relevant candidate target potentially contributing to its growth-suppressive effects.	('Sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('Ewing Sarcoma', 'Disease', (77, 90))	('ErbB4', 'Gene', (96, 101))	('growth-suppressive', 'PosReg', (51, 69))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('miR-193b', 'Var', (33, 41))	('ErbB4', 'Gene', '2066', (96, 101))
298260	28291122	Of 27 tumors with SMARCB1 FISH analysis, 14 showed homozygous (biallelic) deletions and 7 showed heterozygous (monoallelic) deletions.	('deletions', 'Var', (74, 83))	('SMARCB1', 'Gene', (18, 25))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('SMARCB1', 'Gene', '6598', (18, 25))
298334	28291122	Of the 27 cases, 21 tumors (78%) showed abnormal findings with homozygous (biallelic) deletion of the SMARCB1 gene locus seen in 14 cases (Fig.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('SMARCB1', 'Gene', '6598', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('SMARCB1', 'Gene', (102, 109))	('deletion', 'Var', (86, 94))
298338	28291122	Loss of SMARCB1 expression as a result of deletions/mutations has emerged as a defining diagnostic feature in a variety of neoplasms in children and adults, in particular malignant atypical teratoid/rhabdoid tumors of childhood, epithelioid sarcoma and recently several epithelial tumor entities in adults and the elderly.	('neoplasms', 'Disease', (123, 132))	('epithelioid sarcoma', 'Disease', (229, 248))	('tumor', 'Disease', (281, 286))	('neoplasm', 'Phenotype', 'HP:0002664', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('Loss', 'NegReg', (0, 4))	('neoplasms', 'Phenotype', 'HP:0002664', (123, 132))	('tumor', 'Disease', (208, 213))	('children', 'Species', '9606', (136, 144))	('deletions/mutations', 'Var', (42, 61))	('expression', 'MPA', (16, 26))	('SMARCB1', 'Gene', '6598', (8, 15))	('epithelial tumor', 'Phenotype', 'HP:0031492', (270, 286))	('SMARCB1', 'Gene', (8, 15))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('malignant', 'Disease', (171, 180))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('neoplasms', 'Disease', 'MESH:D009369', (123, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (241, 248))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (229, 248))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('rhabdoid tumors', 'Disease', (199, 214))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (199, 214))
298342	28291122	The histological spectrum we described herein in conjunction with uniform SMARCB1 deficiency strongly suggests a distinctive neoplasm defined by SMARCB1 loss among other poorly differentiated sinonasal tract malignancies rather than a heterologous group of sinonasal tumors that happen to carry a shared genetic alteration.	('SMARCB1', 'Gene', (145, 152))	('sinonasal tumors', 'Phenotype', 'HP:0030072', (257, 273))	('malignancies', 'Disease', (208, 220))	('deficiency', 'Var', (82, 92))	('loss', 'NegReg', (153, 157))	('SMARCB1', 'Gene', '6598', (74, 81))	('neoplasm', 'Disease', (125, 133))	('sinonasal tumor', 'Phenotype', 'HP:0030072', (257, 272))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('neoplasm', 'Phenotype', 'HP:0002664', (125, 133))	('SMARCB1', 'Gene', (74, 81))	('sinonasal tumors', 'Disease', 'MESH:C537344', (257, 273))	('sinonasal tumors', 'Disease', (257, 273))	('neoplasm', 'Disease', 'MESH:D009369', (125, 133))	('malignancies', 'Disease', 'MESH:D009369', (208, 220))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('SMARCB1', 'Gene', '6598', (145, 152))
298344	28291122	Although comprehensive genetic studies are still lacking, the one SMARCB1-deficient sinonasal carcinoma analyzed by next-generation sequencing failed to reveal any additional genetic aberrations other than homozygous SMARCB1 deletion.	('genetic aberrations', 'Disease', 'MESH:D030342', (175, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('deletion', 'Var', (225, 233))	('genetic aberrations', 'Disease', (175, 194))	('SMARCB1', 'Gene', '6598', (217, 224))	('SMARCB1-deficient sinonasal carcinoma', 'Disease', (66, 103))	('SMARCB1', 'Gene', (66, 73))	('SMARCB1', 'Gene', '6598', (66, 73))	('SMARCB1', 'Gene', (217, 224))	('SMARCB1-deficient sinonasal carcinoma', 'Disease', 'MESH:C537344', (66, 103))
298354	28291122	Similar to other SMARCB1-deficient neoplasms in other organs, gene mutations not detectable by FISH are likely events causing inactivation of the second allele in cases with monoallelic (heterozygous) deletions.	('SMARCB1-deficient neoplasms', 'Disease', 'MESH:D009369', (17, 44))	('SMARCB1-deficient neoplasms', 'Disease', (17, 44))	('monoallelic', 'Var', (174, 185))	('neoplasm', 'Phenotype', 'HP:0002664', (35, 43))	('mutations', 'Var', (67, 76))	('neoplasms', 'Phenotype', 'HP:0002664', (35, 44))
298355	28291122	Likewise, mutations involving both alleles are likely the cause of SMARCB1 loss in cases with normal FISH findings, but epigenetic mechanisms might play a role as well.	('loss', 'NegReg', (75, 79))	('mutations', 'Var', (10, 19))	('SMARCB1', 'Gene', '6598', (67, 74))	('SMARCB1', 'Gene', (67, 74))
298375	28291122	These findings are consistent with recent studies highlighting concurrent co-inactivation of two or more members of the SWI/SNF complex as a consequence of genetic mutation affecting SMARCB1 (epithelioid sarcoma and rhabdoid gastrointestinal carcinomas with variable loss of other SWI/SNF subunits other than SMARCA4) or involving SMARCA4 mutations (small cell carcinoma of the ovary, hypercalcemic type with dual loss of SMARCA4 and SMARCA2).	('carcinoma of the ovary', 'Disease', (361, 383))	('SMARCA4', 'Gene', (422, 429))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (350, 370))	('loss', 'NegReg', (267, 271))	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (361, 383))	('SMARCA4', 'Gene', '6597', (331, 338))	('SMARCA2', 'Gene', (434, 441))	('SMARCA2', 'Gene', '6595', (434, 441))	('SMARCA4', 'Gene', (309, 316))	('SMARCB1', 'Gene', '6598', (183, 190))	('SMARCB1', 'Gene', (183, 190))	('SMARCA4', 'Gene', '6597', (422, 429))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('SMARCA4', 'Gene', (331, 338))	('mutations', 'Var', (339, 348))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('SMARCA4', 'Gene', '6597', (309, 316))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('epithelioid sarcoma and rhabdoid gastrointestinal carcinomas', 'Disease', 'MESH:D012509', (192, 252))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (225, 252))
298413	27904207	Most tumors express EMA and low and high molecular weight CKs, including CKs 7 and 19.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('CKs', 'Var', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('EMA', 'Protein', (20, 23))
298417	27904207	Positivity for CK AE1/AE3 and negativity for neural, vascular, muscular, and lymphoid markers will lead to the correct diagnosis.	('AE3', 'Gene', '6508', (22, 25))	('negativity', 'Var', (30, 40))	('lead to', 'Reg', (99, 106))	('AE1', 'Gene', (18, 21))	('AE1', 'Gene', '6521', (18, 21))	('AE3', 'Gene', (22, 25))	('Positivity', 'Var', (0, 10))
298497	26942183	Case 2 (Figure 2) shows a 47-year-old female patient with fast recurrence of an incompletely resected high-grade sarcoma of the left forearm (pleomorphic sarcoma, initially T1b, N0, M0, G3).	('G3', 'Var', (186, 188))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (142, 161))	('sarcoma', 'Disease', (113, 120))	('pleomorphic sarcoma', 'Disease', (142, 161))	('patient', 'Species', '9606', (45, 52))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('T1b', 'Var', (173, 176))
298575	23217062	Amsterdam reported the relationship between fgf8 misregulation and neuronal tumors in Zebrafish .	('fgf8', 'Gene', '30538', (44, 48))	('fgf8', 'Gene', (44, 48))	('neuronal tumors', 'Phenotype', 'HP:0025170', (67, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('misregulation', 'Var', (49, 62))	('neuronal tumors', 'Disease', 'MESH:D009410', (67, 82))	('Zebrafish', 'Species', '7955', (86, 95))	('neuronal tumors', 'Disease', (67, 82))
298585	33287361	Approximately one third of sarcomas are characterised by subtype-specific genetic variants, which are routinely detected by the molecular testing of tumour biopsies.	('genetic variants', 'Var', (74, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('tumour', 'Disease', (149, 155))	('sarcomas', 'Disease', (27, 35))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))
298586	33287361	Recent studies have shown the potential use of next generation sequencing (NGS) for variant detection in circulating tumour DNA (ctDNA), which is DNA released from tumour cells into the bloodstream.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('variant', 'Var', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('tumour', 'Disease', (164, 170))	('tumour', 'Disease', (117, 123))
298587	33287361	Our feasibility study is the first to demonstrate the application of a custom NGS gene panel, targeting genetic variants in several sarcoma subtypes using ctDNA samples.	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma', 'Disease', (132, 139))	('variants', 'Var', (112, 120))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
298594	33287361	Most sarcoma-related genetic alterations represent chromosomal translocations that result in fusion genes and it has been estimated that around one third of sarcomas carry a detectable driver fusion gene.	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('sarcomas', 'Disease', (157, 165))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('alterations', 'Var', (29, 40))	('fusion genes', 'Var', (93, 105))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('sarcoma', 'Disease', (5, 12))	('sarcomas', 'Disease', 'MESH:D012509', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('result in', 'Reg', (83, 92))	('sarcoma', 'Disease', (157, 164))
298595	33287361	Some sarcoma subtypes display recurrent, often pathognomonic fusion genes which when identified, can support the diagnosis of specific sarcomas.	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('sarcomas', 'Disease', 'MESH:D012509', (135, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('support', 'Reg', (101, 108))	('sarcoma', 'Disease', (135, 142))	('sarcoma', 'Disease', (5, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('sarcomas', 'Disease', (135, 143))	('fusion genes', 'Var', (61, 73))
298599	33287361	Studies in various cancer types, have demonstrated the potential utility of identifying and monitoring tumour-specific mutations in cfDNA isolated from plasma.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('cfDNA', 'Gene', (132, 137))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (119, 128))	('tumour', 'Disease', (103, 109))
298601	33287361	Sarcomas however are less amenable to such approaches as they harbour complex genomic alterations, such as translocations and copy number changes, and generally have a low mutational burden.	('translocations', 'Var', (107, 121))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('copy number changes', 'Var', (126, 145))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
298603	33287361	Recent investigations into the use of ctDNA in sarcomas with translocations are limited but have shown promise.	('sarcomas', 'Disease', (47, 55))	('translocations', 'Var', (61, 75))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
298608	33287361	To the best of our knowledge, this is the first investigation using a validated pan-sarcoma gene panel targeting 87 fusion genes and 7 sarcoma-related CNVs, to detect structural variants from cfDNA.	('variants', 'Var', (178, 186))	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Disease', (84, 91))	('sarcoma', 'Disease', (135, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))
298609	33287361	Our aims were to assess the feasibility of a comprehensive sarcoma capture-based NGS assay to detect clinically relevant fusion genes and copy number variations in ctDNA samples.	('sarcoma', 'Disease', (59, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('fusion genes', 'Var', (121, 133))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('copy number variations', 'Var', (138, 160))
298618	33287361	No additional SNV mutations were detected in either tumour tissue samples or the matched cfDNA samples.	('tumour', 'Disease', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (18, 27))
298621	33287361	achieved an average unique sequencing depth of 579x (range 151.8-1311.2x) and identified EWSR1 translocations in 41 out of 77 patients (53.3%) with ctDNA levels ranging from 1.4 to 43.2%.	('EWSR1', 'Gene', (89, 94))	('translocations', 'Var', (95, 109))	('patients', 'Species', '9606', (126, 134))	('EWSR1', 'Gene', '2130', (89, 94))
298622	33287361	achieved much deeper coverage with an average unique sequencing depth of 3754x and identified 14 out of 17 EWSR1 translocations (82.3%) in patients with ctDNA levels ranging from 0.16 to 15.67%.	('patients', 'Species', '9606', (139, 147))	('EWSR1', 'Gene', (107, 112))	('ctDNA', 'MPA', (153, 158))	('EWSR1', 'Gene', '2130', (107, 112))	('translocations', 'Var', (113, 127))
298624	33287361	It is important to note that the aforementioned previous studies, focused solely on EWSR1 fusion identification whereas this study investigated a wide range of sarcoma fusions.	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('EWSR1', 'Gene', (84, 89))	('sarcoma', 'Disease', (160, 167))	('fusion', 'Var', (90, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('EWSR1', 'Gene', '2130', (84, 89))
298633	33287361	We performed a brief descriptive analysis and found no notable difference in structural variant detection from cfDNA based on tumour burden, treatment received or localisation of metastasis in these patients.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('structural variant', 'Var', (77, 95))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('patients', 'Species', '9606', (199, 207))
298652	33287361	This sarcoma-specific fusion gene panel has previously shown to be highly efficient in identifying translocations in sarcoma tissue samples and therefore clinically useful as a diagnostic method, using both resected tumour tissue and small biopsies.	('sarcoma', 'Disease', (117, 124))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('tumour', 'Disease', 'MESH:D009369', (216, 222))	('sarcoma', 'Disease', (5, 12))	('translocations', 'Var', (99, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('tumour', 'Disease', (216, 222))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))
298677	32669548	Tumor DNA sequencing detected a somatic variant of PIK3CA Q546R.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PIK3CA', 'Gene', (51, 57))	('Q546R', 'Mutation', 'rs397517201', (58, 63))	('Q546R', 'Var', (58, 63))	('PIK3CA', 'Gene', '5290', (51, 57))
298690	32669548	The Cy/Flu regimen induced grade 4 lymphopenia, with an absolute lymphocyte count of 11-19 cells/mm3 on the day of HER2 CAR T-cell infusion (day 0).	('Cy', 'Chemical', 'MESH:D003545', (4, 6))	('Cy/Flu', 'Var', (4, 10))	('HER2', 'Gene', (115, 119))	('lymphopenia', 'Phenotype', 'HP:0001888', (35, 46))	('HER2', 'Gene', '2064', (115, 119))	('lymphopenia', 'Disease', 'MESH:D008231', (35, 46))	('lymphopenia', 'Disease', (35, 46))
298692	32669548	HER2 CAR T cells were detected in the peripheral blood using quantitative polymerase chain reaction (qPCR) starting at 3 h and up to 8 weeks after each infusion during induction, with the peak in vivo expansion (152-747 copies/mug of DNA) occurring 7 days post infusion (Fig.	('152-747 copies/mug', 'Var', (212, 230))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('CR', 'Species', '2498238', (103, 105))
298716	32669548	The appearance of unique productive TCRbeta rearrangements in the peripheral blood after each CAR T-cell infusion during induction (Fig.	('TCRbeta', 'Gene', '28695', (36, 43))	('rearrangements', 'Var', (44, 58))	('TCRbeta', 'Gene', (36, 43))
298719	32669548	The productive CDR3 rearrangements and the frequency of their distribution were largely comparable between the peripheral blood and the time-matched bone marrow samples.	('CDR3', 'Gene', (15, 19))	('CDR3', 'Gene', '8163', (15, 19))	('rearrangements', 'Var', (20, 34))
298744	32669548	Analysis of serum cytokines showed peripheral blood GM-CSF and IFN-gamma levels peak at 4 h after the CAR T-cell infusions given with Cy/Flu, whereas lymphodepletion did not influence the post-infusion TNFalpha levels (Fig.	('IFN-gamma', 'Gene', (63, 72))	('TNFalpha', 'Gene', (202, 210))	('TNFalpha', 'Gene', '7124', (202, 210))	('GM-CSF', 'Gene', (52, 58))	('Cy', 'Chemical', 'MESH:D003545', (134, 136))	('Cy/Flu', 'Var', (134, 140))	('GM-CSF', 'Gene', '1437', (52, 58))	('IFN-gamma', 'Gene', '3458', (63, 72))
298746	32669548	HER2 CAR T cells expanded in the peripheral blood when infused after Cy/Flu during induction, were better sustained during the consolidation of CR2, and continued to be detected at low levels during off-therapy follow-up (Fig.	('CR2', 'Species', '2498238', (144, 147))	('Cy', 'Chemical', 'MESH:D003545', (69, 71))	('Cy/Flu', 'Var', (69, 75))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
298761	32669548	This led to an increase in the serum levels of the homeostatic cytokine IL-15 after Cy/Flu and improved expansion of the infused HER2 CAR T cells.	('IL-15', 'Gene', '3600', (72, 77))	('expansion', 'CPA', (104, 113))	('HER2', 'Gene', (129, 133))	('Cy', 'Chemical', 'MESH:D003545', (84, 86))	('increase', 'PosReg', (15, 23))	('Cy/Flu', 'Var', (84, 90))	('HER2', 'Gene', '2064', (129, 133))	('IL-15', 'Gene', (72, 77))	('improved', 'PosReg', (95, 103))
298775	32669548	In a patient with chronic lymphocytic leukemia responding to CTL019 therapy, peripheral expansion of a single T-cell clone with disruption of the TET2-gene due to CD19-CAR transgene integration (and hypomorphic mutation in the second allele) was thought to be the predominant mediator of the observed antitumor response.	('CD19', 'Gene', (163, 167))	('patient', 'Species', '9606', (5, 12))	('CD19', 'Gene', '930', (163, 167))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (18, 46))	('TET2', 'Gene', (146, 150))	('leukemia', 'Phenotype', 'HP:0001909', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (18, 46))	('disruption', 'Var', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('TET2', 'Gene', '54790', (146, 150))	('chronic lymphocytic leukemia', 'Disease', (18, 46))	('tumor', 'Disease', (305, 310))
298776	32669548	In our patient with RMS, while some pre-existing T-cell clones were sustained through multiple infusions during induction and increased in frequency to >1% of the homeostatic space, we observed bursts of unique TCRbeta productive rearrangements occupying a substantial percentage of the clonal space after subsequent infusions of the same CAR T-cell product.	('patient', 'Species', '9606', (7, 14))	('TCRbeta', 'Gene', '28695', (211, 218))	('RMS', 'Phenotype', 'HP:0002859', (20, 23))	('TCRbeta', 'Gene', (211, 218))	('rearrangements', 'Var', (230, 244))
298779	32669548	In this child, the distribution of productive CDR3 rearrangements after CAR T-cell infusions given with and without Cy/Flu was distinct in comparison to the pre-infusion peripheral blood obtained 4 weeks after prior cytotoxic chemotherapy only.	('child', 'Species', '9606', (8, 13))	('rearrangements', 'Var', (51, 65))	('Cy', 'Chemical', 'MESH:D003545', (116, 118))	('CDR3', 'Gene', '8163', (46, 50))	('CDR3', 'Gene', (46, 50))
298786	32669548	PD-1 blockade was reported to reinvigorate CD19-CAR T cells and induce clinical response in an adult patient with B cell lymphoma.	('blockade', 'Var', (5, 13))	('induce', 'PosReg', (64, 70))	('B cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('PD-1', 'Gene', (0, 4))	('reinvigorate', 'PosReg', (30, 42))	('CD19', 'Gene', (43, 47))	('clinical response', 'CPA', (71, 88))	('CD19', 'Gene', '930', (43, 47))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('patient', 'Species', '9606', (101, 108))	('B cell lymphoma', 'Disease', (114, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))
298822	32669548	The sequences were quantitated and analyzed to identify frequency of productive TCRbeta CDR3 rearrangements in samples using the ImmunoSEQ Analyzer 3.0 software provided by Adaptive Biotechnologies.	('TCRbeta CDR3', 'Gene', '6962;8163', (80, 92))	('TCRbeta CDR3', 'Gene', (80, 92))	('rearrangements', 'Var', (93, 107))
298830	32669548	The serum IgG and IgM levels at various time points over the course of treatment (pre-infusion, 6 weeks post each infusion during CR1 and at relapse) were determined using IgG (total) Human uncoated ELISA kit (Cat# 88-50550-22, Lot# 175941117) and IgM Human uncoated ELISA kit (Cat# 88-50620-22, Lot# 1666010115), respectively, as per manufacturer's instructions (Invitrogen, Carlsbad, CA).	('kit', 'Gene', '3815', (273, 276))	('Cat# 88-50550-22', 'Var', (210, 226))	('CR', 'Species', '2498238', (130, 132))	('Cat# 88-50620-22', 'Var', (278, 294))	('kit', 'Gene', (205, 208))	('Human', 'Species', '9606', (184, 189))	('kit', 'Gene', '3815', (205, 208))	('kit', 'Gene', (273, 276))	('Human', 'Species', '9606', (252, 257))
298876	25591392	Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model A mouse model that recapitulates the human Ewing's sarcoma-specific chromosomal translocation was generated utilizing the Cre/loxP-mediated recombination technique.	('Fli1', 'Gene', (52, 56))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (154, 169))	('mouse', 'Species', '10090', (99, 104))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (71, 93))	('Ewsr1', 'Gene', (42, 47))	('leads to', 'Reg', (62, 70))	('chromosomal translocation', 'Var', (8, 33))	('Ewsr1', 'Gene', '14030', (42, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('Fli1', 'Gene', '14247', (52, 56))	('human', 'Species', '9606', (148, 153))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (154, 169))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (71, 93))	('mouse', 'Species', '10090', (113, 118))	('dilated cardiomyopathy', 'Disease', (71, 93))	("Ewing's sarcoma", 'Disease', (154, 169))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (79, 93))
298878	25591392	As a result Ewsr1-Fli1 fusion transcripts were expressed, suggesting a functional Ews-Fli1 protein might be synthesized in vivo.	('fusion', 'Var', (23, 29))	('Ews', 'Gene', '14030', (12, 15))	('Ews', 'Gene', (12, 15))	('Ews', 'Gene', '14030', (82, 85))	('Ews', 'Gene', (82, 85))
298879	25591392	However, by two years of age, none of the Ewsr1-loxP/Fli1-loxP/CAG-Cre (EFCC) mice developed any malignancies, including Ewing-like small round cell sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('sarcoma', 'Disease', (149, 156))	('EFCC', 'Chemical', '-', (72, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('Ewsr1-loxP/Fli1-loxP/CAG-Cre', 'Var', (42, 70))	('Ewing-like small round cell sarcoma', 'Phenotype', 'HP:0012254', (121, 156))	('mice', 'Species', '10090', (78, 82))	('malignancies', 'Disease', (97, 109))
298882	25591392	Moreover, expression of Ews-Fli1 in the cultured cardiac myocytes induced apoptosis.	('apoptosis', 'CPA', (74, 83))	('expression', 'Var', (10, 20))	('induced', 'Reg', (66, 73))	('Ews', 'Gene', '14030', (24, 27))	('Ews', 'Gene', (24, 27))
298883	25591392	Collectively, these results indicated that ectopic expression of the Ews-Fli1 oncogene stimulated apoptotic signals, and suggested an important relationship between oncogenic signals and cellular context in the cell-of-origin of Ewing's sarcoma.	('Ews', 'Gene', (69, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('stimulated', 'PosReg', (87, 97))	('ectopic expression', 'Var', (43, 61))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (229, 244))	('apoptotic signals', 'CPA', (98, 115))	("Ewing's sarcoma", 'Disease', (229, 244))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (229, 244))	('Ews', 'Gene', '14030', (69, 72))
298884	25591392	Chromosomal translocation is a common feature of malignant neoplasms.	('malignant neoplasms', 'Disease', 'MESH:D009369', (49, 68))	('neoplasms', 'Phenotype', 'HP:0002664', (59, 68))	('Chromosomal translocation', 'Var', (0, 25))	('malignant neoplasms', 'Disease', (49, 68))
298885	25591392	There is growing evidence that tumor-specific translocations and inversions commonly occur among hematopoietic, mesenchymal and epithelial tumors.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('inversions', 'Var', (65, 75))	('occur', 'Reg', (85, 90))	('tumor', 'Disease', (31, 36))	('translocations', 'Var', (46, 60))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('epithelial tumors', 'Disease', (128, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('mesenchymal', 'Disease', (112, 123))	('hematopoietic', 'Disease', (97, 110))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('epithelial tumors', 'Disease', 'MESH:D002277', (128, 145))
298888	25591392	Another important outcome of translocation in cancer is gene fusion or formation of chimeric genes.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('translocation', 'Var', (29, 42))	('gene fusion', 'Var', (56, 67))
298891	25591392	In contrast to transgenic expression of fusion genes, translocation-mediated gene fusion recapitulates gene expression levels equivalent to, and splice variants similar to those in human tumors.	('human', 'Species', '9606', (181, 186))	('transgenic', 'Species', '10090', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('gene expression levels', 'MPA', (103, 125))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('translocation-mediated gene fusion', 'Var', (54, 88))
298894	25591392	Indeed, a mouse model of Cre-loxP-mediated in vivo gene fusion between Mll and Af9 developed acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (93, 115))	('mouse', 'Species', '10090', (10, 15))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (99, 115))	('Mll', 'Gene', (71, 74))	('Af9', 'Gene', (79, 82))	('gene fusion', 'Var', (51, 62))	('Af9', 'Gene', '70122', (79, 82))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (93, 115))	('acute myeloid leukemia', 'Disease', (93, 115))	('Mll', 'Gene', '214162', (71, 74))
298899	25591392	It is, however, difficult to generate a good animal model by introduction of EWS-FLI1 or EWS-ERG into ES cells or mouse eggs.	('EWS-FLI1', 'Var', (77, 85))	('mouse', 'Species', '10090', (114, 119))	('ERG', 'Gene', '13876', (93, 96))	('ERG', 'Gene', (93, 96))
298900	25591392	Moreover, conditional EWS-FLI1 expression in hematopoietic cells induced myeloid and erythroid leukemia in mice.	('erythroid leukemia', 'Disease', (85, 103))	('erythroid leukemia', 'Disease', 'MESH:C538442', (85, 103))	('EWS-FLI1', 'Gene', (22, 30))	('myeloid', 'Disease', (73, 80))	('mice', 'Species', '10090', (107, 111))	('myeloid and erythroid leukemia', 'Phenotype', 'HP:0005531', (73, 103))	('induced', 'Reg', (65, 72))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('expression', 'Var', (31, 41))
298902	25591392	We therefore hypothesized that EWS-ETS translocation is achieved by chance in human somatic cells of appropriate lineages and differentiation status, and such in vivo translocation could properly induce Ewing's sarcoma.	('induce', 'Reg', (196, 202))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (203, 218))	("Ewing's sarcoma", 'Disease', (203, 218))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (203, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('translocation', 'Var', (167, 180))	('human', 'Species', '9606', (78, 83))
298905	25591392	The result indicates that ectopic chromosomal translocation and gene fusion activates apoptotic signals, resulting in degenerative cardiac disease.	('activates', 'PosReg', (76, 85))	('cardiac disease', 'Disease', (131, 146))	('apoptotic', 'CPA', (86, 95))	('cardiac disease', 'Disease', 'MESH:D006331', (131, 146))	('resulting in', 'Reg', (105, 117))	('ectopic chromosomal translocation', 'Var', (26, 59))	('gene fusion', 'Var', (64, 75))
298910	25591392	The Ewsr1fl/+ and Fli1fl/+ mice were further crossed with CAG-Cre, Mx1-Cre or Rosa26-CreER mice to induce somatic chromosomal translocation between chromosomes 9 and 11 (Fig.	('mice', 'Species', '10090', (91, 95))	('Mx1', 'Gene', (67, 70))	('mice', 'Species', '10090', (27, 31))	('Rosa26', 'Gene', '14910', (78, 84))	('Fli1fl/+', 'Var', (18, 26))	('Rosa26', 'Gene', (78, 84))	('induce', 'Reg', (99, 105))	('Mx1', 'Gene', '17857', (67, 70))
298913	25591392	The translocations in systemic organs were examined in three mice, and both Ewsr1-Fli1 and Fli1-Ewsr1 translocations were detected in all the organs examined (Fig.	('mice', 'Species', '10090', (61, 65))	('Fli1-Ewsr1', 'Var', (91, 101))	('detected', 'Reg', (122, 130))
298915	25591392	When Cre recombinase was inducibly expressed by tamoxifen or polyIpolyC administration in a Rosa26-CreER or Mx1-Cre background, respectively, both Ewsr1-Fli1 and Fli1-Ewsr1 translocations were observed (four mice each) (Fig.	('Rosa26', 'Gene', '14910', (92, 98))	('observed', 'Reg', (193, 201))	('translocations', 'Reg', (173, 187))	('polyIpolyC administration', 'Var', (61, 86))	('Mx1', 'Gene', '17857', (108, 111))	('Rosa26', 'Gene', (92, 98))	('tamoxifen', 'Chemical', 'MESH:D013629', (48, 57))	('mice', 'Species', '10090', (208, 212))	('Fli1-Ewsr1', 'Var', (162, 172))	('Mx1', 'Gene', (108, 111))
298918	25591392	The Ewsr1-Fli1 fusion was detected in all the embryonic organs examined, and the expression of the fusion gene was decreased in bone and liver of the adult mice.	('fusion', 'Var', (15, 21))	('Ewsr1-Fli1', 'Gene', (4, 14))	('decreased', 'NegReg', (115, 124))	('mice', 'Species', '10090', (156, 160))	('expression', 'MPA', (81, 91))
298924	25591392	The heart weight/body weight ratio as well as heart weight itself of EFCC mice was significantly greater than that of control mice from 31 to 42 weeks (Fig 4C, Table 1).	('heart weight/body weight ratio', 'CPA', (4, 34))	('EFCC', 'Var', (69, 73))	('mice', 'Species', '10090', (126, 130))	('EFCC', 'Chemical', '-', (69, 73))	('heart', 'MPA', (46, 51))	('greater', 'PosReg', (97, 104))	('mice', 'Species', '10090', (74, 78))
298931	25591392	Consistent with the pathological findings, echocardiographic analysis revealed reduced wall thickness, significant fractional shortening and decreased ejection fraction in EFCC mice (Fig.	('EFCC', 'Var', (172, 176))	('reduced', 'NegReg', (79, 86))	('EFCC', 'Chemical', '-', (172, 176))	('decreased', 'NegReg', (141, 150))	('wall', 'MPA', (87, 91))	('decreased ejection fraction', 'Phenotype', 'HP:0012664', (141, 168))	('ejection fraction', 'MPA', (151, 168))	('mice', 'Species', '10090', (177, 181))	('fractional', 'MPA', (115, 125))
298932	25591392	In contrast, there was no significant difference in blood pressure, heart rate or diastolic dimension between EFCC and wild-type mice (Table 2).	('EFCC', 'Var', (110, 114))	('diastolic dimension', 'MPA', (82, 101))	('mice', 'Species', '10090', (129, 133))	('EFCC', 'Chemical', '-', (110, 114))
298939	25591392	Indeed, a TUNEL assay using the cardiac sections showed significantly increased apoptosis in EFCC mice compared to wild-type (Fig.	('EFCC', 'Var', (93, 97))	('increased', 'PosReg', (70, 79))	('EFCC', 'Chemical', '-', (93, 97))	('apoptosis', 'CPA', (80, 89))	('mice', 'Species', '10090', (98, 102))
298941	25591392	The Annexin V/PI flow cytometry analysis showed increases of both early and late apoptosis as well as necrosis in cardiac myocytes by Ewsr1-Fli1 expression (Fig.	('expression', 'Var', (145, 155))	('necrosis', 'Disease', (102, 110))	('increases', 'PosReg', (48, 57))	('Annexin V', 'Gene', (4, 13))	('necrosis', 'Disease', 'MESH:D009336', (102, 110))	('Annexin V', 'Gene', '11747', (4, 13))	('Ewsr1-Fli1', 'Gene', (134, 144))
298944	25591392	6D), suggesting that Ewsr1-Fli1 may also play some role in cardiac fibrosis.	('Ewsr1-Fli1', 'Var', (21, 31))	('play', 'Reg', (41, 45))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (59, 75))	('cardiac fibrosis', 'Disease', (59, 75))
298955	25591392	Therefore, when chromosomal translocation between Ewsr1 and Fli1 is efficiently induced in eSZ cells, Ewing's sarcoma can develop in a certain cohort using the current translocation model.	("Ewing's sarcoma", 'Disease', (102, 117))	('Ewsr1', 'Gene', (50, 55))	('chromosomal translocation', 'Var', (16, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (102, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('Fli1', 'Gene', (60, 64))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (102, 117))
298957	25591392	Perhaps eSZ cell-specific Cre expression may enable the induction of Ewing's sarcoma by somatic Ewsr1 and Fli1 translocation, and efficient Cre expression in the specific spatiotemporal manner in the eSZ cell may be achieved using the promoter/enhancer elements of Gdf5 or Erg genes.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (69, 84))	("Ewing's sarcoma", 'Disease', (69, 84))	('translocation', 'Var', (111, 124))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (69, 84))	('Gdf5', 'Gene', '14563', (265, 269))	('Ewsr1', 'Gene', (96, 101))	('Erg', 'Gene', '13876', (273, 276))	('Fli1', 'Gene', (106, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('Erg', 'Gene', (273, 276))	('Gdf5', 'Gene', (265, 269))
298959	25591392	Activation of the Casp3 promoter by EWS-FLI1 was reported, and the activation of caspase 3-dependent signals may be responsible for apoptotic processes in mouse embryonic fibroblasts (MEFs) with ectopic Ews-Fli1 expression.	('Ews', 'Gene', (203, 206))	('EWS-FLI1', 'Gene', (36, 44))	('Casp3', 'Gene', '12367', (18, 23))	('caspase 3', 'Gene', '12367', (81, 90))	('activation', 'PosReg', (67, 77))	('apoptotic processes', 'CPA', (132, 151))	('Ews', 'Gene', '14030', (203, 206))	('mouse', 'Species', '10090', (155, 160))	('Casp3', 'Gene', (18, 23))	('Activation', 'PosReg', (0, 10))	('ectopic', 'Var', (195, 202))	('caspase 3', 'Gene', (81, 90))	('MEFs', 'CellLine', 'CVCL:9115', (184, 188))
298960	25591392	Indeed, Ews-Fli1 expression in cardiac myocytes induced apoptotic cell death, though activation of caspase 3 was not detected in cardiac myocytes unlike in MEFs (data not shown).	('caspase 3', 'Gene', '12367', (99, 108))	('Ews', 'Gene', (8, 11))	('expression', 'Var', (17, 27))	('caspase 3', 'Gene', (99, 108))	('MEFs', 'CellLine', 'CVCL:9115', (156, 160))	('Ews', 'Gene', '14030', (8, 11))	('induced', 'Reg', (48, 55))	('apoptotic cell death', 'CPA', (56, 76))
298965	25591392	The cell type-specific epigenetic status may modulate growth inhibitory and tumorigenic activities of EWS-FLI1.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('growth inhibitory', 'CPA', (54, 71))	('tumor', 'Disease', (76, 81))	('EWS-FLI1', 'Gene', (102, 110))	('epigenetic status', 'Var', (23, 40))	('modulate', 'Reg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
298968	25591392	Interestingly, EWS-FLI1 enhanced COL1A1 expression in human cardiac fibroblasts, suggesting that it might accelerate fibrotic processes in cardiomyopathy.	('expression', 'MPA', (40, 50))	('COL1A1', 'Gene', (33, 39))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (139, 153))	('cardiomyopathy', 'Disease', 'MESH:D009202', (139, 153))	('accelerate', 'PosReg', (106, 116))	('COL1A1', 'Gene', '1277', (33, 39))	('enhanced', 'PosReg', (24, 32))	('EWS-FLI1', 'Var', (15, 23))	('cardiomyopathy', 'Disease', (139, 153))	('human', 'Species', '9606', (54, 59))	('fibrotic processes', 'CPA', (117, 135))
298969	25591392	A number of transcription factors are associated with the development and maintenance of cardiac myocytes, and mutations in these factors affect cardiac homeostasis, structure and functions.	('mutations', 'Var', (111, 120))	('cardiac homeostasis', 'Disease', 'MESH:D006331', (145, 164))	('affect', 'Reg', (138, 144))	('functions', 'MPA', (180, 189))	('structure', 'MPA', (166, 175))	('cardiac homeostasis', 'Disease', (145, 164))
298970	25591392	Over-expression of E2F6 activates gene expression in myocardium and induces dilated cardiomyopathy in mice.	('induces', 'Reg', (68, 75))	('mice', 'Species', '10090', (102, 106))	('E2F6', 'Gene', '50496', (19, 23))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (84, 98))	('gene expression', 'MPA', (34, 49))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (76, 98))	('dilated cardiomyopathy', 'Disease', (76, 98))	('E2F6', 'Gene', (19, 23))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (76, 98))	('Over-expression', 'Var', (0, 15))	('activates', 'PosReg', (24, 33))
298971	25591392	Moreover, mutations in NKX2-5 and PDRM16 were found associated with human congenital dilated cardiomyopathy.	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (85, 107))	('dilated cardiomyopathy', 'Disease', (85, 107))	('human', 'Species', '9606', (68, 73))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (93, 107))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (85, 107))	('NKX2-5', 'Gene', (23, 29))	('associated', 'Reg', (52, 62))	('NKX2-5', 'Gene', '1482;4824', (23, 29))	('mutations', 'Var', (10, 19))	('PDRM16', 'Gene', (34, 40))
298978	25591392	The resultant Ewsr1fl/+ and Fli1fl/+ mice were further crossed with CAG-Cre, Mx1-Cre or Rosa26-CreER mice.	('Rosa26', 'Gene', '14910', (88, 94))	('Mx1', 'Gene', '17857', (77, 80))	('Mx1', 'Gene', (77, 80))	('Rosa26', 'Gene', (88, 94))	('Fli1fl/+', 'Var', (28, 36))	('mice', 'Species', '10090', (101, 105))	('mice', 'Species', '10090', (37, 41))
298981	25591392	The BAC clones, RPCI-23 64E17 downstream from Ewsr1 on mouse chromosome 11 and RPCI-23 218O31 upstream from Fli1 on chromosome 9 were purchased from Invitrogen (Carlsbad, CA) for FISH analysis.	('mouse', 'Species', '10090', (55, 60))	('RPCI-23 64E17 downstream', 'Var', (16, 40))	('RPCI-23 218O31', 'Var', (79, 93))
299019	26823986	A bone marrow biopsy was performed, which revealed a donor derived acute myeloid leukemia (AML), with 22% blasts showing an immature myeloid phenotype by flow cytometry (CD13+, CD34+, HLA-DR+, CD4dim+, CD64dim+, and CD33 partial dim+), negative for CD10 and CD19, both of which had been expressed in the prior B-ALL.	('CD33', 'Gene', (216, 220))	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('ALL', 'Phenotype', 'HP:0006721', (312, 315))	('CD10', 'Gene', '4311', (249, 253))	('B-ALL', 'Phenotype', 'HP:0004812', (310, 315))	('CD19', 'Gene', '930', (258, 262))	('CD34', 'Gene', (177, 181))	('CD10', 'Gene', (249, 253))	('acute myeloid leukemia', 'Disease', (67, 89))	('CD13', 'Gene', (170, 174))	('HLA-DR+', 'Var', (184, 191))	('AML', 'Disease', 'MESH:D015470', (91, 94))	('CD34', 'Gene', '947', (177, 181))	('donor', 'Species', '9606', (53, 58))	('CD4dim+', 'Var', (193, 200))	('AML', 'Disease', (91, 94))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (67, 89))	('AML', 'Phenotype', 'HP:0004808', (91, 94))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (73, 89))	('CD33', 'Gene', '945', (216, 220))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (67, 89))	('CD19', 'Gene', (258, 262))	('CD13', 'Gene', '290', (170, 174))
299026	26823986	By immunohistochemistry, the atypical cells showed an immature myeloid/monocytic immunophenotype: CD34 focal+, CD43+, MPO focal+, CD117 focal+, CD68 weak+, CD163 focal+, PAX5-, CD56-, TdT-, and CD79a focal weak+ (Figure 3).	('CD68', 'Gene', '968', (144, 148))	('CD34', 'Gene', (98, 102))	('TdT', 'Gene', (184, 187))	('CD43', 'Gene', '6693', (111, 115))	('CD163', 'Gene', '9332', (156, 161))	('PAX5', 'Gene', '5079', (170, 174))	('CD68', 'Gene', (144, 148))	('CD79a', 'Gene', '973', (194, 199))	('CD163', 'Gene', (156, 161))	('CD34', 'Gene', '947', (98, 102))	('CD117', 'Gene', '3815', (130, 135))	('TdT', 'Gene', '1791', (184, 187))	('CD56', 'Gene', (177, 181))	('CD79a', 'Gene', (194, 199))	('MPO focal+', 'Var', (118, 128))	('CD43', 'Gene', (111, 115))	('CD56', 'Gene', '4684', (177, 181))	('PAX5', 'Gene', (170, 174))	('CD117', 'Gene', (130, 135))
299038	26823986	The use of molecular testing for chimerism, including short tandem repeats (STR) and variable number of tandem repeats (VNTR), has improved the ability to distinguish host from donor derive neoplasms.	('donor', 'Species', '9606', (177, 182))	('neoplasms', 'Disease', 'MESH:D009369', (190, 199))	('neoplasms', 'Disease', (190, 199))	('improved', 'PosReg', (131, 139))	('neoplasm', 'Phenotype', 'HP:0002664', (190, 198))	('short tandem repeats', 'Var', (54, 74))	('neoplasms', 'Phenotype', 'HP:0002664', (190, 199))
299045	26823986	Shortened telomeres are associated with genomic instability and may favor leukemic transformation.	('leukemic', 'Disease', (74, 82))	('associated', 'Reg', (24, 34))	('genomic instability', 'MPA', (40, 59))	('Shortened', 'Var', (0, 9))	('leukemic', 'Disease', 'MESH:D007938', (74, 82))	('Shortened telomeres', 'Phenotype', 'HP:0031413', (0, 19))	('favor', 'PosReg', (68, 73))
299085	25621034	Hyperintensive signals on T1WI and T2WI were observed in necrotic and cystic areas.	('necrotic', 'Disease', 'MESH:D009336', (57, 65))	('T2WI', 'Var', (35, 39))	('necrotic', 'Disease', (57, 65))
299138	25621034	On T1WI and T2WI, invasive fibroma tends to present with a low-intensity signal due to the high content of fibrous tissues and is gradually enhanced on contrast-enhanced scans.	('fibroma', 'Phenotype', 'HP:0010614', (27, 34))	('T1WI', 'Var', (3, 7))	('low-intensity', 'NegReg', (59, 72))	('enhanced', 'PosReg', (140, 148))	('invasive fibroma', 'Disease', 'MESH:D005350', (18, 34))	('T2WI', 'Var', (12, 16))	('invasive fibroma', 'Disease', (18, 34))
299143	25621034	On T1WI, the tumor exhibits an intensity similar to that of muscle.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('T1WI', 'Var', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
299160	29261159	We were able to characterize a small atypical population consisting of 0.3% of immature erythrocyte precursors (CD36+, Histocompatibility Leukocyte Antigen-D Related (HLADR+), CD71+, CD45-, CD105a+, CD117 weak with abnormal size and complexity, and aberrant CD33 weak co-expression) (Figure 2A).	('CD36+', 'Var', (112, 117))	('CD45', 'Gene', (183, 187))	('CD36', 'Species', '42374', (112, 116))	('CD71', 'Gene', '7037', (176, 180))	('CD33', 'Gene', '945', (258, 262))	('CD33', 'Gene', (258, 262))	('CD71', 'Gene', (176, 180))	('CD117 weak', 'Var', (199, 209))	('co-expression', 'Interaction', (268, 281))	('CD45', 'Gene', '5788', (183, 187))	('CD105a+', 'Var', (190, 197))	('aberrant', 'Var', (249, 257))
299165	29261159	Standardized eight-color FC demonstrated a homogeneous population of erythroid lineage, with the expression of CD36+ weak, CD45+, CD105a+, CD71+, CD117+ weak, CD34+ weak, and CD33+ weak in 100% of the cells.	('CD71', 'Gene', '7037', (139, 143))	('CD34+ weak', 'Var', (159, 169))	('CD45', 'Gene', '5788', (123, 127))	('erythroid lineage', 'CPA', (69, 86))	('CD71', 'Gene', (139, 143))	('CD117+ weak', 'Var', (146, 157))	('CD105a+', 'Var', (130, 137))	('CD45', 'Gene', (123, 127))	('CD36', 'Species', '42374', (111, 115))	('CD33', 'Gene', '945', (175, 179))	('CD33', 'Gene', (175, 179))	('CD36+ weak', 'Var', (111, 121))
299167	29261159	Based on these findings, the IHQ study was completed with the specific markers glycophorin A (Dako M0819, Clone JC 159) and CD71 (Dako f0829, Clone BER-T9), which were specifically indicated for the study of this case, confirming the intense positivity of the proliferating cell population and establishing the erythroid nature of the tumor (Figure 3).	('CD71', 'Gene', (124, 128))	('glycophorin A', 'Gene', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('glycophorin A', 'Gene', '2993', (79, 92))	('Dako', 'Var', (130, 134))	('CD71', 'Gene', '7037', (124, 128))	('tumor', 'Disease', (335, 340))
299170	29261159	However, minimal residual disease was detected by high sensitivity standardized eight-color FC, showing the presence of 0.13% erythroid blasts with a similar phenotype to diagnosis (CD36++, CD45+ weak, CD105a+, CD71+, CD117+, CD34+ weak, CD33+ weak).	('CD71', 'Gene', '7037', (211, 215))	('CD36', 'Species', '42374', (182, 186))	('CD117+', 'Var', (218, 224))	('CD45', 'Gene', (190, 194))	('CD33', 'Gene', '945', (238, 242))	('CD33', 'Gene', (238, 242))	('CD71', 'Gene', (211, 215))	('CD45', 'Gene', '5788', (190, 194))	('CD34+ weak', 'Var', (226, 236))	('CD36++', 'Var', (182, 188))	('CD105a+', 'Var', (202, 209))
299172	29261159	The BM aspirate showed a massive infiltration of 90% erythroid blasts (CD36++, CD45+ weak, CD105a+, CD71+, CD117+ weak, CD34+ weak, CD33-).	('CD45', 'Gene', (79, 83))	('CD71', 'Gene', (100, 104))	('CD33', 'Gene', '945', (132, 136))	('CD33', 'Gene', (132, 136))	('CD45', 'Gene', '5788', (79, 83))	('CD117+ weak', 'Var', (107, 118))	('CD36++', 'Var', (71, 77))	('CD34+ weak', 'Var', (120, 130))	('CD105a+', 'Var', (91, 98))	('CD71', 'Gene', '7037', (100, 104))	('CD36', 'Species', '42374', (71, 75))
299233	26958527	Poor prognostic factors are: Size >5 cm, male sex, age >20 years, extensive tumor necrosis, large number of mitotic figures (>10/10 high-powered fields), neurovascular invasion, and SYT-SSX1 variant.	('SSX1', 'Gene', (186, 190))	('variant', 'Var', (191, 198))	('tumor necrosis', 'Disease', 'MESH:D009336', (76, 90))	('neurovascular invasion', 'CPA', (154, 176))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('SYT', 'Gene', '6857', (182, 185))	('SYT', 'Gene', (182, 185))	('tumor necrosis', 'Disease', (76, 90))	('SSX1', 'Gene', '6756', (186, 190))
299333	26042220	One patient had Li-Fraumeni syndrome, which is characterized by a p53 mutation, resulting in loss of tumor suppression.	('p53', 'Gene', '7157', (66, 69))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (16, 36))	('loss', 'NegReg', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('patient', 'Species', '9606', (4, 11))	('Li-Fraumeni syndrome', 'Disease', (16, 36))	('mutation', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('p53', 'Gene', (66, 69))
299347	26042220	Radiotherapy is often administered when surgery is unfeasible or in an adjunctive setting, either pre- or post-operatively, especially in high-grade tumors or in the presence of positive surgical margins.	('high-grade', 'Var', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))
299405	25591040	Patients were required to have a World Health Organisation (WHO) performance status of 0 or 1, an adequate haematological function (haemoglobin >=9 g/dL, absolute neutrophil count (ANC) >= 1.5 x 103/mm3, platelets >=100.000/mm3), an adequate hepatic function (serum total bilirubin <= upper limit of normal (ULN), serum total ALP <= 2.5 x ULN, serum AST and ALT <= 2.5 x ULN), and an adequate renal function (glomerular filtration rate (calculated by Cockroft-Gault) >= 60 mL/min).	('hepatic function', 'MPA', (242, 258))	('renal function', 'MPA', (393, 407))	('ALT', 'MPA', (358, 361))	('AST', 'Gene', '26503', (350, 353))	('>=9', 'Var', (144, 147))	('serum total ALP', 'MPA', (314, 329))	('Patients', 'Species', '9606', (0, 8))	('AST', 'Gene', (350, 353))
299475	25591040	Gemcitabine is also being evaluated in the combination with the anti-angiogenetic agent pazopanib in several phase I and II trials (NCT01593748, NCT01532687, and NCT01442662); however, no data is available yet.	('NCT01442662', 'Var', (162, 173))	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('NCT01593748', 'Var', (132, 143))	('pazopanib', 'Chemical', 'MESH:C516667', (88, 97))	('NCT01532687', 'Var', (145, 156))
299508	23213546	In case of KSHV, the viral latency seems to be very important for the maintenance of PEL, since the loss of the viral episomes leads to PEL cell death.	('loss', 'Var', (100, 104))	('leads to', 'Reg', (127, 135))	('KSHV', 'Species', '37296', (11, 15))	('PEL', 'Phenotype', 'HP:0030069', (85, 88))	('PEL', 'Phenotype', 'HP:0030069', (136, 139))	('PEL cell death', 'CPA', (136, 150))	('viral episomes', 'Protein', (112, 126))
299526	23213546	KSHV induces LYVE-1, reelin, follistatin, and desmoplakin as well as PROX1.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('reelin', 'Protein', (21, 27))	('LYVE-1', 'Gene', (13, 19))	('induces', 'Reg', (5, 12))
299535	23213546	KSHV causes two B-cell-originated lymphoproliferative diseases: MCD and PEL.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('PEL', 'Phenotype', 'HP:0030069', (72, 75))	('causes', 'Reg', (5, 11))	('MCD', 'Disease', (64, 67))	('PEL', 'Disease', (72, 75))	('lymphoproliferative diseases', 'Phenotype', 'HP:0005523', (34, 62))	('MCD', 'Disease', 'MESH:D012514', (64, 67))	('lymphoproliferative diseases', 'Disease', 'MESH:D008232', (34, 62))	('lymphoproliferative diseases', 'Disease', (34, 62))
299571	23213546	For example, CD79A (NM_001738) and B (NM_000626), which are components of B-cell receptor and contain cytoplasmic immunoreceptor tyrosine-based activation motifs were highly expressed in BL without doubt.	('tyrosine', 'Chemical', 'MESH:D014443', (129, 137))	('CD79A', 'Gene', '973', (13, 18))	('NM_001738', 'Var', (20, 29))	('CD79A', 'Gene', (13, 18))	('NM_000626', 'Var', (38, 47))
299576	23213546	Focused on p21Cip1/WAF1 (NM_000389), IL15 receptor alpha (NM_002189) and HLA-DR (HLA-DRA, NM_019111; HLA-DRB3, AF192259), which are reported to increase by EBV infection, this gene expression was indeed higher in B cell originated PEL and BL with a few exceptions in our analysis (Figure 1, Table 1).	('WAF1', 'Gene', (19, 23))	('HLA-DR', 'Gene', '3122', (101, 107))	('PEL', 'Phenotype', 'HP:0030069', (231, 234))	('higher', 'PosReg', (203, 209))	('HLA-DR', 'Gene', (101, 107))	('HLA-DR', 'Gene', '3122', (81, 87))	('EBV infection', 'Disease', 'MESH:D020031', (156, 169))	('HLA-DRB3', 'Gene', '3125', (101, 109))	('expression', 'MPA', (181, 191))	('HLA-DR', 'Gene', '3122', (73, 79))	('p21Cip1', 'Gene', '1026', (11, 18))	('EBV infection', 'Disease', (156, 169))	('NM_002189', 'Var', (58, 67))	('HLA-DR', 'Gene', (81, 87))	('HLA-DRA', 'Gene', '3122', (81, 88))	('HLA-DRA', 'Gene', (81, 88))	('p21Cip1', 'Gene', (11, 18))	('HLA-DRB3', 'Gene', (101, 109))	('HLA-DR', 'Gene', (73, 79))	('WAF1', 'Gene', '1026', (19, 23))	('increase', 'PosReg', (144, 152))	('NM_000389', 'Var', (25, 34))
299578	23213546	Paying attention to genes characteristic to MCD, a naive B-cell marker: surface Ig lambda (XM_066332), B-cell specific markers: PAX 5 (NM_016734), Oct2 (XM_068123), and a GC B-cell marker: BCL6 (NM_001706) were higher in BL cell lines and preplasma cell markers; IRF4/MUM1 (NM_002460) and PRDM1/BLIMP1 (NM_001198) are definitely higher in PEL cells, assuring that BL should be derived from GC B cell and PEL from post-GC plasmablasts (Figure 2, Table 2).	('Oct2', 'Gene', (147, 151))	('PRDM1', 'Gene', '639', (289, 294))	('NM_002460', 'Var', (274, 283))	('PRDM1', 'Gene', (289, 294))	('MUM1', 'Gene', (268, 272))	('MCD', 'Disease', 'MESH:D012514', (44, 47))	('MCD', 'Disease', (44, 47))	('BCL6', 'Gene', (189, 193))	('GC B', 'Gene', (171, 175))	('IRF4', 'Gene', '3662', (263, 267))	('BLIMP1', 'Gene', '639', (295, 301))	('PAX 5', 'Gene', (128, 133))	('GC B', 'Gene', '2629', (171, 175))	('PEL', 'Phenotype', 'HP:0030069', (404, 407))	('PEL', 'Phenotype', 'HP:0030069', (339, 342))	('BCL6', 'Gene', '604', (189, 193))	('IRF4', 'Gene', (263, 267))	('GC B', 'Gene', (390, 394))	('Oct2', 'Gene', '5452', (147, 151))	('BLIMP1', 'Gene', (295, 301))	('PAX 5', 'Gene', '5079', (128, 133))	('GC B', 'Gene', '2629', (390, 394))	('MUM1', 'Gene', '84939', (268, 272))
299601	33622311	Surgical removal of the tumor with wide safety margins is crucial as minor safety margins are associated with higher rates of local DFSP recurrence.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('DFSP', 'Disease', (132, 136))	('DFSP', 'Disease', 'MESH:D018223', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('minor', 'Var', (69, 74))
299642	32264965	Targeting epigenetics in sarcomas through EZH2 inhibition Soft-tissue sarcomas represent a heterogeneous group of diseases with distinct genetic and clinical features accounting for up to 1% of cancer in adults and 15% of cancer in children.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('inhibition', 'NegReg', (47, 57))	('EZH2', 'Gene', '2146', (42, 46))	('EZH2', 'Gene', (42, 46))	('Soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (58, 78))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('cancer', 'Disease', (222, 228))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('children', 'Species', '9606', (232, 240))	('sarcomas', 'Disease', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('epigenetics', 'Var', (10, 21))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('sarcomas', 'Disease', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))
299658	32264965	Loss of INI1 function leads to elevated expression and recruitment of EZH2 to target genes that become trimethylated on H3K27 and repressed, which results in the upregulation of several oncogenic signaling pathways, including Sonic Hedgehog, Wnt/beta-Catenin, and MYC.	('recruitment', 'MPA', (55, 66))	('expression', 'MPA', (40, 50))	('INI1', 'Gene', (8, 12))	('beta-Catenin', 'Gene', '1499', (246, 258))	('INI1', 'Gene', '6598', (8, 12))	('upregulation', 'PosReg', (162, 174))	('MYC', 'Gene', (264, 267))	('oncogenic signaling pathways', 'Pathway', (186, 214))	('Loss', 'NegReg', (0, 4))	('trimethylated', 'Var', (103, 116))	('EZH2', 'Gene', '2146', (70, 74))	('elevated', 'PosReg', (31, 39))	('Sonic Hedgehog', 'Gene', '6469', (226, 240))	('EZH2', 'Gene', (70, 74))	('Sonic Hedgehog', 'Gene', (226, 240))	('MYC', 'Gene', '4609', (264, 267))	('beta-Catenin', 'Gene', (246, 258))
299659	32264965	INI1 loss was first identified in malignant rhabdoid tumors (MRTs) which are rare and aggressive cancers that principally occur in childhood and can arise in various locations, mainly the kidney, brain, and soft tissues.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('malignant rhabdoid tumors', 'Disease', (34, 59))	('aggressive cancers', 'Disease', (86, 104))	('aggressive cancers', 'Disease', 'MESH:D009369', (86, 104))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('INI1', 'Gene', (0, 4))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (34, 59))	('INI1', 'Gene', '6598', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('loss', 'Var', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))
299660	32264965	MRTs harbor recurrent and specific biallelic-inactivating mutations or deletions of INI1 located in the 22q11.2 region.	('deletions', 'Var', (71, 80))	('INI1', 'Gene', (84, 88))	('INI1', 'Gene', '6598', (84, 88))	('biallelic-inactivating mutations', 'Var', (35, 67))
299663	32264965	Preclinical data showed that EZH2 inhibition leads to specific repression of cellular H3K27 methylation and induces apoptotic death of INI1-negative MRT cells.	('INI1', 'Gene', (135, 139))	('repression', 'NegReg', (63, 73))	('apoptotic death', 'CPA', (116, 131))	('INI1', 'Gene', '6598', (135, 139))	('cellular H3K27', 'Protein', (77, 91))	('inhibition', 'Var', (34, 44))	('induces', 'Reg', (108, 115))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))	('methylation', 'MPA', (92, 103))	('H3K27', 'Protein', (86, 91))
299696	32264965	Together with the recent demonstration that EZH2 inhibition enhances ICI efficacy in pre-clinical models of melanoma and other solid tumors, these findings pave the way for clinical trials combining ICI with tazemetostat in epithelioid sarcoma and other INI1-negative solid tumors.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('solid tumors', 'Disease', 'MESH:D009369', (127, 139))	('solid tumors', 'Disease', (268, 280))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('inhibition', 'Var', (49, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (224, 243))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('solid tumors', 'Disease', 'MESH:D009369', (268, 280))	('melanoma', 'Disease', (108, 116))	('tazemetostat', 'Chemical', 'MESH:C000593333', (208, 220))	('INI1', 'Gene', (254, 258))	('INI1', 'Gene', '6598', (254, 258))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('EZH2', 'Gene', (44, 48))	('EZH2', 'Gene', '2146', (44, 48))	('epithelioid sarcoma', 'Disease', (224, 243))	('solid tumors', 'Disease', (127, 139))	('enhances', 'PosReg', (60, 68))
299735	31600976	The CAIX inhibitor FC12-520A gave the strongest heat decrease response.	('heat', 'MPA', (48, 52))	('heat decrease response', 'Phenotype', 'HP:0002046', (48, 70))	('CAIX', 'Gene', (4, 8))	('FC12-520A', 'Var', (19, 28))	('CAIX', 'Gene', '768', (4, 8))
299739	31600976	Although FC12-520A leads to the strongest response amongst the CAIX inhibitors all CAIX inhibitors show a heat flow reduction in a similar range, demonstrating consistency of CAIX inhibition.	('CAIX', 'Gene', '768', (63, 67))	('CAIX', 'Gene', '768', (83, 87))	('CAIX', 'Gene', (175, 179))	('response', 'MPA', (42, 50))	('reduction', 'NegReg', (116, 125))	('FC12-520A', 'Var', (9, 18))	('CAIX', 'Gene', '768', (175, 179))	('CAIX', 'Gene', (63, 67))	('CAIX', 'Gene', (83, 87))	('heat flow', 'MPA', (106, 115))
299766	31600976	Tissue slices were cultured in TUM medium at 37  C for 24 h. Following this initial incubation period the medium was changed and specific experimental inhibitors (CAIX inhibitors: FC8-325A, FC8-207A, FC12-520A and AQP1 inhibitor TEA (Merck, Sigma-Aldrich Chemie GmbH Buchs, Switzerland) added to final concentrations of 500 muM.	('TEA', 'Chemical', 'MESH:C488288', (229, 232))	('AQP1', 'Gene', (214, 218))	('CAIX', 'Gene', '768', (163, 167))	('AQP1', 'Gene', '358', (214, 218))	('FC12-520A', 'Var', (200, 209))	('CAIX', 'Gene', (163, 167))
299781	30155245	Selective pharmacological inhibition of the seven known classes of 5-HT receptors in sarcoma and breast cancer cells resulted in dose dependent decreases in tumor cell viability, activation of the p53 DNA damage pathway, suppression of MAPK activity, and significantly reduced tumor volume in an in ovo model.	('activity', 'MPA', (241, 249))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('sarcoma', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('inhibition', 'Var', (26, 36))	('suppression', 'NegReg', (221, 232))	('p53', 'Gene', '7157', (197, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('reduced', 'NegReg', (269, 276))	('p53', 'Gene', (197, 200))	('MAPK', 'Pathway', (236, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', (157, 162))	('decreases', 'NegReg', (144, 153))	('5-HT', 'Chemical', 'MESH:D012701', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('activation', 'PosReg', (179, 189))	('breast cancer', 'Disease', (97, 110))
299843	30155245	We next sought to determine if the presence of serotonin alters intracellular signaling of the cancer cell lines.	('presence', 'Var', (35, 43))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('intracellular signaling', 'MPA', (64, 87))	('serotonin', 'Chemical', 'MESH:D012701', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('alters', 'Reg', (57, 63))
299853	30155245	To expand our in vitro results into an in vivo xenograft tumor model, we subjected CosB hemangiosarcoma tumors grown on CAMs to daily treatments of the 5-HT7 antagonist (5x10-9 grams/day) or a control sham.	('5x10-9 grams/day', 'Var', (170, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('hemangiosarcoma tumors', 'Disease', 'MESH:D006394', (88, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('CosB hemangiosarcoma', 'Disease', (83, 103))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('CosB hemangiosarcoma', 'Disease', 'MESH:D006394', (83, 103))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('angiosarcoma', 'Phenotype', 'HP:0200058', (91, 103))	('hemangiosarcoma tumors', 'Disease', (88, 110))	('5-HT', 'Chemical', 'MESH:D012701', (152, 156))
299863	30155245	No difference was found in tumor staging or hormone receptor status between users of SSRIs and non-users; however, in patients with late stage breast cancer, use of SSRIs was significantly associated with increased tumor proliferative index (2.3-fold increase) compared to patients who were non-users of SSRIs (P=0.03) (Table V, Fig.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('SSRIs', 'Var', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patients', 'Species', '9606', (273, 281))	('breast cancer', 'Disease', (143, 156))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('patients', 'Species', '9606', (118, 126))	('increased', 'PosReg', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('hormone receptor', 'Gene', (44, 60))	('hormone receptor', 'Gene', '3164', (44, 60))
299879	30155245	In the current study, we did not observe serotonin-mediated increases in tumor cell proliferation for a panel of breast cancer, soft tissue sarcoma, and bone sarcoma cells, however the addition of this neurotransmitter did indeed enhance the activating phosphorylation of key mitogenic regulators in cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('enhance', 'PosReg', (230, 237))	('breast cancer', 'Disease', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Disease', (120, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (128, 147))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (128, 147))	('bone sarcoma', 'Disease', 'MESH:D001847', (153, 165))	('soft tissue sarcoma', 'Disease', (128, 147))	('cancer', 'Disease', (300, 306))	('addition', 'Var', (185, 193))	('bone sarcoma', 'Phenotype', 'HP:0002669', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('activating phosphorylation', 'MPA', (242, 268))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', (73, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('serotonin', 'Chemical', 'MESH:D012701', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('bone sarcoma', 'Disease', (153, 165))	('cancer', 'Disease', 'MESH:D009369', (300, 306))
299883	30155245	The current study individually blocked the activation of each known 5-HT receptor using highly selective pharmacological antagonists, revealing dose dependent decreases in tumor cell viability across most cell lines when treating with inhibitors of 5-HT1, 4, 5, 6 and 7.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('5-HT', 'Chemical', 'MESH:D012701', (249, 253))	('5-HT', 'Chemical', 'MESH:D012701', (68, 72))	('tumor', 'Disease', (172, 177))	('inhibitors', 'Var', (235, 245))	('5-HT1', 'Gene', (249, 254))	('decreases', 'NegReg', (159, 168))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
299886	30155245	Based on kinome-level profiling, the majority of 5-HT receptor antagonists reduced the activation of downstream signaling proteins involved in proliferation and survival.	('antagonists', 'Var', (63, 74))	('reduced', 'NegReg', (75, 82))	('5-HT', 'Chemical', 'MESH:D012701', (49, 53))	('5-HT', 'Protein', (49, 53))	('activation of downstream signaling proteins', 'MPA', (87, 130))	('proliferation', 'CPA', (143, 156))
299887	30155245	In contrast, inhibition of 5-HT3 (which had no effect on tumor cell viability in our assays) exhibited opposite results, resulting in increased activation of signaling proteins involved in proliferation and survival.	('signaling proteins', 'MPA', (158, 176))	('increased activation', 'PosReg', (134, 154))	('proliferation', 'CPA', (189, 202))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('5-HT', 'Chemical', 'MESH:D012701', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('5-HT3', 'Gene', (27, 32))	('tumor', 'Disease', (57, 62))
299896	30155245	Our findings from this report support the notion that SSRI use may contribute to enhanced tumor growth, given that we observed SSRIs were associated with a significantly increased breast tumor proliferative index in late stage cancer patients.	('SSRIs', 'Var', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('enhanced', 'PosReg', (81, 89))	('breast tumor', 'Disease', 'MESH:D001943', (180, 192))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('increased', 'PosReg', (170, 179))	('tumor', 'Disease', (187, 192))	('breast tumor', 'Disease', (180, 192))	('patients', 'Species', '9606', (234, 242))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('breast tumor', 'Phenotype', 'HP:0100013', (180, 192))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
299913	26034869	Furthermore, the presence of EWSR1 gene rearrangement correlated with strong keratin expression may suggest a myoepithelial carcinoma.	('keratin', 'Protein', (77, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('strong', 'PosReg', (70, 76))	('EWSR1', 'Gene', (29, 34))	('presence', 'Var', (17, 25))	('myoepithelial carcinoma', 'Disease', (110, 133))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (110, 133))	('EWSR1', 'Gene', '2130', (29, 34))
299920	26034869	FISH assays showed EWSR1 and FLI1 rearrangements in all cases.	('rearrangements', 'Var', (34, 48))	('FLI1', 'Gene', (29, 33))	('EWSR1', 'Gene', (19, 24))	('FLI1', 'Gene', '2313', (29, 33))	('EWSR1', 'Gene', '2130', (19, 24))
299988	26034869	Finally, while those features are suggestive of an adamantinoma-like EFT, molecular studies demonstrating rearrangements involving EWSR1 and FLI1 are required to make a definitive diagnosis.	('rearrangements', 'Var', (106, 120))	('FLI1', 'Gene', (141, 145))	('adamantinoma', 'Disease', (51, 63))	('EWSR1', 'Gene', (131, 136))	('FLI1', 'Gene', '2313', (141, 145))	('EWSR1', 'Gene', '2130', (131, 136))	('adamantinoma', 'Disease', 'MESH:D050398', (51, 63))
299996	26034869	The similarities extend at the molecular level, because soft tissue myoepithelial tumors often harbor rearrangements of EWSR1.	('EWSR1', 'Gene', '2130', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (68, 88))	('epithelial tumor', 'Phenotype', 'HP:0031492', (71, 87))	('harbor', 'Reg', (95, 101))	('myoepithelial tumors', 'Disease', (68, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('EWSR1', 'Gene', (120, 125))	('rearrangements', 'Var', (102, 116))
300017	26034869	While desmoplastic small round cell tumor also harbors translocations involving the EWSR1 gene, the fusion partner is WT1.	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (6, 41))	('translocations', 'Var', (55, 69))	('EWSR1', 'Gene', (84, 89))	('harbors', 'Reg', (47, 54))	('desmoplastic small round cell tumor', 'Disease', (6, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('EWSR1', 'Gene', '2130', (84, 89))
300022	26034869	In that circumstance, molecular diagnostics are once again critical, because synovial sarcoma is characterized by translocations involving the SYT gene.	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('synovial sarcoma', 'Disease', (77, 93))	('translocations', 'Var', (114, 128))	('SYT', 'Gene', '6857', (143, 146))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (77, 93))	('synovial sarcoma', 'Disease', 'MESH:D013584', (77, 93))	('SYT', 'Gene', (143, 146))
300030	22312368	The tumors were mainly composed of small blue cells which by immunohistochemical were positive for neural markers, and FISH revealed the translocation 22q12 for the EWSR1 gene.	('EWSR1', 'Gene', '2130', (165, 170))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('translocation 22q12', 'Var', (137, 156))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('EWSR1', 'Gene', (165, 170))
300052	22312368	Fluorescent in situ hybridization analysis using the 22q12 LSI, EWSR1, Dual-Color Break-Apart Probe was performed on fresh tissue and showed 18 (29.5%) of the cells with the translocation pattern 22q12 for the EWSR1 gene.	('EWSR1', 'Gene', (210, 215))	('EWSR1', 'Gene', '2130', (64, 69))	('EWSR1', 'Gene', '2130', (210, 215))	('translocation pattern 22q12', 'Var', (174, 201))	('EWSR1', 'Gene', (64, 69))
300071	22312368	Fluorescent in situ hybridization analysis using the 22q12 LSI, EWSR1, Dual-Color Break-Apart Probe was performed on fresh tissue and showed 57 (95.0%) of the cells with the translocation pattern 22q12 for the EWSR1 gene (Figure 2(f)).	('translocation', 'Var', (174, 187))	('EWSR1', 'Gene', (210, 215))	('EWSR1', 'Gene', '2130', (64, 69))	('EWSR1', 'Gene', '2130', (210, 215))	('EWSR1', 'Gene', (64, 69))
300100	22312368	The differential was performed by morphology of the tumor cells which had stippled chromatin and pleomorphism whereas the lymphoid cells formed a uniform monotonous population with small dark nuclei in the background.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('stippled chromatin', 'Var', (74, 92))	('tumor', 'Disease', (52, 57))	('pleomorphism', 'Var', (97, 109))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
300101	22312368	Fluorescent in situ hybridization analysis using the 22q12 LSI, EWSR1, and Dual-Color Break-Apart Probe showed the translocation pattern 22q12 for the EWSR1 gene.	('EWSR1', 'Gene', (151, 156))	('EWSR1', 'Gene', '2130', (64, 69))	('EWSR1', 'Gene', '2130', (151, 156))	('22q12', 'Var', (137, 142))	('EWSR1', 'Gene', (64, 69))
300106	22312368	Approximately 90% of the translocations involving EWSR1 gene result in t(11; 22) translocation characteristic of EWS/PNET.	('EWSR1', 'Gene', '2130', (50, 55))	('result in', 'Reg', (61, 70))	('EWS', 'Gene', '2130', (50, 53))	('EWS', 'Gene', (50, 53))	('EWS', 'Gene', '2130', (113, 116))	('EWS', 'Gene', (113, 116))	('EWSR1', 'Gene', (50, 55))	('translocations', 'Var', (25, 39))
300118	31370385	The aRMS patient had multiple metastases at diagnosis and showed FAX3-FOXO1 fusion transcripts; she died 22 months after the diagnosis.	('RMS', 'Disease', (5, 8))	('RMS', 'Disease', 'MESH:D012208', (5, 8))	('fusion transcripts', 'Var', (76, 94))	('metastases', 'Disease', (30, 40))	('FOXO1', 'Gene', (70, 75))	('FOXO1', 'Gene', '2308', (70, 75))	('patient', 'Species', '9606', (9, 16))	('metastases', 'Disease', 'MESH:D009362', (30, 40))	('RMS', 'Phenotype', 'HP:0002859', (5, 8))
300134	31370385	An alveolar RMS (aRMS) case was examined for nested reverse transcription polymerase chain reaction (RT-PCR) of FAX3/ TKHR (FOXO1) fusion and FAX7/TKFR (FOXO1) fusion gene transcript.	('RMS', 'Disease', 'MESH:D012208', (12, 15))	('RMS', 'Phenotype', 'HP:0002859', (12, 15))	('RMS', 'Disease', (18, 21))	('RMS', 'Phenotype', 'HP:0002859', (18, 21))	('RMS', 'Disease', (12, 15))	('FAX7/TKFR', 'Var', (142, 151))	('FAX3/ TKHR', 'Gene', (112, 122))	('FOXO1', 'Gene', (124, 129))	('FOXO1', 'Gene', '2308', (124, 129))	('fusion', 'Var', (131, 137))	('FOXO1', 'Gene', (153, 158))	('FOXO1', 'Gene', '2308', (153, 158))	('RMS', 'Disease', 'MESH:D012208', (18, 21))
300196	31370385	Two characteristic cytogenetic changes: t(2;13)(q35;q14) resulting in PAX3-FHKR (FOXO1) fusion and t(1;13)(p13;q14) resulting in PAX7-FKHR (FOXO1) fusion: are identified in about 80% of aRMS cases, which allow aRMS to be distinguished from other types of round cell neoplasms and RMS.	('RMS', 'Disease', 'MESH:D012208', (187, 190))	('RMS', 'Disease', 'MESH:D012208', (211, 214))	('FOXO1', 'Gene', (81, 86))	('RMS', 'Phenotype', 'HP:0002859', (187, 190))	('neoplasms', 'Disease', (266, 275))	('RMS', 'Phenotype', 'HP:0002859', (211, 214))	('t(2;13)(q35;q14', 'Var', (40, 55))	('PAX3', 'Gene', (70, 74))	('FKHR', 'Gene', '2308', (134, 138))	('neoplasms', 'Phenotype', 'HP:0002664', (266, 275))	('t(1;13)(p13;q14', 'Var', (99, 114))	('FOXO1', 'Gene', '2308', (140, 145))	('RMS', 'Disease', 'MESH:D012208', (280, 283))	('PAX7', 'Gene', '5081', (129, 133))	('t(1;13)(p13;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (99, 115))	('RMS', 'Phenotype', 'HP:0002859', (280, 283))	('PAX3', 'Gene', '5077', (70, 74))	('PAX7', 'Gene', (129, 133))	('FOXO1', 'Gene', (140, 145))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (40, 56))	('RMS', 'Disease', (187, 190))	('RMS', 'Disease', (211, 214))	('neoplasms', 'Disease', 'MESH:D009369', (266, 275))	('FOXO1', 'Gene', '2308', (81, 86))	('RMS', 'Disease', (280, 283))	('FKHR', 'Gene', (134, 138))
300197	31370385	These fusions are known to be associated with the activation of transcription from PAX3/PAX7-binding sites and to contribute to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('PAX7', 'Gene', (88, 92))	('activation', 'PosReg', (50, 60))	('PAX7', 'Gene', '5081', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('PAX3', 'Gene', '5077', (83, 87))	('tumor', 'Disease', (128, 133))	('fusions', 'Var', (6, 13))	('PAX3', 'Gene', (83, 87))	('transcription', 'MPA', (64, 77))	('contribute', 'Reg', (114, 124))
300208	31208120	The tumor-targeting efficacy of S. typhimurium A1-R was demonstrated in vivo and vitro using several malignant cell lines including melanoma, sarcoma, glioma, breast, pancreatic, colon, cervical, prostate, and ovarian cancers.	('tumor', 'Disease', (4, 9))	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('sarcoma', 'Disease', (142, 149))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('colon', 'Disease', (179, 184))	('ovarian cancers', 'Phenotype', 'HP:0100615', (210, 225))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cervical', 'Disease', (186, 194))	('prostate', 'Disease', (196, 204))	('pancreatic', 'Disease', 'MESH:D010195', (167, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('S. typhimurium', 'Var', (32, 46))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('S. typhimurium', 'Species', '90371', (32, 46))	('pancreatic', 'Disease', (167, 177))	('ovarian cancer', 'Phenotype', 'HP:0100615', (210, 224))	('ovarian cancers', 'Disease', (210, 225))	('ovarian cancers', 'Disease', 'MESH:D010051', (210, 225))	('glioma', 'Disease', (151, 157))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('breast', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('colon', 'Disease', 'MESH:D015179', (179, 184))
300222	31208120	Intravenous or intratumoral administration of C. novyi-NT induced intratumor infection and necrosis.	('C. novyi-NT', 'Var', (46, 57))	('necrosis', 'Disease', 'MESH:D009336', (91, 99))	('C. novyi-NT', 'Species', '386415', (46, 57))	('infection', 'Disease', 'MESH:D007239', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('induced', 'Reg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('necrosis', 'Disease', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (71, 76))	('infection', 'Disease', (77, 86))	('tumor', 'Disease', (20, 25))
300229	31208120	In addition, tumors treated with S. typhimurium A1-R were significantly smaller than those treated with S. typhimurium VNP20009.	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('S. typhimurium', 'Species', '90371', (104, 118))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('S. typhimurium', 'Species', '90371', (33, 47))	('smaller', 'NegReg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('S. typhimurium A1-R', 'Var', (33, 52))
300230	31208120	The efficacy of S. typhimurium A1-R was demonstrated in orthotopic nude mouse models of prostate, breast, pancreatic, and ovarian cancer, as well as in sarcomas and gliomas.	('ovarian cancer', 'Disease', 'MESH:D010051', (122, 136))	('prostate', 'Disease', (88, 96))	('mouse', 'Species', '10090', (72, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('ovarian cancer', 'Disease', (122, 136))	('pancreatic', 'Disease', 'MESH:D010195', (106, 116))	('S. typhimurium', 'Var', (16, 30))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('S. typhimurium', 'Species', '90371', (16, 30))	('pancreatic', 'Disease', (106, 116))	('breast', 'Disease', (98, 104))	('sarcomas', 'Disease', 'MESH:D012509', (152, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('sarcomas', 'Disease', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gliomas', 'Disease', (165, 172))
300232	31208120	We review in the present report the therapeutic efficacy of S. typhimurium A1-R against malignancies in patient-derived orthotopic xenograft (PDOX) nude mouse models, in which human tumors are orthotopically implanted in mice, to examine future clinical applicability.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('S. typhimurium', 'Var', (60, 74))	('A1-R', 'Gene', (75, 79))	('malignancies', 'Disease', (88, 100))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('human', 'Species', '9606', (176, 181))	('mouse', 'Species', '10090', (153, 158))	('mice', 'Species', '10090', (221, 225))	('patient', 'Species', '9606', (104, 111))	('S. typhimurium', 'Species', '90371', (60, 74))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
300258	31208120	A fluorescent microscope was used to detect GFP-expressing S. typhimurium A1-R in tumors grown in PDOX models treated with S. typhimurium A1-R i.t., i.p., i.v., or i.a.	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('S. typhimurium', 'Var', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('S. typhimurium', 'Species', '90371', (123, 137))	('S. typhimurium', 'Species', '90371', (59, 73))
300263	31208120	Significant tumor growth inhibition occurred after i.v., i.p., i.t., and i.a.	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('i.t.', 'Var', (63, 67))	('i.p.', 'Var', (57, 61))
300266	31208120	In addition, S. typhimurium A1-R showed stronger efficacy administered i.a.	('S. typhimurium', 'Species', '90371', (13, 27))	('S. typhimurium', 'Var', (13, 27))	('stronger', 'PosReg', (40, 48))
300269	31208120	In the osteosarcoma PDOX models, S. typhimurium A1-R was more effective than cisplatinum.	('osteosarcoma', 'Phenotype', 'HP:0002669', (7, 19))	('S. typhimurium', 'Species', '90371', (33, 47))	('osteosarcoma', 'Disease', (7, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('osteosarcoma', 'Disease', 'MESH:D012516', (7, 19))	('cisplatinum', 'Chemical', 'MESH:D002945', (77, 88))	('S. typhimurium A1-R', 'Var', (33, 52))
300270	31208120	In the STS PDOX models, S. typhimurium A1-R resulted in greater tumor growth inhibition compared to doxorubicin treatment.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('S. typhimurium A1-R', 'Var', (24, 43))	('doxorubicin', 'Chemical', 'MESH:D004317', (100, 111))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('STS', 'Phenotype', 'HP:0030448', (7, 10))	('S. typhimurium', 'Species', '90371', (24, 38))
300271	31208120	Moreover, S. typhimurium A1-R showed stronger efficacy than imatinib in the GIST PDOX model.	('S. typhimurium', 'Species', '90371', (10, 24))	('efficacy', 'MPA', (46, 54))	('stronger', 'PosReg', (37, 45))	('GIST PDOX model', 'CPA', (76, 91))	('imatinib', 'Chemical', 'MESH:D000068877', (60, 68))	('S. typhimurium', 'Var', (10, 24))	('GIST', 'Phenotype', 'HP:0100723', (76, 80))
300272	31208120	Synergistic treatment efficacy was observed with combination of S. typhimurium A1-R with chemotherapy, molecular-targeting agents, or rMETase.	('S. typhimurium', 'Var', (64, 78))	('rMETase', 'Gene', '29252', (134, 141))	('rMETase', 'Gene', (134, 141))	('A1-R', 'Gene', (79, 83))	('S. typhimurium', 'Species', '90371', (64, 78))	('combination', 'Interaction', (49, 60))
300273	31208120	In pancreatic cancer PDOX models, S. typhimurium A1-R had additional efficacy when combined with gemcitabine or gemcitabine plus bevacizumab.	('pancreatic cancer', 'Disease', (3, 20))	('gemcitabine', 'Chemical', 'MESH:C056507', (112, 123))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('S. typhimurium', 'Var', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('bevacizumab', 'Chemical', 'MESH:D000068258', (129, 140))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('efficacy', 'MPA', (69, 77))	('S. typhimurium', 'Species', '90371', (34, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))
300274	31208120	Additionally, the combination treatment of S. typhimurium A1-R with temozolomide or vemurafenib significantly reduced tumor growth compared to monotherapy with these agents.	('temozolomide', 'Chemical', 'MESH:D000077204', (68, 80))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('reduced', 'NegReg', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('S. typhimurium', 'Species', '90371', (43, 57))	('vemurafenib', 'Chemical', 'MESH:D000077484', (84, 95))	('combination', 'Interaction', (18, 29))	('S. typhimurium', 'Var', (43, 57))
300278	31208120	As an example, S. typhimurium A1-R caused central tumor necrosis to a large extent in the Ewing's sarcoma PDOX model, while the untreated tumors grew without necrosis (Figure 4C-G).	('necrosis', 'Disease', (158, 166))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (90, 105))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (90, 105))	("Ewing's sarcoma", 'Disease', (90, 105))	('necrosis', 'Disease', (56, 64))	('necrosis', 'Disease', 'MESH:D009336', (158, 166))	('S. typhimurium', 'Species', '90371', (15, 29))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('central tumor necrosis', 'Disease', (42, 64))	('necrosis', 'Disease', 'MESH:D009336', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('S. typhimurium A1-R', 'Var', (15, 34))	('central tumor necrosis', 'Disease', 'MESH:D016543', (42, 64))
300282	31208120	When compared to standard treatment, S. typhimurium A1-R induced a higher degree of necrosis in several PDOX models including pancreatic cancer, STS, osteosarcoma, and GIST.	('osteosarcoma', 'Disease', (150, 162))	('STS', 'Phenotype', 'HP:0030448', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('pancreatic cancer', 'Disease', 'MESH:D010190', (126, 143))	('osteosarcoma', 'Phenotype', 'HP:0002669', (150, 162))	('STS', 'Disease', (145, 148))	('osteosarcoma', 'Disease', 'MESH:D012516', (150, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('S. typhimurium', 'Species', '90371', (37, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (126, 143))	('necrosis', 'Disease', 'MESH:D009336', (84, 92))	('GIST', 'Phenotype', 'HP:0100723', (168, 172))	('necrosis', 'Disease', (84, 92))	('S. typhimurium A1-R', 'Var', (37, 56))	('pancreatic cancer', 'Disease', (126, 143))
300283	31208120	administration of S. typhimurium A1-R led to more extensive necrosis than intravenous administration in the osteosarcoma PDOX model.	('necrosis', 'Disease', 'MESH:D009336', (60, 68))	('S. typhimurium', 'Species', '90371', (18, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (108, 120))	('S. typhimurium A1-R', 'Var', (18, 37))	('osteosarcoma', 'Disease', (108, 120))	('osteosarcoma', 'Disease', 'MESH:D012516', (108, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('necrosis', 'Disease', (60, 68))
300285	31208120	None of the PDOX experiments showed adverse effects, in terms of significant weight loss, in mice treated with S. typhimurium A1-R compared to the untreated control.	('S. typhimurium', 'Species', '90371', (111, 125))	('weight loss', 'Phenotype', 'HP:0001824', (77, 88))	('weight loss', 'Disease', 'MESH:D015431', (77, 88))	('mice', 'Species', '10090', (93, 97))	('S. typhimurium A1-R', 'Var', (111, 130))	('weight loss', 'Disease', (77, 88))
300293	31208120	The antitumor efficacy of S. typhimurium A1-R against many kinds of cancer cell lines was demonstrated and suggested that S. typhimurium A1-R kills cancer cells directly.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('S. typhimurium A1-R', 'Var', (122, 141))	('S. typhimurium', 'Species', '90371', (122, 136))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('S. typhimurium', 'Species', '90371', (26, 40))	('tumor', 'Disease', (8, 13))	('cancer', 'Disease', (68, 74))
300294	31208120	demonstrated that cancer cells infected by S. typhimurium A1-R expanded and burst, resulting in loss of viability.	('burst', 'CPA', (76, 81))	('A1-R', 'Var', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('S. typhimurium', 'Species', '90371', (43, 57))	('loss', 'NegReg', (96, 100))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('S. typhimurium A1-R', 'Var', (43, 62))
300296	31208120	As a result, S. typhimurium A1-R induces central tumor necrosis (Figure 4).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('S. typhimurium', 'Var', (13, 27))	('central tumor necrosis', 'Disease', 'MESH:D016543', (41, 63))	('central tumor necrosis', 'Disease', (41, 63))	('S. typhimurium', 'Species', '90371', (13, 27))	('induces', 'Reg', (33, 40))
300298	31208120	Salmonella enhances both innate and adaptive immunity.	('Salmonella', 'Var', (0, 10))	('enhances', 'PosReg', (11, 19))	('Salmonella', 'Species', '90371', (0, 10))
300301	31208120	demonstrated that intratumoral injection of S. typhimurium resulted in recruitment of CD8+ lymphocytes, CD4+ lymphocytes and B lymphocytes as well as macrophages and granulocytes in the tumor.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('S. typhimurium', 'Var', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('S. typhimurium', 'Species', '90371', (44, 58))	('tumor', 'Disease', (23, 28))	('recruitment', 'CPA', (71, 82))
300302	31208120	We also demonstrated that the antitumor efficacy of S. typhimurium A1-R was correlated with CD8+ lymphocyte infiltration into treated tumors in a pancreatic cancer syngeneic immunocompetent mouse model.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Disease', (34, 39))	('S. typhimurium', 'Species', '90371', (52, 66))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('pancreatic cancer', 'Disease', (146, 163))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('mouse', 'Species', '10090', (190, 195))	('S. typhimurium', 'Var', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (134, 139))
300306	31208120	The present review discusses the antitumor efficacy of S. typhimurium A1-R against recalcitrant cancer PDOX models.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('S. typhimurium', 'Species', '90371', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('S. typhimurium', 'Var', (55, 69))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
300335	31113482	For instance, HPV-associated squamous tumors of the head and neck may harbor more PIK3CA alterations whereas non-HPV tumors may have TP53 and cyclin pathway (CDKN2A and CCND1) alterations.	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('HPV tumors', 'Disease', (113, 123))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('CCND1', 'Gene', '595', (169, 174))	('PIK3CA', 'Gene', '5290', (82, 88))	('HPV tumors', 'Disease', 'MESH:D030361', (113, 123))	('cyclin', 'Gene', '5111', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CCND1', 'Gene', (169, 174))	('tumors of the head and neck', 'Phenotype', 'HP:0012288', (38, 65))	('TP53', 'Gene', '7157', (133, 137))	('alterations', 'Var', (89, 100))	('cyclin', 'Gene', (142, 148))	('PIK3CA', 'Gene', (82, 88))	('CDKN2A', 'Gene', (158, 164))	('squamous tumors', 'Disease', (29, 44))	('squamous tumors', 'Disease', 'MESH:D002294', (29, 44))	('CDKN2A', 'Gene', '1029', (158, 164))	('TP53', 'Gene', (133, 137))
300337	31113482	These upregulated enzymes constitute a crucial part of mammalian innate immunity and are also a major source of mutations in multiple cancer types.	('mammalian', 'Species', '9606', (55, 64))	('enzymes', 'Enzyme', (18, 25))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mutations', 'Var', (112, 121))	('upregulated', 'PosReg', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
300340	31113482	The production of mutations that result in immunogenic neoantigens or presentation of the viral antigens themselves may also explain the fact that malignancies such as virus-related Merkel cell carcinoma and Kaposi sarcoma respond well to ICIs, despite a low tumor mutational burden, the latter usually being associated with a poor response to these immunotherapeutics.	('Kaposi sarcoma', 'Disease', (208, 222))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (208, 222))	('result in', 'Reg', (33, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('low tumor', 'Disease', (255, 264))	('malignancies', 'Disease', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (182, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (208, 222))	('Merkel cell carcinoma', 'Disease', (182, 203))	('low tumor', 'Disease', 'MESH:D009800', (255, 264))	('mutations', 'Var', (18, 27))
300347	31113482	Virally-induced cancers suppress the host DNA damage response machinery and activate enzymes such as APOBEC that mutate both the virus and the host genome; in the latter, the mutations have high hydrophobicity, a feature associated with neopeptide immunogenicity for T cells.	('high hydrophobicity', 'MPA', (190, 209))	('cancers', 'Disease', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('activate', 'PosReg', (76, 84))	('mutations', 'Var', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('suppress', 'NegReg', (24, 32))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
300350	31113482	All of these changes make these tumors hypothetically vulnerable to ICI treatment.	('changes', 'Var', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
300370	27591497	WD/DDLS is characterized by amplification of 12q13-15 (including the oncogenes MDM2 and CDK4), M/RCLS by FUS-DDIT3 translocations, and pleomorphic liposarcoma by loss of p53 and Rb.	('liposarcoma', 'Phenotype', 'HP:0012034', (147, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('loss', 'NegReg', (162, 166))	('p53', 'Protein', (170, 173))	('M/RCLS', 'Var', (95, 101))	('FUS', 'Gene', (105, 108))	('FUS', 'Gene', '2521', (105, 108))	('pleomorphic liposarcoma', 'Disease', (135, 158))	('CDK4', 'Gene', (88, 92))	('CDK4', 'Gene', '1019', (88, 92))	('M/RCLS', 'Phenotype', 'HP:0012268', (95, 101))	('WD', 'Disease', 'MESH:D006527', (0, 2))	('DDIT3', 'Gene', (109, 114))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (135, 158))	('12q13-15', 'Gene', (45, 53))	('DDIT3', 'Gene', '1649', (109, 114))	('amplification', 'Var', (28, 41))
300373	27591497	Among such therapies are CDK4 inhibitors in WD/DDLS and trabectedin, which prevents FUS-DDIT3 binding to DNA, in M/RCLS.	('trabectedin', 'Chemical', 'MESH:D000077606', (56, 67))	('FUS', 'Gene', (84, 87))	('prevents', 'NegReg', (75, 83))	('DDIT3', 'Gene', (88, 93))	('inhibitors', 'Var', (30, 40))	('binding', 'Interaction', (94, 101))	('FUS', 'Gene', '2521', (84, 87))	('WD', 'Disease', 'MESH:D006527', (44, 46))	('M/RCLS', 'Phenotype', 'HP:0012268', (113, 119))	('CDK4', 'Gene', (25, 29))	('DDIT3', 'Gene', '1649', (88, 93))	('CDK4', 'Gene', '1019', (25, 29))
300376	27591497	Each group is characterized by specific genetic alterations presumed to drive tumor initiation (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('genetic alterations', 'Var', (40, 59))	('tumor', 'Disease', (78, 83))
300377	27591497	Well- and dedifferentiated liposarcomas (WD/DDLS) represent over 60% of all LPS and are almost universally associated with amplification of chromosome segment 12q13-15, which carries the oncogenes MDM2, CDK4, and HMGA2.	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('associated', 'Reg', (107, 117))	('LPS', 'Phenotype', 'HP:0012034', (76, 79))	('LPS', 'Disease', (76, 79))	('dedifferentiated liposarcomas', 'Disease', (10, 39))	('HMGA2', 'Gene', '8091', (213, 218))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))	('WD', 'Disease', 'MESH:D006527', (41, 43))	('dedifferentiated liposarcomas', 'Disease', 'MESH:D008080', (10, 39))	('liposarcomas', 'Phenotype', 'HP:0012034', (27, 39))	('HMGA2', 'Gene', (213, 218))	('LPS', 'Disease', 'MESH:C536528', (76, 79))	('amplification', 'Var', (123, 136))	('CDK4', 'Gene', '1019', (203, 207))	('CDK4', 'Gene', (203, 207))	('liposarcoma', 'Phenotype', 'HP:0012034', (27, 38))
300378	27591497	Over 95% of myxoid and round cell liposarcomas carry a translocation of FUS and DDIT3 (CHOP) genes.	('FUS', 'Gene', (72, 75))	('myxoid and round cell liposarcoma', 'Phenotype', 'HP:0012268', (12, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('FUS', 'Gene', '2521', (72, 75))	('DDIT3', 'Gene', (80, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('DDIT3', 'Gene', '1649', (80, 85))	('CHOP', 'Gene', '1649', (87, 91))	('translocation', 'Var', (55, 68))	('liposarcomas', 'Disease', 'MESH:D008080', (34, 46))	('liposarcomas', 'Phenotype', 'HP:0012034', (34, 46))	('liposarcoma', 'Phenotype', 'HP:0012034', (34, 45))	('CHOP', 'Gene', (87, 91))	('liposarcomas', 'Disease', (34, 46))
300405	27591497	For retroperitoneal sarcoma, R2 resection is associated with significantly poorer outcomes than R0 or R1 resection, and, in most series, patients with gross residual disease have outcomes as poor as patients who did not undergo any surgery.	('retroperitoneal sarcoma', 'Disease', (4, 27))	('retroperitoneal sarcoma', 'Disease', 'MESH:D012186', (4, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (199, 207))	('R2 resection', 'Var', (29, 41))	('poorer', 'NegReg', (75, 81))
300445	27591497	As noted above, WD/DDLS almost universally has amplification of 12q13-15.	('amplification', 'Var', (47, 60))	('12q13-15', 'Gene', (64, 72))	('WD', 'Disease', 'MESH:D006527', (16, 18))
300447	27591497	One of the most commonly amplified among these was CDK4, a cell cycle regulator that promotes G1 to S phase transition by phosphorylating RB and inducing transcription of E2F targets.	('transcription', 'MPA', (154, 167))	('phosphorylating', 'Var', (122, 137))	('inducing', 'PosReg', (145, 153))	('promotes', 'PosReg', (85, 93))	('CDK4', 'Gene', (51, 55))	('RB', 'Chemical', 'MESH:D012413', (138, 140))	('G1 to S', 'Disease', (94, 101))	('CDK4', 'Gene', '1019', (51, 55))
300454	27591497	In patient trials, however, MDM2 inhibitors have been associated with significant adverse events (up to 40% of patients), which have precluded their chronic administration.	('patient', 'Species', '9606', (3, 10))	('MDM2', 'Gene', (28, 32))	('patient', 'Species', '9606', (111, 118))	('inhibitors', 'Var', (33, 43))	('patients', 'Species', '9606', (111, 119))
300455	27591497	Recent data do suggest, however, that in vitro abrogation of MDM2 may exert cytostatic effects on the cell (senescence, an irreversible form of growth arrest) without altering cellular levels of p53.	('growth arrest', 'Disease', (144, 157))	('abrogation', 'Var', (47, 57))	('MDM2', 'Gene', (61, 65))	('growth arrest', 'Disease', 'MESH:D006323', (144, 157))	('growth arrest', 'Phenotype', 'HP:0001510', (144, 157))	('cytostatic effects', 'MPA', (76, 94))
300458	27591497	Similarly, studies of dedifferentiation of WDLS have identified potential oncogenes and tumor suppressors that drive tumor progression, such as 11q23-25, 3p14-21, 3q29, and 19q13.	('11q23-25', 'Var', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('19q13', 'Var', (173, 178))	('WD', 'Disease', 'MESH:D006527', (43, 45))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (117, 122))	('3q29', 'Var', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('3p14-21', 'Var', (154, 161))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
300460	27591497	One possible mechanism is targeting the epigenetic modification that contributes to downregulation of these tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('epigenetic modification', 'Var', (40, 63))	('downregulation', 'NegReg', (84, 98))
300461	27591497	For example, methylation of the CEBP-alpha gene was identified in 10 of 42 DDLS samples (24%).	('identified', 'Reg', (52, 62))	('methylation', 'Var', (13, 24))	('CEBP-alpha', 'Gene', (32, 42))	('CEBP-alpha', 'Gene', '1050', (32, 42))
300475	27591497	M/RCLS is most often in the thigh, and given the high morbidity associated with preoperative radiation in this region, we would tend to prescribe radiation in the adjuvant setting unless a tumor were particularly close to the joint.	('tumor', 'Disease', (189, 194))	('M/RCLS', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('M/RCLS', 'Phenotype', 'HP:0012268', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
300489	27591497	Mutations in PI3 kinase and consequent Akt activation have been identified in almost 20% of M/RCLS, so PI3 kinase inhibitors have potential for select patients.	('Akt', 'Gene', '207', (39, 42))	('activation', 'PosReg', (43, 53))	('M/RCLS', 'Phenotype', 'HP:0012268', (92, 98))	('M/RCLS', 'Disease', (92, 98))	('patients', 'Species', '9606', (151, 159))	('Mutations', 'Var', (0, 9))	('PI3', 'Gene', (13, 16))	('Akt', 'Gene', (39, 42))
300493	27591497	Of note, the most substantial improvement in PFS was seen in patients with M/RCLS (median PFS 5.6 months with trabectedin vs 1.5 months with dacarbazine).	('trabectedin', 'Chemical', 'MESH:D000077606', (110, 121))	('M/RCLS', 'Var', (75, 81))	('M/RCLS', 'Phenotype', 'HP:0012268', (75, 81))	('patients', 'Species', '9606', (61, 69))	('PFS', 'MPA', (45, 48))	('improvement', 'PosReg', (30, 41))	('dacarbazine', 'Chemical', 'MESH:D003606', (141, 152))
300517	27591497	Among targeted therapies, CDK4 inhibitors are effective in well- and dedifferentiated liposarcoma and trabectedin, which prevents FUS-DDIT3 binding to DNA, is effective in myxoid/round cell liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (86, 97))	('liposarcoma', 'Phenotype', 'HP:0012034', (190, 201))	('FUS', 'Gene', (130, 133))	('liposarcoma', 'Disease', 'MESH:D008080', (86, 97))	('binding', 'Interaction', (140, 147))	('liposarcoma', 'Disease', 'MESH:D008080', (190, 201))	('FUS', 'Gene', '2521', (130, 133))	('inhibitors', 'Var', (31, 41))	('CDK4', 'Gene', (26, 30))	('liposarcoma', 'Disease', (86, 97))	('dedifferentiated liposarcoma', 'Disease', (69, 97))	('DDIT3', 'Gene', '1649', (134, 139))	('liposarcoma', 'Disease', (190, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('effective', 'Reg', (46, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('CDK4', 'Gene', '1019', (26, 30))	('DDIT3', 'Gene', (134, 139))	('trabectedin', 'Chemical', 'MESH:D000077606', (102, 113))	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (69, 97))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (172, 201))
300559	22726733	Similarly, for the Z9000 and Z9001 patients assigned to receive one year of imatinib (Figure 1B), the difference in recurrence free survival (RFS) for patients undergoing an R1 (n=49) versus an R0 (n=415) resection of GIST was not statistically significant (82% versus 79% at 3 years, HR=1.095, 95% CI: 0.66, 1.82, p=0.73).	('Z9001', 'Var', (29, 34))	('imatinib', 'Chemical', 'MESH:D000068877', (76, 84))	('patients', 'Species', '9606', (151, 159))	('patients', 'Species', '9606', (35, 43))	('Z9000', 'Var', (19, 24))
300592	22726733	The data from this study calls into question the utility of re-resection as, in the absence of tumor rupture, an R1 resection (without tumor rupture) based on pathology review is associated with a similar 3 year RFS to patients with an R0 resection.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor rupture', 'Disease', 'MESH:D012421', (135, 148))	('R1 resection', 'Var', (113, 125))	('tumor rupture', 'Disease', (135, 148))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('patients', 'Species', '9606', (219, 227))	('tumor rupture', 'Disease', (95, 108))	('tumor rupture', 'Disease', 'MESH:D012421', (95, 108))
300649	21316595	On the other hand, a wide range of causative mutations have been implicated in eRMS, such as the loss of heterozygosity at 11p15.5 locus, mutations in tumor suppressor p53 , retinoblastoma (Rb1) , N- and K-ras genes , and PTCH1 haploinsuficiency.	('K-ras', 'Gene', (204, 209))	('K-ras', 'Gene', '16653', (204, 209))	('retinoblastoma', 'Phenotype', 'HP:0009919', (174, 188))	('eRMS', 'Phenotype', 'HP:0006743', (79, 83))	('Rb1', 'Gene', '19645', (190, 193))	('retinoblastoma', 'Disease', (174, 188))	('p53', 'Gene', (168, 171))	('PTCH1 haploinsuficiency', 'Disease', 'None', (222, 245))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('p53', 'Gene', '22060', (168, 171))	('Rb1', 'Gene', (190, 193))	('PTCH1 haploinsuficiency', 'Disease', (222, 245))	('implicated', 'Reg', (65, 75))	('eRMS', 'Disease', (79, 83))	('retinoblastoma', 'Disease', 'MESH:D012175', (174, 188))	('mutations', 'Var', (138, 147))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
300652	21316595	To study the potentials of individual subpopulations of muscle cells in eRMS development, deleted p53 either with or without Ptch1 haploinsuficiency.	('p53', 'Gene', '22060', (98, 101))	('haploinsuficiency', 'Disease', (131, 148))	('deleted', 'Var', (90, 97))	('haploinsuficiency', 'Disease', 'None', (131, 148))	('eRMS', 'Phenotype', 'HP:0006743', (72, 76))	('p53', 'Gene', (98, 101))	('Ptch1', 'Gene', '19206', (125, 130))	('Ptch1', 'Gene', (125, 130))
300657	21316595	Loss of p53 in maturing myoblasts (Myf6+ cells) gave rise to the highest percentage of eRMSs.	('p53', 'Gene', (8, 11))	('eRMSs', 'CPA', (87, 92))	('eRMS', 'Phenotype', 'HP:0006743', (87, 91))	('p53', 'Gene', '22060', (8, 11))	('Loss', 'Var', (0, 4))	('RMSs', 'Phenotype', 'HP:0002859', (88, 92))
300659	21316595	To study the effect of retinoblastoma (Rb1) mutation on eRMS development in combination with the loss of p53, inactivated both p53 and Rb1 with or without Ptch1 haploinsuficiancy.	('mutation', 'Var', (44, 52))	('p53', 'Gene', '22060', (127, 130))	('Rb1', 'Gene', (135, 138))	('inactivated', 'NegReg', (110, 121))	('eRMS', 'Phenotype', 'HP:0006743', (56, 60))	('Rb1', 'Gene', '19645', (135, 138))	('retinoblastoma', 'Disease', 'MESH:D012175', (23, 37))	('retinoblastoma', 'Disease', (23, 37))	('p53', 'Gene', (105, 108))	('Rb1', 'Gene', (39, 42))	('haploinsuficiancy', 'Disease', (161, 178))	('Rb1', 'Gene', '19645', (39, 42))	('haploinsuficiancy', 'Disease', 'None', (161, 178))	('retinoblastoma', 'Phenotype', 'HP:0009919', (23, 37))	('Ptch1', 'Gene', '19206', (155, 160))	('Ptch1', 'Gene', (155, 160))	('p53', 'Gene', (127, 130))	('p53', 'Gene', '22060', (105, 108))
300660	21316595	Loss of Rb1 alone did not lead to tumor initiation.	('Rb1', 'Gene', (8, 11))	('Rb1', 'Gene', '19645', (8, 11))	('tumor initiation', 'Disease', (34, 50))	('tumor initiation', 'Disease', 'MESH:D009369', (34, 50))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
300664	21316595	Rb1 deletion reduced the myodifferentiation potentials of p53 null tumor cells.	('p53', 'Gene', '22060', (58, 61))	('myodifferentiation', 'MPA', (25, 43))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('deletion', 'Var', (4, 12))	('Rb1', 'Gene', (0, 3))	('tumor', 'Disease', (67, 72))	('p53', 'Gene', (58, 61))	('reduced', 'NegReg', (13, 20))	('Rb1', 'Gene', '19645', (0, 3))
300666	21316595	Interestingly, analysis of the global gene expression profiling showed a marked difference between tumors with intact versus mutant Rb1.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('Rb1', 'Gene', (132, 135))	('Rb1', 'Gene', '19645', (132, 135))	('mutant', 'Var', (125, 131))	('difference', 'Reg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))
300675	21316595	The study by provides important new insight into the genetic basis of rhabdomyosarcomas in the context of p53, Rb1, and Ptch1 mutational pathways, and shows the potential of various subpopulations of muscle stem cells and downstream myogenic precursors in rhabdomyosarcomas development.	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('Rb1', 'Gene', '19645', (111, 114))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (70, 86))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (256, 273))	('p53', 'Gene', (106, 109))	('rhabdomyosarcomas', 'Disease', (256, 273))	('p53', 'Gene', '22060', (106, 109))	('Rb1', 'Gene', (111, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (256, 273))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (256, 272))	('sarcomas', 'Phenotype', 'HP:0100242', (265, 273))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (70, 87))	('rhabdomyosarcomas', 'Disease', (70, 87))	('Ptch1', 'Gene', (120, 125))	('mutational', 'Var', (126, 136))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (70, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('Ptch1', 'Gene', '19206', (120, 125))
300677	21316595	The authors rightly argue that there might be additional mutations involving other tumor suppressors that may be involved in rhabdomyosarcomas development.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (125, 142))	('rhabdomyosarcomas', 'Disease', (125, 142))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (125, 141))	('mutations', 'Var', (57, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (125, 142))	('involved', 'Reg', (113, 121))
300684	21316595	In addition, a role for posttranscriptional gene regulation by microRNAs in rhabdomyosarcomas development has also been demonstrated.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (76, 93))	('rhabdomyosarcomas', 'Disease', (76, 93))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (76, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (76, 93))	('microRNAs', 'Var', (63, 72))
300878	24746967	Surface markers (characterized by flow cytometry) in RD-ES and SK-N-MC were, as expected, CD13-, CD44- and CD73- and CD90+, CD105+ and CD99+ (Fig.	('CD13', 'Gene', (90, 94))	('CD44', 'Gene', (97, 101))	('CD90', 'Gene', '7070', (117, 121))	('CD90', 'Gene', (117, 121))	('RD-ES', 'Chemical', '-', (53, 58))	('SK-N-MC', 'CellLine', 'CVCL:0530', (63, 70))	('CD73', 'Gene', '4907', (107, 111))	('CD99', 'Gene', '4267', (135, 139))	('CD105+', 'Var', (124, 130))	('CD13', 'Gene', '290', (90, 94))	('CD73', 'Gene', (107, 111))	('CD44', 'Gene', '960', (97, 101))	('CD99', 'Gene', (135, 139))
300929	24746967	In further support of the adaptive advantage of RD-ES cells cultured in TE-bone, VEGF-alpha mRNA levels were not significantly increased in TE-SK-N-MC and TE-EW-GFP tumor models as compared to TE-bone controls (Fig.	('RD-ES', 'Chemical', '-', (48, 53))	('SK-N-MC', 'CellLine', 'CVCL:0530', (143, 150))	('TE-SK-N-MC', 'Var', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('VEGF-alpha', 'Gene', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('VEGF-alpha', 'Gene', '7422', (81, 91))	('increased', 'PosReg', (127, 136))	('tumor', 'Disease', (165, 170))
300932	24746967	However, these analyses clearly demonstrated that 8 proteins (Angiopoietin, CXCL16, Endothelin-1, FGF-7, IGFBP1-1, PIGF, TGF-beta1 and TIMP4) were highly expressed in TE-RD-ES and TE-EW-GFP tumor models as compared to TE-bone (fold change >3).	('TIMP4', 'Gene', '7079', (135, 140))	('TE-RD-ES', 'Chemical', '-', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Endothelin-1', 'Gene', (84, 96))	('FGF-7', 'Gene', '2252', (98, 103))	('FGF-7', 'Gene', (98, 103))	('TGF-beta1', 'Gene', (121, 130))	('TGF-beta1', 'Gene', '7040', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('TE-RD-ES', 'Var', (167, 175))	('IGFBP1-1', 'Gene', (105, 113))	('Endothelin-1', 'Gene', '1906', (84, 96))	('CXCL16', 'Gene', (76, 82))	('tumor', 'Disease', (190, 195))	('PIGF', 'Gene', (115, 119))	('IGFBP1-1', 'Gene', '3484', (105, 113))	('CXCL16', 'Gene', '58191', (76, 82))	('TIMP4', 'Gene', (135, 140))
300942	24746967	Consistent with all other data, cells in the SK-N-MC model re-expressed VM genes as levels lower than those measured for the TE-RD-ES model.	('VM genes', 'Gene', (72, 80))	('SK-N-MC', 'CellLine', 'CVCL:0530', (45, 52))	('TE-RD-ES', 'Chemical', '-', (125, 133))	('SK-N-MC', 'Var', (45, 52))
301002	23760066	In this retrospective study it was found that age <20 years, KPS score <60, malnutrition, >3 previous chemotherapies and combination therapy of >3 drugs were significantly associated with the occurrence of severe bone marrow suppression, mainly indicated by grade III/IV neotropenia.	('bone marrow suppression', 'Disease', 'MESH:D001855', (213, 236))	('malnutrition', 'Phenotype', 'HP:0004395', (76, 88))	('bone marrow suppression', 'Disease', (213, 236))	('associated', 'Reg', (172, 182))	('malnutrition', 'Disease', 'MESH:D044342', (76, 88))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (213, 236))	('IV neotropenia', 'Disease', 'MESH:D030401', (268, 282))	('IV neotropenia', 'Disease', (268, 282))	('malnutrition', 'Disease', (76, 88))	('KPS score <60', 'Var', (61, 74))
301044	23251510	The 5-year survival rates of women with low grade endometrial stromal sarcoma, endometrial stromal sarcoma, leiomyosarcoma (LMS), and adenosarcoma were 97.5%, 73.5%, 60.1%, and 77.2%, respectively (p<0.0001, log rank test).	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (50, 77))	('women', 'Species', '9606', (29, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('adenosarcoma', 'Disease', (134, 146))	('adenosarcoma', 'Disease', 'MESH:D018195', (134, 146))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (108, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('endometrial stromal sarcoma', 'Disease', (79, 106))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (79, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('endometrial stromal sarcoma', 'Disease', (50, 77))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (108, 122))	('low grade', 'Var', (40, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('leiomyosarcoma', 'Disease', (108, 122))
301083	23251510	Women diagnosed with a primary cancer of the uterus (ICD-O3 C54.0-C54.3, C54.8-C54.9, C55.9) with valid histological codes from 8000-8991, between 1979 and 2008 were eligible for this study.	('Women', 'Species', '9606', (0, 5))	('C55.9', 'Var', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('cancer of the uterus', 'Phenotype', 'HP:0010784', (31, 51))	('C54.8-C54.9', 'Var', (73, 84))
301222	22151733	Recent cytogenetic studies have shown that clear cell sarcoma has a t(12;22) (q13;q12) translocation, a feature not encountered in malignant melanoma.	('t(12;22) (q13', 'Var', (68, 81))	('clear cell sarcoma', 'Disease', (43, 61))	('malignant melanoma', 'Phenotype', 'HP:0002861', (131, 149))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (43, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('malignant melanoma', 'Disease', (131, 149))	('malignant melanoma', 'Disease', 'MESH:D008545', (131, 149))
301259	33403195	Additional immunohistochemistry was performed that demonstrated S100 positivity in the high-grade, spindle-cell component of the tumor and chromogranin A, and synaptophysin staining in the sustentacular cells of the paraganglioma component.	('S100', 'Gene', (64, 68))	('chromogranin A', 'Gene', (139, 153))	('paraganglioma component', 'Disease', 'MESH:D010235', (216, 239))	('synaptophysin', 'Gene', '6855', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('S100', 'Gene', '6271', (64, 68))	('paraganglioma', 'Phenotype', 'HP:0002668', (216, 229))	('positivity', 'Var', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('paraganglioma component', 'Disease', (216, 239))	('synaptophysin', 'Gene', (159, 172))	('chromogranin A', 'Gene', '1113', (139, 153))
301301	33403195	Some SDH mutations (i.e., SDHB) are associated with a significantly increased risk of malignant paraganglioma,  whereas NF1 mutations may predispose to MPNST, as seen in our patient.	('SDH', 'Gene', (5, 8))	('predispose', 'Reg', (138, 148))	('patient', 'Species', '9606', (174, 181))	('mutations', 'Var', (9, 18))	('malignant paraganglioma', 'Disease', (86, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('SDHB', 'Gene', '6390', (26, 30))	('NF1', 'Gene', (120, 123))	('malignant paraganglioma', 'Disease', 'MESH:C565335', (86, 109))	('SDHB', 'Gene', (26, 30))	('SDH', 'Gene', '6390', (26, 29))	('NF1', 'Gene', '4763', (120, 123))	('SDH', 'Gene', '6390', (5, 8))	('MPNST', 'Disease', (152, 157))	('MPNST', 'Phenotype', 'HP:0100697', (152, 157))	('SDH', 'Gene', (26, 29))
301304	33403195	Nevertheless, we believe that characterization of the causative genetic mutation(s) could have helped inform the patient's initial decision to proceed with radiation treatment (e.g., if an underlying NF1 mutation had been identified).	('mutation', 'Var', (204, 212))	('NF1', 'Gene', (200, 203))	('NF1', 'Gene', '4763', (200, 203))	('patient', 'Species', '9606', (113, 120))
301318	33322663	In patients with GMI >1.33, median OS was significantly longer than in those with GMI 0-1.33 (median OS 52.1 months (95% CI not reached) vs. 8.9 months (95% CI 6.3-11.6), p = 0.028).	('2.1', 'Gene', (105, 108))	('2.1', 'Gene', '6700', (105, 108))	('GMI >1.33', 'Var', (17, 26))	('patients', 'Species', '9606', (3, 11))	('GMI', 'Chemical', '-', (17, 20))	('GMI', 'Chemical', '-', (82, 85))	('6.3', 'Gene', '55558', (160, 163))	('6.3', 'Gene', (160, 163))
301365	33322663	Considering those patients treated immediately before trabectedin with other systemic therapy for advanced disease (n = 30), we observed that median PFS for trabectedin (7.5 months (95% CI 3.5-11.5) was more than double the PFS for the previous line (median PFS 3.1 months (95% CI 2.1-4)).	('trabectedin', 'Var', (157, 168))	('2.1', 'Gene', (281, 284))	('2.1', 'Gene', '6700', (281, 284))	('trabectedin', 'Chemical', 'MESH:D000077606', (54, 65))	('patients', 'Species', '9606', (18, 26))	('trabectedin', 'Chemical', 'MESH:D000077606', (157, 168))
301367	33322663	In those patients with GMI >1.33, the median OS for trabectedin was significantly longer than in those patients with GMI 0-1.33 (median OS 52.1 months (95% CI not reached) vs. 8.9 months (95% CI 6.3-11.6), p = 0.028).	('patients', 'Species', '9606', (9, 17))	('GMI >1.33', 'Var', (23, 32))	('trabectedin', 'Chemical', 'MESH:D000077606', (52, 63))	('longer', 'PosReg', (82, 88))	('2.1', 'Gene', (140, 143))	('GMI', 'Chemical', '-', (117, 120))	('2.1', 'Gene', '6700', (140, 143))	('6.3', 'Gene', '55558', (195, 198))	('6.3', 'Gene', (195, 198))	('trabectedin', 'Gene', (52, 63))	('patients', 'Species', '9606', (103, 111))	('GMI', 'Chemical', '-', (23, 26))
301415	33322663	(Paloma Santos), D.M., V.E., S.C., C.M.-C., and J.M.-B.	('C.M.-C.', 'Var', (35, 42))	('Paloma Santos', 'Disease', (1, 14))	('S.C.', 'Disease', (29, 33))	('Paloma Santos', 'Disease', 'MESH:C567819', (1, 14))
301427	31873172	Our findings identify nuclear YAP1 and TAZ positivity as a common feature in subsets of sarcomas of soft tissue and bone and provide evidence of YAP1/TAZ-TEAD signaling as a specific liability to be considered as a new target for therapeutic intervention.	('YAP1/TAZ', 'Gene', (145, 153))	('sarcomas', 'Disease', (88, 96))	('TAZ', 'Gene', '6901', (150, 153))	('TAZ', 'Gene', '6901', (39, 42))	('YAP1/TAZ', 'Gene', '10413;6901', (145, 153))	('YAP1', 'Gene', '10413', (30, 34))	('TAZ', 'Gene', (150, 153))	('TAZ', 'Gene', (39, 42))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('YAP1', 'Gene', (145, 149))	('YAP1', 'Gene', '10413', (145, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('TEAD', 'Gene', '7003;8463;7005;7004', (154, 158))	('TEAD', 'Gene', (154, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('YAP1', 'Gene', (30, 34))	('positivity', 'Var', (43, 53))
301462	31873172	Verteporfin (C41H42N4O8; CAS#: 129497-78-5; Targetmol) was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich).	('C41H42N4O8', 'Chemical', '-', (13, 23))	('DMSO', 'Chemical', 'MESH:D004121', (92, 96))	('Verteporfin', 'Chemical', 'MESH:D000077362', (0, 11))	('C41H42N4O8;', 'Var', (13, 24))	('AS', 'Phenotype', 'HP:0200058', (26, 28))	('Aldrich', 'Disease', (104, 111))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (72, 90))	('Aldrich', 'Disease', 'MESH:D014923', (104, 111))
301489	31873172	Our immunohistochemical analyses suggest that aberrant YAP1/TAZ activity might represent a therapeutic target in MLS, SySa and MPNST.	('MLS', 'Phenotype', 'HP:0012268', (113, 116))	('YAP1/TAZ', 'Gene', '10413;6901', (55, 63))	('YAP1/TAZ', 'Gene', (55, 63))	('SySa', 'Disease', (118, 122))	('SySa', 'Phenotype', 'HP:0012570', (118, 122))	('MPNST', 'Phenotype', 'HP:0100697', (127, 132))	('activity', 'MPA', (64, 72))	('MPNST', 'Disease', (127, 132))	('aberrant', 'Var', (46, 54))	('MLS', 'Disease', 'MESH:C537466', (113, 116))	('MLS', 'Disease', (113, 116))
301500	31873172	3E; *P < 0.05), further supporting the idea that aberrant YAP1/TAZ signaling could represent a new target for therapeutic intervention in sarcoma patients.	('sarcoma', 'Disease', (138, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('aberrant', 'Var', (49, 57))	('YAP1/TAZ', 'Gene', '10413;6901', (58, 66))	('YAP1/TAZ', 'Gene', (58, 66))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('patients', 'Species', '9606', (146, 154))
301509	31873172	For instance, WDLS, SFT and LMS were almost exclusively positive for nuclear YAP1, whereas higher nuclear TAZ levels were detected in MPNST and AS tumor specimens.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('LMS', 'Disease', (28, 31))	('YAP1', 'Gene', '10413', (77, 81))	('LMS', 'Phenotype', 'HP:0100243', (28, 31))	('TAZ', 'Gene', '6901', (106, 109))	('MPNST', 'Phenotype', 'HP:0100697', (134, 139))	('TAZ', 'Gene', (106, 109))	('AS', 'Phenotype', 'HP:0200058', (144, 146))	('positive', 'Reg', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('SFT', 'Disease', (20, 23))	('nuclear', 'Var', (69, 76))	('YAP1', 'Gene', (77, 81))
301510	31873172	In contrast, Fullenkamp et al., analyzing only a smaller cohort (n = 159) with less than 10 samples for the majority of all investigated sarcoma subtypes, reported nuclear TAZ positivity in up to 2/3 of all cases.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('TAZ', 'Gene', '6901', (172, 175))	('positivity', 'Var', (176, 186))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('TAZ', 'Gene', (172, 175))	('sarcoma', 'Disease', (137, 144))
301521	31873172	Alterations in various effectors of the Hippo signaling cascade such as YAP1, LATS2 or SAV1 copy number variations have recently been described in a variety of sarcoma subtypes and point to a major role of aberrant Hippo signals in different soft tissue malignancies.	('LATS2', 'Gene', (78, 83))	('LATS2', 'Gene', '26524', (78, 83))	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('malignancies', 'Disease', 'MESH:D009369', (254, 266))	('copy number variations', 'Var', (92, 114))	('variations', 'Var', (104, 114))	('sarcoma', 'Disease', (160, 167))	('YAP1', 'Gene', (72, 76))	('malignancies', 'Disease', (254, 266))	('YAP1', 'Gene', '10413', (72, 76))	('SAV1', 'Gene', '60485', (87, 91))	('described', 'Reg', (134, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('SAV1', 'Gene', (87, 91))	('Alterations', 'Reg', (0, 11))
301522	31873172	Seidel and colleagues demonstrated a frequent reduction of MST1/2 and LATS1 gene expression by promoter hypermethylation in soft tissue sarcomas.	('expression', 'MPA', (81, 91))	('reduction', 'NegReg', (46, 55))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (124, 144))	('sarcomas', 'Disease', (136, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('MST1/2', 'Gene', '4485;6788', (59, 65))	('promoter hypermethylation', 'Var', (95, 120))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('LATS1', 'Gene', (70, 75))	('LATS1', 'Gene', '9113', (70, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))	('MST1/2', 'Gene', (59, 65))
301524	31873172	In alveolar rhabdomyosarcoma, the chimeric PAX3-FOXO1 oncoprotein was found to promote tumorigenesis by inhibition of MST1, and dysregulation of YAP1.	('inhibition', 'NegReg', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FOXO1', 'Gene', (48, 53))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (12, 28))	('YAP1', 'Gene', (145, 149))	('alveolar rhabdomyosarcoma', 'Disease', (3, 28))	('MST1', 'Gene', '4485', (118, 122))	('promote', 'PosReg', (79, 86))	('chimeric', 'Var', (34, 42))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (3, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('PAX3', 'Gene', (43, 47))	('tumor', 'Disease', (87, 92))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (3, 28))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('dysregulation', 'Var', (128, 141))	('PAX3', 'Gene', '5077', (43, 47))	('FOXO1', 'Gene', '2308', (48, 53))	('MST1', 'Gene', (118, 122))	('YAP1', 'Gene', '10413', (145, 149))
301538	28745431	Cytogenetic analysis of CCS revealed the presence of translocation t(12;22)(q13;q12), resulting in a chimeric EWSR1-ATF1 gene 11, 12, 13, 14.	('chimeric', 'Var', (101, 109))	('ATF1', 'Gene', '466', (116, 120))	('EWSR1', 'Gene', (110, 115))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (67, 84))	('EWSR1', 'Gene', '2130', (110, 115))	('ATF1', 'Gene', (116, 120))
301543	28745431	Clinical trials revealed that trabectedin is particularly active in sarcomas bearing translocations, namely myxoid liposarcoma, Ewing sarcoma, and synovial sarcoma 24, 25.	('myxoid liposarcoma', 'Disease', (108, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (147, 163))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (108, 126))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcomas', 'Disease', (68, 76))	('liposarcoma', 'Phenotype', 'HP:0012034', (115, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('translocations', 'Var', (85, 99))	('Ewing sarcoma', 'Disease', (128, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (108, 126))	('synovial sarcoma', 'Disease', (147, 163))	('trabectedin', 'Chemical', 'MESH:D000077606', (30, 41))	('synovial sarcoma', 'Disease', 'MESH:D013584', (147, 163))
301603	28745431	Since trabectedin appeared to induce melanocytic differentiation by deregulating the activation of ERK, we investigated whether its similar effect on CCS was promoted by the treatment of SCH772984, a specific inhibitor of ERK signaling.	('trabectedin', 'Chemical', 'MESH:D000077606', (6, 17))	('induce', 'PosReg', (30, 36))	('activation', 'MPA', (85, 95))	('deregulating', 'Var', (68, 80))	('SCH772984', 'Chemical', 'MESH:C587178', (187, 196))	('melanocytic differentiation', 'CPA', (37, 64))	('ERK', 'Gene', '5594', (99, 102))	('ERK', 'Gene', '5594', (222, 225))	('ERK', 'Gene', (99, 102))	('ERK', 'Gene', (222, 225))	('SCH772984', 'Var', (187, 196))
301604	28745431	Similar to trabectedin, SCH772984 suppressed ERK activation and upregulated MITF protein level in Hewga-CCS and KAS cells (Fig.	('SCH772984', 'Chemical', 'MESH:C587178', (24, 33))	('ERK', 'Gene', (45, 48))	('SCH772984', 'Var', (24, 33))	('Hewga-CCS', 'Chemical', '-', (98, 107))	('upregulated', 'PosReg', (64, 75))	('suppressed', 'NegReg', (34, 44))	('KAS', 'Chemical', '-', (112, 115))	('activation', 'MPA', (49, 59))	('ERK', 'Gene', '5594', (45, 48))	('MITF', 'Gene', '4286', (76, 80))	('MITF', 'Gene', (76, 80))	('trabectedin', 'Chemical', 'MESH:D000077606', (11, 22))
301615	28745431	reported that PAX3/PAX7-FOXO1 translocation promoted the differentiation arrest in the myogenic lineage, resulting in alveolar rhabdomyosarcoma sarcomagenesis 39.	('alveolar rhabdomyosarcoma sarcomagenesis', 'Disease', (118, 158))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (127, 143))	('promoted', 'PosReg', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('alveolar rhabdomyosarcoma sarcomagenesis', 'Disease', 'MESH:D018232', (118, 158))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('FOXO1', 'Gene', '2308', (24, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('PAX7', 'Gene', '5081', (19, 23))	('FOXO1', 'Gene', (24, 29))	('arrest', 'Disease', (73, 79))	('PAX3', 'Gene', '5077', (14, 18))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (118, 143))	('PAX3', 'Gene', (14, 18))	('PAX7', 'Gene', (19, 23))	('translocation', 'Var', (30, 43))
301620	28745431	CCS is characterized by a chromosomal translocation, t(12;22)(q13;q12), that leads to the fusion of EWSR1 gene with a CREB-family transcription factor gene (ATF1, or more rarely CREB1) 11, 12, 13, 14.	('CREB1', 'Gene', (178, 183))	('EWSR1', 'Gene', (100, 105))	('ATF1', 'Gene', '466', (157, 161))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 70))	('CCS', 'Disease', (0, 3))	('fusion', 'Var', (90, 96))	('EWSR1', 'Gene', '2130', (100, 105))	('CREB1', 'Gene', '1385', (178, 183))	('ATF1', 'Gene', (157, 161))	('leads to', 'Reg', (77, 85))
301644	27191748	Other infrequent variant fusion proteins are the products of ES translocations and are absent in non-tumor cells.	('non-tumor', 'Disease', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('ES', 'Phenotype', 'HP:0012254', (61, 63))	('non-tumor', 'Disease', 'MESH:D009369', (97, 106))	('fusion proteins', 'Protein', (25, 40))	('variant', 'Var', (17, 24))
301650	27191748	EWS-FLI1 expression under the control of the Prx1 promoter resulted in developmental malformations in the limbs, but not tumor formation.	('Prx1', 'Gene', (45, 49))	('expression', 'Var', (9, 19))	('malformations in the limbs', 'Phenotype', 'HP:0040064', (85, 111))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('EWS-FLI1', 'Gene', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('developmental malformations', 'Disease', 'MESH:D000014', (71, 98))	('resulted in', 'Reg', (59, 70))	('Prx1', 'Gene', '18933', (45, 49))	('developmental malformations', 'Disease', (71, 98))
301652	27191748	Moreover, EWS-FLI1 expression under the control of the Mx1 promoter resulted in the rapid development of myeloid/erythroid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('myeloid/erythroid leukemia', 'Phenotype', 'HP:0005531', (105, 131))	('myeloid/erythroid leukemia', 'Disease', 'MESH:D007951', (105, 131))	('resulted in', 'Reg', (68, 79))	('men', 'Species', '9606', (97, 100))	('expression', 'Var', (19, 29))	('myeloid/erythroid leukemia', 'Disease', (105, 131))	('EWS-FLI1', 'Gene', (10, 18))	('Mx1', 'Gene', '17857', (55, 58))	('Mx1', 'Gene', (55, 58))
301657	27191748	The expression of EWS-FLI1 in zebrafish also results in tumor formation, with higher incidences on the p53 null background.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('results in', 'Reg', (45, 55))	('tumor', 'Disease', (56, 61))	('expression', 'Var', (4, 14))	('EWS-FLI1', 'Gene', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('zebrafish', 'Species', '7955', (30, 39))
301659	27191748	Therefore, these models do not fulfill the need for a transgenic mouse that develops spontaneous ES driven by EWS-FLI1 expression.	('mouse', 'Species', '10090', (65, 70))	('ES', 'Phenotype', 'HP:0012254', (97, 99))	('transgenic', 'Species', '10090', (54, 64))	('expression', 'Var', (119, 129))	('EWS-FLI1', 'Gene', (110, 118))
301673	27191748	We failed to detect EWS-FLI1 expression in compound animals of the #784 E/F+/- Runx2-Cre+ and #1634 E/F+/- Runx2-Cre+ lines.	('#784 E/F+/-', 'Var', (67, 78))	('Runx2', 'Gene', (107, 112))	('#1634 E/F+/-', 'Var', (94, 106))	('EWS-FLI1', 'Gene', (20, 28))	('Runx2', 'Gene', '12393', (79, 84))	('Runx2', 'Gene', '12393', (107, 112))	('Runx2', 'Gene', (79, 84))
301679	27191748	While genetic PCR showed that these offspring carried the E/F transgene, no #777 Runx2-Cre expression in parallel could be detected, suggesting negative selection and the loss of double transgenic embryos during early embryonic development.	('E/F transgene', 'Var', (58, 71))	('transgenic', 'Species', '10090', (186, 196))	('Runx2', 'Gene', '12393', (81, 86))	('men', 'Species', '9606', (235, 238))	('Runx2', 'Gene', (81, 86))
301680	27191748	EWS-FLI1 has a growth inhibitory effect in most primary cells, and the loss of p16INK4a enables the cells to tolerate EWS-FLI1 expression in vitro.	('p16INK4a', 'Gene', '12578', (79, 87))	('rat', 'Species', '10116', (113, 116))	('growth inhibitory effect', 'MPA', (15, 39))	('p16INK4a', 'Gene', (79, 87))	('EWS-FLI1', 'Gene', (118, 126))	('loss', 'Var', (71, 75))
301681	27191748	Therefore, we postulated that the lethal effect of EWS-FLI1 on Runx2-Cre-expressing cells could be relieved by deleting the p16ink4a locus.	('Runx2', 'Gene', (63, 68))	('p16ink4a', 'Gene', (124, 132))	('Runx2', 'Gene', '12393', (63, 68))	('deleting', 'Var', (111, 119))	('EWS-FLI1', 'Gene', (51, 59))	('p16ink4a', 'Gene', '12578', (124, 132))
301685	27191748	The deletion of the STOP-cassette was confirmed in the bone and testis, but no expression of EWS-FLI1 could be observed (Supplementary Figure S6).	('men', 'Species', '9606', (127, 130))	('deletion', 'Var', (4, 12))	('EWS-FLI1', 'Gene', (93, 101))
301695	27191748	Osx-Cre-mediated deletion of p53 and Rb in both Osx-Cre+ p53fl/+ pRbfl/+ and Osx-Cre+ p53fl/fl pRbfl/fl mice resulted in osteosarcoma, and the latency of the disease could be delayed using a doxycycline diet.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('resulted in', 'Reg', (109, 120))	('Osx', 'Gene', (77, 80))	('Osx', 'Gene', '170574', (77, 80))	('doxycycline', 'Chemical', 'MESH:D004318', (191, 202))	('mice', 'Species', '10090', (104, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (121, 133))	('p53', 'Gene', (29, 32))	('Osx', 'Gene', '170574', (0, 3))	('osteosarcoma', 'Disease', (121, 133))	('deletion', 'Var', (17, 25))	('Osx', 'Gene', (0, 3))	('Osx', 'Gene', '170574', (48, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (121, 133))	('Osx', 'Gene', (48, 51))
301703	27191748	Therefore, it is possible that EWS-FLI1 is expressed in the hematopoietic lineage and induces leukemia in E/F+/- Osx-Cre+ p53fl/+ pRbfl/+ mice as the result of leakiness of the Osx-Cre system.	('Osx', 'Gene', (177, 180))	('Osx', 'Gene', '170574', (177, 180))	('Osx', 'Gene', '170574', (113, 116))	('induces', 'Reg', (86, 93))	('EWS-FLI1', 'Var', (31, 39))	('Osx', 'Gene', (113, 116))	('mice', 'Species', '10090', (138, 142))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('leukemia', 'Disease', (94, 102))	('leakiness', 'Disease', 'MESH:C535298', (160, 169))	('leukemia', 'Disease', 'MESH:D007938', (94, 102))	('leakiness', 'Disease', (160, 169))
301705	27191748	This mouse model was created by knocking-in (KI) the human FLI1 cDNA (spanning exons 5-9) with a C-terminal FLAG epitope into mouse Ews exon 7 (Supplementary Figure S9 and).	('mouse', 'Species', '10090', (126, 131))	('FLI1', 'Gene', (59, 63))	('men', 'Species', '9606', (150, 153))	('knocking-in', 'Var', (32, 43))	('human', 'Species', '9606', (53, 58))	('mouse', 'Species', '10090', (5, 10))
301713	27191748	Alternatively, low but detectable expression of Cre in non-osseous tissues of the Col 2.3-Cre and Col 3.6-Cre mice (such as the kidney, liver and skin) might have resulted in embryonic lethality.	('Col', 'Var', (98, 101))	('embryonic lethality', 'Disease', 'MESH:D020964', (175, 194))	('Col 2', 'Gene', '12824', (82, 87))	('embryonic lethality', 'Disease', (175, 194))	('mice', 'Species', '10090', (110, 114))	('Col 2', 'Gene', (82, 87))	('resulted in', 'Reg', (163, 174))
301736	27191748	For the conditional approach, an antisense EWS-FLI1 cassette was flanked with single mutated Lox sites (Lox66, Lox71).	('Lox', 'Gene', (93, 96))	('Lox', 'Gene', '16948', (104, 107))	('Lox', 'Gene', (111, 114))	('antisense', 'Var', (33, 42))	('Lox', 'Gene', '16948', (93, 96))	('EWS-FLI1', 'Gene', (43, 51))	('Lox', 'Gene', '16948', (111, 114))	('Lox', 'Gene', (104, 107))
301748	27191748	This led us to speculate about the possible leaky expression of EWS-FLI1 leading to toxicity in Model #10COMET chimeric tissues.	('leading to', 'Reg', (73, 83))	('toxicity', 'Disease', (84, 92))	('EWS-FLI1', 'Gene', (64, 72))	('COMET', 'Species', '302767', (105, 110))	('toxicity', 'Disease', 'MESH:D064420', (84, 92))	('leaky expression', 'Var', (44, 60))
301749	27191748	To overcome a described bidirectional activity of the PGK promoter that may have led to EWS-FLI1 expression, embryonic stem cell clones, 2C12 and 2D8, were transiently transfected with the pCAGGS-Flpe plasmid in order to delete the PGK-Neo selection cassette through FLPe/FRT-mediated excision (Supplementary Figure S16).	('EWS-FLI1', 'Gene', (88, 96))	('PGK-Neo selection cassette', 'Gene', (232, 258))	('delete', 'Var', (221, 227))	('men', 'Species', '9606', (301, 304))	('led to', 'Reg', (81, 87))
301765	27191748	These authors reported severe limb development defects in E14.5 embryos and embryonic lethality in one of their transgenic lines (EF-c), while two other transgenic lines showed milder limb deformities and a normal life span.	('men', 'Species', '9606', (42, 45))	('transgenic', 'Species', '10090', (153, 163))	('limb deformities', 'Disease', 'MESH:D017880', (184, 200))	('transgenic', 'Species', '10090', (112, 122))	('limb development defects', 'CPA', (30, 54))	('embryonic lethality', 'Disease', 'MESH:D020964', (76, 95))	('E14.5', 'Var', (58, 63))	('embryonic lethality', 'Disease', (76, 95))	('limb deformities', 'Disease', (184, 200))	('limb deformities', 'Phenotype', 'HP:0002813', (184, 200))	('severe limb development defects', 'Phenotype', 'HP:0200083', (23, 54))
301782	27191748	Early Cre expression resulted in the deletion of the selection cassettes and the generation of mice with a single lox site in the middle of the Ewsr1 locus (Ewslox/wt) and in the middle of the Fli1 locus (Fli1lox/wt), which was confirmed by genomic DNA sequencing (Supplementary Figure S21A).	('lox', 'Gene', (209, 212))	('men', 'Species', '9606', (271, 274))	('Fli1', 'Gene', (193, 197))	('mice', 'Species', '10090', (95, 99))	('Ewsr1', 'Gene', (144, 149))	('deletion', 'Var', (37, 45))	('Fli1', 'Gene', (205, 209))	('lox', 'Gene', '16948', (160, 163))	('lox', 'Gene', '16948', (209, 212))	('Ewsr1', 'Gene', '14030', (144, 149))	('rat', 'Species', '10116', (85, 88))	('lox', 'Gene', (114, 117))	('Fli1', 'Gene', '14247', (205, 209))	('Fli1', 'Gene', '14247', (193, 197))	('lox', 'Gene', (160, 163))	('lox', 'Gene', '16948', (114, 117))	('S21A', 'Mutation', 'p.S21A', (286, 290))
301798	27191748	The mice in the experimental cohorts were Ewslox/+; Fli1lox/+; Cre+, and those in the control cohorts were Ewslox/+; Fli1lox/+; Cre-.	('Ewslox/+', 'Var', (42, 50))	('men', 'Species', '9606', (22, 25))	('mice', 'Species', '10090', (4, 8))	('Fli1lox/+', 'Var', (52, 61))
301816	27191748	To test whether the loss of the tumor suppressors Ink4a and Arf would enable tumor formation or whether EWS-FLI1 was able to alter the tumors formed with Ink4a/Arf loss, cohorts of mice were generated such that Cre expression would delete the Ink4a/Arf locus as well as induce Ews-Fli1 translocation.	('Ink4a/Arf', 'Gene', '12578', (154, 163))	('mice', 'Species', '10090', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('delete', 'NegReg', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Disease', (135, 141))	('Arf', 'Gene', '12578', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('loss', 'NegReg', (164, 168))	('Ink4a', 'Gene', '12578', (154, 159))	('Ink4a', 'Gene', '12578', (243, 248))	('Arf', 'Gene', (60, 63))	('Ink4a', 'Gene', (154, 159))	('Arf', 'Gene', '12578', (249, 252))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('Ink4a', 'Gene', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('induce', 'Reg', (270, 276))	('Ink4a', 'Gene', '12578', (50, 55))	('Ink4a/Arf', 'Gene', (243, 252))	('Ink4a', 'Gene', (50, 55))	('Arf', 'Gene', (249, 252))	('Cre expression', 'Var', (211, 225))	('tumor', 'Disease', (135, 140))	('Arf', 'Gene', '12578', (160, 163))	('translocation', 'MPA', (286, 299))	('rat', 'Species', '10116', (195, 198))	('tumor', 'Disease', (32, 37))	('Ink4a/Arf', 'Gene', '12578', (243, 252))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('Fli1', 'Gene', '14247', (281, 285))	('Arf', 'Gene', (160, 163))	('Ink4a/Arf', 'Gene', (154, 163))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('Fli1', 'Gene', (281, 285))	('tumor', 'Disease', (77, 82))
301821	27191748	The survival curves for these mice demonstrated that EWS-FLI1 did not enhance or change the tumor phenotype of these mice (Supplementary Figures S22D-F).	('mice', 'Species', '10090', (30, 34))	('EWS-FLI1', 'Gene', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('S22D', 'SUBSTITUTION', 'None', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mice', 'Species', '10090', (117, 121))	('S22D', 'Var', (145, 149))	('tumor', 'Disease', (92, 97))	('rat', 'Species', '10116', (42, 45))
301823	27191748	The loss of Ink4a/Arf alone either with or without EWS-FLI1 expression led to decreased survival of the mice such that the majority of the Ink4a/Arfflox/flox; Cre+ mice died earlier than the control mice.	('survival', 'CPA', (88, 96))	('lox', 'Gene', (154, 157))	('lox', 'Gene', '16948', (149, 152))	('lox', 'Gene', '16948', (154, 157))	('mice', 'Species', '10090', (199, 203))	('mice', 'Species', '10090', (164, 168))	('mice', 'Species', '10090', (104, 108))	('lox', 'Gene', (149, 152))	('Ink4a/Arf', 'Gene', '12578', (139, 148))	('Ink4a/Arf', 'Gene', '12578', (12, 21))	('EWS-FLI1', 'Gene', (51, 59))	('decreased', 'NegReg', (78, 87))	('Ink4a/Arf', 'Gene', (139, 148))	('Ink4a/Arf', 'Gene', (12, 21))	('loss', 'Var', (4, 8))
301825	27191748	By normalizing to a line that did not express mouse Ews-Fli1 and using a positive control for mouse Ews-Fli1 expression (mouse EWS-FLI1-overexpressing MEFs), we demonstrated that none of the tumors from the Ink4a/Arf tumor study expressed Ews-Fli1 at levels above background (Supplementary Figure S21B).	('men', 'Species', '9606', (282, 285))	('MEFs', 'CellLine', 'CVCL:9115', (151, 155))	('mouse', 'Species', '10090', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('Fli1', 'Gene', '14247', (56, 60))	('Ink4a/Arf', 'Gene', (207, 216))	('S21B', 'SUBSTITUTION', 'None', (297, 301))	('Fli1', 'Gene', (56, 60))	('tumor', 'Disease', (217, 222))	('mouse', 'Species', '10090', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('Ink4a/Arf', 'Gene', '12578', (207, 216))	('Fli1', 'Gene', '14247', (243, 247))	('Fli1', 'Gene', (243, 247))	('tumor', 'Disease', (191, 196))	('S21B', 'Var', (297, 301))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('Fli1', 'Gene', '14247', (104, 108))	('mouse', 'Species', '10090', (121, 126))	('rat', 'Species', '10116', (168, 171))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('Fli1', 'Gene', (104, 108))
301831	27191748	Thus, although EWS-FLI1 expression could induce neoplastic transformation of BM-MSCs, the lesions did not recapitulate the morphologic characteristics of the small, round cells observed in human ES.	('neoplastic transformation', 'CPA', (48, 73))	('EWS-FLI1', 'Gene', (15, 23))	('human', 'Species', '9606', (189, 194))	('induce', 'Reg', (41, 47))	('expression', 'Var', (24, 34))	('BM-MSCs', 'Disease', (77, 84))	('ES', 'Phenotype', 'HP:0012254', (195, 197))
301843	27191748	We observed muscle loss, limping, and prolonged clasping of the hind leg in the Ad5-Cre injected leg, but not in the Ad5-eGFP injected leg (Figure 5A and Supplementary Figure S28B).	('S28B', 'Var', (175, 179))	('muscle loss', 'Disease', 'MESH:D009133', (12, 23))	('muscle loss', 'Disease', (12, 23))	('Ad5-Cre', 'Var', (80, 87))	('limping', 'CPA', (25, 32))	('S28B', 'SUBSTITUTION', 'None', (175, 179))	('men', 'Species', '9606', (160, 163))	('clasping', 'CPA', (48, 56))	('muscle loss', 'Phenotype', 'HP:0003202', (12, 23))
301844	27191748	Significant muscle loss was observed in the Ad5-Cre-injected left leg compared to the Ad5-eGFP-injected right leg of the same mouse, which was quantitated as the width of the quadriceps femoris muscle (Figure 5B and 5C).	('mouse', 'Species', '10090', (126, 131))	('muscle loss', 'Disease', 'MESH:D009133', (12, 23))	('quadriceps femoris muscle', 'Disease', 'MESH:D009135', (175, 200))	('muscle loss', 'Disease', (12, 23))	('muscle loss', 'Phenotype', 'HP:0003202', (12, 23))	('quadriceps femoris muscle', 'Disease', (175, 200))	('Ad5-Cre-injected', 'Var', (44, 60))
301847	27191748	Hence, the observed myopathy in the legs injected with Ad5-Cre may have been due to the apoptotic effect of EWS-FLI1 in the myocytes in which Cre-mediated recombination may have occurred.	('Ad5-Cre', 'Var', (55, 62))	('myopathy', 'Phenotype', 'HP:0003198', (20, 28))	('myopathy', 'Disease', (20, 28))	('apoptotic effect', 'CPA', (88, 104))	('EWS-FLI1', 'Gene', (108, 116))	('myopathy', 'Disease', 'MESH:D009135', (20, 28))
301854	27191748	Three weeks following injection in 1-day-old mice, most of the Ad5-Cre mice presented with abdominal distention (Figure 5D and Supplementary Figure S29B).	('mice', 'Species', '10090', (71, 75))	('abdominal distention', 'Phenotype', 'HP:0003270', (91, 111))	('Ad5-Cre', 'Var', (63, 70))	('mice', 'Species', '10090', (45, 49))	('abdominal distention', 'CPA', (91, 111))	('S29B', 'Var', (148, 152))	('men', 'Species', '9606', (133, 136))	('S29B', 'SUBSTITUTION', 'None', (148, 152))
301873	27191748	Therefore, tumor-specific chromosomal translocation products can produce specific types of sarcomas in mice when they are expressed at the right time, in the right cell population and, in some cases, with the help of deleting tumor suppressors.	('produce', 'Reg', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('chromosomal translocation products', 'Var', (26, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('sarcomas', 'Disease', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', (226, 231))
301876	27191748	In most cell types, the expression of EWS-FLI1 induces growth arrest or apoptosis.	('induces', 'Reg', (47, 54))	('growth arrest', 'Phenotype', 'HP:0001510', (55, 68))	('apoptosis', 'CPA', (72, 81))	('expression', 'Var', (24, 34))	('EWS-FLI1', 'Gene', (38, 46))	('growth arrest', 'Disease', 'MESH:D006323', (55, 68))	('growth arrest', 'Disease', (55, 68))
301887	27191748	Furthermore, low but detectable levels of Cre activity were reported in the non-osseous tissues of these mice, suggesting the possibility that non-osseous EWS-FLI1 expression caused embryonic lethality.	('embryonic lethality', 'Disease', 'MESH:D020964', (182, 201))	('caused', 'Reg', (175, 181))	('embryonic lethality', 'Disease', (182, 201))	('expression', 'Var', (164, 174))	('EWS-FLI1', 'Gene', (155, 163))	('mice', 'Species', '10090', (105, 109))
301891	27191748	Similarly to MYC, EWS-FLI1 may function as a transcriptional amplifier of gene expression by binding to open promoters of widely expressed genes; EWS-FLI1 may also activate novel enhancers and superenhancers.	('superenhancers', 'CPA', (193, 207))	('enhancers', 'PosReg', (179, 188))	('activate', 'PosReg', (164, 172))	('EWS-FLI1', 'Var', (146, 154))	('MYC', 'Gene', '17869', (13, 16))	('MYC', 'Gene', (13, 16))
301893	27191748	Alternative splicing is emerging as an important mechanism in carcinogenesis.	('Alternative splicing', 'Var', (0, 20))	('carcinogenesis', 'Disease', (62, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))
301905	27191748	In addition to its diagnostic value, inhibition of CD99 expression or engagement by CD99 antibodies stop growth of ES cell lines both in culture and in xenograft models.	('inhibition', 'Var', (37, 47))	('engagement', 'Interaction', (70, 80))	('stop growth', 'Phenotype', 'HP:0001510', (100, 111))	('CD99', 'Gene', (51, 55))	('men', 'Species', '9606', (76, 79))	('ES', 'Phenotype', 'HP:0012254', (115, 117))	('expression', 'MPA', (56, 66))	('stop', 'NegReg', (100, 104))	('growth of ES cell lines', 'CPA', (105, 128))	('CD99', 'Gene', (84, 88))
301912	27191748	In summary, the ectopic expression of EWS-FLI1 in murine MSCs, neural crest-derived stem cells, or osteochondrogenic progenitor cells could transform primary cells into malignant tumor cells.	('murine', 'Species', '10090', (50, 56))	('ectopic expression', 'Var', (16, 34))	('transform', 'Reg', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('EWS-FLI1', 'Gene', (38, 46))	('tumor', 'Disease', (179, 184))
301917	27191748	E/F mice harboring a Cre-inducible EWS-FLI1 knocked into the ubiquitous ROSA26 locus (ROSA26loxP-STOPloxP-HA-EWS-FLI1 allele) were crossed to three different Runx2-Cre isoforms.	('lox', 'Gene', (92, 95))	('ROSA26', 'Gene', (86, 92))	('Runx2', 'Gene', (158, 163))	('ROSA26', 'Gene', (72, 78))	('lox', 'Gene', '16948', (101, 104))	('mice', 'Species', '10090', (4, 8))	('knocked', 'Var', (44, 51))	('lox', 'Gene', '16948', (92, 95))	('Runx2', 'Gene', '12393', (158, 163))	('ROSA26', 'Gene', '14910', (86, 92))	('ROSA26', 'Gene', '14910', (72, 78))	('EWS-FLI1', 'Gene', (35, 43))	('lox', 'Gene', (101, 104))
301981	27191748	MEFs were isolated as following standard procedures from E13.5 embryos and cultured in DMEM with 10% BGS and 100U/100ug/2 mM Pen/Strep/Glutamine (Invitrogen).	('DMEM', 'Chemical', '-', (87, 91))	('Pen', 'Gene', (125, 128))	('MEFs', 'CellLine', 'CVCL:9115', (0, 4))	('100U/100ug/2', 'Var', (109, 121))	('Glutamine', 'Chemical', 'MESH:D005973', (135, 144))	('Pen', 'Gene', '30052', (125, 128))
301982	27191748	Mouse bone progenitor cells were isolated as previously described and cultured in alpha-MEM supplemented with 20% fetal bovine serum (Omega Scientific) and 100U/100mug/2 mM Pen/Strep/Glutamine (Invitrogen).	('bovine', 'Species', '9913', (120, 126))	('Pen', 'Gene', (173, 176))	('alpha-MEM', 'Chemical', 'MESH:C420642', (82, 91))	('Glutamine', 'Chemical', 'MESH:D005973', (183, 192))	('Mouse', 'Species', '10090', (0, 5))	('Pen', 'Gene', '30052', (173, 176))	('men', 'Species', '9606', (98, 101))	('100U/100mug/2', 'Var', (156, 169))
302092	33453728	3), and the SYT gene rearrangement was detected in 71% of cells; thus confirming the diagnosis of synovial sarcoma.	('SYT', 'Gene', (12, 15))	('synovial sarcoma', 'Disease', (98, 114))	('rearrangement', 'Var', (21, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('SYT', 'Gene', '6760', (12, 15))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (98, 114))	('synovial sarcoma', 'Disease', 'MESH:D013584', (98, 114))
302116	33453728	Focal S100 protein or SOX10 positivity can also be seen in a percentage of cases.	('SOX10', 'Gene', '6663', (22, 27))	('positivity', 'Var', (28, 38))	('SOX10', 'Gene', (22, 27))	('S100', 'Gene', (6, 10))	('S100', 'Gene', '6271', (6, 10))
302138	33453728	The rate of recurrence and metastasis was not significantly different (p > 0.05) when comparing tumor size (less than or equal to 5 cm versus those greater than 5 cm), histology subtype (biphasic versus monophasic), and age (those less than or equal to 40 versus those older than 40).	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('less', 'Var', (108, 112))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))
302204	32691176	Here, we present the first case of a primary SS of the esophagus in the presence of SS18-SSX2 fusion transcripts.	('primary SS', 'Disease', (37, 47))	('SS', 'Phenotype', 'HP:0012570', (84, 86))	('SS', 'Phenotype', 'HP:0012570', (89, 91))	('SS18', 'Gene', (84, 88))	('SSX2', 'Gene', '6757', (89, 93))	('SS', 'Phenotype', 'HP:0012570', (45, 47))	('SSX2', 'Gene', (89, 93))	('fusion transcripts', 'Var', (94, 112))	('SS18', 'Gene', '6760', (84, 88))
302216	32691176	The majority of patients with SS carry the pathognomonic t(X;18) (p11.2;q11.2) translocation, resulting in fusion of the SS18 (formerly SYT) gene on chromosome 18 with an SSX gene on chromosome X.	('SS18', 'Gene', (121, 125))	('SS', 'Phenotype', 'HP:0012570', (30, 32))	('SYT', 'Gene', '6760', (136, 139))	('SS', 'Phenotype', 'HP:0012570', (171, 173))	('patients', 'Species', '9606', (16, 24))	('SSX', 'Gene', '6757', (171, 174))	('fusion', 'Var', (107, 113))	('SSX', 'Gene', (171, 174))	('SS18', 'Gene', '6760', (121, 125))	('SYT', 'Gene', (136, 139))	('SS', 'Phenotype', 'HP:0012570', (121, 123))
302217	32691176	Here, we report the first case of monophasic SS of the esophagus in the presence of SS18-SSX2 fusion transcripts detected by reverse transcription-polymerase chain reaction (RT-PCR) analysis using a paraffin-embedded tumor specimen, which was originally misdiagnosed as leiomyoma.	('SS', 'Phenotype', 'HP:0012570', (84, 86))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('SSX2', 'Gene', (89, 93))	('SS', 'Phenotype', 'HP:0012570', (89, 91))	('SS18', 'Gene', (84, 88))	('SSX2', 'Gene', '6757', (89, 93))	('SS18', 'Gene', '6760', (84, 88))	('SS', 'Phenotype', 'HP:0012570', (45, 47))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('leiomyoma', 'Disease', (270, 279))	('leiomyoma', 'Disease', 'MESH:D007889', (270, 279))	('fusion transcripts', 'Var', (94, 112))	('paraffin', 'Chemical', 'MESH:D010232', (199, 207))
302306	31726650	As expected, distant metastases at diagnosis were predictive of worse OS in our cohort.	('metastases', 'Disease', (21, 31))	('distant', 'Var', (13, 20))	('worse OS', 'Disease', (64, 72))	('metastases', 'Disease', 'MESH:D009362', (21, 31))
302329	31726650	Patients were identified using the ICD-O-3 histology codes for angiosarcoma (M9120), lymphangiosarcoma (M9170), EHE (M9133), and hemangioendothelioma (M9130).	('angiosarcoma', 'Disease', 'MESH:D006394', (90, 102))	('M9133', 'Var', (117, 122))	('angiosarcoma', 'Phenotype', 'HP:0200058', (63, 75))	('EHE', 'Phenotype', 'HP:0032060', (112, 115))	('angiosarcoma', 'Disease', (90, 102))	('Patients', 'Species', '9606', (0, 8))	('lymphangiosarcoma', 'Disease', 'MESH:C537491', (85, 102))	('lymphangiosarcoma', 'Disease', (85, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('angiosarcoma', 'Phenotype', 'HP:0200058', (90, 102))	('angiosarcoma', 'Disease', 'MESH:D006394', (63, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('EHE', 'Disease', (112, 115))	('angiosarcoma', 'Disease', (63, 75))	('hemangioendothelioma', 'Disease', 'MESH:D006390', (129, 149))	('hemangioendothelioma', 'Disease', (129, 149))
302430	25115417	If a tumor can be shown to express a mutated gene as an oncogene or tumor suppressor gene such as p53 or an exaggerated expression of a particular gene that acts as a driving mutation, the potential for therapy is obvious.	('tumor', 'Disease', (68, 73))	('exaggerated', 'PosReg', (108, 119))	('expression', 'MPA', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('p53', 'Gene', (98, 101))	('mutated gene', 'Var', (37, 49))	('tumor', 'Disease', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('p53', 'Gene', '7157', (98, 101))
302431	25115417	This is well described in the identification of the c-kit mutation in gastrointestinal stromal tumors.	('c-kit', 'Gene', (52, 57))	('mutation', 'Var', (58, 66))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (70, 101))	('c-kit', 'Gene', '3815', (52, 57))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (70, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('gastrointestinal stromal tumors', 'Disease', (70, 101))
302434	25115417	With increasing knowledge it has become clear that each selective drug acted presumably against or at least preferentially against one mutation but not others as is seen in the difference between response to the mutated exon 9 and the mutated exon 11 of the c-kit gene.	('c-kit', 'Gene', '3815', (258, 263))	('c-kit', 'Gene', (258, 263))	('mutated', 'Var', (212, 219))
302443	25115417	PIK3CA mutations in myxoid/round-cell liposarcoma were associated with Akt activation and poor clinical outcomes.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('liposarcoma', 'Disease', (38, 49))	('activation', 'PosReg', (75, 85))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('Akt', 'Pathway', (71, 74))	('liposarcoma', 'Phenotype', 'HP:0012034', (38, 49))	('liposarcoma', 'Disease', 'MESH:D008080', (38, 49))	('myxoid/round-cell liposarcoma', 'Phenotype', 'HP:0012268', (20, 49))	('mutations', 'Var', (7, 16))
302448	25115417	Furthermore, PD0332991, a selective CDK4/CDK6 inhibitor, inhibits proliferation by inducing G1 cell-cycle arrest and senescence in dedifferentiated liposarcoma cell lines and xenografts.	('PD0332991', 'Var', (13, 22))	('inducing', 'NegReg', (83, 91))	('arrest', 'Disease', (106, 112))	('CDK4', 'Gene', (36, 40))	('CDK4', 'Gene', '1019', (36, 40))	('liposarcoma', 'Disease', 'MESH:D008080', (148, 159))	('CDK6', 'Gene', (41, 45))	('proliferation', 'CPA', (66, 79))	('liposarcoma', 'Phenotype', 'HP:0012034', (148, 159))	('CDK6', 'Gene', '1021', (41, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('PD0332991', 'Chemical', 'MESH:C500026', (13, 22))	('arrest', 'Disease', 'MESH:D006323', (106, 112))	('senescence', 'CPA', (117, 127))	('liposarcoma', 'Disease', (148, 159))	('inhibits', 'NegReg', (57, 65))
302449	25115417	In a recent phase II trial of PD0332991 in patients with advanced CDK4-amplified liposarcoma, 66% of patients were progression-free at 12 weeks, and a subset had a radiographic response and prolonged stable disease.	('patients', 'Species', '9606', (101, 109))	('liposarcoma', 'Disease', (81, 92))	('patients', 'Species', '9606', (43, 51))	('liposarcoma', 'Disease', 'MESH:D008080', (81, 92))	('liposarcoma', 'Phenotype', 'HP:0012034', (81, 92))	('PD0332991', 'Chemical', 'MESH:C500026', (30, 39))	('CDK4', 'Gene', (66, 70))	('PD0332991', 'Var', (30, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('CDK4', 'Gene', '1019', (66, 70))
302450	25115417	These results provide a rationale for use of MDM2 antagonists and CDK4 inhibitors in patients with well-differentiated and dedifferentiated liposarcoma and show the value of tissue and cell line resources linked to clinical and pathological factors for the discovery of new subtype specific targeted therapy.	('inhibitors', 'Var', (71, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('liposarcoma', 'Disease', (140, 151))	('MDM2', 'Gene', '4193', (45, 49))	('MDM2', 'Gene', (45, 49))	('patients', 'Species', '9606', (85, 93))	('liposarcoma', 'Phenotype', 'HP:0012034', (140, 151))	('liposarcoma', 'Disease', 'MESH:D008080', (140, 151))	('CDK4', 'Gene', (66, 70))	('CDK4', 'Gene', '1019', (66, 70))
302451	25115417	The situation can be expanded to where more extensive genetic or array analysis can then provide further mathematical models looking at significant functional events such as copy number alterations or mutations that begin to dissect the activated signaling pathways by which tumors are driven to grow.	('copy number alterations', 'Var', (174, 197))	('mutations', 'Var', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Disease', (275, 281))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('tumors', 'Disease', 'MESH:D009369', (275, 281))
302457	32290854	Aberrant p53 staining was found in the mural nodules rather than in the mucinous components.	('Aberrant', 'Var', (0, 8))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))
302458	32290854	A concordant KRAS mutation (c.35G > A p.G12A) was identified in both mucinous tumors and mural nodules.	('c.35G > A', 'Mutation', 'rs121913529', (28, 37))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mucinous tumor', 'Phenotype', 'HP:0031495', (69, 83))	('p.G12A', 'Mutation', 'rs121913529', (38, 44))	('mucinous tumors', 'Disease', 'MESH:D002288', (69, 84))	('KRAS', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mural nodules', 'Disease', (89, 102))	('c.35G > A p.G12A', 'Var', (28, 44))	('KRAS', 'Gene', '3845', (13, 17))	('mucinous tumors', 'Disease', (69, 84))
302462	32290854	The adenocarcinomatous component harbored LOH at D18S51 and FGA loci while the sarcomatous component had LOH at D19S433.	('sarcomatous component', 'Disease', 'MESH:D018316', (79, 100))	('FGA', 'Gene', (60, 63))	('adenocarcinomatous component harbored LOH', 'Disease', (4, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomatous component', 'Disease', (79, 100))	('D19S433', 'Var', (112, 119))	('adenocarcinomatous component harbored LOH', 'Disease', 'MESH:C537062', (4, 45))	('FGA', 'Gene', '2243', (60, 63))
302475	32290854	Mutations in K-RAS and PIK3CA have been frequently found in ovarian mucinous borderline tumors and carcinomas.	('K-RAS', 'Gene', '3845', (13, 18))	('K-RAS', 'Gene', (13, 18))	('PIK3CA', 'Gene', (23, 29))	('ovarian mucinous borderline tumors', 'Disease', 'MESH:D010051', (60, 94))	('PIK3CA', 'Gene', '5290', (23, 29))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Disease', 'MESH:D009369', (99, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('ovarian mucinous borderline tumors', 'Disease', (60, 94))	('found', 'Reg', (51, 56))	('carcinomas', 'Disease', (99, 109))
302482	32290854	Strong nuclear staining (> 70% cells) or null staining were defined as aberrant p53 expression (mutant type), and otherwise as normal expression (wild type).	('expression', 'MPA', (84, 94))	('p53', 'Gene', '7157', (80, 83))	('p53', 'Gene', (80, 83))	('aberrant', 'Var', (71, 79))
302485	32290854	Hotspot mutant AKT1 (E17K), KRAS (G12V, G12A, G12D, G13D), HRAS (Q61H), and PI3KCA (E542K, E545K, E546K) alleles were detected by pyrosequencing, a simple, robust, and sensitive method with a limit of approximately 5% mutant alleles even in paraffin embedded tissues.	('G13D', 'Var', (52, 56))	('KRAS', 'Gene', '3845', (28, 32))	('E545K', 'Mutation', 'p.E545K', (91, 96))	('HRAS', 'Gene', '3265', (59, 63))	('AKT1', 'Gene', (15, 19))	('E542K', 'Mutation', 'p.E542K', (84, 89))	('E546K', 'Var', (98, 103))	('KRAS', 'Gene', (28, 32))	('HRAS', 'Gene', (59, 63))	('E546K', 'Mutation', 'p.E546K', (98, 103))	('E17K', 'Var', (21, 25))	('E542K', 'Var', (84, 89))	('G12V', 'Mutation', 'rs121913529', (34, 38))	('E17K', 'Mutation', 'rs121434592', (21, 25))	('G12D', 'Var', (46, 50))	('paraffin', 'Chemical', 'MESH:D010232', (241, 249))	('G12D', 'Mutation', 'rs121913529', (46, 50))	('E545K', 'Var', (91, 96))	('G13D', 'Mutation', 'rs112445441', (52, 56))	('AKT1', 'Gene', '207', (15, 19))	('G12A', 'Mutation', 'rs121913529', (40, 44))	('Q61H', 'Mutation', 'rs121913496', (65, 69))
302488	32290854	Fluorescence multiplex PCR-capillary electrophoresis (FM-CE) was performed to detect microsatellite instability (MSI) and loss of heterozygosity (LOH) in each component of ovarian mucinous tumors and mural nodules (patient 2) by the commercially available AGCU Express Marker 22 Fluorescence Kit (AGCU Scien Tech Incorporation, Wuxi, China).	('mucinous tumor', 'Phenotype', 'HP:0031495', (180, 194))	('component of ovarian mucinous tumors', 'Disease', (159, 195))	('Kit', 'Gene', '3815', (292, 295))	('Kit', 'Gene', (292, 295))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('component of ovarian mucinous tumors', 'Disease', 'MESH:D010051', (159, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('microsatellite instability', 'MPA', (85, 111))	('loss', 'Var', (122, 126))	('ovarian mucinous tumors', 'Phenotype', 'HP:0031494', (172, 195))	('patient', 'Species', '9606', (215, 222))
302489	32290854	The kit can detect 22 short tandem repeats (STR) loci that were labeled with four fluorescent dyes (FAM, HEX, TAMRA and ROX).	('ROX', 'Gene', '84864', (120, 123))	('kit', 'Gene', (4, 7))	('kit', 'Gene', '3815', (4, 7))	('TAMRA', 'Chemical', '-', (110, 115))	('HEX', 'Gene', (105, 108))	('ROX', 'Gene', (120, 123))	('HEX', 'Gene', '3087', (105, 108))	('short tandem repeats', 'Var', (22, 42))
302544	32290854	A concordant KRAS mutation (c.35G > A p.G12A) was identified in both mucinous tumors and mural nodules from patient 1.	('c.35G > A', 'Mutation', 'rs121913529', (28, 37))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mucinous tumor', 'Phenotype', 'HP:0031495', (69, 83))	('p.G12A', 'Mutation', 'rs121913529', (38, 44))	('mucinous tumors', 'Disease', 'MESH:D002288', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patient', 'Species', '9606', (108, 115))	('KRAS', 'Gene', (13, 17))	('c.35G > A p.G12A', 'Var', (28, 44))	('KRAS', 'Gene', '3845', (13, 17))	('mucinous tumors', 'Disease', (69, 84))
302545	32290854	No other hotspot mutant AKT1 (E17K), KRAS (G12V, G12D, G13D), HRAS (Q61H), and PI3KCA (E542K, E545K, E546K) alleles were found in both components from 3 patients.	('HRAS', 'Gene', '3265', (62, 66))	('AKT1', 'Gene', (24, 28))	('HRAS', 'Gene', (62, 66))	('KRAS', 'Gene', (37, 41))	('G12D', 'Var', (49, 53))	('G12D', 'Mutation', 'rs121913529', (49, 53))	('G13D', 'Mutation', 'rs112445441', (55, 59))	('G12V', 'Mutation', 'rs121913529', (43, 47))	('G13D', 'Var', (55, 59))	('E545K', 'Var', (94, 99))	('E17K', 'Var', (30, 34))	('Q61H', 'Mutation', 'rs121913496', (68, 72))	('E17K', 'Mutation', 'rs121434592', (30, 34))	('E545K', 'Mutation', 'p.E545K', (94, 99))	('AKT1', 'Gene', '207', (24, 28))	('patients', 'Species', '9606', (153, 161))	('E542K', 'Mutation', 'p.E542K', (87, 92))	('E546K', 'Var', (101, 106))	('E546K', 'Mutation', 'p.E546K', (101, 106))	('KRAS', 'Gene', '3845', (37, 41))	('E542K', 'Var', (87, 92))
302546	32290854	In patient 2, STR analysis failed in 5 loci (D7S820, D2S414, Penta D, D10S1248 and D6S1043).	('D10S1248', 'Var', (70, 78))	('patient', 'Species', '9606', (3, 10))	('D6S1043', 'Var', (83, 90))	('D7S820', 'Var', (45, 51))	('Penta D', 'Chemical', '-', (61, 68))	('D2S414', 'Var', (53, 59))
302547	32290854	The adenocarcinomatous and sarcomatous component had LOH at D18S51 and FGA loci, and at D19S433 locus, respectively.	('D18S51', 'Var', (60, 66))	('FGA', 'Gene', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcomatous component', 'Disease', 'MESH:D018316', (27, 48))	('adenocarcinomatous and sarcomatous', 'Disease', 'MESH:D018316', (4, 38))	('sarcomatous component', 'Disease', (27, 48))	('D19S433', 'Var', (88, 95))	('FGA', 'Gene', '2243', (71, 74))
302570	32290854	The most frequent genetic alterations in ovarian mucinous tumors are somatic KRAS mutations with a prevalence of 50 to 68% in borderline and malignant tumors generally.	('malignant tumors', 'Disease', 'MESH:D009369', (141, 157))	('ovarian mucinous tumors', 'Disease', (41, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (82, 91))	('KRAS', 'Gene', (77, 81))	('ovarian mucinous tumors', 'Disease', 'MESH:D010051', (41, 64))	('KRAS', 'Gene', '3845', (77, 81))	('malignant tumors', 'Disease', (141, 157))	('mucinous tumor', 'Phenotype', 'HP:0031495', (49, 63))	('ovarian mucinous tumors', 'Phenotype', 'HP:0031494', (41, 64))
302571	32290854	We found that patient 1 had an identical KRAS mutation (c.35G > A p.G12A) in both components in keeping with two previous studies.	('c.35G > A', 'Mutation', 'rs121913529', (56, 65))	('KRAS', 'Gene', '3845', (41, 45))	('c.35G > A p.G12A', 'Var', (56, 72))	('p.G12A', 'Mutation', 'rs121913529', (66, 72))	('patient', 'Species', '9606', (14, 21))	('KRAS', 'Gene', (41, 45))
302572	32290854	suggested that anaplastic mural carcinoma nodules might be more likely to arise in KRAS mutant tumors since 6 of 7 cases harbored somatic KRAS mutations.	('KRAS', 'Gene', (83, 87))	('arise', 'Reg', (74, 79))	('carcinoma nodules', 'Disease', (32, 49))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('KRAS', 'Gene', (138, 142))	('KRAS', 'Gene', '3845', (83, 87))	('KRAS', 'Gene', '3845', (138, 142))	('carcinoma nodules', 'Disease', 'MESH:D009369', (32, 49))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('mutant', 'Var', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
302573	32290854	We observed aberrant p53 expression in the anaplastic carcinomatous nodules and wild-type expression in the mucinous tumors.	('mucinous tumor', 'Phenotype', 'HP:0031495', (108, 122))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mucinous tumors', 'Disease', (108, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('expression', 'MPA', (25, 35))	('p53', 'Gene', '7157', (21, 24))	('mucinous tumors', 'Disease', 'MESH:D002288', (108, 123))	('anaplastic carcinomatous nodules', 'Disease', (43, 75))	('anaplastic carcinomatous nodules', 'Disease', 'MESH:D055756', (43, 75))	('aberrant', 'Var', (12, 20))	('p53', 'Gene', (21, 24))
302574	32290854	Mutant-type p53 expression in anaplastic nodules indicates the potential role of further genomic alterations in an anaplastic morphologic phenotype in some cases.	('Mutant-type', 'Var', (0, 11))	('p53', 'Gene', '7157', (12, 15))	('expression', 'MPA', (16, 26))	('p53', 'Gene', (12, 15))
302575	32290854	showed that p53 mutations were identified only in the anaplastic mural nodules in 2 of their cases.	('p53', 'Gene', '7157', (12, 15))	('mutations', 'Var', (16, 25))	('p53', 'Gene', (12, 15))
302576	32290854	A recent study showed that aberrant p53 staining was exclusively in the undifferentiated component of the dedifferentiated endometrial carcinomas with neuroendocrine features; therefore, p53 mutation was probably crucial for the maintenance of undifferentiated phenotype.	('aberrant', 'Var', (27, 35))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (123, 145))	('p53', 'Gene', (187, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('p53', 'Gene', '7157', (187, 190))	('endometrial carcinomas', 'Disease', (123, 145))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (123, 145))
302581	32290854	No PHF1 and JAZF1 break-apart signals did not support the diagnosis of low grade endometrioid stromal sarcoma, in which, more than 50% cases harbor gene fusions.	('JAZF1', 'Gene', (12, 17))	('PHF1', 'Gene', (3, 7))	('endometrioid stromal sarcoma', 'Disease', (81, 109))	('endometrioid stromal sarcoma', 'Disease', 'MESH:D046152', (81, 109))	('gene fusions', 'Var', (148, 160))	('PHF1', 'Gene', '5252', (3, 7))	('JAZF1', 'Gene', '221895', (12, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
302591	32290854	Only one previous study reported that different KRAS mutations in a case of primary ovarian mucinous adenocarcinoma with mural nodule of high grade sarcoma.	('KRAS', 'Gene', (48, 52))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('KRAS', 'Gene', '3845', (48, 52))	('sarcoma', 'Disease', (148, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('mutations', 'Var', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('primary ovarian mucinous adenocarcinoma', 'Disease', (76, 115))	('primary ovarian mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (76, 115))
302592	32290854	In that study, the presence of KRAS mutations suggested that the sarcomatous component represented a dedifferentiated form of mucinous adenocarcinoma mostly likely.	('KRAS', 'Gene', (31, 35))	('sarcomatous component', 'Disease', 'MESH:D018316', (65, 86))	('sarcomatous component', 'Disease', (65, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('KRAS', 'Gene', '3845', (31, 35))	('mutations', 'Var', (36, 45))	('mucinous adenocarcinoma', 'Disease', (126, 149))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (126, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
302593	32290854	Contradictory to these findings, our molecular investigation on patient 2 observed no somatic mutations in the hotspots of KRA S, AKT1, HRAS, and PI3KCA in both carcinomatous and sarcomatous components.	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('HRAS', 'Gene', (136, 140))	('sarcomatous component', 'Disease', 'MESH:D018316', (179, 200))	('AKT1', 'Gene', (130, 134))	('sarcomatous component', 'Disease', (179, 200))	('patient', 'Species', '9606', (64, 71))	('mutations', 'Var', (94, 103))	('KRA S', 'Gene', (123, 128))	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (161, 190))	('HRAS', 'Gene', '3265', (136, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('AKT1', 'Gene', '207', (130, 134))
302597	32290854	The well circumscription of the nodule, lack of necrosis and vascular invasion, absent or weak expression of multiple epithelial markers and lack of mutations in KRAS, AKT1, HRAS, and PI3KCA hotspots could aid in the diagnosis of SLMN.	('KRAS', 'Gene', (162, 166))	('HRAS', 'Gene', '3265', (174, 178))	('AKT1', 'Gene', '207', (168, 172))	('mutations', 'Var', (149, 158))	('HRAS', 'Gene', (174, 178))	('aid', 'Reg', (206, 209))	('necrosis', 'Disease', (48, 56))	('KRAS', 'Gene', '3845', (162, 166))	('AKT1', 'Gene', (168, 172))	('necrosis', 'Disease', 'MESH:D009336', (48, 56))	('SLMN', 'Disease', (230, 234))	('expression', 'MPA', (95, 105))
302603	32290854	The identical KRAS mutation in both components of mucinous carcinoma and the mural nodules of anaplastic carcinoma provides additional evidence to support that some anaplastic mural nodules represent the dedifferentiation form of mucinous tumors in which p53 mutation may play crucial roles.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (50, 68))	('mutation', 'Var', (19, 27))	('mucinous tumors', 'Disease', 'MESH:D002288', (230, 245))	('KRAS', 'Gene', '3845', (14, 18))	('anaplastic carcinoma', 'Disease', (94, 114))	('anaplastic mural nodules', 'Disease', (165, 189))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (50, 68))	('mucinous carcinoma', 'Disease', (50, 68))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('mucinous tumor', 'Phenotype', 'HP:0031495', (230, 244))	('p53', 'Gene', '7157', (255, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('anaplastic carcinoma', 'Disease', 'MESH:D002277', (94, 114))	('KRAS', 'Gene', (14, 18))	('p53', 'Gene', (255, 258))	('mucinous tumors', 'Disease', (230, 245))
302758	25617839	Ewing Sarcoma Ewsa Protein Regulates Chondrogenesis of Meckel's Cartilage through Modulation of Sox9 in Zebrafish Ewing sarcoma is the second most common skeletal (bone and cartilage) cancer in adolescents, and it is characterized by the expression of the aberrant chimeric fusion gene EWS/FLI1.	('cancer', 'Disease', (184, 190))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Regulates', 'Reg', (27, 36))	('cartilage', 'Disease', 'MESH:D002357', (173, 182))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Sox9', 'Gene', '494585', (96, 100))	('Ewing Sarcoma Ewsa', 'Disease', 'MESH:C563168', (0, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('Sox9', 'Gene', (96, 100))	('FLI1', 'Gene', (290, 294))	('Ewing sarcoma', 'Disease', (114, 127))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('Sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Modulation', 'Var', (82, 92))	('FLI1', 'Gene', '30619', (290, 294))	('cartilage', 'Disease', (173, 182))	('Ewing Sarcoma Ewsa', 'Disease', (0, 18))
302763	25617839	Compared with wt/wt, the Meckel's cartilage of MZ ewsa/ewsa mutants had a higher number of craniofacial prehypertrophic chondrocytes that failed to mature into hypertrophic chondrocytes at 4 days post-fertilization (dpf).	('higher', 'PosReg', (74, 80))	("Meckel's cartilage", 'Disease', 'MESH:C536133', (25, 43))	('hypertrophic', 'Disease', 'MESH:D006984', (160, 172))	("Meckel's cartilage", 'Disease', (25, 43))	('craniofacial prehypertrophic', 'Disease', 'MESH:D019465', (91, 119))	('hypertrophic', 'Disease', (107, 119))	('mutants', 'Var', (60, 67))	('hypertrophic', 'Disease', (160, 172))	('craniofacial prehypertrophic', 'Disease', (91, 119))	('dpf', 'Chemical', '-', (216, 219))	('hypertrophic', 'Disease', 'MESH:D006984', (107, 119))
302767	25617839	Consistently, immunohistochemistry showed that the Ctgf protein is upregulated in the Meckel's cartilage of MZ ewsa/ewsa mutants.	("Meckel's cartilage", 'Disease', 'MESH:C536133', (86, 104))	('Ctgf', 'Gene', (51, 55))	('mutants', 'Var', (121, 128))	("Meckel's cartilage", 'Disease', (86, 104))	('protein', 'Protein', (56, 63))	('Ctgf', 'Gene', '321449', (51, 55))	('upregulated', 'PosReg', (67, 78))
302773	25617839	A major genetic hallmark of Ewing sarcoma is the aberrant fusion gene EWS/FLI1.	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('FLI1', 'Gene', '30619', (74, 78))	('Ewing sarcoma', 'Disease', (28, 41))	('FLI1', 'Gene', (74, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))	('aberrant fusion gene', 'Var', (49, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (28, 41))
302787	25617839	Although the cause of death was undetermined, the EWS knockout mice were smaller in size compared with their wildtype littermates, indicating that EWS may play a role in development.	('EWS', 'Gene', (50, 53))	('mice', 'Species', '10090', (63, 67))	('smaller', 'NegReg', (73, 80))	('knockout', 'Var', (54, 62))
302792	25617839	In this study, we discovered that the maternal zygotic (MZ) ewsa/ewsa mutant zebrafish display defects in chondrogenesis, and sought to address the molecular function of Ewsa.	('mutant', 'Var', (70, 76))	('defects', 'NegReg', (95, 102))	('ewsa/ewsa', 'Gene', (60, 69))	('chondrogenesis', 'CPA', (106, 120))	('Ewsa', 'Chemical', '-', (170, 174))	('zebrafish', 'Species', '7955', (77, 86))
302798	25617839	A heterozygous mutation of SOX9 leads to campomelic dysplasia (CD), a syndrome that is characterized by defective chondrogenesis and sex reversal.	('heterozygous mutation', 'Var', (2, 23))	('sex reversal', 'Phenotype', 'HP:0012245', (133, 145))	('SOX9', 'Gene', (27, 31))	('CD', 'Disease', 'MESH:D006223', (63, 65))	('leads to', 'Reg', (32, 40))	('campomelic dysplasia', 'Disease', 'MESH:D055036', (41, 61))	('campomelic dysplasia', 'Disease', (41, 61))
302800	25617839	The target genes of SOX9 (e.g., pax1/pax9) are known to regulate skeletogenesis, and the knockdown or knockout mutants of these genes often result in a reduction of appendages, body regions, or the entire animal.	('skeletogenesis', 'CPA', (65, 79))	('mutants', 'Var', (111, 118))	('pax9', 'Gene', '30558', (37, 41))	('appendages', 'CPA', (165, 175))	('pax9', 'Gene', (37, 41))	('reduction', 'NegReg', (152, 161))
302811	25617839	The ewsa mutant line was generated via virus-mediated insertional mutagenesis by Znomics, Inc. Oregon AB* and ewsa mutant zebrafish lines were maintained at 28 C using an automatic filtration system from Aquatic Habitats.	('mutant', 'Var', (115, 121))	('rat', 'Species', '10116', (29, 32))	('rat', 'Species', '10116', (185, 188))	('zebrafish', 'Species', '7955', (122, 131))	('insertional mutagenesis', 'Var', (54, 77))
302836	25617839	Welch's t-test was used to compare GAPDH-normalized relative expression of mRNAs obtained by qPCR between the wild type and mutant zebrafish.	('qPCR', 'Gene', (93, 97))	('zebrafish', 'Species', '7955', (131, 140))	('mutant', 'Var', (124, 130))	('GAPDH', 'Gene', (35, 40))	('GAPDH', 'Gene', '317743', (35, 40))
302842	25617839	Zebrafish provides an attractive model because mutants often display a milder phenotype due to a redundant role between two duplicated genes.	('milder phenotype', 'MPA', (71, 87))	('mutants', 'Var', (47, 54))	('Zebrafish', 'Species', '7955', (0, 9))
302851	25617839	The phenotypic discrepancy between the EWS-/- mice and ewsa/ewsa mutant zebrafish may be due to the redundant expression of the ewsb gene in zebrafish.	('mutant', 'Var', (65, 71))	('zebrafish', 'Species', '7955', (72, 81))	('ewsb', 'Gene', (128, 132))	('zebrafish', 'Species', '7955', (141, 150))	('mice', 'Species', '10090', (46, 50))	('expression', 'MPA', (110, 120))
302852	25617839	Three probes for tissue-specific genes, including shh (notochord), eng3 (midbrain-hindbrain boundary), krox20 (rhombomere 2 and 4 in hindbrain) and wnt1, did not exhibit any significant differences in their expression pattern between the wt/wt and MZ ewsa/ewsa mutants, thereby indicating that the overall dorsal-ventral and anterior-posterior patterning, including the brain and notochord, were not affected in the mutant (S1B Fig.).	('wnt1', 'Gene', (148, 152))	('mutant', 'Var', (416, 422))	('dorsal-ventral', 'CPA', (306, 320))	('wnt1', 'Gene', '30128', (148, 152))	('eng3', 'Gene', (67, 71))	('krox20', 'Gene', (103, 109))	('krox20', 'Gene', '368241', (103, 109))	('eng3', 'Gene', '30238', (67, 71))
302854	25617839	The adult MZ ewsa/ewsa mutant zebrafish displayed protruding jaws and curved axial skeleton, suggesting that Ewsa plays a role in skeletogenesis (data not shown).	('protruding jaws', 'Phenotype', 'HP:0000303', (50, 65))	('mutant', 'Var', (23, 29))	('zebrafish', 'Species', '7955', (30, 39))	('protruding', 'PosReg', (50, 60))	('Ewsa', 'Chemical', '-', (109, 113))
302856	25617839	The dentary (the dermal bone that forms the lower jaw) protruded anteriorly in the adult MZ ewsa/ewsa mutants (65%; n = 20 fish) compared to the adult wt/wt zebrafish (0%; n = 11 fish) (Fisher's exact test, p = 0.0004) (Fig.	('mutants', 'Var', (102, 109))	('zebrafish', 'Species', '7955', (157, 166))	('dentary', 'CPA', (4, 11))
302858	25617839	To determine when the MZ ewsa/ewsa mutants started to display skeletal defects, we investigated the formation of chondrocytes because these bones are derived from chondrocytes.	('skeletal defects', 'Disease', (62, 78))	('skeletal defects', 'Disease', 'MESH:C538496', (62, 78))	('skeletal defects', 'Phenotype', 'HP:0000924', (62, 78))	('mutants', 'Var', (35, 42))
302861	25617839	At 4 dpf, the MZ ewsa/ewsa mutants displayed an aberrant angle of Meckel's cartilages compared to the wt/wt embryos (Fig.	('mutants', 'Var', (27, 34))	('dpf', 'Chemical', '-', (5, 8))	("Meckel's cartilages", 'Disease', 'MESH:C536133', (66, 85))	("Meckel's cartilages", 'Disease', (66, 85))
302863	25617839	The average angles in the MZ ewsa/ewsa mutants (4 dpf, 181+- 14o and n = 32; and 7 dpf, 146+- 4o and n = 14) were wider than those in the wt/wt fish (4 dpf, 153+- 8o and n = 28; and 7 dpf, 134+- 3o and n = 7) (Welch's t-test; 4 dpf, p<10-12; and 7 dpf, p<10-4) (Fig.	('dpf', 'Chemical', '-', (83, 86))	('dpf', 'Chemical', '-', (248, 251))	('wider', 'PosReg', (114, 119))	('dpf', 'Chemical', '-', (152, 155))	('dpf', 'Chemical', '-', (228, 231))	('dpf', 'Chemical', '-', (184, 187))	('dpf', 'Chemical', '-', (50, 53))	('mutants', 'Var', (39, 46))
302865	25617839	The overall chondrocyte patterning of the bones was not affected, except the shape of Meckel's cartilage in the 4 dpf MZ ewsa/ewsa mutants (S2 Fig.	('mutants', 'Var', (131, 138))	('dpf', 'Chemical', '-', (114, 117))	("Meckel's cartilage", 'Disease', 'MESH:C536133', (86, 104))	("Meckel's cartilage", 'Disease', (86, 104))
302866	25617839	Because the defects of Meckel's cartilage in the MZ ewsa/ewsa mutant was the earliest major phenotype we observed, we further focused to elucidate the molecular function of Ewsa during formation of Meckel's cartilage.	("Meckel's cartilage", 'Disease', (23, 41))	('mutant', 'Var', (62, 68))	("Meckel's cartilage", 'Disease', 'MESH:C536133', (198, 216))	("Meckel's cartilage", 'Disease', (198, 216))	("Meckel's cartilage", 'Disease', 'MESH:C536133', (23, 41))	('Ewsa', 'Chemical', '-', (173, 177))
302867	25617839	However, it is noteworthy that there is a possibility of other cartilage structure of the mutant may be affected in later stages.	('cartilage', 'Disease', (63, 72))	('cartilage', 'Disease', 'MESH:D002357', (63, 72))	('mutant', 'Var', (90, 96))	('affected', 'Reg', (104, 112))
302871	25617839	We further counted the number of chondrocytes in Meckel's cartilage, and the 4 dpf MZ ewsa/ewsa mutants contained more chondrocytes than the 4 dpf wt/wt embryos (Fig.	('dpf', 'Chemical', '-', (79, 82))	('chondrocytes', 'CPA', (119, 131))	("Meckel's cartilage", 'Disease', 'MESH:C536133', (49, 67))	("Meckel's cartilage", 'Disease', (49, 67))	('dpf', 'Chemical', '-', (143, 146))	('more', 'PosReg', (114, 118))	('mutants', 'Var', (96, 103))
302872	25617839	One possible explanation for the small size and high numbers of chondrocytes in the MZ ewsa/ewsa mutants is that the cells fail to mature into hypertrophic chondrocytes.	('hypertrophic', 'Disease', 'MESH:D006984', (143, 155))	('hypertrophic', 'Disease', (143, 155))	('mutants', 'Var', (97, 104))
302874	25617839	As a result, there was an increase of ihha mRNA level in Meckel's cartilage (100%, n = 10) in MZ ewsa/ewsa mutant compared to wt/wt (n = 9) (Fig.	('mutant', 'Var', (107, 113))	('increase', 'PosReg', (26, 34))	("Meckel's cartilage", 'Disease', 'MESH:C536133', (57, 75))	("Meckel's cartilage", 'Disease', (57, 75))	('ihha', 'Gene', '619520', (38, 42))	('ihha', 'Gene', (38, 42))
302876	25617839	As a result, 100% of 4 dpf MZ ewsa/ewsa mutants (n = 11) and only 12% of wt/wt embryos (n = 10) displayed a high number and strong signal for IHH-positive cells (Fig.	('IHH-positive', 'Protein', (142, 154))	('mutants', 'Var', (40, 47))	('dpf', 'Chemical', '-', (23, 26))
302877	25617839	To further confirm this result, Collagen type X, a marker for hypertrophic chondrocytes, was visualized by immunohistochemistry in the 5 dpf MZ ewsa/ewsa mutants and wt/wt embryos (Fig.	('mutants', 'Var', (154, 161))	('hypertrophic', 'Disease', (62, 74))	('dpf', 'Chemical', '-', (137, 140))	('hypertrophic', 'Disease', 'MESH:D006984', (62, 74))
302878	25617839	Because there is a higher numbers of prehypertrophic chondrocytes in the MZ ewsa/ewsa mutants, these results suggest that Ewsa promotes differentiation of prehypertrophic chondrocytes into hypertrophic chondrocytes.	('hypertrophic', 'Disease', (40, 52))	('mutants', 'Var', (86, 93))	('higher', 'PosReg', (19, 25))	('Ewsa', 'Chemical', '-', (122, 126))	('hypertrophic', 'Disease', 'MESH:D006984', (40, 52))	('hypertrophic', 'Disease', (158, 170))	('hypertrophic', 'Disease', (189, 201))	('differentiation', 'CPA', (136, 151))	('hypertrophic', 'Disease', 'MESH:D006984', (158, 170))	('hypertrophic', 'Disease', 'MESH:D006984', (189, 201))
302881	25617839	In a previous study, SOX9/wt mutant mice developed an expanded hypertrophic zone, and this aberrant phenotype was rescued by knock-in of SOX9.	('hypertrophic', 'Disease', 'MESH:D006984', (63, 75))	('mutant', 'Var', (29, 35))	('mice', 'Species', '10090', (36, 40))	('hypertrophic', 'Disease', (63, 75))
302884	25617839	Because MZ ewsa/ewsa zebrafish mutant displayed a reduced hypertrophic chondrocyte zone, and because EWS has been shown to be a transcriptional modulator, we hypothesized that EWS directly interacts with SOX9 and modulates its target genes during skeletogenesis.	('zebrafish', 'Species', '7955', (21, 30))	('mutant', 'Var', (31, 37))	('modulates', 'Reg', (213, 222))	('hypertrophic', 'Disease', (58, 70))	('reduced', 'NegReg', (50, 57))	('interacts', 'Interaction', (189, 198))	('hypertrophic', 'Disease', 'MESH:D006984', (58, 70))
302907	25617839	The results suggest that the misexpression of Sox9-target genes in the MZ ewsa/ewsa mutants already starts at 27hpf, and this may be the direct cause for inhibition of differentiation prehypertrophic chondrocyte observed at 4dpf.	('hypertrophic', 'Disease', 'MESH:D006984', (187, 199))	('mutants', 'Var', (84, 91))	('dpf', 'Chemical', '-', (225, 228))	('misexpression', 'MPA', (29, 42))	('hypertrophic', 'Disease', (187, 199))
302908	25617839	5, expression of sox5, noggin1, and noggin2, were downregulated and ctgfa, ctgfb, col2a1a, and col2a1b were upregulated in the MZ ewsa/ewsa mutants compared to wt/wt.	('ctgfb', 'Gene', (75, 80))	('col2a1b', 'Gene', (95, 102))	('ctgfa', 'Gene', '321449', (68, 73))	('col2a1a', 'Gene', (82, 89))	('noggin1', 'Gene', (23, 30))	('ctgfb', 'Gene', '100124530', (75, 80))	('expression', 'MPA', (3, 13))	('sox5', 'Gene', (17, 21))	('col2a1a', 'Gene', '562496', (82, 89))	('sox5', 'Gene', '567413', (17, 21))	('ctgfa', 'Gene', (68, 73))	('noggin1', 'Gene', '30174', (23, 30))	('downregulated', 'NegReg', (50, 63))	('noggin2', 'Gene', (36, 43))	('upregulated', 'PosReg', (108, 119))	('noggin2', 'Gene', '30185', (36, 43))	('mutants', 'Var', (140, 147))	('col2a1b', 'Gene', '503730', (95, 102))
302909	25617839	Only the expression of bmp4 was inconsistent with the result of qPCR, displaying a slight upregulation in the MZ ewsa/ewsa mutants.	('bmp4', 'Gene', '30612', (23, 27))	('upregulation', 'PosReg', (90, 102))	('mutants', 'Var', (123, 130))	('bmp4', 'Gene', (23, 27))
302911	25617839	Because EWS can modulate splicing, 5' region of bmp4 gene may have been eliminated in the mRNA due to mis-splicing in the mutant, and it may be the cause for the reduction signal of qPCR in the mutant.	('mis-splicing', 'Var', (102, 114))	('bmp4', 'Gene', '30612', (48, 52))	('qPCR', 'MPA', (182, 186))	('bmp4', 'Gene', (48, 52))	('mutant', 'Var', (122, 128))
302913	25617839	5 and 6, in situ hybridizations using probes against ctgfa displayed increased expression in MZ ewsa/ewsa (100%, n = 11) mutant embryos compared to wt/wt at 3dpf (n = 11) (Fig.	('increased', 'PosReg', (69, 78))	('mutant', 'Var', (121, 127))	('expression', 'MPA', (79, 89))	('ctgfa', 'Gene', (53, 58))	('dpf', 'Chemical', '-', (158, 161))	('ctgfa', 'Gene', '321449', (53, 58))
302917	25617839	To examine whether Ctgf protein level is also increased in the mutant, we further performed immunohistochemistry using antibody against Ctgf protein.	('Ctgf', 'Gene', (136, 140))	('mutant', 'Var', (63, 69))	('Ctgf', 'Gene', '321449', (19, 23))	('increased', 'PosReg', (46, 55))	('Ctgf', 'Gene', '321449', (136, 140))	('Ctgf', 'Gene', (19, 23))
302921	25617839	Ctgf displayed a high level of signal intensity in the craniofacial chondrocytes in all of the 4 dpf MZ ewsa/ewsa mutants (n = 9), whereas, only 22% of wt/wt (n = 9) displayed high level of Ctgf signal intensity (Fig.	('Ctgf', 'Gene', '321449', (190, 194))	('Ctgf', 'Gene', (0, 4))	('dpf', 'Chemical', '-', (97, 100))	('mutants', 'Var', (114, 121))	('signal intensity', 'MPA', (31, 47))	('Ctgf', 'Gene', (190, 194))	('Ctgf', 'Gene', '321449', (0, 4))	('dpf', 'Gene', (97, 100))
302932	25617839	The Meckel's cartilage in the MZ ewsa/ewsa mutants displayed a greater number of prehypertrophic chondrocytes and failed to differentiate into hypertrophic chondrocytes compared with the wt/wt embryos.	("Meckel's cartilage", 'Disease', (4, 22))	('hypertrophic', 'Disease', (143, 155))	('hypertrophic', 'Disease', 'MESH:D006984', (84, 96))	('greater', 'PosReg', (63, 70))	('hypertrophic', 'Disease', 'MESH:D006984', (143, 155))	('mutants', 'Var', (43, 50))	("Meckel's cartilage", 'Disease', 'MESH:C536133', (4, 22))	('hypertrophic', 'Disease', (84, 96))
302938	25617839	Because the MZ ewsa/ewsa mutants failed to mature into hypertrophic chondrocytes and accumulate prehypertrophic chondrocytes, it is conceivable that the impairment of EWS may contribute to Ewing sarcoma development.	('hypertrophic', 'Disease', (99, 111))	('mutants', 'Var', (25, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('contribute', 'Reg', (175, 185))	('Ewing sarcoma', 'Disease', (189, 202))	('hypertrophic', 'Disease', 'MESH:D006984', (99, 111))	('hypertrophic', 'Disease', (55, 67))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (189, 202))	('hypertrophic', 'Disease', 'MESH:D006984', (55, 67))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (189, 202))
302942	25617839	Therefore, the prehypertrophic chondrocytes in MZ ewsa/ewsa mutants may have entered the cell cycle as we observed in a higher number of cells (Fig.	('hypertrophic', 'Disease', 'MESH:D006984', (18, 30))	('hypertrophic', 'Disease', (18, 30))	('mutants', 'Var', (60, 67))	('entered', 'PosReg', (77, 84))	('cell cycle', 'CPA', (89, 99))
302945	25617839	Compromising midzone formation has been shown to lead to higher incidences of aneuploidy.	('midzone formation', 'CPA', (13, 30))	('aneuploidy', 'Disease', 'MESH:D000782', (78, 88))	('Compromising', 'Var', (0, 12))	('midzone', 'Chemical', '-', (13, 20))	('aneuploidy', 'Disease', (78, 88))
302973	22353813	In an adjuvant randomised phase II study by the Canadian sarcoma group, the combination of doxorubicin (50 mg m-2 per cycle) and ifosfamide (5 g m-2 per cycle) was associated with a 29% incidence of grade 3-4 nausea and vomiting and an 8% incidence of grade 3-4 haematological toxicity.	('nausea', 'Phenotype', 'HP:0002018', (209, 215))	('nausea', 'Disease', (209, 215))	('toxicity', 'Disease', (277, 285))	('doxorubicin', 'Chemical', 'MESH:D004317', (91, 102))	('nausea', 'Disease', 'MESH:D009325', (209, 215))	('vomiting', 'Phenotype', 'HP:0002013', (220, 228))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (209, 228))	('50 mg m-2', 'Var', (104, 113))	('vomiting', 'Disease', (220, 228))	('doxorubicin', 'Var', (91, 102))	('vomiting', 'Disease', 'MESH:D014839', (220, 228))	('sarcoma', 'Disease', (57, 64))	('ifosfamide', 'Chemical', 'MESH:D007069', (129, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('toxicity', 'Disease', 'MESH:D064420', (277, 285))
303197	33330082	Median percentage change in sum of target marker lesion diameters for the evaluable population was -8.3% (IQR -26.5 to +5.9) with cediranib versus 13.4% (IQR +1.1 to +21.3) with placebo (p = 0.001).	('cediranib', 'Chemical', 'MESH:C500926', (130, 139))	('cediranib', 'Var', (130, 139))	('met', 'Gene', (59, 62))	('met', 'Gene', '79811', (59, 62))
303209	33330082	Compared to placebo, pazopanib significantly improved the PFS (HR = 0.31, 95% CI 0.24-0.40; p<0.0001), but this did not translate into OS improvement (HR = 0.86, 95% CI 0.67-1.11; p = 0.25) ( Table 4 ).	('PFS', 'MPA', (58, 61))	('pazopanib', 'Chemical', 'MESH:C516667', (21, 30))	('pazopanib', 'Var', (21, 30))	('improved', 'PosReg', (45, 53))
303214	33330082	Pazopanib have been found active in ASPS (NCT02113826), extra-skeletal myxoid chondrosarcoma (NCT02066285), dedifferentiated SFT (NCT02066285) ( Table 2 ).	('skeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (62, 92))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (78, 92))	('dedifferentiated SFT', 'Disease', (108, 128))	('ASPS', 'Gene', (36, 40))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('NCT02066285', 'Var', (94, 105))	('NCT02113826', 'Var', (42, 53))	('ASPS', 'Gene', '79058', (36, 40))	('skeletal myxoid chondrosarcoma', 'Disease', (62, 92))	('NCT02066285', 'Var', (130, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
303239	33330082	Regorafenib failed to improve PFS compared to placebo in liposarcoma patients: PFS was 1.1 months with regorafenib versus 1.7 months with placebo (HR 0.89 [95% CI 0.48-1.64] p = 0.70).	('Regorafenib', 'Chemical', 'MESH:C559147', (0, 11))	('liposarcoma', 'Phenotype', 'HP:0012034', (57, 68))	('liposarcoma', 'Disease', 'MESH:D008080', (57, 68))	('regorafenib', 'Chemical', 'MESH:C559147', (103, 114))	('patients', 'Species', '9606', (69, 77))	('liposarcoma', 'Disease', (57, 68))	('regorafenib', 'Var', (103, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
303254	33330082	The assessment of activity of anti-angiogenic agents in advanced angiosarcoma makes sense, since the phenotype of this sarcoma and the frequent occurrence of KDR mutations, involving in the angiogenic signaling pathways.	('angiosarcoma', 'Disease', (65, 77))	('sarcoma', 'Disease', (70, 77))	('mutations', 'Var', (162, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('occurrence', 'Reg', (144, 154))	('angiosarcoma', 'Phenotype', 'HP:0200058', (65, 77))	('KDR', 'Gene', '3791', (158, 161))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('angiosarcoma', 'Disease', 'MESH:D006394', (65, 77))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('KDR', 'Gene', (158, 161))	('involving', 'Reg', (173, 182))
303554	28547734	In the pazopanib arm of the overall population (n = 240) and in the Japanese subgroup (n = 31), the incidence of increased alanine aminotransferase (ALT) (all grades) was 46% and 52%, respectively; the incidence of increased aspartate aminotransferase (AST) was 51% and 65%, respectively; and the incidence of increased total bilirubin was 29% and 42%, respectively.	('AST', 'Gene', '26503', (253, 256))	('increased aspartate', 'Phenotype', 'HP:0500159', (215, 234))	('pazopanib', 'Chemical', 'MESH:C516667', (7, 16))	('alanine aminotransferase', 'Gene', (123, 147))	('increased alanine', 'Phenotype', 'HP:0003348', (113, 130))	('aspartate aminotransferase', 'Gene', (225, 251))	('alanine aminotransferase', 'Gene', '2875', (123, 147))	('increased total bilirubin', 'Phenotype', 'HP:0003573', (310, 335))	('bilirubin', 'Chemical', 'MESH:D001663', (326, 335))	('increased', 'PosReg', (215, 224))	('increased', 'PosReg', (113, 122))	('pazopanib', 'Var', (7, 16))	('AST', 'Gene', (253, 256))	('total bilirubin', 'MPA', (320, 335))	('aspartate aminotransferase', 'Gene', '26503', (225, 251))
303555	28547734	In the phase III study, pneumothorax occurred in 3% of patients (8/240) in the pazopanib arm, but there were no occurrences in the Japanese subgroup.	('pneumothorax', 'Phenotype', 'HP:0002107', (24, 36))	('pazopanib', 'Chemical', 'MESH:C516667', (79, 88))	('pneumothorax', 'Disease', (24, 36))	('pazopanib', 'Var', (79, 88))	('patients', 'Species', '9606', (55, 63))
303580	28547734	As with pazopanib, trabectedin may also cause the onset or worsening of cardiac dysfunction when administered to patients with a history of treatment with anthracycline drugs and those with cardiac dysfunction.	('cardiac dysfunction', 'Disease', (72, 91))	('cause', 'Reg', (40, 45))	('anthracycline', 'Chemical', 'MESH:D018943', (155, 168))	('pazopanib', 'Chemical', 'MESH:C516667', (8, 17))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (72, 91))	('patients', 'Species', '9606', (113, 121))	('cardiac dysfunction', 'Disease', (190, 209))	('trabectedin', 'Chemical', 'MESH:D000077606', (19, 30))	('trabectedin', 'Var', (19, 30))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (190, 209))
303592	28547734	The incidence of adverse events associated with bone marrow suppression reported in the clinical studies of eribulin was lower than in those of trabectedin, although direct comparison of safety data is difficult because of the different background characteristics of the patients in these studies.	('bone marrow suppression', 'Disease', 'MESH:D001855', (48, 71))	('bone marrow suppression', 'Disease', (48, 71))	('eribulin', 'Var', (108, 116))	('lower', 'NegReg', (121, 126))	('eribulin', 'Chemical', 'MESH:C490954', (108, 116))	('patients', 'Species', '9606', (271, 279))	('trabectedin', 'Chemical', 'MESH:D000077606', (144, 155))
303634	25861239	Molecular Analysis of a Recurrent Sarcoma Identifies a Mutation in FAF1 A patient presented with a recurrent sarcoma (diagnosed as leiomyosarcoma) 12 years after the removal of an initial cancer (diagnosed as extracompartmental osteosarcoma) distally on the same limb.	('Sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('patient', 'Species', '9606', (74, 81))	('recurrent', 'Disease', (99, 108))	('FAF1', 'Gene', (67, 71))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (131, 145))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('sarcoma', 'Disease', (109, 116))	('osteosarcoma', 'Disease', (228, 240))	('osteosarcoma', 'Disease', 'MESH:D012516', (228, 240))	('sarcoma', 'Disease', 'MESH:D012509', (233, 240))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('leiomyosarcoma', 'Disease', (131, 145))	('sarcoma', 'Disease', (233, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcoma', 'Disease', (138, 145))	('men', 'Species', '9606', (221, 224))	('cancer', 'Disease', (188, 194))	('Sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (228, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Mutation', 'Var', (55, 63))	('Sarcoma', 'Disease', (34, 41))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (131, 145))
303637	25861239	A likely culprit for the disease is the point mutation S181G in FAF1, which may cause a loss of apoptotic function consecutive to transforming DNA damage.	('FAF1', 'Gene', (64, 68))	('S181G', 'Var', (55, 60))	('S181G', 'Mutation', 'rs1284558541', (55, 60))	('loss', 'NegReg', (88, 92))	('apoptotic function', 'MPA', (96, 114))	('FAF1', 'Gene', '11124', (64, 68))
303694	25861239	Exome sequencing of the genomic DNAs for tumor, muscle, and bone identified 65546 potential sequence variants.	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('variants', 'Var', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))
303697	25861239	The point mutation S181G (Figure 2) could cause a loss of function in FAF1 and lead to transformation via antiapoptosis.	('transformation', 'CPA', (87, 101))	('FAF1', 'Gene', '11124', (70, 74))	('S181G', 'Var', (19, 24))	('S181G', 'Mutation', 'rs1284558541', (19, 24))	('loss of function', 'NegReg', (50, 66))	('antiapoptosis', 'CPA', (106, 119))	('FAF1', 'Gene', (70, 74))
303710	25861239	The identified point mutation in FAF1 may be pathogenetic for this cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('FAF1', 'Gene', (33, 37))	('cancer', 'Disease', (67, 73))	('FAF1', 'Gene', '11124', (33, 37))	('point mutation', 'Var', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
303730	25861239	The tumor, but not normal muscle, expressed the metastasis protein osteopontin and a single small form (<75 kD) of CD44 that is likely the not alternatively spliced, standard form.	('tumor', 'Disease', (4, 9))	('CD44', 'Gene', (115, 119))	('osteopontin', 'Gene', '6696', (67, 78))	('osteopontin', 'Gene', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('<75 kD', 'Var', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CD44', 'Gene', '960', (115, 119))
303735	25861239	Those alterations may affect choices for drug treatment.	('alterations', 'Var', (6, 17))	('affect', 'Reg', (22, 28))	('men', 'Species', '9606', (51, 54))
303739	25861239	The above-described results indicated that a FAF1 mutation, which replaces serine in position 181, thus preventing FAF1 phosphorylation and activation, may be a driver for leiomyosarcomagenesis.	('serine', 'Chemical', 'MESH:D012694', (75, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('activation', 'MPA', (140, 150))	('FAF1', 'Gene', (115, 119))	('preventing', 'NegReg', (104, 114))	('phosphorylation', 'MPA', (120, 135))	('FAF1', 'Gene', '11124', (115, 119))	('leiomyosarcomagenesis', 'Disease', 'None', (172, 193))	('leiomyosarcomagenesis', 'Disease', (172, 193))	('FAF1', 'Gene', (45, 49))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (172, 186))	('FAF1', 'Gene', '11124', (45, 49))	('mutation', 'Var', (50, 58))
303741	25861239	To assess whether this single nucleotide replacement is common in this type of cancer, we analyzed DNA from 29 leiomyosarcomas and 1 blood sample from a leiomyosarcoma patient.	('leiomyosarcomas', 'Disease', (111, 126))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (153, 167))	('men', 'Species', '9606', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (111, 125))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (111, 125))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (153, 167))	('patient', 'Species', '9606', (168, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('single nucleotide', 'Var', (23, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('leiomyosarcoma', 'Disease', (111, 125))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (111, 126))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (111, 126))	('leiomyosarcoma', 'Disease', (153, 167))
303744	25861239	The FAF1 mutation identified as the likely cause for the cancer under study gives room for an explanation of the sarcomatous transformation (Figure 5).	('mutation', 'Var', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (113, 139))	('cancer', 'Disease', (57, 63))	('FAF1', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('sarcomatous transformation', 'Disease', (113, 139))	('sarcomatous transformation', 'Disease', 'MESH:D018316', (113, 139))	('FAF1', 'Gene', '11124', (4, 8))
303748	25861239	Whereas the mutation S181G is not expected to disrupt the structure of the protein, this site does score high as a possible phosphorylation site for a number of kinases involved in DNA damage repair, supporting the hypothesis that the cancer cells containing this mutation have lost their ability to respond to transforming DNA damage with programmed cell death.	('S181G', 'Mutation', 'rs1284558541', (21, 26))	('S181G', 'Var', (21, 26))	('respond', 'MPA', (300, 307))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('lost', 'NegReg', (278, 282))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
303753	25861239	IGF2BP1 may be upregulated as a consequence of mutated FAF1 not being able to suppress WNT signaling in this specific cancer.	('FAF1', 'Gene', '11124', (55, 59))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('upregulated', 'PosReg', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('IGF2BP1', 'Gene', (0, 7))	('WNT signaling', 'MPA', (87, 100))	('mutated', 'Var', (47, 54))	('FAF1', 'Gene', (55, 59))	('IGF2BP1', 'Gene', '10642', (0, 7))
303760	25861239	Other mutations, beside FAF1, are less likely to be causative for the cancer.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('FAF1', 'Gene', (24, 28))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('mutations', 'Var', (6, 15))	('FAF1', 'Gene', '11124', (24, 28))
303761	25861239	EPHA3 was revealed as mutated in this cancer by DNA exome sequencing and RNASeq.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('EPHA3', 'Gene', (0, 5))	('mutated', 'Var', (22, 29))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('EPHA3', 'Gene', '2042', (0, 5))
303763	25861239	Tumor-suppressive effects of wild-type EPHA3 can be overridden by dominant negative EPHA3 somatic mutations.	('negative', 'NegReg', (75, 83))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (98, 107))	('EPHA3', 'Gene', '2042', (39, 44))	('EPHA3', 'Gene', '2042', (84, 89))	('EPHA3', 'Gene', (84, 89))	('Tumor-suppressive effects', 'CPA', (0, 25))	('EPHA3', 'Gene', (39, 44))
303764	25861239	This mechanism is unlikely to play a role in this sarcoma as the detected mutation is located far N-terminally on the extracellular Ephrin binding domain not on the intracellular kinase domain.	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('mutation', 'Var', (74, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('sarcoma', 'Disease', (50, 57))
303766	25861239	Its depletion due to chromosome breakage can affect prognosis in glioblastoma patients.	('affect', 'Reg', (45, 51))	('prognosis', 'MPA', (52, 61))	('patients', 'Species', '9606', (78, 86))	('glioblastoma', 'Disease', (65, 77))	('chromosome breakage', 'Phenotype', 'HP:0040012', (21, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('depletion', 'MPA', (4, 13))	('chromosome breakage', 'Var', (21, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
303767	25861239	Single nucleotide polymorphisms in FAF1 are associated with a risk for gastric cancer.	('associated', 'Reg', (44, 54))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('FAF1', 'Gene', '11124', (35, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('FAF1', 'Gene', (35, 39))
303768	25861239	While numerous FAF1 mutations are associated with various cancers, none of these genetic changes in the TCGA database affects the amino acid position 181 (Table 4).	('associated', 'Reg', (34, 44))	('FAF1', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('FAF1', 'Gene', '11124', (15, 19))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('TC', 'Chemical', 'MESH:D013667', (104, 106))	('cancers', 'Disease', (58, 65))	('mutations', 'Var', (20, 29))
303775	25861239	The recurrence of a sarcoma after 14 years has two probable explanations, either it is due to a cancer predisposition syndrome based on a germ-line mutation (the age of the patient weakens this hypothesis) or the second tumor is a metastatic colony of the first that was reactivated after dormancy.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('sarcoma', 'Disease', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (220, 225))	('based on', 'Reg', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('patient', 'Species', '9606', (173, 180))	('mutation', 'Var', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
303784	25861239	On the molecular pathology level, sarcomas fall into two groups, comprising tumors with simple karyotypes (with pathogenetic translocations or specific genetic mutations) and tumors with very complex karyotypes (overt chromosome and genomic instability with numerous gains and losses).	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('numerous gains', 'Disease', 'MESH:D015430', (258, 272))	('fall', 'Phenotype', 'HP:0002527', (43, 47))	('overt', 'Var', (212, 217))	('sarcomas', 'Disease', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('genomic instability', 'Var', (233, 252))	('tumors', 'Disease', (76, 82))	('losses', 'NegReg', (277, 283))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('numerous gains', 'Disease', (258, 272))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('sarcomas', 'Disease', 'MESH:D012509', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
303790	25861239	An additional caveat, caused by unique genetic changes in the primary tumor, can affect drug transport and metabolism and needs to be taken into consideration.	('metabolism', 'MPA', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('affect', 'Reg', (81, 87))	('drug transport', 'MPA', (88, 102))	('genetic changes', 'Var', (39, 54))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
303822	20945947	This includes $US65 million in milestones associated with the potential sarcoma indication ($US25 million for acceptance of a new drug application [NDA] by the US FDA, $US25 million for US registration, $US10 million for European registration and $US5 million for Japanese registration), and $US200 million in milestones based on achievement of significant sales thresholds.	('$US25 million', 'Var', (92, 105))	('sarcoma', 'Disease', (72, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	(' $US200 million', 'Var', (291, 306))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	(' $US10 million', 'Var', (202, 216))
303848	20945947	The randomized, double-blind trial will compare ridaforolimus against placebo in patients with a KRAS mutation, a mutation in lung tumors that is recognized as a predictor of poor response to endothelial growth factor receptor inhibitors.	('lung tumors', 'Disease', 'MESH:D008175', (126, 137))	('KRAS', 'Gene', (97, 101))	('mutation', 'Var', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (81, 89))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('ridaforolimus', 'Chemical', 'MESH:C515074', (48, 61))	('lung tumors', 'Phenotype', 'HP:0100526', (126, 137))	('lung tumors', 'Disease', (126, 137))
303940	20945947	In a panel of >100 lung-cancer cell lines, ridaforolimus showed greater inhibition of tumor growth than erlotinib in 79% of cell lines and 84% of KRAS mutant cell lines.	('erlotinib', 'Chemical', 'MESH:D000069347', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutant', 'Var', (151, 157))	('KRAS', 'Var', (146, 150))	('ridaforolimus', 'Chemical', 'MESH:C515074', (43, 56))	('tumor', 'Disease', (86, 91))	('lung-cancer', 'Disease', (19, 30))	('lung-cancer', 'Disease', 'MESH:D008175', (19, 30))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('inhibition', 'NegReg', (72, 82))
303946	20945947	Colony formation of C4-2 in anchorage-independent conditions was inhibited by ~75% with combination treatment, compared with control.	('C4-2', 'Gene', '51654', (20, 24))	('C4-2', 'Gene', (20, 24))	('inhibited', 'NegReg', (65, 74))	('Colony formation', 'CPA', (0, 16))	('combination', 'Var', (88, 99))
303972	20945947	In 145 patients (85 with sarcomas) receiving ridaforolimus, clinical benefit response was classified as stable disease or better lasting for at least 4 cycles of 28 days, and was seen in all regimens in patients with several types of sarcomas and a variety of carcinomas.	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('sarcomas', 'Disease', (25, 33))	('sarcomas', 'Disease', (234, 242))	('ridaforolimus', 'Var', (45, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('patients', 'Species', '9606', (203, 211))	('sarcomas', 'Phenotype', 'HP:0100242', (234, 242))	('carcinomas', 'Phenotype', 'HP:0030731', (260, 270))	('ridaforolimus', 'Chemical', 'MESH:C515074', (45, 58))	('carcinomas', 'Disease', 'MESH:D002277', (260, 270))	('sarcomas', 'Disease', 'MESH:D012509', (234, 242))	('patients', 'Species', '9606', (7, 15))	('carcinomas', 'Disease', (260, 270))
303992	20945947	Previously, in the phase I trials among patients with various solid tumors, ridaforolimus produced stable disease for at least 3 months in 50% of evaluable patients in the daily dosing regimen and in 17% of the evaluable patients in the weekly dosing regimen.	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (221, 229))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (40, 48))	('ridaforolimus', 'Var', (76, 89))	('solid tumors', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('ridaforolimus', 'Chemical', 'MESH:C515074', (76, 89))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))
304010	28630682	Co-expression of PRAME and NY-ESO-1 has been shown to correlate with high-grade histologic features and a worse overall survival in patients with myxoid liposarcomas and synovial sarcomas.	('synovial sarcomas', 'Disease', (170, 187))	('PRAME', 'Gene', '23532', (17, 22))	('PRAME', 'Gene', (17, 22))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (146, 165))	('patients', 'Species', '9606', (132, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('synovial sarcomas', 'Disease', 'MESH:D013584', (170, 187))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (170, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('liposarcoma', 'Phenotype', 'HP:0012034', (153, 164))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (146, 165))	('NY-ESO-1', 'Gene', '1485', (27, 35))	('liposarcomas', 'Phenotype', 'HP:0012034', (153, 165))	('NY-ESO-1', 'Gene', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('myxoid liposarcomas', 'Disease', (146, 165))	('Co-expression', 'Var', (0, 13))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (170, 187))
304071	24548307	When compared with FB-3DCRT, estimated relative life time attributable risk (LAR) of cancer induction after DI-3DCRT was 0.86, 0.76, 0.94 and 0.92 for breast, lung, esophagus and stomach, respectively.	('stomach', 'Disease', (179, 186))	('breast', 'Disease', (151, 157))	('DI', 'Phenotype', 'HP:0002789', (108, 110))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('DI-3DCRT', 'Var', (108, 116))	('cancer', 'Disease', (85, 91))	('lung', 'Disease', (159, 163))	('esophagus', 'Disease', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
304118	24548307	Although, DI-VMAT can reduce soft tissue and bone sarcoma risk by 30-40%, overall a 50% increase of LAR of solid cancer induction can be expected.	('reduce', 'NegReg', (22, 28))	('DI', 'Phenotype', 'HP:0002789', (10, 12))	('bone sarcoma', 'Disease', (45, 57))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('DI-VMAT', 'Var', (10, 17))	('cancer', 'Disease', (113, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('bone sarcoma', 'Disease', 'MESH:D001847', (45, 57))	('bone sarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
304121	24548307	Clearly DI-3DCRT has the potential to decrease the risk of cancer induction.	('DI-3DCRT', 'Var', (8, 16))	('DI', 'Phenotype', 'HP:0002789', (8, 10))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('decrease', 'NegReg', (38, 46))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
304124	24548307	First, in absolute terms, DI-VMAT has a detrimental effect on cancer induction, even with a INRT paradigm, as the second cancer risk is almost as large as with a large mantle field irradiation.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('DI', 'Phenotype', 'HP:0002789', (26, 28))	('cancer', 'Disease', (121, 127))	('DI-VMAT', 'Var', (26, 33))
304216	32652895	Fourteen genes were chosen based on previously reported relationships to human cancers and all 14 were confirmed to be upregulated in the MUPS-1 cells by qRT-PCR (Table 2).	('cancers', 'Disease', (79, 86))	('upregulated', 'PosReg', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('human', 'Species', '9606', (73, 78))	('qRT-PCR', 'Var', (154, 161))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
304242	32652895	Past studies to characterize molecular biomarkers of UPS demonstrated that UPS has a low burden of somatic mutations with 16% carrying RB1 and/or p53 mutations (Cancer Genome Atlas Research Network.	('p53', 'Gene', (146, 149))	('RB1', 'Gene', (135, 138))	('p53', 'Gene', '7157', (146, 149))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Cancer', 'Disease', (161, 167))	('mutations', 'Var', (150, 159))	('Cancer', 'Disease', 'MESH:D009369', (161, 167))	('RB1', 'Gene', '5925', (135, 138))
304246	32652895	Other studies have shown Ras/MAPK activation in 80% of UPS cases, and expression of phospho-STAT3 associated with better prognosis (Bekki et al., 2017; Serrano et al., 2016).	('STAT3', 'Gene', '6774', (92, 97))	('Ras/MAPK', 'Protein', (25, 33))	('STAT3', 'Gene', (92, 97))	('activation', 'PosReg', (34, 44))	('expression', 'Var', (70, 80))	('associated', 'Reg', (98, 108))
304264	32652895	Additionally, expression of TIMPs has paradoxically been related to increased tumor aggressiveness and tumor cell proliferation (Murphy, 2011).	('expression', 'Var', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('TIMP', 'Gene', (28, 32))	('aggressiveness', 'Phenotype', 'HP:0000718', (84, 98))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (78, 98))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (103, 108))	('TIMP', 'Gene', '7076', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (78, 83))	('tumor aggressiveness', 'Disease', (78, 98))	('increased', 'PosReg', (68, 77))
304283	23315028	Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response.	('patients', 'Species', '9606', (9, 17))	('mutation', 'Var', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('cKIT', 'Gene', (101, 105))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('patient', 'Species', '9606', (9, 16))	('patient', 'Species', '9606', (77, 84))	('cKIT', 'Gene', '3815', (101, 105))
304341	23315028	Subsequent molecular testing has revealed that this patient's melanoma harbors an exon-11 c-KIT mutation.	('melanoma', 'Disease', (62, 70))	('c-KIT', 'Gene', (90, 95))	('exon-11', 'Var', (82, 89))	('patient', 'Species', '9606', (52, 59))	('c-KIT', 'Gene', '3815', (90, 95))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
304346	23315028	Despite the presence of a second myelosuppressive agent, the RP2D for dacarbazine in the combination represents a nearly two fold increase in dose intensity as compared with the previous recommended dose for single agent administration.	('dacarbazine', 'Chemical', 'MESH:D003606', (70, 81))	('dose intensity', 'MPA', (142, 156))	('increase', 'PosReg', (130, 138))	('RP2D', 'Var', (61, 65))
304362	23315028	Preclinical data suggest that bortezomib has a dual mode of action against KIT mutant GIST cells involving upregulation of the proapoptotic histone H2AX and downregulation of KIT transcription.	('upregulation', 'PosReg', (107, 119))	('bortezomib', 'Chemical', 'MESH:D000069286', (30, 40))	('KIT transcription', 'MPA', (175, 192))	('mutant', 'Var', (79, 85))	('downregulation', 'NegReg', (157, 171))	('KIT', 'Gene', (75, 78))	('GIST', 'Phenotype', 'HP:0100723', (86, 90))
304364	23315028	Clinical studies in KIT mutated melanoma using imatinib were based on molecular pathways and responses seen in GIST, and responses have been moderate thus far.	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('KIT mutated', 'Var', (20, 31))	('melanoma', 'Disease', (32, 40))	('imatinib', 'Chemical', 'MESH:D000068877', (47, 55))	('GIST', 'Phenotype', 'HP:0100723', (111, 115))
304365	23315028	The finding of a durable CR in response to bortezomib based therapy in a melanoma patient with a KIT exon-11 mutation suggests that a future study of dacarbazine and bortezomib might prove worthwhile in this subpopulation of patients with metastatic melanoma.	('melanoma', 'Disease', (73, 81))	('CR', 'Chemical', '-', (25, 27))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('patients', 'Species', '9606', (225, 233))	('patient', 'Species', '9606', (82, 89))	('dacarbazine', 'Chemical', 'MESH:D003606', (150, 161))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('melanoma', 'Disease', (250, 258))	('bortezomib', 'Chemical', 'MESH:D000069286', (43, 53))	('bortezomib', 'Chemical', 'MESH:D000069286', (166, 176))	('patient', 'Species', '9606', (225, 232))	('KIT exon-11', 'Gene', (97, 108))	('mutation', 'Var', (109, 117))
304385	23688189	Aberrant signaling of this pathway has been implicated in various cancer types, among others sarcomas.	('Aberrant', 'Var', (0, 8))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('implicated', 'Reg', (44, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcomas', 'Disease', (93, 101))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
304402	23688189	Interestingly, the cell line which could not be inhibited with OSI-906, 143B, has a k-ras oncogenic transformation, which is a component of the Ras/Raf/ERK pathway, one of downstream effectors of IGF1R signaling.	('ERK', 'Gene', '5594', (152, 155))	('ERK', 'Gene', (152, 155))	('k-ras oncogenic transformation', 'CPA', (84, 114))	('OSI-906', 'Chemical', 'MESH:C551528', (63, 70))	('Raf', 'Gene', '22882', (148, 151))	('OSI-906', 'Var', (63, 70))	('Raf', 'Gene', (148, 151))
304418	23688189	After 24 hrs, OSI-906 was added in triplicate at different concentrations - 0 nM, 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 muM, and 10 muM.	('muM', 'Gene', '56925', (134, 137))	('0.01 nM', 'Var', (82, 89))	('0.1 nM', 'Var', (91, 97))	('muM', 'Gene', (122, 125))	('muM', 'Gene', (134, 137))	('OSI-906', 'Chemical', 'MESH:C551528', (14, 21))	('muM', 'Gene', '56925', (122, 125))
304435	23688189	An inhibition of intrinsic IRS-1 phosphorylation at Y612 was detected after treatment with OSI-906 in all cell lines (Figure 3), indicating that this inhibitor could affect signaling downstream IGF1R in osteosarcoma cells.	('IGF1R', 'Gene', (194, 199))	('OSI-906', 'Chemical', 'MESH:C551528', (91, 98))	('IRS-1', 'Gene', (27, 32))	('osteosarcoma', 'Disease', (203, 215))	('osteosarcoma', 'Phenotype', 'HP:0002669', (203, 215))	('osteosarcoma', 'Disease', 'MESH:D012516', (203, 215))	('affect', 'Reg', (166, 172))	('Y612', 'Var', (52, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('inhibition', 'NegReg', (3, 13))	('IRS-1', 'Gene', '3667', (27, 32))	('signaling', 'MPA', (173, 182))
304466	23688189	Treatment of osteosarcoma cells with OSI-906 at physiological levels leads to decreased phosphorylation of IRS-1 at Y612.	('phosphorylation', 'MPA', (88, 103))	('osteosarcoma', 'Phenotype', 'HP:0002669', (13, 25))	('osteosarcoma', 'Disease', 'MESH:D012516', (13, 25))	('IRS-1', 'Gene', (107, 112))	('Y612', 'Var', (116, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('OSI-906', 'Chemical', 'MESH:C551528', (37, 44))	('IRS-1', 'Gene', '3667', (107, 112))	('decreased', 'NegReg', (78, 87))	('osteosarcoma', 'Disease', (13, 25))
304467	23688189	Inhibition of IRS-1 at Y612 after treatment with OSI-906 was previously reported by Buck et al.	('IRS-1', 'Gene', (14, 19))	('Y612', 'Var', (23, 27))	('Inhibition', 'NegReg', (0, 10))	('OSI-906', 'Chemical', 'MESH:C551528', (49, 56))	('IRS-1', 'Gene', '3667', (14, 19))
304470	23688189	Surprisingly, total IRS-1 levels were highest in 143B, and were downregulated after treatment with OSI-906 in this cell line, although this had no effect on cell growth in this line, as opposed to the three others, which showed low IC50s.	('IRS-1', 'Gene', (20, 25))	('OSI-906', 'Chemical', 'MESH:C551528', (99, 106))	('143B', 'Var', (49, 53))	('50s', 'Species', '1214577', (234, 237))	('IRS-1', 'Gene', '3667', (20, 25))	('downregulated', 'NegReg', (64, 77))
304481	23688189	Because resistance to highly specific IGF1R inhibitors may develop through IR, blocking both IGF1R and IR with a dual kinase inhibitor will most likely lead to better inhibition of downstream IRS-1 signaling.	('inhibition', 'NegReg', (167, 177))	('IR', 'Gene', '3643', (192, 194))	('IR', 'Gene', '3643', (103, 105))	('blocking', 'Var', (79, 87))	('IGF1R', 'Gene', (38, 43))	('IRS-1', 'Gene', '3667', (192, 197))	('IGF1R', 'Gene', (93, 98))	('IRS-1', 'Gene', (192, 197))	('IR', 'Gene', '3643', (75, 77))
304485	23688189	Patients with tumors exhibiting an activating mutation in downstream pathways will most likely not respond to IGF1R inhibition.	('activating', 'PosReg', (35, 45))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('not', 'NegReg', (95, 98))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutation', 'Var', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
304568	22450682	An abnormality in apoptosis causes malignancy, which may lead to uncontrolled cell growth.	('lead', 'Reg', (57, 61))	('apoptosis', 'Protein', (18, 27))	('malignancy', 'Disease', 'MESH:D009369', (35, 45))	('abnormality', 'Var', (3, 14))	('malignancy', 'Disease', (35, 45))	('causes', 'Reg', (28, 34))	('uncontrolled cell growth', 'CPA', (65, 89))
304583	22450682	After drug administration, the thymus indices of high DELA dosage groups were significantly higher than both the control group and the CTX group.	('higher', 'PosReg', (92, 98))	('CTX', 'Gene', (135, 138))	('DELA', 'Chemical', '-', (54, 58))	('high DELA', 'Var', (49, 58))	('thymus indices', 'CPA', (31, 45))	('CTX', 'Gene', '57276', (135, 138))
304596	22450682	The anti-apoptotic Bcl-2 has generated significant attention as a potential apoptosis regulator in cancer treatment since reports demonstrating that antisense RNA induced leukaemic cell apoptosis by suppression of Bcl-2.	('suppression', 'NegReg', (199, 210))	('leukaemic cell apoptosis', 'CPA', (171, 195))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('antisense RNA', 'Var', (149, 162))	('Bcl-2', 'Gene', '12043', (19, 24))	('cancer', 'Disease', (99, 105))	('Bcl-2', 'Gene', (19, 24))	('Bcl-2', 'Gene', (214, 219))	('Bcl-2', 'Gene', '12043', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
304599	22450682	In the present study, DELA decreased the ratio of Bcl-2/Bax, which suggests that the mitochondrial apoptotic pathway was activated by DELA during murine S180 cell apoptosis.	('Bax', 'Gene', (56, 59))	('murine', 'Species', '10090', (146, 152))	('decreased', 'NegReg', (27, 36))	('ratio', 'MPA', (41, 46))	('Bax', 'Gene', '12028', (56, 59))	('Bcl-2', 'Gene', (50, 55))	('DELA', 'Var', (134, 138))	('mitochondrial apoptotic pathway', 'Pathway', (85, 116))	('DELA', 'Chemical', '-', (22, 26))	('Bcl-2', 'Gene', '12043', (50, 55))	('DELA', 'Chemical', '-', (134, 138))	('activated', 'PosReg', (121, 130))	('S180', 'CellLine', 'CVCL:2874', (153, 157))
304601	22450682	The MS characteristic fragmentations of the lycorenine-type alkaloids are seen at m/z 125 and 96, and originate from a retro-Diels-Alder cleavage of ring C, with a hydroxyl group in position 2.	('alkaloids', 'Chemical', 'MESH:D000470', (60, 69))	('originate from', 'Reg', (102, 116))	('m/z 125', 'Var', (82, 89))	('fragmentations', 'MPA', (22, 36))	('lycorenine', 'Chemical', 'MESH:C023825', (44, 54))
304602	22450682	For example, two ion peaks of hippeastrine at m/z 125 (C and D ring) and 190 (A and B ring) completely account for the two parts of the molecule (i.e., 125 + 190 = 315 = M+).	('125 + 190', 'Var', (152, 161))	('hippeastrine', 'Chemical', 'MESH:C060577', (30, 42))	('account', 'Reg', (103, 110))
304622	22450682	reported that narciclasine at concentrations of 1 microM appears to induce marked apoptosis-mediated cytotoxic effects in human carcinoma cells but not in normal fibroblasts by activation of the death receptor pathway.	('human', 'Species', '9606', (122, 127))	('carcinoma', 'Disease', 'MESH:D002277', (128, 137))	('narciclasine', 'Chemical', 'MESH:C010753', (14, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('death receptor pathway', 'Pathway', (195, 217))	('carcinoma', 'Disease', (128, 137))	('apoptosis-mediated cytotoxic effects', 'CPA', (82, 118))	('narciclasine', 'Var', (14, 26))
304679	22450682	Immune complexes were formed by incubation in antibodies to procaspase-3, Bcl-2, Bax, and actin for 1 h at 37  C. All results are presented as means +- SD from triplicate experiments performed in parallel unless otherwise indicated.	('antibodies', 'Var', (46, 56))	('Bax', 'Gene', (81, 84))	('procaspase-3', 'Protein', (60, 72))	('Bcl-2', 'Gene', '12043', (74, 79))	('Bcl-2', 'Gene', (74, 79))	('Bax', 'Gene', '12028', (81, 84))
304719	32923870	Sarcomas have multiple genomic alterations, including copy number changes, point mutations, insertions and deletions, and fusions.	('point mutations', 'Var', (75, 90))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('fusions', 'Disease', (122, 129))	('copy number changes', 'Var', (54, 73))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('deletions', 'Var', (107, 116))	('Sarcomas', 'Disease', (0, 8))	('insertions', 'Var', (92, 102))
304755	32923870	L-type sarcomas (ie, leiomyosarcoma, liposarcoma) constituted the greatest proportion of cases, and this is indicative by the preponderance of TP53, RB1 alterations and MDM2 and CDK4 amplifications (Table 3).	('leiomyosarcoma', 'Disease', 'MESH:D007890', (21, 35))	('RB1', 'Gene', (149, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('liposarcoma', 'Disease', (37, 48))	('amplifications', 'Var', (183, 197))	('TP53', 'Gene', '7157', (143, 147))	('sarcomas', 'Disease', 'MESH:D012509', (7, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (7, 15))	('leiomyosarcoma', 'Disease', (21, 35))	('RB1', 'Gene', '5925', (149, 152))	('sarcomas', 'Disease', (7, 15))	('liposarcoma', 'Phenotype', 'HP:0012034', (37, 48))	('CDK4', 'Gene', (178, 182))	('MDM2', 'Gene', (169, 173))	('liposarcoma', 'Disease', 'MESH:D008080', (37, 48))	('CDK4', 'Gene', '1019', (178, 182))	('MDM2', 'Gene', '4193', (169, 173))	('TP53', 'Gene', (143, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (21, 35))
304757	32923870	Of the qualified samples (n = 56), RNA failure (32.1%; n = 18), failed RNA metrics (25%; n =14), low tumor purity (14.3%; n =8), noisy copy number alteration data (12.5%; n =7), and contamination (8.9%; n =5) composed > 90% of the causes of incomplete sample CGP (Fig 3B).	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('noisy copy number alteration', 'Var', (129, 157))	('low tumor', 'Disease', (97, 106))	('low tumor', 'Disease', 'MESH:D009800', (97, 106))
304766	32923870	We would anticipate, as time progresses, the types of tumor for which there are defined targetable alterations will increase and thus there would be an increase in physician treatment-decision changes.	('increase', 'PosReg', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('alterations', 'Var', (99, 110))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('increase', 'PosReg', (116, 124))	('tumor', 'Disease', (54, 59))
304768	32923870	A developing example would be that in leiomyosarcoma, where we have previously reported that homologous recombination alterations are a common feature of uterine leiomyosarcomas and may be amenable to PARP inhibition.	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (154, 177))	('leiomyosarcomas', 'Disease', (162, 177))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (162, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('homologous recombination alterations', 'Var', (93, 129))	('alterations', 'Var', (118, 129))	('PARP', 'Gene', '1302', (201, 205))	('leiomyosarcoma', 'Disease', (38, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (38, 52))	('PARP', 'Gene', (201, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (162, 177))	('leiomyosarcoma', 'Disease', (162, 176))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (38, 52))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (162, 177))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (162, 176))
304774	32923870	Employment: Foundation Medicine, Partners Healthcare Stock and Other Ownership Interests: Foundation Medicine Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine, Mirati Therapeutics Consulting or Advisory Role: Revolution Medicines Patents, Royalties, Other Intellectual Property: Receive periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center.	('T790M', 'Var', (389, 394))	('T790M', 'Mutation', 'p.T790M', (389, 394))	('Cancer', 'Disease', (438, 444))	('Cancer', 'Disease', 'MESH:D009369', (438, 444))	('Cancer', 'Phenotype', 'HP:0002664', (438, 444))
304849	24685446	These patients were ideal for this study for several reasons: anesthesia during imaging eliminated motion, given that motion blurring can cause 2 images to appear more similar than they really are; the bone surrounding the nasal cavity guided accurate image registration, because registration inaccuracies can significantly degrade voxel-based correlations; and precise immobilization techniques enabled repeatable positioning.	('inaccuracies', 'Var', (293, 305))	('voxel-based correlations', 'MPA', (332, 356))	('degrade', 'NegReg', (324, 331))	('patients', 'Species', '9606', (6, 14))
305011	29215573	PEGylation (stealth liposomes) improves the stability and circulation time by increasing water solubility, reducing renal clearance and improving "passive" targeting to tumours.	('PE', 'Chemical', '-', (0, 2))	('water solubility', 'MPA', (89, 105))	('tumours', 'Disease', (169, 176))	('increasing', 'PosReg', (78, 88))	('reducing renal clearance', 'Phenotype', 'HP:0012213', (107, 131))	('renal clearance', 'MPA', (116, 131))	('improves', 'PosReg', (31, 39))	('reducing', 'NegReg', (107, 115))	('improving', 'PosReg', (136, 145))	('water', 'Chemical', 'MESH:D014867', (89, 94))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('PEGylation', 'Var', (0, 10))	('stability', 'MPA', (44, 53))	('tumours', 'Disease', 'MESH:D009369', (169, 176))
305055	29215573	MTP-PE encapsulation into liposomes enhances the endocytosis and tissue uptake by the mononuclear phagocyte system and prolongs its half-life in circulation.	('encapsulation', 'Var', (7, 20))	('enhances', 'PosReg', (36, 44))	('prolongs', 'NegReg', (119, 127))	('tissue uptake', 'CPA', (65, 78))	('MTP-PE encapsulation', 'Var', (0, 20))	('MTP-PE', 'Chemical', '-', (0, 6))	('endocytosis', 'MPA', (49, 60))	('half-life in circulation', 'MPA', (132, 156))
305057	29215573	MacEwen and collaborators demonstrated that L-MTP/PE (2 mg/m2 IV, administered twice a week for 8 weeks) significantly prolongs ST and the metastasis free interval (MFI) (median MFI was 168 and 58 days and median ST was 222 and 77 days for L-MTP-PE and free liposomes, respectively) in the treatment group compared to the control group (thirteen dogs that received empty liposomes after surgery).	('dogs', 'Species', '9615', (346, 350))	('prolongs', 'PosReg', (119, 127))	('L-MTP-PE', 'Var', (240, 248))	('L-MTP', 'Chemical', '-', (44, 49))	('metastasis free interval', 'CPA', (139, 163))	('PE', 'Chemical', '-', (50, 52))	('PE', 'Chemical', '-', (246, 248))	('L-MTP/PE', 'Var', (44, 52))	('L-MTP', 'Chemical', '-', (240, 245))	('L-MTP-PE', 'Chemical', '-', (240, 248))
305059	29215573	Both ST and MFI were prolonged for dogs treated with L-MTP-PE after surgical amputation compared to dogs who underwent surgery alone and had no evidence of metastasis at the time of enrolment (from 9.8 months to 14.4 months and 7.6 months to 11.2 months for median ST and median MFI, respectively).	('L-MTP-PE', 'Var', (53, 61))	('prolonged', 'PosReg', (21, 30))	('dogs', 'Species', '9615', (100, 104))	('MFI', 'MPA', (12, 15))	('dogs', 'Species', '9615', (35, 39))	('L-MTP-PE', 'Chemical', '-', (53, 61))
305061	29215573	Although the contradictory results of immunotherapy with L-MTP-PE combined with standard chemotherapy are also described for treatment of children diagnosed with OSA, L-MTP-PE is approved in Europe to use together with chemotherapy for treatment of newly diagnosed OSA in children, as some patients may benefit from it.	('OS', 'Chemical', '-', (265, 267))	('children', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (290, 298))	('OSA', 'Phenotype', 'HP:0002669', (265, 268))	('L-MTP-PE', 'Var', (167, 175))	('OS', 'Chemical', '-', (162, 164))	('OSA', 'Phenotype', 'HP:0002669', (162, 165))	('L-MTP-PE', 'Chemical', '-', (57, 65))	('OSA', 'Disease', (162, 165))	('L-MTP-PE', 'Chemical', '-', (167, 175))	('children', 'Species', '9606', (272, 280))
305064	29215573	Similarly, in randomized clinical trials testing oral melanomas in dogs, L-MTP-PE showed promising anti-metastatic activity only in early stages of the disease (ST increased for more than 2 years), in comparison to in advanced-stage canine oral melanoma, in which L-MTP-PE was administered alone post-surgery or together with recombinant canine granulocyte macrophage colony-stimulating factor, neither resulting in a significant antitumour response.	('tumour', 'Disease', (434, 440))	('canine', 'Species', '9615', (338, 344))	('granulocyte macrophage colony-stimulating factor', 'Gene', '403923', (345, 393))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('canine', 'Species', '9615', (233, 239))	('oral melanoma', 'Disease', (240, 253))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('oral melanoma', 'Disease', 'MESH:D008545', (240, 253))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('oral melanoma', 'Disease', (49, 62))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('oral melanoma', 'Disease', 'MESH:D008545', (49, 62))	('L-MTP-PE', 'Var', (73, 81))	('melanomas', 'Disease', (54, 63))	('anti-metastatic activity', 'MPA', (99, 123))	('L-MTP-PE', 'Chemical', '-', (264, 272))	('L-MTP-PE', 'Chemical', '-', (73, 81))	('granulocyte macrophage colony-stimulating factor', 'Gene', (345, 393))	('tumour', 'Phenotype', 'HP:0002664', (434, 440))	('dogs', 'Species', '9615', (67, 71))	('tumour', 'Disease', 'MESH:D009369', (434, 440))
305066	29215573	Results obtained suggest that the success of additional therapies with L-MTP-PE is probably associated with the staging of the disease, with much better responses in the early stages of cancer.	('L-MTP-PE', 'Var', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('L-MTP-PE', 'Chemical', '-', (71, 79))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
305078	29215573	Khanna and collaborators established, in both in vitro and in vivo studies, that during the use of inhalation therapy, IL-2 liposomes stimulate pulmonary immune antitumour activity much more than free IL-2.	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('stimulate', 'PosReg', (134, 143))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('liposomes', 'Var', (124, 133))	('tumour', 'Disease', (165, 171))	('IL-2', 'Gene', (119, 123))
305104	29215573	Previously performed in vitro studies on canine and human prostate cancer cell lines (Ace-1 and PC3, respectively) demonstrated the ability of CTI-52010 to decrease cell viability and cell survival, induce apoptosis, and cause the rigidity of microtubules in both human and canine castration-resistant prostate cancer.	('human', 'Species', '9606', (264, 269))	('CTI-52010', 'Chemical', '-', (143, 152))	('Ace-1', 'Gene', '1636', (86, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('canine', 'Species', '9615', (274, 280))	('prostate cancer', 'Disease', (58, 73))	('PC3', 'Gene', (96, 99))	('cause', 'Reg', (221, 226))	('apoptosis', 'CPA', (206, 215))	('decrease', 'NegReg', (156, 164))	('rigidity', 'Disease', 'MESH:D009127', (231, 239))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('induce', 'PosReg', (199, 205))	('PC3', 'Gene', '3853', (96, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (302, 317))	('prostate cancer', 'Phenotype', 'HP:0012125', (302, 317))	('cell survival', 'CPA', (184, 197))	('rigidity', 'Disease', (231, 239))	('prostate cancer', 'Disease', (302, 317))	('canine', 'Species', '9615', (41, 47))	('CTI-52010', 'Var', (143, 152))	('rigidity', 'Phenotype', 'HP:0002063', (231, 239))	('cell viability', 'CPA', (165, 179))	('human', 'Species', '9606', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Ace-1', 'Gene', (86, 91))	('prostate cancer', 'Disease', 'MESH:D011471', (58, 73))
305130	29850341	Hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch syndrome, is an autosomal dominant genetic disorder with a high degree of penetrance and variable expressivity caused by a constitutional defect in a mismatch repair (MMR) gene, most commonly affecting the genes MLH1, MSH2, MSH6, and PMS2.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('HNPCC', 'Phenotype', 'HP:0006716', (46, 51))	('autosomal dominant genetic disorder', 'Disease', 'MESH:D030342', (90, 125))	('autosomal dominant genetic disorder', 'Disease', (90, 125))	('caused by', 'Reg', (185, 194))	('MLH1', 'Gene', '4292', (286, 290))	('defect', 'Var', (212, 218))	('MSH2', 'Gene', (292, 296))	('MSH6', 'Gene', (298, 302))	('Lynch syndrome', 'Disease', (68, 82))	('MMR', 'Gene', (241, 244))	('PMS2', 'Gene', '5395', (308, 312))	('affecting', 'Reg', (266, 275))	('Hereditary nonpolyposis colorectal carcinoma', 'Disease', (0, 44))	('Hereditary nonpolyposis colorectal carcinoma', 'Disease', 'MESH:D003123', (0, 44))	('MSH6', 'Gene', '2956', (298, 302))	('HNPCC', 'Disease', 'None', (46, 51))	('HNPCC', 'Disease', (46, 51))	('Hereditary nonpolyposis colorectal carcinoma', 'Phenotype', 'HP:0006716', (0, 44))	('MSH2', 'Gene', '4436', (292, 296))	('Lynch syndrome', 'Disease', 'MESH:D003123', (68, 82))	('PMS2', 'Gene', (308, 312))	('MLH1', 'Gene', (286, 290))
305137	29850341	He presented to UAB with invasive colorectal adenocarcinoma in 2010, and in 2011 he was diagnosed at UAB with Lynch syndrome/MTS with a documented mutation of the MSH6 gene.	('invasive colorectal adenocarcinoma', 'Disease', (25, 59))	('Lynch syndrome', 'Disease', (110, 124))	('invasive colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (25, 59))	('mutation', 'Var', (147, 155))	('Lynch syndrome', 'Disease', 'MESH:D003123', (110, 124))	('MSH6', 'Gene', (163, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('MSH6', 'Gene', '2956', (163, 167))
305158	29850341	Despite the patient's history of a documented mutation of the MSH6 gene, the sample was positive for MLH1, MSH2, MSH6, and PMS2, indicating the absence of microsatellite instability (Figure 3).	('PMS2', 'Gene', '5395', (123, 127))	('MSH6', 'Gene', (62, 66))	('MSH2', 'Gene', '4436', (107, 111))	('microsatellite instability', 'MPA', (155, 181))	('MSH6', 'Gene', '2956', (62, 66))	('MSH6', 'Gene', '2956', (113, 117))	('MSH2', 'Gene', (107, 111))	('MSH6', 'Gene', (113, 117))	('patient', 'Species', '9606', (12, 19))	('mutation', 'Var', (46, 54))	('MLH1', 'Gene', '4292', (101, 105))	('positive', 'Reg', (88, 96))	('PMS2', 'Gene', (123, 127))	('MLH1', 'Gene', (101, 105))
305159	29850341	Although IHC and MSI are considered to be sensitive prescreening tools for the detection of MMR gene defects, with a correspondence of almost 100% between both tests, the presence of MSI is not reflective of the specific gene defect present, and the maintenance of expression of the MMR proteins on IHC does not exclude the possibility of an underlying DNA repair defect.	('MSI', 'Disease', 'None', (17, 20))	('defects', 'Var', (101, 108))	('MSI', 'Disease', (17, 20))	('MSI', 'Disease', 'None', (183, 186))	('MMR', 'Gene', (92, 95))	('MSI', 'Disease', (183, 186))
305160	29850341	showed that the mutations in MSH6 do not always produce microsatellite instability (MSI) in the tumors of HNPCC.	('tumors of HNPCC', 'Disease', (96, 111))	('MSI', 'Disease', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('produce', 'Reg', (48, 55))	('microsatellite instability', 'MPA', (56, 82))	('MSH6', 'Gene', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (16, 25))	('tumors of HNPCC', 'Disease', 'MESH:D009369', (96, 111))	('MSI', 'Disease', 'None', (84, 87))	('HNPCC', 'Phenotype', 'HP:0006716', (106, 111))	('MSH6', 'Gene', '2956', (29, 33))
305173	29490634	Neoplastic cells expressed CD11c, CD14, CD18, CD45, CD172a, CD204, MHC I, and vimentin.	('CD204', 'Var', (60, 65))	('CD45', 'Gene', (46, 50))	('MHC', 'Gene', (67, 70))	('CD', 'Chemical', 'MESH:D002104', (40, 42))	('CD14', 'Var', (34, 38))	('CD', 'Chemical', 'MESH:D002104', (46, 48))	('CD172a', 'Var', (52, 58))	('CD11c', 'Gene', '3687', (27, 32))	('MHC', 'Gene', '3107', (67, 70))	('CD11c', 'Gene', (27, 32))	('CD', 'Chemical', 'MESH:D002104', (60, 62))	('vimentin', 'Gene', '477991', (78, 86))	('CD45', 'Gene', '490255', (46, 50))	('CD', 'Chemical', 'MESH:D002104', (34, 36))	('CD', 'Chemical', 'MESH:D002104', (52, 54))	('CD', 'Chemical', 'MESH:D002104', (27, 29))	('vimentin', 'Gene', (78, 86))	('CD18', 'Gene', (40, 44))
305211	29490634	For immunolabeling with the primary antibodies (CD3, CD18, CD79a and CD204), sections were processed with the Autostainer Link 48 (Dako North America, Carpinteria, CA) using the EnVision Flex+ detection system (Dako North America), and the immunoreaction was visualized with 3,3'-diaminobenzidine substrate (DAB) (Dako North America) and sections were counterstained with haematoxylin.	('CD', 'Chemical', 'MESH:D002104', (69, 71))	('DAB', 'Chemical', '-', (308, 311))	('CD79a', 'Gene', '484483', (59, 64))	('CD', 'Chemical', 'MESH:D002104', (53, 55))	('CD204', 'Var', (69, 74))	('CD79a', 'Gene', (59, 64))	('CD', 'Chemical', 'MESH:D002104', (48, 50))	('haematoxylin', 'Chemical', 'MESH:D006416', (372, 384))	('CD', 'Chemical', 'MESH:D002104', (59, 61))	("3,3'-diaminobenzidine", 'Chemical', 'MESH:D015100', (275, 296))
305237	29490634	Secondary antibodies include IRDye 800CW goat anti-mouse and 680RD goat anti-rabbit (LI-COR).	('goat', 'Species', '9925', (67, 71))	('mouse', 'Species', '10090', (51, 56))	('rabbit', 'Species', '9986', (77, 83))	('goat', 'Species', '9925', (41, 45))	('IRDye 800CW', 'Var', (29, 40))	('680RD goat', 'Var', (61, 71))
305242	29490634	BD cell line expressed CD11c, CD14, CD172a and MHC I at a high level, and MHC II at a lower level (Fig.	('CD11c', 'Gene', '3687', (23, 28))	('CD14', 'Var', (30, 34))	('MHC', 'Gene', (74, 77))	('CD', 'Chemical', 'MESH:D002104', (30, 32))	('CD', 'Chemical', 'MESH:D002104', (36, 38))	('CD', 'Chemical', 'MESH:D002104', (23, 25))	('MHC', 'Gene', (47, 50))	('MHC', 'Gene', '3107', (74, 77))	('CD172a', 'Gene', (36, 42))	('MHC', 'Gene', '3107', (47, 50))	('CD11c', 'Gene', (23, 28))
305263	29490634	Although, several markers have been used to characterize human HS including CD163, CD68, CD11c, lysozyme, and CD14, two different markers were validated for HS tumors in dogs: CD18 (integrin beta chain beta 2) and CD204 (class A macrophage scavenger receptor).	('HS tumors', 'Disease', 'MESH:C567159', (157, 166))	('CD204', 'Gene', (214, 219))	('CD11c', 'Gene', (89, 94))	('CD11c', 'Gene', '3687', (89, 94))	('CD163', 'Gene', '9332', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('CD', 'Chemical', 'MESH:D002104', (176, 178))	('human', 'Species', '9606', (57, 62))	('CD', 'Chemical', 'MESH:D002104', (83, 85))	('CD', 'Chemical', 'MESH:D002104', (89, 91))	('HS tumors', 'Disease', (157, 166))	('CD163', 'Gene', (76, 81))	('CD68', 'Gene', '968', (83, 87))	('CD', 'Chemical', 'MESH:D002104', (214, 216))	('CD18', 'Var', (176, 180))	('CD', 'Chemical', 'MESH:D002104', (110, 112))	('CD68', 'Gene', (83, 87))	('dogs', 'Species', '9615', (170, 174))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('CD', 'Chemical', 'MESH:D002104', (76, 78))
305291	29490634	Another set of studies reported two patients carrying a HS associated with a mutation in BRAFV600E gene, most commonly seen in melanomas in humans.	('BRAFV600E', 'Gene', (89, 98))	('patients', 'Species', '9606', (36, 44))	('mutation', 'Var', (77, 85))	('melanomas', 'Disease', (127, 136))	('humans', 'Species', '9606', (140, 146))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanomas', 'Disease', 'MESH:D008545', (127, 136))	('BRAFV600E', 'Mutation', 'rs113488022', (89, 98))
305292	29490634	Neoplasms that are driven by this mutation are suitable for vemurafenib-based treatment, a B-Raf small molecule inhibitor.	('Neoplasms', 'Phenotype', 'HP:0002664', (0, 9))	('mutation', 'Var', (34, 42))	('Neoplasms', 'Disease', 'MESH:D009369', (0, 9))	('vemurafenib', 'Chemical', 'MESH:D000077484', (60, 71))	('Neoplasms', 'Disease', (0, 9))
305320	33671425	Consistently, the genetic manipulation of myogenic progenitors in different phases of the differentiation process triggers eRMS onset frequently.	('eRMS onset', 'Disease', (123, 133))	('S', 'Chemical', 'MESH:D013455', (126, 127))	('genetic manipulation', 'Var', (18, 38))	('eRMS', 'Phenotype', 'HP:0006743', (123, 127))	('triggers', 'Reg', (114, 122))
305333	33671425	The resulting LSL-KrasG12D/+; Tp53Fl/+ mice were crossed with the LSL-Kras+/+;Tp53Fl/Fl mice in order to generate the LSL-KrasG12D/+;Tp53Fl/Fl mice that were used as a model for eRMS tumor induction.	('LSL-KrasG12D/+', 'Var', (118, 132))	('eRMS', 'Phenotype', 'HP:0006743', (178, 182))	('eRMS tumor', 'Disease', 'MESH:D009369', (178, 188))	('eRMS tumor', 'Disease', (178, 188))	('S', 'Chemical', 'MESH:D013455', (15, 16))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('S', 'Chemical', 'MESH:D013455', (67, 68))	('S', 'Chemical', 'MESH:D013455', (181, 182))	('mice', 'Species', '10090', (88, 92))	('S', 'Chemical', 'MESH:D013455', (119, 120))	('mice', 'Species', '10090', (39, 43))	('mice', 'Species', '10090', (143, 147))
305365	33671425	For magnetic-activated cell sorting (MACS, Miltenyi Biotech, Bologna, Italy) of muscle-cell populations derived from LSL-KrasG12D/+;Tp53Fl/Fl, pellets were resuspended in 500 microL of magnetic bead buffer (MBB) composed of 0.5% BSA and 2 mM EDTA in 1X PBS.	('S', 'Chemical', 'MESH:D013455', (255, 256))	('PBS', 'Chemical', 'MESH:D007854', (253, 256))	('Tp53Fl/Fl', 'Var', (132, 141))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('EDTA', 'Chemical', 'MESH:D004492', (242, 246))	('LSL-KrasG12D/+;Tp53Fl/Fl', 'Var', (117, 141))	('S', 'Chemical', 'MESH:D013455', (40, 41))	('S', 'Chemical', 'MESH:D013455', (230, 231))
305377	33671425	LSL-KrasG12D/+;Tp53Fl/Fl SCs were cultured in a growth medium composed of Dulbecco's Modified Eagle Medium, High Glucose, GlutaMAXTM, 100 U/mL penicillin and 100 mg/mL streptomycin, 1 mM sodium pyruvate, 10 mM HEPES, 20% FBS, 10% horse serum (Euroclone #ECS0090D) and 2% chicken embryo extract (Seralabs, Bergamo, Italy, #CE-650-J).	('streptomycin', 'Chemical', 'MESH:D013307', (168, 180))	('S', 'Chemical', 'MESH:D013455', (25, 26))	('S', 'Chemical', 'MESH:D013455', (223, 224))	('High Glucose', 'Disease', 'MESH:D044882', (108, 120))	('Tp53Fl/Fl', 'Var', (15, 24))	('High Glucose', 'Disease', (108, 120))	('S', 'Chemical', 'MESH:D013455', (1, 2))	('chicken', 'Species', '9031', (271, 278))	('sodium pyruvate', 'Chemical', '-', (187, 202))	('S', 'Chemical', 'MESH:D013455', (214, 215))	('S', 'Chemical', 'MESH:D013455', (256, 257))	('High Glucose', 'Phenotype', 'HP:0003074', (108, 120))	('penicillin', 'Chemical', 'MESH:D010406', (143, 153))	('S', 'Chemical', 'MESH:D013455', (295, 296))	('GlutaMAXTM', 'Chemical', '-', (122, 132))	('HEPES', 'Chemical', 'MESH:C410687', (210, 215))
305407	33671425	Cells were identified by the incorporation of two iridium isotopes, 191Ir (DNA1) and 193Ir (DNA2).	('193Ir', 'Var', (85, 90))	('DNA2', 'Gene', (92, 96))	('iridium', 'Chemical', 'MESH:D007495', (50, 57))	('DNA2', 'Gene', '327762', (92, 96))
305456	33671425	We next asked whether progenitor cells derived from the LSL-KrasG12D/+;Tp53Fl/Fl model could induce the formation of RMS after in vitro infection with the Ad-Cre vector and transplantation into immunocompromised mouse muscles.	('infection', 'Disease', (136, 145))	('infection', 'Disease', 'MESH:D007239', (136, 145))	('Tp53Fl/Fl', 'Var', (71, 80))	('formation', 'CPA', (104, 113))	('S', 'Chemical', 'MESH:D013455', (57, 58))	('induce', 'PosReg', (93, 99))	('S', 'Chemical', 'MESH:D013455', (119, 120))	('mouse', 'Species', '10090', (212, 217))
305460	33671425	To induce the genetic rearrangements leading to the activation of Kras(G12D) and inactivation of Tp53, cells were infected in vitro with the Ad-Cre (Figure 3A).	('infected', 'Disease', 'MESH:D007239', (114, 122))	('Kras(G12D', 'Var', (66, 75))	('G12D', 'Mutation', 'rs121913529', (71, 75))	('Tp53', 'Gene', (97, 101))	('infected', 'Disease', (114, 122))	('inactivation', 'NegReg', (81, 93))	('activation', 'PosReg', (52, 62))
305475	33671425	Tissues inoculated with Ad-Cre FAPs displayed a cell organization more similar to that observed in Ad-Cre SC-inoculated muscles rather than to the Ctrl (Figure 4A), suggesting that both Ad-Cre cell types behaved similarly after injection.	('cell organization', 'CPA', (48, 65))	('Ad-Cre', 'Var', (24, 30))	('FAP', 'Gene', (31, 34))	('S', 'Chemical', 'MESH:D013455', (106, 107))	('FAP', 'Gene', '14089', (31, 34))
305480	33671425	To this purpose, tumors generated by in vivo infection of muscles from conditional LSL-KrasG12D/+;Tp53Fl/Fl mice were surgically resected seven weeks after Ad-Cre in vivo infection and enzymatically digested to extract mononuclear cells.	('infection', 'Disease', (171, 180))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('infection', 'Disease', 'MESH:D007239', (171, 180))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('infection', 'Disease', (45, 54))	('S', 'Chemical', 'MESH:D013455', (84, 85))	('infection', 'Disease', 'MESH:D007239', (45, 54))	('Tp53Fl/Fl', 'Var', (98, 107))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
305485	33671425	This close similarity was also confirmed by a multidimensional scaling plot (MDS) (Figure 5B), which showed that the Ad-Cre FAPs were closer to eRMS cells than to Ad-Cre SCs in the two-dimensional space defined by MDS coordinates.	('S', 'Chemical', 'MESH:D013455', (79, 80))	('S', 'Chemical', 'MESH:D013455', (216, 217))	('FAP', 'Gene', '14089', (124, 127))	('S', 'Chemical', 'MESH:D013455', (147, 148))	('eRMS', 'Phenotype', 'HP:0006743', (144, 148))	('S', 'Chemical', 'MESH:D013455', (170, 171))	('MDS', 'Disease', (77, 80))	('MDS', 'Disease', 'MESH:D009190', (77, 80))	('MDS', 'Disease', (214, 217))	('MDS', 'Disease', 'MESH:D009190', (214, 217))	('Ad-Cre', 'Var', (117, 123))	('FAP', 'Gene', (124, 127))
305489	33671425	When comparing this expression profile with those of Ad-Cre FAPs and Ad-Cre SCs, we observed that only Ad-Cre FAPs expressed a similar expression pattern to most of the analyzed antigens (Figure 5E).	('FAP', 'Gene', '14089', (110, 113))	('FAP', 'Gene', (60, 63))	('S', 'Chemical', 'MESH:D013455', (76, 77))	('FAP', 'Gene', '14089', (60, 63))	('Ad-Cre', 'Var', (103, 109))	('FAP', 'Gene', (110, 113))
305494	33671425	The eRMS is a highly malignant pediatric soft-tissue sarcoma that is often associated to mutations in the Tp53 gene and aberrant expression of RAS and skeletal muscle markers.	('S', 'Chemical', 'MESH:D013455', (7, 8))	('eRMS', 'Phenotype', 'HP:0006743', (4, 8))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (41, 60))	('S', 'Chemical', 'MESH:D013455', (145, 146))	('sarcoma', 'Disease', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('mutations', 'Var', (89, 98))	('associated', 'Reg', (75, 85))	('eRMS', 'Disease', (4, 8))	('Tp53', 'Gene', (106, 110))
305501	33671425	Hettmer and colleagues demonstrated that SCs, if triggered by particular oncogenic lesions (activation of Kras(G12V) and deletion of p16INK4Ap19ARF), can generate murine sarcomas that are very similar to human nonalveolar RMS with pleomorphic features.	('SCs', 'Disease', (41, 44))	('Kras(G12V', 'Var', (106, 115))	('G12V', 'Mutation', 'rs121913529', (111, 115))	('S', 'Chemical', 'MESH:D013455', (41, 42))	('p16INK4Ap19ARF', 'Gene', (133, 147))	('activation', 'PosReg', (92, 102))	('sarcomas', 'Disease', 'MESH:D012509', (170, 178))	('S', 'Chemical', 'MESH:D013455', (224, 225))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('generate', 'Reg', (154, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcomas', 'Disease', (170, 178))	('human', 'Species', '9606', (204, 209))	('deletion', 'Var', (121, 129))	('murine', 'Species', '10090', (163, 169))
305508	33671425	To recapitulate the genetic alterations leading to eRMS, we used a conditional eRMS mouse model (LSL-KrasG12D/+;Tp53Fl/Fl) in which we triggered the activation of the Kras(G12D) and the knockout of Tp53 proteins in a spatially and temporally controlled manner by infecting them with Ad-Cre.	('knockout', 'Var', (186, 194))	('proteins', 'Protein', (203, 211))	('eRMS', 'Phenotype', 'HP:0006743', (51, 55))	('eRMS', 'Phenotype', 'HP:0006743', (79, 83))	('G12D', 'Mutation', 'rs121913529', (105, 109))	('S', 'Chemical', 'MESH:D013455', (98, 99))	('S', 'Chemical', 'MESH:D013455', (54, 55))	('S', 'Chemical', 'MESH:D013455', (82, 83))	('mouse', 'Species', '10090', (84, 89))	('Tp53', 'Gene', (198, 202))	('Kras(G12D', 'Var', (167, 176))	('activation', 'PosReg', (149, 159))	('G12D', 'Mutation', 'rs121913529', (172, 176))
305522	33671425	In particular, it has been suggested that the transformed mesenchymal stem cells can give rise to a particular subtype of sarcoma, depending on the vulnerability to mutations that affect specific developmental pathways.	('give rise', 'Reg', (85, 94))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('mutations', 'Var', (165, 174))	('sarcoma', 'Disease', (122, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
305523	33671425	Moreover, our analysis showed that myogenic progenitors, as well as other identified subpopulations, decreased upon Ad-Cre FAP and Ad-Cre SC inoculation into NOD/SCID mice.	('S', 'Chemical', 'MESH:D013455', (138, 139))	('S', 'Chemical', 'MESH:D013455', (162, 163))	('FAP', 'Gene', (123, 126))	('decreased', 'NegReg', (101, 110))	('FAP', 'Gene', '14089', (123, 126))	('SCID', 'Disease', 'MESH:D053632', (162, 166))	('SCID', 'Disease', (162, 166))	('mice', 'Species', '10090', (167, 171))	('Ad-Cre SC', 'Var', (131, 140))	('myogenic progenitors', 'CPA', (35, 55))
305529	33671425	Figure S3: Characterization of FAP and SC cells isolated from LSL-KrasG12D/+; Tp53Fl/Fl conditional mice and injected into NOD/SCID mice after in vitro infection with Ad-Cre virus.	('S', 'Chemical', 'MESH:D013455', (7, 8))	('S', 'Chemical', 'MESH:D013455', (63, 64))	('S', 'Chemical', 'MESH:D013455', (127, 128))	('SCID', 'Disease', (127, 131))	('mice', 'Species', '10090', (100, 104))	('SCID', 'Disease', 'MESH:D053632', (127, 131))	('Tp53Fl/Fl', 'Var', (78, 87))	('infection', 'Disease', (152, 161))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('infection', 'Disease', 'MESH:D007239', (152, 161))	('mice', 'Species', '10090', (132, 136))	('LSL-KrasG12D/+', 'Var', (62, 76))	('FAP', 'Gene', (31, 34))	('FAP', 'Gene', '14089', (31, 34))
305536	33671425	; validation, L.L.P., C.F., M.F., F.R., G.G., L.P. and S.V.	('S', 'Chemical', 'MESH:D013455', (55, 56))	('G.G.', 'Var', (40, 44))	('P', 'Chemical', 'MESH:D010758', (48, 49))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('C.F.', 'Var', (22, 26))	('L.P.', 'Var', (46, 50))	('M.F.', 'Var', (28, 32))
305620	32033005	Conversely, some phytocannabinoids, such as cannabigerol (CBG) and cannabigerovarin (CBGV), trigger an increase in sebum production in human SZ95 sebocytes cell line, possibly due to various affinities for TRP channels and interference with CB receptors.	('increase', 'PosReg', (103, 111))	('cannabigerovarin', 'Chemical', '-', (67, 83))	('SZ95', 'CellLine', 'CVCL:9803', (141, 145))	('CBG', 'Chemical', 'MESH:C037036', (85, 88))	('CBG', 'Chemical', 'MESH:C037036', (58, 61))	('human', 'Species', '9606', (135, 140))	('phytocannabinoids', 'Chemical', '-', (17, 34))	('CBGV', 'Chemical', '-', (85, 89))	('sebum production', 'MPA', (115, 131))	('cannabigerol', 'Chemical', 'MESH:C037036', (44, 56))	('cannabigerovarin', 'Var', (67, 83))
305626	32033005	Another synthetic cannabinoid, VCE-004.8, has also shown benefits in mouse models of scleroderma, reducing vascular collagen deposits, preventing macrophage infiltration, inhibiting the proliferation and migration of fibroblasts and decreasing overall dermal thickness through mechanisms mediated by CB2 and PPARgamma; while CB2 seems to mediate the anti-inflammatory effects, such as reducing macrophage IL-1beta secretion and reducing the inflammatory infiltrate, PPARgamma seems to exhibit anti-fibrotic effects by inhibiting the TGF-beta production through interaction with Smads signaling.	('PPARgamma', 'Var', (466, 475))	('preventing', 'NegReg', (135, 145))	('inhibiting', 'NegReg', (518, 528))	('reducing', 'NegReg', (98, 106))	('IL-1beta', 'Gene', '16175', (405, 413))	('inhibiting', 'NegReg', (171, 181))	('scleroderma', 'Disease', 'MESH:D012595', (85, 96))	('reducing', 'NegReg', (385, 393))	('mouse', 'Species', '10090', (69, 74))	('scleroderma', 'Phenotype', 'HP:0100324', (85, 96))	('cannabinoid', 'Chemical', 'MESH:D002186', (18, 29))	('IL-1beta', 'Gene', (405, 413))	('scleroderma', 'Disease', (85, 96))	('inflammatory infiltrate', 'MPA', (441, 464))	('interaction', 'Interaction', (561, 572))	('TGF-beta production', 'MPA', (533, 552))	('Smads', 'MPA', (578, 583))	('reducing', 'NegReg', (428, 436))
305643	32033005	THC causes autophagy-dependent apoptosis on melanoma models in vivo and in vitro, and the effects are more potent when CBD is associated, inflicting ROS production and caspase activation, suggesting that the two drugs cooperate in inducing apoptosis via different mechanisms.	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('THC', 'Var', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('autophagy-dependent apoptosis', 'CPA', (11, 40))	('ROS', 'Chemical', 'MESH:D017382', (149, 152))	('THC', 'Chemical', 'MESH:D013759', (0, 3))	('CBD', 'Chemical', 'MESH:D002185', (119, 122))	('ROS production', 'MPA', (149, 163))	('activation', 'PosReg', (176, 186))	('caspase', 'MPA', (168, 175))	('inflicting', 'Reg', (138, 148))
305648	32033005	In another melanoma mouse model using B16 melanoma cell lines, synthetic cannabinoids WIN-55,212-2 and JWH-133 decreased tumor cell proliferation via Akt inhibition, causing cell cycle arrest, but with no effects on the MAPK/ERK pathway.	('melanoma', 'Disease', (42, 50))	('cannabinoids', 'Chemical', 'MESH:D002186', (73, 85))	('MAPK', 'Gene', '5595;5594;26413;5595', (220, 224))	('cell cycle arrest', 'CPA', (174, 191))	('decreased', 'NegReg', (111, 120))	('tumor', 'Disease', (121, 126))	('JWH-133', 'Chemical', 'MESH:C432747', (103, 110))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('mouse', 'Species', '10090', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('JWH-133', 'Var', (103, 110))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('B16', 'CellLine', 'CVCL:N540', (38, 41))	('inhibition', 'NegReg', (154, 164))	('Akt', 'Pathway', (150, 153))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (174, 191))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('MAPK', 'Gene', (220, 224))	('WIN-55', 'Chemical', '-', (86, 92))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('melanoma', 'Disease', (11, 19))
305650	32033005	Conversely, the CB1 receptor was identified as having tumor-promoting effects in knockdown models of melanoma, as the CB1-silenced group demonstrated inhibition of ERK and Akt phosphorylation and cell cycle arrest; these findings lead to the hypothesis that CB1 expression alters communication and feedback loops in the endocannabinoid system, mediating the inhibition of migration and proliferation of melanoma cells in vitro.	('alters', 'Reg', (273, 279))	('inhibition', 'NegReg', (358, 368))	('migration', 'CPA', (372, 381))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (403, 411))	('melanoma', 'Disease', (403, 411))	('ERK', 'Pathway', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cannabinoid', 'Chemical', 'MESH:D002186', (324, 335))	('CB1', 'Gene', (258, 261))	('melanoma', 'Disease', 'MESH:D008545', (403, 411))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('expression', 'Var', (262, 272))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (196, 213))	('tumor', 'Disease', (54, 59))
305655	32033005	Mixed CB1 and CB2 synthetic cannabinoids JWH-018, JWH-122, and JWH-210 demonstrate effective effects in topical application against both carcinogenesis and ear inflammation on a TPA-induced mouse model, hinting at interconnection and interferences between cancer development and inflammation, influenced by CB1 and CB2.	('cancer', 'Disease', (256, 262))	('mouse', 'Species', '10090', (190, 195))	('JWH-210', 'Var', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('TPA', 'Chemical', 'MESH:D013755', (178, 181))	('ear inflammation', 'Disease', 'MESH:D010031', (156, 172))	('inflammation', 'Disease', 'MESH:D007249', (279, 291))	('JWH-018', 'Var', (41, 48))	('CB1', 'Gene', (6, 9))	('CB2', 'Gene', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('ear inflammation', 'Disease', (156, 172))	('inflammation', 'Disease', 'MESH:D007249', (160, 172))	('carcinogenesis', 'Disease', (137, 151))	('inflammation', 'Disease', (279, 291))	('cannabinoids', 'Chemical', 'MESH:D002186', (28, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (137, 151))	('inflammation', 'Disease', (160, 172))	('JWH-122', 'Var', (50, 57))
305677	32033005	Troubling results have been obtained in an oncologic study featuring the effectiveness of associating cannabis to the human IgG4 monoclonal antibody Nivolumab in the treatment of various cancers including melanoma, as cannabis decreased the response rate to the treatment, hinting at possible interactions between the therapeutic substances.	('cannabis', 'Species', '3483', (102, 110))	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancers', 'Disease', (187, 194))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('decreased', 'NegReg', (227, 236))	('melanoma', 'Disease', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('response rate', 'MPA', (241, 254))	('cannabis', 'Var', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('interactions', 'Interaction', (293, 305))	('human', 'Species', '9606', (118, 123))	('cannabis', 'Species', '3483', (218, 226))
305725	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))
305754	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))
305764	24190505	Nevertheless, clear examples of driver gene mutations were observed, including canonical mutations in TP53, PIK3CA, SETD2, AKT1, and subclonal mutation in FBXW7.	('AKT1', 'Gene', (123, 127))	('TP53', 'Gene', (102, 106))	('SETD2', 'Gene', '29072', (116, 121))	('FBXW7', 'Gene', '55294', (155, 160))	('SETD2', 'Gene', (116, 121))	('PIK3CA', 'Gene', (108, 114))	('mutations', 'Var', (89, 98))	('FBXW7', 'Gene', (155, 160))	('TP53', 'Gene', '7157', (102, 106))	('AKT1', 'Gene', '207', (123, 127))	('PIK3CA', 'Gene', '5290', (108, 114))
305765	24190505	Of particular interest were mutations in H3F3A, encoding the variant histone H3.3.	('histone H3.3', 'Gene', (69, 81))	('histone H3.3', 'Gene', '3020', (69, 81))	('H3F3A', 'Gene', '3020', (41, 46))	('H3F3A', 'Gene', (41, 46))	('mutations', 'Var', (28, 37))
305766	24190505	Mutations in this gene have only been previously observed in gliomas.	('gliomas', 'Disease', (61, 68))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('observed', 'Reg', (49, 57))
305775	24190505	At the genetic level, the most characteristic change is a t(12;16)(q13;p11) chromosomal translocation that results in the fusion of the FUS and DDIT3 genes.	('t(12;16)(q13;p11', 'Var', (58, 74))	('DDIT3', 'Gene', '1649', (144, 149))	('fusion', 'Interaction', (122, 128))	('FUS', 'Gene', (136, 139))	('FUS', 'Gene', '2521', (136, 139))	('results in', 'Reg', (107, 117))	('DDIT3', 'Gene', (144, 149))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (58, 75))
305783	24190505	The vast majority of SYNs harbor a reciprocal translocation t(X;18)(p11; q11) resulting in fusion of the SS18 (a.k.a.	('fusion', 'Var', (91, 97))	('p11', 'Gene', (68, 71))	('SS18', 'Gene', (105, 109))	('SYNs', 'Phenotype', 'HP:0012570', (21, 25))	('p11', 'Gene', '6281', (68, 71))
305816	24190505	A number of mutations were identified in unequivocal driver genes in these malignancies.	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('mutations', 'Var', (12, 21))	('malignancies', 'Disease', (75, 87))
305817	24190505	The most frequently mutated gene was TP53, mutated in three osteosarcomas and one SYN.	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('osteosarcomas', 'Phenotype', 'HP:0002669', (60, 73))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('mutated', 'Var', (43, 50))	('osteosarcomas', 'Disease', (60, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('osteosarcomas', 'Disease', 'MESH:D012516', (60, 73))
305818	24190505	Both sarcoma types have previously been shown to harbor mutations in TP53 .	('mutations', 'Var', (56, 65))	('TP53', 'Gene', '7157', (69, 73))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('TP53', 'Gene', (69, 73))	('sarcoma', 'Disease', (5, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))
305819	24190505	Three of the four mutations were missense (C176Y, V216M, A276D), all located at commonly mutated positions in the DNA-binding domain, and the fourth was a nonsense mutation (R306X) resulting in the loss of the domain required for p53-p53 interactions.	('p53', 'Gene', (234, 237))	('p53', 'Gene', '7157', (234, 237))	('A276D', 'Mutation', 'rs786202082', (57, 62))	('V216M', 'Mutation', 'rs730882025', (50, 55))	('R306X', 'Mutation', 'rs121913344', (174, 179))	('C176Y', 'Mutation', 'rs786202962', (43, 48))	('loss', 'NegReg', (198, 202))	('domain required', 'MPA', (210, 225))	('p53', 'Gene', '7157', (230, 233))	('A276D', 'Var', (57, 62))	('R306X', 'Var', (174, 179))	('interactions', 'Interaction', (238, 250))	('C176Y', 'Var', (43, 48))	('V216M', 'Var', (50, 55))	('p53', 'Gene', (230, 233))
305820	24190505	PIK3CA, a well-studied oncogene, was mutated in two out of the eight MLPSs, and it has been previously shown to be mutated in 18% of myxoid/round-cell liposarcomas.	('MLPS', 'Phenotype', 'HP:0012268', (69, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('MLPS', 'Disease', 'None', (69, 73))	('PIK3CA', 'Gene', (0, 6))	('liposarcomas', 'Phenotype', 'HP:0012034', (151, 163))	('liposarcomas', 'Disease', (151, 163))	('MLPSs', 'Phenotype', 'HP:0012268', (69, 74))	('PIK3CA', 'Gene', '5290', (0, 6))	('liposarcomas', 'Disease', 'MESH:D008080', (151, 163))	('MLPS', 'Disease', (69, 73))	('mutated', 'Var', (37, 44))
305821	24190505	One of the mutations (V344G) was in the helical domain, whereas the other (M1043I) was in the catalytic domain, both known hotspot positions.	('M1043I', 'Mutation', 'rs121913283', (75, 81))	('V344G', 'Mutation', 'rs1057519941', (22, 27))	('M1043I', 'Var', (75, 81))	('V344G', 'Var', (22, 27))
305822	24190505	The product of the PIK3CA gene (PI3Kalpha) is known to exert its effects through AKT1, and AKT1 was found to be mutated in a third MLPS.	('MLPS', 'Disease', (131, 135))	('PIK3CA', 'Gene', (19, 25))	('AKT1', 'Gene', '207', (91, 95))	('MLPS', 'Phenotype', 'HP:0012268', (131, 135))	('AKT1', 'Gene', (91, 95))	('PIK3CA', 'Gene', '5290', (19, 25))	('AKT1', 'Gene', (81, 85))	('MLPS', 'Disease', 'None', (131, 135))	('mutated', 'Var', (112, 119))	('PI3Kalpha', 'Gene', '5290', (32, 41))	('PI3Kalpha', 'Gene', (32, 41))	('AKT1', 'Gene', '207', (81, 85))
305823	24190505	The AKT1 mutation (E17K) was unequivocally of functional importance, as it was the canonical mutation observed in breast and colorectal cancers and shown to constitutively activate its kinase activity.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('AKT1', 'Gene', '207', (4, 8))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('breast and colorectal cancers', 'Disease', 'MESH:D015179', (114, 143))	('AKT1', 'Gene', (4, 8))	('activate', 'PosReg', (172, 180))	('E17K', 'Mutation', 'rs121434592', (19, 23))	('kinase activity', 'MPA', (185, 200))	('E17K', 'Var', (19, 23))
305825	24190505	The mutation (G34W) was at codon 34, one of the two positions that are characteristically mutated in childhood gliomas.	('gliomas', 'Disease', (111, 118))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('G34W', 'Mutation', 'p.G34W', (14, 18))	('G34W', 'Var', (14, 18))
305826	24190505	To our knowledge, a childhood acute lymphoblastic leukemia in a study that included 1,003 cases of acute leukemias and non-Hodgkin lymphomas is the only neoplasm other than gliomas that has ever been found to have a mutation at either of the two critical residues (codons 27 and 34).	('non-Hodgkin lymphomas', 'Disease', 'MESH:D008228', (119, 140))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (30, 58))	('gliomas', 'Disease', 'MESH:D005910', (173, 180))	('leukemias', 'Disease', (105, 114))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (30, 58))	('neoplasm', 'Disease', 'MESH:D009369', (153, 161))	('gliomas', 'Phenotype', 'HP:0009733', (173, 180))	('mutation', 'Var', (216, 224))	('lymphomas', 'Phenotype', 'HP:0002665', (131, 140))	('non-Hodgkin lymphomas', 'Disease', (119, 140))	('neoplasm', 'Disease', (153, 161))	('acute leukemias', 'Phenotype', 'HP:0002488', (99, 114))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (36, 58))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('neoplasm', 'Phenotype', 'HP:0002664', (153, 161))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('Hodgkin lymphomas', 'Phenotype', 'HP:0012189', (123, 140))	('leukemias', 'Disease', 'MESH:D007938', (105, 114))	('gliomas', 'Disease', (173, 180))	('non-Hodgkin lymphomas', 'Phenotype', 'HP:0012539', (119, 140))	('leukemias', 'Phenotype', 'HP:0001909', (105, 114))	('acute lymphoblastic leukemia', 'Disease', (30, 58))
305827	24190505	The mutation at codon 34 presumably interferes with trimethylation at the nearby lysine (codon 36), affecting genome wide epigenetic landscapes.	('mutation', 'Var', (4, 12))	('lysine', 'Chemical', 'MESH:D008239', (81, 87))	('trimethylation', 'MPA', (52, 66))	('interferes', 'NegReg', (36, 46))	('affecting', 'Reg', (100, 109))	('genome wide epigenetic landscapes', 'MPA', (110, 143))
305828	24190505	Another osteosarcoma had a mutation (S65L) in an evolutionarily conserved codon in the linker histone H1FX.	('S65L', 'Mutation', 'p.S65L', (37, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (8, 20))	('osteosarcoma', 'Disease', (8, 20))	('osteosarcoma', 'Disease', 'MESH:D012516', (8, 20))	('S65L', 'Var', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))
305829	24190505	Mutations in this gene have not been associated before with cancer, and it is not clear if indeed this mutation is a driver.	('cancer', 'Disease', (60, 66))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
305830	24190505	In the sarcoma set we assessed, we identified one additional mutation of a chromatin-modifying gene that was unequivocally important: a truncating mutation (Q219X) of SETD2 in a SYN.	('Q219X', 'Mutation', 'p.Q219X', (157, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('SETD2', 'Gene', '29072', (167, 172))	('Q219X', 'Var', (157, 162))	('SETD2', 'Gene', (167, 172))	('sarcoma', 'Disease', 'MESH:D012509', (7, 14))	('sarcoma', 'Disease', (7, 14))
305833	24190505	Though each of these genes can drive tumorigenesis when altered in specific ways, none of the mutations we identified was of the type, or at the positions, known to be functionally important for driving cancer, and we considered these mutations to be passengers.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutations', 'Var', (94, 103))	('altered', 'Var', (56, 63))	('drive', 'Reg', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Disease', (203, 209))	('tumor', 'Disease', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
305834	24190505	Other potentially interesting mutations occurred in TIE1 (two osteosarcomas: T398S and A646G).	('T398S', 'Mutation', 'rs1322865700', (77, 82))	('TIE1', 'Gene', (52, 56))	('T398S', 'Var', (77, 82))	('TIE1', 'Gene', '7075', (52, 56))	('osteosarcomas', 'Disease', (62, 75))	('osteosarcomas', 'Phenotype', 'HP:0002669', (62, 75))	('osteosarcoma', 'Phenotype', 'HP:0002669', (62, 74))	('osteosarcomas', 'Disease', 'MESH:D012516', (62, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('A646G', 'Mutation', 'rs111687857', (87, 92))	('A646G', 'Var', (87, 92))
305837	24190505	A third osteosarcoma harbored a mutation (E990G) in KDR, another kinase that regulates angiogenesis.	('A third osteosarcoma', 'Disease', 'MESH:D012516', (0, 20))	('E990G', 'Var', (42, 47))	('KDR', 'Gene', (52, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (8, 20))	('A third osteosarcoma', 'Disease', (0, 20))	('E990G', 'Mutation', 'p.E990G', (42, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('KDR', 'Gene', '3791', (52, 55))
305840	24190505	Usually most of these mutations are artifacts, or passenger mutations present in a fraction of the neoplastic cells in a tumor.	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', (121, 126))
305841	24190505	However, in one MLPS, there was a known driver mutation in FBXW7 (R479Q) present at a low level (17.1%).	('FBXW7', 'Gene', '55294', (59, 64))	('R479Q', 'Mutation', 'rs866987936', (66, 71))	('MLPS', 'Disease', (16, 20))	('MLPS', 'Phenotype', 'HP:0012268', (16, 20))	('FBXW7', 'Gene', (59, 64))	('R479Q', 'Var', (66, 71))	('MLPS', 'Disease', 'None', (16, 20))
305846	24190505	In contrast, 10 of 13 osteosarcomas had LOH in most of their chromosomes (Fig.	('osteosarcomas', 'Disease', 'MESH:D012516', (22, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('osteosarcomas', 'Disease', (22, 35))	('osteosarcomas', 'Phenotype', 'HP:0002669', (22, 35))	('LOH', 'Var', (40, 43))	('osteosarcoma', 'Phenotype', 'HP:0002669', (22, 34))
305854	24190505	Another, nonmutually exclusive possibility is that the gene fusions function as the predominant mechanism for driver mutations, but later during tumor development subclones arise that have distinct driver mutations in other genes.	('tumor', 'Disease', (145, 150))	('mutations', 'Var', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))
305888	32039736	FISH showed a clear separation of red and green signals within a single tumor cell, demonstrating the presence of a EWSR1 gene rearrangement (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EWSR1', 'Gene', '2130', (116, 121))	('rearrangement', 'Var', (127, 140))	('tumor', 'Disease', (72, 77))	('EWSR1', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
305900	32039736	One such case was a EWSR1-CREB1 gene rearranged low grade myxoid sarcoma of the pulmonary artery.	('sarcoma of the pulmonary artery', 'Disease', (65, 96))	('rearranged', 'Var', (37, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('EWSR1', 'Gene', '2130', (20, 25))	('sarcoma of the pulmonary artery', 'Disease', 'MESH:D012509', (65, 96))	('CREB1', 'Gene', '1385', (26, 31))	('EWSR1', 'Gene', (20, 25))	('CREB1', 'Gene', (26, 31))
305906	32039736	This makes a 75% positive rate for EWSR1-CREB1 fusion, 79% for EWSR1 rearrangement, and a negative rate of 21% for ESWR1-CREB1 fusion or ESWR1 rearrangement in the 24 cases where genetic study was performed in the reviewed series of PPMS.	('PPMS', 'Disease', (233, 237))	('CREB1', 'Gene', (121, 126))	('rearrangement', 'Var', (69, 82))	('CREB1', 'Gene', (41, 46))	('EWSR1', 'Gene', (35, 40))	('EWSR1', 'Gene', '2130', (63, 68))	('PPMS', 'Disease', 'MESH:D045888', (233, 237))	('EWSR1', 'Gene', '2130', (35, 40))	('CREB1', 'Gene', '1385', (41, 46))	('EWSR1', 'Gene', (63, 68))	('CREB1', 'Gene', '1385', (121, 126))
305909	32039736	One other case showed fusion loci in exon 7 of EWSR1 and exon 8 of CREB1.	('EWSR1', 'Gene', (47, 52))	('EWSR1', 'Gene', '2130', (47, 52))	('CREB1', 'Gene', '1385', (67, 72))	('CREB1', 'Gene', (67, 72))	('fusion', 'Var', (22, 28))
305928	32039736	PPMS should be also be distinguished from myoepithelial tumors, which can also arise in the lung with endobronchial growth pattern and EWSR1 rearrangements.	('PPMS', 'Disease', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EWSR1', 'Gene', (135, 140))	('PPMS', 'Disease', 'MESH:D045888', (0, 4))	('rearrangements', 'Var', (141, 155))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (42, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('myoepithelial tumors', 'Disease', (42, 62))	('EWSR1', 'Gene', '2130', (135, 140))
305937	32039736	Myxoid liposarcoma, however, often harbors rearrangement involving the DDIT3 gene, which is not present in PPMS.	('DDIT3', 'Gene', '1649', (71, 76))	('Myxoid liposarcoma', 'Phenotype', 'HP:0012268', (0, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('PPMS', 'Disease', (107, 111))	('Myxoid liposarcoma', 'Disease', (0, 18))	('DDIT3', 'Gene', (71, 76))	('Myxoid liposarcoma', 'Disease', 'MESH:D018208', (0, 18))	('PPMS', 'Disease', 'MESH:D045888', (107, 111))	('rearrangement', 'Var', (43, 56))	('harbors', 'Reg', (35, 42))	('liposarcoma', 'Phenotype', 'HP:0012034', (7, 18))
305945	32039736	Molecular fingerprint may play a prognostic role, as patients with EWSR1 rearrangement or EWSR1-CREB1 gene fusion may have more favorable prognosis, while those with no EWSR1-CREB1 fusion or wild type EWSR1 may portend poor clinical outcome.	('EWSR1', 'Gene', '2130', (67, 72))	('patients', 'Species', '9606', (53, 61))	('EWSR1', 'Gene', (90, 95))	('CREB1', 'Gene', (96, 101))	('rearrangement', 'Var', (73, 86))	('EWSR1', 'Gene', (169, 174))	('EWSR1', 'Gene', (67, 72))	('EWSR1', 'Gene', (201, 206))	('CREB1', 'Gene', '1385', (175, 180))	('EWSR1', 'Gene', '2130', (90, 95))	('EWSR1', 'Gene', '2130', (169, 174))	('EWSR1', 'Gene', '2130', (201, 206))	('CREB1', 'Gene', (175, 180))	('CREB1', 'Gene', '1385', (96, 101))
305946	32039736	PPMS is a rare low-grade sarcoma that occurs mostly in middle age women with most harboring the characteristic EWSR1-CREB1 fusion gene.	('PPMS', 'Disease', (0, 4))	('sarcoma', 'Disease', (25, 32))	('CREB1', 'Gene', (117, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('EWSR1', 'Gene', (111, 116))	('PPMS', 'Disease', 'MESH:D045888', (0, 4))	('EWSR1', 'Gene', '2130', (111, 116))	('fusion gene', 'Var', (123, 134))	('sarcoma', 'Disease', 'MESH:D012509', (25, 32))	('women', 'Species', '9606', (66, 71))	('CREB1', 'Gene', '1385', (117, 122))
305958	30268926	Several decades of research revealed that these tumors were transmitted by retroviruses and that retroviruses triggered cancer by insertional mutagenesis or by expression of viral versions of cellular genes, later dubbed oncogenes.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('insertional mutagenesis', 'Var', (130, 153))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('triggered', 'Reg', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
305966	30268926	In addition, some beta-HPVs cause cutaneous squamous cell carcinomas in patients with the rare hereditary skin disorder epidermodysplasia verruciformis and in long-term immunosuppressed individuals, for example organ transplant recipients.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (44, 68))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (34, 67))	('cause', 'Reg', (28, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('cutaneous squamous cell carcinomas', 'Disease', (34, 68))	('hereditary skin disorder epidermodysplasia verruciformis', 'Disease', 'MESH:D004819', (95, 151))	('beta-HPVs', 'Var', (18, 27))	('cutaneous squamous cell carcinomas', 'Phenotype', 'HP:0006739', (34, 68))	('skin disorder', 'Phenotype', 'HP:0000951', (106, 119))	('cutaneous squamous cell carcinomas', 'Disease', 'MESH:D002294', (34, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('patients', 'Species', '9606', (72, 80))
305970	30268926	There are at least three mechanisms by which viral infections can contribute to oncogenesis: (1) viruses can encode viral proteins that are oncogenic, (2) they can cause chronic inflammation and/or (3) promote genomic instability or other host cell alterations that lead to carcinogenesis.	('viral infection', 'Disease', 'MESH:D014777', (45, 60))	('genomic instability', 'CPA', (210, 229))	('cause', 'Reg', (164, 169))	('promote', 'PosReg', (202, 209))	('viral infection', 'Disease', (45, 60))	('inflammation', 'Disease', 'MESH:D007249', (178, 190))	('viruses', 'Var', (97, 104))	('inflammation', 'Disease', (178, 190))
305998	30268926	More recently, it was recognized that deregulation of metabolism, avoidance of immune responses, stimulation of pro-tumorigenic inflammation and genomic instability are also key element of the cancer phenotype.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('inflammation', 'Disease', (128, 140))	('cancer', 'Disease', (193, 199))	('deregulation', 'Var', (38, 50))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('metabolism', 'CPA', (54, 64))	('tumor', 'Disease', (116, 121))	('stimulation', 'PosReg', (97, 108))	('inflammation', 'Disease', 'MESH:D007249', (128, 140))
306011	30268926	Indeed, experiments performed with MCPyV and HPV positive cancer cell lines and transgenic mouse models suggests that inactivation of the viral oncogenic proteins will cause regression of the tumors.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('inactivation', 'Var', (118, 130))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('mouse', 'Species', '10090', (91, 96))	('regression', 'CPA', (174, 184))
306013	30268926	Interestingly, the mutations in non-viral tumors activate or inactivate the very same pathways that the viral oncogenic proteins attack, indicating that the etiology of the tumors is ultimately analogous.	('inactivate', 'NegReg', (61, 71))	('activate', 'PosReg', (49, 57))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
306018	30268926	If the infection is not cleared, the damage and regeneration cycles occur repeatedly, which promotes the accumulation of oncogenic mutations and epigenetic changes that lead to tumorigenesis.	('oncogenic', 'Gene', (121, 130))	('mutations', 'Var', (131, 140))	('tumor', 'Disease', (177, 182))	('infection', 'Disease', (7, 16))	('infection', 'Disease', 'MESH:D007239', (7, 16))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('epigenetic changes', 'Var', (145, 163))	('lead to', 'Reg', (169, 176))
306019	30268926	In addition, inflammatory and immune responses lead to increased production of reactive oxygen species (ROS) and nitrogen reactive species that induce mutations and can thus promote oncogenic transformation of hepatocytes.	('immune responses', 'CPA', (30, 46))	('promote', 'PosReg', (174, 181))	('nitrogen', 'Chemical', 'MESH:D009584', (113, 121))	('oncogenic transformation', 'CPA', (182, 206))	('increased', 'PosReg', (55, 64))	('nitrogen reactive species', 'MPA', (113, 138))	('increased production of reactive oxygen species', 'Phenotype', 'HP:0025464', (55, 102))	('production', 'MPA', (65, 75))	('oxygen', 'Chemical', 'MESH:D010100', (88, 94))	('inflammatory', 'CPA', (13, 25))	('mutations', 'Var', (151, 160))	('induce', 'Reg', (144, 150))
306026	30268926	EBV, KSHV and HPVs can also cause alterations in the cargoes carried by exosomes and other extracellular vesicles that are secreted by cells, thereby altering extracellular signaling, gene expression and biological properties of the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('altering', 'Reg', (150, 158))	('gene expression', 'MPA', (184, 199))	('cause alterations', 'Reg', (28, 45))	('tumor', 'Disease', (233, 238))	('EBV', 'Disease', 'MESH:D020031', (0, 3))	('extracellular signaling', 'MPA', (159, 182))	('KSHV', 'Species', '37296', (5, 9))	('KSHV', 'Var', (5, 9))	('EBV', 'Disease', (0, 3))	('HPVs', 'Var', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('cargoes carried by exosomes', 'MPA', (53, 80))
306028	30268926	Another common contributor to tumorigenesis in all these infections is the development of genomic instability, which accelerates cancer development.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('accelerates', 'PosReg', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('genomic', 'Var', (90, 97))	('infection', 'Disease', (57, 66))	('tumor', 'Disease', (30, 35))	('infection', 'Disease', 'MESH:D007239', (57, 66))
306031	30268926	In addition, since HTLV-1 is a retrovirus that becomes integrated into the host cell genome as part of its normal life cycle, insertional mutagenesis may also cause oncogenic mutations.	('oncogenic mutations', 'CPA', (165, 184))	('HTLV-1', 'Species', '11908', (19, 25))	('insertional mutagenesis', 'Var', (126, 149))	('cause', 'Reg', (159, 164))	('HTLV-1', 'Gene', (19, 25))
306032	30268926	Insertional mutagenesis may also contribute to HBV-induced hepatocellular carcinomas, as the HBV genome is consistently found inserted into cellular DNA in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('contribute', 'Reg', (33, 43))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (59, 84))	('HBV', 'Species', '10407', (47, 50))	('hepatocellular carcinomas', 'Disease', (59, 84))	('Insertional mutagenesis', 'Var', (0, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumors', 'Disease', (162, 168))	('HBV', 'Species', '10407', (93, 96))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (59, 84))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (59, 83))
306033	30268926	Indeed, genomic instability and HBx activity may cause some tumors through a classical oncogene-based mechanism, and this may explain why not all cases of HBV-associated hepatocellular carcinoma are preceded by cirrhosis or fibrosis, in contrast to HCV-related hepatocellular carcinoma.	('HBx', 'Gene', (32, 35))	('HCV', 'Disease', 'MESH:D006526', (249, 252))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (261, 285))	('HBV', 'Species', '10407', (155, 158))	('cause', 'Reg', (49, 54))	('HBV-associated', 'Gene', (155, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('hepatocellular carcinoma', 'Disease', (261, 285))	('fibrosis', 'Disease', 'MESH:D005355', (224, 232))	('fibrosis', 'Disease', (224, 232))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (170, 194))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('HCV', 'Disease', (249, 252))	('cirrhosis', 'Disease', 'MESH:D005355', (211, 220))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 194))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('genomic instability', 'Var', (8, 27))	('tumors', 'Disease', (60, 66))	('cirrhosis', 'Phenotype', 'HP:0001394', (211, 220))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (261, 285))	('cirrhosis', 'Disease', (211, 220))	('hepatocellular carcinoma', 'Disease', (170, 194))	('HBx', 'Gene', '944566', (32, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
306034	30268926	Another source of DNA mutations are cytidine deaminases of the family of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3), which are induced as a cell-intrinsic response to infection.	('apolipoprotein B mRNA', 'Protein', (73, 94))	('mutations', 'Var', (22, 31))	('cytidine', 'Chemical', 'MESH:D003562', (36, 44))	('infection', 'Disease', (200, 209))	('infection', 'Disease', 'MESH:D007239', (200, 209))
306036	30268926	However, these enzymes also generate collateral damage in the form of point mutations in the cellular genome that can drive cancer formation.	('drive', 'PosReg', (118, 123))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('point mutations', 'Var', (70, 85))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
306037	30268926	Consistent with this idea, a significant proportion of cellular mutations in HPV-associated cancers have an APOBEC3 mutational signature.	('APOBEC3', 'Gene', (108, 115))	('HPV-associated', 'Gene', (77, 91))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('mutational signature', 'MPA', (116, 136))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
306040	30268926	HPV E6 and E7, HTLV-1 Tax and the HBx protein also induce a variety of mitotic abnormalities that can cause chromosome missegregation and aneuploidy, the most prevalent manifestation of genomic instability in human solid tumors.	('HTLV-1', 'Species', '11908', (15, 21))	('human', 'Species', '9606', (209, 214))	('cause', 'Reg', (102, 107))	('HBx', 'Gene', '944566', (34, 37))	('aneuploidy', 'Disease', (138, 148))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('induce', 'Reg', (51, 57))	('mitotic abnormalities', 'Disease', 'MESH:D004314', (71, 92))	('HBx', 'Gene', (34, 37))	('HTLV-1 Tax', 'Gene', (15, 25))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('aneuploidy', 'Disease', 'MESH:D000782', (138, 148))	('tumors', 'Disease', (221, 227))	('HPV E6', 'Var', (0, 6))	('mitotic abnormalities', 'Disease', (71, 92))	('chromosome missegregation', 'CPA', (108, 133))
306050	30268926	Non-productive infections can arise as a consequence of accidental and irreversible integration of portions of the viral genome into a host chromosome, aberrations in epigenetic modifications and/or mutations of the viral genome, or infection of a cell type that does not support the viral life cycle.	('infection', 'Disease', (233, 242))	('infection', 'Disease', 'MESH:D007239', (233, 242))	('mutations', 'Var', (199, 208))	('infection', 'Disease', (15, 24))	('aberrations in epigenetic modifications', 'Var', (152, 191))	('infection', 'Disease', 'MESH:D007239', (15, 24))
306073	30268926	Moreover, a large-scale prospective study in Taiwan showed that patients that had antibodies to at least one of two lytic proteins were at least four times more likely to develop nasopharyngeal carcinoma than seronegative patients.	('nasopharyngeal carcinoma', 'Disease', (179, 203))	('patients', 'Species', '9606', (64, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (179, 203))	('patients', 'Species', '9606', (222, 230))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (179, 203))	('antibodies', 'Var', (82, 92))	('develop', 'PosReg', (171, 178))
306074	30268926	Direct evidence of the importance of lytic reactivation in EBV tumors was recently provided by a study examining a naturally occurring polymorphism in the promoter of the EBV BZLF1 protein, which controls the latent-to-lytic switch of the virus.	('polymorphism in', 'Var', (135, 150))	('BZLF1', 'Gene', (175, 180))	('EBV', 'Disease', 'MESH:D020031', (171, 174))	('BZLF1', 'Gene', '3783744', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('EBV', 'Disease', 'MESH:D020031', (59, 62))	('EBV', 'Disease', (171, 174))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('EBV', 'Disease', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
306076	30268926	Interestingly, this cancer-associated polymorphism leads to increased BZLF1 expression in response to reactivation stimuli such as B cell receptor activation and, consequently, increased lytic reactivation.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('polymorphism', 'Var', (38, 50))	('lytic reactivation', 'CPA', (187, 205))	('response to reactivation', 'MPA', (90, 114))	('increased', 'PosReg', (177, 186))	('B cell receptor', 'MPA', (131, 146))	('BZLF1', 'Gene', (70, 75))	('expression', 'MPA', (76, 86))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('BZLF1', 'Gene', '3783744', (70, 75))	('activation', 'PosReg', (147, 157))	('increased', 'PosReg', (60, 69))
306087	30268926	A very recent study showed that the HCMV-encoded chemokine receptor US28 can promote glioma growth and that targeting it with nano-antibodies reduced growth of a HCMV-positive glioma in mouse models.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('glioma', 'Disease', (176, 182))	('US28', 'Gene', (68, 72))	('promote', 'PosReg', (77, 84))	('US28', 'Gene', '3077536', (68, 72))	('reduced', 'NegReg', (142, 149))	('growth', 'MPA', (150, 156))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('HCMV', 'Species', '10359', (162, 166))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('mouse', 'Species', '10090', (186, 191))	('glioma', 'Disease', (85, 91))	('HCMV', 'Species', '10359', (36, 40))	('targeting', 'Var', (108, 117))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
306093	30268926	Also, not all studies have been able to detect HCMV in glioma samples, although these results do not rule out a hit-and-run mechanism (see below) given that HCMV can induce genomic instability.	('glioma', 'Disease', (55, 61))	('HCMV', 'Var', (157, 161))	('HCMV', 'Species', '10359', (157, 161))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('induce', 'Reg', (166, 172))	('HCMV', 'Species', '10359', (47, 51))	('genomic instability', 'MPA', (173, 192))
306096	30268926	It is possible that once a viral infection has caused a sufficient number of oncogenic cellular mutations for tumor initiation, expression of viral proteins or viral infection is no longer required for tumor maintenance, and, consequently, the virus may be lost during cancer progression.	('viral infection', 'Disease', 'MESH:D014777', (27, 42))	('tumor initiation', 'Disease', 'MESH:D009369', (110, 126))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('viral infection', 'Disease', (27, 42))	('tumor', 'Disease', (110, 115))	('tumor initiation', 'Disease', (110, 126))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('viral infection', 'Disease', 'MESH:D014777', (160, 175))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('cancer', 'Disease', (269, 275))	('mutations', 'Var', (96, 105))	('viral infection', 'Disease', (160, 175))
306100	30268926	This mechanism has been replicated experimentally in a recent study using a beta-HPV38 E6/E7 Cre-loxP-based transgenic mouse model, which develop tumors after UV irradiation even after excision of the viral DNA sequences.	('mouse', 'Species', '10090', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('E6/E7', 'Var', (87, 92))	('develop', 'PosReg', (138, 145))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', (146, 152))
306104	30268926	While alpha-HPV oncogene expression is generally maintained in the cancers, alpha-HPVs may contribute to tumorigenesis via a hit-and-run mechanism in Fanconi Anemia patients.	('Fanconi Anemia', 'Disease', 'MESH:D005199', (150, 164))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('contribute', 'Reg', (91, 101))	('Anemia', 'Phenotype', 'HP:0001903', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Fanconi Anemia', 'Phenotype', 'HP:0001994', (150, 164))	('patients', 'Species', '9606', (165, 173))	('alpha-HPVs', 'Var', (76, 86))	('tumor', 'Disease', (105, 110))	('Fanconi Anemia', 'Disease', (150, 164))
306105	30268926	These patients harbor mutations in genes that control genomic stability, and frequently develop oral cancers and squamous cell carcinomas at sites consistent with high-risk HPV infections.	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('HPV infections', 'Disease', (173, 187))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (113, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('HPV infections', 'Disease', 'MESH:D007239', (173, 187))	('develop', 'PosReg', (88, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (113, 137))	('squamous cell carcinomas', 'Disease', (113, 137))
306107	30268926	It is thus conceivable that HPVs may initially trigger carcinogenesis, but that because of the high rate of mutations in Fanconi Anemia patients, the oncogenic pathways initially targeted by E6 and E7 may be rapidly inactivated by mutation.	('Fanconi Anemia', 'Phenotype', 'HP:0001994', (121, 135))	('mutations', 'Var', (108, 117))	('Anemia', 'Phenotype', 'HP:0001903', (129, 135))	('oncogenic pathways', 'Pathway', (150, 168))	('Fanconi Anemia', 'Disease', (121, 135))	('Fanconi Anemia', 'Disease', 'MESH:D005199', (121, 135))	('patients', 'Species', '9606', (136, 144))
306109	30268926	This model is supported by a study in transgenic mice with conditional HPV16 E7 expression.	('E7 expression', 'Var', (77, 90))	('transgenic mice', 'Species', '10090', (38, 53))	('HPV16', 'Gene', (71, 76))	('HPV16', 'Species', '333760', (71, 76))
306110	30268926	While continued E7 expression was necessary for tumor maintenance in wild-type mice, tumors in mice carrying an Fanconi Anemia mutation continued to grow even after E7 was no longer expressed.	('tumor', 'Disease', (85, 90))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('Anemia', 'Phenotype', 'HP:0001903', (120, 126))	('mutation', 'Var', (127, 135))	('mice', 'Species', '10090', (79, 83))	('Fanconi Anemia', 'Phenotype', 'HP:0001994', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('grow', 'PosReg', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Fanconi Anemia', 'Disease', (112, 126))	('Fanconi Anemia', 'Disease', 'MESH:D005199', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Disease', (85, 91))
306184	29196603	Gene profiling showed that Ng2/Cspg4 deletion altered the expression of genes regulating cell proliferation and apoptosis.	('Cspg4', 'Gene', '121021', (31, 36))	('expression of genes', 'MPA', (58, 77))	('cell proliferation', 'CPA', (89, 107))	('deletion', 'Var', (37, 45))	('Cspg4', 'Gene', (31, 36))	('altered', 'Reg', (46, 53))
306185	29196603	Surprisingly, Ng2/Cspg4 deletion at the time of tumor initiation resulted in larger tumors.	('tumor initiation', 'Disease', 'MESH:D009369', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Cspg4', 'Gene', (18, 23))	('tumor initiation', 'Disease', (48, 64))	('larger', 'PosReg', (77, 83))	('tumors', 'Disease', (84, 90))	('deletion', 'Var', (24, 32))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('Cspg4', 'Gene', '121021', (18, 23))
306198	29196603	In human melanomas, NG2/CSPG4 functions to activate the MEK/ERK1/2 pathway by mediating the growth factor-induced activation of receptor tyrosine kinases.	('activation', 'PosReg', (114, 124))	('NG2/CSPG4', 'Var', (20, 29))	('activate', 'PosReg', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('human', 'Species', '9606', (3, 8))	('melanomas', 'Disease', 'MESH:D008545', (9, 18))	('receptor tyrosine kinases', 'Pathway', (128, 153))	('ERK1/2', 'Gene', (60, 66))	('MEK', 'Gene', (56, 59))	('MEK', 'Gene', '5609', (56, 59))	('melanomas', 'Disease', (9, 18))	('ERK1/2', 'Gene', '5595;5594', (60, 66))
306200	29196603	Interestingly, driving oncogenic mutations in Ng2/Cspg4-expressing cells results in the formation of sarcomas.	('Cspg4', 'Gene', (50, 55))	('results in', 'Reg', (73, 83))	('sarcomas', 'Disease', 'MESH:D012509', (101, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('mutations', 'Var', (33, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('Cspg4', 'Gene', '121021', (50, 55))	('sarcomas', 'Disease', (101, 109))
306203	29196603	Inhibition of NG2/CSPG4 expression or treatment with anti-NG2/CSPG4 antibodies inhibits tumor growth in xenografts from some malignancies.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibits', 'NegReg', (79, 87))	('NG2/CSPG4', 'Gene', (14, 23))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('anti-NG2/CSPG4', 'Gene', (53, 67))	('anti-NG2/CSPG4', 'Var', (53, 67))	('malignancies', 'Disease', (125, 137))
306206	29196603	We used an autochthonous mouse model in which undifferentiated soft-tissue sarcoma formation is initiated by deletion of both p53 alleles and expression of an oncogenic mutant Kras driven by either Flp recombinase or Cre recombinase (KP mouse).	('Kras', 'Gene', '16653', (176, 180))	('mouse', 'Species', '10090', (237, 242))	('deletion', 'Var', (109, 117))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (63, 82))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('initiated by', 'Reg', (96, 108))	('p53', 'Gene', '22060', (126, 129))	('mouse', 'Species', '10090', (25, 30))	('sarcoma', 'Disease', (75, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('Kras', 'Gene', (176, 180))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (67, 82))	('p53', 'Gene', (126, 129))
306209	29196603	Primary sarcomas were generated in the hind limbs of these mice by intramuscular injection of adeno-FlpO.	('Primary sarcomas', 'Disease', 'MESH:D012509', (0, 16))	('mice', 'Species', '10090', (59, 63))	('adeno-FlpO', 'Var', (94, 104))	('adeno-FlpO', 'Chemical', '-', (94, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('Primary sarcomas', 'Disease', (0, 16))
306212	29196603	S1) were used to confirm the deletion of Ng2/Cspg4 and its protein product.	('Cspg4', 'Gene', (45, 50))	('deletion', 'Var', (29, 37))	('Cspg4', 'Gene', '121021', (45, 50))
306213	29196603	Immunofluorescence showed a 65% reduction in the proportion of cells expressing NG2/CSPG4 in KPCNG2 mice and an 80% reduction in KPRNG2 mice.	('mice', 'Species', '10090', (136, 140))	('mice', 'Species', '10090', (100, 104))	('NG2/CSPG4', 'Gene', (80, 89))	('reduction', 'NegReg', (32, 41))	('reduction', 'NegReg', (116, 125))	('KPCNG2', 'Var', (93, 99))
306214	29196603	Western analysis showed a relative NG2/CSPG4 protein level of 14% compared with controls in tumors from KPCNG2 mice and 8% compared with controls in tumors from KPRNG2 mice (relative densities are compared using Student's t test, n = 5 in each group, p < 0.01).	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('mice', 'Species', '10090', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mice', 'Species', '10090', (111, 115))	('NG2/CSPG4 protein level', 'MPA', (35, 58))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (149, 155))	('KPCNG2', 'Var', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
306216	29196603	Deletion of Ng2/Cspg4 in established tumors (KrasFRT-STOP-FRT-G12D/+; p53FRT/FRT; Rosa26Cre-ER-T2/+; Ng2/Cspg4f/f) resulted in a significant reduction in tumor size when compared with the KrasFRT-STOP-FRT-G12D/+; p53FRT/FRT; Rosa26+/+; Ng2/Cspg4f/f tumors (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Cspg4', 'Gene', '121021', (105, 110))	('tumor', 'Disease', (249, 254))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('Cspg4', 'Gene', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Cspg4', 'Gene', '121021', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('p53', 'Gene', (213, 216))	('tumors', 'Disease', (37, 43))	('Deletion', 'Var', (0, 8))	('Cspg4', 'Gene', (105, 110))	('p53', 'Gene', '22060', (213, 216))	('Kras', 'Gene', (188, 192))	('G12D', 'Mutation', 'rs121913529', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('Kras', 'Gene', (45, 49))	('reduction', 'NegReg', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Cspg4', 'Gene', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('G12D', 'Mutation', 'rs121913529', (62, 66))	('p53', 'Gene', (70, 73))	('Kras', 'Gene', '16653', (188, 192))	('tumor', 'Disease', (37, 42))	('Kras', 'Gene', '16653', (45, 49))	('p53', 'Gene', '22060', (70, 73))	('Cspg4', 'Gene', '121021', (240, 245))	('tumors', 'Disease', (249, 255))
306217	29196603	Because the Rosa26Cre-ER-T2/+ allele is expressed in tumor cells and non-tumor cells, the results using the Rosa26Cre-ER-T2/+ mice may be due to a non-sarcoma cell effect of NG2/CSPG4 regulating the niche to alter tumor behavior.	('non-sarcoma', 'Disease', (147, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mice', 'Species', '10090', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Rosa26Cre-ER-T2/+', 'Var', (108, 125))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', (53, 58))	('non-sarcoma', 'Disease', 'MESH:D012509', (147, 158))
306222	29196603	Sarcomas were generated in the hind limbs of these mice by intramuscular injection of adeno-FlpO.	('adeno-FlpO', 'Chemical', '-', (86, 96))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('mice', 'Species', '10090', (51, 55))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('Sarcomas', 'Disease', (0, 8))	('adeno-FlpO', 'Var', (86, 96))
306228	29196603	This degree of deletion resulted in a significant reduction in tumor size when compared with tumors from KrasFRT-STOP-FRT-G12D; p53FRT/FRT; Col1a1+/+; Ng2/Cspg4f/f mice (Fig.	('Kras', 'Gene', (105, 109))	('Cspg4', 'Gene', (155, 160))	('G12D', 'Mutation', 'rs121913529', (122, 126))	('Col1a1', 'Gene', (140, 146))	('Kras', 'Gene', '16653', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p53', 'Gene', (128, 131))	('reduction', 'NegReg', (50, 59))	('deletion', 'Var', (15, 23))	('mice', 'Species', '10090', (164, 168))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('p53', 'Gene', '22060', (128, 131))	('tumor', 'Disease', (63, 68))	('Col1a1', 'Gene', '12842', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', (93, 99))	('Cspg4', 'Gene', '121021', (155, 160))	('tumor', 'Disease', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
306229	29196603	Thus, deletion of Ng2/Cspg4 in the neoplastic cells themselves reduced the soft-tissue sarcoma tumor size.	('Cspg4', 'Gene', (22, 27))	('sarcoma tumor', 'Disease', (87, 100))	('reduced', 'NegReg', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (79, 94))	('deletion', 'Var', (6, 14))	('Cspg4', 'Gene', '121021', (22, 27))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (75, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('sarcoma tumor', 'Disease', 'MESH:D012509', (87, 100))
306240	29196603	Within this range of number of cells injected, knockdown of NG2/CSPG4 did not affect the tumor-initiating potential of the sarcoma cells (Table S1).	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('knockdown', 'Var', (47, 56))	('tumor', 'Disease', (89, 94))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('NG2/CSPG4', 'Gene', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('sarcoma', 'Disease', (123, 130))
306241	29196603	Histological analyses of explanted tumors in which NG2/CSPG4 was knocked down showed an indistinguishable morphology from controls (Fig.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NG2/CSPG4', 'Gene', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('knocked', 'Var', (65, 72))
306243	29196603	Xenografts of human tumor cells that had been infected with NG2/CSPG4-lentivirus showed much less NG2/CSPG4 expression (Fig.	('less', 'NegReg', (93, 97))	('human', 'Species', '9606', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('NG2/CSPG4-lentivirus', 'Var', (60, 80))	('NG2/CSPG4', 'MPA', (98, 107))	('tumor', 'Disease', (20, 25))
306244	29196603	Because of the difference in time to engraftment, at any given time, the tumors derived from GFP-lentivirus-infected cells were smaller in size.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('GFP-lentivirus-infected', 'Var', (93, 116))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('smaller', 'NegReg', (128, 135))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
306253	29196603	Because Ng2/Cspg4 is expressed in mesenchymal precursor cells and could play a role in regulating stem cell-like properties, and driving oncogenic mutations in Ng2/Cspg4 expressing cells results in sarcoma formation, we investigated the role of Ng2/Cspg4 in tumor initiation in the mouse.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('mutations', 'Var', (147, 156))	('results in', 'Reg', (187, 197))	('tumor initiation', 'Disease', 'MESH:D009369', (258, 274))	('Cspg4', 'Gene', (164, 169))	('sarcoma', 'Disease', 'MESH:D012509', (198, 205))	('mouse', 'Species', '10090', (282, 287))	('tumor initiation', 'Disease', (258, 274))	('Cspg4', 'Gene', '121021', (12, 17))	('Cspg4', 'Gene', '121021', (249, 254))	('sarcoma', 'Disease', (198, 205))	('Cspg4', 'Gene', '121021', (164, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('Cspg4', 'Gene', (12, 17))	('Cspg4', 'Gene', (249, 254))
306271	29196603	Tumor cells derived from KrasG12D/+; p53f/f; Ng2/Cspg4+/+, and KrasG12D/+; p53f/f; Ng2/Cspg4f/f mice were treated with IGFII followed by real-time PCR analysis for Igfbp3 expression.	('Igfbp3', 'Gene', (164, 170))	('p53', 'Gene', '22060', (75, 78))	('p53', 'Gene', '22060', (37, 40))	('Cspg4', 'Gene', '121021', (87, 92))	('Cspg4', 'Gene', '121021', (49, 54))	('mice', 'Species', '10090', (96, 100))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IGFII', 'Gene', (119, 124))	('Igfbp3', 'Gene', '16009', (164, 170))	('Cspg4', 'Gene', (87, 92))	('p53', 'Gene', (75, 78))	('Cspg4', 'Gene', (49, 54))	('p53', 'Gene', (37, 40))	('KrasG12D/+', 'Var', (25, 35))	('IGFII', 'Gene', '16002', (119, 124))
306275	29196603	Thus, deletion of Ng2/Cspg4 at the time of tumor initiation could result in an increase in tumor size by promoting tumor cell proliferation through down-regulation of Igfbp3.	('increase', 'PosReg', (79, 87))	('Cspg4', 'Gene', (22, 27))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('deletion', 'Var', (6, 14))	('tumor initiation', 'Disease', 'MESH:D009369', (43, 59))	('tumor initiation', 'Disease', (43, 59))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('down-regulation', 'NegReg', (148, 163))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Cspg4', 'Gene', '121021', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('promoting', 'PosReg', (105, 114))	('Igfbp3', 'Gene', '16009', (167, 173))	('Igfbp3', 'Gene', (167, 173))
306281	29196603	Taken together, these data raise the possibility that deleting Ng2/Cspg4 at tumor initiation activates IGF signaling, a pathway known to positively regulate soft-tissue sarcoma growth, whereas in established tumors, there is an opposite effect.	('deleting', 'Var', (54, 62))	('activates', 'PosReg', (93, 102))	('sarcoma growth', 'Disease', (169, 183))	('tumor initiation', 'Disease', 'MESH:D009369', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (161, 176))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('IGF', 'MPA', (103, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('tumors', 'Disease', (208, 214))	('tumor initiation', 'Disease', (76, 92))	('Cspg4', 'Gene', '121021', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('sarcoma growth', 'Disease', 'MESH:D006130', (169, 183))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('Cspg4', 'Gene', (67, 72))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (157, 176))
306283	29196603	Inhibition of Ng2/Cspg4 in established sarcomas by gene deletion or NG2/CSPG4 antibody immunotherapy significantly reduced tumor size in murine and human sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (154, 162))	('sarcomas', 'Disease', (154, 162))	('tumor', 'Disease', (123, 128))	('Inhibition', 'NegReg', (0, 10))	('reduced', 'NegReg', (115, 122))	('Cspg4', 'Gene', (18, 23))	('murine', 'Species', '10090', (137, 143))	('human', 'Species', '9606', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('gene deletion', 'Var', (51, 64))	('sarcomas', 'Disease', 'MESH:D012509', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('sarcomas', 'Disease', 'MESH:D012509', (154, 162))	('sarcomas', 'Disease', (39, 47))	('Cspg4', 'Gene', '121021', (18, 23))
306284	29196603	Surprisingly, deleting Ng2/Cspg4 at the time of tumor initiation resulted in the opposite effect on tumor growth.	('tumor initiation', 'Disease', 'MESH:D009369', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (100, 105))	('tumor initiation', 'Disease', (48, 64))	('Cspg4', 'Gene', (27, 32))	('deleting', 'Var', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Cspg4', 'Gene', '121021', (27, 32))
306285	29196603	We found that deletion of Ng2/Cspg4 at tumor initiation resulted in activation of IGF signaling and a loss of the normal regulation of insulin growth factor-binding proteins, which are known to inhibit IGF signaling and regulate cell proliferation.	('cell proliferation', 'CPA', (229, 247))	('Cspg4', 'Gene', (30, 35))	('IGF', 'MPA', (202, 205))	('IGF signaling', 'MPA', (82, 95))	('inhibit', 'NegReg', (194, 201))	('activation', 'PosReg', (68, 78))	('regulate', 'Reg', (220, 228))	('Cspg4', 'Gene', '121021', (30, 35))	('tumor initiation', 'Disease', 'MESH:D009369', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('loss', 'NegReg', (102, 106))	('deletion', 'Var', (14, 22))	('tumor initiation', 'Disease', (39, 55))
306288	29196603	Another possibility is that because Ng2/Cspg4 is a membrane proteoglycan that interacts with other cells and extracellular matrix, loss of Ng2/Cspg4 at tumor initiation may alter a critical extracellular interaction that promotes tumor growth.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (230, 235))	('Cspg4', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor initiation', 'Disease', 'MESH:D009369', (152, 168))	('Cspg4', 'Gene', (143, 148))	('tumor', 'Disease', (152, 157))	('loss', 'Var', (131, 135))	('critical extracellular interaction', 'MPA', (181, 215))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor initiation', 'Disease', (152, 168))	('Cspg4', 'Gene', '121021', (40, 45))	('promotes', 'PosReg', (221, 229))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('Cspg4', 'Gene', '121021', (143, 148))	('alter', 'Reg', (173, 178))
306289	29196603	Deletion of Ng2/Cspg4 at tumor initiation revealed a pro-apoptotic effect of Ng2/Cspg4, so ablation of Ng2/Cspg4 might account for decreased cell death at the time of tumor initiation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Cspg4', 'Gene', (81, 86))	('tumor initiation', 'Disease', (167, 183))	('Cspg4', 'Gene', '121021', (107, 112))	('pro-apoptotic effect', 'MPA', (53, 73))	('tumor initiation', 'Disease', (25, 41))	('Cspg4', 'Gene', (107, 112))	('tumor initiation', 'Disease', 'MESH:D009369', (167, 183))	('Cspg4', 'Gene', '121021', (81, 86))	('Cspg4', 'Gene', '121021', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor initiation', 'Disease', 'MESH:D009369', (25, 41))	('Cspg4', 'Gene', (16, 21))	('Deletion', 'Var', (0, 8))
306291	29196603	Another possibility is that by deleting Ng2/Cspg4 at tumor initiation, we are changing the cell type that becomes the tumor or changing the type of tumor that develops; however, in our analysis to date, we have not found differences between the sarcomas to suggest a difference in tumor cell type.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('sarcomas', 'Disease', 'MESH:D012509', (245, 253))	('sarcomas', 'Phenotype', 'HP:0100242', (245, 253))	('deleting', 'Var', (31, 39))	('tumor initiation', 'Disease', 'MESH:D009369', (53, 69))	('sarcomas', 'Disease', (245, 253))	('tumor', 'Disease', (281, 286))	('tumor initiation', 'Disease', (53, 69))	('Cspg4', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (148, 153))	('changing', 'Reg', (78, 86))	('Cspg4', 'Gene', '121021', (44, 49))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
306296	29196603	Furthermore, our data also illustrate the complexity in interpreting results from genetically engineered mice, as the data from deletion of Ng2/Cspg4 at tumor initiation probably do not necessarily pertain to the more clinically relevant experiment of Ng2/Cspg4 inhibition in established tumors.	('Cspg4', 'Gene', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('Cspg4', 'Gene', (144, 149))	('tumor initiation', 'Disease', 'MESH:D009369', (153, 169))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Cspg4', 'Gene', '121021', (256, 261))	('tumor initiation', 'Disease', (153, 169))	('Cspg4', 'Gene', '121021', (144, 149))	('mice', 'Species', '10090', (105, 109))	('tumors', 'Disease', (288, 294))	('deletion', 'Var', (128, 136))
306298	29196603	We crossed Ng2/Cspg4-/-, Ng2/Cspg4f/f, LSL-KrasG12D; p53f/f, KrasFRT-STOP-FRT-G12D; p53FRT/FRT, and R26Cre-ER-T2 or Col1a1FRT-STOP-FRT-Cre-ER-T2 transgenic mice.	('p53', 'Gene', '22060', (53, 56))	('p53', 'Gene', '22060', (84, 87))	('Kras', 'Gene', (43, 47))	('Col1a1', 'Gene', '12842', (116, 122))	('Cspg4', 'Gene', '121021', (29, 34))	('Kras', 'Gene', (61, 65))	('Kras', 'Gene', '16653', (43, 47))	('Kras', 'Gene', '16653', (61, 65))	('Cspg4', 'Gene', '121021', (15, 20))	('G12D', 'Mutation', 'rs121913529', (47, 51))	('p53', 'Gene', (53, 56))	('p53', 'Gene', (84, 87))	('G12D', 'Mutation', 'rs121913529', (78, 82))	('Cspg4', 'Gene', (15, 20))	('Cspg4', 'Gene', (29, 34))	('R26Cre-ER-T2', 'Var', (100, 112))	('transgenic mice', 'Species', '10090', (145, 160))	('Col1a1', 'Gene', (116, 122))
306327	26635943	After radiation therapy (3040cGy/19 fractions, 6 MeV electrons), the patient underwent autologous stem cell transplantation and achieved a complete remission.	('autologous stem cell transplantation', 'CPA', (87, 123))	('patient', 'Species', '9606', (69, 76))	('3040cGy/19', 'Var', (25, 35))
306332	26635943	At the molecular level, ES/PNET is characterized by chromosomal translocations that fuse the EWSR1 gene to some members of the ETS family of transcription factors, being FLI1 the most frequently implicated [t (11; 22) (q24; q12)].	('ES/PNET', 'Disease', (24, 31))	('EWSR1', 'Gene', (93, 98))	('FLI1', 'Gene', (170, 174))	('FLI1', 'Gene', '2313', (170, 174))	('EWSR1', 'Gene', '2130', (93, 98))	('[t (11; 22) (q24; q12)]', 'Var', (206, 229))
306369	32599895	The second group comprises the majority of STSs, which are characterised by complex, unstable genomes, and a wide range of abnormalities including chromosome copy-number changes (polyploidy or aneuploidy), unbalanced translocations, amplifications, deletions and chromothripsis.	('deletions', 'Var', (249, 258))	('unbalanced translocations', 'Var', (206, 231))	('amplifications', 'Var', (233, 247))	('polyploidy', 'Disease', 'MESH:D011123', (179, 189))	('aneuploidy', 'Disease', 'MESH:D000782', (193, 203))	('chromothripsis', 'Disease', (263, 277))	('aneuploidy', 'Disease', (193, 203))	('STS', 'Phenotype', 'HP:0030448', (43, 46))	('chromothripsis', 'Disease', 'MESH:D000072837', (263, 277))	('STSs', 'Phenotype', 'HP:0030448', (43, 47))	('polyploidy', 'Disease', (179, 189))	('chromosome copy-number', 'CPA', (147, 169))
306400	32599895	Two low-frequency circulating somatic SNVs were detected in plasma collected 21 weeks post-operatively (TP53; V274V, 0.6%, TP53; intronic variant, 0.7%) but not subsequently.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('TP53', 'Gene', '7157', (123, 127))	('V274V', 'Mutation', 'p.V274V', (110, 115))	('V274V', 'Var', (110, 115))	('TP53', 'Gene', (123, 127))
306410	32599895	No evidence of circulating BRIP1:P971A was identified in any of the plasma samples collected.	('BRIP1', 'Gene', '83990', (27, 32))	('P971A', 'Var', (33, 38))	('P971A', 'Mutation', 'p.P971A', (33, 38))	('BRIP1', 'Gene', (27, 32))
306412	32599895	Two SNVs were tracked in patient 22's plasma, EPHB6:G397R and DACH1:G594D.	('EPHB6', 'Gene', (46, 51))	('EPHB6', 'Gene', '2051', (46, 51))	('G397R', 'Mutation', 'p.G397R', (52, 57))	('G594D', 'Mutation', 'p.G594D', (68, 73))	('DACH1', 'Gene', (62, 67))	('G594D', 'Var', (68, 73))	('patient', 'Species', '9606', (25, 32))	('DACH1', 'Gene', '1602', (62, 67))	('G397R', 'Var', (52, 57))
306414	32599895	No evidence of circulating DACH1:G594D was identified in any of the plasma samples collected.	('DACH1', 'Gene', (27, 32))	('G594D', 'Mutation', 'p.G594D', (33, 38))	('DACH1', 'Gene', '1602', (27, 32))	('G594D', 'Var', (33, 38))
306424	32599895	These involved ABCC5 (R729W, 1.19%), TRIO (H950Y, 0.65%), PLAG1 (D380Y, 0.93%), and HSPA9 (G430D, 0.83%) (Table 4).	('R729W', 'Var', (22, 27))	('R729W', 'Mutation', 'rs769621778', (22, 27))	('TRIO', 'Gene', (37, 41))	('TRIO', 'Gene', '7204', (37, 41))	('PLAG1', 'Gene', (58, 63))	('D380Y', 'Mutation', 'p.D380Y', (65, 70))	('HSPA9', 'Gene', (84, 89))	('ABCC5', 'Gene', (15, 20))	('HSPA9', 'Gene', '3313', (84, 89))	('H950Y', 'Mutation', 'p.H950Y', (43, 48))	('PLAG1', 'Gene', '5324', (58, 63))	('G430D', 'Var', (91, 96))	('G430D', 'Mutation', 'rs146347032', (91, 96))	('ABCC5', 'Gene', '10057', (15, 20))	('D380Y', 'Var', (65, 70))	('H950Y', 'Var', (43, 48))
306456	32599895	Other more focused studies of individual STS subtypes have used selected/subtype specific mutations to track ctDNA with disease progression in 34-50% of patients analysed.	('STS', 'Phenotype', 'HP:0030448', (41, 44))	('ctDNA', 'Disease', (109, 114))	('mutations', 'Var', (90, 99))	('patients', 'Species', '9606', (153, 161))
306485	32599895	'Sarcoma V2' was designed to cover the commonest non-synonymous exonic or splice site single nucleotide variants (SNVs) in TP53, ATRX, and RB1, the 3 most commonly mutated genes in STSs according to cBioportal data (Table S3).	('single nucleotide variants', 'Var', (86, 112))	('Sarcoma', 'Disease', (1, 8))	('STSs', 'Phenotype', 'HP:0030448', (181, 185))	('Sarcoma', 'Disease', 'MESH:D012509', (1, 8))	('ATRX', 'Gene', '546', (129, 133))	('RB1', 'Gene', (139, 142))	('Sarcoma', 'Phenotype', 'HP:0100242', (1, 8))	('TP53', 'Gene', '7157', (123, 127))	('STS', 'Phenotype', 'HP:0030448', (181, 184))	('RB1', 'Gene', '5925', (139, 142))	('ATRX', 'Gene', (129, 133))	('TP53', 'Gene', (123, 127))
306496	32599895	In addition, a commercial validated ddPCR assay was used to detect and quantify circulating TP53; R306* in patient 006 (Bio-Rad Laboratories, California, CA, USA).	('R306*', 'Var', (98, 103))	('Rad', 'Gene', '6236', (124, 127))	('Rad', 'Gene', (124, 127))	('R306*', 'SUBSTITUTION', 'None', (98, 103))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('patient', 'Species', '9606', (107, 114))
306505	32599895	Figure S5: Droplet digital PCR mutation analysis of patient 6 targeting TP53 (17:7577022 C>T)/TP53;R306*.	('R306*', 'Var', (99, 104))	('TP53', 'Gene', '7157', (72, 76))	('7577022 C>T', 'Mutation', 'g.7577022C>T', (81, 92))	('R306*', 'SUBSTITUTION', 'None', (99, 104))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('TP53', 'Gene', (72, 76))	('patient', 'Species', '9606', (52, 59))
306507	32599895	Figure S6: Droplet digital PCR mutation analysis of patient 22 targeting EPHB6 (7: 142563798 G>A)/ EPHB6;G397R.	('142563798 G>A', 'Mutation', 'c.142563798G>A', (83, 96))	('G397R', 'Var', (105, 110))	('EPHB6', 'Gene', (73, 78))	('EPHB6', 'Gene', '2051', (73, 78))	('EPHB6', 'Gene', (99, 104))	('patient', 'Species', '9606', (52, 59))	('EPHB6', 'Gene', '2051', (99, 104))	('G397R', 'Mutation', 'p.G397R', (105, 110))
306593	29744029	Both a recent medical record review study in the US and the Sarcoma Treatment and Burden of Illness in North America and Europe chart review study found that anthracyclines were used most commonly among first-line therapies (either alone or in combination) in younger patient populations.	('Sarcoma', 'Disease', (60, 67))	('anthracyclines', 'Var', (158, 172))	('Sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('anthracyclines', 'Chemical', 'MESH:D018943', (158, 172))	('Sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('patient', 'Species', '9606', (268, 275))
306685	29209518	Recurrent genetic alterations are present in nearly half of STS sub-types; fusion between the SS18 gene and one of the SSX genes is pathognomonic for synovial sarcoma, whilst a PAX3-FOXO1A fusion gene is found in 80% of alveolar rhabdomyosarcomata.	('SS18', 'Gene', (94, 98))	('synovial sarcoma', 'Disease', (150, 166))	('fusion', 'Var', (75, 81))	('PAX3', 'Gene', '5077', (177, 181))	('alveolar rhabdomyosarcomata', 'Phenotype', 'HP:0006779', (220, 247))	('STS', 'Phenotype', 'HP:0030448', (60, 63))	('PAX3', 'Gene', (177, 181))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (229, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (150, 166))	('FOXO1A', 'Gene', (182, 188))	('alveolar rhabdomyosarcomata', 'Disease', (220, 247))	('pathognomonic', 'Reg', (132, 145))	('synovial sarcoma', 'Disease', 'MESH:D013584', (150, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('SS18', 'Gene', '6760', (94, 98))	('FOXO1A', 'Gene', '2308', (182, 188))	('alveolar rhabdomyosarcomata', 'Disease', 'MESH:D002282', (220, 247))
306890	23833678	Subtypes of these translocations have been revealed to correlate with the various histological subtypes of synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (107, 123))	('synovial sarcoma', 'Disease', 'MESH:D013584', (107, 123))	('translocations', 'Var', (18, 32))	('synovial sarcoma', 'Disease', (107, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
307016	22988357	CD99 positivity often are seen in synovial sarcoma which may be seen in kidney also.	('CD99', 'Gene', '4267', (0, 4))	('positivity', 'Var', (5, 15))	('CD99', 'Gene', (0, 4))	('synovial sarcoma', 'Disease', (34, 50))	('seen', 'Reg', (26, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (34, 50))	('synovial sarcoma', 'Disease', 'MESH:D013584', (34, 50))
307027	22988357	As the specific genetic defect can be identified, genetic therapy creating antisense oligonucleotides against the EWS-FLI-1 fusion gene will have good results to prolong the survival of patients.	('EWS', 'Gene', '2130', (114, 117))	('EWS', 'Gene', (114, 117))	('survival', 'CPA', (174, 182))	('prolong', 'PosReg', (162, 169))	('FLI-1', 'Gene', '2313', (118, 123))	('oligonucleotides', 'Chemical', 'MESH:D009841', (85, 101))	('FLI-1', 'Gene', (118, 123))	('antisense oligonucleotides', 'Var', (75, 101))	('patients', 'Species', '9606', (186, 194))
307033	28741122	Adherent treatment was associated with higher 5-year adjusted OS and DSS in stage IIA and IIB/III patients.	('higher', 'PosReg', (39, 45))	('DSS', 'Chemical', '-', (69, 72))	('patients', 'Species', '9606', (98, 106))	('DSS', 'MPA', (69, 72))	('IIB/III', 'Disease', (90, 97))	('stage IIA', 'Disease', (76, 85))	('Adherent', 'Var', (0, 8))
307034	28741122	In Cox models, nonadherent treatment was associated with worse survival both for stage IIA (HR = 2.31, 95% confidence interval [CI] = 2.02-2.63) and stage IIB/III disease (HR = 1.63, 95% CI = 1.53-1.73).	('Cox', 'Gene', '1351', (3, 6))	('nonadherent treatment', 'Var', (15, 36))	('Cox', 'Gene', (3, 6))	('stage IIA', 'Disease', (81, 90))	('survival', 'MPA', (63, 71))	('worse', 'NegReg', (57, 62))
307044	28741122	We hypothesized that patients receiving guideline-adherent treatment would have higher 5-year OS and a lower risk of death than those receiving nonadherent treatment.	('patients', 'Species', '9606', (21, 29))	('death', 'Disease', 'MESH:D003643', (117, 122))	('5-year OS', 'CPA', (87, 96))	('death', 'Disease', (117, 122))	('guideline-adherent treatment', 'Var', (40, 68))	('higher', 'PosReg', (80, 86))
307180	24194746	TSS in the upstream PROM1 gene region based on CAGE were identified from clustered sequence reads using HPeak (Qin et al.,) and mapped to known PROM1 promoters extracted from GenBank gene records (AY275524, AY438641, AY438640), resulting in the confirmation of known promoters P1-4 and identification of a novel promoter, P6.	('AY275524', 'Var', (197, 205))	('PROM1', 'Gene', '8842', (144, 149))	('CAGE', 'Gene', '168400', (47, 51))	('PROM1', 'Gene', '8842', (20, 25))	('P1-4', 'Gene', '11102', (277, 281))	('PROM1', 'Gene', (20, 25))	('AY438640', 'Var', (217, 225))	('CAGE', 'Gene', (47, 51))	('PROM1', 'Gene', (144, 149))	('AY438641', 'Var', (207, 215))	('P1-4', 'Gene', (277, 281))
307205	24194746	In contrast, CD133- sorted Ewing sarcoma cells, CD133- mesenchymal stem cells, and differentiated neural crest stem cells show no significant difference in intensities between probes covering P1-P2 and P6 (Figure 4).	('CD133', 'Gene', (48, 53))	('CD133', 'Gene', '8842', (48, 53))	('Ewing sarcoma', 'Disease', (27, 40))	('P1-P2', 'Var', (192, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (27, 40))	('CD133', 'Gene', (13, 18))	('CD133', 'Gene', '8842', (13, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (27, 40))
307210	24194746	Hypermethylation of CpG islands close to P1-3 has been linked to CD133 expression in glioma stem cells and cell lines (Gopisetty et al.,).	('expression', 'MPA', (71, 81))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('CD133', 'Gene', '8842', (65, 70))	('P1-3', 'Gene', '51013', (41, 45))	('linked', 'Reg', (55, 61))	('Hypermethylation', 'Var', (0, 16))	('P1-3', 'Gene', (41, 45))	('glioma', 'Disease', (85, 91))	('CD133', 'Gene', (65, 70))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
307211	24194746	Differential methylation of the same region observed in ENCODE cell lines indicate an unmethylated CpG island in ENCODE cell lines H1-hESC (embryonic) and HepG2 (liver) and methylation of the same CpG island in K562 (blood, leukemic) and GM12878 (blood, lymphoblastoid), in agreement with their RNA-seq expression status in the same ENCODE cell lines (Figure 2B).	('methylation', 'Var', (173, 184))	('HepG2', 'CellLine', 'CVCL:0027', (155, 160))	('leukemic', 'Disease', (224, 232))	('K562', 'CellLine', 'CVCL:0004', (211, 215))	('leukemic', 'Disease', 'MESH:D007938', (224, 232))
307212	24194746	Observed histone changes support an enhancer upstream of P6 as well as transcriptional activity around P1-3 and P6, whereas P1-3 appears poised or repressed in all other ENCODE cell lines represented, mostly due to H3K27me3 and H3K36me3 silencing.	('H3K27me3', 'Var', (215, 223))	('P1-3 and P6', 'Gene', '51013', (103, 114))	('H3K36me3 silencing', 'Var', (228, 246))	('P1-3', 'Gene', '51013', (103, 107))	('enhancer', 'PosReg', (36, 44))	('P1-3', 'Gene', '51013', (124, 128))	('P1-3', 'Gene', (124, 128))	('P1-3', 'Gene', (103, 107))	('transcriptional activity', 'MPA', (71, 95))
307224	24194746	HMGI/Y (HMG1A) is usually expressed at low levels in adult tissues, but found at high expression levels in embryonic and neoplastic tissues (Chiappetta et al.,), its aberrant expression has been associated with tumorigenesis (Tkachenko et al.,) and high expression is a requirement for the production of CXC ligand 1, a major effector of tumor growth(Amiri et al.,).	('associated', 'Reg', (195, 205))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumor', 'Disease', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('aberrant expression', 'Var', (166, 185))	('tumor', 'Disease', 'MESH:D009369', (338, 343))
307231	24194746	Based on ChIP-qPCR analysis, methylation is thought to affect CD133 expression only in cell lines but not in primary tissues (Pellacani et al.,), although methylation of P2 is thought to be tissue specific (Pleshkan et al.,).	('CD133', 'Gene', (62, 67))	('methylation', 'Var', (29, 40))	('affect', 'Reg', (55, 61))	('expression', 'MPA', (68, 78))	('CD133', 'Gene', '8842', (62, 67))
307262	21663687	The serum concentrations of cancer markers CEA, AFP, CA 19-9, CA 125, HE4, CA 15-3 are within the norm.	('HE4', 'Gene', (70, 73))	('CA 15-3', 'Gene', '4582', (75, 82))	('CA 15-3', 'Gene', (75, 82))	('HE4', 'Gene', '10406', (70, 73))	('CA 125', 'Var', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('CEA', 'Gene', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('AFP', 'Gene', (48, 51))	('CA 19-9', 'Var', (53, 60))	('CEA', 'Gene', '5670', (43, 46))	('cancer', 'Disease', (28, 34))	('AFP', 'Gene', '174', (48, 51))
307395	33445470	PF-03446962 is a humanized monoclonal antibody against ALK1 with promising results in preclinical and early clinical trials.	('PF-03446962', 'Var', (0, 11))	('cal ', 'Gene', '57120', (94, 98))	('is a', 'Gene', (12, 16))	('is a', 'Gene', '312', (12, 16))	('cal ', 'Gene', '57120', (113, 117))	('om', 'Gene', '4951', (67, 69))	('PF-03446962', 'Chemical', 'MESH:C575087', (0, 11))	('cal ', 'Gene', (94, 98))	('ALK1', 'Gene', (55, 59))	('cal ', 'Gene', (113, 117))	('ALK1', 'Gene', '94', (55, 59))
307399	33445470	Moreover, its deficiency produces alterations in vessel structure and inhibits tumor growth.	('er', 'Gene', '2069', (6, 8))	('vessel structure', 'CPA', (49, 65))	('tumor', 'Disease', (79, 84))	('er', 'Gene', '2069', (37, 39))	('inhibits', 'NegReg', (70, 78))	('deficiency', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
307429	33445470	Pazopanib also inhibits intracranial tumor growth and increases survival in animal models.	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('intracranial tumor', 'Disease', 'MESH:D001932', (24, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('increases', 'PosReg', (54, 63))	('inhibits', 'NegReg', (15, 23))	('survival in animal models', 'CPA', (64, 89))	('intracranial tumor', 'Disease', (24, 42))	('Pazopanib', 'Var', (0, 9))
307459	33445470	Neuroblastomas are divided into low-, intermediate-, and high-risk groups based on histology, clinical status, tumor cell ploidy, and MYCN oncogene amplification.	('to', 'Gene', '6999', (29, 31))	('cal ', 'Gene', (99, 103))	('to', 'Gene', '6999', (9, 11))	('tumor cell ploidy', 'Disease', 'MESH:D005935', (111, 128))	('Neuroblastomas', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Neuroblastomas', 'Disease', 'MESH:D009447', (0, 14))	('Neuroblastomas', 'Phenotype', 'HP:0003006', (0, 14))	('to', 'Gene', '6999', (86, 88))	('tumor cell ploidy', 'Disease', (111, 128))	('cal ', 'Gene', '57120', (99, 103))	('amplification', 'Var', (148, 161))	('er', 'Gene', '2069', (41, 43))
307513	33445470	In the PPTP, pazopanib was associated with PFS increase in rhabdomyosarcoma, but no objective responses were seen.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (59, 75))	('pazopanib', 'Chemical', 'MESH:C516667', (13, 22))	('er', 'Gene', '2069', (105, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('PFS increase in rhabdomyosarcoma', 'Disease', 'MESH:D012208', (43, 75))	('pazopanib', 'Var', (13, 22))	('PFS increase in rhabdomyosarcoma', 'Disease', (43, 75))	('PPTP', 'Chemical', '-', (7, 11))
307514	33445470	However, a phase I clinical trial involving sarcomas, brain tumors, and other refractory solid tumors showed that pazopanib can stabilize alveolar rhabdomyosarcoma, and may even produce complete remission in alveolar rhabdomyosarcoma or partial remission in embryonal rhabdomyosarcoma if combined with vincristine and irinotecan.	('alveolar rhabdomyosarcoma', 'Disease', (138, 163))	('om', 'Gene', '4951', (48, 50))	('pazopanib', 'Var', (114, 123))	('cal ', 'Gene', (24, 28))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (268, 284))	('om', 'Gene', '4951', (152, 154))	('om', 'Gene', '4951', (160, 162))	('om', 'Gene', '4951', (222, 224))	('solid tumors', 'Disease', 'MESH:D009369', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (258, 284))	('om', 'Gene', '4951', (230, 232))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (147, 163))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (138, 163))	('irinotecan', 'Chemical', 'MESH:D000077146', (318, 328))	('alveolar rhabdomyosarcoma', 'Disease', (208, 233))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('sarcomas', 'Disease', 'MESH:D012509', (44, 52))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (138, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('pazopanib', 'Chemical', 'MESH:C516667', (114, 123))	('sarcomas', 'Disease', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('to', 'Gene', '6999', (84, 86))	('brain tumors', 'Disease', 'MESH:D001932', (54, 66))	('brain tumors', 'Phenotype', 'HP:0030692', (54, 66))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (217, 233))	('brain tumor', 'Phenotype', 'HP:0030692', (54, 65))	('om', 'Gene', '4951', (273, 275))	('om', 'Gene', '4951', (187, 189))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (208, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (258, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (208, 233))	('solid tumors', 'Disease', (89, 101))	('om', 'Gene', '4951', (289, 291))	('brain tumors', 'Disease', (54, 66))	('er', 'Gene', '2069', (75, 77))	('vincristine', 'Chemical', 'MESH:D014750', (302, 313))	('cal ', 'Gene', '57120', (24, 28))	('er', 'Gene', '2069', (5, 7))	('embryonal rhabdomyosarcoma', 'Disease', (258, 284))	('om', 'Gene', '4951', (281, 283))
307526	33445470	Bevacizumab with gemcitabine and docetaxel produced a partial response in metastatic refractory undifferentiated sarcoma, and 12-month PFS in a patient with angiosarcoma, while combined with vincristine, irinotecan, and temozolomide stabilized the disease in liposarcoma.	('liposarcoma', 'Disease', (259, 270))	('docetaxel', 'Chemical', 'MESH:D000077143', (33, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (96, 120))	('undifferentiated sarcoma', 'Disease', (96, 120))	('gemcitabine', 'Chemical', 'MESH:C056507', (17, 28))	('om', 'Gene', '4951', (117, 119))	('liposarcoma', 'Phenotype', 'HP:0012034', (259, 270))	('om', 'Gene', '4951', (267, 269))	('patient', 'Species', '9606', (144, 151))	('om', 'Gene', '4951', (166, 168))	('PFS', 'Var', (135, 138))	('temozolomide', 'Chemical', 'MESH:D000077204', (220, 232))	('om', 'Gene', '4951', (227, 229))	('liposarcoma', 'Disease', 'MESH:D008080', (259, 270))	('angiosarcoma', 'Disease', 'MESH:D006394', (157, 169))	('om', 'Gene', '4951', (178, 180))	('irinotecan', 'Chemical', 'MESH:D000077146', (204, 214))	('angiosarcoma', 'Phenotype', 'HP:0200058', (157, 169))	('to', 'Gene', '6999', (91, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('angiosarcoma', 'Disease', (157, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (0, 11))	('vincristine', 'Chemical', 'MESH:D014750', (191, 202))
307531	33445470	In combination with other drugs, such as vincristine and irinotecan, pazopanib generates partial remission in undifferentiated sarcoma and long-term stabilization of DSRCT, and improves the response to chemotherapy and reduces recurrence rates in children and adults with large, unresected, intermediate- or high-grade chemosensitive soft-tissue sarcomas.	('er', 'Gene', '2069', (145, 147))	('to', 'Gene', '6999', (199, 201))	('recurrence', 'CPA', (227, 237))	('er', 'Gene', '2069', (82, 84))	('children', 'Species', '9606', (247, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('of', 'Gene', '6688', (335, 337))	('soft', 'Gene', (334, 338))	('irinotecan', 'Chemical', 'MESH:D000077146', (57, 67))	('er', 'Gene', '2069', (294, 296))	('sarcomas', 'Disease', 'MESH:D012509', (346, 354))	('pazopanib', 'Var', (69, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (346, 354))	('sarcomas', 'Disease', (346, 354))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (110, 134))	('undifferentiated sarcoma', 'Disease', (110, 134))	('om', 'Gene', '4951', (131, 133))	('er', 'Gene', '2069', (116, 118))	('er', 'Gene', '2069', (23, 25))	('reduces', 'NegReg', (219, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (346, 353))	('improves', 'PosReg', (177, 185))	('om', 'Gene', '4951', (4, 6))	('soft', 'Gene', '25886', (334, 338))	('pazopanib', 'Chemical', 'MESH:C516667', (69, 78))	('of', 'Gene', '6688', (163, 165))	('vincristine', 'Chemical', 'MESH:D014750', (41, 52))	('om', 'Gene', '4951', (350, 352))	('er', 'Gene', '2069', (209, 211))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (334, 354))
307566	33445470	It is characterized by chromosomal translocation between EWSR1 and FLI1 genes (90% of cases), or by the fusion of EWSR1 with other transcription factors of the ETS gene family (10% of cases).	('to', 'Gene', '6999', (148, 150))	('er', 'Gene', '2069', (13, 15))	('of', 'Gene', '6688', (181, 183))	('er', 'Gene', '2069', (128, 130))	('EWSR1', 'Gene', (114, 119))	('of', 'Gene', '6688', (111, 113))	('fusion', 'Var', (104, 110))	('of', 'Gene', '6688', (153, 155))	('EWSR1', 'Gene', (57, 62))	('om', 'Gene', '4951', (26, 28))	('FLI1', 'Gene', '2313', (67, 71))	('om', 'Gene', '4951', (30, 32))	('of', 'Gene', '6688', (83, 85))	('FLI1', 'Gene', (67, 71))
307625	33176766	The diagnosis was further confirmed by fluorescence in situ hybridization (FISH) by detecting the rearrangements of t (22q12): EWS-FLI1 type 1 translocation (Fig.	('FLI1', 'Gene', (131, 135))	('FLI1', 'Gene', '2313', (131, 135))	('t (22q12)', 'Gene', (116, 125))	('rearrangements', 'Var', (98, 112))	('EWS', 'Gene', '2130', (127, 130))	('EWS', 'Gene', (127, 130))
307639	33176766	ES/PNET is characterized by fixed chromosomal translocation t (11:22) between the genes EWS (22q12) and FLI-1 (11q24).	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('PNET', 'Phenotype', 'HP:0030065', (3, 7))	('FLI-1', 'Gene', '2313', (104, 109))	('FLI-1', 'Gene', (104, 109))	('EWS', 'Gene', '2130', (88, 91))	('EWS', 'Gene', (88, 91))	('22q12', 'Var', (93, 98))
307790	26759307	After we adjusted for tumor size, a 5-69% myxoid component was an independent predictor of worse DSS (Table 2).	('DSS', 'Gene', '5376', (97, 100))	('myxoid component', 'MPA', (42, 58))	('5-69%', 'Var', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('DSS', 'Gene', (97, 100))
307796	26759307	On multivariate analysis, both tumor size and 5-69% myxoid component were associated with worse DRFS (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('myxoid component', 'MPA', (52, 68))	('tumor', 'Disease', (31, 36))	('5-69%', 'Var', (46, 51))	('DRFS', 'Disease', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
307830	26759307	In our dataset, local recurrence developed in 42% of patients who had an R1 resection, compared to 20% of patients with an R0 resection; however, this difference was not statistically significant (p=0.064), perhaps because our study included only 38 R1 patients.	('R1 resection', 'Var', (73, 85))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (253, 261))	('patients', 'Species', '9606', (106, 114))	('local recurrence', 'CPA', (16, 32))
307844	22805310	Using a murine model of soft tissue sarcoma (STS), we demonstrate that disruption of the IFN effector molecule IRF8 decreases pSTAT1 and increases uSTAT1 in STS cells, thereby increasing their metastatic potential.	('pSTAT1', 'MPA', (126, 132))	('IRF8', 'Gene', (111, 115))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (24, 43))	('soft tissue sarcoma', 'Disease', (24, 43))	('disruption', 'Var', (71, 81))	('metastatic potential', 'CPA', (193, 213))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (24, 43))	('uSTAT1', 'MPA', (147, 153))	('decreases', 'NegReg', (116, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('increases', 'PosReg', (137, 146))	('increasing', 'PosReg', (176, 186))	('murine', 'Species', '10090', (8, 14))
307846	22805310	An analysis of 123 human STS specimens revealed that high uSTAT1 levels in tumor cells was correlated with a reduction in disease-specific survival, whereas high pSTAT1 levels in tumor cells was correlated with an increase in disease-specific survival.	('high', 'Var', (53, 57))	('disease-specific survival', 'CPA', (122, 147))	('reduction', 'NegReg', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('increase', 'PosReg', (214, 222))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('uSTAT1', 'MPA', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('human', 'Species', '9606', (19, 24))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', (179, 184))
307847	22805310	RNAi-mediated silencing of STAT1 in STS cells was sufficient to increase expression of the apoptotic mediators Fas and Bad and to elevate the sensitivity of STS cells to Fas-mediated apoptosis.	('elevate', 'PosReg', (130, 137))	('silencing', 'Var', (14, 23))	('STAT1', 'Gene', (27, 32))	('Fas', 'Chemical', 'MESH:C038178', (111, 114))	('Fas', 'Chemical', 'MESH:C038178', (170, 173))	('Fas', 'Protein', (111, 114))	('increase', 'PosReg', (64, 72))	('expression', 'MPA', (73, 83))	('sensitivity', 'MPA', (142, 153))
307853	22805310	Furthermore, STAT1-/- mice formed significantly more carcinogen-induced sarcomas than wt mice.	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('mice', 'Species', '10090', (89, 93))	('STAT1-/-', 'Var', (13, 21))	('more', 'PosReg', (48, 52))	('sarcomas', 'Disease', (72, 80))	('mice', 'Species', '10090', (22, 26))
307864	22805310	In a previous study, we showed that disruption of IRF8 function resulted in a dramatic up-regulation of uSTAT1 in mouse soft tissue sarcoma cells.	('soft tissue sarcoma', 'Disease', (120, 139))	('uSTAT1', 'Gene', (104, 110))	('up-regulation', 'PosReg', (87, 100))	('disruption', 'Var', (36, 46))	('IRF8', 'Gene', (50, 54))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (120, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('mouse', 'Species', '10090', (114, 119))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (120, 139))
307896	22805310	Mouse STS cell line CMS4 was stably transfected with the control vector (CMS4.pcDNA), the IRF8 mutants with a point mutation (K to E) at amino acid 79 (CMS4.K79E), and a point mutation (R to E) at amino acid 289 (CMS4.R289E), respectively.	('CMS4.K79E', 'Var', (152, 161))	('mutants', 'Var', (95, 102))	('IRF8', 'Gene', (90, 94))	('Mouse', 'Species', '10090', (0, 5))	('K79E', 'Mutation', 'p.K79E', (157, 161))	('R to E', 'Var', (186, 192))	('R289E', 'Mutation', 'p.R289E', (218, 223))
307899	22805310	Examination of mouse lungs revealed that disruption of IRF8 function significantly increased the metastatic potential of CMS4 cells (Fig.	('increased', 'PosReg', (83, 92))	('disruption', 'Var', (41, 51))	('mouse', 'Species', '10090', (15, 20))	('metastatic potential of CMS4 cells', 'CPA', (97, 131))	('IRF8', 'Gene', (55, 59))
307905	22805310	Expression intensity of nSTAT1 level was found to be associated with a clear trend towards prolonged disease-specific survival (DSS), however it was not statistically significant; median DSS of STS patients with low nSTAT1 levels was 58 months and has not been reached in the cohort of patients expressing high nSTAT1 levels (p=0.08; Fig.	('prolonged', 'PosReg', (91, 100))	('patients', 'Species', '9606', (198, 206))	('DSS', 'Chemical', '-', (128, 131))	('DSS', 'Chemical', '-', (187, 190))	('disease-specific survival', 'CPA', (101, 126))	('low', 'Var', (212, 215))	('patients', 'Species', '9606', (286, 294))
307906	22805310	In contrast, our data demonstrated that high cSTAT1 expression levels were strongly associated with decreased rates of STS-specific survival; median DSS of patients with high cSTAT1 expression levels was 46 months and has not been reached in the low cSTAT1 group (p=0.03; Fig.	('patients', 'Species', '9606', (156, 164))	('expression', 'MPA', (182, 192))	('DSS', 'Chemical', '-', (149, 152))	('decreased', 'NegReg', (100, 109))	('STS-specific survival', 'CPA', (119, 140))	('high', 'Var', (170, 174))	('cSTAT1', 'Gene', (175, 181))
307914	22805310	While CMS4 cells were not sensitive to FasL-induced apoptosis, silencing uSTAT1 dramatically increased tumor cell sensitivity to FasL-induced apoptosis in vitro (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('uSTAT1', 'Gene', (73, 79))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('silencing', 'Var', (63, 72))
307916	22805310	RT-PCR analysis indicated that silencing uSTAT1 expression up-regulates Bcl-xL expression (Fig.	('silencing', 'Var', (31, 40))	('up-regulates', 'PosReg', (59, 71))	('uSTAT1', 'Gene', (41, 47))	('Bcl-xL', 'Gene', (72, 78))	('Bcl-xL', 'Gene', '12048', (72, 78))
307922	22805310	The observation that silencing STAT1 increases Bcl-xL expression level and at the same time significantly increased the tumor cell sensitivity to Fas-mediated apoptosis suggest that Bcl-xL function is neutralized by increased pro-apoptotic protein.	('Fas', 'Chemical', 'MESH:C038178', (146, 149))	('Bcl-xL', 'Gene', (47, 53))	('Bcl-xL', 'Gene', '12048', (47, 53))	('expression level', 'MPA', (54, 70))	('STAT1', 'Gene', (31, 36))	('Bcl-xL', 'Gene', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Bcl-xL', 'Gene', '12048', (182, 188))	('increases', 'PosReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('increased', 'PosReg', (106, 115))	('silencing', 'Var', (21, 30))	('tumor', 'Disease', (120, 125))
307936	22805310	Analysis of pSTAT1 activity using EMSA indicated that pSTAT1 binding to GAS-containing DNA is also diminished in sarcoma cells overexpressing IRF8 mutants (Fig.	('pSTAT1', 'MPA', (54, 60))	('IRF8', 'Gene', (142, 146))	('diminished', 'NegReg', (99, 109))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('overexpressing', 'PosReg', (127, 141))	('mutants', 'Var', (147, 154))	('binding', 'Interaction', (61, 68))
307938	22805310	RT-PCR analysis revealed that silencing STAT1 in CMS4 cells resulted in up-regulation of Jak1 (Fig.	('Jak1', 'Gene', (89, 93))	('up-regulation', 'PosReg', (72, 85))	('Jak1', 'Gene', '16451', (89, 93))	('silencing', 'Var', (30, 39))	('STAT1', 'Gene', (40, 45))
307953	22805310	The observation that overexpression of STAT1 is associated with resistance of tumor cells to chemotherapeutic agents and radiation suggest that STAT1 might confer tumor cell resistance to apoptosis to promote tumor development.	('promote', 'PosReg', (201, 208))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('overexpression', 'PosReg', (21, 35))	('STAT1', 'Gene', (39, 44))	('resistance to apoptosis', 'CPA', (174, 197))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('STAT1', 'Var', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
307954	22805310	Indeed, silencing STAT1 enhanced tumor cell sensitivity to apoptosis induction by chemotherapeutic agents and radiation.	('STAT1', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('silencing', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('enhanced', 'PosReg', (24, 32))	('tumor', 'Disease', (33, 38))
307955	22805310	In this study, we demonstrated that silencing STAT1 significantly increased sensitivity of sarcoma cells to FasL-induced apoptosis (Fig.	('increased', 'PosReg', (66, 75))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('STAT1', 'Gene', (46, 51))	('sensitivity', 'MPA', (76, 87))	('sarcoma', 'Disease', (91, 98))	('silencing', 'Var', (36, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))
307964	22805310	Silencing STAT1 resulted in up-regulation of Fas (Fig.	('STAT1', 'Gene', (10, 15))	('Fas', 'Disease', (45, 48))	('Fas', 'Chemical', 'MESH:C038178', (45, 48))	('Silencing', 'Var', (0, 9))	('up-regulation', 'PosReg', (28, 41))
308069	30440007	A recent study has shown that the prevalence of BRCA mutations in Korean familial breast cancer patients is similar to that among Western cohorts, but more studies are needed before a concrete conclusion can be drawn.	('familial breast cancer', 'Disease', 'MESH:D001943', (73, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('BRCA', 'Gene', '672', (48, 52))	('BRCA', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('familial breast cancer', 'Disease', (73, 95))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
308079	30440007	A second possible reason for the high SMN rate in soft tissue sarcoma and malignant bone tumors may be associated with cancer-prone mutations; for example, TP53 mutation or RB1 mutation in osteosarcoma.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('associated', 'Reg', (103, 113))	('RB1', 'Gene', (173, 176))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (50, 69))	('osteosarcoma', 'Disease', (189, 201))	('osteosarcoma', 'Disease', 'MESH:D012516', (189, 201))	('TP53', 'Gene', (156, 160))	('soft tissue sarcoma', 'Disease', (50, 69))	('bone tumor', 'Phenotype', 'HP:0010622', (84, 94))	('SMN', 'Gene', (38, 41))	('bone tumors', 'Phenotype', 'HP:0010622', (84, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('mutation', 'Var', (161, 169))	('SMN', 'Gene', '6606', (38, 41))	('cancer', 'Disease', (119, 125))	('RB1', 'Gene', '5925', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('mutation', 'Var', (177, 185))	('osteosarcoma', 'Phenotype', 'HP:0002669', (189, 201))	('TP53', 'Gene', '7157', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('malignant bone tumors', 'Disease', (74, 95))	('malignant bone tumors', 'Disease', 'MESH:D001859', (74, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
308080	30440007	Newly discovered mutations have been reported in various types of sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('sarcomas', 'Disease', (66, 74))	('reported', 'Reg', (37, 45))	('mutations', 'Var', (17, 26))
308110	30219084	We used fluorescence in situ hybridization to detect specific rearrangements including EWSR1, ATF1, CREB1, and cAMP response element modulator (CREM) in 16 CCSST and 6 CCSLGT cases.	('CCSST', 'Disease', (156, 161))	('rearrangements', 'Var', (62, 76))	('EWSR1', 'Gene', (87, 92))	('CREB1', 'Gene', (100, 105))	('ATF1', 'Gene', (94, 98))	('cAMP', 'Chemical', '-', (111, 115))
308111	30219084	We also used reverse transcription polymerase chain reaction (RT-PCR) to detect specific chimeric fusions of EWSR1-ATF1 and EWSR1-CREB1 using fresh tumor samples in available cases.	('EWSR1-CREB1', 'Gene', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('chimeric fusions', 'Var', (89, 105))	('tumor', 'Disease', (148, 153))	('EWSR1-ATF1', 'Gene', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
308121	30219084	Genetically, CCSST and CCSLGT usually have characteristic chimeric fusions of Ewing sarcoma breakpoint region 1 (EWSR1) with cAMP response element-binding protein (CREB) gene family members, EWSR1-activating transcription factor 1 (ATF1) and EWSR1-CREB1, which were derived from each translocation of t(12;22)(q13;q12) and t(2;22)(q34;q12), respectively.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (301, 318))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('EWSR1', 'Gene', (113, 118))	('t(2;22)(q34;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (323, 339))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('chimeric', 'Var', (58, 66))	('cAMP', 'Chemical', '-', (125, 129))	('Ewing sarcoma', 'Disease', (78, 91))
308129	30219084	FISH was conducted as previously described, with the following modifications: baking (1 h at 60  C), deparaffinization, target gene activation (20 min with 0.2 M HCl followed by 30 min with pretreatment solution at 80  C), enzyme treatment (60 min with protease solution at 37  C), re-fixation (10 min in 10% formalin neutral buffer solution), denaturation (5 min with denaturation solution at 72  C), washing and dehydration (1 min each in 70%, 85%, and 100% ethanol), hybridization with 10 mL DNA probe solution (5 min at 90  C followed by 48 h at 37  C), and washing with post-hybridization wash buffer (2 min at 72  C).	('paraffin', 'Chemical', 'MESH:D010232', (103, 111))	('dehydration', 'Disease', (414, 425))	('hybridization', 'Var', (470, 483))	('formalin', 'Chemical', 'MESH:D005557', (309, 317))	('dehydration', 'Phenotype', 'HP:0001944', (414, 425))	('dehydration', 'Disease', 'MESH:D003681', (414, 425))
308133	30219084	We detected chimeric fusions by RT-PCR using fresh tumor samples in several available cases.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('chimeric fusions', 'Var', (12, 28))
308157	30219084	A genetic study revealed EWSR1 fusions with CREB family genes in all of these tumors.	('revealed', 'Reg', (16, 24))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('EWSR1', 'Gene', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('fusions', 'Var', (31, 38))
308285	27352193	We present a case of a 15-year-old female with a tibial tumor that exhibited features of Ewing-like sarcoma, including apparent rearrangement of the EWSR1 gene.	('tibial tumor', 'Disease', 'MESH:D020429', (49, 61))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (89, 107))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('EWSR1', 'Gene', (149, 154))	('rearrangement', 'Var', (128, 141))	('EWSR1', 'Gene', '2130', (149, 154))	('tibial tumor', 'Disease', (49, 61))	('Ewing-like sarcoma', 'Disease', (89, 107))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (89, 107))
308286	27352193	Hybridization capture-based next-generation DNA sequencing showed evidence of complex genomic rearrangements, absence of known pathogenic Ewing-like chromosome translocations, and deletions RB1, PTCH1, and ATRX, supporting the diagnosis of osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (240, 252))	('ATRX', 'Gene', (206, 210))	('PTCH1', 'Gene', (195, 200))	('osteosarcoma', 'Disease', (240, 252))	('RB1', 'Gene', (190, 193))	('osteosarcoma', 'Disease', 'MESH:D012516', (240, 252))	('ATRX', 'Gene', '546', (206, 210))	('PTCH1', 'Gene', '5727', (195, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('RB1', 'Gene', '5925', (190, 193))	('deletions', 'Var', (180, 189))
308290	27352193	For example, classic Ewing bone sarcomas, extraosseous Ewing-like sarcomas, desmoplastic small round cell tumors of the abdomen, and extraskeletal myxoid chondrosarcomas have diverse clinical presentations and histologic morphologies, but all share characteristic translocations involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene and molecular pathogenic mechanisms with poor responses to conventional chemotherapy.	('EWSR1', 'Gene', '2130', (328, 333))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (55, 73))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (55, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('desmoplastic small round cell tumors', 'Disease', (76, 112))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (154, 169))	('bone sarcomas', 'Phenotype', 'HP:0002669', (27, 40))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (147, 169))	('myxoid chondrosarcomas', 'Disease', (147, 169))	('EWSR1', 'Gene', (328, 333))	('extraosseous', 'Disease', (42, 54))	('Ewing sarcoma breakpoint region 1', 'Gene', (293, 326))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (293, 306))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Ewing bone sarcomas', 'Phenotype', 'HP:0012254', (21, 40))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (293, 326))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('Ewing-like sarcomas', 'Disease', (55, 74))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('Ewing bone sarcomas', 'Disease', 'MESH:C563168', (21, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('desmoplastic small round cell tumors', 'Disease', 'MESH:D058405', (76, 112))	('Ewing bone sarcomas', 'Disease', (21, 40))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (55, 74))	('translocations', 'Var', (264, 278))
308292	27352193	In particular, osteosarcomas are characteristically defined by complex genomic rearrangements, including chromothripsis, and inactivating mutations of TP53 and RB1 genes.	('osteosarcomas', 'Phenotype', 'HP:0002669', (15, 28))	('TP53', 'Gene', (151, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('inactivating mutations', 'Var', (125, 147))	('RB1', 'Gene', (160, 163))	('osteosarcomas', 'Disease', (15, 28))	('TP53', 'Gene', '7157', (151, 155))	('chromothripsis', 'Disease', (105, 119))	('osteosarcoma', 'Phenotype', 'HP:0002669', (15, 27))	('RB1', 'Gene', '5925', (160, 163))	('osteosarcomas', 'Disease', 'MESH:D012516', (15, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
308294	27352193	Cases of small cell osteosarcomas with EWSR1 rearrangements have been reported, but it is not known whether this is associated with Ewing-like sarcoma clinical behavior and therapy response, a question with potential therapeutic implications since treatment regimens for osteogenic and Ewing sarcomas have significant differences.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (286, 299))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (292, 300))	('osteosarcomas', 'Phenotype', 'HP:0002669', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('Ewing-like sarcoma', 'Disease', (132, 150))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (132, 150))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (132, 150))	('EWSR1', 'Gene', '2130', (39, 44))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (286, 300))	('rearrangements', 'Var', (45, 59))	('small cell osteosarcomas', 'Disease', 'MESH:D012516', (9, 33))	('Ewing sarcomas', 'Disease', (286, 300))	('small cell osteosarcomas', 'Disease', (9, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (286, 300))	('osteosarcoma', 'Phenotype', 'HP:0002669', (20, 32))	('EWSR1', 'Gene', (39, 44))
308295	27352193	Here, we describe a patient with a tibial tumor, who was found to have a round cell sarcoma with an apparent EWSR1 rearrangement, consistent with a diagnosis of Ewing-like sarcoma, but instead was diagnosed as osteosarcoma based on genomic profiling.	('tibial tumor', 'Disease', 'MESH:D020429', (35, 47))	('Ewing-like sarcoma', 'Disease', (161, 179))	('EWSR1', 'Gene', '2130', (109, 114))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (161, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (161, 179))	('osteosarcoma', 'Phenotype', 'HP:0002669', (210, 222))	('osteosarcoma', 'Disease', (210, 222))	('cell sarcoma', 'Disease', (79, 91))	('osteosarcoma', 'Disease', 'MESH:D012516', (210, 222))	('cell sarcoma', 'Disease', 'MESH:D012509', (79, 91))	('tibial tumor', 'Disease', (35, 47))	('rearrangement', 'Var', (115, 128))	('patient', 'Species', '9606', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('EWSR1', 'Gene', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
308301	27352193	Fluorescence in situ hybridization (FISH) analysis using Vysis probes (Abbott) demonstrated EWSR1 gene rearrangement in 56% of the cells in a focal area of the tumor (Figure 1).	('EWSR1', 'Gene', '2130', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('rearrangement', 'Var', (103, 116))	('EWSR1', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))
308303	27352193	Given the focal nature of EWSR1 rearrangement and recent discovery of round cell Ewing-like sarcomas with CIC gene translocations without EWSR1 rearrangements, FISH for CIC rearrangements was performed and found to be normal (not shown).	('EWSR1', 'Gene', (138, 143))	('EWSR1', 'Gene', '2130', (26, 31))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (81, 100))	('EWSR1', 'Gene', '2130', (138, 143))	('Ewing-like sarcomas', 'Disease', (81, 100))	('CIC gene', 'Gene', (106, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('EWSR1', 'Gene', (26, 31))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (81, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('rearrangement', 'Var', (32, 45))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (81, 100))
308305	27352193	Given the atypical histopathologic tumor appearance and atypical FISH findings, the tumor specimen and matched peripheral blood cell genomic DNA were analyzed using hybridization capture-based next-generation DNA sequencing, specifically designed to identify mutations in 341 genes known to be pathogenically mutated in human cancers.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mutations', 'Var', (259, 268))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('human', 'Species', '9606', (320, 325))	('cancers', 'Disease', 'MESH:D009369', (326, 333))	('tumor', 'Disease', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (326, 333))	('tumor', 'Disease', (84, 89))	('cancers', 'Disease', (326, 333))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
308309	27352193	Given the presence of i) numerous genomic copy number changes, ii) mutations of genes characteristically disrupted in osteosarcomas, and iii) lack of Ewing-like chromosomal rearrangements, the patient's original diagnosis was reassessed.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('changes', 'Var', (54, 61))	('osteosarcoma', 'Phenotype', 'HP:0002669', (118, 130))	('mutations', 'Var', (67, 76))	('osteosarcomas', 'Disease', (118, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('patient', 'Species', '9606', (193, 200))	('osteosarcomas', 'Phenotype', 'HP:0002669', (118, 131))	('osteosarcomas', 'Disease', 'MESH:D012516', (118, 131))
308310	27352193	While genomically complex Ewing sarcomas have been observed, they are invariably associated with mutations of TP53.	('mutations', 'Var', (97, 106))	('TP53', 'Gene', '7157', (110, 114))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (26, 40))	('TP53', 'Gene', (110, 114))	('Ewing sarcomas', 'Disease', (26, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (26, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('associated', 'Reg', (81, 91))
308312	27352193	However, subsets of osteosarcoma have been found to exhibit TP53 rearrangements involving Alu intronic elements, which may evade detection by targeted sequencing such as MSK-IMPACT.	('osteosarcoma', 'Disease', (20, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('Alu intronic', 'Protein', (90, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (20, 32))	('osteosarcoma', 'Disease', 'MESH:D012516', (20, 32))	('exhibit', 'Reg', (52, 59))	('rearrangements', 'Var', (65, 79))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))
308316	27352193	Variants of unknown significance in her germline included only PARP1 p.W481C, FOXP1 p.A15V, RECQL4 p.D1121N, and AMER1 p.E385Q.	('PARP1', 'Gene', (63, 68))	('p.A15V', 'Var', (84, 90))	('AMER1', 'Gene', '139285', (113, 118))	('RECQL4', 'Gene', '9401', (92, 98))	('p.D1121N', 'Var', (99, 107))	('FOXP1', 'Gene', (78, 83))	('p.D1121N', 'Mutation', 'rs377390897', (99, 107))	('p.A15V', 'Mutation', 'rs532329866', (84, 90))	('p.W481C', 'SUBSTITUTION', 'None', (69, 76))	('p.E385Q', 'Mutation', 'rs368719613', (119, 126))	('RECQL4', 'Gene', (92, 98))	('p.W481C', 'Var', (69, 76))	('p.E385Q', 'Var', (119, 126))	('AMER1', 'Gene', (113, 118))	('FOXP1', 'Gene', '27086', (78, 83))
308322	27352193	In addition, genomic instability and chromothripsis that characterize distinct tumors such as osteosarcoma can induce apparent gene rearrangements that are in and of themselves pathogenic.	('induce', 'Reg', (111, 117))	('genomic instability', 'Var', (13, 32))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('osteosarcoma', 'Disease', (94, 106))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('osteosarcoma', 'Phenotype', 'HP:0002669', (94, 106))	('osteosarcoma', 'Disease', 'MESH:D012516', (94, 106))	('gene rearrangements', 'MPA', (127, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
308325	27352193	Indeed, clinical genomic profiling utilized in this case revealed deletions of genes characteristically inactivated in osteosarcomas, such as RB1, ATRX, and PTCH1.	('osteosarcomas', 'Disease', (119, 132))	('PTCH1', 'Gene', (157, 162))	('ATRX', 'Gene', (147, 151))	('RB1', 'Gene', (142, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('osteosarcomas', 'Phenotype', 'HP:0002669', (119, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('RB1', 'Gene', '5925', (142, 145))	('osteosarcomas', 'Disease', 'MESH:D012516', (119, 132))	('PTCH1', 'Gene', '5727', (157, 162))	('ATRX', 'Gene', '546', (147, 151))	('deletions', 'Var', (66, 75))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))
308327	27352193	In this specific case, we identified somatic deletion of PTCH1, consistent with the prior observations of PTCH1 mutations in osteosarcomas, which cause activation of the Hedgehog signaling pathway and susceptibility to emerging targeted inhibitors of Hedgehog signaling such as vismodegib.	('Hedgehog signaling pathway', 'Pathway', (170, 196))	('PTCH1', 'Gene', (57, 62))	('activation', 'PosReg', (152, 162))	('PTCH1', 'Gene', (106, 111))	('osteosarcomas', 'Phenotype', 'HP:0002669', (125, 138))	('osteosarcomas', 'Disease', (125, 138))	('mutations', 'Var', (112, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('PTCH1', 'Gene', '5727', (57, 62))	('PTCH1', 'Gene', '5727', (106, 111))	('osteosarcomas', 'Disease', 'MESH:D012516', (125, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
308390	26909289	Pneumonitis has been reported after TLI in Ewing's sarcoma, but no serious toxicity like we reported in these two patients has previously been presented.	('toxicity', 'Disease', 'MESH:D064420', (75, 83))	('toxicity', 'Disease', (75, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (43, 58))	('Pneumonitis', 'Disease', (0, 11))	('TLI', 'Var', (36, 39))	('patients', 'Species', '9606', (114, 122))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (43, 58))	("Ewing's sarcoma", 'Disease', (43, 58))
308407	26909289	A blood test was performed in Case 2 to look for a mutation in the ataxia telangiectasia mutated gene, which is associated with a higher sensitivity to radiation.	('ataxia telangiectasia mutated', 'Gene', (67, 96))	('ataxia telangiectasia mutated', 'Gene', '472', (67, 96))	('telangiectasia', 'Phenotype', 'HP:0001009', (74, 88))	('mutation', 'Var', (51, 59))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (137, 161))	('ataxia', 'Phenotype', 'HP:0001251', (67, 73))	('associated', 'Reg', (112, 122))
308410	26909289	Impairment of pulmonary function before radiotherapy seems to be a risk factor for higher grade of late toxicity to the lung.	('Impairment', 'Var', (0, 10))	('toxicity', 'Disease', 'MESH:D064420', (104, 112))	('toxicity', 'Disease', (104, 112))	('pulmonary', 'CPA', (14, 23))
308427	21761400	To address this hypothesis, we evaluated the total chemotherapy delivered and AEs in patients with RMS 5-9, 10-14 and 15-20 years of age compared to younger children aged 1-4 years, treated on Intergroup Rhabdomyosarcoma Study (IRS)-IV.	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (204, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('RMS', 'Var', (99, 102))	('AEs', 'Chemical', '-', (78, 81))	('patients', 'Species', '9606', (85, 93))	('Rhabdomyosarcoma', 'Disease', (204, 220))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (204, 220))	('children', 'Species', '9606', (157, 165))
308492	21761400	The total dose of cyclophosphamide on the VAC regimen of D9803 was 30.8 g/m2 compared with 25.1 g/m2 on the VAC/VTC regimen, giving the VAC/VTC regimen 20% less cyclophosphamide.	('VAC', 'Chemical', '-', (42, 45))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (18, 34))	('VAC', 'Chemical', '-', (108, 111))	('VTC', 'Chemical', '-', (140, 143))	('D9803', 'Var', (57, 62))	('VTC', 'Chemical', '-', (112, 115))	('cyclophosphamide', 'MPA', (161, 177))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (161, 177))	('VAC', 'Chemical', '-', (136, 139))	('D9803', 'Chemical', '-', (57, 62))
308494	21761400	Furthermore, cyclophosphamide dose escalation may be implicated in the severe hepatopathy observed in very young children during both IRS-IV and D9803.	('hepatopathy', 'Disease', 'MESH:D020754', (78, 89))	('hepatopathy', 'Disease', (78, 89))	('D9803', 'Var', (145, 150))	('implicated', 'Reg', (53, 63))	('cyclophosphamide', 'MPA', (13, 29))	('children', 'Species', '9606', (113, 121))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (13, 29))	('D9803', 'Chemical', '-', (145, 150))
308644	33902630	They observed that increased CD20+ lymphocytes in sarcomas with wide resection margins were correlated with better survival.	('sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('increased', 'PosReg', (19, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('better', 'PosReg', (108, 114))	('CD20+ lymphocytes', 'Var', (29, 46))	('sarcomas', 'Disease', (50, 58))
308649	33902630	They found a higher percentage (41%) of CD3+ TILs in GISTs (9/22) and low density of TILs expression in LMS, synovial sarcoma, chondrosarcoma and liposarcoma.	('GIST', 'Phenotype', 'HP:0100723', (53, 57))	('chondrosarcoma and liposarcoma', 'Disease', 'MESH:D002813', (127, 157))	('CD3+', 'Var', (40, 44))	('LMS', 'Disease', (104, 107))	('synovial sarcoma', 'Disease', (109, 125))	('LMS', 'Phenotype', 'HP:0100243', (104, 107))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (127, 141))	('liposarcoma', 'Phenotype', 'HP:0012034', (146, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (109, 125))	('synovial sarcoma', 'Disease', 'MESH:D013584', (109, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
308650	33902630	In tumors with higher amounts of infiltrating CD8+ or CD+ , cells were more likely to express PD-L1 and PD-1.	('PD-L1', 'Gene', (94, 99))	('CD8', 'Gene', '925', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('PD-1', 'Gene', (104, 108))	('CD8', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('CD+', 'Var', (54, 57))
308652	33902630	In fact, they reported that CD3+ and CD8+ lymphocytes infiltrating the tumor had a positive impact on survival.	('CD8', 'Gene', (37, 40))	('CD8', 'Gene', '925', (37, 40))	('survival', 'CPA', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('CD3+', 'Var', (28, 32))
308676	33902630	Furthermore, some studies showed that the median survival time of patients exhibiting ganglioside GD2 expression was significantly shorter than that of patients without ganglioside GD2 expression.	('ganglioside GD2 expression', 'Var', (86, 112))	('ganglioside', 'Chemical', 'MESH:D005732', (86, 97))	('ganglioside', 'Chemical', 'MESH:D005732', (169, 180))	('shorter', 'NegReg', (131, 138))	('GD', 'Chemical', 'MESH:D005732', (98, 100))	('patients', 'Species', '9606', (152, 160))	('patients', 'Species', '9606', (66, 74))	('GD', 'Chemical', 'MESH:D005732', (181, 183))
308677	33902630	Other clinical trials, using the autologous anti-GD2-CAR engineered T cells (NCT03635632- NCT04539366- NCT01953900) in subject with advanced sarcomas and neuroblastoma, are currently ongoing.	('CAR', 'Gene', (53, 56))	('GD', 'Chemical', 'MESH:D005732', (49, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('CAR', 'Gene', '653108', (53, 56))	('sarcomas and neuroblastoma', 'Disease', 'MESH:D009447', (141, 167))	('NCT03635632- NCT04539366- NCT01953900', 'Var', (77, 114))	('neuroblastoma', 'Phenotype', 'HP:0003006', (154, 167))
308690	33902630	Adoptive T-cell treatment based on T-Cell Receptor (TCR) modifications is another promising approach to effectively target tumors.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('TCR', 'Gene', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('T-Cell Receptor', 'Gene', '6962', (35, 50))	('T-Cell Receptor', 'Gene', (35, 50))	('modifications', 'Var', (57, 70))	('TCR', 'Gene', '6962', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
308697	33902630	In fact, to improve the affinity of TCR for antigen-MHC complex, which is typically weak in the isolated lymphocytes, TCRs are modified ex vivo through the mutagenesis of one or more specific aminoacids within the complementarity-determining regions (CDRs).	('MHC', 'Gene', (52, 55))	('TCR', 'Gene', '6962', (118, 121))	('TCR', 'Gene', (118, 121))	('TCR', 'Gene', (36, 39))	('mutagenesis', 'Var', (156, 167))	('MHC', 'Gene', '3107', (52, 55))	('improve', 'PosReg', (12, 19))	('affinity', 'MPA', (24, 32))	('TCR', 'Gene', '6962', (36, 39))
308702	33902630	In this study, 42 patients with advanced synovial sarcoma were injected with genetically modified autologous T cells expressing NY-ESO1-1c259, an anti-NY-ESO specific HLA-A*02-restricted peptide SLLMWITQC receptor.	('synovial sarcoma', 'Disease', 'MESH:D013584', (41, 57))	('ES', 'Phenotype', 'HP:0012254', (131, 133))	('synovial sarcoma', 'Disease', (41, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('patients', 'Species', '9606', (18, 26))	('SL', 'Disease', 'MESH:C564794', (195, 197))	('NY-ESO1-1c259', 'Var', (128, 141))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (41, 57))	('ES', 'Phenotype', 'HP:0012254', (154, 156))
308713	33902630	These side effects occur because the most known tumour antigens are not exclusively expressed into tumours, thus triggering alloreactivity reactions.The mismatch after introduction of TCR chains with endogenous TCRs is the cause of unpredictable TCR toxicities related to the generation of T cells with novel and paradoxical specificities.	('toxicities', 'Disease', 'MESH:D064420', (250, 260))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('cause', 'Reg', (223, 228))	('toxicities', 'Disease', (250, 260))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('TCR', 'Gene', (246, 249))	('tumour', 'Disease', (99, 105))	('TCR', 'Gene', (184, 187))	('TCR', 'Gene', '6962', (211, 214))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('TCR', 'Gene', (211, 214))	('tumours', 'Disease', (99, 106))	('mismatch', 'Var', (153, 161))	('TCR', 'Gene', '6962', (184, 187))	('TCR', 'Gene', '6962', (246, 249))
308725	33902630	The most oncolytic viruses used in preclinical and clinical studies are T-VEC, HSV1716, NV1020, G207, M032, rRp450.	('HSV1716', 'Var', (79, 86))	('rRp450', 'Var', (108, 114))	('NV1020', 'Var', (88, 94))	('G207', 'Var', (96, 100))	('M032', 'Var', (102, 106))	('HSV1716', 'CellLine', 'CVCL:9H17', (79, 86))
308727	33902630	Particularly, NV1020 and G207 have been used in osteosarcoma but preclinical studies show modest activity.	('NV1020', 'Var', (14, 20))	('G207', 'Var', (25, 29))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('osteosarcoma', 'Disease', (48, 60))	('osteosarcoma', 'Disease', 'MESH:D012516', (48, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))
308728	33902630	In particular, apre-clinical study on 10 different cell lines of rhabdomyosarcoma, osteosarcoma and ES was performed using both NV1020 and G207 viruses.	('NV1020', 'Var', (128, 134))	('ES', 'Phenotype', 'HP:0012254', (100, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (83, 95))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (65, 81))	('osteosarcoma', 'Disease', (83, 95))	('osteosarcoma', 'Disease', 'MESH:D012516', (83, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('G207', 'Var', (139, 143))	('rhabdomyosarcoma', 'Disease', (65, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (65, 81))
308732	33902630	In vivo the MG1 oncolytic treatment led to a significant increase of survival in mice with sarcomas.	('mice', 'Species', '10090', (81, 85))	('survival', 'CPA', (69, 77))	('MG1', 'Var', (12, 15))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('increase', 'PosReg', (57, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcomas', 'Disease', (91, 99))
308741	33902630	In another preclinical study performed in osteosarcoma, the adenovirus Delta24-RGD showed a strong synergistic anti-tumor effect with cisplatin both in vitro and in vivo.	('osteosarcoma', 'Disease', (42, 54))	('GD', 'Chemical', 'MESH:D005732', (80, 82))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Delta24-RGD', 'Var', (71, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))	('adenovirus', 'Species', '10508', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('tumor', 'Disease', (116, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
308757	33902630	Over-expressed antigens or specific mutated proteins on cell surface are ideal candidates for an anti-cancer vaccine.	('mutated', 'Var', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))
308758	33902630	Some subtypes of sarcomas, despite their strong heterogeneity, can be targets for this therapeutic strategy, because they have specific genetic abnormalities including chromosomal translocations [i.e.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('chromosomal translocations', 'Var', (168, 194))	('genetic abnormalities', 'Disease', 'MESH:D030342', (136, 157))	('sarcomas', 'Disease', (17, 25))	('genetic abnormalities', 'Disease', (136, 157))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
308774	33902630	Some pre-clinical studies observed that the use of epigenetic compounds such as decitabine, up-regulates NY-ESO-1, LAGE-1, SSX, and MAGE -A10 in sarcoma cell lines.	('decitabine', 'Gene', (80, 90))	('sarcoma', 'Disease', (145, 152))	('LAGE-1', 'Gene', '30848', (115, 121))	('ES', 'Phenotype', 'HP:0012254', (108, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('A10', 'Gene', (138, 141))	('SSX', 'Gene', '6757', (123, 126))	('decitabine', 'Chemical', 'MESH:D000077209', (80, 90))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('SS', 'Phenotype', 'HP:0012570', (123, 125))	('SSX', 'Gene', (123, 126))	('NY-ESO-1', 'Gene', '246100', (105, 113))	('epigenetic compounds', 'Var', (51, 71))	('NY-ESO-1', 'Gene', (105, 113))	('LAGE-1', 'Gene', (115, 121))	('A10', 'Gene', '28870', (138, 141))	('up-regulates', 'PosReg', (92, 104))
308820	33902630	In fact, although a high number of CD8+ T cells do not seem to be a clear prognostic marker of survival in patients with STSs, high PD-L1 expression on TILs has been related to worse survival rates in these patients, suggesting that PD-1/PD-L1 pathway in STSs might prompt cancer progression through T-cell inhibition.	('patients', 'Species', '9606', (207, 215))	('prompt', 'PosReg', (266, 272))	('PD-L1', 'Gene', (132, 137))	('cancer', 'Disease', (273, 279))	('high', 'Var', (127, 131))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('STSs', 'Phenotype', 'HP:0030448', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('CD8', 'Gene', (35, 38))	('CD8', 'Gene', '925', (35, 38))	('T-cell', 'CPA', (300, 306))	('patients', 'Species', '9606', (107, 115))	('STSs', 'Phenotype', 'HP:0030448', (255, 259))
308822	33902630	have shown that the treatment with ipilimumab, (antibody anti-CTLA-4) was significantly more effective in patients with melanoma carrying more than 100 mutations per coding genome than those with a lower mutation rate.	('CTLA-4', 'Gene', (62, 68))	('more', 'PosReg', (88, 92))	('mutations', 'Var', (152, 161))	('ipilimumab', 'Chemical', 'MESH:D000074324', (35, 45))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('CTLA-4', 'Gene', '1493', (62, 68))	('patients', 'Species', '9606', (106, 114))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))
308825	33902630	In particular, it has been reported that the epithelioid sarcoma has a mutation rate in coding regions similar to ovarian cancer; this could be exploited for treatment with immune checkpoint inhibitors.	('ovarian cancer', 'Disease', (114, 128))	('mutation', 'Var', (71, 79))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('sarcoma', 'Disease', (57, 64))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
308829	33902630	The MMR complex deficiency can also determine the instability of microsatellites (stretches of short sequences of approximately 16 nucleotide repeated and distributed throughout the genome).	('microsatellites', 'Var', (65, 80))	('instability', 'MPA', (50, 61))	('MMR complex deficiency', 'Disease', 'MESH:C536928', (4, 26))	('MMR complex deficiency', 'Disease', (4, 26))	('determine', 'Reg', (36, 45))
308832	33902630	It is known that the CRC with high MSI manifests an inflammatory phenotype that generates an endogenous immune response, which is counteracted by the expression of inhibitory immune signals such as PD1/PDL1.	('CRC', 'Phenotype', 'HP:0003003', (21, 24))	('MSI', 'Var', (35, 38))	('PDL1', 'Gene', '29126', (202, 206))	('CRC', 'Disease', 'MESH:D015179', (21, 24))	('endogenous immune response', 'MPA', (93, 119))	('PDL1', 'Gene', (202, 206))	('CRC', 'Disease', (21, 24))
308852	33902630	This switch from "equilibrium" to "escape" phase can be due to different mechanisms, including loss/gain of function mutations, epigenetic alterations, affecting genes encoding for pro/anti-apoptotic proteins, MHC, antigen-presenting machinery, etc.	('epigenetic alterations', 'Var', (128, 150))	('mutations', 'Var', (117, 126))	('MHC', 'Gene', '3107', (210, 213))	('loss/gain', 'NegReg', (95, 104))	('MHC', 'Gene', (210, 213))
308854	33902630	Inactivation of BCL2 pro-apoptotic members family (through mutation) is a known example of this phenomenon in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('BCL2', 'Gene', (16, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('mutation', 'Var', (59, 67))	('sarcomas', 'Disease', (110, 118))	('BCL2', 'Gene', '596', (16, 20))	('Inactivation', 'NegReg', (0, 12))
308869	33902630	In conclusion, the main goal for the future clinical trials on immunotherapy in sarcomas setting should be to select innovative and specific biomarkers (tumor antigen expression, gene mutations, structural rearrangements, etc.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('sarcomas', 'Disease', 'MESH:D012509', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('gene mutations', 'Var', (179, 193))	('sarcomas', 'Disease', (80, 88))	('structural rearrangements', 'Var', (195, 220))
308906	30956944	Several studies have examined cell-cell and paracrine interactions between MSCs and tumour-cells, demonstrating a complicated relationship between them, with MSCs potentially promoting or suspending tumour progression even within the same cancer model.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Disease', (84, 90))	('rat', 'Species', '10116', (105, 108))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('tumour', 'Disease', (199, 205))	('cancer', 'Disease', (239, 245))	('suspending', 'NegReg', (188, 198))	('MSCs', 'Var', (158, 162))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('promoting', 'PosReg', (175, 184))
308918	30956944	Regarding specifically T cells, MSCs suppress their activity by inhibiting their proliferation or, by causing apoptosis of already activated T lymphocytes.	('causing', 'Reg', (102, 109))	('apoptosis', 'CPA', (110, 119))	('MSCs', 'Var', (32, 36))	('inhibiting', 'NegReg', (64, 74))	('activity', 'MPA', (52, 60))	('rat', 'Species', '10116', (88, 91))	('suppress', 'NegReg', (37, 45))	('proliferation', 'CPA', (81, 94))
308940	30956944	In vivo animal studies of murine melanoma and renal murine adenocarcinoma (Renca kidney cancer cells) showed that co-implantation of MSCs increased tumour size possibly because of MSC-mediated immunosuppression.	('tumour', 'Disease', (148, 154))	('increased', 'PosReg', (138, 147))	('melanoma and renal murine adenocarcinoma', 'Disease', 'MESH:C538614', (33, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('murine', 'Species', '10090', (26, 32))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('Renca kidney cancer', 'Disease', 'MESH:D007680', (75, 94))	('MSCs', 'Var', (133, 137))	('kidney cancer', 'Phenotype', 'HP:0009726', (81, 94))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('Renca kidney cancer', 'Disease', (75, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('murine', 'Species', '10090', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (148, 154))
308952	30956944	Mice that received MSCs intravenously developed the first detectable metastases significantly earlier (2.93 +- 1.90 days) than those that received local injection of MSCs (6.94 +- 6.78 days) and those that received no MSCs (5.93 +- 4.55 days).	('MSCs', 'Var', (19, 23))	('metastases', 'Disease', 'MESH:D009362', (69, 79))	('metastases', 'Disease', (69, 79))	('Mice', 'Species', '10090', (0, 4))
308966	30956944	Moreover, pre-clinical data showed that BMMSCs could promote osteosarcoma growth through PI3K/Akt and Ras/Erk intracellular cascades, and enhance metastasis through CXCR4 signaling.	('osteosarcoma', 'Disease', (61, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Akt', 'Gene', (94, 97))	('metastasis', 'CPA', (146, 156))	('Erk', 'Gene', '2048', (106, 109))	('enhance', 'PosReg', (138, 145))	('CXCR4', 'Gene', '7852', (165, 170))	('Akt', 'Gene', '207', (94, 97))	('CXCR4', 'Gene', (165, 170))	('BMMSCs', 'Var', (40, 46))	('Erk', 'Gene', (106, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))	('promote', 'PosReg', (53, 60))
309034	30956944	This was despite promising in vitro data demonstrating that MSC-TRAIL could induce significant K-HOS cell apoptosis in direct co-culture.	('MSC-TRAIL', 'Var', (60, 69))	('rat', 'Species', '10116', (48, 51))	('K-HOS', 'CellLine', 'CVCL:0312', (95, 100))	('K-HOS cell apoptosis', 'CPA', (95, 115))
309043	30956944	The tumour volume at day 30 in mice that received MSCs-OPG was reduced by 65.2% compared to those administrated with PBS solution.	('reduced', 'NegReg', (63, 70))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('rat', 'Species', '10116', (106, 109))	('mice', 'Species', '10090', (31, 35))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('MSCs-OPG', 'Var', (50, 58))	('tumour', 'Disease', (4, 10))
309051	30956944	Interestingly, transduced MSCs were more capable of migrating towards osteosarcoma cells than native MSCs.	('osteosarcoma cells', 'Disease', (70, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('migrating towards', 'CPA', (52, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('transduced', 'Var', (15, 25))	('rat', 'Species', '10116', (55, 58))	('osteosarcoma cells', 'Disease', 'MESH:D012516', (70, 88))
309061	30956944	p35 and p40 subunits of IL-12 were expressed in the tumour site, inhibiting tumour growth.	('IL-12', 'Gene', (24, 29))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour growth', 'Disease', (76, 89))	('inhibiting', 'NegReg', (65, 75))	('tumour growth', 'Disease', 'MESH:D006130', (76, 89))	('p40', 'Var', (8, 11))	('p35', 'Gene', '3592', (0, 3))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (52, 58))	('tumour', 'Disease', (76, 82))	('p35', 'Gene', (0, 3))
309158	28260930	The majority of WDLPS/ALTs and DDLPS show MDM2 amplification or overexpression, which represents the key marker for the diagnosis of these tumors and is involved in cell transformation and in the tumorigenesis process.	('LPS', 'Phenotype', 'HP:0012034', (18, 21))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (139, 144))	('LPS', 'Phenotype', 'HP:0012034', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('involved', 'Reg', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('MDM2', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('LPS', 'Disease', (18, 21))	('LPS', 'Disease', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('MDM2', 'Gene', '4193', (42, 46))	('tumors', 'Disease', (139, 145))	('overexpression', 'PosReg', (64, 78))	('amplification', 'Var', (47, 60))	('LPS', 'Disease', 'MESH:C536528', (18, 21))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('LPS', 'Disease', 'MESH:C536528', (33, 36))
309168	28260930	These alterations are considered the primary oncogenic events in sarcoma tumorigenesis.	('alterations', 'Var', (6, 17))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('sarcoma', 'Disease', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))
309225	28260930	Trabectedin has been found to be particularly effective in translocation-related sarcomas (TRS) such as MLPS, exerting an important antitumor activity probably through the inactivation of the FUS-CHOP oncogene, which is thought to alter gene-encoding protein expression and induce lipogenic cell differentiation.	('sarcomas', 'Disease', (81, 89))	('CHOP', 'Gene', '1649', (196, 200))	('Trabectedin', 'Chemical', 'MESH:D000077606', (0, 11))	('MLPS', 'Disease', 'None', (104, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('inactivation', 'Var', (172, 184))	('LPS', 'Phenotype', 'HP:0012034', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('lipogenic cell differentiation', 'CPA', (281, 311))	('CHOP', 'Gene', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('MLPS', 'Disease', (104, 108))	('MLPS', 'Phenotype', 'HP:0012268', (104, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('tumor', 'Disease', (136, 141))	('induce', 'PosReg', (274, 280))
309234	28260930	Trabectedin has been shown to be active in a variety of histological subtypes, including non-L-type sarcoma, especially when characterized by chromosomal translocation (20% of all sarcomas).	('sarcoma', 'Disease', (100, 107))	('chromosomal', 'Var', (142, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcoma', 'Disease', 'MESH:D012509', (180, 187))	('Trabectedin', 'Chemical', 'MESH:D000077606', (0, 11))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('sarcoma', 'Disease', (180, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('sarcomas', 'Disease', (180, 188))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))
309240	28260930	Response rates according to RECIST were higher in patients treated with doxorubicin (27% vs 5.9%) but similar between treatment arms according to Choi criteria (45.9% vs 37.3%).	('patients', 'Species', '9606', (50, 58))	('higher', 'PosReg', (40, 46))	('doxorubicin', 'Var', (72, 83))	('Response', 'MPA', (0, 8))	('doxorubicin', 'Chemical', 'MESH:D004317', (72, 83))
309276	28260930	Some clinical studies have shown that co-treatment with steroids induces hepatic cytochrome P450 3A4 variant activity, reducing hepatic exposure to trabectedin and, consequently, the correlated hepatotoxicity.	('cytochrome P450 3A4', 'Gene', '1576', (81, 100))	('variant', 'Var', (101, 108))	('trabectedin', 'Chemical', 'MESH:D000077606', (148, 159))	('hepatotoxicity', 'Disease', (194, 208))	('cytochrome P450 3A4', 'Gene', (81, 100))	('steroids', 'Chemical', 'MESH:D013256', (56, 64))	('hepatic exposure to trabectedin', 'MPA', (128, 159))	('activity', 'MPA', (109, 117))	('hepatotoxicity', 'Disease', 'MESH:D056486', (194, 208))	('reducing', 'NegReg', (119, 127))
309318	27672333	A recent Phase III study, however, has shown superiority in PFS of trabectedin over dacarbazine in metastatic STS patients who already failed at least two prior regimens.	('dacarbazine', 'Chemical', 'MESH:D003606', (84, 95))	('trabectedin', 'Chemical', 'MESH:D000077606', (67, 78))	('trabectedin', 'Gene', (67, 78))	('patients', 'Species', '9606', (114, 122))	('PFS', 'Var', (60, 63))	('STS', 'Phenotype', 'HP:0030448', (110, 113))	('metastatic STS', 'Disease', (99, 113))
309336	27672333	Other than producing an arrest of mitosis, eribulin has also been shown to inhibit Wnt/beta-catenin signaling in small bowel adenocarcinoma cell line experiments as well as alter tumor vasculature resulting in greater perfusion and drug delivery.	('eribulin', 'Var', (43, 51))	('perfusion', 'MPA', (218, 227))	('beta-catenin', 'Gene', (87, 99))	('eribulin', 'Chemical', 'MESH:C490954', (43, 51))	('arrest of mitosis', 'Disease', 'MESH:D006323', (24, 41))	('inhibit', 'NegReg', (75, 82))	('arrest of mitosis', 'Disease', (24, 41))	('greater', 'PosReg', (210, 217))	('drug delivery', 'MPA', (232, 245))	('small bowel adenocarcinoma', 'Disease', (113, 139))	('beta-catenin', 'Gene', '1499', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('small bowel adenocarcinoma', 'Disease', 'MESH:D000230', (113, 139))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('alter', 'Reg', (173, 178))	('tumor', 'Disease', (179, 184))
309337	27672333	Tumor metastasis also seems to be affected by eribulin via reversing epithelial-mesenchymal transition.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('reversing', 'NegReg', (59, 68))	('affected', 'Reg', (34, 42))	('epithelial-mesenchymal transition', 'CPA', (69, 102))	('Tumor metastasis', 'CPA', (0, 16))	('eribulin', 'Var', (46, 54))	('eribulin', 'Chemical', 'MESH:C490954', (46, 54))
309436	27672333	With regard to symptoms, patients taking eribulin were most affected by systemic side effects of dry mouth, different tastes, irritated eyes, hot flashes, feeling ill, and upset by hair loss, as opposed to those on capecitabine, who suffered more from gastrointestinal adverse effects (eg, diarrhea and vomiting).	('irritated eyes', 'Disease', (126, 140))	('irritated eyes', 'Disease', 'MESH:D005128', (126, 140))	('gastrointestinal adverse', 'Disease', (252, 276))	('gastrointestinal adverse', 'Disease', 'MESH:D005767', (252, 276))	('capecitabine', 'Chemical', 'MESH:D000069287', (215, 227))	('dry mouth', 'Disease', 'MESH:D014987', (97, 106))	('diarrhea', 'Disease', (290, 298))	('dry mouth', 'Disease', (97, 106))	('diarrhea', 'Disease', 'MESH:D003967', (290, 298))	('affected', 'Reg', (60, 68))	('hot flashes', 'Phenotype', 'HP:0031217', (142, 153))	('eribulin', 'Chemical', 'MESH:C490954', (41, 49))	('diarrhea', 'Phenotype', 'HP:0002014', (290, 298))	('patients', 'Species', '9606', (25, 33))	('hair loss', 'Phenotype', 'HP:0001596', (181, 190))	('vomiting', 'Disease', 'MESH:D014839', (303, 311))	('hair loss', 'Disease', (181, 190))	('diarrhea and vomiting', 'Phenotype', 'HP:0002017', (290, 311))	('dry mouth', 'Phenotype', 'HP:0000217', (97, 106))	('eribulin', 'Var', (41, 49))	('vomiting', 'Phenotype', 'HP:0002013', (303, 311))	('vomiting', 'Disease', (303, 311))	('hair loss', 'Disease', 'MESH:D000505', (181, 190))
309455	27672333	In the PALETTE study, pazopanib when compared to placebo in refractory sarcoma also demonstrated a PFS but not OS benefit.	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('pazopanib', 'Var', (22, 31))	('OS', 'Chemical', '-', (111, 113))	('sarcoma', 'Disease', (71, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))
309609	23355100	The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('germline', 'Var', (25, 33))	('cancers', 'Disease', (174, 181))	('affects', 'Reg', (70, 77))	('develop', 'PosReg', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('child', 'Species', '9606', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('rare', 'Disease', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
309624	23355100	TP53 is the most frequently mutated gene in human cancer with the prevalence of acquired TP53 mutations highest in epithelial ovarian cancers (47%), colorectal (43%), head/neck (42%), and esophageal cancers (41%) (International Agency for Research on Cancer (IARC) database, R15 release).	('human', 'Species', '9606', (44, 49))	('epithelial ovarian cancers', 'Disease', (115, 141))	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('cancer', 'Disease', (50, 56))	('esophageal cancers', 'Disease', 'MESH:D004938', (188, 206))	('Cancer', 'Disease', (251, 257))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (115, 141))	('cancer', 'Disease', (134, 140))	('Cancer', 'Disease', 'MESH:D009369', (251, 257))	('highest', 'Reg', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('colorectal', 'Disease', (149, 159))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (94, 103))	('head/neck', 'Disease', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('TP53', 'Gene', (89, 93))	('esophageal cancers', 'Disease', (188, 206))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('ovarian cancers', 'Phenotype', 'HP:0100615', (126, 141))	('Cancer', 'Phenotype', 'HP:0002664', (251, 257))	('colorectal', 'Disease', 'MESH:D015179', (149, 159))
309625	23355100	Cancers with acquired TP53 mutations are also associated with diminished survival rates, increased resistance to chemotherapy and radiation, and elevated relapse rates.	('mutations', 'Var', (27, 36))	('survival rates', 'CPA', (73, 87))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('diminished', 'NegReg', (62, 72))	('resistance to chemotherapy', 'CPA', (99, 125))	('relapse rates', 'CPA', (154, 167))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('increased', 'PosReg', (89, 98))	('TP53', 'Gene', (22, 26))
309627	23355100	In 1989, Lavigueur and colleagues accelerated TP53 research when they reported that 20% of transgenic mice carrying a germline mutant TP53 gene developed lung adenocarcinomas, osteosarcomas, and lymphomas.	('TP53', 'Gene', (134, 138))	('osteosarcoma', 'Phenotype', 'HP:0002669', (176, 188))	('osteosarcomas', 'Disease', 'MESH:D012516', (176, 189))	('lymphomas', 'Disease', 'MESH:D008223', (195, 204))	('lymphomas', 'Phenotype', 'HP:0002665', (195, 204))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('germline mutant', 'Var', (118, 133))	('osteosarcomas', 'Disease', (176, 189))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (154, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('transgenic mice', 'Species', '10090', (91, 106))	('osteosarcomas', 'Phenotype', 'HP:0002669', (176, 189))	('lymphomas', 'Disease', (195, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (154, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('lung adenocarcinomas', 'Disease', (154, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (195, 203))	('developed', 'PosReg', (144, 153))
309629	23355100	showed that TP53 pathway alterations could directly cause human cancer.	('alterations', 'Var', (25, 36))	('human', 'Species', '9606', (58, 63))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('TP53 pathway', 'Pathway', (12, 24))	('cause', 'Reg', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
309630	23355100	Using the active metabolite of benzo[a]pyrene (a byproduct of cigarette smoke), Pfeifer's group induced TP53 mutagenesis, causing malignant transformation with unique genetic alterations.	('causing', 'Reg', (122, 129))	('TP53', 'Gene', (104, 108))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (31, 45))	('induced', 'Reg', (96, 103))	('mutagenesis', 'Var', (109, 120))	('malignant transformation', 'CPA', (130, 154))
309632	23355100	During a similar timeframe, Donehower and colleagues showed that TP53 did not appear to impair normal embryogenesis, growth, or development in genetically engineered mice.	('TP53', 'Var', (65, 69))	('growth', 'CPA', (117, 123))	('men', 'Species', '9606', (135, 138))	('mice', 'Species', '10090', (166, 170))	('impair', 'NegReg', (88, 94))	('development', 'CPA', (128, 139))
309633	23355100	Donehower's observations confirmed that germline mutations in the TP53 gene could be present without lethal consequences; making an inherited human disorder a plausible concept.	('TP53', 'Gene', (66, 70))	('inherited human disorder', 'Disease', (132, 156))	('inherited human disorder', 'Disease', 'MESH:D030342', (132, 156))	('germline mutations', 'Var', (40, 58))
309643	23355100	Breast cancer is most predictive of the presence of a germline TP53 mutation when it is diagnosed before age 30-35 in a woman with a family history of a first- or second-degree relative with a core LFS cancer (other than breast cancer).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('mutation', 'Var', (68, 76))	('TP53', 'Gene', (63, 67))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('woman', 'Species', '9606', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('LFS cancer', 'Disease', (198, 208))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('breast cancer', 'Disease', (221, 234))	('LFS cancer', 'Disease', 'MESH:D016864', (198, 208))	('Breast cancer', 'Disease', (0, 13))	('germline', 'Var', (54, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))
309645	23355100	Recent studies have begun to describe the phenotype of breast cancers in TP53 mutation carriers.	('mutation', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (55, 69))	('TP53', 'Gene', (73, 77))	('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))
309647	23355100	found a significantly greater number of Her2Neu positive tumors among TP53 carriers than among non-carriers (p = 0.0001; table 1).	('Her2Neu', 'Gene', '2064', (40, 47))	('Her2Neu', 'Gene', (40, 47))	('TP53', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('greater', 'PosReg', (22, 29))	('carriers', 'Var', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
309651	23355100	compared sarcomas diagnosed in TP53 mutation carriers in the IARC TP53 database (n=236) to sarcoma diagnoses in the Surveillance, Epidemiology, and End Results (SEER) database (n=34,671).	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('TP53', 'Gene', (31, 35))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('sarcoma', 'Disease', (9, 16))	('sarcoma', 'Disease', (91, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcomas', 'Disease', (9, 17))	('mutation', 'Var', (36, 44))
309652	23355100	They found that 67% of sarcomas in TP53 mutation carriers occurred before the age of 20 compared with only 11.9% in the SEER database; in TP53 carriers only 4.4% of sarcomas occurred after age 50, while 62.7% were diagnosed after 50 in the SEER data.	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('mutation', 'Var', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcomas', 'Disease', (165, 173))	('TP53', 'Gene', (35, 39))	('sarcomas', 'Disease', 'MESH:D012509', (23, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('sarcomas', 'Disease', 'MESH:D012509', (165, 173))	('sarcomas', 'Disease', (23, 31))
309653	23355100	The age distribution of sarcomas in TP53 mutation carriers is biphasic, with one peak in childhood and another between ages 20 and 40.	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcomas', 'Disease', (24, 32))	('mutation', 'Var', (41, 49))	('child', 'Species', '9606', (89, 94))	('TP53', 'Gene', (36, 40))
309654	23355100	Brain Tumors occur in 9-16% of individuals with TP53 mutations.	('Brain Tumors', 'Disease', (0, 12))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('Tumors', 'Phenotype', 'HP:0002664', (6, 12))	('Brain Tumors', 'Disease', 'MESH:D001932', (0, 12))	('Brain Tumors', 'Phenotype', 'HP:0030692', (0, 12))
309656	23355100	Despite limited sample sizes, a compelling body of evidence supports the association between choroid plexus tumors, particularly choroid plexus carcinomas (CPC) and TP53 germline mutations.	('TP53', 'Gene', (165, 169))	('choroid plexus tumors', 'Disease', (93, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (93, 114))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (93, 114))	('choroid plexus carcinomas', 'Disease', (129, 154))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (129, 153))	('CPC', 'Phenotype', 'HP:0030392', (156, 159))	('choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (129, 154))	('germline mutations', 'Var', (170, 188))	('choroid plexus carcinomas', 'Disease', 'MESH:D020288', (129, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
309657	23355100	reported that all 8 individuals in their cohort with choroid plexus tumor (type not specified) and no additional personal or family history reported were positive for a germline TP53 mutation.	('positive', 'Reg', (154, 162))	('TP53', 'Gene', (178, 182))	('mutation', 'Var', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('not specified', 'Species', '32644', (80, 93))	('choroid plexus tumor', 'Disease', 'MESH:D016545', (53, 73))	('choroid plexus tumor', 'Disease', (53, 73))
309659	23355100	As with sarcoma, there appears to be a biphasic age distribution of brain tumors in those with TP53 mutations, with highest prevalence rates before age 10 and after 20 years of age.	('mutations', 'Var', (100, 109))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('brain tumors', 'Phenotype', 'HP:0030692', (68, 80))	('brain tumors', 'Disease', 'MESH:D001932', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('sarcoma', 'Disease', (8, 15))	('brain tumors', 'Disease', (68, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('TP53', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
309660	23355100	Adrenocortical Carcinoma (ACC) accounts for 10-14% of cancers in TP53 mutation carriers overall.	('carriers', 'Reg', (79, 87))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('TP53', 'Gene', (65, 69))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('ACC', 'Phenotype', 'HP:0006744', (26, 29))	('Adrenocortical Carcinoma', 'Disease', (0, 24))	('Carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (0, 24))	('mutation', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
309662	23355100	The highest prevalence rates of ACC are reported in carriers of the Brazilian founder mutation, TP53 R337H.	('R337H', 'Mutation', 'rs121912664', (101, 106))	('TP53 R337H', 'Var', (96, 106))	('ACC', 'Phenotype', 'HP:0006744', (32, 35))	('ACC', 'Disease', (32, 35))
309666	23355100	However, more recent studies have found that the R337H mutation can be found in families with a broad spectrum of LFS-associated cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('LFS-associated', 'Disease', (114, 128))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('found', 'Reg', (71, 76))	('R337H', 'Var', (49, 54))	('cancers', 'Disease', (129, 136))	('R337H', 'Mutation', 'rs121912664', (49, 54))
309673	23355100	Mutations in the DNA binding portion of the gene cause highly penetrant disease with very early onset cancers; mutations outside the core DNA binding domain are associated with slower rates of tumor development.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('highly penetrant disease', 'Disease', (55, 79))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('cause', 'Reg', (49, 54))	('tumor', 'Disease', (193, 198))	('men', 'Species', '9606', (206, 209))
309675	23355100	They (and others) have used yeast-based functional assays to show that TP53 mutant alleles with reduced transactivation capability (including dominant negative acting proteins that reduce the transactivation ability of the p53 wild-type protein) are associated with a higher frequency of multiple tumors and are more likely to be found in germline carriers with strong family histories of cancer.	('transactivation', 'MPA', (192, 207))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('transactivation', 'MPA', (104, 119))	('mutant', 'Var', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('yeast', 'Species', '4932', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('TP53', 'Gene', (71, 75))	('multiple tumors', 'Disease', (288, 303))	('multiple tumors', 'Disease', 'MESH:D009369', (288, 303))	('cancer', 'Disease', (389, 395))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('associated with', 'Reg', (250, 265))
309676	23355100	Inherited genetic variations (including single-nucleotide polymorphisms, SNPs) of the TP53 gene have been reported to impair p53 function in vitro and are associated with worse outcomes in specific subgroups of patients with cancer.	('function', 'MPA', (129, 137))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('patients', 'Species', '9606', (211, 219))	('cancer', 'Disease', (225, 231))	('p53', 'Gene', (125, 128))	('genetic variations', 'Disease', (10, 28))	('associated', 'Reg', (155, 165))	('single-nucleotide polymorphisms', 'Var', (40, 71))	('TP53', 'Gene', (86, 90))	('genetic variations', 'Disease', 'MESH:D030342', (10, 28))	('p53', 'Gene', '7157', (125, 128))	('impair', 'NegReg', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))
309678	23355100	Deleterious (disease causing) mutations in TP53 are only found in ~70% of the patients who meet the classic diagnostic criteria for LFS, underscoring the importance of clinical suspicion and astute diagnostic skills when trying to identify affected patients and families.	('patients', 'Species', '9606', (249, 257))	('patients', 'Species', '9606', (78, 86))	('mutations', 'Var', (30, 39))	('LFS', 'Disease', (132, 135))	('TP53', 'Gene', (43, 47))
309681	23355100	During the 3rd International p53 mutant workshop-LFS symposium in 2007, the Chompret criteria were modified to develop a set of Consensus-based criteria to identify TP53 carriers.	('p53', 'Gene', '7157', (29, 32))	('mutant', 'Var', (33, 39))	('TP53', 'Gene', (165, 169))	('p53', 'Gene', (29, 32))
309682	23355100	Breast Cancer < 30 Some, including the NCCN, advocate testing all individuals with breast cancer under age 30 who are negative for BRCA1 and BRCA2 mutations for TP53 mutations.	('mutations', 'Var', (147, 156))	('TP53', 'Gene', (161, 165))	('mutations', 'Var', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('BRCA2', 'Gene', '675', (141, 146))	('Breast Cancer', 'Disease', (0, 13))	('testing', 'Reg', (54, 61))	('BRCA1', 'Gene', '672', (131, 136))	('breast cancer', 'Disease', (83, 96))	('Breast Cancer', 'Disease', 'MESH:D001943', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast Cancer', 'Phenotype', 'HP:0003002', (0, 13))	('BRCA1', 'Gene', (131, 136))	('BRCA2', 'Gene', (141, 146))
309684	23355100	have suggested that a TP53 mutation is actually more likely than a BRCA1 or BRCA2 mutation in women with breast cancer diagnosed under age 30 without contributory family history.	('women', 'Species', '9606', (94, 99))	('BRCA2', 'Gene', (76, 81))	('BRCA2', 'Gene', '675', (76, 81))	('mutation', 'Var', (27, 35))	('BRCA1', 'Gene', '672', (67, 72))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('TP53', 'Gene', (22, 26))	('BRCA1', 'Gene', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
309687	23355100	Based on the published literature, however, it appears that the probability of finding a TP53 mutation is higher in ACC diagnosed <40, especially those diagnosed in childhood.	('child', 'Species', '9606', (165, 170))	('ACC', 'Phenotype', 'HP:0006744', (116, 119))	('TP53', 'Gene', (89, 93))	('mutation', 'Var', (94, 102))
309689	23355100	GI Cancers TP53 mutation analysis should also be considered in cases of early onset gastrointestinal (GI) cancer who meet the classic LFS or LFL criteria if other more common hereditary GI syndromes have been ruled out.	('mutation', 'Var', (16, 24))	('onset gastrointestinal (GI) cancer', 'Disease', 'MESH:D004067', (78, 112))	('GI Cancers', 'Disease', 'MESH:D009369', (0, 10))	('TP53', 'Gene', (11, 15))	('Cancers', 'Phenotype', 'HP:0002664', (3, 10))	('Cancer', 'Phenotype', 'HP:0002664', (3, 9))	('GI Cancers', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
309693	23355100	Using clinical data from a TP53 clinical testing cohort of 525 patients submitted for testing, with 91 mutations identified, prevalence tables summarizing the individual and family characteristics associated with TP53 mutations were created.	('mutations', 'Var', (218, 227))	('patients', 'Species', '9606', (63, 71))	('TP53', 'Gene', (213, 217))
309694	23355100	Gonzalez and colleagues found that the highest germline TP53 mutation frequency rate (100%; n=5) was in patients who had at least one core cancer during childhood (prior to 18 years of age) and a positive family history for cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('child', 'Species', '9606', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutation', 'Var', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (104, 112))	('TP53', 'Gene', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', (139, 145))
309696	23355100	One of the most common and challenging clinical testing dilemmas is determining the most appropriate testing strategy for a woman who has tested negative for BRCA1 and BRCA2 mutations, but who has a family history consistent with a hereditary breast cancer syndrome.	('BRCA2', 'Gene', '675', (168, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('hereditary breast cancer syndrome', 'Disease', (232, 265))	('hereditary breast cancer syndrome', 'Disease', 'MESH:D001943', (232, 265))	('BRCA1', 'Gene', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('BRCA2', 'Gene', (168, 173))	('mutations', 'Var', (174, 183))	('woman', 'Species', '9606', (124, 129))	('BRCA1', 'Gene', '672', (158, 163))
309698	23355100	However, in the absence of very early age of breast cancer diagnosis, most families with breast cancer have an exceedingly low probability of carrying a TP53 mutation.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('mutation', 'Var', (158, 166))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('TP53', 'Gene', (153, 157))	('early age of breast', 'Phenotype', 'HP:0010314', (32, 51))
309703	23355100	Decisions regarding germline TP53 testing should be made by healthcare professionals with specialized training in clinical cancer genetics and experience interpreting complex, and potentially novel, variant gene mutations of uncertain clinical significance.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('variant gene mutations', 'Var', (199, 221))	('TP53', 'Gene', (29, 33))	('cancer', 'Disease', (123, 129))
309705	23355100	After identifying a mutation, the proband's parent with any pertinent cancer history or family history should be tested first to establish the lineage of the mutation; otherwise, both parents should be tested.	('pertinent cancer', 'Disease', (60, 76))	('mutation', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('pertinent cancer', 'Disease', 'MESH:D009369', (60, 76))
309713	23355100	Partners of patients with a high probability of carrying a TP53 germline mutation have been reported to have elevated levels of distress and have expressed a desire for psychosocial support services.	('patients', 'Species', '9606', (12, 20))	('psychosocial', 'Disease', (169, 181))	('TP53', 'Gene', (59, 63))	('germline mutation', 'Var', (64, 81))	('levels of distress', 'MPA', (118, 136))	('psychosocial', 'Disease', 'MESH:C535569', (169, 181))
309729	23355100	The thirty-three asymptomatic germline TP53 mutation carriers studied self-selected to be followed with enhanced surveillance (n=18) or routine institutional follow-up care (n=16; one LFS patient was in both groups).	('mutation', 'Var', (44, 52))	('TP53', 'Gene', (39, 43))	('patient', 'Species', '9606', (188, 195))
309736	23355100	For instance, genomic assessment of copy number variation (CNV) can yield a pattern associated with LFS-associated cancers compared to other cancers and may identify early stage disease in asymptomatic germline TP53 mutation carriers.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('men', 'Species', '9606', (28, 31))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('identify', 'Reg', (157, 165))	('associated', 'Reg', (84, 94))	('TP53', 'Gene', (211, 215))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))	('copy number variation', 'Var', (36, 57))
309745	23355100	In this small series (n=6) of premenopausal women with germline BRCA1 mutations, mammographic density was significantly reduced at 12 months (median absolute decrease, 8.3%; P = 0.043; representing a 29.2% median reduction in mammographic percent density).	('BRCA1', 'Gene', '672', (64, 69))	('men', 'Species', '9606', (33, 36))	('mutations', 'Var', (70, 79))	('mammographic', 'MPA', (81, 93))	('BRCA1', 'Gene', (64, 69))	('women', 'Species', '9606', (44, 49))	('men', 'Species', '9606', (46, 49))	('decrease', 'NegReg', (158, 166))	('reduction', 'NegReg', (213, 222))	('reduced', 'NegReg', (120, 127))
309750	23355100	The proband had another child, a 4-year-old asymptomatic daughter, who was tested and found to carry the same TP53 mutation.	('child', 'Species', '9606', (24, 29))	('mutation', 'Var', (115, 123))	('TP53', 'Gene', (110, 114))
309751	23355100	Given the mutation and her brother's history, she underwent a brain MRI and two tumors were identified: a low grade glioma and a CPC.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('glioma', 'Disease', (116, 122))	('CPC', 'Disease', (129, 132))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutation', 'Var', (10, 18))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('CPC', 'Phenotype', 'HP:0030392', (129, 132))
309755	23355100	As discussed above, testing for TP53 mutations in children has been quite controversial in the past, but is gaining acceptance due to recent data showing a benefit from screening regimens.	('mutations', 'Var', (37, 46))	('men', 'Species', '9606', (183, 186))	('TP53', 'Gene', (32, 36))	('children', 'Species', '9606', (50, 58))
309761	23355100	In a recent study of 64 choroid plexus tumors from children (with and without LFS), more than 90% of CPCs demonstrated TP53 dysfunction, either due to deleterious TP53 germline mutations (~50%) or due to somatic TP53 sequence variants involving TP53 codon 72 or MDM SNP 309.	('MDM', 'Disease', 'MESH:D007645', (262, 265))	('choroid plexus tumors', 'Disease', (24, 45))	('children', 'Species', '9606', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (24, 45))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (24, 45))	('CPCs', 'Phenotype', 'HP:0030392', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('germline mutations', 'Var', (168, 186))	('TP53', 'Gene', (163, 167))	('CPC', 'Phenotype', 'HP:0030392', (101, 104))	('MDM', 'Disease', (262, 265))	('TP53', 'Gene', (119, 123))	('TP53', 'Gene', (212, 216))
309767	23355100	There is early evidence that PARP inhibition may be a therapeutic target that can trigger selective cell death in high-grade brain cancers (including choroid plexus carcinomas).	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('inhibition', 'Var', (34, 44))	('choroid plexus carcinomas', 'Disease', 'MESH:D020288', (150, 175))	('PARP', 'Gene', '142', (29, 33))	('brain cancers', 'Disease', 'MESH:D001932', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('brain cancers', 'Disease', (125, 138))	('choroid plexus carcinomas', 'Disease', (150, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (150, 174))	('choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (150, 175))	('PARP', 'Gene', (29, 33))
309768	23355100	TP53 mutation carriers are 100 times more likely to develop leukemia; however, only three percent of LFS patients develop a hematopoietic malignancy.	('hematopoietic malignancy', 'Disease', (124, 148))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (105, 113))	('hematopoietic malignancy', 'Phenotype', 'HP:0004377', (124, 148))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('develop', 'PosReg', (52, 59))	('hematopoietic malignancy', 'Disease', 'MESH:D019337', (124, 148))	('leukemia', 'Disease', (60, 68))	('mutation', 'Var', (5, 13))	('leukemia', 'Disease', 'MESH:D007938', (60, 68))
309770	23355100	TP53 alterations were the first biological marker to become incorporated in risk stratification and upfront treatment decisions for chronic lymphocytic leukemia (CLL) patients treated on randomized clinical trials.	('CLL', 'Disease', 'MESH:D015451', (162, 165))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (167, 175))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (132, 160))	('CLL', 'Phenotype', 'HP:0005550', (162, 165))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('CLL', 'Disease', (162, 165))	('alterations', 'Var', (5, 16))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (132, 160))	('men', 'Species', '9606', (113, 116))	('chronic lymphocytic leukemia', 'Disease', (132, 160))
309771	23355100	TP53 inactivation in CLL predicts for an ultra high-risk group of patients with fludarabine-resistant disease and median survival times of less than 12 months.	('CLL', 'Disease', (21, 24))	('TP53', 'Gene', (0, 4))	('CLL', 'Disease', 'MESH:D015451', (21, 24))	('CLL', 'Phenotype', 'HP:0005550', (21, 24))	('inactivation', 'Var', (5, 17))	('fludarabine-resistant disease', 'Disease', (80, 109))	('patients', 'Species', '9606', (66, 74))	('fludarabine', 'Chemical', 'MESH:C024352', (80, 91))
309772	23355100	Therefore, the European Research Initiative on CLL, has recommended that TP53 mutation analysis be performed for all CLL patients and that those with TP53 mutations be considered for allogeneic stem cell transplantation in first remission.	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('CLL', 'Phenotype', 'HP:0005550', (117, 120))	('CLL', 'Disease', (117, 120))	('TP53', 'Gene', (73, 77))	('CLL', 'Disease', 'MESH:D015451', (47, 50))	('men', 'Species', '9606', (61, 64))	('CLL', 'Phenotype', 'HP:0005550', (47, 50))	('CLL', 'Disease', 'MESH:D015451', (117, 120))	('CLL', 'Disease', (47, 50))	('patients', 'Species', '9606', (121, 129))
309774	23355100	A number of strategies have been explored to target TP53-associated cancers and improve outcomes for patients with somatic and germline TP53 mutations.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (141, 150))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('TP53-associated', 'Gene', (52, 67))	('TP53', 'Gene', (136, 140))
309776	23355100	Monoclonal antibodies have been shown to improve outcomes in several disease types, including some promising laboratory and early-phase clinical trials showing an apoptotic affect against TP53-associated leukemia.	('leukemia', 'Disease', 'MESH:D007938', (204, 212))	('leukemia', 'Disease', (204, 212))	('leukemia', 'Phenotype', 'HP:0001909', (204, 212))	('Monoclonal antibodies', 'Var', (0, 21))
309782	23355100	Reactivation of wild-type TP53 activity can be a successful strategy and has caused regression of lymphoma and liver cancer in TP53 deficient in vivo model systems.	('lymphoma', 'Disease', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lymphoma', 'Disease', 'MESH:D008223', (98, 106))	('liver cancer', 'Phenotype', 'HP:0002896', (111, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('Reactivation', 'Var', (0, 12))	('liver cancer', 'Disease', 'MESH:D006528', (111, 123))	('liver cancer', 'Disease', (111, 123))
309783	23355100	These small molecules (currently named PhiKan083, PRIMA-1, CP31398, WR1065, MIRA-1, STIMA-1, RETRA, Nutlin -3, and RITA) reactivate TP53 functional pathways using mechanisms such as raising the melting temperature of the mutant protein to trigger reactivation of function, normalizing the folding conformation of the mutant protein to restore its ability to bind to DNA, or reactivating TP53 wild-type function in TP53-associated cancers.	('TP53', 'Gene', (387, 391))	('cancers', 'Phenotype', 'HP:0002664', (430, 437))	('reactivating', 'NegReg', (374, 386))	('cancers', 'Disease', (430, 437))	('reactivation', 'MPA', (247, 259))	('bind', 'Interaction', (358, 362))	('TP53 functional pathways', 'Pathway', (132, 156))	('cancer', 'Phenotype', 'HP:0002664', (430, 436))	('protein', 'Protein', (324, 331))	('PRIMA-1', 'Gene', '145270', (50, 57))	('DNA', 'Interaction', (366, 369))	('wild-type function', 'MPA', (392, 410))	('mutant', 'Var', (317, 323))	('mutant', 'Var', (221, 227))	('cancers', 'Disease', 'MESH:D009369', (430, 437))	('folding conformation', 'MPA', (289, 309))	('restore', 'PosReg', (335, 342))	('PRIMA-1', 'Gene', (50, 57))	('ability', 'MPA', (347, 354))	('normalizing', 'Var', (273, 284))
309791	23355100	Similarly, studies of TP53 deficient mice have shown prolonged overall survival of more than 5 months when treated with Metformin.	('prolonged', 'PosReg', (53, 62))	('Metformin', 'Chemical', 'MESH:D008687', (120, 129))	('deficient', 'Var', (27, 36))	('TP53', 'Gene', (22, 26))	('mice', 'Species', '10090', (37, 41))
309803	22665999	A group of sarcomas are distinguished by specific molecular aberrations such as somatic mutations, intergene deletions, gene amplifications, reciprocal translocations, and complex karyotypes.	('intergene deletions', 'Var', (99, 118))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcomas', 'Disease', (11, 19))	('reciprocal', 'Disease', (141, 151))
309835	22665999	Activating mutations in Ras have been described in 20-25% of all human tumors and much higher in some specific tumor types.	('described', 'Reg', (38, 47))	('Ras', 'Gene', (24, 27))	('human', 'Species', '9606', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Activating mutations', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumor', 'Disease', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
309872	22665999	However, it was the control of HIV replication with highly antiviral antiretroviral therapies (HAART) combinations that resulted in a significant decline in the incidence of KS in AIDS patients.	('KS', 'Phenotype', 'HP:0100726', (174, 176))	('combinations', 'Var', (102, 114))	('decline', 'NegReg', (146, 153))	('patients', 'Species', '9606', (185, 193))	('AIDS', 'Disease', (180, 184))	('AIDS', 'Disease', 'MESH:D000163', (180, 184))
309882	22665999	Mutations of c-KIT resulted in gain of function of the KIT TK and constitutive activation of its molecular downstream pathways, predominantly the PI3K pathway.	('c-KIT', 'Gene', (13, 18))	('PI3K pathway', 'Pathway', (146, 158))	('molecular downstream pathways', 'Pathway', (97, 126))	('c-KIT', 'Gene', '3815', (13, 18))	('Mutations', 'Var', (0, 9))	('TK', 'Gene', '7294', (59, 61))	('gain of function', 'PosReg', (31, 47))	('activation', 'PosReg', (79, 89))
309883	22665999	Approximately 75-85% of GIST patients express activating mutations of KIT of which exon 11 is the most common (57-70%), followed by exon 9 (5-18%) and rarely exon 13 and 17 domains (<2%).	('patients', 'Species', '9606', (29, 37))	('KIT', 'Gene', (70, 73))	('activating', 'PosReg', (46, 56))	('exon 11', 'Var', (83, 90))
309884	22665999	Only 5% of patients exhibit mutations in PDGFR and some patients exhibit neither KIT nor PDGFR (10-15%).	('patients', 'Species', '9606', (56, 64))	('PDGFR', 'Gene', '5159', (41, 46))	('PDGFR', 'Gene', (89, 94))	('PDGFR', 'Gene', '5159', (89, 94))	('patients', 'Species', '9606', (11, 19))	('mutations', 'Var', (28, 37))	('PDGFR', 'Gene', (41, 46))
309886	22665999	Shortly after, a human GIST cell line expressing an active KIT mutation was completely inhibited by imatinib.	('human', 'Species', '9606', (17, 22))	('imatinib', 'Chemical', 'MESH:D000068877', (100, 108))	('inhibited', 'NegReg', (87, 96))	('mutation', 'Var', (63, 71))
309888	22665999	Thus, GIST became the first solid tumor, where therapeutic interference of a mutated TK mutation showed clear benefit.	('mutation', 'Var', (88, 96))	('tumor', 'Disease', (34, 39))	('TK', 'Gene', '7294', (85, 87))	('mutated', 'Var', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
309889	22665999	Most nonresponsive patients and almost all patients with early relapses were shown to carry an exon 9 KIT, PDGFR mutations or a wild type.	('exon 9', 'Var', (95, 101))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (43, 51))	('mutations', 'Var', (113, 122))	('KIT', 'Gene', (102, 105))	('PDGFR', 'Gene', (107, 112))	('PDGFR', 'Gene', '5159', (107, 112))
309890	22665999	Imatinib resistance has been related to survival pathways that circumvent KIT blockade linked to secondary mutations in KIT exons 13, 14, 17, or 18 which typically develop in tumors with primary exon 11 mutations leading to late progression in 50 to 70% of the patients.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('mutations', 'Var', (107, 116))	('develop', 'Reg', (164, 171))	('KIT exons 13', 'Gene', (120, 132))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patients', 'Species', '9606', (261, 269))	('mutations', 'Var', (203, 212))
309898	22665999	At a molecular level, a group of sarcomas are distinguished by specific molecular aberrations including somatic mutations, intergene deletions, gene amplifications, and reciprocal translocations.	('deletions', 'Var', (133, 142))	('sarcomas', 'Disease', 'MESH:D012509', (33, 41))	('gene amplifications', 'Var', (144, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcomas', 'Disease', (33, 41))
309899	22665999	The majority of high-grade sarcomas with complex karyotypes have a high frequency of protein 53 (p53) and retinoblastoma protein (pRb) mutations as well as impairments in DNA repair and severe chromosomal instability, but no specific genetic alterations.	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('retinoblastoma', 'Phenotype', 'HP:0009919', (106, 120))	('protein 53', 'Gene', (85, 95))	('sarcomas', 'Disease', (27, 35))	('DNA repair', 'MPA', (171, 181))	('mutations', 'Var', (135, 144))	('pRb', 'Gene', (130, 133))	('retinoblastoma', 'Disease', (106, 120))	('retinoblastoma', 'Disease', 'MESH:D012175', (106, 120))	('chromosomal instability', 'Phenotype', 'HP:0040012', (193, 216))	('pRb', 'Gene', '5925', (130, 133))	('protein 53', 'Gene', '7157', (85, 95))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))
309902	22665999	The gain-of-function KIT and PDGFR gene mutations in GIST are the most notable examples of this type of genetic abnormality in soft-tissue sarcomas.	('PDGFR', 'Gene', (29, 34))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (127, 147))	('PDGFR', 'Gene', '5159', (29, 34))	('sarcomas', 'Disease', 'MESH:D012509', (139, 147))	('gain-of-function', 'PosReg', (4, 20))	('mutations', 'Var', (40, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('genetic abnormality', 'Disease', (104, 123))	('KIT', 'Gene', (21, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('genetic abnormality', 'Disease', 'MESH:D030342', (104, 123))	('sarcomas', 'Disease', (139, 147))
309905	22665999	Amplifications of genomic regions are not specific for a given sarcoma subtype, but amplification of the murine double minute gene (MDM2) and the cyclin-dependent kinase 4 (CDK4) at chromosome 12q13-15 are highly characteristic in dedifferentiated liposarcomas (LPS).	('LPS', 'Phenotype', 'HP:0012034', (262, 265))	('LPS', 'Disease', (262, 265))	('MDM2', 'Gene', '17246', (132, 136))	('CDK4', 'Gene', (173, 177))	('cyclin-dependent kinase 4', 'Gene', '12567', (146, 171))	('amplification', 'Var', (84, 97))	('sarcoma subtype', 'Disease', 'MESH:D012509', (63, 78))	('LPS', 'Disease', 'MESH:C536528', (262, 265))	('murine', 'Species', '10090', (105, 111))	('cyclin-dependent kinase 4', 'Gene', (146, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('liposarcomas', 'Phenotype', 'HP:0012034', (248, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('liposarcomas', 'Disease', 'MESH:D008080', (248, 260))	('sarcomas', 'Phenotype', 'HP:0100242', (252, 260))	('liposarcomas', 'Disease', (248, 260))	('MDM2', 'Gene', (132, 136))	('sarcoma subtype', 'Disease', (63, 78))
309909	22665999	These translocations defined the ES family of tumors including the peripheral primitive neuroectodermal tumors (PNET) and became a critical diagnostic tool and a window to the pathogenesis of these and other sarcomas.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ES', 'Phenotype', 'HP:0012254', (33, 35))	('tumors', 'Disease', (104, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('PNET', 'Phenotype', 'HP:0030065', (112, 116))	('peripheral primitive neuroectodermal tumors', 'Phenotype', 'HP:0030067', (67, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Disease', (46, 52))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (88, 110))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (78, 110))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('translocations', 'Var', (6, 20))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (88, 110))	('sarcomas', 'Disease', 'MESH:D012509', (208, 216))	('sarcomas', 'Phenotype', 'HP:0100242', (208, 216))	('neuroectodermal tumors', 'Disease', (88, 110))	('sarcomas', 'Disease', (208, 216))
309910	22665999	Several fusion proteins have been described resulting from translocations that involve the EWS family of genes and the ETS family in various types of sarcomas.	('fusion proteins', 'Protein', (8, 23))	('sarcomas', 'Disease', (150, 158))	('ETS', 'Gene', (119, 122))	('EWS', 'Gene', (91, 94))	('EWS', 'Gene', '2130', (91, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))	('resulting from', 'Reg', (44, 58))	('translocations', 'Var', (59, 73))
309911	22665999	ES includes fusion genes between EWS and FLI1 (85%) and ERG (10%) and rare cases involving ETV1, ETV4, FEV, and other ETS genes.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('ETV1', 'Gene', (91, 95))	('FLI1', 'Gene', '2313', (41, 45))	('ETV1', 'Gene', '2115', (91, 95))	('FEV', 'Gene', (103, 106))	('EWS', 'Gene', (33, 36))	('ETV4', 'Gene', (97, 101))	('EWS', 'Gene', '2130', (33, 36))	('ERG', 'Gene', (56, 59))	('fusion genes', 'Var', (12, 24))	('FEV', 'Gene', '54738', (103, 106))	('ETV4', 'Gene', '2118', (97, 101))	('FLI1', 'Gene', (41, 45))
309921	22665999	ASPS is characterized by a non-EWS translocation between the ASPL locus on chromosome 17 and the TFE3 locus on the X chromosome (der(17)t(X; 17)(p11q25)).	('EWS', 'Gene', (31, 34))	('TFE3', 'Gene', (97, 101))	('ASPL', 'Gene', '79058', (61, 65))	('der(17)t(X; 17)(p11q25', 'Var', (129, 151))	('ASPS', 'Gene', '79058', (0, 4))	('TFE3', 'Gene', '7030', (97, 101))	('ASPL', 'Gene', (61, 65))	('ASPS', 'Phenotype', 'HP:0012218', (0, 4))	('ASPS', 'Gene', (0, 4))	('EWS', 'Gene', '2130', (31, 34))
309932	22665999	The carcinogenic potential of abnormal or unregulated PI3K/AKT or RAS/MAPK pathways' signaling is related to their regulatory role in cell cycle progression, cell growth and proliferation, differentiation, and apoptosis.	('abnormal', 'Var', (30, 38))	('differentiation', 'CPA', (189, 204))	('AKT', 'Gene', (59, 62))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('carcinogenic', 'Disease', (4, 16))	('RAS/MAPK pathways', 'Pathway', (66, 83))	('cell growth', 'CPA', (158, 169))	('AKT', 'Gene', '207', (59, 62))	('cell cycle progression', 'CPA', (134, 156))	('apoptosis', 'CPA', (210, 219))
309933	22665999	Activation of PI3K turns on AKT, key molecular "node" acting as a master switch, which triggers multiple downstream signaling pathways (including mTOR activation) promoting proliferation and increased cell survival, antiapoptotic signals and upregulation of cell-cycle proteins (cyclin D1 and CDK4).	('cyclin D1', 'Gene', '595', (279, 288))	('mTOR', 'Gene', '2475', (146, 150))	('upregulation', 'PosReg', (242, 254))	('antiapoptotic signals', 'MPA', (216, 237))	('cyclin D1', 'Gene', (279, 288))	('mTOR', 'Gene', (146, 150))	('AKT', 'Gene', (28, 31))	('PI3K', 'Var', (14, 18))	('cell-cycle', 'CPA', (258, 268))	('promoting', 'PosReg', (163, 172))	('increased', 'PosReg', (191, 200))	('cell survival', 'CPA', (201, 214))	('proliferation', 'CPA', (173, 186))	('CDK4', 'Protein', (293, 297))	('AKT', 'Gene', '207', (28, 31))
309935	22665999	In a mouse model using and an adenovirus with Cre-recombinase and conditional mutations of Kras and p53 over 90% of the animals developed high grade sarcomas, resembling malignant fibrous histiocytoma (MFH).	('Kras', 'Gene', (91, 95))	('Kras', 'Gene', '16653', (91, 95))	('sarcomas', 'Disease', 'MESH:D012509', (149, 157))	('high', 'Disease', (138, 142))	('mutations', 'Var', (78, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('histiocytoma', 'Phenotype', 'HP:0012315', (188, 200))	('developed', 'Reg', (128, 137))	('mouse', 'Species', '10090', (5, 10))	('sarcomas', 'Disease', (149, 157))	('malignant fibrous histiocytoma', 'Disease', (170, 200))	('p53', 'Gene', (100, 103))
309945	22665999	Other mechanisms explaining over activation of mTOR involve the loss of regulatory inhibitory gene activity of the tuberous sclerosis complex (TSC) proteins or PTEN inactivation by methylation of the promoter, gene mutation, or allelic deletions such as those reported in perivascular epithelioid cell tumors (PEComas).	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (115, 133))	('gene mutation', 'Var', (210, 223))	('tuberous sclerosis', 'Disease', (115, 133))	('activation', 'PosReg', (33, 43))	('methylation', 'Var', (181, 192))	('regulatory inhibitory gene activity', 'MPA', (72, 107))	('allelic deletions', 'Var', (228, 245))	('PTEN', 'Gene', (160, 164))	('loss', 'NegReg', (64, 68))	('mTOR', 'Gene', (47, 51))	('PEComas', 'Disease', 'MESH:D054973', (310, 317))	('epithelioid cell tumors', 'Disease', (285, 308))	('inactivation', 'NegReg', (165, 177))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('PTEN', 'Gene', '5728', (160, 164))	('PEComas', 'Disease', (310, 317))	('mTOR', 'Gene', '2475', (47, 51))	('epithelioid cell tumors', 'Disease', 'MESH:D054973', (285, 308))
309946	22665999	Loss of LKB1 protein also leads to hyper activation of mTOR signaling in a manner similar to the loss of PTEN.	('LKB1', 'Gene', '6794', (8, 12))	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (55, 59))	('LKB1', 'Gene', (8, 12))	('PTEN', 'Gene', (105, 109))	('PTEN', 'Gene', '5728', (105, 109))	('hyper', 'PosReg', (35, 40))	('Loss', 'Var', (0, 4))	('man', 'Species', '9606', (75, 78))	('protein', 'Protein', (13, 20))
309949	22665999	VEGF is overexpressed in 25% of tumors, and high VEGF is associated with an increased risk of metastases and poorer prognosis.	('metastases', 'Disease', (94, 104))	('VEGF', 'Gene', (49, 53))	('high', 'Var', (44, 48))	('VEGF', 'Gene', '7422', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('VEGF', 'Gene', '7422', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('VEGF', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
309952	22665999	STS with high VEGF expression are associated with resistance to chemotherapy.	('associated', 'Reg', (34, 44))	('VEGF', 'Gene', '7422', (14, 18))	('resistance to chemotherapy', 'CPA', (50, 76))	('VEGF', 'Gene', (14, 18))	('high', 'Var', (9, 13))
309953	22665999	As with IGF, the VEGF downstream pathway involves PI3K and MAPK indicative of intermingle of cell membrane signals.	('MAPK', 'Gene', (59, 63))	('VEGF', 'Gene', '7422', (17, 21))	('VEGF', 'Gene', (17, 21))	('PI3K', 'Var', (50, 54))
309962	22665999	ALT positive LPS have higher genetic instability and a worse prognosis than non-ALT tumors.	('higher', 'PosReg', (22, 28))	('ALT', 'Var', (0, 3))	('LPS', 'Disease', 'MESH:C536528', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('LPS', 'Phenotype', 'HP:0012034', (13, 16))	('LPS', 'Disease', (13, 16))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('genetic instability', 'MPA', (29, 48))
309965	22665999	These markers are expressed by embryonal RMS and fusion gene-negative alveolar RMS, whereas FOXO1-PAX3/PAX7 positive ARMS are not.	('FOXO1', 'Gene', (92, 97))	('FOXO1', 'Gene', '2308', (92, 97))	('alveolar RMS', 'Disease', 'MESH:D002282', (70, 82))	('alveolar RMS', 'Disease', (70, 82))	('PAX3', 'Gene', '5077', (98, 102))	('PAX3', 'Gene', (98, 102))	('PAX7', 'Gene', (103, 107))	('fusion', 'Var', (49, 55))	('PAX7', 'Gene', '5081', (103, 107))
309986	22665999	These results support the relationship between MET and an epigenetic switch in chondrosarcoma.	('chondrosarcoma', 'Disease', 'MESH:D002813', (79, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('chondrosarcoma', 'Disease', (79, 93))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (79, 93))	('epigenetic switch', 'Var', (58, 75))	('MET', 'Var', (47, 50))
309999	22665999	Monoclonal antibodies against the IGF-1R have been the favored approach to date.	('IGF-1R', 'Gene', '3480', (34, 40))	('Monoclonal', 'Var', (0, 10))	('IGF-1R', 'Gene', (34, 40))
310000	22665999	Phase I and II studies of IGF1R antagonists figitumumab, cixutumumab, AMG479, R1507, and SCH 717454 either alone or in combination with other agents, are currently under clinical investigation for patients with sarcomas.	('SCH', 'Gene', (89, 92))	('patients', 'Species', '9606', (197, 205))	('SCH 717454', 'Chemical', 'MESH:C573312', (89, 99))	('cixutumumab', 'Chemical', 'MESH:C557414', (57, 68))	('IGF1R', 'Gene', (26, 31))	('R1507', 'Var', (78, 83))	('sarcomas', 'Disease', 'MESH:D012509', (211, 219))	('sarcomas', 'Phenotype', 'HP:0100242', (211, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('cixutumumab', 'Gene', (57, 68))	('IGF1R', 'Gene', '3480', (26, 31))	('AMG479', 'Gene', (70, 76))	('sarcomas', 'Disease', (211, 219))	('figitumumab', 'Chemical', 'MESH:C525021', (44, 55))
310002	22665999	In an ES tumor model, combination of ADW742 with imatinib, vincristine, and doxorubicin induced a significant reduction of tumor cell growth, mainly by increasing apoptosis.	('apoptosis', 'CPA', (163, 172))	('ES', 'Phenotype', 'HP:0012254', (6, 8))	('increasing', 'PosReg', (152, 162))	('reduction of tumor', 'Disease', 'MESH:D009369', (110, 128))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('ADW742', 'Var', (37, 43))	('combination', 'Interaction', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('vincristine', 'Chemical', 'MESH:D014750', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('doxorubicin', 'Chemical', 'MESH:D004317', (76, 87))	('reduction of tumor', 'Disease', (110, 128))	('imatinib', 'Chemical', 'MESH:D000068877', (49, 57))
310003	22665999	Similarly, NVP-AEW541 led to cytotoxicity and induced apoptosis in imatinib resistant or wildtype GIST.	('apoptosis', 'CPA', (54, 63))	('cytotoxicity', 'Disease', (29, 41))	('induced', 'Reg', (46, 53))	('NVP-AEW541', 'Var', (11, 21))	('cytotoxicity', 'Disease', 'MESH:D064420', (29, 41))	('imatinib', 'Chemical', 'MESH:D000068877', (67, 75))	('imatinib resistant', 'MPA', (67, 85))
310029	22665999	Other models have suggested that sarcomas associated with PTEN loss or inactivation may be particularly susceptible to the therapeutic effects of mTOR inhibitors.	('mTOR', 'Gene', '2475', (146, 150))	('mTOR', 'Gene', (146, 150))	('PTEN loss', 'Disease', (58, 67))	('sarcomas', 'Disease', 'MESH:D012509', (33, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcomas', 'Disease', (33, 41))	('PTEN loss', 'Disease', 'MESH:D006223', (58, 67))	('inactivation', 'Var', (71, 83))
310030	22665999	Rapalogs have been shown to be less effective or ineffective in the presence of KRas mutations or overexpression of Bcl2, whereas tumors with cyclin D1 expression and "angiogenesis addiction" are more susceptible.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('cyclin D1', 'Gene', (142, 151))	('Bcl2', 'Gene', '596', (116, 120))	('mutations', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('KRas', 'Gene', '3845', (80, 84))	('cyclin D1', 'Gene', '595', (142, 151))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('KRas', 'Gene', (80, 84))	('Bcl2', 'Gene', (116, 120))
310036	22665999	In an ES in vitro model, melatonin has been shown to induce apoptosis and synergism when combined with chemotherapeutic agents.	('ES', 'Phenotype', 'HP:0012254', (6, 8))	('melatonin', 'Var', (25, 34))	('melatonin', 'Chemical', 'MESH:D008550', (25, 34))	('apoptosis', 'CPA', (60, 69))	('synergism', 'CPA', (74, 83))	('induce', 'PosReg', (53, 59))
310041	22665999	But the existence of fairly specific genetic abnormalities, mainly specific translocations and a generation of discernible fusion genes in various sarcomas make research in these tumors an attractive mold for advancing studies of solid tumors.	('genetic abnormalities', 'Disease', 'MESH:D030342', (37, 58))	('translocations', 'Var', (76, 90))	('sarcomas', 'Disease', (147, 155))	('tumors', 'Disease', (179, 185))	('genetic abnormalities', 'Disease', (37, 58))	('solid tumors', 'Disease', (230, 242))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('solid tumors', 'Disease', 'MESH:D009369', (230, 242))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('sarcomas', 'Disease', 'MESH:D012509', (147, 155))	('tumors', 'Disease', (236, 242))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
310073	33637599	PD-1 inhibitors, potentially one of the most studied inhibitors treatments, has shown clinical efficacy in various cancers, such as melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('died', 'Disease', 'MESH:D003643', (48, 52))	('lung cancer', 'Disease', (157, 168))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (146, 168))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (181, 201))	('PD-1', 'Gene', (0, 4))	('NSCLC', 'Disease', (170, 175))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('died', 'Disease', (48, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('inhibitors', 'Var', (5, 15))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('renal cell carcinoma', 'Disease', (181, 201))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))
310082	33637599	In addition to their selective cytotoxic effects on tumor cells, HDAC inhibitors are reported to augment the efficacy checkpoint blockade therapies and regulate the host immune response.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('HDAC', 'Gene', (65, 69))	('HDAC', 'Gene', '9734', (65, 69))	('tumor', 'Disease', (52, 57))	('efficacy checkpoint blockade therapies', 'MPA', (109, 147))	('augment', 'PosReg', (97, 104))	('inhibitors', 'Var', (70, 80))	('host immune response', 'CPA', (165, 185))	('regulate', 'Reg', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
310083	33637599	In the present study, we reported a copy number variation in sarcoma identified in a drug-targeted gene set using whole-exome sequencing (WES) and highlighted a potentially druggable alteration in the HDAC family genes, which has not been reported previously.	('HDAC', 'Gene', (201, 205))	('HDAC', 'Gene', '9734', (201, 205))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('sarcoma', 'Disease', (61, 68))	('copy number variation', 'Var', (36, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
310105	33637599	Mouse-specific antibodies including anti-CD3, anti-CD4, anti-CD8, anti-CD11b, and anti-Ly6G antibodies were purchased from BD Pharmingen.	('CD8', 'Gene', (61, 64))	('CD3', 'Gene', (41, 44))	('Ly6G', 'Gene', '546644', (87, 91))	('CD8', 'Gene', '925', (61, 64))	('CD3', 'Gene', '12501', (41, 44))	('Ly6G', 'Gene', (87, 91))	('Mouse', 'Species', '10090', (0, 5))	('anti-CD4', 'Var', (46, 54))	('anti-CD11b', 'Var', (66, 76))
310113	33637599	An ELISPOT assay was used to detect interferon-gamma (IFN-gamma) produced by CD8+ and CD4+ T cells, as previously described.	('CD8', 'Gene', (77, 80))	('interferon-gamma', 'Gene', '3458', (36, 52))	('CD8', 'Gene', '925', (77, 80))	('interferon-gamma', 'Gene', (36, 52))	('CD4+ T', 'Var', (86, 92))
310143	33637599	CDK4 inhibitors, such as palbociclib, are FDA approved for breast cancer therapies, and MDM2 inhibitors, including nutlin-3, also display exciting prospects.	('MDM2', 'Gene', '4193', (88, 92))	('MDM2', 'Gene', (88, 92))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('palbociclib', 'Chemical', 'MESH:C500026', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('inhibitors', 'Var', (5, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))
310156	33637599	At 48 hours after siRNA transfection, knockdown of HDAC1 resulted in the highest apoptosis rate including early and late apoptosis stages.	('apoptosis rate', 'CPA', (81, 95))	('HDAC1', 'Gene', (51, 56))	('knockdown', 'Var', (38, 47))	('HDAC1', 'Gene', '3065', (51, 56))
310157	33637599	Moreover, knockdown of class I HDAC genes was responsible for the upregulation of PD-L1 in sarcoma cells (figure 2E-F).	('upregulation', 'PosReg', (66, 78))	('PD-L1', 'Gene', (82, 87))	('HDAC', 'Gene', (31, 35))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('HDAC', 'Gene', '9734', (31, 35))	('sarcoma', 'Disease', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('knockdown', 'Var', (10, 19))
310158	33637599	Thus, class I HDAC expression is associated with a poor prognosis, and the inhibiton of class I HDAC expression induces apoptosis and increases PD-L1 expression in sarcoma.	('HDAC', 'Gene', (14, 18))	('HDAC', 'Gene', '9734', (96, 100))	('expression', 'MPA', (150, 160))	('HDAC', 'Gene', '9734', (14, 18))	('increases PD', 'Phenotype', 'HP:0008151', (134, 146))	('apoptosis', 'CPA', (120, 129))	('inhibiton', 'Var', (75, 84))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('PD-L1', 'Protein', (144, 149))	('increases', 'PosReg', (134, 143))	('induces', 'PosReg', (112, 119))	('HDAC', 'Gene', (96, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
310182	33637599	Both CD8+ and CD4+ TILs upregulated PD-1 after HDAC inhibition (figure 3G-3H).	('CD8', 'Gene', (5, 8))	('CD8', 'Gene', '925', (5, 8))	('CD4+', 'Var', (14, 18))	('HDAC', 'Gene', (47, 51))	('upregulated', 'PosReg', (24, 35))	('HDAC', 'Gene', '9734', (47, 51))	('PD-1', 'Gene', (36, 40))
310207	33637599	Then, we performed a q-PCR analysis to detect HDAC1, HDAC2 and HDAC3 amplification in patients #1, #3 and #6, who achieved PR (figure 5E).	('HDAC2', 'Gene', (53, 58))	('HDAC3', 'Gene', (63, 68))	('HDAC2', 'Gene', '3066', (53, 58))	('HDAC1', 'Gene', '3065', (46, 51))	('HDAC1', 'Gene', (46, 51))	('amplification', 'Var', (69, 82))	('HDAC3', 'Gene', '8841', (63, 68))	('patients', 'Species', '9606', (86, 94))
310219	33637599	Moreover, knockdown of STAT1 by transfecting siRNAs into chidamide-treated sarcoma cells decreased the surface protein and mRNA expression of PD-L1 (figure 6F, G).	('surface protein', 'MPA', (103, 118))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('mRNA expression', 'MPA', (123, 138))	('sarcoma', 'Disease', (75, 82))	('STAT1', 'Gene', '6772', (23, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('STAT1', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))	('chidamide', 'Chemical', 'MESH:C547816', (57, 66))	('PD-L1', 'Gene', (142, 147))	('decreased', 'NegReg', (89, 98))
310220	33637599	Interestingly, knockdown of STAT1 in non-treated HT1080 cells did not significantly change the expression of PD-L1.	('knockdown', 'Var', (15, 24))	('STAT1', 'Gene', (28, 33))	('STAT1', 'Gene', '6772', (28, 33))	('PD-L1', 'Gene', (109, 114))	('HT1080', 'CellLine', 'CVCL:0317', (49, 55))	('expression', 'MPA', (95, 105))
310226	33637599	The effects of HDAC inhibitors include increasing the amounts and cytotoxicity of NK and CD8+ T cells and modulating of Foxp3+ infiltration.	('CD8', 'Gene', (89, 92))	('increasing', 'PosReg', (39, 49))	('cytotoxicity of NK', 'Disease', (66, 84))	('modulating', 'Reg', (106, 116))	('cytotoxicity of NK', 'Disease', 'MESH:D064420', (66, 84))	('CD8', 'Gene', '925', (89, 92))	('inhibitors', 'Var', (20, 30))	('HDAC', 'Gene', (15, 19))	('HDAC', 'Gene', '9734', (15, 19))	('Foxp3', 'Gene', '50943', (120, 125))	('Foxp3', 'Gene', (120, 125))
310227	33637599	HDAC inhibitors can increase the presentation of tumor-associated antigens and activity of immune-related pathways, resulting in an enhanced antitumor response of T cells.	('HDAC', 'Gene', (0, 4))	('activity', 'MPA', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('HDAC', 'Gene', '9734', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('inhibitors', 'Var', (5, 15))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (145, 150))	('enhanced', 'PosReg', (132, 140))	('immune-related pathways', 'Pathway', (91, 114))	('presentation', 'MPA', (33, 45))	('increase', 'PosReg', (20, 28))
310234	33637599	Noh et al reported a significant association between high expression of HDAC2 and a poor prognosis of patients with hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (116, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('patients', 'Species', '9606', (102, 110))	('HDAC2', 'Gene', '3066', (72, 77))	('HDAC2', 'Gene', (72, 77))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (116, 140))	('high expression', 'Var', (53, 68))	('hepatocellular carcinoma', 'Disease', (116, 140))
310239	33637599	Treatment with an anti-PD-1 antibody combined with chidamide is associated with significant tumor regression and an improvement in survival time.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('anti-PD-1', 'Var', (18, 27))	('chidamide', 'Chemical', 'MESH:C547816', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('survival time', 'CPA', (131, 144))	('tumor', 'Disease', (92, 97))	('improvement', 'PosReg', (116, 127))
310317	31243628	In univariate analysis, there was a significant association between shorter DFS and tumor size larger than 5 cm (p = 0.0043), positive surgical margin (p = 0.0233), and the neutrophil-to-lymphocyte ratio (NLR) higher than 2.73 (p = 0.0009).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('positive', 'Var', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('DFS', 'MPA', (76, 79))	('shorter', 'NegReg', (68, 75))
310318	31243628	Furthermore, we observed a significant association between shorter OS and tumor size larger than 5 cm (p = 0.0075), positive surgical margin (p = 0.0101), NLR higher than 2.73 (p = 0.0126), the platelet-to-lymphocyte ratio (PLR) higher than 103.89 (p = 0.0147) and the lymphocyte-to-monocyte ratio (LMR) lower than 4.2 (p = 0.0445).	('higher', 'PosReg', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('lymphocyte-to-monocyte ratio', 'CPA', (269, 297))	('platelet-to-lymphocyte ratio', 'MPA', (194, 222))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('NLR', 'Gene', (155, 158))	('higher than', 'Var', (159, 170))	('tumor', 'Disease', (74, 79))	('lower', 'NegReg', (304, 309))
310322	31243628	Compared with malignant melanoma, CCS often involves a t(12;22)(q13;q12) translocation, which leads to a fusion of the activating transcription factor 1 (ATF1) gene located at 12q13 and the Ewing sarcoma breakpoint region 1 (EWSR1) gene at 22q12, producing the EWSR1-ATF1 fusion protein in a large proportion of patients.	('activating transcription factor 1', 'Gene', (119, 152))	('ATF1', 'Gene', '466', (154, 158))	('EWSR1', 'Gene', (261, 266))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (55, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (190, 203))	('EWSR1', 'Gene', (225, 230))	('malignant melanoma', 'Disease', (14, 32))	('ATF1', 'Gene', (267, 271))	('Ewing sarcoma breakpoint region 1', 'Gene', (190, 223))	('fusion', 'Var', (105, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('activating transcription factor 1', 'Gene', '466', (119, 152))	('patients', 'Species', '9606', (312, 320))	('leads to', 'Reg', (94, 102))	('CCS', 'Disease', (34, 37))	('EWSR1', 'Gene', '2130', (261, 266))	('ATF1', 'Gene', '466', (267, 271))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (190, 223))	('ATF1', 'Gene', (154, 158))	('malignant melanoma', 'Phenotype', 'HP:0002861', (14, 32))	('malignant melanoma', 'Disease', 'MESH:D008545', (14, 32))	('CCS', 'Disease', 'MESH:D018227', (34, 37))	('EWSR1', 'Gene', '2130', (225, 230))
310367	31243628	In case of LMR, one previous study that comprised 340 STS patients revealed that low LMR was proven to be significantly associated with decreased cancer-specific survival (CSS) and DFS.	('DFS', 'CPA', (181, 184))	('LMR', 'Gene', (85, 88))	('STS', 'Phenotype', 'HP:0030448', (54, 57))	('low', 'Var', (81, 84))	('decreased cancer', 'Disease', (136, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('STS', 'Disease', (54, 57))	('patients', 'Species', '9606', (58, 66))	('decreased cancer', 'Disease', 'MESH:D009369', (136, 152))	('STS', 'Disease', 'MESH:D012509', (54, 57))
310383	31243628	found that there was a negative correlation between CD3+ TILs number and NLR and a positive correlation between CD5+ TILs and NLR.	('CD5', 'Gene', '921', (112, 115))	('NLR', 'Disease', (73, 76))	('CD5', 'Gene', (112, 115))	('CD3+ TILs', 'Var', (52, 61))	('negative', 'NegReg', (23, 31))
310529	22583810	In the same study, men who received radiation therapy in the form of radioactive implants or isotopes did not have an increased risk of a second primary cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('isotopes', 'Var', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('men', 'Species', '9606', (19, 22))
310595	31568710	Osteosarcoma without prior retinoblastoma related to RB1 low-penetrance germline pathogenic variants: A novel type of RB1-related hereditary predisposition syndrome?	('RB1', 'Gene', '5925', (53, 56))	('RB1', 'Gene', (118, 121))	('Osteosarcoma without prior retinoblastoma', 'Disease', 'MESH:C566714', (0, 41))	('retinoblastoma', 'Phenotype', 'HP:0009919', (27, 41))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('RB1', 'Gene', (53, 56))	('RB1', 'Gene', '5925', (118, 121))	('related', 'Reg', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('variants', 'Var', (92, 100))	('Osteosarcoma without prior retinoblastoma', 'Disease', (0, 41))
310597	31568710	Predisposition to Rb is linked to RB1 germline mutations with high penetrance, but rare RB1 low-penetrance variants are also known.	('RB1', 'Gene', '5925', (34, 37))	('RB1', 'Gene', (88, 91))	('germline mutations', 'Var', (38, 56))	('Rb', 'Phenotype', 'HP:0009919', (18, 20))	('RB1', 'Gene', (34, 37))	('RB1', 'Gene', '5925', (88, 91))
310601	31568710	Unexpectedly, genetic testing identified a low-penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup; p.(Pro26Leufs*50)].	('RB1', 'Gene', (79, 82))	('RB1', 'Gene', '5925', (79, 82))	('c.45_76dup', 'DUPLICATION', 'None', (97, 107))	('c.45_76dup', 'Var', (97, 107))	('p.(Pro26Leufs*50', 'Var', (109, 125))	('p.(Pro26Leufs*50)', 'FRAMESHIFT', 'None', (109, 126))
310606	31568710	Unexpectedly, genetic testing identified a low-penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup, p.(Pro26Leufs*50)].	('RB1', 'Gene', (79, 82))	('RB1', 'Gene', '5925', (79, 82))	('c.45_76dup', 'DUPLICATION', 'None', (97, 107))	('c.45_76dup', 'Var', (97, 107))	('p.(Pro26Leufs*50', 'Var', (109, 125))	('p.(Pro26Leufs*50)', 'FRAMESHIFT', 'None', (109, 126))
310607	31568710	We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a RB1-related hereditary predisposition syndrome linked to RB1 low-penetrance germline mutations and discuss the screening strategy to implement for unaffected carrier relatives in these families.	('osteosarcoma', 'Disease', (42, 54))	('mutations', 'Var', (184, 193))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('linked', 'Reg', (146, 152))	('RB1', 'Gene', (156, 159))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))	('RB1', 'Gene', '5925', (156, 159))	('sarcoma', 'Disease', (30, 37))	('RB1', 'Gene', (99, 102))	('sarcoma', 'Disease', (47, 54))	('RB1', 'Gene', '5925', (99, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
310608	31568710	Retinoblastoma (Rb) is a rare intraocular malignant tumor in children that is due to biallelic inactivation of the tumor suppressor gene, RB1, in the developing retina.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Rb', 'Phenotype', 'HP:0009919', (16, 18))	('RB1', 'Gene', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('intraocular malignant tumor', 'Disease', (30, 57))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (115, 120))	('RB1', 'Gene', '5925', (138, 141))	('children', 'Species', '9606', (61, 69))	('Retinoblastoma', 'Disease', 'MESH:D012175', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('intraocular malignant tumor', 'Disease', 'MESH:D009798', (30, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Retinoblastoma', 'Disease', (0, 14))	('biallelic inactivation', 'Var', (85, 107))
310609	31568710	Hereditary Rb is linked to RB1 germline mutations with an autosomal-dominant mode of inheritance and high penetrance.	('RB1', 'Gene', '5925', (27, 30))	('germline', 'Var', (31, 39))	('Hereditary Rb', 'Disease', (0, 13))	('Rb', 'Phenotype', 'HP:0009919', (11, 13))	('linked', 'Reg', (17, 23))	('RB1', 'Gene', (27, 30))
310617	31568710	These families carry rare RB1 low-penetrance pathogenic variants.	('pathogenic', 'Reg', (45, 55))	('low-penetrance', 'NegReg', (30, 44))	('RB1', 'Gene', (26, 29))	('variants', 'Var', (56, 64))	('RB1', 'Gene', '5925', (26, 29))
310624	31568710	Subsequent cancer gene panel sequencing (including RB1, TP53, CDKN2A, ATM, BRCA2, and MLH1 among others) revealed a germline heterozygous deleterious frameshift variant in exon 1 of RB1 [NM_000321.2: c.45_76dup, p.(Pro26Leufs*50)].	('p.(Pro26Leufs*50)', 'FRAMESHIFT', 'None', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA2', 'Gene', '675', (75, 80))	('MLH1', 'Gene', (86, 90))	('RB1', 'Gene', '5925', (182, 185))	('c.45_76dup', 'DUPLICATION', 'None', (200, 210))	('TP53', 'Gene', '7157', (56, 60))	('ATM', 'Gene', '472', (70, 73))	('CDKN2A', 'Gene', '1029', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('MLH1', 'Gene', '4292', (86, 90))	('RB1', 'Gene', (51, 54))	('c.45_76dup', 'Var', (200, 210))	('p.(Pro26Leufs*50', 'Var', (212, 228))	('CDKN2A', 'Gene', (62, 68))	('frameshift', 'Var', (150, 160))	('ATM', 'Gene', (70, 73))	('BRCA2', 'Gene', (75, 80))	('RB1', 'Gene', '5925', (51, 54))	('TP53', 'Gene', (56, 60))	('cancer', 'Disease', (11, 17))	('RB1', 'Gene', (182, 185))
310625	31568710	The proband (IV.1) carried the RB1 mutation identified.	('RB1', 'Gene', '5925', (31, 34))	('RB1', 'Gene', (31, 34))	('mutation', 'Var', (35, 43))
310636	31568710	Of note, the absence of pathogenic variants in known or suspected sarcoma genes included in the panel testing strengthened RB1 involvement in this family (Ballinger et al., 2016; Chan et al., 2017; Jouenne et al., 2017; Tlemsani, Leroy, et al., 2018; Tlemsani, Pasmant, et al., 2018).	('sarcoma', 'Disease', (66, 73))	('RB1', 'Gene', '5925', (123, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('variants', 'Var', (35, 43))	('strengthened', 'PosReg', (110, 122))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('RB1', 'Gene', (123, 126))
310637	31568710	On the other hand, we could not rule out that the osteosarcoma developed in the proband's uncle might have occurred independently of the germline RB1 mutation (Taylor et al., 2007 ).	('RB1', 'Gene', (146, 149))	('mutation', 'Var', (150, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('osteosarcoma', 'Disease', (50, 62))	('RB1', 'Gene', '5925', (146, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('osteosarcoma', 'Disease', 'MESH:D012516', (50, 62))
310638	31568710	A literature review retrieved four cases of primary malignancy without prior Rb (sarcoma and nonsarcoma cancers but no osteosarcoma) in families with RB1 low-penetrance hereditary mutations.	('Rb', 'Phenotype', 'HP:0009919', (77, 79))	('nonsarcoma cancers', 'Disease', (93, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('nonsarcoma cancers', 'Disease', 'MESH:D009369', (93, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('RB1', 'Gene', '5925', (150, 153))	('sarcoma', 'Disease', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('mutations', 'Var', (180, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('malignancy', 'Disease', (52, 62))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('osteosarcoma', 'Disease', (119, 131))	('sarcoma', 'Disease', (96, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (119, 131))	('RB1', 'Gene', (150, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
310639	31568710	Sarcoma was diagnosed in a female carrier of a pathogenic RB1 splice variant (c.2520+6T>C) at age 64 (Dommering et al., 2014), leiomyosarcoma in a male carrier of the missense variant p.(Arg661Trp) at age 44 (Dommering et al., 2014); melanoma with no personal history of Rb in a male carrier of a deletion of exon 4 of RB1 (Dryja, Rapaport, McGee, Nork, & Schwartz, 1993); and leiomyosarcoma in a 69-year-old female carrying a missense p.(His483Tyr) variant, showing sebaceous cell carcinoma of the eyelid 3 years later (Serrano et al., 2011).	('p.(His483Tyr', 'Var', (436, 448))	('Sarcoma', 'Disease', (0, 7))	('leiomyosarcoma', 'Disease', (127, 141))	('carcinoma of the eyelid', 'Disease', (482, 505))	('p.(Arg661Trp)', 'Mutation', 'rs137853294', (184, 197))	('c.2520+6T>C', 'Mutation', 'c.2520+6T>C', (78, 89))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (377, 391))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sebaceous cell carcinoma', 'Phenotype', 'HP:0030410', (467, 491))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (377, 391))	('deletion of', 'Var', (297, 308))	('RB1', 'Gene', (58, 61))	('p.(His483Tyr)', 'SUBSTITUTION', 'None', (436, 449))	('carcinoma of the eyelid', 'Disease', 'MESH:D005142', (482, 505))	('carcinoma', 'Phenotype', 'HP:0030731', (482, 491))	('Rb', 'Phenotype', 'HP:0009919', (271, 273))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (127, 141))	('leiomyosarcoma', 'Disease', (377, 391))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('RB1', 'Gene', (319, 322))	('melanoma', 'Disease', (234, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (384, 391))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (127, 141))	('RB1', 'Gene', '5925', (58, 61))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('RB1', 'Gene', '5925', (319, 322))
310640	31568710	A retrospective collection of similar unpublished data was initiated within the Institut Curie and a French network for Rb: four additional families with RB1 mutations and at least one mutation carrier with sarcoma without prior Rb were found (pedigrees depicted in Figure S1).	('Rb', 'Phenotype', 'HP:0009919', (120, 122))	('sarcoma', 'Disease', 'MESH:D012509', (207, 214))	('Rb', 'Phenotype', 'HP:0009919', (229, 231))	('sarcoma', 'Disease', (207, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('RB1', 'Gene', (154, 157))	('mutations', 'Var', (158, 167))	('RB1', 'Gene', '5925', (154, 157))
310641	31568710	In family A, osteosarcoma as a first primary malignancy was diagnosed at age 65 in the father of the proband [c.55del, p.(Glu19Asnfs*48)] and bilateral Rb was diagnosed at age 2 in the proband.	('p.(Glu19Asnfs*48)]', 'Var', (119, 137))	('p.(Glu19Asnfs*48)', 'Mutation', 'p.E19NfsX48', (119, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (13, 25))	('malignancy', 'Disease', 'MESH:D009369', (45, 55))	('osteosarcoma', 'Disease', 'MESH:D012516', (13, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('[c.55del', 'Var', (109, 117))	('malignancy', 'Disease', (45, 55))	('c.55del', 'Mutation', 'c.55del', (110, 117))	('Rb', 'Phenotype', 'HP:0009919', (152, 154))	('osteosarcoma', 'Disease', (13, 25))
310642	31568710	In family B, the proband (S1B: IV.4) had been diagnosed with unilateral Rb at age 18 months, and a germline RB1 mutation [c.1981C>T; p.(Arg661Trp)] was detected.	('RB1', 'Gene', (108, 111))	('[c.1981C>T; p.', 'Var', (121, 135))	('RB1', 'Gene', '5925', (108, 111))	('Rb', 'Phenotype', 'HP:0009919', (72, 74))	('c.1981C>T', 'Mutation', 'rs137853294', (122, 131))	('p.(Arg661Trp)', 'Mutation', 'rs137853294', (133, 146))
310651	31568710	Hence, we questioned if the parent of origin effect demonstrating a higher Rb risk with paternally inherited low-penetrance alleles holds true with sarcoma risk (Eloy et al., 2016).	('Rb', 'Phenotype', 'HP:0009919', (75, 77))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('sarcoma', 'Disease', (148, 155))	('low-penetrance alleles', 'Var', (109, 131))	('higher', 'PosReg', (68, 74))	('alleles', 'Var', (124, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))
310652	31568710	A paternal inheritance was observed (3 out of 3 cases) in families with p.Arg661Trp carriers affected by first primary sarcoma or melanoma without prior Rb (Dommering et al., 2014, family S1B, family S1D) but the number of families is too small to draw any conclusion.	('p.Arg661Trp', 'Var', (72, 83))	('p.Arg661Trp', 'Mutation', 'rs137853294', (72, 83))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', (119, 126))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('melanoma', 'Disease', (130, 138))	('Rb', 'Phenotype', 'HP:0009919', (153, 155))
310655	31568710	This type of model could agree with an apparently permissive state for tumorigenesis of retinal or bone or soft-tissue cells induced by RB1 low-penetrance mutations.	('RB1', 'Gene', '5925', (136, 139))	('mutations', 'Var', (155, 164))	('low-penetrance', 'NegReg', (140, 154))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('RB1', 'Gene', (136, 139))	('tumor', 'Disease', (71, 76))
310664	31568710	Indeed, patients carrying germline mutations in TP53 are at high risk of a wide range of malignancies, including sarcoma.	('TP53', 'Gene', '7157', (48, 52))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('TP53', 'Gene', (48, 52))	('germline mutations', 'Var', (26, 44))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', (113, 120))	('malignancies', 'Disease', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('patients', 'Species', '9606', (8, 16))
310669	31568710	Further prospective assessment of this type of screening by imaging over a longer period of time, with a larger cohort, and including a number of RB1 carriers who are not Rb survivors is needed to address the challenge of optimizing long-term non-Rb follow-up of such carriers.	('RB1', 'Gene', (146, 149))	('Rb', 'Phenotype', 'HP:0009919', (171, 173))	('Rb', 'Phenotype', 'HP:0009919', (247, 249))	('carriers', 'Var', (150, 158))	('RB1', 'Gene', '5925', (146, 149))
310671	31568710	The data we report advocate for considering germline sequencing of RB1 in patients with unexplained sarcoma, especially germline TP53-negative osteosarcoma, regardless of the personal or family history of Rb.	('sarcoma', 'Disease', (100, 107))	('Rb', 'Phenotype', 'HP:0009919', (205, 207))	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('osteosarcoma', 'Disease', (143, 155))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('osteosarcoma', 'Disease', 'MESH:D012516', (143, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcoma', 'Disease', (148, 155))	('patients', 'Species', '9606', (74, 82))	('germline sequencing', 'Var', (44, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('RB1', 'Gene', (67, 70))	('TP53', 'Gene', '7157', (129, 133))	('RB1', 'Gene', '5925', (67, 70))	('TP53', 'Gene', (129, 133))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))
310672	31568710	To conclude, the patients and pedigrees we report shed light on an unusual pattern of expressivity and low-penetrance germline variants in RB1 and raise the question of expanding the tumor spectrum of RB1-related HPS with first primary sarcoma and osteosarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (253, 260))	('sarcoma', 'Disease', 'MESH:D012509', (236, 243))	('osteosarcoma', 'Phenotype', 'HP:0002669', (248, 260))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('sarcoma', 'Disease', (236, 243))	('sarcoma', 'Disease', (253, 260))	('HPS', 'Disease', (213, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('variants', 'Var', (127, 135))	('RB1', 'Gene', (201, 204))	('osteosarcoma', 'Disease', (248, 260))	('osteosarcoma', 'Disease', 'MESH:D012516', (248, 260))	('RB1', 'Gene', (139, 142))	('tumor', 'Disease', (183, 188))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('HPS', 'Disease', 'None', (213, 216))	('RB1', 'Gene', '5925', (201, 204))	('RB1', 'Gene', '5925', (139, 142))
310675	31568710	It also prompts a watchful medical, especially genetic, management of apparently unaffected carriers of RB1 low-penetrance germline mutation.	('RB1', 'Gene', (104, 107))	('low-penetrance', 'Var', (108, 122))	('RB1', 'Gene', '5925', (104, 107))
310677	22729151	The pathogenesis of KSHV-MCD is attributed to proliferation of KSHV-infected B cells, production of KSHV-encoded viral interleukin 6 by these cells, and dysregulation of human interleukin 6 and interleukin 10.	('KSHV-MCD', 'Disease', 'MESH:D012514', (20, 28))	('dysregulation', 'Var', (153, 166))	('KSHV', 'Species', '37296', (20, 24))	('KSHV-infected', 'Disease', (63, 76))	('interleukin 10', 'Gene', '3586', (194, 208))	('KSHV', 'Species', '37296', (63, 67))	('KSHV', 'Species', '37296', (100, 104))	('human', 'Species', '9606', (170, 175))	('human', 'Protein', (170, 175))	('interleukin 10', 'Gene', (194, 208))	('KSHV-MCD', 'Disease', (20, 28))	('KSHV-infected', 'Disease', 'MESH:C537372', (63, 76))
310761	22729151	Additionally, rituximab is associated with worsening Kaposi sarcoma in 35-67% of patients.	('rituximab', 'Var', (14, 23))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (53, 67))	('Kaposi sarcoma', 'Disease', (53, 67))	('patients', 'Species', '9606', (81, 89))	('rituximab', 'Chemical', 'MESH:D000069283', (14, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (53, 67))
310803	22729151	Targeted therapy, combined with HAART, has led to substantial improvements in patient survival.	('improvements', 'PosReg', (62, 74))	('Targeted', 'Var', (0, 8))	('patient survival', 'CPA', (78, 94))	('patient', 'Species', '9606', (78, 85))
310824	25676695	It has long been clear that mutations play a critical role in the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (28, 37))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
310826	25676695	On the other hand, some perhaps more obscure tumors, especially ones affecting younger patients and specific sites, reveal simpler genomic landscapes with characteristic mutations that allow a more focused look at the oncogenic processes.	('obscure tumors', 'Disease', 'MESH:D009369', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutations', 'Var', (170, 179))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('obscure tumors', 'Disease', (37, 51))	('patients', 'Species', '9606', (87, 95))
310844	25676695	Below, we will discuss the cases of the FOXL2 mutation in adult-type granulosa cell tumors (GCTs) as well as the WTR1-CAMTA1 fusion in epithelioid hemangioendotheliomas (EHEs).	('FOXL2', 'Gene', '668', (40, 45))	('CAMTA1', 'Gene', '23261', (118, 124))	('granulosa cell tumors', 'Disease', 'MESH:D006106', (69, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('epithelioid hemangioendotheliomas', 'Phenotype', 'HP:0032060', (135, 168))	('EHEs', 'Phenotype', 'HP:0032060', (170, 174))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (135, 167))	('FOXL2', 'Gene', (40, 45))	('epithelioid hemangioendotheliomas', 'Disease', 'MESH:D018323', (135, 168))	('epithelioid hemangioendotheliomas', 'Disease', (135, 168))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mutation', 'Var', (46, 54))	('granulosa cell tumors', 'Disease', (69, 90))	('CAMTA1', 'Gene', (118, 124))
310852	25676695	The only potential mutation found in all four cases was a C134W mutation in FOXL2.	('FOXL2', 'Gene', '668', (76, 81))	('C134W', 'Var', (58, 63))	('C134W', 'SUBSTITUTION', 'None', (58, 63))	('FOXL2', 'Gene', (76, 81))
310853	25676695	In a validation cohort of an additional 95 sex-cord stromal ovarian tumors, specificity and sensitivity of the C134W mutation in adult-type GCTs was established.	('sex-cord stromal ovarian tumors', 'Disease', 'MESH:D018312', (43, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('C134W', 'SUBSTITUTION', 'None', (111, 116))	('ovarian tumor', 'Phenotype', 'HP:0100615', (60, 73))	('C134W', 'Var', (111, 116))	('ovarian tumors', 'Phenotype', 'HP:0100615', (60, 74))	('sex-cord stromal ovarian tumors', 'Disease', (43, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
310856	25676695	The diagnostic implications of the C134W mutant FOXL2 have already become apparent, and some studies have since looked at potential mechanistic pathways.	('FOXL2', 'Gene', (48, 53))	('C134W', 'Var', (35, 40))	('FOXL2', 'Gene', '668', (48, 53))	('C134W', 'SUBSTITUTION', 'None', (35, 40))
310857	25676695	It has been suggested that the hotspot FOXL2 mutation might have very particular effect in a specific context: the mutant FOXL2 reduces the expression of gonadotropin-releasing hormone (GnRH) receptor and limits the GnRH-induced apoptosis seen in normal human granulosa cells.	('GnRH', 'Gene', (216, 220))	('gonadotropin-releasing hormone (GnRH) receptor', 'Gene', '2798', (154, 200))	('expression', 'MPA', (140, 150))	('human', 'Species', '9606', (254, 259))	('FOXL2', 'Gene', '668', (122, 127))	('FOXL2', 'Gene', (39, 44))	('mutant', 'Var', (115, 121))	('GnRH', 'Gene', '2796', (216, 220))	('reduces', 'NegReg', (128, 135))	('limits', 'NegReg', (205, 211))	('mutation', 'Var', (45, 53))	('FOXL2', 'Gene', (122, 127))	('GnRH', 'Gene', (186, 190))	('GnRH', 'Gene', '2796', (186, 190))	('FOXL2', 'Gene', '668', (39, 44))
310858	25676695	Furthermore, the mutant FOXL2 has also been suggested to be less stable because of increased phosphorylation via GSK3beta and MDM2-mediated ubiquitination and proteasome degradation.	('increased', 'PosReg', (83, 92))	('proteasome degradation', 'MPA', (159, 181))	('FOXL2', 'Gene', '668', (24, 29))	('mutant', 'Var', (17, 23))	('MDM2-mediated ubiquitination', 'Disease', (126, 154))	('GSK3beta', 'Gene', (113, 121))	('GSK3beta', 'Gene', '2932', (113, 121))	('MDM2-mediated ubiquitination', 'Disease', 'MESH:C567355', (126, 154))	('phosphorylation', 'MPA', (93, 108))	('FOXL2', 'Gene', (24, 29))
310859	25676695	Hence, inhibition of GSK3beta has already been identified as a therapeutic target that stabilizes mutant FOXL2 and this stabilization may in turn lead to increased apoptosis.	('FOXL2', 'Gene', '668', (105, 110))	('GSK3beta', 'Gene', '2932', (21, 29))	('FOXL2', 'Gene', (105, 110))	('apoptosis', 'CPA', (164, 173))	('GSK3beta', 'Gene', (21, 29))	('lead to', 'Reg', (146, 153))	('increased', 'PosReg', (154, 163))	('mutant', 'Var', (98, 104))
310860	25676695	Another example of a disease-defining mutation came with EHE, a rare tumor that can present diagnostic challenges.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('disease-defining', 'Reg', (21, 37))	('mutation', 'Var', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('EHE', 'Disease', (57, 60))
310863	25676695	In a validation cohort of 47 cases, they showed that rearrangements of the involved genes happened 87-89 % of the time whereas none of 118 cases of other vascular tumors showed these rearrangements.	('vascular tumors', 'Phenotype', 'HP:0100742', (154, 169))	('vascular tumors', 'Disease', 'MESH:D019043', (154, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('vascular tumors', 'Disease', (154, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('rearrangements', 'Var', (53, 67))
310872	25676695	Endometrial stromal sarcoma (ESS) is a malignancy of the uterus that had been previously linked with recurrent fusions: the fusion of JAZF1, a transcriptional repressor, with members of the polycomb complex including SUZ12, PHF1, and EPC1.	('SUZ12', 'Gene', '23512', (217, 222))	('Endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (0, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('EPC1', 'Gene', (234, 238))	('SUZ12', 'Gene', (217, 222))	('PHF1', 'Gene', (224, 228))	('JAZF1', 'Gene', (134, 139))	('PHF1', 'Gene', '5252', (224, 228))	('EPC1', 'Gene', '80314', (234, 238))	('malignancy', 'Disease', 'MESH:D009369', (39, 49))	('Endometrial stromal sarcoma', 'Disease', (0, 27))	('fusion', 'Var', (124, 130))	('malignancy', 'Disease', (39, 49))	('JAZF1', 'Gene', '221895', (134, 139))
310886	25676695	The ectopic expression of CCNB3 as a result of the fusion event could be the driver of oncogenesis in this novel sarcoma.	('ectopic expression', 'MPA', (4, 22))	('CCNB3', 'Gene', '85417', (26, 31))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', (113, 120))	('fusion', 'Var', (51, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('CCNB3', 'Gene', (26, 31))
310888	25676695	Another recent study established that ameloblastomas, rare benign tumors of the jaw thought to originate from ameloblasts, have distinct recurrent mutations depending on whether they arise in the maxilla versus the mandible.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (147, 156))	('ameloblastomas', 'Disease', 'MESH:D000564', (38, 52))	('benign tumors of the jaw', 'Disease', 'MESH:D002636', (59, 83))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('benign tumors of the jaw', 'Disease', (59, 83))	('ameloblastomas', 'Disease', (38, 52))
310889	25676695	The maxillary ameloblastomas harbor a SMO hotspot mutation, and the mandibular tumors have BRAF hotspot mutations.	('SMO', 'Gene', '6608', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('maxillary ameloblastomas', 'Disease', (4, 28))	('BRAF', 'Gene', '673', (91, 95))	('SMO', 'Gene', (38, 41))	('maxillary ameloblastomas', 'Disease', 'MESH:D000564', (4, 28))	('BRAF', 'Gene', (91, 95))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mutation', 'Var', (50, 58))
310891	25676695	As mutant BRAF, commonly seen in melanomas, can be targeted with new therapies, this finding also has immediate therapeutic implications.	('mutant', 'Var', (3, 9))	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('melanomas', 'Disease', (33, 42))
310892	25676695	Associations of tumor location and defining mutations have also been identified, for instance, in mengiomas: those that arise in the lateral and posterior regions bear NF2 mutation whereas those in the anterior and medial regions do not.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('mengiomas', 'Disease', (98, 107))	('NF2', 'Gene', '4771', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutation', 'Var', (172, 180))	('mengiomas', 'Disease', 'None', (98, 107))	('tumor', 'Disease', (16, 21))	('NF2', 'Gene', (168, 171))
310896	25676695	With whole transcriptome sequencing/exome sequencing, recurrent mutations in ARID1A, a member of the already established SWI/SNF chromatin remodeling complex were found.	('ARID1A', 'Gene', '8289', (77, 83))	('ARID1A', 'Gene', (77, 83))	('mutations', 'Var', (64, 73))
310897	25676695	The mutations were spread across the ARID1A gene and led to its inactivation, thus suggesting that this gene may function as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('inactivation', 'MPA', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('ARID1A', 'Gene', '8289', (37, 43))	('mutations', 'Var', (4, 13))	('ARID1A', 'Gene', (37, 43))
310900	25676695	Additionally, Wiegand and colleagues also showed that the mutation was present in precursor atypical endometriotic lesions of the tumor, and thus was likely an early driver of ovarian clear-cell carcinoma.	('ovarian clear-cell carcinoma', 'Disease', (176, 204))	('mutation', 'Var', (58, 66))	('endometriotic lesions of the tumor', 'Disease', (101, 135))	('endometriotic lesions of the tumor', 'Disease', 'MESH:D051437', (101, 135))	('ovarian clear-cell carcinoma', 'Disease', 'MESH:D008649', (176, 204))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))
310901	25676695	ARID1A mutations were later found in a variety of other more common types of cancer including gastric adenocarcinomas and colorectal cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('colorectal cancers', 'Disease', (122, 140))	('ARID1A', 'Gene', '8289', (0, 6))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancer', 'Disease', (133, 139))	('ARID1A', 'Gene', (0, 6))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (94, 117))	('found', 'Reg', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gastric adenocarcinomas', 'Disease', (94, 117))	('colorectal cancers', 'Disease', 'MESH:D015179', (122, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutations', 'Var', (7, 16))
310904	25676695	Although mutations in SMARCA4 have been described in more common cancers such as lung adenocarcinomas, they occur in a fraction of cases and are not the obvious drivers of oncogenesis.	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (81, 101))	('lung adenocarcinomas', 'Disease', (81, 101))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('described', 'Reg', (40, 49))	('cancers', 'Disease', (65, 72))	('SMARCA4', 'Gene', (22, 29))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (81, 101))	('SMARCA4', 'Gene', '6597', (22, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
310905	25676695	The studies in SCCOHT with loss of SMARCA4 in almost all cases emphasized the driver role of SMARCA4 loss.	('loss', 'Var', (27, 31))	('SMARCA4', 'Gene', (35, 42))	('SMARCA4', 'Gene', '6597', (35, 42))	('SMARCA4', 'Gene', (93, 100))	('SMARCA4', 'Gene', '6597', (93, 100))
310906	25676695	Another example of a critical driver role of SWI/SNF mutations came through the NGS study of familial multiple spinal meningiomas.	('SWI/SNF', 'Gene', (45, 52))	('familial multiple spinal meningiomas', 'Disease', (93, 129))	('spinal meningiomas', 'Phenotype', 'HP:0100010', (111, 129))	('mutations', 'Var', (53, 62))	('meningiomas', 'Phenotype', 'HP:0002858', (118, 129))	('familial multiple spinal meningiomas', 'Disease', 'MESH:D008577', (93, 129))
310907	25676695	In familial cases, which tested negative for previously described NF2 or SMARCB1 mutations, germline SMARCE1 mutations were identified through exome sequencing.	('NF2', 'Gene', (66, 69))	('SMARCE1', 'Gene', '6605', (101, 108))	('SMARCB1', 'Gene', (73, 80))	('familial', 'Disease', (3, 11))	('NF2', 'Gene', '4771', (66, 69))	('mutations', 'Var', (81, 90))	('SMARCE1', 'Gene', (101, 108))	('SMARCB1', 'Gene', '6598', (73, 80))
310908	25676695	Again, the protein was lost in the tumor samples but not in normal tissue, thus suggesting a classic Kundson biallelic inactivation and a tumor suppressor role of SMARCE1.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (138, 143))	('biallelic', 'Var', (109, 118))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('SMARCE1', 'Gene', (163, 170))	('SMARCE1', 'Gene', '6605', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
310909	25676695	It should be noted that the reason for disease specificity of SWI/SNF member mutations and indeed the steps in tumorigenesis associated with their loss are not clear.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('SWI/SNF member', 'Gene', (62, 76))	('tumor', 'Disease', (111, 116))	('mutations', 'Var', (77, 86))
310912	25676695	Thus, much is still to be clarified in this area; however, since the establishment of the association of the SWI/SNF complex with cancer in rather rare entities, we know today that about 20 % of all cancers have mutations in this complex.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('mutations', 'Var', (212, 221))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancers', 'Disease', (199, 206))
310914	25676695	Germline mutations in DICER1 were identified in the rare familial pleuropulmonary blastoma-family tumor and dysplasia syndrome.	('Germline mutations', 'Var', (0, 18))	('familial pleuropulmonary blastoma-family tumor', 'Disease', (57, 103))	('familial pleuropulmonary blastoma-family tumor', 'Disease', 'MESH:C537516', (57, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('DICER1', 'Gene', (22, 28))	('DICER1', 'Gene', '23405', (22, 28))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (66, 90))	('identified', 'Reg', (34, 44))	('dysplasia syndrome', 'Disease', 'MESH:D005348', (108, 126))	('dysplasia syndrome', 'Disease', (108, 126))
310915	25676695	However, the first evidence for somatic oncogenic mutations of DICER1 came from the study of nonepithelial ovarian tumors.	('ovarian tumors', 'Disease', (107, 121))	('ovarian tumors', 'Phenotype', 'HP:0100615', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('DICER1', 'Gene', (63, 69))	('mutations', 'Var', (50, 59))	('DICER1', 'Gene', '23405', (63, 69))	('ovarian tumors', 'Disease', 'MESH:D010051', (107, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian tumor', 'Phenotype', 'HP:0100615', (107, 120))
310916	25676695	Recurrent somatic hotspot mutations in DICER1 were identified across nonepithelial ovarian tumor types and were most predominantly seen in Sertoli-Leydig cell tumors.	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (139, 165))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('seen', 'Reg', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('DICER1', 'Gene', (39, 45))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ovarian tumor', 'Disease', (83, 96))	('ovarian tumor', 'Phenotype', 'HP:0100615', (83, 96))	('Sertoli-Leydig cell tumors', 'Disease', (139, 165))	('DICER1', 'Gene', '23405', (39, 45))	('hotspot', 'PosReg', (18, 25))	('ovarian tumor', 'Disease', 'MESH:D010051', (83, 96))
310917	25676695	Although low expression of DICER1 has been previously associated with worse prognosis in breast cancer and ovarian tumors, the study of these nonepithelial ovarian tumors changed the paradigm as for the first time it was found that a hotspot genetic aberration in DICER1 can drive cancer through the combination of loss of one allele and a functionally deficient protein, this is an aberration of the classic two-hit hypothesis.	('ovarian tumors', 'Disease', (107, 121))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('ovarian tumors', 'Disease', (156, 170))	('breast cancer', 'Disease', (89, 102))	('ovarian tumors', 'Disease', 'MESH:D010051', (107, 121))	('ovarian tumors', 'Disease', 'MESH:D010051', (156, 170))	('loss', 'NegReg', (315, 319))	('cancer', 'Disease', (96, 102))	('low', 'NegReg', (9, 12))	('ovarian tumor', 'Phenotype', 'HP:0100615', (156, 169))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('DICER1', 'Gene', '23405', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian tumor', 'Phenotype', 'HP:0100615', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('protein', 'Protein', (363, 370))	('DICER1', 'Gene', (27, 33))	('ovarian tumors', 'Phenotype', 'HP:0100615', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('genetic aberration', 'Var', (242, 260))	('DICER1', 'Gene', '23405', (264, 270))	('ovarian tumors', 'Phenotype', 'HP:0100615', (156, 170))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('DICER1', 'Gene', (264, 270))	('cancer', 'Disease', (281, 287))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('drive', 'PosReg', (275, 280))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
310920	25676695	The hotspot mutations are found in the RNaseIIIb metal-binding site, reducing RNaseIIIb activity and leading to a global loss in the processing of mature 5p microRNAs but maintenance of 3p processing.	('3p processing', 'MPA', (186, 199))	('loss', 'NegReg', (121, 125))	('mutations', 'Var', (12, 21))	('reducing', 'NegReg', (69, 77))	('activity', 'MPA', (88, 96))	('metal', 'Chemical', 'MESH:D008670', (49, 54))	('processing of mature 5p microRNAs', 'MPA', (133, 166))	('RNaseIIIb', 'Enzyme', (78, 87))
310921	25676695	Later studies showed that oncogenic mutations in DROSHA, another microRNA processing gene, and associated global microRNA changes also occur in Wilm's tumor.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	("Wilm's tumor", 'Disease', (144, 156))	('mutations', 'Var', (36, 45))	("Wilm's tumor", 'Disease', 'MESH:D009396', (144, 156))	('occur', 'Reg', (135, 140))	('DROSHA', 'Gene', '29102', (49, 55))	('DROSHA', 'Gene', (49, 55))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (144, 156))
310923	25676695	Another prime example of insights into cancer biology comes from the identification of mutations in histones in forme fruste tumors.	('forme fruste tumors', 'Disease', (112, 131))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('forme fruste tumors', 'Disease', 'MESH:C566119', (112, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('histones', 'Protein', (100, 108))	('mutations', 'Var', (87, 96))
310924	25676695	Mutations in H3F3A, which encodes histone 3.3, were identified in pediatric diffuse intrinsic pontinegliomas (DIPGs) and pediatric glioblastomas.	('H3F3A', 'Gene', '3020', (13, 18))	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (121, 144))	('identified', 'Reg', (52, 62))	('pediatric glioblastomas', 'Disease', (121, 144))	('H3F3A', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('intrinsic pontinegliomas', 'Disease', 'MESH:D020919', (84, 108))	('glioblastomas', 'Phenotype', 'HP:0012174', (131, 144))	('intrinsic pontinegliomas', 'Disease', (84, 108))
310926	25676695	described H3F3A driver mutations in another tumor type: chondroblastomas.	('chondroblastomas', 'Disease', 'MESH:D002804', (56, 72))	('chondroblastomas', 'Disease', (56, 72))	('H3F3A', 'Gene', '3020', (10, 15))	('chondroblastoma', 'Phenotype', 'HP:0030432', (56, 71))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (23, 32))	('H3F3A', 'Gene', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
310927	25676695	Additionally, they also discovered novel H3F3B mutations in giant cell tumors of bone.	('giant cell tumors of bone', 'Phenotype', 'HP:0011847', (60, 85))	('mutations', 'Var', (47, 56))	('giant cell tumors', 'Disease', (60, 77))	('H3F3B', 'Gene', '3021', (41, 46))	('H3F3B', 'Gene', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('giant cell tumors', 'Disease', 'MESH:D005870', (60, 77))
310935	25676695	Here, we have cited several successful examples of recent findings that have lead to the discovery of pathognomonic mutations, the establishing new subtypes and classifications, such as the case of high-grade ESS, and providing insight into mechanisms of cancer formation such as findings of SWI/SNF and microRNA processing gene abnormalities.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('mutations', 'Var', (116, 125))	('microRNA processing gene abnormalities', 'Gene', (304, 342))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))
310971	24885681	In addition, analysis of JAK2-V617F mutation was performed and showed a negative result.	('JAK2', 'Gene', '3717', (25, 29))	('JAK2', 'Gene', (25, 29))	('V617F', 'Var', (30, 35))	('V617F', 'SUBSTITUTION', 'None', (30, 35))
311050	33445713	In humans, mutations in the ROR2 gene have also been described to cause two genetic disorders associated with severe skeletal defects: brachydactyly type B (BDB) and Robinow syndrome, which points to a central role for ROR2 in human embryogenesis as well.	('brachydactyly', 'Phenotype', 'HP:0001156', (135, 148))	('mutations', 'Var', (11, 20))	('severe skeletal defects', 'Disease', (110, 133))	('genetic disorders', 'Disease', (76, 93))	('human', 'Species', '9606', (3, 8))	('brachydactyly type B', 'Disease', 'MESH:C566196', (135, 155))	('skeletal defects', 'Phenotype', 'HP:0000924', (117, 133))	('human', 'Species', '9606', (227, 232))	('ROR2', 'Gene', (28, 32))	('genetic disorders', 'Disease', 'MESH:D030342', (76, 93))	('cause', 'Reg', (66, 71))	('humans', 'Species', '9606', (3, 9))	('Robinow syndrome', 'Disease', (166, 182))	('brachydactyly type B', 'Disease', (135, 155))	('Robinow syndrome', 'Phenotype', 'HP:0000201', (166, 182))	('severe skeletal defects', 'Disease', 'MESH:D045169', (110, 133))
311051	33445713	Mutations in ROR1 have not been linked to any human disease yet.	('human', 'Species', '9606', (46, 51))	('Mutations', 'Var', (0, 9))	('ROR1', 'Gene', (13, 17))
311063	33445713	However, the amino acid sequence of the TKD of ROR1 displays six deviations from the canonical tyrosine kinase consensus sequence, amongst which three (C482G, K614R, and L634F) are located in the catalytic center.	('tyrosine kinase', 'Gene', (95, 110))	('ROR1', 'Gene', (47, 51))	('K614R', 'Mutation', 'p.K614R', (159, 164))	('K614R', 'Var', (159, 164))	('C482G', 'Var', (152, 157))	('L634F', 'Var', (170, 175))	('tyrosine kinase', 'Gene', '7294', (95, 110))	('L634F', 'Mutation', 'rs1206225008', (170, 175))	('C482G', 'Mutation', 'c.482C>G', (152, 157))
311066	33445713	These isoforms comprise the full-length protein expressed on the cell surface (937 aa, 100-105 kDa, unglycosylated, ROR1-001, ENSP00000360120), an intracellular/secreted variant (393 aa, ~44 kDa, ROR1-002, ENSP00000360121), and a third variant of so far unknown localization (388 aa, ~40 kDa ROR1-201, ENSP00000441637).	('N', 'Chemical', 'MESH:D009584', (207, 208))	('393 aa', 'Var', (179, 185))	('ENSP00000360120', 'Var', (126, 141))	('ENSP00000360121', 'Var', (206, 221))	('N', 'Chemical', 'MESH:D009584', (127, 128))	('ROR1-001', 'Var', (116, 124))	('ENSP00000441637', 'Var', (302, 317))	('N', 'Chemical', 'MESH:D009584', (303, 304))
311070	33445713	In order to assess the targetability of ROR1 and ROR2 as novel therapeutic approach, it is important to determine their pattern and level of expression in healthy tissue, in which ROR-targeted therapies might cause undesired off-target effects, and thus toxicity.	('therapies', 'Var', (193, 202))	('ROR', 'Gene', (49, 52))	('cause', 'Reg', (209, 214))	('ROR', 'Gene', (180, 183))	('toxicity', 'Disease', 'MESH:D064420', (254, 262))	('toxicity', 'Disease', (254, 262))	('ROR', 'Gene', '100885779', (49, 52))	('ROR', 'Gene', (40, 43))	('ROR', 'Gene', '100885779', (180, 183))	('ROR', 'Gene', '100885779', (40, 43))
311081	33445713	ROR1 was described to increase on CLL cells upon disease progression, and patients with high ROR1 expression had significantly shorter therapy-free survival (TFS) as well as overall survival (OS), indicating that ROR1 is associated with a more aggressive disease.	('shorter', 'NegReg', (127, 134))	('high', 'Var', (88, 92))	('CLL', 'Phenotype', 'HP:0005550', (34, 37))	('aggressive disease', 'Disease', (244, 262))	('ROR1', 'Var', (213, 217))	('patients', 'Species', '9606', (74, 82))	('increase', 'PosReg', (22, 30))	('therapy-free', 'MPA', (135, 147))	('ROR1', 'Gene', (93, 97))	('aggressive disease', 'Disease', 'MESH:D001523', (244, 262))	('associated with', 'Reg', (221, 236))	('overall', 'MPA', (174, 181))
311086	33445713	Overexpression of ROR1 has not only been reported in hematological malignancies, but has also gained increasing attention in solid tumors.	('reported', 'Reg', (41, 49))	('solid tumors', 'Disease', 'MESH:D009369', (125, 137))	('hematological malignancies', 'Disease', 'MESH:D019337', (53, 79))	('solid tumors', 'Disease', (125, 137))	('hematological malignancies', 'Phenotype', 'HP:0004377', (53, 79))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('ROR1', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('hematological malignancies', 'Disease', (53, 79))
311088	33445713	reported that high ROR1 expression was associated with a lower pathological tumor (pT) stage and the absence of perineural invasion in gastric cancer patients who underwent gastrectomy and did not receive neoadjuvant chemotherapy.	('gastric cancer', 'Disease', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('ROR1', 'Gene', (19, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('expression', 'MPA', (24, 34))	('pathological tumor', 'Disease', 'MESH:D005598', (63, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('high', 'Var', (14, 18))	('patients', 'Species', '9606', (150, 158))	('pathological tumor', 'Disease', (63, 81))	('lower', 'NegReg', (57, 62))
311089	33445713	However, so far this remains the only analysis that suggested that ROR1 might be associated with limited disease, while the majority of studies indicated that it is rather associated with aggressiveness and poor survival.	('aggressiveness', 'Disease', (188, 202))	('associated', 'Reg', (172, 182))	('limited disease', 'Disease', (97, 112))	('aggressiveness', 'Phenotype', 'HP:0000718', (188, 202))	('aggressiveness', 'Disease', 'MESH:D001523', (188, 202))	('ROR1', 'Var', (67, 71))
311091	33445713	In ovarian cancer, high ROR1 expression was likewise associated with tumor grade as well as lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('high', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('tumor', 'Disease', (69, 74))	('met', 'Gene', '79811', (103, 106))	('ROR1', 'Gene', (24, 28))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('met', 'Gene', (103, 106))	('associated', 'Reg', (53, 63))	('ovarian cancer', 'Disease', (3, 17))	('expression', 'MPA', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
311105	33445713	Although most studies describe ROR2 as a positive prognostic factor in a variety of solid tumor entities, a limited number of reports observed a loss of ROR2 in cancerous compared to normal tissue and an association of high ROR2 expression with a favorable outcome.	('cancerous', 'Disease', 'MESH:D009369', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ROR2', 'Gene', (224, 228))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('loss', 'NegReg', (145, 149))	('association', 'Interaction', (204, 215))	('high', 'Var', (219, 223))	('cancerous', 'Disease', (161, 170))	('ROR2', 'Gene', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('expression', 'MPA', (229, 239))
311124	33445713	WNT signaling is known to regulate many key cellular processes, and aberrant regulation of this pathway has been found to contribute to the development and progression of many human cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('contribute', 'Reg', (122, 132))	('human', 'Species', '9606', (176, 181))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('regulation', 'MPA', (77, 87))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('aberrant', 'Var', (68, 76))
311125	33445713	Likewise, the deregulated expression of the WNT co-receptors ROR1 and ROR2 has been associated with several cellular features that promote malignancy, namely cell proliferation, survival, migration/invasion, and stemness, as it will be discussed in the following chapters.	('expression', 'MPA', (26, 36))	('cell proliferation', 'CPA', (158, 176))	('survival', 'CPA', (178, 186))	('ROR1', 'Gene', (61, 65))	('stemness', 'CPA', (212, 220))	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('deregulated', 'Var', (14, 25))	('associated', 'Reg', (84, 94))	('migration/invasion', 'CPA', (188, 206))	('malignancy', 'Disease', (139, 149))	('ROR2', 'Gene', (70, 74))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('promote', 'PosReg', (131, 138))
311137	33445713	In mice, the knockout of miRNA miR-15/16, leading to the overexpression of the pro-survival factor BCL2 as well as ROR1, induced the development of B cell lymphoma in 23% of the animals, while 77% developed an aggressive acute myeloid leukemia (AML).	('N', 'Chemical', 'MESH:D009584', (28, 29))	('B cell lymphoma', 'Disease', (148, 163))	('induced', 'Reg', (121, 128))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (221, 243))	('BCL2', 'Gene', '12043', (99, 103))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (221, 243))	('leukemia', 'Phenotype', 'HP:0001909', (235, 243))	('ROR1', 'Gene', (115, 119))	('AML', 'Disease', 'MESH:D015470', (245, 248))	('overexpression', 'PosReg', (57, 71))	('miRNA miR-15/16', 'Gene', (25, 40))	('BCL2', 'Gene', (99, 103))	('mice', 'Species', '10090', (3, 7))	('AML', 'Phenotype', 'HP:0004808', (245, 248))	('AML', 'Disease', (245, 248))	('lymphoma', 'Phenotype', 'HP:0002665', (155, 163))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (227, 243))	('B cell lymphoma', 'Disease', 'MESH:D016393', (148, 163))	('knockout', 'Var', (13, 21))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (148, 163))	('acute myeloid leukemia', 'Disease', (221, 243))	('cell lymphoma', 'Phenotype', 'HP:0012191', (150, 163))
311140	33445713	Blockade of ROR1 in lung cancer cells was found to suppress expression of CDK4 and CCNE1, two important cell cycle regulators, as well as Bcl-XL and Bcl-2, two critical anti-apoptotic factors, while it increased the expression of several pro-apoptotic factors including Bak, caspase-3, and caspase-7.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('expression', 'MPA', (60, 70))	('suppress', 'NegReg', (51, 59))	('Bcl-XL', 'Gene', (138, 144))	('Bak', 'Gene', (270, 273))	('Bcl-2', 'Gene', (149, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('caspase-7', 'Gene', '840', (290, 299))	('Bcl-2', 'Gene', '596', (149, 154))	('CDK4', 'Gene', (74, 78))	('expression', 'MPA', (216, 226))	('CCNE1', 'Gene', (83, 88))	('ROR1', 'Gene', (12, 16))	('increased', 'PosReg', (202, 211))	('Blockade', 'Var', (0, 8))	('CDK4', 'Gene', '1019', (74, 78))	('caspase-3', 'Gene', '836', (275, 284))	('lung cancer', 'Disease', (20, 31))	('Bak', 'Gene', '578', (270, 273))	('CCNE1', 'Gene', '898', (83, 88))	('caspase-7', 'Gene', (290, 299))	('caspase-3', 'Gene', (275, 284))	('Bcl-XL', 'Gene', '598', (138, 144))
311148	33445713	ROR2 knockdown led to an accumulation of osteosarcoma cells in the G0/G1 phase suggesting that ROR2 itself is essential for cell cycle progression.	('osteosarcoma', 'Disease', (41, 53))	('ROR2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('osteosarcoma', 'Phenotype', 'HP:0002669', (41, 53))	('accumulation', 'PosReg', (25, 37))	('osteosarcoma', 'Disease', 'MESH:D012516', (41, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
311152	33445713	As several pro-survival RTKs (e.g., epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET), Insulin-like growth factor 1 receptor (IGF1R)) depend on these functions, inhibiting ROR1 in lung cancer was proposed as a novel shortcut to bypass resistance to EGFR tyrosine kinase inhibitors.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('tyrosine kinase', 'Gene', '7294', (285, 300))	('Insulin-like growth factor 1 receptor', 'Gene', '3480', (118, 155))	('EGFR', 'Gene', (280, 284))	('hepatocyte growth factor receptor', 'Gene', (77, 110))	('MET', 'Gene', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('EGFR', 'Gene', '1956', (70, 74))	('ROR1', 'Gene', (203, 207))	('IGF1R', 'Gene', '3480', (157, 162))	('epidermal growth factor receptor', 'Gene', (36, 68))	('RTK', 'Gene', (24, 27))	('lung cancer', 'Disease', (211, 222))	('epidermal growth factor receptor', 'Gene', '1956', (36, 68))	('IGF1R', 'Gene', (157, 162))	('EGFR', 'Gene', '1956', (280, 284))	('RTK', 'Gene', '5979', (24, 27))	('MET', 'Gene', '79811', (112, 115))	('Insulin-like growth factor 1 receptor', 'Gene', (118, 155))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('EGFR', 'Gene', (70, 74))	('tyrosine kinase', 'Gene', (285, 300))	('hepatocyte growth factor receptor', 'Gene', '4233', (77, 110))	('inhibiting', 'Var', (192, 202))
311153	33445713	Indeed, targeting ROR1 helped to reinstall sensitivity to erlotinib treatment in resistant lung cancer cell lines, thus further underlining its potential as a therapeutic target.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('targeting', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('sensitivity to', 'MPA', (43, 57))	('ROR1', 'Gene', (18, 22))	('reinstall', 'PosReg', (33, 42))	('erlotinib', 'Chemical', 'MESH:D000069347', (58, 67))	('lung cancer', 'Disease', (91, 102))
311162	33445713	Indeed, targeting ROR1 in ovarian cancer increased the efficacy of second mitochondria-derived activator of caspase (SMAC) mimetics and taxanes.	('second mitochondria-derived activator of caspase', 'Gene', '56616', (67, 115))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('targeting', 'Var', (8, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (26, 40))	('increased', 'PosReg', (41, 50))	('met', 'Gene', '79811', (125, 128))	('SMAC', 'Gene', '56616', (117, 121))	('SMAC', 'Gene', (117, 121))	('taxanes', 'Chemical', 'MESH:D043823', (136, 143))	('ovarian cancer', 'Disease', (26, 40))	('second mitochondria-derived activator of caspase', 'Gene', (67, 115))	('ROR1', 'Gene', (18, 22))	('met', 'Gene', (125, 128))	('efficacy', 'MPA', (55, 63))	('ovarian cancer', 'Phenotype', 'HP:0100615', (26, 40))
311163	33445713	In line, combining paclitaxel treatment with ROR1 blockade significantly enhanced tumor growth inhibition in a patient-derived xenograft (PDX) model for breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('blockade', 'Var', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('ROR1', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('enhanced', 'PosReg', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('patient', 'Species', '9606', (111, 118))	('paclitaxel', 'Chemical', 'MESH:D017239', (19, 29))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('tumor', 'Disease', (82, 87))	('breast cancer', 'Disease', (153, 166))
311167	33445713	These ROR1+ cells were characterized by enhanced stemness frequency and expressed markers typically associated with stem cells such as e.g., POU5F1, NANOG, or SOX2.	('POU5F1', 'Gene', (141, 147))	('POU5F1', 'Gene', '5460', (141, 147))	('SOX2', 'Gene', (159, 163))	('stemness frequency', 'CPA', (49, 67))	('SOX2', 'Gene', '6657', (159, 163))	('NANOG', 'Gene', '79923', (149, 154))	('enhanced', 'PosReg', (40, 48))	('expressed', 'MPA', (72, 81))	('NANOG', 'Gene', (149, 154))	('ROR1+', 'Var', (6, 11))
311172	33445713	Similar observations have been made in breast cancer in which ROR1 knockdown decreased CXCR4 expression resulting in decreased chemotaxis of the cells towards a CXCL12 gradient.	('CXCL12', 'Gene', (161, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('knockdown', 'Var', (67, 76))	('decreased', 'NegReg', (117, 126))	('CXCL12', 'Gene', '6387', (161, 167))	('CXCR4', 'Gene', '7852', (87, 92))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ROR1', 'Gene', (62, 66))	('decreased', 'NegReg', (77, 86))	('breast cancer', 'Disease', (39, 52))	('CXCR4', 'Gene', (87, 92))
311173	33445713	Moreover, in several in vitro solid tumor models ROR1 knockdown reduced cellular migration/invasion.	('knockdown', 'Var', (54, 63))	('cellular migration/invasion', 'CPA', (72, 99))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ROR1', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('reduced', 'NegReg', (64, 71))	('tumor', 'Disease', (36, 41))
311175	33445713	Another report on melanoma observed that ROR1 was associated with a poorly invasive phenotype, and its knockdown increased invasion in vitro as well as metastasis formation in vivo.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('invasion', 'CPA', (123, 131))	('ROR1', 'Gene', (41, 45))	('met', 'Gene', '79811', (152, 155))	('met', 'Gene', (152, 155))	('increased', 'PosReg', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))	('knockdown', 'Var', (103, 112))
311178	33445713	This has since been confirmed in several solid tumor entities in which knockdown of ROR2 resulted in decreased migration and/or invasion, e.g., in mesothelioma, melanoma, renal cancer, breast cancer, ovarian cancer, prostate cancer, leiomyosarcoma, gastrointestinal stroma tumors, and osteosarcoma.	('mesothelioma', 'Disease', (147, 159))	('leiomyosarcoma, gastrointestinal stroma tumors', 'Disease', 'MESH:D007890', (233, 279))	('migration', 'CPA', (111, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (233, 247))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', (273, 278))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('ovarian cancer', 'Disease', 'MESH:D010051', (200, 214))	('ROR2', 'Gene', (84, 88))	('renal cancer', 'Disease', (171, 183))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('prostate cancer', 'Disease', 'MESH:D011471', (216, 231))	('renal cancer', 'Phenotype', 'HP:0009726', (171, 183))	('prostate cancer', 'Phenotype', 'HP:0012125', (216, 231))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('osteosarcoma', 'Phenotype', 'HP:0002669', (285, 297))	('prostate cancer', 'Disease', (216, 231))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('invasion', 'CPA', (128, 136))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('ovarian cancer', 'Disease', (200, 214))	('renal cancer', 'Disease', 'MESH:D007680', (171, 183))	('decreased', 'NegReg', (101, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('tumor', 'Disease', (47, 52))	('gastrointestinal stroma tumors', 'Phenotype', 'HP:0100723', (249, 279))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('osteosarcoma', 'Disease', (285, 297))	('knockdown', 'Var', (71, 80))	('breast cancer', 'Disease', (185, 198))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('osteosarcoma', 'Disease', 'MESH:D012516', (285, 297))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))
311184	33445713	Further in vitro studies have indeed confirmed higher expression of typical epithelial factors (e.g., CK19, CDH1) and lower expression of mesenchymal factors (e.g., SNAI2, ZEB1, VIM) after ROR1 or ROR2 knockdown in cancer cells.	('VIM', 'Gene', '7431', (178, 181))	('higher', 'PosReg', (47, 53))	('CDH1', 'Gene', '999', (108, 112))	('ROR1', 'Gene', (189, 193))	('CK19', 'Gene', (102, 106))	('VIM', 'Gene', (178, 181))	('CK19', 'Gene', '3880', (102, 106))	('ROR2', 'Gene', (197, 201))	('cancer', 'Disease', (215, 221))	('SNAI2', 'Gene', (165, 170))	('CDH1', 'Gene', (108, 112))	('knockdown', 'Var', (202, 211))	('ZEB1', 'Gene', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('SNAI2', 'Gene', '6591', (165, 170))	('expression', 'MPA', (54, 64))	('mesenchymal', 'CPA', (138, 149))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('expression', 'MPA', (124, 134))	('lower', 'NegReg', (118, 123))	('ZEB1', 'Gene', '6935', (172, 176))
311195	33445713	Evidence suggests that these findings are also valid in vivo, as ROR1 knockdown significantly reduced the capacity of breast cancer cells intravenously injected into immunodeficient mice to invade the lung 24 to 72 h after injection, pointing to a role for ROR1 in extravasation and adhesion due to its control of the EMT phenotype.	('knockdown', 'Var', (70, 79))	('reduced', 'NegReg', (94, 101))	('invade the lung', 'CPA', (190, 205))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mice', 'Species', '10090', (182, 186))	('ROR1', 'Gene', (65, 69))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('immunodeficient', 'Disease', 'MESH:D007153', (166, 181))	('immunodeficient', 'Disease', (166, 181))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
311196	33445713	Similar observations have been made for ROR2: multiple myeloma cells with stable ROR2 knockdown were mostly unable to home into the bone marrow due to a defective adhesion to the bone marrow microenvironment.	('ROR2', 'Gene', (81, 85))	('knockdown', 'Var', (86, 95))	('home', 'MPA', (118, 122))	('unable', 'NegReg', (108, 114))	('adhesion', 'MPA', (163, 171))	('myeloma', 'Disease', 'MESH:D009101', (55, 62))	('multiple myeloma', 'Phenotype', 'HP:0006775', (46, 62))	('myeloma', 'Disease', (55, 62))	('defective', 'NegReg', (153, 162))
311201	33445713	However, a recent study reported a reduction in tumor motility and invasiveness upon ROR2 overexpression, again raising the question whether the regulation of ROR expression levels is critical for determining their functional impact.	('ROR', 'Gene', (159, 162))	('ROR', 'Gene', '100885779', (85, 88))	('overexpression', 'Var', (90, 104))	('ROR', 'Gene', '100885779', (159, 162))	('invasiveness', 'CPA', (67, 79))	('ROR', 'Gene', (85, 88))	('tumor motility', 'Disease', (48, 62))	('tumor motility', 'Disease', 'MESH:D015835', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('reduction', 'NegReg', (35, 44))
311211	33445713	For instance, in melanoma ROR1 knockdown was followed by increased expression of ROR2 and WNT5A, while the knockdown of ROR2 stimulated ROR1 expression, confirming a reciprocal regulation.	('knockdown', 'Var', (107, 116))	('ROR2', 'Gene', (81, 85))	('ROR2', 'Gene', (120, 124))	('ROR1', 'Gene', (26, 30))	('ROR1', 'Gene', (136, 140))	('WNT5A', 'Gene', (90, 95))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('expression', 'MPA', (141, 151))	('increased', 'PosReg', (57, 66))	('expression', 'MPA', (67, 77))	('WNT5A', 'Gene', '7474', (90, 95))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('stimulated', 'PosReg', (125, 135))	('knockdown', 'Var', (31, 40))
311225	33445713	A recent study has reported chemotactic migration of Ewing sarcoma cells towards WNT5A, which was impaired by ROR1 silencing.	('WNT5A', 'Gene', '7474', (81, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('silencing', 'Var', (115, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (53, 66))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('ROR1', 'Gene', (110, 114))	('WNT5A', 'Gene', (81, 86))	('chemotactic migration', 'CPA', (28, 49))	('Ewing sarcoma', 'Disease', (53, 66))
311259	33445713	In CLL patients, blockade of ROR1 by cirmtuzumab reduced mTOR-induced genes.	('CLL', 'Phenotype', 'HP:0005550', (3, 6))	('CLL', 'Disease', (3, 6))	('reduced', 'NegReg', (49, 56))	('blockade', 'Var', (17, 25))	('mTOR', 'Gene', (57, 61))	('mTOR', 'Gene', '2475', (57, 61))	('patients', 'Species', '9606', (7, 15))	('ROR1', 'Gene', (29, 33))
311265	33445713	Indeed, ROR1 can not only regulate FoxO activity, but was additionally shown to inhibit ASK1/p38 signaling.	('inhibit', 'NegReg', (80, 87))	('p38', 'Gene', (93, 96))	('regulate', 'Reg', (26, 34))	('ROR1', 'Var', (8, 12))	('p38', 'Gene', '5594', (93, 96))	('FoxO activity', 'MPA', (35, 48))	('ASK1', 'Gene', '4217', (88, 92))	('ASK1', 'Gene', (88, 92))
311296	33445713	A preclinical study has demonstrated that cirmtuzumab infusions every two weeks inhibited re-engraftment of breast cancer cells and the formation of pulmonary metastases in a mouse PDX model.	('breast cancer', 'Disease', (108, 121))	('re-engraftment', 'CPA', (90, 104))	('mouse', 'Species', '10090', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('cirmtuzumab', 'Var', (42, 53))	('pulmonary metastases', 'Disease', 'MESH:D009362', (149, 169))	('pulmonary metastases', 'Disease', (149, 169))	('inhibited', 'NegReg', (80, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
311344	33445713	In vitro, treatment with KAN0439834 induced apoptosis of ROR1-positive CLL cells.	('N', 'Chemical', 'MESH:D009584', (27, 28))	('apoptosis', 'CPA', (44, 53))	('CLL', 'Phenotype', 'HP:0005550', (71, 74))	('KAN0439834', 'Var', (25, 35))
311345	33445713	Compared with the anti-tumor effects of other inhibitors commonly applied in the treatment of CLL, KAN0439834 reached similar levels of apoptosis induction as venetoclax (Bcl-2 inhibitor) in patient-derived CLL cells, and was more effective than ibrutinib (BTK inhibitor) and idelalisib (PI3K inhibitor).	('CLL', 'Phenotype', 'HP:0005550', (94, 97))	('patient', 'Species', '9606', (191, 198))	('apoptosis', 'CPA', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('venetoclax', 'Chemical', 'MESH:C579720', (159, 169))	('CLL', 'Phenotype', 'HP:0005550', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('ibrutinib', 'Chemical', 'MESH:C551803', (246, 255))	('Bcl-2', 'Gene', (171, 176))	('Bcl-2', 'Gene', '596', (171, 176))	('tumor', 'Disease', (23, 28))	('idelalisib', 'Chemical', 'MESH:C552946', (276, 286))	('KAN0439834', 'Var', (99, 109))	('N', 'Chemical', 'MESH:D009584', (101, 102))
311346	33445713	In a direct comparison with venetoclax, KAN0439834 showed a higher specificity for CLL cells and displayed less cytotoxicity for healthy PBMCs.	('CLL', 'Phenotype', 'HP:0005550', (83, 86))	('higher', 'PosReg', (60, 66))	('cytotoxicity', 'Disease', (112, 124))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('venetoclax', 'Chemical', 'MESH:C579720', (28, 38))	('KAN0439834', 'Var', (40, 50))	('specificity', 'MPA', (67, 78))
311347	33445713	Given the overexpression of ROR1 in many solid tumors and the urgent need for targeted strategies for these entities, as well, KAN0439834 has already been tested for application in pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (181, 198))	('KAN0439834', 'Var', (127, 137))	('pancreatic cancer', 'Disease', (181, 198))	('solid tumors', 'Disease', (41, 53))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (181, 198))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ROR1', 'Gene', (28, 32))	('overexpression', 'PosReg', (10, 24))	('solid tumors', 'Disease', 'MESH:D009369', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
311349	33445713	Interestingly, KAN0439834 was reported to induce significantly higher levels of apoptosis than a ROR1-targeting mAb.	('higher', 'PosReg', (63, 69))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('KAN0439834', 'Var', (15, 25))	('apoptosis', 'MPA', (80, 89))
311350	33445713	On a molecular level, KAN0439834 inhibited the phosphorylation of PI3K/AKT/mTOR/CREB and SRC, both in CLL as well as in pancreatic cancer cells, and thus blocked major pro-survival pathways induced by ROR1.	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('phosphorylation', 'MPA', (47, 62))	('SRC', 'Gene', '6714', (89, 92))	('blocked', 'NegReg', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('SRC', 'Gene', (89, 92))	('major pro-survival pathways', 'Pathway', (162, 189))	('KAN0439834', 'Var', (22, 32))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('CLL', 'Phenotype', 'HP:0005550', (102, 105))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('inhibited', 'NegReg', (33, 42))	('pancreatic cancer', 'Disease', (120, 137))
311351	33445713	As these pathways can also be activated by EGFR, which is frequently overexpressed in pancreatic cancer, the combination of KAN0439834 with erlotinib or ibrutinib (which can also function as an EGFR inhibitor) showed clear additive effects and highlighted the benefit of potential combinatory treatment strategies.	('KAN0439834', 'Var', (124, 134))	('pancreatic cancer', 'Disease', (86, 103))	('ibrutinib', 'Chemical', 'MESH:C551803', (153, 162))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('activated', 'PosReg', (30, 39))	('erlotinib', 'Chemical', 'MESH:D000069347', (140, 149))	('EGFR', 'Gene', '1956', (194, 198))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (194, 198))	('EGFR', 'Gene', (43, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
311354	33445713	KAN0441571C showed a higher cytotoxicity than KAN0439834, impressing with a longer halftime in mice than its predecessor (11 h instead of 1.2 h), although there was no improvement in terms of specificity towards ROR1.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('mice', 'Species', '10090', (95, 99))	('N', 'Chemical', 'MESH:D009584', (2, 3))	('cytotoxicity', 'Disease', (28, 40))	('higher', 'PosReg', (21, 27))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('KAN0441571C', 'Var', (0, 11))
311355	33445713	Inhibition of downstream ROR1 pro-survival signaling was observed as with KAN0439834 and resulted in dose-dependent cytotoxicity.	('Inhibition', 'NegReg', (0, 10))	('cytotoxicity', 'Disease', (116, 128))	('KAN0439834', 'Var', (74, 84))	('cytotoxicity', 'Disease', 'MESH:D064420', (116, 128))	('N', 'Chemical', 'MESH:D009584', (76, 77))
311356	33445713	In cell viability assays KAN0441571C was superior to ibrutinib, but showed similar cytotoxicity as venetoclax.	('cytotoxicity', 'Disease', 'MESH:D064420', (83, 95))	('venetoclax', 'Chemical', 'MESH:C579720', (99, 109))	('ibrutinib', 'Chemical', 'MESH:C551803', (53, 62))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('cytotoxicity', 'Disease', (83, 95))	('KAN0441571C', 'Var', (25, 36))
311357	33445713	However, the combination of KAN0441571C with the latter resulted in almost complete tumor cell killing, again underlining the benefit of combined treatment.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('KAN0441571C', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('tumor', 'Disease', (84, 89))
311361	33445713	This fits to the report discussed earlier that, in lung cancer cells, targeting ROR1 can help to circumvent resistance due to its role in sustaining signaling of several pro-survival RTKs.	('fits', 'Disease', (5, 9))	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('RTK', 'Gene', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('fits', 'Disease', 'MESH:D012640', (5, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('RTK', 'Gene', '5979', (183, 186))	('targeting', 'Var', (70, 79))	('signaling', 'MPA', (149, 158))	('ROR1', 'Gene', (80, 84))
311369	33445713	One potential candidate might be BA3021, a CAB-ROR2-ADC, which reversibly interacts with ROR2 in conditions reflecting the tumor microenvironment, but less so in normal tissue.	('tumor', 'Disease', (123, 128))	('interacts', 'Interaction', (74, 83))	('BA3021', 'Chemical', '-', (33, 39))	('BA3021', 'Var', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
311371	33445713	When looking at the clinical trials registered to date, there are two additional studies investigating the ROR2-specific CAR T cells in solid malignancies expressing ROR2 (NCT03960060) or, more specifically, ROR2-positive renal carcinomas (NCT03393936).	('NCT03960060', 'Var', (172, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('carcinomas', 'Disease', 'MESH:D009369', (228, 238))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('N', 'Chemical', 'MESH:D009584', (240, 241))	('NCT03393936', 'Var', (240, 251))	('CAR', 'Gene', (121, 124))	('N', 'Chemical', 'MESH:D009584', (172, 173))	('carcinomas', 'Disease', (228, 238))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('CAR', 'Gene', '9970', (121, 124))	('ROR2', 'Gene', (166, 170))	('malignancies', 'Disease', (142, 154))	('renal carcinomas', 'Phenotype', 'HP:0005584', (222, 238))
311379	32386107	Nab-paclitaxel is a taxane modified to improve drug exposure and increase intratumoral accumulation and, in combination with gemcitabine, is standard therapy for pancreatic cancer.	('increase', 'PosReg', (65, 73))	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('improve', 'PosReg', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('Nab-paclitaxel', 'Var', (0, 14))	('drug exposure', 'MPA', (47, 60))	('pancreatic cancer', 'Disease', (162, 179))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (125, 136))	('taxane', 'Chemical', 'MESH:C080625', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))	('improve drug exposure', 'Phenotype', 'HP:0020173', (39, 60))	('Nab', 'Chemical', '-', (0, 3))
311406	32386107	Further, nab-paclitaxel also has additive in vivo activity with gemcitabine against a Ewing sarcoma xenograft model, and this combination is approved by the US Food and Drug Administration for treatment of pancreatic cancer.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('nab', 'Chemical', '-', (9, 12))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 99))	('nab-paclitaxel', 'Var', (9, 23))	('pancreatic cancer', 'Disease', (206, 223))	('pancreatic cancer', 'Disease', 'MESH:D010190', (206, 223))	('Ewing sarcoma', 'Disease', (86, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (206, 223))	('paclitaxel', 'Chemical', 'MESH:D017239', (13, 23))	('gemcitabine', 'Chemical', 'MESH:C056507', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
311408	32386107	In our study, we chose to use the same dosages and schedule of administration as approved for pancreatic cancer, given the relative tolerability of this regimen in adults, previous observations that nab-paclitaxel is less myelosuppressive than docetaxel, and the potential activity against Ewing sarcoma of nab-paclitaxel alone and in combination with gemcitabine.	('Ewing sarcoma', 'Disease', (290, 303))	('docetaxel', 'Chemical', 'MESH:D000077143', (244, 253))	('nab', 'Chemical', '-', (307, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (296, 303))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (290, 303))	('myelosuppressive', 'Disease', (222, 238))	('myelosuppressive', 'Disease', 'MESH:D001855', (222, 238))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (290, 303))	('pancreatic cancer', 'Disease', (94, 111))	('activity', 'MPA', (273, 281))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('nab-paclitaxel', 'Var', (199, 213))	('paclitaxel', 'Chemical', 'MESH:D017239', (311, 321))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('nab', 'Chemical', '-', (199, 202))	('gemcitabine', 'Chemical', 'MESH:C056507', (352, 363))	('paclitaxel', 'Chemical', 'MESH:D017239', (203, 213))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
311438	32386107	Eight patients had molecular testing of tumor tissue showing either rearrangements or specific translocations involving EWSR1, while three patients did not have molecular testing reported.	('rearrangements', 'Var', (68, 82))	('EWSR1', 'Gene', '2130', (120, 125))	('patients', 'Species', '9606', (139, 147))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('EWSR1', 'Gene', (120, 125))	('translocations', 'Var', (95, 109))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
311476	32386107	Previous studies suggested that expression of either SPARC or CAV-1 in archival tumor samples may correlate with response to nab-paclitaxel, which fits with the presumed method of drug entry into the tumor cell.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('response', 'MPA', (113, 121))	('fits', 'Disease', 'MESH:D012640', (147, 151))	('nab', 'Chemical', '-', (125, 128))	('CAV-1', 'Gene', (62, 67))	('tumor', 'Disease', (200, 205))	('paclitaxel', 'Chemical', 'MESH:D017239', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('CAV-1', 'Gene', '857', (62, 67))	('archival tumor', 'Disease', (71, 85))	('fits', 'Disease', (147, 151))	('tumor', 'Disease', (80, 85))	('correlate with', 'Reg', (98, 112))	('SPARC', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('expression', 'Var', (32, 42))	('SPARC', 'Gene', '6678', (53, 58))	('archival tumor', 'Disease', 'MESH:D009369', (71, 85))
311479	32386107	Interestingly, the expression of hENT1 in tumor cells was limited to those patients experiencing clinical benefit on our study, which is consistent with expression of hENT1 being associated with sensitivity to gemcitabine in soft-tissue sarcoma patients.	('expression', 'Var', (153, 163))	('hENT1', 'Gene', '2030', (167, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('associated', 'Reg', (179, 189))	('tumor', 'Disease', (42, 47))	('hENT1', 'Gene', (33, 38))	('patients', 'Species', '9606', (245, 253))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('gemcitabine', 'Chemical', 'MESH:C056507', (210, 221))	('hENT1', 'Gene', (167, 172))	('patients', 'Species', '9606', (75, 83))	('soft-tissue', 'Disease', (225, 236))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (225, 244))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('sarcoma', 'Disease', (237, 244))	('hENT1', 'Gene', '2030', (33, 38))	('sensitivity to gemcitabine', 'MPA', (195, 221))
311499	29193688	In addition, radiotherapy can cause radiation pneumonia and pulmonary fibrosis, which in serious cases can significantly impact quality of life.	('pneumonia', 'Phenotype', 'HP:0002090', (46, 55))	('cause', 'Reg', (30, 35))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (60, 78))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (60, 78))	('radiation pneumonia', 'Disease', (36, 55))	('radiotherapy', 'Var', (13, 25))	('radiation pneumonia', 'Disease', 'MESH:D004194', (36, 55))	('impact', 'Reg', (121, 127))	('pulmonary fibrosis', 'Disease', (60, 78))	('quality of life', 'CPA', (128, 143))
311500	29193688	Ablation therapy is increasingly used for lung metastasis treatment because of its unique characteristics, including high efficacy, minimal invasion, and strong repeatability.9, 10, 11, 12, 13, 14, 15 The greatest advantage of ablation therapy is the ability to efficiently eliminate lung metastases and at the same time protect lung tissue.	('lung metastases', 'Disease', 'MESH:D009362', (284, 299))	('ablation', 'Var', (227, 235))	('eliminate', 'NegReg', (274, 283))	('lung metastases', 'Disease', (284, 299))
311515	29193688	Ablation therapy can efficiently inactivate a tumor and reduce the tumor burden in a minimally invasive way; combined with chemotherapy, it can significantly stimulate the chemotherapy effect and help to extend patient survival.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('chemotherapy effect', 'CPA', (172, 191))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Ablation', 'Var', (0, 8))	('stimulate', 'PosReg', (158, 167))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patient survival', 'CPA', (211, 227))	('extend', 'PosReg', (204, 210))	('reduce', 'NegReg', (56, 62))	('tumor', 'Disease', (67, 72))	('patient', 'Species', '9606', (211, 218))	('inactivate', 'NegReg', (33, 43))
311569	27105533	EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPalpha.	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('TIC', 'Disease', 'None', (32, 35))	('inhibited', 'NegReg', (8, 17))	('induced', 'Reg', (46, 53))	('TIC', 'Disease', (32, 35))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('EC-8042', 'Var', (0, 7))	('arrest', 'Disease', (65, 71))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('CEBPalpha', 'Gene', (124, 133))	('CEBPalpha', 'Gene', '12606', (124, 133))	('TIC', 'Phenotype', 'HP:0100033', (32, 35))	('upregulated', 'PosReg', (90, 101))	('apoptosis', 'CPA', (76, 85))
311570	27105533	SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042.	('anti-proliferative', 'CPA', (36, 54))	('EC-8042', 'Chemical', 'MESH:C576677', (74, 81))	('SP1', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))	('SP', 'Chemical', 'MESH:C000604007', (0, 2))
311572	27105533	Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures.	('survival', 'CPA', (67, 75))	('reduced', 'NegReg', (55, 62))	('EC-8042', 'Chemical', 'MESH:C576677', (13, 20))	('doxorubicin', 'Chemical', 'MESH:D004317', (30, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('EC-8042', 'Var', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumorsphere sarcoma', 'Disease', (92, 111))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('CSC-enriched', 'Disease', (79, 91))	('tumorsphere sarcoma', 'Disease', 'MESH:D012509', (92, 111))
311573	27105533	In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence.	('reduction', 'NegReg', (86, 95))	('senescence', 'CPA', (169, 179))	('inhibition', 'NegReg', (36, 46))	('adipogenic differentiation', 'MPA', (138, 164))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mitotic index', 'CPA', (103, 116))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('EC-8042', 'Var', (9, 16))	('tumor', 'Disease', (50, 55))	('EC-8042', 'Chemical', 'MESH:C576677', (9, 16))
311574	27105533	Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ability', 'MPA', (29, 36))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EC-8042', 'Var', (9, 16))	('reduced', 'NegReg', (17, 24))	('EC-8042', 'Chemical', 'MESH:C576677', (9, 16))
311582	27105533	In this line, several members of the SP family of TFs, such as SP1, SP3 and SP4, have been found to play an important role in the pathogenesis of some cancers including sarcomas and may constitute relevant therapeutic targets.	('SP', 'Chemical', 'MESH:C000604007', (76, 78))	('SP', 'Chemical', 'MESH:C000604007', (63, 65))	('SP', 'Chemical', 'MESH:C000604007', (68, 70))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('role', 'Reg', (118, 122))	('sarcomas', 'Disease', 'MESH:D012509', (169, 177))	('SP', 'Chemical', 'MESH:C000604007', (37, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('SP4', 'Var', (76, 79))	('play', 'Reg', (100, 104))	('cancers', 'Disease', (151, 158))	('sarcomas', 'Disease', (169, 177))	('SP1', 'Gene', (63, 66))	('SP3', 'Gene', (68, 71))
311588	27105533	As expected, EC-8042 preferentially binds GC-rich sequences, is a potent inhibitor of SP-driven gene expression and shows pleiotropic anti-angiogenic and anti-oncogenic activities.	('GC-rich sequences', 'Protein', (42, 59))	('inhibitor', 'NegReg', (73, 82))	('SP', 'Chemical', 'MESH:C000604007', (86, 88))	('anti-oncogenic activities', 'CPA', (154, 179))	('EC-8042', 'Chemical', 'MESH:C576677', (13, 20))	('EC-8042', 'Var', (13, 20))	('anti-angiogenic', 'CPA', (134, 149))	('binds', 'Interaction', (36, 41))	('preferentially', 'PosReg', (21, 35))
311589	27105533	EC-8042 altered the expression of cell cycle related genes resulting in cell cycle arrest and apoptosis in breast cancer cell lines.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('expression', 'MPA', (20, 30))	('arrest', 'Disease', (83, 89))	('altered', 'Reg', (8, 15))	('cell cycle related genes', 'Gene', (34, 58))	('EC-8042', 'Var', (0, 7))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('apoptosis', 'CPA', (94, 103))
311590	27105533	In Ewing sarcoma, EC-8042 was substantially less toxic than mithramycin but maintained suppression of EWS-FLI1 at similar concentrations as MTM, and markedly suppressed Ewing sarcoma xenograft growth.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (169, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (169, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('suppressed', 'NegReg', (158, 168))	('suppression', 'NegReg', (87, 98))	('Ewing sarcoma', 'Disease', (3, 16))	('FLI1', 'Gene', '14247', (106, 110))	('EC-8042', 'Chemical', 'MESH:C576677', (18, 25))	('EWS', 'Gene', '14030', (102, 105))	('mithramycin', 'Chemical', 'MESH:D008926', (60, 71))	('EWS', 'Gene', (102, 105))	('EC-8042', 'Var', (18, 25))	('FLI1', 'Gene', (106, 110))	('MTM', 'Chemical', 'MESH:D008926', (140, 143))	('Ewing sarcoma xenograft growth', 'Disease', 'MESH:C563168', (169, 199))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('Ewing sarcoma xenograft growth', 'Disease', (169, 199))
311591	27105533	More importantly, EC-8042 shows a potent in vitro and in vivo antitumor activity against several tumors types similar to other analogues but is 10-fold less toxic in vivo than MTM, enabling it as the lead candidate in the quest for mithralogs with improved therapeutic window potentially useful in the clinical setting.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('MTM', 'Chemical', 'MESH:D008926', (176, 179))	('tumor', 'Disease', (97, 102))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('EC-8042', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('EC-8042', 'Chemical', 'MESH:C576677', (18, 25))
311600	27105533	Thus, MSC-5H-GFP give rise to pleomorphic undifferentiated sarcomas, meanwhile FUS-CHOP-expressing hBMSCs (MSC-4H-FC, and MSC-5H-FC) initiate MLS-like tumors.	('pleomorphic undifferentiated sarcomas', 'Disease', 'MESH:D002277', (30, 67))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('tumors', 'Disease', (151, 157))	('pleomorphic undifferentiated sarcomas', 'Disease', (30, 67))	('MLS', 'Disease', 'MESH:C537466', (142, 145))	('5H', 'Chemical', '-', (10, 12))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('CHOP', 'Gene', '13198', (83, 87))	('5H', 'Chemical', '-', (126, 128))	('MLS', 'Disease', (142, 145))	('CHOP', 'Gene', (83, 87))	('4H', 'Chemical', '-', (111, 113))	('MSC-5H-GFP', 'Var', (6, 16))
311601	27105533	Several cell lines were also derived from xenograft tumors generated by transformed hMSCs (T-4H-FC#1, T-4H-FC#3, T5H-GFP#1 and T5H-FC#1) (Supplementary Figure S1A).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('T-4H-FC#', 'Var', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('xenograft tumors', 'Disease', 'MESH:D009369', (42, 58))	('T5H', 'Chemical', '-', (127, 130))	('T5H-FC#', 'Var', (127, 134))	('T-4H', 'Chemical', '-', (102, 106))	('xenograft tumors', 'Disease', (42, 58))	('T-4H', 'Chemical', '-', (91, 95))	('T-4H-FC#', 'Var', (91, 99))	('T5H', 'Chemical', '-', (113, 116))
311603	27105533	Ingenuity Pathway Analysis (IPA) of differentially expressed genes revealed the upstream regulation signaling most significantly altered in MSC-5H-GFP, MSC-5H-FC and T-5H-FC#1 cells (Supplementary Figure S1B).	('5H', 'Chemical', '-', (144, 146))	('T-5H', 'Chemical', '-', (166, 170))	('5H', 'Chemical', '-', (168, 170))	('MSC-5H-GFP', 'Var', (140, 150))	('5H', 'Chemical', '-', (156, 158))	('altered', 'Reg', (129, 136))	('upstream regulation signaling', 'MPA', (80, 109))
311605	27105533	Accordingly, RT-PCR analysis showed that the expression of SP1 and two known SP1-target genes, C-MYC and XIAP, was upregulated in MSC-5H-GFP, MSC-5H-FC, T-5H-GFP#1 and T-5H-FC#1 cells (Figure 1A).	('T-5H', 'Chemical', '-', (153, 157))	('SP', 'Chemical', 'MESH:C000604007', (59, 61))	('C-MYC', 'Gene', (95, 100))	('5H', 'Chemical', '-', (155, 157))	('MSC-5H-GFP', 'Var', (130, 140))	('XIAP', 'Gene', '11798', (105, 109))	('5H', 'Chemical', '-', (146, 148))	('expression', 'MPA', (45, 55))	('XIAP', 'Gene', (105, 109))	('SP', 'Chemical', 'MESH:C000604007', (77, 79))	('5H', 'Chemical', '-', (170, 172))	('SP1', 'Gene', (59, 62))	('T-5H', 'Chemical', '-', (168, 172))	('5H', 'Chemical', '-', (134, 136))	('upregulated', 'PosReg', (115, 126))
311606	27105533	Importantly, 24 hours-treatment with 0.5 muM EC-8042 efficiently inhibited the expression of SP1 and their downstream targets, both at mRNA and protein level, in MSC-5H-FC#1 and T-5H-FC#1 cells (Figure 1B-1C).	('SP1', 'Gene', (93, 96))	('expression', 'MPA', (79, 89))	('5H', 'Chemical', '-', (180, 182))	('SP', 'Chemical', 'MESH:C000604007', (93, 95))	('5H', 'Chemical', '-', (166, 168))	('EC-8042', 'Chemical', 'MESH:C576677', (45, 52))	('inhibited', 'NegReg', (65, 74))	('EC-8042', 'Var', (45, 52))	('T-5H', 'Chemical', '-', (178, 182))
311607	27105533	Moreover, EC-8042 also decreased the expression of other members of the SP family which may show certain level of overlap with SP1-induced signaling.	('SP', 'Chemical', 'MESH:C000604007', (72, 74))	('EC-8042', 'Var', (10, 17))	('EC-8042', 'Chemical', 'MESH:C576677', (10, 17))	('expression', 'MPA', (37, 47))	('SP', 'Chemical', 'MESH:C000604007', (127, 129))	('decreased', 'NegReg', (23, 32))
311608	27105533	Thus, EC-8042 treatment inhibited the expression of SP3 in both MSC-5H-FC#1 and T-5H-FC#1 cell types and SP4 in MSC-5H-FC (Supplementary Figure S2).	('SP4', 'Var', (105, 108))	('T-5H', 'Chemical', '-', (80, 84))	('expression', 'MPA', (38, 48))	('SP3', 'Gene', (52, 55))	('inhibited', 'NegReg', (24, 33))	('EC-8042', 'Chemical', 'MESH:C576677', (6, 13))	('5H', 'Chemical', '-', (116, 118))	('5H', 'Chemical', '-', (68, 70))	('5H', 'Chemical', '-', (82, 84))
311611	27105533	Opposite to wild type hBMSCs, all cell types of the 4H- (Figure 1E) and 5H- models (Figure 1F) were sensitive to sub-micromolar concentrations of EC-8042 or doxorubicin (IC50 between 0.107 and 0.311 muM for EC-8042 and between 0.086 and 0.604 muM for doxorubicin).	('EC-8042', 'Chemical', 'MESH:C576677', (207, 214))	('5H', 'Chemical', '-', (72, 74))	('doxorubicin', 'Chemical', 'MESH:D004317', (251, 262))	('sensitive', 'Reg', (100, 109))	('doxorubicin', 'Chemical', 'MESH:D004317', (157, 168))	('4H', 'Chemical', '-', (52, 54))	('EC-8042', 'Chemical', 'MESH:C576677', (146, 153))	('EC-8042', 'Var', (207, 214))	('EC-8042', 'Var', (146, 153))
311614	27105533	MSC-5H-FC cells treated with 0.1 muM EC-8042 showed a slow transition through the S-phase followed by G2 arrest, meanwhile cells treated with a higher concentration also showed a relevant increment in the Sub-G1 apoptotic population at latter times (Figure 1G).	('Sub-G1 apoptotic population', 'CPA', (205, 232))	('EC-8042', 'Chemical', 'MESH:C576677', (37, 44))	('EC-8042', 'Var', (37, 44))	('5H', 'Chemical', '-', (4, 6))	('arrest', 'Disease', 'MESH:D006323', (105, 111))	('arrest', 'Disease', (105, 111))
311619	27105533	These SP1 knockdowns correlate with the inhibition of C-MYC and the induction of PARP apoptotic cleavage (Figure 2A).	('SP', 'Chemical', 'MESH:C000604007', (6, 8))	('knockdowns', 'Var', (10, 20))	('C-MYC', 'Protein', (54, 59))	('PARP', 'Gene', (81, 85))	('PARP', 'Gene', '11545', (81, 85))	('inhibition', 'NegReg', (40, 50))	('SP1', 'Gene', (6, 9))
311620	27105533	Likewise, SP1 depletion induces a time-dependent cytotoxic effect (Figure 2B).	('depletion', 'Var', (14, 23))	('cytotoxic effect', 'CPA', (49, 65))	('SP1', 'Gene', (10, 13))	('SP', 'Chemical', 'MESH:C000604007', (10, 12))
311621	27105533	Therefore, SP1 knockdown seems to mimic the anti-proliferative effects induced by EC-8042.	('SP', 'Chemical', 'MESH:C000604007', (11, 13))	('knockdown', 'Var', (15, 24))	('EC-8042', 'Chemical', 'MESH:C576677', (82, 89))	('anti-proliferative effects', 'MPA', (44, 70))	('SP1', 'Gene', (11, 14))
311625	27105533	EC-8042 was able to decrease the expression of ABCB1 (MDR1), ABCG2 (BCRP1) and ABCC1 (MRP1) in MSC-5H cells (Figure 3A).	('ABCB1', 'Gene', (47, 52))	('ABCC1', 'Gene', (79, 84))	('decrease', 'NegReg', (20, 28))	('EC-8042', 'Var', (0, 7))	('ABCC1', 'Gene', '17250', (79, 84))	('BCRP1', 'Gene', '26357', (68, 73))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('ABCG2', 'Gene', (61, 66))	('ABCB1', 'Gene', '18669', (47, 52))	('expression', 'MPA', (33, 43))	('MRP1', 'Gene', (86, 90))	('BCRP1', 'Gene', (68, 73))	('MRP1', 'Gene', '17250', (86, 90))	('5H', 'Chemical', '-', (99, 101))
311631	27105533	EC-8042 and doxorubicin induced statistical significant changes (fold change>=2; p-value<0.05) in the expression of 42 and 30 genes respectively (Figure 4A-4D).	('expression', 'MPA', (102, 112))	('EC-8042', 'Var', (0, 7))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('changes', 'Reg', (56, 63))	('doxorubicin', 'Chemical', 'MESH:D004317', (12, 23))
311633	27105533	Confirming the effect of EC-8042 over SP1-mediated transcription, several genes known to be controlled by SP1 were downregulated in EC-8042 treated cells, including HDAC1, ITGA2, KIT, ENG, PLAUR or C-MYC.	('ITGA2', 'Gene', '16398', (172, 177))	('PLAUR', 'Gene', '18793', (189, 194))	('HDAC1', 'Gene', '433759', (165, 170))	('C-MYC', 'Disease', (198, 203))	('HDAC1', 'Gene', (165, 170))	('ITGA2', 'Gene', (172, 177))	('SP', 'Chemical', 'MESH:C000604007', (106, 108))	('EC-8042', 'Chemical', 'MESH:C576677', (25, 32))	('EC-8042', 'Chemical', 'MESH:C576677', (132, 139))	('ENG', 'Gene', (184, 187))	('SP', 'Chemical', 'MESH:C000604007', (38, 40))	('downregulated', 'NegReg', (115, 128))	('ENG', 'Gene', '13805', (184, 187))	('KIT', 'Gene', (179, 182))	('EC-8042', 'Var', (132, 139))	('PLAUR', 'Gene', (189, 194))
311635	27105533	On the other hand, Doxorubicin upregulated pluripotency genes such as NANOG and POU5F1/OCT3/4, CSC markers like THY1/CD90, ALDH1A1, PROM1/CD133, KIT/CD117, CD24, CD38, genes involved in metastasis like TWIST1, TWIST2 and ZEB2 and genes involved in signaling pathways like NOTCH signaling (DLL1, DLL4 and NOTCH2), while also induced the downregulation of genes like SOX2, ID1 or ZEB1 (Figure 4D).	('CD90', 'Gene', '21838', (117, 121))	('PROM1', 'Gene', '19126', (132, 137))	('ZEB1', 'Gene', '21417', (378, 382))	('CD90', 'Gene', (117, 121))	('CD117', 'Gene', '16590', (149, 154))	('CD133', 'Gene', '19126', (138, 143))	('NOTCH signaling', 'MPA', (272, 287))	('THY1', 'Gene', '21838', (112, 116))	('ALDH1A1', 'Gene', '11668', (123, 130))	('Doxorubicin', 'Var', (19, 30))	('ID1', 'Gene', (371, 374))	('ZEB2', 'Gene', '24136', (221, 225))	('CD24', 'Gene', (156, 160))	('Doxorubicin', 'Chemical', 'MESH:D004317', (19, 30))	('NANOG', 'Gene', '71950', (70, 75))	('DLL4', 'Gene', '54485', (295, 299))	('TWIST2', 'Gene', '13345', (210, 216))	('POU5F1', 'Gene', '18999', (80, 86))	('TWIST2', 'Gene', (210, 216))	('pluripotency', 'Disease', (43, 55))	('SOX2', 'Gene', '20674', (365, 369))	('ZEB1', 'Gene', (378, 382))	('POU5F1', 'Gene', (80, 86))	('OCT3/4', 'Gene', '18999', (87, 93))	('downregulation', 'NegReg', (336, 350))	('DLL1', 'Gene', (289, 293))	('CD24', 'Gene', '12484', (156, 160))	('THY1', 'Gene', (112, 116))	('SOX2', 'Gene', (365, 369))	('CD117', 'Gene', (149, 154))	('DLL1', 'Gene', '13388', (289, 293))	('NOTCH2', 'Gene', (304, 310))	('OCT3/4', 'Gene', (87, 93))	('pluripotency', 'Disease', 'None', (43, 55))	('ALDH1A1', 'Gene', (123, 130))	('CD133', 'Gene', (138, 143))	('TWIST1', 'Gene', (202, 208))	('PROM1', 'Gene', (132, 137))	('ID1', 'Gene', '15901', (371, 374))	('DLL4', 'Gene', (295, 299))	('CD38', 'Gene', (162, 166))	('TWIST1', 'Gene', '22160', (202, 208))	('upregulated', 'PosReg', (31, 42))	('NANOG', 'Gene', (70, 75))	('NOTCH2', 'Gene', '18129', (304, 310))	('CD38', 'Gene', '12494', (162, 166))	('ZEB2', 'Gene', (221, 225))
311636	27105533	IPA analysis of the group of genes differentially expressed after the treatments also showed that pluripotency signaling pathways were activated by doxorubicin but were inhibited by EC-8042 (Figure 4E).	('activated', 'PosReg', (135, 144))	('doxorubicin', 'Var', (148, 159))	('EC-8042', 'Chemical', 'MESH:C576677', (182, 189))	('pluripotency', 'Disease', (98, 110))	('pluripotency', 'Disease', 'None', (98, 110))	('inhibited', 'NegReg', (169, 178))	('doxorubicin', 'Chemical', 'MESH:D004317', (148, 159))
311638	27105533	These data are in line with previous works reporting that CSCs are resistant to doxorubicin treatment and therefore this drug may favor a CSC positive selection, and on the other hand, suggest that EC-8042 treatment may disadvantage the CSC phenotype in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (254, 262))	('EC-8042', 'Chemical', 'MESH:C576677', (198, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (254, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('disadvantage', 'NegReg', (220, 232))	('EC-8042', 'Var', (198, 205))	('sarcomas', 'Disease', (254, 262))	('CSC', 'Disease', (237, 240))	('favor', 'PosReg', (130, 135))	('doxorubicin', 'Chemical', 'MESH:D004317', (80, 91))
311641	27105533	Likewise, EC-8042 treatment efficiently prevent tumorsphere formation from a primary patient-derived cell line (Supplementary Figure S3B).	('patient', 'Species', '9606', (85, 92))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('EC-8042', 'Var', (10, 17))	('EC-8042', 'Chemical', 'MESH:C576677', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('prevent', 'NegReg', (40, 47))
311643	27105533	After treatment with doxorubicin and especially with EC-8042, tumorspheres were smaller and displayed a disrupted and irregular morphology in all cell types (4H and 5H models) (Figure 6B & Supplementary Figure S5A-5B).	('EC-8042', 'Var', (53, 60))	('5H', 'Chemical', '-', (165, 167))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('4H', 'Chemical', '-', (158, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (21, 32))	('smaller', 'NegReg', (80, 87))	('EC-8042', 'Chemical', 'MESH:C576677', (53, 60))
311645	27105533	In any case, EC-8042 was much more efficient than doxorubicin in reducing the cell viability of tumorsphere cultures in all the studied sarcoma TICs (Figure 6E-6H).	('doxorubicin', 'Chemical', 'MESH:D004317', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('sarcoma TICs', 'Disease', (136, 148))	('EC-8042', 'Chemical', 'MESH:C576677', (13, 20))	('reducing', 'NegReg', (65, 73))	('TICs', 'Phenotype', 'HP:0100033', (144, 148))	('tumors', 'Disease', (96, 102))	('EC-8042', 'Var', (13, 20))	('sarcoma TICs', 'Disease', 'MESH:D020323', (136, 148))	('TIC', 'Phenotype', 'HP:0100033', (144, 147))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))
311646	27105533	These results support that, in contrast to doxorubicin, EC-8042 could constitute an effective treatment to eliminate CSC subpopulations in sarcoma.	('CSC', 'Disease', (117, 120))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('doxorubicin', 'Chemical', 'MESH:D004317', (43, 54))	('sarcoma', 'Disease', (139, 146))	('EC-8042', 'Chemical', 'MESH:C576677', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('EC-8042', 'Var', (56, 63))
311653	27105533	More importantly, EC-8042 produced a delay in tumor formation after re-implantation of tumor cells in limiting dilution assays.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('EC-8042', 'Var', (18, 25))	('EC-8042', 'Chemical', 'MESH:C576677', (18, 25))	('delay', 'NegReg', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
311654	27105533	We initially (week 3) observed a 4-fold significant decrease of TIF in EC-8042- versus control-treated tumors (Figure 7G).	('EC-8042', 'Chemical', 'MESH:C576677', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('TIF', 'MPA', (64, 67))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('decrease', 'NegReg', (52, 60))	('EC-8042-', 'Var', (71, 79))
311655	27105533	Although eventually (week 5) tumor growth was detected in nearly all mice (13 out of 15 in control and EC-8042 groups and 12 out of 12 in doxorubicin group), tumor weights in the EC-8042 group were significantly lower than in control group (Figure 7H).	('tumor', 'Disease', (158, 163))	('lower', 'NegReg', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('EC-8042', 'Chemical', 'MESH:C576677', (179, 186))	('mice', 'Species', '10090', (69, 73))	('EC-8042', 'Var', (179, 186))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('EC-8042', 'Chemical', 'MESH:C576677', (103, 110))	('doxorubicin', 'Chemical', 'MESH:D004317', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('EC-8042', 'Var', (103, 110))
311656	27105533	These data suggest that EC-8042 is able to partially reduce CSCs subpopulations in vivo.	('reduce', 'NegReg', (53, 59))	('EC-8042', 'Var', (24, 31))	('CSCs', 'Disease', (60, 64))	('EC-8042', 'Chemical', 'MESH:C576677', (24, 31))
311657	27105533	Intra-tumor pharmacokinetic measurement of EC-8042 concentration at 24h and 48h after 50 mg/kg single dose treatment indicated that the drug accumulated at doses higher that those deemed active in vitro: 1640 +- 105 ng/g (media +- standard deviation) at 24h and 412 +- 267 ng/g at 48h.	('1640 +- 105 ng/g', 'Var', (204, 220))	('EC-8042', 'Chemical', 'MESH:C576677', (43, 50))	('EC-8042', 'Gene', (43, 50))	('Intra-tumor', 'Disease', (0, 11))	('Intra-tumor', 'Disease', 'MESH:D009369', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
311660	27105533	In addition, both doxorubicin and especially EC-8042 treated tumors presented significantly lower mitotic counts than untreated tumor samples (Figure 8A-8B).	('tumors', 'Disease', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('EC-8042', 'Chemical', 'MESH:C576677', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('EC-8042', 'Var', (45, 52))	('tumor', 'Disease', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('doxorubicin', 'Chemical', 'MESH:D004317', (18, 29))	('mitotic counts', 'CPA', (98, 112))	('lower', 'NegReg', (92, 97))	('tumor', 'Disease', (61, 66))
311662	27105533	Therefore, tumors treated with EC-8042 showed a significant reduction in tumor grade according to the score obtained by applying the three-grade FNCLCC system which depend on the necrosis, mitotic counts and differentiation status of the tumors (Figure 8D).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (238, 244))	('tumor', 'Disease', (11, 16))	('reduction', 'NegReg', (60, 69))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('necrosis', 'Disease', 'MESH:D009336', (179, 187))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (238, 243))	('EC-8042', 'Chemical', 'MESH:C576677', (31, 38))	('necrosis', 'Disease', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumors', 'Disease', (11, 17))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('EC-8042', 'Var', (31, 38))
311664	27105533	Likewise, in line with the observed increase in adipogenic differentiation, EC-8042 produced an increase in the expression of C/EBPalpha (Figure 8A & 8F), which is in any case much more modest than that observed in TICs cultures.	('EC-8042', 'Chemical', 'MESH:C576677', (76, 83))	('TICs', 'Phenotype', 'HP:0100033', (215, 219))	('TIC', 'Disease', (215, 218))	('TIC', 'Disease', 'None', (215, 218))	('C/EBPalpha', 'Gene', (126, 136))	('C/EBPalpha', 'Gene', '12606', (126, 136))	('TIC', 'Phenotype', 'HP:0100033', (215, 218))	('increase', 'PosReg', (96, 104))	('EC-8042', 'Var', (76, 83))	('expression', 'MPA', (112, 122))
311670	27105533	Taken together, these results indicate that the in vivo sarcoma growth inhibition induced by EC-8042 is due to the induction of a senescent-state, while the anti-tumor effects of doxorubicin are mainly caused by the promotion of apoptotic cell death.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('sarcoma', 'Disease', (56, 63))	('tumor', 'Disease', (162, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('doxorubicin', 'Chemical', 'MESH:D004317', (179, 190))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('EC-8042', 'Var', (93, 100))	('EC-8042', 'Chemical', 'MESH:C576677', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
311673	27105533	Notably, a pro-tumorigenic role for SP TFs has been reported in several types of soft tissue sarcomas.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (81, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('SP', 'Chemical', 'MESH:C000604007', (36, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('tumor', 'Disease', (15, 20))	('SP TFs', 'Var', (36, 42))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (81, 101))	('soft tissue sarcomas', 'Disease', (81, 101))
311679	27105533	Several studies reported that SP1 and SP3 regulated the expression of ABC family member genes in different types of cancer cells, and that inhibition of SP1 activity with MTM downregulated the expression of ABC family genes and CSC-associated genes, inhibited proliferation and tumorigenicity, suppressed CSC-associated properties and caused chemosensitization to anti-cancer drugs.	('inhibition', 'Var', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('ABC family member genes', 'Gene', (70, 93))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('expression', 'MPA', (193, 203))	('SP', 'Chemical', 'MESH:C000604007', (38, 40))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('caused', 'Reg', (335, 341))	('inhibited', 'NegReg', (250, 259))	('downregulated', 'NegReg', (175, 188))	('suppressed', 'NegReg', (294, 304))	('expression', 'MPA', (56, 66))	('SP', 'Chemical', 'MESH:C000604007', (30, 32))	('activity', 'MPA', (157, 165))	('proliferation', 'CPA', (260, 273))	('CSC-associated properties', 'CPA', (305, 330))	('tumor', 'Disease', (278, 283))	('cancer', 'Disease', (116, 122))	('SP1', 'Gene', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Disease', (369, 375))	('SP', 'Chemical', 'MESH:C000604007', (153, 155))	('chemosensitization', 'CPA', (342, 360))	('MTM', 'Chemical', 'MESH:D008926', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('ABC family genes', 'Gene', (207, 223))
311680	27105533	Similarly, we show that SP1 inhibition using EC-8042 results in the downregulation of ABCG2, ABCB1 and ABCC1.	('SP', 'Chemical', 'MESH:C000604007', (24, 26))	('ABCG2', 'Gene', (86, 91))	('ABCB1', 'Gene', '18669', (93, 98))	('downregulation', 'NegReg', (68, 82))	('ABCC1', 'Gene', (103, 108))	('ABCB1', 'Gene', (93, 98))	('EC-8042', 'Chemical', 'MESH:C576677', (45, 52))	('ABCC1', 'Gene', '17250', (103, 108))	('EC-8042', 'Var', (45, 52))
311681	27105533	In addition, EC-8042, opposite to doxorubicin, repressed the expression of many genes involved in the development of the CSC phenotype.	('EC-8042', 'Chemical', 'MESH:C576677', (13, 20))	('doxorubicin', 'Chemical', 'MESH:D004317', (34, 45))	('EC-8042', 'Var', (13, 20))	('expression', 'MPA', (61, 71))
311682	27105533	The amplification of C-MYC, one of the oncogenic genes with enhanced expression in our model of sarcomagenesis, is a frequent event in many types of sarcoma, including MLS.	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('MLS', 'Disease', 'MESH:C537466', (168, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('MLS', 'Disease', (168, 171))	('sarcoma', 'Disease', (149, 156))	('C-MYC', 'Gene', (21, 26))	('expression', 'MPA', (69, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('amplification', 'Var', (4, 17))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('enhanced', 'PosReg', (60, 68))	('sarcoma', 'Disease', (96, 103))
311685	27105533	We showed that siRNA-mediated knockdown of SP1 induced C-MYC downregulation, suggesting that EC-8042 effect on C-MYC expression is mediated by SP1.	('downregulation', 'NegReg', (61, 75))	('SP', 'Chemical', 'MESH:C000604007', (143, 145))	('SP1', 'Gene', (43, 46))	('SP', 'Chemical', 'MESH:C000604007', (43, 45))	('knockdown', 'Var', (30, 39))	('EC-8042', 'Chemical', 'MESH:C576677', (93, 100))	('C-MYC', 'Protein', (55, 60))
311687	27105533	In a similar way, the expression of the Hedgehog signaling receptor PTCH1 is repressed by EC-8042 but stimulated by doxorubicin.	('PTCH1', 'Gene', (68, 73))	('doxorubicin', 'Chemical', 'MESH:D004317', (116, 127))	('stimulated', 'PosReg', (102, 112))	('EC-8042', 'Chemical', 'MESH:C576677', (90, 97))	('EC-8042', 'Var', (90, 97))	('PTCH1', 'Gene', '19206', (68, 73))	('expression', 'MPA', (22, 32))
311691	27105533	Altogether, these data suggest that EC-8042 could act as an anti-pluripotency therapy able to target both CSCs and non-CSCs populations derived from sarcoma TICs.	('pluripotency', 'Disease', (65, 77))	('EC-8042', 'Var', (36, 43))	('TIC', 'Phenotype', 'HP:0100033', (157, 160))	('EC-8042', 'Chemical', 'MESH:C576677', (36, 43))	('pluripotency', 'Disease', 'None', (65, 77))	('TICs', 'Phenotype', 'HP:0100033', (157, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('sarcoma TICs', 'Disease', 'MESH:D020323', (149, 161))	('sarcoma TICs', 'Disease', (149, 161))
311762	27013034	MFS is generally graded by two-tiered system as low and high-grades rather than low, intermediate, and high grades by mitotic count, nuclear pleomorphism, and necrosis.	('necrosis', 'Disease', 'MESH:D009336', (159, 167))	('nuclear pleomorphism', 'Var', (133, 153))	('MFS', 'Disease', (0, 3))	('necrosis', 'Disease', (159, 167))
311801	26090253	There was a nodular or lobular mass showing T1WI low signal (Figure 1(a)), T2WI high signal (Figure 1(b)), and gadolinium- (Gd-) enhanced T1WI heterogeneous enhancement (Figure 1(c)).	('enhanced', 'PosReg', (129, 137))	('T1WI', 'MPA', (44, 48))	('T1WI heterogeneous enhancement', 'MPA', (138, 168))	('nodular', 'Disease', 'MESH:D020518', (12, 19))	('gadolinium', 'Chemical', 'MESH:D005682', (111, 121))	('low', 'NegReg', (49, 52))	('nodular', 'Disease', (12, 19))	('T2WI', 'Var', (75, 79))
311843	33182685	We also review the molecular alterations that are associated with the pathogenesis of angiosarcoma, including c-Myc, TP53, vascular endothelial growth factor receptors, and others.	('vascular endothelial growth factor', 'Gene', (123, 157))	('as', 'Gene', '112935892', (124, 126))	('TP53', 'Var', (117, 121))	('c-Myc', 'Gene', '4609', (110, 115))	('angiosarcoma', 'Phenotype', 'HP:0200058', (86, 98))	('vascular endothelial growth factor', 'Gene', '7422', (123, 157))	('c-Myc', 'Gene', (110, 115))	('as', 'Gene', '112935892', (50, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('angiosarcoma', 'Gene', (86, 98))	('angiosarcoma', 'Gene', '112935892', (86, 98))
311873	33182685	Case reports of breast cancer patients with BRCA1 or BRCA2 mutations having post-radiation sarcoma have been reported, but a more extensive cohort study of BRCA1 and BRCA2 mutation carriers treated for breast cancer found no increased risk for radiation in-field secondary sarcoma after breast radiotherapy.	('BRCA1', 'Gene', '672', (156, 161))	('as', 'Gene', '112935892', (290, 292))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA1', 'Gene', (156, 161))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('BRCA2', 'Gene', (166, 171))	('BRCA1', 'Gene', (44, 49))	('breast cancer', 'Disease', (16, 29))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('patients', 'Species', '9606', (30, 38))	('sarcoma', 'Disease', (91, 98))	('as', 'Gene', '112935892', (19, 21))	('BRCA2', 'Gene', (53, 58))	('BRCA2', 'Gene', '675', (166, 171))	('sarcoma', 'Disease', 'MESH:D012509', (273, 280))	('as', 'Gene', '112935892', (1, 3))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('sarcoma', 'Disease', (273, 280))	('mutations', 'Var', (59, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('as', 'Gene', '112935892', (230, 232))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('as', 'Gene', '112935892', (205, 207))	('breast cancer', 'Disease', (202, 215))	('BRCA2', 'Gene', '675', (53, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
311929	33182685	In AS, molecules associated with activation of angiogenesis often manifest through genetic mutations (KDR(VEGFR-2), PLCG1, PTPRB) or amplification (FLT4(VEGFR-3)).	('AS', 'Gene', '112935892', (3, 5))	('PLCG1', 'Gene', '5335', (116, 121))	('VEGFR-2', 'Gene', (106, 113))	('KDR', 'Gene', '3791', (102, 105))	('VEGFR-3', 'Gene', '2324', (153, 160))	('PTPRB', 'Gene', '5787', (123, 128))	('amplification', 'Var', (133, 146))	('PTPRB', 'Gene', (123, 128))	('FLT4', 'Gene', '2324', (148, 152))	('AS', 'Phenotype', 'HP:0200058', (3, 5))	('FLT4', 'Gene', (148, 152))	('VEGFR-3', 'Gene', (153, 160))	('KDR', 'Gene', (102, 105))	('as', 'Gene', '112935892', (17, 19))	('PLCG1', 'Gene', (116, 121))	('VEGFR-2', 'Gene', '3791', (106, 113))
311990	33182685	Aberrant MYC activity and overexpression leads to genome-wide dysregulation driving classic cancer hallmarks of proliferative signaling, altered cellular energetics and angiogenesis.	('MYC', 'Gene', '4609', (9, 12))	('Aberrant', 'Var', (0, 8))	('angiogenesis', 'CPA', (169, 181))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('overexpression', 'PosReg', (26, 40))	('as', 'Gene', '112935892', (86, 88))	('cellular energetics', 'MPA', (145, 164))	('MYC', 'Gene', (9, 12))	('dysregulation', 'MPA', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
311991	33182685	The presence of pathological MYC in AS was first reported through array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH) studies.	('MYC', 'Gene', '4609', (29, 32))	('AS', 'Phenotype', 'HP:0200058', (36, 38))	('AS', 'Gene', '112935892', (36, 38))	('as', 'Gene', '112935892', (40, 42))	('MYC', 'Gene', (29, 32))	('pathological', 'Var', (16, 28))
311993	33182685	Detected in 57% of secondary AS cases, the most frequent alteration was amplification of the MYC-containing 8q24.12 chromosomal region.	('AS', 'Phenotype', 'HP:0200058', (29, 31))	('amplification', 'Var', (72, 85))	('as', 'Gene', '112935892', (69, 71))	('MYC', 'Gene', (93, 96))	('as', 'Gene', '112935892', (33, 35))	('AS', 'Gene', '112935892', (29, 31))	('MYC', 'Gene', '4609', (93, 96))
312011	33182685	Therefore, molecular alterations in MYC are also present in a subset of primary AS cases but at a much lower frequency compared to secondary AS.	('MYC', 'Gene', '4609', (36, 39))	('AS', 'Gene', '112935892', (141, 143))	('AS', 'Gene', '112935892', (80, 82))	('as', 'Gene', '112935892', (84, 86))	('MYC', 'Gene', (36, 39))	('molecular alterations', 'Var', (11, 32))	('AS', 'Phenotype', 'HP:0200058', (141, 143))	('AS', 'Phenotype', 'HP:0200058', (80, 82))
312018	33182685	This supports the hypothesis that MYC alterations promote angiogenesis in AS, however, as alterations are not found as ubiquitously across AS, it is evident that this is not an essential event for AS tumourigenesis, and the genetic basis for the disease is complex and diverse.	('tumour', 'Disease', (200, 206))	('as', 'Gene', '112935892', (233, 235))	('MYC', 'Gene', (34, 37))	('AS', 'Gene', '112935892', (74, 76))	('promote', 'PosReg', (50, 57))	('AS', 'Phenotype', 'HP:0200058', (139, 141))	('as', 'Gene', '112935892', (87, 89))	('AS', 'Phenotype', 'HP:0200058', (197, 199))	('AS', 'Phenotype', 'HP:0200058', (74, 76))	('AS', 'Gene', '112935892', (139, 141))	('MYC', 'Gene', '4609', (34, 37))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('as', 'Gene', '112935892', (116, 118))	('as', 'Gene', '112935892', (250, 252))	('AS', 'Gene', '112935892', (197, 199))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('alterations', 'Var', (38, 49))	('angiogenesis', 'CPA', (58, 70))
312020	33182685	TP53 alterations have a particularly high prevalence within leiomyosarcoma (80%) and pleomorphic sarcomas (60-70%).	('pleomorphic sarcomas', 'Disease', (85, 105))	('TP53', 'Gene', (0, 4))	('leiomyosarcoma', 'Disease', (60, 74))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (85, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (60, 74))	('alterations', 'Var', (5, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (60, 74))
312021	33182685	In AS, TP53 mutations have been documented in a range of frequencies between 4% and 52%.	('AS', 'Phenotype', 'HP:0200058', (3, 5))	('mutations', 'Var', (12, 21))	('AS', 'Gene', '112935892', (3, 5))	('TP53', 'Gene', (7, 11))
312022	33182685	Although reports vary on exact incidence, it does appear that TP53 mutations are less common in AS than in other sarcoma types.	('AS', 'Gene', '112935892', (96, 98))	('common', 'Reg', (86, 92))	('TP53', 'Gene', (62, 66))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('mutations', 'Var', (67, 76))	('sarcoma', 'Disease', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('AS', 'Phenotype', 'HP:0200058', (96, 98))
312024	33182685	Zebrafish homozygous for tp53 deletion spontaneously develop tumours consistent with AS histology, as do mice with germline Trp53 deletion.	('tp53', 'Gene', (25, 29))	('AS', 'Gene', '112935892', (85, 87))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('Trp53', 'Gene', (124, 129))	('AS', 'Phenotype', 'HP:0200058', (85, 87))	('deletion', 'Var', (30, 38))	('tumours', 'Disease', (61, 68))	('develop', 'PosReg', (53, 60))	('Trp53', 'Gene', '22059', (124, 129))	('as', 'Gene', '112935892', (99, 101))	('mice', 'Species', '10090', (105, 109))	('tp53', 'Gene', '30590', (25, 29))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('Zebrafish', 'Species', '7955', (0, 9))
312025	33182685	Furthermore, homozygous deletion of Trp53 in cadherin 5-expressing endothelial cells in mice also results in AS tumour development.	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('Trp53', 'Gene', '22059', (36, 41))	('tumour', 'Disease', (112, 118))	('results in', 'Reg', (98, 108))	('AS', 'Phenotype', 'HP:0200058', (109, 111))	('cadherin 5', 'Gene', '12562', (45, 55))	('cadherin 5', 'Gene', (45, 55))	('deletion', 'Var', (24, 32))	('Trp53', 'Gene', (36, 41))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('mice', 'Species', '10090', (88, 92))	('AS', 'Gene', '112935892', (109, 111))
312026	33182685	Interestingly, expression of a gain of function p53 mutant (R172H) in mouse endothelial cells does not lead to AS, but instead triggers lymphoma development.	('p53', 'Gene', (48, 51))	('AS', 'Phenotype', 'HP:0200058', (111, 113))	('lymphoma', 'Disease', (136, 144))	('p53', 'Gene', '22059', (48, 51))	('mouse', 'Species', '10090', (70, 75))	('R172H', 'Mutation', 'p.R172H', (60, 65))	('lymphoma', 'Disease', 'MESH:D008223', (136, 144))	('R172H', 'Var', (60, 65))	('triggers', 'Reg', (127, 135))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('gain of function', 'PosReg', (31, 47))	('AS', 'Gene', '112935892', (111, 113))
312028	33182685	The development of AS in animal models through genetic manipulation of TP53 provides direct evidence that this tumour suppressor is important for this disease.	('as', 'Gene', '112935892', (155, 157))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('AS', 'Phenotype', 'HP:0200058', (19, 21))	('genetic manipulation', 'Var', (47, 67))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('TP53', 'Gene', (71, 75))	('tumour', 'Disease', (111, 117))	('AS', 'Gene', '112935892', (19, 21))
312029	33182685	Further mechanistic studies of TP53 dysfunction in the transgenic models discussed will facilitate elucidation of the role of this tumour suppressor in AS.	('tumour', 'Disease', (131, 137))	('AS', 'Phenotype', 'HP:0200058', (152, 154))	('TP53', 'Gene', (31, 35))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('AS', 'Gene', '112935892', (152, 154))	('dysfunction', 'Var', (36, 47))	('tumour', 'Disease', 'MESH:D009369', (131, 137))
312034	33182685	VEGFR-2 mutations occurred throughout the gene, including in the transmembrane, extracellular and kinase domains.	('VEGFR-2', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('as', 'Gene', '112935892', (101, 103))	('VEGFR-2', 'Gene', '3791', (0, 7))	('occurred', 'Reg', (18, 26))
312035	33182685	Another documented VEGFR alteration is the amplification of VEGFR-3, often co-occurring alongside MYC amplification.	('VEGFR-3', 'Gene', (60, 67))	('VEGFR', 'Gene', (19, 24))	('MYC', 'Gene', '4609', (98, 101))	('amplification', 'Var', (43, 56))	('VEGFR', 'Gene', (60, 65))	('VEGFR-3', 'Gene', '2324', (60, 67))	('VEGFR', 'Gene', '3791', (19, 24))	('MYC', 'Gene', (98, 101))	('VEGFR', 'Gene', '3791', (60, 65))
312043	33182685	Furthermore, higher expression of Ang-1 was associated with a significantly improved OS; with no/weak Ang-1 expressing cases having a median OS of 5 months versus moderate/strong Ang-1 expressing cases of 47 months (p = 0.0049).	('as', 'Gene', '112935892', (41, 43))	('expression', 'MPA', (20, 30))	('as', 'Gene', '112935892', (197, 199))	('no/weak', 'Var', (94, 101))	('improved', 'PosReg', (76, 84))	('Ang-1', 'Gene', (102, 107))	('Ang-1', 'Gene', '284', (102, 107))	('Ang-1', 'Gene', (34, 39))	('Ang-1', 'Gene', (179, 184))	('Ang-1', 'Gene', '284', (179, 184))	('as', 'Gene', '112935892', (120, 122))	('as', 'Gene', '112935892', (44, 46))	('Ang-1', 'Gene', '284', (34, 39))
312044	33182685	The biological rationale for higher Ang-1 expression conferring improved OS is unclear.	('expression', 'MPA', (42, 52))	('Ang-1', 'Gene', (36, 41))	('Ang-1', 'Gene', '284', (36, 41))	('improved', 'PosReg', (64, 72))	('higher', 'Var', (29, 35))
312045	33182685	It is unlikely that in AS, higher Ang-1 expression is triggering enhanced signaling through the downstream FAK, MAPK, and PKB/PI3K/mTOR pathways, as excess activity in these pathways is well documented to enhance tumour progression.	('signaling', 'MPA', (74, 83))	('mTOR', 'Gene', (131, 135))	('AS', 'Phenotype', 'HP:0200058', (23, 25))	('enhanced', 'PosReg', (65, 73))	('enhance', 'PosReg', (205, 212))	('Ang-1', 'Gene', (34, 39))	('MAPK', 'Pathway', (112, 116))	('FAK', 'Gene', (107, 110))	('Ang-1', 'Gene', '284', (34, 39))	('AS', 'Gene', '112935892', (23, 25))	('PKB', 'Gene', (122, 125))	('as', 'Gene', '112935892', (146, 148))	('mTOR', 'Gene', '2475', (131, 135))	('higher', 'Var', (27, 33))	('FAK', 'Gene', '5747', (107, 110))	('PKB', 'Gene', '2185', (122, 125))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('tumour', 'Disease', (213, 219))
312047	33182685	In a study by Behjati et al., PTPRB mutations were identified in 10 out of 39 secondary AS cases, the majority being nonsense mutations occurring prior to or within the tyrosine phosphatase domain, resulting in loss of function of the protein.	('AS', 'Gene', '112935892', (88, 90))	('as', 'Gene', '112935892', (186, 188))	('PTPRB', 'Gene', '5787', (30, 35))	('mutations', 'Var', (36, 45))	('PTPRB', 'Gene', (30, 35))	('AS', 'Phenotype', 'HP:0200058', (88, 90))	('as', 'Gene', '112935892', (92, 94))	('loss of function', 'NegReg', (211, 227))	('protein', 'Protein', (235, 242))	('nonsense', 'Var', (117, 125))
312049	33182685	Thus, loss of function mutations in PTPRB are hypothesised to be driver events in AS pathogenesis, leading to unmodulated Tie-2 and VEGFR-2 signaling.	('AS', 'Gene', '112935892', (82, 84))	('PTPRB', 'Gene', '5787', (36, 41))	('PTPRB', 'Gene', (36, 41))	('VEGFR-2', 'Gene', '3791', (132, 139))	('loss of function', 'NegReg', (6, 22))	('AS', 'Phenotype', 'HP:0200058', (82, 84))	('mutations', 'Var', (23, 32))	('Tie-2', 'Gene', (122, 127))	('VEGFR-2', 'Gene', (132, 139))	('Tie-2', 'Gene', '7010', (122, 127))
312050	33182685	In addition to the identification of PTPRB mutations, the same study also found a recurrent R707Q missense mutation in phospholipase C gamma 1 (PLCG1) in 3 out of 34 cases.	('phospholipase C gamma 1', 'Gene', (119, 142))	('PTPRB', 'Gene', '5787', (37, 42))	('PTPRB', 'Gene', (37, 42))	('R707Q', 'Mutation', 'p.R707Q', (92, 97))	('PLCG1', 'Gene', '5335', (144, 149))	('R707Q missense', 'Var', (92, 106))	('as', 'Gene', '112935892', (167, 169))	('as', 'Gene', '112935892', (129, 131))	('phospholipase C gamma 1', 'Gene', '5335', (119, 142))	('PLCG1', 'Gene', (144, 149))
312055	33182685	In silico predictions illustrate that a glutamine substitution at this site will destabilise the domain, removing the auto-inhibitory capability of PLCG1 and resulting in a constitutively active form.	('constitutively active form', 'MPA', (173, 199))	('PLCG1', 'Gene', (148, 153))	('removing', 'NegReg', (105, 113))	('glutamine substitution', 'Var', (40, 62))	('resulting in', 'Reg', (158, 170))	('auto-inhibitory capability', 'MPA', (118, 144))	('glutamine', 'Chemical', 'MESH:D005973', (40, 49))	('PLCG1', 'Gene', '5335', (148, 153))
312057	33182685	Mutant-expressing cells showed abundant levels of inositol trisphosphate (IP3), a product of PLCG1-mediated cleavage, and had increased phosphorylation levels of the PLCG1-activated MAPK-pathway components.	('PLCG1', 'Gene', (93, 98))	('PLCG1', 'Gene', (166, 171))	('as', 'Gene', '112935892', (131, 133))	('Mutant-expressing', 'Var', (0, 17))	('phosphorylation levels', 'MPA', (136, 158))	('PLCG1', 'Gene', '5335', (93, 98))	('PLCG1', 'Gene', '5335', (166, 171))	('inositol trisphosphate', 'Chemical', '-', (50, 72))	('levels', 'MPA', (40, 46))	('IP3', 'Chemical', 'MESH:D015544', (74, 77))
312058	33182685	Notably, although PTPRB mutations can co-present with either PLCG1 or VEGFR-2 mutations, as detected in 3 out of 10 PTPRB mutated cases by Beca et al., Huang et al.	('PLCG1', 'Gene', '5335', (61, 66))	('VEGFR-2', 'Gene', '3791', (70, 77))	('as', 'Gene', '112935892', (131, 133))	('PTPRB', 'Gene', '5787', (116, 121))	('PTPRB', 'Gene', (116, 121))	('mutations', 'Var', (78, 87))	('PTPRB', 'Gene', '5787', (18, 23))	('VEGFR-2', 'Gene', (70, 77))	('as', 'Gene', '112935892', (89, 91))	('PLCG1', 'Gene', (61, 66))	('mutations', 'Var', (24, 33))	('PTPRB', 'Gene', (18, 23))	('mutated', 'Var', (122, 129))
312059	33182685	reported PLCG1 and VEGFR-2 mutations to be mutually exclusive in an analysis of 116 cases.	('mutations', 'Var', (27, 36))	('VEGFR-2', 'Gene', (19, 26))	('PLCG1', 'Gene', (9, 14))	('VEGFR-2', 'Gene', '3791', (19, 26))	('PLCG1', 'Gene', '5335', (9, 14))	('as', 'Gene', '112935892', (85, 87))
312064	33182685	Although alterations identified in MYC and the angiogenesis-related genes are often reported as having a slight preponderance for primary AS or secondary AS, the evidence is neither clear nor consistent.	('AS', 'Phenotype', 'HP:0200058', (138, 140))	('MYC', 'Gene', (35, 38))	('as', 'Gene', '112935892', (93, 95))	('angiogenesis-related genes', 'Gene', (47, 73))	('alterations', 'Var', (9, 20))	('AS', 'Gene', '112935892', (138, 140))	('AS', 'Phenotype', 'HP:0200058', (154, 156))	('MYC', 'Gene', '4609', (35, 38))	('AS', 'Gene', '112935892', (154, 156))
312066	33182685	In a study by Huang et al., targeted sequencing and FISH analysis of 120 AS cases (61% primary AS, 28% radiation-associated AS, 11% lymphedema-associated AS) reported primary AS-associated alterations in the capicua transcriptional repressor (CIC) gene.	('capicua transcriptional repressor', 'Gene', '23152', (208, 241))	('AS', 'Gene', '112935892', (175, 177))	('as', 'Gene', '112935892', (178, 180))	('AS', 'Phenotype', 'HP:0200058', (124, 126))	('AS', 'Gene', '112935892', (124, 126))	('AS', 'Phenotype', 'HP:0200058', (154, 156))	('CIC', 'Gene', (243, 246))	('as', 'Gene', '112935892', (113, 115))	('AS', 'Gene', '112935892', (154, 156))	('capicua transcriptional repressor', 'Gene', (208, 241))	('lymphedema', 'Phenotype', 'HP:0001004', (132, 142))	('as', 'Gene', '112935892', (143, 145))	('AS', 'Phenotype', 'HP:0200058', (73, 75))	('lymphedema', 'Disease', (132, 142))	('AS', 'Phenotype', 'HP:0200058', (95, 97))	('CIC', 'Gene', '23152', (243, 246))	('lymphedema', 'Disease', 'MESH:D008209', (132, 142))	('AS', 'Gene', '112935892', (73, 75))	('as', 'Gene', '112935892', (77, 79))	('AS', 'Phenotype', 'HP:0200058', (175, 177))	('AS', 'Gene', '112935892', (95, 97))	('alterations', 'Var', (189, 200))
312068	33182685	Eight AS cases out of the 100 analysed by targeted sequencing carried unique missense mutations in exons 15 and 18-20 of CIC.	('CIC', 'Gene', (121, 124))	('as', 'Gene', '112935892', (10, 12))	('AS', 'Gene', '112935892', (6, 8))	('AS', 'Phenotype', 'HP:0200058', (6, 8))	('CIC', 'Gene', '23152', (121, 124))	('missense mutations in', 'Var', (77, 98))
312095	33182685	These sequencing results support prior studies, documenting alterations in MYC, VEGFR-3, and PLCG1, and furthermore finds previously unreported mutations in PIK3CA, GRIN2A and NOTCH2.	('MYC', 'Gene', '4609', (75, 78))	('NOTCH2', 'Gene', (176, 182))	('PLCG1', 'Gene', (93, 98))	('PIK3CA', 'Gene', (157, 163))	('VEGFR-3', 'Gene', '2324', (80, 87))	('PLCG1', 'Gene', '5335', (93, 98))	('MYC', 'Gene', (75, 78))	('GRIN2A', 'Gene', (165, 171))	('alterations', 'Var', (60, 71))	('NOTCH2', 'Gene', '4853', (176, 182))	('PIK3CA', 'Gene', '5290', (157, 163))	('mutations', 'Var', (144, 153))	('VEGFR-3', 'Gene', (80, 87))	('GRIN2A', 'Gene', '2903', (165, 171))
312096	33182685	Of note, activating PIK3CA mutations were identified in 10 of 47 samples, 90% of which were breast primary AS lesions, raising the possibility that these patients may respond favourably to PI3Kalpha inhibitors.	('mutations', 'Var', (27, 36))	('PI3Kalpha', 'Gene', '5290', (189, 198))	('PI3Kalpha', 'Gene', (189, 198))	('PIK3CA', 'Gene', (20, 26))	('patients', 'Species', '9606', (154, 162))	('PIK3CA', 'Gene', '5290', (20, 26))	('breast primary AS lesions', 'Disease', 'MESH:D001943', (92, 117))	('breast primary AS lesions', 'Disease', (92, 117))	('activating', 'PosReg', (9, 19))	('AS', 'Phenotype', 'HP:0200058', (107, 109))
312216	32063753	At a mean of 16 years after initial diagnosis, dexrazoxane-treated patients had significantly higher left ventricular ejection fraction overall compared with controls (those who did not receive dexrazoxane), with significantly higher myocardial wall stress and dysfunction reported in the subset of patients from one study (COG P9404) who had received 360 mg/m2 of doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (365, 376))	('dexrazoxane-treated', 'Var', (47, 66))	('patients', 'Species', '9606', (67, 75))	('dexrazoxane', 'Chemical', 'MESH:D064730', (194, 205))	('dexrazoxane', 'Chemical', 'MESH:D064730', (47, 58))	('dysfunction', 'MPA', (261, 272))	('left ventricular ejection fraction', 'MPA', (101, 135))	('higher', 'PosReg', (227, 233))	('patients', 'Species', '9606', (299, 307))	('higher', 'PosReg', (94, 100))	('myocardial wall stress', 'MPA', (234, 256))
312332	26872011	Frequent HRAS Mutations in Malignant Ectomesenchymoma: Overlapping Genetic Abnormalities with Embryonal Rhabdomyosarcoma Malignant ectomesenchymoma (MEM) is an exceedingly rare pediatric sarcoma, with predilection for infants and young children, composed of dual malignant mesenchymal and neuroectodermal components.	('Genetic Abnormalities', 'Disease', 'MESH:D030342', (67, 88))	('Malignant ectomesenchymoma', 'Disease', 'MESH:D009369', (121, 147))	('Embryonal Rhabdomyosarcoma', 'Disease', (94, 120))	('Embryonal Rhabdomyosarcoma', 'Disease', 'MESH:D018233', (94, 120))	('Genetic Abnormalities', 'Disease', (67, 88))	('pediatric sarcoma', 'Disease', (177, 194))	('infants', 'Species', '9606', (218, 225))	('Malignant Ectomesenchymoma', 'Disease', 'MESH:D009369', (27, 53))	('HRAS', 'Gene', '3265', (9, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('Malignant ectomesenchymoma', 'Disease', (121, 147))	('HRAS', 'Gene', (9, 13))	('Mutations', 'Var', (14, 23))	('Malignant Ectomesenchymoma', 'Disease', (27, 53))	('Embryonal Rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (94, 120))	('children', 'Species', '9606', (236, 244))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (104, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (177, 194))
312336	26872011	No candidate fusion genes were detected by FusionSeq analysis, however, the mutation detection algorithms revealed HRAS and PTPRD hot-spot mutations in both index cases, with one case harbouring an additional FBXW7 mutation.	('FBXW7', 'Gene', '55294', (209, 214))	('mutations', 'Var', (139, 148))	('HRAS', 'Gene', '3265', (115, 119))	('FBXW7', 'Gene', (209, 214))	('hot-spot', 'PosReg', (130, 138))	('HRAS', 'Gene', (115, 119))	('PTPRD', 'Gene', '5789', (124, 129))	('PTPRD', 'Gene', (124, 129))
312339	26872011	By Sanger sequencing, 6 of 7 (86%) MEMs had HRAS mutations, with no additional case harboring PTPRD or FBXW7 mutations.	('mutations', 'Var', (49, 58))	('FBXW7', 'Gene', '55294', (103, 108))	('PTPRD', 'Gene', '5789', (94, 99))	('PTPRD', 'Gene', (94, 99))	('FBXW7', 'Gene', (103, 108))	('HRAS', 'Gene', '3265', (44, 48))	('HRAS', 'Gene', (44, 48))
312342	26872011	In the control ERMS group, 5 of 7 (71%) showed RAS mutations, equally distributed among NRAS, KRAS, and HRAS genes.	('mutations', 'Var', (51, 60))	('KRAS', 'Gene', (94, 98))	('NRAS', 'Gene', (88, 92))	('HRAS', 'Gene', (104, 108))	('KRAS', 'Gene', '3845', (94, 98))	('NRAS', 'Gene', '4893', (88, 92))	('HRAS', 'Gene', '3265', (104, 108))	('RMS', 'Phenotype', 'HP:0002859', (16, 19))	('RAS', 'Gene', (47, 50))
312343	26872011	Our results of common HRAS mutations and composite gene signature with RMS and neuronal/ neuroblastic elements, suggest a closer genetic link of MEM to RMS rather than MPNST.	('mutations', 'Var', (27, 36))	('MPNST', 'Phenotype', 'HP:0100697', (168, 173))	('RMS', 'Disease', (152, 155))	('RMS', 'Phenotype', 'HP:0002859', (152, 155))	('HRAS', 'Gene', '3265', (22, 26))	('RMS', 'Phenotype', 'HP:0002859', (71, 74))	('HRAS', 'Gene', (22, 26))
312372	26872011	The 2 MEMs with a dense/round cell component were negative for FOXO1 gene rearrangements by fluorescence in situ hybridization (data not shown).	('FOXO1', 'Gene', (63, 68))	('negative', 'NegReg', (50, 58))	('rearrangements', 'Var', (74, 88))	('FOXO1', 'Gene', '2308', (63, 68))
312381	26872011	Instead, the bioinformatic mutation detection tools (MuTect and VarScan) revealed recurrent HRAS (exon 2, p.G13R) and PTPRD (exon 20: p.V892A in MEM1; p.V847L in MEM2) mutations in both index cases and FBWX7 (exon 10, p.R505H) mutations in MEM2 (Fig.	('FBWX7', 'Gene', (202, 207))	('p.V892A', 'Var', (134, 141))	('MEM1', 'Gene', (145, 149))	('p.V847L', 'Var', (151, 158))	('p.R505H', 'Mutation', 'rs1057519896', (218, 225))	('HRAS', 'Gene', '3265', (92, 96))	('p.V892A', 'Mutation', 'rs151005956', (134, 141))	('MEM2', 'Gene', (240, 244))	('p.R505H', 'Var', (218, 225))	('p.G13R', 'Mutation', 'rs104894228', (106, 112))	('p.V847L', 'Mutation', 'rs143787300', (151, 158))	('MEM2', 'Gene', (162, 166))	('PTPRD', 'Gene', '5789', (118, 123))	('HRAS', 'Gene', (92, 96))	('PTPRD', 'Gene', (118, 123))
312382	26872011	Based on these RNAseq findings and the previously reported hotspot mutations in RMS we have investigated all 7 MEM and the control RMS group for the following hot spots: HRAS exon 3, NRAS exons 2 and 3, KRAS exon 2, PIK3CA exons 10 and 21, PTPRD exon 25, FBWX7 exon 10 and CTNNB1 exon 3 .	('NRAS', 'Gene', (183, 187))	('KRAS', 'Gene', (203, 207))	('CTNNB1', 'Gene', (273, 279))	('RMS', 'Gene', (80, 83))	('KRAS', 'Gene', '3845', (203, 207))	('NRAS', 'Gene', '4893', (183, 187))	('PTPRD', 'Gene', '5789', (240, 245))	('PTPRD', 'Gene', (240, 245))	('HRAS', 'Gene', '3265', (170, 174))	('PIK3CA', 'Gene', (216, 222))	('CTNNB1', 'Gene', '1499', (273, 279))	('mutations', 'Var', (67, 76))	('HRAS', 'Gene', (170, 174))	('RMS', 'Phenotype', 'HP:0002859', (131, 134))	('PIK3CA', 'Gene', '5290', (216, 222))	('RMS', 'Phenotype', 'HP:0002859', (80, 83))
312383	26872011	In total, 6 of 7 (86%) MEMs harbored HRAS mutations, 4 with p.G13R mutation and 2 with p.Q61L.	('p.Q61L', 'Var', (87, 93))	('p.Q61L', 'Mutation', 'rs121913233', (87, 93))	('HRAS', 'Gene', '3265', (37, 41))	('p.G13R', 'Mutation', 'rs104894228', (60, 66))	('p.G13R mutation', 'Var', (60, 75))	('mutations', 'Var', (42, 51))	('HRAS', 'Gene', (37, 41))
312385	26872011	The cases containing p.G13R mutation (MEM1-3, 7) exhibited the more common combination of classic ERMS and ganglion cells or ganglioneuroma, while the cases with p.Q61L mutation (MEM4, 5) showed either classic or dense ERMS and ganglioneuroma or ganglioneuroblastoma.	('RMS', 'Phenotype', 'HP:0002859', (99, 102))	('classic ERMS', 'Disease', (90, 102))	('ganglioneuroma or ganglioneuroblastoma', 'Disease', (228, 266))	('p.G13R mutation', 'Var', (21, 36))	('ganglioneuroma', 'Disease', (125, 139))	('RMS', 'Phenotype', 'HP:0002859', (220, 223))	('ganglioneuroma', 'Disease', 'MESH:D005729', (125, 139))	('ganglioneuroma or ganglioneuroblastoma', 'Disease', 'MESH:D005729', (228, 266))	('ganglion cells', 'Disease', (107, 121))	('ganglioneuroma', 'Disease', 'MESH:D005729', (228, 242))	('ganglioneuroma', 'Phenotype', 'HP:0003005', (125, 139))	('p.Q61L', 'Var', (162, 168))	('p.Q61L', 'Mutation', 'rs121913233', (162, 168))	('neuroblastoma', 'Phenotype', 'HP:0003006', (253, 266))	('ganglioneuroma', 'Disease', (228, 242))	('p.G13R', 'Mutation', 'rs104894228', (21, 27))	('ganglioneuroblastoma', 'Phenotype', 'HP:0006747', (246, 266))	('ganglioneuroma', 'Phenotype', 'HP:0003005', (228, 242))
312387	26872011	In the control RMS group, we detected 5 RAS mutations in 7 cases (71%), including 1 HRAS (p.Q61K), 2 NRAS (p.Q61K; p.Q61H), and 2 KRAS (p.G12D) mutations (Fig.	('NRAS', 'Gene', (101, 105))	('p.Q61K', 'Mutation', 'rs28933406', (90, 96))	('KRAS', 'Gene', '3845', (130, 134))	('NRAS', 'Gene', '4893', (101, 105))	('p.Q61K; p.Q61H', 'Var', (107, 121))	('HRAS', 'Gene', '3265', (84, 88))	('p.Q61K', 'Mutation', 'rs28933406', (107, 113))	('KRAS', 'Gene', (130, 134))	('mutations', 'Var', (44, 53))	('HRAS', 'Gene', (84, 88))	('RMS', 'Phenotype', 'HP:0002859', (15, 18))	('RAS', 'Gene', (40, 43))	('p.Q61K', 'Var', (90, 96))	('p.G12D', 'Mutation', 'rs121913529', (136, 142))	('p.Q61H', 'Mutation', 'rs17851045', (115, 121))
312388	26872011	No additional PTPRD or FBWX7 mutations were identified in the remaining MEM or the control RMSs.	('mutations', 'Var', (29, 38))	('PTPRD', 'Gene', '5789', (14, 19))	('PTPRD', 'Gene', (14, 19))	('FBWX7', 'Gene', (23, 28))	('RMS', 'Phenotype', 'HP:0002859', (91, 94))
312389	26872011	Both PTPRD exon 20 mutations were located in the 6th fibronectin type III domain.	('PTPRD', 'Gene', '5789', (5, 10))	('PTPRD', 'Gene', (5, 10))	('located', 'Reg', (34, 41))	('mutations', 'Var', (19, 28))
312390	26872011	The FBXW7 missense mutation occurred at one of the critical 3 arginine residues in the WD (tryptophan-aspartic acid) repeat, which mediate substrates binding to the Skp1-Cullin-F-box (SCF) ubiquitin-ligase complex .	('occurred', 'Reg', (28, 36))	('missense mutation', 'Var', (10, 27))	('aspartic acid', 'Chemical', 'MESH:D001224', (102, 115))	('FBXW7', 'Gene', '55294', (4, 9))	('Skp1', 'Gene', (165, 169))	('SCF', 'Gene', (184, 187))	('FBXW7', 'Gene', (4, 9))	('SCF', 'Gene', '4254', (184, 187))	('arginine', 'Chemical', 'MESH:D001120', (62, 70))	('tryptophan', 'Chemical', 'MESH:D014364', (91, 101))	('Skp1', 'Gene', '6500', (165, 169))	('WD', 'Disease', 'MESH:D006527', (87, 89))
312420	26872011	Aside from the similar clinicopathologic features, our MEM cohort also shows a high frequency (86%) of HRAS mutations, in keeping with a homogeneous pathologic and molecular entity.	('HRAS', 'Gene', (103, 107))	('HRAS', 'Gene', '3265', (103, 107))	('mutations', 'Var', (108, 117))
312421	26872011	An activated RAS signaling pathway through oncogenic mutations is also observed in the control pediatric ERMS cases (71%); however, the spectrum of mutations seen spans all NRAS, KRAS, and HRAS members.	('HRAS', 'Gene', '3265', (189, 193))	('KRAS', 'Gene', '3845', (179, 183))	('mutations', 'Var', (148, 157))	('RMS', 'Phenotype', 'HP:0002859', (106, 109))	('NRAS', 'Gene', (173, 177))	('HRAS', 'Gene', (189, 193))	('NRAS', 'Gene', '4893', (173, 177))	('KRAS', 'Gene', (179, 183))
312422	26872011	Notably, the HRAS mutation (p.Q61K) detected in one RMS results in a different amino acid substitution than the one seen in MEM (p.Q61L).	('HRAS', 'Gene', (13, 17))	('amino acid substitution', 'MPA', (79, 102))	('p.Q61K', 'Mutation', 'rs28933406', (28, 34))	('RMS', 'Phenotype', 'HP:0002859', (52, 55))	('p.Q61K', 'Var', (28, 34))	('HRAS', 'Gene', '3265', (13, 17))	('p.Q61L', 'Mutation', 'rs121913233', (129, 135))
312424	26872011	Among the 44 RAS-mutant ERMS from 4 series , NRAS mutations are the most common (27, 61%), followed by KRAS (11, 25%) and HRAS mutations (6, 14%).	('KRAS', 'Gene', (103, 107))	('HRAS', 'Gene', (122, 126))	('KRAS', 'Gene', '3845', (103, 107))	('mutations', 'Var', (50, 59))	('common', 'Reg', (73, 79))	('RMS', 'Phenotype', 'HP:0002859', (25, 28))	('NRAS', 'Gene', (45, 49))	('HRAS', 'Gene', '3265', (122, 126))	('NRAS', 'Gene', '4893', (45, 49))
312425	26872011	The hot spots for both NRAS and HRAS mutations in ERMS occur in the codon 61 .	('NRAS', 'Gene', (23, 27))	('HRAS', 'Gene', '3265', (32, 36))	('RMS', 'Phenotype', 'HP:0002859', (51, 54))	('mutations', 'Var', (37, 46))	('HRAS', 'Gene', (32, 36))	('NRAS', 'Gene', '4893', (23, 27))
312426	26872011	There are 3 ERMS cases reported with identical HRAS p.G13R and p.Q61L mutations as detected in our MEM cases .	('RMS', 'Phenotype', 'HP:0002859', (13, 16))	('ERMS', 'Disease', (12, 16))	('p.Q61L', 'Var', (63, 69))	('p.Q61L', 'Mutation', 'rs121913233', (63, 69))	('HRAS', 'Gene', '3265', (47, 51))	('p.G13R', 'Mutation', 'rs104894228', (52, 58))	('HRAS', 'Gene', (47, 51))
312427	26872011	Interestingly, the HRAS mutations seen in MEM are different than the ones described in Costello syndrome, a rare multisystem disorder caused by heterozygous germline HRAS mutation and showing a phenotype characterized by craniofacial dysmorphology, intellectual disabilities, cardiac malformations, and short stature .	('short stature', 'Disease', (303, 316))	('mutation', 'Var', (171, 179))	('cardiac malformations', 'Disease', 'MESH:D006331', (276, 297))	('mutations', 'Var', (24, 33))	('intellectual disabilities', 'Disease', (249, 274))	('HRAS', 'Gene', '3265', (19, 23))	('HRAS', 'Gene', (19, 23))	('craniofacial dysmorphology', 'Disease', 'MESH:D019465', (221, 247))	('short stature', 'Phenotype', 'HP:0004322', (303, 316))	('cardiac malformations', 'Phenotype', 'HP:0001627', (276, 297))	('Costello syndrome', 'Disease', 'MESH:D056685', (87, 104))	('caused by', 'Reg', (134, 143))	('intellectual disabilities', 'Phenotype', 'HP:0001249', (249, 274))	('Costello syndrome', 'Disease', (87, 104))	('cardiac malformations', 'Disease', (276, 297))	('HRAS', 'Gene', '3265', (166, 170))	('rare multisystem disorder', 'Disease', 'MESH:D035583', (108, 133))	('HRAS', 'Gene', (166, 170))	('craniofacial dysmorphology', 'Disease', (221, 247))	('rare multisystem disorder', 'Disease', (108, 133))
312429	26872011	The HRAS mutation genotype appears to correlate with the phenotype and even with the risk of malignancy .	('mutation', 'Var', (9, 17))	('HRAS', 'Gene', (4, 8))	('malignancy', 'Disease', 'MESH:D009369', (93, 103))	('malignancy', 'Disease', (93, 103))	('HRAS', 'Gene', '3265', (4, 8))
312432	26872011	The cancer-related somatic mutations in Ras members often occur at amino acids 12, 13, or 61, which are the conserved sites for modulating GDP/GTP binding and hydrolysis.	('mutations', 'Var', (27, 36))	('binding', 'Interaction', (147, 154))	('GTP', 'Chemical', 'MESH:D006160', (143, 146))	('occur', 'Reg', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Ras members', 'Gene', (40, 51))	('GDP/GTP', 'Protein', (139, 146))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('GDP', 'Chemical', 'MESH:D006153', (139, 142))
312433	26872011	There is increasing evidence that Ras proteins have isoform-specific biologic functions and tumorigenic effects, possibly attributed to the C-terminal hypervariable region, and that different mutation codons might induce different transformation potential.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Ras proteins', 'Protein', (34, 46))	('mutation', 'Var', (192, 200))	('transformation potential', 'CPA', (231, 255))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('induce', 'Reg', (214, 220))	('tumor', 'Disease', (92, 97))
312435	26872011	In addition, HRAS mutations were detected in both naive and treated MEMs, suggesting an intrinsic event rather than a chemotherapy-induced process.	('HRAS', 'Gene', (13, 17))	('HRAS', 'Gene', '3265', (13, 17))	('mutations', 'Var', (18, 27))
312436	26872011	Other notable mutations detected in rare MEM involve the PTPRD and FBXW7 genes.	('mutations', 'Var', (14, 23))	('FBXW7', 'Gene', (67, 72))	('PTPRD', 'Gene', '5789', (57, 62))	('FBXW7', 'Gene', '55294', (67, 72))	('PTPRD', 'Gene', (57, 62))
312439	26872011	Inactivation of PTPRD by deletion, mutation, or epigenetic methylation has been described in glioblastoma, melanoma, head and neck squamous cell carcinoma, and lung cancer .	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('glioblastoma', 'Disease', (93, 105))	('mutation', 'Var', (35, 43))	('Inactivation', 'NegReg', (0, 12))	('PTPRD', 'Gene', (16, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('epigenetic methylation', 'Var', (48, 70))	('PTPRD', 'Gene', '5789', (16, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('neck squamous cell carcinoma', 'Disease', (126, 154))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (126, 154))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('deletion', 'Var', (25, 33))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('lung cancer', 'Disease', (160, 171))
312440	26872011	Interestingly, recurrent microdeletions of PTPRD are also reported in neuroblastoma .	('PTPRD', 'Gene', (43, 48))	('microdeletions', 'Var', (25, 39))	('neuroblastoma', 'Disease', (70, 83))	('neuroblastoma', 'Phenotype', 'HP:0003006', (70, 83))	('reported', 'Reg', (58, 66))	('PTPRD', 'Gene', '5789', (43, 48))	('neuroblastoma', 'Disease', 'MESH:D009447', (70, 83))
312441	26872011	Most PTPRD mutations are located at conserved domains, such as immunoglobulin-like C2 type, fibronectin type III, or phosphatase catalytic domains.	('PTPRD', 'Gene', '5789', (5, 10))	('mutations', 'Var', (11, 20))	('PTPRD', 'Gene', (5, 10))
312442	26872011	The two PTPRD mutations detected in MEMs occur in the fibronectin type III domain.	('PTPRD', 'Gene', '5789', (8, 13))	('PTPRD', 'Gene', (8, 13))	('mutations', 'Var', (14, 23))	('occur', 'Reg', (41, 46))
312443	26872011	In contrast, RMS show frequent PTEN methylation (70%) or rare PTPN11 mutation (3.3%), the latter belongs to the non-receptor protein tyrosine phosphatases.	('RMS', 'Phenotype', 'HP:0002859', (13, 16))	('PTEN', 'Gene', (31, 35))	('PTEN', 'Gene', '5728', (31, 35))	('PTPN11', 'Gene', '5781', (62, 68))	('PTPN11', 'Gene', (62, 68))	('mutation', 'Var', (69, 77))	('tyrosine', 'Chemical', 'MESH:D014443', (133, 141))	('methylation', 'Var', (36, 47))
312446	26872011	FBXW7 mutations are widely found in human cancers and most mutations occur in the three arginine residues (R465, R479, R505) that are critical for substrate interaction.	('cancers', 'Disease', (42, 49))	('arginine', 'Chemical', 'MESH:D001120', (88, 96))	('FBXW7', 'Gene', '55294', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('R479', 'Var', (113, 117))	('R465', 'Var', (107, 111))	('FBXW7', 'Gene', (0, 5))	('occur', 'Reg', (69, 74))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('human', 'Species', '9606', (36, 41))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('R505', 'Var', (119, 123))
312447	26872011	FBXW7 mutations were occasionally described in fusion-negative RMS (2.4-6.4%) .	('FBXW7', 'Gene', '55294', (0, 5))	('RMS', 'Disease', (63, 66))	('RMS', 'Phenotype', 'HP:0002859', (63, 66))	('FBXW7', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
312455	26872011	The high frequency of HRAS mutations identified in MEM, corroborated with a skeletal muscle-related gene signature and retained H3K27me3 expression, suggest a closer relationship to RMS than MPNST.	('mutations', 'Var', (27, 36))	('MPNST', 'Phenotype', 'HP:0100697', (191, 196))	('RMS', 'Phenotype', 'HP:0002859', (182, 185))	('relationship', 'Interaction', (166, 178))	('HRAS', 'Gene', '3265', (22, 26))	('HRAS', 'Gene', (22, 26))	('RMS', 'Disease', (182, 185))
312493	26503545	This study aimed to determine whether differential morphological-associated genomic changes could aid in ascertaining the histogenesis of SS and to determine whether these sarcomas showed some specific mutated genes between epithelial and spindle cells that would promote tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('sarcomas', 'Phenotype', 'HP:0100242', (172, 180))	('aid', 'Gene', (98, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('tumor', 'Disease', (272, 277))	('sarcomas', 'Disease', (172, 180))	('metastasis', 'CPA', (291, 301))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('aid', 'Gene', '57379', (98, 101))	('SS', 'Phenotype', 'HP:0012570', (138, 140))	('promote', 'PosReg', (264, 271))	('mutated genes', 'Var', (202, 215))	('sarcomas', 'Disease', 'MESH:D012509', (172, 180))
312502	26503545	Here, we integrated the resulting data for 319 target genes with those from existing open-source resources with the following aims: detection of somatic variants between the epithelial and mesenchymal components in SS by genome-wide SNP analysis; linkage of target genes with additional biologically significant pathways and gene sets; and to provide insights into our previous mechanistic studies, thereby providing the basis for further experiments for characterizing the genetic factors that are involved in pathogenesis and that could aid in future targeted therapies for SS.	('aid', 'Gene', (539, 542))	('SS', 'Phenotype', 'HP:0012570', (215, 217))	('SS', 'Phenotype', 'HP:0012570', (576, 578))	('aid', 'Gene', '57379', (539, 542))	('variants', 'Var', (153, 161))
312513	26503545	The DNA was extracted from 24 FFPE tissue samples (12 patients), with quality metrics of A260/280 = 1.7-2.0 and A260/230 > 1.6.	('A260/280 =', 'Var', (89, 99))	('patients', 'Species', '9606', (54, 62))	('A260/230 >', 'Var', (112, 122))
312528	26503545	Approximately 249,101 single-nucleotide variants and small insertion and deletion changes were discovered for the epithelial and spindle cells components in the genomes of the 12 patients on comparison with the current reference haploid human genome sequence (Fig.	('human', 'Species', '9606', (237, 242))	('deletion', 'Var', (73, 81))	('patients', 'Species', '9606', (179, 187))	('single-nucleotide variants', 'Var', (22, 48))
312531	26503545	Mutations in 15 genes were specific for the spindle cell component (15/23, 65.2 %) (CTH, RBM44, LARS, HNRNPA, F13A, PIK3CG, GCN1L1, NGDN, AHNAK2, PRR14, RASAL3, DERL3, CELSR1, KLHL34 and EP300), and those in eight genes were specific for the epithelial cell component (8/23, 34.8 %) (ADAMTS2, TNXB, ADAP1, ACAN, DSEL, ETV2, MUM1L and BCORL1).	('CTH', 'Gene', (84, 87))	('RASAL3', 'Gene', (153, 159))	('RBM44', 'Gene', (89, 94))	('GCN1L1', 'Gene', '10985', (124, 130))	('F13A', 'Gene', (110, 114))	('PRR14', 'Gene', (146, 151))	('AHNAK2', 'Gene', '113146', (138, 144))	('EP300', 'Gene', '2033', (187, 192))	('ADAP1', 'Gene', (299, 304))	('NGDN', 'Gene', '25983', (132, 136))	('RASAL3', 'Gene', '64926', (153, 159))	('KLHL34', 'Gene', '257240', (176, 182))	('ADAMTS2', 'Gene', '9509', (284, 291))	('DSEL', 'Gene', '92126', (312, 316))	('Mutations', 'Var', (0, 9))	('RBM44', 'Gene', '375316', (89, 94))	('KLHL34', 'Gene', (176, 182))	('AHNAK2', 'Gene', (138, 144))	('EP300', 'Gene', (187, 192))	('ADAMTS2', 'Gene', (284, 291))	('DERL3', 'Gene', (161, 166))	('ACAN', 'Gene', '176', (306, 310))	('CTH', 'Gene', '23584', (84, 87))	('DERL3', 'Gene', '91319', (161, 166))	('ETV2', 'Gene', '2116', (318, 322))	('ACAN', 'Gene', (306, 310))	('PIK3CG', 'Gene', (116, 122))	('LARS', 'Gene', '51520', (96, 100))	('TNXB', 'Gene', '7148', (293, 297))	('PRR14', 'Gene', '78994', (146, 151))	('LARS', 'Gene', (96, 100))	('PIK3CG', 'Gene', '5294', (116, 122))	('NGDN', 'Gene', (132, 136))	('BCORL1', 'Gene', '63035', (334, 340))	('DSEL', 'Gene', (312, 316))	('HNRNPA', 'Gene', (102, 108))	('F13A', 'Gene', '2162', (110, 114))	('CELSR1', 'Gene', '9620', (168, 174))	('TNXB', 'Gene', (293, 297))	('ADAP1', 'Gene', '11033', (299, 304))	('ETV2', 'Gene', (318, 322))	('BCORL1', 'Gene', (334, 340))	('CELSR1', 'Gene', (168, 174))	('GCN1L1', 'Gene', (124, 130))
312540	26503545	This gene encodes a protein that contains a mutated melanoma-associated antigen 1 domain.	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('mutated', 'Var', (44, 51))
312541	26503545	Proteins that contain mutated antigens are probably expressed at high levels in certain types of cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('mutated', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Proteins', 'Protein', (0, 8))
312546	26503545	Although the precise function of SYT-SSX has not yet been studied, accumulating evidence suggests its role in gene regulation via epigenetic mechanisms, and the product of SYT-SSX target genes may serve as biomarkers of SS.	('SSX', 'Gene', (176, 179))	('SS', 'Phenotype', 'HP:0012570', (37, 39))	('SSX', 'Gene', '6757', (37, 40))	('SYT', 'Gene', '6760', (172, 175))	('SSX', 'Gene', (37, 40))	('gene regulation', 'MPA', (110, 125))	('epigenetic', 'Var', (130, 140))	('SYT', 'Gene', (33, 36))	('SS', 'Phenotype', 'HP:0012570', (220, 222))	('SS', 'Phenotype', 'HP:0012570', (176, 178))	('SYT', 'Gene', '6760', (33, 36))	('SYT', 'Gene', (172, 175))	('SSX', 'Gene', '6757', (176, 179))
312563	26503545	The differential mutations had 336 SNPs, which contained 319 genes (including TGF-beta1 pathway-related genes).	('TGF-beta1', 'Gene', (78, 87))	('mutations', 'Var', (17, 26))	('TGF-beta1', 'Gene', '7040', (78, 87))
312564	26503545	For example, exm1611770 in EP300, exm412589 in SPP1 and exm648916 in PIK3CG were found to be strongly associated with BSSs.	('exm412589', 'Var', (34, 43))	('associated', 'Reg', (102, 112))	('SPP1', 'Gene', '6696', (47, 51))	('SPP1', 'Gene', (47, 51))	('EP300', 'Gene', (27, 32))	('exm1611770', 'Var', (13, 23))	('EP300', 'Gene', '2033', (27, 32))	('PIK3CG', 'Gene', (69, 75))	('SS', 'Phenotype', 'HP:0012570', (119, 121))	('PIK3CG', 'Gene', '5294', (69, 75))	('BSSs', 'Disease', (118, 122))	('exm648916', 'Var', (56, 65))
312571	26503545	We found some significant mutations in genes whose functional annotations suggested involvement in cell adhesion, ECM-ECM receptor interactions, the TGF-beta signaling pathway and cell junctions and signaling.	('cell adhesion', 'CPA', (99, 112))	('TGF-beta', 'Gene', '7040', (149, 157))	('involvement', 'Reg', (84, 95))	('TGF-beta', 'Gene', (149, 157))	('mutations', 'Var', (26, 35))	('interactions', 'Interaction', (131, 143))	('cell', 'CPA', (180, 184))
312575	24014971	Although the demonstration of the tumor specific translocation, t (x; 18)(p11.2;q11.2) or the resultant fusion gene (SYT-SSX) is the gold standard for diagnosis, this test is not always accessible.	('SSX', 'Gene', '727837', (121, 124))	('SYT', 'Gene', (117, 120))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('t (x; 18)(p11.2', 'Var', (64, 79))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('SYT', 'Gene', '6857', (117, 120))	('SSX', 'Gene', (121, 124))
312593	24014971	Immunoperoxidase studies on paraffin embedded tissue revealed the neoplastic cells to be focally reactive with antibodies to pancytokeratin along with reactivity for epithelial membrane antibody in approximately 25% of the cells.	('paraffin', 'Chemical', 'MESH:D010232', (28, 36))	('pancytokeratin', 'Protein', (125, 139))	('antibodies', 'Var', (111, 121))
312616	20150931	Intralesional bleomycin (BLM) and feline interleukin-12 DNA (fIL-12 DNA) injection combined with trans-lesional electroporation resulted in complete cure of two recurrent World Health Organization (WHO) stageT2bN0M0 oral squamous cell carcinomas (SCCs)and one T2N0M0acanthomatous ameloblastoma.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (221, 245))	('SCCs', 'Phenotype', 'HP:0002860', (247, 251))	('bleomycin', 'Chemical', 'MESH:D001761', (14, 23))	('stageT2bN0M0', 'Var', (203, 215))	('T2N0M0acanthomatous ameloblastoma', 'Disease', (260, 293))	('fIL-12', 'Chemical', '-', (61, 67))	('oral squamous cell carcinomas', 'Disease', (216, 245))	('T2N0M0acanthomatous ameloblastoma', 'Disease', 'MESH:D000564', (260, 293))	('carcinomas', 'Phenotype', 'HP:0030731', (235, 245))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (216, 245))
312620	20150931	The dog with T 3N0M0 fibrosarcoma had tumor regression with recrudescence.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('fibrosarcoma', 'Disease', (21, 33))	('dog', 'Species', '9615', (4, 7))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (21, 33))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('fibrosarcoma', 'Disease', 'MESH:D005354', (21, 33))	('T 3N0M0', 'Var', (13, 20))
312627	20150931	In these studies, IL-12 EGT eradicates tumors and induces long-term anti-tumor memory, but is unable to eradicate large tumors.	('tumors', 'Disease', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('IL-12', 'Gene', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (39, 44))	('eradicates', 'NegReg', (28, 38))	('EGT', 'Var', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('induces', 'PosReg', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
312673	20150931	The most significant side effect was 48 hours of diarrhea for the dog with metastatic melanoma, but this dog had numerous other medical problems and demonstrated marked stress(aggression), making it difficult to directly link the diarrhea to the ECGT.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('diarrhea', 'Phenotype', 'HP:0002014', (230, 238))	('aggression', 'Disease', (176, 186))	('dog', 'Species', '9615', (105, 108))	('diarrhea', 'Disease', 'MESH:D003967', (230, 238))	('diarrhea', 'Disease', (230, 238))	('diarrhea', 'Phenotype', 'HP:0002014', (49, 57))	('diarrhea', 'Disease', 'MESH:D003967', (49, 57))	('diarrhea', 'Disease', (49, 57))	('aggression', 'Phenotype', 'HP:0000718', (176, 186))	('aggression', 'Disease', 'MESH:D001523', (176, 186))	('dog', 'Species', '9615', (66, 69))	('metastatic', 'Var', (75, 85))
312725	20150931	Both of these dogs were not deemed to be candidates for surgery, radiation, or chemotherapy because of their advanced disease; thus ECGT offered a safe, relatively non-invasive, method of local tumor control without the side effects associated with conventional cancer therapies.	('cancer', 'Disease', (262, 268))	('dogs', 'Species', '9615', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('ECGT', 'Var', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
312726	20150931	Electrogene therapy of IL-12 has also reached phase one clinical trials in humans and has had similar positive results.	('Electrogene therapy', 'Var', (0, 19))	('humans', 'Species', '9606', (75, 81))	('IL-12', 'Gene', (23, 28))
312728	20150931	Moreover, IL-12 EGT without any other therapy gave complete regression of non-electroporated distant metastases in 10% of the subjects and produced disease stabilization or partial response in an additional 42%.	('IL-12', 'Gene', (10, 15))	('metastases', 'Disease', (101, 111))	('regression', 'NegReg', (60, 70))	('EGT', 'Var', (16, 19))	('metastases', 'Disease', 'MESH:D009362', (101, 111))	('disease', 'MPA', (148, 155))
312774	32701199	There are several ongoing studies actively enrolling and exploring a number of novel therapies in liposarcoma, including, but not limited to, cabozantinib (NCT01913652) and sitravatinib (NCT02978859).	('liposarcoma', 'Disease', (98, 109))	('sitravatinib', 'Chemical', 'MESH:C000611865', (173, 185))	('cabozantinib', 'Chemical', 'MESH:C558660', (142, 154))	('NCT01913652', 'Var', (156, 167))	('liposarcoma', 'Phenotype', 'HP:0012034', (98, 109))	('liposarcoma', 'Disease', 'MESH:D008080', (98, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
312816	31123491	Moreover, compared with surgery, ablation offers the potential of decreased recovery time, a less invasive procedure, and is often performed in patients deemed not medically fit for surgery.	('recovery', 'MPA', (76, 84))	('ablation', 'Var', (33, 41))	('decreased', 'NegReg', (66, 75))	('patients', 'Species', '9606', (144, 152))
312843	30447641	Specifically, MDM2 amplification was observed to be significantly correlated with the successful establishment of PDX mouse models.	('amplification', 'Var', (19, 32))	('correlated', 'Reg', (66, 76))	('mouse', 'Species', '10090', (118, 123))	('MDM2', 'Gene', (14, 18))
312903	30447641	Target DNA (10 ng) was amplified by multiplex polymerase chain reaction (PCR) using fluorescent dye-linked primers for the 16 loci: 13 autosomal STR loci (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, TH01, TPOX, and vWA), 2 additional STR loci (D2S1338 and D19S433), and the amelogenin locus.	('D13S317', 'Var', (197, 204))	('FGA', 'Gene', (231, 234))	('D3S1358', 'Var', (163, 170))	('D19S433', 'Var', (293, 300))	('D21S11', 'Var', (223, 229))	('FGA', 'Gene', '2243', (231, 234))	('CSF1PO', 'Var', (155, 161))	('D5S818', 'Var', (172, 178))	('D16S539', 'Var', (206, 213))	('D7S820', 'Var', (180, 186))	('D2S1338', 'Var', (281, 288))	('D18S51', 'Var', (215, 221))	('D8S1179', 'Var', (188, 195))
312907	30447641	Test and reference DNA samples were labeled by random priming with either Cy3-dUTP or Cy5-dUTP using the Agilent Genomic DNA Labeling Kit PLUS (Agilent Technologies).	('Cy5-dUTP', 'Chemical', 'MESH:C088942', (86, 94))	('Cy3-dUTP', 'Var', (74, 82))	('Cy3-dUTP', 'Chemical', 'MESH:C088941', (74, 82))	('Cy5-dUTP', 'Var', (86, 94))
312919	30447641	Over 70% of LPSs exhibited MDM2 amplification (Table 1, Figure 2), and tumors were found in retroperitoneal area approximately 65% of the time (Table 1).	('LPSs', 'Chemical', '-', (12, 16))	('MDM2', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('exhibited', 'Reg', (17, 26))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
312926	30447641	These results show that amplification of MDM2 is not only an important factor affecting the malignancy and progression of liposarcoma but also a crucial factor for xenograft efficiency in mice.	('mice', 'Species', '10090', (188, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('xenograft efficiency', 'Disease', 'MESH:C536214', (164, 184))	('affecting', 'Reg', (78, 87))	('liposarcoma', 'Disease', (122, 133))	('malignancy', 'Disease', 'MESH:D009369', (92, 102))	('MDM2', 'Gene', (41, 45))	('amplification', 'Var', (24, 37))	('liposarcoma', 'Phenotype', 'HP:0012034', (122, 133))	('liposarcoma', 'Disease', 'MESH:D008080', (122, 133))	('malignancy', 'Disease', (92, 102))	('xenograft efficiency', 'Disease', (164, 184))
312935	30447641	The efficiency of the tumor growth rate reached 94.2% for DDLPSs and 0% for WDLPSs at the initial passage.	('LPSs', 'Chemical', '-', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('LPSs', 'Chemical', '-', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('DDLPSs', 'Var', (58, 64))
312947	30447641	However, despite the presence of CDK4 amplification in the patient-derived tumor cells, cells treated with LY2835219, the CDK4 inhibitor, did not significantly suppress cell proliferation when compared with control cells (mean growth = 100.0% vs. 80.23% for control and LY2835219-treated cells, respectively; 95% CI = 1.828%-37.72%; P = .377) (Figure 4B).	('LY2835219', 'Chemical', 'MESH:C000590451', (270, 279))	('CDK4', 'Gene', (33, 37))	('suppress', 'NegReg', (160, 168))	('patient', 'Species', '9606', (59, 66))	('LY2835219', 'Var', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('LY2835219', 'Chemical', 'MESH:C000590451', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cell proliferation', 'CPA', (169, 187))	('tumor', 'Disease', (75, 80))
312950	30447641	Liposarcoma is characterized by amplification of MDM2 on chromosome 12.	('Liposarcoma', 'Disease', (0, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Liposarcoma', 'Disease', 'MESH:D008080', (0, 11))	('Liposarcoma', 'Phenotype', 'HP:0012034', (0, 11))	('amplification', 'Var', (32, 45))	('MDM2', 'Gene', (49, 53))
312952	30447641	Moreover, it has been hypothesized that inhibition of MDM2 induces the activity of p53, thereby acting to treat liposarcoma.	('inhibition', 'Var', (40, 50))	('MDM2', 'Gene', (54, 58))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('liposarcoma', 'Disease', (112, 123))	('induces', 'Reg', (59, 66))	('activity', 'MPA', (71, 79))	('liposarcoma', 'Disease', 'MESH:D008080', (112, 123))	('liposarcoma', 'Phenotype', 'HP:0012034', (112, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
312994	30447641	In STR and DNA copy number alterations, the PDX models showed similarities to their corresponding tumors derived from patients.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('DNA', 'Gene', (11, 14))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('STR', 'Gene', (3, 6))	('copy number alterations', 'Var', (15, 38))	('patients', 'Species', '9606', (118, 126))
312995	30447641	In addition, these studies failed to reveal any confident point mutations or indels in the xenograft that could not be found in the original patient tumor.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('indels', 'Var', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('patient', 'Species', '9606', (141, 148))	('tumor', 'Disease', (149, 154))
313144	27894165	A phase II study of the Southwest Oncology Group (SWOG) reported a response rate of 40% (95% CI, 26%-56%), a median OS of 14 months (95% CI, 12-17 months), and tolerable toxicity with a regimen of paclitaxel (175 mg/m2) and carboplatin (AUC 6).	('carboplatin', 'Chemical', 'MESH:D016190', (224, 235))	('paclitaxel', 'Chemical', 'MESH:D017239', (197, 207))	('Oncology', 'Phenotype', 'HP:0002664', (34, 42))	('175 mg/m2', 'Var', (209, 218))	('OS', 'Chemical', '-', (116, 118))	('toxicity', 'Disease', 'MESH:D064420', (170, 178))	('toxicity', 'Disease', (170, 178))	('AUC 6', 'Chemical', '-', (237, 242))
313199	27894165	In a phase III trial, the Pazopanib for metastatic soft-tissue sarcoma (PALETTE) study, which reported interim results in 2012, in patients with metastatic and recurrent uterine LMS, PFS was improved using pazopanib compared with the placebo group (36.5% vs. 12.0% at the cutoff date of October 24, 2011).	('patients', 'Species', '9606', (131, 139))	('sarcoma', 'Disease', (63, 70))	('Pazopanib', 'Chemical', 'MESH:C516667', (26, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('improved', 'PosReg', (191, 199))	('pazopanib', 'Chemical', 'MESH:C516667', (206, 215))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (55, 70))	('PFS', 'MPA', (183, 186))	('pazopanib', 'Var', (206, 215))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
313275	22654552	Several surface markers have been studied in multiple malignancies as identifiers of TIC including CD20, CD24, CD34, CD44, CD90, CD117, and CD133.	('CD44', 'Gene', '12505', (117, 121))	('malignancies', 'Disease', (54, 66))	('CD34', 'Gene', (111, 115))	('CD24', 'Gene', (105, 109))	('CD20', 'Gene', (99, 103))	('CD44', 'Gene', (117, 121))	('CD34', 'Gene', '12490', (111, 115))	('CD133', 'Var', (140, 145))	('CD90', 'Gene', '21838', (123, 127))	('CD24', 'Gene', '12484', (105, 109))	('CD117', 'Gene', '16590', (129, 134))	('CD20', 'Gene', '12482', (99, 103))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('CD117', 'Gene', (129, 134))	('CD90', 'Gene', (123, 127))	('TIC', 'Phenotype', 'HP:0100033', (85, 88))
313280	22654552	In addition, frameshift mutations of CD133 have been associated with retinal degeneration.	('retinal degeneration', 'Disease', 'MESH:D012162', (69, 89))	('retinal degeneration', 'Disease', (69, 89))	('retinal degeneration', 'Phenotype', 'HP:0000546', (69, 89))	('CD133', 'Gene', (37, 42))	('associated', 'Reg', (53, 63))	('frameshift mutations', 'Var', (13, 33))
313301	22654552	Subsequent flow cytometric analysis of 21 human primary sarcomas and 2 osteosarcoma cell lines derived from biopsies again demonstrated that CD133+ cells exhibit stem cell-like properties.	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('human', 'Species', '9606', (42, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('CD133+', 'Var', (141, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcomas', 'Disease', (56, 64))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('osteosarcoma', 'Disease', (71, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))
313319	22654552	Additionally, they found CD133+ Ewing's sarcoma cells capable of differentiation to adipogenic, osteogenic, and chondrogenic lineages.	('chondrogenic lineages', 'CPA', (112, 133))	('differentiation', 'CPA', (65, 80))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (32, 47))	('CD133+', 'Var', (25, 31))	("Ewing's sarcoma", 'Disease', (32, 47))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (32, 47))	('adipogenic', 'MPA', (84, 94))	('osteogenic', 'CPA', (96, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
313335	22654552	As few as 160 ALDH-high cells were able to generate a serially transplantable tumor in NOD/SCID/IL-2Rgamma null mice, while no tumor growth was seen with 80,000 or less ALDH-low cells, and 3 of 7 mice injected with 80,000 unsorted cells grew tumor, but none grew tumor with less than 80,000 unsorted cells injected.	('cells', 'Var', (24, 29))	('mice', 'Species', '10090', (196, 200))	('ALDH', 'Gene', '11670', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (242, 247))	('ALDH', 'Gene', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('SCID', 'Gene', '19090', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('ALDH', 'Gene', (14, 18))	('tumor', 'Disease', (78, 83))	('ALDH', 'Gene', '11670', (169, 173))	('mice', 'Species', '10090', (112, 116))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('SCID', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
313345	22654552	Patients whose tumor expressed a low or intermediate level of CD133 had an overall survival rate of 75%, while patients with high CD133-expressing tumors had a significantly lower overall survival rate of 50%.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('CD133', 'Var', (62, 67))	('patients', 'Species', '9606', (111, 119))
313356	22654552	This issue clouds the ongoing debate about whether SICs reflect mesenchymal stem cells "gone bad" or if they arise from differentiated cells that have acquired stem-like properties as a result of the tumorigenic mutations.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('mutations', 'Var', (212, 221))	('SICs', 'Disease', (51, 55))	('SICs', 'Disease', 'None', (51, 55))
313367	22654552	Some groups have evaluated the combination of CD133 and ALDH, for example, as a means of further purifying a TIC population in a variety of malignancies.	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('malignancies', 'Disease', (140, 152))	('ALDH', 'Gene', '11670', (56, 60))	('CD133', 'Var', (46, 51))	('TIC', 'Phenotype', 'HP:0100033', (109, 112))	('ALDH', 'Gene', (56, 60))
313383	32100146	Regarding adverse events (AEs), apatinib was associated with a higher incidence of hair hypopigmentation and pneumothorax, while anlotinib was associated with a higher incidence of pharyngalgia or hoarseness.	('apatinib', 'Var', (32, 40))	('pneumothorax', 'Disease', 'MESH:D011030', (109, 121))	('hypopigmentation', 'Disease', 'MESH:D017496', (88, 104))	('hair hypopigmentation', 'Phenotype', 'HP:0005599', (83, 104))	('pneumothorax', 'Disease', (109, 121))	('pharyngalgia', 'Disease', (181, 193))	('apatinib', 'Chemical', 'MESH:C553458', (32, 40))	('hypopigmentation', 'Phenotype', 'HP:0001010', (88, 104))	('pharyngalgia', 'Disease', 'MESH:D010608', (181, 193))	('anlotinib', 'Chemical', 'MESH:C000625192', (129, 138))	('pneumothorax', 'Phenotype', 'HP:0002107', (109, 121))	('hypopigmentation', 'Disease', (88, 104))	('hoarseness', 'Disease', (197, 207))	('hoarseness', 'Phenotype', 'HP:0001609', (197, 207))
313449	32100146	AEs appeared to be more prevalent in the apatinib group than in the anlotinib group (Table 6).	('anlotinib', 'Chemical', 'MESH:C000625192', (68, 77))	('apatinib', 'Var', (41, 49))	('apatinib', 'Chemical', 'MESH:C553458', (41, 49))	('AEs', 'Disease', (0, 3))	('prevalent', 'Reg', (24, 33))
313452	32100146	Pharyngalgia or hoarseness was more frequent in the anlotinib group (Table 6).	('anlotinib', 'Var', (52, 61))	('hoarseness', 'Phenotype', 'HP:0001609', (16, 26))	('Pharyngalgia', 'Disease', (0, 12))	('hoarseness', 'Disease', (16, 26))	('Pharyngalgia', 'Disease', 'MESH:D010608', (0, 12))	('anlotinib', 'Chemical', 'MESH:C000625192', (52, 61))
313463	32100146	On the other hand, anlotinib was associated with a higher incidence of pharyngalgia or hoarseness.	('hoarseness', 'Disease', (87, 97))	('pharyngalgia', 'Disease', 'MESH:D010608', (71, 83))	('anlotinib', 'Chemical', 'MESH:C000625192', (19, 28))	('anlotinib', 'Var', (19, 28))	('hoarseness', 'Phenotype', 'HP:0001609', (87, 97))	('pharyngalgia', 'Disease', (71, 83))
313468	32100146	We screened clinical trials registered with ClinicalTrials.gov for nearly all small-molecule TKIs and found that only three TKIs (apatinib, regorafenib, and sorafenib) have been identified as promising for the treatment of osteosarcoma.	('regorafenib', 'Chemical', 'MESH:C559147', (140, 151))	('osteosarcoma', 'Disease', (223, 235))	('small-molecule', 'Var', (78, 92))	('osteosarcoma', 'Phenotype', 'HP:0002669', (223, 235))	('osteosarcoma', 'Disease', 'MESH:D012516', (223, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('sorafenib', 'Chemical', 'MESH:D000077157', (157, 166))	('apatinib', 'Chemical', 'MESH:C553458', (130, 138))
313473	32100146	We further observed an increased incidence of pneumothorax in patients with osteosarcoma who were treated with apatinib rather than with anlotinib.	('apatinib', 'Chemical', 'MESH:C553458', (111, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (76, 88))	('pneumothorax', 'Phenotype', 'HP:0002107', (46, 58))	('anlotinib', 'Chemical', 'MESH:C000625192', (137, 146))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('osteosarcoma', 'Disease', (76, 88))	('pneumothorax', 'Disease', 'MESH:D011030', (46, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('patients', 'Species', '9606', (62, 70))	('pneumothorax', 'Disease', (46, 58))	('apatinib', 'Var', (111, 119))
313537	32459396	The present study indicated that neoadjuvant chemotherapy increased the resectability of high-grade tumors, whereas adjuvant chemotherapy showed an adverse effect on survival (supplementary Table S2), which may be explained by the imbalanced distribution of tumor grade between patients who did and did not receive adjuvant chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('resectability', 'CPA', (72, 85))	('increased', 'PosReg', (58, 67))	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', (100, 105))	('neoadjuvant', 'Var', (33, 44))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('patients', 'Species', '9606', (278, 286))	('survival', 'CPA', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
313541	32459396	We demonstrated that R0/R1 resection, small tumor size, low grade, early-stage, thorough surgery, and adjuvant radiotherapy were predictors of prolonged OS and improved local control.	('low', 'Var', (56, 59))	('local control', 'CPA', (169, 182))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('improved', 'PosReg', (160, 168))	('tumor', 'Disease', (44, 49))	('R0/R1', 'Var', (21, 26))
313587	30405750	Tumor weight of the Tegafur group was higher than the normal saline group, but there was no significant difference (P>0.05).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor weight', 'CPA', (0, 12))	('higher', 'PosReg', (38, 44))	('Tegafur', 'Chemical', 'MESH:D005641', (20, 27))	('Tegafur', 'Var', (20, 27))
313593	30405750	TNF-alpha in the Tegafur group was significantly lower than that in normal saline group (P<0.05) (Table III).	('TNF-alpha', 'Gene', (0, 9))	('Tegafur', 'Chemical', 'MESH:D005641', (17, 24))	('lower', 'NegReg', (49, 54))	('TNF-alpha', 'Gene', '21926', (0, 9))	('Tegafur', 'Var', (17, 24))
313596	30405750	Total cholesterol in the Tegafur group was significantly higher than that in normal saline group (P<0.05).	('cholesterol', 'Chemical', 'MESH:D002784', (6, 17))	('Tegafur', 'Chemical', 'MESH:D005641', (25, 32))	('Tegafur', 'Var', (25, 32))	('higher', 'PosReg', (57, 63))
313597	30405750	BUN in the Tegafur group was significantly higher than that in the normal saline group (P<0.05) (Table IV).	('BUN', 'MPA', (0, 3))	('Tegafur', 'Chemical', 'MESH:D005641', (11, 18))	('Tegafur', 'Var', (11, 18))	('higher', 'PosReg', (43, 49))
313610	30405750	In this study, WBC, TLC, MONO, NEUT and BASO in Barbadian group were higher than that in the normal saline group.	('NEU', 'Gene', (31, 34))	('NEU', 'Gene', '13866', (31, 34))	('MONO', 'MPA', (25, 29))	('Barbadian', 'Var', (48, 57))	('TLC', 'MPA', (20, 23))	('WBC', 'MPA', (15, 18))	('higher', 'PosReg', (69, 75))
313621	30405750	IL-1 and IL-6 of combination therapy group were significantly higher, while TNF-alpha had no significant difference compared with the normal saline group.	('IL-1', 'Gene', '111343', (0, 4))	('combination', 'Var', (17, 28))	('TNF-alpha', 'Gene', '21926', (76, 85))	('IL-6', 'Gene', (9, 13))	('IL-6', 'Gene', '16193', (9, 13))	('TNF-alpha', 'Gene', (76, 85))	('higher', 'PosReg', (62, 68))	('IL-1', 'Gene', (0, 4))
313631	28756624	However, recent studies have suggested that MSCs also appear to contribute to tumor pathogenesis by supporting tumor microenvironments, increasing tumor growth, and eliciting antitumor immune responses.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('eliciting', 'Reg', (165, 174))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('MSCs', 'Var', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('increasing', 'PosReg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (78, 83))	('supporting', 'PosReg', (100, 110))	('tumor', 'Disease', (179, 184))
313654	28756624	Recently, MSCs have been indicated as the cellular origin of certain chromosomal translocation-associated solid tumors.47 Indeed, a number of studies have suggested that the introduction of the FLI-1/EWS fusion protein into MSCs may cause transformation of these cells into malignant sarcoma cells.48 Consistent with these studies, ectopic expression of other oncogenic proteins, such as the FUS/CHOP fusion protein or synovial sarcoma translocated protein (SYT-SSX1), in human MSCs can cause transformation of MSCs into myxoid liposarcomas49 or sarcoma cells,50 respectively.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (419, 435))	('sarcoma', 'Disease', (546, 553))	('sarcoma', 'Disease', 'MESH:D012509', (284, 291))	('sarcoma', 'Disease', 'MESH:D012509', (428, 435))	('sarcoma', 'Disease', (428, 435))	('sarcoma', 'Disease', (284, 291))	('FUS/CHOP', 'Gene', '2521', (392, 400))	('sarcoma', 'Phenotype', 'HP:0100242', (532, 539))	('sarcoma', 'Phenotype', 'HP:0100242', (546, 553))	('myxoid liposarcomas49', 'Disease', 'MESH:D045888', (521, 542))	('FUS/CHOP', 'Gene', (392, 400))	('human', 'Species', '9606', (472, 477))	('EWS', 'Gene', (200, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (428, 435))	('sarcoma', 'Phenotype', 'HP:0100242', (284, 291))	('myxoid liposarcomas49', 'Disease', (521, 542))	('MSCs', 'Disease', (511, 515))	('SYT', 'Gene', (458, 461))	('solid tumors', 'Disease', (106, 118))	('FLI-1', 'Gene', '2313', (194, 199))	('ectopic', 'Var', (332, 339))	('synovial sarcoma', 'Disease', (419, 435))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('SSX1', 'Gene', '6756', (462, 466))	('cause', 'Reg', (487, 492))	('synovial sarcoma', 'Disease', 'MESH:D013584', (419, 435))	('SSX1', 'Gene', (462, 466))	('FLI-1', 'Gene', (194, 199))	('EWS', 'Gene', '2130', (200, 203))	('sarcoma', 'Disease', 'MESH:D012509', (532, 539))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('SYT', 'Gene', '6760', (458, 461))	('sarcoma', 'Disease', (532, 539))	('sarcoma', 'Disease', 'MESH:D012509', (546, 553))
313663	28756624	MSCs recruitment to developing tumors with great affinity may initiate a vicious cycle in tumor progression, causing further recruitment of MSCs to tumor sites, thereby exacerbating various steps of tumor development such as proliferation/apoptosis, invasion, metastasis, and angiogenesis.19, 63  Tumor initiation and progression is not only affected by genetic alterations in the tumor cell itself but potentially also by non-tumor cells present in the microenvironment.	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (427, 432))	('Tumor', 'CPA', (297, 302))	('angiogenesis.19', 'Gene', (276, 291))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('Tumor', 'Phenotype', 'HP:0002664', (297, 302))	('genetic alterations', 'Var', (354, 373))	('tumor', 'Disease', (381, 386))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', (427, 432))	('tumor', 'Disease', 'MESH:D009369', (381, 386))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
313667	28756624	As their potential roles in cancer pathogenesis are still being elucidated in detail, several possible mechanisms through which MSCs promote cancer progression and metastasis are summarized in Table 1.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('promote', 'PosReg', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (28, 34))	('MSCs', 'Var', (128, 132))	('cancer', 'Disease', (141, 147))
313677	28756624	also reported that tumor-suppressive effects of MSCs can be correlated with their ability to inhibit target cell Akt signaling activity in a contact-dependent way.85 A potential mechanism of MSCs-mediated tumor cell suppression could also be related to its immunosuppressive effects.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MSCs-mediated', 'Var', (191, 204))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', (19, 24))	('suppression', 'NegReg', (216, 227))
313682	28756624	Umbilical cord-derived MSCs-EV can protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro.95 Subsequently, Yang et al.96 demonstrated that MSCs-EV were associated with the acquisition of protumorigenic properties by enhancing the expression of MMP-2 and MSCs-specific markers (CD73 and CD90) in breast and ovarian cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('tumor', 'Disease', (227, 232))	('CD90', 'Gene', (323, 327))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('enhancing', 'PosReg', (253, 262))	('CD90', 'Gene', '7070', (323, 327))	('MMP-2', 'Gene', '4313', (281, 286))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (332, 357))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('renal oxidative stress', 'Disease', (69, 91))	('CD73', 'Gene', '4907', (314, 318))	('MSCs-EV', 'Var', (176, 183))	('MMP-2', 'Gene', (281, 286))	('expression', 'MPA', (267, 277))	('ovarian cancer', 'Phenotype', 'HP:0100615', (343, 357))	('CD73', 'Gene', (314, 318))	('oxidative stress', 'Phenotype', 'HP:0025464', (75, 91))	('renal oxidative stress', 'Disease', 'MESH:D004194', (69, 91))
313683	28756624	Lin et al.98 noted that MSCs-EV stimulate the migration and growth of breast cancer cells by enhancing Wnt/beta-catenin signaling.	('stimulate', 'PosReg', (32, 41))	('beta-catenin', 'Gene', (107, 119))	('migration', 'CPA', (46, 55))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('MSCs-EV', 'Var', (24, 31))	('beta-catenin', 'Gene', '1499', (107, 119))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('enhancing', 'PosReg', (93, 102))	('growth', 'CPA', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
313684	28756624	Taken together, these findings suggest that MSCs-EV can mediate intercellular communication to improve tumor growth and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('improve', 'PosReg', (95, 102))	('tumor', 'Disease', (103, 108))	('mediate', 'Reg', (56, 63))	('MSCs-EV', 'Var', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
313690	28756624	It is generally thought that MSCs may be involved in multiple stages of cancer development as a source of soluble regulatory factors to regulate immune surveillance, tumor growth, and tumor angiogenesis and, when in direct contact with cancer cells, MSCs affect tumor growth, apoptosis, and chemodrug resistance.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (262, 267))	('cancer', 'Disease', (236, 242))	('tumor', 'Disease', (166, 171))	('chemodrug resistance', 'CPA', (291, 311))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('affect', 'Reg', (255, 261))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('MSCs', 'Var', (250, 254))	('apoptosis', 'CPA', (276, 285))
313709	27610198	MCT was indeed reported to be a multitargeted cancer therapy rather than a simple anti-angiogenic therapy as in addition to inhibiting tumour angiogenesis, MCT can also restore anticancer immune response, tilting the immune system from immunosuppression to immunostimulation, and inducing tumour dormancy.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('inhibiting', 'NegReg', (124, 134))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('MCT', 'Chemical', '-', (156, 159))	('tumour', 'Phenotype', 'HP:0002664', (289, 295))	('tumour', 'Disease', 'MESH:D009369', (289, 295))	('tumour', 'Disease', (289, 295))	('cancer', 'Disease', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('rat', 'Species', '10116', (61, 64))	('restore', 'PosReg', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', (181, 187))	('tumour', 'Disease', (135, 141))	('MCT', 'Var', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tilting', 'PosReg', (205, 212))	('MCT', 'Chemical', '-', (0, 3))	('inducing', 'Reg', (280, 288))
313753	27610198	Maria Jose Rico (Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Rosario, Argentina) gave a talk on the comparison between four different combined MCT schemes for mammary tumours; (A) Cy + Cel, (B) Cy + Dox, (C) Cy + Met, and (D) Met + Prop.	('Cy + Cel', 'Var', (232, 240))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('Cy', 'Chemical', 'MESH:D003520', (246, 248))	('Prop', 'Chemical', 'MESH:D011433', (284, 288))	('Cy + Dox', 'Var', (246, 254))	('Cy + Met', 'Var', (260, 268))	('MCT', 'Chemical', '-', (195, 198))	('Cy', 'Chemical', 'MESH:D003520', (260, 262))	('tumours', 'Phenotype', 'HP:0002664', (219, 226))	('tumours', 'Disease', 'MESH:D009369', (219, 226))	('Met', 'Chemical', 'MESH:D008687', (278, 281))	('Met', 'Chemical', 'MESH:D008687', (265, 268))	('Met + Prop', 'Var', (278, 288))	('Cel', 'Chemical', 'MESH:D000068579', (237, 240))	('tumours', 'Disease', (219, 226))	('Dox', 'Chemical', 'MESH:D004317', (251, 254))	('Cy', 'Chemical', 'MESH:D003520', (232, 234))
313756	27610198	Initially, she presented the results of the latest drug combination studied; the administration of Cy + Met showed antitumour and antimetastatic effects, prolonged survival, while having low toxicity.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('Cy', 'Chemical', 'MESH:D003520', (99, 101))	('prolonged', 'PosReg', (154, 163))	('low toxicity', 'Disease', (187, 199))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('low toxicity', 'Disease', 'MESH:D009800', (187, 199))	('survival', 'CPA', (164, 172))	('rat', 'Species', '10116', (89, 92))	('Cy + Met', 'Var', (99, 107))	('tumour', 'Disease', (119, 125))	('Met', 'Chemical', 'MESH:D008687', (104, 107))	('antimetastatic effects', 'CPA', (130, 152))
313758	27610198	The per cent of reduction of tumour volume with respect to the control group without treatment was different among treatments being higher for treatment B>C>A>D.	('B>C>A>D', 'Var', (153, 160))	('tumour', 'Disease', (29, 35))	('reduction', 'NegReg', (16, 25))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (29, 35))
313761	27610198	She concluded that taking into account the results of the comparisons the Cy + Dox and Cy + Met schemes were the most effective, having the second combination the advantage of its exclusive oral administration, thus covering fundamental aspects in the oncologic treatment as therapeutic efficacy, better quality of life, along with the always sought low toxicity.	('Dox', 'Chemical', 'MESH:D004317', (79, 82))	('Met', 'Chemical', 'MESH:D008687', (92, 95))	('quality of life', 'CPA', (304, 319))	('Cy', 'Chemical', 'MESH:D003520', (74, 76))	('Cy + Met', 'Var', (87, 95))	('Cy', 'Chemical', 'MESH:D003520', (87, 89))	('low toxicity', 'Disease', (350, 362))	('low toxicity', 'Disease', 'MESH:D009800', (350, 362))	('better', 'PosReg', (297, 303))	('rat', 'Species', '10116', (203, 206))
313773	27610198	A significant decrease in the IC50 was observed following MCT treatment in retinoblastoma and endothelial cell types compared with high single-dose treatment.	('MCT', 'Chemical', '-', (58, 61))	('MCT', 'Var', (58, 61))	('retinoblastoma', 'Disease', 'MESH:D012175', (75, 89))	('decrease', 'NegReg', (14, 22))	('retinoblastoma', 'Disease', (75, 89))	('retinoblastoma', 'Phenotype', 'HP:0009919', (75, 89))	('IC50', 'MPA', (30, 34))
313801	27610198	He mentioned that although patients receiving metronomic MCT had an 3-year OS and EFS higher than that observed in patients who did not receive continuous MCT (3-year OS 0.902 vs. 0.795, p=0.802, EFS 0.782 vs. 0.652, p=0.344), those differences were not statistically significant.	('patients', 'Species', '9606', (115, 123))	('MCT', 'Chemical', '-', (57, 60))	('EFS', 'MPA', (82, 85))	('MCT', 'Chemical', '-', (155, 158))	('metronomic MCT', 'Var', (46, 60))	('patients', 'Species', '9606', (27, 35))	('higher', 'PosReg', (86, 92))
313817	27610198	The first part of his talk was related to the background of the GEIS - 21 trial, based on two previous protocols: 1 - the modified P6 (mP6) that consisted of three courses of CDV (cyclophosphamide/vincristine/doxorubicin) and IE (ifosfamide 14 g/m2/course, instead of 9 g/m2 for poor histological responders, and etoposide), with a 4-year OS and EFS of 92% versus 42%, and 83% versus 28%, for localised versus metastatic disease, respectively; and 2 - the pilot study of G/D for advanced paediatric sarcomas with a reported overall response rate (ORR) of 63%, without major toxicity.	('P6', 'Gene', '50911', (136, 138))	('mP6', 'Gene', '50911', (135, 138))	('mP6', 'Gene', (135, 138))	('ifosfamide', 'Chemical', 'MESH:D007069', (230, 240))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (180, 196))	('sarcomas', 'Disease', 'MESH:D012509', (499, 507))	('doxorubicin', 'Chemical', 'MESH:D004317', (209, 220))	('rat', 'Species', '10116', (541, 544))	('sarcomas', 'Phenotype', 'HP:0100242', (499, 507))	('P6', 'Gene', '50911', (131, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (499, 506))	('toxicity', 'Disease', 'MESH:D064420', (574, 582))	('toxicity', 'Disease', (574, 582))	('sarcomas', 'Disease', (499, 507))	('G/D', 'Var', (471, 474))	('etoposide', 'Chemical', 'MESH:D005047', (313, 322))	('vincristine', 'Chemical', 'MESH:D014750', (197, 208))
313818	27610198	The aims of the study were to reproduce the mP6 results and to test the efficacy of G/D in newly diagnosed, previously untreated, high-risk (HR) ES patients, in a prospective, multicentric, non-randomised study, including patients <=40 years with ES and proved rearrangements of EWSR1.	('patients', 'Species', '9606', (148, 156))	('mP6', 'Gene', '50911', (44, 47))	('EWSR1', 'Gene', (279, 284))	('rearrangements', 'Var', (261, 275))	('patients', 'Species', '9606', (222, 230))	('mP6', 'Gene', (44, 47))	('EWSR1', 'Gene', '2130', (279, 284))
313857	27610198	His group had reported for the first time that dDAVP was capable of inhibiting lung colonisation by bloodborne tumour cells in preclinical mouse models of aggressive breast cancer.	('lung colonisation', 'CPA', (79, 96))	('inhibiting', 'NegReg', (68, 78))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (155, 179))	('aggressive breast cancer', 'Disease', (155, 179))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('bloodborne tumour', 'Disease', 'MESH:D009369', (100, 117))	('dDAVP', 'Var', (47, 52))	('mouse', 'Species', '10090', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('bloodborne tumour', 'Disease', (100, 117))
313915	33761114	Cause of death variable for infections was 001-136, 470-474, and 480-486 in the International Statistical Classification of Diseases and Related Health Problems, the tenth revision [ICD-8 codes] for cases diagnosed between 1975 to 1978, was 001-139, and 480-487 in ICD-9 for cases diagnosed between 1979 and 1998, and was A00-B99 and J09-J18 in ICD-10 for cases diagnosed between 1999 and 2016.	('infections', 'Disease', (28, 38))	('infections', 'Disease', 'MESH:D007239', (28, 38))	('J09-J18', 'Var', (334, 341))	('death', 'Disease', 'MESH:D003643', (9, 14))	('death', 'Disease', (9, 14))
313982	33761114	Higher risks of fatal infections among cancer patients were associated with male gender (HR 1.89, 95% CI 1.87-1.92, p < 0.001), black race (HR: 1.40, 95% CI: 1.37-1.42, p < 0.001), remote year of diagnosis (1975-1989, HR 2.18, 95% CI: 2.13-2.22, p < 0.001), unmarried status (HR 2.25, 95% CI: 2.22-2.28, p < 0.001), non-surgery (HR 1.88, 95% CI 1.86-1.91, p < 0.001), chemotherapy (HR 1.19, 95% CI 1.17-1.20, p < 0.001), and not receiving radiotherapy (HR: 1.36, 95% CI 1.34-1.38, p < 0.001).	('non-surgery', 'Disease', (316, 327))	('patients', 'Species', '9606', (46, 54))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('chemotherapy', 'Var', (368, 380))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('fatal infections', 'Disease', 'MESH:D007239', (16, 32))	('fatal infections', 'Disease', (16, 32))
314041	33761114	For instance, a study based on the SEER database revealed that single marital status is related to increased infectious mortality in women with invasive cervical cancer.	('mortality', 'Disease', 'MESH:D003643', (120, 129))	('women', 'Species', '9606', (133, 138))	('single marital status', 'Var', (63, 84))	('increased infectious mortality', 'Phenotype', 'HP:0002718', (99, 129))	('mortality', 'Disease', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('increased', 'PosReg', (99, 108))	('invasive cervical cancer', 'Disease', (144, 168))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (144, 168))	('infectious', 'CPA', (109, 119))
314227	32340113	In the case of synovial sarcoma >=II, and resection margins >=R1, the association of PNs >5.6 mm, well-defined margin nodules, increased PN size from baseline CT, and a new onset nodule, increases the risk of malignancy up to 28 times.	('synovial sarcoma', 'Disease', (15, 31))	('malignancy', 'Disease', (209, 219))	('PN size', 'MPA', (137, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (15, 31))	('PNs >5.6 mm', 'Var', (85, 96))	('synovial sarcoma', 'Disease', 'MESH:D013584', (15, 31))	('>=R1', 'Var', (60, 64))	('increased PN', 'Phenotype', 'HP:0008151', (127, 139))	('increased', 'PosReg', (127, 136))	('malignancy', 'Disease', 'MESH:D009369', (209, 219))
314335	24004183	Another possible mechanism is genetic variation in proteins involved in MTX metabolism may act independently of renal failure.	('MTX', 'Chemical', 'MESH:D008727', (72, 75))	('proteins', 'Protein', (51, 59))	('renal failure', 'Disease', 'MESH:D051437', (112, 125))	('renal failure', 'Disease', (112, 125))	('genetic variation', 'Var', (30, 47))	('renal failure', 'Phenotype', 'HP:0000083', (112, 125))
314342	24004183	This finding suggests that the incidence of delayed elimination without renal toxicity could not only be related to biliary excretion or genetic variation in transport proteins as suggested above, but may also be secondary to drug-drug interactions.	('renal toxicity', 'Disease', (72, 86))	('renal toxicity', 'Disease', 'MESH:D007674', (72, 86))	('biliary excretion', 'Disease', (116, 133))	('delayed elimination', 'MPA', (44, 63))	('biliary excretion', 'Disease', 'MESH:D001658', (116, 133))	('drug-drug interactions', 'Phenotype', 'HP:0020172', (226, 248))	('genetic variation', 'Var', (137, 154))
314379	24103491	Postoperative immunohistochemistry results indicated ER-, AR-, CK(Pan)+-, CD34-, EMA-, CerbB2-, S-100-, Vimentin+++, EGFR-, P63-, SMA+, Calponin-, D2-40+, MBP-, CD99+++, beta-catenin++, confirming diagnosis of synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (210, 226))	('ER-', 'Var', (53, 56))	('synovial sarcoma', 'Disease', 'MESH:D013584', (210, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('CD34', 'Gene', (74, 78))	('CerbB2', 'Gene', '2064', (87, 93))	('CD34', 'Gene', '947', (74, 78))	('EGFR', 'Gene', '1956', (117, 121))	('CD99', 'Gene', (161, 165))	('EGFR', 'Gene', (117, 121))	('P63', 'Gene', '8626', (124, 127))	('MBP', 'Gene', '4155', (155, 158))	('CerbB2', 'Gene', (87, 93))	('synovial sarcoma', 'Disease', (210, 226))	('MBP', 'Gene', (155, 158))	('CD99', 'Gene', '4267', (161, 165))	('P63', 'Gene', (124, 127))	('D2-40+', 'Var', (147, 153))
314451	30867708	Furthermore, the expression of beta-catenin and c-myc were increased with the combination of CHIR 99021 and resveratrol compared with the resveratrol alone group.	('c-myc', 'Gene', '4609', (48, 53))	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))	('resveratrol', 'Chemical', 'MESH:D000077185', (138, 149))	('expression', 'MPA', (17, 27))	('CHIR 99021', 'Var', (93, 103))	('c-myc', 'Gene', (48, 53))	('resveratrol', 'Chemical', 'MESH:D000077185', (108, 119))	('increased', 'PosReg', (59, 68))
314452	30867708	CHIR99021 reduced the level of active beta-catenin and c-myc by blunting the effect of resveratrol.	('beta-catenin', 'Gene', (38, 50))	('reduced', 'NegReg', (10, 17))	('c-myc', 'Gene', '4609', (55, 60))	('beta-catenin', 'Gene', '1499', (38, 50))	('c-myc', 'Gene', (55, 60))	('resveratrol', 'Chemical', 'MESH:D000077185', (87, 98))	('blunting', 'NegReg', (64, 72))	('CHIR99021', 'Var', (0, 9))
314495	29422483	Our previous study showed that IMPF affects Th1/Th2 cytokines and antibody concentrations, which may switch the immune response to its humoral pathway in BALB/c mice.	('switch', 'Reg', (101, 107))	('Th2', 'Gene', (48, 51))	('affects', 'Reg', (36, 43))	('mice', 'Species', '10090', (161, 165))	('Th2', 'Gene', '15111', (48, 51))	('immune response', 'MPA', (112, 127))	('Th1', 'Gene', '57314', (44, 47))	('IMPF', 'Chemical', 'MESH:D012524', (31, 35))	('IMPF', 'Var', (31, 35))	('Th1', 'Gene', (44, 47))
314567	29422483	It seems that IMPF may affect the autonomic nervous system, crucial to the neuro-immunomodulatory processes.	('IMPF', 'Chemical', 'MESH:D012524', (14, 18))	('autonomic nervous system', 'MPA', (34, 58))	('affect', 'Reg', (23, 29))	('IMPF', 'Var', (14, 18))
314677	24107169	Other tests identify gene-specific mutations, such as for KIT in gastrointestinal stromal tumours (GIST).	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (65, 97))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('gastrointestinal stromal tumours', 'Disease', (65, 97))	('KIT', 'Gene', (58, 61))	('mutations', 'Var', (35, 44))
314681	24107169	It was shown that, in a variable proportion of the cases (depending on the type of sarcoma), the molecular testing contributed significantly, by either confirming a probable diagnosis or providing a diagnosis when conventional analysis was inconclusive.	('sarcoma', 'Disease', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('molecular', 'Var', (97, 106))	('confirming', 'Reg', (152, 162))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))
314682	24107169	It is not cost-effective and it is also labour-intensive to maintain a wide range of individual approved diagnostic tests for the many mutations and translocations that occur in the various sarcoma subtypes.	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('translocations', 'Var', (149, 163))	('mutations', 'Var', (135, 144))	('sarcoma', 'Disease', (190, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))
314696	24107169	In the first group, a large number of chromosomal abnormalities coexist simultaneously; these can include multiple chromosomal translocations, and gene mutations, amplifications, and deletions.	('gene mutations', 'Var', (147, 161))	('large number of chromosomal abnormalities', 'Phenotype', 'HP:0040012', (22, 63))	('chromosomal abnormalities', 'Disease', (38, 63))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (38, 63))	('amplifications', 'Var', (163, 177))	('deletions', 'Var', (183, 192))
314700	24107169	The first comprises gene point mutations, such as those that occur in KIT or PDGFRA in GIST.	('KIT', 'Gene', (70, 73))	('PDGFRA', 'Gene', '5156', (77, 83))	('PDGFRA', 'Gene', (77, 83))	('point mutations', 'Var', (25, 40))
314701	24107169	Another genomic abnormality is that of gene amplification, and an example of this is the amplification of MDM2 that is seen in atypical lipomatous tumour/well-differentiated liposarcoma and the dedifferentiated form of this tumour.	('lipomatous tumour', 'Disease', 'MESH:D008080', (136, 153))	('tumour', 'Disease', (224, 230))	('liposarcoma', 'Phenotype', 'HP:0012034', (174, 185))	('lipomatous tumour', 'Phenotype', 'HP:0012031', (136, 153))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('liposarcoma', 'Disease', (174, 185))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('MDM2', 'Gene', '4193', (106, 110))	('seen in', 'Reg', (119, 126))	('MDM2', 'Gene', (106, 110))	('lipomatous tumour', 'Disease', (136, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('liposarcoma', 'Disease', 'MESH:D008080', (174, 185))	('amplification', 'Var', (89, 102))	('tumour', 'Disease', (147, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
314705	24107169	Since the publication of the review by Demicco and Lazar in 2011, several additional chromosomal translocations have been reported, such as the t(10;17) translocation that characterizes the novel subset of high-grade endometrial stromal sarcomas, the t(5;8) translocation that is found in angiofibroma, and the gene fusion between NAB2 and STAT6 on chromosome 12 in solitary fibrous tumours.	('STAT6', 'Gene', '6778', (340, 345))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('angiofibroma', 'Disease', (289, 301))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (217, 245))	('sarcomas', 'Phenotype', 'HP:0100242', (237, 245))	('solitary fibrous tumours', 'Disease', (366, 390))	('NAB2', 'Gene', (331, 335))	('solitary fibrous tumours', 'Disease', 'MESH:D054364', (366, 390))	('NAB2', 'Gene', '4665', (331, 335))	('angiofibroma', 'Disease', 'MESH:D018322', (289, 301))	('tumour', 'Phenotype', 'HP:0002664', (383, 389))	('STAT6', 'Gene', (340, 345))	('tumours', 'Phenotype', 'HP:0002664', (383, 390))	('gene fusion', 'Var', (311, 322))	('endometrial stromal sarcomas', 'Disease', (217, 245))
314706	24107169	Interestingly, chromosomal translocations have now been reported not only in malignant tumours (sarcomas), but also in benign soft tissue lesions and bone lesions.	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('bone lesions', 'Disease', 'MESH:D001847', (150, 162))	('chromosomal translocations', 'Var', (15, 41))	('reported', 'Reg', (56, 64))	('sarcomas', 'Disease', (96, 104))	('malignant tumours', 'Disease', 'MESH:D009369', (77, 94))	('bone lesions', 'Disease', (150, 162))	('malignant tumours', 'Disease', (77, 94))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))
314710	24107169	The most dramatic example of this is Ewing's sarcoma, in which a large number of genes can be fused with EWSR1 (or less commonly with FUS and other genes) to result in the EWS phenotype.	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('fused', 'Var', (94, 99))	('EWS', 'Disease', (172, 175))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (37, 52))	('result in', 'Reg', (158, 167))	('EWSR1', 'Gene', (105, 110))	('FUS', 'Gene', (134, 137))	('FUS', 'Gene', '2521', (134, 137))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (37, 52))	("Ewing's sarcoma", 'Disease', (37, 52))	('EWSR1', 'Gene', '2130', (105, 110))
314726	24107169	As mentioned above, there have been dramatic increases not only in the number of chromosomal translocations that have been discovered to be diagnostic for a range of tumours, but also in the complexity of these translocations.	('increases', 'PosReg', (45, 54))	('tumours', 'Disease', (166, 173))	('chromosomal translocations', 'Var', (81, 107))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('tumours', 'Disease', 'MESH:D009369', (166, 173))
314733	24107169	With this approach, we could identify translocations in synovial sarcomas (three of three cases), myxoid liposarcoma (three of three cases), and clear cell sarcoma (one of one case).	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (98, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('synovial sarcomas', 'Disease', 'MESH:D013584', (56, 73))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (98, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (145, 163))	('liposarcoma', 'Phenotype', 'HP:0012034', (105, 116))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (56, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('myxoid liposarcoma', 'Disease', (98, 116))	('synovial sarcomas', 'Disease', (56, 73))	('translocations', 'Var', (38, 52))	('clear cell sarcoma', 'Disease', (145, 163))
314745	24109526	FLT3 ITD is generally strongly associated with poor prognosis in AML, and is rarely reported in patients with t(8;21).	('AML', 'Disease', (65, 68))	('AML', 'Phenotype', 'HP:0004808', (65, 68))	('FLT3', 'Gene', '2322', (0, 4))	('associated', 'Reg', (31, 41))	('patients', 'Species', '9606', (96, 104))	('AML', 'Disease', 'MESH:D015470', (65, 68))	('FLT3', 'Gene', (0, 4))	('ITD', 'Var', (5, 8))
314754	24109526	Rarely, it was described the presence of FLT3 internal tandem duplication (ITD) mutation in AML patients presenting with GS.	('FLT3', 'Gene', (41, 45))	('AML', 'Disease', 'MESH:D015470', (92, 95))	('FLT3', 'Gene', '2322', (41, 45))	('patients', 'Species', '9606', (96, 104))	('AML', 'Phenotype', 'HP:0004808', (92, 95))	('AML', 'Disease', (92, 95))	('internal tandem duplication', 'Var', (46, 73))	('GS', 'Disease', 'MESH:D011125', (121, 123))	('mutation', 'Var', (80, 88))
314755	24109526	FLT3 ITD is generally strongly associated with poor prognosis in AML and is rarely reported in patients with t(8;21).	('AML', 'Disease', (65, 68))	('AML', 'Phenotype', 'HP:0004808', (65, 68))	('patients', 'Species', '9606', (95, 103))	('associated', 'Reg', (31, 41))	('AML', 'Disease', 'MESH:D015470', (65, 68))	('FLT3', 'Gene', '2322', (0, 4))	('FLT3', 'Gene', (0, 4))	('ITD', 'Var', (5, 8))
314764	24109526	Serial bone marrow (BM) aspirates, performed after each consolidation course, confirmed the condition of morphologic CR; however, quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) demonstrated the persistence of RUNX1-RUNX1T1 fusion transcript either after induction or consolidation cycles.	('CR', 'Chemical', '-', (117, 119))	('RUNX1', 'Gene', '861', (234, 239))	('RUNX1T1', 'Gene', (240, 247))	('fusion', 'Var', (248, 254))	('CR', 'Chemical', '-', (198, 200))	('RUNX1', 'Gene', (234, 239))	('RUNX1', 'Gene', (240, 245))	('RUNX1T1', 'Gene', '862', (240, 247))	('RUNX1', 'Gene', '861', (240, 245))
314791	24109526	GS associated with translocations t(8;21)(q22;q22)/RUNX1-RUNX1T1 transcript frequently locates in the orbital region in children, while those with inv(16) (p13.1q22)/t(16;16)(p13.1;q22) have a high incidence of gastrointestinal tract or breast involvement, especially in the adults.	('RUNX1', 'Gene', (51, 56))	('RUNX1T1', 'Gene', (57, 64))	('gastrointestinal tract', 'Disease', (211, 233))	('t(8;21)(q22;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (34, 50))	('RUNX1', 'Gene', '861', (51, 56))	('translocations t(8;21)(q22', 'Var', (19, 45))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (211, 233))	('RUNX1', 'Gene', (57, 62))	('RUNX1T1', 'Gene', '862', (57, 64))	('RUNX1', 'Gene', '861', (57, 62))	('breast involvement', 'Disease', (237, 255))	('GS', 'Disease', 'MESH:D011125', (0, 2))	('t(16;16)(p13.1;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (166, 185))	('children', 'Species', '9606', (120, 128))
314794	24109526	In AML, FLT3-ITD mutations appear to be associated with an increased risk of relapse, short duration of disease free, and overall survival.	('relapse', 'CPA', (77, 84))	('FLT3', 'Gene', '2322', (8, 12))	('FLT3', 'Gene', (8, 12))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('mutations', 'Var', (17, 26))	('associated', 'Reg', (40, 50))	('AML', 'Disease', (3, 6))
314795	24109526	The incidence of FLT3-ITD mutations is the highest among AML patients with normal karyotype, whereas it is very low in AML with t(8;21).	('AML', 'Disease', 'MESH:D015470', (57, 60))	('highest', 'Reg', (43, 50))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('patients', 'Species', '9606', (61, 69))	('mutations', 'Var', (26, 35))	('FLT3', 'Gene', '2322', (17, 21))	('AML', 'Phenotype', 'HP:0004808', (119, 122))	('AML', 'Disease', (57, 60))	('AML', 'Disease', (119, 122))	('AML', 'Phenotype', 'HP:0004808', (57, 60))	('FLT3', 'Gene', (17, 21))
314796	24109526	Moreover, FLT3 mutations have been extensively investigated in AML, whereas little is known about their incidence in GS.	('FLT3', 'Gene', (10, 14))	('AML', 'Disease', (63, 66))	('mutations', 'Var', (15, 24))	('FLT3', 'Gene', '2322', (10, 14))	('AML', 'Disease', 'MESH:D015470', (63, 66))	('GS', 'Disease', 'MESH:D011125', (117, 119))	('investigated', 'Reg', (47, 59))	('AML', 'Phenotype', 'HP:0004808', (63, 66))
314797	24109526	To the best of our knowledge, only one report demonstrated that FLT3 ITD mutations occur in approximately 15% of GS and that the mutation was concomitantly present in BM and sarcoma specimens in the large majority of cases.	('FLT3', 'Gene', '2322', (64, 68))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('GS', 'Disease', 'MESH:D011125', (113, 115))	('FLT3', 'Gene', (64, 68))	('sarcoma', 'Disease', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('mutations', 'Var', (73, 82))
314798	24109526	In this report, no patients are reported to have FLT3-ITD mutations and contemporary mastoid or paravertebral involvement.	('mutations', 'Var', (58, 67))	('mastoid or paravertebral involvement', 'Disease', 'MESH:D008417', (85, 121))	('patients', 'Species', '9606', (19, 27))	('FLT3', 'Gene', (49, 53))	('mastoid or paravertebral involvement', 'Disease', (85, 121))	('FLT3', 'Gene', '2322', (49, 53))
314799	24109526	Based on this, there is very little evidence to speculate about the association between FLT3 ITD mutations and occurrence of GS even why we were not able to demonstrate the presence of FLT3-ITD mutation in the mastoid sarcoma tissue.	('mutations', 'Var', (97, 106))	('GS', 'Disease', 'MESH:D011125', (125, 127))	('FLT3', 'Gene', '2322', (88, 92))	('mastoid sarcoma', 'Disease', 'MESH:D008417', (210, 225))	('FLT3', 'Gene', (88, 92))	('FLT3', 'Gene', '2322', (185, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('mastoid sarcoma', 'Disease', (210, 225))	('FLT3', 'Gene', (185, 189))
314818	32888360	Patients with cancer have been impacted by deferral, modification, and even cessation of therapy.	('cancer', 'Disease', (14, 20))	('modification', 'Var', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('deferral', 'Var', (43, 51))
314840	32888360	SARS-CoV-2 causes an overwhelming persistent innate-induced inflammation that can lead to a cytokine storm, cytokine-associated lung injury, and diffuse organ involvement [5].	('SARS-CoV-2', 'Species', '2697049', (0, 10))	('cytokine storm', 'MPA', (92, 106))	('lead to', 'Reg', (82, 89))	('lung injury', 'Disease', 'MESH:D055370', (128, 139))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('lung injury', 'Disease', (128, 139))	('inflammation', 'Disease', (60, 72))	('SARS-CoV-2', 'Var', (0, 10))	('diffuse organ involvement', 'Disease', (145, 170))
314849	32888360	Decisions on whether or not to postpone cancer treatment and clinical trials need to be made on a patient-by-patient basis and according to the inherent tumor risk in each patient and the prevailing situation, because delays could lead to tumor progression and, ultimately, poorer outcomes [11].	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('lead to', 'Reg', (231, 238))	('patient', 'Species', '9606', (109, 116))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('patient', 'Species', '9606', (172, 179))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('delays', 'Var', (218, 224))
314918	31624761	Neurofibromatosis type I (NF1), also known as von Recklinghausen disease, is an autosomal dominant neurocutaneous disorder caused by a mutation in the NF1 gene, and it usually presents during the first decade of life.	('von Recklinghausen disease', 'Disease', 'MESH:D009456', (46, 72))	('Neurofibromatosis type I', 'Disease', (0, 24))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('NF1', 'Gene', (26, 29))	('autosomal dominant neurocutaneous disorder', 'Disease', 'MESH:D020752', (80, 122))	('von Recklinghausen disease', 'Disease', (46, 72))	('NF1', 'Gene', (151, 154))	('NF1', 'Gene', '4763', (26, 29))	('Neurofibromatosis type I', 'Disease', 'MESH:D009456', (0, 24))	('NF1', 'Gene', '4763', (151, 154))	('caused by', 'Reg', (123, 132))	('mutation', 'Var', (135, 143))	('autosomal dominant neurocutaneous disorder', 'Disease', (80, 122))
314922	31624761	The exact pathogenesis of NF1 is unclear, and mutations in the NF1 gene are important causes of NF1.	('mutations', 'Var', (46, 55))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', '4763', (26, 29))	('causes', 'Reg', (86, 92))	('NF1', 'Gene', (96, 99))	('NF1', 'Gene', (63, 66))	('NF1', 'Gene', '4763', (96, 99))	('NF1', 'Gene', '4763', (63, 66))
314950	31624761	NF1, spindle cell sarcoma with mutations in ROS1 genes.	('ROS1', 'Gene', (44, 48))	('mutations', 'Var', (31, 40))	('ROS1', 'Gene', '6098', (44, 48))	('spindle cell sarcoma', 'Disease', 'MESH:D012509', (5, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('spindle cell sarcoma', 'Disease', (5, 25))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))
314958	31624761	Studies have found that mutations in the NF1 gene located in the periphery of the 17q11.2 center are important causes of NF1.	('NF1', 'Gene', '4763', (121, 124))	('causes', 'Reg', (111, 117))	('NF1', 'Gene', (41, 44))	('mutations', 'Var', (24, 33))	('NF1', 'Gene', '4763', (41, 44))	('NF1', 'Gene', (121, 124))
314961	31624761	Mutation in the NF1 gene (such as heterozygous, loss-of-function mutations, etc) results in the loss of function of neurofibromin with increased RAS activity, ultimately leading to increased proliferation and tumorigenesis, especially in the cutaneous and nervous tissues.	('NF1', 'Gene', (16, 19))	('neurofibromin', 'Gene', (116, 129))	('tumor', 'Disease', (209, 214))	('NF1', 'Gene', '4763', (16, 19))	('loss of function', 'NegReg', (96, 112))	('Mutation', 'Var', (0, 8))	('activity', 'MPA', (149, 157))	('increased', 'PosReg', (135, 144))	('neurofibromin', 'Gene', '4763', (116, 129))	('RAS', 'Protein', (145, 148))	('loss-of-function', 'NegReg', (48, 64))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('proliferation', 'CPA', (191, 204))	('increased', 'PosReg', (181, 190))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('mutations', 'Var', (65, 74))
315068	30935298	In particular, H3F3A mutations may help to differentiate GCTB from giant cell-rich sarcomas.	('help', 'Reg', (35, 39))	('mutations', 'Var', (21, 30))	('GCTB', 'Phenotype', 'HP:0011847', (57, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcomas', 'Disease', (83, 91))	('H3F3A', 'Gene', '3020', (15, 20))	('GCTB', 'Disease', (57, 61))	('sarcomas', 'Disease', 'MESH:D012509', (83, 91))	('H3F3A', 'Gene', (15, 20))
315069	30935298	In a recent study, 24 of the 25 GCTBs evaluated had an H3F3A mutation compared with 5 of 35 giant cell-rich sarcomas; all of the sarcomas with the mutation were secondary malignant GCTB.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('GCTBs', 'Chemical', '-', (32, 37))	('GCTB', 'Phenotype', 'HP:0011847', (181, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('mutation', 'Var', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcomas', 'Disease', (108, 116))	('H3F3A', 'Gene', '3020', (55, 60))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('H3F3A', 'Gene', (55, 60))	('GCTB', 'Phenotype', 'HP:0011847', (32, 36))	('sarcomas', 'Disease', (129, 137))
315077	30935298	It is generally accepted that malignant GCTB is a high-grade sarcoma; however, data from the MSKCC show that malignant GCTB behaves like a low- or intermediate-grade sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('GCTB', 'Phenotype', 'HP:0011847', (119, 123))	('sarcoma', 'Disease', (166, 173))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('malignant', 'Var', (109, 118))	('sarcoma', 'Disease', (61, 68))	('GCTB', 'Phenotype', 'HP:0011847', (40, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
315175	22911243	Aldefluor assay and analyses of cell surface antigen expression of CD44, CD90, CD73, CD105, and CD133/2(293C) were performed by flow cytometry, as described previously.	('CD133', 'Gene', (96, 101))	('cell surface antigen', 'Gene', (32, 52))	('CD133', 'Gene', '8842', (96, 101))	('CD73', 'Gene', '4907', (79, 83))	('CD44', 'Gene', '960', (67, 71))	('CD44', 'Gene', (67, 71))	('CD90', 'Gene', (73, 77))	('CD73', 'Gene', (79, 83))	('CD105', 'Var', (85, 90))	('cell surface antigen', 'Gene', '963', (32, 52))	('CD90', 'Gene', '7070', (73, 77))	('293C', 'CellLine', 'CVCL:0045', (104, 108))
315181	22911243	LPS141, SA-4, T778 and SW872 displayed relatively high proliferative capacity and LISA-2, T449, GOT-3, FU-DDLS-1, and T1000 displayed lower proliferative capacity (Figure 1(a)).	('T778', 'Var', (14, 18))	('lower', 'NegReg', (134, 139))	('proliferative capacity', 'CPA', (140, 162))	('SA-4', 'Chemical', '-', (8, 12))	('SW872', 'Var', (23, 28))	('T1000', 'Chemical', '-', (118, 123))	('SW872', 'CellLine', 'CVCL:1730', (23, 28))	('LPS141', 'Chemical', '-', (0, 6))	('proliferative capacity', 'CPA', (55, 77))
315184	22911243	LPS141, SA-4, T778, SW872, and LISA-2 all formed tumors by 6 months (Figure 1(b)).	('T778', 'Var', (14, 18))	('SW872', 'CellLine', 'CVCL:1730', (20, 25))	('LISA-2', 'Gene', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('formed', 'PosReg', (42, 48))	('SA-4', 'Chemical', '-', (8, 12))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('LPS141', 'Chemical', '-', (0, 6))	('SW872', 'Var', (20, 25))	('LPS141', 'Var', (0, 6))
315191	22911243	T778 expressed only CEBPB and FABP4 strongly, a pattern which could not be correlated with hMSC.	('T778', 'Var', (0, 4))	('FABP4', 'Gene', (30, 35))	('FABP4', 'Gene', '2167', (30, 35))	('CEBPB', 'Gene', (20, 25))	('CEBPB', 'Gene', '1051', (20, 25))
315198	22911243	T778 expressed high levels of SOX2 only.	('T778', 'Var', (0, 4))	('SOX2', 'Gene', '6657', (30, 34))	('SOX2', 'Gene', (30, 34))
315199	22911243	We also determined the cell surface expression of CD90, CD105, CD73, CD44 (Figure 4(b)), and CD133 (Figure 4(c)) and measured aldehyde dehydrogenase (ALDH) activity (Figure 4(c)).	('CD133', 'Gene', (93, 98))	('CD133', 'Gene', '8842', (93, 98))	('CD105', 'Var', (56, 61))	('CD73', 'Gene', '4907', (63, 67))	('CD90', 'Gene', '7070', (50, 54))	('activity', 'MPA', (156, 164))	('CD90', 'Gene', (50, 54))	('CD44', 'Gene', '960', (69, 73))	('CD73', 'Gene', (63, 67))	('CD44', 'Gene', (69, 73))	('aldehyde', 'MPA', (126, 134))
315205	22911243	LPS141 displayed significant Aldefluor activity (>3% of the cells), while the other lines contained subpopulations of <0.2%  Aldefluorhigh.	('LPS141', 'Chemical', '-', (0, 6))	('Aldefluor activity', 'MPA', (29, 47))	('LPS141', 'Var', (0, 6))
315207	22911243	LPS141, T778, SW872, FU-DDLS-1, and T1000 had very low colony-forming ability (<10%).	('SW872', 'CellLine', 'CVCL:1730', (14, 19))	('SW872', 'Var', (14, 19))	('colony-forming ability', 'CPA', (55, 77))	('low', 'NegReg', (51, 54))	('T778', 'Var', (8, 12))	('LPS141', 'Chemical', '-', (0, 6))	('T1000', 'Chemical', '-', (36, 41))	('LPS141', 'Var', (0, 6))
315208	22911243	LPS141, T778, and FU-DDLS-1 displayed high capacity to migrate during 22-hour incubation in Boyden Chambers.	('migrate', 'CPA', (55, 62))	('FU-DDLS-1', 'Gene', (18, 27))	('T778', 'Var', (8, 12))	('LPS141', 'Chemical', '-', (0, 6))	('LPS141', 'Var', (0, 6))
315211	22911243	LPS141 and FU-DDLS-1 could efficiently invade through matrigel, T778 and SW872 were moderately invasive and SA-4, LISA-2, T449, GOT-3, and T1000 displayed poor ability to invade (Figure 5).	('SA-4', 'Chemical', '-', (108, 112))	('SW872', 'CellLine', 'CVCL:1730', (73, 78))	('invade through matrigel', 'CPA', (39, 62))	('SW872', 'Var', (73, 78))	('T1000', 'Chemical', '-', (139, 144))	('LPS141', 'Chemical', '-', (0, 6))
315226	22911243	However, FU-DDLS-1 was reported to form tumors in SCID mice when more cells were injected.	('SCID', 'Disease', 'MESH:D053632', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('SCID', 'Disease', (50, 54))	('mice', 'Species', '10090', (55, 59))	('FU-DDLS-1', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
315232	22911243	Surprisingly, T778 expressed the late adipocytic differentiation marker FABP4 strongly, indicating active adipogenesis.	('T778', 'Var', (14, 18))	('active', 'MPA', (99, 105))	('FABP4', 'Gene', '2167', (72, 77))	('FABP4', 'Gene', (72, 77))
315244	22911243	High CD73 expression has been associated with invasion, metastasis and decreased survival in a range of solid tumors.	('metastasis', 'CPA', (56, 66))	('associated', 'Reg', (30, 40))	('CD73', 'Gene', (5, 9))	('survival', 'CPA', (81, 89))	('High', 'Var', (0, 4))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('expression', 'MPA', (10, 20))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('CD73', 'Gene', '4907', (5, 9))	('decreased', 'NegReg', (71, 80))	('invasion', 'CPA', (46, 54))
315255	22911243	T449 is slow growing, nontumorigenic, noninvasive and able to undergo differentiation, while T778 (from the same patient) is fast growing, tumorigenic, invasive and displays resistance to differentiation and the two lines may serve as models for studying tumor progression and recurrence.	('patient', 'Species', '9606', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('T449', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('T778', 'Var', (93, 97))	('tumor', 'Disease', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
315263	20713527	ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round cell liposarcoma cell lines, but not in either ASC or a lung cancer cell line with low ZIC1 expression.	('proliferation', 'CPA', (24, 37))	('liposarcoma cell lines', 'Disease', (121, 143))	('knockdown', 'Var', (5, 14))	('ASC', 'Disease', 'MESH:D065309', (163, 166))	('inhibits', 'NegReg', (15, 23))	('apoptosis', 'CPA', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (121, 143))	('lung cancer', 'Disease', (172, 183))	('ASC', 'Disease', (163, 166))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (103, 132))	('liposarcoma', 'Phenotype', 'HP:0012034', (121, 132))	('induces', 'Reg', (61, 68))	('ZIC1', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('reduces', 'NegReg', (39, 46))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('invasion', 'CPA', (47, 55))
315264	20713527	ZIC1 knockdown is associated with increased nuclear expression of p27 protein, and the down-regulation of pro-survival target genes: BCL2L13, JunD, Fam57A, and EIF3M.	('down-regulation', 'NegReg', (87, 102))	('EIF3M', 'Gene', '10480', (160, 165))	('Fam57A', 'Gene', (148, 154))	('nuclear expression', 'MPA', (44, 62))	('EIF3M', 'Gene', (160, 165))	('knockdown', 'Var', (5, 14))	('p27 protein', 'Protein', (66, 77))	('ZIC1', 'Gene', (0, 4))	('BCL2L13', 'Gene', (133, 140))	('Fam57A', 'Gene', '79850', (148, 154))	('increased', 'PosReg', (34, 43))	('BCL2L13', 'Gene', '23786', (133, 140))
315273	20713527	Heterozygous ZIC1 deletion is associated with Dandy-Walker malformation.	('associated', 'Reg', (30, 40))	('ZIC1', 'Gene', (13, 17))	('Dandy-Walker malformation', 'Disease', (46, 71))	('Dandy-Walker malformation', 'Disease', 'MESH:D003616', (46, 71))	('Dandy-Walker malformation', 'Phenotype', 'HP:0001305', (46, 71))	('deletion', 'Var', (18, 26))
315279	20713527	ZIC1 overexpression in mice decreases neuronal differentiation and expands neural progenitors, functions that could underlie a role in tumor initiation and progression.	('decreases', 'NegReg', (28, 37))	('expands', 'PosReg', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor initiation', 'Disease', 'MESH:D009369', (135, 151))	('ZIC1', 'Gene', (0, 4))	('overexpression', 'Var', (5, 19))	('tumor initiation', 'Disease', (135, 151))	('neuronal differentiation', 'CPA', (38, 62))	('mice', 'Species', '10090', (23, 27))
315280	20713527	Also, ZIC1 overexpression in chick neural tubes blocks differentiation, and when ZIC1 was aberrantly expressed in the ventral spinal cord (where it is normally absent), the cells failed to express markers normally seen on differentiated neuronal cells.	('differentiation', 'CPA', (55, 70))	('chick', 'Species', '9031', (29, 34))	('overexpression', 'Var', (11, 25))	('ZIC1', 'Gene', (81, 85))	('blocks', 'NegReg', (48, 54))	('ZIC1', 'Gene', (6, 10))
315281	20713527	However, in humans, aberrant ZIC1 expression is also seen in other solid tumors, including endometrial cancer and desmoid tumors.	('ZIC1', 'Gene', (29, 33))	('solid tumors', 'Disease', (67, 79))	('endometrial cancer', 'Disease', 'MESH:D016889', (91, 109))	('expression', 'MPA', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('humans', 'Species', '9606', (12, 18))	('aberrant', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('desmoid tumors', 'Phenotype', 'HP:0100245', (114, 128))	('solid tumors', 'Disease', 'MESH:D009369', (67, 79))	('endometrial cancer', 'Disease', (91, 109))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('desmoid tumors', 'Disease', 'MESH:C535944', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('desmoid tumors', 'Disease', (114, 128))
315284	20713527	We also show that the lethal effects of ZIC1 knockdown are selective for liposarcoma cells, but not for cells that do not overexpress ZIC1.	('ZIC1', 'Gene', (40, 44))	('liposarcoma', 'Phenotype', 'HP:0012034', (73, 84))	('liposarcoma', 'Disease', 'MESH:D008080', (73, 84))	('liposarcoma', 'Disease', (73, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('knockdown', 'Var', (45, 54))
315285	20713527	Furthermore, we demonstrate that the anti-proliferative effects of ZIC1 knockdown in liposarcoma cells may be, in part, due to increased expression and activation of p27 protein.	('liposarcoma', 'Disease', (85, 96))	('ZIC1', 'Gene', (67, 71))	('expression', 'MPA', (137, 147))	('activation', 'PosReg', (152, 162))	('anti-proliferative effects', 'CPA', (37, 63))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('liposarcoma', 'Disease', 'MESH:D008080', (85, 96))	('p27 protein', 'Protein', (166, 177))	('protein', 'Protein', (170, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('knockdown', 'Var', (72, 81))	('increased', 'PosReg', (127, 136))
315295	20713527	The myxoid/RC cell line (ML2308) was found to contain the TLS-CHOP fusion transcript variant type 8-2 by RT-PCR.	('variant', 'Var', (85, 92))	('CHOP', 'Gene', '1649', (62, 66))	('TLS', 'Gene', (58, 61))	('TLS', 'Gene', '2521', (58, 61))	('CHOP', 'Gene', (62, 66))
315298	20713527	The lung adenocarcinoma cell line, A549 (ATCC, Manassas, VA) was maintained in F12K with 1.5g/L sodium bicarbonate and 10% FBS.	('lung adenocarcinoma', 'Disease', (4, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('FBS', 'Disease', 'MESH:D005198', (123, 126))	('F12K', 'SUBSTITUTION', 'None', (79, 83))	('F12K', 'Var', (79, 83))	('sodium bicarbonate', 'Chemical', 'MESH:D017693', (96, 114))	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('FBS', 'Disease', (123, 126))
315323	20713527	Z1 knocked down ZIC1 mRNA levels in all liposarcoma cell lines to approximately 30% of levels seen in control cells transduced with scramble shRNA by four days postinfection (P<0.05) (Figure 2b).	('ZIC1', 'Gene', (16, 20))	('knocked', 'Var', (3, 10))	('liposarcoma', 'Phenotype', 'HP:0012034', (40, 51))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (40, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('liposarcoma cell lines', 'Disease', (40, 62))	('mRNA levels', 'MPA', (21, 32))
315326	20713527	Beginning seven days after lentiviral infection, a CyQuant DNA quantification assay (Figure 3a) showed a reduction in cell proliferation in the ZIC1 knockdown liposarcoma cells, compared with the scramble and no-virus controls.	('liposarcoma', 'Disease', 'MESH:D008080', (159, 170))	('knockdown', 'Var', (149, 158))	('liposarcoma', 'Phenotype', 'HP:0012034', (159, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('ZIC1', 'Gene', (144, 148))	('reduction', 'NegReg', (105, 114))	('liposarcoma', 'Disease', (159, 170))	('cell proliferation', 'CPA', (118, 136))
315328	20713527	Thus, ZIC1 knockdown significantly reduced cell proliferation in all 3 liposarcoma cell lines.	('reduced', 'NegReg', (35, 42))	('liposarcoma', 'Phenotype', 'HP:0012034', (71, 82))	('ZIC1', 'Gene', (6, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (71, 93))	('liposarcoma cell lines', 'Disease', (71, 93))	('cell proliferation', 'CPA', (43, 61))	('knockdown', 'Var', (11, 20))
315329	20713527	To confirm the reduced proliferation of liposarcoma cells following ZIC1 knockdown, we determined the percentage of liposarcoma cells that incorporated BrdU, indicating active DNA replication.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('liposarcoma', 'Disease', (40, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('liposarcoma', 'Disease', 'MESH:D008080', (40, 51))	('liposarcoma', 'Disease', (116, 127))	('liposarcoma', 'Phenotype', 'HP:0012034', (40, 51))	('reduced', 'NegReg', (15, 22))	('proliferation', 'CPA', (23, 36))	('BrdU', 'Chemical', 'MESH:D001973', (152, 156))	('liposarcoma', 'Phenotype', 'HP:0012034', (116, 127))	('liposarcoma', 'Disease', 'MESH:D008080', (116, 127))	('BrdU', 'MPA', (152, 156))	('knockdown', 'Var', (73, 82))
315330	20713527	In both ML2308 and LPS141, BrdU uptake was reduced 30% beginning 4 days postinfection, and this peaked on day 6 in ML2308 and on day 10 in LPS141 with a 50% (P<0.001) reduction in the BrdU uptake in the ZIC1 knockdowns versus scramble controls.	('BrdU', 'Chemical', 'MESH:D001973', (184, 188))	('BrdU uptake', 'MPA', (184, 195))	('ML2308', 'Var', (115, 121))	('BrdU', 'Chemical', 'MESH:D001973', (27, 31))	('LPS141', 'Chemical', '-', (19, 25))	('LPS141', 'Var', (139, 145))	('reduction', 'NegReg', (167, 176))	('LPS141', 'Chemical', '-', (139, 145))	('BrdU uptake', 'MPA', (27, 38))	('reduced', 'NegReg', (43, 50))	('knockdowns', 'Var', (208, 218))
315332	20713527	In each liposarcoma cell line studied, the reduction in BrdU uptake in ZIC1 knockdown compared with scramble controls was significant.	('knockdown', 'Var', (76, 85))	('BrdU uptake', 'MPA', (56, 67))	('ZIC1', 'Gene', (71, 75))	('liposarcoma', 'Disease', 'MESH:D008080', (8, 19))	('reduction', 'NegReg', (43, 52))	('liposarcoma', 'Phenotype', 'HP:0012034', (8, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('BrdU', 'Chemical', 'MESH:D001973', (56, 60))	('liposarcoma', 'Disease', (8, 19))
315333	20713527	Thus, ZIC1 knockdown resulted in reduced DNA replication and thus reduced proliferation in liposarcoma cells.	('reduced', 'NegReg', (66, 73))	('liposarcoma', 'Disease', (91, 102))	('DNA replication', 'MPA', (41, 56))	('liposarcoma', 'Disease', 'MESH:D008080', (91, 102))	('ZIC1', 'Gene', (6, 10))	('liposarcoma', 'Phenotype', 'HP:0012034', (91, 102))	('reduced', 'NegReg', (33, 40))	('proliferation', 'CPA', (74, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('knockdown', 'Var', (11, 20))
315334	20713527	We measured apoptosis with Annexin V and 7-AAD staining and found the myxoid/RC cell line (ML2308) showed the earliest effects of decreased ZIC1 transcription with a 2.0-fold increase in Annexin V(+), 7-AAD(-) staining in the ZIC1 knockdowns compared with the scramble controls measured 6 days postinfection (P<0.001) (Figure 3c).	('7-AAD', 'Chemical', 'MESH:C025942', (201, 206))	('knockdowns', 'Var', (231, 241))	('7-AAD', 'Chemical', 'MESH:C025942', (41, 46))	('ZIC1', 'Gene', (226, 230))	('Annexin V', 'Gene', '308', (27, 36))	('Annexin V', 'Gene', (27, 36))	('transcription', 'MPA', (145, 158))	('ZIC1', 'Gene', (140, 144))	('increase', 'PosReg', (175, 183))	('Annexin V', 'Gene', '308', (187, 196))	('Annexin V', 'Gene', (187, 196))	('decreased', 'NegReg', (130, 139))
315336	20713527	For DDLS8817, maximum Annexin V(+), 7-AAD(-) staining occurred 9 days postinfection, with a 1.9-fold increase in staining in the ZIC1 knockdowns compared with the scramble controls (P<0.001).	('staining', 'MPA', (113, 121))	('7-AAD', 'Chemical', 'MESH:C025942', (36, 41))	('increase', 'PosReg', (101, 109))	('DDLS8817', 'Var', (4, 12))	('Annexin V', 'Gene', '308', (22, 31))	('Annexin V', 'Gene', (22, 31))
315337	20713527	In LPS141, Annexin V staining plateaued on day 12 with a 10.9-fold increase in Annexin V(+),7-AAD(-) staining (P<0.001).	('7-AAD', 'Chemical', 'MESH:C025942', (92, 97))	('Annexin V', 'Gene', '308', (79, 88))	('Annexin V', 'Gene', '308', (11, 20))	('Annexin V', 'Gene', (79, 88))	('Annexin V', 'Gene', (11, 20))	('increase', 'PosReg', (67, 75))	('LPS141', 'Chemical', '-', (3, 9))	('LPS141', 'Var', (3, 9))
315338	20713527	Thus, depending on the liposarcoma cell line, ZIC1 knockdown induced a 2- to 11-fold increase in apoptosis compared with scramble controls, which peaked 8-12 days postinfection.	('ZIC1', 'Gene', (46, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('liposarcoma', 'Disease', (23, 34))	('liposarcoma', 'Disease', 'MESH:D008080', (23, 34))	('liposarcoma', 'Phenotype', 'HP:0012034', (23, 34))	('increase', 'PosReg', (85, 93))	('apoptosis', 'CPA', (97, 106))	('knockdown', 'Var', (51, 60))
315340	20713527	ZIC1 knockdown increased cleaved caspase 3 staining: 3.0 +- 0.3-fold in ML2308, 2.0 +- 0.7-fold in DDLS8817, and 2.4 +- 0.8-fold in LPS141 compared to the Scr controls (Supplemental Figure 2).	('LPS141', 'Chemical', '-', (132, 138))	('ML2308', 'Var', (72, 78))	('staining', 'MPA', (43, 51))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (15, 24))	('ZIC1', 'Gene', (0, 4))	('cleaved', 'MPA', (25, 32))	('DDLS8817', 'Var', (99, 107))
315341	20713527	To determine if the induction of apoptosis following ZIC1 knockdown was specific to liposarcoma cells that overexpressed ZIC1, the same shRNA lentiviral system was used to knock down ZIC1 expression in ASCs and in A549 lung cancer cells, both of which have low levels of ZIC1 expression (Figure 4a).	('A549 lung cancer', 'Disease', 'MESH:D008175', (214, 230))	('A549 lung cancer', 'Disease', (214, 230))	('liposarcoma', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ASC', 'Disease', 'MESH:D065309', (202, 205))	('liposarcoma', 'Disease', 'MESH:D008080', (84, 95))	('ASC', 'Disease', (202, 205))	('liposarcoma', 'Phenotype', 'HP:0012034', (84, 95))	('ZIC1', 'Gene', (183, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('knock down', 'Var', (172, 182))
315343	20713527	In the liposarcoma cell lines, the ZIC1 knockdowns resulted in a 3- to 11-fold increase in apoptosis compared with the scramble controls (P<0.05).	('increase', 'PosReg', (79, 87))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (7, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('apoptosis', 'CPA', (91, 100))	('liposarcoma cell lines', 'Disease', (7, 29))	('knockdowns', 'Var', (40, 50))	('ZIC1', 'Gene', (35, 39))	('liposarcoma', 'Phenotype', 'HP:0012034', (7, 18))
315344	20713527	In contrast, in the non-transformed ASCs and in the non-ZIC1 A549 cell line, apoptosis was not significantly increased in the ZIC1 knockdowns compared with controls.	('ASC', 'Disease', (36, 39))	('ZIC1', 'Gene', (126, 130))	('knockdowns', 'Var', (131, 141))	('ASC', 'Disease', 'MESH:D065309', (36, 39))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
315345	20713527	These results suggest that ZIC1 knockdown is specifically lethal to liposarcoma cells that overexpress ZIC1.	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('liposarcoma', 'Phenotype', 'HP:0012034', (68, 79))	('liposarcoma', 'Disease', (68, 79))	('knockdown', 'Var', (32, 41))	('ZIC1', 'Gene', (27, 31))	('liposarcoma', 'Disease', 'MESH:D008080', (68, 79))	('ZIC1', 'Gene', (103, 107))	('overexpress', 'PosReg', (91, 102))
315347	20713527	Twenty-two hours after seeding, ML2308, DDLS8817, and LPS141 ZIC1 knockdown cells demonstrated 21-40% invasion, which was lower than in scramble controls (55-82% invasion, respectively; P<0.01; Figure 4c).	('LPS141', 'Chemical', '-', (54, 60))	('DDLS8817', 'Var', (40, 48))	('invasion', 'CPA', (102, 110))
315352	20713527	To determine the effects of ZIC1 knockdown on p27 protein expression, we performed immunoblots of p27 for liposarcoma cells following ZIC1 knockdown and compared these with scramble controls.	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('knockdown', 'Var', (139, 148))	('liposarcoma', 'Disease', (106, 117))	('liposarcoma', 'Disease', 'MESH:D008080', (106, 117))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))
315353	20713527	All three liposarcoma cell lines with ZIC1 knockdown showed an increase in p27 protein expression by as early as 2 days postinfection compared with scramble controls (Figure 5).	('liposarcoma cell lines', 'Disease', (10, 32))	('increase', 'PosReg', (63, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('knockdown', 'Var', (43, 52))	('ZIC1', 'Gene', (38, 42))	('p27 protein', 'Protein', (75, 86))	('liposarcoma', 'Phenotype', 'HP:0012034', (10, 21))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (10, 32))
315354	20713527	The immunoblot results were validated by immunofluorescence, which identified not only an increase in p27 protein expression, but also increased nuclear localization of p27 in the ZIC1 knockdowns compared with controls in the three liposarcoma cell lines (Figure 5).	('increase', 'PosReg', (90, 98))	('p27 protein', 'Protein', (102, 113))	('nuclear localization', 'MPA', (145, 165))	('increased', 'PosReg', (135, 144))	('knockdowns', 'Var', (185, 195))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (232, 254))	('p27', 'Protein', (169, 172))	('liposarcoma', 'Phenotype', 'HP:0012034', (232, 243))	('expression', 'MPA', (114, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('liposarcoma cell lines', 'Disease', (232, 254))	('ZIC1', 'Gene', (180, 184))
315355	20713527	We performed expression array analysis using both LPS141- and DDLS8817-ZIC1 knockdown and compared the results with scramble controls at four and eight days following shRNA transfection, the time when apoptotic indices began to rise.	('DDLS8817-ZIC1', 'Var', (62, 75))	('LPS141', 'Chemical', '-', (50, 56))	('LPS141-', 'Var', (50, 57))
315359	20713527	Thus, all four of these validated putative ZIC1 target genes are significantly reduced with ZIC1 knockdown in liposarcoma cell lines and are likely to mediate the reduced proliferation and enhanced apoptosis observed following ZIC1 knockdown.	('knockdown', 'Var', (97, 106))	('ZIC1', 'Gene', (92, 96))	('apoptosis', 'CPA', (198, 207))	('reduced', 'NegReg', (79, 86))	('liposarcoma', 'Phenotype', 'HP:0012034', (110, 121))	('enhanced', 'PosReg', (189, 197))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (110, 132))	('reduced', 'NegReg', (163, 170))	('liposarcoma cell lines', 'Disease', (110, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('proliferation', 'CPA', (171, 184))
315361	20713527	Those with simple near-diploid karyotypes bear few chromosomal rearrangements, such as translocations in myxoid/round-cell liposarcoma [t(12;16)(q13;p11), t(12;22)(q13;q12)].	('translocations', 'Var', (87, 101))	('t(12;22)(q13;q12)]', 'Var', (155, 173))	('liposarcoma', 'Disease', (123, 134))	('[t(12;16)(q13;p11', 'Var', (135, 152))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (136, 153))	('liposarcoma', 'Disease', 'MESH:D008080', (123, 134))	('liposarcoma', 'Phenotype', 'HP:0012034', (123, 134))	('myxoid/round-cell liposarcoma', 'Phenotype', 'HP:0012268', (105, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (155, 172))
315363	20713527	Most of these complex liposarcoma types have frequent abnormalities in the Rb, p53, and specific growth-factor signaling pathways, including amplification of the 12q14 chromosome region encompassing the MDM2 and CDK4 loci in dedifferentiated liposarcoma, but many of the key driver genes critical to liposarcomagenesis remain to be discovered.	('amplification', 'Var', (141, 154))	('liposarcoma', 'Phenotype', 'HP:0012034', (22, 33))	('MDM2', 'Gene', (203, 207))	('CDK4', 'Gene', '1019', (212, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('liposarcoma', 'Disease', 'MESH:D008080', (300, 311))	('p53', 'Gene', '7157', (79, 82))	('liposarcoma', 'Phenotype', 'HP:0012034', (242, 253))	('liposarcoma', 'Disease', 'MESH:D008080', (22, 33))	('MDM2', 'Gene', '4193', (203, 207))	('p53', 'Gene', (79, 82))	('liposarcoma', 'Disease', 'MESH:D008080', (242, 253))	('liposarcoma', 'Disease', (300, 311))	('liposarcoma', 'Disease', (22, 33))	('CDK4', 'Gene', (212, 216))	('abnormalities', 'Var', (54, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('liposarcoma', 'Disease', (242, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('liposarcoma', 'Phenotype', 'HP:0012034', (300, 311))
315367	20713527	As GIST tumorigenesis is primarily characterized by mutations in c-KIT and PDGFRA, lesions not characteristic of ZIC1-overexpressing subtypes, it is likely the pathogenesis of the latter is distinct in the requirement for ZIC1 overexpression.	('mutations', 'Var', (52, 61))	('c-KIT', 'Gene', (65, 70))	('GIST', 'Disease', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('GIST', 'Phenotype', 'HP:0100723', (3, 7))	('c-KIT', 'Gene', '3815', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('PDGFRA', 'Gene', (75, 81))	('PDGFRA', 'Gene', '5156', (75, 81))	('characterized', 'Reg', (35, 48))
315372	20713527	The functional effects of ZIC1 knockdown were consistent: decreases in proliferation, BrdU uptake, and Matrigel invasion and increase in apoptosis.	('apoptosis', 'CPA', (137, 146))	('Matrigel invasion', 'CPA', (103, 120))	('decreases', 'NegReg', (58, 67))	('increase', 'PosReg', (125, 133))	('ZIC1', 'Gene', (26, 30))	('BrdU uptake', 'CPA', (86, 97))	('BrdU', 'Chemical', 'MESH:D001973', (86, 90))	('proliferation', 'CPA', (71, 84))	('knockdown', 'Var', (31, 40))
315373	20713527	Specificity of these responses are supported by ZIC1 knockdown having no effect on apoptosis or invasion in normal ASCs, which are neither immortal nor transformed, or in the A549 cell line, which does not to overexpress ZIC1 by RT-PCR and immunofluorescence.	('A549', 'CellLine', 'CVCL:0023', (175, 179))	('knockdown', 'Var', (53, 62))	('invasion', 'CPA', (96, 104))	('apoptosis', 'CPA', (83, 92))	('ASC', 'Disease', 'MESH:D065309', (115, 118))	('ZIC1', 'Gene', (48, 52))	('ASC', 'Disease', (115, 118))
315375	20713527	The majority of ZIC1 studies have investigated its role in the CNS, and as previously mentioned, murine ZIC1 mutants were shown to express elevated p27 and Wnt7a, but decreased cyclin D1.	('elevated', 'PosReg', (139, 147))	('murine', 'Species', '10090', (97, 103))	('Wnt7a', 'Gene', '22421', (156, 161))	('p27', 'Protein', (148, 151))	('cyclin D1', 'Gene', (177, 186))	('ZIC1', 'Gene', (104, 108))	('mutants', 'Var', (109, 116))	('Wnt7a', 'Gene', (156, 161))	('cyclin D1', 'Gene', '12443', (177, 186))	('decreased', 'NegReg', (167, 176))
315376	20713527	While we did not observe a correlation between ZIC1 expression and Wnt7A and/or Cyclin D1, we did demonstrate a relationship between ZIC1 knockdown and an increase in p27 protein expression in vitro.	('knockdown', 'Var', (138, 147))	('increase', 'PosReg', (155, 163))	('p27 protein', 'Protein', (167, 178))	('Cyclin D1', 'Gene', (80, 89))	('ZIC1', 'Gene', (133, 137))	('Wnt7A', 'Gene', (67, 72))	('Cyclin D1', 'Gene', '595', (80, 89))	('Wnt7A', 'Gene', '7476', (67, 72))	('protein', 'Protein', (171, 178))
315378	20713527	Immunoblots demonstrated an increase in p27 protein expression in the ZIC1 knockdowns as early as 2 days after lentivirus infection and reached its maximal level 6 days postinfection.	('lentivirus infection', 'Disease', (111, 131))	('knockdowns', 'Var', (75, 85))	('lentivirus infection', 'Disease', 'MESH:D016180', (111, 131))	('p27 protein', 'Protein', (40, 51))	('increase', 'PosReg', (28, 36))	('ZIC1', 'Gene', (70, 74))
315379	20713527	Thus, the increase in p27 expression in all 3 liposarcoma cell lines following ZIC1 knockdown explains many of the observed early functional effects on cell proliferation and invasion.	('expression', 'MPA', (26, 36))	('increase', 'PosReg', (10, 18))	('knockdown', 'Var', (84, 93))	('invasion', 'CPA', (175, 183))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (46, 68))	('liposarcoma', 'Phenotype', 'HP:0012034', (46, 57))	('ZIC1', 'Gene', (79, 83))	('p27', 'Protein', (22, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('liposarcoma cell lines', 'Disease', (46, 68))	('cell proliferation', 'CPA', (152, 170))
315381	20713527	To discover putative ZIC1 target genes we then performed expression array analysis 4 and 8 days following ZIC1 knockdown and found that BCL2L13 was 4-fold and 2-fold downregulated in DDLS and LPS141, respectively.	('knockdown', 'Var', (111, 120))	('LPS141', 'Gene', (192, 198))	('ZIC1', 'Gene', (106, 110))	('LPS141', 'Chemical', '-', (192, 198))	('downregulated', 'NegReg', (166, 179))	('BCL2L13', 'Gene', (136, 143))	('BCL2L13', 'Gene', '23786', (136, 143))
315386	20713527	Four days following ZIC1 knockdown JunD was 2.4-fold and 2.1-fold downregulated in DDLS8817 and LPS141, respectively.	('DDLS8817', 'Gene', (83, 91))	('LPS141', 'Gene', (96, 102))	('downregulated', 'NegReg', (66, 79))	('LPS141', 'Chemical', '-', (96, 102))	('knockdown', 'Var', (25, 34))
315387	20713527	For example, JunD expression prevents cell death in adult mouse heart cells and in UV/H2O2-stressed mouse embryonic fibroblasts.	('prevents', 'NegReg', (29, 37))	('mouse', 'Species', '10090', (58, 63))	('H2O2', 'Chemical', 'MESH:D006861', (86, 90))	('mouse', 'Species', '10090', (100, 105))	('JunD', 'Gene', (13, 17))	('cell death', 'CPA', (38, 48))	('expression', 'Var', (18, 28))
315388	20713527	JunD has been proposed to protect cells from p53-dependent senescence and apoptosis and its downregulation upon ZIC1 knockdown may account for the induction of apoptosis in our liposarcoma cell lines.	('apoptosis', 'CPA', (74, 83))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('downregulation', 'NegReg', (92, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('liposarcoma', 'Phenotype', 'HP:0012034', (177, 188))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (177, 199))	('liposarcoma cell lines', 'Disease', (177, 199))	('knockdown', 'Var', (117, 126))
315389	20713527	Fam57A (CT120), a membrane-associated gene important for amino acid transport, was found to be 2.6- and 2.5-fold downregulated in DDLS8817 and LPS141, respectively.	('LPS141', 'Gene', (143, 149))	('downregulated', 'NegReg', (113, 126))	('DDLS8817', 'Var', (130, 138))	('Fam57A', 'Gene', '79850', (0, 6))	('CT120', 'Gene', '79850', (8, 13))	('LPS141', 'Chemical', '-', (143, 149))	('CT120', 'Gene', (8, 13))	('Fam57A', 'Gene', (0, 6))
315390	20713527	CT120 has been implicated in lung carcinogenesis and its ectopic expression in NIH3T3 cells has been associated with Raf/MEK/Erk and PI3K/Akt signaling pathways driving cell proliferation, cell survival, and anti-apoptotic pathways.	('cell proliferation', 'CPA', (169, 187))	('lung carcinogenesis', 'Disease', (29, 48))	('CT120', 'Gene', '79850', (0, 5))	('implicated', 'Reg', (15, 25))	('Erk', 'Gene', '26413', (125, 128))	('Akt', 'Gene', (138, 141))	('MEK', 'Gene', '17242', (121, 124))	('ectopic expression', 'Var', (57, 75))	('NIH3T3', 'CellLine', 'CVCL:0594', (79, 85))	('associated', 'Reg', (101, 111))	('Akt', 'Gene', '11651', (138, 141))	('Raf', 'Gene', (117, 120))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (29, 48))	('anti-apoptotic pathways', 'Pathway', (208, 231))	('cell survival', 'CPA', (189, 202))	('Erk', 'Gene', (125, 128))	('MEK', 'Gene', (121, 124))	('Raf', 'Gene', '387609', (117, 120))	('CT120', 'Gene', (0, 5))
315392	20713527	The ectopic expression of the other EIF3 subunits, -3a, -3b, -3c, -3h, or -3i in stably transfected NIH3T3 cells has been shown to induce oncogenic transformation, enhance proliferation, and attenuate apoptosis.	('enhance', 'PosReg', (164, 171))	('EIF3', 'Gene', '13669', (36, 40))	('proliferation', 'CPA', (172, 185))	('induce', 'PosReg', (131, 137))	('NIH3T3', 'CellLine', 'CVCL:0594', (100, 106))	('EIF3', 'Gene', (36, 40))	('oncogenic transformation', 'CPA', (138, 162))	('ectopic expression', 'Var', (4, 22))	('apoptosis', 'CPA', (201, 210))	('attenuate', 'NegReg', (191, 200))
315411	32294103	Therapeutic blockage of the PD-1/PD-L1 receptor-ligand can result in durable clinical responses in lung and bladder cancer but their benefit in various sarcoma subtypes remains unknown, with no phase 3 studies yet published.	('lung', 'Disease', (99, 103))	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('PD-L1', 'Gene', (33, 38))	('bladder cancer', 'Disease', (108, 122))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('blockage', 'Var', (12, 20))	('sarcoma', 'Disease', (152, 159))	('PD-L1', 'Gene', '29126', (33, 38))	('PD-1', 'Gene', (28, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('PD-1', 'Gene', '5133', (28, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
315414	32294103	translocations or amplification) known to drive tumorogenesis (e.g.	('translocations', 'Var', (0, 14))	('amplification', 'Var', (18, 31))	('tumorogenesis', 'Disease', (48, 61))	('tumorogenesis', 'Disease', 'MESH:D002471', (48, 61))
315415	32294103	t(X;18)(p11.2; q11.2) in synovial sarcoma) and sarcomas with complex karyotype (e.g.	('sarcomas', 'Disease', (47, 55))	('t(X;18)(p11.2; q11.2', 'Var', (0, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('synovial sarcoma', 'Disease', (25, 41))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (25, 41))	('synovial sarcoma', 'Disease', 'MESH:D013584', (25, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
315458	32294103	This includes paired samples from the following types: MFS (n = 17), UPS (n = 5), LMS (n = 11), RMS (n = 2), ML (n = 2), pleomorphic LPS (n = 2), angiosarcomas (n = 3), SS (n = 2), ES (n = 1) and DD-LPS (n = 1; Table 1).	('LPS', 'Disease', (199, 202))	('angiosarcomas', 'Phenotype', 'HP:0200058', (146, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('LPS', 'Disease', 'MESH:C536528', (199, 202))	('pleomorphic', 'Var', (121, 132))	('angiosarcomas', 'Disease', (146, 159))	('LPS', 'Disease', (133, 136))	('DD-LPS', 'Disease', (196, 202))	('DD-LPS', 'Disease', 'MESH:C536528', (196, 202))	('angiosarcomas', 'Disease', 'MESH:D006394', (146, 159))	('LPS', 'Disease', 'MESH:C536528', (133, 136))
315480	32294103	When the cases were dichotomised, it was observed that PD-L1 expression was present in 5% (5 of 105) of cases with minimal-to-absent TILs vs. 72% (8 of 11) in those LMS with moderate-to-marked TILs (8 of 11: 72%; <0.0001, Fisher's exact test; Fig 5B).	('PD-L1', 'Gene', '29126', (55, 60))	('TIL', 'Gene', (133, 136))	('TIL', 'Gene', '7096', (193, 196))	('TIL', 'Gene', (193, 196))	('minimal-to-absent', 'Var', (115, 132))	('PD-L1', 'Gene', (55, 60))	('TIL', 'Gene', '7096', (133, 136))
315486	32294103	One of these variables is the use of over 10 commercial and non-commercial PD-L1 antibodies including SP263 and SP142 (Ventana Medical Systems), E1L3N (Cell Signalling Technology), 22C3 (PharmDx kit, Agilent Technologies), 28-8 (PharmDx kit), 5H1 (L. Chen, John Hopkins University), #ab58810 and EPR1161 (Abcam) and #SAB2900365 (Sigma-Aldrich).	('EPR1161', 'Var', (296, 303))	('PD-L1', 'Gene', (75, 80))	('SP142', 'Var', (112, 117))	('PD-L1', 'Gene', '29126', (75, 80))	('E1L3N', 'Var', (145, 150))	('SP263', 'Var', (102, 107))	('#SAB2900365', 'Var', (316, 327))
315487	32294103	Clones differ in the binding site to the PD-L1 protein: extracellular (28-8 and 22C3, SP263 and E1) vs. cytoplasmic (SP142 and E1L3N) (Reviewed in) with further technical differences regarding antigen retrieval conditions, staining platforms and differential binding properties according to cell types (i.e.	('SP263', 'Var', (86, 91))	('PD-L1', 'Gene', (41, 46))	('PD-L1', 'Gene', '29126', (41, 46))
315498	32294103	In some of these series, the frequency of PD-L1 expression ranges from absent (0%) with the Abcam (ab58810 and ab205921) and SP142 clones to low (12%: H-130 clone), intermediate (26-30%: AM2653AF-N. Acris & SP263) and high (58% & 65% with BD Pharmingen and R&D Systems and the H-130, Santa Cruz clones, respectively).	('PD-L1', 'Gene', '29126', (42, 47))	('PD-L1', 'Gene', (42, 47))	('N. Acris', 'Species', '288503', (196, 204))	('AM2653AF-N.', 'Var', (187, 198))
315514	32294103	Based on results of the KENOTE-010 study, patients with high PD-L1 score (>50%) have significantly increased benefit with pembrolizumab compared to those with >1%.	('PD-L1', 'Gene', (61, 66))	('KENOTE', 'Chemical', '-', (24, 30))	('PD-L1', 'Gene', '29126', (61, 66))	('pembrolizumab', 'Chemical', 'MESH:C582435', (122, 135))	('patients', 'Species', '9606', (42, 50))	('benefit', 'PosReg', (109, 116))	('high', 'Var', (56, 60))
315523	32294103	As high density TILs (specifically, CD3+/CD8+) is an independent positive prognostic factor for OS and DFS in sarcomas, it would be expected that absence of TILs would correlate with aggressive behaviour in those sarcomas prone to recur and/or metastasise.	('TIL', 'Gene', '7096', (157, 160))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (183, 203))	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (213, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('aggressive behaviour', 'CPA', (183, 203))	('sarcomas', 'Disease', (213, 221))	('CD8', 'Gene', (41, 44))	('TIL', 'Gene', (157, 160))	('CD8', 'Gene', '925', (41, 44))	('TIL', 'Gene', '7096', (16, 19))	('sarcomas', 'Disease', (110, 118))	('absence', 'Var', (146, 153))	('sarcomas', 'Disease', 'MESH:D012509', (213, 221))	('TIL', 'Gene', (16, 19))
315524	32294103	Induction or oncogeneic activation of PD-L1 in non 'inflamed' tumours occurs through alternative pathways such as loss of PTEN or copy gain / amplification of CD274/PDL1 locus (Ch 9p24.1).	('PDL1', 'Gene', '29126', (165, 169))	('activation', 'PosReg', (24, 34))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('loss of PTEN', 'Disease', 'MESH:D006223', (114, 126))	('PDL1', 'Gene', (165, 169))	('PD-L1', 'Gene', '29126', (38, 43))	('CD274', 'Gene', '29126', (159, 164))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('loss of PTEN', 'Disease', (114, 126))	('PD-L1', 'Gene', (38, 43))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('copy gain / amplification', 'Var', (130, 155))	('tumours', 'Disease', (62, 69))	('CD274', 'Gene', (159, 164))
315551	27764830	Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations.	('CREB1', 'Gene', (152, 157))	('EWSR1', 'Gene', (146, 151))	('exon 7 to', 'Var', (129, 138))	('EWSR1', 'Gene', '2130', (146, 151))	('CREB1', 'Gene', '1385', (152, 157))
315557	27764830	However, CCSTA often shows positivity for melanocytic markers (HMB45, Melan-A, and Tyrosinase), whereas GNET is often negative for melanocytic markers and is positive for synaptophysin.	('positivity', 'Var', (27, 37))	('synaptophysin', 'Gene', (171, 184))	('Melan-A, and Tyrosinase', 'Gene', '2315;7299', (70, 93))	('HMB45', 'Gene', (63, 68))	('synaptophysin', 'Gene', '6855', (171, 184))
315558	27764830	These tumors share common genetic alterations: chromosomal translocation events t(12;22)(q13;q12) and t(2;22)(q34;q12), leading to chimeric fusion proteins EWSR1-ATF1 and EWSR1-CREB1, respectively.	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (80, 97))	('EWSR1', 'Gene', '2130', (156, 161))	('t(2;22)(q34;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (102, 118))	('EWSR1', 'Gene', '2130', (171, 176))	('ATF1', 'Gene', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CREB1', 'Gene', '1385', (177, 182))	('leading to', 'Reg', (120, 130))	('ATF1', 'Gene', '466', (162, 166))	('tumors', 'Disease', (6, 12))	('t(12', 'Var', (80, 84))	('EWSR1', 'Gene', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('EWSR1', 'Gene', (171, 176))	('chimeric fusion', 'MPA', (131, 146))	('CREB1', 'Gene', (177, 182))	('t(2;22)(q34;q12', 'Var', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
315572	27764830	In addition, three variants of unknown significance (VUS) were identified; CTCF P315S, NSD1 V2584L and RARA I258fs*13.	('V2584L', 'Var', (92, 98))	('RARA', 'Gene', '5914', (103, 107))	('NSD1', 'Gene', '64324', (87, 91))	('CTCF', 'Gene', '10664', (75, 79))	('I258fs', 'Mutation', 'p.I258fsX', (108, 114))	('NSD1', 'Gene', (87, 91))	('RARA', 'Gene', (103, 107))	('P315S', 'Mutation', 'rs145727304', (80, 85))	('V2584L', 'Mutation', 'p.V2584L', (92, 98))	('P315S', 'Var', (80, 85))	('CTCF', 'Gene', (75, 79))
315578	27764830	In reviewing 45,632 carcinomas, 3,803 sarcomas, and 1,526 melanomas assayed with CGP in the course of clinical care, we identified 11 additional cases that harbor EWSR1-CREB1 fusions.	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('carcinomas', 'Disease', (20, 30))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('CREB1', 'Gene', '1385', (169, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('sarcomas', 'Disease', (38, 46))	('EWSR1', 'Gene', (163, 168))	('CREB1', 'Gene', (169, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (20, 30))	('melanomas', 'Disease', (58, 67))	('carcinomas', 'Disease', 'MESH:D002277', (20, 30))	('EWSR1', 'Gene', '2130', (163, 168))	('fusions', 'Var', (175, 182))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('sarcomas', 'Disease', 'MESH:D012509', (38, 46))
315581	27764830	All but one cases harbored fusions between EWSR1 exons 1-7/8 and CREB1 exons 6/7-8.	('CREB1', 'Gene', (65, 70))	('EWSR1', 'Gene', (43, 48))	('CREB1', 'Gene', '1385', (65, 70))	('fusions', 'Var', (27, 34))	('EWSR1', 'Gene', '2130', (43, 48))
315586	27764830	The current paradigm of advanced cancer benefitting from targeted therapy relies on the presence of genomic alterations that predict response, such as in the case of NSCLC that harbors oncogenic drivers such as ALK fusions and EGFR mutations.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('EGFR', 'Gene', '1956', (227, 231))	('NSCLC', 'Disease', (166, 171))	('EGFR', 'Gene', (227, 231))	('mutations', 'Var', (232, 241))	('ALK', 'Gene', '238', (211, 214))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('ALK', 'Gene', (211, 214))
315587	27764830	Inherent proof of the specificity of the pairing of therapy and genomic alteration is manifested in very specific mechanisms of acquired resistance, such as base substitutions in ALK fusions and the emergence of T790M or MET amplification in EGFR mutant lung cancer.	('mutant', 'Var', (247, 253))	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('ALK', 'Gene', '238', (179, 182))	('acquired resistance', 'MPA', (128, 147))	('lung cancer', 'Disease', (254, 265))	('EGFR', 'Gene', '1956', (242, 246))	('T790M', 'Mutation', 'rs121434569', (212, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('ALK', 'Gene', (179, 182))	('T790M', 'Var', (212, 217))	('MET amplification', 'Var', (221, 238))	('EGFR', 'Gene', (242, 246))	('base substitutions', 'Var', (157, 175))
315588	27764830	This case may exist outside that paradigm, as EWSR1 fusions are currently not strongly predicted to be sensitizing to any targeted therapies.	('EWSR1', 'Gene', (46, 51))	('EWSR1', 'Gene', '2130', (46, 51))	('fusions', 'Var', (52, 59))
315591	27764830	These paradigm-setting observations suggest that promiscuous multikinase inhibitors can be an effective treatment for a tumor driven by a specific EWSR1 fusion, although the mechanism of action remains unclear.	('EWSR1', 'Gene', (147, 152))	('EWSR1', 'Gene', '2130', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('fusion', 'Var', (153, 159))	('tumor', 'Disease', (120, 125))
315599	27764830	We additionally report other patients that harbor the same EWSR1-CREB1 fusion, with the thought that such patients may also benefit from the combination of crizotinib and pazopanib.	('CREB1', 'Gene', (65, 70))	('EWSR1', 'Gene', (59, 64))	('crizotinib', 'Chemical', 'MESH:D000077547', (156, 166))	('patients', 'Species', '9606', (29, 37))	('pazopanib', 'Chemical', 'MESH:C516667', (171, 180))	('EWSR1', 'Gene', '2130', (59, 64))	('benefit', 'PosReg', (124, 131))	('patients', 'Species', '9606', (106, 114))	('CREB1', 'Gene', '1385', (65, 70))	('fusion', 'Var', (71, 77))
315603	27764830	More broadly, over 10 distinct EWSR1 fusions have been reported across a large range of tumor types, predominantly in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('EWSR1', 'Gene', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('reported', 'Reg', (55, 63))	('fusions', 'Var', (37, 44))	('EWSR1', 'Gene', '2130', (31, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcomas', 'Disease', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
315607	27764830	We have reported a case of GNET harboring an EWSR1-CREB1 fusion in a patient who showed a very good response to combination therapy with the receptor tyrosine kinase inhibitors crizotinib and pazopanib, with clinical benefit for over 1.5 years.	('EWSR1', 'Gene', (45, 50))	('crizotinib', 'Chemical', 'MESH:D000077547', (177, 187))	('pazopanib', 'Chemical', 'MESH:C516667', (192, 201))	('CREB1', 'Gene', (51, 56))	('EWSR1', 'Gene', '2130', (45, 50))	('patient', 'Species', '9606', (69, 76))	('fusion', 'Var', (57, 63))	('CREB1', 'Gene', '1385', (51, 56))
315609	26945340	Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy - Overlapping Genetic Features with Clear Cell Sarcoma of Kidney Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogeneous group of tumors, often lacking known genetic abnormalities.	('Sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('BCOR', 'Gene', '54880', (10, 14))	('NUTM2B', 'Gene', (53, 59))	('Clear Cell Sarcoma of Kidney', 'Disease', 'MESH:D018227', (166, 194))	('BCOR', 'Gene', (10, 14))	('Sarcoma of Kidney', 'Phenotype', 'HP:0008663', (177, 194))	('YWHAE', 'Gene', (47, 52))	('Sarcoma', 'Disease', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('Internal Tandem Duplication', 'Var', (15, 42))	('Clear Cell Sarcoma of Kidney', 'Disease', (166, 194))	('Sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('YWHAE', 'Gene', '7531', (47, 52))	('Fusions', 'Var', (60, 67))	('sarcoma', 'Disease', (235, 242))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('Sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('tumors', 'Disease', (299, 305))	('Clear Cell Sarcoma of Kidney', 'Phenotype', 'HP:0006770', (166, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('infants', 'Species', '9606', (263, 270))	('Sarcoma', 'Disease', (177, 184))	('NUTM2B', 'Gene', '729262', (53, 59))	('Sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('genetic abnormalities', 'Disease', 'MESH:D030342', (327, 348))	('genetic abnormalities', 'Disease', (327, 348))
315611	26945340	Most CCSK are characterized by BCOR exon 16 internal tandem duplications (ITD), while a smaller subset shows YWHAE-NUTM2B/E fusions.	('BCOR', 'Gene', (31, 35))	('YWHAE', 'Gene', (109, 114))	('NUTM2B', 'Gene', (115, 121))	('BCOR', 'Gene', '54880', (31, 35))	('internal tandem duplications', 'Var', (44, 72))	('YWHAE', 'Gene', '7531', (109, 114))	('NUTM2B', 'Gene', '729262', (115, 121))	('CCSK', 'Disease', (5, 9))	('CCSK', 'Chemical', '-', (5, 9))	('CCSK', 'Phenotype', 'HP:0006770', (5, 9))
315624	26945340	In summary, we report recurrent BCOR exon 16 ITD and YWHAE-NUTM2B fusions in half of infantile soft tissue URCS and most PMMTI, but not in other pediatric sarcomas.	('NUTM2B', 'Gene', (59, 65))	('PMMTI', 'Chemical', '-', (121, 126))	('sarcomas', 'Disease', 'MESH:D012509', (155, 163))	('infantile soft tissue URCS', 'Disease', (85, 111))	('BCOR', 'Gene', (32, 36))	('YWHAE', 'Gene', '7531', (53, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcomas', 'Disease', (155, 163))	('NUTM2B', 'Gene', '729262', (59, 65))	('PMMTI', 'Disease', (121, 126))	('BCOR', 'Gene', '54880', (32, 36))	('YWHAE', 'Gene', (53, 58))	('fusions', 'Var', (66, 73))	('infant', 'Species', '9606', (85, 91))
315627	26945340	Based on an index case of a 4-month-old boy with a pelvic round cell sarcoma harboring an identical YWHAE-NUTM2B fusion to clear cell sarcoma of kidney (CCSK), we further investigated the possibility of shared genetic abnormalities between CCSK and infantile soft tissue URCS.	('boy', 'Species', '9606', (40, 43))	('clear cell sarcoma of kidney', 'Phenotype', 'HP:0006770', (123, 151))	('sarcoma of kidney', 'Disease', (134, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('CCSK', 'Disease', (240, 244))	('sarcoma', 'Disease', (69, 76))	('CCSK', 'Chemical', '-', (240, 244))	('NUTM2B', 'Gene', '729262', (106, 112))	('CCSK', 'Chemical', '-', (153, 157))	('sarcoma of kidney', 'Phenotype', 'HP:0008663', (134, 151))	('fusion', 'Var', (113, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('YWHAE', 'Gene', (100, 105))	('NUTM2B', 'Gene', (106, 112))	('YWHAE', 'Gene', '7531', (100, 105))	('infant', 'Species', '9606', (249, 255))	('infantile soft tissue URCS', 'Disease', (249, 275))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('CCSK', 'Phenotype', 'HP:0006770', (240, 244))	('genetic abnormalities', 'Disease', 'MESH:D030342', (210, 231))	('sarcoma', 'Disease', (134, 141))	('sarcoma of kidney', 'Disease', 'MESH:D007674', (134, 151))	('CCSK', 'Phenotype', 'HP:0006770', (153, 157))	('genetic abnormalities', 'Disease', (210, 231))
315633	26945340	However, recent studies have identified recurrent genetic abnormalities in CCSK, characterized by either internal tandem duplication (ITD) in exon 16 of BCOR in the majority of cases or the presence of t(10;17)(q22.3;p13.3) translocation resulting in YWHAE-NUTM2B/E fusions in a smaller subset of cases.	('NUTM2B', 'Gene', (257, 263))	('genetic abnormalities', 'Disease', (50, 71))	('CCSK', 'Phenotype', 'HP:0006770', (75, 79))	('BCOR', 'Gene', (153, 157))	('YWHAE', 'Gene', (251, 256))	('t(10;17)(q22.3;p13.3', 'Var', (202, 222))	('NUTM2B', 'Gene', '729262', (257, 263))	('t(10;17)(q22.3;p13.3)', 'STRUCTURAL_ABNORMALITY', 'None', (202, 223))	('YWHAE', 'Gene', '7531', (251, 256))	('BCOR', 'Gene', '54880', (153, 157))	('genetic abnormalities', 'Disease', 'MESH:D030342', (50, 71))	('internal tandem duplication', 'Var', (105, 132))	('CCSK', 'Disease', (75, 79))	('CCSK', 'Chemical', '-', (75, 79))
315679	26945340	Break-apart FISH assay confirmed YWHAE and NUTM2B/E gene rearrangements in the index case (URCS1) (Fig.	('NUTM2B', 'Gene', '729262', (43, 49))	('YWHAE', 'Gene', '7531', (33, 38))	('NUTM2B', 'Gene', (43, 49))	('YWHAE', 'Gene', (33, 38))	('rearrangements', 'Var', (57, 71))
315697	26945340	There was no obvious association between ITD variants and tumor location, gender, degree of myxoid change, or the presence of a delicate vascular pattern.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('variants', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
315773	26945340	Comparing the spectrum of BCOR ITD variants seen in soft tissue URCS/PMMTI, there were a number of them similar to the ones described in renal CCSK, but also several novel ITD variants, with a wider size range (63-120 bp).	('CCSK', 'Chemical', '-', (143, 147))	('CCSK', 'Phenotype', 'HP:0006770', (143, 147))	('variants', 'Var', (35, 43))	('BCOR', 'Gene', (26, 30))	('PMMTI', 'Chemical', '-', (69, 74))	('BCOR', 'Gene', '54880', (26, 30))
315779	26945340	Genetic alterations in BCOR have been reported in several human diseases.	('Genetic alterations', 'Var', (0, 19))	('human', 'Species', '9606', (58, 63))	('reported', 'Reg', (38, 46))	('BCOR', 'Gene', (23, 27))	('BCOR', 'Gene', '54880', (23, 27))
315780	26945340	Germline BCOR loss of function mutations (truncation, frameshift) result in X-linked oculofaciocardiodental (OFCD) syndromes, presenting with congenital cataracts, dysmorphic facies, cardiac abnormalities, radiculomegaly and associated with male lethality.	('X-linked oculofaciocardiodental (OFCD) syndromes', 'Disease', 'MESH:C537465', (76, 124))	('mutations', 'Var', (31, 40))	('congenital cataracts', 'Disease', (142, 162))	('dysmorphic facies', 'Disease', 'None', (164, 181))	('BCOR', 'Gene', (9, 13))	('loss of function', 'NegReg', (14, 30))	('cardiac abnormalities', 'Phenotype', 'HP:0001627', (183, 204))	('dysmorphic facies', 'Disease', (164, 181))	('cardiac abnormalities', 'Disease', (183, 204))	('radiculomegaly', 'Disease', (206, 220))	('BCOR', 'Gene', '54880', (9, 13))	('frameshift', 'Var', (54, 64))	('congenital cataracts', 'Disease', 'MESH:D002386', (142, 162))	('cardiac abnormalities', 'Disease', 'MESH:D006331', (183, 204))	('radiculomegaly', 'Disease', 'MESH:C537465', (206, 220))	('dysmorphic facies', 'Phenotype', 'HP:0001999', (164, 181))	('congenital cataracts', 'Phenotype', 'HP:0000519', (142, 162))	('cataracts', 'Phenotype', 'HP:0000518', (153, 162))
315786	26945340	Furthermore, BCOR up-regulation was also detected in our YWHAE-NUTM2B fusion positive URCS, similar to the 2 previously reported fusion-positive CCSK cases.	('up-regulation', 'PosReg', (18, 31))	('YWHAE', 'Gene', (57, 62))	('NUTM2B', 'Gene', (63, 69))	('YWHAE', 'Gene', '7531', (57, 62))	('fusion', 'Var', (70, 76))	('CCSK', 'Chemical', '-', (145, 149))	('BCOR', 'Gene', (13, 17))	('NUTM2B', 'Gene', '729262', (63, 69))	('CCSK', 'Phenotype', 'HP:0006770', (145, 149))	('BCOR', 'Gene', '54880', (13, 17))
315797	26945340	In conclusion, we report 17 cases of infantile URCS/PMMTI with identical genetic abnormalities to CCSK, including either ITD in the last exon of BCOR or YWHAE-NUTM2B fusion.	('CCSK', 'Chemical', '-', (98, 102))	('PMMTI', 'Chemical', '-', (52, 57))	('CCSK', 'Gene', (98, 102))	('ITD in', 'Var', (121, 127))	('NUTM2B', 'Gene', (159, 165))	('CCSK', 'Phenotype', 'HP:0006770', (98, 102))	('YWHAE', 'Gene', '7531', (153, 158))	('infantile URCS/PMMTI', 'Disease', (37, 57))	('BCOR', 'Gene', (145, 149))	('genetic abnormalities', 'Disease', 'MESH:D030342', (73, 94))	('genetic abnormalities', 'Disease', (73, 94))	('BCOR', 'Gene', '54880', (145, 149))	('NUTM2B', 'Gene', '729262', (159, 165))	('YWHAE', 'Gene', (153, 158))	('infant', 'Species', '9606', (37, 43))
315869	26375670	The use of Rapa and chemotherapy might promote cancer cells (including sarcoma) to a higher autophagy state, while HCQ blocks their final autolysosome pathway and switches the pro-survival to pro-death process as an example of synthetic lethality, (2.)	('HCQ', 'Chemical', 'MESH:D006886', (115, 118))	('promote', 'PosReg', (39, 46))	('pro-survival', 'CPA', (176, 188))	('Rapa', 'Gene', (11, 15))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('blocks', 'NegReg', (119, 125))	('Rapa', 'Gene', '55809', (11, 15))	('cancer', 'Disease', (47, 53))	('switches', 'Reg', (163, 171))	('sarcoma', 'Disease', (71, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('HCQ', 'Var', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
316063	24856830	Cohesin gene mutations in tumorigenesis: from discovery to clinical significance Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells.	('SMC3', 'Gene', (155, 159))	('SMC1A', 'Gene', '8243', (148, 153))	('mitosis', 'Disease', (305, 312))	('STAG2', 'Gene', '10735', (188, 193))	('mitosis', 'Disease', 'None', (305, 312))	('SMC1A', 'Gene', (148, 153))	('RAD21', 'Gene', (161, 166))	('enabling', 'PosReg', (321, 329))	('RAD21', 'Gene', '5885', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutations', 'Var', (13, 22))	('STAG2', 'Gene', (188, 193))	('SMC3', 'Gene', '9126', (155, 159))
316066	24856830	Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations.	('cancers', 'Disease', (183, 190))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('cohesin', 'Gene', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('inactivation', 'NegReg', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('mutations', 'Var', (209, 218))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cohesin', 'Protein', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
316076	24856830	ESPL1 cleaves the RAD21 subunit of the remaining chromatin-bound cohesin thereby enabling segregation of the sister chromatids.	('enabling', 'PosReg', (81, 89))	('ESPL1', 'Gene', '9700', (0, 5))	('ESPL1', 'Gene', (0, 5))	('cleaves', 'Var', (6, 13))	('segregation', 'CPA', (90, 101))	('RAD21', 'Gene', (18, 23))	('cohesin', 'Protein', (65, 72))	('RAD21', 'Gene', '5885', (18, 23))
316082	24856830	In 2004 mutations in the cohesin regulatory factor NIPBL were discovered to cause Cornelia de Lange (CdL) syndrome (OMIM 122470 and 300590), a rare autosomal dominant disorder characterized by facial dysmorphism, growth delay, mental retardation, and limb abnormalities.	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (148, 175))	('mental retardation', 'Disease', 'MESH:D008607', (227, 245))	('growth delay', 'Disease', (213, 225))	('limb abnormalities', 'Disease', (251, 269))	('limb abnormalities', 'Phenotype', 'HP:0002813', (251, 269))	('limb abnormalities', 'Disease', 'MESH:D017880', (251, 269))	('growth delay', 'Phenotype', 'HP:0001510', (213, 225))	('mutations', 'Var', (8, 17))	('facial dysmorphism', 'Disease', 'None', (193, 211))	('NIPBL', 'Gene', (51, 56))	('autosomal dominant disorder', 'Disease', (148, 175))	('facial dysmorphism', 'Phenotype', 'HP:0001999', (193, 211))	('cause', 'Reg', (76, 81))	('Cornelia de Lange (CdL) syndrome', 'Disease', 'MESH:D003635', (82, 114))	('facial dysmorphism', 'Disease', (193, 211))	('mental retardation', 'Disease', (227, 245))	('mental retardation', 'Phenotype', 'HP:0001249', (227, 245))
316083	24856830	Subsequently, mutations in cohesin core subunits SMC1A, SMC3, and RAD21 have been found in the subset of CdL patients without NIPBL mutations.	('SMC3', 'Gene', (56, 60))	('SMC1A', 'Gene', '8243', (49, 54))	('RAD21', 'Gene', '5885', (66, 71))	('patients', 'Species', '9606', (109, 117))	('SMC3', 'Gene', '9126', (56, 60))	('found', 'Reg', (82, 87))	('CdL', 'Disease', (105, 108))	('SMC1A', 'Gene', (49, 54))	('mutations', 'Var', (14, 23))	('RAD21', 'Gene', (66, 71))
316085	24856830	However, subsequent studies have not observed similar defects in sister chromatid cohesion, calling into question the functional consequence of cohesin mutations in CdL patients.	('cohesin', 'Gene', (144, 151))	('CdL', 'Disease', (165, 168))	('patients', 'Species', '9606', (169, 177))	('mutations', 'Var', (152, 161))
316086	24856830	Genome-wide transcriptional profiling in cells derived from CdL patients with NIPBL or SMC1A mutations versus normal subjects found a conserved pattern of transcriptional dysregulation, identifying a group of 339 genes with recurrently altered expression amongst the CdL patients and a significant correlation between the degree of transcriptional alteration and phenotypic disease severity.	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (64, 72))	('SMC1A', 'Gene', (87, 92))	('altered', 'Reg', (236, 243))	('expression', 'MPA', (244, 254))	('patients', 'Species', '9606', (271, 279))	('NIPBL', 'Gene', (78, 83))	('SMC1A', 'Gene', '8243', (87, 92))
316093	24856830	These studies demonstrate that cohesin inactivation both alters gene expression leading to developmental defects and sister chromatid cohesion leading to aneuploidy and increased tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('gene expression', 'MPA', (64, 79))	('aneuploidy', 'Disease', 'MESH:D000782', (154, 164))	('increased', 'PosReg', (169, 178))	('sister chromatid cohesion', 'CPA', (117, 142))	('alters', 'Reg', (57, 63))	('tumor', 'Disease', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('aneuploidy', 'Disease', (154, 164))	('developmental defects', 'Disease', (91, 112))	('developmental defects', 'Disease', 'MESH:D003147', (91, 112))	('inactivation', 'Var', (39, 51))	('cohesin', 'Protein', (31, 38))	('leading to', 'Reg', (80, 90))
316095	24856830	Most recently, an inactivating mutation of the meiosis-specific cohesin subunit STAG3 was found in a large consanguineous family with premature ovarian failure and was present in each of six affected family members.	('found', 'Reg', (90, 95))	('premature ovarian failure', 'Disease', (134, 159))	('premature ovarian failure', 'Disease', 'MESH:D016649', (134, 159))	('STAG3', 'Gene', (80, 85))	('inactivating mutation', 'Var', (18, 39))	('premature ovarian failure', 'Phenotype', 'HP:0008209', (134, 159))
316099	24856830	Given its function in controlling faithful sister chromatid segregation, dysregulation of the cohesin complex was hypothesized to contribute to the development of aneuploidy during tumorigenesis since its isolation and characterization in the late 1990's.	('tumor', 'Disease', (181, 186))	('aneuploidy', 'Disease', (163, 173))	('contribute', 'Reg', (130, 140))	('dysregulation', 'Var', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('aneuploidy', 'Disease', 'MESH:D000782', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
316100	24856830	The first report of cohesin gene alterations in human tumors was in 2008 wherein Barber et al.	('cohesin', 'Gene', (20, 27))	('human', 'Species', '9606', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('alterations', 'Var', (33, 44))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
316101	24856830	found somatic mutations of SMC1A, SMC3, and NIPBL in 9 out of 132 colorectal adenocarcinomas (see Table 1 for summary of cohesin gene mutations identified in human tumors), wherein they suggested that chromatid cohesion defects may underlie the chromosomal instability present in the vast majority of colorectal cancers.	('colorectal cancers', 'Disease', (301, 319))	('SMC1A', 'Gene', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('SMC1A', 'Gene', '8243', (27, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (66, 92))	('SMC3', 'Gene', '9126', (34, 38))	('colorectal cancers', 'Disease', 'MESH:D015179', (301, 319))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mutations', 'Var', (14, 23))	('NIPBL', 'Gene', (44, 49))	('chromosomal instability', 'Phenotype', 'HP:0040012', (245, 268))	('human', 'Species', '9606', (158, 163))	('tumors', 'Disease', (164, 170))	('colorectal adenocarcinomas', 'Disease', (66, 92))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('SMC3', 'Gene', (34, 38))
316102	24856830	Then in 2010 an array comparative genomic hybridization study of 167 myeloid disease samples identified a chronic myelomonocytic leukemia with a deletion of RAD21 (additionally harboring an NPM1 exon 12 mutation) and a de novo acute myeloid leukemia with a deletion of STAG2 (additionally harboring an IDH1-R132C mutation).	('IDH1', 'Gene', (302, 306))	('NPM1', 'Gene', (190, 194))	('myeloid disease', 'Disease', (69, 84))	('STAG2', 'Gene', '10735', (269, 274))	('RAD21', 'Gene', (157, 162))	('acute myeloid leukemia', 'Disease', (227, 249))	('myelomonocytic leukemia', 'Disease', 'MESH:D054429', (114, 137))	('IDH1', 'Gene', '3417', (302, 306))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (233, 249))	('STAG2', 'Gene', (269, 274))	('myeloid disease', 'Disease', 'MESH:D007951', (69, 84))	('RAD21', 'Gene', '5885', (157, 162))	('R132C', 'Mutation', 'rs121913499', (307, 312))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (227, 249))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (106, 137))	('NPM1', 'Gene', '4869', (190, 194))	('leukemia', 'Phenotype', 'HP:0001909', (241, 249))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (227, 249))	('myelomonocytic leukemia', 'Disease', (114, 137))	('deletion', 'Var', (145, 153))
316103	24856830	These first studies provided tantalizing evidence that the cohesin complex is a frequent target of genetic alterations during tumorigenesis.	('alterations', 'Var', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('genetic alterations', 'Var', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
316105	24856830	In a screen of 155 unique human cancer cell lines, complete loss of STAG2 expression was identified in 3/21 glioblastoma, 5/9 Ewing sarcoma, 1/10 melanoma, 1/6 cervical carcinoma, and 2/20 hematologic cancer cell lines and found truncating mutations or deletions in 10/12 of these samples with STAG2 loss (see Table 2 for summary of cohesin gene mutations identified in human cancer cell lines).	('loss', 'NegReg', (300, 304))	('cancer', 'Disease', (376, 382))	('cancer', 'Disease', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('loss', 'NegReg', (60, 64))	('carcinoma', 'Disease', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('glioblastoma', 'Disease', (108, 120))	('STAG2', 'Gene', '10735', (294, 299))	('human', 'Species', '9606', (26, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))	('hematologic cancer', 'Phenotype', 'HP:0004377', (189, 207))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (126, 139))	('STAG2', 'Gene', (294, 299))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('carcinoma', 'Disease', 'MESH:D002277', (169, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('STAG2', 'Gene', '10735', (68, 73))	('human', 'Species', '9606', (370, 375))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('truncating mutations', 'Var', (229, 249))	('melanoma', 'Disease', (146, 154))	('deletions', 'Var', (253, 262))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Ewing sarcoma', 'Disease', (126, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('STAG2', 'Gene', (68, 73))
316106	24856830	Analysis of primary tumor samples found somatic STAG2 mutations in 4/68 glioblastoma, 1/24 Ewing sarcoma, and 1/48 melanoma samples (see Fig.	('Ewing sarcoma', 'Disease', (91, 104))	('STAG2', 'Gene', '10735', (48, 53))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('mutations', 'Var', (54, 63))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('glioblastoma', 'Disease', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))	('STAG2', 'Gene', (48, 53))	('tumor', 'Disease', (20, 25))
316107	24856830	2 for diagram of STAG2 mutations reported in human tumors to date).	('STAG2', 'Gene', (17, 22))	('STAG2', 'Gene', '10735', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('human', 'Species', '9606', (45, 50))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
316110	24856830	Somatic cell gene targeting was used to correct the endogenous inactivating STAG2 mutations in two aneuploid glioblastoma cell lines (H4 and 42MGBA cells) via homologous recombination and to knockout STAG2 in a near-diploid, chromosomally stable colorectal carcinoma cell line (HCT116 cells).	('colorectal carcinoma', 'Disease', (246, 266))	('aneuploid glioblastoma', 'Disease', (99, 121))	('STAG2', 'Gene', (76, 81))	('STAG2', 'Gene', '10735', (76, 81))	('STAG2', 'Gene', (200, 205))	('HCT116', 'CellLine', 'CVCL:0291', (278, 284))	('STAG2', 'Gene', '10735', (200, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('mutations', 'Var', (82, 91))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (246, 266))	('aneuploid glioblastoma', 'Disease', 'MESH:D005909', (99, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
316111	24856830	Repair of the STAG2 gene led to restoration of the sister chromatid cohesion defect, a decrease in abnormal mitotic figures, and a reduction in chromosomal instability in the two aneuploid glioblastoma cell lines.	('reduction', 'NegReg', (131, 140))	('Repair', 'Var', (0, 6))	('STAG2', 'Gene', (14, 19))	('STAG2', 'Gene', '10735', (14, 19))	('chromosomal instability', 'Phenotype', 'HP:0040012', (144, 167))	('aneuploid glioblastoma', 'Disease', (179, 201))	('chromosomal instability', 'CPA', (144, 167))	('abnormal mitotic figures', 'CPA', (99, 123))	('decrease', 'NegReg', (87, 95))	('aneuploid glioblastoma', 'Disease', 'MESH:D005909', (179, 201))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))	('defect', 'NegReg', (77, 83))	('sister', 'MPA', (51, 57))
316112	24856830	In contrast, STAG2 knockout in HCT116 cells led to precocious sister chromatid separation and aneuploidy including trisomies, monosomies, and de novo translocations.	('monosomies', 'CPA', (126, 136))	('STAG2', 'Gene', '10735', (13, 18))	('knockout', 'Var', (19, 27))	('aneuploidy', 'Disease', (94, 104))	('HCT116', 'CellLine', 'CVCL:0291', (31, 37))	('trisomies', 'Disease', (115, 124))	('aneuploidy', 'Disease', 'MESH:D000782', (94, 104))	('STAG2', 'Gene', (13, 18))
316113	24856830	No significant difference in transcriptional profile was observed in these paired STAG2 mutant and wild-type glioblastoma and colorectal carcinoma cell lines, suggesting that the major tumor suppressive function of STAG2 is due to its canonical role in sister chromatid cohesin and not transcriptional regulation.	('tumor', 'Disease', (185, 190))	('glioblastoma', 'Disease', (109, 121))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (126, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('STAG2', 'Gene', (215, 220))	('STAG2', 'Gene', (82, 87))	('STAG2', 'Gene', '10735', (82, 87))	('mutant', 'Var', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('STAG2', 'Gene', '10735', (215, 220))	('colorectal carcinoma', 'Disease', (126, 146))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
316115	24856830	However, the complete spectrum of tumors harboring cohesin mutations and the precise functional significance of cohesin mutations in the pathogenesis of specific tumor types remained undefined.	('tumors', 'Disease', (34, 40))	('cohesin', 'Gene', (51, 58))	('tumor', 'Disease', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (162, 167))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
316116	24856830	Whole exome sequencing of 8 acute myeloid leukemia (AML) genomes reported in 2012 identified one AML (type M1 arising in an adult female) with an SMC3 missense mutation also harboring DNMT3A, NPM1, and FLT3 mutations.	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('AML', 'Disease', (52, 55))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('FLT3', 'Gene', (202, 206))	('SMC3', 'Gene', '9126', (146, 150))	('AML', 'Phenotype', 'HP:0004808', (97, 100))	('AML', 'Disease', (97, 100))	('FLT3', 'Gene', '2322', (202, 206))	('acute myeloid leukemia', 'Disease', (28, 50))	('NPM1', 'Gene', '4869', (192, 196))	('DNMT3A', 'Gene', (184, 190))	('missense mutation', 'Var', (151, 168))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (28, 50))	('SMC3', 'Gene', (146, 150))	('NPM1', 'Gene', (192, 196))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (34, 50))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (28, 50))	('DNMT3A', 'Gene', '1788', (184, 190))	('AML', 'Disease', 'MESH:D015470', (52, 55))
316117	24856830	This AML at initial presentation had normal diploid karyotype, and upon relapse harbored a single chromosomal aberration (t(10;12) translocation) along with new ETV6 and MYO18B mutations.	('AML', 'Disease', 'MESH:D015470', (5, 8))	('ETV6', 'Gene', '2120', (161, 165))	('mutations', 'Var', (177, 186))	('AML', 'Disease', (5, 8))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (98, 120))	('AML', 'Phenotype', 'HP:0004808', (5, 8))	('MYO18B', 'Gene', '84700', (170, 176))	('MYO18B', 'Gene', (170, 176))	('ETV6', 'Gene', (161, 165))
316118	24856830	A subsequent whole exome sequencing study of 7 secondary AMLs arising in patients with antecedent myelodysplastic syndrome (MDS) found two AMLs with cohesin mutations, one with a truncating mutation in STAG2 and one with a truncating mutation in SMC3.	('cohesin', 'Gene', (149, 156))	('MDS', 'Disease', (124, 127))	('AML', 'Disease', 'MESH:D015470', (139, 142))	('AML', 'Phenotype', 'HP:0004808', (139, 142))	('AML', 'Disease', (139, 142))	('AML', 'Disease', 'MESH:D015470', (57, 60))	('SMC3', 'Gene', (246, 250))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (98, 122))	('mutations', 'Var', (157, 166))	('AML', 'Disease', (57, 60))	('AML', 'Phenotype', 'HP:0004808', (57, 60))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (98, 122))	('MDS', 'Phenotype', 'HP:0002863', (124, 127))	('patients', 'Species', '9606', (73, 81))	('STAG2', 'Gene', '10735', (202, 207))	('MDS', 'Disease', 'MESH:D009190', (124, 127))	('SMC3', 'Gene', '9126', (246, 250))	('myelodysplastic syndrome', 'Disease', (98, 122))	('STAG2', 'Gene', (202, 207))
316119	24856830	The STAG2 mutation was present in both the antecedent MDS and the secondary AML with additional PTPN11 and RUNX1 mutations arising de novo in the secondary AML that had normal cytogenetics.	('AML', 'Disease', 'MESH:D015470', (156, 159))	('AML', 'Disease', (76, 79))	('RUNX1', 'Gene', '861', (107, 112))	('PTPN11', 'Gene', '5781', (96, 102))	('AML', 'Phenotype', 'HP:0004808', (156, 159))	('AML', 'Phenotype', 'HP:0004808', (76, 79))	('AML', 'Disease', (156, 159))	('PTPN11', 'Gene', (96, 102))	('STAG2', 'Gene', '10735', (4, 9))	('MDS', 'Disease', (54, 57))	('mutations', 'Var', (113, 122))	('MDS', 'Disease', 'MESH:D009190', (54, 57))	('MDS', 'Phenotype', 'HP:0002863', (54, 57))	('STAG2', 'Gene', (4, 9))	('AML', 'Disease', 'MESH:D015470', (76, 79))	('RUNX1', 'Gene', (107, 112))
316120	24856830	The SMC3 mutation was present at low frequency in the antecedent MDS and at high frequency in the secondary AML that also harbored NPM1 mutation and had normal cytogenetics.	('NPM1', 'Gene', (131, 135))	('AML', 'Disease', (108, 111))	('AML', 'Phenotype', 'HP:0004808', (108, 111))	('mutation', 'Var', (136, 144))	('NPM1', 'Gene', '4869', (131, 135))	('SMC3', 'Gene', '9126', (4, 8))	('SMC3', 'Gene', (4, 8))	('MDS', 'Phenotype', 'HP:0002863', (65, 68))	('AML', 'Disease', 'MESH:D015470', (108, 111))	('MDS', 'Disease', (65, 68))	('MDS', 'Disease', 'MESH:D009190', (65, 68))
316122	24856830	This study found cohesin mutations in 7/65 type M1 AMLs (11%) but no cohesin gene mutations in the 43 type M3 AMLs (0%).	('AML', 'Disease', (51, 54))	('mutations', 'Var', (25, 34))	('AML', 'Phenotype', 'HP:0004808', (51, 54))	('AML', 'Phenotype', 'HP:0004808', (110, 113))	('AML', 'Disease', (110, 113))	('AML', 'Disease', 'MESH:D015470', (51, 54))	('AML', 'Disease', 'MESH:D015470', (110, 113))
316124	24856830	All seven of these AMLs with cohesin mutations had fewer than three cytogenetic abnormalities, while 6/7 of these AMLs also harbored FLT3 mutations, 3/7 also harbored NPM1 mutations, 2/7 also harbored DNMT3A mutations, and 2/7 also harbored TET2 mutations.	('AML', 'Disease', (114, 117))	('NPM1', 'Gene', (167, 171))	('AML', 'Disease', 'MESH:D015470', (19, 22))	('AML', 'Phenotype', 'HP:0004808', (114, 117))	('mutations', 'Var', (208, 217))	('FLT3', 'Gene', '2322', (133, 137))	('AML', 'Disease', (19, 22))	('AML', 'Phenotype', 'HP:0004808', (19, 22))	('cohesin', 'Gene', (29, 36))	('DNMT3A', 'Gene', (201, 207))	('TET2', 'Gene', (241, 245))	('harbored', 'Reg', (124, 132))	('mutations', 'Var', (37, 46))	('NPM1', 'Gene', '4869', (167, 171))	('mutations', 'Var', (138, 147))	('mutations', 'Var', (172, 181))	('FLT3', 'Gene', (133, 137))	('AML', 'Disease', 'MESH:D015470', (114, 117))	('TET2', 'Gene', '54790', (241, 245))	('DNMT3A', 'Gene', '1788', (201, 207))
316125	24856830	Given the near-diploid karyotype of all AMLs with identified cohesin mutations, the authors speculated that cohesin mutations may be selected for during leukemogenesis not due to loss of sister chromatid cohesion and induction of aneuploidy, but rather other loss of function mechanisms such as transcriptional deregulation.	('mutations', 'Var', (69, 78))	('aneuploidy', 'Disease', (230, 240))	('AML', 'Disease', 'MESH:D015470', (40, 43))	('cohesin', 'Gene', (108, 115))	('aneuploidy', 'Disease', 'MESH:D000782', (230, 240))	('AML', 'Phenotype', 'HP:0004808', (40, 43))	('leukemogenesis', 'Disease', (153, 167))	('sister', 'Protein', (187, 193))	('AML', 'Disease', (40, 43))	('mutations', 'Var', (116, 125))	('loss', 'NegReg', (179, 183))	('cohesin', 'Gene', (61, 68))
316127	24856830	They found cohesin mutations in 26 of these AMLs (13%) including 7 with STAG2 mutations (all truncating), 7 with SMC3 mutations (5/7 missense), 7 with SMC1A mutations (6/7 missense), and 5 with RAD21 mutations (all truncating).	('cohesin', 'Gene', (11, 18))	('RAD21', 'Gene', (194, 199))	('SMC3', 'Gene', '9126', (113, 117))	('STAG2', 'Gene', (72, 77))	('STAG2', 'Gene', '10735', (72, 77))	('SMC3', 'Gene', (113, 117))	('AML', 'Disease', 'MESH:D015470', (44, 47))	('mutations', 'Var', (118, 127))	('RAD21', 'Gene', '5885', (194, 199))	('mutations', 'Var', (19, 28))	('mutations', 'Var', (78, 87))	('AML', 'Disease', (44, 47))	('SMC1A', 'Gene', (151, 156))	('AML', 'Phenotype', 'HP:0004808', (44, 47))	('SMC1A', 'Gene', '8243', (151, 156))
316128	24856830	no AML had multiple cohesin gene mutations) demonstrating that genetic inactivation of a single cohesin subunit is likely sufficient to disrupt the tumor suppressive function of cohesin in myeloid leukemogenesis.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('myeloid leukemogenesis', 'Disease', 'MESH:D007951', (189, 211))	('myeloid leukemogenesis', 'Phenotype', 'HP:0012324', (189, 211))	('myeloid leukemogenesis', 'Disease', (189, 211))	('cohesin', 'Protein', (178, 185))	('genetic inactivation', 'Var', (63, 83))	('disrupt', 'NegReg', (136, 143))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('AML', 'Disease', (3, 6))
316131	24856830	Given the frequent mutations of cohesin genes in AML, Kon et al.	('AML', 'Disease', (49, 52))	('cohesin genes', 'Gene', (32, 45))	('mutations', 'Var', (19, 28))	('AML', 'Disease', 'MESH:D015470', (49, 52))	('AML', 'Phenotype', 'HP:0004808', (49, 52))
316133	24856830	In accordance with previous studies, cohesin mutations were identified in 16/120 de novo AMLs (13%).	('mutations', 'Var', (45, 54))	('AML', 'Disease', 'MESH:D015470', (89, 92))	('cohesin', 'Protein', (37, 44))	('AML', 'Phenotype', 'HP:0004808', (89, 92))	('identified', 'Reg', (60, 70))	('AML', 'Disease', (89, 92))
316134	24856830	Additionally, cohesin mutations were found in 19/224 myelodysplastic syndromes (8%), 3/37 secondary AMLs (8%), 4/64 chronic myelogenous leukemias (6%), 10/88 chronic myelomonocytic leukemias (11%), and 1/77 myeloproliferative neoplasms (1%).	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (158, 189))	('myelomonocytic leukemias', 'Disease', 'MESH:D054429', (166, 190))	('chronic myelomonocytic leukemias', 'Phenotype', 'HP:0012325', (158, 190))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('myelomonocytic leukemias', 'Disease', (166, 190))	('neoplasms', 'Phenotype', 'HP:0002664', (226, 235))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (53, 77))	('leukemias', 'Phenotype', 'HP:0001909', (181, 190))	('myelogenous leukemias', 'Disease', (124, 145))	('cohesin', 'Gene', (14, 21))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (53, 78))	('leukemia', 'Phenotype', 'HP:0001909', (181, 189))	('myelodysplastic syndromes', 'Disease', (53, 78))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (207, 235))	('neoplasms', 'Disease', 'MESH:D009369', (226, 235))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (53, 78))	('AML', 'Disease', 'MESH:D015470', (100, 103))	('mutations', 'Var', (22, 31))	('chronic myelogenous leukemias', 'Phenotype', 'HP:0005506', (116, 145))	('neoplasms', 'Disease', (226, 235))	('AML', 'Disease', (100, 103))	('AML', 'Phenotype', 'HP:0004808', (100, 103))	('found', 'Reg', (37, 42))	('myelogenous leukemias', 'Disease', 'MESH:D007951', (124, 145))	('leukemias', 'Phenotype', 'HP:0001909', (136, 145))	('myelogenous leukemias', 'Phenotype', 'HP:0012324', (124, 145))
316135	24856830	Cohesin mutated leukemia cells had reduced levels of chromatin-bound cohesin components, and the growth of cohesin mutated leukemia cells was suppressed by forced over-expression of the respective wild-type cohesin subunit, thereby leading the authors to speculate that cohesin mutations participate in leukemogenesis through the deregulated expression of genes involved in myeloid development and differentiation.	('leukemia', 'Disease', 'MESH:D007938', (16, 24))	('leukemia', 'Disease', (123, 131))	('mutations', 'Var', (278, 287))	('expression', 'MPA', (342, 352))	('leukemia', 'Disease', 'MESH:D007938', (123, 131))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('reduced', 'NegReg', (35, 42))	('leukemia', 'Phenotype', 'HP:0001909', (16, 24))	('cohesin', 'Gene', (270, 277))	('leukemogenesis', 'Disease', (303, 317))	('deregulated', 'Reg', (330, 341))	('participate', 'Reg', (288, 299))	('suppressed', 'NegReg', (142, 152))	('leukemia', 'Disease', (16, 24))	('levels of', 'MPA', (43, 52))
316136	24856830	In order to explore the clinical significance of cohesin mutations in AML, Thol et al.	('AML', 'Disease', (70, 73))	('AML', 'Phenotype', 'HP:0004808', (70, 73))	('mutations', 'Var', (57, 66))	('cohesin', 'Protein', (49, 56))	('AML', 'Disease', 'MESH:D015470', (70, 73))
316138	24856830	Mutations were identified in 22 patients (6%), all of which were mutually exclusive and were strongly associated with the co-occurrence of NPM1 mutations.	('NPM1', 'Gene', (139, 143))	('patients', 'Species', '9606', (32, 40))	('associated', 'Reg', (102, 112))	('NPM1', 'Gene', '4869', (139, 143))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (144, 153))
316139	24856830	Up to 10% of patients with constitutional trisomy 21 (Down syndrome) experience transient abnormal myelopoiesis (TAM) during infancy, an abnormal myeloproliferative disorder that morphologically resembles acute megakaryoblastic leukemia (AMKL) but is usually self-limiting and spontaneously resolves within 3-4 months after birth.	('abnormal myeloproliferative disorder', 'Disease', (137, 173))	('acute megakaryoblastic leukemia', 'Disease', (205, 236))	('acute megakaryoblastic leukemia', 'Disease', 'MESH:D007947', (205, 236))	('TAM', 'Gene', '8205', (113, 116))	('abnormal myelopoiesis', 'Disease', 'MESH:C563551', (90, 111))	('patients', 'Species', '9606', (13, 21))	('TAM', 'Phenotype', 'HP:0005534', (113, 116))	('AMKL', 'Phenotype', 'HP:0006733', (238, 242))	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (146, 173))	('abnormal myeloproliferative disorder', 'Disease', 'MESH:D009196', (137, 173))	('acute megakaryoblastic leukemia', 'Phenotype', 'HP:0006733', (205, 236))	('abnormal myelopoiesis', 'Disease', (90, 111))	('TAM', 'Gene', (113, 116))	('transient abnormal myelopoiesis', 'Phenotype', 'HP:0005534', (80, 111))	('constitutional trisomy 21', 'Var', (27, 52))	('leukemia', 'Phenotype', 'HP:0001909', (228, 236))
316141	24856830	It was discovered in 2002 that all TAM samples harbor truncating mutations in the 5' coding exons of the GATA1 gene, an essential hematopoietic transcription factor, resulting in downstream re-initiation and production of a shorter GATA1 variant lacking the N-terminal activation domain.	('GATA1', 'Gene', '2623', (232, 237))	('truncating mutations', 'Var', (54, 74))	('GATA1', 'Gene', '2623', (105, 110))	('TAM', 'Gene', (35, 38))	('GATA1', 'Gene', (232, 237))	('TAM', 'Gene', '8205', (35, 38))	('re-initiation', 'PosReg', (190, 203))	('GATA1', 'Gene', (105, 110))	('lacking', 'NegReg', (246, 253))	('N-terminal activation domain', 'MPA', (258, 286))	('TAM', 'Phenotype', 'HP:0005534', (35, 38))
316142	24856830	While the combination of GATA1 mutation and trisomy 21 are sufficient for the induction of TAM, it is unclear what the driving third genetic hit is that results in AMKL in Down syndrome patients.	('TAM', 'Gene', '8205', (91, 94))	('Down syndrome', 'Disease', (172, 185))	('GATA1', 'Gene', (25, 30))	('AMKL', 'Phenotype', 'HP:0006733', (164, 168))	('TAM', 'Phenotype', 'HP:0005534', (91, 94))	('mutation', 'Var', (31, 39))	('trisomy 21', 'Var', (44, 54))	('GATA1', 'Gene', '2623', (25, 30))	('TAM', 'Gene', (91, 94))	('patients', 'Species', '9606', (186, 194))
316143	24856830	An exome sequencing study found that cohesin mutations were present in 23/49 (47%) of Down syndrome-associated AMKL cases (predominantly STAG2 and RAD21 mutations and occasional cases with mutations in cohesin regulatory genes, all of which were mutually exclusive) while cohesin mutations were less commonly found in sporadic AMKL (2/19 cases, 11%) and were never present in TAM (0/41 cases).	('mutations', 'Var', (45, 54))	('Down syndrome-associated AMKL', 'Disease', (86, 115))	('TAM', 'Phenotype', 'HP:0005534', (376, 379))	('mutations', 'Var', (153, 162))	('TAM', 'Gene', (376, 379))	('AMKL', 'Phenotype', 'HP:0006733', (327, 331))	('STAG2', 'Gene', '10735', (137, 142))	('AMKL', 'Phenotype', 'HP:0006733', (111, 115))	('cohesin', 'Gene', (37, 44))	('present', 'Reg', (60, 67))	('RAD21', 'Gene', (147, 152))	('RAD21', 'Gene', '5885', (147, 152))	('STAG2', 'Gene', (137, 142))	('TAM', 'Gene', '8205', (376, 379))
316144	24856830	The majority of cohesin mutated AMKLs had two or fewer chromosomal aberrations other than trisomy 21, again supporting a non-aneuploidy driven mechanism for cohesin inactivation in myeloid leukemogenesis.	('mutated', 'Var', (24, 31))	('aneuploidy', 'Disease', (125, 135))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (55, 77))	('myeloid leukemogenesis', 'Disease', 'MESH:D007951', (181, 203))	('myeloid leukemogenesis', 'Phenotype', 'HP:0012324', (181, 203))	('AMKL', 'Phenotype', 'HP:0006733', (32, 36))	('myeloid leukemogenesis', 'Disease', (181, 203))	('cohesin', 'Gene', (16, 23))	('aneuploidy', 'Disease', 'MESH:D000782', (125, 135))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (55, 78))
316146	24856830	In order to explore the complete tumor spectrum harboring STAG2 inactivation, Solomon et al.	('STAG2', 'Gene', (58, 63))	('inactivation', 'Var', (64, 76))	('STAG2', 'Gene', '10735', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
316149	24856830	No STAG2 loss was found in 18 bladder adenocarcinomas or 15 bladder squamous cell carcinomas, suggesting a specific role for STAG2 inactivation in urothelial carcinoma of the bladder (also referred to as transitional cell carcinoma).	('STAG2', 'Gene', (3, 8))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (204, 231))	('15 bladder squamous cell carcinomas', 'Disease', 'MESH:D002294', (57, 92))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (147, 182))	('bladder adenocarcinomas', 'Disease', (30, 53))	('bladder adenocarcinomas', 'Disease', 'MESH:D001749', (30, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('STAG2', 'Gene', '10735', (125, 130))	('urothelial carcinoma of the bladder', 'Disease', (147, 182))	('carcinoma', 'Disease', 'MESH:D002277', (43, 52))	('carcinoma', 'Disease', 'MESH:D002277', (82, 91))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('carcinoma', 'Disease', (43, 52))	('inactivation', 'Var', (131, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Disease', (222, 231))	('carcinoma', 'Disease', (158, 167))	('STAG2', 'Gene', (125, 130))	('loss', 'NegReg', (9, 13))	('STAG2', 'Gene', '10735', (3, 8))	('15 bladder squamous cell carcinomas', 'Disease', (57, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Disease', 'MESH:D002277', (222, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('carcinoma', 'Disease', 'MESH:D002277', (158, 167))	('carcinoma', 'Disease', (82, 91))
316150	24856830	Sequencing of STAG2 in an independent cohort of urothelial bladder carcinomas identified mutations in 9/25 papillary non-invasive carcinomas (36%), 6/22 superficially invasive carcinomas (27%), and 8/64 muscle invasive carcinomas (13%).	('invasive carcinomas', 'Disease', (167, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('mutations', 'Var', (89, 98))	('urothelial bladder carcinomas', 'Disease', (48, 77))	('urothelial bladder carcinomas', 'Disease', 'MESH:D001749', (48, 77))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (59, 77))	('STAG2', 'Gene', '10735', (14, 19))	('invasive carcinomas', 'Disease', 'MESH:D009361', (210, 229))	('invasive carcinomas', 'Disease', 'MESH:D009361', (121, 140))	('papillary non-invasive carcinomas', 'Disease', 'MESH:D002291', (107, 140))	('STAG2', 'Gene', (14, 19))	('muscle invasive carcinomas', 'Disease', 'MESH:D009217', (203, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (59, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))	('invasive carcinomas', 'Disease', 'MESH:D009361', (167, 186))	('papillary non-invasive carcinomas', 'Disease', (107, 140))	('muscle invasive carcinomas', 'Disease', (203, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
316151	24856830	21/25 of the identified mutations were truncating causing loss of STAG2 expression as seen by immunohistochemistry.	('loss', 'NegReg', (58, 62))	('STAG2', 'Gene', '10735', (66, 71))	('STAG2', 'Gene', (66, 71))	('expression', 'MPA', (72, 82))	('mutations', 'Var', (24, 33))
316153	24856830	These findings highlight the clonal heterogeneity of urothelial bladder carcinoma and suggest that while STAG2 inactivation occurs an early event in most bladder tumors with uniform STAG2 loss throughout, STAG2 mutations are also selected for during the clonal progression in occasional tumors.	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (53, 81))	('urothelial bladder carcinoma', 'Disease', (53, 81))	('STAG2', 'Gene', (105, 110))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (64, 81))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('STAG2', 'Gene', '10735', (182, 187))	('bladder tumors', 'Disease', 'MESH:D001749', (154, 168))	('STAG2', 'Gene', '10735', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('STAG2', 'Gene', (182, 187))	('inactivation', 'NegReg', (111, 123))	('STAG2', 'Gene', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('bladder tumors', 'Disease', (154, 168))	('mutations', 'Var', (211, 220))	('bladder tumors', 'Phenotype', 'HP:0009725', (154, 168))	('STAG2', 'Gene', '10735', (105, 110))	('loss', 'NegReg', (188, 192))	('tumors', 'Disease', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', (287, 293))
316154	24856830	Truncating mutations of STAG2 were also identified in 5/32 urothelial carcinoma cell lines (16%).	('Truncating mutations', 'Var', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (59, 79))	('identified', 'Reg', (40, 50))	('STAG2', 'Gene', '10735', (24, 29))	('urothelial carcinoma', 'Disease', (59, 79))	('STAG2', 'Gene', (24, 29))
316158	24856830	Copy number analysis of 12 STAG2 mutant urothelial bladder carcinomas demonstrated multiple chromosomal aberrations in each of 9 tumors and no aberrations in the other 3 tumors, whereas 10/12 STAG2 wild-type urothelial bladder carcinomas contained detectable chromosomal aberrations.	('urothelial bladder carcinomas', 'Disease', 'MESH:D001749', (208, 237))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (51, 68))	('tumors', 'Disease', (129, 135))	('urothelial bladder carcinomas', 'Disease', (40, 69))	('urothelial bladder carcinomas', 'Disease', 'MESH:D001749', (40, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (92, 115))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (92, 114))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (259, 281))	('mutant', 'Var', (33, 39))	('STAG2', 'Gene', (192, 197))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (51, 69))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (219, 237))	('multiple chromosomal aberrations', 'Phenotype', 'HP:0040012', (83, 115))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (259, 282))	('STAG2', 'Gene', '10735', (27, 32))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (219, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('urothelial bladder carcinomas', 'Disease', (208, 237))	('STAG2', 'Gene', '10735', (192, 197))	('tumors', 'Disease', (170, 176))	('STAG2', 'Gene', (27, 32))
316159	24856830	Re-expression of wild-type STAG2 in three urothelial carcinoma cell lines with truncating STAG2 mutations did not affect cellular proliferation in vitro, tumor growth in vivo, or mean chromosome count per cell.	('STAG2', 'Gene', (27, 32))	('STAG2', 'Gene', (90, 95))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (42, 62))	('STAG2', 'Gene', '10735', (90, 95))	('STAG2', 'Gene', '10735', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mutations', 'Var', (96, 105))	('urothelial carcinoma', 'Disease', (42, 62))	('cellular proliferation', 'CPA', (121, 143))	('tumor', 'Disease', (154, 159))
316160	24856830	shRNA knockdown of STAG2 in a urothelial carcinoma cell line with wild-type STAG2 led to a modest alteration in chromosome count per cell.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('STAG2', 'Gene', (76, 81))	('STAG2', 'Gene', '10735', (76, 81))	('STAG2', 'Gene', (19, 24))	('urothelial carcinoma', 'Disease', (30, 50))	('STAG2', 'Gene', '10735', (19, 24))	('alteration', 'Reg', (98, 108))	('knockdown', 'Var', (6, 15))	('chromosome count per cell', 'CPA', (112, 137))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (30, 50))
316162	24856830	Simultaneous to the publication of this study, two additional whole-exome sequencing studies of urothelial bladder carcinoma identifying frequent mutations of cohesin genes were also published.	('cohesin genes', 'Gene', (159, 172))	('mutations', 'Var', (146, 155))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (107, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (96, 124))	('urothelial bladder carcinoma', 'Disease', (96, 124))
316163	24856830	In the first of these other two studies, cohesin mutations were found in 10/33 papillary non-invasive tumors (30%), 3/32 superficially invasive tumors (9%), and 2/9 muscle invasive tumors (22%).	('cohesin', 'Gene', (41, 48))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('invasive tumors', 'Disease', 'MESH:D009369', (172, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mutations', 'Var', (49, 58))	('invasive tumors', 'Disease', (135, 150))	('invasive tumors', 'Disease', 'MESH:D009369', (93, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('invasive tumors', 'Disease', 'MESH:D009369', (135, 150))	('papillary non-invasive tumors', 'Disease', 'MESH:D002291', (79, 108))	('found', 'Reg', (64, 69))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (165, 187))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('papillary non-invasive tumors', 'Disease', (79, 108))	('muscle invasive tumors', 'Disease', (165, 187))
316164	24856830	These were predominantly truncating mutations of STAG2, with occasional tumors harboring mutations in other core cohesin genes as well as cohesin regulatory genes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('STAG2', 'Gene', '10735', (49, 54))	('STAG2', 'Gene', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('truncating', 'Var', (25, 35))
316165	24856830	In the second of these other two studies, cohesin mutations were found in 10/32 superficially invasive tumors (31%) and 6/61 muscle invasive tumors (10%), with an additional 9 muscle invasive tumors harboring mutations in cohesin regulatory genes, predominantly ESPL1 which encodes the enzyme Separase that cleaves Rad21 at the metaphase to anaphase transition to enable sister chromatid segregation.	('invasive tumors', 'Disease', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('invasive tumors', 'Disease', 'MESH:D009369', (94, 109))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('ESPL1', 'Gene', '9700', (262, 267))	('Rad21', 'Gene', '5885', (315, 320))	('found', 'Reg', (65, 70))	('Separase', 'Gene', (293, 301))	('muscle invasive tumors', 'Disease', (176, 198))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('invasive tumors', 'Disease', 'MESH:D009369', (132, 147))	('ESPL1', 'Gene', (262, 267))	('enable', 'Reg', (364, 370))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (125, 147))	('sister chromatid segregation', 'CPA', (371, 399))	('muscle invasive tumors', 'Disease', (125, 147))	('cohesin', 'Gene', (42, 49))	('mutations', 'Var', (50, 59))	('invasive tumors', 'Disease', 'MESH:D009369', (183, 198))	('Separase', 'Gene', '9700', (293, 301))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('Rad21', 'Gene', (315, 320))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (176, 198))	('mutations', 'Var', (209, 218))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
316166	24856830	In the first study, STAG2 mutation in non-muscle invasive tumors was associated with co-occurrence of FGFR3 mutations and absence of p53 overexpression.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (108, 117))	('mutation', 'Var', (26, 34))	('FGFR3', 'Gene', (102, 107))	('p53', 'Gene', '7157', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('associated', 'Reg', (69, 79))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (42, 64))	('STAG2', 'Gene', (20, 25))	('p53', 'Gene', (133, 136))	('STAG2', 'Gene', '10735', (20, 25))	('muscle invasive tumors', 'Disease', (42, 64))	('FGFR3', 'Gene', '2261', (102, 107))
316171	24856830	shRNA knockdown of STAG2 in urothelial carcinoma cell lines with wild-type STAG2 was not found to significantly alter the mean chromosome count per cell, and re-expression of wild-type STAG2 in cell lines with inactivating STAG2 mutations led to reduced colony formation in vitro .	('STAG2', 'Gene', (223, 228))	('STAG2', 'Gene', '10735', (223, 228))	('mutations', 'Var', (229, 238))	('colony formation in vitro', 'CPA', (254, 279))	('STAG2', 'Gene', (19, 24))	('STAG2', 'Gene', '10735', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('reduced', 'NegReg', (246, 253))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (28, 48))	('STAG2', 'Gene', (75, 80))	('STAG2', 'Gene', '10735', (75, 80))	('STAG2', 'Gene', '10735', (185, 190))	('urothelial carcinoma', 'Disease', (28, 48))	('STAG2', 'Gene', (185, 190))
316172	24856830	In the second study, invasive urothelial carcinomas with STAG2 mutations were significantly more aneuploid than invasive urothelial carcinomas without any alterations in core cohesin or cohesin regulatory genes.	('mutations', 'Var', (63, 72))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (112, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (21, 51))	('invasive urothelial carcinomas', 'Disease', (112, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('STAG2', 'Gene', (57, 62))	('STAG2', 'Gene', '10735', (57, 62))	('invasive urothelial carcinomas', 'Disease', (21, 51))
316173	24856830	Additionally, patients with either superficially invasive or muscle invasive urothelial carcinomas harboring STAG2 mutations were associated with reduced overall survival compared to patients with wild-type tumors.	('mutations', 'Var', (115, 124))	('muscle invasive urothelial carcinomas', 'Disease', 'MESH:D009217', (61, 98))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('reduced', 'NegReg', (146, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('superficially invasive', 'Disease', (35, 57))	('STAG2', 'Gene', (109, 114))	('STAG2', 'Gene', '10735', (109, 114))	('tumors', 'Disease', (207, 213))	('overall survival', 'MPA', (154, 170))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('muscle invasive urothelial carcinomas', 'Disease', (61, 98))	('patients', 'Species', '9606', (183, 191))	('patients', 'Species', '9606', (14, 22))
316175	24856830	In a subsequent in-depth study of STAG2 inactivation in urothelial bladder carcinoma, STAG2 mutations were identified in 46/138 papillary non-invasive tumors (33%), 16/76 superficially invasive tumors (21%), and 10/80 muscle invasive tumors (13%).	('muscle invasive tumors', 'Disease', (218, 240))	('invasive tumors', 'Disease', 'MESH:D009369', (142, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('STAG2', 'Gene', '10735', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('papillary non-invasive tumors', 'Disease', (128, 157))	('STAG2', 'Gene', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('mutations', 'Var', (92, 101))	('invasive tumors', 'Disease', 'MESH:D009369', (225, 240))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (56, 84))	('invasive tumors', 'Disease', (185, 200))	('STAG2', 'Gene', '10735', (34, 39))	('invasive tumors', 'Disease', 'MESH:D009369', (185, 200))	('urothelial bladder carcinoma', 'Disease', (56, 84))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (218, 240))	('identified', 'Reg', (107, 117))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (67, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('papillary non-invasive tumors', 'Disease', 'MESH:D002291', (128, 157))	('STAG2', 'Gene', (34, 39))
316176	24856830	STAG2 mutations were significantly associated with lower tumor grade, lower tumor stage, co-occurrence of FGRF3 and PIK3CA mutations, and wild-type TP53 status.	('PIK3CA', 'Gene', (116, 122))	('STAG2', 'Gene', '10735', (0, 5))	('FGRF3', 'Gene', (106, 111))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('tumor', 'Disease', (76, 81))	('PIK3CA', 'Gene', '5290', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('lower', 'NegReg', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('STAG2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
316177	24856830	No significant association of STAG2 mutation with disease recurrence in either papillary non-invasive carcinomas or invasive carcinomas was found.	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('papillary non-invasive carcinomas', 'Disease', 'MESH:D002291', (79, 112))	('invasive carcinomas', 'Disease', 'MESH:D009361', (93, 112))	('STAG2', 'Gene', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('STAG2', 'Gene', '10735', (30, 35))	('papillary non-invasive carcinomas', 'Disease', (79, 112))	('invasive carcinomas', 'Disease', (116, 135))	('invasive carcinomas', 'Disease', 'MESH:D009361', (116, 135))	('mutation', 'Var', (36, 44))
316180	24856830	Copy number analysis of 220 urothelial bladder carcinomas found that STAG2 mutation was inversely related with chromosomal copy number alterations.	('STAG2', 'Gene', (69, 74))	('STAG2', 'Gene', '10735', (69, 74))	('mutation', 'Var', (75, 83))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (39, 57))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (39, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('urothelial bladder carcinomas', 'Disease', (28, 57))	('urothelial bladder carcinomas', 'Disease', 'MESH:D001749', (28, 57))	('chromosomal', 'MPA', (111, 122))
316182	24856830	In total they identified cohesin mutations in 22/131 muscle invasive carcinomas (17%), including 14 tumors (11%) with STAG2 mutations and 8 tumors with mutations in other core cohesin genes.	('mutations', 'Var', (33, 42))	('14 tumors', 'Disease', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('STAG2', 'Gene', '10735', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('muscle invasive carcinomas', 'Disease', 'MESH:D009217', (53, 79))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (140, 146))	('14 tumors', 'Disease', 'MESH:C567448', (97, 106))	('tumors', 'Disease', (100, 106))	('STAG2', 'Gene', (118, 123))	('muscle invasive carcinomas', 'Disease', (53, 79))	('cohesin', 'Gene', (25, 32))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('mutations', 'Var', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('identified', 'Reg', (14, 24))	('tumors', 'Disease', 'MESH:D009369', (100, 106))
316183	24856830	Additionally, 17/131 tumors (13%) harbored mutations in cohesin regulatory genes including CDCA5, ESPL1, and NIPBL.	('ESPL1', 'Gene', (98, 103))	('NIPBL', 'Gene', (109, 114))	('ESPL1', 'Gene', '9700', (98, 103))	('harbored', 'Reg', (34, 42))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('CDCA5', 'Gene', '113130', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (43, 52))	('cohesin regulatory genes', 'Gene', (56, 80))	('CDCA5', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
316184	24856830	Clustering of the 131 tumors based on mutations and copy number alterations identified three distinct groups, and 11/14 of the tumors with STAG2 mutations belonged to Group B enriched in tumors harboring CDKN2A deletions, FGFR3 mutations, and papillary histology.	('FGFR3', 'Gene', (222, 227))	('CDKN2A', 'Gene', '1029', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (145, 154))	('FGFR3', 'Gene', '2261', (222, 227))	('papillary histology', 'Phenotype', 'HP:0007482', (243, 262))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('deletions', 'Var', (211, 220))	('tumors', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumors', 'Disease', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (228, 237))	('STAG2', 'Gene', '10735', (139, 144))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('CDKN2A', 'Gene', (204, 210))	('STAG2', 'Gene', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (187, 193))
316185	24856830	Why STAG2 mutations occur at higher frequency in particular molecular subgroups of urothelial carcinomas remains undefined.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('STAG2', 'Gene', (4, 9))	('urothelial carcinomas', 'Disease', (83, 104))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (83, 104))	('mutations', 'Var', (10, 19))	('STAG2', 'Gene', '10735', (4, 9))
316186	24856830	Not only have cohesin gene mutations been identified in urothelial carcinomas arising in the bladder, exome sequencing of urothelial carcinomas arising in the upper urothelial tract (e.g.	('mutations', 'Var', (27, 36))	('identified', 'Reg', (42, 52))	('cohesin', 'Gene', (14, 21))	('urothelial carcinomas', 'Disease', (122, 143))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (122, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('urothelial carcinomas', 'Disease', (56, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (56, 77))
316187	24856830	ureter and renal pelvis) have found cohesin mutations in 2/5 papillary non-invasive (40%) and 7/21 invasive urothelial carcinomas (33%) of the upper urothelial tract.	('invasive urothelial carcinomas', 'Disease', 'MESH:D009361', (99, 129))	('ureter and renal pelvis', 'Disease', 'MESH:D014516', (0, 23))	('renal pelvis', 'Phenotype', 'HP:0000125', (11, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('invasive urothelial carcinomas', 'Disease', (99, 129))	('cohesin', 'Gene', (36, 43))	('mutations', 'Var', (44, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('papillary non-invasive', 'Disease', (61, 83))
316189	24856830	As the genomes of additional tumor types are revealed by next generation sequencing, the cohesin complex is emerging as a target of frequent of somatic alterations in a diverse range of tumors.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('alterations', 'Var', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (186, 192))
316190	24856830	Comprehensive genomic characterization of 291 glioblastomas by The Cancer Genome Atlas identified cohesin gene mutations in 23 tumors (8%), including 12 tumors with mutations in STAG2 (one of the most commonly mutated genes identified), as well as 15 additional tumors (5%) with mutations in cohesin regulatory genes.	('15 additional tumors', 'Disease', 'MESH:C567447', (248, 268))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('glioblastomas', 'Disease', (46, 59))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('Cancer', 'Disease', (67, 73))	('glioblastomas', 'Disease', 'MESH:D005909', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutations', 'Var', (111, 120))	('tumors', 'Disease', (127, 133))	('tumors', 'Disease', (262, 268))	('mutations', 'Var', (165, 174))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('cohesin gene', 'Gene', (98, 110))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('glioblastomas', 'Phenotype', 'HP:0012174', (46, 59))	('STAG2', 'Gene', '10735', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('STAG2', 'Gene', (178, 183))	('15 additional tumors', 'Disease', (248, 268))
316191	24856830	In addition to glioblastomas, whole-exome sequencing of medulloblastoma, a primitive neuroectodermal tumor arising in the cerebellum and posterior fossa of the brain of pediatric and young adults, found cohesin mutations in 3/125 cases.	('cohesin', 'Gene', (203, 210))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (85, 106))	('medulloblastoma', 'Disease', (56, 71))	('glioblastomas', 'Disease', (15, 28))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (85, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (15, 27))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (75, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('found', 'Reg', (197, 202))	('mutations', 'Var', (211, 220))	('neuroectodermal tumor', 'Disease', (85, 106))	('medulloblastoma', 'Disease', 'MESH:D008527', (56, 71))	('medulloblastoma', 'Phenotype', 'HP:0002885', (56, 71))	('glioblastomas', 'Phenotype', 'HP:0012174', (15, 28))	('glioblastomas', 'Disease', 'MESH:D005909', (15, 28))
316192	24856830	Whole-exome sequencing of 100 invasive breast adenocarcinomas identified 3 tumors with cohesin gene mutations and 7 tumors with mutations in cohesin regulatory genes.	('tumors', 'Disease', (116, 122))	('mutations', 'Var', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('breast adenocarcinomas', 'Disease', 'MESH:D000230', (39, 61))	('cohesin gene', 'Gene', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('breast adenocarcinomas', 'Disease', (39, 61))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
316193	24856830	Whether cohesin mutations in breast carcinomas are associated with a specific histologic subtype (e.g.	('breast carcinomas', 'Phenotype', 'HP:0003002', (29, 46))	('mutations', 'Var', (16, 25))	('cohesin', 'Gene', (8, 15))	('associated', 'Reg', (51, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('breast carcinomas', 'Disease', 'MESH:D001943', (29, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('breast carcinomas', 'Disease', (29, 46))
316194	24856830	A recent investigation into the genomes of 50 pancreatic ductal adenocarcinomas found two tumors with STAG2 alterations, one with gene deletion and one with missense mutation.	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('alterations', 'Var', (108, 119))	('STAG2', 'Gene', '10735', (102, 107))	('pancreatic ductal adenocarcinomas', 'Disease', (46, 79))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (46, 79))	('STAG2', 'Gene', (102, 107))	('gene deletion', 'Var', (130, 143))	('missense mutation', 'Var', (157, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
316196	24856830	An investigation of microsatellite-unstable gastric and colorectal adenocarcinomas found frequent frameshift mutations in the cohesin regulatory genes PDS5B and SGOL1 which harbor long mononucleotide repeats within their coding sequences.	('SGOL1', 'Gene', (161, 166))	('colorectal adenocarcinomas', 'Disease', (56, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('PDS5B', 'Gene', (151, 156))	('PDS5B', 'Gene', '23047', (151, 156))	('mononucleotide', 'Chemical', '-', (185, 199))	('SGOL1', 'Gene', '151648', (161, 166))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (56, 82))	('frameshift mutations', 'Var', (98, 118))
316197	24856830	In addition to the frequent truncating mutations of STAG2 in Ewing sarcoma cell lines reported by Solomon et al., ongoing as yet unpublished sequencing studies have also identified frequent cohesin mutations (predominantly of the STAG2 subunit) in Ewing sarcoma primary tumors samples as well.	('STAG2', 'Gene', '10735', (230, 235))	('Ewing sarcoma', 'Disease', (61, 74))	('STAG2', 'Gene', (52, 57))	('STAG2', 'Gene', '10735', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('cohesin', 'Protein', (190, 197))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('mutations', 'Var', (198, 207))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('STAG2', 'Gene', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (248, 261))	('Ewing sarcoma primary tumors', 'Disease', (248, 276))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (248, 261))	('Ewing sarcoma primary tumors', 'Disease', 'MESH:C563168', (248, 276))
316198	24856830	The clinical significance of cohesin mutations and the precise mechanism of tumor suppressive function in the pathogenesis of many of these specific tumor types currently remain undefined.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cohesin', 'Protein', (29, 36))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
316199	24856830	Given the high frequency of inactivation in particular cancer types, mechanisms of selectively targeting cancer cells harboring cohesin mutations is of significant clinical interest.	('cohesin', 'Gene', (128, 135))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inactivation', 'Var', (28, 40))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
316200	24856830	The RAD21 gene was originally isolated in the fission yeast S. pombe as a mutant that caused radiation sensitivity and was also found to be essential for mitosis.	('mitosis', 'Disease', 'None', (154, 161))	('caused', 'Reg', (86, 92))	('radiation sensitivity', 'Disease', (93, 114))	('mitosis', 'Disease', (154, 161))	('RAD21', 'Gene', (4, 9))	('fission yeast', 'Species', '4896', (46, 59))	('S. pombe', 'Species', '4896', (60, 68))	('RAD21', 'Gene', '5885', (4, 9))	('mutant', 'Var', (74, 80))
316201	24856830	Of note, SMC1A mutant cells from a CdL patient have shown increased sensitivity to ionizing radiation and interstrand DNA crosslinking agents compared to normal controls, although this sensitivity was to a lesser extent than cells from patients with ataxia telangiectasia or Fanconi anemia syndromes.	('telangiectasia', 'Phenotype', 'HP:0001009', (257, 271))	('ataxia telangiectasia', 'Disease', (250, 271))	('increased', 'PosReg', (58, 67))	('patient', 'Species', '9606', (39, 46))	('SMC1A', 'Gene', '8243', (9, 14))	('patients', 'Species', '9606', (236, 244))	('Fanconi anemia syndromes', 'Disease', (275, 299))	('ataxia', 'Phenotype', 'HP:0001251', (250, 256))	('Fanconi anemia syndromes', 'Disease', 'MESH:D005199', (275, 299))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (275, 289))	('SMC1A', 'Gene', (9, 14))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (250, 271))	('anemia', 'Phenotype', 'HP:0001903', (283, 289))	('mutant', 'Var', (15, 21))	('patient', 'Species', '9606', (236, 243))	('sensitivity', 'MPA', (68, 79))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (58, 101))
316202	24856830	These findings suggest that tumors harboring cohesin mutations might have increased sensitivity to ionizing radiation and/or specific DNA damaging chemotherapeutic agents.	('cohesin', 'Gene', (45, 52))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (74, 117))	('mutations', 'Var', (53, 62))	('sensitivity to', 'MPA', (84, 98))	('increased', 'PosReg', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
316203	24856830	One study has shown that knockdown of STAG2 in a pancreatic adenocarcinoma cell line led to increased sensitivity to platinum-based chemotherapy agents including cisplatin.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('platinum', 'Chemical', 'MESH:D010984', (117, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (49, 74))	('pancreatic adenocarcinoma', 'Disease', (49, 74))	('sensitivity to platinum-based chemotherapy agents', 'MPA', (102, 151))	('increased', 'PosReg', (92, 101))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (49, 74))	('STAG2', 'Gene', '10735', (38, 43))	('cisplatin', 'MPA', (162, 171))	('knockdown', 'Var', (25, 34))	('STAG2', 'Gene', (38, 43))
316204	24856830	Considering the potential for rational targeted therapies, inhibitors of poly(ADP-ribose) polymerase (PARP) such as olaparib have shown promise in ovarian cancers deficient in DNA repair due to mutations in BRCA1 and BRCA2.	('PARP', 'Gene', (102, 106))	('BRCA2', 'Gene', '675', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ovarian cancers', 'Phenotype', 'HP:0100615', (147, 162))	('mutations', 'Var', (194, 203))	('poly(ADP-ribose) polymerase', 'Gene', '142', (73, 100))	('PARP', 'Gene', '142', (102, 106))	('BRCA1', 'Gene', '672', (207, 212))	('ovarian cancers deficient', 'Disease', 'MESH:D010051', (147, 172))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('BRCA2', 'Gene', (217, 222))	('poly(ADP-ribose) polymerase', 'Gene', (73, 100))	('ovarian cancers deficient', 'Disease', (147, 172))	('olaparib', 'Chemical', 'MESH:C531550', (116, 124))	('BRCA1', 'Gene', (207, 212))
316205	24856830	Similarly, glioblastoma cell lines harboring truncating STAG2 mutations were recently shown to have increased sensitivity to multiple unique small molecule inhibitors of PARP, leading to arrest in G2 phase of the cell cycle, more frequent micronuclei, and increased atypical mitotic figures.	('STAG2', 'Gene', (56, 61))	('atypical mitotic figures', 'CPA', (266, 290))	('STAG2', 'Gene', '10735', (56, 61))	('increased', 'PosReg', (100, 109))	('mutations', 'Var', (62, 71))	('micronuclei', 'CPA', (239, 250))	('PARP', 'Gene', '142', (170, 174))	('glioblastoma', 'Disease', (11, 23))	('truncating', 'Var', (45, 55))	('G2 phase of the cell cycle', 'CPA', (197, 223))	('glioblastoma', 'Disease', 'MESH:D005909', (11, 23))	('increased', 'PosReg', (256, 265))	('PARP', 'Gene', (170, 174))	('more', 'PosReg', (225, 229))	('glioblastoma', 'Phenotype', 'HP:0012174', (11, 23))
316207	24856830	Together, these studies demonstrate that tumors harboring cohesin mutations might have specific sensitivities that can be rationally targeted to provide clinical benefit for the many patients with such cohesin altered cancers.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('altered cancers', 'Disease', 'MESH:D009369', (210, 225))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('altered cancers', 'Disease', (210, 225))	('cohesin', 'Gene', (58, 65))	('patients', 'Species', '9606', (183, 191))
316210	24856830	Emerging cancer genomics studies have now documented that cohesin genes are a frequent target of somatic alterations in a number of tumor types including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia.	('urothelial carcinoma', 'Disease', (183, 203))	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (132, 137))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (168, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (168, 181))	('acute myeloid leukemia', 'Disease', (205, 227))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('alterations', 'Var', (105, 116))	('acute megakaryoblastic leukemia', 'Disease', 'MESH:D007947', (233, 264))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (183, 203))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (211, 227))	('acute megakaryoblastic leukemia', 'Phenotype', 'HP:0006733', (233, 264))	('acute megakaryoblastic leukemia', 'Disease', (233, 264))	('leukemia', 'Phenotype', 'HP:0001909', (219, 227))	('glioblastoma', 'Disease', (154, 166))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Ewing sarcoma', 'Disease', (168, 181))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (205, 227))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (205, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('cohesin genes', 'Gene', (58, 71))	('leukemia', 'Phenotype', 'HP:0001909', (256, 264))
316211	24856830	Initial studies demonstrated that cohesin mutations may be a source of chromosomal instability and aneuploidy in tumors, while subsequent studies in other cancer types have found normal karyotypes in tumors harboring cohesin mutations, leading to speculation that cohesin inactivation may be causing dysregulation of other pathways during tumorigenesis, particularly altered gene expression profiles.	('tumor', 'Disease', (339, 344))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('chromosomal instability', 'Phenotype', 'HP:0040012', (71, 94))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('aneuploidy in tumors', 'Disease', 'MESH:D000782', (99, 119))	('tumor', 'Disease', (200, 205))	('aneuploidy in tumors', 'Disease', (99, 119))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('cohesin', 'Protein', (264, 271))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('inactivation', 'Var', (272, 284))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('gene expression profiles', 'MPA', (375, 399))	('dysregulation', 'MPA', (300, 313))	('cancer', 'Disease', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('cohesin', 'Gene', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutations', 'Var', (42, 51))	('altered', 'Reg', (367, 374))
316212	24856830	Recent studies have begun to demonstrate that cohesin mutant tumors might have increased sensitivity to select DNA damaging agents and PARP inhibitors.	('increased', 'PosReg', (79, 88))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('cohesin', 'Protein', (46, 53))	('PARP', 'Gene', '142', (135, 139))	('mutant', 'Var', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('PARP', 'Gene', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('sensitivity to', 'MPA', (89, 103))
316213	24856830	Continued investigation will be necessary to define the precise mechanism(s) by which cohesin inactivation contributes to tumorigenesis and methods to effectively target cancers harboring cohesin mutations.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('inactivation', 'NegReg', (94, 106))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cohesin', 'Gene', (188, 195))	('cohesin', 'Protein', (86, 93))	('tumor', 'Disease', (122, 127))	('mutations', 'Var', (196, 205))
316218	22188815	SCH717454 blocked IGF-1 but not IGF-2 stimulated phosphorylation of Akt in sarcoma cells.	('Akt', 'Gene', '207', (68, 71))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('sarcoma', 'Disease', (75, 82))	('SCH717454', 'Chemical', 'MESH:C573312', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('phosphorylation', 'MPA', (49, 64))	('Akt', 'Gene', (68, 71))	('SCH717454', 'Var', (0, 9))	('blocked', 'NegReg', (10, 17))
316221	22188815	In mice SCH717454 inhibited angiogenesis in VEGF-infused Matrigel plugs, but had no inhibitory activity when plugs contained both VEGF+IGF-2.	('SCH717454', 'Chemical', 'MESH:C573312', (8, 17))	('mice', 'Species', '10090', (3, 7))	('SCH717454', 'Var', (8, 17))	('inhibited', 'NegReg', (18, 27))	('angiogenesis', 'CPA', (28, 40))
316222	22188815	These results reveal for the first time, a role for IGF-1R signaling in VEGF-mediated angiogenesis in vitro and indicate direct anti-angiogenic activity of SCH717454.	('SCH717454', 'Chemical', 'MESH:C573312', (156, 165))	('SCH717454', 'Var', (156, 165))	('anti-angiogenic activity', 'MPA', (128, 152))	('IGF-1R', 'MPA', (52, 58))	('VEGF-mediated', 'Gene', (72, 85))	('angiogenesis', 'CPA', (86, 98))
316229	22188815	For example, the alveolar subtype of rhabdomyosarcoma is associated with t(2;13)(q35;q14) and t(1;13)(q36;q14) which generate PAX3-FKHR or PAX7-FKHR chimeric transcription factors that enhance transcription of target genes including IGF-1R.	('FKHR', 'Gene', '2308', (144, 148))	('PAX3', 'Gene', (126, 130))	('alveolar subtype of rhabdomyosarcoma', 'Disease', 'MESH:D018232', (17, 53))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (37, 53))	('FKHR', 'Gene', (131, 135))	('PAX7', 'Gene', '5081', (139, 143))	('PAX3', 'Gene', '5077', (126, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('t(1;13)(q36;q14', 'Var', (94, 109))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (73, 89))	('PAX7', 'Gene', (139, 143))	('alveolar subtype of rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (17, 53))	('alveolar subtype of rhabdomyosarcoma', 'Disease', (17, 53))	('FKHR', 'Gene', (144, 148))	('FKHR', 'Gene', '2308', (131, 135))	('transcription', 'MPA', (193, 206))	('enhance', 'PosReg', (185, 192))	('t(1;13)(q36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (94, 110))	('IGF-1R', 'Gene', (233, 239))
316230	22188815	For the embryonal subtype of rhabdomyosarcoma, the IGF-2 gene, which normally shows monoallelic expression as a result of silencing of the maternal allele through imprinting, shows biallelic transcription.	('rhabdomyosarcoma', 'Disease', (29, 45))	('IGF-2', 'Gene', (51, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (29, 45))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (29, 45))	('silencing', 'Var', (122, 131))
316234	22188815	EWS-FLI1 silencing leads to increased levels of insulin-like growth factor binding protein-3 gene (IGFBP-3), a major regulator of IGF-1.	('increased', 'PosReg', (28, 37))	('FLI1', 'Gene', '2313', (4, 8))	('FLI1', 'Gene', (4, 8))	('silencing', 'Var', (9, 18))	('levels of', 'MPA', (38, 47))	('IGFBP-3', 'Gene', '3486', (99, 106))	('insulin-like growth factor binding protein-3', 'Gene', '3486', (48, 92))	('insulin-like growth factor binding protein-3', 'Gene', (48, 92))	('increased levels of insulin-like growth factor', 'Phenotype', 'HP:0030269', (28, 74))	('IGFBP-3', 'Gene', (99, 106))	('increased levels of insulin', 'Phenotype', 'HP:0000842', (28, 55))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
316236	22188815	As dysregulated IGF-I signaling is common to several adult malignancies, targeting IGF-IR has become a major focus for therapeutics development.	('dysregulated', 'Var', (3, 15))	('IGF-I', 'Gene', (16, 21))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))	('IGF-I', 'Gene', '3479', (83, 88))	('IGF-IR', 'Gene', (83, 89))	('malignancies', 'Disease', (59, 71))	('IGF-IR', 'Gene', '3480', (83, 89))	('IGF-I', 'Gene', (83, 88))	('IGF-I', 'Gene', '3479', (16, 21))
316241	22188815	Previously it was shown by the Pediatric Preclinical Testing Program (PPTP) that SCH717454, a human antibody that binds IGF-1R to block ligand binding, induced regressions in several sarcoma histotypes, notably osteosarcoma and Ewing sarcoma, tumors that secrete predominantly IGF-1.	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('SCH717454', 'Chemical', 'MESH:C573312', (81, 90))	('osteosarcoma', 'Disease', (211, 223))	('ligand binding', 'Interaction', (136, 150))	('osteosarcoma', 'Disease', 'MESH:D012516', (211, 223))	('SCH717454', 'Var', (81, 90))	('sarcoma', 'Disease', 'MESH:D012509', (234, 241))	('sarcoma', 'Disease', (234, 241))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (228, 241))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (228, 241))	('regressions', 'NegReg', (160, 171))	('human', 'Species', '9606', (94, 99))	('sarcoma', 'Disease', 'MESH:D012509', (216, 223))	('osteosarcoma', 'Phenotype', 'HP:0002669', (211, 223))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('sarcoma', 'Disease', (216, 223))	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('tumors', 'Disease', (243, 249))	('sarcoma', 'Disease', (183, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('Ewing sarcoma', 'Disease', (228, 241))
316243	22188815	Further, SCH717454 was shown to reduce tumor microvessel density indicating anti-angiogenic activity.	('reduce', 'NegReg', (32, 38))	('SCH717454', 'Chemical', 'MESH:C573312', (9, 18))	('SCH717454', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('anti-angiogenic activity', 'CPA', (76, 100))
316246	22188815	Despite the promise of efficacy in tumor models, antibodies that target IGF-1R and block ligand binding have rather limited antitumor activity against pediatric solid tumor xenografts, causing significant retardation of tumor growth, but relatively few objective regressions as single agents.	('retardation of tumor', 'Disease', (205, 225))	('IGF-1R', 'Gene', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('retardation of tumor', 'Disease', 'MESH:D009369', (205, 225))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('antibodies', 'Var', (49, 59))	('ligand binding', 'Interaction', (89, 103))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (167, 172))	('limited', 'NegReg', (116, 123))
316250	22188815	Here we have examined the activity of SCH717454 in blocking IGF-1 and IGF-2 stimulated signaling in sarcoma cells and vascular endothelial cells in vitro, and its effects on angiogenesis in vivo.	('sarcoma', 'Disease', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('blocking', 'NegReg', (51, 59))	('IGF-2', 'Gene', (70, 75))	('angiogenesis', 'CPA', (174, 186))	('IGF-1', 'Gene', (60, 65))	('signaling', 'MPA', (87, 96))	('SCH717454', 'Chemical', 'MESH:C573312', (38, 47))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))	('SCH717454', 'Var', (38, 47))
316282	22188815	To understand whether SCH717454 equally inhibited phosphorylation of Akt induced by IGF-1 and IGF-2, sarcoma cells were serum starved overnight, then incubated with or without antibody (10 mug/ml) for 5 - 60 min, and stimulated with IGF-1 or IGF-2 for 5 min.	('Akt', 'Gene', (69, 72))	('phosphorylation', 'MPA', (50, 65))	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('inhibited', 'NegReg', (40, 49))	('sarcoma', 'Disease', (101, 108))	('IGF-2', 'Var', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('SCH717454', 'Chemical', 'MESH:C573312', (22, 31))	('SCH717454', 'Var', (22, 31))	('Akt', 'Gene', '207', (69, 72))
316283	22188815	As shown in Figure 1A, IGF-1 stimulated phosphorylation of Akt (Ser473) in control (no antibody), but stimulation was rapidly suppressed by SCH717454 in each tumor cell line, with almost complete abrogation of phospho-Akt in EW-8 cells.	('tumor', 'Disease', (158, 163))	('Akt', 'Gene', (59, 62))	('suppressed', 'NegReg', (126, 136))	('stimulated', 'PosReg', (29, 39))	('IGF-1', 'Gene', (23, 28))	('Akt', 'Gene', '207', (218, 221))	('SCH717454', 'Chemical', 'MESH:C573312', (140, 149))	('Akt', 'Gene', '207', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Ser473', 'Chemical', '-', (64, 70))	('Akt', 'Gene', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('SCH717454', 'Var', (140, 149))	('phosphorylation', 'MPA', (40, 55))
316284	22188815	In contrast under the same conditions SCH717454 did not suppress IGF-2-induced phosphorylation of Akt in EW-8 cells, whereas it did slightly reduce IGF-2-induced Akt phosphorylation in Rh18, Rh30 and JR1 cells.	('Akt', 'Gene', (162, 165))	('Akt', 'Gene', '207', (98, 101))	('Rh30', 'Gene', (191, 195))	('phosphorylation', 'MPA', (79, 94))	('Akt', 'Gene', '207', (162, 165))	('SCH717454', 'Chemical', 'MESH:C573312', (38, 47))	('Akt', 'Gene', (98, 101))	('reduce', 'NegReg', (141, 147))	('JR1', 'CellLine', 'CVCL:L880', (200, 203))	('SCH717454', 'Var', (38, 47))	('Rh30', 'Gene', '6007', (191, 195))
316289	22188815	The differential effect of SCH717454 inhibiting ligand stimulated IGF-1R signaling could be due to the antibody blocking IGF-1 binding to the receptor more effectively than IGF-2, or a consequence of IGF-2 signaling through the IN-R, thus circumventing antibody blockade of IGF-1R.	('IGF-1', 'Gene', (121, 126))	('SCH717454', 'Var', (27, 36))	('ligand stimulated IGF-1R signaling', 'MPA', (48, 82))	('binding to', 'Interaction', (127, 137))	('SCH717454', 'Chemical', 'MESH:C573312', (27, 36))	('IN-R', 'Gene', '3643', (228, 232))	('blocking', 'NegReg', (112, 120))	('IN-R', 'Gene', (228, 232))	('inhibiting', 'NegReg', (37, 47))
316290	22188815	To determine between these alternatives, we examined whether SCH717454 equally inhibited IGF-1 and IGF-2 stimulation of IGF-1R phosphorylation and whether maintained signaling in the presence of SCH717454 was through activation of IN-R. EW-8 cells were serum-starved for 24 hr, then incubated a further 24 hr with or without SCH717454 (10 mug/ml), then stimulated for 5 min with either IGF-1 or IGF-2, or not stimulated.	('SCH717454', 'Chemical', 'MESH:C573312', (325, 334))	('IN-R', 'Gene', '3643', (231, 235))	('SCH717454', 'Chemical', 'MESH:C573312', (195, 204))	('SCH717454', 'Chemical', 'MESH:C573312', (61, 70))	('SCH717454', 'Var', (61, 70))	('inhibited', 'NegReg', (79, 88))	('SCH717454', 'Var', (325, 334))	('IN-R', 'Gene', (231, 235))
316291	22188815	Because the antibody recognizing Y1131 of IGF-1R also cross-reacts with Y1146 of the IN-R, cell lysates were prepared and immunoprecipitated using antibody specific for IGF-1R, IN-R or using a non-specific IgG1.	('IN-R', 'Gene', (85, 89))	('Y1131', 'Var', (33, 38))	('Y1146', 'Var', (72, 77))	('IN-R', 'Gene', '3643', (177, 181))	('IN-R', 'Gene', '3643', (85, 89))	('IGF-1R', 'Gene', (42, 48))	('IN-R', 'Gene', (177, 181))
316292	22188815	SCH717545 equally inhibited IGF-1 and IGF-2 stimulated phosphorylation of IGF-1R in EW-8 cells (Figure 1B), and in the other sarcoma cell lines (Supplemental Figure 2), confirming that this antibody prevents binding of both IGF-1 and IGF-2 to the IGF-1 receptor.	('SCH717545', 'Var', (0, 9))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('sarcoma', 'Disease', (125, 132))	('SCH717545', 'Chemical', '-', (0, 9))	('IGF-1R', 'Gene', (74, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('prevents', 'NegReg', (199, 207))	('inhibited', 'NegReg', (18, 27))	('phosphorylation', 'MPA', (55, 70))	('binding', 'Interaction', (208, 215))
316294	22188815	However, IGF-2 potently stimulated IN-R phosphorylation in SCH717454 treated EW-8 cells, and increased phosphorylation slightly in Rh18 and Rh30 cells (Supplemental Figure 2).	('Rh30', 'Gene', (140, 144))	('IN-R', 'Gene', '3643', (35, 39))	('IGF-2', 'Gene', (9, 14))	('Rh30', 'Gene', '6007', (140, 144))	('stimulated', 'PosReg', (24, 34))	('phosphorylation', 'MPA', (103, 118))	('SCH717454', 'Chemical', 'MESH:C573312', (59, 68))	('IN-R', 'Gene', (35, 39))	('SCH717454', 'Var', (59, 68))
316295	22188815	Thus, SCH717454 effectively inhibited IGF-1- and IGF-2-induced phosphorylation of IGF-1R in each cell line.	('inhibited', 'NegReg', (28, 37))	('phosphorylation', 'MPA', (63, 78))	('SCH717454', 'Chemical', 'MESH:C573312', (6, 15))	('IGF-1R', 'Gene', (82, 88))	('SCH717454', 'Var', (6, 15))
316296	22188815	In contrast, IGF-2 still induced phosphorylation of IN-R in the presence of SCH717454, particularly in EW-8 cells, suggesting that signaling through IN-R circumvents inhibition of IGF-1R.	('phosphorylation', 'MPA', (33, 48))	('IN-R', 'Gene', '3643', (52, 56))	('SCH717454', 'Var', (76, 85))	('IN-R', 'Gene', '3643', (149, 153))	('IN-R', 'Gene', (52, 56))	('IN-R', 'Gene', (149, 153))	('SCH717454', 'Chemical', 'MESH:C573312', (76, 85))
316298	22188815	RT-PCR for IN-R isoforms showed that all sarcoma cell lines and human umbilical vein endothelial cells (HUVECs) expressed predominantly the A-variant, although the full length IN-R transcript was also detected in the EW-8 cell line (Supplemental Figure 3A).	('sarcoma', 'Disease', (41, 48))	('human', 'Species', '9606', (64, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('IN-R', 'Gene', '3643', (11, 15))	('IN-R', 'Gene', '3643', (176, 180))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('IN-R', 'Gene', (11, 15))	('IN-R', 'Gene', (176, 180))	('A-variant', 'Var', (140, 149))
316300	22188815	To test if receptor-binding antibodies had direct effects we examined whether SCH717454 inhibited proliferation of VEGF stimulated HUVECs.	('SCH717454', 'Chemical', 'MESH:C573312', (78, 87))	('inhibited', 'NegReg', (88, 97))	('proliferation', 'CPA', (98, 111))	('SCH717454', 'Var', (78, 87))
316301	22188815	Cells were stimulated with PBS (control) or VEGF in the absence or presence of SCH717454 and cell number determined by Alamar Blue staining after 2 days.	('PBS', 'Disease', (27, 30))	('SCH717454', 'Chemical', 'MESH:C573312', (79, 88))	('PBS', 'Disease', 'MESH:D011535', (27, 30))	('SCH717454', 'Var', (79, 88))	('Alamar Blue', 'Chemical', 'MESH:C005843', (119, 130))
316302	22188815	As shown in Figure 2A, VEGF stimulated proliferation compared to PBS, and SCH717454 inhibited VEGF-stimulated proliferation in a concentration-dependent manner with >80% inhibition at 10 mug/ml.	('SCH717454', 'Chemical', 'MESH:C573312', (74, 83))	('SCH717454', 'Var', (74, 83))	('proliferation', 'CPA', (110, 123))	('proliferation', 'CPA', (39, 52))	('inhibited', 'NegReg', (84, 93))	('PBS', 'Disease', 'MESH:D011535', (65, 68))	('PBS', 'Disease', (65, 68))
316303	22188815	Further assays demonstrated similar effects of SCH717454 on migration and invasion through Matrigel coated membranes (Figure 2A).	('invasion through Matrigel coated membranes', 'CPA', (74, 116))	('SCH717454', 'Var', (47, 56))	('migration', 'CPA', (60, 69))	('SCH717454', 'Chemical', 'MESH:C573312', (47, 56))
316304	22188815	SCH717454 also dramatically inhibited VEGF-stimulated tube formation of HUVECs in vitro.	('tube formation of HUVECs', 'CPA', (54, 78))	('SCH717454', 'Var', (0, 9))	('inhibited', 'NegReg', (28, 37))	('SCH717454', 'Chemical', 'MESH:C573312', (0, 9))
316306	22188815	SCH717454 at 5 or 10 mug/ml dramatically inhibited formation of capillary-like structures (Figure 2B), whereas control isotype-matched IgG1 had no effect (Supplemental Figure 4).	('SCH717454', 'Chemical', 'MESH:C573312', (0, 9))	('SCH717454', 'Var', (0, 9))	('inhibited', 'NegReg', (41, 50))	('formation of', 'CPA', (51, 63))
316307	22188815	As IGF-2 can stimulate Akt phosphorylation in the presence of SCH717454 (Figure 1A), we tested whether exogenous ligands could circumvent the effect of SCH717454 in blocking VEGF-induced proliferation of HUVECs.	('SCH717454', 'Chemical', 'MESH:C573312', (152, 161))	('SCH717454', 'Var', (62, 71))	('IGF-2', 'Gene', (3, 8))	('Akt', 'Gene', '207', (23, 26))	('Akt', 'Gene', (23, 26))	('stimulate', 'PosReg', (13, 22))	('SCH717454', 'Chemical', 'MESH:C573312', (62, 71))
316309	22188815	As shown in Figure 3, VEGF stimulated tube formation, and this was completely inhibited by SCH717454.	('stimulated', 'PosReg', (27, 37))	('tube formation', 'CPA', (38, 52))	('SCH717454', 'Chemical', 'MESH:C573312', (91, 100))	('SCH717454', 'Var', (91, 100))
316310	22188815	Exogenous IGF-1 did not significantly overcome the effect of SCH717454, whereas IGF-2, and to a lesser extent exogenous insulin, circumvented the block.	('insulin', 'Gene', (120, 127))	('IGF-2', 'Var', (80, 85))	('SCH717454', 'Chemical', 'MESH:C573312', (61, 70))	('SCH717454', 'Var', (61, 70))	('insulin', 'Gene', '3630', (120, 127))
316313	22188815	From the results presented, one would anticipate that cells secreting IGF-2 could maintain angiogenesis in the presence of SCH717454, whereas those secreting predominantly IGF-1 would not.	('angiogenesis', 'CPA', (91, 103))	('IGF-2', 'Gene', (70, 75))	('maintain', 'PosReg', (82, 90))	('SCH717454', 'Chemical', 'MESH:C573312', (123, 132))	('SCH717454', 'Var', (123, 132))
316321	22188815	These data support the contention that cells secreting IGF-2 into the tumor microenvironment may maintain angiogenesis in the presence of SCH717454 in vivo.	('SCH717454', 'Var', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('IGF-2', 'Gene', (55, 60))	('angiogenesis', 'CPA', (106, 118))	('SCH717454', 'Chemical', 'MESH:C573312', (138, 147))	('maintain', 'PosReg', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
316322	22188815	To directly test the anti-angiogenic activity of SCH717454 in vivo, mice were implanted subcutaneously with Matrigel plugs infused with PBS or VEGF.	('mice', 'Species', '10090', (68, 72))	('SCH717454', 'Chemical', 'MESH:C573312', (49, 58))	('SCH717454', 'Var', (49, 58))	('PBS', 'Disease', 'MESH:D011535', (136, 139))	('PBS', 'Disease', (136, 139))
316325	22188815	SCH717454 reduced vessel formation by ~75% (Figure 5A).	('SCH717454', 'Chemical', 'MESH:C573312', (0, 9))	('SCH717454', 'Var', (0, 9))	('reduced', 'NegReg', (10, 17))	('vessel formation', 'CPA', (18, 34))
316329	22188815	As shown in Figure 5B, inclusion of IGF-2 into the Matrigel plug completely abrogated the anti-angiogenic activity of SCH717454 in this model.	('abrogated', 'NegReg', (76, 85))	('SCH717454', 'Chemical', 'MESH:C573312', (118, 127))	('inclusion', 'Var', (23, 32))	('anti-angiogenic activity', 'CPA', (90, 114))	('IGF-2', 'Gene', (36, 41))
316333	22188815	SCH717454 was effective in blocking IGF-1 stimulated Akt phosphorylation, whereas in many sarcoma cell lines it was less effective against IGF-2 stimulation.	('sarcoma', 'Disease', (90, 97))	('Akt', 'Gene', '207', (53, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('SCH717454', 'Chemical', 'MESH:C573312', (0, 9))	('IGF-1', 'Gene', (36, 41))	('Akt', 'Gene', (53, 56))	('SCH717454', 'Var', (0, 9))	('blocking', 'NegReg', (27, 35))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
316334	22188815	IGF-2 can signal both through IGF-1R, the insulin receptor A variant and through heterodimers of these receptors.	('insulin receptor', 'Gene', (42, 58))	('variant', 'Var', (61, 68))	('insulin receptor', 'Gene', '3643', (42, 58))	('IGF-1R', 'Protein', (30, 36))	('IGF-2', 'Gene', (0, 5))	('heterodimers', 'Interaction', (81, 93))	('signal', 'Reg', (10, 16))
316337	22188815	SCH717454 equally suppressed IGF-1R phosphorylation stimulated by IGF-1 and IGF-2, demonstrating that this antibody blocks binding of both ligands.	('binding', 'Interaction', (123, 130))	('blocks', 'NegReg', (116, 122))	('IGF-1R', 'Protein', (29, 35))	('SCH717454', 'Var', (0, 9))	('SCH717454', 'Chemical', 'MESH:C573312', (0, 9))	('suppressed', 'NegReg', (18, 28))	('phosphorylation', 'MPA', (36, 51))
316340	22188815	We were interested whether SCH717454 exerted a direct effect on angiogenesis using HUVECs in vitro.	('angiogenesis', 'CPA', (64, 76))	('SCH717454', 'Chemical', 'MESH:C573312', (27, 36))	('SCH717454', 'Var', (27, 36))
316341	22188815	In this model system SCH717454 almost completely suppressed proliferation, tube formation and invasive properties of these endothelial cells induced by VEGF.	('SCH717454', 'Chemical', 'MESH:C573312', (21, 30))	('suppressed', 'NegReg', (49, 59))	('proliferation', 'CPA', (60, 73))	('tube formation', 'CPA', (75, 89))	('SCH717454', 'Var', (21, 30))	('invasive properties of these endothelial cells', 'CPA', (94, 140))
316342	22188815	Further, SCH717454 partially suppressed VEGF-stimulated migration.	('suppressed', 'NegReg', (29, 39))	('SCH717454', 'Chemical', 'MESH:C573312', (9, 18))	('VEGF-stimulated migration', 'CPA', (40, 65))	('SCH717454', 'Var', (9, 18))
316344	22188815	Our data predict that tumor cells that secrete adequate IGF-2 may overcome the anti-angiogenic effects of IGF-1R-targeted antibodies, and that absence of circulating IGF-2 in the mouse may lead to over-prediction of the antitumor activity of these antibodies.	('mouse', 'Species', '10090', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('IGF-2', 'Gene', (166, 171))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('absence', 'Var', (143, 150))	('anti-angiogenic effects', 'MPA', (79, 102))	('lead to', 'Reg', (189, 196))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('over-prediction', 'PosReg', (197, 212))
316347	22188815	In these co-culture assays, SCH717454 completely blocked VEGF-stimulated HUVEC proliferation and tube formation.	('VEGF-stimulated', 'Gene', (57, 72))	('HUVEC proliferation', 'CPA', (73, 92))	('tube formation', 'CPA', (97, 111))	('SCH717454', 'Chemical', 'MESH:C573312', (28, 37))	('SCH717454', 'Var', (28, 37))	('blocked', 'NegReg', (49, 56))
316349	22188815	These results clearly support the idea that cells expressing even moderate levels of IGF-2 can maintain angiogenesis in the presence of SCH717454, whereas low levels of IGF-2 expressed by ES-1 and EW-8 cells appear to be inadequate to overcome IGF-1R inhibition.	('angiogenesis', 'CPA', (104, 116))	('low levels of IGF', 'Phenotype', 'HP:0002850', (155, 172))	('SCH717454', 'Var', (136, 145))	('SCH717454', 'Chemical', 'MESH:C573312', (136, 145))
316350	22188815	Thus, one potential biomarker for effective angiogenesis inhibition by IGF-1R-targeted antibodies may be the relative IGF-1/IGF-2 expression in tumors.	('tumors', 'Disease', (144, 150))	('IGF-1R-targeted', 'Gene', (71, 86))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('angiogenesis', 'CPA', (44, 56))	('inhibition', 'NegReg', (57, 67))	('IGF-1/IGF-2', 'Gene', (118, 129))	('antibodies', 'Var', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
316351	22188815	A second prediction, that SCH717454 would have direct anti-angiogenic effects in vivo that could be overcome in the presence of IGF-2, was tested directly using a VEGF-stimulated Matrigel angiogenesis assay in mice.	('anti-angiogenic effects', 'CPA', (54, 77))	('SCH717454', 'Chemical', 'MESH:C573312', (26, 35))	('SCH717454', 'Var', (26, 35))	('mice', 'Species', '10090', (210, 214))
316352	22188815	VEGF stimulated angiogenesis in this in vivo model was largely abrogated by treatment with SCH717454 confirming the anti-angiogenic activity of systemically administered antibody.	('abrogated', 'NegReg', (63, 72))	('angiogenesis', 'CPA', (16, 28))	('SCH717454', 'Chemical', 'MESH:C573312', (91, 100))	('SCH717454', 'Var', (91, 100))
316353	22188815	Thus, as in vitro, IGF-2, but not IGF-1, circumvented the anti-angiogenic effect of SCH717454 in vivo.	('anti-angiogenic effect', 'CPA', (58, 80))	('circumvented', 'NegReg', (41, 53))	('IGF-2', 'Var', (19, 24))	('SCH717454', 'Chemical', 'MESH:C573312', (84, 93))
316354	22188815	This suggests that combination of IGF-1R-targeted antibodies with ligand binding antibodies with high affinity for binding IGF-2, may effectively block IGF-driven tumor angiogenesis.	('IGF-2', 'Gene', (123, 128))	('antibodies', 'Var', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('block', 'NegReg', (146, 151))	('IGF-1R-targeted', 'Gene', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))
316363	33552979	Radiotherapy was associated with significantly improved DFS (92 months vs. not reached in RT vs. no RT groups, respectively; p = 0.008) and pelvic failure-free survival (PFFS) (92 months vs. not reached in RT vs. no RT groups, respectively; p=0.004).	('improved', 'PosReg', (47, 55))	('pelvic failure', 'Disease', (140, 154))	('DFS', 'CPA', (56, 59))	('Radiotherapy', 'Var', (0, 12))	('PFFS', 'Chemical', '-', (170, 174))	('pelvic failure', 'Disease', 'MESH:D006333', (140, 154))
316460	33552979	In this study, patients receiving IMRT had a lower pelvic recurrence rate than did those receiving CRT or 3D-CRT.	('lower', 'NegReg', (45, 50))	('patients', 'Species', '9606', (15, 23))	('IMRT', 'Var', (34, 38))	('pelvic recurrence rate', 'CPA', (51, 73))
316493	31744224	In 85-90% of cases, EWS tumors are characterized by a specific chromosomal translocation, t(11;22)(q24;q12), resulting in the fusion of the EWSR1 (22q12) gene and a member of the ETS family or transcription factor FLI1 (11q24) gene.	('EWS', 'Gene', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('EWSR1', 'Gene', (140, 145))	('EWSR1', 'Gene', '2130', (140, 145))	('tumors', 'Disease', (24, 30))	('fusion', 'Var', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('t(11;22)(q24;q12', 'Var', (90, 106))	('FLI1', 'Gene', (214, 218))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (90, 107))	('FLI1', 'Gene', '2313', (214, 218))	('EWS', 'Phenotype', 'HP:0012254', (20, 23))	('EWS', 'Phenotype', 'HP:0012254', (140, 143))	('EWS', 'Gene', '2130', (140, 143))	('EWS', 'Gene', (140, 143))	('EWS', 'Gene', '2130', (20, 23))
316534	31744224	The detection of EWS-FLI1 fusion transcript expression by RT-qPCR is a rapid, specific, and sensitive (1/106 cells) diagnostic test that has mainly been applied for MRD detection in peripheral blood and bone marrow.	('FLI1', 'Gene', '2313', (21, 25))	('fusion transcript', 'Var', (26, 43))	('EWS', 'Phenotype', 'HP:0012254', (17, 20))	('EWS', 'Gene', '2130', (17, 20))	('EWS', 'Gene', (17, 20))	('FLI1', 'Gene', (21, 25))
316561	31744224	In the case of MRD positivity, it may be feasible to eliminate tumor cells by grafting isolated ovarian follicles or by performing in vitro maturation of oocytes to ensure safer transplantation.	('tumor', 'Disease', (63, 68))	('positivity', 'Var', (19, 29))	('isolated ovarian', 'Disease', 'MESH:D010049', (87, 103))	('isolated ovarian', 'Disease', (87, 103))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MRD', 'Gene', (15, 18))
316597	31744224	We considered an allele positive for EWSR1 rearrangement when the gap between the green and orange signals exceeded the diameter of either one.	('men', 'Species', '9606', (52, 55))	('EWS', 'Phenotype', 'HP:0012254', (37, 40))	('EWSR1', 'Gene', (37, 42))	('rearrangement', 'Var', (43, 56))	('EWSR1', 'Gene', '2130', (37, 42))
316700	29976498	In addition, AEWS1031 was the first trial from the COG Bone Tumor Disease Committee to systematically study surgical and RT techniques and volumes in relation to musculoskeletal complications.	('AEWS1031', 'Var', (13, 21))	('COG', 'Chemical', '-', (51, 54))	('Bone Tumor', 'Phenotype', 'HP:0010622', (55, 65))	('musculoskeletal complications', 'Disease', (162, 191))	('musculoskeletal complications', 'Disease', 'MESH:D009140', (162, 191))	('Tumor', 'Phenotype', 'HP:0002664', (60, 65))
316749	29976498	The trial closed to accrual in 2015 and preliminary analysis indicates that it is safe to utilize therapeutic I-131 MIBG during the induction phase of high-risk neuroblastoma treatment.	('neuroblastoma', 'Disease', 'MESH:D009447', (161, 174))	('I-131', 'Var', (110, 115))	('neuroblastoma', 'Disease', (161, 174))	('I-131 MIBG', 'Chemical', 'MESH:D019797', (110, 120))	('neuroblastoma', 'Phenotype', 'HP:0003006', (161, 174))
316751	29976498	Two of the randomized arms will assess the use of therapeutic I-131 MIBG to improve event-free survival in patients whose tumors have MIBG avidity.	('avidity', 'Var', (139, 146))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('MIBG', 'Chemical', 'MESH:D019797', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('I-131 MIBG', 'Chemical', 'MESH:D019797', (62, 72))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('MIBG', 'Chemical', 'MESH:D019797', (68, 72))	('patients', 'Species', '9606', (107, 115))	('improve', 'PosReg', (76, 83))	('event-free survival', 'MPA', (84, 103))
316809	29976498	Preclinical models that accurately recapitulate the genetics and microenvironment of pediatric cancers may be used to identify those RT/drug combinations that have impact against a majority of models of specific histotypes, or more general broad potentiation of RT effects.	('pediatric cancers', 'Disease', (85, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('pediatric cancers', 'Disease', 'MESH:D009369', (85, 102))	('combinations', 'Var', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
316898	26894994	We established sphere cultures from commercially available cell lines from 3 different sarcoma and 2 carcinoma histotypes (MG-63 for OS, RD for RS, A-673 for ES, MDA-MB-23 for BC, and ACHN for RC), and from a fresh ES biopsy (ES4540).	('carcinoma', 'Disease', 'MESH:D002277', (101, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('ACHN', 'Gene', (184, 188))	('sarcoma', 'Disease', (87, 94))	('carcinoma', 'Disease', (101, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('MDA-MB-23', 'CellLine', 'CVCL:0062', (162, 171))	('ACHN', 'Gene', '55323', (184, 188))	('A-673', 'Var', (148, 153))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
316931	26894994	In particular, as shown in Fig 4, we found that the normalization of Nanog to the geometric mean of the most stable HKG resulted in ***p = 0.0007 for cscMG-63 and **p = 0.0043 for cscACHN, whereas with ACTB normalization we obtained **p = 0.0011 and *p = 0.0130, respectively.	('ACHN', 'Gene', (183, 187))	('Nanog', 'Gene', (69, 74))	('***p = 0.0007', 'Var', (132, 145))	('ACTB', 'Gene', (202, 206))	('ACHN', 'Gene', '55323', (183, 187))	('ACTB', 'Gene', '60', (202, 206))	('Nanog', 'Gene', '79923', (69, 74))	('**p = 0.0043', 'Var', (163, 175))
316948	26894994	In particular, based on the average of the HKG ranking obtained from three different methods, we suggested that the optimal normalization factor could be calculated as the geometric mean of GUSB and 18S rRNA for MG-63, PGK1, HMBS or TBP for RD, PPIA and HPRT1 for A-673, YWHAZ and PPIA for ES4540, TBP and YWHAZ for MDA-MB-231, and PPIA and GUSB for ACHN.	('HMBS', 'Gene', '3145', (225, 229))	('GUSB', 'Gene', '2990', (190, 194))	('PPIA', 'Gene', (281, 285))	('YWHAZ', 'Gene', '7534', (271, 276))	('PPIA', 'Gene', '5478', (245, 249))	('ES4540', 'Var', (290, 296))	('PPIA', 'Gene', '5478', (332, 336))	('GUSB', 'Gene', '2990', (341, 345))	('ACHN', 'Gene', (350, 354))	('GUSB', 'Gene', (190, 194))	('GUSB', 'Gene', (341, 345))	('TBP', 'Gene', (298, 301))	('TBP', 'Gene', (233, 236))	('YWHAZ', 'Gene', (306, 311))	('HPRT1', 'Gene', '3251', (254, 259))	('PPIA', 'Gene', (245, 249))	('PPIA', 'Gene', (332, 336))	('PGK1', 'Gene', '5230', (219, 223))	('TBP', 'Gene', '6908', (298, 301))	('YWHAZ', 'Gene', '7534', (306, 311))	('TBP', 'Gene', '6908', (233, 236))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (316, 326))	('ACHN', 'Gene', '55323', (350, 354))	('PPIA', 'Gene', '5478', (281, 285))	('HPRT1', 'Gene', (254, 259))	('YWHAZ', 'Gene', (271, 276))	('PGK1', 'Gene', (219, 223))	('HMBS', 'Gene', (225, 229))
316968	26167490	noted that daily oral administration of celecoxib in tumor-bearing mice (colon cancer) resulted in enhanced secretion of IFN-gamma by T cells and natural killer cells and altered the immune inhibitory effect in the tumor microenvironment, which in turn induced differentiation of macrophages into M1 macrophages and inhibited tumor growth.	('enhanced', 'PosReg', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Gene', '16793023', (326, 331))	('colon cancer', 'Phenotype', 'HP:0003003', (73, 85))	('celecoxib', 'Var', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Gene', '16793023', (215, 220))	('tumor', 'Gene', (326, 331))	('colon cancer', 'Disease', 'MESH:D015179', (73, 85))	('mice', 'Species', '10090', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('induced', 'Reg', (253, 260))	('tumor', 'Gene', '16793023', (53, 58))	('IFN-gamma', 'Gene', '15978', (121, 130))	('tumor', 'Gene', (215, 220))	('altered', 'Reg', (171, 178))	('immune inhibitory effect in', 'MPA', (183, 210))	('celecoxib', 'Chemical', 'MESH:D000068579', (40, 49))	('colon cancer', 'Disease', (73, 85))	('IFN-gamma', 'Gene', (121, 130))	('differentiation', 'CPA', (261, 276))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('tumor', 'Gene', (53, 58))	('inhibited', 'NegReg', (316, 325))
317014	26167490	As results shown in Figure 3(a), the amounts of M-CSF gene expression in the lungs of normal mice are as follows: group PC is higher at 0.5285 +- 0.07916, and group PB is lower at 0.5012 +- 0.04078.	('M-CSF', 'Gene', (48, 53))	('PC', 'Chemical', '-', (120, 122))	('higher', 'PosReg', (126, 132))	('mice', 'Species', '10090', (93, 97))	('M-CSF', 'Gene', '12977', (48, 53))	('0.5285 +- 0.07916', 'Var', (136, 153))	('PB', 'Chemical', 'MESH:D007854', (165, 167))
317016	26167490	As results shown in Figure 3(b), the amounts of IL-6 gene expression in the lungs of normal mice are as follows: group PB is higher at 0.1297 +- 0.03755, and group PC is lower at 0.1208 +- 0.03685.	('0.1297 +- 0.03755', 'Var', (135, 152))	('PC', 'Chemical', '-', (164, 166))	('higher', 'PosReg', (125, 131))	('PB', 'Chemical', 'MESH:D007854', (119, 121))	('IL-6', 'Gene', (48, 52))	('IL-6', 'Gene', '16193', (48, 52))	('mice', 'Species', '10090', (92, 96))
317017	26167490	As results shown in Figure 3(c), the amounts of IL-10 gene expression in the lungs of normal mice are as follows: group PB is higher at 0.0036 +- 0.00005, and group PC is lower at 0.0035 +- 0.00107.	('higher', 'PosReg', (126, 132))	('IL-10', 'Gene', '16153', (48, 53))	('expression', 'MPA', (59, 69))	('PB', 'Chemical', 'MESH:D007854', (120, 122))	('mice', 'Species', '10090', (93, 97))	('IL-10', 'Gene', (48, 53))	('PC', 'Chemical', '-', (165, 167))	('0.0036', 'Var', (136, 142))
317018	26167490	As results shown in Figure 3(d), the amounts of COX-2 gene expression in the lungs of normal mice are as follows: group PC is higher at 0.0038 +- 0.00087, and group PB is lower at 0.0021 +- 0.00057.	('PC', 'Chemical', '-', (120, 122))	('0.0038 +- 0.00087', 'Var', (136, 153))	('higher', 'PosReg', (126, 132))	('expression', 'MPA', (59, 69))	('mice', 'Species', '10090', (93, 97))	('PB', 'Chemical', 'MESH:D007854', (165, 167))	('COX-2', 'Gene', (48, 53))
317020	26167490	As results shown in Figure 3(e), the amounts of TGF-beta gene expression in the lungs of normal mice are as follows: group PC is higher at 2.1539 +- 0.5294, and group PB is lower at 1.6817 +- 0.07353.	('mice', 'Species', '10090', (96, 100))	('TGF-beta', 'Gene', (48, 56))	('expression', 'MPA', (62, 72))	('2.1539 +- 0.5294', 'Var', (139, 155))	('PB', 'Chemical', 'MESH:D007854', (167, 169))	('PC', 'Chemical', '-', (123, 125))	('TGF-beta', 'Gene', '21803', (48, 56))
317029	26167490	As results shown in Figure 6(a), the amounts of IL-12 gene expression in the lungs of tumor-bearing mice are the highest in group TB at 0.0048 +- 0.0023, followed by group TM at 0.0027 +- 0.00121 and group GX at 0.0024 +- 0.0007, and the lowest in group TC at 0.0018 +- 0.00056.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Gene', '16793023', (86, 91))	('TB', 'Chemical', 'MESH:D013725', (130, 132))	('TM', 'Chemical', 'MESH:D013932', (172, 174))	('IL-12', 'Gene', (48, 53))	('amounts', 'MPA', (37, 44))	('mice', 'Species', '10090', (100, 104))	('tumor', 'Gene', (86, 91))	('expression', 'MPA', (59, 69))	('0.0048 +- 0.0023', 'Var', (136, 152))	('TC', 'Chemical', 'MESH:D013667', (254, 256))
317031	26167490	As results shown in Figure 6(b), the amounts of GM-CSF gene expression in the lungs of tumor-bearing mice are shown to be the highest in group TB at 40.4202 +- 16.8, followed by group TX at 29.9667 +- 3.67509 and group TM at 28.7425 +- 4.58706, and the lowest in group TC at 23.7612 +- 7.77548.	('expression', 'MPA', (60, 70))	('TM', 'Chemical', 'MESH:D013932', (219, 221))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Gene', (87, 92))	('GM-CSF', 'Gene', (48, 54))	('TB', 'Chemical', 'MESH:D013725', (143, 145))	('mice', 'Species', '10090', (101, 105))	('GM-CSF', 'Gene', '12981', (48, 54))	('TC', 'Chemical', 'MESH:D013667', (269, 271))	('40.4202 +- 16.8', 'Var', (149, 164))	('tumor', 'Gene', '16793023', (87, 92))
317034	26167490	As results shown in Figure 7(a), the amounts of M-CSF gene expression in the lungs of tumor-bearing mice are the highest in group TC at 0.4965 +- 0.1044, followed by group TM at 0.4098 +- 0.0458 and group TX at 0.3341 +- 0.02674, and the lowest in group TB at 0.2865 +- 0.06564.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Gene', '16793023', (86, 91))	('TC', 'Chemical', 'MESH:D013667', (130, 132))	('TM', 'Chemical', 'MESH:D013932', (172, 174))	('M-CSF', 'Gene', (48, 53))	('mice', 'Species', '10090', (100, 104))	('tumor', 'Gene', (86, 91))	('expression', 'MPA', (59, 69))	('0.4965 +- 0.1044', 'Var', (136, 152))	('TB', 'Chemical', 'MESH:D013725', (254, 256))	('M-CSF', 'Gene', '12977', (48, 53))
317036	26167490	As results shown in Figure 7(b), the amounts of IL-6 gene expression in the lungs of tumor-bearing mice are the highest in group TC at 0.1788 +- 0.06732, followed by group TX at 0.1505 +- 0.05891 and group TB at 0.1199 +- 0.02936, and the lowest in group TM at 0.0705 +- 0.04733.	('mice', 'Species', '10090', (99, 103))	('tumor', 'Gene', (85, 90))	('IL-6', 'Gene', '16193', (48, 52))	('TC', 'Chemical', 'MESH:D013667', (129, 131))	('amounts', 'MPA', (37, 44))	('expression', 'MPA', (58, 68))	('TM', 'Chemical', 'MESH:D013932', (255, 257))	('TB', 'Chemical', 'MESH:D013725', (206, 208))	('0.1788 +- 0.06732', 'Var', (135, 152))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('IL-6', 'Gene', (48, 52))	('tumor', 'Gene', '16793023', (85, 90))
317037	26167490	As result shown in Figure 7(c), the amounts of IL-10 gene expression in the lungs of tumor-bearing mice are the highest in group TM at 0.0079 +- 0.00559, followed by group TC at 0.0072 +- 0.00153 and group TB at 0.0033 +- 0.00246, and the lowest in group TX at 0.0026 +- 0.0003.	('mice', 'Species', '10090', (99, 103))	('tumor', 'Gene', (85, 90))	('IL-10', 'Gene', '16153', (47, 52))	('expression', 'MPA', (58, 68))	('0.0079 +- 0.00559', 'Var', (135, 152))	('IL-10', 'Gene', (47, 52))	('TB', 'Chemical', 'MESH:D013725', (206, 208))	('TC', 'Chemical', 'MESH:D013667', (172, 174))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('TM', 'Chemical', 'MESH:D013932', (129, 131))	('tumor', 'Gene', '16793023', (85, 90))
317047	26167490	As results shown in Figure 9(b), the amounts of GM-CSF gene expression in tumor tissues of tumor-bearing mice are the highest in group TX at 3.3869 +- 2.38866, followed by group TB at 3.1262 +- 1.58598 and group TC at 2.377 +- 0.76023, and the lowest in group TM at 1.4979 +- 0.99286.	('expression', 'MPA', (60, 70))	('TB', 'Chemical', 'MESH:D013725', (178, 180))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TC', 'Chemical', 'MESH:D013667', (212, 214))	('tumor', 'Gene', '16793023', (74, 79))	('GM-CSF', 'Gene', (48, 54))	('3.3869 +- 2.38866', 'Var', (141, 158))	('GM-CSF', 'Gene', '12981', (48, 54))	('tumor', 'Gene', '16793023', (91, 96))	('tumor', 'Gene', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mice', 'Species', '10090', (105, 109))	('TM', 'Chemical', 'MESH:D013932', (260, 262))	('tumor', 'Gene', (91, 96))
317049	26167490	As results shown in Figure 9(c), the amounts of IFN-gamma gene expression in tumor tissues of tumor-bearing mice are the highest in group TX at 4.755 +- 1.37064, followed by group TB at 2.2302 +- 0.97283 and group TM at 2.1372 +- 0.46061, and the lowest in group TC at 0.4663 +- 0.16811.	('IFN-gamma', 'Gene', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Gene', '16793023', (94, 99))	('expression', 'MPA', (63, 73))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Gene', '16793023', (77, 82))	('TB', 'Chemical', 'MESH:D013725', (180, 182))	('IFN-gamma', 'Gene', '15978', (48, 57))	('4.755 +- 1.37064', 'Var', (144, 160))	('TM', 'Chemical', 'MESH:D013932', (214, 216))	('TC', 'Chemical', 'MESH:D013667', (263, 265))	('tumor', 'Gene', (77, 82))
317051	26167490	As results shown in Figure 10(a), the amounts of M-CSF gene expression in tumor tissues of tumor-bearing mice are the highest in group TC at 2.1827 +- 0.59147, followed by group TB at 1.5069 +- 0.39195 and group TX at 1.1425 +- 0.71354, and the lowest in group TM at 0.6412 +- 0.2704.	('2.1827 +- 0.59147', 'Var', (141, 158))	('expression', 'MPA', (60, 70))	('M-CSF', 'Gene', (49, 54))	('TB', 'Chemical', 'MESH:D013725', (178, 180))	('TM', 'Chemical', 'MESH:D013932', (261, 263))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Gene', '16793023', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Gene', '16793023', (91, 96))	('tumor', 'Gene', (74, 79))	('M-CSF', 'Gene', '12977', (49, 54))	('TC', 'Chemical', 'MESH:D013667', (135, 137))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Gene', (91, 96))
317054	26167490	As results shown in Figure 10(b), the amounts of IL-6 gene expression in tumor tissues of tumor-bearing mice are the highest in group TC at 1.0398 +- 0.24445, followed by group TB at 0.3408 +- 0.03372 and group TM at 0.2742 +- 0.06911, and the lowest in group TX at 0.2463 +- 0.17439.	('TB', 'Chemical', 'MESH:D013725', (177, 179))	('1.0398 +- 0.24445', 'Var', (140, 157))	('TC', 'Chemical', 'MESH:D013667', (134, 136))	('tumor', 'Gene', '16793023', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mice', 'Species', '10090', (104, 108))	('tumor', 'Gene', '16793023', (73, 78))	('expression', 'MPA', (59, 69))	('tumor', 'Gene', (73, 78))	('tumor', 'Gene', (90, 95))	('IL-6', 'Gene', (49, 53))	('IL-6', 'Gene', '16193', (49, 53))	('TM', 'Chemical', 'MESH:D013932', (211, 213))
317057	26167490	As results shown in Figure 10(c), the amounts of IL-10 gene expression in tumor tissues of tumor-bearing mice were demonstrated to be the highest in group TC at 0.0332 +- 0.01199, followed by group TB at 0.0096 +- 0.0042 and group TM at 0.0085 +- 0.00505, and lowest in group TX at 0.0084 +- 0.01108.	('0.0332 +- 0.01199', 'Var', (161, 178))	('expression', 'MPA', (60, 70))	('TB', 'Chemical', 'MESH:D013725', (198, 200))	('TC', 'Chemical', 'MESH:D013667', (155, 157))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Gene', '16793023', (74, 79))	('amounts', 'MPA', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('IL-10', 'Gene', '16153', (49, 54))	('tumor', 'Gene', (74, 79))	('tumor', 'Gene', '16793023', (91, 96))	('TM', 'Chemical', 'MESH:D013932', (231, 233))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Gene', (91, 96))	('IL-10', 'Gene', (49, 54))
317061	26167490	As results shown in Figure 10(e), the amounts of TGF-beta gene expression in tumor tissues of tumor-bearing mice are the highest in group TC at 2.8931 +- 0.18312, followed by group TM at 1.2829 +- 0.13795 and group TX at 1.1744 +- 0.8451, and the lowest in group TB at 1.1555 +- 0.66985.	('TGF-beta', 'Gene', (49, 57))	('TM', 'Chemical', 'MESH:D013932', (181, 183))	('2.8931 +- 0.18312', 'Var', (144, 161))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Gene', '16793023', (94, 99))	('expression', 'MPA', (63, 73))	('mice', 'Species', '10090', (108, 112))	('TC', 'Chemical', 'MESH:D013667', (138, 140))	('tumor', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Gene', '16793023', (77, 82))	('TGF-beta', 'Gene', '21803', (49, 57))	('TB', 'Chemical', 'MESH:D013725', (263, 265))	('tumor', 'Gene', (77, 82))
317189	24101584	In quadriceps muscle samples, Atrogin-1 expression was increased in TBL rats, as compared to controls, in the saline-treated condition (p < 0.05) (Figure 6B).	('expression', 'MPA', (40, 50))	('TBL', 'Var', (68, 71))	('TBL', 'Chemical', 'MESH:C073328', (68, 71))	('quadriceps muscle', 'Disease', (3, 20))	('increased', 'PosReg', (55, 64))	('Atrogin-1', 'Gene', '171043', (30, 39))	('quadriceps muscle', 'Disease', 'MESH:D009135', (3, 20))	('rats', 'Species', '10116', (72, 76))	('saline', 'Chemical', 'MESH:D012965', (110, 116))	('Atrogin-1', 'Gene', (30, 39))
317197	24101584	Plasma insulin levels were significantly lower in TBL and TBU animals, as compared to controls.	('TBL', 'Chemical', 'MESH:C073328', (50, 53))	('TBU', 'Var', (58, 61))	('TBU', 'Chemical', '-', (58, 61))	('lower', 'NegReg', (41, 46))	('insulin', 'Gene', (7, 14))	('TBL', 'Var', (50, 53))	('insulin', 'Gene', '3630', (7, 14))
317221	24101584	While glucose tolerance and insulin sensitivity were not directly measured following Exendin-4 treatment, plasma insulin levels were comparable in control and TB rats treated with Exendin-4, while insulin levels were lower in saline-treated TB rats.	('insulin', 'Gene', (197, 204))	('saline', 'Chemical', 'MESH:D012965', (226, 232))	('insulin', 'Gene', (113, 120))	('insulin', 'Gene', '3630', (197, 204))	('rats', 'Species', '10116', (244, 248))	('insulin', 'Gene', '3630', (113, 120))	('Exendin-4', 'Chemical', 'MESH:D000077270', (180, 189))	('Exendin-4', 'Var', (180, 189))	('insulin', 'Gene', (28, 35))	('rats', 'Species', '10116', (162, 166))	('TB', 'Chemical', '-', (241, 243))	('insulin', 'Gene', '3630', (28, 35))	('TB', 'Chemical', '-', (159, 161))	('Exendin-4', 'Chemical', 'MESH:D000077270', (85, 94))	('glucose', 'Chemical', 'MESH:D005947', (6, 13))
317285	33925683	Of those, 93% (13/14) of the patients in group LSQ <= 0.2 had a lymphedema >= Grade 2 whereas this was the case in only 55% (11/20) in group LSQ > 0.2.	('lymphedema', 'Disease', 'MESH:D008209', (64, 74))	('LSQ <= 0.2', 'Var', (47, 57))	('patients', 'Species', '9606', (29, 37))	('lymphedema', 'Phenotype', 'HP:0001004', (64, 74))	('edema', 'Phenotype', 'HP:0000969', (69, 74))	('lymphedema', 'Disease', (64, 74))	('LSQ', 'Chemical', '-', (47, 50))	('LSQ', 'Chemical', '-', (141, 144))
317294	33925683	A certain amount of subjectivity cannot be denied so testing the variation of the LSQ calculation by different users of the formula could increase the objectivity of the calculation.	('increase', 'PosReg', (138, 146))	('objectivity', 'MPA', (151, 162))	('variation', 'Var', (65, 74))	('LSQ', 'MPA', (82, 85))	('LSQ', 'Chemical', '-', (82, 85))
317300	33925683	stated a significant univariate difference between the development of lymphedema in the group treated with 50 Gy vs. the group with 66 Gy (p = 0.01).	('lymphedema', 'Disease', 'MESH:D008209', (70, 80))	('50 Gy', 'Var', (107, 112))	('lymphedema', 'Phenotype', 'HP:0001004', (70, 80))	('edema', 'Phenotype', 'HP:0000969', (75, 80))	('lymphedema', 'Disease', (70, 80))	('development of lymphedema', 'Phenotype', 'HP:0001004', (55, 80))
317317	33925683	Tonometry also has been used in a study to estimate the involvement of adipose tissue in therapy-related lymphedema as a factor of the potential improvement of an edema through liposuction.	('improvement', 'PosReg', (145, 156))	('edema', 'Disease', 'MESH:D004487', (110, 115))	('edema', 'Disease', 'MESH:D004487', (163, 168))	('lymphedema', 'Disease', (105, 115))	('liposuction', 'Var', (177, 188))	('edema', 'Phenotype', 'HP:0000969', (110, 115))	('edema', 'Phenotype', 'HP:0000969', (163, 168))	('edema', 'Disease', (110, 115))	('edema', 'Disease', (163, 168))	('lymphedema', 'Disease', 'MESH:D008209', (105, 115))	('lymphedema', 'Phenotype', 'HP:0001004', (105, 115))
317338	28885261	Epigenetic alterations in bone and soft tissue tumors Human malignancies are driven by heritable alterations that lead to unchecked cellular proliferation, invasive growth and distant spread.	('Epigenetic alterations', 'Var', (0, 22))	('tumors', 'Disease', (47, 53))	('malignancies', 'Disease', (60, 72))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (35, 53))	('distant spread', 'CPA', (176, 190))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Human', 'Species', '9606', (54, 59))	('invasive growth', 'CPA', (156, 171))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('bone and', 'Disease', (26, 34))	('lead to', 'Reg', (114, 121))
317339	28885261	In recent years, high-throughput sequencing of tumor genomes has revealed a central role for mutations in epigenetic regulatory complexes in oncogenic processes.	('mutations', 'Var', (93, 102))	('oncogenic processes', 'CPA', (141, 160))	('epigenetic regulatory complexes', 'Protein', (106, 137))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
317340	28885261	Dysfunction in these proteins can lead to activation of oncogenic pathways or silencing of tumor suppressors.	('Dysfunction', 'Var', (0, 11))	('oncogenic', 'CPA', (56, 65))	('silencing', 'NegReg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('activation', 'PosReg', (42, 52))	('tumor', 'Disease', (91, 96))
317342	28885261	This review will focus on recent advances in the understanding of the molecular pathogenesis of a subset of tumors in which alterations in the polycomb family of chromatin modifying complexes, the SWI/SNF family of nucleosome remodelers, and histones play a central role in disease pathogenesis.	('polycomb', 'Gene', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('alterations', 'Var', (124, 135))	('polycomb', 'Gene', '40358', (143, 151))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
317350	28885261	Opposition between these protein families was first described in Drosophila development where mutations in brahma (a Drosophila homolog of a SWI/SNF member) suppressed polycomb-mutant phenotypes.	('mutations', 'Var', (94, 103))	('suppressed', 'NegReg', (157, 167))	('brahma', 'Gene', '39744', (107, 113))	('polycomb', 'Gene', (168, 176))	('polycomb', 'Gene', '40358', (168, 176))	('Drosophila', 'Species', '7227', (117, 127))	('Drosophila', 'Species', '7227', (65, 75))	('brahma', 'Gene', (107, 113))
317351	28885261	Mutations in the genes encoding members of chromatin altering complexes are among the commonest alterations in human malignancies, and they disrupt the balance between active and repressed chromatin.	('disrupt', 'NegReg', (140, 147))	('human', 'Species', '9606', (111, 116))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('Mutations', 'Var', (0, 9))	('malignancies', 'Disease', (117, 129))
317352	28885261	These mutations can function as oncogenes or tumor suppressors, depending on the cellular context and the identities of the genes inappropriately expressed or silenced.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
317355	28885261	Each section below will address alterations in particular components of an epigenetic complex and, when known, how they result in tumor formation.	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('result in', 'Reg', (120, 129))	('alterations', 'Var', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
317360	28885261	Over two decades ago, malignant rhabdoid tumor became the first characterized malignancy in which loss-of-function mutation of a SWI/SNF family member was shown to be the primary driver.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('malignancy', 'Disease', (78, 88))	('malignant rhabdoid tumor', 'Disease', (22, 46))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (22, 46))	('loss-of-function', 'NegReg', (98, 114))	('SWI/SNF', 'Gene', (129, 136))	('mutation', 'Var', (115, 123))	('malignancy', 'Disease', 'MESH:D009369', (78, 88))
317363	28885261	It was initially shown that malignant rhabdoid tumor was driven by inactivation of the CDKN2A tumor suppressor (P16INK4A).	('inactivation', 'Var', (67, 79))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('CDKN2A', 'Gene', '1029', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('P16INK4A', 'Gene', (112, 120))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (28, 52))	('P16INK4A', 'Gene', '1029', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('malignant rhabdoid tumor', 'Disease', (28, 52))	('tumor', 'Disease', (47, 52))	('CDKN2A', 'Gene', (87, 93))
317373	28885261	It has also been adopted as a sensitive and specific marker for epithelioid sarcoma, both proximal and distal types (Figure 2A), the overwhelming majority of which have loss of Ini1 expression, most commonly associated with biallelic deletions in the SMARCB1 gene.	('Ini1', 'Gene', (177, 181))	('biallelic deletions', 'Var', (224, 243))	('expression', 'MPA', (182, 192))	('loss', 'NegReg', (169, 173))	('Ini1', 'Gene', '6598', (177, 181))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (64, 83))	('associated', 'Reg', (208, 218))	('SMARCB1', 'Gene', (251, 258))	('SMARCB1', 'Gene', '6598', (251, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('epithelioid sarcoma', 'Disease', (64, 83))
317381	28885261	Moreover, loss of Ini1 staining can be seen in poorly-differentiated carcinomas, either through alterations in SMARCB1 or other SWI/SNF components, further complicating this distinction.	('SMARCB1', 'Gene', '6598', (111, 118))	('Ini1', 'Gene', '6598', (18, 22))	('alterations', 'Var', (96, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('SMARCB1', 'Gene', (111, 118))	('carcinomas', 'Disease', 'MESH:D002277', (69, 79))	('carcinomas', 'Disease', (69, 79))	('Ini1', 'Gene', (18, 22))	('loss', 'NegReg', (10, 14))
317390	28885261	Early genetic studies revealed complex alterations, with numerous mutations, gains and losses, but few recurrent mutations outside of NF1and p53.	('mutations', 'Var', (66, 75))	('losses', 'NegReg', (87, 93))	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('gains', 'PosReg', (77, 82))	('NF1', 'Gene', (134, 137))	('NF1', 'Gene', '4763', (134, 137))
317392	28885261	The mutations were most commonly found in the subunit SUZ12, with a smaller subset harboring mutations in the EED subunit.	('SUZ12', 'Gene', (54, 59))	('found', 'Reg', (33, 38))	('EED', 'Gene', (110, 113))	('EED', 'Gene', '8726', (110, 113))	('SUZ12', 'Gene', '23512', (54, 59))	('mutations', 'Var', (4, 13))
317393	28885261	In some instances, SUZ12 loss was the result of germ-line co-deletion in NF1 patients, since SUZ12 neighbors NF1 on chromosome 17.	('co-deletion', 'Var', (58, 69))	('NF1', 'Gene', '4763', (73, 76))	('SUZ12', 'Gene', '23512', (93, 98))	('NF1', 'Gene', (109, 112))	('SUZ12', 'Gene', (93, 98))	('NF1', 'Gene', '4763', (109, 112))	('patients', 'Species', '9606', (77, 85))	('SUZ12', 'Gene', '23512', (19, 24))	('SUZ12', 'Gene', (19, 24))	('loss', 'NegReg', (25, 29))	('NF1', 'Gene', (73, 76))
317395	28885261	This pathway, already active due to loss of NF1, a Ras-GTPase activating protein, was further amplified upon PRC2 loss.	('NF1', 'Gene', (44, 47))	('loss', 'NegReg', (114, 118))	('amplified', 'PosReg', (94, 103))	('NF1', 'Gene', '4763', (44, 47))	('loss', 'Var', (36, 40))	('PRC2', 'Gene', (109, 113))
317401	28885261	In addition to its utility as a diagnostic marker, several series also found loss of H3K27me3 to have prognostic significance, as it was associated with aggressive disease.	('aggressive disease', 'Disease', (153, 171))	('associated with', 'Reg', (137, 152))	('H3K27me3', 'Protein', (85, 93))	('loss', 'Var', (77, 81))	('aggressive disease', 'Disease', 'MESH:D001523', (153, 171))
317405	28885261	Both gene products involved in SYT-SSX fusions associate with epigenetic regulatory complexes: SYT with the SWI/SNF complex and SSX with polycomb.	('polycomb', 'Gene', (137, 145))	('polycomb', 'Gene', '40358', (137, 145))	('SYT', 'Gene', '6760', (31, 34))	('SYT', 'Gene', (95, 98))	('fusions', 'Var', (39, 46))	('SYT', 'Gene', '6760', (95, 98))	('associate', 'Reg', (47, 56))	('SSX', 'Gene', (35, 38))	('SSX', 'Gene', (128, 131))	('SSX', 'Gene', '6757', (35, 38))	('SSX', 'Gene', '6757', (128, 131))	('SYT', 'Gene', (31, 34))
317410	28885261	Together, these studies highlighted a role for polycomb and gene silencing in synovial sarcoma pathogenesis.	('synovial sarcoma', 'Disease', (78, 94))	('polycomb', 'Gene', (47, 55))	('polycomb', 'Gene', '40358', (47, 55))	('gene silencing', 'Var', (60, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('synovial sarcoma', 'Disease', 'MESH:D013584', (78, 94))
317417	28885261	One way to reconcile these seemingly discordant findings is that, rather than completely eliminating polycomb, the gain-of function phenotype effects a redistribution such that SWI/SNF binds and evicts polycomb from SWI/SNF target genes, de-repressing critical drivers of tumorigenesis, including Sox2.	('polycomb', 'Gene', '40358', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('SWI/SNF', 'Var', (177, 184))	('tumor', 'Disease', (272, 277))	('Sox2', 'Gene', '6657', (297, 301))	('polycomb', 'Gene', (202, 210))	('evicts', 'NegReg', (195, 201))	('polycomb', 'Gene', '40358', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('de-repressing', 'NegReg', (238, 251))	('polycomb', 'Gene', (101, 109))	('Sox2', 'Gene', (297, 301))	('binds', 'Interaction', (185, 190))
317420	28885261	It is similar to that recently described for a histone H3.3 H3K27M mutation in pediatric gliomas.	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('H3K27M', 'Var', (60, 66))	('histone H3.3', 'Gene', '3021', (47, 59))	('histone H3.3', 'Gene', (47, 59))	('gliomas', 'Disease', (89, 96))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))
317422	28885261	Several histologically and clinically distinct soft tissue tumors/sarcomas harbor rearrangements in members of the extended polycomb family.	('rearrangements', 'Var', (82, 96))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('harbor', 'Reg', (75, 81))	('tumors', 'Disease', (59, 65))	('polycomb', 'Gene', (124, 132))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (47, 65))	('sarcomas', 'Disease', (66, 74))	('polycomb', 'Gene', '40358', (124, 132))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
317424	28885261	While these rearrangements already serve as the basis for specific molecular diagnostic tests:either by fluorescence in-situ hybridization (FISH) or next-generation sequencing, less is known about the way in which translocations promote tumorigenesis.	('tumor', 'Disease', (237, 242))	('promote', 'PosReg', (229, 236))	('translocations', 'Var', (214, 228))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
317426	28885261	Both endometrial stromal nodule and low-grade endometrial stromal sarcoma harbor recurrent translocations involving polycomb family members.	('endometrial stromal nodule', 'Disease', (5, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('polycomb', 'Gene', (116, 124))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (46, 73))	('polycomb', 'Gene', '40358', (116, 124))	('translocations', 'Var', (91, 105))	('endometrial stromal sarcoma', 'Disease', (46, 73))
317429	28885261	Tumors with any of the fusions share the same hallmark morphologic features, and none has been shown to have distinct prognostic value within the category of low-grade endometrial stromal sarcoma.	('endometrial stromal sarcoma', 'Disease', (168, 195))	('fusions', 'Var', (23, 30))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (168, 195))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))
317434	28885261	More recent work demonstrated that the fusion protein destabilizes the PRC2 complex in vitro and in tissue culture, reducing both methyltransferase activity and PRC2 localization to several known polycomb target genes.	('polycomb', 'Gene', (196, 204))	('reducing', 'NegReg', (116, 124))	('destabilizes', 'NegReg', (54, 66))	('localization', 'MPA', (166, 178))	('activity', 'MPA', (148, 156))	('polycomb', 'Gene', '40358', (196, 204))	('methyltransferase', 'Enzyme', (130, 147))	('PRC2', 'Gene', (161, 165))	('fusion', 'Var', (39, 45))
317438	28885261	Early cytogenetic studies identified recurrent rearrangements involving the PHF1 locus on chromosome 6.	('rearrangements', 'Var', (47, 61))	('PHF1', 'Gene', '5252', (76, 80))	('PHF1', 'Gene', (76, 80))
317449	28885261	Mutations in BCOR occur in a rare genetic syndrome called occulofaciocardiodental syndrome (OFCD), named for a constellation of abnormalities in the eye, face, heart and teeth.	('constellation of abnormalities in the eye', 'Disease', (111, 152))	('genetic syndrome', 'Disease', 'MESH:D030342', (34, 50))	('occur', 'Reg', (18, 23))	('occulofaciocardiodental syndrome', 'Disease', (58, 90))	('OFCD', 'Disease', 'MESH:C537465', (92, 96))	('Mutations', 'Var', (0, 9))	('BCOR', 'Gene', (13, 17))	('occulofaciocardiodental syndrome', 'Disease', 'MESH:D013577', (58, 90))	('constellation of abnormalities in the eye', 'Disease', 'MESH:D005124', (111, 152))	('genetic syndrome', 'Disease', (34, 50))	('abnormalities in the eye', 'Phenotype', 'HP:0000478', (128, 152))	('BCOR', 'Gene', '54880', (13, 17))	('OFCD', 'Disease', (92, 96))
317451	28885261	Recent genomic and transcriptomic analyses have identified recurrent alterations in the BCOR gene in several distinct mesenchymal malignancies.	('alterations', 'Var', (69, 80))	('malignancies', 'Disease', (130, 142))	('BCOR', 'Gene', (88, 92))	('BCOR', 'Gene', '54880', (88, 92))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))
317454	28885261	Since the identification of BCOR-CCNB3 fusions, other BCOR fusions have been reported in undifferentiated round cell sarcomas occurring in older, predominantly male patients, including BCOR-MAML3 and ZC3H7B-BCOR fusions.	('BCOR', 'Gene', '54880', (185, 189))	('fusions', 'Var', (39, 46))	('ZC3H7B', 'Gene', (200, 206))	('BCOR', 'Gene', '54880', (207, 211))	('patients', 'Species', '9606', (165, 173))	('MAML3', 'Gene', '55534', (190, 195))	('BCOR', 'Gene', (185, 189))	('ZC3H7B', 'Gene', '23264', (200, 206))	('BCOR', 'Gene', (207, 211))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcomas', 'Disease', (117, 125))	('BCOR', 'Gene', '54880', (54, 58))	('CCNB3', 'Gene', '85417', (33, 38))	('BCOR', 'Gene', (54, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('BCOR', 'Gene', '54880', (28, 32))	('CCNB3', 'Gene', (33, 38))	('MAML3', 'Gene', (190, 195))	('BCOR', 'Gene', (28, 32))
317455	28885261	In addition to these fusions, BCOR internal tandem duplications have been identified in several histomorphologically distinct mesenchymal malignancies including undifferentiated small round blue cell sarcomas of infants, as well as in clear cell sarcoma of the kidney and primitive myxoid mesenchymal tumor of infancy.	('infants', 'Species', '9606', (212, 219))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('identified', 'Reg', (74, 84))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (235, 267))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (246, 267))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (246, 267))	('internal tandem duplications', 'Var', (35, 63))	('BCOR', 'Gene', '54880', (30, 34))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (282, 306))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('sarcomas', 'Disease', 'MESH:D012509', (200, 208))	('sarcoma of the kidney', 'Disease', (246, 267))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('BCOR', 'Gene', (30, 34))	('malignancies', 'Disease', (138, 150))	('myxoid mesenchymal tumor', 'Disease', (282, 306))	('sarcomas', 'Disease', (200, 208))
317459	28885261	For example, BCOR internal tandem duplications are seen in the spindled clear cell sarcoma of the kidney, undifferentiated round cell sarcomas, and the variable-appearing spindled, round and myxoid primitive myxoid mesenchymal tumor of infancy.	('internal tandem duplications', 'Var', (18, 46))	('myxoid mesenchymal tumor', 'Disease', (208, 232))	('sarcomas', 'Disease', (134, 142))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (72, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (83, 104))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (83, 104))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (208, 232))	('BCOR', 'Gene', (13, 17))	('sarcoma of the kidney', 'Disease', (83, 104))	('BCOR', 'Gene', '54880', (13, 17))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))
317463	28885261	BCOR IHC, while less specific, is a sensitive marker for tumors with BCOR alterations, including those with internal tandem duplications and variant rearrangements.	('BCOR', 'Gene', (69, 73))	('internal tandem duplications', 'Var', (108, 136))	('BCOR', 'Gene', '54880', (0, 4))	('variant rearrangements', 'Var', (141, 163))	('BCOR', 'Gene', '54880', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('alterations', 'Var', (74, 85))	('tumors', 'Disease', (57, 63))	('BCOR', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
317471	28885261	Recent high-throughput sequencing studies have identified specific recurrent mutations in histone proteins in a number of human neoplasms.	('human', 'Species', '9606', (122, 127))	('neoplasms', 'Phenotype', 'HP:0002664', (128, 137))	('neoplasm', 'Phenotype', 'HP:0002664', (128, 136))	('neoplasms', 'Disease', 'MESH:D009369', (128, 137))	('mutations', 'Var', (77, 86))	('neoplasms', 'Disease', (128, 137))	('histone proteins', 'Protein', (90, 106))
317472	28885261	For example, diffuse intrinsic pontine glioma is characterized by recurrent H3K27M mutations in H3.3, a histone H3 variant.	('mutations', 'Var', (83, 92))	('glioma', 'Disease', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('H3.3', 'Gene', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('H3K27M mutations', 'Var', (76, 92))
317473	28885261	In the past several years, histone mutations have been identified in two different mesenchymal lesions of bone: chondroblastoma and giant cell tumor of bone.	('chondroblastoma', 'Phenotype', 'HP:0030432', (112, 127))	('chondroblastoma', 'Disease', 'MESH:D002804', (112, 127))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (132, 156))	('tumor of bone', 'Phenotype', 'HP:0010622', (143, 156))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('identified', 'Reg', (55, 65))	('giant cell tumor', 'Disease', 'MESH:D005870', (132, 148))	('giant cell tumor', 'Phenotype', 'HP:0011847', (132, 148))	('histone', 'Protein', (27, 34))	('chondroblastoma', 'Disease', (112, 127))	('giant cell tumor', 'Disease', (132, 148))	('mutations', 'Var', (35, 44))
317474	28885261	Both have recurrent driver mutations in histone H3.3, a replication-independent histone H3 variant, that is incorporated at sites of active transcription.	('mutations', 'Var', (27, 36))	('histone H3.3', 'Gene', '3021', (40, 52))	('histone H3.3', 'Gene', (40, 52))
317475	28885261	H3.3 is encoded by two genes, H3F3A and H3F3B, and the mutations identified to date have been almost entirely subtype specific, with chondroblastoma having mutations in the H3F3B gene, and giant cell tumor of bone having mutations in the H3F3A gene.	('giant cell tumor', 'Phenotype', 'HP:0011847', (189, 205))	('H3F3A', 'Gene', '3020', (238, 243))	('mutations', 'Var', (221, 230))	('H3F3A', 'Gene', '3020', (30, 35))	('H3F3A', 'Gene', (238, 243))	('H3F3B', 'Gene', (40, 45))	('H3F3B', 'Gene', '3021', (40, 45))	('chondroblastoma', 'Disease', 'MESH:D002804', (133, 148))	('mutations', 'Var', (156, 165))	('giant cell tumor', 'Disease', 'MESH:D005870', (189, 205))	('H3F3B', 'Gene', (173, 178))	('H3F3B', 'Gene', '3021', (173, 178))	('chondroblastoma', 'Phenotype', 'HP:0030432', (133, 148))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('H3F3A', 'Gene', (30, 35))	('tumor of bone', 'Phenotype', 'HP:0010622', (200, 213))	('chondroblastoma', 'Disease', (133, 148))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (189, 213))	('giant cell tumor', 'Disease', (189, 205))
317476	28885261	Mutant-specific antibodies:for H3K36M mutant protein in chondroblastoma and H3G34W mutation in giant cell tumor-have shown both excellent sensitivity and specificity.	('giant cell tumor', 'Phenotype', 'HP:0011847', (95, 111))	('K36M', 'Mutation', 'p.K36M', (33, 37))	('H3G34W mutation', 'Var', (76, 91))	('giant cell tumor', 'Disease', (95, 111))	('chondroblastoma', 'Phenotype', 'HP:0030432', (56, 71))	('chondroblastoma', 'Disease', (56, 71))	('giant cell tumor', 'Disease', 'MESH:D005870', (95, 111))	('G34W', 'Mutation', 'rs765285880', (78, 82))	('chondroblastoma', 'Disease', 'MESH:D002804', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('H3K36M', 'Var', (31, 37))
317481	28885261	A recurrent K36M mutation in H3F3B, a gene encoding the histone H3 variant H3.3, was recently found in the vast majority of chondroblastomas.	('found', 'Reg', (94, 99))	('K36M', 'Mutation', 'p.K36M', (12, 16))	('chondroblastoma', 'Phenotype', 'HP:0030432', (124, 139))	('K36M', 'Var', (12, 16))	('H3F3B', 'Gene', '3021', (29, 34))	('variant H3.3', 'CellLine', 'CVCL:7204', (67, 79))	('chondroblastomas', 'Disease', (124, 140))	('H3F3B', 'Gene', (29, 34))	('chondroblastomas', 'Disease', 'MESH:D002804', (124, 140))
317482	28885261	Like the H3K27M mutation in gliomas discussed above, this mutation substitutes a methionine residue for a lysine residue at a site that is subject to post translational modification.	('substitutes', 'Reg', (67, 78))	('H3K27M', 'Var', (9, 15))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('methionine', 'Chemical', 'MESH:D008715', (81, 91))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('methionine residue', 'MPA', (81, 99))	('lysine', 'Chemical', 'MESH:D008239', (106, 112))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))
317483	28885261	In cell culture models, H3K36M mutation dramatically decreased global H3K36 methylation levels and showed a concomitant increase in global H3K27me3 levels.	('K36M', 'Mutation', 'p.K36M', (26, 30))	('H3K36M mutation', 'Var', (24, 39))	('global H3K27me3 levels', 'MPA', (132, 154))	('increase', 'PosReg', (120, 128))	('decreased', 'NegReg', (53, 62))	('global H3K36 methylation levels', 'MPA', (63, 94))
317487	28885261	However, whereas chondroblastoma mutations are typically in the H3F3B gene, giant cell tumor mutations are overwhelmingly in H3F3A, with only rare cases of H3F3B mutations.	('chondroblastoma', 'Disease', (17, 32))	('giant cell tumor', 'Disease', (76, 92))	('mutations', 'Var', (93, 102))	('H3F3B', 'Gene', (64, 69))	('H3F3B', 'Gene', '3021', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('chondroblastoma', 'Disease', 'MESH:D002804', (17, 32))	('mutations', 'Var', (33, 42))	('H3F3A', 'Gene', '3020', (125, 130))	('giant cell tumor', 'Disease', 'MESH:D005870', (76, 92))	('chondroblastoma', 'Phenotype', 'HP:0030432', (17, 32))	('giant cell tumor', 'Phenotype', 'HP:0011847', (76, 92))	('H3F3A', 'Gene', (125, 130))	('H3F3B', 'Gene', (156, 161))	('H3F3B', 'Gene', '3021', (156, 161))
317488	28885261	Over 90% of these tumors harbor mutations in H3F3A which result in substitutions at G34.	('G34', 'Var', (84, 87))	('H3F3A', 'Gene', '3020', (45, 50))	('result in', 'Reg', (57, 66))	('substitutions', 'Var', (67, 80))	('tumors', 'Disease', (18, 24))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('H3F3A', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
317489	28885261	The vast majority harbor G34W substitutions (>95% of total mutations identified), but other substitutions, including G34V, G34R, G34L and S28N have been found in rare cases.	('G34W', 'Mutation', 'rs765285880', (25, 29))	('S28N', 'Mutation', 'p.S28N', (138, 142))	('G34W', 'Var', (25, 29))	('G34V', 'Mutation', 'p.G34V', (117, 121))	('S28N', 'Var', (138, 142))	('G34V', 'Var', (117, 121))	('G34L', 'Mutation', 'p.G34L', (129, 133))	('G34R', 'Mutation', 'rs1057519902', (123, 127))	('G34R', 'Var', (123, 127))	('G34L', 'Var', (129, 133))
317490	28885261	The H3F3A mutations in giant cell tumor may affect histone post-translational modification deposition through a steric effect, given the close proximity to H3K36.	('H3F3A', 'Gene', '3020', (4, 9))	('giant cell tumor', 'Phenotype', 'HP:0011847', (23, 39))	('H3F3A', 'Gene', (4, 9))	('histone post-translational modification deposition', 'MPA', (51, 101))	('giant cell tumor', 'Disease', (23, 39))	('affect', 'Reg', (44, 50))	('mutations', 'Var', (10, 19))	('giant cell tumor', 'Disease', 'MESH:D005870', (23, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
317491	28885261	Further work will be required to assess the extent to which these mutations alter global histone post-translational modifications, and how and whether such changes influence transcription of key tumor-mediating genes, as has been seen in other contexts.	('mutations', 'Var', (66, 75))	('tumor', 'Disease', (195, 200))	('transcription', 'MPA', (174, 187))	('influence', 'Reg', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('histone post-translational modifications', 'MPA', (89, 129))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('alter', 'Reg', (76, 81))
317493	28885261	Alterations in epigenetic regulators promote tumor formation by altering the expression of numerous target genes.	('expression', 'MPA', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('promote', 'PosReg', (37, 44))	('epigenetic', 'Protein', (15, 25))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', (45, 50))	('altering', 'Reg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
317497	28885261	Intensive investigations are underway to characterize the way in which alterations in epigenetic regulators affect gene accessibility and expression, and how and why these changes result in tumor progression.	('result in', 'Reg', (180, 189))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('affect', 'Reg', (108, 114))	('gene', 'Protein', (115, 119))	('alterations', 'Var', (71, 82))	('tumor', 'Disease', (190, 195))	('expression', 'MPA', (138, 148))
317499	26462019	Tumor-specific chromosomal translocations create EWS-FLI1 and similar aberrant ETS fusion proteins that drive sarcoma development in patients.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('ETS fusion proteins', 'Protein', (79, 98))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sarcoma', 'Disease', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('patients', 'Species', '9606', (133, 141))	('aberrant', 'Var', (70, 78))	('EWS-FLI1', 'Gene', (49, 57))	('drive', 'PosReg', (104, 109))
317504	26462019	A two-week course of treatment with YK-4-279 significantly reduced white blood cell count, nucleated erythroblasts in the peripheral blood, splenomegaly, and hepatomegaly of erythroleukemic mice.	('hepatomegaly of erythroleukemic', 'Disease', (158, 189))	('reduced', 'NegReg', (59, 66))	('reduced white blood cell count', 'Phenotype', 'HP:0001882', (59, 89))	('splenomegaly', 'Disease', 'MESH:D013163', (140, 152))	('splenomegaly', 'Phenotype', 'HP:0001744', (140, 152))	('hepatomegaly', 'Phenotype', 'HP:0002240', (158, 170))	('nucleated erythroblasts in the', 'CPA', (91, 121))	('white blood cell count', 'CPA', (67, 89))	('hepatomegaly of erythroleukemic', 'Disease', 'MESH:D006529', (158, 189))	('splenomegaly', 'Disease', (140, 152))	('mice', 'Species', '10090', (190, 194))	('YK-4-279', 'Var', (36, 44))
317513	26462019	Anti-sense oligodeoxynucleotide or sequence specific siRNA mediated knockdown of EWS-FLI1 gene expression is detrimental to Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (124, 137))	('Ewing sarcoma', 'Disease', (124, 137))	('EWS-FLI1', 'Gene', (81, 89))	('knockdown', 'Var', (68, 77))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (11, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (124, 137))
317545	26462019	Treatment of CFC cultures with 3 muM or 10 muM YK-4-279 led to 90% or 99% reduction, respectively, in the clonogenic capacity of leukemic stem cells of the same mouse.	('YK-4-279', 'Var', (47, 55))	('leukemic', 'Disease', (129, 137))	('reduction', 'NegReg', (74, 83))	('leukemic', 'Disease', 'MESH:D007938', (129, 137))	('mouse', 'Species', '10090', (161, 166))
317558	26462019	Improved spleen and liver architectures were observed upon YK-4-279 treatment in mice compared to severe infiltration of erythroid progenitors in vehicle treated mice.	('rat', 'Species', '10116', (111, 114))	('mice', 'Species', '10090', (81, 85))	('YK-4-279', 'Var', (59, 67))	('mice', 'Species', '10090', (162, 166))	('Improved', 'PosReg', (0, 8))
317559	26462019	Evaluation of the bone marrow from E/F; Mx1-cre mice showed disease involvement in DMSO treated group, which had reduced number of megakaryocytes, granulocytes and erythroid cells compared to normal mice without the disease (Supplementary Figure S3).	('DMSO treated', 'Var', (83, 95))	('mice', 'Species', '10090', (199, 203))	('Mx1', 'Gene', '17857', (40, 43))	('mice', 'Species', '10090', (48, 52))	('Mx1', 'Gene', (40, 43))	('DMSO', 'Chemical', 'MESH:D004121', (83, 87))	('reduced', 'NegReg', (113, 120))
317568	26462019	On the other hand, YK-4-279 may have induced other form of cell death that doesn't involve caspase 3.	('caspase 3', 'Gene', '12367', (91, 100))	('YK-4-279', 'Var', (19, 27))	('induced', 'Reg', (37, 44))	('cell', 'CPA', (59, 63))	('caspase 3', 'Gene', (91, 100))
317569	26462019	Alternatively, inhibition of EWS-FLI1 function with YK-4-279 may have caused the leukemic cells to differentiate and lose their leukemic property.	('inhibition', 'NegReg', (15, 25))	('EWS-FLI1', 'Gene', (29, 37))	('leukemic property', 'Disease', 'MESH:D007938', (128, 145))	('leukemic', 'Disease', 'MESH:D007938', (128, 136))	('leukemic property', 'Disease', (128, 145))	('leukemic', 'Disease', (81, 89))	('leukemic', 'Disease', (128, 136))	('YK-4-279', 'Var', (52, 60))	('leukemic', 'Disease', 'MESH:D007938', (81, 89))	('lose', 'NegReg', (117, 121))
317570	26462019	YK-4-279 may have also induced cell cycle arrest instead of apoptosis, which could not have been recognized by IHC for cleaved caspase 3.	('caspase 3', 'Gene', (127, 136))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (31, 48))	('caspase 3', 'Gene', '12367', (127, 136))	('induced', 'Reg', (23, 30))	('cell cycle arrest', 'CPA', (31, 48))	('apoptosis', 'CPA', (60, 69))	('YK-4-279', 'Var', (0, 8))
317592	26462019	Inhibition of EWS-FLI1 function with YK-4-279 may cause the leukemic cells to differentiate and lose their leukemic property.	('cause', 'Reg', (50, 55))	('leukemic', 'Disease', (60, 68))	('YK-4-279', 'Var', (37, 45))	('Inhibition', 'NegReg', (0, 10))	('leukemic property', 'Disease', 'MESH:D007938', (107, 124))	('leukemic', 'Disease', 'MESH:D007938', (107, 115))	('leukemic property', 'Disease', (107, 124))	('leukemic', 'Disease', 'MESH:D007938', (60, 68))	('EWS-FLI1', 'Gene', (14, 22))	('lose', 'NegReg', (96, 100))	('leukemic', 'Disease', (107, 115))
317595	26462019	A statistically significant improvement in survival of these leukemic mice treated with YK-4-279 was measured where their median survival was 60.5 days as opposed to 21 days for the control group (Figure 11A).	('improvement', 'PosReg', (28, 39))	('YK-4-279', 'Var', (88, 96))	('leukemic', 'Disease', (61, 69))	('mice', 'Species', '10090', (70, 74))	('leukemic', 'Disease', 'MESH:D007938', (61, 69))	('survival', 'CPA', (43, 51))
317596	26462019	During the two weeks of treatment, mice randomized to YK-4-279 had significantly reduced disease burden as monitored by weekly WBC counts.	('disease burden', 'CPA', (89, 103))	('mice', 'Species', '10090', (35, 39))	('YK-4-279', 'Var', (54, 62))	('reduced', 'NegReg', (81, 88))
317597	26462019	The WBC count of YK-4-279 treated mice compared to controls was lowered by 54% (p < 0.0001) and 67% (p < 0.002) following one week and two weeks of treatment, respectively (Figure 11B).	('lowered', 'NegReg', (64, 71))	('WBC count', 'CPA', (4, 13))	('YK-4-279', 'Var', (17, 25))	('mice', 'Species', '10090', (34, 38))
317598	26462019	Follow-up monitoring beyond the two week treatment period showed that most of the mice that received YK-4-279 retained relatively low WBC counts, while those that received vehicle alone had rapid elevation of WBC that led to deterioration of their health (Figure 11C and 11D).	('mice', 'Species', '10090', (82, 86))	('WBC counts', 'MPA', (134, 144))	('WBC', 'MPA', (209, 212))	('rat', 'Species', '10116', (232, 235))	('low WBC counts', 'Phenotype', 'HP:0020060', (130, 144))	('low', 'NegReg', (130, 133))	('elevation', 'PosReg', (196, 205))	('health', 'MPA', (248, 254))	('deterioration', 'NegReg', (225, 238))	('YK-4-279', 'Var', (101, 109))
317602	26462019	We show that YK-4-279 significantly reduced clonogenic capacity of leukemic stem cells of E/F; Mx1-cre mice in vitro.	('Mx1', 'Gene', '17857', (95, 98))	('YK-4-279', 'Var', (13, 21))	('leukemic', 'Disease', (67, 75))	('mice', 'Species', '10090', (103, 107))	('Mx1', 'Gene', (95, 98))	('leukemic', 'Disease', 'MESH:D007938', (67, 75))	('reduced', 'NegReg', (36, 43))
317605	26462019	Moreover, the normal spleen and liver architecture that was severely affected in terminally diseased leukemic mice was partially restored upon YK-4-279 treatment.	('leukemic', 'Disease', 'MESH:D007938', (101, 109))	('leukemic', 'Disease', (101, 109))	('YK-4-279', 'Var', (143, 151))	('mice', 'Species', '10090', (110, 114))
317614	26462019	More than 50% of prostate cancer patients contain chromosomal translocations that involve members of the ETS transcription factor family.	('prostate cancer', 'Phenotype', 'HP:0012125', (17, 32))	('patients', 'Species', '9606', (33, 41))	('chromosomal translocations', 'Var', (50, 76))	('prostate cancer', 'Disease', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (17, 32))
317617	26462019	TERT promoter mutations are frequently observed in malignant melanoma, glioblastomas, hepatocellular and bladder carcinomas.	('glioblastomas', 'Disease', 'MESH:D005909', (71, 84))	('observed', 'Reg', (39, 47))	('malignant melanoma', 'Phenotype', 'HP:0002861', (51, 69))	('glioblastomas', 'Disease', (71, 84))	('hepatocellular', 'Disease', (86, 100))	('TERT', 'Gene', (0, 4))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (105, 123))	('TERT', 'Gene', '21752', (0, 4))	('malignant melanoma', 'Disease', 'MESH:D008545', (51, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('bladder carcinomas', 'Disease', 'MESH:D001749', (105, 123))	('malignant melanoma', 'Disease', (51, 69))	('bladder carcinomas', 'Disease', (105, 123))	('mutations', 'Var', (14, 23))	('glioblastomas', 'Phenotype', 'HP:0012174', (71, 84))
317619	26462019	Though we still do not know the exact interaction surface, YK-4-279 directly binds to and shows inhibitory activity against EWS-FLI1, ERG, and ETV1 oncoproteins, presumably due to interference with protein-protein interactions.	('interference', 'NegReg', (180, 192))	('protein-protein', 'Protein', (198, 213))	('binds to', 'Interaction', (77, 85))	('inhibitory activity', 'MPA', (96, 115))	('ERG', 'Gene', (134, 137))	('YK-4-279', 'Var', (59, 67))	('ETV1', 'Gene', '14009', (143, 147))	('oncoproteins', 'Protein', (148, 160))	('ERG', 'Gene', '13876', (134, 137))	('EWS-FLI1', 'Gene', (124, 132))	('interactions', 'Interaction', (214, 226))	('ETV1', 'Gene', (143, 147))
317621	26462019	It is plausible that the ability of YK-4-279 to antagonize the activity of a number of ETS family members could pose a risk of toxicity against tissues that expresses ETS transcription factors as part of their normal physiology.	('activity', 'MPA', (63, 71))	('toxicity', 'Disease', 'MESH:D064420', (127, 135))	('toxicity', 'Disease', (127, 135))	('ETS', 'Gene', (167, 170))	('YK-4-279', 'Var', (36, 44))	('antagonize', 'NegReg', (48, 58))
317623	26462019	In this study, YK-4-279 treatment did not suppress but rather enhanced red blood cell counts of E/F; Mx1-cre mice compared to those leukemic mice treated with vehicle alone.	('Mx1', 'Gene', '17857', (101, 104))	('Mx1', 'Gene', (101, 104))	('leukemic', 'Disease', 'MESH:D007938', (132, 140))	('enhanced', 'PosReg', (62, 70))	('enhanced red blood cell', 'Phenotype', 'HP:0001901', (62, 85))	('mice', 'Species', '10090', (141, 145))	('red blood cell counts', 'CPA', (71, 92))	('mice', 'Species', '10090', (109, 113))	('enhanced red blood cell counts', 'Phenotype', 'HP:0020059', (62, 92))	('rat', 'Species', '10116', (55, 58))	('leukemic', 'Disease', (132, 140))	('YK-4-279', 'Var', (15, 23))
317653	26462019	PP64B) in 500 mul volume, overnight at 4 C. Immunoprecipitated DNA was eluted from column and analyzed by qPCR for NR0B1 (5'-GATTCTGTATCAGCTGGTATATACC-3'and 5'-GCATCAGGAAGCCTGGATCC-3').	('NR0B1', 'Gene', '11614', (115, 120))	('PP64B', 'Var', (0, 5))	('NR0B1', 'Gene', (115, 120))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('N', 'Chemical', 'MESH:D009584', (115, 116))
317655	26462019	Direct binding study between EWS-FLI1 and wildtype vs. mutant oligonucleotide was performed on a Biacore T-200 instrument in the presence of 10 muM YK-4-279 or vehicle.	('binding', 'Interaction', (7, 14))	('oligonucleotide', 'Chemical', 'MESH:D009841', (62, 77))	('mutant', 'Var', (55, 61))
317658	26462019	EWS-FL1 binding to wild-type (ATGTAGACCGGAAGTAACTA) and mutant (ATGTAGACC GCTAGTAACTA) ETS oligonucleotides.	('ETS oligonucleotides', 'Chemical', '-', (87, 107))	('binding', 'Interaction', (8, 15))	('mutant', 'Var', (56, 62))	('EWS-FL1', 'Gene', (0, 7))
317696	26462019	The sections were incubated with specific antibodies against Gata1 (Santa Cruz, sc-265) in a 1:120 dilution, cleaved caspase 3 (Cell Signaling, 9661) in a 1:200 dilution, and Ki67 (Cell signaling, 9449) in a 1:1000 dilution at 4 C overnight.	('caspase 3', 'Gene', (117, 126))	('Gata1', 'Gene', '14460', (61, 66))	('caspase 3', 'Gene', '12367', (117, 126))	('Ki67', 'Gene', (175, 179))	('Gata1', 'Gene', (61, 66))	('cleaved', 'Var', (109, 116))	('Ki67', 'Gene', '17345', (175, 179))
317701	26462019	Following a two weeks course treatment with either YK-4-279 or DMSO, the mice were euthanized and 1 ml of blood was collected by cardiac puncture and was transferred onto a tube that is not treated with anticoagulant to allow the blood to clot.	('mice', 'Species', '10090', (73, 77))	('YK-4-279', 'Var', (51, 59))	('DMSO', 'Var', (63, 67))	('DMSO', 'Chemical', 'MESH:D004121', (63, 67))	('blood to clot', 'Phenotype', 'HP:0001907', (230, 243))
317715	26346118	Initiation of chemotherapy was based on high risk disease features (high grade disease, advanced group stage, and multiply recurrent tumors), symptomatology (pain and/or neuropathy), tumor proximity to critical structures, and desired presurgical shrinkage, as well as patient age, comorbidities, and performance status.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('pain', 'Disease', 'MESH:D010146', (158, 162))	('pain', 'Disease', (158, 162))	('neuropathy', 'Disease', (170, 180))	('high', 'Var', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('pain', 'Phenotype', 'HP:0012531', (158, 162))	('neuropathy', 'Disease', 'MESH:D009422', (170, 180))	('neuropathy', 'Phenotype', 'HP:0009830', (170, 180))
317820	20981344	In one study examining patients with tumors of the proximal lower extremity, Vraa and colleagues found that positive surgical margins were associated with a significantly higher rate of local recurrence, but not worse survival.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('patients', 'Species', '9606', (23, 31))	('positive', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('local recurrence', 'CPA', (186, 202))	('lower extremity', 'Phenotype', 'HP:0006385', (60, 75))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
317846	20981344	In this trial, patients who received postoperative radiotherapy tended to have more fibrosis, edema, and joint stiffness; however, the results are not statistically significant.	('patients', 'Species', '9606', (15, 23))	('joint stiffness', 'Phenotype', 'HP:0001387', (105, 120))	('edema', 'Disease', 'MESH:D004487', (94, 99))	('edema', 'Phenotype', 'HP:0000969', (94, 99))	('fibrosis', 'Disease', 'MESH:D005355', (84, 92))	('joint stiffness', 'Disease', 'MESH:C535724', (105, 120))	('joint stiffness', 'Disease', (105, 120))	('edema', 'Disease', (94, 99))	('radiotherapy', 'Var', (51, 63))	('fibrosis', 'Disease', (84, 92))
317851	20981344	Furthermore, evidence suggests that patients treated to a total dose less than 62.5 Gy have significantly poorer survival compared to patients treated to a higher dose.	('survival', 'CPA', (113, 121))	('poorer', 'NegReg', (106, 112))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (134, 142))	('less', 'Var', (69, 73))
317879	20981344	Several other factors, including the use of any external-beam therapy, radiation to the entire circumference of bone, female gender, chemotherapy, marginal excision, and age greater than 50 years have also been associated with an increased risk for fracture, and the risk seems to be compounded when periosteal stripping is performed.	('chemotherapy', 'Disease', (133, 145))	('marginal excision', 'Var', (147, 164))	('fracture', 'Disease', 'MESH:D050723', (249, 257))	('associated', 'Reg', (211, 221))	('fracture', 'Disease', (249, 257))
317903	33019945	Radiotherapy improves local and regional control in patients with breast cancer, and it could even improve relapse-free survival and overall survival in patients with nodal disease.	('relapse-free survival', 'CPA', (107, 128))	('improve', 'PosReg', (99, 106))	('patients', 'Species', '9606', (153, 161))	('Radiotherapy', 'Var', (0, 12))	('improves', 'PosReg', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('nodal disease', 'Disease', 'MESH:D013611', (167, 180))	('nodal disease', 'Disease', (167, 180))	('overall survival', 'CPA', (133, 149))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('patients', 'Species', '9606', (52, 60))
317928	33019945	Histopathologically, five patients had luminal A tumors, one had a BRCA1 mutation, one had a luminal tumor that could not be stablished as A or B because Ki67 was not available, and one had triple-negative disease (Table 1).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('luminal A', 'Disease', (39, 48))	('tumor', 'Disease', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('patients', 'Species', '9606', (26, 34))	('luminal', 'Chemical', 'MESH:D010634', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('BRCA1', 'Gene', '672', (67, 72))	('luminal', 'Chemical', 'MESH:D010634', (39, 46))	('mutation', 'Var', (73, 81))	('BRCA1', 'Gene', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
317952	33019945	Within the genomics of tumors, implication of the rearrangement of the RET proto-oncogene in thyroid cancer and amplification of MYC in cutaneous angiosarcoma after irradiation of the chest wall for breast cancer are known.	('thyroid cancer', 'Disease', (93, 107))	('breast cancer', 'Disease', 'MESH:D001943', (199, 212))	('breast cancer', 'Disease', (199, 212))	('angiosarcoma', 'Phenotype', 'HP:0200058', (146, 158))	('RET', 'Gene', '5979', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('MYC', 'Gene', (129, 132))	('rearrangement', 'Var', (50, 63))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('thyroid cancer', 'Disease', 'MESH:D013964', (93, 107))	('RET', 'Gene', (71, 74))	('cutaneous angiosarcoma', 'Disease', (136, 158))	('tumors', 'Disease', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('thyroid cancer', 'Phenotype', 'HP:0002890', (93, 107))	('amplification', 'Var', (112, 125))	('MYC', 'Gene', '4609', (129, 132))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('cutaneous angiosarcoma', 'Disease', 'MESH:D006394', (136, 158))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
317983	30602726	The role for chromatin regulatory processes in development and disease has been studied in depth and has recently been brought to the forefront of attention by exome-wide and genome-wide studies, which have identified mutations in genes involved in chromatin organization and regulation in over 50% of cancers.	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('mutations', 'Var', (218, 227))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('cancers', 'Disease', (302, 309))	('cancers', 'Disease', 'MESH:D009369', (302, 309))
317984	30602726	In a subset of cancers, such mutations represent the sole genetic abnormalities, providing strong support for their initiating, causative functions, rather than roles as permissive passenger mutations.	('genetic abnormalities', 'Disease', 'MESH:D030342', (58, 79))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('mutations', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('genetic abnormalities', 'Disease', (58, 79))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
317985	30602726	The impetus to mechanistically understand chromatin regulatory machinery in diseases such as cancer stems from several important features, perhaps the most compelling of which is the fact that epigenetic changes are, in principle, reversible.	('cancer', 'Disease', (93, 99))	('epigenetic changes', 'Var', (193, 211))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
317986	30602726	In this Review, we discuss the state of the field investigating epigenetic dysregulation in cancer and highlight the range of current and emerging opportunities for clinical development.	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('epigenetic dysregulation', 'Var', (64, 88))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
317994	30602726	Additionally, regions with highly methylated CpG density have been shown to be associated with high nucleosome occupancy in facultative and constitutive heterochromatin.	('highly methylated', 'Var', (27, 44))	('methyl', 'Chemical', 'MESH:C031105', (34, 40))	('high nucleosome occupancy', 'MPA', (95, 120))
317997	30602726	Early studies have established global levels of hypomethylation with focal hypermethylation of promoters and enhancers as a common feature among several cancers (Fig.	('focal hypermethylation', 'Var', (69, 91))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('methyl', 'Chemical', 'MESH:C031105', (80, 86))	('cancers', 'Disease', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('hypomethylation', 'MPA', (48, 63))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('methyl', 'Chemical', 'MESH:C031105', (52, 58))
318003	30602726	DNMT3A mutations, including those found in the hotspot catalytic domain, are present in ~25% of adult acute myeloid leukaemia (AML) cases, pointing to DNMT3A as an important tumour suppressor (Fig.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (102, 125))	('myeloid leukaemia', 'Disease', 'MESH:D007951', (108, 125))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (108, 125))	('DNMT3A', 'Gene', (151, 157))	('tumour', 'Disease', (174, 180))	('myeloid leukaemia', 'Disease', (108, 125))	('DNMT3A', 'Gene', '1788', (151, 157))	('DNMT3A', 'Gene', (0, 6))	('DNMT3A', 'Gene', '1788', (0, 6))	('AML', 'Phenotype', 'HP:0004808', (127, 130))	('mutations', 'Var', (7, 16))
318006	30602726	Intriguingly, DNMT3A cancer-associated somatic missense mutations of the substrate-binding domain decrease in vitro methyltransferase activity, thereby inducing CpG hypomethylation.	('CpG hypomethylation', 'MPA', (161, 180))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('missense mutations', 'Var', (47, 65))	('decrease', 'NegReg', (98, 106))	('vitro', 'MPA', (110, 115))	('methyl', 'Chemical', 'MESH:C031105', (169, 175))	('methyl', 'Chemical', 'MESH:C031105', (116, 122))	('methyltransferase', 'Enzyme', (116, 133))	('inducing', 'Reg', (152, 160))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('activity', 'MPA', (134, 142))	('DNMT3A', 'Gene', (14, 20))	('DNMT3A', 'Gene', '1788', (14, 20))
318009	30602726	The fact that ~7-10% of all patients with AML harbour deletion or truncating mutations in TET genes highlights the importance of characterizing bidirectional implications of epigenetic modifications in cancer.	('AML', 'Phenotype', 'HP:0004808', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('deletion', 'Var', (54, 62))	('TET genes', 'Gene', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('truncating mutations', 'Var', (66, 86))	('patients', 'Species', '9606', (28, 36))
318018	30602726	Over 150 histone-modifying proteins have been identified and their dysregulation can result in the inappropriate activation of oncogenes or, conversely, the inactivation of tumour suppressors.	('dysregulation', 'Var', (67, 80))	('tumour', 'Disease', (173, 179))	('activation', 'PosReg', (113, 123))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('oncogenes', 'Protein', (127, 136))	('histone-modifying', 'Protein', (9, 26))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('inactivation', 'NegReg', (157, 169))
318028	30602726	PRC2 catalyses the monomethylation, dimethylation and trimethylation of histone H3 (that is, H3K27me, H3K27me2 and H3K27me3, respectively) and is canonically associated with long-term transcriptional silencing through deposition of the H3K27me3 mark.	('H3K27me3', 'Var', (115, 123))	('trimethylation', 'MPA', (54, 68))	('associated', 'Reg', (158, 168))	('histone H3', 'Protein', (72, 82))	('monomethylation', 'MPA', (19, 34))	('methyl', 'Chemical', 'MESH:C031105', (38, 44))	('H3K27me2', 'Chemical', 'MESH:C024755', (102, 110))	('H3K27me', 'Var', (93, 100))	('H3K27me3', 'Var', (236, 244))	('H3K27me2', 'Var', (102, 110))	('methyl', 'Chemical', 'MESH:C031105', (57, 63))	('methyl', 'Chemical', 'MESH:C031105', (23, 29))	('dimethylation', 'MPA', (36, 49))	('PRC2', 'Gene', (0, 4))
318031	30602726	Given that Polycomb can repress both oncogenes and tumour suppressors, misregulation of either gene class could promote oncogenesis in a context-specific manner.	('promote', 'PosReg', (112, 119))	('oncogenesis', 'CPA', (120, 131))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('oncogenes', 'Protein', (37, 46))	('misregulation', 'Var', (71, 84))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))
318032	30602726	Loss-of-function mutations of genes encoding PRC2 subunits have been identified in leukaemia, myeloid disorders and malignant peripheral nerve sheath tumours.	('Loss-of-function', 'NegReg', (0, 16))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('malignant peripheral nerve sheath tumours', 'Disease', (116, 157))	('malignant peripheral nerve', 'Phenotype', 'HP:0100697', (116, 142))	('leukaemia, myeloid disorders', 'Disease', 'MESH:D007951', (83, 111))	('malignant peripheral nerve sheath tumours', 'Disease', 'MESH:D009442', (116, 157))	('mutations', 'Var', (17, 26))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('PRC2', 'Gene', (45, 49))
318033	30602726	Conversely, EZH2 upregulation has also been implicated in various cancers, including melanoma and breast cancers, and gain-of-function mutations in the SET domain of EZH2 have been identified in diffuse large B cell lymphoma.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (209, 224))	('cancers', 'Disease', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('melanoma and breast cancers', 'Disease', 'MESH:D001943', (85, 112))	('B cell lymphoma', 'Disease', (209, 224))	('mutations', 'Var', (135, 144))	('breast cancers', 'Phenotype', 'HP:0003002', (98, 112))	('EZH2', 'Gene', (166, 170))	('large B cell', 'Phenotype', 'HP:0005404', (203, 215))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('B cell lymphoma', 'Disease', 'MESH:D016393', (209, 224))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('upregulation', 'PosReg', (17, 29))	('gain-of-function', 'PosReg', (118, 134))	('EZH2', 'Gene', (12, 16))
318034	30602726	The EED subunit of PRC2 forms an aromatic cage around the H3K27me3 (or Jumonji/ARID domain-containing protein 2 (JARID2)-K116me3) mark, which allosterically activates EZH2.	('aromatic cage', 'MPA', (33, 46))	('JARID2', 'Gene', (113, 119))	('EED', 'Gene', '8726', (4, 7))	('Jumonji/ARID domain-containing protein 2', 'Gene', '3720', (71, 111))	('Jumonji/ARID domain-containing protein 2', 'Gene', (71, 111))	('JARID2', 'Gene', '3720', (113, 119))	('PRC2', 'Gene', (19, 23))	('EED', 'Gene', (4, 7))	('activates', 'PosReg', (157, 166))	('H3K27me3', 'Var', (58, 66))
318035	30602726	Mutations in this recognition site are implicated in cancer and Weaver's syndrome and have been shown to impart deficient allosteric activation profiles.	('deficient', 'NegReg', (112, 121))	('implicated', 'Reg', (39, 49))	('cancer', 'Disease', (53, 59))	('allosteric activation profiles', 'MPA', (122, 152))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Mutations', 'Var', (0, 9))	("Weaver's syndrome", 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	("Weaver's syndrome", 'Disease', 'MESH:C536687', (64, 81))
318036	30602726	Remarkably, although mutants were deficient in activating genome-wide H2K27me3 deposition, no significant changes were observed in their genomic localization profiles, and allosteric activation of the hyperactive Y646N mutation present in diffuse large B cell lymphoma could be selectively inhibited.	('activating genome-wide', 'MPA', (47, 69))	('B cell lymphoma', 'Disease', 'MESH:D016393', (253, 268))	('B cell lymphoma', 'Disease', (253, 268))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (253, 268))	('allosteric activation', 'MPA', (172, 193))	('Y646N', 'Mutation', 'rs267601395', (213, 218))	('large B cell', 'Phenotype', 'HP:0005404', (247, 259))	('Y646N', 'Var', (213, 218))	('lymphoma', 'Phenotype', 'HP:0002665', (260, 268))	('hyperactive', 'Disease', 'MESH:D006948', (201, 212))	('hyperactive', 'Disease', (201, 212))	('H2K27me3', 'Protein', (70, 78))
318039	30602726	PRC1 complexes contain a RING1 E3 ubiquitin ligase (RING1A/B), which catalyses the monoubiquitylation of histone H2A (that is, H2AK119Ub) and PcG RING finger proteins (PCGF1-6), which dictates downstream PRC1 subunit associations and thereby differential genome-wide localization of complexes.	('H2A', 'Chemical', 'MESH:D006859', (127, 130))	('PRC1', 'Gene', (0, 4))	('RING1', 'Gene', '6015', (52, 57))	('PRC1', 'Gene', '9055', (0, 4))	('associations', 'Interaction', (217, 229))	('RING1', 'Gene', '6015', (25, 30))	('H2AK119Ub', 'Var', (127, 136))	('PRC1', 'Gene', (204, 208))	('dictates', 'Reg', (184, 192))	('PRC1', 'Gene', '9055', (204, 208))	('monoubiquitylation', 'MPA', (83, 101))	('RING1', 'Gene', (52, 57))	('E3 ubiquitin ligase', 'Protein', (31, 50))	('RING1', 'Gene', (25, 30))	('H2A', 'Chemical', 'MESH:D006859', (113, 116))
318040	30602726	Additional subcomplex-specific subunits include chromobox proteins, which bind to methylated histones, including PRC2-deposited H3K27 methylation, to promote gene silencing.	('promote', 'PosReg', (150, 157))	('methylation', 'Var', (134, 145))	('H3K27', 'Protein', (128, 133))	('methyl', 'Chemical', 'MESH:C031105', (134, 140))	('methyl', 'Chemical', 'MESH:C031105', (82, 88))	('gene', 'MPA', (158, 162))
318042	30602726	Depletion of BMI1 reduces proliferation and results in apoptosis of epithelial and leukaemic cell lines, and in murine colorectal cancer xenograft models.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('murine', 'Species', '10090', (112, 118))	('colorectal cancer', 'Disease', (119, 136))	('BMI1', 'Gene', (13, 17))	('reduces', 'NegReg', (18, 25))	('results in', 'Reg', (44, 54))	('Depletion', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('apoptosis', 'CPA', (55, 64))
318047	30602726	The MLL gene encodes a histone methyltransferase, translocations of which are implicated in AML and acute lymphoid leukaemia with poor prognosis.	('methyl', 'Chemical', 'MESH:C031105', (31, 37))	('lymphoid leukaemia', 'Disease', 'MESH:D007945', (106, 124))	('MLL', 'Gene', (4, 7))	('MLL', 'Gene', '4297', (4, 7))	('lymphoid leukaemia', 'Phenotype', 'HP:0005526', (106, 124))	('translocations', 'Var', (50, 64))	('implicated', 'Reg', (78, 88))	('lymphoid leukaemia', 'Disease', (106, 124))	('AML', 'Phenotype', 'HP:0004808', (92, 95))	('AML', 'Disease', (92, 95))
318048	30602726	MLL maintains the expression of HOX genes during development, and thus, its rearrangement often upregulates this gene cluster, including HOXA9, which is necessary for leukaemic cell proliferation.	('HOXA9', 'Gene', '3205', (137, 142))	('HOX genes', 'Gene', (32, 41))	('MLL', 'Gene', '4297', (0, 3))	('HOXA9', 'Gene', (137, 142))	('MLL', 'Gene', (0, 3))	('rearrangement', 'Var', (76, 89))	('expression', 'MPA', (18, 28))	('upregulates', 'PosReg', (96, 107))
318053	30602726	3b), resulting in aberrant H3K79 methylation at MLL target genes, such as HOXA9 and MEIS1.	('aberrant', 'Var', (18, 26))	('MEIS1', 'Gene', '4211', (84, 89))	('methyl', 'Chemical', 'MESH:C031105', (33, 39))	('H3K79', 'Protein', (27, 32))	('MLL', 'Gene', (48, 51))	('HOXA9', 'Gene', '3205', (74, 79))	('MLL', 'Gene', '4297', (48, 51))	('methylation', 'MPA', (33, 44))	('HOXA9', 'Gene', (74, 79))	('MEIS1', 'Gene', (84, 89))
318058	30602726	Mutations in histone genes represent some of the most recently identified gene classes and have emerged through exome-wide sequencing of highly rare tumour types.	('histone genes', 'Gene', (13, 26))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('Mutations', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))
318059	30602726	Exome sequencing uncovered mutations in the genes encoding histone H3 variants (H3.1-H3.3) that convert lysine 27 to methionine (H3K27M) or glycine 34 to arginine or valine (H3G34R/V) in aggressive paediatric brain tumours (such as diffuse intrapontine glioma) (Fig.	('mutations', 'Var', (27, 36))	('glycine 34 to arginine or valine', 'Var', (140, 172))	('H3.1-H3.3', 'CellLine', 'CVCL:L520', (80, 89))	('tumours', 'Phenotype', 'HP:0002664', (215, 222))	('glycine 34 to arginine', 'Mutation', 'rs577158315', (140, 162))	('lysine', 'Var', (104, 110))	('glycine 34 to arginine or valine', 'SUBSTITUTION', 'None', (140, 172))	('aggressive paediatric brain tumours', 'Disease', 'MESH:D001927', (187, 222))	('brain tumours', 'Phenotype', 'HP:0030692', (209, 222))	('H3G34R/V', 'Var', (174, 182))	('aggressive paediatric brain tumours', 'Disease', (187, 222))	('glioma', 'Disease', (253, 259))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('convert', 'Reg', (96, 103))	('glioma', 'Disease', 'MESH:D005910', (253, 259))	('lysine 27 to methionine', 'Mutation', 'p.K27M', (104, 127))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))
318060	30602726	Moreover, specific mutations are found in tumours that arise in distinct brain regions, correlating with their distinct molecular characteristics.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (19, 28))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))
318061	30602726	Tumours harbouring the H3K27M mutation show dramatic reduction of H3K27me3 levels, suggesting that such mutants may dominantly inhibit normal lysine methylation pathways, such as those catalysed by PRC2 complexes.	('methyl', 'Chemical', 'MESH:C031105', (149, 155))	('lysine', 'Pathway', (142, 148))	('reduction', 'NegReg', (53, 62))	('H3K27M mutation', 'Var', (23, 38))	('inhibit', 'NegReg', (127, 134))	('H3K27me3 levels', 'MPA', (66, 81))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('lysine', 'Chemical', 'MESH:C114808', (142, 148))
318063	30602726	); however, others have found interaction with bromodomain-containing protein 4 (BRD4), consistent with increased histone acetylation levels observed in H3K27M mutant cells (Fig.	('bromodomain-containing protein 4', 'Gene', (47, 79))	('increased', 'PosReg', (104, 113))	('BRD4', 'Gene', (81, 85))	('mutant', 'Var', (160, 166))	('histone acetylation levels', 'MPA', (114, 140))	('interaction', 'Interaction', (30, 41))	('BRD4', 'Gene', '23476', (81, 85))	('H3K27M mutant', 'Var', (153, 166))	('bromodomain-containing protein 4', 'Gene', '23476', (47, 79))
318064	30602726	Sequencing of chondroblastoma and giant cell tumours of the bone have identified additional oncohistone mutations.	('mutations', 'Var', (104, 113))	('chondroblastoma', 'Phenotype', 'HP:0030432', (14, 29))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('chondroblastoma and giant cell tumours', 'Disease', 'MESH:D002804', (14, 52))	('oncohistone', 'Protein', (92, 103))
318065	30602726	Over 95% of chondroblastomas possess the histone H3.3 lysine 36 to methionine (H3.3K36M) mutation in the H3F3B gene, and about 92% of giant cell tumours of the bone harbour mutations of histone H3.3 glycine 34 to tryptophan or leucine (H3.3G34W/L) (Fig.	('glycine 34 to tryptophan or leucine', 'Var', (199, 234))	('H3F3B', 'Gene', (105, 110))	('chondroblastomas', 'Disease', 'MESH:D002804', (12, 28))	('histone H3.3', 'Gene', '3021', (186, 198))	('glycine 34 to tryptophan', 'Mutation', 'p.G34W', (199, 223))	('histone H3.3', 'Gene', (186, 198))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('mutations', 'Var', (173, 182))	('lysine 36 to methionine', 'Mutation', 'p.K36M', (54, 77))	('giant cell tumours', 'Disease', (134, 152))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('chondroblastoma', 'Phenotype', 'HP:0030432', (12, 27))	('histone H3.3', 'Gene', '3021', (41, 53))	('chondroblastomas', 'Disease', (12, 28))	('glycine 34 to tryptophan or leucine', 'SUBSTITUTION', 'None', (199, 234))	('H3F3B', 'Gene', '3021', (105, 110))	('histone H3.3', 'Gene', (41, 53))	('giant cell tumours', 'Disease', 'MESH:D005870', (134, 152))
318066	30602726	Similar to H3K27M, H3K36M reduces methylation of H3K36 by inhibiting the SETD2 and NSD2 methyltransferases (Fig.	('SETD2', 'Gene', (73, 78))	('NSD2', 'Gene', '7468', (83, 87))	('H3K36M', 'Var', (19, 25))	('methyl', 'Chemical', 'MESH:C031105', (88, 94))	('NSD2', 'Gene', (83, 87))	('inhibiting', 'NegReg', (58, 68))	('H3K36', 'Protein', (49, 54))	('reduces', 'NegReg', (26, 33))	('SETD2', 'Gene', '29072', (73, 78))	('methyl', 'Chemical', 'MESH:C031105', (34, 40))	('methylation', 'MPA', (34, 45))
318067	30602726	These findings extend to mutations in genes encoding histone H1 in follicular lymphoma, which are predominantly single amino acid missense mutations scattered throughout the globular H1 domain involved in chromatin compaction, and have been shown to result in reduced association of histone H1 with chromatin and DNMT3B.	('DNMT3B', 'Gene', (313, 319))	('mutations', 'Var', (25, 34))	('chromatin', 'Protein', (299, 308))	('histone H1', 'Gene', (53, 63))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('amino', 'Chemical', 'MESH:D000596', (119, 124))	('reduced', 'NegReg', (260, 267))	('association', 'Interaction', (268, 279))	('follicular lymphoma', 'Disease', 'MESH:D008224', (67, 86))	('DNMT3B', 'Gene', '1789', (313, 319))	('follicular lymphoma', 'Disease', (67, 86))	('histone H1', 'Protein', (283, 293))
318068	30602726	Taken together, recurrent driver mutations in histone-encoding genes have added a new layer to the mechanisms of chromatin disruption in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (137, 142))	('mutations', 'Var', (33, 42))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
318069	30602726	Moreover, results such as those in paediatric brain tumours have underscored the specific cellular, developmental, anatomical and chromatin architecture contexts required for the high penetrance of such mutations.	('brain tumours', 'Phenotype', 'HP:0030692', (46, 59))	('brain tumours', 'Disease', (46, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('brain tumours', 'Disease', 'MESH:D001932', (46, 59))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('mutations', 'Var', (203, 212))
318079	30602726	Exome-wide sequencing studies have revealed that > 20% of all cancers harbour mutations in mSWI/SNF-encoding genes, several of which are considered to be the key drivers of oncogenesis (Fig.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (78, 87))	('SNF', 'Gene', '31442', (96, 99))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('SNF', 'Gene', (96, 99))	('cancers', 'Disease', (62, 69))	('SWI', 'Gene', (92, 95))	('SWI', 'Gene', '31120', (92, 95))
318080	30602726	In particular, rare cancers, such as synovial sarcoma, malignant rhabdoid tumour (MRT), clear-cell meningioma and others, are known to be uniformly or near-uniformly caused by perturbations to mSWI/SNF complex subunit genes.	('clear-cell meningioma', 'Disease', (88, 109))	('meningioma', 'Phenotype', 'HP:0002858', (99, 109))	('MRT', 'Disease', 'MESH:D018335', (82, 85))	('SNF', 'Gene', (198, 201))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (37, 53))	('SWI', 'Gene', (194, 197))	('SWI', 'Gene', '31120', (194, 197))	('malignant rhabdoid tumour', 'Disease', (55, 80))	('malignant rhabdoid tumour', 'Disease', 'MESH:D018335', (55, 80))	('clear-cell meningioma', 'Disease', 'MESH:D008579', (88, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('caused', 'Reg', (166, 172))	('MRT', 'Disease', (82, 85))	('perturbations', 'Var', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('synovial sarcoma', 'Disease', (37, 53))	('SNF', 'Gene', '31442', (198, 201))	('synovial sarcoma', 'Disease', 'MESH:D013584', (37, 53))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))
318083	30602726	mSWI/SNF complexes were first linked to cancer through the identification of biallelic inactivation of the SMARCB1 gene, which encodes the BAF47 subunit, in ~98% of MRT.	('MRT', 'Disease', (165, 168))	('SMARCB1', 'Gene', (107, 114))	('SMARCB1', 'Gene', '6598', (107, 114))	('SNF', 'Gene', '31442', (5, 8))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('SNF', 'Gene', (5, 8))	('SWI', 'Gene', (1, 4))	('MRT', 'Disease', 'MESH:D018335', (165, 168))	('BAF47', 'Gene', '6598', (139, 144))	('SWI', 'Gene', '31120', (1, 4))	('biallelic inactivation', 'Var', (77, 99))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('BAF47', 'Gene', (139, 144))
318088	30602726	Gain-of-function perturbations of mSWI/SNF subunits have also been recently discovered (Fig.	('SWI', 'Gene', (35, 38))	('SNF', 'Gene', '31442', (39, 42))	('SWI', 'Gene', '31120', (35, 38))	('Gain-of-function', 'PosReg', (0, 16))	('SNF', 'Gene', (39, 42))	('perturbations', 'Var', (17, 30))
318091	30602726	Recent genome-wide studies defined the targeting profiles of the SS18-SSX-containing complexes, and showed that the SSX tail redirects BAF complexes to new genomic loci and, hence, target genes, at which antagonism of PRC2 facilitates transcriptional activation.	('SSX', 'Gene', (70, 73))	('facilitates', 'PosReg', (223, 234))	('SSX', 'Gene', '727837', (70, 73))	('BAF', 'Gene', '8815', (135, 138))	('SS18', 'Gene', '6760', (65, 69))	('SSX', 'Gene', (116, 119))	('PRC2', 'Gene', (218, 222))	('transcriptional activation', 'MPA', (235, 261))	('SSX', 'Gene', '727837', (116, 119))	('BAF', 'Gene', (135, 138))	('SS18', 'Gene', (65, 69))	('antagonism', 'Var', (204, 214))
318093	30602726	Nevertheless, the promising results from cell line and mouse models have prompted the evaluation of EZH2 inhibitors in clinical trials for mSWI/SNF-perturbed MRT and epithelioid sarcoma, with preliminary positive results.	('SWI', 'Gene', '31120', (140, 143))	('inhibitors', 'Var', (105, 115))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (166, 185))	('epithelioid sarcoma', 'Disease', (166, 185))	('EZH2', 'Gene', (100, 104))	('mouse', 'Species', '10090', (55, 60))	('MRT', 'Disease', 'MESH:D018335', (158, 161))	('SNF', 'Gene', '31442', (144, 147))	('MRT', 'Disease', (158, 161))	('SNF', 'Gene', (144, 147))	('SWI', 'Gene', (140, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
318096	30602726	Over the past decade, the field of chromatin regulation has made tremendous progress, ranging from understanding the basic chromatin-associated hallmarks of cancer to identifying the underlying genetic changes driving distinct, oncogenic gene expression programmes and promoting tumour development.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (144, 163))	('promoting', 'PosReg', (269, 278))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('changes', 'Var', (202, 209))	('hallmarks of cancer', 'Disease', (144, 163))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('tumour', 'Disease', (279, 285))
318119	30187231	reported that the immunohistochemical expression of MUC4 was seen in 78% of SEF and when coupled together with FUS gene, rearrangement was a sensitive and relatively specific marker for SEF while Arbajian et al.	('MUC4', 'Gene', '4585', (52, 56))	('FUS', 'Gene', (111, 114))	('MUC4', 'Gene', (52, 56))	('rearrangement', 'Var', (121, 134))	('FUS', 'Gene', '2521', (111, 114))	('SEF', 'Disease', (76, 79))
318120	30187231	found that EWSR1-CREB3L1 gene fusions were distinguishing features between SEF and the morphologically similar low-grade fibromyxoid sarcoma.	('EWSR1', 'Gene', (11, 16))	('fusions', 'Var', (30, 37))	('EWSR1', 'Gene', '2130', (11, 16))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (121, 140))	('fibromyxoid sarcoma', 'Disease', (121, 140))	('CREB3L1', 'Gene', '90993', (17, 24))	('CREB3L1', 'Gene', (17, 24))	('SEF', 'Disease', (75, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
318318	27785137	Such interventions may be associated with major perioperative blood loss, which in turn is associated with hospital mortality, especially in patients requiring additional lung resection.	('blood loss', 'Disease', (62, 72))	('patients', 'Species', '9606', (141, 149))	('interventions', 'Var', (5, 18))	('blood loss', 'Disease', 'MESH:D006473', (62, 72))	('associated', 'Reg', (91, 101))
318347	26366214	However, treatment of ESFT with IGF1R inhibitors has so far yielded less satisfactory results in clinical trials and attention is being given to inhibition of other pathway members as an alternative treatment strategy.	('IGF1R', 'Gene', '3480', (32, 37))	('inhibitors', 'Var', (38, 48))	('IGF1R', 'Gene', (32, 37))
318382	26366214	mTOR and Akt are part of one pathway that is activated subsequent to activation of IGFR and intracellular activation of PI3k.	('PI3k', 'Var', (120, 124))	('IGFR', 'Gene', (83, 87))	('Akt', 'Gene', (9, 12))	('IGFR', 'Gene', '3480', (83, 87))	('Akt', 'Gene', '207', (9, 12))	('mTOR', 'Gene', '2475', (0, 4))	('mTOR', 'Gene', (0, 4))	('activation', 'PosReg', (69, 79))
318393	26366214	Activation of YAP promotes cell proliferation and transformation and has been linked to tumor progression and worse survival in some malignancies.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cell proliferation', 'CPA', (27, 45))	('malignancies', 'Disease', (133, 145))	('YAP', 'Gene', (14, 17))	('linked to', 'Reg', (78, 87))	('promotes', 'PosReg', (18, 26))	('transformation', 'CPA', (50, 64))	('Activation', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('YAP', 'Gene', '10413', (14, 17))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))
318398	26366214	Cross-signaling exists between mTor, Akt and MAP/Erk pathways and inhibition of one pathway may still result in the maintenance of tumor growth via secondary mutations and activation of other pathways.	('Erk', 'Gene', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mTor', 'Gene', (31, 35))	('Akt', 'Gene', '207', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Erk', 'Gene', '5594', (49, 52))	('Akt', 'Gene', (37, 40))	('tumor', 'Disease', (131, 136))	('inhibition', 'Var', (66, 76))	('mTor', 'Gene', '2475', (31, 35))	('activation', 'PosReg', (172, 182))	('mutations', 'Var', (158, 167))
318484	23937858	This trial demonstrated a significantly prolonged primary endpoint of PFS (per independent review) for pazopanib compared with placebo (Hazard Ratio (HR): 0.35 [95% CI: 0.26 - 0.48]; p<0.001).	('pazopanib', 'Var', (103, 112))	('PFS', 'Disease', (70, 73))	('pazopanib', 'Chemical', 'MESH:C516667', (103, 112))
318505	23937858	In the Phase III PALETTE trial, pazopanib was associated with a higher proportion of patients discontinuing treatment due to AEs compared with placebo (Table 4).	('pazopanib', 'Chemical', 'MESH:C516667', (32, 41))	('AEs', 'Chemical', 'MESH:C045560', (125, 128))	('AEs', 'Disease', (125, 128))	('pazopanib', 'Var', (32, 41))	('patients', 'Species', '9606', (85, 93))
318524	23937858	Treatment with q3w 24-hour dosing schedule of trabectedin was associated with significantly greater median PFS and TTP compared with the qw 3-hour schedule, and the combination of gemcitabine and dacarbazine was more effective than dacarbazine monotherapy in terms of 3-month PFS rate, median PFS, and median OS.	('dacarbazine', 'Chemical', 'MESH:D003606', (232, 243))	('TTP', 'MPA', (115, 118))	('q3w 24-hour dosing', 'Var', (15, 33))	('trabectedin', 'Chemical', 'MESH:D000077606', (46, 57))	('PFS', 'MPA', (293, 296))	('PFS', 'MPA', (107, 110))	('dacarbazine', 'Chemical', 'MESH:D003606', (196, 207))	('trabectedin', 'Gene', (46, 57))	('gemcitabine', 'Chemical', 'MESH:C056507', (180, 191))	('PFS', 'MPA', (276, 279))	('greater', 'PosReg', (92, 99))
318603	30770526	Multivariate analysis identified age <20 years and surgical resection of the primary tumor to be significantly associated with improved OS.	('tumor', 'Disease', (85, 90))	('improved OS', 'Disease', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('OS', 'Chemical', '-', (136, 138))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('surgical resection', 'Var', (51, 69))
318623	30770526	The International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) was used to identify patients with ES (ICD-O-3 histologic type: 9260; ICD-O-3 site code: C40.0-40.3, C40.8-41.4, C41.8-41.9), using the case-listing procedure.	('C40.8-41.4', 'Var', (182, 192))	('patients', 'Species', '9606', (102, 110))	('Oncology', 'Phenotype', 'HP:0002664', (49, 57))	('C41.8-41.9', 'CellLine', 'CVCL:2253', (194, 204))	('C40.0-40.3', 'Var', (170, 180))
318667	30770526	Although the findings of the present study showed that tumor size was not associated with either OS or CSS, trends toward increased OS and CSS were observed for patients with tumor size <10 cm compared with patients with a tumor size >=10 cm.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('patients', 'Species', '9606', (207, 215))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('<10 cm', 'Var', (186, 192))	('CSS', 'Chemical', '-', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('OS', 'Chemical', '-', (132, 134))	('CSS', 'Chemical', '-', (139, 142))	('tumor', 'Disease', (55, 60))	('OS', 'Chemical', '-', (97, 99))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
318689	29218853	RNA-sequencing identifies novel GREB1-NCOA2 fusion gene in a uterine sarcoma with the chromosomal translocation t(2;8)(p25;q13) Sarcomas account for 3% of all uterine malignancies and many of them are characterized by acquired, specific fusion genes whose detection has increased pathogenetic knowledge and diagnostic precision.	('malignancies', 'Disease', 'MESH:D009369', (167, 179))	('GREB1', 'Gene', (32, 37))	('uterine malignancies', 'Phenotype', 'HP:0010784', (159, 179))	('Sarcomas', 'Disease', (128, 136))	('t(2;8)(p25;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 127))	('as a', 'Gene', (134, 138))	('sarcoma', 'Disease', (69, 76))	('as a', 'Gene', '11885', (134, 138))	('Sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('NCOA2', 'Gene', '10499', (38, 43))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (61, 76))	('malignancies', 'Disease', (167, 179))	('fusion gene', 'Var', (44, 55))	('GREB1', 'Gene', '9687', (32, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('NCOA2', 'Gene', (38, 43))	('Sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))
318693	29218853	The alteration and recombination of these genes played a role in the tumorigenesis and/or progression of this sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('sarcoma', 'Disease', (110, 117))	('tumor', 'Disease', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('played', 'Reg', (48, 54))	('alteration', 'Var', (4, 14))	('recombination', 'Var', (19, 32))	('progression', 'CPA', (90, 101))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
318696	29218853	In the present study, we report the molecular consequences of a translocation t(2;8)(p25;q13) identified in an undifferentiated uterine sarcoma.	('translocation t', 'Var', (64, 79))	('t(2;8)(p25;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (78, 93))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('ted ', 'Gene', (124, 128))	('ted ', 'Gene', '27112', (124, 128))	('sarcoma', 'Disease', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (128, 143))
318721	29218853	The cytogenetic investigation of the uterine sarcoma cells showed an abnormal karyotype described as 45,XX,t(2;8)(p25;q13),-8,inv(11)(p15q23),del(14)(q22q32),der(17)t(8;17)(q11;p13) [20] (Figure 2A).	('der(17)t(8;17)(q11;p13) [', 'Var', (158, 183))	('del(14)(q22q32', 'Var', (142, 156))	('sarcoma', 'Disease', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('der(17)t(8;17)(q11;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (158, 181))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (37, 52))	('45,XX,t(2;8)(p25;q13),-8', 'STRUCTURAL_ABNORMALITY', 'None', (101, 125))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('t(2;8)(p25;q13', 'Var', (107, 121))
318722	29218853	The FusionCatcher software, with the FASTQ files obtained from the Genomics Core Facility, Oslo University Hospital and University of Oslo (http://oslo.genomics.no/), was used to detect fusion transcripts in the lung metastasis (1999) of the uterine sarcoma.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (242, 257))	('sarcoma', 'Disease', 'MESH:D012509', (250, 257))	('lung metastasis', 'Disease', (212, 227))	('sarcoma', 'Disease', (250, 257))	('lung metastasis', 'Disease', 'MESH:D009362', (212, 227))	('fusion transcripts', 'Var', (186, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))
318728	29218853	The GREB1 and NCOA2 genes map to chromosomal bands 2p25 and 8q13, respectively, making it overwhelmingly likely that the fusion was brought about by the t(2;8)(p25;q13).	('t(2;8)(p25;q13', 'Var', (153, 167))	('NCOA2', 'Gene', '10499', (14, 19))	('GREB1', 'Gene', (4, 9))	('t(2;8)(p25;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (153, 168))	('NCOA2', 'Gene', (14, 19))
318731	29218853	To increase existing knowledge about fusion transcript(s) characteristic of uterine sarcomas in general and this undifferentiated uterine sarcoma in particular, we performed transcriptome sequencing on tumor RNA finding a novel GREB1-NCOA2 fusion gene corresponding to the t(2;8) detected by karyotyping.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (130, 145))	('ted ', 'Gene', '27112', (285, 289))	('NCOA2', 'Gene', '10499', (234, 239))	('tumor', 'Disease', (202, 207))	('ted ', 'Gene', (285, 289))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('ted ', 'Gene', '27112', (126, 130))	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('sarcoma', 'Disease', (84, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('sarcomas', 'Disease', (84, 92))	('ted ', 'Gene', (126, 130))	('sarcoma', 'Disease', (138, 145))	('NCOA2', 'Gene', (234, 239))	('fusion', 'Var', (240, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (76, 91))
318741	29218853	This is strong, albeit indirect, evidence that the translocation t(2;8)(p25;q13) generated the essential pathogenetic change in this sarcoma.	('ted ', 'Gene', (87, 91))	('t(2;8)(p25;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (65, 80))	('translocation t(2', 'Var', (51, 68))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('ted ', 'Gene', '27112', (87, 91))	('sarcoma', 'Disease', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
318743	29218853	Experience tells us that whenever one tumor with a seemingly unique tumor-associated translocation and corresponding fusion gene is reported, other examples of the same alteration eventually turn up.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (38, 43))	('ted ', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('ted ', 'Gene', '27112', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('fusion gene', 'Var', (117, 128))
318744	29218853	Also for this reason it is important that even single rare tumors with credible gene fusion candidates for a primary pathogenetic role are brought to the attention of the scientific community dealing with sarcoma classification and tumorigenesis.	('tumor', 'Disease', (59, 64))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('sarcoma', 'Disease', (205, 212))	('gene fusion', 'Var', (80, 91))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
318775	28706394	Approximately 62% of the patients with multiple osteochondromas have a positive family history, and/or mutation in one of the EXT (EXT1 and EXT2) genes can be detected.	('EXT1', 'Gene', (131, 135))	('osteochondromas', 'Phenotype', 'HP:0030431', (48, 63))	('EXT', 'Gene', (131, 134))	('EXT', 'Gene', '2132', (140, 143))	('EXT', 'Gene', '2132', (126, 129))	('EXT', 'Gene', (126, 129))	('osteochondroma', 'Phenotype', 'HP:0030431', (48, 62))	('EXT1', 'Gene', '2131', (131, 135))	('EXT2', 'Gene', (140, 144))	('multiple osteochondromas', 'Disease', 'MESH:D005097', (39, 63))	('multiple osteochondromas', 'Disease', (39, 63))	('patients', 'Species', '9606', (25, 33))	('EXT2', 'Gene', '2132', (140, 144))	('mutation', 'Var', (103, 111))	('EXT', 'Gene', (140, 143))	('EXT', 'Gene', '2132', (131, 134))
318782	28706394	In peripheral chondrosarcoma, EXT1 and/or EXT2 genes are affected on the genomic level, by mutation and/or deletions.	('affected', 'Reg', (57, 65))	('mutation', 'Var', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('peripheral chondrosarcoma', 'Disease', (3, 28))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (14, 28))	('EXT1', 'Gene', (30, 34))	('EXT2', 'Gene', (42, 46))	('deletions', 'Var', (107, 116))	('EXT1', 'Gene', '2131', (30, 34))	('EXT2', 'Gene', '2132', (42, 46))	('peripheral chondrosarcoma', 'Disease', 'MESH:D002813', (3, 28))
318794	28706394	In multiple osteochondromatosis and in peripheral chondrosarcomas, EXT1 and/or EXT2 genes undergo mutation and/or deletions leading to decreased expression.	('peripheral chondrosarcomas', 'Disease', 'MESH:D002813', (39, 65))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (50, 64))	('EXT1', 'Gene', (67, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('multiple osteochondromatosis', 'Phenotype', 'HP:0005701', (3, 31))	('expression', 'MPA', (145, 155))	('multiple osteochondromatosis', 'Disease', 'MESH:D005097', (3, 31))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (50, 65))	('EXT1', 'Gene', '2131', (67, 71))	('EXT2', 'Gene', '2132', (79, 83))	('decreased', 'NegReg', (135, 144))	('EXT2', 'Gene', (79, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('peripheral chondrosarcomas', 'Disease', (39, 65))	('osteochondroma', 'Phenotype', 'HP:0030431', (12, 26))	('multiple osteochondromatosis', 'Disease', (3, 31))	('deletions', 'Var', (114, 123))
318796	28706394	Mutations and/or deletions of EXT1 and/or EXT2 lead to aberrant heparan sulfate proteoglycans (HSPG) synthesis.	('lead to', 'Reg', (47, 54))	('deletions', 'Var', (17, 26))	('Mutations', 'Var', (0, 9))	('EXT1', 'Gene', (30, 34))	('EXT2', 'Gene', (42, 46))	('EXT1', 'Gene', '2131', (30, 34))	('EXT2', 'Gene', '2132', (42, 46))
318960	23372913	For experimental biological agents, an mTOR (mammalian target of rapamycin) inhibitor caused KS regression and sustained response in a HIV-negative patient.	('sustained response', 'CPA', (111, 129))	('men', 'Species', '9606', (10, 13))	('KS regression', 'CPA', (93, 106))	('mammalian target of rapamycin', 'Gene', '2475', (45, 74))	('mammalian target of rapamycin', 'Gene', (45, 74))	('inhibitor', 'Var', (76, 85))	('mTOR', 'Gene', (39, 43))	('mTOR', 'Gene', '2475', (39, 43))	('KS', 'Phenotype', 'HP:0100726', (93, 95))	('patient', 'Species', '9606', (148, 155))
319076	31692518	Furthermore, CT03338959 is a Phase 1/2 study performed in patients with intermediate- or high-grade STS.	('CT03338959', 'Var', (13, 23))	('STS', 'Disease', 'MESH:D012509', (100, 103))	('STS', 'Phenotype', 'HP:0030448', (100, 103))	('patients', 'Species', '9606', (58, 66))	('STS', 'Disease', (100, 103))
319079	31692518	Similar to NCT03307616, NCT03116529 is a Phase 1/2 study conducted in patients with high-risk STS and the purpose is to estimate the efficacy of radiotherapy plus duvalumab and tremelimumab before operation.	('patients', 'Species', '9606', (70, 78))	('STS', 'Disease', (94, 97))	('NCT03116529', 'Var', (24, 35))	('STS', 'Disease', 'MESH:D012509', (94, 97))	('NCT03307616', 'Chemical', 'MESH:C079985', (11, 22))	('STS', 'Phenotype', 'HP:0030448', (94, 97))
319124	31692518	One study revealed the deletion mutation of a mismatch repair (MMR) gene that might be one cause of the good clinical efficacy of PD-1 blockade in alveolar soft part sarcoma.	('alveolar soft part sarcoma', 'Disease', (147, 173))	('PD-1', 'Gene', (130, 134))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (147, 173))	('PD-1', 'Gene', '5133', (130, 134))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (156, 173))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (147, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('deletion mutation', 'Var', (23, 40))	('MMR', 'Gene', (63, 66))
319132	31692518	As immunological checkpoints are non-redundant and could inhibit T cell activation, proliferation, and effector function within lymph nodes and/or the tumor microenvironment, PD-1 signal pathway blockade combined with other immunomodulatory agents might produce greater antitumor activity than PD-1 blockade alone.	('PD-1', 'Gene', '5133', (294, 298))	('T cell activation', 'CPA', (65, 82))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PD-1', 'Gene', (175, 179))	('PD-1', 'Gene', '5133', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', (151, 156))	('inhibit', 'NegReg', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('blockade', 'Var', (195, 203))	('proliferation', 'CPA', (84, 97))	('effector function', 'CPA', (103, 120))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('PD-1', 'Gene', (294, 298))
319141	31692518	In STS, intratumor infiltration of PD-1-positive lymphocytes and PD-L1 expression was observed in 65% and 58% of the cases, respectively, and multivariate analysis indicated that both PD-1 positivity and PD-L1 positivity were independent prognostic indicators of overall survival and event-free survival.	('STS', 'Disease', (3, 6))	('tumor', 'Disease', (13, 18))	('PD-L1', 'Gene', '29126', (204, 209))	('STS', 'Disease', 'MESH:D012509', (3, 6))	('positivity', 'Var', (210, 220))	('positivity', 'Var', (189, 199))	('PD-L1', 'Gene', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('overall survival', 'CPA', (263, 279))	('PD-1', 'Gene', (184, 188))	('STS', 'Phenotype', 'HP:0030448', (3, 6))	('PD-1', 'Gene', '5133', (184, 188))	('PD-1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PD-1', 'Gene', '5133', (35, 39))	('PD-L1', 'Gene', '29126', (65, 70))	('PD-L1', 'Gene', (204, 209))
319147	31692518	PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from the immune system, indicating that total PD-L1 expression in the tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with PD-L1 expression on tumor cells alone.	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('PD-L1', 'Gene', '29126', (0, 5))	('expression', 'Var', (6, 16))	('PD-1', 'Gene', (247, 251))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (27, 32))	('PD-L1', 'Gene', (133, 138))	('PD-1', 'Gene', '5133', (247, 251))	('PD-L1', 'Gene', '29126', (133, 138))	('lead to', 'Reg', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PD-L1', 'Gene', (252, 257))	('tumor', 'Disease', (310, 315))	('PD-L1', 'Gene', '29126', (252, 257))	('tumor', 'Disease', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('PD-L1', 'Gene', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('PD-L1', 'Gene', '29126', (290, 295))
319149	31692518	High TMB predicts a better response to PD-1 blockade and may induce the formation of tumor-specific neoantigens, which could trigger a more robust immune response driven by TILs.	('PD-1', 'Gene', (39, 43))	('tumor', 'Disease', (85, 90))	('better', 'PosReg', (20, 26))	('PD-1', 'Gene', '5133', (39, 43))	('High TMB', 'Var', (0, 8))	('formation', 'MPA', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('response', 'MPA', (27, 35))	('induce', 'Reg', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('trigger', 'Reg', (125, 132))
319154	31692518	High MSI and deletion mutation of MMR genes are present in a subset of tumors and appear to be biomarkers that predict response to PD-1 blockade therapy.	('MSI', 'Disease', 'MESH:D053842', (5, 8))	('MSI', 'Disease', (5, 8))	('deletion mutation', 'Var', (13, 30))	('PD-1', 'Gene', '5133', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('MMR', 'Gene', (34, 37))	('PD-1', 'Gene', (131, 135))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
319156	31692518	In addition, it was reported that deletion mutation of MMR genes correlates with PD-L1 overexpression.	('MMR genes', 'Gene', (55, 64))	('deletion mutation', 'Var', (34, 51))	('PD-L1', 'Gene', (81, 86))	('correlates', 'Reg', (65, 75))	('PD-L1', 'Gene', '29126', (81, 86))
319166	24714847	Molecular strategies for detecting chromosomal translocations in soft tissue tumors (Review) Approximately one third of soft tissue tumors are characterized by chromosomal aberrations, in particular, translocations and amplifications, which appear to be highly specific.	('soft tissue tumors', 'Disease', (65, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('characterized by', 'Reg', (143, 159))	('translocations', 'Var', (200, 214))	('soft tissue tumors', 'Disease', 'MESH:D012983', (65, 83))	('amplifications', 'Var', (219, 233))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (65, 83))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('soft tissue tumors', 'Disease', (120, 138))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('soft tissue tumors', 'Disease', 'MESH:D012983', (120, 138))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (120, 138))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (160, 183))
319167	24714847	In this review, various molecular techniques that allow the identification of translocations and consequent fusion transcripts generated are discussed in the broad spectrum of soft tissue tumors.	('soft tissue tumors', 'Disease', 'MESH:D012983', (176, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (176, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('translocations', 'Var', (78, 92))	('soft tissue tumors', 'Disease', (176, 194))
319184	24714847	The non-random reciprocal translocation t(12;16)(q13;p11) is a characteristic of MLS.	('t(12;16)(q13;p11', 'Var', (40, 56))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (40, 57))	('MLS', 'Disease', 'MESH:C537466', (81, 84))	('MLS', 'Disease', (81, 84))	('MLS', 'Phenotype', 'HP:0012268', (81, 84))
319187	24714847	Using Southern blot techniques, in samples with cytogenetic rearrangements in the region 12q13, it has been shown that CHOP/DDIT3 t(12;16)(q13;p11) is the gene involved in translocation.	('CHOP', 'Gene', '1649', (119, 123))	('rearrangements', 'Var', (60, 74))	('DDIT3', 'Gene', (124, 129))	('DDIT3', 'Gene', '1649', (124, 129))	('CHOP', 'Gene', (119, 123))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (130, 147))
319196	24714847	FISH is an excellent method for detecting the presence of gene rearrangements in CHOP, but RT-PCR is the only method able to detect fusion partners, FUS or EWS.	('FUS', 'Gene', '2521', (149, 152))	('gene rearrangements', 'Var', (58, 77))	('CHOP', 'Gene', '1649', (81, 85))	('EWS', 'Gene', '2130', (156, 159))	('EWS', 'Gene', (156, 159))	('CHOP', 'Gene', (81, 85))	('FUS', 'Gene', (149, 152))
319215	24714847	The same methodology has allowed to identify additional variants of chimeric transcript, such as the one due to fusion at the level of exon 2 of PDGFB with COL1A1 gene but at the level of exon 41.	('due to', 'Reg', (105, 111))	('PDGFB', 'Gene', (145, 150))	('COL1A1', 'Gene', (156, 162))	('COL1A1', 'Gene', '1277', (156, 162))	('PDGFB', 'Gene', '5155', (145, 150))	('fusion', 'Var', (112, 118))
319221	24714847	Two chromosomal translocations, t(2;13)(q35;q14) and t(1;13)(p36;q14), are present in approximately 80% of all alveolar rhabdomyosarcoma cases.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (120, 136))	('alveolar rhabdomyosarcoma', 'Disease', (111, 136))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (111, 136))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (32, 48))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (111, 136))	('t(2;13)(q35;q14', 'Var', (32, 47))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 69))	('t(1;13)(p36;q14', 'Var', (53, 68))
319225	24714847	Studies on cDNA cloning and sequencing have shown that t(2;13)(q35;q14) produces a fusion transcript between the paired box 3 (PAX3) gene and FKHR gene, respectively; the PAX7-FKHR fusion transcript results from the t(1;13) translocation.	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (55, 71))	('FKHR', 'Gene', (142, 146))	('FKHR', 'Gene', (176, 180))	('PAX7', 'Gene', (171, 175))	('PAX3', 'Gene', '5077', (127, 131))	('paired box 3', 'Gene', (113, 125))	('FKHR', 'Gene', '2308', (142, 146))	('PAX3', 'Gene', (127, 131))	('FKHR', 'Gene', '2308', (176, 180))	('t(2;13)(q35;q14', 'Var', (55, 70))	('paired box 3', 'Gene', '5077', (113, 125))	('PAX7', 'Gene', '5081', (171, 175))
319252	24714847	Less commonly, CCS can be marked by t(2;22)(q34;q12), which produces the fusion transcript, EWSR1/CREB1, typical of gastrointestinal CCS, but that can also characterize CCS of soft tissue.	('gastrointestinal CCS', 'Disease', (116, 136))	('EWSR1', 'Gene', '2130', (92, 97))	('CREB1', 'Gene', '1385', (98, 103))	('t(2;22)(q34;q12', 'Var', (36, 51))	('gastrointestinal CCS', 'Disease', 'MESH:D005767', (116, 136))	('EWSR1', 'Gene', (92, 97))	('t(2;22)(q34;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (36, 52))	('CREB1', 'Gene', (98, 103))	('CCS', 'Disease', (169, 172))
319258	24714847	In addition to these four main transcripts, which may also occur together, there can be out-of-frame fusion between exon 10 of EWS and 3 of ATF1, or between exon 8 of EWS and 4 of ATF1, with insertion of nucleotides at the junction point.	('fusion', 'Var', (101, 107))	('ATF1', 'Gene', (140, 144))	('ATF1', 'Gene', '466', (140, 144))	('ATF1', 'Gene', (180, 184))	('ATF1', 'Gene', '466', (180, 184))	('EWS', 'Gene', '2130', (167, 170))	('EWS', 'Gene', (167, 170))	('EWS', 'Gene', '2130', (127, 130))	('EWS', 'Gene', (127, 130))
319266	24714847	Studies using Southern blot analysis, multi-enzymatic digestion and northern blot analysis have demonstrated that gene rearrangement in the region 22q12 produces the fusion of the EWS gene on 11p13 with WT1, the gene involved in Wilms tumor.	('p13', 'Gene', '440926', (194, 197))	('Wilms tumor', 'Disease', 'MESH:D009396', (229, 240))	('Wilms tumor', 'Phenotype', 'HP:0002667', (229, 240))	('EWS', 'Gene', '2130', (180, 183))	('EWS', 'Gene', (180, 183))	('WT1', 'Gene', '7490', (203, 206))	('Wilms tumor', 'Disease', (229, 240))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('WT1', 'Gene', (203, 206))	('p13', 'Gene', (194, 197))	('gene rearrangement', 'Var', (114, 132))	('fusion', 'Var', (166, 172))
319269	24714847	Chromosomal translocation and fusion with EWS affect two independent biochemical functions of WT1, binding activity to DNA and transcriptional regulation, a deregulation that influences tumorigenesis in intra-abdominal DSRCT.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('Chromosomal translocation', 'Var', (0, 25))	('tumor', 'Disease', (186, 191))	('affect', 'Reg', (46, 52))	('WT1', 'Gene', '7490', (94, 97))	('transcriptional regulation', 'MPA', (127, 153))	('WT1', 'Gene', (94, 97))	('DNA', 'Protein', (119, 122))	('influences', 'Reg', (175, 185))	('binding', 'Interaction', (99, 106))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
319270	24714847	The variability in the breakpoint EWS produces molecular variants of the fusion gene EWS-WT1, as happens for the chimeric gene EWS-FLI1 in ES, such as an in-frame splicing of exon 9 of EWS to exon 8 of WT1, a variant found in a DSRCT unusually arising on hand, or an in-frame junction of EWS to exons 8-10 of WT1.	('WT1', 'Gene', (202, 205))	('EWS', 'Gene', (288, 291))	('ES', 'Gene', '2130', (139, 141))	('EWS-WT1', 'Gene', '7490', (85, 92))	('EWS', 'Gene', '2130', (85, 88))	('EWS-FLI1', 'Gene', '2130;2313', (127, 135))	('EWS', 'Gene', (34, 37))	('EWS', 'Gene', (185, 188))	('WT1', 'Gene', (89, 92))	('WT1', 'Gene', '7490', (202, 205))	('variants', 'Var', (57, 65))	('EWS', 'Gene', (127, 130))	('WT1', 'Gene', '7490', (89, 92))	('EWS', 'Gene', '2130', (288, 291))	('WT1', 'Gene', (309, 312))	('EWS', 'Gene', (85, 88))	('EWS', 'Gene', '2130', (34, 37))	('EWS-WT1', 'Gene', (85, 92))	('EWS', 'Gene', '2130', (185, 188))	('WT1', 'Gene', '7490', (309, 312))	('EWS-FLI1', 'Gene', (127, 135))	('ES', 'Phenotype', 'HP:0012254', (139, 141))	('EWS', 'Gene', '2130', (127, 130))
319272	24714847	RT-PCR can detect all chimeric messages that are formed by fusion between exons 1-7 of EWS and exons 8-10 of WT1.	('WT1', 'Gene', '7490', (109, 112))	('WT1', 'Gene', (109, 112))	('EWS', 'Gene', '2130', (87, 90))	('EWS', 'Gene', (87, 90))	('chimeric', 'Var', (22, 30))
319273	24714847	It is produced by large internal deletions, insertions of small parts of heterologous DNA at the site of the junction between the two exons EWS and WT1, or the loss of exon 6 of EWS or exon 9 of WT1.	('WT1', 'Gene', '7490', (195, 198))	('loss', 'NegReg', (160, 164))	('WT1', 'Gene', (195, 198))	('WT1', 'Gene', '7490', (148, 151))	('EWS', 'Gene', '2130', (178, 181))	('EWS', 'Gene', (178, 181))	('internal deletions', 'Var', (24, 42))	('EWS', 'Gene', (140, 143))	('EWS', 'Gene', '2130', (140, 143))	('insertions', 'Var', (44, 54))	('WT1', 'Gene', (148, 151))
319279	24714847	Approximately half of inflammatory myofibroblastic tumors present rearrangements of the locus of the anaplastic lymphoma kinase (ALK) gene on chromosome 2p23, resulting in the aberrant expression of ALK.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (101, 120))	('ALK', 'Gene', '238', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ALK', 'Gene', (129, 132))	('expression', 'MPA', (185, 195))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (22, 57))	('rearrangements', 'Var', (66, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('ALK', 'Gene', (199, 202))	('anaplastic lymphoma kinase', 'Gene', '238', (101, 127))	('p23', 'Gene', (154, 157))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('inflammatory myofibroblastic tumors', 'Disease', (22, 57))	('ALK', 'Gene', '238', (129, 132))	('p23', 'Gene', '10728', (154, 157))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (35, 56))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (35, 57))	('anaplastic lymphoma kinase', 'Gene', (101, 127))
319286	24714847	RT-PCR with specific pairs of primers and direct sequencing of the amplification products have also enabled the identification of new partners of ALK, such as dynactin-1, when the alteration der t(2;12)(p23;q11) is present, or when the SEC31L1/ALK fusion gene, due to translocation t(2;4)(p23;q21), is present in two variants of different lengths.	('t(2;4)(p23;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (282, 297))	('ALK', 'Gene', '238', (244, 247))	('ALK', 'Gene', '238', (146, 149))	('t(2;12)(p23;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (195, 211))	('SEC31L1', 'Gene', (236, 243))	('ALK', 'Gene', (244, 247))	('SEC31L1', 'Gene', '22872', (236, 243))	('alteration', 'Var', (180, 190))	('ALK', 'Gene', (146, 149))
319305	24714847	The translocation occurs due to different breakpoints in various introns of the gene, EWS and CHN (termed NR4A3, NOR1 or TEC), resulting in different variants of the chimeric products, EWS/CHN.	('NR4A3', 'Gene', (106, 111))	('EWS', 'Gene', '2130', (185, 188))	('EWS', 'Gene', (185, 188))	('variants', 'Var', (150, 158))	('NR4A3', 'Gene', '8013', (106, 111))	('TEC', 'Gene', '7006', (121, 124))	('CHN', 'Gene', (189, 192))	('CHN', 'Gene', (94, 97))	('CHN', 'Gene', '8013', (189, 192))	('NOR1', 'Gene', '8013', (113, 117))	('CHN', 'Gene', '8013', (94, 97))	('TEC', 'Gene', (121, 124))	('EWS', 'Gene', '2130', (86, 89))	('EWS', 'Gene', (86, 89))	('NOR1', 'Gene', (113, 117))
319308	24714847	The mapping of the different regions of breakpoints in the EWS and CHN genes has shown that there are no sequence-specific recombinases or homology to explain the various breakpoints, due to other associated events such as deletions, duplications and inversions.	('EWS', 'Gene', (59, 62))	('inversions', 'CPA', (251, 261))	('CHN', 'Gene', (67, 70))	('deletions', 'Var', (223, 232))	('duplications', 'Var', (234, 246))	('CHN', 'Gene', '8013', (67, 70))	('EWS', 'Gene', '2130', (59, 62))
319311	24714847	Variant translocations were also detected by interphase FISH, such as t(9;15)(q22;q21) and t(7;9;17)(q32;q22;q11), with satellite probes for chromosomes 7, 8 and 12, and telomeric probes for 1q and 19q (Vysis Inc.).	('t(9;15)(q22;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (70, 86))	('t(9;15)(q22;q21', 'Var', (70, 85))	('t(7;9;17)(q32;q22;q11', 'Var', (91, 112))
319320	24714847	FISH, in particular, has shown that an inversion of the ERG gene or part of it may be followed by an insertion in the EWS gene on der.	('inversion', 'Var', (39, 48))	('EWS', 'Gene', '2130', (118, 121))	('EWS', 'Gene', (118, 121))	('ERG', 'Gene', '2078', (56, 59))	('ERG', 'Gene', (56, 59))	('insertion', 'Var', (101, 110))
319327	24714847	It is possible to genotype the allelic discrimination for single nucleotide polymorphisms (SNPs) in the EWS gene using a TaqMan assay real-time-PCR.	('EWS', 'Gene', '2130', (104, 107))	('EWS', 'Gene', (104, 107))	('single nucleotide polymorphisms', 'Var', (58, 89))
319503	30613826	All EWS have a chromosomal translocation involving the EWSR1 gene on chromosome 11 band q12.2 or the related FUS gene (chromosome 16, band p11) and more than 85% of EWS exhibit the chromosomal translocation between chromosome 11 and 22 t(11; 22) (q24.3:q12.2) resulting fusion of ESWR1 gene with FLI1 gene (Friend leukaemia virus integration site).	('EWS', 'Gene', '2130', (165, 168))	('EWS', 'Gene', (165, 168))	('EWS', 'Gene', '2130', (55, 58))	('EWS', 'Gene', (55, 58))	('fusion', 'Var', (270, 276))	('Friend leukaemia virus', 'Disease', 'MESH:D007938', (307, 329))	('Friend leukaemia virus', 'Disease', (307, 329))	('FLI1', 'Gene', (296, 300))	('EWSR1', 'Gene', (55, 60))	('p11', 'Gene', '6281', (139, 142))	('FLI1', 'Gene', '2313', (296, 300))	('FUS', 'Gene', (109, 112))	('EWSR1', 'Gene', '2130', (55, 60))	('FUS', 'Gene', '2521', (109, 112))	('ESWR1 gene', 'Gene', (280, 290))	('EWS', 'Gene', '2130', (4, 7))	('EWS', 'Gene', (4, 7))	('p11', 'Gene', (139, 142))
319550	30613826	First, tumour-associated proteins can be useful in antibody-based diagnosis and LINGO-1 should be important to avoid mis-diagnosis in cases that present with unusual chromosomal translocations that are different from the more consistent translocation hallmarks such as the t (11;2).	('LINGO-1', 'Gene', '84894', (80, 87))	('chromosomal translocations', 'Var', (166, 192))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('LINGO-1', 'Gene', (80, 87))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Disease', (7, 13))
319581	29263653	Overactivity of PDGF/PDGFR is associated with many pathologic states including fibrotic and vascular diseases as well as cancer.	('associated', 'Reg', (30, 40))	('PDGFR', 'Gene', '5159', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('fibrotic', 'Disease', (79, 87))	('vascular diseases', 'Disease', (92, 109))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('vascular diseases', 'Disease', 'MESH:D000783', (92, 109))	('Overactivity', 'Var', (0, 12))	('cancer', 'Disease', (121, 127))	('PDGFR', 'Gene', (21, 26))
319583	29263653	Mutations and overexpression of PDGFR-alpha have been described in numerous malignancies, but the implications of these molecular abnormalities on treatment strategies are not well defined.	('numerous malignancies', 'Disease', 'MESH:D009369', (67, 88))	('PDGFR-alpha', 'Gene', (32, 43))	('numerous malignancies', 'Disease', (67, 88))	('described', 'Reg', (54, 63))	('Mutations', 'Var', (0, 9))	('PDGFR-alpha', 'Gene', '5156', (32, 43))	('overexpression', 'PosReg', (14, 28))
319592	29263653	Coexpression of PDGF and PDGFR-alpha in multiple cancer types as well as gene amplification and activation of PDGFR-alpha provides evidence for the presence of autocrine growth.	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PDGFR-alpha', 'Gene', '5156', (25, 36))	('gene amplification', 'Var', (73, 91))	('PDGFR-alpha', 'Gene', '5156', (110, 121))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('PDGFR-alpha', 'Gene', (25, 36))	('PDGF', 'Gene', (16, 20))	('PDGFR-alpha', 'Gene', (110, 121))	('activation', 'PosReg', (96, 106))
319594	29263653	A second study demonstrated that inducing the PDGF-CC ligand in melanoma cells led to activation of PDGFR-alpha on stromal fibroblasts causing increased tumor growth.	('increased', 'PosReg', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('activation', 'PosReg', (86, 96))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('PDGFR-alpha', 'Gene', '5156', (100, 111))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('PDGFR-alpha', 'Gene', (100, 111))	('inducing', 'Var', (33, 41))
319595	29263653	These findings provide additional rationale as to how disruption of the PDGF/PDGFR pathway may be a reasonable anti-cancer strategy.	('disruption', 'Var', (54, 64))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (116, 122))	('PDGFR', 'Gene', (77, 82))	('PDGFR', 'Gene', '5159', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
319604	29263653	The strongest inhibition was observed with olaratumab, 100% of Akt and 80% of MAPK.	('Akt', 'Gene', (63, 66))	('olaratumab', 'Chemical', 'MESH:C000589393', (43, 53))	('Akt', 'Gene', '207', (63, 66))	('olaratumab', 'Var', (43, 53))
319654	29263653	AEs were more common with combination treatment with increased rates of neutropenia (58% vs 35%), mucositis (53% vs 35%), nausea (73% vs 52%), vomiting (45% vs 18%), and diarrhea (34% vs 23%) compared to single-agent doxorubicin.	('neutropenia', 'Disease', (72, 83))	('AEs', 'Disease', (0, 3))	('nausea', 'Disease', 'MESH:D009325', (122, 128))	('vomiting', 'Phenotype', 'HP:0002013', (143, 151))	('mucositis', 'Disease', (98, 107))	('vomiting', 'Disease', (143, 151))	('vomiting', 'Disease', 'MESH:D014839', (143, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (217, 228))	('neutropenia', 'Disease', 'MESH:D009503', (72, 83))	('neutropenia', 'Phenotype', 'HP:0001875', (72, 83))	('diarrhea', 'Phenotype', 'HP:0002014', (170, 178))	('diarrhea', 'Disease', 'MESH:D003967', (170, 178))	('combination', 'Var', (26, 37))	('mucositis', 'Disease', 'MESH:D052016', (98, 107))	('diarrhea', 'Disease', (170, 178))	('nausea', 'Phenotype', 'HP:0002018', (122, 128))	('nausea', 'Disease', (122, 128))
319655	29263653	Infusion reactions, including two grade 4 events, occurred in 13% of patients treated with combination therapy and in none of the patients treated with doxorubicin alone (Table 2).	('doxorubicin', 'Chemical', 'MESH:D004317', (152, 163))	('Infusion reactions', 'MPA', (0, 18))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (69, 77))	('combination', 'Var', (91, 102))
319657	29263653	About 5%-10% of GISTs have a mutation in PDGFR-alpha.	('PDGFR-alpha', 'Gene', (41, 52))	('mutation', 'Var', (29, 37))	('GISTs', 'Phenotype', 'HP:0100723', (16, 21))	('PDGFR-alpha', 'Gene', '5156', (41, 52))
319661	29263653	Cohort 1 included seven patients with a D842V mutation in PDGFR-alpha.	('PDGFR-alpha', 'Gene', '5156', (58, 69))	('PDGFR-alpha', 'Gene', (58, 69))	('patients', 'Species', '9606', (24, 32))	('D842V', 'Mutation', 'rs121908585', (40, 45))	('D842V', 'Var', (40, 45))
319662	29263653	Cohort 2 included 14 patients without a PDGFR-alpha mutation, 11 with a KIT mutation, and 3 without mutations in KIT or PDGFR-alpha.	('PDGFR-alpha', 'Gene', '5156', (120, 131))	('PDGFR-alpha', 'Gene', (40, 51))	('PDGFR-alpha', 'Gene', (120, 131))	('patients', 'Species', '9606', (21, 29))	('mutation', 'Var', (52, 60))	('PDGFR-alpha', 'Gene', '5156', (40, 51))	('mutation', 'Var', (76, 84))
319666	29263653	This compared favorably to the largest historical series of PDGFR-alpha-mutant GIST patients reporting a median PFS of 2.8 months in patients with D842V mutation versus 28.5 months in patients with all other PDGFR-alpha mutations.	('PDGFR-alpha', 'Gene', '5156', (60, 71))	('D842V', 'Mutation', 'rs121908585', (147, 152))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (84, 92))	('PDGFR-alpha', 'Gene', (60, 71))	('PDGFR-alpha', 'Gene', (208, 219))	('patients', 'Species', '9606', (133, 141))	('D842V mutation', 'Var', (147, 161))	('PDGFR-alpha', 'Gene', '5156', (208, 219))
319667	29263653	Median OS was 14.7 months in D842V mutants and was not yet reached in all other PDGFR-alpha mutants.	('PDGFR-alpha', 'Gene', (80, 91))	('D842V', 'Var', (29, 34))	('D842V', 'Mutation', 'rs121908585', (29, 34))	('PDGFR-alpha', 'Gene', '5156', (80, 91))
319668	29263653	Compared to this historical data obtained in the setting of tyrosine kinase inhibitor treatment, olaratumab preliminarily has demonstrated increased efficacy in the D842V-mutant patients.	('olaratumab', 'Chemical', 'MESH:C000589393', (97, 107))	('patients', 'Species', '9606', (178, 186))	('increased', 'PosReg', (139, 148))	('D842V-mutant', 'Var', (165, 177))	('D842V', 'Mutation', 'rs121908585', (165, 170))
319689	29263653	While it has been hypothesized that olaratumab may alter the tumor stromal cell environment, and potentially increase the efficacy of subsequent treatments, there are a number of other potential explanations.	('olaratumab', 'Var', (36, 46))	('increase', 'PosReg', (109, 117))	('olaratumab', 'Chemical', 'MESH:C000589393', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('alter', 'Reg', (51, 56))	('tumor', 'Disease', (61, 66))
319692	29263653	Also, olaratumab may alter the tumor stromal cell environment, thus potentially increasing the efficacy of subsequent treatment.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('alter', 'Reg', (21, 26))	('olaratumab', 'Var', (6, 16))	('efficacy of subsequent treatment', 'CPA', (95, 127))	('olaratumab', 'Chemical', 'MESH:C000589393', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('increasing', 'PosReg', (80, 90))
319736	29038849	Presence of bimorphism (features suggesting a chondroid tumor adjacent to a markedly different area) should alert to a more aggressive high-grade or dedifferentiated chondrosarcoma.	('bimorphism', 'Var', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('chondrosarcoma', 'Disease', 'MESH:D002813', (166, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('chondrosarcoma', 'Disease', (166, 180))	('chondroid tumor', 'Phenotype', 'HP:0030431', (46, 61))	('chondroid tumor', 'Disease', (46, 61))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (166, 180))	('chondroid tumor', 'Disease', 'MESH:D008949', (46, 61))
319784	29038849	Isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations can be found in primary and secondary chondrosarcomas.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (91, 105))	('chondrosarcomas', 'Disease', (91, 106))	('IDH)-1', 'Gene', '3417', (26, 32))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (91, 106))	('mutations', 'Var', (43, 52))	('found', 'Reg', (60, 65))	('IDH-2', 'Gene', '3418', (37, 42))	('IDH-2', 'Gene', (37, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('chondrosarcomas', 'Disease', 'MESH:D002813', (91, 106))
319794	29038849	Histone-3-Family-Member-3A (H3F3A) mutation analysis appears to be a highly specific, although less sensitive, diagnostic tool for the distinction of GCTB from other giant cell-containing tumors.	('Histone-3-Family-Member-3A', 'Gene', '3020', (0, 26))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('H3F3A', 'Gene', '3020', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('GCTB', 'Phenotype', 'HP:0011847', (150, 154))	('H3F3A', 'Gene', (28, 33))	('mutation', 'Var', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Histone-3-Family-Member-3A', 'Gene', (0, 26))	('GCTB', 'Disease', (150, 154))
319812	29038849	There are several biomarkers that have been correlated to prognosis of high-grade osteosarcoma, such as P-glycoprotein, Her2, TP53 mutation and insulin-like growth factor-binding protein 3 (IGFBP-3), but none of them is prospectively validated and they are not routinely used in clinical practice.	('insulin-like growth factor-binding protein 3', 'Gene', (144, 188))	('TP53', 'Gene', (126, 130))	('P-glycoprotein', 'Gene', '5243', (104, 118))	('P-glycoprotein', 'Gene', (104, 118))	('IGFBP-3', 'Gene', '3486', (190, 197))	('osteosarcoma', 'Disease', 'MESH:D012516', (82, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Her2', 'Gene', (120, 124))	('insulin-like growth factor-binding protein 3', 'Gene', '3486', (144, 188))	('Her2', 'Gene', '2064', (120, 124))	('IGFBP-3', 'Gene', (190, 197))	('osteosarcoma', 'Phenotype', 'HP:0002669', (82, 94))	('TP53', 'Gene', '7157', (126, 130))	('osteosarcoma', 'Disease', (82, 94))	('mutation', 'Var', (131, 139))
319951	29038849	Recently, a driver mutation has associated GCTB with H3F3A in around 92% of cases.	('H3F3A', 'Gene', (53, 58))	('mutation', 'Var', (19, 27))	('GCTB', 'Phenotype', 'HP:0011847', (43, 47))	('associated', 'Reg', (32, 42))	('GCTB', 'Disease', (43, 47))	('H3F3A', 'Gene', '3020', (53, 58))
319989	29038849	Demonstration of Fused in Sarcoma (FUS) or Ewing Sarcoma RNA Binding Protein 1 (EWSR1) rearrangements can help support the diagnosis, as does the combination of Mucin 4 (MUC4) positivity and Special AT-rich sequence-binding protein 2 (SATB2) negativity by immunohistochemistry.	('Special AT-rich sequence-binding protein 2', 'Gene', '23314', (191, 233))	('Sarcoma (FUS) or Ewing Sarcoma', 'Disease', 'MESH:C563168', (26, 56))	('Mucin 4', 'Gene', (161, 168))	('Mucin 4', 'Gene', '4585', (161, 168))	('SATB2', 'Gene', (235, 240))	('Sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('rearrangements', 'Var', (87, 101))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('EWSR1', 'Gene', (80, 85))	('MUC4', 'Gene', '4585', (170, 174))	('SATB2', 'Gene', '23314', (235, 240))	('Special AT-rich sequence-binding protein 2', 'Gene', (191, 233))	('MUC4', 'Gene', (170, 174))	('Sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('EWSR1', 'Gene', '2130', (80, 85))
320036	22469025	Ligands group was defined as follows: i. KIRs 2DL1 and 2DS1 bind the C2 epitope (Asparagine at position 77, Lysine at position 80).	('Asparagine', 'Chemical', 'MESH:D001216', (81, 91))	('Asparagine at', 'Var', (81, 94))	('KIR', 'Gene', (41, 44))	('bind', 'Interaction', (60, 64))	('C2 epitope', 'Disease', 'OMIM:217000', (69, 79))	('C2 epitope', 'Disease', (69, 79))	('Lysine', 'Chemical', 'MESH:D008239', (108, 114))	('KIR', 'Gene', '3811', (41, 44))	('Lysine', 'MPA', (108, 114))
320050	22469025	Conversely, KIR3DS1+/Bw4*80I- frequency resulted still statistically higher in cKS than in controls (py = 0.006; OR:6.00), confirming that the KIR3DS1 positivity, but not the KIR/HLA receptor/ligand combination 3DS1/Bw4*80I, was associated to cKS.	('positivity', 'Var', (151, 161))	('cKS', 'Chemical', '-', (79, 82))	('KIR3DS1', 'Gene', '3813', (143, 150))	('KIR', 'Gene', '3811', (175, 178))	('KIR', 'Gene', '3811', (143, 146))	('Bw4', 'Gene', (216, 219))	('Bw4', 'Gene', '474272', (216, 219))	('KIR', 'Gene', (143, 146))	('KIR', 'Gene', (175, 178))	('KIR3DS1', 'Gene', '3813', (12, 19))	('associated', 'Reg', (229, 239))	('cKS', 'Chemical', '-', (243, 246))	('KIR', 'Gene', '3811', (12, 15))	('cKS', 'Disease', (243, 246))	('KIR3DS1', 'Gene', (143, 150))	('Bw4', 'Gene', (21, 24))	('KIR', 'Gene', (12, 15))	('Bw4', 'Gene', '474272', (21, 24))	('KIR3DS1', 'Gene', (12, 19))
320189	30105217	In the single prostate cancer study, increased pre- and post-RT viral load was associated with increased risk of biochemical failure, but decreased CD4 count was not.	('pre-', 'Var', (47, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (14, 29))	('CD4', 'Gene', (148, 151))	('biochemical', 'Disease', (113, 124))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('increased', 'PosReg', (37, 46))	('CD4', 'Gene', '920', (148, 151))	('prostate cancer', 'Disease', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
320233	29698475	In the non-canonical NF-kappaB pathway, p100 is processed to p52 upon phosphorylation by IKKalpha, which is activated by NF-kappaB inducing kinase (NIK), upon stimulation of receptors of the TNF superfamily including BAFF-R and lymphotoxin beta receptor (LTbetaR).	('p52', 'Gene', (61, 64))	('p52', 'Gene', '4791', (61, 64))	('BAFF-R', 'Gene', '115650', (217, 223))	('lymphotoxin beta receptor', 'Gene', '4055', (228, 253))	('TNF', 'Gene', '7124', (191, 194))	('TNF', 'Gene', (191, 194))	('lymphotoxin beta receptor', 'Gene', (228, 253))	('LTbetaR', 'Gene', '4055', (255, 262))	('p100', 'Var', (40, 44))	('BAFF-R', 'Gene', (217, 223))	('IKKalpha', 'Gene', '1147', (89, 97))	('IKKalpha', 'Gene', (89, 97))	('LTbetaR', 'Gene', (255, 262))
320243	29698475	Mutating the YGFL motif of vGPCR or disrupting the AP2 complex restricts vGPCR localization to the plasma membrane and leads to massive and chronic activation of NF-kappaB.	('Mutating', 'Var', (0, 8))	('NF-kappaB', 'Protein', (162, 171))	('AP2', 'Gene', (51, 54))	('vGPCR', 'Gene', (27, 32))	('activation', 'PosReg', (148, 158))	('AP2', 'Gene', '7020', (51, 54))	('restricts', 'NegReg', (63, 72))	('vGPCR', 'Gene', '4961465', (27, 32))	('vGPCR', 'Gene', (73, 78))	('vGPCR', 'Gene', '4961465', (73, 78))	('disrupting', 'Reg', (36, 46))	('localization to', 'MPA', (79, 94))
320281	29698475	Surprisingly, KSHV-mediated activation of NF-kappaB was impaired in CADM1 knockdown HeLa cells as determined by NF-kappaB activation luciferase assays (S4A Fig).	('CADM1', 'Gene', (68, 73))	('KSHV', 'Species', '37296', (14, 18))	('HeLa', 'CellLine', 'CVCL:0030', (84, 88))	('knockdown', 'Var', (74, 83))	('impaired', 'NegReg', (56, 64))
320293	29698475	To identify the motifs of CADM1 required for vFLIP to activate NF-kappaB, Cadm1-/- MEFs were transfected with vFLIP together with either Flag-tagged wild-type or deletion mutants of CADM1 (Fig 2D) and we found that the cytoplasmic tail and PDZ-BM of CADM1 were required for vFLIP to activate canonical NF-kappaB (Fig 2E).	('deletion', 'Var', (162, 170))	('vFLIP', 'Gene', '4961494', (274, 279))	('vFLIP', 'Gene', (274, 279))	('MEFs', 'CellLine', 'CVCL:9115', (83, 87))	('Cadm1', 'Gene', '23705', (74, 79))	('vFLIP', 'Gene', '4961494', (45, 50))	('vFLIP', 'Gene', (45, 50))	('vFLIP', 'Gene', '4961494', (110, 115))	('activate', 'PosReg', (283, 291))	('Cadm1', 'Gene', (74, 79))	('vFLIP', 'Gene', (110, 115))
320300	29698475	As expected, vGPCR-mediated activation of NF-kappaB was impaired in HeLa cells after knockdown of CADM1 as determined by luciferase assays (Fig 3B).	('vGPCR', 'Gene', (13, 18))	('vGPCR', 'Gene', '4961465', (13, 18))	('HeLa', 'CellLine', 'CVCL:0030', (68, 72))	('knockdown', 'Var', (85, 94))	('CADM1', 'Gene', (98, 103))	('NF-kappaB', 'Protein', (42, 51))	('impaired', 'NegReg', (56, 64))
320304	29698475	Next, to identify the motifs of CADM1 required for vGPCR to activate NF-kappaB, Cadm1-/- MEFs were transfected with vGPCR, and reconstituted with either wild-type or deletion mutants of CADM1.	('deletion mutants', 'Var', (166, 182))	('vGPCR', 'Gene', '4961465', (51, 56))	('vGPCR', 'Gene', '4961465', (116, 121))	('vGPCR', 'Gene', (51, 56))	('MEFs', 'CellLine', 'CVCL:9115', (89, 93))	('Cadm1', 'Gene', '23705', (80, 85))	('Cadm1', 'Gene', (80, 85))	('vGPCR', 'Gene', (116, 121))
320317	29698475	The results clearly indicated that knockdown of CADM1 led to loss of IkappaBalpha phosphorylation and NF-kappaB DNA binding in PEL cell lines (Fig 4A and 4B), and vFLIP and vGPCR-expressing Cadm1-/- MEFs compared to wild-type MEFs (Fig 4C and 4D and S7A and S7B Fig).	('IkappaBalpha', 'Protein', (69, 81))	('knockdown', 'Var', (35, 44))	('CADM1', 'Gene', (48, 53))	('MEFs', 'CellLine', 'CVCL:9115', (226, 230))	('vGPCR', 'Gene', (173, 178))	('MEFs', 'CellLine', 'CVCL:9115', (199, 203))	('vGPCR', 'Gene', '4961465', (173, 178))	('NF-kappaB', 'Protein', (102, 111))	('vFLIP', 'Gene', '4961494', (163, 168))	('loss', 'NegReg', (61, 65))	('Cadm1', 'Gene', '23705', (190, 195))	('Cadm1', 'Gene', (190, 195))	('vFLIP', 'Gene', (163, 168))
320331	29698475	When BC-1, BC-3, and BCBL-1 were stably knocked down for CADM1, we found that vFLIP-mediated processing of p100 to p52 was completely impaired in CADM1 knockdown cells compared to cells expressing control shRNA (S10A Fig).	('S10A', 'Var', (212, 216))	('knockdown', 'Var', (152, 161))	('p52', 'Gene', '4791', (115, 118))	('vFLIP', 'Gene', '4961494', (78, 83))	('vFLIP', 'Gene', (78, 83))	('p100', 'Var', (107, 111))	('CADM1', 'Gene', (146, 151))	('impaired', 'NegReg', (134, 142))	('p52', 'Gene', (115, 118))	('S10A', 'SUBSTITUTION', 'None', (212, 216))
320332	29698475	The p100 processing to p52 by vFLIP was also impaired in Cadm1-/- MEFs compared to wild-type MEFs (S10B Fig).	('Cadm1', 'Gene', '23705', (57, 62))	('Cadm1', 'Gene', (57, 62))	('vFLIP', 'Gene', '4961494', (30, 35))	('vFLIP', 'Gene', (30, 35))	('S10B', 'Var', (99, 103))	('MEFs', 'CellLine', 'CVCL:9115', (93, 97))	('MEFs', 'CellLine', 'CVCL:9115', (66, 70))	('impaired', 'NegReg', (45, 53))	('S10B', 'SUBSTITUTION', 'None', (99, 103))	('p52', 'Gene', (23, 26))	('p52', 'Gene', '4791', (23, 26))
320335	29698475	Indeed, endogenous CADM1 interacted with vFLIP and vGPCR (Fig 5A and S11A Fig), and the interaction was specific since no binding was observed when immunoprecipitations were performed with a control mouse immunoglobulin antibody (Fig 5A and S11A Fig).	('interacted', 'Interaction', (25, 35))	('mouse', 'Species', '10090', (199, 204))	('vGPCR', 'Gene', '4961465', (51, 56))	('vGPCR', 'Gene', (51, 56))	('S11A', 'Var', (241, 245))	('S11A', 'Var', (69, 73))	('vFLIP', 'Gene', '4961494', (41, 46))	('S11A', 'SUBSTITUTION', 'None', (69, 73))	('CADM1', 'Gene', (19, 24))	('S11A', 'SUBSTITUTION', 'None', (241, 245))	('vFLIP', 'Gene', (41, 46))
320337	29698475	As expected, CADM1 interacted with both vFLIP and vGPCR in reconstituted MEFs (Fig 5B and S11B Fig).	('CADM1', 'Gene', (13, 18))	('vFLIP', 'Gene', '4961494', (40, 45))	('vGPCR', 'Gene', '4961465', (50, 55))	('vFLIP', 'Gene', (40, 45))	('interacted', 'Reg', (19, 29))	('S11B', 'SUBSTITUTION', 'None', (90, 94))	('S11B', 'Var', (90, 94))	('MEFs', 'CellLine', 'CVCL:9115', (73, 77))	('vGPCR', 'Gene', (50, 55))
320338	29698475	Since NF-kappaB is chronically activated in vFLIP and vGPCR-expressing PEL cells, and is impaired upon knockdown of CADM1, we examined CADM1 interaction with vFLIP and vGPCR in the PEL cell lines.	('vGPCR', 'Gene', (168, 173))	('vFLIP', 'Gene', '4961494', (44, 49))	('vFLIP', 'Gene', (44, 49))	('vGPCR', 'Gene', '4961465', (54, 59))	('vFLIP', 'Gene', '4961494', (158, 163))	('vFLIP', 'Gene', (158, 163))	('vGPCR', 'Gene', '4961465', (168, 173))	('examined', 'Reg', (126, 134))	('vGPCR', 'Gene', (54, 59))	('impaired', 'NegReg', (89, 97))	('activated', 'PosReg', (31, 40))	('CADM1', 'Gene', (116, 121))	('NF-kappaB', 'Protein', (6, 15))	('knockdown', 'Var', (103, 112))
320339	29698475	Indeed, vFLIP and vGPCR are physically associated with CADM1 in BC-1, BC-3, and BCBL-1, cell lines (Fig 5C and S11C Fig).	('vFLIP', 'Gene', (8, 13))	('vGPCR', 'Gene', (18, 23))	('S11C', 'Var', (111, 115))	('S11C', 'SUBSTITUTION', 'None', (111, 115))	('vGPCR', 'Gene', '4961465', (18, 23))	('CADM1', 'Gene', (55, 60))	('vFLIP', 'Gene', '4961494', (8, 13))	('associated', 'Interaction', (39, 49))
320342	29698475	As expected, CADM1 was not able to interact with either vGPCR or vFLIP when CP or PDZ domains were deleted (S11D and S12 Figs).	('interact', 'Interaction', (35, 43))	('vGPCR', 'Gene', (56, 61))	('vFLIP', 'Gene', '4961494', (65, 70))	('vFLIP', 'Gene', (65, 70))	('vGPCR', 'Gene', '4961465', (56, 61))	('S11D', 'Var', (108, 112))	('S11D', 'SUBSTITUTION', 'None', (108, 112))
320346	29698475	As expected, vFLIP and CADM1 colocalized, and the proteins were found in lipid rafts as visualized by cholera toxin B staining of GM1 gangliosides in PEL (BC-3 and BCBL-1) cell lines (Fig 6A and S13A Fig).	('GM1', 'Gene', (130, 133))	('GM1', 'Gene', '210582', (130, 133))	('vFLIP', 'Gene', '4961494', (13, 18))	('vFLIP', 'Gene', (13, 18))	('S13A', 'Var', (195, 199))	('lipid', 'Chemical', 'MESH:D008055', (73, 78))	('S13A', 'SUBSTITUTION', 'None', (195, 199))
320356	29698475	As expected, disruption of membrane lipid rafts with MbetaCD treatment significantly reduced the lipid raft ring formation as visualized by cholera toxin B staining of GM1 gangliosides in PEL (BC-3 and BCBL-1) cell lines (S13B and S14A Figs).	('men', 'Species', '9606', (66, 69))	('GM1', 'Gene', '210582', (168, 171))	('GM1', 'Gene', (168, 171))	('S13B', 'SUBSTITUTION', 'None', (222, 226))	('disruption', 'Var', (13, 23))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('MbetaCD', 'Chemical', 'MESH:C108732', (53, 60))	('lipid', 'Chemical', 'MESH:D008055', (36, 41))	('reduced', 'NegReg', (85, 92))	('S14A', 'Mutation', 'p.S14A', (231, 235))	('S13B', 'Var', (222, 226))	('lipid raft ring formation', 'MPA', (97, 122))
320358	29698475	However, IKK activation, and vFLIP interaction with NEMO and CADM1 were impaired in the MbetaCD treated BC-3 PEL cells (S14B Fig).	('IKK', 'Protein', (9, 12))	('S14B', 'SUBSTITUTION', 'None', (120, 124))	('activation', 'MPA', (13, 23))	('S14B', 'Var', (120, 124))	('vFLIP', 'Gene', (29, 34))	('impaired', 'NegReg', (72, 80))	('MbetaCD', 'Chemical', 'MESH:C108732', (88, 95))	('vFLIP', 'Gene', '4961494', (29, 34))
320360	29698475	To determine if the loss of cell viability was due to apoptosis, CADM1 was knocked down in BC-1, BC-3, and BCBL-1 PEL cells and they were analyzed by Annexin V and propidium iodide (PI) staining; CADM1 knockdown resulted in significant apoptotic cell death in PEL cells after 96 hours (Fig 7C).	('apoptotic', 'CPA', (236, 245))	('Annexin V', 'Gene', '308', (150, 159))	('Annexin V', 'Gene', (150, 159))	('CADM1', 'Gene', (196, 201))	('propidium iodide', 'Chemical', 'MESH:D011419', (164, 180))	('knockdown', 'Var', (202, 211))
320362	29698475	There was no effect of shRNA-mediated CADM1 knockdown on BJAB cells after 96 hours (S16A-S16C Fig).	('BJAB', 'CellLine', 'CVCL:5711', (57, 61))	('CADM1', 'Gene', (38, 43))	('S16A', 'Mutation', 'p.S16A', (84, 88))	('S16C', 'Mutation', 'p.S16C', (89, 93))	('knockdown', 'Var', (44, 53))
320368	29698475	Although ample studies have demonstrated that CADM1 expression is silenced by promoter methylation in many solid tumors such as lung, melanoma, pancreatic, esophageal, uterine, and cervical cancer, its mechanistic functional roles as a tumor suppressor are unknown.	('lung', 'Disease', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('promoter methylation', 'Var', (78, 98))	('solid tumors', 'Disease', (107, 119))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('pancreatic', 'Disease', 'MESH:D010195', (144, 154))	('melanoma', 'Disease', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('cervical cancer', 'Disease', (181, 196))	('cervical cancer', 'Disease', 'MESH:D002583', (181, 196))	('esophageal', 'Disease', (156, 166))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('uterine', 'Disease', (168, 175))	('pancreatic', 'Disease', (144, 154))	('solid tumors', 'Disease', 'MESH:D009369', (107, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('silenced', 'NegReg', (66, 74))	('CADM1', 'Gene', (46, 51))	('expression', 'MPA', (52, 62))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (236, 241))
320385	29698475	Disruption of membrane lipid rafts using methyl-beta-cyclodextrin (MbetaCD), a selective cholesterol inhibitor, impaired CADM1, vFLIP and NEMO interactions and NF-kappaB activation as well (S14B Fig).	('vFLIP', 'Gene', (128, 133))	('NEMO interactions', 'CPA', (138, 155))	('activation', 'PosReg', (170, 180))	('cholesterol', 'Chemical', 'MESH:D002784', (89, 100))	('NF-kappaB', 'Protein', (160, 169))	('vFLIP', 'Gene', '4961494', (128, 133))	('impaired', 'NegReg', (112, 120))	('MbetaCD', 'Chemical', 'MESH:C108732', (67, 74))	('S14B', 'SUBSTITUTION', 'None', (190, 194))	('CADM1', 'Protein', (121, 126))	('S14B', 'Var', (190, 194))	('methyl-beta-cyclodextrin', 'Chemical', 'MESH:C108732', (41, 65))	('lipid', 'Chemical', 'MESH:D008055', (23, 28))
320395	29698475	K15 is also expressed at the cell surface similar to vGPCR and activates NF-kappaB.	('K15', 'Var', (0, 3))	('vGPCR', 'Gene', (53, 58))	('NF-kappaB', 'Protein', (73, 82))	('vGPCR', 'Gene', '4961465', (53, 58))	('activates', 'PosReg', (63, 72))
320451	29698475	Briefly, KSHV infected cell lines and PBMCs were treated with an antibody cocktail (alpha-CD3, alpha-B220 (BD Biosystems), alpha-CD19 (StemCell Technologies, and alpha-CADM1 (MBL International Corporation)) in 1X FACS buffer on ice for 20 min.	('MBL', 'Gene', (175, 178))	('alpha-CD19', 'Var', (123, 133))	('MBL', 'Gene', '50639', (175, 178))	('KSHV', 'Species', '37296', (9, 13))
320463	28459858	Epistatic interaction between the lipase-encoding genes Pnpla2 and Lipe causes liposarcoma in mice Liposarcoma is an often fatal cancer of fat cells.	('liposarcoma', 'Phenotype', 'HP:0012034', (79, 90))	('Pnpla2', 'Gene', (56, 62))	('lipase', 'Gene', (34, 40))	('cancer', 'Disease', (129, 135))	('causes', 'Reg', (72, 78))	('Pnpla2', 'Gene', '66853', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('liposarcoma', 'Disease', 'MESH:D008080', (79, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('Epistatic interaction', 'Var', (0, 21))	('Liposarcoma', 'Phenotype', 'HP:0012034', (99, 110))	('Lipe', 'Gene', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('liposarcoma', 'Disease', (79, 90))	('Lipe', 'Gene', '16890', (67, 71))	('Liposarcoma', 'Disease', 'MESH:D008080', (99, 110))	('lipase', 'Gene', '16891', (34, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('Liposarcoma', 'Disease', (99, 110))
320472	28459858	These results show that a previously-unknown, fully penetrant epistatic interaction between Pnpla2 and Lipe can cause liposarcoma in mice.	('cause', 'Reg', (112, 117))	('mice', 'Species', '10090', (133, 137))	('liposarcoma', 'Disease', 'MESH:D008080', (118, 129))	('Pnpla2', 'Gene', '66853', (92, 98))	('epistatic interaction', 'Var', (62, 83))	('liposarcoma', 'Phenotype', 'HP:0012034', (118, 129))	('Lipe', 'Gene', '16890', (103, 107))	('Pnpla2', 'Gene', (92, 98))	('Lipe', 'Gene', (103, 107))	('liposarcoma', 'Disease', (118, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
320479	28459858	Our study reveals a novel epistatic interaction in fat cells between these two lipase genes and that causes a unique form of liposarcoma in mice.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('causes', 'Reg', (101, 107))	('mice', 'Species', '10090', (140, 144))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('liposarcoma', 'Disease', 'MESH:D008080', (125, 136))	('lipase', 'Gene', '16891', (79, 85))	('liposarcoma', 'Disease', (125, 136))	('lipase', 'Gene', (79, 85))	('epistatic interaction', 'Var', (26, 47))
320485	28459858	For instance, myxoid liposarcoma has been associated with a specific t12;16 translocation and expression of a FUS-CHOP fusion protein.	('myxoid liposarcoma', 'Disease', (14, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('associated', 'Reg', (42, 52))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (14, 32))	('FUS-CHOP fusion protein', 'Protein', (110, 133))	('t12;16 translocation', 'Var', (69, 89))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (14, 32))	('liposarcoma', 'Phenotype', 'HP:0012034', (21, 32))
320488	28459858	Some dedifferentiated liposarcomas show amplification of STAT6.	('liposarcomas', 'Disease', 'MESH:D008080', (22, 34))	('liposarcoma', 'Phenotype', 'HP:0012034', (22, 33))	('liposarcomas', 'Phenotype', 'HP:0012034', (22, 34))	('amplification', 'Var', (40, 53))	('STAT6', 'Gene', (57, 62))	('dedifferentiated liposarcomas', 'Phenotype', 'HP:0012034', (5, 34))	('liposarcomas', 'Disease', (22, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('STAT6', 'Gene', '20852', (57, 62))
320495	28459858	Of note, deletion of PNPLA2 is reported in well differentiated liposarcoma and sarcoma.	('reported', 'Reg', (31, 39))	('liposarcoma', 'Phenotype', 'HP:0012034', (63, 74))	('deletion', 'Var', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('PNPLA2', 'Gene', (21, 27))	('liposarcoma and sarcoma', 'Disease', 'MESH:D008080', (63, 86))
320497	28459858	Although PNPLA2 deletion has been reported in well differentiated liposarcoma and LIPE deletion, in DDLS with poor outcome, neither ATGL deficiency nor HSL deficiency reportedly causes liposarcoma in mice.	('deficiency nor HSL deficiency', 'Disease', 'MESH:D007153', (137, 166))	('liposarcoma', 'Phenotype', 'HP:0012034', (185, 196))	('deficiency nor HSL deficiency', 'Disease', (137, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('deletion', 'Var', (16, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('LIPE', 'Gene', (82, 86))	('liposarcoma', 'Disease', (66, 77))	('mice', 'Species', '10090', (200, 204))	('liposarcoma', 'Disease', (185, 196))	('liposarcoma', 'Disease', 'MESH:D008080', (66, 77))	('deletion', 'Var', (87, 95))	('ATGL', 'Chemical', '-', (132, 136))	('liposarcoma', 'Disease', 'MESH:D008080', (185, 196))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))
320498	28459858	Increasing evidence suggests that cancer development may be driven by tissue-specific epistatic interactions due to mutations in multiple functionally-related genes.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
320523	28459858	Therapeutic suppression of Gpnmb is currently in phase 2 clinical trials for several types of cancer (ClinicalTrials.gov Identifier: NCT01997333, NCT01156753, NCT02713828, NCT02487979, NCT02302339, NCT02280785, NCT00921570, NCT02363283).	('NCT02487979', 'Var', (172, 183))	('Gpnmb', 'Gene', (27, 32))	('NCT02302339', 'Var', (185, 196))	('NCT02713828', 'Var', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('NCT02280785', 'Var', (198, 209))	('cancer', 'Disease', (94, 100))	('Gpnmb', 'Gene', '93695', (27, 32))	('NCT02363283', 'Var', (224, 235))	('NCT00921570', 'Var', (211, 222))	('NCT01156753', 'Var', (146, 157))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
320552	28459858	Therefore, tissue specific inactivation of Pnpla2 and Lipe causes liposarcoma in mice, and down-regulation of PNPLA2 and LIPE expression occurs in human DDLS.	('Lipe', 'Gene', (54, 58))	('inactivation', 'Var', (27, 39))	('human', 'Species', '9606', (147, 152))	('mice', 'Species', '10090', (81, 85))	('Lipe', 'Gene', '16890', (54, 58))	('Pnpla2', 'Gene', '66853', (43, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('liposarcoma', 'Disease', (66, 77))	('Pnpla2', 'Gene', (43, 49))	('liposarcoma', 'Disease', 'MESH:D008080', (66, 77))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))
320556	28459858	The loss of chromosome 11p15.5 harboring PNPLA2 was significantly associated (p < 0.01, chi-square) with soft tissue sarcomas (S10 Fig).	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (105, 125))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (105, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (105, 125))	('soft tissue sarcomas', 'Disease', (105, 125))	('PNPLA2', 'Gene', (41, 47))	('loss', 'Var', (4, 8))
320557	28459858	Our study showed that the combined deficiency of the two major lipases of adipose tissue, ATGL and HSL, causes a unique form of liposarcoma with complete penetrance in mice.	('ATGL', 'Chemical', '-', (90, 94))	('liposarcoma', 'Phenotype', 'HP:0012034', (128, 139))	('liposarcoma', 'Disease', 'MESH:D008080', (128, 139))	('mice', 'Species', '10090', (168, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('deficiency', 'Var', (35, 45))	('lipase', 'Gene', '16891', (63, 69))	('causes', 'Reg', (104, 110))	('lipase', 'Gene', (63, 69))	('liposarcoma', 'Disease', (128, 139))
320567	28459858	Deficiency of CGI-58, the coactivator of ATGL encoded by ABHD5, results in increased tumorigenesis and malignant transformation in mice and ABHD5 deletions occur in several human cancers.	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('ABHD5', 'Gene', '67469', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('deletions', 'Var', (146, 155))	('Deficiency', 'Var', (0, 10))	('ABHD5', 'Gene', (57, 62))	('ATGL', 'Chemical', '-', (41, 45))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('mice', 'Species', '10090', (131, 135))	('increased', 'PosReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('CGI-58', 'Gene', (14, 20))	('ABHD5', 'Gene', '67469', (57, 62))	('human', 'Species', '9606', (173, 178))	('malignant transformation', 'CPA', (103, 127))	('ABHD5', 'Gene', (140, 145))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))	('CGI-58', 'Gene', '67469', (14, 20))
320573	28459858	A role for HSL in cancer development is less well documented than for MGL and ATGL, but a study of patients with well-differentiated and dedifferentiated liposarcoma showed that loss of the chromosome 19q13 region containing LIPE occurred frequently in DDLS, and that this was associated with decreased survival.	('loss', 'Var', (178, 182))	('LIPE', 'Gene', (225, 229))	('survival', 'MPA', (303, 311))	('ATGL', 'Chemical', '-', (78, 82))	('liposarcoma', 'Disease', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('patients', 'Species', '9606', (99, 107))	('DDLS', 'Disease', (253, 257))	('liposarcoma', 'Disease', 'MESH:D008080', (154, 165))	('decreased', 'NegReg', (293, 302))	('liposarcoma', 'Phenotype', 'HP:0012034', (154, 165))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
320575	28459858	Taken together, these observations suggest that disruption of lipolytic pathway enzymes may occur widely in cancer and sometimes can be the primary and sufficient cause of cancer, as in DAKO liposarcoma.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('liposarcoma', 'Phenotype', 'HP:0012034', (191, 202))	('liposarcoma', 'Disease', (191, 202))	('liposarcoma', 'Disease', 'MESH:D008080', (191, 202))	('disruption', 'Var', (48, 58))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lipolytic pathway enzymes', 'Enzyme', (62, 87))	('cancer', 'Disease', (172, 178))	('cause', 'Reg', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
320580	28459858	Intriguingly, although N1ICP-related liposarcomas occur in white adipocytes whereas DAKO liposarcoma occurs in brown adipose tissue, both the DAKO and N1ICP-related liposarcomas occur with complete penetrance, and in both, intracellular fatty acid pools and PPAR-gamma signaling are predicted to be reduced.	('PPAR-gamma', 'Gene', '19016', (258, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('liposarcomas', 'Disease', 'MESH:D008080', (37, 49))	('liposarcoma', 'Disease', (37, 48))	('liposarcomas', 'Phenotype', 'HP:0012034', (165, 177))	('N1ICP-related', 'Var', (151, 164))	('liposarcoma', 'Phenotype', 'HP:0012034', (165, 176))	('PPAR-gamma', 'Gene', (258, 268))	('liposarcomas', 'Phenotype', 'HP:0012034', (37, 49))	('liposarcoma', 'Disease', (89, 100))	('liposarcoma', 'Phenotype', 'HP:0012034', (37, 48))	('liposarcomas', 'Disease', (165, 177))	('liposarcoma', 'Disease', 'MESH:D008080', (165, 176))	('liposarcomas', 'Disease', (37, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('liposarcoma', 'Disease', 'MESH:D008080', (37, 48))	('liposarcoma', 'Phenotype', 'HP:0012034', (89, 100))	('fatty acid', 'Chemical', 'MESH:D005227', (237, 247))	('intracellular fatty acid pools', 'MPA', (223, 253))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('reduced', 'NegReg', (299, 306))	('liposarcoma', 'Disease', (165, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('N1ICP-related', 'Gene', (23, 36))	('liposarcomas', 'Disease', 'MESH:D008080', (165, 177))	('liposarcoma', 'Disease', 'MESH:D008080', (89, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))
320581	28459858	The discovery of the precise mechanism(s) by which combined deficiencies of ATGL and HSL cause liposarcoma will require further study.	('HSL', 'Gene', (85, 88))	('liposarcoma', 'Disease', (95, 106))	('ATGL', 'Gene', (76, 80))	('ATGL', 'Chemical', '-', (76, 80))	('cause', 'Reg', (89, 94))	('liposarcoma', 'Disease', 'MESH:D008080', (95, 106))	('liposarcoma', 'Phenotype', 'HP:0012034', (95, 106))	('deficiencies', 'Var', (60, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
320594	28459858	The following antibodies were used: ATGL (#10006409-1, Cayman Chemical), HSL, UCP-1 (# RB-10599-P0, Lab vision corporation) and GPNMB (#AF2330-SP, R&D Systems).	('#10006409-1', 'Var', (42, 53))	('ATGL', 'Chemical', '-', (36, 40))	('# RB-10599-P0', 'Var', (85, 98))	('UCP-1', 'Gene', (78, 83))	('UCP-1', 'Gene', '22227', (78, 83))
320604	28459858	CNV data from 265 soft tissue sarcoma patients from the TCGA resource was analyzed to identify gene deletions and losses associated with chromosomal regions harboring PNPLA2 and LIPE.	('losses', 'NegReg', (114, 120))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('deletions', 'Var', (100, 109))	('sarcoma', 'Disease', (30, 37))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (18, 37))	('patients', 'Species', '9606', (38, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
320621	21666582	Recurrent balanced translocations between the X and 18 chromosomes were identified in synovial sarcoma cells in the 1980s.	('synovial sarcoma', 'Disease', 'MESH:D013584', (86, 102))	('balanced translocations', 'Var', (10, 33))	('synovial sarcoma', 'Disease', (86, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (86, 102))
320622	21666582	It was later noted that these translocations generated fusion oncoproteins composed of the amino-terminus of the SYT gene and the carboxy-terminus of one of the SSX genes, most commonly SSX1 or SSX2.	('SSX', 'Gene', '6757', (186, 189))	('SSX', 'Gene', (194, 197))	('SSX1', 'Gene', (186, 190))	('SSX', 'Gene', (186, 189))	('SSX', 'Gene', '6757', (194, 197))	('SSX2', 'Gene', (194, 198))	('oncoproteins', 'Protein', (62, 74))	('SYT', 'Gene', (113, 116))	('SSX', 'Gene', '6757', (161, 164))	('translocations', 'Var', (30, 44))	('SSX', 'Gene', (161, 164))	('SSX1', 'Gene', '6756', (186, 190))	('SSX2', 'Gene', '6757', (194, 198))	('SYT', 'Gene', '6760', (113, 116))
320628	21666582	About one-third of sarcomas have subtype-specific balanced translocations, while the remaining two-thirds have more complex karyotypes.	('sarcomas', 'Disease', 'MESH:D012509', (19, 27))	('balanced translocations', 'Var', (50, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('sarcomas', 'Disease', (19, 27))
320638	21666582	While the small numbers of new diagnoses per year make lumping into groups by type an attractive practice for these trials, lumping sarcoma types together compromises the validity of the outcomes in important ways.	('sarcoma', 'Disease', (132, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('validity', 'MPA', (171, 179))	('lumping', 'Var', (124, 131))	('compromises', 'NegReg', (155, 166))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
320673	21666582	SYT-SSX proteins have been shown to associate with polycomb group proteins, regulating expression of certain targets by epigenetic modifications of histones.	('histones', 'Protein', (148, 156))	('SSX', 'Gene', (4, 7))	('SYT', 'Gene', '6760', (0, 3))	('epigenetic modifications', 'Var', (120, 144))	('expression of', 'MPA', (87, 100))	('SSX', 'Gene', '6757', (4, 7))	('regulating', 'Reg', (76, 86))	('SYT', 'Gene', (0, 3))
320674	21666582	One of the highlighted targets of these epigenetic silencing effects of SYT-SSX is the tumor suppressor early growth response 1 (EGR1).	('SSX', 'Gene', (76, 79))	('SYT', 'Gene', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('EGR1', 'Gene', (129, 133))	('SYT', 'Gene', '6760', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('epigenetic silencing effects', 'Var', (40, 68))	('EGR1', 'Gene', '1958', (129, 133))	('SSX', 'Gene', '6757', (76, 79))
320675	21666582	Increased expression of EGR1 and subsequent phosphatase and tensin homolog (PTEN)-mediated apoptosis can be achieved in synovial sarcoma cell lines by the administration of FK228, an HDACi.	('EGR1', 'Gene', (24, 28))	('FK228', 'Chemical', 'MESH:C087123', (173, 178))	('apoptosis', 'CPA', (91, 100))	('PTEN', 'Gene', (76, 80))	('EGR1', 'Gene', '1958', (24, 28))	('synovial sarcoma', 'Disease', (120, 136))	('PTEN', 'Gene', '5728', (76, 80))	('expression', 'MPA', (10, 20))	('FK228', 'Var', (173, 178))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (120, 136))	('synovial sarcoma', 'Disease', 'MESH:D013584', (120, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
320692	21666582	Developmental effects of such alterations can arise that affect the lifespan and health of the host independent from tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('affect', 'Reg', (57, 63))	('lifespan', 'CPA', (68, 76))	('alterations', 'Var', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
320744	28750090	However, RNAi-mediated knockdown of STAT3 did not phenocopy the biologic effects of LY5 in sarcoma cell lines.	('LY5', 'Chemical', '-', (84, 87))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('knockdown', 'Var', (23, 32))	('sarcoma', 'Disease', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))
320748	28750090	However LY5 did not decrease tumor growth in xenograft mouse models and STAT3 knockdown did not induce concordant biologic effects.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('STAT3', 'Gene', (72, 77))	('knockdown', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mouse', 'Species', '10090', (55, 60))	('tumor', 'Disease', (29, 34))	('LY5', 'Chemical', '-', (8, 11))
320753	28750090	Dysregulation of STAT3 has been associated with increased tumor cell proliferation, survival, invasion and immunosuppression in vitro, and mounting evidence supports the critical role of STAT3 as an oncogene.	('STAT3', 'Gene', (17, 22))	('invasion', 'CPA', (94, 102))	('tumor', 'Disease', (58, 63))	('increased', 'PosReg', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('survival', 'CPA', (84, 92))
320757	28750090	LY5 has greater predicted oral bioavailability and binding activity to the STAT3 SH2 domain compared to its predecessor LLL12, and was designed to inhibit both STAT3 activation and dimerization by blocking the SH2 domain phosphotyrosine binding site.	('binding', 'Interaction', (51, 58))	('STAT3 activation', 'MPA', (160, 176))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (221, 236))	('phosphotyrosine', 'MPA', (221, 236))	('LY5', 'Chemical', '-', (0, 3))	('blocking', 'NegReg', (197, 205))	('LY5', 'Var', (0, 3))	('oral bioavailability', 'MPA', (26, 46))	('greater', 'PosReg', (8, 15))	('inhibit', 'NegReg', (147, 154))	('dimerization', 'MPA', (181, 193))
320758	28750090	LY5 has shown activity in in vivo models of breast and colon cancer as well as in vitro models of medulloblastoma alone and in combination with chemotherapy or radiation.	('medulloblastoma', 'Disease', 'MESH:D008527', (98, 113))	('medulloblastoma', 'Phenotype', 'HP:0002885', (98, 113))	('LY5', 'Chemical', '-', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (55, 67))	('LY5', 'Var', (0, 3))	('medulloblastoma', 'Disease', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast and colon cancer', 'Disease', 'MESH:D001943', (44, 67))
320761	28750090	In RMS, the combination of LY5 with doxorubicin, cisplatin, and a MEK inhibitor (Selumitinib, AZD6244) showed stronger inhibitory effects compared to single-agent therapy alone.	('doxorubicin', 'Chemical', 'MESH:D004317', (36, 47))	('RMS', 'Phenotype', 'HP:0002859', (3, 6))	('AZD6244', 'Chemical', 'MESH:C517975', (94, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('MEK', 'Gene', (66, 69))	('LY5', 'Chemical', '-', (27, 30))	('Selumitinib', 'Chemical', '-', (81, 92))	('LY5', 'Var', (27, 30))	('MEK', 'Gene', '5609', (66, 69))	('stronger', 'PosReg', (110, 118))	('inhibitory effects', 'MPA', (119, 137))	('combination', 'Interaction', (12, 23))
320764	28750090	While LY5 demonstrated good PK parameters and oral bioavailability in vivo, inhibition of the tumor growth of patient-derived xenograft (PDX) models or metastatic disease in lung metastasis models was not observed.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('metastatic disease', 'CPA', (152, 170))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PD', 'Disease', 'MESH:D010300', (137, 139))	('tumor', 'Disease', (94, 99))	('LY5', 'Chemical', '-', (6, 9))	('LY5', 'Var', (6, 9))	('patient', 'Species', '9606', (110, 117))
320765	28750090	These data suggest that while LY5 is capable of inhibiting STAT3 phosphorylation, the anti-cancer effects of LY5 are likely due to as yet undefined off-target effects.	('LY5', 'Chemical', '-', (30, 33))	('LY5', 'Chemical', '-', (109, 112))	('LY5', 'Var', (109, 112))	('STAT3 phosphorylation', 'MPA', (59, 80))	('cancer', 'Disease', (91, 97))	('inhibiting', 'NegReg', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
320805	28750090	To investigate the pharmacodynamics (PD) effects of LY5, pSTAT3 (p-Tyr705, ab76315, Abcam) and total STAT3 (ab119352, Abcam) were evaluated in pulmonary metastatic lesions using IHC in lung samples from mice euthanized 24 hrs after their last dose.	('mice', 'Species', '10090', (203, 207))	('pulmonary metastatic lesions', 'CPA', (143, 171))	('Tyr705', 'Chemical', '-', (67, 73))	('ab76315', 'Var', (75, 82))	('LY5', 'Chemical', '-', (52, 55))	('PD', 'Disease', 'MESH:D010300', (37, 39))	('p-Tyr705', 'Var', (65, 73))
320816	28750090	LY5 was previously demonstrated to inhibit STAT3 phosphorylation in RMS cells.	('LY5', 'Chemical', '-', (0, 3))	('LY5', 'Var', (0, 3))	('STAT3 phosphorylation', 'MPA', (43, 64))	('inhibit', 'NegReg', (35, 42))	('RMS', 'Phenotype', 'HP:0002859', (68, 71))
320817	28750090	Consistent with these results, we found that LY5 inhibited basal STAT3 phosphorylation at Tyr705 in ES and OS cells in addition to RMS cells (Fig 1A).	('ES', 'Phenotype', 'HP:0012254', (100, 102))	('Tyr705', 'Chemical', '-', (90, 96))	('LY5', 'Chemical', '-', (45, 48))	('RMS', 'Phenotype', 'HP:0002859', (131, 134))	('LY5', 'Var', (45, 48))	('inhibited', 'NegReg', (49, 58))	('OS', 'Phenotype', 'HP:0002669', (107, 109))	('basal STAT3 phosphorylation at Tyr705', 'MPA', (59, 96))
320819	28750090	To determine the specificity of STAT blockade, we asked whether LY5 affected the phosphorylation of other family members including STAT1, STAT2, STAT4, and STAT6.	('phosphorylation', 'MPA', (81, 96))	('STAT4', 'Gene', (145, 150))	('affected', 'Reg', (68, 76))	('STAT2', 'Gene', '6773', (138, 143))	('LY5', 'Chemical', '-', (64, 67))	('STAT1', 'Gene', (131, 136))	('LY5', 'Var', (64, 67))	('STAT6', 'Gene', (156, 161))	('STAT1', 'Gene', '6772', (131, 136))	('STAT4', 'Gene', '6775', (145, 150))	('STAT2', 'Gene', (138, 143))	('STAT6', 'Gene', '6778', (156, 161))
320846	28750090	These data demonstrate that biologically achievable exposures of LY5 in mice and dogs are consistent with drug concentrations needed to inhibit STAT3 phosphorylation.	('dogs', 'Species', '9615', (81, 85))	('STAT3 phosphorylation', 'MPA', (144, 165))	('inhibit', 'NegReg', (136, 143))	('LY5', 'Chemical', '-', (65, 68))	('LY5', 'Var', (65, 68))	('mice', 'Species', '10090', (72, 76))
320849	28750090	Consistent with the in vitro study, LY5 inhibited STAT3 phosphorylation in pulmonary metastatic lesions as demonstrated by immunohistochemistry (Fig 4A) and Western blotting (Fig 4B).	('STAT3 phosphorylation', 'MPA', (50, 71))	('LY5', 'Chemical', '-', (36, 39))	('LY5', 'Var', (36, 39))	('inhibited', 'NegReg', (40, 49))
320854	28750090	Upon treatment of LY5 at various doses for 2 hrs, LY5 decreased STAT3 phosphorylation at a concentration of 1 muM in both cell lines (Fig 5B).	('LY5', 'Chemical', '-', (50, 53))	('LY5', 'Var', (50, 53))	('muM', 'Gene', '56925', (110, 113))	('LY5', 'Chemical', '-', (18, 21))	('muM', 'Gene', (110, 113))	('decreased', 'NegReg', (54, 63))	('STAT3 phosphorylation', 'MPA', (64, 85))
320855	28750090	STAT3 phosphorylation was effectively inhibited with exposure to 1 muM LY5 for 0.5 hrs in the MG 63.3 cell line and for 4 hrs in the K7M2 cell lines (Fig 5C).	('LY5', 'Var', (71, 74))	('STAT3 phosphorylation', 'MPA', (0, 21))	('muM', 'Gene', '56925', (67, 70))	('inhibited', 'NegReg', (38, 47))	('muM', 'Gene', (67, 70))	('LY5', 'Chemical', '-', (71, 74))
320858	28750090	Similarly, K7M2 cells showed complete inhibition of STAT3 in vitro only after 10 muM LY5 (Fig 5B), which was reflected in the PuMA assay with a reduction at 10 muM only (Fig 5D).	('muM', 'Gene', (160, 163))	('LY5', 'Chemical', '-', (85, 88))	('LY5', 'Var', (85, 88))	('STAT3', 'MPA', (52, 57))	('muM', 'Gene', '56925', (81, 84))	('inhibition', 'NegReg', (38, 48))	('muM', 'Gene', '56925', (160, 163))	('muM', 'Gene', (81, 84))
320863	28750090	Similar to the lung metastasis growth in Fig 4C, LY5 did not decrease PDX growth compared to control (Table 1, Fig 6A).	('lung metastasis', 'CPA', (15, 30))	('LY5', 'Chemical', '-', (49, 52))	('PD', 'Disease', 'MESH:D010300', (70, 72))	('LY5', 'Var', (49, 52))
320866	28750090	The effect of 1 muM LY5 treatment was significantly different from STAT3 siRNA (p < 0.05) in RH30 and ES-7 cell lines.	('LY5 treatment', 'Var', (20, 33))	('ES', 'Phenotype', 'HP:0012254', (102, 104))	('LY5', 'Chemical', '-', (20, 23))	('muM', 'Gene', '56925', (16, 19))	('RH30', 'Gene', (93, 97))	('muM', 'Gene', (16, 19))	('RH30', 'Gene', '6007', (93, 97))
320871	28750090	Previous studies had described LY5 to have potential anti-tumor activity but its true activity against sarcomas both in vitro and in vivo had not yet been characterized.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Disease', (103, 111))	('LY5', 'Chemical', '-', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('LY5', 'Var', (31, 34))
320874	28750090	However, drug concentrations needed to achieve tumor growth inhibition in both ex vivo and in vivo assays were discordant with those necessary to achieve target inhibition in vitro, suggesting that the anti-tumor effects of LY5 are not due to inhibition of STAT3 phosphorylation.	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('LY5', 'Chemical', '-', (224, 227))	('LY5', 'Var', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (47, 52))
320875	28750090	The mechanism responsible for this observed discrepancy is currently unknown, however our results indicated that the anti-cancer activity observed in sarcoma cells exposed to LY5 was likely due to an off-target effect(s).	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('LY5', 'Chemical', '-', (175, 178))	('LY5', 'Var', (175, 178))	('sarcoma', 'Disease', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))
320877	28750090	Experimental evidence has demonstrated that inhibition of JAK/STAT3 signaling impairs proliferation and survival in sarcoma cell lines, supporting the notion that STAT3 is a relevant therapeutic target.	('impairs', 'NegReg', (78, 85))	('inhibition', 'Var', (44, 54))	('proliferation', 'CPA', (86, 99))	('survival', 'CPA', (104, 112))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('sarcoma', 'Disease', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
320878	28750090	In contrast, almost complete knockdown of STAT3 in the sarcoma cell lines used in this study failed to decrease proliferation in any cell line except RH30.	('STAT3', 'Gene', (42, 47))	('knockdown', 'Var', (29, 38))	('sarcoma', 'Disease', (55, 62))	('RH30', 'Gene', (150, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('RH30', 'Gene', '6007', (150, 154))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))
320882	28750090	Therefore, LY5 was created by utilizing the fragment from LLL12 containing napthoquinonesulfonamide (thought to provide most of the binding energy to STAT3), and combining it with a pyridine ring to provide binding specificity to the SH2 domain side pocket of STAT3.	('napthoquinonesulfonamide', 'Chemical', '-', (75, 99))	('LY5', 'Chemical', '-', (11, 14))	('binding', 'Interaction', (207, 214))	('pyridine', 'Chemical', 'MESH:C023666', (182, 190))	('napthoquinonesulfonamide', 'Var', (75, 99))
320887	28750090	Although some STAT3 inhibitors have been identified to induce antitumor effects in vitro and in vivo, few STAT3 inhibitors have been thoroughly studied for in vivo efficacy and pharmacology.	('STAT3', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('inhibitors', 'Var', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
320905	26799613	Without adjuvant radiation therapy, microscopic disease left at the surgical site causes local recurrence in up to 31% of sarcoma patients.	('local', 'Disease', (89, 94))	('patients', 'Species', '9606', (130, 138))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('sarcoma', 'Disease', (122, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('microscopic disease', 'Var', (36, 55))
320947	26799613	The rationale for this step was if classification was carried out on the 350x300 pixel ROIs, it is likely that small focal areas of tumor would not be detected.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('350x300', 'Var', (73, 80))
321025	25533447	A meta-analysis of clinical trials using antiemetic therapies, including dexamethasone (Dex), showed that the combination of 5-HT3RAs and Dex increased the control rates of acute and delayed nausea and vomiting by about 15%.	('increased', 'PosReg', (142, 151))	('Dex', 'Chemical', 'MESH:D003907', (138, 141))	('vomiting', 'Phenotype', 'HP:0002013', (202, 210))	('vomiting', 'Disease', (202, 210))	('vomiting', 'Disease', 'MESH:D014839', (202, 210))	('dexamethasone', 'Chemical', 'MESH:D003907', (73, 86))	('5-HT3RAs', 'Var', (125, 133))	('Dex', 'Chemical', 'MESH:D003907', (88, 91))	('nausea', 'Phenotype', 'HP:0002018', (191, 197))	('nausea', 'Disease', (191, 197))	('nausea', 'Disease', 'MESH:D009325', (191, 197))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (191, 210))
321026	25533447	A meta-analysis of randomized controlled trials using antiemetic therapies showed that 5-HT3RAs have a superior antiemetic effect on the acute phase compared to conventional antiemetic therapies such as dopamine receptor antagonists and antihistamine drugs, and that 5-HT3RAs still play a central role in antiemetic therapy.	('5-HT3RAs', 'Var', (87, 95))	('dopamine', 'Chemical', 'MESH:D004298', (203, 211))	('antiemetic', 'MPA', (112, 122))
321036	25533447	However, the delayed CR rate was 56.8% in the palonosetron group and 44.5% in the granisetron group.	('palonosetron', 'Var', (46, 58))	('delayed CR', 'CPA', (13, 23))	('granisetron', 'Chemical', 'MESH:D017829', (82, 93))	('palonosetron', 'Chemical', 'MESH:D000077924', (46, 58))	('CR', 'Chemical', '-', (21, 23))
321105	25533447	The time to the first administration of rescue therapy tended to be longer for the granisetron regimen compared to the palonosetron regimen, but the difference was not significant (P = 0.115; hazard ratio = 1.610, 95% confidence interval = 0.864-2.999; Fig.7).	('granisetron', 'Chemical', 'MESH:D017829', (83, 94))	('palonosetron', 'Chemical', 'MESH:D000077924', (119, 131))	('granisetron', 'Var', (83, 94))	('longer', 'PosReg', (68, 74))
321116	25533447	For HER chemotherapy, all guidelines recommend the combination of 5-HT3RA, NK-1RA, and Dex.	('NK-1', 'Gene', '6863', (75, 79))	('NK-1', 'Gene', (75, 79))	('Dex', 'Chemical', 'MESH:D003907', (87, 90))	('5-HT3RA', 'Var', (66, 73))
321136	21067790	Mutation or removal of the AD has no effect on cdk8 interaction.	('interaction', 'Interaction', (52, 63))	('Mutation', 'Var', (0, 8))	('cdk8', 'Protein', (47, 51))	('AD', 'Disease', 'MESH:D000544', (27, 29))	('AD', 'Disease', (27, 29))
321147	21067790	Mutation of valine to serine at position 260 (V260S) within the TAF9 binding motif interferes physically and functionally with TAF9 binding.	('interferes', 'NegReg', (83, 93))	('TAF9', 'Gene', (64, 68))	('V260S', 'Mutation', 'p.V260S', (46, 51))	('V260S', 'Var', (46, 51))	('binding', 'Interaction', (132, 139))	('TAF9', 'Gene', (127, 131))	('TAF9', 'Gene', '6880', (64, 68))	('valine to serine at position 260', 'Mutation', 'p.V260S', (12, 44))	('TAF9', 'Gene', '6880', (127, 131))
321154	21067790	Cdk8 also phosphorylates transcription factor, E2F-1, repressing its inhibition of beta-catenin/T-cell factor-dependent transcription, and serine 10 of histone H3, which leads to GCN5L acetylation of lysine 14, a mark of active transcription.	('histone H3', 'Protein', (152, 162))	('E2F-1', 'Gene', (47, 52))	('GCN5L', 'Chemical', '-', (179, 184))	('lysine', 'Chemical', 'MESH:D008239', (200, 206))	('Cdk8', 'Gene', '1024', (0, 4))	('beta-catenin', 'Gene', (83, 95))	('Cdk8', 'Gene', (0, 4))	('inhibition', 'MPA', (69, 79))	('E2F-1', 'Gene', '1869', (47, 52))	('serine', 'Var', (139, 145))	('beta-catenin', 'Gene', '1499', (83, 95))	('serine', 'Chemical', 'MESH:D012694', (139, 145))	('leads to', 'Reg', (170, 178))	('GCN5L acetylation of lysine 14', 'MPA', (179, 209))
321155	21067790	The dysregulation of either cyclin C or cdk8 has been implicated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cyclin C', 'Protein', (28, 36))	('dysregulation', 'Var', (4, 17))	('implicated', 'Reg', (54, 64))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cdk8', 'Gene', (40, 44))
321157	21067790	In contrast, the gene encoding cdk8 resides in a region of the human genome that is often amplified in colon cancers, and over expression of exogenous cdk8 leads to cell transformation of NIH3T3 cells.	('cell transformation', 'CPA', (165, 184))	('NIH3T3', 'CellLine', 'CVCL:0594', (188, 194))	('exogenous', 'Var', (141, 150))	('expression', 'Species', '29278', (127, 137))	('human', 'Species', '9606', (63, 68))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('colon cancers', 'Phenotype', 'HP:0003003', (103, 116))	('colon cancers', 'Disease', 'MESH:D015179', (103, 116))	('cdk8', 'Gene', (151, 155))	('over expression', 'PosReg', (122, 137))	('cdk8', 'Gene', (31, 35))	('leads to', 'Reg', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colon cancers', 'Disease', (103, 116))
321159	21067790	This transition from G0 to G1 and subsequently to S phase is dependent upon phosphorylation of Rb by cyclin C/cdk3, cyclin D/cdk4/6 and cyclin E/cdk2 complexes as well as by cdk3 complexes with cyclins A and E. These cyclin/cdk pairs phosphorylate Rb at residues S807 and S811 causing its disassociation from E2F transcription factors to allow E2F-dependent transcription.	('cdk3', 'Gene', (174, 178))	('cdk4/6', 'Gene', '1019;1021', (125, 131))	('cdk3', 'Gene', '1018', (174, 178))	('disassociation', 'MPA', (289, 303))	('cdk2', 'Gene', (145, 149))	('cdk3', 'Gene', (110, 114))	('S811', 'Var', (272, 276))	('cdk4/6', 'Gene', (125, 131))	('cdk3', 'Gene', '1018', (110, 114))	('cdk2', 'Gene', '1017', (145, 149))	('cyclins A and E', 'Gene', '890', (194, 209))	('E2F-dependent transcription', 'MPA', (344, 371))
321172	21067790	Mutations at conserved residues, marked by asterisks in figure 1A, are known to disrupt the binding of cyclins A and C to their cdk partners.	('binding', 'Interaction', (92, 99))	('disrupt', 'NegReg', (80, 87))	('Mutations', 'Var', (0, 9))	('cyclins', 'Gene', '9133;335429;892;899;900;901;902;4171', (103, 110))	('cyclins', 'Gene', (103, 110))
321173	21067790	To determine whether the aligned residues, K80 and E111 of rv-cyclin, effect its binding to cdk8, they were each substituted with alanine and the mutated constructs were tested for co-IP with cdk8 (Fig.	('E111', 'Var', (51, 55))	('effect', 'Reg', (70, 76))	('K80', 'Var', (43, 46))	('alanine', 'Chemical', 'MESH:D000409', (130, 137))	('binding', 'Interaction', (81, 88))
321174	21067790	In addition, a double mutation, K80A/E111A (DM), a loss-of-function mutation within the rv-cyclin AD, V260S, and a carboxy-truncated form of the rv-cyclin, amino acids 1-255, were also tested.	('DM', 'Disease', 'MESH:D009223', (44, 46))	('loss-of-function', 'NegReg', (51, 67))	('AD', 'Disease', 'MESH:D000544', (98, 100))	('V260S', 'Mutation', 'p.V260S', (102, 107))	('AD', 'Disease', (98, 100))	('K80A', 'SUBSTITUTION', 'None', (32, 36))	('rv-cyclin', 'Gene', (88, 97))	('E111A', 'Mutation', 'p.E111A', (37, 42))	('K80A', 'Var', (32, 36))
321175	21067790	V260S blocks rv-cyclin pulldown of TAF9 and CBP/p300 but not of Mediator component, Med23 (Sur2), and the 1-255 construct contains the entire predicted cyclin box fold and excludes the AD.	('V260S', 'Mutation', 'p.V260S', (0, 5))	('CBP/p300', 'Gene', '1387;2033', (44, 52))	('V260S', 'Var', (0, 5))	('TAF9', 'Gene', (35, 39))	('Med23', 'Gene', '9439', (84, 89))	('Sur2', 'Gene', (91, 95))	('rv-cyclin pulldown', 'MPA', (13, 31))	('AD', 'Disease', 'MESH:D000544', (185, 187))	('TAF9', 'Gene', '6880', (35, 39))	('Sur2', 'Gene', '9439', (91, 95))	('Med23', 'Gene', (84, 89))	('CBP/p300', 'Gene', (44, 52))	('AD', 'Disease', (185, 187))
321177	21067790	Anti-cdk8 co-IP of mutants K80A, E111A, and DM were greatly reduced.	('K80A', 'Mutation', 'p.K80A', (27, 31))	('mutants K80A', 'Var', (19, 31))	('E111A', 'Var', (33, 38))	('DM', 'Disease', 'MESH:D009223', (44, 46))	('reduced', 'NegReg', (60, 67))	('Anti-cdk8', 'Protein', (0, 9))	('E111A', 'Mutation', 'p.E111A', (33, 38))
321178	21067790	The V260S mutation and deletion of the carboxy end had little or no effect on anti-cdk8 co-precipitation (Fig.	('V260S', 'Var', (4, 9))	('anti-cdk8', 'MPA', (78, 87))	('V260S', 'Mutation', 'p.V260S', (4, 9))	('deletion', 'Var', (23, 31))
321195	21067790	Cyclin C/cdk3 functions in the direct control of cell cycle progression by phosphorylating Rb on residues S807 and S811 to initiate cell cycle and the proliferation of quiescent cells.	('Cyclin C', 'Gene', (0, 8))	('initiate', 'PosReg', (123, 131))	('S811', 'Var', (115, 119))	('cdk3', 'Gene', (9, 13))	('cell cycle', 'CPA', (132, 142))	('cdk3', 'Gene', '1018', (9, 13))	('Cyclin C', 'Gene', '892', (0, 8))
321201	21067790	To increase cdk3 levels further, HA-tagged cdk3 was over expressed in HeLa cells with or without myc-rv-cyclin induction.	('HeLa', 'CellLine', 'CVCL:0030', (70, 74))	('over', 'PosReg', (52, 56))	('cdk3', 'Gene', '1018', (43, 47))	('myc', 'Gene', (97, 100))	('cdk3', 'Gene', (12, 16))	('cdk3', 'Gene', (43, 47))	('cdk3', 'Gene', '1018', (12, 16))	('myc', 'Gene', '4609', (97, 100))	('HA-tagged', 'Var', (33, 42))	('increase', 'PosReg', (3, 11))
321203	21067790	In experiments with HA-tagged rv-cyclin containing cyclin box mutations and FLAG-tagged cdk3, none of the mutations interfered with its co-IP with cdk3 (not shown) indicating alternative contacts between the rv-cyclin and cdk3.	('cdk3', 'Gene', '1018', (147, 151))	('co-IP', 'MPA', (136, 141))	('contacts', 'Interaction', (187, 195))	('cdk3', 'Gene', (88, 92))	('cdk3', 'Gene', (222, 226))	('mutations', 'Var', (106, 115))	('cdk3', 'Gene', '1018', (88, 92))	('cdk3', 'Gene', '1018', (222, 226))	('interfered', 'NegReg', (116, 126))	('cdk3', 'Gene', (147, 151))	('mutations', 'Var', (62, 71))
321207	21067790	During serum starvation for cdk3 induction, a difference was noted in the number and appearance of HeLa cells with or without induced myc-rv-cyclin expression: cells with rv-cyclin expanded to greater numbers and had a higher percentage of viable cells by trypan blue exclusion.	('cdk3', 'Gene', (28, 32))	('cdk3', 'Gene', '1018', (28, 32))	('higher', 'PosReg', (219, 225))	('myc', 'Gene', '4609', (134, 137))	('HeLa', 'CellLine', 'CVCL:0030', (99, 103))	('expression', 'Species', '29278', (148, 158))	('trypan blue', 'Chemical', 'MESH:D014343', (256, 267))	('rv-cyclin', 'Var', (171, 180))	('myc', 'Gene', (134, 137))
321214	21067790	Alteration of host gene expression via cdk8 function could result in the acceleration of all phases of the cell cycle.	('expression', 'Species', '29278', (24, 34))	('cdk8', 'Gene', (39, 43))	('acceleration', 'PosReg', (73, 85))	('Alteration', 'Var', (0, 10))	('all phases of the cell cycle', 'CPA', (89, 117))
321281	31699989	Tissue-specific microRNA expression alters cancer susceptibility conferred by a TP53 noncoding variant A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms.	('TP53', 'Gene', '22059', (144, 148))	('neoplasms', 'Disease', 'MESH:D009369', (262, 271))	('TP53', 'Gene', '22059', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('alters', 'Reg', (36, 42))	('brain tumors', 'Phenotype', 'HP:0030692', (239, 251))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('neoplasms', 'Disease', (262, 271))	('brain tumors', 'Disease', 'MESH:D001932', (239, 251))	('people', 'Species', '9606', (183, 189))	('brain tumor', 'Phenotype', 'HP:0030692', (239, 250))	('rs78378222', 'Var', (129, 139))	('brain tumors', 'Disease', (239, 251))	('rat', 'Species', '10116', (226, 229))	('neoplasms', 'Phenotype', 'HP:0002664', (262, 271))	('TP53', 'Gene', (144, 148))	('rs78378222', 'Mutation', 'rs78378222', (129, 139))	('cancer', 'Disease', (43, 49))	('TP53', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
321284	31699989	We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis.	('delays', 'NegReg', (144, 150))	('rat', 'Species', '10116', (72, 75))	('glioma', 'Disease', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('variant', 'Var', (40, 47))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('tumor', 'Disease', (159, 164))	('accelerates', 'PosReg', (66, 77))	('rat', 'Species', '10116', (7, 10))	('mouse', 'Species', '10090', (15, 20))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
321286	31699989	Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (35, 46))	('glioma', 'Disease', (114, 120))	('mutants', 'Var', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Li-Fraumeni', 'Disease', (35, 46))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('variant', 'Var', (11, 18))	('breast cancer', 'Disease', (67, 80))
321287	31699989	Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.	('genetic variation', 'Var', (93, 110))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('conferred', 'Reg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('altered', 'Reg', (119, 126))
321288	31699989	TP53 mutations can cause increased risk for cancers.	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
321289	31699989	Here, the authors show a noncoding polymorphism in TP53 increases risk of some cancers but delays onset of others, and in a mouse model show this is via alteration of microRNA targeting sites that differ in impact depending on the tissue.	('cancers', 'Disease', (79, 86))	('increases', 'PosReg', (56, 65))	('TP53', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('alteration', 'Reg', (153, 163))	('mouse', 'Species', '10090', (124, 129))	('noncoding polymorphism', 'Var', (25, 47))	('rat', 'Species', '10116', (157, 160))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('delays', 'NegReg', (91, 97))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('microRNA targeting sites', 'MPA', (167, 191))
321291	31699989	Mutations in the coding sequence (CDS) of TP53, encoding the p53 tumor suppressor, are found in ~75% of LFS families; these TP53 mutants produce mutant p53 proteins that lack most or all tumor-suppressive functions and often confer oncogenic properties.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('mutant', 'Var', (145, 151))	('p53', 'Gene', (152, 155))	('TP53', 'Gene', (42, 46))	('proteins', 'Protein', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('TP53', 'Gene', (124, 128))	('lack', 'NegReg', (170, 174))	('tumor', 'Disease', (187, 192))	('Mutations', 'Var', (0, 9))	('confer', 'Reg', (225, 231))	('mutants', 'Var', (129, 136))	('oncogenic properties', 'CPA', (232, 252))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
321292	31699989	Changes in TP53 noncoding sequences, in contrast, have lower penetrance but still confer cancer susceptibility.	('confer', 'Reg', (82, 88))	('penetrance', 'MPA', (61, 71))	('TP53', 'Gene', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Changes', 'Var', (0, 7))	('lower', 'NegReg', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
321293	31699989	A noncoding single-nucleotide polymorphism (SNP, rs78378222) in TP53 is associated with moderate risk of several cancers.	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('associated', 'Reg', (72, 82))	('rs78378222', 'Var', (49, 59))	('rs78378222', 'Mutation', 'rs78378222', (49, 59))	('cancers', 'Disease', (113, 120))	('rat', 'Species', '10116', (92, 95))	('TP53', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
321294	31699989	Unlike LFS mutant and common TP53 CDS variants, such as P72R and P47S, this TP53 noncoding variant produces wild-type (WT) p53 proteins, albeit at a lower level in cells.	('P72R', 'Var', (56, 60))	('TP53', 'Gene', (76, 80))	('P47S', 'Mutation', 'rs1800371', (65, 69))	('proteins', 'Protein', (127, 135))	('P72R', 'Mutation', 'rs1042522', (56, 60))
321295	31699989	Cancer susceptibility conferred by this TP53 noncoding variant does not strictly mirror that of TP53 germline coding mutations in LFS patients (Supplementary Table 1): individuals with the minor allele are at increased risk of brain tumors (particularly glioma), neuroblastoma, skin basal cell carcinoma (BCC), esophageal squamous cell carcinoma (SCC), prostate cancer, colorectal adenoma, and uterine leiomyoma.	('prostate cancer', 'Phenotype', 'HP:0012125', (353, 368))	('colorectal adenoma', 'Disease', 'MESH:C563924', (370, 388))	('leiomyoma', 'Disease', 'MESH:D007889', (402, 411))	('neuroblastoma', 'Disease', (263, 276))	('SCC', 'Gene', (347, 350))	('patients', 'Species', '9606', (134, 142))	('prostate cancer', 'Disease', (353, 368))	('neuroblastoma', 'Phenotype', 'HP:0003006', (263, 276))	('skin basal cell carcinoma', 'Disease', 'MESH:D002280', (278, 303))	('brain tumors', 'Disease', (227, 239))	('neuroblastoma', 'Disease', 'MESH:D009447', (263, 276))	('esophageal squamous cell carcinoma', 'Disease', (311, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('minor', 'Var', (189, 194))	('glioma', 'Disease', (254, 260))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (283, 303))	('leiomyoma', 'Disease', (402, 411))	('glioma', 'Disease', 'MESH:D005910', (254, 260))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('SCC', 'Phenotype', 'HP:0002860', (347, 350))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (322, 345))	('brain tumor', 'Phenotype', 'HP:0030692', (227, 238))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (311, 345))	('glioma', 'Phenotype', 'HP:0009733', (254, 260))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (394, 411))	('BCC', 'Phenotype', 'HP:0002671', (305, 308))	('skin basal cell carcinoma', 'Disease', (278, 303))	('brain tumors', 'Phenotype', 'HP:0030692', (227, 239))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('SCC', 'Gene', '6317', (347, 350))	('brain tumors', 'Disease', 'MESH:D001932', (227, 239))	('colorectal adenoma', 'Disease', (370, 388))	('prostate cancer', 'Disease', 'MESH:D011471', (353, 368))
321303	31699989	Supported by five independent studies, the TP53 noncoding variant (rs78378222[C]) increases glioma risk more significantly than for other tumors with an odds ratio (OR) ranging from 2.35 to 3.74 (Supplementary Table 1).	('increases glioma', 'Disease', 'MESH:D005910', (82, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('increases glioma', 'Disease', (82, 98))	('rat', 'Species', '10116', (158, 161))	('rs78378222', 'Mutation', 'rs78378222', (67, 77))	('rs78378222[', 'Var', (67, 78))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('TP53', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
321305	31699989	Thus, this TP53 variant shares a phenotypic similarity with LFS mutants in brain tumor (glioma) predisposition.	('brain tumor', 'Disease', 'MESH:D001932', (75, 86))	('brain tumor', 'Disease', (75, 86))	('variant', 'Var', (16, 23))	('TP53', 'Gene', (11, 15))	('glioma', 'Disease', (88, 94))	('brain tumor', 'Phenotype', 'HP:0030692', (75, 86))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('mutants', 'Var', (64, 71))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
321309	31699989	This TP53 noncoding variant does neither appear to increase the risk for sporadic breast cancer nor for high-risk breast cancer (Supplementary Table 1); however, in this study, all breast cancer patients and the vast majority of the unaffected controls were genotyped for this variant by imputation, which has relatively low accuracy for infrequent alleles like this TP53 variant.	('breast cancer', 'Disease', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', (181, 194))	('variant', 'Var', (277, 284))	('patients', 'Species', '9606', (195, 203))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('breast cancer', 'Disease', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
321310	31699989	In addition, other cancers to which patients with this variant are predisposed (neuroblastoma, prostate cancer, skin BCC, and esophageal SCC) occur infrequently in patients with LFS.	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('neuroblastoma', 'Disease', (80, 93))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('SCC', 'Gene', '6317', (137, 140))	('neuroblastoma', 'Phenotype', 'HP:0003006', (80, 93))	('prostate cancer', 'Disease', 'MESH:D011471', (95, 110))	('patients', 'Species', '9606', (164, 172))	('neuroblastoma', 'Disease', 'MESH:D009447', (80, 93))	('prostate cancer', 'Phenotype', 'HP:0012125', (95, 110))	('SCC', 'Gene', (137, 140))	('variant', 'Var', (55, 62))	('prostate cancer', 'Disease', (95, 110))	('skin BCC', 'Disease', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('BCC', 'Phenotype', 'HP:0002671', (117, 120))
321311	31699989	In this study, we have performed direct genotyping of this TP53 variant in patients with breast cancer and sarcoma.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('TP53', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('sarcoma', 'Disease', (107, 114))	('patients', 'Species', '9606', (75, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('variant', 'Var', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('coma', 'Phenotype', 'HP:0001259', (110, 114))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))
321312	31699989	We uncover that this TP53 variant increases the risk for soft-tissue sarcoma, but decreases the risk for breast cancer.	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (61, 76))	('TP53', 'Gene', (21, 25))	('coma', 'Phenotype', 'HP:0001259', (72, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (57, 76))	('variant', 'Var', (26, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('decreases', 'NegReg', (82, 91))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (57, 76))	('soft-tissue sarcoma', 'Disease', (57, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('increases', 'PosReg', (34, 43))
321313	31699989	We generate a mouse line carrying this variant and evaluate tumorigenesis in different organs; particularly, we investigate whether and how this variant increases the risk for glioma but not breast cancer.	('glioma', 'Disease', (176, 182))	('mouse', 'Species', '10090', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('variant', 'Var', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('rat', 'Species', '10116', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (60, 65))	('breast cancer', 'Disease', (191, 204))	('variant', 'Var', (145, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
321315	31699989	Our findings uncover a TP53 variant at odds with LFS mutants in regard to breast cancer risk yet consistent with LFS mutants in predisposition to glioma and reveal an underlying mechanism of tissue-specific cancer susceptibility that is mediated by miRNAs.	('breast cancer', 'Disease', (74, 87))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('miR', 'Gene', '735281', (249, 252))	('miR', 'Gene', (249, 252))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (207, 213))	('mutants', 'Var', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('glioma', 'Disease', (146, 152))	('cancer', 'Disease', (81, 87))	('mutants', 'Var', (53, 60))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('TP53', 'Gene', (23, 27))	('variant', 'Var', (28, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
321316	31699989	To determine the association of this TP53 noncoding variant with the risk for breast cancer and sarcoma, we genotyped rs78378222 in adult patients with breast cancer (n = 2373) or sarcoma (n = 130) and their respective unaffected controls (n = 9972 and 8947) of Chinese Han descent (Table 1).	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('rs78378222', 'Mutation', 'rs78378222', (118, 128))	('breast cancer', 'Disease', (78, 91))	('sarcoma', 'Disease', 'MESH:D012509', (180, 187))	('sarcoma', 'Disease', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('coma', 'Phenotype', 'HP:0001259', (99, 103))	('coma', 'Phenotype', 'HP:0001259', (183, 187))	('patients', 'Species', '9606', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('sarcoma', 'Disease', (96, 103))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('rs78378222', 'Var', (118, 128))
321317	31699989	We observed a significant association between rs78378222[C] and the risk of sarcoma (OR = 3.29, P = 0.0014, Cochran-Armitage trend test).	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('sarcoma', 'Disease', (76, 83))	('rs78378222[', 'Var', (46, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('coma', 'Phenotype', 'HP:0001259', (79, 83))	('rs78378222', 'Mutation', 'rs78378222', (46, 56))
321319	31699989	In sharp contrast, this TP53 variant protected against breast cancer (OR = 0.573, P = 0.0078, Cochran-Armitage trend test).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TP53', 'Gene', (24, 28))	('variant', 'Var', (29, 36))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
321322	31699989	Mice carrying the p53C allele had shorter survival than their WT p53+/+ littermates (Fig.	('survival', 'CPA', (42, 50))	('p53C', 'Var', (18, 22))	('shorter', 'NegReg', (34, 41))	('Mice', 'Species', '10090', (0, 4))
321324	31699989	We noted that p53+/C and p53C/C mice had close survival curves, yet p53+/C mice survived better than p53C/C mice (P = 0.017, log-rank test, Fig.	('mice', 'Species', '10090', (75, 79))	('better', 'PosReg', (89, 95))	('mice', 'Species', '10090', (108, 112))	('mice', 'Species', '10090', (32, 36))	('p53+/C', 'Var', (68, 74))
321325	31699989	Tumors developed more frequently in polymorphic mice than in WT controls (Supplementary Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (48, 52))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('polymorphic', 'Var', (36, 47))
321326	31699989	B-cell malignancies were the most frequently occurring cancer in p53+/C and p53C/C mice (without development of thymic lymphoma) (Fig.	('thymic lymphoma', 'Disease', (112, 127))	('p53+/C', 'Var', (65, 71))	('thymic lymphoma', 'Disease', 'MESH:D013953', (112, 127))	('malignancies', 'Disease', 'MESH:D009369', (7, 19))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lymphoma', 'Phenotype', 'HP:0002665', (119, 127))	('mice', 'Species', '10090', (83, 87))	('malignancies', 'Disease', (7, 19))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('p53C/C', 'Var', (76, 82))	('cancer', 'Disease', (55, 61))
321327	31699989	Exome sequencing of lymphomas developed in polymorphic mice showed p53 coding somatic mutations in all tumors, with a relative read ratio of p53 and Gapdh close to 1:1 (Supplementary Table 3, Supplementary Fig.	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('lymphomas', 'Phenotype', 'HP:0002665', (20, 29))	('rat', 'Species', '10116', (132, 135))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('p53', 'Gene', (67, 70))	('Gapdh', 'Gene', '14433', (149, 154))	('Gapdh', 'Gene', (149, 154))	('tumors', 'Disease', (103, 109))	('mice', 'Species', '10090', (55, 59))	('lymphomas', 'Disease', 'MESH:D008223', (20, 29))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (20, 28))	('lymphomas', 'Disease', (20, 29))
321328	31699989	There were a few p53 mutations in Supplementary Table 3 resembling human hotspot TP53 pathogenic mutations.	('p53', 'Gene', (17, 20))	('human', 'Species', '9606', (67, 72))	('mutations', 'Var', (21, 30))
321329	31699989	First, there were two point-nonsense mutants that will result in truncated and nonfunctional p53 proteins lacking DNA-binding domain, tetramerization domains, and extreme carboxyl terminus.	('lacking', 'NegReg', (106, 113))	('mutants', 'Var', (37, 44))	('p53', 'Gene', (93, 96))	('proteins', 'Protein', (97, 105))	('truncated', 'MPA', (65, 74))	('DNA-binding domain', 'MPA', (114, 132))	('tetramerization domains', 'MPA', (134, 157))	('carboxyl', 'Chemical', 'MESH:C041069', (171, 179))
321330	31699989	Second, P38T, the only recurrent mutation, is found in two tumors.	('P38T', 'Mutation', 'p.P38T', (8, 12))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('P38T', 'Var', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
321332	31699989	Irradiation further shortened the survival of p53 polymorphic mice, with increased cancer-associated death and increased thymic lymphoma incidence compared with untreated mice (Supplementary Fig.	('increased', 'PosReg', (73, 82))	('increased', 'PosReg', (111, 120))	('mice', 'Species', '10090', (171, 175))	('shortened', 'NegReg', (20, 29))	('p53', 'Gene', (46, 49))	('survival', 'CPA', (34, 42))	('thymic lymphoma', 'Disease', (121, 136))	('mice', 'Species', '10090', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('thymic lymphoma', 'Disease', 'MESH:D013953', (121, 136))	('death', 'Disease', 'MESH:D003643', (101, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('death', 'Disease', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('polymorphic', 'Var', (50, 61))	('cancer', 'Disease', (83, 89))
321333	31699989	The median survival were 104, 93, and 85 weeks for irradiated p53+/+, p53+/C, and p53C/C mice, respectively.	('p53+/C', 'Var', (70, 76))	('mice', 'Species', '10090', (89, 93))	('p53+/+', 'Var', (62, 68))	('p53C/C', 'Var', (82, 88))
321335	31699989	TP53 is the only gene that (1) causes a rare monogenic Mendelian disorder (LFS) that includes a greatly increased risk of glioma, and (2) has a common inherited SNP (rs78378222) associated with a smaller increased risk of glioma (Supplementary Table 1).	('rs78378222', 'Mutation', 'rs78378222', (166, 176))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('Mendelian disorder', 'Disease', (55, 73))	('Mendelian disorder', 'Disease', 'MESH:D030342', (55, 73))	('glioma', 'Disease', (222, 228))	('glioma', 'Disease', (122, 128))	('causes', 'Reg', (31, 37))	('TP53', 'Var', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (222, 228))	('rs78378222', 'Var', (166, 176))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
321337	31699989	This TP53 variant predispose both GBM and non-GBM glioma.	('GBM', 'Disease', (34, 37))	('predispose', 'Reg', (18, 28))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('glioma', 'Disease', (50, 56))	('TP53', 'Gene', (5, 9))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('variant', 'Var', (10, 17))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))
321338	31699989	Approximately 30% of GBM tumors demonstrate a proneural gene expression pattern, characterized by frequent TP53 mutation and PDGFRA mutation and/or overexpression.	('overexpression', 'PosReg', (148, 162))	('PDGFRA', 'Gene', '18595', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('proneural gene expression pattern', 'MPA', (46, 79))	('mutation', 'Var', (112, 120))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PDGFRA', 'Gene', (125, 131))	('TP53', 'Gene', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('rat', 'Species', '10116', (39, 42))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('mutation', 'Var', (132, 140))
321340	31699989	p53-/- mice receiving retrovirus had the earliest tumor onset, and all succumbed to glioma within 40 days, whereas p53+/- mice survived up to 150 days (Fig.	('mice', 'Species', '10090', (122, 126))	('glioma', 'Disease', (84, 90))	('retrovirus', 'Var', (22, 32))	('mice', 'Species', '10090', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('succumbed', 'Reg', (71, 80))
321342	31699989	Tumors from p53C/C mice were highly infiltrative and invasive with extensive vascularization and necrosis (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('p53C/C', 'Var', (12, 18))	('invasive', 'CPA', (53, 61))	('necrosis', 'Disease', (97, 105))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('necrosis', 'Disease', 'MESH:D009336', (97, 105))	('mice', 'Species', '10090', (19, 23))	('rat', 'Species', '10116', (42, 45))
321345	31699989	These data support that the TP53 variant is pathogenic in gliomagenesis.	('gliomagenesis', 'Disease', 'None', (58, 71))	('TP53', 'Gene', (28, 32))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('variant', 'Var', (33, 40))	('gliomagenesis', 'Disease', (58, 71))	('pathogenic', 'Reg', (44, 54))
321346	31699989	To determine the role of this TP53 variant in the pathogenesis of breast cancer, we first crossed p53+/C mice with mice expressing the polyoma virus middle T antigen (PyVT) driven by the mouse mammary tumor virus long terminal repeat (MMTV) promoter in the mammary gland.	('VT', 'Disease', 'MESH:D017180', (169, 171))	('mice', 'Species', '10090', (115, 119))	('polyoma virus middle T', 'Disease', (135, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mouse mammary tumor virus', 'Species', '11757', (187, 212))	('polyoma virus middle T', 'Disease', 'MESH:D015658', (135, 157))	('breast cancer', 'Disease', (66, 79))	('variant', 'Var', (35, 42))	('mice', 'Species', '10090', (105, 109))
321350	31699989	We examined the precancerous transformation of mammary epithelial cells using whole mounts of mammary gland and found that the p53C allele delays development of epithelial hyperplasia to about 8 weeks of age, compared with 4 to 6 weeks in p53+/+;PyVT littermates (Fig.	('VT', 'Disease', 'MESH:D017180', (248, 250))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (161, 183))	('cancer', 'Disease', (19, 25))	('epithelial hyperplasia', 'Disease', (161, 183))	('delays', 'NegReg', (139, 145))	('p53C', 'Var', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('delays development', 'Phenotype', 'HP:0001263', (139, 157))
321358	31699989	p53 protein staining was strong in mammary tumors that developed in mice with either the polymorphic or WT p53 (Supplementary Fig.	('mice', 'Species', '10090', (68, 72))	('polymorphic', 'Var', (89, 100))	('p53 protein', 'Protein', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
321359	31699989	DNA sequencing of the p53 gene in five mammary tumors from each group revealed all samples carried heterozygous p53 coding mutations, supporting that gain-of-function p53 mutation is needed for mammary tumorigenesis.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('gain-of-function', 'PosReg', (150, 166))	('mutation', 'Var', (171, 179))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('p53', 'Gene', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('p53', 'Gene', (167, 170))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
321360	31699989	p53 protein and mRNA levels, as well as protein phosphorylation upon irradiation, in the brain, colon, and spleen of p53C/C mice were lower than in WT littermates (Fig.	('lower', 'NegReg', (134, 139))	('mRNA levels', 'MPA', (16, 27))	('mice', 'Species', '10090', (124, 128))	('protein phosphorylation', 'MPA', (40, 63))	('p53C/C', 'Var', (117, 123))	('p53 protein', 'MPA', (0, 11))
321361	31699989	p53 protein in the brain of p53C/C mice was significantly lower than that in p53+/+ mice (Fig.	('lower', 'NegReg', (58, 63))	('p53 protein', 'Protein', (0, 11))	('mice', 'Species', '10090', (35, 39))	('p53C/C', 'Var', (28, 34))	('mice', 'Species', '10090', (84, 88))
321363	31699989	In contrast, p53 was upregulated in the mammary gland of p53C/C mice compared with WT littermates.	('p53C/C', 'Var', (57, 63))	('upregulated', 'PosReg', (21, 32))	('mice', 'Species', '10090', (64, 68))	('p53', 'Gene', (13, 16))
321364	31699989	When cDNA was prepared from the total RNAs in mouse tissues and sequenced, the p53C alleles from p53C/C mice were outnumbered by p53A alleles from p53+/+ mice in the brain, whereas the p53C allele outnumbered p53A in the mammary gland (Fig.	('mice', 'Species', '10090', (154, 158))	('p53C/C', 'Var', (97, 103))	('mice', 'Species', '10090', (104, 108))	('p53C', 'Gene', (79, 83))	('mouse', 'Species', '10090', (46, 51))
321369	31699989	Because the variant exerts moderate regulation over p53, we suspected that miRNA expression is a determinant of differential p53 deregulation in polymorphic mice.	('miR', 'Gene', '735281', (75, 78))	('miR', 'Gene', (75, 78))	('variant', 'Var', (12, 19))	('mice', 'Species', '10090', (157, 161))	('regulation', 'MPA', (36, 46))	('rat', 'Species', '10116', (31, 34))
321370	31699989	miR-325 putatively targets the native TP53 3'UTR, whereas miR-382 targets the TP53 3'UTR with the PAS variant in both human and mouse (Fig.	('mouse', 'Species', '10090', (128, 133))	('variant', 'Var', (102, 109))	('miR-325', 'Gene', (0, 7))	('human', 'Species', '9606', (118, 123))
321372	31699989	The ratio of miR-325:miR-382 is lowest in the brain, and highest in the breast/mammary gland in both humans (Fig.	('humans', 'Species', '9606', (101, 107))	('rat', 'Species', '10116', (4, 7))	('miR-382', 'Var', (21, 28))	('miR-325', 'Var', (13, 20))
321378	31699989	miR-382 inhibition resulted in higher p53 protein expression than did miR-325 inhibition in U87 and HCT116 cells, which had higher endogenous miR-382 levels, while opposite results were observed in MCF7 and MCF10a cells, which had higher endogenous miR-325 levels (Fig.	('p53 protein', 'Protein', (38, 49))	('miR-382', 'Gene', (0, 7))	('dog', 'Species', '9615', (133, 136))	('MCF7', 'CellLine', 'CVCL:0031', (198, 202))	('MCF10a', 'CellLine', 'CVCL:0598', (207, 213))	('HCT116', 'CellLine', 'CVCL:0291', (100, 106))	('higher', 'PosReg', (31, 37))	('inhibition', 'Var', (8, 18))	('U87', 'CellLine', 'CVCL:0022', (92, 95))	('dog', 'Species', '9615', (240, 243))
321379	31699989	Similarly, miR-325 inhibition resulted in greater p53 protein expression than did miR-382 inhibition in p53+/+ MEFs, while opposite results were observed in p53C/C MEFs (Fig.	('miR-325', 'Gene', (11, 18))	('inhibition', 'Var', (19, 29))	('greater', 'PosReg', (42, 49))	('MEFs', 'CellLine', 'CVCL:9115', (164, 168))	('MEFs', 'CellLine', 'CVCL:9115', (111, 115))	('p53 protein', 'Protein', (50, 61))
321380	31699989	We introduced miRNA mimics into MEFs and found miR-325 downregulated p53 to a greater extent than did miR-382 in p53+/+ MEFs, whereas miR-382 downregulated p53 to a greater extent than did miR-325 in p53C/C MEFs (Fig.	('miR', 'Gene', '735281', (102, 105))	('miR', 'Gene', (102, 105))	('miR', 'Gene', '735281', (47, 50))	('miR', 'Gene', (47, 50))	('miR', 'Gene', (134, 137))	('miR', 'Gene', '735281', (134, 137))	('MEFs', 'CellLine', 'CVCL:9115', (120, 124))	('miR', 'Gene', '735281', (189, 192))	('p53', 'MPA', (69, 72))	('miR', 'Gene', (189, 192))	('downregulated', 'NegReg', (55, 68))	('downregulated', 'NegReg', (142, 155))	('miR', 'Gene', '735281', (14, 17))	('miR', 'Gene', (14, 17))	('p53+/+', 'Var', (113, 119))	('MEFs', 'CellLine', 'CVCL:9115', (207, 211))	('MEFs', 'CellLine', 'CVCL:9115', (32, 36))
321381	31699989	In human cells with exogenous TP53A, miR-325 downregulated p53 protein levels more than miR-382; in contrast, in cells with TP53C, miR-382 downregulated p53 protein levels more than miR-325 (Supplementary Fig.	('p53 protein levels', 'MPA', (59, 77))	('p53 protein levels', 'MPA', (153, 171))	('human', 'Species', '9606', (3, 8))	('downregulated', 'NegReg', (45, 58))	('downregulated', 'NegReg', (139, 152))	('miR-382', 'Var', (131, 138))
321387	31699989	To further test direct interaction between TP53A/TP53C and miR-325/miR-382, we performed pull-down assays using H1299 cells transfected with biotinylated RNA fragments and streptavidin beads to co-purify their binding partners (Supplementary Fig.	('biotin', 'Chemical', 'MESH:D001710', (141, 147))	('interaction', 'Interaction', (23, 34))	('H1299', 'CellLine', 'CVCL:0060', (112, 117))	('TP53A/TP53C', 'Var', (43, 54))
321389	31699989	Second, biotinylated miRNAs were used to co-purify exogenous 3'UTR in H1299 cells transfected with EGFP-expressing plasmids containing the TP53 3'UTR carrying either the WT PAS or the alternative PAS with a WT or mutant miR-382 targeting site (Supplementary Fig.	('H1299', 'CellLine', 'CVCL:0060', (70, 75))	('TP53', 'Var', (139, 143))	('miR', 'Gene', '735281', (21, 24))	('miR', 'Gene', (21, 24))	('miR', 'Gene', '735281', (220, 223))	('miR', 'Gene', (220, 223))	('biotin', 'Chemical', 'MESH:D001710', (8, 14))	('mutant', 'Var', (213, 219))
321397	31699989	Those receiving both Pdgfb and the miR-382 inhibitor prolonged the survival of p53C/C mice compared with those receiving Pdgfb and the control inhibitor (or the miR-325 inhibitor) (Fig.	('survival', 'CPA', (67, 75))	('Pdgfb', 'Gene', (21, 26))	('Pdgfb', 'Gene', '18591', (21, 26))	('mice', 'Species', '10090', (86, 90))	('Pdgfb', 'Gene', '18591', (121, 126))	('miR-382', 'Gene', (35, 42))	('Pdgfb', 'Gene', (121, 126))	('inhibitor', 'Var', (43, 52))	('prolonged', 'PosReg', (53, 62))
321399	31699989	These data demonstrate that modulating the expression of p53C-targeting miR-382 alters tumor development both in the brain and in the mammary gland of p53C polymorphic mice.	('alters tumor', 'Disease', (80, 92))	('rat', 'Species', '10116', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mice', 'Species', '10090', (168, 172))	('miR-382', 'Gene', (72, 79))	('alters tumor', 'Disease', 'MESH:D004408', (80, 92))	('modulating', 'Var', (28, 38))
321401	31699989	At one end of the spectrum are very rare to rare high-penetrance mutants causing Mendelian diseases, all of which are located in the CDS of tumor suppressor genes (e.g., TP53 germline mutations in LFS).	('germline', 'Var', (175, 183))	('Mendelian diseases', 'Disease', 'MESH:D030342', (81, 99))	('Mendelian diseases', 'Disease', (81, 99))	('TP53 germline', 'Var', (170, 183))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('LFS', 'Gene', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
321403	31699989	Virtually all familial cancer syndromes are caused by these germline coding mutations.	('familial cancer syndromes', 'Disease', (14, 39))	('caused by', 'Reg', (44, 53))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (14, 39))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('germline', 'Var', (60, 68))
321405	31699989	In comparison with other GWAS polymorphisms, the TP53 noncoding variant (rs78378222[C]) is unique in cancer susceptibility, tissue-specificity, and pathogenicity.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('TP53', 'Gene', (49, 53))	('rs78378222[', 'Var', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('rs78378222', 'Mutation', 'rs78378222', (73, 83))
321407	31699989	Given the world population is estimated to reach 7.7 billion this year and assuming the MAF is 1.0 %, characterization of this variant will benefit ~150 million people worldwide at the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('benefit', 'Reg', (140, 147))	('variant', 'Var', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('people', 'Species', '9606', (161, 167))
321408	31699989	Second, it, as a TP53 variant in a Chinese population, protects breast cancer, the most frequent LFS tumor type and increases the risk for soft-tissue sarcoma, the second most frequent LFS tumor type.	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (139, 158))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('protects', 'NegReg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('soft-tissue sarcoma', 'Disease', (139, 158))	('coma', 'Phenotype', 'HP:0001259', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('LFS tumor', 'Disease', (185, 194))	('variant', 'Var', (22, 29))	('LFS tumor', 'Disease', (97, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (143, 158))	('LFS tumor', 'Disease', 'MESH:D009369', (185, 194))	('LFS tumor', 'Disease', 'MESH:D009369', (97, 106))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('increases', 'PosReg', (116, 125))	('breast cancer', 'Disease', (64, 77))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (139, 158))
321409	31699989	The p53C variant delays mammary tumorigenesis in two mouse models.	('p53C', 'Var', (4, 8))	('delays', 'NegReg', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mouse', 'Species', '10090', (53, 58))	('tumor', 'Disease', (32, 37))
321410	31699989	Third, it is bona fide pathogenic in comparison with other reported germline variants potentially disrupting miRNA binding.	('variants', 'Var', (77, 85))	('miR', 'Gene', '735281', (109, 112))	('miR', 'Gene', (109, 112))	('disrupting', 'NegReg', (98, 108))
321412	31699989	Among them, the SNP rs61764370 (also known as LCS6) in a let-7 miRNA complementary site within the 3'UTR of the KRAS oncogene is among the most studied.	('rs61764370', 'Mutation', 'rs61764370', (20, 30))	('SNP', 'Var', (16, 19))	('KRAS', 'Gene', '16653', (112, 116))	('miR', 'Gene', '735281', (63, 66))	('miR', 'Gene', (63, 66))	('KRAS', 'Gene', (112, 116))	('rs61764370', 'Var', (20, 30))
321413	31699989	However, the clinical utility of the KRAS LCS6 variant has been significantly questioned since the initial publications showing it is associated with lung cancer, breast cancer, and ovarian cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('associated', 'Reg', (134, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('lung cancer', 'Disease', (150, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('variant', 'Var', (47, 54))	('KRAS', 'Gene', (37, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (182, 196))	('KRAS', 'Gene', '16653', (37, 41))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ovarian cancer', 'Disease', (182, 196))	('breast cancer', 'Disease', (163, 176))
321414	31699989	In the largest ever study with a total of 140,012 human subjects, the KRAS LCS6 variant did not increase the risk of ovarian cancer or breast cancer, regardless of the BRAC1/2 status; null results were also obtained for associations with overall survival for ovarian cancer, breast cancer, and all other previously reported associations for these cancers.	('ovarian cancer', 'Disease', (259, 273))	('KRAS', 'Gene', (70, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (259, 273))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('human', 'Species', '9606', (50, 55))	('breast cancer', 'Disease', (135, 148))	('cancers', 'Disease', 'MESH:D009369', (347, 354))	('KRAS', 'Gene', '16653', (70, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (275, 288))	('variant', 'Var', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('breast cancer', 'Disease', 'MESH:D001943', (275, 288))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('breast cancer', 'Disease', (275, 288))	('cancers', 'Phenotype', 'HP:0002664', (347, 354))	('ovarian cancer', 'Disease', 'MESH:D010051', (259, 273))	('associations', 'Interaction', (220, 232))	('cancers', 'Disease', (347, 354))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('ovarian cancer', 'Disease', (117, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
321416	31699989	Therefore, ascertaining the pathogenic role of this TP53 variant in this study facilitates our understanding of low-penetrance noncoding cancer susceptibility loci with a low frequency.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('TP53', 'Gene', (52, 56))	('variant', 'Var', (57, 64))	('cancer', 'Disease', (137, 143))
321417	31699989	We compare cancer patients carrying rs78378222[C] to LFS patients.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('patients', 'Species', '9606', (57, 65))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('patients', 'Species', '9606', (18, 26))	('rs78378222[C', 'Var', (36, 48))	('cancer', 'Disease', (11, 17))	('rs78378222', 'Mutation', 'rs78378222', (36, 46))
321418	31699989	The rs78378222[C] differs from LFS mutants in several aspects: mutation sites (over 100 sites vs. a single nucleotide), tumor spectrum (including breast cancer vs. protective against breast cancer), penetrance (high vs. moderate), and the size of the affected population (reported thousands vs. potentially as many as 150 millions) (Table 2).	('rs78378222[', 'Var', (4, 15))	('rs78378222', 'Mutation', 'rs78378222', (4, 14))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('rat', 'Species', '10116', (224, 227))	('breast cancer', 'Disease', (183, 196))	('tumor', 'Disease', (120, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
321420	31699989	The effect of sex on cancer penetrance may not exist or could even be reversed in patients carrying this variant, which confers risk for prostate cancer and protection for breast cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('patients', 'Species', '9606', (82, 90))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('variant', 'Var', (105, 112))	('breast cancer', 'Disease', (172, 185))	('prostate cancer', 'Disease', (137, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (179, 185))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))
321421	31699989	Finally, different miRNAs are involved in regulation of cancer susceptibility by LFS mutants and the noncoding variant.	('miR', 'Gene', '735281', (19, 22))	('miR', 'Gene', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LFS', 'Gene', (81, 84))	('mutants', 'Var', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (56, 62))
321425	31699989	This study shows that differential expression of miRNAs reduces the expression of a pathogenic genetic variant in one tissue yet increases its expression in another and contributes, at least partially, to tissue-specific cancer susceptibility within the same individual.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('expression', 'MPA', (143, 153))	('expression', 'MPA', (68, 78))	('cancer', 'Disease', (221, 227))	('reduces', 'NegReg', (56, 63))	('increases', 'PosReg', (129, 138))	('miR', 'Gene', (49, 52))	('miR', 'Gene', '735281', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('contributes', 'Reg', (169, 180))	('variant', 'Var', (103, 110))
321426	31699989	Collectively, these differences, particularly that these patients with the noncoding variant are protected from breast cancer, argue against calling rs78378222[C] an LFS variant.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('patients', 'Species', '9606', (57, 65))	('rs78378222[', 'Var', (149, 160))	('rs78378222', 'Mutation', 'rs78378222', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
321427	31699989	In the clinical context of cancer clusters found in a family that fit the description (i.e., multiple family members developed various cancers associated with this variant as in Supplementary Table 1), rs78378222 genotyping and a potential targeted cancer surveillance plan, different from the one for LFS, should be considered for those at risk.	('cancer', 'Disease', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancers', 'Disease', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('rs78378222', 'Var', (202, 212))	('cancer', 'Disease', (249, 255))	('rs78378222', 'Mutation', 'rs78378222', (202, 212))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('variant', 'Var', (164, 171))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
321429	31699989	Another strength is that the biological plausibility of this variant in cancer risk and protection is extensively interrogated and ascertained using multiple mouse models and molecular cellular assays.	('mouse', 'Species', '10090', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('variant', 'Var', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
321433	31699989	The p53C allele delayed mammary tumorigenesis in two mouse models.	('p53C', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mouse', 'Species', '10090', (53, 58))	('delayed', 'NegReg', (16, 23))	('tumor', 'Disease', (32, 37))
321434	31699989	We caution that although littermate mice were used, we cannot rule out the possibility that a gene or genes linked to the p53C allele in the C57BL/6 strain influenced the decrease in mammary cancer risk.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('decrease', 'NegReg', (171, 179))	('mice', 'Species', '10090', (36, 40))	('p53C', 'Var', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
321435	31699989	The variant is protective for breast cancer in this study with a Chinese population, yet there was no specific association between this variant and breast cancer in a European population.	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', (30, 43))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('variant', 'Var', (4, 11))
321437	31699989	What types of tumors do patients with TP53C/C and children and adolescents with the variant develop?	('children', 'Species', '9606', (50, 58))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('patients', 'Species', '9606', (24, 32))	('TP53C/C', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
321438	31699989	Are miRNAs behind the protective role of the p53 variant against squamous cell carcinoma of head and neck?	('p53', 'Gene', (45, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('miR', 'Gene', '735281', (4, 7))	('squamous cell carcinoma of head', 'Disease', (65, 96))	('miR', 'Gene', (4, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('variant', 'Var', (49, 56))	('squamous cell carcinoma of head', 'Disease', 'MESH:D002294', (65, 96))
321447	31699989	The association of rs78378222[C] with the risk of cancer was determined using the Cochran-Armitage trend test.	('rs78378222', 'Mutation', 'rs78378222', (19, 29))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('rs78378222[', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
321451	31699989	Antibodies against p53 (for western blotting [WB], CST2524, 1:1000 dilution), phosphorylated-p53 Ser15 (for WB, CST9248, 1:1000 dilution), GAPDH (CST5174, 1:1000 dilution), and beta-actin (CST4970, 1:5000 dilution) were from Cell Signaling Technology (Danvers, MA).	('CST5174', 'Var', (146, 153))	('CST4970', 'Var', (189, 196))	('beta-actin', 'Gene', (177, 187))	('GAPDH', 'Gene', '14433', (139, 144))	('GAPDH', 'Gene', (139, 144))	('p53', 'Gene', (19, 22))	('beta-actin', 'Gene', '11461', (177, 187))	('Ser', 'Chemical', 'MESH:C530429', (97, 100))
321452	31699989	Antibodies against beta-casein (SC-166684, 1:20 dilution) and beta-catenin (SC-7963, 1:50 dilution) were from Santa Cruz Biotechnology (Dallas, TX).	('beta-catenin', 'Gene', (62, 74))	('SC-166684', 'Var', (32, 41))	('SC-166684', 'Chemical', 'MESH:C049999', (32, 41))	('beta-catenin', 'Gene', '12387', (62, 74))	('beta-casein', 'Protein', (19, 30))	('SC-7963', 'Var', (76, 83))
321461	31699989	The p531175A located in the p53 PAS (AATAAA) was mutated to p531175C (AATACA), corresponding to human rs78378222.	('p531175C', 'Chemical', 'MESH:C068201', (60, 68))	('p531175A', 'Var', (4, 12))	('rs78378222', 'Mutation', 'rs78378222', (102, 112))	('human', 'Species', '9606', (96, 101))	('p531175C', 'Var', (60, 68))
321487	31699989	The titer of the viral particles expressing miR-382 was 9.1 x 108 transducing units (TU) per mL with TUs measured by p24 antigen ELISA assays.	('p24', 'Gene', '13088', (117, 120))	('p24', 'Gene', (117, 120))	('miR-382', 'Var', (44, 51))
321506	31699989	3), or co-transfected EGFP-expressing plasmids containing the WT or the alternative PAS TP53 3'UTR with a RFP-expressing plasmid with WT SV40 3'UTR as transfection control (Supplementary Fig.	('RFP', 'Gene', (106, 109))	('RFP', 'Gene', '19720', (106, 109))	('TP53', 'Var', (88, 92))
321517	31699989	The p53 mutation data in mice with spontaneous lymphomas have been deposited in the NCBI BioProject database under the accession code PRJNA575686.	('mice', 'Species', '10090', (25, 29))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('lymphomas', 'Phenotype', 'HP:0002665', (47, 56))	('lymphomas', 'Disease', 'MESH:D008223', (47, 56))	('lymphomas', 'Disease', (47, 56))	('mutation', 'Var', (8, 16))	('p53', 'Gene', (4, 7))
321574	27803495	In 2014 the patient underwent resection of a suspected myxoma (82x41x24 mm) in the left atrium.	('myxoma', 'Disease', (55, 61))	('myxoma', 'Disease', 'MESH:D009232', (55, 61))	('patient', 'Species', '9606', (12, 19))	('82x41x24 mm', 'Var', (63, 74))
321650	21643012	Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood.	('miR', 'Gene', '220972', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('miR', 'Gene', (41, 44))	('aberrant', 'Var', (32, 40))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
321653	21643012	In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1.	('EWS', 'Gene', '2130', (108, 111))	('miR', 'Gene', '220972', (43, 46))	('EWS', 'Gene', (108, 111))	('miR', 'Gene', (43, 46))	('Fli1', 'Gene', '2313', (112, 116))	('Fli1', 'Gene', (112, 116))	('100', 'Var', (49, 52))
321671	21643012	Monoclonal antibody and small molecule inhibitors of IGF-1R impair Ewing sarcoma cell and tumor growth, and are currently in clinical trials as the chief adjunctive biological therapy for this aggressive cancer.	('inhibitors', 'Var', (39, 49))	('cancer', 'Disease', (204, 210))	('impair', 'NegReg', (60, 66))	('IGF-1R', 'Gene', '3480', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('IGF-1R', 'Gene', (53, 59))	('clinical', 'Species', '191496', (125, 133))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('Ewing sarcoma', 'Disease', (67, 80))
321683	21643012	Similar to the approach of others, we employed shRNAs targeted to the 3' end of Fli1 to target the EWS-Fli1 fusion (the unrearranged Fli1 gene is not expressed in Ewing sarcoma), using a lentiviral delivery system.	('Fli1', 'Gene', (103, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (163, 176))	('Fli1', 'Gene', (80, 84))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (163, 176))	('Fli1', 'Gene', '2313', (133, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('Fli1', 'Gene', '2313', (103, 107))	('Fli1', 'Gene', (133, 137))	('Ewing sarcoma', 'Disease', (163, 176))	('fusion', 'Var', (108, 114))	('EWS', 'Gene', (99, 102))	('EWS', 'Gene', '2130', (99, 102))	('Fli1', 'Gene', '2313', (80, 84))
321685	21643012	Importantly, this knockdown was sufficient to downregulate the expression of two established EWS-Fli1 target genes, Nkx2.2 and NR0B1 (; Figure 1b).	('downregulate', 'NegReg', (46, 58))	('Fli1', 'Gene', (97, 101))	('knockdown', 'Var', (18, 27))	('NR0B1', 'Gene', (127, 132))	('EWS', 'Gene', '2130', (93, 96))	('EWS', 'Gene', (93, 96))	('NR0B1', 'Gene', '190', (127, 132))	('expression', 'MPA', (63, 73))	('Nkx2.2', 'Gene', '4821', (116, 122))	('Fli1', 'Gene', '2313', (97, 101))	('Nkx2.2', 'Gene', (116, 122))
321690	21643012	From miRs differentially expressed by array, we initially chose to focus on EWS/Fli1-repressed miRs (that is, those upregulated upon EWS/Fli1 silencing), as these represented candidate tumor suppressors and thus novel antitumor agents in Ewing sarcoma.	('silencing', 'Var', (142, 151))	('miR', 'Gene', '220972', (5, 8))	('EWS', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('EWS', 'Gene', '2130', (133, 136))	('tumor', 'Disease', (185, 190))	('miR', 'Gene', (5, 8))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (238, 251))	('Fli1', 'Gene', (80, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (238, 251))	('upregulated', 'PosReg', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('miR', 'Gene', '220972', (95, 98))	('EWS', 'Gene', '2130', (76, 79))	('Fli1', 'Gene', '2313', (137, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('tumor', 'Disease', (222, 227))	('EWS', 'Gene', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('Ewing sarcoma', 'Disease', (238, 251))	('miR', 'Gene', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('Fli1', 'Gene', (137, 141))	('Fli1', 'Gene', '2313', (80, 84))
321691	21643012	Of the 30 miRs upregulated upon EWS/Fli1 knockdown with a false discovery rate <=0.01, we further focused on those showing the greatest change (at least 1.5-fold by array).	('upregulated', 'PosReg', (15, 26))	('Fli1', 'Gene', (36, 40))	('EWS', 'Gene', '2130', (32, 35))	('EWS', 'Gene', (32, 35))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('knockdown', 'Var', (41, 50))	('Fli1', 'Gene', '2313', (36, 40))
321694	21643012	Given the importance of this pathway in Ewing sarcoma oncogenesis, these miRs, namely miRs 22, 100, 125b, 221, 222, 27a and 29a, were selected for further analysis as potential mediators of EWS/Fli1 oncogenesis through the IGF pathway (Figure 1d).	('Fli1', 'Gene', '2313', (194, 198))	('221', 'Var', (106, 109))	('miR', 'Gene', (73, 76))	('Ewing sarcoma oncogenesis', 'Disease', (40, 65))	('EWS', 'Gene', '2130', (190, 193))	('EWS', 'Gene', (190, 193))	('Fli1', 'Gene', (194, 198))	('miR', 'Gene', (86, 89))	('miR', 'Gene', '220972', (86, 89))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('miR', 'Gene', '220972', (73, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('IGF', 'Pathway', (223, 226))	('Ewing sarcoma oncogenesis', 'Disease', 'MESH:C563168', (40, 65))
321696	21643012	All EWS/Fli1-targeted shRNAs showed increased levels of these miRs relative to matched off-target controls (Figure 1d), confirming that the changes observed were specific to EWS/Fli1 silencing.	('Fli1', 'Gene', (178, 182))	('Fli1', 'Gene', '2313', (8, 12))	('miR', 'Gene', '220972', (62, 65))	('silencing', 'Var', (183, 192))	('miR', 'Gene', (62, 65))	('Fli1', 'Gene', (8, 12))	('levels', 'MPA', (46, 52))	('increased', 'PosReg', (36, 45))	('Fli1', 'Gene', '2313', (178, 182))	('EWS', 'Gene', '2130', (174, 177))	('EWS', 'Gene', (174, 177))	('EWS', 'Gene', '2130', (4, 7))	('EWS', 'Gene', (4, 7))
321701	21643012	As EWS/Fli1 is a transcriptional regulator, we hypothesized that the observed changes in the levels of the mature miRs upon EWS/Fli1 silencing could be because of regulation at the level of the miR primary transcript.	('miR', 'Gene', (194, 197))	('Fli1', 'Gene', (128, 132))	('EWS', 'Gene', (124, 127))	('EWS', 'Gene', '2130', (124, 127))	('levels', 'MPA', (93, 99))	('Fli1', 'Gene', '2313', (128, 132))	('changes', 'Reg', (78, 85))	('miR', 'Gene', '220972', (194, 197))	('silencing', 'Var', (133, 142))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', (114, 117))	('Fli1', 'Gene', '2313', (7, 11))	('EWS', 'Gene', '2130', (3, 6))	('EWS', 'Gene', (3, 6))	('Fli1', 'Gene', (7, 11))
321704	21643012	As shown in Figures 2c and d, EWS/Fli1 expression resulted in downregulation of both the primary transcript and the mature form, respectively, of miRs 100, 125b, 22, 221 and 27a.	('expression', 'Var', (39, 49))	('Fli1', 'Gene', '2313', (34, 38))	('primary transcript', 'MPA', (89, 107))	('EWS', 'Gene', '2130', (30, 33))	('EWS', 'Gene', (30, 33))	('downregulation', 'NegReg', (62, 76))	('miR', 'Gene', '220972', (146, 149))	('miR', 'Gene', (146, 149))	('Fli1', 'Gene', (34, 38))
321711	21643012	As these regions contain the candidate EWS/Fli1 sites (-660 and +120; Figure 2e), this finding suggests that miR-100 downregulation may involve direct transcriptional repression by EWS/Fli1.	('miR-100', 'Gene', '406892', (109, 116))	('Fli1', 'Gene', '2313', (43, 47))	('-660', 'Var', (55, 59))	('Fli1', 'Gene', (185, 189))	('Fli1', 'Gene', '2313', (185, 189))	('downregulation', 'NegReg', (117, 131))	('Fli1', 'Gene', (43, 47))	('EWS', 'Gene', (39, 42))	('EWS', 'Gene', '2130', (39, 42))	('miR-100', 'Gene', (109, 116))	('transcriptional repression', 'MPA', (151, 177))	('EWS', 'Gene', '2130', (181, 184))	('EWS', 'Gene', (181, 184))
321742	21643012	Taken together, our findings support tumor-suppressive functions for miRs 22, 100, 125b, 221, 27a and 29a in Ewing sarcoma, in part through negative regulation of pro-oncogenic components of the IGF-1 signaling pathway.	('negative', 'NegReg', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Ewing sarcoma', 'Disease', (109, 122))	('IGF-1', 'Gene', '3479', (195, 200))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('tumor', 'Disease', (37, 42))	('miR', 'Gene', '220972', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('miR', 'Gene', (69, 72))	('IGF-1', 'Gene', (195, 200))	('221', 'Var', (89, 92))
321745	21643012	When these were subjected to a miR target prediction algorithm (TargetScan), nine of the genes emerged as candidate targets of miRs 22, 100, 125b, 221/222, 27a and 29a (Supplementary Table S1).	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('221/222', 'Var', (147, 154))
321856	31150281	Furthermore, other BCOR alterations (often loss of function mutations) recur in a large variety of mesenchymal, epithelial, neural and hematological tumors, suggesting a central role in cancer evolution.	('loss of function', 'NegReg', (43, 59))	('alterations', 'Var', (24, 35))	('hematological tumors', 'Disease', 'MESH:D006402', (135, 155))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('BCOR', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('hematological tumors', 'Disease', (135, 155))	('mesenchymal', 'Disease', (99, 110))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
321857	31150281	It is known that tumorigenesis depends on the sequential acquisition of proto-oncogene-activating mutations and/or oncosuppressor loss of function.	('loss of function', 'NegReg', (130, 146))	('tumor', 'Disease', (17, 22))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
321862	31150281	Polycomb repressive complexes (PRCs) are molecular complexes involved in histone modification processes that are usually classified into two types: PRC1, which adds an ubiquitin moiety to histone H2A at Lys119 (H2AK119ub1), and PRC2, which catalyzes the addition of one to three methyl groups to histone H3 at Lys27, leading to H3K27me1, H3K27me2 or H3K27me3.	('H3K27me2', 'Var', (338, 346))	('H2AK119', 'Gene', '8337', (211, 218))	('H2A', 'Gene', '8337', (196, 199))	('H2A', 'Gene', (196, 199))	('H2AK119', 'Gene', (211, 218))	('Lys27', 'Chemical', '-', (310, 315))	('H2A', 'Gene', '8337', (211, 214))	('H3K27me3', 'Var', (350, 358))	('Lys119', 'Chemical', '-', (203, 209))	('H3K27me1', 'Var', (328, 336))	('H2A', 'Gene', (211, 214))
321873	31150281	This last mechanism is at least partly responsible for the coordinated activity of PRC1 and PRC2, since it is known that the PRC2-dependent H3K27me3 mark increases affinity and recruits CBX-containing cPRC1, while KDM2B-mediated recruitment to nonmethylated CpG islands of ncPRC1 drives H2AK119ub that conversely promotes binding of PRC2.	('increases', 'PosReg', (154, 163))	('H2AK119', 'Gene', '8337', (287, 294))	('H3K27me3', 'Var', (140, 148))	('H2AK119', 'Gene', (287, 294))	('promotes', 'PosReg', (313, 321))	('CBX', 'Chemical', 'MESH:D002261', (186, 189))	('affinity', 'MPA', (164, 172))	('binding', 'Interaction', (322, 329))
321877	31150281	Specifically, a number of BCOR germinal loss of function mutations (>40 were previously identified) induce oculo-facio-cardio-dental syndrome (OFCD), inherited in an X-linked dominant mode and lethal in males.	('cardio-dental syndrome', 'Disease', (119, 141))	('OFCD', 'Disease', (143, 147))	('dental syndrome', 'Phenotype', 'HP:0000164', (126, 141))	('BCOR', 'Gene', (26, 30))	('mutations', 'Var', (57, 66))	('OFCD', 'Disease', 'MESH:C537465', (143, 147))	('loss of function', 'NegReg', (40, 56))	('cardio-dental syndrome', 'Disease', 'MESH:D059347', (119, 141))
321882	31150281	Due to its central role in pluripotency maintenance, differentiation induction and cell fate determination, it is not surprising that mutations in BCOR play a central role in cancer development.	('pluripotency', 'Disease', 'None', (27, 39))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('BCOR', 'Gene', (147, 151))	('mutations', 'Var', (134, 143))	('role', 'Reg', (167, 171))	('pluripotency', 'Disease', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
321892	31150281	In fact, the features of duplication, that is strictly in-frame and associated with overexpression of the protein encoded by BCOR, suggested important speculations about the origins of CCSK.	('duplication', 'Var', (25, 36))	('CCSK', 'Chemical', '-', (185, 189))	('BCOR', 'Gene', (125, 129))	('CCSK', 'Phenotype', 'HP:0006770', (185, 189))
321894	31150281	Currently, we are still far from having conclusive results on the question, and even though there is evidence supporting a loss-of-function effect of ITD-BCOR, (overexpression of Cyclin D1, of PRC2 targets and of several classes of HOX genes), the lack of any frameshift or nonsense mutation in this setting is instead in favor of a gain-of-function event.	('loss-of-function', 'NegReg', (123, 139))	('nonsense mutation', 'Var', (274, 291))	('gain-of-function', 'PosReg', (333, 349))	('Cyclin D1', 'Gene', '595', (179, 188))	('frameshift', 'Var', (260, 270))	('Cyclin D1', 'Gene', (179, 188))	('ITD-BCOR', 'Gene', (150, 158))
321898	31150281	Actually, few studies that investigated PMMTI at a molecular level have found the presence of ITD-BCOR (Figure 3A) associated with the overexpression of BCOR in almost all the cases analyzed, similarly to CCSK.	('BCOR', 'MPA', (153, 157))	('ITD-BCOR', 'Gene', (94, 102))	('associated', 'Reg', (115, 125))	('presence', 'Var', (82, 90))	('CCSK', 'Chemical', '-', (205, 209))	('CCSK', 'Phenotype', 'HP:0006770', (205, 209))	('overexpression', 'PosReg', (135, 149))
321900	31150281	The typical pediatric tumors of Ewing sarcoma family can be molecularly distinguished by the presence of translocations involving the EWSR1 gene and one of ETS/FLI family genes.	('EWSR1', 'Gene', '2130', (134, 139))	('pediatric tumors of Ewing sarcoma', 'Disease', (12, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (32, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('presence', 'Reg', (93, 101))	('translocations', 'Var', (105, 119))	('pediatric tumors of Ewing sarcoma', 'Disease', 'MESH:C563168', (12, 45))	('EWSR1', 'Gene', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
321902	31150281	However, progressive diffusion of molecular profiling and high-throughput sequencing technologies has allowed the identification of an increasing number of molecular alterations in undifferentiated sarcomas that are morphologically similar or indistinguishable from Ewing's sarcoma, but lacking the aforementioned molecular features.	('undifferentiated sarcomas', 'Disease', (181, 206))	('alterations', 'Var', (166, 177))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (266, 281))	("Ewing's sarcoma", 'Disease', (266, 281))	('sarcomas', 'Phenotype', 'HP:0100242', (198, 206))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (266, 281))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (181, 206))
321918	31150281	An extremely interesting result of this last study is that all SRBCS-carrying BCOR alterations generate a common cluster at the transcriptional level, thus reinforcing a view in which BCOR alterations, either ITD or rearrangements, exert a common pathogenic pathway leading to abnormal activity of the PRC1.1 complex.	('alterations', 'Var', (83, 94))	('exert', 'Reg', (232, 237))	('leading to', 'Reg', (266, 276))	('BCOR', 'Gene', (184, 188))	('BCOR', 'Gene', (78, 82))	('SRBCS', 'Chemical', '-', (63, 68))	('abnormal activity', 'MPA', (277, 294))	('alterations', 'Var', (189, 200))
321927	31150281	A rare subtype of RMS is anaplastic, where a single case was recently reported to carry a BCOR alteration, together with mutation in ARID1A, a member of the SWI/SNF family, and of SETD2, a histone methyl-transferase.	('ARID1A', 'Gene', '8289', (133, 139))	('ARID1A', 'Gene', (133, 139))	('alteration', 'Var', (95, 105))	('RMS', 'Phenotype', 'HP:0002859', (18, 21))	('mutation', 'Var', (121, 129))	('SETD2', 'Gene', '29072', (180, 185))	('BCOR', 'Disease', (90, 94))	('SETD2', 'Gene', (180, 185))
321928	31150281	Two studies confirmed that BCOR mutations in RMS recur in about 7-8% of total cases, with an apparent major involvement in PAX-negative RMS, for which the percentage nears 10% of cases (Table 2).	('RMS', 'Disease', (45, 48))	('RMS', 'Phenotype', 'HP:0002859', (136, 139))	('RMS', 'Phenotype', 'HP:0002859', (45, 48))	('PAX', 'Chemical', '-', (123, 126))	('mutations', 'Var', (32, 41))	('BCOR', 'Gene', (27, 31))
321935	31150281	identified three cases carrying ITD-BCOR, one defined as high-grade ESS and two as undifferentiated ESS, all three cases holding typical immunophenotypic features of ITD-BCOR-positive tumors, such as the overexpression of cyclin D1 and BCOR.	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cyclin D1', 'Gene', '595', (222, 231))	('ITD-BCOR', 'Var', (32, 40))	('cyclin D1', 'Gene', (222, 231))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('BCOR', 'Gene', (236, 240))	('overexpression', 'PosReg', (204, 218))
321943	31150281	Therefore, it is not surprising that several CNS tumors carry BCOR alterations (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('alterations', 'Var', (67, 78))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('BCOR', 'MPA', (62, 66))	('CNS', 'Disease', (45, 48))
321944	31150281	Mutations with supposed loss of function (e.g., nonsense, frameshift, splice sites and deletions) have been identified in up to 13% of retinoblastomas; between 1 and 14% of various glial tumors, particularly in high-grade tumors and also in pediatric patients, with a 25% peak found in recurrent high-grade astroblastoma.	('glial tumors', 'Disease', 'MESH:D005910', (181, 193))	('patients', 'Species', '9606', (251, 259))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Disease', (222, 228))	('frameshift', 'Var', (58, 68))	('splice sites', 'Var', (70, 82))	('retinoblastomas', 'Disease', (135, 150))	('glial tumors', 'Disease', (181, 193))	('retinoblastomas', 'Phenotype', 'HP:0009919', (135, 150))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('loss of function', 'NegReg', (24, 40))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('deletions', 'Var', (87, 96))	('tumors', 'Disease', (187, 193))	('nonsense', 'Var', (48, 56))	('astroblastoma', 'Disease', (307, 320))	('astroblastoma', 'Disease', 'MESH:D018302', (307, 320))	('retinoblastomas', 'Disease', 'MESH:D012175', (135, 150))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('retinoblastoma', 'Phenotype', 'HP:0009919', (135, 149))
321945	31150281	Moreover, BCOR genetic alterations also appear in 2-8% of medulloblastomas, and in particular, such aberrations seem to be more represented in SHH-driven cases, especially in infant patients.	('SHH', 'Gene', (143, 146))	('medulloblastomas', 'Disease', 'MESH:D008527', (58, 74))	('infant', 'Species', '9606', (175, 181))	('medulloblastoma', 'Phenotype', 'HP:0002885', (58, 73))	('genetic alterations', 'Var', (15, 34))	('SHH', 'Gene', '6469', (143, 146))	('patients', 'Species', '9606', (182, 190))	('medulloblastomas', 'Disease', (58, 74))	('BCOR', 'Gene', (10, 14))	('appear', 'Reg', (40, 46))
321952	31150281	In addition to the recurrence of ITD-BCOR, CNS tumors and mesenchymal tumors with BCOR abnormalities also share common characteristics regarding transcriptional regulation.	('tumors', 'Disease', (47, 53))	('abnormalities', 'Var', (87, 100))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (58, 76))	('mesenchymal tumors', 'Disease', (58, 76))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('transcriptional regulation', 'MPA', (145, 171))
321957	31150281	Mutations of this gene in knockout organisms result in hematological abnormalities, consisting in functional deficiency of primitive erythrocytes and lymphocyte depletion, and confirming the relevance of BCOR on the activity of BCL-6, a known mitogenic agent for lymphoid cells.	('functional deficiency', 'Disease', (98, 119))	('BCL-6', 'Gene', (228, 233))	('deficiency of primitive erythrocytes and lymphocyte', 'Phenotype', 'HP:0012133', (109, 160))	('BCL-6', 'Gene', '604', (228, 233))	('functional deficiency', 'Disease', 'OMIM:608852', (98, 119))	('hematological abnormalities', 'Disease', (55, 82))	('Mutations', 'Var', (0, 9))	('hematological abnormalities', 'Phenotype', 'HP:0001871', (55, 82))	('hematological abnormalities', 'Disease', 'MESH:D006402', (55, 82))	('result in', 'Reg', (45, 54))
321959	31150281	Even if the introduction of next-generation sequencing (NGS) techniques for the molecular screening of large cohorts of patients affected by hemolymphopoietic system neoplasms highlighted the clear involvement of BCOR alterations in these diseases, at present it is still challenging to clarify the biological role of BCOR in myeloid and lymphoid precursors and to translate this molecular knowledge for clinical applications.	('neoplasms', 'Phenotype', 'HP:0002664', (166, 175))	('involvement', 'Reg', (198, 209))	('hemolymphopoietic system neoplasms', 'Disease', 'MESH:D009369', (141, 175))	('neoplasm', 'Phenotype', 'HP:0002664', (166, 174))	('patients', 'Species', '9606', (120, 128))	('alterations', 'Var', (218, 229))	('BCOR', 'Gene', (213, 217))	('hemolymphopoietic system neoplasms', 'Disease', (141, 175))
321961	31150281	generated transgenic mice harboring exon 4 deletion leading to loss of the BCL-6-binding domain, which developed lethal acute T-cell lymphoblastic leukemia in a Notch1-dependent manner and demonstrated myc upregulation.	('myc', 'Gene', (202, 205))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('Notch1', 'Gene', (161, 167))	('T-cell lymphoblastic leukemia', 'Disease', (126, 155))	('BCL-6', 'Gene', (75, 80))	('deletion', 'Var', (43, 51))	('myc', 'Gene', '17869', (202, 205))	('Notch1', 'Gene', '18128', (161, 167))	('BCL-6', 'Gene', '604', (75, 80))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (133, 155))	('upregulation', 'PosReg', (206, 218))	('T-cell lymphoblastic leukemia', 'Disease', 'MESH:D054218', (126, 155))	('transgenic mice', 'Species', '10090', (10, 25))	('loss', 'NegReg', (63, 67))
321962	31150281	showed that BCOR is a tumor suppressor in the Emu-myc lymphoma murine model and its loss-of-function mutations act as myc-cooperating events in this setting.	('loss-of-function', 'NegReg', (84, 100))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('lymphoma', 'Phenotype', 'HP:0002665', (54, 62))	('BCOR', 'Gene', (12, 16))	('myc', 'Gene', (118, 121))	('Emu-myc lymphoma', 'Disease', (46, 62))	('Emu-myc lymphoma', 'Disease', 'MESH:D008223', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('myc', 'Gene', (50, 53))	('myc', 'Gene', '17869', (118, 121))	('myc', 'Gene', '17869', (50, 53))	('murine', 'Species', '10090', (63, 69))
321963	31150281	The involvement of BCOR alterations in clonal disorders of myeloid lineage (Table 2) has been assessed primarily for myelodysplasias and acute myeloid leukemia (AML), with cases ranging from less than 1-10% in unselected cohorts.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (137, 159))	('myelodysplasias', 'Disease', 'MESH:D009190', (117, 132))	('myelodysplasia', 'Phenotype', 'HP:0002863', (117, 131))	('alterations', 'Var', (24, 35))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (137, 159))	('leukemia', 'Phenotype', 'HP:0001909', (151, 159))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (143, 159))	('AML', 'Disease', 'MESH:D015470', (161, 164))	('BCOR', 'Gene', (19, 23))	('acute myeloid leukemia', 'Disease', (137, 159))	('AML', 'Phenotype', 'HP:0004808', (161, 164))	('AML', 'Disease', (161, 164))	('myelodysplasias', 'Disease', (117, 132))
321964	31150281	Particularly in AML, it is clear that the frequency of BCOR mutations is significantly higher in older patients than in pediatric ones, with pediatric AMLs with normal karyotype as the exception and higher in secondary AML with respect to primary AML.	('AML', 'Disease', (219, 222))	('BCOR', 'Gene', (55, 59))	('AML', 'Disease', (151, 154))	('AML', 'Phenotype', 'HP:0004808', (16, 19))	('AML', 'Phenotype', 'HP:0004808', (247, 250))	('AML', 'Disease', 'MESH:D015470', (151, 154))	('AML', 'Disease', (16, 19))	('AML', 'Disease', 'MESH:D015470', (219, 222))	('AML', 'Disease', 'MESH:D015470', (247, 250))	('patients', 'Species', '9606', (103, 111))	('AML', 'Phenotype', 'HP:0004808', (219, 222))	('mutations', 'Var', (60, 69))	('AML', 'Disease', (247, 250))	('AML', 'Phenotype', 'HP:0004808', (151, 154))	('AML', 'Disease', 'MESH:D015470', (16, 19))
321965	31150281	In the context of these specific entities, association with BCOR comutations (Table 2) is particularly relevant in the following instances: intermediate cytogenetic prognosis and FLT3-ITD-negative AML in adult patients under 65, nonselected myeloid neoplasms with mutations in cohesin-coding genes, AML with changes associated with myelodysplasia, AML with trisomy 11 or 13, AML with balanced or unbalanced chromosomal rearrangements, AML with normal karyotype (in particular, pediatric AML) or if co-occurring mutations in NPM1, CEBPA, FLT3-ITD, MLL-PTD or RUNX1 are present.	('mutations', 'Var', (264, 273))	('AML', 'Disease', (375, 378))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (241, 258))	('AML', 'Phenotype', 'HP:0004808', (375, 378))	('FLT3', 'Gene', (537, 541))	('NPM1', 'Gene', (524, 528))	('AML', 'Disease', 'MESH:D015470', (487, 490))	('AML', 'Disease', (487, 490))	('myelodysplasia', 'Phenotype', 'HP:0002863', (332, 346))	('FLT3', 'Gene', '2322', (537, 541))	('FLT3', 'Gene', (179, 183))	('myelodysplasia', 'Disease', 'MESH:D009190', (332, 346))	('neoplasms', 'Phenotype', 'HP:0002664', (249, 258))	('FLT3', 'Gene', '2322', (179, 183))	('patients', 'Species', '9606', (210, 218))	('neoplasm', 'Phenotype', 'HP:0002664', (249, 257))	('AML', 'Disease', 'MESH:D015470', (348, 351))	('CEBPA', 'Gene', '1050', (530, 535))	('AML', 'Disease', 'MESH:D015470', (197, 200))	('AML', 'Phenotype', 'HP:0004808', (348, 351))	('AML', 'Disease', 'MESH:D015470', (435, 438))	('myeloid neoplasms', 'Disease', (241, 258))	('AML', 'Disease', (348, 351))	('MLL-PTD', 'Disease', (547, 554))	('RUNX1', 'Gene', (558, 563))	('NPM1', 'Gene', '4869', (524, 528))	('RUNX1', 'Gene', '861', (558, 563))	('AML', 'Disease', (197, 200))	('AML', 'Phenotype', 'HP:0004808', (435, 438))	('AML', 'Phenotype', 'HP:0004808', (197, 200))	('AML', 'Disease', (435, 438))	('AML', 'Disease', 'MESH:D015470', (299, 302))	('CEBPA', 'Gene', (530, 535))	('trisomy 11', 'Var', (357, 367))	('AML', 'Disease', (299, 302))	('AML', 'Phenotype', 'HP:0004808', (299, 302))	('MLL-PTD', 'Disease', 'MESH:C537633', (547, 554))	('myelodysplasia', 'Disease', (332, 346))	('mutations', 'Var', (511, 520))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (241, 258))	('AML', 'Disease', 'MESH:D015470', (375, 378))
321968	31150281	BCOR alterations found in myeloid clonal diseases are apparently clustered around exon 4 and for the most part are mutations with presumed loss-of-function.	('myeloid clonal diseases', 'Disease', 'MESH:C580365', (26, 49))	('alterations', 'Var', (5, 16))	('loss-of-function', 'NegReg', (139, 155))	('BCOR', 'Gene', (0, 4))	('myeloid clonal diseases', 'Disease', (26, 49))
321969	31150281	The prognostic significance of the presence of BCOR mutations in myeloid clonal diseases was also evaluated.	('mutations', 'Var', (52, 61))	('myeloid clonal diseases', 'Disease', (65, 88))	('myeloid clonal diseases', 'Disease', 'MESH:C580365', (65, 88))	('BCOR', 'Gene', (47, 51))
321970	31150281	identified the presence of mutated BCOR as an independent negative prognostic factor in MDS.	('mutated', 'Var', (27, 34))	('presence', 'Var', (15, 23))	('negative', 'NegReg', (58, 66))	('BCOR', 'Protein', (35, 39))	('MDS', 'Disease', (88, 91))	('MDS', 'Disease', 'MESH:D009190', (88, 91))
321972	31150281	Finally, BCOR alterations have been identified and/or described in several studies conducted on acquired aplastic anemia patients, in percentages similar to those described for nonselected MDS and AML.	('alterations', 'Var', (14, 25))	('MDS', 'Disease', (189, 192))	('MDS', 'Disease', 'MESH:D009190', (189, 192))	('AML', 'Disease', 'MESH:D015470', (197, 200))	('aplastic anemia', 'Disease', (105, 120))	('BCOR', 'Gene', (9, 13))	('AML', 'Phenotype', 'HP:0004808', (197, 200))	('AML', 'Disease', (197, 200))	('anemia', 'Phenotype', 'HP:0001903', (114, 120))	('aplastic anemia', 'Phenotype', 'HP:0001915', (105, 120))	('aplastic anemia', 'Disease', 'MESH:D000741', (105, 120))	('patients', 'Species', '9606', (121, 129))
321973	31150281	This suggested the possibility that these mutations may contribute to clonal selection during the onset of myeloid malignancies on the aplastic anemia background.	('myeloid malignancies', 'Disease', 'MESH:D009369', (107, 127))	('aplastic anemia', 'Disease', (135, 150))	('aplastic anemia', 'Phenotype', 'HP:0001915', (135, 150))	('myeloid malignancies', 'Disease', (107, 127))	('aplastic anemia', 'Disease', 'MESH:D000741', (135, 150))	('contribute', 'Reg', (56, 66))	('anemia', 'Phenotype', 'HP:0001903', (144, 150))	('mutations', 'Var', (42, 51))
321974	31150281	BCOR alterations have been identified in up to 9% of prolymphocytic T leukemias, chronic lymphocytic leukemias and, respectively, in 24% and up to 32% of the evaluated cases of diffuse splenic lymphoma of the red pulp and of extranodal NK/T-cells lymphoma, nasal type.	('lymphoma', 'Phenotype', 'HP:0002665', (193, 201))	('identified', 'Reg', (27, 37))	('to 9', 'Species', '1214577', (44, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (247, 255))	('alterations', 'Var', (5, 16))	('splenic lymphoma', 'Disease', (185, 201))	('splenic lymphoma', 'Disease', 'MESH:D013158', (185, 201))	('leukemias', 'Phenotype', 'HP:0001909', (70, 79))	('leukemias', 'Phenotype', 'HP:0001909', (101, 110))	('prolymphocytic T leukemias', 'Disease', (53, 79))	('chronic lymphocytic leukemias', 'Phenotype', 'HP:0005550', (81, 110))	('lymphocytic leukemias', 'Disease', 'MESH:D007945', (89, 110))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('lymphoma', 'Disease', (193, 201))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('-cells lymphoma', 'Phenotype', 'HP:0012191', (240, 255))	('T-cells lymphoma', 'Phenotype', 'HP:0012190', (239, 255))	('BCOR', 'Gene', (0, 4))	('lymphoma', 'Disease', 'MESH:D008223', (193, 201))	('lymphocytic leukemias', 'Disease', (89, 110))	('lymphoma', 'Disease', (247, 255))	('lymphoma', 'Disease', 'MESH:D008223', (247, 255))	('prolymphocytic T leukemias', 'Disease', 'MESH:D015463', (53, 79))	('lymphocytic leukemias', 'Phenotype', 'HP:0005526', (89, 110))
321979	31150281	These studies are partly strengthened by the analysis of tumor histotypes associated with BCOR mutations.	('BCOR', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutations', 'Var', (95, 104))	('tumor', 'Disease', (57, 62))
321981	31150281	In the context of thymic tumors, it is particularly interesting that BCOR mutations recur in 50% of cases of aggressive B3-thymoma.	('BCOR', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('thymic tumors', 'Disease', 'MESH:D013953', (18, 31))	('aggressive B3-thymoma', 'Disease', (109, 130))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (74, 83))	('thymoma', 'Phenotype', 'HP:0100522', (123, 130))	('aggressive B3-thymoma', 'Disease', 'MESH:D013945', (109, 130))	('thymic tumors', 'Disease', (18, 31))
321983	31150281	As for salivary glands tumors, the occurrence of BCOR mutations seems to characterize more aggressive diseases, regardless of the histological type.	('BCOR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('aggressive diseases', 'Disease', 'MESH:D001523', (91, 110))	('characterize', 'Reg', (73, 85))	('aggressive diseases', 'Disease', (91, 110))	('salivary glands tumors', 'Phenotype', 'HP:0100684', (7, 29))	('salivary glands tumors', 'Disease', 'MESH:D012468', (7, 29))	('salivary glands tumors', 'Disease', (7, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
321985	31150281	While definitive publications on the recurrence and role of BCOR mutations in various epithelial malignancies are still lacking, it is evident from comprehensive sequencing efforts (https://portal.gdc.cancer.gov; www.cbioportal.org) that BCOR abnormalities are recurrent in uterine corpus endometrial carcinoma, colon and stomach adenocarcinoma, and lung tumors regardless of histology.	('cancer', 'Disease', (201, 207))	('colon and stomach adenocarcinoma', 'Disease', 'MESH:D013274', (312, 344))	('epithelial malignancies', 'Disease', (86, 109))	('abnormalities', 'Var', (243, 256))	('tumors', 'Phenotype', 'HP:0002664', (355, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('lung tumors', 'Phenotype', 'HP:0100526', (350, 361))	('endometrial carcinoma', 'Disease', (289, 310))	('lung tumors regardless', 'Disease', (350, 372))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('BCOR', 'Gene', (238, 242))	('epithelial malignancies', 'Disease', 'MESH:D002277', (86, 109))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (86, 109))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (289, 310))	('lung tumors regardless', 'Disease', 'MESH:D008175', (350, 372))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (289, 310))
321986	31150281	In the context of The Cancer Genome Atlas project, in the EBV + gastric carcinomas subgroup, the percentage of mutations involving BCOR reached 23%.	('mutations', 'Var', (111, 120))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('BCOR', 'Gene', (131, 135))	('gastric carcinomas', 'Disease', 'MESH:D013274', (64, 82))	('gastric carcinomas', 'Disease', (64, 82))
321987	31150281	The high involvement of BCOR mutations in EBV + gastric carcinomas is emphasized by the consideration that BCOR also affects another EBV-related tumor: extranodal NK/T-cell lymphoma, nasal type.	('T-cell lymphoma', 'Disease', (166, 181))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (166, 181))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('nasal type', 'Disease', (183, 193))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (166, 181))	('lymphoma', 'Phenotype', 'HP:0002665', (173, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cell lymphoma', 'Phenotype', 'HP:0012191', (168, 181))	('mutations', 'Var', (29, 38))	('BCOR', 'Gene', (24, 28))	('tumor', 'Disease', (145, 150))	('gastric carcinomas', 'Disease', 'MESH:D013274', (48, 66))	('gastric carcinomas', 'Disease', (48, 66))	('affects', 'Reg', (117, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
321988	31150281	A special case is that of the uterus because in this organ, BCOR alterations are recurrently involved both in epithelial tumor histotypes (in this case, endometrioid endometrial adenocarcinoma) and in uterine carcinosarcoma (involving BCOR in 23% of cases), in addition to the previously described ESS.	('alterations', 'Var', (65, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (166, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (201, 223))	('BCOR', 'Gene', (60, 64))	('carcinosarcoma', 'Disease', (209, 223))	('epithelial tumor', 'Disease', (110, 126))	('involved', 'Reg', (93, 101))	('endometrioid endometrial adenocarcinoma', 'Disease', (153, 192))	('epithelial tumor', 'Phenotype', 'HP:0031492', (110, 126))	('endometrioid endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (153, 192))	('epithelial tumor', 'Disease', 'MESH:D002277', (110, 126))	('carcinosarcoma', 'Disease', 'MESH:D002296', (209, 223))
321990	31150281	Additionally, loss-of-function mutations were also found in myelodysplasias and acute myeloid leukemias and in selected subtypes of lymphoid neoplasms.	('lymphoid neoplasms', 'Disease', (132, 150))	('myelodysplasia', 'Phenotype', 'HP:0002863', (60, 74))	('mutations', 'Var', (31, 40))	('leukemias', 'Phenotype', 'HP:0001909', (94, 103))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (86, 103))	('lymphoid neoplasms', 'Phenotype', 'HP:0002665', (132, 150))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (80, 103))	('loss-of-function', 'NegReg', (14, 30))	('neoplasm', 'Phenotype', 'HP:0002664', (141, 149))	('myelodysplasias and acute myeloid leukemias', 'Disease', 'MESH:D015470', (60, 103))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (80, 102))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (86, 102))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('neoplasms', 'Phenotype', 'HP:0002664', (141, 150))	('lymphoid neoplasms', 'Disease', 'MESH:D008223', (132, 150))
321991	31150281	A deeper knowledge of the functional role of different BCOR alterations in tumors of the mesenchymal, hematopoietic and neuroectodermal lineages will allow the identification of actionable pathways in these malignancies.	('BCOR', 'Gene', (55, 59))	('malignancies', 'Disease', (207, 219))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('malignancies', 'Disease', 'MESH:D009369', (207, 219))	('alterations', 'Var', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
321993	31150281	In fact, the recognition of recurrent alterations of this gene in tumors such as CCSK, PMMT1, SRBCS and CNS-HGNET-BCOR already plays a key role in the diagnosis of these malignancies and there are many examples of new entities wherein BCOR plays a relevant clinical role.	('malignancies', 'Disease', (170, 182))	('SRBCS', 'Chemical', '-', (94, 99))	('CCSK', 'Chemical', '-', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CCSK', 'Phenotype', 'HP:0006770', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Disease', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('malignancies', 'Disease', 'MESH:D009369', (170, 182))	('alterations', 'Var', (38, 49))	('CCSK', 'Disease', (81, 85))
321996	31150281	PRC1.1 silences genes through ubiquitination of Lys119 in histone H2A (H2AK119).	('H2A', 'Gene', '8337', (66, 69))	('genes', 'Gene', (16, 21))	('H2AK119', 'Gene', (71, 78))	('H2A', 'Gene', (66, 69))	('silences', 'NegReg', (7, 15))	('H2AK119', 'Gene', '8337', (71, 78))	('H2A', 'Gene', '8337', (71, 74))	('Lys119', 'Chemical', '-', (48, 54))	('Lys119', 'Var', (48, 54))	('PRC1.1', 'Gene', (0, 6))	('H2A', 'Gene', (71, 74))	('ubiquitination', 'MPA', (30, 44))
321997	31150281	BCOR germinal loss-of-function mutations determine oculo-facio-cardio-dental syndrome.	('mutations', 'Var', (31, 40))	('cardio-dental syndrome', 'Disease', 'MESH:D059347', (63, 85))	('cardio-dental syndrome', 'Disease', (63, 85))	('loss-of-function', 'NegReg', (14, 30))	('dental syndrome', 'Phenotype', 'HP:0000164', (70, 85))	('BCOR', 'Gene', (0, 4))
321999	31150281	BCOR internal tandem duplications (ITD) are present in more than 75% of CCSK, a pediatric renal sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('pediatric renal sarcoma', 'Disease', (80, 103))	('renal sarcoma', 'Phenotype', 'HP:0008663', (90, 103))	('CCSK', 'Disease', (72, 76))	('internal tandem duplications', 'Var', (5, 33))	('CCSK', 'Chemical', '-', (72, 76))	('CCSK', 'Phenotype', 'HP:0006770', (72, 76))	('pediatric renal sarcoma', 'Disease', 'MESH:D007674', (80, 103))	('BCOR', 'Gene', (0, 4))
322003	31150281	BCOR mutations recur in 10% of PAX-negative rhabdomyosarcomas.	('rhabdomyosarcomas', 'Disease', (44, 61))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (44, 61))	('mutations', 'Var', (5, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('PAX', 'Chemical', '-', (31, 34))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (44, 60))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (44, 61))	('BCOR', 'Gene', (0, 4))
322004	31150281	ZC3H7B-BCOR or ITD-BCOR characterize a subgroup of endometrial stromal sarcomas.	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (51, 79))	('ZC3H7B', 'Gene', (0, 6))	('ITD-BCOR', 'Var', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('ZC3H7B', 'Gene', '23264', (0, 6))	('endometrial stromal sarcomas', 'Disease', (51, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))
322005	31150281	Loss-of-function BCOR mutations are found in retinoblastomas, high-grade glial tumors and medulloblastomas.	('Loss-of-function', 'NegReg', (0, 16))	('retinoblastomas', 'Disease', 'MESH:D012175', (45, 60))	('retinoblastomas', 'Phenotype', 'HP:0009919', (45, 60))	('medulloblastomas', 'Disease', 'MESH:D008527', (90, 106))	('glial tumors', 'Disease', 'MESH:D005910', (73, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('medulloblastomas', 'Disease', (90, 106))	('medulloblastoma', 'Phenotype', 'HP:0002885', (90, 105))	('mutations', 'Var', (22, 31))	('retinoblastoma', 'Phenotype', 'HP:0009919', (45, 59))	('BCOR', 'Gene', (17, 21))	('glial tumors', 'Disease', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('retinoblastomas', 'Disease', (45, 60))
322006	31150281	A subgroup of central nervvous system high-grade primitive neuroectodermal tumors with alterations of BCOR (CNS-PNET) is characterized by ITD-BCOR.	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (49, 81))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (59, 81))	('alterations', 'Var', (87, 98))	('neuroectodermal tumors', 'Disease', (59, 81))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (59, 81))	('BCOR', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
322009	31150281	Loss-of-function mutations of BCOR are present in around 10% of unselected acute myeloid leukemia and myelodysplastic syndrome.	('myelodysplastic syndrome', 'Disease', (102, 126))	('Loss-of-function', 'NegReg', (0, 16))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (102, 126))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('acute myeloid leukemia', 'Disease', (75, 97))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (81, 97))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (75, 97))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (102, 126))	('BCOR', 'Gene', (30, 34))	('mutations', 'Var', (17, 26))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (75, 97))
322010	31150281	BCOR mutations are unfavorable prognostic factors in myelodysplastic syndrome and adult acute myeloid leukemia.	('adult acute myeloid leukemia', 'Disease', 'MESH:D015470', (82, 110))	('mutations', 'Var', (5, 14))	('adult acute myeloid leukemia', 'Disease', (82, 110))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (53, 77))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (88, 110))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (94, 110))	('myelodysplastic syndrome', 'Disease', (53, 77))	('BCOR', 'Gene', (0, 4))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (53, 77))
322011	31150281	Prolymphocytic T leukemias and chronic lymphocytic leukemias carry BCOR mutations in less than 10% of cases.	('mutations', 'Var', (72, 81))	('leukemias', 'Phenotype', 'HP:0001909', (51, 60))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('leukemia', 'Phenotype', 'HP:0001909', (51, 59))	('BCOR', 'Gene', (67, 71))	('lymphocytic leukemias', 'Phenotype', 'HP:0005526', (39, 60))	('chronic lymphocytic leukemias', 'Phenotype', 'HP:0005550', (31, 60))	('Prolymphocytic T leukemias', 'Disease', 'MESH:D015463', (0, 26))	('lymphocytic leukemias', 'Disease', (39, 60))	('leukemias', 'Phenotype', 'HP:0001909', (17, 26))	('lymphocytic leukemias', 'Disease', 'MESH:D007945', (39, 60))	('Prolymphocytic T leukemias', 'Disease', (0, 26))
322013	31150281	BCOR mutations are found in aggressive B3-thymomas, adenoid cystic carcinoma, uterine corpus endometrial carcinoma, EBV + gastric carcinomas, colon and stomach adenocarcinoma, and lung tumors, regardless of histology.	('found', 'Reg', (19, 24))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (52, 76))	('aggressive B3-thymomas', 'Disease', (28, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (93, 114))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (93, 114))	('thymoma', 'Phenotype', 'HP:0100522', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('adenoid cystic carcinoma', 'Disease', (52, 76))	('BCOR', 'Gene', (0, 4))	('colon and stomach adenocarcinoma', 'Disease', 'MESH:D013274', (142, 174))	('mutations', 'Var', (5, 14))	('lung tumors', 'Disease', 'MESH:D008175', (180, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('lung tumors', 'Phenotype', 'HP:0100526', (180, 191))	('gastric carcinomas', 'Disease', (122, 140))	('aggressive B3-thymomas', 'Disease', 'MESH:D013945', (28, 50))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('endometrial carcinoma', 'Disease', (93, 114))	('gastric carcinomas', 'Disease', 'MESH:D013274', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('lung tumors', 'Disease', (180, 191))
322017	29872699	New insights into the mechanisms that lead to dysregulated angiogenesis such as mutation or amplification in known angiogenesis related genes, viral infection, and chromosomal translocations have improved our understanding of the pathogenesis of endothelial malignancies and how they evade anti-angiogenesis drugs.	('viral infection', 'Disease', 'MESH:D001102', (143, 158))	('viral infection', 'Disease', (143, 158))	('mutation', 'Var', (80, 88))	('endothelial malignancies', 'Disease', (246, 270))	('amplification', 'Var', (92, 105))	('chromosomal translocations', 'Var', (164, 190))	('improved', 'PosReg', (196, 204))	('angiogenesis', 'Gene', (115, 127))
322021	29872699	These include VEGFR2 (KDR) and PLCG1 mutations, loss-of-function PTPRB mutations, and amplification of c-MYC and VEGFR3 (FLT4).	('amplification', 'Var', (86, 99))	('VEGFR3', 'Gene', (113, 119))	('c-MYC', 'Gene', (103, 108))	('PLCG1', 'Gene', (31, 36))	('VEGFR2', 'Gene', '3791', (14, 20))	('PTPRB', 'Gene', '5787', (65, 70))	('mutations', 'Var', (37, 46))	('mutations', 'Var', (71, 80))	('PTPRB', 'Gene', (65, 70))	('loss-of-function', 'NegReg', (48, 64))	('FLT4', 'Gene', (121, 125))	('KDR', 'Gene', (22, 25))	('VEGFR3', 'Gene', '2324', (113, 119))	('VEGFR2', 'Gene', (14, 20))	('PLCG1', 'Gene', '5335', (31, 36))	('c-MYC', 'Gene', '4609', (103, 108))	('FLT4', 'Gene', '2324', (121, 125))	('KDR', 'Gene', '3791', (22, 25))
322031	29872699	Each of these entities is classically differentiated by histological appearance, but recent evidence suggests that at least some of the intermediate grade hemangioendotheliomas are driven by chromosomal translocations (Table 1).	('driven by', 'Reg', (181, 190))	('hemangioendotheliomas', 'Disease', 'MESH:D006390', (155, 176))	('hemangioendotheliomas', 'Disease', (155, 176))	('chromosomal translocations', 'Var', (191, 217))
322037	29872699	Secondary angiosarcomas arise from chronic lymphedema in the extremities or from radiation exposure to the chest wall following breast cancer treatment and are often molecularly associated with amplification of c-MYC.	('c-MYC', 'Gene', '4609', (211, 216))	('lymphedema', 'Disease', (43, 53))	('associated', 'Reg', (178, 188))	('amplification', 'Var', (194, 207))	('angiosarcomas', 'Disease', (10, 23))	('angiosarcoma', 'Phenotype', 'HP:0200058', (10, 22))	('lymphedema', 'Phenotype', 'HP:0001004', (43, 53))	('angiosarcomas', 'Disease', 'MESH:D006394', (10, 23))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('c-MYC', 'Gene', (211, 216))	('angiosarcomas', 'Phenotype', 'HP:0200058', (10, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('lymphedema', 'Disease', 'MESH:D008209', (43, 53))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('men', 'Species', '9606', (147, 150))
322043	29872699	Unsurprisingly, endothelial cell neoplasms have aberrant VEGF/VEGFR pathway signaling.	('neoplasms', 'Phenotype', 'HP:0002664', (33, 42))	('VEGFR', 'Gene', '3791', (62, 67))	('aberrant', 'Var', (48, 56))	('neoplasms', 'Disease', 'MESH:D009369', (33, 42))	('neoplasms', 'Disease', (33, 42))	('VEGFR', 'Gene', (62, 67))
322044	29872699	In aggressive angiosarcomas, alterations in VEGF and its receptors have been well characterized, including mutations and amplifications (Fig.	('mutations', 'Var', (107, 116))	('aggressive angiosarcomas', 'Disease', (3, 27))	('aggressive angiosarcomas', 'Disease', 'MESH:D006394', (3, 27))	('angiosarcoma', 'Phenotype', 'HP:0200058', (14, 26))	('amplifications', 'Var', (121, 135))	('VEGF', 'Protein', (44, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('angiosarcomas', 'Phenotype', 'HP:0200058', (14, 27))
322046	29872699	VEGFR2 mutations have been reported in 10% of angiosarcomas and in 2 of 6 angiosarcomas in a smaller series, with mutations identified in the extracellular, transmembrane, and kinase domains.	('angiosarcomas', 'Phenotype', 'HP:0200058', (46, 59))	('reported', 'Reg', (27, 35))	('angiosarcomas', 'Disease', 'MESH:D006394', (74, 87))	('angiosarcomas', 'Disease', 'MESH:D006394', (46, 59))	('VEGFR2', 'Gene', '3791', (0, 6))	('angiosarcomas', 'Phenotype', 'HP:0200058', (74, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('angiosarcoma', 'Phenotype', 'HP:0200058', (46, 58))	('VEGFR2', 'Gene', (0, 6))	('angiosarcomas', 'Disease', (46, 59))	('angiosarcomas', 'Disease', (74, 87))	('angiosarcoma', 'Phenotype', 'HP:0200058', (74, 86))	('mutations', 'Var', (7, 16))
322047	29872699	However, the prevalence of these VEGFR2 mutations in angiosarcomas remains uncertain, as no VEGFR2 mutations were revealed in other studies including whole-genome- or whole-exome sequencing.	('angiosarcomas', 'Disease', 'MESH:D006394', (53, 66))	('angiosarcomas', 'Phenotype', 'HP:0200058', (53, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('VEGFR2', 'Gene', (33, 39))	('mutations', 'Var', (40, 49))	('VEGFR2', 'Gene', '3791', (33, 39))	('VEGFR2', 'Gene', '3791', (92, 98))	('angiosarcoma', 'Phenotype', 'HP:0200058', (53, 65))	('angiosarcomas', 'Disease', (53, 66))	('VEGFR2', 'Gene', (92, 98))
322048	29872699	The functional consequence of these mutations is not fully understood, but at least some are thought to be activating mutations that act as drivers in a subset of angiosarcomas.	('angiosarcomas', 'Phenotype', 'HP:0200058', (163, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('mutations', 'Var', (36, 45))	('angiosarcoma', 'Phenotype', 'HP:0200058', (163, 175))	('angiosarcomas', 'Disease', (163, 176))	('angiosarcomas', 'Disease', 'MESH:D006394', (163, 176))
322050	29872699	These amplifications are generally found in combination with other alterations such as c-MYC amplification and mutations in PLCG1 and PTPRB.	('c-MYC', 'Gene', (87, 92))	('mutations', 'Var', (111, 120))	('PTPRB', 'Gene', '5787', (134, 139))	('PLCG1', 'Gene', (124, 129))	('PTPRB', 'Gene', (134, 139))	('c-MYC', 'Gene', '4609', (87, 92))	('PLCG1', 'Gene', '5335', (124, 129))
322052	29872699	Effective targeting of the VEGF/VEGFR axis either by knocking down VEGF-A, -C, or -D, or treatment with the pan-VEGFR inhibitor axitinib in a mouse model with constitutive mammalian target of rapamycin (mTOR) activation (develop tumors consistent with lymphangiosarcoma) suggests that targeting the upstream ligand or receptor may be a therapeutic option even in cases when downstream activating mutations are identified.	('angiosarcoma', 'Phenotype', 'HP:0200058', (257, 269))	('VEGFR', 'Gene', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('mouse', 'Species', '10090', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('lymphangiosarcoma', 'Disease', (252, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (262, 269))	('mammalian target of rapamycin', 'Gene', '2475', (172, 201))	('tumors', 'Disease', (229, 235))	('men', 'Species', '9606', (94, 97))	('axitinib', 'Chemical', 'MESH:D000077784', (128, 136))	('mammalian target of rapamycin', 'Gene', (172, 201))	('VEGFR', 'Gene', '3791', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('lymphangiosarcoma', 'Disease', 'MESH:C537491', (252, 269))	('VEGFR', 'Gene', (112, 117))	('VEGFR', 'Gene', '3791', (32, 37))	('VEGF-A', 'Gene', (67, 73))	('knocking', 'Var', (53, 61))
322071	29872699	Interestingly, Ang2 is upregulated in solid tumor angiogenesis, and high levels of Ang2 are associated with worse outcomes in multiple cancer types.	('cancer', 'Disease', (135, 141))	('upregulated', 'PosReg', (23, 34))	('Ang2', 'Gene', '285', (83, 87))	('Ang2', 'Gene', '285', (15, 19))	('solid tumor', 'Disease', (38, 49))	('Ang2', 'Gene', (15, 19))	('solid tumor', 'Disease', 'MESH:D009369', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('high levels', 'Var', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('Ang2', 'Gene', (83, 87))
322073	29872699	Loss-of-function mutations in PTPRB are relatively common in angiosarcoma and were found in 26% of angiosarcomas; interestingly, all these mutations were in secondary angiosarcomas.	('angiosarcoma', 'Phenotype', 'HP:0200058', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('angiosarcomas', 'Disease', 'MESH:D006394', (167, 180))	('angiosarcoma', 'Disease', (99, 111))	('angiosarcoma', 'Disease', (61, 73))	('angiosarcomas', 'Phenotype', 'HP:0200058', (99, 112))	('mutations', 'Var', (17, 26))	('angiosarcomas', 'Disease', (99, 112))	('angiosarcomas', 'Phenotype', 'HP:0200058', (167, 180))	('angiosarcoma', 'Disease', 'MESH:D006394', (167, 179))	('angiosarcomas', 'Disease', (167, 180))	('angiosarcoma', 'Phenotype', 'HP:0200058', (167, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('PTPRB', 'Gene', '5787', (30, 35))	('PTPRB', 'Gene', (30, 35))	('angiosarcoma', 'Disease', (167, 179))	('Loss-of-function', 'NegReg', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('angiosarcoma', 'Disease', 'MESH:D006394', (99, 111))	('angiosarcoma', 'Disease', 'MESH:D006394', (61, 73))	('angiosarcomas', 'Disease', 'MESH:D006394', (99, 112))	('angiosarcoma', 'Phenotype', 'HP:0200058', (99, 111))
322074	29872699	Normally, PTPRB dephosphorylates Tie2; thus, loss of PTPRB in angiosarcoma likely increases Ang/Tie2 signaling and may activate multiple pathways downstream from Tie2, such as the protein kinase B (AKT)/phosphoinositide 3-kinase (PI3K)/mTOR, endothelial nitric oxide synthase, focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), and downstream of kinase-related protein/non-catalytic region of tyrosine kinase adaptor protein 1/p21-activated protein kinase (DOCK/NCK/PAK) pathways.	('angiosarcoma', 'Disease', (62, 74))	('MAPK', 'Gene', '5594', (340, 344))	('Tie2', 'Gene', (33, 37))	('Tie2', 'Gene', '7010', (162, 166))	('protein kinase B', 'Gene', '2185', (180, 196))	('increases', 'PosReg', (82, 91))	('FAK', 'Gene', '5747', (300, 303))	('loss', 'Var', (45, 49))	('endothelial nitric oxide synthase', 'Gene', '4846', (242, 275))	('protein kinase B', 'Gene', (180, 196))	('Tie2', 'Gene', '7010', (96, 100))	('NCK', 'Gene', (481, 484))	('focal adhesion kinase', 'Gene', '5747', (277, 298))	('Tie2', 'Gene', '7010', (33, 37))	('PTPRB', 'Gene', '5787', (53, 58))	('PTPRB', 'Gene', (53, 58))	('endothelial nitric oxide synthase', 'Gene', (242, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('angiosarcoma', 'Disease', 'MESH:D006394', (62, 74))	('activate', 'PosReg', (119, 127))	('Tie2', 'Gene', (162, 166))	('focal adhesion kinase', 'Gene', (277, 298))	('MAPK', 'Gene', (340, 344))	('NCK', 'Gene', '4690', (481, 484))	('angiosarcoma', 'Phenotype', 'HP:0200058', (62, 74))	('PTPRB', 'Gene', '5787', (10, 15))	('PTPRB', 'Gene', (10, 15))	('FAK', 'Gene', (300, 303))	('Tie2', 'Gene', (96, 100))	('mitogen-activated protein kinase', 'Pathway', (306, 338))
322075	29872699	Silencing PTPRB in HUVECs led to increased sprouting, even in the presence of VEGFR2 inhibitors such as sunitinib, demonstrating that PTPRB loss represents a mechanism of canonical activation of Tie2 signaling in angiosarcoma.	('angiosarcoma', 'Phenotype', 'HP:0200058', (213, 225))	('VEGFR2', 'Gene', (78, 84))	('PTPRB', 'Gene', '5787', (134, 139))	('Tie2', 'Gene', '7010', (195, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('Silencing', 'Var', (0, 9))	('sprouting', 'CPA', (43, 52))	('sunitinib', 'Chemical', 'MESH:D000077210', (104, 113))	('PTPRB', 'Gene', '5787', (10, 15))	('PTPRB', 'Gene', (134, 139))	('increased', 'PosReg', (33, 42))	('PTPRB', 'Gene', (10, 15))	('angiosarcoma', 'Disease', 'MESH:D006394', (213, 225))	('VEGFR2', 'Gene', '3791', (78, 84))	('loss', 'NegReg', (140, 144))	('Tie2', 'Gene', (195, 199))	('angiosarcoma', 'Disease', (213, 225))
322081	29872699	Additionally, antagonizing Ang1 may diminish its seemingly beneficial effect.	('Ang1', 'Gene', (27, 31))	('antagonizing', 'Var', (14, 26))	('Ang1', 'Gene', '284', (27, 31))	('diminish', 'NegReg', (36, 44))
322088	29872699	Studies in a separate mouse model confirmed that loss of Notch1 heterozygosity leads to endothelial cell neoplasms of varying histological grade with approximately the same penetrance; interestingly, the liver was the primary site.	('loss', 'Var', (49, 53))	('leads to', 'Reg', (79, 87))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('mouse', 'Species', '10090', (22, 27))	('Notch1', 'Gene', (57, 63))	('Notch1', 'Gene', '18128', (57, 63))	('neoplasms', 'Disease', 'MESH:D009369', (105, 114))	('neoplasms', 'Disease', (105, 114))
322111	29872699	Endoglin mutations cause hereditary hemorrhagic telangiectasia type 1, which is characterized by vascular dysplasia and hemorrhage, but to date no mutations in endoglin have been identified in endothelial cell neoplasms.	('cause', 'Reg', (19, 24))	('endoglin', 'Gene', (160, 168))	('vascular dysplasia', 'Disease', (97, 115))	('hemorrhage', 'Disease', 'MESH:D006470', (120, 130))	('neoplasms', 'Disease', 'MESH:D009369', (210, 219))	('mutations', 'Var', (9, 18))	('neoplasms', 'Disease', (210, 219))	('hereditary hemorrhagic telangiectasia', 'Disease', 'MESH:D013683', (25, 62))	('Endoglin', 'Gene', (0, 8))	('telangiectasia', 'Phenotype', 'HP:0001009', (48, 62))	('endoglin', 'Gene', '2022', (160, 168))	('hemorrhage', 'Disease', (120, 130))	('vascular dysplasia', 'Disease', 'MESH:D000783', (97, 115))	('hereditary hemorrhagic telangiectasia', 'Disease', (25, 62))	('Endoglin', 'Gene', '2022', (0, 8))	('neoplasms', 'Phenotype', 'HP:0002664', (210, 219))
322119	29872699	Phosphorylation at PLCG1-Y783 causes a conformational change that relieves the auto-inhibition of the C-terminal SH2 domain, and leads to downstream signaling.	('PLCG1', 'Gene', '5335', (19, 24))	('Phosphorylation', 'Var', (0, 15))	('relieves', 'NegReg', (66, 74))	('auto-inhibition of the C-terminal SH2 domain', 'MPA', (79, 123))	('PLCG1', 'Gene', (19, 24))	('conformational change', 'MPA', (39, 60))	('signaling', 'MPA', (149, 158))	('leads to', 'Reg', (129, 137))
322121	29872699	A recurring mutation in PLCG1, R707Q, has been identified in angiosarcoma, with a prevalence of 9-30% (refs).	('R707Q', 'Mutation', 'rs748157088', (31, 36))	('angiosarcoma', 'Phenotype', 'HP:0200058', (61, 73))	('PLCG1', 'Gene', (24, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('PLCG1', 'Gene', '5335', (24, 29))	('angiosarcoma', 'Disease', 'MESH:D006394', (61, 73))	('angiosarcoma', 'Disease', (61, 73))	('R707Q', 'Var', (31, 36))
322122	29872699	R707 is in the auto-inhibitory SH2 domain of PLCG1, and the missense mutation is hypothesized to destabilize this domain and reduce its auto-inhibitory effect.	('PLCG1', 'Gene', (45, 50))	('auto-inhibitory effect', 'MPA', (136, 158))	('reduce', 'NegReg', (125, 131))	('R707', 'Var', (0, 4))	('missense mutation', 'Var', (60, 77))	('PLCG1', 'Gene', '5335', (45, 50))	('destabilize', 'NegReg', (97, 108))
322126	29872699	In addition to PLCG1 mutations, mutations or amplifications in K-, H-, and N-RAS, B- and C-RAF, and MAPK1 were identified in angiosarcoma.	('angiosarcoma', 'Disease', 'MESH:D006394', (125, 137))	('MAPK1', 'Gene', '5594', (100, 105))	('angiosarcoma', 'Disease', (125, 137))	('N-RAS', 'Gene', (75, 80))	('identified', 'Reg', (111, 121))	('C-RAF', 'Gene', (89, 94))	('amplifications', 'Var', (45, 59))	('mutations', 'Var', (32, 41))	('MAPK1', 'Gene', (100, 105))	('N-RAS', 'Gene', '4893', (75, 80))	('PLCG1', 'Gene', (15, 20))	('angiosarcoma', 'Phenotype', 'HP:0200058', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('C-RAF', 'Gene', '5894', (89, 94))	('PLCG1', 'Gene', '5335', (15, 20))	('mutations', 'Var', (21, 30))
322132	29872699	Overexpression of AKT1 is sufficient to create proliferative neoplasms, but without the ability to metastasize.	('neoplasms', 'Phenotype', 'HP:0002664', (61, 70))	('AKT1', 'Gene', '207', (18, 22))	('AKT1', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('neoplasms', 'Disease', 'MESH:D009369', (61, 70))	('neoplasms', 'Disease', (61, 70))
322137	29872699	Although canine angiosarcoma xenografts in athymic nude mice showed minimal response to temsirolimus alone, temsirolimus sensitized angiosarcomas to MEK inhibition, suggesting cross-talk between the MAPK and PI3K/AKT/mTOR pathways.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('angiosarcomas', 'Phenotype', 'HP:0200058', (132, 145))	('angiosarcoma', 'Disease', (132, 144))	('temsirolimus', 'Var', (108, 120))	('angiosarcomas', 'Disease', (132, 145))	('angiosarcoma', 'Disease', 'MESH:D006394', (16, 28))	('canine', 'Species', '9615', (9, 15))	('angiosarcoma', 'Phenotype', 'HP:0200058', (16, 28))	('sirolimus', 'Chemical', 'MESH:D020123', (91, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('angiosarcoma', 'Disease', (16, 28))	('MAPK', 'Gene', (199, 203))	('PI3K/AKT/mTOR pathways', 'Pathway', (208, 230))	('angiosarcoma', 'Disease', 'MESH:D006394', (132, 144))	('MEK', 'Pathway', (149, 152))	('angiosarcomas', 'Disease', 'MESH:D006394', (132, 145))	('MAPK', 'Gene', '5594', (199, 203))	('sirolimus', 'Chemical', 'MESH:D020123', (111, 120))	('angiosarcoma', 'Phenotype', 'HP:0200058', (132, 144))	('cross-talk', 'Reg', (176, 186))	('nude mice', 'Species', '10090', (51, 60))
322138	29872699	Although the PI3K/AKT/mTOR pathway is activated in angiosarcoma, this activation does not appear to be due to mutations or losses directly affecting this pathway, such as phosphatase and tensin homolog loss or PI3K mutations.	('angiosarcoma', 'Disease', (51, 63))	('PI3K/AKT/mTOR pathway', 'Pathway', (13, 34))	('angiosarcoma', 'Phenotype', 'HP:0200058', (51, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('angiosarcoma', 'Disease', 'MESH:D006394', (51, 63))	('activated', 'PosReg', (38, 47))	('PI3K mutations', 'Var', (210, 224))	('loss', 'NegReg', (202, 206))
322140	29872699	Dysregulation of the transcription factor MYC has been implicated in many cancer types.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('MYC', 'Protein', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('implicated', 'Reg', (55, 65))
322141	29872699	MYC amplification is well described in secondary angiosarcoma and has also been demonstrated in primary angiosarcoma.	('MYC', 'Gene', (0, 3))	('angiosarcoma', 'Disease', (104, 116))	('angiosarcoma', 'Phenotype', 'HP:0200058', (104, 116))	('primary angiosarcoma', 'Disease', (96, 116))	('angiosarcoma', 'Phenotype', 'HP:0200058', (49, 61))	('primary angiosarcoma', 'Disease', 'MESH:D006394', (96, 116))	('amplification', 'Var', (4, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('angiosarcoma', 'Disease', 'MESH:D006394', (49, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('angiosarcoma', 'Disease', 'MESH:D006394', (104, 116))	('angiosarcoma', 'Disease', (49, 61))
322145	29872699	Interestingly, mice in which Cdk6 activity is increased by rendering them insensitive to inhibition by INK4 develop angiosarcomas with a high prevalence (~50%), particularly when the Cdk6 alteration is introduced in a p53 heterozygous or null background.	('angiosarcomas', 'Disease', (116, 129))	('Cdk6', 'Gene', (29, 33))	('angiosarcomas', 'Disease', 'MESH:D006394', (116, 129))	('alteration', 'Var', (188, 198))	('angiosarcomas', 'Phenotype', 'HP:0200058', (116, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('Cdk6', 'Gene', '12571', (183, 187))	('Cdk6', 'Gene', '12571', (29, 33))	('mice', 'Species', '10090', (15, 19))	('angiosarcoma', 'Phenotype', 'HP:0200058', (116, 128))	('Cdk6', 'Gene', (183, 187))
322148	29872699	In primary effusion lymphoma, another malignancy associated with KSHV, MYC is required to maintain the latency of KSHV, and inhibition of bromodomain and extra-terminal domain bromodomain (BET), a therapeutic strategy for targeting pathologic MYC activation, has had promising results in vitro in other KSHV associated tumors.	('BET', 'Gene', (189, 192))	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('tumors', 'Disease', (319, 325))	('primary effusion lymphoma', 'Disease', (3, 28))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (3, 28))	('tumors', 'Disease', 'MESH:D009369', (319, 325))	('malignancy', 'Disease', (38, 48))	('KS', 'Phenotype', 'HP:0100726', (114, 116))	('BET', 'Gene', '92737', (189, 192))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('KS', 'Phenotype', 'HP:0100726', (303, 305))	('tumors', 'Phenotype', 'HP:0002664', (319, 325))	('KSHV', 'Species', '37296', (65, 69))	('KSHV', 'Species', '37296', (303, 307))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (3, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (20, 28))	('KSHV', 'Species', '37296', (114, 118))	('inhibition', 'Var', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))
322153	29872699	In mice, removal of VHL's inhibition of HIF via mosaic VHL knockout led to the formation of vascular lesions ranging from hemangiomas to a single mouse that developed an angiosarcoma.	('angiosarcoma', 'Disease', 'MESH:D006394', (170, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('mice', 'Species', '10090', (3, 7))	('angiosarcoma', 'Disease', (170, 182))	('mouse', 'Species', '10090', (146, 151))	('hemangioma', 'Phenotype', 'HP:0001028', (122, 132))	('angiosarcoma', 'Phenotype', 'HP:0200058', (170, 182))	('knockout', 'Var', (59, 67))	('VHL', 'Gene', (55, 58))	('hemangiomas', 'Disease', (122, 133))	('hemangiomas', 'Phenotype', 'HP:0001028', (122, 133))	('hemangiomas', 'Disease', 'MESH:D006391', (122, 133))
322156	29872699	A G protein-coupled receptor encoded by KSHV (vGPCR) contains an activating V138D mutation, which leads to agonist-independent induction of the MAPK and p38 signaling pathways.	('p38', 'Gene', '5594', (153, 156))	('V138D', 'Mutation', 'p.V138D', (76, 81))	('MAPK', 'Gene', (144, 148))	('induction', 'PosReg', (127, 136))	('vGPCR', 'Gene', (46, 51))	('activating', 'PosReg', (65, 75))	('p38', 'Gene', (153, 156))	('MAPK', 'Gene', '5594', (144, 148))	('KSHV', 'Species', '37296', (40, 44))	('vGPCR', 'Gene', '4961465', (46, 51))	('KS', 'Phenotype', 'HP:0100726', (40, 42))	('KSHV', 'Gene', (40, 44))	('V138D', 'Var', (76, 81))
322167	29872699	vIL-6, a lytic phase protein, induced expression of Notch4, DLL1, DLL4, and downstream targets Hey1 and Hey2, and vGPCR expression induced Notch2, Notch3, and Jagged1.	('Jagged1', 'Gene', (159, 166))	('Hey1', 'Gene', '23462', (95, 99))	('Hey1', 'Gene', (95, 99))	('vIL-6', 'Gene', '4961449', (0, 5))	('Notch3', 'Gene', '4854', (147, 153))	('Notch2', 'Var', (139, 145))	('vGPCR', 'Gene', (114, 119))	('Notch3', 'Gene', (147, 153))	('DLL4', 'Gene', (66, 70))	('DLL1', 'Gene', (60, 64))	('Notch4', 'Gene', (52, 58))	('Jagged1', 'Gene', '182', (159, 166))	('vIL-6', 'Gene', (0, 5))	('vGPCR', 'Gene', '4961465', (114, 119))
322171	29872699	KSHV GPCR also stimulates MAPK signaling.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('MAPK', 'Gene', '5594', (26, 30))	('stimulates', 'PosReg', (15, 25))	('MAPK', 'Gene', (26, 30))
322181	29872699	Targeting bFGF with antisense oligonucleotides inhibits the growth of AIDS-KS cells in vitro and in vivo, suggesting that targeting bFGF is a potential therapeutic strategy for KS.	('oligonucleotides', 'Chemical', 'MESH:D009841', (30, 46))	('KS', 'Phenotype', 'HP:0100726', (75, 77))	('KS', 'Phenotype', 'HP:0100726', (177, 179))	('AIDS', 'Disease', (70, 74))	('AIDS', 'Disease', 'MESH:D000163', (70, 74))	('antisense oligonucleotides', 'Var', (20, 46))	('inhibits', 'NegReg', (47, 55))
322195	29872699	In a mouse model of angiosarcoma, inhibition of tumor-secreted IL-6 decreased macrophage numbers and increased cytotoxic T-cell infiltration, thereby decreasing tumor growth.	('angiosarcoma', 'Phenotype', 'HP:0200058', (20, 32))	('decreased', 'NegReg', (68, 77))	('tumor', 'Disease', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('inhibition', 'Var', (34, 44))	('increased', 'PosReg', (101, 110))	('mouse', 'Species', '10090', (5, 10))	('decreasing', 'NegReg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cytotoxic T-cell infiltration', 'CPA', (111, 140))	('angiosarcoma', 'Disease', 'MESH:D006394', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('macrophage numbers', 'CPA', (78, 96))	('angiosarcoma', 'Disease', (20, 32))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
322197	29872699	In addition to the direct effect of IKK-beta on angiosarcoma cells, knockout of IKK-beta in host myeloid cells decreased neutrophil-derived nitric oxide, increased IL-4, and decreased IL-12 and interferon (IFN)-gamma, thus shifting the myeloid cells to the N2/M2 phenotype and increasing angiosarcoma growth.	('IL-12', 'MPA', (184, 189))	('increasing', 'PosReg', (277, 287))	('angiosarcoma', 'Disease', 'MESH:D006394', (288, 300))	('knockout', 'Var', (68, 76))	('shifting', 'Reg', (223, 231))	('angiosarcoma growth', 'Disease', (288, 307))	('IL-4', 'Gene', (164, 168))	('interferon (IFN)-gamma', 'Gene', '3458', (194, 216))	('IKK-beta', 'Gene', '3551', (80, 88))	('nitric oxide', 'Chemical', 'MESH:D009569', (140, 152))	('IKK-beta', 'Gene', (80, 88))	('angiosarcoma', 'Phenotype', 'HP:0200058', (288, 300))	('IKK-beta', 'Gene', '3551', (36, 44))	('decreased', 'NegReg', (111, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('angiosarcoma', 'Disease', (288, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('neutrophil-derived nitric oxide', 'MPA', (121, 152))	('angiosarcoma', 'Disease', 'MESH:D006394', (48, 60))	('increased', 'PosReg', (154, 163))	('IKK-beta', 'Gene', (36, 44))	('decreased', 'NegReg', (174, 183))	('angiosarcoma growth', 'Disease', 'MESH:D006394', (288, 307))	('angiosarcoma', 'Phenotype', 'HP:0200058', (48, 60))	('interferon (IFN)-gamma', 'Gene', (194, 216))	('angiosarcoma', 'Disease', (48, 60))	('IL-4', 'Gene', '3565', (164, 168))
322198	29872699	Moreover, inhibition of tumor secreted IL-8 has little effect on angiosarcoma cells in vitro, but prevents engraftment in vivo.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('angiosarcoma', 'Disease', (65, 77))	('IL-8', 'Gene', '3576', (39, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('tumor', 'Disease', (24, 29))	('IL-8', 'Gene', (39, 43))	('angiosarcoma', 'Phenotype', 'HP:0200058', (65, 77))	('men', 'Species', '9606', (114, 117))	('prevents', 'NegReg', (98, 106))	('engraftment', 'CPA', (107, 118))	('angiosarcoma', 'Disease', 'MESH:D006394', (65, 77))	('inhibition', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
322212	29872699	The first, t(1;3), results in the fusion of the tafazzin gene TAZ (also known as WWTR1) and the calmodulin-binding transcriptional activator 1 gene CAMTA1.	('fusion', 'Var', (34, 40))	('TAZ', 'Gene', '6901', (62, 65))	('CAMTA1', 'Gene', '23261', (148, 154))	('results in', 'Reg', (19, 29))	('TAZ', 'Gene', (62, 65))	('WWTR1', 'Gene', (81, 86))	('WWTR1', 'Gene', '25937', (81, 86))	('CAMTA1', 'Gene', (148, 154))
322213	29872699	The second translocation results in the fusion of the yes-associated protein 1 gene YAP1 and the transcription factor binding to IGHM gene TFE3.	('fusion', 'Var', (40, 46))	('YAP1', 'Gene', '10413', (84, 88))	('TFE3', 'Gene', (139, 143))	('IGHM', 'Gene', (129, 133))	('TFE3', 'Gene', '7030', (139, 143))	('IGHM', 'Gene', '3507', (129, 133))	('yes-associated protein 1', 'Gene', (54, 78))	('yes-associated protein 1', 'Gene', '22601', (54, 78))	('results in', 'Reg', (25, 35))	('binding', 'Interaction', (118, 125))	('YAP1', 'Gene', (84, 88))
322218	29872699	The pseudomyogenic hemangioendothelioma subtype is also associated with a balanced chromosomal translocation, t(7;19)(q22;q13), which results in a fusion of the serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1 gene SERPINE1 and FBJ murine osteosarcoma viral oncogene homolog B gene FOSB.	('FOSB', 'Gene', (327, 331))	('fusion', 'Var', (147, 153))	('murine', 'Species', '10090', (277, 283))	('hemangioendothelioma subtype', 'Disease', 'MESH:D006390', (19, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (289, 296))	('t(7;19)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (110, 126))	('associated', 'Reg', (56, 66))	('osteosarcoma', 'Phenotype', 'HP:0002669', (284, 296))	('osteosarcoma', 'Disease', (284, 296))	('osteosarcoma', 'Disease', 'MESH:D012516', (284, 296))	('hemangioendothelioma subtype', 'Disease', (19, 47))	('SERPINE1', 'Gene', (260, 268))
322221	29872699	Aberrations included gain or loss of entire chromosomes as well as partial chromosomes; interestingly, 2 of 8 cases in one series had duplication of the region on chromosome 4q that contains KIT and VEGFR2.	('VEGFR2', 'Gene', (199, 205))	('duplication', 'Var', (134, 145))	('KIT', 'Gene', (191, 194))	('gain', 'Disease', (21, 25))	('gain', 'Disease', 'MESH:D015430', (21, 25))	('VEGFR2', 'Gene', '3791', (199, 205))
322224	29872699	Aberrant activation of other regulatory pathways may explain why the majority of these tumors do not respond to VEGF-targeted therapies.	('activation', 'PosReg', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Aberrant', 'Var', (0, 8))	('regulatory pathways', 'Pathway', (29, 48))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
322226	29872699	The currently available genetically engineered mouse models of angiosarcoma are driven by knockout of Notch pathway components or FoxO, or overactivation of the mTOR pathway, but these may not reflect findings in human angiosarcomas.	('angiosarcoma', 'Disease', (219, 231))	('human', 'Species', '9606', (213, 218))	('mTOR pathway', 'Pathway', (161, 173))	('angiosarcomas', 'Disease', (219, 232))	('angiosarcoma', 'Disease', 'MESH:D006394', (219, 231))	('angiosarcoma', 'Phenotype', 'HP:0200058', (63, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('angiosarcoma', 'Phenotype', 'HP:0200058', (219, 231))	('Notch pathway', 'Pathway', (102, 115))	('angiosarcomas', 'Phenotype', 'HP:0200058', (219, 232))	('angiosarcoma', 'Disease', 'MESH:D006394', (63, 75))	('angiosarcomas', 'Disease', 'MESH:D006394', (219, 232))	('overactivation', 'PosReg', (139, 153))	('FoxO', 'Gene', (130, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('angiosarcoma', 'Disease', (63, 75))	('mouse', 'Species', '10090', (47, 52))	('knockout', 'Var', (90, 98))
322287	29435393	Our patient with metastatic synovial sarcoma developing recurrent hemothoraces following the treatment with pazopanib is the first case noting the occurrence of this complication following pazopanib which might be a cumulative dose effect after receiving it over a prolonged period.	('synovial sarcoma', 'Disease', 'MESH:D013584', (28, 44))	('pazopanib', 'Chemical', 'MESH:C516667', (189, 198))	('patient', 'Species', '9606', (4, 11))	('pazopanib', 'Chemical', 'MESH:C516667', (108, 117))	('synovial sarcoma', 'Disease', (28, 44))	('pazopanib', 'Var', (189, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (28, 44))
322469	22787293	On histology, these were Ewing sarcoma/PNET (3 cases) which were PAS+, Syn+, S100+, LCA -ve [Figure 5], infantile rhabdomyosarcoma (1 case) which was PAS + and myosin +.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('Syn', 'Gene', (71, 74))	('myosin', 'Gene', '79784', (160, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('PAS', 'Chemical', '-', (150, 153))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (114, 130))	('PAS', 'Chemical', '-', (65, 68))	('Ewing sarcoma', 'Disease', (25, 38))	('infantile rhabdomyosarcoma', 'Disease', (104, 130))	('Syn', 'Gene', '6855', (71, 74))	('infantile rhabdomyosarcoma', 'Disease', 'MESH:D012208', (104, 130))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (25, 38))	('S100+', 'Var', (77, 82))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (25, 38))	('myosin', 'Gene', (160, 166))
322502	22787293	They included infantile rhabdomyosarcoma (PAS+, Myo +) (1 case) and PNET (PAS+, Syn +, S100+) (3 cases).	('Syn', 'Gene', (80, 83))	('PAS+', 'Var', (74, 78))	('infantile rhabdomyosarcoma', 'Disease', (14, 40))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (24, 40))	('Myo', 'Gene', '79784', (48, 51))	('Myo', 'Gene', (48, 51))	('S100+', 'Var', (87, 92))	('PAS', 'Chemical', '-', (74, 77))	('infantile rhabdomyosarcoma', 'Disease', 'MESH:D012208', (14, 40))	('Syn', 'Gene', '6855', (80, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('PAS', 'Chemical', '-', (42, 45))
322509	21464880	Spinal intradural extraosseous Ewing's sarcoma Extraosseous Ewing's sarcoma (EES) involving the central nervous system is rare, but can be diagnosed and distinguished from other primitive neuroectodermal tumors (PNET) by identification of the chromosomal translocation (11;22)(q24;q12).	("Extraosseous Ewing's sarcoma", 'Disease', 'MESH:C563168', (47, 75))	('neuroectodermal tumors', 'Disease', (188, 210))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (31, 46))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (188, 210))	('11;', 'Var', (270, 273))	("Ewing's sarcoma", 'Disease', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (31, 46))	("Extraosseous Ewing's sarcoma", 'Disease', (47, 75))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (60, 75))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (60, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('PNET', 'Phenotype', 'HP:0030065', (212, 216))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (178, 210))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (188, 210))
322558	21464880	He received one cycle of VCD followed by IE for two cycles and adjuvant radiation to the thoracolumbar spine (5040Gy, 28f).	('5040Gy', 'Var', (110, 116))	('VCD', 'Disease', 'None', (25, 28))	('VCD', 'Disease', (25, 28))
322581	32438562	Spontaneous hybrids, but not their non-fused immortalized myoblast counterparts they are generated from, induced tumors in mice.	('hybrids', 'Var', (12, 19))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mice', 'Species', '10090', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
322583	32438562	This genome remodeling finally produced targeted DMD deletions associated with replicative stress, isoform relocalization and metastatic spreading, exactly as observed in human myogenic sarcomas.	('metastatic spreading', 'CPA', (126, 146))	('associated', 'Reg', (63, 73))	('sarcomas', 'Disease', 'MESH:D012509', (186, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('sarcomas', 'Disease', (186, 194))	('replicative', 'MPA', (79, 90))	('stress', 'Disease', (91, 97))	('stress', 'Disease', 'MESH:D000079225', (91, 97))	('human', 'Species', '9606', (171, 176))	('DMD', 'Var', (49, 52))
322590	32438562	One of the most important consequences of tetraploidization is the generation of aneuploid cells and chromosomal rearrangements.	('aneuploid', 'Disease', 'MESH:D000782', (81, 90))	('aneuploid', 'Disease', (81, 90))	('tetraploidization', 'Var', (42, 59))
322592	32438562	Cytokinesis failure occurs when there is a defect in the cytokinetic proteins or an error in chromosome segregation Cell fusion generates heterokaryons that could lead to synkaryons, i.e., daughter cells with one nucleus.	('synkaryons', 'CPA', (171, 181))	('daughter cells with one nucleus', 'CPA', (189, 220))	('error', 'Var', (84, 89))	('defect', 'NegReg', (43, 49))	('Cytokinesis failure', 'Disease', 'MESH:D006333', (0, 19))	('lead to', 'Reg', (163, 170))	('Cytokinesis failure', 'Disease', (0, 19))
322618	32438562	LP hybrids developed more tumors than those at early passages.	('LP', 'Chemical', '-', (0, 2))	('tumors', 'Disease', (26, 32))	('LP hybrids', 'Var', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
322619	32438562	At 130 days, 54% vs. 14% of mice injected with LP or EP hybrids, respectively, had developed a tumor, indicating that LP hybrids develop tumors more rapidly than EP hybrids (Figure 3B and Figure S3B).	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', (137, 142))	('LP', 'Chemical', '-', (118, 120))	('S3B', 'Gene', '11778', (195, 198))	('LP', 'Chemical', '-', (47, 49))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('mice', 'Species', '10090', (28, 32))	('S3B', 'Gene', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('LP hybrids', 'Var', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (95, 100))
322626	32438562	Results above show that LP cell lines developed tumors faster than EP ones and that hybrid cell lines evolve in culture conditions leading to cell lines with recurrent and specific chromosome number variations.	('variations', 'Var', (199, 209))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('LP', 'Chemical', '-', (24, 26))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
322630	32438562	In contrast, tumors developed from EP hybrids displayed more CNVs than cell lines in vitro, as reflected by an increase in the genomic index (Figure 4A and Figure S5).	('increase', 'PosReg', (111, 119))	('genomic', 'MPA', (127, 134))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('EP hybrids', 'Var', (35, 45))	('CNVs', 'CPA', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
322637	32438562	These genes clustered the samples into four groups (Figure S6B), mainly according to their status: parental (with both parental cell lines and H1 EP), EP hybrids (EP H2, H3, H5 and H6 with H3 LP), LP hybrids (H1, H2, H4, H5 and H6 LP with H4 EP) and tumors.	('H3', 'Chemical', 'MESH:C012616', (189, 191))	('LP', 'Chemical', '-', (231, 233))	('H6', 'Chemical', 'MESH:C003027', (228, 230))	('H3', 'Chemical', 'MESH:C012616', (170, 172))	('LP', 'Chemical', '-', (192, 194))	('H2', 'Chemical', 'MESH:D003903', (213, 215))	('tumors', 'Disease', (250, 256))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('H6', 'Chemical', 'MESH:C003027', (181, 183))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('LP', 'Chemical', '-', (197, 199))	('H1', 'Var', (209, 211))	('H2', 'Chemical', 'MESH:D003903', (166, 168))
322640	32438562	This highlighted three types of structural variants in addition to CNVs (Figure 5A): (i) intra-chromosomic translocations in all cases, (ii) inter-chromosomic rearrangements in two cases (H2-LP-Tumor1 and H4-LP-Tumor3) and (iii) chromothripsis along the entire chromosome 3 of H2-LP-Tumor1.	('H2', 'Chemical', 'MESH:D003903', (277, 279))	('H2', 'Chemical', 'MESH:D003903', (188, 190))	('inter-chromosomic rearrangements', 'Var', (141, 173))	('H2-LP-Tumor1', 'Gene', (277, 289))	('Tumor', 'Phenotype', 'HP:0002664', (194, 199))	('LP', 'Chemical', '-', (191, 193))	('LP', 'Chemical', '-', (208, 210))	('Tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Tumor', 'Phenotype', 'HP:0002664', (283, 288))	('LP', 'Chemical', '-', (280, 282))
322641	32438562	Array CGH analysis of hybrid tumors specifically evidenced focal recurrent intragenic deletions targeting DMD in 82% of cases (Figure 5B and Figure S7A), and occurring only after in vivo tumor growth.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('deletions', 'Var', (86, 95))	('tumors', 'Disease', (29, 35))	('CGH', 'Gene', (6, 9))	('CGH', 'Gene', '3342', (6, 9))
322642	32438562	Since DMD inactivation by deletion has been reported to be a driver event in sarcomas with myogenic differentiation, we further characterized this highly frequent alteration.	('DMD inactivation', 'Var', (6, 22))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('deletion', 'Var', (26, 34))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))
322644	32438562	Note that all deletions occurred in a region that affects Dp427, Dp260, Dp140 and Dp116 isoforms only, systematically preserving the 3' end of the locus coding Dp71 isoform.	('Dp71', 'Gene', (160, 164))	('Dp71', 'Gene', '13405', (160, 164))	('deletions', 'Var', (14, 23))	("3' end", 'MPA', (133, 139))	('Dp427', 'Gene', '13405', (58, 63))	('Dp427', 'Gene', (58, 63))
322649	32438562	This result confirmed that the dystrophin isoform Dp71 is not targeted by these deletions.	('Dp71', 'Gene', '13405', (50, 54))	('Dp71', 'Gene', (50, 54))	('deletions', 'Var', (80, 89))
322653	32438562	The third group was composed of tumors that displayed a DMD deletion (H1-EP-Tumor2, H1-EP-Tumor3, H2-LP-Tumor1 and H4-LP-Tumor3) and maintained a weak expression of Dp427 in differentiation conditions.	('H2', 'Chemical', 'MESH:D003903', (98, 100))	('Tumor', 'Phenotype', 'HP:0002664', (121, 126))	('expression', 'MPA', (151, 161))	('Dp427', 'Gene', '13405', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('Tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('LP', 'Chemical', '-', (101, 103))	('LP', 'Chemical', '-', (118, 120))	('tumors', 'Disease', (32, 38))	('Dp427', 'Gene', (165, 170))	('H1-EP-Tumor3', 'Var', (84, 96))
322655	32438562	DMD deletions did not target the Dp71 ORF and this isoform has been demonstrated to be essential for proliferation in myogenic cancers.	('Dp71', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Dp71', 'Gene', '13405', (33, 37))	('deletions', 'Var', (4, 13))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
322666	32438562	By testing whether cell-cell fusion is involved in the oncogenesis of myogenic sarcoma, we found that cell fusion generates hybrids promoting tumor initiation and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('sarcoma', 'Disease', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('tumor', 'Disease', (142, 147))	('promoting', 'PosReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('hybrids', 'Var', (124, 131))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
322667	32438562	In vivo, upon selection pressure, emerging tumors very frequently harbor DMD deletions similar to those described in human myogenic sarcomas.	('human', 'Species', '9606', (117, 122))	('sarcomas', 'Disease', 'MESH:D012509', (132, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcomas', 'Disease', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('DMD deletions', 'Var', (73, 86))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
322668	32438562	These deletions abrogate Dp427 isoform expression and trigger the relocation of the other isoforms, including Dp71, to the nucleus.	('Dp427', 'Gene', '13405', (25, 30))	('trigger', 'Reg', (54, 61))	('Dp427', 'Gene', (25, 30))	('deletions', 'Var', (6, 15))	('abrogate', 'NegReg', (16, 24))	('Dp71', 'Gene', (110, 114))	('Dp71', 'Gene', '13405', (110, 114))	('relocation', 'MPA', (66, 76))
322675	32438562	One hypothesis of oncogenesis is that the pRb pathway deregulation is the first event, followed by cell fusion that induces a transient tetraploid state followed by aneuploidy and chromosomic instability.	('aneuploidy', 'Disease', (165, 175))	('pRb', 'Gene', '5925', (42, 45))	('induces', 'Reg', (116, 123))	('aneuploidy', 'Disease', 'MESH:D000782', (165, 175))	('tetraploid state', 'MPA', (136, 152))	('deregulation', 'Var', (54, 66))	('chromosomic instability', 'CPA', (180, 203))	('pRb', 'Gene', (42, 45))
322682	32438562	Progressive acquisition of these alterations is correlated with an evolution of the transcriptomic program, from parental cells to tumors.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('alterations', 'Var', (33, 44))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
322686	32438562	Splicing factor upregulation and aberrant splicing are both common in cancer and could account for the expression of specific isoforms related to differentiation and proliferation.	('aberrant splicing', 'Var', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('upregulation', 'PosReg', (16, 28))	('Splicing factor', 'Gene', (0, 15))	('Splicing factor', 'Gene', '10569', (0, 15))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
322692	32438562	DMD deletions are then detected because the locus fits these features and deletions have a tumor suppressor impact on oncogenesis.	('fits', 'Disease', (50, 54))	('deletions', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('fits', 'Disease', 'MESH:D012640', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('oncogenesis', 'CPA', (118, 129))	('tumor', 'Disease', (91, 96))
322693	32438562	Deletion of DMD abrogates the expression of the Dp427 isoform, always preserving Dp71.	('DMD', 'Gene', (12, 15))	('expression', 'MPA', (30, 40))	('Dp427', 'Gene', (48, 53))	('Dp71', 'Gene', (81, 85))	('abrogates', 'NegReg', (16, 25))	('Dp71', 'Gene', '13405', (81, 85))	('Dp427', 'Gene', '13405', (48, 53))	('Deletion', 'Var', (0, 8))
322696	32438562	Deletion of Dp427 seems to confer new properties to Dp71 in a sarcoma context, hypothesizing that Dp71 isoform could have a role in metastasis development.	('role', 'Reg', (124, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Dp427', 'Gene', '13405', (12, 17))	('Dp71', 'Gene', (98, 102))	('Dp71', 'Gene', '13405', (98, 102))	('Dp427', 'Gene', (12, 17))	('Dp71', 'Gene', (52, 56))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('properties', 'MPA', (38, 48))	('Dp71', 'Gene', '13405', (52, 56))	('sarcoma', 'Disease', (62, 69))	('Deletion', 'Var', (0, 8))
322698	32438562	Dp71 isoform have already been described in the nucleus of HeLa cells and is linked to beta-dystroglycan and alpha-sarcoglycan which are anchored in the nuclear membrane.One of the hypotheses on the oncogenic role of Dp71 triggers by Dp427 deletion is that Dp71 and DAPC could have the same function in the nucleus membrane as Dp427 and DAPC in the cellular membrane, thereby participating in the regulation of nuclear processes by modifying the nucleus membrane.	('Dp427', 'Gene', (234, 239))	('Dp427', 'Gene', '13405', (327, 332))	('DAP', 'Gene', '1611', (337, 340))	('Dp71', 'Gene', (257, 261))	('participating', 'Reg', (376, 389))	('Dp71', 'Gene', '13405', (0, 4))	('DAP', 'Gene', (266, 269))	('modifying', 'Reg', (432, 441))	('Dp427', 'Gene', (327, 332))	('DAP', 'Gene', (337, 340))	('Dp71', 'Gene', (217, 221))	('alpha-sarcoglycan', 'Gene', '6442', (109, 126))	('regulation', 'MPA', (397, 407))	('nucleus membrane', 'MPA', (446, 462))	('Dp71', 'Gene', (0, 4))	('Dp71', 'Gene', '13405', (257, 261))	('Dp427', 'Gene', '13405', (234, 239))	('deletion', 'Var', (240, 248))	('HeLa', 'CellLine', 'CVCL:0030', (59, 63))	('Dp71', 'Gene', '13405', (217, 221))	('DAP', 'Gene', '1611', (266, 269))	('alpha-sarcoglycan', 'Gene', (109, 126))
322728	32438562	Primary antibodies used for Dp427 were NCL-DYS1 (1/25, Novacastra, Leica, Wetzlar, Germany) and ab15277 for all the dystrophin isoforms (1/100, Abcam, Cambridge, UK).	('ab15277', 'Var', (96, 103))	('Dp427', 'Gene', (28, 33))	('Dp427', 'Gene', '13405', (28, 33))
322740	32438562	A Circos plot was performed with array-CGH average log2ratio and structural variants.	('structural variants', 'Var', (65, 84))	('CGH', 'Gene', (39, 42))	('CGH', 'Gene', '3342', (39, 42))	('log2ratio', 'Var', (51, 60))
322744	32438562	After wash, membranes were incubated for 1 h at room temperature with appropriate secondary antibodies: anti-rabbit HRP (7074S, 1/1000, Ozyme, Saint-Cyr-l'Ecole, France) and anti-mouse HRP (7076S, 1/1000, Ozyme).	('mouse', 'Species', '10090', (179, 184))	('7076S', 'Var', (190, 195))	('7074S', 'Var', (121, 126))
322747	32438562	The following are available online at , Figure S1: Fluorescence analysis, Figure S2: Genomic analysis of hybrid cells lines at early and late passages shows evolution of genomes, Figure S3: Late passage cell lines developed more tumors than early passage cell lines, Figure S4: Characterization of hybrid tumors developed in mice, Figure S5: Genomic profiling, Figure S6: Transcriptomic program is remodeled toward oncogenesis, Figure S7: Identification and validation of DMD deletions in hybrid tumors, Figure S8: Signal detection on the whole membrane shown on Figure 6A, Figure S9: Detection of Dp427 and other dystrophin isoforms by immunofluorescence analysis, Table S1: Genes used to cluster the samples into four groups.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('mice', 'Species', '10090', (325, 329))	('deletions', 'Var', (476, 485))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('Dp427', 'Gene', '13405', (598, 603))	('tumors', 'Phenotype', 'HP:0002664', (496, 502))	('Dp427', 'Gene', (598, 603))	('tumors', 'Disease', 'MESH:D009369', (305, 311))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (496, 501))	('tumors', 'Disease', 'MESH:D009369', (496, 502))	('tumors', 'Disease', (496, 502))	('tumors', 'Disease', (229, 235))	('tumors', 'Disease', (305, 311))
322827	31959033	Thus, it can be determined that those experiencing LVEDV declines related to decrements in LV preload may also experience myocardial dysfunction related to cancer or its treatment.	('myocardial dysfunction', 'Disease', 'MESH:D009202', (122, 144))	('experience', 'Reg', (111, 121))	('myocardial dysfunction', 'Disease', (122, 144))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('LVEDV', 'Chemical', '-', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('declines', 'NegReg', (57, 65))	('decrements', 'Var', (77, 87))	('LV preload', 'MPA', (91, 101))
322833	31959033	Second, although the precision of CMR measures of LV function reduced the variability of our outcome measures, this same small sample size reduced the biological variability of our patient population.	('patient', 'Species', '9606', (181, 188))	('variability', 'MPA', (74, 85))	('biological variability', 'MPA', (151, 173))	('precision', 'Var', (21, 30))	('reduced', 'NegReg', (139, 146))	('reduced', 'NegReg', (62, 69))
322842	31652776	Sidestepping or resisting apoptosis is a distinct characteristic of human cancers including childhood malignancies.	('resisting apoptosis', 'CPA', (16, 35))	('human', 'Species', '9606', (68, 73))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('malignancies', 'Disease', (102, 114))	('Sidestepping', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
322846	31652776	Dysregulation of apoptosis is an important aspect of cancer pathogenesis as it disrupts the delicate balance between cell proliferation and cell death, and has been widely recognized as a hallmark of cancer.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Dysregulation', 'Var', (0, 13))	('delicate balance between', 'MPA', (92, 116))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('disrupts', 'NegReg', (79, 87))	('apoptosis', 'CPA', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('death', 'Disease', 'MESH:D003643', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('death', 'Disease', (145, 150))	('cancer', 'Disease', (200, 206))
322847	31652776	For decades, defects in apoptosis during development have been implicated in the formation and progression of cancers including childhood malignancies, as many of these embryonal neoplasms and developmental processes share similar biological mechanisms.	('apoptosis', 'Protein', (24, 33))	('cancers', 'Disease', (110, 117))	('embryonal neoplasms', 'Disease', (169, 188))	('embryonal neoplasms', 'Disease', 'MESH:D009373', (169, 188))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('embryonal neoplasms', 'Phenotype', 'HP:0002898', (169, 188))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('neoplasms', 'Phenotype', 'HP:0002664', (179, 188))	('malignancies', 'Disease', (138, 150))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('defects', 'Var', (13, 20))	('implicated', 'Reg', (63, 73))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
322854	31652776	Activated caspase-8 then cleaves a chain of downstream caspases to execute apoptosis.. Caspase-8 also cleaves BID, which then triggers the release of cytochrome c from the mitochondria and activates subsequent intrinsic apoptotic signaling.	('cytochrome c', 'Gene', '54205', (150, 162))	('caspase-8', 'Gene', (10, 19))	('caspases', 'Gene', '841;842', (55, 63))	('BID', 'Gene', (110, 113))	('cleaves', 'Var', (102, 109))	('Caspase-8', 'Gene', (87, 96))	('caspase-8', 'Gene', '841', (10, 19))	('caspases', 'Gene', (55, 63))	('intrinsic apoptotic signaling', 'Pathway', (210, 239))	('triggers', 'Reg', (126, 134))	('cytochrome c', 'Gene', (150, 162))	('activates', 'PosReg', (189, 198))	('BID', 'Gene', '637', (110, 113))	('Caspase-8', 'Gene', '841', (87, 96))
322863	31652776	In this review, two underlying mechanisms: (1) defective death receptor signaling and (2) imbalanced ratio of pro-apoptotic to anti-apoptotic proteins, both of which renders impaired apoptosis or development of resistance to it:will be discussed.	('death', 'Disease', 'MESH:D003643', (57, 62))	('defective', 'NegReg', (47, 56))	('death', 'Disease', (57, 62))	('impaired apoptosis', 'Disease', (174, 192))	('imbalanced', 'Var', (90, 100))	('impaired apoptosis', 'Disease', 'MESH:D060825', (174, 192))
322865	31652776	Different abnormalities in the death signaling pathways have been reported to cause the evasion of the extrinsic apoptotic pathway.	('cause', 'Reg', (78, 83))	('evasion', 'MPA', (88, 95))	('death', 'Disease', 'MESH:D003643', (31, 36))	('extrinsic apoptotic pathway', 'Pathway', (103, 130))	('death', 'Disease', (31, 36))	('abnormalities', 'Var', (10, 23))
322878	31652776	Moreover, a splicing variant of CD95, which resulted in a truncated receptor without its intracytoplasmic death-signaling domain, also provided resistance to CD95-mediated apoptosis.	('CD95', 'Gene', (32, 36))	('resistance', 'CPA', (144, 154))	('death', 'Disease', 'MESH:D003643', (106, 111))	('death', 'Disease', (106, 111))	('CD95-mediated', 'MPA', (158, 171))	('splicing variant', 'Var', (12, 28))
322879	31652776	Altered expression as a result from polymorphisms and deleterious mutations in the CD95 promoter region were identified in childhood T-cell ALL, AML, and NHL.	('mutations', 'Var', (66, 75))	('polymorphisms', 'Var', (36, 49))	('AML', 'Disease', (145, 148))	('Altered', 'Reg', (0, 7))	('AML', 'Disease', 'MESH:D015470', (145, 148))	('CD95', 'Gene', (83, 87))	('expression', 'MPA', (8, 18))	('childhood T-cell ALL', 'Disease', (123, 143))
322885	31652776	For instance, in neuroblastoma, downregulation of TRAIL receptors as a result of promoter hypermethylation was shown to decrease the response and sensitivity to TRAIL ligand, thus weakening the downstream apoptosis signaling.	('neuroblastoma', 'Phenotype', 'HP:0003006', (17, 30))	('downregulation', 'NegReg', (32, 46))	('weakening', 'NegReg', (180, 189))	('response', 'MPA', (133, 141))	('decrease', 'NegReg', (120, 128))	('neuroblastoma', 'Disease', 'MESH:D009447', (17, 30))	('promoter hypermethylation', 'Var', (81, 106))	('neuroblastoma', 'Disease', (17, 30))	('sensitivity to TRAIL ligand', 'MPA', (146, 173))	('TRAIL receptors', 'Protein', (50, 65))
322886	31652776	Hypermethylation or genomic deletions in CASP8 gene were also identified in neuroblastoma.	('neuroblastoma', 'Disease', (76, 89))	('identified', 'Reg', (62, 72))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('Hypermethylation', 'Var', (0, 16))	('CASP8', 'Gene', (41, 46))	('CASP8', 'Gene', '841', (41, 46))	('genomic deletions', 'Var', (20, 37))	('neuroblastoma', 'Disease', 'MESH:D009447', (76, 89))
322896	31652776	The expression of these apoptotic proteins is also influenced by many other survival signaling pathways such as the p53, STAT, and PI3K, which indirectly affect apoptosis.	('survival signaling pathways', 'Pathway', (76, 103))	('apoptotic', 'Gene', (24, 33))	('expression', 'MPA', (4, 14))	('apoptosis', 'CPA', (161, 170))	('p53', 'Gene', '7157', (116, 119))	('affect', 'Reg', (154, 160))	('PI3K', 'Var', (131, 135))	('p53', 'Gene', (116, 119))	('influenced', 'Reg', (51, 61))
322903	31652776	The chromosomal analysis from comparative genomic hybridization (CGH) of the BCL-2 family members identified frequent deletions of pro-apoptotic BAK, BID, and BAD loci, and overexpression of anti-apoptotic BCL-2 and BCL-XL in several tumors including childhood cancers:glioblastoma and acute leukemias.	('overexpression', 'PosReg', (173, 187))	('acute leukemias', 'Phenotype', 'HP:0002488', (286, 301))	('BCL-XL', 'Gene', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('BID', 'Gene', (150, 153))	('leukemias', 'Phenotype', 'HP:0001909', (292, 301))	('BID', 'Gene', '637', (150, 153))	('leukemia', 'Phenotype', 'HP:0001909', (292, 300))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('BCL-XL', 'Gene', '598', (216, 222))	('cancers', 'Disease', (261, 268))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('BCL-2', 'Gene', '596', (206, 211))	('BCL-2', 'Gene', (206, 211))	('glioblastoma', 'Disease', 'MESH:D005909', (269, 281))	('BCL-2', 'Gene', '596', (77, 82))	('BAK', 'Gene', (145, 148))	('BCL-2', 'Gene', (77, 82))	('acute leukemia', 'Phenotype', 'HP:0002488', (286, 300))	('BAD loci', 'Gene', (159, 167))	('tumors', 'Disease', (234, 240))	('BAK', 'Gene', '578', (145, 148))	('acute leukemias', 'Disease', 'MESH:D015470', (286, 301))	('glioblastoma', 'Disease', (269, 281))	('acute leukemias', 'Disease', (286, 301))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('deletions', 'Var', (118, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (269, 281))
322906	31652776	Furthermore, a high BCL-2/BAX ratio was predicted to have a poorer overall survival in AML patients and be associated with relapse in childhood ALL.	('high', 'Var', (15, 19))	('poorer', 'NegReg', (60, 66))	('BAX', 'Gene', '581', (26, 29))	('patients', 'Species', '9606', (91, 99))	('AML', 'Disease', (87, 90))	('BCL-2', 'Gene', (20, 25))	('overall survival', 'MPA', (67, 83))	('associated with', 'Reg', (107, 122))	('AML', 'Disease', 'MESH:D015470', (87, 90))	('BAX', 'Gene', (26, 29))	('BCL-2', 'Gene', '596', (20, 25))
322914	31652776	Therefore, defects in the p53 tumor suppressor gene will lead to downregulation of BAX, hence inhibiting apoptosis.	('defects', 'Var', (11, 18))	('apoptosis', 'CPA', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('p53', 'Gene', (26, 29))	('downregulation', 'NegReg', (65, 79))	('BAX', 'Gene', (83, 86))	('inhibiting', 'NegReg', (94, 104))	('p53', 'Gene', '7157', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('BAX', 'Gene', '581', (83, 86))	('tumor', 'Disease', (30, 35))
322915	31652776	Overexpressing p53 through adenoviral-mediated transduction in childhood sarcomas (rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma) has been observed to sensitize cells to chemotherapeutics.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('osteosarcoma', 'Disease', (101, 113))	('Overexpressing', 'Var', (0, 14))	('osteosarcoma', 'Disease', 'MESH:D012516', (101, 113))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (83, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('p53', 'Gene', '7157', (15, 18))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (83, 99))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (119, 134))	('p53', 'Gene', (15, 18))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (119, 134))	('osteosarcoma', 'Phenotype', 'HP:0002669', (101, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcomas', 'Disease', (73, 81))	('rhabdomyosarcoma', 'Disease', (83, 99))	('adenoviral-mediated transduction', 'Var', (27, 59))	("Ewing's sarcoma", 'Disease', (119, 134))
322920	31652776	Through the phosphorylation by kinases in this pathway, the BCL-2 family of proteins such as BAD or BCL-2 can be inactivated or activated to inhibit or promote apoptosis, respectively.	('apoptosis', 'CPA', (160, 169))	('BCL-2', 'Gene', (60, 65))	('activated', 'PosReg', (128, 137))	('phosphorylation', 'Var', (12, 27))	('BCL-2', 'Gene', '596', (100, 105))	('BCL-2', 'Gene', '596', (60, 65))	('BCL-2', 'Gene', (100, 105))	('inhibit', 'NegReg', (141, 148))	('promote', 'PosReg', (152, 159))
322922	31652776	Inhibition of PI3K and its downstream signaling was observed to enhance apoptosis in Ewing's sarcoma, while treatment of PI3K inhibitors in neuroblastoma cells was found to target anti-apoptotic BCL-2 family proteins and further promote mitochondrial apoptosis through chemosensitization, thus emphasizing the association between PI3K and BCL-2 family-mediated apoptosis.	("Ewing's sarcoma", 'Disease', (85, 100))	('target', 'Reg', (173, 179))	('enhance', 'PosReg', (64, 71))	('BCL-2', 'Gene', '596', (339, 344))	('BCL-2', 'Gene', '596', (195, 200))	('promote', 'PosReg', (229, 236))	('BCL-2', 'Gene', (195, 200))	('mitochondrial apoptosis', 'CPA', (237, 260))	('BCL-2', 'Gene', (339, 344))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('PI3K', 'Gene', (14, 18))	('neuroblastoma', 'Disease', 'MESH:D009447', (140, 153))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (85, 100))	('Inhibition', 'Var', (0, 10))	('apoptosis', 'CPA', (72, 81))	('neuroblastoma', 'Disease', (140, 153))	('neuroblastoma', 'Phenotype', 'HP:0003006', (140, 153))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (85, 100))
322928	31652776	Therefore, activation of Notch signaling either through mutations or amplification of Notch such as those identified in T-cell ALL, medulloblastoma, osteosarcoma, and Ewing's sarcoma, ultimately promotes cell survival and inhibits apoptosis.	("Ewing's sarcoma", 'Disease', (167, 182))	('T-cell ALL', 'Disease', (120, 130))	('osteosarcoma', 'Disease', (149, 161))	('osteosarcoma', 'Disease', 'MESH:D012516', (149, 161))	('activation', 'PosReg', (11, 21))	('inhibits', 'NegReg', (222, 230))	('mutations', 'Var', (56, 65))	('Notch', 'MPA', (25, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('promotes', 'PosReg', (195, 203))	('medulloblastoma', 'Disease', 'MESH:D008527', (132, 147))	('medulloblastoma', 'Phenotype', 'HP:0002885', (132, 147))	('medulloblastoma', 'Disease', (132, 147))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (167, 182))	('osteosarcoma', 'Phenotype', 'HP:0002669', (149, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (167, 182))	('apoptosis', 'CPA', (231, 240))	('Notch', 'Gene', (86, 91))	('cell survival', 'CPA', (204, 217))	('amplification', 'Var', (69, 82))
322944	31652776	The silencing of MCL-1 was shown to sensitize or prime cancer cells to cytotoxic chemotherapy and BCL-2 family antagonists in ALL, rhabdomyosarcoma, and neuroblastoma.	('MCL-1', 'Gene', '4170', (17, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('rhabdomyosarcoma', 'Disease', (131, 147))	('BCL-2', 'Gene', (98, 103))	('MCL-1', 'Gene', (17, 22))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (131, 147))	('neuroblastoma', 'Disease', 'MESH:D009447', (153, 166))	('ALL', 'Disease', (126, 129))	('neuroblastoma', 'Disease', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('prime', 'PosReg', (49, 54))	('sensitize', 'Reg', (36, 45))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (131, 147))	('neuroblastoma', 'Phenotype', 'HP:0003006', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('BCL-2', 'Gene', '596', (98, 103))	('silencing', 'Var', (4, 13))	('cancer', 'Disease', (55, 61))
322962	31652776	Therefore, the increase in expression of IAPs as a result of direct genetic alterations in IAPs' loci or the decrease in pro-apoptotic proteins to inhibit IAPs can impair apoptotic signaling to favor cell survival and contribute to cancer development.	('decrease', 'NegReg', (109, 117))	('cancer', 'Disease', (232, 238))	('increase', 'PosReg', (15, 23))	('expression', 'MPA', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('IAP', 'Gene', (41, 44))	('IAP', 'Gene', '961', (41, 44))	('contribute', 'Reg', (218, 228))	('impair', 'NegReg', (164, 170))	('cell survival', 'CPA', (200, 213))	('apoptotic signaling', 'MPA', (171, 190))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('favor', 'PosReg', (194, 199))	('inhibit', 'NegReg', (147, 154))	('IAP', 'Gene', (155, 158))	('IAP', 'Gene', '961', (155, 158))	('IAP', 'Gene', (91, 94))	('IAP', 'Gene', '961', (91, 94))	('genetic alterations', 'Var', (68, 87))
322965	31652776	The high XIAP level is correlated with immature blast phenotype and cytogenetic profiles of high-risk groups, reduced relapse-free survival, and poor treatment response to induction chemotherapy.	('reduced', 'NegReg', (110, 117))	('relapse-free survival', 'CPA', (118, 139))	('XIAP', 'Gene', (9, 13))	('XIAP', 'Gene', '331', (9, 13))	('high', 'Var', (4, 8))
322966	31652776	Similarly, high XIAP expression is found in childhood T-cell ALL and its expression is associated with poor prednisone treatment response.	('prednisone', 'Chemical', 'MESH:D011241', (108, 118))	('expression', 'MPA', (21, 31))	('associated', 'Reg', (87, 97))	('expression', 'MPA', (73, 83))	('XIAP', 'Gene', (16, 20))	('high', 'Var', (11, 15))	('XIAP', 'Gene', '331', (16, 20))
322973	31652776	Intriguingly, dysregulation of Hippo pathway with overexpression of Yap has been reported in several pediatric cancers whereby Survivin is also overexpressed, suggesting possible implication of Hippo-Survivin signaling in these cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('Yap', 'Gene', (68, 71))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('Survivin', 'Gene', '11799', (127, 135))	('cancers', 'Disease', (228, 235))	('cancers', 'Disease', (111, 118))	('overexpression', 'PosReg', (50, 64))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('Survivin', 'Gene', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('dysregulation', 'Var', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Yap', 'Gene', '10413', (68, 71))	('Survivin', 'Gene', '11799', (200, 208))	('Survivin', 'Gene', (200, 208))	('Hippo pathway', 'Pathway', (31, 44))
322974	31652776	Overexpression of Survivin is commonly found in pediatric cancers and has a correlation with the progression of disease, chemoresistance, metastasis, unfavorable prognosis, and survival.	('correlation', 'Reg', (76, 87))	('metastasis', 'CPA', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('progression', 'CPA', (97, 108))	('Survivin', 'Gene', (18, 26))	('Survivin', 'Gene', '11799', (18, 26))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('Overexpression', 'Var', (0, 14))	('cancers', 'Disease', (58, 65))	('chemoresistance', 'CPA', (121, 136))
322979	31652776	These splice variants can also be dysregulated and play a role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('role', 'Reg', (58, 62))	('tumor', 'Disease', (66, 71))	('splice variants', 'Var', (6, 21))	('play', 'Reg', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
323003	31652776	Neuronal progenitors that are locally deprived of NGF, on the other hand, were shown to undergo intrinsic mitochondrial apoptosis.. Failure of this process has been shown to be implicated in pediatric malignancies including neuroblastoma.	('malignancies', 'Disease', (201, 213))	('neuroblastoma', 'Phenotype', 'HP:0003006', (224, 237))	('NGF', 'Gene', '4803', (50, 53))	('NGF', 'Gene', (50, 53))	('implicated', 'Reg', (177, 187))	('neuroblastoma', 'Disease', 'MESH:D009447', (224, 237))	('Failure', 'Var', (132, 139))	('malignancies', 'Disease', 'MESH:D009369', (201, 213))	('neuroblastoma', 'Disease', (224, 237))
323013	31652776	While LCL161 was found to be potent against several pediatric leukemia and lymphoma cell lines in vitro, LCL161 induced significant differences in event-free survival distribution only in one-third of solid tumor xenografts, such as osteosarcoma and glioblastoma, but not ALL xenografts.	('glioblastoma', 'Disease', 'MESH:D005909', (250, 262))	('osteosarcoma', 'Phenotype', 'HP:0002669', (233, 245))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('glioblastoma', 'Disease', (250, 262))	('glioblastoma', 'Phenotype', 'HP:0012174', (250, 262))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('lymphoma', 'Disease', (75, 83))	('lymphoma', 'Disease', 'MESH:D008223', (75, 83))	('osteosarcoma', 'Disease', (233, 245))	('osteosarcoma', 'Disease', 'MESH:D012516', (233, 245))	('leukemia', 'Disease', (62, 70))	('LCL161', 'Chemical', 'MESH:C574246', (6, 12))	('leukemia', 'Disease', 'MESH:D007938', (62, 70))	('tumor', 'Disease', (207, 212))	('differences', 'Reg', (132, 143))	('event-free survival', 'MPA', (147, 166))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('LCL161', 'Var', (105, 111))	('LCL161', 'Chemical', 'MESH:C574246', (105, 111))
323014	31652776	On the contrary, another Smac mimetic BV6 was reported to be potent in vitro and in vivo as a single agent, as well as enhancing the efficacy of conventional induction chemotherapy including vincristine, dexamethasone, and asparaginase, leading to prolonged remission in pediatric ALL.	('Smac', 'Gene', '56616', (25, 29))	('enhancing', 'PosReg', (119, 128))	('BV6', 'Var', (38, 41))	('Smac', 'Gene', (25, 29))	('vincristine', 'Chemical', 'MESH:D014750', (191, 202))	('dexamethasone', 'Chemical', 'MESH:D003907', (204, 217))
323017	31652776	In addition to Smac mimetic, XIAP can also be targeted using antisense oligonucleotides (ASO), which was demonstrated to be potent against several cancers either as a single agent or in combination with conventional chemotherapeutics.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Smac', 'Gene', (15, 19))	('oligonucleotides', 'Chemical', 'MESH:D009841', (71, 87))	('antisense', 'Var', (61, 70))	('XIAP', 'Gene', (29, 33))	('ASO', 'Chemical', 'MESH:D016376', (89, 92))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('XIAP', 'Gene', '331', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('Smac', 'Gene', '56616', (15, 19))
323019	31652776	AEG35156 also helps in sensitizing these cells to clinically relevant cytotoxic agents.	('sensitizing', 'MPA', (23, 34))	('AEG35156', 'Chemical', 'MESH:C498209', (0, 8))	('AEG35156', 'Var', (0, 8))
323020	31652776	Moreover, the effect of AEG35156 has also been evaluated in early Phase I/II clinical trials in combination with chemotherapy in AML patients.	('AEG35156', 'Chemical', 'MESH:C498209', (24, 32))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('patients', 'Species', '9606', (133, 141))	('AML', 'Disease', (129, 132))	('AEG35156', 'Var', (24, 32))
323025	31652776	In addition to Smac mimetics and XIAP inhibitors, inhibitors targeting Survivin have been widely described and tested in childhood cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('Survivin', 'Gene', (71, 79))	('Survivin', 'Gene', '11799', (71, 79))	('inhibitors', 'Var', (50, 60))	('cancers', 'Disease', (131, 138))	('Smac', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('XIAP', 'Gene', (33, 37))	('XIAP', 'Gene', '331', (33, 37))	('Smac', 'Gene', '56616', (15, 19))
323040	31147574	Targeted depletion of LIN28B or exogenous expression of LET-7b suppressed hBMSC-Tum proliferation, colony formation, and migration.	('migration', 'CPA', (121, 130))	('hBMSC-Tum proliferation', 'CPA', (74, 97))	('colony formation', 'CPA', (99, 115))	('LIN28B', 'Gene', (22, 28))	('LET-7b', 'Gene', (56, 62))	('suppressed', 'NegReg', (63, 73))	('LET-7b', 'Gene', '406884', (56, 62))	('depletion', 'Var', (9, 18))
323060	31147574	To gain more insight into the epigenetic mechanisms leading to transformation of hBMSC-Tum cells, we performed global miRNA expression profiling of the hBMSC-Tum cells compared to non-transformed hBMSC cells.	('miR', 'Gene', (118, 121))	('hBMSC-Tum', 'Var', (152, 161))	('miR', 'Gene', '220972', (118, 121))
323072	31147574	LIN28B is known to inhibit processing and maturation of the LET-7 family miRNAs, while mature LET-7 is also known to target LIN28B.	('inhibit', 'NegReg', (19, 26))	('LIN28B', 'Var', (0, 6))	('processing', 'MPA', (27, 37))	('maturation', 'CPA', (42, 52))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))
323081	31147574	Over expression of LET-7b (as a representative of the LET-7 family), as well as siRNA-mediated knockdown of LIN28B, reduced colony formation (Fig.	('LIN28B', 'Gene', (108, 114))	('LET-7b', 'Gene', '406884', (19, 25))	('knockdown', 'Var', (95, 104))	('LET-7b', 'Gene', (19, 25))	('reduced', 'NegReg', (116, 123))	('colony formation', 'CPA', (124, 140))
323086	31147574	5e demonstrates the progressive tumor growth of the implanted hBMSC-LIN28B cells, whereas the control cells did not form tumors.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('hBMSC-LIN28B', 'Var', (62, 74))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
323110	31147574	LIN28A and LIN28B selectively inhibit LET-7 miRNA expression and biogenesis in embryonic stem cells (ESCs), and block the expression of LET-7 through TUTase-dependent and independent mechanisms.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('expression', 'MPA', (122, 132))	('LIN28A', 'Gene', (0, 6))	('LET-7', 'Gene', (136, 141))	('LIN28A', 'Gene', '79727', (0, 6))	('biogenesis', 'CPA', (65, 75))	('LET-7', 'Gene', (38, 43))	('TUTase', 'Gene', (150, 156))	('inhibit', 'NegReg', (30, 37))	('TUTase', 'Gene', '64852', (150, 156))	('LIN28B', 'Var', (11, 17))	('block', 'NegReg', (112, 117))
323128	31147574	Briefly, lentiviral particles encoding for human LIN28B (LP-OL05603-LX304-0200-S) or control lentiviral particles mCherry (LP-MCHR-LV105-0205) were purchased from Genecopoeia Inc. (Rockville, MD, USA).	('LIN28B', 'Gene', (49, 55))	('LP-OL05603-LX304-0200-S', 'Var', (57, 80))	('human', 'Species', '9606', (43, 48))
323152	31147574	Viability of the negative control cells compared to the pre-miR Let-7b or si-LIN28B cells (hBMSC-Tum) was determined using an alamarBlue assay as previously described.	('miR Let-7b', 'Gene', (60, 70))	('miR Let-7b', 'Gene', '406884', (60, 70))	('si-LIN28B', 'Var', (74, 83))
323153	31147574	The colony forming ability of the control cells compared to the pre-miR Let-7b or si-LIN28B cells (hBMSC-Tum), hBMSC-LIN28B cells, and hBMSC-mCherry cells was determined using a clonogenic assay as previously described.	('miR Let-7b', 'Gene', '406884', (68, 78))	('colony forming ability', 'CPA', (4, 26))	('miR Let-7b', 'Gene', (68, 78))	('si-LIN28B', 'Var', (82, 91))
323178	29861494	Aberrant Src activity is strongly associated with human tumour development, and, in analysis of human tumour samples, increased Src activity arises from an activating mutation at the inhibitory C-terminal tyrosine residue.	('associated', 'Reg', (34, 44))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('Src activity', 'MPA', (128, 140))	('Src activity', 'MPA', (9, 21))	('tyrosine', 'Chemical', 'MESH:D014443', (205, 213))	('human', 'Species', '9606', (96, 101))	('mutation', 'Var', (167, 175))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('increased', 'PosReg', (118, 127))	('tumour', 'Disease', (102, 108))	('activating', 'PosReg', (156, 166))	('human', 'Species', '9606', (50, 55))	('tumour', 'Disease', (56, 62))
323181	29861494	Aberrant Src activation correlates with advanced cancer development and is associated with tumour characteristics, such as increased invasiveness and metastasis.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('increased', 'PosReg', (123, 132))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', (91, 97))	('activation', 'PosReg', (13, 23))	('metastasis', 'CPA', (150, 160))	('invasiveness', 'CPA', (133, 145))	('Src', 'Protein', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('associated', 'Reg', (75, 85))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (49, 55))
323185	29861494	Indeed, c-Src (cellular-Src proto-oncogene) cooperates with the epidermal growth factor (EGF) receptor (EGFR) in murine fibroblast cell lines, and downstream of EGFR signalling with activated (oncogenic) mutations in the Ras (Rat Sarcoma oncogene) small-GTPase.	('small-GTPase', 'Gene', (248, 260))	('mutations', 'Var', (204, 213))	('Sarcoma oncogene', 'Disease', (230, 246))	('GTP', 'Chemical', 'MESH:D006160', (254, 257))	('Ras', 'Gene', (221, 224))	('Rat Sarcoma', 'CellLine', 'CVCL:0492', (226, 237))	('murine', 'Species', '10090', (113, 119))	('Sarcoma oncogene', 'Disease', 'MESH:D000074723', (230, 246))	('epidermal growth factor (EGF) receptor', 'Gene', '13649', (64, 102))	('Sarcoma', 'Phenotype', 'HP:0100242', (230, 237))
323186	29861494	Oncogenic Ras mutations (such as RasV12) locks Ras in the GTP-bound activated state resulting in constitutive signalling through the MAPK (Mitogen activated protein kinase) pathway.	('Ras', 'Gene', (10, 13))	('constitutive signalling', 'MPA', (97, 120))	('GTP', 'Chemical', 'MESH:D006160', (58, 61))	('RasV12', 'Gene', (33, 39))	('RasV12', 'Gene', '41140', (33, 39))	('mutations', 'Var', (14, 23))	('Ras', 'Gene', (47, 50))
323189	29861494	Additionally, combinatorial treatment with inhibitors of EGFR (Gefitinib) and Src (AZD0530) in human head and neck squamous cell carcinoma cell lines show greater reduction of growth and invasion compared with treatment with a single compound.	('human', 'Species', '9606', (95, 100))	('inhibitors', 'Var', (43, 53))	('reduction', 'NegReg', (163, 172))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (101, 138))	('AZD0530', 'Chemical', 'MESH:C515233', (83, 90))	('growth', 'CPA', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('neck squamous cell carcinoma', 'Disease', (110, 138))	('Gefitinib', 'Chemical', 'MESH:D000077156', (63, 72))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (110, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('EGFR', 'Gene', (57, 61))
323201	29861494	Furthermore, expression of C-terminally truncated Src42A or Src64B, rendering constitutive activation, resulted in a more pronounced phenotype.	('Src42A', 'Gene', (50, 56))	('Src64B', 'Gene', '48973', (60, 66))	('Src42A', 'Gene', '35524', (50, 56))	('C-terminally truncated', 'Var', (27, 49))	('phenotype', 'MPA', (133, 142))	('Src64B', 'Gene', (60, 66))
323203	29861494	Genetic analysis revealed that the Csk mutant overgrowth phenotype was suppressed by mutations in Src42A and Src64B, as well as the downstream Src kinase, Btk29A (Tec29).	('Src64B', 'Gene', '48973', (109, 115))	('Src42A', 'Gene', (98, 104))	('Csk mutant', 'Gene', (35, 45))	('Btk29A', 'Gene', '34132', (155, 161))	('Tec29', 'Gene', '34132', (163, 168))	('Src64B', 'Gene', (109, 115))	('mutations', 'Var', (85, 94))	('Src42A', 'Gene', '35524', (98, 104))	('Tec29', 'Gene', (163, 168))	('Btk29A', 'Gene', (155, 161))	('overgrowth', 'Phenotype', 'HP:0001548', (46, 56))	('suppressed', 'NegReg', (71, 81))
323207	29861494	This phenotype was only observed at the borders between wild-type and mutant cells, and required input from E-cadherin, p120-catenin, RhoA, JNK and matrix metalloproteinases (MMP1/2).	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '37386', (108, 118))	('MMP1/2', 'Gene', '37949;35997', (175, 181))	('mutant', 'Var', (70, 76))	('MMP1/2', 'Gene', (175, 181))	('p120-catenin', 'Gene', (120, 132))	('RhoA', 'Gene', '36775', (134, 138))	('p120-catenin', 'Gene', '3355143', (120, 132))	('RhoA', 'Gene', (134, 138))
323216	29861494	Given the strong correlation of aberrant Src function with EGFR-Ras activation in human cancers, the finding that JNK and PI3K are critical mediators of Src-Ras cooperative tumourigenesis may provide specific targets for cancer therapy.	('PI3K', 'Var', (122, 126))	('cancer', 'Disease', (88, 94))	('tumour', 'Disease', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', (221, 227))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('human', 'Species', '9606', (82, 87))
323220	29861494	In contrast, expression of Src42AGS with ey > RasACT enhanced the hyperplastic RasACT eye phenotype resulting in overgrowth of the adult eye (Figure 1C and Figure S1L, and Table 1).	('overgrowth', 'Phenotype', 'HP:0001548', (113, 123))	('Src42AGS', 'Gene', (27, 35))	('overgrowth of the adult eye', 'CPA', (113, 140))	('hyperplastic RasACT eye phenotype', 'CPA', (66, 99))	('ey > RasACT', 'Var', (41, 52))	('Src42AGS', 'Gene', '35524', (27, 35))	('RasACT', 'Chemical', '-', (79, 85))	('hyperplastic RasACT eye', 'Phenotype', 'HP:0001090', (66, 89))	('RasACT', 'Chemical', '-', (46, 52))	('enhanced', 'PosReg', (53, 61))
323222	29861494	The dorsal view (Figure 1Cii) showed enhanced outgrowth of ey > RasACT + Src42AGS.	('RasACT', 'Chemical', '-', (64, 70))	('outgrowth', 'CPA', (46, 55))	('ey > RasACT', 'Var', (59, 70))	('Src42AGS', 'Gene', (73, 81))	('enhanced', 'PosReg', (37, 45))	('Src42AGS', 'Gene', '35524', (73, 81))
323241	29861494	A conserved Tyrosine residue in this region (Tyr527 in chickens and Tyr530 in humans) when phosphorylated by C-terminal Src-like kinase (Csk) C-terminal Src-like kinase (Csk) and/or Csk-Homologous-Kinase (Chk) mediates Src inhibition.	('Csk-Homologous-Kinase', 'Gene', '4145', (182, 203))	('Tyrosine', 'Chemical', 'MESH:D014443', (12, 20))	('C-terminal Src-like kinase', 'Gene', '1445', (109, 135))	('Tyr530', 'Var', (68, 74))	('chickens', 'Species', '9031', (55, 63))	('Chk', 'Gene', '4145', (205, 208))	('Tyr527', 'Chemical', '-', (45, 51))	('Csk-Homologous-Kinase', 'Gene', (182, 203))	('C-terminal Src-like kinase', 'Gene', (142, 168))	('C-terminal Src-like kinase', 'Gene', '1445', (142, 168))	('humans', 'Species', '9606', (78, 84))	('Src inhibition', 'MPA', (219, 233))	('C-terminal Src-like kinase', 'Gene', (109, 135))	('Tyr530', 'Chemical', '-', (68, 74))	('Chk', 'Gene', (205, 208))
323254	29861494	Coexpression of Src64B with ey > RasACT enhanced the RasACT hyperplastic eye phenotype characterised by disorganised ommatidia, ectopic bristles and a larger eye (Figure 1D and Figure S1O).	('RasACT hyperplastic eye phenotype', 'CPA', (53, 86))	('larger eye', 'Phenotype', 'HP:0001090', (151, 161))	('Src64B', 'Gene', (16, 22))	('hyperplastic eye', 'Phenotype', 'HP:0001090', (60, 76))	('ectopic bristles', 'CPA', (128, 144))	('ey > RasACT', 'Var', (28, 39))	('enhanced', 'PosReg', (40, 48))	('Src64B', 'Gene', '48973', (16, 22))	('RasACT', 'Chemical', '-', (33, 39))	('RasACT', 'Chemical', '-', (53, 59))
323266	29861494	Src transgenes were coexpressed with RasACT in clones to determine whether neoplastic overgrowth would occur, similar to that previously observed with mutants in the cell polarity genes, scribbled (scrib), disc large (dlg) and lethal-2-giant larvae (lgl).	('scribbled', 'Gene', (187, 196))	('dlg', 'Gene', '32083', (218, 221))	('mutants', 'Var', (151, 158))	('scrib', 'Gene', (198, 203))	('lethal-2', 'Gene', (227, 235))	('neoplastic overgrowth', 'Disease', (75, 96))	('lgl', 'Gene', '33156', (250, 253))	('scrib', 'Gene', '44448', (187, 192))	('scrib', 'Gene', '44448', (198, 203))	('neoplastic overgrowth', 'Disease', 'MESH:D019214', (75, 96))	('dlg', 'Gene', (218, 221))	('overgrowth', 'Phenotype', 'HP:0001548', (86, 96))	('lethal-2', 'Gene', '3354918', (227, 235))	('lgl', 'Gene', (250, 253))	('RasACT', 'Chemical', '-', (37, 43))	('scribbled', 'Gene', '44448', (187, 196))	('scrib', 'Gene', (187, 192))
323271	29861494	Compared with the regular array of photoreceptors in the posterior region in the control mosaic eye disc (Figure 2A), expression of RasACT resulted in ectopic differentiation within clonal tissue (Figure 2C) located just anterior to the morphogenetic furrow (bar, Figure 2C).	('furrow', 'Gene', (251, 257))	('expression', 'Var', (118, 128))	('RasACT', 'Gene', (132, 138))	('resulted in', 'Reg', (139, 150))	('furrow', 'Gene', '44654', (251, 257))	('ectopic differentiation', 'CPA', (151, 174))	('RasACT', 'Chemical', '-', (132, 138))
323291	29861494	Taken together, the overgrowth, loss of differentiation, and altered cell morphology of clonal tissue suggests that expression of Src42AGS + RasACT in eye disc clones induces neoplastic tumour formation.	('induces', 'Reg', (167, 174))	('overgrowth', 'Phenotype', 'HP:0001548', (20, 30))	('neoplastic tumour', 'Disease', 'MESH:D009369', (175, 192))	('neoplastic tumour', 'Phenotype', 'HP:0002664', (175, 192))	('expression', 'Var', (116, 126))	('Src42AGS', 'Gene', (130, 138))	('neoplastic tumour', 'Disease', (175, 192))	('RasACT', 'Chemical', '-', (141, 147))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('Src42AGS', 'Gene', '35524', (130, 138))
323298	29861494	In addition to the tissue overgrowth observed in the eye disc, GFP-positive tissue was observed in the brain lobes of Src42AGS (Figure 3C), Src42A or Src42AACT transgenes (Figure S3F,G) coexpressed with RasACT.	('Src42A', 'Gene', '35524', (118, 124))	('Src42AACT', 'Gene', (150, 159))	('overgrowth', 'Phenotype', 'HP:0001548', (26, 36))	('Src42A', 'Gene', (150, 156))	('transgenes', 'Var', (160, 170))	('Src42A', 'Gene', (140, 146))	('RasACT', 'Chemical', '-', (203, 209))	('Src42A', 'Gene', '35524', (140, 146))	('Src42A', 'Gene', '35524', (150, 156))	('brain lobes', 'Disease', (103, 114))	('Src42AACT', 'Gene', '35524', (150, 159))	('Src42AGS', 'Gene', (118, 126))	('Src42A', 'Gene', (118, 124))	('Src42AGS', 'Gene', '35524', (118, 126))	('brain lobes', 'Disease', 'MESH:D001927', (103, 114))
323305	29861494	In summary, in the clonal system, expression of Src42A or Src64B cooperated with RasACT to result in neoplastic overgrowth (summarised in Table 2 and Table 3).	('neoplastic overgrowth', 'Disease', 'MESH:D019214', (101, 122))	('result in', 'Reg', (91, 100))	('expression', 'Var', (34, 44))	('Src42A', 'Gene', (48, 54))	('Src64B', 'Gene', '48973', (58, 64))	('RasACT', 'Chemical', '-', (81, 87))	('Src42A', 'Gene', '35524', (48, 54))	('Src64B', 'Gene', (58, 64))	('neoplastic overgrowth', 'Disease', (101, 122))	('overgrowth', 'Phenotype', 'HP:0001548', (112, 122))
323306	29861494	Src + RasACT mosaic eye discs were characterised by overgrowth of the eye antennal tissue, an increase in clonal tissue, loss of differentiation and disruption to F-actin organisation.	('Src + RasACT mosaic', 'Var', (0, 19))	('F-actin', 'Gene', '35526', (163, 170))	('disruption', 'Reg', (149, 159))	('loss', 'NegReg', (121, 125))	('increase', 'PosReg', (94, 102))	('overgrowth', 'PosReg', (52, 62))	('overgrowth', 'Phenotype', 'HP:0001548', (52, 62))	('clonal tissue', 'CPA', (106, 119))	('RasACT', 'Chemical', '-', (6, 12))	('F-actin', 'Gene', (163, 170))	('differentiation', 'CPA', (129, 144))
323311	29861494	Basal sections of the same eye disc indicated the normally apical photoreceptor nuclei were inappropriately located at the base of the epithelium suggesting that cells within Src42AGS-expressing clones may be shorter than the adjacent wild-type tissue (Figure 4E, arrow).	('Src42AGS', 'Gene', '35524', (175, 183))	('clones', 'Var', (195, 201))	('Src42AGS', 'Gene', (175, 183))
323332	29861494	In Src64B-expressing clones within the epithelium proper, aPKC (Figure S4Ei, arrow), Baz (Figure S4Gii, arrow) and Dlg (Figure S4Gi, arrow) were correctly localised in smaller clones that were generally restricted to the posterior region of the eye disc.	('Baz', 'Gene', (85, 88))	('Figure S4Gi', 'Var', (120, 131))	('aPKC', 'Gene', (58, 62))	('Src64B', 'Gene', '48973', (3, 9))	('aPKC', 'Gene', '47594', (58, 62))	('Src64B', 'Gene', (3, 9))	('Baz', 'Gene', '32703', (85, 88))	('Dlg', 'Gene', (115, 118))	('Dlg', 'Gene', '32083', (115, 118))
323338	29861494	Expression of Src42AGS (Figure S5G) or Src64B (Figure S5I) did not discernibly affect the pattern of S phases in either mutant clones or surrounding wild-type tissue in the vicinity of the second mitotic wave or in the posterior of the eye epithelium, where differentiation occurs.	('Src64B', 'Gene', (39, 45))	('Src42AGS', 'Gene', (14, 22))	('Src42AGS', 'Gene', '35524', (14, 22))	('mutant', 'Var', (120, 126))	('Src64B', 'Gene', '48973', (39, 45))
323350	29861494	This non-cell autonomous effect is similar to that observed by "undead" cells, where apoptosis is initiated but prevented by p35 expression, leading to the secretion of morphogens and non-cell autonomous proliferation.	('p35', 'Gene', (125, 128))	('p35', 'Gene', '34385', (125, 128))	('expression', 'Var', (129, 139))	('non-cell autonomous proliferation', 'CPA', (184, 217))	('secretion of morphogens', 'MPA', (156, 179))
323363	29861494	To test whether loss of JNK could suppress Src clonal phenotypes, Src42AGS or Src64B were coexpressed with bskDN in mosaic eye discs and examined for alterations in clone size, and markers of differentiation (Elav) and F-actin organisation (phalloidin).	('Src42AGS', 'Gene', '35524', (66, 74))	('Src64B', 'Gene', '48973', (78, 84))	('Src clonal phenotypes', 'MPA', (43, 64))	('F-actin', 'Gene', (219, 226))	('Src64B', 'Gene', (78, 84))	('F-actin', 'Gene', '35526', (219, 226))	('loss', 'Var', (16, 20))	('Src42AGS', 'Gene', (66, 74))	('Elav', 'Gene', (209, 213))	('Elav', 'Gene', '31000', (209, 213))	('JNK', 'Gene', (24, 27))
323373	29861494	Altogether, these data show that blocking the JNK pathway increases viability of Src-expressing clones and suppresses F-actin accumulation, suggesting that JNK acts downstream of Src to induce cell death and F-actin polymerisation consistent with other studies in the Drosophila wing epithelium, and eye epithelium.	('cell death', 'CPA', (193, 203))	('increases', 'PosReg', (58, 67))	('F-actin', 'Gene', '35526', (118, 125))	('F-actin', 'Gene', (208, 215))	('viability', 'CPA', (68, 77))	('JNK', 'Gene', (46, 49))	('F-actin', 'Gene', '35526', (208, 215))	('Drosophila', 'Species', '7227', (268, 278))	('suppresses', 'NegReg', (107, 117))	('F-actin', 'Gene', (118, 125))	('blocking', 'Var', (33, 41))
323374	29861494	Given the requirement for JNK signalling in Src-expressing clones shown here and previously, and the role of JNK signalling in cooperative interactions observed between cell polarity mutants and Ras-driven tumourigenesis, it is conceivable that JNK activity could be upregulated and/or required for the cooperative overgrowth between Src + RasACT-induced neoplastic overgrowth.	('neoplastic overgrowth', 'Disease', 'MESH:D019214', (355, 376))	('overgrowth', 'Phenotype', 'HP:0001548', (315, 325))	('overgrowth', 'Phenotype', 'HP:0001548', (366, 376))	('RasACT', 'Chemical', '-', (340, 346))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('mutants', 'Var', (183, 190))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('neoplastic overgrowth', 'Disease', (355, 376))	('tumour', 'Disease', (206, 212))
323380	29861494	Similar to that observed for RasACT mosaic eye discs, expression of RasACT + bskDN resulted in pupal lethality.	('RasACT', 'Chemical', '-', (68, 74))	('pupal lethality', 'CPA', (95, 110))	('RasACT', 'Chemical', '-', (29, 35))	('resulted in', 'Reg', (83, 94))	('RasACT + bskDN', 'Var', (68, 82))
323383	29861494	In contrast to Src overexpression with RasACT, where clonal tissue was observed in the brain lobes (Figure 3C,E), co-expression of bskDN resulted in reduced clonal tissue observed in the brain lobes of Src + RasACT mosaic larvae (Figure 7E,F).	('reduced', 'NegReg', (149, 156))	('brain lobes', 'Disease', (87, 98))	('brain lobes', 'Disease', 'MESH:D001927', (87, 98))	('brain lobes', 'Disease', (187, 198))	('clonal tissue', 'MPA', (157, 170))	('RasACT', 'Chemical', '-', (208, 214))	('brain lobes', 'Disease', 'MESH:D001927', (187, 198))	('co-expression', 'Var', (114, 127))	('bskDN', 'Gene', (131, 136))	('RasACT', 'Chemical', '-', (39, 45))
323388	29861494	Thus, expression of Src + RasACT in eye disc clones results in robust upregulation of JNK pathway (as measured by JNK pathway enhancer trap, msn-lacZ), and blocking the JNK pathway partially suppressed tissue overgrowth of the eye-antennal disc, restored the morphology of the eye-antennal disc and partially restored differentiation to the Src + RasACT-expressing clones.	('suppressed', 'NegReg', (191, 201))	('morphology of', 'CPA', (259, 272))	('RasACT', 'Chemical', '-', (26, 32))	('upregulation', 'PosReg', (70, 82))	('morphology of the eye', 'Phenotype', 'HP:0012372', (259, 280))	('JNK pathway', 'Pathway', (86, 97))	('overgrowth', 'Phenotype', 'HP:0001548', (209, 219))	('RasACT', 'Chemical', '-', (347, 353))	('differentiation', 'CPA', (318, 333))	('blocking', 'Var', (156, 164))	('tissue overgrowth of the eye-antennal disc', 'CPA', (202, 244))	('restored', 'PosReg', (246, 254))
323392	29861494	This requirement of Raf-MAPK is likely to be specific as expression of other Ras effectors PI3K or Ral were unable to recapitulate the effects of RasACT in scrib mutant clones.	('Ral', 'Gene', (99, 102))	('scrib', 'Gene', (156, 161))	('scrib', 'Gene', '44448', (156, 161))	('mutant', 'Var', (162, 168))	('Ral', 'Gene', '31332', (99, 102))	('RasACT', 'Chemical', '-', (146, 152))
323394	29861494	As observed in RasACT mosaic eye discs, expression of RafGOF resulted in rounded clones with smooth borders and precocious differentiation anterior to the morphogenetic furrow (Figure 8Ai).	('RasACT', 'Chemical', '-', (15, 21))	('resulted in', 'Reg', (61, 72))	('expression', 'Var', (40, 50))	('smooth borders', 'CPA', (93, 107))	('furrow', 'Gene', (169, 175))	('RafGOF', 'Chemical', '-', (54, 60))	('furrow', 'Gene', '44654', (169, 175))	('precocious', 'CPA', (112, 122))	('RafGOF', 'Gene', (54, 60))
323395	29861494	RafGOF mosaic eye discs exhibited disrupted tissue morphology resulting in an enrichment of F-actin at the borders between wild-type and mutant clonal tissue (Figure 8Aii).	('enrichment', 'MPA', (78, 88))	('F-actin', 'Gene', (92, 99))	('F-actin', 'Gene', '35526', (92, 99))	('RafGOF', 'Chemical', '-', (0, 6))	('mutant', 'Var', (137, 143))
323404	29861494	The RasACT-S35 mutant preferentially signals to the Raf-MAPK pathway and has been characterised in both mammals and Drosophila.	('signals', 'MPA', (37, 44))	('Drosophila', 'Species', '7227', (116, 126))	('RasACT', 'Chemical', '-', (4, 10))	('preferentially', 'PosReg', (22, 36))	('RasACT-S35', 'Gene', (4, 14))	('Raf-MAPK pathway', 'Pathway', (52, 68))	('mutant', 'Var', (15, 21))
323407	29861494	RasACT-S35 mosaic eye discs were characterised by rounded clones with smooth borders (Figure 8C, yellow arrowhead) and ectopic differentiation anterior to the morphogenetic furrow (Figure 8C, asterisk).	('ectopic differentiation', 'CPA', (119, 142))	('furrow', 'Gene', (173, 179))	('RasACT', 'Chemical', '-', (0, 6))	('RasACT-S35', 'Var', (0, 10))	('furrow', 'Gene', '44654', (173, 179))
323408	29861494	Due to tissue misfolding of RasACT-S35 mosaic eye tissue, cells are abnormally arranged, but F-actin appears to be apically localised (Figure 8Ciii and inset, white arrowhead).	('F-actin', 'Gene', '35526', (93, 100))	('white arrowhead', 'Phenotype', 'HP:0025250', (159, 174))	('RasACT', 'Chemical', '-', (28, 34))	('RasACT-S35', 'Var', (28, 38))	('F-actin', 'Gene', (93, 100))
323409	29861494	These effects were similar to that observed in RasACT mosaic eye discs (Figure 2B), and, like RasACT, expression of RasACT-S35 resulted in pupal lethality.	('RasACT', 'Chemical', '-', (116, 122))	('RasACT', 'Chemical', '-', (47, 53))	('pupal lethality', 'CPA', (139, 154))	('resulted in', 'Reg', (127, 138))	('RasACT-S35', 'Gene', (116, 126))	('expression', 'Var', (102, 112))	('RasACT', 'Chemical', '-', (94, 100))
323420	29861494	Strikingly, co-expression of PTEN in Src64B + RasACT eye disc clones dramatically reduced tumour growth and restored differentiation in most clones (Figure 8E,F and Table 4), compared to Src64B + RasACT tumours (Figure 2K,L).	('tumours', 'Disease', (203, 210))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('PTEN', 'Gene', (29, 33))	('tumours', 'Phenotype', 'HP:0002664', (203, 210))	('tumours', 'Disease', 'MESH:D009369', (203, 210))	('reduced', 'NegReg', (82, 89))	('Src64B', 'Gene', '48973', (37, 43))	('differentiation', 'MPA', (117, 132))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour growth', 'Disease', 'MESH:D006130', (90, 103))	('Src64B', 'Gene', '48973', (187, 193))	('co-expression', 'Var', (12, 25))	('Src64B', 'Gene', (37, 43))	('restored', 'PosReg', (108, 116))	('PTEN', 'Gene', '43991', (29, 33))	('RasACT', 'Chemical', '-', (46, 52))	('Src64B', 'Gene', (187, 193))	('RasACT', 'Chemical', '-', (196, 202))	('tumour growth', 'Disease', (90, 103))
323435	29861494	Furthermore, additional expression of Src64B with RasACT in Csk-mutant clones resulted in an enhancement of this phenotype.	('Csk-mutant', 'Gene', (60, 70))	('enhancement', 'PosReg', (93, 104))	('Src64B', 'Gene', '48973', (38, 44))	('Csk-mutant', 'Var', (60, 70))	('Src64B', 'Gene', (38, 44))	('RasACT', 'Chemical', '-', (50, 56))
323439	29861494	While Src is known to affect many proteins that modulate actin dynamics, blocking JNK in Src-expressing clones suppresses the F-actin enrichment that is associated with Src-expressed alone.	('JNK', 'Gene', (82, 85))	('F-actin', 'Gene', (126, 133))	('blocking', 'Var', (73, 81))	('F-actin', 'Gene', '35526', (126, 133))	('suppresses', 'NegReg', (111, 121))
323442	29861494	The loss of chic enhances the hep (Drosophila JNKK) mutant dorsal open phenotype, and ectopic actin polymerization occurs in both hep and chic mutants suggesting that these may be acting via a common pathway to regulate cytoskeletal rearrangements.	('ectopic actin polymerization', 'MPA', (86, 114))	('JNKK', 'Gene', (46, 50))	('loss', 'Var', (4, 8))	('chic', 'Gene', '33834', (12, 16))	('mutant', 'Var', (52, 58))	('dorsal open phenotype', 'CPA', (59, 80))	('hep', 'Gene', '32256', (130, 133))	('enhances', 'PosReg', (17, 25))	('chic', 'Gene', (138, 142))	('hep', 'Gene', (30, 33))	('JNKK', 'Gene', '32256', (46, 50))	('hep', 'Gene', (130, 133))	('chic', 'Gene', '33834', (138, 142))	('hep', 'Gene', '32256', (30, 33))	('Drosophila', 'Species', '7227', (35, 45))	('chic', 'Gene', (12, 16))	('mutants', 'Var', (143, 150))
323443	29861494	Furthermore, a link between JNK and integrins, which can promote actin assembly, has been described: JNK promotes expression of betaPS integrin (encoded by myospheroid, mys) and alphaPS3 integrin (encoded by scab, scb), and the loss of mys and scb results in a similar dorsal open phenotype due to loss of JNK.	('alphaPS3 integrin', 'Gene', '36692', (178, 195))	('promotes', 'PosReg', (105, 113))	('dorsal open phenotype', 'MPA', (269, 290))	('betaPS integrin', 'Gene', (128, 143))	('JNK', 'Gene', (306, 309))	('scrib', 'Gene', (92, 97))	('JNK', 'Gene', (101, 104))	('scrib', 'Gene', '44448', (92, 97))	('betaPS integrin', 'Gene', '44885', (128, 143))	('alphaPS3 integrin', 'Gene', (178, 195))	('loss', 'Var', (228, 232))	('expression', 'MPA', (114, 124))	('results in', 'Reg', (248, 258))	('loss', 'Var', (298, 302))
323448	29861494	Src expression in the embryo induces cell migration, and in corroboration with the potential role of JNK in migratory-like phenotypes in Src + RasACT tumours, the loss of JNK was shown to suppress the migratory effects arising from Src activation.	('induces', 'Reg', (29, 36))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('loss', 'Var', (163, 167))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumours', 'Disease', (150, 157))	('RasACT', 'Chemical', '-', (143, 149))	('migratory effects', 'CPA', (201, 218))	('JNK', 'Gene', (171, 174))	('suppress', 'NegReg', (188, 196))	('cell migration', 'CPA', (37, 51))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
323450	29861494	JNK is activated in RasACT + scrib, dlg or lgl mutant tumours, and also promotes tissue growth and invasive phenotypes.	('scrib', 'Gene', (29, 34))	('RasACT', 'Chemical', '-', (20, 26))	('scrib', 'Gene', '44448', (29, 34))	('mutant', 'Var', (47, 53))	('tumours', 'Disease', (54, 61))	('lgl', 'Gene', '33156', (43, 46))	('invasive phenotypes', 'CPA', (99, 118))	('dlg', 'Gene', (36, 39))	('dlg', 'Gene', '32083', (36, 39))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tissue growth', 'CPA', (81, 94))	('promotes', 'PosReg', (72, 80))	('activated', 'PosReg', (7, 16))	('JNK', 'Gene', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('lgl', 'Gene', (43, 46))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
323451	29861494	Expression profiling has revealed a large number of JNK targets that affect cell differentiation in RasACT + scrib mutant eye-antennal epithelial tissue, or in scrib homozygous wing epithelial tissue.	('affect', 'Reg', (69, 75))	('profilin', 'Gene', '33834', (11, 19))	('scrib', 'Gene', (160, 165))	('profilin', 'Gene', (11, 19))	('mutant', 'Var', (115, 121))	('cell differentiation', 'CPA', (76, 96))	('scrib', 'Gene', (109, 114))	('scrib', 'Gene', '44448', (160, 165))	('RasACT', 'Chemical', '-', (100, 106))	('scrib', 'Gene', '44448', (109, 114))
323456	29861494	However, based on the findings in Drosophila tumour models described here and previously, inhibiting JNK signalling may restore differentiation and suppress the malignant overgrowth and invasive characteristics in many human tumours.	('overgrowth', 'Phenotype', 'HP:0001548', (171, 181))	('Drosophila tumour', 'Disease', (34, 51))	('JNK', 'Protein', (101, 104))	('scrib', 'Gene', (61, 66))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('human', 'Species', '9606', (219, 224))	('invasive characteristics', 'CPA', (186, 210))	('restore', 'PosReg', (120, 127))	('tumours', 'Disease', (225, 232))	('suppress', 'NegReg', (148, 156))	('Drosophila tumour', 'Disease', 'MESH:D009369', (34, 51))	('malignant overgrowth', 'CPA', (161, 181))	('inhibiting', 'Var', (90, 100))	('differentiation', 'CPA', (128, 143))	('scrib', 'Gene', '44448', (61, 66))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))
323461	29861494	Indeed, dlg RasACT tumours have compromised PI3K signalling and knockdown of PI3K pathway signalling is synthetically lethal to tumourigenesis.	('tumour', 'Disease', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('dlg', 'Gene', (8, 11))	('dlg', 'Gene', '32083', (8, 11))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumour', 'Disease', (19, 25))	('tumours', 'Disease', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('PI3K signalling', 'Pathway', (44, 59))	('knockdown', 'Var', (64, 73))	('compromised', 'NegReg', (32, 43))	('RasACT', 'Chemical', '-', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
323465	29861494	Recently, polarity-impaired Ras-driven cancers have been shown to be dependent on induction of autophagy in neighbouring wild-type cells, which suggests that the PI3K-mTOR pathway might be important in this non-cell autonomous mechanism in tumour development.	('mTOR', 'Gene', '36264', (167, 171))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mTOR', 'Gene', (167, 171))	('autophagy', 'CPA', (95, 104))	('tumour', 'Disease', (240, 246))	('polarity-impaired', 'Var', (10, 27))
323475	29861494	ey-GAL4 analysis using p35 and RasACT were carried out using recombinants generated on the second chromosome carrying ey-GAL4 and UAS-p35 or ey-GAL4 and UAS-RasACT.	('ey-GAL4', 'Var', (118, 125))	('ey-GAL4', 'Chemical', '-', (0, 7))	('RasACT', 'Chemical', '-', (31, 37))	('ey-GAL4', 'Chemical', '-', (141, 148))	('RasACT', 'Chemical', '-', (157, 163))	('p35', 'Gene', '34385', (23, 26))	('ey-GAL4', 'Chemical', '-', (118, 125))	('p35', 'Gene', (23, 26))	('ey-GAL4', 'Var', (141, 148))	('p35', 'Gene', '34385', (134, 137))	('p35', 'Gene', (134, 137))
323510	28173193	PFR12wks was achieved by seven of nine patients (77.8%) with myxoid LPS and five of six patients (83.3%) with dedifferentiated LPS.	('PFR12wks', 'Var', (0, 8))	('myxoid LPS', 'Disease', (61, 71))	('achieved', 'Reg', (13, 21))	('LPS', 'Phenotype', 'HP:0012034', (68, 71))	('LPS', 'Phenotype', 'HP:0012034', (127, 130))	('myxoid LPS', 'Disease', 'MESH:C536528', (61, 71))
323511	28173193	In the OTH category, two patients with endometrial stromal sarcoma, one patient with synovial sarcoma, one patient with solitary fibrous tumor and one patient with fibrosarcoma achieved PFR12wks (Online Supplementary Figure S3).	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (39, 66))	('achieved', 'Reg', (177, 185))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (164, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('PFR12wks', 'Var', (186, 194))	('solitary fibrous tumor', 'Disease', (120, 142))	('solitary fibrous tumor', 'Disease', 'MESH:D054364', (120, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (85, 101))	('endometrial stromal sarcoma', 'Disease', (39, 66))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
323544	29703171	This database is a combined effort by the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society, and represents more than 70% of new cancer diagnoses every year from over 1500 accredited cancer programs in the U.S. NCDB Participant User Files were accessed for patients treated at NCDB participating institutions; utilizing the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) topography codes C47.1 (peripheral nerves of the upper limb and shoulder), C47.2 (peripheral nerves of the lower limb and hip), C49.1 (soft tissues of the upper limb and shoulder), and C49.2 (soft tissues of the lower limb and hip), we included only patients with extremity tumor location.	('Oncology', 'Phenotype', 'HP:0002664', (414, 422))	('C47.1', 'Var', (463, 468))	('C47.1', 'CellLine', 'CVCL:L675', (463, 468))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Participant', 'Species', '9606', (261, 272))	('lower limb', 'Phenotype', 'HP:0006385', (553, 563))	('Cancer', 'Disease', (122, 128))	('C47.2', 'CellLine', 'CVCL:L675', (521, 526))	('C49.1', 'Var', (574, 579))	('patients', 'Species', '9606', (696, 704))	('cancer', 'Disease', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (720, 725))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (228, 234))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('Cancer', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('lower limb', 'Phenotype', 'HP:0006385', (658, 668))	('extremity tumor', 'Disease', (710, 725))	('extremity tumor', 'Disease', 'MESH:D009369', (710, 725))	('C49.2', 'Var', (631, 636))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('C47.2', 'Var', (521, 526))	('patients', 'Species', '9606', (302, 310))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
323633	27117317	Patients who had a CD4 T cell count less than 50 cells/mm3 had a high prevalence of P. jirovecii pneumonia (66.9%), CMV infection (56.2%), or esophageal or respiratory candidiasis (56.3%).	('pneumonia', 'Phenotype', 'HP:0002090', (97, 106))	('less than 50', 'Var', (36, 48))	('P. jirovecii', 'Species', '42068', (84, 96))	('esophageal', 'Disease', 'MESH:D004941', (142, 152))	('pneumonia', 'Disease', (97, 106))	('CMV infection', 'Disease', (116, 129))	('pneumonia', 'Disease', 'MESH:D011014', (97, 106))	('jirovecii pneumonia', 'Phenotype', 'HP:0020102', (87, 106))	('Patients', 'Species', '9606', (0, 8))	('CMV infection', 'Disease', 'MESH:D007239', (116, 129))	('CD4', 'Gene', (19, 22))	('respiratory candidiasis', 'Disease', (156, 179))	('CD4', 'Gene', '920', (19, 22))	('esophageal', 'Disease', (142, 152))	('respiratory candidiasis', 'Disease', 'MESH:D012131', (156, 179))
323667	27117317	Smoking could influence inflammatory and immune responses in the oral cavity, and smoking was associated with oral candidiasis in some studies.	('oral candidiasis', 'Disease', 'MESH:D002180', (110, 126))	('smoking', 'Var', (82, 89))	('influence', 'Reg', (14, 23))	('associated', 'Reg', (94, 104))	('oral candidiasis', 'Disease', (110, 126))
323671	27117317	In conclusion, there was a range of ODs among HIV-infected patients in Korea, the most prevalent being candidiasis, M. tuberculosis infection, P. jirovecii pneumonia, CMV infection, and herpes zoster, while toxoplasmosis and HIV-related malignancy, such as Kaposi's sarcoma, were rare.	('candidiasis', 'Disease', (103, 114))	('malignancy', 'Disease', 'MESH:D009369', (237, 247))	('pneumonia', 'Disease', (156, 165))	('CMV infection', 'Disease', 'MESH:D007239', (167, 180))	('candidiasis', 'Disease', 'MESH:D002177', (103, 114))	('tuberculosis infection', 'Disease', (119, 141))	('prevalent', 'Reg', (87, 96))	('herpes zoster', 'Disease', (186, 199))	('malignancy', 'Disease', (237, 247))	('HIV', 'Species', '12721', (46, 49))	('patients', 'Species', '9606', (59, 67))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (257, 273))	('tuberculosis infection', 'Disease', 'MESH:D014376', (119, 141))	('toxoplasmosis', 'Disease', (207, 220))	('toxoplasmosis', 'Disease', 'MESH:D014123', (207, 220))	('CMV infection', 'Disease', (167, 180))	('HIV-infected', 'Disease', (46, 58))	('jirovecii pneumonia', 'Phenotype', 'HP:0020102', (146, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (257, 273))	('HIV-infected', 'Disease', 'MESH:D015658', (46, 58))	("Kaposi's sarcoma", 'Disease', (257, 273))	('pneumonia', 'Phenotype', 'HP:0002090', (156, 165))	('HIV', 'Species', '12721', (225, 228))	('pneumonia', 'Disease', 'MESH:D011014', (156, 165))	('P. jirovecii', 'Species', '42068', (143, 155))	('P. jirovecii', 'Var', (143, 155))
323712	33105807	In contrast, extremity sarcoma patients who had an amputation scored lower on the physical functional scale than those whose limbs were spared.	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('extremity sarcoma', 'Disease', (13, 30))	('lower', 'NegReg', (69, 74))	('extremity sarcoma', 'Disease', 'MESH:D012509', (13, 30))	('patients', 'Species', '9606', (31, 39))	('physical', 'CPA', (82, 90))	('amputation', 'Var', (51, 61))
323749	33105807	Furthermore, in both upper and lower extremity sarcoma survivors, survivors with an amputation more often reported task difficulties compared to survivors without an amputation.	('task difficulties', 'CPA', (115, 132))	('amputation', 'Var', (84, 94))	('lower extremity', 'Phenotype', 'HP:0006385', (31, 46))	('lower extremity sarcoma', 'Disease', 'MESH:D012509', (31, 54))	('lower extremity sarcoma', 'Disease', (31, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
323805	33105807	Only survivors who were diagnosed with sarcoma, independent of the intent of primary treatment, (according to the ICD-10-GM codes C40 and C41 for bone sarcoma and C49 for soft-tissue sarcoma) between 1 April 2008 and 31 December 2016 at one of the six participating sarcoma expertise centers (Radboudumc Nijmegen, The Netherlands Cancer Institute Amsterdam, University Medical Centre Groningen, Leiden University Medical Centre, Erasmus MC Cancer Institute Rotterdam, Maastricht University Medical Centre) were included.	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('Cancer', 'Disease', (330, 336))	('sarcoma', 'Disease', (39, 46))	('Cancer', 'Phenotype', 'HP:0002664', (440, 446))	('Erasmus MC Cancer Institute Rotterdam', 'Disease', (429, 466))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (171, 190))	('bone sarcoma', 'Disease', 'MESH:D012509', (146, 158))	('bone sarcoma', 'Phenotype', 'HP:0002669', (146, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcoma', 'Disease', 'MESH:D012509', (266, 273))	('C49', 'Var', (163, 166))	('Erasmus MC Cancer Institute Rotterdam', 'Disease', 'MESH:D009369', (429, 466))	('Cancer', 'Disease', (440, 446))	('sarcoma', 'Disease', (266, 273))	('Cancer', 'Disease', 'MESH:D009369', (330, 336))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('bone sarcoma', 'Disease', (146, 158))	('C40', 'Gene', '55571', (130, 133))	('Cancer', 'Disease', 'MESH:D009369', (440, 446))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('sarcoma', 'Disease', (183, 190))	('Cancer', 'Phenotype', 'HP:0002664', (330, 336))	('C40', 'Gene', (130, 133))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('C41', 'Var', (138, 141))	('sarcoma', 'Disease', (151, 158))
324017	30833364	Association between TP53 rs1042522 gene polymorphism and the risk of malignant bone tumors: a meta-analysis TP53 is a tumor suppressor gene which is essential for regulating cell division and preventing tumor formation.	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('TP53', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('Association', 'Interaction', (0, 11))	('TP53', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('malignant bone tumors', 'Disease', (69, 90))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('malignant bone tumors', 'Disease', 'MESH:D001859', (69, 90))	('TP53', 'Gene', '7157', (108, 112))	('rs1042522', 'Var', (25, 34))	('TP53', 'Gene', '7157', (20, 24))	('rs1042522', 'Mutation', 'rs1042522', (25, 34))	('bone tumor', 'Phenotype', 'HP:0010622', (79, 89))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (118, 123))	('bone tumors', 'Phenotype', 'HP:0010622', (79, 90))
324018	30833364	Several studies have assessed the associations of TP53 single-nucleotide polymorphisms (SNP) with susceptibility of malignant bone tumors, including osteosarcoma and Ewing sarcoma, but the results are inconsistent.	('associations', 'Interaction', (34, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (166, 179))	('bone tumor', 'Phenotype', 'HP:0010622', (126, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('TP53', 'Gene', '7157', (50, 54))	('bone tumors', 'Phenotype', 'HP:0010622', (126, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('malignant bone tumors', 'Disease', 'MESH:D001859', (116, 137))	('osteosarcoma', 'Phenotype', 'HP:0002669', (149, 161))	('TP53', 'Gene', (50, 54))	('malignant bone tumors', 'Disease', (116, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('single-nucleotide polymorphisms', 'Var', (55, 86))	('osteosarcoma and Ewing sarcoma', 'Disease', 'MESH:C563168', (149, 179))
324019	30833364	In the present meta-analysis, we aimed to elucidate the associations of TP53 rs1042522 genetic polymorphism with the risk of osteosarcoma or Ewing sarcoma.	('osteosarcoma or Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 154))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (141, 154))	('TP53', 'Gene', '7157', (72, 76))	('associations', 'Interaction', (56, 68))	('rs1042522', 'Mutation', 'rs1042522', (77, 86))	('TP53', 'Gene', (72, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('rs1042522', 'Var', (77, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('osteosarcoma or Ewing sarcoma', 'Disease', (125, 154))
324020	30833364	Eligible studies assessing the polymorphisms in the TP53 rs1042522 gene and risk of malignant bone tumors were incorporated.	('TP53', 'Gene', '7157', (52, 56))	('malignant bone tumors', 'Disease', 'MESH:D001859', (84, 105))	('rs1042522', 'Mutation', 'rs1042522', (57, 66))	('TP53', 'Gene', (52, 56))	('malignant bone tumors', 'Disease', (84, 105))	('bone tumors', 'Phenotype', 'HP:0010622', (94, 105))	('polymorphisms', 'Var', (31, 44))	('bone tumor', 'Phenotype', 'HP:0010622', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('rs1042522', 'Var', (57, 66))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
324021	30833364	Meta-analysis of TP53 rs1042522 polymorphism was significantly associated with an increased risk of malignant bone tumors (G versus C: OR = 1.27, 95% CI 1.08-1.50, P=0.005; GG versus GC/CC: OR = 1.55, 95% CI 1.21-2.00, P=0.001).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('malignant bone tumors', 'Disease', (100, 121))	('rs1042522', 'Mutation', 'rs1042522', (22, 31))	('malignant bone tumors', 'Disease', 'MESH:D001859', (100, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('bone tumors', 'Phenotype', 'HP:0010622', (110, 121))	('rs1042522', 'Var', (22, 31))	('bone tumor', 'Phenotype', 'HP:0010622', (110, 120))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
324023	30833364	Our results suggest that there are significant associations of TP53 rs1042522 polymorphism with malignant bone tumors risk.	('rs1042522', 'Var', (68, 77))	('TP53', 'Gene', '7157', (63, 67))	('bone tumors', 'Phenotype', 'HP:0010622', (106, 117))	('TP53', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('bone tumor', 'Phenotype', 'HP:0010622', (106, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('rs1042522', 'Mutation', 'rs1042522', (68, 77))	('malignant bone tumors', 'Disease', 'MESH:D001859', (96, 117))	('associations', 'Interaction', (47, 59))	('malignant bone tumors', 'Disease', (96, 117))
324030	30833364	And recent studies show that the p53 expression level can be altered by the genetic polymorphisms in the TP53 gene.	('genetic polymorphisms', 'Var', (76, 97))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('p53 expression level', 'MPA', (33, 53))	('altered', 'Reg', (61, 68))
324031	30833364	TP53 rs1042522 polymorphism is one of the most known polymorphisms of TP53 and it is the single nucleotide polymorphism (SNP) at codon 72, located at the exon 4 of this gene.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (70, 74))	('rs1042522', 'Mutation', 'rs1042522', (5, 14))	('TP53', 'Gene', (70, 74))	('rs1042522', 'Var', (5, 14))
324032	30833364	This SNP is a non-conservative change of the wild-type variants Arginine (CGC) and Proline (CCC) (Arg72Pro-dbSNP ID: rs1042522), that results in different biological functions of p53.	('p53', 'Gene', (179, 182))	('CCC', 'Chemical', 'MESH:D002716', (92, 95))	('Arg72Pro', 'Var', (98, 106))	('Proline', 'Chemical', 'MESH:D011392', (83, 90))	('rs1042522', 'Mutation', 'rs1042522', (117, 126))	('Arg72Pro', 'SUBSTITUTION', 'None', (98, 106))	('Arginine', 'Chemical', 'MESH:D001120', (64, 72))
324033	30833364	There are several studies published to assess the associations of TP53 rs1042522 genetic polymorphisms with risk of osteosarcoma or Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (132, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('rs1042522', 'Mutation', 'rs1042522', (71, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('osteosarcoma or Ewing sarcoma', 'Disease', (116, 145))	('associations', 'Interaction', (50, 62))	('osteosarcoma or Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 145))	('rs1042522', 'Var', (71, 80))
324035	30833364	In Wang's publication, just two of the included studies, with a total sample size of 410 osteosarcoma patients and 470 controls, are about associations between TP53 rs1042522 gene polymorphism and osteosarcoma risk.	('osteosarcoma', 'Disease', (89, 101))	('rs1042522', 'Var', (165, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('patients', 'Species', '9606', (102, 110))	('TP53', 'Gene', '7157', (160, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('osteosarcoma', 'Disease', (197, 209))	('TP53', 'Gene', (160, 164))	('associations', 'Interaction', (139, 151))	('rs1042522', 'Mutation', 'rs1042522', (165, 174))	('osteosarcoma', 'Phenotype', 'HP:0002669', (197, 209))	('osteosarcoma', 'Disease', 'MESH:D012516', (197, 209))
324036	30833364	Thus, we conducted a meta-analysis of epidemiological studies with a larger sample size to shed some light on the associations of TP53 genetic polymorphisms with risk of malignant bone tumors comprising osteosarcoma and Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('genetic polymorphisms', 'Var', (135, 156))	('associations', 'Interaction', (114, 126))	('malignant bone tumors', 'Disease', (170, 191))	('malignant bone tumors', 'Disease', 'MESH:D001859', (170, 191))	('osteosarcoma', 'Phenotype', 'HP:0002669', (203, 215))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (220, 233))	('osteosarcoma and Ewing sarcoma', 'Disease', 'MESH:C563168', (203, 233))	('bone tumor', 'Phenotype', 'HP:0010622', (180, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('bone tumors', 'Phenotype', 'HP:0010622', (180, 191))
324040	30833364	The following data of each eligible study were extracted independently: name of first author, year of publication, countries, ethnicity, genotype or allele frequencies of TP53 rs1042522 polymorphisms, and OR with its 95% CI.	('TP53', 'Gene', (171, 175))	('rs1042522', 'Var', (176, 185))	('TP53', 'Gene', '7157', (171, 175))	('rs1042522', 'Mutation', 'rs1042522', (176, 185))
324041	30833364	In the review, 18 studies were excluded for the reasons as follows: nine were eliminated because they were neither case-control study or cohort study, four were irrelevant to bone tumor or osteosarcoma or Ewing sarcoma, four studies were not studies on the role of TP53 rs1042522 on patient survival or disease progression, one was not consistent with Hardy-Weinberg equilibrium.	('bone tumor', 'Phenotype', 'HP:0010622', (175, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (205, 218))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('bone tumor', 'Disease', (175, 185))	('rs1042522', 'Mutation', 'rs1042522', (270, 279))	('TP53', 'Gene', '7157', (265, 269))	('osteosarcoma', 'Phenotype', 'HP:0002669', (189, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('TP53', 'Gene', (265, 269))	('bone tumor', 'Disease', 'MESH:D001859', (175, 185))	('osteosarcoma or Ewing sarcoma', 'Disease', 'MESH:C563168', (189, 218))	('rs1042522', 'Var', (270, 279))	('osteosarcoma or Ewing sarcoma', 'Disease', (189, 218))	('patient', 'Species', '9606', (283, 290))
324042	30833364	investigated the role of TP53 rs1042522 in osteosarcoma development amongst Caucasians.	('rs1042522', 'Var', (30, 39))	('osteosarcoma', 'Phenotype', 'HP:0002669', (43, 55))	('TP53', 'Gene', (25, 29))	('osteosarcoma', 'Disease', 'MESH:D012516', (43, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('rs1042522', 'Mutation', 'rs1042522', (30, 39))	('TP53', 'Gene', '7157', (25, 29))	('osteosarcoma', 'Disease', (43, 55))
324046	30833364	Meta-analysis of TP53 rs1042522 polymorphism was associated with an increased risk of malignant bone tumors (G versus C: OR = 1.27, 95% CI 1.08-1.50, P=0.005; GG versus CC: OR = 1.41, 95% CI 0.99-2.01, P=0.057; GG/GC versus CC: OR = 1.13, 95% CI 0.87-1.48, P=0.365; GG versus GC/CC: OR = 1.55, 95% CI 1.21-2.00, P=0.001) (Figures 2-5 respectively).	('malignant bone tumors', 'Disease', (86, 107))	('malignant bone tumors', 'Disease', 'MESH:D001859', (86, 107))	('rs1042522', 'Mutation', 'rs1042522', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('bone tumors', 'Phenotype', 'HP:0010622', (96, 107))	('bone tumor', 'Phenotype', 'HP:0010622', (96, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('rs1042522', 'Var', (22, 31))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
324047	30833364	Subgroup analysis was conducted on the association between TP53 rs1042522 polymorphism and the risk of malignant bone tumors (Table 2).	('malignant bone tumors', 'Disease', (103, 124))	('bone tumors', 'Phenotype', 'HP:0010622', (113, 124))	('malignant bone tumors', 'Disease', 'MESH:D001859', (103, 124))	('TP53', 'Gene', (59, 63))	('bone tumor', 'Phenotype', 'HP:0010622', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('rs1042522', 'Mutation', 'rs1042522', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('TP53', 'Gene', '7157', (59, 63))	('rs1042522', 'Var', (64, 73))
324051	30833364	In fixed-effect model, a statistically significant correlation between the TP53 rs1042522 polymorphism and osteosarcoma risk was observed (GG versus GC/CC: OR = 1.569, 95% CI 1.196-2.057, P=0.001).	('rs1042522', 'Mutation', 'rs1042522', (80, 89))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('osteosarcoma', 'Disease', (107, 119))	('rs1042522', 'Var', (80, 89))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('TP53', 'Gene', (75, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('TP53', 'Gene', '7157', (75, 79))	('significant correlation', 'Reg', (39, 62))
324052	30833364	For Ewing sarcoma, TP53 rs1042522 polymorphism was associated with an increased risk of Ewing sarcoma (GG versus GC/CC: OR = 1.452, 95% CI 0.732-2.882, P=0.262).	('rs1042522', 'Var', (24, 33))	('Ewing sarcoma', 'Disease', (4, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('TP53', 'Gene', '7157', (19, 23))	('rs1042522', 'Mutation', 'rs1042522', (24, 33))	('TP53', 'Gene', (19, 23))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (4, 17))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (4, 17))	('Ewing sarcoma', 'Disease', (88, 101))
324054	30833364	There were several studies assessing the effects of TP53 polymorphisms on the risk of malignant bone tumors, but there was no comprehensive assessment of the effects and the studies reported different results.	('polymorphisms', 'Var', (57, 70))	('TP53', 'Gene', '7157', (52, 56))	('malignant bone tumors', 'Disease', (86, 107))	('malignant bone tumors', 'Disease', 'MESH:D001859', (86, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('TP53', 'Gene', (52, 56))	('bone tumors', 'Phenotype', 'HP:0010622', (96, 107))	('bone tumor', 'Phenotype', 'HP:0010622', (96, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))
324055	30833364	For example, no associations of the TP53 Arg72Pro SNP (TP53 rs1042522) with Ewing sarcoma were found in Thurow et al.	('Arg72Pro', 'SUBSTITUTION', 'None', (41, 49))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('associations', 'Interaction', (16, 28))	('TP53', 'Gene', '7157', (36, 40))	('Arg72Pro', 'Var', (41, 49))	('Ewing sarcoma', 'Disease', (76, 89))	('rs1042522', 'Mutation', 'rs1042522', (60, 69))	('TP53', 'Gene', (36, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (76, 89))
324057	30833364	found that TP53 Arg72Pro SNP (TP53 rs1042522) significantly associated with increased relative risk to develop osteosarcoma.	('TP53', 'Gene', (30, 34))	('develop', 'PosReg', (103, 110))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('Arg72Pro', 'Var', (16, 24))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('osteosarcoma', 'Disease', (111, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (111, 123))	('Arg72Pro', 'SUBSTITUTION', 'None', (16, 24))	('TP53', 'Gene', '7157', (30, 34))	('rs1042522', 'Mutation', 'rs1042522', (35, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('associated', 'Reg', (60, 70))
324058	30833364	demonstrated that subjects with the GG genotype of rs1042522 had significantly increased osteosarcoma risk (OR = 1.89, 95% CI: 1.16-3.07) compared with those who carrying the CC genotype.	('rs1042522', 'Mutation', 'rs1042522', (51, 60))	('osteosarcoma', 'Disease', (89, 101))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('rs1042522', 'Var', (51, 60))
324060	30833364	Here upon, we comprehensively searched the up-to-date electronic databases and enrolled five independent case-control studies with a total of 567 cases and 935 controls into our meta-analysis to reveal the associations between TP53 genetic polymorphisms and risk of malignant bone tumors.	('bone tumors', 'Phenotype', 'HP:0010622', (276, 287))	('TP53', 'Gene', '7157', (227, 231))	('genetic polymorphisms', 'Var', (232, 253))	('malignant bone tumors', 'Disease', (266, 287))	('malignant bone tumors', 'Disease', 'MESH:D001859', (266, 287))	('TP53', 'Gene', (227, 231))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('bone tumor', 'Phenotype', 'HP:0010622', (276, 286))
324062	30833364	The results of our analysis showed that TP53 rs1042522 polymorphism significantly increased the risk of malignant bone tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('malignant bone tumors', 'Disease', 'MESH:D001859', (104, 125))	('malignant bone tumors', 'Disease', (104, 125))	('rs1042522', 'Var', (45, 54))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('increased', 'PosReg', (82, 91))	('bone tumor', 'Phenotype', 'HP:0010622', (114, 124))	('bone tumors', 'Phenotype', 'HP:0010622', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('rs1042522', 'Mutation', 'rs1042522', (45, 54))
324064	30833364	Classically, MDM2 (or MDM4) could bind p53 and then promote proteasomal degradation of the tumor suppressor.	('bind', 'Interaction', (34, 38))	('p53', 'Protein', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('proteasomal degradation', 'MPA', (60, 83))	('tumor', 'Disease', (91, 96))	('promote', 'PosReg', (52, 59))	('MDM2', 'Var', (13, 17))
324067	30833364	The loss of p53 function by mutations in TP53 gene or in genes of proteins that interact with p53 protein ablates its ability to prevent tumor formation and favors cellular proliferation and tumor initiation and progression.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor initiation', 'Disease', 'MESH:D009369', (191, 207))	('p53', 'Gene', (12, 15))	('ablates', 'NegReg', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor initiation', 'Disease', (191, 207))	('favors', 'PosReg', (157, 163))	('cellular proliferation', 'CPA', (164, 186))	('loss', 'NegReg', (4, 8))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ability', 'MPA', (118, 125))
324068	30833364	The TP53 gene mutation has been observed in the classic Li-Fraumeni Syndrome including multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('observed', 'Reg', (32, 40))	('TP53', 'Gene', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('multiple tumors', 'Disease', (87, 102))	('multiple tumors', 'Disease', 'MESH:D009369', (87, 102))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (56, 76))	('mutation', 'Var', (14, 22))	('Li-Fraumeni Syndrome', 'Disease', (56, 76))	('TP53', 'Gene', '7157', (4, 8))
324069	30833364	Although osteosarcoma is commonly observed in this syndrome, not all individuals with TP53 gene variants can develop osteosarcoma.	('variants', 'Var', (96, 104))	('TP53', 'Gene', '7157', (86, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('osteosarcoma', 'Phenotype', 'HP:0002669', (117, 129))	('osteosarcoma', 'Disease', (117, 129))	('osteosarcoma', 'Disease', 'MESH:D012516', (117, 129))	('TP53', 'Gene', (86, 90))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('osteosarcoma', 'Disease', (9, 21))	('develop', 'PosReg', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
324070	30833364	Twelve genetic variations in TP53 have been studied to indicate a link between TP53 polymorphisms and osteosarcoma risk.	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (102, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('polymorphisms', 'Var', (84, 97))	('link', 'Interaction', (66, 70))	('osteosarcoma', 'Disease', (102, 114))
324071	30833364	Amongst those variations in TP53, the Arg72Pro SNP is the most commonly studied mutation amongst Caucasians population.	('Arg72Pro', 'Var', (38, 46))	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('Arg72Pro', 'SUBSTITUTION', 'None', (38, 46))
324075	30833364	Results showed that TP53 rs1042522 polymorphism was significantly associated with an increased risk of osteosarcoma.	('TP53', 'Gene', (20, 24))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('associated', 'Reg', (66, 76))	('rs1042522', 'Var', (25, 34))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('TP53', 'Gene', '7157', (20, 24))	('rs1042522', 'Mutation', 'rs1042522', (25, 34))
324076	30833364	However, no statistically significant correlation between the TP53 rs1042522 polymorphism and Ewing sarcoma risk was observed.	('TP53', 'Gene', '7157', (62, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('rs1042522', 'Mutation', 'rs1042522', (67, 76))	('TP53', 'Gene', (62, 66))	('Ewing sarcoma', 'Disease', (94, 107))	('rs1042522', 'Var', (67, 76))
324077	30833364	genotyped the TP53 Arg72Pro SNP in 24 Ewing sarcoma patients and 91 control individuals and the small sample size may account for the no statistically significant correlation.	('TP53', 'Gene', '7157', (14, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('TP53', 'Gene', (14, 18))	('Arg72Pro', 'Var', (19, 27))	('Ewing sarcoma', 'Disease', (38, 51))	('Arg72Pro', 'SUBSTITUTION', 'None', (19, 27))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))	('patients', 'Species', '9606', (52, 60))
324080	30833364	Therefore, additional studies with other ethnic populations are warranted to assess the association between TP53 rs1042522 polymorphism and the risk of malignant bone tumors.	('malignant bone tumors', 'Disease', (152, 173))	('TP53', 'Gene', '7157', (108, 112))	('malignant bone tumors', 'Disease', 'MESH:D001859', (152, 173))	('TP53', 'Gene', (108, 112))	('rs1042522', 'Mutation', 'rs1042522', (113, 122))	('bone tumor', 'Phenotype', 'HP:0010622', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('bone tumors', 'Phenotype', 'HP:0010622', (162, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('rs1042522', 'Var', (113, 122))
324085	30833364	Fifth, the majority of the included trials mainly reported data on rs1042522 polymorphism, thus we were unable to examine the association of other SNPs of the TP53 gene with malignant bone tumors risk.	('bone tumors', 'Phenotype', 'HP:0010622', (184, 195))	('rs1042522', 'Mutation', 'rs1042522', (67, 76))	('rs1042522 polymorphism', 'Var', (67, 89))	('TP53', 'Gene', '7157', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('TP53', 'Gene', (159, 163))	('bone tumor', 'Phenotype', 'HP:0010622', (184, 194))	('polymorphism', 'Var', (77, 89))	('malignant bone tumors', 'Disease', 'MESH:D001859', (174, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('malignant bone tumors', 'Disease', (174, 195))
324086	30833364	Finally, the web resources such as the 1000 Genomes Browser providing the allele frequencies of TP53 rs1042522 polymorphism amongst different main populations were not considered and utilized in our research.	('rs1042522', 'Mutation', 'rs1042522', (101, 110))	('TP53', 'Gene', '7157', (96, 100))	('rs1042522', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))
324088	30833364	Besides, reasonable utilization of the web resources containing TP53 rs1042522 allele frequencies of different population might be considered to enlarge our control groups and provide us a significant extension of our finding in the future.	('rs1042522', 'Var', (69, 78))	('TP53', 'Gene', '7157', (64, 68))	('rs1042522', 'Mutation', 'rs1042522', (69, 78))	('TP53', 'Gene', (64, 68))
324089	30833364	In conclusion, the present meta-analysis indicates that TP53 rs1042522 polymorphism is the genetic risk factor for the susceptibility of malignant bone tumors.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('risk', 'Reg', (99, 103))	('TP53', 'Gene', '7157', (56, 60))	('rs1042522', 'Mutation', 'rs1042522', (61, 70))	('bone tumors', 'Phenotype', 'HP:0010622', (147, 158))	('bone tumor', 'Phenotype', 'HP:0010622', (147, 157))	('TP53', 'Gene', (56, 60))	('malignant bone tumors', 'Disease', (137, 158))	('rs1042522', 'Var', (61, 70))	('malignant bone tumors', 'Disease', 'MESH:D001859', (137, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
324090	30833364	MDM murine double minute NOS Newcastle-Ottawa Scale OR odds ratio SNP single-nucleotide polymorphism 95% CI 95% confidence interval	('MDM', 'Gene', '22138', (0, 3))	('single-nucleotide polymorphism', 'Var', (70, 100))	('murine', 'Species', '10090', (4, 10))	('MDM', 'Gene', (0, 3))
324099	28145098	MDR multidrug resistance miR-15b microRNA-15b Osteosarcoma is the most common primary bone cancer in children and remains a leading cause of cancer death in adolescents.	('cancer death', 'Disease', 'MESH:D003643', (141, 153))	('Osteosarcoma', 'Disease', (46, 58))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('children', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('bone cancer in children', 'Phenotype', 'HP:0010622', (86, 109))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('bone cancer', 'Disease', 'MESH:D001859', (86, 97))	('drug resistance', 'Phenotype', 'HP:0020174', (9, 24))	('microRNA-15b', 'Var', (33, 45))	('bone cancer', 'Disease', (86, 97))	('cancer death', 'Disease', (141, 153))
324106	28145098	The human ovarian cancer cell line SKOV-3 and the paclitaxel-resistant variant SKOV-3TR, the human breast cancer cell line MCF-7 and the paclitaxel-resistant variant MCF-7TR have been described previously (Duan et al., 2005, 2008).	('SKOV-3TR', 'Gene', (79, 87))	('variant SKOV', 'CellLine', 'CVCL:7204', (71, 83))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('variant', 'Var', (71, 78))	('SKOV-3', 'CellLine', 'CVCL:0532', (79, 85))	('MCF-7', 'CellLine', 'CVCL:0031', (123, 128))	('breast cancer', 'Disease', (99, 112))	('SKOV-3', 'CellLine', 'CVCL:0532', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('MCF-7', 'CellLine', 'CVCL:0031', (166, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (10, 24))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (10, 24))	('ovarian cancer', 'Disease', (10, 24))	('paclitaxel', 'Chemical', 'MESH:D017239', (137, 147))
324129	28145098	To investigate the potential function of miRs in the development of drug resistance in osteosarcoma, global miR expression microarrays were used to analyse the miR expression profiles in the human osteosarcoma cell lines KHOS and U-2OS, and their drug-resistant variants KHOSMR and U-2OSMR.	('drug resistance', 'Phenotype', 'HP:0020174', (68, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('osteosarcoma cell lines KHOS', 'Disease', (197, 225))	('osteosarcoma cell lines KHOS', 'Disease', 'MESH:D012516', (197, 225))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('KHOSMR', 'Var', (271, 277))	('osteosarcoma', 'Phenotype', 'HP:0002669', (197, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
324133	28145098	Additionally, on the basis of animal weight and mortality, no considerable toxicity was observed and the animals appeared to have tolerated miR-15b well in all the treatment regimens (Fig.	('toxicity', 'Disease', 'MESH:D064420', (75, 83))	('miR-15b', 'Var', (140, 147))	('toxicity', 'Disease', (75, 83))
324144	28145098	miR-15b transfection into cancer cells has been shown to lead to decreased expression of Bcl-2, cyclin E and PIM1 proteins, providing additional mechanistic explanations of how miR-15b might play an important role in the development drug resistance (Migliore et al., 2008; Weirauch et al., 2013; Xia et al., 2009).	('drug resistance', 'Phenotype', 'HP:0020174', (233, 248))	('cyclin E', 'Protein', (96, 104))	('PIM1', 'Gene', (109, 113))	('decreased', 'NegReg', (65, 74))	('PIM1', 'Gene', '5292', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('miR-15b', 'Gene', (0, 7))	('Bcl-2', 'Gene', (89, 94))	('Bcl-2', 'Gene', '596', (89, 94))	('transfection', 'Var', (8, 20))	('expression', 'MPA', (75, 85))
324148	28145098	miR-15b/miR-16-2 modulates the cyclin D1, cyclin D2 and IGF-1R genes involved in proliferation and anti-apoptotic pathways in mouse B cells (Wu et al., 2012).	('cyclin D2', 'Gene', '12444', (42, 51))	('modulates', 'Reg', (17, 26))	('cyclin D1', 'Gene', '12443', (31, 40))	('miR-15b/miR-16-2', 'Var', (0, 16))	('cyclin D2', 'Gene', (42, 51))	('IGF-1R', 'Gene', (56, 62))	('cyclin D1', 'Gene', (31, 40))
324151	28145098	For example, inhibition of Wee1 by the selective small-molecule inhibitor MK1775 can abrogate the G2-M checkpoint, resulting in premature mitotic entry and initiation of apoptotic cell death in all sarcoma cells tested.	('inhibition', 'Var', (13, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('apoptotic cell death', 'CPA', (170, 190))	('premature', 'MPA', (128, 137))	('MK1775', 'Chemical', 'MESH:C549567', (74, 80))	('abrogate', 'NegReg', (85, 93))	('MK1775', 'Gene', (74, 80))	('Wee1', 'Gene', (27, 31))	('G2-M checkpoint', 'MPA', (98, 113))
324152	28145098	The cytotoxic effect of Wee1 inhibition on sarcoma cells seems to be p53 status-independent as all sarcoma cell lines with different p53 mutations were highly sensitive to MK1775 treatment.	('p53', 'Gene', '7157', (69, 72))	('p53', 'Gene', (69, 72))	('mutations', 'Var', (137, 146))	('p53', 'Gene', (133, 136))	('p53', 'Gene', '7157', (133, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
324153	28145098	MK1775 significantly enhanced the cytotoxic effect of gemcitabine in sarcoma cells lines with different p53 mutational status (Kreahling et al., 2013).	('p53', 'Gene', (104, 107))	('MK1775', 'Var', (0, 6))	('mutational', 'Var', (108, 118))	('cytotoxic effect', 'CPA', (34, 50))	('enhanced', 'PosReg', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('gemcitabine', 'Chemical', 'MESH:C056507', (54, 65))
324154	28145098	Wee1 inhibition is also effective in patient-derived sarcoma cells; MK1775 as a single agent causes significant apoptotic cell death, suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas.	('MK1775', 'Var', (68, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (217, 225))	('apoptotic cell death', 'CPA', (112, 132))	('sarcomas', 'Disease', (217, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Disease', 'MESH:D012509', (217, 225))
324219	28066805	The V2 Ktrans parameter was an excellent (C = 0.9) early discriminator of optimal versus suboptimal pathological response, while V1 and V2 kep, V1 and V21% Ktrans, V21% ve, and V21% taui were fair-to-good (0.7 <= C <= 0.8) markers for early prediction of response.	('Ktrans', 'Chemical', '-', (7, 13))	('V21%', 'Var', (177, 181))	('Ktrans', 'Chemical', '-', (156, 162))	('V21% ve', 'Var', (164, 171))	('V21% Ktrans', 'Var', (151, 162))
324220	28066805	Compared with good-to-excellent predictive abilities of the Ktrans and kep metrics, the V21% change in RECIST LD was just a fair early predictor of response.	('Ktrans', 'Chemical', '-', (60, 66))	('RECIST LD', 'Gene', (103, 112))	('V21% change', 'Var', (88, 99))
324231	28066805	Under the condition of 100% sensitivity for early prediction of optimal response (ie, correctly classify all optimal responders in the study cohort), the specificities are 40% and 60% for V21% RECIST LD and V21% Ktrans, respectively, indicating less misclassification of suboptimal responders as optimal responders when V21% Ktrans, instead of V21% RECIST LD, is used as the imaging metric for early prediction of response.	('V21', 'Var', (207, 210))	('Ktrans', 'Chemical', '-', (212, 218))	('V21% Ktrans', 'Var', (320, 331))	('V21%', 'Var', (188, 192))	('Ktrans', 'Chemical', '-', (325, 331))
324252	28066805	In this study, both V21% change and V3 tumor taui were fair markers (Table 2) for discriminating optimal and suboptimal response.	('V21% change', 'Var', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
324254	28066805	It is interesting to note that even though sorafenib is an antiangiogenic agent, there were no significant differences in V21% and V31% decreases of Ktrans and kep between the cohort that received sorafenib + standard chemoradiotherapy and the other cohort that received chemoradiotherapy only.	('Ktrans', 'Chemical', '-', (149, 155))	('sorafenib', 'Chemical', 'MESH:D000077157', (197, 206))	('sorafenib', 'Chemical', 'MESH:D000077157', (43, 52))	('decreases', 'NegReg', (136, 145))	('kep', 'Enzyme', (160, 163))	('V31', 'Var', (131, 134))	('Ktrans', 'MPA', (149, 155))
324259	28066805	Similarities in V21% and V31% Ktrans and kep decreases between the 2 cohorts suggest that the added antiangiogenic effects of sorafenib (to IE treatment) on perfusion and permeability, if any, were not measurable by DCE-MRI in this study.	('DCE', 'Gene', (216, 219))	('antiangiogenic effects', 'MPA', (100, 122))	('Ktrans', 'Enzyme', (30, 36))	('V21', 'Var', (16, 19))	('decreases', 'NegReg', (45, 54))	('permeability', 'MPA', (171, 183))	('kep', 'Enzyme', (41, 44))	('V31', 'Var', (25, 28))	('DCE', 'Gene', '1718', (216, 219))	('sorafenib', 'Chemical', 'MESH:D000077157', (126, 135))	('Ktrans', 'Chemical', '-', (30, 36))
324306	27362300	All patients had adequate organ function prior to study entry as defined by Hb >= 8 g/dl, ANC >= 1,500/mm3, platelets >= 50,000/mm3, creatinine < 1.5 upper limit of normal (ULN), total bilirubin < 1.5 x ULN, AST and ALT < 3 x ULN.	('AST', 'Gene', '26503', (208, 211))	('creatinine', 'Chemical', 'MESH:D003404', (133, 143))	('ALT', 'MPA', (216, 219))	('creatinine', 'MPA', (133, 143))	('bilirubin', 'Chemical', 'MESH:D001663', (185, 194))	('>= 8 g/dl', 'Var', (79, 88))	('AST', 'Gene', (208, 211))	('platelets', 'MPA', (108, 117))	('ANC', 'Gene', '8066', (90, 93))	('patients', 'Species', '9606', (4, 12))	('total bilirubin', 'MPA', (179, 194))	('ANC', 'Gene', (90, 93))
324383	27362300	For Group 1, the limited availability of Ki67 in patients makes it difficult to draw any conclusions regarding differences in the efficacy of robatumumab 0.3 mg/kg versus 10 mg/kg on the response rate for tumor proliferation.	('Ki67', 'Chemical', '-', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('0.3', 'Var', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('patients', 'Species', '9606', (49, 57))	('robatumumab', 'Chemical', 'MESH:C573312', (142, 153))
324522	29383713	For multivariate analysis, surgical resection remained the most significant predictor of post-metastases survival followed by a disease-free interval of greater than 12 months and low grade histology of the primary tumor.	('metastases', 'Disease', (94, 104))	('primary tumor', 'Disease', (207, 220))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('low grade', 'Var', (180, 189))	('primary tumor', 'Disease', 'MESH:D009369', (207, 220))
324544	29383713	Most likely these patients had pleural involvement which is associated with higher morbidity, compared to intrapulmonary lesions.29 Median OS and PFS of patients with pulmonary metastases only was highest for patients treated with doxorubicin plus ifosfamide followed by anthracycline monotherapy, ifosfamide and trabectedin or brostallicin.	('ifosfamide', 'Chemical', 'MESH:D007069', (298, 308))	('pulmonary metastases', 'Disease', 'MESH:D009362', (167, 187))	('pulmonary metastases', 'Disease', (167, 187))	('doxorubicin', 'Chemical', 'MESH:D004317', (231, 242))	('trabectedin', 'Chemical', 'MESH:D000077606', (313, 324))	('brostallicin', 'Chemical', 'MESH:C455279', (328, 340))	('patients', 'Species', '9606', (153, 161))	('pulmonary lesions', 'Disease', (111, 128))	('ifosfamide', 'Chemical', 'MESH:D007069', (248, 258))	('patients', 'Species', '9606', (209, 217))	('doxorubicin', 'Var', (231, 242))	('patients', 'Species', '9606', (18, 26))	('pleural involvement', 'Disease', (31, 50))	('anthracycline', 'Chemical', 'MESH:D018943', (271, 284))	('pleural involvement', 'Disease', 'MESH:D010995', (31, 50))	('pulmonary lesions', 'Disease', 'MESH:D008171', (111, 128))
324617	29696133	Inhibition of classical NF-kappaB activity in sarcoma cell lines restored alternative signaling as well as an increased oxidative respiratory metabolic phenotype in vitro.	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('increased', 'PosReg', (110, 119))	('restored', 'PosReg', (65, 73))	('oxidative respiratory metabolic phenotype', 'MPA', (120, 161))	('alternative signaling', 'MPA', (74, 95))	('sarcoma', 'Disease', (46, 53))	('Inhibition', 'Var', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
324618	29696133	In addition, microarray analysis indicated that inhibition of NF-kappaB in sarcoma cells reduced glycolysis.	('glycolysis', 'MPA', (97, 107))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('sarcoma', 'Disease', (75, 82))	('inhibition', 'Var', (48, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('reduced', 'NegReg', (89, 96))	('NF-kappaB', 'Protein', (62, 71))
324620	29696133	Knockdown of HK2 shifted the metabolic profile in sarcoma cells away from aerobic glycolysis, and re-expression of HK2 rescued the metabolic shift induced by inhibition of NF-kappaB activity in OS cells.	('NF-kappaB', 'Protein', (172, 181))	('activity', 'MPA', (182, 190))	('metabolic shift', 'MPA', (131, 146))	('HK2', 'Gene', (115, 118))	('rescued', 'PosReg', (119, 126))	('metabolic profile', 'MPA', (29, 46))	('HK2', 'Gene', '3099', (115, 118))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('OS', 'Phenotype', 'HP:0002669', (194, 196))	('re-expression', 'Var', (98, 111))	('sarcoma', 'Disease', (50, 57))	('HK2', 'Gene', (13, 16))	('HK2', 'Gene', '3099', (13, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('inhibition', 'NegReg', (158, 168))	('shifted', 'Reg', (17, 24))
324640	29696133	Phosphorylation of IKK leads to its activation and subsequent phosphorylation of the inhibitory protein IkappaB.	('kappaB', 'Gene', '4790', (105, 111))	('IKK', 'Protein', (19, 22))	('kappaB', 'Gene', (105, 111))	('Phosphorylation', 'Var', (0, 15))	('phosphorylation', 'MPA', (62, 77))	('activation', 'PosReg', (36, 46))
324671	29696133	The antibodies used included anti-p65 (Millipore, Billerica, MA, USA; Cell Signaling, Danvers, MA, USA), anti-p52 (Cell Signaling), anti-p100 (Cell Signaling), anti-IkappaBalpha (Santa Cruz Biotechnology, Dallas, TX, USA), and anti-HK2 (Cell Signaling).	('IkappaBalpha', 'Gene', (165, 177))	('anti-p100', 'Var', (132, 141))	('HK2', 'Gene', (232, 235))	('HK2', 'Gene', '3099', (232, 235))	('p65', 'Gene', (34, 37))	('p52', 'Gene', (110, 113))	('p52', 'Gene', '4791', (110, 113))	('IkappaBalpha', 'Gene', '4792', (165, 177))	('p65', 'Gene', '5970', (34, 37))
324699	29696133	While normal tissue exhibited low levels of nuclear p65, processing of p100 to p52 was readily visible, indicative of an activated alternative signaling pathway (Figure 1A; Figure S1 in Supplementary Material).	('p65', 'Gene', '5970', (52, 55))	('p52', 'Gene', (79, 82))	('p52', 'Gene', '4791', (79, 82))	('alternative signaling pathway', 'Pathway', (131, 160))	('p100', 'Var', (71, 75))	('p65', 'Gene', (52, 55))
324716	29696133	Deletion of NBD predominantly forces IKKalpha dimerization and activation of the alternative pathway.	('NBD', 'Gene', (12, 15))	('dimerization', 'MPA', (46, 58))	('IKKalpha', 'Gene', '1147', (37, 45))	('IKKalpha', 'Gene', (37, 45))	('alternative pathway', 'Pathway', (81, 100))	('forces', 'Reg', (30, 36))	('Deletion', 'Var', (0, 8))
324732	29696133	To further examine whether HK2 is regulated by NF-kappaB, we performed knockdown of p65 and observed decreased expression of HK2 in RH30 and U2OS cells silenced for p65 (Figure S3 in Supplementary Material).	('p65', 'Gene', (84, 87))	('HK2', 'Gene', (125, 128))	('HK2', 'Gene', '3099', (125, 128))	('RH30', 'Gene', '6007', (132, 136))	('knockdown', 'Var', (71, 80))	('decreased', 'NegReg', (101, 110))	('silenced', 'Var', (152, 160))	('p65', 'Gene', (165, 168))	('expression', 'MPA', (111, 121))	('U2OS', 'CellLine', 'CVCL:0042', (141, 145))	('p65', 'Gene', '5970', (84, 87))	('RH30', 'Gene', (132, 136))	('HK2', 'Gene', (27, 30))	('HK2', 'Gene', '3099', (27, 30))	('OS', 'Phenotype', 'HP:0002669', (143, 145))	('p65', 'Gene', '5970', (165, 168))
324741	29696133	We next utilized the Seahorse Bioscience XFe24 extracellular flux analyzer to examine whether HK2 depletion affected the metabolic profile of sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('depletion', 'Var', (98, 107))	('sarcoma', 'Disease', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('HK2', 'Gene', '3099', (94, 97))	('affected', 'Reg', (108, 116))	('metabolic profile', 'MPA', (121, 138))	('HK2', 'Gene', (94, 97))
324742	29696133	Similar to what we observed in sarcoma cells devoid of NF-kappaB, RH30 and U2OS cells silenced for HK2 also exhibited an increase in ATP-linked mitochondrial oxygen consumption, suggestive of a shift away from the Warburg effect (Figures 5B,C).	('U2OS', 'CellLine', 'CVCL:0042', (75, 79))	('sarcoma', 'Disease', (31, 38))	('ATP-linked mitochondrial oxygen consumption', 'MPA', (133, 176))	('oxygen', 'Chemical', 'MESH:D010100', (158, 164))	('ATP', 'Chemical', 'MESH:D000255', (133, 136))	('increase', 'PosReg', (121, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('OS', 'Phenotype', 'HP:0002669', (77, 79))	('HK2', 'Gene', (99, 102))	('HK2', 'Gene', '3099', (99, 102))	('silenced', 'Var', (86, 94))	('RH30', 'Gene', (66, 70))	('RH30', 'Gene', '6007', (66, 70))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))
324745	29696133	Results showed that expression of HK2 rescued the metabolic shift seen in U2OS IkappaBalpha SR cells (p < 0.05), but not in RH30 cells (Figures 5E,F).	('expression', 'Var', (20, 30))	('metabolic shift', 'MPA', (50, 65))	('rescued', 'PosReg', (38, 45))	('U2OS IkappaBalpha SR', 'CellLine', 'CVCL:0042', (74, 94))	('RH30', 'Gene', (124, 128))	('HK2', 'Gene', '3099', (34, 37))	('RH30', 'Gene', '6007', (124, 128))	('HK2', 'Gene', (34, 37))	('OS', 'Phenotype', 'HP:0002669', (76, 78))
324756	29696133	Previously in our lab, we also demonstrated that the alternative pathway replaced classical NF-kappaB during myogenesis, and activated alternative NF-kappaB promoted mitochondrial biogenesis, resulting in increased ATP production by OXPHOS.	('ATP', 'Chemical', 'MESH:D000255', (215, 218))	('ATP production by OXPHOS', 'MPA', (215, 239))	('promoted', 'PosReg', (157, 165))	('alternative', 'Var', (135, 146))	('increased', 'PosReg', (205, 214))	('OS', 'Phenotype', 'HP:0002669', (237, 239))	('mitochondrial biogenesis', 'MPA', (166, 190))
324771	29696133	Although 2-DG is used as a stand-alone therapy, evidence indicates that 2-DG in combination with chemotherapy or radiotherapy is efficacious as an anticancer treatment.	('2-DG', 'Chemical', 'MESH:D003847', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('2-DG', 'Chemical', 'MESH:D003847', (72, 76))	('2-DG', 'Var', (72, 76))
324775	29696133	We suspect that in RH30 cells, NF-kappaB is inhibiting oxidative metabolism by regulating multiple glycolytic factors including HK2, and simply re-expressing HK2 in cells that completely lack NF-kappaB activity is not sufficient to rescue the metabolic effect that is being maintained by other NF-kappaB regulated genes.	('RH30', 'Gene', '6007', (19, 23))	('inhibiting', 'NegReg', (44, 54))	('metabolic effect', 'MPA', (243, 259))	('HK2', 'Gene', '3099', (128, 131))	('RH30', 'Gene', (19, 23))	('HK2', 'Gene', (158, 161))	('lack', 'NegReg', (187, 191))	('re-expressing', 'Var', (144, 157))	('HK2', 'Gene', '3099', (158, 161))	('oxidative metabolism', 'MPA', (55, 75))	('glycolytic factors', 'MPA', (99, 117))	('activity', 'MPA', (202, 210))	('HK2', 'Gene', (128, 131))
324850	24424260	A total of three patients with pelvic sarcomas, including one RMS, were planned using various techniques and demonstrated a marked reduction in ovarian dose with protons compared to both 3D conformal and IMRT.	('protons', 'Var', (162, 169))	('reduction', 'NegReg', (131, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('RMS', 'Phenotype', 'HP:0002859', (62, 65))	('pelvic sarcomas', 'Disease', 'MESH:D034161', (31, 46))	('pelvic sarcomas', 'Disease', (31, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('ovarian dose', 'MPA', (144, 156))	('patients', 'Species', '9606', (17, 25))
324975	29781567	Analyses were performed on the data derived from 13 studies from the four cooperative groups (IRS-III, IRS-IVp, IRS-IV, COG D9602, COG D9803, COG ARST0331, MMT84, MMT89, MMT95, RMS79, RMS88, RMS96, and RMS2005).	('MMT95', 'Var', (170, 175))	('RMS88', 'Var', (184, 189))	('RMS', 'Phenotype', 'HP:0002859', (202, 205))	('MMT89', 'Var', (163, 168))	('RMS', 'Phenotype', 'HP:0002859', (177, 180))	('COG', 'Chemical', '-', (131, 134))	('MMT84', 'Var', (156, 161))	('ARST0331', 'Chemical', '-', (146, 154))	('IRS', 'Gene', (112, 115))	('RMS2005', 'Var', (202, 209))	('IRS', 'Gene', (94, 97))	('IRS', 'Gene', (103, 106))	('RMS', 'Phenotype', 'HP:0002859', (184, 187))	('RMS', 'Phenotype', 'HP:0002859', (191, 194))	('IRS', 'Gene', '3376', (112, 115))	('RMS96', 'Var', (191, 196))	('D9602', 'Chemical', '-', (124, 129))	('COG', 'Chemical', '-', (120, 123))	('RMS79', 'Var', (177, 182))	('IRS', 'Gene', '3376', (94, 97))	('IRS', 'Gene', '3376', (103, 106))	('COG', 'Chemical', '-', (142, 145))
324981	29781567	In IRS-IV11, IV pilot10, and D980313, systematic RT was given at week 9.	('D980313', 'Var', (29, 36))	('IRS', 'Gene', (3, 6))	('IRS', 'Gene', '3376', (3, 6))
324985	29781567	For patients with group III vaginal primaries with clinical involvement of lymph nodes (N1), RT to primary tumor and nodes was to start at week 12 on D9602 and at week 13 on ARST0331.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('ARST0331', 'Chemical', '-', (174, 182))	('tumor', 'Disease', (107, 112))	('D9602', 'Var', (150, 155))	('D9602', 'Chemical', '-', (150, 155))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
324987	29781567	Patients with genital tumors achieving clinical (RMS79) or histologically confirmed (RMS 88 and 96) CR were not intended to receive RT.	('RMS', 'Phenotype', 'HP:0002859', (85, 88))	('CR', 'Chemical', '-', (100, 102))	('RMS', 'Phenotype', 'HP:0002859', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('genital tumors', 'Disease', 'MESH:D005834', (14, 28))	('Patients', 'Species', '9606', (0, 8))	('genital tumors', 'Disease', (14, 28))	('genital tumors', 'Phenotype', 'HP:0010787', (14, 28))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('RMS79', 'Var', (49, 54))
325061	29781567	In VU RMS, along with the well-known effect of RT, major long-term complications of local therapy can potentially impair genitourinary and digestive functions, sexuality, and fertility, and may have psychological or quality-of-life consequences.	('impair genitourinary', 'Phenotype', 'HP:0000119', (114, 134))	('VU', 'Chemical', '-', (3, 5))	('RMS', 'Phenotype', 'HP:0002859', (6, 9))	('fertility', 'CPA', (175, 184))	('RMS', 'Var', (6, 9))	('impair', 'NegReg', (114, 120))	('genitourinary', 'Disease', (121, 134))	('sexuality', 'CPA', (160, 169))
325085	33436392	Although PAX3:FOXO1 or PAX7:FOXO1 chimeric oncogenes are found in the majority of ARMS cases, 15% of rhabdomyosarcomas with available fusion data are negative for FOXO1 rearrangement.	('PAX7', 'Gene', (23, 27))	('PAX3', 'Gene', '5077', (9, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('FOXO1', 'Gene', '2308', (14, 19))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (101, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('RMS', 'Phenotype', 'HP:0002859', (83, 86))	('FOXO1', 'Gene', (14, 19))	('FOXO1', 'Gene', '2308', (28, 33))	('FOXO1', 'Gene', '2308', (163, 168))	('ARMS', 'Phenotype', 'HP:0006779', (82, 86))	('rearrangement', 'Var', (169, 182))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (101, 118))	('FOXO1', 'Gene', (28, 33))	('rhabdomyosarcomas', 'Disease', (101, 118))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (101, 118))	('FOXO1', 'Gene', (163, 168))	('PAX3', 'Gene', (9, 13))	('PAX7', 'Gene', '5081', (23, 27))
325091	33436392	Data suggest that overall survival outcomes were improved with early detection of tumors through surveillance of patients with TP53 mutations.	('improved', 'PosReg', (49, 57))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('patients', 'Species', '9606', (113, 121))	('mutations', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TP53', 'Gene', (127, 131))
325094	33436392	Most TP53 mutations associated with LFS are missense mutations, which may or may not significantly affect protein function.	('associated', 'Reg', (20, 30))	('LFS', 'Disease', 'MESH:D016864', (36, 39))	('mutations', 'Var', (10, 19))	('TP53', 'Gene', (5, 9))	('LFS', 'Disease', (36, 39))	('missense', 'Var', (44, 52))
325095	33436392	The ambiguity of classifying these mutations as benign or deleterious can make clinicians reluctant to diagnose patients with LFS given the psychological ramifications that can come with diagnosis and active surveillance thereafter.	('LFS', 'Disease', (126, 129))	('LFS', 'Disease', 'MESH:D016864', (126, 129))	('patients', 'Species', '9606', (112, 120))	('mutations', 'Var', (35, 44))
325096	33436392	The International Agency for Research on Cancer (IARC) TP53 Database has compiled TP53 mutations reported in published literature and can be used for further risk assessment.	('TP53', 'Gene', (82, 86))	('Cancer', 'Disease', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (87, 96))
325097	33436392	In the context of rhabdomyosarcoma, TP53 mutations have been associated with increased risk of second neoplastic malignancy and associated with worsened overall survival, suggesting TP53 plays an important role in clinical progression and TP53 status should be investigated in the course of clinical decision making.	('mutations', 'Var', (41, 50))	('neoplastic malignancy', 'Disease', (102, 123))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (18, 34))	('neoplastic malignancy', 'Phenotype', 'HP:0002664', (102, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('overall survival', 'MPA', (153, 169))	('neoplastic malignancy', 'Disease', 'MESH:D009369', (102, 123))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (18, 34))	('worsened', 'NegReg', (144, 152))	('TP53', 'Gene', (36, 40))	('rhabdomyosarcoma', 'Disease', (18, 34))
325114	33436392	However, fluorescence in situ hybridization (FISH) studies were negative for the classic FOXO1 t(2,13) or t(1:13) rearrangements and did not support a diagnosis of ARMS.	('ARMS', 'Phenotype', 'HP:0006779', (164, 168))	('FOXO1', 'Gene', '2308', (89, 94))	('RMS', 'Phenotype', 'HP:0002859', (165, 168))	('FOXO1', 'Gene', (89, 94))	('rearrangements', 'Var', (114, 128))
325150	33436392	Previous testing by OncoPlex identified a TP53 p.V172F (Tier 2A) mutation with associated loss of heterozygosity, suggesting that both copies of the gene are expected to be inactivated in the tumor tissue.	('tumor', 'Disease', (192, 197))	('p.V172F', 'Mutation', 'rs1131691043', (47, 54))	('p.V172F', 'Var', (47, 54))	('TP53', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('heterozygosity', 'MPA', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
325156	33436392	However, two germline mutations were found in TP53, including the same variant found in the patient's mother (c.514G > T p.Val172Phe) (Table 1), which is considered likely pathogenic for hereditary cancer-predisposing syndrome (ClinVar ID: 428909).	('patient', 'Species', '9606', (92, 99))	('p.Val172Phe', 'Mutation', 'rs1131691043', (121, 132))	('hereditary cancer', 'Disease', 'MESH:D009369', (187, 204))	('c.514G > T', 'Mutation', 'rs1131691043', (110, 120))	('c.514G > T', 'Var', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('TP53', 'Gene', (46, 50))	('hereditary cancer', 'Disease', (187, 204))
325157	33436392	Another missense variant in TP53 (c.215C > G p.Pro72Arg) was found to alter drug response in several neoplasms but found to not be associated with Li-Fraumeni syndrome 1 (ClinVar ID: 12351).	('neoplasms', 'Phenotype', 'HP:0002664', (101, 110))	('p.Pro72Arg', 'Mutation', 'rs1042522', (45, 55))	('Li-Fraumeni syndrome', 'Disease', (147, 167))	('c.215C > G', 'Mutation', 'rs1042522', (34, 44))	('c.215C > G p.Pro72Arg', 'Var', (34, 55))	('TP53', 'Gene', (28, 32))	('p.Pro72Arg', 'Var', (45, 55))	('associated', 'Reg', (131, 141))	('neoplasms', 'Disease', 'MESH:D009369', (101, 110))	('neoplasms', 'Disease', (101, 110))	('neoplasm', 'Phenotype', 'HP:0002664', (101, 109))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (147, 167))	('alter', 'Reg', (70, 75))	('drug response', 'MPA', (76, 89))
325158	33436392	TP53 mutations have previously been associated with response to the majority (six of eight) therapeutic regimens administered to the patient (Table 2).	('patient', 'Species', '9606', (133, 140))	('associated with', 'Reg', (36, 51))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
325159	33436392	No somatic mutations were found in genes previously reported to be recurrently mutated in RMS; however, germline protein coding mutations were found in FGFR4 (c.28G > A p.Val10Ile; c.407C > T p.Pro136Leu) and nonsense mediated decay variants were found in NF1 (c.37T > C p.Ter13Arg).	('c.28G > A', 'Var', (159, 168))	('p.Pro136Leu', 'Mutation', 'rs376618', (192, 203))	('c.407C > T', 'Mutation', 'rs376618', (181, 191))	('FGFR4', 'Gene', '2264', (152, 157))	('NF1', 'Gene', (256, 259))	('FGFR4', 'Gene', (152, 157))	('c.37T > C p.Ter13Arg', 'Var', (261, 281))	('NF1', 'Gene', '4763', (256, 259))	('c.28G > A', 'Mutation', 'rs1966265', (159, 168))	('RMS', 'Phenotype', 'HP:0002859', (90, 93))	('p.Val10Ile', 'Mutation', 'rs1966265', (169, 179))	('p.Ter13Arg', 'Mutation', 'rs749998773', (271, 281))	('nonsense mediated decay', 'Var', (209, 232))	('c.407C > T', 'Var', (181, 191))	('c.37T > C', 'Mutation', 'rs749998773', (261, 270))
325160	33436392	In addition to the germline variants found in TP53, a germline disruptive in-frame insertion variant was found in FAM83D (c.345 347dupGGC p.Ala116dup), along with copy-number gain in FAM83D (log2 ratio 0.7).	('FAM83D', 'Gene', (183, 189))	('FAM83D', 'Gene', '81610', (114, 120))	('FAM83D', 'Gene', '81610', (183, 189))	('c.345 347dupGGC', 'Mutation', 'c.345347dupGGC', (122, 137))	('c.345 347dupGGC p.Ala116dup', 'Var', (122, 149))	('p.Ala116dup', 'Mutation', 'p.116dup', (138, 149))	('FAM83D', 'Gene', (114, 120))
325163	33436392	Further, elevated FAM83D was found to correlate with TP53 mutations and genome instability.	('mutations', 'Var', (58, 67))	('FAM83D', 'Gene', '81610', (18, 24))	('genome instability', 'CPA', (72, 90))	('FAM83D', 'Gene', (18, 24))	('TP53', 'Gene', (53, 57))
325173	33436392	Several drugs were highly active, including panobinostat (IC50 = 6 nM, pan HDAC inhibitor), brefeldin A (IC50 = 21 nM, ATPase inhibitor), CUDC-907 (IC50 = 99 nM, HDAC1/2/3/10 + PI3Kalpha inhibitor), YM155 (IC50 = 9 nM, Survivin inhibitor), INK128 (IC50 = 5 nM, mTORC1/2), MK-1775 (IC50 = 79 nM, WEE1), thapsigargin (IC50 = 9 nM, SERCA), BMS-754807 (IC50 = 66 nM, IGF1R + AURK inhibitor), JQ1(IC50 = 92 nM, BET (BRD4) inhibitor), and mithramycin A (IC50 = 89 nM, SP1 inhibitor).	('HDAC', 'Gene', (162, 166))	('BET', 'Gene', '92737', (406, 409))	('panobinostat', 'Chemical', 'MESH:D000077767', (44, 56))	('mithramycin', 'Gene', (433, 444))	('YM155', 'Var', (199, 204))	('WEE1', 'Gene', '7465', (295, 299))	('HDAC', 'Gene', (75, 79))	('mTORC1/2', 'Gene', '74343;382056', (261, 269))	('IGF1R', 'Gene', '3480', (363, 368))	('PI3Kalpha', 'Gene', '5290', (177, 186))	('INK128', 'Chemical', 'MESH:C572449', (240, 246))	('HDAC1/2/3/10', 'Gene', '3065;3066;8841;83933', (162, 174))	('IGF1R', 'Gene', (363, 368))	('ATPase', 'Gene', (119, 125))	('BRD4', 'Gene', (411, 415))	('mTORC1/2', 'Gene', (261, 269))	('BET', 'Gene', (406, 409))	('WEE1', 'Gene', (295, 299))	('ATPase', 'Gene', '1769', (119, 125))	('HDAC1/2/3/10', 'Gene', (162, 174))	('CUDC-907', 'Chemical', 'MESH:C576940', (138, 146))	('HDAC', 'Gene', '9734', (162, 166))	('PI3Kalpha', 'Gene', (177, 186))	('HDAC', 'Gene', '9734', (75, 79))	('BRD4', 'Gene', '23476', (411, 415))	('MK-1775', 'Chemical', 'MESH:C549567', (272, 279))
325187	33436392	Additionally, agents associated with alteration of TP53 expression also demonstrated in vitro efficacy, including prima-1 (IC50 = 135 nM) and CUDC-305 (IC50 = 137 nM, HSP90 inhibitor).	('alteration', 'Var', (37, 47))	('TP53', 'Gene', (51, 55))	('HSP90', 'Gene', '3320', (167, 172))	('CUDC-305', 'Chemical', 'MESH:C543177', (142, 150))	('HSP90', 'Gene', (167, 172))
325188	33436392	Previous studies have found that prima-1 reactivates TP53, which induces high levels of apoptosis, and has demonstrated tumor reduction with no apparent toxicity in p53 mutant tumor xenografts in SCID mice.	('p53', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('SCID', 'Disease', 'MESH:D053632', (196, 200))	('induces', 'Reg', (65, 72))	('SCID', 'Disease', (196, 200))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('mice', 'Species', '10090', (201, 205))	('mutant', 'Var', (169, 175))	('reduction', 'NegReg', (126, 135))	('toxicity', 'Disease', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('toxicity', 'Disease', 'MESH:D064420', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', (120, 125))
325190	33436392	Similarly, TP53 expression can be altered by HSP90 inhibitors (such as CUDC-305) and thus could potentially be beneficial for TP53 mutant patients.	('altered', 'Reg', (34, 41))	('TP53', 'Gene', (126, 130))	('beneficial', 'PosReg', (111, 121))	('TP53', 'Gene', (11, 15))	('mutant', 'Var', (131, 137))	('CUDC-305', 'Chemical', 'MESH:C543177', (71, 79))	('HSP90', 'Gene', (45, 50))	('HSP90', 'Gene', '3320', (45, 50))	('expression', 'MPA', (16, 26))	('patients', 'Species', '9606', (138, 146))
325191	33436392	In this study, we have presented a case of an 11-yr-old male with fusion negative ARMS bearing germline TP53 mutations, one of which (c.514G > T, p.Val172Phe) is a hereditary mutation likely predisposing to LFS.	('LFS', 'Disease', 'MESH:D016864', (207, 210))	('TP53', 'Gene', (104, 108))	('p.Val172Phe', 'Var', (146, 157))	('p.Val172Phe', 'Mutation', 'rs1131691043', (146, 157))	('RMS', 'Phenotype', 'HP:0002859', (83, 86))	('LFS', 'Disease', (207, 210))	('c.514G > T', 'Mutation', 'rs1131691043', (134, 144))	('ARMS', 'Phenotype', 'HP:0006779', (82, 86))	('c.514G > T', 'Var', (134, 144))
325197	33436392	However, missense mutations were found in both TP53 and FGFR4 in the germline, as well as a nonsense-mediated decay mutation in NF1.	('NF1', 'Gene', '4763', (128, 131))	('FGFR4', 'Gene', '2264', (56, 61))	('FGFR4', 'Gene', (56, 61))	('missense mutations', 'Var', (9, 27))	('nonsense-mediated decay mutation', 'Var', (92, 124))	('NF1', 'Gene', (128, 131))	('TP53', 'Gene', (47, 51))
325201	33436392	Germline variants in FGFR4 may play a similar role in promoting the invasion and metastasis of RMS.	('FGFR4', 'Gene', '2264', (21, 26))	('FGFR4', 'Gene', (21, 26))	('invasion', 'CPA', (68, 76))	('promoting', 'PosReg', (54, 63))	('metastasis', 'CPA', (81, 91))	('RMS', 'Disease', (95, 98))	('RMS', 'Phenotype', 'HP:0002859', (95, 98))	('Germline variants', 'Var', (0, 17))
325202	33436392	The index case patient was treated with several targeted therapies, including temsirolimus (mTOR inhibitor), prexasertib (CHEK1 inhibitor), MK01775 (WEE1 inhibitor), pazopanib (multikinase inhibitor specific for VEGFR, PDGFR, c-KIT and FGFR), vorinostat (HDAC inhibitor), and palbociclib (CDK4/6 inhibitor).	('HDAC', 'Gene', '9734', (255, 259))	('VEGFR', 'Gene', '3791', (212, 217))	('MK01775', 'Var', (140, 147))	('CHEK1', 'Gene', (122, 127))	('WEE1', 'Gene', (149, 153))	('VEGFR', 'Gene', (212, 217))	('CDK4/6', 'Gene', '1019;1021', (289, 295))	('mTOR', 'Gene', '2475', (92, 96))	('temsirolimus', 'Chemical', 'MESH:C401859', (78, 90))	('MK01775', 'Chemical', '-', (140, 147))	('HDAC', 'Gene', (255, 259))	('c-KIT', 'Gene', (226, 231))	('c-KIT', 'Gene', '3815', (226, 231))	('prexasertib', 'Chemical', 'MESH:C000608121', (109, 120))	('patient', 'Species', '9606', (15, 22))	('WEE1', 'Gene', '7465', (149, 153))	('pazopanib', 'Chemical', 'MESH:C516667', (166, 175))	('PDGFR', 'Gene', (219, 224))	('CHEK1', 'Gene', '1111', (122, 127))	('CDK4/6', 'Gene', (289, 295))	('PDGFR', 'Gene', '5159', (219, 224))	('mTOR', 'Gene', (92, 96))	('palbociclib', 'Chemical', 'MESH:C500026', (276, 287))	('vorinostat', 'Chemical', 'MESH:D000077337', (243, 253))
325203	33436392	Patient tumor cells were highly sensitive to MK-1775, whereas clinical use resulted in continued disease progression.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('MK-1775', 'Var', (45, 52))	('MK-1775', 'Chemical', 'MESH:C549567', (45, 52))	('Patient', 'Species', '9606', (0, 7))
325208	33436392	Two mTOR-associated agents (INK128 and BKM120) caused reduction in cell viability in vitro, whereas one mTOR agent (sirolimus) had limited in vitro efficacy.	('mTOR', 'Gene', (104, 108))	('mTOR', 'Gene', '2475', (104, 108))	('cell viability in vitro', 'CPA', (67, 90))	('reduction', 'NegReg', (54, 63))	('INK128', 'Var', (28, 34))	('BKM120', 'Var', (39, 45))	('sirolimus', 'Chemical', 'MESH:D020123', (116, 125))	('INK128', 'Chemical', 'MESH:C572449', (28, 34))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('BKM120', 'Chemical', 'MESH:C571178', (39, 45))
325210	33436392	Other therapies that restore TP53 function, such as reactivating p53 and inducing tumor apoptosis (RITA), may merit investigation for PFN ARMS.	('RMS', 'Phenotype', 'HP:0002859', (139, 142))	('inducing', 'Reg', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('ARMS', 'Phenotype', 'HP:0006779', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('reactivating', 'Var', (52, 64))	('tumor', 'Disease', (82, 87))	('p53', 'Protein', (65, 68))
325219	33436392	Tumor and matched normal exome sequencing data were analyzed for the presence of somatic point mutation, somatic functional and structural mutations, potential germline mutations, polynucleotide insertions and deletions, and gene copy-number variation.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('point mutation', 'Var', (89, 103))	('mutations', 'Var', (139, 148))	('polynucleotide insertions', 'Var', (180, 205))	('gene copy-number variation', 'Var', (225, 251))	('deletions', 'Var', (210, 219))	('polynucleotide', 'Chemical', 'MESH:D011119', (180, 194))
325450	23667313	We found that the intracranial CNs affected most often by MPNSTs were CN VIII, followed by CN V and CN VII (see Table 2).	('VIII', 'Gene', '1351', (73, 77))	('MPNST', 'Phenotype', 'HP:0100697', (58, 63))	('MPNSTs', 'Var', (58, 64))	('VIII', 'Gene', (73, 77))
325481	23667313	They proposed seven categories: low-grade MPNST, high-grade MPNST, epithelioid MPNST, MPNST with divergent differentiation, MPNST ex-schwannoma, malignant melanotic schwannoma, and perineural MPNST.	('malignant melanotic schwannoma', 'Disease', 'MESH:D018319', (145, 175))	('perineural MPNST', 'Disease', (181, 197))	('epithelioid MPNST', 'Disease', (67, 84))	('schwannoma', 'Disease', (133, 143))	('MPNST', 'Var', (124, 129))	('schwannoma', 'Disease', 'MESH:D009442', (133, 143))	('MPNST', 'Phenotype', 'HP:0100697', (60, 65))	('schwannoma', 'Disease', 'MESH:D009442', (165, 175))	('schwannoma', 'Disease', (165, 175))	('malignant melanotic schwannoma', 'Disease', (145, 175))	('schwannoma', 'Phenotype', 'HP:0100008', (133, 143))	('MPNST', 'Phenotype', 'HP:0100697', (79, 84))	('MPNST', 'Phenotype', 'HP:0100697', (42, 47))	('schwannoma', 'Phenotype', 'HP:0100008', (165, 175))	('MPNST', 'Phenotype', 'HP:0100697', (124, 129))	('MPNST', 'Phenotype', 'HP:0100697', (86, 91))
325494	23667313	Although hypercellularity, nuclear enlargement, and hyperchromasia have been associated with low-grade MPNST arising in neurofibroma, the lack of objective criteria makes malignant diagnosis difficult to establish.	('hyperchromasia', 'Disease', 'None', (52, 66))	('neurofibroma', 'Disease', 'MESH:D009455', (120, 132))	('low-grade MPNST arising', 'Disease', (93, 116))	('hypercellularity', 'Var', (9, 25))	('MPNST', 'Phenotype', 'HP:0100697', (103, 108))	('neurofibroma', 'Phenotype', 'HP:0001067', (120, 132))	('hyperchromasia', 'Disease', (52, 66))	('neurofibroma', 'Disease', (120, 132))
325615	22275910	Knocking down both of these miRNAs eliminates K15M-induced cell motility.	('Knocking down', 'Var', (0, 13))	('K15M', 'Mutation', 'p.K15M', (46, 50))	('K15M-induced', 'Gene', (46, 58))	('eliminates', 'NegReg', (35, 45))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))
325650	22275910	Moreover, inhibition of miR-K12-11 enhances KSHV reactivation induced by vesicular stomatitis virus infection.	('vesicular stomatitis virus infection', 'Disease', (73, 109))	('vesicular stomatitis virus infection', 'Disease', 'MESH:D054243', (73, 109))	('KSHV', 'Disease', (44, 48))	('miR', 'Gene', '220972', (24, 27))	('KSHV', 'Species', '37296', (44, 48))	('miR', 'Gene', (24, 27))	('inhibition', 'Var', (10, 20))	('stomatitis', 'Phenotype', 'HP:0010280', (83, 93))	('enhances', 'PosReg', (35, 43))	('KS', 'Phenotype', 'HP:0100726', (44, 46))
325692	22275910	Inhibition of IkappaB leads to NFkappaB activation, which suppresses RTA to facilitate viral latency control (Lei et al.,).	('IkappaB', 'Protein', (14, 21))	('viral latency control', 'CPA', (87, 108))	('facilitate', 'PosReg', (76, 86))	('NFkappaB', 'Gene', (31, 39))	('activation', 'PosReg', (40, 50))	('NFkappaB', 'Gene', '4790', (31, 39))	('Inhibition', 'Var', (0, 10))	('suppresses', 'NegReg', (58, 68))	('RTA', 'MPA', (69, 72))
325765	20637078	All cell lines were maintained in RPMI (except TC-71; IMDM) with 10% FBS, L-glutamine (2 mM), penicillin (50 IU/ml) and streptomycin sulphate (50 mug/ml) in a humidified atmosphere at 37 C (5% CO2 in air).	('streptomycin sulphate', 'Chemical', 'MESH:D013307', (120, 141))	('IMDM', 'Chemical', '-', (54, 58))	('FBS', 'Disease', (69, 72))	('CO2', 'Chemical', '-', (193, 196))	('RPMI', 'Chemical', '-', (34, 38))	('TC-71', 'Chemical', '-', (47, 52))	('FBS', 'Disease', 'MESH:D005198', (69, 72))	('L-glutamine', 'Var', (74, 85))	('L-glutamine', 'Chemical', 'MESH:D005973', (74, 85))	('penicillin', 'Chemical', 'MESH:D010406', (94, 104))
325812	20637078	Despite contrasting responses to the initial stimulus, both ES and OS cells demonstrated similar responses to HIF siRNA, with targeted inhibition of HIF-2alpha resulting in increased cell migration under hypoxia (Figure 6B).	('hypoxia', 'Disease', (204, 211))	('hypoxia', 'Disease', 'MESH:D000860', (204, 211))	('cell migration under', 'CPA', (183, 203))	('HIF-2alpha', 'Gene', (149, 159))	('ES', 'Chemical', '-', (60, 62))	('OS', 'Phenotype', 'HP:0002669', (67, 69))	('HIF-2alpha', 'Gene', '2034', (149, 159))	('increased', 'PosReg', (173, 182))	('inhibition', 'Var', (135, 145))
325818	20637078	Also in accordance with previous results, inducible HIF-2alpha stimulated expression of HIF-2-specific genes, e.g.	('expression', 'MPA', (74, 84))	('HIF-2alpha', 'Gene', (52, 62))	('HIF-2alpha', 'Gene', '2034', (52, 62))	('inducible', 'Var', (42, 51))	('stimulated', 'PosReg', (63, 73))
325851	20637078	For example, VEGF blockade decelerates the growth of experimental osteosarcoma and Ewing's sarcoma, demonstrating the viablility of specific targeting of HIF downstream genes.	('VEGF', 'Gene', '7422', (13, 17))	('growth', 'MPA', (43, 49))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (83, 98))	("Ewing's sarcoma", 'Disease', (83, 98))	('osteosarcoma', 'Disease', (66, 78))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (83, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('VEGF', 'Gene', (13, 17))	('blockade', 'Var', (18, 26))	('osteosarcoma', 'Disease', 'MESH:D012516', (66, 78))	('decelerates', 'NegReg', (27, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))
325955	30658711	The tumor markers examined were as follows; cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA), and serum lactate dehydrogenase (LDH) was also checked.	('tumor', 'Disease', (4, 9))	('CEA', 'Gene', '1084', (138, 141))	('carcinoembryonic antigen', 'Gene', '1084', (112, 136))	('CA19-9', 'Var', (99, 105))	('CA125', 'Gene', '94025', (64, 69))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('carbohydrate', 'Chemical', 'MESH:D002241', (72, 84))	('carcinoembryonic antigen', 'Gene', (112, 136))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CA125', 'Gene', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('CEA', 'Gene', (138, 141))
326063	32193604	Notably, this case was subjected to NGS testing and lacked DICER1 mutations, thus arguing against the possibility of primary metachronous pleuropulmonary blastoma in the setting of DICER1 syndrome.	('mutations', 'Var', (66, 75))	('DICER1', 'Gene', (181, 187))	('DICER1', 'Gene', (59, 65))	('DICER1', 'Gene', '23405', (181, 187))	('metachronous pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (125, 162))	('DICER1', 'Gene', '23405', (59, 65))	('lacked', 'NegReg', (52, 58))	('metachronous pleuropulmonary blastoma', 'Disease', (125, 162))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (138, 162))
326072	32193604	Following discovery of STAT6-NAB2 gene fusions as driver events in most of SFTs, STAT6 IHC has emerged as highly sensitive and specific marker for SFT.	('STAT6', 'Gene', '6778', (81, 86))	('SFTs', 'Disease', (75, 79))	('NAB2', 'Gene', (29, 33))	('fusions', 'Var', (39, 46))	('STAT6', 'Gene', (23, 28))	('STAT6', 'Gene', (81, 86))	('STAT6', 'Gene', '6778', (23, 28))	('NAB2', 'Gene', '4665', (29, 33))
326086	32193604	In doubtful cases, it seems that HRAS mutation testing is context-specific for epithelial-myoepithelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('HRAS', 'Gene', '3265', (33, 37))	('HRAS', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))	('epithelial-myoepithelial carcinoma', 'Disease', 'MESH:D002277', (79, 113))	('epithelial-myoepithelial carcinoma', 'Disease', (79, 113))
326094	30976795	Prognostic significance of human telomerase reverse transcriptase promoter region mutations C228T and C250T for overall survival in spinal chordomas Spinal chordomas, a subtype of primary spinal column malignancies (PSCM), are rare tumors with poor prognosis, and we have limited understanding of the molecular drivers of neoplasia.	('C250T', 'Var', (102, 107))	('C228T', 'Mutation', 'c.228C>T', (92, 97))	('human', 'Species', '9606', (27, 32))	('C228T', 'Var', (92, 97))	('PSCM', 'Phenotype', 'HP:0010302', (216, 220))	('spinal chordomas', 'Disease', 'MESH:D002817', (132, 148))	('Spinal chordomas', 'Disease', (149, 165))	('chordoma', 'Phenotype', 'HP:0010762', (139, 147))	('spinal chordomas Spinal', 'Phenotype', 'HP:0010302', (132, 155))	('spinal column malignancies', 'Disease', 'MESH:C536342', (188, 214))	('neoplasia', 'Disease', 'MESH:D009369', (322, 331))	('telomerase reverse transcriptase', 'Gene', (33, 65))	('rare tumors', 'Disease', (227, 238))	('chordomas Spinal chordomas', 'Phenotype', 'HP:0010762', (139, 165))	('rare tumors', 'Disease', 'MESH:D035583', (227, 238))	('C250T', 'Mutation', 'c.250C>T', (102, 107))	('neoplasia', 'Disease', (322, 331))	('Spinal chordomas', 'Disease', 'MESH:D002817', (149, 165))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('telomerase reverse transcriptase', 'Gene', '7015', (33, 65))	('spinal column malignancies', 'Disease', (188, 214))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('neoplasia', 'Phenotype', 'HP:0002664', (322, 331))	('primary spinal column malignancies', 'Phenotype', 'HP:0010302', (180, 214))	('chordoma', 'Phenotype', 'HP:0010762', (156, 164))	('spinal chordomas', 'Disease', (132, 148))
326099	30976795	Eight chordomas, 2 chondrosarcomas, 1 Ewing's sarcoma, and 1 other malignant spinal tumor harbored either a C228T or C250T mutation in the hTERT promoter.	("Ewing's sarcoma", 'Disease', (38, 53))	('C250T', 'Var', (117, 122))	('C228T', 'Mutation', 'c.228C>T', (108, 113))	('malignant spinal tumor', 'Disease', (67, 89))	('chordomas', 'Disease', (6, 15))	('C228T', 'Var', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (19, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('malignant spinal tumor', 'Disease', 'MESH:D013120', (67, 89))	('chondrosarcomas', 'Disease', 'MESH:D002813', (19, 34))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (38, 53))	('hTERT', 'Gene', '7015', (139, 144))	('C250T', 'Mutation', 'c.250C>T', (117, 122))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (38, 53))	('chordoma', 'Phenotype', 'HP:0010762', (6, 14))	('chondrosarcomas', 'Disease', (19, 34))	('spinal tumor', 'Phenotype', 'HP:0010302', (77, 89))	('chordomas', 'Disease', 'MESH:D002817', (6, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('hTERT', 'Gene', (139, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (19, 33))
326101	30976795	hTERT promoter mutation was observed in 8.7% of spinal chordomas, and 100% of chordoma patients harboring the mutation were alive at 10 years postoperative compared with 67% patients without the mutation (P = 0.05).	('chordoma', 'Gene', '121775', (78, 86))	('hTERT', 'Gene', (0, 5))	('chordoma', 'Phenotype', 'HP:0010762', (78, 86))	('chordoma', 'Gene', '121775', (55, 63))	('patients', 'Species', '9606', (174, 182))	('chordoma', 'Phenotype', 'HP:0010762', (55, 63))	('spinal chordomas', 'Disease', (48, 64))	('chordoma', 'Gene', (78, 86))	('mutation', 'Var', (110, 118))	('hTERT', 'Gene', '7015', (0, 5))	('patients', 'Species', '9606', (87, 95))	('spinal chordomas', 'Disease', 'MESH:D002817', (48, 64))	('chordoma', 'Gene', (55, 63))
326102	30976795	We report for the first time that hTERT promoter mutations C228T and C250T are present in approximately 8.7% of spinal chordomas.	('C228T', 'Var', (59, 64))	('chordoma', 'Phenotype', 'HP:0010762', (119, 127))	('spinal chordomas', 'Disease', (112, 128))	('hTERT', 'Gene', (34, 39))	('C250T', 'Var', (69, 74))	('C250T', 'Mutation', 'c.250C>T', (69, 74))	('spinal chordomas', 'Disease', 'MESH:D002817', (112, 128))	('C228T', 'Mutation', 'c.228C>T', (59, 64))	('hTERT', 'Gene', '7015', (34, 39))
326103	30976795	The presence of hTERT mutations conferred a survival benefit and could potentially be a valuable positive prognostic molecular marker in spinal chordomas.	('spinal chordomas', 'Disease', (137, 153))	('chordoma', 'Phenotype', 'HP:0010762', (144, 152))	('hTERT', 'Gene', '7015', (16, 21))	('spinal chordomas', 'Disease', 'MESH:D002817', (137, 153))	('survival benefit', 'CPA', (44, 60))	('mutations', 'Var', (22, 31))	('hTERT', 'Gene', (16, 21))	('presence', 'Var', (4, 12))
326104	30976795	1. hTERT promoter mutations C228T and C250T are present in 8.7% of spinal chordomas.	('spinal chordomas', 'Disease', 'MESH:D002817', (67, 83))	('C250T', 'Var', (38, 43))	('hTERT', 'Gene', (3, 8))	('C250T', 'Mutation', 'c.250C>T', (38, 43))	('spinal chordomas', 'Disease', (67, 83))	('C228T', 'Mutation', 'c.228C>T', (28, 33))	('chordoma', 'Phenotype', 'HP:0010762', (74, 82))	('hTERT', 'Gene', '7015', (3, 8))	('C228T', 'Var', (28, 33))
326105	30976795	2. hTERT promoter mutations are associated with a positive overall survival benefit in spinal chordomas.	('hTERT', 'Gene', (3, 8))	('spinal chordomas', 'Disease', (87, 103))	('chordoma', 'Phenotype', 'HP:0010762', (94, 102))	('spinal chordomas', 'Disease', 'MESH:D002817', (87, 103))	('hTERT', 'Gene', '7015', (3, 8))	('mutations', 'Var', (18, 27))
326108	30976795	We report for the first time that hTERT promoter mutations C228T and C250T are present in 8.7% of spinal chordomas.	('C228T', 'Var', (59, 64))	('spinal chordomas', 'Disease', (98, 114))	('hTERT', 'Gene', (34, 39))	('C250T', 'Var', (69, 74))	('C250T', 'Mutation', 'c.250C>T', (69, 74))	('spinal chordomas', 'Disease', 'MESH:D002817', (98, 114))	('C228T', 'Mutation', 'c.228C>T', (59, 64))	('hTERT', 'Gene', '7015', (34, 39))	('chordoma', 'Phenotype', 'HP:0010762', (105, 113))
326121	30976795	The C228T and C250T promoter mutations generate a de novo binding motif for E-twenty-six transcription factors and can upregulate the transcriptional activity of hTERT by 2- to 6-fold in human melanomas.	('melanomas', 'Disease', (193, 202))	('transcriptional activity', 'MPA', (134, 158))	('binding', 'Interaction', (58, 65))	('hTERT', 'Gene', '7015', (162, 167))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('hTERT', 'Gene', (162, 167))	('upregulate', 'PosReg', (119, 129))	('C250T', 'Var', (14, 19))	('melanomas', 'Disease', 'MESH:D008545', (193, 202))	('C228T', 'Mutation', 'c.228C>T', (4, 9))	('C250T', 'Mutation', 'c.250C>T', (14, 19))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('human', 'Species', '9606', (187, 192))	('C228T', 'Var', (4, 9))
326122	30976795	Although hTERT promoter mutations are frequently associated with worse survival outcomes in thyroid carcinoma, non-small cell lung cancer, and melanoma, the prognostic value of these mutations in central nervous system neoplasms is unclear.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (115, 137))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (92, 109))	('associated', 'Reg', (49, 59))	('hTERT', 'Gene', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('thyroid carcinoma', 'Disease', (92, 109))	('neoplasms', 'Phenotype', 'HP:0002664', (219, 228))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (111, 137))	('mutations', 'Var', (24, 33))	('nervous system neoplasms', 'Disease', 'MESH:D009423', (204, 228))	('neoplasm', 'Phenotype', 'HP:0002664', (219, 227))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (92, 109))	('nervous system neoplasms', 'Phenotype', 'HP:0004375', (204, 228))	('non-small cell lung cancer', 'Disease', (111, 137))	('nervous system neoplasms', 'Disease', (204, 228))	('central nervous system neoplasms', 'Phenotype', 'HP:0100006', (196, 228))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('hTERT', 'Gene', '7015', (9, 14))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (111, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))
326123	30976795	Recent research in glioma patients demonstrated a survival benefit in patients with hTERT promoter mutations in isocitrate dehydrogenase (IDH) wildtype/O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated glioblastoma (GBM) and is strongly associated with IDH mutant-1p/19q codeleted oligodendroglial neoplasm.	('benefit', 'PosReg', (59, 66))	('isocitrate dehydrogenase', 'Gene', (112, 136))	('IDH', 'Gene', '3417', (138, 141))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (152, 190))	('methylated', 'Var', (207, 217))	('patients', 'Species', '9606', (70, 78))	('IDH', 'Gene', (269, 272))	('glioblastoma', 'Disease', 'MESH:D005909', (218, 230))	('hTERT', 'Gene', '7015', (84, 89))	('glioma', 'Disease', (19, 25))	('oligodendroglial neoplasm', 'Disease', 'MESH:D009369', (297, 322))	('oligodendroglial neoplasm', 'Disease', (297, 322))	('neoplasm', 'Phenotype', 'HP:0002664', (314, 322))	('MGMT', 'Gene', (192, 196))	('GBM', 'Phenotype', 'HP:0012174', (232, 235))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('mutant-1p/19q', 'Var', (273, 286))	('associated', 'Reg', (253, 263))	('glioblastoma', 'Disease', (218, 230))	('O6-methylguanine-DNA methyltransferase', 'Gene', (152, 190))	('IDH', 'Gene', '3417', (269, 272))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('isocitrate dehydrogenase', 'Gene', '3417', (112, 136))	('hTERT', 'Gene', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('IDH', 'Gene', (138, 141))	('patients', 'Species', '9606', (26, 34))	('mutations', 'Var', (99, 108))	('MGMT', 'Gene', '4255', (192, 196))
326124	30976795	Few studies have investigated the role of hTERT promoter region mutations in PSCM.	('hTERT', 'Gene', (42, 47))	('PSCM', 'Phenotype', 'HP:0010302', (77, 81))	('PSCM', 'Disease', (77, 81))	('mutations', 'Var', (64, 73))	('hTERT', 'Gene', '7015', (42, 47))
326125	30976795	The present study investigates the prognostic value of hTERT promoter mutations on overall survival (OS) and time to local recurrence in a large international cohort of PSCM patients, with a subgroup analysis focused on spinal chordoma.	('hTERT', 'Gene', '7015', (55, 60))	('mutations', 'Var', (70, 79))	('overall', 'MPA', (83, 90))	('PSCM', 'Phenotype', 'HP:0010302', (169, 173))	('chordoma', 'Phenotype', 'HP:0010762', (227, 235))	('hTERT', 'Gene', (55, 60))	('patients', 'Species', '9606', (174, 182))	('spinal chordoma', 'Disease', 'MESH:D002817', (220, 235))	('spinal chordoma', 'Disease', (220, 235))
326131	30976795	Chordoma histologic subtypes included classic (notochordal cells with regions of chondroid), chondroid (containing chordoma and chondrosarcoma components), and de-differentiated (loss of the integrase interactor 1 gene, increased mitotic potential).	('Chordoma', 'Gene', (0, 8))	('increased', 'PosReg', (220, 229))	('Chordoma', 'Gene', '121775', (0, 8))	('chondroid', 'Chemical', '-', (81, 90))	('chondroid', 'Disease', (93, 102))	('classic', 'Disease', (38, 45))	('chordoma and chondrosarcoma', 'Disease', 'MESH:D002817', (115, 142))	('de-differentiated', 'CPA', (160, 177))	('Chordoma', 'Phenotype', 'HP:0010762', (0, 8))	('chondroid', 'Chemical', '-', (93, 102))	('chordoma', 'Phenotype', 'HP:0010762', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (128, 142))	('loss', 'Var', (179, 183))
326139	30976795	The large amplicon, 193 base pair fragment of the hTERT promoter region spanning the hotspot mutations on chromosome 5 (C228T and C250T) was amplified using the following primers: hTERT-seq-for 5'- CACCCGTCCTGCCCCTTCACCTT-3' and hTERT-seq-rev 5'- GGCTTCCCACGTGCGCAGCAGGA-3'.	('hTERT', 'Gene', '7015', (180, 185))	('C250T', 'Var', (130, 135))	('C250T', 'Mutation', 'c.250C>T', (130, 135))	('C228T', 'Mutation', 'c.228C>T', (120, 125))	('hTERT', 'Gene', '7015', (229, 234))	('hTERT', 'Gene', (180, 185))	('hTERT', 'Gene', '7015', (50, 55))	('C228T', 'Var', (120, 125))	('hTERT', 'Gene', (229, 234))	('hTERT', 'Gene', (50, 55))
326156	30976795	The hTERT mutations were identified in 8 chordomas, 2 chondrosarcomas, 1 Ewing's sarcoma, and 1 other malignant spinal tumor.	('malignant spinal tumor', 'Disease', 'MESH:D013120', (102, 124))	('chordomas', 'Disease', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('chondrosarcomas', 'Disease', (54, 69))	('spinal tumor', 'Phenotype', 'HP:0010302', (112, 124))	('identified', 'Reg', (25, 35))	('chordoma', 'Phenotype', 'HP:0010762', (41, 49))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (73, 88))	('hTERT', 'Gene', '7015', (4, 9))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (73, 88))	('chordomas', 'Disease', 'MESH:D002817', (41, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('hTERT', 'Gene', (4, 9))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (54, 68))	('malignant spinal tumor', 'Disease', (102, 124))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (54, 69))	("Ewing's sarcoma", 'Disease', (73, 88))	('mutations', 'Var', (10, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('chondrosarcomas', 'Disease', 'MESH:D002813', (54, 69))
326161	30976795	The wildtype and C228T/C250T chordoma cohorts were evenly matched in terms of sex distribution (P = 0.43), age at time of surgery (P = 0.27), ethnicity (P = 0.34), and Enneking appropriateness (P = 1.00).	('C228T', 'Var', (17, 22))	('chordoma', 'Gene', (29, 37))	('C228T', 'SUBSTITUTION', 'None', (17, 22))	('chordoma', 'Gene', '121775', (29, 37))	('chordoma', 'Phenotype', 'HP:0010762', (29, 37))	('C250T', 'Mutation', 'c.250C>T', (23, 28))
326164	30976795	Of the patients in the mutation group, 88% had low-grade tumor compared with 80% in the wildtype group (P = 1.00).	('mutation', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('patients', 'Species', '9606', (7, 15))
326167	30976795	Patients who lacked the hTERT mutations in the overall cohort had a significantly worse OS, with an estimated median OS of 5.1 years (95% CI: 4.5 to 6.6) compared with the 12 patients with hTERT mutations, where death was not observed and median OS was not reached by 10 years postoperative (P = 0.03) (Fig.	('hTERT', 'Gene', (189, 194))	('hTERT', 'Gene', (24, 29))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (175, 183))	('mutations', 'Var', (30, 39))	('hTERT', 'Gene', '7015', (24, 29))	('hTERT', 'Gene', '7015', (189, 194))
326168	30976795	In the chordoma-specific cohort, all 8 patients harboring the mutation were alive at 10 years postoperative compared with 56 (67%) of chordoma patients without the mutation (P = 0.05) (Fig.	('chordoma', 'Gene', '121775', (134, 142))	('chordoma', 'Gene', (7, 15))	('patients', 'Species', '9606', (39, 47))	('chordoma', 'Phenotype', 'HP:0010762', (134, 142))	('chordoma', 'Gene', '121775', (7, 15))	('patients', 'Species', '9606', (143, 151))	('chordoma', 'Phenotype', 'HP:0010762', (7, 15))	('mutation', 'Var', (62, 70))	('chordoma', 'Gene', (134, 142))
326171	30976795	In the subgroup analysis, we report the presence of hTERT promoter mutations in 8.7% of spinal chordomas, which is associated with a statistically significant positive OS benefit (100% vs 67% alive at 10 years) without affecting the time to first tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('spinal chordomas', 'Disease', (88, 104))	('hTERT', 'Gene', '7015', (52, 57))	('tumor', 'Disease', (247, 252))	('spinal chordomas', 'Disease', 'MESH:D002817', (88, 104))	('mutations', 'Var', (67, 76))	('hTERT', 'Gene', (52, 57))	('chordoma', 'Phenotype', 'HP:0010762', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (247, 252))
326180	30976795	To our knowledge, there are no reports that specifically evaluate the role of hTERT promoter mutations in prognosticating survival of PSCM.	('mutations', 'Var', (93, 102))	('PSCM', 'Phenotype', 'HP:0010302', (134, 138))	('hTERT', 'Gene', '7015', (78, 83))	('PSCM', 'Disease', (134, 138))	('hTERT', 'Gene', (78, 83))
326181	30976795	In many human cancers, hTERT promoter mutations are associated with higher hTERT expression.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('human', 'Species', '9606', (8, 13))	('hTERT', 'Gene', '7015', (23, 28))	('higher', 'PosReg', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('hTERT', 'Gene', '7015', (75, 80))	('mutations', 'Var', (38, 47))	('hTERT', 'Gene', (23, 28))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('hTERT', 'Gene', (75, 80))
326182	30976795	The C228T and C250T promoter mutations generate a binding motif for E-twenty-six transcription factors and are found to upregulate the transcriptional activity of hTERT by 2- to 6-fold in human melanomas.	('human', 'Species', '9606', (188, 193))	('hTERT', 'Gene', '7015', (163, 168))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanomas', 'Phenotype', 'HP:0002861', (194, 203))	('C228T', 'Mutation', 'c.228C>T', (4, 9))	('C250T', 'Var', (14, 19))	('melanomas', 'Disease', 'MESH:D008545', (194, 203))	('upregulate', 'PosReg', (120, 130))	('C250T', 'Mutation', 'c.250C>T', (14, 19))	('transcriptional activity', 'MPA', (135, 159))	('hTERT', 'Gene', (163, 168))	('binding', 'Interaction', (50, 57))	('C228T', 'Var', (4, 9))	('melanomas', 'Disease', (194, 203))
326183	30976795	Another study, in 48 GBMs, also reported significantly higher hTERT expression in C228T or C250T mutated tumors.	('tumors', 'Disease', (105, 111))	('C250T', 'Mutation', 'c.250C>T', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('C228T', 'Mutation', 'c.228C>T', (82, 87))	('hTERT', 'Gene', (62, 67))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('C228T', 'Var', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('higher', 'PosReg', (55, 61))	('C250T mutated', 'Var', (91, 104))	('hTERT', 'Gene', '7015', (62, 67))
326184	30976795	Although hTERT promoter mutations are associated with poor prognosis in many human cancers, there are reports in CNS tumors suggesting a survival benefit in patients harboring these mutations.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('hTERT', 'Gene', '7015', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (157, 165))	('benefit', 'PosReg', (146, 153))	('CNS tumors', 'Disease', (113, 123))	('CNS tumors', 'Disease', 'MESH:D009369', (113, 123))	('hTERT', 'Gene', (9, 14))	('mutations', 'Var', (24, 33))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
326186	30976795	Conversely, hTERT mutations were found to be negatively prognostic in MGMT unmethylated GBM patients.	('GBM', 'Phenotype', 'HP:0012174', (88, 91))	('negatively', 'NegReg', (45, 55))	('MGMT', 'Gene', (70, 74))	('MGMT', 'Gene', '4255', (70, 74))	('hTERT', 'Gene', '7015', (12, 17))	('patients', 'Species', '9606', (92, 100))	('hTERT', 'Gene', (12, 17))	('mutations', 'Var', (18, 27))
326187	30976795	In a study by You et al, patients with hTERT mutations exhibited improved prognosis when paired with IDH 1 or 2 (IDH1/2) mutations and 1p/19q loss of heterozygosity.	('mutations', 'Var', (45, 54))	('improved', 'PosReg', (65, 73))	('IDH 1 or 2', 'Gene', (101, 111))	('loss of', 'NegReg', (142, 149))	('hTERT', 'Gene', '7015', (39, 44))	('IDH1/2', 'Gene', (113, 119))	('patients', 'Species', '9606', (25, 33))	('hTERT', 'Gene', (39, 44))	('prognosis', 'MPA', (74, 83))	('IDH 1 or 2', 'Gene', '3417;3418', (101, 111))	('IDH1/2', 'Gene', '3417;3418', (113, 119))
326189	30976795	In gliomas, the prognostic influence of hTERT promoter mutation appears to be dependent on the coexistence of other molecular biomarkers and drivers.	('hTERT', 'Gene', (40, 45))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('hTERT', 'Gene', '7015', (40, 45))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('mutation', 'Var', (55, 63))	('gliomas', 'Disease', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))
326190	30976795	This dual prognostic nature of the hTERT promoter mutation can help explain incongruent results in the literature, which mainly suggest that hTERT mutation is a negative prognostic biomarker.	('hTERT', 'Gene', '7015', (35, 40))	('hTERT', 'Gene', '7015', (141, 146))	('mutation', 'Var', (147, 155))	('hTERT', 'Gene', (141, 146))	('hTERT', 'Gene', (35, 40))	('mutation', 'Var', (50, 58))
326191	30976795	The pro-survival benefit of hTERT mutations observed in our study is also likely related to yet to be determined molecular pathways.	('hTERT', 'Gene', (28, 33))	('pro-survival', 'CPA', (4, 16))	('mutations', 'Var', (34, 43))	('hTERT', 'Gene', '7015', (28, 33))
326192	30976795	A recent study by Tarpey et al defined the somatic molecular drivers of 104 cases of sporadic chordoma and found duplication of the notochordal transcription factor brachyury in 27% of cases.	('brachyury', 'Gene', '6899', (165, 174))	('duplication', 'Var', (113, 124))	('chordoma', 'Gene', (94, 102))	('chordoma', 'Phenotype', 'HP:0010762', (94, 102))	('brachyury', 'Gene', (165, 174))	('chordoma', 'Gene', '121775', (94, 102))
326193	30976795	In addition, phosphatidylinositol-3 kinase signaling mutations and LYST inactivation mutations were implicated as potential novel oncologic markers.	('phosphatidylinositol-3 kinase signaling', 'MPA', (13, 52))	('mutations', 'Var', (53, 62))	('mutations', 'Var', (85, 94))	('LYST', 'Gene', (67, 71))	('LYST', 'Gene', '1130', (67, 71))
326196	30976795	Intrinsic to the rarity of these tumors, the small sample sizes between the wildtype and hTERT mutation cohorts could potentially mask important differences between the groups that may only be detectable with larger sampling.	('hTERT', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mask', 'NegReg', (130, 134))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('hTERT', 'Gene', '7015', (89, 94))	('tumors', 'Disease', (33, 39))	('mutation', 'Var', (95, 103))
326199	30976795	Further studies are needed to fully elucidate the interplay between hTERT promoter mutations, telomerase expression, and other molecular markers.	('mutations', 'Var', (83, 92))	('hTERT', 'Gene', '7015', (68, 73))	('hTERT', 'Gene', (68, 73))
326200	30976795	Nevertheless, this study remains the largest contemporary series of primary spinal column tumors and is the first time the hTERT promoter mutations C228T and C250T have been implicated as a positive prognostic factor for survival in chordoma patients.	('spinal column tumors', 'Phenotype', 'HP:0010302', (76, 96))	('C228T', 'Var', (148, 153))	('hTERT', 'Gene', (123, 128))	('C250T', 'Mutation', 'c.250C>T', (158, 163))	('chordoma', 'Phenotype', 'HP:0010762', (233, 241))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('C250T', 'Var', (158, 163))	('chordoma', 'Gene', '121775', (233, 241))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('spinal column tumors', 'Disease', 'MESH:C536342', (76, 96))	('C228T', 'Mutation', 'c.228C>T', (148, 153))	('hTERT', 'Gene', '7015', (123, 128))	('mutations C228T', 'Var', (138, 153))	('spinal column tumors', 'Disease', (76, 96))	('chordoma', 'Gene', (233, 241))	('patients', 'Species', '9606', (242, 250))
326201	30976795	The presence of hTERT mutations conferred a statistically significant survival benefit and could potentially be a valuable positive prognostic molecular marker in spinal chordomas.	('benefit', 'PosReg', (79, 86))	('hTERT', 'Gene', '7015', (16, 21))	('spinal chordomas', 'Disease', (163, 179))	('mutations', 'Var', (22, 31))	('survival', 'CPA', (70, 78))	('hTERT', 'Gene', (16, 21))	('presence', 'Var', (4, 12))	('chordoma', 'Phenotype', 'HP:0010762', (170, 178))	('spinal chordomas', 'Disease', 'MESH:D002817', (163, 179))
326248	29967940	We would likely see such a score as a suggestion that a case may be in some way related to a certain methylation class and would try to find further evidence of such a relation [e.g., sequencing of BRAF in a case with a methylation class (anaplastic) pleomorphic xanthoastrocytoma (PXA) calibrated score of 0.75].	('related', 'Reg', (80, 87))	('BRAF', 'Gene', '673', (198, 202))	('sequencing', 'Var', (184, 194))	('BRAF', 'Gene', (198, 202))	('astrocytoma', 'Phenotype', 'HP:0009592', (269, 280))	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (251, 280))	('pleomorphic xanthoastrocytoma', 'Disease', (251, 280))
326251	29967940	1a, e) and homozygous deletions (e.g., CDKN2A/B, Figs.	('CDKN2A/B', 'Gene', '1029;1030', (39, 47))	('deletions', 'Var', (22, 31))	('CDKN2A/B', 'Gene', (39, 47))
326257	29967940	5a) and the high-level amplification of C19MC on Chr.19 in embryonal tumors with multilayered rosettes (ETMR; Fig.	('Chr', 'Gene', (49, 52))	('rosettes', 'Phenotype', 'HP:0031925', (94, 102))	('embryonal tumors', 'Phenotype', 'HP:0002898', (59, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Chr', 'Gene', '1125', (49, 52))	('embryonal tumors', 'Disease', (59, 75))	('embryonal tumors', 'Disease', 'MESH:D009373', (59, 75))	('rosette', 'Phenotype', 'HP:0031925', (94, 101))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('embryonal tumor', 'Phenotype', 'HP:0002898', (59, 74))	('MC', 'Chemical', 'MESH:D008748', (43, 45))	('C19MC', 'Var', (40, 45))
326259	29967940	Based on this algorithm which is also underlying the MGMT promoter methylation analysis provided by our webpage for uploaded cases, we receive the readouts "methylated", unmethylated, or "not determinable".	('MGMT', 'Gene', (53, 57))	('unmethylated', 'Var', (170, 182))	('MGMT', 'Gene', '4255', (53, 57))
326276	29967940	Of note, the "A IDH, HG" group also contains most of the IDH mutant glioblastomas.	('IDH', 'Gene', '3417', (57, 60))	('glioblastomas', 'Phenotype', 'HP:0012174', (68, 81))	('IDH', 'Gene', (16, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (68, 81))	('mutant', 'Var', (61, 67))	('IDH', 'Gene', '3417', (16, 19))	('IDH', 'Gene', (57, 60))	('glioblastomas', 'Disease', (68, 81))
326278	29967940	However, recent data provide evidence that grading of IDH mutant astrocytoma by assessing copy-number alterations is more powerful than grading by DNA methylation analysis only.	('astrocytoma', 'Disease', 'MESH:D001254', (65, 76))	('astrocytoma', 'Disease', (65, 76))	('copy-number alterations', 'Var', (90, 113))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('IDH', 'Gene', (54, 57))	('IDH', 'Gene', '3417', (54, 57))
326283	29967940	We have so far analyzed one case of a dual genotype astrocytoma/oligodendroglioma and, indeed, observed a different methylation class of A IDH and O IDH, respectively, in different macrodissected tumor areas and an exclusive 1p/19q codeletion in the oligodendroglial tumor regions.	('methylation', 'MPA', (116, 127))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('astrocytoma/oligodendroglioma', 'Disease', 'MESH:D009837', (52, 81))	('tumor', 'Disease', (196, 201))	('IDH', 'Gene', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('IDH', 'Gene', '3417', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('astrocytoma', 'Phenotype', 'HP:0009592', (52, 63))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('1p/19q', 'Var', (225, 231))	('IDH', 'Gene', (139, 142))	('tumor', 'Disease', (267, 272))	('oligodendroglial tumor', 'Disease', 'MESH:D009369', (250, 272))	('astrocytoma/oligodendroglioma', 'Disease', (52, 81))	('IDH', 'Gene', '3417', (139, 142))	('oligodendroglial tumor', 'Disease', (250, 272))
326286	29967940	Consensus of the critique is the demonstration of mutational profiles in these tumors that closely match those of glioblastoma (or, rarely, a more pediatric-type diffuse glioma).	('glioma', 'Disease', (170, 176))	('tumors', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('mutational', 'Var', (50, 60))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('glioblastoma', 'Disease', (114, 126))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
326298	29967940	In some instances, this may result in a higher score for an astrocytoma despite a 1p/19q codeletion.	('astrocytoma', 'Disease', 'MESH:D001254', (60, 71))	('astrocytoma', 'Phenotype', 'HP:0009592', (60, 71))	('astrocytoma', 'Disease', (60, 71))	('1p/19q codeletion', 'Var', (82, 99))
326304	29967940	In case the CNV shows prototypic glioblastoma changes (in particular amplification of EGFR or other amplifications, combined gain of Chr.7, and loss of Chr.10), we would consider the case a glioblastoma, IDH wt.	('glioblastoma', 'Disease', 'MESH:D005909', (190, 202))	('glioblastoma', 'Disease', (33, 45))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('glioblastoma', 'Phenotype', 'HP:0012174', (190, 202))	('EGFR', 'Gene', '1956', (86, 90))	('gain', 'PosReg', (125, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('Chr', 'Gene', '1125', (152, 155))	('Chr', 'Gene', (152, 155))	('EGFR', 'Gene', (86, 90))	('IDH', 'Gene', (204, 207))	('Chr', 'Gene', (133, 136))	('IDH', 'Gene', '3417', (204, 207))	('Chr', 'Gene', '1125', (133, 136))	('amplification', 'Var', (69, 82))	('loss', 'NegReg', (144, 148))	('glioblastoma', 'Disease', (190, 202))
326325	29967940	In case a BRAF V600 mutation is detected and the CNV shows a focal deletion of CDKN2A/B but no additional complex chromosomal changes we consider the case as PXA (and would grade according to WHO by counting mitotic figures).	('CDKN2A/B', 'Gene', (79, 87))	('deletion', 'Var', (67, 75))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('CDKN2A/B', 'Gene', '1029;1030', (79, 87))
326336	29967940	Duplication of the BRAF locus is frequent among pilocytic astrocytomas and can be observed as a focal low-level gain indicative for a duplication on Chr.7q (Fig.	('pilocytic astrocytomas', 'Disease', (48, 70))	('BRAF', 'Gene', '673', (19, 23))	('Chr', 'Gene', '1125', (149, 152))	('Chr', 'Gene', (149, 152))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (48, 70))	('astrocytoma', 'Phenotype', 'HP:0009592', (58, 69))	('BRAF', 'Gene', (19, 23))	('Duplication', 'Var', (0, 11))	('gain', 'PosReg', (112, 116))	('low-level', 'MPA', (102, 111))
326338	29967940	The copy-number pattern of these tumors occasionally also demonstrates BRAF duplications but much more frequently harbor CDKN2A/B deletions and further chromosomal changes (Fig.	('CDKN2A/B', 'Gene', '1029;1030', (121, 129))	('deletions', 'Var', (130, 139))	('BRAF', 'Gene', '673', (71, 75))	('CDKN2A/B', 'Gene', (121, 129))	('BRAF', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('duplications', 'Var', (76, 88))
326340	29967940	The presence of a BRAF V600E mutation seen in approximately 70% of pleomorphic xanthoastrocytomas is not a requirement for classification of these tumors into this class.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('pleomorphic xanthoastrocytomas', 'Disease', (67, 97))	('tumors', 'Disease', (147, 153))	('V600E', 'Mutation', 'rs113488022', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('V600E', 'Var', (23, 28))	('BRAF', 'Gene', '673', (18, 22))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (67, 97))	('BRAF', 'Gene', (18, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (85, 96))
326341	29967940	An established but usually underestimated feature of pleomorphic xanthoastrocytoma is homozygous deletion of CDKN2A previously reported in 50%.	('pleomorphic xanthoastrocytoma', 'Disease', 'MESH:D008228', (53, 82))	('CDKN2A', 'Gene', (109, 115))	('pleomorphic xanthoastrocytoma', 'Disease', (53, 82))	('CDKN2A', 'Gene', '1029', (109, 115))	('astrocytoma', 'Phenotype', 'HP:0009592', (71, 82))	('deletion', 'Var', (97, 105))
326342	29967940	Among cases falling into this methylation, class CDKN2A/B deletions are seen in around 70% of cases (Fig.	('CDKN2A/B', 'Gene', (49, 57))	('falling', 'Phenotype', 'HP:0002527', (12, 19))	('deletions', 'Var', (58, 67))	('CDKN2A/B', 'Gene', '1029;1030', (49, 57))	('fall', 'Phenotype', 'HP:0002527', (12, 16))
326347	29967940	If the mutation is present and the tumor, additionally, harbors a CDKN2A/B deletion, we would consider the case as a molecular PXA with unusual histological features.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('CDKN2A/B', 'Gene', '1029;1030', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('deletion', 'Var', (75, 83))	('tumor', 'Disease', (35, 40))	('CDKN2A/B', 'Gene', (66, 74))
326350	29967940	In our experience, detection of a BRAF duplication in the form of the typical focal low-level gain on Chr.7q representing a 7q34 tandem duplication (Fig.	('duplication', 'Var', (39, 50))	('gain', 'PosReg', (94, 98))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))	('Chr', 'Gene', '1125', (102, 105))	('Chr', 'Gene', (102, 105))
326357	29967940	If these cases, additionally, harbor a CDKN2A/B deletion and/or immunohistochemical ATRX loss (frequent in "anaplastic astrocytoma with piloid features", likely never present in PA), we would consider the case as "anaplastic astrocytoma with piloid features".	('astrocytoma', 'Phenotype', 'HP:0009592', (119, 130))	('anaplastic astrocytoma', 'Disease', (108, 130))	('ATRX', 'Gene', '546', (84, 88))	('CDKN2A/B', 'Gene', '1029;1030', (39, 47))	('anaplastic astrocytoma', 'Disease', (214, 236))	('CDKN2A/B', 'Gene', (39, 47))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (108, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (225, 236))	('deletion', 'Var', (48, 56))	('ATRX', 'Gene', (84, 88))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (214, 236))	('loss', 'NegReg', (89, 93))
326368	29967940	CNV in "ependymoma, spine" are also frequent, with the dominating alteration being chromosome 22 loss (Fig.	('loss', 'NegReg', (97, 101))	('"ependymoma', 'Disease', (7, 18))	('"ependymoma', 'Disease', 'MESH:D004806', (7, 18))	('chromosome 22', 'Var', (83, 96))	('ependymoma', 'Phenotype', 'HP:0002888', (8, 18))
326379	29967940	The "ependymoma, YAP1 fusion" tumors on average have fewer alterations, with loss close to the YAP1 locus on Chr.11q and loss of Chr.22 being most frequent (Fig.	('YAP1', 'Gene', (95, 99))	('YAP1', 'Gene', (17, 21))	('tumors', 'Disease', (30, 36))	('YAP1', 'Gene', '10413', (17, 21))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('YAP1', 'Gene', '10413', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('"ependymoma', 'Disease', (4, 15))	('loss', 'Var', (121, 125))	('ependymoma', 'Phenotype', 'HP:0002888', (5, 15))	('Chr', 'Gene', (109, 112))	('Chr', 'Gene', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('loss', 'NegReg', (77, 81))	('Chr', 'Gene', '1125', (109, 112))	('Chr', 'Gene', '1125', (129, 132))	('"ependymoma', 'Disease', 'MESH:D004806', (4, 15))
326387	29967940	Along the same lines, all so far analyzed subependymoma/ependymoma composition tumors (n = 4) scored as methylation class subependymoma in both tumor areas and we consider the ependymoma parts as a more compact growth pattern of subependymoma.	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('subependymoma', 'Disease', 'MESH:D018315', (229, 242))	('subependymoma', 'Disease', (229, 242))	('ependymoma', 'Phenotype', 'HP:0002888', (125, 135))	('subependymoma/ependymoma composition tumors', 'Disease', (42, 85))	('ependymoma', 'Phenotype', 'HP:0002888', (45, 55))	('subependymoma/ependymoma composition tumors', 'Disease', 'MESH:D018315', (42, 85))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (79, 84))	('ependymoma parts', 'Disease', 'MESH:D004806', (176, 192))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('ependymoma parts', 'Disease', (176, 192))	('ependymoma', 'Phenotype', 'HP:0002888', (176, 186))	('subependymoma', 'Disease', 'MESH:D018315', (122, 135))	('subependymoma', 'Disease', 'MESH:D018315', (42, 55))	('subependymoma', 'Disease', (122, 135))	('ependymoma', 'Phenotype', 'HP:0002888', (232, 242))	('subependymoma', 'Disease', (42, 55))	('methylation', 'Var', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('ependymoma', 'Phenotype', 'HP:0002888', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
326394	29967940	A more conservative approach might designate these tumors as "ependymoma with methylation profile of myxopapillary ependymoma", although this would neglect the additional and independent data from the copy-number profiles pointing to myxopapillary ependymoma.	('myxopapillary ependymoma', 'Disease', 'MESH:D004806', (234, 258))	('myxopapillary ependymoma', 'Disease', (234, 258))	('methylation', 'Var', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('"ependymoma', 'Disease', 'MESH:D004806', (61, 72))	('ependymoma', 'Phenotype', 'HP:0002888', (115, 125))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('myxopapillary ependymoma', 'Disease', 'MESH:D004806', (101, 125))	('myxopapillary ependymoma', 'Disease', (101, 125))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('ependymoma', 'Phenotype', 'HP:0002888', (248, 258))	('"ependymoma', 'Disease', (61, 72))	('ependymoma', 'Phenotype', 'HP:0002888', (62, 72))
326401	29967940	All cases investigated also harbored the recently published PRKCA hotspot mutation.	('harbored', 'Reg', (28, 36))	('PRKCA', 'Gene', (60, 65))	('PRKCA', 'Gene', '5578', (60, 65))	('mutation', 'Var', (74, 82))
326405	29967940	By methylation analysis, a substantial part of astroblastomas are classified as "CNS high-grade neuroepithelial tumor with MN1 alteration".	('MN1', 'Gene', (123, 126))	('astroblastomas', 'Disease', 'MESH:D018302', (47, 61))	('MN1', 'Gene', '4330', (123, 126))	('neuroepithelial tumor', 'Disease', (96, 117))	('astroblastomas', 'Disease', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('alteration', 'Var', (127, 137))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (96, 117))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (96, 117))
326406	29967940	Likely, the remaining cases are not a single tumor entity but rather harbor genetic alterations that suggest classification as other tumor entities.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('genetic alterations', 'Var', (76, 95))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
326411	29967940	Here, we would be more cautious to downgrade the tumor and would remain with the diagnosis of a "not further classifiable pediatric glioma with alterations of MYB/MYBL1 and additional complex chromosomal changes".	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('MYB', 'Gene', '4602', (163, 166))	('glioma', 'Disease', (132, 138))	('MYBL1', 'Gene', '4603', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('MYB', 'Gene', (159, 162))	('MYB', 'Gene', (163, 166))	('tumor', 'Disease', (49, 54))	('MYB', 'Gene', '4602', (159, 162))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('alterations', 'Var', (144, 155))	('MYBL1', 'Gene', (163, 168))
326439	29967940	CNV profiles show no recurrent chromosomal imbalances (Supplementary file 1), while initial data suggest that BRAF mutations may be relatively common in this group.	('imbalances', 'Phenotype', 'HP:0002172', (43, 53))	('BRAF', 'Gene', (110, 114))	('mutations', 'Var', (115, 124))	('BRAF', 'Gene', '673', (110, 114))
326451	29967940	In particular, familial paraganglioma may carry germline SDH mutations associated with a CpG island methylator phenotype (CIMP).	('familial paraganglioma', 'Disease', (15, 37))	('SDH', 'Gene', (57, 60))	('paraganglioma', 'Phenotype', 'HP:0002668', (24, 37))	('familial paraganglioma', 'Disease', 'MESH:D010235', (15, 37))	('mutations', 'Var', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('CIMP', 'Chemical', '-', (122, 126))	('SDH', 'Gene', '10993', (57, 60))	('associated', 'Reg', (71, 81))
326452	29967940	Paraganglioma without SDH mutations constitute the vast majority of sporadic tumors form the "paraganglioma, spinal non-CIMP" methylation class.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('Paraganglioma', 'Disease', (0, 13))	('sporadic tumors', 'Disease', 'MESH:D009369', (68, 83))	('paraganglioma', 'Disease', 'MESH:D010235', (94, 107))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('Paraganglioma', 'Disease', 'MESH:D010235', (0, 13))	('SDH', 'Gene', '10993', (22, 25))	('mutations', 'Var', (26, 35))	('CIMP', 'Chemical', '-', (120, 124))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('sporadic tumors', 'Disease', (68, 83))	('SDH', 'Gene', (22, 25))	('paraganglioma', 'Disease', (94, 107))
326454	29967940	Repeatedly, we have observed cases with a high score for "low-grade glioma, ganglioglioma" methylation class but without clear histologic evidence for ganglionic differentiation.	('glioma', 'Disease', (83, 89))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('methylation', 'Var', (91, 102))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma', 'Disease', (68, 74))
326462	29967940	We observe cases scored as methylation class "diffuse leptomeningeal glioneuronal tumor" more frequently than anticipated.	('glioneuronal tumor', 'Phenotype', 'HP:0025170', (69, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('methylation', 'Var', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
326475	29967940	Typical CNV in "pineoblastoma group A/intracranial retinoblastoma" are gain of Chr.1q, gain of 6p and loss of 16q (Fig.	('pineoblastoma', 'Disease', 'MESH:D010871', (16, 29))	('intracranial retinoblastoma', 'Disease', (38, 65))	('Chr', 'Gene', '1125', (79, 82))	('gain', 'PosReg', (87, 91))	('pineoblastoma', 'Phenotype', 'HP:0030408', (16, 29))	('intracranial retinoblastoma', 'Disease', 'MESH:D012175', (38, 65))	('pineoblastoma', 'Disease', (16, 29))	('retinoblastoma', 'Phenotype', 'HP:0009919', (51, 65))	('loss', 'Var', (102, 106))	('gain', 'PosReg', (71, 75))	('Chr', 'Gene', (79, 82))
326478	29967940	"Papillary tumor of the pineal region group A" exhibits a high number of CNV with gains of 4, 5, 11, and 12 and loss of Chr.10 being most frequent (Fig.	('Papillary tumor', 'Disease', 'MESH:D002291', (1, 16))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('gains', 'PosReg', (82, 87))	('Papillary tumor', 'Disease', (1, 16))	('loss', 'Var', (112, 116))	('Chr', 'Gene', '1125', (120, 123))	('Chr', 'Gene', (120, 123))
326490	29967940	Tumors in both methylation classes frequently show an isochromosome 17q, approximately 60% in group 3 and 80% in group 4.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('isochromosome 17q', 'Var', (54, 71))
326491	29967940	Group 3 medulloblastoma tend to have a higher number of alterations, most frequently gain of 1q and, 7 and loss of 10q (Fig.	('gain', 'PosReg', (85, 89))	('medulloblastoma', 'Disease', (8, 23))	('loss of 10q', 'Var', (107, 118))	('medulloblastoma', 'Phenotype', 'HP:0002885', (8, 23))	('medulloblastoma', 'Disease', 'MESH:D008527', (8, 23))
326492	29967940	Besides isochromosome 17q, most abundant in group 4 medulloblastomas is gain of 7p and loss of 8 (Fig.	('loss', 'Var', (87, 91))	('medulloblastomas', 'Disease', 'MESH:D008527', (52, 68))	('gain', 'PosReg', (72, 76))	('medulloblastomas', 'Disease', (52, 68))	('medulloblastoma', 'Phenotype', 'HP:0002885', (52, 67))
326494	29967940	Embryonal tumor with multilayered rosettes, C19MC-altered is another genetically defined WHO entity.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('MC', 'Chemical', 'MESH:D008748', (47, 49))	('Embryonal tumor', 'Disease', (0, 15))	('rosette', 'Phenotype', 'HP:0031925', (34, 41))	('Embryonal tumor', 'Disease', 'MESH:D009373', (0, 15))	('Embryonal tumor', 'Phenotype', 'HP:0002898', (0, 15))	('C19MC-altered', 'Var', (44, 57))	('rosettes', 'Phenotype', 'HP:0031925', (34, 42))
326497	29967940	The very few cases that we have so far observed of the exceedingly rare non-19q13 amplified embryonal tumors with multilayered rosettes also fall into this group.	('embryonal tumors', 'Disease', 'MESH:D009373', (92, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('rosettes', 'Phenotype', 'HP:0031925', (127, 135))	('embryonal tumor', 'Phenotype', 'HP:0002898', (92, 107))	('non-19q13 amplified', 'Var', (72, 91))	('fall', 'Phenotype', 'HP:0002527', (141, 145))	('embryonal tumors', 'Phenotype', 'HP:0002898', (92, 108))	('embryonal tumors', 'Disease', (92, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('rosette', 'Phenotype', 'HP:0031925', (127, 134))
326504	29967940	Besides "CNS neuroblastoma with FOXR2 activation" the three classes of "CNS high-grade neuroepithelial tumor with BCOR alteration", "CNS Ewing sarcoma family tumor with CIC alteration", and the previously mentioned "CNS high-grade neuroepithelial tumor with MN1 alteration" may frequently present with primitive embryonal histology.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (87, 108))	('MN1', 'Gene', (258, 261))	('BCOR', 'Gene', '54880', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('BCOR', 'Gene', (114, 118))	('FOXR2', 'Gene', (32, 37))	('MN1', 'Gene', '4330', (258, 261))	('FOXR2', 'Gene', '139628', (32, 37))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (231, 252))	('neuroblastoma', 'Disease', (13, 26))	('neuroepithelial tumor', 'Disease', (231, 252))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (87, 108))	('Ewing sarcoma family tumor', 'Disease', 'MESH:C563168', (137, 163))	('neuroblastoma', 'Phenotype', 'HP:0003006', (13, 26))	('alteration', 'Var', (119, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (231, 252))	('neuroepithelial tumor', 'Disease', (87, 108))	('neuroblastoma', 'Disease', 'MESH:D009447', (13, 26))	('Ewing sarcoma family tumor', 'Disease', (137, 163))
326505	29967940	CNV profiles of "CNS Ewing sarcoma family tumor with CIC alteration" and "CNS high-grade neuroepithelial tumor with BCOR alteration" exhibit no characteristic features, whereas "CNS high-grade neuroepithelial tumor with MN1 alteration" very frequently shows extensive alterations on Chr.X reminiscent of chromothripsis (Chr.X not shown in the summary CNV plots).	('MN1', 'Gene', '4330', (220, 223))	('Chr', 'Gene', '1125', (283, 286))	('Ewing sarcoma family tumor', 'Disease', 'MESH:C563168', (21, 47))	('alterations', 'Reg', (268, 279))	('Chr', 'Gene', '1125', (320, 323))	('Ewing sarcoma family tumor', 'Disease', (21, 47))	('alteration', 'Var', (57, 67))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (193, 214))	('Chr', 'Gene', (283, 286))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (89, 110))	('BCOR', 'Gene', '54880', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))	('Chr', 'Gene', (320, 323))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('MN1', 'Gene', (220, 223))	('neuroepithelial tumor', 'Disease', (193, 214))	('neuroepithelial tumor', 'Disease', (89, 110))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (193, 214))	('BCOR', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (89, 110))
326513	29967940	A constellation that may lower the score of an SHH medulloblastoma below the threshold of 0.9 is the rare case of an IDH1 R132 mutant SHH medulloblastomas (score expected in the range of ~ 0.4 to 0.7), so testing for IDH point mutation may be of help in some instances.	('SHH medulloblastoma', 'Disease', 'MESH:D008527', (47, 66))	('SHH medulloblastomas', 'Disease', 'MESH:D008527', (134, 154))	('IDH1', 'Gene', '3417', (117, 121))	('IDH', 'Gene', (217, 220))	('IDH', 'Gene', (117, 120))	('lower', 'NegReg', (25, 30))	('SHH medulloblastoma', 'Disease', (47, 66))	('score', 'MPA', (35, 40))	('R132 mutant', 'Var', (122, 133))	('IDH', 'Gene', '3417', (217, 220))	('IDH', 'Gene', '3417', (117, 120))	('medulloblastoma', 'Phenotype', 'HP:0002885', (51, 66))	('medulloblastoma', 'Phenotype', 'HP:0002885', (138, 153))	('SHH medulloblastoma', 'Disease', 'MESH:D008527', (134, 153))	('SHH medulloblastomas', 'Disease', (134, 154))	('IDH1', 'Gene', (117, 121))
326529	29967940	Such tumors may likely represent not yet defined tumor entities, as proposed for one rare tumor class with recurrent amplification of Chr.6q24.2.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('Chr', 'Gene', '1125', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (117, 130))	('Chr', 'Gene', (134, 137))
326533	29967940	The most frequent CNV in "schwannoma" is loss of 22q seen in approximately 60% of tumors (Fig.	('schwannoma', 'Disease', 'MESH:D009442', (26, 36))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('loss of 22q', 'Var', (41, 52))	('schwannoma', 'Phenotype', 'HP:0100008', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('schwannoma', 'Disease', (26, 36))
326541	29967940	These epigenetic sub-groups, their mutational characteristics, CNV, and the association with histology and outcome have been previously reported: Cases of MC ben-1 have typically no aberrations besides 22q deletion and NF2 mutation.	('MC ben-1', 'Gene', (155, 163))	('NF2', 'Gene', (219, 222))	('22q deletion', 'Var', (202, 214))	('MC', 'Chemical', 'MESH:D008748', (155, 157))	('NF2', 'Gene', '4771', (219, 222))
326542	29967940	MC ben-2 is characterized by flat CNPs and an enrichment for KLF4/TRAF7, AKT1/TRAF7, and SMO mutations.	('KLF4', 'Gene', '9314', (61, 65))	('mutations', 'Var', (93, 102))	('KLF4', 'Gene', (61, 65))	('AKT1', 'Gene', '207', (73, 77))	('MC', 'Chemical', 'MESH:D008748', (0, 2))	('TRAF7', 'Gene', (78, 83))	('TRAF7', 'Gene', '84231', (66, 71))	('AKT1', 'Gene', (73, 77))	('SMO', 'Gene', '6608', (89, 92))	('SMO', 'Gene', (89, 92))	('TRAF7', 'Gene', '84231', (78, 83))	('TRAF7', 'Gene', (66, 71))
326544	29967940	If needed, detection of the exact AKT1 or SMO mutation holds potential for targeted therapy in case of a biologically low grade but not resectable meningioma.	('AKT1', 'Gene', '207', (34, 38))	('SMO', 'Gene', '6608', (42, 45))	('SMO', 'Gene', (42, 45))	('AKT1', 'Gene', (34, 38))	('meningioma', 'Disease', (147, 157))	('meningioma', 'Phenotype', 'HP:0002858', (147, 157))	('mutation', 'Var', (46, 54))	('meningioma', 'Disease', 'MESH:D008577', (147, 157))
326545	29967940	MC ben-3 is the only sub-group harboring many gains of chromosomes, with or without 22q loss and NF2 mutation.	('gains', 'PosReg', (46, 51))	('22q', 'Gene', (84, 87))	('MC', 'Chemical', 'MESH:D008748', (0, 2))	('NF2', 'Gene', '4771', (97, 100))	('NF2', 'Gene', (97, 100))	('mutation', 'Var', (101, 109))
326547	29967940	The intermediate and malignant MCs mostly have 22q deletion and NF2 mutations, with the number of losses of whole chromosomes (10, 14) or chromosomal arms (1p) increasing with malignancy.	('malignancy', 'Disease', 'MESH:D009369', (176, 186))	('22q deletion', 'Var', (47, 59))	('NF2', 'Gene', '4771', (64, 67))	('MC', 'Chemical', 'MESH:D008748', (31, 33))	('malignancy', 'Disease', (176, 186))	('mutations', 'Var', (68, 77))	('NF2', 'Gene', (64, 67))
326548	29967940	These groups, particularly MC mal, can also carry TERT promoter mutations and show CDKN2A deletion.	('deletion', 'Var', (90, 98))	('CDKN2A', 'Gene', '1029', (83, 89))	('TERT', 'Gene', '7015', (50, 54))	('MC', 'Chemical', 'MESH:D008748', (27, 29))	('TERT', 'Gene', (50, 54))	('CDKN2A', 'Gene', (83, 89))
326549	29967940	For example, cases with BAP1 mutations can have no or only focal chromosomal alterations but still be identified as MC mal, in line with their aggressive behavior.	('BAP1', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('aggressive behavior', 'Phenotype', 'HP:0000718', (143, 162))	('MC', 'Chemical', 'MESH:D008748', (116, 118))	('BAP1', 'Gene', '8314', (24, 28))
326568	29967940	The corresponding CNV profiles are inconspicuous (Supplementary file 1), but these tumors are characterized by either CTNNB1 or BRAF V600E mutations, respectively.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BRAF', 'Gene', '673', (128, 132))	('CTNNB1', 'Gene', '1499', (118, 124))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('V600E', 'Var', (133, 138))	('CTNNB1', 'Gene', (118, 124))	('BRAF', 'Gene', (128, 132))
326574	29967940	Interestingly, in a recent series of 66 institutionally diagnosed olfactory neuroblastomas/esthesioneuroblastomas, only 42 (64%) of cases were classified as DNA methylation esthesioneuroblastoma, subclass A or B.	('neuroblastoma', 'Phenotype', 'HP:0003006', (181, 194))	('neuroblastoma', 'Disease', (76, 89))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('olfactory neuroblastomas/esthesioneuroblastomas', 'Disease', 'MESH:D018304', (66, 113))	('olfactory neuroblastomas/esthesioneuroblastomas', 'Disease', (66, 113))	('neuroblastoma', 'Disease', 'MESH:D009447', (99, 112))	('neuroblastoma', 'Disease', 'MESH:D009447', (181, 194))	('neuroblastoma', 'Disease', (99, 112))	('DNA methylation', 'Var', (157, 172))	('neuroblastoma', 'Disease', (181, 194))	('neuroblastoma', 'Phenotype', 'HP:0003006', (99, 112))	('neuroblastoma', 'Disease', 'MESH:D009447', (76, 89))
326625	29967940	However, we fully agree that an adamantinous craniopharyngioma with a CTNBB1 mutation is not in need of additional DNA methylation analysis.	('CTNBB1', 'Gene', (70, 76))	('craniopharyngioma', 'Phenotype', 'HP:0030062', (45, 62))	('adamantinous craniopharyngioma', 'Disease', 'MESH:D003397', (32, 62))	('mutation', 'Var', (77, 85))	('adamantinous craniopharyngioma', 'Disease', (32, 62))
326629	29967940	The latter group frequently turns out to be oligodendroglioma with evident 1p/19q codeletion.	('1p/19q codeletion', 'Var', (75, 92))	('oligodendroglioma', 'Disease', 'MESH:D009837', (44, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('oligodendroglioma', 'Disease', (44, 61))
326634	29967940	Amplifications such as EGFR or MDM2 and homozygous deletions of CDKN2A are even more robust when present in the tumor.	('CDKN2A', 'Gene', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CDKN2A', 'Gene', '1029', (64, 70))	('EGFR', 'Gene', '1956', (23, 27))	('deletions', 'Var', (51, 60))	('tumor', 'Disease', (112, 117))	('MDM2', 'Gene', '4193', (31, 35))	('EGFR', 'Gene', (23, 27))	('MDM2', 'Gene', (31, 35))
326635	29967940	Importantly, we find such tumors to carry multiple chromosomal losses or gains.	('gains', 'PosReg', (73, 78))	('tumors', 'Disease', (26, 32))	('chromosomal losses', 'Var', (51, 69))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
326678	29688859	Meanwhile, the Prkdcscid mutation results in the dysfunction of the PRKDC gene, which encodes a protein responsible for DNA repair in all tissues, including T and B lymphocytes.	('PRKDC', 'Gene', (68, 73))	('mutation', 'Var', (25, 33))	('dysfunction', 'MPA', (49, 60))	('results in', 'Reg', (34, 44))	('scid', 'Gene', (20, 24))	('PRKDC', 'Gene', '5591', (68, 73))	('scid', 'Gene', '19090', (20, 24))
326679	29688859	Thus, it can be inferred that an enhanced therapeutic effect would be achieved when using PDXs established in mice with a Prkdcscid mutational background to test agents that inhibit DNA damage repair (DDR) or DNA-damaging drugs.	('mutational', 'Var', (132, 142))	('inhibit', 'NegReg', (174, 181))	('mice', 'Species', '10090', (110, 114))	('scid', 'Gene', (127, 131))	('scid', 'Gene', '19090', (127, 131))	('DNA damage', 'MPA', (182, 192))	('enhanced', 'PosReg', (33, 41))
326724	29688859	Since alterations in tumor epigenomics and the following gene expression changes greatly influence the initiation and progression of various human malignancies, Guilhamon et al.	('alterations', 'Var', (6, 17))	('tumor', 'Disease', (21, 26))	('influence', 'Reg', (89, 98))	('malignancies', 'Disease', (147, 159))	('initiation', 'CPA', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('human', 'Species', '9606', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('progression', 'CPA', (118, 129))	('changes', 'Var', (73, 80))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))
326725	29688859	performed methylome analysis of two osteosarcoma PDX models and discovered an average of 2.0% (n = 9351) of CpG sites displaying major methylation shifts between the primary PDX models and their parental tumors.	('CpG', 'Gene', (108, 111))	('parental tumors', 'Disease', 'MESH:D063129', (195, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sites', 'Var', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('methylation', 'MPA', (135, 146))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('osteosarcoma', 'Phenotype', 'HP:0002669', (36, 48))	('osteosarcoma', 'Disease', (36, 48))	('osteosarcoma', 'Disease', 'MESH:D012516', (36, 48))	('shifts', 'Reg', (147, 153))	('parental tumors', 'Disease', (195, 210))
326741	29688859	A class of new treatments, for example, inhibitors of serine-threonine kinase GSK3beta or ATR, tyrosine kinase, and EZH2, were also validated in PDX models of soft tissue sarcomas.	('EZH2', 'Gene', (116, 120))	('EZH2', 'Gene', '2146', (116, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (159, 179))	('inhibitors', 'Var', (40, 50))	('soft tissue sarcomas', 'Disease', (159, 179))	('GSK3beta', 'Gene', '2932', (78, 86))	('GSK3beta', 'Gene', (78, 86))	('ATR', 'Gene', '545', (90, 93))	('ATR', 'Gene', (90, 93))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (159, 179))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (159, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))
326773	29688859	Since tumor cells per se cannot recapitulate growth and formation of primary or metastatic lesions and because the initiation and progression of malignant tumors are supported by their microenvironment, the loss of stroma of human origin could lead to alterations in the genetic and biological properties of the tumor, thus undermining the practical value of PDXs for preclinical drug testing, as well as hindering the development of novel antitumor agents targeting stromal components.	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (444, 449))	('tumor', 'Disease', (312, 317))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('undermining', 'NegReg', (324, 335))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('malignant tumors', 'Disease', 'MESH:D018198', (145, 161))	('lead to alterations', 'Reg', (244, 263))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumor', 'Disease', (444, 449))	('malignant tumors', 'Disease', (145, 161))	('tumor', 'Disease', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (444, 449))	('loss', 'Var', (207, 211))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('human', 'Species', '9606', (225, 230))
326900	25880666	Therapeutic properties of a vector carrying the HSV thymidine kinase and GM-CSF genes and delivered as a complex with a cationic copolymer Gene-directed enzyme prodrug therapy (GDEPT) represents a technology to improve drug selectivity for cancer cells.	('GM-CSF', 'Gene', '12981', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('genes', 'Var', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('GDEPT', 'Chemical', '-', (177, 182))	('cancer', 'Disease', (240, 246))	('GM-CSF', 'Gene', (73, 79))	('HSV', 'Gene', (48, 51))
326917	25880666	However, suicide gene therapy hits its targets from within the cancer cell and is therefore expected to be less toxic to normal cells than classic chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('suicide gene therapy', 'Var', (9, 29))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
326938	25880666	To explain the successful antitumor role of GM-CSF in combination with suicide genes, it was suggested that when tumor cells are destroyed and release tumor-specific antigens, GM-CSF in the tumor microenvironment increases antigen uptake and presentation by antigen presenting cells.	('tumor', 'Disease', (113, 118))	('increases', 'PosReg', (213, 222))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('antigen uptake', 'MPA', (223, 237))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('presentation', 'MPA', (242, 254))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('GM-CSF', 'Var', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
327003	25880666	The reference tumor volume varied for different tumors from 500 mm3 for S37 (TGD500) to 1000 mm3 for CSC5 (TGD1000) and 1500 mm3 for C26 (TGD1500).	('TGD', 'Disease', (138, 141))	('TGD', 'Disease', 'MESH:D013631', (107, 110))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', (48, 53))	('TGD', 'Disease', (107, 110))	('TGD', 'Disease', 'MESH:D013631', (77, 80))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('TGD', 'Disease', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('TGD', 'Disease', 'MESH:D013631', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('S37', 'Var', (72, 75))
327011	25880666	Simultaneous expression of two genes under the control of one promoter was enabled by the insertion of the internal ribosome entry site (IRES) between the genes.	('insertion', 'Var', (90, 99))	('expression', 'Species', '29278', (13, 23))	('enabled', 'PosReg', (75, 82))
327032	25880666	The tumor growth in the group of animals inoculated with the TKmGM/PBS combination was markedly slower than that in the TK/PBS group or control groups, and the difference was statistically significant (p < 0.05).	('tumor', 'Disease', (4, 9))	('PBS', 'Chemical', '-', (67, 70))	('TKmGM', 'Chemical', '-', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('PBS', 'Chemical', '-', (123, 126))	('slower', 'NegReg', (96, 102))	('TKmGM/PBS', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
327033	25880666	Since the animals inoculated with TKmGM/PBS or TK/PBS received phosphate buffered saline (PBS) instead of GCV, the suppression of tumor growth in the TKmGM/PBS group was most probably due to the presence of the GM-CSF gene.	('PBS', 'Chemical', '-', (90, 93))	('PBS', 'Chemical', '-', (156, 159))	('TKmGM', 'Chemical', '-', (150, 155))	('PBS', 'Chemical', '-', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('PBS', 'Chemical', '-', (40, 43))	('suppression', 'NegReg', (115, 126))	('TKmGM', 'Chemical', '-', (34, 39))	('phosphate buffered saline', 'Chemical', '-', (63, 88))	('TKmGM/PBS', 'Var', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('GCV', 'Chemical', 'MESH:D015774', (106, 109))	('tumor', 'Disease', (130, 135))
327034	25880666	On day 18 of the experiment, the mean tumor volume in the K/GCV control group exceeded that in the K/PBS control group, however, the difference was not statistically significant (p = 0.262).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('PBS', 'Chemical', '-', (101, 104))	('K/GCV', 'Var', (58, 63))	('GCV', 'Chemical', 'MESH:D015774', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
327039	25880666	This experiment was repeated in triplicate, and in all cases the survival rate in the TKmGM/GCV group was higher than that in the TK/GCV group.	('survival rate', 'CPA', (65, 78))	('GCV', 'Chemical', 'MESH:D015774', (133, 136))	('GCV', 'Chemical', 'MESH:D015774', (92, 95))	('higher', 'PosReg', (106, 112))	('TKmGM/GCV', 'Var', (86, 95))	('TKmGM', 'Chemical', '-', (86, 91))
327045	25880666	The most efficient therapeutic scheme for TKmGM-RRT/GCV was found to be triple intratumoral injection of TKmGM-RRT at a unit dose of 0.04 mug DNA per 1 mm3 tumor volume with 5-day intervals (Table 1A) at the background of GCV injection for 15 days.	('GCV', 'Chemical', 'MESH:D015774', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TKmGM', 'Chemical', '-', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('GCV', 'Chemical', 'MESH:D015774', (222, 225))	('TKmGM', 'Chemical', '-', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (156, 161))	('TKmGM-RRT', 'Var', (105, 114))
327049	25880666	As seen from Table 1 and Figure 3, intratumoral injections of the TK/GCV or TKmGM/GCV polyplexes had a biologically significant antitumor effect.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('polyplexes', 'Var', (86, 96))	('GCV', 'Chemical', 'MESH:D015774', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('GCV', 'Chemical', 'MESH:D015774', (69, 72))	('TKmGM', 'Chemical', '-', (76, 81))
327050	25880666	On day 30, the extension of animal lifespan in mice treated with TKmGM/GCV and TK/GCV was as high as 70 and 62%, respectively.	('GCV', 'Chemical', 'MESH:D015774', (71, 74))	('TK/GCV', 'Var', (79, 85))	('TKmGM', 'Chemical', '-', (65, 70))	('GCV', 'Chemical', 'MESH:D015774', (82, 85))	('TKmGM/GCV', 'Var', (65, 74))	('animal lifespan', 'CPA', (28, 43))	('mice', 'Species', '10090', (47, 51))
327051	25880666	The tumor growth delay (TGD500) for the combination TKmGM/GCV was 14.1 days, and for the combination TK/GCV - 11.6 days.	('TGD', 'Disease', (24, 27))	('tumor growth delay', 'Disease', 'MESH:D006130', (4, 22))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('growth delay', 'Phenotype', 'HP:0001510', (10, 22))	('GCV', 'Chemical', 'MESH:D015774', (58, 61))	('tumor growth delay', 'Disease', (4, 22))	('TKmGM/GCV', 'Var', (52, 61))	('TKmGM', 'Chemical', '-', (52, 57))	('TGD', 'Disease', 'MESH:D013631', (24, 27))	('GCV', 'Chemical', 'MESH:D015774', (104, 107))
327077	25880666	The data obtained showed (Table 2, Figure 5) that treatment with TKmGM-PPT plus GCV had a biologically significant antitumor effect in animals with C26 tumors.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('GCV', 'Chemical', 'MESH:D015774', (80, 83))	('C26 tumors', 'Disease', (148, 158))	('TKmGM-PPT', 'Var', (65, 74))	('tumor', 'Disease', (152, 157))	('C26 tumors', 'Disease', 'MESH:D009369', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('TKmGM-PPT', 'Chemical', '-', (65, 74))
327082	25880666	Thus, treatment of sarcoma 37-bearing mice with TKmGM-PPT/GCV according to the scheme used is effective with respect to both the primary tumor focus (TGD 14.1 days) and metastasis (MI 82%, at the criterion of 35%, FLM 33%) (Table 1, Figure 3).	('TKmGM-PPT', 'Chemical', '-', (48, 57))	('mice', 'Species', '10090', (38, 42))	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('FLM', 'Chemical', '-', (214, 217))	('metastasis', 'CPA', (169, 179))	('TGD', 'Disease', 'MESH:D013631', (150, 153))	('TGD', 'Disease', (150, 153))	('TKmGM-PPT/GCV', 'Var', (48, 61))	('sarcoma', 'Disease', (19, 26))	('GCV', 'Chemical', 'MESH:D015774', (58, 61))	('primary tumor', 'Disease', (129, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('primary tumor', 'Disease', 'MESH:D009369', (129, 142))
327084	25880666	We have also shown that TKmGM-PPT/GCV is efficient for treatment of transplantable tumors C26 and almost ineffective for CSC5.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TKmGM-PPT/GCV', 'Var', (24, 37))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('C26', 'Disease', (90, 93))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('GCV', 'Chemical', 'MESH:D015774', (34, 37))	('TKmGM-PPT', 'Chemical', '-', (24, 33))
327085	25880666	Thus, the efficacy of TKmGM depends on the histological form of the tumor and declines in the row S37 > C26 > CSC5.	('tumor', 'Disease', (68, 73))	('TKmGM', 'Chemical', '-', (22, 27))	('S37 > C26', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('declines', 'NegReg', (78, 86))
327135	25880666	In particular, the treatment of animals with the TKmGM-PPT system was, in most cases, able to inhibit the growth of tumor and metastases and increase lifespan.	('TKmGM-PPT', 'Chemical', '-', (49, 58))	('increase', 'PosReg', (141, 149))	('metastases', 'Disease', 'MESH:D009362', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('metastases', 'Disease', (126, 136))	('lifespan', 'CPA', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TKmGM-PPT', 'Var', (49, 58))	('tumor', 'Disease', (116, 121))	('inhibit', 'NegReg', (94, 101))
327140	22742646	Ewing's Sarcoma: Overcoming the Therapeutic Plateau The hallmark of Ewing's sarcoma (EWS) is a translocation -- t(11;22)(q24;q12) -- that most frequently results in the EWS/FLI1 aberrant chimeric gene.	('EWS', 'Phenotype', 'HP:0012254', (169, 172))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (68, 83))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 129))	('EWS', 'Gene', '2130', (169, 172))	('EWS', 'Gene', (169, 172))	('Sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('EWS', 'Phenotype', 'HP:0012254', (85, 88))	('t(11', 'Var', (112, 116))	('results in', 'Reg', (154, 164))	('sarcoma', 'Disease', (76, 83))	('FLI1', 'Gene', (173, 177))	('EWS', 'Gene', '2130', (85, 88))	('aberrant chimeric gene', 'Var', (178, 200))	('EWS', 'Gene', (85, 88))	('FLI1', 'Gene', '2313', (173, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))
327144	22742646	Specifically, inhibition of insulin-like growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin (mTOR) pathways has emerged as a targeted therapy in EWS, with select patients experiencing dramatic therapeutic responses.	('insulin-like growth factor 1 receptor', 'Gene', '3480', (28, 65))	('mammalian target of rapamycin', 'Gene', '2475', (92, 121))	('mammalian target of rapamycin', 'Gene', (92, 121))	('IGF1R', 'Gene', (67, 72))	('patients', 'Species', '9606', (192, 200))	('insulin-like growth factor 1 receptor', 'Gene', (28, 65))	('IGF1R', 'Gene', '3480', (67, 72))	('mTOR', 'Gene', '2475', (123, 127))	('EWS', 'Phenotype', 'HP:0012254', (175, 178))	('EWS', 'Gene', '2130', (175, 178))	('EWS', 'Gene', (175, 178))	('mTOR', 'Gene', (123, 127))	('inhibition', 'Var', (14, 24))
327152	22742646	Ewing's sarcoma is a translocation-positive sarcoma subtype with the pathognomonic hallmark being fusion of EWS(22q12) and FLI(11q24).	('FLI', 'Gene', '2314', (123, 126))	('EWS', 'Gene', '2130', (108, 111))	('EWS', 'Gene', (108, 111))	('fusion', 'Var', (98, 104))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('EWS', 'Phenotype', 'HP:0012254', (108, 111))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('FLI', 'Gene', (123, 126))	('sarcoma', 'Disease', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('sarcoma', 'Disease', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))
327161	22742646	Recently, inhibitors of the insulin-like growth factor 1 receptor (IGF1R) have ignited considerable excitement in early phase clinical trials.	('insulin-like growth factor 1 receptor', 'Gene', '3480', (28, 65))	('IGF1R', 'Gene', (67, 72))	('IGF1R', 'Gene', '3480', (67, 72))	('insulin-like growth factor 1 receptor', 'Gene', (28, 65))	('inhibitors', 'Var', (10, 20))
327168	22742646	Historically described distinct entities such as extraskeletal Ewing's sarcoma, Askin's tumor, and primitive neuroectodermal tumors (PNET) are each characterized by the pathognomic EWS/FLI1 translocation, identified either by reverse transcription polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH), and all of them belong to the Ewing's sarcoma family of tumors.	('FLI1', 'Gene', '2313', (185, 189))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (359, 374))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (385, 391))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('EWS', 'Gene', '2130', (181, 184))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (109, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	("Askin's tumor", 'Disease', 'MESH:C563168', (80, 93))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (109, 131))	('PNET', 'Phenotype', 'HP:0030065', (133, 137))	('neuroectodermal tumors', 'Disease', (109, 131))	("Askin's tumor", 'Disease', (80, 93))	('tumors', 'Phenotype', 'HP:0002664', (385, 391))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (63, 78))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('sarcoma', 'Disease', 'MESH:D012509', (367, 374))	('sarcoma', 'Disease', (367, 374))	('EWS', 'Gene', (181, 184))	('FLI1', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('tumors', 'Disease', (385, 391))	('sarcoma', 'Disease', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('translocation', 'Var', (190, 203))	('EWS', 'Phenotype', 'HP:0012254', (181, 184))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (99, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (367, 374))
327169	22742646	Histologically, tumor cells harboring the EWS/FLI1 fusion transcript are small, round and blue.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('FLI1', 'Gene', (46, 50))	('fusion', 'Var', (51, 57))	('FLI1', 'Gene', '2313', (46, 50))	('tumor', 'Disease', (16, 21))	('EWS', 'Phenotype', 'HP:0012254', (42, 45))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
327172	22742646	The second most common translocation seen is the fusion of EWS/ERG transcript (around 5-15%).	('EWS', 'Gene', (59, 62))	('ERG', 'Gene', '2078', (63, 66))	('ERG', 'Gene', (63, 66))	('fusion', 'Var', (49, 55))	('EWS', 'Phenotype', 'HP:0012254', (59, 62))	('EWS', 'Gene', '2130', (59, 62))
327180	22742646	In addition to these functions, the EWS/FLI1 fusion transcript interacts with key signaling pathways, including the IGF1/IGF1R-mediated autocrine loop, MAPK signaling and STAT 3 signaling pathways.	('IGF1R', 'Gene', '3480', (121, 126))	('STAT 3', 'Gene', '6774', (171, 177))	('IGF1', 'Gene', (116, 120))	('IGF1', 'Gene', '3479', (121, 125))	('EWS', 'Gene', '2130', (36, 39))	('EWS', 'Gene', (36, 39))	('fusion', 'Var', (45, 51))	('EWS', 'Phenotype', 'HP:0012254', (36, 39))	('FLI1', 'Gene', (40, 44))	('STAT 3', 'Gene', (171, 177))	('MAPK', 'Gene', (152, 156))	('FLI1', 'Gene', '2313', (40, 44))	('MAPK', 'Gene', '5595;5594;5595', (152, 156))	('IGF1', 'Gene', '3479', (116, 120))	('IGF1R', 'Gene', (121, 126))	('interacts', 'Reg', (63, 72))	('IGF1', 'Gene', (121, 125))
327189	22742646	Recently, several studies showed the activity of single-agent IGF1R inhibitors in patients with Ewing's sarcoma.	('IGF1R', 'Gene', '3480', (62, 67))	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('patients', 'Species', '9606', (82, 90))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (96, 111))	('inhibitors', 'Var', (68, 78))	('activity', 'MPA', (37, 45))	('IGF1R', 'Gene', (62, 67))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))
327192	22742646	Because of the limited response rate to single-agent IGF1R inhibitors, their development has stalled.	('IGF1R', 'Gene', (53, 58))	('inhibitors', 'Var', (59, 69))	('IGF1R', 'Gene', '3480', (53, 58))
327195	22742646	The key to deciphering these questions is to use next-generation deep sequencing to profile responders versus non-responders, and to perform a trial that incorporates IGF1R inhibitors early in the course of the disease.	('IGF1R', 'Gene', (167, 172))	('inhibitors', 'Var', (173, 183))	('IGF1R', 'Gene', '3480', (167, 172))
327201	22742646	Briefly, we performed histopathological analysis and applied immunohistochemical probes for p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr705) in initial and resistant tumor specimens.	('Tyr204', 'Chemical', '-', (143, 149))	('STAT3', 'Gene', (166, 171))	('mTOR', 'Gene', '2475', (94, 98))	('Akt', 'Gene', '207', (112, 115))	('Tyr705', 'Chemical', '-', (173, 179))	('STAT3', 'Gene', '6774', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('ERK1/2', 'Gene', (128, 134))	('ERK1/2', 'Gene', '5595;5594', (128, 134))	('Ser2448', 'Chemical', '-', (100, 107))	('Ser2448', 'Var', (100, 107))	('Thr202/Tyr204', 'Var', (136, 149))	('Ser473', 'Var', (117, 123))	('Ser473', 'Chemical', '-', (117, 123))	('Thr202', 'Chemical', '-', (136, 142))	('mTOR', 'Gene', (94, 98))	('tumor', 'Disease', (206, 211))	('Akt', 'Gene', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
327202	22742646	After relapsing following multiple lines of therapy, including three different phase I studies, patient #1 with advanced Ewing's sarcoma had a dramatic response to an IGF1R antibody [(R1507) (NCT00400361)], which continued for 35 months on a phase I study (Figure 1).	('IGF1R', 'Gene', (167, 172))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (121, 136))	('[(R1507) (NCT00400361)]', 'Var', (182, 205))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('patient', 'Species', '9606', (96, 103))	('IGF1R', 'Gene', '3480', (167, 172))	('sarcoma', 'Disease', (129, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
327217	22742646	In spite of the fact that refractory Ewing's sarcoma is fatal, multiple IGF1R inhibitors in phase I and II studies have shown clinical benefit.	('sarcoma', 'Disease', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('inhibitors', 'Var', (78, 88))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('IGF1R', 'Gene', (72, 77))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (37, 52))	('IGF1R', 'Gene', '3480', (72, 77))
327220	22742646	IGF1R inhibitors are particularly attractive for these patients because of their benign side effects.	('patients', 'Species', '9606', (55, 63))	('IGF1R', 'Gene', '3480', (0, 5))	('inhibitors', 'Var', (6, 16))	('IGF1R', 'Gene', (0, 5))
327275	22742646	Given that IGF1R-based signaling occurs through the P13K/AKT pathway, agents targeting it may perhaps be plausible additions in treating Ewing's sarcoma.	('IGF1R', 'Gene', '3480', (11, 16))	('sarcoma', 'Disease', (145, 152))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (137, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('P13K', 'Var', (52, 56))	('IGF1R', 'Gene', (11, 16))	('P13K', 'SUBSTITUTION', 'None', (52, 56))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))
327278	22742646	Specifically, olaparib (AZD2281) had potent activity in cell lines harboring an EWS/FLI1 translocation (Figure 2).	('translocation', 'Var', (89, 102))	('AZD2281', 'Chemical', 'MESH:C531550', (24, 31))	('EWS', 'Phenotype', 'HP:0012254', (80, 83))	('EWS', 'Gene', (80, 83))	('olaparib', 'Chemical', 'MESH:C531550', (14, 22))	('EWS', 'Gene', '2130', (80, 83))	('activity', 'MPA', (44, 52))	('FLI1', 'Gene', (84, 88))	('FLI1', 'Gene', '2313', (84, 88))
327279	22742646	While we know that BRCA1 or BRCA2 mutations confer sensitivity to PARP inhibitors, no similar mutations have been identified in Ewing's sarcoma.	('PARP', 'Gene', '142', (66, 70))	('BRCA2', 'Gene', '675', (28, 33))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('BRCA2', 'Gene', (28, 33))	('sensitivity', 'MPA', (51, 62))	('BRCA1', 'Gene', '672', (19, 24))	('PARP', 'Gene', (66, 70))	('sarcoma', 'Disease', (136, 143))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (128, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('BRCA1', 'Gene', (19, 24))	('mutations', 'Var', (34, 43))
327288	22742646	Additional molecules that warrant testing in the clinic include multi-kinase inhibitors, antagonists of EWS-FLI itself, and PARP inhibitors.	('EWS', 'Gene', '2130', (104, 107))	('EWS', 'Gene', (104, 107))	('EWS', 'Phenotype', 'HP:0012254', (104, 107))	('multi-kinase', 'Protein', (64, 76))	('PARP', 'Gene', (124, 128))	('FLI', 'Gene', '2314', (108, 111))	('FLI', 'Gene', (108, 111))	('antagonists', 'Var', (89, 100))	('PARP', 'Gene', '142', (124, 128))
327312	33391840	The tumour cells were positive for follicular dendritic cell markers such as CD21, CD23, CD35 and D2-40 (podoplanin) but negative for cytokeratin markers (Figure 4b).	('CD35', 'Gene', '1378', (89, 93))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('CD35', 'Gene', (89, 93))	('CD23', 'Gene', (83, 87))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('CD21', 'Gene', (77, 81))	('tumour', 'Disease', (4, 10))	('D2-40', 'Var', (98, 103))	('CD21', 'Gene', '1380', (77, 81))	('CD23', 'Gene', '2208', (83, 87))
327473	27259563	In colorectal cancer, clinical response is correlated with mis-match repair (MMR) deficiency and microsatellite instability.	('microsatellite instability', 'Var', (97, 123))	('deficiency', 'Var', (82, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
327481	27259563	The combined morphological and immunophenotypic features were consistent with EWS (the presence of EWSR1 rearrangement was confirmed on a subsequent biopsy).	('EWSR1', 'Gene', '2130', (99, 104))	('EWS', 'Phenotype', 'HP:0012254', (99, 102))	('EWS', 'Phenotype', 'HP:0012254', (78, 81))	('rearrangement', 'Var', (105, 118))	('EWS', 'Gene', (99, 102))	('EWS', 'Gene', '2130', (99, 102))	('EWS', 'Gene', '2130', (78, 81))	('EWS', 'Gene', (78, 81))	('EWSR1', 'Gene', (99, 104))
327567	27832799	SCR for rectal cancer patients was modelled using the background rate in the patient cohort analysed by Birgisson et al.. Modelled baseline risk was added to the calculated excess LAR of patients treated with 3DCRT and 28 x1.8 Gy and 5 x 5 Gy (Figs.	('patients', 'Species', '9606', (187, 195))	('rectal cancer', 'Phenotype', 'HP:0100743', (8, 21))	('3DCRT', 'Var', (209, 214))	('patients', 'Species', '9606', (22, 30))	('patient', 'Species', '9606', (77, 84))	('patient', 'Species', '9606', (187, 194))	('rectal cancer', 'Disease', 'MESH:D012004', (8, 21))	('rectal cancer', 'Disease', (8, 21))	('patient', 'Species', '9606', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
327581	27832799	Comparing the RT techniques used in this study, organ-specific LAR was significantly lower using 3DCRT than VMAT.	('lower', 'NegReg', (85, 90))	('VMAT', 'Disease', (108, 112))	('organ-specific LAR', 'CPA', (48, 66))	('3DCRT', 'Var', (97, 102))	('VMAT', 'Disease', 'None', (108, 112))
327587	27832799	showed in their work modeling tumor control probability and tumor recurrence time on the basis of the linear quadratic model and SCR on the basis of the IIP model that with hypofractionation, SCR was reduced by 22 % compared to a conventional (2Gy) fractionation schedule.	('hypofractionation', 'Var', (173, 190))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('reduced', 'NegReg', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('SCR', 'MPA', (192, 195))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (30, 35))
327591	27832799	Our group was able to show that sterilization of a large number of cells at higher doses could lead to inflammation or proliferative stress and initiate carcinogenesis.	('carcinogenesis', 'Disease', (153, 167))	('lead to', 'Reg', (95, 102))	('inflammation', 'Disease', (103, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (153, 167))	('sterilization', 'Var', (32, 45))	('initiate', 'Reg', (144, 152))	('proliferative stress', 'CPA', (119, 139))	('inflammation', 'Disease', 'MESH:D007249', (103, 115))
327802	32015676	Serum CA125 and LDH for the diagnosis of uterine sarcomas are limited in present study, and the preoperative CA125 and LDH abnormalities were detected in 24 and 17 of 70 cases, respectively.	('CA125', 'Gene', '94025', (109, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('detected', 'Reg', (142, 150))	('CA125', 'Gene', '94025', (6, 11))	('sarcomas', 'Disease', (49, 57))	('CA125', 'Gene', (6, 11))	('CA125', 'Gene', (109, 114))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (41, 56))	('abnormalities', 'Var', (123, 136))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))	('LDH', 'Gene', (119, 122))
327980	27732941	Advances reveal that changes in NMDAR-binding synaptic plasticity induce long-term potentiation and generate epigenetic spinal hypersensitivity.	('NMDAR', 'Gene', (32, 37))	('hypersensitivity', 'Disease', 'MESH:D004342', (127, 143))	('epigenetic', 'MPA', (109, 119))	('induce', 'Reg', (66, 72))	('generate', 'Reg', (100, 108))	('long-term potentiation', 'MPA', (73, 95))	('changes', 'Var', (21, 28))	('hypersensitivity', 'Disease', (127, 143))	('NMDAR', 'Gene', '14810', (32, 37))
328001	27732941	and our previous researches, inoculation of sarcoma cells induces pain-related behavioral signs of mechanical allodynia and thermal hyperalgesia, and severe bone destruction during 14 days post-operation.	('hyperalgesia', 'Phenotype', 'HP:0031005', (132, 144))	('pain', 'Phenotype', 'HP:0012531', (66, 70))	('bone destruction', 'CPA', (157, 173))	('pain', 'Disease', 'MESH:D010146', (66, 70))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('pain', 'Disease', (66, 70))	('mechanical allodynia', 'Disease', 'MESH:D006930', (99, 119))	('allodynia', 'Phenotype', 'HP:0012533', (110, 119))	('mechanical allodynia', 'Disease', (99, 119))	('bone destruction', 'Phenotype', 'HP:0002797', (157, 173))	('sarcoma', 'Disease', (44, 51))	('hyperalgesia', 'Disease', 'MESH:D006930', (132, 144))	('hyperalgesia', 'Disease', (132, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('behavioral signs', 'Phenotype', 'HP:0000708', (79, 95))	('inoculation', 'Var', (29, 40))
328041	27732941	The filter membranes were blocked with 5% nonfat milk for 1 h at RT (room temperature) and incubated with the primary anti NR2B (rabbit affinity purified polyclonal antibody; 1:1000, Abcam, Hong Kong, China), anti REST (rabbit affinity purified polyclonal antibody; 1:300, Santa Cruz Biotechnology, Santa Cruz, CA) or anti beta-actin (mouse affinity purified monoclonal antibody; 1:1000, ZSGB-BIO, Beijing, China).	('rabbit', 'Species', '9986', (220, 226))	('mouse', 'Species', '10090', (335, 340))	('beta-actin', 'Gene', (323, 333))	('NR2B', 'Gene', (123, 127))	('beta-actin', 'Gene', '100350495', (323, 333))	('rabbit', 'Species', '9986', (129, 135))	('anti', 'Var', (318, 322))
328060	27119100	The development of attenuated, oncolytic herpes simplex virus (oHSV) mutants engineered to achieve tumor-selective virus replication is being actively pursued by many investigators and pharmaceutical companies.	('tumor', 'Disease', (99, 104))	('herpes simplex', 'Phenotype', 'HP:0012302', (41, 55))	('mutants', 'Var', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('oHSV', 'Chemical', '-', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
328061	27119100	Early-phase clinical trials have reported safety of administering attenuated oHSV mutants to humans by intracranial, intralesional, and hepatic artery routes.	('oHSV', 'Gene', (77, 81))	('mutants', 'Var', (82, 89))	('oHSV', 'Chemical', '-', (77, 81))	('humans', 'Species', '9606', (93, 99))
328062	27119100	Recent data reported by Amgen for T-Vec, an HSV-1 mutant engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), are encouraging with 16.3% of melanoma patients exhibiting a durable response, compared with 2% of patients in the control arm using GM-CSF alone without virus.	('HSV-1', 'Gene', (44, 49))	('patients', 'Species', '9606', (177, 185))	('HSV-1', 'Species', '10298', (44, 49))	('mutant', 'Var', (50, 56))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('patients', 'Species', '9606', (237, 245))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
328064	27119100	However, emerging data suggest that oHSV exerts an antitumor effect through multiple distinct mechanisms including stimulation of antitumor T-cell immunity.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('oHSV', 'Chemical', '-', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('oHSV', 'Var', (36, 40))	('tumor', 'Disease', (134, 139))	('stimulation', 'PosReg', (115, 126))
328074	27119100	We tested two previously established cell line models of mouse RMS, 76-9 (methylchloranthrene-induced) and M3-9-M (p53-/- and transgenic for hepatocyte growth factor/scatter factor (HGF/SF)), and HGF116, which we derived from a spontaneous neck mass in a female HGF/SFtg, INK4a/Arf--/- mouse, previously reported to promote rhabdomyosarcomagenesis.	('HGF116', 'Var', (196, 202))	('mouse', 'Species', '10090', (286, 291))	('methylchloranthrene', 'Chemical', '-', (74, 93))	('HGF/SF', 'Gene', (182, 188))	('rhabdomyosarcomagenesis', 'Disease', (324, 347))	('INK4a', 'Gene', (272, 277))	('hepatocyte growth factor/scatter factor', 'Gene', (141, 180))	('INK4a', 'Gene', '12578', (272, 277))	('rhabdomyosarcomagenesis', 'Disease', 'None', (324, 347))	('RMS', 'Phenotype', 'HP:0002859', (63, 66))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (324, 340))	('M3-9-M', 'Var', (107, 113))	('promote', 'PosReg', (316, 323))	('HGF/SF)', 'Gene', '15234', (182, 189))	('hepatocyte growth factor/scatter factor', 'Gene', '15234', (141, 180))	('mouse', 'Species', '10090', (57, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (333, 340))
328078	27119100	We confirmed functional Nectin-1 on human and mouse cell lines by gene transfer assays using receptor-restricted HSV glycoprotein D mutant viruses, whose cell specificity we previously confirmed using Chinese hamster ovary cells normally lacking HSV-1 receptors that were retrovirally transduced to express specific receptors (Supplementary Figure S1 in ref.	('glycoprotein D', 'Gene', (117, 131))	('mutant', 'Var', (132, 138))	('Chinese hamster', 'Species', '10029', (201, 216))	('mouse', 'Species', '10090', (46, 51))	('HSV-1', 'Species', '10298', (246, 251))	('human', 'Species', '9606', (36, 41))	('glycoprotein D', 'Gene', '13349', (117, 131))
328079	27119100	Cells were infected with K26GFP (wild-type gD), or its receptor-restricted derivatives d5-28V (Nectin-1-restricted) and A3C/Y38C (HVEM-restricted).	('K26GFP', 'Var', (25, 31))	('HVEM', 'Gene', (130, 134))	('A3C', 'Mutation', 'c.3A>C', (120, 123))	('Y38C', 'Mutation', 'p.Y38C', (124, 128))	('d5-28V', 'Var', (87, 93))	('A3C/Y38C', 'Var', (120, 128))	('HVEM', 'Gene', '230979', (130, 134))
328083	27119100	As measured by cell survival, 76-9 was highly resistant to killing by oHSV mutant rRp450 (ICP6-/-) in vitro with a concentration inhibiting 50% growth (IC50) at 4 days postinfection of greater than 10 plaque-forming units (pfu)/cell (multiplicity of infection (MOI) = 10; Figure 2a).	('oHSV', 'Chemical', '-', (70, 74))	('rRp450', 'Gene', (82, 88))	('inhibiting', 'NegReg', (129, 139))	('growth', 'MPA', (144, 150))	('resistant', 'NegReg', (46, 55))	('mutant', 'Var', (75, 81))	('oHSV', 'Gene', (70, 74))
328100	27119100	M3-9-M tumor growth was modestly delayed, and survival extended following rRp450 injection; however, we did not observe any tumor shrinkage as seen when tumors were implanted in immunocompetent C57Bl/6 mice (Figure 3b).	('delayed', 'NegReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (7, 12))	('mice', 'Species', '10090', (202, 206))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumors', 'Disease', (153, 159))	('injection', 'Var', (81, 90))	('extended', 'PosReg', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('survival', 'CPA', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('rRp450', 'Gene', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
328116	27119100	In addition to higher expression of MHC class I molecules, potentially rendering these cells more susceptible to T-cell-mediated cytolysis, M3-9-M, which was derived from a male C57Bl/6 mouse, expresses the HY antigen receptor complex (data not shown) which is a potential immunogenic target when tumors are grown in female mice.	('susceptible', 'MPA', (98, 109))	('tumors', 'Disease', 'MESH:D009369', (297, 303))	('higher', 'PosReg', (15, 21))	('mice', 'Species', '10090', (324, 328))	('M3-9-M', 'Var', (140, 146))	('mouse', 'Species', '10090', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumors', 'Disease', (297, 303))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('expression', 'MPA', (22, 32))
328123	27119100	The sensitive model M3-9-M displayed the highest baseline levels of neutrophils (Figure 6c), which have previously been reported to correlate with high endogenous IFN responsiveness and contribute to oHSV antitumor efficacy through unknown mechanisms.	('high endogenous IFN responsiveness', 'MPA', (147, 181))	('tumor', 'Disease', (209, 214))	('oHSV', 'Chemical', '-', (200, 204))	('M3-9-M', 'Var', (20, 26))	('neu', 'Gene', '13866', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('neu', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('contribute', 'Reg', (186, 196))
328129	27119100	We observed no differences in baseline or virus-induced intratumoral GM-CSF levels; however, M3-9-M did display significantly higher G-CSF.	('M3-9-M', 'Var', (93, 99))	('G-CSF', 'Gene', (133, 138))	('G-CSF', 'Gene', '12985', (133, 138))	('higher', 'PosReg', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
328133	27119100	Although these authors went on to demonstrate that antiviral CD8 T cells have the potential to kill bystander uninfected tumor cells in in vitro T-cell killing assays, the contribution of anti-HSV T cells to the overall therapeutic response in tolerized tumor models is unclear.	('tumor', 'Disease', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('uninfected tumor', 'Disease', 'MESH:D009369', (110, 126))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('antiviral', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('uninfected tumor', 'Disease', (110, 126))
328135	27119100	However, the similar pattern of tumor-growth delay observed in C57Bl/6 mice and athymic nude mice suggest that it could be T-cell independent.	('mice', 'Species', '10090', (71, 75))	('C57Bl/6', 'Var', (63, 70))	('nude mice', 'Species', '10090', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (93, 97))	('growth delay', 'Phenotype', 'HP:0001510', (38, 50))	('tumor', 'Disease', (32, 37))
328162	27119100	2.5 x 103 RMS cells were plated in 96-well dishes and incubated at 37  C overnight and then infected with oHSV mutant rRp450 at MOIs 0.001, 0.01, 0.1, 1, and 10 in sextuplicate.	('mutant', 'Var', (111, 117))	('RMS', 'Phenotype', 'HP:0002859', (10, 13))	('oHSV', 'Chemical', '-', (106, 110))	('rRp450', 'Gene', (118, 124))
328175	27119100	RMS cells were seeded at a density of 2 x 105 cells per well in a 12-well dish, incubated overnight, and then infected with 20-200 genome copies per well with GFP-expressing wild-type gD virus (K26GFP) and its receptor restricted derivatives K26-gD:d5-28V (Nectin-1 restricted) and K26gD: A3C/Y38C (HVEM-restricted).	('HVEM', 'Gene', '230979', (299, 303))	('K26gD: A3C/Y38C', 'Var', (282, 297))	('RMS', 'Phenotype', 'HP:0002859', (0, 3))	('K26-gD:d5-28V', 'Var', (242, 255))	('Y38C', 'Mutation', 'p.Y38C', (293, 297))	('HVEM', 'Gene', (299, 303))	('A3C', 'Mutation', 'c.3A>C', (289, 292))
328179	27119100	sc-6918), Nectin-2 (R2.525 sc-32804), and HVEM (CW10 sc-21718), or mouse IgG isotype control (sc-3878) (Santa Cruz Biotechnology, Santa Cruz, CA) for 20 minutes at room temperature.	('HVEM', 'Gene', '230979', (42, 46))	('mouse', 'Species', '10090', (67, 72))	('HVEM', 'Gene', (42, 46))	('R2.525', 'Var', (20, 26))
328224	25364450	The proportion of cells exhibiting an abnormal signal indicating the genetic disruption of EWSR1 was 71% (Fig.	('genetic disruption', 'Var', (69, 87))	('EWSR1', 'Gene', (91, 96))	('EWSR1', 'Gene', '2130', (91, 96))
328228	25364450	CCS tumors have been associated with a balanced chromosome translocation t(12;22)(q13;q12), which results in the fusion of EWSR1 (located at 22q12) and ATF1 (located at 12q13).	('EWSR1', 'Gene', (123, 128))	('fusion', 'Var', (113, 119))	('EWSR1', 'Gene', '2130', (123, 128))	('results in', 'Reg', (98, 108))	('associated', 'Reg', (21, 31))	('CCS tumors', 'Disease', 'MESH:D009369', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('ATF1', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ATF1', 'Gene', '466', (152, 156))	('CCS tumors', 'Disease', (0, 10))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (73, 90))
328229	25364450	GNETs also exhibit EWSR1 gene rearrangements, confirming that this is not a tumor-specific characteristic.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('EWSR1', 'Gene', (19, 24))	('rearrangements', 'Var', (30, 44))	('EWSR1', 'Gene', '2130', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
328239	25364450	Furthermore, almost all synovial sarcomas exhibit the constant translocation t(X;18)(p11;q11).	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (77, 93))	('t(X;18)(p11;q11', 'Var', (77, 92))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (24, 41))	('synovial sarcomas', 'Disease', 'MESH:D013584', (24, 41))	('synovial sarcomas', 'Disease', (24, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (24, 40))
328241	25364450	The NF1 gene inactivation may be used to confirm the diagnosis of MPNST.	('NF1', 'Gene', '4763', (4, 7))	('inactivation', 'Var', (13, 25))	('NF1', 'Gene', (4, 7))	('MPNST', 'Disease', (66, 71))	('MPNST', 'Phenotype', 'HP:0100697', (66, 71))
328247	24497984	M002 has deletions in both copies of the gamma134.5 gene, enabling replication in tumor cells but precluding infection of normal cells.	('infection', 'Disease', 'MESH:D007239', (109, 118))	('enabling', 'PosReg', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('gamma134.5', 'Gene', (41, 51))	('replication', 'MPA', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('M002', 'Gene', (0, 4))	('deletions', 'Var', (9, 18))	('tumor', 'Disease', (82, 87))	('infection', 'Disease', (109, 118))
328250	24497984	We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines.	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('replicated', 'Var', (41, 51))	('renal sarcoma', 'Disease', (137, 150))	('oHSV', 'Chemical', '-', (19, 23))	('malignant rhabdoid kidney tumor', 'Disease', 'MESH:D018335', (100, 131))	('infected', 'Var', (31, 39))	('hepatoblastoma', 'Disease', 'MESH:D018197', (84, 98))	('kidney tumor', 'Phenotype', 'HP:0009726', (119, 131))	('M002', 'Var', (25, 29))	('hepatoblastoma', 'Disease', (84, 98))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (84, 98))	('cell survival', 'CPA', (67, 80))	('decreased', 'NegReg', (57, 66))	('renal sarcoma', 'Disease', 'MESH:D007674', (137, 150))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('renal sarcoma', 'Phenotype', 'HP:0008663', (137, 150))	('malignant rhabdoid kidney tumor', 'Disease', (100, 131))
328253	24497984	We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.	('pediatric solid tumors', 'Disease', 'MESH:D009369', (161, 183))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('aggressive tumor', 'Disease', 'MESH:D001523', (55, 71))	('M002', 'Var', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('aggressive tumor', 'Disease', (55, 71))	('children', 'Species', '9606', (122, 130))	('pediatric solid tumors', 'Disease', (161, 183))
328275	24497984	Also, we have recently noted that M002 was effective in decreasing cell survival and xenograft tumor growth in another pediatric solid tumor, neuroblastoma.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('neuroblastoma', 'Phenotype', 'HP:0003006', (142, 155))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('M002', 'Var', (34, 38))	('cell survival', 'CPA', (67, 80))	('decreasing', 'NegReg', (56, 66))	('neuroblastoma', 'Disease', 'MESH:D009447', (142, 155))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('neuroblastoma', 'Disease', (142, 155))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
328276	24497984	These previous studies led us to hypothesize that M002 would be cytotoxic for pediatric solid tumors of the liver and kidney.	('pediatric solid tumors of the liver', 'Disease', 'MESH:D009369', (78, 113))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('pediatric solid tumors of the liver', 'Disease', (78, 113))	('tumors of the liver', 'Phenotype', 'HP:0002896', (94, 113))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('M002', 'Var', (50, 54))
328286	24497984	Formalin-fixed, paraffin-embedded hepatoblastoma and malignant rhabdoid kidney tumor specimens were obtained after approval by the University of Alabama, Birmingham, Institutional Review Board for Human Use (X100930009 and X110825022, respectively) and waiver of informed consent.	('Human', 'Species', '9606', (197, 202))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('malignant rhabdoid kidney tumor', 'Disease', (53, 84))	('hepatoblastoma', 'Disease', (34, 48))	('X110825022', 'Var', (223, 233))	('X100930009', 'Var', (208, 218))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (34, 48))	('malignant rhabdoid kidney tumor', 'Disease', 'MESH:D018335', (53, 84))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('hepatoblastoma', 'Disease', 'MESH:D018197', (34, 48))	('kidney tumor', 'Phenotype', 'HP:0009726', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
328305	24497984	Phycoerythrin (PE) conjugated anti-human CD111 or CD112 antibodies (340403, 337410, respectively, Biolegend, San Diego, CA) were added and cells incubated at 4 C in the dark for 20 minutes.	('CD111', 'Gene', (41, 46))	('human', 'Species', '9606', (35, 40))	('CD112', 'Gene', '5819', (50, 55))	('337410', 'Var', (76, 82))	('340403', 'Var', (68, 74))	('CD112', 'Gene', (50, 55))
328315	24497984	The human subject samples were obtained after protocol approval by the University of Alabama, Birmingham Institutional Review Board for Human Use (X100930009 and X110825022) under waiver of informed consent.	('Human', 'Species', '9606', (136, 141))	('X100930009', 'Var', (147, 157))	('human', 'Species', '9606', (4, 9))	('X110825022', 'Var', (162, 172))
328336	24497984	Immunoblotting with CD111 specific antibody demonstrated that CD111 was present in whole cell lysates of HuH6, G401, and SK-NEP-1 cell lines (Figure 1.	('G401', 'Var', (111, 115))	('SK-NEP-1', 'CellLine', 'CVCL:0631', (121, 129))	('CD111', 'Gene', (62, 67))
328354	24497984	In addition, increasing the MOI of the M002 by a factor of 10 resulted in a significant increase in the production of murine IL-12 in the HuH6 and the G401 cell lines compared to the lower MOI (Figure 3.	('production of murine IL-12', 'MPA', (104, 130))	('murine', 'Species', '10090', (118, 124))	('M002', 'Var', (39, 43))	('increase', 'PosReg', (88, 96))
328363	24497984	Therefore, half of the animals in each group also received a low dose of irradiation to the tumor immediately following injection with vehicle or M002.	('M002', 'Var', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))
328365	24497984	The HuH6 tumor xenografts were weighed at euthanasia and those treated with M002 alone or M002+ XRT were significantly smaller than tumors from animals treated with vehicle or vehicle+XRT (Figure 5.	('M002', 'Var', (76, 80))	('smaller', 'NegReg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('M002+ XRT', 'Var', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (132, 137))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
328373	24497984	In addition, change in tumor volumes were decreased in animals treated with M002 (Figure 6.	('decreased', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('M002', 'Var', (76, 80))	('tumor', 'Disease', (23, 28))
328374	24497984	In addition, there was no significant difference in change in tumor volume between tumors treated with M002 or M002+ XRT (3.4+-2.2 mm3 vs. 5.8+-0.6 mm3, M002 vs. M002+ XRT, p = 0.2).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (62, 67))	('tumors', 'Disease', (83, 89))	('M002+ XRT', 'Var', (111, 120))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('M002', 'Var', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
328378	24497984	Tumor weights following M002 treatment were also nearly half of those of vehicle treated tumors (1.51+-0.45 g vs. 3.32+-0.89 g, M002 vs. vehicle, p = 0.04) (Figure 7.	('tumors', 'Disease', (89, 95))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('M002', 'Var', (24, 28))	('M002', 'Var', (128, 132))	('Tumor weights', 'CPA', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
328389	24497984	Cell proliferation as measure by Ki67 immunostaining tended to have less positive cells in xenografts treated with M002, but there was not a significant difference in the mean percentages between vehicle versus M002 treated xenografts (Figure S3 ,  S4 ).	('Ki67', 'Chemical', '-', (33, 37))	('less', 'NegReg', (68, 72))	('Cell proliferation', 'CPA', (0, 18))	('M002', 'Var', (115, 119))
328397	24497984	Finally, investigators have demonstrated that oHSVs will infect and have oncolytic effects in some sarcoma cell lines and xenografts.	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('oHSVs', 'Var', (46, 51))	('oncolytic effects', 'CPA', (73, 90))	('oHSVs', 'Chemical', '-', (46, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcoma', 'Disease', (99, 106))	('infect', 'NegReg', (57, 63))
328401	24497984	Previously, colleagues in our group demonstrated that CD111 was a critical entry molecule for oHSV in tumor cell lines, but found that not all tumors of the same histological type had sufficient levels of CD111 positive cells for oHSV to produce a relevant anti-tumor effect.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (143, 148))	('oHSV', 'Chemical', '-', (94, 98))	('CD111', 'Var', (205, 210))	('tumors', 'Disease', (143, 149))	('tumor', 'Disease', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('oHSV', 'Chemical', '-', (230, 234))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
328421	24497984	They found that ionizing radiation (10 Gy) combined with R7020 recombinant oHSV resulted in a greater reduction in xenograft growth than either radiation or virus alone in one hepatocellular carcinoma cell line.	('R7020', 'Var', (57, 62))	('oHSV', 'Gene', (75, 79))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('xenograft growth', 'CPA', (115, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('hepatocellular carcinoma', 'Disease', (176, 200))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (176, 200))	('reduction', 'NegReg', (102, 111))	('oHSV', 'Chemical', '-', (75, 79))
328428	24497984	Obviously, it was not possible to measure the immune contribution that the IL-12 had in tumor cell killing in our models since the mice were immunocompromised, but we believe that the addition of the IL-12 cytokine will produce a significant bystander effect in the clinical setting leading to tumor cells that were not infected by the virus to be destroyed by the immune system.	('tumor', 'Disease', (294, 299))	('leading to', 'Reg', (283, 293))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('IL-12', 'Gene', (200, 205))	('addition', 'Var', (184, 192))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mice', 'Species', '10090', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', (88, 93))
328449	24497984	Also, although the M002 treated xenografts were all significantly smaller than the treated xenografts, there likely remained viable tumor cells in the specimens that would naturally tend to proliferate.	('M002', 'Var', (19, 23))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))
328454	24497984	Administration of M002 to murine xenograft models of hepatoblastoma, renal Ewing sarcoma, and malignant rhabdoid kidney tumors resulted in a significant increase in survival and a significant decrease in xenograft growth.	('renal Ewing sarcoma', 'Disease', 'MESH:C563168', (69, 88))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('decrease', 'NegReg', (192, 200))	('murine', 'Species', '10090', (26, 32))	('kidney tumor', 'Phenotype', 'HP:0009726', (113, 125))	('kidney tumors', 'Phenotype', 'HP:0009726', (113, 126))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('malignant rhabdoid kidney tumors', 'Disease', (94, 126))	('hepatoblastoma', 'Disease', 'MESH:D018197', (53, 67))	('xenograft growth', 'CPA', (204, 220))	('increase', 'PosReg', (153, 161))	('M002', 'Var', (18, 22))	('malignant rhabdoid kidney tumors', 'Disease', 'MESH:D018335', (94, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (53, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('renal Ewing sarcoma', 'Disease', (69, 88))	('hepatoblastoma', 'Disease', (53, 67))
328455	24497984	These findings suggest that the humanized form of M002 oHSV may have therapeutic potential for children with these difficult to treat solid tumors.	('oHSV', 'Chemical', '-', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('solid tumors', 'Disease', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('children', 'Species', '9606', (95, 103))	('M002 oHSV', 'Var', (50, 59))	('human', 'Species', '9606', (32, 37))	('solid tumors', 'Disease', 'MESH:D009369', (134, 146))
328476	32503455	Checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA-4 antibodies) have become an appealing new option for the treatment of several advanced cancers, and are now first-line and/or second-line therapies for non-small cell lung carcinoma, melanoma, and renal cell carcinomas.	('cancers', 'Disease', (146, 153))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (211, 240))	('PDL1', 'Gene', (38, 42))	('lung carcinoma', 'Disease', (226, 240))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (215, 240))	('PDL1', 'Gene', '29126', (38, 42))	('anti-PD1', 'Var', (23, 31))	('men', 'Species', '9606', (121, 124))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('melanoma', 'Disease', (242, 250))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (256, 277))	('lung carcinoma', 'Disease', 'MESH:D008175', (226, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (267, 277))	('renal cell carcinomas', 'Disease', (256, 277))	('CTLA-4', 'Gene', '1493', (53, 59))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (256, 277))	('CTLA-4', 'Gene', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
328479	32503455	Moreover, patients whose sarcomas contain increased copy numbers of the PD1 gene have poorer survival outcomes.	('increased', 'PosReg', (42, 51))	('survival outcomes', 'CPA', (93, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('PD1', 'Gene', (72, 75))	('patients', 'Species', '9606', (10, 18))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('copy numbers', 'Var', (52, 64))
328517	32503455	Of the patients who had PD1 tumor expression testing, positive expression of PD1 was significantly associated with improved PFS versus those whose tumors were negative for PD1 expression (26 versus 7.6 weeks; p = 0.0037) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (28, 33))	('tumors', 'Disease', (147, 153))	('PFS', 'Disease', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('positive expression', 'Var', (54, 73))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('improved', 'PosReg', (115, 123))	('PD1', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('patients', 'Species', '9606', (7, 15))
328524	32503455	Alternatively, there was no statistical OS difference between patients who had PDL1 positive tumors compared to those who had PDL1 negative tumors (159.7 versus 44.8 weeks; p = 0.2800) (Fig.	('positive', 'Var', (84, 92))	('PDL1', 'Gene', '29126', (126, 130))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PDL1', 'Gene', '29126', (79, 83))	('PDL1', 'Gene', (126, 130))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PDL1', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Disease', (93, 99))	('patients', 'Species', '9606', (62, 70))
328560	32503455	Of the PD1i-treated patients who had PD1 testing, positive expression of PD1 was found to be positively associated with longer PFS and OS than those who did not have PD1 tumor expression.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('PD1', 'Gene', (73, 76))	('positive expression', 'Var', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('patients', 'Species', '9606', (20, 28))	('PFS', 'Disease', (127, 130))
328580	32503455	It is also possible that other tumor variables may be affecting PD1i responsiveness; for example, the presence of microsatellite instability is strongly correlated to the checkpoint inhibitor responses in other malignancies.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('microsatellite instability', 'Var', (114, 140))	('correlated', 'Reg', (153, 163))	('tumor', 'Disease', (31, 36))	('checkpoint inhibitor responses', 'MPA', (171, 201))	('malignancies', 'Disease', 'MESH:D009369', (211, 223))	('presence', 'Var', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('malignancies', 'Disease', (211, 223))
328581	32503455	Prior studies suggest that microsatellite instability may play a role in sarcoma pathogenesis and may also affect checkpoint inhibitor response.	('role', 'Reg', (65, 69))	('affect', 'Reg', (107, 113))	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))	('play', 'Reg', (58, 62))	('checkpoint inhibitor response', 'MPA', (114, 143))	('microsatellite instability', 'Var', (27, 53))
328584	32503455	There are currently several ongoing sarcoma clinical trials to study the addition of checkpoint inhibitors with other systemic therapies, such as cyclophosphamide (NCT02406781), nab-rapamycin (NCT03190174), and axitinib.	('axitinib', 'Chemical', 'MESH:D000077784', (211, 219))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (146, 162))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('nab-rapamycin', 'Chemical', '-', (178, 191))	('NCT02406781', 'Var', (164, 175))	('sarcoma', 'Disease', (36, 43))	('NCT03190174', 'Var', (193, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))
328591	32503455	These caveats notwithstanding, in our cohort, PD1i-treated patients who had positive expression of PD1 or PDL1 had longer PFS and OS than those who did not have PD1 or PDL1 expression.	('PDL1', 'Gene', '29126', (106, 110))	('PDL1', 'Gene', '29126', (168, 172))	('PDL1', 'Gene', (106, 110))	('PDL1', 'Gene', (168, 172))	('positive', 'Var', (76, 84))	('patients', 'Species', '9606', (59, 67))	('PD1', 'Gene', (99, 102))	('longer', 'PosReg', (115, 121))
328724	29533018	There were no events in 5-year OS in uterine leiomyosarcoma patients showing AR immune-reaction compared to the no expression group (100% vs. 54.8%; p=0.014), and patients having a co-expression of AR with ER and/or PR showed statistically significant better 5-year DFS and OS compared with ER and/or PR positive patients with negative AR expression.	('better', 'PosReg', (252, 258))	('ER', 'Gene', '2099', (206, 208))	('patients', 'Species', '9606', (163, 171))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (45, 59))	('co-expression', 'Var', (181, 194))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (37, 59))	('patients', 'Species', '9606', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('PR', 'Gene', '5241', (301, 303))	('DFS', 'CPA', (266, 269))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (45, 59))	('ER', 'Gene', '2099', (291, 293))	('leiomyosarcoma', 'Disease', (45, 59))	('patients', 'Species', '9606', (313, 321))	('PR', 'Gene', '5241', (216, 218))
328731	29533018	As with previous studies in endometrial cancer, the expression of AR was related to the lower rate of recurrence and death events in our study.	('endometrial cancer', 'Disease', (28, 46))	('endometrial cancer', 'Phenotype', 'HP:0012114', (28, 46))	('endometrial cancer', 'Disease', 'MESH:D016889', (28, 46))	('recurrence', 'CPA', (102, 112))	('death', 'Disease', 'MESH:D003643', (117, 122))	('death', 'Disease', (117, 122))	('expression', 'Var', (52, 62))	('lower', 'NegReg', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
328733	29533018	AR positivity in uterine leiomyosarcoma independently correlated with better DFS in this study as it did in Leitao et al..	('leiomyosarcoma', 'Disease', 'MESH:D007890', (25, 39))	('positivity', 'Var', (3, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('better', 'PosReg', (70, 76))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (17, 39))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (25, 39))	('leiomyosarcoma', 'Disease', (25, 39))	('DFS', 'Disease', (77, 80))
328735	29533018	In our series, uterine leiomyosarcoma having co-expression of AR with ER and/or PR showed significantly better DFS and OS than those with ER and/or PR positive patients with negative AR expression.	('leiomyosarcoma', 'Disease', (23, 37))	('patients', 'Species', '9606', (160, 168))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (15, 37))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (23, 37))	('PR', 'Gene', '5241', (80, 82))	('PR', 'Gene', '5241', (148, 150))	('ER', 'Gene', '2099', (70, 72))	('ER', 'Gene', '2099', (138, 140))	('co-expression', 'Var', (45, 58))	('better', 'PosReg', (104, 110))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (23, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('DFS', 'MPA', (111, 114))
328770	26807198	However, a variety of evidence also suggest that EWS-FLI-1 alone cannot fully explain the Ewing sarcomagenesis: 1) EWS-FLI-1 alone cannot transform any human cell types including mesenchymal stem cells (MSCs) which are the putative cells of origin of Ewing sarcoma; 2) Generating a transgenic mouse model of Ewing sarcoma by using EWS-FLI-1 alone has been unsuccessful; and 3) Other genetic alterations such as mutations of INK4a and p53, although far less common than EWS-FLI-1 translocation, confer worse clinical outcome.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('EWS-FLI-1', 'Gene', (469, 478))	('Ewing sarcoma', 'Disease', (251, 264))	('EWS-FLI-1', 'Gene', '2130', (469, 478))	('human', 'Species', '9606', (152, 157))	('Ewing sarcomagenesis', 'Disease', 'MESH:C563168', (90, 110))	('INK4a', 'Gene', '12578', (424, 429))	('EWS-FLI-1', 'Gene', (49, 58))	('EWS-FLI-1', 'Gene', '2130', (49, 58))	('Ewing sarcomagenesis', 'Disease', (90, 110))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (308, 321))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (308, 321))	('mouse', 'Species', '10090', (293, 298))	('INK4a', 'Gene', (424, 429))	('mutations', 'Var', (411, 420))	('EWS-FLI-1', 'Gene', (331, 340))	('EWS-FLI-1', 'Gene', '2130', (331, 340))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (251, 264))	('EWS-FLI-1', 'Gene', (115, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (251, 264))	('EWS-FLI-1', 'Gene', '2130', (115, 124))	('Ewing sarcoma', 'Disease', (308, 321))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (314, 321))	('p53', 'Gene', (434, 437))	('p53', 'Gene', '22060', (434, 437))	('Ewing sarcomagenesis', 'Phenotype', 'HP:0012254', (90, 110))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 103))
328771	26807198	Recent genome sequencing studies confirmed the long-held view that EWS-FLI-1 translocation is the only recurrent genetic alteration commonly found in Ewing sarcoma.	('Ewing sarcoma', 'Disease', (150, 163))	('EWS-FLI-1', 'Gene', (67, 76))	('EWS-FLI-1', 'Gene', '2130', (67, 76))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (150, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (150, 163))	('translocation', 'Var', (77, 90))
328772	26807198	This chromosomal translocation generates two fusion genes, EWS-FLI-1 and FLI-1-EWS (Figure 1A).	('EWS-FLI-1', 'Gene', '2130', (59, 68))	('FLI-1-EWS', 'Var', (73, 82))	('EWS-FLI-1', 'Gene', (59, 68))
328779	26807198	The EWS-FLI-1 fusion transcript (type 1) was detectable in A673, CHLA-9, and TC71, but not in 293 (Figure 1B and Supplementary Table S1).	('CHLA-9', 'CellLine', 'CVCL:M150', (65, 71))	('EWS-FLI-1', 'Gene', (4, 13))	('EWS-FLI-1', 'Gene', '2130', (4, 13))	('TC71', 'CellLine', 'CVCL:2213', (77, 81))	('A673', 'Var', (59, 63))
328791	26807198	Importantly, silencing of FLI-1-EWS in A673 cells resulted in dramatic inhibition of soft agar colony formation (Figure 4), indicating that FLI-1-EWS plays an essential role in anchorage-independent growth of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (209, 222))	('inhibition', 'NegReg', (71, 81))	('soft agar colony formation', 'CPA', (85, 111))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (209, 222))	('agar', 'Chemical', 'MESH:D000362', (90, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (209, 222))	('FLI-1-EWS', 'Gene', (26, 35))	('silencing', 'Var', (13, 22))
328795	26807198	Induction of neural genes upon FLI-1-EWS silencing might suggest that FLI-1-EWS prevents neural differentiation of Ewing sarcoma cells and maintains their continuous proliferation.	('FLI-1-EWS', 'Var', (70, 79))	('prevents', 'NegReg', (80, 88))	('continuous proliferation', 'CPA', (155, 179))	('silencing', 'Var', (41, 50))	('maintains', 'Reg', (139, 148))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (115, 128))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (115, 128))	('FLI-1-EWS', 'Gene', (31, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('neural differentiation', 'CPA', (89, 111))	('Ewing sarcoma', 'Disease', (115, 128))
328798	26807198	As shown in Figure 6, FLI-1-EWS silencing reduced xenograft tumor growth (p = 0.0576).	('reduced', 'NegReg', (42, 49))	('xenograft tumor', 'Disease', (50, 65))	('xenograft tumor', 'Disease', 'MESH:D009369', (50, 65))	('silencing', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('FLI-1-EWS', 'Gene', (22, 31))
328801	26807198	To test whether FLI-1-EWS cooperates with EWS-FLI-1 by alleviating the toxicity of EWS-FLI-1, we co-expressed FLI-1-EWS and EWS-FLI-1 in human mesenchymal stem cells (MSCs), putative cells of origin of Ewing sarcoma.	('EWS-FLI-1', 'Gene', '2130', (83, 92))	('toxicity', 'Disease', (71, 79))	('human', 'Species', '9606', (137, 142))	('FLI-1-EWS', 'Var', (110, 119))	('EWS-FLI-1', 'Gene', '2130', (124, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('toxicity', 'Disease', 'MESH:D064420', (71, 79))	('Ewing sarcoma', 'Disease', (202, 215))	('EWS-FLI-1', 'Gene', (42, 51))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (202, 215))	('EWS-FLI-1', 'Gene', '2130', (42, 51))	('EWS-FLI-1', 'Gene', (83, 92))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (202, 215))	('EWS-FLI-1', 'Gene', (124, 133))	('alleviating', 'NegReg', (55, 66))
328806	26807198	Chromosomal translocation is frequently associated with sarcomas and hematological malignancies and often generates two fusion genes.	('hematological malignancies', 'Phenotype', 'HP:0004377', (69, 95))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('Chromosomal translocation', 'Var', (0, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('hematological malignancies', 'Disease', (69, 95))	('sarcomas', 'Disease', (56, 64))	('generates', 'Reg', (106, 115))	('hematological malignancies', 'Disease', 'MESH:D019337', (69, 95))	('associated', 'Reg', (40, 50))
328808	26807198	Accumulating evidence, however, suggests that reciprocal fusion genes can contribute to tumorigenesis and disease phenotype in conjunction with their reciprocal oncogenic fusion partners.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('reciprocal', 'Var', (46, 56))	('contribute', 'Reg', (74, 84))	('disease phenotype', 'CPA', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
328811	26807198	FLI-1-EWS abrogated the toxicity displayed by EWS-FLI-1 in human MSCs, which is in principle consistent with the notion that the two fusion genes cooperate at the early stage of Ewing sarcomagenesis.	('abrogated', 'NegReg', (10, 19))	('EWS-FLI-1', 'Gene', '2130', (46, 55))	('human', 'Species', '9606', (59, 64))	('EWS-FLI-1', 'Gene', (46, 55))	('Ewing sarcomagenesis', 'Disease', 'MESH:C563168', (178, 198))	('toxicity', 'Disease', 'MESH:D064420', (24, 32))	('toxicity', 'Disease', (24, 32))	('FLI-1-EWS', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('Ewing sarcomagenesis', 'Phenotype', 'HP:0012254', (178, 198))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (178, 191))	('Ewing sarcomagenesis', 'Disease', (178, 198))
328812	26807198	Although the EWS-FLI-1 transcript, which is driven by the gene promoter for highly expressed EWS, was one to two orders of magnitude more abundant than the FLI-1-EWS transcript in Ewing sarcoma cell lines and tumors (Supplementary Table S1 and S3), silencing FLI-1-EWS nonetheless impaired anchorage-dependent and anchorage-independent growth as well as tumorigenicity of Ewing sarcoma, indicating that FLI-1-EWS plays an important role in this tumor.	('tumor', 'Disease', (354, 359))	('FLI-1-EWS', 'Gene', (259, 268))	('tumor', 'Phenotype', 'HP:0002664', (445, 450))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (372, 385))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (372, 385))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('tumor', 'Disease', (209, 214))	('impaired', 'NegReg', (281, 289))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (180, 193))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (180, 193))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('Ewing sarcoma', 'Disease', (372, 385))	('silencing', 'Var', (249, 258))	('EWS-FLI-1', 'Gene', (13, 22))	('EWS-FLI-1', 'Gene', '2130', (13, 22))	('tumor', 'Disease', (445, 450))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (378, 385))	('tumor', 'Disease', 'MESH:D009369', (445, 450))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('Ewing sarcoma cell lines and tumors', 'Disease', 'MESH:C563168', (180, 215))	('Ewing sarcoma', 'Disease', (180, 193))
328818	26807198	Alternatively, FLI-1-EWS might have a gain of function as is the case for EWS-FLI-1.	('gain', 'PosReg', (38, 42))	('EWS-FLI-1', 'Gene', (74, 83))	('EWS-FLI-1', 'Gene', '2130', (74, 83))	('FLI-1-EWS', 'Var', (15, 24))	('function', 'MPA', (46, 54))
328832	26807198	The PCR cycle numbers were FLI-1-EWS (40), EWS-FLI-1 (25), FLI-1 (40), EWS (25), and RNA polymerase II (25).	('EWS-FLI-1', 'Gene', (43, 52))	('EWS-FLI-1', 'Gene', '2130', (43, 52))	('FLI-1', 'Var', (59, 64))
328959	33723761	IMTs may show the presence of anaplastic lymphoma kinase (ALK) gene rearrangements and its expression in IMT is indicative of oncogenic ALK expression representing an important mechanism in the pathogenesis of IMT and supporting the concept that IMTs are neoplastic.	('ALK', 'Gene', '238', (136, 139))	('expression', 'MPA', (91, 101))	('rearrangements', 'Var', (68, 82))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (30, 49))	('anaplastic lymphoma kinase', 'Gene', (30, 56))	('ALK', 'Gene', (58, 61))	('men', 'Species', '9606', (77, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (41, 49))	('ALK', 'Gene', (136, 139))	('ALK', 'Gene', '238', (58, 61))	('anaplastic lymphoma kinase', 'Gene', '238', (30, 56))
328960	33723761	Of note, while > 90% of pediatric IMTs show gene rearrangements, 90% of fusion negative IMTs occur in adults , so the absence of ALK would not exclude a possible diagnosis of IMT.	('gene rearrangements', 'Var', (44, 63))	('ALK', 'Gene', '238', (129, 132))	('men', 'Species', '9606', (58, 61))	('ALK', 'Gene', (129, 132))
329026	33445667	Recent investigations suggested that the hepatotoxicity was related to the inhibition of farnesoid-X receptor signaling and germline variants in genes involved in bile acid flow and disposition (e.g., ABCB4 and ABCB11).	('ABCB11', 'Gene', '8647', (211, 217))	('ABCB4', 'Gene', '5244', (201, 206))	('hepatotoxicity', 'Disease', (41, 55))	('bile acid', 'Chemical', 'MESH:D001647', (163, 172))	('inhibition', 'NegReg', (75, 85))	('ABCB4', 'Gene', (201, 206))	('ABCB11', 'Gene', (211, 217))	('farnesoid-X receptor signaling', 'MPA', (89, 119))	('hepatotoxicity', 'Disease', 'MESH:D056486', (41, 55))	('variants', 'Var', (133, 141))
329032	33445667	Even though Sp1-controlled transcription has been viewed historically as a prominent target of mithramycin, ultimately, the effect of mithramycin on cancer cells is likely to be an indirect consequence of perturbing the function of Sp1 or some other transcription factor.	('perturbing', 'Reg', (205, 215))	('cancer', 'Disease', (149, 155))	('mithramycin', 'Chemical', 'MESH:D008926', (134, 145))	('mithramycin', 'Chemical', 'MESH:D008926', (95, 106))	('function', 'MPA', (220, 228))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Sp1', 'Protein', (232, 235))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mithramycin', 'Var', (134, 145))
329039	33445667	Due to the central role of Sp1 in cell cycle regulation and cell growth, aberrations in its expression, specifically upregulation, have been linked to tumorigenesis in a number of malignancies, including ovarian cancer (Figure 3).	('linked to', 'Reg', (141, 150))	('malignancies', 'Disease', (180, 192))	('ovarian cancer', 'Disease', (204, 218))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Sp1', 'Gene', (27, 30))	('aberrations', 'Var', (73, 84))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('ovarian cancer', 'Phenotype', 'HP:0100615', (204, 218))	('malignancies', 'Disease', 'MESH:D009369', (180, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (204, 218))	('upregulation', 'PosReg', (117, 129))	('expression', 'MPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
329047	33445667	In a large cohort of patients with ovarian cancer, Knappskog and colleagues demonstrated that MDM2 promoter polymorphisms resulted in decreased SP1 promoter binding with reduced SP1 expression and a resulting decrease in ovarian cancer risk, suggesting Sp1 inhibition as a potential therapeutic target in ovarian cancer.	('MDM2', 'Gene', (94, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (305, 319))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('reduced', 'NegReg', (170, 177))	('patients', 'Species', '9606', (21, 29))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))	('MDM2', 'Gene', '4193', (94, 98))	('SP1', 'Protein', (144, 147))	('ovarian cancer', 'Disease', (305, 319))	('decrease in ovarian cancer', 'Disease', (209, 235))	('SP1 expression', 'MPA', (178, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (305, 319))	('ovarian cancer', 'Disease', (35, 49))	('decreased', 'NegReg', (134, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('ovarian cancer', 'Disease', 'MESH:D010051', (221, 235))	('decrease in ovarian cancer', 'Disease', 'MESH:D002303', (209, 235))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('polymorphisms', 'Var', (108, 121))
329076	33445667	Mithramycin analogs are synthesized by semisynthetic techniques using a mutant strain of a bacterial producer that generates a mithramycin precursor or a shunt product, which is then elaborated by standard chemical synthesis.	('mithramycin', 'MPA', (127, 138))	('mithramycin', 'Chemical', 'MESH:D008926', (127, 138))	('mutant', 'Var', (72, 78))	('Mithramycin', 'Chemical', 'MESH:D008926', (0, 11))
329080	33445667	One of the most promising mithralogs, demycarosyl-3D-betat-D-digitoxosyl-mithramycin SK (MTM-DIG-MSK or EC-8042), has demonstrated retained anti-tumor properties, including in vitro ovarian cancer lines, but reduced in vitro toxicity in fibroblasts and mononuclear blood cells, compared to mithramycin.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('demycarosyl-3D-betat-D-digitoxosyl-mithramycin SK', 'Chemical', '-', (38, 87))	('mithramycin', 'Chemical', 'MESH:D008926', (290, 301))	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('MTM-DIG-MSK', 'Chemical', '-', (89, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (182, 196))	('tumor', 'Disease', (145, 150))	('EC-8042', 'Chemical', 'MESH:C576677', (104, 111))	('reduced', 'NegReg', (208, 215))	('toxicity', 'Disease', 'MESH:D064420', (225, 233))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('ovarian cancer', 'Disease', (182, 196))	('mithramycin', 'Chemical', 'MESH:D008926', (73, 84))	('toxicity', 'Disease', (225, 233))	('demycarosyl-3D-betat-D-digitoxosyl-mithramycin', 'Var', (38, 84))
329082	33445667	EC-8042 inhibited SP1 transcription in sarcoma cell lines with the induction of cell cycle arrest and apoptosis, and interestingly was not a substrate for several drug resistance efflux pumps.	('inhibited', 'NegReg', (8, 17))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('apoptosis', 'CPA', (102, 111))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('EC-8042', 'Var', (0, 7))	('arrest', 'Disease', 'MESH:D006323', (91, 97))	('drug resistance', 'Phenotype', 'HP:0020174', (163, 178))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('sarcoma', 'Disease', (39, 46))	('SP1 transcription', 'Gene', (18, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('arrest', 'Disease', (91, 97))
329086	33445667	EC-8042 potentiated the effect of docetaxel in triple-negative breast cancer cells in mouse xenograft models.	('potentiated', 'PosReg', (8, 19))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('mouse', 'Species', '10090', (86, 91))	('EC-8042', 'Var', (0, 7))	('breast cancer', 'Disease', (63, 76))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('docetaxel', 'Chemical', 'MESH:D000077143', (34, 43))
329089	33445667	EC-8042 displayed significant anti-tumor activity against ovarian cancer cell lines with significantly lower toxicity to fibroblasts and peripheral blood cells compared to mithramycin; while strongly inhibiting Sp1 transcription and reduction in several genes implicated in tumorigenesis including VEGF, BRCA2, cMyc, and src.	('VEGF', 'Gene', '7422', (298, 302))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ovarian cancer', 'Disease', 'MESH:D010051', (58, 72))	('BRCA2', 'Gene', '675', (304, 309))	('VEGF', 'Gene', (298, 302))	('tumor', 'Disease', (274, 279))	('toxicity', 'Disease', 'MESH:D064420', (109, 117))	('transcription', 'MPA', (215, 228))	('genes', 'MPA', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', (35, 40))	('mithramycin', 'Chemical', 'MESH:D008926', (172, 183))	('Sp1', 'Gene', (211, 214))	('src', 'Gene', '6714', (321, 324))	('inhibiting', 'NegReg', (200, 210))	('reduction', 'NegReg', (233, 242))	('ovarian cancer', 'Disease', (58, 72))	('toxicity', 'Disease', (109, 117))	('cMyc', 'Gene', (311, 315))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('ovarian cancer', 'Phenotype', 'HP:0100615', (58, 72))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('cMyc', 'Gene', '4609', (311, 315))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('src', 'Gene', (321, 324))	('BRCA2', 'Gene', (304, 309))	('EC-8042', 'Var', (0, 7))
329090	33445667	In one of the most detailed studies involving ovarian cancer and MTM analogs, MTM-SDK and MTM-SK, demonstrated considerable inhibition of Sp1 dependent transcription in vitro.	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('inhibition', 'NegReg', (124, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('Sp1 dependent transcription', 'MPA', (138, 165))	('ovarian cancer', 'Disease', (46, 60))	('MTM-SK', 'Var', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
329092	33445667	In an orthotopic xenograft model, MTM-SDK demonstrated a significant increase in the median time of abdominal distension/ascites and median survival.	('MTM-SDK', 'Var', (34, 41))	('increase', 'PosReg', (69, 77))	('abdominal distension', 'Phenotype', 'HP:0003270', (100, 120))	('ascites', 'Disease', (121, 128))	('ascites', 'Disease', 'MESH:D001201', (121, 128))	('ascites', 'Phenotype', 'HP:0001541', (121, 128))
329098	33445667	Mithramycin analogs MTM-SK and MTM-SDK were also placed in polymer micelles in order to increase bioavailability and drug targeting, with improved cytotoxicity compared to free drug in non-small cell lung cancer lines.	('MTM-SDK', 'Var', (31, 38))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (185, 211))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('improved', 'PosReg', (138, 146))	('cytotoxicity', 'Disease', (147, 159))	('increase', 'PosReg', (88, 96))	('drug targeting', 'MPA', (117, 131))	('lung cancer', 'Disease', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Mithramycin', 'Chemical', 'MESH:D008926', (0, 11))	('cytotoxicity', 'Disease', 'MESH:D064420', (147, 159))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (189, 211))	('bioavailability', 'MPA', (97, 112))
329150	29228466	Multifocality of the tumor was associated with shorter DFS, but not with OS consistent with our previous report.	('Multifocality', 'Var', (0, 13))	('shorter', 'NegReg', (47, 54))	('tumor', 'Disease', (21, 26))	('DFS', 'MPA', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
329297	30785874	In an independent validation set of 70 LMS cases, we verified using immunohistochemistry with automated scoring that high protein expression of HMMR was associated with a shorter DFI (p = 0.0061) (Fig 3c & 3d).	('HMMR', 'Gene', '3161', (144, 148))	('DFI', 'MPA', (179, 182))	('HMMR', 'Gene', (144, 148))	('high', 'Var', (117, 121))	('LMS', 'Phenotype', 'HP:0100243', (39, 42))
329308	30785874	For trichostatin A (TSA) an IC50 ranging from 39 to 474 nM was found (JA192: 474 nM; LMS04: 229 nM; LMS05: 178 nM; SYO-1: 39 nM).	('SYO-1', 'Gene', '55027', (115, 120))	('LMS', 'Phenotype', 'HP:0100243', (100, 103))	('TSA', 'Chemical', 'MESH:C012589', (20, 23))	('SYO-1', 'Gene', (115, 120))	('LMS04', 'Var', (85, 90))	('LMS', 'Phenotype', 'HP:0100243', (85, 88))	('LMS05', 'Var', (100, 105))	('trichostatin A', 'Chemical', 'MESH:C012589', (4, 18))
329310	30785874	However, for quisinostat a low IC50 was found for all cell-lines; between 15 and 41 nM (JA192: 41 nM, LMS04: 34 nM; LMS05: 39 nM; SYO-1: 15 nM).	('LMS', 'Phenotype', 'HP:0100243', (116, 119))	('quisinostat', 'Chemical', 'MESH:C541788', (13, 24))	('LMS05', 'Var', (116, 121))	('SYO-1', 'Gene', '55027', (130, 135))	('SYO-1', 'Gene', (130, 135))	('LMS', 'Phenotype', 'HP:0100243', (102, 105))
329334	30785874	For one of the identified genes, HMMR, we confirmed that high protein expression was associated with poor outcome of LMS.	('LMS', 'Disease', (117, 120))	('LMS', 'Phenotype', 'HP:0100243', (117, 120))	('high', 'Var', (57, 61))	('HMMR', 'Gene', '3161', (33, 37))	('associated', 'Reg', (85, 95))	('HMMR', 'Gene', (33, 37))
329337	30785874	HMMR forms a complex with BRCA1 or BRCA2 together with other proteins, and high expression of HMMR was associated with poor survival in liver, pancreatic and lung cancer.	('pancreatic and lung cancer', 'Disease', 'MESH:D010190', (143, 169))	('high expression', 'Var', (75, 90))	('HMMR', 'Gene', '3161', (0, 4))	('BRCA1', 'Gene', (26, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('BRCA2', 'Gene', '675', (35, 40))	('poor', 'NegReg', (119, 123))	('HMMR', 'Gene', (0, 4))	('liver', 'Disease', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('HMMR', 'Gene', '3161', (94, 98))	('associated with', 'Reg', (103, 118))	('BRCA1', 'Gene', '672', (26, 31))	('HMMR', 'Gene', (94, 98))	('BRCA2', 'Gene', (35, 40))
329338	30785874	Possibly, defects in the homologous repair pathway could result in over-expression of HMMR in an attempt to compensate for other defective proteins.	('result', 'Reg', (57, 63))	('HMMR', 'Gene', '3161', (86, 90))	('over-expression', 'MPA', (67, 82))	('homologous repair pathway', 'Pathway', (25, 50))	('HMMR', 'Gene', (86, 90))	('defects', 'Var', (10, 17))
329432	27574465	OS was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median OS =13.5 vs 11.5 months; HR =0.77).	('improved', 'PosReg', (21, 29))	('patients', 'Species', '9606', (33, 41))	('dacarbazine', 'Chemical', 'MESH:D003606', (95, 106))	('OS', 'Gene', '17451', (115, 117))	('eribulin', 'Var', (54, 62))	('OS', 'Gene', '17451', (0, 2))
329438	27574465	Median PFS was significantly longer in the pazopanib arm, 4.6 vs 1.6 months (HR =0.31, 95% CI =0.24-0.40, P<0.0001), but no significant difference in median OS was found (12.5 vs 10.7 months, HR =0.85, 95% CI =0.67-1.11, P=0.25).	('PFS', 'MPA', (7, 10))	('pazopanib', 'Var', (43, 52))	('OS', 'Gene', '17451', (157, 159))	('longer', 'PosReg', (29, 35))	('pazopanib', 'Chemical', 'MESH:C516667', (43, 52))
329446	27574465	This impact on transcription is especially of interest in translocation-related sarcomas, such as myxoid liposarcoma and Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (121, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (98, 116))	('sarcomas', 'Disease', 'MESH:D012509', (80, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('liposarcoma', 'Phenotype', 'HP:0012034', (105, 116))	('Ewing sarcoma', 'Disease', (121, 134))	('translocation-related', 'Var', (58, 79))	('myxoid liposarcoma', 'Disease', (98, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcomas', 'Disease', (80, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (121, 134))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (98, 116))
329447	27574465	In myxoid liposarcomas, the presence of t(12;16) or t(12;22) translocations leads to FUS-CHOP or EWS-CHOP fusion proteins.	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (3, 22))	('EWS', 'Gene', (97, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (14, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('EWS', 'Gene', '2130', (97, 100))	('leads to', 'Reg', (76, 84))	('translocations', 'Var', (61, 75))	('liposarcomas', 'Phenotype', 'HP:0012034', (10, 22))	('FUS-CHOP', 'Disease', (85, 93))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (3, 21))	('myxoid liposarcomas', 'Disease', (3, 22))	('FUS-CHOP', 'Disease', 'None', (85, 93))	('t(12;16', 'Var', (40, 47))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (3, 22))	('liposarcoma', 'Phenotype', 'HP:0012034', (10, 21))
329449	27574465	In Ewing sarcoma, the translocation t(11;22) results in an oncogenic fusion gene EWS-FLI1, a crucial driver for the oncogenic transformation and survival of Ewing sarcoma cells.	('translocation t', 'Var', (22, 37))	('FLI1', 'Gene', '2313', (85, 89))	('FLI1', 'Gene', (85, 89))	('Ewing sarcoma', 'Disease', (157, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('Ewing sarcoma', 'Disease', (3, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('EWS', 'Gene', '2130', (81, 84))	('EWS', 'Gene', (81, 84))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (157, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('results in', 'Reg', (45, 55))
329475	27574465	Again, ORRs were numerically higher in doxorubicin-treated patients (27% vs 5.9%), although this was not statistically significant.	('higher', 'PosReg', (29, 35))	('doxorubicin', 'Chemical', 'MESH:D004317', (39, 50))	('ORRs', 'MPA', (7, 11))	('patients', 'Species', '9606', (59, 67))	('doxorubicin-treated', 'Var', (39, 58))
329523	23403859	Seroprevalence increased with increasing age of the child (P = 0.0003) and was higher among those with KSHV seropositive mothers than in those without (12% vs 9%; odds ratio: 1.4, 95% confidence interval: 1.1 to 2.0).	('KSHV', 'Species', '37296', (103, 107))	('increased', 'PosReg', (15, 24))	('KSHV', 'Gene', (103, 107))	('seropositive', 'Var', (108, 120))	('higher', 'PosReg', (79, 85))	('child', 'Species', '9606', (52, 57))	('Seroprevalence', 'MPA', (0, 14))
329535	23403859	We have previously reported a high prevalence of antibodies to KSHV in pregnant women in Uganda, and risk factors for infection among these women included certain parasites.	('women', 'Species', '9606', (80, 85))	('KSHV', 'Species', '37296', (63, 67))	('women', 'Species', '9606', (140, 145))	('KSHV', 'Gene', (63, 67))	('antibodies', 'Var', (49, 59))	('infection', 'Disease', (118, 127))	('infection', 'Disease', 'MESH:D007239', (118, 127))
329537	23403859	This analysis describes the association between antibodies to KSHV in Ugandan children aged 1-5 years and common local exposures including HIV, malaria, and helminths in addition to maternal and household factors.	('KSHV', 'Species', '37296', (62, 66))	('association', 'Interaction', (28, 39))	('malaria', 'Disease', 'MESH:D008288', (144, 151))	('antibodies', 'Var', (48, 58))	('children', 'Species', '9606', (78, 86))	('KSHV', 'Gene', (62, 66))	('malaria', 'Disease', (144, 151))
329558	23403859	The Kappa score for agreement for the duplicate samples for K8.1 was 0.86 and for ORF 73 was 0.92.	('K8.1', 'Var', (60, 64))	('ORF 73', 'Gene', (82, 88))	('ORF 73', 'Gene', '4961527', (82, 88))
329580	23403859	The seroprevalence of KSHV among children was 9% to K8.1, 6% to ORF 73, 4% to both antigens, and 11% to either ORF 73 or K8.1.	('ORF 73', 'Gene', (64, 70))	('KSHV', 'Gene', (22, 26))	('KSHV', 'Species', '37296', (22, 26))	('K8.1', 'Var', (52, 56))	('ORF 73', 'Gene', '4961527', (64, 70))	('ORF 73', 'Gene', (111, 117))	('children', 'Species', '9606', (33, 41))	('ORF 73', 'Gene', '4961527', (111, 117))
329583	23403859	Of childhood factors, increasing age of the child was strongly associated with KSHV seropositivity in crude and adjusted analyses (model 2).	('seropositivity', 'Var', (84, 98))	('KSHV', 'Species', '37296', (79, 83))	('associated', 'Reg', (63, 73))	('child', 'Species', '9606', (44, 49))	('child', 'Species', '9606', (3, 8))	('KSHV', 'Disease', (79, 83))
329586	23403859	In an analysis restricted to HIV seropositive mothers, being a HIV seropositive child was associated with a 2-fold increase in the risk of being KSHV seropositive compared with being a HIV-negative child (odds ratio: 1.9, 95% confidence interval: 0.6 to 5.4).	('child', 'Species', '9606', (80, 85))	('child', 'Species', '9606', (198, 203))	('KSHV', 'Species', '37296', (145, 149))	('seropositive', 'Var', (150, 162))	('KSHV', 'Gene', (145, 149))
329589	23403859	In this study of children aged 1-5 years in Uganda, we have demonstrated for the first time an association between KSHV seropositivity and the presence of asymptomatic malaria parasitemia.	('seropositivity', 'Var', (120, 134))	('malaria parasitemia', 'Disease', (168, 187))	('KSHV', 'Species', '37296', (115, 119))	('malaria parasitemia', 'Disease', 'MESH:D018512', (168, 187))	('children', 'Species', '9606', (17, 25))	('KSHV', 'Gene', (115, 119))
329593	23403859	Ecological studies from Italy report substantial declines in KSHV seroprevalence and Kaposi sarcoma incidence in association with eradication of mosquitoes.	('seroprevalence', 'Var', (66, 80))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (85, 99))	('declines', 'NegReg', (49, 57))	('KSHV', 'Gene', (61, 65))	('Kaposi sarcoma', 'Disease', (85, 99))	('incidence', 'MPA', (100, 109))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (85, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('KSHV', 'Species', '37296', (61, 65))
329599	23403859	We have previously reported an association between KSHV seropositivity and malaria in women in Uganda.	('KSHV', 'Species', '37296', (51, 55))	('malaria', 'Disease', (75, 82))	('KSHV', 'Gene', (51, 55))	('seropositivity', 'Var', (56, 70))	('women', 'Species', '9606', (86, 91))	('malaria', 'Disease', 'MESH:D008288', (75, 82))
329627	23403859	Selection biases may have underestimated the association with HIV and antibodies to KSHV.	('antibodies', 'Var', (70, 80))	('KSHV', 'Gene', (84, 88))	('KSHV', 'Species', '37296', (84, 88))	('association', 'Interaction', (45, 56))
329701	30666289	also documented a 100% local control rate for six patients treated with wide resection and RT, but only 50% local control rate in four patients treated with surgery exclusively.	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (50, 58))	('wide', 'Var', (72, 76))	('local control', 'CPA', (23, 36))
329755	30223066	Next, we summarize the incidence data and potential mechanisms of sexual dimorphism in ten human cancer types with higher incidence ratios of at least 2-fold.	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('sexual', 'Var', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (91, 96))
329804	30223066	Although neither ERbeta nor GPER1 is expressed in normal liver and liver tumors from rodents and humans, one recent study showed that global but not liver-specific ablation of Gper1 accelerated hepatocarcinogenesis.	('GPER1', 'Gene', (28, 33))	('liver tumors', 'Phenotype', 'HP:0002896', (67, 79))	('liver tumors', 'Disease', (67, 79))	('humans', 'Species', '9606', (97, 103))	('GPER1', 'Gene', '2852', (28, 33))	('Gper1', 'Gene', '2852', (176, 181))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (194, 214))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ERbeta', 'Gene', '2100', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('accelerated', 'PosReg', (182, 193))	('ablation', 'Var', (164, 172))	('Gper1', 'Gene', (176, 181))	('ERbeta', 'Gene', (17, 23))	('hepatocarcinogenesis', 'Disease', (194, 214))	('liver tumors', 'Disease', 'MESH:D008113', (67, 79))
329808	30223066	Li et al found that both of the ERalpha-mediated protection and AR-mediated facilitation of hepatic tumorigenesis in mice depended on Foxa1/2, while deficiency of Foxa1 and Foxa2 in the mouse liver would reverse the protective role of ERalpha and the detrimental role of AR for HCC; and genetic variants that affected the binding of FOXA2 and ERalpha were associated with the increased incidence of HCC in patients.	('FOXA2', 'Gene', (333, 338))	('Foxa1', 'Gene', (163, 168))	('tumor', 'Disease', (100, 105))	('mice', 'Species', '10090', (117, 121))	('men', 'Species', '9606', (256, 259))	('deficiency', 'Var', (149, 159))	('HCC', 'Disease', (278, 281))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('binding', 'Interaction', (322, 329))	('HCC', 'Disease', 'MESH:D006528', (399, 402))	('HCC', 'Phenotype', 'HP:0001402', (278, 281))	('associated', 'Reg', (356, 366))	('Foxa1/2', 'Gene', '15375;15376', (134, 141))	('Foxa1', 'Gene', '15375', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('genetic variants', 'Var', (287, 303))	('Foxa1', 'Gene', (134, 139))	('mouse', 'Species', '10090', (186, 191))	('HCC', 'Disease', 'MESH:D006528', (278, 281))	('HCC', 'Disease', (399, 402))	('Foxa2', 'Gene', '15376', (173, 178))	('patients', 'Species', '9606', (406, 414))	('HCC', 'Phenotype', 'HP:0001402', (399, 402))	('Foxa1/2', 'Gene', (134, 141))	('Foxa2', 'Gene', (173, 178))	('Foxa1', 'Gene', '15375', (163, 168))	('FOXA2', 'Gene', '15376', (333, 338))	('ERalpha', 'Gene', (343, 350))
329824	30223066	For example, estrogen signaling, through ERalpha or a splicing variant of ERalpha, promoted the growth of gastric cancer cells whereas ERbeta-mediated estrogen signaling inhibited the growth of gastric cancer cells and genetic variants in the ESR2 gene were highly associated with survival in patients with locally advanced gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ERbeta', 'Gene', (135, 141))	('associated with', 'Reg', (265, 280))	('genetic variants', 'Var', (219, 235))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (194, 208))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('inhibited', 'NegReg', (170, 179))	('gastric cancer', 'Disease', (324, 338))	('estrogen', 'Chemical', 'MESH:D004967', (151, 159))	('growth', 'MPA', (184, 190))	('ESR2', 'Gene', '2100', (243, 247))	('gastric cancer', 'Disease', 'MESH:D013274', (324, 338))	('gastric cancer', 'Disease', (194, 208))	('estrogen', 'Chemical', 'MESH:D004967', (13, 21))	('ESR2', 'Gene', (243, 247))	('gastric cancer', 'Disease', (106, 120))	('growth', 'MPA', (96, 102))	('promoted', 'PosReg', (83, 91))	('splicing variant', 'Var', (54, 70))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('gastric cancer', 'Disease', 'MESH:D013274', (194, 208))	('gastric cancer', 'Phenotype', 'HP:0012126', (324, 338))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('ERbeta', 'Gene', '2100', (135, 141))	('patients', 'Species', '9606', (293, 301))	('ERalpha', 'Gene', (74, 81))
329830	30223066	The evidence of estrogen signaling in the growth of kidney cancer cells is limited, e.g., ESR1 polymorphism was associated with the risk of kidney cancer; GPER1 promoted the growth and metastasis of kidney cancer cells; and AR-mediated androgen signaling promoted the growth of kidney cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('kidney cancer', 'Disease', (140, 153))	('kidney cancer', 'Phenotype', 'HP:0009726', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('kidney cancer', 'Disease', (52, 65))	('GPER1', 'Gene', '2852', (155, 160))	('kidney cancer', 'Disease', 'MESH:D007680', (199, 212))	('kidney cancer', 'Disease', 'MESH:D007680', (278, 291))	('metastasis of kidney cancer', 'Disease', 'MESH:D009362', (185, 212))	('GPER1', 'Gene', (155, 160))	('growth', 'CPA', (174, 180))	('ESR1', 'Gene', '2099', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('kidney cancer', 'Phenotype', 'HP:0009726', (199, 212))	('kidney cancer', 'Phenotype', 'HP:0009726', (278, 291))	('metastasis of kidney cancer', 'Disease', (185, 212))	('estrogen', 'Chemical', 'MESH:D004967', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('kidney cancer', 'Disease', (278, 291))	('ESR1', 'Gene', (90, 94))	('polymorphism', 'Var', (95, 107))	('kidney cancer', 'Disease', 'MESH:D007680', (140, 153))	('kidney cancer', 'Disease', 'MESH:D007680', (52, 65))	('androgen', 'Chemical', 'MESH:D000728', (236, 244))	('promoted', 'PosReg', (255, 263))	('growth', 'CPA', (268, 274))	('promoted', 'PosReg', (161, 169))	('associated', 'Reg', (112, 122))	('kidney cancer', 'Phenotype', 'HP:0009726', (140, 153))
329883	28441176	One of the most commonly used recreational drugs is nitrite inhalants (amyl nitrite, butyl nitrite, isobutyl nitrite; commonly referred to as 'poppers').	('butyl nitrite', 'Chemical', 'MESH:C024225', (85, 98))	('butyl nitrite', 'MPA', (85, 98))	('isobutyl nitrite', 'Chemical', 'MESH:C018086', (100, 116))	('nitrite', 'Chemical', 'MESH:D009573', (52, 59))	('nitrite', 'Chemical', 'MESH:D009573', (76, 83))	('butyl nitrite', 'Chemical', 'MESH:C024225', (103, 116))	('amyl nitrite', 'Chemical', 'MESH:D000680', (71, 83))	('isobutyl', 'Var', (100, 108))	('nitrite', 'Chemical', 'MESH:D009573', (91, 98))	('nitrite', 'Chemical', 'MESH:D009573', (109, 116))
329916	28441176	Analyses restricted to HIV-infected study participants were adjusted for age, race, heavy popper use, calendar period, and time-varying CD4+ cell count (<200 vs. >=200 cells/mul) and plasma viral load (>400 vs. <= 400 HIV RNA copies/ml).	('HIV-infected', 'Disease', 'MESH:D015658', (23, 35))	('CD4', 'Gene', '920', (136, 139))	('participants', 'Species', '9606', (42, 54))	('>400', 'Var', (202, 206))	('HIV-infected', 'Disease', (23, 35))	('CD4', 'Gene', (136, 139))
329940	28441176	By contrast, low CD4+ cell count (<200 cells/mul) was associated with increased risk of Kaposi sarcoma (IRR, 2.83; 95% CI, 1.33-5.99), NHL (IRR, 5.31; 95% CI, 2.46-11.46), and anal cancer (IRR, 3.75; 95% CI, 1.36-10.36), whereas viral load (>400 copies/ml) was associated with increased risk of Kaposi sarcoma (IRR, 8.3; 95% CI, 3.54-9.46), NHL (IRR, 11.92; 95% CI, 4.46-31.88), and squamous cell carcinoma of the skin (IRR, 4.63; 95% CI, 1.9-11.27).	('sarcoma', 'Phenotype', 'HP:0100242', (302, 309))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (383, 418))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (88, 102))	('anal cancer', 'Phenotype', 'HP:0032186', (176, 187))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (295, 309))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('Kaposi sarcoma', 'Disease', (88, 102))	('Kaposi sarcoma', 'Disease', (295, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (397, 406))	('squamous cell carcinoma of the skin', 'Disease', (383, 418))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (88, 102))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (295, 309))	('CD4', 'Gene', '920', (17, 20))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (383, 418))	('NHL', 'Disease', 'MESH:D008228', (341, 344))	('NHL', 'Disease', (341, 344))	('cancer', 'Disease', (181, 187))	('NHL', 'Disease', (135, 138))	('CD4', 'Gene', (17, 20))	('<200 cells/mul', 'Var', (34, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (383, 406))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('NHL', 'Disease', 'MESH:D008228', (135, 138))
329966	28441176	Furthermore, HHV-8 and high-risk HPV seroprevalence is likely to be higher among HIV-infected compared with HIV-uninfected study participants, irrespective of popper use.	('participants', 'Species', '9606', (129, 141))	('HPV', 'Disease', (33, 36))	('HIV-infected', 'Disease', 'MESH:D015658', (81, 93))	('higher', 'PosReg', (68, 74))	('HHV-8', 'Gene', (13, 18))	('seroprevalence', 'Var', (37, 51))	('HIV-uninfected', 'Disease', (108, 122))	('HIV-uninfected', 'Disease', 'MESH:D015658', (108, 122))	('HPV', 'Disease', 'MESH:D030361', (33, 36))	('HHV-8', 'Species', '37296', (13, 18))	('HIV-infected', 'Disease', (81, 93))
329969	28441176	While low time-updated CD4+ cell count was associated with risk of anal cancer in HIV-infected individuals, consistent with, time-updated viral load (> 400 copies/ml) was associated with risk of squamous cell carcinoma of the skin.	('HIV-infected', 'Disease', (82, 94))	('HIV-infected', 'Disease', 'MESH:D015658', (82, 94))	('anal cancer', 'Phenotype', 'HP:0032186', (67, 78))	('> 400 copies/ml', 'Var', (150, 165))	('squamous cell carcinoma of the skin', 'Disease', (195, 230))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('CD4', 'Gene', '920', (23, 26))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (195, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (195, 230))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('CD4', 'Gene', (23, 26))	('associated', 'Reg', (171, 181))	('cancer', 'Disease', (72, 78))
329991	28441176	The MACS is funded by the National Institute of Allergy and Infectious Diseases (NIAID; U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, and UM1-AI35043), with additional cofunding from the National Cancer Institute (NCI), National Institute on Drug Abuse (NIDA), and National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH).	('U01', 'CellLine', 'CVCL:2220', (101, 104))	('U01', 'CellLine', 'CVCL:2220', (88, 91))	('U01', 'CellLine', 'CVCL:2220', (127, 130))	('U01-AI35039', 'Var', (88, 99))	('U01-AI35040', 'Var', (101, 112))	('Cancer', 'Disease', (202, 208))	('UM1-AI35043', 'Var', (144, 155))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Cancer', 'Disease', 'MESH:D009369', (202, 208))	('U01-AI35041', 'Var', (114, 125))	('U01', 'CellLine', 'CVCL:2220', (114, 117))	('Allergy', 'Phenotype', 'HP:0012393', (48, 55))	('U01-AI35042', 'Var', (127, 138))
329993	26776507	Functional genomic screening reveals splicing of the EWS-FLI1 fusion transcript as a vulnerability in Ewing sarcoma Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival.	('Ewing sarcoma', 'Disease', (116, 129))	('EWS-FLI1', 'Gene', (150, 158))	('FLI1', 'Gene', '2313', (57, 61))	('EWS-FLI1', 'Gene', (53, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('EWS', 'Gene', (150, 153))	('splicing', 'Var', (37, 45))	('EWS', 'Gene', '2130', (53, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('EWS-FLI1', 'Gene', '2130;2313', (150, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('EWS-FLI1', 'Gene', '2130;2313', (53, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('FLI1', 'Gene', (154, 158))	('Ewing sarcoma', 'Disease', (102, 115))	('EWS', 'Gene', '2130', (150, 153))	('EWS', 'Gene', (53, 56))	('FLI1', 'Gene', (57, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('FLI1', 'Gene', '2313', (154, 158))
329997	26776507	Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1 driven expression.	('protein', 'Protein', (62, 69))	('driven expression', 'MPA', (94, 111))	('EWS-FLI1', 'Gene', (53, 61))	('Disrupted splicing', 'Var', (0, 18))	('EWS-FLI1', 'Gene', '2130;2313', (53, 61))	('EWS-FLI1', 'Gene', (26, 34))	('EWS-FLI1', 'Gene', (85, 93))	('EWS-FLI1', 'Gene', '2130;2313', (26, 34))	('EWS-FLI1', 'Gene', '2130;2313', (85, 93))	('alters', 'Reg', (46, 52))
329999	26776507	Chromosomal translocations that generate fusion genes encoding oncogenic transcription factors are associated with the initiation and maintenance of many cancers, including leukemias and epithelial and mesenchymal solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('fusion genes', 'Var', (41, 53))	('leukemias', 'Phenotype', 'HP:0001909', (173, 182))	('leukemias', 'Disease', (173, 182))	('Chromosomal', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('mesenchymal solid tumors', 'Disease', (202, 226))	('mesenchymal solid tumors', 'Disease', 'MESH:C535700', (202, 226))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('leukemias', 'Disease', 'MESH:D007938', (173, 182))	('associated', 'Reg', (99, 109))
330001	26776507	The primary oncogenic event in ~85% of ES tumors is a t(11:22)(q24:q12) translocation.	('ES tumors', 'Disease', 'MESH:C563168', (39, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('t(11:22)(q24:q12)', 'STRUCTURAL_ABNORMALITY', 'None', (54, 71))	('ES tumors', 'Disease', (39, 48))	('ES', 'Phenotype', 'HP:0012254', (39, 41))	('t(11:22)(q24:q12', 'Var', (54, 70))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
330013	26776507	Specifically, translocations that retain exon 8 of EWSR1 generate an out-of-frame transcript unless this exon is removed.	('EWSR1', 'Gene', (51, 56))	('transcript', 'MPA', (82, 92))	('EWSR1', 'Gene', '2130', (51, 56))	('out-of-frame', 'NegReg', (69, 81))	('translocations that', 'Var', (14, 33))
330014	26776507	A recent study showed 15 of 42 ES tumors harbored translocations in which the EWSR1 exon 8 must be spliced out to express an in-frame EWS-FLI1 transcript.	('ES tumors', 'Disease', (31, 40))	('EWSR1', 'Gene', '2130', (78, 83))	('ES', 'Phenotype', 'HP:0012254', (31, 33))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('EWS-FLI1', 'Gene', (134, 142))	('ES tumors', 'Disease', 'MESH:C563168', (31, 40))	('EWSR1', 'Gene', (78, 83))	('translocations', 'Var', (50, 64))	('EWS-FLI1', 'Gene', '2130;2313', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
330016	26776507	We also show ES cell lines harboring 7/6 or 7/5 EWS-FLI1 fusions are sensitive to the inhibition of the core splicing factor, SF3B1.	('EWS-FLI1', 'Gene', '2130;2313', (48, 56))	('SF3B1', 'Gene', (126, 131))	('sensitive', 'Reg', (69, 78))	('fusions', 'Var', (57, 64))	('SF3B1', 'Gene', '23451', (126, 131))	('EWS-FLI1', 'Gene', (48, 56))	('ES', 'Phenotype', 'HP:0012254', (13, 15))
330020	26776507	To prioritize genes for confirmation, we focused on genes for which the median seed adjusted Zdiff (ZNR0B1-ZCMV) for the 3 siRNAs per gene was either < -1.5 (the top 1% of candidates) or > 2 (the top 0.25% of candidates).	('NR0B1', 'Gene', '190', (101, 106))	('< -1.5', 'Var', (150, 156))	('NR0B1', 'Gene', (101, 106))
330024	26776507	Further analysis of the effects of silencing SF3B1, SUPT6H, or HNRNPH1 in the TC32 reporter assay (6 siRNAs per gene, see Supplemental Experimental Procedures) confirmed that the depletion of these proteins induces a selective decrease in the NR0B1-luc reporter (Figure 1D).	('HNRNPH1', 'Gene', (63, 70))	('NR0B1', 'Gene', (243, 248))	('silencing', 'Var', (35, 44))	('SUPT6H', 'Gene', (52, 58))	('NR0B1', 'Gene', '190', (243, 248))	('SUPT6H', 'Gene', '6830', (52, 58))	('SF3B1', 'Gene', (45, 50))	('TC32', 'CellLine', 'CVCL:7151', (78, 82))	('HNRNPH1', 'Gene', '3187', (63, 70))	('depletion', 'MPA', (179, 188))	('decrease', 'NegReg', (227, 235))	('SF3B1', 'Gene', '23451', (45, 50))
330026	26776507	To determine if silencing SF3B1, SUPT6H, or HNRNPH1 results in specific changes in expression of genes that are deregulated in ES or a broad, pleiotropic effect because of their importance in the processing of RNA, we conducted gene set enrichment analysis (GSEA) using a set of genes previously shown to exhibit altered expression in ES (Figure 2A).	('SF3B1', 'Gene', (26, 31))	('GSEA', 'Chemical', '-', (258, 262))	('HNRNPH1', 'Gene', '3187', (44, 51))	('SF3B1', 'Gene', '23451', (26, 31))	('ES', 'Phenotype', 'HP:0012254', (127, 129))	('HNRNPH1', 'Gene', (44, 51))	('silencing', 'Var', (16, 25))	('ES', 'Phenotype', 'HP:0012254', (335, 337))	('changes', 'Reg', (72, 79))	('expression', 'MPA', (83, 93))	('SUPT6H', 'Gene', (33, 39))	('SUPT6H', 'Gene', '6830', (33, 39))
330034	26776507	Importantly, though the transcriptome of SF3B1-silenced TC32 cells showed no enrichment for the altered expression of ES specific genes or decreased expression of NR0B1, several genes recently reported as activated by EWS-FLI1 were down-regulated following silencing of SF3B1 (Figure S2H).	('silencing', 'Var', (257, 266))	('SF3B1', 'Gene', (270, 275))	('TC32', 'CellLine', 'CVCL:7151', (56, 60))	('ES', 'Phenotype', 'HP:0012254', (118, 120))	('EWS-FLI1', 'Gene', (218, 226))	('SF3B1', 'Gene', (41, 46))	('NR0B1', 'Gene', (163, 168))	('SF3B1', 'Gene', '23451', (270, 275))	('decreased', 'NegReg', (139, 148))	('EWS-FLI1', 'Gene', '2130;2313', (218, 226))	('expression', 'MPA', (149, 159))	('down-regulated', 'NegReg', (232, 246))	('NR0B1', 'Gene', '190', (163, 168))	('SF3B1', 'Gene', '23451', (41, 46))
330035	26776507	Overall, these data suggest that the silencing of SF3B1, SUPT6H, or HNRNPH1 results in some selective changes in the expression of genes that are deregulated in ES.	('SUPT6H', 'Gene', '6830', (57, 63))	('SF3B1', 'Gene', (50, 55))	('HNRNPH1', 'Gene', '3187', (68, 75))	('expression of genes', 'MPA', (117, 136))	('changes', 'Reg', (102, 109))	('silencing', 'Var', (37, 46))	('SF3B1', 'Gene', '23451', (50, 55))	('HNRNPH1', 'Gene', (68, 75))	('SUPT6H', 'Gene', (57, 63))	('ES', 'Phenotype', 'HP:0012254', (161, 163))
330036	26776507	We next assessed whether each protein is required for the expression of the EWS-FLI1 fusion transcript itself using qPCR primers spanning the fusion breakpoint (EWSR1 exon 7/FLI1 exon 7, E7/F7).	('FLI1', 'Gene', '2313', (174, 178))	('FLI1', 'Gene', (174, 178))	('EWS-FLI1', 'Gene', '2130;2313', (76, 84))	('E7/F7', 'Var', (187, 192))	('EWSR1', 'Gene', '2130', (161, 166))	('FLI1', 'Gene', (80, 84))	('FLI1', 'Gene', '2313', (80, 84))	('EWSR1', 'Gene', (161, 166))	('EWS-FLI1', 'Gene', (76, 84))
330037	26776507	Depletion of SF3B1 mediated a 5.5-fold decrease in EWS-FLI1 expression, while depletion of HNRNPH1 resulted in a 3.75-fold decrease and depletion of SUPT6H a 1.9-fold decrease (Figure 2C).	('expression', 'MPA', (60, 70))	('HNRNPH1', 'Gene', '3187', (91, 98))	('depletion', 'Var', (78, 87))	('decrease', 'NegReg', (39, 47))	('decrease', 'NegReg', (123, 131))	('SF3B1', 'Gene', (13, 18))	('HNRNPH1', 'Gene', (91, 98))	('Depletion', 'Var', (0, 9))	('SUPT6H', 'Gene', (149, 155))	('depletion', 'MPA', (136, 145))	('SF3B1', 'Gene', '23451', (13, 18))	('EWS-FLI1', 'Gene', (51, 59))	('SUPT6H', 'Gene', '6830', (149, 155))	('EWS-FLI1', 'Gene', '2130;2313', (51, 59))
330038	26776507	Analysis of EWS-FLI1 protein (Figure 2D) showed silencing of HNRNPH1 in TC32 cells mediated an almost complete elimination of oncoprotein expression.	('oncoprotein expression', 'MPA', (126, 148))	('silencing', 'Var', (48, 57))	('HNRNPH1', 'Gene', '3187', (61, 68))	('EWS-FLI1', 'Gene', '2130;2313', (12, 20))	('TC32', 'CellLine', 'CVCL:7151', (72, 76))	('elimination', 'NegReg', (111, 122))	('HNRNPH1', 'Gene', (61, 68))	('EWS-FLI1', 'Gene', (12, 20))
330039	26776507	Silencing of SUPT6H also decreased EWS-FLI1 protein levels, but to a lesser extent.	('SUPT6H', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (25, 34))	('SUPT6H', 'Gene', '6830', (13, 19))	('EWS-FLI1', 'Gene', (35, 43))	('EWS-FLI1', 'Gene', '2130;2313', (35, 43))
330040	26776507	Interestingly, while qPCR detected a decrease in EWS-FLI1 RNA levels following silencing of SF3B1, immunoblot analysis of EWS-FLI1 detected multiple products, leading us to speculate that silencing of SF3B1 results in expression of EWS-FLI1 transcript variants undetected by the E7/F7 primers.	('variants', 'Var', (252, 260))	('decrease', 'NegReg', (37, 45))	('SF3B1', 'Gene', '23451', (92, 97))	('SF3B1', 'Gene', '23451', (201, 206))	('EWS-FLI1', 'Gene', (232, 240))	('EWS-FLI1', 'Gene', (122, 130))	('EWS-FLI1', 'Gene', '2130;2313', (232, 240))	('EWS-FLI1', 'Gene', (49, 57))	('EWS-FLI1', 'Gene', '2130;2313', (49, 57))	('expression', 'MPA', (218, 228))	('EWS-FLI1', 'Gene', '2130;2313', (122, 130))	('silencing', 'Var', (79, 88))	('silencing', 'Var', (188, 197))	('SF3B1', 'Gene', (92, 97))	('SF3B1', 'Gene', (201, 206))
330042	26776507	ES cells depend on the activity of EWS-FLI1 for survival and so disruption of the maturation of the EWS-FLI1 transcript should result in a reduction in viability of ES cells.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('ES', 'Phenotype', 'HP:0012254', (165, 167))	('reduction', 'NegReg', (139, 148))	('disruption', 'Var', (64, 74))	('viability', 'CPA', (152, 161))	('maturation', 'MPA', (82, 92))	('EWS-FLI1', 'Gene', (100, 108))	('EWS-FLI1', 'Gene', '2130;2313', (100, 108))	('EWS-FLI1', 'Gene', (35, 43))	('EWS-FLI1', 'Gene', '2130;2313', (35, 43))
330047	26776507	EWS-FLI1 expression was reduced in all 4 ES cell lines following silencing of SF3B1 (Figure 3B), and to a lesser extent following silencing of SUPT6H (Figure S3A).	('silencing', 'Var', (65, 74))	('ES', 'Phenotype', 'HP:0012254', (41, 43))	('reduced', 'NegReg', (24, 31))	('SUPT6H', 'Gene', (143, 149))	('SF3B1', 'Gene', '23451', (78, 83))	('SUPT6H', 'Gene', '6830', (143, 149))	('EWS-FLI1', 'Gene', (0, 8))	('expression', 'MPA', (9, 19))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('SF3B1', 'Gene', (78, 83))
330048	26776507	In contrast, silencing of HNRNPH1 in SKNMC cells mediated a decrease in the expression of EWS-FLI1, similar to TC32 cells but induced minimal changes in EWS-FLI1 expression in the other ES cell lines (Figure 3C).	('EWS-FLI1', 'Gene', (153, 161))	('decrease', 'NegReg', (60, 68))	('EWS-FLI1', 'Gene', '2130;2313', (90, 98))	('ES', 'Phenotype', 'HP:0012254', (186, 188))	('TC32', 'CellLine', 'CVCL:7151', (111, 115))	('silencing', 'Var', (13, 22))	('HNRNPH1', 'Gene', (26, 33))	('EWS-FLI1', 'Gene', '2130;2313', (153, 161))	('SKNMC', 'CellLine', 'CVCL:0530', (37, 42))	('expression', 'MPA', (76, 86))	('EWS-FLI1', 'Gene', (90, 98))	('HNRNPH1', 'Gene', '3187', (26, 33))
330052	26776507	We also detected a single PCR product following silencing of HNRNPH1 in TC71 or RDES cells (Figure 3D).	('silencing', 'Var', (48, 57))	('TC71', 'CellLine', 'CVCL:2213', (72, 76))	('HNRNPH1', 'Gene', '3187', (61, 68))	('ES', 'Phenotype', 'HP:0012254', (82, 84))	('HNRNPH1', 'Gene', (61, 68))
330060	26776507	The selective effect of silencing of HNRNPH1 on EWS-FLI1 expression and thus its activity in TC32 and SKNMC cells was further validated when we examined EZH2, PRKCB, and VRK1 protein expression in these cell lines following silencing of HNRNPH1 versus HNRNPH1-silenced TC71 or RD-ES cells (Figure 4B).	('HNRNPH1', 'Gene', '3187', (252, 259))	('VRK1', 'Gene', '7443', (170, 174))	('TC71', 'CellLine', 'CVCL:2213', (269, 273))	('ES', 'Phenotype', 'HP:0012254', (280, 282))	('EZH2', 'Gene', (153, 157))	('EZH2', 'Gene', '2146', (153, 157))	('PRKCB', 'Gene', '5579', (159, 164))	('activity', 'MPA', (81, 89))	('SKNMC', 'CellLine', 'CVCL:0530', (102, 107))	('EWS-FLI1', 'Gene', '2130;2313', (48, 56))	('HNRNPH1', 'Gene', '3187', (37, 44))	('TC32', 'CellLine', 'CVCL:7151', (93, 97))	('VRK1', 'Gene', (170, 174))	('HNRNPH1', 'Gene', (237, 244))	('HNRNPH1', 'Gene', (252, 259))	('silencing', 'Var', (224, 233))	('HNRNPH1', 'Gene', '3187', (237, 244))	('PRKCB', 'Gene', (159, 164))	('HNRNPH1', 'Gene', (37, 44))	('EWS-FLI1', 'Gene', (48, 56))	('silencing', 'Var', (24, 33))
330061	26776507	Importantly, the silencing of HNRNPH1 in TC32 cells resulted in a highly significant decrease in cell viability, similar to the direct silencing of EWS-FLI1, while the silencing of HNRNPH1 in TC71 resulted in minimal changes in cell viability (Figure 4C).	('HNRNPH1', 'Gene', '3187', (30, 37))	('TC32', 'CellLine', 'CVCL:7151', (41, 45))	('EWS-FLI1', 'Gene', '2130;2313', (148, 156))	('HNRNPH1', 'Gene', (30, 37))	('decrease', 'NegReg', (85, 93))	('HNRNPH1', 'Gene', '3187', (181, 188))	('TC71', 'CellLine', 'CVCL:2213', (192, 196))	('EWS-FLI1', 'Gene', (148, 156))	('cell viability', 'CPA', (97, 111))	('silencing', 'Var', (17, 26))	('HNRNPH1', 'Gene', (181, 188))
330070	26776507	One possibility is that SF3B1 silencing results in both reduced expression of full length EWS-FLI1 and the expression of mis-spliced EWS-FLI1 variant transcripts that are in-frame.	('variant', 'Var', (142, 149))	('EWS-FLI1', 'Gene', '2130;2313', (90, 98))	('expression', 'MPA', (64, 74))	('EWS-FLI1', 'Gene', (133, 141))	('SF3B1', 'Gene', (24, 29))	('reduced', 'NegReg', (56, 63))	('expression', 'MPA', (107, 117))	('EWS-FLI1', 'Gene', '2130;2313', (133, 141))	('silencing', 'NegReg', (30, 39))	('SF3B1', 'Gene', '23451', (24, 29))	('EWS-FLI1', 'Gene', (90, 98))
330071	26776507	To test this hypothesis, we performed PCR analysis of RNA from siRNA-transfected SKNMC cells using the E7/F7 primer pair and a second primer pair consisting of the same forward primer, but a FLI1 exon 9 reverse primer (E7/F9) (Figure 5B).	('FLI1', 'Gene', '2313', (191, 195))	('E7/F9', 'Var', (219, 224))	('FLI1', 'Gene', (191, 195))	('SKNMC', 'CellLine', 'CVCL:0530', (81, 86))	('E7/F7', 'Var', (103, 108))
330073	26776507	The E7/F7 primer pair detected a similar reduction in EWS-FLI1 expression in SF3B1-silenced SKNMC cells, but the E7/F9 primer pair detected only a partial loss of EWS-FLI1 expression, indicating the expression of a variant EWS-FLI1 transcript that excludes FLI1 exon 7, but includes FLI1 exon 9.	('EWS-FLI1', 'Gene', (54, 62))	('FLI1', 'Gene', '2313', (58, 62))	('SF3B1', 'Gene', '23451', (77, 82))	('FLI1', 'Gene', '2313', (167, 171))	('loss', 'NegReg', (155, 159))	('EWS-FLI1', 'Gene', '2130;2313', (223, 231))	('variant', 'Var', (215, 222))	('EWS-FLI1', 'Gene', '2130;2313', (54, 62))	('SKNMC', 'CellLine', 'CVCL:0530', (92, 97))	('FLI1', 'Gene', (283, 287))	('EWS-FLI1', 'Gene', (163, 171))	('FLI1', 'Gene', (257, 261))	('FLI1', 'Gene', (227, 231))	('FLI1', 'Gene', '2313', (283, 287))	('FLI1', 'Gene', '2313', (257, 261))	('reduction', 'NegReg', (41, 50))	('SF3B1', 'Gene', (77, 82))	('FLI1', 'Gene', (58, 62))	('FLI1', 'Gene', '2313', (227, 231))	('EWS-FLI1', 'Gene', '2130;2313', (163, 171))	('expression', 'MPA', (172, 182))	('EWS-FLI1', 'Gene', (223, 231))	('FLI1', 'Gene', (167, 171))
330074	26776507	These results suggest that physiological levels of SF3B1 are required for the generation of an EWS-FLI1 transcript that includes all exons and disruption of spliceosome activity can result in the generation of variant EWS-FLI1 transcripts with altered exon usage.	('EWS-FLI1', 'Gene', (95, 103))	('transcripts', 'MPA', (227, 238))	('EWS-FLI1', 'Gene', (218, 226))	('EWS-FLI1', 'Gene', '2130;2313', (95, 103))	('EWS-FLI1', 'Gene', '2130;2313', (218, 226))	('SF3B1', 'Gene', (51, 56))	('variant', 'Var', (210, 217))	('result in', 'Reg', (182, 191))	('SF3B1', 'Gene', '23451', (51, 56))
330081	26776507	The silencing of other U2 snRNP components identified by the RNAi screen mediated a similar decrease in the expression and mis-splicing of EWS-FLI1 (Figure S5B and S5C).	('decrease', 'NegReg', (92, 100))	('EWS-FLI1', 'Gene', (139, 147))	('EWS-FLI1', 'Gene', '2130;2313', (139, 147))	('S5B', 'Gene', '5711', (156, 159))	('expression', 'MPA', (108, 118))	('mis-splicing', 'MPA', (123, 135))	('S5B', 'Gene', (156, 159))	('silencing', 'Var', (4, 13))
330086	26776507	To confirm we were detecting the same EWS-FLI1 transcript variants as observed in SF3B1-silenced ES cells, we assessed the splicing of EWS-FLI1 in ES cells treated with 5 nM PlaB (6h).	('SF3B1', 'Gene', (82, 87))	('variants', 'Var', (58, 66))	('EWS-FLI1', 'Gene', '2130;2313', (135, 143))	('SF3B1', 'Gene', '23451', (82, 87))	('EWS-FLI1', 'Gene', '2130;2313', (38, 46))	('ES', 'Phenotype', 'HP:0012254', (97, 99))	('PlaB', 'Chemical', 'MESH:C522342', (174, 178))	('ES', 'Phenotype', 'HP:0012254', (147, 149))	('EWS-FLI1', 'Gene', (38, 46))	('EWS-FLI1', 'Gene', (135, 143))
330087	26776507	Following PlaB treatment, we observed the failure of TC32 cells to exclude EWSR1 exon 8 when processing EWS-FLI1 (Figure S5E) and mis-splicing of EWS-FLI1 at the exons adjacent to the breakpoint (Figures 5E and S5F).	('EWSR1', 'Gene', '2130', (75, 80))	('mis-splicing', 'Var', (130, 142))	('EWS-FLI1', 'Gene', '2130;2313', (104, 112))	('EWS-FLI1', 'Gene', '2130;2313', (146, 154))	('TC32', 'CellLine', 'CVCL:7151', (53, 57))	('PlaB', 'Chemical', 'MESH:C522342', (10, 14))	('EWS-FLI1', 'Gene', (104, 112))	('EWSR1', 'Gene', (75, 80))	('EWS-FLI1', 'Gene', (146, 154))
330092	26776507	PCR analysis of the splicing of FLI1 exons following PlaB treatment of ES cells (or the silencing of SF3B1) detected transcripts in which FLI1 exon 7 is excluded (Figure 5H, Figure S5H) suggesting that mis-spliced EWS-FLI1 transcripts may have the potential to express variant EWS-FLI1 proteins, though further study will be required to confirm this.	('EWS-FLI1', 'Gene', (214, 222))	('EWS-FLI1', 'Gene', (277, 285))	('FLI1', 'Gene', '2313', (32, 36))	('PlaB', 'Chemical', 'MESH:C522342', (53, 57))	('EWS-FLI1', 'Gene', '2130;2313', (214, 222))	('ES', 'Phenotype', 'HP:0012254', (71, 73))	('EWS-FLI1', 'Gene', '2130;2313', (277, 285))	('variant', 'Var', (269, 276))	('FLI1', 'Gene', (138, 142))	('express', 'Reg', (261, 268))	('SF3B1', 'Gene', (101, 106))	('FLI1', 'Gene', (218, 222))	('FLI1', 'Gene', (281, 285))	('FLI1', 'Gene', '2313', (138, 142))	('proteins', 'Protein', (286, 294))	('FLI1', 'Gene', (32, 36))	('FLI1', 'Gene', '2313', (218, 222))	('FLI1', 'Gene', '2313', (281, 285))	('SF3B1', 'Gene', '23451', (101, 106))
330103	26776507	Overall, we observed a substantial decrease in the expression of each EWS-FLI1 activated gene following either PlaB treatment or silencing of SF3B1.	('EWS-FLI1', 'Gene', '2130;2313', (70, 78))	('silencing', 'Var', (129, 138))	('decrease', 'NegReg', (35, 43))	('SF3B1', 'Gene', (142, 147))	('expression', 'MPA', (51, 61))	('SF3B1', 'Gene', '23451', (142, 147))	('EWS-FLI1', 'Gene', (70, 78))	('PlaB', 'Chemical', 'MESH:C522342', (111, 115))
330104	26776507	Importantly, with the exception of EZH2 (Figure S6C) we observed no direct effect of PlaB or the silencing of SF3B1 on the splicing of these genes (data not shown).	('silencing', 'Var', (97, 106))	('splicing', 'MPA', (123, 131))	('PlaB', 'Chemical', 'MESH:C522342', (85, 89))	('EZH2', 'Gene', (35, 39))	('SF3B1', 'Gene', (110, 115))	('EZH2', 'Gene', '2146', (35, 39))	('SF3B1', 'Gene', '23451', (110, 115))
330105	26776507	Extending our analysis to assessment of protein, we observed variable decreases in the expression of NR0B1 following PlaB and silencing of SF3B1, but we observed complete depletion of PRKCB protein expression (Figure 6F).	('SF3B1', 'Gene', '23451', (139, 144))	('depletion', 'NegReg', (171, 180))	('decreases', 'NegReg', (70, 79))	('PRKCB', 'Gene', (184, 189))	('NR0B1', 'Gene', (101, 106))	('expression', 'MPA', (87, 97))	('protein expression', 'MPA', (190, 208))	('PRKCB', 'Gene', '5579', (184, 189))	('SF3B1', 'Gene', (139, 144))	('NR0B1', 'Gene', '190', (101, 106))	('PlaB', 'Chemical', 'MESH:C522342', (117, 121))	('silencing', 'Var', (126, 135))
330108	26776507	Taken together, these data suggest that the identification by RNAi screening of multiple members of the U2 snRNP as required for EWS-FLI1 activity is because the EWS-FLI1 transcript is particularly sensitive to disruption of spliceosome function.	('sensitive', 'MPA', (198, 207))	('disruption', 'Var', (211, 221))	('EWS-FLI1', 'Gene', '2130;2313', (162, 170))	('EWS-FLI1', 'Gene', (129, 137))	('EWS-FLI1', 'Gene', '2130;2313', (129, 137))	('EWS-FLI1', 'Gene', (162, 170))
330109	26776507	In particular, this altered splicing of the EWS-FLI1 transcript is sufficient to disrupt the ability of the EWS-FLI1 to activate the expression of EWS-FLI1 target genes including genes associated with ES tumorigenesis.	('EWS-FLI1', 'Gene', '2130;2313', (108, 116))	('expression', 'MPA', (133, 143))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('activate', 'PosReg', (120, 128))	('altered', 'Var', (20, 27))	('EWS-FLI1', 'Gene', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('EWS-FLI1', 'Gene', '2130;2313', (44, 52))	('EWS-FLI1', 'Gene', (147, 155))	('ES', 'Phenotype', 'HP:0012254', (201, 203))	('tumor', 'Disease', (204, 209))	('EWS-FLI1', 'Gene', (108, 116))	('ability', 'MPA', (93, 100))	('EWS-FLI1', 'Gene', '2130;2313', (147, 155))	('disrupt', 'NegReg', (81, 88))
330117	26776507	Disruption of the splicing of EWS-FLI1 alters the expression of the EWS-FLI1 protein and reverses the expression of a significant proportion of the genes EWS-FLI1 deregulates, including many of the genes required for the survival of ES cells.	('alters', 'Reg', (39, 45))	('reverses', 'NegReg', (89, 97))	('expression', 'MPA', (102, 112))	('EWS-FLI1', 'Gene', (68, 76))	('deregulates', 'PosReg', (163, 174))	('EWS-FLI1', 'Gene', (30, 38))	('EWS-FLI1', 'Gene', (154, 162))	('protein', 'Protein', (77, 84))	('EWS-FLI1', 'Gene', '2130;2313', (68, 76))	('EWS-FLI1', 'Gene', '2130;2313', (154, 162))	('EWS-FLI1', 'Gene', '2130;2313', (30, 38))	('expression', 'MPA', (50, 60))	('ES', 'Phenotype', 'HP:0012254', (233, 235))	('Disruption', 'Var', (0, 10))
330127	26776507	The importance of SF3B1 in tumorigenesis has recently become appreciated with the identification of mutations in SF3B1.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (100, 109))	('tumor', 'Disease', (27, 32))	('SF3B1', 'Gene', (113, 118))	('SF3B1', 'Gene', (18, 23))	('SF3B1', 'Gene', '23451', (113, 118))	('SF3B1', 'Gene', '23451', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
330128	26776507	In this study, we showed that the effect of silencing of SF3B1 on the splicing of EWS-FLI1 is phenocopied by a small molecule inhibitor of the spliceosome, Pladienolide B.	('SF3B1', 'Gene', (57, 62))	('EWS-FLI1', 'Gene', (82, 90))	('SF3B1', 'Gene', '23451', (57, 62))	('EWS-FLI1', 'Gene', '2130;2313', (82, 90))	('Pladienolide B', 'Chemical', 'MESH:C522342', (156, 170))	('silencing', 'Var', (44, 53))	('splicing', 'MPA', (70, 78))
330131	26776507	The aberrant splicing of EWS-FLI1 resulting from inhibition of spliceosome function also provided insight into the biology of ES.	('spliceosome function', 'MPA', (63, 83))	('aberrant splicing', 'Var', (4, 21))	('EWS-FLI1', 'Gene', (25, 33))	('ES', 'Phenotype', 'HP:0012254', (126, 128))	('EWS-FLI1', 'Gene', '2130;2313', (25, 33))	('inhibition', 'NegReg', (49, 59))
330133	26776507	It could be that activated targets of EWS-FLI1 are more vulnerable to a reduction in expression of the full length EWS-FLI1 oncoprotein because of the need for binding of multimers of EWS-FLI1 to GGAA microsatellite sequences, or the variant EWS-FLI1 proteins encoded by mis-spliced EWS-FLI1 transcripts could have different binding affects at GGAA microsatellites than at repressive ETS consensus sites.	('reduction', 'NegReg', (72, 81))	('expression', 'MPA', (85, 95))	('EWS-FLI1', 'Gene', (242, 250))	('EWS-FLI1', 'Gene', (184, 192))	('binding', 'Interaction', (325, 332))	('EWS-FLI1', 'Gene', (283, 291))	('EWS-FLI1', 'Gene', '2130;2313', (242, 250))	('EWS-FLI1', 'Gene', '2130;2313', (184, 192))	('EWS-FLI1', 'Gene', '2130;2313', (115, 123))	('EWS-FLI1', 'Gene', '2130;2313', (283, 291))	('EWS-FLI1', 'Gene', (38, 46))	('variant', 'Var', (234, 241))	('EWS-FLI1', 'Gene', (115, 123))	('EWS-FLI1', 'Gene', '2130;2313', (38, 46))
330134	26776507	Further analysis of the transcriptional activity of variant proteins generated following the mis-splicing of EWS-FLI1 may give insight into how the oncoprotein deregulates the expression of specific genes.	('EWS-FLI1', 'Gene', (109, 117))	('deregulates', 'NegReg', (160, 171))	('EWS-FLI1', 'Gene', '2130;2313', (109, 117))	('expression', 'MPA', (176, 186))	('mis-splicing', 'Var', (93, 105))
330151	23558962	As aberrant microRNA (miRNA) expression patterns represent putative diagnostic cancer markers, we aimed to identify miRNA expression profiles of the major uterine sarcoma subtypes and mixed epithelial-mesenchymal tumors of the uterus.	('miR', 'Gene', '220972', (22, 25))	('epithelial-mesenchymal tumors', 'Disease', (190, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('aberrant', 'Var', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', (116, 119))	('epithelial-mesenchymal tumors', 'Disease', 'MESH:C535700', (190, 219))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (163, 179))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (155, 170))	('cancer', 'Disease', (79, 85))	('miR', 'Gene', (22, 25))	('tumors of the uterus', 'Phenotype', 'HP:0010784', (213, 233))	('sarcoma subtypes', 'Disease', (163, 179))
330153	23558962	Tumor and control samples significantly (P < 0.05) differed in the expression of miR-23b, miR-1, let-7f, and let-7c in endometrial sarcomas, and miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214 in mixed epithelial-mesenchymal tumors.	('miR-222', 'Gene', '407007', (219, 226))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-143', 'Gene', '406935', (178, 185))	('miR-23b', 'Gene', (81, 88))	('let-7c', 'Gene', (109, 115))	('miR-143', 'Gene', (178, 185))	('miR-1', 'Gene', (160, 165))	('let-7i', 'Gene', '406891', (228, 234))	('miR-1', 'Gene', '79187', (178, 183))	('endometrial sarcomas', 'Disease', 'MESH:D018203', (119, 139))	('let-7c', 'Gene', '406885', (152, 158))	('let-7b', 'Gene', '406884', (170, 176))	('miR-1', 'Gene', '79187', (145, 150))	('miR-1', 'Gene', '79187', (90, 95))	('endometrial sarcomas', 'Disease', (119, 139))	('let-7f', 'Gene', (97, 103))	('epithelial-mesenchymal tumors', 'Disease', 'MESH:C535700', (257, 286))	('let-7a', 'Var', (187, 193))	('miR-214', 'Gene', '406996', (240, 247))	('epithelial-mesenchymal tumors', 'Disease', (257, 286))	('let-7d', 'Gene', '406886', (195, 201))	('miR-133b', 'Gene', (160, 168))	('let-7c', 'Gene', '406885', (109, 115))	('let-7i', 'Gene', (228, 234))	('let-7b', 'Gene', (170, 176))	('miR-1', 'Gene', '79187', (160, 165))	('let-7d', 'Gene', (195, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('miR-222', 'Gene', (219, 226))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('miR-23b', 'Gene', '407011', (81, 88))	('miR-1', 'Gene', (178, 183))	('miR-214', 'Gene', (240, 247))	('let-7e', 'Gene', (203, 209))	('miR-1', 'Gene', (145, 150))	('miR-1', 'Gene', (90, 95))	('let-7g', 'Gene', '406890', (211, 217))	('let-7c', 'Gene', (152, 158))	('miR-133b', 'Gene', '442890', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('differed', 'Reg', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('expression', 'MPA', (67, 77))	('let-7e', 'Gene', '406887', (203, 209))	('let-7g', 'Gene', (211, 217))
330193	23558962	The expression levels of 12 miRs, miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214, which were down-regulated in mixed epithelial-mesenchymal tumors are presented in Fig.	('let-7c', 'Gene', '406885', (41, 47))	('miR-143', 'Gene', (67, 74))	('miR-1', 'Gene', (49, 54))	('miR-1', 'Gene', '79187', (67, 72))	('let-7i', 'Gene', '406891', (117, 123))	('miR-1', 'Gene', '79187', (34, 39))	('miR-222', 'Gene', '407007', (108, 115))	('let-7b', 'Gene', '406884', (59, 65))	('miR', 'Gene', (108, 111))	('miR', 'Gene', '220972', (28, 31))	('epithelial-mesenchymal tumors', 'Disease', 'MESH:C535700', (173, 202))	('miR', 'Gene', (67, 70))	('miR-214', 'Gene', '406996', (129, 136))	('miR', 'Gene', '220972', (129, 132))	('let-7a', 'Var', (76, 82))	('let-7d', 'Gene', '406886', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('epithelial-mesenchymal tumors', 'Disease', (173, 202))	('miR-133b', 'Gene', (49, 57))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', '220972', (49, 52))	('miR-1', 'Gene', '79187', (49, 54))	('let-7i', 'Gene', (117, 123))	('let-7b', 'Gene', (59, 65))	('miR', 'Gene', (28, 31))	('down-regulated', 'NegReg', (149, 163))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('miR', 'Gene', (129, 132))	('let-7d', 'Gene', (84, 90))	('miR', 'Gene', '220972', (67, 70))	('miR-214', 'Gene', (129, 136))	('miR-1', 'Gene', (67, 72))	('miR', 'Gene', (34, 37))	('miR', 'Gene', (49, 52))	('let-7e', 'Gene', (92, 98))	('miR-1', 'Gene', (34, 39))	('miR-222', 'Gene', (108, 115))	('let-7g', 'Gene', '406890', (100, 106))	('let-7c', 'Gene', (41, 47))	('miR-133b', 'Gene', '442890', (49, 57))	('let-7e', 'Gene', '406887', (92, 98))	('let-7g', 'Gene', (100, 106))	('miR', 'Gene', '220972', (108, 111))	('miR-143', 'Gene', '406935', (67, 74))
330215	23558962	As we showed here, mixed epithelial-mesenchymal tumors compared to the normal uterine fragments, expressed decreased levels of 12 miRs (miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214).	('let-7e', 'Gene', '406887', (194, 200))	('let-7g', 'Gene', (202, 208))	('miR', 'Gene', '220972', (210, 213))	('miR', 'Gene', '220972', (169, 172))	('miR-143', 'Gene', '406935', (169, 176))	('miR-143', 'Gene', (169, 176))	('miR-1', 'Gene', '79187', (169, 174))	('levels', 'MPA', (117, 123))	('let-7c', 'Gene', '406885', (143, 149))	('miR-1', 'Gene', (151, 156))	('let-7i', 'Gene', '406891', (219, 225))	('miR-1', 'Gene', '79187', (136, 141))	('miR', 'Gene', '220972', (130, 133))	('let-7b', 'Gene', '406884', (161, 167))	('miR-222', 'Gene', '407007', (210, 217))	('miR', 'Gene', (210, 213))	('miR', 'Gene', (169, 172))	('let-7a', 'Var', (178, 184))	('miR-214', 'Gene', '406996', (231, 238))	('let-7d', 'Gene', '406886', (186, 192))	('miR', 'Gene', '220972', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('epithelial-mesenchymal tumors', 'Disease', 'MESH:C535700', (25, 54))	('miR-133b', 'Gene', (151, 159))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (130, 133))	('let-7b', 'Gene', (161, 167))	('miR-1', 'Gene', '79187', (151, 156))	('let-7i', 'Gene', (219, 225))	('epithelial-mesenchymal tumors', 'Disease', (25, 54))	('let-7d', 'Gene', (186, 192))	('miR', 'Gene', (231, 234))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('miR', 'Gene', (151, 154))	('miR-214', 'Gene', (231, 238))	('miR-1', 'Gene', (169, 174))	('miR', 'Gene', (136, 139))	('decreased', 'NegReg', (107, 116))	('miR-1', 'Gene', (136, 141))	('let-7e', 'Gene', (194, 200))	('miR-133b', 'Gene', '442890', (151, 159))	('miR-222', 'Gene', (210, 217))	('let-7g', 'Gene', '406890', (202, 208))	('let-7c', 'Gene', (143, 149))
330219	23558962	Studies in a mouse model of rhabdomyosarcoma have shown that reconstitution of miR-29b/c and miR-206 inhibits tumor growth and stimulates muscle differentiation, suggesting their role of a tumor suppressor.	('mouse', 'Species', '10090', (13, 18))	('tumor', 'Disease', (189, 194))	('miR-29b', 'Gene', '407024', (79, 86))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (28, 44))	('stimulates', 'PosReg', (127, 137))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('miR-29b', 'Gene', (79, 86))	('inhibits', 'NegReg', (101, 109))	('miR-206', 'Var', (93, 100))	('rhabdomyosarcoma', 'Disease', (28, 44))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('muscle differentiation', 'CPA', (138, 160))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (28, 44))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
330226	23558962	proved that phosphatase and tensin homolog (PTEN) is a target of miR-132, and that the induction of MCP-1 occurs via PTEN repression.	('PTEN', 'Gene', (117, 121))	('PTEN', 'Gene', '5728', (117, 121))	('MCP-1', 'Gene', (100, 105))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('miR-132', 'Var', (65, 72))	('MCP-1', 'Gene', '6347', (100, 105))
330227	23558962	Mutational inactivation of PTEN is not a common event in uterine sarcomas, though in carcinosarcomas it may play a tumorogenic role.	('play', 'Reg', (108, 112))	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('sarcomas', 'Disease', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('carcinosarcomas', 'Disease', 'MESH:D002296', (85, 100))	('sarcomas', 'Disease', (65, 73))	('tumor', 'Disease', (115, 120))	('Mutational inactivation', 'Var', (0, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('carcinosarcomas', 'Disease', (85, 100))	('PTEN', 'Gene', (27, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('PTEN', 'Gene', '5728', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (57, 72))
330240	23558962	Yet our findings on a common decrease in the expression of the let-7 family members (let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g and let-7i) in tumor samples support the notion of let-7 family members as tumor suppressors influencing survival [ and references therein].	('tumor', 'Disease', (155, 160))	('let-7i', 'Gene', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('decrease', 'NegReg', (29, 37))	('let-7b', 'Gene', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('let-7d', 'Gene', '406886', (109, 115))	('let-7c', 'Gene', (101, 107))	('let-7', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('let-7e', 'Gene', (117, 123))	('let-7f', 'Var', (125, 131))	('let-7d', 'Gene', (109, 115))	('let-7c', 'Gene', '406885', (101, 107))	('let-7g', 'Gene', '406890', (133, 139))	('tumor', 'Disease', (215, 220))	('let-7e', 'Gene', '406887', (117, 123))	('let-7i', 'Gene', '406891', (144, 150))	('let-7g', 'Gene', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('expression', 'MPA', (45, 55))	('let-7b', 'Gene', '406884', (93, 99))	('let-7a', 'Gene', (85, 91))
330319	33409290	We observed that the proportions of males and patients with advanced age, high grade, large tumor size, axial location, and progressive disease increased among the higher risk groups (all p < 0.05).	('patients', 'Species', '9606', (46, 54))	('high grade', 'Var', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('axial location', 'CPA', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('age', 'Gene', (69, 72))	('progressive disease', 'CPA', (124, 143))	('tumor', 'Disease', (92, 97))	('age', 'Gene', '5973', (69, 72))
330324	33409290	Patients with a score of 157.7-222.8 or >222.8 were categorized as AJCC stage III (59.3%) and IV (39.0%), and these patients were entered as nomogram stage IV and V, respectively.	('age', 'Gene', '5973', (152, 155))	('patients', 'Species', '9606', (116, 124))	('age', 'Gene', '5973', (74, 77))	('Patients', 'Species', '9606', (0, 8))	('>222.8', 'Var', (40, 46))	('AJCC', 'Disease', (67, 71))	('age', 'Gene', (152, 155))	('age', 'Gene', (74, 77))
330360	33409290	In nomogram stage IV patients, those received radiotherapy had significantly higher 5-year OS and CSS rates compared to patients without adjuvant treatment (radiotherapy vs. no adjuvant treatment: 5-year OS 41.3% vs. 13.8%, p = 0.008; 5-year CSS 41.3% vs. 15.6%, p = 0.015).	('radiotherapy', 'Var', (46, 58))	('higher', 'PosReg', (77, 83))	('CSS', 'Chemical', '-', (242, 245))	('5-year', 'CPA', (84, 90))	('age', 'Gene', (14, 17))	('patients', 'Species', '9606', (21, 29))	('age', 'Gene', '5973', (14, 17))	('patients', 'Species', '9606', (120, 128))	('CSS', 'Chemical', '-', (98, 101))	('CSS', 'CPA', (98, 101))
330387	31738427	Since the discovery of an oncogenic NTRK gene fusion in colorectal cancer in 1986, over 80 different fusion partner genes have been identified in a wide array of adult and paediatric tumours, providing actionable targets for targeted therapy.	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('TRK', 'Gene', (37, 40))	('TRK', 'Gene', '4914', (37, 40))	('tumours', 'Disease', (183, 190))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('fusion', 'Var', (46, 52))	('tumours', 'Disease', 'MESH:D009369', (183, 190))
330388	31738427	This review describes the normal function and physiology of TRK receptors and the biology behind NTRK gene fusions and how they act as oncogenic drivers in cancer.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('TRK', 'Gene', (60, 63))	('TRK', 'Gene', '4914', (60, 63))	('TRK', 'Gene', (98, 101))	('TRK', 'Gene', '4914', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('gene fusions', 'Var', (102, 114))
330389	31738427	Finally, an overview of the incidence and prevalence of NTRK gene fusions in various types of cancers is discussed.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('TRK', 'Gene', (57, 60))	('TRK', 'Gene', '4914', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gene fusions', 'Var', (61, 73))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
330392	31738427	The identification of gene fusions in a variety of cancers has provided actionable targets that have expanded therapeutic options and facilitated precision medicine.	('pan', 'Gene', (103, 106))	('pan', 'Gene', '51816', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('gene fusions', 'Var', (22, 34))
330406	31738427	Alternative splicing of TRK proteins can alter the interaction between a TRK receptor and its specific neurotrophin (Figure 2).	('neurotrophin', 'Gene', (103, 115))	('TRK', 'Gene', '4914', (73, 76))	('interaction', 'Interaction', (51, 62))	('neurotrophin', 'Gene', '627', (103, 115))	('TRK', 'Gene', (24, 27))	('alter', 'Reg', (41, 46))	('TRK', 'Gene', '4914', (24, 27))	('Alternative splicing', 'Var', (0, 20))	('TRK', 'Gene', (73, 76))
330409	31738427	In contrast, with this insertion, the TRKA splice variant is activated by NT-3 in addition to NGF and the TRKB splice variant is readily activated by NT-3 and NT-4 in addition to BDNF.	('insertion', 'Var', (23, 32))	('NT-3', 'Gene', '4908', (150, 154))	('NT-3', 'Gene', (150, 154))	('TRKA', 'Gene', (38, 42))	('BDNF', 'Gene', '627', (179, 183))	('activated', 'PosReg', (61, 70))	('NT-4', 'Gene', '4909', (159, 163))	('TRKB', 'Gene', '4915', (106, 110))	('NT-3', 'Gene', '4908', (74, 78))	('BDNF', 'Gene', (179, 183))	('NGF', 'Gene', '4803', (94, 97))	('NT-4', 'Gene', (159, 163))	('TRKB', 'Gene', (106, 110))	('NGF', 'Gene', (94, 97))	('NT-3', 'Gene', (74, 78))
330410	31738427	Alternative splicing of exons encoding parts of the intracellular domains of TRK receptors may also affect downstream signalling initiated by neurotrophin binding to the receptor.	('neurotrophin', 'Gene', (142, 154))	('affect', 'Reg', (100, 106))	('TRK', 'Gene', (77, 80))	('binding', 'Interaction', (155, 162))	('TRK', 'Gene', '4914', (77, 80))	('neurotrophin', 'Gene', '627', (142, 154))	('Alternative splicing', 'Var', (0, 20))
330412	31738427	For example, alternative splicing of the NTRK3 gene may lead to amino acid insertion into the TRKC tyrosine kinase domain, which in turn results in modified kinase substrate specificity and impaired ability to promote neuronal cell differentiation.	('impaired', 'NegReg', (190, 198))	('modified', 'Reg', (148, 156))	('NTRK3', 'Gene', (41, 46))	('neuronal cell differentiation', 'CPA', (218, 247))	('ability', 'MPA', (199, 206))	('alternative splicing', 'Var', (13, 33))	('TRKC', 'Gene', '4916', (94, 98))	('tyrosine', 'Chemical', 'None', (99, 107))	('promote', 'PosReg', (210, 217))	('TRKC', 'Gene', (94, 98))	('amino acid insertion', 'Var', (64, 84))	('kinase substrate specificity', 'MPA', (157, 185))	('lead to', 'Reg', (56, 63))
330414	31738427	The dimerised receptor autophosphorylates specific tyrosine residues in the activation loop of the kinase domain [Y676, Y680 and Y681 in TRKA (Figure 3B) and the corresponding residues in TRKB and TRKC].	('Y680', 'Var', (120, 124))	('[Y676', 'Var', (113, 118))	('tyrosine', 'Chemical', 'None', (51, 59))	('Y681', 'Var', (129, 133))	('TRKB', 'Gene', '4915', (188, 192))	('TRKB', 'Gene', (188, 192))	('TRKC', 'Gene', '4916', (197, 201))	('TRKC', 'Gene', (197, 201))
330415	31738427	This phosphorylation is required for activation of the TRK receptor and leads to subsequent phosphorylation of additional tyrosine residues (Y496 and Y791 in TRKA), enabling docking of cytoplasmic adaptors and enzymes, which in turn drives a variety of downstream signalling pathways.	('phosphorylation', 'MPA', (92, 107))	('downstream signalling pathways', 'Pathway', (253, 283))	('docking', 'Interaction', (174, 181))	('enabling', 'Reg', (165, 173))	('tyrosine', 'Chemical', 'None', (122, 130))	('Y496', 'Var', (141, 145))	('TRK', 'Gene', (158, 161))	('TRK', 'Gene', '4914', (158, 161))	('drives', 'Reg', (233, 239))	('TRK', 'Gene', (55, 58))	('TRK', 'Gene', '4914', (55, 58))	('Y791', 'Var', (150, 154))
330425	31738427	Loss-of-function mutations in NTRK genes can result in several diseases, indicating the role of TRK receptors in normal regulation and function.	('Loss-of-function', 'NegReg', (0, 16))	('TRK', 'Gene', (96, 99))	('TRK', 'Gene', '4914', (96, 99))	('TRK', 'Gene', (31, 34))	('diseases', 'Disease', (63, 71))	('mutations', 'Var', (17, 26))	('TRK', 'Gene', '4914', (31, 34))
330426	31738427	TRKA receptors are involved in pain sensation; loss-of-function mutations in TRKA are observed in class IV hereditary sensory and autonomic neuronal disorders (such as congenital insensitivity to pain with anhidrosis), which result in impaired ability to sense differences in temperature or feel pain.	('pain', 'Disease', (296, 300))	('hereditary sensory and autonomic neuronal disorders', 'Disease', 'MESH:D030342', (107, 158))	('pain', 'Disease', 'MESH:D010146', (31, 35))	('impaired', 'NegReg', (235, 243))	('anhidrosis', 'Disease', (206, 216))	('pain', 'Phenotype', 'HP:0012531', (296, 300))	('mutations', 'Var', (64, 73))	('TRKA', 'Gene', (77, 81))	('autonomic neuronal disorders', 'Phenotype', 'HP:0012332', (130, 158))	('pain', 'Disease', (196, 200))	('pain', 'Disease', 'MESH:D010146', (296, 300))	('insensitivity to pain', 'Phenotype', 'HP:0007021', (179, 200))	('pain', 'Disease', (31, 35))	('sense differences in temperature', 'MPA', (255, 287))	('pain', 'Phenotype', 'HP:0012531', (196, 200))	('anhidrosis', 'Phenotype', 'HP:0000970', (206, 216))	('anhidrosis', 'Disease', 'MESH:D007007', (206, 216))	('pain', 'Phenotype', 'HP:0012531', (31, 35))	('loss-of-function', 'NegReg', (47, 63))	('ability', 'MPA', (244, 251))	('pain', 'Disease', 'MESH:D010146', (196, 200))
330427	31738427	Loss-of-function mutations in TRKB result in energy imbalances, loss of appetite control and subsequent obesity, in addition to defects in learning, memory and nociception.	('Loss-of-function', 'NegReg', (0, 16))	('defects', 'NegReg', (128, 135))	('appetite', 'CPA', (72, 80))	('loss of appetite', 'Phenotype', 'HP:0004396', (64, 80))	('obesity', 'Phenotype', 'HP:0001513', (104, 111))	('imbalances', 'Phenotype', 'HP:0002172', (52, 62))	('loss', 'NegReg', (64, 68))	('obesity', 'Disease', 'MESH:D009765', (104, 111))	('nociception', 'CPA', (160, 171))	('TRKB', 'Gene', '4915', (30, 34))	('energy imbalances', 'MPA', (45, 62))	('learning', 'CPA', (139, 147))	('obesity', 'Disease', (104, 111))	('mutations', 'Var', (17, 26))	('memory', 'CPA', (149, 155))	('TRKB', 'Gene', (30, 34))
330433	31738427	The majority of characterised NTRK gene fusions contain a 5' partner gene sequence encoding one or more dimerisation domains.	('TRK', 'Gene', (31, 34))	('fusions', 'Var', (40, 47))	('TRK', 'Gene', '4914', (31, 34))
330436	31738427	NTRK gene fusions have been identified in two main categories of tumours with vastly differing rates of occurrence; certain rare cancers present with a high frequency (>80%) of NTRK gene fusions, while some more common cancers present with a lower frequency of NTRK gene fusions (<25%).	('gene fusions', 'Var', (182, 194))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('TRK', 'Gene', (178, 181))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('tumours', 'Disease', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('TRK', 'Gene', '4914', (178, 181))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('TRK', 'Gene', (1, 4))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('TRK', 'Gene', (262, 265))	('cancers', 'Disease', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('TRK', 'Gene', '4914', (1, 4))	('TRK', 'Gene', '4914', (262, 265))
330438	31738427	Gene fusion events appear to arise more commonly in the NTRK1 and NTRK3 genes, with the possible exception of brain tumours.	('arise', 'Reg', (29, 34))	('brain tumours', 'Phenotype', 'HP:0030692', (110, 123))	('NTRK1', 'Gene', (56, 61))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('NTRK3', 'Gene', (66, 71))	('brain tumours', 'Disease', 'MESH:D001932', (110, 123))	('brain tumours', 'Disease', (110, 123))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('Gene fusion', 'Var', (0, 11))
330440	31738427	Of note, only 5.9% of these showed NTRK gene rearrangements, while 88.2% of cases displayed NTRK1 gene copy number gain without amplification.	('TRK', 'Gene', (36, 39))	('TRK', 'Gene', '4914', (36, 39))	('rearrangements', 'Var', (45, 59))	('gain', 'PosReg', (115, 119))	('TRK', 'Gene', (93, 96))	('TRK', 'Gene', '4914', (93, 96))
330446	31738427	discovered a recurrent ETV6-NTRK3 gene fusion in IFS, which was found to occur in ~70% of cases of IFS.	('ETV6', 'Gene', '2120', (23, 27))	('IFS', 'Disease', (49, 52))	('ETV6', 'Gene', (23, 27))	('fusion', 'Var', (39, 45))
330452	31738427	first reported an ETV6-NTRK3 gene fusion in 12 out of the 13 cases of SBC by identifying the corresponding chromosomal translocation t(12; 15)(p13; q25).	('ETV6', 'Gene', (18, 22))	('t(12; 15)(p13; q25', 'Var', (133, 151))	('ETV6', 'Gene', '2120', (18, 22))	('SBC', 'Disease', (70, 73))
330456	31738427	On the other hand, no partner genes other than ETV6 have been described in cases of MASC harbouring NTRK3 rearrangement (Figure 4).	('ETV6', 'Gene', '2120', (47, 51))	('NTRK3', 'Gene', (100, 105))	('MASC', 'Disease', (84, 88))	('ETV6', 'Gene', (47, 51))	('rearrangement', 'Var', (106, 119))
330459	31738427	in 1989, the reported frequency of NTRK1 rearrangement in PTC has been shown to range from <5% to 25%.	('rearrangement', 'Var', (41, 54))	('NTRK1', 'Gene', (35, 40))	('PTC', 'Disease', 'MESH:C536915', (58, 61))	('PTC', 'Phenotype', 'HP:0002895', (58, 61))	('PTC', 'Disease', (58, 61))
330465	31738427	Further cases of CRC harbouring either NTRK1 or NTRK3 gene fusions involving different partner genes have subsequently been reported and, in some cases, demonstrated pharmacologically actionable (Figure 4).	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('CRC', 'Disease', 'MESH:D015179', (17, 20))	('NTRK3', 'Gene', (48, 53))	('NTRK1', 'Gene', (39, 44))	('gene fusions', 'Var', (54, 66))	('CRC', 'Disease', (17, 20))
330466	31738427	A recent molecular profiling study used a plasma-based cell-free circulating tumour DNA NGS assay to detect gene fusions in 4290 patients with CRC.	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('CRC', 'Disease', 'MESH:D015179', (143, 146))	('patients', 'Species', '9606', (129, 137))	('gene fusions', 'Var', (108, 120))	('tumour', 'Disease', (77, 83))	('CRC', 'Disease', (143, 146))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))
330468	31738427	Notably, gene fusions seem to be associated with high mutation burden, and microsatellite instability (MSI) is frequently found in CRCs harbouring NTRK gene fusions.	('TRK', 'Gene', '4914', (148, 151))	('CRC', 'Disease', (131, 134))	('high mutation burden', 'MPA', (49, 69))	('gene fusions', 'Var', (9, 21))	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('associated', 'Reg', (33, 43))	('CRC', 'Disease', 'MESH:D015179', (131, 134))	('microsatellite', 'MPA', (75, 89))	('TRK', 'Gene', (148, 151))
330469	31738427	Hypothetically, the increased mutational frequency in MSI-high CRCs could explain the higher incidence of NTRK gene rearrangements as well as NTRK mutations.	('mutations', 'Var', (147, 156))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('TRK', 'Gene', (143, 146))	('TRK', 'Gene', '4914', (143, 146))	('CRC', 'Disease', 'MESH:D015179', (63, 66))	('MSI-high', 'Gene', (54, 62))	('TRK', 'Gene', (107, 110))	('TRK', 'Gene', '4914', (107, 110))	('CRC', 'Disease', (63, 66))	('rearrangements', 'Var', (116, 130))
330470	31738427	To date, only NTRK2 fusions have been identified in cases of appendiceal adenocarcinoma.	('identified', 'Reg', (38, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('appendiceal adenocarcinoma', 'Disease', (61, 87))	('NTRK2', 'Gene', (14, 19))	('appendiceal adenocarcinoma', 'Disease', 'MESH:D001063', (61, 87))	('fusions', 'Var', (20, 27))	('NTRK2', 'Gene', '4915', (14, 19))
330473	31738427	NTRK1 gene rearrangements in NSCLC were first described in 2013 among a subset of patients with NSCLC with adenocarcinoma histology and no detectable EGFR, KRAS, ALK or ROS1 alterations (3/91; 3.3%).	('NTRK1', 'Gene', (0, 5))	('EGFR', 'Gene', (150, 154))	('NSCLC', 'Disease', (96, 101))	('KRAS', 'Gene', (156, 160))	('patients', 'Species', '9606', (82, 90))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('rearrangements', 'Var', (11, 25))	('ALK', 'Gene', '238', (162, 165))	('NSCLC', 'Disease', (29, 34))	('KRAS', 'Gene', '3845', (156, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('adenocarcinoma', 'Disease', (107, 121))	('ROS1', 'Gene', (169, 173))	('ALK', 'Gene', (162, 165))	('EGFR', 'Gene', '1956', (150, 154))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('ROS1', 'Gene', '6098', (169, 173))
330475	31738427	NTRK2 and NTRK3 gene fusions in NSCLC have also been described.	('NTRK3', 'Gene', (10, 15))	('NTRK2', 'Gene', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('NSCLC', 'Disease', (32, 37))	('fusions', 'Var', (21, 28))	('NTRK2', 'Gene', '4915', (0, 5))
330478	31738427	Testing on 1272 soft tissue sarcoma samples identified eight cases (<1%) with NTRK1 or NTRK3 gene fusions, with one-half of these found in patients under the age of 5 years.	('patients', 'Species', '9606', (139, 147))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (16, 35))	('gene fusions', 'Var', (93, 105))	('NTRK3', 'Gene', (87, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('soft tissue sarcoma', 'Disease', (16, 35))	('NTRK1', 'Gene', (78, 83))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (16, 35))
330479	31738427	Recurrent NTRK1 gene fusions have been noted in soft tissue sarcomas characterised by a prominent myopericytic/haemangiopericytic growth pattern.	('sarcomas', 'Disease', (60, 68))	('soft tissue sarcoma', 'Disease', (48, 67))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (48, 68))	('NTRK1', 'Gene', (10, 15))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (48, 67))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('noted', 'Reg', (39, 44))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (48, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('fusions', 'Var', (21, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))
330484	31738427	This discovery suggested a novel uterine sarcoma subtype defined by the presence of recurrent NTRK gene fusions.	('sarcoma', 'Disease', (41, 48))	('TRK', 'Gene', (95, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('TRK', 'Gene', '4914', (95, 98))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (33, 48))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('fusions', 'Var', (104, 111))
330490	31738427	Several additional NTRK translocations have subsequently been described in GBM (Figure 4).	('TRK', 'Gene', (20, 23))	('TRK', 'Gene', '4914', (20, 23))	('GBM', 'Disease', (75, 78))	('GBM', 'Disease', 'MESH:D005909', (75, 78))	('translocations', 'Var', (24, 38))
330492	31738427	reported recurrent fusions involving NTRK genes in 4% of diffuse intrinsic pontine gliomas and 10% of non-brainstem HGGs (NBS-HGGs).	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('fusions', 'Var', (19, 26))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('TRK', 'Gene', (38, 41))	('TRK', 'Gene', '4914', (38, 41))	('non-brainstem HGGs', 'Disease', (102, 120))
330494	31738427	Different fusions involving NTRK genes have also been reported in low-grade gliomas (Figure 2).	('gliomas', 'Disease', (76, 83))	('TRK', 'Gene', (29, 32))	('TRK', 'Gene', '4914', (29, 32))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('reported', 'Reg', (54, 62))	('fusions', 'Var', (10, 17))
330497	31738427	also utilised whole-genome sequencing to analyse 91 less common LGNTs and identified two tumours harbouring NTRK2 translocations, including a novel SLMAP-NTRK2 gene fusion found in a case of parietal ganglioglioma.	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('NTRK2', 'Gene', '4915', (154, 159))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('NTRK2', 'Gene', (154, 159))	('parietal ganglioglioma', 'Disease', (191, 213))	('translocations', 'Var', (114, 128))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('NTRK2', 'Gene', '4915', (108, 113))	('tumours', 'Disease', (89, 96))	('parietal ganglioglioma', 'Disease', 'MESH:D018303', (191, 213))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('NTRK2', 'Gene', (108, 113))
330498	31738427	NTRK rearrangements have also been reported in diffuse leptomeningeal glioneuronal tumours; rare CNS neoplasms that were included in the 2016 update of the World Health Organization classification.	('neoplasms', 'Phenotype', 'HP:0002664', (101, 110))	('glioneuronal tumours', 'Disease', (70, 90))	('TRK', 'Gene', (1, 4))	('reported', 'Reg', (35, 43))	('TRK', 'Gene', '4914', (1, 4))	('glioneuronal tumours', 'Phenotype', 'HP:0025170', (70, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('glioneuronal tumours', 'Disease', 'MESH:D009369', (70, 90))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('neoplasm', 'Phenotype', 'HP:0002664', (101, 109))	('CNS neoplasms', 'Phenotype', 'HP:0100006', (97, 110))	('rearrangements', 'Var', (5, 19))
330499	31738427	In addition, cancers that can harbour NTRK gene fusions, such as lung cancers and melanomas, have a proclivity for CNS metastases.	('TRK', 'Gene', '4914', (39, 42))	('melanomas', 'Disease', 'MESH:D008545', (82, 91))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('lung cancers', 'Disease', 'MESH:D008175', (65, 77))	('melanomas', 'Disease', (82, 91))	('lung cancers', 'Disease', (65, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('lung cancers', 'Phenotype', 'HP:0100526', (65, 77))	('cancers', 'Disease', (70, 77))	('metastases', 'Disease', 'MESH:D009362', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('metastases', 'Disease', (119, 129))	('cancers', 'Disease', (13, 20))	('gene fusions', 'Var', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TRK', 'Gene', (39, 42))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('cancers', 'Disease', 'MESH:D009369', (70, 77))
330500	31738427	Various translocations involving NTRK1 or NTRK3 have been reported in spitzoid melanocytic neoplasms as well as in compound Spitz nevi.	('NTRK3', 'Gene', (42, 47))	('reported', 'Reg', (58, 66))	('translocations', 'Var', (8, 22))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (79, 100))	('neoplasms', 'Phenotype', 'HP:0002664', (91, 100))	('compound Spitz nevi', 'Disease', (115, 134))	('NTRK1', 'Gene', (33, 38))	('spitzoid melanocytic neoplasms', 'Disease', 'MESH:D009508', (70, 100))	('neoplasm', 'Phenotype', 'HP:0002664', (91, 99))	('spitzoid melanocytic neoplasms', 'Disease', (70, 100))	('nevi', 'Phenotype', 'HP:0003764', (130, 134))
330501	31738427	in order to assess the frequency of NTRK gene rearrangements in non-spitzoid metastatic melanomas.	('TRK', 'Gene', (37, 40))	('TRK', 'Gene', '4914', (37, 40))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('melanomas', 'Disease', 'MESH:D008545', (88, 97))	('rearrangements', 'Var', (46, 60))	('melanomas', 'Disease', (88, 97))
330505	31738427	Preclinical studies with inhibitors of TRK proteins have further substantiated the role of NTRK gene fusions as oncogenic drivers.	('fusions', 'Var', (101, 108))	('TRK', 'Gene', (92, 95))	('TRK', 'Gene', (39, 42))	('TRK', 'Gene', '4914', (92, 95))	('TRK', 'Gene', '4914', (39, 42))
330511	31738427	Importantly, NTRK gene fusions appear to be mutually exclusive to other gene alterations, suggesting that they may act as the sole oncogenic drivers in the tumours that harbour them.	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('gene fusions', 'Var', (18, 30))	('tumours', 'Disease', (156, 163))	('fusions', 'Var', (23, 30))	('TRK', 'Gene', (14, 17))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('TRK', 'Gene', '4914', (14, 17))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))
330515	31738427	Larotrectinib inhibited fusion protein signalling, in vitro proliferation and in vivo tumour growth in models derived from human cancer cells harbouring NTRK gene fusions, as well as demonstrated clinical efficacy and safety in three clinical trials.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gene fusions', 'Var', (158, 170))	('human', 'Species', '9606', (123, 128))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('TRK', 'Gene', (154, 157))	('tumour growth', 'Disease', (86, 99))	('cancer', 'Disease', (129, 135))	('TRK', 'Gene', '4914', (154, 157))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('inhibited', 'NegReg', (14, 23))	('fusion', 'Protein', (24, 30))	('tumour growth', 'Disease', 'MESH:D006130', (86, 99))
330516	31738427	Resistance to larotrectinib and entrectinib can occur through the development of NTRK gene mutations, which involves amino acid substitutions in the solvent-front, gatekeeper residues of the NTRK genes (NTRK1 p. G667C, NTRK3 p. G696A) and xDFG motif substitutions.	('TRK', 'Gene', (204, 207))	('G696A', 'SUBSTITUTION', 'None', (228, 233))	('TRK', 'Gene', '4914', (204, 207))	('G696A', 'Var', (228, 233))	('occur', 'Reg', (48, 53))	('G667C', 'SUBSTITUTION', 'None', (212, 217))	('TRK', 'Gene', (82, 85))	('TRK', 'Gene', '4914', (82, 85))	('TRK', 'Gene', (192, 195))	('TRK', 'Gene', (220, 223))	('TRK', 'Gene', '4914', (220, 223))	('mutations', 'Var', (91, 100))	('G667C', 'Var', (212, 217))	('TRK', 'Gene', '4914', (192, 195))	('gatekeeper', 'Species', '111938', (164, 174))	('amino', 'Var', (117, 122))
330518	31738427	Other NTRK alterations, such as mutations, amplifications and mRNA overexpression, were found in ~14% of 13 467 adult and paediatric pan-cancer tumour samples obtained from The Cancer Genome Atlas and the St Jude PeCan database.	('mRNA', 'MPA', (62, 66))	('alterations', 'Var', (11, 22))	('PeCan', 'Species', '32201', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('Cancer', 'Phenotype', 'HP:0002664', (177, 183))	('overexpression', 'PosReg', (67, 81))	('pan', 'Gene', '51816', (133, 136))	('cancer tumour', 'Disease', (137, 150))	('amplifications', 'MPA', (43, 57))	('mutations', 'Var', (32, 41))	('pan', 'Gene', (133, 136))	('TRK', 'Gene', (7, 10))	('TRK', 'Gene', '4914', (7, 10))	('cancer tumour', 'Disease', 'MESH:D009369', (137, 150))
330519	31738427	NTRK mutations occur less frequently than amplifications or mRNA overexpression, but may be enriched in MSI-high CRCs.	('CRC', 'Disease', 'MESH:D015179', (113, 116))	('TRK', 'Gene', (1, 4))	('TRK', 'Gene', '4914', (1, 4))	('mutations', 'Var', (5, 14))	('CRC', 'Disease', (113, 116))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))
330520	31738427	These NTRK mutations are different from the acquired mutations described as a resistance mechanism to TRK inhibitors; as expected, the known acquired NTRK mutations that confer resistance were not observed in any of the 13 467 treatment-naive tumours.	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('mutations', 'Var', (11, 20))	('tumours', 'Phenotype', 'HP:0002664', (243, 250))	('TRK', 'Gene', (102, 105))	('tumours', 'Disease', 'MESH:D009369', (243, 250))	('TRK', 'Gene', '4914', (102, 105))	('tumours', 'Disease', (243, 250))	('TRK', 'Gene', (151, 154))	('TRK', 'Gene', (7, 10))	('TRK', 'Gene', '4914', (151, 154))	('TRK', 'Gene', '4914', (7, 10))
330521	31738427	NTRK point mutations themselves are generally not activating oncogenic events and have limited response to larotrectinib, as demonstrated in a phase I clinical trial of larotrectinib where none of the patients with NTRK point mutations had an objective response to larotrectinib; in contrast, objective responses were seen in seven of eight patients with tumours harbouring NTRK gene fusions.	('patients', 'Species', '9606', (201, 209))	('patients', 'Species', '9606', (341, 349))	('tumours', 'Disease', 'MESH:D009369', (355, 362))	('tumours', 'Disease', (355, 362))	('TRK', 'Gene', (1, 4))	('TRK', 'Gene', '4914', (1, 4))	('tumour', 'Phenotype', 'HP:0002664', (355, 361))	('point mutations', 'Var', (220, 235))	('TRK', 'Gene', (216, 219))	('TRK', 'Gene', '4914', (216, 219))	('tumours', 'Phenotype', 'HP:0002664', (355, 362))	('TRK', 'Gene', (375, 378))	('TRK', 'Gene', '4914', (375, 378))
330523	31738427	In the same trial with larotrectinib, one patient with a tumour harbouring an NTRK1 gene amplification had a single 11 mm target lesion shrink by 5 mm (45.5%).	('tumour', 'Disease', (57, 63))	('patient', 'Species', '9606', (42, 49))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('NTRK1', 'Gene', (78, 83))	('amplification', 'Var', (89, 102))	('shrink', 'NegReg', (136, 142))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
330526	31738427	Specific NTRK gene fusions have been identified in various tumours and can be found with high prevalence in certain rare adult and paediatric tumour types, even becoming a defining diagnostic feature, and at low prevalence in most common cancers.	('tumour', 'Disease', (142, 148))	('cancers', 'Disease', (238, 245))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	('found', 'Reg', (78, 83))	('fusions', 'Var', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('TRK', 'Gene', (10, 13))	('identified', 'Reg', (37, 47))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('TRK', 'Gene', '4914', (10, 13))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('tumour', 'Disease', (59, 65))	('tumours', 'Disease', (59, 66))	('tumour', 'Disease', 'MESH:D009369', (59, 65))
330628	28817404	They are in keeping with a "BCOR-alteration family" of renal and extra-renal neoplasms which includes CCSK and URCS/PMMTI (which typically harbor BCOR internal tandem duplication), and BCOR-CCNB3 sarcomas, all of which are primarily driven by BCOR overexpression and have overlapping (but not identical) clinicopathologic features.	('BCOR', 'Gene', '54880', (185, 189))	('neoplasms', 'Phenotype', 'HP:0002664', (77, 86))	('CCNB3', 'Gene', (190, 195))	('sarcomas', 'Disease', 'MESH:D012509', (196, 204))	('BCOR', 'Gene', (185, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (196, 204))	('neoplasm', 'Phenotype', 'HP:0002664', (77, 85))	('sarcomas', 'Disease', (196, 204))	('CCSK', 'Phenotype', 'HP:0006770', (102, 106))	('renal neoplasms', 'Phenotype', 'HP:0009726', (71, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('internal tandem duplication', 'Var', (151, 178))	('renal', 'Disease', (55, 60))	('extra-renal neoplasms', 'Disease', 'MESH:D007680', (65, 86))	('BCOR', 'Gene', '54880', (243, 247))	('CCNB3', 'Gene', '85417', (190, 195))	('CCSK', 'Disease', (102, 106))	('overexpression', 'PosReg', (248, 262))	('CCSK', 'Chemical', '-', (102, 106))	('BCOR', 'Gene', '54880', (28, 32))	('BCOR', 'Gene', '54880', (146, 150))	('renal neoplasm', 'Phenotype', 'HP:0009726', (71, 85))	('BCOR', 'Gene', (243, 247))	('extra-renal neoplasms', 'Disease', (65, 86))	('BCOR', 'Gene', (28, 32))	('BCOR', 'Gene', (146, 150))
330636	28817404	The majority (>90%) of CCSK harbor internal tandem duplications (ITD) in the last exon of the BCOR (Bcl6 interacting co-repressor) gene, which in CCSK is thought to regulate gene transcription through an epigenetic silencing mechanism.	('BCOR', 'Gene', (94, 98))	('Bcl6 interacting co-repressor', 'Gene', '54880', (100, 129))	('CCSK', 'Chemical', '-', (23, 27))	('BCOR', 'Gene', '54880', (94, 98))	('CCSK', 'Chemical', '-', (146, 150))	('Bcl6 interacting co-repressor', 'Gene', (100, 129))	('regulate', 'Reg', (165, 173))	('CCSK', 'Phenotype', 'HP:0006770', (146, 150))	('CCSK', 'Disease', (23, 27))	('internal tandem duplications', 'Var', (35, 63))	('CCSK', 'Phenotype', 'HP:0006770', (23, 27))
330637	28817404	A smaller subset of CCSK harbor a YWHAE-NUTM2B gene fusion resulting from a t(10;17)(q22.3;p13.3) translocation which is identical to that seen in high grade endometrial stromal sarcoma.	('t(10;17)(q22.3;p13.3)', 'STRUCTURAL_ABNORMALITY', 'None', (76, 97))	('CCSK', 'Disease', (20, 24))	('YWHAE', 'Gene', (34, 39))	('endometrial stromal sarcoma', 'Disease', (158, 185))	('NUTM2B', 'Gene', '729262', (40, 46))	('CCSK', 'Chemical', '-', (20, 24))	('CCSK', 'Phenotype', 'HP:0006770', (20, 24))	('resulting from', 'Reg', (59, 73))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (158, 185))	('NUTM2B', 'Gene', (40, 46))	('YWHAE', 'Gene', '7531', (34, 39))	('translocation', 'Var', (98, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
330643	28817404	Second, a BCOR-CCNB3 gene fusion resulting from an X chromosomal pericentric inversion has been identified in previously unclassified soft tissue and bone sarcomas which typically affect teenagers and young adults with a male predominance.	('fusion', 'Var', (26, 32))	('BCOR', 'Gene', '54880', (10, 14))	('identified', 'Reg', (96, 106))	('CCNB3', 'Gene', (15, 20))	('bone sarcomas', 'Disease', 'MESH:D001847', (150, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('bone sarcomas', 'Disease', (150, 163))	('soft tissue and bone sarcomas', 'Phenotype', 'HP:0030448', (134, 163))	('soft tissue', 'Disease', (134, 145))	('BCOR', 'Gene', (10, 14))	('CCNB3', 'Gene', '85417', (15, 20))	('bone sarcomas', 'Phenotype', 'HP:0002669', (150, 163))
330653	28817404	All of the cases in the review cohort were screened by immunohistochemistry by BCOR, and positively-labeling cases were analyzed for the presence of BCOR and CCNB3 fusion/inversion by FISH.	('BCOR', 'Gene', '54880', (79, 83))	('BCOR', 'Gene', (149, 153))	('CCNB3', 'Gene', '85417', (158, 163))	('fusion/inversion', 'Var', (164, 180))	('BCOR', 'Gene', '54880', (149, 153))	('CCNB3', 'Gene', (158, 163))	('BCOR', 'Gene', (79, 83))
330661	28817404	We identified 7 genetically confirmed primary renal synovial sarcomas from our files, all of which demonstrated SS18 rearrangements by FISH.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (52, 68))	('rearrangements', 'Var', (117, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (52, 69))	('SS18', 'Gene', (112, 116))	('primary renal synovial sarcomas', 'Disease', 'MESH:D013584', (38, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('primary renal synovial sarcomas', 'Disease', (38, 69))	('SS18', 'Gene', '6760', (112, 116))
330666	28817404	Of the 5 cases studied genetically, 4 demonstrated BCOR internal tandem duplication (ITD), while one demonstrated the YWHAE-NUTM2B gene fusion.	('BCOR', 'Gene', '54880', (51, 55))	('YWHAE', 'Gene', '7531', (118, 123))	('NUTM2B', 'Gene', (124, 130))	('internal tandem duplication', 'Var', (56, 83))	('NUTM2B', 'Gene', '729262', (124, 130))	('BCOR', 'Gene', (51, 55))	('YWHAE', 'Gene', (118, 123))
330718	28817404	Despite their common transcriptional profile driven by a consistent upregulation of BCOR mRNA expression, some differences exist between soft tissue undifferentiated round cell sarcoma (URCS)/primitive myxoid mesenchymal tumor of infancy (PMMTI), which harbors BCOR internal tandem duplication (ITD), and BCOR-CCNB3 bone and soft tissue sarcomas.	('CCNB3', 'Gene', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('BCOR', 'Gene', (305, 309))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (325, 344))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (325, 345))	('sarcoma', 'Disease', 'MESH:D012509', (337, 344))	('sarcomas', 'Disease', 'MESH:D012509', (337, 345))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('sarcoma', 'Disease', (337, 344))	('sarcomas', 'Phenotype', 'HP:0100242', (337, 345))	('sarcoma', 'Disease', (177, 184))	('BCOR', 'Gene', '54880', (261, 265))	('sarcomas', 'Disease', (337, 345))	('upregulation', 'PosReg', (68, 80))	('BCOR', 'Gene', '54880', (84, 88))	('myxoid mesenchymal tumor', 'Disease', 'MESH:C535700', (202, 226))	('CCNB3', 'Gene', '85417', (310, 315))	('BCOR', 'Gene', (261, 265))	('BCOR', 'Gene', (84, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (337, 344))	('myxoid mesenchymal tumor', 'Disease', (202, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('internal tandem duplication', 'Var', (266, 293))	('BCOR', 'Gene', '54880', (305, 309))
330744	28817404	Along these lines, a case of a poorly differentiated synovial sarcoma with a variant SS18L1-SSX1 gene fusion and complex rearrangements affecting the Xp11.22-4 region including disruption of BCOR and upregulation of BCOR protein has been reported.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('SS18L1', 'Gene', (85, 91))	('synovial sarcoma', 'Disease', (53, 69))	('SSX1', 'Gene', (92, 96))	('variant', 'Var', (77, 84))	('BCOR', 'Gene', (191, 195))	('upregulation', 'PosReg', (200, 212))	('disruption', 'Var', (177, 187))	('BCOR', 'Gene', '54880', (216, 220))	('BCOR', 'Gene', '54880', (191, 195))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (53, 69))	('BCOR', 'Gene', (216, 220))	('SS18L1', 'Gene', '26039', (85, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (53, 69))	('SSX1', 'Gene', '6756', (92, 96))
330762	27612915	NB001 decreased the concentrations of cAMP and the levels of GluN2A, GluN2B, p-GluA1 (831), and p-GluA1 (845) in the anterior cingulate cortex, and inhibited the frequency of presynaptic neurotransmitter release in the anterior cingulate cortex of the mouse models.	('GluN2A', 'Gene', (61, 67))	('GluA1', 'Gene', (98, 103))	('cAMP', 'MPA', (38, 42))	('GluA1', 'Gene', '14799', (79, 84))	('decreased', 'NegReg', (6, 15))	('GluN2B', 'Gene', (69, 75))	('GluN2B', 'Gene', '14812', (69, 75))	('GluA1', 'Gene', (79, 84))	('frequency of presynaptic neurotransmitter release', 'MPA', (162, 211))	('cAMP', 'Chemical', 'MESH:D000242', (38, 42))	('NB001', 'Var', (0, 5))	('inhibited', 'NegReg', (148, 157))	('mouse', 'Species', '10090', (252, 257))	('concentrations', 'MPA', (20, 34))	('GluN2A', 'Gene', '14811', (61, 67))	('GluA1', 'Gene', '14799', (98, 103))
330782	27612915	The inhibition of the AC activity, especially AC1, provides well-documented benefits that alleviate chronic pain and neuronal excitotoxicity.	('alleviate', 'NegReg', (90, 99))	('neuronal excitotoxicity', 'Disease', (117, 140))	('AC1', 'Gene', '432530', (46, 49))	('pain', 'Phenotype', 'HP:0012531', (108, 112))	('inhibition', 'Var', (4, 14))	('chronic pain', 'Disease', 'MESH:D059350', (100, 112))	('chronic pain', 'Phenotype', 'HP:0012532', (100, 112))	('neuronal excitotoxicity', 'Disease', 'MESH:D009410', (117, 140))	('AC1', 'Gene', (46, 49))	('chronic pain', 'Disease', (100, 112))
330813	27612915	The following primary antibodies were used: anti-GluN2A (1:300; Millipore, MAB MAB5216), anti-GluN2B (1:400; Millipore, MAB5780), anti-GluA1 (1:300; Abcam, ab31232), anti-Ser845-phospho-GluA1 (1:400; Abcam, ab76321), anti-Ser831-phospho-GluA1 (1:1000; Abcam, ab109464), and anti-beta-actin (1:10000; Sigma, A5316).	('1:300;', 'Var', (142, 148))	('GluA1', 'Gene', '14799', (237, 242))	('GluN2B', 'Gene', (94, 100))	('GluA1', 'Gene', (237, 242))	('1:400', 'Var', (102, 107))	('GluN2A', 'Gene', '14811', (49, 55))	('GluN2A', 'Gene', (49, 55))	('GluA1', 'Gene', '14799', (135, 140))	('GluN2B', 'Gene', '14812', (94, 100))	('GluA1', 'Gene', '14799', (186, 191))	('GluA1', 'Gene', (135, 140))	('GluA1', 'Gene', (186, 191))
330826	27612915	Considering that NB001 is an inhibitor of AC1, we determined whether NB001 inhibits cAMP production.	('NB001', 'Var', (69, 74))	('cAMP', 'Chemical', 'MESH:D000242', (84, 88))	('AC1', 'Gene', (42, 45))	('cAMP production', 'MPA', (84, 99))	('AC1', 'Gene', '432530', (42, 45))	('inhibits', 'NegReg', (75, 83))
330855	27612915	The analgesic effects of AC1 genetic reduction are also caused by the inhibition of synaptic plasticity in the ACC neurons associated with pain.	('inhibition', 'NegReg', (70, 80))	('synaptic plasticity', 'MPA', (84, 103))	('analgesic', 'Disease', (4, 13))	('AC1', 'Gene', (25, 28))	('reduction', 'NegReg', (37, 46))	('pain', 'Phenotype', 'HP:0012531', (139, 143))	('pain', 'Disease', 'MESH:D010146', (139, 143))	('pain', 'Disease', (139, 143))	('AC1', 'Gene', '432530', (25, 28))	('ACC', 'Gene', (111, 114))	('ACC', 'Gene', '104371', (111, 114))	('genetic', 'Var', (29, 36))
330856	27612915	further demonstrated that the genetic deletion of AC1 significantly attenuates neuronal death induced by glutamate in primary cultures of cortical neurons; by contrast, AC8 deletion does not elicit any significant effect.	('attenuates', 'NegReg', (68, 78))	('AC8', 'Gene', (169, 172))	('neuronal death', 'Disease', (79, 93))	('AC1', 'Gene', '432530', (50, 53))	('AC8', 'Gene', '11514', (169, 172))	('deletion', 'Var', (38, 46))	('neuronal death', 'Disease', 'MESH:D009410', (79, 93))	('AC1', 'Gene', (50, 53))	('glutamate', 'Chemical', 'MESH:D018698', (105, 114))
330860	27612915	Furthermore, NB001 possible elicits inhibitory effects similar to those found in the AC1-KO mice.	('elicits', 'Reg', (28, 35))	('inhibitory effects', 'MPA', (36, 54))	('AC1', 'Gene', '432530', (85, 88))	('NB001', 'Var', (13, 18))	('mice', 'Species', '10090', (92, 96))	('AC1', 'Gene', (85, 88))
330868	27612915	Among the drugs administered to treat bone cancer pain, morphine elicits the strongest analgesic effect.	('morphine', 'Var', (56, 64))	('pain', 'Phenotype', 'HP:0012531', (50, 54))	('morphine', 'Chemical', 'MESH:D009020', (56, 64))	('analgesic effect', 'MPA', (87, 103))	('bone cancer pain', 'Disease', 'MESH:D001859', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('bone cancer pain', 'Disease', (38, 54))	('bone cancer pain', 'Phenotype', 'HP:0002653', (38, 54))
331023	24563786	SS is characterized by unique t(X; 18)(p11.2; q11.2) translocation resulting in the fusion of the SYT gene on chromosome 18 to either of two closely related genes: SSX1 and SSX2 on chromosome X.	('SSX2', 'Gene', '6757', (173, 177))	('SS', 'Phenotype', 'HP:0012570', (173, 175))	('SYT', 'Gene', '6760', (98, 101))	('SSX1', 'Gene', '6756', (164, 168))	('SSX2', 'Gene', (173, 177))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SS', 'Phenotype', 'HP:0012570', (164, 166))	('SSX1', 'Gene', (164, 168))	('SYT', 'Gene', (98, 101))	('fusion', 'Var', (84, 90))
331035	32825119	By using target RNA-seq, we have identified novel and known fusion genes in BSTS that were previously related to unclassified sarcomas or were diagnosed incorrectly.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcomas', 'Disease', (126, 134))	('related', 'Reg', (102, 109))	('BSTS', 'Gene', (76, 80))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))	('fusion genes', 'Var', (60, 72))
331039	32825119	In this study, we have generated a novel mouse model for novel NTRK3 fusion gene-associated sarcomas, and tested the therapeutic efficiency of the NTRK inhibitor, LOXO-101.	('sarcomas', 'Disease', (92, 100))	('mouse', 'Species', '10090', (41, 46))	('TRK', 'Gene', (64, 67))	('TRK', 'Gene', '18211', (148, 151))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('fusion', 'Var', (69, 75))	('LOXO-101', 'Chemical', 'MESH:C000609083', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('TRK', 'Gene', '18211', (64, 67))	('TRK', 'Gene', (148, 151))
331045	32825119	Fusion genes were detected in 29 of the 55 BSTS cases by target RNA-seq, with 19 of those being spindle cell sarcomas and 10 being round cell sarcomas.	('Fusion genes', 'Var', (0, 12))	('detected', 'Reg', (18, 26))	('sarcomas', 'Disease', 'MESH:D012509', (142, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('sarcomas', 'Disease', (142, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcomas', 'Disease', (109, 117))
331046	32825119	Notably, eight of 12 spindle cell sarcoma cases, for which the original diagnosis was a solitary fibrous tumor, were positive for fusion genes.	('fibrous tumor', 'Disease', 'MESH:D054364', (97, 110))	('sarcoma', 'Disease', (34, 41))	('fusion genes', 'Var', (130, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('positive', 'Reg', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('fibrous tumor', 'Disease', (97, 110))
331050	32825119	Recurrent fusions between AHRR and NCOA2, an NCOA3 homolog, by t (5;8) (p15;q13), have been reported in angiofibroma of soft tissue, which was also identified in case #45, for which the original diagnosis was hemangiopericytoma.	('fusions', 'Var', (10, 17))	('AHRR', 'Gene', '11624', (26, 30))	('hemangiopericytoma', 'Disease', (209, 227))	('NCOA3', 'Gene', '17979', (45, 50))	('NCOA2', 'Gene', '17978', (35, 40))	('angiofibroma', 'Disease', 'MESH:D018322', (104, 116))	('hemangiopericytoma', 'Disease', 'MESH:D006393', (209, 227))	('p15', 'Gene', (72, 75))	('p15', 'Gene', '12579', (72, 75))	('AHRR', 'Gene', (26, 30))	('NCOA2', 'Gene', (35, 40))	('NCOA3', 'Gene', (45, 50))	('reported', 'Reg', (92, 100))	('angiofibroma', 'Disease', (104, 116))
331053	32825119	In a previous study, RAF1 fusions were reported in soft tissue sarcoma, in which the fusion counterparts, PDZRN3, SLMAP and TMF1, were identified in three of eight cases.	('sarcoma', 'Disease', (63, 70))	('TMF1', 'Gene', (124, 128))	('fusions', 'Var', (26, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('PDZRN3', 'Gene', (106, 112))	('RAF1', 'Gene', (21, 25))	('SLMAP', 'Gene', (114, 119))	('TMF1', 'Gene', '232286', (124, 128))	('PDZRN3', 'Gene', '55983', (106, 112))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (51, 70))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('SLMAP', 'Gene', '83997', (114, 119))
331054	32825119	It is likely that replacement of the RAS-binding domain of RAF1 by the p21-Rho binding domain of PAK2 significantly modulates the RAS/RAF signaling and may induce upregulation of the downstream molecules of the pathway.	('upregulation', 'PosReg', (163, 175))	('RAF', 'Gene', (59, 62))	('replacement', 'Var', (18, 29))	('RAF', 'Gene', '109880;5894;110157', (134, 137))	('induce', 'Reg', (156, 162))	('p21', 'Gene', (71, 74))	('downstream molecules of the pathway', 'Pathway', (183, 218))	('RAF', 'Gene', '109880;5894;110157', (59, 62))	('PAK2', 'Gene', (97, 101))	('p21', 'Gene', '644914', (71, 74))	('modulates', 'Reg', (116, 125))	('RAF', 'Gene', (134, 137))
331057	32825119	EPC1 is found fused to PHF1 in endometrial stromal sarcomas and ossifying fibromyxoid tumors, and the present study also identified the EPC1-PHF1 fusion in the round cell sarcoma case #28.	('PHF1', 'Gene', '21652', (141, 145))	('endometrial stromal sarcomas and ossifying fibromyxoid tumors', 'Disease', 'MESH:D018203', (31, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('PHF1', 'Gene', (141, 145))	('EPC1', 'Gene', '13831', (136, 140))	('EPC1', 'Gene', '13831', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EPC1', 'Gene', (136, 140))	('EPC1', 'Gene', (0, 4))	('sarcoma', 'Disease', 'MESH:D012509', (171, 178))	('sarcoma', 'Disease', (171, 178))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('fusion', 'Var', (146, 152))	('sarcoma', 'Disease', (51, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('PHF1', 'Gene', '21652', (23, 27))	('PHF1', 'Gene', (23, 27))
331059	32825119	Deregulation of PRC1.1 was reported in various human malignancies, such as gynecologic cancer and myelodysplastic syndrome.	('cancer', 'Disease', (87, 93))	('reported', 'Reg', (27, 35))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('malignancies', 'Disease', (53, 65))	('Deregulation', 'Var', (0, 12))	('PRC1.1', 'Gene', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (98, 122))	('human', 'Species', '9606', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('myelodysplastic syndrome', 'Disease', (98, 122))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (98, 122))
331060	32825119	As shown in Figure 2C, conservation of the EPC1 protein interaction domain of EPC1 as a NuA4 member and the KDM2B catalytic domain suggests that fusion affects the functions of both the Nu4A and PRC1.1 complexes.	('affects', 'Reg', (152, 159))	('EPC1', 'Gene', (78, 82))	('KDM2B', 'Gene', '30841', (108, 113))	('EPC1', 'Gene', (43, 47))	('KDM2B', 'Gene', (108, 113))	('EPC1', 'Gene', '13831', (43, 47))	('EPC1', 'Gene', '13831', (78, 82))	('fusion', 'Var', (145, 151))	('functions', 'MPA', (164, 173))
331075	32825119	In both NTRK3 fusions herein, the protein kinase domain was preserved in the fusion proteins (Figure 4A,B), and the transforming capacity of PPFIBP1-ALK suggests that these NTRK3 fusions upregulate signaling downstream of NTRK3.	('upregulate', 'PosReg', (187, 197))	('NTRK3', 'Gene', (8, 13))	('signaling', 'MPA', (198, 207))	('ALK', 'Gene', '11682', (149, 152))	('NTRK3', 'Gene', (173, 178))	('ALK', 'Gene', (149, 152))	('fusions', 'Var', (179, 186))	('fusions', 'Var', (14, 21))	('protein kinase domain', 'MPA', (34, 55))
331076	32825119	Morphological analysis of the cases with the YWHAE-NTRK3 or PPFIBP1-NTRK3 fusions showed proliferation of short spindle tumor cells with occasional storiform pattern (Figure 4A,B).	('storiform pattern', 'CPA', (148, 165))	('PPFIBP1-NTRK3', 'Gene', (60, 73))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('fusions', 'Var', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
331098	32825119	This method identified the EWSR1-FLI1 fusion in an Ewing sarcoma case (case #8), in which it was difficult to detect the fusion by RT-PCR, probably due to high GC content of the target region.	('FLI1', 'Gene', '14247', (33, 37))	('EWSR1', 'Gene', '14030', (27, 32))	('EWSR1', 'Gene', (27, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('fusion', 'Var', (38, 44))	('FLI1', 'Gene', (33, 37))	('Ewing sarcoma', 'Disease', (51, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
331101	32825119	we identified two known NTRK1 fusions, two novel NTRK3 fusions and the recently discovered USP6 fusion associated with malignant nodular fasciitis.	('malignant nodular fasciitis', 'Disease', 'MESH:D005208', (119, 146))	('NTRK1', 'Gene', (24, 29))	('associated', 'Reg', (103, 113))	('NTRK1', 'Gene', '18211', (24, 29))	('NTRK3', 'Gene', (49, 54))	('fusions', 'Var', (30, 37))	('malignant nodular fasciitis', 'Disease', (119, 146))	('fasciitis', 'Phenotype', 'HP:0100537', (137, 146))
331103	32825119	It has been reported that most of the fusion products of BSTS function in transcriptional modulation; however, the identification of NTRK fusions, as well as PAK2-RAF1, GAB1-ABL1 and MSN-ERAS in this study, indicates that more than a few fusion genes of BSTS are involved in inducing the upregulation of signal transduction.	('TRK', 'Gene', '18211', (134, 137))	('MSN', 'Gene', '17698', (183, 186))	('MSN', 'Gene', (183, 186))	('BSTS', 'Gene', (254, 258))	('upregulation', 'PosReg', (288, 300))	('TRK', 'Gene', (134, 137))	('signal transduction', 'MPA', (304, 323))	('fusions', 'Var', (138, 145))
331107	32825119	In this study, the expression of YWHAE-NTRK3 induced sarcomas at 40% penetrance, whereas that of four other fusions, namely PPFIBP1-NTRK3, PAK2-RAF1, GAB1-ABL1 and wild-type ERAS, did not.	('YWHAE-NTRK3', 'Var', (33, 44))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('induced', 'Reg', (45, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcomas', 'Disease', (53, 61))
331115	32825119	Moreover, in vivo tumor growth was almost completely abolished by LOXO-101.	('tumor', 'Disease', (18, 23))	('LOXO-101', 'Var', (66, 74))	('LOXO-101', 'Chemical', 'MESH:C000609083', (66, 74))	('abolished', 'NegReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
331116	32825119	The growth suppressive effect of LOXO-101 in vivo has also been reported in a PDX model of NTRK1/3 fusions.	('NTRK1/3', 'Gene', (91, 98))	('LOXO-101', 'Chemical', 'MESH:C000609083', (33, 41))	('NTRK1/3', 'Gene', '18211;18213', (91, 98))	('fusions', 'Var', (99, 106))	('growth suppressive', 'CPA', (4, 22))
331122	32825119	It is currently unknown whether these fusions affect tumorigenesis or if they are passenger mutations, and further study is needed to clarify their natures.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('affect', 'Reg', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('fusions', 'Var', (38, 45))
331141	32825119	The antibodies used were FLAG (F3165; Sigma-Aldrich, St. Louis, MO, USA), phospho-TRK (ab197071; Abcam), phospho-AKT (#4060; Cell Signaling Technology, Danvers, MA, USA), pan-AKT (#4691; Cell Signaling Technology), phospho-p44/42 MAPK (#9101; Cell Signaling Technology), p44/42 MAPK (#9102; Cell Signaling Technology) and alpha-tubulin (T5168; Sigma-Aldrich).	('#9102', 'Var', (284, 289))	('F3165', 'Var', (31, 36))	('TRK', 'Gene', (82, 85))	('AKT', 'Gene', '11651', (113, 116))	('AKT', 'Gene', (113, 116))	('AKT', 'Gene', '11651', (175, 178))	('#4060;', 'Var', (118, 124))	('TRK', 'Gene', '18211', (82, 85))	('#9101', 'Var', (236, 241))	('AKT', 'Gene', (175, 178))
331146	32825119	Target RNA-seq identifies novel fusion genes effectively in BSTS diagnosed as tumors of unknown categories or misdiagnosed as different types, which resulted in the correction of diagnoses and will contribute to therapeutic directions.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('contribute', 'Reg', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('BSTS', 'Disease', (60, 64))	('fusion genes', 'Var', (32, 44))	('resulted in', 'Reg', (149, 160))
331165	31560833	For standard immunohistochemistry, 5 microm thick paraffin sections were processed using routine diagnostic antibodies and immunostaining protocols (Ventana immunostainer) of the Institute for Pathology, Regensburg for staining of CD3, CD20, CD56, CD68 (KP1), and LCA (CD45).	('LCA', 'Gene', (264, 267))	('LCA', 'Gene', '5788', (264, 267))	('CD45', 'Gene', (269, 273))	('CD45', 'Gene', '5788', (269, 273))	('CD56', 'Gene', '4684', (242, 246))	('CD3', 'Gene', (231, 234))	('CD68', 'Var', (248, 252))	('CD20', 'Var', (236, 240))	('paraffin', 'Chemical', 'MESH:D010232', (50, 58))	('CD56', 'Gene', (242, 246))	('CD3', 'Gene', '12503', (231, 234))
331170	31560833	For CD1d, in addition to the number of specifically positive cells per HPF, the immunostaining of tumor/normal thyroid cells was assessed by an expert pathologist (FW) and a trained pathologist (NVC) according to relative intensity of cytoplasmic (c) and membranous (m) staining, that is c > m, c = m, or m > c; some samples showed a completely negative staining reaction, and only one sample had nuclear positivity (Figure 1).	('m > c', 'Var', (305, 310))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('c = m', 'Var', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('negative', 'NegReg', (345, 353))	('c > m', 'Var', (288, 293))	('CD1d', 'Gene', (4, 8))
331189	31560833	SRC cells were either negative (6/11) or showed a predominantly membranous staining pattern (5/11), while MM cells showed a heterogeneous profile with all patterns present (3/7 with m > c, 2/7 with c > m, 2/7 neg.).	('c > m', 'Var', (198, 203))	('m > c', 'Var', (182, 187))	('SRC', 'Gene', '6714', (0, 3))	('SRC', 'Gene', (0, 3))	('membranous staining', 'MPA', (64, 83))
331208	29321818	Silencing of pappalysin-1 strongly inhibited anchorage-dependent and anchorage-independent growth as well as xenograft tumorigenicity of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (137, 150))	('pappalysin-1', 'Gene', (13, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('xenograft tumor', 'Disease', (109, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('xenograft tumor', 'Disease', 'MESH:D009369', (109, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (137, 150))	('inhibited', 'NegReg', (35, 44))	('Silencing', 'Var', (0, 9))
331222	29321818	Silencing of pappalysin-1 resulted in accumulation of IGFBPs and reduced bioactive IGF-1 in Ewing sarcoma cell secretome, leading to suppression of IGF signaling.	('pappalysin-1', 'Gene', (13, 25))	('IGFBPs', 'Gene', (54, 60))	('reduced', 'NegReg', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('accumulation', 'PosReg', (38, 50))	('IGF-1', 'Gene', '3479', (83, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('suppression', 'NegReg', (133, 144))	('Silencing', 'Var', (0, 9))	('IGF-1', 'Gene', (83, 88))	('IGF signaling', 'MPA', (148, 161))	('Ewing sarcoma', 'Disease', (92, 105))
331225	29321818	To dissect the impact of EWS-FLI-1 on Ewing sarcoma cell secretome, we silenced EWS-FLI-1 using lentiviruses expressing an shRNA against FLI-1 C-terminal region in A673 Ewing sarcoma cells (Figure 1A; luciferase shRNA as control) and analyzed the proteins secreted in the conditioned medium by GeLC-MS/MS and spectral counting.	('silenced', 'Var', (71, 79))	('EWS-FLI-1', 'Gene', '2130', (80, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (169, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (169, 182))	('Ewing sarcoma', 'Disease', (38, 51))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('EWS-FLI-1', 'Gene', (25, 34))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))	('Ewing sarcoma', 'Disease', (169, 182))	('EWS-FLI-1', 'Gene', '2130', (25, 34))	('EWS-FLI-1', 'Gene', (80, 89))
331226	29321818	From this, we found dramatically reduced pappalysin-1 protein levels in A673 cell secretome upon EWS-FLI-1 silencing (Figure 1B).	('EWS-FLI-1', 'Gene', (97, 106))	('pappalysin-1 protein levels', 'MPA', (41, 68))	('silencing', 'Var', (107, 116))	('reduced', 'NegReg', (33, 40))	('EWS-FLI-1', 'Gene', '2130', (97, 106))
331227	29321818	EWS-FLI-1 silencing also reduced pappalysin-1 transcript levels in A673 cells (Figure 1C).	('reduced', 'NegReg', (25, 32))	('pappalysin-1 transcript levels', 'MPA', (33, 63))	('EWS-FLI-1', 'Gene', (0, 9))	('EWS-FLI-1', 'Gene', '2130', (0, 9))	('silencing', 'Var', (10, 19))
331232	29321818	Pappalysin-1 is a cell surface metalloproteinase that cleaves IGFBP2, IGFBP4, and IGFBP5 and releases IGF from inhibitory IGFBPs, leading to increased local bioavailability of IGF and enhanced IGF signaling.	('IGFBP2', 'Gene', (62, 68))	('releases IGF', 'MPA', (93, 105))	('local bioavailability of IGF', 'MPA', (151, 179))	('IGF signaling', 'MPA', (193, 206))	('IGFBP4', 'Gene', '3487', (70, 76))	('increased', 'PosReg', (141, 150))	('IGFBP5', 'Gene', (82, 88))	('enhanced IGF signaling', 'Phenotype', 'HP:0030269', (184, 206))	('IGFBP4', 'Gene', (70, 76))	('IGFBP5', 'Gene', '3488', (82, 88))	('IGFBP2', 'Gene', '3485', (62, 68))	('cleaves', 'Var', (54, 61))	('enhanced', 'PosReg', (184, 192))	('Pappalysin-1', 'Gene', (0, 12))	('Pappalysin-1', 'Gene', '5069', (0, 12))
331234	29321818	The accumulation of IGFBP2, 4, and 5 upon pappalysin-1 silencing was accompanied by reduced cleavage product of IGFBP2, 4, and 5 in the secretome (supplementary Figure 1).	('cleavage product', 'MPA', (92, 108))	('accumulation', 'PosReg', (4, 16))	('pappalysin-1', 'Gene', (42, 54))	('silencing', 'Var', (55, 64))	('IGFBP2', 'Gene', '3485', (112, 118))	('reduced', 'NegReg', (84, 91))	('IGFBP2', 'Gene', '3485', (20, 26))	('IGFBP2', 'Gene', (112, 118))	('IGFBP2', 'Gene', (20, 26))
331236	29321818	Tyrosine auto-phosphorylation of IGF-1 receptor and serine 473 phosphorylation of Akt were significantly reduced upon pappalysin-1 silencing in all four Ewing sarcoma cell lines (Figure 4).	('silencing', 'Var', (131, 140))	('Akt', 'Gene', '207', (82, 85))	('IGF-1', 'Gene', (33, 38))	('IGF-1', 'Gene', '3479', (33, 38))	('serine 473 phosphorylation', 'MPA', (52, 78))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (153, 166))	('serine', 'Chemical', 'MESH:D012694', (52, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('Tyrosine auto-phosphorylation', 'MPA', (0, 29))	('Tyrosine', 'Chemical', 'MESH:D014443', (0, 8))	('reduced', 'NegReg', (105, 112))	('pappalysin-1', 'Gene', (118, 130))	('Akt', 'Gene', (82, 85))	('Ewing sarcoma', 'Disease', (153, 166))
331238	29321818	In accordance with pappalysin-1 being a transcriptional target of EWS-FLI-1 (Figure 1 and 2), EWS-FLI-1 silencing recapitulated the effect of pappalysin-1 silencing on IGFBPs and IGF signaling in Ewing sarcoma cells (Figure 4B): silencing of EWS- FLI-1 by FLI-1 C-terminus shRNA resulted in reduced pappalysin-1 and accumulation of IGFBP2, 4, and 5 in the secretome and reduced tyrosine phosphorylation of IGF-1 receptor and reduced serine 473 phosphorylation of Akt.	('reduced', 'NegReg', (425, 432))	('reduced', 'NegReg', (370, 377))	('pappalysin-1', 'MPA', (299, 311))	('serine 473 phosphorylation', 'MPA', (433, 459))	('serine', 'Chemical', 'MESH:D012694', (433, 439))	('Ewing sarcoma', 'Disease', (196, 209))	('silencing', 'Var', (229, 238))	('FLI-1', 'Gene', (256, 261))	('tyrosine phosphorylation', 'MPA', (378, 402))	('IGFBP2', 'Gene', '3485', (332, 338))	('EWS- FLI-1', 'Gene', (242, 252))	('Akt', 'Gene', (463, 466))	('EWS-FLI-1', 'Gene', (94, 103))	('IGF-1', 'Gene', (406, 411))	('EWS-FLI-1', 'Gene', '2130', (94, 103))	('Akt', 'Gene', '207', (463, 466))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (196, 209))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (196, 209))	('IGFBP2', 'Gene', (332, 338))	('IGF-1', 'Gene', '3479', (406, 411))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('accumulation', 'PosReg', (316, 328))	('EWS-FLI-1', 'Gene', (66, 75))	('reduced', 'NegReg', (291, 298))	('EWS-FLI-1', 'Gene', '2130', (66, 75))
331242	29321818	Proliferation arrest induced by pappalysin-1 silencing was completely rescued by the addition of recombinant pappalysin-1 protein to the culture medium (Figure 6C), indicating that Ewing sarcoma is dependent on extracellular pappalysin-1 protein.	('silencing', 'Var', (45, 54))	('arrest', 'Disease', 'MESH:D006323', (14, 20))	('Ewing sarcoma', 'Disease', (181, 194))	('arrest', 'Disease', (14, 20))	('pappalysin-1', 'Gene', (32, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (181, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (181, 194))
331243	29321818	Importantly, silencing of pappalysin-1 in A673 and EW8 cells resulted in dramatic inhibition of soft agar colony formation (Figure 6E), indicating that pappalysin-1 plays an essential role in anchorage-independent growth of Ewing sarcoma cells.	('pappalysin-1', 'Gene', (26, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('Ewing sarcoma', 'Disease', (224, 237))	('inhibition', 'NegReg', (82, 92))	('agar', 'Chemical', 'MESH:D000362', (101, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (224, 237))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (224, 237))	('soft agar colony formation', 'CPA', (96, 122))	('silencing', 'Var', (13, 22))
331245	29321818	As shown in Figure 6F, pappalysin-1 silencing strongly inhibited xenograft tumor growth (p < 0.05).	('silencing', 'Var', (36, 45))	('xenograft tumor', 'Disease', (65, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('pappalysin-1', 'Gene', (23, 35))	('inhibited', 'NegReg', (55, 64))	('xenograft tumor', 'Disease', 'MESH:D009369', (65, 80))
331249	29321818	High levels of IGF-1 and IGF-1R are expressed in Ewing sarcoma cell lines and tumors and inhibition of IGF-1R suppresses the xenograft tumorigenicity of Ewing sarcoma cells.	('IGF-1', 'Gene', '3479', (103, 108))	('IGF-1', 'Gene', '3479', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (153, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('High levels of IGF-1', 'Phenotype', 'HP:0030269', (0, 20))	('xenograft tumor', 'Disease', (125, 140))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('xenograft tumor', 'Disease', 'MESH:D009369', (125, 140))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('inhibition', 'Var', (89, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('Ewing sarcoma', 'Disease', (153, 166))	('Ewing sarcoma cell lines and tumors', 'Disease', 'MESH:C563168', (49, 84))	('Ewing sarcoma', 'Disease', (49, 62))	('IGF-1', 'Gene', (103, 108))	('IGF-1', 'Gene', (25, 30))	('suppresses', 'NegReg', (110, 120))	('IGF-1', 'Gene', (15, 20))	('IGF-1', 'Gene', '3479', (25, 30))
331252	29321818	Our data suggest that pappalysin-1 stimulates IGF signaling in Ewing sarcoma by increasing the bioactive IGF levels in the vicinity of cell surface where IGF and IGF-1R interaction occurs.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Ewing sarcoma', 'Disease', (63, 76))	('pappalysin-1', 'Var', (22, 34))	('bioactive IGF levels', 'MPA', (95, 115))	('stimulates', 'PosReg', (35, 45))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('increasing', 'PosReg', (80, 90))	('IGF signaling', 'MPA', (46, 59))
331258	29321818	Because IGFBP2, 4, and 5 bind and inhibit both IGF-1 and IGF-2, targeting pappalysin-1 would inhibit both IGF-1 and IGF-2 and potentially reduce therapy resistance in Ewing sarcoma.	('IGFBP2', 'Gene', '3485', (8, 14))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (167, 180))	('IGF-1', 'Gene', '3479', (47, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (167, 180))	('bind', 'Interaction', (25, 29))	('IGFBP2', 'Gene', (8, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('IGF-1', 'Gene', (106, 111))	('IGF-2', 'Gene', (116, 121))	('Ewing sarcoma', 'Disease', (167, 180))	('inhibit', 'NegReg', (93, 100))	('IGF-2', 'Gene', '3481', (116, 121))	('targeting', 'Var', (64, 73))	('IGF-1', 'Gene', '3479', (106, 111))	('pappalysin-1', 'Gene', (74, 86))	('reduce', 'NegReg', (138, 144))	('therapy resistance', 'CPA', (145, 163))	('IGF-1', 'Gene', (47, 52))	('IGF-2', 'Gene', (57, 62))	('inhibit', 'NegReg', (34, 41))	('IGF-2', 'Gene', '3481', (57, 62))
331267	29321818	The following siRNAs were used: human pappalysin-1 siRNA SMARTpool (M-005130-02-0005, Dharmacon) and Non-Targeting siRNA Pool #2 (D-001206-14-05, Dharmacon).	('M-005130-02-0005', 'Var', (68, 84))	('D-001206-14-05', 'Var', (130, 144))	('human', 'Species', '9606', (32, 37))
331313	28293120	While the earlier literature suggested rates of GR positivity of ~25%-50% in TNBC samples, rates based on the IHC assay were >=80% using a minimum cutoff of 10% tumor cells staining positively.	('positivity', 'Var', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('TNBC', 'Disease', (77, 81))	('tumor', 'Disease', (161, 166))	('GR', 'Gene', '2908', (48, 50))
331372	28293120	Research is needed to determine if tumors with low staining and H-scores (colon, gastric, and endometrial cancers) are good candidates for GR-targeted therapeutics.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('H-scores', 'Var', (64, 72))	('GR', 'Gene', '2908', (139, 141))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('endometrial cancer', 'Phenotype', 'HP:0012114', (94, 112))	('endometrial cancers', 'Disease', 'MESH:D016889', (94, 113))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Disease', (35, 41))	('endometrial cancers', 'Disease', (94, 113))	('gastric', 'Disease', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
331376	28293120	An initial assessment of GR as a therapeutic target and predictive factor is ongoing in a clinical trial testing the selective GR modulator CORT125134 in combination with nab-paclitaxel in solid tumors (NCT02762981).	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('GR', 'Gene', '2908', (25, 27))	('solid tumors', 'Disease', (189, 201))	('paclitaxel', 'Chemical', 'MESH:D017239', (175, 185))	('CORT125134', 'Var', (140, 150))	('GR', 'Gene', '2908', (127, 129))	('solid tumors', 'Disease', 'MESH:D009369', (189, 201))
331418	21934684	After adjustment for period of diagnosis, the risk of death was higher for 10-14-year olds compared with those aged 0-9 years (HR=1.76; 95% CI=1.35-2.30).	('death', 'Disease', 'MESH:D003643', (54, 59))	('death', 'Disease', (54, 59))	('10-14-year', 'Var', (75, 85))
331511	25501833	FUS knockdown also correlated with increased expression of the closely related protein EWS (Ewing's sarcoma).	('EWS', 'Gene', '14030', (87, 90))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (92, 107))	('increased', 'PosReg', (35, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('EWS', 'Gene', (87, 90))	('expression', 'MPA', (45, 55))	('FUS', 'Gene', (0, 3))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (92, 107))	('knockdown', 'Var', (4, 13))	("Ewing's sarcoma", 'Disease', (92, 107))	('EWS', 'Phenotype', 'HP:0012254', (87, 90))
331512	25501833	We demonstrate that the maladaptive phenotype resulting from FUS knockdown is reversible and can be rescued by re-expression of FUS or partially rescued by the small-molecule rolipram.	('rolipram', 'Chemical', 'MESH:D020889', (175, 183))	('knockdown', 'Var', (65, 74))	('FUS', 'Gene', (61, 64))
331518	25501833	Similarly, fusion of FUS with either the transcription factor ERG or FEV has been found in some cases of EWS family tumors or acute myeloid leukemia, and fusion with ATF1 and either CREB3 L2 or CREB3 L1 will cause angiomatoid fibrous histiocytoma and low-grade fibromyxoid sarcoma, respectively.	('EWS', 'Gene', '14030', (105, 108))	('found', 'Reg', (82, 87))	('ATF1', 'Gene', '11908', (166, 170))	('acute myeloid leukemia', 'Disease', (126, 148))	('EWS', 'Gene', (105, 108))	('ATF1', 'Gene', (166, 170))	('CREB3 L2', 'Gene', '208647', (182, 190))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('histiocytoma', 'Phenotype', 'HP:0012315', (234, 246))	('CREB3 L1', 'Gene', '26427', (194, 202))	('fusion', 'Var', (154, 160))	('EWS', 'Phenotype', 'HP:0012254', (105, 108))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (214, 246))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (261, 280))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (132, 148))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (126, 148))	('tumors', 'Disease', (116, 122))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (126, 148))	('angiomatoid fibrous histiocytoma', 'Disease', (214, 246))	('FEV', 'Gene', (69, 72))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('FEV', 'Gene', '260298', (69, 72))	('ERG', 'Gene', '13876', (62, 65))	('CREB3 L1', 'Gene', (194, 202))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('ERG', 'Gene', (62, 65))	('CREB3 L2', 'Gene', (182, 190))	('fibromyxoid sarcoma', 'Disease', (261, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('cause', 'Reg', (208, 213))
331528	25501833	Cell viability as determined by the MTT assay was reduced 40-50% in NSC-34 cells expressing shFUS and in HEK-293T cells expressing si3'UTR relative to controls (Figure 1c).	('MTT', 'Chemical', 'MESH:C070243', (36, 39))	('NSC-34', 'CellLine', 'CVCL:D356', (68, 74))	('shFUS', 'Var', (92, 97))	('Cell viability', 'CPA', (0, 14))	('HEK-293T cells', 'CellLine', 'CVCL:0063', (105, 119))	('reduced', 'NegReg', (50, 57))	("si3'UTR", 'Var', (131, 138))
331534	25501833	However, cells undergoing FUS knockdown for 96 h exhibited a robust and significant increase in phosphorylated histone H3 (p-H3) signal as assessed by immunofluorescence microscopy (Figure 4f), indicative of mitotic arrest.	('FUS', 'Gene', (26, 29))	('increase', 'PosReg', (84, 92))	('knockdown', 'Var', (30, 39))	('mitotic arrest', 'Disease', (208, 222))	('mitotic arrest', 'Disease', 'MESH:D006323', (208, 222))
331535	25501833	In fact, the percentage of cells undergoing FUS knockdown for 96 h that were p-H3-positive (~45%) was comparable to cells treated with nocodazole, an inducer of mitotic arrest (Figure 4g).	('nocodazole', 'Chemical', 'MESH:D015739', (135, 145))	('mitotic arrest', 'Disease', (161, 175))	('mitotic arrest', 'Disease', 'MESH:D006323', (161, 175))	('knockdown', 'Var', (48, 57))
331536	25501833	These data suggest that a defect in mitosis is responsible for the overall reduction in cellular proliferation upon FUS knockdown.	('cellular proliferation', 'CPA', (88, 110))	('mitosis', 'Disease', (36, 43))	('mitosis', 'Disease', 'None', (36, 43))	('knockdown', 'Var', (120, 129))	('FUS', 'Gene', (116, 119))	('reduction', 'NegReg', (75, 84))
331537	25501833	After this analysis, one compound, rolipram (Figure 5a), was found to partially restore the 25% decrease in cell number induced by FUS knockdown (Figure 5b).	('knockdown', 'Var', (135, 144))	('FUS', 'Gene', (131, 134))	('decrease', 'NegReg', (96, 104))	('cell number', 'CPA', (108, 119))	('rolipram', 'Chemical', 'MESH:D020889', (35, 43))
331546	25501833	Of these, energy homeostasis, calcium-related and metal ion binding were more prominent at 96 than 24 h, suggesting these changes are triggered by FUS knockdown and become more pronounced with time.	('calcium-related', 'MPA', (30, 45))	('metal', 'Interaction', (50, 55))	('calcium', 'Chemical', 'MESH:D002118', (30, 37))	('energy homeostasis', 'MPA', (10, 28))	('metal', 'Chemical', 'MESH:D008670', (50, 55))	('knockdown', 'Var', (151, 160))
331552	25501833	The RNA-binding protein EWS, which like FUS is a member of the TET family of proteins, also increased in expression in shFUS cells (Table 1,Figures 7b and 7d), as well as in HEK-293T cells transiently transfected with si3'UTR for FUS knockdown (Figure 7d), consistent with a previous report.	('RNA-binding protein EWS', 'Gene', (4, 27))	('RNA-binding protein EWS', 'Gene', '2130', (4, 27))	('TET', 'Chemical', 'MESH:C010349', (63, 66))	('increased', 'PosReg', (92, 101))	('HEK-293T cells', 'CellLine', 'CVCL:0063', (174, 188))	('knockdown', 'Var', (234, 243))	('EWS', 'Phenotype', 'HP:0012254', (24, 27))	('expression', 'MPA', (105, 115))
331553	25501833	This appears to be a specific relationship between FUS and EWS expression as FUS knockdown did not influence the expression of other related RNA-binding proteins such as TDP43 and hnRNPA1, or the other TET family member TAF15 (data not shown).	('EWS', 'Gene', (59, 62))	('expression', 'MPA', (113, 123))	('TDP43', 'Gene', (170, 175))	('TDP43', 'Gene', '230908', (170, 175))	('hnRNPA1', 'Gene', (180, 187))	('TET', 'Chemical', 'MESH:C010349', (202, 205))	('hnRNPA1', 'Gene', '15382', (180, 187))	('influence', 'Reg', (99, 108))	('FUS', 'Gene', (77, 80))	('knockdown', 'Var', (81, 90))	('TAF15', 'Gene', (220, 225))	('EWS', 'Gene', '14030', (59, 62))	('TAF15', 'Gene', '70439', (220, 225))	('EWS', 'Phenotype', 'HP:0012254', (59, 62))
331554	25501833	Similar to EWS, thymosin beta-10, a 5 kDa monomeric actin-binding protein that inhibits actin polymerization, also increased in expression upon FUS knockdown (Table 1 and Figure 7b), but could not be detected by western blot.	('thymosin beta-10', 'Gene', '19240', (16, 32))	('inhibits', 'NegReg', (79, 87))	('increased', 'PosReg', (115, 124))	('actin polymerization', 'MPA', (88, 108))	('EWS', 'Gene', '14030', (11, 14))	('thymosin beta-10', 'Gene', (16, 32))	('expression', 'MPA', (128, 138))	('EWS', 'Phenotype', 'HP:0012254', (11, 14))	('knockdown', 'Var', (148, 157))	('EWS', 'Gene', (11, 14))
331555	25501833	Genetic alterations in FUS cause human diseases such as cancer and neurodegeneration.	('Genetic alterations', 'Var', (0, 19))	('neurodegeneration', 'Phenotype', 'HP:0002180', (67, 84))	('FUS', 'Gene', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cause', 'Reg', (27, 32))	('neurodegeneration', 'Disease', (67, 84))	('human', 'Species', '9606', (33, 38))	('neurodegeneration', 'Disease', 'MESH:D019636', (67, 84))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
331556	25501833	In the study of sarcomas caused by fusion of FUS with various transcription factors, overexpression of the transcription factor component alone was unable to promote tumor growth, suggesting that FUS is essential for the oncogenic role of FUS-fusion proteins.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('sarcomas', 'Disease', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('fusion', 'Var', (35, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))	('caused by', 'Reg', (25, 34))
331558	25501833	Consistent with the latter, signs of apoptosis or gross cellular death were not observed here upon knockdown of FUS in cultured mammalian cells (Figure 3).	('FUS', 'Gene', (112, 115))	('mammalian', 'Species', '9606', (128, 137))	('knockdown', 'Var', (99, 108))
331562	25501833	One of these proteins, S100A6, exhibited reduced expression after 96 h (Figure 7, Table 1), consistent with previous reports describing reduced cell proliferation upon S100A6 knockdown.	('reduced', 'NegReg', (41, 48))	('S100A6', 'Gene', '20200', (168, 174))	('cell proliferation', 'CPA', (144, 162))	('S100A6', 'Gene', (23, 29))	('expression', 'MPA', (49, 59))	('S100A6', 'Gene', (168, 174))	('reduced', 'NegReg', (136, 143))	('knockdown', 'Var', (175, 184))	('S100A6', 'Gene', '20200', (23, 29))
331567	25501833	That expression of MT2 was higher in shFUS cells relative to shSC cells at 24 h, a difference that became more pronounced at 96 h (Figure 7,Table 1), implicates a role for one of the aforementioned stressors in the FUS knockdown-induced proliferation defect.	('expression', 'MPA', (5, 15))	('knockdown-induced', 'Var', (219, 236))	('MT2', 'Gene', (19, 22))	('higher', 'PosReg', (27, 33))	('MT2', 'Gene', '17750', (19, 22))
331569	25501833	In support of this notion, rolipram partially rescued the proliferation defect upon FUS knockdown (Figure 5).	('rolipram', 'Chemical', 'MESH:D020889', (27, 35))	('proliferation', 'CPA', (58, 71))	('knockdown', 'Var', (88, 97))
331573	25501833	Consistent with a previous report, we also detected an increase in EWS expression upon FUS knockdown (Figure 7,Table 1).	('EWS', 'Phenotype', 'HP:0012254', (67, 70))	('increase', 'PosReg', (55, 63))	('EWS', 'Gene', (67, 70))	('knockdown', 'Var', (91, 100))	('EWS', 'Gene', '14030', (67, 70))
331575	25501833	An alternative, although not mutually exclusive, explanation is that regulation of EWS at the RNA level is directly impacted by FUS knockdown.	('impacted', 'Reg', (116, 124))	('EWS', 'Phenotype', 'HP:0012254', (83, 86))	('EWS', 'Gene', (83, 86))	('knockdown', 'Var', (132, 141))	('EWS', 'Gene', '14030', (83, 86))	('regulation', 'MPA', (69, 79))
331581	25501833	Moreover, the processes and proteins that are altered here upon FUS knockdown, particularly those relating to cytoskeletal organization, oxidative stress and calcium handling, are relevant to the homeostasis of mature neurons.	('oxidative stress', 'Phenotype', 'HP:0025464', (137, 153))	('FUS', 'Gene', (64, 67))	('altered', 'Reg', (46, 53))	('calcium', 'Chemical', 'MESH:D002118', (158, 165))	('knockdown', 'Var', (68, 77))
331663	24950962	The neoplastic cells express terminal deoxynucleotidyl transferase (TdT), CD34, CD99 and variable CD2, CD3, CD4, CD5, CD7, CD8.	('CD8', 'Gene', (123, 126))	('CD34', 'Gene', (74, 78))	('CD4', 'Gene', '920', (108, 111))	('CD7', 'Gene', '924', (118, 121))	('TdT', 'Gene', '1791', (68, 71))	('CD4', 'Gene', (108, 111))	('CD7', 'Gene', (118, 121))	('terminal deoxynucleotidyl transferase', 'Gene', '1791', (29, 66))	('CD5', 'Gene', (113, 116))	('CD99', 'Gene', (80, 84))	('CD2', 'Gene', '914', (98, 101))	('CD2', 'Gene', (98, 101))	('CD34', 'Gene', '947', (74, 78))	('terminal deoxynucleotidyl transferase', 'Gene', (29, 66))	('CD99', 'Gene', '4267', (80, 84))	('CD8', 'Gene', '925', (123, 126))	('CD5', 'Gene', '921', (113, 116))	('TdT', 'Gene', (68, 71))	('CD3', 'Var', (103, 106))
331702	24950962	Nonetheless, experimental evidence have shown that aberrant Pax-5 expression in thymocytes drives malignant transformation.	('Pax-5', 'Gene', (60, 65))	('aberrant', 'Var', (51, 59))	('drives', 'Reg', (91, 97))	('expression', 'MPA', (66, 76))	('malignant transformation', 'CPA', (98, 122))	('Pax-5', 'Gene', '5079', (60, 65))
331735	22140550	A stock concentration of 10 mM in 100 % dimethyl sulfoxide (DMSO) of specific inhibitors for ataxia telangiectasia mutated (ATM), KU 55933 (Tocris bioscience, Ellisville, MO) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), NU7441 (Tocris bioscience) were diluted to a working concentration of 10 microM in 1% DMSO.	('DNA-PK', 'Gene', (227, 233))	('telangiectasia', 'Phenotype', 'HP:0001009', (100, 114))	('DNA-PKcs', 'Gene', (227, 235))	('KU 55933', 'Var', (130, 138))	('DNA-dependent protein kinase catalytic subunit', 'Gene', '5591', (179, 225))	('DNA-PK', 'Gene', '5591', (227, 233))	('Tocris bioscience', 'Disease', 'None', (246, 263))	('DMSO', 'Chemical', 'MESH:D004121', (60, 64))	('Tocris bioscience', 'Disease', 'None', (140, 157))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (40, 58))	('Tocris bioscience', 'Disease', (246, 263))	('DNA-dependent protein kinase catalytic subunit', 'Gene', (179, 225))	('ataxia', 'Phenotype', 'HP:0001251', (93, 99))	('Tocris bioscience', 'Disease', (140, 157))	('ataxia telangiectasia mutated', 'Gene', (93, 122))	('DNA-PKcs', 'Gene', '5591', (227, 235))	('ataxia telangiectasia mutated', 'Gene', '472', (93, 122))	('DMSO', 'Chemical', 'MESH:D004121', (324, 328))
331784	32082662	A FISH assay of tumoral tissue showed a 22q12 rearrangement.	('tumoral', 'Disease', (16, 23))	('tumoral', 'Disease', 'MESH:D009369', (16, 23))	('22q12 rearrangement', 'Var', (40, 59))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))
331824	32082662	TK216 is a novel small-molecule that directly binds to EWS-FLI1 and inhibits its function by blocking binding to RNA helicase A. TK216 demonstrates potent antiproliferative effects on ES cell lines and xenografts and is currently being tested in clinical trials.	('FLI1', 'Gene', (59, 63))	('EWS', 'Gene', '2130', (55, 58))	('EWS', 'Gene', (55, 58))	('function', 'MPA', (81, 89))	('antiproliferative effects', 'CPA', (155, 180))	('blocking', 'NegReg', (93, 101))	('binding', 'Interaction', (102, 109))	('FLI1', 'Gene', '2313', (59, 63))	('RNA helicase', 'Protein', (113, 125))	('binds', 'Interaction', (46, 51))	('ES', 'Disease', 'MESH:D012512', (184, 186))	('ES', 'Phenotype', 'HP:0012254', (184, 186))	('TK216', 'Var', (129, 134))	('inhibits', 'NegReg', (68, 76))
331825	32082662	Another exciting target is the enzyme lysine-specific demethylase 1 (LSD1) which is highly expressed in ES cell lines, and inhibitors of LSD1 could offer a ray of hope against this lethal disease.	('LSD1', 'Gene', (69, 73))	('lysine-specific demethylase 1', 'Gene', '23028', (38, 67))	('LSD1', 'Gene', '23028', (69, 73))	('ES', 'Phenotype', 'HP:0012254', (104, 106))	('ES', 'Disease', 'MESH:D012512', (104, 106))	('inhibitors', 'Var', (123, 133))	('LSD1', 'Gene', (137, 141))	('LSD1', 'Gene', '23028', (137, 141))	('lysine-specific demethylase 1', 'Gene', (38, 67))
331826	32082662	In preclinical studies, it has been shown that focal adhesion kinase (FAK) inhibitors and Aurora kinase B inhibitors synergistically impair Ewing sarcoma cell growth and significantly inhibit tumor progression; this treatment approach needs to be validated in clinical trials.	('impair', 'NegReg', (133, 139))	('inhibit', 'NegReg', (184, 191))	('focal adhesion kinase', 'Gene', (47, 68))	('tumor', 'Disease', (192, 197))	('Ewing sarcoma', 'Disease', (140, 153))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (140, 153))	('FAK', 'Gene', '5747', (70, 73))	('Aurora kinase B', 'Gene', (90, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('inhibitors', 'Var', (106, 116))	('focal adhesion kinase', 'Gene', '5747', (47, 68))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (140, 153))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('Aurora kinase B', 'Gene', '9212', (90, 105))	('FAK', 'Gene', (70, 73))
331873	32038880	In our case 1, we described a patient with high expression of PD-L1, which presented with remarkable response but died of severe immune related toxicity.	('PD-L1', 'Gene', '29126', (62, 67))	('high expression', 'Var', (43, 58))	('patient', 'Species', '9606', (30, 37))	('toxicity', 'Disease', 'MESH:D064420', (144, 152))	('toxicity', 'Disease', (144, 152))	('PD-L1', 'Gene', (62, 67))
331925	30879106	The antibodies used were directed against CD163 (NCL-L-CD163, Novocastra, 1:200), CD80 (MAB140, RnD, 20 microg/ml), CD8 (M7103, DAKO, 1:75), FOXP3 (ab20034, Abcam, 10 microg/ml, IHC), FOXP3 (12653, Cell Signaling, 1:100, immunofluorescence with liquid permanent red as below), CD68 (M0876, DAKO, 1:50), CD20 (M0755, DAKO, 1:200), CD19 (M7296, DAKO, 1:50) and PAX5 (12709, Cell Signaling, 1:100).	('CD8', 'Gene', (116, 119))	('CD80', 'Gene', '941', (82, 86))	('CD163', 'Gene', (55, 60))	('CD68', 'Gene', '968', (277, 281))	('PAX5', 'Gene', (359, 363))	('FOXP3', 'Gene', '50943', (141, 146))	('CD80', 'Gene', (82, 86))	('M7296', 'Var', (336, 341))	('CD8', 'Gene', (82, 85))	('CD163', 'Gene', '9332', (42, 47))	('FOXP3', 'Gene', (184, 189))	('CD20', 'Gene', (303, 307))	('CD68', 'Gene', (277, 281))	('PAX5', 'Gene', '5079', (359, 363))	('CD163', 'Gene', (42, 47))	('CD8', 'Gene', '925', (116, 119))	('CD19', 'Gene', (330, 334))	('CD20', 'Gene', '931', (303, 307))	('NCL-L-CD163', 'Gene', '9332', (49, 60))	('FOXP3', 'Gene', '50943', (184, 189))	('NCL-L-CD163', 'Gene', (49, 60))	('CD8', 'Gene', '925', (82, 85))	('CD163', 'Gene', '9332', (55, 60))	('FOXP3', 'Gene', (141, 146))	('CD19', 'Gene', '930', (330, 334))
332032	28860931	Various studies have shown a favourable effect of PTX and methyloxantine in the course of septic shock, a significant protective effect in infection of Gram-negative sepsis and peritonitis in animal models.	('peritonitis', 'Disease', (177, 188))	('sepsis', 'Disease', 'MESH:D018805', (166, 172))	('septic shock', 'Disease', (90, 102))	('shock', 'Phenotype', 'HP:0031273', (97, 102))	('methyloxantine', 'Chemical', '-', (58, 72))	('methyloxantine', 'Var', (58, 72))	('septic shock', 'Phenotype', 'HP:0100806', (90, 102))	('sepsis', 'Phenotype', 'HP:0100806', (166, 172))	('peritonitis', 'Phenotype', 'HP:0002586', (177, 188))	('septic shock', 'Disease', 'MESH:D012772', (90, 102))	('peritonitis', 'Disease', 'MESH:D010534', (177, 188))	('PTX', 'Chemical', 'MESH:D010431', (50, 53))	('sepsis', 'Disease', (166, 172))
332035	28860931	In addition, PTX reduces intestinal bacterial overgrowth, bacterial translocation, and spontaneous bacterial peritonitis in animal (rat) model and reduces oxidative stress in intestinal mucosa.	('bacterial peritonitis', 'Disease', (99, 120))	('reduces', 'NegReg', (147, 154))	('reduces', 'NegReg', (17, 24))	('PTX', 'Chemical', 'MESH:D010431', (13, 16))	('rat', 'Species', '10116', (132, 135))	('bacterial peritonitis', 'Disease', 'MESH:D010534', (99, 120))	('oxidative stress', 'Phenotype', 'HP:0025464', (155, 171))	('peritonitis', 'Phenotype', 'HP:0002586', (109, 120))	('intestinal bacterial overgrowth', 'CPA', (25, 56))	('PTX', 'Var', (13, 16))	('overgrowth', 'Phenotype', 'HP:0001548', (46, 56))	('oxidative stress', 'MPA', (155, 171))	('bacterial translocation', 'CPA', (58, 81))
332044	28860931	PTX augments the production of prostacyclins, the vasodilator eicosanoids, and can inhibit the production of inflammatory cytokines, thus, reduces neutrophil adhesiveness to endothelial cells, enhances chemotaxis and lowers the production of free radicals that can damage tissues.	('lowers', 'NegReg', (217, 223))	('eicosanoids', 'Chemical', 'MESH:D015777', (62, 73))	('production of free radicals', 'MPA', (228, 255))	('PTX', 'Var', (0, 3))	('production of inflammatory cytokines', 'MPA', (95, 131))	('PTX', 'Chemical', 'MESH:D010431', (0, 3))	('free radicals', 'Chemical', 'MESH:D005609', (242, 255))	('prostacyclins', 'Chemical', 'MESH:D044062', (31, 44))	('production of prostacyclins', 'MPA', (17, 44))	('reduces neutrophil adhesiveness', 'Phenotype', 'HP:0008352', (139, 170))	('neutrophil adhesiveness to', 'CPA', (147, 173))	('chemotaxis', 'CPA', (202, 212))	('vasodilator eicosanoids', 'MPA', (50, 73))	('reduces', 'NegReg', (139, 146))	('augments', 'PosReg', (4, 12))	('inhibit', 'NegReg', (83, 90))	('enhances', 'PosReg', (193, 201))
332062	28860931	Sunil showed that PTX decreases the number of proinflammatory macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while increases those with anti- inflammatory phenotype CD163+ and Gal-3+.	('MMP-9', 'Gene', (95, 100))	('decreased', 'NegReg', (106, 115))	('pentoxifylline', 'MPA', (122, 136))	('increases', 'PosReg', (144, 153))	('pentoxifylline', 'Chemical', 'MESH:D010431', (122, 136))	('PTX', 'Chemical', 'MESH:D010431', (18, 21))	('COX-2', 'Gene', (85, 90))	('Sunil', 'Chemical', '-', (0, 5))	('MMP-9', 'Gene', '17395', (95, 100))	('CD163+', 'Var', (194, 200))	('decreases', 'NegReg', (22, 31))
332078	28860931	There are evidences that indicate the main mechanism of action for traditional NSAIDs and selective for COX-2 NSAIDs (coxibs) is the inhibition of COX-2 dependent PGE2.	('COX-2', 'Gene', (104, 109))	('NSAIDs', 'Var', (110, 116))	('COX-2 dependent PGE2', 'Enzyme', (147, 167))	('inhibition', 'NegReg', (133, 143))	('PGE2', 'Chemical', 'MESH:D015232', (163, 167))
332079	28860931	It is suspected also, that coxibs may have antiangiogenic properties and in such way may cause heart ischemia and infarction.	('antiangiogenic properties', 'CPA', (43, 68))	('cause', 'Reg', (89, 94))	('heart ischemia', 'Phenotype', 'HP:0002637', (95, 109))	('heart ischemia and infarction', 'Disease', 'MESH:D007511', (95, 124))	('coxibs', 'Var', (27, 33))
332150	25298548	C04.557.450.565.575.650.800 C04.557.450.795.620.800 A user might begin the search with Ewings sarcoma but realizes after viewing hierarchy that they really wanted sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('sarcoma', 'Disease', (163, 170))	('sarcoma', 'Disease', (94, 101))	('C04.557.450.795.620.800', 'Var', (28, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewings sarcoma', 'Disease', (87, 101))	('Ewings sarcoma', 'Disease', 'MESH:C563168', (87, 101))	('Ewings sarcoma', 'Phenotype', 'HP:0012254', (87, 101))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))
332211	23497062	Although a rare complication, death is usually a result of nodular expansion into vital organs with interference of normal organ function.	('nodular expansion', 'Var', (59, 76))	('death', 'Disease', 'MESH:D003643', (30, 35))	('death', 'Disease', (30, 35))
332233	21997189	Mutations of p53 have been implicated in the development of ~50% of human cancers, including those instigated by exposure to mutagens.	('human', 'Species', '9606', (68, 73))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('implicated', 'Reg', (27, 37))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
332234	21997189	Although numerically rare, cancers can arise due to inherited mutations, such as in the Li-Fraumeni Syndrome, which is caused by mutation of one p53 allele.	('Li-Fraumeni Syndrome', 'Disease', (88, 108))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutation', 'Var', (129, 137))	('p53', 'Gene', (145, 148))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('caused by', 'Reg', (119, 128))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (88, 108))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('cancers', 'Disease', (27, 34))
332236	21997189	On a C57BL/6 background, p53-deficient mice develop primarily thymic lymphoma and more rarely sarcoma.	('thymic lymphoma', 'Disease', (62, 77))	('sarcoma', 'Disease', (94, 101))	('primarily thymic lymphoma', 'Phenotype', 'HP:0030069', (52, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('thymic lymphoma', 'Disease', 'MESH:D013953', (62, 77))	('develop', 'PosReg', (44, 51))	('p53-deficient', 'Var', (25, 38))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('mice', 'Species', '10090', (39, 43))
332239	21997189	These data show that, collectively, Bcl-2, Bcl-xL and Bcl-w play only minor roles in thymic lymphoma development elicited by defects in p53 and this may indicate that Mcl-1 and/or A1 may feature more prominently in this process.	('elicited by', 'Reg', (113, 124))	('thymic lymphoma', 'Disease', 'MESH:D013953', (85, 100))	('defects', 'Var', (125, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('p53', 'Protein', (136, 139))	('thymic lymphoma', 'Disease', (85, 100))
332242	21997189	Obligatory loss or mutation of the wild-type p53 allele plus additional lesions in oncogenes and/or tumour suppressor genes drive the development of cancers in these individuals.	('p53', 'Gene', (45, 48))	('cancers', 'Disease', (149, 156))	('mutation', 'Var', (19, 27))	('loss', 'NegReg', (11, 15))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('development of', 'CPA', (134, 148))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumour', 'Disease', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
332243	21997189	To establish a mouse model of Li-Fraumeni syndrome, several groups have performed gene targeting in ES cells to generate mice that either lack p53  or carry point mutations in p53 that are commonly found in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('p53', 'Gene', (176, 179))	('point mutations', 'Var', (157, 172))	('lack', 'NegReg', (138, 142))	('carry', 'Reg', (151, 156))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (30, 50))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('mice', 'Species', '10090', (121, 125))	('mouse', 'Species', '10090', (15, 20))	('rat', 'Species', '10116', (116, 119))	('p53', 'Protein', (143, 146))	('cancers', 'Disease', (213, 220))	('human', 'Species', '9606', (207, 212))	('Li-Fraumeni syndrome', 'Disease', (30, 50))
332244	21997189	p53 mutant mice are highly prone to develop a similar range of cancers as those found in Li-Fraumeni Syndrome patients, although lymphomas and sarcomas predominate with their relative frequencies affected by the genetic background.	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (89, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('sarcomas', 'Disease', (143, 151))	('mutant', 'Var', (4, 10))	('lymphoma', 'Phenotype', 'HP:0002665', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('lymphomas', 'Disease', 'MESH:D008223', (129, 138))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('lymphomas', 'Phenotype', 'HP:0002665', (129, 138))	('cancers', 'Disease', (63, 70))	('p53', 'Gene', (0, 3))	('prone', 'Reg', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mice', 'Species', '10090', (11, 15))	('develop', 'PosReg', (36, 43))	('Li-Fraumeni Syndrome', 'Disease', (89, 109))	('lymphomas', 'Disease', (129, 138))	('sarcomas', 'Disease', 'MESH:D012509', (143, 151))	('patients', 'Species', '9606', (110, 118))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
332248	21997189	Somatically acquired mutation or loss of p53 have been implicated in the development of ~50% of sporadic human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('loss', 'NegReg', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('p53', 'Gene', (41, 44))	('mutation', 'Var', (21, 29))	('human', 'Species', '9606', (105, 110))	('implicated', 'Reg', (55, 65))
332249	21997189	Importantly, loss of p53 function also increases resistance of tumour cells to a broad range of anti-cancer therapeutics, particularly those that elicit DNA damage.	('function', 'Var', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('increases', 'PosReg', (39, 48))	('loss', 'Var', (13, 17))	('tumour', 'Disease', (63, 69))	('p53', 'Gene', (21, 24))	('resistance', 'MPA', (49, 59))
332262	21997189	Given that evasion of apoptosis, often due to deregulated expression of pro-survival Bcl-2 family members, is thought to be critical for tumour development, it is theoretically possible that BH3 mimetics may find utility as a prophylactic strategy to prevent or delay development of malignant disease in genetically predisposed individuals, such as Li-Fraumeni patients.	('deregulated', 'Var', (46, 57))	('malignant disease', 'Disease', (283, 300))	('patients', 'Species', '9606', (361, 369))	('rat', 'Species', '10116', (241, 244))	('Bcl-2 family members', 'Gene', (85, 105))	('expression', 'MPA', (58, 68))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('tumour', 'Disease', (137, 143))	('delay', 'NegReg', (262, 267))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('delay development', 'Phenotype', 'HP:0001263', (262, 279))	('BH3', 'Chemical', 'MESH:C006008', (191, 194))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (349, 360))	('Bcl-2 family members', 'Gene', '10018', (85, 105))	('malignant disease', 'Disease', 'MESH:D009369', (283, 300))	('evasion', 'MPA', (11, 18))	('Li-Fraumeni', 'Disease', (349, 360))
332270	21997189	Surprisingly, ABT-737 had no significant impact on the incidence or rate of tumour development in the p53+/- (p=0.0623) or p53-/- mice (p=0.5477; Figure 1a).	('ABT-737', 'Chemical', 'MESH:C501332', (14, 21))	('mice', 'Species', '10090', (130, 134))	('ABT-737', 'Gene', (14, 21))	('p53-/-', 'Var', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour', 'Disease', (76, 82))	('rat', 'Species', '10116', (68, 71))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('p53+/-', 'Var', (102, 108))
332274	21997189	The ABT-737 treated p53+/- mice presented with lower spleen and lymph node weights and lower white blood cell counts compared to the vehicle treated animals, but none of these differences were statistically significant (Figures 2a-c).	('ABT-737', 'Gene', (4, 11))	('lower', 'NegReg', (47, 52))	('ABT-737', 'Chemical', 'MESH:C501332', (4, 11))	('mice', 'Species', '10090', (27, 31))	('lower', 'NegReg', (87, 92))	('lower white blood cell counts', 'Phenotype', 'HP:0001882', (87, 116))	('white blood cell counts', 'MPA', (93, 116))	('p53+/-', 'Var', (20, 26))
332276	21997189	This result is consistent with previous reports that loss of heterozygosity is essential for thymic lymphoma development in p53+/- mice.	('lymphoma', 'Phenotype', 'HP:0002665', (100, 108))	('p53+/-', 'Var', (124, 130))	('thymic lymphoma', 'Disease', (93, 108))	('thymic lymphoma', 'Disease', 'MESH:D013953', (93, 108))	('mice', 'Species', '10090', (131, 135))	('loss', 'Var', (53, 57))
332281	21997189	Our analysis revealed a trend towards a decrease in thymus, spleen and lymph node weights as well as blood leukocyte counts in sick, tumour burdened p53-/- mice that had been prophylactically treated with ABT-737 in comparison to mice that had been treated with vehicle, but none of these differences reached statistical significance (Figures 3a and b).	('decrease', 'NegReg', (40, 48))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('blood leukocyte', 'MPA', (101, 116))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('mice', 'Species', '10090', (230, 234))	('ABT-737', 'Chemical', 'MESH:C501332', (205, 212))	('ABT-737', 'Var', (205, 212))	('thymus', 'CPA', (52, 58))	('tumour', 'Disease', (133, 139))	('p53-/-', 'Var', (149, 155))	('decrease in thymus', 'Phenotype', 'HP:0000778', (40, 58))	('mice', 'Species', '10090', (156, 160))
332283	21997189	Collectively, these data show that prophylactic treatment with ABT-737 is unable to delay spontaneous tumour development or reduce severity of malignant disease in p53+/- and p53-/- mice.	('ABT-737', 'Gene', (63, 70))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('ABT-737', 'Chemical', 'MESH:C501332', (63, 70))	('malignant disease', 'Disease', 'MESH:D009369', (143, 160))	('mice', 'Species', '10090', (182, 186))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('malignant disease', 'Disease', (143, 160))	('tumour', 'Disease', (102, 108))	('delay', 'NegReg', (84, 89))	('reduce', 'NegReg', (124, 130))	('p53+/-', 'Var', (164, 170))
332285	21997189	Repeated exposure to low-dose gamma-radiation elicits thymic lymphoma development in certain strains of mice, including C57BL/6, due to activation of the endogenous radiation induced leukemia virus (RadLV) and generation of oncogenic mutations resulting from DNA strand breaks.	('oncogenic mutations', 'CPA', (224, 243))	('thymic lymphoma', 'Disease', 'MESH:D013953', (54, 69))	('DNA strand breaks', 'Var', (259, 276))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('mice', 'Species', '10090', (104, 108))	('rat', 'Species', '10116', (214, 217))	('leukemia virus', 'Disease', 'MESH:D007938', (183, 197))	('leukemia', 'Phenotype', 'HP:0001909', (183, 191))	('activation', 'PosReg', (136, 146))	('thymic lymphoma', 'Disease', (54, 69))	('elicits', 'Reg', (46, 53))	('leukemia virus', 'Disease', (183, 197))
332286	21997189	Loss of one or both alleles of p53 significantly accelerates gamma-radiation thymic lymphoma development, most likely due to loss of p53's ability to coordinate cell cycle arrest and DNA repair responses.	('rat', 'Species', '10116', (55, 58))	('p53', 'Gene', (31, 34))	('loss', 'NegReg', (125, 129))	('arrest', 'Disease', (172, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (161, 178))	('thymic lymphoma', 'Disease', (77, 92))	('accelerates', 'PosReg', (49, 60))	('Loss', 'Var', (0, 4))	('arrest', 'Disease', 'MESH:D006323', (172, 178))	('thymic lymphoma', 'Disease', 'MESH:D013953', (77, 92))
332287	21997189	As expected, when compared to non-irradiated p53+/- mice, both treatment cohorts (ABT-737 prophylactic treatment or vehicle) of gamma-irradiated p53+/- mice displayed a considerably accelerated tumour onset (compare Figures 1a and 4a).	('p53+/-', 'Var', (145, 151))	('tumour', 'Disease', (194, 200))	('mice', 'Species', '10090', (52, 56))	('rat', 'Species', '10116', (188, 191))	('accelerated', 'PosReg', (182, 193))	('mice', 'Species', '10090', (152, 156))	('ABT-737', 'Chemical', 'MESH:C501332', (82, 89))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (194, 200))
332288	21997189	The median survival and tumour incidence of gamma-irradiated p53+/- mice did not significantly differ between animals that had been treated prophylactically with ABT-737 compared to vehicle treated mice (172 vs. 190 days, respectively, p=0.8992, Figures 4a and b).	('mice', 'Species', '10090', (68, 72))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('ABT-737', 'Chemical', 'MESH:C501332', (162, 169))	('ABT-737', 'Gene', (162, 169))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (24, 30))	('mice', 'Species', '10090', (198, 202))	('p53+/-', 'Var', (61, 67))
332290	21997189	Analysis of thymus, spleen and lymph node weights (Figure 5a) as well as blood leukocyte counts (Figure 5b) of sick, tumour-burdened gamma-irradiated p53+/- mice revealed no significant differences between the treatment groups despite a trend towards a decrease in lymph node weights (p=0.0691; Figure 5a).	('lymph node weights', 'CPA', (265, 283))	('decrease', 'NegReg', (253, 261))	('mice', 'Species', '10090', (157, 161))	('decrease in lymph node weights', 'Phenotype', 'HP:0002732', (253, 283))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('p53+/-', 'Var', (150, 156))	('tumour', 'Disease', (117, 123))
332298	21997189	Most of these tumours were CD8 SP or CD4LowCD8High (Supplementary Figure 3), a phenotype frequently observed in radiation induced thymic lymphomas.	('lymphomas', 'Disease', 'MESH:D008223', (137, 146))	('lymphomas', 'Phenotype', 'HP:0002665', (137, 146))	('thymic lymphoma', 'Disease', 'MESH:D013953', (130, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('lymphomas', 'Disease', (137, 146))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('CD4', 'Gene', (37, 40))	('thymic lymphoma', 'Disease', (130, 145))	('CD8 SP', 'Var', (27, 33))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))	('CD4', 'Gene', '12504', (37, 40))
332305	21997189	Taken together, these data show that ABT-737 prophylaxis does not alter the response of thymic lymphomas originating in p53 deficient mice to ABT-737 or dexamethasone.	('mice', 'Species', '10090', (134, 138))	('thymic lymphoma', 'Disease', 'MESH:D013953', (88, 103))	('ABT-737', 'Chemical', 'MESH:C501332', (142, 149))	('lymphomas', 'Phenotype', 'HP:0002665', (95, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (95, 103))	('ABT-737', 'Chemical', 'MESH:C501332', (37, 44))	('lymphomas', 'Disease', (95, 104))	('thymic lymphoma', 'Disease', (88, 103))	('lymphomas', 'Disease', 'MESH:D008223', (95, 104))	('p53', 'Gene', (120, 123))	('dexamethasone', 'Chemical', 'MESH:D003907', (153, 166))	('deficient', 'Var', (124, 133))
332307	21997189	In certain tumours, however, we occasionally observed a minor increase in protein levels of Mcl-1 and/or Bcl-xL of ABT-737 or vehicle treated animals compared to extracts from C57BL/6 thymii, which were used as a control.	('protein levels of Mcl-1', 'MPA', (74, 97))	('ABT-737', 'Chemical', 'MESH:C501332', (115, 122))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('ABT-737', 'Var', (115, 122))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))	('Bcl-xL', 'MPA', (105, 111))	('increase', 'PosReg', (62, 70))
332318	21997189	Moreover, although Bcl-w is not readily detectable in thymic lymphomas elicited by p53 deficiency (Figure 8b) and not essential for T cell development, it is expressed in T lymphoid cells (including progenitors) and hence might contribute to the survival of nascent thymic lymphoma cells.	('thymic lymphoma', 'Disease', 'MESH:D013953', (54, 69))	('p53', 'Gene', (83, 86))	('contribute', 'Reg', (228, 238))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (273, 281))	('lymphomas', 'Disease', (61, 70))	('deficiency', 'Var', (87, 97))	('thymic lymphoma', 'Disease', (54, 69))	('thymic lymphoma', 'Disease', (266, 281))	('lymphomas', 'Disease', 'MESH:D008223', (61, 70))	('elicited by', 'Reg', (71, 82))	('lymphomas', 'Phenotype', 'HP:0002665', (61, 70))	('thymic lymphoma', 'Disease', 'MESH:D013953', (266, 281))
332325	21997189	Consistent with previous studies, the gamma-irradiated p53-/- and p53+/- mice succumbed to tumours, almost exclusively thymic lymphomas, considerably faster than their non-irradiated counterparts.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('lymphomas', 'Disease', 'MESH:D008223', (126, 135))	('p53+/-', 'Var', (66, 72))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('thymic lymphoma', 'Disease', 'MESH:D013953', (119, 134))	('lymphomas', 'Phenotype', 'HP:0002665', (126, 135))	('mice', 'Species', '10090', (73, 77))	('tumours', 'Disease', (91, 98))	('succumbed', 'CPA', (78, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (126, 134))	('p53-/-', 'Var', (55, 61))	('lymphomas', 'Disease', (126, 135))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('thymic lymphoma', 'Disease', (119, 134))
332326	21997189	Interestingly, the gamma-irradiated p53-/- mice prophylactically treated with ABT-737 survived significantly, albeit only marginally, longer (p**=0.0070) than the corresponding control mice injected with vehicle (Figure 4a).	('mice', 'Species', '10090', (43, 47))	('longer', 'PosReg', (134, 140))	('mice', 'Species', '10090', (185, 189))	('ABT-737', 'Chemical', 'MESH:C501332', (78, 85))	('ABT-737', 'Var', (78, 85))
332328	21997189	These observations indicate that Bcl-2, Bcl-xL and Bcl-w may play a minor role, in maintaining the survival of the "cancer initiating cells" that give rise to gamma-radiation induced thymic lymphoma but appear dispensable for the survival of the "cancer initiating cells" giving rise to sarcomas.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('gamma-radiation', 'Var', (159, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (247, 253))	('thymic lymphoma', 'Disease', (183, 198))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rise to sarcomas', 'Disease', (279, 295))	('thymic lymphoma', 'Disease', 'MESH:D013953', (183, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	('rise to sarcomas', 'Disease', 'MESH:D012509', (279, 295))	('sarcomas', 'Phenotype', 'HP:0100242', (287, 295))
332335	21997189	Our observations may indicate that blockade of Mcl-1 and/or A1, rather than inhibition of Bcl-2, Bcl-xL and/or Bcl-w is required to impede tumorigenesis in patients with germline mutations in p53.	('tumorigenesis', 'CPA', (139, 152))	('patients', 'Species', '9606', (156, 164))	('impede', 'NegReg', (132, 138))	('rat', 'Species', '10116', (64, 67))	('p53', 'Gene', (192, 195))	('germline mutations', 'Var', (170, 188))
332338	21997189	Mice (p53+/- and p53-/-) at the age of 4 weeks were either left untreated or exposed to 1.5 Gy of gamma-radiation once a week for four consecutive weeks using a 60Co source to elicit thymic lymphoma development.	('p53+/-', 'Var', (6, 12))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('p53-/-', 'Var', (17, 23))	('thymic lymphoma', 'Disease', 'MESH:D013953', (183, 198))	('thymic lymphoma', 'Disease', (183, 198))	('Mice', 'Species', '10090', (0, 4))	('elicit', 'Reg', (176, 182))
332346	21997189	DNA samples from tail biopsies of mice or thymic lymphoma cells were analysed by PCR using primer sets that can detect wild-type and deleted p53 alleles.	('thymic lymphoma', 'Disease', (42, 57))	('deleted', 'Var', (133, 140))	('p53', 'Gene', (141, 144))	('mice', 'Species', '10090', (34, 38))	('thymic lymphoma', 'Disease', 'MESH:D013953', (42, 57))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))
332399	31750352	EWSR1 gene rearrangement was positively confirmed by fluorescent in situ hybridization (FISH) analysis (Figure 4).	('EWSR1', 'Gene', (0, 5))	('rearrangement', 'Var', (11, 24))	('EWSR1', 'Gene', '2130', (0, 5))
332426	31750352	Both of our cases were CD99-positive, and although Case 1 was negative for vimentin, we did show the translocation of the EWSR1 gene in tumor cells via FISH analysis, confirming the PNET diagnosis.	('CD99', 'Gene', (23, 27))	('PNET', 'Disease', 'MESH:D018242', (182, 186))	('PNET', 'Phenotype', 'HP:0030065', (182, 186))	('EWSR1', 'Gene', '2130', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('translocation', 'Var', (101, 114))	('vimentin', 'Gene', '7431', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('CD99', 'Gene', '4267', (23, 27))	('EWSR1', 'Gene', (122, 127))	('vimentin', 'Gene', (75, 83))	('tumor', 'Disease', (136, 141))	('PNET', 'Disease', (182, 186))
332427	31750352	Because both patients' FISH analyses showed EWSR1 gene rearrangement, there was no need to test them by RT-PCR.	('EWSR1', 'Gene', '2130', (44, 49))	('gene rearrangement', 'Var', (50, 68))	('patients', 'Species', '9606', (13, 21))	('EWSR1', 'Gene', (44, 49))
332431	31750352	A main characteristic of PNET is the detection of t (11; 22) (q24; q12) translocation, wherein an EWS-FLI-1 fusion gene is formed.	('PNET', 'Disease', 'MESH:D018242', (25, 29))	('PNET', 'Phenotype', 'HP:0030065', (25, 29))	('EWS', 'Gene', '2130', (98, 101))	('EWS', 'Gene', (98, 101))	('FLI-1', 'Gene', '2313', (102, 107))	('t (11; 22) (q24; q12', 'Var', (50, 70))	('FLI-1', 'Gene', (102, 107))	('PNET', 'Disease', (25, 29))
332434	31750352	In addition, some researchers discovered that another translocation in chromosome t (4; 22) (q31n; q12) led to EWSR1-SMARCA5 gene fusion in patients with PNET.	('PNET', 'Disease', 'MESH:D018242', (154, 158))	('led to', 'Reg', (104, 110))	('SMARCA5', 'Gene', '8467', (117, 124))	('EWSR1', 'Gene', (111, 116))	('EWSR1', 'Gene', '2130', (111, 116))	('patients', 'Species', '9606', (140, 148))	('PNET', 'Disease', (154, 158))	('SMARCA5', 'Gene', (117, 124))	('q31n; q12', 'Var', (93, 102))	('PNET', 'Phenotype', 'HP:0030065', (154, 158))
332576	29313488	In the original study, mouse mesenchymal cells transformed with the EWS-FLI1 rearrangement and SK-N-MC cells were found to have similar sensitivities to olaparib, whereas mesenchymal cells transformed with the FUS-CHOP rearrangement displayed a reduced sensitivity to olaparib (Figure 4E; Garnett et al., 2012).	('rearrangement', 'Var', (77, 90))	('sensitivities', 'MPA', (136, 149))	('EWS-FLI1', 'Gene', (68, 76))	('olaparib', 'Chemical', 'MESH:C531550', (268, 276))	('mouse', 'Species', '10090', (23, 28))	('FUS-CHOP', 'Chemical', '-', (210, 218))	('olaparib', 'Chemical', 'MESH:C531550', (153, 161))	('SK-N-MC', 'CellLine', 'CVCL:0530', (95, 102))
332581	29313488	In addition to capturing expected gene-drug interactions, several unpredicted associations were identified, including an enhanced sensitivity between the EWS-FLI1 translocation of Ewing's sarcoma family tumors and poly(ADP-ribose) polymerase (PARP) inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('PARP', 'Gene', (243, 247))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	("Ewing's sarcoma family tumors", 'Disease', (180, 209))	('enhanced', 'PosReg', (121, 129))	('translocation', 'Var', (163, 176))	('EWS-FLI1', 'Gene', (154, 162))	('PARP', 'Gene', '142', (243, 247))	("Ewing's sarcoma family tumors", 'Disease', 'MESH:C563168', (180, 209))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (180, 195))	('poly(ADP-ribose) polymerase', 'Gene', '142', (214, 241))	('sensitivity', 'MPA', (130, 141))	('poly(ADP-ribose) polymerase', 'Gene', (214, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))
332583	29313488	Further, the EWS-FLI1 translocation was reported to be sufficient for increased sensitivity of cells to olaparib, while transient depletion of EWS-FLI1 from Ewing's sarcoma cells resulted in partial rescue of olaparib sensitivity, suggesting the sensitivity of Ewing's sarcoma cells to olaparib might be related to EWS-FLI1 transcriptional activity.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (261, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (157, 172))	("Ewing's sarcoma", 'Disease', (157, 172))	('rescue', 'NegReg', (199, 205))	('olaparib sensitivity', 'MPA', (209, 229))	('depletion', 'Var', (130, 139))	("Ewing's sarcoma", 'Disease', (261, 276))	('increased', 'PosReg', (70, 79))	('olaparib', 'Chemical', 'MESH:C531550', (209, 217))	('sensitivity', 'MPA', (80, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (261, 276))	('olaparib', 'Chemical', 'MESH:C531550', (104, 112))	('EWS-FLI1', 'Gene', (143, 151))	('olaparib', 'Chemical', 'MESH:C531550', (286, 294))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (157, 172))
332586	29313488	In agreement with these observations, a new methodology for biomarker discovery, that accounts for variability in general levels of drug sensitivity, failed to find a statistically significant association of PARP inhibitors and the EWS-FLI1 translocation.	('PARP', 'Gene', (208, 212))	('drug sensitivity', 'Phenotype', 'HP:0020174', (132, 148))	('EWS-FLI1', 'Gene', (232, 240))	('PARP', 'Gene', '142', (208, 212))	('inhibitors', 'Var', (213, 223))
332588	29313488	Furthermore, a recent study reported that cells with SLFN11 inactivation are more resistant to PARP inhibitors, as single agents or in combination with temozolomide; however combination with an ATR inhibitor can overcome this resistance.	('ATR', 'Gene', (194, 197))	('PARP', 'Gene', (95, 99))	('SLFN11', 'Gene', (53, 59))	('temozolomide', 'Chemical', 'MESH:D000077204', (152, 164))	('SLFN11', 'Gene', '91607', (53, 59))	('resistant', 'MPA', (82, 91))	('PARP', 'Gene', '142', (95, 99))	('inactivation', 'Var', (60, 72))	('ATR', 'Gene', '545', (194, 197))
332603	29313488	The EWS-FLI1 rearrangement is characteristic of Ewing's sarcoma tumors and in the original study was identified as a statistically significant association with olaparib sensitivity.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('rearrangement', 'Var', (13, 26))	('olaparib', 'Chemical', 'MESH:C531550', (160, 168))	("Ewing's sarcoma tumors", 'Disease', (48, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (48, 63))	('EWS-FLI1', 'Gene', (4, 12))	('association', 'Reg', (143, 154))	("Ewing's sarcoma tumors", 'Disease', 'MESH:C563168', (48, 70))	('olaparib sensitivity', 'MPA', (160, 180))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
332604	29313488	To test whether the sensitivity to olaparib was due to the EWS-FLI1 rearrangement, we independently replicated an experiment comparing olaparib sensitivity in mouse mesenchymal cells transformed with EWS-FLI1, or FUS-CHOP a related liposarcoma-associated translocation.	('liposarcoma', 'Disease', (232, 243))	('liposarcoma', 'Disease', 'MESH:D008080', (232, 243))	('mouse', 'Species', '10090', (159, 164))	('olaparib', 'Chemical', 'MESH:C531550', (35, 43))	('liposarcoma', 'Phenotype', 'HP:0012034', (232, 243))	('olaparib', 'Chemical', 'MESH:C531550', (135, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('FUS-CHOP', 'Chemical', '-', (213, 221))	('EWS-FLI1', 'Var', (200, 208))
332613	29313488	A673 cells transfected with EWS-FLI1 siRNA resulted in an average reduction of 65% in EWS-FLI1 expression relative to control siRNA whether cells were treated with vehicle control or olaparib (Figure 3B).	('EWS-FLI1', 'Var', (28, 36))	('olaparib', 'Chemical', 'MESH:C531550', (183, 191))	('EWS-FLI1', 'Gene', (86, 94))	('expression', 'MPA', (95, 105))	('reduction', 'NegReg', (66, 75))
332638	29313488	The A673 Ewing's sarcoma cell line was seeded at 5,000 cells per well in a 96 well plate (non-edge wells) and immediately reverse transfected with 25 nM AllStars negative control siRNA (Qiagen, cat# 1027281) or an siRNA targeting the EWS-FLI1 translocation (Qiagen, cat# 1027423; custom order: 5'-GGCAGCAGAACCCUUCUUACG-3') with Lipofectamine RNAiMAX with the cells in suspension according to manufacturer's instructions.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('Qiagen', 'Var', (258, 264))	('EWS-FLI1', 'Gene', (234, 242))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (9, 24))	("Ewing's sarcoma", 'Disease', (9, 24))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (9, 24))
332650	29313488	We also included an additional test to confirm the EWS-FLI1 rearrangement in the mouse mesenchymal progenitor cells shared for this replication attempt.	('EWS-FLI1', 'Gene', (51, 59))	('rearrangement', 'Var', (60, 73))	('mouse', 'Species', '10090', (81, 86))
332654	29313488	Another key experiment involving knockdown of EWS-FLI is also inconclusive, due to the relatively poor siRNA knockdown of EWS-FLI relative to the original paper.	('FLI', 'Gene', (50, 53))	('FLI', 'Gene', '2314', (126, 129))	('FLI', 'Gene', (126, 129))	('knockdown', 'Var', (109, 118))	('FLI', 'Gene', '2314', (50, 53))
332656	29313488	Although additional experiments cannot be requested at this point, the revised Discussion should include a statement saying that more cell lines would need to be tested to move beyond the current "inconclusive" nature of the report, as well as a more robust EWS-FLI knockdown.	('FLI', 'Gene', (262, 265))	('knockdown', 'Var', (266, 275))	('FLI', 'Gene', '2314', (262, 265))
332750	26076008	Mice harboring either a homo- or a heterozygous mutation were injected intramuscularly with MCA to induce sarcoma formation.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('MCA', 'Chemical', 'MESH:D008748', (92, 95))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('mutation', 'Var', (48, 56))	('Mice', 'Species', '10090', (0, 4))	('sarcoma', 'Disease', (106, 113))	('induce', 'Reg', (99, 105))
332773	26076008	ROS can drive tumorigenesis though the activation of oncogenes such as c-myc and NF-kB, through up-regulation of pro-EMT proteins such as matrix metalloproteinases, and through direct DNA damage producing somatic mutations that further potentiate tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Disease', (14, 19))	('up-regulation', 'PosReg', (96, 109))	('activation', 'PosReg', (39, 49))	('tumor', 'Disease', (247, 252))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('EMT', 'Gene', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('ROS', 'Gene', (0, 3))	('EMT', 'Gene', '16428', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('NF-kB', 'Gene', (81, 86))	('mutations', 'Var', (213, 222))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('potentiate', 'PosReg', (236, 246))	('c-myc', 'Protein', (71, 76))	('drive', 'PosReg', (8, 13))	('matrix metalloproteinases', 'Protein', (138, 163))
332776	26076008	In addition to their direct effects on the cancer cells' biology, ROS exhibit indirect effects by suppressing intrinsic anti-tumor immune responses.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('ROS', 'Var', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Disease', (43, 49))	('suppressing', 'NegReg', (98, 109))	('ROS', 'Chemical', 'MESH:D017382', (66, 69))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
332779	26076008	Additionally, ROS seem to lend a survival advantage to Tregs, leading to an increased suppressive feedback loop.	('increased', 'PosReg', (76, 85))	('ROS', 'Var', (14, 17))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('suppressive feedback loop', 'MPA', (86, 111))	('Tregs', 'Chemical', '-', (55, 60))
332781	26076008	To this end, we have taken advantage of a mouse model in which NCF1, a gene encoding the subunit p47phox of the NOX2 complex, has a single nucleotide mutation leading to a loss of function.	('p47phox', 'Gene', (97, 104))	('NOX2', 'Gene', (112, 116))	('single nucleotide mutation', 'Var', (132, 158))	('NCF1', 'Gene', (63, 67))	('mouse', 'Species', '10090', (42, 47))	('NOX2', 'Gene', '13058', (112, 116))	('NCF1', 'Gene', '17969', (63, 67))	('p47phox', 'Gene', '17969', (97, 104))	('loss of function', 'NegReg', (172, 188))
332782	26076008	We report that MCA-induced tumors developed at a similar rate in litter-paired homozygous and heterozygous NCF1 mutant mice.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mice', 'Species', '10090', (119, 123))	('MCA', 'Chemical', 'MESH:D008748', (15, 18))	('NCF1', 'Gene', '17969', (107, 111))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('NCF1', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mutant', 'Var', (112, 118))
332783	26076008	Furthermore, we observed a sarcoma-induced accumulation of MDSC and Tregs irrespective of the NCF1 mutational status.	('sarcoma', 'Disease', (27, 34))	('accumulation', 'PosReg', (43, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('Tregs', 'CPA', (68, 73))	('MDSC', 'CPA', (59, 63))	('NCF1', 'Gene', '17969', (94, 98))	('Tregs', 'Chemical', '-', (68, 73))	('NCF1', 'Gene', (94, 98))	('mutational', 'Var', (99, 109))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))
332786	26076008	NCF1m1J mutant mice (NCF1*) NCF1* mice were previously backcrossed into C57Bl/10.Q/rhd mice.	('NCF1', 'Gene', '17969', (0, 4))	('NCF1', 'Gene', (21, 25))	('mice', 'Species', '10090', (34, 38))	('NCF1', 'Gene', (28, 32))	('NCF1', 'Gene', '17969', (28, 32))	('mice', 'Species', '10090', (87, 91))	('mutant', 'Var', (8, 14))	('NCF1*', 'Gene', '17969', (28, 33))	('NCF1*', 'Gene', (21, 26))	('NCF1*', 'Gene', '17969', (21, 26))	('NCF1*', 'Gene', (28, 33))	('mice', 'Species', '10090', (15, 19))	('NCF1', 'Gene', '17969', (21, 25))	('NCF1', 'Gene', (0, 4))
332787	26076008	They were genotyped as previously described and crossed to generate heterozygous NCF1*/+ and homozygous NCF1*/* mutant mice.	('NCF1*', 'Gene', '17969', (104, 109))	('mice', 'Species', '10090', (119, 123))	('NCF1*', 'Gene', (81, 86))	('NCF1*', 'Gene', '17969', (81, 86))	('mutant', 'Var', (112, 118))	('NCF1*', 'Gene', (104, 109))
332817	26076008	Mice with a single point mutation in the NCF1 gene, which encodes for the protein p47phox, were backcrossed onto C57Bl/10.Q background.	('single point mutation', 'Var', (12, 33))	('NCF1', 'Gene', (41, 45))	('p47phox', 'Gene', (82, 89))	('p47phox', 'Gene', '17969', (82, 89))	('Mice', 'Species', '10090', (0, 4))	('NCF1', 'Gene', '17969', (41, 45))
332819	26076008	To confirm this functional deficit, splenocytes from homozygous NCF1*/* and heterozygous (NCF1*/+) mutant mice were labeled with DHR-123 and treated with NOX2 stimulating PMA.	('NCF1*', 'Gene', '17969', (90, 95))	('mice', 'Species', '10090', (106, 110))	('NOX2', 'Gene', (154, 158))	('NOX2', 'Gene', '13058', (154, 158))	('PMA', 'Chemical', '-', (171, 174))	('DHR-123', 'Chemical', '-', (129, 136))	('NCF1*', 'Gene', (64, 69))	('NCF1*', 'Gene', '17969', (64, 69))	('mutant', 'Var', (99, 105))	('NCF1*', 'Gene', (90, 95))
332846	26076008	Only a small fraction of CD4 T cells secreted IL-17 with NCF1*/* mutant mice trending towards more IL-17 positive CD4 cells (Fig 4E).	('NCF1*', 'Gene', '17969', (57, 62))	('IL-17', 'Gene', (46, 51))	('IL-17', 'Gene', '16171', (46, 51))	('CD4', 'Gene', '12504', (25, 28))	('mutant', 'Var', (65, 71))	('CD4', 'Gene', (114, 117))	('NCF1*', 'Gene', (57, 62))	('IL-17', 'Gene', '16171', (99, 104))	('CD4', 'Gene', '12504', (114, 117))	('mice', 'Species', '10090', (72, 76))	('IL-17', 'Gene', (99, 104))	('more', 'PosReg', (94, 98))	('CD4', 'Gene', (25, 28))
332856	26076008	While many cancers display oxidative stress as a result of mitochondrial dysfunctions some types of prostate carcinomas and melanoma have been found to over-express NOX2, leading us to evaluate whether the tumor cell lines produced amounts of oxidative stress related to their NCF1 mutation status.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mitochondrial dysfunction', 'Disease', (59, 84))	('NOX2', 'Gene', (165, 169))	('mutation', 'Var', (282, 290))	('NCF1', 'Gene', (277, 281))	('prostate carcinomas', 'Disease', 'MESH:D011472', (100, 119))	('oxidative stress', 'MPA', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (100, 118))	('NOX2', 'Gene', '13058', (165, 169))	('mitochondrial dysfunctions', 'Phenotype', 'HP:0003287', (59, 85))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('oxidative stress', 'Phenotype', 'HP:0025464', (243, 259))	('oxidative stress', 'Phenotype', 'HP:0025464', (27, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('prostate carcinomas', 'Disease', (100, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (59, 84))	('tumor', 'Disease', (206, 211))	('over-express', 'PosReg', (152, 164))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('NCF1', 'Gene', '17969', (277, 281))	('cancers', 'Disease', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (59, 84))
332864	26076008	Next, we applied a single 2 Gy dose, and followed the metabolic activity up to nine days in both homozygous and heterozygous mutant tumor cell lines.	('mutant', 'Var', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))
332871	26076008	To study the role of NOX2-derived ROS we used a mouse strain in which a mutation in the NCF1 gene causes a loss of functional p46phox, a key organizational protein for the NOX2 complex.	('NOX2', 'Gene', (21, 25))	('NOX2', 'Gene', '13058', (21, 25))	('mouse', 'Species', '10090', (48, 53))	('ROS', 'Chemical', 'MESH:D017382', (34, 37))	('NOX2', 'Gene', (172, 176))	('NOX2', 'Gene', '13058', (172, 176))	('loss of functional', 'NegReg', (107, 125))	('NCF1', 'Gene', (88, 92))	('mutation', 'Var', (72, 80))	('NCF1', 'Gene', '17969', (88, 92))	('p46phox', 'MPA', (126, 133))
332879	26076008	In addition N-acetyl-cysteine was able to reduce tumor volume after one week of daily treatment.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('N-acetyl-cysteine', 'Chemical', 'MESH:D000111', (12, 29))	('tumor', 'Disease', (49, 54))	('N-acetyl-cysteine', 'Var', (12, 29))	('reduce', 'NegReg', (42, 48))
332888	26076008	In contrast to the findings presented here, the growth of the transplantable mouse B16 melanoma and the Lewis lung carcinoma was, when tested in the same NCF1 mutant model, found to be significantly enhanced by NOX2 complex derived ROS.	('NCF1', 'Gene', (154, 158))	('growth', 'CPA', (48, 54))	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('enhanced', 'PosReg', (199, 207))	('mutant', 'Var', (159, 165))	('Lewis lung carcinoma', 'Disease', (104, 124))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (104, 124))	('mouse', 'Species', '10090', (77, 82))	('ROS', 'Chemical', 'MESH:D017382', (232, 235))	('NOX2', 'Gene', (211, 215))	('NOX2', 'Gene', '13058', (211, 215))	('NCF1', 'Gene', '17969', (154, 158))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
332900	26076008	Additionally, the tumors contained an even higher number of MDSCs than did the spleens, but with no significant differences between the NCF1 mutant homozygous and heterozygous mice.	('mutant', 'Var', (141, 147))	('higher', 'PosReg', (43, 49))	('mice', 'Species', '10090', (176, 180))	('tumors', 'Disease', (18, 24))	('MDSCs', 'MPA', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('NCF1', 'Gene', '17969', (136, 140))	('NCF1', 'Gene', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
332909	26076008	While the MCA did elicit increased Tregs populations in the blood, spleen and tumor no difference was found in tumorigenesis due to non-functional NOX2 despite the large increase in this suppressive cell population; indicating that the key suppressive mechanism utilized by Tregs in this model is not ROS production.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('increased', 'PosReg', (25, 34))	('NOX2', 'Gene', (147, 151))	('NOX2', 'Gene', '13058', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Tregs', 'Chemical', '-', (274, 279))	('Tregs populations', 'CPA', (35, 52))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (111, 116))	('non-functional', 'Var', (132, 146))	('ROS', 'Chemical', 'MESH:D017382', (301, 304))	('tumor', 'Disease', (78, 83))	('MCA', 'Chemical', 'MESH:D008748', (10, 13))	('Tregs', 'Chemical', '-', (35, 40))
332911	26076008	ROS, as a mechanism of suppression, can inhibit T cell function.	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('ROS', 'Var', (0, 3))	('T cell function', 'CPA', (48, 63))	('inhibit', 'NegReg', (40, 47))
332918	26076008	Previously it has been demonstrated that MCA generated sarcomas undergo immune editing when developing in WT mice, but not when developing in RAG-/- mice, leading to rejection of RAG-/- initiated tumors but not WT initiated ones.	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('RAG-/- initiated', 'Var', (179, 195))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcomas', 'Disease', (55, 63))	('rejection', 'MPA', (166, 175))	('mice', 'Species', '10090', (149, 153))	('MCA', 'Chemical', 'MESH:D008748', (41, 44))	('mice', 'Species', '10090', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))
332920	26076008	Although a slight trend towards increased tumor take of sarcomas transplanted from NCF1*/* mutant mice was observed, this difference was not significant and did not support a role for NOX2 produced ROS in immune editing of MCA induced sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcomas', 'Disease', (56, 64))	('tumor', 'Disease', (42, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcomas', 'Disease', 'MESH:D012509', (235, 243))	('sarcomas', 'Phenotype', 'HP:0100242', (235, 243))	('NCF1*', 'Gene', '17969', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('ROS', 'Chemical', 'MESH:D017382', (198, 201))	('mice', 'Species', '10090', (98, 102))	('sarcomas', 'Disease', (235, 243))	('NOX2', 'Gene', (184, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('MCA', 'Chemical', 'MESH:D008748', (223, 226))	('NCF1*', 'Gene', (83, 88))	('NOX2', 'Gene', '13058', (184, 188))	('increased', 'PosReg', (32, 41))	('mutant', 'Var', (91, 97))
332924	26076008	Their growth and invasive phenotypes were uniformly found to be independent of NCF1 mutation status.	('NCF1', 'Gene', (79, 83))	('NCF1', 'Gene', '17969', (79, 83))	('mutation', 'Var', (84, 92))
332987	21630428	In neuroblastoma, primary neuroblastoma tumor specimens express IGF-2 and IGF1R mRNA, and inhibition of IGF1R blocks the mitogenic effects of IGF-1 and IGF-2 on cultured neuroblastoma cell lines providing further evidence for the role of IGF1R in pediatric solid tumors.	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('neuroblastoma', 'Disease', 'MESH:D009447', (3, 16))	('neuroblastoma', 'Disease', (26, 39))	('solid tumor', 'Disease', 'MESH:D009369', (257, 268))	('inhibition', 'Var', (90, 100))	('neuroblastoma', 'Phenotype', 'HP:0003006', (26, 39))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('neuroblastoma tumor', 'Disease', (26, 45))	('IGF-2', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('IGF-2', 'Gene', '16002', (64, 69))	('mitogenic effects', 'CPA', (121, 138))	('neuroblastoma tumor', 'Disease', 'MESH:D009447', (26, 45))	('neuroblastoma', 'Disease', 'MESH:D009447', (26, 39))	('IGF1R', 'Gene', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('neuroblastoma', 'Disease', (170, 183))	('IGF-2', 'Gene', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('neuroblastoma', 'Phenotype', 'HP:0003006', (170, 183))	('solid tumor', 'Disease', (257, 268))	('blocks', 'NegReg', (110, 116))	('IGF-2', 'Gene', '16002', (152, 157))	('neuroblastoma', 'Disease', (3, 16))	('tumors', 'Disease', (263, 269))	('neuroblastoma', 'Disease', 'MESH:D009447', (170, 183))	('IGF1R', 'Gene', (74, 79))
332990	21630428	It has been previously reported for Ewing sarcoma, rhabdomyosarcoma and osteosarcoma that inhibition of mTOR may increase the dependency of tumors on IGF signaling.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('dependency of tumors', 'Disease', 'MESH:D019966', (126, 146))	('inhibition', 'Var', (90, 100))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (51, 67))	('Ewing sarcoma', 'Disease', (36, 49))	('mTOR', 'Gene', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (51, 67))	('osteosarcoma', 'Phenotype', 'HP:0002669', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('dependency of tumors', 'Disease', (126, 146))	('increase', 'PosReg', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('mTOR', 'Gene', '56717', (104, 108))	('osteosarcoma', 'Disease', (72, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (36, 49))	('rhabdomyosarcoma', 'Disease', (51, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (72, 84))
332991	21630428	Inhibitors of IGF1R act synergistically with rapamycin in sarcoma xenografts by inhibiting hyperphosphorylation of Akt in response to mTOR inhibition.	('Akt', 'Gene', '11651', (115, 118))	('Akt', 'Gene', (115, 118))	('Inhibitors', 'Var', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('rapamycin', 'Chemical', 'MESH:D020123', (45, 54))	('hyperphosphorylation', 'MPA', (91, 111))	('inhibiting', 'NegReg', (80, 90))	('IGF1R', 'Gene', (14, 19))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('mTOR', 'Gene', (134, 138))	('sarcoma', 'Disease', (58, 65))	('mTOR', 'Gene', '56717', (134, 138))
332994	21630428	CB17SC scid-/- female mice (Taconic Farms, Germantown, NY) were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('osteosarcoma', 'Disease', (148, 160))	('glioma', 'Phenotype', 'HP:0009733', (269, 275))	('brain tumors', 'Phenotype', 'HP:0030692', (217, 229))	('osteosarcoma', 'Disease', 'MESH:D012516', (148, 160))	('mice', 'Species', '10090', (22, 26))	('non-glioblastoma brain tumors', 'Disease', 'MESH:D005909', (200, 229))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (162, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (162, 178))	('neuroblastoma', 'Disease', (181, 194))	('mice', 'Species', '10090', (250, 254))	('rhabdoid tumors', 'Disease', (114, 129))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (114, 129))	('neuroblastoma', 'Phenotype', 'HP:0003006', (181, 194))	('non-glioblastoma brain tumors', 'Disease', (200, 229))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('neuroblastoma', 'Disease', 'MESH:D009447', (181, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (148, 160))	('sarcomas', 'Disease', (131, 139))	('CB17SC', 'Var', (0, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('glioma', 'Disease', (269, 275))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('glioma', 'Disease', 'MESH:D005910', (269, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('rhabdomyosarcoma', 'Disease', (162, 178))
333029	21630428	The effect of releasing the negative feedback inhibition of Akt by inhibition mTOR is to increase cellular dependence on IGF1R-AKT mediated signaling.	('inhibition', 'Var', (67, 77))	('increase', 'PosReg', (89, 97))	('releasing', 'PosReg', (14, 23))	('Akt', 'Gene', '11651', (60, 63))	('cellular dependence', 'MPA', (98, 117))	('mTOR', 'Gene', (78, 82))	('Akt', 'Gene', (60, 63))	('increase cellular dependence on IGF1R', 'Phenotype', 'HP:0030269', (89, 126))	('AKT', 'Gene', '11651', (127, 130))	('mTOR', 'Gene', '56717', (78, 82))	('negative feedback inhibition', 'MPA', (28, 56))	('AKT', 'Gene', (127, 130))
333039	32299819	Common uterine LMS (uLMS) alterations were loss-of-function mutations in TP53 (56%), RB1 (51%), and ATRX (31%).	('loss-of-function', 'NegReg', (43, 59))	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('ATRX', 'Gene', (100, 104))	('ATRX', 'Gene', '546', (100, 104))	('uterine LMS', 'Disease', (7, 18))	('RB1', 'Gene', (85, 88))	('mutations', 'Var', (60, 69))	('RB1', 'Gene', '5925', (85, 88))
333042	32299819	Genomes of low-grade tumors were largely silent, while 50.5% of high-grade tumors had whole genome duplication.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('whole genome duplication', 'Var', (86, 110))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
333043	32299819	Potentially actionable mutations were identified in 48 patients (45%), eight (17%) of whom received matched therapy with two achieving clinical responses.	('patients', 'Species', '9606', (55, 63))	('mutations', 'Var', (23, 32))	('actionable', 'Reg', (12, 22))
333044	32299819	Among uLMS patients with somatic BRCA2 alterations, sustained partial responses were observed with PARP inhibitor-containing therapy.	('PARP', 'Gene', (99, 103))	('BRCA2', 'Gene', (33, 38))	('BRCA2', 'Gene', '675', (33, 38))	('alterations', 'Var', (39, 50))	('PARP', 'Gene', '142', (99, 103))	('patients', 'Species', '9606', (11, 19))
333046	32299819	There was evidence of clinical benefit in uLMS patients with somatic BRCA2 alterations treated with PARP inhibitors.	('uLMS', 'Disease', (42, 46))	('BRCA2', 'Gene', '675', (69, 74))	('benefit', 'PosReg', (31, 38))	('patients', 'Species', '9606', (47, 55))	('PARP', 'Gene', (100, 104))	('alterations', 'Var', (75, 86))	('BRCA2', 'Gene', (69, 74))	('PARP', 'Gene', '142', (100, 104))
333052	32299819	By comparison, a subset of HG-ESS harbor t(10;17)(q22;p13) translocations that result in expression of a YWHAE-NUTM2A/B fusion and have an aggressive disease course while others have BCOR alterations that are of unknown prognostic significance.	('BCOR', 'Gene', (183, 187))	('expression', 'MPA', (89, 99))	('aggressive disease', 'Disease', (139, 157))	('t(10;17)(', 'Var', (41, 50))	('NUTM2A', 'Gene', '728118', (111, 117))	('BCOR', 'Gene', '54880', (183, 187))	('NUTM2A', 'Gene', (111, 117))	('YWHAE', 'Gene', '7531', (105, 110))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (41, 58))	('result in', 'Reg', (79, 88))	('YWHAE', 'Gene', (105, 110))	('aggressive disease', 'Disease', 'MESH:D001523', (139, 157))	('translocations', 'Var', (59, 73))
333055	32299819	Instead, these tumors often have multiple chromosomal abnormalities associated with chromothripsis, TP53 and RB1 inactivation, and whole genome duplication (WGD).	('TP53', 'Gene', '7157', (100, 104))	('RB1', 'Gene', '5925', (109, 112))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('multiple chromosomal abnormalities', 'Phenotype', 'HP:0040012', (33, 67))	('TP53', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (42, 67))	('chromothripsis', 'Disease', (84, 98))	('chromosomal abnormalities', 'Disease', (42, 67))	('chromothripsis', 'Disease', 'MESH:D000072837', (84, 98))	('RB1', 'Gene', (109, 112))	('whole genome duplication', 'Var', (131, 155))	('tumors', 'Disease', (15, 21))
333071	32299819	Based on the prior clinical validation of MSIsensor using MSK-IMPACT data, MSI status was defined as follows: <3: microsatellite stable (MSS); >=3 and <10: MSI-indeterminate (MSI-I); and >=10: MSI-high (MSI-H).	('MSI-high', 'Var', (193, 201))	('MSK', 'Gene', (58, 61))	('MSK', 'Gene', '150094', (58, 61))	('MSI-indeterminate', 'Var', (156, 173))
333073	32299819	To better characterize the mutational processes driving acquisition of somatic alterations, mutational signature decomposition analysis was performed for tumor samples with ten or more single nucleotide variant (SNV) somatic mutations, as previously described.	('single nucleotide variant', 'Var', (185, 210))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
333079	32299819	Germline annotation for pathogenic or likely pathogenic variants was performed by MSK-IMPACT for 76 genes previously associated with cancer predisposition syndromes using a clinically validated platform.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('variants', 'Var', (56, 64))	('MSK', 'Gene', '150094', (82, 85))	('MSK', 'Gene', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
333081	32299819	To confirm that deletions of PDCD1 (the gene that encodes PD-1) were associated with loss of protein expression in tumor samples with homozygous deletion of PDCD1, IHC with an anti-PD-1 monoclonal antibody (clone NAT105; Abcam, Cambridge, MA) using a Leica Bond-3 automated platform (Leica, Buffalo Grove, IL) was performed.	('PDCD1', 'Gene', (157, 162))	('deletions', 'Var', (16, 25))	('PDCD1', 'Gene', '5133', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('PD-1', 'Gene', (181, 185))	('PD-1', 'Gene', '5133', (181, 185))	('tumor', 'Disease', (115, 120))	('PD-1', 'Gene', (58, 62))	('protein expression', 'MPA', (93, 111))	('PD-1', 'Gene', '5133', (58, 62))	('loss', 'NegReg', (85, 89))	('PDCD1', 'Gene', '5133', (29, 34))	('PDCD1', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('deletion', 'Var', (145, 153))
333082	32299819	A level 1 alteration is an FDA-recognized biomarker in the patient's tumor type; a level 2 alteration is a biomarker routinely used to guide prescribing of an FDA-approved drug in the patient's tumor type (2A) or another indication (2B); and a level 3 alteration has compelling clinical evidence to support its use as a biomarker predictive of treatment response.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (69, 74))	('patient', 'Species', '9606', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('alteration', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('patient', 'Species', '9606', (184, 191))
333093	32299819	The most common alterations in uLMS were loss-of-function mutations or homozygous deletions in TP53 (56%), RB1 (51%), and ATRX (31%), Figure 2A.	('mutations', 'Var', (58, 67))	('uLMS', 'Disease', (31, 35))	('ATRX', 'Gene', (122, 126))	('RB1', 'Gene', (107, 110))	('loss-of-function', 'NegReg', (41, 57))	('ATRX', 'Gene', '546', (122, 126))	('RB1', 'Gene', '5925', (107, 110))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
333096	32299819	uLMS was also characterized by recurrent homozygous deletions of PDCD1, which encodes PD-1.	('PDCD1', 'Gene', (65, 70))	('PDCD1', 'Gene', '5133', (65, 70))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))	('deletions', 'Var', (52, 61))	('uLMS', 'Disease', (0, 4))
333097	32299819	Indeed, uLMS had the highest rate of PDCD1 homozygous deletions among all cancer types with at least 25 cases in the contemporary MSK-IMPACT clinical series cohort of prospective sequenced cancers (n=15816), Figure 2B.	('homozygous deletions', 'Var', (43, 63))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('uLMS', 'Disease', (8, 12))	('cancer', 'Disease', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('cancers', 'Disease', (189, 196))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('MSK', 'Gene', '150094', (130, 133))	('PDCD1', 'Gene', '5133', (37, 42))	('MSK', 'Gene', (130, 133))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('PDCD1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (189, 195))
333098	32299819	To determine whether PDCD1 homozygous deletion was associated with loss of PDCD1 expression, we performed IHC in affected cases with sufficient archival material (n=2 of 7), which confirmed PDCD1 was negative in both cases (Figure S1).	('PDCD1', 'Gene', (21, 26))	('PDCD1', 'Gene', '5133', (21, 26))	('homozygous deletion', 'Var', (27, 46))	('loss', 'NegReg', (67, 71))	('PDCD1', 'Gene', (190, 195))	('PDCD1', 'Gene', '5133', (190, 195))	('PDCD1', 'Gene', '5133', (75, 80))	('expression', 'MPA', (81, 91))	('PDCD1', 'Gene', (75, 80))
333099	32299819	Similarly, amplifications of MAP2K4 and RIT1 were most common in uterine sarcomas compared to the same contemporary MSK-IMPACT clinical cohort, Figures 2C and 2D.	('MAP2K4', 'Gene', '6416', (29, 35))	('common', 'Reg', (55, 61))	('RIT1', 'Gene', '6016', (40, 44))	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('RIT1', 'Gene', (40, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('MAP2K4', 'Gene', (29, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('amplifications', 'Var', (11, 25))	('sarcomas', 'Disease', (73, 81))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (65, 80))	('MSK', 'Gene', '150094', (116, 119))	('MSK', 'Gene', (116, 119))
333100	32299819	Furthermore, RIT1 was amplified at a significantly higher frequency in high-grade non-LMSs at 24% (5/21), compared to only 2.5% (2/80) of uLMSs (p=0.004).	('RIT1', 'Gene', (13, 17))	('high-grade non-LMSs', 'Disease', (71, 90))	('amplified', 'Var', (22, 31))	('RIT1', 'Gene', '6016', (13, 17))
333101	32299819	There were no significant differences in mutation patterns between primary and metastatic samples except for PTEN alterations which were more frequent in the metastasis samples (p=0.046).	('PTEN', 'Gene', '5728', (109, 113))	('PTEN', 'Gene', (109, 113))	('alterations', 'Var', (114, 125))
333102	32299819	Only 11% of uLMS patients harbored MED12 mutations, an alteration present in an estimated 70% of benign uterine leiomyomas.	('mutations', 'Var', (41, 50))	('MED12', 'Gene', '9968', (35, 40))	('leiomyomas', 'Disease', 'MESH:D007889', (112, 122))	('uLMS', 'Disease', (12, 16))	('patients', 'Species', '9606', (17, 25))	('MED12', 'Gene', (35, 40))	('benign uterine leiomyomas', 'Phenotype', 'HP:0000131', (97, 122))	('leiomyomas', 'Disease', (112, 122))
333110	32299819	Following permanent anonymization (excluding the two MSI phenotype patients), two patients were found to be carriers of pathogenic germline TP53 mutations, one of which was accompanied by somatic biallelic inactivation of TP53.	('patients', 'Species', '9606', (67, 75))	('TP53', 'Gene', (140, 144))	('mutations', 'Var', (145, 154))	('patients', 'Species', '9606', (82, 90))	('pathogenic', 'Reg', (120, 130))	('TP53', 'Gene', '7157', (222, 226))	('TP53', 'Gene', (222, 226))	('TP53', 'Gene', '7157', (140, 144))
333113	32299819	Alterations in TP53 were significantly more common in non-uterine LMS, 71% (52/68) compared to uLMS 56% (45/80), p=0.01.	('non-uterine LMS', 'Disease', (54, 69))	('Alterations', 'Var', (0, 11))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('common', 'Reg', (44, 50))
333115	32299819	uLMSs had a significantly higher frequency of MED12 mutations, 11% (9/80) compared to non-uterine LMSs where MED12 alterations are absent, p=0.01.	('mutations', 'Var', (52, 61))	('MED12', 'Gene', '9968', (46, 51))	('MED12', 'Gene', (109, 114))	('MED12', 'Gene', '9968', (109, 114))	('uLMSs', 'Disease', (0, 5))	('MED12', 'Gene', (46, 51))
333116	32299819	Furthermore, in a comparison of uLMSs from this study to those of a small cohort (n=27) from TCGA, RB1 alterations were significantly more frequent in the MSK cohort, 51% (41/80) vs. 22% (6/27), p=0.02.	('MSK', 'Gene', '150094', (155, 158))	('MSK', 'Gene', (155, 158))	('alterations', 'Var', (103, 114))	('frequent', 'Reg', (139, 147))	('RB1', 'Gene', (99, 102))	('RB1', 'Gene', '5925', (99, 102))
333117	32299819	In order to determine whether any of the alterations detected were prognostic for OS, we performed univariate Cox regression analysis on all USARC-relevant genes with oncogenic (or likely oncogenic) alterations in at least five of the LMS and high-grade non-LMS cases (LG-ESS and STUMP tumors were excluded from the survival analysis due to small sample size (n=6) and their known long-survival prognoses).	('alterations', 'Var', (199, 210))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('tumors', 'Disease', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('LMS', 'Disease', (235, 238))
333120	32299819	Among these was a tumor with an LBH-ALK fusion, which was initially missed by IMPACT DNA-based sequencing as the breakpoint was located in an intron not commonly targeted by ALK fusions found in lung cancers.	('fusion', 'Var', (40, 46))	('lung cancers', 'Disease', (195, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('tumor', 'Disease', (18, 23))	('ALK', 'Gene', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('ALK', 'Gene', '238', (36, 39))	('LBH', 'Gene', (32, 35))	('lung cancers', 'Disease', 'MESH:D008175', (195, 207))	('lung cancers', 'Phenotype', 'HP:0100526', (195, 207))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('ALK', 'Gene', '238', (174, 177))	('ALK', 'Gene', (36, 39))	('LBH', 'Gene', '81606', (32, 35))
333129	32299819	BCOR mutations have been described as diagnostic markers of a specific subset of high-grade endometrial stromal sarcomas, and as histologic mimickers of myxoid LMS.	('BCOR', 'Gene', '54880', (0, 4))	('mutations', 'Var', (5, 14))	('endometrial stromal sarcomas', 'Disease', (92, 120))	('myxoid LMS', 'Disease', (153, 163))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (92, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('BCOR', 'Gene', (0, 4))
333131	32299819	Additional diagnostically relevant fusions were identified in three more patients by MSK-Fusion - YWHAE/NUTM2 rearrangements in two high-grade, non-pleomorphic stromal sarcomas and one JAZF1-SUZ12 in a LG-ESS.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('MSK', 'Gene', '150094', (85, 88))	('JAZF1', 'Gene', '221895', (185, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('YWHAE', 'Gene', '7531', (98, 103))	('rearrangements', 'Var', (110, 124))	('JAZF1', 'Gene', (185, 190))	('SUZ12', 'Gene', '23512', (191, 196))	('stromal sarcomas', 'Disease', (160, 176))	('MSK', 'Gene', (85, 88))	('stromal sarcomas', 'Disease', 'MESH:D046152', (160, 176))	('patients', 'Species', '9606', (73, 81))	('SUZ12', 'Gene', (191, 196))	('YWHAE', 'Gene', (98, 103))
333132	32299819	Additional potentially actionable alterations included seven BRCA2 alterations (four homozygous deletions (all high-grade uLMS) three somatic BRCA2 mutations (two high-grade uLMS, one high-grade non-LMS), two BRAF activating mutations (V600E and K601E; both uLMS), two MSI tumors, and one ESR1 Y537S ligand-binding domain mutation.	('V600E', 'Mutation', 'rs113488022', (236, 241))	('alterations', 'Var', (67, 78))	('K601E', 'Var', (246, 251))	('ESR1', 'Gene', '2099', (289, 293))	('activating', 'PosReg', (214, 224))	('BRCA2', 'Gene', (142, 147))	('ESR1', 'Gene', (289, 293))	('V600E', 'Var', (236, 241))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('BRCA2', 'Gene', '675', (142, 147))	('BRCA2', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumors', 'Disease', (273, 279))	('Y537S', 'Mutation', 'p.Y537S', (294, 299))	('K601E', 'Mutation', 'rs121913364', (246, 251))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('BRCA2', 'Gene', '675', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (273, 279))
333136	32299819	Biopsy at progression confirmed JAZF1 fusion-positive LG-ESS, and IMPACT detected an ESR1 ligand-binding domain mutation (Y537S).	('ESR1', 'Gene', (85, 89))	('JAZF1', 'Gene', (32, 37))	('Y537S', 'Mutation', 'p.Y537S', (122, 127))	('fusion-positive', 'Reg', (38, 53))	('ESR1', 'Gene', '2099', (85, 89))	('JAZF1', 'Gene', '221895', (32, 37))	('Y537S', 'Var', (122, 127))
333137	32299819	Since ESR1 mutations have been described in the context of estrogen receptor-positive breast cancer to confer ligand-independent signaling and thus resistance to aromatase inhibitors, her hormonal therapy was changed to the selective estrogen modulator fulvestrant, resulting in tumor regression.	('mutations', 'Var', (11, 20))	('cancer', 'Disease', (93, 99))	('ESR1', 'Gene', (6, 10))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('estrogen receptor', 'Gene', (59, 76))	('resistance', 'MPA', (148, 158))	('tumor', 'Disease', (279, 284))	('estrogen receptor', 'Gene', '2099', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('ligand-independent signaling', 'MPA', (110, 138))	('ESR1', 'Gene', '2099', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
333138	32299819	The second patient to achieve radiographic response had high-grade uLMS with somatic BRCA2 deletion.	('patient', 'Species', '9606', (11, 18))	('BRCA2', 'Gene', (85, 90))	('deletion', 'Var', (91, 99))	('BRCA2', 'Gene', '675', (85, 90))
333141	32299819	The BRAF V600-mutant patient was treated with an oral BRAF inhibitor on a basket trial, experiencing progression within 4 weeks.	('BRAF', 'Gene', '673', (54, 58))	('patient', 'Species', '9606', (21, 28))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('V600-mutant', 'Var', (9, 20))
333142	32299819	The patient with the BRAF K601E mutation, a class two dimer-dependent BRAF mutant which has been previously biologically characterized and is resistant to first-generation BRAF inhibitors, was enrolled on a clinical trial of a pan-RAF inhibitor.	('RAF', 'Gene', (173, 176))	('RAF', 'Gene', '22882', (22, 25))	('patient', 'Species', '9606', (4, 11))	('RAF', 'Gene', '22882', (173, 176))	('BRAF', 'Gene', '673', (21, 25))	('RAF', 'Gene', (22, 25))	('RAF', 'Gene', (231, 234))	('K601E', 'Mutation', 'rs121913364', (26, 31))	('RAF', 'Gene', '22882', (71, 74))	('BRAF', 'Gene', (21, 25))	('RAF', 'Gene', (71, 74))	('BRAF', 'Gene', '673', (172, 176))	('BRAF', 'Gene', '673', (70, 74))	('RAF', 'Gene', '22882', (231, 234))	('K601E', 'Var', (26, 31))	('BRAF', 'Gene', (172, 176))	('BRAF', 'Gene', (70, 74))
333144	32299819	Given the activity of PARP inhibitors in BRCA-mutated advanced breast and ovarian cancers, we sought to validate the actionability of BRCA2 alterations that our analysis identified as common in uLMS patients.	('PARP', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('activity', 'MPA', (10, 18))	('BRCA', 'Gene', (41, 45))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (63, 89))	('ovarian cancers', 'Phenotype', 'HP:0100615', (74, 89))	('BRCA', 'Gene', (134, 138))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('uLMS', 'Disease', (194, 198))	('BRCA2', 'Gene', (134, 139))	('BRCA', 'Gene', '672;675', (134, 138))	('BRCA', 'Gene', '672;675', (41, 45))	('alterations', 'Var', (140, 151))	('PARP', 'Gene', '142', (22, 26))	('patients', 'Species', '9606', (199, 207))	('BRCA2', 'Gene', '675', (134, 139))
333145	32299819	Post data freeze, five subsequent high-grade uLMS patients with BRCA2 alterations were identified by routine clinical MSK-IMPACT testing (three with somatic biallelic inactivation and one each with a somatic and germline truncating mutations accompanied by LOH).	('BRCA2', 'Gene', '675', (64, 69))	('alterations', 'Var', (70, 81))	('patients', 'Species', '9606', (50, 58))	('MSK', 'Gene', '150094', (118, 121))	('MSK', 'Gene', (118, 121))	('BRCA2', 'Gene', (64, 69))
333146	32299819	Four received PARP inhibitor-containing therapy as part of various clinical trials, and the remaining patient harboring a germline BRCA2 mutation received PARP inhibitor off-label.	('BRCA2', 'Gene', (131, 136))	('mutation', 'Var', (137, 145))	('PARP', 'Gene', '142', (155, 159))	('patient', 'Species', '9606', (102, 109))	('BRCA2', 'Gene', '675', (131, 136))	('PARP', 'Gene', (14, 18))	('PARP', 'Gene', (155, 159))	('PARP', 'Gene', '142', (14, 18))
333148	32299819	These results demonstrate the potential actionability of BRCA2 alterations in uLMS and the potential durability of responses.	('uLMS', 'Disease', (78, 82))	('BRCA2', 'Gene', (57, 62))	('alterations', 'Var', (63, 74))	('BRCA2', 'Gene', '675', (57, 62))
333150	32299819	A subset of uterine sarcomas have distinct molecular diagnostic characteristics (e.g., fusion rearrangements involving JAZF1 in LG-ESS and YWHAE/NUTM2 rearrangements in high-grade, non-pleomorphic stromal sarcomas).	('stromal sarcomas', 'Disease', 'MESH:D046152', (197, 213))	('high-grade', 'Disease', (169, 179))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (12, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('YWHAE', 'Gene', '7531', (139, 144))	('sarcomas', 'Disease', (20, 28))	('JAZF1', 'Gene', (119, 124))	('sarcomas', 'Disease', 'MESH:D012509', (205, 213))	('sarcomas', 'Phenotype', 'HP:0100242', (205, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('fusion rearrangements', 'Var', (87, 108))	('YWHAE', 'Gene', (139, 144))	('stromal sarcomas', 'Disease', (197, 213))	('sarcomas', 'Disease', (205, 213))	('JAZF1', 'Gene', '221895', (119, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
333154	32299819	Findings of clinical utility included BCOR rearrangement for more precise diagnosis, detection of potentially actionable mutations in ALK, BRAF, ESR1, and BRCA2, and identification of MSI-H tumors, each of which could guide selection of FDA-approved therapies or influence clinical trial eligibility.	('guide', 'Reg', (218, 223))	('rearrangement', 'Var', (43, 56))	('BRAF', 'Gene', (139, 143))	('mutations', 'Var', (121, 130))	('ESR1', 'Gene', '2099', (145, 149))	('BCOR', 'Gene', '54880', (38, 42))	('BCOR', 'Gene', (38, 42))	('BRCA2', 'Gene', '675', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('ALK', 'Gene', (134, 137))	('MSI-H tumors', 'Disease', 'MESH:D009369', (184, 196))	('MSI-H tumors', 'Disease', (184, 196))	('ESR1', 'Gene', (145, 149))	('ALK', 'Gene', '238', (134, 137))	('BRCA2', 'Gene', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('BRAF', 'Gene', '673', (139, 143))	('influence', 'Reg', (263, 272))
333158	32299819	The frequency of MED12 mutations in uLMS patients (11%) was much lower than one would expect if uLMS commonly evolved from antecedent benign leiomyomas, which harbor MED12 mutations in ~70% of cases.	('uLMS', 'Disease', (96, 100))	('MED12', 'Gene', '9968', (166, 171))	('uLMS', 'Disease', (36, 40))	('lower', 'NegReg', (65, 70))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (41, 49))	('MED12', 'Gene', (17, 22))	('benign leiomyomas', 'Disease', (134, 151))	('benign leiomyomas', 'Disease', 'MESH:D007889', (134, 151))	('MED12', 'Gene', (166, 171))	('MED12', 'Gene', '9968', (17, 22))
333165	32299819	In contrast, the prolonged disease control achieved with PARP inhibition among the six patients with IMPACT detected BRCA2 alterations, which occur in 8% of high-grade uLMSs, suggests that BRCA2 may be a therapeutically relevant target.	('PARP', 'Gene', (57, 61))	('BRCA2', 'Gene', '675', (117, 122))	('patients', 'Species', '9606', (87, 95))	('PARP', 'Gene', '142', (57, 61))	('alterations', 'Var', (123, 134))	('BRCA2', 'Gene', (189, 194))	('BRCA2', 'Gene', (117, 122))	('BRCA2', 'Gene', '675', (189, 194))
333167	32299819	In addition to relatively high incidences of homozygous deletions in BRCA2, BRCA1 promoter hypermethylation as a potential mechanism of BRCA1 downregulation in uLMS and other hallmarks of "BRCAness" such as homologous recombination deficiency (HRD) mutational signatures have been identified in uterine sarcomas.	('BRCAness', 'Disease', 'None', (189, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (303, 310))	('uLMS', 'Disease', (160, 164))	('BRCA1', 'Gene', '672', (76, 81))	('BRCA1', 'Gene', (76, 81))	('deficiency', 'Disease', 'MESH:D007153', (232, 242))	('downregulation', 'NegReg', (142, 156))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (295, 310))	('deficiency', 'Disease', (232, 242))	('BRCA1', 'Gene', '672', (136, 141))	('BRCA2', 'Gene', (69, 74))	('HRD', 'Disease', (244, 247))	('BRCA1', 'Gene', (136, 141))	('HRD', 'Disease', 'None', (244, 247))	('deletions', 'Var', (56, 65))	('BRCA2', 'Gene', '675', (69, 74))	('sarcomas', 'Disease', 'MESH:D012509', (303, 311))	('sarcomas', 'Phenotype', 'HP:0100242', (303, 311))	('sarcomas', 'Disease', (303, 311))	('BRCAness', 'Disease', (189, 197))
333169	32299819	However, whether BRCA1 promotor hypermethylated uterine sarcoma tumors would respond to PARP inhibition requires further investigation, not least identifying whether hypermethylation of the BRCA1 promotor leads to an HRD phenotype in uLMS tumors.	('HRD', 'Disease', (217, 220))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('HRD', 'Disease', 'None', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('uLMS tumors', 'Disease', 'MESH:D009369', (234, 245))	('hypermethylation', 'Var', (166, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcoma tumors', 'Disease', 'MESH:D012509', (56, 70))	('leads to', 'Reg', (205, 213))	('sarcoma tumors', 'Disease', (56, 70))	('BRCA1', 'Gene', '672', (17, 22))	('BRCA1', 'Gene', (17, 22))	('PARP', 'Gene', '142', (88, 92))	('BRCA1', 'Gene', '672', (190, 195))	('uLMS tumors', 'Disease', (234, 245))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (48, 63))	('BRCA1', 'Gene', (190, 195))	('PARP', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))
333171	32299819	Genomic alterations such as RIT1 and MAP2K4 amplifications, despite their association with poor prognosis and other phenotypes in other cancer types, were not associated with prognostic differences in our cohort.	('amplifications', 'Var', (44, 58))	('MAP2K4', 'Gene', '6416', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('MAP2K4', 'Gene', (37, 43))	('RIT1', 'Gene', '6016', (28, 32))	('RIT1', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
333176	32299819	Furthermore, our cohort identified PDCD1 deletions as more common in uLMS than in non-uterine LMS.	('common', 'Reg', (59, 65))	('uLMS', 'Disease', (69, 73))	('PDCD1', 'Gene', (35, 40))	('PDCD1', 'Gene', '5133', (35, 40))	('deletions', 'Var', (41, 50))
333186	32299819	There was evidence of clinical benefit in uterine leiomyosarcoma patients with somatic BRCA2 alterations treated with PARP inhibitors.	('leiomyosarcoma', 'Disease', (50, 64))	('benefit', 'PosReg', (31, 38))	('alterations', 'Var', (93, 104))	('BRCA2', 'Gene', '675', (87, 92))	('PARP', 'Gene', '142', (118, 122))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (50, 64))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (42, 64))	('patients', 'Species', '9606', (65, 73))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (50, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('BRCA2', 'Gene', (87, 92))	('PARP', 'Gene', (118, 122))
333193	29312631	Gene silencing analysis of the TKs upregulated in 1273/99 cells showed differing effects on cell growth: PDGFRB, MET, and PYK2 knockdown induced cell growth inhibition, whereas DDR1 and AXL knockdown did not influence cell growth.	('AXL', 'Gene', '558', (186, 189))	('MET', 'Gene', (113, 116))	('knockdown', 'Var', (127, 136))	('DDR1', 'Gene', '780', (177, 181))	('AXL', 'Gene', (186, 189))	('PYK2', 'Gene', '2185', (122, 126))	('DDR1', 'Gene', (177, 181))	('PDGFRB', 'Gene', '5159', (105, 111))	('cell growth inhibition', 'CPA', (145, 167))	('PYK2', 'Gene', (122, 126))	('PDGFRB', 'Gene', (105, 111))
333195	29312631	Moreover, the results for overexpressed and aberrantly activated TKs in pazopanib-resistant cells showed no overlap.	('pazopanib', 'Chemical', 'MESH:C516667', (72, 81))	('TKs', 'Gene', (65, 68))	('aberrantly', 'Var', (44, 54))
333216	29312631	Using western blotting, we confirmed that the expression levels decreased after transfection with small interfering RNAs against the overexpressed TKs (PDGFRB, MET, PYK2, DDR1, and AXL; Figure 3A).	('AXL', 'Gene', (181, 184))	('RNAs', 'Protein', (116, 120))	('small interfering', 'Var', (98, 115))	('expression levels', 'MPA', (46, 63))	('PDGFRB', 'Gene', '5159', (152, 158))	('AXL', 'Gene', '558', (181, 184))	('DDR1', 'Gene', '780', (171, 175))	('PDGFRB', 'Gene', (152, 158))	('PYK2', 'Gene', '2185', (165, 169))	('DDR1', 'Gene', (171, 175))	('PYK2', 'Gene', (165, 169))	('decreased', 'NegReg', (64, 73))
333239	29312631	reported that SRC is a potential target in drug-resistant BRAF mutant melanoma.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('mutant', 'Var', (63, 69))	('BRAF', 'Gene', '673', (58, 62))	('SRC', 'Gene', '6714', (14, 17))	('SRC', 'Gene', (14, 17))	('BRAF', 'Gene', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
333245	29312631	reported that alterations in the kinome affected drug resistance in leukemia.	('alterations', 'Var', (14, 25))	('affected', 'Reg', (40, 48))	('kinome', 'Protein', (33, 39))	('leukemia', 'Disease', (68, 76))	('leukemia', 'Phenotype', 'HP:0001909', (68, 76))	('leukemia', 'Disease', 'MESH:D007938', (68, 76))	('drug resistance', 'Phenotype', 'HP:0020174', (49, 64))	('drug resistance', 'MPA', (49, 64))
333380	27994830	The positivity for SMA and desmin in this context may reflect myofibroblastic differentiation.	('desmin', 'Gene', (27, 33))	('SMA', 'Gene', '6606', (19, 22))	('positivity', 'Var', (4, 14))	('desmin', 'Gene', '1674', (27, 33))	('SMA', 'Gene', (19, 22))	('reflect', 'Reg', (54, 61))	('myofibroblastic differentiation', 'CPA', (62, 93))
333412	27994830	Factors that are associated with worse prognosis include necrosis, high mitotic count, and metastasis.	('metastasis', 'CPA', (91, 101))	('high', 'Var', (67, 71))	('necrosis', 'Disease', (57, 65))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
333435	27524931	Ewing's sarcoma family encompasses a group of highly aggressive, undifferentiated, intra- and extraosseous, mesenchymal tumors, caused by several types of translocations usually involving the EWSR1 gene.	('translocations', 'Var', (155, 169))	('caused by', 'Reg', (128, 137))	("Ewing's sarcoma", 'Disease', (0, 15))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('EWSR1', 'Gene', '2130', (192, 197))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('mesenchymal tumors', 'Disease', (108, 126))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (108, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('EWSR1', 'Gene', (192, 197))
333436	27524931	Translocation associated sarcomas, such as Ewing sarcoma, are only rarely encountered as therapy associated secondary tumors.	('Ewing sarcoma', 'Disease', (43, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Translocation', 'Var', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
333464	27524931	For the assessment of EWSR1 gene rearrangements at least 50 nonoverlapping tumor nuclei were analyzed.	('EWSR1', 'Gene', '2130', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('rearrangements', 'Var', (33, 47))	('EWSR1', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
333480	27524931	The diagnosis was confirmed by RT-PCR demonstrating the t(11;22) translocation with the EWSR1/FLI1 fusion transcript (Figure 1(c)).	('translocation', 'Var', (65, 78))	('FLI1', 'Gene', (94, 98))	('FLI1', 'Gene', '2313', (94, 98))	('EWSR1', 'Gene', (88, 93))	('EWSR1', 'Gene', '2130', (88, 93))
333486	27524931	Bone marrow aspiration showed 95% blasts infiltration: CD3c+; CD3+; CD4+; CD8+; CD7+; CD5+; CD34+; CD56+; CD2+; TDT+; TCR a/b+.	('CD56', 'Gene', '4684', (99, 103))	('CD56', 'Gene', (99, 103))	('CD34', 'Gene', (92, 96))	('blasts infiltration', 'CPA', (34, 53))	('CD34', 'Gene', '947', (92, 96))	('aspiration', 'Phenotype', 'HP:0002835', (12, 22))	('CD3c+', 'Var', (55, 60))	('CD2+', 'Var', (106, 110))
333497	27524931	Cytogenetic analysis of the bone marrow aspiration revealed t(1;16), loss of TLX3, and biallelic deletion of 12p.	('loss', 'NegReg', (69, 73))	('TLX3', 'Gene', (77, 81))	('aspiration', 'Phenotype', 'HP:0002835', (40, 50))	('biallelic deletion of', 'Var', (87, 108))	('TLX3', 'Gene', '30012', (77, 81))
333526	27524931	Therapy associated angiosarcomas show recurrent amplifications of the c-myc gene.	('angiosarcomas', 'Disease', 'MESH:D006394', (19, 32))	('c-myc', 'Gene', '4609', (70, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('amplifications', 'Var', (48, 62))	('c-myc', 'Gene', (70, 75))	('angiosarcomas', 'Disease', (19, 32))
333527	27524931	Alternatively, sarcomas with simple karyotypes, carrying specific translocations or point mutations, have only rarely been described in the context of secondary, therapy associated tumors.	('point mutations', 'Var', (84, 99))	('translocations', 'Var', (66, 80))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('sarcomas', 'Disease', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
333537	27524931	The pathogenesis of Ewing sarcoma is strongly linked to the presence of a translocation between the EWSR1 gene and a member of the ETS gene family.	('EWSR1', 'Gene', (100, 105))	('presence', 'Var', (60, 68))	('Ewing sarcoma', 'Disease', (20, 33))	('linked', 'Reg', (46, 52))	('EWSR1', 'Gene', '2130', (100, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('translocation', 'Var', (74, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))
333539	27524931	Recently published observations of a different frequency of SNPs variants of the EGR2 gene related to Ewing sarcoma susceptibility and may account for this observation, since the frequency of the SNP variant is significantly higher in the non-Africans than in patients of African origin.	('Ewing sarcoma', 'Disease', (102, 115))	('EGR2', 'Gene', '1959', (81, 85))	('EGR2', 'Gene', (81, 85))	('SNPs', 'Var', (60, 64))	('related', 'Reg', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('variants', 'Var', (65, 73))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('patients', 'Species', '9606', (260, 268))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))
333540	27524931	This important study provides deeper insights into the etiology of the occurrence of this specific translocation associated sarcoma and allows the conclusion that this is not a random disease but rather the expression of a germ line predisposition syndrome, thus accounting for the strong predilection of the Ewing sarcoma to occur in young patients, similar to other genetically linked tumors.	('patients', 'Species', '9606', (341, 349))	('translocation', 'Var', (99, 112))	('sarcoma', 'Disease', (124, 131))	('tumors', 'Phenotype', 'HP:0002664', (387, 393))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('sarcoma', 'Disease', 'MESH:D012509', (315, 322))	('Ewing sarcoma', 'Disease', (309, 322))	('linked tumors', 'Disease', (380, 393))	('linked tumors', 'Disease', 'MESH:D009369', (380, 393))	('sarcoma', 'Phenotype', 'HP:0100242', (315, 322))	('tumor', 'Phenotype', 'HP:0002664', (387, 392))	('sarcoma', 'Disease', (315, 322))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (309, 322))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (309, 322))	('associated', 'Reg', (113, 123))
333544	27524931	Interestingly, in the recent comprehensive study of germ line mutations in the best characterized genes associated with cancer predisposition syndromes in pediatric cancer patients, 5 patients with relevant mutations (3 patients with TP53 gene mutations, one patients with PMS2 gene mutation, and one patient with RET gene mutation) were identified among 46 (10.8%) patients with Ewing sarcoma, frequency of which was higher than in cases of rhabdomyosarcoma (7%, 3/43).	('patient', 'Species', '9606', (366, 373))	('PMS2', 'Gene', '5395', (273, 277))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (442, 458))	('cancer', 'Disease', (120, 126))	('patients', 'Species', '9606', (220, 228))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (442, 458))	('patient', 'Species', '9606', (301, 308))	('patient', 'Species', '9606', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('RET', 'Gene', (314, 317))	('TP53', 'Gene', (234, 238))	('patients', 'Species', '9606', (259, 267))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (380, 393))	('mutations', 'Var', (207, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (451, 458))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (380, 393))	('patients', 'Species', '9606', (172, 180))	('mutations', 'Var', (244, 253))	('mutations', 'Var', (62, 71))	('PMS2', 'Gene', (273, 277))	('pediatric cancer', 'Disease', 'MESH:D009369', (155, 171))	('patient', 'Species', '9606', (172, 179))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('patient', 'Species', '9606', (220, 227))	('pediatric cancer', 'Disease', (155, 171))	('cancer', 'Disease', (165, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (386, 393))	('patient', 'Species', '9606', (259, 266))	('TP53', 'Gene', '7157', (234, 238))	('patients', 'Species', '9606', (184, 192))	('Ewing sarcoma', 'Disease', (380, 393))	('rhabdomyosarcoma', 'Disease', (442, 458))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('patients', 'Species', '9606', (366, 374))	('RET', 'Gene', '5979', (314, 317))
333587	27453756	The mechanisms of genomic instability may be facilitated by the repetitive DNA sequences found in the human genome, particularly low copy repeats.	('genomic instability', 'CPA', (18, 37))	('human', 'Species', '9606', (102, 107))	('low copy repeats', 'Var', (129, 145))
333589	27453756	CIN is the elevated rate of gain or loss of entire chromosomes or big parts of chromosomes, and it appears to have a significant role in the pathogenesis of osteosarcoma tumors, resulting in variable structural and numerical aberrations.	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('gain', 'PosReg', (28, 32))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (157, 176))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('loss', 'NegReg', (36, 40))	('structural', 'MPA', (200, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('CIN', 'Var', (0, 3))	('osteosarcoma tumors', 'Disease', (157, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))
333590	27453756	The pathogenesis is based on the inactivation of tumor suppressor genes, particularly p53 and the retinoblastoma susceptibility gene (RB1).	('p53', 'Gene', '7157', (86, 89))	('RB1', 'Gene', '5925', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('retinoblastoma', 'Disease', 'MESH:D012175', (98, 112))	('retinoblastoma', 'Disease', (98, 112))	('retinoblastoma', 'Phenotype', 'HP:0009919', (98, 112))	('inactivation', 'Var', (33, 45))	('RB1', 'Gene', (134, 137))	('p53', 'Gene', (86, 89))
333591	27453756	The combination of constitutional mutation of the RB gene (germline retinoblastoma) and radiation therapy is linked with a particularly high risk of developing osteosarcoma, Li-Fraumeni syndrome (germline p53 mutation), and Rothmund-Thomson syndrome (autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, and cataract).	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('cataract', 'Phenotype', 'HP:0000518', (355, 363))	('hypogonadism', 'Disease', (337, 349))	('Rothmund-Thomson syndrome', 'Disease', 'MESH:D011038', (224, 249))	('hypogonadism', 'Phenotype', 'HP:0000135', (337, 349))	('retinoblastoma', 'Phenotype', 'HP:0009919', (68, 82))	('hypogonadism', 'Disease', 'MESH:D007006', (337, 349))	('radiation', 'Disease', (88, 97))	('mutation', 'Var', (34, 42))	('autosomal recessive association of congenital bone defects, hair and skin dysplasias', 'Disease', 'MESH:D001848', (251, 335))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (174, 194))	('osteosarcoma', 'Phenotype', 'HP:0002669', (160, 172))	('Rothmund-Thomson syndrome', 'Disease', (224, 249))	('Li-Fraumeni syndrome', 'Disease', (174, 194))	('developing osteosarcoma', 'Disease', (149, 172))	('cataract', 'Disease', 'MESH:D002386', (355, 363))	('cataract', 'Disease', (355, 363))	('radiation', 'Disease', 'MESH:D004194', (88, 97))
333592	27453756	Translocation of EWSR1 (Ewing sarcoma breakpoint region 1) with an ETS (E26 transformation-specific) transcription factor gene occurs in more than 95% of Ewing sarcomas.	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (154, 168))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (24, 57))	('Translocation', 'Var', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (24, 37))	('EWSR1', 'Gene', '2130', (17, 22))	('Ewing sarcomas', 'Disease', (154, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('Ewing sarcoma breakpoint region 1', 'Gene', (24, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (154, 167))	('EWS', 'Gene', '2130', (17, 20))	('EWS', 'Gene', (17, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('EWSR1', 'Gene', (17, 22))
333597	27453756	Different gene mutations were identified in patients with Ewing sarcoma: TP53 mutations occurred in 5% - 20% of cases, amplifications of MDM2 occurred in up to 10% of the cases, deletions of the CDKN2A in about 15% of the cases .	('TP53', 'Gene', '7157', (73, 77))	('MDM2', 'Gene', '4193', (137, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('MDM2', 'Gene', (137, 141))	('CDKN2A', 'Gene', (195, 201))	('occurred', 'Reg', (88, 96))	('deletions', 'Var', (178, 187))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('Ewing sarcoma', 'Disease', (58, 71))	('CDKN2A', 'Gene', '1029', (195, 201))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('amplifications', 'MPA', (119, 133))
333607	26827688	MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('sarcomas', 'Disease', (85, 93))	('attenuates', 'NegReg', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('efficacy', 'MPA', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('MDR', 'Var', (0, 3))	('sarcomas', 'Disease', 'MESH:D012509', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('results in', 'Reg', (52, 62))	('cancer', 'Disease', (35, 41))
333610	26827688	Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects.	('doses', 'MPA', (189, 194))	('proliferation', 'CPA', (59, 72))	('resistance to chemotherapeutic drugs', 'MPA', (125, 161))	('Inhibiting', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('sarcoma', 'Disease', (87, 94))	('reduce', 'NegReg', (178, 184))	('reverse', 'NegReg', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('protein kinases', 'Enzyme', (17, 32))	('cancer', 'Disease', (202, 208))	('growth', 'CPA', (77, 83))	('decrease', 'NegReg', (46, 54))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
333629	26827688	There is a wide range of mechanisms that contribute to drug sensitivity/resistance, including ATP-binding cassette transporter (ABC transporters) mediated drug efflux, alteration of apoptosis, cancer stem cells (CSC), alteration/mutation of specific targets of the drugs, aberrant activation cell signaling pathways, DNA damage and repair, autophagy induction, miRNA regulation, hypoxia induction, epigenetic regulation, tumor microenvironment, etc.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('hypoxia', 'Disease', (379, 386))	('alteration/mutation', 'Var', (218, 237))	('hypoxia', 'Disease', 'MESH:D000860', (379, 386))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (421, 426))	('tumor', 'Phenotype', 'HP:0002664', (421, 426))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('ATP', 'Chemical', 'MESH:D000255', (94, 97))	('tumor', 'Disease', (421, 426))	('miRNA regulation', 'CPA', (361, 377))	('drug sensitivity', 'Phenotype', 'HP:0020174', (55, 71))	('autophagy induction', 'CPA', (340, 359))
333645	26827688	Aberrant expression of certain tyrosine kinases and/or constitutive activation of downstream pathways may be responsible for the progression of sarcoma, including tumor cell survival, apoptosis, neovascularization, and invasion, particularly in MDR.	('sarcoma', 'Disease', (144, 151))	('tyrosine', 'Chemical', 'MESH:D014443', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('downstream pathways', 'Pathway', (82, 101))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('responsible', 'Reg', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('activation', 'PosReg', (68, 78))	('tyrosine kinases', 'Enzyme', (31, 47))	('expression', 'MPA', (9, 19))	('invasion', 'CPA', (219, 227))	('tumor', 'Disease', (163, 168))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('MDR', 'Disease', (245, 248))	('neovascularization', 'CPA', (195, 213))	('apoptosis', 'CPA', (184, 193))
333650	26827688	EGFR dimerization and the subsequent autophosphorylation of tyrosines induces various downstream signal transduction cascades and lysosomal degradation.	('tyrosines', 'Chemical', 'MESH:D014443', (60, 69))	('EGFR', 'Gene', (0, 4))	('autophosphorylation', 'MPA', (37, 56))	('dimerization', 'Var', (5, 17))	('induces', 'Reg', (70, 77))	('lysosomal degradation', 'CPA', (130, 151))	('EGFR', 'Gene', '1956', (0, 4))
333661	26827688	Furthermore, gefitinib decreased anti-apoptotic factor Bcl-2 levels and increased intracellular doxorubicin retention.	('Bcl-2', 'Gene', (55, 60))	('increased', 'PosReg', (72, 81))	('gefitinib', 'Chemical', 'MESH:D000077156', (13, 22))	('Bcl-2', 'Gene', '596', (55, 60))	('intracellular doxorubicin retention', 'MPA', (82, 117))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('gefitinib', 'Var', (13, 22))	('decreased', 'NegReg', (23, 32))
333671	26827688	Collectively, targeting EGFR represents a promising therapeutic strategy for overcoming MDR in sarcoma.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('targeting', 'Var', (14, 23))	('sarcoma', 'Disease', (95, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('MDR', 'Disease', (88, 91))
333699	26827688	Overexpression and/or aberrant activation of VEGFR are associated with poor prognosis in sarcomas.	('aberrant', 'Var', (22, 30))	('sarcomas', 'Disease', (89, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('VEGFR', 'Gene', '3791', (45, 50))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))	('VEGFR', 'Gene', (45, 50))
333703	26827688	Overexpression and aberrantly activated MET triggers cell growth, angiogenesis, invasion, and metastasis correlated with poor prognosis in various sarcomas.	('invasion', 'CPA', (80, 88))	('aberrantly activated', 'Var', (19, 39))	('metastasis', 'CPA', (94, 104))	('cell growth', 'CPA', (53, 64))	('sarcomas', 'Disease', (147, 155))	('MET triggers', 'Gene', (40, 52))	('sarcomas', 'Disease', 'MESH:D012509', (147, 155))	('angiogenesis', 'CPA', (66, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
333705	26827688	PHA-665752 and neutralizing anti-HGF antibody substantially decreased the levels of pAKT with no changes on total AKT levels.	('HGF', 'Gene', (33, 36))	('AKT', 'Gene', '207', (114, 117))	('decreased', 'NegReg', (60, 69))	('neutralizing', 'Var', (15, 27))	('HGF', 'Gene', '3082', (33, 36))	('AKT', 'Gene', '207', (85, 88))	('AKT', 'Gene', (114, 117))	('AKT', 'Gene', (85, 88))	('PHA-665752', 'Var', (0, 10))
333712	26827688	Several small molecule kinase inhibitors of SFKs have demonstrated efficacy in sarcoma cells, such as SI-83 in osteosarcoma; AP23994 in Ewing sarcoma; dasatinib in osteosarcoma, Ewing sarcoma, liposarcoma and synovial sarcoma; SI221 in rhabdomyosarcoma; and saracatinib in fibrosarcoma A-770041 is a potent SFK (Lck and SRC) inhibitor, which not only showed inhibition of SRC, but also reversed MDR ability in osteosarcoma.	('inhibition', 'NegReg', (358, 368))	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('sarcoma', 'Disease', (79, 86))	('SI', 'Disease', 'None', (102, 104))	('sarcoma', 'Disease', (278, 285))	('sarcoma', 'Disease', (142, 149))	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('sarcoma', 'Disease', 'MESH:D012509', (245, 252))	('synovial sarcoma', 'Disease', (209, 225))	('A-770041', 'Var', (286, 294))	('sarcoma', 'Disease', (197, 204))	('SI', 'Disease', 'None', (227, 229))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('sarcoma', 'Disease', (245, 252))	('osteosarcoma', 'Disease', (410, 422))	('SFK', 'Gene', (307, 310))	('fibrosarcoma', 'Disease', 'MESH:D005354', (273, 285))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (136, 149))	('SRC', 'Gene', '6714', (372, 375))	('liposarcoma', 'Disease', (193, 204))	('osteosarcoma', 'Disease', 'MESH:D012516', (410, 422))	('saracatinib', 'Chemical', 'MESH:C515233', (258, 269))	('synovial sarcoma', 'Disease', 'MESH:D013584', (209, 225))	('SFK', 'Gene', (44, 47))	('fibrosarcoma', 'Disease', (273, 285))	('Lck', 'Gene', '3932', (312, 315))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (236, 252))	('osteosarcoma', 'Disease', (164, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('Ewing sarcoma', 'Disease', (178, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('A-770041', 'Chemical', 'MESH:C505452', (286, 294))	('dasatinib', 'Chemical', 'MESH:D000069439', (151, 160))	('osteosarcoma', 'Disease', 'MESH:D012516', (164, 176))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('SI221 in rhabdomyosarcoma', 'Disease', 'MESH:D012208', (227, 252))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('SFK', 'Gene', '2268;2534;6714', (307, 310))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (209, 225))	('sarcoma', 'Disease', (116, 123))	('Lck', 'Gene', (312, 315))	('SRC', 'Gene', (372, 375))	('AP23994', 'Var', (125, 132))	('SFK', 'Gene', '2268;2534;6714', (44, 47))	('sarcoma', 'Disease', 'MESH:D012509', (169, 176))	('Ewing sarcoma', 'Disease', (136, 149))	('liposarcoma', 'Phenotype', 'HP:0012034', (193, 204))	('sarcoma', 'Disease', 'MESH:D012509', (218, 225))	('sarcoma', 'Disease', (169, 176))	('sarcoma', 'Disease', 'MESH:D012509', (415, 422))	('sarcoma', 'Disease', (218, 225))	('SRC', 'Gene', '6714', (320, 323))	('osteosarcoma', 'Phenotype', 'HP:0002669', (410, 422))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('MDR ability', 'MPA', (395, 406))	('sarcoma', 'Disease', (415, 422))	('SI221 in rhabdomyosarcoma', 'Disease', (227, 252))	('sarcoma', 'Disease', 'MESH:D012509', (184, 191))	('liposarcoma', 'Disease', 'MESH:D008080', (193, 204))	('osteosarcoma', 'Phenotype', 'HP:0002669', (164, 176))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (273, 285))	('sarcoma', 'Disease', (184, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('osteosarcoma', 'Disease', (111, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (111, 123))	('SRC', 'Gene', (320, 323))	('sarcoma', 'Disease', 'MESH:D012509', (278, 285))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (178, 191))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (178, 191))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
333713	26827688	The combination of A-770041 with paclitaxel and doxorubicin sensitized and reversed chemotherapeutic drugs resistance in MDR human osteosarcoma cell lines.	('chemotherapeutic drugs resistance', 'MPA', (84, 117))	('drugs resistance', 'Phenotype', 'HP:0020174', (101, 117))	('reversed', 'Reg', (75, 83))	('human', 'Species', '9606', (125, 130))	('paclitaxel', 'Chemical', 'MESH:D017239', (33, 43))	('osteosarcoma', 'Phenotype', 'HP:0002669', (131, 143))	('A-770041', 'Var', (19, 27))	('osteosarcoma', 'Disease', (131, 143))	('osteosarcoma', 'Disease', 'MESH:D012516', (131, 143))	('doxorubicin', 'Chemical', 'MESH:D004317', (48, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('A-770041', 'Chemical', 'MESH:C505452', (19, 27))
333715	26827688	A-770041 significantly increased intracellular accumulation of drug concentration in MDR osteosarcoma cell lines that overexpressed ABCB1 (also known as P-gp, MDR1) in a dose-dependent manner without altering the expression of ABCB1 protein levels.	('MDR1', 'Gene', '5243', (159, 163))	('A-770041', 'Var', (0, 8))	('osteosarcoma', 'Disease', (89, 101))	('A-770041', 'Chemical', 'MESH:C505452', (0, 8))	('ABCB1', 'Gene', '5243', (132, 137))	('increased intracellular accumulation', 'Phenotype', 'HP:0003575', (23, 59))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('ABCB1', 'Gene', (227, 232))	('overexpressed', 'PosReg', (118, 131))	('increased', 'PosReg', (23, 32))	('intracellular accumulation of drug concentration', 'MPA', (33, 81))	('ABCB1', 'Gene', '5243', (227, 232))	('P-gp', 'Gene', '283871', (153, 157))	('MDR1', 'Gene', (159, 163))	('P-gp', 'Gene', (153, 157))	('ABCB1', 'Gene', (132, 137))
333716	26827688	These results indicated that A-770041 inhibited ABCB1 efflux function via interaction with ABCB1 and contributed to the reversal of MDR.	('ABCB1', 'Gene', '5243', (91, 96))	('efflux function', 'MPA', (54, 69))	('MDR', 'MPA', (132, 135))	('ABCB1', 'Gene', (91, 96))	('inhibited', 'NegReg', (38, 47))	('A-770041', 'Var', (29, 37))	('ABCB1', 'Gene', (48, 53))	('ABCB1', 'Gene', '5243', (48, 53))	('interaction', 'Interaction', (74, 85))	('A-770041', 'Chemical', 'MESH:C505452', (29, 37))
333717	26827688	In addition, A-770041 in combination with doxorubicin increased apoptosis to further enhance chemosensitization in MDR osteosarcoma cell lines.	('A-770041', 'Chemical', 'MESH:C505452', (13, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (119, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('apoptosis', 'CPA', (64, 73))	('increased', 'PosReg', (54, 63))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('A-770041', 'Var', (13, 21))	('osteosarcoma', 'Disease', (119, 131))	('chemosensitization', 'CPA', (93, 111))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('enhance', 'PosReg', (85, 92))
333718	26827688	Dasatinib also showed a potent sensitization effect with doxorubicin treatment in TP53 mutant chemoresistant chondrosarcoma cells exhibited by increased doxorubicin induced-apoptosis.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('sensitization', 'MPA', (31, 44))	('increased', 'PosReg', (143, 152))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (109, 123))	('mutant', 'Var', (87, 93))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('doxorubicin induced-apoptosis', 'MPA', (153, 182))	('chondrosarcoma', 'Disease', (109, 123))	('chondrosarcoma', 'Disease', 'MESH:D002813', (109, 123))	('doxorubicin', 'Chemical', 'MESH:D004317', (153, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('doxorubicin', 'Chemical', 'MESH:D004317', (57, 68))
333739	26827688	In addition, inhibitor of STAT3 CDDO-Me reduced resistance to doxorubicin in MDR osteosarcoma through down-regulate STAT3-mediated antiapoptotic proteins in both dose and time dependent manner.	('CDDO-Me', 'Chemical', 'MESH:C445068', (32, 39))	('osteosarcoma', 'Disease', (81, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('inhibitor', 'Var', (13, 22))	('down-regulate', 'NegReg', (102, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('STAT3', 'Gene', '6774', (26, 31))	('STAT3', 'Gene', '6774', (116, 121))	('doxorubicin', 'Chemical', 'MESH:D004317', (62, 73))	('reduced', 'NegReg', (40, 47))	('resistance to doxorubicin', 'MPA', (48, 73))	('STAT3', 'Gene', (26, 31))	('STAT3', 'Gene', (116, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))
333743	26827688	Dysregulation of STKs has been implicated to be associated with tumor growth, metastasis, recurrence, and chemoresistance in a variety of sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('tumor', 'Disease', (64, 69))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (48, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('sarcomas', 'Disease', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('chemoresistance', 'CPA', (106, 121))	('STKs', 'Gene', (17, 21))	('recurrence', 'CPA', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('metastasis', 'CPA', (78, 88))
333760	26827688	In rhabdomyosarcoma, BI 2536 and BI 6727 also synergistically induced apoptosis and mitotic arrest with co-treatment with vincristine in vitro and in vivo.	('BI 6727', 'Var', (33, 40))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (3, 19))	('vincristine', 'Chemical', 'MESH:D014750', (122, 133))	('BI 2536', 'Chemical', 'MESH:C518477', (21, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (3, 19))	('induced', 'Reg', (62, 69))	('rhabdomyosarcoma', 'Disease', (3, 19))	('mitotic arrest', 'Disease', (84, 98))	('mitotic arrest', 'Disease', 'MESH:D006323', (84, 98))	('BI 2536', 'Var', (21, 28))	('apoptosis', 'CPA', (70, 79))	('BI 6727', 'Chemical', 'MESH:C541363', (33, 40))
333761	26827688	The group also confirmed that the combination of BI 2536 with eribulin showed synergistic inhibition effects in rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', (112, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (112, 128))	('combination', 'Interaction', (34, 45))	('BI 2536', 'Chemical', 'MESH:C518477', (49, 56))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (112, 128))	('BI 2536', 'Var', (49, 56))
333762	26827688	These findings present targeting PLK1 as a promising therapeutic strategy to reverse MDR in sarcoma.	('targeting', 'Var', (23, 32))	('PLK1', 'Gene', (33, 37))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('PLK1', 'Gene', '5347', (33, 37))	('sarcoma', 'Disease', (92, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
333772	26827688	Recently, a study demonstrated that BI-78D3, an ATP-non-competitive JNK inhibitor, blocked JIP1-JNK binding and sensitized osteosarcoma cells to doxorubicin.	('osteosarcoma', 'Phenotype', 'HP:0002669', (123, 135))	('osteosarcoma', 'Disease', (123, 135))	('osteosarcoma', 'Disease', 'MESH:D012516', (123, 135))	('JNK', 'Gene', '5599', (96, 99))	('BI-78D3', 'Var', (36, 43))	('JIP1', 'Gene', '9479', (91, 95))	('BI', 'Chemical', 'MESH:D001729', (36, 38))	('JIP1', 'Gene', (91, 95))	('JNK', 'Gene', (68, 71))	('JNK', 'Gene', (96, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('doxorubicin', 'Chemical', 'MESH:D004317', (145, 156))	('sensitized', 'Reg', (112, 122))	('JNK', 'Gene', '5599', (68, 71))	('blocked', 'NegReg', (83, 90))
333774	26827688	Furthermore, they found that JIP1 was more highly expressed in human osteosarcoma cell lines than in primary osteoblasts, and the combination of BI-78D3 with doxorubicin decreased JNK and JNK-JIP1 complex expression levels.	('osteosarcoma', 'Disease', (69, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (69, 81))	('JNK-JIP1', 'Gene', '5599;9479', (188, 196))	('JIP1', 'Gene', (29, 33))	('BI', 'Chemical', 'MESH:D001729', (145, 147))	('human', 'Species', '9606', (63, 68))	('doxorubicin', 'Chemical', 'MESH:D004317', (158, 169))	('combination', 'Interaction', (130, 141))	('JNK', 'Gene', (188, 191))	('JNK', 'Gene', '5599', (188, 191))	('JNK', 'Gene', (180, 183))	('JIP1', 'Gene', '9479', (29, 33))	('JIP1', 'Gene', (192, 196))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('JNK', 'Gene', '5599', (180, 183))	('JIP1', 'Gene', '9479', (192, 196))	('BI-78D3', 'Var', (145, 152))	('decreased', 'NegReg', (170, 179))	('JNK-JIP1', 'Gene', (188, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
333775	26827688	In addition, BI-78D3 enhanced doxorubicin-induced apoptosis by inhibiting the anti-apoptotic JNK signaling pathway.	('JNK', 'Gene', (93, 96))	('doxorubicin', 'Chemical', 'MESH:D004317', (30, 41))	('enhanced', 'PosReg', (21, 29))	('JNK', 'Gene', '5599', (93, 96))	('BI-78D3', 'Var', (13, 20))	('inhibiting', 'NegReg', (63, 73))	('BI', 'Chemical', 'MESH:D001729', (13, 15))	('doxorubicin-induced', 'MPA', (30, 49))
333780	26827688	CDK-cyclin complexes tightly control and monitor four sequential phases of cell cycle namely, G1, S, G2, and M phase, and dysregulation in any phase results in uncontrolled cell growth and tumorigenesis.	('tumor', 'Disease', (189, 194))	('dysregulation', 'Var', (122, 135))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('uncontrolled cell growth', 'CPA', (160, 184))	('results in', 'Reg', (149, 159))
333782	26827688	Targeting with the small molecule kinase inhibitor PD0332991 decreased rhabdomyosarcoma in vitro and in vivo through cell cycle G1 arrest.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (71, 87))	('PD0332991', 'Chemical', 'MESH:C500026', (51, 60))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (71, 87))	('PD0332991', 'Var', (51, 60))	('rhabdomyosarcoma', 'Disease', (71, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('cell cycle G1 arrest', 'CPA', (117, 137))	('decreased', 'NegReg', (61, 70))
333784	26827688	A Phase II trial reported that PD0332991 could inhibit tumor cell growth and improve progression-free survival rates in patients with a CDK4 amplification and Rb expression in liposarcoma.	('improve', 'PosReg', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('PD0332991', 'Chemical', 'MESH:C500026', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('progression-free survival rates', 'CPA', (85, 116))	('liposarcoma', 'Disease', 'MESH:D008080', (176, 187))	('liposarcoma', 'Phenotype', 'HP:0012034', (176, 187))	('PD0332991', 'Var', (31, 40))	('CDK4', 'Gene', (136, 140))	('tumor', 'Disease', (55, 60))	('inhibit', 'NegReg', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('CDK4', 'Gene', '1019', (136, 140))	('patients', 'Species', '9606', (120, 128))	('liposarcoma', 'Disease', (176, 187))
333792	26827688	AKT is a downstream mediator of the PI3K pathway, and is fully activated through simultaneous phosphorylation at two key sites: Thr308 (phosphorylated by PDK1) and Ser473 (phosphorylated by mTORC2).	('AKT', 'Gene', (0, 3))	('mTORC2', 'Gene', (190, 196))	('Thr308', 'Var', (128, 134))	('PI3', 'Gene', (36, 39))	('mTORC2', 'Gene', '74343', (190, 196))	('PDK1', 'Gene', '5163', (154, 158))	('PDK1', 'Gene', (154, 158))	('Ser473', 'Var', (164, 170))	('AKT', 'Gene', '207', (0, 3))	('Thr308', 'Chemical', '-', (128, 134))	('Ser473', 'Chemical', '-', (164, 170))	('PI3', 'Gene', '5266', (36, 39))
333797	26827688	Mutations in PTEN and dysregulation of upstream effectors (e.g.	('PTEN', 'Gene', (13, 17))	('dysregulation', 'Var', (22, 35))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', '5728', (13, 17))
333800	26827688	To date, mutation or constitutive activation of PI3K/AKT/mTOR has been found in most types of sarcomas, including osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, synovial sarcoma, and liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('liposarcoma', 'Disease', 'MESH:D008080', (183, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('synovial sarcoma', 'Disease', (161, 177))	('activation', 'PosReg', (34, 44))	('Ewing sarcoma', 'Disease', (146, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('synovial sarcoma', 'Disease', 'MESH:D013584', (161, 177))	('rhabdomyosarcoma', 'Disease', (128, 144))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('osteosarcoma', 'Disease', (114, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (114, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('mTOR', 'Gene', (57, 61))	('PI3', 'Gene', '5266', (48, 51))	('AKT', 'Gene', (53, 56))	('sarcomas', 'Disease', (94, 102))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (161, 177))	('liposarcoma', 'Disease', (183, 194))	('mutation', 'Var', (9, 17))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (128, 144))	('found', 'Reg', (71, 76))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (128, 144))	('mTOR', 'Gene', '2475', (57, 61))	('PI3', 'Gene', (48, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (146, 159))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (146, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (114, 126))	('liposarcoma', 'Phenotype', 'HP:0012034', (183, 194))	('AKT', 'Gene', '207', (53, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))
333802	26827688	PI103, a dual PI3K/mTOR kinase inhibitor, can reverse MDR in fibrosarcoma and rhabdomyosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('mTOR', 'Gene', '2475', (19, 23))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('mTOR', 'Gene', (19, 23))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (78, 94))	('MDR', 'MPA', (54, 57))	('PI3', 'Gene', '5266', (14, 17))	('PI103', 'Var', (0, 5))	('PI3', 'Gene', (14, 17))	('fibrosarcoma and rhabdomyosarcoma', 'Disease', 'MESH:D005354', (61, 94))
333803	26827688	A study demonstrated that PI103 increased intracellular doxorubicin accumulation through decreased expression of ABCB1 and ABCC1.	('expression', 'MPA', (99, 109))	('ABCB1', 'Gene', (113, 118))	('ABCB1', 'Gene', '5243', (113, 118))	('ABCC1', 'Gene', (123, 128))	('intracellular doxorubicin accumulation', 'MPA', (42, 80))	('ABCC1', 'Gene', '4363', (123, 128))	('increased', 'PosReg', (32, 41))	('PI103', 'Var', (26, 31))	('doxorubicin', 'Chemical', 'MESH:D004317', (56, 67))	('decreased', 'NegReg', (89, 98))
333806	26827688	Another dual PI3K/mTOR kinase inhibitor NVP-BEZ235 did, on the other hand, show synergistic effects with chloroquine to induce apoptosis in rhabdomyosarcoma at subtoxic concentrations.	('mTOR', 'Gene', (18, 22))	('BEZ235', 'Chemical', 'MESH:C531198', (44, 50))	('PI3', 'Gene', '5266', (13, 16))	('induce', 'PosReg', (120, 126))	('mTOR', 'Gene', '2475', (18, 22))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (140, 156))	('apoptosis', 'CPA', (127, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('rhabdomyosarcoma', 'Disease', (140, 156))	('PI3', 'Gene', (13, 16))	('NVP-BEZ235', 'Var', (40, 50))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (140, 156))	('chloroquine', 'Chemical', 'MESH:D002738', (105, 116))
333811	26827688	Besides small molecule kinase inhibitor and siRNA, complementary targeting of the 3'-untranslated region (UTR) of mTOR by miRNA-100 also sensitized chondrosarcoma cells to cisplatin.	('sensitized', 'Reg', (137, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (172, 181))	('miRNA-100', 'Var', (122, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('mTOR', 'Gene', '2475', (114, 118))	('chondrosarcoma', 'Disease', 'MESH:D002813', (148, 162))	('mTOR', 'Gene', (114, 118))	('chondrosarcoma', 'Disease', (148, 162))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (148, 162))	('miRNA-100', 'Chemical', '-', (122, 131))
333817	26827688	Recently, another report also confirmed that the combination of VX-680 with cisplatin, doxorubicin, and methotrexate exhibited a synthetic lethal interaction in osteosarcoma cell lines.	('osteosarcoma', 'Disease', (161, 173))	('VX-680', 'Var', (64, 70))	('methotrexate', 'Chemical', 'MESH:D008727', (104, 116))	('osteosarcoma', 'Phenotype', 'HP:0002669', (161, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (161, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))
333819	26827688	The combination of aurora kinase inhibitor MSC1992371A with gemcitabine was investigated in a Phase I study in patients with solid tumors, including in sarcoma patients.	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('gemcitabine', 'Chemical', 'MESH:C056507', (60, 71))	('solid tumors', 'Disease', 'MESH:D009369', (125, 137))	('patients', 'Species', '9606', (160, 168))	('MSC1992371A', 'Var', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('sarcoma', 'Disease', (152, 159))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('solid tumors', 'Disease', (125, 137))	('patients', 'Species', '9606', (111, 119))
333821	26827688	Aberrant activation and/or overexpression of upstream signaling components constitutively activate ERK, which is often exhibited in different types of sarcomas, and targeting this pathway demonstrates an inhibition effect on tumors.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('activation', 'PosReg', (9, 19))	('sarcomas', 'Disease', (151, 159))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ERK', 'Gene', '5594', (99, 102))	('ERK', 'Gene', (99, 102))	('activate', 'PosReg', (90, 98))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('overexpression', 'PosReg', (27, 41))	('tumors', 'Disease', (225, 231))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))
333828	26827688	Moreover, the combination of MK-1775 with gemcitabine showed a synergistic effect in vitro and in vivo through increased apoptosis.	('increased', 'PosReg', (111, 120))	('MK-1775', 'Var', (29, 36))	('MK-1775', 'Chemical', 'MESH:C549567', (29, 36))	('gemcitabine', 'Chemical', 'MESH:C056507', (42, 53))	('combination', 'Interaction', (14, 25))	('apoptosis', 'CPA', (121, 130))
333829	26827688	In addition, targeting CHK1 by kinase inhibitor LY2603618 increased cisplatin sensitivity in osteosarcoma.	('CHK1', 'Gene', (23, 27))	('cisplatin sensitivity', 'MPA', (68, 89))	('increased', 'PosReg', (58, 67))	('CHK1', 'Gene', '1111', (23, 27))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('osteosarcoma', 'Disease', (93, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (93, 105))	('LY2603618', 'Var', (48, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
333846	25777468	Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement.	('tumor', 'Disease', (79, 84))	('ATF-3', 'Gene', '467', (70, 75))	('upregulation', 'PosReg', (54, 66))	('ATF-3', 'Gene', (70, 75))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('20S proteasome', 'Protein', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
333853	25777468	Ixazomib is currently being investigated in phase 3 trials in MM (Clinicaltrials.gov identifiers NCT01564537 and NCT01850524) and primary systemic AL amyloidosis (NCT01659658).	('NCT01659658', 'Var', (163, 174))	('systemic AL amyloidosis', 'Disease', (138, 161))	('systemic AL amyloidosis', 'Disease', 'MESH:D000075363', (138, 161))	('Ixazomib', 'Chemical', 'MESH:C548400', (0, 8))	('amyloidosis', 'Phenotype', 'HP:0011034', (150, 161))
333861	25777468	Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, absolute neutrophil count (ANC) >=1,500/mm3, platelet count >=100,000/mm3, total bilirubin <=1.5 x the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5 x ULN (<=5 x ULN if the elevation can be reasonably ascribed to metastatic disease), creatinine clearance or calculated creatinine clearance >=60 mL/min, and QTc <470 ms on 12-lead electrocardiogram were required.	('alanine aminotransferase', 'Gene', '2875', (201, 225))	('<=1.5', 'Var', (160, 165))	('AST', 'Gene', (264, 267))	('aspartate aminotransferase', 'Gene', '26503', (236, 262))	('creatinine clearance', 'MPA', (360, 380))	('Oncology', 'Phenotype', 'HP:0002664', (20, 28))	('AST', 'Gene', '26503', (264, 267))	('aspartate aminotransferase', 'Gene', (236, 262))	('alanine aminotransferase', 'Gene', (201, 225))	('calculated creatinine clearance', 'MPA', (384, 415))
334049	32211974	in 2007 compared mechanical properties of reconstructed Achilles tendon with Peroneus Brevis tendon or Flexor Hallucis Longus tendon, concluding that they perform similarly, regarding stiffness and energy, but Peroneus Brevis tendon transfer displayed a higher load to failure.	('load', 'MPA', (261, 265))	('Peroneus Brevis tendon or Flexor Hallucis Longus tendon', 'Disease', 'MESH:D052256', (77, 132))	('Peroneus Brevis', 'Phenotype', 'HP:0009049', (210, 225))	('Peroneus', 'Var', (210, 218))	('Peroneus Brevis', 'Phenotype', 'HP:0009049', (77, 92))	('Achilles tendon', 'Phenotype', 'HP:0001771', (56, 71))
334053	22885357	This study investigated the in vitro and in vivo antitumor effects of trachylobane-360, as well as its cytotoxicity in mouse erythrocytes.	('mouse', 'Species', '10090', (119, 124))	('trachylobane-360', 'Chemical', 'MESH:C572780', (70, 86))	('cytotoxicity', 'Disease', 'MESH:D064420', (103, 115))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('cytotoxicity', 'Disease', (103, 115))	('trachylobane-360', 'Var', (70, 86))
334057	22885357	Leukopenia was observed after 5-FU treatment, but this effect was not seen with trachylobane-360 treatment.	('Leukopenia', 'Disease', 'MESH:D007970', (0, 10))	('5-FU', 'Var', (30, 34))	('Leukopenia', 'Disease', (0, 10))	('trachylobane-360', 'Chemical', 'MESH:C572780', (80, 96))	('5-FU', 'Chemical', '-', (30, 34))	('Leukopenia', 'Phenotype', 'HP:0001882', (0, 10))
334070	22885357	We have previously reported that trachylobane-360 inhibits cell growth and induces differentiation in human leukemia cell lines (HL60, U937 and K562).	('differentiation', 'CPA', (83, 98))	('K562', 'CellLine', 'CVCL:0004', (144, 148))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('leukemia', 'Disease', 'MESH:D007938', (108, 116))	('trachylobane-360', 'Var', (33, 49))	('trachylobane-360', 'Chemical', 'MESH:C572780', (33, 49))	('U937', 'CellLine', 'CVCL:0007', (135, 139))	('leukemia', 'Disease', (108, 116))	('HL60', 'CellLine', 'CVCL:0002', (129, 133))	('inhibits', 'NegReg', (50, 58))	('cell growth', 'CPA', (59, 70))	('induces', 'Reg', (75, 82))	('human', 'Species', '9606', (102, 107))
334071	22885357	Moreover, trachylobane-360 shows weak cytotoxicity against V79 cells and rat hepatocytes.	('trachylobane-360', 'Chemical', 'MESH:C572780', (10, 26))	('trachylobane-360', 'Var', (10, 26))	('cytotoxicity', 'Disease', (38, 50))	('cytotoxicity', 'Disease', 'MESH:D064420', (38, 50))	('rat', 'Species', '10116', (73, 76))
334084	22885357	The present data demonstrate that trachylobane-360 inhibited the proliferation of sarcoma 180 cells in both cytotoxicity assays.	('proliferation', 'CPA', (65, 78))	('rat', 'Species', '10116', (72, 75))	('cytotoxicity', 'Disease', 'MESH:D064420', (108, 120))	('rat', 'Species', '10116', (24, 27))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('trachylobane-360', 'Var', (34, 50))	('cytotoxicity', 'Disease', (108, 120))	('inhibited', 'NegReg', (51, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('trachylobane-360', 'Chemical', 'MESH:C572780', (34, 50))	('sarcoma', 'Disease', (82, 89))
334088	22885357	Comparing these results to the IC50 value obtained for sarcoma 180, trachylobane-360 appears to be more cytotoxic to tumor cells than non neoplastic normal cells.	('trachylobane-360', 'Var', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('sarcoma', 'Disease', (55, 62))	('cytotoxic', 'CPA', (104, 113))	('tumor', 'Disease', (117, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('trachylobane-360', 'Chemical', 'MESH:C572780', (68, 84))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
334090	22885357	showed that trachylobane-360 is more cytotoxic in human leukemia cells (HL60, U937 and K562) than in hepatocytes and V79.	('trachylobane-360', 'Chemical', 'MESH:C572780', (12, 28))	('K562', 'CellLine', 'CVCL:0004', (87, 91))	('HL60', 'CellLine', 'CVCL:0002', (72, 76))	('leukemia', 'Disease', (56, 64))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('leukemia', 'Disease', 'MESH:D007938', (56, 64))	('cytotoxic', 'CPA', (37, 46))	('human', 'Species', '9606', (50, 55))	('U937', 'CellLine', 'CVCL:0007', (78, 82))	('trachylobane-360', 'Var', (12, 28))
334094	22885357	On day 8, the average tumor weight of the control mice inoculated with sarcoma 180 was 2.19 +- 0.17 g. In the presence of trachylobane-360, the sarcoma 180 weight was reduced to 1.19 +- 0.15 and 0.61 +- 0.05 g at doses of 12.5 and 25 mg/kg, respectively.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('trachylobane-360', 'Var', (122, 138))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('sarcoma', 'Disease', (71, 78))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('trachylobane-360', 'Chemical', 'MESH:C572780', (122, 138))	('tumor', 'Disease', (22, 27))	('mice', 'Species', '10090', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('reduced', 'NegReg', (167, 174))
334098	22885357	Trachylobane-360 inhibited tumor growth in vivo in a dose-dependent manner, reducing the weight of the tumor, with no significant difference between the inhibition rate observed with the higher dose (25 mg/kg) of diterpene and that observed with the chemotherapeutic agent 5-FU (Figure 4).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('Trachylobane-360', 'Chemical', 'MESH:C572780', (0, 16))	('tumor', 'Disease', (27, 32))	('Trachylobane-360', 'Var', (0, 16))	('tumor', 'Disease', (103, 108))	('5-FU', 'Chemical', '-', (273, 277))	('diterpene', 'Chemical', 'MESH:D004224', (213, 222))	('inhibited', 'NegReg', (17, 26))	('reducing', 'NegReg', (76, 84))	('rat', 'Species', '10116', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
334108	22885357	No significant changes in body weight gain were seen among the groups treated with trachylobane-360, the control-S180 group and healthy mice.	('mice', 'Species', '10090', (136, 140))	('trachylobane-360', 'Chemical', 'MESH:C572780', (83, 99))	('weight gain', 'Disease', 'MESH:D015430', (31, 42))	('trachylobane-360', 'Var', (83, 99))	('weight gain', 'Phenotype', 'HP:0004324', (31, 42))	('weight gain', 'Disease', (31, 42))
334109	22885357	Meanwhile, animals treated with 5-FU showed weight reduction when compared to control animals.	('5-FU', 'Var', (32, 36))	('reduction', 'NegReg', (51, 60))	('weight', 'CPA', (44, 50))	('5-FU', 'Chemical', '-', (32, 36))
334112	22885357	showed that 5-FU causes apoptosis in different cell types including hepatocytes, thymocytes and splenocytes, which is partially mediated by the CD95 system due to an up-regulation of CD95 and CD95L, causing liver, thymus and spleen involution, which agrees with our results.	('CD95', 'Gene', '14102', (192, 196))	('liver', 'Disease', (207, 212))	('causing', 'Reg', (199, 206))	('up-regulation', 'PosReg', (166, 179))	('5-FU', 'Chemical', '-', (12, 16))	('CD95', 'Gene', '14102', (144, 148))	('CD95', 'Gene', (192, 196))	('CD95L', 'Gene', '14103', (192, 197))	('CD95', 'Gene', '14102', (183, 187))	('apoptosis', 'CPA', (24, 33))	('CD95', 'Gene', (144, 148))	('CD95L', 'Gene', (192, 197))	('5-FU', 'Var', (12, 16))	('CD95', 'Gene', (183, 187))
334114	22885357	Therefore, the data show that trachylobane-360 has no immunostimulant effect, nor does it produce immunosuppression, which is a major side effect of most chemotherapy drugs currently used in clinical practice.	('trachylobane-360', 'Var', (30, 46))	('trachylobane-360', 'Chemical', 'MESH:C572780', (30, 46))	('immunostimulant effect', 'MPA', (54, 76))
334115	22885357	In assessing the effects on the animal's body weight, it was found that there was a significant decrease in weight only in the group treated with 5-FU, which corroborates findings in the literature.	('weight', 'MPA', (108, 114))	('rat', 'Species', '10116', (191, 194))	('5-FU', 'Var', (146, 150))	('decrease', 'NegReg', (96, 104))	('rat', 'Species', '10116', (165, 168))	('decrease in weight', 'Phenotype', 'HP:0004325', (96, 114))	('5-FU', 'Chemical', '-', (146, 150))
334120	22885357	List separately as Table 3, Table 4, Table 5 However, the results show that there was a significant decrease in the red blood cell (RBC) count and hemoglobin level (Hb) in the control-S180 group compared to the healthy mice.	('decrease', 'NegReg', (100, 108))	('control-S180', 'Var', (176, 188))	('rat', 'Species', '10116', (9, 12))	('mice', 'Species', '10090', (219, 223))
334125	22885357	Additionally, animals treated with 5-FU showed an increase in the percentage of lymphocytes compared to the control-S180 group.	('increase', 'PosReg', (50, 58))	('5-FU', 'Var', (35, 39))	('5-FU', 'Chemical', '-', (35, 39))
334136	22885357	However, all hematological parameters after treatment with trachylobane-360 remained unchanged compared to the control-S180 group.	('hematological parameters', 'MPA', (13, 37))	('trachylobane-360', 'Var', (59, 75))	('trachylobane-360', 'Chemical', 'MESH:C572780', (59, 75))
334144	22885357	Animals treated with 5-FU suffered greater liver damage compared to those treated with either dose of trachylobane-360.	('liver damage', 'Disease', (43, 55))	('liver damage', 'Disease', 'MESH:D056486', (43, 55))	('5-FU', 'Chemical', '-', (21, 25))	('trachylobane-360', 'Chemical', 'MESH:C572780', (102, 118))	('5-FU', 'Var', (21, 25))
334191	22885357	In conclusion, the data presented here reinforce the anticancer potential of natural products, since trachylobane-360 caused in vitro and in vivo growth inhibition of tumor cells, without major changes in biochemical, hematological and histopathological parameters.	('growth inhibition', 'CPA', (146, 163))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('trachylobane-360', 'Chemical', 'MESH:C572780', (101, 117))	('cancer', 'Disease', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('trachylobane-360', 'Var', (101, 117))	('tumor', 'Disease', (167, 172))
334291	29509716	Synovial sarcoma is a high-grade soft tissue sarcoma (STS) with three histological subtypes (biphasic, monophasic, and poorly differentiated) that are characterized by variable degree of spindle and epithelial cell differentiation, and by a specific chromosomal translocation t(X:18)(p11:q11).	('sarcoma', 'Disease', (45, 52))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (33, 52))	('STS', 'Phenotype', 'HP:0030448', (54, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('t(X:18)(p11:q11', 'Var', (276, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('t(X:18)(p11:q11)', 'STRUCTURAL_ABNORMALITY', 'None', (276, 292))
334304	29509716	The diagnosis of all cases was confirmed by either typical chromosomal translocation and/or by expert sarcoma pathologists in academic institutions where the cases were submitted for consultation (including Stanford University, Mayo Clinic, Emory University, and Harvard Medical School).	('chromosomal translocation', 'Var', (59, 84))	('Mayo', 'Species', '162683', (228, 232))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
334351	29509716	Consistent with this, our study with 130 cases of early-stage synovial sarcoma showed that tumor size > 5.0 cm was associated with approximately three-fold worse DFS, sarcoma-specific mortality, and all-cause mortality.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (62, 78))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('synovial sarcoma', 'Disease', 'MESH:D013584', (62, 78))	('all-cause mortality', 'CPA', (199, 218))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('sarcoma', 'Disease', (71, 78))	('synovial sarcoma', 'Disease', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('> 5.0 cm', 'Var', (102, 110))	('DFS', 'MPA', (162, 165))	('tumor', 'Disease', (91, 96))	('worse', 'NegReg', (156, 161))	('sarcoma', 'Disease', (167, 174))
334377	28521819	The hypoxia-induced phosphorylation of H2AX to form gamma-H2AX in spheroids is attenuated by the ATM inhibitor KU55933, but not the ATR inhibitor VE-821.	('attenuated', 'NegReg', (79, 89))	('H2AX', 'Gene', (58, 62))	('ATR', 'Gene', '545', (132, 135))	('ATM', 'Gene', '472', (97, 100))	('KU55933', 'Chemical', 'MESH:C495818', (111, 118))	('KU55933', 'Var', (111, 118))	('H2AX', 'Gene', '3014', (39, 43))	('gamma-H2AX', 'Chemical', '-', (52, 62))	('hypoxia', 'Disease', 'MESH:D000860', (4, 11))	('H2AX', 'Gene', (39, 43))	('hypoxia', 'Disease', (4, 11))	('H2AX', 'Gene', '3014', (58, 62))	('ATM', 'Gene', (97, 100))	('VE-821', 'Chemical', 'MESH:C560580', (146, 152))	('ATR', 'Gene', (132, 135))
334404	28521819	Human Ewing Sarcoma A673 (CRL-1598; ATCC, Manassas, VA) and LLC (CRL-1642; ATCC, Manassas, VA); Dulbecco's Modified Eagles Medium, DMEM, (11,965,092; Thermoscientific, Waltham, MA); Fetal Bovine serum - FBS, (TMS-013-B; Millipore, Billerica, MA); Agar (J637; Amresco, Solon, OH); DMSO (67-68-5, Sigma, St. Louis, MO); Proox-p110 ProCO2 Hypoxia Chamber (Biospherix, Parish, NY); Inflatable Glove Bag Model X-37-27 (108D; Glas-Col, Terre Haute, IN); ATM inhibitor KU55933 (S1092; Selleckchem, Houston, TX); ATR inhibitor VE-821 (S8007; Selleckchem, Houston, TX); Click-IT Plus EdU imaging kit (MP10637, Life technologies, Carlsbad, CA).	('Human', 'Species', '9606', (0, 5))	('ATM', 'Gene', (448, 451))	('EdU', 'Chemical', '-', (575, 578))	('KU55933', 'Chemical', 'MESH:C495818', (462, 469))	('DMEM', 'Chemical', '-', (131, 135))	('VE-821', 'Chemical', 'MESH:C560580', (519, 525))	('Hypoxia', 'Disease', 'MESH:D000860', (336, 343))	('Bovine', 'Species', '9913', (188, 194))	('Hypoxia', 'Disease', (336, 343))	("Dulbecco's Modified Eagles Medium", 'Chemical', '-', (96, 129))	('S1092;', 'Var', (471, 477))	('Ewing Sarcoma', 'Disease', (6, 19))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (6, 19))	('ATR', 'Gene', (505, 508))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (6, 19))	('Sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('ATM', 'Gene', '472', (448, 451))	('DMSO', 'Chemical', 'MESH:D004121', (280, 284))	('S8007;', 'Var', (527, 533))	('CO2', 'Chemical', '-', (332, 335))	('ATR', 'Gene', '545', (505, 508))
334405	28521819	The following antibodies were used in these studies: mouse anti-gamma-H2AX (JBW301; Millipore, Billerica, MA), rabbit anti-Ki-67 (MA5-1452; Thermoscientific, Waltham, MA), rabbit anti-cleaved caspase-3 (5A1E; Cell Signaling Technology, Danvers, MA), mouse anti-HIF1-alpha (810,958; BD Biosciences, San Jose, CA), mouse anti-phospho-serine 1981 ATM (05-740; Millipore, Billerica, MA), rabbit anti-phospho-serine 428 ATR (2853P; Cell Signaling Technology, Danvers, MA), mouse anti-pimonidazole (HP1; Hypoxyprobe, Burlington, MA), goat anti-mouse IgG (H + L) Alexa Fluor 647 (A-21235; Thermoscientific, Waltham, MA), goat anti-mouse IgG Cyanine 5 (A-10524; Thermoscientific, Waltham, MA), donkey anti-rabbit Alexa Fluor 594 (A-21027; Thermoscientific, Waltham, MA), rabbit anti-phosphoserine 345 Chk1 (2341; Cell Signaling Technology, Danvers, MA), horse radish peroxidase-conjugated goat anti-mouse (A120-11P; Bethyl, Montgomery, TX), horse radish peroxidase-conjugated goat anti-mouse (A120-201P; Bethyl, Montgomery, TX).	('serine', 'Chemical', 'MESH:D012694', (404, 410))	('mouse', 'Species', '10090', (468, 473))	('mouse', 'Species', '10090', (978, 983))	('serine', 'Chemical', 'MESH:D012694', (332, 338))	('Chk1', 'Gene', (793, 797))	('goat', 'Species', '9925', (614, 618))	('rabbit', 'Species', '9986', (384, 390))	('Chk1', 'Gene', '1111', (793, 797))	('mouse', 'Species', '10090', (538, 543))	('radish', 'Species', '3726', (852, 858))	('goat', 'Species', '9925', (881, 885))	('goat', 'Species', '9925', (968, 972))	('serine', 'Chemical', 'MESH:D012694', (782, 788))	('ATR', 'Gene', '545', (415, 418))	('radish', 'Species', '3726', (939, 945))	('mouse', 'Species', '10090', (53, 58))	('rabbit', 'Species', '9986', (111, 117))	('mouse', 'Species', '10090', (624, 629))	('rabbit', 'Species', '9986', (763, 769))	('mouse', 'Species', '10090', (313, 318))	('ATM', 'Gene', '472', (344, 347))	('Ki-67', 'Chemical', '-', (123, 128))	('horse', 'Species', '9796', (846, 851))	('mouse', 'Species', '10090', (250, 255))	('horse', 'Species', '9796', (933, 938))	('A120-201P;', 'Var', (985, 995))	('rabbit', 'Species', '9986', (698, 704))	('A-21027', 'Var', (722, 729))	('gamma-H2AX', 'Chemical', '-', (64, 74))	('goat', 'Species', '9925', (528, 532))	('pimonidazole', 'Chemical', 'MESH:C033815', (479, 491))	('donkey', 'Species', '9793', (686, 692))	('ATR', 'Gene', (415, 418))	('rabbit', 'Species', '9986', (172, 178))	('ATM', 'Gene', (344, 347))	('mouse', 'Species', '10090', (891, 896))
334426	28521819	10 muM KU55933 or 2.5 muM VE-821 in DMEM supplemented with 2% FBS and containing 0.025% vv-1 DMSO were used.	('muM', 'Gene', '56925', (3, 6))	('VE-821', 'Chemical', 'MESH:C560580', (26, 32))	('muM', 'Gene', (3, 6))	('muM', 'Gene', '56925', (22, 25))	('DMEM', 'Chemical', '-', (36, 40))	('DMSO', 'Chemical', 'MESH:D004121', (93, 97))	('KU55933', 'Chemical', 'MESH:C495818', (7, 14))	('muM', 'Gene', (22, 25))	('KU55933', 'Var', (7, 14))
334436	28521819	In each case cells were seeded in appropriate medium (DMEM +2% FBS for A673, and DMEM +10% FBS for LLC).	('A673', 'Var', (71, 75))	('DMEM', 'Chemical', '-', (81, 85))	('DMEM +10% FBS', 'Var', (81, 94))	('DMEM', 'Chemical', '-', (54, 58))
334441	28521819	A673 and LLC spheroids consisted of uniformly and densely packed cells with onset of necrosis apparent in the center of spheroids that were 550-650 mum in diameter.	('mum', 'Gene', '56925', (148, 151))	('mum', 'Gene', (148, 151))	('necrosis', 'Disease', 'MESH:D009336', (85, 93))	('A673', 'Var', (0, 4))	('necrosis', 'Disease', (85, 93))
334451	28521819	In small (~400-500 mum) A673 spheroids PAS staining was observed sporadically throughout the spheroid, with sometimes a greater concentration near the center.	('A673', 'Var', (24, 28))	('PAS', 'Chemical', 'MESH:D011478', (39, 42))	('mum', 'Gene', '56925', (19, 22))	('mum', 'Gene', (19, 22))
334474	28521819	We were unable to detect either pATR (pSer428) or pChk1 (pSer345) in spheroids.	('pSer428', 'Var', (38, 45))	('ATR', 'Gene', '545', (33, 36))	('ATR', 'Gene', (33, 36))	('pSer345', 'Chemical', '-', (57, 64))	('Chk1', 'Gene', (51, 55))	('pSer428', 'Chemical', '-', (38, 45))	('Chk1', 'Gene', '1111', (51, 55))	('pSer345', 'Var', (57, 64))
334475	28521819	This observation is consistent with compelling evidence that phosphorylation at ATR Ser-428 is not associated with activation of its kinase activity, although Ser-428 phosphorylation has been associated with DNA damage.	('ATR', 'Gene', '545', (80, 83))	('ATR', 'Gene', (80, 83))	('associated', 'Reg', (192, 202))	('Ser-428', 'Var', (159, 166))	('phosphorylation', 'MPA', (167, 182))	('Ser', 'Chemical', 'MESH:D012694', (159, 162))	('Ser', 'Chemical', 'MESH:D012694', (84, 87))	('DNA damage', 'Disease', (208, 218))
334476	28521819	To further evaluate the roles of ATM and ATR in gamma-H2AX formation we used pharmacological inhibitors; KU55933 specific to ATM and VE-821 specific to ATR.	('ATR', 'Gene', (152, 155))	('ATM', 'Gene', (125, 128))	('gamma-H2AX', 'Chemical', '-', (48, 58))	('ATM', 'Gene', (33, 36))	('ATM', 'Gene', '472', (125, 128))	('ATR', 'Gene', '545', (41, 44))	('VE-821', 'Chemical', 'MESH:C560580', (133, 139))	('KU55933', 'Var', (105, 112))	('ATR', 'Gene', (41, 44))	('KU55933', 'Chemical', 'MESH:C495818', (105, 112))	('ATM', 'Gene', '472', (33, 36))	('ATR', 'Gene', '545', (152, 155))
334479	28521819	Both KU55933 and VE-821 treatment inhibited the growth of spheroids.	('growth of spheroids', 'CPA', (48, 67))	('inhibited', 'NegReg', (34, 43))	('VE-821', 'Chemical', 'MESH:C560580', (17, 23))	('KU55933', 'Var', (5, 12))	('KU55933', 'Chemical', 'MESH:C495818', (5, 12))
334480	28521819	After 5 days of treatment with either KU55933 or VE-821 spheroids stopped growing any further (reaching a plateau at an average diameter of 660 mum), while vehicle-treated spheroids typically increased in diameter by about 25% over 5 more days.	('KU55933', 'Chemical', 'MESH:C495818', (38, 45))	('mum', 'Gene', '56925', (144, 147))	('VE-821', 'Var', (49, 55))	('VE-821', 'Chemical', 'MESH:C560580', (49, 55))	('mum', 'Gene', (144, 147))	('KU55933', 'Var', (38, 45))
334484	28521819	Interestingly, while KU55933 had no significant effect on the percentage of Ki-67-positive cells in the spheroids, VE-821 decreased it by over 50% suggesting a strong effect on the proliferative index (Fig.	('VE-821', 'Chemical', 'MESH:C560580', (115, 121))	('proliferative index', 'CPA', (181, 200))	('Ki-67-positive', 'Protein', (76, 90))	('KU55933', 'Var', (21, 28))	('Ki-67', 'Chemical', '-', (76, 81))	('KU55933', 'Chemical', 'MESH:C495818', (21, 28))	('VE-821', 'Var', (115, 121))	('decreased', 'NegReg', (122, 131))
334494	28521819	Control spheroids maintained in vehicle for the 12 h of hypoxia displayed an increase in gamma-H2AX-positive cells, while there was no increase in gamma-H2AX when the spheroids were subject to 1% O2 in the presence of KU55933 (Fig.	('gamma-H2AX', 'Chemical', '-', (89, 99))	('gamma-H2AX-positive', 'Protein', (89, 108))	('gamma-H2AX', 'Chemical', '-', (147, 157))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('KU55933', 'Chemical', 'MESH:C495818', (218, 225))	('increase', 'PosReg', (77, 85))	('KU55933', 'Var', (218, 225))	('hypoxia', 'Disease', (56, 63))	('O2', 'Chemical', 'MESH:D010100', (196, 198))
334506	28521819	In 2D culture, treatment of A673 cells with KU55933 attenuated the hypoxia-induced increase in the percentage of gamma-H2AX-positive cells (Fig.	('hypoxia', 'Disease', (67, 74))	('gamma-H2AX', 'Chemical', '-', (113, 123))	('hypoxia', 'Disease', 'MESH:D000860', (67, 74))	('gamma-H2AX-positive', 'Protein', (113, 132))	('attenuated', 'NegReg', (52, 62))	('KU55933', 'Chemical', 'MESH:C495818', (44, 51))	('KU55933', 'Var', (44, 51))
334549	28521819	The ATR inhibitor VE-821 is also known to decrease the percentage of cells in the S-phase of the cell cycle under normal conditions, and to abrogate the DNA damage-induced checkpoint (G2/M) after irradiation and hypoxia, thus reducing cell survival.	('reducing', 'NegReg', (226, 234))	('hypoxia', 'Disease', (212, 219))	('hypoxia', 'Disease', 'MESH:D000860', (212, 219))	('ATR', 'Gene', '545', (4, 7))	('ATR', 'Gene', (4, 7))	('decrease', 'NegReg', (42, 50))	('VE-821', 'Var', (18, 24))	('abrogate', 'NegReg', (140, 148))	('VE-821', 'Chemical', 'MESH:C560580', (18, 24))	('DNA damage-induced checkpoint', 'MPA', (153, 182))
334550	28521819	This effect is particularly pronounced in p53-deficient cells; the Ewing Sarcoma cell line A673 used herein, contains both the oncogenic transcription factor EWS/FlI1 and mutations in the TP53 gene making them p53-null.	('p53', 'Gene', (42, 45))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('p53', 'Gene', '7157', (210, 213))	('Ewing Sarcoma', 'Disease', (67, 80))	('TP53', 'Gene', '7157', (188, 192))	('p53', 'Gene', '7157', (42, 45))	('Sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('FlI1', 'Gene', (162, 166))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('FlI1', 'Gene', '2313', (162, 166))	('EWS', 'Gene', '2130', (158, 161))	('EWS', 'Gene', (158, 161))	('mutations', 'Var', (171, 180))	('TP53', 'Gene', (188, 192))	('p53', 'Gene', (210, 213))
334571	25500074	PAZ significantly delayed tumor growth by decreasing proliferation and inhibited angiogenesis in all models tested.	('PAZ', 'Var', (0, 3))	('PAZ', 'Chemical', 'MESH:C516667', (0, 3))	('inhibited', 'NegReg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('angiogenesis', 'CPA', (81, 93))	('delayed', 'NegReg', (18, 25))	('proliferation', 'CPA', (53, 66))	('decreasing', 'NegReg', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
334576	25500074	ALT and DDLPS, which are the most common subtypes, are cytogenetically characterized by chromosome 12q amplification leading to mouse double minute 2 homolog (MDM2) and/or cyclin-dependent kinase 4 gene amplification.	('amplification', 'PosReg', (203, 216))	('DDLPS', 'Disease', (8, 13))	('mouse', 'Species', '10090', (128, 133))	('ALT', 'Disease', (0, 3))	('cyclin-dependent kinase 4 gene', 'Gene', (172, 202))	('amplification', 'Var', (103, 116))
334630	25500074	Tumors reached +- 100 mm3 within 2 to 4 months in early passages (p.0 to p.3).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('p.0', 'Var', (66, 69))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p.0', 'SUBSTITUTION', 'None', (66, 69))
334632	25500074	At the end of the 14-day treatment, the tumor volumes in the control group increased nearly five times in UZLX-STS3, four times in UZLX-STS5, and more than two times in SW872.	('UZLX-STS3', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('increased', 'PosReg', (75, 84))	('SW872', 'CellLine', 'CVCL:1730', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
334633	25500074	Although DOX treatment slightly delayed the tumor growth in UZLX-STS3 and UZLX-STS5, the difference in tumor volume compared to untreated controls was significant only in the latter model (P < .005; Table 1 and Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('DOX', 'Chemical', 'MESH:D004317', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('delayed', 'NegReg', (32, 39))	('UZLX-STS5', 'Var', (74, 83))	('tumor', 'Disease', (44, 49))
334635	25500074	Treatment with PAZ as a single agent significantly delayed the tumor growth compared with control animals in all models (P < .005 in SW872 and UZLX-STS3; P < .05 in UZLX-STS5) and DOX-treated groups in UZLX-STS3 and SW872 (P < .005), although it did not cause tumor shrinkage (Table 1 and Figure 2).	('tumor', 'Disease', (260, 265))	('tumor', 'Disease', (63, 68))	('SW872', 'Var', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('DOX', 'Chemical', 'MESH:D004317', (180, 183))	('delayed', 'NegReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PAZ', 'Chemical', 'MESH:C516667', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('SW872', 'CellLine', 'CVCL:1730', (133, 138))	('SW872', 'CellLine', 'CVCL:1730', (216, 221))
334639	25500074	PAZ alone significantly reduced mitotic activity in all the models in comparison with either control or DOX-treated cohorts, but the reduction was most pronounced in SW872 and UZLX-STS3 (P < .005, compared to untreated tumors).	('mitotic activity', 'CPA', (32, 48))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('reduced', 'NegReg', (24, 31))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('PAZ', 'Chemical', 'MESH:C516667', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('SW872', 'CellLine', 'CVCL:1730', (166, 171))	('DOX', 'Chemical', 'MESH:D004317', (104, 107))	('SW872', 'Var', (166, 171))
334655	25500074	Therefore, it was hypothesized by some researchers that acquired growth advantage due to genetic alternations correlated to mouse stromal compartment during engraftment may contribute to the change in the growth rate of the xenograft.	('alternations', 'Var', (97, 109))	('growth', 'MPA', (205, 211))	('mouse', 'Species', '10090', (124, 129))	('genetic alternations', 'Var', (89, 109))	('change', 'Reg', (191, 197))	('growth', 'MPA', (65, 71))
334662	25500074	PAZ delayed tumor growth, although there was no tumor shrinkage observed in any model.	('tumor', 'Disease', (48, 53))	('PAZ', 'Var', (0, 3))	('PAZ', 'Chemical', 'MESH:C516667', (0, 3))	('delayed', 'NegReg', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
334667	25500074	Furthermore, emerging evidence indicates that PAZ does not only inhibit VEGF-induced endothelial cell proliferation in vitro but also blocks angiogenesis in vivo and in patients with STS.	('angiogenesis', 'CPA', (141, 153))	('patients', 'Species', '9606', (169, 177))	('blocks', 'NegReg', (134, 140))	('VEGF', 'Gene', (72, 76))	('inhibit', 'NegReg', (64, 71))	('VEGF', 'Gene', '7422', (72, 76))	('PAZ', 'Var', (46, 49))	('PAZ', 'Chemical', 'MESH:C516667', (46, 49))
334676	25500074	This may partially explain why VEGFR2 expression was remarkably higher in SW872 than those in UZLX-STS3 and UZLX-STS5, in which VEGFR2 may mostly originate from vessels rather than from tumor cells.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('VEGFR2', 'Gene', '3791', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('expression', 'MPA', (38, 48))	('higher', 'PosReg', (64, 70))	('VEGFR2', 'Gene', '3791', (128, 134))	('tumor', 'Disease', (186, 191))	('SW872', 'CellLine', 'CVCL:1730', (74, 79))	('VEGFR2', 'Gene', (31, 37))	('SW872', 'Var', (74, 79))	('VEGFR2', 'Gene', (128, 134))
334684	25500074	In synovial sarcoma cells, PAZ inhibited cell proliferation in vitro through inducing G1 arrest.	('inducing', 'Reg', (77, 85))	('PAZ', 'Var', (27, 30))	('PAZ', 'Chemical', 'MESH:C516667', (27, 30))	('cell proliferation in vitro', 'CPA', (41, 68))	('inhibited', 'NegReg', (31, 40))	('synovial sarcoma', 'Disease', (3, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (3, 19))	('G1 arrest', 'CPA', (86, 95))	('synovial sarcoma', 'Disease', 'MESH:D013584', (3, 19))
334685	25500074	However, PAZ did not cause any effect on cell viability in vitro in rhabdomyosarcoma and bone sarcoma cell lines, although tumor growth delay and inhibition of angiogenesis were observed in vivo .	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (68, 84))	('bone sarcoma', 'Disease', (89, 101))	('growth delay', 'Phenotype', 'HP:0001510', (129, 141))	('angiogenesis', 'CPA', (160, 172))	('inhibition', 'NegReg', (146, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (68, 84))	('tumor growth delay', 'Disease', 'MESH:D006130', (123, 141))	('rhabdomyosarcoma', 'Disease', (68, 84))	('bone sarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('PAZ', 'Var', (9, 12))	('PAZ', 'Chemical', 'MESH:C516667', (9, 12))	('bone sarcoma', 'Disease', 'MESH:D001847', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('tumor growth delay', 'Disease', (123, 141))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
334709	25341037	Using siRNA to knock down SIRT1 and SIRT2, we show that the expression of both proteins is crucial for the survival of rhabdomyosarcoma cells and that the loss of SIRT1 expression results in a decreased LC3II expression.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (119, 135))	('LC3', 'Gene', '84557', (203, 206))	('SIRT1', 'Gene', (163, 168))	('LC3', 'Gene', (203, 206))	('SIRT2', 'Gene', (36, 41))	('loss', 'Var', (155, 159))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (119, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('rhabdomyosarcoma', 'Disease', (119, 135))	('decreased', 'NegReg', (193, 202))	('SIRT2', 'Gene', '22933', (36, 41))
334719	25341037	This was first demonstrated for SIRT1 that deacetylates lysine 382 of the p53 tumor suppressor protein (K382-p53), a post-translational modification that favors p53 degradation.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (78, 83))	('favors', 'PosReg', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lysine 382', 'Var', (56, 66))	('p53 degradation', 'MPA', (161, 176))	('lysine', 'Chemical', 'MESH:D008239', (56, 62))
334721	25341037	SIRT1 relocates at double- and single-strand break sites and deacetylates proteins involved in DNA repair such as Ku70, and the mutant mice have an impaired DNA damage response and are prone to develop tumors.	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('impaired', 'NegReg', (148, 156))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('mutant', 'Var', (128, 134))	('SIRT1', 'Gene', (0, 5))	('DNA damage response', 'MPA', (157, 176))	('mice', 'Species', '10090', (135, 139))	('proteins', 'Protein', (74, 82))	('prone', 'Reg', (185, 190))	('deacetylates', 'MPA', (61, 73))	('develop', 'PosReg', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
334724	25341037	In the present study, we have analyzed the expression and activity of SIRT1 and SIRT2 in the most common pediatric soft tissue sarcomas, rhabdomyosarcoma and synovial sarcoma can be of two histological subtypes; the embryonal subtype (ERMS) is genetically characterized by the loss of the short arm of chromosome 11.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (137, 153))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (115, 135))	('short arm', 'Phenotype', 'HP:0009824', (289, 298))	('synovial sarcoma', 'Disease', 'MESH:D013584', (158, 174))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (115, 134))	('rhabdomyosarcoma', 'Disease', (137, 153))	('SIRT2', 'Gene', '22933', (80, 85))	('synovial sarcoma', 'Disease', (158, 174))	('soft tissue sarcomas', 'Disease', (115, 135))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (137, 153))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (115, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('loss', 'Var', (277, 281))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (158, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('SIRT2', 'Gene', (80, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
334726	25341037	Synovial sarcoma is the second most frequent soft tissue sarcoma (STS) developing in children and young adults, and is genetically characterized by the translocation t(18;X) and subsequent expression of the SS18/SSX fusion gene.	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('SS18', 'Gene', (207, 211))	('SS', 'Phenotype', 'HP:0100242', (212, 214))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('children', 'Species', '9606', (85, 93))	('sarcoma', 'Disease', (9, 16))	('SSX', 'Gene', '6757', (212, 215))	('SS18', 'Gene', '6760', (207, 211))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (45, 64))	('SSX', 'Gene', (212, 215))	('STS', 'Phenotype', 'HP:0030448', (66, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcoma', 'Disease', (57, 64))	('SS', 'Phenotype', 'HP:0100242', (207, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('t(18;X', 'Var', (166, 172))
334742	25341037	These results show that Tv6 induces apoptosis in a dose-dependent manner (Figure 2b).	('Tv6', 'Chemical', 'MESH:C574854', (24, 27))	('apoptosis', 'CPA', (36, 45))	('Tv6', 'Var', (24, 27))
334745	25341037	We verified the p53 status in the cell lines used in this study by sequencing the exon 5-11 of the p53 gene and we confirmed that all synovial sarcomas carry copies of wild-type p53 gene, whereas the alveolar rhabdomyosarcomas RMS and RH carry a mutation in exon 8 of p53 (Table 1).	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (209, 225))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (134, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('mutation in', 'Var', (246, 257))	('p53', 'Gene', (268, 271))	('synovial sarcomas', 'Disease', 'MESH:D013584', (134, 151))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (209, 226))	('synovial sarcomas', 'Disease', (134, 151))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (134, 150))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (200, 226))	('alveolar rhabdomyosarcomas RMS', 'Disease', (200, 230))	('p53', 'Gene', (99, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (218, 226))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (200, 225))	('alveolar rhabdomyosarcomas RMS', 'Disease', 'MESH:D018232', (200, 230))
334746	25341037	The embryonal rhabdomysarcoma cell line RD carries a mutated p53 gene as reported.	('embryonal rhabdomysarcoma', 'Disease', (4, 29))	('mutated', 'Var', (53, 60))	('embryonal rhabdomysarcoma', 'Disease', 'MESH:D009373', (4, 29))	('RD', 'Phenotype', 'HP:0002859', (40, 42))	('p53', 'Gene', (61, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('embryonal rhabdomysarcoma', 'Phenotype', 'HP:0006743', (4, 29))
334747	25341037	Cell lines were exposed to Tv6 (2 muM) for 6 and 24 h, and the acetylation of K382-p53 was evaluated.	('muM', 'Gene', '56925', (34, 37))	('Tv6', 'Chemical', 'MESH:C574854', (27, 30))	('muM', 'Gene', (34, 37))	('K382-p53', 'Var', (78, 86))	('acetylation', 'MPA', (63, 74))
334748	25341037	Tv6 did not induce any change on SIRT1, SIRT2, p53 or K382-p53 expression in both cells with wild-type or mutant p53.	('SIRT2', 'Gene', '22933', (40, 45))	('mutant', 'Var', (106, 112))	('Tv6', 'Chemical', 'MESH:C574854', (0, 3))	('SIRT2', 'Gene', (40, 45))	('p53', 'Gene', (113, 116))
334754	25341037	However, with the exception of RMS, sirtuin activity in either cytoplasmic or/and nuclear extracts was decreased in all cell lines exposed to Tv6.	('Tv6', 'Chemical', 'MESH:C574854', (142, 145))	('decreased', 'NegReg', (103, 112))	('sirtuin activity', 'MPA', (36, 52))	('Tv6', 'Var', (142, 145))
334759	25341037	First, we looked at the expression of the autophagy-associated protein LC3I and its conversion to the autophagosomal form LC3-II and observed that Tv6 induced a time-dependent accumulation of LC3-II in all cell lines indicating autophagosome accumulation (data not shown).	('LC3', 'Gene', '84557', (192, 195))	('LC3', 'Gene', (192, 195))	('autophagosome accumulation', 'CPA', (228, 254))	('Tv6', 'Chemical', 'MESH:C574854', (147, 150))	('LC3', 'Gene', (122, 125))	('Tv6', 'Var', (147, 150))	('accumulation', 'PosReg', (176, 188))	('LC3', 'Gene', '84557', (71, 74))	('LC3', 'Gene', (71, 74))	('LC3', 'Gene', '84557', (122, 125))
334781	25341037	To investigate a possible association between SIRT1 or SIRT2 expression and autophagy, we determined the expression of the autophagy-associated proteins LC3II and p62 in SIRT1 and SIRT2 knocked down cells.	('knocked', 'Var', (186, 193))	('SIRT2', 'Gene', '22933', (180, 185))	('SIRT2', 'Gene', '22933', (55, 60))	('p62', 'Gene', '8878', (163, 166))	('LC3', 'Gene', '84557', (153, 156))	('p62', 'Gene', (163, 166))	('SIRT2', 'Gene', (180, 185))	('LC3', 'Gene', (153, 156))	('SIRT2', 'Gene', (55, 60))
334782	25341037	Figure 7c shows that LC3 expression was decreased in SIRT1 knockdown cells, suggesting an association between SIRT1 and autophagy.	('LC3', 'Gene', '84557', (21, 24))	('LC3', 'Gene', (21, 24))	('SIRT1', 'Gene', (53, 58))	('expression', 'MPA', (25, 35))	('association', 'Interaction', (90, 101))	('knockdown', 'Var', (59, 68))	('autophagy', 'CPA', (120, 129))	('decreased', 'NegReg', (40, 49))
334795	25341037	Similarly, other reports have shown that SIRT1 is overexpressed in malignant epithelial tumors, breast cancer, prostate tumors, soft tissue sarcomas, cutaneous T-cell lymphomas and melanoma, and high SIRT1 expression is associated with poor prognosis in diffuse B-cell lymphomas, ovarian and breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (292, 306))	('ovarian and breast cancers', 'Disease', 'MESH:D010051', (280, 306))	('soft tissue sarcomas', 'Disease', (128, 148))	('lymphomas', 'Disease', 'MESH:D008223', (269, 278))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (160, 176))	('overexpressed', 'PosReg', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('breast cancer', 'Disease', (96, 109))	('lymphomas', 'Disease', (167, 176))	('cutaneous T-cell lymphomas', 'Disease', 'MESH:D016410', (150, 176))	('lymphomas', 'Phenotype', 'HP:0002665', (269, 278))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (128, 148))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (128, 147))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (128, 148))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('breast cancer', 'Disease', (292, 305))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanoma', 'Disease', (181, 189))	('prostate tumors', 'Disease', (111, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('SIRT1', 'Gene', (200, 205))	('lymphomas', 'Disease', (269, 278))	('expression', 'MPA', (206, 216))	('prostate tumors', 'Disease', 'MESH:D011471', (111, 126))	('high', 'Var', (195, 199))	('lymphomas', 'Disease', 'MESH:D008223', (167, 176))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('SIRT1', 'Gene', (41, 46))	('lymphomas', 'Phenotype', 'HP:0002665', (167, 176))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (262, 278))	('malignant epithelial tumors', 'Phenotype', 'HP:0031492', (67, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cutaneous T-cell lymphomas', 'Phenotype', 'HP:0012192', (150, 176))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('malignant epithelial tumors', 'Disease', (67, 94))	('cutaneous T-cell lymphomas', 'Disease', (150, 176))	('malignant epithelial tumors', 'Disease', 'MESH:D002277', (67, 94))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))
334799	25341037	As this drug inhibits SIRT1 from deacetylating p53 at K382 in several tumor cells stabilizing p53 expression and reactivating its apoptotic function, we hypothesized that acetylation of K382-p53 could be as well compromised in Tv6-treated sarcoma cells; however, we found that the antiproliferative effect of Tv6 was independent of the p53 gene status (wild type or mutated), K382-p53 acetylation or apoptotic function.	('K382-p53', 'Var', (376, 384))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('sarcoma', 'Disease', 'MESH:D012509', (239, 246))	('Tv6', 'Chemical', 'MESH:C574854', (309, 312))	('tumor', 'Disease', (70, 75))	('antiproliferative', 'MPA', (281, 298))	('Tv6', 'Chemical', 'MESH:C574854', (227, 230))	('sarcoma', 'Disease', (239, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('inhibits', 'NegReg', (13, 21))
334815	25341037	Both methods showed that Tv6 induces a clear accumulation of autophagosomes.	('Tv6', 'Var', (25, 28))	('Tv6', 'Chemical', 'MESH:C574854', (25, 28))	('accumulation', 'PosReg', (45, 57))	('autophagosomes', 'CPA', (61, 75))
334816	25341037	Similarly, McCallum and colleagues have reported that Tv6 dysregulates autophagy in CLL cells, although the association of autophagy with sirtuin activity was not investigated in this study.	('CLL', 'Phenotype', 'HP:0005550', (84, 87))	('dysregulates', 'Var', (58, 70))	('autophagy', 'CPA', (71, 80))	('Tv6', 'Chemical', 'MESH:C574854', (54, 57))	('Tv6', 'Gene', (54, 57))
334819	25341037	Consistently, sirtuin inhibition studies with agents such as sirtinol, EX-527 and with siRNA have shown that SIRT1 inhibition impairs autophagy.	('sirtinol', 'Chemical', 'MESH:C439060', (61, 69))	('impairs', 'NegReg', (126, 133))	('SIRT1', 'Gene', (109, 114))	('inhibition', 'Var', (115, 125))	('autophagy', 'CPA', (134, 143))
334821	25341037	In our study, autophagic cell death induced by sirtuin inhibition was enhanced in nutrient-deprived conditions, and the proliferation of SIRT1 and SIRT2 knockdown cells was only evident after 2 days in culture, a time point in which nutrient availability is limited in the culture media.	('knockdown', 'Var', (153, 162))	('sirtuin', 'Gene', (47, 54))	('autophagic cell death', 'CPA', (14, 35))	('SIRT2', 'Gene', '22933', (147, 152))	('enhanced', 'PosReg', (70, 78))	('SIRT2', 'Gene', (147, 152))	('SIRT1', 'Gene', (137, 142))	('inhibition', 'NegReg', (55, 65))
334823	25341037	Using siRNA to knock down SIRT1 and SIRT2 expression, we demonstrated that SIRT1 and SIRT2 expression is crucial for the survival of sarcoma cells.	('SIRT2', 'Gene', '22933', (85, 90))	('knock', 'Var', (15, 20))	('SIRT2', 'Gene', (36, 41))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('SIRT2', 'Gene', (85, 90))	('sarcoma', 'Disease', (133, 140))	('SIRT2', 'Gene', '22933', (36, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
334824	25341037	We also showed that SIRT1-siRNA knocked out cells had a decreased expression of LC3-II, adding support to the association between SIRT1 and autophagy and suggesting that acetylation of the autophagy-related proteins such as atg 5, atg7 or atg8 could be affected as a consequence of SIRT1 inhibition with Tv6.	('acetylation', 'MPA', (170, 181))	('atg8', 'Gene', (239, 243))	('atg7', 'Gene', (231, 235))	('atg8', 'Gene', '23710', (239, 243))	('decreased', 'NegReg', (56, 65))	('inhibition', 'NegReg', (288, 298))	('association', 'Interaction', (110, 121))	('knocked out', 'Var', (32, 43))	('expression', 'MPA', (66, 76))	('LC3', 'Gene', '84557', (80, 83))	('LC3', 'Gene', (80, 83))	('Tv6', 'Chemical', 'MESH:C574854', (304, 307))	('autophagy', 'CPA', (140, 149))	('atg7', 'Gene', '10533', (231, 235))
334841	25341037	After blocking in 5% BSA (Sigma-Aldrich), the membranes were incubated overnight at 4  C with the primary antibodies: p53 DO1 (Calbiochem, Darmstadt, Germany), Acetyl K382p53 (Cell Signaling Technology, Danvers, MA, USA), beta-actin, SirT1 and sirT2 (Atlas Antibodies, Stockhom, Sweden), LC3-II and p62 (Cell Signaling Technology).	('p53', 'Var', (118, 121))	('sirT2', 'Gene', '22933', (244, 249))	('beta-actin', 'Gene', '728378', (222, 232))	('p62', 'Gene', '8878', (299, 302))	('beta-actin', 'Gene', (222, 232))	('LC3', 'Gene', (288, 291))	('p62', 'Gene', (299, 302))	('SirT1', 'Gene', (234, 239))	('LC3', 'Gene', '84557', (288, 291))	('sirT2', 'Gene', (244, 249))	('SirT1', 'Gene', '23411', (234, 239))
334843	25341037	Gene expression analysis was performed in quadruplicates of each sample in a total volume of 20 mul using TaqMan probes: hs01009005(SIRT1) and hs00247263(SIRT2) (TaqMan, Life Technologies).	('hs00247263', 'Var', (143, 153))	('hs01009005', 'Var', (121, 131))	('SIRT2', 'Gene', (154, 159))	('SIRT2', 'Gene', '22933', (154, 159))
334851	25341037	HRP-conjugated anti-rabbit (NA934V), and anti-mouse (NXA931) antibodies, ECL system (RPN2106) were from GE Healthcare (Pittsburgh, PA, USA).	('RPN2106', 'CellLine', 'CVCL:N283', (85, 92))	('mouse', 'Species', '10090', (46, 51))	('rabbit', 'Species', '9986', (20, 26))	('NA934V', 'Var', (28, 34))	('NXA931', 'Gene', (53, 59))
334887	21544244	Although some of the transcriptional repression mediated by LANA occurs indirectly via interactions with corepressors including mSin3, SAP30, CIR, the methyl CpG-binding protein MeCP2, or the histone methyltransferase SUV39H1, this viral protein inhibits TGF-beta signaling through epigenetic silencing of the TGF-beta typealphareceptor.	('SAP30', 'Gene', (135, 140))	('CIR', 'Gene', (142, 145))	('LANA', 'Gene', (60, 64))	('MeCP2', 'Gene', '4204', (178, 183))	('TGF-beta', 'Gene', '7040', (310, 318))	('LANA', 'Gene', '4961527', (60, 64))	('interactions', 'Interaction', (87, 99))	('TGF-beta', 'Gene', (310, 318))	('MeCP2', 'Gene', (178, 183))	('SAP30', 'Gene', '8819', (135, 140))	('epigenetic silencing', 'Var', (282, 302))	('SUV39H1', 'Gene', (218, 225))	('SUV39H1', 'Gene', '6839', (218, 225))	('TGF-beta', 'Gene', '7040', (255, 263))	('transcriptional', 'MPA', (21, 36))	('inhibits', 'NegReg', (246, 254))	('TGF-beta', 'Gene', (255, 263))	('CIR', 'Gene', '9541', (142, 145))
334915	21544244	To investigate the regulation of IL-22R1 gene expression, a reporter plasmid (pIL22R1) was constructed by cloning the putative wide-type IL-22R1 promoter including the 5' untranslated region (-2139 to +39, with +1 being the transcription initiation site) and inserting it upstream of the luciferase gene in the promoterless pGL3-basic vector.	('IL-22R1', 'Gene', '58985', (33, 40))	('IL-22R1', 'Gene', (137, 144))	('-2139', 'Var', (192, 197))	('IL-22R1', 'Gene', '58985', (137, 144))	('pGL3', 'Gene', (324, 328))	('IL22R1', 'Gene', (79, 85))	('IL22R1', 'Gene', '58985', (79, 85))	('pGL3', 'Gene', '6391', (324, 328))	('IL-22R1', 'Gene', (33, 40))
334922	21544244	To test more possibilities in transcription regulation, we used a longer reporter, pIL22R1 (-2139 to +39), to do the following experiments.	('IL22R1', 'Gene', '58985', (84, 90))	('IL22R1', 'Gene', (84, 90))	('-2139', 'Var', (92, 97))
334932	21544244	To confirm our hypothesis, we deleted nucleotides -64 to -51 from the pIL22R1 to construct pIL22R1DeltaLBS-like (-64 to -51), and introduced substitution mutations in the LBS-like sequence to construct pIL22R1-mLBS-like (Figure 3A).	('LBS', 'Chemical', '-', (171, 174))	('LBS', 'Chemical', '-', (103, 106))	('IL22R1', 'Gene', (203, 209))	('IL22R1', 'Gene', '58985', (203, 209))	('LBS', 'Chemical', '-', (211, 214))	('IL22R1', 'Gene', (71, 77))	('IL22R1', 'Gene', '58985', (71, 77))	('IL22R1', 'Gene', (92, 98))	('IL22R1', 'Gene', '58985', (92, 98))	('substitution mutations', 'Var', (141, 163))
334943	21544244	However, the LANA-C protein did not bind the negative control, a DNA fragment from M13 DNA or the probe bearing mutants in the LBS-like sequence (Figure 4B, lanes 4 and 8).	('LANA', 'Gene', '4961527', (13, 17))	('LANA', 'Gene', (13, 17))	('LBS', 'Chemical', '-', (127, 130))	('mutants', 'Var', (112, 119))
334974	21544244	Meanwhile, when the LBS-like region was mutated, the ability of LANA to down-regulate IL-22R1 was dramatically reduced.	('IL-22R1', 'Gene', (86, 93))	('LANA', 'Gene', (64, 68))	('LANA', 'Gene', '4961527', (64, 68))	('IL-22R1', 'Gene', '58985', (86, 93))	('reduced', 'NegReg', (111, 118))	('down-regulate', 'NegReg', (72, 85))	('mutated', 'Var', (40, 47))	('LBS', 'Chemical', '-', (20, 23))
334996	21544244	We also hypothesize that low expression level of IL-22R1 exacerbates KS pathogenesis.	('IL-22R1', 'Gene', (49, 56))	('KS', 'Phenotype', 'HP:0100726', (69, 71))	('low expression', 'Var', (25, 39))	('exacerbates', 'PosReg', (57, 68))	('IL-22R1', 'Gene', '58985', (49, 56))
335068	33072594	The fusion genes and proteins are mostly tumor-promoting and serve as diagnostic factors in the differential diagnosis in tumors such as synovial sarcoma.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('synovial sarcoma', 'Disease', (137, 153))	('tumor', 'Disease', (41, 46))	('fusion genes', 'Var', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (137, 153))	('synovial sarcoma', 'Disease', 'MESH:D013584', (137, 153))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('proteins', 'Protein', (21, 29))	('tumor', 'Disease', (122, 127))
335070	33072594	Both gene copy number gain and loss are detected in different cancer types.	('loss', 'NegReg', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('copy number gain', 'Var', (10, 26))
335071	33072594	For example, tumor suppressor genes such as TP53 and RB1 are found mutated while amplification of MDM2, CKD4 are detected in various sarcoma types.	('RB1', 'Gene', '5925', (53, 56))	('tumor', 'Disease', (13, 18))	('CKD4', 'Gene', (104, 108))	('MDM2', 'Gene', '4193', (98, 102))	('MDM2', 'Gene', (98, 102))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('mutated', 'Var', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('RB1', 'Gene', (53, 56))	('TP53', 'Gene', '7157', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('sarcoma', 'Disease', (133, 140))	('TP53', 'Gene', (44, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
335074	33072594	More importantly, the loss of SMARCB1/INI1 leads to the deregulation of EZH2, and drugs targeting EZH2 have been proven successful in controlling tumor growth and are currently approved to be used in treating epithelioid sarcoma.	('deregulation', 'MPA', (56, 68))	('EZH2', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('SMARCB1', 'Gene', '6598', (30, 37))	('tumor', 'Disease', (146, 151))	('SMARCB1', 'Gene', (30, 37))	('INI1', 'Gene', '6598', (38, 42))	('EZH2', 'Gene', '2146', (72, 76))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (209, 228))	('INI1', 'Gene', (38, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('EZH2', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('epithelioid sarcoma', 'Disease', (209, 228))	('loss', 'Var', (22, 26))	('EZH2', 'Gene', '2146', (98, 102))
335139	31686912	By analyzing the specificity and sensitivity of each value, the optimal cutoff values of NLR, PLR, MLR, SII, LDH and ALP were taken as 5.22, 154, 0.38, 1048.5, 184 and 89.5, respectively.	('ALP', 'Gene', (117, 120))	('0.38', 'Var', (146, 150))	('1048.5', 'Var', (152, 158))	('ALP', 'Gene', '470', (117, 120))
335144	31686912	The tumor size served as another potential predictor for poor prognosis with a median survival of 16.3 months in tumors >=5 cm vs 31.5 months in tumors <5 cm.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('>=5 cm', 'Var', (120, 126))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
335216	30030882	On MVA (Table 1 for NCDB analysis and Table 2 for SEER analysis), amputation had significantly inferior OS compared to LSS alone (hazard ratio [HR], 1.31; 95% confidence interval [CI]: 1.13-1.51 for NCDB and HR, 1.59; 95% CI: 1.24-2.04 for SEER).	('inferior', 'NegReg', (95, 103))	('amputation', 'Var', (66, 76))	('OS', 'Chemical', '-', (104, 106))
335217	30030882	SM was also increased with amputation in the SEER analysis (HR, 1.52; 95% CI: 1.12-2.07).	('amputation', 'Var', (27, 37))	('SM', 'Chemical', '-', (0, 2))	('increased', 'PosReg', (12, 21))
335244	30030882	No significant difference in OS was seen between pre-RT vs post-RT in two SEER studies.10, 11 An NCDB study showed improved rates of negative surgical margins in patients receiving preoperative RT compared to postoperative RT; however, survival between these two treatment strategies was not directly compared.9 In contrast, a study of the National Oncology Database showed a significant OS and cause-specific survival benefit to preoperative RT compared to postoperative RT.	('patients', 'Species', '9606', (162, 170))	('preoperative RT', 'Var', (430, 445))	('benefit', 'PosReg', (419, 426))	('Oncology', 'Phenotype', 'HP:0002664', (349, 357))	('OS', 'Chemical', '-', (29, 31))	('OS', 'Chemical', '-', (388, 390))
335576	24472748	We have recently reported that transcutaneous application of carbon dioxide (CO2) increases mitochondrial biogenesis in skeletal muscle and that CO2 therapy induces mitochondrial apoptosis with mitochondrial proliferation via PGC-1alpha expression in human malignant fibrous histiocytoma (MFH).	('mitochondrial biogenesis', 'MPA', (92, 116))	('carbon dioxide', 'Chemical', 'MESH:D002245', (61, 75))	('mitochondrial proliferation', 'CPA', (194, 221))	('induces', 'Reg', (157, 164))	('human', 'Species', '9606', (251, 256))	('mitochondrial apoptosis', 'CPA', (165, 188))	('PGC-1alpha', 'Gene', (226, 236))	('CO2', 'Chemical', 'MESH:D002245', (145, 148))	('increases', 'PosReg', (82, 91))	('malignant fibrous histiocytoma', 'Disease', (257, 287))	('histiocytoma', 'Phenotype', 'HP:0012315', (275, 287))	('malignant fibrous histiocytoma', 'Disease', 'MESH:D051677', (257, 287))	('CO2', 'Chemical', 'MESH:D002245', (77, 80))	('CO2', 'Var', (145, 148))
335591	24472748	In sarcoma cell lines, Nara-H, TNMY-1, KTHOS and MG-63, transfection with PGC-1alpha plasmid/control siRNA strongly increased the number of apoptotic cells, along with an increase in mitochondrial proliferation (Fig.	('increased', 'PosReg', (116, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('mitochondrial proliferation', 'CPA', (183, 210))	('Nara-H', 'CellLine', 'CVCL:W998', (23, 29))	('sarcoma', 'Disease', 'MESH:D012509', (3, 10))	('MG-63', 'Chemical', '-', (49, 54))	('transfection', 'Var', (56, 68))	('increase', 'PosReg', (171, 179))	('sarcoma', 'Disease', (3, 10))
335601	24472748	The results indicated that increasing mitochondrial numbers by PGC-1alpha overexpression could induce mitochondrial apoptosis in human sarcoma cells.	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('mitochondrial apoptosis', 'CPA', (102, 125))	('mitochondrial numbers', 'MPA', (38, 59))	('increasing', 'PosReg', (27, 37))	('sarcoma', 'Disease', (135, 142))	('human', 'Species', '9606', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('PGC-1alpha', 'Gene', (63, 73))	('increasing mitochondrial numbers', 'Phenotype', 'HP:0040014', (27, 59))	('induce', 'PosReg', (95, 101))	('overexpression', 'Var', (74, 88))
335609	24472748	Mutations in the D-loop region are very common in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
335627	24472748	It has also been reported that mitochondrial amplification selectively increased sensitivity to doxorubicin in antiestrogen-resistant breast cancer cells.	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mitochondrial amplification', 'Var', (31, 58))	('sensitivity to doxorubicin', 'MPA', (81, 107))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('increased', 'PosReg', (71, 80))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
335634	24472748	In conclusion, we observed a decrease in mitochondrial biogenesis in human malignant musculoskeletal tumors and that increasing mitochondrial numbers by PGC-1alpha overexpression induced cell apoptosis in human sarcoma cell lines, but not in normal chondrocytes.	('overexpression', 'Var', (164, 178))	('cell apoptosis', 'CPA', (187, 201))	('malignant musculoskeletal tumors', 'Disease', (75, 107))	('decrease', 'NegReg', (29, 37))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('mitochondrial biogenesis', 'MPA', (41, 65))	('increasing mitochondrial numbers', 'Phenotype', 'HP:0040014', (117, 149))	('sarcoma', 'Disease', (211, 218))	('human', 'Species', '9606', (69, 74))	('malignant musculoskeletal tumors', 'Disease', 'MESH:D009140', (75, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('mitochondrial numbers', 'MPA', (128, 149))	('increasing', 'PosReg', (117, 127))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('human', 'Species', '9606', (205, 210))	('PGC-1alpha', 'Gene', (153, 163))
335671	30627328	Analysis of mutations in primary and metastatic synovial sarcoma Synovial sarcoma is the most common pediatric non-rhabdomyosarcoma soft tissue sarcoma and accounts for about 8-10% of all soft tissue sarcoma in childhood and adolescence.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (65, 81))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('sarcoma', 'Disease', (124, 131))	('primary and', 'Disease', (25, 36))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (115, 131))	('synovial sarcoma', 'Disease', (48, 64))	('synovial sarcoma', 'Disease', 'MESH:D013584', (48, 64))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (188, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('sarcoma', 'Disease', (74, 81))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (132, 151))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (48, 64))	('non-rhabdomyosarcoma soft tissue sarcoma', 'Disease', (111, 151))	('non-rhabdomyosarcoma soft tissue sarcoma', 'Disease', 'MESH:D012509', (111, 151))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('mutations', 'Var', (12, 21))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('sarcoma', 'Disease', (200, 207))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('sarcoma', 'Disease', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
335672	30627328	The presence of a chromosomal translocation-associated SS18-SSX-fusion gene is causally linked to development of primary synovial sarcoma.	('primary synovial sarcoma', 'Disease', 'MESH:D013584', (113, 137))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (121, 137))	('SSX', 'Gene', '6757', (60, 63))	('SS', 'Phenotype', 'HP:0012570', (60, 62))	('SSX', 'Gene', (60, 63))	('linked to', 'Reg', (88, 97))	('primary synovial sarcoma', 'Disease', (113, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('SS', 'Phenotype', 'HP:0012570', (55, 57))	('presence', 'Var', (4, 12))
335675	30627328	Selected from the candidates yielded from this effort, we examined the effect of the multiple missense mutations of ADAM17, which were identified solely in metastatic synovial sarcoma.	('synovial sarcoma', 'Disease', (167, 183))	('ADAM17', 'Gene', (116, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (167, 183))	('synovial sarcoma', 'Disease', 'MESH:D013584', (167, 183))	('missense mutations', 'Var', (94, 112))
335677	30627328	The ADAM17-P729H mutation was shown to enhance cell migration, a phenotype associated with metastasis.	('enhance', 'PosReg', (39, 46))	('P729H', 'Mutation', 'rs768949233', (11, 16))	('cell migration', 'CPA', (47, 61))	('ADAM17-P729H', 'Var', (4, 16))	('rat', 'Species', '10116', (55, 58))
335682	30627328	At the genetic level, primary SS is associated with translocations between human chromosome 18 and X, t(X;18) (p11.2;q11.2), which may result in fusions between exon 10 of SS18 and exon 6 of SSX.	('SSX', 'Gene', '6757', (191, 194))	('translocations', 'Var', (52, 66))	('primary SS', 'Disease', (22, 32))	('SSX', 'Gene', (191, 194))	('result in', 'Reg', (135, 144))	('human', 'Species', '9606', (75, 80))	('p11', 'Gene', '6281', (111, 114))	('SS', 'Phenotype', 'HP:0012570', (30, 32))	('SS', 'Phenotype', 'HP:0012570', (191, 193))	('associated', 'Reg', (36, 46))	('SS', 'Phenotype', 'HP:0012570', (172, 174))	('p11', 'Gene', (111, 114))	('fusions', 'Var', (145, 152))	('SS18', 'Gene', (172, 176))
335691	30627328	Such efforts have identified differential mutational profiles between primary and metastatic tumors for lung cancer, breast cancer, hepatocellular carcinoma, colorectal cancer, and non-melanoma skin cancer, laying the ground for uncovering potential biomarkers and drivers for tumor progression and metastasis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('tumors for lung cancer', 'Disease', (93, 115))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (181, 205))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (132, 156))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('mutational', 'Var', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (132, 156))	('non-melanoma skin cancer', 'Disease', (181, 205))	('breast cancer', 'Disease', (117, 130))	('tumors for lung cancer', 'Disease', 'MESH:D008175', (93, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('skin cancer', 'Phenotype', 'HP:0008069', (194, 205))	('colorectal cancer', 'Disease', (158, 175))	('hepatocellular carcinoma', 'Disease', (132, 156))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
335698	30627328	This approach of studying multiple segments of the same tumor or multiple tumors from the same patient facilitates identification of driver mutations.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('patient', 'Species', '9606', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('multiple tumors', 'Disease', 'MESH:D009369', (65, 80))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('multiple tumors', 'Disease', (65, 80))	('facilitates', 'PosReg', (103, 114))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
335700	30627328	Among the genes with the mutations identified (Supplementary Table 1), they include Cancer Gene Census genes and other cancer-associated genes with three of which carried multiple mutations (ARID1B, CSMD1 and ADAM17) (Table 1).	('mutations', 'Var', (25, 34))	('Cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('ARID1B', 'Gene', (191, 197))	('cancer', 'Disease', (119, 125))	('ADAM17', 'Gene', (209, 215))	('CSMD1', 'Gene', (199, 204))	('CSMD1', 'Gene', '64478', (199, 204))	('ARID1B', 'Gene', '57492', (191, 197))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('Cancer', 'Disease', (84, 90))
335701	30627328	Importantly, a significant number of the mutations were detected solely in the metastatic SS (Table 1 and Supplementary Table 1), which include the missense mutations in ADAM17, ADAM17-P729H (nt: C2186A) and ADAM17-K805T (nt: A2414C) detected in Samples SARC5001 and SARC5003, respectively (Table 1 and Supplementary Table 1).	('ADAM17', 'Gene', (170, 176))	('C2186A', 'Mutation', 'rs768949233', (196, 202))	('A2414C', 'Mutation', 'c.2414A>C', (226, 232))	('P729H', 'Mutation', 'rs768949233', (185, 190))	('SS', 'Phenotype', 'HP:0012570', (90, 92))	('K805T', 'Mutation', 'p.K805T', (215, 220))	('ADAM17-K805T', 'Var', (208, 220))
335702	30627328	Our data showed these ADAM17 mutations were present in six separate foci of metastatic tumors in two patients with each mutation from three foci in each patient (Figure 1; Supplementary Table 1).	('patients', 'Species', '9606', (101, 109))	('rat', 'Species', '10116', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutations', 'Var', (29, 38))	('ADAM17', 'Gene', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('patient', 'Species', '9606', (153, 160))	('patient', 'Species', '9606', (101, 108))	('present', 'Reg', (44, 51))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
335703	30627328	Because ADAM17 has been extensively implicated in metastasis and its mutations detected in our multiple metastatic SS samples in different patients, but not in primary SS (Table 1), we decided to choose ADAM17-P729H and ADAM17-K805T in our first attempt to reveal the potential impacts of the mutations identified solely in metastatic SS.	('ADAM17-P729H', 'Var', (203, 215))	('patients', 'Species', '9606', (139, 147))	('K805T', 'Mutation', 'p.K805T', (227, 232))	('ADAM17', 'Gene', (8, 14))	('SS', 'Phenotype', 'HP:0012570', (115, 117))	('SS', 'Phenotype', 'HP:0012570', (335, 337))	('implicated', 'Reg', (36, 46))	('ADAM17-K805T', 'Var', (220, 232))	('SS', 'Phenotype', 'HP:0012570', (168, 170))	('P729H', 'Mutation', 'rs768949233', (210, 215))
335706	30627328	ADAM17-P729H and ADAM17-K805T mutations were introduced through GeneArt Site-Directed Mutagenesis System (Invitrogen).	('K805T', 'Mutation', 'p.K805T', (24, 29))	('P729H', 'Mutation', 'rs768949233', (7, 12))	('ADAM17-P729H', 'Var', (0, 12))	('ADAM17-K805T', 'Var', (17, 29))
335707	30627328	The mutated ADAM17 and the wild-type ADAM17 full-length cDNA were then individually inserted into KpnI and ApaI sites of pcDNA3.1-Puro+ expression vector to generate the expression vectors pcDNA3.1-ADAM17-P729H and pCDNA3.1-ADAM17-K805T (Figure 2), in addition to the control vector pcDNA3.1-ADAM17-WT.	('pcDNA3.1-ADAM17-P729H', 'Var', (189, 210))	('P729H', 'Mutation', 'rs768949233', (205, 210))	('K805T', 'Mutation', 'p.K805T', (231, 236))	('pCDNA3.1-ADAM17-K805T', 'Var', (215, 236))	('rat', 'Species', '10116', (161, 164))	('expression', 'Species', '29278', (170, 180))	('expression', 'Species', '29278', (136, 146))	('expression vectors', 'Species', '29278', (170, 188))
335710	30627328	It has been established that the presence of either translocation-associated SS18-SSX1- or SS18-SSX2 is causally linked to development of primary synovial sarcoma.	('primary synovial sarcoma', 'Disease', (138, 162))	('translocation-associated', 'Var', (52, 76))	('SS', 'Phenotype', 'HP:0012570', (77, 79))	('SS', 'Phenotype', 'HP:0012570', (91, 93))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (146, 162))	('SS18-SSX1-', 'Gene', (77, 87))	('SS', 'Phenotype', 'HP:0012570', (82, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('presence', 'Var', (33, 41))	('primary synovial sarcoma', 'Disease', 'MESH:D013584', (138, 162))	('SSX2', 'Gene', '6757', (96, 100))	('SS', 'Phenotype', 'HP:0012570', (96, 98))	('linked to', 'Reg', (113, 122))	('SSX2', 'Gene', (96, 100))
335711	30627328	In addition, it has been shown that the expression of either SS18-SSX1 or SS18-SSX2 is sufficient to result in formation of synovial sarcoma in mouse models.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (124, 140))	('mouse', 'Species', '10090', (144, 149))	('expression', 'Species', '29278', (40, 50))	('synovial sarcoma', 'Disease', 'MESH:D013584', (124, 140))	('SS', 'Phenotype', 'HP:0012570', (74, 76))	('SSX2', 'Gene', '6757', (79, 83))	('SS', 'Phenotype', 'HP:0012570', (66, 68))	('SS18-SSX1', 'Var', (61, 70))	('synovial sarcoma', 'Disease', (124, 140))	('SS', 'Phenotype', 'HP:0012570', (79, 81))	('SSX2', 'Gene', (79, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('result in', 'Reg', (101, 110))	('SS', 'Phenotype', 'HP:0012570', (61, 63))
335712	30627328	These conclusions facilitate the experimental designs for analyzing potential metastatic drivers, such as ADAM17-P729H and ADAM17-K805T, from two different angles.	('ADAM17-K805T', 'Var', (123, 135))	('K805T', 'Mutation', 'p.K805T', (130, 135))	('ADAM17-P729H', 'Var', (106, 118))	('P729H', 'Mutation', 'rs768949233', (113, 118))
335717	30627328	As one of the most widely used SS cell lines, SYO-1 also harbors a significant number of other genetic alterations, which include loss of a sex chromosome, del(3)(p13q21), t(6;6) (p23;q21), trisomy 7, trisomy 8, t(10;20)(q22;q11.2), del(11)(q23), and monosomy 13.	('monosomy', 'Disease', (251, 259))	('p23', 'Gene', (180, 183))	('p23', 'Gene', '8851', (180, 183))	('SYO-1', 'Gene', '55027', (46, 51))	('trisomy 8', 'Var', (201, 210))	('SYO-1', 'Gene', (46, 51))	('trisomy 7', 'Var', (190, 199))	('t(10;20)(q22;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (212, 231))	('SS', 'Phenotype', 'HP:0012570', (31, 33))	('t(10;20)(q22;q11.2', 'Var', (212, 230))	('loss', 'NegReg', (130, 134))	('del(11)(q23', 'Var', (233, 244))	('del(3)(p13q21', 'Var', (156, 169))	('rat', 'Species', '10116', (107, 110))
335728	30627328	Therefore, we compared the migration rates among the pooled clones expressing the wild-type ADAM17, ADAM17-P729H or ADAM17-K805T.	('ADAM17-K805T', 'Var', (116, 128))	('K805T', 'Mutation', 'p.K805T', (123, 128))	('ADAM17', 'Gene', (92, 98))	('rat', 'Species', '10116', (37, 40))	('rat', 'Species', '10116', (30, 33))	('P729H', 'Mutation', 'rs768949233', (107, 112))	('ADAM17-P729H', 'Var', (100, 112))
335729	30627328	The result showed the clones expressing ADAM17-P729H or ADAM17-K805T have faster migration rates than the pooled clones expressing the wild-type ADAM17 (Figure 5).	('rat', 'Species', '10116', (91, 94))	('K805T', 'Mutation', 'p.K805T', (63, 68))	('rat', 'Species', '10116', (84, 87))	('ADAM17-P729H', 'Var', (40, 52))	('P729H', 'Mutation', 'rs768949233', (47, 52))	('migration rates', 'CPA', (81, 96))	('ADAM17-K805T', 'Var', (56, 68))	('faster', 'PosReg', (74, 80))
335730	30627328	However, the difference is statistically significant only in the comparison between the pooled clones expressing ADAM17-P729H vs. the pooled clones expressing the wild-type ADAM17 (P = 0.037), but not statistically significant in the comparison between the pooled clones expressing ADAM17-K805T vs. the pooled clones expressing the wild-type ADAM17 (P = 0.170).	('P729H', 'Mutation', 'rs768949233', (120, 125))	('ADAM17-P729H', 'Var', (113, 125))	('ADAM17-K805T', 'Var', (282, 294))	('K805T', 'Mutation', 'p.K805T', (289, 294))
335731	30627328	These results suggest that ADAM17-P729H mutation may directly contribute to metastatic phenotype of SS while ADAM17-K805T may contribute to metastasis of SS through interaction with another factor(s).	('ADAM17-K805T', 'Var', (109, 121))	('K805T', 'Mutation', 'p.K805T', (116, 121))	('metastatic', 'CPA', (76, 86))	('interaction', 'Interaction', (165, 176))	('SS', 'Phenotype', 'HP:0012570', (154, 156))	('contribute', 'Reg', (126, 136))	('SS', 'Phenotype', 'HP:0012570', (100, 102))	('P729H', 'Mutation', 'rs768949233', (34, 39))	('metastasis', 'CPA', (140, 150))	('contribute', 'Reg', (62, 72))	('ADAM17-P729H', 'Var', (27, 39))
335733	30627328	Different from these efforts, our study described here is the first comparative analysis of mutations associated with primary and metastatic SS using whole exome sequencing.	('SS', 'Phenotype', 'HP:0012570', (141, 143))	('associated', 'Reg', (102, 112))	('rat', 'Species', '10116', (73, 76))	('mutations', 'Var', (92, 101))
335736	30627328	For example, the number of mutations is significantly lower in the tumor sample isolated from Patient SARC5007 when compared with other SS samples, even though it is a metastatic tumor.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('Patient', 'Species', '9606', (94, 101))	('SS', 'Phenotype', 'HP:0012570', (136, 138))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', (67, 72))	('lower', 'NegReg', (54, 59))	('tumor', 'Disease', (179, 184))
335739	30627328	ADAM17 is expressed in most tissues, and its unusual importance is illustrated by the fact that quadruple-knockout mice that lack ADAM9, ADAM12, ADAM15 and ADAM17 resemble Adam17-/- mice.	('ADAM12', 'Gene', '11489', (137, 143))	('ADAM17', 'Var', (156, 162))	('ADAM15', 'Gene', (145, 151))	('Adam17', 'Gene', '11491', (172, 178))	('ADAM15', 'Gene', '11490', (145, 151))	('mice', 'Species', '10090', (182, 186))	('rat', 'Species', '10116', (73, 76))	('lack', 'NegReg', (125, 129))	('ADAM9', 'Gene', '11502', (130, 135))	('mice', 'Species', '10090', (115, 119))	('ADAM12', 'Gene', (137, 143))	('Adam17', 'Gene', (172, 178))	('ADAM9', 'Gene', (130, 135))
335741	30627328	While the extracellular domain of ADAM17 is involved in substrate recognition and cleavage, it is interesting that the mutations we detected in metastatic SS are located in the cytoplasmic domain of this protein because the cytoplasmic domain contains phosphorylation sites, including Thr735, Ser791 and Ser819, and interacts with intracellular signaling molecules.	('phosphorylation', 'MPA', (252, 267))	('Thr735', 'Chemical', '-', (285, 291))	('Ser819', 'Chemical', '-', (304, 310))	('Thr735', 'Var', (285, 291))	('rat', 'Species', '10116', (61, 64))	('Ser791', 'Var', (293, 299))	('Ser819', 'Var', (304, 310))	('ADAM17', 'Gene', (34, 40))	('Ser791', 'Chemical', '-', (293, 299))	('SS', 'Phenotype', 'HP:0012570', (155, 157))	('interacts', 'Reg', (316, 325))
335743	30627328	Because of the positional proximity, P729H may have an impact on phosphorylation/dephosphorylation of neighboring Thr735.	('phosphorylation/dephosphorylation', 'MPA', (65, 98))	('Thr735', 'Protein', (114, 120))	('P729H', 'Var', (37, 42))	('Thr735', 'Chemical', '-', (114, 120))	('P729H', 'Mutation', 'rs768949233', (37, 42))	('impact', 'Reg', (55, 61))
335744	30627328	P729H may also have an impact on the interaction between the PAPQTPGR motif (amino acids 731-738) of ADAM17 and MAD2, a critical mediator of the genome instability.	('MAD2', 'Gene', (112, 116))	('impact', 'Reg', (23, 29))	('ADAM17', 'Gene', (101, 107))	('MAD2', 'Gene', '4085', (112, 116))	('P729H', 'Var', (0, 5))	('P729H', 'Mutation', 'rs768949233', (0, 5))	('interaction', 'Interaction', (37, 48))
335745	30627328	Therefore, ADAM17-P729H may act as a critical driver in metastasis of SS in the presence of SS18-SSX through one or more above-mentioned mechanisms.	('metastasis', 'CPA', (56, 66))	('SSX', 'Gene', (97, 100))	('ADAM17-P729H', 'Var', (11, 23))	('SS', 'Phenotype', 'HP:0012570', (92, 94))	('SS', 'Phenotype', 'HP:0012570', (70, 72))	('P729H', 'Mutation', 'rs768949233', (18, 23))	('SSX', 'Gene', '6757', (97, 100))	('SS', 'Phenotype', 'HP:0012570', (97, 99))
335746	30627328	Ser819 in ADAM17 is a target for growth-factor-induced phosphorylation via MAPK/ERK, whereas Ser791 undergoes dephosphorylation in response to growth factor stimulation.	('ADAM17', 'Gene', (10, 16))	('MAPK', 'Gene', (75, 79))	('ERK', 'Gene', '5594', (80, 83))	('ERK', 'Gene', (80, 83))	('dephosphorylation', 'MPA', (110, 127))	('Ser791', 'Var', (93, 99))	('Ser791', 'Chemical', '-', (93, 99))	('phosphorylation', 'MPA', (55, 70))	('Ser819', 'Chemical', '-', (0, 6))	('MAPK', 'Gene', '5594', (75, 79))	('Ser819', 'Var', (0, 6))
335747	30627328	Because of the positional proximity, we speculated that ADAM17-K805T may have the impact on metastasis-associated cell migration via affecting phosphorylation and dephosphorylation of neighboring Ser791 and Ser819, respectively.	('affecting', 'Reg', (133, 142))	('Ser791', 'Protein', (196, 202))	('Ser791', 'Chemical', '-', (196, 202))	('K805T', 'Mutation', 'p.K805T', (63, 68))	('phosphorylation', 'MPA', (143, 158))	('Ser819', 'Var', (207, 213))	('impact', 'Reg', (82, 88))	('ADAM17-K805T', 'Var', (56, 68))	('rat', 'Species', '10116', (122, 125))	('dephosphorylation', 'MPA', (163, 180))	('metastasis-associated cell migration', 'CPA', (92, 128))	('Ser819', 'Chemical', '-', (207, 213))
335748	30627328	However, despite showing a tendency, the increase in cell migration caused by ADAM17-K805T is not statistically significant, suggesting alteration of another factor(s) may be needed in interacting with this mutation to facilitate metastasis of SS.	('ADAM17-K805T', 'Var', (78, 90))	('facilitate', 'PosReg', (219, 229))	('K805T', 'Mutation', 'p.K805T', (85, 90))	('SS', 'Phenotype', 'HP:0012570', (244, 246))	('rat', 'Species', '10116', (61, 64))	('cell migration', 'CPA', (53, 67))	('rat', 'Species', '10116', (140, 143))	('metastasis', 'CPA', (230, 240))
335749	30627328	In addition to ADAM17, mutations of ARID1B and CSMD1 were identified in the SS samples isolated from 3 out of 8 cancer patients in this study.	('ARID1B', 'Gene', '57492', (36, 42))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (119, 127))	('CSMD1', 'Gene', (47, 52))	('CSMD1', 'Gene', '64478', (47, 52))	('ARID1B', 'Gene', (36, 42))	('mutations', 'Var', (23, 32))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('identified', 'Reg', (58, 68))
335750	30627328	Although the sample size of our study is limited, it is still a surprise that over 37% of our tumor samples harbor mutations of these two genes.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))
335752	30627328	For example, only 5 out of 72 cases of pediatric neuroblastoma harbor mutations of ARID1B and only 5 out of 26 cases of colorectal cancers harbor mutations of CSMD1.	('CSMD1', 'Gene', (159, 164))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('mutations', 'Var', (70, 79))	('colorectal cancers', 'Disease', 'MESH:D015179', (120, 138))	('CSMD1', 'Gene', '64478', (159, 164))	('colorectal cancers', 'Disease', (120, 138))	('pediatric neuroblastoma', 'Disease', (39, 62))	('ARID1B', 'Gene', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('neuroblastoma', 'Phenotype', 'HP:0003006', (49, 62))	('ARID1B', 'Gene', '57492', (83, 89))	('pediatric neuroblastoma', 'Disease', 'MESH:D009447', (39, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))
335753	30627328	Although both ARID1B and CSMD1 have been implicated in tumorigenesis, our current data alone is not sufficient to implicate a link between ARID1B or CSMD1 mutations and metastasis because the mutations were identified in both primary and metastatic SS.	('CSMD1', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('SS', 'Phenotype', 'HP:0012570', (249, 251))	('CSMD1', 'Gene', (149, 154))	('mutations', 'Var', (155, 164))	('CSMD1', 'Gene', '64478', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ARID1B', 'Gene', (139, 145))	('ARID1B', 'Gene', (14, 20))	('tumor', 'Disease', (55, 60))	('ARID1B', 'Gene', '57492', (14, 20))	('identified', 'Reg', (207, 217))	('ARID1B', 'Gene', '57492', (139, 145))	('implicated', 'Reg', (41, 51))	('CSMD1', 'Gene', '64478', (25, 30))
335754	30627328	Therefore, the strategy described here for studying ADAM17 mutations could be used to analyze the impacts of individual ARID1B and CSMD1 mutations identified in metastatic SS on metastasis-associated phenotypes.	('CSMD1', 'Gene', (131, 136))	('CSMD1', 'Gene', '64478', (131, 136))	('ARID1B', 'Gene', '57492', (120, 126))	('mutations', 'Var', (137, 146))	('SS', 'Phenotype', 'HP:0012570', (172, 174))	('mutations', 'Var', (59, 68))	('rat', 'Species', '10116', (17, 20))	('ARID1B', 'Gene', (120, 126))	('metastatic SS', 'Disease', (161, 174))
335756	30627328	Our analysis of ADAM17 mutations described in this study demonstrates the mutations we identified solely in metastatic SS through whole exome sequencing are desirable candidates for the studies with the goal to understand the metastatic process of SS, which in turn can lay the foundation for rational development of novel therapeutic strategies to improve the prognosis of this deadly sarcoma.	('rat', 'Species', '10116', (337, 340))	('sarcoma', 'Disease', 'MESH:D012509', (386, 393))	('SS', 'Phenotype', 'HP:0012570', (119, 121))	('mutations', 'Var', (74, 83))	('ADAM17', 'Gene', (16, 22))	('rat', 'Species', '10116', (64, 67))	('mutations', 'Var', (23, 32))	('sarcoma', 'Disease', (386, 393))	('sarcoma', 'Phenotype', 'HP:0100242', (386, 393))	('SS', 'Phenotype', 'HP:0012570', (248, 250))	('metastatic', 'Disease', (108, 118))	('rat', 'Species', '10116', (293, 296))
335764	30627328	To express ADAM17, ADAM17-P729H, and ADAM17-K805T, the expression vectors pcDNA3.1-ADAM17-WT, pcDNA3.1-ADAM17-P729H, and pcDNA3.1-ADAM17-K805T were constructed, respectively (Figure 2; see Results section).	('ADAM17-K805T', 'Var', (37, 49))	('P729H', 'Mutation', 'rs768949233', (110, 115))	('K805T', 'Mutation', 'p.K805T', (137, 142))	('expression vectors', 'Species', '29278', (55, 73))	('P729H', 'Mutation', 'rs768949233', (26, 31))	('ADAM17-P729H', 'Var', (19, 31))	('ADAM17', 'Var', (11, 17))	('K805T', 'Mutation', 'p.K805T', (44, 49))
335767	30627328	The cell clones expressing human wild-type ADAM17, ADAM17-P729H or ADAM17-K805T were established by transfecting Clone 4-5 cells individually with the expression vectors pcDNA3.1-ADAM17-WT, pcDNA3.1-ADAM17-P729H or pcDNA3.1-ADAM17-K805T, respectively.	('pcDNA3.1-ADAM17-WT', 'Var', (170, 188))	('ADAM17-K805T', 'Var', (67, 79))	('human', 'Species', '9606', (27, 32))	('K805T', 'Mutation', 'p.K805T', (231, 236))	('K805T', 'Mutation', 'p.K805T', (74, 79))	('pcDNA3.1-ADAM17-P729H', 'Var', (190, 211))	('pcDNA3.1-ADAM17-K805T', 'Var', (215, 236))	('P729H', 'Mutation', 'rs768949233', (206, 211))	('expression vectors', 'Species', '29278', (151, 169))	('P729H', 'Mutation', 'rs768949233', (58, 63))	('ADAM17-P729H', 'Var', (51, 63))
335814	27588121	Immunohistochemical staining revealed positivity for vimentin, periodic acid-Schiff, cluster of differentiation (CD)68, CD34, S100 and negativity for cytokeratin, epithelial membrane antigen and desmin.	('CD', 'Disease', 'MESH:D006223', (120, 122))	('positivity', 'Var', (38, 48))	('CD', 'Disease', 'MESH:D006223', (113, 115))	('desmin', 'Gene', (195, 201))	('cytokeratin', 'Protein', (150, 161))	('desmin', 'Gene', '1674', (195, 201))	('vimentin', 'Gene', '7431', (53, 61))	('CD34', 'Gene', (120, 124))	('CD34', 'Gene', '947', (120, 124))	('S100', 'Protein', (126, 130))	('vimentin', 'Gene', (53, 61))	('periodic acid', 'Chemical', 'MESH:D010504', (63, 76))	('epithelial', 'Protein', (163, 173))
335839	27588121	These results were consistent with the immunohistochemical staining results observed in the patient of the present case: Vimentin(+), CD68(+), CD34(+) and S100(+).	('patient', 'Species', '9606', (92, 99))	('Vimentin', 'Gene', (121, 129))	('CD34', 'Gene', (143, 147))	('Vimentin', 'Gene', '7431', (121, 129))	('CD34', 'Gene', '947', (143, 147))	('S100(+', 'Var', (155, 161))	('CD68', 'Gene', (134, 138))	('CD68', 'Gene', '968', (134, 138))
335879	25082406	Single antigen-based vaccines have been shown to result in target antigen-negative tumor cell variants, a phenomenon seen less frequently with whole tumor cell-derived vaccines.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('variants', 'Var', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
335894	25082406	Mutated EGFRvIII is a transmembrane glycoprotein with constitutive tyrosine kinase activity that plays an important role in tumorigenesis and development of chemoresistance.	('EGFRvIII', 'Gene', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('Mutated', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
335895	25082406	Phase I/II trials using rindopepimut in adults with glioma have demonstrated improved progression-free survival and overall survival with minimal side effects, and it is currently in a randomized phase III trial for adults with newly diagnosed glioblastoma (Clinicaltrials.gov registry number NCT01480479).	('N', 'Chemical', 'MESH:D009584', (293, 294))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('rindopepimut', 'Var', (24, 36))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('progression-free survival', 'CPA', (86, 111))	('glioblastoma', 'Disease', (244, 256))	('glioblastoma', 'Disease', 'MESH:D005909', (244, 256))	('glioma', 'Disease', (52, 58))	('overall survival', 'CPA', (116, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (244, 256))	('improved', 'PosReg', (77, 85))
335908	25082406	This study also aims to simultaneously target the CMV protein pp65, expressed in >65% of glioblastoma samples studied.	('glioblastoma', 'Disease', (89, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('pp65', 'Var', (62, 66))
335930	25082406	In a randomized phase III study of MAb targeting GD2, when compared with standard maintenance therapy using isotretinoin alone, the addition of ch14.18, IL-2 and GM-CSF was associated with an improvement in both 2-year event-free and overall survival (46% versus 66% and 75% versus 86%, respectively).	('GM-CSF', 'Gene', '1437', (162, 168))	('event-free', 'CPA', (219, 229))	('GD2', 'Gene', (49, 52))	('addition', 'Var', (132, 140))	('IL-2', 'Gene', '3558', (153, 157))	('isotretinoin', 'Chemical', 'MESH:D015474', (108, 120))	('IL-2', 'Gene', (153, 157))	('ch14.18', 'Var', (144, 151))	('GM-CSF', 'Gene', (162, 168))	('improvement', 'PosReg', (192, 203))	('overall survival', 'CPA', (234, 250))
335954	25082406	For example, in the event of unwanted side effects from increased expansion of CAR T cells on NCT01822652, these T cells are also modified with inducible iCaspase 9 suicide gene that can be activated in vivo with the drug AP1903 that, upon activation, leads to programmed cell death.	('programmed cell death', 'CPA', (261, 282))	('iCaspase', 'Gene', (154, 162))	('NCT01822652', 'Var', (94, 105))	('leads to', 'Reg', (252, 260))	('N', 'Chemical', 'MESH:D009584', (94, 95))
335994	25082406	However, genetically modified T cells redirected to HER2 have been demonstrated to induce tumor regression in both local and metastatic murine models of osteosarcoma.	('HER2', 'Protein', (52, 56))	('redirected', 'Var', (38, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('murine', 'Species', '10090', (136, 142))	('osteosarcoma', 'Disease', (153, 165))	('osteosarcoma', 'Phenotype', 'HP:0002669', (153, 165))	('osteosarcoma', 'Disease', 'MESH:D012516', (153, 165))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
336019	25082406	NKTs are an evolutionary-conserved subset of T cells characterized by expression of an invariant TCR alpha-chain (Valpha24-Jalpha18).	('Valpha24-Jalpha18', 'Var', (114, 131))	('NKTs', 'Disease', (0, 4))	('N', 'Chemical', 'MESH:D009584', (0, 1))
336023	25082406	NKTs have also been shown to suppress tumor growth by killing the CD1-d+ tumor-associated monocytes/macrophages (TAMs) in pre-clinical models of human neuroblastoma.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('NKTs', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('suppress', 'NegReg', (29, 37))	('neuroblastoma', 'Phenotype', 'HP:0003006', (151, 164))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('human', 'Species', '9606', (145, 150))	('CD1-d', 'Gene', '912', (66, 71))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CD1-d', 'Gene', (66, 71))	('neuroblastoma', 'Disease', 'MESH:D009447', (151, 164))	('neuroblastoma', 'Disease', (151, 164))
336114	26103446	In addition, the presence of anal hrHPV infection at baseline increased the risk of acquisition of any HPV type by 65% (95% CI 1%-170%), and the presence of anal low risk HPV infection increased the risk of acquisition of another HPV type by 80% (95% CI 8%-200%).	('HPV', 'Species', '10566', (171, 174))	('HPV', 'Species', '10566', (230, 233))	('HPV infection', 'Disease', (36, 49))	('HPV infection', 'Disease', 'MESH:D030361', (171, 184))	('HPV infection', 'Disease', (171, 184))	('presence', 'Var', (145, 153))	('HPV', 'Species', '10566', (103, 106))	('HPV', 'Species', '10566', (36, 39))	('HPV infection', 'Disease', 'MESH:D030361', (36, 49))	('presence', 'Var', (17, 25))	('acquisition', 'MPA', (84, 95))
336119	26103446	In addition, risk of anal infection was enhanced by the presence of multiple HPV types in the cervix.	('anal infection', 'Disease', (21, 35))	('enhanced', 'PosReg', (40, 48))	('presence', 'Var', (56, 64))	('HPV', 'Species', '10566', (77, 80))
336208	26103446	Risk increased with low CD4 nadir.	('CD4', 'Gene', (24, 27))	('CD4', 'Gene', '920', (24, 27))	('low', 'Var', (20, 23))
336295	26103446	Older regimens using cyclosporine and azathioprine were associated with the highest risk of anal cancer whereas newer regimens using tacrolimus and mycophenolate appeared to be protective against anal cancer.	('anal cancer', 'Disease', (196, 207))	('men', 'Species', '9606', (10, 13))	('anal cancer', 'Phenotype', 'HP:0032186', (196, 207))	('azathioprine', 'Chemical', 'MESH:D001379', (38, 50))	('tacrolimus', 'Chemical', 'MESH:D016559', (133, 143))	('anal cancer', 'Phenotype', 'HP:0032186', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('anal cancer', 'Disease', (92, 103))	('anal cancer', 'Disease', 'MESH:D001005', (92, 103))	('mycophenolate', 'Chemical', 'MESH:D009173', (148, 161))	('cyclosporine', 'Var', (21, 33))	('cyclosporine', 'Chemical', 'MESH:D016572', (21, 33))	('anal cancer', 'Disease', 'MESH:D001005', (196, 207))	('men', 'Species', '9606', (122, 125))	('azathioprine', 'Var', (38, 50))
336302	26103446	Solid organ transplantation was associated with an anal cancer SIR of 14.4 (C.I.	('Solid', 'Var', (0, 5))	('anal cancer', 'Phenotype', 'HP:0032186', (51, 62))	('anal cancer', 'Disease', 'MESH:D001005', (51, 62))	('anal cancer', 'Disease', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
336327	26103446	No drug dose or duration effect was seen, however, hematologic abnormalities (particularly cytopenia), and anticardiolipin and antithyroid globulin antibodies were associated with overall cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('antithyroid globulin', 'Protein', (127, 147))	('associated', 'Reg', (164, 174))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('hematologic abnormalities', 'Phenotype', 'HP:0001871', (51, 76))	('cancer', 'Disease', (188, 194))	('anticardiolipin', 'Var', (107, 122))
336430	26103446	In this study, the risk of AIN increased significantly in the presence of multicentric LGTN.	('LGTN', 'Chemical', '-', (87, 91))	('multicentric LGTN', 'Var', (74, 91))	('AIN', 'Disease', (27, 30))
336438	26103446	Biopsy proven AIN was higher in the women with LGTN [10.4%, (95%CI 5.6-17.3%)] than in women without LGTN (1.4% (95% CI 0.1-6.5%, p = 0.016).	('LGTN', 'Chemical', '-', (101, 105))	('LGTN', 'Chemical', '-', (47, 51))	('higher', 'PosReg', (22, 28))	('LGTN', 'Var', (47, 51))	('women', 'Species', '9606', (36, 41))	('women', 'Species', '9606', (87, 92))
336479	26103446	Attempts to enhance the suboptimal accuracy of the anal cytology have included the use of immunostaining for p16/Ki67 on the slide and detection of HPV16/18 DNA or HPV E6/E7 mRNA in the residual liquid-based specimen.	('detection', 'Reg', (135, 144))	('HPV16/18 DNA', 'Var', (148, 160))	('E6/E7', 'Gene', '25479186', (168, 173))	('HPV', 'Species', '10566', (148, 151))	('E6/E7', 'Gene', (168, 173))	('p16/Ki67', 'Var', (109, 117))	('HPV16', 'Species', '333760', (148, 153))	('men', 'Species', '9606', (213, 216))	('HPV', 'Species', '10566', (164, 167))
336527	26103446	For women with vulvar cancers or high-grade VIN, immediate screening is recommended.	('vulvar cancers', 'Disease', (15, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('VIN', 'Gene', '440900', (44, 47))	('men', 'Species', '9606', (77, 80))	('high-grade', 'Var', (33, 43))	('women', 'Species', '9606', (4, 9))	('VIN', 'Gene', (44, 47))	('vulvar cancer', 'Phenotype', 'HP:0030416', (15, 28))	('vulvar cancers', 'Disease', 'MESH:D014846', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('men', 'Species', '9606', (6, 9))
336528	26103446	For women with cervical or vaginal cancers or high-grade CIN or VaIN, screening with cytology or DARE and symptom review within 5 years of initial diagnosis is suggested.	('CIN', 'Disease', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CIN', 'Disease', 'MESH:D007674', (57, 60))	('high-grade', 'Var', (46, 56))	('women', 'Species', '9606', (4, 9))	('vaginal cancer', 'Phenotype', 'HP:0100650', (27, 41))	('vaginal cancers', 'Disease', 'MESH:D014625', (27, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cervical', 'Disease', (15, 23))	('vaginal cancers', 'Disease', (27, 42))
336673	31616634	NGS of the primary tumor re-biopsy identified a nonsense mutation in SMARCB1 encoding INI1, confirmed by IHC loss of INI1 expression; no actionable mutation(s) outside of clinical trials were identified (FoundationOne CDx , Foundation Medicine, Cambridge, MA; Supplemental Table 3).	('SMARCB1', 'Gene', (69, 76))	('SMARCB1', 'Gene', '6598', (69, 76))	('expression', 'MPA', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('loss', 'NegReg', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('nonsense mutation', 'Var', (48, 65))	('INI1', 'Gene', '6598', (117, 121))	('INI1', 'Gene', (86, 90))	('INI1', 'Gene', (117, 121))	('INI1', 'Gene', '6598', (86, 90))
336692	31616634	Radiation modality may also contribute to lymphopenia, as esophageal cancer patients treated with photons experienced more Grade 4 lymphopenia compared to those treated with protons, suggesting a dependence on total integral dose to lymphocyte-containing normal structures such as the vasculature.	('patients', 'Species', '9606', (76, 84))	('lymphopenia', 'Disease', (131, 142))	('esophageal cancer', 'Disease', (58, 75))	('lymphopenia', 'Phenotype', 'HP:0001888', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('lymphopenia', 'Disease', 'MESH:D008231', (42, 53))	('lymphopenia', 'Disease', 'MESH:D008231', (131, 142))	('lymphopenia', 'Phenotype', 'HP:0001888', (131, 142))	('photons', 'Var', (98, 105))	('lymphopenia', 'Disease', (42, 53))
336716	31616634	Inhibition of EZH2 using tazemetostat has shown promise in treating solid tumors with mutations of SMARC family genes, including epithelioid sarcoma.	('mutations', 'Var', (86, 95))	('solid tumors', 'Disease', (68, 80))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (129, 148))	('tazemetostat', 'Chemical', 'None', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('solid tumors', 'Disease', 'MESH:D009369', (68, 80))	('SMARC family genes', 'Gene', (99, 117))	('epithelioid sarcoma', 'Disease', (129, 148))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
336723	31616634	Molecular profiling using NGS identified a SMARCB1 nonsense mutation and IHC identified loss of INI1 expression in the primary tumor that was also documented in a recent case report of the abscopal effect following EZH2 inhibition and radiotherapy for a sacral chordoma.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('sacral chordoma', 'Disease', 'MESH:D002817', (254, 269))	('tumor', 'Disease', (127, 132))	('chordoma', 'Phenotype', 'HP:0010762', (261, 269))	('Mole', 'Phenotype', 'HP:0003764', (0, 4))	('loss', 'NegReg', (88, 92))	('abscopal effect', 'MPA', (189, 204))	('SMARCB1', 'Gene', '6598', (43, 50))	('INI1', 'Gene', (96, 100))	('INI1', 'Gene', '6598', (96, 100))	('SMARCB1', 'Gene', (43, 50))	('sacral chordoma', 'Disease', (254, 269))	('EZH2', 'Gene', (215, 219))	('expression', 'MPA', (101, 111))	('EZH2', 'Gene', '2146', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('nonsense mutation', 'Var', (51, 68))
336739	31521948	This work reports the impact of stress-induced TNC expression on enhancing cell invadopodia formation, provides evidence for a feed forward loop between TNC and Src to promote cell metastatic behavior, and highlights a pathway by which microenvironment-driven TNC expression could be therapeutically targeted in Ewing sarcoma.	('TNC', 'Gene', (260, 263))	('cell metastatic behavior', 'CPA', (176, 200))	('TNC', 'Gene', (47, 50))	('Src', 'Gene', (161, 164))	('cell invadopodia formation', 'CPA', (75, 101))	('Src', 'Gene', '6714', (161, 164))	('promote', 'PosReg', (168, 175))	('enhancing', 'PosReg', (65, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (312, 325))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (312, 325))	('TNC', 'Gene', '3371', (153, 156))	('TNC', 'Gene', '3371', (260, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (318, 325))	('TNC', 'Gene', '3371', (47, 50))	('expression', 'Var', (51, 61))	('TNC', 'Gene', (153, 156))	('Ewing sarcoma', 'Disease', (312, 325))
336783	31521948	Antibodies were obtained from the following sources: pSrc (Tyr418 Cat # 44-660G Invitrogen/Thermo Fisher, Waltham, MA), Src (Cat # 710449 Thermo, Rockford, IL), vinculin (Cat # 6896 R&D, Minneapolis, MN) and tenascin C (Cat # T2551 Sigma Aldrich).	('Src', 'Gene', '6714', (54, 57))	('Src', 'Gene', (120, 123))	('vinculin', 'Gene', (161, 169))	('tenascin C', 'Gene', '3371', (208, 218))	('Src', 'Gene', '6714', (120, 123))	('tenascin C', 'Gene', (208, 218))	('Cat # 6896 R&', 'Var', (171, 184))	('MN', 'CellLine', 'CVCL:U508', (200, 202))	('Tyr418', 'Chemical', '-', (59, 65))	('Cat # 710449 Thermo', 'Var', (125, 144))	('Src', 'Gene', (54, 57))	('vinculin', 'Gene', '7414', (161, 169))
336801	31521948	Src activity is largely mediated through the phosphorylation of the positive regulatory Tyr418/419.	('Tyr418', 'Chemical', '-', (88, 94))	('Tyr418/419', 'Var', (88, 98))	('Src', 'Gene', '6714', (0, 3))	('Src', 'Gene', (0, 3))	('phosphorylation', 'MPA', (45, 60))
336802	31521948	Tyr418/419 is phosphorylated upon the interaction of Src with plasma membrane-bound molecular partners, such as integrins (resulting in cell cytoskeletal reorganization) or receptor tyrosine kinases (resulting in altered cell migration and proliferation).	('Src', 'Gene', (53, 56))	('Tyr418/419', 'Var', (0, 10))	('proliferation', 'CPA', (240, 253))	('cell cytoskeletal reorganization', 'CPA', (136, 168))	('tyrosine', 'Chemical', 'MESH:D014443', (182, 190))	('Src', 'Gene', '6714', (53, 56))	('cell migration', 'CPA', (221, 235))	('Tyr418', 'Chemical', '-', (0, 6))	('altered', 'Reg', (213, 220))	('interaction', 'Interaction', (38, 49))
336823	31521948	Given our findings that the presence of TNC in the Ewing sarcoma cell microenvironment enhances invadopodia formation (Figure 3A), and that TNC directly impacts Src activation (Figure 2), we next sought to determine if formation of stress-induced invadopodia requires endogenous TNC.	('TNC', 'Gene', '3371', (279, 282))	('presence', 'Var', (28, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('TNC', 'Gene', (140, 143))	('Src', 'Gene', (161, 164))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('TNC', 'Gene', (279, 282))	('Src', 'Gene', '6714', (161, 164))	('Ewing sarcoma', 'Disease', (51, 64))	('invadopodia formation', 'MPA', (96, 117))	('TNC', 'Gene', '3371', (40, 43))	('TNC', 'Gene', (40, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('TNC', 'Gene', '3371', (140, 143))	('impacts', 'Reg', (153, 160))	('enhances', 'PosReg', (87, 95))
336825	31521948	As shown in Figure 3, C-F and Supplemental Figure 2, knockdown of TNC in Ewing sarcoma cells significantly impeded their ability to induce invadopodia and to degrade matrix under conditions of stress.	('TNC', 'Gene', '3371', (66, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('TNC', 'Gene', (66, 69))	('degrade', 'NegReg', (158, 165))	('knockdown', 'Var', (53, 62))	('Ewing sarcoma', 'Disease', (73, 86))	('impeded', 'NegReg', (107, 114))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (73, 86))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (73, 86))
336835	31521948	Having shown that stress increases both Src activation and TNC expression in Ewing cells, and that stress-induced invadopodia formation is abrogated by either TNC knockdown or Src inhibition, we next questioned whether Src activation can contribute to TNC expression.	('TNC', 'Gene', '3371', (59, 62))	('Src', 'Gene', '6714', (40, 43))	('knockdown', 'Var', (163, 172))	('TNC', 'Gene', '3371', (159, 162))	('activation', 'PosReg', (44, 54))	('TNC', 'Gene', (59, 62))	('TNC', 'Gene', (159, 162))	('Src', 'Gene', (219, 222))	('Src', 'Gene', '6714', (219, 222))	('Src', 'Gene', (176, 179))	('TNC', 'Gene', '3371', (252, 255))	('TNC', 'Gene', (252, 255))	('Src', 'Gene', '6714', (176, 179))	('Src', 'Gene', (40, 43))
336878	31521948	Thus, inhibition of Src may be a potential therapeutic avenue by which to manipulate microenvironmentally driven TNC expression.	('TNC', 'Gene', (113, 116))	('Src', 'Gene', '6714', (20, 23))	('Src', 'Gene', (20, 23))	('inhibition', 'Var', (6, 16))	('TNC', 'Gene', '3371', (113, 116))
336951	30454036	In a univariate analysis of the entire cohort, the following prognostic factors were found to correlate with the mortality rate: LF (HR: 2.7,95% CI: 1.31-5.95, p = 0,006), absence of DF (HR: 0.43,95% CI: 0.18-0.99, p = 0.042), recurrent retroperitoneal sarcoma (HR: 2.81,95% CI 1.33-5.94, p = 0.007), and sarcoma histology (HR: 2.75,95% CI 1.31-5.75, p = 0.007).	('retroperitoneal sarcoma', 'Disease', 'MESH:D012186', (237, 260))	('sarcoma', 'Disease', 'MESH:D012509', (305, 312))	('sarcoma', 'Disease', 'MESH:D012509', (253, 260))	('sarcoma', 'Disease', (305, 312))	('absence', 'Var', (172, 179))	('sarcoma', 'Disease', (253, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('retroperitoneal sarcoma', 'Disease', (237, 260))
336966	30454036	In a multivariate analysis, only the degree of resection statistically significantly influenced LC, such that the patients who underwent R2 resection had a 2.2-fold higher risk of treatment failure (95% CI: 1.2-4.1; p = 0.007).	('patients', 'Species', '9606', (114, 122))	('treatment failure', 'Disease', 'MESH:D016609', (180, 197))	('R2 resection', 'Var', (137, 149))	('treatment failure', 'Disease', (180, 197))
336982	30454036	For example, in a study by Roeder et al., patients with a status of R0 after the resection of locally recurrent rectal cancer were found to have 5 year LC and OS rates that were respectively threefold and fivefold better than those of patients with incomplete resections.	('rectal cancer', 'Disease', 'MESH:D012004', (112, 125))	('rectal cancer', 'Disease', (112, 125))	('patients', 'Species', '9606', (235, 243))	('OS', 'Chemical', '-', (159, 161))	('rectal cancer', 'Phenotype', 'HP:0100743', (112, 125))	('status', 'Var', (58, 64))	('patients', 'Species', '9606', (42, 50))	('better', 'PosReg', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
337009	30454036	For all patients, resections R1 and R2 resection have a decreasing in 5 years survival rate by 7.6% and by 34.7% respectively compared to R0 resection.	('decreasing', 'NegReg', (56, 66))	('patients', 'Species', '9606', (8, 16))	('R2 resection', 'Var', (36, 48))
337018	30454036	Furthermore, R2 resection was associated with a worse 5 year OS rate, compared with R0 or R1 resection (31% vs 13%, p = 0.01).	('R2 resection', 'Var', (13, 25))	('worse', 'NegReg', (48, 53))	('OS', 'Chemical', '-', (61, 63))
337031	30454036	In a study involving 36 patients with recurrent gynecological malignancies conducted by Arias et al., an endometrial histology was found to correlate with better rates of local PFS (p = 0.017) and OS (p = 0.038).	('local PFS', 'CPA', (171, 180))	('endometrial', 'Var', (105, 116))	('OS', 'Chemical', '-', (197, 199))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('better', 'PosReg', (155, 161))	('patients', 'Species', '9606', (24, 32))	('malignancies', 'Disease', (62, 74))
337069	28819372	SyS is histologically defined by the following International Classification of Diseases for Oncology, Third Edition, histology codes for malignant cases: synovial sarcoma, not otherwise specified (NOS) (9040/3), synovial sarcoma, spindle cell (9041/3), synovial sarcoma, epithelioid cell (9042/3), and synovial sarcoma, biphasic (9043/3).	('9041/3', 'Var', (244, 250))	('synovial sarcoma', 'Disease', (154, 170))	('synovial sarcoma', 'Disease', 'MESH:D013584', (154, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (262, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (154, 170))	('synovial sarcoma', 'Disease', (302, 318))	('synovial sarcoma', 'Disease', (253, 269))	('Oncology', 'Phenotype', 'HP:0002664', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('synovial sarcoma', 'Disease', (212, 228))	('synovial sarcoma', 'Disease', 'MESH:D013584', (302, 318))	('synovial sarcoma', 'Disease', 'MESH:D013584', (253, 269))	('SyS', 'Phenotype', 'HP:0012570', (0, 3))	('synovial sarcoma', 'Disease', 'MESH:D013584', (212, 228))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (302, 318))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (253, 269))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (212, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (311, 318))
337108	28819372	In addition, the internal under-registration and misclassification of SyS inside SEER database may be the potential sources of error and bias.	('misclassification', 'Var', (49, 66))	('error and bias', 'Disease', 'MESH:D012030', (127, 141))	('SyS inside', 'Gene', (70, 80))	('SyS', 'Phenotype', 'HP:0012570', (70, 73))
337126	28491372	Haematology revealed mild anaemia (haematocrit 19%, reference interval [RI] 26-45%) and marked leukocytosis (140.0 x 109/l, RI 5.5-19.5), with absolute neutrophilia (133.0 x 109/l, RI 2.5-12.5) and monocytosis (4.2 x 109/l, RI 0-1.5).	('monocytosis', 'Phenotype', 'HP:0012311', (198, 209))	('anaemia', 'Disease', (26, 33))	('leukocytosis', 'Disease', 'MESH:D007964', (95, 107))	('monocytosis', 'MPA', (198, 209))	('leukocytosis', 'Phenotype', 'HP:0001974', (95, 107))	('anaemia', 'Phenotype', 'HP:0001903', (26, 33))	('absolute neutrophilia', 'Disease', 'MESH:C563010', (143, 164))	('neutrophilia', 'Phenotype', 'HP:0011897', (152, 164))	('absolute neutrophilia', 'Disease', (143, 164))	('140.0 x 109/l', 'Var', (109, 122))	('leukocytosis', 'Disease', (95, 107))	('anaemia', 'Disease', 'MESH:D000740', (26, 33))
337185	27703409	Inhibition of mTOR has been shown to strongly influence vaccine induced CD8+ T-cell response, leading to greater antitumor efficacy.	('influence', 'Reg', (46, 55))	('mTOR', 'Gene', '2475', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('CD8', 'Gene', (72, 75))	('Inhibition', 'Var', (0, 10))	('greater', 'PosReg', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('mTOR', 'Gene', (14, 18))	('CD8', 'Gene', '925', (72, 75))
337195	27703409	Although attempts to use adjuvants such as GM-CSF to increase the immune system response have not yet translated to increased efficacy, an ongoing phase I trial is exploring the role of the antigen bi-shRNAfurin and GMCSF autologous tumor cell (Vigil ) vaccine in patients with Ewing's sarcoma (NCT01061840).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (278, 293))	('GM-CSF', 'Gene', '1437', (43, 49))	('tumor', 'Disease', (233, 238))	('GMCSF', 'Gene', (216, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (286, 293))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (278, 293))	("Ewing's sarcoma", 'Disease', (278, 293))	('GMCSF', 'Gene', '1437', (216, 221))	('patients', 'Species', '9606', (264, 272))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('GM-CSF', 'Gene', (43, 49))	('NCT01061840', 'Var', (295, 306))
337212	27703409	The critical role of T-cells in the antitumor effects of imatinib and GIST is being further explored through a phase Ib/II study of ipilimumab with dasatinib, another tyrosine kinase inhibitor, for patients with soft tissue sarcoma with an expansion of GIST (NCT01643278).	('soft tissue sarcoma', 'Disease', (212, 231))	('patients', 'Species', '9606', (198, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('GIST', 'Gene', (253, 257))	('tumor', 'Disease', (40, 45))	('imatinib', 'Chemical', 'MESH:D000068877', (57, 65))	('ipilimumab', 'Chemical', 'MESH:D000074324', (132, 142))	('dasatinib', 'Chemical', 'MESH:D000069439', (148, 157))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (212, 231))	('expansion', 'Var', (240, 249))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (212, 231))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('NCT01643278', 'Var', (259, 270))
337245	27703409	In another early-phase study, repression of survivin led to increased sensitization of rhabdomyosarcoma cells to T-cell attack.	('sensitization', 'MPA', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('repression', 'Var', (30, 40))	('survivin', 'Gene', (44, 52))	('rhabdomyosarcoma', 'Disease', (87, 103))	('increased', 'PosReg', (60, 69))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (87, 103))
337254	27703409	The cells also contain two costimulatory molecules (CD28 and OX40 genes) (NCT01953900).	('OX40', 'Gene', '7293', (61, 65))	('OX40', 'Gene', (61, 65))	('NCT01953900', 'Var', (74, 85))	('CD28', 'Gene', (52, 56))	('CD28', 'Gene', '940', (52, 56))
337256	27703409	One method of optimizing the efficacy of current immunotherapy technologies is through upregulation or modification of tumor cell antigens, increasing their immunogenicity in vivo.	('tumor', 'Disease', (119, 124))	('increasing', 'PosReg', (140, 150))	('immunogenicity', 'MPA', (157, 171))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('modification', 'Var', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('upregulation', 'PosReg', (87, 99))
337257	27703409	The demethylating agent decitabine has been shown to epigenetically modify sarcoma cells, effectively increasing the expression of various antigens and peptides that increase the probability of a targeted T-cell response.	('epigenetically', 'Var', (53, 67))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('expression', 'MPA', (117, 127))	('sarcoma', 'Disease', (75, 82))	('increasing', 'PosReg', (102, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('peptides', 'Protein', (152, 160))	('antigens', 'Protein', (139, 147))	('decitabine', 'Chemical', 'MESH:D000077209', (24, 34))
337260	27703409	There remain unanswered questions regarding the role of epigenetic elements with known immunotherapy modalities in the management of sarcoma.	('sarcoma', 'Disease', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('epigenetic elements', 'Var', (56, 75))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))
337265	27703409	Various clinical trials combining ipilimumab and radiotherapy in patients with melanoma are currently open (NCT01449279, NCT01565837, and NCT01497808).	('NCT01449279', 'Var', (108, 119))	('NCT01497808', 'Var', (138, 149))	('patients', 'Species', '9606', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('NCT01565837', 'Var', (121, 132))	('melanoma', 'Disease', (79, 87))	('ipilimumab', 'Chemical', 'MESH:D000074324', (34, 44))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
337302	27618037	Besides these shared TAA, recently, patient-specific mutations have attracted attention as tumor-specific neoantigens that are recognized by specific T cells and to which no immune tolerance is present.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('patient', 'Species', '9606', (36, 43))
337343	27618037	The protein data for hTERT showed positivity in 75.6% of EMCAR samples and in 59.3% of US samples.	('hTERT', 'Gene', '7015', (21, 26))	('positivity', 'Var', (34, 44))	('hTERT', 'Gene', (21, 26))	('EMCAR', 'Phenotype', 'HP:0012114', (57, 62))	('EMCAR', 'Disease', (57, 62))	('US', 'Phenotype', 'HP:0002891', (87, 89))
337464	27618037	To identify antigen-specific T cells, the cells were stained with the following antibodies: CD4-FITC (BD Pharmingen, Erembodegem, Belgium), CD137-PE (BD Pharmingen), CD3-PerCp-Cy5.5 (BioLegend, London, UK), CD19-PE-CY7 (BioLegend) and CD8-APC-H7 (BD Pharmingen).	('Erembodegem', 'Disease', 'None', (117, 128))	('CD4', 'Gene', '920', (92, 95))	('CD3-PerCp-Cy5.5', 'Var', (166, 181))	('CD19', 'Gene', '930', (207, 211))	('Erembodegem', 'Disease', (117, 128))	('CD8-APC-H7', 'Disease', 'MESH:C563824', (235, 245))	('CD8-APC-H7', 'Disease', (235, 245))	('CD137', 'Gene', (140, 145))	('CD137', 'Gene', '3604', (140, 145))	('CD4', 'Gene', (92, 95))	('CD19', 'Gene', (207, 211))
337783	33147377	They also described a dependency on the technique: for tangential arc VMAT the EAR at the contralateral breast and lung was significantly reduced with FFF, no differences were observed for VMAT, and for IMRT the EAR for the contralateral lung even increased with FFF.	('a', 'Gene', '351', (63, 64))	('reduced', 'NegReg', (138, 145))	('a', 'Gene', '351', (111, 112))	('a', 'Gene', '351', (56, 57))	('a', 'Gene', '351', (229, 230))	('FFF', 'Var', (151, 154))	('a', 'Gene', '351', (253, 254))	('a', 'Gene', '351', (95, 96))	('a', 'Gene', '351', (101, 102))	('a', 'Gene', '351', (195, 196))	('a', 'Gene', '351', (20, 21))	('a', 'Gene', '351', (83, 84))	('a', 'Gene', '351', (107, 108))	('A', 'Gene', '351', (72, 73))	('A', 'Gene', '351', (80, 81))	('a', 'Gene', '351', (132, 133))	('a', 'Gene', '351', (5, 6))	('A', 'Gene', '351', (191, 192))	('a', 'Gene', '351', (235, 236))	('A', 'Gene', '351', (213, 214))	('a', 'Gene', '351', (121, 122))	('a', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (97, 98))	('a', 'Gene', '351', (231, 232))
337871	32181596	Results showed that the combination high-dose anlotinib and epirubicin showed stronger tumor inhibition than low-dose anlotinib plus epirubicin, or anlotinib alone (P < .001) or epirubicin alone (P < .001).	('stronger', 'PosReg', (78, 86))	('anlotinib', 'Chemical', 'MESH:C000625192', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('anlotinib', 'Chemical', 'MESH:C000625192', (118, 127))	('anlotinib', 'Chemical', 'MESH:C000625192', (46, 55))	('tumor', 'Disease', (87, 92))	('anlotinib', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('epirubicin', 'Chemical', 'MESH:D015251', (60, 70))	('epirubicin', 'Chemical', 'MESH:D015251', (133, 143))	('epirubicin', 'Chemical', 'MESH:D015251', (178, 188))
337884	32181596	Necrosis and apoptosis were most notable in the combined high-dose anlotinib and epirubicin group (Figure 5).	('Necrosis', 'Disease', 'MESH:D009336', (0, 8))	('Necrosis', 'Disease', (0, 8))	('apoptosis', 'CPA', (13, 22))	('anlotinib', 'Chemical', 'MESH:C000625192', (67, 76))	('epirubicin', 'Chemical', 'MESH:D015251', (81, 91))	('anlotinib', 'Var', (67, 76))
337972	31488201	In a study of extremity soft tissue sarcomas, a cohort study and a retrospective study reported that postoperative radiation therapy may improve the survival advantage in large (> 5 cm) high-grade lesions.	('soft tissue sarcomas', 'Disease', (24, 44))	('improve', 'PosReg', (137, 144))	('high-grade', 'Var', (186, 196))	('survival advantage', 'CPA', (149, 167))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (24, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (24, 44))
338032	26962353	The chromosomal abnormalities detected were monosomy 7, trisomy 8, trisomy 4, and monosomy 16.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (4, 29))	('chromosomal abnormalities', 'Disease', (4, 29))	('monosomy 7', 'Disease', (44, 54))	('trisomy', 'Disease', (56, 63))	('monosomy 16', 'Var', (82, 93))	('trisomy', 'Disease', (67, 74))
338144	24167613	We also investigated the in vitro cell growth inhibition induced by MIF and SCD1 inhibitors in a mouse MFH cell line.	('inhibitors', 'Var', (81, 91))	('SCD1', 'Gene', (76, 80))	('mouse', 'Species', '10090', (97, 102))	('cell growth', 'CPA', (34, 45))	('MIF', 'Gene', (68, 71))
338157	24167613	We defined the integrated statistic p' as p 1 x p 2, where p 1 indicates the p value calculated by Welch's t-test and p 2 indicates the p value calculated by the log-rank test.	('p 1', 'Gene', '1423', (42, 45))	('p 1', 'Gene', '1423', (59, 62))	('p 1', 'Gene', (42, 45))	('p 1', 'Gene', (59, 62))	('rat', 'Species', '10116', (20, 23))	('p 2', 'Var', (118, 121))
338190	24167613	Figure 3B shows that the survival rate of the MIF-positive group (n = 44) was significantly lower than that of the MIF-negative group (n = 44) (p = 0.0146 as calculated by the log-rank test).	('survival rate', 'CPA', (25, 38))	('MIF-positive', 'Var', (46, 58))	('lower', 'NegReg', (92, 97))	('rat', 'Species', '10116', (34, 37))
338191	24167613	Similarly, Figure 3C shows that the survival rate of the SCD1 positive group (n = 44) was significantly lower than that of the SCD1-negative group (n = 44) (p = 0.00606 as calculated by the log-rank test).	('positive', 'Var', (62, 70))	('SCD1', 'Gene', (57, 61))	('lower', 'NegReg', (104, 109))	('survival rate', 'CPA', (36, 49))	('rat', 'Species', '10116', (45, 48))
338192	24167613	Furthermore, Figure 3D shows that the survival rates among groups that are double-positive (n = 20), single-positive (n = 48), and double-negative (n = 20) for MIF and SCD1 are significantly different (p = 0.000327 as calculated by the log-rank test), and that the survival rate of the double-positive group (n = 20) was much lower than that of the double-negative group (n = 20) with greater significance (p = 0.000116 as calculated by the log-rank test).	('double-negative', 'Var', (131, 146))	('rat', 'Species', '10116', (274, 277))	('survival', 'CPA', (38, 46))	('single-positive', 'Var', (101, 116))	('rat', 'Species', '10116', (47, 50))	('SCD1', 'Gene', (168, 172))	('MIF', 'Gene', (160, 163))	('different', 'Reg', (191, 200))	('double-positive', 'Var', (75, 90))	('lower', 'NegReg', (326, 331))
338196	24167613	The survival rates among groups that are double-positive (n = 2), single-positive (n = 13), and double-negative (n = 5) for MIF and SCD1 are significantly different (p = 0.0150 as calculated by the log-rank test) for MLS patients, as shown in Figure 4 and Table 5.	('patients', 'Species', '9606', (221, 229))	('double-negative', 'Var', (96, 111))	('MLS', 'Disease', 'MESH:C537466', (217, 220))	('MLS', 'Disease', (217, 220))	('different', 'Reg', (155, 164))	('rat', 'Species', '10116', (13, 16))	('single-positive', 'Var', (66, 81))
338212	24167613	For example, MIF depletion or pharmacologic inhibition in breast tumor cells changed tumor growth only slightly, but blocked metastasis, as reported by Simpson et al.	('tumor', 'Disease', (85, 90))	('breast tumor', 'Disease', (58, 70))	('metastasis', 'CPA', (125, 135))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('depletion', 'Var', (17, 26))	('breast tumor', 'Phenotype', 'HP:0100013', (58, 70))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('MIF', 'Var', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('breast tumor', 'Disease', 'MESH:D001943', (58, 70))	('blocked', 'NegReg', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
338220	24167613	In addition, a single in vivo study has been conducted using a human gastric cancer xenograft model that was inhibited by A939572.	('gastric cancer', 'Disease', (69, 83))	('human', 'Species', '9606', (63, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('A939572', 'Var', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('A939572', 'Chemical', '-', (122, 129))
338224	24167613	Moreover, gene silencing of MIF or SCD1 has been carried out for many kinds of cancers, again with the exception of STS.	('MIF', 'Gene', (28, 31))	('cancers', 'Disease', (79, 86))	('SCD1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('gene silencing', 'Var', (10, 24))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
338229	24167613	MIF also can induce invasion and metastasis via G-protein-coupled chemokine receptors (CXCR2 and CXCR4).	('MIF', 'Var', (0, 3))	('CXCR4', 'Gene', (97, 102))	('CXCR2', 'Gene', '3579', (87, 92))	('induce', 'PosReg', (13, 19))	('CXCR2', 'Gene', (87, 92))	('CXCR4', 'Gene', '7852', (97, 102))	('G-protein-coupled chemokine receptors', 'Protein', (48, 85))
338258	22964594	The use of high dose chemotherapy to eradicate disease in these aggressive pediatric malignancies, specifically alkylating agents, anthracyclines, and epipodophyllotoxins increased the risk of SMNs.	('aggressive pediatric malignancies', 'Disease', (64, 97))	('SMNs', 'Disease', (193, 197))	('aggressive pediatric malignancies', 'Disease', 'MESH:D063766', (64, 97))	('epipodophyllotoxins', 'Var', (151, 170))	('SMNs', 'Chemical', '-', (193, 197))	('anthracyclines', 'Chemical', 'MESH:D018943', (131, 145))	('epipodophyllotoxins', 'Chemical', 'MESH:D011034', (151, 170))
338452	32076484	ATR-CHK1 pathway blockade in systems with high RS via CHK1 inhibitors results in unscheduled DNA synthesis even in the presence of DNA damage; the bypass of the RS response checkpoint (also known as the intra-S checkpoint) results in DNA fragmentation, replication catastrophe, and cell death.	('CHK1', 'Gene', (4, 8))	('CHK1', 'Gene', '1111', (54, 58))	('bypass', 'Var', (147, 153))	('ATR', 'Gene', (0, 3))	('ATR', 'Gene', '545', (0, 3))	('cell death', 'CPA', (282, 292))	('results in', 'Reg', (223, 233))	('DNA fragmentation', 'CPA', (234, 251))	('CHK1', 'Gene', '1111', (4, 8))	('CHK1', 'Gene', (54, 58))	('results in', 'Reg', (70, 80))	('replication catastrophe', 'CPA', (253, 276))
338457	32076484	A phase 1 clinical trial (NCT01115790) of single-agent prexasertib in head and neck squamous cell carcinoma (HNSCC) and squamous cell carcinoma of the anus (SCCA) identified loss-of-function (LOF) mutations in the E3 ubiquitin ligase FBXW7 in patients with clinical benefit.	('loss-of-function', 'NegReg', (174, 190))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (70, 107))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (79, 107))	('patients', 'Species', '9606', (243, 251))	('FBXW7', 'Gene', '55294', (234, 239))	('squamous cell carcinoma of the anus', 'Disease', (120, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('neck squamous cell carcinoma', 'Disease', (79, 107))	('mutations', 'Var', (197, 206))	('FBXW7', 'Gene', (234, 239))	('squamous cell carcinoma of the anus', 'Disease', 'MESH:D002294', (120, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('HNSCC', 'Disease', 'MESH:C535575', (109, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('HNSCC', 'Disease', (109, 114))
338465	32076484	Previously, loss-of-function mutations in BRCA1 and FBXW7, an E3 ubiquitin ligase that marks cyclin E for proteolytic destruction, were associated with clinical benefit in patients with HNSCC or SCCA.	('BRCA1', 'Gene', '672', (42, 47))	('cyclin', 'Gene', (93, 99))	('HNSCC', 'Disease', 'MESH:C535575', (186, 191))	('HNSCC', 'Disease', (186, 191))	('BRCA1', 'Gene', (42, 47))	('mutations', 'Var', (29, 38))	('FBXW7', 'Gene', '55294', (52, 57))	('SCCA', 'Disease', (195, 199))	('loss-of-function', 'NegReg', (12, 28))	('patients', 'Species', '9606', (172, 180))	('FBXW7', 'Gene', (52, 57))	('cyclin', 'Gene', '5111', (93, 99))
338466	32076484	We hypothesized that loss of FBXW7 would lead to increased cyclin E1 and thus shift the equilibrium of CDK2 towards its active state, resulting in elevated basal level of RS and sensitivity to CHK1 inhibition.	('loss', 'Var', (21, 25))	('basal level of RS', 'MPA', (156, 173))	('CHK1', 'Gene', '1111', (193, 197))	('sensitivity', 'MPA', (178, 189))	('shift', 'Reg', (78, 83))	('CDK2', 'Gene', (103, 107))	('increased', 'PosReg', (49, 58))	('FBXW7', 'Gene', '55294', (29, 34))	('cyclin E1', 'Gene', '898', (59, 68))	('elevated', 'PosReg', (147, 155))	('CHK1', 'Gene', (193, 197))	('CDK2', 'Gene', '1017', (103, 107))	('cyclin E1', 'Gene', (59, 68))	('FBXW7', 'Gene', (29, 34))
338468	32076484	FBXW7 mutations and amplification of CCNE1 (the gene that encodes cyclin E1) occur in these tumor types (FBXW7 mutations: approximately 1.5% of breast and ovarian cancers; CCNE1 amplification [> 4 copies]: 2.3% in breast cancer, 17.6% in ovarian cancer based on TCGA_B38 data).	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('FBXW7', 'Gene', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('FBXW7', 'Gene', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('breast cancer', 'Disease', (214, 227))	('cyclin E1', 'Gene', (66, 75))	('ovarian cancer', 'Disease', (155, 169))	('mutations', 'Var', (111, 120))	('CCNE1', 'Gene', (37, 42))	('breast and ovarian cancers', 'Disease', 'MESH:D061325', (144, 170))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CCNE1', 'Gene', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('FBXW7', 'Gene', '55294', (105, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (238, 252))	('CCNE1', 'Gene', '898', (37, 42))	('FBXW7', 'Gene', '55294', (0, 5))	('amplification', 'PosReg', (178, 191))	('CCNE1', 'Gene', '898', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('ovarian cancer', 'Disease', (238, 252))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cyclin E1', 'Gene', '898', (66, 75))	('ovarian cancer', 'Phenotype', 'HP:0100615', (238, 252))	('tumor', 'Disease', (92, 97))	('ovarian cancer', 'Disease', 'MESH:D010051', (155, 169))	('ovarian cancers', 'Phenotype', 'HP:0100615', (155, 170))
338469	32076484	Relative to a non-target control (siNT), siRNA-mediated knockdown of FBXW7 in the triple-negative breast cancer (TNBC) cell line MDA-MB-468 resulted in elevated cyclin E1, DNA damage as evidenced by increased gammaH2AX, and CHK1 pathway activation as measured by CHK1 phosphorylation at S317 (the ATR-mediated phosphorylation site), (Figure 1A).	('CHK1', 'Gene', (224, 228))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cyclin E1', 'Gene', (161, 170))	('CHK1', 'Gene', (263, 267))	('gammaH2AX', 'MPA', (209, 218))	('FBXW7', 'Gene', (69, 74))	('CHK1', 'Gene', '1111', (224, 228))	('ATR', 'Gene', (297, 300))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('elevated', 'PosReg', (152, 160))	('CHK1', 'Gene', '1111', (263, 267))	('activation', 'PosReg', (237, 247))	('increased', 'PosReg', (199, 208))	('knockdown', 'Var', (56, 65))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Disease', (98, 111))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (129, 139))	('cyclin E1', 'Gene', '898', (161, 170))	('FBXW7', 'Gene', '55294', (69, 74))	('DNA damage', 'MPA', (172, 182))	('ATR', 'Gene', '545', (297, 300))
338470	32076484	In addition, increased phosphorylation of the CDK2 substrate nucleophosmin was observed, indicative of elevated CDK2 activity following FBXW7 knockdown (Figure 1A).	('FBXW7', 'Gene', '55294', (136, 141))	('CDK2', 'Gene', '1017', (46, 50))	('activity', 'MPA', (117, 125))	('knockdown', 'Var', (142, 151))	('FBXW7', 'Gene', (136, 141))	('increased', 'PosReg', (13, 22))	('CDK2', 'Gene', '1017', (112, 116))	('nucleophosmin', 'Gene', '4869', (61, 74))	('CDK2', 'Gene', (46, 50))	('elevated', 'PosReg', (103, 111))	('nucleophosmin', 'Gene', (61, 74))	('CDK2', 'Gene', (112, 116))
338471	32076484	In contrast to MDA-MB-468, FBXW7 knockdown did not increase, cyclin E1 levels, CHK1 activation, DNA damage, or RS in a second TNBC cell line, MDA-MB-231.	('activation', 'PosReg', (84, 94))	('knockdown', 'Var', (33, 42))	('FBXW7', 'Gene', '55294', (27, 32))	('CHK1', 'Gene', (79, 83))	('FBXW7', 'Gene', (27, 32))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (142, 152))	('cyclin E1', 'Gene', (61, 70))	('CHK1', 'Gene', '1111', (79, 83))	('DNA damage', 'MPA', (96, 106))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (15, 25))	('cyclin E1', 'Gene', '898', (61, 70))
338474	32076484	Consistent with a link between CDK2 activation and drug response, FBXW7 knockdown sensitized MDA-MB-468 but not MDA-MB-231 cells to the CHK1 inhibitor (Figure 1B).	('CHK1', 'Gene', (136, 140))	('FBXW7', 'Gene', '55294', (66, 71))	('CHK1', 'Gene', '1111', (136, 140))	('CDK2', 'Gene', (31, 35))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (93, 103))	('CDK2', 'Gene', '1017', (31, 35))	('FBXW7', 'Gene', (66, 71))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))	('knockdown', 'Var', (72, 81))	('sensitized', 'Reg', (82, 92))
338475	32076484	Interestingly, BRCA1 knockdown was not associated with elevated RS or DNA damage (Figure 1A), nor did it sensitize to prexasertib response in a cell viability assay (Figure 1B).	('elevated RS', 'Disease', (55, 66))	('BRCA1', 'Gene', '672', (15, 20))	('sensitize', 'Reg', (105, 114))	('elevated RS', 'Disease', 'MESH:D041441', (55, 66))	('BRCA1', 'Gene', (15, 20))	('knockdown', 'Var', (21, 30))	('DNA damage', 'MPA', (70, 80))
338480	32076484	To identify molecular traits tracking with prexasertib response across the pan-cancer cell line panel genetic variants, including mutations, insertion/deletions, frame-shift alterations, splice mutations, and copy number alterations derived from whole-exome analysis were investigated for association with response to prexasertib.	('frame-shift alterations', 'Var', (162, 185))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('insertion/deletions', 'Var', (141, 160))	('mutations', 'Var', (130, 139))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
338490	32076484	As expected, copy number amplification of MYCN was detected in the KELLY and IMR-32 neuroblastoma models as were characteristic gene rearrangements in alveolar rhabdomyosarcoma (aRMS) (PAX3-FOXO1) and Ewing sarcoma (EWS-FLT1) models (Supplementary Table 4).	('MYCN', 'Gene', '4613', (42, 46))	('Ewing sarcoma', 'Disease', (201, 214))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (201, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('EWS', 'Gene', (216, 219))	('FOXO1', 'Gene', (190, 195))	('alveolar rhabdomyosarcoma', 'Disease', (151, 176))	('FLT1', 'Gene', (220, 224))	('MYCN', 'Gene', (42, 46))	('neuroblastoma', 'Disease', (84, 97))	('FLT1', 'Gene', '2321', (220, 224))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (160, 176))	('neuroblastoma', 'Phenotype', 'HP:0003006', (84, 97))	('PAX3', 'Gene', (185, 189))	('EWS', 'Gene', '2130', (216, 219))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (151, 176))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (201, 214))	('neuroblastoma', 'Disease', 'MESH:D009447', (84, 97))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (151, 176))	('PAX3', 'Gene', '5077', (185, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('copy number amplification', 'Var', (13, 38))	('FOXO1', 'Gene', '2308', (190, 195))
338491	32076484	MYCN mRNA expression appeared to track with evidence of genomic amplification in NBL.	('NBL', 'Gene', (81, 84))	('MYCN', 'Gene', '4613', (0, 4))	('genomic amplification', 'Var', (56, 77))	('MYCN', 'Gene', (0, 4))
338493	32076484	Prexasertib response appeared to track with the presence of MYC/MYCN amplification and PAX3-FOXO1 rearrangements (Supplementary Table 4).	('FOXO1', 'Gene', (92, 97))	('FOXO1', 'Gene', '2308', (92, 97))	('MYC', 'Gene', '4609', (60, 63))	('MYC', 'Gene', '4609', (64, 67))	('MYC', 'Gene', (64, 67))	('PAX3', 'Gene', '5077', (87, 91))	('MYC', 'Gene', (60, 63))	('PAX3', 'Gene', (87, 91))	('MYCN', 'Gene', (64, 68))	('MYCN', 'Gene', '4613', (64, 68))	('rearrangements', 'Var', (98, 112))
338499	32076484	Western blot analysis of NCI-H520 and NCI-H520R whole cell lysates revealed only subtle differences at baseline, with higher levels of BRCA1 in NCI-H520R compared to parental cells being one of the more noteworthy distinctions (Figure 6B).	('higher', 'PosReg', (118, 124))	('levels', 'MPA', (125, 131))	('BRCA1', 'Gene', '672', (135, 140))	('H520R', 'Mutation', 'rs751058150', (42, 47))	('BRCA1', 'Gene', (135, 140))	('NCI-H520R', 'Var', (144, 153))	('H520R', 'Mutation', 'rs751058150', (148, 153))
338501	32076484	Importantly, decreasing auto-phosphorylation of CHK1 at S296 was observed in drug-treated cells for both parental and resistant tumor lines, indicative that prexasertib was still inhibiting CHK1 kinase activity (Figure 6B).	('auto-phosphorylation', 'MPA', (24, 44))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CHK1', 'Gene', '1111', (190, 194))	('inhibiting', 'NegReg', (179, 189))	('decreasing', 'NegReg', (13, 23))	('CHK1', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('CHK1', 'Gene', (190, 194))	('activity', 'MPA', (202, 210))	('at S296', 'Var', (53, 60))	('CHK1', 'Gene', '1111', (48, 52))
338504	32076484	A distinct difference in markers of epithelial-mesenchymal transition (EMT) between NCI-H520 and NCI-H520R was clearly evident, with mesenchymal markers (e. g. vimentin, N-cadherin) present in the parental line and epithelial markers (e. g. E-cadherin) in the resistant line (Supplementary Figure 1A and 1B).	('NCI-H520', 'Var', (84, 92))	('N-cadherin', 'Gene', '1000', (170, 180))	('vimentin', 'Gene', '7431', (160, 168))	('vimentin', 'Gene', (160, 168))	('H520R', 'Mutation', 'rs751058150', (101, 106))	('E-cadherin', 'Gene', (241, 251))	('E-cadherin', 'Gene', '999', (241, 251))	('NCI-H520R', 'Var', (97, 106))	('N-cadherin', 'Gene', (170, 180))
338506	32076484	HH4 methylation has been associated with enhanced DNA damage repair and protection against replication stress.	('H4', 'Chemical', 'MESH:D006859', (1, 3))	('enhanced', 'PosReg', (41, 49))	('methylation', 'Var', (4, 15))	('HH4', 'Gene', (0, 3))	('DNA damage repair', 'MPA', (50, 67))	('replication stress', 'CPA', (91, 109))
338507	32076484	Other interesting changes in protein levels included cyclin' A2 and HLA-ABC elevation in NCI-H520R versus NCI-H520 (Supplementary Figure 1A).	("cyclin' A2", 'Gene', (53, 63))	('protein levels', 'MPA', (29, 43))	("cyclin' A2", 'Gene', '890', (53, 63))	('NCI-H520R', 'Var', (89, 98))	('H520R', 'Mutation', 'rs751058150', (93, 98))	('elevation', 'PosReg', (76, 85))	('HLA-ABC', 'Gene', (68, 75))
338510	32076484	In contrast, microarray analysis revealed a marked difference in transcriptional profile between NCI-H520R and NCI-H520 with 1,999 genes displaying >1.5-fold change and 2,052 genes displaying <-1.5-fold change in resistant versus parental (FDR<0.05) (Supplementary Table 7).	('NCI-H520R', 'Var', (97, 106))	('H520R', 'Mutation', 'rs751058150', (101, 106))	('transcriptional', 'MPA', (65, 80))
338514	32076484	Genes down regulated in H520 resistant/parental were predominantly mesenchymal markers (VIM, FN1, ZEB1), consistent with the mesenchymal/epithelial shift revealed by proteomic analyses (Supplementary Figure 1).	('H520 resistant/parental', 'Var', (24, 47))	('down regulated', 'NegReg', (6, 20))	('mesenchymal', 'CPA', (67, 78))	('ZEB1', 'Gene', (98, 102))	('VIM', 'Gene', (88, 91))	('ZEB1', 'Gene', '6935', (98, 102))	('FN1', 'Gene', '2335', (93, 96))	('FN1', 'Gene', (93, 96))	('VIM', 'Gene', '7431', (88, 91))
338526	32076484	SJC-Rh30, SJC-Rh30R, and SJC-Rh30reS showed the expected increases in pRPA2 and gammaH2AX following prexasertib treatment, with SJC-Rh30reS appearing to have intermediate expression of these markers when compared to the parental or resistant lines (Figure 9B).	('RPA2', 'Gene', (71, 75))	('RPA2', 'Gene', '6118', (71, 75))	('SJC-Rh30reS', 'Var', (128, 139))	('increases', 'PosReg', (57, 66))	('gammaH2AX', 'MPA', (80, 89))
338530	32076484	Striking upregulation of multiple immune-related pathways was observed across all Rh41R cultures (Figures 8 and 10; Supplementary Table 10).	('Rh41', 'Chemical', 'MESH:D012238', (82, 86))	('Rh41R', 'Var', (82, 87))	('upregulation', 'PosReg', (9, 21))	('immune-related pathways', 'Pathway', (34, 57))
338531	32076484	Similar to previous findings in the pan-cancer cell line panel, multiple components of the innate immunity/STING pathway (including PRR, IFN signaling, MHC presentation, and PD-L1-mediated immune checkpoints) were identified as at least two-fold higher in Rh41R (FDR< 0.05) (Figure 10).	('Rh41', 'Chemical', 'MESH:D012238', (256, 260))	('IFN', 'Gene', '3439', (137, 140))	('STING', 'Gene', (107, 112))	('MHC', 'Gene', (152, 155))	('higher', 'PosReg', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('MHC', 'Gene', '3107', (152, 155))	('IFN', 'Gene', (137, 140))	('Rh41R', 'Var', (256, 261))	('cancer', 'Disease', (40, 46))	('PD-L1', 'Gene', (174, 179))	('PRR', 'MPA', (132, 135))	('STING', 'Gene', '340061', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('PD-L1', 'Gene', '29126', (174, 179))
338539	32076484	GSEA revealed an enrichment for MYC targets, G2M checkpoint, and E2F targets as the most statistically significant genes sets which sensitized NCI-H520R cells to prexasertib upon knockdown (FDR< 7E-20) (Figure 11A).	('H520R', 'Mutation', 'rs751058150', (147, 152))	('MYC', 'Gene', (32, 35))	('knockdown', 'Var', (179, 188))	('sensitized', 'Reg', (132, 142))	('MYC', 'Gene', '4609', (32, 35))
338541	32076484	The single-stranded DNA-binding protein encoding genes, RPA1 and RPA2 as well as several minichromosome maintenance complex genes (MCM10, MCM2, and MCM7) induced the strongest sensitization effect on NCI-H520R upon siRNA-mediated knockdown relative to the non-target control.	('H520R', 'Mutation', 'rs751058150', (204, 209))	('MCM7', 'Gene', '4176', (148, 152))	('NCI-H520R', 'Gene', (200, 209))	('sensitization', 'MPA', (176, 189))	('MCM10', 'Gene', (131, 136))	('MCM10', 'Gene', '55388', (131, 136))	('RPA1', 'Gene', (56, 60))	('MCM7', 'Gene', (148, 152))	('knockdown', 'Var', (230, 239))	('RPA2', 'Gene', (65, 69))	('RPA2', 'Gene', '6118', (65, 69))	('RPA1', 'Gene', '6117', (56, 60))	('MCM2', 'Gene', '4171', (138, 142))	('MCM2', 'Gene', (138, 142))
338542	32076484	The tertiary screen demonstrated that knockdown of BRCA1, BRCA2, FOXM1, CCNK, and CDK12 did not sensitize NCI-H520R cells to prexasertib.	('CDK12', 'Gene', '51755', (82, 87))	('BRCA2', 'Gene', '675', (58, 63))	('BRCA1', 'Gene', '672', (51, 56))	('CDK12', 'Gene', (82, 87))	('CCNK', 'Gene', (72, 76))	('CCNK', 'Gene', '8812', (72, 76))	('BRCA1', 'Gene', (51, 56))	('H520R', 'Mutation', 'rs751058150', (110, 115))	('FOXM1', 'Gene', (65, 70))	('BRCA2', 'Gene', (58, 63))	('knockdown', 'Var', (38, 47))	('FOXM1', 'Gene', '2305', (65, 70))	('sensitize', 'Reg', (96, 105))
338543	32076484	The absence of sensitization to prexasertib with BRCA1 knockdown in this experiment parallels observations made with TNBC tumor lines where depletion of this gene had no effect on prexasertib sensitivity (Figure 1).	('knockdown', 'Var', (55, 64))	('BRCA1', 'Gene', '672', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('BRCA1', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
338544	32076484	To further characterize NCI-H520 and NCI-H520R following siRNA-mediated knockdown of replication fork components, cells were transfected with non-target control or with siRNA targeting MCM7, MCM10, or RPA2.	('MCM7', 'Gene', '4176', (185, 189))	('RPA2', 'Gene', '6118', (201, 205))	('MCM7', 'Gene', (185, 189))	('H520R', 'Mutation', 'rs751058150', (41, 46))	('MCM10', 'Gene', (191, 196))	('MCM10', 'Gene', '55388', (191, 196))	('RPA2', 'Gene', (201, 205))	('knockdown', 'Var', (72, 81))
338545	32076484	All three replication fork genes sensitized the resistant tumor line to prexasertib upon knockdown but had no effect on parental cell sensitivity (Figure 11C, 11D).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('sensitized', 'Reg', (33, 43))	('knockdown', 'Var', (89, 98))
338548	32076484	Higher protein levels of MCM10 could be observed in NCI-H520R compared to the parental line (Figure 12), consistent with RNASeq data (Supplementary Table 7).	('MCM10', 'Gene', '55388', (25, 30))	('MCM10', 'Gene', (25, 30))	('Higher', 'PosReg', (0, 6))	('H520R', 'Mutation', 'rs751058150', (56, 61))	('NCI-H520R', 'Var', (52, 61))	('protein levels', 'MPA', (7, 21))
338551	32076484	CCNA2 emerged as an unexpected outlier in inducing a profound de-sensitizing effect upon knockdown (Figure 13A).	('CCNA2', 'Gene', '890', (0, 5))	('de-sensitizing', 'NegReg', (62, 76))	('CCNA2', 'Gene', (0, 5))	('knockdown', 'Var', (89, 98))
338554	32076484	However, CCNA2 knockdown did not change MRE11A protein levels in neither NCI-H520 nor in OVCAR-3 tumor cells (Supplementary Figures 3 and 4).	('MRE11A', 'Gene', '4361', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('knockdown', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CCNA2', 'Gene', (9, 14))	('tumor', 'Disease', (97, 102))	('MRE11A', 'Gene', (40, 46))	('CCNA2', 'Gene', '890', (9, 14))
338556	32076484	Knockout of replication fork-associated genes enhanced the sensitivity of OV90 to prexasertib and knockout of DREAM complex genes, CDC25A, CDK2, LIN54, CCNA2, had the largest de-sensitizing effect (Supplementary Figure 5 and Supplementary Table 15).	('LIN54', 'Gene', (145, 150))	('OV90 to prexasertib', 'MPA', (74, 93))	('CDK2', 'Gene', '1017', (139, 143))	('sensitivity', 'MPA', (59, 70))	('knockout', 'Var', (98, 106))	('CCNA2', 'Gene', (152, 157))	('Knockout', 'Var', (0, 8))	('CDK2', 'Gene', (139, 143))	('enhanced', 'PosReg', (46, 54))	('LIN54', 'Gene', '132660', (145, 150))	('CDC25A', 'Gene', (131, 137))	('CDC25A', 'Gene', '993', (131, 137))	('CCNA2', 'Gene', '890', (152, 157))	('de-sensitizing', 'MPA', (175, 189))
338557	32076484	Approximately 10-15% of patients across separate clinical trials (NCT01115790, HNSCC, SCC; NCT02735980, SCLC; NCT02203513 HGSOC) have had some evidence of clinical benefit in response to prexasertib monotherapy.	('HNSCC', 'Disease', (79, 84))	('benefit', 'PosReg', (164, 171))	('NCT01115790', 'Var', (66, 77))	('clinical', 'MPA', (155, 163))	('response', 'MPA', (175, 183))	('patients', 'Species', '9606', (24, 32))	('SCLC', 'Disease', (104, 108))	('SCLC', 'Disease', 'MESH:D018288', (104, 108))	('HNSCC', 'Disease', 'MESH:C535575', (79, 84))
338558	32076484	An initial search for predictive biomarkers in these patients revealed a signal centered on cyclin E1, such as LOF mutations in the E3 ubiquitin ligase FBXW7 and elevation of cyclin E1 protein levels.	('mutations', 'Var', (115, 124))	('cyclin E1', 'Gene', '898', (175, 184))	('LOF', 'NegReg', (111, 114))	('patients', 'Species', '9606', (53, 61))	('elevation', 'PosReg', (162, 171))	('FBXW7', 'Gene', '55294', (152, 157))	('cyclin E1', 'Gene', (92, 101))	('FBXW7', 'Gene', (152, 157))	('cyclin E1', 'Gene', (175, 184))	('cyclin E1', 'Gene', '898', (92, 101))
338559	32076484	Here, we confirmed that FBXW7 knockdown is associated with elevation of cyclin E1 protein levels, CDK2 activation, CHK1 signaling, and increased RS (as measured by pRPA2) and DNA damage (evidenced by gammaH2AX).	('cyclin E1', 'Gene', (72, 81))	('CHK1', 'Gene', '1111', (115, 119))	('FBXW7', 'Gene', '55294', (24, 29))	('CDK2', 'Gene', '1017', (98, 102))	('RPA2', 'Gene', (165, 169))	('DNA damage', 'MPA', (175, 185))	('increased', 'PosReg', (135, 144))	('FBXW7', 'Gene', (24, 29))	('elevation', 'PosReg', (59, 68))	('CHK1', 'Gene', (115, 119))	('RPA2', 'Gene', '6118', (165, 169))	('knockdown', 'Var', (30, 39))	('cyclin E1', 'Gene', '898', (72, 81))	('activation', 'PosReg', (103, 113))	('CDK2', 'Gene', (98, 102))
338560	32076484	Relative to its non-target control, FBXW7 knockdown enhanced the cytotoxic activity of prexasertib, supporting the hypothesis that FBXW7 LOF mutations play a role in driving clinical response.	('FBXW7', 'Gene', '55294', (36, 41))	('cytotoxic', 'CPA', (65, 74))	('mutations', 'Var', (141, 150))	('FBXW7', 'Gene', (36, 41))	('FBXW7', 'Gene', '55294', (131, 136))	('enhanced', 'PosReg', (52, 60))	('LOF', 'NegReg', (137, 140))	('FBXW7', 'Gene', (131, 136))	('knockdown', 'Var', (42, 51))
338562	32076484	Importantly, we observed one cancer cell line in which elevated cyclin E1 caused by knockdown of FBXW7 did not appear to activate CDK2 (as measured by pNPM).	('CDK2', 'Gene', (130, 134))	('cancer', 'Disease', (29, 35))	('cyclin E1', 'Gene', '898', (64, 73))	('CDK2', 'Gene', '1017', (130, 134))	('knockdown', 'Var', (84, 93))	('FBXW7', 'Gene', '55294', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('elevated', 'PosReg', (55, 63))	('FBXW7', 'Gene', (97, 102))	('cyclin E1', 'Gene', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
338564	32076484	reported that excessive p21 limits S phase DNA damage caused by the WEE1 inhibitor MK1775 (adavosertib), again supporting the notion that negative regulators of CDK2 may limit cytotoxicity to agents that target the ATR-CHK1-WEE1 pathway.	('ATR', 'Gene', (215, 218))	('MK1775', 'Chemical', 'MESH:C549567', (83, 89))	('CDK2', 'Gene', '1017', (161, 165))	('WEE1', 'Gene', (68, 72))	('limit', 'NegReg', (170, 175))	('CHK1', 'Gene', '1111', (219, 223))	('cytotoxicity', 'Disease', (176, 188))	('CDK2', 'Gene', (161, 165))	('cytotoxicity', 'Disease', 'MESH:D064420', (176, 188))	('p21', 'Gene', (24, 27))	('p21', 'Gene', '644914', (24, 27))	('adavosertib', 'Chemical', 'None', (91, 102))	('WEE1', 'Gene', (224, 228))	('limits', 'NegReg', (28, 34))	('ATR', 'Gene', '545', (215, 218))	('MK1775', 'Var', (83, 89))	('WEE1', 'Gene', '7465', (68, 72))	('CHK1', 'Gene', (219, 223))	('S phase DNA damage', 'MPA', (35, 53))	('WEE1', 'Gene', '7465', (224, 228))
338574	32076484	Microarray analysis, in contrast, identified the E2F/G2M/SAC signature previously observed in the pan-cancer panel and sarcoma/neuroblastoma xenograft study as a driver of sensitivity to prexasertib.	('E2F/G2M/SAC', 'Var', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('sarcoma/neuroblastoma', 'Disease', 'MESH:D009447', (119, 140))	('neuroblastoma', 'Phenotype', 'HP:0003006', (127, 140))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcoma/neuroblastoma', 'Disease', (119, 140))
338576	32076484	The source of RS could be oncogene-driven mechanisms like increased or dysregulated cyclin E but they could also be drug-induced such as chronic prexasertib exposure, a mechanism known to trigger DNA damage.	('dysregulated', 'Var', (71, 83))	('cyclin', 'Gene', '5111', (84, 90))	('increased', 'PosReg', (58, 67))	('cyclin', 'Gene', (84, 90))
338587	32076484	BRCA2 deficiency activated a cGAS/TNFalpha inflammatory signal.	('BRCA2', 'Gene', '675', (0, 5))	('TNFalpha', 'Gene', (34, 42))	('TNFalpha', 'Gene', '7124', (34, 42))	('deficiency', 'Var', (6, 16))	('activated', 'PosReg', (17, 26))	('BRCA2', 'Gene', (0, 5))
338599	32076484	Interestingly, siRNA-mediated knockdown of CCNA2 had a profound de-sensitizing effect to prexasertib treatment.	('CCNA2', 'Gene', '890', (43, 48))	('de-sensitizing', 'NegReg', (64, 78))	('CCNA2', 'Gene', (43, 48))	('knockdown', 'Var', (30, 39))
338611	32076484	Our findings are relevant to other targetable components of the CHK1 pathway (e. g. ATM, ATR, WEE1) as inhibitors of these protein kinases may, like prexasertib, stimulate a STING-mediated IFN response upon DNA damage.	('STING', 'Gene', (174, 179))	('WEE1', 'Gene', '7465', (94, 98))	('ATM', 'Gene', (84, 87))	('WEE1', 'Gene', (94, 98))	('ATR', 'Gene', (89, 92))	('CHK1', 'Gene', '1111', (64, 68))	('ATR', 'Gene', '545', (89, 92))	('STING', 'Gene', '340061', (174, 179))	('IFN', 'Gene', '3439', (189, 192))	('ATM', 'Gene', '472', (84, 87))	('inhibitors', 'Var', (103, 113))	('stimulate', 'PosReg', (162, 171))	('IFN', 'Gene', (189, 192))	('CHK1', 'Gene', (64, 68))
338614	32076484	Drug studies were conducted with LY2940930, the mesylate monohydrate salt of LY2606368 (prexasertib, Eli Lilly and Company), and is referred to as prexasertib in this study.	('LY2940930', 'Var', (33, 42))	('LY2606368', 'Var', (77, 86))	('mesylate', 'Chemical', 'MESH:D008698', (48, 56))	('LY2940930', 'Chemical', 'MESH:C430423', (33, 42))
338616	32076484	Parental NCI-H520 and its prexasertib-resistant version are referred to in abbreviated form as H520 and H520R in figure titles.	('H520R', 'Var', (104, 109))	('H520', 'Var', (95, 99))	('H520R', 'Mutation', 'rs751058150', (104, 109))
338633	32076484	Therefore five comparisons using MAGeCK were derived: DMSO_vs_Base, IC20_vs_Base, IC90_vs_Base, IC20_vs_DMSO, IC90_vs_DMSO.	('DMSO_vs_Base', 'Var', (54, 66))	('IC90_vs_Base', 'Var', (82, 94))	('DMSO', 'Chemical', 'MESH:D004121', (118, 122))	('IC20_vs_Base', 'Var', (68, 80))	('DMSO', 'Chemical', 'MESH:D004121', (54, 58))	('IC20_vs_DMSO', 'Var', (96, 108))	('DMSO', 'Chemical', 'MESH:D004121', (104, 108))	('IC90_vs_DMSO', 'Var', (110, 122))
338659	30588089	Ewing's sarcoma (ES) is characterized by chromosomal translocation involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene, and 85% of cases are associated with translocations of EWSR1 on chromosome 22 to chromosome 11.	('associated', 'Reg', (150, 160))	("Ewing's sarcoma", 'Disease', (0, 15))	('EWSR1', 'Gene', '2130', (116, 121))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('translocations', 'Var', (166, 180))	('EWSR1', 'Gene', (184, 189))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (81, 114))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('Ewing sarcoma breakpoint region 1', 'Gene', (81, 114))	('EWSR1', 'Gene', '2130', (184, 189))	('EWSR1', 'Gene', (116, 121))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))
338700	30588089	Inhibition or blockade of VEGF can result in the suppression of ES tumor growth.	('suppression', 'NegReg', (49, 60))	('ES tumor', 'Disease', (64, 72))	('ES tumor', 'Disease', 'MESH:C563168', (64, 72))	('blockade', 'NegReg', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('VEGF', 'Gene', (26, 30))	('Inhibition', 'Var', (0, 10))	('VEGF', 'Gene', '7422', (26, 30))
338753	30131550	Successful utilisation of ctDNA for disease prognostication and association with response to therapy in patients with carcinomas has relied on the identification of highly recurrent single-nucleotide variants (SNVs).	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('carcinomas', 'Disease', (118, 128))	('carcinomas', 'Disease', 'MESH:D002277', (118, 128))	('single-nucleotide variants', 'Var', (182, 208))	('patients', 'Species', '9606', (104, 112))
338756	30131550	Ewing sarcoma is characterised by a simple translocation-driven genome, with STAG2 and TP53 loss-of-function mutations found in a minority of tumours.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('tumours', 'Disease', (142, 149))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('Ewing sarcoma', 'Disease', (0, 13))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('STAG2', 'Gene', (77, 82))	('STAG2', 'Gene', '10735', (77, 82))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('mutations', 'Var', (109, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('loss-of-function', 'NegReg', (92, 108))
338757	30131550	The majority of Ewing sarcoma tumours express an EWSR1/ETS translocation with a patient-specific intronic breakpoint, precluding the use of an assay that detects a single breakpoint across patients.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('translocation', 'Var', (59, 72))	('EWSR1', 'Gene', (49, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('patient', 'Species', '9606', (189, 196))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('EWSR1', 'Gene', '2130', (49, 54))	('Ewing sarcoma tumours', 'Disease', (16, 37))	('patients', 'Species', '9606', (189, 197))	('EWS', 'Phenotype', 'HP:0012254', (49, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('patient', 'Species', '9606', (80, 87))	('Ewing sarcoma tumours', 'Disease', 'MESH:C563168', (16, 37))
338761	30131550	8q gains are relatively common, may reflect MYC copy number gain/amplification, and may confer an inferior prognosis.	('copy number', 'Var', (48, 59))	('gain/amplification', 'PosReg', (60, 78))	('8q', 'Chemical', '-', (0, 2))
338767	30131550	Finally, we leveraged these techniques to study additional tumour characteristics (STAG2 and TP53 mutations in Ewing sarcoma; 8q gain in osteosarcoma) in ctDNA.	('osteosarcoma', 'Phenotype', 'HP:0002669', (137, 149))	('TP53', 'Gene', (93, 97))	('gain', 'PosReg', (129, 133))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('ctDNA', 'Disease', (154, 159))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))	('STAG2', 'Gene', '10735', (83, 88))	('osteosarcoma', 'Disease', (137, 149))	('osteosarcoma', 'Disease', 'MESH:D012516', (137, 149))	('TP53', 'Gene', '7157', (93, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('Ewing sarcoma', 'Disease', (111, 124))	('8q', 'Chemical', '-', (126, 128))	('STAG2', 'Gene', (83, 88))	('mutations', 'Var', (98, 107))
338776	30131550	All patients signed written informed consent at the time of enrollment to AEWS07B1 or AOST06B1.	('EWS', 'Phenotype', 'HP:0012254', (75, 78))	('AOST06B1', 'Var', (86, 94))	('EWS', 'Gene', '2130', (75, 78))	('EWS', 'Gene', (75, 78))	('patients', 'Species', '9606', (4, 12))
338780	30131550	This approach, termed TranSS-Seq, allows for the detection of translocations involving these genes and any translocation partner as well as coding mutations in TP53 and STAG2.	('translocations', 'Var', (62, 76))	('coding mutations', 'Var', (140, 156))	('STAG2', 'Gene', '10735', (169, 174))	('STAG2', 'Gene', (169, 174))	('TP53', 'Gene', '7157', (160, 164))	('TP53', 'Gene', (160, 164))
338788	30131550	The primary independent variable was ctDNA coded as positive or negative ('ctDNA positivity') for detectable fusion ctDNA in the Ewing sarcoma cohort or detectable copy number alterations in the osteosarcoma cohort.	('osteosarcoma cohort', 'Disease', 'MESH:D012516', (195, 214))	('copy number alterations', 'Var', (164, 187))	('osteosarcoma', 'Phenotype', 'HP:0002669', (195, 207))	('Ewing sarcoma cohort', 'Disease', 'MESH:C563168', (129, 149))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (129, 142))	('ctDNA', 'Gene', (116, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('Ewing sarcoma cohort', 'Disease', (129, 149))	('osteosarcoma cohort', 'Disease', (195, 214))	('ctDNA positivity', 'Phenotype', 'HP:0032229', (75, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('negative', 'NegReg', (64, 72))
338809	30131550	Among patients with tumour size collected (n = 21), 83.3% of patients with tumour size >=8 cm maximum diameter had detectable ctDNA compared to 33.3% of patients with tumour size <8 cm maximum diameter (p = 0.063, Table 2).	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('patients', 'Species', '9606', (153, 161))	('tumour', 'Disease', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))	('patients', 'Species', '9606', (61, 69))	('tumour', 'Disease', (75, 81))	('tumour', 'Disease', (20, 26))	('>=8 cm', 'Var', (87, 93))	('patients', 'Species', '9606', (6, 14))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('ctDNA', 'MPA', (126, 131))
338827	30131550	We were able to detect loss-of-function STAG2 mutations in three patients and TP53 mutations in four patients.	('loss-of-function', 'NegReg', (23, 39))	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (101, 109))	('mutations', 'Var', (46, 55))	('STAG2', 'Gene', (40, 45))	('STAG2', 'Gene', '10735', (40, 45))	('TP53', 'Gene', '7157', (78, 82))	('patients', 'Species', '9606', (65, 73))	('TP53', 'Gene', (78, 82))
338828	30131550	The allelic fraction of these mutations correlated with the % ctDNA levels observed in the patient sample suggesting these are likely somatic events.	('% ctDNA levels', 'MPA', (60, 74))	('patient', 'Species', '9606', (91, 98))	('mutations', 'Var', (30, 39))
338829	30131550	Furthermore, as germline STAG2 loss-of-function mutations have not been described, these mutations are expected to be somatic.	('STAG2', 'Gene', '10735', (25, 30))	('STAG2', 'Gene', (25, 30))	('mutations', 'Var', (48, 57))	('loss-of-function', 'NegReg', (31, 47))
338830	30131550	Although germline TP53 mutations in Ewing sarcoma are rare, we cannot definitively confirm that these events were somatic in the absence of germline DNA.	('TP53', 'Gene', '7157', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('TP53', 'Gene', (18, 22))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (36, 49))	('mutations', 'Var', (23, 32))	('Ewing sarcoma', 'Disease', (36, 49))
338839	30131550	Finally, we identified additional genomic features from ctDNA including identification of a previously undescribed EWSR1 fusion, STAG2 loss in Ewing sarcoma, and 8q gain in osteosarcoma.	('gain', 'PosReg', (165, 169))	('EWS', 'Phenotype', 'HP:0012254', (115, 118))	('EWSR1', 'Gene', (115, 120))	('Ewing sarcoma', 'Disease', (143, 156))	('loss', 'NegReg', (135, 139))	('fusion', 'Var', (121, 127))	('STAG2', 'Gene', (129, 134))	('STAG2', 'Gene', '10735', (129, 134))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (143, 156))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (143, 156))	('8q', 'Chemical', '-', (162, 164))	('osteosarcoma', 'Disease', (173, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('EWSR1', 'Gene', '2130', (115, 120))	('osteosarcoma', 'Phenotype', 'HP:0002669', (173, 185))	('osteosarcoma', 'Disease', 'MESH:D012516', (173, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
338845	30131550	Leveraging thematic genome alterations in these two genomically diverse tumours provided an avenue to efficiently detect ctDNA in diseases without highly recurrent SNVs.	('ctDNA', 'Disease', (121, 126))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('detect', 'Reg', (114, 120))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))	('alterations', 'Var', (27, 38))
338857	30131550	Yet, we could detect mutations in TP53 and STAG2 in a limited set of ctDNA Ewing sarcoma samples.	('TP53', 'Gene', (34, 38))	('Ewing sarcoma', 'Disease', (75, 88))	('detect', 'Reg', (14, 20))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('STAG2', 'Gene', (43, 48))	('STAG2', 'Gene', '10735', (43, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('TP53', 'Gene', '7157', (34, 38))	('mutations', 'Var', (21, 30))
338858	30131550	We caution that these mutations, particularly mutations in TP53, may in fact be heterozygous germline mutations.	('TP53', 'Gene', '7157', (59, 63))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (59, 63))
338869	30131550	); and the following support to COG: St. Baldrick's Foundation, U10CA180884, U10CA180886, U10CA180899, U10CA098543, U10CA098413, and U24CA114766 (COG).	('U10CA098543', 'Var', (103, 114))	('U10CA180899', 'Var', (90, 101))	('COG', 'Chemical', '-', (146, 149))	('U24CA114766', 'Var', (133, 144))	('U10CA098413', 'Var', (116, 127))	('U10CA180884', 'Var', (64, 75))	('COG', 'Chemical', '-', (32, 35))	('U10CA180886', 'Var', (77, 88))
339057	26675259	Mutation and/or overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcomas', 'Disease', (151, 159))	('RTK', 'Gene', '5979', (66, 69))	('PDGFR', 'Gene', (89, 94))	('PDGFR', 'Gene', '5159', (89, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('IGF1-R', 'Gene', '3480', (106, 112))	('c-Met', 'Gene', (82, 87))	('c-Kit', 'Gene', (96, 101))	('c-Kit', 'Gene', '3815', (96, 101))	('receptor tyrosine kinase', 'Gene', '5979', (39, 63))	('IGF1-R', 'Gene', (106, 112))	('overexpression', 'PosReg', (16, 30))	('Mutation', 'Var', (0, 8))	('defective signaling pathways', 'Pathway', (119, 147))	('c-Met', 'Gene', '4233', (82, 87))	('receptor tyrosine kinase', 'Gene', (39, 63))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('RTK', 'Gene', (66, 69))
339061	26675259	Furthermore, MGCD516 treatment of tumor xenografts in vivo resulted in significant suppression of tumor growth.	('suppression', 'NegReg', (83, 94))	('tumor', 'Disease', (34, 39))	('MGCD516', 'Chemical', 'MESH:C000611865', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MGCD516', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
339085	26675259	Both in vitro and in vivo efficacy of MGCD516 was significantly better that the other two multi-kinase inhibitors, imatinib and crizotinib.	('crizotinib', 'Chemical', 'MESH:D000077547', (128, 138))	('MGCD516', 'Var', (38, 45))	('better', 'PosReg', (64, 70))	('imatinib', 'Chemical', 'MESH:D000068877', (115, 123))	('MGCD516', 'Chemical', 'MESH:C000611865', (38, 45))
339103	26675259	MGCD516 is a potent broad-spectrum RTK inhibitor (Figure 1C) with multiple targets including Axl, c-Met, Ephrin receptor family (EphA1, A2, B1, B2, B4), as well as PDGFR and VEGFR family of kinases (Table 1).	('VEGFR', 'Gene', '3791', (174, 179))	('RTK', 'Gene', '5979', (35, 38))	('VEGFR', 'Gene', (174, 179))	('Axl', 'Gene', '558', (93, 96))	('c-Met', 'Gene', (98, 103))	('A2, B1, B2, B4)', 'Gene', '23545', (136, 151))	('MGCD516', 'Var', (0, 7))	('Eph', 'Gene', (105, 108))	('Eph', 'Gene', (129, 132))	('Axl', 'Gene', (93, 96))	('A2, B1, B2, B4', 'Gene', (136, 150))	('Eph', 'Gene', '2041', (105, 108))	('Eph', 'Gene', '2041', (129, 132))	('PDGFR', 'Gene', (164, 169))	('PDGFR', 'Gene', '5159', (164, 169))	('EphA1', 'Gene', '2041', (129, 134))	('EphA1', 'Gene', (129, 134))	('MGCD516', 'Chemical', 'MESH:C000611865', (0, 7))	('c-Met', 'Gene', '4233', (98, 103))	('RTK', 'Gene', (35, 38))
339106	26675259	As shown in Figure 2A, all the cell lines tested were sensitive to increasing concentrations of MGCD516 with three cell lines, DDLS, LS141 and MPNST, showing greater inhibition of proliferation at low nanomolar concentrations than the other two cell lines (A673, Saos2).	('inhibition', 'NegReg', (166, 176))	('proliferation', 'CPA', (180, 193))	('LS141', 'Chemical', '-', (133, 138))	('MPNST', 'Phenotype', 'HP:0100697', (143, 148))	('MGCD516', 'Chemical', 'MESH:C000611865', (96, 103))	('Saos2', 'Chemical', '-', (263, 268))	('MGCD516', 'Var', (96, 103))
339110	26675259	In addition to the down-regulation of RTK phosphorylation, we also observed significant down-regulation of p-AKT (Ser473) with increasing concentrations of MGCD516 (Figure 2B).	('MGCD516', 'Chemical', 'MESH:C000611865', (156, 163))	('Ser473', 'Chemical', '-', (114, 120))	('AKT', 'Gene', '207', (109, 112))	('down-regulation', 'NegReg', (19, 34))	('MGCD516', 'Var', (156, 163))	('RTK', 'Gene', '5979', (38, 41))	('down-regulation', 'NegReg', (88, 103))	('AKT', 'Gene', (109, 112))	('RTK', 'Gene', (38, 41))
339112	26675259	MGCD516 treatment resulted in significant down-regulation of RTK phosphorylation including the canonical RTKs PDGFRalpha, PDGFRbeta, IGF1-R and c-Met (Figure 3).	('RTK', 'Gene', '5979', (61, 64))	('PDGFRalpha', 'Gene', '5156', (110, 120))	('PDGFRbeta', 'Gene', (122, 131))	('RTK', 'Gene', (105, 108))	('IGF1-R', 'Gene', '3480', (133, 139))	('PDGFRbeta', 'Gene', '5159', (122, 131))	('PDGFRalpha', 'Gene', (110, 120))	('down-regulation', 'NegReg', (42, 57))	('RTK', 'Gene', (61, 64))	('IGF1-R', 'Gene', (133, 139))	('MGCD516', 'Var', (0, 7))	('RTK', 'Gene', '5979', (105, 108))	('MGCD516', 'Chemical', 'MESH:C000611865', (0, 7))	('c-Met', 'Gene', (144, 149))	('c-Met', 'Gene', '4233', (144, 149))
339114	26675259	Interestingly, MGCD516 demonstrated inhibition of RTKs including IGF1R and ALK that were not potently inhibited in RTK enzymatic assays (Table 1) suggesting that the inhibitory effects observed for these kinases may be mediated via heterodimerization with direct RTK targets of MGCD516 such as c-Met.	('RTK', 'Gene', '5979', (50, 53))	('ALK', 'Gene', (75, 78))	('RTK', 'Gene', (115, 118))	('MGCD516', 'Chemical', 'MESH:C000611865', (15, 22))	('inhibition', 'NegReg', (36, 46))	('heterodimerization', 'MPA', (232, 250))	('MGCD516', 'Var', (15, 22))	('RTK', 'Gene', (50, 53))	('RTK', 'Gene', (263, 266))	('IGF1R', 'Gene', (65, 70))	('ALK', 'Gene', '238', (75, 78))	('RTK', 'Gene', '5979', (263, 266))	('RTK', 'Gene', '5979', (115, 118))	('c-Met', 'Gene', (294, 299))	('IGF1R', 'Gene', '3480', (65, 70))	('c-Met', 'Gene', '4233', (294, 299))	('MGCD516', 'Chemical', 'MESH:C000611865', (278, 285))
339118	26675259	Our results (Figure 4A) showed that MGCD516 treatment was able to inhibit proliferation of LS141 and DDLS cell lines significantly better than pazopanib especially at 1000 nM/L concentration (p<0.0005) suggesting better pathway inhibition by MGCD516.	('MGCD516', 'Chemical', 'MESH:C000611865', (242, 249))	('pazopanib', 'Chemical', 'MESH:C516667', (143, 152))	('LS141', 'Chemical', '-', (91, 96))	('MGCD516', 'Chemical', 'MESH:C000611865', (36, 43))	('pathway', 'CPA', (220, 227))	('MGCD516', 'Var', (36, 43))	('inhibit', 'NegReg', (66, 73))	('proliferation', 'CPA', (74, 87))
339119	26675259	Inhibition of MPNST cell proliferation was similar for pazopanib and MGCD516 (Figure 4A) given the ability of both pazopanib and MGCD516 to inhibit PDGFR and c-Kit, the two main RTKs driving MPNST cell proliferation.	('PDGFR', 'Gene', (148, 153))	('MPNST', 'Phenotype', 'HP:0100697', (191, 196))	('PDGFR', 'Gene', '5159', (148, 153))	('RTK', 'Gene', '5979', (178, 181))	('c-Kit', 'Gene', (158, 163))	('c-Kit', 'Gene', '3815', (158, 163))	('MGCD516', 'Chemical', 'MESH:C000611865', (129, 136))	('inhibit', 'NegReg', (140, 147))	('MPNST', 'Phenotype', 'HP:0100697', (14, 19))	('MGCD516', 'Var', (129, 136))	('pazopanib', 'Chemical', 'MESH:C516667', (115, 124))	('pazopanib', 'Chemical', 'MESH:C516667', (55, 64))	('RTK', 'Gene', (178, 181))	('MGCD516', 'Chemical', 'MESH:C000611865', (69, 76))
339120	26675259	Next, we determined the efficacy of MGCD516 against crizotinib, an ALK and c-Met inhibitor, and imatinib, a PDGFR and c-Kit inhibitor.	('imatinib', 'Chemical', 'MESH:D000068877', (96, 104))	('PDGFR', 'Gene', (108, 113))	('c-Kit', 'Gene', '3815', (118, 123))	('PDGFR', 'Gene', '5159', (108, 113))	('ALK', 'Gene', '238', (67, 70))	('MGCD516', 'Chemical', 'MESH:C000611865', (36, 43))	('MGCD516', 'Var', (36, 43))	('c-Met', 'Gene', '4233', (75, 80))	('c-Met', 'Gene', (75, 80))	('crizotinib', 'Chemical', 'MESH:D000077547', (52, 62))	('crizotinib', 'Disease', (52, 62))	('c-Kit', 'Gene', (118, 123))	('ALK', 'Gene', (67, 70))
339121	26675259	Treatment with MGCD516 showed significant inhibition of proliferation as compared to crizotinib in all the three cell lines tested (p<0.005) (Figure 4B).	('MGCD516', 'Chemical', 'MESH:C000611865', (15, 22))	('crizotinib', 'Chemical', 'MESH:D000077547', (85, 95))	('MGCD516', 'Var', (15, 22))	('proliferation', 'CPA', (56, 69))	('inhibition', 'NegReg', (42, 52))
339124	26675259	Western blot analysis comparing MGCD516 against imatinib and crizotinib either alone or in combination, in the two sensitive cell lines DDLS and MPNST, showed that MGCD516 was efficient in blocking multiple RTKs and showed significantly better inhibition of downstream effectors such as p-AKT (Ser473) than the other two drugs (Figure 4C).	('AKT', 'Gene', '207', (289, 292))	('imatinib', 'Chemical', 'MESH:D000068877', (48, 56))	('inhibition', 'NegReg', (244, 254))	('blocking', 'NegReg', (189, 197))	('crizotinib', 'Chemical', 'MESH:D000077547', (61, 71))	('RTK', 'Gene', (207, 210))	('better', 'PosReg', (237, 243))	('MGCD516', 'Chemical', 'MESH:C000611865', (32, 39))	('AKT', 'Gene', (289, 292))	('Ser473', 'Chemical', '-', (294, 300))	('MGCD516', 'Chemical', 'MESH:C000611865', (164, 171))	('RTK', 'Gene', '5979', (207, 210))	('MGCD516', 'Var', (164, 171))	('MPNST', 'Phenotype', 'HP:0100697', (145, 150))
339126	26675259	In MPNST cell line, treatment with MGCD516 at 500 nmol/L, concentration similar to the one used for cell proliferation assay comparisons, resulted in significant reduction in colony number compared to no drug control as well as compared to imatinib and crizotinib treatment alone (p<0.05, Figure 4D).	('reduction', 'NegReg', (162, 171))	('MGCD516', 'Var', (35, 42))	('colony number', 'CPA', (175, 188))	('crizotinib', 'Chemical', 'MESH:D000077547', (253, 263))	('MPNST', 'Phenotype', 'HP:0100697', (3, 8))	('imatinib', 'Chemical', 'MESH:D000068877', (240, 248))	('MGCD516', 'Chemical', 'MESH:C000611865', (35, 42))
339128	26675259	Furthermore, comparison against two structurally similar drugs, carbozantinib and foretinib, showed that MGCD516 had a significantly higher anti-proliferative effect (p < 0.05, Supplementary Figure S2A).	('MGCD516', 'Chemical', 'MESH:C000611865', (105, 112))	('higher', 'PosReg', (133, 139))	('anti-proliferative effect', 'CPA', (140, 165))	('MGCD516', 'Var', (105, 112))	('carbozantinib', 'Chemical', '-', (64, 77))	('foretinib', 'Chemical', 'MESH:C544831', (82, 91))
339130	26675259	To test whether the inhibition of cell proliferation by MGCD516 is due to cytostatic rather than cytotoxic effects, we carried out flow cytometry cell-cycle analysis after MGCD516 treatment in MPNST cell line.	('MGCD516', 'Chemical', 'MESH:C000611865', (56, 63))	('MGCD516', 'Var', (56, 63))	('cell proliferation', 'CPA', (34, 52))	('MPNST', 'Phenotype', 'HP:0100697', (193, 198))	('inhibition', 'NegReg', (20, 30))	('MGCD516', 'Chemical', 'MESH:C000611865', (172, 179))
339133	26675259	Western blot analysis after treatment with MGCD516 induced significant down-regulation of cyclin D1 and a significant decrease in hyperphosphorylated form of retinoblastoma protein (p-Rb) but no induction of cleaved PARP was seen (Supplementary Figure S2B, right panel) thus indicating that MGCD516 is a cytostatic than a cytotoxic drug.	('cyclin D1', 'Gene', '595', (90, 99))	('p-Rb', 'Gene', (182, 186))	('PARP', 'Gene', '1302', (216, 220))	('PARP', 'Gene', (216, 220))	('cyclin D1', 'Gene', (90, 99))	('p-Rb', 'Gene', '5925', (182, 186))	('down-regulation', 'NegReg', (71, 86))	('retinoblastoma', 'Phenotype', 'HP:0009919', (158, 172))	('MGCD516', 'Chemical', 'MESH:C000611865', (43, 50))	('MGCD516', 'Chemical', 'MESH:C000611865', (291, 298))	('MGCD516', 'Var', (43, 50))	('decrease', 'NegReg', (118, 126))	('retinoblastoma', 'Disease', 'MESH:D012175', (158, 172))	('retinoblastoma', 'Disease', (158, 172))
339135	26675259	Combination treatment with doxorubicin, at two different concentrations, 10 nM/L and 100 nM/L did not show any significant inhibition of cell proliferation by MGCD516 compared with MGCD516 treatment alone (Supplementary Figure S2C).	('MGCD516', 'Chemical', 'MESH:C000611865', (159, 166))	('MGCD516', 'Var', (159, 166))	('cell proliferation', 'CPA', (137, 155))	('doxorubicin', 'Chemical', 'MESH:D004317', (27, 38))	('MGCD516', 'Chemical', 'MESH:C000611865', (181, 188))
339136	26675259	In order to confirm the role played by potential driver RTKs in each of the three cell lines (DDLS, LS141 and MPNST), we next carried out siRNA mediated knockdown of these kinases either alone or in combination and compared the anti-proliferative effect against MGCD516 treatment.	('MGCD516', 'Chemical', 'MESH:C000611865', (262, 269))	('knockdown', 'Var', (153, 162))	('RTK', 'Gene', (56, 59))	('RTK', 'Gene', '5979', (56, 59))	('MPNST', 'Phenotype', 'HP:0100697', (110, 115))	('LS141', 'Chemical', '-', (100, 105))
339140	26675259	For MPNST cell line, combined knockdown of c-Met and PDGFRbeta showed lesser anti-proliferative effect (Figure 5B), however, as shown previously, combined knockdown of PDGFRbeta and c-Kit resulted in similar anti-proliferative effect as that of MGCD516 (Figure 5C) suggesting a role of these two RTKs in driving MPNST cell proliferation.	('anti-proliferative', 'MPA', (208, 226))	('knockdown', 'Var', (155, 164))	('PDGFRbeta', 'Gene', (168, 177))	('PDGFRbeta', 'Gene', '5159', (53, 62))	('MPNST', 'Phenotype', 'HP:0100697', (312, 317))	('RTK', 'Gene', '5979', (296, 299))	('MGCD516', 'Chemical', 'MESH:C000611865', (245, 252))	('anti-proliferative effect', 'MPA', (77, 102))	('MPNST', 'Phenotype', 'HP:0100697', (4, 9))	('c-Kit', 'Gene', (182, 187))	('PDGFRbeta', 'Gene', (53, 62))	('c-Met', 'Gene', (43, 48))	('PDGFRbeta', 'Gene', '5159', (168, 177))	('c-Met', 'Gene', '4233', (43, 48))	('c-Kit', 'Gene', '3815', (182, 187))	('RTK', 'Gene', (296, 299))
339148	26675259	Western blot analysis of tissue samples obtained after 3 weeks of treatment showed greater inhibition of phosphorylation of potential driver kinases such as c-Kit, IGF1-R and PDGFRbeta compared to imatinib and crizotinib as well as significant down-regulation of downstream effector pathways such as p-AKT (Ser473) and p-S6 (Ser235/236) (Figure 6A and 6B).	('p-S6', 'Gene', (319, 323))	('phosphorylation', 'MPA', (105, 120))	('Ser473', 'Var', (307, 313))	('c-Kit', 'Gene', (157, 162))	('Ser473', 'Chemical', '-', (307, 313))	('imatinib', 'Chemical', 'MESH:D000068877', (197, 205))	('AKT', 'Gene', (302, 305))	('Ser235', 'Chemical', '-', (325, 331))	('IGF1-R', 'Gene', (164, 170))	('PDGFRbeta', 'Gene', (175, 184))	('crizotinib', 'Chemical', 'MESH:D000077547', (210, 220))	('AKT', 'Gene', '207', (302, 305))	('down-regulation', 'NegReg', (244, 259))	('inhibition', 'NegReg', (91, 101))	('PDGFRbeta', 'Gene', '5159', (175, 184))	('c-Kit', 'Gene', '3815', (157, 162))	('IGF1-R', 'Gene', '3480', (164, 170))	('downstream effector pathways', 'Pathway', (263, 291))	('p-S6', 'Gene', '338413', (319, 323))
339150	26675259	Tumor samples treated with MGCD516 for 3 weeks showed significantly less Ki67 staining compared to vehicle control (Figure 6C).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Ki67', 'Gene', '17345', (73, 77))	('less', 'NegReg', (68, 72))	('MGCD516', 'Chemical', 'MESH:C000611865', (27, 34))	('Ki67', 'Gene', (73, 77))	('MGCD516', 'Var', (27, 34))
339153	26675259	Sarcomas are traditionally categorized into two broad categories: tumors with translocations or activating mutations, whereas, the second category includes more complex tumors showing multiple genomic aberrations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumors', 'Disease', (66, 72))	('activating', 'PosReg', (96, 106))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('translocations', 'Var', (78, 92))	('tumors', 'Disease', (169, 175))	('Sarcomas', 'Disease', (0, 8))
339155	26675259	Many sarcoma subtypes belonging to both these categories show aberration and/or mutation in signal transduction pathways, particularly defects in receptor tyrosine kinase (RTK) signaling.	('defects', 'NegReg', (135, 142))	('signal transduction pathways', 'Pathway', (92, 120))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('RTK', 'Gene', '5979', (172, 175))	('receptor tyrosine kinase', 'Gene', (146, 170))	('aberration', 'Var', (62, 72))	('receptor tyrosine kinase', 'Gene', '5979', (146, 170))	('sarcoma', 'Disease', (5, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('RTK', 'Gene', (172, 175))	('mutation', 'Var', (80, 88))
339158	26675259	Even though RTKs present an attractive therapeutic target, in many cases, cells rapidly acquire resistance via compensatory activation and/or mutation of signaling pathways.	('activation', 'PosReg', (124, 134))	('signaling pathways', 'Pathway', (154, 172))	('RTK', 'Gene', (12, 15))	('acquire', 'PosReg', (88, 95))	('RTK', 'Gene', '5979', (12, 15))	('mutation', 'Var', (142, 150))	('resistance', 'MPA', (96, 106))
339165	26675259	This could probably be due to the fact that A673 cell line, in addition to having high basal expression and phosphorylation levels of many RTKs (IGF1-R, ErbB4, EphA4, EphA10, and ALK), also carries a (BRAF V600E) mutation which could potentially play a role in reduced sensitivity to the drug.	('EphA4', 'Gene', (160, 165))	('phosphorylation levels', 'MPA', (108, 130))	('reduced', 'NegReg', (261, 268))	('ALK', 'Gene', '238', (179, 182))	('V600E', 'Mutation', 'p.V600E', (206, 211))	('EphA10', 'Gene', '284656', (167, 173))	('IGF1-R', 'Gene', (145, 151))	('RTK', 'Gene', (139, 142))	('BRAF V600E', 'Var', (201, 211))	('sensitivity', 'MPA', (269, 280))	('expression', 'MPA', (93, 103))	('ALK', 'Gene', (179, 182))	('ErbB4', 'Gene', (153, 158))	('ErbB4', 'Gene', '2066', (153, 158))	('EphA4', 'Gene', '2043', (160, 165))	('EphA10', 'Gene', (167, 173))	('RTK', 'Gene', '5979', (139, 142))	('IGF1-R', 'Gene', '3480', (145, 151))
339173	26675259	MGCD516 is unique in a way that it has broad spectrum activity against many RTKs including c-Met, c-Kit, Axl, PDGFR, and Eph receptors that are known to play a role in driving sarcoma cell growth, and thus, it is able to inhibit many of the internal compensatory pathways.	('RTK', 'Gene', (76, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('RTK', 'Gene', '5979', (76, 79))	('inhibit', 'NegReg', (221, 228))	('c-Kit', 'Gene', '3815', (98, 103))	('c-Met', 'Gene', (91, 96))	('MGCD516', 'Var', (0, 7))	('c-Kit', 'Gene', (98, 103))	('PDGFR', 'Gene', (110, 115))	('PDGFR', 'Gene', '5159', (110, 115))	('Eph', 'Gene', (121, 124))	('Axl', 'Gene', '558', (105, 108))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('Axl', 'Gene', (105, 108))	('Eph', 'Gene', '2041', (121, 124))	('sarcoma', 'Disease', (176, 183))	('internal compensatory pathways', 'Pathway', (241, 271))	('c-Met', 'Gene', '4233', (91, 96))	('MGCD516', 'Chemical', 'MESH:C000611865', (0, 7))
339174	26675259	Our studies comparing MGCD516 against imatinib and crizotinib showed that MGCD516 was clearly superior to the other two drugs in terms of inhibition of cell proliferation as well as blockade of signaling pathways.	('inhibition', 'NegReg', (138, 148))	('MGCD516', 'Chemical', 'MESH:C000611865', (22, 29))	('imatinib', 'Chemical', 'MESH:D000068877', (38, 46))	('MGCD516', 'Chemical', 'MESH:C000611865', (74, 81))	('MGCD516', 'Var', (74, 81))	('signaling pathways', 'Pathway', (194, 212))	('cell proliferation', 'CPA', (152, 170))	('crizotinib', 'Chemical', 'MESH:D000077547', (51, 61))
339176	26675259	In the present study, we also carried out silencing of the target RTKs using siRNA mediated approach to verify that blockade of RTK signaling by MGCD516 was indeed responsible for inhibition of cell proliferation in DDLS, LS141, and MPNST cell lines.	('RTK', 'Gene', (128, 131))	('MGCD516', 'Chemical', 'MESH:C000611865', (145, 152))	('blockade', 'Var', (116, 124))	('LS141', 'Chemical', '-', (222, 227))	('RTK', 'Gene', '5979', (66, 69))	('MPNST', 'Phenotype', 'HP:0100697', (233, 238))	('RTK', 'Gene', '5979', (128, 131))	('cell proliferation', 'CPA', (194, 212))	('inhibition', 'NegReg', (180, 190))	('MGCD516', 'Gene', (145, 152))	('RTK', 'Gene', (66, 69))
339179	26675259	In LS141 cell line, siRNA mediated knockdown of IGF1-R and PDGFRbeta resulted in higher inhibition of proliferation than MGCD516 treatment, presumably due to the fact that the IC50 value for IGF1-R inhibition by MGCD516 is much higher than for other kinases.	('knockdown', 'Var', (35, 44))	('MGCD516', 'Chemical', 'MESH:C000611865', (121, 128))	('inhibition', 'NegReg', (198, 208))	('IGF1-R', 'Gene', (48, 54))	('inhibition', 'NegReg', (88, 98))	('higher', 'PosReg', (81, 87))	('IGF1-R', 'Gene', '3480', (48, 54))	('PDGFRbeta', 'Gene', '5159', (59, 68))	('MGCD516', 'Chemical', 'MESH:C000611865', (212, 219))	('IGF1-R', 'Gene', (191, 197))	('proliferation', 'CPA', (102, 115))	('LS141', 'Chemical', '-', (3, 8))	('PDGFRbeta', 'Gene', (59, 68))	('IGF1-R', 'Gene', '3480', (191, 197))
339180	26675259	Nevertheless, these results clearly indicate that MGCD516 is efficient in blocking multiple pathways that are critical for sarcoma cell proliferation and this effect can be mimicked by siRNA mediated knockdown of individual RTKs.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('MGCD516', 'Var', (50, 57))	('MGCD516', 'Chemical', 'MESH:C000611865', (50, 57))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('RTK', 'Gene', '5979', (224, 227))	('blocking', 'NegReg', (74, 82))	('sarcoma', 'Disease', (123, 130))	('RTK', 'Gene', (224, 227))
339181	26675259	Similar to the anti-proliferative effect observed, MGCD516 showed significant inhibition of colony growth and has a greater inhibitory effect on cell colonization than imatinib and crizotinib treatment alone, potentially owing to its greater broad-spectrum activity.	('MGCD516', 'Var', (51, 58))	('imatinib', 'Chemical', 'MESH:D000068877', (168, 176))	('crizotinib', 'Chemical', 'MESH:D000077547', (181, 191))	('cell colonization', 'CPA', (145, 162))	('inhibitory', 'NegReg', (124, 134))	('inhibition', 'NegReg', (78, 88))	('colony growth', 'CPA', (92, 105))	('MGCD516', 'Chemical', 'MESH:C000611865', (51, 58))
339185	26675259	Western immunoblotting showed that MGCD516 treatment not only resulted in significant blockade of phosphorylation of multiple RTKs such as PDGFR, c-Kit and IGF1-R but also inhibited downstream effectors such as p-AKT and p-S6 which are critical for tumor cell survival and proliferation.	('IGF1-R', 'Gene', '3480', (156, 162))	('MGCD516', 'Var', (35, 42))	('phosphorylation', 'MPA', (98, 113))	('p-S6', 'Gene', (221, 225))	('tumor', 'Disease', (249, 254))	('inhibited', 'NegReg', (172, 181))	('c-Kit', 'Gene', '3815', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('blockade', 'NegReg', (86, 94))	('AKT', 'Gene', '207', (213, 216))	('c-Kit', 'Gene', (146, 151))	('IGF1-R', 'Gene', (156, 162))	('MGCD516', 'Chemical', 'MESH:C000611865', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('RTK', 'Gene', (126, 129))	('PDGFR', 'Gene', (139, 144))	('PDGFR', 'Gene', '5159', (139, 144))	('RTK', 'Gene', '5979', (126, 129))	('p-S6', 'Gene', '338413', (221, 225))	('AKT', 'Gene', (213, 216))
339186	26675259	Since MGCD516 can inhibit RTKs such as PDGFR and VEGFR, we speculate that the significant tumor suppression achieved in vivo is not only limited to inhibition of signaling pathways in tumor cells but also due to an effect on stromal cell signaling mediated via these kinases.	('inhibit', 'NegReg', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('inhibition', 'NegReg', (148, 158))	('MGCD516', 'Chemical', 'MESH:C000611865', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('VEGFR', 'Gene', '3791', (49, 54))	('tumor', 'Disease', (90, 95))	('PDGFR', 'Gene', (39, 44))	('signaling pathways', 'Pathway', (162, 180))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('RTK', 'Gene', (26, 29))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('PDGFR', 'Gene', '5159', (39, 44))	('MGCD516', 'Var', (6, 13))	('VEGFR', 'Gene', (49, 54))	('RTK', 'Gene', '5979', (26, 29))
339187	26675259	Even though MGCD516 does show inhibition of VEGFR family in vitro, differentiated effects are observed from other more well-studied VEGFR inhibitors such as sunitinib, which do not share additional MGCD516 targets (personal communication with Dr. James Christensen, Mirati Therapeutics).	('VEGFR', 'Gene', '3791', (44, 49))	('MGCD516', 'Var', (12, 19))	('VEGFR', 'Gene', (132, 137))	('MGCD516', 'Chemical', 'MESH:C000611865', (12, 19))	('MGCD516', 'Chemical', 'MESH:C000611865', (198, 205))	('VEGFR', 'Gene', (44, 49))	('inhibition', 'NegReg', (30, 40))	('VEGFR', 'Gene', '3791', (132, 137))	('sunitinib', 'Chemical', 'MESH:D000077210', (157, 166))
339191	26675259	This is the first pre-clinical report describing MGCD516 (Sitravatinib) as a potent and broad spectrum inhibitor of RTKs.	('MGCD516', 'Var', (49, 56))	('RTK', 'Gene', '5979', (116, 119))	('Sitravatinib', 'Chemical', 'MESH:C000611865', (58, 70))	('RTK', 'Gene', (116, 119))	('MGCD516', 'Chemical', 'MESH:C000611865', (49, 56))
339193	26675259	We believe that our data would support the development of MGCD516 as a potential therapy for patients with soft-tissue sarcoma.	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (107, 126))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('MGCD516', 'Chemical', 'MESH:C000611865', (58, 65))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('MGCD516', 'Var', (58, 65))	('patients', 'Species', '9606', (93, 101))
339210	26675259	Protein concentrations were measured using Bio-Rad protein assay dye (Bio-Rad) and equal amounts of protein (20-30 mg) were loaded on 4%-12% gradient gels (Invitrogen) and transferred to PVDF membrane (Immobilon, Millipore) or Nitrocellulose (ThermoFisher) for the detection of phosphorylated c-Kit.	('phosphorylated', 'Var', (278, 292))	('Rad', 'Gene', '6236', (74, 77))	('PVDF', 'Chemical', 'MESH:C024865', (187, 191))	('Rad', 'Gene', (74, 77))	('Rad', 'Gene', (47, 50))	('Rad', 'Gene', '6236', (47, 50))	('c-Kit', 'Gene', (293, 298))	('c-Kit', 'Gene', '3815', (293, 298))
339295	23824589	Mouse genotypes used to generate sarcomas included LSL-KrasG12D/+;Trp53Flox/Flox  and Braf Ca/+;Trp53 Flox/Flox .	('sarcomas', 'Disease', (33, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('Braf', 'Gene', (86, 90))	('Trp53', 'Gene', (96, 101))	('Trp53', 'Gene', (66, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Trp53', 'Gene', '22059', (66, 71))	('sarcomas', 'Disease', 'MESH:D012509', (33, 41))	('Mouse', 'Species', '10090', (0, 5))	('Trp53', 'Gene', '22059', (96, 101))	('Braf', 'Gene', '109880', (86, 90))	('LSL-KrasG12D/+', 'Var', (51, 65))
339432	20377868	Kaplan-Meier analyses showed a significant decrease of overall survival for the three groups with high OPN protein levels compared to the group with the lowest tumor (p = 0.007; log-rank test) and serum (p = 0.04; log-rank test) OPN protein levels.	('decrease', 'NegReg', (43, 51))	('OPN', 'Gene', '6696', (103, 106))	('OPN', 'Gene', (103, 106))	('high', 'Var', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('OPN', 'Gene', '6696', (229, 232))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('OPN', 'Gene', (229, 232))	('tumor', 'Disease', (160, 165))
339455	20377868	Furthermore, own in vitro studies detected a clear decrease of extracellular OPN protein levels after transfection with OPN siRNA in MDA-MB231 cells.	('transfection', 'Var', (102, 114))	('OPN', 'Gene', (120, 123))	('MDA-MB231', 'CellLine', 'CVCL:0062', (133, 142))	('OPN', 'Gene', '6696', (77, 80))	('decrease', 'NegReg', (51, 59))	('OPN', 'Gene', (77, 80))	('OPN', 'Gene', '6696', (120, 123))
339467	20377868	However, antisense oligodeoxynucleotides against human OPN reduced the tumorigenicity of xenotransplanted osteosarcoma tumors in nude mice.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (119, 124))	('reduced', 'NegReg', (59, 66))	('antisense oligodeoxynucleotides', 'Var', (9, 40))	('OPN', 'Gene', '6696', (55, 58))	('OPN', 'Gene', (55, 58))	('human', 'Species', '9606', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (19, 40))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (106, 125))	('nude mice', 'Species', '10090', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('osteosarcoma tumors', 'Disease', (106, 125))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('tumor', 'Disease', (71, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
339470	20377868	In contrast, another study of 41 osteosarcoma patients did show that a high OPN mRNA level is correlative with overall survival, event-free survival and relapse-free survival.	('event-free', 'CPA', (129, 139))	('relapse-free survival', 'CPA', (153, 174))	('patients', 'Species', '9606', (46, 54))	('high', 'Var', (71, 75))	('OPN', 'Gene', '6696', (76, 79))	('overall survival', 'CPA', (111, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('OPN', 'Gene', (76, 79))	('osteosarcoma', 'Phenotype', 'HP:0002669', (33, 45))	('osteosarcoma', 'Disease', (33, 45))	('osteosarcoma', 'Disease', 'MESH:D012516', (33, 45))
339472	20377868	In addition, OPN splice variants may be involved in tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('splice variants', 'Var', (17, 32))	('tumor', 'Disease', (52, 57))	('OPN', 'Gene', '6696', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('OPN', 'Gene', (13, 16))	('involved', 'Reg', (40, 48))
339581	29512717	Additional studies have indicated that physiological and supranutritional selenium exhibit chemopreventive or therapeutic activities on human solid cancers, such as lung cancer, colorectal cancer and leukemia, by inducing apoptosis in cancer cells with minimal side effects to normal cells, within a proper dose range.	('cancer', 'Disease', (170, 176))	('apoptosis', 'CPA', (222, 231))	('colorectal cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('leukemia', 'Disease', (200, 208))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('leukemia', 'Disease', 'MESH:D007938', (200, 208))	('human', 'Species', '9606', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('lung cancer', 'Disease', (165, 176))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('supranutritional', 'Var', (57, 73))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('inducing', 'PosReg', (213, 221))	('cancer', 'Disease', (189, 195))	('cancer', 'Disease', (148, 154))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancer', 'Disease', (235, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('selenium', 'Chemical', 'MESH:D012643', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('leukemia', 'Phenotype', 'HP:0001909', (200, 208))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
339600	29512717	Results from the present study may provide the first evidence to suggest that sodium selenite induces apoptosis and inhibits autophagy in SW982 cells in vitro.	('autophagy', 'CPA', (125, 134))	('apoptosis', 'CPA', (102, 111))	('induces', 'PosReg', (94, 101))	('sodium', 'Var', (78, 84))	('SW982', 'CellLine', 'CVCL:1734', (138, 143))	('sodium selenite', 'Chemical', 'MESH:D018038', (78, 93))	('inhibits', 'NegReg', (116, 124))
339642	29512717	SW982 cells were treated with sodium selenite at concentrations ranging between 0 and 30 microM, which included both nutritious and toxic doses, for 0 to 72 h. The results indicated that sodium selenite significantly inhibited SW982 cell viability in a time- and dose-dependent manner (Fig.	('sodium selenite', 'Var', (187, 202))	('SW982', 'CellLine', 'CVCL:1734', (0, 5))	('sodium selenite', 'Chemical', 'MESH:D018038', (187, 202))	('inhibited', 'NegReg', (217, 226))	('SW982', 'CellLine', 'CVCL:1734', (227, 232))	('sodium selenite', 'Chemical', 'MESH:D018038', (30, 45))
339688	29512717	PI3K converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate, which subsequently recruits Akt to the membrane, where it is activated and facilitates the downstream activation of mTOR.	('PI3K', 'Var', (0, 4))	('recruits', 'PosReg', (115, 123))	('Akt', 'Gene', (124, 127))	('facilitates', 'PosReg', (171, 182))	('phosphatidylinositol 3,4,5-triphosphate', 'Chemical', 'MESH:C060974', (55, 94))	('phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (14, 51))	('mTOR', 'Gene', (212, 216))	('mTOR', 'Gene', '2475', (212, 216))	('Akt', 'Gene', '207', (124, 127))
339689	29512717	Akt/mTOR activation suppresses autophagy in mammalian cells, which suggested that inactivation of Akt/mTOR may promote autophagy.	('autophagy in mammalian', 'CPA', (31, 53))	('promote', 'PosReg', (111, 118))	('Akt', 'Gene', '207', (98, 101))	('Akt', 'Gene', '207', (0, 3))	('suppresses', 'NegReg', (20, 30))	('mammalian', 'Species', '9606', (44, 53))	('mTOR', 'Gene', (102, 106))	('Akt', 'Gene', (98, 101))	('mTOR', 'Gene', '2475', (102, 106))	('mTOR', 'Gene', (4, 8))	('Akt', 'Gene', (0, 3))	('mTOR', 'Gene', '2475', (4, 8))	('inactivation', 'Var', (82, 94))	('autophagy', 'CPA', (119, 128))
339694	29512717	Akt/mTOR pathway activation is associated with sarcoma oncogenesis through a number of mechanisms, such as: Mast/stem cell growth factor receptor Kit and platelet-derived growth receptor-alpha mutations in gastrointestinal stromal tumours; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit-alpha isoform mutations in myxoid/round-cell liposarcomas; or other pathognomonic alterations that promote reliance upon the pathway, such as the dependence of RNA binding protein EWS-friend leukemia integration 1 transcription factor gene fusion-driven oncogenesis upon the IGF-1 receptor in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (598, 611))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (598, 611))	('mutations', 'Var', (193, 202))	('Akt', 'Gene', '207', (0, 3))	('sarcoma oncogenesis', 'Disease', (47, 66))	('liposarcomas', 'Disease', (350, 362))	('mutations', 'Var', (319, 328))	('mTOR', 'Gene', '2475', (4, 8))	('sarcomas', 'Phenotype', 'HP:0100242', (354, 362))	('sarcoma', 'Phenotype', 'HP:0100242', (604, 611))	('gastrointestinal stromal tumours', 'Disease', (206, 238))	('leukemia', 'Phenotype', 'HP:0001909', (496, 504))	('Ewing sarcoma', 'Disease', (598, 611))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit-alpha isoform', 'Gene', '5290', (240, 318))	('sarcoma', 'Phenotype', 'HP:0100242', (354, 361))	('liposarcomas', 'Disease', 'MESH:D008080', (350, 362))	('leukemia', 'Disease', (496, 504))	('leukemia', 'Disease', 'MESH:D007938', (496, 504))	('liposarcomas', 'Phenotype', 'HP:0012034', (350, 362))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (206, 238))	('sarcoma oncogenesis', 'Disease', 'MESH:D063646', (47, 66))	('mTOR', 'Gene', (4, 8))	('Akt', 'Gene', (0, 3))
339707	29670090	In the present study, we report that CDK4 is highly expressed in human synovial sarcoma, and high CDK4 expressions are associated with poor prognosis in sarcomas patients and the clinical stage and the TNM grade in synovial sarcoma patients.	('human', 'Species', '9606', (65, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('CDK4', 'Gene', (37, 41))	('expressions', 'MPA', (103, 114))	('associated', 'Reg', (119, 129))	('synovial sarcoma', 'Disease', (215, 231))	('TNM', 'Gene', '10178', (202, 205))	('CDK4', 'Gene', (98, 102))	('CDK4', 'Gene', '1019', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('synovial sarcoma', 'Disease', 'MESH:D013584', (215, 231))	('TNM', 'Gene', (202, 205))	('high', 'Var', (93, 97))	('patients', 'Species', '9606', (162, 170))	('synovial sarcoma', 'Disease', (71, 87))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (215, 231))	('synovial sarcoma', 'Disease', 'MESH:D013584', (71, 87))	('CDK4', 'Gene', '1019', (98, 102))	('patients', 'Species', '9606', (232, 240))	('sarcomas', 'Disease', 'MESH:D012509', (153, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (71, 87))	('sarcomas', 'Disease', (153, 161))
339718	29670090	Aberrations in cell cycle control is defined as one of the hallmarks of cancer, and may be a favorable target for the improvement of new therapeutic options for the treatment of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Aberrations in cell cycle', 'Phenotype', 'HP:0011018', (0, 25))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('cell cycle control', 'CPA', (15, 33))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Aberrations', 'Var', (0, 11))	('sarcoma', 'Disease', (178, 185))	('cancer', 'Disease', (72, 78))
339726	29670090	Activation and amplification of the cyclin D/CDK4/Rb pathway has been shown to correlate with uncontrolled tumor cell growth and proliferation in various types of malignancies, including in sarcoma.	('cyclin', 'Gene', '5111', (36, 42))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('amplification', 'Var', (15, 28))	('tumor', 'Disease', (107, 112))	('cyclin', 'Gene', (36, 42))	('sarcoma', 'Disease', (190, 197))	('malignancies', 'Disease', 'MESH:D009369', (163, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('proliferation', 'CPA', (129, 142))	('CDK4', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('CDK4', 'Gene', '1019', (45, 49))	('malignancies', 'Disease', (163, 175))
339758	29670090	Importantly, Kaplan-Meier survival analysis shows that the outcomes for patients in the CDK4 high-staining (>=3) group are worse than for those in the CDK4 low-staining (<3) group (Fig.	('CDK4', 'Gene', '1019', (88, 92))	('CDK4', 'Gene', (88, 92))	('high-staining', 'Var', (93, 106))	('CDK4', 'Gene', '1019', (151, 155))	('CDK4', 'Gene', (151, 155))	('patients', 'Species', '9606', (72, 80))
339759	29670090	In patients with sarcomas, high CDK4 expression is associated with shorter overall survival period vs. low CDK4 expression (P < 0.05).	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('CDK4', 'Gene', '1019', (107, 111))	('CDK4', 'Gene', (32, 36))	('sarcomas', 'Disease', (17, 25))	('CDK4', 'Gene', '1019', (32, 36))	('high', 'Var', (27, 31))	('patients', 'Species', '9606', (3, 11))	('overall survival', 'MPA', (75, 91))	('shorter', 'NegReg', (67, 74))	('expression', 'MPA', (37, 47))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('CDK4', 'Gene', (107, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
339765	29670090	Furthermore, western blotting shows that CDK4 siRNA transfection significantly reduces CDK4 expression, whereas the expression of CDK6 remains unchanged.	('CDK6', 'Gene', '1021', (130, 134))	('CDK6', 'Gene', (130, 134))	('reduces', 'NegReg', (79, 86))	('CDK4', 'Gene', (41, 45))	('transfection', 'Var', (52, 64))	('CDK4', 'Gene', '1019', (41, 45))	('CDK4', 'Gene', '1019', (87, 91))	('CDK4', 'Gene', (87, 91))	('expression', 'MPA', (92, 102))
339796	29670090	A knockdown of CDK4 in fusion-gene positive rhabdomyosarcoma cells has also been shown to abrogate transformation and proliferation via G1-phase cell-cycle arrest, demonstrating that CDK4 is also essential for sarcoma cell survival and growth.	('CDK4', 'Gene', (183, 187))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('abrogate', 'NegReg', (90, 98))	('CDK4', 'Gene', (15, 19))	('sarcoma', 'Disease', (210, 217))	('knockdown', 'Var', (2, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('rhabdomyosarcoma', 'Disease', (44, 60))	('arrest', 'Disease', 'MESH:D006323', (156, 162))	('CDK4', 'Gene', '1019', (15, 19))	('sarcoma', 'Disease', (53, 60))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (44, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('arrest', 'Disease', (156, 162))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (44, 60))	('CDK4', 'Gene', '1019', (183, 187))
339797	29670090	More recently, amplification and over-activation of the CDK4/Rb pathway has been found in another sarcoma type, chordoma.	('chordoma', 'Phenotype', 'HP:0010762', (112, 120))	('sarcoma type, chordoma', 'Disease', 'MESH:D002817', (98, 120))	('CDK4', 'Gene', (56, 60))	('CDK4', 'Gene', '1019', (56, 60))	('amplification', 'Var', (15, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('over-activation', 'PosReg', (33, 48))
339820	29670090	Specific somatic loss of p16INK4A through point mutations or small deletions, and silencing of p16INK4A through promoter methylation, have been reported at high frequency in many human cancers.	('p16INK4A', 'Gene', (95, 103))	('human', 'Species', '9606', (179, 184))	('small deletions', 'Var', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('point mutations', 'Var', (42, 57))	('silencing', 'NegReg', (82, 91))	('p16INK4A', 'Gene', (25, 33))	('p16INK4A', 'Gene', '1029', (95, 103))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('loss', 'NegReg', (17, 21))	('p16INK4A', 'Gene', '1029', (25, 33))	('cancers', 'Disease', (185, 192))
339822	29670090	A deletion of p16INK4A causes altered activity of CDK4, leading to hyperphosphorylation of Rb and aberrant regulation of the cell cycle.	('p16INK4A', 'Gene', '1029', (14, 22))	('activity', 'MPA', (38, 46))	('CDK4', 'Gene', '1019', (50, 54))	('CDK4', 'Gene', (50, 54))	('deletion', 'Var', (2, 10))	('hyperphosphorylation', 'MPA', (67, 87))	('p16INK4A', 'Gene', (14, 22))	('altered', 'Reg', (30, 37))	('leading to', 'Reg', (56, 66))	('regulation', 'MPA', (107, 117))
339826	29670090	In synovial sarcoma, the deletion of p16INK4A is also a frequent genetic event.	('p16INK4A', 'Gene', (37, 45))	('synovial sarcoma', 'Disease', (3, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('p16INK4A', 'Gene', '1029', (37, 45))	('deletion', 'Var', (25, 33))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (3, 19))	('synovial sarcoma', 'Disease', 'MESH:D013584', (3, 19))
339835	29670090	Overexpression of CDK4 correlates with higher clinical stages and higher TNM grades in synovial sarcomas and poor survival outcomes of sarcoma patients.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('higher', 'PosReg', (39, 45))	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('sarcoma', 'Disease', (135, 142))	('Overexpression', 'Var', (0, 14))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (87, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('synovial sarcomas', 'Disease', (87, 104))	('CDK4', 'Gene', (18, 22))	('TNM', 'Gene', '10178', (73, 76))	('higher', 'PosReg', (66, 72))	('TNM', 'Gene', (73, 76))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('synovial sarcomas', 'Disease', 'MESH:D013584', (87, 104))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (87, 103))	('CDK4', 'Gene', '1019', (18, 22))	('sarcoma', 'Disease', (96, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('clinical stages', 'CPA', (46, 61))	('patients', 'Species', '9606', (143, 151))
339859	29670090	The human nonspecific siRNA and CDK4 siRNAs (#SASI_Hs01_00122488, NM_000075.2, 5'-CUCUUAUCUACAUAAGGAU-3' and #SASI_Hs01_00122490, NM_000075.2, 5'-CACUUACACCCGUGGUUGU-3') were purchased from Sigma-Aldrich (St. Louis, MO, USA).	('#SASI_Hs01_00122488', 'Var', (45, 64))	('human', 'Species', '9606', (4, 9))	('CDK4', 'Gene', (32, 36))	('#SASI_Hs01_00122490', 'Var', (109, 128))	('CDK4', 'Gene', '1019', (32, 36))	('NM_000075.2', 'Var', (130, 141))	('NM_000075.2', 'Var', (66, 77))
339864	29670090	Palbociclib (PD-0332991) HCl (#S1116, Selleck Chemicals, Houston, TX, USA) is a highly selective inhibitor of CDK4/6 activity.	('PD-0332991', 'Var', (13, 23))	('activity', 'MPA', (117, 125))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('PD-0332991)', 'Chemical', 'MESH:C500026', (13, 24))	('CDK4/6', 'Enzyme', (110, 116))	('HCl', 'Chemical', '-', (25, 28))
339874	29670090	SYO-1 and Fuji cells were collected and fixed in 70% ethanol at 4  C overnight, followed by incubation with RNase A (100ug/mL, Thermo Scientific, Waltham, MA, USA) at 37  C for 30 min and stained with Propidium Iodide (50ug/mL, Sigma-Aldrich, St. Louis, MO, USA) for an additional 30 min.	('RNase A', 'Gene', (108, 115))	('ethanol', 'Chemical', 'MESH:D000431', (53, 60))	('Propidium Iodide', 'Chemical', 'MESH:D011419', (201, 217))	('RNase A', 'Gene', '6035', (108, 115))	('SYO-1', 'Gene', '55027', (0, 5))	('100ug/mL', 'Var', (117, 125))	('SYO-1', 'Gene', (0, 5))
339896	29100397	The mismatch repair (MMR) system is of pivotal importance for the rectification of DNA sequence mismatches during DNA replication, and loss of function of one of the MMR proteins (MLH1, MSH2, MSH6, PMS2) leads to high rates of mutations that accumulate in repetitive nucleotide regions (microsatellites).	('MSH6', 'Gene', '2956', (192, 196))	('MLH1', 'Gene', '4292', (180, 184))	('PMS2', 'Gene', '5395', (198, 202))	('accumulate', 'PosReg', (242, 252))	('loss of function', 'NegReg', (135, 151))	('MSH2', 'Gene', (186, 190))	('PMS2', 'Gene', (198, 202))	('MLH1', 'Gene', (180, 184))	('MSH6', 'Gene', (192, 196))	('MSH2', 'Gene', '4436', (186, 190))	('mutations', 'Var', (227, 236))
339898	29100397	The majority of sporadic MSI tumors are caused by an epigenetic inactivation of MLH1 or MSH2.	('MSH2', 'Gene', '4436', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('caused by', 'Reg', (40, 49))	('sporadic MSI tumors', 'Disease', 'MESH:D009369', (16, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('MLH1', 'Gene', '4292', (80, 84))	('epigenetic inactivation', 'Var', (53, 76))	('MLH1', 'Gene', (80, 84))	('sporadic MSI tumors', 'Disease', (16, 35))	('MSH2', 'Gene', (88, 92))
339928	29100397	In the present study, we identified PD-L1 positivity (>=1% tumor cells, SP142 Ab clone) in 16.5% of samples from a large cohort of 430 clinically annotated solid tumor patients, and noted significant relationship with MMR status across anatomic tumor types (P = 0.01).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('PD-L1', 'Gene', (36, 41))	('positivity', 'Var', (42, 52))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('PD-L1', 'Gene', '29126', (36, 41))	('patients', 'Species', '9606', (168, 176))	('tumor', 'Disease', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('SP142', 'Chemical', '-', (72, 77))
339937	29100397	Tumors with germline or acquired somatic alterations in the main mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) accumulate genomic alterations and dMMR is a proxy for elevated tumor mutational burden and presumably neoantigen load.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('accumulate', 'PosReg', (118, 128))	('genomic alterations', 'CPA', (129, 148))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MLH1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('PMS2', 'Gene', '5395', (112, 116))	('MSH2', 'Gene', (100, 104))	('Tumors', 'Disease', (0, 6))	('MLH1', 'Gene', '4292', (94, 98))	('alterations', 'Var', (41, 52))	('elevated tumor', 'Disease', 'MESH:D009369', (173, 187))	('MSH2', 'Gene', '4436', (100, 104))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('MSH6', 'Gene', (106, 110))	('MMR', 'Gene', (82, 85))	('dMMR', 'Chemical', '-', (153, 157))	('PMS2', 'Gene', (112, 116))	('elevated tumor', 'Disease', (173, 187))	('MSH6', 'Gene', '2956', (106, 110))	('dMMR', 'Var', (153, 157))
339943	29100397	Mechanistically, the relationship between PD-L1+ and dMMR may be related to the increased neoantigen load resulting from dMMR which induces immune recognition and response, often pathologically supported by increased tumor infiltrating lymphocytes, an environment where tumor cells might be expected to increase PD-1/L1.	('response', 'MPA', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('PD-L1+', 'Gene', '29126', (42, 48))	('PD-1/L1', 'Gene', '5133;3897', (312, 319))	('tumor', 'Disease', (217, 222))	('dMMR', 'Chemical', '-', (53, 57))	('PD-L1+', 'Gene', (42, 48))	('induces', 'Reg', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('neoantigen load', 'MPA', (90, 105))	('dMMR', 'Chemical', '-', (121, 125))	('PD-1/L1', 'Gene', (312, 319))	('tumor', 'Disease', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('dMMR', 'Var', (121, 125))	('increased', 'PosReg', (80, 89))	('increase PD', 'Phenotype', 'HP:0008151', (303, 314))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('immune recognition', 'MPA', (140, 158))
339957	29100397	Importantly, other genomic mechanisms such as POLE mutations can recapitulate the elevated neoantigen burden in dMMR tumors, and are not identified by MMR or PD-1/L1 testing alone.	('PD-1/L1', 'Gene', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('dMMR', 'Chemical', '-', (112, 116))	('neoantigen burden', 'MPA', (91, 108))	('tumors', 'Disease', (117, 123))	('elevated', 'PosReg', (82, 90))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('PD-1/L1', 'Gene', '5133;3897', (158, 165))
339981	27608846	We present in vivo evidence from mouse xenograft models that STA-8666 results in more persistent inhibition of topoisomerase 1 and prolonged DNA damage compared to irinotecan.	('DNA damage', 'MPA', (141, 151))	('inhibition', 'NegReg', (97, 107))	('irinotecan', 'Chemical', 'MESH:D000077146', (164, 174))	('STA-8666', 'Var', (61, 69))	('prolonged', 'PosReg', (131, 140))	('mouse', 'Species', '10090', (33, 38))	('topoisomerase 1', 'Enzyme', (111, 126))
339983	27608846	Gene expression analysis performed on xenograft tumors treated with either irinotecan or STA-8666 showed that STA-8666 affected expression of DNA damage and repair genes more robustly than irinotecan.	('affected', 'Reg', (119, 127))	('STA-8666', 'Var', (110, 118))	('irinotecan', 'Chemical', 'MESH:D000077146', (75, 85))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('irinotecan', 'Chemical', 'MESH:D000077146', (189, 199))	('expression', 'MPA', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
339984	27608846	These results suggest that STA-8666 may be a promising new agent for patients with pediatric-type sarcoma.	('pediatric-type sarcoma', 'Disease', 'MESH:D063766', (83, 105))	('pediatric-type sarcoma', 'Disease', (83, 105))	('STA-8666', 'Var', (27, 35))	('patients', 'Species', '9606', (69, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
339997	27608846	Compared to irinotecan, SN-38 has between a 100 and 1000-fold greater antitumor activity in vitro, but cannot be administered directly to patients due to difficulties with solubility and toxicity.	('greater', 'PosReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('SN-38', 'Var', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('toxicity', 'Disease', 'MESH:D064420', (187, 195))	('tumor', 'Disease', (74, 79))	('toxicity', 'Disease', (187, 195))	('SN-38', 'Chemical', 'MESH:D000077146', (24, 29))	('patients', 'Species', '9606', (138, 146))	('irinotecan', 'Chemical', 'MESH:D000077146', (12, 22))
340006	27608846	In vivo, it has been observed that HSP90 inhibitors negatively affect the growth of tumor cells, while minimally affecting normal tissues.	('negatively', 'NegReg', (52, 62))	('affect', 'Reg', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('HSP90', 'Protein', (35, 40))	('inhibitors', 'Var', (41, 51))	('tumor', 'Disease', (84, 89))
340009	27608846	Whatever its basis, this unique property makes HSP90 inhibitors ideal intracellular delivery vehicles for chemotherapeutic drugs, allowing for high tumor exposure and low systemic toxicity.	('inhibitors', 'Var', (53, 63))	('high tumor', 'Disease', 'MESH:D009369', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('toxicity', 'Disease', 'MESH:D064420', (180, 188))	('toxicity', 'Disease', (180, 188))	('HSP90', 'Protein', (47, 52))	('high tumor', 'Disease', (143, 153))
340017	27608846	An initial xenograft pilot experiment was conducted to compare the antitumor activity of STA-8666 to that of vehicle and an HSP90 inhibitor.	('STA-8666', 'Var', (89, 97))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
340025	27608846	STA-8666 at a dose of 150 mg/kg (an equimolar dose of 75 mg/kg STA-8663), which is the maximally tolerated dose (MTD) for this agent in this strain of mouse, produced superior antitumor efficacy compared with vehicle and ganetespib.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('ganetespib', 'Chemical', 'MESH:C533237', (221, 231))	('mouse', 'Species', '10090', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('STA-8666', 'Var', (0, 8))
340037	27608846	However, mice treated with STA-8666 at any dose had longer and more persistent remissions, compared to the irinotecan group (Figure 2A and 2B).	('mice', 'Species', '10090', (9, 13))	('irinotecan', 'Chemical', 'MESH:D000077146', (107, 117))	('remissions', 'CPA', (79, 89))	('STA-8666', 'Var', (27, 35))
340052	27608846	Overall survival was significantly superior for the mice receiving STA-8666 (p = 0.0023) (Figure 3B).	('mice', 'Species', '10090', (52, 56))	('STA-8666', 'Var', (67, 75))	('superior', 'PosReg', (35, 43))	('Overall survival', 'CPA', (0, 16))
340069	27608846	These findings are consistent with our previous data suggesting that (1) ES tumors are more responsive to STA-8666 compared to RMS tumors, and (2) HSP90 inhibition per se contributed little to the anti-tumor activity of STA-8666 in either model.	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('RMS tumors', 'Disease', 'MESH:D009369', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (202, 207))	('ES', 'Phenotype', 'HP:0012254', (73, 75))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('ES tumors', 'Disease', 'MESH:C563168', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('STA-8666', 'Var', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('HSP90', 'Protein', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('RMS tumors', 'Disease', (127, 137))	('ES tumors', 'Disease', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('inhibition', 'NegReg', (153, 163))	('RMS', 'Phenotype', 'HP:0002859', (127, 130))	('responsive to', 'MPA', (92, 105))
340070	27608846	Because the RMS PDX was derived from a patient who had previously failed irinotecan, we investigated whether STA-8666 would be efficacious in an additional, non-RMS, irinotecan-resistant pediatric sarcoma model.	('irinotecan', 'Chemical', 'MESH:D000077146', (166, 176))	('patient', 'Species', '9606', (39, 46))	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('RMS', 'Phenotype', 'HP:0002859', (161, 164))	('STA-8666', 'Var', (109, 117))	('sarcoma', 'Disease', (197, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('RMS', 'Phenotype', 'HP:0002859', (12, 15))	('irinotecan', 'Chemical', 'MESH:D000077146', (73, 83))
340077	27608846	However, mice treated with STA-8666 uniformly experienced durable tumor regression, with no evidence of regrowth at 134 days post-tumor cell inoculation, and superior survival (Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('survival', 'CPA', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('superior', 'PosReg', (158, 166))	('STA-8666', 'Var', (27, 35))	('mice', 'Species', '10090', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (130, 135))
340081	27608846	The proposed mechanism of action of STA-8666 is based on enhanced delivery and sustained retention of SN-38 in tumor cells, compared to systemic administration of irinotecan.	('delivery', 'MPA', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('STA-8666', 'Gene', (36, 44))	('SN-38', 'Var', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('SN-38', 'Chemical', 'MESH:D000077146', (102, 107))	('irinotecan', 'Chemical', 'MESH:D000077146', (163, 173))	('enhanced', 'PosReg', (57, 65))
340086	27608846	At day 3, gammaH2AX intensity in the tumor treated with STA-8666 was similar to that in the tumor treated with irinotecan.	('STA-8666', 'Var', (56, 64))	('gammaH2AX', 'Gene', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('gammaH2AX', 'Gene', '15270', (10, 19))	('irinotecan', 'Chemical', 'MESH:D000077146', (111, 121))	('tumor', 'Disease', (92, 97))
340088	27608846	This is consistent with published data in breast cancer xenografts showing that gammaH2AX peaked 1 day post irinotecan treatment and 7-10 days post STA-8666 treatment, and suggests that in this ES sarcoma model, STA-8666 likewise causes sustained inhibition of topoisomerase 1, compared with irinotecan.	('sarcoma', 'Disease', 'MESH:D012509', (197, 204))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('sarcoma', 'Disease', (197, 204))	('ES', 'Phenotype', 'HP:0012254', (194, 196))	('gammaH2AX', 'Gene', (80, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('breast cancer', 'Disease', (42, 55))	('STA-8666', 'Var', (212, 220))	('topoisomerase 1', 'Enzyme', (261, 276))	('inhibition', 'NegReg', (247, 257))	('irinotecan', 'Chemical', 'MESH:D000077146', (292, 302))	('gammaH2AX', 'Gene', '15270', (80, 89))	('irinotecan', 'Chemical', 'MESH:D000077146', (108, 118))
340089	27608846	As an additional method to investigate the mechanism of action of STA-8666, RNA expression analysis of a panel of 180 known DNA damage and repair genes was performed on TC32 xenograft tumors harvested five days after treatment with a single dose of vehicle, ganetespib (IV, 150 mg/kg), irinotecan (IP, 50 mg/kg) or STA-8666 (IV, 100 mg/kg).	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('ganetespib', 'Chemical', 'MESH:C533237', (258, 268))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Disease', (184, 190))	('TC32', 'CellLine', 'CVCL:7151', (169, 173))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('irinotecan', 'Chemical', 'MESH:D000077146', (286, 296))	('STA-8666', 'Var', (315, 323))
340092	27608846	For each of these 20 genes, but particularly for the 10 downregulated genes, the fold-change compared to vehicle control was greater for the STA-8666 treated tumors than for the irinotecan treated tumors, suggesting that, 5 days after treatment, STA-8666 affects expression of DNA damage and repair genes more robustly than does irinotecan administered at an equimolar dose.	('tumors', 'Disease', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('irinotecan', 'Chemical', 'MESH:D000077146', (329, 339))	('tumors', 'Disease', (197, 203))	('STA-8666', 'Var', (246, 254))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('irinotecan', 'Chemical', 'MESH:D000077146', (178, 188))	('affects', 'Reg', (255, 262))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('expression', 'MPA', (263, 273))
340108	27608846	In the majority of the models tested, all dose levels of STA-8666 resulted in superior tumor regression, longer time to relapse, and markedly prolonged overall survival compared with the HSP90 inhibitor ganetespib, irinotecan administered on a weekly schedule, irinotecan administered on a protracted schedule, and irinotecan administered in combination with ganetespib.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('irinotecan', 'Chemical', 'MESH:D000077146', (215, 225))	('irinotecan', 'Chemical', 'MESH:D000077146', (315, 325))	('tumor', 'Disease', (87, 92))	('STA-8666', 'Var', (57, 65))	('overall survival', 'CPA', (152, 168))	('ganetespib', 'Chemical', 'MESH:C533237', (203, 213))	('prolonged', 'PosReg', (142, 151))	('superior', 'PosReg', (78, 86))	('irinotecan', 'Chemical', 'MESH:D000077146', (261, 271))	('ganetespib', 'Chemical', 'MESH:C533237', (359, 369))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
340111	27608846	Several dosing regimens were tested in an effort to thoroughly compare the activity of STA-8666 to irinotecan, the clinically available form of SN-38.	('activity', 'MPA', (75, 83))	('STA-8666', 'Var', (87, 95))	('SN-38', 'Chemical', 'MESH:D000077146', (144, 149))	('irinotecan', 'Chemical', 'MESH:D000077146', (99, 109))
340112	27608846	When equimolar doses (100 mg/kg STA-8666 and 50 mg/kg irinotecan) were given, STA-8666 was more efficacious in both ES and RMS, resulting in later relapse and prolonged overall survival.	('irinotecan', 'Chemical', 'MESH:D000077146', (54, 64))	('overall survival', 'CPA', (169, 185))	('ES', 'Phenotype', 'HP:0012254', (116, 118))	('prolonged', 'PosReg', (159, 168))	('STA-8666', 'Var', (78, 86))	('later', 'PosReg', (141, 146))	('relapse', 'CPA', (147, 154))	('RMS', 'Disease', (123, 126))	('RMS', 'Phenotype', 'HP:0002859', (123, 126))
340113	27608846	Furthermore, STA-8666 retained superior efficacy in both ES and RMS, even when tested at half the equimolar dose of irinotecan.	('RMS', 'Phenotype', 'HP:0002859', (64, 67))	('irinotecan', 'Chemical', 'MESH:D000077146', (116, 126))	('STA-8666', 'Var', (13, 21))	('ES', 'Phenotype', 'HP:0012254', (57, 59))	('RMS', 'Disease', (64, 67))
340116	27608846	In all but one case (RMS PDX, derived from an irinotecan-refractory tumor), STA-8666 resulted in superior outcomes, compared to irinotecan.	('tumor', 'Disease', (68, 73))	('STA-8666', 'Var', (76, 84))	('irinotecan', 'Chemical', 'MESH:D000077146', (46, 56))	('superior', 'PosReg', (97, 105))	('RMS', 'Phenotype', 'HP:0002859', (21, 24))	('outcomes', 'MPA', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('irinotecan', 'Chemical', 'MESH:D000077146', (128, 138))
340120	27608846	Specifically, gammaH2AX was readily detected in tumor samples from mice 7 days after a single dose of STA-8666, whereas mice receiving irinotecan had no detectable gammaH2AX at this time point.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('gammaH2AX', 'Gene', (164, 173))	('gammaH2AX', 'Gene', (14, 23))	('tumor', 'Disease', (48, 53))	('mice', 'Species', '10090', (120, 124))	('gammaH2AX', 'Gene', '15270', (164, 173))	('gammaH2AX', 'Gene', '15270', (14, 23))	('STA-8666', 'Var', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('irinotecan', 'Chemical', 'MESH:D000077146', (135, 145))	('mice', 'Species', '10090', (67, 71))
340122	27608846	The observation that none of the STA-8666 treated mice experienced clinical signs of toxicity during or after treatment suggests that even in the context of prolonged topoisomerase 1 inhibition in the tumor, STA-8666 may spare normal tissue from such exposure.	('inhibition', 'NegReg', (183, 193))	('toxicity', 'Disease', 'MESH:D064420', (85, 93))	('toxicity', 'Disease', (85, 93))	('STA-8666', 'Var', (208, 216))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('topoisomerase 1', 'Enzyme', (167, 182))	('mice', 'Species', '10090', (50, 54))	('tumor', 'Disease', (201, 206))
340123	27608846	STA-8666 thus meets the aforementioned criteria of an ideal SN-38 delivery system in that it is easily bioavailable, produces prolonged exposure in tumors and is well tolerated.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('exposure', 'MPA', (136, 144))	('SN-38', 'Chemical', 'MESH:D000077146', (60, 65))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('STA-8666', 'Var', (0, 8))
340125	27608846	Further mechanistic insight may be gained from an examination of the functions of the most strongly affected genes, PIK3R1 (expression increased 70-fold with STA-8666 and 50-fold with irinotecan) and RPS27A (expression decreased 16-fold with STA-8666 and 10-fold with irinotecan).	('RPS27A', 'Gene', '78294', (200, 206))	('RPS27A', 'Gene', (200, 206))	('irinotecan', 'Chemical', 'MESH:D000077146', (184, 194))	('increased', 'PosReg', (135, 144))	('PIK3R1', 'Gene', '18708', (116, 122))	('expression', 'MPA', (124, 134))	('expression', 'MPA', (208, 218))	('STA-8666', 'Var', (158, 166))	('irinotecan', 'Chemical', 'MESH:D000077146', (268, 278))	('PIK3R1', 'Gene', (116, 122))
340204	21508354	When we looked for synergy of PCI-24781 with chemotherapeutic agents, we found that PCI-24781 reverses drug resistance in all four multidrug resistant sarcoma cell lines and synergizes with chemotherapeutic agents to enhance caspase-3/7 activity.	('enhance', 'PosReg', (217, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('activity', 'MPA', (237, 245))	('PCI-24781', 'Chemical', 'MESH:C512352', (84, 93))	('caspase-3', 'Gene', (225, 234))	('PCI-24781', 'Chemical', 'MESH:C512352', (30, 39))	('caspase-3', 'Gene', '836', (225, 234))	('reverses', 'NegReg', (94, 102))	('PCI-24781', 'Var', (84, 93))	('drug resistance', 'Phenotype', 'HP:0020174', (103, 118))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('drug resistance', 'MPA', (103, 118))	('sarcoma', 'Disease', (151, 158))
340205	21508354	Expression of RAD51 (a marker for DNA double-strand break repair) was inhibited and the expression of GADD45alpha (a marker for growth arrest and DNA-damage) was induced by PCI-24781 in multidrug resistant sarcoma cell lines.	('growth arrest', 'Disease', (128, 141))	('sarcoma', 'Disease', (206, 213))	('RAD51', 'Gene', (14, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('PCI-24781', 'Chemical', 'MESH:C512352', (173, 182))	('RAD51', 'Gene', '5888', (14, 19))	('Expression', 'MPA', (0, 10))	('GADD45alpha', 'Gene', (102, 113))	('GADD45alpha', 'Gene', '1647', (102, 113))	('growth arrest', 'Phenotype', 'HP:0001510', (128, 141))	('induced', 'PosReg', (162, 169))	('PCI-24781', 'Var', (173, 182))	('sarcoma', 'Disease', 'MESH:D012509', (206, 213))	('inhibited', 'NegReg', (70, 79))	('expression', 'MPA', (88, 98))	('growth arrest', 'Disease', 'MESH:D006323', (128, 141))
340216	21508354	Since aberrant epigenetic changes are common and significant mechanisms in cancer development and progression, HDACs are promising targets for pharmacological inhibition.	('HDAC', 'Gene', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('HDAC', 'Gene', '9734', (111, 115))	('cancer', 'Disease', (75, 81))	('mechanisms', 'Reg', (61, 71))	('aberrant epigenetic changes', 'Var', (6, 33))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
340227	21508354	While increases in DNA accessibility caused by changes in acetylation may also enhance DNA damage and repair the damages more directly , the efficacy of PCI-24781 on mutidrug resistant sarcoma cells has not been reported before.	('PCI-24781', 'Chemical', 'MESH:C512352', (153, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('DNA damage', 'MPA', (87, 97))	('DNA accessibility', 'MPA', (19, 36))	('changes', 'Var', (47, 54))	('enhance', 'PosReg', (79, 86))	('acetylation', 'MPA', (58, 69))	('sarcoma', 'Disease', 'MESH:D012509', (185, 192))	('sarcoma', 'Disease', (185, 192))	('increases', 'PosReg', (6, 15))
340271	21508354	The IC50 values for ET 743 in parental TC-ET cells (IC50=2.58) were 1.8 fold more than PCI-24871 treated TC-ET cells (IC50=1.43).	('IC50', 'MPA', (4, 8))	('ET 743', 'Var', (20, 26))	('TC-ET', 'CellLine', 'CVCL:6996', (105, 110))	('TC-ET', 'CellLine', 'CVCL:6996', (39, 44))
340273	21508354	The same concentration of drugs induced only a small increase in caspase-3/7 activity in multidrug resistant cell lines, however, these effects were significantly enhanced by PCI-24781 (Fig.4) RAD51 is a homologous recombination (HR) and DNA repair protein.	('caspase-3', 'Gene', '836', (65, 74))	('PCI-24781', 'Chemical', 'MESH:C512352', (175, 184))	('RAD51', 'Gene', (193, 198))	('DNA repair protein', 'Gene', (238, 256))	('activity', 'MPA', (77, 85))	('enhanced', 'PosReg', (163, 171))	('PCI-24781', 'Var', (175, 184))	('caspase-3', 'Gene', (65, 74))	('DNA repair protein', 'Gene', '442459', (238, 256))	('RAD51', 'Gene', '5888', (193, 198))
340291	21508354	The accumulation of various biomarkers of apoptosis, including acetylated histones and p21, suggests PCI-24781 induces apoptosis.	('p21', 'Gene', '1026', (87, 90))	('accumulation', 'PosReg', (4, 16))	('PCI-24781', 'Var', (101, 110))	('p21', 'Gene', (87, 90))	('apoptosis', 'CPA', (119, 128))	('induces', 'PosReg', (111, 118))	('PCI-24781', 'Chemical', 'MESH:C512352', (101, 110))	('acetylated', 'MPA', (63, 73))
340301	21508354	Furthermore, Gadd45alpha, which plays an important role in both cell cycle control, survival and apoptosis, was found to be induced in multidrug resistant sarcoma cell lines treated with PCI-24781, although cells treated with chemotherapy alone did not express GADD45alpha.	('Gadd45alpha', 'Gene', '1647', (13, 24))	('sarcoma', 'Disease', (155, 162))	('PCI-24781', 'Chemical', 'MESH:C512352', (187, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('GADD45alpha', 'Gene', (261, 272))	('GADD45alpha', 'Gene', '1647', (261, 272))	('PCI-24781', 'Var', (187, 196))	('induced', 'Reg', (124, 131))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('Gadd45alpha', 'Gene', (13, 24))
340368	32986888	In parallel, drugs targeted to specific molecules have been introduced to clinical practice, with many reports that specific mutations in target genes are highly predictive of efficacy; examples include imatinib in chronic myeloid leukemia 43  and gastrointestinal stromal tumors, 44  as well as gefitinib in non-small cell lung cancer (NSCLC), 45  published in the early 2000s.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (248, 279))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (309, 335))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (223, 239))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (248, 279))	('NSCLC', 'Disease', 'MESH:D002289', (337, 342))	('non-small cell lung cancer', 'Disease', (309, 335))	('chronic myeloid leukemia', 'Disease', (215, 239))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('imatinib', 'Chemical', 'MESH:D000068877', (203, 211))	('mutations', 'Var', (125, 134))	('gastrointestinal stromal tumors', 'Disease', (248, 279))	('NSCLC', 'Disease', (337, 342))	('NSCLC', 'Phenotype', 'HP:0030358', (337, 342))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('imatinib', 'Gene', (203, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (324, 335))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (309, 335))	('gefitinib', 'Chemical', 'MESH:D000077156', (296, 305))	('leukemia', 'Phenotype', 'HP:0001909', (231, 239))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (215, 239))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (313, 335))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (215, 239))
340369	32986888	For example, although the oncogenic BRAFV600E mutation predicts the efficacy of vemurafenib treatment for melanoma, 47  hairy cell leukemia, 48  and NSCLC, 49  a phase II basket trial revealed that targeting BRAFV600E did not yield the expected results in colorectal cancers.	('BRAFV600E', 'Gene', (36, 45))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (120, 139))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('colorectal cancers', 'Disease', 'MESH:D015179', (256, 274))	('vemurafenib', 'Chemical', 'MESH:D000077484', (80, 91))	('NSCLC', 'Disease', (149, 154))	('BRAFV600E', 'Var', (208, 217))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))	('hairy cell leukemia', 'Disease', (120, 139))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('BRAFV600E', 'Mutation', 'rs113488022', (36, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (256, 273))	('colorectal cancers', 'Disease', (256, 274))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('BRAFV600E', 'Mutation', 'rs113488022', (208, 217))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))
340425	29553955	NTRK Fusions Define a Novel Uterine Sarcoma Subtype with Features of Fibrosarcoma Tropomyosin receptor kinase (Trk) inhibitors have shown high response rates in patients with tumors harboring NTRK fusions.	('Uterine Sarcoma', 'Phenotype', 'HP:0002891', (28, 43))	('tumors', 'Disease', (175, 181))	('fusions', 'Var', (197, 204))	('Fibrosarcoma', 'Disease', (69, 81))	('Fibrosarcoma', 'Disease', 'MESH:D005354', (69, 81))	('TRK', 'Gene', (193, 196))	('Tropomyosin receptor kinase', 'Gene', '4914', (82, 109))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('Sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('Trk', 'Gene', '4914', (111, 114))	('Sarcoma', 'Disease', (36, 43))	('TRK', 'Gene', '4914', (193, 196))	('TRK', 'Gene', (1, 4))	('patients', 'Species', '9606', (161, 169))	('Sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('Trk', 'Gene', (111, 114))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('TRK', 'Gene', '4914', (1, 4))	('Fibrosarcoma', 'Phenotype', 'HP:0100244', (69, 81))	('Tropomyosin receptor kinase', 'Gene', (82, 109))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
340427	29553955	NTRK rearrangements were detected by fluorescence in situ hybridization (FISH) and/or targeted RNA or DNA sequencing in four undifferentiated uterine sarcomas with spindle cell morphology.	('TRK', 'Gene', (1, 4))	('sarcomas', 'Disease', (150, 158))	('TRK', 'Gene', '4914', (1, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (142, 157))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))	('rearrangements', 'Var', (5, 19))
340431	29553955	FISH and/or targeted RNA or DNA sequencing in the study group showed TPM3-NTRK1, LMNA-NTRK1, RBPMS-NTRK3, and TPR-NTRK1 fusions.	('NTRK1', 'Gene', '4914', (114, 119))	('NTRK1', 'Gene', '4914', (74, 79))	('NTRK1', 'Gene', (86, 91))	('TPM3', 'Gene', '7170', (69, 73))	('NTRK1', 'Gene', (114, 119))	('NTRK1', 'Gene', (74, 79))	('LMNA-NTRK1', 'Gene', (81, 91))	('TPR', 'Gene', (110, 113))	('RBPMS', 'Gene', (93, 98))	('fusions', 'Var', (120, 127))	('TPR', 'Gene', '7175', (110, 113))	('LMNA-NTRK1', 'Gene', '4000;4914', (81, 91))	('RBPMS', 'Gene', '11030', (93, 98))	('NTRK3', 'Gene', '4916', (99, 104))	('TPM3', 'Gene', (69, 73))	('NTRK1', 'Gene', '4914', (86, 91))	('NTRK3', 'Gene', (99, 104))
340444	29553955	While most if not all undifferentiated uterine sarcomas have a reportedly dismal prognosis, the scope of clinicopathologic studies describing the entity has been severely limited due to the rarity of this tumor type and likely contamination by morphologically high-grade endometrial stromal sarcomas harboring various genetic aberrations, particularly gene fusions that are distinct from low-grade endometrial stromal sarcomas .	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (271, 299))	('sarcomas', 'Disease', 'MESH:D012509', (418, 426))	('endometrial stromal sarcomas', 'Disease', (398, 426))	('endometrial stromal sarcomas', 'Disease', (271, 299))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (418, 426))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcomas', 'Disease', (47, 55))	('sarcomas', 'Disease', (418, 426))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('sarcomas', 'Disease', 'MESH:D012509', (291, 299))	('sarcoma', 'Phenotype', 'HP:0100242', (418, 425))	('sarcomas', 'Phenotype', 'HP:0100242', (291, 299))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('sarcomas', 'Disease', (291, 299))	('gene fusions', 'Var', (352, 364))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (39, 54))	('tumor', 'Disease', (205, 210))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (398, 426))
340447	29553955	However, only limited molecular data exist among undifferentiated uterine sarcomas, which appear to have complex karyotypes and harbor TP53 mutations in approximately 30% of cases .	('sarcomas', 'Disease', (74, 82))	('TP53', 'Gene', '7157', (135, 139))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (66, 81))	('TP53', 'Gene', (135, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('mutations', 'Var', (140, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
340450	29553955	We also assess the frequency of TrkA and pan-Trk expression and NTRK gene rearrangement among uterine spindle cell leiomyosarcomas which represents the most important differential diagnosis in the assessment of these rare spindle cell sarcomas.	('TrkA', 'Gene', '4914', (32, 36))	('pan', 'Gene', '51816', (41, 44))	('uterine spindle cell leiomyosarcomas', 'Phenotype', 'HP:0002891', (94, 130))	('Trk', 'Gene', '4914', (32, 35))	('rearrangement', 'Var', (74, 87))	('pan', 'Gene', (41, 44))	('sarcomas', 'Disease', 'MESH:D012509', (235, 243))	('sarcomas', 'Phenotype', 'HP:0100242', (235, 243))	('TRK', 'Gene', (65, 68))	('Trk', 'Gene', (32, 35))	('sarcomas', 'Disease', (235, 243))	('Trk', 'Gene', '4914', (45, 48))	('TrkA', 'Gene', (32, 36))	('uterine spindle cell leiomyosarcoma', 'Phenotype', 'HP:0002891', (94, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('sarcomas', 'Disease', 'MESH:D012509', (122, 130))	('TRK', 'Gene', '4914', (65, 68))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (115, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('leiomyosarcomas', 'Disease', (115, 130))	('sarcomas', 'Disease', (122, 130))	('Trk', 'Gene', (45, 48))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (115, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (115, 129))
340455	29553955	Immunohistochemical staining for TrkA, TrkB, and TrkC expression and TrkA only was performed on the study cohort and tissue microarrays of leiomyosarcoma using a commercially available pan-Trk monoclonal antibody, clone EPR17341 (Abcam, Cambridge, MA) at 6 mug/mL and a commercially available TrkA monoclonal antibody, clone (Abcam, Cambridge, MA) at 0.684 mg/mL, respectively.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (139, 153))	('TrkC', 'Gene', (49, 53))	('pan', 'Gene', '51816', (185, 188))	('TrkA', 'Gene', '4914', (33, 37))	('Trk', 'Gene', '4914', (49, 52))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (139, 153))	('Trk', 'Gene', '4914', (33, 36))	('pan', 'Gene', (185, 188))	('TrkA', 'Gene', '4914', (293, 297))	('TrkC', 'Gene', '4916', (49, 53))	('Trk', 'Gene', '4914', (293, 296))	('Trk', 'Gene', (49, 52))	('Trk', 'Gene', '4914', (39, 42))	('TrkA', 'Gene', '4914', (69, 73))	('EPR17341', 'Var', (220, 228))	('leiomyosarcoma', 'Disease', (139, 153))	('Trk', 'Gene', (33, 36))	('TrkA', 'Gene', (33, 37))	('Trk', 'Gene', '4914', (69, 72))	('Trk', 'Gene', '4914', (189, 192))	('TrkB', 'Gene', '4915', (39, 43))	('Trk', 'Gene', (293, 296))	('clone EPR17341', 'Chemical', 'MESH:C080161', (214, 228))	('TrkA', 'Gene', (293, 297))	('Trk', 'Gene', (39, 42))	('Trk', 'Gene', (189, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('TrkB', 'Gene', (39, 43))	('Trk', 'Gene', (69, 72))	('TrkA', 'Gene', (69, 73))
340496	29553955	CD34 staining was negative, while H3K27me3 expression was retained in all tumors.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CD34', 'Gene', '947', (0, 4))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('H3K27me3', 'Var', (34, 42))	('CD34', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
340502	29553955	The TPR-NTRK1 fusion was also confirmed by targeted DNA sequencing in one tumor, while the other fusions in the three remaining tumors were confirmed by FISH (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('NTRK1', 'Gene', '4914', (8, 13))	('TPR', 'Gene', (4, 7))	('TPR', 'Gene', '7175', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('fusion', 'Var', (14, 20))	('NTRK1', 'Gene', (8, 13))	('tumor', 'Disease', (74, 79))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
340504	29553955	TrkA expression was diffuse, defined as >95% of cells staining, with weakly cytoplasmic and strongly perinuclear staining in the tumor harboring LMNA-NTRK1 fusion (Figure 4).	('LMNA-NTRK1', 'Gene', (145, 155))	('LMNA-NTRK1', 'Gene', '4000;4914', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('TrkA', 'Gene', '4914', (0, 4))	('TrkA', 'Gene', (0, 4))	('tumor', 'Disease', (129, 134))	('fusion', 'Var', (156, 162))
340505	29553955	There was strong and diffuse cytoplasmic TrkA staining in the tumor harboring TPM3-NTRK1 fusion.	('fusion', 'Var', (89, 95))	('NTRK1', 'Gene', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TPM3', 'Gene', (78, 82))	('tumor', 'Disease', (62, 67))	('TrkA', 'Gene', (41, 45))	('TPM3', 'Gene', '7170', (78, 82))	('TrkA', 'Gene', '4914', (41, 45))	('NTRK1', 'Gene', '4914', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
340506	29553955	Pan-Trk expression was strong and diffuse with mostly cytoplasmic staining and dot-like aggregates as well as rare nuclear staining and accentuation of the nuclear envelope in the tumor harboring TPR-NTRK1 fusion.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('TPR', 'Gene', (196, 199))	('Trk', 'Gene', '4914', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Trk', 'Gene', (4, 7))	('NTRK1', 'Gene', (200, 205))	('TPR', 'Gene', '7175', (196, 199))	('tumor', 'Disease', (180, 185))	('fusion', 'Var', (206, 212))	('Pan', 'Gene', (0, 3))	('accentuation', 'PosReg', (136, 148))	('Pan', 'Gene', '51816', (0, 3))	('NTRK1', 'Gene', '4914', (200, 205))
340507	29553955	The tumor with RBPMS-NTRK3 fusion showed diffuse moderate to strong cytoplasmic pan-Trk expression.	('tumor', 'Disease', (4, 9))	('Trk', 'Gene', (84, 87))	('RBPMS', 'Gene', '11030', (15, 20))	('NTRK3', 'Gene', (21, 26))	('pan', 'Gene', (80, 83))	('fusion', 'Var', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('pan', 'Gene', '51816', (80, 83))	('Trk', 'Gene', '4914', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('NTRK3', 'Gene', '4916', (21, 26))	('RBPMS', 'Gene', (15, 20))
340511	29553955	We report for the first time the presence of NTRK gene rearrangements in a subset of undifferentiated uterine sarcomas with fibrosarcoma-like morphology.	('TRK', 'Gene', (46, 49))	('TRK', 'Gene', '4914', (46, 49))	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (102, 117))	('fibrosarcoma', 'Disease', 'MESH:D005354', (124, 136))	('rearrangements', 'Var', (55, 69))	('fibrosarcoma', 'Disease', (124, 136))	('sarcomas', 'Disease', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (124, 136))	('presence', 'Reg', (33, 41))
340520	29553955	Binding of neurotrophins to Trk proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma .	('downstream signaling cascades', 'Pathway', (111, 140))	('activation', 'PosReg', (93, 103))	('receptor dimerization', 'MPA', (49, 70))	('ERK', 'Gene', '2048', (160, 163))	('Trk', 'Gene', '4914', (28, 31))	('Trk', 'Gene', (28, 31))	('phosphorylation', 'MPA', (72, 87))	('induces', 'Reg', (41, 48))	('ERK', 'Gene', (160, 163))	('PI3K', 'Var', (145, 149))	('Binding', 'Interaction', (0, 7))
340521	29553955	Trk pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many human cancers, with NTRK gene fusions being the most commonly validated oncogenic events to date.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('gene fusions', 'Var', (35, 47))	('cancers', 'Disease', (163, 170))	('protein', 'Protein', (49, 56))	('overexpression', 'PosReg', (57, 71))	('Trk', 'Gene', '4914', (0, 3))	('aberrations', 'Var', (12, 23))	('implicated', 'Reg', (118, 128))	('Trk', 'Gene', (0, 3))	('single nucleotide alterations', 'Var', (77, 106))	('TRK', 'Gene', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('TRK', 'Gene', '4914', (178, 181))	('human', 'Species', '9606', (157, 162))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
340524	29553955	Among soft tissue sarcomas, ETV6-NTRK3 fusions and NTRK1 gene rearrangements appear to define the vast majority of infantile fibrosarcomas  and lipofibromatosis-like neural tumors , respectively.	('infantile fibrosarcomas', 'Disease', 'MESH:D005354', (115, 138))	('lipofibromatosis-like neural tumors', 'Disease', 'MESH:C536408', (144, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('fusions', 'Var', (39, 46))	('ETV6', 'Gene', '2120', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('NTRK1', 'Gene', '4914', (51, 56))	('rearrangements', 'Var', (62, 76))	('NTRK1', 'Gene', (51, 56))	('infantile fibrosarcomas', 'Disease', (115, 138))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (125, 137))	('ETV6', 'Gene', (28, 32))	('sarcomas', 'Disease', 'MESH:D012509', (130, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (6, 26))	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('sarcomas', 'Disease', (130, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('NTRK3', 'Gene', '4916', (33, 38))	('sarcomas', 'Disease', (18, 26))	('NTRK3', 'Gene', (33, 38))	('lipofibromatosis-like neural tumors', 'Disease', (144, 179))
340525	29553955	Interestingly, rare NTRK3-negative infantile fibrosarcomas have been reported to instead harbor NTRK1 gene rearrangements , suggesting that oncogenic activation of various NTRK genes through chromosomal translocations are involved interchangeably in the pathogenesis of certain soft tissue sarcomas.	('TRK', 'Gene', '4914', (173, 176))	('TRK', 'Gene', '4914', (21, 24))	('infantile fibrosarcomas', 'Disease', (35, 58))	('sarcomas', 'Disease', 'MESH:D012509', (290, 298))	('NTRK3', 'Gene', '4916', (20, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (290, 298))	('NTRK1', 'Gene', '4914', (96, 101))	('TRK', 'Gene', (97, 100))	('sarcomas', 'Disease', (290, 298))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (45, 57))	('involved', 'Reg', (222, 230))	('NTRK3', 'Gene', (20, 25))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (278, 298))	('NTRK1', 'Gene', (96, 101))	('sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('rearrangements', 'Var', (107, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('sarcomas', 'Disease', (50, 58))	('TRK', 'Gene', '4914', (97, 100))	('TRK', 'Gene', (173, 176))	('infantile fibrosarcomas', 'Disease', 'MESH:D005354', (35, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('TRK', 'Gene', (21, 24))
340527	29553955	NTRK rearrangements appear to underpin a subset of high-grade uterine sarcomas with spindle cell morphology.	('TRK', 'Gene', (1, 4))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('TRK', 'Gene', '4914', (1, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (62, 77))	('underpin', 'Reg', (30, 38))	('rearrangements', 'Var', (5, 19))
340528	29553955	We identified a novel RBPMS-NTRK3 fusion in a uterine sarcoma that has not been previously reported in other tumor types with NTRK rearrangement.	('RBPMS', 'Gene', (22, 27))	('RBPMS', 'Gene', '11030', (22, 27))	('fusion', 'Var', (34, 40))	('TRK', 'Gene', (29, 32))	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('NTRK3', 'Gene', (28, 33))	('TRK', 'Gene', '4914', (29, 32))	('TRK', 'Gene', (127, 130))	('TRK', 'Gene', '4914', (127, 130))	('sarcoma', 'Disease', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (46, 61))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('NTRK3', 'Gene', '4916', (28, 33))	('tumor', 'Disease', (109, 114))
340529	29553955	Among tumors with NTRK1-related fusions, there are numerous gene partners involved, with three in particular emerging as recurrent, such as TPR, TMP3 and LMNA, all located on the long arm of chromosome 1 (1q21-q23), in the vicinity of NTRK1.	('NTRK1', 'Gene', (18, 23))	('TPR', 'Gene', (140, 143))	('fusions', 'Var', (32, 39))	('NTRK1', 'Gene', '4914', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('LMNA', 'Gene', (154, 158))	('TMP3', 'Gene', (145, 149))	('TPR', 'Gene', '7175', (140, 143))	('TMP3', 'Chemical', 'MESH:C058833', (145, 149))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('NTRK1', 'Gene', (235, 240))	('NTRK1', 'Gene', '4914', (18, 23))	('LMNA', 'Gene', '4000', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
340531	29553955	Among the uterine sarcomas with NTRK1 rearrangements, breakpoints include exon 10 (TPR-NTRK1) and exon 12 (LMNA-NTRK1).	('LMNA-NTRK1', 'Gene', (107, 117))	('rearrangements', 'Var', (38, 52))	('LMNA-NTRK1', 'Gene', '4000;4914', (107, 117))	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('NTRK1', 'Gene', (87, 92))	('NTRK1', 'Gene', '4914', (112, 117))	('NTRK1', 'Gene', '4914', (32, 37))	('exon 12', 'Var', (98, 105))	('sarcomas', 'Disease', (18, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('TPR', 'Gene', (83, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (10, 25))	('NTRK1', 'Gene', (112, 117))	('NTRK1', 'Gene', (32, 37))	('TPR', 'Gene', '7175', (83, 86))	('NTRK1', 'Gene', '4914', (87, 92))
340534	29553955	A recent study from our group suggested that pan-Trk immunoreactivity is associated with a fusion partner-specific pattern of staining, with cytoplasmic expression and nuclear membrane accentuation in tumors with LMNA-NTRK1 fusions and cellular membrane accentuation in all TPM3/4 fusions, while half of tumors with ETV6-NTRK3 fusions display nuclear staining .	('tumors', 'Disease', (304, 310))	('Trk', 'Gene', '4914', (49, 52))	('TPM3', 'Gene', (274, 278))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('ETV6', 'Gene', (316, 320))	('Trk', 'Gene', (49, 52))	('pan', 'Gene', '51816', (45, 48))	('NTRK3', 'Gene', '4916', (321, 326))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('TPM3', 'Gene', '7170', (274, 278))	('NTRK3', 'Gene', (321, 326))	('fusions', 'Var', (224, 231))	('pan', 'Gene', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('LMNA-NTRK1', 'Gene', '4000;4914', (213, 223))	('ETV6', 'Gene', '2120', (316, 320))	('LMNA-NTRK1', 'Gene', (213, 223))
340535	29553955	While cytoplasmic and nuclear membrane TrkA staining was seen in one of our tumors with LMNA-NTRK1 fusion, only cytoplasmic TrkA and pan-Trk expression was present in the tumors harboring TPM3-NTRK1 and RBPMS-NTRK3 fusions, respectively.	('RBPMS', 'Gene', '11030', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('fusion', 'Var', (99, 105))	('Trk', 'Gene', (137, 140))	('NTRK1', 'Gene', '4914', (193, 198))	('TrkA', 'Gene', '4914', (39, 43))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('NTRK1', 'Gene', (193, 198))	('Trk', 'Gene', '4914', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('pan', 'Gene', '51816', (133, 136))	('TPM3', 'Gene', '7170', (188, 192))	('TrkA', 'Gene', '4914', (124, 128))	('tumors', 'Disease', (171, 177))	('LMNA-NTRK1', 'Gene', '4000;4914', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Trk', 'Gene', '4914', (124, 127))	('RBPMS', 'Gene', (203, 208))	('LMNA-NTRK1', 'Gene', (88, 98))	('tumors', 'Disease', (76, 82))	('NTRK3', 'Gene', '4916', (209, 214))	('pan', 'Gene', (133, 136))	('NTRK1', 'Gene', '4914', (93, 98))	('Trk', 'Gene', (39, 42))	('NTRK3', 'Gene', (209, 214))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('TrkA', 'Gene', (39, 43))	('NTRK1', 'Gene', (93, 98))	('TPM3', 'Gene', (188, 192))	('Trk', 'Gene', (124, 127))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('Trk', 'Gene', '4914', (137, 140))	('TrkA', 'Gene', (124, 128))
340557	29553955	Since NTRK fusion-positive uterine sarcomas appear to affect premenopausal women, early identification of NTRK fusions in limited tissue samples also raises the possibility for neoadjuvant Trk inhibition in the setting of fertility preservation.	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('fusions', 'Var', (111, 118))	('women', 'Species', '9606', (75, 80))	('Trk', 'Gene', '4914', (189, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('Trk', 'Gene', (189, 192))	('sarcomas', 'Disease', (35, 43))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (27, 42))	('TRK', 'Gene', (7, 10))	('affect', 'Reg', (54, 60))	('TRK', 'Gene', '4914', (7, 10))	('TRK', 'Gene', (107, 110))	('TRK', 'Gene', '4914', (107, 110))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))
340581	27418251	The fusion proteins which were generated by chromosome translocation cause to change of phenotypic properties in cell to contribute to the tumorigenic pathway.	('change', 'Reg', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('phenotypic properties in cell', 'MPA', (88, 117))	('contribute', 'Reg', (121, 131))	('chromosome translocation', 'Var', (44, 68))
340586	27418251	Recent cytogenetic and molecular genetic studies of EMCS have found reciprocal translocations, typically t(9;22)(q22;q12.2), resulting in fusion of EWSR1 to NR4A3.	('fusion', 'Interaction', (138, 144))	('NR4A3', 'Gene', (157, 162))	('EWSR1', 'Gene', (148, 153))	('t(9;22)(q22;q12.2)', 'STRUCTURAL_ABNORMALITY', 'None', (105, 123))	('t(9;22)(q22;q12.2', 'Var', (105, 122))	('EWSR1', 'Gene', '2130', (148, 153))	('NR4A3', 'Gene', '8013', (157, 162))
340619	27418251	A high rate of characteristic chromosome translocations, i.e., t(9;22)(q22;q12) and t(9;17)(q22;q11), and resulting fused genes, i.e., EWSR1-NR4A3 and TAF15-NR4A3, are seen in the tumors.	('NR4A3', 'Gene', (157, 162))	('TAF15', 'Gene', '8148', (151, 156))	('NR4A3', 'Gene', '8013', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('EWSR1', 'Gene', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('NR4A3', 'Gene', (141, 146))	('t(9;17)(q22;q11', 'Var', (84, 99))	('tumors', 'Disease', (180, 186))	('TAF15', 'Gene', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('t(9;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (63, 79))	('NR4A3', 'Gene', '8013', (141, 146))	('EWSR1', 'Gene', '2130', (135, 140))	('t(9;17)(q22;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (84, 100))	('t(9;22)(q22;q12', 'Var', (63, 78))
340632	27418251	In research in vitro, trabectedin has been reported to inhibit the transcription factor function of fused proteins produced as a result of the chromosome translocations in some human bone and soft tissue sarcoma cell lines that have a chromosome translocation.	('transcription factor function of fused', 'MPA', (67, 105))	('trabectedin', 'Chemical', 'MESH:D000077606', (22, 33))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (192, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (192, 211))	('human', 'Species', '9606', (177, 182))	('chromosome translocations', 'Var', (143, 168))	('inhibit', 'NegReg', (55, 62))	('soft tissue sarcoma', 'Disease', (192, 211))
340633	27418251	This appears to be one of the mechanisms by which trabectedin exhibits a strong antitumor effect against soft tissue sarcomas that have chromosome translocations.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (105, 124))	('chromosome translocations', 'Var', (136, 161))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('trabectedin', 'Chemical', 'MESH:D000077606', (50, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (105, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcomas', 'Disease', (117, 125))	('soft tissue sarcoma', 'Disease', (105, 124))	('tumor', 'Disease', (84, 89))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (105, 125))
340714	26252771	In those cells where we found Warburg effect (TC-71) melatonin induces cell death, whereas in those cells that present "normal" glycolytic metabolism with little or no participation of the aerobic glycolysis (sw-1353) melatonin inhibits cell proliferation.	('cell death', 'CPA', (71, 81))	('melatonin', 'Chemical', 'MESH:D008550', (53, 62))	('melatonin', 'Chemical', 'MESH:D008550', (218, 227))	('sw-1353', 'CellLine', 'CVCL:0543', (209, 216))	('cell proliferation', 'CPA', (237, 255))	('melatonin', 'Var', (53, 62))	('inhibits', 'NegReg', (228, 236))	('TC-71', 'CellLine', 'CVCL:2213', (46, 51))	('TC-71) melatonin', 'Var', (46, 62))
340721	26252771	Moreover, CP316819, a specific inhibitor of glycogen breakdown, strongly enhanced melatonin-induced cell death in TC-71 cells (Fig 2E), indicating that normal glycogen breakdown was essential for cell viability.	('CP316819', 'Chemical', 'MESH:C504712', (10, 18))	('melatonin', 'Chemical', 'MESH:D008550', (82, 91))	('glycogen', 'Chemical', 'MESH:D006003', (159, 167))	('TC-71', 'CellLine', 'CVCL:2213', (114, 119))	('enhanced', 'PosReg', (73, 81))	('glycogen', 'Chemical', 'MESH:D006003', (44, 52))	('CP316819', 'Var', (10, 18))	('melatonin-induced', 'MPA', (82, 99))
340723	26252771	In addition, CP316819 did not alter melatonin antiproliferative effects (Fig 3D).	('CP316819', 'Chemical', 'MESH:C504712', (13, 21))	('CP316819', 'Var', (13, 21))	('melatonin', 'Chemical', 'MESH:D008550', (36, 45))	('antiproliferative effects', 'MPA', (46, 71))
340736	26252771	On the other hand, rapamycin or LY294002, specific inhibitors of mTOR and PI3K respectively, did not prevent melatonin-induced decrease in TC-71 cell viability (Fig 5E, left panel).	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('rapamycin', 'Chemical', 'MESH:D020123', (19, 28))	('decrease', 'NegReg', (127, 135))	('melatonin', 'Chemical', 'MESH:D008550', (109, 118))	('LY294002', 'Var', (32, 40))	('LY294002', 'Chemical', 'MESH:C085911', (32, 40))	('TC-71', 'CellLine', 'CVCL:2213', (139, 144))
340749	26252771	Inhibition of LDH activity kills cancer cells that are metabolically dependent on the Warburg effect and, consistently, oxamate kills Ewing sarcoma cells but not chondrosarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('cancer', 'Disease', (33, 39))	('Ewing sarcoma', 'Disease', (134, 147))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('chondrosarcoma', 'Disease', 'MESH:D002813', (162, 176))	('oxamate', 'Chemical', 'MESH:D010072', (120, 127))	('chondrosarcoma', 'Disease', (162, 176))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (162, 176))	('Inhibition', 'Var', (0, 10))	('LDH', 'Protein', (14, 17))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (134, 147))
340755	26252771	This is confirmed by the fact that blockage of glycogen breakdown enhances the toxicity of melatonin and is highly lethal for these cells.	('melatonin', 'Chemical', 'MESH:D008550', (91, 100))	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('toxicity', 'Disease', (79, 87))	('glycogen breakdown', 'MPA', (47, 65))	('enhances', 'PosReg', (66, 74))	('glycogen', 'Chemical', 'MESH:D006003', (47, 55))	('blockage', 'Var', (35, 43))
340758	26252771	These include genetic or pharmacological inhibition of glycolytic enzymes or LDH; or the use of non-metabolizable analogues, such as 2-Deoxyglucose (2-DG) or 3-Bromopyruvate.	('LDH', 'Protein', (77, 80))	('2-DG', 'Chemical', 'MESH:D003847', (149, 153))	('glycolytic enzymes', 'Enzyme', (55, 73))	('2-Deoxyglucose', 'Chemical', 'MESH:D003847', (133, 147))	('genetic', 'Var', (14, 21))	('3-Bromopyruvate', 'Chemical', 'MESH:C017092', (158, 173))
340811	24707321	The final diagnosis of synovial sarcoma was obtained by the demonstration of a chimera transcript of SYT-SSX1 by RT-PCR using paraffin sections.	('SSX1', 'Gene', (105, 109))	('SYT', 'Gene', (101, 104))	('synovial sarcoma', 'Disease', (23, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (23, 39))	('SYT', 'Gene', '6760', (101, 104))	('synovial sarcoma', 'Disease', 'MESH:D013584', (23, 39))	('chimera transcript', 'Var', (79, 97))	('SSX1', 'Gene', '6756', (105, 109))	('paraffin', 'Chemical', 'MESH:D010232', (126, 134))
340826	24707321	Translocation of chromosomes t(X;18) gives rise to a SYT-SSX chimera transcript, which is detected exclusively in synovial sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (114, 130))	('Translocation', 'Var', (0, 13))	('synovial sarcoma', 'Disease', 'MESH:D013584', (114, 130))	('SSX', 'Gene', '6757', (57, 60))	('SSX', 'Gene', (57, 60))	('SYT', 'Gene', (53, 56))	('synovial sarcoma', 'Disease', (114, 130))	('gives rise to', 'Reg', (37, 50))	('SYT', 'Gene', '6760', (53, 56))
340845	23036192	Sarcomas in hereditary retinoblastoma Children diagnosed with the hereditary form of retinoblastoma (Rb), a rare eye cancer caused by a germline mutation in the RB1 tumor suppressor gene, have excellent survival, but face an increased risk of bone and soft tissue sarcomas.	('caused by', 'Reg', (124, 133))	('Rb', 'Gene', '5925', (101, 103))	('Sarcomas in hereditary retinoblastoma', 'Disease', (0, 37))	('RB1', 'Gene', '5925', (161, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('germline mutation', 'Var', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('eye cancer', 'Disease', 'MESH:D005134', (113, 123))	('retinoblastoma', 'Gene', '5925', (85, 99))	('retinoblastoma', 'Phenotype', 'HP:0009919', (85, 99))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('retinoblastoma', 'Gene', (23, 37))	('tumor suppressor', 'Gene', (165, 181))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (252, 271))	('eye cancer', 'Disease', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Sarcomas in hereditary retinoblastoma', 'Disease', 'MESH:D012175', (0, 37))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (252, 272))	('RB1', 'Gene', (161, 164))	('tumor suppressor', 'Gene', '7248', (165, 181))	('retinoblastoma', 'Gene', (85, 99))	('sarcomas', 'Disease', 'MESH:D012509', (264, 272))	('Children', 'Species', '9606', (38, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (264, 272))	('eye cancer', 'Phenotype', 'HP:0100012', (113, 123))	('sarcomas', 'Disease', (264, 272))	('retinoblastoma', 'Gene', '5925', (23, 37))	('retinoblastoma', 'Phenotype', 'HP:0009919', (23, 37))
340846	23036192	This predisposition to sarcomas has been attributed to genetic susceptibility due to inactivation of the RB1 gene as well as past radiotherapy for Rb.	('inactivation', 'Var', (85, 97))	('RB1', 'Gene', (105, 108))	('sarcomas', 'Disease', 'MESH:D012509', (23, 31))	('RB1', 'Gene', '5925', (105, 108))	('Rb', 'Gene', '5925', (147, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcomas', 'Disease', (23, 31))
340855	23036192	It is caused by mutations in the RB1 tumor suppressor gene, located on chromosome 13q14 with very high penetrance and expressivity .	('tumor suppressor', 'Gene', (37, 53))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('RB1', 'Gene', (33, 36))	('tumor suppressor', 'Gene', '7248', (37, 53))	('caused by', 'Reg', (6, 15))	('RB1', 'Gene', '5925', (33, 36))
340856	23036192	Approximately 80%-90% of RB1 gene carriers develop ocular tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('ocular tumors', 'Disease', 'MESH:D009369', (51, 64))	('RB1', 'Gene', '5925', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('ocular tumors', 'Phenotype', 'HP:0100012', (51, 64))	('ocular tumors', 'Disease', (51, 64))	('gene carriers', 'Var', (29, 42))	('RB1', 'Gene', (25, 28))	('develop', 'PosReg', (43, 50))
340859	23036192	Hereditary retinoblastoma is caused by a germline mutation in one allele of the RB1 gene and an acquired somatic mutation in the other allele, whereas the non-hereditary form is caused by somatic mutations in both alleles.	('caused by', 'Reg', (29, 38))	('Hereditary retinoblastoma', 'Disease', 'MESH:D012175', (0, 25))	('RB1', 'Gene', (80, 83))	('germline mutation', 'Var', (41, 58))	('retinoblastoma', 'Phenotype', 'HP:0009919', (11, 25))	('Hereditary retinoblastoma', 'Disease', (0, 25))	('RB1', 'Gene', '5925', (80, 83))
340861	23036192	About 10-15% of patients with unilateral Rb, however, carry a germline mutation and are considered hereditary.	('Rb', 'Gene', '5925', (41, 43))	('germline mutation', 'Var', (62, 79))	('carry', 'Reg', (54, 59))	('patients', 'Species', '9606', (16, 24))
340866	23036192	Survivors of non-hereditary Rb are at much lower risk of a subsequent primary cancer, similar to the risk in the general population .	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('non-hereditary', 'Var', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Rb', 'Gene', '5925', (28, 30))
340879	23036192	In a case-control study of bone and soft tissue sarcomas after hereditary Rb, risk increased with increasing dose up to 10.7-fold at doses greater than 60 Gy .	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (36, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('Rb', 'Gene', '5925', (74, 76))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (36, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('sarcomas', 'Disease', (48, 56))	('hereditary', 'Var', (63, 73))
340895	23036192	An increased risk for liposarcomas that began 10 years after diagnosis of hereditary Rb was observed in the study by Kleinerman et al.	('hereditary', 'Var', (74, 84))	('Rb', 'Gene', '5925', (85, 87))	('liposarcomas', 'Disease', 'MESH:D008080', (22, 34))	('liposarcoma', 'Phenotype', 'HP:0012034', (22, 33))	('liposarcomas', 'Phenotype', 'HP:0012034', (22, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('liposarcomas', 'Disease', (22, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))
340897	23036192	Following this observation, a RB1 mutation was identified in lipomas from hereditary Rb patients .	('lipomas', 'Phenotype', 'HP:0012032', (61, 68))	('Rb', 'Gene', '5925', (85, 87))	('patients', 'Species', '9606', (88, 96))	('mutation', 'Var', (34, 42))	('lipomas', 'Disease', (61, 68))	('lipomas', 'Disease', 'MESH:D008067', (61, 68))	('RB1', 'Gene', (30, 33))	('RB1', 'Gene', '5925', (30, 33))
340898	23036192	It has been suggested that females may be at higher risk of STS after hereditary Rb , but studies of Rb survivors have not consistently reported a higher risk among females.	('hereditary', 'Var', (70, 80))	('Rb', 'Gene', '5925', (101, 103))	('Rb', 'Gene', '5925', (81, 83))	('STS', 'Disease', (60, 63))
340904	23036192	In additional to the epidemiologic evidence of an excess risk for both bone and STS in hereditary Rb patients, structural alterations of the RB1 gene are well documented in primary bone sarcomas  and soft tissue sarcomas .	('RB1', 'Gene', (141, 144))	('sarcomas', 'Disease', 'MESH:D012509', (212, 220))	('sarcomas', 'Phenotype', 'HP:0100242', (212, 220))	('patients', 'Species', '9606', (101, 109))	('sarcomas', 'Disease', (212, 220))	('RB1', 'Gene', '5925', (141, 144))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (200, 220))	('Rb', 'Gene', '5925', (98, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('structural alterations', 'Var', (111, 133))	('sarcomas', 'Disease', 'MESH:D012509', (186, 194))	('bone sarcomas', 'Disease', 'MESH:D001847', (181, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('bone sarcomas', 'Disease', (181, 194))	('sarcomas', 'Disease', (186, 194))	('bone sarcomas', 'Phenotype', 'HP:0002669', (181, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('bone sarcoma', 'Phenotype', 'HP:0002669', (181, 193))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (200, 219))
340910	23036192	Risk of bone and STS begins within 10 years of treatment for hereditary Rb and continues throughout adulthood, most notably for STS.	('hereditary', 'Var', (61, 71))	('STS', 'Disease', (17, 20))	('STS', 'Disease', (128, 131))	('Rb', 'Gene', '5925', (72, 74))	('bone', 'Disease', (8, 12))
340916	23036192	There is on-going research to try to identify whether specific RB1 mutations or location of mutations predispose to sarcomas, which could lead to identification of those survivors at greatest risk .	('sarcomas', 'Disease', (116, 124))	('RB1', 'Gene', '5925', (63, 66))	('mutations', 'Var', (67, 76))	('sarcomas', 'Disease', 'MESH:D012509', (116, 124))	('predispose', 'Reg', (102, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('RB1', 'Gene', (63, 66))
139855	32373921	Immunohistochemistry showed CK-, EMA-, Vim+, CD31++, S-100-, AACT+, a few cells were CD68+, actin+, and desmin-.	('AACT', 'Gene', '12', (61, 65))	('S-100-', 'Var', (53, 59))	('CD31++', 'Var', (45, 51))	('desmin', 'Gene', (104, 110))	('AACT', 'Gene', (61, 65))	('Vim', 'Gene', (39, 42))	('desmin', 'Gene', '1674', (104, 110))	('CK', 'Gene', '51727', (28, 30))	('Vim', 'Gene', '7431', (39, 42))
340983	31477090	Immunohistochemistry staining of the recurrent tumor and metastasis lesion showed Gata3 (-) CD45 (-) ALK-P (-) melanA(-), S100 (-) and INI-1 with an intact expression.	('CD45', 'Gene', '5788', (92, 96))	('S100 (-', 'Var', (122, 129))	('metastasis lesion', 'Disease', (57, 74))	('Gata3', 'Gene', (82, 87))	('INI-1', 'Gene', '6598', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('CD45', 'Gene', (92, 96))	('Gata3', 'Gene', '2625', (82, 87))	('INI-1', 'Gene', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ALK-P (-) melanA', 'Var', (101, 117))	('metastasis lesion', 'Disease', 'MESH:D009362', (57, 74))	('tumor', 'Disease', (47, 52))
341055	30349653	At the individual-level, associations between the three endpoints and OS were moderate, with the highest correlation observed for PFS.	('PFS', 'Var', (130, 133))	('associations', 'Interaction', (25, 37))	('OS', 'Chemical', '-', (70, 72))
341100	26205404	Cell culture data demonstrated that GLV-5b451 efficiently infected and destroyed all four tested canine cancer cell lines including: mammary carcinoma (MTH52c), mammary adenoma (ZMTH3), prostate carcinoma (CT1258), and soft tissue sarcoma (STSA-1).	('carcinoma', 'Disease', 'MESH:D002277', (141, 150))	('destroyed', 'NegReg', (71, 80))	('efficiently infected', 'Disease', (46, 66))	('prostate carcinoma', 'Disease', 'MESH:D011472', (186, 204))	('adenoma', 'Disease', 'MESH:D000236', (169, 176))	('MTH52c', 'Chemical', '-', (152, 158))	('carcinoma', 'Disease', 'MESH:D002277', (195, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (231, 238))	('cancer', 'Disease', (104, 110))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (186, 204))	('efficiently infected', 'Disease', 'MESH:D007239', (46, 66))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CT1258', 'CellLine', 'CVCL:W737', (206, 212))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (133, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('canine', 'Species', '9615', (97, 103))	('GLV-5b451', 'Var', (36, 45))	('prostate carcinoma', 'Disease', (186, 204))	('carcinoma', 'Disease', (141, 150))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (219, 238))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (219, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('soft tissue sarcoma', 'Disease', (219, 238))	('carcinoma', 'Disease', (195, 204))	('GLV-5b451', 'Chemical', '-', (36, 45))	('adenoma', 'Disease', (169, 176))
341103	26205404	Finally, in canine soft tissue sarcoma (CSTS) xenografted mice, a single systemic administration of GLV-5b451 was found to be safe and led to anti-tumor effects resulting in the significant reduction and substantial long-term inhibition of tumor growth.	('GLV-5b451', 'Chemical', '-', (100, 109))	('tumor', 'Disease', (147, 152))	('reduction', 'NegReg', (190, 199))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (240, 245))	('ca', 'Species', '9615', (185, 187))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (19, 38))	('canine', 'Species', '9615', (12, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (19, 38))	('mice', 'Species', '10090', (58, 62))	('ca', 'Species', '9615', (12, 14))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('soft tissue sarcoma', 'Disease', (19, 38))	('inhibition', 'NegReg', (226, 236))	('GLV-5b451', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
341105	26205404	In summary, these findings indicate that GLV-5b451 has potential for use as a therapeutic agent in the treatment of CSTS.	('CSTS', 'Disease', (116, 120))	('GLV-5b451', 'Var', (41, 50))	('ca', 'Species', '9615', (31, 33))	('GLV-5b451', 'Chemical', '-', (41, 50))
341120	26205404	We have already demonstrated that VACV expressing anti-VEGF antibodies exhibited significant reduction of tumor growth in canine xenografts and enhanced inhibition of angiogenesis in comparison to control animals.	('reduction', 'NegReg', (93, 102))	('inhibition', 'NegReg', (153, 163))	('antibodies', 'Var', (60, 70))	('VACV', 'Species', '10245', (34, 38))	('enhanced', 'PosReg', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('canine', 'Species', '9615', (122, 128))	('anti-VEGF', 'Gene', (50, 59))	('ca', 'Species', '9615', (122, 124))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('anti-VEGF antibodies', 'Var', (50, 70))	('ca', 'Species', '9615', (88, 90))	('tumor', 'Disease', (106, 111))
341124	26205404	The MTH52c is derived from a malignant small-cell canine carcinoma.	('MTH52c', 'Chemical', '-', (4, 10))	('carcinoma', 'Disease', 'MESH:D002277', (57, 66))	('canine', 'Species', '9615', (50, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('MTH52c', 'Var', (4, 10))	('carcinoma', 'Disease', (57, 66))
341132	26205404	The sequence analysis of LIVP 6.1.1 revealed the presence of different mutations in the J2R gene locus encoding the thymidine kinase.	('mutations', 'Var', (71, 80))	('J2R', 'Gene', '3707550', (88, 91))	('J2R', 'Gene', (88, 91))
341142	26205404	For the viral replication assay, MTH52c, ZMTH3, CT1258 or STSA-1 cancer cells were infected with LIVP 6.1.1 or GLV-5b451 at an MOI of 0.1.	('infect', 'Disease', (83, 89))	('GLV-5b451', 'Chemical', '-', (111, 120))	('ca', 'Species', '9615', (65, 67))	('CT1258', 'CellLine', 'CVCL:W737', (48, 54))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('MTH52c', 'Chemical', '-', (33, 39))	('infect', 'Disease', 'MESH:D007239', (83, 89))	('ca', 'Species', '9615', (19, 21))	('GLV-5b451', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
341178	26205404	The results revealed that CT1258 cells produced about 25-fold more canine VEGF compared to STSA-1 cells at these two different time points.	('canine', 'Species', '9615', (67, 73))	('canine VEGF', 'MPA', (67, 78))	('more', 'PosReg', (62, 66))	('CT1258', 'CellLine', 'CVCL:W737', (26, 32))	('CT1258', 'Var', (26, 32))
341179	26205404	The oncolytic effect of GLV-5b451 and the parental strain LIVP 6.1.1 (control) against four different canine cancer cell lines including mammary carcinoma (MTH52c), mammary adenoma (ZMTH3), prostate carcinoma (CT1258) and soft tissue sarcoma (STSA-1) cells was examined.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('prostate carcinoma', 'Disease', (190, 208))	('carcinoma', 'Disease', (145, 154))	('GLV-5b451', 'Chemical', '-', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (222, 241))	('carcinoma', 'Disease', (199, 208))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (222, 241))	('soft tissue sarcoma', 'Disease', (222, 241))	('adenoma', 'Disease', (173, 180))	('carcinoma', 'Disease', 'MESH:D002277', (145, 154))	('cancer', 'Disease', (109, 115))	('MTH52c', 'Chemical', '-', (156, 162))	('prostate carcinoma', 'Disease', 'MESH:D011472', (190, 208))	('adenoma', 'Disease', 'MESH:D000236', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('carcinoma', 'Disease', 'MESH:D002277', (199, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('CT1258', 'CellLine', 'CVCL:W737', (210, 216))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (190, 208))	('GLV-5b451', 'Var', (24, 33))	('canine', 'Species', '9615', (102, 108))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (137, 154))
341183	26205404	The data demonstrated that GLV-5b451 and LIVP 6.1.1 efficiently infected and destroyed different canine cancer cells under these cell culture conditions.	('efficiently infected', 'Disease', 'MESH:D007239', (52, 72))	('GLV-5b451', 'Chemical', '-', (27, 36))	('canine', 'Species', '9615', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('destroyed', 'NegReg', (77, 86))	('GLV-5b451', 'Var', (27, 36))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('efficiently infected', 'Disease', (52, 72))
341206	26205404	Interestingly, the GLV-5b451 injection led to significantly better inhibition of the tumor growth (* p = 0.04981) compared to the LIVP 6.1.1-treated animals on 42 dpvi.	('GLV-5b451', 'Var', (19, 28))	('tumor', 'Disease', (85, 90))	('dpvi', 'Chemical', '-', (163, 167))	('inhibition', 'NegReg', (67, 77))	('GLV-5b451', 'Chemical', '-', (19, 28))	('ca', 'Species', '9615', (53, 55))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
341211	26205404	To investigate the possible reasons for different outcome of the virotherapy, we started a second therapeutic experiment in which virus distribution and tumor vascularization after injection with GLV-5b451, LIVP 6.1.1 or PBS were compared.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('GLV-5b451', 'Var', (196, 205))	('PBS', 'Chemical', 'MESH:D007854', (221, 224))	('GLV-5b451', 'Chemical', '-', (196, 205))
341225	26205404	In this experimental setting, FIs of vessel-related pixels of LIVP 6.1.1- and GLV-5b451-tumors were significantly increased in comparison to PBS-injected control tumors (Figure 7C).	('FIs', 'MPA', (30, 33))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('ca', 'Species', '9615', (107, 109))	('GLV-5b451-tumors', 'Disease', (78, 94))	('increased', 'PosReg', (114, 123))	('LIVP', 'Var', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (162, 168))	('PBS', 'Chemical', 'MESH:D007854', (141, 144))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('GLV-5b451-tumors', 'Disease', 'MESH:D009369', (78, 94))
341229	26205404	The results showed that GLV-5b451 was able to effectively infect, replicate in and lyse all tested canine cells.	('lyse', 'CPA', (83, 87))	('infect', 'Disease', 'MESH:D007239', (58, 64))	('canine', 'Species', '9615', (99, 105))	('replicate in', 'CPA', (66, 78))	('GLV-5b451', 'Var', (24, 33))	('ca', 'Species', '9615', (71, 73))	('GLV-5b451', 'Chemical', '-', (24, 33))	('ca', 'Species', '9615', (99, 101))	('infect', 'Disease', (58, 64))
341239	26205404	In addition, we have already found, that the presence of GLAF-2 antibody in GLV-5b451-infected feline xenograft tumors led to significant reduction of the VEGF levels when compared to the control tumors.	('infect', 'Disease', (86, 92))	('VEGF levels', 'MPA', (155, 166))	('GLV-5b451', 'Chemical', '-', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('infect', 'Disease', 'MESH:D007239', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('presence', 'Var', (45, 53))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('ca', 'Species', '9615', (133, 135))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumors', 'Disease', (112, 118))	('reduction', 'NegReg', (138, 147))
341246	26205404	In our STSA-1 xenograft model, the vascular density of GLV-5b451 tumors was significantly decreased in comparison to that of LIVP 6.1.1- and PBS-treated-tumors at 17 dpvi (Figure 7B).	('PBS-treated-tumors', 'Disease', 'MESH:D011535', (141, 159))	('GLV-5b451', 'Var', (55, 64))	('PBS-treated-tumors', 'Disease', (141, 159))	('dpvi', 'Chemical', '-', (166, 170))	('GLV-5b451', 'Chemical', '-', (55, 64))	('ca', 'Species', '9615', (83, 85))	('decreased', 'NegReg', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('vascular density', 'CPA', (35, 51))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
341253	26205404	In addition, in current study, we demonstrated that treatment with GLV-5b451 not only inhibited tumor growth, but actually reduced tumor volume by 90% within 42 dpvi.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('GLV-5b451', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (96, 101))	('GLV-5b451', 'Chemical', '-', (67, 76))	('tumor', 'Disease', (131, 136))	('dpvi', 'Chemical', '-', (161, 165))	('inhibited', 'NegReg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('reduced', 'NegReg', (123, 130))
341254	26205404	Moreover, we were able to show complete eradication of tumors in 30% of mice treated with GLV-5b451.	('ca', 'Species', '9615', (45, 47))	('GLV-5b451', 'Chemical', '-', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('eradication', 'NegReg', (40, 51))	('mice', 'Species', '10090', (72, 76))	('GLV-5b451', 'Var', (90, 99))
341256	26205404	Taken all together, the oncolytic vaccinia virus strain GLV-5b451 may be a better oncolytic therapy agent compared to GLV-1h109 or LIVP6.1.1 and a promising candidate for therapy of canine cancer patients with CSTS.	('GLV-5b451', 'Chemical', '-', (56, 65))	('cancer', 'Disease', (189, 195))	('ca', 'Species', '9615', (189, 191))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('patients', 'Species', '9606', (196, 204))	('vaccinia virus', 'Species', '10245', (34, 48))	('CSTS', 'Disease', (210, 214))	('canine', 'Species', '9615', (182, 188))	('GLV-5b451', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('ca', 'Species', '9615', (182, 184))	('ca', 'Species', '9615', (157, 159))
341286	24376795	Although the tumor was weakly positive for INI1 analyzed by immunohistochemistry, fluorescence in situ hybridization (FISH) analysis revealed the heterozygous deletion of INI1 in 17 of 50 tumor cells (34%) (Figure S1D).	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', (13, 18))	('INI1', 'Gene', (43, 47))	('INI1', 'Gene', '6598', (43, 47))	('INI1', 'Gene', (171, 175))	('INI1', 'Gene', '6598', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('deletion', 'Var', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
341296	24376795	Cells (1x106) were suspended in ALDEFLUOR assay buffer containing an ALDH1 substrate, bodipy-aminoacetaldehyde, at the concentration of 1mumol/L and incubated for 50 min at 37 C according to the manufacturer's protocol.	('ALDH1', 'Gene', (69, 74))	('bodipy-aminoacetaldehyde', 'Chemical', '-', (86, 110))	('ALDH1', 'Gene', '216', (69, 74))	('ALDEFLUOR', 'Chemical', '-', (32, 41))	('bodipy-aminoacetaldehyde', 'Var', (86, 110))
341312	24376795	A dye swap experiment was also done to label ALDHhigh and ALDHlow cells with Cy3 and Cy5, respectively.	('Cy3', 'Chemical', '-', (77, 80))	('Cy3', 'Var', (77, 80))	('Cy5', 'Var', (85, 88))	('Cy5', 'Chemical', 'MESH:C085321', (85, 88))
341343	24376795	However, the frequency of tumor formation was lower for ALDHlow cells than for ALDHhigh cells (Figure 3F).	('ALDHlow cells', 'Var', (56, 69))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('lower', 'NegReg', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
341374	24376795	We examined whether downregulation of ALDH1A1 and upregulation of TGFbeta1R1 were induced by silencing of CD109.	('ALDH1A1', 'Gene', (38, 45))	('silencing', 'Var', (93, 102))	('CD109', 'Gene', (106, 111))	('TGFbeta1R1', 'Gene', (66, 76))	('upregulation', 'PosReg', (50, 62))	('downregulation', 'NegReg', (20, 34))	('ALDH1A1', 'Gene', '216', (38, 45))	('CD109', 'Gene', '135228', (106, 111))
341377	24376795	Moreover, silencing of CD109 reduced the ALDHhigh population in ESX cells (Figure 7, D and E).	('CD109', 'Gene', '135228', (23, 28))	('ALDHhigh population', 'CPA', (41, 60))	('reduced', 'NegReg', (29, 36))	('silencing', 'Var', (10, 19))	('CD109', 'Gene', (23, 28))
341385	24376795	As shown in Figure 8B and 8C, positive CD109 expression, including in well-differentiated liposarcomas, was significantly associated with decreased probabilities of overall survival (OS) and disease-free survival (DFS) (P=8.3x10-5 and 4.5x10-4, respectively).	('overall survival', 'CPA', (165, 181))	('liposarcomas', 'Disease', 'MESH:D008080', (90, 102))	('disease-free survival', 'CPA', (191, 212))	('positive', 'Var', (30, 38))	('liposarcomas', 'Disease', (90, 102))	('CD109', 'Gene', '135228', (39, 44))	('decreased', 'NegReg', (138, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('OS', 'Chemical', '-', (183, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('CD109', 'Gene', (39, 44))	('liposarcomas', 'Phenotype', 'HP:0012034', (90, 102))
341386	24376795	Moreover, excluding well-differentiated liposarcomas, positive CD109 expression was also significantly associated with decreased probabilities of OS and DFS (P=0.006 and 0.049, respectively).	('DFS', 'Disease', (153, 156))	('liposarcomas', 'Phenotype', 'HP:0012034', (40, 52))	('decreased', 'NegReg', (119, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('liposarcomas', 'Disease', 'MESH:D008080', (40, 52))	('liposarcomas', 'Disease', (40, 52))	('CD109', 'Gene', (63, 68))	('OS', 'Chemical', '-', (146, 148))	('expression', 'MPA', (69, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('CD109', 'Gene', '135228', (63, 68))	('positive', 'Var', (54, 62))
341409	24376795	reported that high expression of Sox2 was correlated with good prognosis in patients with non-small cell lung carcinomas.	('patients', 'Species', '9606', (76, 84))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (94, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('Sox2', 'Gene', '6657', (33, 37))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (90, 120))	('high', 'Var', (14, 18))	('Sox2', 'Gene', (33, 37))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (90, 120))	('non-small cell lung carcinomas', 'Disease', (90, 120))
341423	24376795	In addition, silencing of CD109 upregulated TGFbeta1R1 mRNA in ESX cells.	('CD109', 'Gene', (26, 31))	('CD109', 'Gene', '135228', (26, 31))	('TGFbeta1R1', 'Gene', (44, 54))	('mRNA', 'MPA', (55, 59))	('silencing', 'Var', (13, 22))	('upregulated', 'PosReg', (32, 43))
341428	24376795	In addition, knockdown of CD109 decreased ALDH1 activity in ESX cells.	('ALDH1', 'Gene', '216', (42, 47))	('CD109', 'Gene', (26, 31))	('activity', 'MPA', (48, 56))	('CD109', 'Gene', '135228', (26, 31))	('knockdown', 'Var', (13, 22))	('decreased', 'NegReg', (32, 41))	('ALDH1', 'Gene', (42, 47))
341497	21569511	Cyclophosphamide in high doses, such as those used in bone marrow pre-conditioning, can also lead to veno-occlusive disease.	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (0, 16))	('veno-occlusive disease', 'Disease', (101, 123))	('occlusive disease', 'Phenotype', 'HP:0004950', (106, 123))	('veno-occlusive disease', 'Disease', 'MESH:D006504', (101, 123))	('lead to', 'Reg', (93, 100))	('Cyclophosphamide', 'Var', (0, 16))
341546	32523036	A few days later, results of fluorescent in situ hybridization (FISH) testing from the second kidney biopsy returned positive for PML-RARalpha t(15;17) gene rearrangements consistent with APL, as well as gains of 11q and 21q.	('rearrangements', 'Var', (157, 171))	('21q', 'CPA', (221, 224))	('RARalpha', 'Gene', (134, 142))	('gains', 'PosReg', (204, 209))	('PML', 'Gene', '5371', (130, 133))	('11q', 'CPA', (213, 216))	('t(15;17', 'Gene', (143, 150))	('RARalpha', 'Gene', '5914', (134, 142))	('APL', 'Disease', 'MESH:D015473', (188, 191))	('PML', 'Gene', (130, 133))	('APL', 'Phenotype', 'HP:0004836', (188, 191))	('APL', 'Disease', (188, 191))
341686	30835582	Furthermore, the mean tumor weight of CDDP implants-H group was significantly lower than CDDP implants-L group.	('CDDP implants-H', 'Var', (38, 53))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('CDDP', 'Chemical', '-', (89, 93))	('lower', 'NegReg', (78, 83))	('CDDP', 'Chemical', '-', (38, 42))
341689	30835582	In CDDP implants-H group (51.5 mg/kg), one death was observed on day 16 after treatment.	('CDDP', 'Chemical', '-', (3, 7))	('51.5 mg/kg', 'Var', (26, 36))	('death', 'Disease', 'MESH:D003643', (43, 48))	('death', 'Disease', (43, 48))
341802	24607745	Among the 13 CDKs expressed in human cells, CDK2, CKD4, and CKD6 are involved in the interphase, and CDK1 is involved in mitosis.	('mitosis', 'Disease', (121, 128))	('CDKs', 'Gene', (13, 17))	('CDK1', 'Gene', '983', (101, 105))	('mitosis', 'Disease', 'None', (121, 128))	('interphase', 'CPA', (85, 95))	('involved', 'Reg', (69, 77))	('human', 'Species', '9606', (31, 36))	('CKD4', 'Var', (50, 54))	('CDKs', 'Gene', '34411;983;54237;1017;12566;362817', (13, 17))	('CKD6', 'Var', (60, 64))	('CDK2', 'Gene', (44, 48))	('involved', 'Reg', (109, 117))	('CDK1', 'Gene', (101, 105))
341804	24607745	Tumor-associated mutations frequently deregulate certain CDK-cyclin complexes, resulting in either continued proliferation or unscheduled reentry into the cell cycle.	('cyclin', 'Gene', '5111', (61, 67))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('deregulate', 'Reg', (38, 48))	('ra', 'Chemical', 'MESH:D011883', (116, 118))	('cyclin', 'Gene', (61, 67))	('continued proliferation', 'CPA', (99, 122))	('mutations', 'Var', (17, 26))
341916	24607745	To illustrate the different collective behaviors, we consider three cell motility values (m1, m10, m100) and simulate growing cell colonies starting with identical initial conditions shown in the inset of Figure 5A.	('m100', 'Var', (99, 103))	('m1', 'Var', (90, 92))	('m10', 'Var', (94, 97))	('ra', 'Chemical', 'MESH:D011883', (9, 11))
341931	24607745	The age of each cell is drawn from a uniform distribution between 0 and 24 hours, which determines the values of all cell cycle-related variables (a, NCDK1, NCDK2, NWEE1, NCDK2E, NCDK1y, Q, and P) in accordance with the graphs in Figure 2.	('CDK1', 'Gene', (180, 184))	('ra', 'Chemical', 'MESH:D011883', (221, 223))	('NCDK2', 'Var', (157, 162))	('CDK1', 'Gene', '983', (151, 155))	('CDK1', 'Gene', (151, 155))	('ra', 'Chemical', 'MESH:D011883', (25, 27))	('WEE1', 'Gene', '7465', (165, 169))	('WEE1', 'Gene', (165, 169))	('NCDK2E', 'Var', (171, 177))	('CDK1', 'Gene', '983', (180, 184))
341953	24607745	CDK1 inhibition is expected to cause cell arrest at the G2/M checkpoint because the low amount of uninhibited CDK1 diminishes HR stimulation, which in turn may result in cell entry into the M phase with a DNA damage index that is too high to allow for cell reproduction.	('HR stimulation', 'MPA', (126, 140))	('result in', 'Reg', (160, 169))	('inhibition', 'Var', (5, 15))	('M phase', 'CPA', (190, 197))	('diminishes', 'NegReg', (115, 125))	('CDK1', 'Gene', (0, 4))	('CDK1', 'Gene', '983', (0, 4))	('CDK1', 'Gene', '983', (110, 114))	('CDK1', 'Gene', (110, 114))	('cell entry', 'CPA', (170, 180))
341962	24607745	CDK1 inhibition can stop some of the cells at the G2/M checkpoint and prevent them from completing the first proliferation.	('inhibition', 'Var', (5, 15))	('ra', 'Chemical', 'MESH:D011883', (116, 118))	('CDK1', 'Gene', (0, 4))	('prevent', 'NegReg', (70, 77))	('CDK1', 'Gene', '983', (0, 4))	('cells', 'CPA', (37, 42))	('stop', 'NegReg', (20, 24))
341967	24607745	The corresponding population growth curves in log scale over 60 hours for four cases (control, CDK2, CDK1, or combined inhibition) are shown in Figure 9A.	('CDK1', 'Gene', '983', (101, 105))	('CDK2', 'Var', (95, 99))	('CDK1', 'Gene', (101, 105))
341987	24607745	With CDK2 inhibition, most of the cells in the G1 phase are considerably older than those in the control case, indicating that the cells become G1 arrested early in the simulation and remain arrested for a long period.	('inhibition', 'Var', (10, 20))	('CDK2', 'Protein', (5, 9))	('ra', 'Chemical', 'MESH:D011883', (67, 69))
342096	24607745	The latter has been shown to abrogate the G2/M checkpoint forcing cells with DNA damage to enter into unscheduled mitosis to undergo cell death, often referred to as mitotic catastrophe.	('abrogate', 'NegReg', (29, 37))	('G2/M checkpoint', 'MPA', (42, 57))	('mitosis', 'Disease', (114, 121))	('mitosis', 'Disease', 'None', (114, 121))	('cell death', 'CPA', (133, 143))	('DNA', 'Gene', (77, 80))	('damage', 'Var', (81, 87))
342097	24607745	MK1775 has broad activity across sarcoma subtypes and lead to differentiation and necrosis in a xenograft model of osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('ra', 'Chemical', 'MESH:D011883', (101, 103))	('differentiation', 'CPA', (62, 77))	('MK1775', 'Var', (0, 6))	('lead to', 'Reg', (54, 61))	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('osteosarcoma', 'Disease', (115, 127))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcoma', 'Disease', (33, 40))	('osteosarcoma', 'Phenotype', 'HP:0002669', (115, 127))	('necrosis', 'Disease', (82, 90))	('osteosarcoma', 'Disease', 'MESH:D012516', (115, 127))	('activity', 'MPA', (17, 25))	('sarcoma', 'Disease', (120, 127))	('MK1775', 'Chemical', 'MESH:C549567', (0, 6))
342131	28341759	The effects of drug-drug interactions and genetic variants on hepatic metabolism are important [5], [6], [7], and co-administration with ritonavir, a strong CYP3A4 inhibitor, is a possible contributor to the poor tolerability in Cohort R1 [7], [8].	('effects', 'Reg', (4, 11))	('drug-drug interactions', 'Phenotype', 'HP:0020172', (15, 37))	('CYP3A4', 'Gene', (157, 163))	('hepatic metabolism', 'MPA', (62, 80))	('CYP3A4', 'Gene', '1576', (157, 163))	('genetic variants', 'Var', (42, 58))	('ritonavir', 'Chemical', 'MESH:D019438', (137, 146))	('variants', 'Var', (50, 58))
342229	27547480	Immunohistochemical (IHC) staining revealed periodic acid Schiff- (PAS-) positive and diastase-resistant crystalline structures with rhomboid and rod-like structure of some tumor cells (Figure 3), diffuse and strongly positive for CD 10 and TFE3 (Figure 4) but negative for AE1/AE 3, CAM5.2, cytokeratin 34betaE12, vimentin, RCC, p504s, desmin, S-100, HMB45, melan-A, chromogranin-A, CD 34, and CD 68.	('vimentin', 'Gene', (315, 323))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('S-100', 'Gene', (345, 350))	('AE 3', 'Gene', (278, 282))	('AE1', 'Gene', (274, 277))	('TFE3', 'Gene', (241, 245))	('S-100', 'Gene', '6271', (345, 350))	('TFE3', 'Gene', '7030', (241, 245))	('chromogranin-A', 'Gene', (368, 382))	('CD 68', 'Gene', '968', (395, 400))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('chromogranin-A', 'Gene', '1113', (368, 382))	('CD 10', 'Gene', '4311', (231, 236))	('AE 3', 'Gene', '6508', (278, 282))	('RCC', 'Disease', (325, 328))	('CD 10', 'Gene', (231, 236))	('CD 68', 'Gene', (395, 400))	('CD 34', 'Gene', (384, 389))	('p504s', 'Var', (330, 335))	('RCC', 'Disease', 'MESH:C538614', (325, 328))	('tumor', 'Disease', (173, 178))	('CD 34', 'Gene', '947', (384, 389))	('AE1', 'Gene', '6521', (274, 277))	('vimentin', 'Gene', '7431', (315, 323))
342230	27547480	A diagnosis of alveolar soft part sarcoma was established based on the compatible histomorphological finding, presence of crystal, and the positivity of TFE3 on IHC staining and by exclusion of other bladder tumors.	('TFE3', 'Gene', (153, 157))	('bladder tumors', 'Phenotype', 'HP:0009725', (200, 214))	('bladder tumors', 'Disease', (200, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('alveolar soft part sarcoma', 'Disease', (15, 41))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (15, 41))	('TFE3', 'Gene', '7030', (153, 157))	('presence', 'Reg', (110, 118))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('positivity', 'Var', (139, 149))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (15, 41))	('bladder tumors', 'Disease', 'MESH:D001749', (200, 214))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (24, 41))
342308	23401820	In particular, the in vitro production of proinflammatory mediators, such as interleukin-6 (IL-6) and CCL2, was markedly downregulated by trabectedin in circulating monocytes, macrophages, and tumor-associated macrophages (TAM) from human tumors.	('CCL2', 'Gene', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('interleukin-6', 'Gene', (77, 90))	('human', 'Species', '9606', (233, 238))	('interleukin-6', 'Gene', '3569', (77, 90))	('IL-6', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('trabectedin', 'Var', (138, 149))	('CCL2', 'Gene', '6347', (102, 106))	('IL-6', 'Gene', '3569', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('downregulated', 'NegReg', (121, 134))
342446	33260481	Possible resistance mechanisms that could explain the disappointing results of IGF1R inhibitors in the clinical setting are: (1) inadequate inhibition of the pathway downstream of IGF1R, as this pathway can be activated through the IGF1R but, also, through the insulin receptor A (IRA) or hybrids between the two receptors; (2) the disruption of negative feedback loops in the pituitary, whereby the IGF1R ligands IGF1, IGF2 and insulin, and other endocrine-signaling molecules such as the growth hormone (GH) and glucose, increase by inhibiting the receptors, leading to tumor growth; (3) the existence of autocrine or paracrine feedback loops in the tumor, through which the IGF1R pathway is continuously activated, perhaps via intracellular routes and (4) tumor growth and survival due to other driver mutations downstream of the IGF1R pathway or in other oncogenic pathways, which makes inhibiting IGF1R irrelevant.	('IGF1R', 'Gene', (400, 405))	('insulin receptor', 'Gene', (261, 277))	('IGF1', 'Gene', '3479', (79, 83))	('GH', 'Gene', '2688', (506, 508))	('glucose', 'Chemical', 'MESH:D005947', (514, 521))	('IGF1R', 'Gene', '3480', (232, 237))	('IGF1', 'Gene', (677, 681))	('IGF1', 'Gene', '3479', (833, 837))	('IGF1R', 'Gene', (677, 682))	('IGF1', 'Gene', (414, 418))	('IGF1R', 'Gene', '3480', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (759, 764))	('IGF1R', 'Gene', (232, 237))	('IGF2', 'Gene', '3481', (420, 424))	('IGF1', 'Gene', (232, 236))	('survival', 'CPA', (776, 784))	('IGF1R', 'Gene', '3480', (833, 838))	('growth hormone', 'Gene', (490, 504))	('IGF1', 'Gene', '3479', (180, 184))	('IGF1R', 'Gene', (79, 84))	('IGF1', 'Gene', '3479', (902, 906))	('IGF1', 'Gene', (79, 83))	('insulin', 'Gene', '3630', (261, 268))	('tumor', 'Disease', (572, 577))	('insulin', 'Gene', '3630', (429, 436))	('IGF1', 'Gene', (833, 837))	('IGF1R', 'Gene', (833, 838))	('tumor', 'Disease', (652, 657))	('IGF1R', 'Gene', '3480', (180, 185))	('IGF1', 'Gene', '3479', (400, 404))	('tumor', 'Disease', 'MESH:D009369', (572, 577))	('IGF1R', 'Gene', '3480', (902, 907))	('growth hormone', 'Gene', '2688', (490, 504))	('tumor', 'Disease', 'MESH:D009369', (652, 657))	('IGF1R', 'Gene', (180, 185))	('IGF1', 'Gene', (180, 184))	('IGF1', 'Gene', '3479', (677, 681))	('IGF1R', 'Gene', (902, 907))	('IGF1', 'Gene', (902, 906))	('tumor', 'Disease', (759, 764))	('mutations', 'Var', (805, 814))	('insulin receptor', 'Gene', '3643', (261, 277))	('IGF1R', 'Gene', '3480', (400, 405))	('IR', 'Gene', '3643', (281, 283))	('IGF2', 'Gene', (420, 424))	('IGF1', 'Gene', '3479', (414, 418))	('tumor', 'Phenotype', 'HP:0002664', (572, 577))	('insulin', 'Gene', (429, 436))	('IGF1', 'Gene', '3479', (232, 236))	('insulin', 'Gene', (261, 268))	('tumor', 'Disease', 'MESH:D009369', (759, 764))	('IGF1R', 'Gene', '3480', (677, 682))	('IGF1', 'Gene', (400, 404))	('tumor', 'Phenotype', 'HP:0002664', (652, 657))
342453	33260481	Epidemiological studies have shown a relationship between high circulating IGF1 levels and cancer incidence.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('IGF1', 'Gene', (75, 79))	('high circulating IGF1', 'Phenotype', 'HP:0030269', (58, 79))	('high', 'Var', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('IGF1', 'Gene', '3479', (75, 79))
342455	33260481	High baseline IGF1 was counterintuitively associated with improved event-free survival (EFS) in Ewing sarcoma patients.	('IGF1', 'Gene', '3479', (14, 18))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('High baseline IGF1', 'Phenotype', 'HP:0030269', (0, 18))	('improved', 'PosReg', (58, 66))	('High', 'Var', (0, 4))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('IGF1', 'Gene', (14, 18))	('Ewing sarcoma', 'Disease', (96, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('patients', 'Species', '9606', (110, 118))	('event-free', 'Disease', (67, 77))
342483	33260481	Patients whose tumors express IGF1R but not IRA may, however, benefit from IGF1R inhibitors, which might explain why these compounds caused long-lasting tumor response in two cases in clinical trials (Table 1).	('benefit', 'PosReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('IR', 'Gene', '3643', (44, 46))	('inhibitors', 'Var', (81, 91))	('IGF1R', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('IGF1R', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('Patients', 'Species', '9606', (0, 8))	('IGF1R', 'Gene', '3480', (30, 35))	('tumor', 'Disease', (15, 20))	('IGF1R', 'Gene', '3480', (75, 80))	('tumors', 'Disease', (15, 21))
342496	33260481	In support of this, it has been shown that IGF1R inhibition can lead to compensatory IR activation in colorectal cancer, ovarian carcinoma, and Ewing sarcoma in vitro.	('colorectal cancer', 'Disease', (102, 119))	('activation', 'PosReg', (88, 98))	('ovarian carcinoma', 'Disease', (121, 138))	('IGF1R', 'Gene', (43, 48))	('IR', 'Gene', '3643', (85, 87))	('Ewing sarcoma', 'Disease', (144, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('IGF1R', 'Gene', '3480', (43, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (144, 157))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (144, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (121, 138))	('inhibition', 'Var', (49, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
342500	33260481	Alternatively, (short-term) fasting during treatment with an IGF1R inhibitor may have similar effects, as it causes a significant decrease in insulin serum levels.	('IGF1R', 'Gene', (61, 66))	('decrease', 'NegReg', (130, 138))	('IGF1R', 'Gene', '3480', (61, 66))	('insulin', 'Gene', (142, 149))	('inhibitor', 'Var', (67, 76))	('insulin', 'Gene', '3630', (142, 149))
342513	33260481	Accordingly, patients with acromegaly, who have high GH plasma levels, show a higher incidence of cancer, while patients with Laron syndrome who are resistant to GH due to a defective GHR and patients with GH deficiency have reduced cancer susceptibility.	('defective', 'Var', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('patients', 'Species', '9606', (13, 21))	('acromegaly', 'Disease', 'MESH:D000172', (27, 37))	('cancer', 'Disease', (98, 104))	('GH', 'Gene', '2688', (162, 164))	('GH', 'Gene', '2688', (184, 186))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('acromegaly', 'Phenotype', 'HP:0000845', (27, 37))	('acromegaly', 'Disease', (27, 37))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('GH deficiency have reduced cancer', 'Disease', 'MESH:D009369', (206, 239))	('patients', 'Species', '9606', (192, 200))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('GHR', 'Gene', '2690', (184, 187))	('GH', 'Gene', '2688', (206, 208))	('GH', 'Gene', '2688', (53, 55))	('GH deficiency have reduced cancer', 'Disease', (206, 239))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Disease', (233, 239))	('GHR', 'Gene', (184, 187))
342515	33260481	For example, an excess of IGF1 reverses the inhibitory effect of figitumumab in preclinical studies, which is presumed to be due to their similar affinity for the IGF1R.	('reverses', 'NegReg', (31, 39))	('excess', 'Var', (16, 22))	('IGF1', 'Gene', (26, 30))	('IGF1R', 'Gene', '3480', (163, 168))	('figitumumab', 'Chemical', 'MESH:C525021', (65, 76))	('IGF1', 'Gene', '3479', (163, 167))	('inhibitory effect', 'MPA', (44, 61))	('excess of IGF1', 'Phenotype', 'HP:0030269', (16, 30))	('IGF1', 'Gene', (163, 167))	('IGF1', 'Gene', '3479', (26, 30))	('IGF1R', 'Gene', (163, 168))
342520	33260481	Again, an IRA inhibitor and/or short-term fasting in combination with IGF1 inhibitors may be an effective approach to decrease insulin signaling and adequately inhibit the downstream pathway.	('inhibitors', 'Var', (75, 85))	('inhibit', 'NegReg', (160, 167))	('IGF1', 'Gene', '3479', (70, 74))	('IR', 'Gene', '3643', (10, 12))	('insulin', 'Gene', (127, 134))	('decrease', 'NegReg', (118, 126))	('downstream pathway', 'Pathway', (172, 190))	('insulin', 'Gene', '3630', (127, 134))	('IGF1', 'Gene', (70, 74))
342523	33260481	Furthermore, stimulation with insulin increased AKT phosphorylation in cells treated with an IGF1R inhibitor.	('IGF1R', 'Gene', '3480', (93, 98))	('insulin', 'Gene', (30, 37))	('inhibitor', 'Var', (99, 108))	('AKT', 'Gene', (48, 51))	('insulin', 'Gene', '3630', (30, 37))	('IGF1R', 'Gene', (93, 98))	('AKT', 'Gene', '207', (48, 51))	('increased', 'PosReg', (38, 47))
342524	33260481	This indicates that lowering insulin levels or blocking the IRA may increase the efficacy of IGF1R inhibitors.	('insulin', 'Gene', (29, 36))	('IR', 'Gene', '3643', (60, 62))	('IGF1R', 'Gene', '3480', (93, 98))	('insulin', 'Gene', '3630', (29, 36))	('inhibitors', 'Var', (99, 109))	('efficacy', 'MPA', (81, 89))	('lowering', 'NegReg', (20, 28))	('increase', 'PosReg', (68, 76))	('IGF1R', 'Gene', (93, 98))
342525	33260481	Additionally, IGF1R blocking can induce hyperglycemia and hyperinsulinemia in patients, which could activate the IRA in response to IGF1R inhibition.	('IR', 'Gene', '3643', (113, 115))	('IGF1R', 'Gene', (132, 137))	('IGF1R', 'Gene', '3480', (132, 137))	('activate', 'PosReg', (100, 108))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (58, 74))	('hyperglycemia', 'Disease', 'MESH:D006943', (40, 53))	('blocking', 'Var', (20, 28))	('patients', 'Species', '9606', (78, 86))	('hyperinsulinemia', 'Disease', (58, 74))	('hyperglycemia', 'Disease', (40, 53))	('IGF1R', 'Gene', (14, 19))	('induce', 'Reg', (33, 39))	('IGF1R', 'Gene', '3480', (14, 19))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (58, 74))	('hyperglycemia', 'Phenotype', 'HP:0003074', (40, 53))
342526	33260481	However, the exact mechanism for the observed hyperglycemia as a side effect of IGF1 inhibitors is unclear, but cross-reactivity with the IRB, which is involved in the glucose metabolism, is likely to be an important factor.	('glucose metabolism', 'Disease', 'MESH:D044882', (168, 186))	('hyperglycemia', 'Disease', (46, 59))	('inhibitors', 'Var', (85, 95))	('IGF1', 'Gene', '3479', (80, 84))	('hyperglycemia', 'Phenotype', 'HP:0003074', (46, 59))	('glucose metabolism', 'Disease', (168, 186))	('IR', 'Gene', '3643', (138, 140))	('IGF1', 'Gene', (80, 84))	('hyperglycemia', 'Disease', 'MESH:D006943', (46, 59))
342530	33260481	Finally, resistance may occur when the IGF1R pathway is activated through downstream mutations of the pathway (such as PTEN) or in bypassing oncogenic pathways (such as epidermal growth factor receptor (EGFR)).	('IGF1R', 'Gene', (39, 44))	('EGFR', 'Gene', '1956', (203, 207))	('EGFR', 'Gene', (203, 207))	('IGF1R', 'Gene', '3480', (39, 44))	('epidermal growth factor receptor', 'Gene', (169, 201))	('mutations', 'Var', (85, 94))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('activated', 'PosReg', (56, 65))	('epidermal growth factor receptor', 'Gene', '1956', (169, 201))
342538	33260481	In 85% of cases, the somatic translocation t(11;22) results in the aberrant product of the Ewing sarcoma breakpoint region 1 (EWSR1) gene and Friend leukemia virus integration 1 (FLI1) gene and other variants of the involved gene families in the remaining cases.	('FLI1', 'Gene', (179, 183))	('Ewing sarcoma breakpoint region 1', 'Gene', (91, 124))	('EWSR1', 'Gene', '2130', (126, 131))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (91, 124))	('results in', 'Reg', (52, 62))	('aberrant product', 'Var', (67, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leukemia', 'Phenotype', 'HP:0001909', (149, 157))	('Friend leukemia virus integration 1', 'Gene', (142, 177))	('EWSR1', 'Gene', (126, 131))	('Friend leukemia virus integration 1', 'Gene', '2313', (142, 177))	('FLI1', 'Gene', '2313', (179, 183))
342548	33260481	Since mTOR signaling is a downstream target of both the IGF1R and the IRA, inhibiting mTOR might indeed be a viable treatment option, in addition to IGF1R inhibition.	('IGF1R', 'Gene', '3480', (56, 61))	('mTOR', 'Gene', '2475', (86, 90))	('mTOR', 'Gene', (86, 90))	('IGF1R', 'Gene', '3480', (149, 154))	('mTOR', 'Gene', (6, 10))	('IR', 'Gene', '3643', (70, 72))	('IGF1R', 'Gene', (56, 61))	('inhibiting', 'Var', (75, 85))	('mTOR', 'Gene', '2475', (6, 10))	('IGF1R', 'Gene', (149, 154))
342563	33260481	Short-term fasting may also be a valuable addition to IGF1R inhibition, as it dramatically lowers the insulin and IGF1.	('IGF1', 'Gene', (54, 58))	('inhibition', 'Var', (60, 70))	('IGF1R', 'Gene', (54, 59))	('IGF1R', 'Gene', '3480', (54, 59))	('insulin', 'Gene', (102, 109))	('IGF1', 'Gene', '3479', (114, 118))	('IGF1', 'Gene', '3479', (54, 58))	('insulin', 'Gene', '3630', (102, 109))	('lowers', 'NegReg', (91, 97))	('IGF1', 'Gene', (114, 118))
342573	33260481	Tumors of patients included in phase I trials may be resistant to IGF1R inhibition treatment due to secondary mutations caused by (extensive) pretreatment, and IGF1R inhibition might be more effective as a first-line treatment.	('IGF1R', 'Gene', (160, 165))	('mutations', 'Var', (110, 119))	('IGF1R', 'Gene', '3480', (160, 165))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (10, 18))	('IGF1R', 'Gene', (66, 71))	('IGF1R', 'Gene', '3480', (66, 71))
342575	33260481	The failure of IGF1R inhibitors in clinical studies may be caused by resistant tumors due to secondary mutations in pretreated patients.	('mutations', 'Var', (103, 112))	('IGF1R', 'Gene', (15, 20))	('IGF1R', 'Gene', '3480', (15, 20))	('patients', 'Species', '9606', (127, 135))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
342761	22948772	VEGF serum levels were elevated in ILP with rhTNF-alpha, although without a statistically significant difference, compared to patients after ILP without rhTNF-alpha (Table 3, Fig.	('TNF-alpha', 'Gene', '7124', (155, 164))	('elevated', 'PosReg', (23, 31))	('TNF-alpha', 'Gene', '7124', (46, 55))	('TNF-alpha', 'Gene', (155, 164))	('TNF-alpha', 'Gene', (46, 55))	('ILP', 'Var', (35, 38))	('patients', 'Species', '9606', (126, 134))	('VEGF serum levels', 'MPA', (0, 17))
342763	22948772	In rhTNF-alpha-treated patients, a significant peak of Ang-2 was observed at 24 h (6024 +- 2085 pg/ml, P = 0.000), 48 h (6286 +- 2117 pg/ml, P = 0.001), and 1 week (4555 +- 762 pg/ml, P = 0.001) compared to values before ILP (2929 +- 960 pg/ml).	('patients', 'Species', '9606', (23, 31))	('TNF-alpha', 'Gene', '7124', (5, 14))	('Ang-2', 'Gene', '285', (55, 60))	('Ang-2', 'Gene', (55, 60))	('6024 +- 2085 pg/ml', 'Var', (83, 101))	('TNF-alpha', 'Gene', (5, 14))	('6286 +- 2117 pg/ml', 'Var', (121, 139))
342764	22948772	Within the no-TNF group, a significant increase of Ang-2 was observed 24 h after ILP (3404 +- 417 pg/ml, P = 0.031) compared to basal values (2402 +- 606 pg/ml, Table 3, Fig.	('TNF', 'Gene', (14, 17))	('3404 +- 417 pg/ml', 'Var', (86, 103))	('Ang-2', 'Gene', (51, 56))	('TNF', 'Gene', '7124', (14, 17))	('increase', 'PosReg', (39, 47))	('Ang-2', 'Gene', '285', (51, 56))
342774	22948772	A big part of the explanation must be the consequence of rhTNF-alpha treatment, causing a higher degree of ischemia and anoxia in the perfused limb.	('TNF-alpha', 'Gene', (59, 68))	('ischemia', 'Disease', 'MESH:D007511', (107, 115))	('anoxia', 'Disease', (120, 126))	('treatment', 'Var', (69, 78))	('TNF-alpha', 'Gene', '7124', (59, 68))	('men', 'Species', '9606', (74, 77))	('anoxia', 'Disease', 'MESH:D000860', (120, 126))	('ischemia', 'Disease', (107, 115))
342779	22948772	Studies in animals show that EPCs participate in tumor angiogenesis, thereby enhancing tumor growth.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (49, 54))	('EPCs', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('enhancing', 'PosReg', (77, 86))
342781	22948772	Although the exact phenotype of cEPCs is still controversially discussed, the presence of CD34, CD133, and VEGFR-2 seems to be well supported and is therefore used in this study.	('CD133', 'Gene', (96, 101))	('CD133', 'Gene', '8842', (96, 101))	('VEGFR-2', 'Gene', '3791', (107, 114))	('presence', 'Var', (78, 86))	('VEGFR-2', 'Gene', (107, 114))	('CD34', 'Gene', (90, 94))	('CD34', 'Gene', '947', (90, 94))
342782	22948772	demonstrated in a murine model that local VEGF production induces a massive infiltration of BMD cells in tumors but does not lead to vessel wall integration of these cells, suggesting that during tumor progression, vascularization occurs primarily via classical tumor angiogenesis.	('local', 'Var', (36, 41))	('infiltration', 'MPA', (76, 88))	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('vascularization', 'CPA', (215, 230))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (105, 110))	('murine', 'Species', '10090', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
342794	22948772	Several reports demonstrate, however, that the specific ablation of BMD EPC results in significant impaired tumor growth and vascularization.	('EPC', 'Gene', (72, 75))	('vascularization', 'CPA', (125, 140))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('impaired tumor growth', 'Disease', (99, 120))	('impaired tumor growth', 'Disease', 'MESH:D006130', (99, 120))	('ablation', 'Var', (56, 64))
342831	30827931	In the literature, the five-year survival rate for RIS patients is estimated to be between 10 and 36%, lower than the survival rate for patients with sporadic sarcomas (from 54% to 76%).	('sporadic sarcomas', 'Disease', 'MESH:D012509', (150, 167))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('sporadic sarcomas', 'Disease', (150, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('lower', 'NegReg', (103, 108))	('RIS', 'Var', (51, 54))
342846	26432433	have advocated use of the proliferation index (by detecting Ki-67) in a risk model of outcome for Ewing's sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (98, 113))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (98, 113))	("Ewing's sarcoma", 'Disease', (98, 113))	('Ki-67', 'Var', (60, 65))
342854	26432433	A meta-analysis of the prognostic value of blood NLR on clinical outcome in solid tumors showed that high NLR was associated with shorter survival.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('solid tumors', 'Disease', (76, 88))	('high', 'Var', (101, 105))	('shorter', 'NegReg', (130, 137))
342883	26432433	In subgroup analyses of the four major histologic types (undifferentiated [spindle cell and pleomorphic] sarcoma, fibrosarcoma, liposarcoma, and leiomyosarcoma), high PLR was associated with shorter OS in undifferentiated sarcoma in univariate analysis (HR: 3.50; 95 % CI: 1.21-10.11; P = 0.021; Table 5) and remained significant in multivariate analysis (HR: 3.91; 95 % CI: 1.02-14.99; P = 0.047; Table 5).	('fibrosarcoma', 'Disease', 'MESH:D005354', (114, 126))	('liposarcoma', 'Disease', 'MESH:D008080', (128, 139))	('sarcoma', 'Disease', 'MESH:D012509', (222, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('fibrosarcoma', 'Disease', (114, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcoma', 'Disease', (222, 229))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (145, 159))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))	('OS', 'Chemical', '-', (199, 201))	('high PLR', 'Var', (162, 170))	('sarcoma', 'Disease', (132, 139))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (145, 159))	('liposarcoma', 'Disease', (128, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (205, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('undifferentiated sarcoma', 'Disease', (205, 229))	('sarcoma', 'Disease', (105, 112))	('leiomyosarcoma', 'Disease', (145, 159))	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (114, 126))	('liposarcoma', 'Phenotype', 'HP:0012034', (128, 139))	('sarcoma', 'Disease', (152, 159))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))
342892	26432433	Thus, high lymphocytic infiltrate is associated with improved survival and superior response to systemic therapy whereas a low peripheral blood lymphocyte counts are related to poor cancer prognoses.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('poor cancer', 'Disease', (177, 188))	('low peripheral blood lymphocyte counts', 'Phenotype', 'HP:0001888', (123, 161))	('poor cancer', 'Disease', 'MESH:D009369', (177, 188))	('survival', 'CPA', (62, 70))	('improved', 'PosReg', (53, 61))	('high lymphocytic infiltrate', 'Var', (6, 33))
342894	26432433	Recently, a meta-analysis, comprising 12,754 patients, of the association of blood PLR and overall survival in solid tumors concluded that high PLR was independently associated with shorter OS in various solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('OS', 'Chemical', '-', (190, 192))	('solid tumors', 'Disease', 'MESH:D009369', (204, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('high PLR', 'Var', (139, 147))	('patients', 'Species', '9606', (45, 53))	('solid tumors', 'Disease', (111, 123))	('shorter OS', 'Disease', (182, 192))	('solid tumors', 'Disease', (204, 216))
343006	24681846	Current efforts in identifying the optimal target antigens for adoptive immunotherapy are mainly focused on the neoantigens generated by somatic mutations present in tumors but absent in normal tissues, on antigens expressed on dispensable normal tissues, and on a group of genes that encode for the cancer-testis (CT) antigens.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutations', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('cancer-testis', 'Disease', (300, 313))	('tumors', 'Disease', (166, 172))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('cancer-testis', 'Disease', 'MESH:D013736', (300, 313))
343060	24681846	Recognition of 938-A2 endogenous SSX2 was stronger in TCR-5-transduced lymphocytes, as evidenced by a 2-fold higher IFNg secretion by those cells compared to that of T cells transduced with TCR-9 and -11 (figure 2C).	('938-A2', 'Var', (15, 21))	('TCR-5-transduced', 'Var', (54, 70))	('SSX2', 'Gene', (33, 37))	('higher', 'PosReg', (109, 115))	('IFNg secretion', 'MPA', (116, 130))	('stronger', 'PosReg', (42, 50))	('SSX2', 'Gene', '6757', (33, 37))
343082	24681846	As shown in figure 4 B, codon optimization increased the density of membrane expression of TCR in CD8 T cells as evidenced by an increased mean fluorescence intensity (MFI) of SSX241-49 tetramer staining in cells transduced with the codon-optimized TCR-5 (910 fluorescence units), compared to those transduced with the wild-type version (656 fluorescence units).	('CD8', 'Gene', (98, 101))	('SSX2', 'Gene', (176, 180))	('TCR', 'Gene', (91, 94))	('density', 'MPA', (57, 64))	('increased', 'PosReg', (129, 138))	('CD8', 'Gene', '925', (98, 101))	('codon optimization', 'Var', (24, 42))	('increased', 'PosReg', (43, 52))	('membrane expression', 'MPA', (68, 87))	('SSX2', 'Gene', '6757', (176, 180))	('expression', 'Species', '29278', (77, 87))
343084	24681846	The biological activity of the TCRs was tested in coculture experiments where the TCR-transduced lymphocytes were exposed to multiple HLA-A*0201-positive target cells that were positive for SSX2 (Cos-A2-SSX2, 293-A2-SSX2, K562-A2, 624, 938-A2 and U251).	('293-A2', 'CellLine', 'CVCL:6910', (209, 215))	('HLA-A', 'Gene', '3105', (134, 139))	('K562', 'CellLine', 'CVCL:0004', (222, 226))	('K562-A2', 'Var', (222, 229))	('SSX2', 'Gene', (190, 194))	('Cos-A2-SSX2', 'Gene', '6757', (196, 207))	('SSX2', 'Gene', '6757', (216, 220))	('HLA-A', 'Gene', (134, 139))	('Cos-A2-SSX2', 'Gene', (196, 207))	('U251', 'Var', (247, 251))	('SSX2', 'Gene', '6757', (203, 207))	('SSX2', 'Gene', (216, 220))	('SSX2', 'Gene', '6757', (190, 194))	('SSX2', 'Gene', (203, 207))
343087	24681846	The ability of each variant of TCR-5 to induce antigen-specific cell lysis of tumor targets by human lymphocytes was determined using a chromium release assay.	('TCR-5', 'Gene', (31, 36))	('human', 'Species', '9606', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('antigen-specific', 'MPA', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('induce', 'Reg', (40, 46))	('variant', 'Var', (20, 27))
343091	24681846	Similarly, 624 and SKmel37 cells, which are HLA-A*0201 positive and naturally express SSX2, were lysed by lymphocytes transduced with either TCR-5 variant, whereas HLA-A*0201-negative 888 cells were not.	('HLA-A', 'Gene', '3105', (44, 49))	('SKmel37', 'CellLine', 'CVCL:3878', (19, 26))	('SSX2', 'Gene', (86, 90))	('HLA-A', 'Gene', '3105', (164, 169))	('HLA-A', 'Gene', (44, 49))	('HLA-A', 'Gene', (164, 169))	('variant', 'Var', (147, 154))	('lysed', 'CPA', (97, 102))	('SSX2', 'Gene', '6757', (86, 90))
343096	24681846	The six clones expressing the highest levels of vector RNA (A8, A10, C3, D8, F2 and H2) were amplified and the supernatants were tested for their ability to induce TCR expression in OKT3-stimulated PBL from three different donors.	('expression', 'Species', '29278', (168, 178))	('A10', 'Var', (64, 67))	('TCR', 'Gene', (164, 167))	('induce', 'PosReg', (157, 163))
343099	24681846	IFNg release after overnight coculture of 1x105 lymphocytes with 1x105 624 cells was (5023+/- 295) pg/mL, whereas transduced lymphocytes released only background levels of IFNg when exposed to HLA-A*0201-negative 938 cells or SSX2-negative CosA2 cells.	('SSX2', 'Gene', '6757', (226, 230))	('HLA-A', 'Gene', (193, 198))	('IFNg release', 'MPA', (0, 12))	('Cos', 'Chemical', '-', (240, 243))	('SSX2', 'Gene', (226, 230))	('5023+/-', 'Var', (86, 93))	('HLA-A', 'Gene', '3105', (193, 198))
343138	24681846	The theoretical possibility of off-target toxicity resulting from those neospecificities has prompted researchers to develop multiple strategies to prevent mispairing, including transcriptional silencing or genetic ablation of endogenous TCR expression.	('TCR', 'Gene', (238, 241))	('transcriptional silencing', 'Var', (178, 203))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('toxicity', 'Disease', (42, 50))	('expression', 'Species', '29278', (242, 252))	('genetic ablation', 'Var', (207, 223))
343142	24681846	An important feature of cancer-testis antigens is that their expression can be induced by epigenetic modification of the tumor cells as a consequence of treatment with pharmacological agents.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer-testis', 'Disease', 'MESH:D013736', (24, 37))	('tumor', 'Disease', (121, 126))	('cancer-testis', 'Disease', (24, 37))	('epigenetic modification', 'Var', (90, 113))	('expression', 'Species', '29278', (61, 71))	('induced', 'Reg', (79, 86))	('expression', 'MPA', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
343257	33580183	PD-L1 expression was detected in most canine malignant cancers including OMM, and survival was significantly longer in the c4G12 treatment group (median 143 days) when compared to a historical control group (n = 15, median 54 days).	('c4G12', 'Chemical', '-', (123, 128))	('longer', 'PosReg', (109, 115))	('survival', 'CPA', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('malignant cancers', 'Disease', (45, 62))	('PD-L1', 'Gene', (0, 5))	('canine', 'Species', '9615', (38, 44))	('OMM', 'Disease', (73, 76))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('c4G12', 'Var', (123, 128))	('malignant cancers', 'Disease', 'MESH:D009369', (45, 62))
343267	33580183	In another study, NSCLC patients treated with pembrolizumab showed objective response rate (ORR) of 45.2% if >=50% of the tumor cells were PD-L1-positive on immunohistochemistry (IHC), whereas only 16.5% of patients responded to treatment if 1-49% of the tumor cells were PD-L1-positive.	('rat', 'Species', '10116', (86, 89))	('patients', 'Species', '9606', (207, 215))	('PD-L1-positive', 'Var', (139, 153))	('NSCLC', 'Disease', (18, 23))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('pembrolizumab', 'Chemical', 'MESH:C582435', (46, 59))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', (122, 127))
343275	33580183	Some canine cancers, including OMM, were reported to express PD-L1, and specific anti-PD-1/PD-L1 mAbs induced immune-cell activation in vitro.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('PD-L1', 'Gene', (61, 66))	('canine', 'Species', '9615', (5, 11))	('OMM', 'Disease', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('immune-cell activation', 'CPA', (110, 132))	('anti-PD-1/PD-L1', 'Var', (81, 96))
343288	33580183	In osteosarcoma samples, specific staining was confirmed by both mAbs, and expectedly, 6C11-3A11 produced higher staining intensity (n = 5 for each cancer type, Supplementary Fig.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('6C11-3A11', 'Var', (87, 96))	('osteosarcoma', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('higher', 'PosReg', (106, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('staining intensity', 'MPA', (113, 131))
343294	33580183	Of note, infiltrating plasma cells and lymphocytes were also PD-L1-positive in some specimens, while stromal cells surrounding the tumor cells were predominantly PD-L1-negative.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('PD-L1-positive', 'Var', (61, 75))	('tumor', 'Disease', (131, 136))
343298	33580183	To evaluate the safety and clinical benefits of anti-PD-L1 mAb in canine pulmonary metastatic OMM, we conducted a veterinary clinical study of c4G12 in our hospital involving 29 dogs (see Supplementary Table 2 for details of each dog).	('c4G12', 'Chemical', '-', (143, 148))	('pulmonary metastatic OMM', 'Disease', (73, 97))	('dogs', 'Species', '9615', (178, 182))	('dog', 'Species', '9615', (178, 181))	('dog', 'Species', '9615', (230, 233))	('c4G12', 'Var', (143, 148))	('canine', 'Species', '9615', (66, 72))
343310	33580183	One dog developed grade 3 pneumonitis after the second dose of c4G12, but recovered with treatment discontinuation and supportive care including glucocorticoid administration.	('pneumonitis', 'Disease', (26, 37))	('rat', 'Species', '10116', (168, 171))	('c4G12', 'Var', (63, 68))	('dog', 'Species', '9615', (4, 7))	('pneumonitis', 'Disease', 'MESH:D011014', (26, 37))	('c4G12', 'Chemical', '-', (63, 68))
343323	33580183	The concomitant or previous (within 8 weeks of treatment initiation) use of radiation was significantly associated with improved overall survival (OS) in the c4G12 treatment group (P = 0.02; Fig.	('c4G12', 'Var', (158, 163))	('improved', 'PosReg', (120, 128))	('overall survival', 'MPA', (129, 145))	('c4G12', 'Chemical', '-', (158, 163))
343330	33580183	In dogs with pulmonary metastatic OMM, c4G12 treatment was safe and induced tumor response in some dogs.	('dogs', 'Species', '9615', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('induced', 'Reg', (68, 75))	('tumor', 'Disease', (76, 81))	('c4G12', 'Var', (39, 44))	('dogs', 'Species', '9615', (3, 7))	('c4G12', 'Chemical', '-', (39, 44))	('pulmonary metastatic OMM', 'Disease', (13, 37))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
343331	33580183	Importantly, the survival of dogs with c4G12 treatment was significantly longer than that of the historical control group.	('c4G12 treatment', 'Var', (39, 54))	('survival', 'CPA', (17, 25))	('c4G12', 'Chemical', '-', (39, 44))	('dogs', 'Species', '9615', (29, 33))	('longer', 'PosReg', (73, 79))
343343	33580183	The c4G12 treatment was well-tolerated, and the frequency and severity of TRAEs were consistent with previous reports of human clinical trials using anti-PD-1/PD-L1 mAbs.	('TRAEs', 'Disease', (74, 79))	('rat', 'Species', '10116', (33, 36))	('human', 'Species', '9606', (121, 126))	('c4G12', 'Var', (4, 9))	('c4G12', 'Chemical', '-', (4, 9))
343347	33580183	The ORR of 7.7% in c4G12 treatment was low compared with previous human studies of advanced melanoma using anti-PD-L1 mAbs, with 17.3%-30.2% patients having objected responses.	('human', 'Species', '9606', (66, 71))	('c4G12', 'Var', (19, 24))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('c4G12', 'Chemical', '-', (19, 24))	('melanoma', 'Disease', (92, 100))	('patients', 'Species', '9606', (141, 149))
343349	33580183	In human cutaneous melanoma, mean TMB was 49.17 mutations/Mb, while acral or mucosal melanoma had mean TMB of only 2.64 mutations/Mb.	('mucosal melanoma', 'Disease', 'MESH:D008545', (77, 93))	('mutations/Mb', 'Var', (48, 60))	('human', 'Species', '9606', (3, 8))	('TMB', 'Chemical', '-', (34, 37))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('TMB', 'Chemical', '-', (103, 106))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('mucosal melanoma', 'Disease', (77, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
343354	33580183	Peripheral blood CRP level was also associated with improved OS in the c4G12 treatment group, consistent with a previous report of cancer patients who were treated with anti-PD-1/PD-L1 therapy.	('cancer', 'Disease', (131, 137))	('improved', 'PosReg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Peripheral blood CRP level', 'MPA', (0, 26))	('c4G12', 'Var', (71, 76))	('c4G12', 'Chemical', '-', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('patients', 'Species', '9606', (138, 146))
343357	33580183	Similarly, OS with c4G12 treatment was significantly longer in dogs with high LMR, as with a previous report on pembrolizumab treatment in metastatic melanoma patients.	('high LMR', 'Var', (73, 81))	('dogs', 'Species', '9615', (63, 67))	('c4G12', 'Var', (19, 24))	('c4G12', 'Chemical', '-', (19, 24))	('pembrolizumab', 'Chemical', 'MESH:C582435', (112, 125))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('patients', 'Species', '9606', (159, 167))	('LMR', 'Chemical', '-', (78, 81))
343362	33580183	Because prolongation of survival by c4G12 treatment was strongly suggested, further studies involving more appropriate control (e.g.	('c4G12', 'Chemical', '-', (36, 41))	('prolongation', 'PosReg', (8, 20))	('c4G12', 'Var', (36, 41))	('survival', 'CPA', (24, 32))
343365	33580183	In conclusion, PD-L1 appears to be a promising target for canine cancer immunotherapy, and c4G12, an immune checkpoint-inhibiting antibody for dogs, deserves further investigation.	('dogs', 'Species', '9615', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('c4G12', 'Var', (91, 96))	('c4G12', 'Chemical', '-', (91, 96))	('canine', 'Species', '9615', (58, 64))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
343408	30201954	In addition, only a few of the single nucleotide variants in WDLS were present in more than one lesion, suggesting that such mutations are of little significance in tumor development.	('single nucleotide variants', 'Var', (31, 57))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('WDLS', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
343411	30201954	They show that sarcomas driven by gene fusion or amplification display few additional changes over time, whereas sarcomas with complex karyotypes show a gradual increase of nucleotide- and chromosome-level mutations.	('sarcomas', 'Disease', (113, 121))	('amplification', 'Var', (49, 62))	('gene fusion', 'Var', (34, 45))	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('sarcomas', 'Disease', (15, 23))
343412	30201954	Genetic instability is considered an obligate feature of cancer cells.	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Genetic', 'Var', (0, 7))
343422	30201954	The third and largest subgroup shows various and often extensive combinations of genomic imbalances and point mutations, none of which is specific for any given tumor type; these sarcomas are typically medium-high grade malignant.	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('imbalances', 'Phenotype', 'HP:0002172', (89, 99))	('sarcomas', 'Disease', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('point mutations', 'Var', (104, 119))	('sarcomas', 'Disease', 'MESH:D012509', (179, 187))	('tumor', 'Disease', (161, 166))
343427	30201954	We show that the extensive single-cell variation in WDLS has little impact on key amplicons in chromosome 12, that MLS displays few mutations other than the FUS-DDIT3 fusion, and that CXS in general shows a gradual increase of both nucleotide- and chromosome-level mutations.	('WDLS', 'Gene', (52, 56))	('FUS', 'Gene', (157, 160))	('DDIT3', 'Gene', (161, 166))	('FUS', 'Gene', '2521', (157, 160))	('MLS', 'Disease', 'MESH:C537466', (115, 118))	('MLS', 'Disease', (115, 118))	('MLS', 'Phenotype', 'HP:0012268', (115, 118))	('DDIT3', 'Gene', '1649', (161, 166))	('variation', 'Var', (39, 48))
343446	30201954	Of the 70 genes that displayed mutations, only 8 are included in COSMIC's Cancer Gene Census (https://cancer.sanger.ac.uk/census), and none of these mutations has been reported before in soft tissue tumors.	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (187, 205))	('cancer', 'Disease', (102, 108))	("COSMIC's Cancer", 'Disease', (65, 80))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	("COSMIC's Cancer", 'Disease', 'MESH:D009369', (65, 80))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
343453	30201954	Some 35% of the patients develop metastases and it has been suggested that certain mutations, e.g., in PIK3CA and TP53, are associated with aggressive behavior.	('mutations', 'Var', (83, 92))	('metastases', 'Disease', (33, 43))	('aggressive behavior', 'Disease', 'MESH:D001523', (140, 159))	('aggressive behavior', 'Disease', (140, 159))	('patients', 'Species', '9606', (16, 24))	('develop', 'Reg', (25, 32))	('TP53', 'Gene', '7157', (114, 118))	('PIK3CA', 'Gene', (103, 109))	('associated with', 'Reg', (124, 139))	('aggressive behavior', 'Phenotype', 'HP:0000718', (140, 159))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('TP53', 'Gene', (114, 118))	('PIK3CA', 'Gene', '5290', (103, 109))
343457	30201954	Thus, the cell population that gave rise to all metastases had been replaced by a subclone with a much higher level of nucleotide level instability; the allele frequencies of CHEK2 (54-68%) and TP53 (36-43%) mutations in this subclone suggest that they occurred early and may have triggered the massive accumulation of ESV.	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('CHEK2', 'Gene', (175, 180))	('mutations', 'Var', (208, 217))	('TP53', 'Gene', '7157', (194, 198))	('TP53', 'Gene', (194, 198))	('ESV', 'MPA', (319, 322))	('metastases', 'Disease', (48, 58))	('CHEK2', 'Gene', '11200', (175, 180))
343458	30201954	Case 4 notwithstanding, the results show that MLS cells are genetically relatively stable, and that clonal evolution in MLS is mainly driven by nucleotide level mutations.	('MLS', 'Disease', 'MESH:C537466', (120, 123))	('MLS', 'Disease', (120, 123))	('MLS', 'Phenotype', 'HP:0012268', (120, 123))	('nucleotide level mutations', 'Var', (144, 170))	('driven', 'Reg', (134, 140))	('MLS', 'Disease', 'MESH:C537466', (46, 49))	('MLS', 'Disease', (46, 49))	('MLS', 'Phenotype', 'HP:0012268', (46, 49))
343459	30201954	The slow accrual of new mutations, or even reduction of genetic complexity, in MLS with time and tumor progression has several important implications.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('MLS', 'Disease', 'MESH:C537466', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('reduction', 'NegReg', (43, 52))	('tumor', 'Disease', (97, 102))	('MLS', 'Disease', (79, 82))	('MLS', 'Phenotype', 'HP:0012268', (79, 82))	('mutations', 'Var', (24, 33))	('genetic complexity', 'MPA', (56, 74))
343460	30201954	First, as already suggested by Reiter et al., cells that eventually form metastases may arise relatively early in the primary tumor; studying pancreatic carcinomas, they showed that metastases share most if not all important driver mutations with their PT.	('metastases', 'Disease', (73, 83))	('metastases', 'Disease', 'MESH:D009362', (182, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (142, 163))	('metastases', 'Disease', 'MESH:D009362', (73, 83))	('mutations', 'Var', (232, 241))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('pancreatic carcinomas', 'Disease', (142, 163))	('metastases', 'Disease', (182, 192))	('tumor', 'Disease', (126, 131))
343461	30201954	Second, although we cannot exclude an impact of mutations in non-coding sequences, much of the morphological and clinical variation in MLS, such as the transition from a low-grade to a high-grade tumor in cases 3, 6, and 9, could be caused by epigenetic factors.	('tumor', 'Disease', (196, 201))	('epigenetic factors', 'Var', (243, 261))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('MLS', 'Disease', 'MESH:C537466', (135, 138))	('MLS', 'Disease', (135, 138))	('MLS', 'Phenotype', 'HP:0012268', (135, 138))	('caused by', 'Reg', (233, 242))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
343468	30201954	Of these, only TP53 mutations have been implicated in sarcoma development before.	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('sarcoma', 'Disease', (54, 61))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('mutations', 'Var', (20, 29))
343473	30201954	In conclusion, the present study shows that the rate by which new mutations become predominant and that the type of clonal evolution, i.e., whether nucleotide or chromosome level mutations prevail, vary considerably among sarcomas caused by different pathogenetic mechanisms (Fig.	('mutations', 'Var', (66, 75))	('sarcomas', 'Disease', (222, 230))	('sarcomas', 'Disease', 'MESH:D012509', (222, 230))	('sarcomas', 'Phenotype', 'HP:0100242', (222, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
343479	30201954	Furthermore, the slow accumulation of DNA level mutations in some sarcomas does not exclude that epigenetic changes could be important in tumor progression.	('DNA level', 'Gene', (38, 47))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('tumor', 'Disease', (138, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('sarcomas', 'Disease', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
343495	30201954	In order to enrich for true somatic missense mutations, and limit the number of sequencing artifacts known to be generated by WES, variants were further filtered as follows: read depth of >=20 in tumor and >=10 in corresponding normal sample, average base quality >=20, mutated allele frequency (MAF) of >=10% in tumor and <1% in the normal sample, and only non-synonymous exonic somatic variants (ESV) were kept.	('>=20', 'Var', (264, 268))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (313, 318))	('mutated', 'Var', (270, 277))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))
343502	29507692	Using a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice we showed that activation of this enzyme by SDRT-induced damage in the endothelium is mandatory for tumor cure.	('Acid Sphingomyelinase', 'Gene', (25, 46))	('SDRT', 'Chemical', '-', (115, 119))	('SDRT-induced', 'Gene', (115, 127))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mice', 'Species', '10090', (66, 70))	('tumor', 'Disease', (171, 176))	('Acid Sphingomyelinase', 'Gene', '20597', (25, 46))	('damage', 'Var', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('activation', 'PosReg', (86, 96))
343517	29507692	We recently reported that SDRT induces a rapid wave of endothelial cell apoptosis via ceramide generation in both normal gastrointestinal tract and tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SDRT', 'Var', (26, 30))	('SDRT', 'Chemical', '-', (26, 30))	('ceramide', 'Chemical', 'MESH:D002518', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('endothelial cell apoptosis', 'CPA', (55, 81))	('gastrointestinal tract and tumors', 'Disease', 'MESH:D004067', (121, 154))	('ceramide generation', 'MPA', (86, 105))
343528	29507692	Pazopanib, (GW786034B, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide), a novel and potent vascular endothelial growth factor receptor inhibitor, is a small-molecule inhibitor shown to target both tumor and endothelial cells in multiple myeloma.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide', 'Chemical', '-', (23, 121))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('multiple myeloma', 'Disease', 'MESH:D009101', (280, 296))	('GW786034B', 'Chemical', 'MESH:C516667', (12, 21))	('multiple myeloma', 'Phenotype', 'HP:0006775', (280, 296))	('tumor', 'Disease', (249, 254))	('multiple myeloma', 'Disease', (280, 296))	('GW786034B', 'Var', (12, 21))
343530	29507692	Pre-clinical studies have shown that Pazopanib can inhibit tumor angiogenesis and the growth of several human tumor xenografts (multiple myeloma, colon, melanoma, prostate, kidney) in mice.	('colon', 'Disease', 'MESH:D015179', (146, 151))	('tumor', 'Disease', (59, 64))	('Pazopanib', 'Chemical', 'MESH:C516667', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('multiple myeloma', 'Disease', (128, 144))	('colon', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('human', 'Species', '9606', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('growth', 'CPA', (86, 92))	('multiple myeloma', 'Phenotype', 'HP:0006775', (128, 144))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('mice', 'Species', '10090', (184, 188))	('inhibit', 'NegReg', (51, 58))	('Pazopanib', 'Var', (37, 46))	('prostate', 'Disease', (163, 171))	('multiple myeloma', 'Disease', 'MESH:D009101', (128, 144))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
343548	29507692	We showed above that Pazopanib enhanced SDRT effect in two human sarcoma tumor models.	('sarcoma tumor', 'Disease', (65, 78))	('human', 'Species', '9606', (59, 64))	('enhanced', 'PosReg', (31, 39))	('SDRT effect', 'MPA', (40, 51))	('Pazopanib', 'Var', (21, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SDRT', 'Chemical', '-', (40, 44))	('Pazopanib', 'Chemical', 'MESH:C516667', (21, 30))	('sarcoma tumor', 'Disease', 'MESH:D012509', (65, 78))
343557	29507692	These results indicate that Pazopanib enhances SDRT effect on tumor growth delay by significantly increasing SDRT-induced TEC apoptosis and reducing angiogenesis in these tumors.	('Pazopanib', 'Var', (28, 37))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('angiogenesis', 'CPA', (149, 161))	('increasing', 'PosReg', (98, 108))	('SDRT-induced TEC apoptosis', 'MPA', (109, 135))	('reducing', 'NegReg', (140, 148))	('SDRT', 'Chemical', '-', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('growth delay', 'Phenotype', 'HP:0001510', (68, 80))	('SDRT', 'Chemical', '-', (47, 51))	('Pazopanib', 'Chemical', 'MESH:C516667', (28, 37))	('tumor growth delay', 'Disease', 'MESH:D006130', (62, 80))	('SDRT', 'MPA', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('enhances', 'PosReg', (38, 46))	('tumor growth delay', 'Disease', (62, 80))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
343586	29507692	Recent studies revealed that C16-ceramide was preferentially associated with stress-induced apoptosis in a variety of cell types.	('C16-ceramide', 'Chemical', 'MESH:C097760', (29, 41))	('associated', 'Reg', (61, 71))	('C16-ceramide', 'Var', (29, 41))
343590	29507692	These results indicate that Pazopanib potentiates radiation-induced apoptosis in endothelial cells via modulation of ASMase/ceramide signaling.	('Pazopanib', 'Var', (28, 37))	('ceramide', 'Chemical', 'MESH:D002518', (124, 132))	('ASMase/ceramide signaling', 'MPA', (117, 142))	('Pazopanib', 'Chemical', 'MESH:C516667', (28, 37))	('modulation', 'Reg', (103, 113))	('potentiates', 'PosReg', (38, 49))
343607	29507692	SDRT can induce rapid apoptosis of TEC, whereas the importance of vascular damage in tumors receiving conventionally fractionated radiation therapy (CFRT: 1.8-2 Gy per fraction) is more controversial.	('vascular damage in tumors', 'Disease', 'MESH:D000783', (66, 91))	('vascular damage in tumors', 'Disease', (66, 91))	('SDRT', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('SDRT', 'Chemical', '-', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
343614	29507692	This process requires intact microtubules, phosphorylation of Ser508 of ASMase, as well as functional lipid rafts.	('Ser508', 'Chemical', '-', (62, 68))	('Ser508', 'Var', (62, 68))	('lipid', 'Chemical', 'MESH:D008055', (102, 107))	('phosphorylation', 'Var', (43, 58))
343616	29507692	What is becoming clear from this and our other most recent studies (14) is that anti-VEGF pathway inhibitors synergistically increased SDRT-induced ASMase activity by reversing the effect of VEGF.	('reversing', 'NegReg', (167, 176))	('increased', 'PosReg', (125, 134))	('VEGF', 'Gene', (191, 195))	('VEGF', 'Gene', '7422', (85, 89))	('inhibitors', 'Var', (98, 108))	('SDRT', 'Chemical', '-', (135, 139))	('SDRT-induced ASMase activity', 'MPA', (135, 163))	('VEGF', 'Gene', '7422', (191, 195))	('VEGF', 'Gene', (85, 89))
343623	29507692	The increase of C16-ceramide contributes to the reorganization of membrane rafts into large signaling platforms, CRMs, which affords a mechanism by which SDRT induces endothelial apoptosis and generates microvascular dysfunction.	('microvascular dysfunction', 'Disease', 'MESH:D017566', (203, 228))	('microvascular dysfunction', 'Disease', (203, 228))	('reorganization', 'MPA', (48, 62))	('endothelial apoptosis', 'CPA', (167, 188))	('SDRT', 'Chemical', '-', (154, 158))	('C16-ceramide', 'MPA', (16, 28))	('induces', 'Reg', (159, 166))	('C16-ceramide', 'Chemical', 'MESH:C097760', (16, 28))	('SDRT', 'Var', (154, 158))	('increase', 'PosReg', (4, 12))
343624	29507692	Recently, increasing studies using LC-MS to determine the changes in specific ceramide species revealed that C16-ceramide was preferentially associated with stress-induced apoptosis in a variety of cell types.	('C16-ceramide', 'Chemical', 'MESH:C097760', (109, 121))	('C16-ceramide', 'Var', (109, 121))	('associated', 'Reg', (141, 151))	('preferentially', 'PosReg', (126, 140))	('ceramide', 'Chemical', 'MESH:D002518', (113, 121))	('ceramide', 'Chemical', 'MESH:D002518', (78, 86))
343625	29507692	C16-ceramide has also been shown to increase the sensitivity of Jurkat T cells and hepatocytes, and human chronic myelogenous leukemia (CML) to Fas-mediated apoptosis.	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (106, 134))	('chronic myelogenous leukemia', 'Disease', (106, 134))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (106, 134))	('CML', 'Disease', 'MESH:D015464', (136, 139))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('increase', 'PosReg', (36, 44))	('sensitivity', 'MPA', (49, 60))	('C16-ceramide', 'Chemical', 'MESH:C097760', (0, 12))	('Jurkat T', 'CellLine', 'CVCL:0065', (64, 72))	('human', 'Species', '9606', (100, 105))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (114, 134))	('CML', 'Phenotype', 'HP:0005506', (136, 139))	('CML', 'Disease', (136, 139))	('Fas', 'Chemical', 'MESH:C038178', (144, 147))	('C16-ceramide', 'Var', (0, 12))
343629	29507692	In addition to its crucial role in the formation of CRMs to mediate apoptotic signaling, C16-ceramide may also induce apoptosis by repression of pro-survival pathways.	('apoptosis', 'CPA', (118, 127))	('C16-ceramide', 'Chemical', 'MESH:C097760', (89, 101))	('induce', 'PosReg', (111, 117))	('pro-survival pathways', 'Pathway', (145, 166))	('C16-ceramide', 'Var', (89, 101))	('repression', 'NegReg', (131, 141))
343630	29507692	C16-Ceramide has been shown to activate ceramide-activated protein phosphatase leading to the dephosphorylation of p38 and Akt, which may negatively regulate the activities of downstream factors implicated in the regulation of apoptosis.	('regulate', 'Reg', (149, 157))	('activate', 'PosReg', (31, 39))	('ceramide-activated protein phosphatase', 'Enzyme', (40, 78))	('activities', 'MPA', (162, 172))	('p38', 'Gene', (115, 118))	('negatively', 'NegReg', (138, 148))	('C16-Ceramide', 'Chemical', 'MESH:C097760', (0, 12))	('Akt', 'Gene', '207', (123, 126))	('dephosphorylation', 'MPA', (94, 111))	('Akt', 'Gene', (123, 126))	('ceramide', 'Chemical', 'MESH:D002518', (40, 48))	('p38', 'Gene', '1432', (115, 118))	('C16-Ceramide', 'Var', (0, 12))
343633	29507692	Furthermore, they also showed that pazopanib and BYL719 combination killed HCT116 cells that express a mutated active K-RAS protein and an activated PI3K-AKT-mTOR signaling pathway indicating that pazopanib-dependent activation of the pERK/eIF2alpha pathway might be stress- and cell type-specific.	('HCT116', 'CellLine', 'CVCL:0291', (75, 81))	('mutated', 'Var', (103, 110))	('activated', 'PosReg', (139, 148))	('AKT', 'Gene', '207', (154, 157))	('pERK', 'Gene', '9451', (235, 239))	('eIF2alpha', 'Gene', '83939', (240, 249))	('pazopanib', 'Chemical', 'MESH:C516667', (35, 44))	('K-RAS', 'Gene', '3845', (118, 123))	('AKT', 'Gene', (154, 157))	('pERK', 'Gene', (235, 239))	('K-RAS', 'Gene', (118, 123))	('pazopanib', 'Chemical', 'MESH:C516667', (197, 206))	('eIF2alpha', 'Gene', (240, 249))
343641	29507692	Although the underlying mechanism remains elusive, given that SDRT increased ASMase activity and ceramide generation just within minutes, it is reasonable to assume that anti-angiogenic agents should be delivered immediately prior to irradiation to de-repress ASMase.	('SDRT', 'Var', (62, 66))	('de-repress', 'NegReg', (249, 259))	('ceramide generation', 'MPA', (97, 116))	('ceramide', 'Chemical', 'MESH:D002518', (97, 105))	('increased', 'PosReg', (67, 76))	('ASMase activity', 'MPA', (77, 92))	('ASMase', 'MPA', (260, 266))	('SDRT', 'Chemical', '-', (62, 66))
343676	27056897	The reduction of glycolysis and mRNA translation in U2OS (osteosarcoma), S180 (fibrosarcoma) and SW1535 (chondrosarcoma) cells observed in our study, indicate that, IS inhibits aberrant energy homeostasis.	('inhibits', 'NegReg', (168, 176))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('SW1535', 'CellLine', 'CVCL:X250', (97, 103))	('reduction', 'NegReg', (4, 13))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (79, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('mRNA translation', 'MPA', (32, 48))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (105, 119))	('SW1535', 'Var', (97, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('fibrosarcoma', 'Disease', 'MESH:D005354', (79, 91))	('osteosarcoma', 'Disease', (58, 70))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))	('fibrosarcoma', 'Disease', (79, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('IS', 'Chemical', 'MESH:C060988', (165, 167))	('U2OS', 'CellLine', 'CVCL:0042', (52, 56))	('S180', 'CellLine', 'CVCL:2874', (73, 77))	('glycolysis', 'MPA', (17, 27))	('chondrosarcoma', 'Disease', 'MESH:D002813', (105, 119))	('chondrosarcoma', 'Disease', (105, 119))
343687	27056897	Aberrant energy homeostasis is a key factor in metabolic disorders such as cancer.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('Aberrant', 'Var', (0, 8))	('metabolic disorders', 'Disease', 'MESH:D008659', (47, 66))	('cancer', 'Disease', (75, 81))	('metabolic disorders', 'Disease', (47, 66))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
343694	27056897	Thus, modulation of aberrant energy homeostasis might be a potential therapeutic strategy for sarcoma chemotherapy.	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('modulation', 'Var', (6, 16))	('sarcoma', 'Disease', (94, 101))
343732	27056897	Moreover, the inhibition of IS on the interaction between eIF4G and eIF4E was significantly reduced in 4E-BP1 knockdown sarcoma U2OS cells (Figure 2E), suggesting that IS inhibited cap-dependent translation initiation through 4E-BP1.	('knockdown', 'Var', (110, 119))	('inhibited', 'NegReg', (171, 180))	('U2OS', 'CellLine', 'CVCL:0042', (128, 132))	('IS', 'Chemical', 'MESH:C060988', (28, 30))	('eIF4E', 'Gene', (68, 73))	('4E-BP1', 'Gene', (103, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('IS', 'Chemical', 'MESH:C060988', (168, 170))	('eIF4E', 'Gene', '1977', (68, 73))	('cap-dependent translation initiation', 'MPA', (181, 217))	('inhibition', 'NegReg', (14, 24))	('eIF4G', 'Gene', (58, 63))	('cap', 'Chemical', '-', (181, 184))	('4E-BP1', 'Gene', '1978', (226, 232))	('eIF4G', 'Gene', '1981', (58, 63))	('4E-BP1', 'Gene', '1978', (103, 109))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('reduced', 'NegReg', (92, 99))	('4E-BP1', 'Gene', (226, 232))	('sarcoma', 'Disease', (120, 127))	('interaction', 'Interaction', (38, 49))
343740	27056897	Raptor depletion decreased the phosphorylation of S6K (Thr389) and increased the phosphorylation of Akt (Ser473) (Figure 3B), while Rictor knockdown reduced the phosphorylation of Akt (Ser473) and had no effect on the phosphorylation of S6K (Thr389) (Figure 3C).	('phosphorylation', 'MPA', (81, 96))	('phosphorylation', 'MPA', (161, 176))	('Thr389', 'Chemical', '-', (55, 61))	('S6K', 'Gene', (237, 240))	('Akt', 'Gene', (100, 103))	('decreased', 'NegReg', (17, 26))	('knockdown', 'Var', (139, 148))	('Akt', 'Gene', (180, 183))	('Akt', 'Gene', '207', (100, 103))	('phosphorylation', 'MPA', (31, 46))	('increased', 'PosReg', (67, 76))	('Ser473', 'Chemical', '-', (105, 111))	('Raptor', 'Gene', '57521', (0, 6))	('Akt', 'Gene', '207', (180, 183))	('S6K', 'Gene', '6198', (50, 53))	('Ser473', 'Chemical', '-', (185, 191))	('Rictor', 'Gene', (132, 138))	('Thr389', 'Chemical', '-', (242, 248))	('reduced', 'NegReg', (149, 156))	('S6K', 'Gene', '6198', (237, 240))	('Raptor', 'Gene', (0, 6))	('depletion', 'Var', (7, 16))	('S6K', 'Gene', (50, 53))	('Rictor', 'Gene', '253260', (132, 138))
343741	27056897	Raptor and Rictor knockdown both diminished the glycolysis in sarcoma U2OS cells (Figure 3D-3I).	('knockdown', 'Var', (18, 27))	('diminished', 'NegReg', (33, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('U2OS', 'CellLine', 'CVCL:0042', (70, 74))	('Raptor', 'Gene', (0, 6))	('Raptor', 'Gene', '57521', (0, 6))	('Rictor', 'Gene', '253260', (11, 17))	('glycolysis', 'MPA', (48, 58))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('sarcoma', 'Disease', (62, 69))	('Rictor', 'Gene', (11, 17))
343747	27056897	As shown in Figure 4A, IS rapidly inhibited insulin-stimulated mTORC1 signaling as manifest by the reduced phosphorylation of S6K (Thr389), S6 (Ser235/236) and 4E-BP1 (Thr37/46, Ser65).	('S6K', 'Gene', (126, 129))	('insulin', 'Gene', (44, 51))	('IS', 'Chemical', 'MESH:C060988', (23, 25))	('Thr389', 'Chemical', '-', (131, 137))	('Thr389', 'Var', (131, 137))	('Ser235', 'Chemical', '-', (144, 150))	('insulin', 'Gene', '3630', (44, 51))	('inhibited', 'NegReg', (34, 43))	('S6K', 'Gene', '6198', (126, 129))	('mTORC1', 'Gene', '382056', (63, 69))	('4E-BP1', 'Gene', (160, 166))	('Thr37/46', 'Var', (168, 176))	('4E-BP1', 'Gene', '1978', (160, 166))	('phosphorylation', 'MPA', (107, 122))	('reduced', 'NegReg', (99, 106))	('mTORC1', 'Gene', (63, 69))	('Ser65', 'Chemical', '-', (178, 183))	('Thr37', 'Chemical', '-', (168, 173))
343749	27056897	We found that IS still inhibited mTORC1 signaling in TSC2 knockdown sarcoma U2OS cells as indicated by the reduction of p-S6K (Thr389), p-S6 (Ser235/236) and p-4E-BP1 (Ser65) (Figure 4B), indicating that IS inhibited mTORC1 signaling mainly through TSC2-independent pathway.	('mTORC1', 'Gene', (217, 223))	('TSC2', 'Gene', '7249', (53, 57))	('Thr389', 'Chemical', '-', (127, 133))	('reduction', 'NegReg', (107, 116))	('Ser65', 'Chemical', '-', (168, 173))	('mTORC1', 'Gene', '382056', (217, 223))	('mTORC1', 'Gene', (33, 39))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('TSC2', 'Gene', '7249', (249, 253))	('4E-BP1', 'Gene', (160, 166))	('mTORC1', 'Gene', '382056', (33, 39))	('Ser235', 'Chemical', '-', (142, 148))	('sarcoma', 'Disease', (68, 75))	('knockdown', 'Var', (58, 67))	('TSC2', 'Gene', (53, 57))	('TSC2', 'Gene', (249, 253))	('IS', 'Chemical', 'MESH:C060988', (204, 206))	('p-S6K', 'Gene', '6198', (120, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('inhibited', 'NegReg', (207, 216))	('inhibited', 'NegReg', (23, 32))	('p-S6', 'Gene', '338413', (136, 140))	('p-S6K', 'Gene', (120, 125))	('p-S6', 'Gene', '338413', (120, 124))	('IS', 'Chemical', 'MESH:C060988', (14, 16))	('U2OS', 'CellLine', 'CVCL:0042', (76, 80))	('p-S6', 'Gene', (136, 140))	('p-S6', 'Gene', (120, 124))	('4E-BP1', 'Gene', '1978', (160, 166))
343750	27056897	It is reported that dephosphorylation of PRAS40 at Thr246 disrupts the assembly of mTORC1, which is necessary for mTORC1 function.	('dephosphorylation', 'MPA', (20, 37))	('assembly', 'MPA', (71, 79))	('Thr246', 'Var', (51, 57))	('disrupts', 'NegReg', (58, 66))	('mTORC1', 'Gene', '382056', (83, 89))	('PRAS40', 'Gene', '84335', (41, 47))	('PRAS40', 'Gene', (41, 47))	('mTORC1', 'Gene', '382056', (114, 120))	('Thr246', 'Chemical', '-', (51, 57))	('mTORC1', 'Gene', (83, 89))	('mTORC1', 'Gene', (114, 120))
343770	27056897	Although c-myc expression was substantial increased in MG132 treated cells, IS still effectively decreased the level of c-myc protein (Figure 5J), confirming that reduction in the c-myc mRNA translation was correlated with IS inhibition of c-myc protein.	('increased', 'PosReg', (42, 51))	('c-myc', 'Gene', '4609', (240, 245))	('reduction', 'NegReg', (163, 172))	('c-myc', 'Gene', (120, 125))	('IS', 'Chemical', 'MESH:C060988', (223, 225))	('c-myc', 'Gene', '4609', (180, 185))	('MG132', 'Var', (55, 60))	('c-myc', 'Gene', (240, 245))	('c-myc', 'Gene', (180, 185))	('c-myc', 'Gene', '4609', (9, 14))	('MG132', 'Chemical', 'MESH:C072553', (55, 60))	('decreased', 'NegReg', (97, 106))	('expression', 'MPA', (15, 25))	('c-myc', 'Gene', (9, 14))	('IS', 'Chemical', 'MESH:C060988', (76, 78))	('c-myc', 'Gene', '4609', (120, 125))
343778	27056897	It has been proved that hyperactivated eIF4F results in stimulating translation of a subset of mRNAs including c-myc mRNA, characterized by lengthy, G-C rich and highly structured 5-UTRs.	('eIF4F', 'Gene', '1977', (39, 44))	('c-myc', 'Gene', '4609', (111, 116))	('translation', 'MPA', (68, 79))	('c-myc', 'Gene', (111, 116))	('hyperactivated', 'Var', (24, 38))	('stimulating', 'PosReg', (56, 67))	('eIF4F', 'Gene', (39, 44))
343782	27056897	Moreover, 4E-BP1 knockdown abolished the effect of IS on the inhibition of glycolysis and ATP production (Figure 6C-6E) in sarcoma U2OS cells.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('abolished', 'NegReg', (27, 36))	('inhibition', 'NegReg', (61, 71))	('ATP production', 'MPA', (90, 104))	('glycolysis', 'MPA', (75, 85))	('4E-BP1', 'Gene', '1978', (10, 16))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('IS', 'Chemical', 'MESH:C060988', (51, 53))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('U2OS', 'CellLine', 'CVCL:0042', (131, 135))	('knockdown', 'Var', (17, 26))	('sarcoma', 'Disease', (123, 130))	('4E-BP1', 'Gene', (10, 16))
343784	27056897	Aberrant energy homeostasis is a common mediator in cancer which is positively correlated with proliferation rates.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('proliferation rates', 'CPA', (95, 114))
343798	27056897	The inhibition of mTORC1 signaling by IS was also evidenced by decreased phosphorylation levels of S6K (Thr389), S6 (Ser235/236), 4E-BP1 (Thr37/46, Ser65) (Figure 8E), as well as the disassembly of mTORC1 (Figure 8F).	('Ser65', 'Var', (148, 153))	('Thr37', 'Chemical', '-', (138, 143))	('S6K', 'Gene', '6198', (99, 102))	('decreased', 'NegReg', (63, 72))	('Ser235', 'Chemical', '-', (117, 123))	('4E-BP1', 'Gene', '1978', (130, 136))	('mTORC1', 'Gene', (18, 24))	('disassembly', 'MPA', (183, 194))	('mTORC1', 'Gene', (198, 204))	('Ser65', 'Chemical', '-', (148, 153))	('IS', 'Chemical', 'MESH:C060988', (38, 40))	('mTORC1', 'Gene', '382056', (18, 24))	('mTORC1', 'Gene', '382056', (198, 204))	('inhibition', 'NegReg', (4, 14))	('S6K', 'Gene', (99, 102))	('phosphorylation levels', 'MPA', (73, 95))	('Thr389', 'Var', (104, 110))	('S6 (Ser235/236', 'Var', (113, 127))	('4E-BP1', 'Gene', (130, 136))	('Thr389', 'Chemical', '-', (104, 110))
343813	27056897	Dephosphorylation of PRAS40 at Thr246 promotes PRAS40 inhibition of mTORC1.	('PRAS40', 'Gene', '84335', (47, 53))	('mTORC1', 'Gene', '382056', (68, 74))	('PRAS40', 'Gene', (47, 53))	('inhibition', 'NegReg', (54, 64))	('PRAS40', 'Gene', '84335', (21, 27))	('PRAS40', 'Gene', (21, 27))	('mTORC1', 'Gene', (68, 74))	('Thr246', 'Chemical', '-', (31, 37))	('Dephosphorylation', 'MPA', (0, 17))	('Thr246', 'Var', (31, 37))
343832	27056897	In TSC2-deficient cells, the hyperactivation of mTORC1 increases the transcription of glycolytic enzymes and promotes glycolysis, which is blocked by the mTORC1 inhibitor rapamycin.	('glycolysis', 'MPA', (118, 128))	('glycolytic enzymes', 'MPA', (86, 104))	('transcription', 'MPA', (69, 82))	('hyperactivation', 'Var', (29, 44))	('mTORC1', 'Gene', '382056', (48, 54))	('mTORC1', 'Gene', (154, 160))	('increases', 'PosReg', (55, 64))	('TSC2-deficient', 'Disease', 'MESH:C566021', (3, 17))	('TSC2-deficient', 'Disease', (3, 17))	('mTORC1', 'Gene', (48, 54))	('promotes', 'PosReg', (109, 117))	('mTORC1', 'Gene', '382056', (154, 160))
343951	27514518	However, the most critical problem associated with EBRT is that it can cause a number of common, well-described side effects, such as muscle fibrosis, severe neuropathy, joint contracture, vascular obstruction, and lymphatic edema.	('lymphatic edema', 'Phenotype', 'HP:0001004', (215, 230))	('EBRT', 'Var', (51, 55))	('cause', 'Reg', (71, 76))	('neuropathy', 'Disease', 'MESH:D009422', (158, 168))	('vascular obstruction', 'Disease', 'MESH:D019043', (189, 209))	('edema', 'Disease', 'MESH:D004487', (225, 230))	('muscle fibrosis', 'Disease', 'MESH:D005355', (134, 149))	('joint contracture', 'Disease', 'MESH:D003286', (170, 187))	('muscle fibrosis', 'Phenotype', 'HP:0030951', (134, 149))	('neuropathy', 'Phenotype', 'HP:0009830', (158, 168))	('joint contracture', 'Phenotype', 'HP:0001371', (170, 187))	('edema', 'Phenotype', 'HP:0000969', (225, 230))	('neuropathy', 'Disease', (158, 168))	('joint contracture', 'Disease', (170, 187))	('EBRT', 'Chemical', '-', (51, 55))	('edema', 'Disease', (225, 230))	('vascular obstruction', 'Disease', (189, 209))	('muscle fibrosis', 'Disease', (134, 149))
344068	26819567	Four cases were also tested and found to be positive for the translocation between chromosome X and chromosome 18 (SYT-SSX), which is specific for synovial sarcomas.	('translocation', 'Var', (61, 74))	('SYT', 'Gene', '6857', (115, 118))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (147, 164))	('SYT', 'Gene', (115, 118))	('SSX', 'Gene', (119, 122))	('SSX', 'Gene', '727837', (119, 122))	('synovial sarcomas', 'Disease', (147, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (147, 163))
344147	24216984	Thus, inhibition of mTOR also results in an antiangiogenic effect in sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcomas', 'Disease', (69, 77))	('inhibition', 'Var', (6, 16))	('mTOR', 'Protein', (20, 24))	('antiangiogenic effect', 'CPA', (44, 65))	('sarcomas', 'Disease', 'MESH:D012509', (69, 77))
344148	24216984	Additionally, the loss of p53, a common event in cancer, promotes mTOR activation.	('loss', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('mTOR activation', 'MPA', (66, 81))	('cancer', 'Disease', (49, 55))	('promotes', 'PosReg', (57, 65))
344149	24216984	Multiple familial cancer syndromes occur due to mutations in genes encoding proteins that signal upstream of the mTOR complexes, (including tuberous sclerosis proteins 1 and 2 (TSC1/2), serine threonine kinase 11 (STK11 or Lkb1), phosphatase and tensin homolog (PTEN), and neurofibromatosis type 1 (NF1).	('PTEN', 'Gene', '5728', (262, 266))	('STK11', 'Gene', '6794', (214, 219))	('cancer', 'Disease', (18, 24))	('NF1', 'Gene', '4763', (299, 302))	('mutations', 'Var', (48, 57))	('TSC1/2', 'Gene', '7248;7249', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('Lkb1', 'Gene', (223, 227))	('NF1', 'Gene', (299, 302))	('neurofibromatosis type 1', 'Gene', (273, 297))	('Lkb1', 'Gene', '6794', (223, 227))	('TSC1/2', 'Gene', (177, 183))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (273, 290))	('serine threonine kinase 11', 'Gene', '6794', (186, 212))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('STK11', 'Gene', (214, 219))	('PTEN', 'Gene', (262, 266))	('serine threonine kinase 11', 'Gene', (186, 212))	('neurofibromatosis type 1', 'Gene', '4763', (273, 297))
344150	24216984	Oncogenic activation of mTOR induces several processes required for cancer cell growth, survival, and proliferation.	('induces', 'Reg', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Oncogenic activation', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('mTOR', 'Gene', (24, 28))
344151	24216984	Thus, inhibition of mTOR kinase activity impacts multiple pathways that are important for tumor maintenance such as the protein translation of several oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('protein translation', 'MPA', (120, 139))	('inhibition', 'Var', (6, 16))	('impacts', 'Reg', (41, 48))	('mTOR', 'Protein', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
344167	24216984	We hypothesized that mTOR inhibition could potentiate the clinical activity of irinotecan by preventing the regulation of cancer cell survival.	('preventing', 'NegReg', (93, 103))	('inhibition', 'Var', (26, 36))	('cancer', 'Disease', (122, 128))	('irinotecan', 'Chemical', 'MESH:D000077146', (79, 89))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mTOR', 'Protein', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('potentiate', 'PosReg', (43, 53))
344308	30560187	This tumor is associated with a t(12;16)(q13;p11) translocation resulting in a FUS/DDIT3 fusion protein (>90% of cases).	('DDIT3', 'Gene', (83, 88))	('resulting in', 'Reg', (64, 76))	('FUS', 'Gene', '2521', (79, 82))	('DDIT3', 'Gene', '1649', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('t(12;16)(q13;p11', 'Var', (32, 48))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (32, 49))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('FUS', 'Gene', (79, 82))
344326	24733560	In healthy individuals, EBV can cause infectious mononucleosis, and is a significant risk factor for Burkitt's lymphoma and nasopharyngeal carcinoma.	('EBV', 'Species', '10376', (24, 27))	('infectious mononucleosis', 'Disease', (38, 62))	("Burkitt's lymphoma", 'Disease', (101, 119))	('EBV', 'Var', (24, 27))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (124, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (124, 148))	('nasopharyngeal carcinoma', 'Disease', (124, 148))	('infectious mononucleosis', 'Disease', 'MESH:D007244', (38, 62))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (101, 119))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (101, 119))	('cause', 'Reg', (32, 37))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))
344379	24733560	kK3 and kK5 induce rapid endocytosis and lysosomal degradation of cell surface glycoproteins (see next section).	('kK5', 'Var', (8, 11))	('rapid endocytosis', 'MPA', (19, 36))	('lysosomal degradation', 'MPA', (41, 62))	('cell surface glycoproteins', 'MPA', (66, 92))	('K3', 'Gene', '102626', (1, 3))	('induce', 'Reg', (12, 18))
344391	24733560	kK3 and kK5 lead to ubiquitination of the cytosolic tail of MHC-I molecules, thus enhancing their endocytosis from the cell surface.	('kK5', 'Var', (8, 11))	('ubiquitination', 'MPA', (20, 34))	('K3', 'Gene', '102626', (1, 3))	('MHC-I', 'Gene', (60, 65))	('endocytosis from the cell surface', 'MPA', (98, 131))	('enhancing', 'PosReg', (82, 91))
344414	24733560	gp42 does not affect peptide-loading on MHC-II molecules, but can block the interaction of TCR with peptide-MHC-II complex, thereby inhibiting antigenic recognition by CD4+ T helper cells.	('CD4', 'Gene', (168, 171))	('CD4', 'Gene', '920', (168, 171))	('block', 'NegReg', (66, 71))	('interaction', 'Interaction', (76, 87))	('TCR', 'Gene', (91, 94))	('TCR', 'Gene', '6962', (91, 94))	('antigenic', 'MPA', (143, 152))	('inhibiting', 'NegReg', (132, 142))	('gp42', 'Var', (0, 4))
344428	24733560	Moreover, the kK5-triggered downregulation of CD86 and ICAM-1 expression on the BJAB (a B lymphoma cell line) results in a reduced natural killer (NK) cell-mediated cytotoxicity.	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('ICAM-1', 'Gene', '3383', (55, 61))	('kK5-triggered', 'Var', (14, 27))	('B lymphoma', 'Phenotype', 'HP:0012191', (88, 98))	('expression', 'MPA', (62, 72))	('ICAM-1', 'Gene', (55, 61))	('cytotoxicity', 'Disease', (165, 177))	('downregulation', 'NegReg', (28, 42))	('cytotoxicity', 'Disease', 'MESH:D064420', (165, 177))	('lymphoma', 'Disease', (90, 98))	('BJAB', 'CellLine', 'CVCL:5711', (80, 84))	('lymphoma', 'Disease', 'MESH:D008223', (90, 98))	('CD86', 'Gene', '942', (46, 50))	('CD86', 'Gene', (46, 50))	('reduced', 'NegReg', (123, 130))
344447	24733560	In MHV-68-infected mice, IL-10-producing CD8+ T cells account for 1% of total CD8+ T cells, of which around 10% are specific to ORF61524-531, a dominant epitope of MHV-68.	('CD8', 'Gene', (78, 81))	('ORF61524-531', 'Var', (128, 140))	('CD8', 'Gene', '925', (78, 81))	('CD8', 'Gene', (41, 44))	('CD8', 'Gene', '925', (41, 44))	('MHV-68', 'Species', '1440122', (164, 170))	('MHV-68', 'Species', '1440122', (3, 9))	('mice', 'Species', '10090', (19, 23))
344451	24733560	Interestingly, it is also reported that MHV-68 can reduce the frequency and activity of naturally occurring CD4+CD25+ Tregs following infection.	('CD25', 'Gene', (112, 116))	('MHV-68', 'Var', (40, 46))	('activity', 'MPA', (76, 84))	('CD4', 'Gene', (108, 111))	('MHV-68', 'Species', '1440122', (40, 46))	('CD4', 'Gene', '920', (108, 111))	('frequency', 'CPA', (62, 71))	('CD25', 'Gene', '3559', (112, 116))	('reduce', 'NegReg', (51, 57))
344486	24733560	Substitution of isoleucine at position 87 with alanine (corresponding to the vIL-10 residue) abrogates the immunostimulatory activity of cIL-10 but preserves its immunosuppressive activity.	('Substitution', 'Var', (0, 12))	('isoleucine at position 87 with alanine', 'Mutation', 'p.I87A', (16, 54))	('abrogates', 'NegReg', (93, 102))	('immunostimulatory activity', 'MPA', (107, 133))	('preserves', 'NegReg', (148, 157))	('cIL-10', 'Chemical', '-', (137, 143))	('vIL-10', 'Chemical', '-', (77, 83))	('immunosuppressive activity', 'MPA', (162, 188))
344487	24733560	These data suggest that vIL-10 may derive from a captured and mutated cIL-10 gene, and the alteration is beneficial to the virus by disrupting host immune responses.	('host immune responses', 'CPA', (143, 164))	('cIL-10', 'Gene', (70, 76))	('cIL-10', 'Chemical', '-', (70, 76))	('vIL-10', 'Chemical', '-', (24, 30))	('disrupting', 'NegReg', (132, 142))	('mutated', 'Var', (62, 69))
344496	31616462	Non-Coding RNAs in Pediatric Solid Tumors Pediatric solid tumors are a diverse group of extracranial solid tumors representing approximately 40% of childhood cancers.	('Pediatric solid tumors', 'Disease', (42, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('Pediatric solid tumors', 'Disease', 'MESH:D063766', (42, 64))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('Tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('extracranial solid tumors', 'Disease', 'MESH:D018241', (88, 113))	('extracranial solid tumors', 'Disease', (88, 113))	('childhood cancers', 'Disease', (148, 165))	('Tumors', 'Disease', (35, 41))	('Tumors', 'Disease', 'MESH:D009369', (35, 41))	('Tumors', 'Phenotype', 'HP:0002664', (35, 41))	('Non-Coding RNAs', 'Var', (0, 15))	('childhood cancers', 'Disease', 'MESH:D009369', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
344507	31616462	Solid tumors can originate from cells of any of the three germ layers, the ectoderm, mesoderm, or endoderm, and likely arise due to disruptions in the developmental processes of these precursor cells, leading them to develop cancerous phenotypes.	('develop', 'PosReg', (217, 224))	('cancerous', 'Disease', (225, 234))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('arise due to', 'Reg', (119, 131))	('originate', 'Reg', (17, 26))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('cancerous', 'Disease', 'MESH:D009369', (225, 234))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('disruptions', 'Var', (132, 143))
344509	31616462	As a result, adult cancers often display a high occurrence of genetic mutations, whereas pediatric solid tumors tend to feature a relatively low number of genetic mutations.	('pediatric solid tumors', 'Disease', 'MESH:D063766', (89, 111))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('genetic mutations', 'Var', (62, 79))	('pediatric solid tumors', 'Disease', (89, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
344512	31616462	The most widely studied ncRNAs are the microRNAs (miRNAs), small 20- to 25-nucleotide-long RNAs that play an important role in regulating translation and messenger RNA stability via complementary base pairing.	('miR', 'Gene', '220972', (50, 53))	('RNAs', 'Protein', (91, 95))	('miR', 'Gene', (50, 53))	('complementary base pairing', 'Var', (182, 208))	('regulating translation', 'MPA', (127, 149))	('ncRNA', 'Gene', (24, 29))	('messenger RNA stability', 'MPA', (154, 177))	('25-nucleotide', 'Chemical', 'MESH:D009711', (72, 85))	('ncRNA', 'Gene', '220202', (24, 29))
344517	31616462	Additionally, genome-wide association studies have suggested that over 80% of single nucleotide polymorphisms found associated with cancer are outside of coding regions.	('single nucleotide polymorphisms', 'Var', (78, 109))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
344520	31616462	In 2002, two miRNAs were identified as potential tumor suppressors due to their frequent downregulation or deletion in chronic lymphocytic leukemia.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (119, 147))	('miR', 'Gene', '220972', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('miR', 'Gene', (13, 16))	('chronic lymphocytic leukemia', 'Disease', (119, 147))	('downregulation', 'NegReg', (89, 103))	('tumor', 'Disease', (49, 54))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('deletion', 'Var', (107, 115))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (119, 147))
344546	31616462	Germline inactivation of the Wilms Tumor 1 (WT1) transcription factor has been linked to a genetic predisposition towards Wilms tumor.	('WT1', 'Gene', (44, 47))	('Wilms Tumor', 'Disease', 'MESH:D009396', (29, 40))	('Wilms Tumor', 'Disease', (29, 40))	('linked', 'Reg', (79, 85))	('Germline inactivation', 'Var', (0, 21))	('Tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Wilms tumor', 'Disease', 'MESH:D009396', (122, 133))	('Wilms tumor', 'Phenotype', 'HP:0002667', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Wilms Tumor', 'Phenotype', 'HP:0002667', (29, 40))	('Wilms tumor', 'Disease', (122, 133))	('WT1', 'Gene', '7490', (44, 47))
344551	31616462	Recent studies have shown that impairments of the miRNA processing machinery are common in Wilms tumor and likely contribute to this disease.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('Wilms tumor', 'Disease', (91, 102))	('Wilms tumor', 'Disease', 'MESH:D009396', (91, 102))	('Wilms tumor', 'Phenotype', 'HP:0002667', (91, 102))	('impairments', 'Var', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('common', 'Reg', (81, 87))	('contribute', 'Reg', (114, 124))
344552	31616462	For example, a study by found mutations in miRNA processing genes in 33% of tumors, most commonly occurring in the Drosha gene, with other mutations in DICER1, XPO5, DGCR8 and TARBP2.	('occurring', 'Reg', (98, 107))	('miR', 'Gene', '220972', (43, 46))	('XPO5', 'Gene', '57510', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('miR', 'Gene', (43, 46))	('TARBP2', 'Gene', '6895', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('TARBP2', 'Gene', (176, 182))	('tumors', 'Disease', (76, 82))	('Drosha gene', 'Disease', 'MESH:D058495', (115, 126))	('mutations', 'Var', (30, 39))	('DICER1', 'Gene', '23405', (152, 158))	('DGCR8', 'Gene', (166, 171))	('XPO5', 'Gene', (160, 164))	('mutations', 'Var', (139, 148))	('DGCR8', 'Gene', '54487', (166, 171))	('Drosha gene', 'Disease', (115, 126))	('DICER1', 'Gene', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (76, 82))
344553	31616462	's study, they further examined the potential consequences of several of these mutations and found that Drosha mutations often led to a loss of RNAse IIIB activity, which prevented processing of pri-miRNAs, leading to a global reduction in mature miRNAs.	('RNAse III', 'Gene', '29102', (144, 153))	('mutations', 'Var', (111, 120))	('prevented', 'NegReg', (171, 180))	('activity', 'MPA', (155, 163))	('Drosha', 'Gene', '29102', (104, 110))	('miR', 'Gene', '220972', (247, 250))	('miR', 'Gene', (247, 250))	('processing', 'MPA', (181, 191))	('miR', 'Gene', '220972', (199, 202))	('miR', 'Gene', (199, 202))	('loss', 'NegReg', (136, 140))	('Drosha', 'Gene', (104, 110))	('RNAse III', 'Gene', (144, 153))	('reduction', 'NegReg', (227, 236))
344554	31616462	DICER1 mutations also frequently affected the RNAse IIIB domain; however, this mutation only affected processing of 5p miRNAs from precursors, as DICER1 contains a second RNAse domain for 3p processing.	('DICER1', 'Gene', (0, 6))	('affected', 'Reg', (33, 41))	('DICER1', 'Gene', '23405', (0, 6))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (119, 122))	('RNAse III', 'Gene', '29102', (46, 55))	('DICER1', 'Gene', (146, 152))	('processing', 'MPA', (102, 112))	('RNAse III', 'Gene', (46, 55))	('DICER1', 'Gene', '23405', (146, 152))	('affected', 'Reg', (93, 101))	('mutations', 'Var', (7, 16))
344556	31616462	These mutations have interesting consequences for global miRNA expression and most likely favor expression of oncogenic miRNAs or reduce expression of miRNAs with tumor-suppressive effects.	('reduce', 'NegReg', (130, 136))	('expression', 'MPA', (137, 147))	('miR', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('consequences', 'Reg', (33, 45))	('favor', 'PosReg', (90, 95))	('miR', 'Gene', (120, 123))	('miR', 'Gene', (151, 154))	('miR', 'Gene', '220972', (120, 123))	('expression', 'MPA', (96, 106))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', '220972', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('mutations', 'Var', (6, 15))
344557	31616462	In line with this, the let-7 family is predominantly 5p-derived, and lower expression of several of its 5p members was found in both Drosha and DICER1 mutants in two of these studies.	('let-7', 'Gene', '266952', (23, 28))	('let-7', 'Gene', (23, 28))	('mutants', 'Var', (151, 158))	('Drosha', 'Gene', (133, 139))	('lower', 'NegReg', (69, 74))	('Drosha', 'Gene', '29102', (133, 139))	('DICER1', 'Gene', (144, 150))	('DICER1', 'Gene', '23405', (144, 150))	('expression', 'MPA', (75, 85))
344558	31616462	Additionally, the miR-200 family was found downregulated in Wilms tumors with mutated miRNA processing genes, which is known to regulate the mesenchymal-to-epithelial transition and has been associated with highly aggressive forms of cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('downregulated', 'NegReg', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('Wilms tumor', 'Phenotype', 'HP:0002667', (60, 71))	('mesenchymal-to-epithelial', 'CPA', (141, 166))	('miR', 'Gene', '220972', (86, 89))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('miR', 'Gene', (86, 89))	('Wilms tumors', 'Phenotype', 'HP:0002667', (60, 72))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('Wilms tumors', 'Disease', (60, 72))	('mutated', 'Var', (78, 85))	('associated', 'Reg', (191, 201))	('cancer', 'Disease', (234, 240))	('Wilms tumors', 'Disease', 'MESH:D009396', (60, 72))
344569	31616462	miR-18a and miR-19a have also been shown to repress estrogen receptor (ESR1) expression, and prolonged knockdown of miR-18a induced morphological differentiation of SK-N-BE neuroblastoma cells.	('expression', 'MPA', (77, 87))	('induced', 'Reg', (124, 131))	('estrogen receptor', 'Gene', (52, 69))	('ESR1', 'Gene', '2099', (71, 75))	('neuroblastoma', 'Gene', (173, 186))	('estrogen receptor', 'Gene', '2099', (52, 69))	('miR-18a', 'Gene', '406953', (116, 123))	('miR-18a', 'Gene', '406953', (0, 7))	('neuroblastoma', 'Phenotype', 'HP:0003006', (173, 186))	('miR-19a', 'Gene', (12, 19))	('morphological differentiation', 'CPA', (132, 161))	('repress', 'NegReg', (44, 51))	('ESR1', 'Gene', (71, 75))	('neuroblastoma', 'Gene', '230972', (173, 186))	('miR-18a', 'Gene', (116, 123))	('knockdown', 'Var', (103, 112))	('miR-18a', 'Gene', (0, 7))	('miR-19a', 'Gene', '406979', (12, 19))
344579	31616462	Given that MYC/MYCN and E2F have previously been shown to induce each other's expression, miR-20a appears to play an important role in keeping this positive feedback loop in check.	('MYC', 'Gene', (11, 14))	('expression', 'MPA', (78, 88))	('MYC', 'Gene', '4609', (15, 18))	('E2F', 'Var', (24, 27))	('induce', 'PosReg', (58, 64))	('MYC', 'Gene', (15, 18))	('miR-20a', 'Gene', (90, 97))	('miR-20a', 'Gene', '406982', (90, 97))	('MYC', 'Gene', '4609', (11, 14))
344581	31616462	RB1 plays a key role in inhibiting cell cycle progression, and germline mutations of this gene can lead to familial retinoblastoma formation.	('retinoblastoma', 'Phenotype', 'HP:0009919', (116, 130))	('familial retinoblastoma', 'Disease', (107, 130))	('lead to', 'Reg', (99, 106))	('cell cycle progression', 'CPA', (35, 57))	('familial retinoblastoma', 'Disease', 'MESH:D012175', (107, 130))	('inhibiting', 'NegReg', (24, 34))	('RB1', 'Gene', (0, 3))	('germline mutations', 'Var', (63, 81))
344595	31616462	Overexpression of Lin28 tends to drive cells towards oncogenesis and is a common feature in cancers.	('cells towards oncogenesis', 'CPA', (39, 64))	('Lin28', 'Gene', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('drive', 'PosReg', (33, 38))
344599	31616462	investigated Lin28b in neuroblastoma and demonstrated that Lin28b could enhance MYCN protein levels via let-7 regulation.	('enhance', 'PosReg', (72, 79))	('Lin28b', 'Var', (59, 65))	('neuroblastoma', 'Gene', (23, 36))	('MYCN protein levels', 'MPA', (80, 99))	('neuroblastoma', 'Phenotype', 'HP:0003006', (23, 36))	('neuroblastoma', 'Gene', '230972', (23, 36))	('let-7', 'Gene', '266952', (104, 109))	('let-7', 'Gene', (104, 109))
344608	31616462	Loss of Let-7 plays a key role in many pediatric solid tumors as its loss enables expression of transcription factors and other genes that participate in oncogenesis.	('Let-7', 'Gene', '266952', (8, 13))	('expression', 'MPA', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Let-7', 'Gene', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('loss enables', 'NegReg', (69, 81))	('pediatric solid tumors', 'Disease', 'MESH:D063766', (39, 61))	('pediatric solid tumors', 'Disease', (39, 61))	('Loss', 'Var', (0, 4))	('transcription', 'Protein', (96, 109))
344614	31616462	In a study by, miR-9 knockdown suppressed cell growth and migration of osteosarcoma cells.	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('suppressed', 'NegReg', (31, 41))	('knockdown', 'Var', (21, 30))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('miR', 'Gene', '220972', (15, 18))	('osteosarcoma', 'Disease', (71, 83))	('miR', 'Gene', (15, 18))
344629	31616462	In particular, loss of 1p36 occurs in 20-30% of neuroblastoma cases and correlates with MYCN amplification, whereas loss of 11q23 in occurs in approximately 40% of cases but almost never occurs with MYCN amplification ( Figure 1A ).	('MYCN amplification', 'MPA', (88, 106))	('neuroblastoma', 'Gene', (48, 61))	('loss of 11q23', 'Var', (116, 129))	('neuroblastoma', 'Phenotype', 'HP:0003006', (48, 61))	('neuroblastoma', 'Gene', '230972', (48, 61))	('loss of 1p36', 'Var', (15, 27))
344634	31616462	In most cases, overexpression did not lead to a noticeable change in phenotype; however, miR-34a and miR-34c induced significant growth inhibition in cell lines with 1p36 deletion.	('miR-34c', 'Gene', (101, 108))	('miR-34c', 'Gene', '407042', (101, 108))	('growth inhibition', 'CPA', (129, 146))	('miR-34a', 'Gene', '407040', (89, 96))	('deletion', 'Var', (171, 179))	('miR-34a', 'Gene', (89, 96))
344639	31616462	Prior studies have shown correlations between high mir-34a expression and patient survival, which would indicate a tumor-suppressive role for mir-34a.	('high', 'Var', (46, 50))	('patient', 'Species', '9606', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mir-34a', 'Gene', (142, 149))	('tumor', 'Disease', (115, 120))	('mir-34a', 'Gene', '407040', (51, 58))	('expression', 'MPA', (59, 69))	('mir-34a', 'Gene', '407040', (142, 149))	('patient survival', 'CPA', (74, 90))	('correlations', 'Interaction', (25, 37))	('mir-34a', 'Gene', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
344667	31616462	Originally thought of as transcriptional noise, lncRNAs have now emerged as functional regulators of nearly all essential cellular processes including growth, differentiation, cell state maintenance, apoptosis, splicing, and epigenetic regulation.	('ncRNA', 'Gene', '220202', (49, 54))	('epigenetic regulation', 'Var', (225, 246))	('ncRNA', 'Gene', (49, 54))
344681	31616462	Malat1 is abundantly expressed and highly conserved across species, unlike many other lncRNAs, and displays remarkably diverse functions in cellular processes including alternative splicing, nuclear organization, and epigenetic modulation.	('epigenetic modulation', 'Var', (217, 238))	('ncRNA', 'Gene', '220202', (87, 92))	('alternative splicing', 'MPA', (169, 189))	('Malat1', 'Gene', (0, 6))	('ncRNA', 'Gene', (87, 92))	('nuclear', 'MPA', (191, 198))
344686	31616462	They found that N-Myc upregulated JMJD1A via direct binding of its promoter region and that JMJD1A could demethylate histone H3K9 near the promoter region of Malat1, leading to its upregulation.	('upregulated', 'PosReg', (22, 33))	('JMJD1A', 'Gene', (34, 40))	('N-Myc', 'Gene', (16, 21))	('histone H3K9', 'Protein', (117, 129))	('N-Myc', 'Gene', '4613', (16, 21))	('JMJD1A', 'Gene', '55818', (34, 40))	('binding', 'Interaction', (52, 59))	('JMJD1A', 'Gene', '55818', (92, 98))	('upregulation', 'PosReg', (181, 193))	('demethylate', 'Var', (105, 116))	('JMJD1A', 'Gene', (92, 98))
344687	31616462	MYCN-mediated upregulation of Malat1 provides one mechanism in which its amplification can lead to increased metastasis in neuroblastoma patients.	('neuroblastoma', 'Phenotype', 'HP:0003006', (123, 136))	('Malat1', 'Gene', (30, 36))	('neuroblastoma', 'Gene', '230972', (123, 136))	('patients', 'Species', '9606', (137, 145))	('metastasis', 'CPA', (109, 119))	('increased', 'PosReg', (99, 108))	('neuroblastoma', 'Gene', (123, 136))	('upregulation', 'PosReg', (14, 26))	('amplification', 'Var', (73, 86))
344699	31616462	The capacity for Malat1 to drive proliferation and metastasis in pediatric solid tumors suggests that dysregulation of any of these regulatory components can be sufficient for the development of cancer and highlights the value of further research into the relatively new field of lncRNAs.	('metastasis', 'CPA', (51, 61))	('dysregulation', 'Var', (102, 115))	('ncRNA', 'Gene', (281, 286))	('pediatric solid tumors', 'Disease', (65, 87))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('pediatric solid tumors', 'Disease', 'MESH:D063766', (65, 87))	('ncRNA', 'Gene', '220202', (281, 286))	('proliferation', 'CPA', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
344709	31616462	However, this model suggested that H19 may simply serve as a marker for epigenetic disruptions and left open the question of what H19's actual function is.	('H19', 'Gene', (35, 38))	('H19', 'Gene', '283120', (35, 38))	('epigenetic disruptions', 'Var', (72, 94))	('H19', 'Gene', '283120', (130, 133))	('H19', 'Gene', (130, 133))
344726	31616462	Here, the authors found that H19 functioned as a promoter of differentiation during the embryonic period and that absence of H19 at this stage could leave cells vulnerable to forming cancer, thereby seemingly acting as a tumor suppressor.	('absence', 'Var', (114, 121))	('cancer', 'Disease', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('H19', 'Gene', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('H19', 'Gene', '283120', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('H19', 'Gene', '283120', (29, 32))	('leave', 'Reg', (149, 154))	('differentiation', 'MPA', (61, 76))	('H19', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
344741	31616462	Additionally, several lncRNAs are downregulated in osteosarcoma with potential tumor-suppressive activity such as loc285194, MEG3, and TUSC7.	('MEG3', 'Gene', (125, 129))	('ncRNA', 'Gene', (23, 28))	('downregulated', 'NegReg', (34, 47))	('tumor', 'Disease', (79, 84))	('MEG3', 'Gene', '55384', (125, 129))	('osteosarcoma', 'Phenotype', 'HP:0002669', (51, 63))	('osteosarcoma', 'Disease', (51, 63))	('osteosarcoma', 'Disease', 'MESH:D012516', (51, 63))	('ncRNA', 'Gene', '220202', (23, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('TUSC7', 'Gene', (135, 140))	('TUSC7', 'Gene', '285194', (135, 140))	('loc285194', 'Var', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
344742	31616462	loc285194 has been identified as a transcriptional target of p53 and can downregulate miR-211.	('miR-211', 'Gene', '406993', (86, 93))	('miR-211', 'Gene', (86, 93))	('loc285194', 'Var', (0, 9))	('p53', 'Gene', '7157', (61, 64))	('downregulate', 'NegReg', (73, 85))	('p53', 'Gene', (61, 64))
344756	31616462	Finally, an isoform of lncRNA CASC15, CASC15-S, was also implicated as a key element in neuronal differentiation, and low expression was associated with a poor outcome in patients.	('expression', 'MPA', (122, 132))	('low', 'Var', (118, 121))	('CASC15', 'Gene', (30, 36))	('CASC15', 'Gene', '401237', (30, 36))	('patients', 'Species', '9606', (171, 179))	('ncRNA', 'Gene', (24, 29))	('CASC15', 'Gene', (38, 44))	('CASC15', 'Gene', '401237', (38, 44))	('ncRNA', 'Gene', '220202', (24, 29))
344762	31616462	CRNDE is known to be frequently upregulated in hepatoblastoma, and knockdown of CRNDE activated the mTOR pathway and inhibited tumor growth and angiogenesis with a corresponding decrease in VEGFA and Ang-2 levels.	('Ang-2', 'Gene', (200, 205))	('activated', 'PosReg', (86, 95))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('knockdown', 'Var', (67, 76))	('VEGFA', 'Gene', (190, 195))	('decrease', 'NegReg', (178, 186))	('CRNDE', 'Gene', (0, 5))	('CRNDE', 'Gene', '643911', (0, 5))	('angiogenesis', 'CPA', (144, 156))	('CRNDE', 'Gene', '643911', (80, 85))	('CRNDE', 'Gene', (80, 85))	('Ang-2', 'Gene', '285', (200, 205))	('VEGFA', 'Gene', '7422', (190, 195))	('mTOR', 'Gene', (100, 104))	('hepatoblastoma', 'Disease', (47, 61))	('upregulated', 'PosReg', (32, 43))	('tumor', 'Disease', (127, 132))	('hepatoblastoma', 'Disease', 'MESH:D018197', (47, 61))	('inhibited', 'NegReg', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mTOR', 'Gene', '2475', (100, 104))
344769	31616462	Despite the relatively rare occurrence of mutations in pediatric solid tumors, copy number variations are common and often occur at regions of the genome that harbor ncRNAs with tumor-suppressive roles.	('ncRNA', 'Gene', '220202', (166, 171))	('tumor', 'Disease', (178, 183))	('pediatric solid tumors', 'Disease', (55, 77))	('ncRNA', 'Gene', (166, 171))	('occur', 'Reg', (123, 128))	('pediatric solid tumors', 'Disease', 'MESH:D063766', (55, 77))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('copy number variations', 'Var', (79, 101))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mutations', 'Var', (42, 51))
344772	31616462	Functional studies have revealed that dysregulation of ncRNAs is capable of driving progenitor cells towards oncogenesis.	('oncogenesis', 'CPA', (109, 120))	('ncRNA', 'Gene', '220202', (55, 60))	('driving', 'Reg', (76, 83))	('dysregulation', 'Var', (38, 51))	('ncRNA', 'Gene', (55, 60))
344775	31616462	However, genetic mutations of protein-coding genes are only one way in which disruptions of miRNA processing can be revealed.	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('genetic mutations', 'Var', (9, 26))
344843	26742032	However, the comparative study of perillyl alcohol and perillaldehyde 8,9-epoxide against three human tumor cell lines in vitro showed that perillaldehyde 8,9-epoxide exhibited a higher inhibition percentage in all cell lines tested as compared to perillyl alcohol.	('perillaldehyde 8,9-epoxide', 'Chemical', 'MESH:C000611748', (55, 81))	('inhibition', 'NegReg', (186, 196))	('human', 'Species', '9606', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('perillaldehyde 8,9-epoxide', 'Chemical', 'MESH:C000611748', (140, 166))	('perillyl alcohol', 'Chemical', 'MESH:C032208', (34, 50))	('perillaldehyde', 'Var', (140, 154))	('tumor', 'Disease', (102, 107))	('perillyl alcohol', 'Chemical', 'MESH:C032208', (248, 264))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
344861	26742032	Interestingly, the AST values presented by the groups of mice inoculated with S-180 are higher than the values of the healthy mice groups.	('mice', 'Species', '10090', (57, 61))	('higher', 'PosReg', (88, 94))	('S-180', 'Var', (78, 83))	('mice', 'Species', '10090', (126, 130))	('AST', 'Gene', '235504', (19, 22))	('AST', 'Gene', (19, 22))
344922	25685232	Pain, touch and temperature modalities were diminished in C6-T1 dermatomes.	('C6-T1', 'Var', (58, 63))	('diminished', 'NegReg', (44, 54))	('Pain', 'Phenotype', 'HP:0012531', (0, 4))	('Pain', 'Disease', 'MESH:D010146', (0, 4))	('Pain', 'Disease', (0, 4))
345016	22294416	We also show that knockdown of ROR2 significantly reduces tumour mass in vivo using a xenotransplantation model of LMS.	('knockdown', 'Var', (18, 27))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('ROR2', 'Gene', (31, 35))	('LMS', 'Phenotype', 'HP:0100243', (115, 118))	('ROR2', 'Gene', '4920', (31, 35))	('tumour', 'Disease', (58, 64))	('reduces', 'NegReg', (50, 57))
345023	22294416	Over the past 20 years, deregulation of RTKs has been shown to play critical roles in cancer development and progression.	('progression', 'CPA', (109, 120))	('deregulation', 'Var', (24, 36))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('RTKs', 'Protein', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
345025	22294416	ROR2 expression is required to mediate the migration of cells during palate development in mammals, and mutations in the ROR2 gene have been shown to cause diseases such as brachydactyly type B and autosomal recessive Robinow syndrome.	('mutations', 'Var', (104, 113))	('Robinow syndrome', 'Phenotype', 'HP:0000201', (218, 234))	('cause', 'Reg', (150, 155))	('ROR2', 'Gene', (0, 4))	('brachydactyly type B', 'Disease', 'MESH:C566196', (173, 193))	('ROR2', 'Gene', '4920', (0, 4))	('autosomal recessive Robinow syndrome', 'Disease', 'MESH:C562492', (198, 234))	('autosomal recessive Robinow syndrome', 'Disease', (198, 234))	('ROR2', 'Gene', (121, 125))	('ROR2', 'Gene', '4920', (121, 125))	('brachydactyly type B', 'Disease', (173, 193))	('brachydactyly', 'Phenotype', 'HP:0001156', (173, 186))
345039	22294416	LMS05 and GIST48 cells transfected with pooled siRNAs targeting ROR2 (siROR2) showed approximately a 70% reduction in ROR2 mRNA levels 48h after transfection whereas cells treated with control non-targeting siRNAs (siNT) showed no reduction in ROR2 expression; ROR2 levels remained undetectable in LMS04 upon siNT and siROR2 treatment (Fig.	('LMS', 'Phenotype', 'HP:0100243', (0, 3))	('ROR2', 'Gene', (64, 68))	('ROR2', 'Gene', (244, 248))	('ROR2', 'Gene', '4920', (244, 248))	('ROR2', 'Gene', '4920', (261, 265))	('ROR2', 'Gene', '4920', (320, 324))	('reduction', 'NegReg', (105, 114))	('ROR2', 'Gene', (72, 76))	('ROR2', 'Gene', (261, 265))	('ROR2', 'Gene', (320, 324))	('GIST', 'Phenotype', 'HP:0100723', (10, 14))	('ROR2', 'Gene', '4920', (72, 76))	('ROR2', 'Gene', '4920', (118, 122))	('LMS', 'Phenotype', 'HP:0100243', (298, 301))	('ROR2', 'Gene', (118, 122))	('ROR2', 'Gene', '4920', (64, 68))	('targeting', 'Var', (54, 63))
345058	22294416	In GIST, tumors with high ROR2 expression were associated with decreased overall survival rates when compared to cases that expressed ROR2 weakly or not at all (HR = 1.417, CI: 1.060 to 1.893, P = 0.0186; Fig.	('ROR2', 'Gene', '4920', (26, 30))	('ROR2', 'Gene', (26, 30))	('ROR2', 'Gene', '4920', (134, 138))	('ROR2', 'Gene', (134, 138))	('decreased', 'NegReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('high', 'Var', (21, 25))	('GIST', 'Phenotype', 'HP:0100723', (3, 7))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('expression', 'MPA', (31, 41))	('overall survival rates', 'MPA', (73, 95))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
345061	22294416	Experimental and clinical studies have shown that the deregulated RTKs can play important roles in cancer development and progression.	('deregulated', 'Var', (54, 65))	('RTKs', 'Protein', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('progression', 'CPA', (122, 133))	('play', 'Reg', (75, 79))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('roles', 'Reg', (90, 95))
345070	22294416	Similar to results shown for melanoma, osteosarcoma, and RCC cell lines, inhibition of ROR2 expression strongly decreased the in vitro invasiveness of two ROR2-positive LMS and GIST cell lines.	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('decreased', 'NegReg', (112, 121))	('LMS', 'Phenotype', 'HP:0100243', (169, 172))	('ROR2', 'Gene', (155, 159))	('ROR2', 'Gene', '4920', (155, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (39, 51))	('inhibition', 'Var', (73, 83))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('invasiveness of two', 'CPA', (135, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('GIST', 'Phenotype', 'HP:0100723', (177, 181))	('ROR2', 'Gene', '4920', (87, 91))	('ROR2', 'Gene', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('osteosarcoma', 'Disease', (39, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (39, 51))
345079	22294416	The majority of GIST tumors show activation of the tyrosine kinase proteins KIT or PDGFRa and specific mutations in the genes transcribing these proteins predict response to the tyrosine kinase inhibitor imatinib and other small molecule therapies.	('mutations', 'Var', (103, 112))	('PDGFRa', 'Gene', (83, 89))	('activation', 'PosReg', (33, 43))	('GIST tumors', 'Disease', 'MESH:D046152', (16, 27))	('GIST', 'Phenotype', 'HP:0100723', (16, 20))	('GIST tumors', 'Disease', (16, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('imatinib', 'Chemical', 'MESH:D000068877', (204, 212))	('PDGFRa', 'Gene', '5156', (83, 89))	('response to the tyrosine kinase inhibitor imatinib', 'MPA', (162, 212))
345081	22294416	In summary, ROR2 is highly expressed in a subset of LMS, GIST, and DTF cases and high ROR2 protein expression is significantly associated with poor clinical outcome in patients with LMS and GIST.	('expression', 'MPA', (99, 109))	('associated with', 'Reg', (127, 142))	('GIST', 'Phenotype', 'HP:0100723', (57, 61))	('LMS', 'Disease', (52, 55))	('high', 'Var', (81, 85))	('LMS', 'Phenotype', 'HP:0100243', (52, 55))	('GIST', 'Phenotype', 'HP:0100723', (190, 194))	('protein', 'Protein', (91, 98))	('ROR2', 'Gene', (86, 90))	('patients', 'Species', '9606', (168, 176))	('ROR2', 'Gene', '4920', (86, 90))	('LMS', 'Disease', (182, 185))	('ROR2', 'Gene', '4920', (12, 16))	('LMS', 'Phenotype', 'HP:0100243', (182, 185))	('ROR2', 'Gene', (12, 16))
345097	22294416	LMS04, LMS05, and GIST48 cells were derived from primary clinical specimens (LMS04: retroperitoneal lesion that spread from primary uterine LMS tumor; LMS05: primary thigh LMS tumor; GIST48: primary GIST with homozygous exon 11 KIT mutation (V560D) and heterozygous exon 17 KIT mutation (D820A)).	('LMS', 'Phenotype', 'HP:0100243', (0, 3))	('LMS', 'Phenotype', 'HP:0100243', (151, 154))	('LMS', 'Phenotype', 'HP:0100243', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('LMS tumor', 'Disease', (140, 149))	('V560D', 'Var', (242, 247))	('D820A', 'Mutation', 'p.D820A', (288, 293))	('LMS tumor', 'Disease', (172, 181))	('LMS', 'Phenotype', 'HP:0100243', (77, 80))	('V560D', 'Mutation', 'rs121913521', (242, 247))	('GIST', 'Phenotype', 'HP:0100723', (199, 203))	('GIST', 'Phenotype', 'HP:0100723', (183, 187))	('GIST', 'Phenotype', 'HP:0100723', (18, 22))	('LMS tumor', 'Disease', 'MESH:C535903', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('LMS tumor', 'Disease', 'MESH:C535903', (172, 181))	('LMS', 'Phenotype', 'HP:0100243', (7, 10))
345142	22606423	It is common in patients with M2, M4, or M5 class of French-American British (FAB) classification.	('FAB', 'Chemical', '-', (78, 81))	('common', 'Reg', (6, 12))	('patients', 'Species', '9606', (16, 24))	('M5 class', 'Var', (41, 49))
345219	32195970	Copy number gains and overexpression of mouse double minute 2 homolog (MDM2) and cyclin dependent kinase 4 (CDK4) were observed in the primary lesion, and additional gene amplification of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), Succinate Dehydrogenase Complex II subunit C (SDHC), and thyroid stimulating hormone receptor (TSHR) Q720H were found in the recurrent tumors.	('mouse double minute 2 homolog', 'Gene', (40, 69))	('mouse double minute 2 homolog', 'Gene', '17246', (40, 69))	('Q720H', 'Mutation', 'p.Q720H', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('overexpression', 'PosReg', (22, 36))	('thyroid stimulating hormone receptor', 'Gene', '22095', (297, 333))	('MDM2', 'Gene', (71, 75))	('gains', 'PosReg', (12, 17))	('cyclin dependent kinase 4', 'Gene', '12567', (81, 106))	('tumors', 'Disease', (375, 381))	('SDHC', 'Gene', (286, 290))	('Q720H', 'Var', (341, 346))	('tumors', 'Disease', 'MESH:D009369', (375, 381))	('tumors', 'Phenotype', 'HP:0002664', (375, 381))	('CDK4', 'Gene', (108, 112))	('cyclin dependent kinase 4', 'Gene', (81, 106))	('thyroid stimulating hormone receptor', 'Gene', (297, 333))	('DDR2', 'Gene', (233, 237))
345224	32195970	Clinically, tumors >3 cm with focal and vascular invasion and nuclear pleomorphism are suggestive of malignant behavior and poor prognosis.	('malignant behavior', 'Disease', (101, 119))	('nuclear pleomorphism', 'Var', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('malignant behavior', 'Disease', 'MESH:D009369', (101, 119))
345226	32195970	We hypothesized that genetic changes determined the malignancy of the lesion and could serve as a reference to elucidate their prognosis.	('determined', 'Reg', (37, 47))	('changes', 'Var', (29, 36))	('malignancy of the lesion', 'Disease', (52, 76))	('malignancy of the lesion', 'Disease', 'MESH:D009369', (52, 76))
345240	32195970	The kit was used to detect mutations in 409 genes related to cancer diagnosis and prognosis.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
345241	32195970	Staining was performed as per the standard protocol using following primary antibodies: anti-ALK antibody (Zymed, San Francisco, CA; 1:100 dilution), anti-MDM2 antibody (Santa Cruz Biotechnology, Santa Cruz, CA; 1:50 dilution), and anti-CDK4 (Santa Cruz Biotechnology, Santa Cruz, CA; 1:50 dilution).	('anti-CDK4', 'Var', (232, 241))	('ALK', 'Gene', '238', (93, 96))	('ALK', 'Gene', (93, 96))	('anti-MDM2', 'Var', (150, 159))
345246	32195970	Massively parallel sequencing for a panel of 409 cancer-related genes identified 6 germline mutations (PARP1 p.V69I, ATR p.S1007N, GRM8 p.T97A, MLLT10 p.G409R, TCF7L2 p.N185S, SMARCA4 p.A321T) and 1 somatic mutation (TSHR p.Q720H) in the recurrent IMT samples (Table 1).	('p.Q720H', 'Mutation', 'p.Q720H', (222, 229))	('SMARCA4', 'Gene', (176, 183))	('p.T97A', 'Var', (136, 142))	('cancer', 'Disease', (49, 55))	('p.G409R', 'Var', (151, 158))	('p.A321T', 'Mutation', 'rs1344296942', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('MLLT10', 'Gene', '8028', (144, 150))	('p.Q720H', 'Var', (222, 229))	('ATR', 'Gene', (117, 120))	('PARP1', 'Gene', (103, 108))	('p.T97A', 'Mutation', 'rs557753346', (136, 142))	('p.G409R', 'Mutation', 'rs573639267', (151, 158))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('p.V69I', 'Var', (109, 115))	('SMARCA4', 'Gene', '6597', (176, 183))	('TCF7L2', 'Gene', (160, 166))	('p.N185S', 'Mutation', 'rs778461209', (167, 174))	('p.A321T', 'Var', (184, 191))	('TCF7L2', 'Gene', '6934', (160, 166))	('MLLT10', 'Gene', (144, 150))	('p.S1007N', 'Var', (121, 129))	('p.N185S', 'Var', (167, 174))	('ATR', 'Gene', '545', (117, 120))	('p.S1007N', 'Mutation', 'rs531735564', (121, 129))	('p.V69I', 'Mutation', 'rs762887304', (109, 115))
345247	32195970	Copy number analysis revealed copy number gains for cyclin dependent kinase 4 (CDK4) and mouse double minute 2 homolog (MDM2) in the primary IMT, and of CDK4, MDM2, Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), and Succinate Dehydrogenase Complex II subunit C (SDHC) in the recurrent IMT (Fig.	('MDM2', 'Gene', (159, 163))	('cyclin dependent kinase 4', 'Gene', (52, 77))	('CDK4', 'Gene', (153, 157))	('mouse double minute 2 homolog', 'Gene', (89, 118))	('mouse double minute 2 homolog', 'Gene', '17246', (89, 118))	('copy', 'Var', (30, 34))	('CDK4', 'Gene', (79, 83))	('cyclin dependent kinase 4', 'Gene', '12567', (52, 77))	('SDHC', 'Gene', (267, 271))	('DDR2', 'Gene', (210, 214))	('gains', 'PosReg', (42, 47))
345248	32195970	In the recurrent lesion that occurred after 8 years of the radiotherapy, copy number amplification was observed for CDK4, MDM2, DDR2, and SDHC gene loci, and 1 new mutation was identified at TSHR p.Q720H.	('DDR2', 'Gene', (128, 132))	('p.Q720H', 'Mutation', 'p.Q720H', (196, 203))	('SDHC', 'Gene', (138, 142))	('MDM2', 'Gene', (122, 126))	('CDK4', 'Gene', (116, 120))	('copy number', 'MPA', (73, 84))	('p.Q720H', 'Var', (196, 203))
345249	32195970	Cytogenetic studies have shown that the rearrangement and overexpression of the ALK gene are the most frequent molecular abnormalities in 34% to 70% of IMTs.	('rearrangement', 'Var', (40, 53))	('frequent', 'Reg', (102, 110))	('ALK', 'Gene', '238', (80, 83))	('overexpression', 'PosReg', (58, 72))	('ALK', 'Gene', (80, 83))
345252	32195970	In our case, the primary IMT exhibited copy number gain and positive immunoreactivity for MDM2 and CDK4, the well-established biomarkers for well-differentiated and dedifferentiated liposarcomas (WDLS and DDLS).	('immunoreactivity', 'MPA', (69, 85))	('positive', 'PosReg', (60, 68))	('gain', 'PosReg', (51, 55))	('copy number', 'Var', (39, 50))	('liposarcomas', 'Phenotype', 'HP:0012034', (182, 194))	('liposarcoma', 'Phenotype', 'HP:0012034', (182, 193))	('CDK4', 'Gene', (99, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('liposarcomas', 'Disease', 'MESH:D008080', (182, 194))	('liposarcomas', 'Disease', (182, 194))	('MDM2', 'Gene', (90, 94))
345258	32195970	Although rare, radiotherapy has been reported to induce inflammatory changes and lead to IMT or sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('lead to', 'Reg', (81, 88))	('radiotherapy', 'Var', (15, 27))	('induce', 'Reg', (49, 55))	('inflammatory changes', 'CPA', (56, 76))	('IMT', 'Disease', (89, 92))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('sarcoma', 'Disease', (96, 103))
345264	32195970	It remains to be elucidated whether radiation therapy had any role to play in the newly developed SDHC gene amplification and TSHR p.Q720H mutation in recurring tumors.	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('TSHR', 'Gene', (126, 130))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('p.Q720H', 'Var', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('p.Q720H', 'Mutation', 'p.Q720H', (131, 138))	('SDHC', 'Gene', (98, 102))
345307	32214419	Alkylation and oxidation of compound 37 lead to nucleosides 38 and 39, respectively.	('nucleosides 38', 'MPA', (48, 62))	('lead to', 'Reg', (40, 47))	('Alkylation', 'Var', (0, 10))	('nucleosides', 'Chemical', 'MESH:D009705', (48, 59))	('Al', 'Chemical', 'MESH:D000535', (0, 2))	('oxidation', 'Var', (15, 24))
345385	32214419	The methylation of compound 126 led to the methylsulfanyl derivative 127.	('methylsulfanyl derivative 127', 'MPA', (43, 72))	('led to', 'Reg', (32, 38))	('methylsulfanyl', 'Chemical', '-', (43, 57))	('methylation', 'Var', (4, 15))
345478	30422399	CRISPR/Cas9-mediated K-Ras depletion suppressed the malignant phenotype and prevented these synergic toxicities in these murine cells.	('toxicities', 'Disease', (101, 111))	('K-Ras', 'Protein', (21, 26))	('malignant phenotype', 'CPA', (52, 71))	('depletion', 'Var', (27, 36))	('prevented', 'NegReg', (76, 85))	('murine', 'Species', '10090', (121, 127))	('toxicities', 'Disease', 'MESH:D064420', (101, 111))	('suppressed', 'NegReg', (37, 47))
345484	30422399	For instance, gain-of-function mutations and overexpression of RAS family members (KRAS, HRAS, and NRAS) are among the most prevalent oncogenic lesions in human cancers (Prior et al., 2012), and high levels of Ras activity are necessary to maintain the transformed phenotype in some Ras-driven cancers (Singh et al., 2009).	('KRAS', 'Gene', (83, 87))	('HRAS', 'Gene', (89, 93))	('mutations', 'Var', (31, 40))	('KRAS', 'Gene', '3845', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('human', 'Species', '9606', (155, 160))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', (294, 301))	('NRAS', 'Gene', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('gain-of-function', 'PosReg', (14, 30))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('NRAS', 'Gene', '4893', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('HRAS', 'Gene', '3265', (89, 93))	('overexpression', 'PosReg', (45, 59))
345497	30422399	Despite the many different protumor roles attributed to FGF2 signaling (reviewed by Turner and Grose, 2010), a set of articles unequivocally demonstrate that FGF2 can also induce cytostatic and cytotoxic responses in different cancer cells, both in vivo and in vitro (Fogarty et al., 2007; Sturla et al., 2000; Wang et al., 1998; Williamson et al., 2004).	('FGF2', 'Var', (158, 162))	('rat', 'Species', '10116', (148, 151))	('induce', 'PosReg', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('tumor', 'Disease', (30, 35))
345501	30422399	We found that in K-Ras-driven mouse Y1 malignant cells FGF2 stimulation disrupts proteostasis and enhances tonic replication stress and DNA damage response (DDR) activation.	('DNA damage response', 'MPA', (136, 155))	('disrupts proteostasis', 'Disease', 'MESH:D057165', (72, 93))	('tonic replication stress', 'MPA', (107, 131))	('enhances', 'PosReg', (98, 106))	('FGF2', 'Gene', (55, 59))	('stimulation', 'Var', (60, 71))	('disrupts proteostasis', 'Disease', (72, 93))	('activation', 'PosReg', (162, 172))	('mouse', 'Species', '10090', (30, 35))
345506	30422399	The Y1D1 subline (Schwindt et al., 2003) was cultured in the same conditions as Y1, and the growth medium was supplemented with 0.1 mg mL-1 geneticin (G418; Invitrogen, Carlsbad, CA, USA).	('mL-1', 'Gene', (135, 139))	('mL-1', 'Gene', '23961', (135, 139))	('G418;', 'Var', (151, 156))
345510	30422399	Where indicated, cells were treated with recombinant human FGF2 protein (Abcam ab9596, Cambridge, MA, USA); colchicine (Sigma C9754, St. Louis, MO, USA); the MEK inhibitor U0126 (Promega V1121, Madison, WI, USA); bortezomib (#S1013); ATM inhibitor KU55933 (#S1092); ATR inhibitor VE-821 (#S8007); p38 inhibitor SB202190 (S1077); and MEK inhibitors selumetinib (#S1008) and trametinib (S2673); all these last inhibitors from Selleckchem (Houston, TX, USA).	('MEK', 'Gene', (158, 161))	('MEK', 'Gene', '5609', (333, 336))	('MEK', 'Gene', '5609', (158, 161))	('VE-821', 'Chemical', 'MESH:C560580', (280, 286))	('ATR', 'Gene', (266, 269))	('ATR', 'Gene', '545', (266, 269))	('U0126', 'Chemical', 'MESH:C113580', (172, 177))	('trametinib', 'Chemical', 'MESH:C560077', (373, 383))	('selumetinib', 'Chemical', 'MESH:C517975', (348, 359))	('bortezomib', 'Chemical', 'MESH:D000069286', (213, 223))	('colchicine', 'Chemical', 'MESH:D003078', (108, 118))	('ATM', 'Gene', (234, 237))	('human', 'Species', '9606', (53, 58))	('S1077', 'Var', (321, 326))	('ATM', 'Gene', '472', (234, 237))	('MEK', 'Gene', (333, 336))
345518	30422399	Antibodies for western blot were as follows: IRE1alpha (3294; Cell signaling, Danvers, MA, USA), Bip (3183; Cell signaling), phospho-S6 Ser235/236 (4856; Cell Signaling), phospho-eIF4E Ser209 (9741; Cell Signaling), alpha-tubulin (sc-8035; Santa Cruz, Santa Cruz, CA, USA), phospho-H2AX S139 (ab11174; Abcam), ChK1 (ab47574; Abcam), phospho-ChK1 S345 (sc-17922; Santa Cruz), phospho-ChK2 T383 (ab59408; Abcam), p38 (9212; Cell Signaling); phospho-p38 T180/Y182 (sc-15852-R; Santa Cruz), p21 (sc-397; Santa Cruz), HPRT (sc-20975; Santa Cruz), K-Ras (sc-30; Santa Cruz), actin (ab6276; Abcam), phospho-ERK Thr202/204 (4370 and 9101; Cell Signaling), and ERK (4695 and 9102; Cell Signaling).	('p21', 'Gene', '644914', (487, 490))	('H2AX', 'Gene', (282, 286))	('HPRT', 'Gene', '3251', (513, 517))	('eIF4E', 'Gene', '1977', (179, 184))	('ERK', 'Gene', '5594', (652, 655))	('ERK', 'Gene', (600, 603))	('H2AX', 'Gene', '3014', (282, 286))	('ChK1 S', 'Gene', '1111', (341, 347))	('ChK2', 'Gene', '11200', (383, 387))	('alpha-tubulin', 'Gene', (216, 229))	('IRE1alpha', 'Gene', '2081', (45, 54))	('ERK', 'Gene', (652, 655))	('ChK1', 'Gene', '1111', (310, 314))	('ChK1', 'Gene', '1111', (341, 345))	('Bip', 'Gene', '2662', (97, 100))	('alpha-tubulin', 'Gene', '10376', (216, 229))	('4370', 'Var', (616, 620))	('ChK2', 'Gene', (383, 387))	('ChK1 S', 'Gene', (341, 347))	('HPRT', 'Gene', (513, 517))	('ChK1', 'Gene', (341, 345))	('ChK1', 'Gene', (310, 314))	('IRE1alpha', 'Gene', (45, 54))	('phospho-p38 T180/Y182', 'Var', (439, 460))	('ERK', 'Gene', '5594', (600, 603))	('eIF4E', 'Gene', (179, 184))	('p21', 'Gene', (487, 490))	('Bip', 'Gene', (97, 100))
345524	30422399	After 10 min, 5 muL of PI 50 mug mL-1 was added to each tube and mixed by inversion.	('PI 50', 'Var', (23, 28))	('mL-1', 'Gene', (33, 37))	('mL-1', 'Gene', '23961', (33, 37))
345556	30422399	Checkpoint inhibition prevents cell cycle arrest induced by DNA damaging chemotherapy, forcing cancer cells into a defective mitosis and consequent cell death (Huntoon et al., 2013).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (31, 48))	('mitosis', 'Disease', (125, 132))	('arrest', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('mitosis', 'Disease', 'None', (125, 132))	('cell cycle', 'CPA', (31, 41))	('cancer', 'Disease', (95, 101))	('inhibition', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('defective', 'NegReg', (115, 124))	('arrest', 'Disease', 'MESH:D006323', (42, 48))
345579	30422399	We next enquired whether K-Ras depletion impacted on viability and proliferation of Y1 cells, as well as its likely protective effect from FGF2 toxicity.	('impacted', 'Reg', (41, 49))	('toxicity', 'Disease', 'MESH:D064420', (144, 152))	('toxicity', 'Disease', (144, 152))	('rat', 'Species', '10116', (74, 77))	('proliferation', 'CPA', (67, 80))	('K-Ras', 'Protein', (25, 30))	('depletion', 'Var', (31, 40))	('viability', 'CPA', (53, 62))
345581	30422399	Conversely, K-Ras depletion restrained the proliferation of Y1 DeltaK cells under nonadherent growth conditions (Fig.	('rat', 'Species', '10116', (50, 53))	('restrained', 'NegReg', (28, 38))	('depletion', 'Var', (18, 27))	('proliferation', 'CPA', (43, 56))	('K-Ras', 'Protein', (12, 17))
345582	30422399	This set of results shows that K-Ras depletion elicited robust survival and proliferation in solid substrate but suppressed some malignant phenotype traits in this cell model.	('elicited', 'Reg', (47, 55))	('rat', 'Species', '10116', (83, 86))	('suppressed', 'NegReg', (113, 123))	('depletion', 'Var', (37, 46))	('malignant phenotype traits in this', 'CPA', (129, 163))	('survival', 'CPA', (63, 71))	('K-Ras', 'Protein', (31, 36))	('proliferation in solid substrate', 'CPA', (76, 108))	('rat', 'Species', '10116', (104, 107))
345585	30422399	The results for Y1-scb cells, as expected, were similar to those shown for Y1 parental cells, with the combinations of FGF2 with VE-821 or bortezomib inducing about 40% and 30% of cell death, respectively (Fig.	('FGF2', 'Gene', (119, 123))	('inducing', 'Reg', (150, 158))	('VE-821', 'Chemical', 'MESH:C560580', (129, 135))	('combinations', 'Var', (103, 115))	('cell death', 'CPA', (180, 190))	('bortezomib', 'Chemical', 'MESH:D000069286', (139, 149))
345586	30422399	On the other hand, in Y1DeltaK cells, K-Ras depletion largely prevented the cell death induced by the combinations of FGF2 and VE-821 (Fig.	('combinations', 'Interaction', (102, 114))	('depletion', 'Var', (44, 53))	('K-Ras', 'Protein', (38, 43))	('prevented', 'NegReg', (62, 71))	('VE-821', 'Chemical', 'MESH:C560580', (127, 133))	('cell death', 'CPA', (76, 86))	('VE-821', 'Gene', (127, 133))	('FGF2', 'Gene', (118, 122))
345588	30422399	To address the effects of these toxicities on long-term cell viability, we treated both cells using the same regimens described above, washed out FGF2 and the inhibitors, and cultured the cells for additional 10 days.	('FGF2', 'Gene', (146, 150))	('washed', 'Var', (135, 141))	('toxicities', 'Disease', (32, 42))	('toxicities', 'Disease', 'MESH:D064420', (32, 42))
345589	30422399	In agreement with the flow cytometry results, combinations of FGF2 and VE-821 or bortezomib strongly reduced the long-term viability of Y1-scb cells (Fig.	('bortezomib', 'Chemical', 'MESH:D000069286', (81, 91))	('VE-821', 'Chemical', 'MESH:C560580', (71, 77))	('VE-821', 'Gene', (71, 77))	('FGF2', 'Gene', (62, 66))	('reduced', 'NegReg', (101, 108))	('combinations', 'Var', (46, 58))	('long-term viability', 'CPA', (113, 132))
345603	30422399	While the association of FGF2 and KU-55933 resulted in significant increased toxicity only in A673 cells (Fig.	('toxicity', 'Disease', 'MESH:D064420', (77, 85))	('toxicity', 'Disease', (77, 85))	('association', 'Interaction', (10, 21))	('FGF2', 'Gene', (25, 29))	('increased', 'PosReg', (67, 76))	('KU-55933', 'Var', (34, 42))
345606	30422399	We treated A673, SK-N-MC, and TC-32 cells as described above, washed out FGF2 and the inhibitors, and cultured the cells for additional 10 days.	('FGF2', 'Gene', (73, 77))	('SK-N-MC', 'CellLine', 'CVCL:0530', (17, 24))	('washed', 'Var', (62, 68))	('TC-32', 'CellLine', 'CVCL:7151', (30, 35))
345614	30422399	Coherently, K-Ras depletion, which we showed above to protect from FGF2 toxicity and sensitization to proteasome and checkpoint inhibition, also prevented sustained MAPK overactivation in Y1DeltaK cells (Fig.	('MAPK', 'Protein', (165, 169))	('prevented', 'NegReg', (145, 154))	('depletion', 'Var', (18, 27))	('toxicity', 'Disease', 'MESH:D064420', (72, 80))	('toxicity', 'Disease', (72, 80))	('overactivation', 'MPA', (170, 184))	('FGF2', 'Gene', (67, 71))
345618	30422399	The results showed that U0126 poorly alleviates the sustained MAPK-ERK1/2 activation induced by FGF2 in Y1 and ESFT cells, comparing to selumetinib and trametinib (Fig.	('alleviates', 'NegReg', (37, 47))	('U0126', 'Chemical', 'MESH:C113580', (24, 29))	('FGF2', 'Gene', (96, 100))	('activation', 'PosReg', (74, 84))	('U0126', 'Var', (24, 29))	('selumetinib', 'Chemical', 'MESH:C517975', (136, 147))	('trametinib', 'Chemical', 'MESH:C560077', (152, 162))	('MAPK-ERK1/2', 'Enzyme', (62, 73))
345631	30422399	Many different mechanisms by which growth factors' mitogenic signaling pathways contribute to the malignant progression have been emphasized in the cancer literature, and gain-of-function mutations along these mitogenic pathways are recognized driver oncogenic lesions in most human cancers.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancers', 'Disease', 'MESH:D009369', (283, 290))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('malignant progression', 'CPA', (98, 119))	('cancers', 'Disease', (283, 290))	('cancer', 'Disease', (283, 289))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gain-of-function', 'PosReg', (171, 187))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('mutations', 'Var', (188, 197))	('rat', 'Species', '10116', (159, 162))	('human', 'Species', '9606', (277, 282))
345641	30422399	Moreover, transgenic mice overexpressing FGF2 in all major organs developed into old age showing no increased tumorigenesis (Coffin et al., 1995).	('FGF2', 'Gene', (41, 45))	('overexpressing', 'Var', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('transgenic mice', 'Species', '10090', (10, 25))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
345662	30422399	It is noteworthy that FGF2 stimulation increased the activation of checkpoint proteins, reactivating this anticancer barrier and restraining cell proliferation in this K-Ras-driven model.	('FGF2', 'Gene', (22, 26))	('cancer', 'Disease', (110, 116))	('checkpoint proteins', 'Protein', (67, 86))	('rat', 'Species', '10116', (153, 156))	('reactivating', 'PosReg', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cell proliferation', 'CPA', (141, 159))	('restraining', 'NegReg', (129, 140))	('increased', 'PosReg', (39, 48))	('activation', 'MPA', (53, 63))	('stimulation', 'Var', (27, 38))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
345673	30422399	This scenario is supported by our data showing not only that FGF2 induced sustained higher levels of active ERK1/2, but also that MAPK inhibition, even 8 h after FGF2 stimulus, restored cell homeostasis and rescued ESFT and Y1 cells from the synergic toxicities which we described above.	('MAPK', 'Gene', (130, 134))	('inhibition', 'NegReg', (135, 145))	('higher', 'PosReg', (84, 90))	('cell homeostasis', 'MPA', (186, 202))	('toxicities', 'Disease', 'MESH:D064420', (251, 261))	('levels', 'MPA', (91, 97))	('rescued', 'Reg', (207, 214))	('restored', 'PosReg', (177, 185))	('FGF2', 'Var', (61, 65))	('toxicities', 'Disease', (251, 261))
345686	29358035	The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression.	('FLI', 'Gene', '2314', (78, 81))	('FLI', 'Gene', (78, 81))	('synthetic', 'Species', '2086595', (113, 122))	('FLI', 'Gene', '2314', (183, 186))	('THZ531', 'Var', (34, 40))	('impairs', 'NegReg', (42, 49))	('THZ531', 'Chemical', 'MESH:C000618758', (34, 40))	('DNA damage repair', 'MPA', (50, 67))	('THZ531', 'Chemical', 'MESH:C000618758', (168, 174))	('FLI', 'Gene', (183, 186))	('THZ1', 'Chemical', '-', (163, 167))
345688	29358035	find that inhibition of CDK12 is synthetic lethal with EWS/FLI expression.	('synthetic', 'Species', '2086595', (33, 42))	('FLI', 'Gene', '2314', (59, 62))	('FLI', 'Gene', (59, 62))	('inhibition', 'Var', (10, 20))	('CDK12', 'Gene', (24, 29))
345689	29358035	CDK12/13 inhibitors impair DNA damage repair in cells expressing EWS/FLI, and the combination of CDK12/13 and PARP inhibitors synergistically reduces tumor growth and extends survival in Ewing sarcoma mouse models.	('survival', 'CPA', (175, 183))	('DNA damage repair', 'MPA', (27, 44))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('Ewing sarcoma', 'Disease', (187, 200))	('impair', 'NegReg', (20, 26))	('FLI', 'Gene', (69, 72))	('extends', 'PosReg', (167, 174))	('FLI', 'Gene', '2314', (69, 72))	('reduces', 'NegReg', (142, 149))	('CDK12/13', 'Gene', (97, 105))	('inhibitors', 'Var', (115, 125))	('tumor', 'Disease', (150, 155))	('CDK12/13', 'Gene', (0, 8))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (187, 200))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (187, 200))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('PARP', 'Gene', (110, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('mouse', 'Species', '10090', (201, 206))	('inhibitors', 'Var', (9, 19))
345695	29358035	One approach to treating these tumors is the direct targeting of the aberrant transcription factor.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('aberrant', 'Var', (69, 77))	('tumors', 'Disease', 'MESH:D009369', (31, 37))
345699	29358035	These studies provided rationale for an inroad into treating cancers defined by aberrant transcription factors.	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('aberrant', 'Var', (80, 88))
345712	29358035	Furthermore, THZ1 induced apoptosis as demonstrated by an increase in the percentage of Annexin V+ cells and PARP cleavage (Figure 1C, D) and strongly decreased the colony formation capacity of Ewing sarcoma cell lines (Figure 1E).	('increase', 'PosReg', (58, 66))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (194, 207))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (194, 207))	('PARP cleavage', 'CPA', (109, 122))	('THZ1', 'Chemical', '-', (13, 17))	('THZ1', 'Var', (13, 17))	('decreased', 'NegReg', (151, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('Annexin V', 'Gene', '308', (88, 97))	('Annexin V', 'Gene', (88, 97))	('Ewing sarcoma', 'Disease', (194, 207))
345718	29358035	We identified that CDK7 disruption is pan-lethal with the depletion of guides targeting CDK7 similar to the depletion seen for known common essential genes in the screen, raising some concerns about the therapeutic window of a potent CDK7 inhibitor (Figure S2A).	('CDK7', 'Gene', '1022', (234, 238))	('CDK7', 'Gene', (19, 23))	('CDK7', 'Gene', (88, 92))	('disruption', 'Var', (24, 34))	('CDK7', 'Gene', '1022', (19, 23))	('CDK7', 'Gene', (234, 238))	('CDK7', 'Gene', '1022', (88, 92))	('depletion', 'MPA', (58, 67))
345721	29358035	Among the CDK12 dependent cell lines was SK-N-MC, the one Ewing sarcoma cell line included in the screen harboring an EWS/FLI rearrangement, with three of the 11 neuroblastoma cell lines included in the screen scoring between -0.4 and -0.5.	('neuroblastoma', 'Disease', (162, 175))	('rearrangement', 'Var', (126, 139))	('SK-N-MC', 'CellLine', 'CVCL:0530', (41, 48))	('FLI', 'Gene', '2314', (122, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('neuroblastoma', 'Phenotype', 'HP:0003006', (162, 175))	('FLI', 'Gene', (122, 125))	('Ewing sarcoma', 'Disease', (58, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (58, 71))	('neuroblastoma', 'Disease', 'MESH:D009447', (162, 175))
345728	29358035	The authors reported that THZ531 inhibits CDK12 and CDK13 with IC50 concentrations of 158 nM and 69 nM, respectively, whereas, THZ531 inhibits CDK7 and CDK9 at 8.5 microM and 10.5 microM, respectively.	('inhibits', 'NegReg', (134, 142))	('CDK9', 'Gene', (152, 156))	('CDK13', 'Gene', (52, 57))	('CDK9', 'Gene', '1025', (152, 156))	('CDK13', 'Gene', '8621', (52, 57))	('THZ531', 'Chemical', 'MESH:C000618758', (26, 32))	('THZ531', 'Var', (26, 32))	('CDK7', 'Gene', (143, 147))	('CDK12', 'Gene', (42, 47))	('inhibits', 'NegReg', (33, 41))	('THZ531', 'Chemical', 'MESH:C000618758', (127, 133))	('THZ531', 'Var', (127, 133))	('CDK7', 'Gene', '1022', (143, 147))
345730	29358035	In order to identify which kinase target of THZ1 is primarily responsible for the potent anti-viability effects observed, we treated a panel of Ewing sarcoma cell lines with three compounds: THZ1, a pan CDK7/12/13 inhibitor; THZ531, a CDK12/13 selective inhibitor; and THZ531R, a non-cysteine reactive analog with reduced anti-CDK12/13 activity (Figure 2A).	('THZ1', 'Var', (191, 195))	('THZ531', 'Chemical', 'MESH:C000618758', (269, 275))	('THZ1', 'Chemical', '-', (44, 48))	('CDK7', 'Gene', '1022', (203, 207))	('Ewing sarcoma', 'Disease', (144, 157))	('THZ531', 'Var', (225, 231))	('anti-CDK12/13', 'MPA', (322, 335))	('THZ531', 'Chemical', 'MESH:C000618758', (225, 231))	('cysteine', 'Chemical', 'MESH:D003545', (284, 292))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (144, 157))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (144, 157))	('THZ531R', 'Chemical', '-', (269, 276))	('CDK7', 'Gene', (203, 207))	('THZ531R', 'Var', (269, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('THZ1', 'Chemical', '-', (191, 195))
345731	29358035	We found that Ewing sarcoma cell lines were nearly as sensitive to THZ531 as they were to THZ1, with IC50 concentrations in the low nanomolar range with both small molecules in viability assays (Figure 2A and Table S2).	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('THZ531', 'Chemical', 'MESH:C000618758', (67, 73))	('THZ531', 'Var', (67, 73))	('Ewing sarcoma', 'Disease', (14, 27))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (14, 27))	('THZ1', 'Chemical', '-', (90, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (14, 27))
345733	29358035	Additionally, Ewing sarcoma cell lines were completely insensitive to THZ531R (Figure 2A).	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('Ewing sarcoma', 'Disease', (14, 27))	('THZ531R', 'Chemical', '-', (70, 77))	('THZ531R', 'Var', (70, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (14, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (14, 27))
345734	29358035	Furthermore, Ewing sarcoma cell lines were 3-10-fold more sensitive to THZ1 and THZ531 than non-EWS/FLI expressing osteosarcoma cell lines (Figure 2A and Table S2), suggesting that sensitivity to CDK7/12/13 inhibition may be enhanced in EWS/FLI rearranged cells.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('THZ531', 'Chemical', 'MESH:C000618758', (80, 86))	('FLI', 'Gene', '2314', (241, 244))	('Ewing sarcoma', 'Disease', (13, 26))	('THZ1', 'Chemical', '-', (71, 75))	('FLI', 'Gene', '2314', (100, 103))	('FLI', 'Gene', (241, 244))	('osteosarcoma', 'Disease', (115, 127))	('FLI', 'Gene', (100, 103))	('CDK7', 'Gene', (196, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (115, 127))	('enhanced', 'PosReg', (225, 233))	('osteosarcoma', 'Disease', 'MESH:D012516', (115, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))	('rearranged', 'Var', (245, 255))	('CDK7', 'Gene', '1022', (196, 200))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))
345735	29358035	Interestingly, all ten Ewing sarcoma cell lines tested were uniformly sensitive to THZ1 and THZ531, indicating that CDK12/13 inhibition may be broadly effective as a treatment strategy for Ewing tumors defined by EWS/FLI rearrangements (Table S2).	('Ewing tumors', 'Disease', (189, 201))	('Ewing sarcoma', 'Disease', (23, 36))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('CDK12/13', 'Protein', (116, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (23, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (23, 36))	('FLI', 'Gene', '2314', (217, 220))	('Ewing tumors', 'Disease', 'MESH:C563168', (189, 201))	('THZ531', 'Chemical', 'MESH:C000618758', (92, 98))	('rearrangements', 'Var', (221, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('FLI', 'Gene', (217, 220))	('THZ1', 'Chemical', '-', (83, 87))	('Ewing tumors', 'Phenotype', 'HP:0012254', (189, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('inhibition', 'NegReg', (125, 135))
345736	29358035	To confirm the selectivity of these compounds in Ewing sarcoma cells, we performed THZ1-biotin immunoprecipitation of samples treated with THZ1 or THZ531 and probed for Cyclin K (binding partner of CDK12/13) or Cyclin H (binding partner of CDK7).	('Cyclin H', 'Gene', (211, 219))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('THZ1', 'Var', (139, 143))	('CDK7', 'Gene', '1022', (240, 244))	('THZ1', 'Chemical', '-', (139, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('Cyclin K', 'Gene', '8812', (169, 177))	('Cyclin H', 'Gene', '902', (211, 219))	('Cyclin K', 'Gene', (169, 177))	('Ewing sarcoma', 'Disease', (49, 62))	('CDK7', 'Gene', (240, 244))	('THZ1', 'Chemical', '-', (83, 87))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))	('THZ531', 'Chemical', 'MESH:C000618758', (147, 153))	('THZ1-biotin', 'Chemical', '-', (83, 94))	('THZ531', 'Var', (147, 153))
345741	29358035	We found that genetic suppression of CDK12 decreased the viability of Ewing sarcoma cells (Figure 2F, G), while in contrast, suppression of CDK13 had a minimal effect (Figure 2F, G).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('CDK13', 'Gene', '8621', (140, 145))	('CDK12', 'Gene', (37, 42))	('viability', 'CPA', (57, 66))	('Ewing sarcoma', 'Disease', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('genetic suppression', 'Var', (14, 33))	('CDK13', 'Gene', (140, 145))	('decreased', 'NegReg', (43, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (70, 83))
345742	29358035	Additionally, CRISPR-Cas9 mediated knockout of CDK12 strongly reduced Ewing sarcoma cell viability (Figure 2H, I).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('CDK12', 'Gene', (47, 52))	('reduced', 'NegReg', (62, 69))	('Ewing sarcoma', 'Disease', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('knockout', 'Var', (35, 43))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (70, 83))
345746	29358035	Consistent with the effects of THZ1, THZ531 reduced the phosphorylation of the RNA Pol II CTD at Ser2 and Ser5, but in contrast, did not strongly reduce the phosphorylation at Ser7 (Figure S2D).	('phosphorylation', 'MPA', (157, 172))	('THZ531', 'Chemical', 'MESH:C000618758', (37, 43))	('THZ531', 'Var', (37, 43))	('RNA', 'Protein', (79, 82))	('Ser2', 'Gene', (97, 101))	('Ser2', 'Gene', '3714', (97, 101))	('reduced', 'NegReg', (44, 51))	('Ser7', 'Chemical', '-', (176, 180))	('phosphorylation', 'MPA', (56, 71))	('Ser5', 'Chemical', '-', (106, 110))	('THZ1', 'Chemical', '-', (31, 35))
345747	29358035	Additionally, THZ531 increased PARP cleavage and Annexin V+ cell populations and decreased anchorage independent growth in soft agar in Ewing sarcoma cells (Figure S2E-G).	('decreased', 'NegReg', (81, 90))	('increased', 'PosReg', (21, 30))	('Ewing sarcoma', 'Disease', (136, 149))	('THZ531', 'Chemical', 'MESH:C000618758', (14, 20))	('THZ531', 'Var', (14, 20))	('Annexin V', 'Gene', '308', (49, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('agar', 'Chemical', 'MESH:D000362', (128, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('Annexin V', 'Gene', (49, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (136, 149))	('PARP cleavage', 'CPA', (31, 44))	('anchorage independent growth', 'CPA', (91, 119))
345754	29358035	Remarkably few genes were upregulated by THZ531 at either 100 nM or 500 nM, consistent with the known role of CDK12/13 in transcriptional initiation and elongation.	('genes', 'Gene', (15, 20))	('THZ531', 'Var', (41, 47))	('THZ531', 'Chemical', 'MESH:C000618758', (41, 47))	('upregulated', 'PosReg', (26, 37))
345767	29358035	Low-throughput validation of select genes (BRCA1, RAD51, FANCF, XRCC2) by qPCR confirmed that THZ531 strongly suppresses expression of these genes (Figure S3D).	('BRCA1', 'Gene', (43, 48))	('suppresses', 'NegReg', (110, 120))	('THZ531', 'Chemical', 'MESH:C000618758', (94, 100))	('THZ531', 'Var', (94, 100))	('FANCF', 'Gene', (57, 62))	('XRCC2', 'Gene', '7516', (64, 69))	('expression', 'MPA', (121, 131))	('XRCC2', 'Gene', (64, 69))	('FANCF', 'Gene', '2188', (57, 62))	('RAD51', 'Gene', (50, 55))	('BRCA1', 'Gene', '672', (43, 48))	('RAD51', 'Gene', '5888', (50, 55))
345769	29358035	Box plots show the log-fold change (LFC) in gene expression of all genes, typical enhancer-associated genes (TE), SE genes, and EWS/FLI target genes following THZ531 treatment (Figure S3E).	('gene expression', 'MPA', (44, 59))	('THZ531', 'Chemical', 'MESH:C000618758', (159, 165))	('THZ531', 'Var', (159, 165))	('FLI', 'Gene', '2314', (132, 135))	('FLI', 'Gene', (132, 135))
345770	29358035	In this analysis, enhancers were ranked by H3K27Ac ChIP-sequencing signal, and EWS/FLI target genes were identified as 1) genes associated with EWS/FLI ChIP-sequencing signal and 2) genes with a decrease in transcript expression following EWS/FLI knockdown in A673 cells as described in.	('FLI', 'Gene', (243, 246))	('decrease', 'NegReg', (195, 203))	('FLI', 'Gene', '2314', (83, 86))	('FLI', 'Gene', '2314', (148, 151))	('FLI', 'Gene', (83, 86))	('transcript expression', 'MPA', (207, 228))	('knockdown', 'Var', (247, 256))	('FLI', 'Gene', '2314', (243, 246))	('FLI', 'Gene', (148, 151))
345771	29358035	Interestingly, we found that SE-associated genes and EWS/FLI target genes were not preferentially repressed by THZ531 compared to all genes.	('THZ531', 'Chemical', 'MESH:C000618758', (111, 117))	('FLI', 'Gene', '2314', (57, 60))	('SE-associated', 'Disease', (29, 42))	('FLI', 'Gene', (57, 60))	('THZ531', 'Var', (111, 117))
345775	29358035	To test this hypothesis, we knocked down EWS/FLI using a TRIPZ inducible system.	('FLI', 'Gene', (45, 48))	('FLI', 'Gene', '2314', (45, 48))	('knocked down', 'Var', (28, 40))
345777	29358035	Furthermore, suppression of EWS/FLI can partially rescue the anti-viability effects of CDK12 knockdown (Figure 3I).	('knockdown', 'Var', (93, 102))	('FLI', 'Gene', (32, 35))	('anti-viability effects', 'CPA', (61, 83))	('FLI', 'Gene', '2314', (32, 35))	('CDK12', 'Gene', (87, 92))
345781	29358035	These results suggest that the EWS/FLI oncoprotein imparts vulnerability to compounds that induce defects in DNA damage repair and suggest that the presence of EWS/FLI itself is synthetic lethal with CDK12 inhibition in Ewing sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('FLI', 'Gene', '2314', (164, 167))	('FLI', 'Gene', (164, 167))	('presence', 'Var', (148, 156))	('Ewing sarcoma', 'Disease', (220, 233))	('FLI', 'Gene', '2314', (35, 38))	('synthetic', 'Species', '2086595', (178, 187))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (220, 233))	('FLI', 'Gene', (35, 38))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (220, 233))	('vulnerability', 'MPA', (59, 72))	('inhibition', 'NegReg', (206, 216))
345785	29358035	EWS/FLI was also a biomarker of sensitivity to the ATM inhibitor, CP466722, an interesting finding in light of a recent publication identifying ATR inhibitors as active in Ewing sarcoma.	('CP466722', 'Chemical', 'MESH:C532253', (66, 74))	('ATM', 'Gene', '472', (51, 54))	('FLI', 'Gene', '2314', (4, 7))	('CP466722', 'Var', (66, 74))	('Ewing sarcoma', 'Disease', (172, 185))	('ATR', 'Gene', '545', (144, 147))	('FLI', 'Gene', (4, 7))	('ATR', 'Gene', (144, 147))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (172, 185))	('ATM', 'Gene', (51, 54))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (172, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
345789	29358035	Ovarian tumors with loss-of-function mutations in CDK12 have reduced BRCA1 levels, deficient HR, and are highly sensitive to PARP inhibition.	('Ovarian tumors', 'Disease', (0, 14))	('BRCA1', 'Gene', '672', (69, 74))	('deficient HR', 'Disease', (83, 95))	('loss-of-function', 'NegReg', (20, 36))	('deficient HR', 'Disease', 'MESH:D001919', (83, 95))	('BRCA1', 'Gene', (69, 74))	('CDK12', 'Gene', (50, 55))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Ovarian tumors', 'Phenotype', 'HP:0100615', (0, 14))	('Ovarian tumors', 'Disease', 'MESH:D010051', (0, 14))	('reduced', 'NegReg', (61, 68))
345792	29358035	These previous studies, in addition to our gene expression data identifying that THZ531 preferentially downregulates HR repair genes in Ewing sarcoma, led us to hypothesize that THZ531 would synergize with PARP inhibitors.	('THZ531', 'Gene', (81, 87))	('Ewing sarcoma', 'Disease', (136, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('THZ531', 'Chemical', 'MESH:C000618758', (81, 87))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('downregulates', 'NegReg', (103, 116))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (136, 149))	('THZ531', 'Chemical', 'MESH:C000618758', (178, 184))	('THZ531', 'Var', (178, 184))	('HR repair genes', 'Gene', (117, 132))
345796	29358035	Moreover, we observed that THZ531 strongly synergizes with cisplatin, mitomycin C, the ATR inhibitor VE821, and the ATM inhibitor KU5593, in Ewing sarcoma cells (Figure S4A-D).	('synergizes', 'Reg', (43, 53))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (141, 154))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (141, 154))	('mitomycin C', 'Chemical', '-', (70, 81))	('ATM', 'Gene', (116, 119))	('THZ531', 'Chemical', 'MESH:C000618758', (27, 33))	('Ewing sarcoma', 'Disease', (141, 154))	('ATR', 'Gene', (87, 90))	('ATR', 'Gene', '545', (87, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('ATM', 'Gene', '472', (116, 119))	('THZ531', 'Var', (27, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('KU5593', 'Chemical', '-', (130, 136))
345799	29358035	Taken together, these findings suggest that Ewing sarcoma is a disease marked by DNA damage repair deficiency rendering tumor cells highly sensitive to these combination strategies.	('deficiency', 'Var', (99, 109))	('Ewing sarcoma', 'Disease', (44, 57))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (44, 57))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (44, 57))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
345801	29358035	We found that genetic suppression of CDK12, but not CDK13, sensitizes cells to olaparib (Figure 4C).	('sensitizes', 'Reg', (59, 69))	('olaparib', 'Chemical', 'MESH:C531550', (79, 87))	('CDK13', 'Gene', (52, 57))	('CDK12', 'Gene', (37, 42))	('CDK13', 'Gene', '8621', (52, 57))	('genetic', 'Var', (14, 21))	('suppression', 'NegReg', (22, 33))
345804	29358035	THZ531 and olaparib alone induced gammaH2AX foci staining in Ewing sarcoma cells (Figure 5A, B), and the combination synergistically induced gammaH2AX foci formation, suggesting that this combination impairs the ability of Ewing sarcoma cells to repair DNA damage.	('Ewing sarcoma', 'Disease', (61, 74))	('induced', 'Reg', (26, 33))	('olaparib', 'Chemical', 'MESH:C531550', (11, 19))	('repair DNA damage', 'MPA', (246, 263))	('ability', 'MPA', (212, 219))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (61, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (223, 236))	('Ewing sarcoma', 'Disease', (223, 236))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (223, 236))	('gammaH2AX foci staining', 'MPA', (34, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('THZ531', 'Chemical', 'MESH:C000618758', (0, 6))	('impairs', 'NegReg', (200, 207))	('THZ531', 'Var', (0, 6))
345807	29358035	Interestingly, THZ531 prevented the induction of RAD51 foci formation in olaparib-treated Ewing sarcoma cells, suggesting that THZ531 is impairing HR and the ability of RAD51 to be recruited to sites of DNA damage.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('RAD51', 'Gene', (49, 54))	('RAD51', 'Gene', '5888', (49, 54))	('THZ531', 'Chemical', 'MESH:C000618758', (15, 21))	('RAD51', 'Gene', (169, 174))	('olaparib', 'Chemical', 'MESH:C531550', (73, 81))	('RAD51', 'Gene', '5888', (169, 174))	('Ewing sarcoma', 'Disease', (90, 103))	('impairing', 'NegReg', (137, 146))	('THZ531', 'Chemical', 'MESH:C000618758', (127, 133))	('THZ531', 'Var', (127, 133))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 103))
345808	29358035	We found that both THZ531 treatment and knockout of CDK12 led to a decrease in total RAD51 protein levels (Figure 5E, F).	('knockout', 'Var', (40, 48))	('decrease', 'NegReg', (67, 75))	('THZ531', 'Chemical', 'MESH:C000618758', (19, 25))	('CDK12', 'Gene', (52, 57))	('RAD51', 'Gene', (85, 90))	('RAD51', 'Gene', '5888', (85, 90))
345821	29358035	In the TC71 xenograft study, both THZ1 and olaparib significantly reduced the tumor growth rate and extended survival as single agents (Figure 6C, D), and the combination of THZ1 and olaparib significantly reduced tumor growth rate compared to either agent used alone (Figure 6C).	('reduced', 'NegReg', (66, 73))	('reduced', 'NegReg', (206, 213))	('THZ1', 'Var', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('combination', 'Var', (159, 170))	('THZ1', 'Chemical', '-', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('olaparib', 'Chemical', 'MESH:C531550', (183, 191))	('THZ1', 'Chemical', '-', (34, 38))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', (78, 83))	('extended survival', 'CPA', (100, 117))	('olaparib', 'Chemical', 'MESH:C531550', (43, 51))
345831	29358035	For example, chromosomal translocations that result in EWS/ETS rearrangements characterizing Ewing sarcoma tumors have yet to be successfully targeted.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('EWS/ETS', 'Gene', (55, 62))	('rearrangements', 'Var', (63, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (93, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Ewing sarcoma tumors', 'Disease', (93, 113))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (93, 113))
345842	29358035	The connection between EWS/ETS rearranged Ewing sarcoma and response to PARP inhibitors was highlighted.	('Ewing sarcoma', 'Disease', (42, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('rearranged', 'Var', (31, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (42, 55))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (42, 55))
345851	29358035	In the current study, we hypothesized that a CDK12 inhibitor would synergize with a PARP inhibitor because CDK12 loss-of-function mutations in ovarian cancer have rendered sensitivity to PARP inhibitors.	('sensitivity', 'MPA', (172, 183))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('ovarian cancer', 'Disease', 'MESH:D010051', (143, 157))	('mutations', 'Var', (130, 139))	('ovarian cancer', 'Disease', (143, 157))	('PARP inhibitors', 'MPA', (187, 202))	('loss-of-function', 'NegReg', (113, 129))	('CDK12', 'Gene', (107, 112))
345852	29358035	Indeed, THZ531/THZ1 and olaparib were highly synergistic in vitro, and THZ1 and olaparib were highly active in combination in vivo with a subset of the mice remarkably "cured" of disease without bone marrow toxicity.	('combination', 'Interaction', (111, 122))	('THZ1', 'Chemical', '-', (15, 19))	('THZ1', 'Chemical', '-', (71, 75))	('THZ531', 'Chemical', 'MESH:C000618758', (8, 14))	('bone marrow toxicity', 'Disease', 'MESH:D001855', (195, 215))	('olaparib', 'Chemical', 'MESH:C531550', (24, 32))	('THZ531/THZ1', 'Var', (8, 19))	('mice', 'Species', '10090', (152, 156))	('olaparib', 'Chemical', 'MESH:C531550', (80, 88))	('bone marrow toxicity', 'Disease', (195, 215))
345856	29358035	Moreover, this combination is predicted to be broadly applicable for cancers with BRCA1/2 mutations, which are highly sensitive to PARP inhibitors.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('BRCA1/2', 'Gene', '672;675', (82, 89))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA1/2', 'Gene', (82, 89))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
345888	29358035	Taqman probes for RPL13A (Hs01926559_g1), BRCA1 (Hs01556193_m1), RAD51 (Hs00427442_m1), FANCF (Hs00256030_s1), and XRCC2 (Hs03044154_m1) were obtained from Life Technologies.	('BRCA1', 'Gene', '672', (42, 47))	('Hs01556193_m1', 'Var', (49, 62))	('RAD51', 'Gene', '5888', (65, 70))	('FANCF', 'Gene', (88, 93))	('BRCA1', 'Gene', (42, 47))	('RPL13A', 'Gene', (18, 24))	('FANCF', 'Gene', '2188', (88, 93))	('XRCC2', 'Gene', '7516', (115, 120))	('RPL13A', 'Gene', '23521', (18, 24))	('Hs00427442_m1', 'Var', (72, 85))	('Hs03044154_m1', 'Var', (122, 135))	('Hs00256030_s1', 'Var', (95, 108))	('Hs01926559_g1', 'Var', (26, 39))	('XRCC2', 'Gene', (115, 120))	('RAD51', 'Gene', (65, 70))
345901	29358035	The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.7 and the GSEA v2.1.0 software were used to identify functional associations of the molecular phenotypes induced by THZ531 at 100 nM vs. vehicle and by THZ531 at 500 nM vs. vehicle.	('THZ531', 'Chemical', 'MESH:C000618758', (195, 201))	('THZ531', 'Var', (195, 201))	('THZ531', 'Chemical', 'MESH:C000618758', (231, 237))	('THZ531', 'Var', (231, 237))	('GSEA', 'Chemical', '-', (89, 93))
345902	29358035	The enrichment results for THZ531 at 100 nM vs. vehicle and for THZ531 at 500 nM vs. vehicle were visualized on GSEA plots and heatmaps for selected gene signatures.	('THZ531', 'Chemical', 'MESH:C000618758', (64, 70))	('THZ531', 'Var', (64, 70))	('GSEA', 'Chemical', '-', (112, 116))	('THZ531', 'Chemical', 'MESH:C000618758', (27, 33))	('THZ531', 'Var', (27, 33))
345903	29358035	The molecular gene set signatures of THZ531 100 nM and THZ531 500 nM vs. vehicle were visualized as dots in the volcano plots of normalized enrichment scores (NES) vs. -log10(p value) scores.	('THZ531 500 nM', 'Var', (55, 68))	('THZ531', 'Chemical', 'MESH:C000618758', (55, 61))	('THZ531', 'Chemical', 'MESH:C000618758', (37, 43))	('THZ531 100 nM', 'Var', (37, 50))
345904	29358035	Gene signatures (down and up) for 100 nM THZ531 vs. vehicle and 500 nM THZ531 vs. vehicle were defined separately for each of the A673 and TC32 cell lines based on the cut-offs SNR permutation p value <= 0.05, Benjamini-Hochberg false discovery rate (FDR) <= 0.05, and absolute fold change [FC] >= 2.	('THZ531', 'Var', (71, 77))	('TC32', 'CellLine', 'CVCL:7151', (139, 143))	('THZ531', 'Chemical', 'MESH:C000618758', (71, 77))	('THZ531', 'Chemical', 'MESH:C000618758', (41, 47))	('THZ531', 'Var', (41, 47))
345907	29358035	The correlation between the expression fold changes induced by THZ531 vs. vehicle in the A673 and TC32 cell lines was estimated by fitting a linear regression model.	('THZ531', 'Chemical', 'MESH:C000618758', (63, 69))	('TC32', 'CellLine', 'CVCL:7151', (98, 102))	('THZ531', 'Var', (63, 69))	('expression', 'MPA', (28, 38))
345910	29358035	The A673 enhancer and FLI1 region/gene target data were created and published by the Rivera lab.	('FLI1', 'Gene', (22, 26))	('FLI1', 'Gene', '2313', (22, 26))	('A673', 'Var', (4, 8))
345935	29358035	The preferential sensitivity of Ewing sarcoma cells to THZ1/THZ531 is imparted by the tumor-specific expression of the fusion oncoprotein EWS/FLI.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Ewing sarcoma', 'Disease', (32, 45))	('tumor', 'Disease', (86, 91))	('THZ1/THZ531', 'Var', (55, 66))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (32, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (32, 45))	('FLI', 'Gene', '2314', (142, 145))	('THZ531', 'Chemical', 'MESH:C000618758', (60, 66))	('FLI', 'Gene', (142, 145))	('THZ1', 'Chemical', '-', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
345940	29358035	CDK12/13 inhibitors impair DNA damage repair in fusion-positive Ewing sarcoma.	('CDK12/13', 'Gene', (0, 8))	('impair', 'NegReg', (20, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (64, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (64, 77))	('DNA damage repair', 'MPA', (27, 44))	('inhibitors', 'Var', (9, 19))	('Ewing sarcoma', 'Disease', (64, 77))
346017	28556791	Use of single agent EGFR inhibitors is now a part of standard care in biologically appropriate subsets in cancers of the lung, colon, pancreas and the head and neck.	('pancreas', 'Disease', (134, 142))	('EGFR', 'Gene', (20, 24))	('cancers of the lung', 'Disease', (106, 125))	('colon', 'Disease', (127, 132))	('cancers of the lung', 'Disease', 'MESH:D008175', (106, 125))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('inhibitors', 'Var', (25, 35))	('pancreas', 'Disease', 'MESH:D010190', (134, 142))	('EGFR', 'Gene', '1956', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
346049	28556791	Seven STS cell lines were screened for mutations in the TK domain (exons 18-24) of the EGFR gene and no rare sequence variants were detected.	('STS', 'Phenotype', 'HP:0030448', (6, 9))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (87, 91))	('mutations', 'Var', (39, 48))
346050	28556791	In a cohort of 958 patients, only two of 38 samples from the sarcoma subset were positive for any EGFR mutation.	('EGFR', 'Gene', (98, 102))	('patients', 'Species', '9606', (19, 27))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('EGFR', 'Gene', '1956', (98, 102))	('mutation', 'Var', (103, 111))	('sarcoma', 'Disease', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
346051	28556791	In a synovial sarcoma study, only two of 13 tissue samples were positive for EGFR TK mutation, with no EGFR amplification on FISH analysis and a further study on EGFR gene amplification from patients with endometrial stromal sarcoma also showed 10/10 negative results.	('positive', 'Reg', (64, 72))	('EGFR', 'Gene', '1956', (103, 107))	('synovial sarcoma', 'Disease', (5, 21))	('patients', 'Species', '9606', (191, 199))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (205, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', (162, 166))	('mutation', 'Var', (85, 93))	('synovial sarcoma', 'Disease', 'MESH:D013584', (5, 21))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (5, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('EGFR', 'Gene', '1956', (77, 81))	('endometrial stromal sarcoma', 'Disease', (205, 232))	('EGFR', 'Gene', (77, 81))
346053	28556791	It has been reported that KRAS and BRAF mutations were negatively correlated with the response to targeting EGFR treatment in lung and colorectal cancers.	('BRAF', 'Gene', (35, 39))	('lung', 'Disease', (126, 130))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('EGFR', 'Gene', '1956', (108, 112))	('negatively', 'NegReg', (55, 65))	('EGFR', 'Gene', (108, 112))	('mutations', 'Var', (40, 49))	('colorectal cancers', 'Disease', 'MESH:D015179', (135, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('KRAS', 'Gene', (26, 30))	('colorectal cancers', 'Disease', (135, 153))	('BRAF', 'Gene', '673', (35, 39))	('KRAS', 'Gene', '3845', (26, 30))	('response', 'MPA', (86, 94))
346054	28556791	On mutation analysis of KRAS and BRAF genes, all STS cell lines were found to be KRAS wild-type at codons 12, 13 and 61.	('KRAS', 'Gene', '3845', (81, 85))	('BRAF', 'Gene', '673', (33, 37))	('KRAS', 'Gene', '3845', (24, 28))	('BRAF', 'Gene', (33, 37))	('mutation', 'Var', (3, 11))	('KRAS', 'Gene', (81, 85))	('STS', 'Phenotype', 'HP:0030448', (49, 52))	('KRAS', 'Gene', (24, 28))
346055	28556791	SW872, SW982 and GCT (3/7 STS cell lines) demonstrated the BRAF V600E mutation (dbSNP: rs113488022, p.Val600Glu).	('SW872', 'CellLine', 'CVCL:1730', (0, 5))	('rs113488022', 'Mutation', 'rs113488022', (87, 98))	('STS', 'Phenotype', 'HP:0030448', (26, 29))	('p.Val600Glu', 'Mutation', 'rs113488022', (100, 111))	('BRAF', 'Gene', (59, 63))	('p.Val600Glu', 'Var', (100, 111))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('BRAF', 'Gene', '673', (59, 63))	('SW982', 'CellLine', 'CVCL:1734', (7, 12))	('V600E', 'Var', (64, 69))
346056	28556791	This was consistent with previous studies, which showed only two of 54 samples from patients with STS had KRAS mutations.	('KRAS', 'Gene', '3845', (106, 110))	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (84, 92))	('STS', 'Phenotype', 'HP:0030448', (98, 101))	('KRAS', 'Gene', (106, 110))
346057	28556791	Similarly, although unexpectedly, we discovered that 3 STS cell lines SW872, SW982 and GCT contained a BRAF V600E mutation, a recent study found that none of the samples from 108 sarcoma patients were BRAF mutation positive.	('patients', 'Species', '9606', (187, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('BRAF', 'Gene', '673', (201, 205))	('SW872', 'CellLine', 'CVCL:1730', (70, 75))	('V600E', 'Mutation', 'rs113488022', (108, 113))	('SW982', 'CellLine', 'CVCL:1734', (77, 82))	('V600E', 'Var', (108, 113))	('STS', 'Phenotype', 'HP:0030448', (55, 58))	('BRAF', 'Gene', '673', (103, 107))	('sarcoma', 'Disease', 'MESH:D012509', (179, 186))	('sarcoma', 'Disease', (179, 186))	('BRAF', 'Gene', (103, 107))	('BRAF', 'Gene', (201, 205))
346111	23782480	Sub-clinical cardiac abnormalities may develop into symptomatic cardiomyopathy in adulthood.	('develop', 'Reg', (39, 46))	('Sub-clinical', 'Var', (0, 12))	('cardiomyopathy', 'Disease', (64, 78))	('cardiac abnormalities', 'Phenotype', 'HP:0001627', (13, 34))	('cardiac abnormalities', 'Disease', (13, 34))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (64, 78))	('cardiac abnormalities', 'Disease', 'MESH:D006331', (13, 34))	('cardiomyopathy', 'Disease', 'MESH:D009202', (64, 78))
346113	23782480	Treatment-related drug effects and interactions are considerably more prevalent and directly challenge the cardiovascular system through lipid abnormalities with protease inhibitors (PIs) and an increased statin serum concentration with PIs.	('lipid abnormalities', 'Disease', (137, 156))	('lipid abnormalities', 'Disease', 'MESH:C562935', (137, 156))	('protease inhibitor', 'Gene', (162, 180))	('challenge', 'Reg', (93, 102))	('interactions', 'Var', (35, 47))	('statin serum concentration', 'MPA', (205, 231))	('protease inhibitor', 'Gene', '388007', (162, 180))	('cardiovascular system', 'MPA', (107, 128))	('lipid abnormalities', 'Phenotype', 'HP:0003119', (137, 156))	('increased', 'PosReg', (195, 204))
346121	23782480	Synergistic causes may include traditional risk factors such as family history, high LDL cholesterol, low HDL cholesterol, diabetes, hypertension, age >55, HIV viral load, and medication specific ART exposure.	('diabetes', 'Disease', 'MESH:D003920', (123, 131))	('ART', 'Chemical', '-', (196, 199))	('hypertension', 'Disease', (133, 145))	('cholesterol', 'Chemical', 'MESH:D002784', (89, 100))	('low HDL cholesterol', 'Phenotype', 'HP:0003233', (102, 121))	('hypertension', 'Phenotype', 'HP:0000822', (133, 145))	('HIV', 'Species', '12721', (156, 159))	('high', 'Disease', (80, 84))	('low', 'Var', (102, 105))	('cholesterol', 'Chemical', 'MESH:D002784', (110, 121))	('diabetes', 'Disease', (123, 131))	('hypertension', 'Disease', 'MESH:D006973', (133, 145))	('high LDL cholesterol', 'Phenotype', 'HP:0003141', (80, 100))
346218	23782480	Electrolyte imbalances and deficiencies in elemental nutrients are often a result of diarrhoea and poor absorption.	('deficiencies', 'Var', (27, 39))	('Electrolyte imbalances', 'Phenotype', 'HP:0003111', (0, 22))	('diarrhoea', 'Disease', 'MESH:D003967', (85, 94))	('diarrhoea', 'Phenotype', 'HP:0002014', (85, 94))	('diarrhoea', 'Disease', (85, 94))	('imbalances', 'Phenotype', 'HP:0002172', (12, 22))	('Electrolyte imbalances', 'MPA', (0, 22))
346219	23782480	Deficiencies of trace elements have been associated with cardiomyopathy.	('Deficiencies', 'Var', (0, 12))	('associated', 'Reg', (41, 51))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (57, 71))	('cardiomyopathy', 'Disease', 'MESH:D009202', (57, 71))	('cardiomyopathy', 'Disease', (57, 71))
346379	23782480	In culture, AZT causes a dose-dependent destruction of human myotubes.	('AZT', 'Chemical', 'MESH:D015215', (12, 15))	('AZT', 'Var', (12, 15))	('destruction', 'NegReg', (40, 51))	('human', 'Species', '9606', (55, 60))
346479	23737702	Eighteen tumors (21.4%), 28 (33.3%), 34 (40.5%), and 4 (4.8%) were categorized as having margin widths of 1-4 mm, 5-9 mm, 10-19 mm, and >=20 mm, respectively.	('5-9 mm', 'Var', (114, 120))	('10-19 mm', 'Var', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
346531	29991551	Histopathological diagnosis was of high-grade dedifferentiated liposarcoma with MDM2 gene amplification.	('MDM2', 'Gene', (80, 84))	('liposarcoma', 'Phenotype', 'HP:0012034', (63, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('liposarcoma', 'Disease', (63, 74))	('gene amplification', 'Var', (85, 103))	('MDM2', 'Gene', '4193', (80, 84))	('liposarcoma', 'Disease', 'MESH:D008080', (63, 74))
346603	29937942	The dose constraints of the OARs were based on the TD5/5 described by Emami except for the optic nerve (D20<30 GyE), brain stem (Dmax< 45 GyE), spinal cord (Dmax< 30 GyE), and temporal lobes (V40<7.66 cc; V50<4.66 cc), which were based on previous experience from the National Institute or Radiation Science of Japan.	('temporal lobes', 'Disease', (176, 190))	('V50<', 'Var', (205, 209))	('temporal lobes', 'Disease', 'MESH:C538521', (176, 190))	('Dmax< 45 GyE', 'Var', (129, 141))	('D20<30 GyE', 'Var', (104, 114))	('V40<7.66 cc; V50<', 'Var', (192, 209))	('Dmax< 30 GyE', 'Var', (157, 169))
346680	29937942	Furthermore, the use of CIRT is reportedly safe and effective for primary skull base chondrosarcomas treated with CIRT to 60 GyE (3 GyE/fraction).	('chondrosarcomas', 'Disease', 'MESH:D002813', (85, 100))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (85, 99))	('chondrosarcomas', 'Disease', (85, 100))	('CIRT', 'Var', (114, 118))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (85, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
346728	24455040	It has been described that patients with the variant PAX7-FKHR translocation have a more favorable prognosis and there has been a strikingly better outcome in patients with metastatic disease and variant-trans location-positive alveolar RMS (estimated 4-year overall survival, 75% vs. 8% for patients with PAX3-FKHR-positive alveolar RMS).	('FKHR', 'Gene', '2308', (311, 315))	('alveolar RMS', 'Disease', (228, 240))	('PAX7', 'Gene', '5081', (53, 57))	('patients', 'Species', '9606', (292, 300))	('PAX7', 'Gene', (53, 57))	('metastatic disease', 'CPA', (173, 191))	('alveolar RMS', 'Disease', 'MESH:D002282', (228, 240))	('patients', 'Species', '9606', (27, 35))	('FKHR', 'Gene', (58, 62))	('PAX3', 'Gene', (306, 310))	('alveolar RMS', 'Disease', (325, 337))	('FKHR', 'Gene', (311, 315))	('variant', 'Var', (45, 52))	('PAX3', 'Gene', '5077', (306, 310))	('patients', 'Species', '9606', (159, 167))	('better', 'PosReg', (141, 147))	('alveolar RMS', 'Disease', 'MESH:D002282', (325, 337))	('FKHR', 'Gene', '2308', (58, 62))	('variant-trans', 'Var', (196, 209))
346733	24455040	A variety of differentiated cell types can be converted into skeletal muscle after transfection with MyoD1 through the activation of muscle-specific genes.	('muscle-specific', 'Gene', (133, 148))	('MyoD1', 'Gene', (101, 106))	('MyoD1', 'Gene', '4654', (101, 106))	('activation', 'PosReg', (119, 129))	('muscle-specific', 'Gene', '27335', (133, 148))	('transfection', 'Var', (83, 95))
346739	24455040	It is speculated that Li-Fraumeni p53 mutant alleles may be weak alleles that lack dominant negative activity and can be tolerated and passed in the germline of families.	('mutant', 'Var', (38, 44))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))
346740	24455040	In nonfamilial, sporadic cases of rhabdomyosarcoma, there is a high frequency and diversity of p53 mutation.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (34, 50))	('mutation', 'Var', (99, 107))	('rhabdomyosarcoma', 'Disease', (34, 50))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (34, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
346742	24455040	The wild type p53 controls cell proliferation at a G1/S checkpoint in the cell cycle and the mutated type presumably loses this regulatory function so that the affected tissue undergoes tumorous growth.	('mutated', 'Var', (93, 100))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('loses', 'NegReg', (117, 122))	('cell proliferation', 'CPA', (27, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('undergoes tumorous growth', 'Disease', (176, 201))	('undergoes tumorous growth', 'Disease', 'MESH:D006130', (176, 201))
346745	24455040	Loss of heterozygosity with inactivation of the paternal Rb gene, that is, by DNA methylation or other events, would lead to tumorous growth.	('Rb', 'Chemical', 'MESH:D012413', (57, 59))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumorous growth', 'Disease', 'MESH:D006130', (125, 140))	('inactivation', 'Var', (28, 40))	('Loss', 'NegReg', (0, 4))	('tumorous growth', 'Disease', (125, 140))	('lead to', 'Reg', (117, 124))
346749	24455040	Besides these three lines of study, activation and mutation of oncogenes, particularly the RAS oncogenes, have been demonstrated in rhabdomyosarcomas.	('RAS oncogenes', 'Gene', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('activation', 'PosReg', (36, 46))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (132, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('rhabdomyosarcomas', 'Disease', (132, 149))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (132, 148))	('mutation', 'Var', (51, 59))	('oncogenes', 'Gene', (63, 72))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (132, 149))
346754	24455040	Loss of alleles and imprinting at 11p15.5 together with disruption of genes such as IGF2 have also been implicated in rhabdomyosarcoma development.	('rhabdomyosarcoma', 'Disease', (118, 134))	('implicated', 'Reg', (104, 114))	('IGF2', 'Gene', '3481', (84, 88))	('IGF2', 'Gene', (84, 88))	('Loss', 'NegReg', (0, 4))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (118, 134))	('disruption', 'Var', (56, 66))	('p15', 'Gene', '1030', (36, 39))	('p15', 'Gene', (36, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (118, 134))
346760	24455040	The discovery that p16 gene is mutated or deleted in a striking proportion of human tumors raised the possibility that abnormalities in p16 might predispose to cancer development.	('p16', 'Gene', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('p16', 'Gene', (136, 139))	('deleted', 'Var', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('predispose', 'Reg', (146, 156))	('p16', 'Gene', '1029', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('p16', 'Gene', '1029', (136, 139))	('abnormalities', 'Var', (119, 132))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('human', 'Species', '9606', (78, 83))
346771	24455040	Additionally, CpG hypermethylation of the E-cadherin promoter is an important mechanism of E-cadherin gene inactivation.	('E-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', '999', (91, 101))	('inactivation', 'NegReg', (107, 119))	('E-cadherin', 'Gene', (42, 52))	('CpG', 'Var', (14, 17))	('E-cadherin', 'Gene', '999', (42, 52))
346813	24455040	Alveolar tumors harbor a distinguishing chromosomal translocation marker, typically t(q35;q14).	('t(q35;q14', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('Alveolar tumors', 'Disease', 'MESH:D002282', (0, 15))	('Alveolar tumors', 'Disease', (0, 15))
346866	23388156	Other eligibility criteria were age older than 18 years; performance status 0 or 1; no functionally important cardiovascular disease, no prior cancer (except adequately treated in situ carcinoma of cervix or basal cell carcinoma); presence of measurable lesions not previously irradiated, no central nervous system metastases; adequate bone marrow reserve (neutrophils > 2,000/mm3, platelet count > 100,000/mm3); and adequate renal and hepatic functions: serum creatinin less than 120 mumol/L or calculated creatinin clearance (Cockroft method) greater than 60 mL/min, bilirubin > 30 mumol/L, AST and ALT less than 1.5 U/L (<2.5 U/L in case of liver metastases), alkaline phosphatase less than 2.5 U/L and albumine > 25 g/L.	('> 30', 'Var', (579, 583))	('carcinoma of cervix', 'Phenotype', 'HP:0030079', (185, 204))	('less', 'NegReg', (684, 688))	('albumine', 'MPA', (706, 714))	('serum creatinin', 'MPA', (455, 470))	('bilirubin', 'MPA', (569, 578))	('less', 'NegReg', (471, 475))	('situ carcinoma of cervix or basal cell carcinoma', 'Disease', (180, 228))	('AST', 'Gene', '26503', (593, 596))	('less', 'NegReg', (605, 609))	('metastases', 'Disease', 'MESH:D009362', (650, 660))	('cancer', 'Disease', (143, 149))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (110, 132))	('liver metastases', 'Disease', (644, 660))	('cardiovascular disease', 'Disease', 'MESH:D002318', (110, 132))	('ALT', 'MPA', (601, 604))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('metastases', 'Disease', (650, 660))	('cardiovascular disease', 'Disease', (110, 132))	('alkaline phosphatase', 'MPA', (663, 683))	('AST', 'Gene', (593, 596))	('metastases', 'Disease', 'MESH:D009362', (315, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('situ carcinoma of cervix or basal cell carcinoma', 'Disease', 'MESH:D002278', (180, 228))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (208, 228))	('metastases', 'Disease', (315, 325))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('liver metastases', 'Disease', 'MESH:D009362', (644, 660))
346922	23388156	Interestingly, OS and PFS of translocation-related sarcomas excluding myxoid liposarcoma was not different of that of other sarcoma types.	('myxoid liposarcoma', 'Disease', (70, 88))	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('sarcoma', 'Disease', (51, 58))	('sarcoma', 'Disease', (124, 131))	('translocation-related', 'Var', (29, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('sarcomas', 'Disease', (51, 59))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (70, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('OS', 'Chemical', '-', (15, 17))	('liposarcoma', 'Phenotype', 'HP:0012034', (77, 88))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (70, 88))
346971	23189013	In their study comprising 18 cases of EMC, the positive results of 72% for EWSR1 and 61% for NR4A3 gene rearrangements led to the conclusion that FISH analysis of formalin-fixed, paraffin-embedded specimens for the said new probes is useful, convenient, and may provide an ancillary method for diagnosis, especially in difficult cases.	('formalin', 'Chemical', 'MESH:D005557', (163, 171))	('EWSR1', 'Gene', '2130', (75, 80))	('paraffin', 'Chemical', 'MESH:D010232', (179, 187))	('NR4A3', 'Gene', '8013', (93, 98))	('rearrangements', 'Var', (104, 118))	('NR4A3', 'Gene', (93, 98))	('EWSR1', 'Gene', (75, 80))
347193	21386844	(172) Joseph WL, Morton DL, Adkins PC (1971) Variation in tumor doubling time in patients with pulmonary metastatic disease.	('Variation', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('pulmonary metastatic disease', 'Disease', (95, 123))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('pulmonary metastatic disease', 'Disease', 'MESH:C538445', (95, 123))
347328	21386844	(290) Schulten MF, Heiskell CA, Shields TW (1976) The incidence of solitary pulmonary metastasis from carcinoma of the large intestine.	('solitary pulmonary metastasis', 'Disease', 'MESH:D009362', (67, 96))	('Schulten', 'Var', (6, 14))	('solitary pulmonary metastasis', 'Disease', (67, 96))	('carcinoma', 'Disease', 'MESH:D002277', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('carcinoma', 'Disease', (102, 111))
347406	32807122	AMPK inactivation is accompanied by the activation of multiple oncogenic pathways associated with cell adhesion, calcium signaling and extracellular matrix organization.	('AMPK', 'Gene', '5563', (0, 4))	('activation', 'PosReg', (40, 50))	('calcium', 'Chemical', 'MESH:D002118', (113, 120))	('AMPK', 'Gene', (0, 4))	('oncogenic pathways', 'Pathway', (63, 81))	('inactivation', 'Var', (5, 17))
347436	32807122	Focusing on the genomic and transcriptomic landscape of 92 genes associated with AMPK signaling retrieved from KEGG across 21 cancer types involving 18,484 patients (Additional file 1), we interrogated somatic copy number alterations (SCNA) and mRNA expression (see Additional file 2 for a flowchart illustrating the study design).	('patients', 'Species', '9606', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('AMPK', 'Gene', '5563', (81, 85))	('mRNA', 'MPA', (245, 249))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('copy number alterations', 'Var', (210, 233))	('AMPK', 'Gene', (81, 85))
347437	32807122	To determine the effects of genomic alterations in AMPK pathway genes, we classified genes as having high-level amplifications (gains), low-level amplifications, deep (homozygous) deletions and shallow (heterozygous) deletions.	('deep', 'Var', (162, 166))	('AMPK', 'Gene', (51, 55))	('AMPK', 'Gene', '5563', (51, 55))
347442	32807122	In contrast, PPP2R2A was the most deleted gene found in > 20% of samples across 17 cancers, followed by the deletion of SLC2A4 in 16 cancers and five additional genes (FOXO3, PPP2CB, PPP2R2D, PPP2R5C and PPP2R5E) in 15 cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('PPP2CB', 'Gene', (175, 181))	('FOXO3', 'Gene', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('PPP2CB', 'Gene', '5516', (175, 181))	('PPP2R5E', 'Gene', (204, 211))	('PPP2R2A', 'Gene', '5520', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('FOXO3', 'Gene', '2309', (168, 173))	('PPP2R5C', 'Gene', '5527', (192, 199))	('deletion', 'Var', (108, 116))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('PPP2R5C', 'Gene', (192, 199))	('SLC2A4', 'Gene', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancer', 'Disease', (133, 139))	('cancers', 'Disease', (133, 140))	('PPP2R2D', 'Gene', (183, 190))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('SLC2A4', 'Gene', '6517', (120, 126))	('PPP2R2D', 'Gene', '55844', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('PPP2R2A', 'Gene', (13, 20))	('cancer', 'Disease', (83, 89))	('PPP2R5E', 'Gene', '5529', (204, 211))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
347450	32807122	1), none of the genes harbored prognostic information, suggesting that alterations in AMPK signaling components have minimal roles in driving tumor progression and patient outcomes.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('patient', 'Species', '9606', (164, 171))	('alterations', 'Var', (71, 82))	('AMPK', 'Gene', '5563', (86, 90))	('AMPK', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
347459	32807122	In contrast, high expression of the 24 genes was associated with increased mortality rates in stomach adenocarcinoma (P = 0.033) (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('adenocarcinoma', 'Disease', (102, 116))	('mortality', 'Disease', 'MESH:D003643', (75, 84))	('high', 'Var', (13, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('mortality', 'Disease', (75, 84))
347467	32807122	3a); consistent with our previous observation that high pathway scores were associated with good prognosis in sarcoma (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('high', 'Var', (51, 55))	('sarcoma', 'Disease', (110, 117))
347473	32807122	Within the leiomyosarcoma histological subtype, AUC was even higher at 0.869 (Fig.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (11, 25))	('0.869', 'Var', (71, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('leiomyosarcoma', 'Disease', (11, 25))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (11, 25))
347474	32807122	AMPK pathway inactivation was associated with altered survival outcomes in patients (Figs.	('AMPK', 'Gene', '5563', (0, 4))	('inactivation', 'Var', (13, 25))	('patients', 'Species', '9606', (75, 83))	('AMPK', 'Gene', (0, 4))	('survival', 'CPA', (54, 62))
347482	32807122	Five TFs, SUZ12, SMAD4, REST, EZH2 and NFE2L2, were found to be enriched in all four cancers, suggesting that transcriptional dysregulation of tumors with aberrant AMPK signaling involved direct physical associations of these TFs with target DEGs (Fig.	('NFE2L2', 'Gene', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('AMPK', 'Gene', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('SMAD4', 'Gene', '4089', (17, 22))	('transcriptional', 'MPA', (110, 125))	('tumors', 'Disease', (143, 149))	('dysregulation', 'NegReg', (126, 139))	('SUZ12', 'Gene', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('aberrant', 'Var', (155, 163))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('NFE2L2', 'Gene', '4780', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EZH2', 'Gene', '2146', (30, 34))	('SUZ12', 'Gene', '23512', (10, 15))	('EZH2', 'Gene', (30, 34))	('AMPK', 'Gene', '5563', (164, 168))	('associations', 'Interaction', (204, 216))	('SMAD4', 'Gene', (17, 22))
347485	32807122	EZH2, NFE2L2, REST, SMAD4 and SUZ12 were all implicated as common transcriptional regulators of DEGs in glioma, sarcoma, breast and stomach cancers, suggesting that altered AMPK signaling converged on similar groups of transcriptional targets.	('AMPK', 'Gene', (173, 177))	('NFE2L2', 'Gene', '4780', (6, 12))	('stomach cancers', 'Phenotype', 'HP:0012126', (132, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('SUZ12', 'Gene', (30, 35))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('SMAD4', 'Gene', (20, 25))	('NFE2L2', 'Gene', (6, 12))	('SUZ12', 'Gene', '23512', (30, 35))	('breast and stomach cancers', 'Disease', 'MESH:D001943', (121, 147))	('glioma', 'Disease', (104, 110))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('stomach cancer', 'Phenotype', 'HP:0012126', (132, 146))	('AMPK', 'Gene', '5563', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('SMAD4', 'Gene', '4089', (20, 25))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('sarcoma', 'Disease', (112, 119))	('DEGs', 'Var', (96, 100))
347491	32807122	2), which mirrored the behavior of DEGs identified as a result of aberrant AMPK signaling (Fig.	('AMPK', 'Gene', (75, 79))	('aberrant', 'Var', (66, 74))	('AMPK', 'Gene', '5563', (75, 79))
347501	32807122	We subsequently categorized patients into four groups using the median cutoff of the AMPK scores and TF expression values: 1) low-low, 2) high-high, 3) low AMPK score and high TF expression and 4) high AMPK score and low TF expression.	('low', 'NegReg', (152, 155))	('AMPK', 'Gene', '5563', (202, 206))	('AMPK', 'Gene', '5563', (85, 89))	('AMPK', 'Gene', (156, 160))	('TF expression', 'MPA', (176, 189))	('TF expression', 'MPA', (221, 234))	('AMPK', 'Gene', (85, 89))	('low-low', 'Var', (126, 133))	('AMPK', 'Gene', (202, 206))	('AMPK', 'Gene', '5563', (156, 160))	('patients', 'Species', '9606', (28, 36))	('high-high', 'Var', (138, 147))
347521	32807122	These putative loss- or gain-of-function genes are more likely to impact tumor progression as they are altered at both macromolecular levels.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('loss-', 'NegReg', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('gain-of-function', 'PosReg', (24, 40))	('tumor', 'Disease', (73, 78))	('genes', 'Var', (41, 46))
347528	32807122	Ablation of LKB1 results in enhanced risk of developing gastrointestinal, lung and skin squamous cell cancers.	('gastrointestinal', 'Disease', (56, 72))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('skin squamous cell cancers', 'Disease', 'MESH:D002294', (83, 109))	('Ablation', 'Var', (0, 8))	('skin squamous cell cancers', 'Disease', (83, 109))	('enhanced', 'PosReg', (28, 36))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (88, 109))	('LKB1', 'Gene', (12, 16))	('lung', 'Disease', (74, 78))	('LKB1', 'Gene', '6794', (12, 16))
347532	32807122	However, when tested in mice models, metformin contributes to enhanced tumor progression and increased angiogenesis, providing us with a glimpse of potential pro-neoplastic effects of AMPK activation.	('metformin', 'Chemical', 'MESH:D008687', (37, 46))	('AMPK', 'Gene', (184, 188))	('mice', 'Species', '10090', (24, 28))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('enhanced', 'PosReg', (62, 70))	('AMPK', 'Gene', '5563', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('angiogenesis', 'CPA', (103, 115))	('metformin', 'Var', (37, 46))
347538	32807122	AMPK knockdown in pancreatic cancer cells impairs anchorage-dependent growth and reduces cell viability under glucose deprived conditions.	('glucose', 'Chemical', 'MESH:D005947', (110, 117))	('anchorage-dependent growth', 'CPA', (50, 76))	('AMPK', 'Gene', '5563', (0, 4))	('pancreatic cancer', 'Disease', (18, 35))	('knockdown', 'Var', (5, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('impairs', 'NegReg', (42, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))	('AMPK', 'Gene', (0, 4))	('reduces', 'NegReg', (81, 88))	('cell viability', 'CPA', (89, 103))
347539	32807122	AMPK signaling induces cell migration in prostate cancer cells while AMPK knockdown inhibits cell proliferation and promotes apoptosis.	('AMPK', 'Gene', (0, 4))	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('AMPK', 'Gene', '5563', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('promotes', 'PosReg', (116, 124))	('AMPK', 'Gene', '5563', (69, 73))	('knockdown', 'Var', (74, 83))	('cell proliferation', 'CPA', (93, 111))	('cell migration', 'CPA', (23, 37))	('prostate cancer', 'Disease', (41, 56))	('apoptosis', 'CPA', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('inhibits', 'NegReg', (84, 92))	('AMPK', 'Gene', (69, 73))
347553	32807122	Restoration of SMAD4 expression in pancreatic cancer cells inhibits tumor function in vivo by influencing angiogenesis through decreased VEGF expression.	('tumor', 'Disease', (68, 73))	('SMAD4', 'Gene', (15, 20))	('decreased', 'NegReg', (127, 136))	('VEGF', 'Gene', '7422', (137, 141))	('inhibits', 'NegReg', (59, 67))	('Restoration', 'Var', (0, 11))	('influencing', 'Reg', (94, 105))	('pancreatic cancer', 'Disease', 'MESH:D010190', (35, 52))	('pancreatic cancer', 'Disease', (35, 52))	('VEGF', 'Gene', (137, 141))	('angiogenesis', 'CPA', (106, 118))	('SMAD4', 'Gene', '4089', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('expression', 'MPA', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 52))
347561	32807122	Our study provides a comprehensive catalog of clinically actionable genetic variations which could be used for patient stratification in prospective clinical trials testing the capabilities of AMPK antagonists or agonists as potential treatments for cancer.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('variations', 'Var', (76, 86))	('AMPK', 'Gene', '5563', (193, 197))	('patient', 'Species', '9606', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('genetic variations', 'Var', (68, 86))	('AMPK', 'Gene', (193, 197))
347591	29977622	Nonsurgical options for treatment of cardiac sarcomas can be difficult due to radiation effects on the surrounding heart and the high levels of radiation (6000-6500 cGy) that is typically needed.	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('cardiac sarcomas', 'Phenotype', 'HP:0031350', (37, 53))	('6000-6500', 'Var', (155, 164))	('cardiac sarcomas', 'Disease', (37, 53))	('cardiac sarcoma', 'Phenotype', 'HP:0031350', (37, 52))	('cardiac sarcomas', 'Disease', 'MESH:D006331', (37, 53))
347628	27928479	Overall, constitutional genetic changes play a role in increasing susceptibility to childhood cancer in fewer than 3% of cases.	('constitutional genetic changes', 'Var', (9, 39))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
347715	30705899	Laboratory findings included CA125, 189.5 U/mL; albumin, 29.5 g/L; alanine aminotransferase, 7.8 U/L; creatinine, 50.0 mumol/L; indirect bilirubin, 3.3 mumol/L; direct bilirubin, 2.1 mumol/L; total bilirubin, 5.4 mumol/L; prothrombin time, 12.6 s; and platelet volume distribution width, 9.6%.	('prothrombin', 'MPA', (222, 233))	('CA125', 'Var', (29, 34))	('creatinine', 'Chemical', 'MESH:D003404', (102, 112))	('bilirubin', 'Chemical', 'MESH:D001663', (168, 177))	('alanine', 'MPA', (67, 74))	('indirect bilirubin', 'MPA', (128, 146))	('bilirubin', 'Chemical', 'MESH:D001663', (198, 207))	('bilirubin', 'Chemical', 'MESH:D001663', (137, 146))	('total bilirubin', 'MPA', (192, 207))	('direct bilirubin', 'MPA', (161, 177))	('creatinine', 'MPA', (102, 112))	('albumin', 'MPA', (48, 55))
347754	30705899	ESTSCLEs are prone to t (7;17) (p15;q21) JAZF1-SUZ12 (JJAZ1) gene fusion, while UTROSCTs have no JAZF1-SUZ12 gene fusion.	('JAZF1', 'Gene', '221895', (41, 46))	('JAZF1', 'Gene', '221895', (97, 102))	('SUZ12', 'Gene', '23512', (103, 108))	('SUZ12', 'Gene', (103, 108))	('t (7;17) (p15;q21', 'Var', (22, 39))	('JJAZ1', 'Gene', '23512', (54, 59))	('JAZF1', 'Gene', (41, 46))	('JAZF1', 'Gene', (97, 102))	('SUZ12', 'Gene', '23512', (47, 52))	('JJAZ1', 'Gene', (54, 59))	('SUZ12', 'Gene', (47, 52))
347776	28701835	Immunohistochemistry for cytokeratin, p63, S-100, desmin, and myogenin was negative in the tumor cells with strong positivity for vimentin [Figure 1b, inset] and focal positivity for smooth muscle actin (SMA).	('S-100', 'Gene', (43, 48))	('negative', 'NegReg', (75, 83))	('myogenin', 'Gene', (62, 70))	('p63', 'Gene', (38, 41))	('myogenin', 'Gene', '4656', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('positivity', 'Var', (115, 125))	('p63', 'Gene', '8626', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('S-100', 'Gene', '6271', (43, 48))	('vimentin', 'Gene', '7431', (130, 138))	('tumor', 'Disease', (91, 96))	('smooth', 'Protein', (183, 189))	('vimentin', 'Gene', (130, 138))
347850	28424084	5a, b) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (7.6 cm, previous 20 cm) and a fistula between her small intestine and vagina.	('Tumors', 'Phenotype', 'HP:0002664', (58, 64))	('fistula', 'Disease', 'MESH:D005402', (114, 121))	('fistula', 'Disease', (114, 121))	('Solid Tumors', 'Disease', 'MESH:D009369', (52, 64))	('7.6', 'Var', (84, 87))	('Solid Tumors', 'Disease', (52, 64))
347916	27606300	This study confirmed the preexisting data that positive VEGF expression was concordant with high histological grade (90% concordance).	('VEGF', 'Gene', (56, 60))	('positive', 'Var', (47, 55))	('expression', 'MPA', (61, 71))	('VEGF', 'Gene', '7422', (56, 60))
347929	27606300	identified two independent variables in stepwise multivariable analysis as predictive of histological necrosis: in cases V1 (prechemotherapy volume) was <=300 mL and SUV2:SUV1 ratio was <=0.48, observed good histologic response proportion was 83%, whereas in cases V1 was more than300 mL and SUV2:SUV1 ratio exceeded 0.48, the same was 0%.	('histological necrosis', 'Phenotype', 'HP:0010885', (89, 110))	('<=300', 'Var', (153, 158))	('necrosis', 'Disease', 'MESH:D009336', (102, 110))	('necrosis', 'Disease', (102, 110))
347943	27606300	The investigators found high rates of nutritional depletion at baseline in patients (Vitamin B12-48%, iron deficiency - 59%, anemia - 17%), besides low albumin levels, as predictive of poor OS.	('iron deficiency', 'Disease', (102, 117))	('nutritional depletion', 'Phenotype', 'HP:0004395', (38, 59))	('nutritional depletion', 'MPA', (38, 59))	('anemia', 'Phenotype', 'HP:0001903', (125, 131))	('OS', 'Chemical', '-', (190, 192))	('iron', 'Chemical', 'MESH:D007501', (102, 106))	('patients', 'Species', '9606', (75, 83))	('low albumin', 'Phenotype', 'HP:0003073', (148, 159))	('albumin', 'Gene', (152, 159))	('albumin', 'Gene', '213', (152, 159))	('Vitamin B12-48', 'Var', (85, 99))	('anemia', 'Disease', (125, 131))	('Vitamin B12', 'Chemical', 'MESH:D014805', (85, 96))	('anemia', 'Disease', 'MESH:D000740', (125, 131))	('low', 'NegReg', (148, 151))
347963	27606300	They also observed ectopically expressing this region in Ewing sarcoma cells inhibited tumorigenicity, and EWS-FLI1 target genes indicating a dominant negative biological effect.	('Ewing sarcoma', 'Disease', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('EWS', 'Gene', '2130', (107, 110))	('EWS', 'Gene', (107, 110))	('inhibited', 'NegReg', (77, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('tumor', 'Disease', (87, 92))	('FLI1', 'Gene', (111, 115))	('ectopically expressing', 'Var', (19, 41))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('FLI1', 'Gene', '2313', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
348005	27606300	They identified Hb <10 g%, tumor size >10 cm and single modality treatment as poor prognostic factors, in terms of OS.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('<10 g', 'Var', (19, 24))	('tumor', 'Disease', (27, 32))	('OS', 'Chemical', '-', (115, 117))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
348012	27606300	Jamema et al., from TMH, Mumbai, Maharashtra, India conducted a dosimetric study quantitatively comparing electron arc (EA) versus photon intensity modulated radiotherapy (IMRT) for Askin's tumors and concluded that IMRT resulted in superior planning target volume coverage and sparing of organs at risk compared to EA plans.	('Jamema', 'Disease', 'None', (0, 6))	("Askin's tumors", 'Disease', (182, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('planning target volume coverage', 'CPA', (242, 273))	('IMRT', 'Var', (216, 220))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('TMH', 'Chemical', '-', (20, 23))	('superior', 'PosReg', (233, 241))	('Jamema', 'Disease', (0, 6))	("Askin's tumors", 'Disease', 'MESH:C563168', (182, 196))
348025	27606300	As per hospital registry data, OGS is the most common bone sarcoma, followed by Ewing sarcoma and chondrosarcoma Percentage of post-NACT tumor necrosis is significantly associated with survival in conventional high-grade OGSs VEGF expression has been shown to correlate with histological necrosis, pre- and post-chemotherapy in OGS.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (98, 112))	('VEGF', 'Gene', '7422', (226, 230))	('necrosis', 'Disease', 'MESH:D009336', (143, 151))	('OGS', 'Chemical', '-', (31, 34))	('OGS', 'Chemical', '-', (221, 224))	('VEGF', 'Gene', (226, 230))	('bone sarcoma', 'Disease', (54, 66))	('necrosis', 'Disease', (143, 151))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('expression', 'MPA', (231, 241))	('bone sarcoma', 'Disease', 'MESH:D001847', (54, 66))	('chondrosarcoma', 'Disease', 'MESH:D002813', (98, 112))	('Ewing sarcoma', 'Disease', (80, 93))	('tumor necrosis', 'Disease', 'MESH:D009336', (137, 151))	('chondrosarcoma', 'Disease', (98, 112))	('OGS', 'Chemical', '-', (328, 331))	('histological necrosis', 'Phenotype', 'HP:0010885', (275, 296))	('necrosis', 'Disease', 'MESH:D009336', (288, 296))	('high-grade', 'Var', (210, 220))	('bone sarcoma', 'Phenotype', 'HP:0002669', (54, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('NACT', 'Chemical', '-', (132, 136))	('tumor necrosis', 'Disease', (137, 151))	('associated', 'Reg', (169, 179))	('necrosis', 'Disease', (288, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
348136	20830232	Cytogenetic studies have detected the chromosomal translocation t (x;18) (p11;q11) in synovial sarcoma and have determined that the translocation fuses the SYT gene from chromosome 18 with the SSX1 and SSX2 genes on chromosome X to form SYT-SSX1 or SYT-SSX2, which is thought to function as an aberrant transcriptional regulator.	('SYT-SSX1', 'Gene', '6760;6756', (237, 245))	('SYT', 'Gene', (249, 252))	('SSX2', 'Gene', (253, 257))	('SYT', 'Gene', '6760', (156, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('SSX2', 'Gene', '6757', (253, 257))	('synovial sarcoma', 'Disease', (86, 102))	('coma', 'Phenotype', 'HP:0001259', (98, 102))	('SSX1', 'Gene', '6756', (193, 197))	('SSX2', 'Gene', (202, 206))	('translocation', 'Var', (132, 145))	('SYT', 'Gene', (237, 240))	('SYT', 'Gene', '6760', (249, 252))	('SSX1', 'Gene', (193, 197))	('synovial sarcoma', 'Disease', 'MESH:D013584', (86, 102))	('SSX2', 'Gene', '6757', (202, 206))	('SSX1', 'Gene', '6756', (241, 245))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (86, 102))	('SSX1', 'Gene', (241, 245))	('SYT-SSX1', 'Gene', (237, 245))	('SYT', 'Gene', '6760', (237, 240))	('SYT', 'Gene', (156, 159))
348138	20830232	It has also been demonstrated that patients with the SYT-SSX2 fusion transcripts have a better prognosis than those with SYT-SSXI fusion transcripts.	('SYT', 'Gene', (121, 124))	('SSX', 'Gene', (125, 128))	('SSX2', 'Gene', '6757', (57, 61))	('SSX', 'Gene', '6757', (125, 128))	('SSX', 'Gene', '6757', (57, 60))	('SSX2', 'Gene', (57, 61))	('SYT', 'Gene', '6760', (121, 124))	('SYT', 'Gene', (53, 56))	('SSX', 'Gene', (57, 60))	('fusion transcripts', 'Var', (62, 80))	('patients', 'Species', '9606', (35, 43))	('SYT', 'Gene', '6760', (53, 56))
348151	20830232	The cDNA was amplified using the forward primer (5'CAACAGCAAGATGCATACCA3') and reverse primer (5'CACTTGCTATGCACCTGATG3' for SSX; 5'GGTGCAGTTGTTTCCCATCG3' for SSX1; or 5'GGCACAGCTCTTTCCCATCA3' for SSX2).	('SSX2', 'Gene', '6757', (196, 200))	('SSX1', 'Gene', '6756', (158, 162))	('SSX', 'Gene', (158, 161))	('SSX', 'Gene', '6757', (158, 161))	('SSX1', 'Gene', (158, 162))	('SSX', 'Gene', '6757', (196, 199))	('SSX2', 'Gene', (196, 200))	("5'CACTTGCTATGCACCTGATG3", 'Var', (95, 118))	('SSX', 'Gene', (196, 199))	('SSX', 'Gene', '6757', (124, 127))	('SSX', 'Gene', (124, 127))
348152	20830232	The PCR products were then electrophoresed on a 1.5% agarose gel, stained with ethidium bromide, and subsequently identified as an SYT-SSX (585 bp) or SYT-SSX2 (331 bp) gene (Fig.	('SSX', 'Gene', '6757', (135, 138))	('SSX2', 'Gene', (155, 159))	('SYT', 'Gene', '6760', (151, 154))	('SSX', 'Gene', (135, 138))	('agarose', 'Chemical', 'MESH:D012685', (53, 60))	('SYT', 'Gene', (131, 134))	('331', 'Var', (161, 164))	('SYT', 'Gene', '6760', (131, 134))	('SSX2', 'Gene', '6757', (155, 159))	('ethidium bromide', 'Chemical', 'MESH:D004996', (79, 95))	('SSX', 'Gene', (155, 158))	('SYT', 'Gene', (151, 154))	('SSX', 'Gene', '6757', (155, 158))	('585 bp', 'Var', (140, 146))
348159	20830232	have suggested that the most reliable findings are positivity for EMA or cytokeratins AE1/AE3 and negativity for CD34.	('negativity', 'Var', (98, 108))	('AE1', 'Gene', (86, 89))	('CD34', 'Gene', (113, 117))	('EMA', 'Gene', (66, 69))	('CD34', 'Gene', '947', (113, 117))	('AE1', 'Gene', '6521', (86, 89))	('positivity', 'Var', (51, 61))	('AE3', 'Gene', (90, 93))	('EMA', 'Gene', '4582', (66, 69))	('AE3', 'Gene', '6508', (90, 93))
348165	20830232	Recently, through cytogenetic studies, the translocation of specific genes has been identified in various synovial-sarcoma-like forms of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('synovial-sarcoma', 'Phenotype', 'HP:0012570', (106, 122))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('coma', 'Phenotype', 'HP:0001259', (118, 122))	('sarcoma', 'Disease', (115, 122))	('synovial-sarcoma', 'Disease', 'MESH:D013584', (106, 122))	('identified', 'Reg', (84, 94))	('synovial-sarcoma', 'Disease', (106, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('coma', 'Phenotype', 'HP:0001259', (140, 144))	('translocation', 'Var', (43, 56))	('sarcoma', 'Disease', (137, 144))
348171	20830232	The detection of fusion genes has been reported to have a sensitivity of 96% and a specificity of 100% for the diagnosis of synovial sarcoma, which has made this technique a widely used and important method for establishing a definite diagnosis of this tumor.	('fusion genes', 'Var', (17, 29))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (124, 140))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('synovial sarcoma', 'Disease', 'MESH:D013584', (124, 140))	('coma', 'Phenotype', 'HP:0001259', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('synovial sarcoma', 'Disease', (124, 140))	('tumor', 'Disease', (253, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
348183	20830232	Although some investigators have indicated that patients with SYT-SSX1 fusion genes have a poorer prognosis than do those with SYT-SSX2 fusion genes, Guillou et al.	('SYT-SSX1', 'Gene', (62, 70))	('SYT', 'Gene', '6760', (62, 65))	('SSX2', 'Gene', '6757', (131, 135))	('SYT-SSX1', 'Gene', '6760;6756', (62, 70))	('SSX2', 'Gene', (131, 135))	('SYT', 'Gene', '6760', (127, 130))	('SYT', 'Gene', (127, 130))	('SYT', 'Gene', (62, 65))	('patients', 'Species', '9606', (48, 56))	('fusion genes', 'Var', (71, 83))
348185	20830232	We have reported a case that was definitively diagnosed as primary pulmonary biphasic sarcoma based on the detection of an SYT-SSX2 fusion gene.	('primary pulmonary biphasic sarcoma', 'Disease', 'MESH:D008175', (59, 93))	('SSX2', 'Gene', '6757', (127, 131))	('fusion gene', 'Var', (132, 143))	('primary pulmonary biphasic sarcoma', 'Disease', (59, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('SYT', 'Gene', (123, 126))	('SSX2', 'Gene', (127, 131))	('coma', 'Phenotype', 'HP:0001259', (89, 93))	('SYT', 'Gene', '6760', (123, 126))
348195	33568624	A gastrointestinal stromal tumor (GIST), the most common sarcoma, is most often driven by oncogenic KIT or PDGFRA mutations.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('KIT', 'Gene', (100, 103))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (2, 32))	('PDGFRA', 'Gene', (107, 113))	('mutations', 'Var', (114, 123))	('A gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (0, 32))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('PDGFRA', 'Gene', '5156', (107, 113))	('GIST', 'Phenotype', 'HP:0100723', (34, 38))	('A gastrointestinal stromal tumor', 'Disease', (0, 32))	('sarcoma', 'Disease', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
348200	33568624	It is well established that crosstalk between epithelial cancers and CAFs can promote tumor progression and chemoresistance.	('epithelial cancers', 'Disease', 'MESH:D009369', (46, 64))	('chemoresistance', 'CPA', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('promote', 'PosReg', (78, 85))	('tumor', 'Disease', (86, 91))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('epithelial cancers', 'Disease', (46, 64))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('crosstalk', 'Var', (28, 37))
348223	33568624	Notably, CAFscr CM significantly activated several phosphokinase proteins, including JNK1/2/3, AKT, FAK, PRAS40, c-Jun, and STAT3, while these effects were abrogated by loss of PDGFC (Fig.	('c-Jun', 'Gene', '3725', (113, 118))	('c-Jun', 'Gene', (113, 118))	('FAK', 'Gene', '5747', (100, 103))	('PRAS40', 'Gene', '84335', (105, 111))	('AKT', 'Gene', '207', (95, 98))	('CAFscr CM', 'Disease', (9, 18))	('CAFscr CM', 'Disease', 'MESH:D009202', (9, 18))	('activated', 'PosReg', (33, 42))	('STAT3', 'Gene', (124, 129))	('PDGFC', 'Gene', '56034', (177, 182))	('JNK1/2/3', 'Gene', (85, 93))	('STAT3', 'Gene', '6774', (124, 129))	('PRAS40', 'Gene', (105, 111))	('loss', 'Var', (169, 173))	('phosphokinase', 'Enzyme', (51, 64))	('AKT', 'Gene', (95, 98))	('PDGFC', 'Gene', (177, 182))	('JNK1/2/3', 'Gene', '5599;5601;5602', (85, 93))	('FAK', 'Gene', (100, 103))
348246	33568624	The assays showed that CM of GISTs (GIST-T1, GIST882, and GIST430) in GFs increased GIST-T1 migration, while this effect was abrogated by anti-TGF-beta1 antibody (Fig.	('GIST', 'Phenotype', 'HP:0100723', (36, 40))	('GIST', 'Phenotype', 'HP:0100723', (84, 88))	('GIST882', 'Chemical', '-', (45, 52))	('GIST430', 'Chemical', '-', (58, 65))	('GIST430', 'Var', (58, 65))	('GIST', 'Phenotype', 'HP:0100723', (45, 49))	('increased', 'PosReg', (74, 83))	('GIST', 'Phenotype', 'HP:0100723', (58, 62))	('GIST-T1 migration', 'CPA', (84, 101))	('GIST', 'Phenotype', 'HP:0100723', (29, 33))
348279	33568624	Normal GFs were purchased from Science Research Laboratories (Carlsbad, CA), and CAFs were isolated from a human PDGFRA mutant GIST by a serial trypsinization method.	('PDGFRA', 'Gene', '5156', (113, 119))	('GIST', 'Phenotype', 'HP:0100723', (127, 131))	('human', 'Species', '9606', (107, 112))	('PDGFRA', 'Gene', (113, 119))	('mutant', 'Var', (120, 126))
348340	29852316	At the early development stages of NCIt, there were more neoplasm concepts (5901) than non-neoplasm concepts (4620) in the Disease, Disorder or Finding subhierarchy.	('neoplasm', 'Disease', (91, 99))	('5901', 'Var', (76, 80))	('neoplasm', 'Phenotype', 'HP:0002664', (91, 99))	('neoplasm', 'Disease', (57, 65))	('non-neoplasm', 'Disease', (87, 99))	('non-neoplasm', 'Disease', 'MESH:C580335', (87, 99))	('neoplasm', 'Disease', 'MESH:D009369', (57, 65))	('neoplasm', 'Disease', 'MESH:D009369', (91, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (57, 65))
348474	27528222	Tumor cell heterogeneity can arise by irreversible genetic mutation, as well as by non-mutational mechanisms, which can be reversibly modulated by the tumor microenvironment and the epigenome.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('genetic mutation', 'Var', (51, 67))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
348479	27528222	Mechanistically, our results show that, in ambient conditions where CXCR4 expression is low, the CXCR4 promoter exists in a poised, bivalent state with simultaneous enrichment of both activating (H3K4me3) and repressive (H3K27me3) post-translational histone modifications.	('H3K4me3', 'Var', (196, 203))	('K27', 'Gene', '342574', (223, 226))	('K27', 'Gene', (223, 226))	('activating', 'PosReg', (184, 194))
348493	27528222	In addition, we evaluated the chromatin state of the CXCR4 locus in a panel of Ewing sarcoma cell lines to determine if epigenetic plasticity contributes to stress-dependent activation of CXCR4.	('CXCR4', 'MPA', (188, 193))	('Ewing sarcoma', 'Disease', (79, 92))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('activation', 'PosReg', (174, 184))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (79, 92))	('epigenetic plasticity', 'Var', (120, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
348494	27528222	The findings from these studies demonstrate that Ewing sarcoma cells transition between CXCR4 negative and CXCR4 positive states in vivo, that this phenotypic heterogeneity contributes to tumor growth and is, at least in part, driven by epigenetic plasticity of the CXCR4 promoter in response to microenvironmental stress.	('tumor', 'Disease', (188, 193))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('epigenetic plasticity', 'Var', (237, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('Ewing sarcoma', 'Disease', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))	('contributes', 'PosReg', (173, 184))
348500	27528222	Examination of gene expression in the excised tumors revealed that CXCR4 transcript levels in resected tumors directly correlated with tumor volume, suggesting that expression of CXCR4 in established tumors might promote tumor growth (Figure 1D).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CXCR4 transcript levels', 'MPA', (67, 90))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('CXCR4', 'Var', (179, 184))	('promote', 'PosReg', (213, 220))	('tumor', 'Disease', (200, 205))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (200, 206))
348512	27528222	In particular, rapid induction of gene expression in stem cells is achieved by the simultaneous presence of both activating (H3K4me3) and repressive (H3K27me3) histone marks at key developmental gene promoters, creating loci that are silenced but poised for rapid activation in response to appropriate cues.	('K27', 'Gene', '342574', (152, 155))	('activating', 'PosReg', (113, 123))	('H3K4me3', 'Var', (125, 132))	('K27', 'Gene', (152, 155))
348514	27528222	As shown, analysis of the ENCODE database revealed that both H3K27me3 and H3K4me3 histone modifications are enriched at the CXCR4 promoter in human embryonic stem cells, consistent with a bivalent state (Figure 3A, top).	('K27', 'Gene', '342574', (63, 66))	('human', 'Species', '9606', (142, 147))	('H3K4me3', 'Var', (74, 81))	('K27', 'Gene', (63, 66))
348515	27528222	In contrast, in HeLa cells, the CXCR4 promoter is characterized by a univalent state, with enrichment of only the H3K4me3 mark and complete absence of the repressive H3K27me3 modification (Figure 3A, bottom).	('K27', 'Gene', '342574', (168, 171))	('absence', 'NegReg', (140, 147))	('K27', 'Gene', (168, 171))	('HeLa', 'CellLine', 'CVCL:0030', (16, 20))	('H3K4me3', 'Var', (114, 121))
348518	27528222	To evaluate the chromatin state of the CXCR4 promoter in Ewing sarcoma we performed ChIP-PCR studies using antibodies directed against the H3K4me3 and H3K27me3 histone modifications and genomic PCR primers specific for the CXCR4 promoter (Supplementary Figure S1A).	('K27', 'Gene', '342574', (153, 156))	('H3K4me3', 'Var', (139, 146))	('Ewing sarcoma', 'Disease', (57, 70))	('K27', 'Gene', (153, 156))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))
348521	27528222	Relative enrichment of the H3K4me3 modification was positively correlated (r = 0.9630) with CXCR4 expression in the tested cell lines while H3K27me3 was negatively correlated (r = -0.6929) with CXCR4 transcript expression (Figure 3E).	('H3K4me3', 'Var', (27, 34))	('K27', 'Gene', '342574', (142, 145))	('K27', 'Gene', (142, 145))	('CXCR4 expression', 'MPA', (92, 108))	('CXCR4 transcript expression', 'MPA', (194, 221))
348529	27528222	Moreover, analysis of histone modifications demonstrated preferential enrichment of H3K27me3 in the CXCR4 negative populations (Figure 5C) and H3K4me3 in the CXCR4 high populations (Figure 5D), supporting a role for these modifications in gene regulation.	('K27', 'Gene', (86, 89))	('H3K4me3', 'Var', (143, 150))	('K27', 'Gene', '342574', (86, 89))
348541	27528222	Ewing sarcomas are aggressive bone and soft tissue tumors that are characterized by the presence of pathognomonic chromosomal translocations that most commonly result in creation of an EWS-FLI1, or related EWS-ERG, oncogenic fusion gene.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))	('EWS', 'Gene', (185, 188))	('result', 'Reg', (160, 166))	('FLI1', 'Gene', (189, 193))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (0, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWS', 'Gene', (206, 209))	('FLI1', 'Gene', '2313', (189, 193))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (39, 56))	('soft tissue tumors', 'Disease', (39, 57))	('Ewing sarcomas', 'Disease', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (0, 14))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (39, 57))	('creation', 'Var', (170, 178))	('EWS', 'Gene', '2130', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('soft tissue tumors', 'Disease', 'MESH:D012983', (39, 57))	('EWS', 'Gene', '2130', (206, 209))
348545	27528222	Thus, it is likely that epigenetic plasticity plays a key role in mediating Ewing sarcoma tumor cell heterogeneity.	('Ewing sarcoma tumor', 'Disease', 'MESH:C563168', (76, 95))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('epigenetic plasticity', 'Var', (24, 45))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Ewing sarcoma tumor', 'Disease', (76, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
348564	27528222	However, given our current findings, it will be important to consider that use of EZH2 inhibitors as anti-cancer agents in Ewing sarcoma could have the on-target, but undesirable, effect of activating CXCR4.	('EZH2', 'Gene', (82, 86))	('EZH2', 'Gene', '2146', (82, 86))	('activating CXCR4', 'MPA', (190, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('Ewing sarcoma', 'Disease', (123, 136))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (123, 136))	('inhibitors', 'Var', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
348584	27528222	In the context of Ewing sarcoma, epigenetic plasticity is likely to play a major role in mediating this heterogeneity and promoting disease progression.	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('Ewing sarcoma', 'Disease', (18, 31))	('epigenetic plasticity', 'Var', (33, 54))	('promoting', 'PosReg', (122, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (18, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (18, 31))
348628	26023506	Siebel et al found that in NWTS-4, patients treated with vincristine, doxorubicin, and dactinomycin for 15 months had an improved relapse-free survival rate compared with patients treated for 6 months (87.5% vs 60.6% at 8 y).	('doxorubicin', 'Var', (70, 81))	('dactinomycin', 'Var', (87, 99))	('improved', 'PosReg', (121, 129))	('dactinomycin', 'Chemical', 'MESH:D003609', (87, 99))	('relapse-free survival', 'CPA', (130, 151))	('patients', 'Species', '9606', (171, 179))	('doxorubicin', 'Chemical', 'MESH:D004317', (70, 81))	('patients', 'Species', '9606', (35, 43))	('vincristine', 'Chemical', 'MESH:D014750', (57, 68))
348650	23087796	Systemic treatments for MCD have included chemotherapy, anti-herpes virus, highly active antiretroviral therapy and, more recently, monoclonal antibodies against both IL6 and CD20.	('monoclonal', 'Var', (132, 142))	('CD20', 'Gene', '54474', (175, 179))	('IL6', 'Gene', '3569', (167, 170))	('CD20', 'Gene', (175, 179))	('MCD', 'Disease', 'MESH:D012514', (24, 27))	('IL6', 'Gene', (167, 170))	('MCD', 'Disease', (24, 27))
348676	23087796	HIV PCR was less than 40 copies/mL, CD4 was 30.5% (VR 35-62%) and 716 mm3 (VR 398-1535 mm3), CD8 was 50.7% (VR 17-43%) and 1190 mm3 (VR 255-1720mm3) and C-reactive protein 40 mg/L.	('C-reactive protein', 'Gene', (153, 171))	('C-reactive protein', 'Gene', '1401', (153, 171))	('CD4', 'Gene', (36, 39))	('CD8', 'Gene', (93, 96))	('CD8', 'Gene', '925', (93, 96))	('CD4', 'Gene', '920', (36, 39))	('716 mm3', 'Var', (66, 73))
348682	23087796	Immunohistoche-mistry showed HHV-8 positivity in scattered cells and polyclonal plasmacytosis.	('plasmacytosis', 'Phenotype', 'HP:0030150', (80, 93))	('HHV-8', 'Species', '37296', (29, 34))	('positivity', 'Var', (35, 45))	('HHV-8', 'Gene', (29, 34))
348709	23087796	For aggressive disease, treatment successes were obtained with rituximab (375 mg/m2) with weekly etoposide (100 mg/m2) i.v.	('375 mg/m2', 'Var', (74, 83))	('etoposide', 'Chemical', 'MESH:D005047', (97, 106))	('rituximab', 'Chemical', 'MESH:D000069283', (63, 72))	('aggressive disease', 'Disease', 'MESH:D001523', (4, 22))	('aggressive disease', 'Disease', (4, 22))
348760	32921685	The immunohistochemical findings of these atypical cells showed positivity for alpha-SMA (Fig.	('positivity', 'Var', (64, 74))	('alpha-SMA', 'Gene', '58', (79, 88))	('alpha-SMA', 'Gene', (79, 88))
348761	32921685	Immunohistochemically, these cells were negative for CK AE1/3, CK7, CK20, CD3, CD20, CD56, CD30, D2-40, CD31, S-100, HMB45, and desmin.	('CD31', 'Gene', '5175', (104, 108))	('desmin', 'Gene', '1674', (128, 134))	('CD56', 'Gene', (85, 89))	('CD56', 'Gene', '4684', (85, 89))	('D2-40', 'Var', (97, 102))	('CD20', 'Gene', '54474', (79, 83))	('CD20', 'Gene', (79, 83))	('desmin', 'Gene', (128, 134))	('CD30', 'Gene', '943', (91, 95))	('CK20', 'Gene', (68, 72))	('CD30', 'Gene', (91, 95))	('CK20', 'Gene', '54474', (68, 72))	('CK7', 'Gene', (63, 66))	('CD31', 'Gene', (104, 108))	('CK7', 'Gene', '3855', (63, 66))
348897	30816108	For example, cumulative-dose and dose-intense doxorubicin cause cardiomyopathy, with an associated mortality risk.	('cardiomyopathy', 'Disease', (64, 78))	('cause', 'Reg', (58, 63))	('doxorubicin', 'Var', (46, 57))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (64, 78))	('cardiomyopathy', 'Disease', 'MESH:D009202', (64, 78))	('doxorubicin', 'Chemical', 'MESH:D004317', (46, 57))
349032	30816108	Furthermore, there is currently no feasible biomarker for predicting response to apatinib treatment, even though apatinib can reportedly inhibit VEGFR2 and regulate PD-L1 expression, apoptosis, autophagy, and epithelial-mesenchymal transition.	('expression', 'MPA', (171, 181))	('epithelial-mesenchymal transition', 'CPA', (209, 242))	('apatinib', 'Var', (113, 121))	('VEGFR2', 'Gene', '3791', (145, 151))	('apatinib', 'Chemical', 'MESH:C553458', (113, 121))	('autophagy', 'CPA', (194, 203))	('inhibit', 'NegReg', (137, 144))	('PD-L1', 'Gene', (165, 170))	('apatinib', 'Chemical', 'MESH:C553458', (81, 89))	('PD-L1', 'Gene', '29126', (165, 170))	('VEGFR2', 'Gene', (145, 151))	('apoptosis', 'CPA', (183, 192))	('regulate', 'Reg', (156, 164))
349197	29479833	Three categories were established based on the number of cycles in which T42.5*60 was achieved: poor hyperthermia, T42.5*60 was not achieved; mild hyperthermia, T42.5*60 was achieved in 1-3 cycles; and complete hyperthermia, T42.5*60 was achieved in 4-5 cycles 12.	('hyperthermia', 'Disease', 'MESH:D005334', (101, 113))	('hyperthermia', 'Disease', 'MESH:D005334', (211, 223))	('poor hyperthermia', 'Phenotype', 'HP:0002045', (96, 113))	('poor', 'Disease', (96, 100))	('hyperthermia', 'Phenotype', 'HP:0001945', (101, 113))	('hyperthermia', 'Phenotype', 'HP:0001945', (211, 223))	('hyperthermia', 'Disease', (211, 223))	('T42.5*60', 'Var', (161, 169))	('hyperthermia', 'Disease', (101, 113))	('hyperthermia', 'Disease', 'MESH:D005334', (147, 159))	('hyperthermia', 'Phenotype', 'HP:0001945', (147, 159))	('hyperthermia', 'Disease', (147, 159))	('T42.5', 'Var', (73, 78))
349219	29479833	T42.5*60 was achieved in 68.3% of patients, and 48.3% of patients were considered to achieve complete hyperthermia (T42.5*60 = 4-5 cycles).	('patients', 'Species', '9606', (57, 65))	('hyperthermia', 'Disease', 'MESH:D005334', (102, 114))	('T42.5*60', 'Var', (0, 8))	('patients', 'Species', '9606', (34, 42))	('hyperthermia', 'Phenotype', 'HP:0001945', (102, 114))	('hyperthermia', 'Disease', (102, 114))
349260	29479833	However, RHC might eradicate tumor progression around the surgical site, thereby improving the local control rate.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('RHC', 'Var', (9, 12))	('improving', 'PosReg', (81, 90))	('local control', 'CPA', (95, 108))	('tumor', 'Disease', (29, 34))	('eradicate', 'NegReg', (19, 28))
349298	32220056	7  Trabectedin treatment was delayed until the following criteria were met; neutrophil count more than 1500 cells per muL, platelet count more than 10  x 104 cells per muL, blood albumin more than 2.5 g/dL, total bilirubin less than 1.5 mg/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine phosphokinase (CPK) less than 2.5 times of upper limit of normal, and creatinine clearance more than 30 mL per minutes.	('muL', 'Gene', (118, 121))	('muL', 'Gene', '4591', (168, 171))	('total bilirubin', 'MPA', (207, 222))	('more than', 'Var', (187, 196))	('less', 'NegReg', (343, 347))	('AST', 'Gene', (272, 275))	('creatinine clearance', 'MPA', (393, 413))	('muL', 'Gene', '4591', (118, 121))	('creatinine', 'Chemical', 'MESH:D003404', (393, 403))	('more', 'Var', (93, 97))	('aspartate aminotransferase', 'Gene', '26503', (244, 270))	('less', 'NegReg', (223, 227))	('more than', 'Reg', (414, 423))	('aspartate aminotransferase', 'Gene', (244, 270))	('muL', 'Gene', (168, 171))	('creatine phosphokinase', 'MPA', (314, 336))	('AST', 'Gene', '26503', (272, 275))	('alanine aminotransferase', 'Gene', (278, 302))	('alanine aminotransferase', 'Gene', '2875', (278, 302))	('more than', 'Var', (138, 147))
349473	25806369	EWS is a highly invasive, undifferentiated tumor of unknown histogenic origin whose molecular underpinnings, in approximately 85% of tumors, are associated with the expression of the EWS-FLI1 fusion product generated by the t(11;22)(q24;q12) chromosomal translocation (Arvand and Denny,).	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('EWS', 'Gene', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('FLI1', 'Gene', (187, 191))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (224, 241))	('EWS', 'Gene', (0, 3))	('EWS', 'Phenotype', 'HP:0012254', (183, 186))	('t(11;22)(q24;q12', 'Var', (224, 240))	('tumors', 'Disease', (133, 139))	('rat', 'Species', '10116', (211, 214))	('FLI1', 'Gene', '2313', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (133, 138))	('EWS', 'Phenotype', 'HP:0012254', (0, 3))	('mole', 'Phenotype', 'HP:0003764', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('EWS', 'Gene', '2130', (183, 186))	('associated', 'Reg', (145, 155))	('EWS', 'Gene', '2130', (0, 3))
349514	25806369	Cells were incubated with primary antibody overnight at 4 C, washed with PBST, and incubated with DyLight 650 (ab98371 or ab102464; Abcam) conjugated secondary antibody.	('ab102464', 'Var', (122, 130))	('PBS', 'Disease', 'MESH:D011535', (73, 76))	('PBS', 'Disease', (73, 76))
349515	25806369	Rat monoclonal to SSEA3 (ab16286), mouse monoclonal to SSEA4 (ab16287), and mouse monoclonal to TRA-1-60 (ab16288) antibodies were supplied by Abcam, in addition to rat IgM (ab35768) and mouse IgM (ab18401) isotype controls.	('TRA-1', 'Gene', (96, 101))	('Rat', 'Species', '10116', (0, 3))	('mouse', 'Species', '10090', (76, 81))	('mouse', 'Species', '10090', (35, 40))	('ab35768', 'Var', (174, 181))	('mouse', 'Species', '10090', (187, 192))	('rat', 'Species', '10116', (165, 168))	('TRA-1', 'Gene', '362862', (96, 101))
349583	25806369	Consistent with the observed EWS promoter hypomethylation, quantitative PCR revealed equivalent expression of the EWS-FLI1 fusion transcript among EWS-iPS and the CHLA-10 parental cells from which they were derived (Figure 4B), indicating that erasure of the epigenetic modifications during cellular reprogramming does not disrupt EWS-FLI1 oncogene expression in EWS-iPS cells.	('FLI1', 'Gene', (335, 339))	('EWS', 'Gene', (114, 117))	('EWS', 'Phenotype', 'HP:0012254', (331, 334))	('EWS', 'Phenotype', 'HP:0012254', (29, 32))	('EWS', 'Gene', '2130', (363, 366))	('EWS', 'Phenotype', 'HP:0012254', (147, 150))	('EWS', 'Phenotype', 'HP:0012254', (114, 117))	('FLI1', 'Gene', '2313', (335, 339))	('EWS', 'Gene', '2130', (331, 334))	('FLI1', 'Gene', (118, 122))	('EWS', 'Gene', '2130', (29, 32))	('iPS', 'Gene', '51477', (367, 370))	('EWS', 'Gene', '2130', (147, 150))	('EWS', 'Gene', '2130', (114, 117))	('expression', 'MPA', (349, 359))	('iPS', 'Gene', (367, 370))	('EWS', 'Gene', (363, 366))	('FLI1', 'Gene', '2313', (118, 122))	('CHLA-10', 'Chemical', '-', (163, 170))	('iPS', 'Gene', '51477', (151, 154))	('epigenetic', 'Var', (259, 269))	('EWS', 'Gene', (331, 334))	('EWS', 'Gene', (29, 32))	('EWS', 'Phenotype', 'HP:0012254', (363, 366))	('iPS', 'Gene', (151, 154))	('EWS', 'Gene', (147, 150))
349588	25806369	This suggests that epigenetic alterations imposed during the reprogramming process provided the EWS cells drug resistance.	('EWS', 'Gene', '2130', (96, 99))	('EWS', 'Gene', (96, 99))	('drug resistance', 'CPA', (106, 121))	('drug resistance', 'Phenotype', 'HP:0020174', (106, 121))	('epigenetic alterations', 'Var', (19, 41))	('provided', 'Reg', (83, 91))	('rat', 'Species', '10116', (34, 37))	('EWS', 'Phenotype', 'HP:0012254', (96, 99))
349598	25806369	Given that both the MAPK/ERK and PI3K/AKT/mTOR signaling cascades serve as major modulators of the oncogenic phenotype in both EWS and EWS-FLI1 expressing cancer cell lines (Silvany et al.,; Zenali et al.,), we chose U-0126, rapamycin, and LY294002 pharmacological agents (targeted inhibitors of ERK1/2, mTOR, and PI3K, respectively) for investigation in subsequent chemo-sensitivity studies.	('rapamycin', 'Chemical', 'MESH:D020123', (225, 234))	('MAPK', 'Gene', (20, 24))	('EWS', 'Gene', '2130', (135, 138))	('ERK', 'Gene', '5594', (25, 28))	('mTOR', 'Gene', (304, 308))	('ERK', 'Gene', (296, 299))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('LY294002', 'Var', (240, 248))	('AKT', 'Gene', (38, 41))	('mTOR', 'Gene', (42, 46))	('U-0126', 'Chemical', 'MESH:C113580', (217, 223))	('mTOR', 'Gene', '2475', (304, 308))	('ERK', 'Gene', (25, 28))	('EWS', 'Gene', (127, 130))	('mTOR', 'Gene', '2475', (42, 46))	('EWS', 'Gene', (135, 138))	('FLI1', 'Gene', (139, 143))	('EWS', 'Phenotype', 'HP:0012254', (127, 130))	('LY294002', 'Chemical', 'MESH:C085911', (240, 248))	('AKT', 'Gene', '207', (38, 41))	('cancer', 'Disease', (155, 161))	('MAPK', 'Gene', '5595;5594;5595', (20, 24))	('EWS', 'Phenotype', 'HP:0012254', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('FLI1', 'Gene', '2313', (139, 143))	('ERK', 'Gene', '5594', (296, 299))	('EWS', 'Gene', '2130', (127, 130))
349602	25806369	As shown in Figure 6B, in vitro differentiated iPS cells exhibited recuperated sensitivity to rapamycin and LY294002, inhibitors targeting mTOR and PI3K, respectively; an effect that was more pronounced in EWS-iPS clone B compared to clone C. In an analogous fashion, both differentiated iPS cell clones showed a similar degree of drug response recovery to the ERK inhibitor, U-0126; however the magnitude of reduction in cell viability of the iPS cells was less severe vis-a-vis CHLA-10 parental (Figure 6B).	('ERK', 'Gene', '5594', (361, 364))	('iPS', 'Gene', (444, 447))	('mTOR', 'Gene', (139, 143))	('iPS', 'Gene', (47, 50))	('LY294002', 'Chemical', 'MESH:C085911', (108, 116))	('rat', 'Species', '10116', (73, 76))	('iPS', 'Gene', '51477', (210, 213))	('ERK', 'Gene', (361, 364))	('mTOR', 'Gene', '2475', (139, 143))	('iPS', 'Gene', '51477', (288, 291))	('iPS', 'Gene', (210, 213))	('U-0126', 'Chemical', 'MESH:C113580', (376, 382))	('EWS', 'Gene', (206, 209))	('iPS', 'Gene', (288, 291))	('EWS', 'Phenotype', 'HP:0012254', (206, 209))	('CHLA-10', 'Chemical', '-', (480, 487))	('rapamycin', 'Chemical', 'MESH:D020123', (94, 103))	('LY294002', 'Var', (108, 116))	('iPS', 'Gene', '51477', (444, 447))	('iPS', 'Gene', '51477', (47, 50))	('EWS', 'Gene', '2130', (206, 209))
349613	25806369	However, maintenance of specific epigenetic marks, or rather maintaining some "epigenetic memory" of the original EWS cell line, could prove advantageous for the purpose of accurately modeling a particular disease following successful re-differentiation.	('epigenetic marks', 'Var', (33, 49))	('EWS', 'Gene', '2130', (114, 117))	('EWS', 'Gene', (114, 117))	('EWS', 'Phenotype', 'HP:0012254', (114, 117))	('rat', 'Species', '10116', (177, 180))	('rat', 'Species', '10116', (54, 57))	('particular disease', 'Disease', (195, 213))	('particular disease', 'Disease', 'MESH:D004194', (195, 213))
349629	25806369	This suggests that epigenetic modifications during the reprogramming process or activation of specific pathways required for iPS cell maintenance may supersede downstream EWS-FLI1-mediated pathways.	('iPS', 'Gene', (125, 128))	('epigenetic modifications', 'Var', (19, 43))	('FLI1', 'Gene', '2313', (175, 179))	('iPS', 'Gene', '51477', (125, 128))	('EWS', 'Phenotype', 'HP:0012254', (171, 174))	('FLI1', 'Gene', (175, 179))	('EWS', 'Gene', '2130', (171, 174))	('EWS', 'Gene', (171, 174))	('activation', 'PosReg', (80, 90))
349632	25806369	The expression of the EWS-FLI1 fusion gene in EWS induces post-transcriptional derepression of IGF pathway components (Prieur et al.,; McKinsey et al.,) which consequently enhances MAPK/ERK as well as PI3K/AKT/mTOR signaling (Silvany et al.,; Zenali et al.,).	('AKT', 'Gene', (206, 209))	('mTOR', 'Gene', (210, 214))	('ERK', 'Gene', '5594', (186, 189))	('post-transcriptional', 'MPA', (58, 78))	('EWS', 'Gene', '2130', (22, 25))	('EWS', 'Gene', '2130', (46, 49))	('FLI1', 'Gene', '2313', (26, 30))	('mTOR', 'Gene', '2475', (210, 214))	('ERK', 'Gene', (186, 189))	('AKT', 'Gene', '207', (206, 209))	('expression', 'Var', (4, 14))	('MAPK', 'Gene', '5595;5594;5595', (181, 185))	('EWS', 'Gene', (22, 25))	('EWS', 'Gene', (46, 49))	('IGF pathway', 'Pathway', (95, 106))	('EWS', 'Phenotype', 'HP:0012254', (46, 49))	('MAPK', 'Gene', (181, 185))	('EWS', 'Phenotype', 'HP:0012254', (22, 25))	('enhances', 'PosReg', (172, 180))	('FLI1', 'Gene', (26, 30))
349680	21845069	No association is seen with p21WAF1 mdm-2, S-phase fraction or ploidy.	('S-phase fraction', 'CPA', (43, 59))	('mdm-2', 'Gene', (36, 41))	('p21WAF1', 'Var', (28, 35))	('mdm-2', 'Gene', '4193', (36, 41))
349694	21845069	Some studies have demonstrated that P53 protein mutation is implicated in the pathogenesis and progression, but not initiation of KS.	('P53', 'Gene', '7157', (36, 39))	('implicated', 'Reg', (60, 70))	('mutation', 'Var', (48, 56))	('KS', 'Phenotype', 'HP:0100726', (130, 132))	('protein', 'Protein', (40, 47))	('P53', 'Gene', (36, 39))
349695	21845069	Indeed, p53 mutation was found to be more commonly expressed in cases with a more advanced stage and therefore, was found to be a useful adjunct to identify cases with a potential to have a more aggressive clinical behaviour.	('aggressive clinical behaviour', 'Phenotype', 'HP:0000718', (195, 224))	('p53', 'Gene', (8, 11))	('expressed', 'Reg', (51, 60))	('p53', 'Gene', '7157', (8, 11))	('mutation', 'Var', (12, 20))
349701	21242332	The Utah Cancer Registry (UCR) and Utah Population Database (UPBD) were interrogated for sarcoma diagnostic codes grouped by genetic type, either complex genotype/karyotype sarcoma or balanced translocation-associated sarcoma.	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('sarcoma', 'Disease', (173, 180))	('sarcoma', 'Disease', 'MESH:D012509', (218, 225))	('Cancer', 'Disease', 'MESH:D009369', (9, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('complex genotype/karyotype', 'Var', (146, 172))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Disease', (218, 225))	('Cancer', 'Disease', (9, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))	('balanced', 'Disease', (184, 192))
349705	21242332	There was no evidence for excess relatedness for the balanced translocation group using the GIF test (p=0.657) and no significantly elevated RRs.	('elevated', 'PosReg', (132, 140))	('GIF', 'Gene', (92, 95))	('balanced translocation', 'Var', (53, 75))	('RRs', 'CPA', (141, 144))	('GIF', 'Gene', '36615', (92, 95))
349742	21242332	Such heritable predispositions to generate translocations could be either generalized or locus (sarcoma sub-type) specific.	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('translocations', 'Var', (43, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('sarcoma', 'Disease', (96, 103))
349743	21242332	Silencing of the p53 pathway, for example, is common even among balanced translocation sarcomas.	('balanced translocation sarcomas', 'Disease', (64, 95))	('p53', 'Gene', (17, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Silencing', 'Var', (0, 9))	('balanced translocation sarcomas', 'Disease', 'MESH:D014178', (64, 95))	('p53', 'Gene', '7157', (17, 20))
349752	21242332	These patients typically bear point mutations in specific genes, rather than balanced translocations, but are otherwise simple genetic sarcomas.	('point mutations', 'Var', (30, 45))	('genetic sarcomas', 'Disease', 'MESH:D030342', (127, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('patients', 'Species', '9606', (6, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('genetic sarcomas', 'Disease', (127, 143))	('bear', 'Reg', (25, 29))
349778	21242332	There were 229 individuals with balanced translocation or simple genetic sarcomas identified in the UCR with at least 3 generations of ancestral genealogy recorded in the UPDB.	('genetic sarcomas', 'Disease', (65, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('genetic sarcomas', 'Disease', 'MESH:D030342', (65, 81))	('balanced translocation', 'Var', (32, 54))	('simple', 'Disease', (58, 64))
349792	21242332	Examples, include Li Fraumeni syndrome, arising from inherited disruption of p53, recognized for the strong predisposition to a variety of carcinomas, but also including osteosarcoma and pleiomorphic rhabdomyosarcoma; hereditary retinoblastoma, in which syndrome osteosarcoma is the second most common cancer but the first is almost universally penetrant; and neurofibromatosis type I, which is recognized from a broad array of non-oncologic clinical manifestations, but also predisposes patients to MPNST.	('neurofibromatosis type I', 'Disease', 'MESH:C537392', (360, 384))	('Fraumeni syndrome', 'Disease', (21, 38))	('disruption', 'Var', (63, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (263, 275))	('cancer', 'Disease', (302, 308))	('syndrome osteosarcoma', 'Disease', (254, 275))	('retinoblastoma', 'Phenotype', 'HP:0009919', (229, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('p53', 'Gene', '7157', (77, 80))	('carcinomas', 'Disease', (139, 149))	('Li Fraumeni', 'Disease', 'MESH:D016864', (18, 29))	('patients', 'Species', '9606', (488, 496))	('syndrome osteosarcoma', 'Disease', 'MESH:D012516', (254, 275))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (218, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('p53', 'Gene', (77, 80))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (200, 216))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (360, 377))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('neurofibromatosis type I', 'Disease', (360, 384))	('Li Fraumeni', 'Disease', (18, 29))	('osteosarcoma and pleiomorphic rhabdomyosarcoma', 'Disease', 'MESH:D012516', (170, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('carcinomas', 'Disease', 'MESH:D002277', (139, 149))	('Fraumeni syndrome', 'Disease', 'MESH:D016864', (21, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (170, 182))	('hereditary retinoblastoma', 'Disease', (218, 243))
349857	26034386	Upon many abnormalities that have been identified, two translocations are pathognostic for RMS: t(2;13)(q35;q14) and t(1;13)(p36;q14), which are observed in 80% of cases of ARMS.	('t(2;13)(q35;q14', 'Var', (96, 111))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (117, 133))	('RMS', 'Phenotype', 'HP:0002859', (91, 94))	('RMS', 'Disease', (91, 94))	('t(1;13)(p36;q14', 'Var', (117, 132))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (96, 112))	('pathognostic', 'Reg', (74, 86))	('RMS', 'Phenotype', 'HP:0002859', (174, 177))
349863	26034386	On the other hand ARMS in 80-85% has the chromosomal translocations 't(2;13)(q35;q14) or t(1;13)(p36;q14).	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (89, 105))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (69, 85))	('t(1;13)(p36;q14', 'Var', (89, 104))	("'t(2;13)(q35;q14", 'Var', (68, 84))	('RMS', 'Phenotype', 'HP:0002859', (19, 22))
349864	26034386	It was further described that reported chromosomal translocations t(2;13)(q35;q14) or t(1;13)(p36;q14) result in PAX3/FOXO1 and PAX7/FOXO1 fusion genes expression.	('FOXO1', 'Gene', (133, 138))	('FOXO1', 'Gene', '2308', (133, 138))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (66, 82))	('PAX3', 'Gene', '5077', (113, 117))	('fusion', 'Protein', (139, 145))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (86, 102))	('FOXO1', 'Gene', '2308', (118, 123))	('PAX3', 'Gene', (113, 117))	('PAX7', 'Gene', '5081', (128, 132))	('t(2;13)(q35;q14', 'Var', (66, 81))	('t(1;13)(p36;q14', 'Var', (86, 101))	('PAX7', 'Gene', (128, 132))	('expression', 'MPA', (152, 162))	('result in', 'Reg', (103, 112))	('FOXO1', 'Gene', (118, 123))
349867	26034386	PAX/FOXO1 fusion gene status also influence prognosis with fusion-gene-negative ARMS patients having a prognosis similar to that of patients with ERMS.	('prognosis', 'MPA', (44, 53))	('RMS', 'Phenotype', 'HP:0002859', (147, 150))	('FOXO1', 'Gene', (4, 9))	('FOXO1', 'Gene', '2308', (4, 9))	('fusion', 'Var', (10, 16))	('fusion-gene-negative', 'Var', (59, 79))	('influence', 'Reg', (34, 43))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (132, 140))	('RMS', 'Phenotype', 'HP:0002859', (81, 84))
349870	26034386	Insulin-like growth factor 1 receptor-mediated signaling was shown as essential for continued proliferation of RMS cells and Igf1r overexpression induce MAPK activation and Her2 overexpression.	('Insulin-like growth factor 1 receptor', 'Gene', (0, 37))	('Insulin-like growth factor 1 receptor', 'Gene', '3480', (0, 37))	('Her2', 'Gene', (173, 177))	('overexpression', 'PosReg', (178, 192))	('Her2', 'Gene', '2064', (173, 177))	('overexpression', 'Var', (131, 145))	('activation', 'PosReg', (158, 168))	('Igf1r', 'Gene', (125, 130))	('Igf1r', 'Gene', '3480', (125, 130))	('RMS', 'Phenotype', 'HP:0002859', (111, 114))	('MAPK', 'Protein', (153, 157))
349873	26034386	At the same time co-expression of IGF-1R and ALK was detected in ERMS and ARMS and combined inhibition of both pathways with ALK inhibitor (NVP-TAE684, Novartis), and anti-IGF-1R antibody (R1507, Roche) was shown to have synergistic cytotoxic effects on RMS cells.	('ALK', 'Gene', '238', (45, 48))	('R1507', 'Var', (189, 194))	('RMS', 'Phenotype', 'HP:0002859', (66, 69))	('RMS', 'Phenotype', 'HP:0002859', (254, 257))	('ALK', 'Gene', '238', (125, 128))	('inhibition', 'NegReg', (92, 102))	('IGF-1R', 'Gene', '3480', (34, 40))	('ALK', 'Gene', (45, 48))	('IGF-1R', 'Gene', '3480', (172, 178))	('IGF-1R', 'Gene', (34, 40))	('IGF-1R', 'Gene', (172, 178))	('RMS', 'Phenotype', 'HP:0002859', (75, 78))	('ALK', 'Gene', (125, 128))
349877	26034386	The presence of the PAX3/7-FOXO1 fusion genes and high RMS proliferative capacity is also associated with high N-Myc levels.	('N-Myc', 'Gene', '4613', (111, 116))	('high RMS proliferative capacity', 'CPA', (50, 81))	('RMS', 'Phenotype', 'HP:0002859', (55, 58))	('PAX3', 'Gene', '5077', (20, 24))	('associated', 'Reg', (90, 100))	('PAX3', 'Gene', (20, 24))	('FOXO1', 'Gene', (27, 32))	('FOXO1', 'Gene', '2308', (27, 32))	('fusion genes', 'Var', (33, 45))	('N-Myc', 'Gene', (111, 116))
349879	26034386	Low prevalence of TP53 mutations and/or MDM2 amplifications in RMS suggests inactivation of p53 function by other mechanisms and remains to be elucidated.	('MDM2', 'Gene', '4193', (40, 44))	('MDM2', 'Gene', (40, 44))	('RMS', 'Disease', (63, 66))	('TP53', 'Gene', '7157', (18, 22))	('function', 'MPA', (96, 104))	('RMS', 'Phenotype', 'HP:0002859', (63, 66))	('TP53', 'Gene', (18, 22))	('amplifications', 'Var', (45, 59))	('mutations', 'Var', (23, 32))	('p53', 'Gene', (92, 95))	('p53', 'Gene', '7157', (92, 95))
349880	26034386	Nevertheless, RMS tumors that develop in TP53 germline mutation carriers present usually non-alveolar, anaplastic histology.	('TP53', 'Gene', '7157', (41, 45))	('germline mutation', 'Var', (46, 63))	('TP53', 'Gene', (41, 45))	('RMS tumors', 'Disease', (14, 24))	('RMS tumors', 'Disease', 'MESH:D009369', (14, 24))	('RMS', 'Phenotype', 'HP:0002859', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('non-alveolar', 'CPA', (89, 101))
349881	26034386	Moreover, de novo germline TP53 mutations have been found in patients with RMS and RMS are often reported in patients with Li-Fraumeni syndrome (LFS).	('found', 'Reg', (52, 57))	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('patients', 'Species', '9606', (109, 117))	('RMS', 'Disease', (83, 86))	('LFS', 'Disease', (145, 148))	('patients', 'Species', '9606', (61, 69))	('RMS', 'Phenotype', 'HP:0002859', (83, 86))	('reported', 'Reg', (97, 105))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (123, 143))	('mutations', 'Var', (32, 41))	('RMS', 'Disease', (75, 78))	('RMS', 'Phenotype', 'HP:0002859', (75, 78))	('LFS', 'Disease', 'MESH:D016864', (145, 148))	('Li-Fraumeni syndrome', 'Disease', (123, 143))
349886	26034386	This fetal overgrowth syndrome is associated with abnormalities on 11p15 + the locus of the insulin-like growth factor II (IGFII) gene.	('insulin-like growth factor II', 'Gene', (92, 121))	('IGFII', 'Gene', '3481', (123, 128))	('associated', 'Reg', (34, 44))	('abnormalities', 'Var', (50, 63))	('overgrowth syndrome', 'Disease', (11, 30))	('IGFII', 'Gene', (123, 128))	('overgrowth syndrome', 'Disease', 'MESH:C537340', (11, 30))	('fetal overgrowth', 'Phenotype', 'HP:0001548', (5, 21))	('insulin-like growth factor II', 'Gene', '3481', (92, 121))
349890	26034386	The authors have shown that ERMS develops in cells with inactivated p53, Rb and CDKN2A/B.	('CDKN2A/B', 'Gene', '1029;1030', (80, 88))	('CDKN2A/B', 'Gene', (80, 88))	('p53', 'Gene', (68, 71))	('ERMS', 'Disease', (28, 32))	('p53', 'Gene', '7157', (68, 71))	('inactivated', 'Var', (56, 67))	('RMS', 'Phenotype', 'HP:0002859', (29, 32))
349893	26034386	FGFR4, a tyrosine kinase receptor, is overexpressed in 20% of cases, while GLI1, a Hh-pathway transcription factor, is abnormally activated in more than 50% of cases and NF1, a tumor suppressor and inhibitor of Ras, is deleted in 15% of patients with deletion of NF1 and activating Ras mutations mutually exclusive.	('tumor', 'Disease', (177, 182))	('NF1', 'Gene', (170, 173))	('mutations', 'Var', (286, 295))	('NF1', 'Gene', '4763', (170, 173))	('overexpressed', 'PosReg', (38, 51))	('activated', 'PosReg', (130, 139))	('NF1', 'Gene', (263, 266))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('GLI1', 'Gene', '2735', (75, 79))	('NF1', 'Gene', '4763', (263, 266))	('deletion', 'Var', (251, 259))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('FGFR4', 'Gene', '2264', (0, 5))	('FGFR4', 'Gene', (0, 5))	('patients', 'Species', '9606', (237, 245))	('GLI1', 'Gene', (75, 79))
349971	26034386	It has been proved in animal models that some antiangiogenic factors, such as antibodies against endothelial growth factor, can inhibit sarcoma cell growth.	('inhibit', 'NegReg', (128, 135))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('antibodies', 'Var', (78, 88))	('sarcoma', 'Disease', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))
349986	22546864	Though the molecular mechanisms that propel the development of these cancers are not well understood, identification of tumor-specific translocations in many sarcomas has provided significant insight into their tumorigenesis.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('translocations', 'Var', (135, 149))	('sarcomas', 'Disease', (158, 166))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))	('sarcomas', 'Disease', 'MESH:D012509', (158, 166))
349987	22546864	Each fusion protein resulting from these chromosomal translocations is thought to act as a driving force in the tumor, either as an aberrant transcription factor, constitutively active growth factor, or ligand-independent receptor tyrosine kinase.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('chromosomal translocations', 'Var', (41, 67))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))
349988	22546864	This review summarizes the molecular pathology of a subset of pediatric sarcomas with tumor-associated translocations and how increased understanding at the molecular level is being translated to novel therapeutic advances.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('tumor', 'Disease', (86, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('pediatric sarcomas', 'Disease', (62, 80))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (62, 80))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('translocations', 'Var', (103, 117))
349996	22546864	Pediatric sarcomas with tumor-associated translocations include Ewing sarcoma, rhabdomyosarcoma, synovial sarcoma, and dermatofibrosarcoma protuberans.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (64, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (64, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('synovial sarcoma', 'Disease', (97, 113))	('translocations', 'Var', (41, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('synovial sarcoma', 'Disease', 'MESH:D013584', (97, 113))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (126, 138))	('rhabdomyosarcoma', 'Disease', (79, 95))	('Pediatric sarcomas', 'Disease', (0, 18))	('Ewing sarcoma', 'Disease', (64, 77))	('tumor', 'Disease', (24, 29))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (97, 113))	('dermatofibrosarcoma protuberans', 'Disease', (119, 150))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (79, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (10, 18))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (79, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Pediatric sarcomas', 'Disease', 'MESH:D063766', (0, 18))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (119, 150))
349998	22546864	Depending on the genes involved in the fusion, the resulting protein can promote tumor progression through transcriptional modulation, epigenetic modifications, or activation of oncogenic signaling pathways.	('transcriptional modulation', 'CPA', (107, 133))	('epigenetic modifications', 'Var', (135, 159))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('activation', 'PosReg', (164, 174))	('promote', 'PosReg', (73, 80))	('oncogenic signaling pathways', 'Pathway', (178, 206))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('protein', 'Protein', (61, 68))	('tumor', 'Disease', (81, 86))
350001	22546864	This review focuses on four pediatric sarcomas with tumor-associated translocations and will discuss the molecular genetics of these malignancies, potential therapeutic targets, and the status of agents directed against these targets in clinical trials.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('translocations', 'Var', (69, 83))	('tumor', 'Disease', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('malignancies', 'Disease', (133, 145))	('pediatric sarcomas', 'Disease', (28, 46))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (28, 46))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))
350007	22546864	The pathognomonic genetic aberration in ES fuses the EWS gene (also known as EWSR1, Ewing sarcoma breakpoint region 1) to one of five ETS (erythroblast transformation-specific) transcription factors (Table 1).	('Ewing sarcoma breakpoint region 1', 'Gene', (84, 117))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (84, 117))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('fuses', 'Var', (43, 48))	('ETS', 'Chemical', '-', (134, 137))	('rat', 'Species', '10116', (30, 33))	('EWS', 'Gene', (77, 80))	('EWS', 'Gene', '2130', (77, 80))	('EWS', 'Gene', (53, 56))	('EWS', 'Gene', '2130', (53, 56))	('EWSR1', 'Gene', (77, 82))	('ES', 'Phenotype', 'HP:0012254', (40, 42))	('EWSR1', 'Gene', '2130', (77, 82))
350010	22546864	Initial reports suggested EWS-FLI1 type 1 fusions confer a prognostic advantage to patients with localized disease, but more recent studies have demonstrated there is no difference in clinical outcome based on fusion type.	('rat', 'Species', '10116', (152, 155))	('patients', 'Species', '9606', (83, 91))	('EWS-FLI1', 'Gene', (26, 34))	('localized disease', 'Disease', (97, 114))	('EWS-FLI1', 'Gene', '2130;2313', (26, 34))	('localized disease', 'Disease', 'MESH:D012594', (97, 114))	('fusions', 'Var', (42, 49))
350025	22546864	Moreover, IGF1R is necessary for EWS/FLI1-mediated cellular transformation and inhibition of IGF1R suppresses tumor growth in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('suppresses', 'NegReg', (99, 109))	('inhibition', 'Var', (79, 89))	('EWS', 'Gene', (33, 36))	('EWS', 'Gene', '2130', (33, 36))	('FLI1', 'Gene', (37, 41))	('IGF1R', 'Gene', (93, 98))	('FLI1', 'Gene', '2313', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
350043	22546864	In addition to histologic differences, ARMS is distinguished from ERMS by the presence of specific chromosomal translocations present in the majority of ARMS tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('ARMS tumors', 'Disease', 'MESH:D009369', (153, 164))	('ARMS tumors', 'Disease', (153, 164))	('ARMS', 'Disease', (39, 43))	('chromosomal translocations', 'Var', (99, 125))	('RMS', 'Phenotype', 'HP:0002859', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('RMS', 'Phenotype', 'HP:0002859', (154, 157))	('RMS', 'Phenotype', 'HP:0002859', (40, 43))
350044	22546864	The predominant translocation, t(2;13)(q35;q14), fuses PAX3 (paired box 3) to FOXO1 (forkhead box O1, also known as FKHR).	('FKHR', 'Gene', '2308', (116, 120))	('forkhead box O1', 'Gene', '2308', (85, 100))	('FOXO1', 'Gene', (78, 83))	('forkhead box O1', 'Gene', (85, 100))	('FKHR', 'Gene', (116, 120))	('paired box 3', 'Gene', (61, 73))	('paired box 3', 'Gene', '5077', (61, 73))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (31, 47))	('fuses', 'Var', (49, 54))
350051	22546864	The role of MET in ARMS tumorigenesis was further characterized by experiments that demonstrated MET is required for PAX3-FOXO1-mediated transformation of mouse embryonal fibroblasts and shRNA knock down of MET results in decreased tumor growth in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('rat', 'Species', '10116', (91, 94))	('tumor', 'Disease', (24, 29))	('RMS', 'Phenotype', 'HP:0002859', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('knock down', 'Var', (193, 203))	('tumor', 'Disease', (232, 237))	('mouse', 'Species', '10090', (155, 160))	('decreased tumor', 'Disease', 'MESH:D009369', (222, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('decreased tumor', 'Disease', (222, 237))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('MET', 'Gene', (207, 210))
350055	22546864	Heterologous expression of the PAX3-FOXO1 fusion results in an increase in IGF1R levels and overexpression of insulin-like growth factor 2 (IGF2) and IGF1R has been observed in ARMS and ERMS tumors and cell lines.	('ERMS tumors', 'Disease', (186, 197))	('IGF1R levels', 'MPA', (75, 87))	('increase', 'PosReg', (63, 71))	('RMS', 'Phenotype', 'HP:0002859', (178, 181))	('ERMS tumors', 'Disease', 'MESH:D009369', (186, 197))	('overexpression', 'PosReg', (92, 106))	('PAX3-FOXO1', 'Gene', (31, 41))	('fusion', 'Var', (42, 48))	('insulin-like growth factor 2', 'Gene', '3481', (110, 138))	('increase in IGF1R levels', 'Phenotype', 'HP:0030269', (63, 87))	('insulin-like growth factor 2', 'Gene', (110, 138))	('RMS', 'Phenotype', 'HP:0002859', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))
350062	22546864	Resistance has also been observed with anti-IGF1R therapy, which may be due to activation of other growth factor receptors such as HER-2 (human epidermal growth factor receptor 2, also known as ERBB2) and PDGFRalpha.	('epidermal growth factor receptor 2', 'Gene', (144, 178))	('HER-2', 'Gene', (131, 136))	('human', 'Species', '9606', (138, 143))	('epidermal growth factor receptor 2', 'Gene', '2064', (144, 178))	('activation', 'PosReg', (79, 89))	('HER-2', 'Gene', '2064', (131, 136))	('anti-IGF1R', 'Var', (39, 49))	('ERBB2', 'Gene', (194, 199))	('ERBB2', 'Gene', '2064', (194, 199))
350074	22546864	The underlying genetic aberration in SS results from a specific t(X;18)(p11.2;q11.2) translocation that fuses SS18 (synovial sarcoma translocation, chromosome 18, also known as SYT) to either SSX1, SSX2, or SSX4 (synovial sarcoma, X breakpoint 1, 2, or 4) (Figure 2A).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (213, 229))	('SYT', 'Gene', (177, 180))	('SSX2', 'Gene', (198, 202))	('SS', 'Phenotype', 'HP:0012570', (192, 194))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('SSX2', 'Gene', '6757', (198, 202))	('SS', 'Phenotype', 'HP:0012570', (207, 209))	('SYT', 'Gene', '6760', (177, 180))	('SS', 'Phenotype', 'HP:0012570', (110, 112))	('SS18', 'Gene', (110, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('SS', 'Phenotype', 'HP:0012570', (37, 39))	('SS', 'Phenotype', 'HP:0012570', (198, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('rat', 'Species', '10116', (27, 30))	('synovial sarcoma', 'Disease', (213, 229))	('synovial sarcoma', 'Disease', 'MESH:D013584', (213, 229))	('SSX4', 'Gene', (207, 211))	('synovial sarcoma', 'Disease', (116, 132))	('SSX4', 'Gene', '6759', (207, 211))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (64, 84))	('synovial sarcoma', 'Disease', 'MESH:D013584', (116, 132))	('fuses', 'Var', (104, 109))
350086	22546864	Although initial studies showed patients with SS18-SSX2 fusions had improved survival rates, an expanded study performed more recently concluded there was no correlation between fusion variant and survival.	('fusions', 'Var', (56, 63))	('patients', 'Species', '9606', (32, 40))	('SS', 'Phenotype', 'HP:0012570', (46, 48))	('SSX2', 'Gene', '6757', (51, 55))	('survival rates', 'MPA', (77, 91))	('SS', 'Phenotype', 'HP:0012570', (51, 53))	('SSX2', 'Gene', (51, 55))	('rat', 'Species', '10116', (86, 89))	('improved', 'PosReg', (68, 76))
350087	22546864	While fusion type may not determine survival, it is strongly associated with histology as biphasic and monophasic tumors contain the SS18-SSX1 and SS18-SSX2 transcripts, respectively.	('SS', 'Phenotype', 'HP:0012570', (152, 154))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('SSX2', 'Gene', (152, 156))	('SS', 'Phenotype', 'HP:0012570', (133, 135))	('SS18-SSX1', 'Var', (133, 142))	('SS', 'Phenotype', 'HP:0012570', (147, 149))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('biphasic', 'Disease', (90, 98))	('SS', 'Phenotype', 'HP:0012570', (138, 140))	('SSX2', 'Gene', '6757', (152, 156))
350092	22546864	This data combined with active chromatin marks observed upon induction of SS18-SSX2 suggests the fusion interacts with BRG1 to epigenetically modulate IGF2 expression.	('modulate', 'Reg', (142, 150))	('SS', 'Phenotype', 'HP:0012570', (74, 76))	('epigenetically', 'Var', (127, 141))	('SSX2', 'Gene', '6757', (79, 83))	('BRG1', 'Gene', (119, 123))	('SS', 'Phenotype', 'HP:0012570', (79, 81))	('expression', 'MPA', (156, 166))	('BRG1', 'Gene', '6597', (119, 123))	('SSX2', 'Gene', (79, 83))	('IGF2', 'Gene', (151, 155))
350094	22546864	IGF2 expression results in activation of IGF1R and phosphorylation of the downstream proteins Akt (v-akt murine thymoma viral oncogene homolog) and MAPK (mitogen-activated protein kinase).	('thymoma viral', 'Disease', (112, 125))	('Akt', 'Gene', (94, 97))	('murine', 'Species', '10090', (105, 111))	('expression', 'Var', (5, 15))	('akt', 'Gene', '207', (101, 104))	('thymoma', 'Phenotype', 'HP:0100522', (112, 119))	('MAPK', 'Gene', (148, 152))	('thymoma viral', 'Disease', 'MESH:D013945', (112, 125))	('phosphorylation', 'MPA', (51, 66))	('activation', 'PosReg', (27, 37))	('Akt', 'Gene', '11651', (94, 97))	('IGF1R', 'Gene', (41, 46))	('IGF2', 'Gene', (0, 4))	('akt', 'Gene', (101, 104))
350098	22546864	Furthermore, BCL-2 antisense oligonucleotide treatment of a translocation positive SS cell line resulted in increased sensitivity to doxorubicin treatment, implying BCL-2 may be a promising therapeutic target.	('BCL-2', 'Gene', '596', (165, 170))	('sensitivity to doxorubicin treatment', 'MPA', (118, 154))	('BCL-2', 'Gene', '596', (13, 18))	('BCL-2', 'Gene', (165, 170))	('increased', 'PosReg', (108, 117))	('BCL-2', 'Gene', (13, 18))	('SS', 'Phenotype', 'HP:0012570', (83, 85))	('doxorubicin', 'Chemical', 'MESH:D004317', (133, 144))	('antisense oligonucleotide', 'Var', (19, 44))	('oligonucleotide', 'Chemical', 'MESH:D009841', (29, 44))
350114	22546864	DFSP tumors contain either the t(17;22)(q22;q13.1) reciprocal chromosomal translocation or a supernumerary ring chromosome derived from t(17;22).	('DFSP tumors', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('t(17;22)(q22;q13.1)', 'STRUCTURAL_ABNORMALITY', 'None', (31, 50))	('t(17;22)(q22;q13.1', 'Var', (31, 49))	('contain', 'Reg', (12, 19))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('DFSP tumors', 'Disease', 'MESH:D018223', (0, 11))
350115	22546864	Both of these karyotypic aberrations result in a fusion of the genes COL1A1 (encoding the pro-alpha1 chain of type I collagen) on 17q21-22 and PDGFB (encoding the platelet-derived growth factor B chain) on 22q13.1 (Figure 3A).	('aberrations', 'Var', (25, 36))	('COL1A1', 'Gene', (69, 75))	('platelet-derived growth factor B chain', 'Gene', (163, 201))	('result in', 'Reg', (37, 46))	('rat', 'Species', '10116', (29, 32))	('fusion', 'Var', (49, 55))	('PDGFB', 'Gene', (143, 148))	('platelet-derived growth factor B chain', 'Gene', '5155', (163, 201))
350116	22546864	In contrast, all pediatric tumors contain translocations.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('translocations', 'Var', (42, 56))
350117	22546864	DFSP variants and related malignancies such as giant cell fibroblastoma have also been found to contain the COL1A1-PDGFB fusion.	('giant cell fibroblastoma', 'Disease', 'MESH:D018223', (47, 71))	('DFSP', 'Disease', (0, 4))	('malignancies', 'Disease', 'MESH:D009369', (26, 38))	('malignancies', 'Disease', (26, 38))	('DFSP', 'Disease', 'MESH:D018223', (0, 4))	('variants', 'Var', (5, 13))	('giant cell fibroblastoma', 'Disease', (47, 71))	('COL1A1-PDGFB', 'Gene', (108, 120))
350120	22546864	The COL1A1-PDGFB fusion has been shown to transform NIH3T3 cells.	('NIH3T3 cells', 'CPA', (52, 64))	('NIH3T3', 'CellLine', 'CVCL:0594', (52, 58))	('fusion', 'Var', (17, 23))	('COL1A1-PDGFB', 'Gene', (4, 16))	('transform', 'Reg', (42, 51))
350151	33912776	Electrocardiography showed sinus tachycardia with T-wave inversion in leads V1 to V3.	('sinus tachycardia', 'Disease', 'MESH:D013616', (27, 44))	('sinus tachycardia', 'Phenotype', 'HP:0011703', (27, 44))	('T-wave inversion', 'Phenotype', 'HP:0010872', (50, 66))	('sinus tachycardia', 'Disease', (27, 44))	('T-wave', 'Var', (50, 56))	('T-wave', 'Phenotype', 'HP:0005135', (50, 56))	('tachycardia', 'Phenotype', 'HP:0001649', (33, 44))
350171	33912776	However, Neuville et al reported that intimal sarcoma was the most common type upon reclassifying cardiac tumors that exhibit murine double minute 2 amplification and are often located in the left heart.	('cardiac tumor', 'Phenotype', 'HP:0100544', (98, 111))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('murine', 'Var', (126, 132))	('cardiac tumors', 'Phenotype', 'HP:0100544', (98, 112))	('cardiac tumors', 'Disease', (98, 112))	('murine', 'Species', '10090', (126, 132))	('sarcoma', 'Disease', (46, 53))	('cardiac tumors', 'Disease', 'MESH:D006338', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
350194	32322516	Final histopathology later demonstrated undifferentiated malignant small round blue cell tumor with EWSR1-FLI-1 fusion gene rearrangement consistent with renal ES (Fig.	('fusion gene rearrangement', 'Var', (112, 137))	('renal ES', 'Disease', (154, 162))	('undifferentiated malignant small round blue cell tumor', 'Disease', 'MESH:D058405', (40, 94))	('EWSR1', 'Gene', (100, 105))	('ES', 'Phenotype', 'HP:0012254', (160, 162))	('EWSR1', 'Gene', '2130', (100, 105))	('FLI-1', 'Gene', (106, 111))	('FLI-1', 'Gene', '2313', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
350207	32322516	FISH analysis may demonstrate multiple diagnostic translocations with the most common being a (11; 22) (q24; q12) translocation resulting in a EWSR-FLI-1 fusion gene, with a t (21; 22) resulting in a EWS-ERG gene fusion also being possible.	('11', 'Var', (95, 97))	('FLI-1', 'Gene', '2313', (148, 153))	('FLI-1', 'Gene', (148, 153))	('EWS', 'Gene', '2130', (200, 203))	('EWS', 'Gene', (200, 203))	('ERG', 'Gene', '2078', (204, 207))	('translocation', 'Var', (114, 127))	('EWS', 'Gene', '2130', (143, 146))	('ERG', 'Gene', (204, 207))	('EWS', 'Gene', (143, 146))
350208	32322516	Additionally, it has been demonstrated that mutations in DNA repair genes, such as ATM, are enriched in patients with Ewing Sarcoma, however, the exact significance is unknown.	('Ewing Sarcoma', 'Disease', (118, 131))	('DNA repair genes', 'Gene', (57, 73))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('Sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('ATM', 'Gene', '472', (83, 86))	('ATM', 'Gene', (83, 86))	('mutations', 'Var', (44, 53))	('patients', 'Species', '9606', (104, 112))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (118, 131))
350230	31049235	De novo immunohistochemistry showed positivity for S-100 and ML actine, focal for HMB45 and MART-1, negativity for P63.	('P63', 'Gene', (115, 118))	('HMB45', 'Gene', (82, 87))	('MART-1', 'Gene', '2315', (92, 98))	('S-100', 'Protein', (51, 56))	('P63', 'Gene', '8626', (115, 118))	('MART-1', 'Gene', (92, 98))	('ML actine', 'Protein', (61, 70))	('positivity', 'Var', (36, 46))
350240	31049235	Moreover, a study demonstrated that UV-induced p53 mutations and CCND1/CDK4 were essential in tumorigenesis of both AFX and PDS, supporting the theory that AFX is a superficial variant of PDS.	('mutations', 'Var', (51, 60))	('PDS', 'Disease', (124, 127))	('CCND1', 'Gene', '595', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CDK4', 'Gene', (71, 75))	('CDK4', 'Gene', '1019', (71, 75))	('CCND1', 'Gene', (65, 70))	('AFX', 'Disease', (116, 119))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('tumorigenesis', 'CPA', (94, 107))
350241	31049235	Furthermore, activating mutations in HRAS and PIK3CA were also observed in both tumor types, even if with a greater frequency of HRAS mutations in PDS than AFX.	('PIK3CA', 'Gene', '5290', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('activating', 'PosReg', (13, 23))	('HRAS', 'Gene', (37, 41))	('HRAS', 'Gene', '3265', (129, 133))	('HRAS', 'Gene', '3265', (37, 41))	('mutations', 'Var', (134, 143))	('HRAS', 'Gene', (129, 133))	('PIK3CA', 'Gene', (46, 52))
350260	28494941	They generate the Ewing sarcoma t(11;22) translocation in human mesenchymal and induced pluripotent stem cells using RNPs and ssODNs.	('RNP', 'Gene', '55599', (117, 120))	('translocation', 'Var', (41, 54))	('human', 'Species', '9606', (58, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('Ewing sarcoma', 'Disease', (18, 31))	('t(11;22', 'Gene', (32, 39))	('RNP', 'Gene', (117, 120))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (18, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (18, 31))
350261	28494941	The generation of targeted translocations in human stem cells opens up new avenues in modeling Ewing sarcoma and human neoplasias.	('modeling Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 108))	('neoplasias', 'Disease', 'MESH:D009369', (119, 129))	('targeted translocations', 'Var', (18, 41))	('neoplasias', 'Disease', (119, 129))	('modeling Ewing sarcoma', 'Disease', (86, 108))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('human', 'Species', '9606', (45, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('human', 'Species', '9606', (113, 118))	('neoplasias', 'Phenotype', 'HP:0002664', (119, 129))
350262	28494941	Chromosome translocations are common genomic events in cancer and are the initiating event in many leukemias and sarcomas (http://cgap.nci.nih.gov/Chromosomes/Mitelman).	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('leukemias', 'Phenotype', 'HP:0001909', (99, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Chromosome translocations', 'Var', (0, 25))	('cancer', 'Disease', (55, 61))	('leukemias and sarcomas', 'Disease', 'MESH:D012509', (99, 121))
350263	28494941	Cancer-associated chromosomal translocations generate novel chromosomes, placing genes in new linkage relationships that can result in the generation of fusion genes or the overexpression of proto-oncogenes.	('overexpression', 'PosReg', (173, 187))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('expression', 'Species', '29278', (177, 187))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('fusion', 'Var', (153, 159))	('chromosomal', 'Var', (18, 29))
350264	28494941	Given their contribution to cancer pathogenesis, chromosomal translocations have been widely studied to better understand the mechanisms involved in their formation and the downstream molecular consequences.	('cancer', 'Disease', (28, 34))	('chromosomal translocations', 'Var', (49, 75))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))
350268	28494941	Cancer is generally studied after the transformation events are completed, and patient samples are therefore not amenable to analysis of the mechanisms through which cancer-specific chromosomal translocations initiate oncogenesis.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('oncogenesis', 'CPA', (218, 229))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('patient', 'Species', '9606', (79, 86))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('chromosomal translocations', 'Var', (182, 208))	('initiate', 'Reg', (209, 217))
350288	28494941	HEK293 eGFPhigh cells had a 2.3-fold higher translocation rate than unsorted cells (from 0.77% to 1.73%), whereas eGFPlow cells showed no significant increase (from 0.77 to 0.45%) (Figure 2D and Table S1).	('translocation', 'MPA', (44, 57))	('HEK293 eGFPhigh', 'Var', (0, 15))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('higher', 'PosReg', (37, 43))
350320	28494941	FISH analysis confirmed that co-nucleofection with RNP complexes and ssODNs increased translocation frequency by 3.2-fold (from 0.42% to 1.39%) compared with the 2xNLS approach (Figure 6D).	('increased', 'PosReg', (76, 85))	('co-nucleofection', 'Var', (29, 45))	('RNP', 'Gene', (51, 54))	('translocation frequency', 'CPA', (86, 109))	('RNP', 'Gene', '55599', (51, 54))
350321	28494941	Importantly, hiPSCs were subcloned and a t(11;22)+ hiPSC clone was expanded for 8 weeks, revealing maintenance of the translocation (Figure S6), with no differences in cell/colony morphology, expression of the pluripotency markers OCT4 and SSEA-4, and growth rate (Figure 6E).	('expression', 'Species', '29278', (192, 202))	('OCT4', 'Gene', '5460', (231, 235))	('OCT4', 'Gene', (231, 235))	('translocation', 'Var', (118, 131))	('growth', 'CPA', (252, 258))
350328	28494941	We therefore hypothesized that donor ssODN templates containing homology arms flanking the junction region of a translocation-derived chromosome breakpoint would guide the rejoining of the derivative chromosome, thus facilitating translocation.	('rejoining', 'CPA', (172, 181))	('translocation', 'CPA', (230, 243))	('guide', 'PosReg', (162, 167))	('facilitating', 'PosReg', (217, 229))	('homology', 'Var', (64, 72))	('donor', 'Species', '9606', (31, 36))
350340	28494941	Translocation rates were further improved by co-nucleofecting RNPs and translocation-ssODNs, demonstrating a synergistic effect between these approaches.	('translocation-ssODNs', 'Var', (71, 91))	('RNP', 'Gene', (62, 65))	('co-nucleofecting', 'Var', (45, 61))	('RNP', 'Gene', '55599', (62, 65))	('improved', 'PosReg', (33, 41))	('Translocation', 'MPA', (0, 13))
350346	28494941	Co-nucleofection with RNPs and translocation-ssODNs was able to induce targeted t(11;22) translocations in hiPSCs while maintaining the pluripotent phenotype.	('pluripotent phenotype', 'MPA', (136, 157))	('RNP', 'Gene', (22, 25))	('RNP', 'Gene', '55599', (22, 25))	('t(11;22', 'Gene', (80, 87))	('translocations', 'Var', (89, 103))
350492	30310394	According to the 7th edition of the TNM lung tumour classification published in 2009 by the UICC and AJCC, stages of development were determined as follows: T1N0 - 3 (13.6%) patients, T2N0 - 6 (27%) patients, T3N0 - 9 (41%) patients, T4N0 - 4 (18%) patients.	('T1N0 - 3', 'Var', (157, 165))	('men', 'Species', '9606', (124, 127))	('patients', 'Species', '9606', (249, 257))	('lung tumour', 'Phenotype', 'HP:0100526', (40, 51))	('T3N0 -', 'Var', (209, 215))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('patients', 'Species', '9606', (174, 182))	('TNM lung tumour', 'Disease', 'MESH:D008175', (36, 51))	('patients', 'Species', '9606', (224, 232))	('patients', 'Species', '9606', (199, 207))	('T2N0 - 6', 'Var', (184, 192))	('TNM lung tumour', 'Disease', (36, 51))
350736	26173023	In sarcomas, ACT with NY-ESO-1 TCR has demonstrated objective clinical responses in four of six patients with synovial cell sarcoma.	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('synovial cell sarcoma', 'Disease', (110, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('NY-ESO-1 TCR', 'Var', (22, 34))	('sarcomas', 'Disease', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('synovial cell sarcoma', 'Disease', 'MESH:D013584', (110, 131))	('patients', 'Species', '9606', (96, 104))	('synovial cell sarcoma', 'Phenotype', 'HP:0012570', (110, 131))
350745	26173023	Thus, ROR1 CAR T-cell therapy in sarcomas may yield an effective treatment with minimal off-target toxicity.	('ROR1', 'Var', (6, 10))	('toxicity', 'Disease', 'MESH:D064420', (99, 107))	('toxicity', 'Disease', (99, 107))	('sarcomas', 'Disease', 'MESH:D012509', (33, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcomas', 'Disease', (33, 41))
350759	26173023	SaOS2-fflucN, Rh30-fflucN and TC71-fflucN were lentivirally transduced cell lines expressing firefly luciferase and NGFR using pEhfflucmCNsin as previously described.	('SaOS2-fflucN', 'Chemical', '-', (0, 12))	('OS', 'Phenotype', 'HP:0002669', (2, 4))	('Rh30', 'Gene', (14, 18))	('Rh30', 'Gene', '6007', (14, 18))	('NGFR', 'Var', (116, 120))
350777	26173023	Breeding pairs of NOD.CB17-Pkrdc scid/J (NOD/scid, stock number 001303) and NOD.Cg-Prkdc scid IL2rg tm1WjI/SzJ (NSG, stock number 005557) mice were purchased from the Jackson Laboratory (Bar Harbor, ME) and housed in the specific pathogen free facility with autoclaved cages,food and water.	('water', 'Chemical', 'MESH:D014867', (284, 289))	('NOD.Cg-Prkdc', 'Var', (76, 88))	('NOD.CB17-Pkrdc', 'Var', (18, 32))	('mice', 'Species', '10090', (138, 142))
350793	26173023	PBMCs from at least 8 healthy donors and 3 pediatric sarcoma patients were nucleofected with SB100X transposase plus SB-IGF1R CAR (pKT2-CaIG and pKT2-CaIG:Z), SB-ROR1 CAR (pKT2-CaRG and pKT2-CaRG:Z), or without DNA as mock.	('SB', 'Chemical', '-', (159, 161))	('SB', 'Chemical', '-', (93, 95))	('patients', 'Species', '9606', (61, 69))	('donor', 'Species', '9606', (30, 35))	('SB-ROR1 CAR', 'Var', (159, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('SB', 'Chemical', '-', (117, 119))	('pediatric sarcoma', 'Disease', (43, 60))	('SB-IGF1R', 'Gene', (117, 125))	('SB100X', 'Gene', (93, 99))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (43, 60))
350824	26173023	ROR1 CAR T cells (PBL7-RGZ and PBL8-RGZ) significantly killed ROR1+ SaOS2, but not ROR1- DB and EBV-LCL cells, which were negative for ROR1 by flow cytometry (Fig 2F) (p < 0.01 at E/T of 20:1 and 6:1, Fig 2G, a low level of non-specific cytotoxicity against K562 was noted).	('cytotoxicity', 'Disease', 'MESH:D064420', (237, 249))	('OS', 'Phenotype', 'HP:0002669', (70, 72))	('cytotoxicity', 'Disease', (237, 249))	('ROR1+', 'Var', (62, 67))
350830	26173023	IGF1R CAR T cells produced higher amounts of IL-6 and IL-18 than ROR1 CAR T cells in response to certain sarcoma lines.	('IGF1R', 'Var', (0, 5))	('sarcoma lines', 'Disease', 'MESH:D012509', (105, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('IL-18', 'Gene', '3606', (54, 59))	('IL-6', 'Gene', (45, 49))	('IL-18', 'Gene', (54, 59))	('higher', 'PosReg', (27, 33))	('sarcoma lines', 'Disease', (105, 118))	('IL-6', 'Gene', '3569', (45, 49))
350832	26173023	Mock T cells or CAR T cells co-cultured with ROR1- K562 cells did not release cytokines whereas IGF1R CAR T cells co-cultured with IGF1R+/- K562 cells produced a low level of cytokines compared to IGF1R+ sarcomas.	('IGF1R', 'Var', (96, 101))	('sarcomas', 'Disease', 'MESH:D012509', (204, 212))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('IGF1R+/-', 'Var', (131, 139))	('cytokines', 'MPA', (175, 184))	('sarcomas', 'Disease', (204, 212))
350841	26173023	The administration of 2 infusions of either IGF1R CAR or ROR1 CAR T cells derived from patient 1 into tumor-bearing mice significantly suppressed sarcoma growth at days 5, 11, 18, 25 and 32 post T-cell infusions compared to mock T-cell treated mice (p <= 0.01 at days 5, 11, 18, 25; p <0.01 at day 32 for IGZ; p < 0.05 at day 32 for RGZ; IGZ vs RGZ, p > 0.05 at all day points, Fig 4B and 4C).	('IGF1R', 'Var', (44, 49))	('mice', 'Species', '10090', (116, 120))	('mice', 'Species', '10090', (244, 248))	('sarcoma', 'Disease', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('ROR1 CAR', 'Gene', (57, 65))	('patient', 'Species', '9606', (87, 94))	('suppressed', 'NegReg', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
350846	26173023	The administration of 3 infusions IGF1R CAR T cells derived from patient 1 also significantly inhibited tumor growth compared to untreated group at days 6, 14 and 21 post T-cell infusions (p < 0.001, Fig 5B and 5C).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('IGF1R', 'Var', (34, 39))	('tumor', 'Disease', (104, 109))	('patient', 'Species', '9606', (65, 72))	('inhibited', 'NegReg', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
350849	26173023	It seems that IGF1R CAR T cells were more potent than ROR1 CAR T cells in suppressing tumor growth in this localized model (p < 0.01, Fig 5B and 5C) and extending survival as up to 40% of the treated mice by IGF1R CAR T cells survived to at least until at day 160 whereas no ROR1 CAR T cell treated mice survived up to day 90 (p = 0.0186).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('suppressing', 'NegReg', (74, 85))	('tumor', 'Disease', (86, 91))	('mice', 'Species', '10090', (299, 303))	('extending', 'PosReg', (153, 162))	('mice', 'Species', '10090', (200, 204))	('survival', 'CPA', (163, 171))	('IGF1R', 'Var', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
350853	26173023	Co-culture of PBMCs with IGF1R and ROR1 CAR T cells derived from a sarcoma patient and a healthy donor revealed a low level of recognition of PBMCs by IGF1R CAR T cells but not ROR1 CAR T cells compared to sarcoma cells.	('sarcoma', 'Disease', (206, 213))	('donor', 'Species', '9606', (97, 102))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('IGF1R', 'Var', (151, 156))	('sarcoma', 'Disease', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcoma', 'Disease', 'MESH:D012509', (206, 213))	('patient', 'Species', '9606', (75, 82))
350863	26173023	In addition to IGF1R inhibitors and mabs, IGF1R has been considered to be immunogenic and tested as a cancer vaccine.	('cancer', 'Disease', (102, 108))	('IGF1R', 'Var', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
350880	26173023	Our preclinical data suggest that IGF1R CAR T cells mounted more potent anti-sarcoma activity than ROR1 CAR T cells in vivo (Figs 4C, 5C and 5D).	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('IGF1R', 'Var', (34, 39))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))
350883	26173023	Increasing ROR1 CAR affinity by substituting the 2A2 clone with the R12 clone (Fab, 0.56 x 10-9 M, 58 fold higher affinity than the 2A2 clone) could be considered to enhance ROR1 CAR T cell potency.	('Increasing', 'PosReg', (0, 10))	('substituting', 'Var', (32, 44))	('affinity', 'MPA', (20, 28))	('enhance', 'PosReg', (166, 173))	('ROR1 CAR', 'Protein', (11, 19))	('Fab', 'Gene', '2187', (79, 82))	('Fab', 'Gene', (79, 82))
350971	28614235	Fluorescence in situ hybridization (FISH) detection of ALK t(2P23) rearrangements indicated that <5% of tumor cells had separate red and green signals, and the synovial sarcoma-associated t(X;18)(p11;q11) translocation was also not observed.	('rat', 'Species', '10116', (124, 127))	('synovial sarcoma', 'Disease', (160, 176))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (188, 204))	('ALK', 'Gene', '238', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('men', 'Species', '9606', (76, 79))	('synovial sarcoma', 'Disease', 'MESH:D013584', (160, 176))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (160, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('ALK', 'Gene', (55, 58))	('rearrangements', 'Var', (67, 81))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
350991	28614235	Recent comprehensive genomic profiling studies showed that genomic alterations of tumor protein p53 (74%), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (34%), hepatocyte growth factor receptor gene (MET) (13.6%), epidermal growth factor receptor (8.8%), V-raf murine sarcoma viral oncogene homolog B (7.2%), human epidermal growth factor receptor 2 (1.6%), or ret proto-oncogene (0.8%) were identified in PSCs, and tyrosine-protein kinase Met (C-MET) exon 14 alterations were more frequently in PSC (12%) than in non-PSC non-small cell lung cancers (3%).	('hepatocyte growth factor receptor', 'Gene', '24553', (167, 200))	('C-MET', 'Gene', (452, 457))	('rat', 'Species', '10116', (71, 74))	('cancers', 'Phenotype', 'HP:0002664', (549, 556))	('MET', 'Gene', (454, 457))	('MET', 'Gene', '4233', (454, 457))	('p53', 'Gene', '301300', (96, 99))	('PSC', 'Disease', (503, 506))	('epidermal growth factor receptor', 'Gene', (221, 253))	('MET', 'Gene', '4233', (207, 210))	('V-raf murine sarcoma viral oncogene homolog B', 'Gene', (262, 307))	('tumor', 'Disease', (82, 87))	('MET', 'Gene', (207, 210))	('sarcoma', 'Disease', 'MESH:D012509', (275, 282))	('sarcoma', 'Disease', (275, 282))	('epidermal growth factor receptor', 'Gene', '24329', (322, 354))	('cell lung cancers', 'Disease', 'MESH:D008175', (539, 556))	('p53', 'Gene', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (549, 555))	('lung cancers', 'Phenotype', 'HP:0100526', (544, 556))	('V-raf murine sarcoma viral oncogene homolog B', 'Gene', '114486', (262, 307))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (529, 556))	('cell lung cancers', 'Disease', (539, 556))	('SC', 'Phenotype', 'HP:0100242', (504, 506))	('ret', 'Gene', (368, 371))	('PSCs', 'Disease', (413, 417))	('ret', 'Gene', '5979', (368, 371))	('SC', 'Phenotype', 'HP:0100242', (526, 528))	('rat', 'Species', '10116', (125, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('SC', 'Phenotype', 'HP:0100242', (414, 416))	('C-MET', 'Gene', '4233', (452, 457))	('human', 'Species', '9606', (316, 321))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (533, 556))	('sarcoma', 'Disease', (129, 136))	('epidermal growth factor receptor 2', 'Gene', '2064', (322, 356))	('rat', 'Species', '10116', (471, 474))	('alterations', 'Var', (467, 478))	('hepatocyte growth factor receptor', 'Gene', (167, 200))	('Met', 'Gene', (447, 450))	('Met', 'Gene', '4233', (447, 450))	('epidermal growth factor receptor', 'Gene', '24329', (221, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('epidermal growth factor receptor 2', 'Gene', (322, 356))
350998	28614235	ALK gene rearrangement is a feature of IMT.	('men', 'Species', '9606', (18, 21))	('rearrangement', 'Var', (9, 22))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', '238', (0, 3))
351028	26258070	Ewing sarcomas are characterized by chromosomal translocations that fuse the EWSR1 gene to some members of the ETS family of transcription factors, being FLI1 the most frequently implicated [t(11;22)(q24;q12)].	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('FLI1', 'Gene', (154, 158))	('[t(11;22)(q24;q12)]', 'Var', (190, 209))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (191, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))	('Ewing sarcomas', 'Disease', (0, 14))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (0, 14))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (0, 14))	('EWSR1', 'Gene', (77, 82))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('EWSR1', 'Gene', '2130', (77, 82))
351034	26258070	Germline mutations in this gene are the cause of dosage-sensitive sex reversal (DSS) in XY individuals and adrenal hypoplasia congenital (AHC), which is characterized by adrenal insufficiency, and hypogonadotropic hypogonadism in males.	('Germline mutations', 'Var', (0, 18))	('hypogonadotropic hypogonadism', 'Phenotype', 'HP:0000044', (197, 226))	('adrenal insufficiency', 'Disease', (170, 191))	('adrenal hypoplasia congenital', 'Phenotype', 'HP:0008244', (107, 136))	('cause', 'Reg', (40, 45))	('AHC', 'Phenotype', 'HP:0008244', (138, 141))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (107, 125))	('adrenal hypoplasia congenital', 'Disease', (107, 136))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (170, 191))	('AHC', 'Disease', (138, 141))	('hypogonadism', 'Phenotype', 'HP:0000135', (214, 226))	('dosage-sensitive sex reversal', 'Disease', (49, 78))	('hypogonadotropic hypogonadism', 'Disease', 'MESH:D007006', (197, 226))	('hypogonadism in males', 'Phenotype', 'HP:0000026', (214, 235))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (170, 191))	('hypoplasia congenital', 'Phenotype', 'HP:0011451', (115, 136))	('adrenal hypoplasia congenital', 'Disease', 'MESH:D000312', (107, 136))	('sex reversal', 'Phenotype', 'HP:0012245', (66, 78))	('hypogonadotropic hypogonadism', 'Disease', (197, 226))	('AHC', 'Disease', 'MESH:D000312', (138, 141))
351039	26258070	Gene expression profiles performed in two heterologous cell models ectopically expressing EWS/FLI1 (HEK293 and HeLa cells) demonstrated that DAX-1 was specifically induced by EWS/FLI1, but not by wildtype FLI1.	('induced', 'PosReg', (164, 171))	('DAX-1', 'Gene', (141, 146))	('HEK293', 'CellLine', 'CVCL:0045', (100, 106))	('rat', 'Species', '10116', (130, 133))	('EWS/FLI1', 'Gene', (90, 98))	('EWS/FLI1', 'Var', (175, 183))	('HeLa', 'CellLine', 'CVCL:0030', (111, 115))
351041	26258070	Finally, DAX-1 expression was demonstrated to depend on EWS/FLI1 expression in the A673 Ewing sarcoma cell line upon EWS/FLI1 knockdown.	('DAX-1', 'Gene', (9, 14))	('rat', 'Species', '10116', (37, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('EWS/FLI1', 'Gene', (56, 64))	('depend', 'Reg', (46, 52))	('knockdown', 'Var', (126, 135))	('Ewing sarcoma', 'Disease', (88, 101))
351042	26258070	Several functional studies have demonstrated that DAX-1 plays a critical role in Ewing sarcoma pathogenesis: DAX-1 knockdown impairs Ewing sarcoma cell proliferation, G1 cell arrest induction, inhibits anchorage independent growth of colonies in soft agar, and drastically inhibits growth of xenotransplanted tumor cells in immunodeficient mice.	('impairs Ewing sarcoma', 'Disease', (125, 146))	('mice', 'Species', '10090', (340, 344))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('knockdown', 'Var', (115, 124))	('G1', 'CellLine', 'CVCL:1929', (167, 169))	('agar', 'Chemical', 'MESH:D000362', (251, 255))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (133, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (133, 146))	('rat', 'Species', '10116', (39, 42))	('DAX-1', 'Gene', (109, 114))	('tumor', 'Disease', (309, 314))	('Ewing sarcoma', 'Disease', (81, 94))	('G1 cell arrest induction', 'CPA', (167, 191))	('inhibits', 'NegReg', (193, 201))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('inhibits', 'NegReg', (273, 281))	('impairs Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('rat', 'Species', '10116', (159, 162))
351049	26258070	The fact that DAX-1 expression is regulated through a polymorphic repeat of the GGAA motif raised the question if the number of repeats could be somehow linked to the level of DAX-1 expression and, as a consequence, to the malignant phenotype of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (246, 259))	('expression', 'MPA', (182, 192))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (246, 259))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (246, 259))	('polymorphic repeat', 'Var', (54, 72))	('linked', 'Reg', (153, 159))	('regulated', 'Reg', (34, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('GGAA', 'Gene', (80, 84))	('DAX-1', 'Gene', (14, 19))
351051	26258070	However, the attempts to establish a relationship between the length of the microsatellite located in DAX-1 promoter and the clinical prognosis have raised contradictory results.	('DAX-1', 'Gene', (102, 107))	('clinical', 'Species', '191496', (125, 133))	('microsatellite', 'Var', (76, 90))
351052	26258070	For instance, GGAA microsatellites were longer in African populations, which are known to have a lower incidence of Ewing sarcoma but a worse overall survival when compared to European populations.	('Ewing sarcoma', 'Disease', (116, 129))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('microsatellites', 'Var', (19, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
351053	26258070	Conversely, in another study based on 112 patients, the length of the DAX-1 microsatellite showed no influence on clinical outcomes.	('DAX-1', 'Gene', (70, 75))	('patients', 'Species', '9606', (42, 50))	('microsatellite', 'Var', (76, 90))	('clinical', 'Species', '191496', (114, 122))
351060	26258070	On the other hand, it has been shown that DAX-1 C-terminal domain contains a potent transcriptional repressor domain that, when altered by mutations in AHC patients, impairs its nuclear localization, and therefore its transcriptional activity, suggesting that there is a potential field for developing drugs to modulate DAX-1 subcellular localization and consequently its function.	('patients', 'Species', '9606', (156, 164))	('impairs', 'NegReg', (166, 173))	('transcriptional repressor domain', 'MPA', (84, 116))	('AHC', 'Disease', 'MESH:D000312', (152, 155))	('mutations', 'Var', (139, 148))	('AHC', 'Disease', (152, 155))	('altered', 'Reg', (128, 135))	('AHC', 'Phenotype', 'HP:0008244', (152, 155))	('DAX-1', 'Gene', (42, 47))	('nuclear localization', 'MPA', (178, 198))	('transcriptional activity', 'MPA', (218, 242))
351062	26258070	For instance, prolonged DAX-1 blockage may lead to disequilibrium in steroid hormones production, which could lead to Cushing-like syndrome.	('steroid hormones production', 'MPA', (69, 96))	('Cushing-like syndrome', 'Disease', 'MESH:D003480', (118, 139))	('disequilibrium', 'MPA', (51, 65))	('Cushing-like syndrome', 'Disease', (118, 139))	('Cushing-like syndrome', 'Phenotype', 'HP:0003118', (118, 139))	('lead to', 'Reg', (43, 50))	('steroid hormone', 'Chemical', 'MESH:D013256', (69, 84))	('blockage', 'Var', (30, 38))	('lead to', 'Reg', (110, 117))	('DAX-1', 'Gene', (24, 29))
351070	26258070	Moreover, when GLI1 expression was knocked-down by RNA interference, the transformed phenotype was reduced (demonstrated by a decrease in the anchorage independent growth) indicating that GLI1 plays an important role in the maintenance of the malignant phenotype induced by EWS/FLI1.	('expression', 'MPA', (20, 30))	('rat', 'Species', '10116', (115, 118))	('decrease', 'NegReg', (126, 134))	('GLI1', 'Gene', (15, 19))	('knocked-down', 'Var', (35, 47))	('transformed phenotype', 'CPA', (73, 94))	('RNA interference', 'MPA', (51, 67))	('reduced', 'NegReg', (99, 106))
351072	26258070	In TC32 Ewing sarcoma cells, EWS/FLI1 knocking down using RNA interference produced a reduction in GLI1 expression levels.	('reduction', 'NegReg', (86, 95))	('knocking', 'Var', (38, 46))	('GLI1 expression levels', 'MPA', (99, 121))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (8, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (8, 21))	('Ewing sarcoma', 'Disease', (8, 21))	('TC32', 'CellLine', 'CVCL:7151', (3, 7))
351075	26258070	Interestingly, and in contrast with what it is usually observed in other types of cancer, GLI1 deregulation in Ewing sarcoma is independent of Shh since its activation did not produce phenotypic changes nor did a pharmacological blockage of SMO using cyclopamine (an inhibitor of Shh signaling by direct binding to SMO).	('GLI1', 'Gene', (90, 94))	('cancer', 'Disease', (82, 88))	('Shh', 'Gene', (143, 146))	('Shh', 'Gene', '6469', (280, 283))	('SMO', 'Gene', (315, 318))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('SMO', 'Gene', '6608', (241, 244))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('Shh', 'Gene', '6469', (143, 146))	('SMO', 'Gene', (241, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Ewing sarcoma', 'Disease', (111, 124))	('Shh', 'Gene', (280, 283))	('cyclopamine', 'Chemical', 'MESH:C000541', (251, 262))	('activation', 'PosReg', (157, 167))	('SMO', 'Gene', '6608', (315, 318))	('deregulation', 'Var', (95, 107))
351079	26258070	Deregulation of the Shh-GLI1 pathway has been showed to lead to tumorigenesis and aggressive phenotypes (progression, metastasis and therapeutic resistance) of numerous cancer types such as basal cell carcinomas, colorectal carcinoma, breast cancer, and bone and soft tissue sarcomas.	('Shh', 'Gene', '6469', (20, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('colorectal carcinoma', 'Disease', (213, 233))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('sarcomas', 'Disease', 'MESH:D012509', (275, 283))	('sarcomas', 'Phenotype', 'HP:0100242', (275, 283))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (213, 233))	('metastasis', 'CPA', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('sarcomas', 'Disease', (275, 283))	('breast cancer', 'Disease', 'MESH:D001943', (235, 248))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (263, 283))	('breast cancer', 'Disease', (235, 248))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (190, 211))	('numerous cancer', 'Disease', 'MESH:D009369', (160, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('therapeutic resistance', 'CPA', (133, 155))	('Shh', 'Gene', (20, 23))	('basal cell carcinomas', 'Disease', (190, 211))	('tumor', 'Disease', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('Deregulation', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('numerous cancer', 'Disease', (160, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (190, 211))	('lead to', 'Reg', (56, 63))
351087	26258070	ATO was also found to inhibit Ewing cells (RDES and A673) migration and invasiveness, thus implying that it could also have a therapeutic effect on metastasis.	('A673', 'Var', (52, 56))	('invasiveness', 'CPA', (72, 84))	('inhibit', 'NegReg', (22, 29))	('metastasis', 'CPA', (148, 158))	('rat', 'Species', '10116', (61, 64))	('ATO', 'Chemical', 'MESH:D000077237', (0, 3))	('ATO', 'Var', (0, 3))
351093	26258070	Some examples are breast cancer, where high GLI1 expression measured in a TMA containing 204 tumor samples was associated with poor prognosis and progressive stages of disease or bone and soft tissue sarcomas, where higher GLI1 expression correlated with more aggressive outcomes.	('TMA', 'Disease', (74, 77))	('high', 'Var', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('sarcomas', 'Disease', 'MESH:D012509', (200, 208))	('TMA', 'Disease', 'MESH:D000783', (74, 77))	('tumor', 'Disease', (93, 98))	('breast cancer', 'Disease', (18, 31))	('associated', 'Reg', (111, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (188, 208))	('progressive', 'Disease', (146, 157))	('sarcomas', 'Disease', (200, 208))	('GLI1', 'Protein', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
351117	26258070	This effect was mediated at least in part by FOXO1, since the knockdown of endogenously induced FOXO1 significantly reduced the apoptotic effect of MSA.	('MSA', 'Chemical', 'MESH:C008493', (148, 151))	('apoptotic effect', 'CPA', (128, 144))	('FOXO1', 'Gene', '2308', (96, 101))	('FOXO1', 'Gene', (45, 50))	('FOXO1', 'Gene', '2308', (45, 50))	('FOXO1', 'Gene', (96, 101))	('reduced', 'NegReg', (116, 123))	('knockdown', 'Var', (62, 71))
351122	26258070	Since reactivation of FOXO1 in Ewing sarcoma cells has shown to be effective both in vitro and in vivo, more studies are necessary to understand the mechanism involved in the regulation of FOXO1 expression and its transcriptional activity in order to identify new therapeutic targets.	('FOXO1', 'Gene', (22, 27))	('FOXO1', 'Gene', '2308', (22, 27))	('FOXO1', 'Gene', (189, 194))	('FOXO1', 'Gene', '2308', (189, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('Ewing sarcoma', 'Disease', (31, 44))	('reactivation', 'Var', (6, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (31, 44))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (31, 44))
351151	26258070	The first data demonstrating a relationship between CCK expression and EWS/FLI1 came from studies performed in heterologous systems: ectopic expression of EWS/FLI1 in the RD rhabdomyosarcoma cell line and in HeLa cells upregulated CCK mRNA levels.	('CCK', 'Gene', (52, 55))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (174, 190))	('CCK', 'Gene', '885', (52, 55))	('CCK', 'Gene', (231, 234))	('rat', 'Species', '10116', (22, 25))	('HeLa', 'CellLine', 'CVCL:0030', (208, 212))	('CCK', 'Gene', '885', (231, 234))	('EWS/FLI1', 'Gene', (155, 163))	('upregulated', 'PosReg', (219, 230))	('rhabdomyosarcoma', 'Disease', (174, 190))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (174, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('ectopic expression', 'Var', (133, 151))
351153	26258070	Thus, EWS/FLI1 knockdown in A673 and SK-PN-DW Ewing sarcoma cell lines downregulated CCK mRNA levels, demonstrating that CCK expression is dependent on EWS/FLI1.	('CCK', 'Gene', '885', (121, 124))	('downregulated', 'NegReg', (71, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('knockdown', 'Var', (15, 24))	('EWS/FLI1', 'Gene', (6, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('CCK', 'Gene', '885', (85, 88))	('rat', 'Species', '10116', (109, 112))	('SK-PN-DW Ewing sarcoma', 'Disease', (37, 59))	('CCK', 'Gene', (85, 88))	('SK-PN-DW Ewing sarcoma', 'Disease', 'MESH:C563168', (37, 59))	('CCK', 'Gene', (121, 124))
351156	26258070	In addition, CCK-rich culture media or exogenous CCK-8 was able to stimulate Ewing sarcoma cell proliferation in vitro, suggesting that CCK is an autocrine growth factor in Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (173, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('Ewing sarcoma', 'Disease', (77, 90))	('rat', 'Species', '10116', (103, 106))	('stimulate', 'PosReg', (67, 76))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (173, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('CCK', 'Gene', '885', (13, 16))	('exogenous', 'Var', (39, 48))	('CCK', 'Gene', (13, 16))	('CCK', 'Gene', (136, 139))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('CCK', 'Gene', '885', (136, 139))	('CCK', 'Gene', (49, 52))	('CCK', 'Gene', '885', (49, 52))
351166	26258070	In addition, one specific antagonist of the CCKB receptor (L365 260) had no effect on Ewing sarcoma cell proliferation or viability.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('CCKB receptor', 'Gene', (44, 57))	('CCKB receptor', 'Gene', '887', (44, 57))	('viability', 'CPA', (122, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 99))	('L365 260', 'Var', (59, 67))	('Ewing sarcoma', 'Disease', (86, 99))	('rat', 'Species', '10116', (112, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
351181	26258070	Thus, LOX antisense cDNA was able to retransform H-ras-transformed revertants and confer tumorigenic features to normal rat kidney fibroblasts (NRK-49F).	('confer', 'Reg', (82, 88))	('NRK-49F', 'CellLine', 'CVCL:2144', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('rat', 'Species', '10116', (120, 123))	('H-ras-transformed', 'CPA', (49, 66))	('antisense', 'Var', (10, 19))	('tumor', 'Disease', (89, 94))
351183	26258070	described for the first time that recombinant LOX-PP was able to inhibit neoplastic transformation features in Ras-transformed mouse fibroblasts such as growth in anchorage independent conditions and Ras-dependent induction of NFkappaB.	('mouse', 'Species', '10090', (127, 132))	('LOX-PP', 'Var', (46, 52))	('neoplastic transformation features', 'CPA', (73, 107))	('NFkappaB', 'Gene', (227, 235))	('NFkappaB', 'Gene', '18033', (227, 235))	('inhibit', 'NegReg', (65, 72))
351187	26258070	Interestingly, in these cases, metastatic and invasive properties have been related to the lysyl oxidase activity of LOX, rather than to LOX-PP.	('metastatic', 'CPA', (31, 41))	('LOX', 'Var', (117, 120))	('lysyl oxidase', 'Gene', (91, 104))	('lysyl oxidase', 'Gene', '4015', (91, 104))	('related', 'Reg', (76, 83))	('rat', 'Species', '10116', (122, 125))	('invasive properties', 'CPA', (46, 65))
351189	26258070	Data obtained until now indicate that LOX-PP can act at different levels, and that the pathways and functions affected can depend of the cancer or cell model studied.	('depend of the cancer', 'Disease', 'MESH:D009369', (123, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('depend of the cancer', 'Disease', (123, 143))	('LOX-PP', 'Var', (38, 44))
351190	26258070	For example, in Her-2/neu-transformed NF639 breast cancer cells, ectopic expression of LOX-PP interferes with fibronectin-stimulated tyrosine phosphorylation of cellular proteins involved in integrin signaling, inactivating the focal adhesion kinase (FAK), and consequently diminishes the migratory response.	('migratory response', 'CPA', (289, 307))	('cellular', 'Protein', (161, 169))	('interferes', 'NegReg', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('FAK', 'Gene', '5747', (251, 254))	('tyrosine', 'Chemical', 'MESH:D014443', (133, 141))	('rat', 'Species', '10116', (292, 295))	('fibronectin', 'Gene', (110, 121))	('Her-2/neu', 'Gene', (16, 25))	('diminishes', 'NegReg', (274, 284))	('inactivating', 'NegReg', (211, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('focal adhesion kinase', 'Gene', '5747', (228, 249))	('fibronectin', 'Gene', '2335', (110, 121))	('LOX-PP', 'Var', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Disease', (44, 57))	('FAK', 'Gene', (251, 254))	('Her-2/neu', 'Gene', '13866', (16, 25))	('focal adhesion kinase', 'Gene', (228, 249))
351191	26258070	In other breast cancer cells driven by Her-2/neu (ERBB2), LOX-PP expression suppressed AKT, ERK, and NFkappaB activation, as well as cell migration, growth in soft agar and tumor formation in nude mice.	('cell migration', 'CPA', (133, 147))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('NFkappaB', 'Gene', '18033', (101, 109))	('ERBB2', 'Gene', (50, 55))	('nude mice', 'Species', '10090', (192, 201))	('rat', 'Species', '10116', (141, 144))	('NFkappaB', 'Gene', (101, 109))	('ERBB2', 'Gene', '13866', (50, 55))	('Her-2/neu', 'Gene', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('agar', 'Chemical', 'MESH:D000362', (164, 168))	('suppressed', 'NegReg', (76, 86))	('AKT', 'Pathway', (87, 90))	('expression', 'Var', (65, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('activation', 'PosReg', (110, 120))	('ERK', 'Pathway', (92, 95))	('tumor', 'Disease', (173, 178))	('growth in soft agar', 'CPA', (149, 168))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('breast cancer', 'Disease', (9, 22))	('Her-2/neu', 'Gene', '13866', (39, 48))	('LOX-PP', 'Gene', (58, 64))
351193	26258070	On the other hand, LOX-PP decreased the levels of NF-kappaB and cyclin D1 in Her-2/neu-transformed NF639 breast cancer cells and MIA PaCa-2 pancreatic cancer cells, together with a reduction in migration and growth in soft agar.	('MIA PaCa-2 pancreatic cancer', 'Disease', (129, 157))	('agar', 'Chemical', 'MESH:D000362', (223, 227))	('levels', 'MPA', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('decreased', 'NegReg', (26, 35))	('Her-2/neu', 'Gene', '13866', (77, 86))	('rat', 'Species', '10116', (197, 200))	('LOX-PP', 'Var', (19, 25))	('MIA PaCa-2 pancreatic cancer', 'Disease', 'MESH:D010190', (129, 157))	('growth in soft agar', 'CPA', (208, 227))	('NF-kappaB', 'MPA', (50, 59))	('cyclin D1', 'Gene', (64, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Her-2/neu', 'Gene', (77, 86))	('migration', 'CPA', (194, 203))	('cyclin D1', 'Gene', '595', (64, 73))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('reduction', 'NegReg', (181, 190))
351194	26258070	Finally, in PANC-1 pancreatic cancer cells, LOX-PP also impaired AKT and ERK activity and growth in soft agar and cell migration.	('ERK activity', 'CPA', (73, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('LOX-PP', 'Var', (44, 50))	('PANC-1', 'CellLine', 'CVCL:0480', (12, 18))	('cell migration', 'CPA', (114, 128))	('growth in soft agar', 'CPA', (90, 109))	('rat', 'Species', '10116', (122, 125))	('pancreatic cancer', 'Disease', (19, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (19, 36))	('agar', 'Chemical', 'MESH:D000362', (105, 109))	('impaired', 'NegReg', (56, 64))
351196	26258070	Thus, EWS/FLI1 knockdown in Ewing sarcoma cells induces the expression of LOX indicating that this gene is strongly repressed by EWS/FLI1 in these cells.	('expression', 'MPA', (60, 70))	('knockdown', 'Var', (15, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('EWS/FLI1', 'Gene', (6, 14))	('Ewing sarcoma', 'Disease', (28, 41))	('induces', 'Reg', (48, 55))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (28, 41))
351199	26258070	Thus, ectopic expression of LOX-PP in the A673 Ewing sarcoma cell line reduced cell proliferation, cell migration, anchorage independent growth, and impaired tumor growth in vivo, indicating that it had tumor suppressor activities in this cell, in line with what was observed in other tumors.	('tumor', 'Disease', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cell migration', 'CPA', (99, 113))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('cell proliferation', 'CPA', (79, 97))	('impaired tumor', 'Disease', (149, 163))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (47, 60))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (47, 60))	('tumors', 'Disease', (285, 291))	('reduced', 'NegReg', (71, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('impaired tumor', 'Disease', 'MESH:D015417', (149, 163))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('rat', 'Species', '10116', (91, 94))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('rat', 'Species', '10116', (107, 110))	('tumor', 'Disease', (158, 163))	('Ewing sarcoma', 'Disease', (47, 60))	('tumor', 'Disease', (285, 290))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('LOX-PP', 'Var', (28, 34))	('anchorage independent growth', 'CPA', (115, 143))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
351202	26258070	The mechanisms involved in LOX-PP-mediated suppression in Ewing sarcoma have only been partially studied.	('LOX-PP-mediated', 'Var', (27, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('Ewing sarcoma', 'Disease', (58, 71))	('suppression', 'NegReg', (43, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (58, 71))
351210	26258070	In all cases, exogenous LOX-PP reduced tumor cells growth, supporting the therapeutic usefulness of this strategy.	('reduced', 'NegReg', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('LOX-PP', 'Var', (24, 30))	('tumor', 'Disease', (39, 44))	('rat', 'Species', '10116', (107, 110))
351211	26258070	Interestingly, in one study, the combination of LOX-PP with the chemotherapeutic agent doxorubicin in breast and pancreatic cancer cells in vitro showed an enhanced cytotoxic effect of doxorubicin when the cells were first sensitize by incubation with LOX-PP.	('cytotoxic effect', 'CPA', (165, 181))	('combination', 'Interaction', (33, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (185, 196))	('pancreatic cancer', 'Disease', (113, 130))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('enhanced', 'PosReg', (156, 164))	('LOX-PP', 'Var', (48, 54))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))
351212	26258070	These results mean that even if LOX-PP is not capable of inducing complete cell death by itself, it could potentially sensitize cancer cells to standard therapies thus allowing to lower the doses and adverse side effects associated to conventional chemotherapy and radiotherapy.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('LOX-PP', 'Var', (32, 38))	('doses', 'MPA', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lower', 'NegReg', (180, 185))	('cancer', 'Disease', (128, 134))
351218	26258070	However, induction of LOX expression to achieve an increased production of anti-tumorigenic LOX-PP in Ewing sarcoma cells may not be as beneficial as expected: while induction of LOX expression would cause an increase in LOX-PP, it also would produce an increase in the production of the LOX mature enzyme, which has been showed to be pro-oncogenic in Ewing sarcoma cells and other tumors.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (352, 365))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (352, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (358, 365))	('induction', 'Var', (166, 175))	('tumors', 'Disease', (382, 388))	('production', 'MPA', (270, 280))	('tumor', 'Disease', (382, 387))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('LOX-PP', 'MPA', (221, 227))	('Ewing sarcoma', 'Disease', (352, 365))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('tumors', 'Disease', 'MESH:D009369', (382, 388))	('LOX mature enzyme', 'Enzyme', (288, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('tumor', 'Disease', (80, 85))	('increase', 'PosReg', (209, 217))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Ewing sarcoma', 'Disease', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('expression', 'Var', (183, 193))	('tumors', 'Phenotype', 'HP:0002664', (382, 388))	('increase', 'PosReg', (254, 262))
351219	26258070	Other opportunities for therapeutic interventions could be derived from the identification and characterization of LOX-PP interactions with other proteins, mainly intracellular proteins involved in cell signaling and regulation of tumorigenic processes.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('LOX-PP', 'Var', (115, 121))	('interactions', 'Interaction', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))
351221	26258070	In summary, LOX, and more specifically LOX-PP, has been showed to have anti-tumorigenic properties, which could be exploited to treat cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('LOX', 'Var', (12, 15))	('tumor', 'Disease', (76, 81))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
351234	25666852	Flow cytometry indicated presence of 92.4% of immature myeloid cells with t (15: 17) and q (22: 12) mutations, and FISH analysis for PML-RARA demonstrated a long-form fusion transcript, positive for APL.	('mutations', 'Var', (100, 109))	('APL', 'Phenotype', 'HP:0004836', (199, 202))	('APL', 'Disease', (199, 202))	('APL', 'Disease', 'MESH:D015473', (199, 202))
351246	25666852	She also was thrombocytopenic with 3000 platelets (normal value 150 000-400 000 cells/uL), fibrin degradation products >20 mcg/ml (normal value: <5 mcg/ml) and D-Dimer >35.2 mg/L FEU (normal value: <0.53 mg/L FEU).	('fibrin degradation products', 'MPA', (91, 118))	('D-Dimer', 'MPA', (160, 167))	('thrombocytopenic', 'Disease', (13, 29))	('thrombocytopenic', 'Disease', 'MESH:D011696', (13, 29))	('>35.2', 'Var', (168, 173))
351275	25223734	Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations Ewing sarcoma is a primary bone tumor initiated by EWSR1-ETS gene fusions.	('Ewing sarcoma', 'Disease', (21, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (113, 126))	('STAG2', 'Gene', (88, 93))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (113, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('EWSR1', 'Gene', (164, 169))	('mutations', 'Var', (103, 112))	('bone tumor', 'Phenotype', 'HP:0010622', (140, 150))	('bone tumor', 'Disease', (140, 150))	('TP53', 'Gene', (98, 102))	('Ewing sarcoma', 'Disease', (113, 126))	('bone tumor', 'Disease', 'MESH:D001859', (140, 150))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('EWSR1', 'Gene', '2130', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('STAG2', 'Gene', '10735', (88, 93))	('TP53', 'Gene', '7157', (98, 102))
351277	25223734	Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants and copy-number alterations.	('copy-number alterations', 'Var', (109, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (9, 22))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (9, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('structural variants', 'Var', (85, 104))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('Ewing sarcoma tumors', 'Disease', (9, 29))	('single-nucleotide variants', 'Var', (49, 75))
351279	25223734	Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('deletions', 'Var', (39, 48))	('CDKN2A', 'Gene', (32, 38))	('CDKN2A', 'Gene', '1029', (32, 38))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 103))	('STAG2', 'Gene', (12, 17))	('STAG2', 'Gene', '10735', (12, 17))	('Ewing sarcoma', 'Disease', (90, 103))	('mutations', 'Var', (18, 27))
351280	25223734	In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome.	('patients', 'Species', '9606', (29, 37))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('STAG2', 'Gene', (77, 82))	('STAG2', 'Gene', '10735', (77, 82))	('associated with', 'Reg', (131, 146))
351281	25223734	Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2 immuno-negative cells in relapsed tumors as compared with matched diagnostic samples.	('STAG2', 'Gene', (31, 36))	('tumors', 'Disease', (61, 67))	('STAG2', 'Gene', '10735', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('STAG2', 'Gene', '10735', (31, 36))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('STAG2', 'Gene', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
351286	25223734	Genetically, most Ewing sarcomas are characterized by a specific t(11;22)(q12;q11.2) translocation that fuses the EWSR1 gene on chromosome (chr) 22 with the FLI1 gene on chr 11.	('FLI1', 'Gene', '2313', (157, 161))	('Ewing sarcomas', 'Disease', (18, 32))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (18, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('EWSR1', 'Gene', (114, 119))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (18, 32))	('EWSR1', 'Gene', '2130', (114, 119))	('t(11;22)(q12;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (65, 84))	('FLI1', 'Gene', (157, 161))	('fuses', 'Var', (104, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (18, 31))
351292	25223734	The long arm of chr 16 and the CDKN2A locus on chr 9p are the most common copy-number losses in Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('Ewing sarcoma', 'Disease', (96, 109))	('CDKN2A', 'Gene', (31, 37))	('copy-number losses', 'Var', (74, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('CDKN2A', 'Gene', '1029', (31, 37))
351293	25223734	The adverse prognosis conferred by chr 1q gain and chr 16q or CDKN2A loss has been reported, as has the negative impact of TP53 mutations.	('loss', 'NegReg', (69, 73))	('gain', 'PosReg', (42, 46))	('CDKN2A', 'Gene', '1029', (62, 68))	('CDKN2A', 'Gene', (62, 68))	('chr 1q', 'Var', (35, 41))	('TP53', 'Gene', '7157', (123, 127))	('chr 16q', 'Var', (51, 58))	('TP53', 'Gene', (123, 127))
351294	25223734	Finally, somatic STAG2 mutations were recently observed in a significant fraction of Ewing sarcoma cases (21%).	('Ewing sarcoma', 'Disease', (85, 98))	('STAG2', 'Gene', (17, 22))	('STAG2', 'Gene', '10735', (17, 22))	('observed', 'Reg', (47, 55))	('mutations', 'Var', (23, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))
351297	25223734	The most frequent point mutations involved the STAG2 and TP53 genes, and the prognostic significance of these mutations was further demonstrated in a series of 299 cases.	('point mutations', 'Var', (18, 33))	('STAG2', 'Gene', (47, 52))	('STAG2', 'Gene', '10735', (47, 52))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
351298	25223734	STAG2 mutations were significantly associated with the occurrence of structural variations and were mutually exclusive with CDKN2A deletions.	('CDKN2A', 'Gene', (124, 130))	('STAG2', 'Gene', '10735', (0, 5))	('CDKN2A', 'Gene', '1029', (124, 130))	('associated', 'Reg', (35, 45))	('structural variations', 'MPA', (69, 90))	('deletions', 'Var', (131, 140))	('STAG2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
351303	25223734	Eighty percent of the tumors had >70% tumor purity leading to a 98% power for detecting mutations present in the predominant tumor clones in this cohort (Supplementary Table S2a).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('mutations', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (22, 27))	('tumors', 'Disease', (22, 28))
351306	25223734	Five cases (SJ001303, SJ001320, IC198, IC273, IC086) exhibited chromothripsis, including three cases with chromothripsis on chr 21 and 22 associated with EWSR1-ERG fusions (SJ001303, IC198 and IC273) and one case involving chr 22 associated with an EWSR1-FLI1 fusion (SJ001320).	('FLI1', 'Gene', '2313', (255, 259))	('SJ001303', 'Var', (12, 20))	('EWSR1', 'Gene', '2130', (154, 159))	('SJ001303', 'Var', (173, 181))	('EWSR1', 'Gene', (249, 254))	('IC273', 'Var', (39, 44))	('SJ001320', 'Var', (22, 30))	('associated', 'Reg', (138, 148))	('IC273', 'Var', (193, 198))	('ERG', 'Gene', '2078', (160, 163))	('ERG', 'Gene', (160, 163))	('exhibited', 'Reg', (53, 62))	('EWSR1', 'Gene', (154, 159))	('chromothripsis', 'MPA', (63, 77))	('FLI1', 'Gene', (255, 259))	('EWSR1', 'Gene', '2130', (249, 254))
351308	25223734	The most frequent CNAs were gain of whole chr 8 (49/103; 47%), gain of whole chr 12 (22/103; 21%), gain of the long arm of chr 1 (19/103; 18%), deletion of the long arm of chr 16 (18/103; 17%), and deletion of the CDKN2A locus on the short arm of chr 9 (12/103; 12%) (Fig.	('CDKN2A', 'Gene', (214, 220))	('gain', 'PosReg', (28, 32))	('deletion', 'Var', (198, 206))	('CDKN2A', 'Gene', '1029', (214, 220))	('short arm', 'Phenotype', 'HP:0009824', (234, 243))	('deletion', 'Var', (144, 152))
351316	25223734	In contrast, STAG2 status was not associated with the number of SNVs or indels (Fig.	('STAG2', 'Gene', (13, 18))	('indels', 'Var', (72, 78))	('STAG2', 'Gene', '10735', (13, 18))
351318	25223734	All mutations were missense, with the exception of one nonsense mutation (p.R317* according to NM_000546), and were described in the COSMIC database.	('missense', 'Var', (19, 27))	('p.R317*', 'Var', (74, 81))	('p.R317*', 'Mutation', 'p.R317*', (74, 81))
351320	25223734	All three EZH2 mutations were missense mutations within the SET domain (Y646F, Y646H, and A682G according to NM_004456).	('Y646F', 'Var', (72, 77))	('Y646F', 'Mutation', 'rs267601394', (72, 77))	('EZH2', 'Gene', '2146', (10, 14))	('A682G', 'Mutation', 'rs1057519833', (90, 95))	('Y646H', 'Var', (79, 84))	('EZH2', 'Gene', (10, 14))	('A682G', 'Var', (90, 95))	('Y646H', 'Mutation', 'rs267601395', (79, 84))
351321	25223734	BCOR exhibited one missense mutation (S1083I, according to NM_017745), one indel leading to a frameshift (M1259fs) and one 116-kb intragenic deletion (Fig.	('S1083I', 'Mutation', 'p.S1083I', (38, 44))	('M1259fs', 'Mutation', 'p.M1259fsX', (106, 113))	('BCOR', 'Gene', '54880', (0, 4))	('S1083I', 'Var', (38, 44))	('M1259fs', 'Var', (106, 113))	('BCOR', 'Gene', (0, 4))
351322	25223734	ZMYM3 exhibited two indels (L82fs according to NM_201599) and one 17-kb intragenic deletion (Fig.	('ZMYM3', 'Gene', '9203', (0, 5))	('L82fs', 'Mutation', 'p.L82fsX', (28, 33))	('ZMYM3', 'Gene', (0, 5))	('L82fs', 'Var', (28, 33))
351323	25223734	Mutations affecting epigenetic regulators have been found to be significantly associated with some pediatric cancers.	('associated', 'Reg', (78, 88))	('pediatric cancers', 'Disease', (99, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('pediatric cancers', 'Disease', 'MESH:D009369', (99, 116))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
351324	25223734	In addition to the mutations in EZH2, BCOR, and ZMYM3, we identified novel somatic mutations in SETD2, MLL2, MLL3, and PRDM9 (Fig.	('mutations', 'Var', (83, 92))	('MLL3', 'Gene', (109, 113))	('BCOR', 'Gene', '54880', (38, 42))	('EZH2', 'Gene', (32, 36))	('MLL2', 'Gene', '9757', (103, 107))	('ZMYM3', 'Gene', (48, 53))	('MLL3', 'Gene', '58508', (109, 113))	('SETD2', 'Gene', '29072', (96, 101))	('EZH2', 'Gene', '2146', (32, 36))	('ZMYM3', 'Gene', '9203', (48, 53))	('PRDM9', 'Gene', (119, 124))	('BCOR', 'Gene', (38, 42))	('SETD2', 'Gene', (96, 101))	('PRDM9', 'Gene', '56979', (119, 124))	('MLL2', 'Gene', (103, 107))
351325	25223734	Of note, two novel missense mutations were observed in EWSR1.	('EWSR1', 'Gene', (55, 60))	('EWSR1', 'Gene', '2130', (55, 60))	('missense mutations', 'Var', (19, 37))
351328	25223734	When investigating the relationships between gene mutations, SVs, and CNAs, we found a mutually exclusive pattern of STAG2 and CDKN2A genetic alterations (Fig.	('STAG2', 'Gene', (117, 122))	('STAG2', 'Gene', '10735', (117, 122))	('genetic alterations', 'Var', (134, 153))	('CDKN2A', 'Gene', (127, 133))	('CDKN2A', 'Gene', '1029', (127, 133))	('SV', 'Disease', 'None', (61, 63))
351330	25223734	STAG2 mutations and CDKN2A deletions were observed in 9 and 6 of the 19 cell lines, respectively (Table 1).	('STAG2', 'Gene', '10735', (0, 5))	('CDKN2A', 'Gene', (20, 26))	('deletions', 'Var', (27, 36))	('CDKN2A', 'Gene', '1029', (20, 26))	('STAG2', 'Gene', (0, 5))	('observed', 'Reg', (42, 50))	('mutations', 'Var', (6, 15))
351332	25223734	Across the 15 cell lines that could be investigated by western blot, all cases with STAG2 mutations but one (MHH-ES-1) expressed p16.	('mutations', 'Var', (90, 99))	('p16', 'Gene', (129, 132))	('STAG2', 'Gene', '10735', (84, 89))	('STAG2', 'Gene', (84, 89))	('p16', 'Gene', '1029', (129, 132))
351333	25223734	Reciprocally, all cases with CDKN2A deletion expressed STAG2 (Supplementary Fig.	('CDKN2A', 'Gene', (29, 35))	('deletion', 'Var', (36, 44))	('STAG2', 'Gene', '10735', (55, 60))	('STAG2', 'Gene', (55, 60))	('expressed', 'Reg', (45, 54))	('CDKN2A', 'Gene', '1029', (29, 35))
351335	25223734	The frequency of TP53 mutations was extremely high in the cell lines (Table 1).	('TP53', 'Gene', '7157', (17, 21))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (17, 21))
351337	25223734	To determine whether STAG2 and/or TP53 mutations are associated with outcome in Ewing sarcoma, we analyzed these genes by targeted capture sequencing in an additional 199 French Ewing sarcoma patients.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('TP53', 'Gene', (34, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('Ewing sarcoma', 'Disease', (178, 191))	('patients', 'Species', '9606', (192, 200))	('mutations', 'Var', (39, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('associated', 'Reg', (53, 63))	('STAG2', 'Gene', '10735', (21, 26))	('Ewing sarcoma', 'Disease', (80, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (178, 191))	('TP53', 'Gene', '7157', (34, 38))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (178, 191))	('STAG2', 'Gene', (21, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
351340	25223734	3A and Supplementary Table S4) and 16 patients (5.2%) had TP53 mutations.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))	('patients', 'Species', '9606', (38, 46))
351341	25223734	The STAG2 mutations included 15 nonsense, 4 missense, 17 frameshift, and 4 splice site mutations, 2 in-frame deletions, and 1 exon duplication (Figs.	('frameshift', 'Var', (57, 67))	('STAG2', 'Gene', (4, 9))	('mutations', 'Var', (10, 19))	('missense', 'Var', (44, 52))	('STAG2', 'Gene', '10735', (4, 9))
351344	25223734	The presence of a STAG2 mutation was not significantly associated with dismal prognostic factors including tumor size, response to chemotherapy, resection quality, or tumor spread.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutation', 'Var', (24, 32))	('STAG2', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (167, 172))	('STAG2', 'Gene', '10735', (18, 23))
351345	25223734	However, patients with STAG2 mutations demonstrated a significantly lower probability of survival, similar to patients with TP53-mutated tumors (Fig.	('patients', 'Species', '9606', (9, 17))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('lower', 'NegReg', (68, 73))	('TP53', 'Gene', '7157', (124, 128))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('TP53', 'Gene', (124, 128))	('STAG2', 'Gene', (23, 28))	('STAG2', 'Gene', '10735', (23, 28))	('survival', 'MPA', (89, 97))	('patients', 'Species', '9606', (110, 118))
351346	25223734	Patients with neither STAG2 nor TP53 mutations had the highest probability of survival, and patients whose tumors carried mutations in both genes had the worst outcome (Fig.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('TP53', 'Gene', '7157', (32, 36))	('patients', 'Species', '9606', (92, 100))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mutations', 'Var', (122, 131))	('TP53', 'Gene', (32, 36))	('STAG2', 'Gene', (22, 27))	('STAG2', 'Gene', '10735', (22, 27))
351348	25223734	In our cohort, STAG2 and TP53 mutations were significantly co-associated (P = 2.4x10-4, Fisher exact test).	('TP53', 'Gene', (25, 29))	('co-associated', 'Interaction', (59, 72))	('STAG2', 'Gene', (15, 20))	('STAG2', 'Gene', '10735', (15, 20))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (25, 29))
351350	25223734	Expanding the CDKN2A cohort confirmed the exclusion pattern with STAG2 mutations.	('STAG2', 'Gene', (65, 70))	('CDKN2A', 'Gene', '1029', (14, 20))	('mutations', 'Var', (71, 80))	('STAG2', 'Gene', '10735', (65, 70))	('CDKN2A', 'Gene', (14, 20))
351351	25223734	Indeed, we identified only 2 tumors with both STAG2 mutations and CDKN2A deletions.	('mutations', 'Var', (52, 61))	('STAG2', 'Gene', (46, 51))	('STAG2', 'Gene', '10735', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CDKN2A', 'Gene', '1029', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('deletions', 'Var', (73, 82))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('CDKN2A', 'Gene', (66, 72))
351355	25223734	Seven diagnostic samples showed evidence of subclonal mutations, i.e., a mutant allele frequency <0.25 despite high tumor purity (Supplementary Table S4; example in Fig.	('mutant', 'Var', (73, 79))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))
351359	25223734	Consistent with the immunostaining result, loss of function STAG2 mutations were detected at relapse with high allelic fractions but were either not detected (SJEWS001303) or detected at a subclonal level at diagnosis (SJEWS014721) (Supplementary Table S5).	('mutations', 'Var', (66, 75))	('STAG2', 'Gene', (60, 65))	('STAG2', 'Gene', '10735', (60, 65))
351363	25223734	The Ewing sarcoma mutation rate is much lower than that usually observed in adult cancers and in the upper range of what is described in other pediatric solid malignancies and brain tumors including neuroblastoma, retinoblastoma, rhabdomyosarcoma, medulloblastoma, pilocytic astrocytoma, pediatric glioblastoma, and osteosarcoma.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('Ewing sarcoma', 'Disease', (4, 17))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('retinoblastoma', 'Disease', (214, 228))	('cancers', 'Disease', (82, 89))	('osteosarcoma', 'Disease', (316, 328))	('osteosarcoma', 'Disease', 'MESH:D012516', (316, 328))	('malignancies', 'Disease', (159, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('neuroblastoma', 'Disease', (199, 212))	('brain tumors', 'Disease', 'MESH:D001932', (176, 188))	('brain tumors', 'Phenotype', 'HP:0030692', (176, 188))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('neuroblastoma', 'Phenotype', 'HP:0003006', (199, 212))	('glioblastoma', 'Phenotype', 'HP:0012174', (298, 310))	('neuroblastoma', 'Disease', 'MESH:D009447', (199, 212))	('rhabdomyosarcoma', 'Disease', (230, 246))	('mutation', 'Var', (18, 26))	('brain tumors', 'Disease', (176, 188))	('pediatric glioblastoma', 'Disease', (288, 310))	('retinoblastoma', 'Disease', 'MESH:D012175', (214, 228))	('osteosarcoma', 'Phenotype', 'HP:0002669', (316, 328))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (321, 328))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (4, 17))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (230, 246))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (4, 17))	('lower', 'NegReg', (40, 45))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (265, 286))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (230, 246))	('astrocytoma', 'Phenotype', 'HP:0009592', (275, 286))	('medulloblastoma', 'Disease', 'MESH:D008527', (248, 263))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (288, 310))	('pilocytic astrocytoma', 'Disease', (265, 286))	('medulloblastoma', 'Phenotype', 'HP:0002885', (248, 263))	('retinoblastoma', 'Phenotype', 'HP:0009919', (214, 228))	('medulloblastoma', 'Disease', (248, 263))
351370	25223734	STAG2 mutations were initially observed in a diverse range of cancers including glioblastoma, melanoma, and Ewing sarcoma.	('Ewing sarcoma', 'Disease', (108, 121))	('STAG2', 'Gene', '10735', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('cancers', 'Disease', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('observed', 'Reg', (31, 39))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('STAG2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
351371	25223734	Subsequently STAG2 mutations were described in a significant proportion of bladder cancers and myeloid neoplasms.	('bladder cancers', 'Disease', 'MESH:D001749', (75, 90))	('STAG2', 'Gene', '10735', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('bladder cancers', 'Disease', (75, 90))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (95, 112))	('mutations', 'Var', (19, 28))	('bladder cancers', 'Phenotype', 'HP:0009725', (75, 90))	('neoplasms', 'Phenotype', 'HP:0002664', (103, 112))	('STAG2', 'Gene', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('myeloid neoplasms', 'Disease', (95, 112))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (95, 112))	('described', 'Reg', (34, 43))
351372	25223734	Although experimental systems have shown that STAG1 and STAG2 inactivation drives aneuploidy, STAG2 mutations were not found to be associated with aneuploidy or copy-number alterations in bladder cancer.	('mutations', 'Var', (100, 109))	('STAG2', 'Gene', (56, 61))	('STAG2', 'Gene', '10735', (56, 61))	('STAG1', 'Gene', '10274', (46, 51))	('aneuploidy', 'Disease', 'MESH:D000782', (82, 92))	('STAG2', 'Gene', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('inactivation', 'NegReg', (62, 74))	('STAG2', 'Gene', '10735', (94, 99))	('associated', 'Reg', (131, 141))	('aneuploidy', 'Disease', 'MESH:D000782', (147, 157))	('STAG1', 'Gene', (46, 51))	('bladder cancer', 'Disease', 'MESH:D001749', (188, 202))	('bladder cancer', 'Disease', (188, 202))	('aneuploidy', 'Disease', (82, 92))	('aneuploidy', 'Disease', (147, 157))
351373	25223734	The case may be slightly different in Ewing sarcoma, as we observed a positive correlation between the presence of STAG2 mutation and the number of SVs.	('presence', 'Var', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('STAG2', 'Gene', (115, 120))	('STAG2', 'Gene', '10735', (115, 120))	('Ewing sarcoma', 'Disease', (38, 51))	('SV', 'Disease', 'None', (148, 150))	('mutation', 'Var', (121, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))
351374	25223734	However, the interpretation of this correlation must take into account the strong co-association of STAG2 and TP53 mutations in our cohort.	('STAG2', 'Gene', (100, 105))	('mutations', 'Var', (115, 124))	('TP53', 'Gene', '7157', (110, 114))	('STAG2', 'Gene', '10735', (100, 105))	('TP53', 'Gene', (110, 114))
351375	25223734	When cases with only one of these two mutations are considered, the positive correlation between STAG2 mutation and the number of SVs is no longer significant.	('mutation', 'Var', (103, 111))	('STAG2', 'Gene', '10735', (97, 102))	('SV', 'Disease', 'None', (130, 132))	('STAG2', 'Gene', (97, 102))
351376	25223734	The analysis of survival data must also take into account the association between STAG2 and TP53 mutations.	('mutations', 'Var', (97, 106))	('association', 'Interaction', (62, 73))	('STAG2', 'Gene', (82, 87))	('STAG2', 'Gene', '10735', (82, 87))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))
351377	25223734	Indeed, in our extended series of patients, the prognostic significance of STAG2 mutation appears to be strongly dependent on the co-existence of a TP53 mutation.	('dependent', 'Reg', (113, 122))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('mutation', 'Var', (81, 89))	('STAG2', 'Gene', (75, 80))	('STAG2', 'Gene', '10735', (75, 80))	('patients', 'Species', '9606', (34, 42))
351379	25223734	Together, these data suggest that STAG2 and TP53 mutation may cooperate to increase genetic instability in a particularly aggressive subtype of Ewing sarcoma.	('genetic instability', 'Disease', (84, 103))	('Ewing sarcoma', 'Disease', (144, 157))	('STAG2', 'Gene', '10735', (34, 39))	('mutation', 'Var', (49, 57))	('genetic instability', 'Disease', 'MESH:D030342', (84, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (144, 157))	('TP53', 'Gene', '7157', (44, 48))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (144, 157))	('increase', 'PosReg', (75, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('STAG2', 'Gene', (34, 39))	('TP53', 'Gene', (44, 48))
351380	25223734	Consistent with this hypothesis, it is noteworthy that STAG2 and TP53 mutations are much more frequent in cell lines derived mainly from aggressive cases.	('frequent', 'Reg', (94, 102))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('STAG2', 'Gene', '10735', (55, 60))	('TP53', 'Gene', (65, 69))	('STAG2', 'Gene', (55, 60))
351383	25223734	We observed a previously unreported, mutually exclusive pattern of STAG2 and CDKN2A mutation in Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('CDKN2A', 'Gene', (77, 83))	('CDKN2A', 'Gene', '1029', (77, 83))	('STAG2', 'Gene', (67, 72))	('STAG2', 'Gene', '10735', (67, 72))	('Ewing sarcoma', 'Disease', (96, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('mutation', 'Var', (84, 92))
351387	25223734	However, as previously reported, methylation is not a common mechanisms for CDKN2A inactivation in Ewing sarcoma and is therefore not expected to occur in most STAG2-wild type cases.	('CDKN2A', 'Gene', '1029', (76, 82))	('methylation', 'Var', (33, 44))	('inactivation', 'NegReg', (83, 95))	('Ewing sarcoma', 'Disease', (99, 112))	('STAG2', 'Gene', (160, 165))	('STAG2', 'Gene', '10735', (160, 165))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (99, 112))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (99, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('CDKN2A', 'Gene', (76, 82))
351389	25223734	Three EZH2 mutations (Y646F, Y646H, and A682G, all in the SET domain) were observed in our cohort of patients.	('patients', 'Species', '9606', (101, 109))	('EZH2', 'Gene', '2146', (6, 10))	('Y646H', 'Mutation', 'rs267601395', (29, 34))	('EZH2', 'Gene', (6, 10))	('Y646F', 'Var', (22, 27))	('Y646F', 'Mutation', 'rs267601394', (22, 27))	('A682G', 'Mutation', 'rs1057519833', (40, 45))	('Y646H', 'Var', (29, 34))	('A682G', 'Var', (40, 45))
351391	25223734	Residues Y646 and to a lesser extent A682 are frequently mutated in B-cell lymphoma, and these mutations have been shown to enhance EZH2 enzymatic activity and promote malignant lymphoid transformation.	('A682', 'Var', (37, 41))	('promote', 'PosReg', (160, 167))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (68, 83))	('malignant lymphoid transformation', 'CPA', (168, 201))	('enhance', 'PosReg', (124, 131))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('EZH2', 'Gene', '2146', (132, 136))	('EZH2', 'Gene', (132, 136))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (68, 83))	('enzymatic activity', 'MPA', (137, 155))	('malignant lymphoid transformation', 'Phenotype', 'HP:0002665', (168, 201))	('B-cell lymphoma', 'Disease', (68, 83))
351392	25223734	Mutations of EZH2 have also been observed in a subset of acute T-cell and myeloid malignancies.	('EZH2', 'Gene', (13, 17))	('EZH2', 'Gene', '2146', (13, 17))	('acute T-cell', 'Disease', (57, 69))	('observed', 'Reg', (33, 41))	('myeloid malignancies', 'Disease', 'MESH:D009369', (74, 94))	('Mutations', 'Var', (0, 9))	('myeloid malignancies', 'Disease', (74, 94))
351393	25223734	In addition to EZH2, potentially deleterious mutations in ZMYM3 and BCOR, which also encode epigenetic regulators, were reported in three cases each.	('mutations', 'Var', (45, 54))	('ZMYM3', 'Gene', '9203', (58, 63))	('ZMYM3', 'Gene', (58, 63))	('BCOR', 'Gene', (68, 72))	('BCOR', 'Gene', '54880', (68, 72))	('EZH2', 'Gene', (15, 19))	('EZH2', 'Gene', '2146', (15, 19))
351394	25223734	In total, we observed recurrent mutations in epigenetic regulators in 17/112 Ewing sarcoma cases (15.2%).	('Ewing sarcoma', 'Disease', (77, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('epigenetic regulators', 'Protein', (45, 66))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('mutations', 'Var', (32, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))
351396	25223734	This finding reinforces the need for studies that clarify how mutations affecting the epigenetic landscape of Ewing sarcoma may cooperate with the EWSR1-ETS fusion to promote the development of overt Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (200, 213))	('EWSR1', 'Gene', (147, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (110, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (110, 123))	('promote', 'PosReg', (167, 174))	('EWSR1', 'Gene', '2130', (147, 152))	('Ewing sarcoma', 'Disease', (200, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('Ewing sarcoma', 'Disease', (110, 123))	('mutations', 'Var', (62, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (200, 213))
351399	25223734	They also observed the association of TP53 and STAG2 mutations.	('association', 'Interaction', (23, 34))	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (53, 62))	('STAG2', 'Gene', (47, 52))	('STAG2', 'Gene', '10735', (47, 52))	('TP53', 'Gene', '7157', (38, 42))
351403	25223734	In conclusion, our comprehensive genetic analysis of Ewing sarcoma identified recurrent mutations in STAG2, TP53, and epigenetic regulators.	('TP53', 'Gene', '7157', (108, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('TP53', 'Gene', (108, 112))	('STAG2', 'Gene', (101, 106))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (53, 66))	('mutations', 'Var', (88, 97))	('STAG2', 'Gene', '10735', (101, 106))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('Ewing sarcoma', 'Disease', (53, 66))
351404	25223734	We showed that a STAG2 mutation gains prognostic significance when associated with TP53 mutations and that a STAG2-mutated subclone may expand during the course of the disease.	('TP53', 'Gene', '7157', (83, 87))	('STAG2', 'Gene', (17, 22))	('STAG2', 'Gene', '10735', (17, 22))	('mutation', 'Var', (23, 31))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('gains', 'PosReg', (32, 37))	('STAG2', 'Gene', (109, 114))	('STAG2', 'Gene', '10735', (109, 114))	('associated', 'Interaction', (67, 77))
351405	25223734	Finally, the mutual exclusion between STAG2 and CDKN2A loss-of-function mutations suggest that these alterations may be, at least partially, redundant.	('mutations', 'Var', (72, 81))	('STAG2', 'Gene', (38, 43))	('loss-of-function', 'NegReg', (55, 71))	('CDKN2A', 'Gene', (48, 54))	('CDKN2A', 'Gene', '1029', (48, 54))	('STAG2', 'Gene', '10735', (38, 43))
351415	25223734	Cell lines were authenticated by their TP53 genotype, which included mutations previously described.	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
351425	25223734	The only case (case SJ001301) that could not be investigated by RT-PCR was shown by WGS to harbor a EWSR1-FLI1 rearrangement.	('EWSR1', 'Gene', (100, 105))	('rearrangement', 'Var', (111, 124))	('EWSR1', 'Gene', '2130', (100, 105))	('FLI1', 'Gene', (106, 110))	('FLI1', 'Gene', '2313', (106, 110))
351443	25223734	Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('STAG2', 'Gene', '10735', (19, 24))	('STAG2', 'Gene', (19, 24))	('Tumors', 'Disease', (0, 6))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (34, 43))
351445	23737213	Novel YAP1-TFE3 Fusion Defines a Distinct Subset of Epithelioid Hemangioendothelioma Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene.	('WWTR1', 'Gene', '25937', (254, 259))	('epithelioid hemangioendotheliomas', 'Disease', (98, 131))	('Epithelioid Hemangioendothelioma', 'Phenotype', 'HP:0032060', (52, 84))	('EHE', 'Phenotype', 'HP:0032060', (133, 136))	('YAP1', 'Gene', (6, 10))	('YAP1', 'Gene', '10413', (6, 10))	('TFE3', 'Gene', '7030', (11, 15))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (98, 130))	('CAMTA1', 'Gene', (260, 266))	('Fusion', 'Var', (16, 22))	('CAMTA1', 'Gene', '23261', (260, 266))	('WWTR1', 'Gene', (254, 259))	('epithelioid hemangioendotheliomas', 'Disease', 'MESH:D018323', (98, 131))	('TFE3', 'Gene', (11, 15))	('Epithelioid Hemangioendothelioma', 'Disease', (52, 84))	('Epithelioid Hemangioendothelioma', 'Disease', 'MESH:D018323', (52, 84))
351461	23737213	This detailed investigation was triggered by an index case showing strong TFE3 immunoreactivity, which prompted screening for TFE3 gene rearrangement in the index case as well as in other WWTR1-CAMTA1 fusion-negative epithelioid vascular tumors.	('CAMTA1', 'Gene', (194, 200))	('TFE3', 'Gene', '7030', (126, 130))	('vascular tumors', 'Phenotype', 'HP:0100742', (229, 244))	('rearrangement', 'Var', (136, 149))	('epithelioid vascular tumors', 'Phenotype', 'HP:0032060', (217, 244))	('epithelioid vascular tumors', 'Disease', 'MESH:D012509', (217, 244))	('CAMTA1', 'Gene', '23261', (194, 200))	('TFE3', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('TFE3', 'Gene', '7030', (74, 78))	('TFE3', 'Gene', (126, 130))	('WWTR1', 'Gene', (188, 193))	('WWTR1', 'Gene', '25937', (188, 193))	('epithelioid vascular tumors', 'Disease', (217, 244))
351498	23737213	Alignment of the reads suggested a fusion of YAP1 exon 1 with exon 4 of TFE3 (Fig.	('TFE3', 'Gene', (72, 76))	('YAP1', 'Gene', '10413', (45, 49))	('YAP1', 'Gene', (45, 49))	('TFE3', 'Gene', '7030', (72, 76))	('fusion', 'Var', (35, 41))
351513	23737213	The presence of a YAP1 gene rearrangement in this EHE subset, which shares significant functional and sequence homology with WWTR1, is noteworthy.	('WWTR1', 'Gene', (125, 130))	('YAP1', 'Gene', (18, 22))	('YAP1', 'Gene', '10413', (18, 22))	('WWTR1', 'Gene', '25937', (125, 130))	('rearrangement', 'Var', (28, 41))	('EHE', 'Phenotype', 'HP:0032060', (50, 53))
351519	23737213	Although abnormal activation of YAP and WWTR1 (TAZ) has been associated with human cancers, suggesting an important role for the Hippo pathway in tumorigenesis, the mechanism of YAP1 dysregulation in the tumorigenesis of this EHE subset appears distinct.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('YAP1', 'Gene', (178, 182))	('TAZ', 'Gene', '6901', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', (146, 151))	('TAZ', 'Gene', (47, 50))	('EHE', 'Phenotype', 'HP:0032060', (226, 229))	('WWTR1', 'Gene', '25937', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('YAP', 'Gene', '10413', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('YAP', 'Gene', (178, 181))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('WWTR1', 'Gene', (40, 45))	('human', 'Species', '9606', (77, 82))	('dysregulation', 'Var', (183, 196))	('YAP1', 'Gene', '10413', (178, 182))	('tumor', 'Disease', (204, 209))	('YAP', 'Gene', (32, 35))	('YAP', 'Gene', '10413', (178, 181))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
351526	23737213	The various TFE3 fusion partners are typically expressed at a consistently high-level in the given tumor type, suggesting that mis-expression of TFE3 is sufficient to promote tumorigenesis.	('tumor', 'Disease', (99, 104))	('TFE3', 'Gene', (145, 149))	('tumor', 'Disease', (175, 180))	('mis-expression', 'Var', (127, 141))	('TFE3', 'Gene', (12, 16))	('promote', 'PosReg', (167, 174))	('TFE3', 'Gene', '7030', (145, 149))	('TFE3', 'Gene', '7030', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
351527	23737213	Because dysregulation of the MiT family in cancer uniformly preserves the DNA-binding domain, it is likely that these factors promote oncogenesis by altering target gene expression.	('dysregulation', 'Var', (8, 21))	('DNA-binding domain', 'MPA', (74, 92))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('oncogenesis', 'CPA', (134, 145))	('cancer', 'Disease', (43, 49))	('promote', 'PosReg', (126, 133))	('altering', 'Reg', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('expression', 'MPA', (170, 180))
351529	23737213	The presence of diffuse expression of CD31 and/or ERG endothelial markers helps in the distinction from other TFE3-positive neoplasms, such as alveolar soft part sarcoma, PEComa, and Xp11-translocation positive renal cell carcinomas.	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (143, 169))	('PEComa', 'Disease', (171, 177))	('renal cell carcinomas', 'Disease', (211, 232))	('neoplasm', 'Phenotype', 'HP:0002664', (124, 132))	('CD31', 'Gene', '5175', (38, 42))	('alveolar soft part sarcoma', 'Disease', (143, 169))	('neoplasms', 'Phenotype', 'HP:0002664', (124, 133))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (211, 232))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('TFE3', 'Gene', (110, 114))	('ERG', 'Gene', (50, 53))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (152, 169))	('TFE3', 'Gene', '7030', (110, 114))	('neoplasms', 'Disease', 'MESH:D009369', (124, 133))	('CD31', 'Gene', (38, 42))	('ERG', 'Gene', '2078', (50, 53))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (143, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('neoplasms', 'Disease', (124, 133))	('PEComa', 'Disease', 'MESH:D054973', (171, 177))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (211, 232))	('Xp11-translocation', 'Var', (183, 201))
351539	23737213	In summary, we are reporting recurrent TFE3 oncogenic activation secondary to gene rearrangements and common fusion with YAP1 in what appears to be a distinctive subset of EHE.	('gene rearrangements', 'Var', (78, 97))	('TFE3', 'Gene', (39, 43))	('YAP1', 'Gene', (121, 125))	('activation', 'PosReg', (54, 64))	('YAP1', 'Gene', '10413', (121, 125))	('EHE', 'Phenotype', 'HP:0032060', (172, 175))	('TFE3', 'Gene', '7030', (39, 43))
351567	22327363	MPNST may in theory arise from similar precursors, but in addition to NF1 loss, mutations in multiple tumor suppressor genes (TP53, CDKN2A) and receptor tyrosine kinase amplification (e.g.	('CDKN2A', 'Gene', (132, 138))	('TP53', 'Gene', (126, 130))	('mutations', 'Var', (80, 89))	('CDKN2A', 'Gene', '1029', (132, 138))	('MPNST', 'Phenotype', 'HP:0100697', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('loss', 'NegReg', (74, 78))	('TP53', 'Gene', '7157', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('NF1', 'Gene', (70, 73))
351572	22327363	Conversely, in mouse models of neurofibromas, tumor formation is greatly facilitated by a NF1 hemizygous genetic background in non-neoplastic cells in the microenvironment (see below).	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('neurofibroma', 'Phenotype', 'HP:0001067', (31, 43))	('neurofibromas', 'Phenotype', 'HP:0001067', (31, 44))	('hemizygous genetic background', 'Var', (94, 123))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('neurofibromas', 'Disease', 'MESH:D009455', (31, 44))	('mouse', 'Species', '10090', (15, 20))	('facilitated', 'PosReg', (73, 84))	('neurofibromas', 'Disease', (31, 44))	('men', 'Species', '9606', (167, 170))	('NF1', 'Gene', (90, 93))
351614	22327363	DOG1 ("discovered on GIST 1/Anoctamin-1") is a recently described membrane protein, a highly sensitive and specific marker for GIST, expressed even in tumors lacking KIT or PDGFRA mutations.	('DOG1', 'Gene', '55107', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mutations', 'Var', (180, 189))	('DOG1', 'Gene', (0, 4))	('tumors', 'Disease', (151, 157))	('KIT', 'Gene', (166, 169))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('PDGFRA', 'Gene', (173, 179))	('PDGFRA', 'Gene', '5156', (173, 179))	('Anoctamin-1"', 'Gene', '55107', (28, 40))	('Anoctamin-1"', 'Gene', (28, 40))
351733	22327363	Although MPNST lack a distinctive cytogenetic signature that allows for a specific diagnosis, molecular alterations including EGFR amplification, and deletions of NF1 or CDKN2A (p16) are supportive in the appropriate setting.	('NF1', 'Gene', (163, 166))	('deletions', 'Var', (150, 159))	('CDKN2A', 'Gene', (170, 176))	('EGFR', 'Gene', (126, 130))	('p16', 'Gene', (178, 181))	('CDKN2A', 'Gene', '1029', (170, 176))	('p16', 'Gene', '1029', (178, 181))	('MPNST', 'Phenotype', 'HP:0100697', (9, 14))	('EGFR', 'Gene', '1956', (126, 130))
351748	22327363	However, a recent study restricted to NF1 patients suggests that atypical neurofibromas, defined as neurofibromas with increased cellularity and nuclear hyperchromasia/enlargement lacking mitotic figures, represent early malignant change in neurofibroma, with CDKN2A/B deletions (seen in MPNST) in the majority (94%) of tested cases.	('neurofibroma', 'Disease', (100, 112))	('neurofibromas', 'Disease', (74, 87))	('neurofibroma', 'Phenotype', 'HP:0001067', (241, 253))	('neurofibroma', 'Disease', 'MESH:D009455', (241, 253))	('MPNST', 'Phenotype', 'HP:0100697', (288, 293))	('CDKN2A/B', 'Gene', '1029;1030', (260, 268))	('neurofibroma', 'Phenotype', 'HP:0001067', (74, 86))	('atypical neurofibroma', 'Phenotype', 'HP:0007524', (65, 86))	('neurofibroma', 'Disease', (74, 86))	('neurofibromas', 'Phenotype', 'HP:0001067', (100, 113))	('hyperchromasia/enlargement', 'Disease', 'MESH:D006529', (153, 179))	('neurofibromas', 'Disease', 'MESH:D009455', (100, 113))	('neurofibroma', 'Phenotype', 'HP:0001067', (100, 112))	('malignant change', 'Phenotype', 'HP:0002664', (221, 237))	('neurofibromas', 'Phenotype', 'HP:0001067', (74, 87))	('neurofibroma', 'Disease', 'MESH:D009455', (100, 112))	('neurofibroma', 'Disease', (241, 253))	('neurofibromas', 'Disease', 'MESH:D009455', (74, 87))	('patients', 'Species', '9606', (42, 50))	('CDKN2A/B', 'Gene', (260, 268))	('hyperchromasia/enlargement', 'Disease', (153, 179))	('neurofibroma', 'Disease', 'MESH:D009455', (74, 86))	('neurofibromas', 'Disease', (100, 113))	('deletions', 'Var', (269, 278))	('atypical neurofibromas', 'Phenotype', 'HP:0007524', (65, 87))
351754	22327363	Molecular techniques, including fluorescence in situ hybridization and array comparative genomic hybridization may be more objective tools in identifying molecular alterations relatively specific for MPNST, in particular CDKN2A/B deletions as described above (Figure 16).	('deletions', 'Var', (230, 239))	('CDKN2A/B', 'Gene', (221, 229))	('MPNST', 'Phenotype', 'HP:0100697', (200, 205))	('CDKN2A/B', 'Gene', '1029;1030', (221, 229))
351816	20368975	Cluster 7 (Src, Ras and PI3K activation) was associated with higher probability of adriamycin resistance (Mann-Whitney p = 0.002), clusters 4 and 5 (Src with or without PI3K activation) were associated with higher probability of cyclophosphamide resistance (p = 0.01) and clusters 2 and 3 (Ras or no pathway activation) were associated with higher probability of docetaxel resistance (p = 0.01) compared to the rest of the samples.	('docetaxel resistance', 'MPA', (363, 383))	('cyclophosphamide resistance', 'MPA', (229, 256))	('PI3K', 'Var', (24, 28))	('Src', 'Gene', (11, 14))	('Src', 'Gene', '6714', (11, 14))	('Src', 'Gene', (149, 152))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (229, 245))	('Src', 'Gene', '6714', (149, 152))	('adriamycin resistance', 'MPA', (83, 104))	('docetaxel', 'Chemical', 'MESH:D000077143', (363, 372))	('adriamycin', 'Chemical', 'MESH:D004317', (83, 93))
351876	23355199	Only 2.7% of 1,140 carcinomas from various sites exhibited cathepsin K labeling, thus suggesting that among carcinomas, cathepsin K labeling is highly specific for translocation RCC.	('cathepsin K', 'Gene', (120, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('translocation', 'Var', (164, 177))	('cathepsin K', 'Gene', (59, 70))	('cathepsin K', 'Gene', '1513', (120, 131))	('cathepsin K', 'Gene', '1513', (59, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('carcinomas', 'Disease', (108, 118))	('carcinomas', 'Disease', 'MESH:D002277', (108, 118))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('carcinomas', 'Disease', (19, 29))	('carcinomas', 'Disease', 'MESH:D002277', (19, 29))
351879	23355199	Germline mutations in the cathepsin K gene underlie the sclerosing bone disorder pycnodysostosis.	('Germline mutations', 'Var', (0, 18))	('bone disorder pycnodysostosis', 'Disease', 'MESH:D058631', (67, 96))	('bone disorder pycnodysostosis', 'Disease', (67, 96))	('underlie', 'Reg', (43, 51))	('cathepsin K', 'Gene', (26, 37))	('cathepsin K', 'Gene', '1513', (26, 37))
351884	23355199	Among them, TFE3 and TFEB are implicated in gene fusions resulting from chromosome translocations in a subset of renal cell carcinoma (RCC), including the Xp11 translocation RCC and the t(6;11)(p21;q12) RCC.	('p11', 'Gene', '6281', (156, 159))	('TFE3', 'Gene', (12, 16))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('t(6;11)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (186, 202))	('TFEB', 'Gene', (21, 25))	('TFE3', 'Gene', '7030', (12, 16))	('p11', 'Gene', (156, 159))	('RCC', 'Disease', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('renal cell carcinoma', 'Disease', (113, 133))	('TFEB', 'Gene', '7942', (21, 25))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (113, 133))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('t(6;11)(p21;q12', 'Var', (186, 201))	('resulting', 'Reg', (57, 66))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('RCC', 'Disease', (135, 138))	('implicated', 'Reg', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (113, 133))
351917	23355199	This suggests that cathepsin K can be helpful in distinguishing translocation RCCs from other carcinomas, and that positive labeling for cathepsin K in an epithelial neoplasm is highly suggestive of an MiTF family- related carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (94, 103))	('carcinomas', 'Disease', (94, 104))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('carcinoma', 'Disease', (223, 232))	('epithelial neoplasm', 'Disease', (155, 174))	('RCCs', 'Phenotype', 'HP:0005584', (78, 82))	('epithelial neoplasm', 'Phenotype', 'HP:0031492', (155, 174))	('epithelial neoplasm', 'Disease', 'MESH:D002277', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('carcinomas', 'Disease', 'MESH:D002277', (94, 104))	('carcinoma', 'Disease', (94, 103))	('MiTF', 'Gene', '4286', (202, 206))	('cathepsin K', 'Gene', (19, 30))	('translocation', 'Var', (64, 77))	('carcinoma', 'Disease', 'MESH:D002277', (223, 232))	('cathepsin K', 'Gene', '1513', (19, 30))	('cathepsin K', 'Gene', (137, 148))	('cathepsin K', 'Gene', '1513', (137, 148))	('neoplasm', 'Phenotype', 'HP:0002664', (166, 174))	('MiTF', 'Gene', (202, 206))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))
351925	23355199	For example, the ASPL-TFE3 gene fusion is present in both ASPS and a subset of translocation RCCs; however, in contrast to consistent diffuse cathepsin K positivity of ASPS, ASPL-TFE3 translocation RCCs are almost always negative for cathepsin K. Along these lines, clear cell sarcoma harbors a unique chromosome translocation t(12;22)(q13;q13), causing fusion of the Ewing sarcoma- associated gene (EWS) to the activity transcription factor 1 (ATF1) gene.	('ASPS', 'Gene', (168, 172))	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('activity transcription factor 1', 'Gene', '466', (412, 443))	('RCC', 'Disease', (93, 96))	('ASPL', 'Gene', '79058', (174, 178))	('cathepsin K', 'Gene', (142, 153))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('EWS', 'Gene', (400, 403))	('ASPS', 'Gene', '79058', (58, 62))	('ASPL', 'Gene', (17, 21))	('cathepsin K', 'Gene', '1513', (142, 153))	('fusion', 'Var', (354, 360))	('ASPS', 'Phenotype', 'HP:0012218', (58, 62))	('ATF1', 'Gene', '466', (445, 449))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('clear cell sarcoma', 'Disease', (266, 284))	('Ewing sarcoma- associated gene', 'Gene', '2130', (368, 398))	('sarcoma', 'Phenotype', 'HP:0100242', (374, 381))	('t(12;22)(q13;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (327, 344))	('ASPS', 'Gene', '79058', (168, 172))	('RCCs', 'Phenotype', 'HP:0005584', (198, 202))	('activity transcription factor 1', 'Gene', (412, 443))	('ASPS', 'Phenotype', 'HP:0012218', (168, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('Ewing sarcoma- associated gene', 'Gene', (368, 398))	('causing', 'Reg', (346, 353))	('ASPL', 'Gene', '79058', (17, 21))	('cathepsin K', 'Gene', (234, 245))	('RCCs', 'Phenotype', 'HP:0005584', (93, 97))	('cathepsin K', 'Gene', '1513', (234, 245))	('EWS', 'Gene', '2130', (400, 403))	('ASPL', 'Gene', (174, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (368, 381))	('ASPS', 'Gene', (58, 62))	('TFE3', 'Gene', (22, 26))	('TFE3', 'Gene', (179, 183))	('RCC', 'Disease', (198, 201))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('ATF1', 'Gene', (445, 449))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (266, 284))	('TFE3', 'Gene', '7030', (22, 26))	('TFE3', 'Gene', '7030', (179, 183))
352017	22331985	In a study of three iatrogenic KS patients, conversion of their immunosuppressive drug regime from calcineurin inhibitors to sirolimus (also known as rapamycin, as described above) led to an increase in the frequency of naive and central memory T cells in the general population of circulating CD8 T cells in conjunction with KS regression.	('KS', 'Phenotype', 'HP:0100726', (326, 328))	('CD8', 'Gene', (294, 297))	('iatrogenic KS', 'Disease', (20, 33))	('increase', 'PosReg', (191, 199))	('CD8', 'Gene', '925', (294, 297))	('sirolimus', 'Chemical', 'MESH:D020123', (125, 134))	('KS', 'Phenotype', 'HP:0100726', (31, 33))	('rapamycin', 'Chemical', 'MESH:D020123', (150, 159))	('iatrogenic KS', 'Disease', 'MESH:D007049', (20, 33))	('patients', 'Species', '9606', (34, 42))	('conversion', 'Var', (44, 54))
352037	22331985	The longitudinal study of three iatrogenic KS patients described in the CD8 response section above reported the emergence of CD4 responses to K12 (latent) and K8.1 (late lytic), in conjunction with KS regression in two of these three individuals.	('patients', 'Species', '9606', (46, 54))	('iatrogenic KS', 'Disease', 'MESH:D007049', (32, 45))	('CD4', 'Gene', (125, 128))	('CD8', 'Gene', (72, 75))	('CD4', 'Gene', '920', (125, 128))	('K8.1', 'Var', (159, 163))	('KS', 'Phenotype', 'HP:0100726', (43, 45))	('KS', 'Phenotype', 'HP:0100726', (198, 200))	('iatrogenic KS', 'Disease', (32, 45))	('CD8', 'Gene', '925', (72, 75))
352066	33872216	Improper mitosis may lead to aneuploidy which is found in many types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mitosis', 'CPA', (9, 16))	('lead to', 'Reg', (21, 28))	('tumors', 'Disease', (72, 78))	('aneuploidy', 'Disease', (29, 39))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('aneuploidy', 'Disease', 'MESH:D000782', (29, 39))	('Improper', 'Var', (0, 8))
352067	33872216	As a key mediator in mitosis, the dysregulated expression of BUBs has been proven to be highly associated with various malignancies, such as leukemia, gastric cancer, breast cancer, and liver cancer.	('breast cancer', 'Disease', (167, 180))	('liver cancer', 'Disease', 'MESH:D006528', (186, 198))	('gastric cancer', 'Disease', (151, 165))	('associated', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))	('malignancies', 'Disease', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('liver cancer', 'Phenotype', 'HP:0002896', (186, 198))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	('liver cancer', 'Disease', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('expression', 'MPA', (47, 57))	('dysregulated', 'Var', (34, 46))	('leukemia', 'Disease', 'MESH:D007938', (141, 149))	('leukemia', 'Disease', (141, 149))	('BUBs', 'Gene', (61, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
352073	33872216	Incorrect segregation of sister chromatids during mitosis may lead to aneuploidy which is found in many types of tumors.	('aneuploidy', 'Disease', (70, 80))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('Incorrect', 'Var', (0, 9))	('aneuploidy', 'Disease', 'MESH:D000782', (70, 80))	('lead to', 'Reg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
352080	33872216	Errors in this process may result in chromosomal mis-segregation and subsequent mitotic catastrophes, leading to chromosomal instability and the formation of tetraploid or aneuploid cells.	('mitotic catastrophes', 'CPA', (80, 100))	('aneuploid', 'Disease', 'MESH:D000782', (172, 181))	('chromosomal instability', 'CPA', (113, 136))	('Errors', 'Var', (0, 6))	('tetraploid', 'Disease', 'MESH:D057891', (158, 168))	('leading to', 'Reg', (102, 112))	('aneuploid', 'Disease', (172, 181))	('chromosomal mis-segregation', 'CPA', (37, 64))	('tetraploid', 'Disease', (158, 168))	('result in', 'Reg', (27, 36))	('chromosomal instability', 'Phenotype', 'HP:0040012', (113, 136))
352081	33872216	As a key mediator of the spindle checkpoint, deregulation of BUBs has been shown to be highly associated with various malignancies such as leukemia, gastric cancer, breast cancer, and liver cancer.	('leukemia', 'Disease', (139, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('gastric cancer', 'Disease', (149, 163))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('deregulation', 'Var', (45, 57))	('breast cancer', 'Disease', (165, 178))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('associated', 'Reg', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Disease', 'MESH:D006528', (184, 196))	('malignancies', 'Disease', (118, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('liver cancer', 'Phenotype', 'HP:0002896', (184, 196))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('BUBs', 'Gene', (61, 65))	('liver cancer', 'Disease', (184, 196))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('leukemia', 'Disease', 'MESH:D007938', (139, 147))
352115	33872216	For BUB1 and BUB3, they were 0.62 (GEPIA) and 0.5179 (Linked Omics).	('0.5179', 'Var', (46, 52))	('BUB3', 'Gene', '9184', (13, 17))	('BUB3', 'Gene', (13, 17))
352119	33872216	Dysregulation in BUB genes have been reported in many cancers.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('BUB genes', 'Gene', (17, 26))	('reported', 'Reg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
352124	33872216	Deviations from their normal expression level may cause chromosome mis-segregation, aneuploidy, and cancer predisposition.	('cause', 'Reg', (50, 55))	('chromosome mis-segregation', 'CPA', (56, 82))	('Deviations', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('aneuploidy', 'Disease', (84, 94))	('aneuploidy', 'Disease', 'MESH:D000782', (84, 94))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
352126	33872216	Delocalization of AURKB strongly compromises the cells' ability to efficiently correct spindle attachment errors which results in an increased rate of chromosome alignment defects.	('spindle attachment errors', 'CPA', (87, 112))	('chromosome alignment defects', 'CPA', (151, 179))	('compromises', 'NegReg', (33, 44))	('AURKB', 'Gene', (18, 23))	('AURKB', 'Gene', '20877', (18, 23))	('Delocalization', 'Var', (0, 14))	('increased', 'PosReg', (133, 142))
352136	33872216	This effect was produced by phosphorylation of its activator CDC20.	('phosphorylation', 'Var', (28, 43))	('CDC20', 'Gene', '991', (61, 66))	('CDC20', 'Gene', (61, 66))
352138	33872216	Inhibition of BUB3 could enhance tumor chemosensitivity.	('enhance', 'PosReg', (25, 32))	('BUB3', 'Gene', '9184', (14, 18))	('BUB3', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (33, 38))
352151	33872216	In the meantime, gene therapy targeting the BUB family can be a promising approach in the treatment of sarcomas.	('BUB family', 'Gene', (44, 54))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Disease', (103, 111))	('gene', 'Var', (17, 21))
352197	33198775	Partial resections of the iliac wing leaving the pelvic ring intact were defined as type Ia, isolated type I resections as type Ib, and a resection with supraacetabular and sacral ala osteotomies with resection of the sacroiliac joint (type I and type IV) as type Ic resections.	('sacral ala osteotomies', 'Disease', (173, 195))	('sacral ala osteotomies', 'Disease', 'MESH:C537221', (173, 195))	('iliac wing', 'Phenotype', 'HP:0009780', (26, 36))	('Partial resections', 'Var', (0, 18))
352286	33198775	published a rate of 20% for deep wound infections, which occurred more frequently in reconstructed patients (26%) compared with patients without reconstruction (15%).	('reconstructed', 'Var', (85, 98))	('infections', 'Disease', 'MESH:D007239', (39, 49))	('infections', 'Disease', (39, 49))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (128, 136))	('wound infections', 'Phenotype', 'HP:0001581', (33, 49))
352340	30214092	The adenocarcinoma was positive for EMA, CAM5.2, CK7, and CA19-9.	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('CK7', 'Gene', '3855', (49, 52))	('CA19-9', 'Var', (58, 64))	('adenocarcinoma', 'Disease', (4, 18))	('CK7', 'Gene', (49, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))
352344	30214092	Thus, the tumor was diagnosed as HCS, T3bN0M0 according to the UICC 7th edition.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('T3bN0M0', 'Var', (38, 45))	('tumor', 'Disease', (10, 15))	('HCS', 'Disease', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
352420	33690666	We identified and validated six drugs, targeting different mechanisms and with good efficiency across the cell lines: MLN2238 -a proteasome inhibitor, GSK2126458 -a PI3K/mTOR inhibitor, JNJ-26481585 -a histone deacetylase inhibitor, triptolide-a multi-target drug, YM155 -a survivin inhibitor, and APO866 (FK866)-a nicotinamide phosphoribosyl transferase inhibitor.	('MLN2238', 'Chemical', 'MESH:C000595706', (118, 125))	('GSK2126458', 'Chemical', 'MESH:C561454', (151, 161))	('FK866', 'Chemical', 'MESH:C480543', (306, 311))	('mTOR', 'Gene', (170, 174))	('triptolide', 'Chemical', 'MESH:C001899', (233, 243))	('mTOR', 'Gene', '2475', (170, 174))	('APO866', 'Chemical', 'MESH:C480543', (298, 304))	('MLN2238 -a', 'Var', (118, 128))	('YM155', 'Chemical', 'MESH:C523798', (265, 270))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (186, 198))
352436	33690666	In case of liposarcomas, several studies on their genome landscapes have been done, but mainly two characteristic molecular markers are known, amplification of the 12q13-15 region (including MDM2, FRS2 and usually also CDK4), which is detected in almost all WDLPS or DDLPS, and the fusion oncogenes FUS-DDIT3 or EWSR1-DDIT3 in myxoid and round cell liposarcoma.	('EWSR1', 'Gene', '2130', (312, 317))	('FUS', 'Gene', '2521', (299, 302))	('liposarcoma', 'Disease', (11, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('liposarcoma', 'Disease', 'MESH:D008080', (349, 360))	('WD', 'Disease', 'MESH:D006527', (258, 260))	('CDK4', 'Gene', (219, 223))	('FRS2', 'Gene', '10818', (197, 201))	('myxoid', 'Disease', (327, 333))	('EWSR1', 'Gene', (312, 317))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('DDIT3', 'Gene', '1649', (318, 323))	('liposarcomas', 'Disease', 'MESH:D008080', (11, 23))	('CDK4', 'Gene', '1019', (219, 223))	('MDM2', 'Gene', (191, 195))	('liposarcoma', 'Phenotype', 'HP:0012034', (11, 22))	('liposarcoma', 'Disease', (349, 360))	('DDIT3', 'Gene', '1649', (303, 308))	('DDIT3', 'Gene', (318, 323))	('amplification', 'Var', (143, 156))	('liposarcomas', 'Phenotype', 'HP:0012034', (11, 23))	('liposarcoma', 'Disease', 'MESH:D008080', (11, 22))	('MDM2', 'Gene', '4193', (191, 195))	('myxoid and round cell liposarcoma', 'Phenotype', 'HP:0012268', (327, 360))	('FUS', 'Gene', (299, 302))	('sarcoma', 'Phenotype', 'HP:0100242', (353, 360))	('DDIT3', 'Gene', (303, 308))	('FRS2', 'Gene', (197, 201))	('liposarcoma', 'Phenotype', 'HP:0012034', (349, 360))	('liposarcomas', 'Disease', (11, 23))
352439	33690666	They identified mutations in PIK3CA in myxoid/round cell liposarcoma and TP53 and NF1 in pleomorphic liposarcoma.	('PIK3CA', 'Gene', '5290', (29, 35))	('TP53', 'Gene', '7157', (73, 77))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (39, 68))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (89, 112))	('liposarcoma', 'Phenotype', 'HP:0012034', (101, 112))	('liposarcoma', 'Disease', 'MESH:D008080', (101, 112))	('liposarcoma', 'Disease', 'MESH:D008080', (57, 68))	('NF1', 'Gene', (82, 85))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (16, 25))	('liposarcoma', 'Phenotype', 'HP:0012034', (57, 68))	('NF1', 'Gene', '4763', (82, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('PIK3CA', 'Gene', (29, 35))	('pleomorphic liposarcoma', 'Disease', (89, 112))	('liposarcoma', 'Disease', (101, 112))	('liposarcoma', 'Disease', (57, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
352440	33690666	Although those mutations might help to identify tumors that might be responsive to PI3K or mTOR inhibitors, they were only present in some patients.	('patients', 'Species', '9606', (139, 147))	('tumors', 'Disease', (48, 54))	('mutations', 'Var', (15, 24))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
352441	33690666	Moreover, a clinical trial with a dual PI3K/mTOR inhibitor has shown no association of responses with PIK3CA mutations.	('PIK3CA', 'Gene', (102, 108))	('mTOR', 'Gene', (44, 48))	('PIK3CA', 'Gene', '5290', (102, 108))	('mTOR', 'Gene', '2475', (44, 48))	('mutations', 'Var', (109, 118))
352443	33690666	They also showed recurrent deletions of ATRX and CDKN2A in a minority of samples but pointed out the importance of overall methylation status as a biomarker in DDLPS.	('CDKN2A', 'Gene', '1029', (49, 55))	('ATRX', 'Gene', '546', (40, 44))	('deletions', 'Var', (27, 36))	('ATRX', 'Gene', (40, 44))	('CDKN2A', 'Gene', (49, 55))
352448	33690666	Just recently, the first multidrug screening of 3 myxoid liposarcoma cell lines was published, showing the survivin inhibitor YM155 to limit tumor growth.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('liposarcoma cell', 'Disease', (57, 73))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (50, 68))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('liposarcoma', 'Phenotype', 'HP:0012034', (57, 68))	('tumor', 'Disease', (141, 146))	('YM155', 'Chemical', 'MESH:C523798', (126, 131))	('limit', 'NegReg', (135, 140))	('myxoid liposarcoma', 'Disease', (50, 68))	('YM155', 'Var', (126, 131))	('liposarcoma cell', 'Disease', 'MESH:D008080', (57, 73))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (50, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
352453	33690666	Cell lines from dedifferentiated liposarcomas: LPS141, LPS510 and LPS853 (all DDLPS) were received from J. Fletcher, GOT3 from Aman and NRH-LS1 derived in-house.	('dedifferentiated liposarcomas', 'Disease', (16, 45))	('LPS510', 'Chemical', '-', (55, 61))	('LPS510', 'Var', (55, 61))	('dedifferentiated liposarcomas', 'Disease', 'MESH:D008080', (16, 45))	('liposarcomas', 'Phenotype', 'HP:0012034', (33, 45))	('LPS141', 'Chemical', '-', (47, 53))	('LPS141', 'Var', (47, 53))	('liposarcoma', 'Phenotype', 'HP:0012034', (33, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('LPS853', 'Chemical', '-', (66, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('LPS853', 'Var', (66, 72))
352459	33690666	Actinomycin D (#A9415) and melphalan (#M2011) were from Sigma Aldrich (St. Louis, USA) and trofosfamide (#T892000) from Toronto Research Chemicals (Canada).	('#T892000', 'Var', (105, 113))	('trofosfamide', 'Chemical', 'MESH:C003726', (91, 103))	('#A9415', 'Var', (15, 21))	('#M2011', 'Var', (38, 44))	('Actinomycin D', 'Chemical', 'MESH:D003609', (0, 13))	('melphalan', 'Chemical', 'MESH:D008558', (27, 36))
352492	33690666	We decided to further investigate 6 drugs: MLN2238 -a proteasome inhibitor, GSK2126458 -a PI3K/mTOR inhibitor, JNJ-26481585 -a histone deacetylase inhibitor, triptolide-a multi-target drug, YM155 -a survivin inhibitor, and APO866 (or FK866)-a nicotinamide phosphoribosyl transferase (NAMPT) inhibitor.	('YM155', 'Chemical', 'MESH:C523798', (190, 195))	('GSK2126458', 'Chemical', 'MESH:C561454', (76, 86))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (111, 123))	('triptolide', 'Chemical', 'MESH:C001899', (158, 168))	('MLN2238', 'Chemical', 'MESH:C000595706', (43, 50))	('NAMPT', 'Gene', (284, 289))	('NAMPT', 'Gene', '10135', (284, 289))	('MLN2238 -a', 'Var', (43, 53))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('APO866', 'Chemical', 'MESH:C480543', (223, 229))	('FK866', 'Chemical', 'MESH:C480543', (234, 239))
352495	33690666	Notably, MLN2238 has recently been registered for a liposarcoma clinical trial but is not recruiting patients yet.	('patients', 'Species', '9606', (101, 109))	('liposarcoma', 'Phenotype', 'HP:0012034', (52, 63))	('liposarcoma', 'Disease', 'MESH:D008080', (52, 63))	('MLN2238', 'Chemical', 'MESH:C000595706', (9, 16))	('MLN2238', 'Var', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('liposarcoma', 'Disease', (52, 63))
352498	33690666	The results largely confirm those from the primary screen (Fig 1C), with APO866 and triptolide being the most effective while MLN9708 and GSK2126458 least effective for the majority of the cell lines.	('APO866', 'Chemical', 'MESH:C480543', (73, 79))	('MLN9708', 'Var', (126, 133))	('GSK2126458', 'Chemical', 'MESH:C561454', (138, 148))	('APO866', 'Var', (73, 79))	('GSK2126458', 'Var', (138, 148))	('triptolide', 'Chemical', 'MESH:C001899', (84, 94))
352500	33690666	Selectivity towards specific cell lines was also confirmed for APO866, MLN9708 and to a lesser extent, YM155.	('YM155', 'Chemical', 'MESH:C523798', (103, 108))	('APO866', 'Var', (63, 69))	('MLN9708', 'Var', (71, 78))	('APO866', 'Chemical', 'MESH:C480543', (63, 69))
352502	33690666	In case of GSK2126458 and JNJ-26481585, the main responses remained comparable.	('JNJ-26481585', 'Chemical', 'MESH:C541788', (26, 38))	('GSK2126458', 'Var', (11, 21))	('GSK2126458', 'Chemical', 'MESH:C561454', (11, 21))	('JNJ-26481585', 'Var', (26, 38))
352504	33690666	Similarly, for JNJ-26481585, LPS141 and NRH-LS1 having the highest GR50 values were also most resistant in the primary screen, while T778 was sensitive in both experiments.	('JNJ-26481585', 'Chemical', 'MESH:C541788', (15, 27))	('LPS141', 'Chemical', '-', (29, 35))	('LPS141', 'Var', (29, 35))	('JNJ-26481585', 'Var', (15, 27))	('NRH-LS1', 'Gene', (40, 47))
352508	33690666	Fig 2 shows that triptolide and APO866 were the most efficient compounds, arresting the majority of the cell lines already at 10 nM, consistent with the observed GR50s.	('APO866', 'Chemical', 'MESH:C480543', (32, 38))	('triptolide', 'Chemical', 'MESH:C001899', (17, 27))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('APO866', 'Var', (32, 38))	('arrest', 'Disease', (74, 80))
352509	33690666	Similarly, the least effective compound MLN9708 required at least 1 muM to completely arrest more than half of the cell lines tested.	('MLN9708', 'Var', (40, 47))	('completely arrest', 'Disease', 'MESH:D006323', (75, 92))	('completely arrest', 'Disease', (75, 92))
352510	33690666	YM155 and MLN9708 had the widest range of growth inhibitory concentrations from 1 nM to 10 muM in the different cell lines.	('MLN9708', 'Var', (10, 17))	('growth inhibitory concentrations', 'MPA', (42, 74))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))
352511	33690666	GSK2126458, and to a lesser extent APO866 and triptolide, permanently arrested cell growth at the same concentration for at least half of the cell lines, suggesting they act broadly against liposarcoma cells.	('GSK2126458', 'Chemical', 'MESH:C561454', (0, 10))	('APO866', 'Chemical', 'MESH:C480543', (35, 41))	('liposarcoma cell', 'Disease', 'MESH:D008080', (190, 206))	('arrest', 'Disease', (70, 76))	('liposarcoma', 'Phenotype', 'HP:0012034', (190, 201))	('GSK2126458', 'Var', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('cell growth', 'CPA', (79, 90))	('liposarcoma cell', 'Disease', (190, 206))	('triptolide', 'Chemical', 'MESH:C001899', (46, 56))	('arrest', 'Disease', 'MESH:D006323', (70, 76))
352512	33690666	The growth inhibitory concentrations correlated well with both GR50s and the drug screen data for APO866, MLN9708 and YM155.	('YM155', 'Chemical', 'MESH:C523798', (118, 123))	('MLN9708', 'Var', (106, 113))	('APO866', 'Gene', (98, 104))	('YM155', 'Var', (118, 123))	('growth inhibitory concentrations', 'MPA', (4, 36))	('APO866', 'Chemical', 'MESH:C480543', (98, 104))
352520	33690666	The results showed that triptolide induces strong apoptosis (above 15%), JNJ-26481585, MLN9708 and YM155 induce moderate apoptosis (above 5%) while APO866 and GSK2126458 did not induce apoptosis above 5% for majority of cell lines (Fig 3B).	('JNJ-26481585', 'Var', (73, 85))	('APO866', 'Chemical', 'MESH:C480543', (148, 154))	('GSK2126458', 'Chemical', 'MESH:C561454', (159, 169))	('YM155', 'Chemical', 'MESH:C523798', (99, 104))	('MLN9708', 'Var', (87, 94))	('triptolide', 'Chemical', 'MESH:C001899', (24, 34))	('YM155', 'Var', (99, 104))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (73, 85))	('apoptosis', 'CPA', (50, 59))
352521	33690666	Triptolide is mainly blocking the cells in S phase, GSK2126458 in G1 phase and JNJ-26481585 in G1 and G2 phases.	('GSK2126458', 'Chemical', 'MESH:C561454', (52, 62))	('S phase', 'CPA', (43, 50))	('cells', 'CPA', (34, 39))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (79, 91))	('GSK2126458', 'Var', (52, 62))	('Triptolide', 'Chemical', 'MESH:C001899', (0, 10))	('blocking', 'NegReg', (21, 29))	('JNJ-26481585', 'Var', (79, 91))
352522	33690666	APO866, MLN9708 and YM155 lead to less specific arrest.	('arrest', 'Disease', 'MESH:D006323', (48, 54))	('APO866', 'Var', (0, 6))	('arrest', 'Disease', (48, 54))	('YM155', 'Chemical', 'MESH:C523798', (20, 25))	('MLN9708', 'Var', (8, 15))	('less', 'NegReg', (34, 38))	('YM155', 'Var', (20, 25))	('APO866', 'Chemical', 'MESH:C480543', (0, 6))
352523	33690666	Overall, in the initial phase, APO866 does not induce apoptosis but non-specific cell cycle arrest, consistent with previous reports showing that NAMP inhibitors induce oncosis and not apoptosis.	('APO866', 'Var', (31, 37))	('oncosis', 'Disease', (169, 176))	('oncosis', 'Disease', 'None', (169, 176))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (81, 98))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('induce', 'Reg', (162, 168))	('arrest', 'Disease', (92, 98))	('APO866', 'Chemical', 'MESH:C480543', (31, 37))
352524	33690666	JNJ-26481585 induces apoptosis and arrests the cells outside the S phase.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('cells outside the S phase', 'CPA', (47, 72))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (0, 12))	('arrest', 'Disease', (35, 41))	('apoptosis', 'CPA', (21, 30))	('JNJ-26481585', 'Var', (0, 12))
352525	33690666	GSK2126458, while not inducing apoptosis, blocks the cells in G1 phase.	('GSK2126458', 'Var', (0, 10))	('cells in G1 phase', 'CPA', (53, 70))	('GSK2126458', 'Chemical', 'MESH:C561454', (0, 10))	('blocks', 'NegReg', (42, 48))
352526	33690666	MLN9708 and YM155 induce both apoptosis and non-specific cell cycle arrest, while triptolide is a strong inducer of S phase arrest and apoptosis for all cell lines tested.	('arrest', 'Disease', (68, 74))	('MLN9708', 'Var', (0, 7))	('S phase', 'CPA', (116, 123))	('YM155', 'Chemical', 'MESH:C523798', (12, 17))	('YM155', 'Var', (12, 17))	('apoptosis', 'CPA', (30, 39))	('arrest', 'Disease', 'MESH:D006323', (124, 130))	('triptolide', 'Chemical', 'MESH:C001899', (82, 92))	('arrest', 'Disease', (124, 130))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('arrest', 'Disease', 'MESH:D006323', (68, 74))
352530	33690666	APO866, triptolide, JNJ-26481585 and MLN9708 irreversibly inhibited growth of all tested cell lines within that period (except for cell line T778 with MLN9708) (Fig 4).	('MLN9708', 'Var', (37, 44))	('APO866', 'Var', (0, 6))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (20, 32))	('APO866', 'Chemical', 'MESH:C480543', (0, 6))	('inhibited', 'NegReg', (58, 67))	('triptolide', 'Chemical', 'MESH:C001899', (8, 18))	('JNJ-26481585', 'Var', (20, 32))	('growth', 'CPA', (68, 74))
352531	33690666	Some cell lines such as LPS141, T778 and SA-4 resumed growth after removal of YM155.	('SA-4', 'Chemical', '-', (41, 45))	('growth', 'MPA', (54, 60))	('YM155', 'Chemical', 'MESH:C523798', (78, 83))	('YM155', 'Var', (78, 83))	('LPS141', 'Chemical', '-', (24, 30))	('resumed', 'PosReg', (46, 53))
352532	33690666	However, the growth of those cell lines could be irreversibly inhibited, if a 10x higher concentration of YM155 was used (S5 Fig).	('inhibited', 'NegReg', (62, 71))	('YM155', 'Var', (106, 111))	('growth', 'CPA', (13, 19))	('YM155', 'Chemical', 'MESH:C523798', (106, 111))
352534	33690666	To irreversibly arrest cell proliferation GSK2126458 had to be used at 10x higher concentrations (100x for GOT3) (S5 Fig).	('GSK2126458', 'Var', (42, 52))	('arrest', 'Disease', 'MESH:D006323', (16, 22))	('arrest', 'Disease', (16, 22))	('cell proliferation', 'CPA', (23, 41))	('GSK2126458', 'Chemical', 'MESH:C561454', (42, 52))
352539	33690666	Two notable exceptions were triptolide and JNJ-26481585, which were more toxic to bone marrow cells in vitro than to liposarcoma cell lines (Fig 5, top and middle panels).	('liposarcoma', 'Phenotype', 'HP:0012034', (117, 128))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (43, 55))	('liposarcoma cell', 'Disease', 'MESH:D008080', (117, 133))	('triptolide', 'Chemical', 'MESH:C001899', (28, 38))	('JNJ-26481585', 'Var', (43, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('liposarcoma cell', 'Disease', (117, 133))
352549	33690666	We observed good response to YM155, concordant with a previous study on myxLPS, but also the general sensitivity pattern was promising also for this subtype.	('YM155', 'Var', (29, 34))	('myxLPS', 'Disease', (72, 78))	('myxLPS', 'Disease', 'None', (72, 78))	('YM155', 'Chemical', 'MESH:C523798', (29, 34))
352553	33690666	We were also unable to correlate the expression of most of the genes from the PI3K and mTOR pathways with the response to GSK2126458 with the exception of tumor suppressor TSC2 (rho = -0.74).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mTOR', 'Gene', '2475', (87, 91))	('GSK2126458', 'Var', (122, 132))	('TSC2', 'Gene', '7249', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('TSC2', 'Gene', (172, 176))	('PI3K', 'Pathway', (78, 82))	('tumor', 'Disease', (155, 160))	('GSK2126458', 'Chemical', 'MESH:C561454', (122, 132))	('mTOR', 'Gene', (87, 91))
352554	33690666	GSK2126458 is expected to work in cells with altered PI3K signaling, and mutations in PIK3CA or NF1 have been shown to be some of the few mutations identified in soft tissue sarcomas.	('altered', 'Reg', (45, 52))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (162, 181))	('GSK2126458', 'Chemical', 'MESH:C561454', (0, 10))	('sarcomas', 'Disease', (174, 182))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (162, 182))	('PIK3CA', 'Gene', (86, 92))	('PIK3CA', 'Gene', '5290', (86, 92))	('NF1', 'Gene', '4763', (96, 99))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('NF1', 'Gene', (96, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('mutations', 'Var', (73, 82))	('PI3K signaling', 'MPA', (53, 67))
352557	33690666	The identified top biomarkers included, not surprisingly, high STAT2 expression for response to GSK2126458 consistent with JAK/STAT signaling leading to activation of the PI3K/mTOR pathway.	('GSK2126458', 'Chemical', 'MESH:C561454', (96, 106))	('STAT', 'Gene', '6773', (127, 131))	('activation', 'PosReg', (153, 163))	('mTOR', 'Gene', '2475', (176, 180))	('STAT2', 'Gene', '6773', (63, 68))	('mTOR', 'Gene', (176, 180))	('GSK2126458', 'Var', (96, 106))	('STAT', 'Gene', (127, 131))	('STAT2', 'Gene', (63, 68))	('STAT', 'Gene', '6773', (63, 67))	('high', 'PosReg', (58, 62))	('STAT', 'Gene', (63, 67))
352560	33690666	In case of proteasome inhibitor MLN2238, we noted correlation of response to the drug and STK26 expression, which is a known activator of cancer progression autophagy.	('cancer', 'Disease', (138, 144))	('MLN2238', 'Chemical', 'MESH:C000595706', (32, 39))	('MLN2238', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('STK26', 'Gene', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('STK26', 'Gene', '51765', (90, 95))
352564	33690666	Similarly, immune-related pathways, including interferon signaling and antigen processing, were enriched for biomarkers of poor response to MLN2238 and YM155.	('antigen processing', 'MPA', (71, 89))	('interferon signaling', 'Pathway', (46, 66))	('immune-related pathways', 'Pathway', (11, 34))	('MLN2238', 'Chemical', 'MESH:C000595706', (140, 147))	('MLN2238', 'Var', (140, 147))	('YM155', 'Var', (152, 157))	('YM155', 'Chemical', 'MESH:C523798', (152, 157))
352565	33690666	Interestingly, pathway correlations of sensitivity to MLN2238 and YM155 were very similar, indicating that these drugs are likely to target similar cellular states.	('YM155', 'Chemical', 'MESH:C523798', (66, 71))	('MLN2238', 'Chemical', 'MESH:C000595706', (54, 61))	('MLN2238', 'Var', (54, 61))	('YM155', 'Var', (66, 71))
352567	33690666	Finally, the sensitivity to GSK2126458 was correlated with expression of pathways involved in respiratory electron transport and DNA strand elongation and polymerase switching, indicating that high activity of such pathways may result in a better response to treatment.	('result in', 'Reg', (228, 237))	('GSK2126458', 'Var', (28, 38))	('response', 'MPA', (247, 255))	('better', 'PosReg', (240, 246))	('GSK2126458', 'Chemical', 'MESH:C561454', (28, 38))
352574	33690666	Based on sensitivities found in our drug screen, we selected 6 compounds which were not previously used for the treatment of liposarcoma: the proteasome inhibitor MLN2238, the PI3K/mTOR inhibitor GSK2126458, the histone deacetylase inhibitor JNJ-26481585, the multi-target drug triptolide, the survivin inhibitor YM155, and the NAMPT inhibitor APO866.	('MLN2238', 'Var', (163, 170))	('mTOR', 'Gene', '2475', (181, 185))	('GSK2126458', 'Chemical', 'MESH:C561454', (196, 206))	('APO866', 'Chemical', 'MESH:C480543', (344, 350))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('liposarcoma', 'Disease', 'MESH:D008080', (125, 136))	('NAMPT', 'Gene', '10135', (328, 333))	('GSK2126458', 'Var', (196, 206))	('triptolide', 'Chemical', 'MESH:C001899', (278, 288))	('NAMPT', 'Gene', (328, 333))	('YM155', 'Chemical', 'MESH:C523798', (313, 318))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (242, 254))	('liposarcoma', 'Disease', (125, 136))	('MLN2238', 'Chemical', 'MESH:C000595706', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('mTOR', 'Gene', (181, 185))
352575	33690666	Importantly, YM155 was during this work shown to have activity against both our explants of myxLPS cells from patient samples (Fig 5), confirming the finding reported previously.	('myxLPS', 'Disease', (92, 98))	('YM155', 'Chemical', 'MESH:C523798', (13, 18))	('patient', 'Species', '9606', (110, 117))	('activity', 'MPA', (54, 62))	('YM155', 'Var', (13, 18))	('myxLPS', 'Disease', 'None', (92, 98))
352576	33690666	GSK2126458, YM155 and APO866 have been used in the Genomics of Drug Sensitivity in Cancer Project where genomic features correlating with drug sensitivity have been determined in cells from some other sarcoma types.	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (63, 79))	('drug sensitivity', 'Phenotype', 'HP:0020174', (138, 154))	('YM155', 'Chemical', 'MESH:C523798', (12, 17))	('sarcoma', 'Disease', 'MESH:D012509', (201, 208))	('GSK2126458', 'Chemical', 'MESH:C561454', (0, 10))	('YM155', 'Var', (12, 17))	('APO866', 'Chemical', 'MESH:C480543', (22, 28))	('sarcoma', 'Disease', (201, 208))	('GSK2126458', 'Var', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('Cancer', 'Disease', (83, 89))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))	('APO866', 'Gene', (22, 28))
352577	33690666	Interestingly, in that study, the presence of the Ewing sarcoma-specific EWSR1-FLI1 fusion protein correlated with sensitivity to each of those compounds, which might be mechanistically relevant to sensitivity also in other sarcomas although lacking this specific fusion gene.	('sarcomas', 'Phenotype', 'HP:0100242', (224, 232))	('FLI1', 'Gene', (79, 83))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (50, 63))	('FLI1', 'Gene', '2313', (79, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (50, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('sarcomas', 'Disease', (224, 232))	('EWSR1', 'Gene', (73, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('correlated', 'Reg', (99, 109))	('sensitivity', 'MPA', (115, 126))	('EWSR1', 'Gene', '2130', (73, 78))	('Ewing sarcoma', 'Disease', (50, 63))	('sarcomas', 'Disease', 'MESH:D012509', (224, 232))	('presence', 'Var', (34, 42))
352590	33690666	Another potent drug candidate for liposarcomas, APO866, is an anti-metabolic drug which induces cell death by specifically inhibiting the biosynthesis of NAD+.	('APO866', 'Var', (48, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('inhibiting', 'NegReg', (123, 133))	('NAD+', 'Chemical', 'MESH:D009243', (154, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('liposarcomas', 'Disease', 'MESH:D008080', (34, 46))	('liposarcomas', 'Phenotype', 'HP:0012034', (34, 46))	('APO866', 'Chemical', 'MESH:C480543', (48, 54))	('liposarcoma', 'Phenotype', 'HP:0012034', (34, 45))	('biosynthesis of NAD+', 'MPA', (138, 158))	('liposarcomas', 'Disease', (34, 46))
352595	33690666	JNJ-26481585 was very efficient but also had some toxicity towards bone marrow cells in our study.	('JNJ-26481585', 'Var', (0, 12))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (0, 12))	('toxicity', 'Disease', (50, 58))	('toxicity', 'Disease', 'MESH:D064420', (50, 58))
352598	33690666	MLN2238 is a proteasome inhibitor with improved pharmacodynamic profile and antitumor activity in vitro and in vivo compared to bortezomib.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('pharmacodynamic', 'MPA', (48, 63))	('tumor', 'Disease', (80, 85))	('MLN2238', 'Chemical', 'MESH:C000595706', (0, 7))	('bortezomib', 'Chemical', 'MESH:D000069286', (128, 138))	('MLN2238', 'Var', (0, 7))	('improved', 'PosReg', (39, 47))
352599	33690666	A phase I study of intravenous MLN2238 showed manageable safety profile, limited antitumor activity and Cmax of up to 1400 nM at maximum tolerated dose.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MLN2238', 'Chemical', 'MESH:C000595706', (31, 38))	('MLN2238', 'Var', (31, 38))
352601	33690666	YM155 is an inhibitor of survivin, a member of the inhibitor of apoptosis (IAP) protein family, and often is activated in various cancers.	('survivin', 'Protein', (25, 33))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('activated', 'PosReg', (109, 118))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('YM155', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
352607	33690666	Though clinical trials and our data comparing toxicity of GSK2126458 towards normal cells versus tumor cells indicate the compound has selective and permanent efficacy, it is important to note that we have observed only a temporary growth arrest with GSK2126458 used in the physiological range, whereas higher, and perhaps more toxic, concentrations were needed for permanent growth arrest (Table 2, Figs 4 and S5).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('growth arrest', 'Phenotype', 'HP:0001510', (376, 389))	('growth arrest', 'Disease', 'MESH:D006323', (232, 245))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('growth arrest', 'Disease', (232, 245))	('GSK2126458', 'Var', (58, 68))	('GSK2126458', 'Var', (251, 261))	('tumor', 'Disease', (97, 102))	('growth arrest', 'Phenotype', 'HP:0001510', (232, 245))	('toxicity', 'Disease', 'MESH:D064420', (46, 54))	('growth arrest', 'Disease', (376, 389))	('toxicity', 'Disease', (46, 54))	('GSK2126458', 'Chemical', 'MESH:C561454', (58, 68))	('GSK2126458', 'Chemical', 'MESH:C561454', (251, 261))	('growth arrest', 'Disease', 'MESH:D006323', (376, 389))
352627	32038721	Collectively, similar variants of ORF-73 markers involved in the immune response may interact with targeted host proteins as predicted by our computational analysis.	('interact', 'Reg', (85, 93))	('ORF-73', 'Gene', '4961527', (34, 40))	('variants', 'Var', (22, 30))	('ORF-73', 'Gene', (34, 40))
352639	32038721	The KSHV is closely related to the subfamily Rhadinoviridae (gamma-2-herpesviruses), which is also close to the Herpes virus saimiri (HVS); therefore, similarities between ORFs of KSHV and HVS may influence the pathogenesis of KS.	('KSHV', 'Species', '37296', (4, 8))	('influence', 'Reg', (197, 206))	('KSHV', 'Species', '37296', (180, 184))	('KS', 'Disease', 'MESH:D012514', (4, 6))	('KS', 'Disease', 'MESH:D012514', (227, 229))	('similarities', 'Var', (151, 163))	('KS', 'Disease', 'MESH:D012514', (180, 182))	('ORFs', 'Var', (172, 176))	('herpesvirus', 'Species', '39059', (69, 80))
352657	32038721	Six tegument proteins have been identified: ORF21, ORF33, ORF45, ORF63, ORF64, ORF73 and ORF75.	('ORF33', 'Var', (51, 56))	('ORF45', 'Var', (58, 63))	('ORF75', 'Var', (89, 94))	('ORF63', 'Var', (65, 70))	('ORF73', 'Gene', '4961527', (79, 84))	('ORF64', 'Var', (72, 77))	('ORF21', 'Var', (44, 49))	('ORF73', 'Gene', (79, 84))
352671	32038721	We submitted the primary sequence of ORF-73 to FUGUE to show the sequence-structural homology by identifying distant sequence-structure homologues and alignments comparing amino acid insertions/deletions.	('ORF-73', 'Gene', (37, 43))	('insertions/deletions', 'Var', (183, 203))	('ORF-73', 'Gene', '4961527', (37, 43))
352680	32038721	A search for proteins similar to the selected marker ORF-73 resulted in8 protein accessions (ORF21, ORF33, ORF45, ORF63, ORF64, and ORF75), and 2 CDS regions (accession numbers AAC57158.1 and AAC55944.1).	('ORF-73', 'Gene', (53, 59))	('ORF45', 'Var', (107, 112))	('ORF64', 'Var', (121, 126))	('ORF-73', 'Gene', '4961527', (53, 59))	('ORF63', 'Var', (114, 119))	('ORF75', 'Var', (132, 137))	('ORF21', 'Var', (93, 98))	('ORF33', 'Var', (100, 105))
352739	30508944	As for the genomic alterations, we found 9 gene mutations in all the samples, including checkpoint kinase 2(CHEK2), FAT atypical cadherin 1 (FAT1), tumor protein 53 (TP53), DPYD, ERBB2 interacting protein (ERBB2IP), FBXW7, KMT2D, PPP2R1A, TSC2, whereas amplification of MYC was only in the metastatic example.	('FAT1', 'Gene', (141, 145))	('DPYD', 'Gene', (173, 177))	('FAT atypical cadherin 1', 'Gene', (116, 139))	('CHEK2', 'Gene', (108, 113))	('KMT2D', 'Gene', (223, 228))	('mutations', 'Var', (48, 57))	('ERBB2 interacting protein', 'Gene', '55914', (179, 204))	('FBXW7', 'Gene', '55294', (216, 221))	('PPP2R1A', 'Gene', '5518', (230, 237))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CHEK2', 'Gene', '11200', (108, 113))	('TP53', 'Gene', '7157', (166, 170))	('ERBB2IP', 'Gene', (206, 213))	('checkpoint kinase 2', 'Gene', (88, 107))	('MYC', 'Gene', (270, 273))	('DPYD', 'Gene', '1806', (173, 177))	('FAT1', 'Gene', '2195', (141, 145))	('ERBB2 interacting protein', 'Gene', (179, 204))	('FAT atypical cadherin 1', 'Gene', '2195', (116, 139))	('PPP2R1A', 'Gene', (230, 237))	('tumor protein 53', 'Gene', (148, 164))	('ERBB2IP', 'Gene', '55914', (206, 213))	('tumor protein 53', 'Gene', '7157', (148, 164))	('checkpoint kinase 2', 'Gene', '11200', (88, 107))	('TSC2', 'Gene', '7249', (239, 243))	('KMT2D', 'Gene', '8085', (223, 228))	('MYC', 'Gene', '4609', (270, 273))	('FBXW7', 'Gene', (216, 221))	('TP53', 'Gene', (166, 170))	('TSC2', 'Gene', (239, 243))
352740	30508944	The analysis of clonal evolution and phylogenetic tree showed the propagation and replay of polyclonal esophageal FDC sarcoma.	('esophageal FDC sarcoma', 'Disease', 'MESH:C536231', (103, 125))	('FDC sarcoma', 'Phenotype', 'HP:0031350', (114, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('polyclonal', 'Var', (92, 102))	('esophageal FDC sarcoma', 'Disease', (103, 125))
352741	30508944	At the same time, the detection of biomarkers for immunotherapy revealed microsatellite stable and mismatch repair-proficient (pMMR), which predicted a relatively poor anti-programmed death (PD-1)/programmed death ligand (PD-L1) immunotherapy outcome.	('poor', 'NegReg', (163, 167))	('PD-L1', 'Gene', (222, 227))	('microsatellite', 'Var', (73, 87))	('PD-L1', 'Gene', '29126', (222, 227))	('anti-programmed', 'MPA', (168, 183))	('PD-1', 'Gene', (191, 195))	('PD-1', 'Gene', '5133', (191, 195))
352792	30508944	To date, tumor protein 53 (TP53), PTEN mutations had been identified by NGS in 3 patients with FDCS in 2 studies.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('patients', 'Species', '9606', (81, 89))	('mutations', 'Var', (39, 48))	('tumor protein 53', 'Gene', (9, 25))	('tumor protein 53', 'Gene', '7157', (9, 25))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
352802	30508944	Meanwhile, MYC gene amplification predicts the poorest prognosis in patients with non-small cell lung cancers.DPYD mutation has been reported to be associated with fluorouracil drug toxicity.	('MYC', 'Gene', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('DPYD', 'Gene', '1806', (110, 114))	('toxicity', 'Disease', 'MESH:D064420', (182, 190))	('toxicity', 'Disease', (182, 190))	('patients', 'Species', '9606', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('non-small cell lung cancers', 'Disease', (82, 109))	('associated', 'Reg', (148, 158))	('MYC', 'Gene', '4609', (11, 14))	('fluorouracil', 'Chemical', 'MESH:D005472', (164, 176))	('mutation', 'Var', (115, 123))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (82, 109))	('DPYD', 'Gene', (110, 114))
352808	30508944	To in-depth discuss the heterogeneity of our case, we analyzed the mutation profiles of primary and metastatic tumor specimens and plasma ctDNA mutations and then performed mutation clonal clustering to aggregated 3 clones.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('mutations', 'Var', (144, 153))	('ctDNA', 'Gene', (138, 143))
352811	30508944	The patient was treated with carboplatin and veliparib based on BRCA2 mutation after a failure of frontline surgery and chemoradiotherapy and achieved a durable disease stabilization.	('BRCA2', 'Gene', '675', (64, 69))	('patient', 'Species', '9606', (4, 11))	('BRCA2', 'Gene', (64, 69))	('veliparib', 'Chemical', 'MESH:C521013', (45, 54))	('mutation', 'Var', (70, 78))	('carboplatin', 'Chemical', 'MESH:D016190', (29, 40))
352815	30508944	In our sample, the detection of biomarkers for immunotherapy revealed microsatellite stable (MSS) and mismatch repair-proficient (pMMR), which predicted a relatively poor anti-PD-1/PD-L1 immunotherapy outcome.	('microsatellite', 'Var', (70, 84))	('PD-L1', 'Gene', (181, 186))	('PD-1', 'Gene', (176, 180))	('PD-1', 'Gene', '5133', (176, 180))	('PD-L1', 'Gene', '29126', (181, 186))
352830	29879220	Interestingly, CPI-613 along with chloroquine, which inhibits the fusion of autophagosomes with lysosomes, significantly induced necrosis of HS-MM CCS cell growth in vitro.	('CPI-613', 'Var', (15, 22))	('fusion', 'CPA', (66, 72))	('CPI-613', 'Chemical', 'MESH:C568850', (15, 22))	('necrosis of HS-MM CCS', 'Disease', 'MESH:C567159', (129, 150))	('necrosis of HS-MM CCS', 'Disease', (129, 150))	('inhibits', 'NegReg', (53, 61))	('chloroquine', 'Chemical', 'MESH:D002738', (34, 45))	('induced', 'Reg', (121, 128))
352840	29879220	CPI-613 can also induce a burst of mitochondrial reactive oxygen species in cancer cells.	('induce', 'Reg', (17, 23))	('mitochondrial reactive oxygen species', 'MPA', (35, 72))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CPI-613', 'Var', (0, 7))	('CPI-613', 'Chemical', 'MESH:C568850', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (49, 72))
352869	29879220	Subsequently, we asked whether CPI-613 along with chloroquine, which blocks lysosome function and the degradation of autophagy cargo, impaired the growth of HS-MM cells.	('lysosome function', 'CPA', (76, 93))	('degradation', 'MPA', (102, 113))	('chloroquine', 'Chemical', 'MESH:D002738', (50, 61))	('impaired', 'NegReg', (134, 142))	('CPI-613', 'Var', (31, 38))	('CPI-613', 'Chemical', 'MESH:C568850', (31, 38))	('blocks', 'NegReg', (69, 75))	('HS-MM', 'CellLine', 'CVCL:W472', (157, 162))	('growth of HS-MM cells', 'CPA', (147, 168))
352871	29879220	Since a necroptosis inhibitor, necrostatin-1 did not affect cell death, noted as Annexin V negative and PI positive (Fig 2H and 2I), we assume that CPI-613 along with chloroquine induced necrotic cell death.	('necrotic cell death', 'Disease', (187, 206))	('chloroquine', 'Chemical', 'MESH:D002738', (167, 178))	('Annexin V', 'Gene', (81, 90))	('necrotic cell death', 'Disease', 'MESH:D003643', (187, 206))	('CPI-613', 'Var', (148, 155))	('Annexin V', 'Gene', '308', (81, 90))	('CPI-613', 'Chemical', 'MESH:C568850', (148, 155))
352877	29879220	As demonstrated in Fig 3J, RT-PCR demonstrated EWSR1-ATF1 fusion gene expression in both primary injected and metastatic HS-MM cells.	('EWSR1', 'Gene', '2130', (47, 52))	('HS-MM', 'CellLine', 'CVCL:W472', (121, 126))	('ATF1', 'Gene', (53, 57))	('EWSR1', 'Gene', (47, 52))	('fusion gene', 'Var', (58, 69))	('ATF1', 'Gene', '466', (53, 57))
352885	29879220	Furthermore, CPI-613 disrupts the redox balance in cancer cell mitochondria.	('CPI-613', 'Var', (13, 20))	('disrupts', 'NegReg', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CPI-613', 'Chemical', 'MESH:C568850', (13, 20))	('redox balance in', 'MPA', (34, 50))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
352886	29879220	In the present study, we first noted that CPI-613 markedly increased autolysosome formation (Fig 1B, 1C and 1F), but with a small amount of cell death (Fig 2B).	('CPI-613', 'Chemical', 'MESH:C568850', (42, 49))	('CPI-613', 'Var', (42, 49))	('increased', 'PosReg', (59, 68))	('autolysosome formation', 'MPA', (69, 91))
352959	28633560	LOX cross-linking increases both cancer cell migration and ECM stiffness.	('LOX', 'Gene', (0, 3))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('increases', 'PosReg', (18, 27))	('cross-linking', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('ECM stiffness', 'CPA', (59, 72))	('LOX', 'Gene', '4015', (0, 3))
352965	28633560	Changes in these factors have been suggested to lead to changes in cancer cell growth and migration.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('migration', 'CPA', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Changes', 'Var', (0, 7))	('changes', 'Reg', (56, 63))
353066	28633560	have conjugated cell-adhesive sites [L-arginine, glycine, L-aspartic acid (RGD)] into alginate chains to enhance cellular activities.	('L-aspartic acid', 'Chemical', 'MESH:D001224', (58, 73))	('L-arginine', 'Chemical', 'MESH:D001120', (37, 47))	('[L-arginine', 'Var', (36, 47))	('glycine', 'Chemical', 'MESH:D005998', (49, 56))	('cellular activities', 'CPA', (113, 132))	('alginate', 'Chemical', 'MESH:D000464', (86, 94))	('enhance', 'PosReg', (105, 112))
353157	28633560	In addition, the researchers noticed that inhibition of proteolytic degradation of matrices reduced the formation of spheroids and that incorporating laminin-411 and HA further facilitated spheroid growth within the gelatin-based hydrogels.	('facilitated', 'PosReg', (177, 188))	('spheroid growth', 'CPA', (189, 204))	('formation of spheroids', 'CPA', (104, 126))	('reduced', 'NegReg', (92, 99))	('HA', 'Chemical', 'MESH:D006820', (166, 168))	('laminin-411', 'Var', (150, 161))
353209	29024938	TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation.	('TYRO3', 'Gene', (0, 5))	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (28, 35))	('TYRO3', 'Gene', '7301', (0, 5))	('AXL', 'Gene', (9, 12))	('cell proliferation/colony formation', 'CPA', (36, 71))	('AXL', 'Gene', '558', (9, 12))
353213	29024938	Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS.	('patients', 'Species', '9606', (15, 23))	('PROS1', 'Gene', (56, 61))	('high expression', 'Var', (29, 44))	('PFS', 'MPA', (92, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('worse', 'NegReg', (86, 91))	('Leiomyosarcoma', 'Disease', 'MESH:D007890', (0, 14))	('PROS1', 'Gene', '5627', (56, 61))	('GAS6', 'Gene', (48, 52))	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (0, 14))	('GAS6', 'Gene', '2621', (48, 52))	('Leiomyosarcoma', 'Disease', (0, 14))
353223	29024938	The TAM receptors are structurally homologous and share the same vitamin K-dependent ligands: GAS6 (growth arrest-specific 6); and Protein S. GAS6 is upregulated in response to growth arrest in many different cell types, and is structurally related to Protein S. Upon ligation, the tyrosine kinase receptors initiate a downstream signalling promoting cell survival, proliferation, migration and adhesion, among other functions.	('GAS6', 'Gene', (94, 98))	('adhesion', 'CPA', (395, 403))	('man', 'Species', '9606', (194, 197))	('growth arrest-', 'Phenotype', 'HP:0031164', (100, 114))	('migration', 'CPA', (381, 390))	('growth arrest', 'Phenotype', 'HP:0001510', (100, 113))	('promoting', 'PosReg', (341, 350))	('growth arrest-specific 6', 'Gene', '2621', (100, 124))	('cell survival', 'CPA', (351, 364))	('growth arrest', 'Phenotype', 'HP:0001510', (177, 190))	('tyrosine kinase receptors', 'Enzyme', (282, 307))	('growth arrest-specific 6', 'Gene', (100, 124))	('vitamin K', 'Chemical', 'MESH:D014812', (65, 74))	('GAS6', 'Gene', '2621', (142, 146))	('GAS6', 'Gene', (142, 146))	('GAS6', 'Gene', '2621', (94, 98))	('ligation', 'Var', (268, 276))
353235	29024938	Five cell lines were established from primary tumours at Institut Bergonie (France): IB112 derived from a LMS of upper limb in a female patient; IB118 is derived from a tumour of the soft part of the head/neck of a man; IB133 from a retroperitoneal tumour in a female patient; IB134 is a uterine LMS; and IB136 derived from a soft tissue tumour of the lower limb in a female patient.	('patient', 'Species', '9606', (136, 143))	('retroperitoneal tumour', 'Disease', (233, 255))	('IB134', 'Gene', (277, 282))	('tumour', 'Disease', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (338, 344))	('tumour', 'Disease', 'MESH:D009369', (338, 344))	('tumour', 'Disease', (338, 344))	('man', 'Species', '9606', (215, 218))	('lower limb', 'Phenotype', 'HP:0006385', (352, 362))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('IB112', 'Gene', (85, 90))	('IB136', 'Chemical', '-', (305, 310))	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('tumour', 'Disease', 'MESH:D009369', (249, 255))	('tumour', 'Disease', (169, 175))	('IB118', 'Var', (145, 150))	('tumours', 'Disease', (46, 53))	('tumour', 'Disease', (249, 255))	('IB134', 'Chemical', '-', (277, 282))	('patient', 'Species', '9606', (268, 275))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('soft tissue tumour', 'Phenotype', 'HP:0031459', (326, 344))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('patient', 'Species', '9606', (375, 382))	('retroperitoneal tumour', 'Disease', 'MESH:D012186', (233, 255))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('IB118', 'Chemical', '-', (145, 150))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
353264	29024938	Two TYRO3 short hairpins (shRNA), TRCN0000002178 (sh1) and TRCN0000002179 (sh2), two AXL shRNA, TRCN0000000572 (sh3) and TRCN0000000576 (sh4), and a prion protein (shPRPC) were produced into the retroviral vector pRS.	('prion', 'Species', '36469', (149, 154))	('TRCN0000002179', 'Var', (59, 73))	('N', 'Chemical', 'MESH:D009584', (37, 38))	('AXL', 'Gene', '558', (85, 88))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('TYRO3', 'Gene', '7301', (4, 9))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('PRPC', 'Gene', '5621', (166, 170))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('TRCN0000000576', 'Disease', 'None', (121, 135))	('AXL', 'Gene', (85, 88))	('PRPC', 'Gene', (166, 170))	('TYRO3', 'Gene', (4, 9))	('N', 'Chemical', 'MESH:D009584', (124, 125))	('TRCN0000000576', 'Disease', (121, 135))
353301	29024938	Quantification of the western blot results is presented in Figure 3B and C. Crizotinib and foretinib thus inhibit AXL and TYRO3 activation in cell cultures.	('TYRO3', 'Gene', '7301', (122, 127))	('AXL', 'Gene', (114, 117))	('Crizotinib', 'Chemical', 'MESH:D000077547', (76, 86))	('inhibit', 'NegReg', (106, 113))	('AXL', 'Gene', '558', (114, 117))	('foretinib', 'Chemical', 'MESH:C544831', (91, 100))	('Crizotinib', 'Var', (76, 86))	('C. Crizotinib', 'Var', (73, 86))	('TYRO3', 'Gene', (122, 127))
353305	29024938	The IC50 values for crizotinib were 8.7, 8.8, 7.5, 3.5, 7.0 and 4.2  muM for IB112, IB118, IB133, IB134, IB136 and SK-LMS-1, respectively, and 1.73, 0.78, 1.39, 0.92, 0.79 and 0.84 muM, respectively, for foretinib consistent with the lowest Kd of foretinib for TAM receptors (Figure 3D and E).	('IB136', 'Chemical', '-', (105, 110))	('IB118', 'Chemical', '-', (84, 89))	('muM', 'Gene', '56925', (69, 72))	('muM', 'Gene', '56925', (181, 184))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (115, 123))	('IB134', 'Var', (98, 103))	('IB112', 'Var', (77, 82))	('foretinib', 'Chemical', 'MESH:C544831', (204, 213))	('muM', 'Gene', (69, 72))	('IB118', 'Var', (84, 89))	('muM', 'Gene', (181, 184))	('crizotinib', 'Chemical', 'MESH:D000077547', (20, 30))	('IB134', 'Chemical', '-', (98, 103))	('IB133', 'Var', (91, 96))	('foretinib', 'Chemical', 'MESH:C544831', (247, 256))	('IB136', 'Var', (105, 110))
353311	29024938	Using propidium iodide (PI) staining, crizotinib and foretinib were found to induce a G2/M arrest in the majority of LMS cells tested (Figure 4A).	('crizotinib', 'Var', (38, 48))	('foretinib', 'Gene', (53, 62))	('foretinib', 'Chemical', 'MESH:C544831', (53, 62))	('crizotinib', 'Chemical', 'MESH:D000077547', (38, 48))	('G2/M arrest', 'MPA', (86, 97))	('propidium iodide', 'Chemical', 'MESH:D011419', (6, 22))	('induce', 'Reg', (77, 83))
353312	29024938	An increase in G2 was observed for IB112, IB133 and IB136, and to a limited extent in SK-LMS-1, while IB134 presented a G1 arrest with an increase in sub-G1 DNA content after exposure to crizotinib and foretinib, respectively (Figure 4A).	('sub-G1 DNA content', 'MPA', (150, 168))	('increase', 'PosReg', (138, 146))	('crizotinib', 'Chemical', 'MESH:D000077547', (187, 197))	('foretinib', 'Chemical', 'MESH:C544831', (202, 211))	('G1 arrest', 'CPA', (120, 129))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (86, 94))	('IB136', 'Var', (52, 57))	('IB112', 'Var', (35, 40))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('IB136', 'Chemical', '-', (52, 57))	('IB134', 'Chemical', '-', (102, 107))	('increase', 'PosReg', (3, 11))
353319	29024938	As shown in Figure 4D, crizotinib inhibited soft-colony formation in a significant manner only for SK-LMS-1 cell line, whereas foretinib efficiently inhibited colony formation in soft agar for both cell lines IB136 and SK-LMS-1 (P<0.05, t-test).	('IB136', 'Chemical', '-', (209, 214))	('crizotinib', 'Chemical', 'MESH:D000077547', (23, 33))	('inhibited', 'NegReg', (34, 43))	('colony formation in soft agar', 'CPA', (159, 188))	('foretinib', 'Chemical', 'MESH:C544831', (127, 136))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (99, 107))	('man', 'Species', '9606', (83, 86))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (219, 227))	('soft-colony formation', 'CPA', (44, 65))	('crizotinib', 'Var', (23, 33))	('inhibited', 'NegReg', (149, 158))
353341	29024938	However a trend for a better PFS for low expressors of GAS6 and PROS1 was observed (data not shown).	('PROS1', 'Gene', '5627', (64, 69))	('GAS6', 'Gene', (55, 59))	('low expressors', 'Var', (37, 51))	('GAS6', 'Gene', '2621', (55, 59))	('better', 'PosReg', (22, 28))	('PROS1', 'Gene', (64, 69))	('PFS', 'MPA', (29, 32))
353342	29024938	Because GAS6 and PROS1 are both ligands of TYRO3 and AXL, we grouped the patients according to GAS6 and PROS1 expression above or under the mean expression of the series (low/low vs high/low ('mixed'), vs high/high).	('GAS6', 'Gene', (8, 12))	('TYRO3', 'Gene', '7301', (43, 48))	('PROS1', 'Gene', (17, 22))	('AXL', 'Gene', '558', (53, 56))	('GAS6', 'Gene', '2621', (8, 12))	('PROS1', 'Gene', '5627', (17, 22))	('PROS1', 'Gene', (104, 109))	('low/low', 'Var', (171, 178))	('GAS6', 'Gene', '2621', (95, 99))	('GAS6', 'Gene', (95, 99))	('AXL', 'Gene', (53, 56))	('high/low', 'Var', (182, 190))	('TYRO3', 'Gene', (43, 48))	('PROS1', 'Gene', '5627', (104, 109))	('patients', 'Species', '9606', (73, 81))
353353	29024938	Phosphorylation of TYRO3 was entirely abolished by crizotinib or foretinib in the most sensitive LMS cells.	('crizotinib', 'Chemical', 'MESH:D000077547', (51, 61))	('foretinib', 'Chemical', 'MESH:C544831', (65, 74))	('abolished', 'NegReg', (38, 47))	('crizotinib', 'Var', (51, 61))	('Phosphorylation', 'MPA', (0, 15))	('TYRO3', 'Gene', (19, 24))	('TYRO3', 'Gene', '7301', (19, 24))
353390	28510278	TFG-MET fusion in an infantile spindle cell sarcoma with neural features An increasing number of congenital and infantile sarcomas displaying a primitive, monomorphic spindle cell phenotype have been characterized to harbor recurrent gene fusions, including infantile fibrosarcoma and congenital spindle cell rhabdomyosarcoma.	('TFG', 'Gene', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (318, 325))	('congenital and infantile sarcomas', 'Disease', 'MESH:D012509', (97, 130))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('sarcoma', 'Disease', (44, 51))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (268, 280))	('sarcoma', 'Disease', 'MESH:D012509', (273, 280))	('infantile fibrosarcoma', 'Disease', (258, 280))	('fusion', 'Var', (8, 14))	('sarcoma', 'Disease', (273, 280))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (258, 280))	('sarcoma', 'Disease', (122, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('TFG', 'Gene', '10342', (0, 3))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (309, 325))	('congenital spindle cell rhabdomyosarcoma', 'Disease', (285, 325))	('sarcoma', 'Disease', 'MESH:D012509', (318, 325))	('congenital spindle cell rhabdomyosarcoma', 'Disease', 'MESH:D002277', (285, 325))	('sarcoma', 'Disease', (318, 325))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
353394	28510278	The TFG-MET gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital spindle cell sarcomas, with yet another example of kinase oncogenic activation through chromosomal translocation.	('TFG', 'Gene', '10342', (4, 7))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('fusion', 'Var', (17, 23))	('TFG', 'Gene', (4, 7))	('congenital spindle cell sarcomas', 'Disease', 'MESH:D012509', (87, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('congenital spindle cell sarcomas', 'Disease', (87, 119))
353396	28510278	For example, the presence of ETV6-NTRK3 fusion represents the gold-standard for diagnosis of congenital/infantile fibrosarcoma, while the VGLL2-related fusions are often associated with congenital spindle cell rhabdomyosarcoma.	('fusion', 'Var', (40, 46))	('congenital/infantile fibrosarcoma', 'Disease', (93, 126))	('NTRK3', 'Gene', (34, 39))	('ETV6', 'Gene', '2120', (29, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (114, 126))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (210, 226))	('congenital/infantile fibrosarcoma', 'Disease', 'MESH:D005354', (93, 126))	('VGLL2', 'Gene', '245806', (138, 143))	('congenital spindle cell rhabdomyosarcoma', 'Disease', (186, 226))	('VGLL2', 'Gene', (138, 143))	('ETV6', 'Gene', (29, 33))	('congenital spindle cell rhabdomyosarcoma', 'Disease', 'MESH:D002277', (186, 226))	('presence', 'Var', (17, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('NTRK3', 'Gene', '4916', (34, 39))	('associated', 'Reg', (170, 180))
353399	28510278	In contrast, most fusion-positive infantile spindle cell sarcomas are associated with a favorable outcome, in which a surgically removed lesion might not require adjuvant therapy, such as chemo or radiation therapy.	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('fusion-positive', 'Var', (18, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('infant', 'Species', '9606', (34, 40))	('sarcomas', 'Disease', (57, 65))
353401	28510278	Another example is the identification of NTRK1-related fusions in a group of locally aggressive, S100 protein-positive lipofibromatosis-like neural tumors occurring in children, which allowed distinction from malignant peripheral nerve sheath tumors.	('children', 'Species', '9606', (168, 176))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('malignant peripheral nerve sheath tumors', 'Disease', (209, 249))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (209, 248))	('NTRK1', 'Gene', (41, 46))	('S100', 'Gene', '6285', (97, 101))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (209, 249))	('lipofibromatosis-like neural tumors', 'Disease', (119, 154))	('lipofibromatosis-like neural tumors', 'Disease', 'MESH:C536149', (119, 154))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (209, 249))	('NTRK1', 'Gene', '4914', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('S100', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('fusions', 'Var', (55, 62))
353429	28510278	Two cytogenetic case reports of congenital plexiform (multinodular) cellular schwannoma revealed a similar trisomy 17, without any other abnormalities.	('schwannoma', 'Disease', (77, 87))	('schwannoma', 'Disease', 'MESH:D009442', (77, 87))	('trisomy 17', 'Var', (107, 117))	('schwannoma', 'Phenotype', 'HP:0100008', (77, 87))
353434	28510278	However, they also show CD34 and NTRK1 reactivity and NTRK1 gene rearrangements.	('NTRK1', 'Gene', '4914', (33, 38))	('NTRK1', 'Gene', '4914', (54, 59))	('rearrangements', 'Var', (65, 79))	('NTRK1', 'Gene', (33, 38))	('CD34', 'Gene', (24, 28))	('CD34', 'Gene', '947', (24, 28))	('reactivity', 'MPA', (39, 49))	('NTRK1', 'Gene', (54, 59))
353435	28510278	Our case was negative for both NTRK1 overexpression and break-apart NTRK1 by FISH.	('NTRK1', 'Gene', (31, 36))	('break-apart', 'Var', (56, 67))	('NTRK1', 'Gene', '4914', (68, 73))	('NTRK1', 'Gene', '4914', (31, 36))	('NTRK1', 'Gene', (68, 73))
353436	28510278	Interestingly, mesenchymal tumors with recurrent gene fusions often lack an established histogenesis or a characteristic immunoprofile, thus having an ambiguous line of differentiation.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('gene fusions', 'Var', (49, 61))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('lack', 'NegReg', (68, 72))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (15, 33))	('mesenchymal tumors', 'Disease', (15, 33))
353441	28510278	Lastly, the most recent example is the lipofibromatosis-like neural tumor with recurrent NTRK1-related fusions, in which the neural phenotype was defined based on its consistent S100 protein reactivity, but similarly lacking SOX10 positivity.	('NTRK1', 'Gene', (89, 94))	('SOX10', 'Gene', (225, 230))	('fusions', 'Var', (103, 110))	('SOX10', 'Gene', '6663', (225, 230))	('lipofibromatosis-like neural tumor', 'Disease', 'MESH:C536149', (39, 73))	('S100', 'Gene', '6285', (178, 182))	('lipofibromatosis-like neural tumor', 'Disease', (39, 73))	('S100', 'Gene', (178, 182))	('NTRK1', 'Gene', '4914', (89, 94))	('reactivity', 'MPA', (191, 201))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
353444	28510278	Genetic alterations of the MET gene, including translocations, amplifications, deletions and point mutations, have been observed in different tumor types, suggesting a potential role for MET activation in oncogenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('MET', 'Gene', (27, 30))	('deletions', 'Var', (79, 88))	('translocations', 'Var', (47, 61))	('amplifications', 'Var', (63, 77))	('point mutations', 'Var', (93, 108))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
353448	28510278	More recently, MET fusions have been reported in a subset of pediatric glioblastomas, with similar MET breakpoints as ours.	('pediatric glioblastomas', 'Disease', (61, 84))	('pediatric glioblastomas', 'Disease', 'MESH:D005909', (61, 84))	('MET fusions', 'Var', (15, 26))	('reported', 'Reg', (37, 45))	('glioblastomas', 'Phenotype', 'HP:0012174', (71, 84))
353451	28510278	This is the first example of MET protooncogene activation through chromosomal translocation in a sarcoma patient and expands the pathologic spectrum of fusion-positive infantile sarcomas.	('patient', 'Species', '9606', (105, 112))	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('MET protooncogene', 'Gene', (29, 46))	('infantile sarcomas', 'Disease', (168, 186))	('activation', 'PosReg', (47, 57))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('infantile sarcomas', 'Disease', 'MESH:D012509', (168, 186))	('chromosomal translocation', 'Var', (66, 91))	('sarcoma', 'Disease', (178, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (178, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
353454	28510278	Further studies are also needed to establish if the infantile sarcomas with MET related fusions represent a stand-alone pathologic entity or else may fit within the infantile fibrosarcoma spectrum despite strong S100 protein reactivity.	('S100', 'Gene', '6285', (212, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('infantile sarcomas', 'Disease', (52, 70))	('S100', 'Gene', (212, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('fusions', 'Var', (88, 95))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (175, 187))	('reactivity', 'MPA', (225, 235))	('infantile sarcomas', 'Disease', 'MESH:D012509', (52, 70))	('infantile fibrosarcoma', 'Disease', (165, 187))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (165, 187))
353459	28377632	Genomic aberrations in 138 known cancer driver genes and 491 established fusion genes were found in 1,127 tumors (78%).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('found', 'Reg', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Genomic aberrations', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
353463	28377632	Examples of such therapies include EGFR inhibitors, which target point mutations in EGFR , anti-HER2 antibodies recognizing the product of the ERBB2 gene amplification, and ALK inhibitors, which target the EML4-ALK fusion gene.	('EML4', 'Gene', (206, 210))	('EGFR', 'Gene', '1956', (35, 39))	('ERBB2', 'Gene', (143, 148))	('EGFR', 'Gene', (35, 39))	('ERBB2', 'Gene', '2064', (143, 148))	('point mutations', 'Var', (65, 80))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (84, 88))	('EML4', 'Gene', '27436', (206, 210))	('ALK', 'Gene', '238', (173, 176))	('ALK', 'Gene', '238', (211, 214))	('HER2', 'Gene', (96, 100))	('ALK', 'Gene', (173, 176))	('HER2', 'Gene', '2064', (96, 100))	('ALK', 'Gene', (211, 214))
353469	28377632	Gene expression analysis is requisite to confirm the status of tumor-specific genomic alterations, including mutations and amplifications, as actionable cancer driver genes.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Disease', (63, 68))	('cancer', 'Disease', (153, 159))	('amplifications', 'Var', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
353479	28377632	(37% for variant 2 and 35% for variant 4), FLT3 (44%) and ERBB2  (34%) in breast cancer; CSF1R (47%), DNMT1 (42%), and MYD88 (31%) in sarcoma; KIT  (100%), AR (71%), SMO (50%), PDGFRA  (43%), and BCL2  (variant alpha) (42%) in gastrointestinal stromal tumors (GISTs).	('gastrointestinal stromal tumors', 'Disease', (227, 258))	('BCL2', 'Gene', (196, 200))	('ERBB2', 'Gene', '2064', (58, 63))	('SMO', 'Gene', (166, 169))	('DNMT1', 'Gene', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('MYD88', 'Gene', '4615', (119, 124))	('variant', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('FLT3', 'Gene', (43, 47))	('MYD88', 'Gene', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('GISTs', 'Phenotype', 'HP:0100723', (260, 265))	('CSF1R', 'Gene', '1436', (89, 94))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (227, 258))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (227, 258))	('FLT3', 'Gene', '2322', (43, 47))	('PDGFRA', 'Gene', '5156', (177, 183))	('DNMT1', 'Gene', '1786', (102, 107))	('CSF1R', 'Gene', (89, 94))	('PDGFRA', 'Gene', (177, 183))	('BCL2', 'Gene', '596', (196, 200))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Disease', (74, 87))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('SMO', 'Gene', '6608', (166, 169))	('ERBB2', 'Gene', (58, 63))	('sarcoma', 'Disease', (134, 141))
353481	28377632	These include nine genes frequently overexpressed with copy number gain, including six amplification-based oncogenes (MYC, MYCL, MYCN, MDM2, NKX2-1, and SKP2) and three mutation-based oncogenes (HIST1H3B, EZH2, and CARD11) (Supplementary Fig.	('MYC', 'Gene', (129, 132))	('overexpressed', 'PosReg', (36, 49))	('CARD11', 'Gene', (215, 221))	('MYC', 'Gene', '4609', (123, 126))	('EZH2', 'Gene', (205, 209))	('EZH2', 'Gene', '2146', (205, 209))	('MYCN', 'Gene', (129, 133))	('copy number', 'Var', (55, 66))	('CARD11', 'Gene', '84433', (215, 221))	('HIST1H3B', 'Gene', (195, 203))	('HIST1H3B', 'Gene', '8358', (195, 203))	('MYC', 'Gene', '4609', (129, 132))	('SKP2', 'Gene', (153, 157))	('NKX2-1', 'Gene', '7080', (141, 147))	('MYC', 'Gene', (118, 121))	('MYCL', 'Gene', (123, 127))	('MDM2', 'Gene', (135, 139))	('SKP2', 'Gene', '6502', (153, 157))	('NKX2-1', 'Gene', (141, 147))	('MYCL', 'Gene', '4610', (123, 127))	('MDM2', 'Gene', '4193', (135, 139))	('MYC', 'Gene', (123, 126))	('MYCN', 'Gene', '4613', (129, 133))	('MYC', 'Gene', '4609', (118, 121))
353483	28377632	One group contained genes where overexpression was frequent among those with high genomic amplification (copy number >=6), and included EGFR (variant 1), ERBB2, and MDM2.	('overexpression', 'PosReg', (32, 46))	('high genomic amplification', 'Var', (77, 103))	('ERBB2', 'Gene', (154, 159))	('ERBB2', 'Gene', '2064', (154, 159))	('MDM2', 'Gene', '4193', (165, 169))	('MDM2', 'Gene', (165, 169))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
353485	28377632	In addition to EGFR variant 1, ERBB2, and MDM2, samples overexpressing FGFR2, KRAS, and EGFR variant 3 were abundant among those high-level genomic amplification of these genes, specifically in stomach cancer (FGFR2), colorectal and stomach cancer (KRAS), and lung, and head and neck cancer (EGFR variant 3) samples (Fig.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('head and neck cancer', 'Disease', 'MESH:D006258', (270, 290))	('colorectal and stomach cancer', 'Disease', 'MESH:D015179', (218, 247))	('EGFR', 'Gene', '1956', (15, 19))	('stomach cancer', 'Disease', (194, 208))	('KRAS', 'Gene', '3845', (249, 253))	('EGFR', 'Gene', '1956', (292, 296))	('stomach cancer', 'Disease', (233, 247))	('FGFR2', 'Gene', (210, 215))	('KRAS', 'Gene', (249, 253))	('MDM2', 'Gene', (42, 46))	('ERBB2', 'Gene', (31, 36))	('EGFR', 'Gene', (88, 92))	('FGFR2', 'Gene', '2263', (210, 215))	('stomach cancer', 'Disease', 'MESH:D013274', (194, 208))	('stomach cancer', 'Phenotype', 'HP:0012126', (194, 208))	('MDM2', 'Gene', '4193', (42, 46))	('EGFR', 'Gene', (15, 19))	('ERBB2', 'Gene', '2064', (31, 36))	('FGFR2', 'Gene', (71, 76))	('head and neck cancer', 'Phenotype', 'HP:0012288', (270, 290))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('KRAS', 'Gene', '3845', (78, 82))	('stomach cancer', 'Disease', 'MESH:D013274', (233, 247))	('stomach cancer', 'Phenotype', 'HP:0012126', (233, 247))	('variant', 'Var', (93, 100))	('lung', 'Disease', (260, 264))	('EGFR', 'Gene', (292, 296))	('KRAS', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (88, 92))	('FGFR2', 'Gene', '2263', (71, 76))
353486	28377632	When samples overexpressing EGFR variants 1 and 3 included samples with both high and moderate-levels of genomic amplification, samples in which both EGFR variants were overexpressed with genomic amplification were abundant in lung, and head and neck cancer samples (Fig.	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (150, 154))	('head and neck cancer', 'Phenotype', 'HP:0012288', (237, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('variants', 'Var', (155, 163))	('EGFR', 'Gene', (28, 32))	('lung', 'Disease', (227, 231))	('head and neck cancer', 'Disease', 'MESH:D006258', (237, 257))	('EGFR', 'Gene', '1956', (150, 154))	('variants', 'Var', (33, 41))
353488	28377632	EGFR variant 3 mRNA translates a soluble EGFR protein, p60 (isoform C), lacking transmembrane and tyrosine kinase domains, whereas EGFR variant 1 mRNA translates the full-length p170 EGFR (isoform A).	('EGFR', 'Gene', (41, 45))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('lacking', 'NegReg', (72, 79))	('p60', 'Gene', '29997', (55, 58))	('variant', 'Var', (5, 12))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'Gene', '1956', (0, 4))	('p60', 'Gene', (55, 58))
353489	28377632	Because the formation of inactive heterodimers between different isoforms competitively prevents the formation of functional holoreceptors, this result suggested that oncogenesis involving the EGFR pathway differs in samples with or without overexpressing EGFR variant 3 exhibiting genomic amplification.	('prevents', 'NegReg', (88, 96))	('EGFR', 'Gene', '1956', (193, 197))	('EGFR', 'Gene', (193, 197))	('EGFR', 'Gene', '1956', (256, 260))	('formation of functional holoreceptors', 'MPA', (101, 138))	('variant', 'Var', (261, 268))	('inactive heterodimers', 'MPA', (25, 46))	('EGFR', 'Gene', (256, 260))
353490	28377632	Using Pearson correlation coefficient, ERBB2 and MDM2 showed moderate relationships between copy number and FC (r = 0.53 and 0.49, respectively), whereas SKP2 (r = 0.35), EGFR variant 1 (r = 0.28), MYCL variants 1 and 2 (r = 0.26), and EZH2 (r = 0.20) were in the range between 0.2 and 0.4, indicating weak relationships.	('EGFR', 'Gene', (171, 175))	('relationships', 'Interaction', (70, 83))	('EZH2', 'Gene', (236, 240))	('ERBB2', 'Gene', '2064', (39, 44))	('EZH2', 'Gene', '2146', (236, 240))	('MYCL', 'Gene', '4610', (198, 202))	('copy number', 'Var', (92, 103))	('SKP2', 'Gene', '6502', (154, 158))	('MYCL', 'Gene', (198, 202))	('MDM2', 'Gene', '4193', (49, 53))	('EGFR', 'Gene', '1956', (171, 175))	('MDM2', 'Gene', (49, 53))	('SKP2', 'Gene', (154, 158))	('ERBB2', 'Gene', (39, 44))
353491	28377632	In particular, the majority of samples with high-level amplification of MYC were not overexpressed (r = 0.13), suggesting that these amplifications were passenger-like.	('amplification', 'Var', (55, 68))	('MYC', 'Gene', '4609', (72, 75))	('MYC', 'Gene', (72, 75))
353493	28377632	For these eight genes, Pearson correlation coefficient between copy number and FC among the samples overexpressed with FC >=5 demonstrated moderate and weak relationships in EGFR variant 1 (r = 0.52) and MYC (r = 0.33), respectively (Supplementary Fig.	('EGFR', 'Gene', (174, 178))	('MYC', 'Gene', '4609', (204, 207))	('variant 1', 'Var', (179, 188))	('relationships', 'Interaction', (157, 170))	('MYC', 'Gene', (204, 207))	('EGFR', 'Gene', '1956', (174, 178))
353494	28377632	This result indicates that overexpression with FC >=5 of EGFR variant 1 and MYC is frequently involved in copy number gain.	('variant 1', 'Var', (62, 71))	('MYC', 'Gene', (76, 79))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (57, 61))	('MYC', 'Gene', '4609', (76, 79))
353496	28377632	The frequency of amplification-dependent overexpression, in which overexpression was accompanied by either high or moderate levels of genomic amplification, was calculated for individual tumor types (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('amplification-dependent', 'Var', (17, 40))
353504	28377632	Since amplification-dependent overexpression is predicted to be involved in oncogenesis, the genes amplified with overexpression are potential target molecules for anti-cancer agents.	('involved', 'Reg', (64, 72))	('cancer', 'Disease', (169, 175))	('amplification-dependent', 'Var', (6, 29))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
353512	28377632	INHBA overexpression promotes cell proliferation in esophageal adenocarcinoma, while RECQL4 is associated with breast cancer tumor aggressiveness, due to both amplification and overexpression.	('breast cancer tumor aggressiveness', 'Disease', 'MESH:D001943', (111, 145))	('overexpression', 'Var', (6, 20))	('promotes', 'PosReg', (21, 29))	('INHBA', 'Gene', (0, 5))	('associated', 'Reg', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (52, 77))	('RECQL4', 'Gene', '9401', (85, 91))	('overexpression', 'PosReg', (177, 191))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (52, 77))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('RECQL4', 'Gene', (85, 91))	('esophageal adenocarcinoma', 'Disease', (52, 77))	('breast cancer tumor aggressiveness', 'Disease', (111, 145))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (111, 130))	('amplification', 'Var', (159, 172))	('cell proliferation', 'CPA', (30, 48))	('INHBA', 'Gene', '3624', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('aggressiveness', 'Phenotype', 'HP:0000718', (131, 145))
353518	28377632	Among the 1,454 tumors, 327 were categorized as having undetermined driver origins following mutation, copy number, and expression analyses of 138 driver and 491 fusion genes (Fig.	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('mutation', 'Var', (93, 101))
353527	28377632	In addition, SKP2 overexpression and amplification has been related to metastasis in lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('related', 'Reg', (60, 67))	('SKP2', 'Gene', '6502', (13, 17))	('amplification', 'Var', (37, 50))	('metastasis in lung squamous cell carcinoma', 'Disease', (71, 113))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (85, 113))	('SKP2', 'Gene', (13, 17))	('metastasis in lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 113))	('overexpression', 'PosReg', (18, 32))
353537	28377632	Although LMO1 duplication was associated with more advanced disease and survival in neuroblastoma, our analysis identified four samples from lung adenocarcinoma exhibiting LMO1 amplification and overexpression, three of which were derived from stage I and no stage information provided for the remaining sample.	('associated', 'Reg', (30, 40))	('lung adenocarcinoma', 'Disease', (141, 160))	('LMO1', 'Gene', (172, 176))	('neuroblastoma', 'Disease', 'MESH:D009447', (84, 97))	('LMO1', 'Gene', '4004', (172, 176))	('LMO1', 'Gene', (9, 13))	('neuroblastoma', 'Disease', (84, 97))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('overexpression', 'PosReg', (195, 209))	('LMO1', 'Gene', '4004', (9, 13))	('neuroblastoma', 'Phenotype', 'HP:0003006', (84, 97))	('duplication', 'Var', (14, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
353542	28377632	Recurrent amplification-dependent overexpression of AXL was observed only in two sarcomas (myxofibrosarcoma and leiomyosarcoma).	('amplification-dependent', 'Var', (10, 33))	('sarcomas', 'Disease', (81, 89))	('AXL', 'Gene', (52, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (112, 126))	('overexpression', 'PosReg', (34, 48))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('myxofibrosarcoma and leiomyosarcoma', 'Disease', 'MESH:D007890', (91, 126))	('AXL', 'Gene', '558', (52, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
353565	28377632	Driver mutations in 138 known driver genes were defined as those identified as pathogenic in the ClinVar database, or those contained in the Database of Curated Mutations (DoCM, http://docm.genome.wustl.edu) or the UMD TP53 mutation database.	('TP53', 'Gene', (219, 223))	('TP53', 'Gene', '7157', (219, 223))	('mutations', 'Var', (7, 16))
353760	24464916	Inhibition of Focal Adhesion Kinase (FAK) Leads to Abrogation of the Malignant Phenotype in Aggressive Pediatric Renal Malignancies Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and non-osseous renal Ewing sarcoma.	('Focal Adhesion Kinase', 'Gene', '5747', (14, 35))	('FAK', 'Gene', (37, 40))	('non-osseous renal Ewing sarcoma', 'Disease', (347, 378))	('Focal Adhesion Kinase', 'Gene', (14, 35))	('Renal Malignancies', 'Phenotype', 'HP:0009726', (113, 131))	('malignant rhabdoid kidney tumors', 'Disease', 'MESH:D018335', (310, 342))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (365, 378))	('pediatric renal tumors', 'Disease', 'MESH:D007674', (233, 255))	('FAK', 'Gene', '5747', (37, 40))	('non-osseous renal Ewing sarcoma', 'Disease', 'MESH:C563168', (347, 378))	('Aggressive Pediatric Renal Malignancies', 'Disease', 'MESH:D007674', (92, 131))	('childhood kidney tumors', 'Disease', 'MESH:D007674', (184, 207))	('kidney tumors', 'Phenotype', 'HP:0009726', (194, 207))	('renal tumors', 'Phenotype', 'HP:0009726', (243, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (371, 378))	('Aggressive Pediatric Renal Malignancies', 'Disease', (92, 131))	('kidney tumor', 'Phenotype', 'HP:0009726', (329, 341))	('kidney tumors', 'Phenotype', 'HP:0009726', (329, 342))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('childhood kidney tumors', 'Disease', (184, 207))	('Inhibition', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('renal tumor', 'Phenotype', 'HP:0009726', (243, 254))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('kidney tumor', 'Phenotype', 'HP:0009726', (194, 206))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('pediatric renal tumors', 'Disease', (233, 255))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('malignant rhabdoid kidney tumors', 'Disease', (310, 342))
353763	24464916	FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading us to hypothesize that FAK would be present in pediatric kidney tumors and would impact their cellular survival.	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('adult renal cellular carcinoma', 'Disease', (58, 88))	('impact', 'Reg', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('adult renal cellular carcinoma', 'Disease', 'MESH:C538614', (58, 88))	('pediatric kidney tumors', 'Disease', (145, 168))	('kidney tumor', 'Phenotype', 'HP:0009726', (155, 167))	('kidney tumors', 'Phenotype', 'HP:0009726', (155, 168))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('pediatric kidney tumors', 'Disease', 'MESH:D007674', (145, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('FAK', 'Var', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cellular survival', 'CPA', (192, 209))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', (44, 50))	('renal cellular carcinoma', 'Phenotype', 'HP:0005584', (64, 88))	('tumors', 'Disease', (162, 168))
353780	24464916	However, it is believed that Y397 autophosphorylation site the primary site responsible for the role of FAK in tumor cell migration, invasion and survival.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('invasion', 'CPA', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Y397', 'Var', (29, 33))	('tumor', 'Disease', (111, 116))
353781	24464916	Abrogation of FAK phosphorylation at this site using dominant negative constructs and small molecule inhibitors, has been shown to decreased tumor cellular migration, invasion, and survival.	('decreased tumor', 'Disease', 'MESH:D009369', (131, 146))	('FAK', 'Protein', (14, 17))	('Abrogation', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('decreased tumor', 'Disease', (131, 146))	('invasion', 'CPA', (167, 175))	('survival', 'CPA', (181, 189))	('phosphorylation', 'MPA', (18, 33))
353782	24464916	In the current study, we hypothesized that rare pediatric renal tumors would express FAK, and that inhibition of FAK would result in a less aggressive phenotype in these cell lines.	('pediatric renal tumors', 'Disease', 'MESH:D007674', (48, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('renal tumor', 'Phenotype', 'HP:0009726', (58, 69))	('renal tumors', 'Phenotype', 'HP:0009726', (58, 70))	('inhibition', 'Var', (99, 109))	('FAK', 'Protein', (85, 88))	('pediatric renal tumors', 'Disease', (48, 70))	('less aggressive phenotype', 'MPA', (135, 160))	('result in', 'Reg', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('express', 'Reg', (77, 84))
353783	24464916	We demonstrated that abrogation of FAK in renal tumor cell lines resulted in decreased tumor cell survival in vitro and decreased xenograft growth in vivo.	('decreased', 'NegReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('decreased tumor', 'Disease', 'MESH:D009369', (77, 92))	('renal tumor', 'Disease', 'MESH:D007674', (42, 53))	('renal tumor', 'Phenotype', 'HP:0009726', (42, 53))	('decreased tumor', 'Disease', (77, 92))	('FAK', 'Gene', (35, 38))	('abrogation', 'Var', (21, 31))	('renal tumor', 'Disease', (42, 53))	('xenograft growth', 'CPA', (130, 146))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
353860	24464916	Using immunoblotting, we showed that Y15 treatment resulted in decreased FAK phosphorylation in both the G401 and the SK-NEP-1 cell lines (Figure 4A).	('Y15', 'Var', (37, 40))	('FAK phosphorylation', 'MPA', (73, 92))	('decreased', 'NegReg', (63, 72))	('SK-NEP-1', 'CellLine', 'CVCL:0631', (118, 126))	('decreased FAK', 'Phenotype', 'HP:0032341', (63, 76))
353861	24464916	Both G401 and SK-NEP-1 cell lines showed significantly decreased cell survival following treatment with Y15 (Figure 4B).	('decreased', 'NegReg', (55, 64))	('cell survival', 'CPA', (65, 78))	('Y15', 'Var', (104, 107))	('SK-NEP-1', 'CellLine', 'CVCL:0631', (14, 22))
353862	24464916	The calculated LD50 for Y15 was 3.3 muM in the G401 and 18.2 muM in the SK-NEP-1 cell line.	('Y15', 'Var', (24, 27))	('SK-NEP-1', 'CellLine', 'CVCL:0631', (72, 80))	('G401', 'Var', (47, 51))
353874	24464916	Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tumor samples for FAK Y397.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('FAK Y397', 'Var', (90, 98))	('paraffin', 'Chemical', 'MESH:D010232', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('formalin', 'Chemical', 'MESH:D005557', (38, 46))
353875	24464916	There was less FAK Y397 staining in the tumors from animals treated with Y15 compared to vehicle treated tumors (Figure 6C).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Y15', 'Var', (73, 76))	('less', 'NegReg', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('FAK', 'MPA', (15, 18))	('Y397', 'Protein', (19, 23))	('tumors', 'Disease', (40, 46))
353877	24464916	To further confirm target knockdown in the tumor specimens, immunoblotting for FAK was performed on tumor lysates.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('knockdown', 'Var', (26, 35))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
353878	24464916	Tumors treated with Y15 showed a decrease in FAK phosphorylation (Y397) compared to those treated with saline (vehicle).	('decrease', 'NegReg', (33, 41))	('saline', 'Chemical', 'MESH:D012965', (103, 109))	('Y15', 'Var', (20, 23))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('FAK phosphorylation', 'MPA', (45, 64))	('Y397', 'Var', (66, 70))
353880	24464916	There was a significant decrease in the FAK phosphorylation (Y397) in the tumors from the animals treated with Y15 (Figure 6E).	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('decrease', 'NegReg', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('Y397', 'Var', (61, 65))	('FAK phosphorylation', 'MPA', (40, 59))	('Y15', 'Var', (111, 114))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
353891	24464916	Another group examined FAK phosphorylation at the Y861 site by immunohistochemistry in 57 human renal cell carcinoma specimens and noted staining in over 30% of the samples, and on multivariate analysis, there was a correlation between FAK phosphorylation and cancer specific survival.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (96, 116))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('human', 'Species', '9606', (90, 95))	('correlation', 'Reg', (216, 227))	('renal cell carcinoma', 'Disease', (96, 116))	('FAK', 'Var', (236, 239))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (96, 116))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
353904	24464916	We obtained two different pediatric renal tumor cell lines, G401 (MRKT) and SK-NEP-1 (renal Ewing sarcoma) and confirmed that FAK was present and was phosphorylated at the Y397 site in these cell lines.	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('pediatric renal tumor', 'Disease', 'MESH:D007674', (26, 47))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('pediatric renal tumor', 'Disease', (26, 47))	('SK-NEP-1', 'CellLine', 'CVCL:0631', (76, 84))	('renal tumor', 'Phenotype', 'HP:0009726', (36, 47))	('renal Ewing sarcoma', 'Disease', (86, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('renal Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 105))	('G401', 'Var', (60, 64))
353907	24464916	Both the G401 and SK-NEP-1 cell lines were originally thought to be Wilms tumor.	('SK-NEP-1', 'CellLine', 'CVCL:0631', (18, 26))	('Wilms tumor', 'Disease', 'MESH:D009396', (68, 79))	('Wilms tumor', 'Disease', (68, 79))	('Wilms tumor', 'Phenotype', 'HP:0002667', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('G401', 'Var', (9, 13))
353916	24464916	In addition, the cellular responses to inhibition of FAK phosphorylation with PF-573,228 and Y15 may be explained in a similar fashion.	('Y15', 'Var', (93, 96))	('PF', 'Chemical', 'MESH:C002997', (78, 80))	('inhibition', 'NegReg', (39, 49))	('FAK', 'Protein', (53, 56))
353918	24464916	Investigators have postulated that certain tumor cell lines are physiologically more dependent upon specific survival factors, and inhibition of these specific cellular factors will have a more profound effect upon those cells than others even of the same tumor type.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (43, 48))	('inhibition', 'Var', (131, 141))	('tumor', 'Disease', (256, 261))
353928	24464916	The addition of Y15 to gemcitabine treatment was shown to have an additive affect on survival in a nude mouse model of pancreatic cancer.	('pancreatic cancer', 'Disease', (119, 136))	('mouse', 'Species', '10090', (104, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('affect', 'Reg', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Y15', 'Var', (16, 19))	('gemcitabine', 'Chemical', 'MESH:C056507', (23, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (119, 136))
353929	24464916	In another pediatric solid tumor, neuroblastoma, Y15-induced FAK inhibition resulted in a significant decrease in both flank xenograft tumor growth and in liver metastases.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('inhibition', 'NegReg', (65, 75))	('neuroblastoma', 'Phenotype', 'HP:0003006', (34, 47))	('liver metastases', 'Disease', (155, 171))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (27, 32))	('flank xenograft tumor', 'Disease', 'MESH:D021501', (119, 140))	('decrease', 'NegReg', (102, 110))	('FAK', 'Gene', (61, 64))	('flank xenograft tumor', 'Disease', (119, 140))	('tumor', 'Disease', (135, 140))	('liver metastases', 'Disease', 'MESH:D009362', (155, 171))	('neuroblastoma', 'Disease', 'MESH:D009447', (34, 47))	('Y15-induced', 'Var', (49, 60))	('neuroblastoma', 'Disease', (34, 47))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
353930	24464916	These studies provided the rationale for utilizing Y15 as a FAK inhibitor for the current in vivo investigation, where we noted that Y15 treatment led to decreased tumor volumes of renal subcapsular SK-NEP-1 tumors.	('Y15', 'Var', (133, 136))	('SK-NEP-1', 'CellLine', 'CVCL:0631', (199, 207))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('decreased tumor', 'Disease', 'MESH:D009369', (154, 169))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('subcapsular SK', 'Phenotype', 'HP:0000523', (187, 201))	('decreased tumor', 'Disease', (154, 169))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
353937	24464916	The small molecules PF-573,228 and Y15 have been reported to inhibit FAK phosphorylation at the Y397 autophosphorylation site and that is why they were chosen for these investigations.	('Y15', 'Var', (35, 38))	('PF', 'Chemical', 'MESH:C002997', (20, 22))	('inhibit', 'NegReg', (61, 68))
353938	24464916	Many consider the FAK autophosphorylation site (Y397) to play the primary role in how FAK affects tumor cell migration, invasion and survival.	('survival', 'CPA', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('invasion', 'CPA', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('affects', 'Reg', (90, 97))	('Y397', 'Var', (48, 52))
353944	24464916	Another novel aspect of the current studies was the demonstration that FAK inhibition in a nude mouse model incorporating a subcapsular renal tumor resulted in significantly smaller renal tumors when compared to controls.	('renal tumor', 'Disease', 'MESH:D007674', (182, 193))	('smaller', 'NegReg', (174, 181))	('renal tumors', 'Phenotype', 'HP:0009726', (182, 194))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('renal tumor', 'Phenotype', 'HP:0009726', (182, 193))	('renal tumor', 'Disease', (136, 147))	('mouse', 'Species', '10090', (96, 101))	('renal tumors', 'Disease', 'MESH:D007674', (182, 194))	('renal tumor', 'Disease', 'MESH:D007674', (136, 147))	('renal tumors', 'Disease', (182, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('renal tumor', 'Phenotype', 'HP:0009726', (136, 147))	('FAK', 'Var', (71, 74))
353964	21810919	While there has been a paucity of antigens associated with the unique specificity of this tumor model, genetic analysis of a MCA-induced sarcoma after CTL immunoselection revealed a deletion in a region rich with oncogenes and tumor suppressor genes.	('MCA-induced', 'Disease', (125, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('MCA', 'Chemical', 'MESH:D008748', (125, 128))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('deletion', 'Var', (182, 190))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('sarcoma', 'Disease', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
353971	21810919	Based on these findings, we propose that the broad array of tumor antigens contained in autophagosomes is dependent upon ubiquitinated SLiPs incorporated by the sequestosome and that cross-presentation of these autophagosomes primes a unique cross-protective immune response.	('primes', 'PosReg', (226, 232))	('cross-protective immune response', 'CPA', (242, 274))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cross-presentation', 'Var', (183, 201))	('tumor', 'Disease', (60, 65))
354030	21810919	Surprisingly, MCA 304-derived autophagosomes pulsed onto APCs primed an immune response to not only MCA-304, but also to other independently derived sarcomas (Figure 1B, grey bars).	('APC', 'Disease', 'MESH:D011125', (57, 60))	('APC', 'Disease', (57, 60))	('sarcomas', 'Disease', 'MESH:D012509', (149, 157))	('MCA-304', 'Var', (100, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('MCA', 'Chemical', 'MESH:D008748', (100, 103))	('immune response', 'CPA', (72, 87))	('sarcomas', 'Disease', (149, 157))	('MCA', 'Chemical', 'MESH:D008748', (14, 17))
354047	21810919	In contrast, the turnover of the short-lived model antigen (rGFP-OVA) was proteasome-dependent; blockade of the proteasome with bortezomib increased the expression of the rGFP-OVA protein.	('OVA', 'Gene', (65, 68))	('increased', 'PosReg', (139, 148))	('blockade', 'Var', (96, 104))	('OVA', 'Gene', '282665', (65, 68))	('OVA', 'Gene', (176, 179))	('OVA', 'Gene', '282665', (176, 179))	('bortezomib', 'Chemical', 'MESH:D000069286', (128, 138))	('expression', 'MPA', (153, 163))
354086	21810919	Interestingly, higher molecular weight bands were detected with anti-GFP in HEK 293rGFP-OVA autophagosomes isolated from bortezomib-treated cells (Figure 6A), but not in the cells used to produce the autophagosomes (Figure 4B).	('higher', 'PosReg', (15, 21))	('HEK 293', 'CellLine', 'CVCL:0045', (76, 83))	('anti-GFP', 'Var', (64, 72))	('bortezomib', 'Chemical', 'MESH:D000069286', (121, 131))	('OVA', 'Gene', (88, 91))	('OVA', 'Gene', '282665', (88, 91))
354089	21810919	The anti-ubiquitin antibody bound only to the higher molecular weight proteins found in autophagosomes isolated from cells treated with bortezomib (+/- CHX) (Figure 6B) but not in autophagosomes from untreated 293rGFP-OVA cells or bortezomib-treated parental HEK 293T cells.	('bortezomib', 'Chemical', 'MESH:D000069286', (136, 146))	('bortezomib', 'Chemical', 'MESH:D000069286', (231, 241))	('bound', 'Interaction', (28, 33))	('bortezomib', 'Var', (136, 146))	('HEK 293T', 'CellLine', 'CVCL:0063', (259, 267))	('CHX', 'Chemical', '-', (152, 155))	('OVA', 'Gene', (218, 221))	('OVA', 'Gene', '282665', (218, 221))
354093	21810919	To understand how the sequestosome may influence trafficking of specific proteins to autophagosomes, p62 expression was knocked down in HEK 293T cells.	('trafficking', 'MPA', (49, 60))	('influence', 'Reg', (39, 48))	('knocked', 'Var', (120, 127))	('p62', 'Gene', (101, 104))	('HEK 293T', 'CellLine', 'CVCL:0063', (136, 144))
354096	21810919	The knockdown of p62 in both rGFP-OVA and mGFP-OVA transfected cells greatly reduced the level of the GFP-OVA.	('OVA', 'Gene', (47, 50))	('OVA', 'Gene', (106, 109))	('OVA', 'Gene', (34, 37))	('level of', 'MPA', (89, 97))	('p62', 'Gene', (17, 20))	('OVA', 'Gene', '282665', (106, 109))	('OVA', 'Gene', '282665', (47, 50))	('OVA', 'Gene', '282665', (34, 37))	('reduced', 'NegReg', (77, 84))	('knockdown', 'Var', (4, 13))
354098	21810919	While the p62 knockdown diminished the proliferation of T cells stimulated with mGFP-OVA autophagosomes, the inhibition of proliferation was even greater with rGFP-OVA autophagosomes knocked down for p62.	('OVA', 'Gene', (164, 167))	('OVA', 'Gene', '282665', (85, 88))	('OVA', 'Gene', '282665', (164, 167))	('p62', 'Gene', (10, 13))	('diminished', 'NegReg', (24, 34))	('proliferation', 'CPA', (39, 52))	('knockdown', 'Var', (14, 23))	('OVA', 'Gene', (85, 88))
354124	21810919	While using siRNA to knockdown expression of p62 may destabilize or limit expression of the GFP-OVA construct, these experiments corroborate sequestosome's role in antigen delivery to autophagosomes as reduced expression of p62 limited the model antigen found in the autophagosomes and diminished proliferation of antigen-specific T cell stimulated with these autophagosomes.	('reduced', 'NegReg', (202, 209))	('expression', 'MPA', (74, 84))	('destabilize', 'NegReg', (53, 64))	('OVA', 'Gene', (96, 99))	('limit', 'NegReg', (68, 73))	('OVA', 'Gene', '282665', (96, 99))	('p62', 'Var', (224, 227))	('diminished', 'NegReg', (286, 296))	('limited', 'NegReg', (228, 235))	('proliferation', 'CPA', (297, 310))	('model antigen', 'MPA', (240, 253))
354125	21810919	Autophagosomes isolated from HEK293rGFP-OVA cells treated with p62 siRNA had a greater impairment in their ability to stimulate T-cell proliferation than autophagosomes isolated from p62 siRNA-treated cells expressing the more stable mGFP-OVA antigen (Figure 7C), suggesting a correlation between the stability or state of ubiquitination of the protein and the necessity of p62 to transfer the protein into the autophagosome.	('impairment', 'NegReg', (87, 97))	('T-cell proliferation', 'CPA', (128, 148))	('OVA', 'Gene', '282665', (239, 242))	('p62', 'Var', (63, 66))	('OVA', 'Gene', (40, 43))	('OVA', 'Gene', '282665', (40, 43))	('OVA', 'Gene', (239, 242))	('HEK293', 'CellLine', 'CVCL:0045', (29, 35))	('stimulate', 'PosReg', (118, 127))
354135	21810919	Additionally, this strategy could be useful in priming immune responses against tumor-antigen loss variants seen with a progressively growing tumor and may even serve as an alternative vaccine to treat patients coming out of remission.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('variants', 'Var', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('loss', 'NegReg', (94, 98))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (80, 85))	('patients', 'Species', '9606', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
354166	29955031	Cytology of bone marrow documented a diffuse tumor infiltration with 56% of blasts suggesting a monocytic AML without FLT3 gene duplication and NPM1 mutation (M5 subtype according to French-American-British, FAB classification).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('FLT3', 'Gene', '2322', (118, 122))	('tumor', 'Disease', (45, 50))	('AML', 'Disease', 'MESH:D015470', (106, 109))	('FAB', 'Gene', '2187', (208, 211))	('NPM1', 'Gene', (144, 148))	('FLT3', 'Gene', (118, 122))	('FAB', 'Gene', (208, 211))	('NPM1', 'Gene', '4869', (144, 148))	('mutation', 'Var', (149, 157))	('AML', 'Phenotype', 'HP:0004808', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('AML', 'Disease', (106, 109))
354172	29955031	MS is reported in 2% to 14% of cases of AML, most commonly in patients with specific cytogenetic abnormalities, e.g., t (8; 21) or inv (16) or FAB class M2.	('AML', 'Disease', 'MESH:D015470', (40, 43))	('inv (16', 'Var', (131, 138))	('t (8; 21', 'Var', (118, 126))	('AML', 'Phenotype', 'HP:0004808', (40, 43))	('AML', 'Disease', (40, 43))	('FAB', 'Gene', '2187', (143, 146))	('patients', 'Species', '9606', (62, 70))	('FAB', 'Gene', (143, 146))
354211	29308311	In epithelial malignancies, this high mutational load, as well as the presence of a spontaneous anti-tumor immune reaction prior to treatment, have been associated with predicting better response to immune checkpoint inhibitors.	('mutational load', 'Var', (38, 53))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (3, 26))	('epithelial malignancies', 'Disease', (3, 26))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('epithelial malignancies', 'Disease', 'MESH:D002277', (3, 26))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
354253	29308311	PD-L1 positivity and high T-cell infiltration were strongly correlated (p < 0.0001).	('PD-L1', 'Gene', (0, 5))	('positivity', 'Var', (6, 16))	('PD-L1', 'Gene', '29126', (0, 5))	('high T-cell infiltration', 'CPA', (21, 45))
354306	29308311	We have learnt from melanoma studies that combination of CTLA-4 and PD-1 inhibitors was more efficacious than the respective monotherapies.	('PD-1', 'Gene', '5133', (68, 72))	('CTLA-4', 'Gene', '1493', (57, 63))	('CTLA-4', 'Gene', (57, 63))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('inhibitors', 'Var', (73, 83))	('PD-1', 'Gene', (68, 72))	('combination', 'Interaction', (42, 53))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
354307	29308311	Actually, two clinical trials assessing efficacy and safety of combined immune checkpoint inhibitors in sarcoma are ongoing (NCT03138161 and NCT02428192).	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('NCT02428192', 'Var', (141, 152))	('NCT03138161', 'Var', (125, 136))
354323	29308311	For immunohistochemistry, antibodies were detected using poly-HRP (ImmunoLogic), visualized with a DAB+ substrate chromogen system (Dako) and slides were counterstained with hematoxylin, dehydrated and mounted using CV Mount (Leica Microsystems).	('dehydrated', 'Disease', 'MESH:D003681', (187, 197))	('hematoxylin', 'Chemical', 'MESH:D006416', (174, 185))	('DAB', 'Chemical', 'MESH:C000469', (99, 102))	('dehydrated', 'Disease', (187, 197))	('poly-HRP', 'Var', (57, 65))
354339	28233365	ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements CIC rearrangements have been reported in two-thirds of EWSR1-negative small blue round cell tumors (SBRCTs).	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('rearrangements', 'Var', (157, 171))	('CIC', 'Gene', '23152', (153, 156))	('cell tumors', 'Disease', (240, 251))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('SBRCT', 'Chemical', '-', (253, 258))	('CIC', 'Gene', '23152', (129, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('CIC', 'Gene', (153, 156))	('rearrangements', 'Var', (138, 152))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('cell tumors', 'Disease', 'MESH:D005935', (240, 251))	('CIC', 'Gene', (129, 132))	('sarcomas', 'Disease', (115, 123))
354363	28233365	Since CIC-DUX4 fusions are the most common genetic events among the EWSR1-negative SBRCTs, we further examined the RNA sequencing data for ETV1/4/5 and WT1 gene expressions, manual inspection of CIC sequences, FISH for CIC and DUX4 genetic abnormalities and immunohistochemistry for ETV4.	('CIC', 'Gene', (219, 222))	('genetic abnormalities', 'Disease', (232, 253))	('DUX4', 'Gene', (10, 14))	('fusions', 'Var', (15, 22))	('DUX4', 'Gene', (227, 231))	('SBRCT', 'Chemical', '-', (83, 88))	('DUX4', 'Gene', '100288687', (10, 14))	('CIC', 'Gene', '23152', (6, 9))	('DUX4', 'Gene', '100288687', (227, 231))	('CIC', 'Gene', '23152', (219, 222))	('CIC', 'Gene', '23152', (195, 198))	('genetic abnormalities', 'Disease', 'MESH:D030342', (232, 253))	('CIC', 'Gene', (195, 198))	('CIC', 'Gene', (6, 9))
354397	28233365	Manual inspection of the CIC sequences showed CIC-DUX4 reads in 7 cases: 5 with fusion junction reads (individual reads spanning both CIC and DUX4 sequences and the fusion junctions) and 2 with only chimeric reads (CIC and DUX4 sequences on each of the paired-end reads) (Supporting Information Table 2).	('CIC', 'Gene', '23152', (46, 49))	('fusion junction reads', 'Var', (80, 101))	('CIC', 'Gene', '23152', (215, 218))	('DUX4', 'Gene', (223, 227))	('DUX4', 'Gene', '100288687', (223, 227))	('CIC', 'Gene', (46, 49))	('DUX4', 'Gene', (142, 146))	('CIC', 'Gene', (215, 218))	('DUX4', 'Gene', '100288687', (142, 146))	('CIC', 'Gene', '23152', (25, 28))	('CIC', 'Gene', '23152', (134, 137))	('DUX4', 'Gene', (50, 54))	('DUX4', 'Gene', '100288687', (50, 54))	('CIC', 'Gene', (25, 28))	('CIC', 'Gene', (134, 137))
354398	28233365	Consistently all cases showed CIC breakpoints within the coding region of the last exon (exon 20) (Figure 2A), while DUX4 breakpoints were scattered in exons 1-2 or intron 1 (sequence reference: uc001lns.2).	('breakpoints', 'Var', (34, 45))	('CIC', 'Gene', '23152', (30, 33))	('DUX4', 'Gene', (117, 121))	('DUX4', 'Gene', '100288687', (117, 121))	('CIC', 'Gene', (30, 33))
354401	28233365	The projected amino acids of the CIC-DUX4 fusion protein were in-frame in all cases except two (cases #6, 7), in which fusion of CIC exon 20 to DUX4 resulted in a stop codon right after the fusion junction (Figure 2C).	('DUX4', 'Gene', '100288687', (37, 41))	('CIC', 'Gene', (129, 132))	('DUX4', 'Gene', (144, 148))	('fusion', 'Var', (119, 125))	('CIC', 'Gene', '23152', (33, 36))	('DUX4', 'Gene', '100288687', (144, 148))	('CIC', 'Gene', '23152', (129, 132))	('CIC', 'Gene', (33, 36))	('DUX4', 'Gene', (37, 41))	('resulted in', 'Reg', (149, 160))
354413	28233365	Fusion FISH assays confirmed telomeric CIC and centromeric DUX4 (4q35) fusions in 2 cases (cases# 11, 12), while no association between CIC and DUX4 (both 4q35 and 10q26 loci) was found in cases #13, 14.	('DUX4', 'Gene', (59, 63))	('DUX4', 'Gene', (144, 148))	('DUX4', 'Gene', '100288687', (144, 148))	('fusions', 'Var', (71, 78))	('CIC', 'Gene', '23152', (39, 42))	('DUX4', 'Gene', '100288687', (59, 63))	('CIC', 'Gene', '23152', (136, 139))	('CIC', 'Gene', (39, 42))	('CIC', 'Gene', (136, 139))
354427	28233365	The failure of algorithmic analysis to detect CIC-DUX4 fusions has also been reported by Panagopoulos et al.	('CIC', 'Gene', '23152', (46, 49))	('CIC', 'Gene', (46, 49))	('DUX4', 'Gene', (50, 54))	('DUX4', 'Gene', '100288687', (50, 54))	('fusions', 'Var', (55, 62))
354428	28233365	CIC-DUX4 was not included among their fusion candidates from a SBRCT arising in the thoracic wall of a 40 year-old female, despite the fact that conventional cytogenetics and metaphase FISH showed a t(4;19) (q35;q13).	('DUX4', 'Gene', (4, 8))	('DUX4', 'Gene', '100288687', (4, 8))	('CIC', 'Gene', '23152', (0, 3))	('t(4;19) (q35;q13', 'Var', (199, 215))	('SBRCT', 'Chemical', '-', (63, 68))	('CIC', 'Gene', (0, 3))
354433	28233365	This hypothesis is further supported by a recently identified group of DUX4-rearranged B-cell precursor acute lymphoblastic leukemia, which harbors IGH-DUX4 or less often ERG-DUX4 fusions through insertion of part of DUX4 into the 5' partner gene.	('DUX4', 'Gene', '100288687', (71, 75))	('DUX4', 'Gene', (175, 179))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (110, 132))	('fusions', 'Var', (180, 187))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (110, 132))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (104, 132))	('DUX4', 'Gene', (217, 221))	('DUX4', 'Gene', '100288687', (175, 179))	('DUX4', 'Gene', '100288687', (217, 221))	('insertion', 'Var', (196, 205))	('leukemia', 'Phenotype', 'HP:0001909', (124, 132))	('DUX4', 'Gene', (152, 156))	('DUX4', 'Gene', '100288687', (152, 156))	('lymphoblastic leukemia', 'Disease', (110, 132))	('DUX4', 'Gene', (71, 75))
354434	28233365	The fusions of IGH/ERG-DUX4 were detected in only 7 out of 28 positive cases through their standard RNAseq bioinformatics pipeline and required guided analysis to investigate the regions of interest in the remaining cases.	('DUX4', 'Gene', (23, 27))	('fusions', 'Var', (4, 11))	('DUX4', 'Gene', '100288687', (23, 27))
354440	28233365	An unusual feature of SBRCTs with CIC-DUX4 fusions is the consistent exonic DNA breakpoint for CIC, compared with the prevalent intronic DNA break seen in most other translocation-associated sarcomas.	('CIC', 'Gene', '23152', (95, 98))	('DUX4', 'Gene', (38, 42))	('DUX4', 'Gene', '100288687', (38, 42))	('sarcomas', 'Disease', 'MESH:D012509', (191, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (191, 199))	('CIC', 'Gene', (95, 98))	('fusions', 'Var', (43, 50))	('SBRCT', 'Chemical', '-', (22, 27))	('CIC', 'Gene', '23152', (34, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('sarcomas', 'Disease', (191, 199))	('SBRCTs', 'Disease', (22, 28))	('CIC', 'Gene', (34, 37))
354441	28233365	Likewise, all CIC-FOXO4 and CIC-LEUTX fusions reported to date have exonic DNA breakpoints.	('CIC', 'Gene', (28, 31))	('CIC', 'Gene', (14, 17))	('exonic DNA breakpoints', 'Disease', (68, 90))	('CIC', 'Gene', '23152', (28, 31))	('CIC', 'Gene', '23152', (14, 17))	('fusions', 'Var', (38, 45))
354442	28233365	Another intriguing finding is that in 2 of our cases, the CIC-DUX4 fusion resulted in a stop codon right after the fusion junction (case #6, #7).	('stop codon', 'MPA', (88, 98))	('resulted in', 'Reg', (74, 85))	('DUX4', 'Gene', (62, 66))	('CIC', 'Gene', '23152', (58, 61))	('DUX4', 'Gene', '100288687', (62, 66))	('CIC', 'Gene', (58, 61))	('fusion', 'Var', (67, 73))
354445	28233365	Gambarotti et al described 2 CIC-DUX4 fusion variants with immediate stop codons after the fusion junction.	('CIC', 'Gene', '23152', (29, 32))	('variants', 'Var', (45, 53))	('CIC', 'Gene', (29, 32))	('DUX4', 'Gene', (33, 37))	('DUX4', 'Gene', '100288687', (33, 37))
354446	28233365	Our findings demonstrate that cases with this fusion variant showed similar morphology and downstream effect of PEA3 family up-regulation akin to other CIC-DUX4 fusions variants.	('up-regulation', 'PosReg', (124, 137))	('CIC', 'Gene', '23152', (152, 155))	('PEA3', 'Gene', (112, 116))	('variant', 'Var', (53, 60))	('CIC', 'Gene', (152, 155))	('DUX4', 'Gene', (156, 160))	('DUX4', 'Gene', '100288687', (156, 160))	('PEA3', 'Gene', '2118', (112, 116))
354448	28233365	One hypothesis is that truncation of CIC is sufficient to induce tumorigenesis.	('induce', 'Reg', (58, 64))	('CIC', 'Gene', '23152', (37, 40))	('tumor', 'Disease', (65, 70))	('CIC', 'Gene', (37, 40))	('truncation', 'Var', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
354453	28233365	High ETV1/4/5 expression is also seen in oligodendroglioma with concurrent 1p19q deletion and inactivating mutations of CIC (19q13.2), resulting in biallelic disruption of CIC gene and loss of CIC protein expression by IHC, presumably due to enhanced degradation of mutant CIC protein.	('CIC', 'Gene', '23152', (193, 196))	('loss', 'NegReg', (185, 189))	('CIC', 'Gene', (172, 175))	('oligodendroglioma', 'Disease', 'MESH:D009837', (41, 58))	('CIC', 'Gene', (193, 196))	('deletion', 'Var', (81, 89))	('1p19q', 'Gene', (75, 80))	('disruption', 'Var', (158, 168))	('inactivating mutations', 'Var', (94, 116))	('CIC', 'Gene', '23152', (273, 276))	('CIC', 'Gene', '23152', (120, 123))	('CIC', 'Gene', (273, 276))	('CIC', 'Gene', '23152', (172, 175))	('enhanced', 'PosReg', (242, 250))	('degradation', 'MPA', (251, 262))	('expression', 'MPA', (205, 215))	('oligodendroglioma', 'Disease', (41, 58))	('CIC', 'Gene', (120, 123))
152592	28233365	The exact role in tumorigenesis of DUX4 dysregulation in the setting of CIC-DUX4 fusion remains poorly defined.	('tumor', 'Disease', (18, 23))	('CIC', 'Gene', (72, 75))	('dysregulation', 'Var', (40, 53))	('DUX4', 'Gene', (76, 80))	('DUX4', 'Gene', '100288687', (76, 80))	('DUX4', 'Gene', (35, 39))	('DUX4', 'Gene', '100288687', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('CIC', 'Gene', '23152', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
354457	28233365	DUX4 is normally expressed in testis and epigenetically silenced through CpG methylation in differentiated somatic cells.	('methylation', 'Var', (77, 88))	('DUX4', 'Gene', (0, 4))	('epigenetically silenced', 'Var', (41, 64))	('DUX4', 'Gene', '100288687', (0, 4))
354458	28233365	Aberrant expression of DUX4 in primary human myoblasts activates genes associated with stem cell development.	('DUX4', 'Gene', '100288687', (23, 27))	('Aberrant expression', 'Var', (0, 19))	('genes', 'MPA', (65, 70))	('activates', 'PosReg', (55, 64))	('DUX4', 'Gene', (23, 27))	('human', 'Species', '9606', (39, 44))
354461	28233365	In this study, 7 of 14 SBRCTs showed CIC-DUX4 fusion junction reads or chimeric reads upon manual inspection of RNAseq data.	('CIC', 'Gene', '23152', (37, 40))	('DUX4', 'Gene', (41, 45))	('DUX4', 'Gene', '100288687', (41, 45))	('SBRCT', 'Chemical', '-', (23, 28))	('CIC', 'Gene', (37, 40))	('chimeric reads', 'Var', (71, 85))
354610	30762142	When poorly controlled, CINV can negatively impact the patient's ability to tolerate chemotherapy and can affect their quality of life.	('negatively impact', 'NegReg', (33, 50))	('ability to tolerate chemotherapy', 'CPA', (65, 97))	('CINV', 'Chemical', '-', (24, 28))	('quality of life', 'CPA', (119, 134))	('CINV', 'Var', (24, 28))	('patient', 'Species', '9606', (55, 62))	('affect', 'Reg', (106, 112))
354627	28178285	PSP significantly increased the percentage of CD4+ T lymphocytes, the ratio of CD4+/CD8+/CD14+/CD16_ and the quantity and percentage of the B lymphocytes and finally enhanced the immune system of cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('increased', 'PosReg', (18, 27))	('CD16_', 'Gene', (95, 100))	('CD16_', 'Gene', '2214', (95, 100))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('patients', 'Species', '9606', (203, 211))	('immune system', 'CPA', (179, 192))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('cancer', 'Disease', (196, 202))	('enhanced', 'PosReg', (166, 174))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('PSP', 'Var', (0, 3))	('C', 'Chemical', 'MESH:D002244', (79, 80))
354628	28178285	CVP could induce cell cycle arrest or slowing, apoptosi, and caspase-3 expression.	('expression', 'MPA', (71, 81))	('slowing', 'CPA', (38, 45))	('apoptosi', 'CPA', (47, 55))	('arrest', 'Disease', (28, 34))	('CV', 'Species', '5325', (0, 2))	('caspase-3', 'Gene', '12367', (61, 70))	('caspase-3', 'Gene', (61, 70))	('CVP', 'Var', (0, 3))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (17, 34))	('arrest', 'Disease', 'MESH:D006323', (28, 34))
354631	28178285	CVPs-B can inhibit proliferation and enhance apoptosis of Eca109 cells; inhibit the expression of the osteopontin (OPN) gene; down-regulate glycosaminoglycan (GAG) expression on the surface of macrophages; affect the expression of inflammatory chemotactic factor; and enable the cells proceed rapidly to the resting phase of cell growth.	('CVPs-B', 'Var', (0, 6))	('osteopontin', 'Gene', '6696', (102, 113))	('enable', 'PosReg', (268, 274))	('affect', 'Reg', (206, 212))	('down-regulate', 'NegReg', (126, 139))	('expression', 'MPA', (164, 174))	('glycosaminoglycan', 'MPA', (140, 157))	('expression', 'MPA', (217, 227))	('OPN', 'Gene', '6696', (115, 118))	('CV', 'Species', '5325', (0, 2))	('proliferation', 'CPA', (19, 32))	('OPN', 'Gene', (115, 118))	('inhibit', 'NegReg', (72, 79))	('inhibit', 'NegReg', (11, 18))	('apoptosis', 'CPA', (45, 54))	('osteopontin', 'Gene', (102, 113))	('enhance', 'PosReg', (37, 44))	('expression', 'MPA', (84, 94))
354646	28178285	The carbohydrate composition of CVG analyzed consists of D-Fuc, D-Ara,D-Man, D-Gal and D-Glc, with a molar ratio of 1.0/1.1/3.0/3.9/ 350.7 respectively (Fig 1).	('carbohydrate', 'Chemical', 'MESH:D002241', (4, 16))	('D-Ara', 'Var', (64, 69))	('D-Man', 'Var', (70, 75))	('D-Glc', 'Chemical', 'MESH:D005947', (87, 92))	('D-Ara', 'Chemical', '-', (64, 69))	('D-Gal', 'Chemical', '-', (77, 82))	('D-Glc', 'Var', (87, 92))	('D-Fuc', 'Var', (57, 62))	('D-Fuc', 'Chemical', '-', (57, 62))	('CV', 'Species', '5325', (32, 34))	('D-Gal', 'Var', (77, 82))
354667	28178285	The growth inhibition of S-180 cells achieved about 95% at CVG 20mg/ml; and might be attributed to its high molecular weight as reported previously.	('CV', 'Species', '5325', (59, 61))	('growth', 'MPA', (4, 10))	('CVG 20mg/ml', 'Var', (59, 70))
354668	28178285	The results indicate a significant antitumor effect of CVG (Fig 4) compared with the control group (P< 0.01).	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CVG', 'Var', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('CV', 'Species', '5325', (55, 57))
354670	28178285	Also, CVG increased the thymus and spleen index in tumor- bearing mice (S2 Table).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CVG', 'Var', (6, 9))	('tumor', 'Disease', (51, 56))	('mice', 'Species', '10090', (66, 70))	('CV', 'Species', '5325', (6, 8))	('increased the thymus', 'Phenotype', 'HP:0010516', (10, 30))	('increased', 'PosReg', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
354673	28178285	Specifically, Cyclophosphamide decreases the organism leukocytes and deteriorates the immune functions.	('Cyclophosphamide', 'Var', (14, 30))	('decreases', 'NegReg', (31, 40))	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (14, 30))	('deteriorates', 'NegReg', (69, 81))	('immune functions', 'CPA', (86, 102))	('organism leukocytes', 'MPA', (45, 64))
354679	28178285	The phagocytosis of macrophages was significantly decreased by CVG compared with the model control (Fig 6); but slightly higher compared with the normal and positive groups.	('CVG', 'Var', (63, 66))	('CV', 'Species', '5325', (63, 65))	('decreased', 'NegReg', (50, 59))	('phagocytosis of macrophages', 'CPA', (4, 31))	('higher', 'PosReg', (121, 127))
354696	28178285	Also, CVG glucan significantly increased the white blood cell count in the tumor-bearing mice leading to engulfment and growth suppression of S-180 cells, thereby contributing to the immunity.	('engulfment', 'CPA', (105, 115))	('growth suppression', 'CPA', (120, 138))	('increased', 'PosReg', (31, 40))	('CVG', 'Var', (6, 9))	('mice', 'Species', '10090', (89, 93))	('contributing', 'Reg', (163, 175))	('white blood cell count', 'MPA', (45, 67))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('increased the white blood cell count', 'Phenotype', 'HP:0001974', (31, 67))	('glucan', 'Chemical', 'MESH:D005936', (10, 16))	('CV', 'Species', '5325', (6, 8))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
354699	28178285	Thymus, spleen, T-Cells, B-Cells, and white blood cells can play an important role to an inactivation the oncogene, which lead to tumor regression both through a direct effect on tumor cells as well as by recruiting immune effectors that can remodel the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('tumor', 'Disease', (254, 259))	('inactivation', 'Var', (89, 101))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('oncogene', 'Gene', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('tumor', 'Disease', (179, 184))
354791	26629326	Histology was reviewed within the French Sarcoma Network (Reseau de Reference en Pathologie des Sarcomes, RRePS) and the diagnosis of mammary DT was retained, confirmed by the evidence of beta-catenin exon 3 T41A mutation.	('DT', 'Phenotype', 'HP:0100245', (142, 144))	('Sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('T41A mutation', 'Var', (208, 221))	('mammary DT', 'Disease', (134, 144))	('T41A', 'Mutation', 'rs121913412', (208, 212))	('Sarcoma', 'Disease', (41, 48))	('Sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('beta-catenin', 'Gene', (188, 200))	('beta-catenin', 'Gene', '1499', (188, 200))
354848	25615615	Myc, a master regulator of metabolism, is commonly overexpressed in both of these pediatric malignancies and recent studies have established that Myc causes cancer cells to become "addicted" to glutamine.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('malignancies', 'Disease', (92, 104))	('Myc', 'Var', (146, 149))	('overexpressed', 'PosReg', (51, 64))	('glutamine', 'Chemical', 'MESH:D005973', (194, 203))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('malignancies', 'Disease', 'MESH:D009369', (92, 104))
354857	25615615	Targeting aberrant cancer metabolism including acquisition of aerobic glycolysis (Warburg effect), alteration of lipid synthesis, and addiction to glutamine offers a potentially exploitable "Achilles' Heel" for treating NBL and EWS.	('NBL', 'Disease', (220, 223))	('glutamine', 'Chemical', 'MESH:D005973', (147, 156))	('lipid', 'Chemical', 'MESH:D008055', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('EWS', 'Phenotype', 'HP:0012254', (228, 231))	('EWS', 'Gene', '2130', (228, 231))	('cancer', 'Disease', (19, 25))	('EWS', 'Gene', (228, 231))	('lipid synthesis', 'MPA', (113, 128))	('acquisition', 'PosReg', (47, 58))	('N', 'Chemical', 'MESH:D009584', (220, 221))	('alteration', 'Reg', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('NBL', 'Phenotype', 'HP:0003006', (220, 223))	('aerobic glycolysis', 'MPA', (62, 80))	('addiction', 'Var', (134, 143))
354865	25615615	Amplification of MYCN, a c-Myc family member, is associated with both poor prognosis and high-risk disease in NBL.	('MYCN', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('MYCN', 'Gene', '4613', (17, 21))	('NBL', 'Disease', (110, 113))	('c-Myc', 'Gene', (25, 30))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('NBL', 'Phenotype', 'HP:0003006', (110, 113))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('c-Myc', 'Gene', '4609', (25, 30))
354873	25615615	In the pediatric study, all six solid tumor patients that received a >300 mg/m2 twice-weekly dose of DON showed improvements.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('patients', 'Species', '9606', (44, 52))	('DON', 'Chemical', 'MESH:D003980', (101, 104))	('improvements', 'PosReg', (112, 124))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('>300 mg/m2', 'Var', (69, 79))
354886	25615615	The following metabolic inhibitors were obtained from Sigma-Aldrich and solubilized in water: 6-diazo-5-oxo-L-norleucine (DON, #D2141), Oxamate (#O2751), Bromopyruvate (#16490) Dichloroacetate (#347795), Etomoxir (#E1905), and Trimetazidine (#653322).	('Etomoxir', 'Chemical', 'MESH:C054207', (204, 212))	('#O2751', 'Var', (145, 151))	('water', 'Chemical', 'MESH:D014867', (87, 92))	('D2141', 'Chemical', '-', (128, 133))	('#16490', 'Var', (169, 175))	('Bromopyruvate', 'Chemical', 'MESH:C017092', (154, 167))	('#E1905', 'Var', (214, 220))	('Dichloroacetate', 'Chemical', 'MESH:D003999', (177, 192))	('#653322', 'Var', (242, 249))	('Trimetazidine', 'Chemical', 'MESH:D014292', (227, 240))	('Oxamate', 'Chemical', 'MESH:D010072', (136, 143))	('DON', 'Chemical', 'MESH:D003980', (122, 125))	('#347795', 'Var', (194, 201))	('6-diazo-5-oxo-L-norleucine', 'Chemical', 'MESH:D003980', (94, 120))
354911	25615615	Paraffin-embedded tissue sections were then stained for BrdU incorporation and cleaved caspase 3 by the St. Jude Veterinary Pathology Core.	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('caspase 3', 'Gene', (87, 96))	('caspase 3', 'Gene', '836', (87, 96))	('cleaved', 'Var', (79, 86))	('BrdU incorporation', 'MPA', (56, 74))	('BrdU', 'Chemical', 'MESH:D001973', (56, 60))
354925	25615615	shRNAmiR plasmid sets for knockdown of human Bax (TRHS1000-581) and Bak (TRHS1000-578) were purchased from TransOmic, along with Non-Targeting shRNA-miR negative control.	('miR', 'Gene', '220972', (5, 8))	('miR', 'Gene', (5, 8))	('Bax', 'Gene', '581', (45, 48))	('human', 'Species', '9606', (39, 44))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('miR', 'Gene', '220972', (149, 152))	('Bak', 'Gene', (68, 71))	('miR', 'Gene', (149, 152))	('Bak', 'Gene', '578', (68, 71))	('Bax', 'Gene', (45, 48))	('TRHS1000-578', 'Var', (73, 85))	('TRHS1000-581', 'Var', (50, 62))	('N', 'Chemical', 'MESH:D009584', (146, 147))
354955	25615615	We used subcutaneous tumors from the most DON-resistant cell line, SK-N-FI, reasoning that any treatment schedule that showed efficacy against SK-N-FI would likely show efficacy against the other cell lines.	('SK-N-FI', 'Chemical', '-', (67, 74))	('DON', 'Chemical', 'MESH:D003980', (42, 45))	('SK-N-FI', 'Var', (143, 150))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (8, 26))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('SK-N-FI', 'Chemical', '-', (143, 150))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (8, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
354976	25615615	Prior studies suggest that interfering with glutamine utilization in nucleotide synthesis causes a Myc-independent loss in proliferation, while blocking glutaminolysis increases apoptosis in Myc overexpressing cell lines.	('proliferation', 'CPA', (123, 136))	('glutamine utilization', 'MPA', (44, 65))	('loss', 'NegReg', (115, 119))	('glutaminolysis', 'MPA', (153, 167))	('interfering', 'Var', (27, 38))	('apoptosis', 'CPA', (178, 187))	('glutamine', 'Chemical', 'MESH:D005973', (44, 53))	('blocking', 'NegReg', (144, 152))
355002	25615615	Similar to our in vivo results, our in vitro QVD data show Myc expression sensitizes cells to DON-induced apoptosis.	('sensitizes', 'Reg', (74, 84))	('Myc', 'Gene', (59, 62))	('expression', 'Var', (63, 73))	('DON', 'Chemical', 'MESH:D003980', (94, 97))
355005	25615615	Interference with glutamine metabolism is known to cause cellular stress that leads to apoptosis with a recent publication demonstrating that glutamine deprivation in neuroblastoma cell lines leads to cell death via Bax but not Bak.	('glutamine', 'Chemical', 'MESH:D005973', (142, 151))	('Bax', 'Gene', '581', (216, 219))	('Bak', 'Gene', (228, 231))	('neuroblastoma', 'Disease', 'MESH:D009447', (167, 180))	('Bak', 'Gene', '578', (228, 231))	('glutamine', 'MPA', (142, 151))	('neuroblastoma', 'Disease', (167, 180))	('neuroblastoma', 'Phenotype', 'HP:0003006', (167, 180))	('Interference', 'Var', (0, 12))	('Bax', 'Gene', (216, 219))	('glutamine', 'Chemical', 'MESH:D005973', (18, 27))	('cell death', 'CPA', (201, 211))	('leads', 'Reg', (78, 83))
355008	25615615	In contrast, significant knockdown of Bak with three individual shRNAs (#1-#3) was unable to rescue cells from DON (Fig.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('Bak', 'Gene', '578', (38, 41))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('DON', 'Chemical', 'MESH:D003980', (111, 114))	('Bak', 'Gene', (38, 41))	('knockdown', 'Var', (25, 34))
355042	25615615	Recent studies have established that Myc oncogenes create a reliance on glutamine and have suggested interfering with glutamine utilization as a therapy for Myc-overexpressing cancers.	('glutamine', 'Chemical', 'MESH:D005973', (72, 81))	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('glutamine', 'Chemical', 'MESH:D005973', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('glutamine', 'MPA', (72, 81))	('interfering', 'Var', (101, 112))	('reliance', 'MPA', (60, 68))
355063	22587772	Efficacy of first-line doxorubicin and ifosfamide in myxoid liposarcoma Myxoid liposarcoma (MLS) is a soft tissue sarcoma with adipocytic differentiation characterized by a unique chromosome rearrangement, t(12;16)(q13;p11).	('MLS', 'Disease', 'MESH:C537466', (92, 95))	('MLS', 'Disease', (92, 95))	('liposarcoma', 'Phenotype', 'HP:0012034', (79, 90))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (53, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (206, 223))	('liposarcoma', 'Phenotype', 'HP:0012034', (60, 71))	('ifosfamide', 'Chemical', 'MESH:D007069', (39, 49))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('Myxoid liposarcoma', 'Disease', (72, 90))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('sarcoma', 'Disease', (83, 90))	('sarcoma', 'Disease', (114, 121))	('doxorubicin', 'Chemical', 'MESH:D004317', (23, 34))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (102, 121))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (53, 71))	('t(12;16)(q13;p11', 'Var', (206, 222))	('Myxoid liposarcoma', 'Disease', 'MESH:D018208', (72, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('myxoid liposarcoma', 'Disease', (53, 71))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Disease', (64, 71))
355071	22587772	Approximately half of these tumors are further sub-classified as myxoid/round cell liposarcomas (MLSs) based on a multinodular gelatinous appearance and a unique chromosome rearrangement, t(12;16)(q13;p11), involving the DDIT3 and FUS genes, respectively.	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (188, 205))	('liposarcomas', 'Disease', 'MESH:D008080', (83, 95))	('FUS', 'Gene', (231, 234))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('liposarcomas', 'Phenotype', 'HP:0012034', (83, 95))	('myxoid/round cell liposarcomas', 'Phenotype', 'HP:0012268', (65, 95))	('MLSs', 'Phenotype', 'HP:0012268', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('liposarcoma', 'Phenotype', 'HP:0012034', (83, 94))	('MLSs', 'Chemical', '-', (97, 101))	('tumors', 'Disease', (28, 34))	('FUS', 'Gene', '2521', (231, 234))	('DDIT3', 'Gene', '1649', (221, 226))	('liposarcomas', 'Disease', (83, 95))	('DDIT3', 'Gene', (221, 226))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('t(12;16)(q13;p11', 'Var', (188, 204))
355221	22435068	A noticeably lowered yield of progeny virions was obtained from ORF45-null recombinant mutant virus reconstituted cells as compared to that obtained from cells reconstituted with the wild-type virus though viral gene expression and viral DNA replication remained unaffected in the absence of ORF45 (Zhu et al.,).	('ORF45', 'Gene', '4961474', (64, 69))	('ORF45', 'Gene', (64, 69))	('ORF45', 'Gene', '4961474', (292, 297))	('lowered', 'NegReg', (13, 20))	('ORF45', 'Gene', (292, 297))	('mutant', 'Var', (87, 93))
355224	22435068	Inhibition of KIF3A-ORF45 interaction with a headless dominant negative (DN) mutant of KIF3A or by an shRNA-mediated silencing of endogenous KIF3A expression decreased KSHV particle release noticeably.	('ORF45', 'Gene', '4961474', (20, 25))	('KIF3A', 'Gene', (14, 19))	('KIF3A', 'Gene', (87, 92))	('decreased', 'NegReg', (158, 167))	('KIF3A', 'Gene', (141, 146))	('KSHV', 'Species', '37296', (168, 172))	('KIF3A', 'Gene', '11127', (14, 19))	('KIF3A', 'Gene', '11127', (141, 146))	('KIF3A', 'Gene', '11127', (87, 92))	('KS', 'Phenotype', 'HP:0100726', (168, 170))	('ORF45', 'Gene', (20, 25))	('KSHV particle release', 'MPA', (168, 189))	('interaction', 'Interaction', (26, 37))	('mutant', 'Var', (77, 83))	('silencing', 'NegReg', (117, 126))
355233	22435068	Analysis of these partially tegumented capsids revealed the presence of capsid proteins and tegument proteins such as ORF64 and ORF67 but the absence of other tegument proteins such as ORF45 and ORF42 (Bortz et al.,).	('men', 'Species', '9606', (96, 99))	('ORF45', 'Gene', '4961474', (185, 190))	('ORF64', 'Gene', '4961441', (118, 123))	('men', 'Species', '9606', (163, 166))	('ORF45', 'Gene', (185, 190))	('men', 'Species', '9606', (32, 35))	('ORF64', 'Gene', (118, 123))	('ORF67', 'Var', (128, 133))
355235	22435068	Failure of an ORF52 mutant (lacking the N-terminal alpha-helix) in compensating defective virion production seen with a MHV-68 ORF52-null mutant virus clearly demonstrated the necessity of the interactions between ORF52 and other tegument proteins (Benach et al.,).	('ORF52', 'Gene', '4961496', (14, 19))	('ORF52', 'Gene', (14, 19))	('ORF52', 'Gene', '4961496', (127, 132))	('ORF52', 'Gene', (127, 132))	('mutant', 'Var', (138, 144))	('MHV-68', 'Gene', (120, 126))	('MHV-68', 'Species', '1440122', (120, 126))	('ORF52', 'Gene', '4961496', (214, 219))	('interactions', 'Interaction', (193, 205))	('ORF52', 'Gene', (214, 219))	('mutant', 'Var', (20, 26))	('men', 'Species', '9606', (234, 237))
355294	22435068	In addition, a lentiviral mediated ectopic expression of ORF45 in human fibroblast cells diminished the host cell elicited type I IFN anti-viral responses (Zhu et al.,).	('ORF45', 'Gene', (57, 62))	('IFN', 'Gene', '3439', (130, 133))	('diminished', 'NegReg', (89, 99))	('human', 'Species', '9606', (66, 71))	('IFN', 'Gene', (130, 133))	('ORF45', 'Gene', '4961474', (57, 62))	('ectopic expression', 'Var', (35, 53))
355303	22435068	The critical role of NLRP1 in combating KSHV was evidenced by the fact that knockdown of NLRP1 expression in BCBL-1 cells resulted in increased KSHV genomic DNA replication and infectious virion titers subsequent to lytic reactivation.	('NLRP1', 'Gene', (21, 26))	('knockdown', 'Var', (76, 85))	('KSHV', 'Gene', (144, 148))	('BCBL-1', 'CellLine', 'CVCL:0165', (109, 115))	('NLRP1', 'Gene', '22861', (89, 94))	('KSHV', 'Species', '37296', (40, 44))	('NLRP1', 'Gene', (89, 94))	('infectious virion titers', 'CPA', (177, 201))	('increased', 'PosReg', (134, 143))	('NLRP1', 'Gene', '22861', (21, 26))	('KS', 'Phenotype', 'HP:0100726', (40, 42))	('KS', 'Phenotype', 'HP:0100726', (144, 146))	('KSHV', 'Species', '37296', (144, 148))
355304	22435068	Conversely, an siRNA-mediated knockdown of ORF63 resulted in reduced KSHV lytic gene expression and virion production along with significantly increased expression levels of IL-1beta (Gregory et al.,).	('expression', 'MPA', (85, 95))	('KSHV lytic gene', 'Gene', (69, 84))	('increased', 'PosReg', (143, 152))	('KSHV', 'Species', '37296', (69, 73))	('IL-1beta', 'Gene', (174, 182))	('virion production', 'CPA', (100, 117))	('KS', 'Phenotype', 'HP:0100726', (69, 71))	('expression levels', 'MPA', (153, 170))	('ORF63', 'Gene', '4961466', (43, 48))	('IL-1beta', 'Gene', '3553', (174, 182))	('knockdown', 'Var', (30, 39))	('reduced', 'NegReg', (61, 68))	('ORF63', 'Gene', (43, 48))
355310	22435068	Among the K48- and K63-linked Ub chains commonly targeted by DUBs, KSHV ORF64 has no distinct specificity to either of them and was capable of targeting both (Gonzalez et al.,).	('ORF64', 'Gene', (72, 77))	('K48-', 'Var', (10, 14))	('targeting', 'Reg', (143, 152))	('KS', 'Phenotype', 'HP:0100726', (67, 69))	('KSHV', 'Species', '37296', (67, 71))	('K63-linked', 'Var', (19, 29))	('ORF64', 'Gene', '4961441', (72, 77))
355312	22435068	An siRNA-mediated knockdown of ORF64 resulted in decreased reactivation of KSHV from latency accompanied with decreased levels of viral lytic replication, suggesting a possible role of ORF64 in influencing the KSHV lytic cycle through its deubiquitination function (Gonzalez et al.,).	('knockdown', 'Var', (18, 27))	('deubiquitination function', 'MPA', (239, 264))	('levels of viral lytic replication', 'MPA', (120, 153))	('KSHV', 'Species', '37296', (210, 214))	('KSHV', 'Gene', (75, 79))	('ORF64', 'Gene', (31, 36))	('KS', 'Phenotype', 'HP:0100726', (210, 212))	('lytic cycle', 'CPA', (215, 226))	('decreased', 'NegReg', (110, 119))	('decreased', 'NegReg', (49, 58))	('ORF64', 'Gene', '4961441', (185, 190))	('influencing', 'Reg', (194, 205))	('KS', 'Phenotype', 'HP:0100726', (75, 77))	('KSHV', 'Species', '37296', (75, 79))	('ORF64', 'Gene', '4961441', (31, 36))	('ORF64', 'Gene', (185, 190))	('reactivation', 'MPA', (59, 71))
355315	22435068	A persistent presence of KSHV was noticed in RIG-1 deficient cells indicating an important role of this protein in influencing the outcome of primary KSHV infection.	('KSHV', 'Species', '37296', (150, 154))	('RIG-1', 'Gene', (45, 50))	('KSHV', 'Species', '37296', (25, 29))	('primary KSHV infection', 'Disease', (142, 164))	('KS', 'Phenotype', 'HP:0100726', (25, 27))	('primary KSHV infection', 'Disease', 'MESH:C537372', (142, 164))	('deficient', 'Var', (51, 60))	('KS', 'Phenotype', 'HP:0100726', (150, 152))	('RIG-1', 'Gene', '5920', (45, 50))
355328	22435068	Similar to EBV BNRF1, the pp71 tegument protein of HCMV also interacts with Daxx.	('HCMV', 'Species', '10359', (51, 55))	('men', 'Species', '9606', (35, 38))	('interacts', 'Interaction', (61, 70))	('Daxx', 'Gene', (76, 80))	('BNRF1', 'Gene', '3783722', (15, 20))	('Daxx', 'Gene', '1616', (76, 80))	('BNRF1', 'Gene', (15, 20))	('pp71', 'Var', (26, 30))	('EBV', 'Species', '10376', (11, 14))
355329	22435068	Unlike the BNRF1, pp71 induces the degradation of Daxx subsequent to displacement of ATRX (Lukashchuk et al.,).	('BNRF1', 'Gene', (11, 16))	('degradation', 'MPA', (35, 46))	('ATRX', 'Gene', (85, 89))	('pp71', 'Var', (18, 22))	('displacement', 'MPA', (69, 81))	('Daxx', 'Gene', (50, 54))	('men', 'Species', '9606', (77, 80))	('ATRX', 'Gene', '546', (85, 89))	('Daxx', 'Gene', '1616', (50, 54))	('BNRF1', 'Gene', '3783722', (11, 16))
355330	22435068	Furthermore, HSV-1 ICP0 mediates a proteasomal degradation of PML (Maul et al.,; Everett et al.,; Boutell et al.,).	('ICP0', 'Var', (19, 23))	('PML', 'Gene', '5371', (62, 65))	('proteasomal degradation', 'MPA', (35, 58))	('HSV-1', 'Gene', (13, 18))	('HSV-1', 'Species', '10298', (13, 18))	('PML', 'Gene', (62, 65))
355338	22435068	On the other hand, inhibition of NF-kappaB activity in latently infected cells facilitates KSHV lytic protein synthesis reflective of viral reactivation (Grossmann and Ganem,).	('KSHV lytic protein synthesis', 'MPA', (91, 119))	('NF-kappaB', 'Gene', (33, 42))	('inhibition', 'Var', (19, 29))	('facilitates', 'PosReg', (79, 90))	('activity', 'MPA', (43, 51))	('KS', 'Phenotype', 'HP:0100726', (91, 93))	('NF-kappaB', 'Gene', '4790', (33, 42))	('KSHV', 'Species', '37296', (91, 95))
355346	22435068	A dramatic reduction in lytic gene expression and virion titers following lytic reactivation was seen in the cells exhibiting siRNA-mediated RSK knockdown, suggesting a role of these RSKs in pathways subsequent to KSHV lytic reactivation (Kuang et al.,).	('reduction', 'NegReg', (11, 20))	('knockdown', 'Var', (145, 154))	('virion titers', 'CPA', (50, 63))	('RSK', 'Gene', '6197', (183, 186))	('RSK', 'Gene', (141, 144))	('RSK', 'Gene', (183, 186))	('KS', 'Phenotype', 'HP:0100726', (214, 216))	('KSHV', 'Species', '37296', (214, 218))	('lytic gene', 'Gene', (24, 34))	('RSK', 'Gene', '6197', (141, 144))
355348	22435068	ORF45-null mutant virus exhibited noticeably reduced activation of ERK/RSK in the cells infected in comparison to the levels with wild-type viral infection, indicating a role of ORF45 in the ERK/RSK activation (Kuang et al.,).	('ERK', 'Gene', '5594', (191, 194))	('mutant', 'Var', (11, 17))	('RSK', 'Gene', (195, 198))	('reduced', 'NegReg', (45, 52))	('viral infection', 'Disease', (140, 155))	('ERK', 'Gene', (67, 70))	('activation', 'PosReg', (53, 63))	('ORF45', 'Gene', '4961474', (178, 183))	('ORF45', 'Gene', (178, 183))	('ORF45', 'Gene', (0, 5))	('ERK', 'Gene', (191, 194))	('RSK', 'Gene', '6197', (71, 74))	('ERK', 'Gene', '5594', (67, 70))	('RSK', 'Gene', (71, 74))	('viral infection', 'Disease', 'MESH:D001102', (140, 155))	('RSK', 'Gene', '6197', (195, 198))	('ORF45', 'Gene', '4961474', (0, 5))
355361	22435068	Pharmacological inhibition of Hsp90 or its knockdown by siRNA has been shown to inhibit replication of several RNA viruses such as HCV and VSV (Connor et al.,; Nakagawa et al.,), indicating the significance of virus associated cellular proteins.	('HCV', 'Disease', (131, 134))	('replication', 'MPA', (88, 99))	('inhibit', 'NegReg', (80, 87))	('RNA', 'Disease', (111, 114))	('VSV', 'Disease', (139, 142))	('knockdown', 'Var', (43, 52))	('VSV', 'Species', '11276', (139, 142))	('Hsp90', 'Gene', '111042', (30, 35))	('Hsp90', 'Gene', (30, 35))
355425	29147265	The EFT with typical EWS gene rearrangements exhibit CD99/MIC2 expression; however, the histogenetic origin of EFT is not clear.	('MIC2', 'Gene', (58, 62))	('exhibit', 'Reg', (45, 52))	('CD99', 'Gene', (53, 57))	('MIC2', 'Gene', '4267', (58, 62))	('CD99', 'Gene', '4267', (53, 57))	('EWS', 'Gene', '2130', (21, 24))	('EWS', 'Gene', (21, 24))	('rearrangements', 'Var', (30, 44))
355426	29147265	The rate-limiting EWS rearrangement by random fusion with Fli1 or other Ets transcription factor genes is likely to occur in a bone-associated CD99/MIC2-positive normal cell type.	('Fli1', 'Gene', (58, 62))	('EWS', 'Gene', (18, 21))	('MIC2', 'Gene', (148, 152))	('EWS', 'Gene', '2130', (18, 21))	('CD99', 'Gene', (143, 147))	('CD99', 'Gene', '4267', (143, 147))	('MIC2', 'Gene', '4267', (148, 152))	('Fli1', 'Gene', '2313', (58, 62))	('rearrangement', 'Var', (22, 35))
355460	29147265	Classical ES and PNET possessing variable degrees of differentiation are now known to be the same tumor type, defined by a translocation between the EWS gene on chromosome 22 with one of three ETS-like genes, especially the Fli1 gene on chromosome 11.	('translocation', 'Var', (123, 136))	('EWS', 'Gene', (149, 152))	('EWS', 'Gene', '2130', (149, 152))	('ES', 'Phenotype', 'HP:0012254', (10, 12))	('Classical ES', 'Disease', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Fli1', 'Gene', '2313', (224, 228))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PNET', 'Disease', (17, 21))	('tumor', 'Disease', (98, 103))	('Fli1', 'Gene', (224, 228))	('PNET', 'Phenotype', 'HP:0030065', (17, 21))
355475	29147265	EWS-Fli1 is important for the maintenance of tumor growth and thus, antisense modulation of this fusion protein effects decreased growth.	('decreased', 'NegReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('growth', 'MPA', (130, 136))	('tumor', 'Disease', (45, 50))	('antisense modulation', 'Var', (68, 88))	('Fli1', 'Gene', '2313', (4, 8))	('decreased growth', 'Phenotype', 'HP:0001510', (120, 136))	('Fli1', 'Gene', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
355477	29147265	The lineage of the cell developing the EWS/Fli1 gene fusion has not been fully characterized but is generally considered to be of either mesenchymal or neural crest origin.	('Fli1', 'Gene', '2313', (43, 47))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	('Fli1', 'Gene', (43, 47))	('fusion', 'Var', (53, 59))
355479	29147265	Moreover, ES cell lines can differentiate along the osteogenic or adipogenic lineage upon EWS-Fli1 silencing, when incubated in appropriate differentiation media.	('EWS', 'Gene', (90, 93))	('ES', 'Phenotype', 'HP:0012254', (10, 12))	('adipogenic lineage', 'CPA', (66, 84))	('Fli1', 'Gene', (94, 98))	('EWS', 'Gene', '2130', (90, 93))	('Fli1', 'Gene', '2313', (94, 98))	('silencing', 'Var', (99, 108))	('osteogenic', 'CPA', (52, 62))	('differentiate', 'Reg', (28, 41))
355498	29147265	Disrupting interactions between Runx2 and EWS-Fli1 may promote differentiation of the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('interactions', 'Interaction', (11, 23))	('Fli1', 'Gene', (46, 50))	('Disrupting', 'Var', (0, 10))	('Runx2', 'Gene', (32, 37))	('promote', 'PosReg', (55, 62))	('Runx2', 'Gene', '860', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('Fli1', 'Gene', '2313', (46, 50))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
355500	29147265	Tirode and colleagues showed that the profile of ES lines converge to that of normal mesenchymal stem cells after EWS-Fli1 abrogation.	('Fli1', 'Gene', '2313', (118, 122))	('EWS', 'Gene', '2130', (114, 117))	('EWS', 'Gene', (114, 117))	('ES', 'Phenotype', 'HP:0012254', (49, 51))	('Fli1', 'Gene', (118, 122))	('abrogation', 'Var', (123, 133))
355522	28032089	Univariate analysis showed that a larger tumor size, axial primary, high LDH was associated with poorer RFS and OS.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('RFS', 'CPA', (104, 107))	('high', 'Var', (68, 72))	('tumor', 'Disease', (41, 46))	('LDH', 'Gene', (73, 76))	('poorer', 'NegReg', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
355527	23906982	We show that loss of HIF1alpha or PLOD2 expression disrupts collagen modification, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSLKrasG12D/+; Trp53fl/fl murine sarcoma models.	('murine', 'Species', '10090', (211, 217))	('pulmonary metastasis', 'Disease', (102, 122))	('expression', 'Species', '29278', (40, 50))	('Kras', 'Gene', (188, 192))	('cell migration', 'CPA', (83, 97))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (102, 122))	('HIF1alpha', 'Gene', (21, 30))	('sarcoma', 'Disease', 'MESH:D012509', (218, 225))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('disrupts', 'NegReg', (51, 59))	('Kras', 'Gene', '3845', (188, 192))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('sarcoma', 'Disease', (218, 225))	('collagen modification', 'MPA', (60, 81))	('loss', 'Var', (13, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('PLOD2', 'Gene', (34, 39))	('tumor', 'Disease', (140, 145))
355528	23906982	Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1alpha-deficient tumors, and analysis of human sarcomas reveal elevated HIF1alpha and PLOD2 expression in metastatic primary lesions.	('expression', 'Species', '29278', (180, 190))	('expression', 'Species', '29278', (27, 37))	('sarcomas', 'Disease', 'MESH:D012509', (135, 143))	('HIF1alpha-deficient tumors', 'Disease', 'MESH:D009369', (85, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('HIF1alpha-deficient tumors', 'Disease', (85, 111))	('migration', 'CPA', (47, 56))	('PLOD2', 'Var', (21, 26))	('ectopic PLOD2', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('elevated', 'PosReg', (151, 159))	('restores', 'PosReg', (38, 46))	('HIF1alpha', 'Gene', (160, 169))	('sarcomas', 'Disease', (135, 143))	('human', 'Species', '9606', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
355545	23906982	One mouse model for investigating UPS employs simultaneous Cre-dependent expression of oncogenic KrasG12D and deletion of p53 in the left gastrocnemius muscle.	('mouse', 'Species', '10090', (4, 9))	('Kras', 'Gene', '3845', (97, 101))	('expression', 'Species', '29278', (73, 83))	('deletion', 'Var', (110, 118))	('Kras', 'Gene', (97, 101))	('p53', 'Gene', (122, 125))
355561	23906982	Mutations in PLOD2 cause the autosomal recessive disorder, Bruck syndrome, in which patients suffer osteoporosis, scoliosis, and joint contractures due to underhydroxylated collagen I; however, very little is known about the role of PLOD2 in tumorigenesis.	('scoliosis', 'Phenotype', 'HP:0002650', (114, 123))	('osteoporosis', 'Disease', (100, 112))	('osteoporosis', 'Phenotype', 'HP:0000939', (100, 112))	('tumor', 'Disease', (242, 247))	('joint contractures', 'Disease', (129, 147))	('scoliosis', 'Disease', 'MESH:D012600', (114, 123))	('osteoporosis', 'Disease', 'MESH:D010024', (100, 112))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('Mutations', 'Var', (0, 9))	('joint contractures', 'Disease', 'MESH:D003286', (129, 147))	('PLOD2', 'Gene', (13, 18))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (29, 57))	('autosomal recessive disorder', 'Disease', (29, 57))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('Bruck syndrome', 'Disease', (59, 73))	('joint contractures', 'Phenotype', 'HP:0001371', (129, 147))	('scoliosis', 'Disease', (114, 123))	('cause', 'Reg', (19, 24))	('Bruck syndrome', 'Disease', 'MESH:C537406', (59, 73))	('underhydroxylated collagen I', 'MPA', (155, 183))
355569	23906982	Specifically, whereas HIF1alpha-driven LOX and PLOD2 expression have been shown to modify the premetastatic niche in breast cancers, PLOD2, but not LOX, modifies the collagen network in primary sarcomas, with consequent effects on tumor cell migration and metastasis.	('primary sarcomas', 'Disease', 'MESH:D012509', (186, 202))	('breast cancers', 'Phenotype', 'HP:0003002', (117, 131))	('modifies', 'Reg', (153, 161))	('collagen network', 'CPA', (166, 182))	('expression', 'Species', '29278', (53, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('PLOD2', 'Var', (133, 138))	('tumor', 'Disease', (231, 236))	('effects', 'Reg', (220, 227))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('primary sarcomas', 'Disease', (186, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('modify', 'Reg', (83, 89))	('premetastatic niche', 'CPA', (94, 113))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('breast cancers', 'Disease', 'MESH:D001943', (117, 131))	('breast cancers', 'Disease', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('metastasis', 'CPA', (256, 266))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))
355577	23906982	In this model, injection of Adenovirus expressing Cre recombinase (Adeno-Cre) into the left gastrocnemius muscle results in KrasG12D expression and Trp53 deletion, producing sarcomas within approximately 8 weeks.	('expression', 'MPA', (133, 143))	('sarcomas', 'Disease', (174, 182))	('Trp53', 'Gene', (148, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('producing', 'Reg', (164, 173))	('deletion', 'Var', (154, 162))	('Kras', 'Gene', (124, 128))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('expression', 'Species', '29278', (133, 143))	('Kras', 'Gene', '3845', (124, 128))
355580	23906982	KP and KPH animals developed tumors of similar size and latency indicating that loss of HIF1alpha did not alter primary tumor formation (Fig.1C) or growth (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('loss', 'Var', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (29, 35))	('tumor', 'Disease', (120, 125))	('HIF1alpha', 'Gene', (88, 97))
355581	23906982	However, HIF1alpha deletion dramatically reduced the occurrence of pulmonary metastasis in this model, indicating that HIF1alpha specifically modulates tumor cell dissemination in sarcomas (Fig.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('reduced', 'NegReg', (41, 48))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (67, 87))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('modulates', 'Reg', (142, 151))	('deletion', 'Var', (19, 27))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('tumor', 'Disease', (152, 157))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('pulmonary metastasis', 'Disease', (67, 87))	('sarcomas', 'Disease', (180, 188))	('HIF1alpha', 'Gene', (9, 18))
355582	23906982	Analysis of primary sarcomas by Masson's Trichrome staining of KP and KPH tumors revealed that HIF1alpha deletion significantly alters deposited collagen (Fig.	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))	('HIF1alpha', 'Gene', (95, 104))	('deletion', 'Var', (105, 113))	('KPH tumors', 'Disease', (70, 80))	('deposited collagen', 'MPA', (135, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('primary sarcomas', 'Disease', (12, 28))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('KPH tumors', 'Disease', 'MESH:D009369', (70, 80))	('alters', 'Reg', (128, 134))	('primary sarcomas', 'Disease', 'MESH:D012509', (12, 28))
355586	23906982	Picrosirius red staining revealed that HIF1alpha deletion has an unexpected effect on collagen organization (Fig.	('HIF1alpha', 'Gene', (39, 48))	('effect', 'Reg', (76, 82))	('Picrosirius red', 'Chemical', 'MESH:C009798', (0, 15))	('collagen organization', 'CPA', (86, 107))	('deletion', 'Var', (49, 57))
355592	23906982	Collectively, these findings suggest that the loss of HIF1alpha alters collagen fiber deposition in primary sarcomas, and that PLOD2 may be a critical downstream target.	('alters', 'Reg', (64, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('loss', 'Var', (46, 50))	('collagen fiber deposition', 'MPA', (71, 96))	('HIF1alpha', 'Gene', (54, 63))	('primary sarcomas', 'Disease', 'MESH:D012509', (100, 116))	('primary sarcomas', 'Disease', (100, 116))
355602	23906982	Deletion of HIF1alpha using lentiviral-mediated shRNA significantly abrogated hypoxia-induced PLOD2 expression (P= 0.0008).	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('hypoxia', 'Disease', (78, 85))	('expression', 'Species', '29278', (100, 110))	('abrogated', 'NegReg', (68, 77))	('HIF1alpha', 'Gene', (12, 21))	('Deletion', 'Var', (0, 8))
355604	23906982	Quantification of 3 independent western blots showed that PLOD2 was significantly upregulated under hypoxia (P= 0.0301) (data not shown) and deletion of HIF1alpha significantly abrogated hypoxia-induced PLOD2 expression (P= 0.0095).	('hypoxia', 'Disease', (187, 194))	('deletion', 'Var', (141, 149))	('expression', 'MPA', (209, 219))	('hypoxia', 'Disease', 'MESH:D000860', (187, 194))	('upregulated', 'PosReg', (82, 93))	('abrogated', 'NegReg', (177, 186))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('hypoxia', 'Disease', (100, 107))	('HIF1alpha', 'Gene', (153, 162))	('expression', 'Species', '29278', (209, 219))
355608	23906982	To establish a role for the HIF1alpha/PLOD2 pathway in sarcoma metastasis, we initially performed tail vein injections using 100,000 HT-1080 cells transduced with lentivirus expressing Scr, HIF1alpha, or PLOD2 shRNA (Supplemental Fig.	('Scr', 'Gene', (185, 188))	('sarcoma metastasis', 'Disease', 'MESH:D009362', (55, 73))	('sarcoma metastasis', 'Disease', (55, 73))	('PLOD2 shRNA', 'Var', (204, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('HIF1alpha', 'Var', (190, 199))	('HT-1080', 'CellLine', 'CVCL:0317', (133, 140))	('Scr', 'Gene', '109559', (185, 188))
355609	23906982	Silencing either HIF1alpha or PLOD2 significantly inhibited HT-1080 cell lung colonization, suggesting a role for this pathway in sarcoma pulmonary metastasis.	('HT-1080 cell lung colonization', 'CPA', (60, 90))	('sarcoma pulmonary metastasis', 'Disease', (130, 158))	('sarcoma pulmonary metastasis', 'Disease', 'MESH:D009362', (130, 158))	('HIF1alpha', 'Protein', (17, 26))	('PLOD2', 'Gene', (30, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('Silencing', 'Var', (0, 9))	('HT-1080', 'CellLine', 'CVCL:0317', (60, 67))	('inhibited', 'NegReg', (50, 59))
355613	23906982	Subsequently, we performed similar experiments in KIA cells harboring PLOD2 shRNA for comparison to those treated with Scr or HIF1alpha shRNA (Fig.	('PLOD2 shRNA', 'Var', (70, 81))	('KIA', 'Gene', (50, 53))	('Scr', 'Gene', (119, 122))	('Scr', 'Gene', '109559', (119, 122))	('KIA', 'Gene', '4288', (50, 53))
355616	23906982	2A), demonstrating that HIF1alpha and PLOD2 have little effect on primary tumor growth.	('PLOD2', 'Var', (38, 43))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
355617	23906982	However, silencing HIF1alpha or PLOD2 caused a striking reduction in lung metastases in KIA transplanted tumors (Fig.	('lung metastases in KIA transplanted tumors', 'Disease', 'MESH:D009362', (69, 111))	('HIF1alpha', 'Protein', (19, 28))	('silencing', 'Var', (9, 18))	('PLOD2', 'Gene', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('reduction', 'NegReg', (56, 65))	('lung metastases in KIA transplanted tumors', 'Disease', (69, 111))
355619	23906982	HIF1alpha ablation did not affect the expression of related HIF1alpha targets, other than Plod2, including Lox, Serpine 2, Col5a1, and Itgav in HIF1alpha-depleted KIA tumors (data not shown) and cultured cells (Supplementary Fig.	('expression', 'Species', '29278', (38, 48))	('Itgav', 'Gene', '16410', (135, 140))	('Serpine 2', 'Gene', '20720', (112, 121))	('Itgav', 'Gene', (135, 140))	('Col5a1', 'Gene', (123, 129))	('KIA tumors', 'Disease', (163, 173))	('Col5a1', 'Gene', '12831', (123, 129))	('ablation', 'Var', (10, 18))	('Serpine 2', 'Gene', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('KIA tumors', 'Disease', 'MESH:D009369', (163, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
355624	23906982	We have observed that KP sarcoma cells lack these trimer structures, and dimer intermediates, in favor of monomeric collagen I. Deletion of the HIF1alpha/PLOD2 pathway allows normal maturation to occur in these cells.	('Deletion', 'Var', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('KP sarcoma', 'Disease', 'MESH:D012509', (22, 32))	('KP sarcoma', 'Disease', (22, 32))	('maturation', 'MPA', (182, 192))	('HIF1alpha/PLOD2 pathway', 'Pathway', (144, 167))
355625	23906982	Interestingly, a recent study examining mutations involved in Bruck syndrome and osteogenesis imperfecta has shown that biallelic mutations in PLOD2 promote collagen I trimer formation in patient-derived dermal fibroblasts.	('Bruck syndrome', 'Disease', 'MESH:C537406', (62, 76))	('osteogenesis imperfecta', 'Disease', 'MESH:D010013', (81, 104))	('patient', 'Species', '9606', (188, 195))	('Bruck syndrome', 'Disease', (62, 76))	('biallelic mutations', 'Var', (120, 139))	('osteogenesis imperfecta', 'Disease', (81, 104))	('collagen I trimer formation', 'MPA', (157, 184))	('promote', 'PosReg', (149, 156))	('PLOD2', 'Gene', (143, 148))
355626	23906982	This finding is consistent with our observation that deletion of HIF1alpha-mediated PLOD2 expression promotes the formation of higher order collagen I structures.	('deletion', 'Var', (53, 61))	('expression', 'Species', '29278', (90, 100))	('formation of higher order collagen I structures', 'CPA', (114, 161))	('promotes', 'PosReg', (101, 109))	('HIF1alpha-mediated', 'Gene', (65, 83))
355627	23906982	Deletion of HIF1alpha and PLOD2 results in increased hydroxyproline levels in KIA tumors (Fig.2I), indicating that a high level of PLOD2 activity, resulting in elevated lysine hydroxylation, suppresses proline hydroxylation and mature "normal" collagen organization.	('hydroxyproline', 'Chemical', 'MESH:D006909', (53, 67))	('increased hydroxyproline levels', 'Phenotype', 'HP:0003260', (43, 74))	('mature "normal" collagen organization', 'CPA', (228, 265))	('proline', 'Chemical', 'MESH:D011392', (60, 67))	('HIF1alpha', 'Gene', (12, 21))	('proline', 'Chemical', 'MESH:D011392', (202, 209))	('hydroxyproline levels', 'MPA', (53, 74))	('increased', 'PosReg', (43, 52))	('Deletion', 'Var', (0, 8))	('KIA tumors', 'Disease', (78, 88))	('elevated', 'PosReg', (160, 168))	('suppresses', 'NegReg', (191, 201))	('lysine', 'Chemical', 'MESH:D008239', (169, 175))	('KIA tumors', 'Disease', 'MESH:D009369', (78, 88))	('lysine hydroxylation', 'MPA', (169, 189))	('elevated lysine', 'Phenotype', 'HP:0002161', (160, 175))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('PLOD2', 'Gene', (26, 31))	('proline hydroxylation', 'MPA', (202, 223))
355631	23906982	Boyden chamber based migration assays, using immunoflourescent staining of migratory cell nuclei with 4',6-diamidino-2-phenylindole (DAPI), showed that shRNA-mediated knockdown of HIF1alpha and PLOD2 significantly decreased sarcoma cell motility under hypoxia in KP (Supplementary Fig.	('DAPI', 'Chemical', 'MESH:C007293', (133, 137))	('hypoxia', 'Disease', (252, 259))	('hypoxia', 'Disease', 'MESH:D000860', (252, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('PLOD2', 'Gene', (194, 199))	('sarcoma cell motility', 'Disease', 'MESH:D012509', (224, 245))	('knockdown', 'Var', (167, 176))	('decreased', 'NegReg', (214, 223))	('HIF1alpha', 'Gene', (180, 189))	("4',6-diamidino-2-phenylindole", 'Chemical', 'MESH:C007293', (102, 131))	('sarcoma cell motility', 'Disease', (224, 245))
355633	23906982	Loss of KP cell motility due to HIF1alpha and PLOD2 deletion under normoxic conditions (Supplemental Fig.	('PLOD2', 'Gene', (46, 51))	('Loss of KP cell motility', 'Disease', 'MESH:D015835', (0, 24))	('Loss of KP cell motility', 'Disease', (0, 24))	('deletion', 'Var', (52, 60))	('HIF1alpha', 'Gene', (32, 41))
355641	23906982	To determine whether HIF1alpha-mediated migration and invasion were PLOD2-dependent, we ectopically expressed PLOD2 in HIF1alpha-deficient KIA (Fig.	('HIF1alpha-deficient KIA', 'Disease', (119, 142))	('HIF1alpha-deficient KIA', 'Disease', 'MESH:D007153', (119, 142))	('PLOD2', 'Var', (110, 115))
355648	23906982	PLOD2 lysyl hydroxylase activity is dependent upon association with several essential cofactors, including Fe2+ and 2-oxoglutarate, which requires a conserved aspartate residue (D689 in human PLOD2; D668 in mouse), and mutation of these amino acids inactivates PLOD2.	('PLOD2', 'Gene', (261, 266))	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (116, 130))	('Fe2+', 'Chemical', 'MESH:C038178', (107, 111))	('activity', 'MPA', (24, 32))	('D668', 'Var', (199, 203))	('D689', 'Var', (178, 182))	('association', 'Interaction', (51, 62))	('mutation', 'Var', (219, 227))	('inactivates', 'NegReg', (249, 260))	('human', 'Species', '9606', (186, 191))	('mouse', 'Species', '10090', (207, 212))	('aspartate', 'Chemical', 'MESH:D001224', (159, 168))
355649	23906982	Using site-directed mutagenesis, we generated inactive PLOD2 (D689A, D668A) to determine if the enzymatic activity of PLOD2 was essential for its ability to rescue cell migration in HIF1alpha-deficient cells.	('cell migration', 'CPA', (164, 178))	('D668A', 'Var', (69, 74))	('D668A', 'Mutation', 'p.D668A', (69, 74))	('D689A', 'Mutation', 'p.D689A', (62, 67))
355650	23906982	We performed migration assays on stable Scr control and HIF1alpha-deficient HT-1080 and KIA cells that had also been transduced with lentivirus bearing a mutant PLOD2 expression vector.	('KIA', 'Gene', '4288', (88, 91))	('HIF1alpha-deficient HT-1080', 'Disease', 'MESH:D006973', (56, 83))	('Scr', 'Gene', '109559', (40, 43))	('HIF1alpha-deficient HT-1080', 'Disease', (56, 83))	('Scr', 'Gene', (40, 43))	('expression', 'Species', '29278', (167, 177))	('KIA', 'Gene', (88, 91))	('mutant', 'Var', (154, 160))
355651	23906982	We observed that expression of inactive PLOD2 mutants failed to rescue migration in HIF1alpha-deficient KIA (Fig.5A) and HT-1080 cells (Fig.	('expression', 'Species', '29278', (17, 27))	('HIF1alpha-deficient KIA', 'Disease', 'MESH:D007153', (84, 107))	('HIF1alpha-deficient KIA', 'Disease', (84, 107))	('HT-1080', 'CellLine', 'CVCL:0317', (121, 128))	('migration', 'CPA', (71, 80))	('PLOD2', 'Gene', (40, 45))	('mutants', 'Var', (46, 53))
355652	23906982	Furthermore, mutant PLOD2 behaves as a dominant negative in KIA and HT-1080 cells, suppressing hypoxia-induced migration.	('mutant', 'Var', (13, 19))	('KIA', 'Gene', '4288', (60, 63))	('hypoxia', 'Disease', (95, 102))	('hypoxia', 'Disease', 'MESH:D000860', (95, 102))	('suppressing', 'NegReg', (83, 94))	('PLOD2', 'Gene', (20, 25))	('HT-1080', 'CellLine', 'CVCL:0317', (68, 75))	('KIA', 'Gene', (60, 63))
355653	23906982	Interestingly, significant overexpression of mutant PLOD2 modestly inhibited endogenous PLOD2 and HIF1alpha levels as shown by qRT-PCR (Supplementary Fig.	('PLOD2', 'Gene', (52, 57))	('mutant', 'Var', (45, 51))	('inhibited', 'NegReg', (67, 76))	('expression', 'Species', '29278', (31, 41))	('endogenous PLOD2', 'MPA', (77, 93))	('HIF1alpha levels', 'MPA', (98, 114))	('overexpression', 'PosReg', (27, 41))
355671	23906982	Furthermore, HIF1alpha deletion causes a four-fold decrease in % collagen area (Figure 6C) and a concomitant four-fold decrease in murine lung metastasis (Figure 2D, middle).	('murine', 'Species', '10090', (131, 137))	('decrease', 'NegReg', (119, 127))	('deletion', 'Var', (23, 31))	('HIF1alpha', 'Gene', (13, 22))	('decrease', 'NegReg', (51, 59))	('murine lung metastasis', 'CPA', (131, 153))
355676	23906982	Immunofluorescence anaylsis of GFP+ KIA tumor sections stained for GFP and the mesenchymal marker, Vimentin, showed that a small percentage of cells in the tumor were GFP-; Vimentin+ as expected for an infiltrating fibroblast population (Supplementary Fig.	('Vimentin', 'Gene', '7431', (173, 181))	('KIA tumor', 'Disease', (36, 45))	('KIA tumor', 'Disease', 'MESH:D009369', (36, 45))	('Vimentin', 'Gene', '7431', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Vimentin', 'Gene', (173, 181))	('tumor', 'Disease', (156, 161))	('GFP-', 'Var', (167, 171))	('tumor', 'Disease', (40, 45))	('Vimentin', 'Gene', (99, 107))
355682	23906982	These findings are consistent with the overall conclusion that loss of HIF1alpha prevents tumor cells from migrating to vessels and escaping the primary lesion.	('loss', 'Var', (63, 67))	('HIF1alpha', 'Protein', (71, 80))	('prevents', 'NegReg', (81, 89))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('migrating to vessels', 'CPA', (107, 127))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
355683	23906982	PLOD2 ablation results in defects in collagen/vessel association similar to that of HIF1alpha-deficiency (Fig.	('collagen/vessel association', 'MPA', (37, 64))	('defects', 'NegReg', (26, 33))	('HIF1alpha-deficiency', 'Disease', (84, 104))	('HIF1alpha-deficiency', 'Disease', 'MESH:D007153', (84, 104))	('PLOD2', 'Gene', (0, 5))	('ablation', 'Var', (6, 14))
355690	23906982	Soft tissue sarcomas are a highly complex set of malignancies, comprising more than 50 histologically distinct subtypes associated with genetic alterations in diverse molecular pathways.	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('Soft tissue sarcomas', 'Phenotype', 'HP:0030448', (0, 20))	('genetic alterations', 'Var', (136, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('malignancies', 'Disease', (49, 61))	('sarcomas', 'Disease', (12, 20))
355703	23906982	Deletion of HIF1alpha collagen modification and organization, preventing its association with tumor cells.	('preventing', 'NegReg', (62, 72))	('association', 'Interaction', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('collagen modification', 'CPA', (22, 43))	('HIF1alpha', 'Gene', (12, 21))	('Deletion', 'Var', (0, 8))
355705	23906982	For example, HIF1alpha reduces E-cadherin expression and promotes invasiveness and the epithelial to mesenchymal transition (EMT) in renal cancers.	('expression', 'Species', '29278', (42, 52))	('invasiveness', 'CPA', (66, 78))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('expression', 'MPA', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('HIF1alpha', 'Var', (13, 22))	('renal cancers', 'Disease', 'MESH:D007680', (133, 146))	('reduces', 'NegReg', (23, 30))	('renal cancers', 'Disease', (133, 146))	('E-cadherin', 'Gene', (31, 41))	('E-cadherin', 'Gene', '999', (31, 41))	('epithelial to mesenchymal transition', 'CPA', (87, 123))	('promotes', 'PosReg', (57, 65))
355711	23906982	Interestingly, PLOD2 has been recently identified as a novel prognostic factor in hepatocellular carcinoma, in which it is associated with disease recurrence and intrahepatic metastases.	('associated', 'Reg', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('intrahepatic metastases', 'Disease', (162, 185))	('PLOD2', 'Var', (15, 20))	('intrahepatic metastases', 'Disease', 'MESH:D009362', (162, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('hepatocellular carcinoma', 'Disease', (82, 106))
355740	23906982	Ectopic expression of wild type and mutant PLOD2 was achieved using pCDH-CMV-MCS-EF1-Puro expression vectors (System Biosciences) and were cloned in via Xba1 and NHE1 restriction sites from murine or human pCMV-SPORT6 PLOD2 (Open Biosystems).	('murine', 'Species', '10090', (190, 196))	('expression', 'Species', '29278', (90, 100))	('expression', 'Species', '29278', (8, 18))	('human', 'Species', '9606', (200, 205))	('mutant', 'Var', (36, 42))	('expression vectors', 'Species', '29278', (90, 108))	('Ectopic expression', 'MPA', (0, 18))
355771	22043171	Several oncogenic and tumour suppressor proteins are known to localize to the centrosomes, deregulation of which may evoke centrosome abnormalities.	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('centrosome', 'MPA', (123, 133))	('tumour', 'Disease', (22, 28))	('evoke', 'Reg', (117, 122))	('deregulation', 'Var', (91, 103))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
355774	22043171	Moreover, the frequent association with extensive karyotypic aberrations and poor patient outcome supports its clinical significance in human cancer [Tables 1-3].	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('human', 'Species', '9606', (136, 141))	('patient', 'Species', '9606', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('extensive karyotypic aberrations', 'Var', (40, 72))	('cancer', 'Disease', (142, 148))
355782	22043171	These defects, collective referred to as CA, are major contributors to mechanisms underlying loss of cell cycle fidelity, genomic instability and loss of tissue architecture in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', (183, 190))	('loss', 'NegReg', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cell cycle fidelity', 'CPA', (101, 120))	('human', 'Species', '9606', (177, 182))	('defects', 'Var', (6, 13))	('genomic instability', 'CPA', (122, 141))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
355785	22043171	At the same time, a limited level of CIN that permits continued bipolar cell division may be maintained consequent to segregation errors via merotelic kinetochore-microtubule attachment possibly during a transient 'multipolar spindle intermediate' prior to centrosome clustering and anaphase.	('bipolar', 'CPA', (64, 71))	('CIN', 'Disease', 'MESH:D007674', (37, 40))	('merotelic kinetochore-microtubule attachment', 'Protein', (141, 185))	('errors', 'Var', (130, 136))	('CIN', 'Disease', (37, 40))
355796	22043171	Interestingly, tumours with excess PCM are highly anaplastic, lack normal cell polarity, and tend to have a higher median frequency of abnormal mitoses compared to tumours with other centrosome abnormalities.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('tumours', 'Disease', (15, 22))	('lack', 'NegReg', (62, 66))	('abnormal mitoses', 'CPA', (135, 151))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('tumours', 'Disease', (164, 171))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('PCM', 'Var', (35, 38))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
355801	22043171	In keeping with earlier studies, greater CA, along with aberrant mitotic spindles are observed in genomically-unstable and clinically more aggressive aneuploid breast cancers with high SSI, compared to genomically-stable aneuploid and diploid counterparts.	('aggressive aneuploid breast cancers', 'Disease', (139, 174))	('neu', 'Gene', '2064', (222, 225))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('neu', 'Gene', (222, 225))	('neu', 'Gene', '2064', (151, 154))	('aggressive aneuploid breast cancers', 'Disease', 'MESH:D001943', (139, 174))	('breast cancers', 'Phenotype', 'HP:0003002', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('high', 'Var', (180, 184))	('neu', 'Gene', (151, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
355814	22043171	Inhibition of BRCA1 causes rapid centrosome overduplication and possibly fragmentation in human breast cell lines, as well as stimulates centrosome microtubule nucleation function.	('stimulates', 'PosReg', (126, 136))	('fragmentation', 'CPA', (73, 86))	('BRCA1', 'Gene', (14, 19))	('centrosome microtubule nucleation function', 'MPA', (137, 179))	('human', 'Species', '9606', (90, 95))	('Inhibition', 'Var', (0, 10))	('centrosome overduplication', 'MPA', (33, 59))
355815	22043171	Consistent with these reports, disruption of the BRCA1 gene in mice leads to CA and aneuploidy.	('aneuploidy', 'Disease', (84, 94))	('mice', 'Species', '10090', (63, 67))	('BRCA1', 'Gene', (49, 54))	('disruption', 'Var', (31, 41))	('aneuploidy', 'Disease', 'MESH:D000782', (84, 94))	('leads to', 'Reg', (68, 76))
355819	22043171	Dysfunction of this regulation might be involved in the tumourigenesis of breast cancer through both centrosome overduplication and fragmentation.	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('Dysfunction', 'Var', (0, 11))	('centrosome overduplication', 'CPA', (101, 127))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumour', 'Disease', (56, 62))	('involved', 'Reg', (40, 48))
355830	22043171	Abolishing the expression of CDK4/cyclin D1 or Nek2 abrogates Ras-induced CA in human mammary epithelial cells, whereas silencing cyclin E1 or B2 has no such effect, suggesting that Ras-evoked CA may be an early breast oncogenic event that occurs through a Nek2 and CDK4/cyclin D1-dependent pathway.	('cyclin D1', 'Gene', (271, 280))	('cyclin E1', 'Gene', '898', (130, 139))	('CDK4', 'Gene', (29, 33))	('CDK4', 'Gene', (266, 270))	('Nek2', 'Gene', (47, 51))	('Nek2', 'Gene', '4751', (47, 51))	('CDK4', 'Gene', '1019', (29, 33))	('CDK4', 'Gene', '1019', (266, 270))	('Nek2', 'Gene', (257, 261))	('cyclin E1', 'Gene', (130, 139))	('cyclin D1', 'Gene', '595', (34, 43))	('human', 'Species', '9606', (80, 85))	('Nek2', 'Gene', '4751', (257, 261))	('Abolishing', 'Var', (0, 10))	('cyclin D1', 'Gene', (34, 43))	('cyclin D1', 'Gene', '595', (271, 280))	('abrogates', 'NegReg', (52, 61))
355836	22043171	In transgenic mice, YB-1 expression in mammary epithelial cells provokes breast carcinomas of different histologic types through induction of CIN that emerges from mitotic failure and CA.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('breast carcinoma', 'Phenotype', 'HP:0003002', (73, 89))	('mitotic failure', 'Disease', (164, 179))	('breast carcinomas', 'Phenotype', 'HP:0003002', (73, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('mitotic failure', 'Disease', 'MESH:C536987', (164, 179))	('YB-1', 'Gene', (20, 24))	('breast carcinomas', 'Disease', 'MESH:D001943', (73, 90))	('breast carcinomas', 'Disease', (73, 90))	('CIN', 'Disease', (142, 145))	('induction', 'Reg', (129, 138))	('transgenic mice', 'Species', '10090', (3, 18))	('expression', 'Var', (25, 35))	('CIN', 'Disease', 'MESH:D007674', (142, 145))	('provokes', 'Reg', (64, 72))
355839	22043171	Several other mechanisms implicated in the generation of CA in breast cancer include the aberrant expression of LMO4, centrosome overduplication via nuclear expression of endogenous aryl hydrocarbon receptor (AhR) and cyclin E, as well as cell fusion following ectopic expression of the RAD6 ubiquitin conjugating enzyme.	('centrosome overduplication', 'MPA', (118, 144))	('LMO4', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('aryl hydrocarbon receptor', 'Gene', '196', (182, 207))	('aberrant', 'Var', (89, 97))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('aryl hydrocarbon receptor', 'Gene', (182, 207))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('AhR', 'Gene', (209, 212))	('cell fusion', 'CPA', (239, 250))	('AhR', 'Gene', '196', (209, 212))	('LMO4', 'Gene', '8543', (112, 116))
355846	22043171	Non-functional p53 also promotes the formation of increased centrosome number and size in prostate cancer cell lines by abrogating the G2/M checkpoint control.	('Non-functional', 'Var', (0, 14))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('abrogating', 'NegReg', (120, 130))	('increased', 'PosReg', (50, 59))	('p53', 'Gene', (15, 18))	('size', 'MPA', (82, 86))	('promotes', 'PosReg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('prostate cancer', 'Disease', (90, 105))	('G2/M checkpoint control', 'MPA', (135, 158))	('centrosome', 'MPA', (60, 70))
355852	22043171	Like in breast cancers, the association of CA with 20q13.2 copy number gain and Aurora-A kinase overexpression has been reported in urothelial carcinoma, specifically in those harbouring CIN and aneuploidy rather than MIN.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('CA with', 'Var', (43, 50))	('urothelial carcinoma', 'Disease', (132, 152))	('CIN and aneuploidy', 'Disease', 'MESH:D000782', (187, 205))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('breast cancers', 'Phenotype', 'HP:0003002', (8, 22))	('copy number', 'Var', (59, 70))	('Aurora-A kinase', 'Enzyme', (80, 95))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (132, 152))	('overexpression', 'PosReg', (96, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('gain', 'PosReg', (71, 75))	('breast cancers', 'Disease', 'MESH:D001943', (8, 22))	('breast cancers', 'Disease', (8, 22))
355857	22043171	Overall, a cooperative mechanism for CA in bladder cancers is suggested through both disinhibition of centrosome duplication (as a result of cyclin E and/or cyclin D overactivity) and cytokinesis failure (as a result of p53 mutation and/or Aurora-A overexpression).	('p53', 'Gene', (220, 223))	('bladder cancers', 'Disease', 'MESH:D001749', (43, 58))	('disinhibition', 'Phenotype', 'HP:0000734', (85, 98))	('mutation', 'Var', (224, 232))	('bladder cancers', 'Disease', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cytokinesis failure', 'CPA', (184, 203))	('centrosome duplication', 'CPA', (102, 124))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('disinhibition', 'NegReg', (85, 98))	('bladder cancers', 'Phenotype', 'HP:0009725', (43, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (43, 57))	('cyclin E', 'MPA', (141, 149))	('cyclin D', 'MPA', (157, 165))
355860	22043171	CA and telomeric dysfunction, in the generation of genetic instability of RCC.	('RCC', 'Disease', (74, 77))	('telomeric dysfunction', 'Disease', 'MESH:C536801', (7, 28))	('telomeric dysfunction', 'Disease', (7, 28))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('genetic instability', 'Var', (51, 70))
355861	22043171	Overexpression of miR-210, a downstream target of HIF1alpha, has recently been reported to evoke CA and multipolar spindle formation in renal carcinoma cells.	('renal carcinoma', 'Disease', 'MESH:C538614', (136, 151))	('miR-210', 'Gene', '406992', (18, 25))	('renal carcinoma', 'Disease', (136, 151))	('evoke', 'Reg', (91, 96))	('HIF1alpha', 'Gene', '3091', (50, 59))	('renal carcinoma', 'Phenotype', 'HP:0005584', (136, 151))	('Overexpression', 'Var', (0, 14))	('HIF1alpha', 'Gene', (50, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('miR-210', 'Gene', (18, 25))
355864	22043171	Centrosome aberration has been demonstrated in cervical dysplasia and invasive cervical carcinoma, most of which are aneuploid and positive for high-risk HPV infection.	('neu', 'Gene', '2064', (118, 121))	('Centrosome aberration', 'Var', (0, 21))	('neu', 'Gene', (118, 121))	('HPV infection', 'Disease', (154, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cervical dysplasia', 'Disease', (47, 65))	('invasive cervical carcinoma', 'Disease', 'MESH:D002575', (70, 97))	('invasive cervical carcinoma', 'Disease', (70, 97))	('cervical dysplasia', 'Disease', 'MESH:D002575', (47, 65))	('HPV infection', 'Disease', 'MESH:D030361', (154, 167))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (47, 65))
355866	22043171	Furthermore, CA is detected in organotypic raft cultures of human keratinocytes containing episomal HPV-16 DNA, even in basal cells with low copy numbers of HPV-16 genome, supporting its involvement in tumour initiation and progression.	('tumour initiation', 'Disease', 'MESH:D009369', (202, 219))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('episomal', 'Var', (91, 99))	('tumour initiation', 'Disease', (202, 219))	('HPV-16', 'Gene', (100, 106))	('HPV-16', 'Species', '333760', (157, 163))	('HPV-16', 'Species', '333760', (100, 106))	('human', 'Species', '9606', (60, 65))
355871	22043171	However, E6 plus E7 additionally elevate centrosome copy number and create large, extensively invasive cancers, supporting the cooperative mechanism.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('invasive cancers', 'Disease', 'MESH:D009362', (94, 110))	('invasive cancers', 'Disease', (94, 110))	('E6 plus E7', 'Var', (9, 19))	('elevate', 'PosReg', (33, 40))	('centrosome copy number', 'MPA', (41, 63))	('create', 'Reg', (68, 74))
355873	22043171	The absolute requirement of CDK2 dysregulation is consistent with the known effects of E7 on pRB inactivation and the resultant release of E2F transcription factors as well as upregulation of CDK2/cyclin E activity needed for S phase entry.	('dysregulation', 'Var', (33, 46))	('CDK2', 'Gene', (192, 196))	('upregulation', 'PosReg', (176, 188))	('pRB', 'Gene', '5925', (93, 96))	('CDK2', 'Gene', (28, 32))	('CDK2', 'Gene', '1017', (192, 196))	('inactivation', 'NegReg', (97, 109))	('pRB', 'Gene', (93, 96))	('CDK2', 'Gene', '1017', (28, 32))	('release', 'MPA', (128, 135))
355874	22043171	Interestingly, although a E7 deletion mutant lacking pRB binding/degradation properties is unable to induce centriole overduplication, wild-type E7 is able to induce centriole abnormalities in pRB/p107/p130-deficient cells, implying that pRB degradation is not the only mechanism by which oncogenic E7 induces centriole overduplication.	('p130', 'Gene', (202, 206))	('pRB', 'Gene', '5925', (193, 196))	('p107', 'Gene', '5933', (197, 201))	('centriole abnormalities', 'CPA', (166, 189))	('pRB', 'Gene', '5925', (238, 241))	('deletion mutant', 'Var', (29, 44))	('lacking', 'NegReg', (45, 52))	('p130', 'Gene', '5934', (202, 206))	('induce', 'Reg', (159, 165))	('pRB', 'Gene', '5925', (53, 56))	('p107', 'Gene', (197, 201))	('pRB', 'Gene', (238, 241))	('pRB', 'Gene', (193, 196))	('pRB', 'Gene', (53, 56))
355878	22043171	The involvement of E6 in the early stages of cervical carcinogenesis is supported by studies demonstrating the presence of centrosome abnormalities in raft cultures harbouring genomes mutated in E7 expression.	('carcinogenesis', 'Disease', (54, 68))	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('involvement', 'Reg', (4, 15))	('mutated', 'Var', (184, 191))
355882	22043171	Taken together, it may be speculated that in the early stages of HPV-induced cervical carcinogenesis, centrosome accumulation triggered by E6 and/or E2 may be the predominant mechanisms for the generation of supernumerary centrosomes; in the later stages, it is possible that the loss of E2 may then permit E7 to take on a predominant role through centrosome overduplication, whilst E6 takes on a cooperative role by creating a permissive milieu for genomic disintegrity and centrosome accumulation, through the relaxation of p53 checkpoint control.	('HPV-induced cervical carcinogenesis', 'Disease', 'MESH:D030361', (65, 100))	('relaxation', 'PosReg', (512, 522))	('HPV-induced cervical carcinogenesis', 'Disease', (65, 100))	('loss', 'Var', (280, 284))	('p53 checkpoint', 'Gene', (526, 540))
355883	22043171	Interestingly, recent evidence suggests that genital infection by Chlamydia trachomatis may contribute to HPV-induced cervical cancer formation through its disruptive effects on centrosome homeostasis.	('cervical cancer', 'Disease', (118, 133))	('genital infection', 'Disease', 'MESH:D060737', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('contribute', 'Reg', (92, 102))	('genital infection', 'Disease', (45, 62))	('Chlamydia trachomatis', 'Var', (66, 87))	('centrosome homeostasis', 'MPA', (178, 200))	('cervical cancer', 'Disease', 'MESH:D002583', (118, 133))	('Chlamydia trachomatis', 'Species', '813', (66, 87))	('HPV', 'Species', '10566', (106, 109))
355888	22043171	This implicates upon two distinct but possibly inter-related mechanisms for the generation of chromosomal aberration in ovarian carcinoma - one via copy-number instability associated with mitotic segregation abnormalities, cytokinesis errors and CA, and the other through structural change possibly as a result of impaired DNA repair.	('copy-number instability', 'Var', (148, 171))	('chromosomal aberration in ovarian carcinoma', 'Disease', (94, 137))	('implicates', 'Reg', (5, 15))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (94, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('mitotic segregation abnormalities', 'Var', (188, 221))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (120, 137))	('cytokinesis errors', 'Var', (223, 241))	('chromosomal aberration in ovarian carcinoma', 'Disease', 'MESH:D002869', (94, 137))
355896	22043171	Ectopic expression of Aurora-A kinase renders ovarian cancer cells resistant to drug-evoked apoptosis by activating the AKT survival pathway in a p53-dependent manner.	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('AKT', 'Gene', (120, 123))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('ovarian cancer', 'Disease', (46, 60))	('Ectopic expression', 'Var', (0, 18))	('AKT', 'Gene', '207', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('activating', 'PosReg', (105, 115))
355901	22043171	In addition to the association with aneuploidy, a proportion of CRC cell lines with CA also contains p53 mutations or overexpression, gains or genomic amplification of 20q, as well as increased copies of 16p.	('aneuploidy', 'Disease', 'MESH:D000782', (36, 46))	('overexpression', 'PosReg', (118, 132))	('p53', 'Gene', (101, 104))	('gains', 'PosReg', (134, 139))	('aneuploidy', 'Disease', (36, 46))	('mutations', 'Var', (105, 114))	('genomic amplification of 20q', 'Var', (143, 171))
355904	22043171	Loss of hSgo1, a protein regulating chromosome segregation that is downregulated in CRC, results in G2/M arrest and apoptosis, while promoting CIN and CA, cytokinesis defects and mitotic catastrophe.	('hSgo1', 'Gene', '151648', (8, 13))	('M arrest', 'Disease', (103, 111))	('hSgo1', 'Gene', (8, 13))	('apoptosis', 'CPA', (116, 125))	('CIN', 'Disease', (143, 146))	('CIN', 'Disease', 'MESH:D007674', (143, 146))	('mitotic catastrophe', 'CPA', (179, 198))	('cytokinesis defects', 'CPA', (155, 174))	('promoting', 'PosReg', (133, 142))	('M arrest', 'Disease', 'MESH:D006323', (103, 111))	('Loss', 'Var', (0, 4))	('downregulated', 'NegReg', (67, 80))
355908	22043171	Interestingly, centrosome aberrancies are less frequent in frank adenocarcinoma compared to Barrett's metaplasia, perhaps suggesting its relative importance in earlier stages of carcinogenesis.	('frank adenocarcinoma', 'Disease', 'MESH:D000230', (59, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (92, 112))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('centrosome', 'Var', (15, 25))	('less', 'NegReg', (42, 46))	('carcinogenesis', 'Disease', (178, 192))	('frank adenocarcinoma', 'Disease', (59, 79))	("Barrett's metaplasia", 'Disease', (92, 112))
355914	22043171	CA is associated with p53 mutation but is not related to tumour stage, size or proliferative activity.	('tumour', 'Disease', (57, 63))	('mutation', 'Var', (26, 34))	('associated', 'Reg', (6, 16))	('p53', 'Gene', (22, 25))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
355920	22043171	Using orthotopic transplantation of Suit-2 human pancreatic carcinoma cells into nude mice as a model, supernumerary centrosome numbers are found at higher frequencies in metastatic foci than in pancreatic xenografts, correlating with multipolar mitotic spindles and enhanced degree of CIN.	('CIN', 'Disease', 'MESH:D007674', (286, 289))	('pancreatic xenografts', 'Disease', (195, 216))	('metastatic foci', 'CPA', (171, 186))	('pancreatic xenografts', 'Disease', 'MESH:D010195', (195, 216))	('supernumerary centrosome numbers', 'Var', (103, 135))	('pancreatic carcinoma', 'Disease', (49, 69))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (49, 69))	('human', 'Species', '9606', (43, 48))	('multipolar mitotic spindles', 'CPA', (235, 262))	('nude mice', 'Species', '10090', (81, 90))	('CIN', 'Disease', (286, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('enhanced', 'PosReg', (267, 275))
355924	22043171	In the context of p53 deficiency, uncontrolled polyploid progression ensues due to evasion of the tetraploidy checkpoint during cytokinesis failure, leading to a rapid exacerbation of CA and aneuplody.	('evasion', 'MPA', (83, 90))	('p53', 'Gene', (18, 21))	('neu', 'Gene', '2064', (192, 195))	('neu', 'Gene', (192, 195))	('exacerbation', 'PosReg', (168, 180))	('deficiency', 'Var', (22, 32))
355933	22043171	CA has been demonstrated in several neural cancers, including aneuploid cerebral primitive neuroectodermal tumours (PNET) with p53 mutation, diffuse astrocytic gliomas of various histological grades, pituitary adenomas (PA), as well as in medulloblastoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (239, 254))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (149, 167))	('primitive neuroectodermal tumours', 'Phenotype', 'HP:0030065', (81, 114))	('cerebral primitive neuroectodermal tumours', 'Phenotype', 'HP:0030070', (72, 114))	('astrocytic gliomas', 'Disease', (149, 167))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('medulloblastoma', 'Disease', (239, 254))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('mutation', 'Var', (131, 139))	('aneuploid cerebral primitive neuroectodermal tumours', 'Disease', 'MESH:D008527', (62, 114))	('p53', 'Gene', (127, 130))	('pituitary adenomas', 'Disease', 'MESH:D010911', (200, 218))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (200, 218))	('pituitary adenomas', 'Disease', (200, 218))	('neural cancers', 'Disease', (36, 50))	('neural cancers', 'Disease', 'MESH:D009369', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))	('medulloblastoma', 'Disease', 'MESH:D008527', (239, 254))
355946	22043171	Ploidy divergence accompanying tetraploid cells, implying cytokinesis failure, occurs very frequently in infant diploid but not infant triploid tumours.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('Ploidy divergence', 'Var', (0, 17))	('triploid tumours', 'Disease', (135, 151))	('triploid tumours', 'Disease', 'MESH:D057885', (135, 151))	('infant', 'Species', '9606', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('infant', 'Species', '9606', (105, 111))
355961	22043171	There is evidence to support cytokinesis failure as the major mechanism underlying CA in HNSCC, which may involve Aurora-A kinase upregulation, MDM2-p53 dysregulation, and decreased myosin light chain phosphorylation.	('dysregulation', 'Var', (153, 166))	('myosin', 'Gene', (182, 188))	('MDM2-p53 dysregulation', 'Var', (144, 166))	('decreased', 'NegReg', (172, 181))	('myosin', 'Gene', '79784', (182, 188))	('Aurora-A kinase', 'Enzyme', (114, 129))	('SCC', 'Gene', (91, 94))	('upregulation', 'PosReg', (130, 142))	('SCC', 'Gene', '6317', (91, 94))
355963	22043171	Interestingly, in tumours that retained wild-type p53, CA is associated with MDM2 overexpression instead.	('tumours', 'Disease', (18, 25))	('wild-type', 'Var', (40, 49))	('MDM2', 'Gene', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('overexpression', 'PosReg', (82, 96))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('associated', 'Reg', (61, 71))	('tumours', 'Disease', 'MESH:D009369', (18, 25))
355966	22043171	Dysfunctional telomeres have been suggested to play a possible role in the generation of CA in HNSCC.	('SCC', 'Gene', (97, 100))	('SCC', 'Gene', '6317', (97, 100))	('Dysfunctional', 'Var', (0, 13))
355977	22043171	Analysis of p53-mutant osteosarcoma cell lines reveals a wide range of aneusomy, high levels of atypical mitotic figures, and high frequencies of abnormal centrosome numbers, as compared to p53 wild-type cell lines.	('p53-mutant', 'Gene', (12, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('neu', 'Gene', (72, 75))	('p53-mutant', 'Var', (12, 22))	('osteosarcoma', 'Phenotype', 'HP:0002669', (23, 35))	('centrosome numbers', 'CPA', (155, 173))	('osteosarcoma', 'Disease', (23, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (23, 35))	('neu', 'Gene', '2064', (72, 75))
355986	22043171	In human and mouse primary fibroblasts, K cyclin expression results in a p53-dependent growth arrest, abortive cytokinesis and centrosome accumulation.	('growth arrest', 'Phenotype', 'HP:0001510', (87, 100))	('mouse', 'Species', '10090', (13, 18))	('human', 'Species', '9606', (3, 8))	('abortive cytokinesis', 'CPA', (102, 122))	('growth arrest', 'Disease', 'MESH:D006323', (87, 100))	('p53-dependent', 'Protein', (73, 86))	('centrosome accumulation', 'CPA', (127, 150))	('growth arrest', 'Disease', (87, 100))	('K cyclin expression', 'Var', (40, 59))
355998	22043171	In FL, the number of cells with CA correlates with increased histological grading; whilst in MCL, CA occurs at a higher frequency in blastoid variants harbouring near-tetraploid chromosome numbers as compared to the less aggressive diploid subtypes.	('MCL', 'Disease', (93, 96))	('MCL', 'Disease', 'MESH:C535516', (93, 96))	('near-tetraploid chromosome numbers', 'Var', (162, 196))
356002	22043171	However, there is no correlation with IgVH gene mutation status or cytogenetically-defined risk groups (11q22-23, 17p13 and 13q14 deletions; trisomy 12).	('11q22-23', 'Var', (104, 112))	('trisomy 12', 'Disease', (141, 151))	('IgVH', 'Gene', '28402', (38, 42))	('IgVH', 'Gene', (38, 42))
356003	22043171	Apart from B-cell neoplasms, numerical and structural centrosome aberrations are present in ALK-positive anaplastic large cell lymphoma (ALCL) as well, a T-cell derived neoplasm characterized by t(2;5) rearrangements, resulting in the creation of fusion genes involving the ALK locus.	('neoplasms', 'Disease', (18, 27))	('neoplasm', 'Disease', 'MESH:D009369', (18, 26))	('ALK', 'Gene', '238', (274, 277))	('ALK', 'Gene', '238', (92, 95))	('neoplasm', 'Disease', 'MESH:D009369', (169, 177))	('ALK', 'Gene', (274, 277))	('neoplasm', 'Disease', (18, 26))	('ALK', 'Gene', (92, 95))	('cell lymphoma', 'Disease', (122, 135))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('neoplasm', 'Disease', (169, 177))	('neoplasms', 'Phenotype', 'HP:0002664', (18, 27))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (105, 135))	('cell lymphoma', 'Phenotype', 'HP:0012191', (122, 135))	('cell lymphoma', 'Disease', 'MESH:D016399', (122, 135))	('neoplasm', 'Phenotype', 'HP:0002664', (18, 26))	('fusion', 'Var', (247, 253))	('neoplasm', 'Phenotype', 'HP:0002664', (169, 177))	('neoplasms', 'Disease', 'MESH:D009369', (18, 27))	('B-cell neoplasms', 'Phenotype', 'HP:0012191', (11, 27))
356013	22043171	Numerical and structural CA has been described as a potential cause of aneuploidy in AML.	('structural', 'Var', (14, 24))	('AML', 'Disease', 'MESH:D015470', (85, 88))	('aneuploidy', 'Disease', (71, 81))	('AML', 'Disease', (85, 88))	('Numerical', 'Disease', (0, 9))	('aneuploidy', 'Disease', 'MESH:D000782', (71, 81))
356028	22043171	In MM patients, a high CI is associated with poor prognostic features, including chromosome 13 deletion, t(4;14), t(14;16) and high plasma cell labelling index.	('chromosome 13', 'Gene', (81, 94))	('patients', 'Species', '9606', (6, 14))	('t(14;16', 'Var', (114, 121))	('deletion', 'Var', (95, 103))
356054	22043171	For example, the partial inhibition of PARP1 in BRCA1-deficient cells has been suggested to represent a possible chemopreventive or therapeutic approach for BRCA1-deficient breast cancers, via its induction of severe chromosome aberrations, CA, telomere dysfunction and apoptosis.	('BRCA1-deficient breast cancers', 'Disease', 'MESH:D001943', (157, 187))	('BRCA1-deficient', 'Disease', (157, 172))	('apoptosis', 'CPA', (270, 279))	('PARP1', 'Gene', '142', (39, 44))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (48, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (173, 187))	('BRCA1-deficient breast cancers', 'Disease', (157, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (157, 172))	('severe chromosome aberrations', 'CPA', (210, 239))	('telomere dysfunction', 'Disease', (245, 265))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('deficient breast', 'Phenotype', 'HP:0003187', (163, 179))	('PARP1', 'Gene', (39, 44))	('induction', 'Reg', (197, 206))	('telomere dysfunction', 'Disease', 'MESH:C536801', (245, 265))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('partial', 'Var', (17, 24))	('BRCA1-deficient', 'Disease', (48, 63))
356055	22043171	Survivin inhibition in glioma cells has also been shown to enhance CIN and radiosensitivity via induction of CA.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('CIN', 'Disease', 'MESH:D007674', (67, 70))	('enhance', 'PosReg', (59, 66))	('Survivin', 'Protein', (0, 8))	('glioma', 'Disease', (23, 29))	('CIN', 'Disease', (67, 70))	('inhibition', 'Var', (9, 19))	('radiosensitivity', 'CPA', (75, 91))
356058	22043171	In addition, cancer cells which evade apoptosis despite being induced with a greater degree of centrosome aberration and genomic instability may eventually develop an even more aggressive phenotype.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', (13, 19))	('centrosome aberration', 'Var', (95, 116))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('genomic instability', 'Var', (121, 140))	('develop', 'PosReg', (156, 163))	('aggressive', 'CPA', (177, 187))
356101	24420711	Several PMs as a candidate for clinical uses have been licensed toward the chemotherapy of solid tumors (such as human gastric cancer and pancreatic cancer), DNA and RNA viruses (such as HSV, HIV, influenza, and SARS), and drug-resistant bacteria (such as MRSA and VRSA) in recent years: [NH3Pri]6[Mo7O24] 3H2O (PM-8) and [Me3NH]6[H2MoV 12O28(OH)12(MoVIO3)4] 2H2O (PM-17) for solid tumors; K7[PTi2W10O40] 6H2O (PM-19), [PriNH3]6H[PTi2W10O38(O2)2] H2O (PM-523), and K11H[(VO)3(SbW9O33)2] 27H2O (PM-1002) for viruses; and K6[P2W18O62] 14H2O (PM-27), K4[SiMo12O40] 3H2O (SiMo12), and PM-19 for MRSA and VRSA.	('K6[P2W18O62] 14H2O', 'Chemical', '-', (520, 538))	('SiMo12', 'Chemical', '-', (551, 557))	('PM-19', 'Species', '1551643', (581, 586))	('K4[SiMo12O40] 3H2O', 'Var', (548, 566))	('K11H[(VO)3(SbW9O33)2] 27H2O', 'Chemical', '-', (465, 492))	('gastric cancer', 'Disease', (119, 133))	('V', 'Chemical', '-', (600, 601))	('[NH3Pri]6[Mo7O24] 3H2O', 'Chemical', 'MESH:C081971', (288, 310))	('K4[SiMo12O40] 3H2O', 'Chemical', '-', (548, 566))	('solid tumors', 'Disease', (91, 103))	('human', 'Species', '9606', (113, 118))	('K7[PTi2W10O40] 6H2O', 'Chemical', '-', (390, 409))	('V', 'Chemical', '-', (194, 195))	('K11H', 'Var', (465, 469))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('PM-1', 'Species', '1147034', (581, 585))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('solid tumors', 'Disease', (376, 388))	('PM-19', 'Species', '1551643', (411, 416))	('V', 'Chemical', '-', (351, 352))	('V', 'Chemical', '-', (471, 472))	('V', 'Chemical', '-', (265, 266))	('PM-19', 'Var', (581, 586))	('PM-1', 'Species', '1147034', (494, 498))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('pancreatic cancer', 'Disease', (138, 155))	('solid tumors', 'Disease', 'MESH:D009369', (91, 103))	('V', 'Chemical', '-', (335, 336))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('PM-1', 'Species', '1147034', (365, 369))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('PM-523', 'Chemical', '-', (452, 458))	('influenza', 'Species', '11320', (197, 206))	('solid tumors', 'Disease', 'MESH:D009369', (376, 388))	('PM-1', 'Species', '1147034', (411, 415))	('[PriNH3]6H[PTi2W10O38(O2)2] H2O', 'Chemical', '-', (419, 450))	('[Me3NH]6[H2MoV 12O28(OH)12(MoVIO3)4] 2H2O', 'Chemical', 'MESH:C527543', (322, 363))	('PM-27', 'Chemical', '-', (540, 545))	('SiMo12', 'Chemical', '-', (568, 574))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('K6[P2W18O62] 14H2O', 'Var', (520, 538))	('PM-8', 'Species', '1214577', (312, 316))	('V', 'Chemical', '-', (189, 190))	('PM-17', 'Chemical', '-', (365, 370))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (382, 388))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('HIV', 'Species', '12721', (192, 195))	('PMs', 'Chemical', 'MESH:C102296', (8, 11))
356103	24420711	Therefore, PMs under the physiological condition let us expect to induce some modifications in a variety of biological systems such as the adsorption to receptor, the penetration of substances through the cellular membrane, and the multiple enzymes which can work independently or cooperatively.	('rat', 'Species', '10116', (286, 289))	('PMs', 'Var', (11, 14))	('adsorption to receptor', 'Interaction', (139, 161))	('modifications', 'Reg', (78, 91))	('rat', 'Species', '10116', (172, 175))	('PMs', 'Chemical', 'MESH:C102296', (11, 14))
356106	24420711	Historically, 40 years ago Raynaud and Jasmin first found the biological activity of PMs against various non-retro RNA and DNA viruses in vitro and in vivo and demonstrated the inhibition of Friend leukemia virus and Moloney murine sarcoma virus in vitro by [SiW12O40]4- as a Keggin structure PM and in vivo by [Na(SbW7O24)3(Sb3O7)2]18- (as a French drug [NH4]17Na[Na(SbW7O24)3(Sb3O7)2] 14H2O historically called HPA-23) (Jasmin et al.).	('Friend leukemia virus', 'Disease', 'None', (191, 212))	('Friend leukemia virus', 'Disease', (191, 212))	('[SiW12O40]', 'Var', (258, 268))	('W', 'Chemical', 'MESH:D014414', (370, 371))	('Keggin', 'Chemical', '-', (276, 282))	('inhibition', 'NegReg', (177, 187))	('PM', 'Chemical', 'MESH:C102296', (293, 295))	('PMs', 'Chemical', 'MESH:C102296', (85, 88))	('ago Raynaud', 'Phenotype', 'HP:0030880', (23, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('DNA viruses', 'Species', '2080735', (123, 134))	('[NH4]17Na[Na(SbW7O24)3(Sb3O7)2] 14H2O', 'Chemical', '-', (355, 392))	('W', 'Chemical', 'MESH:D014414', (261, 262))	('W', 'Chemical', 'MESH:D014414', (317, 318))	('PM', 'Chemical', 'MESH:C102296', (85, 87))	('rat', 'Species', '10116', (167, 170))	('Moloney murine sarcoma virus', 'Species', '11809', (217, 245))	('leukemia', 'Phenotype', 'HP:0001909', (198, 206))
356109	24420711	In spite of the negativity of in vivo anti-HIV activity of HPA-23, the assay of the antiviral activity for PMs by other groups has been continued, and many polyoxotungstates with Keggin or Wells-Dawson related (lacunary and multiply condensed) structures, in particular, K13[Ce(SiW11O39)2] 26H2O (JM1590), K6[BGa(H2O)W11O39] 15H2O (JM2766), [Me3NH]8[(SiNb3W9O37)2O3] (JM2820), K7[PTi2W10O40] 6H2O (PM-19), K9H5[(GeTi3W9O37)2O3] 16H2O (PM-504), [PriNH3]6H[PTi2W10O38(O2)2] H2O (PM-523), K10[Fe4(H2O)2(PW9O34)2] xH2O (HS-058), K7[P2W17NbO62], and K7[P2W17(NbO2)O61], were found to be in vitro active against DNA and RNA viruses (Hill et al.	('W', 'Chemical', 'MESH:D014414', (417, 418))	('W', 'Chemical', 'MESH:D014414', (384, 385))	(')2] 26H2O', 'Chemical', '-', (286, 295))	('H2O', 'Chemical', '-', (313, 316))	('W', 'Chemical', 'MESH:D014414', (550, 551))	('PM-19', 'Species', '1551643', (398, 403))	('xH2', 'Gene', (510, 513))	('H2O', 'Chemical', '-', (494, 497))	('HS-058', 'Chemical', '-', (516, 522))	('H2O', 'Chemical', '-', (511, 514))	('xH2', 'Gene', '22589', (510, 513))	('W', 'Chemical', 'MESH:D014414', (280, 281))	('H2O', 'Chemical', '-', (430, 433))	('[PriNH3]6H[PTi2W10O38(O2)2] H2O', 'Chemical', '-', (444, 475))	('polyoxotungstates', 'Chemical', '-', (156, 173))	('H2O', 'Chemical', '-', (327, 330))	('W', 'Chemical', 'MESH:D014414', (501, 502))	('RNA', 'Disease', (614, 617))	('[Me3NH]8[(SiNb3W9O37)2O3]', 'Chemical', '-', (341, 366))	('W', 'Chemical', 'MESH:D014414', (317, 318))	('K13[Ce(SiW11O39)2] 26H2O (JM1590', 'Var', (271, 303))	('W', 'Chemical', 'MESH:D014414', (459, 460))	('K6[BGa', 'Var', (306, 312))	('W', 'Chemical', 'MESH:D014414', (356, 357))	('H2O', 'Chemical', '-', (292, 295))	('W', 'Chemical', 'MESH:D014414', (189, 190))	('K7[P2W17NbO62]', 'Var', (525, 539))	('PM-523', 'Chemical', '-', (477, 483))	('W', 'Chemical', 'MESH:D014414', (530, 531))	('PM-504', 'Chemical', '-', (435, 441))	('Keggin', 'Chemical', '-', (179, 185))	('PMs', 'Chemical', 'MESH:C102296', (107, 110))	('K7[P2W17', 'Var', (545, 553))	('K7[PTi2W10O40] 6H2O', 'Chemical', '-', (377, 396))	('] 15H2O', 'Chemical', '-', (323, 330))	('K9H5[(GeTi3W9O37)2O3] 16H2O', 'Chemical', '-', (406, 433))	('H2O', 'Chemical', '-', (393, 396))	('JM2820', 'Chemical', 'MESH:C087529', (368, 374))	('H2O', 'Chemical', '-', (472, 475))	('HIV', 'Species', '12721', (43, 46))	('K7[PTi2W10O40] 6H2O', 'Var', (377, 396))	('DNA', 'Disease', (606, 609))
356117	24420711	In addition, most of the antiviral polyoxotungstates exhibit a great synergistic effect with beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA) strains (Yamase et al.	('vancomycin', 'Chemical', 'MESH:D014640', (180, 190))	('synergistic', 'MPA', (69, 80))	('polyoxotungstates', 'Chemical', '-', (35, 52))	('methicillin-resistant Staphylococcus aureus', 'Disease', (125, 168))	('Staphylococcus aureus', 'Species', '1280', (147, 168))	('polyoxotungstates', 'Var', (35, 52))	('beta-lactam', 'Chemical', 'MESH:D047090', (93, 104))	('methicillin', 'Chemical', 'MESH:D008712', (125, 136))	('V', 'Chemical', '-', (224, 225))	('Staphylococcus aureus', 'Species', '1280', (201, 222))
356121	24420711	Also, PMs enhanced nerve growth factor (NGF)-induced neurite growth of PC12 cells with expression of the axonal growth associated protein 43 (GAP-43) (Oda et al.).	('growth associated protein 43', 'Gene', '29423', (112, 140))	('PC12', 'CellLine', 'CVCL:0481', (71, 75))	('PMs', 'Var', (6, 9))	('enhanced', 'PosReg', (10, 18))	('growth associated protein 43', 'Gene', (112, 140))	('GAP-43', 'Gene', '29423', (142, 148))	('PMs', 'Chemical', 'MESH:C102296', (6, 9))	('GAP-43', 'Gene', (142, 148))	('nerve', 'CPA', (19, 24))
356132	24420711	In [PTi2W10O40]7-, two W atoms in T d-symmetric Keggin-structural [PW12O40]3- are substituted by Ti atoms to yield a C 2-symmetric anion (Domaille and Knoth; Yamase et al.	('[PTi2W10O40]', 'Var', (3, 15))	('Ti', 'Chemical', 'MESH:D014025', (97, 99))	('W', 'Chemical', 'MESH:D014414', (23, 24))	('Ti', 'Chemical', 'MESH:D014025', (5, 7))	('W', 'Chemical', 'MESH:D014414', (68, 69))	('C 2-symmetric anion', 'MPA', (117, 136))	('[PW12O40]3-', 'Var', (66, 77))	('W', 'Chemical', 'MESH:D014414', (8, 9))	('Keggin', 'Chemical', '-', (48, 54))
356134	24420711	The anion of [(VIVO)3(SbW9O33)2]12- for K11H[(VO)3(SbW9O33)2] 27H2O (PM-1002) as a potently antiviral (especially anti-SARS) active compound is shown in Fig.	('V', 'Chemical', '-', (15, 16))	('W', 'Chemical', 'MESH:D014414', (53, 54))	('V', 'Chemical', '-', (46, 47))	('K11H[', 'Var', (40, 45))	('antiviral', 'MPA', (92, 101))	('PM-1', 'Species', '1147034', (69, 73))	('W', 'Chemical', 'MESH:D014414', (24, 25))	('K11H[(VO)3(SbW9O33)2] 27H2O', 'Chemical', '-', (40, 67))	('V', 'Chemical', '-', (17, 18))
356137	24420711	for K6[P2W18O62] 14H2O (PM-27) is antiviral and also synergistically antibacterial against MRSA and VRSA strains in the coexistence of beta-lactam antibody, the structure of which is shown in Fig.	('lactam antibody', 'Phenotype', 'HP:0031028', (140, 155))	('beta-lactam', 'Chemical', 'MESH:D047090', (135, 146))	('beta-lactam', 'Protein', (135, 146))	('antiviral', 'MPA', (34, 43))	('K6[P2W18O62] 14H2O', 'Chemical', '-', (4, 22))	('V', 'Chemical', '-', (100, 101))	('PM-27', 'Chemical', '-', (24, 29))	('K6[P2W18O62] 14H2O', 'Var', (4, 22))	('antibacterial', 'NegReg', (69, 82))
356143	24420711	Especially, [NH3Pri]6[Mo7O24] 3H2O (PM-8) suppresses significantly the tumor growth in mice bearing methylcholanthrene-induced tumor (Meth-A sarcoma), MM-46 adenocarcinoma, and human cancer xenografts such as MX-1, CO-4, and OAT (Yamase et al.).	('suppresses', 'NegReg', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('[NH3Pri]6[Mo7O24] 3H2O', 'Var', (12, 34))	('human', 'Species', '9606', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Disease', (183, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('OAT', 'Disease', 'MESH:D015799', (225, 228))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Meth-A sarcoma', 'Disease', 'MESH:D012509', (134, 148))	('PM-8', 'Species', '1214577', (36, 40))	('Meth-A sarcoma', 'Disease', (134, 148))	('MM-46 adenocarcinoma', 'Disease', 'MESH:D000230', (151, 171))	('methylcholanthrene', 'Chemical', 'MESH:D008748', (100, 118))	('OAT', 'Disease', (225, 228))	('tumor', 'Disease', (71, 76))	('CO-4', 'Gene', (215, 219))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('CO-4', 'Gene', '720', (215, 219))	('tumor', 'Disease', (127, 132))	('[NH3Pri]6[Mo7O24] 3H2O', 'Chemical', 'MESH:C081971', (12, 34))	('mice', 'Species', '10090', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('MM-46 adenocarcinoma', 'Disease', (151, 171))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
356145	24420711	Table 4.1 shows results of antitumor activities of PM-8, [NH4]6[Mo7O24] 4H2O, K6[Mo7O24] 4H2O, [NH3Pri]Cl, and PM-17 as the brown-colored powder (the photoreduction product of PM-8) against Meth-A sarcoma and MM-46 adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('[NH4]6[Mo7O24] 4H2O', 'Chemical', '-', (57, 76))	('tumor', 'Disease', (31, 36))	('K6[Mo7O24] 4H2O', 'Chemical', '-', (78, 93))	('[NH3Pri]Cl', 'Chemical', '-', (95, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('PM-17', 'Chemical', '-', (111, 116))	('Meth-A sarcoma and MM-46 adenocarcinoma', 'Disease', 'MESH:D000230', (190, 229))	('PM-8', 'Species', '1214577', (51, 55))	('PM-8', 'Species', '1214577', (176, 180))	('PM-8', 'Gene', (51, 55))	('K6[Mo7O24] 4H2O', 'Var', (78, 93))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
356152	24420711	It is easy to see the dose schedule in which ILS values for PM-8 are higher than for 5-FU and ACNU.	('PM-8', 'Species', '1214577', (60, 64))	('PM-8', 'Var', (60, 64))	('ACNU', 'Chemical', '-', (94, 98))	('5-FU', 'Chemical', 'MESH:D005472', (85, 89))	('higher', 'PosReg', (69, 75))	('ILS values', 'MPA', (45, 55))
356158	24420711	To study the structure-activity relationship of PM-8, the effect of chemical variation against the Meth-A sarcoma is investigated by a use of three different ways (1) [NH3Pri]+ in PM-8 was replaced by [NH4]+ and K+, (2) [Mo7O24]6- was replaced by Cl-, (3) PM-17, the photoreduction product (with brown color) of PM-8, was used, the anion ([H2MoV 12O28(OH)12(MoVIO3)4]6-) of which was X-ray crystallographically characterized for [Me3NH]+ salt (Yamase and Ikawa; Yamase and Ishikawa).	('Meth-A sarcoma', 'Disease', 'MESH:D012509', (99, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Meth-A sarcoma', 'Disease', (99, 113))	('PM-8', 'Species', '1214577', (180, 184))	('Mo7O24]6-', 'Chemical', '-', (221, 230))	('PM-8', 'Species', '1214577', (312, 316))	('[Mo7O24]6', 'Chemical', '-', (220, 229))	('PM-8', 'Species', '1214577', (48, 52))	('[H2MoV 12O28(OH)12(MoVIO3)4]6-', 'Chemical', '-', (339, 369))	('[Me3NH]+ salt', 'Var', (429, 442))	('PM-17', 'Chemical', '-', (256, 261))
356160	24420711	As shown in Table 4.1, [NH4][Mo7O24] 4H2O and K4[Mo7O24] 4H2O are effective as well as PM-8, while [NH3Pri]Cl (100 mg/kg) is hardly effective.	('[NH4][Mo7O24] 4H2O', 'Chemical', '-', (23, 41))	('K4[Mo7O24] 4H2O', 'Var', (46, 61))	('K4[Mo7O24] 4H2O', 'Chemical', '-', (46, 61))	('[NH4][Mo7O24] 4H2O', 'Var', (23, 41))	('PM-8', 'Species', '1214577', (87, 91))	('[NH3Pri]Cl', 'Chemical', '-', (99, 109))
356163	24420711	Since PM-17 is a multiply photoreduced species originated from PM-8, the toxicity reflected by the negative change in the body weight seems to be associated with the high condensation structure produced as a result of the 12-electron reduction of [Mo7O24]6-.	('PM-17', 'Chemical', '-', (6, 11))	('Mo7O24]6-', 'Chemical', '-', (248, 257))	('Si', 'Chemical', 'MESH:D012825', (0, 2))	('[Mo7O24]', 'Var', (247, 255))	('toxicity', 'Disease', 'MESH:D064420', (73, 81))	('toxicity', 'Disease', (73, 81))	('[Mo7O24]6', 'Chemical', '-', (247, 256))	('PM-8', 'Species', '1214577', (63, 67))	('high condensation structure', 'MPA', (166, 193))	('PM-8', 'Gene', (63, 67))
356177	24420711	Thus, it is possible to say that PM-17 exhibits a cancerocidal potency similar to PM-8 but is strongly toxic, indicating that an optimum of the administration schedule should be taken into consideration, as below exemplified for the nude mice loaded by AsPC-1 (human pancreatic cancer ) and MKN-45 (human gastric cancer).	('cancer', 'Disease', (50, 56))	('rat', 'Species', '10116', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('mum', 'Gene', (133, 136))	('cancer', 'Disease', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (267, 284))	('gastric cancer', 'Phenotype', 'HP:0012126', (305, 319))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('pancreatic cancer', 'Disease', (267, 284))	('AsPC-1', 'CellLine', 'CVCL:0152', (253, 259))	('rat', 'Species', '10116', (196, 199))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('human', 'Species', '9606', (299, 304))	('mum', 'Gene', '56925', (133, 136))	('human', 'Species', '9606', (261, 266))	('gastric cancer', 'Disease', (305, 319))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('PM-17', 'Chemical', '-', (33, 38))	('PM-17', 'Var', (33, 38))	('MKN-45', 'Chemical', '-', (291, 297))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (267, 284))	('PM-8', 'Species', '1214577', (82, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (305, 319))	('nude mice', 'Species', '10090', (233, 242))	('cancer', 'Disease', (313, 319))
356188	24420711	The comparison of the amounts of Mo atoms between PM-8-treated and untreated mice indicates that PM-8 is preferentially distributed to the kidney and tumor but hardly to the brain or liver (Fig.	('mice', 'Species', '10090', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('PM-8', 'Species', '1214577', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('preferentially', 'PosReg', (105, 119))	('tumor', 'Disease', (150, 155))	('PM-8', 'Var', (97, 101))	('PM-8', 'Species', '1214577', (50, 54))
356196	24420711	The variety of cations in the [Mo7O24]6- system will modify the residence time of [Mo7O24]6- within the tumor cells (leading to a high amount of Mo atoms) as well as the solubility (or stability) under the physiological condition.	('stability', 'MPA', (185, 194))	('Mo7O24]6-', 'Chemical', '-', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('modify', 'Reg', (53, 59))	('[Mo7O24]', 'Var', (82, 90))	('[Mo7O24]6', 'Chemical', '-', (82, 91))	('Mo7O24]6-', 'Chemical', '-', (31, 40))	('tumor', 'Disease', (104, 109))	('amount', 'MPA', (135, 141))	('[Mo7O24]6', 'Chemical', '-', (30, 39))	('residence time', 'MPA', (64, 78))	('solubility', 'MPA', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
356217	24420711	USA) containing PM-17, IC50 values of PM-17 against AsPC-1 cells and MKN-45 cells were 175 mug/ml (63 muM) and 40 mug/ml (14 muM), respectively, which are much smaller than IC50 values of PM-8, 1.65 mg/ml (1.12 mM) and 0.90 mg/ml (0.62 mM).	('PM-17', 'Gene', (38, 43))	('muM', 'Gene', (102, 105))	('PM-8', 'Species', '1214577', (188, 192))	('PM-17', 'Chemical', '-', (38, 43))	('muM', 'Gene', '56925', (125, 128))	('muM', 'Gene', (125, 128))	('PM-17', 'Chemical', '-', (16, 21))	('PM-17', 'Var', (16, 21))	('MKN-45', 'Chemical', '-', (69, 75))	('AsPC-1', 'CellLine', 'CVCL:0152', (52, 58))	('muM', 'Gene', '56925', (102, 105))
356240	24420711	The expression of LC3 (I and II) proteins for the PM-17-treated AsPC-1 cells indicated the autophagy in contrast to the control showing no expression of LC3 on a Western blotting picture (Fig.	('LC3', 'Gene', '84557', (18, 21))	('PM-17-treated', 'Var', (50, 63))	('LC3', 'Gene', (18, 21))	('LC3', 'Gene', '84557', (153, 156))	('AsPC-1', 'CellLine', 'CVCL:0152', (64, 70))	('LC3', 'Gene', (153, 156))	('autophagy', 'CPA', (91, 100))	('PM-17', 'Chemical', '-', (50, 55))
356251	24420711	Thus, the photochemically 12-electron-reduced species of [Mo7O24]6-, [H2MoV 12O28(OH)12(MoVIO3)4]6-, which may be a candidate of metabolites of PM-8, is in vitro and in vivo more inhibitory against solid cancer growth than [Mo7O24]6-.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('Mo7O24]6-', 'Chemical', '-', (58, 67))	('inhibitory', 'NegReg', (179, 189))	('[Mo7O24]', 'Var', (57, 65))	('[Mo7O24]6', 'Chemical', '-', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('PM-8', 'Species', '1214577', (144, 148))	('[H2MoV 12O28(OH)12(MoVIO3)4]6-', 'Chemical', '-', (69, 99))	('[Mo7O24]6', 'Chemical', '-', (223, 232))	('Mo7O24]6-', 'Chemical', '-', (224, 233))
356255	24420711	4.1c) exhibited a potent inhibition both in vitro and in vivo against a broad spectrum of DNA viruses including herpes simplex virus (HSV) type 1 (HSV-1) and HSV type 2 (HSV-2), thymidine kinase-deficient (TK-) HSV mutant, and human cytomegalovirus (HCMV) (Fukuma et al.	('V', 'Chemical', '-', (149, 150))	('V', 'Chemical', '-', (253, 254))	('HCMV', 'Species', '10359', (250, 254))	('V', 'Chemical', '-', (160, 161))	('human cytomegalovirus', 'Species', '10359', (227, 248))	('V', 'Chemical', '-', (172, 173))	('herpes simplex', 'Phenotype', 'HP:0012302', (112, 126))	('thymidine kinase', 'Gene', '1487307', (178, 194))	('V', 'Chemical', '-', (136, 137))	('V', 'Chemical', '-', (213, 214))	('DNA', 'Disease', (90, 93))	('mutant', 'Var', (215, 221))	('inhibition', 'NegReg', (25, 35))	('HSV-2', 'Species', '10310', (170, 175))	('thymidine kinase', 'Gene', (178, 194))	('HSV-1', 'Species', '10298', (147, 152))	('DNA viruses', 'Species', '2080735', (90, 101))
356272	24420711	CC50 and EC50 (median cytotoxic and effective concentrations, respectively) values for seven PMs including four V/W-mixed PMs (PM-43, PM-47, PM-1001, and PM-1002) and three Ti/W-mixed PMs (PM-518, PM-520, and PM-523) against RNA viruses are listed in Tables 4.5 and 4.6, respectively (Shigeta et al.).	('PMs', 'Chemical', 'MESH:C102296', (184, 187))	('PM-1001', 'Var', (141, 148))	('PM-', 'Chemical', 'MESH:C102296', (127, 130))	('W', 'Chemical', 'MESH:D014414', (176, 177))	('W', 'Chemical', 'MESH:D014414', (114, 115))	('PM-520', 'Chemical', '-', (197, 203))	('PM-', 'Chemical', 'MESH:C102296', (141, 144))	('PM-', 'Chemical', 'MESH:C102296', (197, 200))	('PM-523', 'Chemical', '-', (209, 215))	('PM-1', 'Species', '1147034', (154, 158))	('PM-', 'Chemical', 'MESH:C102296', (134, 137))	('PM-', 'Chemical', 'MESH:C102296', (189, 192))	('PM-1002', 'Var', (154, 161))	('PMs', 'Chemical', 'MESH:C102296', (93, 96))	('PM-523', 'Var', (209, 215))	('V', 'Chemical', '-', (112, 113))	('RNA', 'Disease', (225, 228))	('PM-', 'Chemical', 'MESH:C102296', (209, 212))	('PM-', 'Chemical', 'MESH:C102296', (154, 157))	('rat', 'Species', '10116', (53, 56))	('PM-518', 'Var', (189, 195))	('Ti', 'Chemical', 'MESH:D014025', (173, 175))	('PM-1', 'Species', '1147034', (141, 145))	('PM-47', 'Var', (134, 139))	('PMs', 'Chemical', 'MESH:C102296', (122, 125))	('PM-43', 'Var', (127, 132))
356277	24420711	The listed PMs were inhibitory to the replication of HIV-1(IIIb) in EC50 values at the range of 0.03-2.0 muM and were selectively inhibitory against other RNA viruses such as dengue fever virus (DFV), influenza virus A (FluV-A), respiratory syncytial virus (RSV), parainfluenza virus type 2 (PfluV-2), and canine distemper virus (CDV) with more inhibitive values than ribavirin as an inhibitor of the viral RNA synthesis due to its inhibition of inosine monophosphate dehydrogenase activity in cells (Gilbert and Knight): PM-43, PM-518, and PM-523 were not inhibitory against PfluV-2, CDV, and DFV, respectively, as indicated by EC50 values more than 50 muM.	('PM-43', 'Var', (522, 527))	('ribavirin', 'Chemical', 'MESH:D012254', (368, 377))	('dengue fever', 'Phenotype', 'HP:0032249', (175, 187))	('muM', 'Gene', '56925', (654, 657))	('muM', 'Gene', '56925', (105, 108))	('PM-', 'Chemical', 'MESH:C102296', (522, 525))	('muM', 'Gene', (105, 108))	('muM', 'Gene', (654, 657))	('inosine monophosphate dehydrogenase activity', 'MPA', (446, 490))	('PfluV-2', 'Species', '11212', (292, 299))	('parainfluenza virus type 2', 'Species', '11212', (264, 290))	('fever', 'Phenotype', 'HP:0001945', (182, 187))	('PM-', 'Chemical', 'MESH:C102296', (529, 532))	('dengue fever', 'Disease', 'MESH:D003715', (175, 187))	('PM-523', 'Chemical', '-', (541, 547))	('RSV', 'Species', '12814', (258, 261))	('phosphate', 'Chemical', 'MESH:D010710', (458, 467))	('respiratory syncytial virus', 'Species', '12814', (229, 256))	('PMs', 'Chemical', 'MESH:C102296', (11, 14))	('inhibition', 'NegReg', (432, 442))	('influenza virus', 'Species', '11308', (268, 283))	('DFV', 'Chemical', '-', (594, 597))	('PM-523', 'Var', (541, 547))	('PfluV-2', 'Species', '11212', (576, 583))	('canine distemper virus', 'Species', '11232', (306, 328))	('HIV-1(IIIb)', 'Disease', 'MESH:D009084', (53, 64))	('CDV', 'Species', '11232', (330, 333))	('PM-518', 'Var', (529, 535))	('PM-', 'Chemical', 'MESH:C102296', (541, 544))	('dengue fever', 'Disease', (175, 187))	('CDV', 'Species', '11232', (585, 588))	('FluV-A', 'Chemical', 'MESH:D000077340', (220, 226))	('DFV', 'Chemical', '-', (195, 198))	('influenza virus', 'Species', '11308', (201, 216))
356283	24420711	K13[Ce(SiW11O39)2] 26H2O (JM1590) and K6[BGa(H2O)W11O39] 15H2O (JM2766), which inhibited HIV-1 and simian immunodeficiency viruses at concentrations as low as 0.008-0.8 muM, seem to be the most potent anti-HIV compounds (Yamamoto et al.).	('HIV', 'Species', '12721', (206, 209))	('rat', 'Species', '10116', (141, 144))	('H2O', 'Chemical', '-', (21, 24))	('] 15H2O', 'Chemical', '-', (55, 62))	('H2O', 'Chemical', '-', (59, 62))	('H2O', 'Chemical', '-', (45, 48))	('muM', 'Gene', '56925', (169, 172))	(')2] 26H2O', 'Chemical', '-', (15, 24))	('K6[', 'Var', (38, 41))	('inhibited', 'NegReg', (79, 88))	('muM', 'Gene', (169, 172))	('HIV-1 and simian immunodeficiency viruses', 'Disease', 'MESH:D016097', (89, 130))	('immunodeficiency', 'Phenotype', 'HP:0002721', (106, 122))	('W', 'Chemical', 'MESH:D014414', (49, 50))	('HIV', 'Species', '12721', (89, 92))	('W', 'Chemical', 'MESH:D014414', (9, 10))
356286	24420711	Selective indices, SI (=CC50/EC50), of the V/W-mixed Keggin PMs (especially PM-1001 and PM-1002) against HIV-1 in MT-4 cell line were higher than those of AZT (as the inhibitor for the reverse transcriptase) (Mitsuya et al.)	('PMs', 'Chemical', 'MESH:C102296', (60, 63))	('Keggin', 'Chemical', '-', (53, 59))	('V', 'Chemical', '-', (43, 44))	('higher', 'PosReg', (134, 140))	('HIV-1', 'Species', '11676', (105, 110))	('SI', 'Chemical', '-', (19, 21))	('PM-1', 'Species', '1147034', (76, 80))	('W', 'Chemical', 'MESH:D014414', (45, 46))	('AZT', 'Chemical', 'MESH:D015215', (155, 158))	('PM-1002', 'Var', (88, 95))	('V', 'Chemical', '-', (107, 108))	('PM-1', 'Species', '1147034', (88, 92))	('MT-4', 'CellLine', 'CVCL:2632', (114, 118))
356289	24420711	Table 4.7 shows the result of the multinuclear activation of the galactosidase indicator (MAGI) assay for HeLa CD4/LTR-beta-Gal cell line (Kimpton and Emerman), which indicates SI values (>10,000 and >5,500 for PM-1001 and PM-1002, respectively) are higher than for DS5000 (>3,000) and AZT (>2,700), strongly supports their high antiviral activity against HIV-1.	('AZT', 'Chemical', 'MESH:D015215', (286, 289))	('antiviral activity', 'MPA', (329, 347))	('PM-1002', 'Var', (223, 230))	('PM-1', 'Species', '1147034', (223, 227))	('CD4', 'Gene', (111, 114))	('HeLa', 'CellLine', 'CVCL:0030', (106, 110))	('CD4', 'Gene', '920', (111, 114))	('HIV-1', 'Species', '11676', (356, 361))	('PM-1', 'Species', '1147034', (211, 215))	('SI', 'Chemical', '-', (177, 179))	('PM-1001', 'Var', (211, 218))
356292	24420711	In vivo anti-HIV activity was carried out by using recombinant vaccinia viruses (rVV), vPE16 expressing HIV-1 env gene (vPE16-env), vP1206 expressing HIV-IIIb gag/pol gene (vP1206-gag/pol), and wild WR strain (WR, control rVV).	('pol', 'Gene', '17276', (184, 187))	('vP1206-gag/pol', 'Gene', '17276', (173, 187))	('HIV', 'Species', '12721', (104, 107))	('HIV-1', 'Species', '11676', (104, 109))	('W', 'Chemical', 'MESH:D014414', (199, 200))	('W', 'Chemical', 'MESH:D014414', (210, 211))	('vP1206-gag/pol', 'Gene', (173, 187))	('HIV', 'Species', '12721', (150, 153))	('pol', 'Gene', (163, 166))	('HIV', 'Species', '12721', (13, 16))	('pol', 'Gene', (184, 187))	('vP1206', 'Var', (132, 138))	('pol', 'Gene', '17276', (163, 166))
356298	24420711	4.11a, the PM dose for the challenge was determined along with the result of in vivo cytotoxicity of PMs: each of PM-523, PM-1002, and PM-1208 provided a100 % survival rate on the 4th day after its i.p.	('PM-1002', 'Var', (122, 129))	('PM', 'Chemical', 'MESH:C102296', (11, 13))	('PMs', 'Chemical', 'MESH:C102296', (101, 104))	('PM-1', 'Species', '1147034', (122, 126))	('PM-1208', 'Chemical', '-', (135, 142))	('PM', 'Chemical', 'MESH:C102296', (114, 116))	('PM', 'Chemical', 'MESH:C102296', (101, 103))	('PM-523', 'Var', (114, 120))	('PM', 'Chemical', 'MESH:C102296', (135, 137))	('cytotoxicity', 'Disease', (85, 97))	('PM-1208', 'Var', (135, 142))	('rat', 'Species', '10116', (168, 171))	('PM-523', 'Chemical', '-', (114, 120))	('PM-1', 'Species', '1147034', (135, 139))	('PM', 'Chemical', 'MESH:C102296', (122, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))
356300	24420711	All PM-523, PM-1002, and PM-1208 suppressed the viral activity of both vPE16-env and vP1206-gag/pol in vivo with almost the same activity for administrations of 12.5 and 125 mg/kg/day/mouse.	('PM-1208', 'Var', (25, 32))	('PM-1', 'Species', '1147034', (25, 29))	('PM-523', 'Var', (4, 10))	('rat', 'Species', '10116', (150, 153))	('viral activity', 'MPA', (48, 62))	('PM-1002', 'Var', (12, 19))	('mouse', 'Species', '10090', (184, 189))	('PM-523', 'Chemical', '-', (4, 10))	('vPE16-env', 'Protein', (71, 80))	('vP1206-gag/pol', 'Gene', '17276', (85, 99))	('PM-1208', 'Chemical', '-', (25, 32))	('vP1206-gag/pol', 'Gene', (85, 99))	('suppressed', 'NegReg', (33, 43))	('PM-1', 'Species', '1147034', (12, 16))
356301	24420711	Especially, PM-523 and PM-1208 exhibited a potent antiviral activity against vPE16-env (with p < 0.01) and vP1206-gag/pol (with p < 0.05), respectively (Fig.	('PM-523', 'Chemical', '-', (12, 18))	('vP1206-gag/pol', 'Gene', (107, 121))	('vPE16-env', 'Gene', (77, 86))	('PM-1208', 'Chemical', '-', (23, 30))	('PM-1208', 'Var', (23, 30))	('antiviral activity', 'MPA', (50, 68))	('vP1206-gag/pol', 'Gene', '17276', (107, 121))
356314	24420711	Interestingly, PM-523 (as Keggin structure), a Ti/W-mixed PM, did not inhibit the adsorption of the influenza A virus (FluV-A) onto the cell membrane (0-1.5 h after infection) but inhibits the fusion between the FluV-A envelope and the cellular membrane (1.5-120 h after infection) (Shigeta et al.).	('influenza A virus', 'Species', '11320', (100, 117))	('W', 'Chemical', 'MESH:D014414', (50, 51))	('PM', 'Chemical', 'MESH:C102296', (58, 60))	('infection', 'Disease', (165, 174))	('FluV-A', 'Chemical', 'MESH:D000077340', (119, 125))	('infection', 'Disease', 'MESH:D007239', (165, 174))	('FluV-A', 'Chemical', 'MESH:D000077340', (212, 218))	('infection', 'Disease', (271, 280))	('Keggin', 'Chemical', '-', (26, 32))	('infection', 'Disease', 'MESH:D007239', (271, 280))	('inhibits', 'NegReg', (180, 188))	('Ti', 'Chemical', 'MESH:D014025', (47, 49))	('PM', 'Chemical', 'MESH:C102296', (15, 17))	('PM-523', 'Var', (15, 21))	('PM-523', 'Chemical', '-', (15, 21))	('fusion', 'MPA', (193, 199))
356329	24420711	Thus, the survival rate for the mice treated with the combination of PM-523 and ribavirin at a ratio of 1:16 was significantly high compared with the one with either 4.8-mM PM-523 or 80-mM ribavirin.	('survival rate', 'CPA', (10, 23))	('ribavirin', 'Chemical', 'MESH:D012254', (80, 89))	('rat', 'Species', '10116', (95, 98))	('high', 'PosReg', (127, 131))	('PM-523', 'Var', (69, 75))	('rat', 'Species', '10116', (19, 22))	('mice', 'Species', '10090', (32, 36))	('PM-523', 'Chemical', '-', (69, 75))	('PM-523', 'Chemical', '-', (173, 179))	('ribavirin', 'Chemical', 'MESH:D012254', (189, 198))
356335	24420711	The viral titers in the lungs for the infected mice treated with the combination of 2.4-mM PM-523 and 40-mM ribavirin were consistently lower than for the infected mice treated with either 2.4-mM PM-523 or 40-mM ribavirin.	('lower', 'NegReg', (136, 141))	('infected', 'Disease', (155, 163))	('infected', 'Disease', 'MESH:D007239', (38, 46))	('infected', 'Disease', 'MESH:D007239', (155, 163))	('mice', 'Species', '10090', (164, 168))	('PM-523', 'Chemical', '-', (196, 202))	('ribavirin', 'Chemical', 'MESH:D012254', (108, 117))	('2.4-mM PM-523', 'Var', (84, 97))	('infected', 'Disease', (38, 46))	('ribavirin', 'Chemical', 'MESH:D012254', (212, 221))	('viral titers', 'MPA', (4, 16))	('mice', 'Species', '10090', (47, 51))	('PM-523', 'Chemical', '-', (91, 97))
356337	24420711	The mutations conferring resistance to PM-523 indicated that isoleucine 202 and lysine 189, which were located at the interface edges of the trimer molecules of HA1, were substituted with threonine and asparagine, respectively.	('HA1', 'Gene', (161, 164))	('lysine', 'Chemical', 'MESH:D008239', (80, 86))	('lysine 189', 'Var', (80, 90))	('isoleucine 202', 'Var', (61, 75))	('HA1', 'Gene', '16660', (161, 164))	('isoleucine', 'Chemical', 'MESH:D007532', (61, 71))	('PM-523', 'Chemical', '-', (39, 45))	('asparagine', 'Chemical', 'MESH:D001216', (202, 212))	('threonine', 'Chemical', 'MESH:D013912', (188, 197))
356338	24420711	This strongly implies that PM-523 binds to the interface edges of HA trimers and inhibits the opening of HA1 trimers to lead to the inhibition of the fusion of viral envelope to cellular membrane by HA2 hydrophobic amino acids at the edge of the cleavage site (Shigeta; Shigeta et al.).	('inhibits', 'NegReg', (81, 89))	('inhibition', 'NegReg', (132, 142))	('fusion', 'MPA', (150, 156))	('HA1', 'Gene', '16660', (105, 108))	('PM-523', 'Chemical', '-', (27, 33))	('opening', 'MPA', (94, 101))	('HA1', 'Gene', (105, 108))	('viral envelope to', 'Protein', (160, 177))	('HA2 hydrophobic amino acids', 'Var', (199, 226))
356340	24420711	PM-523 and its congeners Ti/W-mixed PMs (e.g., PM-19 and PM-504) and V/W-mixed PMs have a broad antiviral activity against enveloped RNA viruses (Table 4.6) and may be developed as broad-spectrum drugs for acute respiratory infection (ARI) caused by orthomyxoviruses (influenza viruses A, B, and C) and paramyxoviruses (human parainfluenza viruses 1, 3, 2, and 4; measles virus; and RSV).	('human', 'Species', '9606', (320, 325))	('PM-504', 'Chemical', '-', (57, 63))	('antiviral activity', 'MPA', (96, 114))	('PMs', 'Chemical', 'MESH:C102296', (79, 82))	('influenza viruses', 'Species', '11308', (268, 285))	('V', 'Chemical', '-', (69, 70))	('measles virus', 'Species', '11234', (364, 377))	('PM-504', 'Var', (57, 63))	('PM-19', 'Species', '1551643', (47, 52))	('Ti', 'Chemical', 'MESH:D014025', (25, 27))	('V', 'Chemical', '-', (385, 386))	('influenza viruses', 'Species', '11308', (330, 347))	('respiratory infection', 'Disease', 'MESH:D012141', (212, 233))	('parainfluenza', 'Species', '11212', (326, 339))	('PMs', 'Chemical', 'MESH:C102296', (36, 39))	('W', 'Chemical', 'MESH:D014414', (71, 72))	('enveloped RNA viruses', 'Protein', (123, 144))	('respiratory infection', 'Phenotype', 'HP:0011947', (212, 233))	('PM-523', 'Chemical', '-', (0, 6))	('W', 'Chemical', 'MESH:D014414', (28, 29))	('RSV', 'Species', '12814', (383, 386))	('respiratory infection', 'Disease', (212, 233))
356348	24420711	Together with the specific binding of PM-19 with HVEM as a TNF receptor superfamily (which was suggested by the investigation of anti-HSV activity of PM-19) (Dan and Yamase), therefore, the antiviral mechanism of the PMs, which inhibit the adsorption of the enveloped RNA (or DNA) viruses toward the host cells, is likely to involve the functional quenching of the sialic acid residues of the carbohydrate side chains of cellular proteins, if we considered that binding between multiple HA ligands of influenza virus and sialic acid surface receptors of an erythrocyte for the cell during viral infection occurs with extremely strong affinity of 1015 per molar, while the association constant for a single sialic acid-HA interaction is only 103 per molar (Mammen et al.).	('1015', 'Var', (646, 650))	('inhibit', 'NegReg', (228, 235))	('V', 'Chemical', '-', (50, 51))	('sialic acid', 'Chemical', 'MESH:D019158', (365, 376))	('carbohydrate', 'Chemical', 'MESH:D002241', (393, 405))	('influenza virus', 'Species', '11308', (501, 516))	('sialic acid', 'Chemical', 'MESH:D019158', (706, 717))	('viral infection', 'Disease', 'MESH:D001102', (589, 604))	('DNA) viruses', 'Species', '2080735', (276, 288))	('sialic acid', 'Chemical', 'MESH:D019158', (521, 532))	('Dan', 'Gene', '4681', (158, 161))	('V', 'Chemical', '-', (136, 137))	('binding', 'Interaction', (462, 469))	('viral infection', 'Disease', (589, 604))	('PM-19', 'Species', '1551643', (150, 155))	('Dan', 'Gene', (158, 161))	('PM-19', 'Species', '1551643', (38, 43))	('PMs', 'Chemical', 'MESH:C102296', (217, 220))
356354	24420711	): for example, PM-504 inhibited ST3Gal-1 activity with inhibition constant (K i) ~ 0.5 nM (0.47 and 0.53 nM for core 1 as an acceptor and CMP-Neu5Ac as a donor, respectively) which were much lower than K i = 29 nM for the previously reported lowest inhibitors of glycosides analogues (Schworer and Schmidt).	('ST3Gal-1', 'Gene', '20442', (33, 41))	('CMP-Neu5Ac', 'Chemical', 'MESH:C561601', (139, 149))	('activity', 'MPA', (42, 50))	('inhibited', 'NegReg', (23, 32))	('PM-504', 'Var', (16, 22))	('ST3Gal-1', 'Gene', (33, 41))	('PM-504', 'Chemical', '-', (16, 22))
356357	24420711	The steady-state kinetics results indicate the noncompetitive inhibition of PM-504 against ST3Gal-1, suggesting the interaction of PM-504 with a variety of the binding sites of ST3Gal-1.	('ST3Gal-1', 'Gene', '20442', (91, 99))	('noncompetitive inhibition', 'MPA', (47, 72))	('ST3Gal-1', 'Gene', '20442', (177, 185))	('ST3Gal-1', 'Gene', (91, 99))	('PM-504', 'Chemical', '-', (131, 137))	('PM-504', 'Chemical', '-', (76, 82))	('ST3Gal-1', 'Gene', (177, 185))	('PM-504', 'Var', (131, 137))	('interaction', 'Interaction', (116, 127))
356359	24420711	IC50 values of PM-19, PM-43, PM-518, PM-523, and PM-1002 for ST3Gal-1 were extremely small, 0.4, 0.2, 0.3, 0.6, and 0.4 nM, respectively.	('PM-1002', 'Var', (49, 56))	('PM-', 'Chemical', 'MESH:C102296', (22, 25))	('ST3Gal-1', 'Gene', '20442', (61, 69))	('PM-1', 'Species', '1147034', (49, 53))	('PM-', 'Chemical', 'MESH:C102296', (37, 40))	('PM-', 'Chemical', 'MESH:C102296', (29, 32))	('PM-19', 'Species', '1551643', (15, 20))	('PM-', 'Chemical', 'MESH:C102296', (15, 18))	('ST3Gal-1', 'Gene', (61, 69))	('PM-', 'Chemical', 'MESH:C102296', (49, 52))	('PM-1', 'Species', '1147034', (15, 19))	('PM-523', 'Chemical', '-', (37, 43))
356360	24420711	On the other hand, the spherical polyoxovanadates inhibited both enzymatic activities in the same order of magnitude of nanomolar concentrations: IC50 values of K5[H6KV13O31(MePO3)3] 16.5H2O, Na12H2[H2V18O44(N3)] 30H2O, K10[H2V18O42(H2O)] 16H2O, and K10H3[V18O42(Cl)] 12H2O were 7, 9, 7, and 7 nM, respectively, for ST3Gal-1 and were all 3 nM for ST3Gal-1.	('ST3Gal-1', 'Gene', (316, 324))	('ST3Gal-1', 'Gene', (347, 355))	('polyoxovanadates', 'Chemical', '-', (33, 49))	('K5[H6KV13O31', 'Var', (161, 173))	('H2O', 'Chemical', '-', (241, 244))	('H2O', 'Chemical', '-', (233, 236))	('V', 'Chemical', '-', (201, 202))	('V', 'Chemical', '-', (167, 168))	('V', 'Chemical', '-', (226, 227))	('V', 'Chemical', '-', (256, 257))	('H2O', 'Chemical', '-', (187, 190))	('rat', 'Species', '10116', (137, 140))	('Na12H2', 'CellLine', 'CVCL:U766', (192, 198))	('H2O', 'Chemical', '-', (215, 218))	('ST3Gal-1', 'Gene', '20442', (316, 324))	('ST3Gal-1', 'Gene', '20442', (347, 355))	('H2O', 'Chemical', '-', (270, 273))	('inhibited', 'NegReg', (50, 59))
356362	24420711	The result for the inhibitory effect of PM-504 on the mutated ST3Gal-1 enzymes implied that the inhibition of PMs against the adsorption of the enveloped RNA viruses toward the host cells is due to the strong interaction of the PMs not only with 335Arg residue in the C-terminal region of ST3Gal-1 but also with other basic amino acids residue (Seko et al.).	('335Arg', 'Var', (246, 252))	('ST3Gal-1', 'Gene', (289, 297))	('interaction', 'Interaction', (209, 220))	('PMs', 'Chemical', 'MESH:C102296', (228, 231))	('basic amino acids', 'Chemical', 'MESH:D024361', (318, 335))	('adsorption', 'Interaction', (126, 136))	('PM-504', 'Chemical', '-', (40, 46))	('enveloped', 'Protein', (144, 153))	('ST3Gal-1', 'Gene', '20442', (62, 70))	('PMs', 'Chemical', 'MESH:C102296', (110, 113))	('inhibition', 'NegReg', (96, 106))	('ST3Gal-1', 'Gene', '20442', (289, 297))	('ST3Gal-1', 'Gene', (62, 70))
356363	24420711	Thus, some types of PMs have the ability to inhibit specific sialyl/sulfotransferases, indicating that the PMs directly inhibit the activities of enzymes involved in carbohydrate metabolism to lead to the inhibition of the binding of the HA ligands of influenza virus with sialic acid surface receptors.	('sialic acid surface receptors', 'Protein', (273, 302))	('inhibition', 'NegReg', (205, 215))	('inhibit', 'NegReg', (44, 51))	('enzymes', 'Enzyme', (146, 153))	('carbohydrate', 'Chemical', 'MESH:D002241', (166, 178))	('binding', 'Interaction', (223, 230))	('sialic acid', 'Chemical', 'MESH:D019158', (273, 284))	('activities', 'MPA', (132, 142))	('inhibit', 'NegReg', (120, 127))	('PMs', 'Var', (107, 110))	('sialyl/sulfotransferases', 'Enzyme', (61, 85))	('PMs', 'Chemical', 'MESH:C102296', (20, 23))	('influenza virus', 'Species', '11308', (252, 267))	('PMs', 'Chemical', 'MESH:C102296', (107, 110))
356377	24420711	In particular, the synergistic potential of Keggin-structural polyoxotungstates and their lacunary species, [XW11O39]n- and [XW9O34]n-, were high: FIC indices of these compounds against SR3605 and ATCC43300 were 0.010-0.156.	('SR3605', 'Chemical', '-', (186, 192))	(']n', 'Chemical', 'MESH:D009584', (131, 133))	('polyoxotungstates', 'Chemical', '-', (62, 79))	('W', 'Chemical', 'MESH:D014414', (126, 127))	('Keggin', 'Chemical', '-', (44, 50))	(']n', 'Chemical', 'MESH:D009584', (116, 118))	('synergistic', 'MPA', (19, 30))	('W', 'Chemical', 'MESH:D014414', (110, 111))	('[XW11O39]n-', 'Var', (108, 119))	('ATCC43300', 'Chemical', '-', (197, 206))	('[XW9O34]n-', 'Var', (124, 134))
356379	24420711	Dodeca- and nanotungstosilicates such as Na4[SiW12O40] nH2O, A-beta-Na9[SiW9O34H] 23H2O (PM-30), and A-alpha-Na10[SiW9O34] 18H2O were highly synergistic (with FIC = 0.019, 0.018, and 0.010, respectively) against ATCC43300, suggesting a significance of the Si atom as a hetero atom in polyoxotungstates against this strain.	('Si', 'Chemical', 'MESH:D012825', (72, 74))	('ATCC43300', 'Chemical', '-', (212, 221))	('A-beta', 'Gene', '11820', (61, 67))	('Si', 'Chemical', 'MESH:D012825', (45, 47))	('Si', 'Chemical', 'MESH:D012825', (114, 116))	('nanotungstosilicates', 'Disease', 'None', (12, 32))	('A-alpha-Na10[SiW9O34] 18H2O', 'Var', (101, 128))	('PM-', 'Chemical', 'MESH:C102296', (89, 92))	('Na4[SiW12O40] nH2O', 'Chemical', '-', (41, 59))	('A-alpha', 'Species', '355258', (101, 108))	('H2O', 'Chemical', '-', (56, 59))	('A-beta', 'Gene', (61, 67))	('H2O', 'Chemical', '-', (125, 128))	('polyoxotungstates', 'Chemical', '-', (284, 301))	('H2O', 'Chemical', '-', (84, 87))	('Si', 'Chemical', 'MESH:D012825', (256, 258))	('Na4[SiW12O40] nH2O', 'Var', (41, 59))	('nanotungstosilicates', 'Disease', (12, 32))
356382	24420711	Similarly, most of the polyoxovanadates seemed to exhibit no significant synergism, although K7[MnV13O38] 18H2O with FIC = 0.28 was synergistic.	('synergism', 'Interaction', (73, 82))	('polyoxovanadates', 'Chemical', '-', (23, 39))	('V', 'Chemical', '-', (98, 99))	('H2O', 'Chemical', '-', (108, 111))	('K7[MnV13O38] 18H2O', 'Var', (93, 111))	('Si', 'Chemical', 'MESH:D012825', (0, 2))
356385	24420711	Mechanistic details on the synergistic activity of PMs against MRSA and VRSA strains have been investigated by using K6[P2W18O62] 14H2O (PM-27) as a Wells-Dawson-structural polyoxotungstate (Fig.	('W', 'Chemical', 'MESH:D014414', (122, 123))	('W', 'Chemical', 'MESH:D014414', (149, 150))	('K6[P2W18O62] 14H2O', 'Chemical', '-', (117, 135))	('pol', 'Gene', '17276', (173, 176))	('pol', 'Gene', (173, 176))	('PMs', 'Chemical', 'MESH:C102296', (51, 54))	('K6[P2W18O62]', 'Var', (117, 129))	('PM-27', 'Chemical', '-', (137, 142))	('V', 'Chemical', '-', (72, 73))
356386	24420711	4.1f), K4[SiMo12O40] 3H2O (SiMo12) as a Keggin-structural polyoxomolybdate, and K7[PTi2W10O40] 6H2O (PM-19) as a Ti/W-mixed Keggin-structural polyoxotungstate (Inoue et al.).	('K4[SiMo12O40] 3H2O', 'Chemical', '-', (7, 25))	('PM-19', 'Species', '1551643', (101, 106))	('Keggin', 'Chemical', '-', (124, 130))	('Ti', 'Chemical', 'MESH:D014025', (84, 86))	('W', 'Chemical', 'MESH:D014414', (116, 117))	('pol', 'Gene', (58, 61))	('K7[PTi2W10O40] 6H2O', 'Var', (80, 99))	('pol', 'Gene', '17276', (58, 61))	('W', 'Chemical', 'MESH:D014414', (87, 88))	('pol', 'Gene', (142, 145))	('K4[SiMo12O40] 3H2O', 'Var', (7, 25))	('Ti', 'Chemical', 'MESH:D014025', (113, 115))	('Keggin', 'Chemical', '-', (40, 46))	('SiMo12', 'Chemical', '-', (10, 16))	('pol', 'Gene', '17276', (142, 145))	('SiMo12', 'Chemical', '-', (27, 33))	('K7[PTi2W10O40] 6H2O', 'Chemical', '-', (80, 99))	('polyoxomolybdate', 'Chemical', '-', (58, 74))
356396	24420711	Also, PM-27 and PM-19 caused Mu3 to be changed from homo- to hetero-resistance with a decrease of resistance to beta-lactam (phenotype change).	('beta-lactam', 'Chemical', 'MESH:D047090', (112, 123))	('resistance to beta-lactam', 'MPA', (98, 123))	('Mu3', 'Gene', (29, 32))	('PM-19', 'Species', '1551643', (16, 21))	('PM-19', 'Var', (16, 21))	('changed', 'Reg', (39, 46))	('PM-27', 'Chemical', '-', (6, 11))	('decrease', 'NegReg', (86, 94))	('PM-27', 'Var', (6, 11))
356399	24420711	The difference in the synergism between PM-27 and Na3[PMo12O40] nH2O is associated with the structural stability of the anion at physiological pH level, which was verified by the cyclic voltammetric measurements shown below.	('nH2O', 'Gene', (64, 68))	('synergism', 'MPA', (22, 31))	('Na3[PMo12O40] nH2O', 'Chemical', '-', (50, 68))	('PM-27', 'Chemical', '-', (40, 45))	('structural stability of the', 'MPA', (92, 119))	('Na3[PMo12O40]', 'Var', (50, 63))
356403	24420711	As a next step, the possibility of the inhibition of the transcription from mecA gene to mRNA by PMs with and without oxacillin was investigated by using the reverse transcription polymerase chain reaction (RT-PCR) analysis of the MRSA and VRSA strains which were cultured until the initial stage of logarithmic growth phase (OD660 = 0.1-0.2) both in the presence of PM (PM-27, SiMo12, or PM-19) alone (at less than MIC) and in the coexistence of PM and oxacillin (at 1/4 MIC for each).	('oxacillin', 'Chemical', 'MESH:D010068', (118, 127))	('polymer', 'Chemical', 'MESH:D011108', (180, 187))	('PM-27', 'Chemical', '-', (371, 376))	('PM', 'Chemical', 'MESH:C102296', (367, 369))	('MIC', 'Gene', '17316', (472, 475))	('PM-19', 'Species', '1551643', (389, 394))	('PM', 'Chemical', 'MESH:C102296', (389, 391))	('PM', 'Chemical', 'MESH:C102296', (97, 99))	('MIC', 'Gene', '17316', (416, 419))	('V', 'Chemical', '-', (240, 241))	('MIC', 'Gene', (472, 475))	('oxacillin', 'Chemical', 'MESH:D010068', (454, 463))	('SiMo12', 'Var', (378, 384))	('mecA', 'Gene', (76, 80))	('SiMo12', 'Chemical', '-', (378, 384))	('MIC', 'Gene', (416, 419))	('PM', 'Chemical', 'MESH:C102296', (371, 373))	('PM-19', 'Var', (389, 394))	('PM', 'Chemical', 'MESH:C102296', (447, 449))	('PMs', 'Chemical', 'MESH:C102296', (97, 100))
356406	24420711	4.16a and 4.17a, each of PM-27, SiMo12, and PM-19 showed a decrease in the band intensities of the mecA-induced mRNA at concentrations less than MIC (1/2 MIC PM-27 displayed the inhibition of 30 % for SR3605 and 10 % for Mu50, although the depression of the band intensities by PM-27 alone at its concentrations less than 1/4 MIC), and the extent of the decrease increased with an increase in its concentration in comparison with that of 16S rRNA, indicating that the transcription process from mecA to mRNA was inhibited by the PMs.	('depression', 'Disease', 'MESH:D000275', (240, 250))	('rat', 'Species', '10116', (127, 130))	('MIC', 'Gene', (326, 329))	('inhibited', 'NegReg', (512, 521))	('depression', 'Phenotype', 'HP:0000716', (240, 250))	('SR3605', 'Var', (201, 207))	('SiMo12', 'Chemical', '-', (32, 38))	('PM-27', 'Var', (25, 30))	('rat', 'Species', '10116', (404, 407))	('MIC', 'Gene', '17316', (154, 157))	('SR3605', 'Chemical', '-', (201, 207))	('decrease', 'NegReg', (59, 67))	('PMs', 'Chemical', 'MESH:C102296', (529, 532))	('MIC', 'Gene', '17316', (145, 148))	('PM-27', 'Var', (158, 163))	('depression', 'Disease', (240, 250))	('MIC', 'Gene', (154, 157))	('band', 'MPA', (258, 262))	('PM-27', 'Chemical', '-', (278, 283))	('PM-27', 'Chemical', '-', (25, 30))	('MIC', 'Gene', (145, 148))	('rat', 'Species', '10116', (304, 307))	('MIC', 'Gene', '17316', (326, 329))	('PM-19', 'Species', '1551643', (44, 49))	('Mu50', 'Chemical', '-', (221, 225))	('transcription process', 'MPA', (468, 489))	('PM-27', 'Chemical', '-', (158, 163))	('less', 'Var', (135, 139))
356413	24420711	Similarly, 1/4 MIC oxacillin in VRSA Mu50 enhanced 8-fold (1/2 to 1/16 MIC) for PM-27 and 4-fold (1/4 to 1/16 MIC) for SiMo12 and PM-19.	('MIC', 'Gene', '17316', (15, 18))	('MIC', 'Gene', (110, 113))	('PM-27', 'Chemical', '-', (80, 85))	('MIC', 'Gene', '17316', (71, 74))	('MIC', 'Gene', '17316', (110, 113))	('V', 'Chemical', '-', (32, 33))	('MIC', 'Gene', (15, 18))	('enhanced', 'PosReg', (42, 50))	('MIC', 'Gene', (71, 74))	('PM-27', 'Var', (80, 85))	('PM-19', 'Species', '1551643', (130, 135))	('Si', 'Chemical', 'MESH:D012825', (119, 121))	('SiMo12', 'Chemical', '-', (119, 125))	('oxacillin', 'Chemical', 'MESH:D010068', (19, 28))	('Mu50', 'Chemical', '-', (37, 41))	('Si', 'Chemical', 'MESH:D012825', (0, 2))
356414	24420711	The enhancement of the PM inhibition of the transcription of mecA for the SR3605 strain by a help of 1/4 MIC oxacillin was approximately 2-fold high compared with the case for the Mu50 strain.	('enhancement', 'PosReg', (4, 15))	('oxacillin', 'Chemical', 'MESH:D010068', (109, 118))	('transcription', 'MPA', (44, 57))	('MIC', 'Gene', '17316', (105, 108))	('PM', 'Chemical', 'MESH:C102296', (23, 25))	('MIC', 'Gene', (105, 108))	('inhibition', 'NegReg', (26, 36))	('SR3605', 'Var', (74, 80))	('Mu50', 'Chemical', '-', (180, 184))	('SR3605', 'Chemical', '-', (74, 80))	('mecA', 'Gene', (61, 65))
356415	24420711	The treatment (for 15 min) of both the cells of MRSA SR3605 and VRSA Mu50 with PM-27 (or SiMo12) induced the blue coloration of the cells, in a strong contrast with the case (no coloration) of the (dead) cells treated with ethanol for 1 day.	('induced', 'Reg', (97, 104))	('blue coloration', 'MPA', (109, 124))	('ethanol', 'Chemical', 'MESH:D000431', (223, 230))	('rat', 'Species', '10116', (118, 121))	('V', 'Chemical', '-', (64, 65))	('Mu50', 'Var', (69, 73))	('Mu50', 'Chemical', '-', (69, 73))	('SR3605', 'Chemical', '-', (53, 59))	('SiMo12', 'Chemical', '-', (89, 95))	('rat', 'Species', '10116', (182, 185))	('PM-27', 'Chemical', '-', (79, 84))	('PM-27', 'Var', (79, 84))
356419	24420711	The biological reduction of SiMo12 was noted also in the photosystem II of the photosynthesis, where the electron transfer from photoreduced pheophytin to primary plastoquinone acceptor occurred through SiMo12 (Giaquinta and Dilley; Zilinskas and Govindjee).	('plastoquinone', 'Chemical', 'MESH:D010971', (163, 176))	('SiMo12', 'Var', (203, 209))	('electron transfer', 'MPA', (105, 122))	('SiMo12', 'Chemical', '-', (203, 209))	('SiMo12', 'Chemical', '-', (28, 34))	('pheophytin', 'Chemical', 'MESH:D010674', (141, 151))
356422	24420711	The observation of the W/Ti atomic ratio of 5.3 (which is close to the one (5) of PM-19) at the periphery of the cell treated with PM-19 strongly implies that the PMs enter the cells and are localized at the cell periphery to keep their structure of the anion to be intact.	('PMs', 'Chemical', 'MESH:C102296', (163, 166))	('PM-19', 'Species', '1551643', (131, 136))	('PM-19', 'Var', (131, 136))	('W', 'Chemical', 'MESH:D014414', (23, 24))	('structure of the anion', 'MPA', (237, 259))	('PM-19', 'Species', '1551643', (82, 87))	('Ti', 'Chemical', 'MESH:D014025', (25, 27))	('rat', 'Species', '10116', (35, 38))
356429	24420711	Therefore, the fact that PM-27 and SiMo12 had two orders of magnitude lower MIC than PM-19 (Table 4.12) is associated with the blocking of the electron transfer system for the respiration leading to the inhibition of the ATP production.	('PM-27', 'Chemical', '-', (25, 30))	('SiMo12', 'Chemical', '-', (35, 41))	('MIC', 'Gene', (76, 79))	('electron', 'Enzyme', (143, 151))	('lower', 'NegReg', (70, 75))	('ATP production', 'MPA', (221, 235))	('rat', 'Species', '10116', (181, 184))	('PM-19', 'Species', '1551643', (85, 90))	('inhibition', 'NegReg', (203, 213))	('ATP', 'Chemical', 'MESH:D000255', (221, 224))	('SiMo12', 'Var', (35, 41))	('blocking', 'NegReg', (127, 135))	('MIC', 'Gene', '17316', (76, 79))
356441	24420711	Both MRSA SR3605 and VRSA Mu50 provided the highest amounts of W (or Mo) atoms for the culture with PM and oxacillin compared with the case with PM alone.	('Mu50', 'Var', (26, 30))	('PM', 'Chemical', 'MESH:C102296', (100, 102))	('Mu50', 'Chemical', '-', (26, 30))	('SR3605', 'Chemical', '-', (10, 16))	('PM', 'Chemical', 'MESH:C102296', (145, 147))	('W', 'Chemical', 'MESH:D014414', (63, 64))	('oxacillin', 'Chemical', 'MESH:D010068', (107, 116))	('V', 'Chemical', '-', (21, 22))	('amounts', 'MPA', (52, 59))	('SR3605', 'Var', (10, 16))
356443	24420711	4.20 where the cultivation of the bacteria cells in the coexistence of oxacillin and PM-19 (at 1/4 MIC for each) enhanced the uptake of W atoms (of PM-19) into both MRSA SR3605 (a) and VRSA Mu50 (b) cells with p < 0.01 for n = 3 (Hino K, Inoue M, Oda M, Nakamura Y, Yamase T Unpublished results in paper preparation).	('PM-19', 'Species', '1551643', (148, 153))	('rat', 'Species', '10116', (309, 312))	('W', 'Chemical', 'MESH:D014414', (136, 137))	('MIC', 'Gene', '17316', (99, 102))	('SR3605', 'Chemical', '-', (170, 176))	('MIC', 'Gene', (99, 102))	('uptake', 'MPA', (126, 132))	('PM-19', 'Var', (85, 90))	('Mu50', 'Chemical', '-', (190, 194))	('PM-19', 'Species', '1551643', (85, 90))	('V', 'Chemical', '-', (185, 186))	('enhanced', 'PosReg', (113, 121))	('oxacillin', 'Chemical', 'MESH:D010068', (71, 80))
356458	24420711	However, other mechanisms of the synergy are not necessarily excluded, since the RT-PCR result for a double Keggin-structural PM, K9H5[(GeTi3W9O37)2O3] 16H2O (PM-504) with a larger ionic size suggests the inhibition of the posttranscription process of either translation from mRNA to PBP2' or posttranslations of the folding of the translated polypeptide chain (Inoue et al.).	('Keggin', 'Chemical', '-', (108, 114))	('pol', 'Gene', '17276', (343, 346))	('folding', 'MPA', (317, 324))	('K9H5[', 'Var', (130, 135))	('inhibition', 'NegReg', (205, 215))	('PM-504', 'Chemical', '-', (159, 165))	('PM', 'Chemical', 'MESH:C102296', (159, 161))	("PBP2'", 'Gene', '76400', (284, 289))	("PBP2'", 'Gene', (284, 289))	('K9H5[(GeTi3W9O37)2O3] 16H2O', 'Chemical', '-', (130, 157))	('PM', 'Chemical', 'MESH:C102296', (126, 128))	('pol', 'Gene', (343, 346))
356463	24420711	Many polyoxotungstates with Keggin or Wells-Dawson related (lacunary and multiply condensed) structures, in particular, K13[Ce(SiW11O39)2] 26H2O (JM1590), K6[BGa(H2O)W11O39] 15H2O (JM2766), [Me3NH]8[(SiNb3W9O37)2O3] (JM2820), K7[PTi2W10O40] 6H2O (PM-19), K9H5[(GeTi3W9O37)2O3] 16H2O (PM-504), [PriNH3]6H[PTi2W10O38(O2)2] H2O (PM-523), K10[Fe4(H2O)2(PW9O34)2] xH2O (HS-058), K7[P2W17NbO62], K7[P2W17(NbO2)O61], and K11H[(VO)3(SbW9O33)2] 27H2O (PM-1002), were in vitro active against DNA and RNA viruses.	('W', 'Chemical', 'MESH:D014414', (266, 267))	('W', 'Chemical', 'MESH:D014414', (233, 234))	(')2] 26H2O', 'Chemical', '-', (135, 144))	('H2O', 'Chemical', '-', (162, 165))	('RNA', 'Disease', (490, 493))	('xH2', 'Gene', '22589', (359, 362))	('PM-19', 'Species', '1551643', (247, 252))	('H2O', 'Chemical', '-', (343, 346))	('HS-058', 'Chemical', '-', (365, 371))	('K11H[(VO)3(SbW9O33)2] 27H2O', 'Chemical', '-', (414, 441))	('PM-1', 'Species', '1147034', (247, 251))	('H2O', 'Chemical', '-', (360, 363))	('W', 'Chemical', 'MESH:D014414', (350, 351))	('W', 'Chemical', 'MESH:D014414', (129, 130))	('H2O', 'Chemical', '-', (279, 282))	('H2O', 'Chemical', '-', (176, 179))	('polyoxotungstates', 'Chemical', '-', (5, 22))	('H2O', 'Chemical', '-', (438, 441))	('xH2', 'Gene', (359, 362))	('K13[Ce', 'Var', (120, 126))	('W', 'Chemical', 'MESH:D014414', (166, 167))	('[Me3NH]8[(SiNb3W9O37)2O3]', 'Chemical', '-', (190, 215))	('Keggin', 'Chemical', '-', (28, 34))	('DNA', 'Disease', (482, 485))	('[PriNH3]6H[PTi2W10O38(O2)2] H2O', 'Chemical', '-', (293, 324))	('K6[BGa', 'Var', (155, 161))	('K7[PTi2W10O40]', 'Var', (226, 240))	('W', 'Chemical', 'MESH:D014414', (308, 309))	('H2O', 'Chemical', '-', (141, 144))	('W', 'Chemical', 'MESH:D014414', (395, 396))	('W', 'Chemical', 'MESH:D014414', (38, 39))	('K7[P2W17NbO62]', 'Var', (374, 388))	('PM-504', 'Chemical', '-', (284, 290))	('K9H5[(GeTi3W9O37)2O3] 16H2O', 'Chemical', '-', (255, 282))	('K11H', 'Var', (414, 418))	('W', 'Chemical', 'MESH:D014414', (379, 380))	('] 15H2O', 'Chemical', '-', (172, 179))	('W', 'Chemical', 'MESH:D014414', (205, 206))	('W', 'Chemical', 'MESH:D014414', (427, 428))	('PM-1', 'Species', '1147034', (443, 447))	('PM-523', 'Chemical', '-', (326, 332))	('JM2820', 'Chemical', 'MESH:C087529', (217, 223))	('K7[PTi2W10O40] 6H2O', 'Chemical', '-', (226, 245))	('H2O', 'Chemical', '-', (242, 245))	('H2O', 'Chemical', '-', (321, 324))
356467	24420711	A significant in vivo potentiality against HIV was recognized for PM-523 and PM-1002.	('PM-523', 'Var', (66, 72))	('PM-523', 'Chemical', '-', (66, 72))	('PM-1002', 'Var', (77, 84))	('HIV', 'Species', '12721', (43, 46))	('PM-1', 'Species', '1147034', (77, 81))
356468	24420711	While most of PMs are inhibitory only at the virus adsorption stage (e.g., due to the binding of PMs with HIV-1 gp120), PM-523 did not inhibit the adsorption of the influenza A virus (FluV-A) onto the cell membrane (0-1.5 h after infection) but inhibited the fusion between the FluV-A envelope and the cellular membrane (1.5-120 h after infection).	('infection', 'Disease', (230, 239))	('PM-523', 'Chemical', '-', (120, 126))	('PMs', 'Chemical', 'MESH:C102296', (97, 100))	('infection', 'Disease', 'MESH:D007239', (230, 239))	('inhibit', 'NegReg', (135, 142))	('W', 'Chemical', 'MESH:D014414', (0, 1))	('FluV-A', 'Chemical', 'MESH:D000077340', (278, 284))	('infection', 'Disease', (337, 346))	('FluV-A', 'Chemical', 'MESH:D000077340', (184, 190))	('gp120', 'Gene', '3700', (112, 117))	('infection', 'Disease', 'MESH:D007239', (337, 346))	('fusion', 'MPA', (259, 265))	('PMs', 'Chemical', 'MESH:C102296', (14, 17))	('HIV-1', 'Species', '11676', (106, 111))	('gp120', 'Gene', (112, 117))	('PM-523', 'Var', (120, 126))	('influenza A virus', 'Species', '11320', (165, 182))	('inhibited', 'NegReg', (245, 254))
356470	24420711	It is found that some of above PMs inhibited specific sialyl/sulfotransferases with in vitro enzymatic activities of at least 100- to 1,000-fold stronger than any other known inhibitors, implying that the PMs directly inhibit the activities of enzymes involved in carbohydrate metabolism to lead to the inhibition of the binding of the HA ligands of influenza virus with sialic acid surface receptors.	('PMs', 'Chemical', 'MESH:C102296', (205, 208))	('inhibition', 'NegReg', (303, 313))	('activities', 'MPA', (230, 240))	('enzymes', 'Enzyme', (244, 251))	('carbohydrate', 'Chemical', 'MESH:D002241', (264, 276))	('sialic acid surface receptors', 'Protein', (371, 400))	('PMs', 'Var', (31, 34))	('influenza virus', 'Species', '11308', (350, 365))	('inhibit', 'NegReg', (218, 225))	('sialyl/sulfotransferases', 'Enzyme', (54, 78))	('PMs', 'Var', (205, 208))	('inhibited', 'NegReg', (35, 44))	('sialic acid', 'Chemical', 'MESH:D019158', (371, 382))	('PMs', 'Chemical', 'MESH:C102296', (31, 34))	('binding', 'Interaction', (321, 328))
356479	24420711	Intraperitoneal or intraperitoneally IC50 50 % Inhibitory concentration ILS Increase in life-span JM1590 K13[Ce(SiW11O39)2] 26H2O JM2766 K6[BGa(H2O)W11O39] 15H2O JM2820 [Me3NH]8[(SiNb3W9O37)2O3] Ki Inhibition constant LC3 Light-chain3 LD50 50 % Lethal dose M1 Ribonucleoprotein sheath M2 Matrix protein ion channel MAGI Multinuclear activation of the galactosidase indicator assay MDCK Madin-Darby canine kidney MIC Minimum inhibitory concentration MRSA Methicillin-resistant Staphylococcus aureus  MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetry NA Neuraminidase PBP Penicillin-binding protein as the peptidoglycan-synthetic enzyme on the membrane surface PBS Phosphate-buffered saline PfluV-2 Parainfluenza virus type 2 PM-1 K5[BW12O40] 15H2O PM-1001 K10Na[(VO)3(SbW9O33)2] 26H2O PM-1002 K11H[(VO)3(SbW9O33)2] 27H2O PM-104 [NH4]12H2[Eu4(MoO4)(H2O)16(Mo7O24)4] 13H2O PM-1207 K12[(VO)3(AsW9O33)2] 12H2O PM-1208 K12[(VO)3(BiW9O33)2] 29H2O PM-1213 K12[(VO)3(PW9O34)2] nH2O PM-17 [Me3NH]6[H2MoV 12O28(OH)12(MoVIO3)4] 2H2O PM-19 K7[PTi2W10O40] 6H2O PM-27 K6[P2W18O62] 14H2O PM-30 A-beta-Na9[SiW9O34H] 23H2O PM-32 Na5[IMo6O24] 34H2O PM-43 K5[SiVW11O40] nH2O PM-44 K5[PVW11O40] 6H2O PM-46 K6[BVW11O40] nH2O PM-47 K7[BVW11O40] nH2O PM-504 K9H5[(GeTi3W9O37)2O3] 16H2O PM-518 [Et2NH2] 7[PTi2W10O40] 4H2O PM-520 [Pri 2NH2]5[PTiW11O40] 4H2O PM-523 [PriNH3]6H[PTi2W10O38(O2)2] H2O PM-8 [NH3Pri]6[Mo7O24] 3H2O RNP Ribonucleoprotein RSV Respiratory syncytial virus RT-PCR Reverse transcription polymerase chain reaction S. aureus  Staphylococcus aureus  s.c. Subcutaneous or subcutaneously SARS-V Severe acute respiratory syndrome coronavirus SARS-V Severe acute respiratory syndrome coronavirus SDS-PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis SI Selective index SiMo12 K4[SiMo12O40] 3H2O SRC Subrenal capsule in kidney assay ST3Gal-I and -III Gal:alpha2,3-sialyltransferase-1 and Gal:alpha2,3-sialyltransferase-1II ST6Gal-I Gal:alpha2,6-sialyltransferase-1 ST6GalNAc-I GalNAc:alpha2,6-sialyltransferase-1 TCID50 Median tissue culture infection dose TEM Transmission electron microscope TGEV Transmissible gastroenteritis virus of swine TK- Thymidine kinase deficient TUNEL Terminal deoxynucleotidyl transferase-mediated "nick-end" labeling staining TWI Tumor weight inhibition VRSA Vancomycin-resistant Staphylococcus aureus  beta3Gn-T2 beta1,3-GlcNAc-transferase-2 beta4Gal-TI beta1,4-galactosyltransferase-I	('K5[BW12O40] 15H2O', 'Chemical', '-', (756, 773))	('PM-', 'Chemical', 'MESH:C102296', (1398, 1401))	('V', 'Chemical', '-', (2124, 2125))	('PM-1', 'Species', '1147034', (751, 755))	('nH2O', 'Chemical', '-', (1249, 1253))	(')2] 26H2O', 'Chemical', '-', (801, 810))	('H2O', 'Chemical', '-', (1202, 1205))	('W', 'Chemical', 'MESH:D014414', (1169, 1170))	('K12', 'Gene', (940, 943))	('K12', 'Gene', '268482', (940, 943))	('W', 'Chemical', 'MESH:D014414', (114, 115))	('V', 'Chemical', '-', (1035, 1036))	('PM-520', 'Chemical', '-', (1324, 1330))	('PM-1', 'Species', '1147034', (932, 936))	('H2O', 'Chemical', '-', (1819, 1822))	('[Me3NH]8[(SiNb3W9O37)2O3]', 'Chemical', '-', (169, 194))	('TGEV', 'Species', '11149', (2121, 2125))	('PM-', 'Chemical', 'MESH:C102296', (897, 900))	('Thymidine kinase', 'Gene', '1487307', (2175, 2191))	('PBP', 'Gene', '23980', (593, 596))	('PM-', 'Chemical', 'MESH:C102296', (1230, 1233))	('[NH3Pri]6[Mo7O24] 3H2O', 'Chemical', 'MESH:C081971', (1403, 1425))	('Terminal deoxynucleotidyl transferase', 'Gene', (2208, 2245))	('V', 'Chemical', '-', (789, 790))	('V', 'Chemical', '-', (1019, 1020))	('V', 'Chemical', '-', (1168, 1169))	('H2O', 'Chemical', '-', (843, 846))	('H2O', 'Chemical', '-', (874, 877))	('RSV', 'Species', '12814', (1448, 1451))	('V', 'Chemical', '-', (2312, 2313))	('K5[PVW11O40] 6H2O', 'Chemical', '-', (1188, 1205))	('H2O', 'Chemical', '-', (144, 147))	('ST6GalNAc-I', 'Gene', '20445', (1992, 2003))	('[Me3NH]6[H2MoV 12O28(OH)12(MoVIO3)4] 2H2O', 'Chemical', 'MESH:C527543', (1006, 1047))	('K6[P2W18O62] 14H2O', 'Chemical', '-', (1080, 1098))	('rat', 'Species', '10116', (442, 445))	('A-beta', 'Gene', '11820', (1105, 1111))	('W', 'Chemical', 'MESH:D014414', (760, 761))	('H2O', 'Chemical', '-', (1285, 1288))	('LC3', 'Gene', (218, 221))	('H2O', 'Chemical', '-', (807, 810))	('SiMo12', 'Chemical', '-', (1807, 1813))	('H2O', 'Chemical', '-', (126, 129))	('PM-', 'Chemical', 'MESH:C102296', (774, 777))	('Staphylococcus aureus', 'Species', '1280', (476, 497))	('K4[SiMo12O40] 3H2O', 'Chemical', '-', (1804, 1822))	('PM-', 'Chemical', 'MESH:C102296', (1359, 1362))	('PM-', 'Chemical', 'MESH:C102296', (932, 935))	('Staphylococcus aureus', 'Species', '1280', (1546, 1567))	('ST6Gal-I', 'Gene', '20440', (1950, 1958))	('K5[SiVW11O40] nH2O', 'Chemical', '-', (1163, 1181))	('PfluV-2', 'Species', '11212', (716, 723))	('nH2O', 'Chemical', '-', (995, 999))	('H2O', 'Chemical', '-', (1226, 1229))	('K9H5[(GeTi3W9O37)2O3] 16H2O', 'Chemical', '-', (1261, 1288))	('nH2O', 'Chemical', '-', (1225, 1229))	('[PriNH3]6H[PTi2W10O38(O2)2] H2O', 'Chemical', '-', (1366, 1397))	('PM-', 'Chemical', 'MESH:C102296', (811, 814))	('mum', 'Gene', (420, 423))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (503, 563))	('Staphylococcus aureus', 'Species', '1280', (2338, 2359))	('W', 'Chemical', 'MESH:D014414', (986, 987))	('beta3Gn-T2', 'Gene', (2361, 2371))	('[Pri 2NH2]5[PTiW11O40] 4H2O', 'Chemical', '-', (1331, 1358))	('rat', 'Species', '10116', (1683, 1686))	('W', 'Chemical', 'MESH:D014414', (184, 185))	('H2O', 'Chemical', '-', (1153, 1156))	('W', 'Chemical', 'MESH:D014414', (1272, 1273))	('PM-', 'Chemical', 'MESH:C102296', (1000, 1003))	('PM-19', 'Species', '1551643', (1048, 1053))	('PM-', 'Chemical', 'MESH:C102296', (1324, 1327))	('Methicillin', 'Chemical', 'MESH:D008712', (454, 465))	('swine', 'Species', '9823', (2165, 2170))	('PM-504', 'Chemical', '-', (1254, 1260))	('Phosphate-buffered saline', 'Chemical', '-', (690, 715))	('W', 'Chemical', 'MESH:D014414', (952, 953))	('W', 'Chemical', 'MESH:D014414', (1381, 1382))	('PM-1', 'Species', '1147034', (811, 815))	('PM-1213', 'Chemical', '-', (967, 974))	('V', 'Chemical', '-', (1192, 1193))	('[NH4]12H2', 'Chemical', '-', (854, 863))	('PM-27', 'Chemical', '-', (1074, 1079))	('H2O', 'Chemical', '-', (158, 161))	('PM-523', 'Chemical', '-', (1359, 1365))	('PM-', 'Chemical', 'MESH:C102296', (1132, 1135))	('W', 'Chemical', 'MESH:D014414', (1085, 1086))	('PM-1', 'Species', '1147034', (897, 901))	('H2O', 'Chemical', '-', (928, 931))	('H2O', 'Chemical', '-', (770, 773))	('K7[PTi2W10O40] 6H2O', 'Chemical', '-', (1054, 1073))	('influenza virus', 'Species', '11308', (728, 743))	('Na5[IMo6O24] 34H2O', 'Chemical', '-', (1138, 1156))	('H2O', 'Chemical', '-', (1355, 1358))	('PM-', 'Chemical', 'MESH:C102296', (1099, 1102))	('V', 'Chemical', '-', (825, 826))	('polymer', 'Chemical', 'MESH:D011108', (1509, 1516))	('respiratory syndrome', 'Phenotype', 'HP:0011947', (1678, 1698))	('beta3Gn-T2', 'Gene', '53625', (2361, 2371))	('Sodium dodecyl sulfate-polyacrylamide gel', 'Chemical', '-', (1720, 1761))	('MIC', 'Gene', '17316', (412, 415))	('W', 'Chemical', 'MESH:D014414', (917, 918))	('PM-17', 'Chemical', '-', (1000, 1005))	('PM-', 'Chemical', 'MESH:C102296', (1074, 1077))	('] 15H2O', 'Chemical', '-', (154, 161))	('nH2O', 'Chemical', '-', (1177, 1181))	('K7[BVW11O40] nH2O', 'Chemical', '-', (1236, 1253))	('K12', 'Gene', (975, 978))	('W', 'Chemical', 'MESH:D014414', (148, 149))	('V', 'Chemical', '-', (1450, 1451))	('SDS', 'Chemical', 'MESH:D012967', (1711, 1714))	('A-beta', 'Gene', (1105, 1111))	('SiMo12', 'Chemical', '-', (1797, 1803))	('H2O', 'Chemical', '-', (1044, 1047))	('ST6Gal-I', 'Gene', (1950, 1958))	('H2O', 'Chemical', '-', (1250, 1253))	('] 15H2O', 'Chemical', '-', (766, 773))	('H2O', 'Chemical', '-', (893, 896))	('W', 'Chemical', 'MESH:D014414', (1311, 1312))	('V', 'Chemical', '-', (720, 721))	('H2O', 'Chemical', '-', (996, 999))	('MIC', 'Gene', (412, 415))	('PBP', 'Gene', (593, 596))	('H2O', 'Chemical', '-', (1320, 1323))	('PM-', 'Chemical', 'MESH:C102296', (1157, 1160))	('PM-1', 'Species', '1147034', (774, 778))	('LC3', 'Gene', '84557', (218, 221))	('W', 'Chemical', 'MESH:D014414', (1193, 1194))	('W', 'Chemical', 'MESH:D014414', (1241, 1242))	('V', 'Chemical', '-', (980, 981))	('respiratory syndrome', 'Phenotype', 'HP:0011947', (1625, 1645))	('PM-1', 'Species', '1147034', (1048, 1052))	('PM-', 'Chemical', 'MESH:C102296', (967, 970))	('ST6GalNAc-I', 'Gene', (1992, 2003))	('GalNAc', 'Chemical', '-', (1995, 2001))	('V', 'Chemical', '-', (1240, 1241))	('S. aureus', 'Species', '1280', (1535, 1544))	('K6[BVW11O40] nH2O', 'Chemical', '-', (1212, 1229))	('mum', 'Gene', '56925', (420, 423))	('PM-', 'Chemical', 'MESH:C102296', (847, 850))	('H2O', 'Chemical', '-', (1095, 1098))	('Vancomycin', 'Chemical', 'MESH:D014640', (2317, 2327))	('Terminal deoxynucleotidyl transferase', 'Gene', '21673', (2208, 2245))	('PM-', 'Chemical', 'MESH:C102296', (751, 754))	('PBS', 'Chemical', '-', (686, 689))	('H2O', 'Chemical', '-', (1070, 1073))	('ST3Gal-I', 'Gene', (1860, 1868))	('K12', 'Gene', (905, 908))	('V', 'Chemical', '-', (945, 946))	('K12', 'Gene', '268482', (905, 908))	('PM-1', 'Species', '1147034', (1000, 1004))	('W', 'Chemical', 'MESH:D014414', (832, 833))	('infection', 'Disease', (2069, 2078))	('W', 'Chemical', 'MESH:D014414', (2285, 2286))	('infection', 'Disease', 'MESH:D007239', (2069, 2078))	('PM-', 'Chemical', 'MESH:C102296', (1289, 1292))	('V', 'Chemical', '-', (1610, 1611))	('Penicillin', 'Chemical', 'MESH:D010406', (597, 607))	('W', 'Chemical', 'MESH:D014414', (1061, 1062))	('V', 'Chemical', '-', (2317, 2318))	('Tumor', 'Phenotype', 'HP:0002664', (2288, 2293))	('JM2820', 'Chemical', 'MESH:C087529', (162, 168))	(')2] 26H2O', 'Chemical', '-', (120, 129))	('SI', 'Chemical', '-', (1778, 1780))	('rat', 'Species', '10116', (65, 68))	('PM-', 'Chemical', 'MESH:C102296', (1048, 1051))	('PM-', 'Chemical', 'MESH:C102296', (1254, 1257))	('H2O', 'Chemical', '-', (1394, 1397))	('[Et2NH2] 7[PTi2W10O40] 4H2O', 'Chemical', '-', (1296, 1323))	('H2O', 'Chemical', '-', (1178, 1181))	('PM-1208', 'Chemical', '-', (932, 939))	('K12', 'Gene', '268482', (975, 978))	('W', 'Chemical', 'MESH:D014414', (796, 797))	('H2O', 'Chemical', '-', (963, 966))	('Mo7O24', 'Chemical', '-', (1413, 1419))	('Mo7O24', 'Chemical', '-', (881, 887))	('V', 'Chemical', '-', (910, 911))	('Transmissible gastroenteritis virus', 'Species', '11149', (2126, 2161))	('PM-', 'Chemical', 'MESH:C102296', (1182, 1185))	('K11H[(VO)3(SbW9O33)2] 27H2O', 'Chemical', '-', (819, 846))	('PM-', 'Chemical', 'MESH:C102296', (1206, 1209))	('W', 'Chemical', 'MESH:D014414', (1217, 1218))	('GalNAc', 'Chemical', '-', (2004, 2010))	('V', 'Chemical', '-', (1663, 1664))	('H2O', 'Chemical', '-', (1422, 1425))	('MTT', 'Chemical', 'MESH:C070243', (499, 502))	('canine', 'Species', '9615', (398, 404))	('H2O', 'Chemical', '-', (1128, 1131))	('W', 'Chemical', 'MESH:D014414', (1118, 1119))	('V', 'Chemical', '-', (1216, 1217))	('rat', 'Species', '10116', (1457, 1460))	('ST3Gal-I', 'Gene', '20442', (1860, 1868))	('MoO4', 'Gene', '100035774', (868, 872))	('SRC', 'Gene', (1823, 1826))	('Thymidine kinase', 'Gene', (2175, 2191))	('PM-1208', 'Var', (932, 939))	('] 13H2O', 'Chemical', '-', (889, 896))	('SRC', 'Gene', '20779', (1823, 1826))	('K10Na[(VO)3(SbW9O33)2] 26H2O', 'Chemical', '-', (782, 810))	('PM-1', 'Species', '1147034', (967, 971))	('SARS-V', 'Species', '694009', (1605, 1611))	('MoO4', 'Gene', (868, 872))	('SARS-V', 'Species', '694009', (1658, 1664))	('W', 'Chemical', 'MESH:D014414', (1346, 1347))	('rat', 'Species', '10116', (1630, 1633))	('PM-8', 'Species', '1214577', (1398, 1402))	('PM-1', 'Species', '1147034', (847, 851))
356483	30031766	Ewing Sarcoma is consistently associated with chromosomal translocation and functional fusion of the EWSR1 gene to any of several structurally related transcription factor genes of the E26 transformation-specific (ETS) family.	('associated', 'Reg', (30, 40))	('Sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', (101, 106))	('Ewing Sarcoma', 'Disease', (0, 13))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing Sarcoma', 'Disease', 'MESH:D012512', (0, 13))	('EWSR1', 'Gene', '2130', (101, 106))	('chromosomal translocation', 'Var', (46, 71))
356531	30031766	ESFT are characterized by specific rearrangements of one of the five alternative Ets family member genes, i.e, FLI1, ERG, ETV1, E1AF, and FEV with EWSR1 (Figure 1).	('ETV1', 'Gene', (122, 126))	('EWSR1', 'Gene', (147, 152))	('E1AF', 'Gene', (128, 132))	('ESFT', 'Disease', (0, 4))	('ERG', 'Gene', '2078', (117, 120))	('rearrangements', 'Var', (35, 49))	('E1AF', 'Gene', '2118', (128, 132))	('ETV1', 'Gene', '2115', (122, 126))	('FLI1', 'Gene', (111, 115))	('ERG', 'Gene', (117, 120))	('EWSR1', 'Gene', '2130', (147, 152))	('ESFT', 'Disease', 'MESH:D012512', (0, 4))
356533	30031766	This genetic mutation is thought to lead to the oncogenic conversion of EWS by exchanging its RNA binding domain with different DNA binding domains, thus generating tumor-specific fusions proteins.	('lead', 'Reg', (36, 40))	('exchanging', 'Var', (79, 89))	('fusions proteins', 'MPA', (180, 196))	('mutation', 'Var', (13, 21))	('RNA', 'MPA', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('generating', 'Reg', (154, 164))	('tumor', 'Disease', (165, 170))
356534	30031766	The second most common cytogenetic aberration after EWS-FL11, seen in only 5%-10% of ESFT, is the translocation t(21;22)(q22;q12), which is referred to as EWS-ERG (Figure 1).	('ESFT', 'Disease', (85, 89))	('ERG', 'Gene', '2078', (159, 162))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 129))	('ERG', 'Gene', (159, 162))	('t(21;22)(q22;q12', 'Var', (112, 128))	('ESFT', 'Disease', 'MESH:D012512', (85, 89))
356540	30031766	This evaluation did however, find that patients with non-type 1/non-type 2 EWS-FLI1 demonstrated a small but insignificant risk of progression or relapse than other fusion types.	('non-type 1/non-type 2', 'Var', (53, 74))	('patients', 'Species', '9606', (39, 47))	('EWS-FLI1', 'Gene', (75, 83))
356562	30031766	These approaches appear promising in that we are now able to routinely detect the EWS-Ets fusion transcripts in enriched exosomes from clinical samples (Samuel and Godwin, unpublished data).	('clinical samples', 'Species', '191496', (135, 151))	('EWS-Ets', 'Gene', (82, 89))	('fusion', 'Var', (90, 96))	('detect', 'Reg', (71, 77))
356627	30498397	Cells from tumors with gammaH2AX expression higher than the sample population mean had fourfold greater relative survival after carboplatin exposure than cells from tumors with gammaH2AX expression less than the mean.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('greater', 'PosReg', (96, 103))	('expression', 'Var', (33, 43))	('gammaH2AX expression', 'Var', (23, 43))	('gammaH2AX', 'Chemical', '-', (177, 186))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (165, 171))	('gammaH2AX', 'Chemical', '-', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('relative', 'MPA', (104, 112))	('carboplatin', 'Chemical', 'MESH:D016190', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
356628	30498397	There was no association between relative survival after carboplatin exposure and p53 expression (P = 0.1608), and there was no association between relative survival after doxorubicin exposure and either gammaH2AX (P = 0.6124) or p53 (P = 0.8645) expression.	('gammaH2AX', 'Chemical', '-', (204, 213))	('gammaH2AX', 'Var', (204, 213))	('doxorubicin', 'Chemical', 'MESH:D004317', (172, 183))	('p53', 'Gene', (82, 85))	('carboplatin', 'Chemical', 'MESH:D016190', (57, 68))	('p53', 'Gene', (230, 233))
356637	30498397	In a meta-analysis, adjuvant chemotherapy including doxorubicin was associated with increased time to local and distant recurrence; however, there was no impact on overall survival (HR, 0.89; 95% CI, 0.76-1.03; P = 0.12).	('local and distant recurrence', 'CPA', (102, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (52, 63))	('increased', 'PosReg', (84, 93))	('doxorubicin', 'Var', (52, 63))
356651	30498397	The combination of preoperative radiotherapy, surgical excision, and adjuvant carboplatin chemotherapy was associated with a median time to first event > 986 days (N = 19), but this was not statistically different from cats that received no chemotherapy (584 days, N = 59) or cats that received other chemotherapeutics (365 days, N = 14).	('cats', 'Species', '9685', (276, 280))	('carboplatin', 'Chemical', 'MESH:D016190', (78, 89))	('radiotherapy', 'Var', (32, 44))	('cats', 'Species', '9685', (219, 223))	('carboplatin', 'Gene', (78, 89))	('surgical excision', 'Var', (46, 63))
356662	30498397	We compared the chemosensitivity of the cell lines to gammaH2AX and p53 expression in the original tumors.	('gammaH2AX', 'Chemical', '-', (54, 63))	('gammaH2AX', 'Var', (54, 63))	('original tumors', 'Disease', 'MESH:D009369', (90, 105))	('original tumors', 'Disease', (90, 105))	('p53', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
356718	30498397	Using qRT-PCR, all tumors were found to express wild type p53 (Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('wild type p53', 'Var', (48, 61))
356723	30498397	Mean relative survival after carboplatin exposure was 38% in cell lines established from tumors with gammaH2AX expression greater than the sample population mean of 13.3%, compared to mean relative survival of 10% in cell lines established from tumors with gammaH2AX expression less than 13.3%.	('expression', 'Var', (111, 121))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('gammaH2AX', 'Chemical', '-', (257, 266))	('carboplatin', 'Chemical', 'MESH:D016190', (29, 40))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('gammaH2AX', 'Gene', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumors', 'Disease', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('gammaH2AX', 'Chemical', '-', (101, 110))
356747	30498397	In our study, cells from tumors with higher levels of gammaH2AX were more resistant to carboplatin, whereas there was no association with gammaH2AX and resistance to doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (166, 177))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('gammaH2AX', 'Chemical', '-', (54, 63))	('gammaH2AX', 'Var', (54, 63))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('resistant to carboplatin', 'MPA', (74, 98))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('carboplatin', 'Chemical', 'MESH:D016190', (87, 98))	('gammaH2AX', 'Chemical', '-', (138, 147))
356771	30498397	Alterations in NER are well-recognized as a mechanism of carboplatin resistance, whereas doxorubicin resistance is most often associated with increases in P-glycoprotein, a membranous pump that transports doxorubicin out of cells.	('doxorubicin', 'Chemical', 'MESH:D004317', (205, 216))	('P-glycoprotein', 'Gene', '5243', (155, 169))	('P-glycoprotein', 'Gene', (155, 169))	('doxorubicin', 'Chemical', 'MESH:D004317', (89, 100))	('Alterations', 'Var', (0, 11))	('increases', 'PosReg', (142, 151))	('NER', 'Gene', (15, 18))	('carboplatin', 'Chemical', 'MESH:D016190', (57, 68))	('carboplatin resistance', 'MPA', (57, 79))
356772	30498397	Variations in topoisomerase IIalpha can also contribute to doxorubicin resistance.	('topoisomerase IIalpha', 'Enzyme', (14, 35))	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))	('Variations', 'Var', (0, 10))	('doxorubicin resistance', 'MPA', (59, 81))	('contribute', 'Reg', (45, 55))
356773	30498397	Unlike our findings with the anthracycline doxorubicin in FISS, the presence of gammaH2AX foci in breast cancer cells was associated with resistance to a different anthracycline chemotherapeutic, epirubicin.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('gammaH2AX', 'Chemical', '-', (80, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('resistance to', 'MPA', (138, 151))	('breast cancer', 'Disease', (98, 111))	('associated with', 'Reg', (122, 137))	('doxorubicin', 'Chemical', 'MESH:D004317', (43, 54))	('anthracycline', 'Chemical', 'MESH:D018943', (29, 42))	('gammaH2AX', 'Gene', (80, 89))	('presence', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('epirubicin', 'Chemical', 'MESH:D015251', (196, 206))	('anthracycline', 'Chemical', 'MESH:D018943', (164, 177))
356776	30498397	The evolutionarily conserved DNA-binding domain of p53 is the most frequent site of somatic mutations in various human cancers and is typically associated with aggressive phenotypes.	('p53', 'Gene', (51, 54))	('associated', 'Reg', (144, 154))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('mutations', 'Var', (92, 101))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (113, 118))
356777	30498397	p53 mutations have been detected in up to 50% of human STS tumors, with mutations occurring more frequently in metastatic sarcomas and high-grade lesions.	('p53', 'Gene', (0, 3))	('mutations', 'Var', (72, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('sarcomas', 'Disease', (122, 130))	('human', 'Species', '9606', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('sarcomas', 'Disease', 'MESH:D012509', (122, 130))	('mutations', 'Var', (4, 13))	('STS', 'Phenotype', 'HP:0030448', (55, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
356778	30498397	Interestingly, feline neoplasms do not seem to harbor p53 mutations with the same frequency as that observed in man.	('mutations', 'Var', (58, 67))	('man', 'Species', '9606', (112, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (22, 31))	('p53', 'Gene', (54, 57))	('neoplasms', 'Disease', 'MESH:D009369', (22, 31))	('neoplasms', 'Disease', (22, 31))
356780	30498397	In a separate study, cytoplasmic expression of p53 was associated with shorter time to tumor recurrence compared to those cats with tumors exhibiting nuclear p53 staining.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('p53', 'Gene', (47, 50))	('cats', 'Species', '9685', (122, 126))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (132, 137))	('cytoplasmic expression', 'Var', (21, 43))	('tumors', 'Disease', (132, 138))	('shorter', 'NegReg', (71, 78))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
356781	30498397	We did not evaluate whether any tumors in our study had p53 mutations, and this may have been why we did not detect any associations with cell survival.	('p53', 'Gene', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('mutations', 'Var', (60, 69))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
356783	30498397	In STS cells harboring p53 mutations, reintroduction of wild type p53 enhanced chemosensitivity to doxorubicin through inhibition of MDR-1 P-glycoprotein expression.	('mutations', 'Var', (27, 36))	('doxorubicin', 'Chemical', 'MESH:D004317', (99, 110))	('MDR-1', 'Gene', (133, 138))	('P-glycoprotein', 'Gene', '5243', (139, 153))	('chemosensitivity to doxorubicin', 'MPA', (79, 110))	('P-glycoprotein', 'Gene', (139, 153))	('inhibition', 'NegReg', (119, 129))	('STS', 'Phenotype', 'HP:0030448', (3, 6))	('enhanced', 'PosReg', (70, 78))	('p53', 'Gene', (23, 26))	('reintroduction', 'Var', (38, 52))
356792	30498397	As gammaH2AX only represents one element of the complex DNA damage response pathway, future research evaluating other downstream proteins such as DNA repair factors 53BP1 or BRCA1 may allow development of a more fine-tuned algorithm predicting chemoresistance or chemosensitivity in STS.	('chemoresistance', 'CPA', (244, 259))	('BRCA1', 'Gene', (174, 179))	('STS', 'Phenotype', 'HP:0030448', (283, 286))	('BRCA1', 'Gene', '493761', (174, 179))	('gammaH2AX', 'Chemical', '-', (3, 12))	('gammaH2AX', 'Var', (3, 12))
356795	30498397	ATM ataxia-telangiectasia mutated ATR ATM and Rad3-related AUC area under the concentration-versus-time curve Cmax maximum plasma concentration DDR DNA damage response DNA-PKcs DNA-dependent protein kinase and catalytic subunit FISS feline injection-site sarcoma IACUC Institutional Animal Care and Use Committee NER nucleotide excision repair STS soft tissue sarcoma	('telangiectasia', 'Phenotype', 'HP:0001009', (11, 25))	('ataxia-telangiectasia', 'Disease', (4, 25))	('ATM', 'Gene', '101089291', (38, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (360, 367))	('ataxia', 'Phenotype', 'HP:0001251', (4, 10))	('ATM', 'Gene', (0, 3))	('ATR', 'Gene', '101088023', (34, 37))	('STS', 'Phenotype', 'HP:0030448', (344, 347))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (348, 367))	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (4, 25))	('mutated', 'Var', (26, 33))	('ATM', 'Gene', (38, 41))	('sarcoma', 'Disease', 'MESH:D012509', (360, 367))	('ATM', 'Gene', '101089291', (0, 3))	('sarcoma', 'Disease', 'MESH:D012509', (255, 262))	('sarcoma', 'Disease', (255, 262))	('sarcoma', 'Disease', (360, 367))	('ATR', 'Gene', (34, 37))
356953	24910640	In contrast to many other types of solid tumor, mesotheliomas generally lack mutations of the fundamental tumor suppressor genes, p53 and RB.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('mesotheliomas', 'Disease', 'MESH:D008654', (48, 61))	('mesotheliomas', 'Disease', (48, 61))	('p53', 'Gene', '7157', (130, 133))	('lack', 'NegReg', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutations', 'Var', (77, 86))	('solid tumor', 'Disease', (35, 46))	('men', 'Species', '9606', (99, 102))	('p53', 'Gene', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (106, 111))	('solid tumor', 'Disease', 'MESH:D009369', (35, 46))
356957	24910640	The more commonly noted losses occur on the short arms of chromosomes 1 (notably 1p21-p22), 3 (notably 3p21.3), and 9 (notably 9p14/p16), and on the long arms of chromosomes 6 (notably 6q14-q21, 6q16.6-q21, 6q21-q23.2, and 6q25), 15 (notably 15q11.1-q15), and both arms of chromosome 22 (Pisick and Salgia,; Pass et al.,).	('p22', 'Gene', '11331', (86, 89))	('3p21.3', 'Var', (103, 109))	('p16', 'Gene', '1029', (132, 135))	('losses', 'NegReg', (24, 30))	('p16', 'Gene', (132, 135))	('Pisick and Salgia', 'Disease', 'None', (288, 305))	('p22', 'Gene', (86, 89))	('short arms', 'Phenotype', 'HP:0009824', (44, 54))
356961	24910640	These authors identified a slightly wider range of associated chromosomal alterations including losses at 1p, 3p, 4q, 6q, 13p, 14q, and 22q, and gains at 1q, 5p, 7p, 8q, and 17q and noted that more specific mutations on chromosome 22 (e.g., deletions at the neurofibromatosis 2 locus, 22q12), chromosome 9 (e.g., INK4 genes, specifically deletions at cyclin-dependent kinase inhibitor genes CDKN2A and CDKN2B at 9p21.3), and chromosome 17 (TP53 gene deletion at 17p13.1, though less common) have been associated with mesothelioma in recent reports.	('p13', 'Gene', (464, 467))	('associated', 'Reg', (501, 511))	('deletions', 'Var', (338, 347))	('TP53', 'Gene', (440, 444))	('p13', 'Gene', '440926', (464, 467))	('mutations', 'Var', (207, 216))	('CDKN2A', 'Gene', (391, 397))	('deletions', 'Var', (241, 250))	('deletion', 'Var', (450, 458))	('CDKN2B', 'Gene', (402, 408))	('mesothelioma', 'Disease', (517, 529))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (258, 275))	('mesothelioma', 'Disease', 'MESH:D008654', (517, 529))	('INK4', 'Gene', '1029', (313, 317))	('CDKN2B', 'Gene', '1030', (402, 408))	('CDKN2A', 'Gene', '1029', (391, 397))	('neurofibromatosis', 'Disease', 'MESH:C537392', (258, 275))	('TP53', 'Gene', '7157', (440, 444))	('INK4', 'Gene', (313, 317))	('neurofibromatosis', 'Disease', (258, 275))
356962	24910640	However, these mutations occur with several other cancer types (Jean et al.,).	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (15, 24))	('occur', 'Reg', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
356963	24910640	They noted a new association between mesotheliomas and increased microRNA expression of certain types (MiR-31, -141, -192, -193, -200a-c, -203, -205, and -429); greater DNA methylation at certain loci, and increases in markers of telomere length maintenance mechanisms were also reportedly associated with mesotheliomas (Ivanov et al.,; Jean et al.,).	('methylation', 'Var', (173, 184))	('MiR-31', 'Gene', (103, 109))	('greater', 'PosReg', (161, 168))	('MiR-31', 'Gene', '407035', (103, 109))	('increased', 'PosReg', (55, 64))	('increases', 'PosReg', (206, 215))	('mesotheliomas', 'Disease', 'MESH:D008654', (306, 319))	('mesotheliomas', 'Disease', (306, 319))	('microRNA expression', 'MPA', (65, 84))	('mesotheliomas', 'Disease', 'MESH:D008654', (37, 50))	('mesotheliomas', 'Disease', (37, 50))	('associated', 'Reg', (290, 300))	('DNA', 'MPA', (169, 172))
356966	24910640	First, there is recent evidence suggesting that telomere status and telomere maintenance mechanisms tied to P53, ATRX and DAXX mutations may be helpful in distinguishing more aggressive mesotheliomas (Durant,; Gocha et al.,; Tallet et al.,).	('ATRX', 'Gene', '546', (113, 117))	('DAXX', 'Gene', (122, 126))	('aggressive mesotheliomas', 'Disease', 'MESH:D008654', (175, 199))	('aggressive mesotheliomas', 'Disease', (175, 199))	('P53', 'Gene', (108, 111))	('DAXX', 'Gene', '1616', (122, 126))	('mutations', 'Var', (127, 136))	('P53', 'Gene', '7157', (108, 111))	('ATRX', 'Gene', (113, 117))
356968	24910640	Second, the mutations leading to telomere lengthening and survival of clonally expanding mesothelioma cells using ALT mechanisms are reported to form ALT-associated promyelocytic bodies that may be akin to micronuclei observed in tumor cells and blood polynucleated lymphocytes with exposure to asbestos (Dopp et al.,; Bolognesi et al.,; Martini et al.,).	('telomere', 'Gene', (33, 41))	('tumor', 'Disease', (230, 235))	('ALT', 'Gene', (150, 153))	('mesothelioma', 'Disease', (89, 101))	('ALT', 'Gene', '76282', (114, 117))	('mutations', 'Var', (12, 21))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('ALT', 'Gene', '76282', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('ALT', 'Gene', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('asbestos', 'Chemical', 'MESH:D001194', (295, 303))
356970	24910640	And fourth, germline mutations in nuclear deubiquitinase BRCA1-associated protein 1 (BAP1) have been observed in familial clusters of mesothelioma not necessarily linked to asbestos (Testa et al.,) and in a fraction of pleural mesotheliomas in other case series (Bott et al.,; Jean et al.,; Tallet et al.,).	('BAP1', 'Gene', (85, 89))	('observed', 'Reg', (101, 109))	('mesothelioma', 'Disease', (134, 146))	('linked', 'Reg', (163, 169))	('germline mutations', 'Var', (12, 30))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (219, 240))	('mesothelioma', 'Disease', 'MESH:D008654', (134, 146))	('mesothelioma', 'Disease', (227, 239))	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (219, 240))	('asbestos', 'Chemical', 'MESH:D001194', (173, 181))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (219, 239))	('mesothelioma', 'Disease', 'MESH:D008654', (227, 239))	('BRCA1-associated protein 1', 'Gene', '8314', (57, 83))	('BAP1', 'Gene', '8314', (85, 89))	('pleural mesotheliomas', 'Disease', (219, 240))	('BRCA1-associated protein 1', 'Gene', (57, 83))
356984	24910640	GCTs can arise from germ cell tissues in the testes, the prostate, and other tissue locations (extragonadal GCT) as a result of a mutation and abnormal migration of germ cells during embryonic development (Blossom et al.,; Sarma et al.,).	('GCTs', 'Disease', (0, 4))	('mutation', 'Var', (130, 138))	('men', 'Species', '9606', (200, 203))	('GCTs', 'Phenotype', 'HP:0100728', (0, 4))	('abnormal migration', 'Phenotype', 'HP:0002269', (143, 161))	('arise', 'Reg', (9, 14))	('result', 'Reg', (118, 124))
357007	24910640	Indeed, PSC in many ways can mimic epithelioid mesothelioma, but unlike mesothelioma, PSC is linked to hereditary and sporadic mutations of two breast cancer susceptibility genes (BRCA-1 and BRCA-2).	('BRCA-1', 'Gene', '672', (180, 186))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('epithelioid mesothelioma', 'Disease', (35, 59))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('mesothelioma', 'Disease', 'MESH:D008654', (47, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('linked', 'Reg', (93, 99))	('mesothelioma', 'Disease', (72, 84))	('BRCA-2', 'Gene', '675', (191, 197))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (35, 59))	('BRCA-2', 'Gene', (191, 197))	('PSC', 'Disease', (86, 89))	('mutations', 'Var', (127, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (72, 84))	('mesothelioma', 'Disease', (47, 59))	('BRCA-1', 'Gene', (180, 186))	('PSC', 'Disease', (8, 11))
357008	24910640	Primary epithelial cancers of the fallopian tubes (particularly the fimbria) appear to be linked to more aggressive and early-onset PSC in women with the BRCA-1 mutation (Sobol et al.,; Zweemer et al.,; Aziz et al.,; Paley et al.,; Levine et al.,; Piek et al.,; Finch et al.,; Medeiros et al.,; Kindelberger et al.,), while ovarian surface epithelium tumors have been linked to both BRCA-1 and BRCA-2 mutations (Werness et al.,; Colgan et al.,; Piura et al.,; Risch et al.,; Agoff et al.,; Brose et al.,; Geisler et al.,; Hilton et al.,; Cass et al.,).	('BRCA-2', 'Gene', (394, 400))	('Primary epithelial cancers of the fallopian tubes', 'Disease', 'MESH:D005185', (0, 49))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('linked', 'Reg', (368, 374))	('tumors', 'Disease', 'MESH:D009369', (351, 357))	('BRCA-1', 'Gene', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('BRCA-1', 'Gene', '672', (154, 160))	('mutation', 'Var', (161, 169))	('BRCA-1', 'Gene', (383, 389))	('BRCA-1', 'Gene', '672', (383, 389))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('Primary epithelial cancers of the fallopian tubes', 'Disease', (0, 49))	('mutations', 'Var', (401, 410))	('women', 'Species', '9606', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('BRCA-2', 'Gene', '675', (394, 400))	('tumors', 'Disease', (351, 357))	('ovarian surface epithelium tumors', 'Phenotype', 'HP:0025318', (324, 357))
357009	24910640	More advanced PSC tumors originating from ovarian surface epithelium or tubal fimbria epithelium are subject to genomic instability, loss of WT-1 gene expression, and the presence of both BRCA and p53 mutations, sometimes making the site or origin difficult to distinguish in more advanced stages of the disease (Schorge et al.,; Piek et al.,; Kindelberger et al.,; Lee et al.,; Gilks et al.,).	('mutations', 'Var', (201, 210))	('loss', 'NegReg', (133, 137))	('p53', 'Gene', (197, 200))	('p53', 'Gene', '7157', (197, 200))	('PSC tumors', 'Disease', 'MESH:D015209', (14, 24))	('WT-1', 'Gene', (141, 145))	('BRCA', 'Gene', '672', (188, 192))	('PSC tumors', 'Disease', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('presence', 'Var', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('BRCA', 'Gene', (188, 192))	('WT-1', 'Gene', '7490', (141, 145))
357012	24910640	Three familial genetic syndromes associated with excess ovarian cancer risk have been identified: certain BRCA-1 or BRCA-2 mutations result in Breast Ovarian Cancer Syndrome, Site-Specific Ovarian Cancer Syndrome, and Hereditary Non-Polyposis Colon Cancer (or Lynch II Syndrome) which are associated with mutations in DNA mismatch repair genes in affected families (Muto,).	('excess ovarian cancer', 'Disease', 'MESH:D010051', (49, 70))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (150, 164))	('Lynch II Syndrome', 'Disease', 'MESH:D055847', (260, 277))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (189, 203))	('Lynch II Syndrome', 'Disease', (260, 277))	('Cancer', 'Phenotype', 'HP:0002664', (249, 255))	('BRCA-1', 'Gene', (106, 112))	('BRCA-1', 'Gene', '672', (106, 112))	('Breast Ovarian Cancer', 'Disease', (143, 164))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('Non-Polyposis Colon Cancer', 'Disease', (229, 255))	('Non-Polyposis Colon Cancer', 'Disease', 'MESH:D015179', (229, 255))	('Site-Specific Ovarian Cancer Syndrome', 'Disease', 'MESH:D010051', (175, 212))	('Breast Ovarian Cancer', 'Disease', 'MESH:D010051', (143, 164))	('Cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Site-Specific Ovarian Cancer Syndrome', 'Disease', (175, 212))	('familial genetic syndromes', 'Disease', (6, 32))	('excess ovarian cancer', 'Disease', (49, 70))	('familial genetic syndromes', 'Disease', 'MESH:D030342', (6, 32))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('BRCA-2', 'Gene', '675', (116, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('result in', 'Reg', (133, 142))	('Colon Cancer', 'Phenotype', 'HP:0003003', (243, 255))	('mutations', 'Var', (123, 132))	('BRCA-2', 'Gene', (116, 122))
357021	24910640	Many congenital heart defects are related to trisomies of chromosomes 13, 15, 18, and 21, and deletions in chromosome 22 (22q11.2) are thought to play a major role in congenital heart disorders of the conotruncus and the brachial arches (Kumar et al.,).	('congenital heart defects', 'Phenotype', 'HP:0001627', (5, 29))	('brachial arches', 'Disease', (221, 236))	('congenital heart defects', 'Disease', (5, 29))	('congenital heart disorders', 'Disease', 'MESH:D006330', (167, 193))	('heart defects', 'Phenotype', 'HP:0030680', (16, 29))	('congenital heart disorders', 'Phenotype', 'HP:0001627', (167, 193))	('trisomies', 'Var', (45, 54))	('deletions', 'Var', (94, 103))	('congenital heart disorders', 'Disease', (167, 193))	('22q11.2', 'Gene', (122, 129))	('congenital heart defects', 'Disease', 'MESH:D006330', (5, 29))	('brachial arches', 'Disease', 'MESH:D020968', (221, 236))	('conotruncus', 'Disease', (201, 212))
357033	24910640	Indeed, Sandberg provides a summary of specific chromosomal translocations corresponding to a variety of soft tissue sarcomas including synovial sarcoma where:the translocation is the sole cytogenetic anomaly, indicating the probable causative role of this translocation in the genesis of these tumors.	('tumors', 'Disease', (295, 301))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (105, 125))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (105, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('synovial sarcoma', 'Disease', (136, 152))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('anomaly', 'Disease', (201, 208))	('translocation', 'Var', (163, 176))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (105, 125))	('soft tissue sarcomas', 'Disease', (105, 125))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('anomaly', 'Disease', 'MESH:D000014', (201, 208))	('synovial sarcoma', 'Disease', 'MESH:D013584', (136, 152))
357035	24910640	The available evidence suggests that the specific type of translocation may be related to the aggressiveness of the synovial sarcoma and its prognosis.	('translocation', 'Var', (58, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('aggressiveness of the synovial sarcoma', 'Disease', 'MESH:D013584', (94, 132))	('related', 'Reg', (79, 86))	('aggressiveness of the synovial sarcoma', 'Disease', (94, 132))	('aggressiveness', 'Phenotype', 'HP:0000718', (94, 108))
357041	24910640	Certain inherited disorders produce multiple cancers that are prone to develop chromosomal instability and present at a late stage with histological features that mimic disseminated mesothelioma (Hawley and Pandolfi,).	('inherited disorders', 'Disease', (8, 27))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mesothelioma', 'Disease', (182, 194))	('inherited disorders', 'Disease', 'MESH:D030342', (8, 27))	('chromosomal instability', 'Var', (79, 102))	('multiple cancers', 'Disease', (36, 52))	('chromosomal instability', 'Phenotype', 'HP:0040012', (79, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('multiple cancers', 'Disease', 'MESH:D009369', (36, 52))
357043	24910640	Both syndromes are known to have diagnostic genetic mutations in somatic cells that identify the syndrome and overt clinical outcome which consists of multiple, but often survivable, cancers in affected subjects and their blood relatives.	('mutations', 'Var', (52, 61))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('cancers', 'Disease', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
357049	24910640	Late stage tumors of MEN-1 patients have been associated with chromosomal instability that may plausibly lead to local tissue invasion and conversion to mixed neoplastic cell types including soft tissue sarcomas that may mimic mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (227, 240))	('soft tissue sarcomas', 'Disease', (191, 211))	('MEN-1', 'Gene', '4221', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (191, 211))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (191, 210))	('chromosomal instability', 'Var', (62, 85))	('chromosomal instability', 'Phenotype', 'HP:0040012', (62, 85))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (191, 211))	('MEN-1', 'Gene', (21, 26))	('patients', 'Species', '9606', (27, 35))	('local tissue invasion', 'CPA', (113, 134))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('lead to', 'Reg', (105, 112))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('mesotheliomas', 'Disease', (227, 240))	('tumors', 'Disease', (11, 17))
357050	24910640	Thus, it is suggested that persons with characteristic prior cancers and/or ZES and distal gastrectomy who present with apparent mesothelioma should be tested for the somatic cell mutation (11q13) of the MEN-1 tumor suppressor gene, in addition to testing for other translocations that may be diagnostic for various types of soft tissue sarcoma that may be relevant to the tumor/site (Sandberg,).	('mesothelioma', 'Disease', (129, 141))	('MEN-1', 'Gene', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (325, 344))	('tumor', 'Disease', (210, 215))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('sarcoma', 'Disease', 'MESH:D012509', (337, 344))	('sarcoma', 'Disease', (337, 344))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (373, 378))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('persons', 'Species', '9606', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (337, 344))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('11q13', 'Var', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (373, 378))	('ZES', 'Phenotype', 'HP:0002044', (76, 79))	('MEN-1', 'Gene', '4221', (204, 209))
357053	24910640	Also, late stage tumors in HNPCC patients are associated with chromosomal instability that may plausibly lead to local tissue invasion and conversion to mixed neoplastic cell types including soft tissue sarcomas that may mimic mesotheliomas.	('tumors', 'Disease', (17, 23))	('mesotheliomas', 'Disease', 'MESH:D008654', (227, 240))	('soft tissue sarcomas', 'Disease', (191, 211))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (191, 211))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (191, 210))	('chromosomal instability', 'Var', (62, 85))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('chromosomal instability', 'Phenotype', 'HP:0040012', (62, 85))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (191, 211))	('local tissue invasion', 'CPA', (113, 134))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('lead to', 'Reg', (105, 112))	('HNPCC', 'Gene', (27, 32))	('HNPCC', 'Gene', '4436', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('patients', 'Species', '9606', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('mesotheliomas', 'Disease', (227, 240))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
357054	24910640	Thus, persons with characteristic prior cancers who present with apparent mesothelioma should be tested for the somatic cell mutations of HNPCC, in addition to testing for other translocations that may be diagnostic for various types of soft tissue sarcoma that may be relevant to the tumor/site (Sandberg,).	('mutations', 'Var', (125, 134))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('tumor', 'Disease', (285, 290))	('HNPCC', 'Gene', (138, 143))	('persons', 'Species', '9606', (6, 13))	('cancers', 'Disease', (40, 47))	('sarcoma', 'Disease', 'MESH:D012509', (249, 256))	('sarcoma', 'Disease', (249, 256))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (237, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('HNPCC', 'Gene', '4436', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mesothelioma', 'Disease', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
357157	24604982	MEN2A patients usually have RET-oncogene mutations; whereas, MEN2B have codon 918 mutations.	('mutations', 'Var', (41, 50))	('MEN2A', 'Gene', '5979', (0, 5))	('MEN2B', 'Gene', '5979', (61, 66))	('MEN2A', 'Gene', (0, 5))	('RET', 'Gene', '5979', (28, 31))	('patients', 'Species', '9606', (6, 14))	('RET', 'Gene', (28, 31))	('codon 918 mutations', 'Var', (72, 91))	('MEN2B', 'Gene', (61, 66))
357306	21774838	In the field of radiation therapy, the use of FDG-PET in combination with CT has been shown to enable efficient planning of treatment, since FDG-PET enables more accurate calculation of the actual extent of tumor than macroscopic evaluation of target tumor volume with CT or MRI.	('tumor', 'Disease', (251, 256))	('FDG-PET', 'Var', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
357355	30680044	Due to intracellular linker cleavage, the cytotoxic potency of the liberated tubugi-1 that, however, still bears the thiol spacer (tubugi-1-SH) was restored and up to 10-fold higher compared to the entire peptide-toxin conjugate.	('thiol', 'MPA', (117, 122))	('higher', 'PosReg', (175, 181))	('cleavage', 'Var', (28, 36))	('cytotoxic potency', 'MPA', (42, 59))	('tubugi-1', 'Gene', (77, 85))	('restored', 'PosReg', (148, 156))	('thiol', 'Chemical', 'MESH:D013438', (117, 122))
357370	30680044	Amongst the GPCRs, the neuropeptide Y (NPY) receptor family comprises four closely related receptor subtypes in human (hY1R, hY2R, hY4R, and hY5R) that have been discussed in the context of several diseases.	('hY5R', 'Var', (141, 145))	('GPCR', 'Gene', (12, 16))	('GPCR', 'Gene', '441931', (12, 16))	('hY4R', 'Var', (131, 135))	('neuropeptide Y', 'Gene', '4852', (23, 37))	('neuropeptide Y', 'Gene', (23, 37))	('human', 'Species', '9606', (112, 117))	('hY2R', 'Var', (125, 129))	('hY1R', 'Var', (119, 123))
357373	30680044	Reubi and co-workers detected its pathological overexpression in  85% of the studied breast tumor samples and virtually all of the infiltrated lymph nodes, whereas the surrounding healthy breast tissue was found to express negligible amounts of hY1R but predominantly the closely related Y2 receptor subtype (hY2R).	('overexpression', 'PosReg', (47, 61))	('breast tumor', 'Phenotype', 'HP:0100013', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('breast tumor', 'Disease', 'MESH:D001943', (85, 97))	('hY1R', 'Var', (245, 249))	('breast tumor', 'Disease', (85, 97))
357380	30680044	Recently, Ahrens et al., in cooperation with OntoChem GmbH amongst others, tested [F7,P34]-pNPY as well as a peptide-tubulysin A conjugate [K4(C(TubA)-betaA-),F7,P34]-pNPY - representing a comparable PDC - compared to wildtype pNPY for their binding affinities at the NPY Y1 receptor subtype.	('[K4', 'Var', (139, 142))	('PDC', 'Gene', (200, 203))	('TubA', 'Gene', (145, 149))	('PDC', 'Gene', '5132', (200, 203))	('binding', 'Interaction', (242, 249))	('TubA', 'Gene', '23268', (145, 149))
357383	30680044	Interestingly, at the NPY Y2 receptor subtype the EC50 value of the subtype-unspecific wildtype pNPY was found in the same range, but the EC50 values of [F7,P34]-pNPY and [K4(C(TubA)-betaA-),F7,P34]-pNPY were detected with higher than 100 nM, i.e., around two magnitudes higher than at the Y1 receptor subtype.	('TubA', 'Gene', '23268', (177, 181))	('NPY Y2 receptor', 'Gene', '4887', (22, 37))	('NPY Y2 receptor', 'Gene', (22, 37))	('[F7', 'Var', (153, 156))	('TubA', 'Gene', (177, 181))
357391	30680044	More recently, further approaches of hY1R-addressing PDCs for therapeutic applications have been published, whereby the peptide moiety always is based on [F7,P34]-pNPY.	('PDC', 'Gene', (53, 56))	('PDC', 'Gene', '5132', (53, 56))	('[F7', 'Var', (154, 157))
357402	30680044	For tubugi conjugates we learned that alkyl amide bonds and several types of linkers are unsuitable, as they rendered the peptide inactive (results not shown).	('rendered', 'Reg', (109, 117))	('alkyl', 'Var', (38, 43))	('alkyl amide', 'Chemical', '-', (38, 49))	('peptide inactive', 'MPA', (122, 138))
357412	30680044	Several linker chemistries were tested with tubulysin-like peptides - amongst them amide and ester linkers, hydrazone linker, VC linker etc.	('ester', 'Chemical', 'MESH:D004952', (93, 98))	('hydrazone', 'Chemical', 'MESH:D006835', (108, 117))	('hydrazone', 'Var', (108, 117))	('amide', 'Chemical', 'MESH:D000577', (83, 88))	('amide', 'Var', (83, 88))
357438	30680044	Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8.	('hY1R', 'MPA', (36, 40))	('PDC', 'Gene', '5132', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('MDA-MB-468', 'Var', (86, 96))	('cytotoxic activity', 'CPA', (9, 27))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('SK-N-MC', 'Var', (76, 83))	('SK-N-MC', 'CellLine', 'CVCL:0530', (76, 83))	('tumor', 'Disease', (190, 195))	('MDA-MB-231', 'Var', (99, 109))	('PDC', 'Gene', (219, 222))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (99, 109))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (86, 96))
357443	30680044	Most importantly, the cytotoxic potential of tubugi-1-SS-NPY correlates very well with the hY1R expression levels of a panel of tumor cell lines.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('hY1R', 'MPA', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cytotoxic potential', 'CPA', (22, 41))	('tumor', 'Disease', (128, 133))	('tubugi-1-SS-NPY', 'Var', (45, 60))
357451	26887042	Based on these as well as mathematic modeling, we have carried out a successful preclinical study using CDK4 and IGF1R inhibitors in liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('inhibitors', 'Var', (119, 129))	('liposarcoma', 'Disease', (133, 144))	('IGF1R', 'Gene', (113, 118))	('CDK4', 'Gene', (104, 108))	('liposarcoma', 'Disease', 'MESH:D008080', (133, 144))	('IGF1R', 'Gene', '3480', (113, 118))	('liposarcoma', 'Phenotype', 'HP:0012034', (133, 144))	('CDK4', 'Gene', '1019', (104, 108))
357452	26887042	MLN8237 has been shown to be a potent and selective inhibitor of Aurora A. MLN-8237, as per our results, induces a differential inhibition of Aurora A and B in a dose dependent manner.	('inhibition', 'NegReg', (128, 138))	('Aurora A', 'Gene', '6790', (65, 73))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('Aurora A', 'Gene', '6790', (142, 150))	('MLN-8237', 'Var', (75, 83))	('Aurora A and B', 'Gene', '6790;9212', (142, 156))	('Aurora A', 'Gene', (65, 73))	('MLN-8237', 'Chemical', 'MESH:C550258', (75, 83))	('Aurora A', 'Gene', (142, 150))
357454	26887042	However, micromolar dose of MLN-8237 induced polyploidy, a hallmark effect of Aurora B inhibition.	('polyploidy', 'Disease', (45, 55))	('Aurora B', 'Gene', (78, 86))	('Aurora B', 'Gene', '9212', (78, 86))	('MLN-8237', 'Chemical', 'MESH:C550258', (28, 36))	('induced', 'Reg', (37, 44))	('polyploidy', 'Disease', 'MESH:D011123', (45, 55))	('MLN-8237', 'Var', (28, 36))
357468	26887042	Both overexpression and gene amplification of Aurora A have been characterized in human tumors and have been shown to correlate with tumor proliferation rates and prognostic markers.	('gene amplification', 'Var', (24, 42))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Aurora A', 'Gene', '6790', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', (88, 93))	('human', 'Species', '9606', (82, 87))	('Aurora A', 'Gene', (46, 54))
357471	26887042	ZM447439, AZD 1152, MK-0457, MK8745, PHA739358, MLN8054 and MLN8237 are few of the small molecule inhibitors of Aurora Kinase B, A or A/B which are under different stages of clinical development.	('MLN8237', 'Chemical', 'MESH:C550258', (60, 67))	('PHA739358', 'Var', (37, 46))	('MLN8054', 'Var', (48, 55))	('AZD', 'Chemical', '-', (10, 13))	('MLN8237', 'Var', (60, 67))	('Aurora Kinase B, A or A', 'Gene', '9212;6790', (112, 135))	('MK8745', 'Var', (29, 35))
357472	26887042	Our studies on AZD1152 have shown its selective inhibition of Aurora B kinase and the effect of endoreduplication and polyploidy at a very low nanomolar concentration despite the p53 status.	('AZD1152', 'Var', (15, 22))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('AZD1152', 'Chemical', 'MESH:C520647', (15, 22))	('Aurora B', 'Gene', '9212', (62, 70))	('polyploidy', 'Disease', (118, 128))	('Aurora B', 'Gene', (62, 70))	('inhibition', 'NegReg', (48, 58))	('polyploidy', 'Disease', 'MESH:D011123', (118, 128))
357473	26887042	However, MK-8745, a selective Aurora A Kinase inhibitor was shown to induce apoptosis versus polyploidy in a p53 dependent manner.	('MK-8745', 'Var', (9, 16))	('apoptosis versus polyploidy', 'Disease', (76, 103))	('apoptosis versus polyploidy', 'Disease', 'MESH:D011123', (76, 103))	('Aurora A', 'Gene', (30, 38))	('p53', 'Gene', (109, 112))	('induce', 'PosReg', (69, 75))	('p53', 'Gene', '7157', (109, 112))	('Aurora A', 'Gene', '6790', (30, 38))	('MK-8745', 'Chemical', 'MESH:C574019', (9, 16))
357477	26887042	For example liposarcoma which is the most common type of soft tissue sarcoma in adults, accounting for approximately 20% of all adult soft tissue sarcomas, is characterized by amplifications of CDK4 and MDM2.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (57, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('MDM2', 'Gene', (203, 207))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('CDK4', 'Gene', (194, 198))	('sarcoma', 'Disease', (69, 76))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (134, 153))	('liposarcoma', 'Phenotype', 'HP:0012034', (12, 23))	('MDM2', 'Gene', '4193', (203, 207))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('liposarcoma', 'Disease', 'MESH:D008080', (12, 23))	('sarcoma', 'Disease', (146, 153))	('CDK4', 'Gene', '1019', (194, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('sarcomas', 'Disease', (146, 154))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (134, 154))	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('sarcoma', 'Disease', (16, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('amplifications', 'Var', (176, 190))	('liposarcoma', 'Disease', (12, 23))
357479	26887042	It has been shown in MPNST that HMMR/RHAMM is critical in sensitizing cells to MLN8237.	('MLN8237', 'Chemical', 'MESH:C550258', (79, 86))	('HMMR', 'Gene', '3161', (32, 36))	('RHAMM', 'Gene', '3161', (37, 42))	('RHAMM', 'Gene', (37, 42))	('MLN8237', 'Var', (79, 86))	('HMMR', 'Gene', (32, 36))
357484	26887042	In the present study, we evaluated the biological activity and effect of MLN-8237, a putative Aurora A inhibitor against a panel of sarcoma cell lines.	('Aurora A', 'Gene', (94, 102))	('sarcoma', 'Disease', (132, 139))	('MLN-8237', 'Chemical', 'MESH:C550258', (73, 81))	('Aurora A', 'Gene', '6790', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('MLN-8237', 'Var', (73, 81))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
357486	26887042	Sarcoma cell lines were tested for their sensitivity towards MLN 8237, a selective inhibitor of Aurora A kinase.	('Aurora A', 'Gene', '6790', (96, 104))	('MLN 8237', 'Chemical', 'MESH:C550258', (61, 69))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('Aurora A', 'Gene', (96, 104))	('MLN 8237', 'Var', (61, 69))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
357487	26887042	Chemical structure of the small molecule inhibitor, MLN 8237 is shown in Figure 1A(i) and (ii) summarizes the IC50 values obtained for different sarcoma cell types as determined by colorimetric cell proliferation assay.	('sarcoma', 'Disease', (145, 152))	('MLN 8237', 'Var', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('MLN 8237', 'Chemical', 'MESH:C550258', (52, 60))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))
357488	26887042	MLN-8237 seems to be very potent inhibitor of tumor growth across multiple sarcoma subtypes.	('MLN-8237', 'Chemical', 'MESH:C550258', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('tumor', 'Disease', (46, 51))	('sarcoma', 'Disease', (75, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('MLN-8237', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
357489	26887042	In view of the reported overexpression of Aurora A in liposarcoma, our initial focus was to assess the effect of MLN-8237 in liposarcoma cells.	('liposarcoma', 'Disease', (54, 65))	('Aurora A', 'Gene', '6790', (42, 50))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('liposarcoma', 'Disease', 'MESH:D008080', (125, 136))	('MLN-8237', 'Var', (113, 121))	('liposarcoma', 'Phenotype', 'HP:0012034', (54, 65))	('liposarcoma', 'Disease', 'MESH:D008080', (54, 65))	('overexpression', 'PosReg', (24, 38))	('Aurora A', 'Gene', (42, 50))	('MLN-8237', 'Chemical', 'MESH:C550258', (113, 121))	('liposarcoma', 'Disease', (125, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
357490	26887042	Time-dose and concentration dependency of MLN-8237 to inhibit Aurora A and B was tested in LS141 by choosing a range of concentrations from 10 nM to 10 muM from 12 to 48 hours of exposure.	('Aurora A and B', 'Gene', '6790;9212', (62, 76))	('MLN-8237', 'Var', (42, 50))	('inhibit', 'NegReg', (54, 61))	('MLN-8237', 'Chemical', 'MESH:C550258', (42, 50))
357496	26887042	It is interesting to note that at 1000 nM phospho H3S10 is completely inhibited at all time points tested.	('inhibited', 'NegReg', (70, 79))	('phospho', 'Var', (42, 49))	('H3S10', 'Chemical', '-', (50, 55))
357499	26887042	The specificity of MLN-8237 in inhibiting Aurora A at low and Aurora B at high concentrations was validated further by using specific siRNA to inhibit Aurora A and B.	('Aurora A', 'Gene', '6790', (151, 159))	('Aurora A and B', 'Gene', '6790;9212', (151, 165))	('Aurora A', 'Gene', '6790', (42, 50))	('MLN-8237', 'Var', (19, 27))	('Aurora B', 'Gene', '9212', (62, 70))	('Aurora A', 'Gene', (151, 159))	('Aurora B', 'Gene', (62, 70))	('inhibiting', 'NegReg', (31, 41))	('inhibit', 'NegReg', (143, 150))	('Aurora A', 'Gene', (42, 50))	('MLN-8237', 'Chemical', 'MESH:C550258', (19, 27))
357500	26887042	We have previously reported that Aurora B inhibition induced polyploidy which is distinct from Aurora A inhibition which is associated with an increase in mitotic index and apoptosis.	('Aurora B', 'Gene', (33, 41))	('Aurora A', 'Gene', (95, 103))	('apoptosis', 'CPA', (173, 182))	('inhibition', 'Var', (42, 52))	('Aurora A', 'Gene', '6790', (95, 103))	('polyploidy', 'Disease', (61, 71))	('mitotic index', 'CPA', (155, 168))	('increase', 'PosReg', (143, 151))	('Aurora B', 'Gene', '9212', (33, 41))	('polyploidy', 'Disease', 'MESH:D011123', (61, 71))
357501	26887042	The cellular effect of mitotic arrest and apoptosis with 100 nM MLN-8237 for 48 hours is comparable to the effects upon specifically inhibiting Aurora A by using siRNA.	('Aurora A', 'Gene', '6790', (144, 152))	('MLN-8237', 'Var', (64, 72))	('Aurora A', 'Gene', (144, 152))	('apoptosis', 'CPA', (42, 51))	('mitotic arrest', 'Disease', (23, 37))	('MLN-8237', 'Chemical', 'MESH:C550258', (64, 72))	('mitotic arrest', 'Disease', 'MESH:D006323', (23, 37))
357502	26887042	With MLN-8237 there was an increase in mitotic fraction from 2% to 12% when compared to untreated controls at 24 hours and this was maintained though at reduced numbers for 48 hours of continuous drug exposure.	('MLN-8237', 'Chemical', 'MESH:C550258', (5, 13))	('increase', 'PosReg', (27, 35))	('MLN-8237', 'Var', (5, 13))	('mitotic fraction', 'CPA', (39, 55))
357503	26887042	In contrast, polyploidy with induction of an 8N peak was the cellular fate upon inhibiting Aurora B by specific siRNA and with 48 hours of exposure to 1000 nM of MLN-8237.	('polyploidy', 'Disease', 'MESH:D011123', (13, 23))	('MLN-8237', 'Chemical', 'MESH:C550258', (162, 170))	('8N peak', 'MPA', (45, 52))	('inhibiting', 'NegReg', (80, 90))	('polyploidy', 'Disease', (13, 23))	('Aurora B', 'Gene', (91, 99))	('MLN-8237', 'Var', (162, 170))	('Aurora B', 'Gene', '9212', (91, 99))
357504	26887042	The knock down of Aurora A and B as well as the apoptotic and polyploidy effects were further confirmed by western blot analysis.	('polyploidy', 'Disease', (62, 72))	('knock down', 'Var', (4, 14))	('Aurora A and B', 'Gene', '6790;9212', (18, 32))	('polyploidy', 'Disease', 'MESH:D011123', (62, 72))	('apoptotic', 'CPA', (48, 57))
357505	26887042	As shown in Figure 2B(ii) at 100 nM phospho H3 (S10) was induced followed by apoptosis (cleaved PARP) at 48 hours comparable to inhibition of Aurora A by siRNA knock down.	('apoptosis', 'CPA', (77, 86))	('PARP', 'Gene', (96, 100))	('Aurora A', 'Gene', '6790', (142, 150))	('phospho H3 (S10', 'Var', (36, 51))	('H3', 'Chemical', 'MESH:C012616', (44, 46))	('Aurora A', 'Gene', (142, 150))	('PARP', 'Gene', '142', (96, 100))
357506	26887042	However, only with 1000 nM of MLN-8237 and with Aurora B siRNA knockdown resulted in polyploidy with induced hypophosphorylation of Rb.	('polyploidy', 'Disease', 'MESH:D011123', (85, 95))	('hypophosphorylation of Rb', 'Disease', (109, 134))	('MLN-8237', 'Var', (30, 38))	('Aurora B', 'Gene', (48, 56))	('hypophosphorylation of Rb', 'Disease', 'None', (109, 134))	('Aurora B', 'Gene', '9212', (48, 56))	('polyploidy', 'Disease', (85, 95))	('resulted in', 'Reg', (73, 84))	('MLN-8237', 'Chemical', 'MESH:C550258', (30, 38))
357511	26887042	Of the 5 cell lines three undergo apoptosis with induced phospho H3 (S10) at a lower concentration and lacking the apoptotic effect at a higher concentration except for OCM3.	('induced phospho H3', 'Var', (49, 67))	('H3', 'Chemical', 'MESH:C012616', (65, 67))	('undergo', 'Reg', (26, 33))
357518	26887042	As shown in Figure 3B with 100 nM of MLN-8237 there was a slight induction of a sub G1 peak consistent with apoptosis and a marked increase in the G2M fraction with some induction of polyploidy (8N).	('MLN-8237', 'Var', (37, 45))	('G2M fraction', 'CPA', (147, 159))	('increase', 'PosReg', (131, 139))	('polyploidy', 'Disease', (183, 193))	('sub G1 peak', 'MPA', (80, 91))	('MLN-8237', 'Chemical', 'MESH:C550258', (37, 45))	('polyploidy', 'Disease', 'MESH:D011123', (183, 193))
357520	26887042	By western blot analysis the low dose of MLN-8237 induced cleaved PARP and caspase 3 along with induction of phospho H3 (S0), p53, p21 and Aurora A consistent with an Aurora A effect whereas with the higher concentration though there was a similar pattern for the other proteins there was no apoptosis and inhibition of phospho H3 (S10), consistent with an Aurora B effect.	('induced', 'Reg', (50, 57))	('Aurora B', 'Gene', '9212', (357, 365))	('Aurora A', 'Gene', '6790', (167, 175))	('MLN-8237', 'Chemical', 'MESH:C550258', (41, 49))	('H3', 'Chemical', 'MESH:C012616', (328, 330))	('PARP', 'Gene', '142', (66, 70))	('Aurora A', 'Gene', (139, 147))	('p53', 'Gene', '7157', (126, 129))	('PARP', 'Gene', (66, 70))	('cleaved', 'MPA', (58, 65))	('H3', 'Chemical', 'MESH:C012616', (117, 119))	('p53', 'Gene', (126, 129))	('Aurora B', 'Gene', (357, 365))	('Aurora A', 'Gene', (167, 175))	('p21', 'Gene', (131, 134))	('MLN-8237', 'Var', (41, 49))	('caspase 3', 'Gene', (75, 84))	('p21', 'Gene', '644914', (131, 134))	('Aurora A', 'Gene', '6790', (139, 147))	('caspase 3', 'Gene', '836', (75, 84))
357521	26887042	The effect of MLN-8237 was further confirmed by time lapse video microscopy using HCT 116 cells transiently transfected with GFP H2B followed by treatment with either 1000 nM or 100 nM of MLN-8237 (Supplementary 1A and 1B, Movies).	('MLN-8237', 'Chemical', 'MESH:C550258', (14, 22))	('HCT 116', 'CellLine', 'CVCL:0291', (82, 89))	('MLN-8237', 'Var', (188, 196))	('GFP', 'Var', (125, 128))	('MLN-8237', 'Chemical', 'MESH:C550258', (188, 196))	('H2B', 'Gene', (129, 132))
357524	26887042	This further confirms the finding that cells upon exposure to low dose MLN-8237 undergo apoptosis following Aurora A inhibition; whereas cells exposed to high dose undergo endoreduplication and polyploidy by inhibition of Aurora B.	('Aurora B', 'Gene', (222, 230))	('apoptosis', 'CPA', (88, 97))	('Aurora A', 'Gene', (108, 116))	('Aurora B', 'Gene', '9212', (222, 230))	('MLN-8237', 'Var', (71, 79))	('Aurora A', 'Gene', '6790', (108, 116))	('polyploidy', 'Disease', (194, 204))	('endoreduplication', 'CPA', (172, 189))	('inhibition', 'NegReg', (117, 127))	('polyploidy', 'Disease', 'MESH:D011123', (194, 204))	('undergo', 'Reg', (80, 87))	('MLN-8237', 'Chemical', 'MESH:C550258', (71, 79))
357525	26887042	In order to determine whether the dose dependent differential inhibition has an impact in vivo we tested MLN-8237 in LS141 xenografts and checked the inhibition of the pathway.	('MLN-8237', 'Chemical', 'MESH:C550258', (105, 113))	('MLN-8237', 'Var', (105, 113))	('tested', 'Reg', (98, 104))
357526	26887042	Figure 5A clearly shows efficient tumor growth suppression at 30 mg/kg of MLN-8237.	('MLN-8237', 'Var', (74, 82))	('tumor', 'Disease', (34, 39))	('MLN-8237', 'Chemical', 'MESH:C550258', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
357528	26887042	Upon analyzing the lysates from the MLN-8237 treated tumor versus the vehicle treated controls by western blot analysis, we observed induction of phospho H3 (S10) and cleaved PARP indicative of inhibition of Aurora A but not Aurora B at the dose tested (Figure 5A(ii)).	('Aurora A', 'Gene', (208, 216))	('PARP', 'Gene', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('phospho', 'MPA', (146, 153))	('MLN-8237 treated', 'Var', (36, 52))	('cleaved', 'MPA', (167, 174))	('H3', 'Chemical', 'MESH:C012616', (154, 156))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('MLN-8237', 'Chemical', 'MESH:C550258', (36, 44))	('PARP', 'Gene', '142', (175, 179))	('Aurora A', 'Gene', '6790', (208, 216))	('tumor', 'Disease', (53, 58))	('Aurora B', 'Gene', (225, 233))	('Aurora B', 'Gene', '9212', (225, 233))
357530	26887042	Immunohistochemistry of the xenografts confirmed the induction of apoptosis and phospho H3 (S10) again supporting the fact that the tumor suppression observed with MLN-8237 is predominantly a result of Aurora A (and not Aurora B) inhibition.	('Aurora A', 'Gene', '6790', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('MLN-8237', 'Chemical', 'MESH:C550258', (164, 172))	('Aurora B', 'Gene', (220, 228))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Aurora B', 'Gene', '9212', (220, 228))	('H3', 'Chemical', 'MESH:C012616', (88, 90))	('tumor', 'Disease', (132, 137))	('MLN-8237', 'Var', (164, 172))	('Aurora A', 'Gene', (202, 210))
357535	26887042	MLN-8237 is an Aurora Kinase inhibitor being developed by Millennium Pharmaceuticals.	('MLN-8237', 'Chemical', 'MESH:C550258', (0, 8))	('MLN-8237', 'Var', (0, 8))	('Aurora Kinase', 'Gene', '41446', (15, 28))	('Aurora Kinase', 'Gene', (15, 28))
357536	26887042	MLN-8237 is an adenosine triphosphate (ATP) competitive and reversible inhibitor of Aurora Kinase A with an inhibition constant of 0.43 nM.	('MLN-8237', 'Chemical', 'MESH:C550258', (0, 8))	('Aurora Kinase A', 'Gene', (84, 99))	('ATP', 'Chemical', 'MESH:D000255', (39, 42))	('MLN-8237', 'Var', (0, 8))	('Aurora Kinase A', 'Gene', '6790', (84, 99))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (15, 37))
357537	26887042	MLN-8237 showed about 200 fold more selectivity for Aurora kinase A compared to Aurora kinase B in HCT116 cells and in vitro kinase assays have shown 250 fold selectivity for Aurora A compared to other kinases tested in vitro.	('MLN-8237', 'Chemical', 'MESH:C550258', (0, 8))	('Aurora kinase B', 'Gene', '9212', (80, 95))	('Aurora kinase A', 'Gene', (52, 67))	('Aurora kinase A', 'Gene', '6790', (52, 67))	('HCT116', 'CellLine', 'CVCL:0291', (99, 105))	('Aurora A', 'Gene', (175, 183))	('MLN-8237', 'Var', (0, 8))	('Aurora kinase B', 'Gene', (80, 95))	('selectivity', 'MPA', (36, 47))	('more', 'PosReg', (31, 35))	('Aurora A', 'Gene', '6790', (175, 183))
357538	26887042	MLN8237 has been shown to be potent in tumor suppression in peripheral T Cell Lymphomas.	('peripheral T Cell Lymphomas', 'Disease', (60, 87))	('T Cell Lymphomas', 'Phenotype', 'HP:0012190', (71, 87))	('peripheral T Cell Lymphomas', 'Disease', 'MESH:D016411', (60, 87))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Lymphomas', 'Phenotype', 'HP:0002665', (78, 87))	('Cell Lymphoma', 'Phenotype', 'HP:0012191', (73, 86))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('MLN8237', 'Var', (0, 7))	('Lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('tumor', 'Disease', (39, 44))
357546	26887042	Reports on the amplification of chromosome 12q13-15, containing oncogenes MDM2, HMGA2 and CDK4 in about 90% of well and dedifferentiated liposarcoma led to the development of new targeted agents.	('MDM2', 'Gene', '4193', (74, 78))	('CDK4', 'Gene', '1019', (90, 94))	('CDK4', 'Gene', (90, 94))	('HMGA2', 'Gene', (80, 85))	('MDM2', 'Gene', (74, 78))	('amplification', 'Var', (15, 28))	('liposarcoma', 'Disease', (137, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('liposarcoma', 'Phenotype', 'HP:0012034', (137, 148))	('liposarcoma', 'Disease', 'MESH:D008080', (137, 148))	('HMGA2', 'Gene', '8091', (80, 85))
357549	26887042	Based on this study as well as mathematical modeling we have carried out a preclinical study successfully by using CDK4 and IGF1R inhibitors in liposarcoma.	('IGF1R', 'Gene', '3480', (124, 129))	('CDK4', 'Gene', (115, 119))	('CDK4', 'Gene', '1019', (115, 119))	('inhibitors', 'Var', (130, 140))	('liposarcoma', 'Disease', (144, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('liposarcoma', 'Disease', 'MESH:D008080', (144, 155))	('liposarcoma', 'Phenotype', 'HP:0012034', (144, 155))	('IGF1R', 'Gene', (124, 129))
357550	26887042	Our results indicate that MLN-8237 is highly active against multiple sarcoma subtypes in low nanomolar concentrations even in the absence of Aurora A amplification.	('Aurora A', 'Gene', (141, 149))	('sarcoma', 'Disease', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Aurora A', 'Gene', '6790', (141, 149))	('MLN-8237', 'Var', (26, 34))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('MLN-8237', 'Chemical', 'MESH:C550258', (26, 34))
357551	26887042	Though described as an Aurora A inhibitor, our results indicate that MLN8237 in fact, inhibits both Aurora A and B in a dose dependent nature.	('Aurora A', 'Gene', '6790', (100, 108))	('Aurora A', 'Gene', (23, 31))	('Aurora A and B', 'Gene', '6790;9212', (100, 114))	('inhibits', 'NegReg', (86, 94))	('Aurora A', 'Gene', (100, 108))	('MLN8237', 'Chemical', 'MESH:C550258', (69, 76))	('Aurora A', 'Gene', '6790', (23, 31))	('MLN8237', 'Var', (69, 76))
357552	26887042	The concentration dependent induction of polyploidy by MLN8237 has also been reported in bladder cancer cell lines.	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('induction', 'Reg', (28, 37))	('polyploidy', 'Disease', 'MESH:D011123', (41, 51))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('MLN8237', 'Chemical', 'MESH:C550258', (55, 62))	('MLN8237', 'Var', (55, 62))	('polyploidy', 'Disease', (41, 51))
357555	26887042	This differential effect of MLN-8237 on Aurora A and B has also been reported in Peripheral T-Cell Lymphoma cells.	('MLN-8237', 'Chemical', 'MESH:C550258', (28, 36))	('T-Cell Lymphoma', 'Phenotype', 'HP:0012190', (92, 107))	('Peripheral T-Cell Lymphoma', 'Disease', 'MESH:D016411', (81, 107))	('Cell Lymphoma', 'Phenotype', 'HP:0012191', (94, 107))	('MLN-8237', 'Var', (28, 36))	('Lymphoma', 'Phenotype', 'HP:0002665', (99, 107))	('Aurora A and B', 'Gene', '6790;9212', (40, 54))	('Peripheral T-Cell Lymphoma', 'Disease', (81, 107))
357556	26887042	Here ex vivo treatment of PTCL derived patient cells treated with MLN-8237 induced polyploidy at high concentration consistent with an Aurora B effect.	('induced', 'Reg', (75, 82))	('patient', 'Species', '9606', (39, 46))	('MLN-8237', 'Chemical', 'MESH:C550258', (66, 74))	('polyploidy', 'Disease', (83, 93))	('polyploidy', 'Disease', 'MESH:D011123', (83, 93))	('MLN-8237', 'Var', (66, 74))	('Aurora B', 'Gene', (135, 143))	('Aurora B', 'Gene', '9212', (135, 143))
357561	26887042	MLN8237, a small molecule inhibitor of Aurora A Kinase), was provided by Millennium.	('Aurora A', 'Gene', '6790', (39, 47))	('Aurora A', 'Gene', (39, 47))	('MLN8237', 'Var', (0, 7))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))
357572	26887042	Athymic mice bearing MPNST or CHP100 tumors (7 mice/cohort) of 150 mm3 diameters were either treated with vehicle control, 30 mg/kg of MLN-8237 p.o.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('CHP100 tumors', 'Disease', 'MESH:D009369', (30, 43))	('MLN-8237', 'Chemical', 'MESH:C550258', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mice', 'Species', '10090', (8, 12))	('CHP100 tumors', 'Disease', (30, 43))	('mice', 'Species', '10090', (47, 51))	('MLN-8237', 'Var', (135, 143))
357596	26266019	FISH indicated rearrangement involving the EWSR1 gene region.	('rearrangement', 'Var', (15, 28))	('EWSR1', 'Gene', (43, 48))	('EWSR1', 'Gene', '2130', (43, 48))
357631	26266019	Pazopanib targets vascular endothelial growth factor (VEGFR) 1-3 as well as platelet derived growth factors, and targeting of VEGFR2 and PDGF have been shown to inhibit Ewing sarcoma preclinically.	('PDGF', 'Gene', (137, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (169, 182))	('VEGFR2', 'Gene', (126, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (169, 182))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('VEGFR', 'Gene', '7422', (126, 131))	('targeting', 'Var', (113, 122))	('VEGFR', 'Gene', (54, 59))	('vascular endothelial growth factor', 'Gene', (18, 52))	('VEGFR', 'Gene', '7422', (54, 59))	('VEGFR', 'Gene', (126, 131))	('inhibit', 'NegReg', (161, 168))	('vascular endothelial growth factor', 'Gene', '7422', (18, 52))	('VEGFR2', 'Gene', '3791', (126, 132))	('Ewing sarcoma', 'Disease', (169, 182))
357688	24368932	We use the random splitting probabilities Y00   G(B00   B0) ~ Be(a00, a01) and Y10   G(B10   B1) ~ Be(a10, a11).	('a01', 'CellLine', 'CVCL:X698', (70, 73))	('Y10   G(B10   B1', 'Var', (79, 95))	('Y00   G(B00   B0', 'Var', (42, 58))	('B10   B1', 'Species', '414454', (87, 95))
357696	24368932	A popular choice for cm is cm = cm2, which guarantees an absolutely continous random probability measure G. On the other hand, with aepsilon = alphaG (Bepsilon), and thus aepsilon = aepsilon0 + aepsilon1, the PT reduces to a DP(alpha, G ) prior with an a.s. discrete random probability measure G. Example 2 (Prostate cancer study).	('DP', 'Chemical', '-', (225, 227))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('Prostate cancer', 'Disease', (308, 323))	('si', 'Chemical', 'MESH:D012825', (197, 199))	('aepsilon =', 'Var', (132, 142))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('Prostate cancer', 'Disease', 'MESH:D011471', (308, 323))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('PT', 'Chemical', '-', (209, 211))	('aepsilon =', 'Var', (171, 181))	('Prostate cancer', 'Phenotype', 'HP:0012125', (308, 323))	('si', 'Chemical', 'MESH:D012825', (185, 187))
357739	24368932	The truncated DP is particularly attractive for posterior computation.	('truncated', 'Var', (4, 13))	('DP', 'Chemical', '-', (14, 16))	('posterior computation', 'Disease', (48, 69))
357848	24368932	Assuming epsiloni ~ G and a nonparametric prior G ~ p(G) reduces the problem to essentially the earlier discussed density estimation problem, the only difference being that now the i.i.d.	('G ~ p', 'Var', (48, 53))	('si', 'Chemical', 'MESH:D012825', (11, 13))	('epsiloni ~ G', 'Var', (9, 21))	('si', 'Chemical', 'MESH:D012825', (117, 119))
357919	24368932	Let yij = thetai + beta'xij + epsilonij denote a randomized block ANOVA with residuals epsilonij ~ N(0, sigma2), fixed effects beta and random effects thetai for blocks of experimental units, i = 1, .	('si', 'Chemical', 'MESH:D012825', (79, 81))	('eta', 'Gene', '1909', (20, 23))	('eta', 'Gene', (20, 23))	('eta', 'Gene', '1909', (128, 131))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('epsilonij ~', 'Var', (87, 98))	('eta', 'Gene', (128, 131))	('eta', 'Gene', '1909', (12, 15))	('eta', 'Gene', (12, 15))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('eta', 'Gene', '1909', (153, 156))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('eta', 'Gene', (153, 156))
357951	24368932	We assume yi1 ~ Poi(mui), yi2 Poi(muibetai) and yi3 ~ Poi(muideltai) for random effects (mui, betai, deltai).	('yi1 ~ Poi', 'Var', (10, 19))	('yi2 Poi', 'Var', (26, 33))	('eta', 'Gene', '1909', (38, 41))	('yi3 ~ Poi', 'Var', (48, 57))	('eta', 'Gene', (38, 41))	('eta', 'Gene', '1909', (95, 98))	('eta', 'Gene', (95, 98))
358005	24368932	with location theta and scale h. We consider DPM models of the form  with G ~ DP(G , M).	('DP', 'Chemical', '-', (78, 80))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('G ~ DP', 'Var', (74, 80))	('DP', 'Chemical', '-', (45, 47))	('eta', 'Gene', '1909', (16, 19))	('eta', 'Gene', (16, 19))
358063	24144362	In addition to its antimicrobial properties, salinomycin selectively depletes breast cancer stem cells from tumorspheres and impedes breast tumor growth in mice xenograft experiments.	('depletes', 'NegReg', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('salinomycin', 'Var', (45, 56))	('breast tumor', 'Phenotype', 'HP:0100013', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('salinomycin', 'Chemical', 'MESH:C010327', (45, 56))	('breast tumor', 'Disease', 'MESH:D001943', (133, 145))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('mice', 'Species', '10090', (156, 160))	('breast tumor', 'Disease', (133, 145))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('impedes', 'NegReg', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
358092	24144362	Membranes were incubated for detection with secondary antibodies raised against rabbit labeled with CyDye800 (Licor, Bad Homburg, Germany) and mouse labeled with CyDye700 (Licor, Bad Homburg, Germany) for 1 h at room temperature.	('mouse', 'Species', '10090', (143, 148))	('rabbit', 'Species', '9986', (80, 86))	('CyDye700', 'Var', (162, 170))	('CyDye800', 'Var', (100, 108))
358160	24144362	In contrast, we were able to show that even at low salinomycin doses, which did not directly provoke cell death, salinomycin was able to enhance the cellular response to doxorubicin.	('cellular response to doxorubicin', 'MPA', (149, 181))	('enhance', 'PosReg', (137, 144))	('salinomycin', 'Chemical', 'MESH:C010327', (113, 124))	('doxorubicin', 'Chemical', 'MESH:D004317', (170, 181))	('salinomycin', 'Chemical', 'MESH:C010327', (51, 62))	('salinomycin', 'Var', (113, 124))
358194	26262627	Thereafter, Eisai Research Institute licensed the technology and accomplished the synthesis and future development of the resulting drug, eribulin mesylate (Halaven , also known as eribulin mesilate, INN codename E7389, and before that, ER-086526 and B1939, US NCI designation NSC-707389).	('ER-086526', 'Var', (237, 246))	('eribulin mesilate', 'Chemical', 'MESH:C490954', (181, 198))	('as', 'Chemical', 'MESH:D001151', (178, 180))	('E7389', 'Var', (213, 218))	('B1939', 'Var', (251, 256))	('Halaven', 'Chemical', 'MESH:C490954', (157, 164))	('eribulin mesylate', 'Chemical', 'MESH:C490954', (138, 155))
358215	26262627	Eribulin retained full in vitro potency in cells harboring beta-tubulin mutations that leads to substantial resistance to taxanes, as seen in paclitaxel-resistant ovarian cancer sublines.	('mutations', 'Var', (72, 81))	('resistance to taxanes', 'MPA', (108, 129))	('ovarian cancer', 'Disease', (163, 177))	('Eribulin', 'Chemical', 'MESH:C490954', (0, 8))	('paclitaxel', 'Chemical', 'MESH:D017239', (142, 152))	('as', 'Chemical', 'MESH:D001151', (131, 133))	('leads to', 'Reg', (87, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (163, 177))	('taxanes', 'Chemical', 'MESH:D043823', (122, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (163, 177))	('beta-tubulin', 'Protein', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
358232	26262627	As compared to additional paclitaxel treatment, eribulin also showed a reduced tendency to exacerbate preexisting paclitaxel-induced polyneuropathy.	('polyneuropathy', 'Disease', 'MESH:D011115', (133, 147))	('polyneuropathy', 'Disease', (133, 147))	('paclitaxel', 'Chemical', 'MESH:D017239', (114, 124))	('neuropathy', 'Phenotype', 'HP:0009830', (137, 147))	('eribulin', 'Var', (48, 56))	('polyneuropathy', 'Phenotype', 'HP:0001271', (133, 147))	('paclitaxel', 'Chemical', 'MESH:D017239', (26, 36))	('eribulin', 'Chemical', 'MESH:C490954', (48, 56))	('exacerbate', 'PosReg', (91, 101))
358255	26262627	Thus, it appears that eribulin induces tumor vasculature remodeling in breast cancer models, leading to increased perfusion and decreased hypoxia which might lead to better penetration of subsequent anticancer agents and subsequent enhanced antitumor activity.	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('hypoxia', 'Disease', 'MESH:D000860', (138, 145))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('enhanced', 'PosReg', (232, 240))	('perfusion', 'MPA', (114, 123))	('breast cancer', 'Disease', (71, 84))	('as', 'Chemical', 'MESH:D001151', (46, 48))	('as', 'Chemical', 'MESH:D001151', (109, 111))	('eribulin', 'Chemical', 'MESH:C490954', (22, 30))	('as', 'Chemical', 'MESH:D001151', (133, 135))	('decreased', 'NegReg', (128, 137))	('penetration', 'MPA', (173, 184))	('eribulin', 'Var', (22, 30))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', (203, 209))	('rat', 'Species', '10116', (178, 181))	('tumor', 'Disease', (245, 250))	('tumor', 'Disease', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('increased', 'PosReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('as', 'Chemical', 'MESH:D001151', (74, 76))	('hypoxia', 'Disease', (138, 145))	('better', 'PosReg', (166, 172))
358306	26262627	Therefore, eribulin does not seem to inhibit the metabolism of concurrently-administered drugs metabolized by CYP3A4 or CYP1A, suggesting a minimal risk of drug-drug interactions.	('metabolism', 'MPA', (49, 59))	('inhibit', 'NegReg', (37, 44))	('CYP3A4', 'Gene', (110, 116))	('eribulin', 'Chemical', 'MESH:C490954', (11, 19))	('interactions', 'Interaction', (166, 178))	('CYP1A', 'Var', (120, 125))	('CYP3A4', 'Gene', '1576', (110, 116))
358600	26262627	Though eribulin showed a significant response rate (12% with eribulin vs. 5% with TPC; p = 0.002), it was on the lower side.	('TPC', 'Gene', (82, 85))	('eribulin', 'Var', (61, 69))	('TPC', 'Gene', '8030', (82, 85))	('rat', 'Species', '10116', (46, 49))	('eribulin', 'Chemical', 'MESH:C490954', (61, 69))	('eribulin', 'Chemical', 'MESH:C490954', (7, 15))	('as', 'Chemical', 'MESH:D001151', (103, 105))
358606	26262627	Hematological side effects and peripheral neuropathy were more common with eribulin, whereas gastrointestinal side effects like nausea, vomiting, and diarrhea were more common with capecitabine.	('common', 'Reg', (63, 69))	('diarrhea', 'Disease', (150, 158))	('vomiting', 'Phenotype', 'HP:0002013', (136, 144))	('Hematological side effects', 'Disease', (0, 26))	('nausea', 'Phenotype', 'HP:0002018', (128, 134))	('vomiting', 'Disease', (136, 144))	('as', 'Chemical', 'MESH:D001151', (94, 96))	('diarrhea', 'Disease', 'MESH:D003967', (150, 158))	('nausea', 'Disease', (128, 134))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (31, 52))	('peripheral neuropathy', 'Disease', (31, 52))	('capecitabine', 'Chemical', 'MESH:D000069287', (181, 193))	('eribulin', 'Chemical', 'MESH:C490954', (75, 83))	('gastrointestinal side', 'Disease', 'MESH:D005767', (93, 114))	('nausea', 'Disease', 'MESH:D009325', (128, 134))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (31, 52))	('as', 'Chemical', 'MESH:D001151', (90, 92))	('diarrhea', 'Phenotype', 'HP:0002014', (150, 158))	('eribulin', 'Var', (75, 83))	('neuropathy', 'Phenotype', 'HP:0009830', (42, 52))	('vomiting', 'Disease', 'MESH:D014839', (136, 144))	('gastrointestinal side', 'Disease', (93, 114))
358628	26262627	The most frequent G 3/4 AEs with eribulin were neutropenia (28.6%), decreased neutrophil count (21.2%), and decreased WBC count (13.4%).	('eribulin', 'Chemical', 'MESH:C490954', (33, 41))	('decreased', 'NegReg', (68, 77))	('neutropenia', 'Phenotype', 'HP:0001875', (47, 58))	('neutropenia', 'Disease', 'MESH:D009503', (47, 58))	('as', 'Chemical', 'MESH:D001151', (113, 115))	('neutrophil count', 'MPA', (78, 94))	('decreased', 'NegReg', (108, 117))	('neutropenia', 'Disease', (47, 58))	('WBC count', 'MPA', (118, 127))	('as', 'Chemical', 'MESH:D001151', (73, 75))	('eribulin', 'Var', (33, 41))
358682	21509779	After 14-21 days of G418 selection, the proportion of KSHV-GFP+ fibroblasts had increased to 25-40% with a wide (2 logs) range of GFP expression (Fig.	('G418', 'Chemical', 'MESH:C010680', (20, 24))	('KSHV-GFP+', 'Gene', (54, 63))	('increased', 'PosReg', (80, 89))	('KSHV', 'Species', '37296', (54, 58))	('G418', 'Var', (20, 24))	('KS', 'Phenotype', 'HP:0100726', (54, 56))
358684	21509779	After G418 selection, LANA was detected in all cells indicating that both GFP- and GFP+ fibroblasts had been infected with recombinant virus.	('G418', 'Chemical', 'MESH:C010680', (6, 10))	('LANA', 'Gene', '4961527', (22, 26))	('G418', 'Var', (6, 10))	('LANA', 'Gene', (22, 26))
358693	21509779	Figures 2A and 2B show that chronically KSHV-infected fibroblasts and uninfected control fibroblasts had similar high geo-mean fluorescence levels of MHC class I (231+-57 and 234+-79, respectively) and ICAM-1 (340+-65 and 300+-116, respectively).	('ICAM-1', 'Gene', (202, 208))	('KSHV-infected', 'Disease', (40, 53))	('231+-57', 'Var', (163, 170))	('KSHV-infected', 'Disease', 'MESH:C537372', (40, 53))	('KS', 'Phenotype', 'HP:0100726', (40, 42))	('ICAM-1', 'Gene', '3383', (202, 208))
358869	21837668	In another phase 2 trial, pegylated liposomal doxorubicin demonstrated similar efficacy and reduced myelosuppression compared with doxorubicin in patients with advanced STS.	('doxorubicin', 'Chemical', 'MESH:D004317', (131, 142))	('STS', 'Phenotype', 'HP:0030448', (169, 172))	('myelosuppression', 'Disease', 'MESH:D001855', (100, 116))	('pegylated liposomal', 'Var', (26, 45))	('reduced', 'NegReg', (92, 99))	('patients', 'Species', '9606', (146, 154))	('myelosuppression', 'Disease', (100, 116))	('doxorubicin', 'Chemical', 'MESH:D004317', (46, 57))
358878	21837668	In a phase 3 ECOG trial, the combination of ifosfamide and doxorubicin produced a significantly higher ORR compared with single-agent doxorubicin (88% vs 20%; P = .02) in a small subgroup of patients with advanced synovial sarcoma (N = 20), whereas a PR rate of 42% and a median OS of 11 months were observed in a follow-up study.	('synovial sarcoma', 'Disease', (214, 230))	('patients', 'Species', '9606', (191, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('doxorubicin', 'Gene', (59, 70))	('doxorubicin', 'Chemical', 'MESH:D004317', (134, 145))	('OS', 'Chemical', '-', (279, 281))	('synovial sarcoma', 'Disease', 'MESH:D013584', (214, 230))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (214, 230))	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))	('ORR', 'MPA', (103, 106))	('combination', 'Var', (29, 40))	('higher', 'PosReg', (96, 102))	('ifosfamide', 'Chemical', 'MESH:D007069', (44, 54))
358890	21837668	TH-302, a hypoxia-activated cytotoxic prodrug, was administered in combination with doxorubicin and produced a 25% PR rate in a phase 1/2 trial of patients with advanced or metastatic STS (N = 20).	('TH-302', 'Var', (0, 6))	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('STS', 'Phenotype', 'HP:0030448', (184, 187))	('metastatic', 'CPA', (173, 183))	('hypoxia', 'Disease', 'MESH:D000860', (10, 17))	('patients', 'Species', '9606', (147, 155))	('hypoxia', 'Disease', (10, 17))	('TH-302', 'Chemical', 'MESH:C552526', (0, 6))
358895	21837668	Compared with historical controls receiving second-line chemotherapy, pazopanib prolonged PFS and OS in patients with STS (including leiomyosarcomas and synovial sarcomas).	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('pazopanib', 'Var', (70, 79))	('STS', 'Phenotype', 'HP:0030448', (118, 121))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (133, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('OS', 'Chemical', '-', (98, 100))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (153, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('PFS', 'MPA', (90, 93))	('pazopanib', 'Chemical', 'MESH:C516667', (70, 79))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (133, 147))	('prolonged', 'PosReg', (80, 89))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (153, 170))	('leiomyosarcomas and synovial sarcomas', 'Disease', 'MESH:D013584', (133, 170))	('patients', 'Species', '9606', (104, 112))
358945	21837668	The incidence of stomatitis and other AEs was higher in patients receiving ridaforolimus, and the overall safety profile was considered to be similar to that of other mTOR inhibitors.	('patients', 'Species', '9606', (56, 64))	('stomatitis', 'Disease', 'MESH:D013280', (17, 27))	('higher', 'PosReg', (46, 52))	('stomatitis', 'Disease', (17, 27))	('ridaforolimus', 'Chemical', 'MESH:C515074', (75, 88))	('stomatitis', 'Phenotype', 'HP:0010280', (17, 27))	('mTOR', 'Gene', '2475', (167, 171))	('mTOR', 'Gene', (167, 171))	('ridaforolimus', 'Var', (75, 88))	('AEs', 'Disease', (38, 41))
358960	20152043	CEF and CNR cells were infected with transforming, non-transforming, and temperature sensitive mutants of RSV to identify the patterns of gene expression in response to v-Src-transformation.	('CEF', 'Chemical', '-', (0, 3))	('RSV', 'Species', '11886', (106, 109))	('RSV', 'Gene', (106, 109))	('mutants', 'Var', (95, 102))
358976	20152043	An activating mutation resulting in the deletion of the c-Src C-terminal region adjacent to the negative regulatory tyrosine (Y530) has also been identified in a subset of patients with advanced colon carcinomas.	('c-Src', 'Gene', '6714', (56, 61))	('colon carcinomas', 'Disease', 'MESH:D015179', (195, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('deletion', 'Var', (40, 48))	('activating', 'PosReg', (3, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('patients', 'Species', '9606', (172, 180))	('tyrosine', 'Chemical', 'MESH:D014443', (116, 124))	('colon carcinomas', 'Disease', (195, 211))	('c-Src', 'Gene', (56, 61))
358977	20152043	This mutation mimics the oncogenic activation of v-Src, whose C-terminus lacks the C-terminal Src kinase (Csk) phosphorylation site.	('C-terminal Src kinase', 'Gene', (83, 104))	('Csk', 'Gene', (106, 109))	('Csk', 'Gene', '1445', (106, 109))	('C-terminal Src kinase', 'Gene', '1445', (83, 104))	('lacks', 'NegReg', (73, 78))	('mutation', 'Var', (5, 13))
359028	20152043	NY315 RSV is a group A virus encoding a catalytically active deletion mutant of the v-Src kinase lacking amino acids 2-14 of the SH4 domain.	('amino acids 2-14', 'MPA', (105, 121))	('RSV', 'Species', '11886', (6, 9))	('lacking', 'NegReg', (97, 104))	('deletion mutant', 'Var', (61, 76))
359029	20152043	As a result of this deletion, the v-Src kinase of NY315 RSV is not myristoylated, does not associate with the plasma membrane and is non-transforming.	('RSV', 'Species', '11886', (56, 59))	('associate', 'Interaction', (91, 100))	('not', 'NegReg', (87, 90))	('v-Src kinase', 'Enzyme', (34, 46))	('non-transforming', 'CPA', (133, 149))	('NY315', 'Var', (50, 55))	('deletion', 'Var', (20, 28))
359032	20152043	A total of 3254 probe sets, corresponding to 2904 unique genes were differentially expressed by two fold or greater in cells infected by either NY315 or SR-A RSV (Additional File 2).	('RSV', 'Species', '11886', (158, 161))	('differentially', 'Reg', (68, 82))	('SR-A', 'Var', (153, 157))	('NY315', 'Var', (144, 149))
359033	20152043	Within regulated sequences, 2455, 1691 and 730 transcripts were differentially expressed in pair-wise comparisons between SR-A and RCASBP(A), NY315 and RCASBP(A), and SR-A and NY315 infected CEF, respectively.	('NY315', 'Var', (176, 181))	('RCASBP', 'Chemical', '-', (131, 137))	('CEF', 'Chemical', '-', (191, 194))	('differentially', 'Reg', (64, 78))	('RCASBP', 'Chemical', '-', (152, 158))	('SR-A', 'Gene', (122, 126))	('NY315', 'Var', (142, 147))
359038	20152043	A pair-wise comparison of CEF infected with NY72-4 revealed that 568 transcripts encoded by 477 unique genes (261 up- and 216 down-regulated) were differentially expressed at the permissive versus non-permissive temperatures (Figure 2 and Additional File 4).	('down-regulated', 'NegReg', (126, 140))	('NY72-4', 'Var', (44, 50))	('CEF', 'Chemical', '-', (26, 29))	('up-', 'PosReg', (114, 117))	('expressed', 'MPA', (162, 171))
359046	20152043	Therefore, ts NY72-4 RSV infected CNR are quiescent at the non-permissive temperature of 41.5 C but are actively dividing and transformed at the permissive temperature of 37.5 C. Gene profiling analyses of CNR cells identified 1062 transcripts, consisting of 485 up- and 577 down-regulated RNA species, with a two-fold or greater difference in gene expression between the two temperatures (Additional File 6).	('RSV', 'Species', '11886', (21, 24))	('ts NY72-4 RSV', 'Var', (11, 24))	('up-', 'PosReg', (263, 266))	('down-regulated', 'NegReg', (275, 289))
359047	20152043	A significant fraction of the v-Src regulated genes identified in ts NY72-4 RSV (31%) and SR-A/NY315/RCASBP(A) infected CEF (21%) overlapped with the corresponding set of genes in CNR cells (Figure 2).	('RSV', 'Species', '11886', (76, 79))	('SR-A/NY315/RCASBP', 'Var', (90, 107))	('v-Src regulated genes', 'Gene', (30, 51))	('RCASBP', 'Chemical', '-', (101, 107))	('ts NY72-4', 'Var', (66, 75))	('CEF', 'Chemical', '-', (120, 123))
359049	20152043	A second group of 91 genes was regulated in ts NY72-4 RSV infected CEF and CNR cells but not in SR-A RSV transformed CEF (Additional File 8).	('RSV', 'Species', '11886', (101, 104))	('CEF', 'Chemical', '-', (117, 120))	('CEF', 'Chemical', '-', (67, 70))	('RSV', 'Species', '11886', (54, 57))	('ts NY72-4', 'Var', (44, 53))	('RSV infected CEF', 'Disease', 'MESH:D007239', (54, 70))	('RSV infected CEF', 'Disease', (54, 70))
359051	20152043	In contrast, the cyclin kinase inhibitor p27Kip1 was down-regulated in NY72-4 RSV transformed CEF and CNR cells.	('CEF', 'Chemical', '-', (94, 97))	('NY72-4 RSV transformed', 'Var', (71, 93))	('RSV', 'Species', '11886', (78, 81))	('cyclin kinase inhibitor p27Kip1', 'MPA', (17, 48))	('down-regulated', 'NegReg', (53, 67))
359061	20152043	A strong CD44 signal was observed in SR-A RSV transformed CEF but was absent in cells infected with RCASBP(A) and NY315 RSV.	('RCASBP', 'Chemical', '-', (100, 106))	('RSV', 'Var', (42, 45))	('CD44', 'MPA', (9, 13))	('RSV', 'Species', '11886', (120, 123))	('CEF', 'Chemical', '-', (58, 61))	('RSV', 'Species', '11886', (42, 45))
359068	20152043	HMOX1 also provided an example of a gene with partial activation in CEF infected with NY315 RSV, both at the RNA and protein level (Figure 3C &3E).	('NY315 RSV', 'Var', (86, 95))	('RSV', 'Species', '11886', (92, 95))	('activation', 'PosReg', (54, 64))	('CEF', 'Chemical', '-', (68, 71))	('CEF', 'Disease', (68, 71))
359075	20152043	High levels of phospho-PKB and phospho-GSK3beta were detected in SR-A RSV transformed CEF but not in cells infected with RCASBP(A) or NY315 RSV, even when these cells were actively cycling (Additional File 13).	('SR-A', 'Gene', (65, 69))	('PKB', 'Gene', (23, 26))	('RCASBP', 'Chemical', '-', (121, 127))	('RSV', 'Species', '11886', (70, 73))	('GSK3beta', 'Gene', (39, 47))	('RSV', 'Var', (70, 73))	('RSV', 'Species', '11886', (140, 143))	('GSK3beta', 'Gene', '2932', (39, 47))	('PKB', 'Gene', '207', (23, 26))	('CEF', 'Chemical', '-', (86, 89))
359095	20152043	Similarly, using bone metastasis data from the same study, the high aggressive signature expressing tumors were associated with reduced metastasis-free survival in patients (mean estimated survival 6.4 years versus 9.3 years, P < 0.05; Figure 5Bii).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('metastasis-free survival', 'CPA', (136, 160))	('reduced', 'NegReg', (128, 135))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (164, 172))	('high aggressive', 'Var', (63, 78))
359096	20152043	Analysis of a second breast tumor data set also shows that patients whose tumors express high levels of the aggressive signature genes have a reduced disease-free survival (mean estimated survival 71 months versus 106 months, P < 0.02; Figure 5Biii).	('disease-free survival', 'CPA', (150, 171))	('Biii', 'Gene', '774', (244, 248))	('reduced', 'NegReg', (142, 149))	('breast tumor', 'Phenotype', 'HP:0100013', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('high levels', 'Var', (89, 100))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('breast tumor', 'Disease', 'MESH:D001943', (21, 33))	('patients', 'Species', '9606', (59, 67))	('Biii', 'Gene', (244, 248))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('breast tumor', 'Disease', (21, 33))	('tumors', 'Disease', (74, 80))
359107	20152043	Third, Masker and co-workers identified some transcription factors such as c-Jun and c-Myc, as being up-regulated by v-Src while we did not.	('c-Myc', 'Gene', (85, 90))	('up-regulated', 'PosReg', (101, 113))	('as c', 'Gene', (72, 76))	('c-Myc', 'Gene', '4609', (85, 90))	('as c', 'Gene', '29108', (72, 76))	('v-Src', 'Var', (117, 122))
359108	20152043	We previously established that early immediate genes such as c-Myc are activated by v-Src in quiescent cells but are not differentially expressed when actively dividing cells are compared.	('as c', 'Gene', (58, 62))	('activated', 'PosReg', (71, 80))	('v-Src', 'Var', (84, 89))	('c-Myc', 'Gene', '4609', (61, 66))	('as c', 'Gene', '29108', (58, 62))	('c-Myc', 'Gene', (61, 66))
359112	20152043	Interestingly, tumor suppressor genes such as DKK3 and gamma FBPalpha, the avian homolog of HIC-1 (hypermethylated in cancer 1), were repressed markedly by v-Src in CEF.	('cancer', 'Disease', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('v-Src', 'Var', (156, 161))	('gamma FBPalpha', 'Gene', (55, 69))	('DKK3', 'Gene', '27122', (46, 50))	('tumor', 'Disease', (15, 20))	('DKK3', 'Gene', (46, 50))	('HIC-1', 'Gene', '3090', (92, 97))	('CEF', 'Chemical', '-', (165, 168))	('HIC-1', 'Gene', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
359137	20152043	Therefore, genes of the aggressive tumor signature may limit the effects of oncogenic stress and provide a survival advantage to the cell.	('aggressive tumor', 'Disease', 'MESH:D001523', (24, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('survival advantage', 'CPA', (107, 125))	('genes', 'Var', (11, 16))	('aggressive tumor', 'Disease', (24, 40))	('limit', 'NegReg', (55, 60))	('effects of oncogenic stress', 'MPA', (65, 92))
359158	20152043	Since forced expression of Twist1 is sufficient to induce the EMT in mammary epithelial cells, the regulation of this factor provides a mechanism by which v-Src may induce the EMT and enhance chemoresistance.	('Twist1', 'Gene', (27, 33))	('v-Src', 'Var', (155, 160))	('induce', 'PosReg', (165, 171))	('EMT', 'CPA', (176, 179))	('Twist1', 'Gene', '7291', (27, 33))	('enhance', 'PosReg', (184, 191))	('chemoresistance', 'CPA', (192, 207))	('EMT', 'CPA', (62, 65))
359292	26000096	Translocation fusions between the various FET (FUS-EWS-TAF15) and ETS (E twenty-six) genes are the causative agent of Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('causative', 'Reg', (99, 108))	('Translocation fusions', 'Var', (0, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (118, 131))	('TAF15', 'Gene', '8148', (55, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('FET', 'Gene', (42, 45))	('FUS', 'Gene', (47, 50))	('TAF15', 'Gene', (55, 60))	('FUS', 'Gene', '2521', (47, 50))	('agent', 'Reg', (109, 114))	('Ewing sarcoma', 'Disease', (118, 131))
359294	26000096	The fusion of the DNA-binding domain of FLI1 with the strong transactivation domain of EWSR1 yields an aberrant transcription factor.	('transcription factor', 'MPA', (112, 132))	('EWSR1', 'Gene', (87, 92))	('fusion', 'Var', (4, 10))	('FLI1', 'Gene', (40, 44))	('EWSR1', 'Gene', '2130', (87, 92))
359295	26000096	Although genomic sequencing of tumor samples revealed occasional loss of STAG2 and CDKN2A, as well as mutations in TP53, this pediatric malignancy is largely genomically stable, suggesting that transcriptional dysregulation by EWS/FLI is the primary oncogenic driver.	('loss', 'NegReg', (65, 69))	('malignancy', 'Disease', (136, 146))	('CDKN2A', 'Gene', '1029', (83, 89))	('FLI', 'Gene', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('STAG2', 'Gene', (73, 78))	('TP53', 'Gene', '7157', (115, 119))	('tumor', 'Disease', (31, 36))	('STAG2', 'Gene', '10735', (73, 78))	('TP53', 'Gene', (115, 119))	('mutations', 'Var', (102, 111))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('FLI', 'Gene', '2314', (231, 234))	('CDKN2A', 'Gene', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
359300	26000096	Deletion of its fly ortholog vnd (ventral nervous system defective) results to a complete loss of the ventral region of the central nervous system (CNS) and embryonic lethality.	('nervous system defective', 'Phenotype', 'HP:0000707', (42, 66))	('vnd', 'Gene', '31003', (29, 32))	('ventral region of the central nervous system', 'MPA', (102, 146))	('embryonic lethality', 'Disease', 'MESH:D020964', (157, 176))	('loss', 'NegReg', (90, 94))	('embryonic lethality', 'Disease', (157, 176))	('vnd', 'Gene', (29, 32))	('Deletion', 'Var', (0, 8))
359303	26000096	Mice homozygous for a null Nkx2.2 mutation die postnatally due to a complete loss of beta-islet cells and severe hyperglycemia.	('hyperglycemia', 'Phenotype', 'HP:0003074', (113, 126))	('Nkx2.2', 'Gene', (27, 33))	('Nkx2.2', 'Gene', '18088', (27, 33))	('hyperglycemia', 'Disease', 'MESH:D006943', (113, 126))	('mutation', 'Var', (34, 42))	('beta-islet cells', 'MPA', (85, 101))	('hyperglycemia', 'Disease', (113, 126))	('loss', 'NegReg', (77, 81))	('Mice', 'Species', '10090', (0, 4))
359308	26000096	Furthermore, Ewing sarcoma cells overexpressing AES (amino enhancer of split), a dominant-negative Gro/TLE protein, or treated with the HDAC inhibitor vorinostat display diminished transformation, consistent with NKX2-2 recruitment of Gro/TLE co-repressors and HDACs.	('diminished', 'NegReg', (170, 180))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))	('NKX2-2', 'Gene', '4821', (213, 219))	('TLE', 'Disease', (103, 106))	('AES', 'Var', (48, 51))	('Ewing sarcoma', 'Disease', (13, 26))	('vorinostat', 'Chemical', 'MESH:D000077337', (151, 161))	('overexpressing', 'PosReg', (33, 47))	('TLE', 'Disease', 'MESH:D004833', (239, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('TLE', 'Disease', (239, 242))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))	('transformation', 'CPA', (181, 195))	('NKX2-2', 'Gene', (213, 219))	('TLE', 'Disease', 'MESH:D004833', (103, 106))
359320	26000096	This confirms microarray data we previously published and suggests that modulation of NKX2-2, and indeed any other transcription factor, can be utilized by EWS/FLI to amplify its transcriptional effect.	('FLI', 'Gene', (160, 163))	('NKX2-2', 'Gene', (86, 92))	('modulation', 'Var', (72, 82))	('NKX2-2', 'Gene', '4821', (86, 92))	('FLI', 'Gene', '2314', (160, 163))	('transcriptional effect', 'MPA', (179, 201))
359326	26000096	Indeed, NKX2-2 knockdown in A673 cells (Fig.	('NKX2-2', 'Gene', '4821', (8, 14))	('NKX2-2', 'Gene', (8, 14))	('knockdown', 'Var', (15, 24))
359328	26000096	Furthermore, while in control knockdown cells there is a diffuse signal of phalloidin staining, indicating short fragments of filamentous actin, upon NKX2-2 or EWS/FLI depletion actin organizes into long, thick stress fibers (Fig.	('NKX2-2', 'Gene', '4821', (150, 156))	('FLI', 'Gene', '2314', (164, 167))	('FLI', 'Gene', (164, 167))	('phalloidin', 'Chemical', 'MESH:D010590', (75, 85))	('depletion', 'Var', (168, 177))	('NKX2-2', 'Gene', (150, 156))
359329	26000096	As predicted, we observed that significantly more focal adhesions (FA) form upon NKX2-2 or EWS/FLI knockdown, as shown by immunofluorescence staining for paxillin, one of the myriad proteins that populate FAs (Fig.	('focal adhesions', 'CPA', (50, 65))	('FLI', 'Gene', (95, 98))	('more', 'PosReg', (45, 49))	('knockdown', 'Var', (99, 108))	('NKX2-2', 'Gene', (81, 87))	('FLI', 'Gene', '2314', (95, 98))	('NKX2-2', 'Gene', '4821', (81, 87))
359334	26000096	The de-repression of ZYX might partially explain how NKX2-2 or EWS/FLI knockdown allows Ewing sarcoma cells to manifest mesenchymal characteristics.	('ZYX', 'Gene', (21, 24))	('de-repression', 'NegReg', (4, 17))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('knockdown', 'Var', (71, 80))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('NKX2-2', 'Gene', (53, 59))	('FLI', 'Gene', '2314', (67, 70))	('NKX2-2', 'Gene', '4821', (53, 59))	('Ewing sarcoma', 'Disease', (88, 101))	('ZYX', 'Gene', '7791', (21, 24))	('FLI', 'Gene', (67, 70))
359335	26000096	Predictably, when we knock down NKX2-2, zyxin is upregulated, as shown both by western blot (Fig.	('zyxin', 'Protein', (40, 45))	('NKX2-2', 'Gene', (32, 38))	('upregulated', 'PosReg', (49, 60))	('NKX2-2', 'Gene', '4821', (32, 38))	('knock down', 'Var', (21, 31))
359338	26000096	Specifically, cell area and number of focal adhesions increase when NKX2-2 or EWS/FLI is knocked down in these cells (Fig 3b, 3d).	('FLI', 'Gene', '2314', (82, 85))	('FLI', 'Gene', (82, 85))	('NKX2-2', 'Gene', '4821', (68, 74))	('knocked down', 'Var', (89, 101))	('increase', 'PosReg', (54, 62))	('cell area', 'CPA', (14, 23))	('NKX2-2', 'Gene', (68, 74))
359339	26000096	In addition, while F-actin signals remain diffuse in EWS502 and TC71 control knockdown cells, actin stress fibers form upon NKX22 or EWS/FLI depletion in either cell line, with thicker and more pronounced fibers in the EWS/FLI knockdown condition (Fig.	('FLI', 'Gene', '2314', (137, 140))	('thicker', 'PosReg', (177, 184))	('actin stress fibers', 'MPA', (94, 113))	('F-actin signals', 'MPA', (19, 34))	('FLI', 'Gene', (137, 140))	('TC71', 'Gene', (64, 68))	('FLI', 'Gene', '2314', (223, 226))	('more', 'PosReg', (189, 193))	('TC71', 'CellLine', 'CVCL:2213', (64, 68))	('FLI', 'Gene', (223, 226))	('NKX22', 'Gene', (124, 129))	('depletion', 'Var', (141, 150))	('NKX22', 'Gene', '4821', (124, 129))
359341	26000096	In addition, in these two cell lines zyxin is de-repressed slightly upon NKX2-2 depletion, and markedly upon EWS/FLI depletion, mirroring our initial findings in A673 cells (Fig.	('de-repressed', 'NegReg', (46, 58))	('FLI', 'Gene', (113, 116))	('NKX2-2', 'Gene', (73, 79))	('NKX2-2', 'Gene', '4821', (73, 79))	('depletion', 'Var', (117, 126))	('zyxin', 'Protein', (37, 42))	('depletion', 'Var', (80, 89))	('FLI', 'Gene', '2314', (113, 116))
359343	26000096	To attribute increases in cell area and number of focal adhesions specifically to depletion of NKX2-2 either by an NKX2-2-specific shRNA or by knocking down EWS/FLI, we performed rescue experiments in A673 cells (Fig.	('increases', 'PosReg', (13, 22))	('FLI', 'Gene', '2314', (161, 164))	('NKX2-2', 'Gene', (115, 121))	('FLI', 'Gene', (161, 164))	('depletion', 'MPA', (82, 91))	('cell area', 'CPA', (26, 35))	('NKX2-2', 'Gene', '4821', (115, 121))	('NKX2-2', 'Gene', (95, 101))	('knocking down', 'Var', (143, 156))	('NKX2-2', 'Gene', '4821', (95, 101))
359344	26000096	The increase in cell area due to NKX2-2 knockdown was partially rescued by the RNAi-resistant cDNA construct of NKX2-2, confirming that our shRNA has few off-target effects (Fig.	('knockdown', 'Var', (40, 49))	('NKX2-2', 'Gene', (33, 39))	('cell area', 'CPA', (16, 25))	('NKX2-2', 'Gene', (112, 118))	('NKX2-2', 'Gene', '4821', (33, 39))	('increase', 'PosReg', (4, 12))	('NKX2-2', 'Gene', '4821', (112, 118))
359349	26000096	Since Ewing sarcoma cells form more focal adhesions upon depletion of NKX2-2, we reasoned that they also adhere more effectively to the substrate.	('focal adhesions', 'CPA', (36, 51))	('depletion', 'Var', (57, 66))	('NKX2-2', 'Gene', (70, 76))	('NKX2-2', 'Gene', '4821', (70, 76))	('Ewing sarcoma', 'Disease', (6, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (6, 19))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (6, 19))	('more', 'PosReg', (31, 35))
359353	26000096	Indeed, in a monolayer scratch assay, depletion of NKX2-2 allows cells to more rapidly heal the wound than control-knockdown cells, but more slowly than EWS/FLI-knockdown cells (Fig.	('FLI', 'Gene', '2314', (157, 160))	('NKX2-2', 'Gene', (51, 57))	('FLI', 'Gene', (157, 160))	('depletion', 'Var', (38, 47))	('NKX2-2', 'Gene', '4821', (51, 57))
359376	26000096	Interestingly, zyxin and alpha5 integrin double re-expression is sufficient to capture the full EWS/FLI phenotype.	('FLI', 'Gene', '2314', (100, 103))	('FLI', 'Gene', (100, 103))	('double re-expression', 'Var', (41, 61))	('alpha5 integrin', 'Protein', (25, 40))	('zyxin', 'Protein', (15, 20))
359377	26000096	Importantly, double re-expression also reduces colony growth in soft agar, suggesting that these two genes somehow contribute to transformation, while simultaneously shortening the latency of metastatic lesions in an intratibial xenograft model.	('colony growth in soft agar', 'CPA', (47, 73))	('agar', 'Chemical', 'MESH:D000362', (69, 73))	('double re-expression', 'Var', (13, 33))	('latency of metastatic lesions', 'CPA', (181, 210))	('shortening', 'NegReg', (166, 176))	('transformation', 'CPA', (129, 143))	('contribute', 'Reg', (115, 125))	('reduces', 'NegReg', (39, 46))
359379	26000096	However, zyxin and alpha5 integrin double re-expression does not cause the full loss of transformation that depletion of NKX2-2 does, suggesting that there are additional, uncharacterized transcriptional targets of NKX2-2 that contribute to other arms of tumorigenesis.	('NKX2-2', 'Gene', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('NKX2-2', 'Gene', '4821', (121, 127))	('NKX2-2', 'Gene', (215, 221))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('double re-expression', 'Var', (35, 55))	('NKX2-2', 'Gene', '4821', (215, 221))
359557	32392854	EWSR1-FL1 fusion is found in 85 to 95% of Ewing's sarcomas and is responsible for enhancing genes involved in cell proliferation and survival.	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (42, 58))	('EWSR1', 'Gene', '2130', (0, 5))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (42, 57))	('FL1', 'Gene', '100306940', (6, 9))	('fusion', 'Var', (10, 16))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (42, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('FL1', 'Gene', (6, 9))	('EWSR1', 'Gene', (0, 5))	('enhancing', 'PosReg', (82, 91))	('genes', 'MPA', (92, 97))	("Ewing's sarcomas", 'Disease', (42, 58))
359560	32392854	JAK2 mutation has been detected in multiple triple-negative myeloproliferative neoplasms, but the role of this specific mutation in the prognosis of our patient is unknown.	('neoplasm', 'Phenotype', 'HP:0002664', (79, 87))	('JAK2', 'Gene', '3717', (0, 4))	('myeloproliferative neoplasms', 'Disease', (60, 88))	('JAK2', 'Gene', (0, 4))	('detected', 'Reg', (23, 31))	('neoplasms', 'Phenotype', 'HP:0002664', (79, 88))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (60, 88))	('patient', 'Species', '9606', (153, 160))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (60, 88))	('mutation', 'Var', (5, 13))
359594	32392854	The alkylating agent, cyclophosphamide, was also found to increase the sarcoma risk in a dose-dependent manner.	('increase', 'PosReg', (58, 66))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (22, 38))	('sarcoma', 'Disease', (71, 78))	('cyclophosphamide', 'Var', (22, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))
359836	31633108	Flow cytometric evaluation of peripheral blood demonstrated positivity for ZAP70 in 13% of the CD19-positive B cells.	('positivity', 'Var', (60, 70))	('ZAP70', 'Gene', '7535', (75, 80))	('CD19', 'Gene', (95, 99))	('ZAP70', 'Gene', (75, 80))	('CD19', 'Gene', '930', (95, 99))
359850	31633108	Flow cytometry performed on a core biopsy of the left neck mass demonstrated a kappa-restricted B cell neoplasm with expression of CD19 (dim), CD20 (dim), CD5 (dim), CD23 (dim-moderate), and FMC7 (dim, minor subset).	('CD20', 'Gene', '54474', (143, 147))	('CD20', 'Gene', (143, 147))	('CD23', 'Gene', '2208', (166, 170))	('CD19', 'Gene', (131, 135))	('kappa-restricted', 'CPA', (79, 95))	('CD5', 'Gene', (155, 158))	('CD19', 'Gene', '930', (131, 135))	('neoplasm', 'Phenotype', 'HP:0002664', (103, 111))	('CD5', 'Gene', '921', (155, 158))	('CD23', 'Gene', (166, 170))	('FMC7', 'Var', (191, 195))	('B cell neoplasm', 'Phenotype', 'HP:0012191', (96, 111))
359853	31633108	The small cells (SLL) demonstrated a heterozygous or homozygous 13q deletion in approximately 90% of the nuclei.	('SLL', 'Gene', (17, 20))	('13q deletion', 'Var', (64, 76))	('SLL', 'Gene', '347734', (17, 20))
359856	31633108	For reference, the normal cutoffs for paraffin-embedded tissue for this assay include <21% for 6q deletion, 11q deletion, 13q deletion, and 17p deletion; <10% for homozygous 13q deletion; <15% for trisomy 12; and <3.0% for CCND1/IGH fusion.	('IGH', 'Gene', '3492', (229, 232))	('CCND1', 'Gene', '595', (223, 228))	('paraffin', 'Chemical', 'MESH:D010232', (38, 46))	('IGH', 'Gene', (229, 232))	('17p del', 'Mutation', 'c.17del', (140, 147))	('13q deletion', 'Var', (122, 134))	('CCND1', 'Gene', (223, 228))	('11q deletion', 'Var', (108, 120))
359872	31633108	Foundation One testing (Foundation Medicine, Inc, Cambridge, MA, USA) performed on formalin-fixed, paraffin-embedded tissue from the resection including LCS and low-grade B-cell lymphoma identified IGH-BCL2 rearrangement, MAP2K1 (MEK1) mutation (K59_V60insQK), PTEN loss, CARD11 K215del, CDKN2A/B loss, FAS loss, HISTH1D S87fs*3, SF3B1 E862K, TNFAIP3 R685fs*3, and TNFRSF14 loss.	('PTEN', 'Gene', (261, 265))	('loss', 'NegReg', (307, 311))	('loss', 'NegReg', (266, 270))	('TNFAIP3', 'Gene', '7128', (343, 350))	('S87fs', 'Mutation', 'p.S87fsX', (321, 326))	('MAP2K1', 'Gene', '5604', (222, 228))	('TNFRSF14', 'Gene', '8764', (365, 373))	('IGH', 'Gene', (198, 201))	('MEK1', 'Gene', (230, 234))	('MAP2K1', 'Gene', (222, 228))	('TNFAIP3', 'Gene', (343, 350))	('CARD11', 'Gene', '84433', (272, 278))	('TNFRSF14', 'Gene', (365, 373))	('K215del', 'Mutation', 'p.215delK', (279, 286))	('SF3B1', 'Gene', '23451', (330, 335))	('K59', 'Chemical', 'MESH:D011188', (246, 249))	('lymphoma', 'Disease', (178, 186))	('lymphoma', 'Disease', 'MESH:D008223', (178, 186))	('BCL2', 'Gene', (202, 206))	('PTEN', 'Gene', '5728', (261, 265))	('CDKN2A/B', 'Gene', '1029;1030', (288, 296))	('R685fs*3', 'Var', (351, 359))	('loss', 'NegReg', (297, 301))	('rearrangement', 'Var', (207, 220))	('R685fs', 'Mutation', 'p.R685fsX', (351, 357))	('paraffin', 'Chemical', 'MESH:D010232', (99, 107))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (171, 186))	('HISTH1D', 'Gene', (313, 320))	('IGH', 'Gene', '3492', (198, 201))	('MEK1', 'Gene', '5604', (230, 234))	('S87fs*3', 'Var', (321, 328))	('K215del', 'Var', (279, 286))	('K59_V60insQK', 'Var', (246, 258))	('BCL2', 'Gene', '596', (202, 206))	('loss', 'NegReg', (374, 378))	('E862K', 'Var', (336, 341))	('V60insQK', 'Mutation', 'c.60insV,QK', (250, 258))	('FAS', 'Gene', (303, 306))	('lymphoma', 'Phenotype', 'HP:0002665', (178, 186))	('E862K', 'Mutation', 'p.E862K', (336, 341))	('LCS', 'Disease', 'MESH:D054752', (153, 156))	('SF3B1', 'Gene', (330, 335))	('formalin', 'Chemical', 'MESH:D005557', (83, 91))	('CDKN2A/B', 'Gene', (288, 296))	('CARD11', 'Gene', (272, 278))	('LCS', 'Disease', (153, 156))
359874	31633108	A staging bone marrow biopsy demonstrated low-level involvement (less than 5%) by low-grade B-cell lymphoma (follicular lymphoma in light of the Foundation One results) and no evidence of LCS.	('follicular lymphoma', 'Disease', 'MESH:D008224', (109, 128))	('follicular lymphoma', 'Disease', (109, 128))	('LCS', 'Disease', (188, 191))	('lymphoma', 'Disease', (120, 128))	('lymphoma', 'Disease', 'MESH:D008223', (120, 128))	('lymphoma', 'Disease', (99, 107))	('lymphoma', 'Disease', 'MESH:D008223', (99, 107))	('lymphoma', 'Phenotype', 'HP:0002665', (99, 107))	('lymphoma', 'Phenotype', 'HP:0002665', (120, 128))	('LCS', 'Disease', 'MESH:D054752', (188, 191))	('low-grade', 'Var', (82, 91))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (92, 107))
359878	31633108	Based on the Foundation One results, other potentially useful targeted therapies could include cobimetinib, trametinib, or binimetinib (due to the MEK1 mutation) and temsirolimus, everolimus, or copanlisib (due to PTEN loss).	('temsirolimus', 'Chemical', 'MESH:C401859', (166, 178))	('MEK1', 'Gene', '5604', (147, 151))	('PTEN', 'Gene', (214, 218))	('PTEN', 'Gene', '5728', (214, 218))	('cobimetinib', 'Chemical', 'MESH:C574276', (95, 106))	('MEK1', 'Gene', (147, 151))	('everolimus', 'Chemical', 'MESH:C107135', (180, 190))	('trametinib', 'Chemical', 'MESH:C560077', (108, 118))	('binimetinib', 'Chemical', 'MESH:C581313', (123, 134))	('loss', 'NegReg', (219, 223))	('mutation', 'Var', (152, 160))
359879	31633108	There is a case report of a 62-year-old man with follicular lymphoma and histiocytic sarcoma with an activating MAP2K1 (MEK1) mutation, who showed complete clinical response and response on imaging to trametinib, an MEK1 and 2 inhibitor.	('man', 'Species', '9606', (40, 43))	('MEK1', 'Gene', '5604', (120, 124))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (73, 92))	('MAP2K1', 'Gene', '5604', (112, 118))	('MEK1', 'Gene', '5604', (216, 220))	('follicular lymphoma', 'Disease', 'MESH:D008224', (49, 68))	('lymphoma', 'Phenotype', 'HP:0002665', (60, 68))	('follicular lymphoma', 'Disease', (49, 68))	('histiocytic sarcoma', 'Disease', (73, 92))	('mutation', 'Var', (126, 134))	('MAP2K1', 'Gene', (112, 118))	('MEK1', 'Gene', (120, 124))	('MEK1 and 2', 'Gene', '5604;5605', (216, 226))	('MEK1', 'Gene', (216, 220))	('trametinib', 'Chemical', 'MESH:C560077', (201, 211))	('activating', 'PosReg', (101, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
359884	31633108	Patients with 13q deletion in >65.5% of the CLL nuclei have been shown to have a lower 5-year untreated rate than patients with isolated 13q deletion in a low number of cells.	('lower', 'NegReg', (81, 86))	('CLL', 'Disease', 'MESH:D015451', (44, 47))	('5-year untreated rate', 'MPA', (87, 108))	('Patients', 'Species', '9606', (0, 8))	('CLL', 'Phenotype', 'HP:0005550', (44, 47))	('CLL', 'Disease', (44, 47))	('13q deletion', 'Var', (14, 26))	('patients', 'Species', '9606', (114, 122))
359885	31633108	Our patient (case 1) had 13q deletion in most of his CLL cells and subsequently developed an associated histiocytic sarcoma with rapid clinical decline.	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (104, 123))	('CLL', 'Disease', 'MESH:D015451', (53, 56))	('patient', 'Species', '9606', (4, 11))	('histiocytic sarcoma', 'Disease', (104, 123))	('CLL', 'Phenotype', 'HP:0005550', (53, 56))	('CLL', 'Disease', (53, 56))	('13q deletion', 'Var', (25, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
359898	31633108	Other studies have also demonstrated identical IGH and/or IGK rearrangements in low-grade B cell lymphomas and associated secondary histiocytic sarcoma.	('B cell lymphoma', 'Phenotype', 'HP:0012191', (90, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (132, 151))	('rearrangements', 'Var', (62, 76))	('lymphomas', 'Disease', (97, 106))	('lymphomas', 'Disease', 'MESH:D008223', (97, 106))	('IGK', 'Gene', (58, 61))	('IGH', 'Gene', '3492', (47, 50))	('lymphomas', 'Phenotype', 'HP:0002665', (97, 106))	('IGH', 'Gene', (47, 50))	('histiocytic sarcoma', 'Disease', (132, 151))	('IGK', 'Gene', '50802', (58, 61))	('B cell lymphoma', 'Disease', (90, 105))	('B cell lymphoma', 'Disease', 'MESH:D016393', (90, 105))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (90, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (97, 105))
359901	31633108	Both neoplasms demonstrated trisomy 12, with 16q gains in the interdigitating dendritic cell sarcoma by array comparative genomic hybridization.	('gains', 'PosReg', (49, 54))	('neoplasms', 'Phenotype', 'HP:0002664', (5, 14))	('interdigitating dendritic cell sarcoma', 'Disease', (62, 100))	('trisomy 12', 'Var', (28, 38))	('interdigitating dendritic cell sarcoma', 'Disease', 'MESH:D054739', (62, 100))	('neoplasms', 'Disease', 'MESH:D009369', (5, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('neoplasms', 'Disease', (5, 14))	('neoplasm', 'Phenotype', 'HP:0002664', (5, 13))
359902	31633108	In a 2011 study of 7 cases of CLL/SLL with transformation to histiocytic/dendritic cell sarcomas, 2 had 17p deletion in both the CLL/SLL and sarcoma components.	('17p deletion', 'Var', (104, 116))	('sarcoma', 'Disease', (141, 148))	('dendritic cell sarcomas', 'Disease', 'MESH:D054740', (73, 96))	('dendritic cell sarcomas', 'Disease', (73, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('CLL', 'Phenotype', 'HP:0005550', (30, 33))	('CLL/SLL', 'Gene', (30, 37))	('CLL', 'Phenotype', 'HP:0005550', (129, 132))	('CLL/SLL', 'Gene', '347734', (30, 37))	('CLL/SLL', 'Gene', (129, 136))	('sarcoma', 'Disease', (88, 95))	('CLL/SLL', 'Gene', '347734', (129, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('17p del', 'Mutation', 'c.17del', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))
359913	31633108	In Case 1, both the CLL/SLL cells and histiocytic sarcoma cells demonstrated del(13q) by FISH.	('CLL', 'Phenotype', 'HP:0005550', (20, 23))	('histiocytic sarcoma', 'Disease', (38, 57))	('CLL/SLL', 'Gene', (20, 27))	('CLL/SLL', 'Gene', '347734', (20, 27))	('del(13q', 'Var', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (38, 57))
360068	30344829	Undifferentiated cardiac intimal sarcomas demonstrate atypical and tightly packed spindle-shaped cells arranged in long fascicles, areas of necrosis, cellular atypia and nuclear polymorphisms.	('necrosis', 'Disease', (140, 148))	('cardiac intimal sarcomas', 'Disease', (17, 41))	('necrosis', 'Disease', 'MESH:D009336', (140, 148))	('cardiac intimal sarcomas', 'Disease', 'MESH:D006331', (17, 41))	('nuclear polymorphisms', 'Var', (170, 191))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))
360075	30344829	Genomic analysis showing frequent alteration in genes like MDM2, PDGFRA and EGFR has led to further research on targeted therapeutic approach, thus, paving a way for other treatment modalities such as chemotherapy and radiation therapy for the treatment of cardiac intimal sarcomas.	('cardiac intimal sarcomas', 'Disease', (257, 281))	('alteration', 'Var', (34, 44))	('EGFR', 'Gene', '1956', (76, 80))	('MDM2', 'Gene', '4193', (59, 63))	('PDGFRA', 'Gene', (65, 71))	('PDGFRA', 'Gene', '5156', (65, 71))	('MDM2', 'Gene', (59, 63))	('cardiac intimal sarcomas', 'Disease', 'MESH:D006331', (257, 281))	('EGFR', 'Gene', (76, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (273, 281))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))
360082	30344829	Factors that are associated with worse prognosis include necrosis, high mitotic count, metastasis and anatomical location of the tumor within the heart (intracavitary versus intramural).	('high', 'Var', (67, 71))	('metastasis', 'CPA', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('necrosis', 'Disease', (57, 65))	('tumor', 'Disease', (129, 134))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
360089	27166877	Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma The EWS/FLI1 fusion gene is well characterized as a driver of Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (155, 170))	('EWS', 'Gene', (97, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('EWS', 'Gene', '2130', (97, 100))	('fusion', 'Var', (106, 112))	('FLI1', 'Gene', '2313', (101, 105))	("Ewing's sarcoma", 'Disease', (155, 170))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (155, 170))	("Ewing's Sarcoma", 'Disease', (77, 92))	('FLI1', 'Gene', (101, 105))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (77, 92))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (77, 92))	('FLI1', 'Gene', (43, 47))	('Sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('FLI1', 'Gene', '2313', (43, 47))
360090	27166877	Previous preclinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency.	('rat', 'Species', '10116', (130, 133))	('knockdown', 'Var', (170, 179))	('RNA interference', 'MPA', (69, 85))	('mRNA and', 'MPA', (146, 154))
360098	27166877	Ewing's sarcoma fusion gene breakpoint sites are optimal targets for sarcoma specific RNA interference (RNAi)-mediated knockdown that has demonstrated preclinical therapeutic efficacy in both in vitro and in vivo testing.	("Ewing's sarcoma", 'Disease', (0, 15))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('sarcoma', 'Disease', (69, 76))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcoma', 'Disease', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('knockdown', 'Var', (119, 128))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('rat', 'Species', '10116', (145, 148))
360099	27166877	In a variety of models, both antisense oligonucleotides and siRNA's have confirmed targeting relevance and have proven safe in conjunction with down regulation of EWS/FLI1 gene expression.	('EWS/FLI1', 'Gene', (163, 171))	('antisense oligonucleotides', 'Var', (29, 55))	('oligonucleotides', 'Chemical', 'MESH:D009841', (39, 55))
360121	27166877	The functional outcome of knockdown was demonstrated by selective growth inhibition of the SK-N-MC cells in vitro (Figure 2b).	('rat', 'Species', '10116', (47, 50))	('knockdown', 'Var', (26, 35))	('growth inhibition', 'CPA', (66, 83))	('SK-N-MC', 'Chemical', '-', (91, 98))
360135	27166877	The fusion gene protein expression knockdown ranged from 64 to 84% (Figure 4, lanes 3-6) with reduction in CD99 protein expression from 21 to 72%.	('knockdown', 'Var', (35, 44))	('fusion', 'Protein', (4, 10))	('reduction', 'NegReg', (94, 103))	('CD99', 'Gene', '4267', (107, 111))	('protein', 'Protein', (16, 23))	('CD99', 'Gene', (107, 111))
360143	27166877	Two dose levels were tested, 0.128 mg/kg (low) and 0.384 mg/kg (high), equivalent to 25 and 75 microg infusion per mouse, respectively.	('mouse', 'Species', '10090', (115, 120))	('0.128 mg/kg', 'Var', (29, 40))	('0.384 mg/kg', 'Var', (51, 62))
360144	27166877	The predicted human equivalents of these dose levels are 0.0846 and 0.2538 mg/kg, respectively.	('human', 'Species', '9606', (14, 19))	('0.0846', 'Var', (57, 63))	('0.2538 mg/kg', 'Var', (68, 80))
360154	27166877	One 0.384 mg/kg male (study animal #7326) displayed decreased activity with tremors, head tilt, and coughing, and was euthanized on Study Day 21.	('activity', 'MPA', (62, 70))	('decreased', 'NegReg', (52, 61))	('tremors', 'Phenotype', 'HP:0001337', (76, 83))	('head tilt', 'CPA', (85, 94))	('0.384 mg/kg', 'Var', (4, 15))	('tremors', 'Disease', (76, 83))	('coughing', 'CPA', (100, 108))	('coughing', 'Phenotype', 'HP:0012735', (100, 108))	('tremors', 'Disease', 'MESH:D014202', (76, 83))
360162	27166877	Blood AST level transiently elevated eight to ninefold for #7326 two days after treatment, but was only slightly elevated with subsequent treatment.	('AST', 'Gene', '26503', (6, 9))	('AST', 'Gene', (6, 9))	('elevated', 'PosReg', (28, 36))	('#7326', 'Var', (59, 64))
360165	27166877	The 0.128 mg/kg cohort had only a slight increase of blood total bilirubin (TBIL) level on the first day of the first dose, the TBIL level returned to normal with subsequent doses.	('bilirubin', 'Chemical', 'MESH:D001663', (65, 74))	('TBIL', 'Chemical', 'MESH:D001663', (128, 132))	('TBIL', 'Chemical', 'MESH:D001663', (76, 80))	('0.128 mg/kg', 'Var', (4, 15))	('increase of blood total bilirubin', 'Phenotype', 'HP:0003573', (41, 74))	('increase', 'PosReg', (41, 49))
360166	27166877	Blood GGT level was not elevated for 0.128 mg/kg group, but did rise three to fivefold in #7326 (high dose) throughout the course of the treatment (Figure 6), it might be worth noting that #7326 already had slightly higher GGT level 6 days prior to treatment.	('GGT', 'Gene', (6, 9))	('GGT', 'Gene', '653590', (6, 9))	('GGT', 'Gene', (223, 226))	('rise', 'PosReg', (64, 68))	('higher', 'PosReg', (216, 222))	('GGT', 'Gene', '653590', (223, 226))	('#7326', 'Var', (189, 194))
360175	27166877	In vitro results confirmed the efficacy of pbi-shRNA EWS/FLI1 LPX with marked knockdown of Ewing's type 1 fusion protein correlating with tumor growth reduction.	('knockdown', 'MPA', (78, 87))	("Ewing's type", 'Disease', 'MESH:C563168', (91, 103))	('tumor', 'Disease', (138, 143))	('pbi', 'Chemical', '-', (43, 46))	("Ewing's type", 'Disease', (91, 103))	('LPX', 'Chemical', '-', (62, 65))	('pbi-shRNA', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('reduction', 'NegReg', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
360180	27166877	Demonstration of target gene knockdown in the treated xenografted tumors verified the modality of drug action in correlation with tumor response and survival advantage.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('knockdown', 'Var', (29, 38))	('tumor', 'Disease', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('rat', 'Species', '10116', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (130, 135))
360181	27166877	We first demonstrated EWSR/FLI1 knockdown in the type 1-specific SK-N-MC cell lines in vitro.	('rat', 'Species', '10116', (16, 19))	('SK-N-MC', 'Chemical', '-', (65, 72))	('knockdown', 'Var', (32, 41))	('EWSR/FLI1', 'Gene', (22, 31))
360237	27166877	Release testing includes LPX physical characterization (OD400, Z-average size, polydispersity index, and zeta potential), DNA identity and integrity analysis (DNA extraction and restriction enzyme digest), and purity assessment (thin layer chromatography, sterility, and endotoxin).	('OD400', 'Var', (56, 61))	('LPX', 'Chemical', '-', (25, 28))	('Z-average size', 'MPA', (63, 77))	('polydispersity index', 'MPA', (79, 99))
360258	27166877	Animals were dosed with pbi-shRNA EWS/FLI1 LPX (Lot # 031815B-P) ((0.128 mg/kg (n = 2 females + 2 males) or 0.384 mg/kg (n = 2 females + 2 males)) twice weekly x 4 weeks.	('0.384 mg/kg', 'Var', (108, 119))	('pbi', 'Chemical', '-', (24, 27))	('LPX', 'Chemical', '-', (43, 46))	('(0.128 mg/kg', 'Var', (66, 78))
360332	26051470	Membranes were blocked using Protein Free T20 (TBS) Blocking Buffer (Pierce Thermo Scientific) and incubated with primary antibodies (Santa Cruz Biotechnologies) directed against RANK-ligand (1:500) and MCSF (1:500) Archival primary sarcoma biopsy samples that were collected from patients prior to therapy (n=5 Ewing's sarcoma of bone and n=5 osteosarcoma) were sectioned and stained for hematoxylin and eosin (H&E), the ESB specific marker CD99 (1:250), MCSF (1:100) and RANK-ligand (1:200).	("Ewing's sarcoma of bone", 'Disease', 'MESH:C563168', (312, 335))	("Ewing's sarcoma of bone", 'Disease', (312, 335))	('sarcoma', 'Phenotype', 'HP:0100242', (349, 356))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (312, 327))	('osteosarcoma', 'Disease', (344, 356))	('MCSF', 'Var', (456, 460))	('osteosarcoma', 'Disease', 'MESH:D012516', (344, 356))	('sarcoma', 'Disease', 'MESH:D012509', (233, 240))	('sarcoma', 'Disease', (233, 240))	('sarcoma', 'Disease', 'MESH:D012509', (320, 327))	('H&E', 'Chemical', '-', (412, 415))	('sarcoma', 'Disease', (320, 327))	('patients', 'Species', '9606', (281, 289))	('hematoxylin', 'Chemical', 'MESH:D006416', (389, 400))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('sarcoma', 'Disease', 'MESH:D012509', (349, 356))	('sarcoma', 'Phenotype', 'HP:0100242', (320, 327))	('osteosarcoma', 'Phenotype', 'HP:0002669', (344, 356))	('sarcoma', 'Disease', (349, 356))	('eosin', 'Chemical', 'MESH:D004801', (405, 410))
360363	26051470	Surprisingly, experiments that tested the ESBCM, MB321CM or HBL100CM effects on bone marrow derived monocytes produced significant increases of 43.4%, 35.9% and 28.3% in monocyte numbers for the 0.1%, 0.5% and 1% ESBCM concentrations relative to control conditioned media (p<0.02).	('HBL100CM', 'Var', (60, 68))	('increases', 'PosReg', (131, 140))	('monocyte numbers', 'CPA', (170, 186))	('MB321CM', 'Var', (49, 56))	('ESBCM', 'Chemical', '-', (213, 218))	('ESBCM', 'Chemical', '-', (42, 47))
360364	26051470	(Figure 5c) An analysis of gene expression demonstrated that the ESB cell-lines (RDES, HS822.t, HS863.t) express MCSF and not RANK-ligand while, in parallel, MCSF and RANK-ligand were expressed in SaOS2 osteosarcoma tumor cells and human MSC.	('MCSF', 'Var', (113, 117))	('osteosarcoma tumor', 'Disease', (203, 221))	('osteosarcoma', 'Phenotype', 'HP:0002669', (203, 215))	('human', 'Species', '9606', (232, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('osteosarcoma tumor', 'Disease', 'MESH:D012516', (203, 221))
360396	23006414	Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression Langerhans cell sarcoma is a rare and aggressive high grade hematopoietic neoplasm with a dismal prognosis.	('hematopoietic neoplasm', 'Phenotype', 'HP:0004377', (128, 150))	('Langerhans cell sarcoma', 'Disease', (68, 91))	('neoplasm', 'Phenotype', 'HP:0002664', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('CD3 expression', 'Gene', (53, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('Langerhans cell sarcoma', 'Disease', (0, 23))	('hematopoietic neoplasm', 'Disease', 'MESH:D019337', (128, 150))	('aberrant', 'Var', (32, 40))	('Langerhans cell sarcoma', 'Disease', 'MESH:D054752', (68, 91))	('Langerhans cell sarcoma', 'Disease', 'MESH:D054752', (0, 23))	('hematopoietic neoplasm', 'Disease', (128, 150))
360428	23006414	This was compatible with immunohistochemical findings of CD4 positivity of tumor cells and scatter normal lymphocytes at the background in the tissue block.	('CD4', 'Gene', '920', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CD4 positivity', 'Phenotype', 'HP:0005407', (57, 71))	('CD4', 'Gene', (57, 60))	('positivity', 'Var', (61, 71))	('tumor', 'Disease', (75, 80))
360435	23006414	Furthermore aberrant CD3 expression has been reported in other hemotopoietic tumours such as diffuse large B cell lymphoma, primary mediastinal large B cell lymphoma, plasmablastic lymphoma and classical Hodgkin's lymphoma but not in histiocytic sarcoma.	('lymphoma', 'Disease', 'MESH:D008223', (214, 222))	('lymphoma', 'Disease', (157, 165))	('lymphoma', 'Disease', (181, 189))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (204, 222))	('lymphoma', 'Disease', 'MESH:D008223', (157, 165))	('lymphoma', 'Disease', 'MESH:D008223', (181, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (107, 122))	('cell lymphoma', 'Phenotype', 'HP:0012191', (109, 122))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (204, 222))	('large B cell', 'Phenotype', 'HP:0005404', (101, 113))	('expression', 'MPA', (25, 35))	('lymphoma', 'Disease', (114, 122))	('lymphoma', 'Disease', 'MESH:D008223', (114, 122))	('hemotopoietic tumours', 'Disease', (63, 84))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('plasmablastic lymphoma', 'Disease', (167, 189))	("Hodgkin's lymphoma", 'Disease', (204, 222))	('lymphoma', 'Phenotype', 'HP:0002665', (214, 222))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (150, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (157, 165))	('cell lymphoma', 'Phenotype', 'HP:0012191', (152, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (181, 189))	('aberrant', 'Var', (12, 20))	('plasmablastic lymphoma', 'Disease', 'MESH:D000069293', (167, 189))	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('reported', 'Reg', (45, 53))	('sarcoma', 'Disease', 'MESH:D012509', (246, 253))	('CD3', 'Gene', (21, 24))	('sarcoma', 'Disease', (246, 253))	('large B cell', 'Phenotype', 'HP:0005404', (144, 156))	('hemotopoietic tumours', 'Disease', 'MESH:D009369', (63, 84))	('lymphoma', 'Disease', (214, 222))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
360440	23006414	Although the prognostic factors in LCS were not known, they might include prognostic factors common to other rare sarcomas, such as patient age, tumor size, tumor cell grade, proliferation rate, and/or stage.. DNA ploidy had been proposed as one of the prognostic factors in some subtypes of sarcoma, although another study does not show ploidy status to be an independent prognostic factor.	('tumor', 'Disease', (157, 162))	('sarcoma', 'Disease', (292, 299))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('sarcoma', 'Disease', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', (114, 122))	('tumor', 'Disease', (145, 150))	('ploidy', 'Var', (214, 220))	('sarcoma', 'Disease', 'MESH:D012509', (292, 299))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('patient', 'Species', '9606', (132, 139))
360443	23006414	In summary, we reported the first case of Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression, which initially with insufficient immunophenotyping created diagnostic difficulty, especially about lineage assignment.	('insufficient', 'Disease', (132, 144))	('Langerhans cell sarcoma', 'Disease', (42, 65))	('CD3', 'Gene', (95, 98))	('insufficient', 'Disease', 'MESH:D000309', (132, 144))	('Langerhans cell sarcoma', 'Disease', 'MESH:D054752', (42, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('aberrant', 'Var', (74, 82))
360456	23829867	Refractory bone and soft tissue sarcomas are challenging diseases to treat with an unmet need for effective systemic therapy.1, 2 Several molecularly targeted agents, such as mammalian target of rapamycin (mTOR) inhibitor3 and antibody to the insulin-like growth factor 1 receptor (IGF-1R),4 have shown clinical benefits in a subgroup of sarcoma patients with refractory sarcomas, achieving a median survival time (MST) of 7.6-9.2 months.	('antibody', 'Var', (227, 235))	('refractory sarcomas', 'Disease', (360, 379))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (20, 40))	('mammalian target of rapamycin', 'Gene', (175, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('sarcoma', 'Disease', 'MESH:D012509', (371, 378))	('sarcomas', 'Disease', 'MESH:D012509', (371, 379))	('sarcoma', 'Disease', (371, 378))	('sarcoma', 'Disease', 'MESH:D012509', (338, 345))	('sarcomas', 'Phenotype', 'HP:0100242', (371, 379))	('insulin-like growth factor 1 receptor', 'Gene', (243, 280))	('sarcoma', 'Disease', (338, 345))	('sarcomas', 'Disease', (371, 379))	('patients', 'Species', '9606', (346, 354))	('inhibitor3', 'Gene', (212, 222))	('mTOR', 'Gene', (206, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (371, 378))	('sarcoma', 'Phenotype', 'HP:0100242', (338, 345))	('benefits', 'PosReg', (312, 320))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (243, 280))	('IGF-1R', 'Gene', '3480', (282, 288))	('IGF-1R', 'Gene', (282, 288))	('mTOR', 'Gene', '2475', (206, 210))	('inhibitor3', 'Gene', '6992', (212, 222))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('sarcoma', 'Disease', (32, 39))	('mammalian target of rapamycin', 'Gene', '2475', (175, 204))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('refractory sarcomas', 'Disease', 'MESH:D012509', (360, 379))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (20, 39))	('sarcomas', 'Disease', (32, 40))
360465	23829867	All patients were required to show positive IgG responses to at least two of the 31 different vaccine candidate peptides, as reported previously.10, 11, 12 Other inclusion criteria were as follows: age between 20 and 80 years; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; positive status for the HLA-A2, -A24, -A3 supertypes (A3, A11, A31, or A33), or -A26 types; life expectancy of at least 12 weeks; and adequate hematologic, hepatic, and renal function.	('A3', 'Var', (356, 358))	('-A26', 'Gene', '28906', (382, 386))	('Oncology', 'Phenotype', 'HP:0002664', (250, 258))	('A11', 'Gene', '28874', (360, 363))	('A33', 'Gene', '10223', (373, 376))	('positive IgG', 'Phenotype', 'HP:0003237', (35, 47))	('A31', 'Var', (365, 368))	('A33', 'Gene', (373, 376))	('-A26', 'Gene', (382, 386))	('patients', 'Species', '9606', (4, 12))	('A11', 'Gene', (360, 363))
360537	23829867	IL-6 is a multifunctional cytokine that regulates various aspects of immune responses, acute phase reactions, and hematopoiesis.19, 20 In addition, IL-6 has recently been reported to be one of the critical cytokines for inducing suppressive immune cell subsets, such as myeloid-derived suppressor cells and Th17, which are known to negatively affect anti-tumor immunity.21, 22, 23 It thus might be possible that high levels of IL-6 innibit immune responses to cancer vaccines.	('IL-6', 'Gene', (148, 152))	('high levels', 'Var', (412, 423))	('IL-6', 'Gene', '3569', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('immune responses', 'CPA', (440, 456))	('IL-6', 'Gene', (427, 431))	('cancer', 'Phenotype', 'HP:0002664', (460, 466))	('innibit', 'Reg', (432, 439))	('tumor', 'Disease', (355, 360))	('IL-6', 'Gene', (0, 4))	('IL-6', 'Gene', '3569', (427, 431))	('cancer', 'Disease', 'MESH:D009369', (460, 466))	('hematopoiesis.19', 'Disease', 'MESH:C000657245', (114, 130))	('hematopoiesis.19', 'Disease', (114, 130))	('suppressive immune cell', 'Phenotype', 'HP:0002721', (229, 252))	('cancer', 'Disease', (460, 466))	('IL-6', 'Gene', '3569', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (355, 360))
360590	28761924	Although we did not complete chromosomal and immunohistochemical examinations in our patients, the several inspections for pathogenesis of RT-induced sarcoma have been reported as follows: the loss of material from 3p21-3pter detected by comparative genomic hybridization, a role of p53 gene mutations, and the KIT protein overexpression without mutation.	('mutations', 'Var', (292, 301))	('loss', 'NegReg', (193, 197))	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('p53', 'Gene', (283, 286))	('patients', 'Species', '9606', (85, 93))	('sarcoma', 'Disease', (150, 157))	('p53', 'Gene', '7157', (283, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))
360741	24216990	Both WD and DD tumor cells exhibit amplification of chromosome 12q13-15, a region which contains several hundred genes including MDM2, an inhibitor of the tumor suppressor p53, and CDK4, a critical regulator of cell cycling.	('MDM2', 'Gene', '4193', (129, 133))	('amplification', 'Var', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('MDM2', 'Gene', (129, 133))	('DD tumor', 'Disease', 'MESH:D009369', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('WD', 'Disease', 'MESH:D006527', (5, 7))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('DD tumor', 'Disease', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('p53', 'Gene', '7157', (172, 175))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (15, 20))	('CDK4', 'Gene', (181, 185))	('CDK4', 'Gene', '1019', (181, 185))	('p53', 'Gene', (172, 175))
360756	24216990	In rare cases, an alternative translocation event can occur (t12;22)(q13;q12), that results in an EWS-CHOP fusion gene.	('t12;22)(q13;q12', 'Var', (61, 76))	('results in', 'Reg', (84, 94))	('CHOP', 'Gene', '1649', (102, 106))	('CHOP', 'Gene', (102, 106))	('EWS', 'Gene', (98, 101))	('EWS', 'Gene', '2130', (98, 101))
360769	24216990	A single characteristic genetic abnormality has not yet been identified; instead, complex changes are seen with chromosomal duplications, gains, losses, and rearrangements.	('gains', 'PosReg', (138, 143))	('losses', 'NegReg', (145, 151))	('rearrangements', 'Var', (157, 171))	('oma', 'Disease', (119, 122))	('genetic abnormality', 'Disease', 'MESH:D030342', (24, 43))	('genetic abnormality', 'Disease', (24, 43))	('oma', 'Disease', 'None', (119, 122))
360776	24216990	Histologic examination, ideally by an experienced soft tissue sarcoma pathologist, is best supplemented with molecular studies (e.g., MDM2 amplification by fluorescence in situ hybridization in WD/DD liposarcoma) for accurate diagnosis.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('amplification', 'Var', (139, 152))	('liposarcoma', 'Phenotype', 'HP:0012034', (200, 211))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (50, 69))	('MDM2', 'Gene', '4193', (134, 138))	('MDM2', 'Gene', (134, 138))	('soft tissue sarcoma', 'Disease', (50, 69))	('WD/DD liposarcoma', 'Disease', 'MESH:D006527', (194, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('WD/DD liposarcoma', 'Disease', (194, 211))
360782	24216990	Although anthracycline based combinations tend to have higher response rates compared to single agent therapy, a survival benefit has not been demonstrated in the trials so far.	('anthracycline', 'Var', (9, 22))	('higher', 'PosReg', (55, 61))	('anthracycline', 'Chemical', 'MESH:D018943', (9, 22))	('response', 'MPA', (62, 70))
360840	24216990	In well differentiated (WD) and dedifferentiated (DD) liposarcomas, amplification of MDM2 is seen in virtually all tumors and in fact, is a reliable method for clinical diagnosis.	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('liposarcomas', 'Phenotype', 'HP:0012034', (54, 66))	('MDM2', 'Gene', '4193', (85, 89))	('liposarcomas', 'Disease', 'MESH:D008080', (54, 66))	('MDM2', 'Gene', (85, 89))	('liposarcomas', 'Disease', (54, 66))	('liposarcoma', 'Phenotype', 'HP:0012034', (54, 65))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('WD', 'Disease', 'MESH:D006527', (24, 26))	('amplification', 'Var', (68, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
360841	24216990	This observation and the knowledge of the important role of MDM2 as a negative regulator of p53, suggest that targeting MDM2 may be a promising approach to therapy, specifically for WD/DD liposarcoma.	('MDM2', 'Gene', '4193', (60, 64))	('WD/DD liposarcoma', 'Disease', 'MESH:D006527', (182, 199))	('MDM2', 'Gene', (60, 64))	('MDM2', 'Gene', '4193', (120, 124))	('WD/DD liposarcoma', 'Disease', (182, 199))	('MDM2', 'Gene', (120, 124))	('p53', 'Gene', (92, 95))	('liposarcoma', 'Phenotype', 'HP:0012034', (188, 199))	('targeting', 'Var', (110, 119))	('p53', 'Gene', '7157', (92, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
360875	24216990	In vitro studies suggest that inhibition (as opposed to activation) of the PPAR-delta isoform may have anti-proliferative effect specifically for liposarcoma.	('liposarcoma', 'Disease', 'MESH:D008080', (146, 157))	('PPAR-delta', 'Gene', '5467', (75, 85))	('inhibition', 'Var', (30, 40))	('liposarcoma', 'Phenotype', 'HP:0012034', (146, 157))	('PPAR-delta', 'Gene', (75, 85))	('anti-proliferative', 'MPA', (103, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('liposarcoma', 'Disease', (146, 157))
360877	24216990	Alterations in sterol regulatory element binding protein-1 (SREBP-1), a master transcriptional regulator of fatty acid and cholesterol synthesis, are thought to be the underlying mechanism for HIV PI lipodystrophy.	('sterol regulatory element binding protein-1', 'Gene', '6720', (15, 58))	('lipodystrophy', 'Phenotype', 'HP:0009125', (200, 213))	('fatty acid', 'Chemical', 'MESH:D005227', (108, 118))	('cholesterol', 'Chemical', 'MESH:D002784', (123, 134))	('Alterations', 'Var', (0, 11))	('SREBP-1', 'Gene', '6720', (60, 67))	('SREBP-1', 'Gene', (60, 67))	('HIV PI lipodystrophy', 'Disease', (193, 213))	('sterol regulatory element binding protein-1', 'Gene', (15, 58))	('HIV PI lipodystrophy', 'Disease', 'MESH:D039682', (193, 213))
360886	24216990	In tumor cells, TKRs and their associated downstream molecules are frequently over-expressed or mutated, leading to constitutive activation or aberrant signaling.	('mutated', 'Var', (96, 103))	('over-expressed', 'PosReg', (78, 92))	('tumor', 'Disease', (3, 8))	('TKR', 'Gene', '8277', (16, 19))	('aberrant signaling', 'MPA', (143, 161))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('TKR', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('constitutive activation', 'MPA', (116, 139))
360920	24216990	The authors also identified a high frequency (18%) of mutations in PI3K in MRC liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (79, 90))	('PI3K', 'Gene', (67, 71))	('MRC liposarcoma', 'Disease', 'MESH:D008080', (75, 90))	('mutations', 'Var', (54, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('MRC liposarcoma', 'Disease', (75, 90))
360921	24216990	Patients with either kinase or helical domain mutations had worse disease specific survival, although the numbers of such patients were small.	('disease specific survival', 'CPA', (66, 91))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (122, 130))	('oma', 'Disease', (40, 43))	('kinase', 'Var', (21, 27))	('oma', 'Disease', 'None', (40, 43))	('worse', 'NegReg', (60, 65))
360935	24216990	reported that up to 17% of cases exhibit mutations in p53.	('mutations', 'Var', (41, 50))	('p53', 'Gene', '7157', (54, 57))	('p53', 'Gene', (54, 57))
360947	24216990	Within each histologic subtype of liposarcoma, the multiple key genetic and molecular aberrations are often found together in the same tumor (e.g., MDM2 and CDK4 amplification in WD/DD liposarcoma).	('CDK4', 'Gene', '1019', (157, 161))	('WD/DD liposarcoma', 'Disease', 'MESH:D006527', (179, 196))	('amplification', 'Var', (162, 175))	('liposarcoma', 'Phenotype', 'HP:0012034', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('liposarcoma', 'Disease', (34, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('WD/DD liposarcoma', 'Disease', (179, 196))	('tumor', 'Disease', (135, 140))	('CDK4', 'Gene', (157, 161))	('liposarcoma', 'Phenotype', 'HP:0012034', (34, 45))	('liposarcoma', 'Disease', 'MESH:D008080', (34, 45))	('liposarcoma', 'Disease', (185, 196))	('MDM2', 'Gene', '4193', (148, 152))	('MDM2', 'Gene', (148, 152))	('liposarcoma', 'Disease', 'MESH:D008080', (185, 196))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
360957	33203838	Silencing of GARP in bone sarcoma cell lines blocked their proliferation and induced apoptosis.	('proliferation', 'CPA', (59, 72))	('induced', 'Reg', (77, 84))	('GARP', 'Gene', (13, 17))	('apoptosis', 'CPA', (85, 94))	('bone sarcoma', 'Disease', 'MESH:D012509', (21, 33))	('bone sarcoma', 'Phenotype', 'HP:0002669', (21, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('blocked', 'NegReg', (45, 52))	('Silencing', 'Var', (0, 9))	('bone sarcoma', 'Disease', (21, 33))
360960	33203838	We propose that targeting GARP in bone sarcomas could reduce tumour burden while simultaneously improving the efficacy of chemo- and radiotherapy.	('GARP', 'Var', (26, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('targeting GARP', 'Var', (16, 30))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('bone sarcoma', 'Phenotype', 'HP:0002669', (34, 46))	('bone sarcomas could reduce tumour', 'Disease', 'MESH:D001859', (34, 67))	('improving', 'PosReg', (96, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('bone sarcomas', 'Phenotype', 'HP:0002669', (34, 47))	('bone sarcomas could reduce tumour', 'Disease', (34, 67))
360969	33203838	A conformational change in the LAP induced by integrins, proteases, or reactive oxygen species releases TGF-beta, which then can bind its receptors and induce signalling via canonical (mothers against decapentaplegic homolog; SMADs) and non-canonical pathways.	('receptors', 'Protein', (138, 147))	('signalling', 'MPA', (159, 169))	('conformational change', 'Var', (2, 23))	('TGF-beta', 'Gene', (104, 112))	('LAP', 'Gene', '7040', (31, 34))	('bind', 'Interaction', (129, 133))	('canonical', 'Pathway', (174, 183))	('induce', 'Reg', (152, 158))	('LAP', 'Gene', (31, 34))
360973	33203838	GARP-overexpression in colorectal and lung cancer is associated with a worse prognosis due to a TGF-beta-dependent pro-metastatic effect and to the induction of an immunosuppressive tumour microenvironment.	('GARP-overexpression', 'Var', (0, 19))	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (23, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('men', 'Species', '9606', (201, 204))	('pro-metastatic effect', 'CPA', (115, 136))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', (182, 188))	('TGF-beta-dependent', 'Gene', (96, 114))
360977	33203838	However, whether GARP is expressed on bone sarcoma cells and if GARP can promote their tumorigenicity and/or chemo/radioresistance are unknown.	('tumorigenicity', 'CPA', (87, 101))	('bone sarcoma', 'Disease', (38, 50))	('bone sarcoma', 'Disease', 'MESH:D012509', (38, 50))	('GARP', 'Var', (64, 68))	('bone sarcoma', 'Phenotype', 'HP:0002669', (38, 50))	('promote', 'PosReg', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
360980	33203838	Importantly, GARP was found to be overexpressed in human osteo-, chondro-, and pleomorphic sarcomas and was associated with a significantly worse clinical prognosis.	('pleomorphic sarcomas', 'Disease', (79, 99))	('GARP', 'Var', (13, 17))	('chondro-', 'Disease', (65, 73))	('osteo-', 'Disease', (57, 63))	('human', 'Species', '9606', (51, 56))	('associated', 'Reg', (108, 118))	('pleomorphic sarcomas', 'Disease', 'MESH:D012509', (79, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('overexpressed', 'PosReg', (34, 47))
360997	33203838	Immunohistochemistry was performed on paraffin-embedded tissue sections using monoclonal antibodies against human Ki67 (MIB-1, DAKO/Agilent, Santa Clara, CA, Agilent, Cat#: F726801) and phosphorylated-SMAD3 (phosphoS423 + S425, EP823Y, Abcam, Cambridge, UK, Abcam, Cat#: 1880-1) as described in Supplementary materials and methods.	('EP823Y', 'Var', (228, 234))	('MIB-1', 'Gene', (120, 125))	('paraffin', 'Chemical', 'MESH:D010232', (38, 46))	('MIB-1', 'Gene', '57534', (120, 125))	('men', 'Species', '9606', (301, 304))	('human', 'Species', '9606', (108, 113))	('phosphoS423 + S425', 'Var', (208, 226))	('SMAD3', 'Gene', '4088', (201, 206))	('SMAD3', 'Gene', (201, 206))
361015	33203838	Silencing of GARP in BM-MSCs, G292, T1-73, and SAOS-2 cells (Figs.	('SAOS-2', 'CellLine', 'CVCL:0548', (47, 53))	('Silencing', 'Var', (0, 9))	('GARP', 'Gene', (13, 17))
361020	33203838	GARP++ cells exhibited an increased proliferative capacity compared to NT and EGFP++ cells (Fig.	('GARP++', 'Var', (0, 6))	('NT', 'Chemical', '-', (71, 73))	('increased', 'PosReg', (26, 35))	('proliferative capacity', 'CPA', (36, 58))
361022	33203838	However, using a TGF-beta activity reporter cell line, we found that GARP++ cells produced significantly higher levels of active TGF-beta compared to NT cells (Figs.	('NT', 'Chemical', '-', (150, 152))	('higher', 'PosReg', (105, 111))	('GARP++', 'Var', (69, 75))	('levels', 'MPA', (112, 118))	('TGF-beta', 'Protein', (129, 137))
361023	33203838	Blocking TGF-beta signalling with SB431542 or neutralising TGF-beta using an anti-TGF-beta1/2/3 antibody significantly reduced the proliferation of the GARP++ cells (Fig.	('TGF-beta', 'Gene', (59, 67))	('neutralising', 'Var', (46, 58))	('proliferation', 'CPA', (131, 144))	('SB431542', 'Chemical', 'MESH:C459179', (34, 42))	('TGF-beta1/2/3', 'Gene', '7040', (82, 95))	('TGF-beta', 'Protein', (9, 17))	('reduced', 'NegReg', (119, 126))	('TGF-beta1/2/3', 'Gene', (82, 95))
361025	33203838	GARP++ G292 tumours exhibited a significantly increased growth in vivo compared to NT G292 tumours, whereas smaller tumours were found in only three out of eight mice injected with GARPKO2 G292 cells (Fig.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('increased', 'PosReg', (46, 55))	('GARP++ G292', 'Var', (0, 11))	('tumours', 'Disease', (12, 19))	('tumours', 'Disease', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('mice', 'Species', '10090', (162, 166))	('tumours', 'Disease', (116, 123))	('NT', 'Chemical', '-', (83, 85))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('growth', 'MPA', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
361028	33203838	GARP++ tumours contained significantly higher levels of proliferating Ki67+ cells compared to NT tumours while an opposite trend was observed between GARPKO2 and LV-CTRL tumours.	('higher', 'PosReg', (39, 45))	('tumours', 'Disease', (170, 177))	('LV-CTRL tumours', 'Disease', 'MESH:D009369', (162, 177))	('Ki67+', 'Var', (70, 75))	('tumours', 'Phenotype', 'HP:0002664', (170, 177))	('tumours', 'Disease', 'MESH:D009369', (170, 177))	('tumours', 'Disease', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumours', 'Disease', (7, 14))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))	('GARP++', 'Var', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('tumours', 'Disease', 'MESH:D009369', (7, 14))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('NT', 'Chemical', '-', (94, 96))	('LV-CTRL tumours', 'Disease', (162, 177))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('proliferating', 'MPA', (56, 69))
361029	33203838	Finally, we analysed the activation of SMAD3 in the GARP++ and NT tumours by IHC and observed an increased fraction of cells with high SMAD3-phosphorylation in GARP++ tumours compared to NT tumours (Fig.	('NT', 'Chemical', '-', (187, 189))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours by IHC', 'Disease', 'MESH:D009369', (66, 80))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('SMAD3', 'Gene', '4088', (135, 140))	('tumours', 'Disease', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('SMAD3', 'Gene', '4088', (39, 44))	('GARP++', 'Var', (160, 166))	('activation', 'PosReg', (25, 35))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('tumours', 'Disease', (190, 197))	('tumours by IHC', 'Disease', (66, 80))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('SMAD3', 'Gene', (135, 140))	('NT', 'Chemical', '-', (63, 65))	('SMAD3', 'Gene', (39, 44))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))	('tumours', 'Disease', 'MESH:D009369', (190, 197))	('tumours', 'Disease', (66, 73))
361033	33203838	Inhibition of TGF-beta signalling (SB431542) or neutralisation of TGF-beta (1D11) significantly reversed the survival of GARP-overexpressing cells, suggesting a mechanism dependent on TGF-beta (Fig.	('TGF-beta (1D11', 'Gene', '7039', (66, 80))	('reversed', 'NegReg', (96, 104))	('neutralisation', 'Var', (48, 62))	('SB431542', 'Chemical', 'MESH:C459179', (35, 43))	('survival', 'CPA', (109, 117))
361034	33203838	Similarly, GARP++ cells were more resistant to cell death induced by doxorubicin, although to a lesser extent compared to etoposide.	('resistant', 'CPA', (34, 43))	('GARP++', 'Var', (11, 17))	('death', 'Disease', 'MESH:D003643', (52, 57))	('etoposide', 'Chemical', 'MESH:D005047', (122, 131))	('death', 'Disease', (52, 57))	('doxorubicin', 'Chemical', 'MESH:D004317', (69, 80))
361038	33203838	Colony counting showed that GARP++ cells were more resistant to radiation-induced cell death compared to NT cells.	('GARP++', 'Var', (28, 34))	('NT', 'Chemical', '-', (105, 107))	('death', 'Disease', 'MESH:D003643', (87, 92))	('death', 'Disease', (87, 92))
361044	33203838	The OST-4 cell line expressed GARP at a high level and silencing of GARP reduced its proliferation (Figs.	('OST-4', 'Gene', '100128731', (4, 9))	('GARP', 'Gene', (68, 72))	('reduced', 'NegReg', (73, 80))	('silencing', 'Var', (55, 64))	('OST-4', 'Gene', (4, 9))	('proliferation', 'CPA', (85, 98))
361061	33203838	Silencing of GARP in these cell lines decreased their proliferation, suggesting that GARP could serve as a therapeutic target to inhibit bone sarcoma growth.	('decreased', 'NegReg', (38, 47))	('GARP', 'Gene', (13, 17))	('inhibit', 'NegReg', (129, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('bone sarcoma', 'Disease', 'MESH:D012509', (137, 149))	('bone sarcoma', 'Phenotype', 'HP:0002669', (137, 149))	('proliferation', 'CPA', (54, 67))	('Silencing', 'Var', (0, 9))	('bone sarcoma', 'Disease', (137, 149))
361067	33203838	This could be due to shortcomings of the experimental setup and to the fact that GARP-mediated activation of TGF-beta occurs in a cell-contact-dependent manner, inducing a response that differs from that of TGF-beta activated in the absence of GARP.	('inducing', 'Reg', (161, 169))	('activation', 'PosReg', (95, 105))	('GARP-mediated', 'Var', (81, 94))	('TGF-beta', 'Gene', (109, 117))	('men', 'Species', '9606', (47, 50))	('response', 'MPA', (172, 180))
361068	33203838	Third, we found that high GARP expression on human sarcoma tumours correlated with a significantly worse overall survival.	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('high GARP expression', 'Var', (21, 41))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('sarcoma tumours', 'Disease', 'MESH:D012509', (51, 66))	('human', 'Species', '9606', (45, 50))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('overall', 'MPA', (105, 112))	('sarcoma tumours', 'Disease', (51, 66))	('worse', 'NegReg', (99, 104))
361140	27105514	Similar to some human adenocarcinomas, urethane induces specific mutations in Kras at codon 61 and mutations in p53 during later stages of disease progression.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('Kras', 'Gene', (78, 82))	('Kras', 'Gene', '3845', (78, 82))	('mutations', 'Var', (99, 108))	('urethane', 'Chemical', 'MESH:D014520', (39, 47))	('p53', 'Gene', (112, 115))	('adenocarcinomas', 'Disease', 'MESH:D000230', (22, 37))	('human', 'Species', '9606', (16, 21))	('p53', 'Gene', '7157', (112, 115))	('mutations', 'Var', (65, 74))	('adenocarcinomas', 'Disease', (22, 37))
361153	27105514	A semi-quantitative assessment of spleen histopathology, based on number of lesions and percent area affected (scored on a scale of 0 - 3), revealed a significant increase in the spleen lesion score for the urethane treated Nlrx1-/- mice compared to all other genotypes and treatments (Figure 3C).	('urethane', 'Var', (207, 215))	('increase', 'PosReg', (163, 171))	('mice', 'Species', '10090', (233, 237))	('urethane', 'Chemical', 'MESH:D014520', (207, 215))	('Nlrx1', 'Gene', '270151', (224, 229))	('spleen', 'MPA', (179, 185))	('Nlrx1', 'Gene', (224, 229))
361207	27105514	Each pathway downstream of AKT signaling was found to be up-regulated in the absence of NLRX1 during histiocytic sarcoma (Figure 6B).	('AKT', 'Gene', (27, 30))	('absence', 'Var', (77, 84))	('NLRX1', 'Gene', (88, 93))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (101, 120))	('histiocytic sarcoma', 'Disease', (101, 120))	('AKT', 'Gene', '11651', (27, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('up-regulated', 'PosReg', (57, 69))
361216	27105514	In the presence of TNF, NLRX1 knockdown resulted in significantly increased tumor volume, whereas overexpression attenuated tumor growth.	('TNF', 'Gene', '21926', (19, 22))	('increased', 'PosReg', (66, 75))	('attenuated tumor', 'Disease', 'MESH:C538265', (113, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (124, 129))	('attenuated tumor', 'Disease', (113, 129))	('TNF', 'Gene', (19, 22))	('knockdown', 'Var', (30, 39))	('NLRX1', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
361222	27105514	In both the xenograft as well as the AOM/DSS models, the loss of NLRX1 was suggested to have implications in cell death leading to tumorigenesis, which is supported by our data as well.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('implications', 'Reg', (93, 105))	('cell death', 'CPA', (109, 119))	('DSS', 'Chemical', 'MESH:D016264', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('AOM', 'Chemical', 'MESH:D001397', (37, 40))	('NLRX1', 'Gene', (65, 70))	('loss', 'Var', (57, 61))
361242	27105514	These human data were complemented by studies using Ink4a/Arf deficient mice, which recapitulate genetic traits observed in human angiosarcoma patients and xenograft mice.	('human', 'Species', '9606', (6, 11))	('patients', 'Species', '9606', (143, 151))	('angiosarcoma', 'Disease', 'MESH:D006394', (130, 142))	('human', 'Species', '9606', (124, 129))	('Ink4a/Arf', 'Gene', (52, 61))	('mice', 'Species', '10090', (166, 170))	('deficient', 'Var', (62, 71))	('Ink4a/Arf', 'Gene', '1029', (52, 61))	('angiosarcoma', 'Disease', (130, 142))	('mice', 'Species', '10090', (72, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('angiosarcoma', 'Phenotype', 'HP:0200058', (130, 142))
361243	27105514	In these models, animals developed angiosarcoma in the lung, liver, and spleen and systemic inhibition of Ikkbeta, IL-6 or STAT3 significantly inhibited angiosarcoma growth.	('inhibition', 'Var', (92, 102))	('Ikkbeta', 'Gene', (106, 113))	('angiosarcoma', 'Disease', (35, 47))	('angiosarcoma', 'Disease', 'MESH:D006394', (153, 165))	('angiosarcoma', 'Phenotype', 'HP:0200058', (35, 47))	('angiosarcoma', 'Disease', (153, 165))	('inhibited', 'NegReg', (143, 152))	('angiosarcoma growth', 'Disease', 'MESH:D006394', (153, 172))	('angiosarcoma', 'Phenotype', 'HP:0200058', (153, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('angiosarcoma', 'Disease', 'MESH:D006394', (35, 47))	('Ikkbeta', 'Gene', '16150', (106, 113))	('angiosarcoma growth', 'Disease', (153, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
361244	27105514	In other sarcomas, inhibition of the NF-lambdaB pathway has also been shown to significantly attenuate tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inhibition', 'Var', (19, 29))	('tumor', 'Disease', (103, 108))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('attenuate', 'NegReg', (93, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcomas', 'Disease', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('NF-lambdaB pathway', 'Pathway', (37, 55))
361245	27105514	In a study utilizing a myxoid liposarcoma cell line, inhibition of the NF-lambdaB signaling pathway was shown to decrease cell viability, reduce phosphorylation of NF-lambdaB proteins, and attenuate caspase-3 regulated apoptosis.	('inhibition', 'Var', (53, 63))	('decrease', 'NegReg', (113, 121))	('reduce', 'NegReg', (138, 144))	('NF-lambdaB proteins', 'Protein', (164, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('attenuate', 'NegReg', (189, 198))	('caspase-3', 'Gene', '12367', (199, 208))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (23, 41))	('NF-lambdaB signaling pathway', 'Pathway', (71, 99))	('myxoid liposarcoma', 'Disease', (23, 41))	('phosphorylation', 'MPA', (145, 160))	('liposarcoma', 'Phenotype', 'HP:0012034', (30, 41))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (23, 41))	('caspase-3', 'Gene', (199, 208))	('cell viability', 'CPA', (122, 136))
361256	27105514	In this model, loss of PTEN results in aberrant activation of the PI3K/AKT signaling pathway, as well as, the RAS/MAPK pathway.	('MAPK', 'Gene', '26413;26417', (114, 118))	('AKT', 'Gene', '11651', (71, 74))	('PTEN', 'Gene', '19211', (23, 27))	('PTEN', 'Gene', (23, 27))	('loss', 'Var', (15, 19))	('activation', 'PosReg', (48, 58))	('AKT', 'Gene', (71, 74))	('MAPK', 'Gene', (114, 118))
361292	27105514	Samples were evaluated using the manufacturer's protocols for the following arrays: PAMM-033Z; PAMM-084Z; PAMM-011Z; PAMM-064Z; PAMM-025Z.	('PAMM-084Z', 'Var', (95, 104))	('PAMM-025Z', 'Var', (128, 137))	('PAMM-011Z', 'Var', (106, 115))	('PAMM-033Z', 'Chemical', '-', (84, 93))	('PAMM-064Z; PAMM-025Z', 'Var', (117, 137))	('PAMM-011Z', 'Chemical', '-', (106, 115))	('PAMM-025Z', 'Chemical', '-', (128, 137))	('PAMM-084Z', 'Chemical', '-', (95, 104))	('PAMM-064Z', 'Chemical', '-', (117, 126))	('PAMM-033Z', 'Var', (84, 93))
361294	27105514	The following array data series were analyzed to generate the human patient data: GSE7553; GSE66354; GSE32490; GSE37470; GSE34823; GSE7339; GSE36474; GSE50579; GSE9750; GSE28511; GSE29431; GSE19750; GSE7553; GSE29491; GSE2719; GSE49972; GSE13898; and GSE36982.	('GSE28511', 'Var', (169, 177))	('GSE29491; GSE2719; GSE49972', 'Var', (208, 235))	('GSE50579', 'Var', (150, 158))	('GSE34823; GSE7339', 'Var', (121, 138))	('GSE19750', 'Var', (189, 197))	('GSE29431; GSE19750', 'Var', (179, 197))	('GSE7553', 'Chemical', '-', (199, 206))	('GSE7553', 'Var', (199, 206))	('GSE7339', 'Chemical', '-', (131, 138))	('GSE49972', 'Var', (227, 235))	('GSE37470', 'Var', (111, 119))	('GSE36982', 'Var', (251, 259))	('GSE9750', 'Var', (160, 167))	('GSE2719', 'Chemical', '-', (218, 225))	('human', 'Species', '9606', (62, 67))	('GSE7339', 'Var', (131, 138))	('GSE9750', 'Chemical', '-', (160, 167))	('GSE66354; GSE32490', 'Var', (91, 109))	('GSE36474', 'Var', (140, 148))	('patient', 'Species', '9606', (68, 75))	('GSE7553', 'Chemical', '-', (82, 89))	('GSE7553', 'Var', (82, 89))	('GSE32490', 'Var', (101, 109))	('GSE13898', 'Var', (237, 245))
361304	25307292	18FDG PET-CT has the highest specificity (96%) and sensitivity (92%) of imaging modalities to detect bone metastases.	('PET-CT', 'Gene', (6, 12))	('bone metastases', 'Disease', (101, 116))	('18FDG', 'Var', (0, 5))	('bone metastases', 'Disease', 'MESH:D009362', (101, 116))
361397	23894400	High Frequency of Germline TP53 Mutations in a Prospective Adult-Onset Sarcoma Cohort Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations.	('TP53', 'Gene', '7157', (27, 31))	('Li-Fraumeni', 'Disease', (116, 127))	('TP53', 'Gene', (27, 31))	('Sarcoma Cohort', 'Disease', (71, 85))	('associated', 'Reg', (161, 171))	('Sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('Mutations', 'Var', (32, 41))	('Sarcomas', 'Disease', (86, 94))	('TP53', 'Gene', '7157', (186, 190))	('Sarcomas', 'Disease', 'MESH:D012509', (86, 94))	('Sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('Sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('TP53', 'Gene', (186, 190))	('Sarcoma Cohort', 'Disease', 'MESH:D012509', (71, 85))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (116, 127))
361398	23894400	Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias.	('mutations', 'Var', (38, 47))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))
361400	23894400	The entire cohort was screened for mutations in TP53 using high-resolution melting analysis and Sanger sequencing, and multiplex-ligation-dependent probe amplification and targeted massively parallel sequencing for copy number changes.	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (35, 44))
361401	23894400	Pathogenic TP53 mutations were detected in blood DNA of 20/559 sarcoma probands (3.6%); 17 were germline and 3 appeared to be somatically acquired.	('sarcoma', 'Disease', (63, 70))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('Pathogenic', 'Reg', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('mutations', 'Var', (16, 25))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
361403	23894400	Germline mutation carriers were more likely to have multiple cancers (47% vs 15% for non-carriers, P = 3.0x10-3), and earlier cancer onset (33 vs 48 years, P = 1.19x10-3).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Germline mutation carriers', 'Var', (0, 26))	('multiple cancers', 'Disease', (52, 68))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('multiple cancers', 'Disease', 'MESH:D009369', (52, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
361404	23894400	The median survival of mutation carriers following first cancer diagnosis was not significantly different from non-carriers.	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutation', 'Var', (23, 31))
361405	23894400	In summary, germline TP53 mutations are not rare in adult patients with sarcoma, with implications for screening, surveillance, treatment and genetic counselling of carriers and family members.	('TP53', 'Gene', (21, 25))	('sarcoma', 'Disease', (72, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('mutations', 'Var', (26, 35))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('patients', 'Species', '9606', (58, 66))	('TP53', 'Gene', '7157', (21, 25))
361406	23894400	Germline TP53 mutations result in the classical Li-Fraumeni or Li-Fraumeni-like syndromes (LFS/LFL), rare inherited syndromes with a lifetime cancer penetrance up to 73% for males and ~100% for females.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('inherited syndromes', 'Disease', (106, 125))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (48, 59))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Li-Fraumeni', 'Disease', (63, 74))	('TP53', 'Gene', '7157', (9, 13))	('Li-Fraumeni', 'Disease', (48, 59))	('TP53', 'Gene', (9, 13))	('result in', 'Reg', (24, 33))	('inherited syndromes', 'Disease', 'None', (106, 125))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', (142, 148))
361410	23894400	Moreover, studies of LFS-associated cancers suggest many germline TP53 mutation carriers have little family history, or will be increasingly identified through genomic screens of cancer populations unselected for family history.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (66, 70))	('TP53', 'Gene', '7157', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (36, 42))	('cancers', 'Disease', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (179, 185))
361413	23894400	To determine the incidence and clinical spectrum of germline TP53 mutations in adult-onset sarcoma populations, a systematic screen using multiplexed ligation-dependent probe amplification and Sanger sequencing was undertaken in 559 probands consecutively recruited from adult sarcoma clinics-agnostic to family history-on the Australian arm of the International Sarcoma Kindred Study (ISKS; http://www.anzctr.org.au; http://www.australiansarcomagroup.org/sarcomakindredstudy/index.html).	('mutations', 'Var', (66, 75))	('Sarcoma', 'Disease', 'MESH:D012509', (363, 370))	('sarcoma', 'Disease', 'MESH:D012509', (277, 284))	('sarcomakindredstudy', 'Disease', 'None', (456, 475))	('sarcoma', 'Disease', (277, 284))	('TP53', 'Gene', (61, 65))	('Sarcoma', 'Disease', (363, 370))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('sarcoma', 'Disease', 'MESH:D012509', (439, 446))	('sarcoma', 'Disease', (91, 98))	('sarcoma', 'Disease', (439, 446))	('Sarcoma', 'Phenotype', 'HP:0100242', (363, 370))	('sarcoma', 'Disease', 'MESH:D012509', (456, 463))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('sarcoma', 'Disease', (456, 463))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('TP53', 'Gene', '7157', (61, 65))	('sarcomakindredstudy', 'Disease', (456, 475))	('sarcoma', 'Phenotype', 'HP:0100242', (439, 446))	('sarcoma', 'Phenotype', 'HP:0100242', (456, 463))
361414	23894400	Pathogenic or putatively pathogenic TP53 events occurred in the peripheral blood DNA of 20/559 probands (3.6%), comprising 18 single nucleotide mutations or indels, and 2 whole gene deletions (Table 1).	('single nucleotide mutations', 'Var', (126, 153))	('Pathogenic', 'Reg', (0, 10))	('TP53', 'Gene', '7157', (36, 40))	('indels', 'Var', (157, 163))	('TP53', 'Gene', (36, 40))	('pathogenic', 'Reg', (25, 35))
361415	23894400	The age of sarcoma onset in individuals carrying pathogenic variants was not significantly different from those carrying putatively pathogenic variants (mean+-standard deviation: 38+-17 years versus 40+-19 years, compared to 48+-18 years for non-carriers in the ISKS cohort).	('sarcoma onset', 'Disease', (11, 24))	('variants', 'Var', (60, 68))	('sarcoma onset', 'Disease', 'MESH:D012509', (11, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))
361416	23894400	Seventeen were putative germline events, with the mutant allele also detected in tumor DNA and 8 tumors also demonstrating loss of heterozygosity.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Disease', (97, 103))	('mutant', 'Var', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Disease', (81, 86))
361418	23894400	While neither cases 19 or 20 had clinical evidence of MDS, both cases 18 and 19 showed widespread copy number changes in the peripheral blood-including the RB1 locus in case 19-suggestive of somatic tumor changes rather than germline events.	('tumor', 'Disease', (199, 204))	('RB1', 'Gene', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('MDS', 'Disease', (54, 57))	('copy number changes', 'Var', (98, 117))	('MDS', 'Disease', 'MESH:D009190', (54, 57))	('RB1', 'Gene', '5925', (156, 159))	('MDS', 'Phenotype', 'HP:0002863', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
361419	23894400	Case 14 showed somatic mosaicism, with 20-25% of mutant alleles (estimated by both Sanger sequencing and HRM analysis) in the peripheral blood, heterozygosity in the tumor, and absent in adjacent buccal mucosa (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mutant', 'Var', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('heterozygosity', 'Var', (144, 158))	('tumor', 'Disease', (166, 171))
361420	23894400	Somatic mosaicism for TP53 mutations has been previously reported.	('mutations', 'Var', (27, 36))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
361421	23894400	Of the putatively pathogenic variants, 1 occurred in a family fitting classical Li-Fraumeni criteria (case 4); two occurred in individuals fitting Chompret criteria (cases 6 & 8), and three did not demonstrate an unusual family history of cancer (cases 14, 16 & 17).	('pathogenic', 'Reg', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('Li-Fraumeni criteria', 'Disease', (80, 100))	('variants', 'Var', (29, 37))	('cancer', 'Disease', (239, 245))	('Li-Fraumeni criteria', 'Disease', 'MESH:D016864', (80, 100))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
361422	23894400	Regardless of family history, carriers of TP53 mutations appeared at increased personal risk for cancer.	('TP53', 'Gene', '7157', (42, 46))	('cancer', 'Disease', (97, 103))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carriers', 'Reg', (30, 38))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
361424	23894400	Eight of 17 mutation carriers had multiple primary cancers (Table 2), three occurring within prior radiation fields.	('multiple primary cancers', 'Disease', 'MESH:D009369', (34, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('multiple primary cancers', 'Disease', (34, 58))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('mutation', 'Var', (12, 20))
361425	23894400	Mutation carriers had an increased incidence of multiple cancers (47% versus 15% of non-carriers, Fisher's exact test 2-tailed P = 3.0x10-3).	('multiple cancers', 'Disease', (48, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('Mutation', 'Var', (0, 8))	('multiple cancers', 'Disease', 'MESH:D009369', (48, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
361429	23894400	Excluding probands, the median age at first cancer onset in TP53 mutation positive families was 54+-22yrs versus 60+-18yrs in TP53 negative families (P = 9.3x10-3).	('TP53', 'Gene', (126, 130))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('TP53', 'Gene', '7157', (60, 64))	('mutation', 'Var', (65, 73))	('TP53', 'Gene', (60, 64))	('TP53', 'Gene', '7157', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
361431	23894400	The germline mutation rate observed in the ISKS cohort (3%) matches the 2-4%   in childhood osteosarcoma, 2-3% reported in early onset breast cancer, but is less than reported for choroid plexus carcinomas (44%).	('osteosarcoma', 'Disease', 'MESH:D012516', (92, 104))	('choroid plexus carcinomas', 'Disease', (180, 205))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (180, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('breast cancer', 'Disease', (135, 148))	('germline mutation', 'Var', (4, 21))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('choroid plexus carcinomas', 'Disease', 'MESH:D020288', (180, 205))	('osteosarcoma', 'Disease', (92, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('osteosarcoma', 'Phenotype', 'HP:0002669', (92, 104))
361432	23894400	Only 60% of carriers had a family history potentially recognisable as associated with germline TP53 mutations.	('mutations', 'Var', (100, 109))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
361433	23894400	Somatic TP53 mutations are common in hematologic cancers, and cancer-prone individuals may harbour preclinical genetic evidence of dysplasia even in apparently normal blood.	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('dysplasia', 'Disease', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('dysplasia', 'Disease', 'MESH:D004476', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hematologic cancers', 'Disease', (37, 56))	('hematologic cancers', 'Disease', 'MESH:D009369', (37, 56))	('cancer', 'Disease', (62, 68))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (49, 55))	('common', 'Reg', (27, 33))
361435	23894400	It is clinically important to confirm the presence of putative germline TP53 mutations in more than one tissue, including the tumor tissue.	('TP53', 'Gene', '7157', (72, 76))	('TP53', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
361437	23894400	As genomic technologies are increasingly applied to cancer cohorts, regardless of clinical or family history, more TP53 mutation carriers will be identified and require counselling and care from their medical supports.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TP53', 'Gene', '7157', (115, 119))	('mutation', 'Var', (120, 128))	('TP53', 'Gene', (115, 119))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
361438	23894400	While more common than expected, the outlook for TP53 mutation carriers with sarcoma appears comparable to non-carriers, and options are emerging for cancer screening, family planning, and the selection of less carcinogenic cancer treatments.	('mutation', 'Var', (54, 62))	('TP53', 'Gene', '7157', (49, 53))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('TP53', 'Gene', (49, 53))	('carcinogenic cancer', 'Disease', 'MESH:D009369', (211, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('sarcoma', 'Disease', (77, 84))	('carcinogenic cancer', 'Disease', (211, 230))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
361439	23894400	Continued research into germline TP53 mutations is critical to understanding the impact of these mutations on cancer treatments and outcomes, and to develop effective cancer screening strategies for our patients and their families.	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('TP53', 'Gene', '7157', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (203, 211))	('TP53', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
361446	23894400	High resolution melt (HRM) analysis was used to screen for mutations in exons 2-11 of the TP53 gene.	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('mutations in', 'Var', (59, 71))
361447	23894400	Variants were defined as pathogenic if previously reported to be associated with Li-Fraumeni syndrome in the IARC TP53 database (R16, accessed February 2013), or they resulted in a frameshift, premature stop codon, or affected an essential splice site.	('R16', 'Gene', '6510', (129, 132))	('Variants', 'Var', (0, 8))	('affected', 'Reg', (218, 226))	('resulted in', 'Reg', (167, 178))	('R16', 'Gene', (129, 132))	('TP53', 'Gene', '7157', (114, 118))	('associated', 'Reg', (65, 75))	('essential splice site', 'MPA', (230, 251))	('frameshift', 'Var', (181, 191))	('TP53', 'Gene', (114, 118))	('Li-Fraumeni syndrome', 'Disease', (81, 101))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (81, 101))	('premature stop codon', 'MPA', (193, 213))
361449	23894400	R333C was included because a known pathogenic variant (R337H) is located in the same region (the tetramerization domain of TP53), and has been reported to result in loss of function by Kato et al.	('R333C', 'Var', (0, 5))	('pathogenic', 'Reg', (35, 45))	('function', 'MPA', (173, 181))	('R337H', 'Var', (55, 60))	('R333C', 'Mutation', 'rs769934890', (0, 5))	('R337H', 'Mutation', 'rs121912664', (55, 60))	('TP53', 'Gene', '7157', (123, 127))	('loss', 'NegReg', (165, 169))	('TP53', 'Gene', (123, 127))
361477	31217320	On the one side sarcomas with very simple genetics (50% of all sarcomas) based on point mutation (gastrointestinal stromal tumour (GIST), desmoid tumour) or a specific and recurrent translocation (Ewing, Synovial sarcoma, Myxoid liposarcoma and so on); and on the other side, sarcomas with a very complex genetics (50% of all sarcomas, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and so on).	('gastrointestinal stromal tumour', 'Disease', (98, 129))	('gastrointestinal stromal tumour', 'Disease', 'MESH:D046152', (98, 129))	('sarcomas', 'Disease', (326, 334))	('angiosarcoma', 'Disease', 'MESH:D006394', (352, 364))	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('sarcoma', 'Disease', (63, 70))	('translocation', 'Var', (182, 195))	('sarcoma', 'Disease', 'MESH:D012509', (276, 283))	('sarcomas', 'Disease', (63, 71))	('sarcomas', 'Disease', 'MESH:D012509', (276, 284))	('sarcoma', 'Disease', (276, 283))	('angiosarcoma', 'Phenotype', 'HP:0200058', (352, 364))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (366, 402))	('liposarcoma', 'Phenotype', 'HP:0012034', (229, 240))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (336, 350))	('sarcoma', 'Disease', 'MESH:D012509', (395, 402))	('sarcomas', 'Disease', (276, 284))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (336, 350))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))	('sarcomas', 'Disease', 'MESH:D012509', (63, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (276, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('desmoid tumour', 'Disease', (138, 152))	('Myxoid liposarcoma', 'Phenotype', 'HP:0012268', (222, 240))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('sarcoma', 'Disease', (395, 402))	('sarcomas', 'Disease', (16, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('angiosarcoma', 'Disease', (352, 364))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('undifferentiated pleomorphic sarcoma', 'Disease', (366, 402))	('sarcoma', 'Disease', 'MESH:D012509', (233, 240))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('sarcoma', 'Disease', (233, 240))	('Myxoid liposarcoma', 'Disease', (222, 240))	('leiomyosarcoma', 'Disease', (336, 350))	('sarcoma', 'Disease', 'MESH:D012509', (343, 350))	('desmoid tumour', 'Disease', 'MESH:C535944', (138, 152))	('sarcoma', 'Disease', (343, 350))	('point mutation', 'Var', (82, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (204, 220))	('desmoid tumour', 'Phenotype', 'HP:0100245', (138, 152))	('sarcoma', 'Disease', (16, 23))	('Myxoid liposarcoma', 'Disease', 'MESH:D018208', (222, 240))	('sarcoma', 'Disease', 'MESH:D012509', (326, 333))	('sarcoma', 'Disease', 'MESH:D012509', (357, 364))	('sarcomas', 'Disease', 'MESH:D012509', (326, 334))	('sarcoma', 'Disease', 'MESH:D012509', (213, 220))	('sarcomas', 'Phenotype', 'HP:0100242', (326, 334))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('sarcoma', 'Disease', (326, 333))	('sarcoma', 'Disease', (357, 364))	('sarcoma', 'Disease', (213, 220))
361503	31217320	Exploring specific chemicals or agents, positive associations have been found with wood dust, radium and 1-3 butadiene for soft-tissue sarcoma.	('soft-tissue sarcoma', 'Disease', (123, 142))	('associations', 'Interaction', (49, 61))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (123, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('1-3 butadiene', 'Chemical', 'MESH:C031763', (105, 118))	('1-3', 'Var', (105, 108))
361579	27929501	This study verifies the suitability of VMAT-MCO for sarcoma cancer and highlighted the comparability in plan quality and improvement in treatment efficiency offered by VMAT-MCO as compared to IMRT-MCO.	('MCO', 'Chemical', '-', (173, 176))	('VMAT-MCO for sarcoma cancer', 'Disease', (39, 66))	('MCO', 'Chemical', '-', (197, 200))	('VMAT-MCO for sarcoma cancer', 'Disease', 'MESH:D009369', (39, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('MCO', 'Chemical', '-', (44, 47))	('VMAT-MCO', 'Var', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('improvement', 'PosReg', (121, 132))
361621	27929501	To overcome this, we compared a relevant OAR DVH point for each plan pair, and we observed a general improvement for VMAT-MCO over IMRT-MCO plans, as seen in Table 3.	('MCO', 'Chemical', '-', (122, 125))	('VMAT-MCO', 'Var', (117, 125))	('improvement', 'PosReg', (101, 112))	('MCO', 'Chemical', '-', (136, 139))
361626	27929501	Plan delivery time showed statistically significant improvements of 213% on average for VMAT-MCO plans (average delivery time of  s) as compared to IMRT-MCO plans (average delivery time of  seconds), as illustrated in Fig.	('improvements', 'PosReg', (52, 64))	('VMAT-MCO plans', 'Var', (88, 102))	('MCO', 'Chemical', '-', (153, 156))	('MCO', 'Chemical', '-', (93, 96))
361627	27929501	Monitor unit number also showed statistically significant improvements for VMAT-MCO plans (average of  monitor units) as compared to IMRT-MCO (average of  monitor units), as seen in Fig.	('MCO', 'Chemical', '-', (80, 83))	('MCO', 'Chemical', '-', (138, 141))	('improvements', 'PosReg', (58, 70))	('VMAT-MCO', 'Var', (75, 83))
361628	27929501	VMAT-MCO plan deliverability was confirmed and dosimetric measurements showed a slight improvement in gamma passing rate average for VMAT-MCO  as compared to IMRT-MCO .	('MCO', 'Chemical', '-', (163, 166))	('VMAT-MCO', 'Var', (133, 141))	('improvement', 'PosReg', (87, 98))	('MCO', 'Chemical', '-', (5, 8))	('gamma passing rate', 'MPA', (102, 120))	('MCO', 'Chemical', '-', (138, 141))
361647	27929501	This study highlights the advantages in treatment efficiency and uncompromised plan quality made possible by VMAT-MCO as compared to IMRT-MCO.	('MCO', 'Chemical', '-', (114, 117))	('VMAT-MCO', 'Var', (109, 117))	('MCO', 'Chemical', '-', (138, 141))	('advantages', 'PosReg', (26, 36))
361707	31653220	The NF-kappaB protein family consists of five members, p65 (RelA), RelB, c-Rel, p105 (p50), and p100 (p52), which exist as homo- or heterodimers.	('RelA', 'Gene', '101096604', (60, 64))	('RelA', 'Gene', (60, 64))	('p100', 'Var', (96, 100))	('NF-kappaB', 'Gene', '4790', (4, 13))	('p65', 'Var', (55, 58))	('RelB', 'Gene', '101085762', (67, 71))	('NF-kappaB', 'Gene', (4, 13))	('p105', 'Var', (80, 84))	('RelB', 'Gene', (67, 71))
361713	31653220	With the broad effects of NF-kappaB, most NF-kappaB inhibitors bring side effects, such as bone marrow toxicity identified in animal studies, since hematopoietic cells rely on the NF-kappaB signaling pathway.	('NF-kappaB', 'Gene', '4790', (26, 35))	('NF-kappaB', 'Gene', (26, 35))	('NF-kappaB', 'Gene', '4790', (42, 51))	('bone marrow toxicity', 'Disease', (91, 111))	('NF-kappaB', 'Gene', '4790', (180, 189))	('inhibitors', 'Var', (52, 62))	('NF-kappaB', 'Gene', (42, 51))	('NF-kappaB', 'Gene', (180, 189))	('bone marrow toxicity', 'Disease', 'MESH:D001855', (91, 111))
361730	31653220	Positivity of alpha-SMA and negativity of desmin, taken together, are able to conclude the diagnosis of these three cases as myofibroblast-rich sarcoma.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('desmin', 'Gene', (42, 48))	('desmin', 'Gene', '101097010', (42, 48))	('negativity', 'Var', (28, 38))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('Positivity', 'Var', (0, 10))	('alpha-SMA', 'Protein', (14, 23))
361732	31653220	After application of NF-kappaB inhibitor DHMEQ to tumor cells, as expected, nuclear translocation of p65 NF-kappaB was successfully suppressed (Fig.	('DHMEQ', 'Chemical', 'MESH:C464444', (41, 46))	('NF-kappaB', 'Gene', '4790', (105, 114))	('NF-kappaB', 'Gene', (105, 114))	('NF-kappaB', 'Gene', '4790', (21, 30))	('nuclear translocation', 'MPA', (76, 97))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('NF-kappaB', 'Gene', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('p65', 'Var', (101, 104))	('tumor', 'Disease', (50, 55))	('suppressed', 'NegReg', (132, 142))
361741	31653220	As the FISS cells treated with the DHMEQ at concentrations higher than 20 mug/ml already resulted in cell detachment, the experiment was performed by treating FISS cells with 20, 10, 5, and 2.5 mug/ml DHMEQ, DMSO alone, and only 0.1% serum medium for 24 h. Wound healing was significantly inhibited by DHMEQ at the concentration of 10 mug/ml for FISS-07, and 20 mug/ml for FISS-08 and FISS-10 (P < 0.05) (Fig.	('DMSO', 'Chemical', 'MESH:D004121', (208, 212))	('DHMEQ', 'Chemical', 'MESH:C464444', (302, 307))	('DHMEQ', 'Chemical', 'MESH:C464444', (35, 40))	('DHMEQ', 'Var', (302, 307))	('DHMEQ', 'Chemical', 'MESH:C464444', (201, 206))	('Wound healing', 'CPA', (257, 270))	('inhibited', 'NegReg', (289, 298))
361743	31653220	To evaluate the ability of DHMEQ to reduce clonogenic survival of FISS cells, a clonogenic assay was performed.	('DHMEQ', 'Chemical', 'MESH:C464444', (27, 32))	('DHMEQ', 'Var', (27, 32))	('reduce', 'NegReg', (36, 42))	('clonogenic survival of FISS cells', 'CPA', (43, 76))
361745	31653220	Our result demonstrated that the colony formation was significantly inhibited by DHMEQ at a concentration of 20 mug/ml for FISS-08 and 10 mug/ml for FISS-10 (P < 0.05) (Fig.	('colony formation', 'CPA', (33, 49))	('DHMEQ', 'Chemical', 'MESH:C464444', (81, 86))	('inhibited', 'NegReg', (68, 77))	('DHMEQ', 'Var', (81, 86))
361762	31653220	In cell proliferation assays, DHMEQ caused significant inhibition of cell growth, with an IC50 of approximately 14-17 mug/ml, indicating that activation of NF-kappaB acts in a key role in the proliferation of these cells.	('DHMEQ', 'Var', (30, 35))	('NF-kappaB', 'Gene', '4790', (156, 165))	('DHMEQ', 'Chemical', 'MESH:C464444', (30, 35))	('NF-kappaB', 'Gene', (156, 165))	('inhibition', 'NegReg', (55, 65))	('cell growth', 'CPA', (69, 80))
361768	31653220	DHMEQ in the present study caused a dose-dependent increase in the levels of DNA breakage in FISS cells, which is a hallmark of apoptotic cell death.	('increase', 'PosReg', (51, 59))	('DNA breakage in', 'MPA', (77, 92))	('levels', 'MPA', (67, 73))	('DHMEQ', 'Chemical', 'MESH:C464444', (0, 5))	('DHMEQ', 'Var', (0, 5))
361769	31653220	Furthermore, FISS-07 cells may be more dependent on the survival benefits resulting from NF-kappaB activation than other cells, since DHMEQ at 10 and 20 mug/ml caused a higher degree of apoptosis than in FISS-08 and FISS-10 cells.	('NF-kappaB', 'Gene', '4790', (89, 98))	('NF-kappaB', 'Gene', (89, 98))	('DHMEQ', 'Chemical', 'MESH:C464444', (134, 139))	('apoptosis', 'CPA', (186, 195))	('DHMEQ', 'Var', (134, 139))
361771	31653220	In other functional assays, DHMEQ at concentrations of 10 and 20 mug/ml was able to significantly decrease cell migration in FISS-07, FISS-08 and FISS-10 and colonization in FISS-08 and FISS-10, which are key steps in tumor expansion and invasiveness.	('DHMEQ', 'Var', (28, 33))	('decrease', 'NegReg', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('cell migration', 'CPA', (107, 121))	('colonization', 'CPA', (158, 170))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('DHMEQ', 'Chemical', 'MESH:C464444', (28, 33))
361801	31653220	Immunocytochemistry staining was used to characterize the phenotypes of the primary cell cultures with their corresponding FFPE section cells, and to confirm if NF-kappaB inhibitor, DHMEQ, would inhibit nuclear translocation of p65 NF-kappaB in cell culture or not.	('NF-kappaB', 'Gene', '4790', (232, 241))	('nuclear translocation', 'MPA', (203, 224))	('NF-kappaB', 'Gene', '4790', (161, 170))	('DHMEQ', 'Var', (182, 187))	('NF-kappaB', 'Gene', (232, 241))	('NF-kappaB', 'Gene', (161, 170))	('inhibit', 'NegReg', (195, 202))	('p65', 'Protein', (228, 231))	('DHMEQ', 'Chemical', 'MESH:C464444', (182, 187))
361954	27688604	Eribulin was associated with a significant 2-month improvement in median overall survival compared to dacarbazine (13.5 vs. 11.5 months, heart rate: 0.768) despite no documented significant difference in progression-free survival.	('Eribulin', 'Chemical', 'MESH:C490954', (0, 8))	('improvement', 'PosReg', (51, 62))	('dacarbazine', 'Chemical', 'MESH:D003606', (102, 113))	('Eribulin', 'Var', (0, 8))	('overall survival', 'MPA', (73, 89))
361977	27688604	These changes to the microenvironment alleviate the tumor-induced hypoxia and may possibly enhance the efficacy of subsequent drug therapies through the reduction of hypoxia-driven chemoresistance and the enhancement of intratumoral delivery of drugs.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('drug therapies', 'CPA', (126, 140))	('reduction', 'NegReg', (153, 162))	('enhancement', 'PosReg', (205, 216))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('alleviate', 'NegReg', (38, 47))	('tumor', 'Disease', (225, 230))	('changes', 'Var', (6, 13))	('efficacy', 'CPA', (103, 111))	('hypoxia', 'Disease', (66, 73))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('hypoxia', 'Disease', 'MESH:D000860', (166, 173))	('enhance', 'PosReg', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('hypoxia', 'Disease', (166, 173))
362022	27688604	Furthermore, patients with a PS of 0 had a better survival outcome with eribulin (19.9 vs. 13.1 months, HR: 0.579; 95%CI: 0.407-0.823) compared to patients with a PS of 1-2 (9.2 vs. 9.9 months, HR: 1.09; 95%CI: 0.82-1.44).	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (13, 21))	('survival', 'MPA', (50, 58))	('eribulin', 'Var', (72, 80))
362048	27688604	Compared to previously approved therapies for soft tissue sarcoma, eribulin is the first to demonstrate a statistically significant improvement in OS.	('OS', 'Chemical', '-', (147, 149))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (46, 65))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (46, 65))	('improvement', 'PosReg', (132, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('soft tissue sarcoma', 'Disease', (46, 65))	('eribulin', 'Var', (67, 75))
362089	24575008	Molecular analysis, performed on formalin-fixed paraffin-embedded tissue by fluorescent in situ hybridization (FISH), showed a SYT gene rearrangement, highly consistent with the diagnosis of a monophasic SVS, fibrous type.	('rearrangement', 'Var', (136, 149))	('paraffin', 'Chemical', 'MESH:D010232', (48, 56))	('men', 'Species', '9606', (145, 148))	('formalin', 'Chemical', 'MESH:D005557', (33, 41))	('SYT', 'Gene', '6857', (127, 130))	('SYT', 'Gene', (127, 130))	('SVS', 'Phenotype', 'HP:0012570', (204, 207))
362153	21403834	Most desmoid tumors arise via perturbations within the wnt signaling pathway (Figure 2).	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('arise via', 'Reg', (20, 29))	('wnt signaling pathway', 'Pathway', (55, 76))	('perturbations', 'Var', (30, 43))	('desmoid tumors', 'Disease', (5, 19))	('desmoid tumor', 'Phenotype', 'HP:0100245', (5, 18))	('desmoid tumors', 'Disease', 'MESH:C535944', (5, 19))	('desmoid tumors', 'Phenotype', 'HP:0100245', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
362154	21403834	In FAP, desmoid tumors arise from mutations in the adenomatous polyposis coli (APC) gene, located on chromosome 5q21-22, which encodes a tumor suppressor protein, although its function may be more complex than simply a tumor suppressor.	('desmoid tumors', 'Disease', (8, 22))	('tumor', 'Disease', (219, 224))	('APC', 'Phenotype', 'HP:0005227', (79, 82))	('APC', 'Disease', 'MESH:D011125', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('desmoid tumors', 'Disease', 'MESH:C535944', (8, 22))	('APC', 'Disease', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('arise from', 'Reg', (23, 33))	('mutations', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('desmoid tumor', 'Phenotype', 'HP:0100245', (8, 21))	('FAP', 'Disease', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('FAP', 'Disease', 'MESH:C567782', (3, 6))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (51, 77))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (51, 77))	('desmoid tumors', 'Phenotype', 'HP:0100245', (8, 22))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('adenomatous polyposis coli', 'Disease', (51, 77))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (51, 72))
362155	21403834	Inactivation of APC leads to nuclear accumulation of beta-catenin, causing increased transcription and cell proliferation.	('transcription', 'MPA', (85, 98))	('cell proliferation', 'CPA', (103, 121))	('nuclear accumulation', 'MPA', (29, 49))	('beta-catenin', 'Gene', (53, 65))	('APC', 'Phenotype', 'HP:0005227', (16, 19))	('increased', 'PosReg', (75, 84))	('beta-catenin', 'Gene', '1499', (53, 65))	('APC', 'Disease', 'MESH:D011125', (16, 19))	('Inactivation', 'Var', (0, 12))	('APC', 'Disease', (16, 19))
362156	21403834	Most APC mutations associated with desmoid tumors are found 3' to codon 1400.	('APC', 'Disease', 'MESH:D011125', (5, 8))	('APC', 'Disease', (5, 8))	('desmoid tumors', 'Phenotype', 'HP:0100245', (35, 49))	('mutations', 'Var', (9, 18))	('desmoid tumors', 'Disease', 'MESH:C535944', (35, 49))	('desmoid tumor', 'Phenotype', 'HP:0100245', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('desmoid tumors', 'Disease', (35, 49))	('APC', 'Phenotype', 'HP:0005227', (5, 8))
362157	21403834	Some sporadic desmoid tumors also arise from APC inactivation but most (>80%) are APC wild type with activating mutations of the CTNNB1 gene, which is located on chromosome 3p22-p21.3.	('APC', 'Disease', 'MESH:D011125', (82, 85))	('APC', 'Phenotype', 'HP:0005227', (45, 48))	('APC', 'Disease', (82, 85))	('CTNNB1', 'Gene', (129, 135))	('desmoid tumors', 'Phenotype', 'HP:0100245', (14, 28))	('desmoid tumor', 'Phenotype', 'HP:0100245', (14, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (112, 121))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))	('CTNNB1', 'Gene', '1499', (129, 135))	('sporadic desmoid tumors', 'Disease', (5, 28))	('sporadic desmoid tumors', 'Disease', 'MESH:C535944', (5, 28))	('activating', 'PosReg', (101, 111))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('APC', 'Phenotype', 'HP:0005227', (82, 85))
362159	21403834	Mutations almost exclusively occur at codons 41 and 45 in exon 3 of CTNNB1 ; mutational analysis of CTNNB1 is usually not necessary in typical cases of desmoids tumors but can be helpful in unusual cases as well as helpful in distinguishing recurrent desmoid from scar.	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('scar', 'Phenotype', 'HP:0100699', (264, 268))	('CTNNB1', 'Gene', (68, 74))	('mutational', 'Var', (77, 87))	('CTNNB1', 'Gene', (100, 106))	('desmoids tumors', 'Phenotype', 'HP:0100245', (152, 167))	('CTNNB1', 'Gene', '1499', (68, 74))	('CTNNB1', 'Gene', '1499', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('desmoids tumors', 'Disease', 'MESH:C535944', (152, 167))	('desmoids tumors', 'Disease', (152, 167))
362160	21403834	It remains to be determined whether particular CTNNB1 mutations help predict local recurrence after surgical resection.	('CTNNB1', 'Gene', (47, 53))	('mutations', 'Var', (54, 63))	('local recurrence', 'CPA', (77, 93))	('CTNNB1', 'Gene', '1499', (47, 53))
362161	21403834	One report found that tumors harboring S45F mutations in exon 3 of CTNNB1 had significantly poorer disease-free survival compared to wild-type tumors or codon 41 mutants, whereas another report showed no significant differences in recurrence-free survival among CTNNB1 mutants but did show worse outcome among all mutants compared to wild-type tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (344, 350))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('CTNNB1', 'Gene', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('S45F', 'Mutation', 'rs121913409', (39, 43))	('tumors', 'Disease', (22, 28))	('CTNNB1', 'Gene', '1499', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('disease-free survival', 'CPA', (99, 120))	('S45F mutations in', 'Var', (39, 56))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('CTNNB1', 'Gene', '1499', (67, 73))	('tumors', 'Disease', (344, 350))	('CTNNB1', 'Gene', (262, 268))	('poorer', 'NegReg', (92, 98))
362163	21403834	In our experience, beta-catenin immunohistochemistry is less reliable than the literature reports, particularly in needle biopsies, and molecular testing for mutations in the beta-catenin gene may be more reliable.	('beta-catenin', 'Gene', '1499', (19, 31))	('beta-catenin', 'Gene', '1499', (175, 187))	('beta-catenin', 'Gene', (19, 31))	('mutations', 'Var', (158, 167))	('beta-catenin', 'Gene', (175, 187))
362176	21403834	Tumors with ALK rearrangements are associated with younger age and strongly correlate with ALK protein expression detected by immunohistochemistry in some labs, but in other labs ALK immunohistochemistry is nearly always negative.	('ALK', 'Gene', (12, 15))	('ALK', 'Gene', '238', (179, 182))	('ALK', 'Gene', (91, 94))	('ALK', 'Gene', '238', (12, 15))	('ALK', 'Gene', '238', (91, 94))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ALK', 'Gene', (179, 182))	('rearrangements', 'Var', (16, 30))	('correlate', 'Reg', (76, 85))
362186	21403834	This resistance was suspected to occur via the neuroblastoma-associated F1174L ALK mutation that has been well studied in neuroblastomas as a mechanism of resistance to some ALK inhibitors.	('ALK', 'Gene', '238', (79, 82))	('ALK', 'Gene', (174, 177))	('neuroblastoma', 'Disease', 'MESH:D009447', (47, 60))	('neuroblastomas', 'Disease', 'MESH:D009447', (122, 136))	('neuroblastomas', 'Phenotype', 'HP:0003006', (122, 136))	('neuroblastoma', 'Disease', 'MESH:D009447', (122, 135))	('neuroblastoma', 'Disease', (47, 60))	('ALK', 'Gene', (79, 82))	('F1174L', 'Mutation', 'rs863225281', (72, 78))	('neuroblastoma', 'Disease', (122, 135))	('neuroblastoma', 'Phenotype', 'HP:0003006', (122, 135))	('neuroblastomas', 'Disease', (122, 136))	('neuroblastoma', 'Phenotype', 'HP:0003006', (47, 60))	('ALK', 'Gene', '238', (174, 177))	('F1174L', 'Var', (72, 78))
362192	21403834	ALK function is poorly characterized at this time, so it is difficult to postulate the exact mechanism of oncogenesis; nevertheless, these fusions clearly lead to a survival and growth advantage to the cells harboring the translocation.	('survival', 'CPA', (165, 173))	('fusions', 'Var', (139, 146))	('ALK', 'Gene', (0, 3))	('lead to', 'Reg', (155, 162))	('growth advantage', 'CPA', (178, 194))	('translocation', 'Var', (222, 235))	('ALK', 'Gene', '238', (0, 3))
362197	21403834	A few patients with germline PDGFRA mutations have been reported in the literature.	('PDGFRA', 'Gene', '5156', (29, 35))	('patients', 'Species', '9606', (6, 14))	('PDGFRA', 'Gene', (29, 35))	('mutations', 'Var', (36, 45))
362199	21403834	IFPs are rare benign tumors of uncertain histogenesis and were considered reactive processes, but recently, mutations in platelet-derived growth factor receptor alpha (PDGFRA, chromosome 4q12) were described in IFPs located in the stomach and small bowel.	('PDGFRA', 'Gene', (168, 174))	('PDGFRA', 'Gene', '5156', (168, 174))	('mutations', 'Var', (108, 117))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (121, 166))	('tumors', 'Disease', (21, 27))	('IFPs', 'Disease', (211, 215))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('platelet-derived growth factor receptor alpha', 'Gene', (121, 166))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('described', 'Reg', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
362201	21403834	In the small bowel series, 33/60 (55%) harbored mutations in PDGFRA, 31 of which were located in exon 12, and 2 were in exon 18.	('PDGFRA', 'Gene', '5156', (61, 67))	('mutations', 'Var', (48, 57))	('harbored', 'Reg', (39, 47))	('PDGFRA', 'Gene', (61, 67))
362214	21403834	As discussed below, rearrangements in the EWRS1 gene occur in CCS, not melanoma, which can be invaluable in separating CCS from melanoma.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('rearrangements', 'Var', (20, 34))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('CCS', 'Disease', (62, 65))	('EWRS1', 'Gene', (42, 47))	('occur', 'Reg', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
362218	21403834	More than 90% of CCS of soft tissue are associated with the reciprocal translocation t(12;22)(q13;q12), which results in fusion of the EWSR1 gene and the ATF1 gene.	('ATF1', 'Gene', (154, 158))	('CCS of', 'Disease', (17, 23))	('ATF1', 'Gene', '466', (154, 158))	('EWSR1', 'Gene', (135, 140))	('fusion', 'Var', (121, 127))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (85, 102))	('EWSR1', 'Gene', '2130', (135, 140))	('associated', 'Reg', (40, 50))
362226	21403834	In EWSR1/ATF1 translocations, the activating domain of EWSR1 replaces the kinase inducible domain of ATF1, and the protein product has been shown to bind to microphthalmia-associated transcription factor, which in turn activates melanocyte stimulating hormone.	('translocations', 'Var', (14, 28))	('microphthalmia', 'Disease', (157, 171))	('EWSR1', 'Gene', (55, 60))	('bind', 'Interaction', (149, 153))	('microphthalmia', 'Disease', 'MESH:D008850', (157, 171))	('ATF1', 'Gene', (101, 105))	('ATF1', 'Gene', '466', (101, 105))	('EWSR1', 'Gene', '2130', (3, 8))	('EWSR1', 'Gene', '2130', (55, 60))	('microphthalmia', 'Phenotype', 'HP:0000568', (157, 171))	('ATF1', 'Gene', (9, 13))	('melanocyte stimulating hormone', 'MPA', (229, 259))	('ATF1', 'Gene', '466', (9, 13))	('activating domain', 'MPA', (34, 51))	('EWSR1', 'Gene', (3, 8))	('activates', 'PosReg', (219, 228))
362230	21403834	It remains to be determined whether these S-100 protein positive tumors harboring EWSR1 translocations represent a clinical, morphologic, immunophenotype, and genetic spectrum of one tumor or are two distinct tumors.	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('translocations', 'Var', (88, 102))	('tumors', 'Disease', (65, 71))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', (65, 70))	('S-100', 'Gene', (42, 47))	('S-100', 'Gene', '6285', (42, 47))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('EWSR1', 'Gene', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumor', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Disease', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('EWSR1', 'Gene', '2130', (82, 87))
362237	21403834	The characteristic molecular alteration in SS is the t(X;18)(p11;q11) translocation, which usually fuses SYT on chromosome 18 with SSX1 or SSX2 on the X chromosome.	('SSX1', 'Gene', (131, 135))	('t(X;18)(p11;q11', 'Var', (53, 68))	('SS', 'Phenotype', 'HP:0012570', (43, 45))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 69))	('SS', 'Phenotype', 'HP:0012570', (139, 141))	('SSX2', 'Gene', (139, 143))	('SYT', 'Gene', (105, 108))	('SS', 'Phenotype', 'HP:0012570', (131, 133))	('fuses', 'NegReg', (99, 104))	('SYT', 'Gene', '6760', (105, 108))	('SSX1', 'Gene', '6756', (131, 135))	('SSX2', 'Gene', '6757', (139, 143))
362241	21403834	Other genetic events may be necessary for sarcomagenesis and other molecular alterations have been described, including ERBB2 expression, IGF2 upregulation, CD44 repression, PTEN inactivation, and mutations associated with the wnt pathway.	('PTEN', 'Gene', '5728', (174, 178))	('sarcomagenesis', 'Disease', 'None', (42, 56))	('IGF2', 'Gene', (138, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('ERBB2', 'Gene', '2064', (120, 125))	('inactivation', 'Var', (179, 191))	('PTEN', 'Gene', (174, 178))	('CD44', 'Gene', '960', (157, 161))	('ERBB2', 'Gene', (120, 125))	('mutations', 'Var', (197, 206))	('CD44', 'Gene', (157, 161))	('wnt pathway', 'Pathway', (227, 238))	('upregulation', 'PosReg', (143, 155))	('IGF2', 'Gene', '3481', (138, 142))	('sarcomagenesis', 'Disease', (42, 56))	('repression', 'NegReg', (162, 172))
362262	21403834	In addition, GI schwannomas show no NF2 mutations and only rare LOH of ch.	('NF2', 'Gene', '4771', (36, 39))	('schwannomas', 'Phenotype', 'HP:0100008', (16, 27))	('NF2', 'Gene', (36, 39))	('mutations', 'Var', (40, 49))	('GI schwannomas', 'Disease', 'MESH:D009442', (13, 27))	('GI schwannomas', 'Disease', (13, 27))
362265	21403834	A recent study reported BRAF mutations in 63% of the epithelial component of these polyps.	('mutations', 'Var', (29, 38))	('polyps', 'Disease', (83, 89))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('polyps', 'Disease', 'MESH:D011127', (83, 89))
362271	21403834	No molecular characterization of GI lipomas exists; conventional soft tissue lipomas exhibit abnormal karyotypes in about 60% of cases, most commonly involving rearrangement of chromosome 12q13~15 encompassing the chromatin remodeling gene HGMA2 .	('involving', 'Reg', (150, 159))	('lipomas', 'Disease', (36, 43))	('lipomas', 'Disease', 'MESH:D008067', (77, 84))	('HGMA2', 'Gene', (240, 245))	('lipomas', 'Disease', 'MESH:D008067', (36, 43))	('lipomas', 'Disease', (77, 84))	('GI lipomas', 'Disease', 'MESH:D008067', (33, 43))	('lipomas', 'Phenotype', 'HP:0012032', (77, 84))	('GI lipomas', 'Disease', (33, 43))	('lipomas', 'Phenotype', 'HP:0012032', (36, 43))	('rearrangement', 'Var', (160, 173))
362286	21403834	Powerful prognostic data also is emerging such as in inflammatory myofibroblastic tumor with ALK rearrangements and possibly CTNNB1 mutations in desmoids.	('inflammatory myofibroblastic tumor', 'Disease', (53, 87))	('ALK', 'Gene', '238', (93, 96))	('mutations', 'Var', (132, 141))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (66, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CTNNB1', 'Gene', (125, 131))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (53, 87))	('rearrangements', 'Var', (97, 111))	('ALK', 'Gene', (93, 96))	('CTNNB1', 'Gene', '1499', (125, 131))
362321	33567690	Cancer cells expressing high GS are self-sufficient for glutamine and can survive in glutamine-deprived conditions.	('glutamine', 'Chemical', 'MESH:D005973', (56, 65))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('glutamine', 'MPA', (56, 65))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('high GS', 'Var', (24, 31))	('glutamine', 'Chemical', 'MESH:D005973', (85, 94))
362346	33567690	In addition, inhibition of glutamine uptake by its transporter (ASCT2, SNAT2, and LAT2) inhibitors blocks the proliferation of OD cells.	('blocks', 'NegReg', (99, 105))	('SNAT2', 'Gene', (71, 76))	('LAT2', 'Gene', (82, 86))	('inhibition', 'Var', (13, 23))	('ASCT2', 'Gene', '6510', (64, 69))	('LAT2', 'Gene', '7462', (82, 86))	('proliferation of OD cells', 'CPA', (110, 135))	('ASCT2', 'Gene', (64, 69))	('SNAT2', 'Gene', '54407', (71, 76))	('inhibitors', 'Var', (88, 98))	('glutamine', 'Protein', (27, 36))	('glutamine', 'Chemical', 'MESH:D005973', (27, 36))
362364	33567690	Moreover, a recent study reported that beta-catenin mutation induces metabolic changes and autophagy, increasing the sensitivity of HCC cells to sorafenib by regulating GS expression.	('induces', 'Reg', (61, 68))	('sensitivity', 'MPA', (117, 128))	('metabolic changes', 'CPA', (69, 86))	('HCC', 'Phenotype', 'HP:0001402', (132, 135))	('regulating', 'Reg', (158, 168))	('sorafenib', 'Chemical', 'MESH:D000077157', (145, 154))	('increasing', 'PosReg', (102, 112))	('beta-catenin', 'Protein', (39, 51))	('mutation', 'Var', (52, 60))	('autophagy', 'CPA', (91, 100))
362371	33567690	Furthermore, YAP1 is co-expressed with beta-catenin, and YAP1/beta-catenin mutants induce GS promoter activity in HB.	('HB', 'Phenotype', 'HP:0002884', (114, 116))	('GS promoter activity', 'MPA', (90, 110))	('YAP1', 'Gene', '10413', (57, 61))	('induce', 'PosReg', (83, 89))	('mutants', 'Var', (75, 82))	('YAP1', 'Gene', '10413', (13, 17))	('YAP1', 'Gene', (57, 61))	('YAP1', 'Gene', (13, 17))
362380	33567690	GLUL knockdown inhibits the proliferation of HER2-positive SK-BR-3 cells, which express higher GS than other types of breast cancer cells by blocking the ERK and p38 MAPK signaling pathways.	('proliferation', 'CPA', (28, 41))	('knockdown', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('HER2', 'Gene', '2064', (45, 49))	('ERK', 'Gene', '5594', (154, 157))	('blocking', 'NegReg', (141, 149))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('inhibits', 'NegReg', (15, 23))	('ERK', 'Gene', (154, 157))	('HER2', 'Gene', (45, 49))	('SK-BR-3', 'CellLine', 'CVCL:0033', (59, 66))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
362386	33567690	The tumor growth is suppressed when GS is overexpressed in OVC cells expressing low GS (GSlow OVC cells) in vitro and in vivo.	('tumor', 'Disease', (4, 9))	('suppressed', 'NegReg', (20, 30))	('OVC', 'Phenotype', 'HP:0100615', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('OVC', 'Phenotype', 'HP:0100615', (94, 97))	('low GS', 'Var', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
362387	33567690	In line with this result, inhibition of the glutamine transporter ASCT2 is more effective in impeding proliferation of GSlow OVC cells than GShigh OVC cells.	('ASCT2', 'Gene', '6510', (66, 71))	('ASCT2', 'Gene', (66, 71))	('impeding', 'NegReg', (93, 101))	('inhibition', 'Var', (26, 36))	('OVC', 'Phenotype', 'HP:0100615', (147, 150))	('glutamine', 'Chemical', 'MESH:D005973', (44, 53))	('proliferation', 'CPA', (102, 115))	('OVC', 'Phenotype', 'HP:0100615', (125, 128))
362394	33567690	In addition, GLUL mRNA level, but not GLS1, is increased in KRAS mutated non-small cell lung cancer (NSCLC) compared to wild-type.	('lung cancer', 'Disease', (88, 99))	('GLS1', 'Gene', (38, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('NSCLC', 'Disease', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('GLUL mRNA level', 'MPA', (13, 28))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('increased', 'PosReg', (47, 56))	('KRAS', 'Gene', (60, 64))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (73, 99))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (77, 99))	('KRAS', 'Gene', '3845', (60, 64))	('GLS1', 'Gene', '2744', (38, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))	('mutated', 'Var', (65, 72))
362397	33567690	PC knockdown decreases NSCLC cell proliferation, colony formation, and tumor growth in a mouse xenograft model.	('decreases', 'NegReg', (13, 22))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('NSCLC', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('knockdown', 'Var', (3, 12))	('tumor', 'Disease', (71, 76))	('colony formation', 'CPA', (49, 65))	('mouse', 'Species', '10090', (89, 94))
362402	33567690	Conversely, GS knockout decreases sensitivity to gefitinib and induces metastasis.	('decreases', 'NegReg', (24, 33))	('knockout', 'Var', (15, 23))	('sensitivity to gefitinib', 'MPA', (34, 58))	('gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))	('metastasis', 'CPA', (71, 81))	('induces', 'Reg', (63, 70))
362404	33567690	showed that GS ablation induces drug resistance by increasing the capacity of the malate-aspartate shuttle, which increases metabolic fitness, escaping drug pressure.	('drug resistance', 'MPA', (32, 47))	('ablation', 'Var', (15, 23))	('metabolic fitness', 'Disease', (124, 141))	('metabolic fitness', 'Disease', 'MESH:D012640', (124, 141))	('escaping drug pressure', 'MPA', (143, 165))	('malate', 'Chemical', 'MESH:C030298', (82, 88))	('malate-aspartate shuttle', 'MPA', (82, 106))	('induces', 'Reg', (24, 31))	('increases', 'PosReg', (114, 123))	('aspartate', 'Chemical', 'MESH:D001224', (89, 98))	('drug resistance', 'Phenotype', 'HP:0020174', (32, 47))	('increasing', 'PosReg', (51, 61))
362414	33567690	Moreover, GLUL ablation suppresses LSL-KrasG12D/+; Trp53f/f; Pdx1-Cre (KPC) tumor growth and increases the survival of mice.	('mice', 'Species', '10090', (119, 123))	('ablation', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('increases', 'PosReg', (93, 102))	('Trp53', 'Gene', (51, 56))	('survival', 'CPA', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('suppresses', 'NegReg', (24, 34))	('Trp53', 'Gene', '22059', (51, 56))	('Pdx1', 'Gene', (61, 65))	('LSL-KrasG12D/+', 'Var', (35, 49))	('Pdx1', 'Gene', '18609', (61, 65))
362429	33567690	GS knockdown in irradiated NPC cells increases basal respiration, mitochondrial ATP, basal glycolysis, and energy anaplerosis ability.	('basal glycolysis', 'MPA', (85, 101))	('energy anaplerosis ability', 'Disease', 'MESH:D011502', (107, 133))	('energy anaplerosis ability', 'Disease', (107, 133))	('increases', 'PosReg', (37, 46))	('knockdown', 'Var', (3, 12))	('basal respiration', 'MPA', (47, 64))	('NPC', 'Phenotype', 'HP:0100630', (27, 30))	('mitochondrial ATP', 'MPA', (66, 83))	('ATP', 'Chemical', 'MESH:D000255', (80, 83))
362430	33567690	In addition, GS promotes radiation-induced G2/M arrest recovery, and genetic ablation of GS re-sensitizes radiation-resistant NPC cells to radiation therapy in vivo.	('promotes', 'PosReg', (16, 24))	('M arrest', 'Disease', 'MESH:D006323', (46, 54))	('M arrest', 'Disease', (46, 54))	('radiation-induced', 'CPA', (25, 42))	('genetic ablation', 'Var', (69, 85))	('NPC', 'Phenotype', 'HP:0100630', (126, 129))
362442	33567690	These findings show that CAFs increases glutamine synthesis through dysregulated metabolism compared to NOFs.	('dysregulated metabolism', 'MPA', (68, 91))	('CAFs', 'Var', (25, 29))	('glutamine', 'Chemical', 'MESH:D005973', (40, 49))	('glutamine synthesis', 'MPA', (40, 59))	('increases', 'PosReg', (30, 39))	('increases glutamine synthesis', 'Phenotype', 'HP:0003217', (30, 59))
362454	33567690	Similar to ALL, PDAC cells use glutamine produced by GShigh adipocyte, and cell proliferation is supported by GShigh adipocyte.	('glutamine', 'Chemical', 'MESH:D005973', (31, 40))	('GShigh adipocyte', 'Var', (110, 126))	('ALL', 'Phenotype', 'HP:0006721', (11, 14))	('glutamine produced', 'MPA', (31, 49))	('cell proliferation', 'CPA', (75, 93))
362460	33567690	GS inhibition also suppresses vascularization by regulating endothelial capillary formation and metastasis by modulating cancer cell motility.	('metastasis', 'CPA', (96, 106))	('endothelial capillary formation', 'CPA', (60, 91))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('suppresses', 'NegReg', (19, 29))	('inhibition', 'Var', (3, 13))	('modulating', 'Reg', (110, 120))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('vascularization', 'CPA', (30, 45))	('cancer', 'Disease', (121, 127))
362461	33567690	GS inhibition suppresses angiogenesis of ocular and inflammatory skin disease without affecting healthy endothelial cells.	('skin disease', 'Phenotype', 'HP:0000951', (65, 77))	('inhibition', 'Var', (3, 13))	('skin disease', 'Disease', (65, 77))	('inflammatory skin disease', 'Phenotype', 'HP:0011123', (52, 77))	('skin disease', 'Disease', 'MESH:D012871', (65, 77))	('angiogenesis', 'CPA', (25, 37))	('ocular', 'Disease', (41, 47))	('suppresses', 'NegReg', (14, 24))
362472	33567690	GS silencing inhibits such effect of Myc activation.	('silencing', 'Var', (3, 12))	('inhibits', 'NegReg', (13, 21))	('Myc', 'Gene', '4609', (37, 40))	('Myc', 'Gene', (37, 40))
362473	33567690	Labeled ribonucleoside is not significantly increased in Myc-overexpressing MCF10A cells, whereas GS silencing markedly reduced the 15N incorporation into the ribonucleoside.	('15N', 'Chemical', '-', (132, 135))	('ribonucleoside', 'Chemical', 'MESH:D012263', (8, 22))	('Myc', 'Gene', '4609', (57, 60))	('MCF10A', 'CellLine', 'CVCL:0598', (76, 82))	('Myc', 'Gene', (57, 60))	('15N incorporation into the ribonucleoside', 'MPA', (132, 173))	('silencing', 'Var', (101, 110))	('ribonucleoside', 'Chemical', 'MESH:D012263', (159, 173))	('reduced', 'NegReg', (120, 127))
362478	33567690	Among them, the S45F mutant increases reporter activity to the greatest extent.	('reporter activity', 'MPA', (38, 55))	('S45F', 'Var', (16, 20))	('increases', 'PosReg', (28, 37))	('S45F', 'Mutation', 'rs780361249', (16, 20))
362482	33567690	Silencing of GATA3 reduces both GS mRNA and protein levels in MCF7, the luminal type cells.	('MCF7', 'CellLine', 'CVCL:0031', (62, 66))	('luminal', 'Chemical', 'MESH:D010634', (72, 79))	('Silencing', 'Var', (0, 9))	('MCF7', 'Gene', (62, 66))	('GATA3', 'Gene', (13, 18))	('reduces', 'NegReg', (19, 26))
362489	33567690	GLUL mRNA is upregulated in YAP transgenic zebrafish liver, and YAP inhibition decreases GS expression.	('decreases', 'NegReg', (79, 88))	('transgenic', 'Var', (32, 42))	('upregulated', 'PosReg', (13, 24))	('GS expression', 'MPA', (89, 102))	('zebrafish', 'Species', '7955', (43, 52))
362525	33567690	The factors affecting glutamine's fate in cancers include tissue of origin, genetic mutation, presence of the drug, and culture methods.	('cancers', 'Disease', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('genetic mutation', 'Var', (76, 92))	('glutamine', 'Chemical', 'MESH:D005973', (22, 31))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
362542	33567690	If the role of the transcriptional or epigenetic regulators of GS in cancer is clearly identified, targeting GS by its regulators could be an effective therapeutic strategy.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('epigenetic', 'Var', (38, 48))	('cancer', 'Disease', (69, 75))
362550	31988250	Deregulation of the tumor suppressive Hippo pathway is also linked to poor outcome in these patients.	('Deregulation', 'Var', (0, 12))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('linked', 'Reg', (60, 66))	('tumor', 'Disease', (20, 25))
25070	31988250	YAP1 is unusually stable in UPS and potentially other sarcomas due to epigenetic silencing of its inhibitor, Angiomotin (AMOT), and Hippo kinase copy number loss.	('YAP1', 'Gene', (0, 4))	('copy number loss', 'Var', (145, 161))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('epigenetic silencing', 'Var', (70, 90))	('Hippo', 'Protein', (132, 137))	('sarcomas', 'Disease', (54, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('AMOT', 'Gene', '154796', (121, 125))	('AMOT', 'Gene', (121, 125))	('Angiomotin', 'Gene', '154796', (109, 119))	('Angiomotin', 'Gene', (109, 119))
362572	31988250	In the present study we report that TGFbeta signaling promotes NF-kappaB activity as well, lending further support to our assertion that Hippo pathway deregulation and TGFbeta activation cooperatively enhance sarcomagenesis.	('sarcomagenesis', 'Disease', 'None', (209, 223))	('Hippo', 'Protein', (137, 142))	('activity', 'MPA', (73, 81))	('deregulation', 'Var', (151, 163))	('NF-kappaB', 'Gene', '4790', (63, 72))	('TGFbeta', 'Gene', (168, 175))	('sarcomagenesis', 'Disease', (209, 223))	('NF-kappaB', 'Gene', (63, 72))	('enhance', 'PosReg', (201, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))
362574	31988250	RHAMM is also associated with fibrosarcoma progression.	('RHAMM', 'Var', (0, 5))	('fibrosarcoma', 'Disease', (30, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('associated with', 'Reg', (14, 29))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (30, 42))	('fibrosarcoma', 'Disease', 'MESH:D005354', (30, 42))
362609	31988250	Values were divided by 1000 for graphical representation purposes.The following antibodies concentrations were used: rabbit anti-p-Smad3 (phospho S423/S425) (52903; 1:50) (Abcam), rabbit anti-Ki-67 (15580; 1:100) (Abcam), rabbit anti-CD168 antibody (124729, 1:100) (Abcam).	('Smad3', 'Gene', (131, 136))	('124729', 'Var', (250, 256))	('15580; 1:100', 'Var', (199, 211))	('CD168', 'Gene', (234, 239))	('Smad3', 'Gene', '4088', (131, 136))	('52903;', 'Var', (158, 164))	('CD168', 'Gene', '3161', (234, 239))
362631	31988250	Our recent work demonstrated that de-regulation of the Hippo pathway, which results in stabilization of YAP1, promotes UPS initiation and growth.	('de-regulation', 'Var', (34, 47))	('YAP1', 'Gene', (104, 108))	('UPS initiation', 'Disease', 'MESH:D017118', (119, 133))	('growth', 'CPA', (138, 144))	('UPS initiation', 'Disease', (119, 133))	('promotes', 'PosReg', (110, 118))	('stabilization', 'MPA', (87, 100))	('Hippo pathway', 'Pathway', (55, 68))
362636	31988250	In this model, adenovirus expressing Cre recombinase is injected into the gastrocnemius muscle, activating oncogenic Kras expression and deleting p53 in muscle progenitor cells.	('Kras', 'Gene', '3845', (117, 121))	('adenovirus', 'Species', '10508', (15, 25))	('deleting', 'Var', (137, 145))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('activating', 'PosReg', (96, 106))	('Kras', 'Gene', (117, 121))	('oncogenic', 'MPA', (107, 116))
362638	31988250	To fully characterize MAPK status in our experimental systems we evaluated p-ERK1/2 levels and sensitivity to MEKi in HT-1080 human fibrosarcoma cells, which express mutant oncogenic N-Ras (ATCC), and murine cells derived from KP tumors.	('murine', 'Species', '10090', (201, 207))	('N-Ras', 'Gene', '4893', (183, 188))	('human', 'Species', '9606', (126, 131))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (132, 144))	('KP tumors', 'Disease', (227, 236))	('fibrosarcoma', 'Disease', 'MESH:D005354', (132, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('HT-1080', 'CellLine', 'CVCL:0317', (118, 125))	('N-Ras', 'Gene', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('mutant', 'Var', (166, 172))	('fibrosarcoma', 'Disease', (132, 144))	('KP tumors', 'Disease', 'MESH:D009369', (227, 236))
362641	31988250	Lastly, we found that treating each cell type with a dose of Trametinib that halts proliferation (HT-1080; 50 nM and KP; 150 nM) results in roughly the same cellular responses.	('KP; 150 nM', 'Var', (117, 127))	('proliferation', 'CPA', (83, 96))	('halts', 'NegReg', (77, 82))	('Trametinib', 'Gene', (61, 71))	('Trametinib', 'Chemical', 'MESH:C560077', (61, 71))	('HT-1080', 'CellLine', 'CVCL:0317', (98, 105))
362643	31988250	Importantly, Yap1 is stabilized in KP GEMM tumors, and deletion of YAP1 in this system (KPY) increased tumor latency and reduced tumor weight and volume, relative to KP.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('KP GEMM tumors', 'Disease', 'MESH:D009369', (35, 49))	('Yap1', 'Gene', (13, 17))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('reduced', 'NegReg', (121, 128))	('YAP1', 'Gene', (67, 71))	('Yap1', 'Gene', '10413', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('deletion', 'Var', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('KP GEMM tumors', 'Disease', (35, 49))
362648	31988250	The majority of tumors with enhanced expression of TGFbeta pathway members including, TGFbetaR1, TGFbeta1, and SMAD3, also bear mutations in common sarcoma tumor suppressors like TP53 and ATRX, and express high levels of FOXM1, a YAP1 transcriptional target.	('ATRX', 'Gene', '546', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('TGFbeta pathway', 'Gene', (51, 66))	('tumors', 'Disease', (16, 22))	('TP53', 'Gene', (179, 183))	('FOXM1', 'Gene', '2305', (221, 226))	('mutations', 'Var', (128, 137))	('SMAD3', 'Gene', '4088', (111, 116))	('TGFbeta1', 'Gene', '7040', (97, 105))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('sarcoma tumor', 'Disease', (148, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('SMAD3', 'Gene', (111, 116))	('TGFbeta1', 'Gene', (97, 105))	('expression', 'MPA', (37, 47))	('sarcoma tumor', 'Disease', 'MESH:D012509', (148, 161))	('TP53', 'Gene', '7157', (179, 183))	('FOXM1', 'Gene', (221, 226))	('enhanced', 'PosReg', (28, 36))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('ATRX', 'Gene', (188, 192))	('TGFbetaR1', 'Gene', (86, 95))
362650	31988250	In contrast, mutations in the TGFbeta pathway are uncommon in colorectal cancer (CRC) (Supplemental Fig.	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('colorectal cancer', 'Disease', (62, 79))	('TGFbeta pathway', 'Pathway', (30, 45))	('mutations', 'Var', (13, 22))
362677	31988250	Inhibition of YAP1 suppressed HMMR levels in HT-1080 (Fig.	('HMMR levels', 'MPA', (30, 41))	('HT-1080', 'CellLine', 'CVCL:0317', (45, 52))	('YAP1', 'Gene', (14, 18))	('suppressed', 'NegReg', (19, 29))	('Inhibition', 'Var', (0, 10))
362685	31988250	Importantly, high HMMR expression correlated with poor clinical outcome in MFS patients (Fig.	('MFS', 'Disease', 'MESH:D008382', (75, 78))	('high', 'Var', (13, 17))	('MFS', 'Disease', (75, 78))	('patients', 'Species', '9606', (79, 87))	('HMMR', 'Protein', (18, 22))
362716	31988250	Lastly, we tested the hypothesis that altered Rhamm expression resulted in a feed-back loop, which modulated SMAD3 phosphorylation and TGFbeta activity.	('Rhamm', 'Gene', (46, 51))	('Rhamm', 'Gene', '3161', (46, 51))	('SMAD3', 'Gene', (109, 114))	('altered', 'Var', (38, 45))	('modulated', 'Reg', (99, 108))	('activity', 'MPA', (143, 151))	('SMAD3', 'Gene', '4088', (109, 114))
362726	31988250	Ectopic expression of Rhamm increased migration in a scratch assay, whereas loss of Yap1 reduced migration.	('increased', 'PosReg', (28, 37))	('Yap1', 'Gene', '10413', (84, 88))	('migration', 'CPA', (97, 106))	('Yap1', 'Gene', (84, 88))	('loss', 'Var', (76, 80))	('Rhamm', 'Gene', (22, 27))	('migration in a scratch assay', 'CPA', (38, 66))	('Rhamm', 'Gene', '3161', (22, 27))	('reduced', 'NegReg', (89, 96))
362727	31988250	In combination, we observed that ectopic expression of Rhamm in Yap1-depleted cells returned migration to control levels (Fig.	('Rhamm', 'Gene', '3161', (55, 60))	('Yap1', 'Gene', (64, 68))	('ectopic expression', 'Var', (33, 51))	('Rhamm', 'Gene', (55, 60))	('Yap1', 'Gene', '10413', (64, 68))	('migration', 'MPA', (93, 102))	('returned', 'PosReg', (84, 92))
362739	31988250	We and others have performed similar studies using MDA-MB-231 breast cancer cells and other tumor cell types and have observed predominantly single cell migration in MDA-MB-231, whereas other tumor cell types cluster prior to extravasation.	('single cell migration', 'CPA', (141, 162))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (51, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('MDA-MB-231', 'Var', (166, 176))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('breast cancer', 'Disease', (62, 75))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (166, 176))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
362745	31988250	The goal of our recent work has been to delineate mechanisms by which Hippo pathway deregulation contributes to sarcomagenesis.	('sarcomagenesis', 'Disease', (112, 126))	('deregulation', 'Var', (84, 96))	('contributes', 'Reg', (97, 108))	('sarcomagenesis', 'Disease', 'None', (112, 126))	('Hippo pathway', 'Pathway', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
362748	31988250	TGFbeta signaling has been shown to promote YAP1 activity through phosphorylated SMAD3.	('SMAD3', 'Gene', (81, 86))	('activity', 'MPA', (49, 57))	('promote', 'PosReg', (36, 43))	('phosphorylated', 'Var', (66, 80))	('SMAD3', 'Gene', '4088', (81, 86))	('YAP1', 'Gene', (44, 48))
362768	28720588	Therefore, the metabolic effects of silencing EF in Ewing sarcoma cells were determined.	('Ewing sarcoma', 'Disease', (52, 65))	('silencing', 'Var', (36, 45))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
362769	28720588	Mitochondrial stress tests demonstrated that knockdown of EF increased respiratory as well as glycolytic functions.	('glycolytic functions', 'MPA', (94, 114))	('respiratory', 'MPA', (71, 82))	('increased', 'PosReg', (61, 70))	('Mito', 'Species', '262676', (0, 4))	('knockdown', 'Var', (45, 54))
362772	28720588	PHGDH knockdown or pharmacological inhibition in vitro caused impaired proliferation and cell death.	('impaired', 'NegReg', (62, 70))	('PHGDH', 'Gene', '26227', (0, 5))	('PHGDH', 'Gene', (0, 5))	('cell death', 'CPA', (89, 99))	('knockdown', 'Var', (6, 15))	('inhibition', 'Var', (35, 45))
362773	28720588	Interestingly, PHGDH modulation also led to elevated histone expression and methylation.	('modulation', 'Var', (21, 31))	('histone expression', 'MPA', (53, 71))	('PHGDH', 'Gene', (15, 20))	('elevated', 'PosReg', (44, 52))	('methylation', 'MPA', (76, 87))	('PHGDH', 'Gene', '26227', (15, 20))
362782	28720588	Instead, oncogenesis of Ewing sarcoma is almost entirely due to the far-reaching consequences of a single genetic lesion: a translocation event between chromosomes 11 and 22.	('genetic lesion', 'Disease', (106, 120))	('genetic lesion', 'Disease', 'MESH:D020022', (106, 120))	('Ewing sarcoma', 'Disease', (24, 37))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (24, 37))	('translocation event', 'Var', (124, 143))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (24, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
362838	28720588	During the glycolysis stress test, addition of glucose and oligomycin caused greater increases of extracellular acidification rate (ECAR) in shEF vs. shLUC cells (Fig.	('oligomycin', 'Var', (59, 69))	('glucose', 'Chemical', 'MESH:D005947', (47, 54))	('oligomycin', 'Chemical', 'MESH:D009840', (59, 69))	('extracellular acidification rate', 'MPA', (98, 130))	('increases', 'PosReg', (85, 94))
362840	28720588	These data suggest that silencing of EF results in increased utilization of glucose by glycolysis (Table 1 & Fig.	('increased', 'PosReg', (51, 60))	('utilization of glucose by glycolysis', 'MPA', (61, 97))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('silencing', 'Var', (24, 33))
362843	28720588	The apparent increase of glycolytic rate caused by EF knockdown is surprising, and is possibly explained by de-repression of hexokinase 1 (HK1) by shEF (Fig.	('HK1', 'Gene', '3098', (139, 142))	('HK1', 'Gene', (139, 142))	('knockdown', 'Var', (54, 63))	('hexokinase 1', 'Gene', '3098', (125, 137))	('increase', 'PosReg', (13, 21))	('de-repression', 'NegReg', (108, 121))	('hexokinase 1', 'Gene', (125, 137))	('glycolytic rate', 'MPA', (25, 40))
362846	28720588	These data indicate that silencing EF results in increased maximal respiration and spare respiratory capacity, with no change in basal respiration, ATP production, proton leak, non-mitochondrial respiration, and coupling efficiency (Table 1 & Fig.	('silencing', 'Var', (25, 34))	('ATP', 'MPA', (148, 151))	('spare respiratory capacity', 'MPA', (83, 109))	('increased', 'PosReg', (49, 58))	('non-mitochondrial respiration', 'MPA', (177, 206))	('ATP', 'Chemical', 'MESH:D000255', (148, 151))	('maximal respiration', 'MPA', (59, 78))	('proton leak', 'MPA', (164, 175))	('coupling', 'MPA', (212, 220))
362850	28720588	Pathways significantly affected by EF silencing included alanine, aspartate and glutamine metabolism, and glycine, serine and threonine metabolism.	('glutamine', 'Chemical', 'MESH:D005973', (80, 89))	('affected', 'Reg', (23, 31))	('glutamine metabolism', 'MPA', (80, 100))	('alanine', 'MPA', (57, 64))	('glycine', 'MPA', (106, 113))	('aspartate', 'Chemical', 'MESH:D001224', (66, 75))	('serine', 'Chemical', 'MESH:D012694', (115, 121))	('glycine', 'Chemical', 'MESH:D005998', (106, 113))	('alanine', 'Chemical', 'MESH:D000409', (57, 64))	('threonine', 'Chemical', 'MESH:D013912', (126, 135))	('silencing', 'Var', (38, 47))
362851	28720588	Intriguingly, the enzymes of serine and glycine synthesis were found to be significantly downregulated by EF silencing in the RNA-seq dataset, and corresponding decreases in serine and glycine were observed in our metabolomic dataset (Fig.	('decreases', 'NegReg', (161, 170))	('serine', 'Chemical', 'MESH:D012694', (174, 180))	('glycine', 'Chemical', 'MESH:D005998', (185, 192))	('downregulated', 'NegReg', (89, 102))	('enzymes', 'MPA', (18, 25))	('silencing', 'Var', (109, 118))	('serine', 'Chemical', 'MESH:D012694', (29, 35))	('glycine', 'Chemical', 'MESH:D005998', (40, 47))
362857	28720588	Protein levels of phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSPH) - the two enzymes downstream of PHGDH in the serine synthesis pathway - were also lower upon silencing of EF (Fig.	('PSAT', 'Gene', '29968', (50, 54))	('lower', 'NegReg', (175, 180))	('phosphoserine aminotransferase', 'Gene', (18, 48))	('silencing', 'Var', (186, 195))	('serine', 'Chemical', 'MESH:D012694', (25, 31))	('phosphatase', 'Gene', (74, 85))	('PSPH', 'Gene', (87, 91))	('serine', 'Chemical', 'MESH:D012694', (67, 73))	('PHGDH', 'Gene', '26227', (125, 130))	('serine', 'Chemical', 'MESH:D012694', (138, 144))	('phosphatase', 'Gene', '5723', (74, 85))	('PHGDH', 'Gene', (125, 130))	('PSPH', 'Gene', '5723', (87, 91))	('PSAT', 'Gene', (50, 54))	('Protein levels', 'MPA', (0, 14))	('phosphoserine aminotransferase', 'Gene', '29968', (18, 48))
362865	28720588	Inhibition of PHGDH function by NCT502 and NCT503 caused growth defects and cell death in Ewing sarcoma cell lines, including the EWS/ERG-harboring TTC466 line (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('growth defects', 'Disease', 'MESH:D006130', (57, 71))	('EWS', 'Gene', (130, 133))	('Inhibition', 'NegReg', (0, 10))	('ERG', 'Gene', (134, 137))	('PHGDH', 'Gene', '26227', (14, 19))	('growth defects', 'Disease', (57, 71))	('NCT502', 'Var', (32, 38))	('ERG', 'Gene', '2078', (134, 137))	('PHGDH', 'Gene', (14, 19))	('cell death', 'CPA', (76, 86))	('Ewing sarcoma', 'Disease', (90, 103))	('EWS', 'Gene', '2130', (130, 133))	('NCT503', 'Var', (43, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 103))
362869	28720588	2-HG has been shown to be oncogenic in high amounts, typically resulting from neomorphic mutations of isocitrate dehydrogenase enzymes.	('resulting from', 'Reg', (63, 77))	('isocitrate dehydrogenase', 'Gene', '3417', (102, 126))	('mutations', 'Var', (89, 98))	('isocitrate dehydrogenase', 'Gene', (102, 126))
362874	28720588	However, knockdown of EF or PHGDH had no effect on 5-mC levels (Fig.	('knockdown', 'Var', (9, 18))	('PHGDH', 'Gene', '26227', (28, 33))	('5-mC', 'Chemical', 'MESH:D044503', (51, 55))	('PHGDH', 'Gene', (28, 33))	('5-mC levels', 'MPA', (51, 62))
362875	28720588	PSPH was also silenced to distinguish between serine synthesis and 2-HG producing functions of PHGDH, and disruption of serine synthesis downstream of PHGDH also had no effect on 5-mC levels.	('serine', 'MPA', (46, 52))	('serine', 'Chemical', 'MESH:D012694', (120, 126))	('PHGDH', 'Gene', '26227', (95, 100))	('PSPH', 'Gene', (0, 4))	('5-mC', 'Chemical', 'MESH:D044503', (179, 183))	('5-mC levels', 'MPA', (179, 190))	('PHGDH', 'Gene', (95, 100))	('PHGDH', 'Gene', '26227', (151, 156))	('PSPH', 'Gene', '5723', (0, 4))	('PHGDH', 'Gene', (151, 156))	('disruption', 'Var', (106, 116))	('serine', 'Chemical', 'MESH:D012694', (46, 52))
362876	28720588	To further assess whether modulation of PHGDH affects chromatin, we immunoblotted histone proteins.	('PHGDH', 'Gene', (40, 45))	('modulation', 'Var', (26, 36))	('PHGDH', 'Gene', '26227', (40, 45))	('affects', 'Reg', (46, 53))
362878	28720588	Interestingly, methylation of histone H3 at lysine (K) 9 and K27 was increased by PHGDH knockdown in UTES-14-01872 and TTC466 cells, but not in A673 cells (Fig.	('increased', 'PosReg', (69, 78))	('K27', 'Gene', '342574', (61, 64))	('PHGDH', 'Gene', (82, 87))	('histone H3', 'Protein', (30, 40))	('K27', 'Gene', (61, 64))	('knockdown', 'Var', (88, 97))	('lysine', 'Chemical', 'MESH:D008239', (44, 50))	('methylation', 'MPA', (15, 26))	('PHGDH', 'Gene', '26227', (82, 87))
362879	28720588	Additionally, total histone protein was increased by PHGDH knockdown in two of the three cell lines.	('PHGDH', 'Gene', (53, 58))	('increased', 'PosReg', (40, 49))	('histone protein', 'MPA', (20, 35))	('knockdown', 'Var', (59, 68))	('PHGDH', 'Gene', '26227', (53, 58))
362882	28720588	Overexpression of EF in NIH3T3 murine fibroblasts results in oncogenic transformation, and silencing EF expression in patient-derived cell lines results in a loss of tumorigenesis.	('oncogenic transformation', 'CPA', (61, 85))	('NIH3T3', 'CellLine', 'CVCL:0594', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('results in', 'Reg', (50, 60))	('expression', 'MPA', (104, 114))	('silencing', 'Var', (91, 100))	('patient', 'Species', '9606', (118, 125))	('murine', 'Species', '10090', (31, 37))	('loss', 'NegReg', (158, 162))
362906	28720588	Additionally, oncogene-driven transcriptional misregulation in other malignancies (e.g., HER2, SP1, NFY, NRF2, ATF4) has been shown to increase expression of enzymes of de novo serine synthesis.	('increase', 'PosReg', (135, 143))	('transcriptional misregulation', 'Var', (30, 59))	('expression', 'MPA', (144, 154))	('NRF2', 'Gene', '4780', (105, 109))	('SP1', 'Gene', (95, 98))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('ATF4', 'Gene', '468', (111, 115))	('misregulation', 'Var', (46, 59))	('NFY', 'Gene', (100, 103))	('HER2', 'Gene', (89, 93))	('NRF2', 'Gene', (105, 109))	('enzymes of de novo serine synthesis', 'MPA', (158, 193))	('serine', 'Chemical', 'MESH:D012694', (177, 183))	('malignancies', 'Disease', (69, 81))	('HER2', 'Gene', '2064', (89, 93))	('ATF4', 'Gene', (111, 115))
362908	28720588	Existing transcription profiling data suggest that SP1 is an upregulated target of EF, while NFY, NRF2 and ATF4 are not differentially expressed after EF knockdown; HER2 may be slightly downregulated by EF (data not shown).	('upregulated', 'PosReg', (61, 72))	('ATF4', 'Gene', '468', (107, 111))	('knockdown', 'Var', (154, 163))	('NRF2', 'Gene', '4780', (98, 102))	('HER2', 'Gene', (165, 169))	('downregulated', 'NegReg', (186, 199))	('HER2', 'Gene', '2064', (165, 169))	('NRF2', 'Gene', (98, 102))	('ATF4', 'Gene', (107, 111))
362913	28720588	It is likely that this is also clinically relevant, as patients with high levels of SHMT also have worse overall survival (Fig.	('SHMT', 'Gene', (84, 88))	('high levels', 'Var', (69, 80))	('overall survival', 'MPA', (105, 121))	('patients', 'Species', '9606', (55, 63))	('SHMT', 'Gene', '6470', (84, 88))	('worse', 'NegReg', (99, 104))
362926	28720588	In addition, previous work has suggested that amplified PHGDH may play a role in cancer through production of 2-HG.	('role', 'Reg', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('amplified', 'Var', (46, 55))	('PHGDH', 'Gene', '26227', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PHGDH', 'Gene', (56, 61))	('play', 'Reg', (66, 70))
362927	28720588	2-HG is a known oncometabolite when overproduced by neomorphic mutations in IDH enzymes.	('neomorphic mutations', 'Var', (52, 72))	('IDH', 'Gene', '3417', (76, 79))	('IDH', 'Gene', (76, 79))	('overproduced', 'PosReg', (36, 48))
362930	28720588	Additionally, IDH mutations are rare in Ewing sarcoma.	('IDH', 'Gene', (14, 17))	('Ewing sarcoma', 'Disease', (40, 53))	('IDH', 'Gene', '3417', (14, 17))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (40, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('mutations', 'Var', (18, 27))
362933	28720588	Rather, knockdown of PHGDH did not affect DNA methylation (Fig.	('PHGDH', 'Gene', '26227', (21, 26))	('knockdown', 'Var', (8, 17))	('DNA methylation', 'MPA', (42, 57))	('PHGDH', 'Gene', (21, 26))
362936	28720588	While most research of Ewing sarcoma has previously focused on transcriptional regulation, epigenetic modification and other nuclear processes, little attention has been focused on metabolic pathways.	('transcriptional', 'MPA', (63, 78))	('Ewing sarcoma', 'Disease', (23, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (23, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (23, 36))	('focused', 'Reg', (52, 59))	('epigenetic', 'Var', (91, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))
362937	28720588	Indeed, metabolic systems that are co-opted or altered by the presence of EWS/FLI might include targetable enzymes that could be modulated by new therapies.	('FLI', 'Gene', '2314', (78, 81))	('FLI', 'Gene', (78, 81))	('EWS', 'Gene', '2130', (74, 77))	('EWS', 'Gene', (74, 77))	('metabolic', 'MPA', (8, 17))	('altered', 'Reg', (47, 54))	('presence', 'Var', (62, 70))
362938	28720588	An EWS/FLI-specific metabolic program could provide a targetable surrogate for EWS/FLI itself, providing a way to specifically destroy EWS/FLI-harboring cells through pharmacological modulation of metabolic or other enzymes.	('EWS', 'Gene', '2130', (79, 82))	('EWS', 'Gene', (79, 82))	('FLI', 'Gene', (139, 142))	('FLI', 'Gene', '2314', (7, 10))	('FLI', 'Gene', (7, 10))	('EWS', 'Gene', (135, 138))	('modulation', 'Var', (183, 193))	('EWS', 'Gene', '2130', (135, 138))	('FLI', 'Gene', '2314', (83, 86))	('FLI', 'Gene', (83, 86))	('EWS', 'Gene', '2130', (3, 6))	('EWS', 'Gene', (3, 6))	('FLI', 'Gene', '2314', (139, 142))	('destroy', 'NegReg', (127, 134))
363000	26356700	Six trials involving 270 examinations addressed bone sarcoma recurrence using 18F-FDG PET/CT.	('18F-FDG', 'Chemical', '-', (78, 85))	('bone sarcoma', 'Disease', (48, 60))	('18F-FDG PET/CT', 'Var', (78, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('bone sarcoma', 'Disease', 'MESH:D001847', (48, 60))	('bone sarcoma', 'Phenotype', 'HP:0002669', (48, 60))
363014	26356700	Six trials involving 998 examinations addressed bone metastasis of bone sarcoma using 18F-FDG PET/CT on an examination-based level.	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('bone sarcoma', 'Disease', 'MESH:D001847', (67, 79))	('bone sarcoma', 'Phenotype', 'HP:0002669', (67, 79))	('addressed', 'Reg', (38, 47))	('bone metastasis', 'CPA', (48, 63))	('18F-FDG', 'Chemical', '-', (86, 93))	('bone sarcoma', 'Disease', (67, 79))	('18F-FDG PET/CT', 'Var', (86, 100))
363038	26356700	Iagaru et al examined 106 bone and soft-tissue sarcomas, and the FN rates for lung metastases were significantly higher in patients with subcentimeter nodules.	('sarcomas', 'Disease', (47, 55))	('bone', 'Disease', (26, 30))	('subcentimeter nodules', 'Var', (137, 158))	('higher', 'PosReg', (113, 119))	('patients', 'Species', '9606', (123, 131))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (35, 55))	('lung metastases', 'Disease', (78, 93))	('lung metastases', 'Disease', 'MESH:D009362', (78, 93))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
363045	26356700	In agreement, the present meta-analysis revealed remarkable sensitivity and specificity of PET/CT for the detection of bone metastases, suggesting that PET/CT could improve survival outcome because of an enhanced ability for detecting bone metastases.	('bone metastases', 'Disease', 'MESH:D009362', (119, 134))	('bone metastases', 'Disease', (235, 250))	('bone metastases', 'Disease', (119, 134))	('improve', 'PosReg', (165, 172))	('survival outcome', 'CPA', (173, 189))	('PET/CT', 'Var', (152, 158))	('enhanced', 'PosReg', (204, 212))	('bone metastases', 'Disease', 'MESH:D009362', (235, 250))
363174	25557134	Causes of death were categorized into five groups: neoplastic (ICD-9 codes 140-239 & ICD-10 codes C00-C97, D00-D48); infectious (ICD-9 codes 001-018, 020-037, 039-088, 090-139, 461, 480-487, 541 & ICD-10 codes A00-A08, A15-A33,A40-B99,J09-J18); cardiac/vascular (ICD-9 codes 390-398, 401-404, 410-438, 440-448, 451-453, 456-459 & ICD-10 codes I00-I13, I20-I51, I60-I78,); external (ICD-9 codes 800-999 & ICD-10 codes U01-U03, V00-X59, X60-Y09, Y35, Y85-Y87, Y89); and the others.	('infectious', 'Var', (117, 127))	('800-999', 'Var', (394, 401))	('death', 'Disease', 'MESH:D003643', (10, 15))	('ICD-10', 'Var', (404, 410))	('U01-U03', 'Var', (417, 424))	('ICD-10', 'Var', (197, 203))	('V00-X59', 'Var', (426, 433))	('death', 'Disease', (10, 15))	('X60-Y09', 'Var', (435, 442))	('U01', 'CellLine', 'CVCL:2220', (417, 420))
363230	32014859	Somatic mutation analysis identified mutations in IQGAP1, CCNC, and ATXN1L in pre- and post-treatment tissue samples, as well as a CIC-DUX4 fusion that was confirmed by qPCR and DUX4 immunohistochemistry.	('CCNC', 'Gene', '892', (58, 62))	('CIC', 'Gene', '23152', (131, 134))	('ATXN1L', 'Gene', '342371', (68, 74))	('CIC', 'Gene', (131, 134))	('DUX4', 'Gene', (178, 182))	('IQGAP1', 'Gene', '8826', (50, 56))	('IQGAP1', 'Gene', (50, 56))	('CCNC', 'Gene', (58, 62))	('mutations', 'Var', (37, 46))	('DUX4', 'Gene', '100288687', (178, 182))	('DUX4', 'Gene', (135, 139))	('ATXN1L', 'Gene', (68, 74))	('DUX4', 'Gene', '100288687', (135, 139))
363241	32014859	Prior to the identification of the CIC-DUX4 rearrangement, the patient was treated as an UPS, which has varying clinical treatment approaches that are minimally effective.	('CIC', 'Gene', (35, 38))	('UPS', 'Disease', (89, 92))	('rearrangement', 'Var', (44, 57))	('UPS', 'Disease', 'MESH:D002277', (89, 92))	('patient', 'Species', '9606', (63, 70))	('CIC', 'Gene', '23152', (35, 38))	('DUX4', 'Gene', (39, 43))	('DUX4', 'Gene', '100288687', (39, 43))
363263	32014859	Tissue samples from the first excision of the right lung metastatic tumor were also sent to Human Longevity Inc. (HLI) for whole-genome sequencing (WGS) (113x coverage) and RNA sequencing together revealed no cancer-relevant somatic alterations or copy-number variations (CNVs).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('copy-number variations', 'Var', (248, 270))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Human', 'Species', '9606', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
363264	32014859	Of note, because of the low tumor purity observed in the samples, the sensitivity to capture low allele fractions variants was reported to be suboptimal; thus, some low-frequency alterations may not be called.	('variants', 'Var', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('low tumor', 'Disease', (24, 33))	('low tumor', 'Disease', 'MESH:D009800', (24, 33))
363271	32014859	No pathogenic variants associated with inherited cancer risks and no variants associated with adverse drug reaction or drug metabolism were reported.	('associated', 'Reg', (78, 88))	('inherited cancer', 'Disease', 'MESH:D009386', (39, 55))	('adverse drug reaction', 'Phenotype', 'HP:0020172', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('variants', 'Var', (14, 22))	('inherited cancer', 'Disease', (39, 55))	('associated', 'Reg', (23, 33))
363287	32014859	We analyzed tumor and matched normal genome sequencing data for the presence of somatic point mutation, somatic functional and structural mutations, potential germline mutations, polynucleotide insertions/deletions, and gene CNVs.	('polynucleotide insertions/deletions', 'Var', (179, 214))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('point mutation', 'Var', (88, 102))	('mutations', 'Var', (138, 147))
363288	32014859	IQGAP1, CCNC, and ATXN1L were identified as genes bearing high- or medium-impact mutations in the pretreatment sample that were not found in the matched normal genome.	('ATXN1L', 'Gene', (18, 24))	('IQGAP1', 'Gene', '8826', (0, 6))	('IQGAP1', 'Gene', (0, 6))	('CCNC', 'Gene', '892', (8, 12))	('ATXN1L', 'Gene', '342371', (18, 24))	('mutations', 'Var', (81, 90))	('CCNC', 'Gene', (8, 12))
363295	32014859	For example, the breakpoint (190069535) is between GC04P190068 (190068071-190069067) and DUX4L7 (190071232-190072516).	('DUX4L7', 'Gene', '653543', (89, 95))	('190071232-190072516', 'Var', (97, 116))	('DUX4L7', 'Gene', (89, 95))	('190068071-190069067', 'Var', (64, 83))
363298	32014859	These findings point to the potential need to develop a FISH panel for CIC-DUX variant fusions.	('CIC', 'Gene', '23152', (71, 74))	('CIC', 'Gene', (71, 74))	('variant', 'Var', (79, 86))
363314	32014859	In hierarchical clustering of both somatic mutations and gene expression, the patient clusters closest to CTG-1542, a PDX model of metastatic ERMS (Fig.	('patient', 'Species', '9606', (78, 85))	('ERMS', 'Disease', 'MESH:D018233', (142, 146))	('ERMS', 'Phenotype', 'HP:0006743', (142, 146))	('mutations', 'Var', (43, 52))	('ERMS', 'Disease', (142, 146))	('CTG-1542', 'Chemical', 'MESH:C081036', (106, 114))	('CTG-1542', 'Gene', (106, 114))
363337	32014859	Given that CRS is a new entity that can go unrecognized, increased scrutiny of round cell histology undifferentiated sarcomas and development of confirmatory tools such as methylation profiling or FISH for variant CIC-DUX4-like fusions appears warranted.	('DUX4', 'Gene', '100288687', (218, 222))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('CIC', 'Gene', '23152', (214, 217))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcomas', 'Disease', (117, 125))	('CRS', 'Disease', 'MESH:D012509', (11, 14))	('CRS', 'Disease', (11, 14))	('variant', 'Var', (206, 213))	('CIC', 'Gene', (214, 217))	('DUX4', 'Gene', (218, 222))
363347	32014859	RMS559, CW9019, CCA, RD, Hs729T, COG-R-486h, and SMS-CTR were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin.	('streptomycin', 'Chemical', 'MESH:D013307', (176, 188))	('COG-R-486h', 'Chemical', '-', (33, 43))	('CW9019', 'Var', (8, 14))	('DMEM', 'Chemical', '-', (105, 109))	('CTR', 'Gene', '799', (53, 56))	('penicillin', 'Chemical', 'MESH:D010406', (165, 175))	('Hs729T', 'Var', (25, 31))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (71, 103))	('CTR', 'Gene', (53, 56))	('CW9019', 'CellLine', 'CVCL:N820', (8, 14))
363367	30830877	Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation Bone osteogenic sarcoma has a poor prognosis, as the exact cell of origin and the signaling pathways underlying tumor formation remain undefined.	('osteogenic tumors', 'Disease', (60, 77))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('tumor', 'Disease', (216, 221))	('osteogenic sarcoma', 'Disease', (109, 127))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('Lkb1', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (109, 127))	('osteogenic tumors', 'Disease', 'MESH:D012516', (60, 77))	('induces', 'Reg', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (71, 76))	('mTORC1', 'Gene', (86, 92))	('Lkb1', 'Gene', '20869', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mTORC1', 'Gene', '382056', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
363368	30830877	Here, we report an osteogenic tumor mouse model based on the conditional knockout of liver kinase b1 (Lkb1, also known as Stk11) in Cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells.	('Stk11', 'Gene', '20869', (122, 127))	('Lkb1', 'Gene', (102, 106))	('Stk11', 'Gene', (122, 127))	('osteogenic tumor', 'Disease', (19, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('liver kinase b1', 'Gene', (85, 100))	('osteogenic tumor', 'Disease', 'MESH:D012516', (19, 35))	('knockout', 'Var', (73, 81))	('mouse', 'Species', '10090', (36, 41))	('liver kinase b1', 'Gene', '20869', (85, 100))
363379	30830877	Mutations in p53 and/or Rb genes, as well as other components involved in their pathways, have been identified in human osteogenic sarcoma patients, and mouse models for studying the cell of origin for osteogenic sarcoma have been developed via conditional mesenchymal/osteogenic lineage-restricted knockout of p53 and/or Rb genes.	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (120, 138))	('osteogenic sarcoma', 'Disease', (120, 138))	('patients', 'Species', '9606', (139, 147))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (202, 220))	('osteogenic sarcoma', 'Disease', (202, 220))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (120, 138))	('p53', 'Gene', (311, 314))	('Mutations', 'Var', (0, 9))	('mouse', 'Species', '10090', (153, 158))	('human', 'Species', '9606', (114, 119))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (202, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('p53', 'Gene', (13, 16))
363380	30830877	The disruption of p53/Rb in mesenchymal progenitors (Prx1-cre), osteoblast precursors (Osx-Cre), and osteoblast committed cells (Col1a1-Cre and OCN-Cre) leading to osteogenic sarcoma confirmed that cells with mesenchymal origin and osteogenic lineage were responsible for osteogenic tumor formation.	('Col1a1', 'Gene', (129, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('osteogenic sarcoma', 'Disease', (164, 182))	('osteogenic tumor', 'Disease', (272, 288))	('Col1a1', 'Gene', '12842', (129, 135))	('osteogenic tumor', 'Disease', 'MESH:D012516', (272, 288))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (164, 182))	('Prx1', 'Gene', (53, 57))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (164, 182))	('Prx1', 'Gene', '18933', (53, 57))	('p53/Rb', 'Gene', (18, 24))	('Osx', 'Gene', '170574', (87, 90))	('disruption', 'Var', (4, 14))	('Osx', 'Gene', (87, 90))
363381	30830877	Moreover, NOTCH activation in committed osteoblasts (Col1a1-Cre) was sufficient to induce osteogenic sarcoma, also suggesting committed osteoblasts as the potential sources of osteogenic tumor.	('Col1a1', 'Gene', '12842', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('induce', 'Reg', (83, 89))	('osteogenic tumor', 'Disease', (176, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('NOTCH', 'Var', (10, 15))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (90, 108))	('osteogenic sarcoma', 'Disease', (90, 108))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (90, 108))	('osteogenic tumor', 'Disease', 'MESH:D012516', (176, 192))	('Col1a1', 'Gene', (53, 59))
363383	30830877	Loss of Lkb1 in a variety of organs has been reported to initiate both hyperplasia and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Lkb1', 'Gene', (8, 12))	('hyperplasia', 'Disease', (71, 82))	('tumor', 'Disease', (87, 92))	('initiate', 'PosReg', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('hyperplasia', 'Disease', 'MESH:D006965', (71, 82))	('Loss', 'Var', (0, 4))
363384	30830877	Cancers with Lkb1 inactivation tend to exhibit aggressive clinical characteristics, and their therapeutic sensitivity differs from those without Lkb1 inactivation.	('Cancers', 'Disease', (0, 7))	('inactivation', 'Var', (18, 30))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Lkb1', 'Gene', (13, 17))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))
363388	30830877	Although the loss of Lkb1 has been suggested as correlating with osteogenic tumor, the involved cell type and the underlying pathway remain unclear; however, these details are central for a complete understanding of osteogenic tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('osteogenic tumor', 'Disease', (65, 81))	('osteogenic tumor', 'Disease', 'MESH:D012516', (216, 232))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Lkb1', 'Gene', (21, 25))	('osteogenic tumor', 'Disease', 'MESH:D012516', (65, 81))	('loss', 'Var', (13, 17))	('osteogenic tumor', 'Disease', (216, 232))	('correlating', 'Reg', (48, 59))
363391	30830877	A recent study demonstrated that Ctsk-Cre-expressing cells can be chondroprogenitor cells, as Ptpn11 deletion in Ctsk-Cre-expressing cells resulted in metachondromatosis by activating Hedgehog signaling.	('deletion', 'Var', (101, 109))	('Hedgehog signaling', 'Pathway', (184, 202))	('Ptpn11', 'Gene', (94, 100))	('resulted in', 'Reg', (139, 150))	('rat', 'Species', '10116', (22, 25))	('metachondromatosis', 'Disease', 'MESH:C562938', (151, 169))	('metachondromatosis', 'Disease', (151, 169))	('Ptpn11', 'Gene', '19247', (94, 100))	('activating', 'PosReg', (173, 183))
363392	30830877	Lack of Lkb1 within chondrocytes (Col2a1-Cre) of the endochondral skeleton caused a dramatic disruption of the skeletal growth plate and formation of cartilage tumors.	('Lkb1', 'Gene', (8, 12))	('disruption', 'NegReg', (93, 103))	('Col2a1', 'Gene', (34, 40))	('Lack', 'Var', (0, 4))	('cartilage tumors', 'Disease', (150, 166))	('skeletal growth plate', 'CPA', (111, 132))	('Col2a1', 'Gene', '12824', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cartilage tumors', 'Disease', 'MESH:D002357', (150, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('formation', 'CPA', (137, 146))
363393	30830877	This suggests that Lkb1 deletion in Ctsk-Cre-expressing cells causes cartilage tumors.	('Lkb1', 'Gene', (19, 23))	('cartilage tumors', 'Disease', 'MESH:D002357', (69, 85))	('causes', 'Reg', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('deletion', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cartilage tumors', 'Disease', (69, 85))
363394	30830877	Interestingly, in this study, we found that deletion of Lkb1 in Ctsk-Cre-expressing cells caused an osteogenic tumor-like phenotype, but not cartilage tumors.	('cartilage tumors', 'Disease', (141, 157))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('osteogenic tumor', 'Disease', (100, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('caused', 'Reg', (90, 96))	('deletion', 'Var', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('cartilage tumors', 'Disease', 'MESH:D002357', (141, 157))	('osteogenic tumor', 'Disease', 'MESH:D012516', (100, 116))	('Lkb1', 'Gene', (56, 60))
363397	30830877	Moreover, these results indicated the therapeutic potential of mTORC1 inhibitors for the treatment of osteogenic sarcoma.	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (102, 120))	('osteogenic sarcoma', 'Disease', (102, 120))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (102, 120))	('mTORC1', 'Gene', '382056', (63, 69))	('inhibitors', 'Var', (70, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('mTORC1', 'Gene', (63, 69))
363400	30830877	Strikingly, Ctsk-CKO mice did not display cartilage tumors, as indicated by H&E staining and safranin O (SO) staining in both the femurs and tibiae and the sternums (Supplemental Figure 1, A and B; supplemental material available online with this article; https://doi.org/10.1172/JCI124590DS1), but these mice exhibited a specific skeleton phenotype (Supplemental Figure 2A).	('mice', 'Species', '10090', (305, 309))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tibia', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mice', 'Species', '10090', (21, 25))	('cartilage tumors', 'Disease', 'MESH:D002357', (42, 58))	('Ctsk-CKO', 'Var', (12, 20))	('specific skeleton', 'CPA', (322, 339))	('H&E', 'Chemical', 'MESH:D006371', (76, 79))	('mice', 'Reg', (305, 309))	('cartilage tumors', 'Disease', (42, 58))	('tibia', 'Disease', 'MESH:C535563', (141, 146))	('CKO', 'Chemical', '-', (17, 20))
363405	30830877	muCT analysis showed disorganized bone architecture and the presence of ossified spicules outside the periosteum in both axial and appendicular skeletons of Ctsk-CKO mice (Figure 1, C and D).	('disorganized bone architecture', 'CPA', (21, 51))	('CKO', 'Chemical', '-', (162, 165))	('mice', 'Species', '10090', (166, 170))	('ossified spicules', 'CPA', (72, 89))	('Ctsk-CKO', 'Var', (157, 165))
363409	30830877	As lack of Lkb1 in Ctsk+ cells led to a tumor-like mass in the cortical bone, the expression levels of genes involved in the cell cycle, including Ccnd1, Cdkn1a, Cdkn2a, and Cdkn2b, were determined to characterize the tumor and it was found that they were significantly increased in Ctsk-CKO tibiae at the age of 20 weeks (Figure 1H).	('Ctsk-CKO', 'Var', (283, 291))	('tumor', 'Disease', (218, 223))	('tibia', 'Disease', 'MESH:C535563', (292, 297))	('Cdkn1a', 'Gene', (154, 160))	('Lkb1', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('Cdkn2b', 'Gene', (174, 180))	('lack', 'NegReg', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('Cdkn1a', 'Gene', '12575', (154, 160))	('Ccnd1', 'Gene', (147, 152))	('tibia', 'Disease', (292, 297))	('Cdkn2a', 'Gene', '12578', (162, 168))	('Ccnd1', 'Gene', '12443', (147, 152))	('Cdkn2b', 'Gene', '12579', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (40, 45))	('Cdkn2a', 'Gene', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('increased', 'PosReg', (270, 279))	('CKO', 'Chemical', '-', (288, 291))
363411	30830877	The expression levels of the tumor suppressors Rb and Bub3 were decreased in Ctsk-CKO mice as expected, while decreased expression levels of the tumor suppressor genes p53, Wif, and Fgfr2 were not detected in Ctsk-CKO mice (Figure 1H).	('expression levels', 'MPA', (4, 21))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Fgfr2', 'Gene', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('decreased', 'NegReg', (64, 73))	('Bub3', 'Gene', '12237', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mice', 'Species', '10090', (86, 90))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (29, 34))	('Fgfr2', 'Gene', '14183', (182, 187))	('Bub3', 'Gene', (54, 58))	('mice', 'Species', '10090', (218, 222))	('CKO', 'Chemical', '-', (82, 85))	('CKO', 'Chemical', '-', (214, 217))	('Ctsk-CKO', 'Var', (77, 85))
363412	30830877	We also examined expression of these genes between control and mutant mice before the tumor mass appeared at the age of 5 weeks and found that expression levels of cell cycle-related genes showed more moderate changes (Supplemental Figure 2D).	('expression levels', 'MPA', (143, 160))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutant', 'Var', (63, 69))	('rat', 'Species', '10116', (205, 208))	('tumor', 'Disease', (86, 91))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
363414	30830877	To examine bone architecture of Ctsk-CKO mice before tumor formation, we did a quantitative muCT analysis and found an increase in the cortical bone thickness and heterotopic bone formation within the cortex in Ctsk-CKO mice (Figure 2, A and B).	('heterotopic bone formation within', 'CPA', (163, 196))	('CKO', 'Chemical', '-', (216, 219))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mice', 'Species', '10090', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('heterotopic bone formation', 'Phenotype', 'HP:0011986', (163, 189))	('cortical bone thickness', 'CPA', (135, 158))	('Ctsk-CKO', 'Var', (211, 219))	('CKO', 'Chemical', '-', (37, 40))	('increase', 'PosReg', (119, 127))	('tumor', 'Disease', (53, 58))	('heterotopic bone', 'Phenotype', 'HP:0011986', (163, 179))
363420	30830877	The mineral apposition rate (MAR) and BFR at the periosteal surface of the tibiae of 5-week-old Ctsk-CKO mice were significantly increased compared with those of Ctsk-Ctrl mice (Figure 2, D and E).	('Ctsk-CKO', 'Var', (96, 104))	('rat', 'Species', '10116', (23, 26))	('CKO', 'Chemical', '-', (101, 104))	('increased', 'PosReg', (129, 138))	('tibia', 'Disease', 'MESH:C535563', (75, 80))	('mice', 'Species', '10090', (172, 176))	('tibia', 'Disease', (75, 80))	('mineral apposition rate', 'CPA', (4, 27))	('mice', 'Species', '10090', (105, 109))
363421	30830877	Moreover, higher mRNA levels of marker genes, representing stages of osteoblast differentiation, were detected in tumors of 20-week-old Ctsk-CKO mice compared with the cortical bone of tibiae from Ctsk-Ctrl mice (Figure 2F).	('Ctsk-CKO', 'Var', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CKO', 'Chemical', '-', (141, 144))	('mice', 'Species', '10090', (145, 149))	('mRNA levels of marker genes', 'MPA', (17, 44))	('mice', 'Species', '10090', (207, 211))	('higher', 'PosReg', (10, 16))	('tumors', 'Disease', (114, 120))	('tibia', 'Disease', (185, 190))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tibia', 'Disease', 'MESH:C535563', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
363422	30830877	The results showed that preosteoblast markers Alp and Col1a1 were specifically increased, indicating activation of bone formation in Ctsk-CKO mice (Supplemental Figure 2E).	('increased', 'PosReg', (79, 88))	('Col1a1', 'Gene', (54, 60))	('Col1a1', 'Gene', '12842', (54, 60))	('bone formation', 'CPA', (115, 129))	('activation', 'PosReg', (101, 111))	('CKO', 'Chemical', '-', (138, 141))	('preosteoblast markers', 'CPA', (24, 45))	('mice', 'Species', '10090', (142, 146))	('Alp', 'Gene', (46, 49))	('Ctsk-CKO', 'Var', (133, 141))
363424	30830877	Lkb1 deficiency in osteoclast precursors does not induce osteogenic tumor-like phenotype.	('deficiency', 'Var', (5, 15))	('osteogenic tumor', 'Disease', 'MESH:D012516', (57, 73))	('Lkb1', 'Gene', (0, 4))	('osteogenic tumor', 'Disease', (57, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
363426	30830877	We next assessed whether this increased bone mass in Ctsk-CKO mice was the result of impaired osteoclast activity.	('increased bone mass', 'Phenotype', 'HP:0011001', (30, 49))	('bone mass', 'CPA', (40, 49))	('mice', 'Species', '10090', (62, 66))	('osteoclast activity', 'CPA', (94, 113))	('impaired osteoclast activity', 'Phenotype', 'HP:0030328', (85, 113))	('Ctsk-CKO', 'Var', (53, 61))	('impaired', 'NegReg', (85, 93))	('increased', 'PosReg', (30, 39))	('CKO', 'Chemical', '-', (58, 61))
363427	30830877	We used tartrate-resistant acid phosphatase (TRAP) staining and found that osteoclast numbers in the periosteum, endosteum, and trabecular bone were increased in Ctsk-CKO mice when compared with the control mice (Figure 3A).	('TRAP', 'Gene', (45, 49))	('mice', 'Species', '10090', (171, 175))	('trabecular bone', 'CPA', (128, 143))	('increased', 'PosReg', (149, 158))	('TRAP', 'Gene', '11433', (45, 49))	('Ctsk-CKO', 'Var', (162, 170))	('mice', 'Species', '10090', (207, 211))	('tartrate-resistant acid phosphatase', 'Gene', '11433', (8, 43))	('tartrate-resistant acid phosphatase', 'Gene', (8, 43))	('osteoclast numbers in the periosteum', 'CPA', (75, 111))	('CKO', 'Chemical', '-', (167, 170))
363430	30830877	These data indicate that the increased bone mass of Ctsk-CKO mice was not due to impaired resorption ability.	('mice', 'Species', '10090', (61, 65))	('bone mass', 'CPA', (39, 48))	('Ctsk-CKO', 'Var', (52, 60))	('increased', 'PosReg', (29, 38))	('increased bone mass', 'Phenotype', 'HP:0011001', (29, 48))	('CKO', 'Chemical', '-', (57, 60))
363432	30830877	LysM-CKO mice did not show a discernible osteogenic tumor-like phenotype at the age of 20 weeks (Figure 3, D-F) and 40 weeks (data not shown), indicating that the osteogenic tumor-like phenotype in Ctsk-CKO mice was not the result of altered osteoclast function.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CKO', 'Chemical', '-', (203, 206))	('osteogenic tumor', 'Disease', (41, 57))	('osteogenic tumor', 'Disease', (163, 179))	('LysM', 'Gene', (0, 4))	('osteogenic tumor', 'Disease', 'MESH:D012516', (41, 57))	('mice', 'Species', '10090', (207, 211))	('LysM', 'Gene', '17105', (0, 4))	('Ctsk-CKO', 'Var', (198, 206))	('osteogenic tumor', 'Disease', 'MESH:D012516', (163, 179))	('CKO', 'Chemical', '-', (5, 8))	('mice', 'Species', '10090', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
363438	30830877	The osteoid tumor area in Ctsk-CKO tibiae was mainly formed by GFP-positive cells by the age of 20 week (Figure 4C and Supplemental Figure 3B), indicating that the osteogenic tumor in Ctsk-CKO mice was caused by intrinsic Lkb1 deletion in Ctsk-Cre-expressing cells.	('osteoid tumor', 'Phenotype', 'HP:0030433', (4, 17))	('tibia', 'Disease', (35, 40))	('CKO', 'Chemical', '-', (189, 192))	('osteogenic tumor', 'Disease', (164, 180))	('CKO', 'Chemical', '-', (31, 34))	('osteoid tumor', 'Disease', (4, 17))	('osteoid tumor', 'Disease', 'MESH:D009369', (4, 17))	('Lkb1', 'Gene', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mice', 'Species', '10090', (193, 197))	('osteogenic tumor', 'Disease', 'MESH:D012516', (164, 180))	('caused by', 'Reg', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('deletion', 'Var', (227, 235))	('tibia', 'Disease', 'MESH:C535563', (35, 40))
363446	30830877	The results confirmed deletion of LKB1 expression in Ctsk+ periosteal cells from Ctsk-CKO; Rosa-Ai9 mice, but not in Ctsk-Ai9 cells from Ctsk-Ctrl; Rosa-Ai9 mice (Figure 4, G and H).	('LKB1', 'Gene', (34, 38))	('CKO', 'Chemical', '-', (86, 89))	('mice', 'Species', '10090', (157, 161))	('mice', 'Species', '10090', (100, 104))	('deletion', 'Var', (22, 30))	('periosteal cells', 'Phenotype', 'HP:0031485', (59, 75))
363464	30830877	After 7-day culture, the cells from Ctsk-CKO; Rosa-Ai9 mice showed enhanced proliferative ability compared with cells from Ctsk-Ctrl; Rosa-Ai9 mice (Figure 5, C and D).	('rat', 'Species', '10116', (83, 86))	('proliferative ability', 'CPA', (76, 97))	('mice', 'Species', '10090', (55, 59))	('Ctsk-CKO', 'Var', (36, 44))	('mice', 'Species', '10090', (143, 147))	('CKO', 'Chemical', '-', (41, 44))	('enhanced', 'PosReg', (67, 75))
363468	30830877	We reasoned that loss of Lkb1 in periosteum-derived Ctsk+ cells caused the expansion of CD44-positive cells and drove osteogenic tumor formation.	('drove', 'PosReg', (112, 117))	('osteogenic tumor', 'Disease', (118, 134))	('CD44', 'Gene', '12505', (88, 92))	('CD44', 'Gene', (88, 92))	('Lkb1', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('expansion', 'PosReg', (75, 84))	('osteogenic tumor', 'Disease', 'MESH:D012516', (118, 134))	('loss', 'Var', (17, 21))
363470	30830877	Consistently, expression of osteoblast marker genes, including Osx, Col1a1 and Opn, increased in Adv-Cre-infected cells (Figure 5I).	('Opn', 'Gene', (79, 82))	('Col1a1', 'Gene', (68, 74))	('Opn', 'Gene', '20750', (79, 82))	('osteoblast marker genes', 'Gene', (28, 51))	('Adv-Cre-infected', 'Var', (97, 113))	('Col1a1', 'Gene', '12842', (68, 74))	('expression', 'MPA', (14, 24))	('increased', 'PosReg', (84, 93))	('Osx', 'Gene', '170574', (63, 66))	('Osx', 'Gene', (63, 66))
363473	30830877	Moreover, periosteal cells from Ctsk-CKO; Rosa-Ai9 mice developed larger bone organoids than cells from Ctsk-Ctrl; Rosa-Ai9 mice (Figure 5, J-L).	('larger', 'PosReg', (66, 72))	('mice', 'Species', '10090', (51, 55))	('mice', 'Species', '10090', (124, 128))	('Ctsk-CKO', 'Var', (32, 40))	('CKO', 'Chemical', '-', (37, 40))	('periosteal cells', 'CPA', (10, 26))	('bone organoids', 'CPA', (73, 87))	('periosteal cells', 'Phenotype', 'HP:0031485', (10, 26))
363477	30830877	To investigate the mechanism with which Lkb1 deletion induces the osteogenic tumor from Ctsk-Cre-positive periosteal mesenchymal stem cells, we focused on the mTORC1 pathway, which is a critical target downstream of LKB1-dependent AMP kinases (AMPKs).	('mTORC1', 'Gene', (159, 165))	('Lkb1', 'Gene', (40, 44))	('osteogenic tumor', 'Disease', (66, 82))	('osteogenic tumor', 'Disease', 'MESH:D012516', (66, 82))	('mTORC1', 'Gene', '382056', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('periosteal mesenchymal stem', 'Phenotype', 'HP:0031485', (106, 133))	('induces', 'Reg', (54, 61))	('deletion', 'Var', (45, 53))
363478	30830877	Phosphorylation of mTORC1 catalytic substrate ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) were increased in Ctsk-CKO mice (Figure 6A), indicating hyperactivation of mTORC1 signaling in Ctsk-CKO mice.	('hyperactivation', 'PosReg', (203, 218))	('Ctsk-CKO', 'Var', (165, 173))	('mice', 'Species', '10090', (251, 255))	('4E-BP1', 'Gene', '13685', (139, 145))	('4E-BP1', 'Gene', (139, 145))	('mice', 'Species', '10090', (174, 178))	('increased', 'PosReg', (152, 161))	('mTORC1', 'Gene', (19, 25))	('mTORC1', 'Gene', (222, 228))	('Phosphorylation', 'MPA', (0, 15))	('CKO', 'Chemical', '-', (170, 173))	('4E-binding protein 1', 'Gene', (117, 137))	('rat', 'Species', '10116', (41, 44))	('mTORC1', 'Gene', '382056', (222, 228))	('4E-binding protein 1', 'Gene', '13685', (117, 137))	('mTORC1', 'Gene', '382056', (19, 25))	('CKO', 'Chemical', '-', (247, 250))
363479	30830877	We postulated that if LKB1 deletion indeed induces the osteogenic tumor-like phenotype via activation of the mTORC1 pathway, the deletion of Raptor (the core binding factor of mTORC1) in vivo should lead to amelioration of the osteogenic tumor-like phenotype in Lkb1fl/fl; Ctsk-CKO mice.	('activation', 'PosReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('rat', 'Species', '10116', (213, 216))	('Raptor', 'Gene', '74370', (141, 147))	('mTORC1', 'Gene', (176, 182))	('LKB1', 'Gene', (22, 26))	('CKO', 'Chemical', '-', (278, 281))	('osteogenic tumor', 'Disease', (55, 71))	('mice', 'Species', '10090', (282, 286))	('mTORC1', 'Gene', '382056', (176, 182))	('osteogenic tumor', 'Disease', 'MESH:D012516', (227, 243))	('deletion', 'Var', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('induces', 'Reg', (43, 50))	('amelioration', 'PosReg', (207, 219))	('osteogenic tumor', 'Disease', (227, 243))	('mTORC1', 'Gene', (109, 115))	('deletion', 'Var', (129, 137))	('Raptor', 'Gene', (141, 147))	('osteogenic tumor', 'Disease', 'MESH:D012516', (55, 71))	('mTORC1', 'Gene', '382056', (109, 115))
363480	30830877	We constructed Ctsk-DKO mice (Ctsk Cre; Lkb1fl/fl; Raptorfl/fl) and found that delayed tumor progression in Ctsk-DKO mice was indicated by an extended median life span of 42.3 weeks compared with the life span of 23.9 weeks for Lkb1fl/fl; Ctsk-CKO mice (Figure 6B).	('Ctsk-DKO', 'Var', (108, 116))	('CKO', 'Chemical', '-', (244, 247))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mice', 'Species', '10090', (24, 28))	('tumor', 'Disease', (87, 92))	('mice', 'Species', '10090', (117, 121))	('mice', 'Species', '10090', (248, 252))	('Raptor', 'Gene', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Raptor', 'Gene', '74370', (51, 57))
363481	30830877	The disorganized architecture in the tibiae was partially rescued in Ctsk-DKO mice, as indicated by the results of x-ray and muCT analyses (Figure 6C and Supplemental Figure 6A).	('Ctsk-DKO', 'Var', (69, 77))	('tibia', 'Disease', (37, 42))	('rescued', 'PosReg', (58, 65))	('tibia', 'Disease', 'MESH:C535563', (37, 42))	('mice', 'Species', '10090', (78, 82))
363483	30830877	As expected, both mineralization of the heterotopic bone within the cortical bone by von Kossa staining and increased periosteal MAR and BFR via double labeling were rescued in Ctsk-DKO mice when compared with Ctsk-CKO mice (Figure 6, D and E).	('von', 'Disease', (85, 88))	('mice', 'Species', '10090', (219, 223))	('increased', 'PosReg', (108, 117))	('mineralization', 'CPA', (18, 32))	('periosteal MAR', 'CPA', (118, 132))	('periosteal MAR', 'Phenotype', 'HP:0031485', (118, 132))	('von', 'Disease', 'MESH:D014842', (85, 88))	('CKO', 'Chemical', '-', (215, 218))	('Ctsk-DKO', 'Var', (177, 185))	('mice', 'Species', '10090', (186, 190))	('heterotopic bone', 'Phenotype', 'HP:0011986', (40, 56))	('rescued', 'PosReg', (166, 173))
363498	30830877	These data demonstrate that LKB1 knockdown promotes tumor formation of human osteosarcoma cells, while rapamycin inhibits tumor growth in established tumors using human osteosarcoma cell xenografts.	('rat', 'Species', '10116', (18, 21))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('osteosarcoma', 'Phenotype', 'HP:0002669', (169, 181))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (122, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('osteosarcoma', 'Disease', (77, 89))	('tumors', 'Disease', (150, 156))	('osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('LKB1', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('rapamycin', 'Chemical', 'MESH:D020123', (103, 112))	('human', 'Species', '9606', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('promotes', 'PosReg', (43, 51))	('knockdown', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('osteosarcoma', 'Disease', (169, 181))	('osteosarcoma', 'Disease', 'MESH:D012516', (169, 181))	('tumor', 'Disease', (150, 155))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('human', 'Species', '9606', (163, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
363499	30830877	Our results suggest that Lkb1 deletion in Ctsk+ periosteal cells caused osteogenic tumor-like phenotype by increasing mTORC1 activity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mTORC1', 'Gene', (118, 124))	('caused', 'Reg', (65, 71))	('osteogenic tumor', 'Disease', (72, 88))	('Lkb1', 'Gene', (25, 29))	('deletion', 'Var', (30, 38))	('mTORC1', 'Gene', '382056', (118, 124))	('increasing', 'PosReg', (107, 117))	('osteogenic tumor', 'Disease', 'MESH:D012516', (72, 88))	('periosteal cells', 'Phenotype', 'HP:0031485', (48, 64))
363500	30830877	Previous reports demonstrated that Ptpn11 deficiency in Ctsk+ cells induced metachondroma with decreased ERK activity and more production of the growth stimulators Ihh and Pthrp (Figure 7F).	('decreased', 'NegReg', (95, 104))	('metachondroma', 'Disease', (76, 89))	('Ptpn11', 'Gene', (35, 41))	('metachondroma', 'Disease', 'None', (76, 89))	('more', 'PosReg', (122, 126))	('induced', 'Reg', (68, 75))	('deficiency', 'Var', (42, 52))	('ERK', 'Gene', (105, 108))	('Pthrp', 'Gene', (172, 177))	('Pthrp', 'Gene', '19227', (172, 177))	('ERK', 'Gene', '26413', (105, 108))	('Ptpn11', 'Gene', '19247', (35, 41))	('rat', 'Species', '10116', (24, 27))	('decreased ERK', 'Phenotype', 'HP:0000654', (95, 108))	('production of the', 'MPA', (127, 144))	('Ihh', 'MPA', (164, 167))
363501	30830877	To further understand why Lkb1-deficient mice developed osteogenic tumor, but not cartilage tumor, we examined expression of pErk in Lkb1-deficient Ctsk+ cells by immunostaining and Western blot and found that Lkb1 deletion had no obvious effect on inhibition of Erk signaling (Supplemental Figure 7, A, B, and C; see complete unedited blots in the supplemental material) and production of Ihh and Pthrp (Supplemental Figure 7D).	('pErk', 'Gene', '13666', (125, 129))	('Erk', 'Gene', '26413', (263, 266))	('deletion', 'Var', (215, 223))	('mice', 'Species', '10090', (41, 45))	('cartilage tumor', 'Disease', (82, 97))	('Pthrp', 'Gene', (398, 403))	('Pthrp', 'Gene', '19227', (398, 403))	('osteogenic tumor', 'Disease', (56, 72))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Lkb1', 'Gene', (210, 214))	('Erk', 'Gene', (263, 266))	('Erk', 'Gene', '26413', (126, 129))	('cartilage tumor', 'Disease', 'MESH:D002357', (82, 97))	('osteogenic tumor', 'Disease', 'MESH:D012516', (56, 72))	('pErk', 'Gene', (125, 129))	('Erk', 'Gene', (126, 129))	('inhibition', 'MPA', (249, 259))
363502	30830877	It has been proven that hypoactivation of Erk signaling in Ctsk+ cells could induce cartilage tumor.	('induce', 'PosReg', (77, 83))	('Erk', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cartilage tumor', 'Disease', (84, 99))	('cartilage tumor', 'Disease', 'MESH:D002357', (84, 99))	('Erk', 'Gene', '26413', (42, 45))	('hypoactivation', 'Var', (24, 38))
363503	30830877	However, Lkb1 deficiency in Ctsk+ cells could not inhibit Erk/Ihh signaling and induce cartilage tumor.	('Lkb1', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('inhibit', 'NegReg', (50, 57))	('induce', 'Reg', (80, 86))	('Erk', 'Gene', '26413', (58, 61))	('deficiency', 'Var', (14, 24))	('Erk', 'Gene', (58, 61))	('cartilage tumor', 'Disease', (87, 102))	('cartilage tumor', 'Disease', 'MESH:D002357', (87, 102))
363506	30830877	Deletion of Lkb1 in Ctsk+ cells leading to osteosarcoma formation demonstrated that Ctsk+ cells cannot only serve as a physiologic precursor of periosteal osteoblasts, but also as a pathological precursor in osteogenic tumor.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Lkb1', 'Gene', (12, 16))	('osteogenic tumor', 'Disease', 'MESH:D012516', (208, 224))	('osteosarcoma', 'Disease', 'MESH:D012516', (43, 55))	('leading to', 'Reg', (32, 42))	('rat', 'Species', '10116', (73, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('osteogenic tumor', 'Disease', (208, 224))	('osteosarcoma', 'Phenotype', 'HP:0002669', (43, 55))	('osteosarcoma', 'Disease', (43, 55))	('Deletion', 'Var', (0, 8))
363507	30830877	Regulation of the cell fate of this periosteal stem cell by deleting transcription factor OSX or tumor-suppressor LKB1 can lead to abnormal cortical architecture or even tumor formation, which shows the importance of understanding the cellular basis of skeletal pathology.	('deleting', 'Var', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('OSX', 'Gene', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('periosteal stem', 'Phenotype', 'HP:0031485', (36, 51))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('lead to', 'Reg', (123, 130))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (170, 175))	('Regulation', 'Reg', (0, 10))	('abnormal cortical architecture', 'CPA', (131, 161))	('LKB1', 'Gene', (114, 118))	('cell', 'CPA', (18, 22))	('OSX', 'Gene', '170574', (90, 93))	('skeletal pathology', 'Phenotype', 'HP:0000924', (253, 271))
363508	30830877	To clarify the role of Lkb1 function in human osteosarcomagenesis, we first searched for genetic mutations in Lkb1 in human osteosarcoma patients.	('mutations', 'Var', (97, 106))	('osteosarcomagenesis', 'Disease', (46, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('osteosarcoma', 'Disease', (124, 136))	('osteosarcoma', 'Disease', 'MESH:D012516', (46, 58))	('patients', 'Species', '9606', (137, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcoma', 'Disease', (46, 58))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('human', 'Species', '9606', (118, 123))	('Lkb1', 'Gene', (110, 114))	('osteosarcomagenesis', 'Disease', 'None', (46, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('human', 'Species', '9606', (40, 45))
363509	30830877	However, genetic mutations in Lkb1 have not yet been commonly found in human osteosarcoma, with the exception of one case report (c.937C>A), which might be restricted by the low incidence rate of the disease and the low availability of samples for sequencing.	('osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('c.937C>A', 'Var', (130, 138))	('genetic mutations', 'Var', (9, 26))	('Lkb1', 'Gene', (30, 34))	('c.937C>A', 'Mutation', 'c.937C>A', (130, 138))	('rat', 'Species', '10116', (188, 191))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('human', 'Species', '9606', (71, 76))	('osteosarcoma', 'Disease', (77, 89))
363510	30830877	In addition, allelic loss, LKB1 promoter hypermethylation, or reduced LKB1 expression is observed in a wide variety of sporadic cancers.	('hypermethylation', 'Var', (41, 57))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('sporadic cancers', 'Disease', 'MESH:D009369', (119, 135))	('LKB1', 'Gene', (27, 31))	('promoter hypermethylation', 'Var', (32, 57))	('allelic loss', 'Var', (13, 25))	('sporadic cancers', 'Disease', (119, 135))	('LKB1', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('expression', 'MPA', (75, 85))	('reduced', 'NegReg', (62, 69))
363512	30830877	Our study has proven that loss of Lkb1 in Ctsk+ cells can lead to osteosarcoma formation in mice and that LKB1 deficiency in a human osteosarcoma cell line could accelerate tumor formation, suggesting that further examination of mutations in Lkb1 and/or its upstream genes in human osteosarcoma is warranted.	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('LKB1 deficiency', 'Disease', 'MESH:D007153', (106, 121))	('LKB1 deficiency', 'Disease', (106, 121))	('Lkb1', 'Gene', (34, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	('mice', 'Species', '10090', (92, 96))	('human', 'Species', '9606', (276, 281))	('lead to', 'Reg', (58, 65))	('osteosarcoma', 'Disease', (282, 294))	('osteosarcoma', 'Disease', 'MESH:D012516', (282, 294))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))	('human', 'Species', '9606', (127, 132))	('osteosarcoma', 'Disease', (66, 78))	('accelerate', 'PosReg', (162, 172))	('osteosarcoma', 'Disease', 'MESH:D012516', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (282, 294))	('tumor', 'Disease', (173, 178))	('rat', 'Species', '10116', (168, 171))	('loss', 'Var', (26, 30))	('osteosarcoma', 'Disease', (133, 145))
363520	30830877	Collaborative multicenter, international, deep-sequencing efforts to study this disease might lead to the discovery of new mutations in osteosarcoma patients in the future.	('osteosarcoma', 'Disease', (136, 148))	('patients', 'Species', '9606', (149, 157))	('osteosarcoma', 'Phenotype', 'HP:0002669', (136, 148))	('osteosarcoma', 'Disease', 'MESH:D012516', (136, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('rat', 'Species', '10116', (7, 10))	('mutations', 'Var', (123, 132))
363523	30830877	Previous evidence indicates that LKB1 alterations contribute to cancer progression by modulating VEGF production.	('VEGF production', 'MPA', (97, 112))	('contribute', 'Reg', (50, 60))	('modulating', 'Reg', (86, 96))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('LKB1', 'Gene', (33, 37))	('alterations', 'Var', (38, 49))	('rat', 'Species', '10116', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
363524	30830877	We examined the expression of VEGF in the tumor region of Ctsk-CKO mice and found increased VEGF production in Ctsk-CKO mice (Supplemental Figure 7, E and F; see complete unedited blots in the supplemental material).	('CKO', 'Chemical', '-', (63, 66))	('tumor', 'Disease', (42, 47))	('mice', 'Species', '10090', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Ctsk-CKO', 'Var', (111, 119))	('VEGF production', 'MPA', (92, 107))	('increased', 'PosReg', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CKO', 'Chemical', '-', (116, 119))	('mice', 'Species', '10090', (67, 71))
363526	30830877	The fact that deletion of Lkb1 in LysM+ cells does not lead to tumor mass formation within the cortical bone confirms that osteoclasts are not involved in the pathogenesis of Lkb1-related osteosarcomas.	('osteosarcomas', 'Disease', (188, 201))	('tumor', 'Disease', (63, 68))	('osteosarcomas', 'Phenotype', 'HP:0002669', (188, 201))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('osteosarcomas', 'Disease', 'MESH:D012516', (188, 201))	('Lkb1', 'Gene', (26, 30))	('LysM', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('LysM', 'Gene', '17105', (34, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('deletion', 'Var', (14, 22))	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))
363527	30830877	Actually, both Ctsk-CKO and LysM-CKO mice showed increased osteoclast formation (Figure 3, B and C, and Supplemental Figure 7, G and H), and the tumor mass in Ctsk-CKO mice contained a large number of osteoclasts and osteoclast precursors (Figure 3A).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Ctsk-CKO', 'Var', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('increased', 'PosReg', (49, 58))	('mice', 'Species', '10090', (168, 172))	('Ctsk-CKO', 'Var', (15, 23))	('tumor', 'Disease', (145, 150))	('LysM', 'Gene', (28, 32))	('osteoclasts', 'CPA', (201, 212))	('osteoclast formation', 'CPA', (59, 79))	('CKO', 'Chemical', '-', (33, 36))	('LysM', 'Gene', '17105', (28, 32))	('mice', 'Species', '10090', (37, 41))	('CKO', 'Chemical', '-', (164, 167))	('CKO', 'Chemical', '-', (20, 23))
363528	30830877	Our previous study demonstrated that mTORC1 signaling plays a determinative role in osteoclast differentiation, as Raptor deficiency in osteoclasts resulted in increased bone mass with decreased bone resorption.	('increased bone mass', 'Phenotype', 'HP:0011001', (160, 179))	('decreased', 'NegReg', (185, 194))	('deficiency', 'Var', (122, 132))	('mTORC1', 'Gene', (37, 43))	('increased', 'PosReg', (160, 169))	('osteoclast', 'CPA', (84, 94))	('rat', 'Species', '10116', (26, 29))	('bone resorption', 'Phenotype', 'HP:0002797', (195, 210))	('mTORC1', 'Gene', '382056', (37, 43))	('Raptor', 'Gene', '74370', (115, 121))	('Raptor', 'Gene', (115, 121))	('bone resorption', 'CPA', (195, 210))	('bone mass', 'CPA', (170, 179))
363674	28852958	showed that antisense oligonucleotides against VEGF inhibit tumor cell proliferation in human cancer, including one patient with chondrosarcoma.	('inhibit', 'NegReg', (52, 59))	('chondrosarcoma', 'Disease', 'MESH:D002813', (129, 143))	('oligonucleotides', 'Chemical', 'MESH:D009841', (22, 38))	('patient', 'Species', '9606', (116, 123))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (129, 143))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('antisense oligonucleotides', 'Var', (12, 38))	('VEGF', 'Gene', (47, 51))	('human', 'Species', '9606', (88, 93))	('chondrosarcoma', 'Disease', (129, 143))	('tumor', 'Disease', (60, 65))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
363677	28852958	There are currently studies analyzing the efficacy of pazopanib in the management of surgically unresectable or metastatic chondrosarcoma patients (NCT01330966, NCT02066285).	('chondrosarcoma', 'Disease', 'MESH:D002813', (123, 137))	('man', 'Species', '9606', (71, 74))	('NCT02066285', 'Var', (161, 172))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (123, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('NCT01330966', 'Var', (148, 159))	('pazopanib', 'Chemical', 'MESH:C516667', (54, 63))	('patients', 'Species', '9606', (138, 146))	('chondrosarcoma', 'Disease', (123, 137))
363700	26549970	In surgical pathology, the PAP technique was originally used in ancillary diagnosis of hematological neoplasms, primarily to demonstrate monoclonality.	('neoplasms', 'Phenotype', 'HP:0002664', (101, 110))	('hematological neoplasms', 'Phenotype', 'HP:0004377', (87, 110))	('neoplasm', 'Phenotype', 'HP:0002664', (101, 109))	('hematological neoplasms', 'Disease', 'MESH:D019337', (87, 110))	('monoclonality', 'Var', (137, 150))	('hematological neoplasms', 'Disease', (87, 110))
363712	26549970	This was a major step forward in ancillary diagnosis but quickly became plagued with exceptions, such as leiomyosarcomas expressing cytokeratin.	('leiomyosarcomas', 'Disease', (105, 120))	('cytokeratin', 'Var', (132, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (105, 120))
363729	26549970	Abnormalities in imprinting were found to be common in embryonal neoplasms, tumors that look similar to embryonal tissues.	('common', 'Reg', (45, 51))	('embryonal neoplasms', 'Disease', (55, 74))	('embryonal neoplasms', 'Disease', 'MESH:D009373', (55, 74))	('Abnormalities', 'Var', (0, 13))	('neoplasm', 'Phenotype', 'HP:0002664', (65, 73))	('embryonal neoplasms', 'Phenotype', 'HP:0002898', (55, 74))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('imprinting', 'Gene', (17, 27))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('neoplasms', 'Phenotype', 'HP:0002664', (65, 74))
363743	26549970	However, exploration in the chromosome 22q deletions that repeatedly occurred, particularly in CNS tumors (known as atypical teratoid/rhabdoid tumors), revealed a single gene locus, SMARCB1, that was lost in lesions arising at all sites, primarily in aggressive infantile neoplasms.	('deletions', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('CNS tumors', 'Disease', 'MESH:D009369', (95, 105))	('neoplasm', 'Phenotype', 'HP:0002664', (272, 280))	('rhabdoid tumors', 'Disease', (134, 149))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (134, 149))	('CNS tumors', 'Disease', (95, 105))	('SMARCB1', 'Gene', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('neoplasms', 'Phenotype', 'HP:0002664', (272, 281))	('aggressive infantile neoplasms', 'Disease', (251, 281))	('SMARCB1', 'Gene', '6598', (182, 189))	('aggressive infantile neoplasms', 'Disease', 'MESH:D001523', (251, 281))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
363748	26549970	The field of tumor biology was revolutionized in the 1980s and 1990s by the discovery of fusion genes resulting from reciprocal translocations characteristic of specific diagnoses (Table 2).	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('fusion genes', 'Var', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
363750	26549970	One of the more common childhood lymphomas, anaplastic large cell lymphoma (ALCL), was found to have a characteristic gene fusion caused by a translocation t(2;5) that fuses the anaplastic lymphoma kinase 1 (ALK) and nucleophosmin 1 (NPM1) genes and their protein products.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (178, 197))	('lymphomas', 'Disease', (33, 42))	('cell lymphoma', 'Disease', (61, 74))	('caused by', 'Reg', (130, 139))	('NPM1', 'Gene', '4869', (234, 238))	('cell lymphoma', 'Phenotype', 'HP:0012191', (61, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (66, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('cell lymphoma', 'Disease', 'MESH:D016399', (61, 74))	('anaplastic lymphoma kinase', 'Gene', '238', (178, 204))	('anaplastic lymphoma kinase', 'Gene', (178, 204))	('nucleophosmin 1', 'Gene', '4869', (217, 232))	('lymphomas', 'Disease', 'MESH:D008223', (33, 42))	('ALK', 'Gene', '238', (208, 211))	('NPM1', 'Gene', (234, 238))	('lymphomas', 'Phenotype', 'HP:0002665', (33, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('ALK', 'Gene', (208, 211))	('nucleophosmin 1', 'Gene', (217, 232))	('fuses', 'Var', (168, 173))
363785	26549970	Tumors with high c-kit expression resulting from mutations may be recognized by IHC using anti-CD117 (Fig.	('CD117', 'Gene', (95, 100))	('high', 'PosReg', (12, 16))	('mutations', 'Var', (49, 58))	('c-kit', 'Gene', (17, 22))	('c-kit', 'Gene', '3815', (17, 22))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CD117', 'Gene', '3815', (95, 100))	('expression', 'MPA', (23, 33))
363787	26549970	The best known neoplasm with this mutation is the gastrointestinal stromal tumor (GIST).	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (50, 80))	('gastrointestinal stromal tumor', 'Disease', (50, 80))	('GIST', 'Phenotype', 'HP:0100723', (82, 86))	('mutation', 'Var', (34, 42))	('neoplasm', 'Disease', (15, 23))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (50, 80))	('neoplasm', 'Phenotype', 'HP:0002664', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('neoplasm', 'Disease', 'MESH:D009369', (15, 23))
363788	26549970	GISTs contain activating mutations that lead to high c-kit expression and a strong CD117 IHC staining pattern.	('mutations', 'Var', (25, 34))	('CD117', 'Gene', '3815', (83, 88))	('CD117', 'Gene', (83, 88))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('expression', 'MPA', (59, 69))	('high', 'PosReg', (48, 52))	('c-kit', 'Gene', '3815', (53, 58))	('c-kit', 'Gene', (53, 58))
363804	21170377	The percentage lung metastatic volume at 5 weeks (p = 0.08) and number of spontaneous deaths secondary to systemic tumor burden were lower in MMP1 silenced cell bearing mice.	('deaths', 'Disease', 'MESH:D003643', (86, 92))	('deaths', 'Disease', (86, 92))	('silenced', 'Var', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('lung metastatic volume at 5 weeks', 'CPA', (15, 48))	('mice', 'Species', '10090', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('lower', 'NegReg', (133, 138))	('MMP1', 'Gene', (142, 146))
363827	21170377	Subsequent studies demonstrated the correlation of MMP1 silencing by antisense oligonucleotides and shRNA with reduced invasive potential of sarcoma cells in vitro .	('sarcoma', 'Disease', (141, 148))	('antisense oligonucleotides', 'Var', (69, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('reduced', 'NegReg', (111, 118))	('oligonucleotides', 'Chemical', 'MESH:D009841', (79, 95))	('MMP1', 'Gene', (51, 55))	('silencing', 'NegReg', (56, 65))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))
363833	21170377	The results demonstrate that MMP1 silencing was associated with a trend of decreased rate of pulmonary metastasis but also increases in primary tumor volume and vascularization.	('vascularization', 'CPA', (161, 176))	('increases', 'PosReg', (123, 132))	('tumor', 'Disease', (144, 149))	('MMP1', 'Gene', (29, 33))	('pulmonary metastasis', 'Disease', (93, 113))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('silencing', 'Var', (34, 43))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (93, 113))	('decreased', 'NegReg', (75, 84))
363852	21170377	Tumors were visibly larger in mice bearing the MMP1 silenced clone and continued to show increased growth over time as depicted in the histogram.	('mice', 'Species', '10090', (30, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('growth', 'MPA', (99, 105))	('silenced', 'Var', (52, 60))	('MMP1', 'Gene', (47, 51))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('larger', 'PosReg', (20, 26))	('increased', 'PosReg', (89, 98))
363853	21170377	The differences in the mean tumor volume in two groups were statistically significant at 2, 4, and 5 weeks, (p<.04) (control = 349+-79; MMP1 = 900+-180 mm3 2 wks, control  = 3568+-277; MMP1 = 4690+-404 mm3 4 wks, and control  = 5636+-615; MMP1 = 7891+-716 mm3 5 wks respectively).	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('MMP1 = 4690+-404 mm3', 'Var', (185, 205))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('MMP1 = 900+-180 mm3', 'Var', (136, 155))
363854	21170377	Further analysis revealed that MMP1 silenced group had a constant rate of tumor growth over 5 weeks whereas mice bearing control group showed a plateau in tumor growth over time.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (155, 160))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Disease', (74, 79))	('silenced', 'Var', (36, 44))	('MMP1', 'Gene', (31, 35))
363864	21170377	The tumor containing MMP1 silenced cells demonstrates increased vascularity and increased number small vessels approaching the tumor cells.	('tumor', 'Disease', (4, 9))	('silenced', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('increased', 'PosReg', (80, 89))	('increased', 'PosReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('MMP1', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('vascularity', 'CPA', (64, 75))
363865	21170377	Analysis of vascularity revealed a statistically significant increase in mean vascular volume per unit volume of tumor for MMP1 silenced group (321233+-41140 threshold pixels) as compared to control (184283+-78021 threshold pixels) group (p = 0.01) (Figure 4E).	('tumor', 'Disease', (113, 118))	('321233+-41140', 'Var', (144, 157))	('vascular volume', 'MPA', (78, 93))	('MMP1', 'Gene', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('increase', 'PosReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
363902	21170377	It demonstrates that MMP1 silencing results in increased local tumor growth and increased vascularity of the primary tumor but less systemic disease burden in a xenogenic murine model of human sarcoma.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('sarcoma', 'Disease', 'MESH:D012509', (193, 200))	('murine', 'Species', '10090', (171, 177))	('tumor', 'Disease', (117, 122))	('increased', 'PosReg', (80, 89))	('vascularity', 'CPA', (90, 101))	('sarcoma', 'Disease', (193, 200))	('increased', 'PosReg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('MMP1', 'Gene', (21, 25))	('silencing', 'Var', (26, 35))	('human', 'Species', '9606', (187, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
363920	21170377	The observation that MMP1 silencing is associated with increased primary tumor volume is novel and is in contrast to what has been observed in breast cancer where MMP1 silenced tumors demonstrated reduced primary tumor size.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', (143, 156))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('increased', 'PosReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Disease', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('reduced', 'NegReg', (197, 204))	('tumor', 'Disease', (73, 78))	('MMP1', 'Gene', (21, 25))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('silencing', 'Var', (26, 35))	('tumors', 'Disease', (177, 183))
363939	21170377	The precise cellular and molecular mechanisms of MMP1 silenced cells leading to increase in local tumor growth; angiogenesis and a lower pulmonary burden are currently being pursued.	('increase', 'PosReg', (80, 88))	('angiogenesis', 'CPA', (112, 124))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('pulmonary burden', 'MPA', (137, 153))	('local', 'MPA', (92, 97))	('lower', 'NegReg', (131, 136))	('tumor', 'Disease', (98, 103))	('silenced', 'Var', (54, 62))	('MMP1', 'Gene', (49, 53))
364157	26718153	In addition to potential improvement in oncologic outcome (especially after R1 resections and/or in histological subtypes more prone to local relapse such as myxofibrosarcoma and malignant peripheral nerve sheath tumor), these combinations may also offer opportunities to decrease the RT dose for patients where local control would be anticipated to be high but there is concern about the potential toxicity of radiation.	('toxicity', 'Disease', (399, 407))	('RT dose', 'MPA', (285, 292))	('patients', 'Species', '9606', (297, 305))	('myxofibrosarcoma and malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (158, 218))	('decrease', 'NegReg', (272, 280))	('combinations', 'Var', (227, 239))	('toxicity', 'Disease', 'MESH:D064420', (399, 407))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (179, 218))	('improvement', 'PosReg', (25, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
364313	21807172	Histologic diagnosis is frequently required as the presence of pulmonary metastases elevates disease staging in bone sarcomas and, thus, alters therapy.	('disease staging', 'MPA', (93, 108))	('bone sarcomas', 'Disease', 'MESH:D001847', (112, 125))	('alters', 'Reg', (137, 143))	('bone sarcoma', 'Phenotype', 'HP:0002669', (112, 124))	('bone sarcomas', 'Disease', (112, 125))	('elevates', 'Reg', (84, 92))	('pulmonary metastases', 'Disease', (63, 83))	('pulmonary metastases', 'Disease', 'MESH:D009362', (63, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('therapy', 'MPA', (144, 151))	('bone sarcomas', 'Phenotype', 'HP:0002669', (112, 125))	('presence', 'Var', (51, 59))
364326	21807172	Though rare (occurring in about 2% - 6.5% of cases of high-grade osteosarcoma and even fewer in Ewing sarcoma), skip lesions impart a significantly worse patient outcome;; and necessitate modification of the surgical procedure; (Figure 1).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('patient', 'Species', '9606', (154, 161))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('skip lesions', 'Var', (112, 124))	('Ewing sarcoma', 'Disease', (96, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))
364341	21807172	A prognostically significant role of 18F-FDG PET/PET-CT based upon the intensity of metabolic activity in the primary tumor at the time of diagnosis has been suggested.	('18F-FDG', 'Chemical', 'MESH:D019788', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('primary tumor', 'Disease', (110, 123))	('18F-FDG', 'Var', (37, 44))	('primary tumor', 'Disease', 'MESH:D009369', (110, 123))
364589	30845657	(2004), who demonstrated that rapid tumor growth and shortened disease-free survival are associated with high Ki-67 expression, which is correlated with involvement of the vascular space.	('shortened', 'NegReg', (53, 62))	('high', 'Var', (105, 109))	('expression', 'MPA', (116, 126))	('disease-free survival', 'CPA', (63, 84))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Ki-67', 'Gene', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
364592	30845657	(2011), confirmed the fact that high Ki-67 expression correlated with worsened long-term prognosis for the patient (p = 0.01).	('worsened', 'NegReg', (70, 78))	('high', 'Var', (32, 36))	('Ki-67', 'Protein', (37, 42))	('long-term prognosis', 'CPA', (79, 98))	('patient', 'Species', '9606', (107, 114))	('expression', 'MPA', (43, 53))
364603	30845657	Also, p53 displays features of a transcription factor, so mutations within the DNA-binding domain inhibit the transcription of protein-encoding genes, which are responsible for cell protection against tumor invasion.	('mutations', 'Var', (58, 67))	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('D', 'Chemical', 'MESH:D003903', (79, 80))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('transcription of protein-encoding', 'MPA', (110, 143))	('inhibit', 'NegReg', (98, 105))	('tumor', 'Disease', (201, 206))
364604	30845657	Mutations in the TP53 gene which encodes the p53 protein are correlated with unfavorable prognosis for the affected patients.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('patients', 'Species', '9606', (116, 124))	('correlated', 'Reg', (61, 71))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
364637	30845657	p16 loss was detected in 5 out of 10 myxoid tumors and 2 out of 11 LMSs, but it was not found in IMTs (p = 0.0005), correlating with CDKN2A deletion (p = 0.014).	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('p16', 'Gene', (0, 3))	('LMSs', 'Phenotype', 'HP:0100243', (67, 71))	('CDKN2A', 'Gene', (133, 139))	('deletion', 'Var', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CDKN2A', 'Gene', '1029', (133, 139))	('myxoid tumors', 'Disease', (37, 50))	('myxoid tumors', 'Disease', 'MESH:D045888', (37, 50))	('p16', 'Gene', '1029', (0, 3))	('loss', 'NegReg', (4, 8))
364656	30845657	(2015), who evaluated changes in proliferating and apoptotic markers of UFs after SPRMs or GnRH agonists, PCNA and caspase-3 protein expression was found to be higher in the LM tissue after SPRMs in comparison to the control group (no difference between the control and GnRH agonists groups).	('GnRH', 'Gene', (91, 95))	('higher', 'PosReg', (160, 166))	('GnRH', 'Gene', '2796', (91, 95))	('PCNA', 'Gene', (106, 110))	('caspase-3', 'Gene', '836', (115, 124))	('SPRMs', 'Var', (190, 195))	('PCNA', 'Gene', '5111', (106, 110))	('GnRH', 'Gene', (270, 274))	('GnRH', 'Gene', '2796', (270, 274))	('caspase-3', 'Gene', (115, 124))
364665	30845657	Damage to the BCL2 gene has been identified as a causative agent in various cancers where overexpression of the anti-apoptotic genes and under-expression of the pro-apoptotic genes might occur.	('D', 'Chemical', 'MESH:D003903', (0, 1))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('BCL2', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Damage', 'Var', (0, 6))	('causative', 'Reg', (49, 58))	('under-expression', 'NegReg', (137, 153))	('overexpression', 'PosReg', (90, 104))	('BCL2', 'Gene', '596', (14, 18))
364667	30845657	As far as LM diagnostics and Bcl-2 are concerned, higher Bcl-2 expression was demonstrated in LMs cell as compared to the normal, healthy myometrium.	('higher', 'PosReg', (50, 56))	('expression', 'MPA', (63, 73))	('Bcl-2', 'Gene', (29, 34))	('Bcl-2', 'Gene', '596', (29, 34))	('Bcl-2', 'Gene', (57, 62))	('Bcl-2', 'Gene', '596', (57, 62))	('LMs', 'Var', (94, 97))
364674	30845657	These authors concluded that amplification of the BCL2 gene present in the STUMPs and its multiple copies suggest its potential role as a marker of STUMP malignancy potential.	('amplification', 'Var', (29, 42))	('BCL2', 'Gene', '596', (50, 54))	('BCL2', 'Gene', (50, 54))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('malignancy', 'Disease', (154, 164))
364676	30845657	According to Lusby et al., high Bcl-2 expression also predicted longer disease-specific survival in women with uterine LMS.	('longer', 'PosReg', (64, 70))	('expression', 'MPA', (38, 48))	('high', 'Var', (27, 31))	('Bcl-2', 'Gene', (32, 37))	('Bcl-2', 'Gene', '596', (32, 37))	('women', 'Species', '9606', (100, 105))	('disease-specific survival', 'CPA', (71, 96))	('uterine LMS', 'Disease', (111, 122))
364771	30845657	In comparative analysis, they disclosed that patients with LMS had much higher frequencies of genetic changes than those with benign tumors.	('benign tumors', 'Disease', (126, 139))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('genetic changes', 'Var', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('benign tumors', 'Disease', 'MESH:D009369', (126, 139))	('patients', 'Species', '9606', (45, 53))	('LMS', 'Disease', (59, 62))
364772	30845657	Specificity and sensitivity of the loss of heterozygosity and/or microsatellite instability markers were 92% and 95%, respectively.	('vit', 'Gene', (23, 26))	('loss of heterozygosity', 'Var', (35, 57))	('vit', 'Gene', '5212', (23, 26))	('microsatellite instability', 'Var', (65, 91))
364784	30845657	P.R., M.C., L.H., M.Z., T.L., P.D.	('P.R.', 'Var', (0, 4))	('M.Z.', 'Var', (18, 22))	('M.C.', 'Var', (6, 10))	('L.H.', 'Var', (12, 16))	('D', 'Chemical', 'MESH:D003903', (32, 33))
364785	30845657	P.R., C.K., P.D.	('P.R.', 'Var', (0, 4))	('C.K.', 'Var', (6, 10))	('D', 'Chemical', 'MESH:D003903', (14, 15))
364795	28073774	Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from immune control, indicating that total PD-L1 expression in the immediate tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared to monitoring PD-L1 expression on tumor cells alone.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('expression', 'Var', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (80, 85))	('PD-L1', 'Gene', (136, 141))	('tumor', 'Disease', (170, 175))	('PD-L1', 'Gene', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('rat', 'Species', '10116', (218, 221))	('tumor', 'Disease', (33, 38))	('lead to', 'Reg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('tumor', 'Disease', (332, 337))
364807	28073774	Resequencing of d42m1-T3 and d42m1-T9 cells confirmed their genomic stability over time.	('genomic stability', 'CPA', (60, 77))	('d42m1-T9', 'Var', (29, 37))	('d42m1-T3', 'Var', (16, 24))	('m1-T9', 'CellLine', 'CVCL:W349', (32, 37))
364808	28073774	As variant calling algorithms have become significantly more accurate since our initial reporting of these cell lines, we reassessed the mutational landscapes of T3 and T9 cells using the original sequence data and data from tumor cell line resequencing and found that the number of expressed missense mutations in T3 and T9 were 827 and 815, respectively.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('missense mutations', 'Var', (293, 311))	('rat', 'Species', '10116', (65, 68))
364823	28073774	Hamster anti-IFNgamma (H22) (Leinco Technologies) was used to neutralize mouse IFNgamma.	('Hamster', 'Species', '10034', (0, 7))	('IFNgamma', 'Gene', (13, 21))	('IFNgamma', 'Gene', '15978', (13, 21))	('neutralize', 'Var', (62, 72))	('mouse', 'Species', '10090', (73, 78))	('IFNgamma', 'Gene', (79, 87))	('IFNgamma', 'Gene', '15978', (79, 87))
364830	28073774	The procedures for detection of mutant Spectrin-beta2 by RT-PCR followed by restriction enzyme digestion were previously described in detail.	('mutant', 'Var', (32, 38))	('Spectrin-beta2', 'Gene', '20742', (39, 53))	('Spectrin-beta2', 'Gene', (39, 53))
364831	28073774	For detection of mutant Lama4 by qRT-PCR, a forward primer (5'-GGATGCCCAGAGGACTCTCTG-3') and a reverse primer (5'-GTAATGTTCGGAAATTGAAGCCTA-3') were used.	('Lama4', 'Gene', (24, 29))	('mutant', 'Var', (17, 23))	('Lama4', 'Gene', '16775', (24, 29))
364832	28073774	For detection of mutant Alg8 by qRT-PCR, a forward primer (5'-TCCCGTTTACCTCCTGGAAGC-3') and a reverse primer (5'-AGCATACAGCCTGGTCCAGGT-3') were used.	('Alg8', 'Gene', '381903', (24, 28))	('mutant', 'Var', (17, 23))	('Alg8', 'Gene', (24, 28))
364843	28073774	Tumor cells were transiently transfected with pX330-PD-L1 and pmaxGFP (Lonza) using FuGENE HD (Promega) according to the manufacture's instruction.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('HD', 'Disease', 'MESH:D006816', (91, 93))	('pmaxGFP', 'Gene', (62, 69))	('pX330-PD-L1', 'Var', (46, 57))
364845	28073774	PD-L1 wild-type parental tumor cells treated with pX330 and pmaxGFP, and the PD-L1 knockout cells were subsequently transduced with either the RV or the RV-PD-L1 to generate T3WT-Mock, T3DeltaPDL1-Mock, and T3DeltaPDL1-PDL1.	('rat', 'Species', '10116', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PDL1', 'Gene', (214, 218))	('PDL1', 'Gene', '60533', (214, 218))	('PDL1', 'Gene', (192, 196))	('pX330', 'Var', (50, 55))	('PDL1', 'Gene', '60533', (192, 196))	('PDL1', 'Gene', (219, 223))	('parental tumor', 'Disease', (16, 30))	('parental tumor', 'Disease', 'MESH:D063129', (16, 30))	('PDL1', 'Gene', '60533', (219, 223))
364855	28073774	The major subset, comprising ~80% of d42m1 cells (exemplified by d42m1-T9 (T9) cells), represents the highly immunogenic, unedited variant because it expresses an R913L somatic point mutation in Spectrin-beta2 (mSbeta2) that functions as a strong rejection neoantigen responsible, at least in part, for the spontaneous elimination of T9 cells when transplanted into naive syngeneic wild-type (WT) recipients.	('R913L', 'Var', (163, 168))	('mSbeta2', 'Gene', (211, 218))	('Spectrin-beta2', 'Gene', (195, 209))	('Spectrin-beta2', 'Gene', '20742', (195, 209))	('m1-T9', 'CellLine', 'CVCL:W349', (68, 73))	('R913L', 'Mutation', 'p.R913L', (163, 168))
364859	28073774	Such checkpoint blockade-induced immune rejection of T3 tumors is the result of reinvigoration of T cells with specificities against two dominant neoantigens specifically expressed in T3 cells derived from somatic point mutations in Laminin alpha subunit 4 (mLama4) and Asparagine-linked glycosylation 8 (alpha-1,3-glucosyltransferase) (mAlg8).	('Asparagine', 'Chemical', 'MESH:D001216', (270, 280))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mLama4', 'Gene', (258, 264))	('mLama4', 'Gene', '16775', (258, 264))	('T3 tumors', 'Disease', 'MESH:C537047', (53, 62))	('T3 tumors', 'Disease', (53, 62))	('Alg8', 'Gene', '381903', (338, 342))	('rat', 'Species', '10116', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('Alg8', 'Gene', (338, 342))	('point mutations', 'Var', (214, 229))
364871	28073774	When the capacities of parental T3 and two representative T3DeltaPDL1 lines to stimulate IFNgamma production from CTL74.17 mLama4-specific cytotoxic T-lymphocyte (CTL) clones were compared, T3DeltaPDL1 cells stimulated significantly more IFNgamma than T3WT cells, revealing that PD-L1 expression on T3 sarcoma cells functionally suppresses activation of tumor-specific CTL (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (302, 309))	('suppresses', 'NegReg', (329, 339))	('PDL1', 'Gene', '60533', (197, 201))	('tumor', 'Disease', (354, 359))	('PDL1', 'Gene', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('activation', 'MPA', (340, 350))	('PDL1', 'Gene', '60533', (65, 69))	('IFNgamma', 'Gene', '15978', (238, 246))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('PDL1', 'Gene', (65, 69))	('PD-L1 expression', 'Var', (279, 295))	('IFNgamma', 'Gene', '15978', (89, 97))	('IFNgamma', 'Gene', (238, 246))	('sarcoma', 'Disease', 'MESH:D012509', (302, 309))	('sarcoma', 'Disease', (302, 309))	('mLama4', 'Gene', (123, 129))	('mLama4', 'Gene', '16775', (123, 129))	('IFNgamma', 'Gene', (89, 97))
364902	28073774	Because the only source of PD-L1 in these experiments was from host cells, we treated mice with progressively growing T3DeltaPDL1 tumors with anti-PD-L1 or control mAb and found that therapeutic administration of the former but not the latter induced tumor rejection (Figs.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('PDL1', 'Gene', '60533', (125, 129))	('tumor', 'Disease', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('anti-PD-L1', 'Var', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mice', 'Species', '10090', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (130, 135))	('rat', 'Species', '10116', (203, 206))	('PDL1', 'Gene', (125, 129))
364911	28073774	Third, PD-L1 expression on TAMs was increased in tumor-bearing mice treated with either saturating doses of neutralizing anti-IFNgamma (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('expression', 'MPA', (13, 23))	('TAMs', 'Chemical', '-', (27, 31))	('tumor', 'Disease', (49, 54))	('mice', 'Species', '10090', (63, 67))	('rat', 'Species', '10116', (92, 95))	('increased', 'PosReg', (36, 45))	('neutralizing', 'Var', (108, 120))	('IFNgamma', 'Gene', (126, 134))	('IFNgamma', 'Gene', '15978', (126, 134))	('PD-L1', 'Gene', (7, 12))
364950	28386017	Given the frequency of alterations in this pathway, multiple clinical trials have been initiated to target mTOR in the setting of sarcoma, though with limited success.	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('mTOR', 'Gene', (107, 111))	('mTOR', 'Gene', '2475', (107, 111))	('sarcoma', 'Disease', (130, 137))	('alterations', 'Var', (23, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
364956	28386017	Inhibition of mTORC1 leads to the down-regulation of the phosphorylation status of the ribosomal protein S6 (S6) with a subsequent reduction of energy (ATP) and cofactors (NADPH), both essential for glucose metabolism and for other biosynthetic processes.	('mTORC1', 'Gene', (14, 20))	('reduction', 'NegReg', (131, 140))	('glucose metabolism', 'Disease', 'MESH:D044882', (199, 217))	('ribosomal protein S6', 'Gene', (87, 107))	('NADPH', 'Chemical', 'MESH:D009249', (172, 177))	('ribosomal protein S6', 'Gene', '6194', (87, 107))	('glucose metabolism', 'Disease', (199, 217))	('mTORC1', 'Gene', '382056', (14, 20))	('down-regulation', 'NegReg', (34, 49))	('Inhibition', 'Var', (0, 10))	('phosphorylation status', 'MPA', (57, 79))	('ATP', 'Chemical', 'MESH:D000255', (152, 155))
364964	28386017	Using dDNP, many substrates have been hyperpolarized and a strong enhancement of MR signal can been obtained (>104 fold increase) at various magnetic field strengths, permitting the evaluation of metabolism non-invasively.	('MR signal', 'MPA', (81, 90))	('dDNP', 'Chemical', '-', (6, 10))	('increase', 'PosReg', (120, 128))	('enhancement', 'PosReg', (66, 77))	('dDNP', 'Var', (6, 10))
364975	28386017	After washing and blocking, pS6K, PFK, pPKM2, pLDH-a and beta-actine antibody (1 mug/ml) (Cell Signaling Techology), diluted in TBS-T containing 5% BSA, was added and incubated for overnight at 4 C. The bound antibodies were detected by horseradish peroxidase-conjugated anti-goat Ig secondary antibody (Santa Cruz Biotechnology) followed by ECL detection system (Thermo Scientific) according to the manufacturer's instruction.	('pS6K', 'Gene', '6198', (28, 32))	('goat', 'Species', '9925', (276, 280))	('pS6K', 'Gene', (28, 32))	('TBS-T', 'Disease', 'MESH:D001260', (128, 133))	('TBS-T', 'Disease', (128, 133))	('pPKM2', 'Var', (39, 44))	('horseradish', 'Species', '3704', (237, 248))
365024	28386017	However, in all cell lines analyzed, the largest difference was a decrease in glycolytic flux from glucose to lactate after mTOR inhibition.	('mTOR', 'Gene', '2475', (124, 128))	('mTOR', 'Gene', (124, 128))	('glycolytic flux from glucose to lactate', 'MPA', (78, 117))	('inhibition', 'Var', (129, 139))	('glucose', 'Chemical', 'MESH:D005947', (99, 106))	('decrease', 'NegReg', (66, 74))	('lactate', 'Chemical', 'MESH:D019344', (110, 117))
365035	28386017	Upon entering the cell, HP [1-13C]pyruvate can be rapidly reduced to [1-13C] lactate, transaminated to [1-13C] alanine and oxidized, resulting in the formation of CO2 and later bicarbonate (HCO3) via carbonic anhydrase.	('bicarbonate', 'Chemical', 'MESH:D001639', (177, 188))	('[1-13C] alanine', 'Chemical', '-', (103, 118))	('HP [', 'Var', (24, 28))	('HCO3', 'Chemical', 'MESH:D001639', (190, 194))	('[1-13C] lactate', 'Chemical', '-', (69, 84))	('HP [1-13C]pyruvate', 'Chemical', '-', (24, 42))	('carbonic anhydrase', 'Enzyme', (200, 218))	('CO2', 'MPA', (163, 166))	('CO2', 'Chemical', '-', (163, 166))
365049	28386017	However, only JJ012 and CS1 tumors had a significant decrease in cell proliferation (p<0.05 for both) (Figure 4C).	('decrease', 'NegReg', (53, 61))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('JJ012', 'Var', (14, 19))	('cell proliferation', 'CPA', (65, 83))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
365143	31737137	Positivity of CD99 is highly specific for ES and is seen in our present case.	('CD99', 'Gene', '4267', (14, 18))	('ES', 'Phenotype', 'HP:0012254', (42, 44))	('ES', 'Disease', 'MESH:D012512', (42, 44))	('CD99', 'Gene', (14, 18))	('Positivity', 'Var', (0, 10))
365267	29731980	Mouse genetic background influences whether HrasG12V expression plus Cdkn2a knockdown causes angiosarcoma or undifferentiated pleomorphic sarcoma Soft tissue sarcomas are rare mesenchymal tumours accounting for 1% of adult malignancies and are fatal in approximately one third of patients.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('angiosarcoma', 'Disease', (93, 105))	('Cdkn2a', 'Gene', '12578', (69, 75))	('sarcomas', 'Disease', 'MESH:D012509', (158, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('knockdown', 'Var', (76, 85))	('sarcomas', 'Disease', (158, 166))	('malignancies', 'Disease', 'MESH:D009369', (223, 235))	('causes', 'Reg', (86, 92))	('malignancies', 'Disease', (223, 235))	('Cdkn2a', 'Gene', (69, 75))	('patients', 'Species', '9606', (280, 288))	('tumours', 'Disease', (188, 195))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (109, 145))	('Soft tissue sarcomas', 'Phenotype', 'HP:0030448', (146, 166))	('angiosarcoma', 'Disease', 'MESH:D006394', (93, 105))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('tumours', 'Disease', 'MESH:D009369', (188, 195))	('angiosarcoma', 'Phenotype', 'HP:0200058', (93, 105))	('HrasG12V expression', 'Var', (44, 63))	('Mouse', 'Species', '10090', (0, 5))	('undifferentiated pleomorphic sarcoma', 'Disease', (109, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
365270	29731980	Mice were intraveneously injected with MuLE lentiviruses expressing combinations of shRNA against Cdkn2a, Trp53, Tsc2 and Pten with or without expression of HrasG12V, PIK3CAH1047R or Myc.	('combinations', 'Var', (68, 80))	('Tsc2', 'Gene', (113, 117))	('Pten', 'Gene', '5728', (122, 126))	('Pten', 'Gene', (122, 126))	('Cdkn2a', 'Gene', (98, 104))	('Mice', 'Species', '10090', (0, 4))	('Trp53', 'Gene', (106, 111))	('MuLE', 'Species', '319699', (39, 43))
365275	29731980	Based on molecular characteristics, soft tissue sarcomas can be divided in two broad categories: sarcomas with simple karyotypes, such as chromosomal translocations, and sarcomas with more complex genetic profiles, including TP53 mutation, CDKN2A deletion and MDM2 amplification.	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('sarcomas', 'Disease', (48, 56))	('MDM2', 'Gene', (260, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('chromosomal', 'Disease', (138, 149))	('TP53', 'Gene', (225, 229))	('CDKN2A', 'Gene', (240, 246))	('sarcomas', 'Disease', 'MESH:D012509', (170, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('mutation', 'Var', (230, 238))	('sarcomas', 'Disease', (170, 178))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (36, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (36, 56))	('deletion', 'Var', (247, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcomas', 'Disease', (97, 105))
365279	29731980	HRAS and KRAS mutations have been identified in up to 50% of human UPS tumours.	('HRAS', 'Gene', (0, 4))	('KRAS', 'Gene', (9, 13))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('UPS tumours', 'Disease', 'MESH:D017118', (67, 78))	('human', 'Species', '9606', (61, 66))	('mutations', 'Var', (14, 23))	('UPS tumours', 'Disease', (67, 78))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
365280	29731980	Mouse studies have confirmed that the cooperation of oncogenic Kras and Trp53 or Cdkn2a deficiency resulted in the development of undifferentiated pleomorphic sarcomas in different tissues.	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('resulted in', 'Reg', (99, 110))	('Trp53', 'Gene', (72, 77))	('Cdkn2a deficiency', 'Phenotype', 'HP:0032421', (81, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('Cdkn2a', 'Gene', (81, 87))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (130, 167))	('undifferentiated pleomorphic sarcomas', 'Disease', (130, 167))	('Mouse', 'Species', '10090', (0, 5))	('Kras', 'Gene', (63, 67))	('Kras', 'Gene', '16653', (63, 67))	('deficiency', 'Var', (88, 98))
365285	29731980	Genetic mutations and amplifications of VEGF, MDM2, TP53, CDKN2A, KRAS and MYC have been described in angiosarcoma patients.	('patients', 'Species', '9606', (115, 123))	('VEGF', 'Gene', (40, 44))	('TP53', 'Gene', (52, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('angiosarcoma', 'Disease', 'MESH:D006394', (102, 114))	('MYC', 'Gene', (75, 78))	('angiosarcoma', 'Phenotype', 'HP:0200058', (102, 114))	('CDKN2A', 'Gene', (58, 64))	('angiosarcoma', 'Disease', (102, 114))	('VEGF', 'Gene', '7422', (40, 44))	('amplifications', 'Var', (22, 36))	('described', 'Reg', (89, 98))	('MDM2', 'Gene', (46, 50))	('KRAS', 'Gene', (66, 70))
365286	29731980	MYC gene amplifications are commonly found in radiation-induced angiosarcomas.	('MYC gene', 'Gene', (0, 8))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('angiosarcomas', 'Disease', 'MESH:D006394', (64, 77))	('found', 'Reg', (37, 42))	('angiosarcomas', 'Phenotype', 'HP:0200058', (64, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('amplifications', 'Var', (9, 23))	('angiosarcoma', 'Phenotype', 'HP:0200058', (64, 76))	('angiosarcomas', 'Disease', (64, 77))
365287	29731980	A recent publication reported that the majority of genetic alterations were found in the p53 and MAPK pathways.	('MAPK pathways', 'Pathway', (97, 110))	('p53', 'Gene', (89, 92))	('p53', 'Gene', '22059', (89, 92))	('genetic alterations', 'Var', (51, 70))
365288	29731980	53% of angiosarcomas displayed MAPK pathway activation, and harboured genetic activating mutations in KRAS, HRAS, NRAS, BRAF, MAPK1 or inactivating mutations in NF1 and PTPRB1.	('activation', 'PosReg', (44, 54))	('HRAS', 'Gene', (108, 112))	('BRAF', 'Gene', (120, 124))	('PTPRB1', 'Gene', (169, 175))	('NRAS', 'Gene', '18176', (114, 118))	('NRAS', 'Gene', (114, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('angiosarcomas', 'Disease', 'MESH:D006394', (7, 20))	('MAPK pathway', 'Pathway', (31, 43))	('activating', 'PosReg', (78, 88))	('inactivating mutations', 'Var', (135, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('angiosarcomas', 'Phenotype', 'HP:0200058', (7, 20))	('MAPK1', 'Gene', '26413', (126, 131))	('NF1', 'Gene', '18015', (161, 164))	('MAPK1', 'Gene', (126, 131))	('BRAF', 'Gene', '109880', (120, 124))	('angiosarcoma', 'Phenotype', 'HP:0200058', (7, 19))	('angiosarcomas', 'Disease', (7, 20))	('NF1', 'Gene', (161, 164))	('KRAS', 'Gene', (102, 106))
365290	29731980	In addition, the in vivo deletion of Cdkn2a in mice lead to the development of lesions which recapitulate human angiosarcoma, however, only 30% of the mice displayed angiosarcomas within 100 days.	('angiosarcomas', 'Disease', 'MESH:D006394', (166, 179))	('human', 'Species', '9606', (106, 111))	('angiosarcomas', 'Phenotype', 'HP:0200058', (166, 179))	('mice', 'Species', '10090', (151, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('angiosarcoma', 'Disease', (166, 178))	('Cdkn2a', 'Gene', (37, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('angiosarcoma', 'Disease', 'MESH:D006394', (112, 124))	('angiosarcoma', 'Phenotype', 'HP:0200058', (166, 178))	('deletion', 'Var', (25, 33))	('angiosarcomas', 'Disease', (166, 179))	('angiosarcoma', 'Disease', (112, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('angiosarcoma', 'Phenotype', 'HP:0200058', (112, 124))	('mice', 'Species', '10090', (47, 51))	('angiosarcoma', 'Disease', 'MESH:D006394', (166, 178))
365291	29731980	Furthermore, alterations in the PI3K/AKT/mTOR pathway have been identified in a small percentage of patients and deletion of Tsc1, a tumour suppressor that negatively regulates the pathway, induced the formation of hemangiosarcomas in mice.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (223, 231))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('angiosarcomas', 'Phenotype', 'HP:0200058', (218, 231))	('patients', 'Species', '9606', (100, 108))	('tumour', 'Disease', (133, 139))	('Tsc1', 'Gene', '7248', (125, 129))	('Tsc1', 'Gene', (125, 129))	('mice', 'Species', '10090', (235, 239))	('angiosarcoma', 'Phenotype', 'HP:0200058', (218, 230))	('mTOR', 'Gene', (41, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('AKT', 'Gene', (37, 40))	('mTOR', 'Gene', '2475', (41, 45))	('hemangiosarcomas', 'Disease', (215, 231))	('induced', 'Reg', (190, 197))	('hemangiosarcomas', 'Disease', 'MESH:D006394', (215, 231))	('deletion', 'Var', (113, 121))	('AKT', 'Gene', '207', (37, 40))
365292	29731980	Another report showed that the in vivo deletion of Notch1 resulted in the development of hepatic angiosarcomas with a penetrance of 86% at 50 weeks after gene deletion, although genetic alterations in the Notch pathway have not been reported in human angiosarcomas.	('angiosarcomas', 'Disease', (251, 264))	('Notch1', 'Gene', (51, 57))	('Notch1', 'Gene', '4851', (51, 57))	('angiosarcomas', 'Phenotype', 'HP:0200058', (97, 110))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('Notch', 'Gene', '4851;18128', (51, 56))	('deletion', 'Var', (39, 47))	('angiosarcomas', 'Disease', 'MESH:D006394', (97, 110))	('angiosarcomas', 'Disease', (97, 110))	('Notch', 'Gene', (51, 56))	('human', 'Species', '9606', (245, 250))	('angiosarcoma', 'Phenotype', 'HP:0200058', (97, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('hepatic angiosarcomas', 'Disease', (89, 110))	('angiosarcomas', 'Disease', 'MESH:D006394', (251, 264))	('angiosarcoma', 'Phenotype', 'HP:0200058', (251, 263))	('hepatic angiosarcomas', 'Disease', 'MESH:D006394', (89, 110))	('angiosarcomas', 'Phenotype', 'HP:0200058', (251, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('Notch', 'Gene', '4851;18128', (205, 210))	('Notch', 'Gene', (205, 210))	('sarcomas', 'Phenotype', 'HP:0100242', (256, 264))
365295	29731980	Different mouse strains were injected intraveneously with ecotropic MuLE lentiviruses expressing combinations of shRNA against Cdkn2a, Trp53, Tsc2 and Pten with or without expression of HrasG12V, PIK3CAH1047R or Myc.	('mouse', 'Species', '10090', (10, 15))	('Trp53', 'Gene', (135, 140))	('Pten', 'Gene', '5728', (151, 155))	('Pten', 'Gene', (151, 155))	('combinations', 'Var', (97, 109))	('MuLE', 'Species', '319699', (68, 72))	('Tsc2', 'Gene', (142, 146))	('Cdkn2a', 'Gene', (127, 133))
365299	29731980	We first utilised these ecotropic MuLE lentiviruses expressing combinations of shRNA or shRNA-miR30 against Cdkn2a, Trp53, Tsc2 and Pten with or without expression of oncogenic HrasG12V, oncogenic PIK3CAH1047R or Myc vectors to attempt to generate panels of genetically-engineered angiosarcoma cell lines by infecting a disease-relevant cell type, namely primary murine endothelial cells from the spleen (pMSECs).	('Cdkn2a', 'Gene', (108, 114))	('MuLE', 'Species', '319699', (34, 38))	('angiosarcoma', 'Phenotype', 'HP:0200058', (281, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (286, 293))	('Tsc2', 'Gene', (123, 127))	('combinations', 'Var', (63, 75))	('shRNA-miR30', 'Gene', (88, 99))	('angiosarcoma', 'Disease', 'MESH:D006394', (281, 293))	('murine', 'Species', '10090', (363, 369))	('Pten', 'Gene', '5728', (132, 136))	('angiosarcoma', 'Disease', (281, 293))	('Trp53', 'Gene', (116, 121))	('Pten', 'Gene', (132, 136))
365301	29731980	The absence of increased proliferation induced by oncogenic HrasG12V or oncogenic HrasG12V plus Trp53 knockdown is likely to be mediated by the upregulation of p16INK4A protein expression observed in pMSEC cells infected with these vectors (Supplementary Figure 1B) as removal of this putative proliferative barrier by knockdown of Cdkn2a increased cellular proliferation (Supplementary Figure 2A).	('p16INK4A', 'Gene', '12578', (160, 168))	('p16INK4A', 'Gene', (160, 168))	('Trp53', 'Gene', (96, 101))	('Supplementary Figure 1B', 'Disease', (241, 264))	('cellular proliferation', 'CPA', (349, 371))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (241, 264))	('knockdown', 'Var', (319, 328))	('Cdkn2a', 'Gene', (332, 338))	('upregulation', 'PosReg', (144, 156))	('increased', 'PosReg', (339, 348))
365310	29731980	From 32 mice injected with shCdkn2a plus HrasG12V MuLE vectors, 21 mice developed a total of 24 tumours in various tissues including testicle (n = 9, 38%), brain (n = 7, 30%), spleen (n = 2, 8%), uterus (n = 2, 8%), ovary (n = 1, 4%), lung (n = 1, 4%), colon (n = 1, 4%) and eye (n = 1, 4%).	('mice', 'Species', '10090', (67, 71))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('colon', 'Disease', 'MESH:D015179', (253, 258))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('MuLE', 'Species', '319699', (50, 54))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumours', 'Disease', (96, 103))	('colon', 'Disease', (253, 258))	('mice', 'Species', '10090', (8, 12))	('shCdkn2a', 'Var', (27, 35))
365318	29731980	Tumours that arose in Trp53 knockdown plus oncogenic HrasG12V injected mice displayed an identical histological appearance and immunohistochemical staining profile to tumours in Cdkn2a knockdown plus oncogenic HrasG12V injected mice (Figure 2B).	('mice', 'Species', '10090', (71, 75))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('tumours', 'Disease', (167, 174))	('knockdown', 'Var', (28, 37))	('Trp53', 'Gene', (22, 27))	('mice', 'Species', '10090', (228, 232))
365332	29731980	Intraveneous injections of shCdkn2a plus HrasG12V MuLE viruses in 129/Sv mice (n = 8) caused a strong luciferase signal increase and the development of multiple tumours with 100% penetrance within 4 weeks (Figure 3A and 3B, Supplementary Figure 6A).	('multiple tumours', 'Disease', 'MESH:D009369', (152, 168))	('129/Sv', 'Species', '10090', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('mice', 'Species', '10090', (73, 77))	('increase', 'PosReg', (120, 128))	('tumours', 'Phenotype', 'HP:0002664', (161, 168))	('luciferase', 'Enzyme', (102, 112))	('MuLE', 'Species', '319699', (50, 54))	('multiple tumours', 'Disease', (152, 168))	('shCdkn2a', 'Var', (27, 35))
365349	29731980	While normal skin showed strong nuclear p63 immunoreactivity as an internal positive control, only a small number of scattered cells in tumours in 129/Sv mice displayed weak cytoplasmic staining for p63 (Figure 4G), arguing against a diagnosis of sarcomatoid squamous cell carcinoma.	('129/Sv', 'Species', '10090', (147, 153))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('mice', 'Species', '10090', (154, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (259, 282))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('tumours', 'Disease', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('sarcomatoid squamous cell carcinoma', 'Disease', 'MESH:C538614', (247, 282))	('sarcomatoid squamous cell carcinoma', 'Disease', (247, 282))	('sarcoma', 'Phenotype', 'HP:0100242', (247, 254))	('p63', 'Var', (199, 202))
365361	29731980	Based on these results we conclude that shCdkn2a plus HrasG12V MuLE viruses solely cause high-grade UPS in C57BL/6 mice.	('high-grade UPS', 'MPA', (89, 103))	('MuLE', 'Species', '319699', (63, 67))	('shCdkn2a', 'Var', (40, 48))	('cause', 'Reg', (83, 88))	('mice', 'Species', '10090', (115, 119))
365366	29731980	Guided by the genetics of human angiosarcomas and UPS tumours, we functionally tested the contributions of the candidate sarcoma tumour suppressors Cdkn2a, Trp53, Tsc2 and Pten and the candidate oncogenes HrasG12V, PIK3CAH1047R or Myc.	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('PIK3CAH1047R', 'Var', (215, 227))	('Pten', 'Gene', '5728', (172, 176))	('Pten', 'Gene', (172, 176))	('human', 'Species', '9606', (26, 31))	('tested', 'Reg', (79, 85))	('sarcoma tumour', 'Disease', 'MESH:D012509', (121, 135))	('angiosarcoma', 'Phenotype', 'HP:0200058', (32, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('Cdkn2a', 'Gene', (148, 154))	('angiosarcomas', 'Phenotype', 'HP:0200058', (32, 45))	('Trp53', 'Gene', (156, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('Tsc2', 'Gene', (163, 167))	('angiosarcomas and UPS tumours', 'Disease', 'MESH:D017118', (32, 61))	('sarcoma tumour', 'Disease', (121, 135))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
365369	29731980	These observations are consistent with the fact that RAS-MAPK and p53 pathway alterations are frequently found in high-grade soft tissue sarcomas, such as angiosarcomas and UPS.	('angiosarcomas', 'Phenotype', 'HP:0200058', (155, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('angiosarcomas', 'Disease', (155, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('found', 'Reg', (105, 110))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (125, 144))	('p53', 'Gene', '22059', (66, 69))	('sarcomas', 'Disease', 'MESH:D012509', (137, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('angiosarcomas', 'Disease', 'MESH:D006394', (155, 168))	('sarcomas', 'Disease', (137, 145))	('angiosarcoma', 'Phenotype', 'HP:0200058', (155, 167))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (125, 145))	('sarcomas', 'Disease', 'MESH:D012509', (160, 168))	('alterations', 'Var', (78, 89))	('UPS', 'Disease', (173, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('sarcomas', 'Disease', (160, 168))	('p53', 'Gene', (66, 69))
365383	29731980	Our data demonstrate that the same combination of genetic drivers can cause different types of tumours based not only on the site of viral delivery, likely due to infection of different cell types, but also based on the genetic background of the mouse strain.	('genetic', 'Var', (50, 57))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumours', 'Disease', (95, 102))	('mouse', 'Species', '10090', (246, 251))	('infection', 'Disease', (163, 172))	('cause', 'Reg', (70, 75))	('infection', 'Disease', 'MESH:D007239', (163, 172))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
365384	29731980	Why does intraveneous, lentiviral-mediated delivery of the same genetic alterations cause different tumours in different strains of mice?	('tumours', 'Disease', (100, 107))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('mice', 'Species', '10090', (132, 136))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('genetic alterations', 'Var', (64, 83))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('cause', 'Reg', (84, 89))
365385	29731980	One possibility relates to genetic modifiers such as allelic variants, sequence differences, epigenetic modifications and gene expression levels that could potentially influence tumour phenotypes.	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('sequence differences', 'Var', (71, 91))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('influence', 'Reg', (168, 177))	('epigenetic modifications', 'Var', (93, 117))	('tumour', 'Disease', (178, 184))	('allelic variants', 'Var', (53, 69))
365389	29731980	In the context of the results of the present study, it might be possible in future long-term and large-scale studies to utilise multi-generational interbreeding strategies between C57BL/6 and Fox Chase CB17 strains, coupled with genomic analyses, to narrow down loci that contribute to the type of sarcoma that develops in response to oncogenic HrasG12V expression and Cdkn2a knockdown.	('Cdkn2a', 'Gene', (369, 375))	('HrasG12V expression', 'Var', (345, 364))	('sarcoma', 'Disease', 'MESH:D012509', (298, 305))	('sarcoma', 'Disease', (298, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (298, 305))	('knockdown', 'Var', (376, 385))
365390	29731980	By extension, our observations highlight the fact that also in humans the genetic background of every individual may potentially influence the outcome of oncogenic mutations in terms of what type of sarcoma develops.	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('influence', 'Reg', (129, 138))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('mutations', 'Var', (164, 173))	('humans', 'Species', '9606', (63, 69))	('sarcoma', 'Disease', (199, 206))
365391	29731980	In this context, it is noteworthy that a study of UPS tumours in Korean patients identified a high frequency of oncogenic KRAS and HRAS mutations, but a study by the same authors of UPS tumours in American patients revealed that these tumours lacked KRAS and HRAS mutations, arguing that different human genetic backgrounds (or environmental factors) may select for different oncogenic mutations during the course of sarcoma development.	('human', 'Species', '9606', (298, 303))	('tumours', 'Phenotype', 'HP:0002664', (235, 242))	('tumours', 'Disease', (186, 193))	('tumours', 'Disease', 'MESH:D009369', (235, 242))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (136, 145))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('sarcoma', 'Disease', 'MESH:D012509', (417, 424))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('sarcoma', 'Disease', (417, 424))	('HRAS', 'Gene', (131, 135))	('KRAS', 'Gene', (122, 126))	('UPS tumours', 'Disease', 'MESH:D017118', (50, 61))	('UPS tumours', 'Disease', (50, 61))	('tumours', 'Disease', (54, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (417, 424))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('UPS tumours', 'Disease', 'MESH:D017118', (182, 193))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('UPS tumours', 'Disease', (182, 193))	('tumours', 'Disease', (235, 242))	('patients', 'Species', '9606', (206, 214))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('patients', 'Species', '9606', (72, 80))
365395	29731980	However, the majority of these tumours exhibit loss-of-function point mutations or copy number deletions of the TP53 and CDKN2A tumour suppressor genes and all but one of these tumours exhibit multiple copy number gains or amplifications of genes involved in the RAS-RAF-MEK-MAPK signalling cascade, as well as copy number losses of the NF1 tumour suppressor gene that negatively regulates signalling by this cascade.	('tumours', 'Disease', (177, 184))	('copy number deletions', 'Var', (83, 104))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('CDKN2A', 'Gene', (121, 127))	('RAF', 'Gene', '387609', (267, 270))	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('amplifications', 'PosReg', (223, 237))	('tumours exhibit multiple copy number gains', 'Disease', 'MESH:D015430', (177, 219))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('MEK', 'Gene', '17242', (271, 274))	('tumours', 'Disease', (31, 38))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumours exhibit multiple copy number gains', 'Disease', (177, 219))	('tumour', 'Disease', (177, 183))	('NF1', 'Gene', '18015', (337, 340))	('copy number losses', 'Var', (311, 329))	('tumour', 'Phenotype', 'HP:0002664', (341, 347))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (341, 347))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('NF1', 'Gene', (337, 340))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Disease', (341, 347))	('TP53', 'Gene', (112, 116))	('tumour', 'Disease', (128, 134))	('point mutations', 'Var', (64, 79))	('MEK', 'Gene', (271, 274))	('loss-of-function', 'NegReg', (47, 63))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('RAF', 'Gene', (267, 270))	('tumour', 'Disease', (31, 37))
365396	29731980	These results give rise to a hypothesis that could be tested in future studies, namely that chromosomal copy number alterations rather than point mutations account for activation of the RAS-signalling pathway in combination with loss of the CDKN2A-TP53 tumour suppressor pathways to drive UPS tumour formation in non-Asian individuals.	('CDKN2A-TP53', 'Gene', (241, 252))	('drive', 'PosReg', (283, 288))	('tumour', 'Disease', (293, 299))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('UPS tumour', 'Disease', 'MESH:D017118', (289, 299))	('tumour', 'Disease', (253, 259))	('loss', 'NegReg', (229, 233))	('UPS tumour', 'Disease', (289, 299))	('chromosomal copy number alterations', 'Var', (92, 127))	('tumour', 'Phenotype', 'HP:0002664', (293, 299))	('activation', 'PosReg', (168, 178))	('RAS-signalling pathway', 'Pathway', (186, 208))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('tumour', 'Disease', 'MESH:D009369', (293, 299))
365402	29731980	Consistent with the idea that angiosarcoma and UPS tumours might arise due to the infection of different cell types it is noteworthy that all of the UPS tumours that arose in 129/Sv and C57BL/6 mice were subcutaneous, whereas angiosargomas in 129/Sv, Fox Chase CB17 and SCID/beige mice were found in several different organs.	('UPS tumours', 'Disease', (47, 58))	('UPS tumours', 'Disease', 'MESH:D017118', (47, 58))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('angiosarcoma', 'Disease', (30, 42))	('angiosargomas', 'Disease', (226, 239))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('angiosargomas', 'Disease', 'None', (226, 239))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('C57BL/6', 'Var', (186, 193))	('129/Sv', 'Species', '10090', (243, 249))	('mice', 'Species', '10090', (194, 198))	('SCID', 'Disease', 'MESH:D053632', (270, 274))	('mice', 'Species', '10090', (281, 285))	('129/Sv', 'Species', '10090', (175, 181))	('SCID', 'Disease', (270, 274))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('129/Sv', 'Var', (175, 181))	('angiosarcoma', 'Disease', 'MESH:D006394', (30, 42))	('UPS tumours', 'Disease', (149, 160))	('UPS tumours', 'Disease', 'MESH:D017118', (149, 160))	('infection', 'Disease', (82, 91))	('infection', 'Disease', 'MESH:D007239', (82, 91))	('angiosarcoma', 'Phenotype', 'HP:0200058', (30, 42))
365414	29731980	While it is somewhat surprising that the other tested candidate tumour suppressors and oncogenes were not sufficient to cause tumour formation, given their frequent mutational alteration in human angiosarcomas and UPS, the flexible nature of the MuLE system should also allow the testing of other candidate oncogenes, modifier genes or tumour suppressor genes that will likely continue to emerge from ongoing genomic studies of these rare tumours.	('tumours', 'Phenotype', 'HP:0002664', (439, 446))	('tumours', 'Disease', 'MESH:D009369', (439, 446))	('angiosarcomas', 'Disease', (196, 209))	('mutational alteration', 'Var', (165, 186))	('MuLE', 'Species', '319699', (246, 250))	('tumour', 'Phenotype', 'HP:0002664', (439, 445))	('tumour', 'Disease', 'MESH:D009369', (439, 445))	('tumour', 'Disease', (439, 445))	('human', 'Species', '9606', (190, 195))	('tumour', 'Phenotype', 'HP:0002664', (336, 342))	('sarcomas', 'Phenotype', 'HP:0100242', (201, 209))	('tumour', 'Disease', 'MESH:D009369', (336, 342))	('angiosarcomas', 'Disease', 'MESH:D006394', (196, 209))	('tumour', 'Disease', (336, 342))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('angiosarcoma', 'Phenotype', 'HP:0200058', (196, 208))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (64, 70))	('tumour', 'Disease', (126, 132))	('tumours', 'Disease', (439, 446))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('angiosarcomas', 'Phenotype', 'HP:0200058', (196, 209))
365441	27897164	Approximately 95% of SSs are characterized by fusion between one of the SSX genes (SSX1, SSX2, or SSX4) on the X chromosome and the SYT gene on chromosome 18.	('SSX', 'Gene', (72, 75))	('SS', 'Phenotype', 'HP:0012570', (89, 91))	('SS', 'Phenotype', 'HP:0012570', (98, 100))	('SSX2', 'Gene', '6757', (89, 93))	('SYT', 'Gene', '6760', (132, 135))	('SS', 'Phenotype', 'HP:0012570', (72, 74))	('SSX', 'Gene', '6757', (83, 86))	('SSX', 'Gene', '6757', (89, 92))	('SSX', 'Gene', '6757', (98, 101))	('SSX1', 'Gene', '6756', (83, 87))	('SS', 'Phenotype', 'HP:0012570', (83, 85))	('SSX1', 'Gene', (83, 87))	('SSs', 'Disease', (21, 24))	('SSX', 'Gene', (83, 86))	('SSX', 'Gene', (89, 92))	('SSX', 'Gene', (98, 101))	('SSX4', 'Gene', (98, 102))	('SS', 'Phenotype', 'HP:0012570', (21, 23))	('SSX', 'Gene', '6757', (72, 75))	('SYT', 'Gene', (132, 135))	('SSX4', 'Gene', '6759', (98, 102))	('SSX2', 'Gene', (89, 93))	('fusion', 'Var', (46, 52))
365442	27897164	It has been confirmed that the morphological characteristics of SS are closely associated with SYT-SSX gene fusion.	('associated', 'Reg', (79, 89))	('SS', 'Phenotype', 'HP:0012570', (99, 101))	('SS', 'Phenotype', 'HP:0012570', (64, 66))	('SSX', 'Gene', '6757', (99, 102))	('SYT', 'Gene', (95, 98))	('SSX', 'Gene', (99, 102))	('gene fusion', 'Var', (103, 114))	('SYT', 'Gene', '6760', (95, 98))
365443	27897164	Oxymatrine(OMT), an alkaloid extracted from a traditional Chinese medicinal herb, Sophora flavescens, with a molecular formula of C15H24N2O2, has attracted much attention because of its multiple pharmacological effects and low toxicity.	('toxicity', 'Disease', 'MESH:D064420', (227, 235))	('Sophora flavescens', 'Species', '49840', (82, 100))	('C15H24N2O2', 'Chemical', '-', (130, 140))	('Oxymatrine', 'Chemical', 'MESH:C037573', (0, 10))	('alkaloid', 'Chemical', 'MESH:D000470', (20, 28))	('toxicity', 'Disease', (227, 235))	('C15H24N2O2', 'Var', (130, 140))	('OMT', 'Chemical', 'MESH:C037573', (11, 14))
365462	27897164	To further investigate whether OMT regulates autophagic flux, we used two autophagic inhibitors: Baf A1, a lysosomal inhibitor, to block the autophagic pathway at a late step, and E64D/pepstatin A, an inhibitor of lysosomal enzymes.	('OMT', 'Chemical', 'MESH:C037573', (31, 34))	('E64D', 'Var', (180, 184))	('block', 'NegReg', (131, 136))	('E64D', 'SUBSTITUTION', 'None', (180, 184))	('pepstatin A', 'Chemical', 'MESH:C031375', (185, 196))	('Baf A1', 'Gene', (97, 103))	('autophagic pathway', 'CPA', (141, 159))
365463	27897164	The results showed that the expression of LC3-II was further increased in the presence of Baf A1 or E64d/pepstatin A via 2 mM OMT treatment in SW982 cells (Fig.	('LC3-II', 'Gene', '84557', (42, 48))	('OMT', 'Chemical', 'MESH:C037573', (126, 129))	('E64d/pepstatin', 'Var', (100, 114))	('pepstatin A', 'Chemical', 'MESH:C031375', (105, 116))	('expression', 'MPA', (28, 38))	('LC3-II', 'Gene', (42, 48))	('SW982', 'CellLine', 'CVCL:1734', (143, 148))	('increased', 'PosReg', (61, 70))	('Baf A1', 'Gene', (90, 96))
365472	27897164	3c, after 1 mM or 4 mM OMT treatment for 48 h, cleavage of PARP increased more dramatically in the presence of 3-MA.	('cleavage', 'CPA', (47, 55))	('PARP', 'Gene', (59, 63))	('OMT', 'Chemical', 'MESH:C037573', (23, 26))	('PARP', 'Gene', '142', (59, 63))	('3-MA', 'Var', (111, 115))	('increased', 'PosReg', (64, 73))	('3-MA', 'Chemical', 'MESH:C031080', (111, 115))
365473	27897164	Because of concerns for the specificity of 3-MA as an autophagy inhibitor, we also examined the role of OMT-induced autophagy via knockdown of ATG7 gene.	('3-MA', 'Chemical', 'MESH:C031080', (43, 47))	('ATG7', 'Gene', '10533', (143, 147))	('OMT', 'Chemical', 'MESH:C037573', (104, 107))	('knockdown', 'Var', (130, 139))	('examined', 'Reg', (83, 91))	('ATG7', 'Gene', (143, 147))
365507	27897164	The concentrations of OMT used in the present study ranged from 0.5 mM to 4 mM, and the culture periods ranged from 6 h to 48 h of continuous exposure to OMT; 5 mM 3-MA, 5 muM MK-2206 2HCL or 100 nM Rapa was used to pretreat the cells for 2 h prior to OMT treatment, and E64d/pepstatin A (10 mug/ml E64d and 10 mug/ml pepstatin A) or 100 nM Baf A1 was added to the cell cultures for the last 24 h of OMT treatment.	('MK-2206 2HCL', 'Chemical', '-', (176, 188))	('E64d/pepstatin', 'Var', (271, 285))	('pepstatin A', 'Chemical', 'MESH:C031375', (276, 287))	('pepstatin A', 'Chemical', 'MESH:C031375', (318, 329))	('3-MA', 'Chemical', 'MESH:C031080', (164, 168))	('OMT', 'Chemical', 'MESH:C037573', (252, 255))	('E64d', 'Var', (299, 303))	('OMT', 'Chemical', 'MESH:C037573', (400, 403))	('OMT', 'Chemical', 'MESH:C037573', (22, 25))	('OMT', 'Chemical', 'MESH:C037573', (154, 157))	('Rapa', 'Chemical', 'MESH:D020123', (199, 203))
365513	27897164	Following different treatments, proteins were extracted with RIPA buffer (Beyotime, Shanghai, China) supplemented with protease inhibitor cocktail (Beyotime, Shanghai, China) on ice and then quantified using the BCA method (Thermo Scientific, Waltham, MA, USA).	('RIPA buffer', 'Chemical', '-', (61, 72))	('Beyotime', 'Var', (148, 156))	('proteins', 'Protein', (32, 40))
365525	27897164	In the present study, we demonstrated that OMT inhibited cell viability and induced apoptosis and autophagy in SW982 cells.	('inhibited', 'NegReg', (47, 56))	('apoptosis', 'CPA', (84, 93))	('OMT', 'Var', (43, 46))	('autophagy', 'CPA', (98, 107))	('OMT', 'Chemical', 'MESH:C037573', (43, 46))	('SW982', 'CellLine', 'CVCL:1734', (111, 116))	('cell viability', 'CPA', (57, 71))	('induced', 'Reg', (76, 83))
365526	27897164	OMT-induced autophagy is an adaptive mechanism, and inhibition of autophagy enhanced OMT-induced cell apoptosis.	('OMT-induced', 'Disease', (85, 96))	('autophagy', 'CPA', (66, 75))	('inhibition', 'Var', (52, 62))	('enhanced', 'PosReg', (76, 84))	('OMT', 'Chemical', 'MESH:C037573', (85, 88))	('OMT', 'Chemical', 'MESH:C037573', (0, 3))
365532	27897164	Our results indicated that OMT inhibited cell viability and induced apoptosis in SW982 cells.	('induced', 'Reg', (60, 67))	('SW982', 'CellLine', 'CVCL:1734', (81, 86))	('cell viability', 'CPA', (41, 55))	('apoptosis', 'CPA', (68, 77))	('OMT', 'Var', (27, 30))	('inhibited', 'NegReg', (31, 40))	('OMT', 'Chemical', 'MESH:C037573', (27, 30))
365536	27897164	Transmission electron microscopy studies revealed that more autophagosomes were present in OMT treated cells than in non-treated cells.	('OMT', 'Chemical', 'MESH:C037573', (91, 94))	('OMT treated', 'Var', (91, 102))	('autophagosomes', 'CPA', (60, 74))	('more', 'PosReg', (55, 59))
365538	27897164	We found that the expression of LC3-II was further increased in the presence of Baf A1 or E64d/pepstatin A via 2 mM OMT treatment in SW982 cells.	('E64d/pepstatin', 'Var', (90, 104))	('pepstatin A', 'Chemical', 'MESH:C031375', (95, 106))	('SW982', 'CellLine', 'CVCL:1734', (133, 138))	('increased', 'PosReg', (51, 60))	('expression', 'MPA', (18, 28))	('LC3-II', 'Gene', '84557', (32, 38))	('Baf A1', 'Gene', (80, 86))	('OMT', 'Chemical', 'MESH:C037573', (116, 119))	('LC3-II', 'Gene', (32, 38))
365539	27897164	These findings indicate that autophagy was induced by OMT in SW982 cells.	('SW982', 'CellLine', 'CVCL:1734', (61, 66))	('OMT', 'Var', (54, 57))	('induced', 'Reg', (43, 50))	('autophagy', 'CPA', (29, 38))	('OMT', 'Chemical', 'MESH:C037573', (54, 57))
365547	27897164	After knockdown of HMGB1 by siRNA, the expression of LC3-II decreased significantly, which indicated that OMT-induced autophagy may be regulated by HMGB1.	('HMGB1', 'Gene', '3146', (19, 24))	('OMT', 'Chemical', 'MESH:C037573', (106, 109))	('decreased', 'NegReg', (60, 69))	('LC3-II', 'Gene', '84557', (53, 59))	('HMGB1', 'Gene', (148, 153))	('HMGB1', 'Gene', '3146', (148, 153))	('expression', 'MPA', (39, 49))	('knockdown', 'Var', (6, 15))	('HMGB1', 'Gene', (19, 24))	('LC3-II', 'Gene', (53, 59))
365555	27897164	found that endogenous HMGB1 was an intrinsic regulator of autophagy in leukemia cells and that it enhanced leukemia cell chemoresistance, most likely through the PI3K/Akt/mTORC1 pathway.	('HMGB1', 'Gene', (22, 27))	('enhanced', 'PosReg', (98, 106))	('HMGB1', 'Gene', '3146', (22, 27))	('leukemia', 'Disease', (71, 79))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('Akt', 'Gene', '207', (167, 170))	('mTORC1', 'Gene', (171, 177))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('endogenous', 'Var', (11, 21))	('leukemia', 'Disease', (107, 115))	('Akt', 'Gene', (167, 170))	('leukemia', 'Disease', 'MESH:D007938', (71, 79))	('mTORC1', 'Gene', '382056', (171, 177))
365557	27897164	Suppressing HMGB1 expression with HMGB1 siRNA increased the expression of p-Akt and p-mTOR and decreased the expression of LC3-II in SW982 cells treated with OMT, but did not decrease the expression of LC3-II, when an Akt inhibitor or mTOR inhibitor was present.	('expression', 'MPA', (60, 70))	('mTOR', 'Gene', '2475', (86, 90))	('LC3-II', 'Gene', (123, 129))	('LC3-II', 'Gene', (202, 208))	('mTOR', 'Gene', '2475', (235, 239))	('LC3-II', 'Gene', '84557', (123, 129))	('LC3-II', 'Gene', '84557', (202, 208))	('SW982', 'CellLine', 'CVCL:1734', (133, 138))	('HMGB1', 'Gene', '3146', (12, 17))	('HMGB1', 'Gene', (12, 17))	('decreased', 'NegReg', (95, 104))	('Suppressing', 'Var', (0, 11))	('HMGB1', 'Gene', (34, 39))	('Akt', 'Gene', (76, 79))	('HMGB1', 'Gene', '3146', (34, 39))	('Akt', 'Gene', (218, 221))	('Akt', 'Gene', '207', (76, 79))	('expression', 'MPA', (109, 119))	('Akt', 'Gene', '207', (218, 221))	('increased', 'PosReg', (46, 55))	('mTOR', 'Gene', (86, 90))	('mTOR', 'Gene', (235, 239))	('OMT', 'Chemical', 'MESH:C037573', (158, 161))
365574	24321600	VDC was associated with greater neutropenia on day 8 whereas IE had greater neutropenia on day 12 (P-value <0.001).	('neutropenia', 'Phenotype', 'HP:0001875', (32, 43))	('neutropenia', 'Disease', (76, 87))	('IE', 'Chemical', '-', (61, 63))	('neutropenia', 'Disease', 'MESH:D009503', (76, 87))	('neutropenia', 'Disease', (32, 43))	('VDC', 'Var', (0, 3))	('neutropenia', 'Phenotype', 'HP:0001875', (76, 87))	('VDC', 'Chemical', '-', (0, 3))	('neutropenia', 'Disease', 'MESH:D009503', (32, 43))
365603	24321600	Blood counts were taken on Day 8, 12 and 15 for the first 6 cycles of chemotherapy and dose escalation (DE) was implemented if the neutrophil and platelet count did not fall below 1.5x109/L or 100x109/L, respectively, in the absence of non-hematologic toxicities of concern.	('men', 'Species', '9606', (117, 120))	('toxicities', 'Disease', (252, 262))	('neutrophil', 'CPA', (131, 141))	('100x109/L', 'Var', (193, 202))	('toxicities', 'Disease', 'MESH:D064420', (252, 262))	('fall', 'Phenotype', 'HP:0002527', (169, 173))
365626	24321600	VDC was associated with greater neutropenia on day 8 (ANC: D8: 0.98 +- 0.97 x 109/L, P-value <0.001) whereas IE had greater neutropenia on day 12 (ANC: D12: 3.74 +- 3.04 x 109/L, P-value <0.001).	('neutropenia', 'Phenotype', 'HP:0001875', (32, 43))	('neutropenia', 'Disease', (124, 135))	('greater', 'PosReg', (24, 31))	('neutropenia', 'Disease', (32, 43))	('VDC', 'Var', (0, 3))	('neutropenia', 'Phenotype', 'HP:0001875', (124, 135))	('IE', 'Chemical', '-', (109, 111))	('neutropenia', 'Disease', 'MESH:D009503', (124, 135))	('VDC', 'Chemical', '-', (0, 3))	('neutropenia', 'Disease', 'MESH:D009503', (32, 43))
365677	24082883	The translocation alters the open reading frame of the EWSR1 gene on chromosome 22 by substituting a sequence encoding a putative RNA-binding domain with that of the DNA-binding domain of FLI-1, the human homologue of murine Fli-1.	('FLI-1', 'Gene', (188, 193))	('translocation', 'Var', (4, 17))	('human', 'Species', '9606', (199, 204))	('murine', 'Species', '10090', (218, 224))	('EWSR1', 'Gene', (55, 60))	('Fli-1', 'Gene', '14247', (225, 230))	('Fli-1', 'Gene', (225, 230))	('alters', 'Reg', (18, 24))	('FLI-1', 'Gene', '2313', (188, 193))	('substituting', 'Var', (86, 98))
365680	24082883	Thus, the oncogenic conversion of EWS follows a common scheme of activation, by exchanging its RNA binding domain with different DNA binding domains, thus generating tumor-specific fusions proteins.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('oncogenic conversion', 'CPA', (10, 30))	('generating', 'Reg', (155, 165))	('tumor', 'Disease', (166, 171))	('exchanging', 'Var', (80, 90))	('RNA', 'MPA', (95, 98))	('fusions proteins', 'MPA', (181, 197))
365697	24082883	Notably, this triplet encodes Serine 325, which is a putative casein kinase II phosphorylation site and may represent a posttranslational modification that distinguishes between the two protein isoforms of EWS.	('encodes', 'Reg', (22, 29))	('Serine', 'Chemical', 'MESH:D012694', (30, 36))	('Serine 325', 'Var', (30, 40))
365704	24082883	Interestingly, inactivation of Ews in mouse embryonic fibroblasts resulted in hypersensitivity to ionizing radiation and caused premature cellular senescence, possibly due to lack of the reported interaction of the EWS protein with nuclear lamin A/C.	('mouse', 'Species', '10090', (38, 43))	('Ews', 'Gene', (31, 34))	('interaction', 'Interaction', (196, 207))	('caused', 'Reg', (121, 127))	('hypersensitivity', 'Disease', 'MESH:D004342', (78, 94))	('cellular senescence', 'CPA', (138, 157))	('hypersensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (78, 116))	('hypersensitivity', 'Disease', (78, 94))	('inactivation', 'Var', (15, 27))
365705	24082883	In particular, deletion of Ews promoted stem cell exit from a quiescent state and entrance into the cell cycle, which is one of the common features found in HSCs from aged wild-type mice.	('deletion', 'Var', (15, 23))	('mice', 'Species', '10090', (182, 186))	('promoted', 'PosReg', (31, 39))	('entrance', 'CPA', (82, 90))	('Ews', 'Gene', (27, 30))	('stem cell exit', 'CPA', (40, 54))
365728	24082883	Notably, the c-fos and ErbB2 promoters contain G-rich sequences that could potentially form G-quadruplex structures.	('ErbB2', 'Gene', (23, 28))	('c-fos', 'Gene', '2353', (13, 18))	('G-rich sequences', 'Var', (47, 63))	('G-quadruplex', 'MPA', (92, 104))	('form', 'Reg', (87, 91))	('ErbB2', 'Gene', '2064', (23, 28))	('c-fos', 'Gene', (13, 18))
365730	24082883	Moreover, enzymatic methylation of arginine residues by protein arginine N-methyltransferase 3 (PRMT3) reduces the affinity of EWS RGG (RGG3) domain toward G-quadruplex, while it increases its binding to single-strand DNA and RNA.	('increases', 'PosReg', (179, 188))	('arginine', 'Chemical', 'MESH:D001120', (64, 72))	('G-quadruplex', 'Protein', (156, 168))	('arginine', 'Chemical', 'MESH:D001120', (35, 43))	('reduces', 'NegReg', (103, 110))	('protein arginine N-methyltransferase 3', 'Gene', '10196', (56, 94))	('methylation', 'Var', (20, 31))	('protein arginine N-methyltransferase 3', 'Gene', (56, 94))	('binding', 'Interaction', (193, 200))	('PRMT3', 'Gene', (96, 101))	('affinity', 'MPA', (115, 123))	('PRMT3', 'Gene', '10196', (96, 101))
365731	24082883	Conversely, replacement of the arginine methylated by PRMT3 with lysine residues within the RGG domains decreases the binding affinity of EWS toward G-quadruplex DNA and RNA.	('lysine', 'Chemical', 'MESH:D008239', (65, 71))	('PRMT3', 'Gene', (54, 59))	('EWS', 'Protein', (138, 141))	('decreases', 'NegReg', (104, 113))	('arginine', 'Chemical', 'MESH:D001120', (31, 39))	('G-quadruplex', 'Protein', (149, 161))	('replacement', 'Var', (12, 23))	('PRMT3', 'Gene', '10196', (54, 59))	('binding', 'Interaction', (118, 125))	('RNA', 'Interaction', (170, 173))
365732	24082883	Furthermore, EWS methylation by PRMT1 (a homologue of PRMT3) reduces CBP-dependent EWS transcriptional activity and induces EWS translocation into the cytoplasm.	('PRMT3', 'Gene', (54, 59))	('CBP', 'Gene', '1387', (69, 72))	('CBP', 'Gene', (69, 72))	('induces', 'Reg', (116, 123))	('methylation', 'Var', (17, 28))	('PRMT3', 'Gene', '10196', (54, 59))	('PRMT1', 'Gene', '3276', (32, 37))	('EWS translocation into the cytoplasm', 'MPA', (124, 160))	('reduces', 'NegReg', (61, 68))	('PRMT1', 'Gene', (32, 37))
365751	24082883	These AS events parallel the events induced either by EWS or YB-1 knockdown (Figure 2(b), left scheme), suggesting that CPT inhibits the splicing activity of these two RNA binding proteins (RBPs).	('RBP', 'Gene', '57794', (190, 193))	('inhibits', 'NegReg', (124, 132))	('splicing activity', 'MPA', (137, 154))	('YB-1', 'Gene', (61, 65))	('CPT', 'Var', (120, 123))	('YB-1', 'Gene', '4904', (61, 65))	('RBP', 'Gene', (190, 193))	('CPT', 'Chemical', 'MESH:D002166', (120, 123))
365768	24082883	Interestingly, defects in lymphocyte development, meiosis, and cellular senescence (or aging) are features also observed in mice deficient in Atm and c-abl , two genes that are critical for the DDR pathway.	('lymphocyte development', 'CPA', (26, 48))	('c-abl', 'Gene', (150, 155))	('deficient', 'Var', (129, 138))	('Atm', 'Gene', (142, 145))	('defects', 'NegReg', (15, 22))	('meiosis', 'CPA', (50, 57))	('mice', 'Species', '10090', (124, 128))	('cellular senescence', 'CPA', (63, 82))	('c-abl', 'Gene', '11350', (150, 155))	('Atm', 'Gene', '11920', (142, 145))
365777	24082883	CHK2 (the protein product of the CHEK2 gene) is an effector protein conserved in eukaryotes and phosphorylated by the sensor kinases ATM/ATR in response to DNA damage; upon phosphorylation by ATM/ATR, CHK2 phosphorylates and thus modifies the function of key targets of the checkpoint response.	('function', 'MPA', (243, 251))	('CHK2', 'Gene', '11200', (201, 205))	('phosphorylation', 'Var', (173, 188))	('ATM', 'Gene', (133, 136))	('ATR', 'Gene', '545', (137, 140))	('CHK2', 'Gene', (0, 4))	('ATM', 'Gene', (192, 195))	('ATR', 'Gene', (137, 140))	('ATR', 'Gene', (196, 199))	('ATR', 'Gene', '545', (196, 199))	('CHEK2', 'Gene', '11200', (33, 38))	('CHK2', 'Gene', '11200', (0, 4))	('modifies', 'Reg', (230, 238))	('ATM', 'Gene', '472', (133, 136))	('CHEK2', 'Gene', (33, 38))	('ATM', 'Gene', '472', (192, 195))	('phosphorylates', 'MPA', (206, 220))	('CHK2', 'Gene', (201, 205))
365778	24082883	Interestingly, upon EWS knockdown an mRNA isoform of CHEK2 is generated that lacks the exon 2 containing the translation initiation codon, thus leading to a decrease of the levels of CHK2 protein.	('CHK2', 'Gene', '11200', (183, 187))	('lacks', 'NegReg', (77, 82))	('decrease', 'NegReg', (157, 165))	('CHEK2', 'Gene', '11200', (53, 58))	('CHK2', 'Gene', (183, 187))	('CHEK2', 'Gene', (53, 58))	('knockdown', 'Var', (24, 33))
365780	24082883	EWS knockdown could therefore lead to defective CHK2 response and explain the higher sensitivity to UV irradiation.	('defective', 'NegReg', (38, 47))	('CHK2', 'Gene', (48, 52))	('knockdown', 'Var', (4, 13))	('CHK2', 'Gene', '11200', (48, 52))	('EWS', 'Gene', (0, 3))
365783	24082883	Regulation of RNA metabolism in the nervous system plays a crucial role, as highlighted by the development of devastating neurological diseases, including spinal muscular atrophy and certain trinucleotide repeat expansions, upon mutation or misregulation of key RBPs.	('mutation', 'Var', (229, 237))	('spinal muscular atrophy', 'Disease', (155, 178))	('trinucleotide repeat expansions', 'Var', (191, 222))	('neurological diseases', 'Disease', (122, 143))	('muscular atrophy', 'Phenotype', 'HP:0003202', (162, 178))	('misregulation', 'Var', (241, 254))	('RBP', 'Gene', (262, 265))	('RBP', 'Gene', '57794', (262, 265))	('spinal muscular atrophy', 'Phenotype', 'HP:0007269', (155, 178))	('spinal muscular atrophy', 'Disease', 'MESH:D009134', (155, 178))	('trinucleotide', 'Chemical', '-', (191, 204))	('neurological diseases', 'Disease', 'MESH:D019636', (122, 143))
365784	24082883	Mutations in FUS/TLS, as well as in the RBP TAR DNA-binding protein 43 (TDP-43), were found to be causative of familial cases of amyotrophic lateral sclerosis (ALS), further implicating altered RNA metabolism as a central feature of these diseases.	('familial cases', 'Disease', (111, 125))	('TDP-43', 'Gene', (72, 78))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (129, 158))	('Mutations', 'Var', (0, 9))	('FUS/TLS', 'Gene', (13, 20))	('ALS', 'Disease', 'MESH:C565957', (160, 163))	('RBP', 'Gene', '57794', (40, 43))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (129, 158))	('TDP-43', 'Gene', '23435', (72, 78))	('causative', 'Reg', (98, 107))	('FUS/TLS', 'Gene', '2521', (13, 20))	('amyotrophic lateral sclerosis', 'Disease', (129, 158))	('RBP', 'Gene', (40, 43))	('ALS', 'Disease', (160, 163))
365785	24082883	FUS/TLS protein was also reported to be the major component of poly-Q aggregates in cellular models of spinal cerebellar ataxia and in intracellular inclusions in neurons of patients with Huntington's disease.	('spinal cerebellar ataxia', 'Disease', 'MESH:D013132', (103, 127))	('poly-Q', 'Chemical', 'MESH:C097188', (63, 69))	("Huntington's disease", 'Disease', (188, 208))	("Huntington's disease", 'Disease', 'MESH:D006816', (188, 208))	('cerebellar ataxia', 'Phenotype', 'HP:0001251', (110, 127))	('patients', 'Species', '9606', (174, 182))	('FUS/TLS', 'Gene', (0, 7))	('poly-Q aggregates', 'Var', (63, 80))	('spinal cerebellar ataxia', 'Disease', (103, 127))	('FUS/TLS', 'Gene', '2521', (0, 7))
365790	24082883	Most disease-causing mutations in TDP-43 and some disease-causing mutations in FUS/TLS are found within the glycine-rich domain, which is rich in uncharged, polar amino acids, similar to that observed in the nucleation domains found in many yeast prions.	('mutations', 'Var', (66, 75))	('FUS/TLS', 'Gene', '2521', (79, 86))	('disease-causing', 'Reg', (5, 20))	('glycine', 'Chemical', 'MESH:D005998', (108, 115))	('TDP-43', 'Gene', '23435', (34, 40))	('yeast', 'Species', '4932', (241, 246))	('prion', 'Species', '36469', (247, 252))	('TDP-43', 'Gene', (34, 40))	('FUS/TLS', 'Gene', (79, 86))	('mutations', 'Var', (21, 30))
365796	24082883	Similar to TDP-43, FUS/TLS, and TAF15, expression of EWSR1 cDNA in yeast resulted in cytoplasmic aggregation and toxicity in a functional screen.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('TAF15', 'Gene', (32, 37))	('expression', 'Var', (39, 49))	('yeast', 'Species', '4932', (67, 72))	('FUS/TLS', 'Gene', (19, 26))	('EWSR1', 'Gene', (53, 58))	('TAF15', 'Gene', '8148', (32, 37))	('TDP-43', 'Gene', (11, 17))	('TDP-43', 'Gene', '23435', (11, 17))	('FUS/TLS', 'Gene', '2521', (19, 26))	('resulted in', 'Reg', (73, 84))	('cytoplasmic aggregation', 'MPA', (85, 108))
365798	24082883	Since most of the pathogenic mutations in FUS/TLS are located in the C-terminal domain of the protein, the last four exons of the EWSR1 gene (exons 15-18) were sequenced in 817 individuals diagnosed with ALS and in 1082 healthy population control individuals.	('pathogenic', 'Reg', (18, 28))	('FUS/TLS', 'Gene', '2521', (42, 49))	('mutations', 'Var', (29, 38))	('ALS', 'Disease', 'MESH:C565957', (204, 207))	('EWSR1', 'Gene', (130, 135))	('FUS/TLS', 'Gene', (42, 49))	('ALS', 'Disease', (204, 207))
365799	24082883	This approach identified two patient-specific missense variants in exon 16 (1532G>C, G511A, corresponding to the first RGG domain) and in exon 17 (1655C>T, P552L, corresponding to the second RGG domain) of EWSR1 in two unrelated ALS patients with sporadic disease.	('patient', 'Species', '9606', (29, 36))	('EWSR1', 'Gene', (206, 211))	('G511A', 'Mutation', 'rs1202316445', (85, 90))	('patient', 'Species', '9606', (233, 240))	('sporadic disease', 'Disease', (247, 263))	('1655C>T', 'Var', (147, 154))	('sporadic disease', 'Disease', 'MESH:D004421', (247, 263))	('1532G>C', 'Mutation', 'rs747642485', (76, 83))	('1655C>T', 'Mutation', 'rs149288880', (147, 154))	('ALS', 'Disease', 'MESH:C565957', (229, 232))	('P552L', 'Mutation', 'rs149288880', (156, 161))	('1532G>C, G511A', 'Var', (76, 90))	('ALS', 'Disease', (229, 232))	('patients', 'Species', '9606', (233, 241))
365801	24082883	Notably, whether EWS RNA binding affinity and pre-mRNA regulation are affected in the ALS-related mutants is also still unknown.	('ALS', 'Disease', 'MESH:C565957', (86, 89))	('affected', 'Reg', (70, 78))	('ALS', 'Disease', (86, 89))	('mutants', 'Var', (98, 105))
365806	24082883	Cancer progression is thought to be dependent on the accumulation of mutations that change the transcriptional profile of the cell to support its escape from the tight regulation of cell cycle progression.	('mutations', 'Var', (69, 78))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('transcriptional profile', 'MPA', (95, 118))	('change', 'Reg', (84, 90))
365809	24082883	BRCA1 is a tumor suppressor and germline mutations in BRCA1 gene predispose individuals to breast and ovarian cancers.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('BRCA1', 'Gene', (0, 5))	('predispose', 'Reg', (65, 75))	('germline mutations', 'Var', (32, 50))	('tumor', 'Disease', (11, 16))	('ovarian cancers', 'Phenotype', 'HP:0100615', (102, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('BRCA1', 'Gene', '672', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('BRCA1', 'Gene', '672', (0, 5))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (91, 117))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('BRCA1', 'Gene', (54, 59))
365811	24082883	Mutations have been described in BRCA1 gene that result in skipping of more than one exons leading either to shorter transcripts or to frameshift and premature stop codons, thus rendering mis-spliced mRNAs subject to non-mediated decay (NMD).	('skipping', 'MPA', (59, 67))	('frameshift', 'Var', (135, 145))	('Mutations', 'Var', (0, 9))	('rendering', 'Reg', (178, 187))	('BRCA1', 'Gene', '672', (33, 38))	('shorter transcripts', 'MPA', (109, 128))	('non-mediated decay', 'MPA', (217, 235))	('BRCA1', 'Gene', (33, 38))	('subject', 'Reg', (206, 213))
365812	24082883	Thus, these mutations yield either a truncated BRCA1 protein or loss of a BRCA1 transcript.	('BRCA1', 'Gene', (47, 52))	('mutations', 'Var', (12, 21))	('transcript', 'MPA', (80, 90))	('BRCA1', 'Gene', '672', (74, 79))	('loss', 'NegReg', (64, 68))	('protein', 'Protein', (53, 60))	('BRCA1', 'Gene', '672', (47, 52))	('BRCA1', 'Gene', (74, 79))	('truncated', 'MPA', (37, 46))
365815	24082883	EWSR1 knockdown in HeLa cells resulted also in a significantly high incidence of abnormal spindles and mislocalization of Aurora B kinase, the enzymatic core of the chromosomal passenger complex (CPC), which orchestrates in space and time chromosome alignment, histone modification, and cytokinesis.	('Aurora B', 'Gene', (122, 130))	('CPC', 'Chemical', '-', (196, 199))	('HeLa', 'CellLine', 'CVCL:0030', (19, 23))	('Aurora B', 'Gene', '9212', (122, 130))	('abnormal spindles', 'CPA', (81, 98))	('knockdown', 'Var', (6, 15))	('mislocalization', 'MPA', (103, 118))	('EWSR1', 'Gene', (0, 5))
365845	32357417	This creates a plateau of relapse-free survival in patients with previously incurable cancers and supports the development of CD19 CAR T cells as stand-alone cancer therapeutics, to increase the probabilities of survival and to replace more toxic components of current regimens.	('increase', 'PosReg', (182, 190))	('CD19', 'Var', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('patients', 'Species', '9606', (51, 59))	('cancers', 'Disease', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (86, 92))
365858	32357417	Due to a lack of cancer-driving antigens selectively expressed on the tumor cell surface, most of the antigens used are not critical for tumor growth and maintenance, thus low-expression variants do not have a clonal disadvantage.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('variants', 'Var', (187, 195))	('cancer', 'Disease', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
365864	32357417	In clinical studies using CD22-redirected CAR T cells to treat ALL, leukemia escape was caused by emergence of leukemia variants with low-level CD22 expression in the absence of mutations, as observed with CD19.	('CD22', 'Gene', (26, 30))	('leukemia', 'Disease', (68, 76))	('variants', 'Var', (120, 128))	('leukemia', 'Disease', 'MESH:D007938', (68, 76))	('caused by', 'Reg', (88, 97))	('CD22', 'Gene', '933', (26, 30))	('low-level', 'NegReg', (134, 143))	('leukemia', 'Phenotype', 'HP:0001909', (68, 76))	('CD22', 'Gene', (144, 148))	('CD22', 'Gene', '933', (144, 148))	('leukemia', 'Disease', (111, 119))	('leukemia', 'Phenotype', 'HP:0001909', (111, 119))	('leukemia', 'Disease', 'MESH:D007938', (111, 119))	('ALL', 'Phenotype', 'HP:0006721', (63, 66))
365865	32357417	Low densities of surface CD22 were further associated with poor early expansion and short-term activity of CAR T cells as well as with impaired ability to persist as memory populations.	('short-term activity', 'CPA', (84, 103))	('CD22', 'Gene', '933', (25, 29))	('CD22', 'Gene', (25, 29))	('early expansion', 'CPA', (64, 79))	('poor', 'NegReg', (59, 63))	('Low densities', 'Var', (0, 13))
365876	32357417	were the first to provide preclinical evidence that epigenetic antigen modulation can sensitize tumor cells to CAR-mediated recognition.	('sensitize', 'Reg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('epigenetic antigen modulation', 'Var', (52, 81))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
365888	32357417	In preclinical studies, inhibitors of EZH2 reliably, reversibly, and selectively upregulated GD2 surface expression in GD2-low or GD2-negative Ewing sarcoma cells to levels inducing effective antigen-specific activation of CAR T cells.	('upregulated', 'PosReg', (81, 92))	('Ewing sarcoma', 'Disease', (143, 156))	('EZH2', 'Gene', '2146', (38, 42))	('surface expression', 'MPA', (97, 115))	('EZH2', 'Gene', (38, 42))	('GD2', 'Gene', (93, 96))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (143, 156))	('inhibitors', 'Var', (24, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (143, 156))
365890	32357417	Thus, administration of epigenetic agents could be an attractive strategy to prevent immune escape of tumor cells that express target antigens below the detection thresholds of CAR T cells.	('epigenetic agents', 'Var', (24, 41))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('immune escape', 'CPA', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
365891	32357417	Clinical trials of such combinations should employ a window design with the use of the upregulating agent, followed by re-biopsies to confirm the postulated effects on antigen expression levels and their tumor selectivity in human patients.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('patients', 'Species', '9606', (231, 239))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('combinations', 'Var', (24, 36))	('tumor', 'Disease', (204, 209))	('human', 'Species', '9606', (225, 230))	('antigen expression levels', 'MPA', (168, 193))
365896	32357417	Another example is the capacity of small-molecule gamma-secretase inhibitors to increase expression of BCMA on multiple myeloma cells by preventing cleavage of the antigen from the cell surface (Figure 1D).	('expression', 'MPA', (89, 99))	('BCMA', 'Gene', '608', (103, 107))	('increase', 'PosReg', (80, 88))	('multiple myeloma', 'Disease', 'MESH:D009101', (111, 127))	('multiple myeloma', 'Phenotype', 'HP:0006775', (111, 127))	('gamma-secretase', 'Protein', (50, 65))	('multiple myeloma', 'Disease', (111, 127))	('BCMA', 'Gene', (103, 107))	('small-molecule', 'Var', (35, 49))	('cleavage of the antigen from the cell surface', 'MPA', (148, 193))	('preventing', 'NegReg', (137, 147))
365904	32357417	In addition, manipulation of antigen expression in cancer cells by epigenetic modulators could affect their malignant phenotype and even promote aggressive, tumor-propagating, or metastatic behavior.	('metastatic behavior', 'CPA', (179, 198))	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('aggressive', 'CPA', (145, 155))	('promote', 'PosReg', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('manipulation', 'Reg', (13, 25))	('affect', 'Reg', (95, 101))	('malignant phenotype', 'CPA', (108, 127))	('epigenetic modulators', 'Var', (67, 88))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('antigen', 'Protein', (29, 36))
365906	32357417	Epigenetic reprogramming indeed is a key mechanism of memory T cell formation, homeostasis, and the plasticity of recall responses.	('memory T', 'Disease', 'MESH:D008569', (54, 62))	('Epigenetic', 'Var', (0, 10))	('memory T', 'Disease', (54, 62))
365907	32357417	The effects of individual epigenetic agents on T cell subpopulations and tumor-infiltrating bystander cells are unpredictable and will have to be addressed.	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('epigenetic', 'Var', (26, 36))
365910	32357417	Preclinical efforts, now followed by clinical studies, have been focusing on B cell malignancies, specifically the combinations of the B-lineage antigens CD19 and CD22 in ALL and CD19 and CD20 in NHL.	('malignancies', 'Disease', (84, 96))	('CD22', 'Gene', '933', (163, 167))	('CD20', 'Gene', (188, 192))	('CD20', 'Gene', '931', (188, 192))	('CD19', 'Var', (154, 158))	('CD19', 'Var', (179, 183))	('ALL', 'Phenotype', 'HP:0006721', (171, 174))	('NHL', 'Phenotype', 'HP:0012539', (196, 199))	('CD22', 'Gene', (163, 167))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))
365913	32357417	CD19-negative and/or CD22-low relapses still occurred in a proportion of patients, and neither of the studies was powered to compare the incidence of antigen-negative relapses following single-antigen targeting.	('CD22', 'Gene', (21, 25))	('CD22', 'Gene', '933', (21, 25))	('CD19-negative', 'Var', (0, 13))	('relapses', 'CPA', (30, 38))	('patients', 'Species', '9606', (73, 81))
365914	32357417	In a mouse model mimicking CD19-negative disease relapse, CD19/CD123 dual-targeted T cells had increased antitumor activity compared to CD19-specific CAR T cells alone.	('CD19/CD123 dual-targeted', 'Var', (58, 82))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mouse', 'Species', '10090', (5, 10))	('increased', 'PosReg', (95, 104))	('tumor', 'Disease', (109, 114))
365924	32357417	To what extent dual antigen targeting can prevent the emergence of new or preexisting antigen loss variants remains to be demonstrated even in B-lineage neoplasias, and the concept is not easily transferred to solid cancers with their high intra- and interpatient variability of surface antigen expression and lack of truly tumor-selective targets.	('variants', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('loss', 'NegReg', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', (324, 329))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('neoplasias', 'Disease', 'MESH:D009369', (153, 163))	('neoplasias', 'Phenotype', 'HP:0002664', (153, 163))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('tumor', 'Disease', 'MESH:D009369', (324, 329))	('antigen', 'Gene', (86, 93))	('patient', 'Species', '9606', (256, 263))	('neoplasias', 'Disease', (153, 163))
365935	32357417	In a first-in-human clinical trial in patients with melanoma, the clinical impact of adoptive transfer of CAR T cells transduced to secrete IL-12 was limited by systemic toxicities, attributed to high serum levels of the cytokine.	('toxicities', 'Disease', 'MESH:D064420', (170, 180))	('secrete', 'Var', (132, 139))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('human', 'Species', '9606', (14, 19))	('serum levels', 'MPA', (201, 213))	('toxicities', 'Disease', (170, 180))	('patients', 'Species', '9606', (38, 46))
365964	32508922	Aberrant DNA methylation shows close association with the pathogenesis and tumor progression.	('Aberrant', 'Var', (0, 8))	('association', 'Reg', (37, 48))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('DNA', 'Protein', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
365980	32508922	Aberrant DNA methylation plays a crucial role in cancer pathogenesis and progression.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('DNA', 'Protein', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
365981	32508922	Hypermethylation of the promotor regions inhibits certain tumor suppressor genes, which is considered as a shared trait of many malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('inhibits', 'NegReg', (41, 49))	('tumor', 'Disease', (138, 143))	('Hypermethylation', 'Var', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('malignant tumors', 'Disease', (128, 144))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('malignant tumors', 'Disease', 'MESH:D009369', (128, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
365985	32508922	For example, in renal cell carcinoma, GATA5 hypermethylation is frequently presented and shows a significant association with shortened progression-free survival.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('GATA5', 'Gene', (38, 43))	('progression-free survival', 'CPA', (136, 161))	('renal cell carcinoma', 'Disease', (16, 36))	('shortened', 'NegReg', (126, 135))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (16, 36))	('GATA5', 'Gene', '140628', (38, 43))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (16, 36))	('hypermethylation', 'Var', (44, 60))
365986	32508922	Hypomethylation of long interspersed nucleotide element-1 (LINE-1) is unfavorable with regard to the prognosis of colorectal cancer in patients.	('LINE-1', 'Gene', (59, 65))	('patients', 'Species', '9606', (135, 143))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('colorectal cancer', 'Disease', (114, 131))	('LINE-1', 'CellLine', 'CVCL:B526', (59, 65))
365987	32508922	Hypermethylation of RASSF1A promoter is associated with shorter duration of survival in patients with stage II and III STS.	('RASSF1A', 'Gene', (20, 27))	('Hypermethylation', 'Var', (0, 16))	('duration', 'MPA', (64, 72))	('patients', 'Species', '9606', (88, 96))	('shorter', 'NegReg', (56, 63))	('STS', 'Phenotype', 'HP:0030448', (119, 122))	('RASSF1A', 'Gene', '11186', (20, 27))
366001	32508922	First, the Cox proportional hazards hypothesis test (P > 0.05) and univariate Cox proportional hazards regression analysis (P < 0.01) were used to screen DNA methylation sites that were significantly associated with the OS of STS patients, and sites in the training dataset that satisfied the requirements were used as candidate markers.	('sites', 'Var', (170, 175))	('patients', 'Species', '9606', (230, 238))	('methylation sites', 'Var', (158, 175))	('STS', 'Phenotype', 'HP:0030448', (226, 229))	('associated', 'Reg', (200, 210))
366010	32508922	The univariate Cox proportional hazards regression analysis and Cox proportional hazards hypothesis test were used to identify the DNA methylation sites that were significantly associated with the OS of patients with STS in the training dataset.	('methylation sites', 'Var', (135, 152))	('patients', 'Species', '9606', (203, 211))	('sites', 'Var', (147, 152))	('associated', 'Reg', (177, 187))	('STS', 'Phenotype', 'HP:0030448', (217, 220))
366011	32508922	Finally, a biomarker model containing three CpG sites (cg19804488, cg20542822, and cg07898500) was selected to analyze the prognosis of patients.	('cg20542822', 'Chemical', '-', (67, 77))	('cg07898500', 'Chemical', '-', (83, 93))	('cg20542822', 'Var', (67, 77))	('cg19804488', 'Chemical', '-', (55, 65))	('cg19804488', 'Var', (55, 65))	('cg07898500', 'Var', (83, 93))	('patients', 'Species', '9606', (136, 144))
366012	32508922	According to the Cox regression coefficient of each site in the model, the risk score formula was presented as follows:where betacg19804488represents the beta value of cg19804488, and the same represents the other two sites cg20542822 and cg07898500.	('cg19804488', 'Var', (168, 178))	('cg20542822', 'Var', (224, 234))	('betacg19804488represents', 'Var', (125, 149))	('cg20542822', 'Chemical', '-', (224, 234))	('cg07898500', 'Chemical', '-', (239, 249))	('cg19804488', 'Chemical', '-', (129, 139))	('cg19804488', 'Chemical', '-', (168, 178))
366013	32508922	Obviously, high DNA methylation level of cg19804488 can result in the increasing risk of STS patients, while high methylation levels of cg20542822 and cg07898500 reduce the risk.	('reduce', 'NegReg', (162, 168))	('cg07898500', 'Chemical', '-', (151, 161))	('cg19804488', 'Var', (41, 51))	('cg07898500', 'Var', (151, 161))	('cg19804488', 'Chemical', '-', (41, 51))	('STS', 'Phenotype', 'HP:0030448', (89, 92))	('cg20542822', 'Chemical', '-', (136, 146))	('cg20542822', 'Var', (136, 146))	('STS patients', 'Disease', (89, 101))	('patients', 'Species', '9606', (93, 101))	('DNA methylation level', 'MPA', (16, 37))
366016	32508922	Figure 2 explicates that the methylation level of cg19804488 in the group of patients with short-term survival was significantly higher than that in the group of patients with long-term survival (P = 1.03E - 03).	('patients', 'Species', '9606', (162, 170))	('higher', 'PosReg', (129, 135))	('patients', 'Species', '9606', (77, 85))	('methylation level', 'MPA', (29, 46))	('cg19804488', 'Chemical', '-', (50, 60))	('cg19804488', 'Var', (50, 60))
366017	32508922	In contrast, both cg20542822 and cg07898500 had a higher methylation level in patients with long-term survival compared with patients with short-term survival; the P values were 9.91E-05 and 2.07E-03 separately.	('cg20542822', 'Var', (18, 28))	('higher', 'PosReg', (50, 56))	('cg07898500', 'Chemical', '-', (33, 43))	('patients', 'Species', '9606', (78, 86))	('cg07898500', 'Var', (33, 43))	('methylation level', 'MPA', (57, 74))	('cg20542822', 'Chemical', '-', (18, 28))	('patients', 'Species', '9606', (125, 133))
366039	32508922	Hypermethylation of MST1 showed significant correlation with favorable prognosis in patients with STS.	('MST1', 'Gene', (20, 24))	('patients', 'Species', '9606', (84, 92))	('Hypermethylation', 'Var', (0, 16))	('STS', 'Phenotype', 'HP:0030448', (98, 101))	('MST1', 'Gene', '4485', (20, 24))	('STS', 'Disease', (98, 101))
366046	32508922	As a result, a 3-DNA methylation biomarker containing 3 CpG sites (cg19804488, cg20542822, and cg07898500) was identified through univariate and multivariate Cox regression screening.	('cg20542822', 'Chemical', '-', (79, 89))	('cg19804488', 'Chemical', '-', (67, 77))	('cg19804488', 'Var', (67, 77))	('cg07898500', 'Chemical', '-', (95, 105))	('cg20542822', 'Var', (79, 89))	('cg07898500', 'Var', (95, 105))
366055	32508922	Type 6 collagen 5 chain (COL6A5) is also known as COL29A1, and its variation is closely associated with specific dermatitis.	('COL29A1', 'Gene', '256076', (50, 57))	('COL29A1', 'Gene', (50, 57))	('COL6A5', 'Gene', '256076', (25, 31))	('dermatitis', 'Disease', 'MESH:D003872', (113, 123))	('associated', 'Reg', (88, 98))	('dermatitis', 'Disease', (113, 123))	('COL6A5', 'Gene', (25, 31))	('variation', 'Var', (67, 76))	('dermatitis', 'Phenotype', 'HP:0011123', (113, 123))
366070	32508922	Moreover, the 3-DNA methylation biomarker exhibited more advantages in predicting the survival of STS patients when compared with other prognostic markers that were reported previously.	('advantages', 'PosReg', (57, 67))	('patients', 'Species', '9606', (102, 110))	('STS', 'Phenotype', 'HP:0030448', (98, 101))	('3-DNA', 'Var', (14, 19))	('survival', 'CPA', (86, 94))
366088	32102165	In particular, the soft tissues of the craniofacial region are only occasionally affected by MFH; the sinonasal tract (30%) and the facial skeleton (15-25%) are the most common head and neck sites.	('craniofacial', 'Disease', 'MESH:D019465', (39, 51))	('craniofacial', 'Disease', (39, 51))	('MFH', 'Var', (93, 96))
366104	32102165	Immunohistochemical positivity for vimentin was reported in 6 studies; in 5 of these, it was associated with positivity for CD68.	('vimentin', 'Gene', (35, 43))	('CD68', 'Gene', (124, 128))	('CD68', 'Gene', '968', (124, 128))	('associated', 'Reg', (93, 103))	('positivity', 'Var', (109, 119))	('vimentin', 'Gene', '7431', (35, 43))
366235	29625604	reported landmark phase II cohort trials of sorafenib or sorafenib combined with everolimus in advanced refractory osteosarcoma.. PALETTE study proved that pazopanib could obviously prolong the progression-free survival (PFS) by 3 months but the partial response rate was only 6%.	('pazopanib', 'Var', (156, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('osteosarcoma', 'Disease', (115, 127))	('everolimus', 'Chemical', 'MESH:D000068338', (81, 91))	('osteosarcoma', 'Phenotype', 'HP:0002669', (115, 127))	('sorafenib', 'Chemical', 'MESH:D000077157', (57, 66))	('progression-free survival', 'CPA', (194, 219))	('osteosarcoma', 'Disease', 'MESH:D012516', (115, 127))	('pazopanib', 'Chemical', 'MESH:C516667', (156, 165))	('prolong', 'PosReg', (182, 189))	('sorafenib', 'Chemical', 'MESH:D000077157', (44, 53))
366445	29398759	Complete blood count showed normocytic, normochromic anaemia (10.4 g/dl) with mild neutropenia (32x109/L) and normal platelet count (180x109/L).	('anaemia', 'Disease', (53, 60))	('neutropenia', 'Disease', (83, 94))	('normocytic', 'Disease', (28, 38))	('anaemia', 'Phenotype', 'HP:0001903', (53, 60))	('32x109/L', 'Var', (96, 104))	('neutropenia', 'Disease', 'MESH:D009503', (83, 94))	('normochromic anaemia', 'Phenotype', 'HP:0001895', (40, 60))	('neutropenia', 'Phenotype', 'HP:0001875', (83, 94))	('anaemia', 'Disease', 'MESH:D000740', (53, 60))
366456	29398759	While MSP is positive for CD68, S-100, and negative for CD31, CD34, Kaposi's sarcoma is positive for CD31, CD34 and negative for CD68, S-100, and ZN stain.	('CD34', 'Var', (107, 111))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (68, 84))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (68, 84))	('CD31', 'Var', (101, 105))	("Kaposi's sarcoma", 'Disease', (68, 84))	('ZN', 'Chemical', '-', (146, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('positive', 'Reg', (88, 96))
366470	24455580	T (x; 18) (p11.2; q11.2) is highly specific gene mutation for synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (62, 78))	('synovial sarcoma', 'Disease', 'MESH:D013584', (62, 78))	('synovial sarcoma', 'Disease', (62, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('T (x', 'Var', (0, 4))
366491	24455580	Tumor size more than 5 cm, male gender, advanced age >20 years, high mitotic activity >10 mitosis/10 HPF, presence of tumor necrosis, and SYT-SSX1 gene variant are the poor prognostic factors.	('SYT', 'Gene', (138, 141))	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mitosis', 'Disease', 'None', (90, 97))	('variant', 'Var', (152, 159))	('Tumor', 'Disease', (0, 5))	('SYT', 'Gene', '6760', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor necrosis', 'Disease', 'MESH:D009336', (118, 132))	('SSX1', 'Gene', '6756', (142, 146))	('SSX1', 'Gene', (142, 146))	('tumor necrosis', 'Disease', (118, 132))	('mitosis', 'Disease', (90, 97))
366685	23029416	Decreased Mdm2 Expression Inhibits Tumor Development and Extends Survival Independent of Arf and Dependent on p53 Inactivation of the Arf-Mdm2-p53 tumor suppressor pathway is a necessary event for tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('Inactivation', 'Var', (114, 126))	('Arf', 'Gene', (134, 137))	('Extends', 'PosReg', (57, 64))	('Mdm2', 'Gene', (138, 142))	('tumor', 'Disease', (147, 152))	('Tumor Development', 'CPA', (35, 52))	('Survival', 'CPA', (65, 73))	('Decreased', 'NegReg', (0, 9))	('Inhibits', 'NegReg', (26, 34))	('Mdm2', 'Gene', (10, 14))	('Arf', 'Gene', '12578', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('p53', 'Gene', (110, 113))	('Arf', 'Gene', (89, 92))	('Mdm2', 'Gene', '17246', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('Mdm2', 'Gene', '17246', (10, 14))	('Tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Arf', 'Gene', '12578', (134, 137))	('tumor', 'Disease', (197, 202))
366689	23029416	Mdm2 heterozygosity significantly inhibited tumor development in the absence of Arf, and in contrast to Myc oncogene-driven cancer, this delay in tumorigenesis could not be rescued with the presence of one allele of Arf.	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Arf', 'Gene', (80, 83))	('heterozygosity', 'Var', (5, 19))	('inhibited', 'NegReg', (34, 43))	('tumor', 'Disease', (146, 151))	('Arf', 'Gene', '12578', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Mdm2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Arf', 'Gene', (216, 219))	('Myc', 'Gene', (104, 107))	('Myc', 'Gene', '17869', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Arf', 'Gene', '12578', (216, 219))	('tumor', 'Disease', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
366690	23029416	Notably, Mdm2 haploinsufficieny blocked the accelerated tumor development in Arf deficient mice caused by p53 heterozygosity.	('mice', 'Species', '10090', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Arf', 'Gene', (77, 80))	('blocked', 'NegReg', (32, 39))	('accelerated', 'PosReg', (44, 55))	('tumor', 'Disease', (56, 61))	('Arf', 'Gene', '12578', (77, 80))	('haploinsufficieny', 'Disease', (14, 31))	('p53 heterozygosity', 'Var', (106, 124))	('heterozygosity', 'Var', (110, 124))	('haploinsufficieny', 'Disease', 'None', (14, 31))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Mdm2', 'Gene', (9, 13))
366692	23029416	Surprisingly, loss of Arf accelerated tumor development in p53-null mice.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('loss', 'Var', (14, 18))	('accelerated', 'PosReg', (26, 37))	('Arf', 'Gene', (22, 25))	('Arf', 'Gene', '12578', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
366701	23029416	Deletion of p53 or Arf in mice results in tumor development with 100% penetrance, cementing their roles as tumor suppressors.	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('Arf', 'Gene', (19, 22))	('Arf', 'Gene', '12578', (19, 22))	('p53', 'Gene', (12, 15))	('mice', 'Species', '10090', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('results in', 'Reg', (31, 41))	('Deletion', 'Var', (0, 8))
366702	23029416	p53-null mice have an average life span of six months, whereas the mean life span of an Arf-/- mice is ten months.	('mice', 'Species', '10090', (95, 99))	('Arf', 'Gene', '12578', (88, 91))	('Arf', 'Gene', (88, 91))	('p53-null', 'Var', (0, 8))	('mice', 'Species', '10090', (9, 13))
366703	23029416	Thymic T cell lymphomas or sarcomas develop in p53-/- mice, whereas Arf-null mice have a slightly different tumor spectrum.	('mice', 'Species', '10090', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('p53-/-', 'Var', (47, 53))	('T cell lymphomas', 'Disease', 'MESH:D016399', (7, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('T cell lymphomas', 'Disease', (7, 23))	('sarcomas', 'Disease', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('lymphomas', 'Phenotype', 'HP:0002665', (14, 23))	('tumor', 'Disease', (108, 113))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (7, 23))	('Arf', 'Gene', '12578', (68, 71))	('Arf', 'Gene', (68, 71))	('lymphoma', 'Phenotype', 'HP:0002665', (14, 22))	('mice', 'Species', '10090', (54, 58))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))
366705	23029416	Both p53-/- and Arf-/- mice rarely develop carcinoma.	('p53-/-', 'Var', (5, 11))	('Arf', 'Gene', '12578', (16, 19))	('Arf', 'Gene', (16, 19))	('carcinoma', 'Disease', 'MESH:D002277', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinoma', 'Disease', (43, 52))	('mice', 'Species', '10090', (23, 27))
366706	23029416	Sarcomas are reported to be the primary tumor type that develops in C57Bl/6X129Sv mixed Arf-null mice, but other studies have shown lymphomas predominate in Arf-/- mice with a C57Bl/6 background.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('mice', 'Species', '10090', (164, 168))	('lymphomas', 'Disease', (132, 141))	('Arf', 'Gene', (88, 91))	('lymphomas', 'Disease', 'MESH:D008223', (132, 141))	('C57Bl/6X129Sv', 'Var', (68, 81))	('Arf', 'Gene', '12578', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Arf', 'Gene', (157, 160))	('mice', 'Species', '10090', (97, 101))	('129Sv', 'Species', '10090', (76, 81))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('Arf', 'Gene', '12578', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Sarcomas', 'Disease', (0, 8))	('lymphomas', 'Phenotype', 'HP:0002665', (132, 141))
366711	23029416	It was previously reported that deletion of both alleles of Arf does not cooperate to accelerate tumorigenesis in mice with a bialleleic deletion of p53 , but deletion of Arf did cooperate with overexpression of Mdm2 to accelerate tumorigenesis.	('deletion', 'Var', (32, 40))	('p53', 'Gene', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Arf', 'Gene', (60, 63))	('accelerate', 'PosReg', (220, 230))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (231, 236))	('Arf', 'Gene', (171, 174))	('Arf', 'Gene', '12578', (60, 63))	('mice', 'Species', '10090', (114, 118))	('Arf', 'Gene', '12578', (171, 174))	('deletion', 'Var', (159, 167))
366714	23029416	Another study showed Mdm2+/-p53-/- mice had a six day longer average survival and had a higher incidence of sarcomas compared to p53-null only and Mdm2/p53-double null mice.	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('longer', 'PosReg', (54, 60))	('average survival', 'CPA', (61, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('mice', 'Species', '10090', (168, 172))	('sarcomas', 'Disease', (108, 116))	('mice', 'Species', '10090', (35, 39))	('Mdm2+/-p53-/-', 'Var', (21, 34))
366717	23029416	Although our study indicates Mdm2 heterozygosity can influence tumor development in the presence of p53, we did not test whether this outcome on tumorigenesis of Mdm2 haploinsufficiency was dependent on p53.	('tumor', 'Disease', (63, 68))	('influence', 'Reg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('heterozygosity', 'Var', (34, 48))	('haploinsufficiency', 'Disease', 'MESH:D058495', (167, 185))	('tumor', 'Disease', (145, 150))	('haploinsufficiency', 'Disease', (167, 185))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Mdm2', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Mdm2', 'Gene', (29, 33))
366721	23029416	Unexpectedly, loss of Arf cooperated with deletion of p53 to accelerate tumorigenesis.	('accelerate', 'PosReg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Arf', 'Gene', '12578', (22, 25))	('Arf', 'Gene', (22, 25))	('tumor', 'Disease', (72, 77))	('p53', 'Gene', (54, 57))	('deletion', 'Var', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('loss', 'NegReg', (14, 18))
366727	23029416	Moreover, alterations in the levels of Arf, Mdm2, or p53 can significantly change tumor development, but the impact of altered levels of these genes on each other during tumor development is less understood.	('change', 'Reg', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('alterations', 'Var', (10, 21))	('Arf', 'Gene', (39, 42))	('Mdm2', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Arf', 'Gene', '12578', (39, 42))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p53', 'Gene', (53, 56))	('tumor', 'Disease', (82, 87))
366729	23029416	Mdm2 heterozygous Arf-/-p53+/- mice had a significantly protracted rate of tumor development compared to Mdm2 wild-type Arf-/-p53+/- mice, resulting in increased survival (Fig.	('mice', 'Species', '10090', (133, 137))	('Mdm2', 'Var', (0, 4))	('increased', 'PosReg', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mice', 'Species', '10090', (31, 35))	('Arf', 'Gene', '12578', (120, 123))	('Arf', 'Gene', (120, 123))	('survival', 'CPA', (162, 170))	('Arf', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('Arf', 'Gene', '12578', (18, 21))
366732	23029416	These data also show that loss of one allele of p53 is insufficient to rescue the effects of Mdm2 haploinsufficiency.	('p53', 'Gene', (48, 51))	('haploinsufficiency', 'Disease', 'MESH:D058495', (98, 116))	('haploinsufficiency', 'Disease', (98, 116))	('loss', 'Var', (26, 30))	('Mdm2', 'Gene', (93, 97))
366739	23029416	It is well established that loss of functional p53 accelerates tumor development.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('loss of functional', 'Var', (28, 46))	('accelerates', 'PosReg', (51, 62))	('p53', 'Gene', (47, 50))
366740	23029416	This occurs even in an Arf-null background, indicating loss of p53 is dominant.	('loss', 'Var', (55, 59))	('Arf', 'Gene', (23, 26))	('Arf', 'Gene', '12578', (23, 26))	('p53', 'Var', (63, 66))
366743	23029416	Since Mdm2 heterozygosity greatly delays tumor development in Arf-null mice that have both alleles of p53, the difference in mean survival between p53+/+ and the p53+/- Arf-null Mdm2+/-mice was much larger than their Mdm2 wild-type counterparts and quite significant (p<0.0001, log-rank test; Fig.	('Arf', 'Gene', (169, 172))	('mice', 'Species', '10090', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Arf', 'Gene', '12578', (169, 172))	('p53', 'Var', (102, 105))	('delays tumor', 'Disease', 'MESH:D009369', (34, 46))	('mice', 'Species', '10090', (185, 189))	('Arf', 'Gene', (62, 65))	('delays tumor', 'Disease', (34, 46))	('Arf', 'Gene', '12578', (62, 65))	('p53+/+', 'Var', (147, 153))
366747	23029416	Previously, we reported in Myc oncogene-driven cancer, loss of one allele of Arf rescued the delay in tumorigenesis caused by Mdm2 heterozygosity, demonstrating Arf levels regulate Mdm2 during oncogene-induced tumorigenesis.	('Arf', 'Gene', (77, 80))	('loss', 'Var', (55, 59))	('heterozygosity', 'Var', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Arf', 'Gene', '12578', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('Myc', 'Gene', (27, 30))	('Arf', 'Gene', (161, 164))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Arf', 'Gene', '12578', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Myc', 'Gene', '17869', (27, 30))	('delay', 'NegReg', (93, 98))	('Mdm2', 'Gene', (126, 130))
366748	23029416	Data above show that in the absence of Arf, Mdm2 heterozygosity inhibited tumor development when at least one allele of p53 was present (Fig.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Arf', 'Gene', (39, 42))	('Mdm2', 'Gene', (44, 48))	('inhibited', 'NegReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Arf', 'Gene', '12578', (39, 42))	('tumor', 'Disease', (74, 79))	('heterozygosity', 'Var', (49, 63))
366749	23029416	To assess the influence Arf expression has on Mdm2 in the absence of overt oncogene overexpression, we generated, and followed for tumor development, p53 heterozygous mice that were Mdm2 wild-type or heterozygous and with only one allele of Arf.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Mdm2', 'Var', (182, 186))	('tumor', 'Disease', (131, 136))	('Arf', 'Gene', (241, 244))	('Arf', 'Gene', '12578', (241, 244))	('Arf', 'Gene', (24, 27))	('mice', 'Species', '10090', (167, 171))	('Arf', 'Gene', '12578', (24, 27))
366757	23029416	Deletion of both alleles of Arf also significantly accelerates tumor development in p53 heterozygous mice (Fig.	('tumor', 'Disease', (63, 68))	('Arf', 'Gene', '12578', (28, 31))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('accelerates', 'PosReg', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Arf', 'Gene', (28, 31))	('Deletion', 'Var', (0, 8))
366758	23029416	However, loss of only one allele of Arf does not alter the rate of tumorigenesis in p53+/- mice, indicating that p53 heterozygosity is dominant in this situation.	('mice', 'Species', '10090', (91, 95))	('Arf', 'Gene', '12578', (36, 39))	('Arf', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('loss', 'Var', (9, 13))	('tumor', 'Disease', (67, 72))
366760	23029416	To determine whether Arf expression influences tumor development in the context of Mdm2 haploinsufficiency and independent of p53, we generated and evaluated Mdm2+/-p53-/- mice that had one, both, or no alleles of Arf and Mdm2+/+ littermate controls.	('tumor', 'Disease', (47, 52))	('haploinsufficiency', 'Disease', (88, 106))	('haploinsufficiency', 'Disease', 'MESH:D058495', (88, 106))	('Arf', 'Gene', (214, 217))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mice', 'Species', '10090', (172, 176))	('Mdm2+/-p53-/-', 'Var', (158, 171))	('Arf', 'Gene', (21, 24))	('Arf', 'Gene', '12578', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Arf', 'Gene', '12578', (21, 24))	('influences', 'Reg', (36, 46))
366764	23029416	Surprisingly however, a similar trend was observed for the Mdm2 wild-type p53-null mice with loss of Arf accelerating tumorigenesis (Fig.	('Arf', 'Gene', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('Arf', 'Gene', '12578', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('loss', 'Var', (93, 97))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Disease', (118, 123))	('accelerating', 'PosReg', (105, 117))
366765	23029416	The difference in survival between Mdm2+/+Arf+/+p53-/- and Mdm2+/+Arf-/-p53-/- mice was significant (p = 0.0011, log-rank test), suggesting loss of Arf cooperated with deletion of p53 to decrease tumor latency.	('Arf', 'Gene', '12578', (42, 45))	('Arf', 'Gene', (148, 151))	('tumor', 'Disease', (196, 201))	('Arf', 'Gene', '12578', (148, 151))	('p53', 'Gene', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('mice', 'Species', '10090', (79, 83))	('decrease', 'NegReg', (187, 195))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Arf', 'Gene', '12578', (66, 69))	('Arf', 'Gene', (66, 69))	('deletion', 'Var', (168, 176))	('Arf', 'Gene', (42, 45))	('loss', 'Var', (140, 144))
366772	23029416	Alterations in tumor spectrum can reveal functions of a gene even when the rate of tumor development is unaltered.	('reveal', 'Reg', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('functions', 'MPA', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (83, 88))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
366774	23029416	In both Mdm2+/+ and Mdm2+/- mice of different Arf and/or p53 deficiencies analyzed, the expected tumor types arose.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Arf', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mice', 'Species', '10090', (28, 32))	('Mdm2+/+', 'Var', (8, 15))	('Arf', 'Gene', '12578', (46, 49))	('tumor', 'Disease', (97, 102))	('p53', 'Gene', (57, 60))	('deficiencies', 'Var', (61, 73))
366792	23029416	Although there were strong trends towards different tumor spectrums between Mdm2+/- and Mdm2+/+ mice of various Arf/p53 genotypes with some approaching statistical significance, only the three comparisons described above and as presented in Table 2 reached statistical significance.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Disease', (52, 57))	('Arf', 'Gene', (112, 115))	('Arf', 'Gene', '12578', (112, 115))	('Mdm2+/-', 'Var', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
366804	23029416	These data suggest loss of Arf allows for soft tissue sarcomas to emerge more readily, whereas with loss of p53, hemangiosarcomas dominated.	('hemangiosarcomas', 'Disease', (113, 129))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (42, 62))	('loss', 'Var', (100, 104))	('Arf', 'Gene', '12578', (27, 30))	('p53', 'Gene', (108, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('soft tissue sarcomas', 'Disease', (42, 62))	('hemangiosarcomas', 'Disease', 'MESH:D006394', (113, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('Arf', 'Gene', (27, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('loss', 'Var', (19, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (42, 62))
366810	23029416	Moreover, levels of Arf, Mdm2, and/or p53 are typically altered in cancer cells, which contributes to the development and/or progression of the malignancy.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('levels', 'MPA', (10, 16))	('contributes to', 'Reg', (87, 101))	('cancer', 'Disease', (67, 73))	('malignancy', 'Disease', (144, 154))	('Mdm2', 'MPA', (25, 29))	('altered', 'Reg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Arf', 'Gene', (20, 23))	('p53', 'Var', (38, 41))	('Arf', 'Gene', '12578', (20, 23))	('malignancy', 'Disease', 'MESH:D009369', (144, 154))
366812	23029416	For example, a single nucleotide polymorphism (SNP) in the promoter of Mdm2 (SNP309), leading to increased transcription, or codon 72 of p53, altering protein stability or function, can in certain circumstances increase a person's susceptibility to tumor development.	('protein stability', 'MPA', (151, 168))	('increased', 'PosReg', (97, 106))	('Mdm2', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('increase', 'PosReg', (211, 219))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('transcription', 'MPA', (107, 120))	('altering', 'Reg', (142, 150))	('function', 'MPA', (172, 180))	('SNP309', 'Var', (77, 83))	('tumor', 'Disease', (249, 254))	('person', 'Species', '9606', (222, 228))	('single nucleotide polymorphism', 'Var', (15, 45))	('p53', 'Gene', (137, 140))
366814	23029416	Specifically, data here, which are consistent with our previous study, show that lower levels of Mdm2 due to Mdm2 heterozygosity were protective against tumors initiated from an Arf deficiency.	('lower', 'NegReg', (81, 86))	('Mdm2', 'Gene', (109, 113))	('Arf deficiency', 'Disease', (178, 192))	('levels', 'MPA', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Arf deficiency', 'Disease', 'MESH:D007153', (178, 192))	('tumors', 'Disease', (153, 159))	('Mdm2', 'MPA', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('heterozygosity', 'Var', (114, 128))
366816	23029416	Importantly, our data here also show reduced Mdm2 levels inhibited tumor development in the context of p53 heterozygosity regardless of Arf status.	('p53', 'Gene', (103, 106))	('inhibited', 'NegReg', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Mdm2', 'MPA', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('heterozygosity', 'Var', (107, 121))	('Arf', 'Gene', (136, 139))	('tumor', 'Disease', (67, 72))	('reduced', 'NegReg', (37, 44))	('Arf', 'Gene', '12578', (136, 139))
366817	23029416	However, loss of p53 was dominant, and dictated the rate of tumor development independent of Mdm2 haploinsufficiency.	('haploinsufficiency', 'Disease', 'MESH:D058495', (98, 116))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('loss', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('haploinsufficiency', 'Disease', (98, 116))	('p53', 'Protein', (17, 20))	('tumor', 'Disease', (60, 65))
366818	23029416	Mdm2 heterozygosity also significantly altered tumor spectrum in some of the genotypes of mice.	('heterozygosity', 'Var', (5, 19))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Mdm2', 'Gene', (0, 4))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('altered', 'Reg', (39, 46))	('tumor', 'Disease', (47, 52))
366825	23029416	Similar to Myc oncogene-induced tumorigenesis, we showed Mdm2 heterozygosity inhibited tumor development in Arf-null mice and in Arf-/-p53+/- mice.	('Arf', 'Gene', '12578', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Mdm2', 'Gene', (57, 61))	('Myc', 'Gene', (11, 14))	('inhibited', 'NegReg', (77, 86))	('Arf', 'Gene', (108, 111))	('tumor', 'Disease', (87, 92))	('Arf', 'Gene', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Arf', 'Gene', '12578', (129, 132))	('mice', 'Species', '10090', (142, 146))	('heterozygosity', 'Var', (62, 76))	('Myc', 'Gene', '17869', (11, 14))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (32, 37))
366826	23029416	However, in contrast to Myc-driven tumor development, loss of one allele of Arf did not rescue the delay in tumor development caused by an Mdm2 haploinsufficiency.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Mdm2', 'Gene', (139, 143))	('Arf', 'Gene', (76, 79))	('Arf', 'Gene', '12578', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('haploinsufficiency', 'Disease', 'MESH:D058495', (144, 162))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (108, 113))	('loss', 'Var', (54, 58))	('Myc', 'Gene', (24, 27))	('Myc', 'Gene', '17869', (24, 27))	('haploinsufficiency', 'Disease', (144, 162))
366831	23029416	For example, Mdm2 overexpression in the context of p53 deletion does not alter tumor latency but does change tumor spectrum.	('p53', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('change', 'Reg', (102, 108))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('deletion', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (109, 114))
366832	23029416	In a previous study, loss of one but not both alleles of Mdm2 led to an increase in the number of primary tumors, sarcoma development, and a slight (6 day) statistically significant delay in tumorigenesis in p53-null mice, suggesting a p53-independent consequence of Mdm2 haploinsufficiency.	('increase', 'PosReg', (72, 80))	('haploinsufficiency', 'Disease', 'MESH:D058495', (272, 290))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('haploinsufficiency', 'Disease', (272, 290))	('tumor', 'Disease', (106, 111))	('loss', 'Var', (21, 25))	('primary tumors', 'Disease', 'MESH:D009369', (98, 112))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('Mdm2', 'Gene', (57, 61))	('sarcoma', 'Disease', (114, 121))	('mice', 'Species', '10090', (217, 221))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('delay', 'NegReg', (182, 187))	('primary tumors', 'Disease', (98, 112))
366833	23029416	Similarly, we observed an analogous increase in the number of primary tumors in Mdm2+/-p53-/- mice.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('primary tumors', 'Disease', (62, 76))	('increase', 'PosReg', (36, 44))	('primary tumors', 'Disease', 'MESH:D009369', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mice', 'Species', '10090', (94, 98))	('Mdm2+/-p53-/-', 'Var', (80, 93))
366836	23029416	Our results on the Mdm2+/-p53-/- mice were consistent with another study that showed no change in tumor latency and minor alterations in tumor spectrum compared to p53-/- mice.	('tumor', 'Disease', (137, 142))	('mice', 'Species', '10090', (171, 175))	('Mdm2+/-p53-/-', 'Var', (19, 32))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mice', 'Species', '10090', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
366840	23029416	Therefore, alterations in Mdm2 levels can predispose mice to developing certain types of cancers, and this can be independent from p53.	('alterations', 'Var', (11, 22))	('Mdm2', 'MPA', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('mice', 'Species', '10090', (53, 57))	('predispose', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
366842	23029416	Specifically, the Donehower group reported that overexpression of Mdm2 and loss of Arf cooperated to accelerate tumorigenesis, suggesting that suppression of p53 and inactivation of Arf have independent effects in tumor development.	('Arf', 'Gene', '12578', (83, 86))	('Arf', 'Gene', '12578', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('loss', 'Var', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('inactivation', 'Var', (166, 178))	('Arf', 'Gene', (182, 185))	('Mdm2', 'Gene', (66, 70))	('tumor', 'Disease', (214, 219))	('overexpression', 'PosReg', (48, 62))	('tumor', 'Disease', (112, 117))	('Arf', 'Gene', (83, 86))	('accelerate', 'PosReg', (101, 111))
366843	23029416	Consistent with these results, our data show that loss of both Arf and p53 accelerated the rate of tumorigenesis over that of p53-null only mice.	('tumor', 'Disease', (99, 104))	('mice', 'Species', '10090', (140, 144))	('accelerated', 'PosReg', (75, 86))	('loss', 'Var', (50, 54))	('p53', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Arf', 'Gene', (63, 66))	('Arf', 'Gene', '12578', (63, 66))
366845	23029416	that biallelic deletion of both p53 and Arf have tumor latencies analogous to deletion of both alleles of p53 alone.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Arf', 'Gene', (40, 43))	('tumor', 'Disease', (49, 54))	('p53', 'Gene', (32, 35))	('Arf', 'Gene', '12578', (40, 43))	('biallelic deletion', 'Var', (5, 23))
366852	23029416	p53+/-Mdm2+/- (C57BL/6x129Sv) mice were originally obtained from Dr. Guillermina Lozano (MD Anderson Cancer Center), and Arf-null mice (C57BL/6x129Sv) were originally provided by Drs.	('mice', 'Species', '10090', (130, 134))	('mice', 'Species', '10090', (30, 34))	('p53+/-Mdm2+/-', 'Var', (0, 13))	('Arf', 'Gene', '12578', (121, 124))	('MD Anderson Cancer', 'Disease', (89, 107))	('129Sv', 'Species', '10090', (144, 149))	('Drs', 'Gene', (179, 182))	('C57BL/6x129Sv', 'Var', (136, 149))	('Drs', 'Gene', '51795', (179, 182))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('129Sv', 'Species', '10090', (23, 28))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (89, 107))	('Arf', 'Gene', (121, 124))
366864	23029416	A 2x2 contingency table Chi-squared test was performed to determine significant differences in the tumor types that arose in each of the Mdm2+/+ and Mdm2+/- genotypes.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Mdm2+/+', 'Var', (137, 144))	('Mdm2+/-', 'Var', (149, 156))
366922	30166462	Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors Sarcomas are cancers of the bone and soft tissue often defined by their gene fusions.	('Rearrangement', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Sarcomas', 'Disease', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (65, 82))	('cancers of the bone', 'Phenotype', 'HP:0010622', (97, 116))	('Sarcomas', 'Phenotype', 'HP:0100242', (84, 92))
366923	30166462	We explored this in Ewing sarcoma, a cancer driven by EWSR1-ETS fusions, with very few cooperating mutations.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('EWSR1', 'Gene', '2130', (54, 59))	('cancer', 'Disease', (37, 43))	('fusions', 'Var', (64, 71))	('Ewing sarcoma', 'Disease', (20, 33))	('EWSR1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (20, 33))
366925	30166462	We found the same pattern of rearrangements in three additional types of sarcoma.	('sarcoma', 'Disease', (73, 80))	('rearrangements', 'Var', (29, 43))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))
366929	30166462	Rearrangements can generate cancer-driving mutations through several mechanisms, including the formation of gene fusions.	('Rearrangements', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('generate', 'Reg', (19, 27))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
366931	30166462	Oncogenic gene fusions are particularly common in leukemia and bone and soft tissue tumors, often acting as the sole driver mutation and delineating clinically relevant tumor entities and subgroups.	('soft tissue tumor', 'Phenotype', 'HP:0031459', (72, 89))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('soft tissue tumors', 'Disease', 'MESH:D012983', (72, 90))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (72, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('common', 'Reg', (40, 46))	('leukemia', 'Disease', (50, 58))	('leukemia', 'Disease', 'MESH:D007938', (50, 58))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('soft tissue tumors', 'Disease', (72, 90))	('Oncogenic gene fusions', 'Var', (0, 22))
366932	30166462	In leukemia, RAG-mediated recombination has been identified as the leading mutational process that creates canonical gene fusions and drives oncogenesis through translocations and deletions.	('drives', 'PosReg', (134, 140))	('creates', 'Reg', (99, 106))	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('leukemia', 'Disease', 'MESH:D007938', (3, 11))	('leukemia', 'Disease', (3, 11))	('oncogenesis', 'CPA', (141, 152))	('deletions', 'Var', (180, 189))	('translocations', 'Var', (161, 175))
366935	30166462	It represents the prototypical fusion-driven sarcoma, defined by fusions between EWSR1 and an ETS transcription factor, including FLI1 and ERG.	('EWSR1', 'Gene', '2130', (81, 86))	('sarcoma', 'Disease', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('EWSR1', 'Gene', (81, 86))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('ERG', 'Gene', '2078', (139, 142))	('FLI1', 'Gene', (130, 134))	('ERG', 'Gene', (139, 142))	('FLI1', 'Gene', '2313', (130, 134))	('fusions', 'Var', (65, 72))
366951	30166462	Similarly, TP53 mutations, another established marker of poor prognosis, were enriched in chromoplexy ES (16% vs. 3%, p < 0.05).	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('chromoplexy ES', 'Disease', (90, 104))	('ES', 'Phenotype', 'HP:0012254', (102, 104))
366952	30166462	There was no enrichment for CDKN2A or STAG2 mutations (fig.	('STAG2', 'Gene', (38, 43))	('CDKN2A', 'Gene', (28, 34))	('mutations', 'Var', (44, 53))	('CDKN2A', 'Gene', '1029', (28, 34))	('STAG2', 'Gene', '10735', (38, 43))
366958	30166462	Taken together, these findings in human bone and soft tissue tumors show that canonical gene fusions are frequently caused by complex rearrangement processes, predominantly chromoplexy, but also chromothripsis.	('human', 'Species', '9606', (34, 39))	('soft tissue tumors', 'Disease', 'MESH:D012983', (49, 67))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (49, 67))	('chromoplexy', 'Disease', (173, 184))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (49, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('caused', 'Reg', (116, 122))	('soft tissue tumors', 'Disease', (49, 67))	('chromothripsis', 'Disease', (195, 209))	('canonical gene fusions', 'Var', (78, 100))
366967	30166462	Both prostate cancer and ES loops were characterized by focal intra-chromosomal rearrangements - deletion bridges - that acted as local mediators of large-scale loops (illustrated in fig.	('ES', 'Phenotype', 'HP:0012254', (25, 27))	('prostate cancer', 'Disease', (5, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ES loops', 'Disease', (25, 33))	('prostate cancer', 'Disease', 'MESH:D011471', (5, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (5, 20))	('deletion', 'Var', (97, 105))
366971	30166462	In chondromyxoid fibromas with chromoplectic GRM1 fusions (3/4 cases), the rearrangement breakpoint did not actually reside within the GRM1 gene body.	('GRM1', 'Gene', '2911', (135, 139))	('fibroma', 'Phenotype', 'HP:0010614', (17, 24))	('chondromyxoid fibromas', 'Disease', 'MESH:D005350', (3, 25))	('fusions', 'Var', (50, 57))	('chondromyxoid fibromas', 'Disease', (3, 25))	('GRM1', 'Gene', '2911', (45, 49))	('GRM1', 'Gene', (135, 139))	('fibromas', 'Phenotype', 'HP:0010614', (17, 25))	('GRM1', 'Gene', (45, 49))
366973	30166462	Thus, chromoplexy plus conventional splicing leads to the promoter swap that is characteristic of this cancer (see).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('leads to', 'Reg', (45, 53))	('promoter swap', 'MPA', (58, 71))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('chromoplexy', 'Var', (6, 17))
366994	30166462	As is the cases in most tumor types, relapse and metastatic ES tumors acquired many new mutations (average 50% private).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (63, 68))	('ES tumors', 'Disease', 'MESH:C563168', (60, 69))	('tumor', 'Disease', (24, 29))	('mutations', 'Var', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('ES tumors', 'Disease', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ES', 'Phenotype', 'HP:0012254', (60, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
367001	30166462	Overall, our analyses have revealed rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors.	('soft tissue tumors', 'Disease', (124, 142))	('human', 'Species', '9606', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('rearrangement bursts', 'Var', (36, 56))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (124, 142))	('soft tissue tumors', 'Disease', 'MESH:D012983', (124, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (124, 141))
367002	30166462	It is known that ES with complex karyotypes have worse prognosis, and here we show chromoplexy as the mechanism in 42% of tumors.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Disease', (122, 128))	('ES', 'Phenotype', 'HP:0012254', (17, 19))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('complex', 'Var', (25, 32))
367003	30166462	It is possible that it is the chromoplectic tumor's additional gene disruptions and fusions that contribute to this survival difference.	('fusions', 'Var', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('chromoplectic tumor', 'Phenotype', 'HP:0002666', (30, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
367006	30166462	As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers.	('human', 'Species', '9606', (209, 214))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('fusion', 'Var', (151, 157))	('cancers', 'Disease', (215, 222))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
367013	30166462	Of the 25 high-coverage genomes sequenced, EWSR1-ETS fusions were detected in all patients except for a 37-year-old who was instead found to have a FUS-ERG translocation.	('FUS', 'Gene', (148, 151))	('fusions', 'Var', (53, 60))	('FUS', 'Gene', '2521', (148, 151))	('patients', 'Species', '9606', (82, 90))	('detected', 'Reg', (66, 74))	('ERG', 'Gene', '2078', (152, 155))	('EWSR1', 'Gene', (43, 48))	('ERG', 'Gene', (152, 155))	('EWSR1', 'Gene', '2130', (43, 48))
367015	30166462	The validation cohort consisted of 119 tumor-normal samples sequenced by Tirode F. et al, which we downloaded from the European Genome-phenome Archive (accessions: EGAS00001000855 and EGAS00001000839).	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('EGAS00001000839', 'Var', (184, 199))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (39, 44))
367016	30166462	Of these, 19 patient samples were omitted either because the EWSR1-ETS fusion was not detected by our pipeline and manual inspection of the aligned reads, or because they harbored an excess of artefactual small inversions or deletions.	('EWSR1', 'Gene', '2130', (61, 66))	('small inversions', 'Var', (205, 221))	('patient', 'Species', '9606', (13, 20))	('EWSR1', 'Gene', (61, 66))	('deletions', 'Var', (225, 234))
367018	30166462	For substitutions, we removed common single-nucleotide polymorphisms (SNPs) as previously described and a required >10X coverage at the mutated locus (10 kb window), in both tumor and normal.	('tumor', 'Disease', (174, 179))	('single-nucleotide polymorphisms', 'Var', (37, 68))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('substitutions', 'Var', (4, 17))
367019	30166462	For rearrangements, this filter required >= 4 discordant read-pairs in the tumor.	('rearrangements', 'Var', (4, 18))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
367023	30166462	We then developed custom code to increase specificity of putative substitution and rearrangement detection, as follows:   First, a de novo extraction was performed on the catalogue of Ewing sarcoma point mutations to produce novel consensus mutational signatures.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (184, 197))	('point mutations', 'Var', (198, 213))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (184, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('Ewing sarcoma', 'Disease', (184, 197))
367032	30166462	As expected, the BAF of germline CNV deletions followed a bimodal distribution with peaks at 0.5 and 1.0, for heterozygous and homozygous rearrangements, respectively (fig.	('deletions', 'Var', (37, 46))	('BAF', 'Gene', (17, 20))	('BAF', 'Gene', '8815', (17, 20))	('CNV', 'Gene', (33, 36))
367047	30166462	Disease-defining fusions in sarcoma frequently emerge by rearrangement burst, creating complex genomic loops and disrupting additional genes, in an early clone that may develop multiple years before diagnosis.	('sarcoma', 'Disease', (28, 35))	('creating', 'Reg', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('disrupting', 'NegReg', (113, 123))	('fusions', 'Var', (17, 24))	('rearrangement burst', 'Var', (57, 76))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))
367051	33648449	Overall, a total of 12 studies with 500 cases were included, and the results indicated that the expression of Ki-67 was significantly associated with Enneking stage (OR = 6.88, 95% CI: 2.92-16.22, p < 0.05), distant metastasis (OR = 3.04, 95% CI: 1.51-6.12, p < 0.05) and overall survival (OR = 8.82, 95% CI: 4.68-16.65, p < 0.05) in OS patients.	('associated with', 'Reg', (134, 149))	('overall survival', 'CPA', (272, 288))	('distant metastasis', 'CPA', (208, 226))	('Ki-67', 'Gene', (110, 115))	('OS', 'Phenotype', 'HP:0002669', (334, 336))	('Enneking', 'Disease', (150, 158))	('patients', 'Species', '9606', (337, 345))	('Ki-67', 'Chemical', '-', (110, 115))	('expression', 'Var', (96, 106))
367075	33648449	The search strategies were as follows: (1) marker of proliferation Ki-67 or MKI67 or Ki-67 or MIB-1 or Mindbomb E3 ubiquitin protein ligase 1; (2) osteogenic tumor or osteosarcoma; and (3) prognostic or prognosis or survival.	('MIB-1', 'Gene', '57534', (94, 99))	('osteosarcoma', 'Disease', (167, 179))	('osteosarcoma', 'Disease', 'MESH:D012516', (167, 179))	('Ki-67', 'Chemical', '-', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('Ki-67', 'Chemical', '-', (85, 90))	('osteosarcoma', 'Phenotype', 'HP:0002669', (167, 179))	('osteogenic tumor', 'Disease', 'MESH:D012516', (147, 163))	('MIB-1', 'Gene', (94, 99))	('MKI67', 'Gene', (76, 81))	('MKI67', 'Gene', '4288', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Ki-67', 'Var', (67, 72))	('Ki-67', 'Gene', (85, 90))	('osteogenic tumor', 'Disease', (147, 163))
367104	33648449	Li and Zhang suggested that the level of Ki-67 was related to the prognosis of patients with OS, but Junior and colleagues were not able to find a correlation between the marker and the prognosis, possibly because of the small number of cases.	('OS', 'Phenotype', 'HP:0002669', (93, 95))	('Ki-67', 'Var', (41, 46))	('patients', 'Species', '9606', (79, 87))	('Ki-67', 'Chemical', '-', (41, 46))	('related', 'Reg', (51, 58))
367110	33648449	Additionally, the relationship between Ki-67 and worse survival outcomes in sarcoma was further confirmed using the TCGA dataset and Kaplan-Meier plotter dataset.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('sarcoma', 'Disease', (76, 83))	('Ki-67', 'Var', (39, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Ki-67', 'Chemical', '-', (39, 44))
367117	33648449	Our study showed that Ki-67 positivity was related to the OS Enneking stage and distant metastasis.	('Ki-67', 'Chemical', '-', (22, 27))	('positivity', 'Var', (28, 38))	('related', 'Reg', (43, 50))	('Ki-67', 'Protein', (22, 27))	('OS Enneking', 'Disease', (58, 69))	('OS', 'Phenotype', 'HP:0002669', (58, 60))	('distant metastasis', 'CPA', (80, 98))
367248	29443775	In a retrospective study, Huber et al suggested that adjuvant radiotherapy should be recommended for large tumors (>4 cm), high histological grade, tumors close the resection-margins, or those with positive margins.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('high histological', 'Var', (123, 140))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
367277	29208319	Topographical codes C480, C490, C491, C492, C493, C494, C495, and C496 were included and histologic diagnoses were individually reviewed to exclude those that were non-sarcomatous or mixed as previously described (Supplemental Table 1).	('C493', 'Var', (44, 48))	('C492', 'Var', (38, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('C495', 'Var', (56, 60))	('non-sarcomatous', 'Disease', (164, 179))	('non-sarcomatous', 'Disease', 'MESH:D018316', (164, 179))	('C496', 'Var', (66, 70))	('C480', 'Var', (20, 24))	('C494', 'Var', (50, 54))	('C491', 'Var', (32, 36))	('C490', 'Var', (26, 30))
367299	29208319	Patients with LN metastasis in the absence of distant metastatic disease had intermediate OS compared to those with N0M0 and M1 disease (median OS in years: N0M0=8.5, pN1M0=2.4, cN1M0=1.1, M1=0.8; 5-year OS: N0M0=61.1%, pN1M0=34.1%, cN1M0=21.9%, M1=10%).	('cN1', 'Gene', (178, 181))	('M1 disease', 'Disease', (125, 135))	('OS', 'Chemical', '-', (90, 92))	('cN1', 'Gene', (233, 236))	('pN1', 'Gene', '5270', (167, 170))	('N0M0=61.1', 'Var', (208, 217))	('OS', 'Chemical', '-', (204, 206))	('pN1', 'Gene', (167, 170))	('Patients', 'Species', '9606', (0, 8))	('M1 disease', 'Disease', 'MESH:D015470', (125, 135))	('pN1', 'Gene', '5270', (220, 223))	('cN1', 'Gene', '84618', (178, 181))	('pN1', 'Gene', (220, 223))	('cN1', 'Gene', '84618', (233, 236))	('OS', 'Chemical', '-', (144, 146))
367305	29208319	Survival curves of patients with N1M0 disease more closely approximates those of M1 patients than N0M0 patients for histologies such as leiomyosarcoma, clear cell sarcoma and angiosarcoma compared to epithelioid sarcoma, for example (Figure 3).	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (200, 219))	('patients', 'Species', '9606', (19, 27))	('epithelioid sarcoma', 'Disease', (200, 219))	('patients', 'Species', '9606', (84, 92))	('angiosarcoma', 'Phenotype', 'HP:0200058', (175, 187))	('clear cell sarcoma', 'Disease', (152, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('leiomyosarcoma', 'Disease', (136, 150))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (152, 170))	('N1M0', 'Var', (33, 37))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (136, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('angiosarcoma', 'Disease', 'MESH:D006394', (175, 187))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (136, 150))	('angiosarcoma', 'Disease', (175, 187))	('patients', 'Species', '9606', (103, 111))
367367	29246026	Moreover, cytokine therapies seem to be crucial in orchestrating the immune response in OS; for example, administration of IL-2 was able to induce immune activation, probably via NK cells activation, improving prognosis of OS patients.	('immune activation', 'MPA', (147, 164))	('prognosis', 'CPA', (210, 219))	('improving', 'PosReg', (200, 209))	('administration', 'Var', (105, 119))	('patients', 'Species', '9606', (226, 234))	('IL-2', 'Gene', '3558', (123, 127))	('IL-2', 'Gene', (123, 127))
367389	29246026	An increasing body of data showed how aberrantly expressed miRNAs contribute to the pathogenesis of several types of tumours, acting as oncogenes or tumour suppressors.	('tumours', 'Disease', (117, 124))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('tumours', 'Disease', 'MESH:D009369', (117, 124))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('contribute', 'Reg', (66, 76))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('aberrantly expressed', 'Var', (38, 58))	('tumour', 'Disease', (117, 123))	('tumour', 'Disease', (149, 155))
367415	29246026	Several studies showed that miRNA deregulation was closely associated with the development of chemoresistance, also in OS.	('chemoresistance', 'CPA', (94, 109))	('deregulation', 'Var', (34, 46))	('associated', 'Reg', (59, 69))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))
367460	29246026	In OS cell lines, silencing of miR-17 leads to increased PTEN expression with decreased cell proliferation, migration and invasion.	('miR-17', 'Gene', (31, 37))	('silencing', 'Var', (18, 27))	('PTEN', 'Protein', (57, 61))	('miR-17', 'Gene', '406952', (31, 37))	('expression', 'MPA', (62, 72))	('increased', 'PosReg', (47, 56))	('cell proliferation', 'CPA', (88, 106))	('decreased', 'NegReg', (78, 87))
367461	29246026	High PTEN tissue expression frequently occurred in OS patients with a better prognosis, while upregulation of circulating miR-17 was associated with a poor prognosis.	('High', 'Var', (0, 4))	('PTEN', 'Protein', (5, 9))	('upregulation', 'PosReg', (94, 106))	('patients', 'Species', '9606', (54, 62))	('expression', 'MPA', (17, 27))	('occurred', 'Reg', (39, 47))	('miR-17', 'Gene', (122, 128))	('miR-17', 'Gene', '406952', (122, 128))
367475	29246026	In detail, inhibition of miR-24 could overcome chemoresistance, increasing sensitivity of DOX-resistant OS cell lines to chemotherapy.	('increasing', 'PosReg', (64, 74))	('DOX', 'Chemical', 'MESH:D004317', (90, 93))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('inhibition', 'Var', (11, 21))	('chemoresistance', 'CPA', (47, 62))	('sensitivity', 'MPA', (75, 86))
367476	29246026	MiR-24 silencing led to upregulation of the pro-apoptotic protein BIM, a member of the Bcl-2 family, and promoted the release of apoptotic factors (such as Smac/DIABLO) from mitochondria, with consequent activation of caspases-dependent cell death.	('release', 'MPA', (118, 125))	('MiR', 'Gene', (0, 3))	('promoted', 'PosReg', (105, 113))	('activation', 'PosReg', (204, 214))	('Bcl-2', 'Gene', (87, 92))	('Smac', 'Gene', (156, 160))	('DIABLO', 'Gene', '56616', (161, 167))	('Bcl-2', 'Gene', '596', (87, 92))	('MiR', 'Gene', '220972', (0, 3))	('apoptotic', 'MPA', (129, 138))	('DIABLO', 'Gene', (161, 167))	('caspases-dependent cell death', 'CPA', (218, 247))	('Smac', 'Gene', '56616', (156, 160))	('upregulation', 'PosReg', (24, 36))	('BIM', 'Gene', '10018', (66, 69))	('silencing', 'Var', (7, 16))	('BIM', 'Gene', (66, 69))
367491	29246026	High TUG1 levels were detected in OS tissues when compared with corresponding adjacent normal tissues; in addition, OS patients with high tissue TUG1 levels had a significantly worse prognosis, and TUG1 resulted as an independent prognostic marker for both overall and progression-free survival.	('high', 'Var', (133, 137))	('TUG1', 'Gene', '55000', (145, 149))	('patients', 'Species', '9606', (119, 127))	('TUG1', 'Gene', '55000', (5, 9))	('TUG1', 'Gene', '55000', (198, 202))	('TUG1', 'Gene', (145, 149))	('TUG1', 'Gene', (5, 9))	('TUG1', 'Gene', (198, 202))
367493	29246026	Circulating expression profile of 91H, a lncRNA located on the position of the H19/insulin-like growth factor 2(IGF2) locus, was investigated in the serum of OS patients and in healthy controls; interestingly, 91H overexpression was correlated with advanced clinical stage, chemotherapy after surgery and tumour size (when greater than 5 cm).	('H19', 'Gene', '283120', (79, 82))	('tumour', 'Disease', 'MESH:D009369', (305, 311))	('overexpression', 'PosReg', (214, 228))	('IGF2', 'Gene', '3481', (112, 116))	('H19', 'Gene', (79, 82))	('tumour', 'Disease', (305, 311))	('91H', 'Var', (210, 213))	('patients', 'Species', '9606', (161, 169))	('IGF2', 'Gene', (112, 116))	('tumour', 'Phenotype', 'HP:0002664', (305, 311))
367525	29246026	More recently, a prospective clinical study described a new method to quantify OS CTCs from blood; this is based on abnormal chromosome numbers (aneuploidy) in CTCs instead of surface markers.	('aneuploidy', 'Disease', 'MESH:D000782', (145, 155))	('abnormal chromosome numbers', 'Phenotype', 'HP:0031411', (116, 143))	('aneuploidy', 'Disease', (145, 155))	('abnormal chromosome numbers', 'Var', (116, 143))
367528	29246026	Cell-free circulating tumour DNA (ctDNA) can be considered as a potential surrogate for the entire tumour genome, as analysis of ctDNA for somatic mutations may be a way to detect and follow the progression of a patient's tumour.	('mutations', 'Var', (147, 156))	('tumour', 'Disease', 'MESH:D009369', (222, 228))	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (222, 228))	('tumour', 'Disease', (22, 28))	('tumour', 'Disease', (99, 105))	('patient', 'Species', '9606', (212, 219))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))
367533	29246026	In a recent study on primary breast tumours, not all the mutations identified in the metastasis could be detected in the primary lesion; conversely, all mutations identified in plasma-derived DNA were accurately detected (by sequencing analysis of DNA) in tissue biopsies of both primary breast cancer and its synchronous liver metastasis.	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (288, 301))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('breast tumours', 'Disease', 'MESH:D001943', (29, 43))	('mutations', 'Var', (153, 162))	('breast tumours', 'Disease', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('detected', 'Reg', (212, 220))	('breast cancer', 'Disease', 'MESH:D001943', (288, 301))	('breast cancer', 'Phenotype', 'HP:0003002', (288, 301))
367535	29246026	One of the most commonly used liquid biopsy analysis is the search of epidermal growth factor receptor (EGFR) mutations, which predicts responsiveness to EGF receptor (EGFR)-tyrosine kinase inhibitors in a distinct clinicopathologic subset of non-small-cell lung cancer patients.	('mutations', 'Var', (110, 119))	('patients', 'Species', '9606', (270, 278))	('EGFR', 'Gene', (168, 172))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (168, 172))	('cell lung cancer', 'Disease', 'MESH:D008175', (253, 269))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (243, 269))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (247, 269))	('epidermal growth factor receptor', 'Gene', (70, 102))	('EGF receptor', 'Gene', '1956', (154, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (258, 269))	('EGF receptor', 'Gene', (154, 166))	('epidermal growth factor receptor', 'Gene', '1956', (70, 102))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('responsiveness', 'MPA', (136, 150))	('EGFR', 'Gene', '1956', (104, 108))	('cell lung cancer', 'Disease', (253, 269))
367546	29246026	They later confirmed elevated IRX1 expression in metastatic OS patients due to hypomethylation of its own promoter.	('hypomethylation', 'Var', (79, 94))	('metastatic OS', 'Disease', (49, 62))	('expression', 'MPA', (35, 45))	('elevated', 'PosReg', (21, 29))	('IRX1', 'Gene', (30, 34))	('IRX1', 'Gene', '79192', (30, 34))	('patients', 'Species', '9606', (63, 71))
367549	29246026	The analysis of the methylation status of IRX1 promoter in the serum of primary OS patients highlighted that hypomethylated IRX1 correlated with worse lung metastasis-free survival, thus suggesting IRX1 hypomethylation as a potential biomarker for early detection of lung metastasis in OS patients.	('patients', 'Species', '9606', (289, 297))	('IRX1', 'Gene', (198, 202))	('IRX1', 'Gene', '79192', (198, 202))	('worse', 'NegReg', (145, 150))	('IRX1', 'Gene', (42, 46))	('hypomethylated', 'Var', (109, 123))	('patients', 'Species', '9606', (83, 91))	('lung metastasis-free survival', 'CPA', (151, 180))	('IRX1', 'Gene', '79192', (42, 46))	('IRX1', 'Gene', (124, 128))	('IRX1', 'Gene', '79192', (124, 128))
367570	29246026	In particular, exosomes were purified by multidrug resistant human OS MG-63DXR30 (Exo/DXR) and MG-63 parental cells (Exo/S); incubation of OS cells with Exo/DXR decreased the sensitivity of parental cells to doxorubicin, while treatment with Exo/S was irrelevant.	('decreased', 'NegReg', (161, 170))	('sensitivity', 'MPA', (175, 186))	('doxorubicin', 'Chemical', 'MESH:D004317', (208, 219))	('human', 'Species', '9606', (61, 66))	('Exo/DXR', 'Var', (153, 160))
367718	24521144	documented a considerable variation in HHV-8 seroprevalence in different geographical sub-regions and ethnic groups, and a threefold increased risk for HHV-8 seropositivity in HIV-infected compared with HIV-uninfected individuals .	('men', 'Species', '9606', (4, 7))	('HHV-8', 'Gene', (39, 44))	('HHV-8', 'Species', '37296', (152, 157))	('HIV-uninfected', 'Disease', (203, 217))	('seropositivity', 'Var', (158, 172))	('sero', 'Chemical', '-', (158, 162))	('sero', 'Chemical', '-', (45, 49))	('HHV-8', 'Species', '37296', (39, 44))	('HIV-uninfected', 'Disease', 'MESH:D015658', (203, 217))	('HIV-infected', 'Disease', (176, 188))	('HIV-infected', 'Disease', 'MESH:D015658', (176, 188))	('HHV-8', 'Gene', (152, 157))
367748	24521144	Because many risk factors for HHV-8 seropositivity have been described, which may act as potential confounders, it is particularly important to assess whether the outcomes of interest have been adjusted or stratified for relevant confounders.	('HHV-8', 'Gene', (30, 35))	('sero', 'Chemical', '-', (36, 40))	('HHV-8', 'Species', '37296', (30, 35))	('seropositivity', 'Var', (36, 50))
367864	22355501	Aberrant keratin staining is not unusual in dendritic cell neoplasms and this is the best explanation for an S-100 positive/CD4-positive neoplasm with dendritic cytoplasmic processes.	('neoplasm', 'Disease', (59, 67))	('keratin', 'Protein', (9, 16))	('S-100', 'Gene', (109, 114))	('Aberrant', 'Var', (0, 8))	('neoplasm', 'Phenotype', 'HP:0002664', (59, 67))	('CD4', 'Gene', (124, 127))	('neoplasm', 'Disease', 'MESH:D009369', (59, 67))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (44, 68))	('CD4', 'Gene', '920', (124, 127))	('neoplasms', 'Phenotype', 'HP:0002664', (59, 68))	('neoplasm', 'Disease', (137, 145))	('dendritic cell neoplasms', 'Disease', (44, 68))	('S-100', 'Gene', '6271', (109, 114))	('neoplasm', 'Phenotype', 'HP:0002664', (137, 145))	('neoplasm', 'Disease', 'MESH:D009369', (137, 145))
367958	33674685	Further reinforcing the idea that transcriptomics has a role in the molecular classification of fusion driven sarcomas, the same group showed that consensus clustering of gene expression data in endometrial stromal sarcomas (ESS) was capable of identifying a high grade group comprised of tumours harbouring BCOR rearrangements, and a low grade group composed of tumours with a fusion of a PRC2 zinc finger protein (such as JAZF1 and PHF1).	('tumour', 'Phenotype', 'HP:0002664', (363, 369))	('tumours', 'Disease', (289, 296))	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('JAZF1', 'Gene', '221895', (424, 429))	('PRC2 zinc finger protein', 'Protein', (390, 414))	('sarcomas', 'Disease', (110, 118))	('tumours', 'Phenotype', 'HP:0002664', (289, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('PHF1', 'Gene', (434, 438))	('tumours', 'Disease', 'MESH:D009369', (289, 296))	('JAZF1', 'Gene', (424, 429))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('tumour', 'Phenotype', 'HP:0002664', (289, 295))	('BCOR', 'Gene', '54880', (308, 312))	('PHF1', 'Gene', '5252', (434, 438))	('rearrangements', 'Var', (313, 327))	('BCOR', 'Gene', (308, 312))	('tumours', 'Disease', (363, 370))	('tumours', 'Phenotype', 'HP:0002664', (363, 370))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (195, 223))	('sarcomas', 'Disease', 'MESH:D012509', (215, 223))	('tumours', 'Disease', 'MESH:D009369', (363, 370))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('endometrial stromal sarcomas', 'Disease', (195, 223))	('sarcomas', 'Disease', (215, 223))
367963	33674685	The underlying rationale for characterising these tumours is that non-translocation-related sarcomas, including LMS, undifferentiated pleomorphic sarcomas (UPS) and dedifferentiated liposarcomas, are prone to metastasis.	('non-translocation-related', 'Var', (66, 91))	('tumours', 'Disease', (50, 57))	('liposarcomas', 'Disease', (182, 194))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcomas', 'Disease', (92, 100))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('sarcomas', 'Disease', 'MESH:D012509', (186, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcomas', 'Disease', (146, 154))	('sarcomas', 'Disease', (186, 194))	('liposarcomas', 'Disease', 'MESH:D008080', (182, 194))	('LMS', 'Disease', (112, 115))	('metastasis', 'CPA', (209, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (117, 154))	('undifferentiated pleomorphic sarcomas', 'Disease', (117, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('liposarcomas', 'Phenotype', 'HP:0012034', (182, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('liposarcoma', 'Phenotype', 'HP:0012034', (182, 193))
367986	33674685	GGI was shown to reclassify grade 2 breast cancers into two prognostic groups, with high GGI expression (GGI-high) associated with higher risk of recurrence and worse prognosis compared to low GGI expression (GGI-low).	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('high', 'Var', (84, 88))	('GGI', 'Protein', (89, 92))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancers', 'Phenotype', 'HP:0003002', (36, 50))	('breast cancers', 'Disease', 'MESH:D001943', (36, 50))	('breast cancers', 'Disease', (36, 50))
368023	33674685	Prognostic value of the hypoxic gene signature was enhanced by CINSARC with significantly worse DMFS in combined high-hypoxia/C2 patients than low-hypoxia/C1 tumours (HR 6.74, 95% CI 3.84-11.84, p = 3.13 x 10-11).	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('CINSARC', 'Var', (63, 70))	('patients', 'Species', '9606', (129, 137))	('hypoxia', 'Disease', 'MESH:D000860', (118, 125))	('hypoxia', 'Disease', (147, 154))	('hypoxia', 'Disease', 'MESH:D000860', (147, 154))	('enhanced', 'PosReg', (51, 59))	('worse', 'NegReg', (90, 95))	('low-hypoxia/C1 tumours', 'Disease', 'MESH:D000860', (143, 165))	('low-hypoxia/C1 tumours', 'Disease', (143, 165))	('DMFS', 'MPA', (96, 100))	('hypoxia', 'Disease', (118, 125))
368048	33674685	assessed expression of PD-L1 and PARP-1 in separate retrospective series of genomically-complex STS, and found that tumours with high PD-L1 or PARP-1 expression had worse MFS.	('expression', 'MPA', (150, 160))	('PARP-1', 'Gene', '142', (143, 149))	('PD-L1', 'Gene', (23, 28))	('high', 'Var', (129, 133))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('PARP-1', 'Gene', (33, 39))	('PD-L1', 'Gene', (134, 139))	('PD-L1', 'Gene', '29126', (23, 28))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumours', 'Disease', (116, 123))	('PARP-1', 'Gene', '142', (33, 39))	('MFS', 'MPA', (171, 174))	('PD-L1', 'Gene', '29126', (134, 139))	('PARP-1', 'Gene', (143, 149))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
368051	33674685	A better understanding of orthogonal molecular features (such as copy number alterations and DNA methylation status) as well as the regulatory mechanisms driving the observed transcriptional signatures will be key to delineating sarcomagenesis and identifying potential therapeutic targets.	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('sarcomagenesis', 'Disease', (229, 243))	('sarcomagenesis', 'Disease', 'None', (229, 243))	('copy number alterations', 'Var', (65, 88))
368063	33457085	The Th1 pathway was significantly activated in UPS with high levels of PD-L1 and improved survival.	('improved', 'PosReg', (81, 89))	('Th1', 'Gene', (4, 7))	('PD-L1', 'Protein', (71, 76))	('high levels', 'Var', (56, 67))	('activated', 'PosReg', (34, 43))	('Th1', 'Gene', '51497', (4, 7))	('survival', 'CPA', (90, 98))
368065	33457085	Patients with UPS and OSA with high levels of PD-L1 had better overall survival than those with low expression levels.	('PD-L1', 'Gene', (46, 51))	('overall survival', 'MPA', (63, 79))	('high levels', 'Var', (31, 42))	('UPS', 'Disease', (14, 17))	('better', 'PosReg', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('OSA', 'Phenotype', 'HP:0002669', (22, 25))
368076	33457085	PD-L1 positivity detected by IHC on tissue microarrays (TMAs) from formalin-fixed paraffin-embedded (FFPE) tissues predicted favorable survival, but was found to be a negative prognostic factor in another study.	('positivity', 'Var', (6, 16))	('formalin', 'Chemical', 'MESH:D005557', (67, 75))	('PD-L1', 'Gene', (0, 5))	('paraffin', 'Chemical', 'MESH:D010232', (82, 90))	('favorable', 'PosReg', (125, 134))
368123	33457085	ROC curve analysis demonstrated strong potential for use of mRNA level to predict the presence/absence of PDL-1 at the protein level in sarcoma (Supplementary Figure 2).	('PDL-1', 'Gene', '29126', (106, 111))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('PDL-1', 'Gene', (106, 111))	('presence/absence', 'NegReg', (86, 102))	('sarcoma', 'Disease', (136, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('presence/absence', 'Var', (86, 102))
368124	33457085	For 29 non-metastatic UPS patients, OS tended to be better in the group with high PD-L1 expression compared to those with low PD-L1 expression (Figure 5a: Log-rank p = .054; Tables 6 and 7: univariate Cox model HR = 4.47, 95%CI = (0.93,43.1), P(LRT) = 0.0622).	('expression', 'Var', (88, 98))	('PD-L1', 'Gene', (82, 87))	('non-metastatic UPS', 'Disease', (7, 25))	('high', 'Var', (77, 81))	('better', 'PosReg', (52, 58))	('patients', 'Species', '9606', (26, 34))
368143	33457085	The presence of TILs in cancers has been associated with the presence of neoantigens produced by tumors with high mutational loads (for review, please see ref.).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('tumors', 'Disease', (97, 103))	('neoantigens produced', 'MPA', (73, 93))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('cancers', 'Disease', (24, 31))	('mutational loads', 'Var', (114, 130))
368150	33457085	Previous studies in various cancer types including sarcomas have reported conflicting results on the relationship between PD-L1 tumor expression and clinical outcome, however, studies of a variety of malignancies coincided with our finding that high PD-L1 expression was associated with significantly better survival.	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('high', 'Var', (245, 249))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('PD-L1', 'Gene', (250, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Disease', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('malignancies', 'Disease', 'MESH:D009369', (200, 212))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('PD-L1 tumor', 'Disease', (122, 133))	('cancer', 'Disease', (28, 34))	('better', 'PosReg', (301, 307))	('malignancies', 'Disease', (200, 212))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (122, 133))
368151	33457085	We found that, although a proportion of UPS and MFS patients has tumors that contain TILs and express PD-L1, better survival was associated with high PD-L1 expression in UPS and OSA; we did not detect any association with survival in MFS.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('OSA', 'Disease', (178, 181))	('PD-L1', 'Gene', (102, 107))	('PD-L1', 'Gene', (150, 155))	('tumors', 'Disease', (65, 71))	('survival', 'MPA', (116, 124))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('patients', 'Species', '9606', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('expression', 'MPA', (156, 166))	('UPS', 'Disease', (170, 173))	('better', 'PosReg', (109, 115))	('high', 'Var', (145, 149))	('OSA', 'Phenotype', 'HP:0002669', (178, 181))
368155	33457085	A group of Th1 genes including TBX21, STAT1, lymphotoxin alpha and CD40LG are known to distinguish tumors with high (HEV) versus low endothelial venules and the presence of HEVs correlates with improved survival in a variety of cancers (for reviews, see refs.	('lymphotoxin alpha', 'Gene', (45, 62))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('CD40LG', 'Gene', (67, 73))	('TBX21', 'Gene', '30009', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('CD40LG', 'Gene', '959', (67, 73))	('STAT1', 'Gene', (38, 43))	('cancers', 'Disease', (228, 235))	('Th1', 'Gene', (11, 14))	('survival', 'CPA', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Th1', 'Gene', '51497', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('high', 'MPA', (111, 115))	('tumors', 'Disease', (99, 105))	('STAT1', 'Gene', '6772', (38, 43))	('TBX21', 'Gene', (31, 36))	('improved', 'PosReg', (194, 202))	('lymphotoxin alpha', 'Gene', '4049', (45, 62))	('presence', 'Var', (161, 169))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
368172	33457085	PD-L1 expression and Th1 pathway activation were shown to be of potential importance in discriminating sarcomas with high vs low PD-L1 expression and better clinical outcome.	('Th1', 'Gene', (21, 24))	('PD-L1', 'Gene', (129, 134))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Disease', (103, 111))	('Th1', 'Gene', '51497', (21, 24))	('expression', 'MPA', (135, 145))	('high', 'Var', (117, 121))	('low', 'NegReg', (125, 128))
368188	32279088	Patients often present with extensively disseminated disease at diagnosis, and their tumors are characterized by a t(11;22)(p13;q12) genetic translocation resulting in the oncogenic fusion protein EWS-WT1.	('t(11', 'Var', (115, 119))	('extensively disseminated disease', 'Disease', (28, 60))	('extensively disseminated disease', 'Disease', 'MESH:D000079822', (28, 60))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (115, 132))	('EWS-WT1', 'Gene', '7490', (197, 204))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('EWS-WT1', 'Gene', (197, 204))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
368196	32279088	Inhibition of PARP1 leads to an accumulation of SSBs and trapping of PARP1 to the DNA.	('PARP1', 'Gene', (14, 19))	('PARP1', 'Gene', '142', (69, 74))	('PARP1', 'Gene', (69, 74))	('trapping', 'MPA', (57, 65))	('Inhibition', 'Var', (0, 10))	('SSBs', 'MPA', (48, 52))	('accumulation', 'PosReg', (32, 44))	('PARP1', 'Gene', '142', (14, 19))
368197	32279088	Inadequate repair of the SSBs causes double-stranded breaks (DSBs) during DNA replication, and PARP1 trapping prevents the formation of replication forks.	('causes', 'Reg', (30, 36))	('double-stranded breaks', 'MPA', (37, 59))	('Inadequate', 'Var', (0, 10))	('PARP1', 'Gene', '142', (95, 100))	('PARP1', 'Gene', (95, 100))
368241	32279088	#12302/2348) and anti-phosphorylated Chk2 (pChk2 Thr68, 1:500; cat.	('Chk2', 'Gene', '11200', (37, 41))	('Chk2', 'Gene', '11200', (44, 48))	('Chk2', 'Gene', (37, 41))	('Chk2', 'Gene', (44, 48))	('anti-phosphorylated', 'Var', (17, 36))	('Thr68', 'Chemical', '-', (49, 54))
368261	32279088	previously showed in a variety of sarcomas that high PARP1 expression correlated with PAR activity and sensitivity to PARP inhibitor-based combination treatment in vitro (Pignochino et al.).	('PARP', 'Gene', (53, 57))	('correlated', 'Reg', (70, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('sarcomas', 'Disease', (34, 42))	('PARP', 'Gene', '142', (118, 122))	('PARP1', 'Gene', '142', (53, 58))	('PAR activity', 'MPA', (86, 98))	('PARP1', 'Gene', (53, 58))	('PARP', 'Gene', '142', (53, 57))	('expression', 'MPA', (59, 69))	('high', 'Var', (48, 52))	('sarcomas', 'Disease', 'MESH:D012509', (34, 42))	('PARP', 'Gene', (118, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (34, 42))
368262	32279088	In addition, patients with tumors expressing high PARP1 experienced a significantly higher progression-free survival rate post-olaparib and trabectedin combination treatment compared to patients with low-level PARP1 expression in the tumor (Grignani et al.).	('tumor', 'Disease', (234, 239))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('higher', 'PosReg', (84, 90))	('olaparib', 'Chemical', 'MESH:C531550', (127, 135))	('tumor', 'Disease', (27, 32))	('PARP1', 'Gene', (210, 215))	('high', 'Var', (45, 49))	('PARP1', 'Gene', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('progression-free survival', 'CPA', (91, 116))	('patients', 'Species', '9606', (186, 194))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('PARP1', 'Gene', '142', (210, 215))	('tumors', 'Disease', (27, 33))	('PARP1', 'Gene', '142', (50, 55))
368267	32279088	The relatively high IC50 value of TMZ was comparable with that of the Ewing sarcoma cells we tested (ES7 143 microM and ES8 234 microM) and those tested by Engert et al.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('ES', 'Chemical', 'MESH:D004540', (120, 122))	('ES8 234 microM', 'Var', (120, 134))	('ES7 143 microM', 'Var', (101, 115))	('Ewing sarcoma', 'Disease', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('TMZ', 'Chemical', 'MESH:D000077204', (34, 37))	('ES', 'Chemical', 'MESH:D004540', (101, 103))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (70, 83))
368269	32279088	Similar to ES, combination treatment significantly decreased cell viability of DSRCT cells compared to the respective single-agent treatments, except for the 1.875-microM olaparib combinations and 10-microM TMZ combinations (Fig.	('olaparib', 'Chemical', 'MESH:C531550', (171, 179))	('1.875-microM', 'Var', (158, 170))	('cell viability of DSRCT cells', 'CPA', (61, 90))	('TMZ', 'Chemical', 'MESH:D000077204', (207, 210))	('decreased', 'NegReg', (51, 60))	('ES', 'Chemical', 'MESH:D004540', (11, 13))
368270	32279088	In line with cell viability effects, the level of drug synergy reduced in a dose-dependent manner with slight to moderate synergy seen for the combination of either 1.25 or 1.875 microM olaparib with 250-microM TMZ (Fig.	('reduced', 'NegReg', (63, 70))	('1.875 microM', 'Var', (173, 185))	('TMZ', 'Chemical', 'MESH:D000077204', (211, 214))	('olaparib', 'Chemical', 'MESH:C531550', (186, 194))	('1.25', 'Var', (165, 169))
368277	32279088	Similar to the findings of Engert et al., low-dose combination treatment induced a G2-M phase arrest.	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('arrest', 'Disease', (94, 100))	('low-dose', 'Var', (42, 50))
368330	32279088	Inhibition of DNA repair proteins was shown to enhance antitumor effects of chemotherapeutic agents in various models in a preclinical setting, and has recently shown encouraging clinical results (Baz et al.	('enhance', 'PosReg', (47, 54))	('tumor', 'Disease', (59, 64))	('DNA repair proteins', 'Protein', (14, 33))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
368337	32279088	DSRCT Desmoplastic small round cell tumor ES Ewing sarcoma PARP Poly(ADP-ribose) polymerase SLFN11 Schlafen-11 SSB Single-stranded breaks STS Soft tissue sarcoma TMZ Temozolomide All authors contributed to the study conception and design.	('Ewing sarcoma', 'Disease', (45, 58))	('PARP', 'Gene', '142', (59, 63))	('tumor', 'Disease', (36, 41))	('PARP', 'Gene', (59, 63))	('ES', 'Chemical', 'MESH:D004540', (42, 44))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('STS', 'Phenotype', 'HP:0030448', (138, 141))	('sarcoma', 'Disease', (51, 58))	('Single-stranded breaks', 'Var', (115, 137))	('SLFN11', 'Gene', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Soft tissue sarcoma', 'Phenotype', 'HP:0030448', (142, 161))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('Temozolomide', 'Chemical', 'MESH:D000077204', (166, 178))	('TMZ', 'Chemical', 'MESH:D000077204', (162, 165))	('SLFN11', 'Gene', '91607', (92, 98))
368365	29692531	All nine patients with postoperative changes showed high average ADC values >1.4 x 10-3 mm2/s (the estimated cut-off for recurrence/residual), whereas 23 out of 27 patients with recurrent/residual tumors showed ADC values <=1.4 x 10-3 mm2/s.	('patients', 'Species', '9606', (9, 17))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('changes', 'Var', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('ADC', 'MPA', (65, 68))	('patients', 'Species', '9606', (164, 172))	('tumors', 'Disease', (197, 203))
368371	29692531	In our study, most recurrences were hypo or isointense to muscle on T1-weighted sequences and hyperintense to muscle on T2-weighted and STIR sequences with a sensitivity of 81.48% and specificity 11.11%.	('hyperintense', 'Var', (94, 106))	('hypo', 'Disease', 'MESH:D052456', (36, 40))	('isointense', 'MPA', (44, 54))	('hypo', 'Disease', (36, 40))
368393	27507014	However, anthracyclines can also contribute to myocardial dysfunction and congestive heart failure, ultimately limiting the therapeutic potential of the drug.	('congestive heart failure', 'Disease', 'MESH:D006333', (74, 98))	('congestive heart failure', 'Phenotype', 'HP:0001635', (74, 98))	('contribute', 'Reg', (33, 43))	('limiting', 'NegReg', (111, 119))	('congestive heart failure', 'Disease', (74, 98))	('therapeutic potential', 'MPA', (124, 145))	('heart failure', 'Phenotype', 'HP:0001635', (85, 98))	('anthracyclines', 'Chemical', 'MESH:D018943', (9, 23))	('myocardial dysfunction', 'Disease', 'MESH:D009202', (47, 69))	('anthracyclines', 'Var', (9, 23))	('myocardial dysfunction', 'Disease', (47, 69))
368407	27507014	Among several cancer therapies responsible for cardiotoxicity, anthracyclines predominantly cause myocardial dysfunction and congestive heart failure (CHF).	('cancer', 'Disease', (14, 20))	('cause', 'Reg', (92, 97))	('cardiotoxicity', 'Disease', (47, 61))	('CHF', 'Disease', 'MESH:D006333', (151, 154))	('CHF', 'Disease', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('anthracyclines', 'Var', (63, 77))	('cardiotoxicity', 'Disease', 'MESH:D066126', (47, 61))	('myocardial dysfunction', 'Disease', 'MESH:D009202', (98, 120))	('heart failure', 'Phenotype', 'HP:0001635', (136, 149))	('congestive heart failure', 'Phenotype', 'HP:0001635', (125, 149))	('anthracyclines', 'Chemical', 'MESH:D018943', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('CHF', 'Phenotype', 'HP:0001635', (151, 154))	('congestive heart failure', 'Disease', (125, 149))	('congestive heart failure', 'Disease', 'MESH:D006333', (125, 149))	('myocardial dysfunction', 'Disease', (98, 120))
368433	27507014	found that DRZ significantly reduced the risk of subclinical cardiotoxicity (22 versus 67 %) and reduced the decline in LVEF without negatively affecting rates of response.	('cardiotoxicity', 'Disease', (61, 75))	('decline', 'MPA', (109, 116))	('LVEF', 'MPA', (120, 124))	('reduced', 'NegReg', (97, 104))	('reduced', 'NegReg', (29, 36))	('cardiotoxicity', 'Disease', 'MESH:D066126', (61, 75))	('DRZ', 'Chemical', 'MESH:D064730', (11, 14))	('DRZ', 'Var', (11, 14))
368533	26314219	Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182 Accumulating evidence indicates that microRNAs (miRs) regulate cancer metastasis.	('miR', 'Gene', (85, 88))	('cancer metastasis', 'Disease', (156, 173))	('increases', 'PosReg', (46, 55))	('regulate', 'Reg', (147, 155))	('miR', 'Gene', '751557', (85, 88))	('expression', 'MPA', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('miR', 'Gene', (141, 144))	('Epigenetic silencing', 'Var', (0, 20))	('Kruppel like factor-3', 'Gene', (24, 45))	('cancer metastasis', 'Disease', 'MESH:D009362', (156, 173))	('Kruppel like factor-3', 'Gene', '16599', (24, 45))	('miR', 'Gene', '751557', (141, 144))
368538	26314219	Using Methylation Specific PCR (MSP) and pyrosequencing assays, we found that Klf-3 is epigenetically silenced by DNA hypermethylation both in mouse and human sarcoma cells.	('mouse', 'Species', '10090', (143, 148))	('sarcoma', 'Disease', (159, 166))	('hypermethylation', 'Var', (118, 134))	('MSP', 'Gene', (32, 35))	('MSP', 'Gene', '19144', (32, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('human', 'Species', '9606', (153, 158))	('silenced', 'NegReg', (102, 110))	('Klf-3', 'Gene', (78, 83))	('sarcoma', 'Disease', 'MESH:D012509', (159, 166))
368550	26314219	Moreover, deleting one allele of Dicer in this model decreased global miRNA expression that promoted metastasis in vivo.	('miR', 'Gene', '751557', (70, 73))	('promoted', 'PosReg', (92, 100))	('metastasis', 'CPA', (101, 111))	('deleting', 'Var', (10, 18))	('Dicer', 'Gene', (33, 38))	('miR', 'Gene', (70, 73))	('decreased', 'NegReg', (53, 62))
368552	26314219	Using novel genetically engineered conditional mutant mice to either delete or overexpress miR-182 in primary sarcomas, we showed that deletion of miR-182 in primary sarcomas significantly decreased, while overexpression of miR-182 significantly increased the rate of lung metastasis.	('deletion', 'Var', (135, 143))	('lung metastasis', 'CPA', (268, 283))	('delete', 'Var', (69, 75))	('decreased', 'NegReg', (189, 198))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('miR-182', 'Gene', (147, 154))	('primary sarcomas', 'Disease', 'MESH:D012509', (102, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (166, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('primary sarcomas', 'Disease', 'MESH:D012509', (158, 174))	('primary sarcomas', 'Disease', (102, 118))	('mice', 'Species', '10090', (54, 58))	('primary sarcomas', 'Disease', (158, 174))
368554	26314219	Others have also correlated a high level of miR-182 to cancer progression in a number of other human cancers such as metastatic melanomas, gliomas and follicular carcinomas.	('follicular carcinomas', 'Disease', 'MESH:D018263', (151, 172))	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('metastatic melanomas', 'Disease', (117, 137))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('gliomas', 'Disease', (139, 146))	('cancer', 'Disease', (55, 61))	('human', 'Species', '9606', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('miR-182', 'Var', (44, 51))	('metastatic melanomas', 'Disease', 'MESH:D008545', (117, 137))	('follicular carcinomas', 'Phenotype', 'HP:0031548', (151, 172))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('cancer', 'Disease', (101, 107))	('cancers', 'Disease', (101, 108))	('follicular carcinomas', 'Disease', (151, 172))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (55, 61))
368568	26314219	To delete miR-182 in primary sarcomas, KP mice were first crossed to mice expressing a Cre-activated Yellow Fluoroscent Protein (LSL-YFP) reporter to generate KPY mice.	('mice', 'Species', '10090', (42, 46))	('mice', 'Species', '10090', (69, 73))	('miR-182', 'Gene', (10, 17))	('mice', 'Species', '10090', (163, 167))	('primary sarcomas', 'Disease', 'MESH:D012509', (21, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('delete', 'Var', (3, 9))	('primary sarcomas', 'Disease', (21, 37))
368570	26314219	Injection of adenovirus-expressing Cre recombinase into the hind limb of KPY; miR-182 flox/flox mice generated primary sarcomas with miR-182 deletion (miR-182 KO).	('primary sarcomas', 'Disease', 'MESH:D012509', (111, 127))	('primary sarcomas', 'Disease', (111, 127))	('mice', 'Species', '10090', (96, 100))	('miR-182 deletion', 'Var', (133, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))
368592	26314219	For stable knockdown experiments, two independent KP sarcoma cell lines were infected with a lentivirus expressing either scramble or shRNA against Klf-3 (Origene).	('KP sarcoma', 'Disease', 'MESH:D012509', (50, 60))	('KP sarcoma', 'Disease', (50, 60))	('Klf-3', 'Gene', (148, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('shRNA against', 'Var', (134, 147))	('scramble', 'Var', (122, 130))
368622	26314219	Additionally, these Klfs are capable of repressing transcription, and they can regulate proliferation in Kras mutant cells.	('Kras', 'Gene', (105, 109))	('Kras', 'Gene', '16653', (105, 109))	('mutant', 'Var', (110, 116))	('repressing transcription', 'MPA', (40, 64))	('regulate', 'Reg', (79, 87))	('proliferation', 'CPA', (88, 101))
368624	26314219	No effect on miR-182 levels was seen with knockdown of Klf-11 nor Klf-15.	('miR-182 levels', 'MPA', (13, 27))	('Klf-15', 'Gene', (66, 72))	('Klf-15', 'Gene', '66277', (66, 72))	('Klf-11', 'Gene', (55, 61))	('knockdown', 'Var', (42, 51))	('Klf-11', 'Gene', '194655', (55, 61))
368644	26314219	Co-transfection of these reporter constructs and Klf-3 into mouse primary sarcoma cells and 293T cells demonstrated that Klf-3 inhibited the activity of the miR-182 promoter, but had no effect on the construct that lacks Klf-3 binding sites (Supplementary figure 3A-C).	('Klf-3', 'Var', (121, 126))	('activity', 'MPA', (141, 149))	('miR-182', 'Gene', (157, 164))	('inhibited', 'NegReg', (127, 136))	('primary sarcoma', 'Disease', (66, 81))	('293T', 'CellLine', 'CVCL:0063', (92, 96))	('primary sarcoma', 'Disease', 'MESH:D012509', (66, 81))	('mouse', 'Species', '10090', (60, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
368651	26314219	To determine if Klf-3 requires miR-182 to suppress in vitro metastatic phenotypes, we overexpressed Klf-3 in sarcoma cells with miR-182 deleteion (derived from primary sarcomas in miR-182flox/flox; LSL-KrasG12D; p53flox/flox mice).	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('deleteion', 'Var', (136, 145))	('primary sarcomas', 'Disease', 'MESH:D012509', (160, 176))	('p53', 'Gene', '22060', (212, 215))	('primary sarcomas', 'Disease', (160, 176))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('Klf-3', 'Gene', (100, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('Kras', 'Gene', (202, 206))	('Kras', 'Gene', '16653', (202, 206))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('mice', 'Species', '10090', (225, 229))	('sarcoma', 'Disease', (109, 116))	('p53', 'Gene', (212, 215))	('miR-182', 'Gene', (128, 135))	('sarcoma', 'Disease', (168, 175))
368656	26314219	Mice with sarcomas overexpressing Klf-3 had improved metastasis-free survival after amputation (Supplementary Figure 4I).	('Klf-3', 'Gene', (34, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (10, 18))	('overexpressing', 'Var', (19, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('sarcomas', 'Disease', (10, 18))	('Mice', 'Species', '10090', (0, 4))	('improved', 'PosReg', (44, 52))	('metastasis-free survival', 'CPA', (53, 77))	('sarcomas', 'Disease', 'MESH:D012509', (10, 18))
368661	26314219	In contrast, a dual PI3K/mTOR inhibitor, BEZ235, and a Mek inhibitor, PD0325901, increased Klf-3 expression by approximately two fold (p<0.01) (Figure 3A).	('PD0325901', 'Chemical', 'MESH:C506614', (70, 79))	('mTOR', 'Gene', '56717', (25, 29))	('BEZ235', 'Var', (41, 47))	('Mek', 'Gene', '17242', (55, 58))	('BEZ235', 'Chemical', 'MESH:C531198', (41, 47))	('Klf-3', 'Gene', (91, 96))	('Mek', 'Gene', (55, 58))	('PD0325901', 'Var', (70, 79))	('increased', 'PosReg', (81, 90))	('expression', 'MPA', (97, 107))	('mTOR', 'Gene', (25, 29))
368664	26314219	Although two different PI3K inhibitors BEZ235 and BKM120 reduced miR-182 expression by 40% and 30%, respectively and doxorubicin caused a 20% reduction in miR-182 expression, these differences did not reach statistical significance (Figure 3B).	('reduction', 'NegReg', (142, 151))	('BKM120', 'Chemical', 'MESH:C571178', (50, 56))	('miR-182 expression', 'MPA', (155, 173))	('BKM120', 'Var', (50, 56))	('miR-182', 'Gene', (65, 72))	('expression', 'MPA', (73, 83))	('BEZ235', 'Var', (39, 45))	('doxorubicin', 'Chemical', 'MESH:D004317', (117, 128))	('reduced', 'NegReg', (57, 64))	('BEZ235', 'Chemical', 'MESH:C531198', (39, 45))
368669	26314219	Additionally, mouse MyoD1 levels were also reduced by Aza treatment (Supplementary figure 5C).	('Aza', 'Chemical', 'MESH:D001374', (54, 57))	('mouse', 'Species', '10090', (14, 19))	('Aza', 'Var', (54, 57))	('mouse MyoD1 levels', 'MPA', (14, 32))	('reduced', 'NegReg', (43, 50))
368676	26314219	MSP detected PCR bands with both methylated and unmethylated primer pairs suggesting that methylation occurs at the Klf-3 promoter in multiple primary cells derived from KP mouse sarcomas and in primary human STS cells (Figure 3E & Supplementary Figure 5H).	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('human', 'Species', '9606', (203, 208))	('sarcomas', 'Disease', (179, 187))	('mouse', 'Species', '10090', (173, 178))	('STS', 'Phenotype', 'HP:0030448', (209, 212))	('methylation', 'Var', (90, 101))	('sarcomas', 'Disease', 'MESH:D012509', (179, 187))	('MSP', 'Gene', (0, 3))	('MSP', 'Gene', '19144', (0, 3))
368677	26314219	To our surprise, we did not see any products using the methylation-specific primers in primary cell lines derived from sarcomas generated with deletion of NF1 and Ink4a/Arf (NI) (Figure 3E).	('sarcomas', 'Disease', (119, 127))	('NF1', 'Gene', '18015', (155, 158))	('deletion', 'Var', (143, 151))	('Ink4a/Arf', 'Gene', '12578', (163, 172))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('Ink4a/Arf', 'Gene', (163, 172))	('NF1', 'Gene', (155, 158))
368688	26314219	Klf-3 induction was highest in the cells treated with siRNA against Dnmt3b compared to the siRNA against Dnmt3a (Figure 4E-F).	('Dnmt3b', 'Gene', '13436', (68, 74))	('Dnmt3a', 'Gene', '13435', (105, 111))	('Dnmt3b', 'Gene', (68, 74))	('siRNA', 'Var', (54, 59))	('highest', 'Reg', (20, 27))	('induction', 'MPA', (6, 15))	('Dnmt3a', 'Gene', (105, 111))	('Klf-3', 'Gene', (0, 5))
368691	26314219	Taken together, our findings suggest that Dnmt3b methylates the Klf-3 promoter in KP sarcomas, which can lead to high expression of miR-182.	('KP sarcomas', 'Disease', 'MESH:D012509', (82, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('Dnmt3b', 'Gene', '13436', (42, 48))	('high', 'PosReg', (113, 117))	('lead to', 'Reg', (105, 112))	('Dnmt3b', 'Gene', (42, 48))	('methylates', 'Var', (49, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('miR-182', 'Gene', (132, 139))	('expression', 'MPA', (118, 128))	('KP sarcomas', 'Disease', (82, 93))
368705	26314219	Because DNA hypermethylation in CpG rich promoters blocks the initiation of transcription of a gene, and is now established as a common mechanism for silencing of tumor suppressor genes such as INK4a-ARF and MLH1 in human cancers, we studied the CpG islands in the Klf-3 promoter.	('MLH1', 'Gene', (208, 212))	('INK4a-ARF', 'Gene', '12578', (194, 203))	('initiation of transcription of a', 'MPA', (62, 94))	('human', 'Species', '9606', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('hypermethylation', 'Var', (12, 28))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancers', 'Disease', (222, 229))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('tumor', 'Disease', (163, 168))	('blocks', 'NegReg', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('INK4a-ARF', 'Gene', (194, 203))	('MLH1', 'Gene', '4292', (208, 212))
368708	26314219	For example, primary sarcomas cells expressing oncogenic K-ras and deletion of p53 have high methylation of the Klf-3 promoter compared to sarcoma cells with deletion of NF1 and Ink4a-Arf.	('Ink4a-Arf', 'Gene', '12578', (178, 187))	('methylation', 'MPA', (93, 104))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('primary sarcomas', 'Disease', (13, 29))	('sarcoma', 'Disease', (21, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('Ink4a-Arf', 'Gene', (178, 187))	('p53', 'Gene', (79, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('primary sarcomas', 'Disease', 'MESH:D012509', (13, 29))	('K-ras', 'Gene', '16653', (57, 62))	('NF1', 'Gene', '18015', (170, 173))	('p53', 'Gene', '22060', (79, 82))	('K-ras', 'Gene', (57, 62))	('sarcoma', 'Disease', (139, 146))	('NF1', 'Gene', (170, 173))	('deletion', 'Var', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))
368709	26314219	Similar to our finding, a study investigating the expression of various Klfs in mutated Kras cell lines reported lower expression of Klf-3 in Kras mutated cells, however the mechanism for Klf-3 expression was not identified.	('expression', 'MPA', (119, 129))	('Kras', 'Gene', (88, 92))	('Kras', 'Gene', '16653', (88, 92))	('lower', 'NegReg', (113, 118))	('Kras', 'Gene', '16653', (142, 146))	('Klf-3', 'Gene', (133, 138))	('Kras', 'Gene', (142, 146))	('mutated', 'Var', (147, 154))
368715	26314219	Thus, our results show a unique pathway where sarcomas with Ras and p53 mutations are more prone to methylate Klf-3 than sarcomas with loss of NF1 and Ink4a-Arf.	('methylate Klf-3', 'MPA', (100, 115))	('mutations', 'Var', (72, 81))	('sarcomas', 'Disease', 'MESH:D012509', (121, 129))	('p53', 'Gene', '22060', (68, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('Ink4a-Arf', 'Gene', '12578', (151, 160))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('Ink4a-Arf', 'Gene', (151, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('sarcomas', 'Disease', (121, 129))	('prone', 'Reg', (91, 96))	('NF1', 'Gene', (143, 146))	('Ras', 'Gene', (60, 63))	('p53', 'Gene', (68, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('sarcomas', 'Disease', (46, 54))	('NF1', 'Gene', '18015', (143, 146))
368716	26314219	Because downregulation of Klf-3 in sarcoma occurs due to DNA hypermethylation, it would be interesting to investigate whether low Klf-3 expression due to hypermethylation exists in other cancers, particularly if they harbor mutations in Ras and p53.	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('expression', 'MPA', (136, 146))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('downregulation', 'NegReg', (8, 22))	('sarcoma', 'Disease', (35, 42))	('cancers', 'Disease', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('p53', 'Gene', (245, 248))	('low', 'NegReg', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('mutations', 'Var', (224, 233))	('p53', 'Gene', '22060', (245, 248))	('Klf-3', 'Gene', (26, 31))	('Klf-3', 'Gene', (130, 135))	('hypermethylation', 'Var', (154, 170))	('Ras', 'Gene', (237, 240))
368725	31484926	In addition, high levels of RPSAP52 in patient samples associate with a worse prognosis in sarcomas.	('patient', 'Species', '9606', (39, 46))	('high', 'Var', (13, 17))	('RPSAP52', 'Gene', (28, 35))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('RPSAP52', 'Gene', '204010', (28, 35))	('sarcomas', 'Disease', (91, 99))
368732	31484926	Although some pseudogenes do code for proteins, the majority are thought to be lncRNAs owing to the accumulation of mutations in the definition of the open reading frames, and as such their biological functions include the ability to regulate gene expression similarly to lncRNAs, and are thereby also involved in growth-regulatory roles in cancer.	('gene expression', 'MPA', (243, 258))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('regulate', 'Reg', (234, 242))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('involved', 'Reg', (302, 310))	('code', 'Reg', (29, 33))	('cancer', 'Disease', (341, 347))
368737	31484926	Both genes are generally expressed at low levels in differentiated normal tissues and overexpressed in a number of human cancers, including breast cancer, concomitant with a hypomethylation of the associated CpG island (Fig.	('hypomethylation', 'Var', (174, 189))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('overexpressed', 'PosReg', (86, 99))	('human', 'Species', '9606', (115, 120))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
368740	31484926	Other studies have reported that high HMGA2 expression predicts poor outcome in breast cancer patients.	('expression', 'MPA', (44, 54))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (94, 102))	('HMGA2', 'Gene', '8091', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('HMGA2', 'Gene', (38, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
368744	31484926	The quantitative measurement of expression levels indicates that HMGA2 mRNA and the two isoforms of RPSAP52 are 2-3 orders of magnitude overexpressed when there is hypomethylation of the promoter-associated CpG island, as shown with Illumina's HumanMethylation450 BeadChip analysis (Fig.	('hypomethylation', 'Var', (164, 179))	('HMGA2', 'Gene', '8091', (65, 70))	('Human', 'Species', '9606', (244, 249))	('HMGA2', 'Gene', (65, 70))	('RPSAP52', 'Gene', (100, 107))	('RPSAP52', 'Gene', '204010', (100, 107))	('overexpressed', 'PosReg', (136, 149))
368762	31484926	The most abundantly expressed members of the family are let-7a/b/e in MCF10A cells, and let-7a/d/f/g/i in Hs578T cells (Supplementary Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (70, 76))	('let-7', 'Chemical', '-', (88, 93))	('let-7a/b/e', 'Var', (56, 66))	('let-7a/d/f/g/i', 'Var', (88, 102))	('let-7', 'Chemical', '-', (56, 61))
368767	31484926	Of note, gapmer-mediated depletion of HMGA2 increased both RPSAP52 isoforms and resulted in a decrease in let-7 levels, suggesting that the negative regulation exerted by RPSAP52 on the miRNAs is not through HMGA2 pathway (Fig.	('let-7 levels', 'MPA', (106, 118))	('HMGA2', 'Gene', '8091', (208, 213))	('HMGA2', 'Gene', (208, 213))	('let-7', 'Chemical', '-', (106, 111))	('RPSAP52', 'Gene', (171, 178))	('HMGA2', 'Gene', '8091', (38, 43))	('RPSAP52', 'Gene', '204010', (171, 178))	('RPSAP52', 'Gene', (59, 66))	('RPSAP52', 'Gene', '204010', (59, 66))	('HMGA2', 'Gene', (38, 43))	('depletion', 'Var', (25, 34))	('increased', 'PosReg', (44, 53))	('decrease', 'NegReg', (94, 102))
368775	31484926	Upon RPSAP52 knockdown, all three breast cell lines tested (the non-transformed MCF10A and the tumorigenic Hs578T and HCC1143 cells) proved to be significantly less proliferative in the sulforhodamine B (SRB) assay (Fig.	('less', 'NegReg', (160, 164))	('RPSAP52', 'Gene', (5, 12))	('sulforhodamine B', 'Gene', '10575', (186, 202))	('RPSAP52', 'Gene', '204010', (5, 12))	('MCF10A', 'CellLine', 'CVCL:0598', (80, 86))	('SRB', 'Gene', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('sulforhodamine B', 'Gene', (186, 202))	('proliferative', 'CPA', (165, 178))	('HCC1143', 'CellLine', 'CVCL:1245', (118, 125))	('SRB', 'Gene', '10575', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', (95, 100))
368776	31484926	Interestingly, RPSAP52 depletion was also associated with a decreased migration potential (Fig.	('RPSAP52', 'Gene', (15, 22))	('decreased', 'NegReg', (60, 69))	('depletion', 'Var', (23, 32))	('RPSAP52', 'Gene', '204010', (15, 22))	('migration potential', 'CPA', (70, 89))
368778	31484926	Given the observed reduction in proliferation and migration following RPSAP52 knockdown, we next assessed the levels of markers of cell stemness (Fig.	('reduction', 'NegReg', (19, 28))	('knockdown', 'Var', (78, 87))	('migration', 'CPA', (50, 59))	('RPSAP52', 'Gene', (70, 77))	('RPSAP52', 'Gene', '204010', (70, 77))	('proliferation', 'CPA', (32, 45))
368780	31484926	This was further confirmed in soft-agar colony formation experiments, in which the measure of the anchorage-independent growth of the cells showed a significant decrease upon depletion of RPSAP52 (Fig.	('RPSAP52', 'Gene', (188, 195))	('RPSAP52', 'Gene', '204010', (188, 195))	('depletion', 'Var', (175, 184))	('decrease', 'NegReg', (161, 169))	('agar', 'Chemical', 'MESH:D000362', (35, 39))	('anchorage-independent growth of the cells', 'CPA', (98, 139))
368783	31484926	Tumors originating from RPSAP52 knockdown cells had a significantly lower volume and weight at end point than control tumors, both for the non-tumorigenic and the tumorigenic cells (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('volume', 'MPA', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('lower', 'NegReg', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('RPSAP52', 'Gene', '204010', (24, 31))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Disease', (143, 148))	('knockdown', 'Var', (32, 41))	('tumor', 'Disease', (118, 123))	('RPSAP52', 'Gene', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
368810	31484926	Interestingly, whereas binding to IGF1R and IGF2BP2 mRNAs was not altered, binding of IGF2BP2 to LIN28B mRNA was reduced upon stable knockdown of RPSAP52 (Fig.	('LIN28B', 'Gene', (97, 103))	('IGF2BP2', 'Gene', '10644', (44, 51))	('IGF2BP2', 'Gene', (44, 51))	('IGF1R', 'Gene', '3480', (34, 39))	('knockdown', 'Var', (133, 142))	('IGF1R', 'Gene', (34, 39))	('IGF2BP2', 'Gene', '10644', (86, 93))	('reduced', 'NegReg', (113, 120))	('RPSAP52', 'Gene', (146, 153))	('LIN28B', 'Gene', '389421', (97, 103))	('binding', 'Interaction', (75, 82))	('IGF2BP2', 'Gene', (86, 93))	('RPSAP52', 'Gene', '204010', (146, 153))
368815	31484926	Remarkably, knockdown of RPSAP52 resulted in a specific decrease in the number of 3'UTR peaks revealed by iCLIP and an increase in intronic regions (Fig.	('intronic', 'MPA', (131, 139))	('knockdown', 'Var', (12, 21))	('RPSAP52', 'Gene', (25, 32))	('RPSAP52', 'Gene', '204010', (25, 32))	('increase', 'PosReg', (119, 127))	('decrease', 'NegReg', (56, 64))	('iCLIP', 'MPA', (106, 111))
368823	31484926	Previous CLIP-seq studies with IGF2BP2 had revealed binding sites on the 3'UTR of LIN28B mRNA in HEK293T cells, and we detected similar sites in our experimental setting and a tendency to decrease upon RPSAP52 depletion, although without any statistical power (Fig.	('HEK293T', 'CellLine', 'CVCL:0063', (97, 104))	('decrease', 'NegReg', (188, 196))	('RPSAP52', 'Gene', (202, 209))	('RPSAP52', 'Gene', '204010', (202, 209))	('binding', 'Interaction', (52, 59))	('IGF2BP2', 'Gene', '10644', (31, 38))	('LIN28B', 'Gene', (82, 88))	('depletion', 'Var', (210, 219))	('IGF2BP2', 'Gene', (31, 38))	('LIN28B', 'Gene', '389421', (82, 88))
368825	31484926	In this case, binding is dramatically lost upon RPSAP52 knockdown (Fig.	('lost', 'NegReg', (38, 42))	('binding', 'Interaction', (14, 21))	('RPSAP52', 'Gene', (48, 55))	('RPSAP52', 'Gene', '204010', (48, 55))	('knockdown', 'Var', (56, 65))
368834	31484926	We observed no major changes in the polysome profiles of cells depleted of RPSAP52 when compared with control cells, indicating that RPSAP52 knockdown does not alter the global translational output of the cell (see gradient profiles in Fig.	('knockdown', 'Var', (141, 150))	('RPSAP52', 'Gene', (75, 82))	('RPSAP52', 'Gene', '204010', (75, 82))	('RPSAP52', 'Gene', (133, 140))	('RPSAP52', 'Gene', '204010', (133, 140))
368841	31484926	6b, c), its co-sedimentation with translating poly-ribosomes is markedly reduced upon RPSAP52 knockdown (Fig.	('knockdown', 'Var', (94, 103))	('reduced', 'NegReg', (73, 80))	('RPSAP52', 'Gene', (86, 93))	('RPSAP52', 'Gene', '204010', (86, 93))	('co-sedimentation with', 'MPA', (12, 33))
368843	31484926	Taken together, the results suggest that the absence of the pseudogene decreases the recruitment of IGF2BP2 to large polysomes, thereby impacting on the translation of specific mRNAs.	('pseudogene', 'Protein', (60, 70))	('impacting', 'Reg', (136, 145))	('IGF2BP2', 'Gene', '10644', (100, 107))	('recruitment', 'MPA', (85, 96))	('absence', 'Var', (45, 52))	('decreases', 'NegReg', (71, 80))	('IGF2BP2', 'Gene', (100, 107))	('translation of specific mRNAs', 'MPA', (153, 182))
368845	31484926	To identify such processes we interrogated general gene expression with an expression microarray platform under conditions of RPSAP52 knockdown by shRNAs.	('knockdown', 'Var', (134, 143))	('RPSAP52', 'Gene', (126, 133))	('RPSAP52', 'Gene', '204010', (126, 133))
368849	31484926	Among the upregulated genes, genes involved in cytoskeletal protein binding were enriched and included MTSS1, a regulator of actin dynamics whose loss increases metastatic potential in a number of cancer types (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('increases', 'PosReg', (151, 160))	('cancer', 'Disease', (197, 203))	('loss', 'Var', (146, 150))	('upregulated', 'PosReg', (10, 21))	('MTSS1', 'Gene', (103, 108))	('MTSS1', 'Gene', '9788', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('metastatic potential', 'CPA', (161, 181))
368851	31484926	These results indicate that RPSAP52 depletion implies a decrease in proliferative and self-renewal programs and suggests its potential as a biomarker in human samples.	('depletion', 'Var', (36, 45))	('RPSAP52', 'Gene', (28, 35))	('human', 'Species', '9606', (153, 158))	('RPSAP52', 'Gene', '204010', (28, 35))	('decrease', 'NegReg', (56, 64))
368852	31484926	In support of this, patients with high RPSAP52 expression levels had poorer prognosis than cases with low expression in the sarcoma patients cohort from TCGA database, whereas HMGA2 expression did not show any prognostic effect in the same cohort (Fig.	('HMGA2', 'Gene', (176, 181))	('prognosis', 'CPA', (76, 85))	('RPSAP52', 'Gene', (39, 46))	('sarcoma', 'Disease', (124, 131))	('RPSAP52', 'Gene', '204010', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('poorer', 'NegReg', (69, 75))	('high', 'Var', (34, 38))	('patients', 'Species', '9606', (20, 28))	('HMGA2', 'Gene', '8091', (176, 181))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('patients', 'Species', '9606', (132, 140))	('expression', 'MPA', (47, 57))
368881	31484926	In accordance with let-7 anti-pluripotency properties, we observe a decrease in NANOG and OCT4 levels as well as in clonogenicity upon RPSAP52 depletion (Fig.	('RPSAP52', 'Gene', (135, 142))	('RPSAP52', 'Gene', '204010', (135, 142))	('OCT4', 'Gene', '5460', (90, 94))	('let-7', 'Chemical', '-', (19, 24))	('decrease', 'NegReg', (68, 76))	('OCT4', 'Gene', (90, 94))	('depletion', 'Var', (143, 152))	('NANOG', 'Gene', '79923', (80, 85))	('pluripotency', 'Disease', (30, 42))	('clonogenicity', 'CPA', (116, 129))	('pluripotency', 'Disease', 'None', (30, 42))	('NANOG', 'Gene', (80, 85))
368898	31484926	The detected proteins were IGF2BP2 (H00010644-M01, Abnova, 1:500), RAS (ab55391, Abcam, 1:500, which recognizes all RAS proteins), LIN28B (ab71415, Abcam, 1:1000), IGF1R (#3027, Cell Signaling, 1:1000), ERK (#4695, Cell Signaling, 1:1000), p-ERK (#9101, Cell Signaling, 1:1000), LAMIN B1 (ab16048, Abcam, 1:4000), LIN28A (#8641, Cell Signaling, 1:750), alpha-TUBULIN HRP (ab40742, Abcam, 1:5000), HNRNPQ (ab184946, Abcam, 1:10,000), beta-ACTIN HRP (a3854, Sigma, 1:20,000), NANOG (#4903, Cell Signaling, 1:2000), OCT4 (#2750, Cell Signaling, 1:1000), SOX2 (#4195, Cell Signaling, 1:1000), NUCLEOLIN (#8031, Santa Cruz, 1:2000), HMGA2 (ab97276, Abcam, 1:1000), HISTONE H3 (ab1791, Abcam, 1:5000), RPSA (ab133645, Abcam, 1:1000), and RPL5 (A303-933A, Company Bethyl, 1:1000).	('LAMIN B1', 'Gene', '4001', (279, 287))	('RPSA', 'Gene', (696, 700))	('RPL5', 'Gene', (732, 736))	('LAMIN B1', 'Gene', (279, 287))	('SOX2', 'Gene', '6657', (551, 555))	('HNRNPQ', 'Gene', (397, 403))	('SOX2', 'Gene', (551, 555))	('ERK', 'Gene', (242, 245))	('ab97276', 'Var', (635, 642))	('OCT4', 'Gene', '5460', (513, 517))	('RPSA', 'Gene', '3921', (696, 700))	('ERK', 'Gene', (203, 206))	('NUCLEOLIN', 'Gene', '4691', (589, 598))	('beta-ACTIN', 'Gene', '728378', (433, 443))	('LIN28A', 'Gene', '79727', (314, 320))	('RPL5', 'Gene', '6125', (732, 736))	('HMGA2', 'Gene', '8091', (628, 633))	('IGF2BP2', 'Gene', (27, 34))	('A303-933A', 'Var', (738, 747))	('LIN28B', 'Gene', (131, 137))	('HNRNPQ', 'Gene', '10492', (397, 403))	('beta-ACTIN', 'Gene', (433, 443))	('NUCLEOLIN', 'Gene', (589, 598))	('OCT4', 'Gene', (513, 517))	('H00010644-M01, Abnova', 'Disease', 'None', (36, 57))	('LIN28A', 'Gene', (314, 320))	('alpha-TUBULIN', 'Gene', (353, 366))	('IGF1R', 'Gene', '3480', (164, 169))	('ERK', 'Gene', '5594', (242, 245))	('NANOG', 'Gene', '79923', (474, 479))	('NANOG', 'Gene', (474, 479))	('LIN28B', 'Gene', '389421', (131, 137))	('IGF2BP2', 'Gene', '10644', (27, 34))	('IGF1R', 'Gene', (164, 169))	('ERK', 'Gene', '5594', (203, 206))	('ab133645', 'Var', (702, 710))	('ab1791', 'Var', (672, 678))	('HMGA2', 'Gene', (628, 633))	('alpha-TUBULIN', 'Gene', '10376', (353, 366))
368915	31484926	One milligram of total protein was incubated overnight with 2 mug of anti-IGF2BP2 polyclonal antibody (#H00010644-M01, Abnova) or control mouse IgG antibody (#12-371, Millipore) and 40 mul of Dynabeads  M-280 anti-mouse IgG beads (#11202D, ThermoFisher) in 1 ml of RIP buffer (150 mM KCl, 25 mM Hepes at pH 7.9, 5 mM EDTA, 0.5 mM DTT, 0.5% NP40, 1x protease inhibitor cocktail (Roche)).	('EDTA', 'Chemical', 'MESH:D004492', (317, 321))	('RIP', 'Gene', '3267', (265, 268))	('Hepes', 'Chemical', 'MESH:D006531', (295, 300))	('IGF2BP2', 'Gene', '10644', (74, 81))	('H00010644-M01, Abnova', 'Disease', 'None', (104, 125))	('NP40', 'Chemical', 'MESH:C010615', (340, 344))	('mouse', 'Species', '10090', (138, 143))	('IGF2BP2', 'Gene', (74, 81))	('#11202D', 'Var', (231, 238))	('KCl', 'Chemical', 'MESH:D011189', (284, 287))	('mouse', 'Species', '10090', (214, 219))	('IgG antibody', 'Phenotype', 'HP:0003237', (144, 156))	('RIP', 'Gene', (265, 268))	('DTT', 'Chemical', 'MESH:D004229', (330, 333))
368924	31484926	All the media were supplemented with 10% fetal bovine serum (FBS) (#10270, Gibco), and the cells were grown at 37  C in a humidified atmosphere of 5% CO2 and 95% air.	('FBS', 'Disease', 'MESH:D005198', (61, 64))	('CO2', 'Chemical', '-', (150, 153))	('FBS', 'Disease', (61, 64))	('#10270', 'Var', (67, 73))	('bovine', 'Species', '9913', (47, 53))
368929	31484926	For siRNA-mediated knockdown of LIN28B, cells were transfected with a 1:1 mix of two different siRNAs against LIN28B (#216387-216388, Ambion) and a negative control (C-) (#AM4611, Ambion), using LipofectamineTM RNAiMAX Transfection Reagent (#13778, Invitrogen) according to the manufacturer's recommendations.	('LIN28B', 'Gene', (110, 116))	('LIN28B', 'Gene', (32, 38))	('mix', 'Gene', '83881', (74, 77))	('knockdown', 'Var', (19, 28))	('#216387-216388', 'Var', (118, 132))	('mix', 'Gene', (74, 77))	('LIN28B', 'Gene', '389421', (110, 116))	('LIN28B', 'Gene', '389421', (32, 38))	('LipofectamineTM', 'Chemical', '-', (195, 210))
368952	31484926	Cells were incubated for 24 h in serum-free medium, rinsed with PBS, trypsinized and resuspended in medium supplemented with 10% FBS to inactivate the trypsin, followed by centrifugation and resuspension in serum-free medium.	('inactivate', 'Var', (136, 146))	('FBS', 'Disease', 'MESH:D005198', (129, 132))	('trypsin', 'Protein', (151, 158))	('PBS', 'Chemical', 'MESH:D007854', (64, 67))	('FBS', 'Disease', (129, 132))
368971	31484926	For protein quantification, total extracts from a recorded number of cells was analyzed by western blot in parallel with known amounts of the following recombinant proteins: LIN28B (ab134596, Abcam), IGF2BP2 (ab153107, Abcam), HNRNPQ (ab153089, Abcam).	('ab153107', 'Var', (209, 217))	('IGF2BP2', 'Gene', (200, 207))	('LIN28B', 'Gene', (174, 180))	('HNRNPQ', 'Gene', '10492', (227, 233))	('HNRNPQ', 'Gene', (227, 233))	('ab153089', 'Var', (235, 243))	('IGF2BP2', 'Gene', '10644', (200, 207))	('LIN28B', 'Gene', '389421', (174, 180))
368976	31484926	Beads were then washed twice with high-salt buffer and twice with PNK buffer, and 20% of beads were radioactively labeled with gamma-[32P]-ATP and 0.5 U microl-1 PNK (#M0201, New England Biolabs) for 5 min at 37  C, added to the remaining cold beads and incubated in 20 microl 1xNuPAGE buffer for 5 min at 70  C prior to loading the supernatant on a 4-12% NuPAGE Bis-Tris gel (#NP0341BOX, ThermoFisher).	('Bis-Tris', 'Chemical', 'MESH:C026272', (363, 371))	('PNK', 'Gene', (66, 69))	('gamma-[32P]-ATP', 'Chemical', '-', (127, 142))	('PNK', 'Gene', '11284', (66, 69))	('PNK', 'Gene', (162, 165))	('salt', 'Chemical', 'MESH:D012492', (39, 43))	('PNK', 'Gene', '11284', (162, 165))	('#NP0341BOX', 'Var', (377, 387))
368992	31484926	For primary samples, an average of HMGA2/RPSAP52 promoter methylation >0.26 (median of the population) was considered as hypermethylated.	('RPSAP52', 'Gene', (41, 48))	('RPSAP52', 'Gene', '204010', (41, 48))	('methylation', 'Var', (58, 69))	('HMGA2', 'Gene', '8091', (35, 40))	('HMGA2', 'Gene', (35, 40))
368999	31484926	Immunoprecipitation and sample digestion for mass spectrometry analysis: 1 mg of pre-cleared protein extract from three replicates of control cells (scr) and cells depleted for RPSAP52 (sh4 B11 clone) were immunoprecipitated overnight at 4  C using 5 microg of anti-IGF2BP2 antibody (#H00010644-M01, Abnova) and 40 microl of Dynabeads  M-280 anti-mouse IgG beads (#11202D, ThermoFisher) in 1 ml RIP buffer (150 mM KCl, 25 mM Hepes at pH 7.9, 5 mM EDTA, 0.5 mM DTT, 0.5% NP40, 1x protease inhibitor cocktail (Roche)).	('#11202D', 'Var', (364, 371))	('IGF2BP2', 'Gene', '10644', (266, 273))	('RPSAP52', 'Gene', (177, 184))	('sh4', 'Gene', (186, 189))	('EDTA', 'Chemical', 'MESH:D004492', (447, 451))	('RIP', 'Gene', '3267', (395, 398))	('RPSAP52', 'Gene', '204010', (177, 184))	('H00010644-M01, Abnova', 'Disease', 'None', (285, 306))	('mouse', 'Species', '10090', (347, 352))	('Hepes', 'Chemical', 'MESH:D006531', (425, 430))	('IGF2BP2', 'Gene', (266, 273))	('NP40', 'Chemical', 'MESH:C010615', (470, 474))	('sh4', 'Gene', '100125850', (186, 189))	('KCl', 'Chemical', 'MESH:D011189', (414, 417))	('DTT', 'Chemical', 'MESH:D004229', (460, 463))	('RIP', 'Gene', (395, 398))
369020	31484926	Conception and design: S.G., C.O.-M. and L.F. Development of methodology: C.O.-M., A.S.-C., A.O.-G., R.B.-S., M.S., T.R., J.P., A.G., M.M.-I., D.H.-M., L.F. and S.G. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc): O.M.T., A.V., and M.E.	('M.E', 'Var', (281, 284))	('O.M.T.', 'Var', (263, 269))	('patients', 'Species', '9606', (226, 234))
369132	28740917	Peripheral neuropathy rates were higher with IORT/EBRT, which was attributed to overlapping IORT fields and misonidazole.	('Peripheral neuropathy', 'Disease', (0, 21))	('misonidazole', 'Chemical', 'MESH:D008920', (108, 120))	('IORT/EBRT', 'Var', (45, 54))	('Peripheral neuropathy', 'Phenotype', 'HP:0009830', (0, 21))	('Peripheral neuropathy', 'Disease', 'MESH:D010523', (0, 21))	('EBRT', 'Chemical', '-', (50, 54))
369135	28740917	However, IORT, which is generally one 10 to 15 Gy fraction, can be associated with neural injury or ureteral stricture.	('ureteral stricture', 'Disease', (100, 118))	('neural injury', 'Disease', (83, 96))	('associated', 'Reg', (67, 77))	('neural injury', 'Disease', 'MESH:C565640', (83, 96))	('IORT', 'Var', (9, 13))
369211	28740917	Because of the risk of normal tissue toxicity in the volumes receiving the CTV2 dose, it is important to emphasize that the reported results are based on a very close collaboration between the surgical and radiation oncologists to define the high-risk volume and determine which organs and/or structures should be resected.	('toxicity', 'Disease', (37, 45))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))	('CTV2', 'Var', (75, 79))
369382	28587165	Since SSB is also observable in an alkaline comet assay, it can be expected that DNA-fragments produced by direct DSB will be flanked by those initially produced by SSB.	('DSB', 'Var', (114, 117))	('SSB', 'Gene', (6, 9))	('SSB', 'Gene', (165, 168))	('SSB', 'Gene', '6741', (6, 9))	('SSB', 'Gene', '6741', (165, 168))	('comet', 'Species', '302767', (44, 49))
369395	32490123	Recurrent EGFR alterations in NTRK3 fusion negative congenital mesoblastic nephroma To identify oncogenic driver mutations in congenital mesoblastic nephroma (CMN) cases lacking ETV6-NTRK3 fusion and discuss their diagnostic value.	('NTRK3', 'Gene', (30, 35))	('EGFR', 'Gene', '1956', (10, 14))	('congenital mesoblastic nephroma', 'Disease', 'MESH:D018201', (126, 157))	('ETV6', 'Gene', (178, 182))	('congenital mesoblastic nephroma', 'Disease', (52, 83))	('CMN', 'Phenotype', 'HP:0100881', (159, 162))	('EGFR', 'Gene', (10, 14))	('congenital mesoblastic nephroma', 'Disease', 'MESH:D018201', (52, 83))	('NTRK3', 'Gene', '4916', (183, 188))	('congenital mesoblastic nephroma', 'Phenotype', 'HP:0100881', (52, 83))	('alterations', 'Var', (15, 26))	('ETV6', 'Gene', '2120', (178, 182))	('NTRK3', 'Gene', '4916', (30, 35))	('NTRK3', 'Gene', (183, 188))	('mutations', 'Var', (113, 122))	('congenital mesoblastic nephroma', 'Disease', (126, 157))	('congenital mesoblastic nephroma', 'Phenotype', 'HP:0100881', (126, 157))
369396	32490123	Cases positive for ETV6 rearrangement or with unavailable blocks were excluded.	('rearrangement', 'Var', (24, 37))	('ETV6', 'Gene', '2120', (19, 23))	('ETV6', 'Gene', (19, 23))	('positive', 'Reg', (6, 14))
369398	32490123	All three outside cases are positive for EGFR alterations, including KDD in two and a splicing site mutation in one.	('EGFR', 'Gene', (41, 45))	('splicing site mutation', 'Var', (86, 108))	('positive', 'Reg', (28, 36))	('alterations', 'Var', (46, 57))	('KDD', 'Disease', (69, 72))	('EGFR', 'Gene', '1956', (41, 45))
369399	32490123	The splicing site mutation is predicted to be EGFR activating.	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (46, 50))	('mutation', 'Var', (18, 26))
369406	32490123	The frequency of NTRK3 fusions in the mixed type of CMN varies greatly by study.	('NTRK3', 'Gene', (17, 22))	('CMN', 'Disease', (52, 55))	('CMN', 'Phenotype', 'HP:0100881', (52, 55))	('fusions', 'Var', (23, 30))	('NTRK3', 'Gene', '4916', (17, 22))
369407	32490123	For the classic subtype and the subset of cellular/mixed CMNs lacking NTRK3 fusions, no recurrent genetic aberration had been identified, until a recently published series found EGFR kinase domain duplications (KDD), rare NTRK1 fusions, and BRAF fusions and intragenic rearrangements.	('EGFR', 'Gene', '1956', (178, 182))	('NTRK1', 'Gene', '4914', (222, 227))	('fusions', 'Var', (228, 235))	('fusions', 'Var', (246, 253))	('EGFR', 'Gene', (178, 182))	('NTRK3', 'Gene', (70, 75))	('BRAF', 'Gene', '673', (241, 245))	('CMN', 'Phenotype', 'HP:0100881', (57, 60))	('NTRK1', 'Gene', (222, 227))	('BRAF', 'Gene', (241, 245))	('NTRK3', 'Gene', '4916', (70, 75))
369410	32490123	Intragenic tandem duplication is a well-known mechanism to activate oncogenes, for example, FLT3 internal tandem duplication (ITD) in acute myeloid leukemia and BCOR ITD in clear cell sarcoma of kidney (CCSK).	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('sarcoma of kidney', 'Disease', (184, 201))	('BCOR', 'Gene', '54880', (161, 165))	('FLT3', 'Gene', '2322', (92, 96))	('activate', 'PosReg', (59, 67))	('CCSK', 'Chemical', '-', (203, 207))	('acute myeloid leukemia', 'Disease', (134, 156))	('CCSK', 'Phenotype', 'HP:0006770', (203, 207))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('sarcoma of kidney', 'Disease', 'MESH:D012509', (184, 201))	('internal tandem duplication', 'Var', (97, 124))	('BCOR', 'Gene', (161, 165))	('FLT3', 'Gene', (92, 96))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('sarcoma of kidney', 'Phenotype', 'HP:0008663', (184, 201))	('clear cell sarcoma of kidney', 'Phenotype', 'HP:0006770', (173, 201))
369412	32490123	We herein analyze a separate cohort and confirm that EGFR mutations, and in particular KDD, are important recurrent genetic alterations in many of these NTRK3 fusion negative CMNs, and we discuss the clinicopathologic features of such cases in detail.	('mutations', 'Var', (58, 67))	('NTRK3', 'Gene', '4916', (153, 158))	('KDD', 'Gene', (87, 90))	('NTRK3', 'Gene', (153, 158))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('CMN', 'Phenotype', 'HP:0100881', (175, 178))
369414	32490123	Cases positive for ETV6 rearrangement by fluorescence in situ hybridization (FISH) or t(12;15)(p13;q25) by conventional karyotype, or cases with unavailable blocks were excluded.	('positive', 'Reg', (6, 14))	('rearrangement', 'Var', (24, 37))	('t(12;15)(p13;q25', 'Var', (86, 102))	('t(12;15)(p13;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (86, 103))	('ETV6', 'Gene', (19, 23))	('ETV6', 'Gene', '2120', (19, 23))
369416	32490123	Mutational profiling was performed using an institutionally-developed, hybrid capture-based next-generation sequencing (NGS) assay targeting 130 genes entirely or in part, which detects single nucleotide variants, short insertions and deletions, selected fusions, and selected amplifications in solid tumors, with tumor-only sequencing.	('deletions', 'Var', (235, 244))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('solid tumors', 'Disease', (295, 307))	('single nucleotide variants', 'Var', (186, 212))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Disease', (301, 306))	('tumor', 'Disease', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('solid tumors', 'Disease', 'MESH:D009369', (295, 307))	('fusions', 'Var', (255, 262))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))
369431	32490123	By the standard clinical pipeline, no tumor-specific genetic alterations were identified except equivocal amplification of EGFR (Fig.	('EGFR', 'Gene', (123, 127))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('amplification', 'Var', (106, 119))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('EGFR', 'Gene', '1956', (123, 127))
369437	32490123	Another two CMN cases with EGFR alterations were contributed by our collaborators.	('alterations', 'Var', (32, 43))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('CMN', 'Phenotype', 'HP:0100881', (12, 15))
369439	32490123	Interestingly, case 6 harbors a splice site mutation in EGFR.	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('splice site mutation', 'Var', (32, 52))
369440	32490123	This splice site mutation involves a canonical donor splice site of intron 26 and is predicted to cause exon 26 skipping, and consequent EGFR activation based on the current knowledge on the function of the carboxyl-terminus of EGFR.	('EGFR', 'Gene', (137, 141))	('activation', 'PosReg', (142, 152))	('mutation', 'Var', (17, 25))	('exon 26', 'MPA', (104, 111))	('EGFR', 'Gene', '1956', (228, 232))	('skipping', 'NegReg', (112, 120))	('EGFR', 'Gene', (228, 232))	('EGFR', 'Gene', '1956', (137, 141))
369449	32490123	NGS identified an EGFR KDD but no evidence of BCOR ITD or an NTRK gene rearrangement.	('EGFR', 'Gene', '1956', (18, 22))	('BCOR', 'Gene', (46, 50))	('KDD', 'Var', (23, 26))	('EGFR', 'Gene', (18, 22))	('BCOR', 'Gene', '54880', (46, 50))
369450	32490123	In addition to the EGFR mutation, a subclonal activating mutation in PIK3CA and a loss-of-function mutation in ARID1A were also identified.	('loss-of-function', 'NegReg', (82, 98))	('EGFR', 'Gene', '1956', (19, 23))	('mutation', 'Var', (99, 107))	('ARID1A', 'Gene', '8289', (111, 117))	('ARID1A', 'Gene', (111, 117))	('PIK3CA', 'Gene', (69, 75))	('mutation', 'Var', (24, 32))	('EGFR', 'Gene', (19, 23))	('PIK3CA', 'Gene', '5290', (69, 75))	('activating', 'PosReg', (46, 56))
369451	32490123	Conventional karyotyping revealed +8,+11,+17,+19,der(20)t(1;20)(q12;q13.2).	('+17', 'Var', (41, 44))	('der(20)t(1;20)(q12;q13.2)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 74))	('der(20)t(1;20)(q12;q13.2', 'Var', (49, 73))
369466	32490123	However, variants of EGFR KDD can occur, as seen in case 2.	('variants', 'Var', (9, 17))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (21, 25))
369467	32490123	Considering the in-frame nature and the duplication of the intact kinase domain, the reported variants are predicted to be functionally similar to prototypical EGFR KDD.	('EGFR', 'Gene', '1956', (160, 164))	('variants', 'Var', (94, 102))	('EGFR', 'Gene', (160, 164))
369477	32490123	Additionally, a conventional karyotyping showed +8,+11,+17,+19, der(20)t(1;20)(q12;q13.2).	('der(20)t(1;20)(q12;q13.2', 'Var', (64, 88))	('der(20)t(1;20)(q12;q13.2)', 'STRUCTURAL_ABNORMALITY', 'None', (64, 89))	('+17', 'Var', (55, 58))
369478	32490123	Polysomies, particularly trisomy 11 and less commonly polysomy 8, 17 and 20, are recurrent cytogenetic findings in CMN and infantile fibrosarcoma (IFS).	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('infantile fibrosarcoma', 'Disease', (123, 145))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (133, 145))	('CMN', 'Disease', (115, 118))	('CMN', 'Phenotype', 'HP:0100881', (115, 118))	('IFS', 'Chemical', '-', (147, 150))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (123, 145))	('trisomy 11', 'Var', (25, 35))
369483	32490123	If EGFR mutations are only seen in CMN in this differential, then the presence of this alteration would be useful to separate the two tumors in cases like this where the site of origin is obscure.	('EGFR', 'Gene', '1956', (3, 7))	('tumors', 'Disease', (134, 140))	('EGFR', 'Gene', (3, 7))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('CMN', 'Phenotype', 'HP:0100881', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
369487	32490123	In addition, as discussed above, a subclonal activating PIK3CA mutation and a pathogenic ARID1A mutation were also detected in case 7.	('ARID1A', 'Gene', '8289', (89, 95))	('ARID1A', 'Gene', (89, 95))	('mutation', 'Var', (96, 104))	('mutation', 'Var', (63, 71))	('PIK3CA', 'Gene', (56, 62))	('activating', 'PosReg', (45, 55))	('PIK3CA', 'Gene', '5290', (56, 62))
369489	32490123	No pathogenic PIK3CA mutations and three pathogenic ARID1A mutations (two of which were germline) were identified in a whole genome sequencing study of 117 cases of Wilms' tumor.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('ARID1A', 'Gene', '8289', (52, 58))	("Wilms' tumor", 'Disease', (165, 177))	('ARID1A', 'Gene', (52, 58))	("Wilms' tumor", 'Disease', 'MESH:D009396', (165, 177))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (165, 177))	('PIK3CA', 'Gene', (14, 20))	('PIK3CA', 'Gene', '5290', (14, 20))	('mutations', 'Var', (21, 30))
369490	32490123	To our knowledge, recurrent mutations in these genes have not been described in other pediatric soft tissue tumors, including CCSK and IFS, although in each case the number of cases examined comprehensively is currently very small.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CCSK', 'Chemical', '-', (126, 130))	('IFS', 'Chemical', '-', (135, 138))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (96, 114))	('CCSK', 'Phenotype', 'HP:0006770', (126, 130))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (28, 37))	('CCSK', 'Disease', (126, 130))
369491	32490123	Thus, while these mutations may contribute to pathogenesis in this particular tumor, they do not appear to be highly recurrent events in CMN or related tumors.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('contribute', 'Reg', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('CMN', 'Phenotype', 'HP:0100881', (137, 140))	('tumor', 'Disease', (78, 83))	('tumors', 'Disease', (152, 158))	('CMN', 'Disease', (137, 140))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (18, 27))
369506	32490123	These patients may benefit from genetic alteration-specific targeted therapies, such as larotrectinib or merestinib in cases with NTRK fusions, or potentially EGFR-directed therapies for cases carrying EGFR KDD.	('EGFR', 'Gene', (202, 206))	('EGFR', 'Gene', '1956', (159, 163))	('fusions', 'Var', (135, 142))	('larotrectinib', 'Chemical', 'MESH:C000609083', (88, 101))	('NTRK', 'Gene', (130, 134))	('EGFR', 'Gene', (159, 163))	('patients', 'Species', '9606', (6, 14))	('EGFR', 'Gene', '1956', (202, 206))	('merestinib', 'Chemical', 'MESH:C586252', (105, 115))
369507	32490123	In this study, immunohistochemistry for EGFR did not distinguish CMNs with EGFR KDD from those with ETV6-NTRK3 fusion.	('CMN', 'Phenotype', 'HP:0100881', (65, 68))	('ETV6', 'Gene', (100, 104))	('KDD', 'Var', (80, 83))	('CMNs', 'Disease', (65, 69))	('NTRK3', 'Gene', '4916', (105, 110))	('ETV6', 'Gene', '2120', (100, 104))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (75, 79))	('NTRK3', 'Gene', (105, 110))	('EGFR', 'Gene', (75, 79))
369511	32490123	The splicing site mutation identified in case 7 is predicted to cause EGFR exon 26 skipping, or a potentially larger deletion involving more downstream exons.	('cause', 'Reg', (64, 69))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (70, 74))	('mutation', 'Var', (18, 26))	('skipping', 'NegReg', (83, 91))
369513	32490123	A separate study showed exons 25 and 26-deleted EGFR mutant led to EGFR activation and cytokine independent proliferation.	('activation', 'PosReg', (72, 82))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', (48, 52))	('cytokine independent proliferation', 'CPA', (87, 121))	('mutant', 'Var', (53, 59))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))
369515	32490123	Therefore, the EGFR splicing site mutation found in case 7 is likely to cause EGFR activation via exon 26 skipping and may have potential therapeutic significance.	('mutation', 'Var', (34, 42))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('activation', 'PosReg', (83, 93))
369517	32490123	suggested some cases could be explained by less recurrent rearrangement variants of BRAF, NTRK1 or NTRK3, our data show that the breakpoints of EGFR KDD are not invariant, and non-duplication activating mutations such as some splice site mutations can occur, both of which could also explain a false negative RT-PCR result.	('EGFR', 'Gene', (144, 148))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('NTRK1', 'Gene', (90, 95))	('variants', 'Var', (72, 80))	('NTRK3', 'Gene', '4916', (99, 104))	('EGFR', 'Gene', '1956', (144, 148))	('NTRK1', 'Gene', '4914', (90, 95))	('NTRK3', 'Gene', (99, 104))
369518	32490123	More cases are needed to clarify the frequency of BRAF or NTRK1 alterations in non-NTRK3, non-EGFR CMNs.	('BRAF', 'Gene', (50, 54))	('NTRK1', 'Gene', (58, 63))	('NTRK3', 'Gene', (83, 88))	('NTRK3', 'Gene', '4916', (83, 88))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (94, 98))	('NTRK1', 'Gene', '4914', (58, 63))	('alterations', 'Var', (64, 75))	('CMN', 'Phenotype', 'HP:0100881', (99, 102))	('BRAF', 'Gene', '673', (50, 54))
369521	32490123	Interestingly, BRAF fusions have recently been reported in a subset of NTRK fusion negative pediatric sarcomas showing morphologic overlap with IFS.	('sarcomas', 'Disease', (102, 110))	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (15, 19))	('NTRK', 'Gene', (71, 75))	('sarcomas', 'Disease', 'MESH:D012509', (102, 110))	('fusion', 'Var', (76, 82))	('IFS', 'Chemical', '-', (144, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
369531	32490123	As EGFR mutations seem to be most common in the classic subtype, this would imply that they might be associated with more favorable outcomes.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))	('associated', 'Reg', (101, 111))	('common', 'Reg', (34, 40))
369532	32490123	Case 7 from this study, however, would seem to argue against a simple relationship between the presence of EGFR mutations in these tumors and outcomes.	('EGFR', 'Gene', '1956', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('EGFR', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (112, 121))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
369533	32490123	In summary, although the correlation of histology and molecular changes is not absolute, it appears that most if not all classic-type CMNs are driven by EGFR mutations, and as we have already known, most cellular-type CMNs are driven by NTRK3 fusions.	('NTRK3', 'Gene', (237, 242))	('classic-type CMNs', 'Disease', (121, 138))	('CMN', 'Phenotype', 'HP:0100881', (134, 137))	('EGFR', 'Gene', '1956', (153, 157))	('NTRK3', 'Gene', '4916', (237, 242))	('CMN', 'Phenotype', 'HP:0100881', (218, 221))	('EGFR', 'Gene', (153, 157))	('mutations', 'Var', (158, 167))	('driven', 'Reg', (143, 149))
369535	32490123	Additional work will be required to determine how much these mutations differ in function from more common activating EGFR mutations and whether tyrosine kinase inhibitors will be clinically useful.	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))
369536	32490123	Another interesting question is whether EGFR KDD may be present in other entities showing recurrent ETV6-NTRK3 fusions such as secretory carcinoma of breast and salivary glands.	('carcinoma of breast', 'Disease', 'MESH:D001943', (137, 156))	('ETV6', 'Gene', (100, 104))	('fusions', 'Var', (111, 118))	('carcinoma of breast', 'Disease', (137, 156))	('NTRK3', 'Gene', '4916', (105, 110))	('salivary glands', 'Disease', (161, 176))	('ETV6', 'Gene', '2120', (100, 104))	('EGFR', 'Gene', '1956', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('EGFR', 'Gene', (40, 44))	('NTRK3', 'Gene', (105, 110))
369595	30204247	The patient was a boy aged 12 years at the time of enrollment with a tropomyosin 3 (TPM3)-NTRK1 fusion, localized, poorly classified spindle cell sarcoma arising in the pelvis and involving the acetabulum (Fig.	('sarcoma', 'Disease', (146, 153))	('fusion', 'Var', (96, 102))	('patient', 'Species', '9606', (4, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('boy', 'Species', '9606', (18, 21))	('TPM3)-NTRK1', 'Gene', (84, 95))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
369612	30204247	The patient was a girl aged 2 years at the time of enrollment with a large sequestosome 1 (SQSTM1)-NTRK1 fusion, localized, infantile fibrosarcoma of the shoulder, extending to the neck, back, and axilla.	('SQSTM1)-NTRK1', 'Gene', (91, 104))	('fusion', 'Var', (105, 111))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (124, 146))	('patient', 'Species', '9606', (4, 11))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (134, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('infantile fibrosarcoma', 'Disease', (124, 146))	('girl', 'Species', '9606', (18, 22))
369662	24728494	As molecular biology techniques have progressed, the driver mutation of several cancers revealed abnormalities in tyrosine kinases that work in the signal transduction of cancer cells.	('mutation', 'Var', (60, 68))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('abnormalities', 'Var', (97, 110))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tyrosine kinases', 'Enzyme', (114, 130))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
369718	30627019	MRI features of LMS include nodular borders, flow-void areas, T1 hyperintensity areas, and rapid enhancement at the early phase post-injection of contrast medium; and shared features with that of uterine sarcomas include heterogeneous, intermediate T2 signal, and high signal on DWI with low ADC value, associated with intratumoral hemorrhage and necrosis.	('hemorrhage', 'Disease', 'MESH:D006470', (332, 342))	('os', 'Chemical', 'MESH:D009992', (351, 353))	('enhancement', 'PosReg', (97, 108))	('os', 'Chemical', 'MESH:D009992', (129, 131))	('ADC value', 'MPA', (292, 301))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('sarcomas', 'Disease', 'MESH:D012509', (204, 212))	('necrosis', 'Disease', 'MESH:D009336', (347, 355))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('sarcomas', 'Disease', (204, 212))	('hemorrhage', 'Disease', (332, 342))	('necrosis', 'Disease', (347, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('high signal', 'Var', (264, 275))	('T2 signal', 'MPA', (249, 258))	('flow-void', 'MPA', (45, 54))	('heterogeneous', 'MPA', (221, 234))	('tumor', 'Disease', (324, 329))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (196, 211))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
369727	30627019	Hyperintensity on DWI is reported to have high sensitivity but limited specificity in differentiation between LMS/STUMP and benign leiomyoma.	('benign leiomyoma', 'Disease', 'MESH:D007889', (124, 140))	('benign leiomyoma', 'Disease', (124, 140))	('LMS/STUMP', 'Disease', (110, 119))	('Hyperintensity', 'Var', (0, 14))
369776	30627019	Study shows that similar to the majority of malignant tumors, UCS demonstrates low ADC values on DWI which are significantly higher than that of grade II and III EC, corresponding to the hypocellular regions caused by intratumoral necrosis.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('malignant tumors', 'Disease', (44, 60))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('malignant tumors', 'Disease', 'MESH:D018198', (44, 60))	('ADC values', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('low', 'NegReg', (79, 82))	('necrosis', 'Disease', (231, 239))	('DWI', 'Var', (97, 100))	('higher', 'PosReg', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('intratumoral necrosis', 'Phenotype', 'HP:0010885', (218, 239))	('tumor', 'Disease', (54, 59))	('necrosis', 'Disease', 'MESH:D009336', (231, 239))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
369794	30627019	Meta-analysis conducted in 2014 shows similar pooled sensitivity under DWI and DCE-MRI; although the specificity is slightly higher under DWI versus DCE-MRI, without significance.	('DCE-MRI', 'Var', (79, 86))	('DCE', 'Chemical', '-', (79, 82))	('DCE', 'Chemical', '-', (149, 152))	('higher', 'PosReg', (125, 131))	('specificity', 'MPA', (101, 112))
369800	30627019	In premenopausal patients with EC planning to undergo fertility-preserving treatment, DCE-MRI is superior to DWI in terms of excluding the possibility of the myometrial invasion.	('myometrial invasion', 'CPA', (158, 177))	('DCE-MRI', 'Var', (86, 93))	('DCE', 'Chemical', '-', (86, 89))	('os', 'Chemical', 'MESH:D009992', (140, 142))	('patients', 'Species', '9606', (17, 25))
369832	27664537	Thus, we analyzed eleven formalin fixed paraffin embedded CIC-DUX4 sarcoma tissue samples (including three sample pairs) using targeted Ion Torrent based multiplexed polymerase chain reaction (PCR) next generation sequencing to characterize potential somatic driver alterations in 409 genes.	('CIC-DUX4 sarcoma', 'Disease', 'MESH:D012509', (58, 74))	('CIC-DUX4 sarcoma', 'Disease', (58, 74))	('alterations', 'Var', (266, 277))	('formalin', 'Chemical', 'MESH:D005557', (25, 33))	('paraffin', 'Chemical', 'MESH:D010232', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('409 genes', 'Gene', (281, 290))
369833	27664537	In one sample pair (untreated primary and local recurrence resections), we identified similar copy number profiles and a somatic ARID1A R963X nonsense mutation exclusively in the local recurrence sample.	('ARID1A', 'Gene', '8289', (129, 135))	('R963X', 'Mutation', 'p.R963X', (136, 141))	('R963X', 'Var', (136, 141))	('ARID1A', 'Gene', (129, 135))
369835	27664537	In summary, next generation sequencing identified limited somatic driver mutations in CIC-DUX4 sarcomas.	('CIC-DUX4 sarcomas', 'Disease', (86, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (86, 103))	('mutations', 'Var', (73, 82))
369836	27664537	However, we identified novel, recurrent copy number alterations, including chromosome 1p, which is also the locus of ARID1A.	('ARID1A', 'Gene', (117, 123))	('copy number alterations', 'Var', (40, 63))	('ARID1A', 'Gene', '8289', (117, 123))
369841	27664537	reported that some aggressive URCSs harbored fusions of CIC (a human homolog of Drosophila capicua) to DUX 4 (double homeobox 4), as a result of t(4;19)(q35;q13.1) translocations.	('capicua', 'Gene', '53560', (91, 98))	('human', 'Species', '9606', (63, 68))	('t(4;19)(q35;q13.1)', 'STRUCTURAL_ABNORMALITY', 'None', (145, 163))	('CIC', 'Gene', (56, 59))	('capicua', 'Gene', (91, 98))	('translocations', 'Var', (164, 178))	('fusions', 'Var', (45, 52))	('Drosophila', 'Species', '7227', (80, 90))	('CIC', 'Gene', '23152', (56, 59))
369843	27664537	The CIC-DUX4 fusion results in a chimeric protein that includes the majority of the CIC gene but lacks the homeodomains of DUX4.	('chimeric protein', 'MPA', (33, 49))	('CIC', 'Gene', '23152', (84, 87))	('DUX4', 'Gene', '100288687', (123, 127))	('fusion', 'Var', (13, 19))	('results in', 'Reg', (20, 30))	('CIC', 'Gene', (84, 87))	('CIC', 'Gene', '23152', (4, 7))	('DUX4', 'Gene', (8, 12))	('DUX4', 'Gene', '100288687', (8, 12))	('DUX4', 'Gene', (123, 127))	('CIC', 'Gene', (4, 7))
369845	27664537	DUX4 has primarily been characterized in the context of muscular dystrophy, where aberrant DUX4 expression due to epigenetic changes are thought to cause facioscapulohmueral muscular dystrophy (FSHD).	('DUX4', 'Gene', (91, 95))	('DUX4', 'Gene', '100288687', (91, 95))	('DUX4', 'Gene', (0, 4))	('FSHD', 'Gene', '2489', (194, 198))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (174, 192))	('muscular dystrophy', 'Disease', (174, 192))	('muscular dystrophy', 'Disease', 'MESH:D009136', (174, 192))	('DUX4', 'Gene', '100288687', (0, 4))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (56, 74))	('FSHD', 'Gene', (194, 198))	('muscular dystrophy', 'Disease', (56, 74))	('cause', 'Reg', (148, 153))	('muscular dystrophy', 'Disease', 'MESH:D009136', (56, 74))	('epigenetic changes', 'Var', (114, 132))	('aberrant', 'Var', (82, 90))
369846	27664537	Previous research has shown CIC-DUX4 fusions expose the DUX4 C-terminus, resulting in increased activation of CIC, even though the DNA binding of the CIC HMG domain is largely not affected.	('CIC', 'Gene', '23152', (110, 113))	('CIC', 'Gene', (28, 31))	('CIC', 'Gene', (110, 113))	('increased activation', 'PosReg', (86, 106))	('CIC', 'Gene', '23152', (150, 153))	('fusions', 'Var', (37, 44))	('DUX4', 'Gene', (56, 60))	('DUX4 C', 'Gene', '100288711', (56, 62))	('DUX4', 'Gene', (32, 36))	('CIC', 'Gene', (150, 153))	('CIC', 'Gene', '23152', (28, 31))	('DUX4', 'Gene', '100288687', (56, 60))	('DUX4 C', 'Gene', (56, 62))	('DUX4', 'Gene', '100288687', (32, 36))
369849	27664537	Previous karyotyping and fluorescence in situ hybridization (FISH) studies support chromosome (chr) 8 trisomy and MYC amplification as recurrent alterations in CIC-DUX4 sarcomas, however a more comprehensive analysis of the genomic landscape of CIC-DUX4 sarcomas, including assessment of somatic point mutations, small insertions/deletions (indels), and copy number alterations (CNAs), is lacking.	('sarcomas', 'Phenotype', 'HP:0100242', (254, 262))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (160, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (245, 262))	('MYC', 'Gene', (114, 117))	('CIC-DUX4 sarcomas', 'Disease', (160, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('CIC-DUX4 sarcomas', 'Disease', (245, 262))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('MYC', 'Gene', '4609', (114, 117))	('small insertions/deletions', 'Var', (313, 339))
369851	27664537	Likewise, it is unclear whether CIC-DUX4 sarcomas are similar to Ewing sarcoma at the genomic level, as Ewing sarcomas have few recurrent point mutations/indels (most frequently involving TP53 and STAG2) but several recurrent, broad, copy number alterations (CNAs).	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('point mutations/indels', 'Var', (138, 160))	('copy number alterations', 'Var', (234, 257))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (32, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (104, 117))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('Ewing sarcoma', 'Disease', (65, 78))	('STAG2', 'Gene', '10735', (197, 202))	('TP53', 'Gene', '7157', (188, 192))	('involving', 'Reg', (178, 187))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (104, 118))	('STAG2', 'Gene', (197, 202))	('CIC-DUX4 sarcomas', 'Disease', (32, 49))	('Ewing sarcomas', 'Disease', (104, 118))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (104, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (65, 78))	('TP53', 'Gene', (188, 192))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))
369858	27664537	CIC-DUX4 rearrangement for all samples was confirmed by RT-PCR and/or FISH as described prior to inclusion in our sequencing cohort.	('DUX4', 'Gene', (4, 8))	('DUX4', 'Gene', '100288687', (4, 8))	('CIC', 'Gene', '23152', (0, 3))	('rearrangement', 'Var', (9, 22))	('CIC', 'Gene', (0, 3))
369861	27664537	Data analysis was performed essentially as described using validated pipelines based on Torrent Suite 4.0.2, with alignment by TMAP using default parameters, and variant calling using the Torrent Variant Caller plugin (version 4.0-r76860) with low-stringency default somatic variant settings.	('TMA', 'Disease', (127, 130))	('TMA', 'Disease', 'MESH:D000783', (127, 130))	('variant', 'Var', (162, 169))
369862	27664537	Called variants were filtered to remove synonymous or non-coding variants, those with flow corrected read depths (FDP) <=30, flow corrected variant allele containing reads (FAO) <=6, variant allele frequencies (FAO/FDP) <0.10, extreme skewing of forward/reverse flow corrected reads (FSAF/FSAR <0.2 or >5), FSAF and FSAR >1, or indels within homopolymer runs >4 bases.	('FSAF', 'Disease', (307, 311))	('FSAF', 'Disease', 'None', (284, 288))	('FSAF', 'Disease', (284, 288))	('<=6', 'Var', (178, 181))	('FSAF', 'Disease', 'None', (307, 311))	('variant', 'Var', (140, 147))
369863	27664537	From these somatic variants, hotspots (>1 observation at that residue in COSMIC) in oncogenes, or hotspot or deleterious alterations (nonsense/frameshift variants) in tumor suppressors were then considered as prioritized variants.	('oncogenes', 'Gene', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('variants', 'Var', (19, 27))	('tumor', 'Disease', (167, 172))
369875	27664537	Importantly, no genes were recurrently mutated across patients (Samples 7A and 7B harbor the same KMT2D A3318G variant at near 0.50 variant allele frequency, which although passing our somatic filtering is likely to be germline; Sample 1 also harbors a KMT2D mutation that is a known rare germline variant, but the observed variant allele frequency (0.39) is just below our germline filtering threshold (0.40) used herein.	('A3318G', 'Mutation', 'g.3318A>G', (104, 110))	('KMT2D', 'Gene', '8085', (253, 258))	('KMT2D', 'Gene', (253, 258))	('KMT2D', 'Gene', '8085', (98, 103))	('patients', 'Species', '9606', (54, 62))	('KMT2D', 'Gene', (98, 103))	('A3318G', 'Var', (104, 110))
369876	27664537	An activating CTNNB1 E54K was identified in Sample 6A; however as this variant was present at low variant allele frequency (0.11) and was not detected in the matched brain metastasis from this case (6B), this alteration likely represents a subclonal alteration.	('CTNNB1', 'Gene', '1499', (14, 20))	('activating', 'PosReg', (3, 13))	('E54K', 'Var', (21, 25))	('E54K', 'Mutation', 'p.E54K', (21, 25))	('CTNNB1', 'Gene', (14, 20))
369877	27664537	TP53 C238Y and D208fs mutations were identified in Sample 1, with variant allele frequencies of 0.32 and 0.68, respectively, consistent with loss of TP53 function.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('D208fs', 'Mutation', 'p.D208fsX', (15, 21))	('TP53', 'Gene', '7157', (149, 153))	('TP53', 'Gene', (149, 153))	('D208fs', 'Var', (15, 21))	('C238Y', 'Mutation', 'rs730882005', (5, 10))	('C238Y', 'Var', (5, 10))
369878	27664537	Lastly, a prioritized ARID1A R693X mutation was identified exclusively in Sample 7B (variant allele frequency 157/417=38% vs. 1/355=0.3% in 7A, Tables 1 & S2).	('R693X', 'Var', (29, 34))	('ARID1A', 'Gene', '8289', (22, 28))	('R693X', 'Mutation', 'p.R693X', (29, 34))	('ARID1A', 'Gene', (22, 28))
369880	27664537	As shown in Figures 2&3A, in contrast to the limited mutational landscape of CIC-DUX4 tumors, we identified CNAs in all samples, including areas of recurrent gain/loss.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('identified', 'Var', (97, 107))	('recurrent', 'PosReg', (148, 157))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('CIC-DUX4 tumors', 'Disease', 'MESH:D009369', (77, 92))	('CIC-DUX4 tumors', 'Disease', (77, 92))
369881	27664537	Consistent with previous karyotyping/FISH studies that demonstrated chromosome (chr) 8 gain and focal MYC (8q24) amplification in CIC-DUX4 sarcomas, we observed broad, low-level chr 8 gain in 4 of nine cases (Figs.	('gain', 'PosReg', (87, 91))	('chr 8', 'Gene', (178, 183))	('MYC', 'Gene', '4609', (102, 105))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (130, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('gain', 'PosReg', (184, 188))	('amplification', 'Var', (113, 126))	('CIC-DUX4 sarcomas', 'Disease', (130, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('MYC', 'Gene', (102, 105))
369885	27664537	Of note, we also identified recurrent, low level deletions centered on the tumor suppressor ARID1A on chr 1p36 (Fig 2 and 3A), which were present in 4 of 8 profiled cases (including concordant loss in Samples 6A & B; loss in case 5A but not 5B).	('loss', 'NegReg', (193, 197))	('p36', 'Gene', '51251', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('deletions', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('p36', 'Gene', (107, 110))	('ARID1A', 'Gene', '8289', (92, 98))	('tumor', 'Disease', (75, 80))	('ARID1A', 'Gene', (92, 98))
369886	27664537	Importantly, case 3, which harbored this chr 1p deletion by NGS, was previously reported to harbor a deletion of chr 1p21-p36 by karyotyping (Table 1), consistent with our NGS results.	('deletion', 'Var', (101, 109))	('p36', 'Gene', (122, 125))	('p36', 'Gene', '51251', (122, 125))	('deletion', 'Var', (48, 56))	('chr 1p', 'Gene', (41, 47))
369894	27664537	Hence, here we performed targeted NGS on eleven FFPE CIC-DUX4 samples (from eight patients) to identify somatic mutations and CNAs in CIC-DUX4 sarcomas as well as assess the molecular relationship to Ewing sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('sarcomas', 'Phenotype', 'HP:0100242', (206, 214))	('mutations', 'Var', (112, 121))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (134, 151))	('CIC', 'Gene', (134, 137))	('DUX4', 'Gene', '100288687', (57, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (200, 214))	('CIC', 'Gene', (53, 56))	('Ewing sarcomas', 'Disease', (200, 214))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (200, 214))	('patients', 'Species', '9606', (82, 90))	('DUX4', 'Gene', (138, 142))	('CIC', 'Gene', '23152', (134, 137))	('CIC-DUX4 sarcomas', 'Disease', (134, 151))	('CIC', 'Gene', '23152', (53, 56))	('DUX4', 'Gene', '100288687', (138, 142))	('DUX4', 'Gene', (57, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (200, 213))
369895	27664537	However, one sample (6A) harbored a prioritized potentially driving activating oncogenic mutation (CTNNB1 E54K, likely subclonal), while Sample 1 harbored TP53 C238Y and D208fs mutations, and Sample 7B (local recurrence) harbored an ARID1A R693X nonsense mutation.	('D208fs', 'Mutation', 'p.D208fsX', (170, 176))	('C238Y', 'Mutation', 'rs730882005', (160, 165))	('CTNNB1', 'Gene', (99, 105))	('TP53', 'Gene', '7157', (155, 159))	('activating', 'PosReg', (68, 78))	('ARID1A', 'Gene', '8289', (233, 239))	('ARID1A', 'Gene', (233, 239))	('E54K', 'Var', (106, 110))	('R693X', 'Var', (240, 245))	('E54K', 'Mutation', 'p.E54K', (106, 110))	('TP53', 'Gene', (155, 159))	('R693X', 'Mutation', 'p.R693X', (240, 245))	('CTNNB1', 'Gene', '1499', (99, 105))	('D208fs', 'Var', (170, 176))
369896	27664537	Our cohort included six previously treated samples (five post-chemotherapy and one post-radiation), suggesting that point mutations/indels are not major drivers of treatment resistance in CIC-DUX4 sarcomas.	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (188, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (197, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('point mutations/indels', 'Var', (116, 138))	('CIC-DUX4 sarcomas', 'Disease', (188, 205))
369901	27664537	Likewise, we identified recurrent low level chr 1 p deletions that included the frequently mutated tumor suppressor AR1D1A (at 1p36), in 4 of 8 cases, in addition to the ARID1A R693X nonsense mutation exclusively in the local recurrence sample of case 7 (Sample 7B).	('tumor', 'Disease', (99, 104))	('R693X', 'Mutation', 'p.R693X', (177, 182))	('chr 1 p', 'Gene', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('p36', 'Gene', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('R693X', 'Var', (177, 182))	('p36', 'Gene', '51251', (128, 131))	('ARID1A', 'Gene', '8289', (170, 176))	('ARID1A', 'Gene', (170, 176))
369903	27664537	Results from our small series suggest that this alteration may be more frequent in CIC-DUX4 sarcomas, and the identification of both ARID1A copy loss in multiple samples and a deleterious mutation in Sample 7B is intriguing.	('ARID1A', 'Gene', '8289', (133, 139))	('ARID1A', 'Gene', (133, 139))	('CIC-DUX4 sarcomas', 'Disease', (83, 100))	('copy', 'Var', (140, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (83, 100))
369906	27664537	Hence, although ARID1A alterations have shown to be subclonal in other tumors through NGS, whether ARID1A has a role in CIC-DUX4 sarcoma development or progression is unclear and requires validation in larger cohorts and through functional studies.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('ARID1A', 'Gene', (99, 105))	('ARID1A', 'Gene', '8289', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('alterations', 'Var', (23, 34))	('tumors', 'Disease', (71, 77))	('CIC-DUX4 sarcoma', 'Disease', 'MESH:D012509', (120, 136))	('CIC-DUX4 sarcoma', 'Disease', (120, 136))	('ARID1A', 'Gene', (16, 22))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('ARID1A', 'Gene', '8289', (99, 105))
369907	27664537	Notably, other recurrent copy number alterations seen in Ewing sarcomas (1q gain, 16q loss, 12q gain, and TP53 (chr 17) deletion, were not recurrent in our limited cohort.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('loss', 'NegReg', (86, 90))	('Ewing sarcomas', 'Disease', (57, 71))	('16q', 'Var', (82, 85))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (57, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('gain', 'PosReg', (76, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('12q gain', 'Var', (92, 100))	('deletion', 'Var', (120, 128))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (57, 71))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
369908	27664537	However, case 3 showed broad 1q gain, while case 1:which showed atypical morphology:harbored deleterious TP53 mutations and CDKN2A two copy loss.	('CDKN2A', 'Gene', (124, 130))	('mutations', 'Var', (110, 119))	('CDKN2A', 'Gene', '1029', (124, 130))	('TP53', 'Gene', '7157', (105, 109))	('gain', 'PosReg', (32, 36))	('TP53', 'Gene', (105, 109))
369911	27664537	Samples 6A and 6B showed clonal copy number alterations (including chr 8 gain and 18 loss), however the primary tumor exclusively harbored a CTNNB1 E54K mutation (at subclonal variant frequency) and low level chr 17q gain (involving ETV4), supporting potentially relevant intertumoral heterogeneity.	('E54K', 'Mutation', 'p.E54K', (148, 152))	('gain', 'PosReg', (217, 221))	('CTNNB1', 'Gene', '1499', (141, 147))	('gain', 'PosReg', (73, 77))	('ETV4', 'Gene', (233, 237))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CTNNB1', 'Gene', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('loss', 'NegReg', (85, 89))	('ETV4', 'Gene', '2118', (233, 237))	('E54K', 'Var', (148, 152))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (277, 282))	('chr 17q', 'Gene', (209, 216))
369915	27664537	Likewise, although our NGS panel was designed to assess over 400 known cancer genes and is capable of detecting both mutations and CNAs, more comprehensive platforms will be needed to assess the existence of chromosomal rearrangements or recurrent mutations/focal CNAs in genes not targeted herein (e.g.	('mutations/focal', 'Var', (248, 263))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CNAs', 'Gene', (264, 268))
369919	27664537	Like Ewing sarcomas, we identify a very low mutational rate amongst a large panel of cancer related genes in CIC-DUX4 sarcomas.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (5, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (109, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('Ewing sarcomas', 'Disease', (5, 19))	('cancer', 'Disease', (85, 91))	('mutational', 'Var', (44, 54))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (5, 19))	('CIC-DUX4 sarcomas', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (5, 19))
369920	27664537	chr 8 gain) and novel alterations in CIC-DUX4 sarcomas, including copy number loss and a deleterious mutation in ARID1A (chr 1p36).	('ARID1A', 'Gene', (113, 119))	('number loss', 'Disease', (71, 82))	('CIC-DUX4 sarcomas', 'Disease', 'MESH:D012509', (37, 54))	('alterations', 'Reg', (22, 33))	('number loss', 'Disease', 'MESH:D016388', (71, 82))	('CIC-DUX4 sarcomas', 'Disease', (37, 54))	('p36', 'Gene', '51251', (126, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('p36', 'Gene', (126, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('mutation', 'Var', (101, 109))	('ARID1A', 'Gene', '8289', (113, 119))
369982	25345462	These tumors can be differentiated from histiocytic sarcoma by positivity for GFAP and synaptophysin, and negativity for histiocytic markers.	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('synaptophysin', 'Gene', '6855', (87, 100))	('sarcoma', 'Disease', (52, 59))	('GFAP', 'Gene', (78, 82))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('positivity', 'Var', (63, 73))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('GFAP', 'Gene', '2670', (78, 82))	('negativity', 'Var', (106, 116))	('synaptophysin', 'Gene', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
370140	28463396	To determine whether this association was due to a random influx of T cells into the tumor or a more organized tumor-specific infiltrate, we also tested whether clonality was associated with these staining patterns and clonality also was found to be significantly associated with both PD-1 (P = .00711) and PD-L1 (P = .00369).	('associated', 'Reg', (175, 185))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tested', 'Reg', (146, 152))	('associated', 'Reg', (264, 274))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('PD-1', 'Gene', (285, 289))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('PD-1', 'Gene', '5133', (285, 289))	('PD-L1', 'Disease', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('clonality', 'Var', (219, 228))
370143	28463396	Our analysis suggests these mutations may contribute to greater immunogenicity of this subtype, and result in the robust and more oligoclonal T-cell infiltrates observed herein.	('oligoclonal T-cell', 'Disease', 'MESH:D016399', (130, 148))	('immunogenicity', 'MPA', (64, 78))	('greater', 'PosReg', (56, 63))	('oligoclonal T-cell', 'Disease', (130, 148))	('mutations', 'Var', (28, 37))
370148	28463396	Nevertheless, we suspect that combination therapy may be necessary to treat these tumors because other investigators have suggested that immunosuppressive tumor-associated macrophages may be critical to immune evasion in these tumors.29, 41, 42 Combinations of checkpoint inhibitors with drugs aimed at depleting or modulating these cells may prove successful in providing durable responses for these patients.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('Combinations', 'Var', (245, 257))	('immunosuppressive tumor', 'Disease', (137, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('patients', 'Species', '9606', (401, 409))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (137, 160))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
370175	25500911	Cell- and Developmental Stage-Specific Dicer1 Ablation in the Lung Epithelium Models Cystic Pleuropulmonary Blastoma Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing human disease.	('Dicer1', 'Gene', '192119', (39, 45))	('Cystic Pleuropulmonary Blastoma', 'Disease', (85, 116))	('Pleuropulmonary Blastoma', 'Phenotype', 'HP:0100528', (92, 116))	('Cystic Pleuropulmonary Blastoma', 'Disease', 'MESH:C537516', (85, 116))	('Ablation', 'Var', (46, 54))	('Dicer1', 'Gene', (39, 45))	('human', 'Species', '9606', (214, 219))
370176	25500911	We previously identified germline loss-of-function DICER1 mutations in a human syndrome defined by the childhood lung neoplasm, pleuropulmonary blastoma (PPB), which arises during lung development.	('pleuropulmonary blastoma', 'Disease', (128, 152))	('mutations', 'Var', (58, 67))	('lung neoplasm', 'Disease', (113, 126))	('lung neoplasm', 'Phenotype', 'HP:0100526', (113, 126))	('DICER1', 'Gene', (51, 57))	('loss-of-function', 'NegReg', (34, 50))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('human', 'Species', '9606', (73, 78))	('lung neoplasm', 'Disease', 'MESH:D008175', (113, 126))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (128, 152))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (128, 152))
370178	25500911	Herein we report generation of a murine model for PPB and demonstrate that precise temporal and cell type-specific Dicer1 ablation is necessary and sufficient for development of cystic lungs that histologically and phenotypically model PPB.	('murine', 'Species', '10090', (33, 39))	('PPB', 'Disease', (236, 239))	('cystic lung', 'Disease', (178, 189))	('Dicer1', 'Gene', (115, 121))	('rat', 'Species', '10116', (21, 24))	('cystic lung', 'Disease', 'MESH:C563237', (178, 189))	('cystic lungs', 'Phenotype', 'HP:0005948', (178, 190))	('ablation', 'Var', (122, 130))	('cystic lung', 'Phenotype', 'HP:0005948', (178, 189))	('rat', 'Species', '10116', (65, 68))
370179	25500911	Dicer1 ablation in the distal airway epithelium during early stages of lung development resulted in a cystic lung phenotype indistinguishable from PPB whereas DICER1 function was not required for development of the proximal airway epithelium or during later stages of organogenesis.	('Dicer1', 'Gene', (0, 6))	('resulted in', 'Reg', (88, 99))	('cystic lung', 'Disease', (102, 113))	('cystic lung', 'Disease', 'MESH:C563237', (102, 113))	('ablation', 'Var', (7, 15))	('cystic lung', 'Phenotype', 'HP:0005948', (102, 113))
370181	25500911	These studies define precise temporal and epithelial cell type-specific DICER1 functions in the developing lung and demonstrate that loss of these DICER1 functions is sufficient for development of cystic PPB.	('DICER1', 'Gene', (147, 153))	('DICER1', 'Gene', (72, 78))	('cystic PPB', 'Disease', (197, 207))	('rat', 'Species', '10116', (123, 126))	('loss', 'Var', (133, 137))
370197	25500911	We identified germline loss-of-function DICER1 mutations in a human syndrome defined by inherited predisposition to PPB.	('loss-of-function', 'NegReg', (23, 39))	('human', 'Species', '9606', (62, 67))	('mutations', 'Var', (47, 56))	('PPB', 'Disease', (116, 119))	('DICER1', 'Gene', (40, 46))
370198	25500911	This represents the first described human disease with germline DICER1 mutations, making PPB an important model for studying how loss of DICER1, and the miRNAs it generates, manifests biologically in human disease.	('loss', 'Var', (129, 133))	('mutations', 'Var', (71, 80))	('human', 'Species', '9606', (200, 205))	('DICER1', 'Gene', (64, 70))	('rat', 'Species', '10116', (167, 170))	('human', 'Species', '9606', (36, 41))	('DICER1', 'Gene', (137, 143))
370199	25500911	Heterozygous germline DICER1 mutations are detected in 66% of PPB cases, demonstrating that DICER1 loss promotes PPB pathogenesis.	('rat', 'Species', '10116', (80, 83))	('mutations', 'Var', (29, 38))	('PPB', 'Disease', (113, 116))	('PPB', 'Disease', (62, 65))	('promotes', 'PosReg', (104, 112))	('loss', 'NegReg', (99, 103))	('DICER1', 'Gene', (22, 28))	('DICER1', 'Gene', (92, 98))
370205	25500911	Double transgenic Dicer1f/f or Dicer1w/w wild type mice were bred with the previously described ROSA26 reporter strain.	('mice', 'Species', '10090', (51, 55))	('ROSA26', 'Gene', '14910', (96, 102))	('Dicer1f/f', 'Var', (18, 27))	('transgenic', 'Species', '10090', (7, 17))	('ROSA26', 'Gene', (96, 102))
370219	25500911	Epithelial-specific Dicer1 ablation induced throughout lung development resulted in neonatal death (Fig.	('Dicer1', 'Gene', (20, 26))	('neonatal death', 'Disease', 'MESH:D066087', (84, 98))	('ablation', 'Var', (27, 35))	('neonatal death', 'Disease', (84, 98))	('resulted in', 'Reg', (72, 83))
370227	25500911	The finding that haploinsufficiency alone is not sufficient for PPB initiation is consistent with human carriers of DICER1 mutations not developing PPB and heterozygous germline Dicer1 null mice being viable and without lung abnormalities.	('lung abnormalities', 'Disease', 'MESH:D008171', (220, 238))	('haploinsufficiency', 'Disease', 'MESH:D058495', (17, 35))	('lung abnormalities', 'Phenotype', 'HP:0002088', (220, 238))	('DICER1', 'Gene', (116, 122))	('lung abnormalities', 'Disease', (220, 238))	('mice', 'Species', '10090', (190, 194))	('haploinsufficiency', 'Disease', (17, 35))	('human', 'Species', '9606', (98, 103))	('mutations', 'Var', (123, 132))
370228	25500911	These data demonstrate that Dicer1 ablation, but not haploinsufficiency, in the developing lung epithelium is sufficient to induce a phenotype that morphologically and phenotypically mimics cystic Type I PPB.	('rat', 'Species', '10116', (18, 21))	('haploinsufficiency', 'Disease', 'MESH:D058495', (53, 71))	('Dicer1', 'Gene', (28, 34))	('haploinsufficiency', 'Disease', (53, 71))	('cystic Type I PPB', 'Disease', (190, 207))	('cystic Type I PPB', 'Disease', 'MESH:C537516', (190, 207))	('induce', 'Reg', (124, 130))	('ablation', 'Var', (35, 43))
370230	25500911	To directly assess for potential region-specific DICER1 functions, Dicer1 deletion was targeted to the developing conducting airway epithelium by generating double transgenic Dicer1f/f mice under control of the rat Clara cell secretory protein (CCSP, Scgb1a1 or Clara cell-specific 10-kDa protein, CC10) (hereafter designated Dicer1CCSPcKO).	('Clara cell secretory protein', 'Gene', '25575', (215, 243))	('Clara cell secretory protein', 'Gene', (215, 243))	('CCSP', 'Gene', '25575', (245, 249))	('rat', 'Species', '10116', (211, 214))	('deletion', 'Var', (74, 82))	('Scgb1a1', 'Gene', (251, 258))	('mice', 'Species', '10090', (185, 189))	('CCSP', 'Gene', '25575', (332, 336))	('Dicer1f/f', 'Gene', (175, 184))	('rat', 'Species', '10116', (150, 153))	('Scgb1a1', 'Gene', '25575', (251, 258))	('Dicer1', 'Gene', (67, 73))	('CCSP', 'Gene', (245, 249))	('transgenic', 'Species', '10090', (164, 174))	('CCSP', 'Gene', (332, 336))
370232	25500911	Successful targeting of Dicer1 ablation to conducting airways was demonstrated by crossing mice into the ROSA26 reporter strain, wherein cells with functional Cre activity and their descendants are marked by beta-galactosidase expression.	('Dicer1', 'Gene', (24, 30))	('mice', 'Species', '10090', (91, 95))	('ROSA26', 'Gene', '14910', (105, 111))	('beta-galactosidase', 'Gene', (208, 226))	('beta-galactosidase', 'Gene', '12091', (208, 226))	('ROSA26', 'Gene', (105, 111))	('ablation', 'Var', (31, 39))	('rat', 'Species', '10116', (73, 76))
370237	25500911	Distal epithelial cell apoptosis was further increased in E15.5 DICER1-deficient lungs and was associated with distal tubule dilation (Fig.	('deficient lung', 'Disease', (71, 85))	('distal tubule dilation', 'MPA', (111, 133))	('deficient lung', 'Phenotype', 'HP:0002089', (71, 85))	('deficient lung', 'Disease', 'MESH:D008171', (71, 85))	('increased', 'PosReg', (45, 54))	('Distal epithelial cell apoptosis', 'CPA', (0, 32))	('E15.5', 'Var', (58, 63))	('deficient lungs', 'Phenotype', 'HP:0002089', (71, 86))	('associated', 'Reg', (95, 105))
370241	25500911	Increased epithelial cell proliferation followed the apoptotic phenotype, being initially detected at E16.5 and sustained at E18.5 (Figs.	('epithelial cell proliferation', 'CPA', (10, 39))	('E18.5', 'Var', (125, 130))	('E16.5', 'Var', (102, 107))	('rat', 'Species', '10116', (33, 36))
370243	25500911	A transient increase in proliferation was detected in E16.5 DICER1-deficient lungs but was not sustained in E18.5 lungs (Fig.	('E16.5', 'Var', (54, 59))	('proliferation', 'CPA', (24, 37))	('deficient lung', 'Phenotype', 'HP:0002089', (67, 81))	('deficient lung', 'Disease', 'MESH:D008171', (67, 81))	('increase', 'PosReg', (12, 20))	('rat', 'Species', '10116', (31, 34))	('deficient lungs', 'Phenotype', 'HP:0002089', (67, 82))	('deficient lung', 'Disease', (67, 81))
370248	25500911	In contrast, the expected ratio of double transgenic mice was obtained when Dicer1 ablation was induced during late development (10/27 (37%) vs. 50% expected; p=0.178).	('Dicer1', 'Gene', (76, 82))	('rat', 'Species', '10116', (26, 29))	('transgenic mice', 'Species', '10090', (42, 57))	('late development', 'Phenotype', 'HP:0001263', (111, 127))	('ablation', 'Var', (83, 91))
370249	25500911	Double transgenic Dicer1f/f E18.5 pups were obtained at the expected ratios for all three treatment groups, demonstrating that Dicer1 ablation in the lung epithelium resulted in early postnatal death, consistent with death being due to a lung phenotype.	('postnatal death', 'Disease', (184, 199))	('postnatal death', 'Disease', 'MESH:D003643', (184, 199))	('rat', 'Species', '10116', (115, 118))	('Dicer1', 'Gene', (127, 133))	('ablation', 'Var', (134, 142))	('rat', 'Species', '10116', (69, 72))	('transgenic', 'Species', '10090', (7, 17))
370250	25500911	Thus, the distinct lung phenotypes seen after Dicer1 ablation during early versus late lung development are due to timing of Dicer1 loss rather than differences in extent or cell types targeted for Dicer1 ablation.	('Dicer1', 'Gene', (125, 131))	('loss', 'NegReg', (132, 136))	('ablation', 'Var', (53, 61))	('rat', 'Species', '10116', (137, 140))	('Dicer1', 'Gene', (46, 52))
370254	25500911	Although these findings represent a single animal to date, the results further support that Dicer1 ablation is not sufficient to induce sustained mesenchymal proliferation characteristic of PPB progression.	('rat', 'Species', '10116', (165, 168))	('PPB', 'Gene', (190, 193))	('ablation', 'Var', (99, 107))	('Dicer1', 'Gene', (92, 98))
370255	25500911	Using in vivo genetic analyses, we demonstrate that Dicer1 ablation targeted to the developing lung epithelium results in a lung phenotype indistinguishable from cystic Type I PPB.	('results in', 'Reg', (111, 121))	('cystic Type I PPB', 'Disease', (162, 179))	('Dicer1', 'Gene', (52, 58))	('cystic Type I PPB', 'Disease', 'MESH:C537516', (162, 179))	('lung phenotype', 'MPA', (124, 138))	('ablation', 'Var', (59, 67))	('rat', 'Species', '10116', (42, 45))
370258	25500911	Together, these data demonstrate that Dicer1 ablation in the developing airway epithelium results in cystic lungs that model the earliest stage of PPB.	('cystic lung', 'Disease', 'MESH:C563237', (101, 112))	('Dicer1', 'Gene', (38, 44))	('cystic lungs', 'Phenotype', 'HP:0005948', (101, 113))	('rat', 'Species', '10116', (28, 31))	('cystic lung', 'Phenotype', 'HP:0005948', (101, 112))	('ablation', 'Var', (45, 53))	('cystic lung', 'Disease', (101, 112))	('results in', 'Reg', (90, 100))
370261	25500911	DICER1 expression was lost in PPB-associated epithelium but retained in the tumor mesenchyme, and Dicer1 ablation targeted to the developing lung epithelium resulted in a cystic PPB phenotype, providing direct evidence that epithelial-specific Dicer1 loss is sufficient for PPB initiation.	('Dicer1', 'Gene', (98, 104))	('cystic PPB phenotype', 'MPA', (171, 191))	('ablation', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Dicer1', 'Gene', (244, 250))	('resulted in', 'Reg', (157, 168))	('loss', 'NegReg', (251, 255))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
370262	25500911	Although Dicer1 ablation in the lung epithelium induced mesenchymal expansion, epithelial Dicer1 loss did not lead to sustained mesenchymal proliferation, septal overgrowth and cellular anaplasia that indicate sarcomatous progression.	('loss', 'NegReg', (97, 101))	('sarcomatous', 'Disease', (210, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('septal overgrowth', 'CPA', (155, 172))	('Dicer1', 'Gene', (90, 96))	('ablation', 'Var', (16, 24))	('mesenchymal expansion', 'CPA', (56, 77))	('overgrowth', 'Phenotype', 'HP:0001548', (162, 172))	('anaplasia', 'Disease', 'MESH:D000708', (186, 195))	('anaplasia', 'Disease', (186, 195))	('rat', 'Species', '10116', (147, 150))	('sarcomatous', 'Disease', 'MESH:D018316', (210, 221))
370264	25500911	Of note, the mesenchyme in the current mouse models is not haploinsufficient for DICER1; thus the mice may be less susceptible to sarcomatous transformation than humans with heterozygous germline loss of function DICER1 mutations.	('DICER1', 'Gene', (213, 219))	('loss of', 'NegReg', (196, 203))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (130, 156))	('sarcomatous', 'Disease', 'MESH:D018316', (130, 141))	('humans', 'Species', '9606', (162, 168))	('haploinsufficient', 'Disease', 'MESH:D058495', (59, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('less', 'NegReg', (110, 114))	('sarcomatous', 'Disease', (130, 141))	('haploinsufficient', 'Disease', (59, 76))	('mouse', 'Species', '10090', (39, 44))	('mutations', 'Var', (220, 229))	('mice', 'Species', '10090', (98, 102))
370265	25500911	However, mesenchymal transformation to high grade sarcoma in both hereditary and sporadic PPB is associated with biallelic DICER1 mutations in mesenchymal cells, consisting predominantly of germline loss of function mutations and somatic missense mutations in the RNase IIIb domain, that lead to defects in 5p miRNA generation.	('PPB', 'Disease', (90, 93))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('5p miRNA generation', 'MPA', (307, 326))	('mesenchymal transformation', 'CPA', (9, 35))	('sarcoma', 'Disease', (50, 57))	('loss of function', 'NegReg', (199, 215))	('defects', 'NegReg', (296, 303))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('mutations', 'Var', (130, 139))	('mutations', 'Var', (216, 225))	('missense mutations', 'Var', (238, 256))	('rat', 'Species', '10116', (320, 323))	('DICER1', 'Gene', (123, 129))
370266	25500911	Biallelic p53 inactivation is also found in the majority of cases.	('Biallelic', 'Var', (0, 9))	('p53', 'Gene', '22059', (10, 13))	('p53', 'Gene', (10, 13))	('inactivation', 'Var', (14, 26))
370267	25500911	These data support a model for PPB pathogenesis wherein DICER1 loss in the developing lung epithelium results in PPB initiation, followed by acquisition of additional genetic mutations altering DICER1 RNase IIIb and/or p53 function in the mesenchymal cells, resulting in progression to sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (286, 293))	('DICER1', 'Gene', (56, 62))	('altering', 'Reg', (185, 193))	('sarcoma', 'Disease', (286, 293))	('RNase IIIb', 'Enzyme', (201, 211))	('p53', 'Gene', '22059', (219, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (286, 293))	('progression', 'PosReg', (271, 282))	('DICER1', 'Gene', (194, 200))	('PPB', 'Disease', (113, 116))	('function', 'MPA', (223, 231))	('mutations', 'Var', (175, 184))	('loss', 'NegReg', (63, 67))	('p53', 'Gene', (219, 222))
370270	25500911	Germline DICER1 loss of function mutations and somatic 'hotspot' missense mutations in the DICER1 RNase IIIb domain seen in PPB are also detected in cystic nephromas and Sertoli-Leydig cell tumors, supporting similar tumor pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('cystic nephromas', 'Disease', (149, 165))	('PPB', 'Gene', (124, 127))	('cystic nephromas', 'Disease', 'MESH:D018201', (149, 165))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('DICER1', 'Gene', (9, 15))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (190, 195))	('missense mutations', 'Var', (65, 83))	('DICER1', 'Gene', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (178, 196))	('loss of function', 'NegReg', (16, 32))	('Sertoli-Leydig cell tumors', 'Disease', (170, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (170, 196))
370275	25500911	This phenotypic progression differs from the lung phenotype reported after Dicer1 ablation induced by Sonic Hedgehog (Shh)-promoted Cre, that consisted of arrested branching morphogenesis resulting in large pouches lined by a heterogeneous epithelium detached from the underlying mesenchyme and characterized as stratified, pseudostratified and simple columnar epithelium, suggesting divergent proximal conducting and distal respiratory epithelial differentiation.	('Sonic Hedgehog', 'Gene', '20423', (102, 116))	('rat', 'Species', '10116', (314, 317))	('Shh', 'Gene', '20423', (118, 121))	('ablation', 'Var', (82, 90))	('rat', 'Species', '10116', (332, 335))	('Sonic Hedgehog', 'Gene', (102, 116))	('rat', 'Species', '10116', (430, 433))	('Dicer1', 'Gene', (75, 81))	('Shh', 'Gene', (118, 121))
370278	25500911	Shh-induced Dicer1 ablation is not restricted to the lung and occurs earlier in foregut development, before lung initiation.	('Dicer1', 'Gene', (12, 18))	('ablation', 'Var', (19, 27))	('Shh', 'Gene', '20423', (0, 3))	('Shh', 'Gene', (0, 3))
370279	25500911	Additionally, Dicer1 ablation in the Shh model is accompanied by loss of one wild-type Shh allele.	('Shh', 'Gene', '20423', (87, 90))	('Shh', 'Gene', (37, 40))	('Dicer1', 'Gene', (14, 20))	('Shh', 'Gene', '20423', (37, 40))	('ablation', 'Var', (21, 29))	('Shh', 'Gene', (87, 90))
370283	25500911	Early lethality of germline Dicer1-/- embryos combined with the failure to observe Dicer1 null tumors and homozygous DICER1 loss-of-function alterations in murine models and human tumors, respectively, led to the notion that DICER1 is essential for tumor formation and may be required for cell survival.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('DICER1', 'Gene', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('Dicer1', 'Gene', (83, 89))	('tumor', 'Disease', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('human', 'Species', '9606', (174, 179))	('murine', 'Species', '10090', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('rat', 'Species', '10116', (145, 148))	('tumor', 'Disease', (95, 100))	('alterations', 'Var', (141, 152))	('tumor', 'Disease', (180, 185))	('loss-of-function', 'NegReg', (124, 140))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
370352	24179411	The incidence of osteosarcoma is increased in several genetic disorders associated with genetic mutations of tumor suppressor genes.	('osteosarcoma', 'Disease', (17, 29))	('genetic mutations', 'Var', (88, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (17, 29))	('genetic disorders', 'Disease', (54, 71))	('associated', 'Reg', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('increased', 'PosReg', (33, 42))	('genetic disorders', 'Disease', 'MESH:D030342', (54, 71))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('tumor', 'Disease', (109, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))
370354	24179411	Osteosarcoma has great chromosomal complexity, with numerous chromosome and gene alterations resulting in various molecular pathway changes.	('changes', 'Reg', (132, 139))	('resulting in', 'Reg', (93, 105))	('molecular pathway', 'Pathway', (114, 131))	('Osteosarcoma', 'Disease', (0, 12))	('alterations', 'Var', (81, 92))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))
370380	24179411	When the tumor invades the cervical region, the cervical roots (and the Th1) at this area are functionally important; in contrast, for osteosarcoma in the thoracic and thoracolumbar regions damage to these nerves causes less significant neurologic impairment and a solely posterior approach may be enough for en-block resection of the tumor.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('neurologic impairment', 'Disease', (237, 258))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('osteosarcoma', 'Disease', (135, 147))	('Th1', 'Gene', (72, 75))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('damage', 'Var', (190, 196))	('neurologic impairment', 'Disease', 'MESH:D009422', (237, 258))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('osteosarcoma', 'Disease', 'MESH:D012516', (135, 147))	('Th1', 'Gene', '51497', (72, 75))	('tumor', 'Disease', (335, 340))
370401	24179411	Heavy charged particles have also been thought to be advantageous, since there appears to be an increased energy deposition in the abnormal tissue; they have thus been used for the treatment of sarcomas, with promising results.	('increased', 'PosReg', (96, 105))	('energy deposition in', 'MPA', (106, 126))	('sarcomas', 'Disease', 'MESH:D012509', (194, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('Heavy charged', 'Var', (0, 13))	('sarcomas', 'Disease', (194, 202))	('abnormal tissue', 'Phenotype', 'HP:0002664', (131, 146))
370488	33409103	CD99 along with positive staining for cytokeratin, mainly CK5/6, and strong diffuse positivity for p63 and p40 are evident in tumor cells.	('CD99', 'Var', (0, 4))	('p63', 'Var', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('p40', 'Var', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
370492	33409103	Immunohistochemical staining showed positivity of tumor cells for P16, CK5/6, CK8/18, P63, CD99 (strong and diffuse membranous staining), PGP9.5, and focally for CK20, chromogranin and CD56.	('P16', 'Var', (66, 69))	('CD99', 'Gene', (91, 95))	('CD56', 'Gene', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('P63', 'Var', (86, 89))	('PGP9.5', 'Gene', (138, 144))	('CK8/18', 'Var', (78, 84))	('CK20', 'Var', (162, 166))	('CK5/6', 'Gene', (71, 76))	('chromogranin', 'Protein', (168, 180))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
370520	33409103	These tumors also harbor translocations involving the EWSR1 gene with WT1 as a fusion partner, which can be detected by RT-PCR.	('harbor', 'Reg', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('EWSR1', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('translocations', 'Var', (25, 39))
370617	32358363	However, in our study, no nuclear staining for p-Akt (serine 473)/p-mTOR (serine 2448) was performed.	('serine', 'Chemical', 'MESH:D012694', (54, 60))	('mTOR', 'Gene', '2475', (68, 72))	('serine 2448', 'Var', (74, 85))	('mTOR', 'Gene', (68, 72))	('Akt', 'Gene', '207', (49, 52))	('serine 473', 'Var', (54, 64))	('serine', 'Chemical', 'MESH:D012694', (74, 80))	('Akt', 'Gene', (49, 52))
370622	32358363	The absence of CD117 (ckit) and CD34, along with atypical clinical manifestations, eliminates GIST.	('GIST', 'Phenotype', 'HP:0100723', (94, 98))	('CD34', 'Gene', (32, 36))	('CD117', 'Gene', '3815', (15, 20))	('GIST', 'MPA', (94, 98))	('CD117', 'Gene', (15, 20))	('absence', 'Var', (4, 11))	('eliminates', 'NegReg', (83, 93))
370635	30397176	The combination of CDK4/6 and IGF1R inhibitors were synergistic in vitro and active in mouse models.	('IGF1R', 'Gene', (30, 35))	('CDK4/6', 'Protein', (19, 25))	('inhibitors', 'Var', (36, 46))	('mouse', 'Species', '10090', (87, 92))
370641	30397176	A drug class that has gained traction in multiple adult malignancies is inhibitors against cyclin-dependent kinase (CDK)4/6.	('cyclin', 'Gene', '5111', (91, 97))	('cyclin', 'Gene', (91, 97))	('CDK)4/6', 'Gene', '1019;1021', (116, 123))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('inhibitors', 'Var', (72, 82))	('malignancies', 'Disease', (56, 68))
370643	30397176	In this disease, CDK4/6 overexpression, as well as CCND1 amplification, are frequent driver events and were found to underlie resistance to estrogen receptor (ER) antagonists, a backbone of HR+ breast cancer treatment.	('underlie', 'Reg', (117, 125))	('estrogen receptor', 'Gene', (140, 157))	('CCND1', 'Gene', (51, 56))	('estrogen receptor', 'Gene', '2099', (140, 157))	('amplification', 'Var', (57, 70))	('CCND1', 'Gene', '595', (51, 56))	('ER', 'Gene', '2099', (159, 161))	('resistance', 'MPA', (126, 136))	('overexpression', 'PosReg', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('CDK4/6', 'Gene', (17, 23))	('HR+ breast cancer', 'Disease', (190, 207))	('HR+ breast cancer', 'Disease', 'MESH:D001943', (190, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
370645	30397176	CDK4/6 inhibitors have subsequently been found to have efficacy for patients with liposarcoma, who frequently have CDK4 amplifications, as well as for patients with KRAS mutant non-small cell lung cancer (NSCLC).	('amplifications', 'Var', (120, 134))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (177, 203))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('CDK4', 'Gene', (115, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('liposarcoma', 'Disease', (82, 93))	('non-small cell lung cancer', 'Disease', (177, 203))	('patients', 'Species', '9606', (68, 76))	('NSCLC', 'Disease', (205, 210))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('CDK4', 'Gene', '1019', (115, 119))	('CDK4', 'Gene', (0, 4))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (177, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('liposarcoma', 'Phenotype', 'HP:0012034', (82, 93))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (181, 203))	('KRAS', 'Gene', '3845', (165, 169))	('patients', 'Species', '9606', (151, 159))	('liposarcoma', 'Disease', 'MESH:D008080', (82, 93))	('CDK4', 'Gene', '1019', (0, 4))	('KRAS', 'Gene', (165, 169))
370651	30397176	Despite our own and others' investigation of CDK4/6 inhibitors in preclinical models of Ewing sarcoma, CDK4/6 inhibitors have yet to be tested in clinical trials in children with this disease.	('children', 'Species', '9606', (165, 173))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('inhibitors', 'Var', (52, 62))	('CDK4/6', 'Gene', (45, 51))	('Ewing sarcoma', 'Disease', (88, 101))
370652	30397176	In addition to Ewing sarcoma data, there is pre-clinical data supporting the activity of CDK4/6 inhibitors in rhabdomyosarcoma, neuroblastoma, as well as T-ALL.	('neuroblastoma', 'Disease', 'MESH:D009447', (128, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (15, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (15, 28))	('neuroblastoma', 'Disease', (128, 141))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (110, 126))	('neuroblastoma', 'Phenotype', 'HP:0003006', (128, 141))	('CDK4/6', 'Gene', (89, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('activity', 'MPA', (77, 85))	('inhibitors', 'Var', (96, 106))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (110, 126))	('rhabdomyosarcoma', 'Disease', (110, 126))	('Ewing sarcoma', 'Disease', (15, 28))
370654	30397176	CDK4/6 inhibitors typically induce cell cycle arrest rather than cell death.	('CDK4/6', 'Protein', (0, 6))	('induce', 'Reg', (28, 34))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('inhibitors', 'Var', (7, 17))	('cell death', 'CPA', (65, 75))	('arrest', 'Disease', (46, 52))
370657	30397176	In the case of CDK4/6 inhibitors, acquired resistance has been observed both in pre-clinical models and in patient samples through mechanisms such as inactivating mutations in RB1, a tumor suppressor whose function is required for the activity of CDK4/6 inhibitors.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('RB1', 'Gene', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('RB1', 'Gene', '5925', (176, 179))	('tumor', 'Disease', (183, 188))	('patient', 'Species', '9606', (107, 114))	('inactivating mutations', 'Var', (150, 172))
370685	30397176	2217), p-Ser240/244-S6 Ribosomal Protein (Cell Signaling Technology 2215), p-Ser235/236-S6 Ribomal Protein (Cell Signaling Technology Cat.	('Ser240', 'Chemical', '-', (9, 15))	('Ser235', 'Chemical', '-', (77, 83))	('p-Ser235/236-S6', 'Var', (75, 90))	('p-Ser240/244-S6', 'Var', (7, 22))
370690	30397176	9662), cleaved caspase 3 (Cell Signaling Technology Cat.	('caspase 3', 'Gene', '836', (15, 24))	('caspase 3', 'Gene', (15, 24))	('cleaved', 'Var', (7, 14))
370694	30397176	TC32 and SKNEP1 Ewing sarcoma cells were grown in 6-well plates at a starting density of 100-400k cells per well and, 24 hours after plating, were treated with 1 muM AEW541, 1 muM ribociclib, a combination of 1 muM AEW541 and 1 muM ribociclib, or DMSO controls.	('Ewing sarcoma', 'Disease', (16, 29))	('AEW541', 'Chemical', '-', (166, 172))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('AEW541', 'Chemical', '-', (215, 221))	('muM', 'Gene', '56925', (162, 165))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (16, 29))	('muM', 'Gene', '56925', (176, 179))	('muM', 'Gene', '56925', (211, 214))	('muM', 'Gene', '56925', (228, 231))	('DMSO', 'Chemical', 'MESH:D004121', (247, 251))	('muM', 'Gene', (176, 179))	('muM', 'Gene', (162, 165))	('AEW541', 'Var', (166, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('muM', 'Gene', (211, 214))	('muM', 'Gene', (228, 231))	('TC32', 'CellLine', 'CVCL:7151', (0, 4))
370697	30397176	Ewing sarcoma cells lines were assessed for cell death after single or combined small-molecule treatment at 120 hours post-treatment.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('small-molecule', 'Var', (80, 94))
370702	30397176	When tumors measured 100-150 mm3, mice were divided into four groups: vehicle control, AEW541, ribociclib, and AEW541 and ribociclib in combination.	('AEW541', 'Chemical', '-', (87, 93))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('mice', 'Species', '10090', (34, 38))	('AEW541', 'Var', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('AEW541', 'Var', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('AEW541', 'Chemical', '-', (111, 117))
370708	30397176	We validated this finding by CRISPR knockout of CDK4 in the Ewing sarcoma cell line A673 and demonstrated marked impairment in cell growth (Figure 1B-C).	('knockout', 'Var', (36, 44))	('CDK4', 'Gene', '1019', (48, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (60, 73))	('cell growth', 'CPA', (127, 138))	('impairment', 'NegReg', (113, 123))	('Ewing sarcoma', 'Disease', (60, 73))	('CDK4', 'Gene', (48, 52))
370709	30397176	CDK4/6 inhibitors have efficacy in HR+ breast cancer and have been FDA-approved for up-front therapy in combination with ER antagonists in this disease.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('CDK4/6', 'Protein', (0, 6))	('ER', 'Gene', '2099', (121, 123))	('HR+ breast cancer', 'Disease', (35, 52))	('inhibitors', 'Var', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('HR+ breast cancer', 'Disease', 'MESH:D001943', (35, 52))
370714	30397176	As has been extensively reported in pre-clinical breast cancer studies, CDK4/6 inhibitors are generally ineffective as single agents, where acquired resistance is observed via mechanisms such as the loss of RB1, amplification or upregulation of other CDKs leading to alternative cell cycle entry, or activation of growth signaling pathways, such as PI3K/AKT.	('CDKs', 'Gene', '983;1017;1019;12567;1021;12571;1022;51755', (251, 255))	('amplification', 'PosReg', (212, 225))	('loss', 'Var', (199, 203))	('AKT', 'Gene', (354, 357))	('upregulation', 'PosReg', (229, 241))	('CDKs', 'Gene', (251, 255))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('RB1', 'Gene', (207, 210))	('growth signaling pathways', 'Pathway', (314, 339))	('alternative cell cycle entry', 'CPA', (267, 295))	('breast cancer', 'Disease', (49, 62))	('RB1', 'Gene', '5925', (207, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('AKT', 'Gene', '207', (354, 357))	('activation', 'PosReg', (300, 310))
370721	30397176	After confirmation of overexpression of IGF1R by immunoblotting (Figure 1F), we combined each IGF1R ORF-infected cell population with TC32 cells infected with a GFP control ORF in a 1:1 ratio.	('IGF1R', 'Gene', (94, 99))	('TC32', 'CellLine', 'CVCL:7151', (134, 138))	('ORF-infected', 'Var', (100, 112))
370727	30397176	Importantly, as acquired RB1 mutations are observed in resistance to CDK4/6 inhibitors, we confirmed that phospho and total Rb expression were still present by immunoblotting in SKNEP1-R cells.	('RB1', 'Gene', (25, 28))	('mutations', 'Var', (29, 38))	('Rb', 'Chemical', 'MESH:D012413', (124, 126))	('RB1', 'Gene', '5925', (25, 28))
370733	30397176	Importantly, whole exome sequencing of the SKNEP1-R line revealed no mutations in RB1 or IGF1R, and no copy number changes in any of the upregulated cyclin/CDK proteins compared with parental SKNEP1 (Supplemental Figure 1C, Supplemental Table 3).	('mutations', 'Var', (69, 78))	('cyclin', 'Gene', (149, 155))	('RB1', 'Gene', '5925', (82, 85))	('upregulated', 'PosReg', (137, 148))	('IGF1R', 'Gene', (89, 94))	('RB1', 'Gene', (82, 85))	('cyclin', 'Gene', '5111', (149, 155))
370744	30397176	As these well-established cell lines have been highly passaged in vitro, we also tested these combinations in two newly derived, minimally passaged Ewing sarcoma cell lines (CCLF_PEDS_0009_T and CCLF_PEDS_0010_T), which were confirmed to express Rb by western immunoblotting and the EWS/FLI fusion by RT-PCR (Supplemental Figure 2).	('FLI', 'Gene', '2314', (287, 290))	('Rb', 'Chemical', 'MESH:D012413', (246, 248))	('CCLF_PEDS_0009_T', 'Var', (174, 190))	('tested', 'Reg', (81, 87))	('CCLF_PEDS_0010_T', 'Var', (195, 211))	('FLI', 'Gene', (287, 290))	('Ewing sarcoma', 'Disease', (148, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (148, 161))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (148, 161))
370750	30397176	As there is interest in the combination of PI3K inhibitors with CDK4/6 inhibitors in other malignancies, and as we found that PI3K and mTOR inhibitors also scored as synergistic with CDK4/6 inhibitors in our chemical library screen, we tested GDC0941, a combined PI3K/mTOR inhibitor, in combination with ribociclib in a subset of these cell lines and observed synergy.	('mTOR', 'Gene', '2475', (268, 272))	('malignancies', 'Disease', (91, 103))	('mTOR', 'Gene', (268, 272))	('tested', 'Reg', (236, 242))	('mTOR', 'Gene', '2475', (135, 139))	('mTOR', 'Gene', (135, 139))	('GDC0941', 'Var', (243, 250))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('GDC0941', 'Chemical', 'MESH:C532162', (243, 250))
370755	30397176	We next performed cell cycle analysis by propidium iodide staining with flow cytometry where we observed a G1 arrest with ribociclib treatment but an increase in the sub-G0 peak in the combination treatment consistent with cell death (Figure 4B).	('ribociclib', 'Var', (122, 132))	('arrest', 'Disease', 'MESH:D006323', (110, 116))	('sub-G0 peak', 'MPA', (166, 177))	('arrest', 'Disease', (110, 116))	('increase', 'PosReg', (150, 158))	('propidium iodide', 'Chemical', 'MESH:D011419', (41, 57))
370772	30397176	Given the strong synergy observed in vitro, we next tested AEW541 in combination with ribociclib in an A673 cell line xenograft, an aggressive model of Ewing sarcoma frequently used for in vivo studies.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (152, 165))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('AEW541', 'Var', (59, 65))	('tested', 'Reg', (52, 58))	('Ewing sarcoma', 'Disease', (152, 165))	('AEW541', 'Chemical', '-', (59, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
370797	30397176	We have observed this in Ewing sarcoma in vitro, where there is predominantly cell cycle arrest with ribociclib treatment, as well as in vivo, where growth is attenuated; however, there is no tumor shrinkage.	('arrest', 'Disease', (89, 95))	('tumor', 'Disease', (192, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Ewing sarcoma', 'Disease', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('ribociclib', 'Var', (101, 111))	('arrest', 'Disease', 'MESH:D006323', (89, 95))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (25, 38))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (25, 38))
370803	30397176	In the case of IGF1R inhibitors, durable responses have been observed in patients with Ewing sarcoma; however, biomarkers of response have been elusive.	('IGF1R', 'Gene', (15, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('inhibitors', 'Var', (21, 31))	('Ewing sarcoma', 'Disease', (87, 100))	('patients', 'Species', '9606', (73, 81))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (87, 100))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (87, 100))
370806	30397176	To our knowledge, however, there have been no described loss-of-function events and no recurrent copy number alterations involving RB1 in primary Ewing sarcoma patient tumors, suggesting that this mechanism of intrinsic resistance is unlikely to be a roadblock for advancing these compounds in Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (146, 159))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (146, 159))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (294, 307))	('RB1', 'Gene', (131, 134))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (294, 307))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (300, 307))	('RB1', 'Gene', '5925', (131, 134))	('alterations', 'Var', (109, 120))	('Ewing sarcoma', 'Disease', (146, 159))	('patient', 'Species', '9606', (160, 167))	('Ewing sarcoma', 'Disease', (294, 307))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
370808	30397176	In addition, as previously reported in breast cancer, deletion of CDKN2A, the negative regulator of the cyclin D1/CDK4/6 axis, which is seen in a large subset of Ewing sarcoma, is also not correlated with differential sensitivity to CDK4/6 inhibitors in our data.	('cyclin D1', 'Gene', '595', (104, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (162, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (162, 175))	('cyclin D1', 'Gene', (104, 113))	('deletion', 'Var', (54, 62))	('CDKN2A', 'Gene', '1029', (66, 72))	('Ewing sarcoma', 'Disease', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('CDKN2A', 'Gene', (66, 72))	('breast cancer', 'Disease', (39, 52))
370810	30397176	Further, the combination of CDK4/6 inhibitors and IGF1R inhibitors is synergistic in pre-clinical models of this disease, leading to enhanced cell death in vitro and prolongation of survival in xenograft models of Ewing sarcoma, including PDXs.	('prolongation', 'PosReg', (166, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (214, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('IGF1R', 'Gene', (50, 55))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (214, 227))	('survival', 'CPA', (182, 190))	('inhibitors', 'Var', (56, 66))	('CDK4/6', 'Gene', (28, 34))	('PDXs', 'Disease', (239, 243))	('enhanced', 'PosReg', (133, 141))	('Ewing sarcoma', 'Disease', (214, 227))	('cell death', 'CPA', (142, 152))
370815	30397176	Thus, combination therapies that can enhance this known, measured effect of IGF1R inhibitors are of interest, making the results of this study of particular interest to the Ewing sarcoma clinical community.	('Ewing sarcoma', 'Disease', (173, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (173, 186))	('inhibitors', 'Var', (82, 92))	('IGF1R', 'Gene', (76, 81))
370816	30397176	Though there has been longstanding interest in IGF1R inhibitors in Ewing sarcoma, and while IGF1R and CDK4/6 inhibitors have been studied individually in this disease, there have been no prior reports of this combination of agents in Ewing sarcoma.	('inhibitors', 'Var', (53, 63))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('IGF1R', 'Gene', (47, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('Ewing sarcoma', 'Disease', (234, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (234, 247))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (234, 247))	('Ewing sarcoma', 'Disease', (67, 80))
370830	30397176	Furthermore, we established synergy between IGF1R inhibitors and CDK4/6 inhibitors in vitro, as well as in vivo, in Ewing sarcoma cell line and patient-derived xenograft (PDX) models.	('Ewing sarcoma', 'Disease', (116, 129))	('inhibitors', 'Var', (50, 60))	('IGF1R', 'Gene', (44, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('patient', 'Species', '9606', (144, 151))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('CDK4/6', 'Gene', (65, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
370844	29900014	After cycle 2 of IE, while receiving supportive hydration and antiemetics in the outpatient setting, Ms. M was found to have anisocoria (unequal pupil size; Figure 1), with a fully dilated, unreactive right pupil without ptosis (drooping of the upper eyelid), diplopia, pain or impaired extraocular movement, or other neurologic changes.	('impaired extraocular movement', 'Disease', (278, 307))	('outpatient', 'Species', '9606', (81, 91))	('ptosis', 'Phenotype', 'HP:0000508', (221, 227))	('Ms. M', 'Var', (101, 106))	('diplopia', 'Disease', 'MESH:D004172', (260, 268))	('pain', 'Phenotype', 'HP:0012531', (270, 274))	('ptosis', 'Disease', 'MESH:C564553', (221, 227))	('pain', 'Disease', 'MESH:D010146', (270, 274))	('anisocoria', 'Phenotype', 'HP:0009916', (125, 135))	('diplopia', 'Disease', (260, 268))	('pain', 'Disease', (270, 274))	('diplopia', 'Phenotype', 'HP:0000651', (260, 268))	('drooping of the upper eyelid', 'Phenotype', 'HP:0000508', (229, 257))	('unequal pupil', 'Phenotype', 'HP:0009916', (137, 150))	('neurologic changes', 'Phenotype', 'HP:0000707', (318, 336))	('anisocoria', 'Disease', (125, 135))	('ptosis', 'Disease', (221, 227))	('impaired extraocular movement', 'Disease', 'MESH:D009069', (278, 307))
370916	27307968	The sorafenib and anti-VEGF combination potentiates the effect of each component.	('sorafenib', 'Chemical', 'MESH:D000077157', (4, 13))	('potentiates', 'PosReg', (40, 51))	('combination', 'Var', (28, 39))	('VEGF', 'Gene', (23, 27))	('VEGF', 'Gene', '7422', (23, 27))
370959	26579494	Immunostimulation by OX40 Ligand Transgenic Ewing Sarcoma Cells Interleukin-2 (IL-2) transgenic Ewing sarcoma cells can induce tumor specific T and NK cell responses and reduce tumor growth in vivo and in vitro.	('OX40', 'Gene', (21, 25))	('Transgenic Ewing Sarcoma', 'Disease', 'MESH:C563168', (33, 57))	('OX40', 'Gene', '22163', (21, 25))	('Transgenic Ewing Sarcoma', 'Disease', (33, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('Interleukin-2', 'Gene', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('induce', 'PosReg', (120, 126))	('tumor', 'Disease', (177, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Interleukin-2', 'Gene', '16183', (64, 77))	('IL-2', 'Gene', '16183', (79, 83))	('IL-2', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('transgenic', 'Var', (85, 95))	('Ewing sarcoma', 'Disease', (96, 109))	('reduce', 'NegReg', (170, 176))	('tumor', 'Disease', (127, 132))	('transgenic', 'Species', '10090', (85, 95))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (44, 57))	('Sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
370963	26579494	In the present investigation, we generated OX40L transgenic Ewing sarcoma cells and tested their immunostimulatory activity in vitro.	('tested', 'Reg', (84, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('OX40L transgenic', 'Var', (43, 59))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (60, 73))	('Ewing sarcoma', 'Disease', (60, 73))	('transgenic', 'Species', '10090', (49, 59))
370965	26579494	OX40L-expressing tumor cells showed a trend for enhanced immune stimulation against Ewing sarcoma cells in combination with IL-2 and stimulation of CD137.	('Ewing sarcoma', 'Disease', (84, 97))	('tumor', 'Disease', (17, 22))	('IL-2', 'Gene', '16183', (124, 128))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('enhanced', 'PosReg', (48, 56))	('IL-2', 'Gene', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('immune stimulation', 'MPA', (57, 75))	('OX40L-expressing', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
370976	26579494	We demonstrated that interleukin-2 (IL-2) transgenic EFT cells can induce immune responses against wild-type tumor cells in vitro and in a xenotransplantation model.	('interleukin-2', 'Gene', (21, 34))	('transgenic', 'Var', (42, 52))	('IL-2', 'Gene', '16183', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('interleukin-2', 'Gene', '16183', (21, 34))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IL-2', 'Gene', (36, 40))	('induce', 'PosReg', (67, 73))	('transgenic', 'Species', '10090', (42, 52))	('immune responses', 'CPA', (74, 90))	('tumor', 'Disease', (109, 114))
370983	26579494	OX40 (CD134) and CD137 (4-1BB) and their ligands OX40L (CD252) and 4-1BBL are examples of such co-stimulatory molecules.	('CD137', 'Var', (17, 22))	('CD134', 'Gene', '22163', (6, 11))	('CD134', 'Gene', (6, 11))
370994	26579494	Activation of the OX40 receptor by OX40L or an agonistic antibody leads to increased expression of antiapoptotic molecules and reduced expression of the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA4).	('reduced', 'NegReg', (127, 134))	('CTLA4', 'Gene', '12477', (198, 203))	('expression of antiapoptotic molecules', 'MPA', (85, 122))	('expression', 'MPA', (135, 145))	('cytotoxic T-lymphocyte antigen 4', 'Gene', '12477', (164, 196))	('increased', 'PosReg', (75, 84))	('OX40L', 'Var', (35, 40))	('CTLA4', 'Gene', (198, 203))	('cytotoxic T-lymphocyte antigen 4', 'Gene', (164, 196))
371019	26579494	We transfected cells from the Ewing sarcoma cell lines A673 and SK-N-MC with OX40L in vector pIRES2-eGFP.	('Ewing sarcoma', 'Disease', (30, 43))	('OX40L', 'Var', (77, 82))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (30, 43))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (30, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('SK-N-MC', 'CellLine', 'CVCL:0530', (64, 71))
371024	26579494	OX40L transgenic Ewing sarcoma cells showed the same gene expression pattern as wild-type cells or mock-transfected cells (Figure 3).	('Ewing sarcoma', 'Disease', (17, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (17, 30))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (17, 30))	('OX40L transgenic', 'Var', (0, 16))	('transgenic', 'Species', '10090', (6, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))
371030	26579494	As expected, the presence of interleukin 2 increased the number of cells that reacted with the sarcoma cells.	('interleukin 2', 'Gene', '16183', (29, 42))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('presence', 'Var', (17, 25))	('interleukin 2', 'Gene', (29, 42))	('increased', 'PosReg', (43, 52))	('sarcoma', 'Disease', (95, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))
371031	26579494	In combination with interleukin 2, OX40L-transfected A673 cells marginally increased the reactivity of the primed cells compared to mock-transfected cells.	('interleukin 2', 'Gene', (20, 33))	('OX40L-transfected', 'Var', (35, 52))	('interleukin 2', 'Gene', '16183', (20, 33))	('increased', 'PosReg', (75, 84))	('reactivity', 'MPA', (89, 99))
371032	26579494	In the presence of interleukin 2, the combination of anti-CD137 stimulation and OX40L transfected cells showed significantly enhanced immune stimulation in comparison to anti-CD137 antibodies or OX40L-transfected cells alone.	('immune stimulation', 'MPA', (134, 152))	('interleukin 2', 'Gene', '16183', (19, 32))	('anti-CD137', 'Var', (53, 63))	('interleukin 2', 'Gene', (19, 32))	('enhanced', 'PosReg', (125, 133))
371033	26579494	The combination of OX40L transgenic cells with 4-1BBL transgenic cells showed a trend for higher stimulatory activity compared to 4-1BBL transgenic cells alone (Figure 4).	('OX40L transgenic', 'Var', (19, 35))	('transgenic', 'Species', '10090', (54, 64))	('stimulatory activity', 'MPA', (97, 117))	('transgenic', 'Species', '10090', (25, 35))	('transgenic', 'Species', '10090', (137, 147))	('higher', 'PosReg', (90, 96))
371034	26579494	After priming in the presence of OX40L transgenic A673 cells, the cells showed a higher specificity for A673 cells than for SK-N-MC cells or the neuroblastoma cell line SH-SY5Y (Figure 5).	('neuroblastoma', 'Disease', (145, 158))	('higher', 'PosReg', (81, 87))	('SK-N-MC', 'CellLine', 'CVCL:0530', (124, 131))	('transgenic', 'Species', '10090', (39, 49))	('neuroblastoma', 'Phenotype', 'HP:0003006', (145, 158))	('A673', 'Var', (50, 54))	('OX40L transgenic A673', 'Var', (33, 54))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (169, 176))	('A673', 'Var', (104, 108))	('neuroblastoma', 'Disease', 'MESH:D009447', (145, 158))	('specificity', 'MPA', (88, 99))
371039	26579494	For instance, the tumor microenvironment can reduce activation of T cells, tumor cells can escape immune recognition by downregulation of tumor-associated antigens or antigen-presenting HLA molecules, tumor cells can produce antigen-loss variants, tumor cells can secrete immunosuppressive factors (e.g., indoleamine-2,3-dioxygenase), and co-stimulatory signals can be absent from antigen-presenting cells.	('tumor', 'Disease', (138, 143))	('T cells', 'MPA', (66, 73))	('antigen-loss', 'MPA', (225, 237))	('escape', 'NegReg', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', (18, 23))	('activation', 'MPA', (52, 62))	('variants', 'Var', (238, 246))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('reduce', 'NegReg', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('HL', 'CellLine', 'CVCL:2492', (186, 188))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('downregulation', 'NegReg', (120, 134))	('HL', 'Phenotype', 'HP:0012189', (186, 188))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('reduce activation of T cells', 'Phenotype', 'HP:0005419', (45, 73))
371044	26579494	OX40 (CD134) and CD137 (4-1BB) and their ligands OX40L (CD252) and 4-1BBL are examples of such co-stimulatory effective molecules.	('CD137', 'Var', (17, 22))	('CD134', 'Gene', '22163', (6, 11))	('CD134', 'Gene', (6, 11))
371045	26579494	We have shown in previous studies that transgenic expression of IL-2 on EFT cells enhances the immunostimulatory activity but could not completely inhibit the growth of the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('enhances', 'PosReg', (82, 90))	('transgenic', 'Species', '10090', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('transgenic expression', 'Var', (39, 60))	('immunostimulatory activity', 'MPA', (95, 121))	('IL-2', 'Gene', '16183', (64, 68))	('IL-2', 'Gene', (64, 68))
371047	26579494	In the present study, we present preliminary data that OX40L transgenic EFT cells not only preserve expression of typical Ewing sarcoma-associated antigens but also might enhance the immune response against EFT cells in combination with IL-2 and stimulation of CD137.	('IL-2', 'Gene', '16183', (237, 241))	('enhance', 'PosReg', (171, 178))	('Ewing sarcoma', 'Disease', (122, 135))	('OX40L transgenic', 'Var', (55, 71))	('IL-2', 'Gene', (237, 241))	('transgenic', 'Species', '10090', (61, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (122, 135))	('expression', 'MPA', (100, 110))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (122, 135))	('immune response', 'CPA', (183, 198))
371048	26579494	The presence of OX40-positive T cells at sites of tumor metastases suggests that engagement of OX40 by OX40L or agonistic antibodies may enhance function of tumor-reactive T cells.	('tumor', 'Disease', (157, 162))	('tumor metastases', 'Disease', 'MESH:D009362', (50, 66))	('enhance', 'PosReg', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('OX40L', 'Var', (103, 108))	('function', 'CPA', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (50, 55))	('tumor metastases', 'Disease', (50, 66))
371050	26579494	treated subcutaneous tumors of melanoma, Lewis lung carcinoma, and adenocarcinoma with intratumoral injection of tumor cells expressing mouse OX40L.	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mouse OX40L', 'Var', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('adenocarcinoma', 'Disease', (67, 81))	('tumor', 'Disease', (113, 118))	('subcutaneous tumors of melanoma, Lewis lung carcinoma', 'Disease', 'MESH:D018827', (8, 61))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (8, 27))	('mouse', 'Species', '10090', (136, 141))
371051	26579494	It was shown that the treatment of tumor-bearing mice with tumor cells expressing OX40L induced significant suppression of tumor growth and enhanced survival of the treated mice.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (59, 64))	('OX40L', 'Var', (82, 87))	('enhanced', 'PosReg', (140, 148))	('tumor', 'Disease', (123, 128))	('suppression of tumor', 'Disease', 'OMIM:146850', (108, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('mice', 'Species', '10090', (49, 53))	('suppression of tumor', 'Disease', (108, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('survival', 'CPA', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mice', 'Species', '10090', (173, 177))
371056	26579494	Furthermore, in several preclinical models, treatment of tumor-bearing hosts with anti-OX40 agonistic antibodies or OX40L-Fc fusion protein resulted in a significant tumor regression [for review, see Ref.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('OX40L-Fc', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
371057	26579494	In these studies, it was suggested that activation of OX40 receptor by agonistic antibody or OX40L transgenic tumor cells pushes regulatory T cells (Treg) in suppressing or depletion depending on the context of simulation and the cytokine milieu.	('OX40L transgenic', 'Var', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('depletion', 'MPA', (173, 182))	('activation', 'PosReg', (40, 50))	('transgenic', 'Species', '10090', (99, 109))	('OX40 receptor', 'Protein', (54, 67))	('suppressing', 'MPA', (158, 169))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
371058	26579494	This activation of OX40 on different T cells with agonistic antibody or OX40L-expressing tumor cells may lead to decreased inhibitory effects mediated by Treg cells and thereby might promote antitumor responses of CD8-positive T cell which is necessary to maintain long-term antitumor responses.	('CD8', 'Gene', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (279, 284))	('CD8', 'Gene', '925', (214, 217))	('OX40L-expressing', 'Var', (72, 88))	('tumor', 'Disease', (89, 94))	('inhibitory effects mediated', 'MPA', (123, 150))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('decreased', 'NegReg', (113, 122))	('promote', 'PosReg', (183, 190))	('OX40', 'Var', (19, 23))
371062	26579494	showed a potential benefit of anti-CD137 and anti-OX40 antibodies in enhancing the immune responses in combination with dendritic cell-based vaccines in a Her-2/neu tumor model.	('Her-2/neu', 'Gene', (155, 164))	('anti-OX40', 'Var', (45, 54))	('enhancing', 'PosReg', (69, 78))	('immune responses', 'CPA', (83, 99))	('Her-2/neu', 'Gene', '13866', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('anti-CD137', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
371063	26579494	The authors showed that joint co-stimulation with anti-CD137 and anti-OX40 agonistic antibodies induce strong effector immune responses depending on both CD4-positive and CD8-positive T cells.	('effector immune', 'MPA', (110, 125))	('CD8', 'Gene', (171, 174))	('CD8', 'Gene', '925', (171, 174))	('anti-CD137', 'Var', (50, 60))
371069	26579494	These observations suggested that anti-OX40 antibodies enhanced the helper function of CD4-positive T cells that increased the number or activity of CD8-positive T cells against the tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('enhanced', 'PosReg', (55, 63))	('helper function', 'CPA', (68, 83))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('anti-OX40 antibodies', 'Var', (34, 54))	('CD8', 'Gene', (149, 152))	('activity', 'MPA', (137, 145))	('CD8', 'Gene', '925', (149, 152))	('increased', 'PosReg', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
371072	26579494	In our previous investigations, we observed activation of T and NK cells by IL-2 transgenic Ewing sarcoma cells.	('IL-2', 'Gene', '16183', (76, 80))	('activation', 'PosReg', (44, 54))	('transgenic', 'Species', '10090', (81, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('transgenic', 'Var', (81, 91))	('IL-2', 'Gene', (76, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('Ewing sarcoma', 'Disease', (92, 105))
371074	26579494	Whether antigenic peptides in combination with major histocompatibility complex (MHC) molecules are recognized by T cells or whether activated NK cells are triggered by receptors like CD226 or CD314 requires further investigations.	('CD226', 'Gene', '225825', (184, 189))	('CD226', 'Gene', (184, 189))	('CD314', 'Var', (193, 198))
371075	26579494	Our data suggest that OX40L-expressing tumor cells might enhance immune response against Ewing sarcoma cells in combination with IL-2 and activation of the CD137/4-1BBL co-stimulatory pathway.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Ewing sarcoma', 'Disease', (89, 102))	('OX40L-expressing', 'Var', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('immune response against', 'CPA', (65, 88))	('IL-2', 'Gene', '16183', (129, 133))	('CD137/4-1BBL co-stimulatory pathway', 'Pathway', (156, 191))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('tumor', 'Disease', (39, 44))	('IL-2', 'Gene', (129, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('enhance', 'PosReg', (57, 64))
371092	22550418	For example, tumors with genetic alterations in p53 or p16/p14ARF have more aggressive behavior and a worse response to chemotherapy.	('p53', 'Gene', (48, 51))	('aggressive behavior', 'Phenotype', 'HP:0000718', (76, 95))	('p14ARF', 'Gene', '1029', (59, 65))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('more', 'PosReg', (71, 75))	('p53', 'Gene', '7157', (48, 51))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('p16', 'Gene', (55, 58))	('p14ARF', 'Gene', (59, 65))	('aggressive behavior', 'Disease', (76, 95))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('aggressive behavior', 'Disease', 'MESH:D001523', (76, 95))	('genetic alterations', 'Var', (25, 44))	('p16', 'Gene', '1029', (55, 58))
371274	32315454	On univariable analyses, S+RT (HR, 1.74; 95% CI, 1.12-2.69; P = .013), older age (HR, 1.042; 95% CI, 1.03-1.06; P <= .001), a mitotic count >4 mitoses per HPF (HR, 3.29; 95% CI, 2.09-5.18; P <= .001), and greater tumor size (HR, 1.05; 95% CI, 1.03-1.08; P <= .001) were all significantly associated with worse OS (Tables 3 and 4).	('tumor', 'Disease', (213, 218))	('mitotic count', 'CPA', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('worse OS', 'Disease', (304, 312))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('S+RT', 'Var', (25, 29))
371275	32315454	After correction for age, mitotic count, and tumor size, the association between S+RT and OS disappeared and did not remain significant (HR, 1.11; 95% CI, 0.64-1.95; P = .704) (Tables 5 and 6).	('S+RT', 'Var', (81, 85))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))
371276	32315454	5   More acute and late toxicities of any grade were observed in the S+RT subgroup compared with the S subgroup (7.5% vs 58.7%; P < .001 [predominantly grade 1 skin erythema]; and 2.6% vs 24.0%; P < .001, respectively).	('skin erythema', 'Disease', (160, 173))	('toxicities', 'Disease', 'MESH:D064420', (24, 34))	('erythema', 'Phenotype', 'HP:0010783', (165, 173))	('toxicities', 'Disease', (24, 34))	('skin erythema', 'Disease', 'MESH:D012871', (160, 173))	('S+RT', 'Var', (69, 73))
371321	31483578	Furthermore, among patients with locally advanced disease treated with limb sparing surgery, those with Medicaid (OR = 0.87, 95% CI: 0.77- 0.98, P = .021) and the uninsured (OR = 0.73, 95% CI: 0.63-0.85, P < .001) were less likely to receive neoadjuvant or adjuvant radiotherapy as compared to those with commercial insurance.	('patients', 'Species', '9606', (19, 27))	('neoadjuvant', 'CPA', (242, 253))	('adjuvant radiotherapy', 'CPA', (257, 278))	('Medicaid', 'Var', (104, 112))	('less', 'NegReg', (219, 223))
371328	31483578	Studies from several disease sites have shown that health insurance coverage influences receipt of guideline recommended care, timely treatment, as well as participation in clinical trials.3 For instance, a recent study evaluating the impact of insurance coverage on outcomes of patients with breast sarcoma showed that Medicaid and uninsured patients were more likely to present with advanced disease and have worse outcomes as compared to privately insured patients.4 Other studies in adult patients with STS have similarly demonstrated that noncommercial insurance is associated with a longer time to treatment initiation5 and a lower likelihood of receiving guideline concordant care2 as compared to privately insured patients.	('breast sarcoma', 'Disease', 'MESH:D061325', (293, 307))	('patients', 'Species', '9606', (459, 467))	('patients', 'Species', '9606', (493, 501))	('patients', 'Species', '9606', (343, 351))	('sarcoma', 'Phenotype', 'HP:0100242', (300, 307))	('lower', 'NegReg', (632, 637))	('STS', 'Phenotype', 'HP:0030448', (507, 510))	('patients', 'Species', '9606', (279, 287))	('noncommercial insurance', 'Var', (544, 567))	('breast sarcoma', 'Disease', (293, 307))	('patients', 'Species', '9606', (722, 730))
371351	31483578	In patients <65 years, Medicaid (OR: 1.74, 95% CI: 1.57-1.93, P < .001) and no insurance (OR: 1.71, 95% CI: 1.51-1.94, P < .001) were associated with a higher likelihood of presenting with Stage IV disease as compared to commercial insurance.	('Medicaid', 'Var', (23, 31))	('patients', 'Species', '9606', (3, 11))	('Stage IV disease', 'Disease', (189, 205))
371373	31483578	In general, patients with Medicare have better access to high quality care compared to Medicaid patients.	('patients', 'Species', '9606', (12, 20))	('access', 'MPA', (47, 53))	('Medicare', 'Var', (26, 34))	('patients', 'Species', '9606', (96, 104))
371534	28350009	In the PALETTE study, a randomised, double-blinded, placebo-controlled phase III trial of pazopanib in pretreated metastatic sarcoma, pazopanib resulted in a statistically significant improvement in progression-free survival (PFS) of approximately 3 months.	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('improvement', 'PosReg', (184, 195))	('progression-free survival', 'CPA', (199, 224))	('pazopanib', 'Var', (134, 143))	('sarcoma', 'Disease', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('pazopanib', 'Chemical', 'MESH:C516667', (90, 99))	('pazopanib', 'Chemical', 'MESH:C516667', (134, 143))
371543	28350009	In the presence of pazopanib, parental clones exhibited a decrease in the proportion of cells in S phase in a dose-dependent manner.	('decrease', 'NegReg', (58, 66))	('pazopanib', 'Var', (19, 28))	('pazopanib', 'Chemical', 'MESH:C516667', (19, 28))
371544	28350009	On the other hand, pazopanib-resistant clones exhibited an increase in the proportion of cells in S phase and a decrease of those in G1 phase, regardless of pazopanib, in comparison with parental clones (Fig 1b and c).	('pazopanib', 'Chemical', 'MESH:C516667', (157, 166))	('G1 phase', 'CPA', (133, 141))	('decrease', 'NegReg', (112, 120))	('pazopanib', 'Chemical', 'MESH:C516667', (19, 28))	('pazopanib-resistant', 'Var', (19, 38))	('increase', 'PosReg', (59, 67))
371564	28350009	As we expected, pazopanib-resistant xenograft mice treated with 0.1 mg/kg trametinib showed a significant decrease in tumour burden while parental xenograft mice treated with the same dose of trametinib showed no significant decrease (Fig.	('0.1 mg/kg', 'Var', (64, 73))	('mice', 'Species', '10090', (157, 161))	('trametinib', 'Chemical', 'MESH:C560077', (74, 84))	('trametinib', 'Gene', (74, 84))	('trametinib', 'Chemical', 'MESH:C560077', (192, 202))	('decrease', 'NegReg', (106, 114))	('tumour burden', 'Disease', (118, 131))	('mice', 'Species', '10090', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour burden', 'Disease', 'MESH:D009369', (118, 131))	('pazopanib', 'Chemical', 'MESH:C516667', (16, 25))
371565	28350009	Finally, to examine whether inhibition of activated ERK1/2 would overcome pazopanib resistance, the pazopanib-resistant SS cells were simultaneously treated with pazopanib and a low dose of trametinib.	('ERK1/2', 'Gene', (52, 58))	('ERK1/2', 'Gene', '5595;5594', (52, 58))	('pazopanib resistance', 'MPA', (74, 94))	('SS', 'Phenotype', 'HP:0012570', (120, 122))	('inhibition', 'Var', (28, 38))	('pazopanib', 'Chemical', 'MESH:C516667', (100, 109))	('pazopanib', 'Chemical', 'MESH:C516667', (162, 171))	('trametinib', 'Chemical', 'MESH:C560077', (190, 200))	('pazopanib', 'Chemical', 'MESH:C516667', (74, 83))
371577	28350009	These findings suggest that upstream signalling elements of ERK1/2, including gatekeeper mutations of PDGFRalpha, are not involved in the activation of ERK1/2 in pazopanib-resistant SS cells, and pazopanib-resistant clones are resistant to pazopanib inhibition of ERK1/2 phosphorylation.	('PDGFRalpha', 'Gene', (102, 112))	('pazopanib', 'Chemical', 'MESH:C516667', (240, 249))	('ERK1/2', 'Gene', (264, 270))	('ERK1/2', 'Gene', '5595;5594', (264, 270))	('pazopanib', 'Chemical', 'MESH:C516667', (196, 205))	('SS', 'Phenotype', 'HP:0012570', (182, 184))	('ERK1/2', 'Gene', (152, 158))	('gatekeeper', 'Species', '111938', (78, 88))	('pazopanib', 'Chemical', 'MESH:C516667', (162, 171))	('mutations', 'Var', (89, 98))	('ERK1/2', 'Gene', (60, 66))	('ERK1/2', 'Gene', '5595;5594', (152, 158))	('PDGFRalpha', 'Gene', '5156', (102, 112))	('ERK1/2', 'Gene', '5595;5594', (60, 66))
371616	28350009	The causative molecular mechanisms of increased phosphorylated ERK1/2 have been proposed to be the activation of kinases upstream of ERK1/2 and/or the inhibition of downstream phosphatases.	('ERK1/2', 'Gene', (63, 69))	('ERK1/2', 'Gene', '5595;5594', (63, 69))	('ERK1/2', 'Gene', '5595;5594', (133, 139))	('activation', 'PosReg', (99, 109))	('phosphorylated', 'Var', (48, 62))	('kinases', 'Enzyme', (113, 120))	('inhibition', 'NegReg', (151, 161))	('increased', 'PosReg', (38, 47))	('ERK1/2', 'Gene', (133, 139))
371617	28350009	With regard to upstream molecules in the MAPK pathway, gatekeeper mutations of PDGFRalpha cause phosphorylation of ERK1/2 through the RAS-RAF-MEK pathway.	('mutations', 'Var', (66, 75))	('PDGFRalpha', 'Gene', '5156', (79, 89))	('PDGFRalpha', 'Gene', (79, 89))	('RAF', 'Gene', '22882', (138, 141))	('ERK1/2', 'Gene', (115, 121))	('RAF', 'Gene', (138, 141))	('phosphorylation', 'MPA', (96, 111))	('MEK', 'Gene', (142, 145))	('ERK1/2', 'Gene', '5595;5594', (115, 121))	('MEK', 'Gene', '5609', (142, 145))	('cause', 'Reg', (90, 95))	('gatekeeper', 'Species', '111938', (55, 65))
371618	28350009	It has been reported that in cases of GIST, gatekeeper mutations of PDGFRalpha are frequently observed in resistance to other tyrosine kinase inhibitors such as imatinib.	('PDGFRalpha', 'Gene', (68, 78))	('GIST', 'Disease', 'MESH:D046152', (38, 42))	('mutations', 'Var', (55, 64))	('observed', 'Reg', (94, 102))	('GIST', 'Disease', (38, 42))	('resistance to other tyrosine kinase inhibitors', 'MPA', (106, 152))	('gatekeeper', 'Species', '111938', (44, 54))	('imatinib', 'Chemical', 'MESH:D000068877', (161, 169))	('PDGFRalpha', 'Gene', '5156', (68, 78))
371621	28350009	4a), phosphorylation of ERK1/2 was partially inhibited by pazopanib (Fig.	('phosphorylation', 'MPA', (5, 20))	('pazopanib', 'Chemical', 'MESH:C516667', (58, 67))	('pazopanib', 'Var', (58, 67))	('inhibited', 'NegReg', (45, 54))	('ERK1/2', 'Gene', '5595;5594', (24, 30))	('ERK1/2', 'Gene', (24, 30))
371636	28350009	Conversely, DUSP6 knockdown in parental HS-SY-II cells apparently induced pazopanib resistance, accompanied by an increase in phosphorylated ERK1/2 (Fig.	('knockdown', 'Var', (18, 27))	('ERK1/2', 'Gene', (141, 147))	('increase', 'PosReg', (114, 122))	('induced', 'PosReg', (66, 73))	('pazopanib resistance', 'MPA', (74, 94))	('ERK1/2', 'Gene', '5595;5594', (141, 147))	('DUSP6', 'Gene', (12, 17))	('DUSP6', 'Gene', '1848', (12, 17))	('HS-SY-II', 'CellLine', 'CVCL:8719', (40, 48))	('pazopanib', 'Chemical', 'MESH:C516667', (74, 83))
371684	24994750	These results suggest that PTEN is lost in a significant fraction of primary tumors and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF-1R inhibition while increasing activity of mTOR inhibitors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('IGF-1R', 'Gene', '3480', (184, 190))	('IGF-1R', 'Gene', (184, 190))	('activity', 'MPA', (219, 227))	('mTOR', 'Gene', '2475', (231, 235))	('primary tumors', 'Disease', (69, 83))	('attenuating', 'NegReg', (154, 165))	('mTOR', 'Gene', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('deficiency', 'Var', (93, 103))	('PTEN', 'Gene', (27, 31))	('primary tumors', 'Disease', 'MESH:D009369', (69, 83))	('PTEN', 'Gene', '5728', (27, 31))	('increasing', 'PosReg', (208, 218))
371690	24994750	The resulting chimeric EWS-FLI1 protein is a potent transcriptional modulator that regulates multiple genes implicated in malignant transformation.	('FLI1', 'Gene', '2313', (27, 31))	('protein', 'Protein', (32, 39))	('regulates', 'Reg', (83, 92))	('chimeric', 'Var', (14, 22))	('FLI1', 'Gene', (27, 31))
371699	24994750	Phosphorylation of AKT at serine-473 (S473) and threonine-308 (T308) promotes cell cycle progression, cell survival, migration, and metabolism through differential interactions with multiple substrates including mTOR.	('T308', 'Var', (63, 67))	('S473', 'Var', (38, 42))	('threonine', 'Chemical', 'MESH:D013912', (48, 57))	('cell cycle progression', 'CPA', (78, 100))	('migration', 'CPA', (117, 126))	('interactions', 'Interaction', (164, 176))	('AKT', 'Gene', '207', (19, 22))	('promotes', 'PosReg', (69, 77))	('Phosphorylation', 'MPA', (0, 15))	('metabolism', 'CPA', (132, 142))	('T308', 'Chemical', '-', (63, 67))	('mTOR', 'Gene', (212, 216))	('AKT', 'Gene', (19, 22))	('mTOR', 'Gene', '2475', (212, 216))	('serine', 'Chemical', 'MESH:D012694', (26, 32))	('cell survival', 'CPA', (102, 115))
371702	24994750	The loss or mutation of PTEN has been demonstrated in a range of cancers; however, the function of PTEN in Ewing sarcoma has yet to be investigated.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (107, 120))	('PTEN', 'Gene', '5728', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Ewing sarcoma', 'Disease', (107, 120))	('PTEN', 'Gene', '5728', (99, 103))	('PTEN', 'Gene', (99, 103))	('loss', 'NegReg', (4, 8))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('mutation', 'Var', (12, 20))	('cancers', 'Disease', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (107, 120))	('PTEN', 'Gene', (24, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
371721	24994750	AKT (#4691), pAKT T308 (#2965), pAKT S473 (#4060) and LC3B (#3868), cleaved PARP (#5625) were used for immunoblotting (Cell Signaling Technology).	('#5625', 'Var', (82, 87))	('AKT', 'Gene', (0, 3))	('#3868', 'Var', (60, 65))	('AKT', 'Gene', (14, 17))	('LC3B', 'Gene', '81631', (54, 58))	('PARP', 'Gene', '1302', (76, 80))	('#2965', 'Var', (24, 29))	('AKT', 'Gene', '207', (33, 36))	('AKT', 'Gene', '207', (0, 3))	('LC3B', 'Gene', (54, 58))	('PARP', 'Gene', (76, 80))	('AKT', 'Gene', (33, 36))	('AKT', 'Gene', '207', (14, 17))	('#4060', 'Var', (43, 48))	('T308', 'Chemical', '-', (18, 22))
371753	24994750	The potential deletion encompassed several genes including the terminal exons of PTEN (Fig.	('deletion', 'Var', (14, 22))	('PTEN', 'Gene', (81, 85))	('PTEN', 'Gene', '5728', (81, 85))
371754	24994750	Since deletion of PTEN had yet to be detected in Ewing sarcoma using high throughput sequencing approaches, we verified this deletion by fluorescence in situ hybridization (FISH) using two probes that overlap the PTEN locus, as well as a control centromeric probe.	('PTEN', 'Gene', '5728', (213, 217))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('PTEN', 'Gene', (18, 22))	('PTEN', 'Gene', '5728', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('deletion', 'Var', (6, 14))	('Ewing sarcoma', 'Disease', (49, 62))	('PTEN', 'Gene', (213, 217))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))
371758	24994750	However, EWS894 and SK-N-MC cells exhibited PTEN/centromeric probe ratios not equal to one suggesting other cytogenetic aberrations involving the long arm or centromere of chromosome 10 (Fig.	('EWS894', 'Var', (9, 15))	('SK-N-MC', 'CellLine', 'CVCL:0530', (20, 27))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))
371760	24994750	The PTEN/centromeric probe ratio was equivalent for the remaining cell lines; MHH-ES-1 and RD-ES exhibited triploidy of chromosome 10 (Sup.	('PTEN', 'Gene', '5728', (4, 8))	('PTEN', 'Gene', (4, 8))	('triploidy', 'Var', (107, 116))
371781	24994750	This observation is consistent with other tumors in which PTEN expression is lost due to gene silencing or focal deletions.	('lost', 'NegReg', (77, 81))	('PTEN', 'Gene', '5728', (58, 62))	('focal deletions', 'Var', (107, 122))	('gene silencing', 'Var', (89, 103))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('expression', 'MPA', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('PTEN', 'Gene', (58, 62))
371782	24994750	To determine the effect of PTEN loss on AKT signaling across Ewing sarcoma cell lines we examined phosphorylation at S473 and T308.	('Ewing sarcoma', 'Disease', (61, 74))	('loss', 'NegReg', (32, 36))	('AKT', 'Gene', '207', (40, 43))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('T308', 'Chemical', '-', (126, 130))	('AKT', 'Gene', (40, 43))	('PTEN', 'Gene', (27, 31))	('T308', 'Var', (126, 130))	('PTEN', 'Gene', '5728', (27, 31))
371784	24994750	Among the cell lines tested, EWS502 had the highest level of pAKT (Fig.	('EWS502', 'Var', (29, 35))	('AKT', 'Gene', (62, 65))	('EWS502', 'Chemical', '-', (29, 35))	('AKT', 'Gene', '207', (62, 65))
371786	24994750	PDK1-associated phosphorylation of T308 is associated with full AKT activation and was only observed in the absence of PTEN suggesting that AKT activation is augmented by PTEN loss.	('AKT', 'Gene', (140, 143))	('T308', 'Chemical', '-', (35, 39))	('loss', 'NegReg', (176, 180))	('T308', 'Var', (35, 39))	('PDK1', 'Gene', '5163', (0, 4))	('PDK1', 'Gene', (0, 4))	('AKT', 'Gene', '207', (64, 67))	('activation', 'PosReg', (68, 78))	('activation', 'PosReg', (144, 154))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('PTEN', 'Gene', (171, 175))	('AKT', 'Gene', '207', (140, 143))	('PTEN', 'Gene', '5728', (171, 175))	('AKT', 'Gene', (64, 67))
371788	24994750	Increasing PTEN was associated with a progressive decrease in pAKT at S473 and T308 (Fig.	('PTEN', 'Gene', (11, 15))	('T308', 'Var', (79, 83))	('PTEN', 'Gene', '5728', (11, 15))	('AKT', 'Gene', (63, 66))	('AKT', 'Gene', '207', (63, 66))	('T308', 'Chemical', '-', (79, 83))	('decrease', 'NegReg', (50, 58))
371789	24994750	3B) suggesting that AKT activation in EWS502 is due in part to PTEN deficiency.	('AKT', 'Gene', (20, 23))	('EWS502', 'Var', (38, 44))	('EWS502', 'Chemical', '-', (38, 44))	('part to PTEN deficiency', 'Disease', 'MESH:D006223', (55, 78))	('part to PTEN deficiency', 'Disease', (55, 78))	('AKT', 'Gene', '207', (20, 23))	('activation', 'PosReg', (24, 34))
371797	24994750	To address whether the reduction in cell proliferation following PTEN expression could be attributed to increased apoptosis, we assayed annexin V reactivity by flow cytometry and observed a significant increase relative to control cells (Fig.	('PTEN', 'Gene', (65, 69))	('PTEN', 'Gene', '5728', (65, 69))	('expression', 'Var', (70, 80))	('reduction', 'NegReg', (23, 32))	('annexin V', 'Gene', '308', (136, 145))	('increase', 'PosReg', (202, 210))	('annexin V', 'Gene', (136, 145))	('cell proliferation', 'CPA', (36, 54))
371801	24994750	Since clinical trials of IGF-1-targeted inhibitors have demonstrated robust but limited patient responses, we asked whether PTEN loss might mitigate the effect of these compounds in Ewing sarcoma cells.	('patient', 'Species', '9606', (88, 95))	('PTEN', 'Gene', (124, 128))	('PTEN', 'Gene', '5728', (124, 128))	('inhibitors', 'Var', (40, 50))	('loss', 'NegReg', (129, 133))	('Ewing sarcoma', 'Disease', (182, 195))	('IGF-1-targeted', 'Gene', (25, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))
371805	24994750	This differential sensitivity was detectable by phosphorylation at both S473 and T308.	('T308', 'Var', (81, 85))	('T308', 'Chemical', '-', (81, 85))	('S473', 'Var', (72, 76))
371806	24994750	Interestingly, intermediate sensitivity to these inhibitors was observed for EWS894 and SK-ES, both of which demonstrated lower PTEN levels and detectable pAKT-S473.	('lower', 'NegReg', (122, 127))	('AKT', 'Gene', '207', (156, 159))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('AKT', 'Gene', (156, 159))	('EWS894', 'Var', (77, 83))
371808	24994750	Transduced PTEN resulted in enhanced sensitivity for NVP-AEW541 with an IC50 approximating the other PTEN-expressing Ewing sarcoma cells (Fig.	('PTEN', 'Gene', (11, 15))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (117, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('PTEN', 'Gene', '5728', (11, 15))	('PTEN', 'Gene', (101, 105))	('enhanced', 'PosReg', (28, 36))	('PTEN', 'Gene', '5728', (101, 105))	('Ewing sarcoma', 'Disease', (117, 130))	('sensitivity', 'MPA', (37, 48))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (117, 130))	('Transduced', 'Var', (0, 10))
371809	24994750	The enhanced sensitivity for NVP-AEW541 was associated with increased cellular toxicity (Fig.	('sensitivity', 'MPA', (13, 24))	('enhanced', 'PosReg', (4, 12))	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('toxicity', 'Disease', (79, 87))	('increased', 'PosReg', (60, 69))	('NVP-AEW541', 'Var', (29, 39))
371817	24994750	Since EWS502 but not A673 cells demonstrated induction of temsirolimus-induced autophagy, we examined the effect of modulating PTEN.	('temsirolimus', 'Chemical', 'MESH:C401859', (58, 70))	('EWS502', 'Var', (6, 12))	('EWS502', 'Chemical', '-', (6, 12))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', '5728', (127, 131))
371818	24994750	Silencing PTEN in A673 cells augmented the autophagic response to temsirolimus whereas exogenous PTEN expression in EWS502 eliminated the effect of temsirolimus (but not chloroquine) (Fig.	('PTEN', 'Gene', '5728', (10, 14))	('PTEN', 'Gene', (97, 101))	('temsirolimus', 'Chemical', 'MESH:C401859', (66, 78))	('PTEN', 'Gene', '5728', (97, 101))	('autophagic', 'CPA', (43, 53))	('temsirolimus', 'Chemical', 'MESH:C401859', (148, 160))	('augmented', 'PosReg', (29, 38))	('chloroquine', 'Chemical', 'MESH:D002738', (170, 181))	('Silencing', 'Var', (0, 9))	('PTEN', 'Gene', (10, 14))	('EWS502', 'Chemical', '-', (116, 122))
371823	24994750	The unexpected identification of PTEN deletion in a Ewing Sarcoma cell line led us to explore the status of PTEN in primary tumors.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (52, 65))	('primary tumors', 'Disease', 'MESH:D009369', (116, 130))	('PTEN', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PTEN', 'Gene', '5728', (108, 112))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('Ewing Sarcoma', 'Disease', (52, 65))	('deletion', 'Var', (38, 46))	('primary tumors', 'Disease', (116, 130))	('Sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
371825	24994750	Small deletions and other mutations undetectable by FISH, in addition to gene silencing, remain alterative mechanisms that result in PTEN loss in Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (146, 159))	('loss', 'NegReg', (138, 142))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (146, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('PTEN', 'Gene', (133, 137))	('Ewing sarcoma', 'Disease', (146, 159))	('PTEN', 'Gene', '5728', (133, 137))	('Small deletions', 'Var', (0, 15))
371826	24994750	However, our observation of PTEN loss is consistent with a recent study that used high resolution SNP arrays to examine copy number variation in Ewing sarcoma and observed PTEN deletion in 14% of the tumors.	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (172, 176))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (145, 158))	('PTEN', 'Gene', '5728', (28, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (145, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('deletion', 'Var', (177, 185))	('loss', 'NegReg', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('Ewing sarcoma', 'Disease', (145, 158))	('PTEN', 'Gene', (172, 176))
371829	24994750	Intriguingly, ETS deregulation may cooperate with PTEN loss to accelerate tumorigenesis.	('loss', 'NegReg', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('deregulation', 'Var', (18, 30))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PTEN', 'Gene', (50, 54))	('PTEN', 'Gene', '5728', (50, 54))	('accelerate', 'PosReg', (63, 73))	('tumor', 'Disease', (74, 79))	('ETS', 'Gene', (14, 17))
371832	24994750	In addition to potentially contributing to a more transformed phenotype, hyperactivation of AKT may decrease sensitivity of Ewing sarcoma cells to chemotherapy.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (124, 137))	('hyperactivation', 'Var', (73, 88))	('AKT', 'Gene', '207', (92, 95))	('Ewing sarcoma', 'Disease', (124, 137))	('decrease', 'NegReg', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('AKT', 'Gene', (92, 95))	('sensitivity', 'MPA', (109, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (124, 137))	('contributing', 'Reg', (27, 39))
371833	24994750	We have demonstrated that loss of PTEN decreases sensitivity to IGF-1R inhibition, as measured by AKT phosphorylation.	('PTEN', 'Gene', (34, 38))	('sensitivity', 'MPA', (49, 60))	('IGF-1R', 'Gene', (64, 70))	('AKT', 'Gene', '207', (98, 101))	('IGF-1R', 'Gene', '3480', (64, 70))	('decreases', 'NegReg', (39, 48))	('loss', 'Var', (26, 30))	('AKT', 'Gene', (98, 101))	('PTEN', 'Gene', '5728', (34, 38))
371836	24994750	These findings are consistent with a prior study demonstrating that PTEN silencing in cultured glioblastoma decreased response to NVP-AEW541.	('silencing', 'Var', (73, 82))	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('PTEN', 'Gene', (68, 72))	('decreased', 'NegReg', (108, 117))	('PTEN', 'Gene', '5728', (68, 72))	('response to NVP-AEW541', 'MPA', (118, 140))
371843	24994750	The promise of personalized therapy for cancer depends on the identification of genetic alterations in specific tumors.	('genetic alterations', 'Var', (80, 99))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Disease', (112, 118))	('cancer', 'Disease', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
371845	24994750	Our results indicate that loss of PTEN expression may diminish the therapeutic response of Ewing sarcoma to IGF-1R inhibitors.	('IGF-1R', 'Gene', (108, 114))	('IGF-1R', 'Gene', '3480', (108, 114))	('Ewing sarcoma', 'Disease', (91, 104))	('diminish', 'NegReg', (54, 62))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('therapeutic', 'MPA', (67, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('loss', 'Var', (26, 30))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
371867	23519678	In over 85% of cases the translocation occurs between chromosomes 11 and 22 resulting in the creation of a pathognomonic chimeric fusion gene, EWSR1/FLI1 that encodes the EWS/FLI protein (Delattre et al.,).	('EWSR1', 'Gene', (143, 148))	('EWS', 'Gene', '2130', (143, 146))	('translocation', 'Var', (25, 38))	('FLI', 'Gene', '2314', (175, 178))	('EWSR1', 'Gene', '2130', (143, 148))	('FLI', 'Gene', (175, 178))	('FLI1', 'Gene', (149, 153))	('FLI', 'Gene', '2314', (149, 152))	('FLI', 'Gene', (149, 152))	('FLI1', 'Gene', '2313', (149, 153))	('EWS', 'Gene', '2130', (171, 174))	('EWS', 'Gene', (171, 174))	('EWS', 'Gene', (143, 146))
371988	23118721	In Vivo Induction of Apoptosis by Fucoxanthin, a Marine Carotenoid, Associated with Down-Regulating STAT3/EGFR Signaling in Sarcoma 180 (S180) Xenografts-Bearing Mice Previous in vitro researches have showed that fucoxanthin, a natural carotenoid isolated from sargassum, can inhibit proliferation or induce apoptosis in human neuroblastoma, hepatoma, leukemia, colon carcinoma, prostate cancer or urinary bladder cancer cells.	('neuroblastoma', 'Disease', (327, 340))	('apoptosis', 'CPA', (308, 317))	('neuroblastoma', 'Phenotype', 'HP:0003006', (327, 340))	('cancer', 'Phenotype', 'HP:0002664', (414, 420))	('proliferation', 'CPA', (284, 297))	('carotenoid', 'Chemical', 'MESH:D002338', (236, 246))	('Sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('neuroblastoma', 'Disease', 'MESH:D009447', (327, 340))	('leukemia', 'Disease', (352, 360))	('leukemia', 'Disease', 'MESH:D007938', (352, 360))	('EGFR', 'Gene', (106, 110))	('STAT3', 'Gene', '20848', (100, 105))	('EGFR', 'Gene', '13649', (106, 110))	('inhibit', 'NegReg', (276, 283))	('fucoxanthin', 'Chemical', 'MESH:C025164', (213, 224))	('Sarcoma', 'Disease', (124, 131))	('urinary bladder cancer', 'Disease', (398, 420))	('hepatoma', 'Disease', 'MESH:D006528', (342, 350))	('induce', 'PosReg', (301, 307))	('bladder cancer', 'Phenotype', 'HP:0009725', (406, 420))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('STAT3', 'Gene', (100, 105))	('Sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('Carotenoid', 'Chemical', 'MESH:D002338', (56, 66))	('prostate cancer', 'Disease', 'MESH:D011471', (379, 394))	('prostate cancer', 'Phenotype', 'HP:0012125', (379, 394))	('colon carcinoma', 'Disease', (362, 377))	('prostate cancer', 'Disease', (379, 394))	('leukemia', 'Phenotype', 'HP:0001909', (352, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (398, 420))	('hepatoma', 'Disease', (342, 350))	('colon carcinoma', 'Disease', 'MESH:D015179', (362, 377))	('fucoxanthin', 'Var', (213, 224))	('human', 'Species', '9606', (321, 326))	('Fucoxanthin', 'Chemical', 'MESH:C025164', (34, 45))
371996	23118721	These results indicated that in vivo induction of apoptosis by fucoxanthin is associated with down-regulating STAT3/EGFR signaling in S180 xenografts-bearing mice.	('down-regulating', 'NegReg', (94, 109))	('mice', 'Species', '10090', (158, 162))	('STAT3/EGFR signaling', 'MPA', (110, 130))	('fucoxanthin', 'Var', (63, 74))	('fucoxanthin', 'Chemical', 'MESH:C025164', (63, 74))
372000	23118721	Previous in vitro researches have showed that fucoxanthin can inhibit proliferation or induce apoptosis in human neuroblastoma, hepatoma, leukemia, colon carcinoma, prostate cancer or urinary bladder cancer cells.	('fucoxanthin', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('neuroblastoma', 'Disease', (113, 126))	('inhibit', 'NegReg', (62, 69))	('apoptosis', 'CPA', (94, 103))	('neuroblastoma', 'Phenotype', 'HP:0003006', (113, 126))	('urinary bladder cancer', 'Disease', (184, 206))	('hepatoma', 'Disease', 'MESH:D006528', (128, 136))	('bladder cancer', 'Phenotype', 'HP:0009725', (192, 206))	('neuroblastoma', 'Disease', 'MESH:D009447', (113, 126))	('proliferation', 'CPA', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('fucoxanthin', 'Chemical', 'MESH:C025164', (46, 57))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (184, 206))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('colon carcinoma', 'Disease', (148, 163))	('induce', 'PosReg', (87, 93))	('hepatoma', 'Disease', (128, 136))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('human', 'Species', '9606', (107, 112))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('leukemia', 'Disease', (138, 146))	('leukemia', 'Disease', 'MESH:D007938', (138, 146))	('prostate cancer', 'Disease', (165, 180))	('colon carcinoma', 'Disease', 'MESH:D015179', (148, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
372002	23118721	In our previous study, we have also found that fucoxanthin downregulated the expressions of cyclinB1 and survivin, induced cell cycle arrest in G2/M phase and apoptosis in human gastric adenocarcinoma MGC-803 cells.	('expressions', 'MPA', (77, 88))	('cell cycle arrest in G2/M phase', 'CPA', (123, 154))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (178, 200))	('MGC-803', 'CellLine', 'CVCL:5334', (201, 208))	('downregulated', 'NegReg', (59, 72))	('gastric adenocarcinoma', 'Disease', (178, 200))	('induced', 'Reg', (115, 122))	('human', 'Species', '9606', (172, 177))	('fucoxanthin', 'Var', (47, 58))	('survivin', 'Protein', (105, 113))	('fucoxanthin', 'Chemical', 'MESH:C025164', (47, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cyclinB1', 'Gene', (92, 100))	('cyclinB1', 'Gene', '891', (92, 100))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (123, 140))	('apoptosis', 'CPA', (159, 168))
372008	23118721	Aberrant activation of STAT3 is commonly observed in tumors and is strongly associated with tumor development and progression.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('STAT3', 'Gene', (23, 28))	('associated with', 'Reg', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('progression', 'CPA', (114, 125))	('tumors', 'Disease', (53, 59))
372020	23118721	As shown in Table 1, fucoxanthin (at the dose of 50 and 100 mg/kg) caused a significant decline of sarcoma weight in a dose-dependent manner compared with the model control group (p < 0.05 or p < 0.01).	('decline of sarcoma weight', 'Disease', (88, 113))	('decline of sarcoma weight', 'Disease', 'MESH:D015431', (88, 113))	('fucoxanthin', 'Chemical', 'MESH:C025164', (21, 32))	('fucoxanthin', 'Var', (21, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
372027	23118721	Following treatment with fucoxanthin (50 and 100 mg/kg), the number of TUNEL-positive cells also markedly elevated (9.03 +- 0.58 apoptotic cells/x200 field in 50 mg/kg fucoxanthin group; 17.53 +- 0.62 apoptotic cells/x200 field in 100 mg/kg fucoxanthin group, p < 0.05 or p < 0.01,  vs. model control group).	('fucoxanthin', 'Chemical', 'MESH:C025164', (241, 252))	('fucoxanthin', 'Chemical', 'MESH:C025164', (25, 36))	('elevated', 'PosReg', (106, 114))	('fucoxanthin', 'Chemical', 'MESH:C025164', (168, 179))	('fucoxanthin', 'Var', (25, 36))
372075	23118721	The sources of primary antibodies used in this study were as follows: VEGF, EGFR (ab1316 abcam, ab2430 abcam, UK), survivin, bcl-2, caspase-3, STAT3, p-STAT3 (tyrosine 705), beta-actin (sc-47750, sc-7382, sc-56055, sc-8019, sc-8059, sc-47778, Santa Cruz, CA, USA).	('VEGF', 'Gene', (70, 74))	('sc-47778', 'Var', (233, 241))	('caspase-3', 'Gene', (132, 141))	('tyrosine', 'Chemical', 'MESH:D014443', (159, 167))	('VEGF', 'Gene', '7422', (70, 74))	('sc-7382', 'Var', (196, 203))	('beta-actin', 'Gene', '728378', (174, 184))	('sc-8019', 'Var', (215, 222))	('sc-56055', 'Var', (205, 213))	('bcl-2', 'Gene', (125, 130))	('beta-actin', 'Gene', (174, 184))	('caspase-3', 'Gene', '836', (132, 141))	('sc-47750', 'Var', (186, 194))	('bcl-2', 'Gene', '596', (125, 130))	('sc-8059', 'Var', (224, 231))
372079	23118721	In vivo, Fucoxanthin significantly upregulated the expression of pro-apoptotic cleaved caspase-3, decreased the expressions of bcl-2, EGFR, STAT3, survivin and VEGF in a dose-dependent manner, which are EGFR/STAT signal pathway-related genes.	('VEGF', 'Gene', '7422', (160, 164))	('survivin', 'Gene', (147, 155))	('expressions', 'MPA', (112, 123))	('EGFR', 'Gene', (134, 138))	('STAT3', 'Gene', (140, 145))	('caspase-3', 'Gene', '836', (87, 96))	('VEGF', 'Gene', (160, 164))	('bcl-2', 'Gene', (127, 132))	('upregulated', 'PosReg', (35, 46))	('expression', 'MPA', (51, 61))	('bcl-2', 'Gene', '596', (127, 132))	('Fucoxanthin', 'Chemical', 'MESH:C025164', (9, 20))	('decreased', 'NegReg', (98, 107))	('Fucoxanthin', 'Var', (9, 20))	('caspase-3', 'Gene', (87, 96))
372233	32631436	Although NF1 gene inactivation and loss of neurofibromin expression characterize the majority of MPNST cases, biallelic NF1 loss is insufficient for malignant transformation, and mutations in TP53, CDKN2A, EGFR, and SUZ12 have all been reported as secondary cooperating mutations facilitating malignant progression.	('neurofibromin', 'Gene', (43, 56))	('loss', 'NegReg', (124, 128))	('NF1', 'Gene', (9, 12))	('NF1', 'Gene', (120, 123))	('inactivation', 'NegReg', (18, 30))	('neurofibromin', 'Gene', '4763', (43, 56))	('TP53', 'Gene', (192, 196))	('SUZ12', 'Gene', (216, 221))	('CDKN2A', 'Gene', (198, 204))	('EGFR', 'Gene', (206, 210))	('mutations', 'Var', (179, 188))	('MPNST', 'Disease', (97, 102))	('SUZ12', 'Gene', '23512', (216, 221))	('malignant progression', 'CPA', (293, 314))	('CDKN2A', 'Gene', '1029', (198, 204))	('NF1', 'Gene', '4763', (9, 12))	('NF1', 'Gene', '4763', (120, 123))	('MPNST', 'Phenotype', 'HP:0100697', (97, 102))	('TP53', 'Gene', '7157', (192, 196))	('EGFR', 'Gene', '1956', (206, 210))
372246	32631436	Compared with other soft tissue sarcomas, MPNST has the highest risk of sarcoma-specific death.	('sarcoma', 'Disease', (72, 79))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (20, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('death', 'Disease', 'MESH:D003643', (89, 94))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('sarcoma', 'Disease', (32, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('death', 'Disease', (89, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('MPNST', 'Phenotype', 'HP:0100697', (42, 47))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (20, 39))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('sarcomas', 'Disease', (32, 40))	('MPNST', 'Var', (42, 47))
372269	29756042	Lower muscle SUV was associated with lower serum hemoglobin and albumin.	('albumin', 'Gene', (64, 71))	('albumin', 'Gene', '213', (64, 71))	('Lower', 'Var', (0, 5))	('serum hemoglobin', 'MPA', (43, 59))	('lower', 'NegReg', (37, 42))	('lower serum hemoglobin', 'Phenotype', 'HP:0001903', (37, 59))
372306	29756042	A significant difference between the HUmax of the DCR group and the no DCR group implied that patients with lower HUmax were more likely to have DCR while those with a higher HUmax tended to have a lower rate of DCR.	('DCR', 'Disease', (145, 148))	('DCR', 'Chemical', '-', (50, 53))	('patients', 'Species', '9606', (94, 102))	('DCR', 'Chemical', '-', (71, 74))	('HUmax', 'Var', (114, 119))	('DCR', 'Chemical', '-', (212, 215))	('lower', 'NegReg', (108, 113))	('DCR', 'Chemical', '-', (145, 148))
372342	24321325	This paper presents the results of a retrospective study into CMSs and discusses the clinical features of the analyzed tumors, the expression of intermediate filaments CK, Vim, Des and alpha-SMA, and the expression of p63, Ki67, ERalpha, PR and p53 protein.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('ERalpha', 'Gene', '403640', (229, 236))	('p53', 'Gene', '403869', (245, 248))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('Vim', 'Gene', '477991', (172, 175))	('Ki67', 'Var', (223, 227))	('p53', 'Gene', (245, 248))	('intermediate', 'Protein', (145, 157))	('Des', 'Gene', (177, 180))	('p63', 'Var', (218, 221))	('protein', 'Protein', (249, 256))	('PR', 'Gene', '403621', (238, 240))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Vim', 'Gene', (172, 175))	('ERalpha', 'Gene', (229, 236))	('Des', 'Gene', '497091', (177, 180))
372372	24321325	Positive immunostaining for Vim, CK, Des and alpha-SMA was observed as a brown cytoplasmic precipitate, and for p63 - as a brown nuclear precipitate.	('Vim', 'Gene', (28, 31))	('Des', 'Gene', '497091', (37, 40))	('Vim', 'Gene', '477991', (28, 31))	('p63 -', 'Var', (112, 117))	('Des', 'Gene', (37, 40))
372373	24321325	Positive immunostaining for Ki67, ERalpha, PR and p53 was defined as nuclear pattern (brown precipitate).	('p53', 'Gene', '403869', (50, 53))	('ERalpha', 'Gene', (34, 41))	('p53', 'Gene', (50, 53))	('Ki67', 'Var', (28, 32))	('ERalpha', 'Gene', '403640', (34, 41))	('PR', 'Gene', '403621', (43, 45))
372496	20149259	In fact the development of a tumor usually implies several mutations.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (59, 68))
372510	20149259	A variation of the repopulation parameter R between 0 and 1 yields a variation of carcinoma risk reduction between 5.2% and 10.3% and of sarcoma risk reduction between 12.5% and 13.8%.	('reduction', 'NegReg', (97, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('variation', 'Var', (2, 11))	('carcinoma', 'Disease', 'MESH:D002277', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('reduction', 'NegReg', (150, 159))	('carcinoma', 'Disease', (82, 91))	('sarcoma', 'Disease', (137, 144))
372511	20149259	A variation of alpha between 0.05 and 0.15 yields a variation of carcinoma risk reduction between 8.3% and 12.4% and of sarcoma risk reduction between 12.0% and 14.5%.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('reduction', 'NegReg', (80, 89))	('variation', 'Var', (2, 11))	('carcinoma', 'Disease', (65, 74))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('carcinoma', 'Disease', 'MESH:D002277', (65, 74))	('sarcoma', 'Disease', (120, 127))
372576	31598169	We observed that patients with sarcoma with an age of more than 65 years, residual tumor (R1/R2/Rx), and multinodular were significantly associated with a poor OS (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('sarcoma', 'Disease', (31, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (17, 25))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))	('R1/R2/Rx', 'Gene', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('multinodular', 'Var', (105, 117))	('R1/R2/Rx', 'Gene', '910;6241', (90, 98))
372587	31598169	The hub DEGs in the WGCNA co-expression network of sarcoma tumor tissues were as follows: chromosome 10 open reading frame 71 (C10orf71), myoglobin (MB), nebulin related anchoring protein (NRAP), AC104831.1, apolipoprotein B mRNA editing enzyme catalytic subunit 2 (APOBEC2), creatine kinase, M-type (CKM), leiomodin 2 (LMOD2), myotilin (MYOT), myozenin 1 (MYOZ1), and nebulin (NEB).	('nebulin', 'Gene', '4703', (369, 376))	('sarcoma tumor', 'Disease', (51, 64))	('myozenin 1', 'Gene', (345, 355))	('LMOD2', 'Gene', (320, 325))	('C10orf71', 'Gene', '118461', (127, 135))	('MYOT', 'Gene', '9499', (338, 342))	('MYOT', 'Gene', (338, 342))	('LMOD2', 'Gene', '442721', (320, 325))	('GC', 'Disease', 'MESH:D013274', (21, 23))	('creatine kinase, M-type (CKM)', 'Gene', '1158', (276, 305))	('myozenin 1', 'Gene', '58529', (345, 355))	('myotilin', 'Gene', '9499', (328, 336))	('sarcoma tumor', 'Disease', 'MESH:D012509', (51, 64))	('APOBEC2', 'Gene', '10930', (266, 273))	('NRAP', 'Gene', (189, 193))	('myoglobin', 'Gene', (138, 147))	('AC104831.1', 'Var', (196, 206))	('myotilin', 'Gene', (328, 336))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('nebulin', 'Gene', (154, 161))	('GC', 'Phenotype', 'HP:0012126', (21, 23))	('nebulin related anchoring protein', 'Gene', '4892', (154, 187))	('leiomodin 2', 'Gene', '442721', (307, 318))	('MYOZ1', 'Gene', '58529', (357, 362))	('creatine kinase, M-type (CKM', 'Gene', (276, 304))	('NRAP', 'Gene', '4892', (189, 193))	('nebulin', 'Gene', (369, 376))	('nebulin related anchoring protein', 'Gene', (154, 187))	('myoglobin', 'Gene', '4151', (138, 147))	('C10orf71', 'Gene', (127, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('nebulin', 'Gene', '4703', (154, 161))	('APOBEC2', 'Gene', (266, 273))	('MYOZ1', 'Gene', (357, 362))	('leiomodin 2', 'Gene', (307, 318))	('apolipoprotein B mRNA editing enzyme catalytic subunit 2', 'Gene', '10930', (208, 264))	('MB', 'Gene', '4151', (149, 151))
372589	31598169	Survival analysis (Figure 7A-J) of the top ten hub DEGs indicate that overexpression of AC104831.1, CKM, and NEB was significantly associated with poor OS in patients with sarcoma.	('sarcoma', 'Disease', (172, 179))	('poor OS', 'Disease', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('AC104831.1', 'Var', (88, 98))	('CKM', 'Gene', '1158', (100, 103))	('CKM', 'Gene', (100, 103))	('NEB', 'Gene', (109, 112))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('patients', 'Species', '9606', (158, 166))	('overexpression', 'PosReg', (70, 84))
372602	31598169	GSEA of c5 a priori defined gene sets indicate that the prognosis of PVT1 overexpression is mainly involved in the difference of the following multiple biological processes: posttranscriptional regulation of gene expression, ncRNA processing, ncRNA metabolic process, nuclear factor kappa B (NF-KB) signaling pathway, inactivation of mitogen-activated protein kinase (MAPK) activity, osteoblast differentiation and development, regulation of apoptotic signaling pathway, and Wnt signaling pathway (Figure 13A-L, Table S7).	('activity', 'MPA', (374, 382))	('osteoblast differentiation', 'CPA', (384, 410))	('involved', 'Reg', (99, 107))	('PVT1', 'Gene', '5820', (69, 73))	('Wnt signaling pathway', 'Pathway', (475, 496))	('PVT1', 'Gene', (69, 73))	('inactivation', 'Var', (318, 330))	('apoptotic signaling pathway', 'Pathway', (442, 469))
372611	31598169	also performed a large-scale survival analysis of PVT1 by using the TCGA RNA-seq data from the UCSC Xena website (https://xenabrowser.net/heatmap/) and assessed this data by a univariate Cox proportional hazards model, they observed that low- and high-expression of PVT1 grouped by the median values were significantly associated with sarcoma OS.	('Cox', 'Gene', (187, 190))	('PVT1', 'Gene', '5820', (50, 54))	('PVT1', 'Gene', '5820', (266, 270))	('sarcoma', 'Disease', 'MESH:D012509', (335, 342))	('sarcoma', 'Phenotype', 'HP:0100242', (335, 342))	('high-expression', 'Var', (247, 262))	('low-', 'Var', (238, 242))	('sarcoma', 'Disease', (335, 342))	('PVT1', 'Gene', (266, 270))	('Cox', 'Gene', '1351', (187, 190))	('PVT1', 'Gene', (50, 54))	('associated', 'Reg', (319, 329))
372621	31598169	Extensive previous studies have observed that the high expression of PVT1 significantly increased the risk of death in patients with GC, CRC, NSCLC, ccRCC, uveal melanoma, HNSCC, PDAC, NPC, PC, ESCC, ovarian cancer (OC), high-grade serous carcinoma, cervical cancer, and osteosarcoma.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Disease', (208, 214))	('osteosarcoma', 'Phenotype', 'HP:0002669', (271, 283))	('NSCLC', 'Disease', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('uveal melanoma', 'Disease', (156, 170))	('uveal melanoma', 'Disease', 'MESH:C536494', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('GC', 'Disease', 'MESH:D013274', (133, 135))	('ovarian cancer', 'Disease', 'MESH:D010051', (200, 214))	('PC', 'Disease', 'MESH:D011471', (186, 188))	('high expression', 'Var', (50, 65))	('ESCC', 'Disease', (194, 198))	('ccRCC', 'Disease', 'MESH:D002292', (149, 154))	('OC', 'Disease', 'MESH:D010051', (216, 218))	('PDAC', 'Phenotype', 'HP:0006725', (179, 183))	('uveal melanoma', 'Phenotype', 'HP:0007716', (156, 170))	('serous carcinoma', 'Disease', (232, 248))	('CRC', 'Disease', (137, 140))	('PVT1', 'Gene', (69, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('PC', 'Phenotype', 'HP:0012125', (190, 192))	('death', 'Disease', (110, 115))	('NPC', 'Phenotype', 'HP:0100630', (185, 188))	('ccRCC', 'Disease', (149, 154))	('cancer', 'Disease', (259, 265))	('ovarian cancer', 'Disease', (200, 214))	('PVT1', 'Gene', '5820', (69, 73))	('NPC', 'Disease', 'MESH:C538339', (185, 188))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('GC', 'Phenotype', 'HP:0012126', (133, 135))	('NPC', 'Disease', (185, 188))	('osteosarcoma', 'Disease', (271, 283))	('osteosarcoma', 'Disease', 'MESH:D012516', (271, 283))	('increased', 'PosReg', (88, 97))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('OC', 'Phenotype', 'HP:0100615', (216, 218))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('serous carcinoma', 'Disease', 'MESH:D018284', (232, 248))	('PC', 'Disease', 'MESH:D011471', (190, 192))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('HNSCC', 'Disease', (172, 177))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('CRC', 'Disease', 'MESH:D015179', (137, 140))	('patients', 'Species', '9606', (119, 127))	('PDAC', 'Disease', 'MESH:D021441', (179, 183))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('PC', 'Phenotype', 'HP:0012125', (186, 188))	('PDAC', 'Disease', (179, 183))	('death', 'Disease', 'MESH:D003643', (110, 115))	('ESCC', 'Disease', 'MESH:C562729', (194, 198))
372633	31598169	PVT1 may participate in the induction of apoptosis by regulating p53, and play an oncogenic role by regulating mutant p53.	('p53', 'Gene', (65, 68))	('regulating', 'Reg', (54, 64))	('p53', 'Gene', '7157', (65, 68))	('mutant', 'Var', (111, 117))	('participate', 'Reg', (9, 20))	('p53', 'Gene', (118, 121))	('PVT1', 'Gene', (0, 4))	('p53', 'Gene', '7157', (118, 121))	('regulating', 'Reg', (100, 110))	('PVT1', 'Gene', '5820', (0, 4))
372662	28699227	Some patients showed the clinical responses, and the characteristics of those patients were that: (i) the target lesion was small (<=2 cm); and (ii) they did not receive chemotherapy.2 These characteristics suggest that chemotherapy can kill sarcoma cells but simultaneously weakens immune surveillance and that intensive chemotherapy has poor compatibility with immunotherapy.	('sarcoma', 'Disease', 'MESH:D012509', (242, 249))	('weakens', 'NegReg', (275, 282))	('chemotherapy', 'Var', (220, 232))	('immune surveillance', 'MPA', (283, 302))	('patients', 'Species', '9606', (5, 13))	('patients', 'Species', '9606', (78, 86))	('sarcoma', 'Disease', (242, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('weakens immune surveillance', 'Phenotype', 'HP:0002721', (275, 302))
372727	28699227	generated TSCM from naive subsets using CD3 and CD28 stimulation and culture with IL-7 and IL-15 cytokines.13 However, the resultant TSCM cells expressed both CD45RA and CD45RO.	('CD45RA', 'Var', (159, 165))	('IL-15', 'Gene', (91, 96))	('CD28', 'Gene', '940', (48, 52))	('IL-15', 'Gene', '3600', (91, 96))	('IL-7', 'Gene', '3574', (82, 86))	('CD28', 'Gene', (48, 52))	('IL-7', 'Gene', (82, 86))	('CD45RO', 'Var', (170, 176))
372744	22949909	The finding of a chromosomal translocation EWSR1-ATF1 gene fusion as a result of the t(12:22)(q13:q12) chromosomal translocation distinguishes it from melanoma.	('t(12:22)(q13', 'Var', (85, 97))	('EWSR1', 'Gene', '2130', (43, 48))	('ATF1', 'Gene', (49, 53))	('ATF1', 'Gene', '466', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('EWSR1', 'Gene', (43, 48))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('t(12:22)(q13:q12)', 'STRUCTURAL_ABNORMALITY', 'None', (85, 102))
372814	32931516	The clinical parameters we considered were gender, age at diagnosis, pathological stage and pathologic M, N and T. In addition we considered known subtype definitions:PAM50 for breast cancer and the French-American-British classification (FAB) for AML.	('breast cancer', 'Disease', (177, 190))	('AML', 'Disease', (248, 251))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('PAM50', 'Var', (167, 172))	('AML', 'Disease', 'MESH:D015470', (248, 251))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
372870	32931516	As another example, in disease, the GBM G-CIMP subtype is associated with IDH mutations and a characteristic methylation phenotype, while its expression profile does not define the subtype as distinctly.	('IDH', 'Gene', '3417', (74, 77))	('IDH', 'Gene', (74, 77))	('associated', 'Reg', (58, 68))	('mutations', 'Var', (78, 87))
372972	27655679	The two NF1 patients showed relatively diffuse tumoral staining (density score 2-3), but the intensity varied from weak (1+) in the recurrent tumor (patient #129) to strong (3+) in the primary thigh NF1-MPNST.	('3+', 'Var', (174, 176))	('NF1', 'Gene', (8, 11))	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('NF1', 'Gene', '4763', (8, 11))	('tumor', 'Disease', (142, 147))	('patient', 'Species', '9606', (12, 19))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('MPNST', 'Phenotype', 'HP:0100697', (203, 208))	('patient', 'Species', '9606', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('NF1', 'Gene', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', (47, 52))	('NF1', 'Gene', '4763', (199, 202))
373223	28170253	The latter modification led to potent analogues with cyclopropyl, cyclohexyl, or phenyl substitution at C-7 (39-41), indicating that the C-7 position may be tolerant of further modification, at least in this series.	('cyclopropyl', 'Var', (53, 64))	('C-7', 'Gene', '730', (137, 140))	('phenyl substitution', 'Var', (81, 100))	('C-7', 'Gene', (137, 140))	('C-7', 'Gene', '730', (104, 107))	('C-7', 'Gene', (104, 107))
373241	28170253	An increase in intracellular calcium concentration was found after englerin exposure, and this was interpreted as evidence for a necrotic mechanism.	('necrotic', 'Disease', 'MESH:D009336', (129, 137))	('intracellular calcium concentration', 'MPA', (15, 50))	('englerin', 'Gene', (67, 75))	('necrotic', 'Disease', (129, 137))	('increase', 'PosReg', (3, 11))	('exposure', 'Var', (76, 84))
373259	28170253	The Waldmann group reported that transfection of TRPC4 into HEK293T cells rendered the otherwise insensitive cells sensitive to englerin A.	('transfection', 'Var', (33, 45))	('TRPC4', 'Gene', (49, 54))	('HEK293T', 'CellLine', 'CVCL:0063', (60, 67))
373282	28170253	PKCtheta is overexpressed in gastrointestinal stromal tumors, promotes mammary tumorigenesis by a novel epigenetic mechanism involving c-Rel, and has been proposed as a target for T cell leukemias.	('epigenetic', 'Var', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('c-Rel', 'Gene', '5966', (135, 140))	('leukemias', 'Phenotype', 'HP:0001909', (187, 196))	('gastrointestinal stromal tumors', 'Disease', (29, 60))	('promotes', 'PosReg', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('T cell leukemias', 'Disease', (180, 196))	('leukemia', 'Phenotype', 'HP:0001909', (187, 195))	('c-Rel', 'Gene', (135, 140))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (29, 60))	('T cell leukemias', 'Disease', 'MESH:D015458', (180, 196))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (29, 60))	('overexpressed', 'PosReg', (12, 25))	('mammary tumorigenesis', 'CPA', (71, 92))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
373290	29724044	The mechanisms most likely involve reducing the quantity and/or quality of antitumor lymphocytes, which ultimately are driven by any number of developments: tumor mutations and adaptations, reduced neoantigen generation or expression, indoleamine 2,3-dioxygenase (IDO) overexpression, loss of phosphatase and tensin homologue (PTEN) expression, and overexpression of the Wnt-beta-catenin pathway.	('tumor', 'Disease', (157, 162))	('loss', 'NegReg', (285, 289))	('PTEN', 'Gene', (327, 331))	('mutations', 'Var', (163, 172))	('tumor', 'Disease', (79, 84))	('phosphatase and tensin homologue', 'Gene', '5728', (293, 325))	('neoantigen generation', 'MPA', (198, 219))	('expression', 'MPA', (223, 233))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('beta-catenin', 'Gene', (375, 387))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('overexpression', 'PosReg', (349, 363))	('reduced', 'NegReg', (190, 197))	('beta-catenin', 'Gene', '1499', (375, 387))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('IDO', 'Gene', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('overexpression', 'PosReg', (269, 283))
373297	29724044	As recently as 2017, the US Food and Drug Administration (FDA) approved pembrolizumab for patients whose tumors have mutations in mismatch repair or microsatellite instability.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (117, 126))	('pembrolizumab', 'Chemical', 'MESH:C582435', (72, 85))	('microsatellite instability', 'Var', (149, 175))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mismatch repair', 'Var', (130, 145))	('patients', 'Species', '9606', (90, 98))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
373304	29724044	Several such mechanisms have been proposed, including the loss of T cell function, the lack of T cell recognition due to immunoediting, and the development of escape mutation variant tumor cells.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('escape mutation variant', 'Var', (159, 182))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('loss of T', 'Disease', 'MESH:D015431', (58, 67))	('tumor', 'Disease', (183, 188))	('loss of T cell', 'Phenotype', 'HP:0005403', (58, 72))	('lack of T cell recognition', 'Phenotype', 'HP:0005354', (87, 113))	('loss of T', 'Disease', (58, 67))	('loss of T cell function', 'Phenotype', 'HP:0005354', (58, 81))
373310	29724044	Once activated, CD8+ T cells recognize the presented antigens on the MHC I receptors of tumor cells, bind via a mechanism mediated by CD8-MHC I and CD28-B7, and release perforin and granzymes to induce caspase-mediated apoptosis.	('induce', 'PosReg', (195, 201))	('bind', 'Interaction', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CD8', 'Gene', (134, 137))	('CD8', 'Gene', '925', (134, 137))	('CD8', 'Gene', '925', (16, 19))	('MHC I', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CD8', 'Gene', (16, 19))	('tumor', 'Disease', (88, 93))	('caspase-mediated apoptosis', 'CPA', (202, 228))	('CD28-B7', 'Var', (148, 155))
373327	29724044	For example, microsatellite-instable (MSI) colon cancers, which have mutations in the mismatch repair gene, generate 10 to 50 times more neoantigens than do microsatellite-stable (MSS) colon cancers without such mutations.	('mutations', 'Var', (69, 78))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('colon cancers', 'Disease', 'MESH:D015179', (185, 198))	('colon cancer', 'Phenotype', 'HP:0003003', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colon cancers', 'Disease', (43, 56))	('MSI', 'Disease', 'None', (38, 41))	('colon cancer', 'Phenotype', 'HP:0003003', (185, 197))	('colon cancers', 'Phenotype', 'HP:0003003', (43, 56))	('neoantigens', 'MPA', (137, 148))	('MSI', 'Disease', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('colon cancers', 'Disease', (185, 198))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('colon cancers', 'Disease', 'MESH:D015179', (43, 56))	('more', 'PosReg', (132, 136))	('colon cancers', 'Phenotype', 'HP:0003003', (185, 198))
373331	29724044	The progeny of tumor cells with low antigen expression tend to have fewer immunologic targets, so the tumor can continue to grow.	('low', 'Var', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('antigen', 'Protein', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('fewer', 'NegReg', (68, 73))
373340	29724044	Those markers are targets for current immunotherapy: PD-1 inhibitors prevent PD-1/PD-L1 binding; and CTLA-4 inhibitors prevent CTLA-4/CD-80 binding.	('PD-1', 'Gene', (53, 57))	('binding', 'Interaction', (140, 147))	('prevent', 'NegReg', (119, 126))	('PD-1/PD-L1', 'Protein', (77, 87))	('inhibitors', 'Var', (58, 68))	('CD-80', 'Gene', (134, 139))	('CTLA-4', 'Gene', (101, 107))	('prevent', 'NegReg', (69, 76))	('inhibitors', 'Var', (108, 118))	('CD-80', 'Gene', '941', (134, 139))	('binding', 'Interaction', (88, 95))
373345	29724044	One clinical trial found better disease-free survival rates in gastric cancer patients with high MICA expression who were treated with CIK cells and adjuvant chemotherapy.	('gastric cancer', 'Disease', (63, 77))	('MICA', 'Gene', (97, 101))	('high', 'Var', (92, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('MICA', 'Gene', '100507436', (97, 101))	('better', 'PosReg', (25, 31))	('patients', 'Species', '9606', (78, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('disease-free survival rates', 'CPA', (32, 59))
373352	29724044	Other treatments proposed for enhancing MICA expression include sodium butyrate, matrix metalloproteinase inhibitor III, and phenylarsine oxide, all of which were recently shown, in multiple myeloma cell lines, to enhance MICA expression and increase cytotoxicity.	('multiple myeloma', 'Disease', (182, 198))	('phenylarsine oxide', 'Chemical', 'MESH:C029341', (125, 143))	('multiple myeloma', 'Phenotype', 'HP:0006775', (182, 198))	('increase', 'PosReg', (242, 250))	('sodium butyrate', 'Chemical', 'MESH:D020148', (64, 79))	('cytotoxicity', 'Disease', (251, 263))	('MICA', 'Gene', (40, 44))	('cytotoxicity', 'Disease', 'MESH:D064420', (251, 263))	('MICA', 'Gene', '100507436', (222, 226))	('MICA', 'Gene', '100507436', (40, 44))	('MICA', 'Gene', (222, 226))	('multiple myeloma', 'Disease', 'MESH:D009101', (182, 198))	('enhance', 'PosReg', (214, 221))	('phenylarsine', 'Var', (125, 137))
373363	29724044	Yet numerous other tumor cell alterations involving enzymatic activity and metabolism can also create changes within the tumor microenvironment, resulting in an inhibited response to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('inhibited', 'NegReg', (161, 170))	('tumor', 'Disease', (121, 126))	('changes', 'Reg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('alterations', 'Var', (30, 41))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
373364	29724044	Four such mechanisms that have been proposed are induction of indoleamine 2,3-dioxygenase (IDO), loss of phosphatase and tensin homologue (PTEN) expression, deregulated expression of the Wnt-beta-catenin pathway, and mutations in the interferon gamma (IFN-gamma) Pathway.	('loss', 'NegReg', (97, 101))	('beta-catenin', 'Gene', (191, 203))	('deregulated', 'Var', (157, 168))	('PTEN', 'Gene', (139, 143))	('phosphatase and tensin homologue', 'Gene', '5728', (105, 137))	('beta-catenin', 'Gene', '1499', (191, 203))	('interferon gamma (IFN-gamma', 'Gene', '3458', (234, 261))	('expression', 'MPA', (169, 179))	('mutations', 'Var', (217, 226))
373374	29724044	recently showed that immunostimulatory treatments:including radiotherapy and the use of CpG oligodeoxynucleotide (a toll-like receptor 9 agonist):was associated with a significant increase in cells expressing IDO (vs. controls), particularly in neoplastic epithelial cells.	('CpG oligodeoxynucleotide', 'Var', (88, 112))	('increase', 'PosReg', (180, 188))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (92, 112))	('IDO', 'Disease', (209, 212))	('cells', 'MPA', (192, 197))
373380	29724044	Loss of PTEN, a tumor suppressor, has also been implicated in resistance to immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('PTEN', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('resistance to immunotherapy', 'CPA', (62, 89))	('Loss', 'Var', (0, 4))	('implicated', 'Reg', (48, 58))
373382	29724044	Several studies of tissue specimens of glioblastoma demonstrated that T cells more effectively lysed tumor cells with wild-type PTEN and were less effective in lysing tumor cells with mutant PTEN: the decrease in lysis was associated with an increase in B7-H1 cell receptor expression.	('expression', 'MPA', (274, 284))	('lysis', 'MPA', (213, 218))	('glioblastoma', 'Disease', (39, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (39, 51))	('mutant', 'Var', (184, 190))	('increase', 'PosReg', (242, 250))	('PTEN', 'Gene', (191, 195))	('tumor', 'Disease', (101, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('B7-H1', 'CellLine', 'CVCL:0I14', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('decrease', 'NegReg', (201, 209))	('B7-H1 cell receptor', 'Protein', (254, 273))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
373384	29724044	showed that silencing PTEN decreased T-cell activity against tumor cells, both in vitro and in vivo, demonstrating resistance to T-cell-mediated killing of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('decreased', 'NegReg', (27, 36))	('decreased T-cell', 'Phenotype', 'HP:0005403', (27, 43))	('silencing', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PTEN', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (61, 66))
373385	29724044	showed that PTEN was correlated with decreased tumor infiltration, decreased function of T cells, and poorer outcomes in human melanoma patients treated with checkpoint therapy.	('decreased tumor infiltration', 'Disease', 'MESH:D017254', (37, 65))	('PTEN', 'Var', (12, 16))	('decreased tumor infiltration', 'Disease', (37, 65))	('patients', 'Species', '9606', (136, 144))	('human', 'Species', '9606', (121, 126))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('melanoma', 'Disease', (127, 135))	('decreased', 'NegReg', (67, 76))	('function of T cells', 'CPA', (77, 96))
373386	29724044	The mechanism of such resistance in PTEN-negative tumors is currently unclear, although errors in PTEN might confer resistance to tumors via the release of anti-inflammatory cytokines, such as CCL2 and vascular endothelial growth factor (VEGF), resulting in reduced tumor cell infiltration by CD8+ T cells.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('reduced', 'NegReg', (258, 265))	('errors', 'Var', (88, 94))	('tumor', 'Disease', (266, 271))	('tumor', 'Disease', (130, 135))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('CD8', 'Gene', '925', (293, 296))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('CCL2', 'Gene', (193, 197))	('PTEN', 'Gene', (98, 102))	('release', 'MPA', (145, 152))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('vascular endothelial growth factor', 'Gene', '7422', (202, 236))	('CD8', 'Gene', (293, 296))	('VEGF', 'Gene', '7422', (238, 242))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (130, 136))	('CCL2', 'Gene', '6347', (193, 197))	('VEGF', 'Gene', (238, 242))	('vascular endothelial growth factor', 'Gene', (202, 236))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))
373394	29724044	Previous studies have demonstrated that CCL4 expression is associated with an improved response to immunotherapy, including ipilimumab, in melanoma.	('response', 'MPA', (87, 95))	('CCL4', 'Gene', '6351', (40, 44))	('CCL4', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('ipilimumab', 'Chemical', 'MESH:D000074324', (124, 134))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('improved', 'PosReg', (78, 86))	('expression', 'Var', (45, 55))
373398	29724044	In human patients with melanoma, responders (vs nonresponders) to ipilimumab have been found to be much more likely to have mutations involving IFN-gamma.	('patients', 'Species', '9606', (9, 17))	('IFN-gamma', 'Protein', (144, 153))	('mutations', 'Var', (124, 133))	('ipilimumab', 'Chemical', 'MESH:D000074324', (66, 76))	('human', 'Species', '9606', (3, 8))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))
373400	29724044	Similarly, human patients with metastatic melanoma and metastatic colon carcinoma who lost IFN-gamma function, due to JAK mutations, had innate resistance to PD-1 checkpoint therapy.	('melanoma', 'Disease', (42, 50))	('IFN-gamma', 'Protein', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('human', 'Species', '9606', (11, 16))	('colon carcinoma', 'Disease', 'MESH:D015179', (66, 81))	('colon carcinoma', 'Disease', (66, 81))	('mutations', 'Var', (122, 131))	('lost', 'NegReg', (86, 90))	('patients', 'Species', '9606', (17, 25))	('function', 'MPA', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
373410	29724044	By regulating transcription, epigenetic markers can either prime or inhibit the immune response in the tumor microenvironment; they are also thought to contribute to reduced immunological expression in resistant tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('immunological expression', 'MPA', (174, 198))	('tumors', 'Disease', (212, 218))	('tumor', 'Disease', (103, 108))	('transcription', 'MPA', (14, 27))	('prime', 'PosReg', (59, 64))	('reduced', 'NegReg', (166, 173))	('inhibit', 'NegReg', (68, 75))	('regulating', 'Reg', (3, 13))	('tumor', 'Disease', (212, 217))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('epigenetic markers', 'Var', (29, 47))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))
373412	29724044	For example, HDAC inhibitors have been shown to enhance T cell function and survival.	('T cell function', 'CPA', (56, 71))	('enhance T cell', 'Phenotype', 'HP:0100828', (48, 62))	('enhance', 'PosReg', (48, 55))	('HDAC', 'Gene', (13, 17))	('survival', 'CPA', (76, 84))	('HDAC', 'Gene', '9734', (13, 17))	('inhibitors', 'Var', (18, 28))
373413	29724044	Currently, multiple clinical trials of combination treatment with epigenetic drugs and immunotherapy are enrolling patients with various cancers, including non-small cell lung cancer, breast cancer, and melanoma.	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('non-small cell lung cancer', 'Disease', (156, 182))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('epigenetic', 'Var', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (156, 182))	('patients', 'Species', '9606', (115, 123))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (160, 182))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (156, 182))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('breast cancer', 'Disease', (184, 197))
373415	29724044	It works by selectively blocking essential biochemical pathways or by inhibiting mutant proteins that are crucial for tumor cell growth and survival, such as tyrosine kinases.	('tyrosine kinases', 'MPA', (158, 174))	('essential biochemical pathways', 'Pathway', (33, 63))	('blocking', 'NegReg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('inhibiting', 'NegReg', (70, 80))	('tumor', 'Disease', (118, 123))	('proteins', 'Protein', (88, 96))	('mutant', 'Var', (81, 87))
373421	29724044	The use of checkpoint inhibitors has expanded to treat patients with numerous types of cancer, including melanoma, renal cell carcinoma, and non-small cell lung cancer; it has also been approved for patients whose tumors have mutations in mismatch repair (e.g., MSI colon cancers.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('tumors', 'Disease', (214, 220))	('cancer', 'Disease', (161, 167))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('colon cancers', 'Disease', 'MESH:D015179', (266, 279))	('renal cell carcinoma', 'Disease', (115, 135))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (115, 135))	('colon cancers', 'Disease', (266, 279))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutations', 'Var', (226, 235))	('non-small cell lung cancer', 'Disease', (141, 167))	('colon cancer', 'Phenotype', 'HP:0003003', (266, 278))	('MSI', 'Disease', 'None', (262, 265))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (115, 135))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('patients', 'Species', '9606', (199, 207))	('MSI', 'Disease', (262, 265))	('patients', 'Species', '9606', (55, 63))	('colon cancers', 'Phenotype', 'HP:0003003', (266, 279))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
373573	29113210	The following are the diagnostic criteria of primary bone lymphoma proposed by the World Health Organization: i) Single-bone invasion, with/without local lymph node involvement; and ii) multiple-bone invasion, without involvement of the lymph nodes and internal organs.	('primary bone lymphoma', 'Disease', 'MESH:D001859', (45, 66))	('multiple-bone', 'Var', (186, 199))	('bone lymphoma', 'Phenotype', 'HP:0011953', (53, 66))	('primary bone lymphoma', 'Disease', (45, 66))	('Single-bone', 'Disease', (113, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (58, 66))
373591	28938660	Our meta-analysis indicated that high PD-L1 expression is likely to be a negative factor for patients with sarcomas and that it predicts worse survival outcomes.	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('expression', 'MPA', (44, 54))	('high', 'Var', (33, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('negative', 'NegReg', (73, 81))	('sarcomas', 'Disease', (107, 115))	('patients', 'Species', '9606', (93, 101))	('PD-L1', 'Protein', (38, 43))
373609	28938660	As for individual histological type, PD-L1 was a poor prognostic factor for osteosarcoma with a pooled HR of 1.908 (95% CI: 1.093-3.331, p = 0.023) (Figure 2B).	('PD-L1', 'Var', (37, 42))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('osteosarcoma', 'Disease', (76, 88))	('osteosarcoma', 'Disease', 'MESH:D012516', (76, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
373616	28938660	Using a fixed-effects model, pooled OR was calculated to be 4.012 (95% CI: 2.391-6.733, p = 0.000), indicating that PD-L1 expression was significantly associated with the infiltration of PD-1 positive lymphocytes (Figure 4A).	('associated with', 'Reg', (151, 166))	('expression', 'Var', (122, 132))	('PD-L1', 'Gene', (116, 121))	('infiltration', 'CPA', (171, 183))	('PD-1', 'Gene', (187, 191))	('PD-1', 'Gene', '5133', (187, 191))
373626	28938660	Recent studies have indicated that high expression of PD-L1 is associated with poor prognosis in non-small cell lung cancer, kidney cancer, bladder cancer, prostate and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('high expression', 'Var', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('non-small cell lung cancer', 'Disease', (97, 123))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('prostate', 'Disease', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('kidney cancer', 'Disease', 'MESH:D007680', (125, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('PD-L1', 'Gene', (54, 59))	('bladder cancer', 'Disease', 'MESH:D001749', (140, 154))	('bladder cancer', 'Disease', (140, 154))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (97, 123))	('prostate', 'Disease', 'MESH:D011472', (156, 164))	('gastric cancer', 'Disease', (169, 183))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (101, 123))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('kidney cancer', 'Phenotype', 'HP:0009726', (125, 138))	('kidney cancer', 'Disease', (125, 138))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (97, 123))
373629	28938660	For all sarcoma patients, we found that the expression of PD-L1 was significantly associated with poor event-free survival.	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('associated', 'Reg', (82, 92))	('patients', 'Species', '9606', (16, 24))	('expression', 'Var', (44, 54))	('sarcoma', 'Disease', (8, 15))	('poor', 'NegReg', (98, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('PD-L1', 'Gene', (58, 63))	('event-free survival', 'CPA', (103, 122))
373631	28938660	As for patient ethnicity, there was a significant association between PD-L1 expression and poor overall survival in non-Asian patients, but one should draw conclusions carefully, in consideration of bias caused by the cut-off.	('overall', 'MPA', (96, 103))	('patient', 'Species', '9606', (7, 14))	('patient', 'Species', '9606', (126, 133))	('patients', 'Species', '9606', (126, 134))	('expression', 'Var', (76, 86))	('PD-L1', 'Gene', (70, 75))
373636	28938660	In this case, blockade of PD-L1 might help reactivate inhibited T cells to increase the antitumor immune response.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('PD-L1', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('blockade', 'Var', (14, 22))	('tumor', 'Disease', (92, 97))	('increase', 'PosReg', (75, 83))
373645	28938660	In conclusion, this meta-analysis demonstrated that PD-L1 expression may be an effective predictive factor of poor prognosis and clinicopathological features for bone and soft tissue sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (183, 191))	('soft tissue sarcoma', 'Disease', (171, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (171, 190))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (171, 190))	('expression', 'Var', (58, 68))	('sarcomas', 'Disease', (183, 191))	('PD-L1', 'Gene', (52, 57))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (171, 191))
373670	27566104	The development and progression of solid tumors is dependent on both tumor cell autonomous factors, such as the presence of oncogenic mutations, and on the contributions of the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (69, 74))	('solid tumors', 'Disease', (35, 47))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('solid tumors', 'Disease', 'MESH:D009369', (35, 47))	('mutations', 'Var', (134, 143))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
373709	27566104	Immunofluorescence labeling of Ewing cells with conjugated phalloidin revealed alterations in F-actin filament distribution in all three cell lines following 24 hours in SFM.	('phalloidin', 'Chemical', 'MESH:D010590', (59, 69))	('SFM', 'Var', (170, 173))	('alterations', 'Reg', (79, 90))	('F-actin filament distribution', 'MPA', (94, 123))
373737	27566104	Indeed, we found that Src phosphorylation at tyrosine 416 increased in Ewing sarcoma cells following exposure to the dual stress of hypoxia and SFM (Figure 5A), raising the possibility that inhibition of Src might result in inhibition of stress-mediated invadopodia formation and matrix degradation.	('tyrosine', 'Chemical', 'MESH:D014443', (45, 53))	('Src', 'Gene', '6714', (22, 25))	('inhibition', 'NegReg', (224, 234))	('Ewing sarcoma', 'Disease', (71, 84))	('matrix degradation', 'CPA', (280, 298))	('increased', 'PosReg', (58, 67))	('hypoxia', 'Disease', 'MESH:D000860', (132, 139))	('inhibition', 'Var', (190, 200))	('Src', 'Gene', '6714', (204, 207))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (71, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('Src', 'Gene', (22, 25))	('Src', 'Gene', (204, 207))	('hypoxia', 'Disease', (132, 139))	('phosphorylation', 'MPA', (26, 41))
373740	27566104	While other in vitro Src inhibitors such as PP2 and SU6656 are commercially available, we chose to test dasatinib as the Src inhibitor for our studies given its immediate clinical applicability.	('PP2', 'Gene', '4888', (44, 47))	('Src', 'Gene', '6714', (121, 124))	('SU6656', 'Chemical', 'MESH:C416927', (52, 58))	('Src', 'Gene', (21, 24))	('Src', 'Gene', '6714', (21, 24))	('SU6656', 'Var', (52, 58))	('dasatinib', 'Chemical', 'MESH:D000069439', (104, 113))	('Src', 'Gene', (121, 124))	('PP2', 'Gene', (44, 47))
373746	27566104	Finally, we assessed whether dasatinib could also inhibit stress-enhanced matrix degradation and observed that inhibition of Src kinase activation could indeed effectively block matrix degradation (Figure 6A).	('stress-enhanced', 'MPA', (58, 73))	('inhibition', 'Var', (111, 121))	('Src', 'Gene', '6714', (125, 128))	('block', 'NegReg', (172, 177))	('inhibit', 'NegReg', (50, 57))	('matrix degradation', 'CPA', (74, 92))	('matrix degradation', 'CPA', (178, 196))	('Src', 'Gene', (125, 128))	('dasatinib', 'Chemical', 'MESH:D000069439', (29, 38))
373783	27401493	The fusion transcripts included SS18-SSX1 (15/22, 68.2 %), SS18-SSX2 including variants (6/22, 27.3 %), and SS18-SSX4 (1/22, 4.5 %) fusions.	('SSX1', 'Gene', '6756', (37, 41))	('fusions', 'Var', (132, 139))	('SSX4', 'Gene', (113, 117))	('SS18', 'Gene', '6760', (59, 63))	('SSX1', 'Gene', (37, 41))	('SS18', 'Gene', (32, 36))	('SSX2', 'Gene', '6757', (64, 68))	('variants', 'Var', (79, 87))	('SS18', 'Gene', '6760', (108, 112))	('SSX2', 'Gene', (64, 68))	('SS18', 'Gene', (59, 63))	('SS18', 'Gene', '6760', (32, 36))	('SS18', 'Gene', (108, 112))	('SSX4', 'Gene', '6759', (113, 117))
373790	27401493	SSs are characterized by the t(X;18)(p11.2;q11.2) translocation, which leads to SS18-SSX gene fusion, and extremely rare neoplasms harbor SS18L1-SSX1, resulting from t(X;20).	('neoplasms', 'Disease', (121, 130))	('SSX', 'Gene', (85, 88))	('SS18L1', 'Gene', '26039', (138, 144))	('SSX', 'Gene', '6757', (145, 148))	('SSs', 'Disease', (0, 3))	('SS18', 'Gene', '6760', (138, 142))	('t(X;20', 'Var', (166, 172))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (29, 49))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))	('SSX', 'Gene', (145, 148))	('leads to', 'Reg', (71, 79))	('SS18', 'Gene', (80, 84))	('neoplasm', 'Phenotype', 'HP:0002664', (121, 129))	('SS18L1', 'Gene', (138, 144))	('SSX1', 'Gene', '6756', (145, 149))	('SSX1', 'Gene', (145, 149))	('neoplasms', 'Disease', 'MESH:D009369', (121, 130))	('SSX', 'Gene', '6757', (85, 88))	('SS18', 'Gene', '6760', (80, 84))	('SS18', 'Gene', (138, 142))
373862	27401493	The fusion transcripts included SS18-SSX1 (15/22, 68.2 %), SS18-SSX2 (6/22, 27.3 %), and SS18-SSX4 (1/22, 4.5 %) fusions.	('SSX1', 'Gene', '6756', (37, 41))	('SS18', 'Gene', '6760', (59, 63))	('SSX1', 'Gene', (37, 41))	('SS18', 'Gene', (32, 36))	('fusions', 'Var', (113, 120))	('SS18', 'Gene', '6760', (89, 93))	('SSX2', 'Gene', (64, 68))	('SS18', 'Gene', (89, 93))	('SS18', 'Gene', (59, 63))	('SSX4', 'Gene', '6759', (94, 98))	('SS18', 'Gene', '6760', (32, 36))	('SSX4', 'Gene', (94, 98))	('SSX2', 'Gene', '6757', (64, 68))
373872	27401493	Log-rank analyses on the prognostic parameters were as follows: gender (chi2 = 1.25, p = 0.246 > 0.05), age (>=37 vs. <37; chi2 = 0.064, p = 0.800 > 0.05), tumor size (>=5 cm vs. <5 cm; chi2 = 0.56, p = 0.454 > 0.05), FNCLCC grade (chi2 = 0.17, p = 0.685 > 0.05), fusion gene types (SS18-SSX1 vs. SS18-SSX2; chi2 = 0.10, p = 0.756 > 0.05), mitotic rate (>=10/10 HPFs vs. <10/10 HPFs; chi2 = 0.01, p = 0.925 > 0.05), tumor resection (yes vs. no; chi2 = 5.13, p = 0.024 < 0.05) and tumor residual status (yes vs. no; chi2 = 8.55, p = 0.004 < 0.05).	('SSX2', 'Gene', (302, 306))	('SS18', 'Gene', (297, 301))	('SSX2', 'Gene', '6757', (302, 306))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (480, 485))	('SS18', 'Gene', '6760', (283, 287))	('tumor', 'Disease', (416, 421))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (480, 485))	('FNCLCC grade', 'CPA', (218, 230))	('tumor', 'Disease', 'MESH:D009369', (416, 421))	('>=10/10 HPFs', 'Var', (354, 366))	('SS18', 'Gene', '6760', (297, 301))	('SSX1', 'Gene', '6756', (288, 292))	('SSX1', 'Gene', (288, 292))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (480, 485))	('tumor', 'Phenotype', 'HP:0002664', (416, 421))	('SS18', 'Gene', (283, 287))	('mitotic rate', 'CPA', (340, 352))
373877	27401493	The mean age of patients with PPMSS in this study was somewhat lower than that reported in the largest series (37.8 years vs. 42 years) and much lower than that of the Japanese series (37.8 years vs. 58 years).	('lower', 'NegReg', (145, 150))	('PPMSS', 'Var', (30, 35))	('patients', 'Species', '9606', (16, 24))	('lower', 'NegReg', (63, 68))
373897	27401493	This finding has not been described in PPMSSs, although it has been reported in soft tissue SSs, and the presence of aneuploidy or amplificon of chromosome 18q might account for this event.	('amplificon', 'Var', (131, 141))	('aneuploidy', 'Disease', 'MESH:D000782', (117, 127))	('aneuploidy', 'Disease', (117, 127))
373978	25974965	siRNA-mediated knockdown of UXT was associated with a considerable increase in p53 abundance (Figure 2A).	('p53', 'Gene', '7157', (79, 82))	('increase', 'PosReg', (67, 75))	('p53', 'Gene', (79, 82))	('knockdown', 'Var', (15, 24))
373979	25974965	The use of multiple siRNA sequences of UXT indicated that p53 activation was specifically caused by UXT knockdown.	('UXT', 'MPA', (100, 103))	('p53', 'Gene', (58, 61))	('activation', 'PosReg', (62, 72))	('knockdown', 'Var', (104, 113))	('p53', 'Gene', '7157', (58, 61))
373983	25974965	This increase of p21 in UXT-depleted cells was p53-dependent as siRNA-mediated p53 knockdown or E6-mediated p53 degradation completely abolished this effect of UXT (Supplementary Figure 2).	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('p21', 'Gene', '644914', (17, 20))	('increase', 'PosReg', (5, 13))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('knockdown', 'Var', (83, 92))	('p21', 'Gene', (17, 20))
373987	25974965	Consistent with the data of cell proliferation, U2OS_UXT cells developed into significantly larger tumors than U2OS_EV cells (Supplementary.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('U2OS', 'CellLine', 'CVCL:0042', (48, 52))	('U2OS_UXT cells', 'Var', (48, 62))	('U2OS', 'CellLine', 'CVCL:0042', (111, 115))	('larger', 'PosReg', (92, 98))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
373988	25974965	Immunohistochemistry analysis of Ki67, a commonly used proliferation marker, indicated a higher rate of cell proliferation in U2OS_UXT cells than U2OS_EV cells (Figure 2F).	('U2OS', 'CellLine', 'CVCL:0042', (126, 130))	('cell proliferation', 'CPA', (104, 122))	('higher', 'PosReg', (89, 95))	('U2OS', 'CellLine', 'CVCL:0042', (146, 150))	('U2OS_UXT', 'Var', (126, 134))
373993	25974965	Indeed, a clear increase in nuclear localization of p65 was evident when U2OS_UXT expressing cells were compared with the U2OS_EV cells (Figure 3B).	('U2OS', 'CellLine', 'CVCL:0042', (122, 126))	('nuclear localization', 'MPA', (28, 48))	('p65', 'Gene', '5970', (52, 55))	('U2OS_UXT', 'Var', (73, 81))	('U2OS', 'CellLine', 'CVCL:0042', (73, 77))	('increase', 'PosReg', (16, 24))	('p65', 'Gene', (52, 55))
373994	25974965	In support of increased NF-kappaB activity, Immunoblot with a phosphor-specific antibody revealed that p65 was markedly phosphorylated in U2OS_UXT but not U2OS_EV cells (Figure 3C).	('activity', 'MPA', (34, 42))	('increased', 'PosReg', (14, 23))	('U2OS_UXT', 'Var', (138, 146))	('p65', 'Gene', '5970', (103, 106))	('NF-kappaB', 'Gene', '4790', (24, 33))	('U2OS', 'CellLine', 'CVCL:0042', (138, 142))	('U2OS', 'CellLine', 'CVCL:0042', (155, 159))	('NF-kappaB', 'Gene', (24, 33))	('p65', 'Gene', (103, 106))
374011	25974965	Interestingly, the expression of multiple glycolytic genes including GLUT-1 & 3, HK-2 & 3, LDHA and ENO was significantly increased in UXT expressing cells when compared with the control cells (Figure 4D).	('LDHA', 'Gene', '3939', (91, 95))	('expression', 'MPA', (19, 29))	('GLUT-1 &', 'Gene', (69, 77))	('was', 'PosReg', (104, 107))	('glycolytic genes', 'Gene', (42, 58))	('increased in', 'Var', (122, 134))	('LDHA', 'Gene', (91, 95))
374024	25974965	However, treatment with 2DG was associated with a much greater increase in gammaH2AX-positive cells in U2OS_UXT cells than U2OS_EV cells (Figure 5C), indicating that inhibition of glycolysis preferentially sensitized U2OS_UXT cells over U2OS_EV cells.	('increase', 'PosReg', (63, 71))	('U2OS', 'CellLine', 'CVCL:0042', (217, 221))	('gammaH2AX-positive', 'Protein', (75, 93))	('U2OS', 'CellLine', 'CVCL:0042', (237, 241))	('U2OS', 'CellLine', 'CVCL:0042', (103, 107))	('2DG', 'Chemical', 'MESH:D003847', (24, 27))	('U2OS', 'CellLine', 'CVCL:0042', (123, 127))	('inhibition', 'Var', (166, 176))
374036	25974965	P53 inactivation would not only result in impediment of its canonical tumor suppressive activities such as cell cycle arrest, senescence or apoptosis, but also unleashing its restraint on NF-kappaB leading to the activation this oncogenic transcription factor.	('inactivation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('oncogenic transcription', 'Gene', (229, 252))	('NF-kappaB', 'Gene', '4790', (188, 197))	('tumor', 'Disease', (70, 75))	('apoptosis', 'CPA', (140, 149))	('cell cycle arrest', 'CPA', (107, 124))	('NF-kappaB', 'Gene', (188, 197))	('activation', 'PosReg', (213, 223))	('restraint', 'MPA', (175, 184))	('P53', 'Gene', (0, 3))	('senescence', 'CPA', (126, 136))	('P53', 'Gene', '7157', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (107, 124))
374041	25974965	The increased sensitivity by inhibition of glycolysis could be due to reduced DNA damage repair since we recently showed that inhibition of glycolysis in cancer cells resulted in chromatin compaction, impeding the assess of DNA damage repair proteins.	('inhibition', 'Var', (126, 136))	('impeding', 'NegReg', (201, 209))	('chromatin compaction', 'CPA', (179, 199))	('resulted in', 'Reg', (167, 178))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('glycolysis', 'MPA', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('assess', 'MPA', (214, 220))
374087	24729433	Infection with HHV-8 is a necessary, but not sufficient, cause of Kaposi's Sarcoma (KS).	('cause', 'Reg', (57, 62))	('HHV-8', 'Gene', (15, 20))	("Kaposi's Sarcoma", 'Disease', (66, 82))	('HHV-8', 'Species', '37296', (15, 20))	("Kaposi's Sarcoma", 'Phenotype', 'HP:0100726', (66, 82))	('Sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('Infection', 'Var', (0, 9))	("Kaposi's Sarcoma", 'Disease', 'MESH:D012514', (66, 82))
374257	25699174	For example, cyclosporine (calcineurin inhibition) is known to promote tumour cell invasiveness and boost vascular endothelial growth factor-induced angiogenesis that nourishes cancer growth.	('cancer', 'Disease', (177, 183))	('vascular endothelial growth factor', 'Gene', (106, 140))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('tumour cell invasiveness', 'Disease', 'MESH:D009361', (71, 95))	('vascular endothelial growth factor', 'Gene', '7422', (106, 140))	('cyclosporine', 'Var', (13, 25))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('promote', 'PosReg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cyclosporine', 'Chemical', 'MESH:D016572', (13, 25))	('tumour cell invasiveness', 'Disease', (71, 95))	('boost', 'PosReg', (100, 105))
374263	25699174	Inhibition of mTOR sets up a unique molecular scenario whereby it is plausible that various aspects of tumour development could be inhibited while at the same time causing a general immunosuppression that protects allografts from rejection.	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('Inhibition', 'Var', (0, 10))	('inhibited', 'NegReg', (131, 140))	('tumour', 'Disease', (103, 109))	('causing', 'Reg', (164, 171))	('mTOR', 'Gene', (14, 18))
374272	25699174	Another aspect is the multitude of mutations in key signalling molecules that have been described upstream of the mTOR complex 1 signalling node that result in constitutive activation of the mTOR pathway and thus uncontrolled cell growth and proliferation; included in this extensive list are mutations in PTEN, TSC1/2 and Ras/Raf that lead to mTOR complex 1 activation.	('activation', 'PosReg', (359, 369))	('Raf', 'Gene', (327, 330))	('PTEN', 'Gene', (306, 310))	('PTEN', 'Gene', '5728', (306, 310))	('mutations', 'Var', (293, 302))	('mTOR complex 1', 'Enzyme', (344, 358))	('TSC1/2', 'Gene', '7248;7249', (312, 318))	('Raf', 'Gene', '22882', (327, 330))	('TSC1/2', 'Gene', (312, 318))	('mTOR pathway', 'Pathway', (191, 203))	('mutations', 'Var', (35, 44))
374273	25699174	Pkd-1 mutations can also result in triggering of the mTOR pathway and have been linked to cell proliferation and the development of polycystic kidney disease; blocking mTOR with rapamycin can substantially inhibit the proliferation of cysts in mice with this conditionally expressed mutation.	('mTOR', 'Gene', (168, 172))	('mTOR pathway', 'Pathway', (53, 65))	('proliferation of cysts', 'CPA', (218, 240))	('mice', 'Species', '10090', (244, 248))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (132, 157))	('Pkd-1', 'Gene', '18763', (0, 5))	('polycystic kidney disease', 'Disease', (132, 157))	('kidney disease', 'Phenotype', 'HP:0000112', (143, 157))	('rapamycin', 'Chemical', 'MESH:D020123', (178, 187))	('blocking', 'Var', (159, 167))	('polycystic kidney', 'Phenotype', 'HP:0000113', (132, 149))	('inhibit', 'NegReg', (206, 213))	('Pkd-1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
374274	25699174	Therefore, inhibition of mTOR has substantial mechanistic potential to be considered overall as an anti-cancer agent.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('inhibition', 'Var', (11, 21))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('mTOR', 'Gene', (25, 29))
374277	25699174	While the mechanisms for the anti-viral effect are not well understood yet, it seems some viruses are responsive to mTOR inhibition, and mTOR inhibitors have been shown to boost CD8 T cell responses induced by viral vaccines, even at immunosuppressive doses in non-human primates.	('inhibitors', 'Var', (142, 152))	('CD8', 'Gene', (178, 181))	('CD8', 'Gene', '925', (178, 181))	('human', 'Species', '9606', (265, 270))	('boost', 'PosReg', (172, 177))
374309	25699174	While suppression of the immune reactivity against cancer cannot be completely avoided with an immunosuppressive drug, mTOR inhibitors have a unique potential to both suppress an immune response to the organ allograft and promote mechanisms that can potentially inhibit tumour development.	('tumour', 'Disease', 'MESH:D009369', (270, 276))	('promote', 'PosReg', (222, 229))	('tumour', 'Disease', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('immune', 'MPA', (179, 185))	('mTOR', 'Gene', (119, 123))	('suppress', 'NegReg', (167, 175))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('inhibitors', 'Var', (124, 134))	('inhibit', 'NegReg', (262, 269))
374310	25699174	The basic research to better understand this phenomenon continues to evolve at a steady pace, but in the meantime, clinical trials in transplant recipients already indicate that skin cancer can be reduced by substitution of calcineurin inhibitors with mTOR inhibitors.	('skin cancer', 'Phenotype', 'HP:0008069', (178, 189))	('substitution', 'Var', (208, 220))	('skin cancer', 'Disease', (178, 189))	('skin cancer', 'Disease', 'MESH:D012878', (178, 189))	('reduced', 'NegReg', (197, 204))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))
374413	33293655	There was a higher proportion of recipients who suffered from graft failure in the PTM group than the non-PTM group (P < 0.001).	('PTM', 'Var', (83, 86))	('graft failure', 'Disease', (62, 75))	('graft failure', 'Disease', 'MESH:D006333', (62, 75))
374488	33293655	The ICD-10-CM codes for CMV disease were B27.1, B25.0, B25.1, B25.8, and B25.9.	('B25.1', 'Var', (55, 60))	('B25.9', 'Var', (73, 78))	('CMV disease', 'Disease', 'MESH:D003141', (24, 35))	('B25.0', 'Var', (48, 53))	('B27.1', 'Var', (41, 46))	('B25.8', 'Var', (62, 67))	('CMV disease', 'Disease', (24, 35))
374752	30519038	It is demonstrated that the aberrant miRNAs expression profiles are involved in tumor initiation, progression and metastasis, including Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (136, 151))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('miR', 'Gene', '220972', (37, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('miR', 'Gene', (37, 40))	('metastasis', 'CPA', (114, 124))	('involved', 'Reg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('aberrant', 'Var', (28, 36))	('tumor', 'Disease', (80, 85))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (136, 151))	("Ewing's sarcoma", 'Disease', (136, 151))
374758	30519038	In addition, it is demonstrated that miR-185 is associated with the prognosis of patients with colorectal cancer, high expression of miR-185 is correlated with poor survival and metastasis.	('miR-185', 'Gene', (37, 44))	('poor', 'NegReg', (160, 164))	('miR-185', 'Gene', (133, 140))	('high', 'Var', (114, 118))	('colorectal cancer', 'Disease', (95, 112))	('associated', 'Reg', (48, 58))	('patients', 'Species', '9606', (81, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('miR-185', 'Gene', '406961', (37, 44))	('metastasis', 'CPA', (178, 188))	('miR-185', 'Gene', '406961', (133, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
374769	30519038	The primer for mature miR-185 and U6 RNA was obtained from Ribo-bio, and the primer sequences were as follows: miR-185, 5'-TGGAGAGAAAGGCAGTTCCTGA-3' (forward) and the reverse primer was obtained from the miRNA qPCR Assay Kit; U6, 5'-CTCGCTTCGGCAGCACA-3' (forward) and AACGCTTCACGAATTTGCGT (reverse).	('miR', 'Gene', '220972', (22, 25))	('miR-185', 'Gene', '406961', (111, 118))	('miR', 'Gene', (22, 25))	('miR', 'Gene', '220972', (204, 207))	('miR-185', 'Gene', '406961', (22, 29))	('AACGCTTCACGAATTTGCGT', 'Var', (268, 288))	('miR-185', 'Gene', (111, 118))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))	('miR', 'Gene', (204, 207))	('miR-185', 'Gene', (22, 29))
374787	30519038	The wide-type (wt) or mutated (mut) E2F6 3'UTR was constructed into pmirGLO vector.	('mutated', 'Var', (22, 29))	('E2F6', 'Gene', '1876', (36, 40))	('E2F6', 'Gene', (36, 40))
374814	30519038	Wnt/beta-catenin pathway is also essential for several cellular processes, and its dysregulation will be involved in the progression of malignancy.	('malignancy', 'Disease', (136, 146))	('beta-catenin', 'Gene', '1499', (4, 16))	('dysregulation', 'Var', (83, 96))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('involved', 'Reg', (105, 113))	('beta-catenin', 'Gene', (4, 16))
374826	30519038	In addition, we observed that E2F6 knockdown (E2F6-KD) significantly reduced the expression of p-Akt and beta-catenin (Figure 5E), resulting in an inhibition on Akt/mTOR and Wnt/beta-catenin pathways in RD-ES cells, while E2F6 overexpression (E2F6-OE) did no significant effect on expression of p-Akt and beta-catenin.	('beta-catenin', 'Gene', '1499', (105, 117))	('expression', 'MPA', (81, 91))	('Akt', 'Gene', (297, 300))	('E2F6', 'Gene', '1876', (46, 50))	('E2F6', 'Gene', (46, 50))	('E2F6', 'Gene', '1876', (222, 226))	('E2F6', 'Gene', (222, 226))	('Akt', 'Gene', '207', (297, 300))	('knockdown', 'Var', (35, 44))	('beta-catenin', 'Gene', (178, 190))	('inhibition', 'NegReg', (147, 157))	('E2F6', 'Gene', (243, 247))	('mTOR', 'Gene', (165, 169))	('Akt', 'Gene', (161, 164))	('E2F6', 'Gene', '1876', (243, 247))	('E2F6', 'Gene', '1876', (30, 34))	('E2F6', 'Gene', (30, 34))	('beta-catenin', 'Gene', '1499', (178, 190))	('Akt', 'Gene', (97, 100))	('reduced', 'NegReg', (69, 76))	('beta-catenin', 'Gene', (105, 117))	('Akt', 'Gene', '207', (161, 164))	('beta-catenin', 'Gene', (305, 317))	('mTOR', 'Gene', '2475', (165, 169))	('Akt', 'Gene', '207', (97, 100))	('beta-catenin', 'Gene', '1499', (305, 317))
374870	30519038	We further revealed that loss of E2F6 could suppress the Akt/mTOR and Wnt/beta-catenin pathways in RD-ES cells, while upregulation of E2F6 had no significant effect on these signaling pathway, indicating that the regulation of E2F6 on Akt/mTOR and Wnt/beta-catenin signaling pathways requires synergy of other factors.	('Akt', 'Gene', '207', (57, 60))	('E2F6', 'Gene', '1876', (33, 37))	('E2F6', 'Gene', (33, 37))	('mTOR', 'Gene', '2475', (61, 65))	('mTOR', 'Gene', (239, 243))	('Akt', 'Gene', (235, 238))	('E2F6', 'Gene', (134, 138))	('E2F6', 'Gene', '1876', (134, 138))	('Akt', 'Gene', '207', (235, 238))	('mTOR', 'Gene', '2475', (239, 243))	('beta-catenin', 'Gene', (252, 264))	('beta-catenin', 'Gene', '1499', (252, 264))	('loss', 'Var', (25, 29))	('E2F6', 'Gene', '1876', (227, 231))	('E2F6', 'Gene', (227, 231))	('suppress', 'NegReg', (44, 52))	('beta-catenin', 'Gene', (74, 86))	('mTOR', 'Gene', (61, 65))	('Akt', 'Gene', (57, 60))	('beta-catenin', 'Gene', '1499', (74, 86))
374928	28122321	The presence of staining with S100 is associated with non-mesenchymal malignant tumours.	('malignant tumours', 'Disease', (70, 87))	('associated', 'Reg', (38, 48))	('S100', 'Gene', (30, 34))	('staining', 'Var', (16, 24))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('presence', 'Var', (4, 12))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('malignant tumours', 'Disease', 'MESH:D009369', (70, 87))
374947	27956588	show that PI3'-lipid signaling potentiates metastasis in a genetically engineered mouse model of synovial sarcomagenesis and drives cancer cells to express CSF1, recruiting macrophages to the tumor microenvironment.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('cancer', 'Disease', (132, 138))	('CSF1', 'Gene', (156, 160))	('tumor', 'Disease', (192, 197))	('mouse', 'Species', '10090', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	("PI3'-lipid", 'Var', (10, 20))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (97, 113))	('synovial sarcoma', 'Disease', 'MESH:D013584', (97, 113))	('lipid', 'Chemical', 'MESH:D008055', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('metastasis', 'CPA', (43, 53))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (97, 120))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('recruiting', 'PosReg', (162, 172))	('potentiates', 'PosReg', (31, 42))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('synovial sarcoma', 'Disease', (97, 113))
374949	27956588	PI3'-lipid signaling has been associated with metastasis and inflammation in many cancers, but the relationship between tumor cell-intrinsic PI3'-lipid signaling and inflammatory cell recruitment has remained enigmatic.	('associated', 'Reg', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('metastasis', 'CPA', (46, 56))	('lipid', 'Chemical', 'MESH:D008055', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('inflammation in many cancers', 'Disease', (61, 89))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('inflammation in many cancers', 'Disease', 'MESH:D007249', (61, 89))	('lipid', 'Chemical', 'MESH:D008055', (5, 10))	("PI3'-lipid", 'Var', (0, 10))	('tumor', 'Disease', (120, 125))
374951	27956588	Here, we show in genetically engineered mouse models of locally induced expression of SS18-SSX1 or SS18-SSX2 that Pten silencing dramatically accelerated and enhanced sarcomagenesis without compromising synovial sarcoma characteristics.	('synovial sarcoma', 'Disease', 'MESH:D013584', (203, 219))	('SS', 'Phenotype', 'HP:0012570', (104, 106))	('sarcoma', 'Disease', 'MESH:D012509', (212, 219))	('silencing', 'Var', (119, 128))	('mouse', 'Species', '10090', (40, 45))	('sarcoma', 'Disease', (212, 219))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (203, 219))	('accelerated', 'PosReg', (142, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('SSX', 'Gene', '727837', (104, 107))	('SSX', 'Gene', (91, 94))	('SS', 'Phenotype', 'HP:0012570', (86, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('Pten', 'Gene', (114, 118))	('rat', 'Species', '10116', (148, 151))	('enhanced', 'PosReg', (158, 166))	('SSX', 'Gene', (104, 107))	('SS', 'Phenotype', 'HP:0012570', (99, 101))	('SS', 'Phenotype', 'HP:0012570', (91, 93))	('expression', 'Species', '29278', (72, 82))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('synovial sarcoma', 'Disease', (203, 219))	('SSX', 'Gene', '727837', (91, 94))	('sarcoma', 'Disease', (167, 174))
374953	27956588	PTEN-deficient sarcomas revealed infiltrating myeloid-derived hematopoietic cells, particularly macrophages and neutrophils, recruited via PI3'-lipid-induced CSF1 expression in tumor cells.	('PTEN-deficient sarcomas', 'Disease', 'MESH:D006223', (0, 23))	('lipid', 'Chemical', 'MESH:D008055', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	("PI3'-lipid-induced", 'Var', (139, 157))	('expression', 'Species', '29278', (163, 173))	('rat', 'Species', '10116', (39, 42))	('PTEN-deficient sarcomas', 'Disease', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('CSF1', 'Gene', (158, 162))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('tumor', 'Disease', (177, 182))
374960	27956588	This has raised the question of what additional genetic or epigenetic changes are necessary for progression to metastasis, as distinct from initiation of sarcomagenesis.	('metastasis', 'CPA', (111, 121))	('initiation of sarcomagenesis', 'Disease', (140, 168))	('initiation of sarcomagenesis', 'Disease', 'MESH:D007319', (140, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('epigenetic', 'Var', (59, 69))
374964	27956588	Loss of PTEN associates with tumor aggressiveness and progression to metastasis in some cancers.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (29, 49))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('PTEN', 'Gene', (8, 12))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancers', 'Disease', (88, 95))	('tumor aggressiveness', 'Disease', (29, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Loss', 'Var', (0, 4))	('aggressiveness', 'Phenotype', 'HP:0000718', (35, 49))
374973	27956588	Pten silencing did not change the development of the classic histological features of SS in the mouse tumors (Fig.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('mouse', 'Species', '10090', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('silencing', 'Var', (5, 14))	('SS', 'Phenotype', 'HP:0012570', (86, 88))	('Pten', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
374985	27956588	To determine whether Pten silencing enabled greater tumor cell dissemination to the lungs or simply greater growth after dissemination, we developed a PCR assay to detect a recombined genomic DNA segment in the Rosa26 locus that would only be present in tumor cells disseminated to the lung.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Rosa26', 'Gene', '14910', (211, 217))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', (52, 57))	('Rosa26', 'Gene', (211, 217))	('Pten', 'Gene', (21, 25))	('silencing', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
374990	27956588	This suggests that Pten silencing specifically promoted sarcoma cell dissemination.	('Pten', 'Gene', (19, 23))	('sarcoma', 'Disease', (56, 63))	('promoted', 'PosReg', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('silencing', 'Var', (24, 33))
375001	27956588	Although SS is considered a strongly angiogenic tumor, with characteristic hemangiopericytomatous vascular patterns as one of the diagnostic features, Pten silencing increased the vascularity of primary tumors significantly (Fig.	('SS', 'Phenotype', 'HP:0012570', (9, 11))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('vascularity', 'MPA', (180, 191))	('tumor', 'Disease', (48, 53))	('silencing', 'Var', (156, 165))	('primary tumors', 'Disease', 'MESH:D009369', (195, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('increased', 'PosReg', (166, 175))	('hemangiopericytomatous', 'Disease', (75, 97))	('Pten', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('primary tumors', 'Disease', (195, 209))
375031	27956588	6 D), only the first two were significantly up-regulated in tumors with silenced Pten compared with wild-type Pten.	('Pten', 'Gene', (81, 85))	('silenced', 'Var', (72, 80))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('up-regulated', 'PosReg', (44, 56))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
375035	27956588	Immunohistochemistry demonstrated macrophages with phosphorylated CSF1R, which indicates ligand activation, in PTEN-deficient tumor sections (Fig.	('CSF1R', 'Gene', (66, 71))	('CSF1R', 'Gene', '12978', (66, 71))	('PTEN-deficient tumor', 'Disease', 'MESH:D006223', (111, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('phosphorylated', 'Var', (51, 65))	('PTEN-deficient tumor', 'Disease', (111, 131))	('demonstrated', 'Reg', (21, 33))	('rat', 'Species', '10116', (28, 31))
375040	27956588	As indicated by flow cytometry analysis for F4/80+ macrophages and immunohistochemical analysis for CD68+ macrophages, inhibition of CSF1R reduced their presence in dissociated tumors and FFPE tumors (Fig.	('presence', 'MPA', (153, 161))	('CD68', 'Gene', (100, 104))	('inhibition', 'Var', (119, 129))	('CSF1R', 'Gene', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('dissociated tumors and FFPE tumors', 'Disease', 'MESH:D009369', (165, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('reduced', 'NegReg', (139, 146))	('CSF1R', 'Gene', '12978', (133, 138))	('F4/80', 'Gene', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('CD68', 'Gene', '12514', (100, 104))	('F4/80', 'Gene', '13733', (44, 49))
375044	27956588	To assess the broader relationship between increased PI3'-lipid signaling and myeloid chemoattractant expression, we transfected an active mutant (H1047R) of PIK3CA into two human SS cell lines.	('expression', 'Species', '29278', (102, 112))	('human', 'Species', '9606', (174, 179))	('H1047R', 'Mutation', 'rs121913279', (147, 153))	('PIK3CA', 'Gene', (158, 164))	('lipid', 'Chemical', 'MESH:D008055', (58, 63))	('SS', 'Phenotype', 'HP:0012570', (180, 182))	('H1047R', 'Var', (147, 153))
375049	27956588	Although it lacks the superior pharmacokinetics of developed drugs, LY294002 has also demonstrated PI3'-lipid kinase inhibition in vivo.	("PI3'-lipid kinase", 'MPA', (99, 116))	('LY294002', 'Chemical', 'MESH:C085911', (68, 76))	('lipid', 'Chemical', 'MESH:D008055', (104, 109))	('LY294002', 'Var', (68, 76))	('rat', 'Species', '10116', (93, 96))
375050	27956588	To test the dependence of chemoattractant signal expression on PI3'-lipid signaling in vivo, Ptenfl/fl;hSS mice with large tumors were randomized to daily oral gavage administration of LY294002 or vehicle control for 1 wk before tumor harvest.	('lipid', 'Chemical', 'MESH:D008055', (68, 73))	('LY294002', 'Var', (185, 193))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (123, 128))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('expression', 'Species', '29278', (49, 59))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('LY294002', 'Chemical', 'MESH:C085911', (185, 193))	('tumor', 'Disease', (229, 234))	('mice', 'Species', '10090', (107, 111))	('rat', 'Species', '10116', (175, 178))	('SS', 'Phenotype', 'HP:0012570', (104, 106))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
375052	27956588	S4 B), confirming our anticipation that LY294002 was not likely to demonstrate serious tumor-impacting PI3'-lipid inhibition.	('LY294002', 'Chemical', 'MESH:C085911', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('rat', 'Species', '10116', (74, 77))	('lipid', 'Chemical', 'MESH:D008055', (108, 113))	('LY294002', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
375054	27956588	Further, tumor infiltrating CD11b+ by flow cytometry and Leder-stained neutrophil counts on histological sections were also reduced after LY294002 administration compared with vehicle control treatment (Fig.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('reduced', 'NegReg', (124, 131))	('LY294002', 'Var', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('rat', 'Species', '10116', (21, 24))	('LY294002', 'Chemical', 'MESH:C085911', (138, 146))	('rat', 'Species', '10116', (155, 158))
375056	27956588	Nevertheless, it was expedient to assay the disseminated tumor cells in the circulation to see if LY294002 treatments decreased the presence of these cells in the blood.	('LY294002', 'Chemical', 'MESH:C085911', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('decreased', 'NegReg', (118, 127))	('tumor', 'Disease', (57, 62))	('LY294002', 'Var', (98, 106))	('presence', 'MPA', (132, 140))
375058	27956588	The ratio of lung/blood tumor DNA was reduced significantly in the LY294002-treated samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('reduced', 'NegReg', (38, 45))	('LY294002', 'Chemical', 'MESH:C085911', (67, 75))	('blood tumor', 'Phenotype', 'HP:0004377', (18, 29))	('LY294002-treated', 'Var', (67, 83))	('lung/blood tumor', 'Disease', (13, 29))	('rat', 'Species', '10116', (4, 7))	('lung/blood tumor', 'Disease', 'MESH:D008175', (13, 29))
375059	27956588	Silencing of Pten in the mouse tumors primarily represents an experimental in vivo boost to PI3'-lipid signaling.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	("PI3'-lipid signaling", 'MPA', (92, 112))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('mouse', 'Species', '10090', (25, 30))	('Pten', 'Gene', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('Silencing', 'Var', (0, 9))	('boost', 'PosReg', (83, 88))
375068	27956588	There is evidence for epigenetic down-regulation of PTEN in many human SS cell lines, which have also shown PI3'-lipid activity by pAKT levels and the inhibition of pAKT and proliferation with the PI3'-lipid kinase inhibitor LY294002.	('LY294002', 'Chemical', 'MESH:C085911', (225, 233))	('human', 'Species', '9606', (65, 70))	('lipid', 'Chemical', 'MESH:D008055', (113, 118))	('PTEN', 'Gene', (52, 56))	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('lipid', 'Chemical', 'MESH:D008055', (202, 207))	('epigenetic', 'Var', (22, 32))	('down-regulation', 'NegReg', (33, 48))	("PI3'-lipid activity", 'MPA', (108, 127))	('rat', 'Species', '10116', (181, 184))	('inhibition', 'NegReg', (151, 161))	('proliferation', 'CPA', (174, 187))
375070	27956588	Although PTEN loss, PIK3CA-activating mutations, RAS-activating mutations, and other genetic means of increasing PI3'-lipid signaling have each been identified in only a small minority of human SSs, we used one of these to effect a material change in the metastatic potential of SS18-SSX-driven tumors in mice.	('tumors', 'Disease', (295, 301))	('SS', 'Phenotype', 'HP:0012570', (194, 196))	('PIK3CA-activating', 'Gene', (20, 37))	('SSX', 'Gene', (284, 287))	('SS', 'Phenotype', 'HP:0012570', (279, 281))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('mutations', 'Var', (64, 73))	('mutations', 'Var', (38, 47))	('metastatic potential', 'CPA', (255, 275))	('SS', 'Phenotype', 'HP:0012570', (284, 286))	('mice', 'Species', '10090', (305, 309))	('PTEN', 'Gene', (9, 13))	('change', 'Reg', (241, 247))	('SSX', 'Gene', '727837', (284, 287))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('human', 'Species', '9606', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('lipid', 'Chemical', 'MESH:D008055', (118, 123))	('loss', 'NegReg', (14, 18))
375072	27956588	Importantly, the PI3'-lipid alterations in this model were tumor cell-intrinsic, distinct from any myeloid cell PI3'-lipid signaling.	('tumor', 'Disease', (59, 64))	('rat', 'Species', '10116', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('lipid', 'Chemical', 'MESH:D008055', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	("PI3'-lipid", 'Var', (17, 27))	('lipid', 'Chemical', 'MESH:D008055', (22, 27))
375073	27956588	Several other mouse genetic models of cancer have demonstrated increased metastasis upon the addition of Pten silencing.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('increased', 'PosReg', (63, 72))	('mouse', 'Species', '10090', (14, 19))	('metastasis', 'CPA', (73, 83))	('silencing', 'Var', (110, 119))	('Pten', 'Protein', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('rat', 'Species', '10116', (57, 60))	('cancer', 'Disease', (38, 44))
375075	27956588	We have shown already that Pten silencing-mediated proliferation alone has not enabled this phenotype by mere outgrowth of already disseminated cells.	('silencing-mediated', 'Var', (32, 50))	('Pten', 'Gene', (27, 31))	('rat', 'Species', '10116', (58, 61))	('mere outgrowth', 'Phenotype', 'HP:0001548', (105, 119))
375081	27956588	The mechanism for this PI3'-lipid-related inflammation and metastasis has been somewhat elusive, and generally attributed to increased growth rates, increased necrosis, or genetic instability driving the creation of neoantigens.	('inflammation', 'Disease', (42, 54))	('increased', 'PosReg', (125, 134))	('lipid', 'Chemical', 'MESH:D008055', (28, 33))	('necrosis', 'Disease', (159, 167))	('increased', 'PosReg', (149, 158))	("PI3'-lipid-related", 'Var', (23, 41))	('increased necrosis', 'Phenotype', 'HP:0010885', (149, 167))	('growth rates', 'CPA', (135, 147))	('necrosis', 'Disease', 'MESH:D009336', (159, 167))	('genetic instability', 'Var', (172, 191))	('inflammation', 'Disease', 'MESH:D007249', (42, 54))	('rat', 'Species', '10116', (142, 145))
375085	27956588	In the SS mice and in human cell lines and tumor samples, we have linked Csf1/CSF1 expression to increased PI3'-lipid signaling and found this to be a manipulable program for myeloid recruitment.	('Csf1/CSF1', 'Gene', (73, 82))	('lipid', 'Chemical', 'MESH:D008055', (112, 117))	('increased', 'PosReg', (97, 106))	('human', 'Species', '9606', (22, 27))	('mice', 'Species', '10090', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('expression', 'Species', '29278', (83, 93))	('SS', 'Phenotype', 'HP:0012570', (7, 9))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	("PI3'-lipid signaling", 'MPA', (107, 127))	('tumor', 'Disease', (43, 48))	('expression', 'Var', (83, 93))
375087	27956588	Studies in human leiomyosarcoma have associated macrophage recruitment to high CSF1 expression in the sarcoma, which correlates to a worse prognosis.	('expression', 'Var', (84, 94))	('sarcoma', 'Disease', (24, 31))	('human', 'Species', '9606', (11, 16))	('high', 'Var', (74, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('expression', 'Species', '29278', (84, 94))	('leiomyosarcoma', 'Disease', (17, 31))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('macrophage recruitment', 'MPA', (48, 70))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (17, 31))	('CSF1', 'Gene', (79, 83))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (17, 31))
375100	27956588	As a result of the genetic simplicity of the SS mouse model with Pten conditional ablation alleles and working with a fully competent immune system, we may begin to unravel the complexities of PI3'-lipid signaling that result in tumor inflammation and metastasis.	('mouse', 'Species', '10090', (48, 53))	('tumor inflammation', 'Disease', (229, 247))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor inflammation', 'Disease', 'MESH:D007249', (229, 247))	('metastasis', 'CPA', (252, 262))	('SS', 'Phenotype', 'HP:0012570', (45, 47))	('Pten', 'Gene', (65, 69))	('result in', 'Reg', (219, 228))	('alleles', 'Var', (91, 98))	('lipid', 'Chemical', 'MESH:D008055', (198, 203))
375137	27956588	S1 shows Pten disruption enhances synovial sarcomagenesis.	('Pten', 'Gene', (9, 13))	('enhances', 'PosReg', (25, 33))	('synovial sarcoma', 'Disease', (34, 50))	('disruption', 'Var', (14, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (34, 57))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (34, 50))	('synovial sarcoma', 'Disease', 'MESH:D013584', (34, 50))
375139	27956588	S3 shows Pten disruption associates with increased infiltration of myeloid-derived cells.	('increased', 'PosReg', (41, 50))	('Pten', 'Gene', (9, 13))	('infiltration of myeloid-derived cells', 'CPA', (51, 88))	('rat', 'Species', '10116', (57, 60))	('disruption', 'Var', (14, 24))
375204	27737652	Radiofrequency was the first reported percutaneous thermal ablation technique, and its efficacy has been widely reported for various tumor types.	('tumor', 'Disease', (133, 138))	('Radiofrequency', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
375213	27737652	Additionally, cryoablation for oligometastatic renal cell carcinoma has been implicated to result in higher overall survival compared to systematic treatments alone.	('cryoablation', 'Var', (14, 26))	('higher', 'PosReg', (101, 107))	('overall', 'MPA', (108, 115))	('oligometastatic renal cell carcinoma', 'Disease', 'MESH:C538614', (31, 67))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('oligometastatic renal cell carcinoma', 'Disease', (31, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
375222	26908627	In vitro, JQ1 (but not the inactive enantiomer JQ1R) inhibited cell proliferation, and increased G1 fraction of cells, although there was no correlation between cell line sensitivity and suppression of c-MYC or MYCN.	('increased', 'PosReg', (87, 96))	('c-MYC', 'Gene', (202, 207))	('G1 fraction of cells', 'CPA', (97, 117))	('inhibited', 'NegReg', (53, 62))	('c-MYC', 'Gene', '4609', (202, 207))	('cell proliferation', 'CPA', (63, 81))	('MYCN', 'Gene', (211, 215))	('JQ1', 'Var', (10, 13))	('MYCN', 'Gene', '4613', (211, 215))
375223	26908627	Further investigation showed that JQ1 reduced tumor vascularization.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('reduced', 'NegReg', (38, 45))	('tumor', 'Disease', (46, 51))	('JQ1', 'Var', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
375226	26908627	In HUVECs JQ1 partially suppressed c-MYC levels, but dramatically reduced AP-1 levels and activity through suppression of the AP-1 associated protein FOSL1.	('FOSL1', 'Gene', '8061', (150, 155))	('reduced', 'NegReg', (66, 73))	('AP-1', 'Gene', (74, 78))	('activity', 'MPA', (90, 98))	('suppression', 'NegReg', (107, 118))	('c-MYC', 'Gene', (35, 40))	('AP-1', 'Gene', '3726', (126, 130))	('suppressed', 'NegReg', (24, 34))	('AP-1', 'Gene', (126, 130))	('c-MYC', 'Gene', '4609', (35, 40))	('JQ1', 'Var', (10, 13))	('FOSL1', 'Gene', (150, 155))	('AP-1', 'Gene', '3726', (74, 78))
375230	26908627	C-MYC is overexpressed in Ewing sarcoma, and expression of the EWS-FLI1 fusion protein upregulates c-MYC expression through an indirect mechanism.	('upregulates', 'PosReg', (87, 98))	('Ewing sarcoma', 'Disease', (26, 39))	('EWS', 'Gene', '2130', (63, 66))	('EWS', 'Gene', (63, 66))	('expression', 'Var', (45, 55))	('EWS', 'Phenotype', 'HP:0012254', (63, 66))	('c-MYC', 'Gene', '4609', (99, 104))	('C-MYC', 'Gene', (0, 5))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('C-MYC', 'Gene', '4609', (0, 5))	('FLI1', 'Gene', '2313', (67, 71))	('FLI1', 'Gene', (67, 71))	('expression', 'MPA', (105, 115))	('c-MYC', 'Gene', (99, 104))
375231	26908627	Thus c-MYC oncogene amplification or overexpression may play an important role in the development of childhood sarcomas as it has been found for other human malignancies.	('overexpression', 'PosReg', (37, 51))	('malignancies', 'Disease', 'MESH:D009369', (157, 169))	('sarcomas', 'Disease', 'MESH:D012509', (111, 119))	('human', 'Species', '9606', (151, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('malignancies', 'Disease', (157, 169))	('c-MYC', 'Gene', (5, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcomas', 'Disease', (111, 119))	('amplification', 'Var', (20, 33))	('c-MYC', 'Gene', '4609', (5, 10))
375239	26908627	JQ1 has been shown to impair estrogen-mediated growth and transcription, and inhibit androgen receptor variants from chromatin binding in prostate cancer cells thereby overcoming resistance to endocrine-based therapies.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('estrogen-mediated growth', 'CPA', (29, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (138, 153))	('inhibit', 'NegReg', (77, 84))	('overcoming', 'NegReg', (168, 178))	('androgen receptor', 'Gene', '367', (85, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('variants', 'Var', (103, 111))	('prostate cancer', 'Disease', (138, 153))	('chromatin binding', 'Interaction', (117, 134))	('transcription', 'CPA', (58, 71))	('androgen receptor', 'Gene', (85, 102))	('impair', 'NegReg', (22, 28))
375240	26908627	JQ1 reduced oncogenic IkappaB activity in diffuse large B-cell lymphoma (DLBCL), and has been proposed for the treatment of DLBCL, although the in vivo activity against the one xenograft model tested was marginal with an increase in event-free survival advantage of only 3 days for JQ1 treated mice over control animals.	('reduced', 'NegReg', (4, 11))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (56, 71))	('mice', 'Species', '10090', (294, 298))	('JQ1', 'Var', (0, 3))	('lymphoma', 'Phenotype', 'HP:0002665', (63, 71))	('diffuse large B-cell lymphoma', 'Disease', (42, 71))	('DLBCL', 'Disease', (124, 129))	('oncogenic', 'MPA', (12, 21))
375241	26908627	JQ1 suppressed TNF-alpha mediated NF-kappaB activation and NF-kappaB-dependent target gene activation in A549 lung adenocarcinoma cells.	('A549 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 129))	('activation', 'PosReg', (91, 101))	('activation', 'PosReg', (44, 54))	('A549 lung adenocarcinoma', 'Disease', (105, 129))	('TNF-alpha', 'Gene', '7124', (15, 24))	('suppressed', 'NegReg', (4, 14))	('JQ1', 'Var', (0, 3))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('TNF-alpha', 'Gene', (15, 24))
375243	26908627	JQ1 reduces osteosarcoma viability and is a potent inhibitor of osteoblast and osteoclast differentiation associated with suppression of MYC and RUNX2 expression.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('osteosarcoma viability', 'Disease', 'MESH:D012516', (12, 34))	('reduces', 'NegReg', (4, 11))	('RUNX2', 'Gene', '860', (145, 150))	('expression', 'MPA', (151, 161))	('MYC', 'Gene', '4609', (137, 140))	('RUNX2', 'Gene', (145, 150))	('osteosarcoma', 'Phenotype', 'HP:0002669', (12, 24))	('JQ1', 'Var', (0, 3))	('osteosarcoma viability', 'Disease', (12, 34))	('MYC', 'Gene', (137, 140))	('osteoblast', 'CPA', (64, 74))	('suppression', 'NegReg', (122, 133))
375250	26908627	Our data demonstrate that JQ1 can regulate angiogenesis to block tumor-derived angiogenic factors, directly suppress VEGF-driven angiogenesis, and impair the proliferation and differentiation of human vascular endothelial cells.	('human', 'Species', '9606', (195, 200))	('block', 'NegReg', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('impair', 'NegReg', (147, 153))	('JQ1', 'Var', (26, 29))	('VEGF-driven', 'MPA', (117, 128))	('proliferation', 'CPA', (158, 171))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('suppress', 'NegReg', (108, 116))
375297	26908627	To evaluate the sensitivity of RMS and EWS cell lines to JQ1 and JQ1R (inactive enantiomer), cells were incubated with or without drugs for 4 days, and viability was assessed by Alamar Blue staining (Table 1).	('RMS', 'Phenotype', 'HP:0002859', (31, 34))	('EWS', 'Phenotype', 'HP:0012254', (39, 42))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	('JQ1R', 'Var', (65, 69))	('Alamar Blue', 'Chemical', 'MESH:C005843', (178, 189))
375301	26908627	Flow cytometric analysis revealed significant changes in the cell-cycle distribution profile of EWS and RMS cells after exposure to JQ1(500 nM).	('cell-cycle distribution profile', 'MPA', (61, 92))	('EWS', 'Gene', '2130', (96, 99))	('EWS', 'Gene', (96, 99))	('changes', 'Reg', (46, 53))	('JQ1', 'Var', (132, 135))	('RMS', 'Phenotype', 'HP:0002859', (104, 107))	('EWS', 'Phenotype', 'HP:0012254', (96, 99))
375303	26908627	JQ1 potently inhibits Binding of a tetra-acetylated Histone H4 peptide to BRD4 with IC50 values of 77 nM and 33 nM for the first and second bromodomain, respectively Thus, to examine whether JQ1 induced significant changes in MYC levels cells were incubated 24 hr with or without JQ1 (500 nM), and processed for immunoblotting for c-MYC and MYCN proteins.	('MYC', 'Gene', (226, 229))	('BRD4', 'Gene', (74, 78))	('tetra', 'Species', '42554', (35, 40))	('BRD4', 'Gene', '23476', (74, 78))	('c-MYC', 'Gene', (331, 336))	('MYC', 'Gene', '4609', (333, 336))	('MYC', 'Gene', '4609', (226, 229))	('MYC', 'Gene', (341, 344))	('MYCN', 'Gene', (341, 345))	('Binding', 'Interaction', (22, 29))	('c-MYC', 'Gene', '4609', (331, 336))	('JQ1', 'Var', (0, 3))	('MYCN', 'Gene', '4613', (341, 345))	('MYC', 'Gene', (333, 336))	('inhibits', 'NegReg', (13, 21))	('MYC', 'Gene', '4609', (341, 344))
375312	26908627	JQ1 significantly inhibited growth of each tumor line relative to controls (P<0.0001 for Rh10 and Rh28; P=0.0044 and 0.0016 for EW-5 and EW-8, respectively).	('growth', 'CPA', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('JQ1', 'Var', (0, 3))	('inhibited', 'NegReg', (18, 27))	('tumor', 'Disease', (43, 48))	('Rh28', 'Var', (98, 102))
375313	26908627	These results suggest that JQ1 is cytostatic during the period of treatment, and has minimal cytotoxicity in vivo.	('JQ1', 'Var', (27, 30))	('cytotoxicity', 'Disease', (93, 105))	('cytotoxicity', 'Disease', 'MESH:D064420', (93, 105))
375324	26908627	These data suggest that in part, JQ1 suppresses tumor growth through downregulation of tumor-derived angiogenic factors.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (48, 53))	('suppresses', 'NegReg', (37, 47))	('tumor', 'Disease', (87, 92))	('JQ1', 'Var', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('downregulation', 'NegReg', (69, 83))
375325	26908627	Relative to control xenograft tumors, JQ1 treated tumors showed a significant decrease of VEGF, Angiopoietin, tissue factor (TF) and FGF-1, critical regulators of angiogenesis (Supplemental Figure 5).	('decrease', 'NegReg', (78, 86))	('VEGF', 'Protein', (90, 94))	('xenograft tumors', 'Disease', (20, 36))	('tissue factor', 'Gene', (110, 123))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('xenograft tumors', 'Disease', 'MESH:D009369', (20, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('FGF-1', 'Gene', (133, 138))	('JQ1', 'Var', (38, 41))	('tumors', 'Disease', (30, 36))	('TF', 'Gene', '2152', (125, 127))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('FGF-1', 'Gene', '2246', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tissue factor', 'Gene', '2152', (110, 123))	('Angiopoietin', 'MPA', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))
375332	26908627	As shown in Figure 4D, JQ1 inhibited proliferation in a concentration-dependent manner with 70% or more inhibition at 2 muM.	('muM', 'Gene', '56925', (120, 123))	('muM', 'Gene', (120, 123))	('JQ1', 'Var', (23, 26))	('proliferation', 'CPA', (37, 50))	('inhibited', 'NegReg', (27, 36))
375333	26908627	The inactive enantiomer, JQ1R also had no effect on either tube formation or cell proliferation at concentrations up to 2 muM (data not shown).	('tube formation', 'CPA', (59, 73))	('muM', 'Gene', (122, 125))	('JQ1R', 'Var', (25, 29))	('cell proliferation', 'CPA', (77, 95))	('muM', 'Gene', '56925', (122, 125))
375341	26908627	The JQ1 sensitivity of lung adenocarcinoma cells has previously been related to drug-induced decrease in the AP-1 component FOSL1, and not to decreased c-MYC.	('AP-1 component FOSL1', 'Disease', 'MESH:C562869', (109, 129))	('AP-1 component FOSL1', 'Disease', (109, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (23, 42))	('c-MYC', 'Gene', (152, 157))	('lung adenocarcinoma', 'Disease', (23, 42))	('decrease', 'NegReg', (93, 101))	('c-MYC', 'Gene', '4609', (152, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (23, 42))	('JQ1', 'Var', (4, 7))
375342	26908627	As shown in Figure 5C, JQ1 treatment only slightly decreased c-MYC levels in HUVECs, however it had a far greater effect on suppressing FOSL1, Figure 5D.	('FOSL1', 'Gene', '8061', (136, 141))	('c-MYC', 'Gene', '4609', (61, 66))	('decreased', 'NegReg', (51, 60))	('JQ1', 'Var', (23, 26))	('suppressing', 'NegReg', (124, 135))	('FOSL1', 'Gene', (136, 141))	('c-MYC', 'Gene', (61, 66))
375347	26908627	JQ1 clearly downregulated c-MYC (Rh4, Rh41) and MYCN (Rh5), cell lines sensitive to JQ1, while c-MYC levels were low in Rh18 and Rh30 cells that were intrinsically resistant to drug (IC50>10muM).	('c-MYC', 'Gene', (95, 100))	('JQ1', 'Gene', (0, 3))	('downregulated', 'NegReg', (12, 25))	('Rh30', 'Gene', '6007', (129, 133))	('c-MYC', 'Gene', '4609', (95, 100))	('c-MYC', 'Gene', '4609', (26, 31))	('JQ1', 'Var', (84, 87))	('MYCN', 'Gene', (48, 52))	('Rh4', 'Gene', '6007', (33, 36))	('Rh4', 'Gene', (38, 41))	('MYCN', 'Gene', '4613', (48, 52))	('muM', 'Gene', '56925', (190, 193))	('c-MYC', 'Gene', (26, 31))	('Rh30', 'Gene', (129, 133))	('Rh4', 'Gene', (33, 36))	('Rh4', 'Gene', '6007', (38, 41))	('muM', 'Gene', (190, 193))
375350	26908627	These data are concordant with those generated in lung adenocarcinoma cell lines treated with JQ1, and several other studies suggesting that the antitumor activity of JQ1 is independent of its ability to suppress MYC.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('MYC', 'Gene', '4609', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('lung adenocarcinoma', 'Disease', (50, 69))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (50, 69))	('tumor', 'Disease', (149, 154))	('JQ1', 'Var', (167, 170))	('MYC', 'Gene', (213, 216))
375355	26908627	Further, given that growth of tumor xenografts generated from both sensitive and resistant cell lines was equally impacted by JQ1 treatment in vivo, JQ1 was likely impacting tumor growth through an indirect mechanism.	('tumor', 'Disease', (174, 179))	('JQ1', 'Gene', (126, 129))	('impacting', 'Reg', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('impacted', 'Reg', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (30, 35))	('JQ1', 'Var', (149, 152))
375356	26908627	Although JQ1 modulates tumor growth of in several different models, a direct effect upon tumor angiogenesis has not been previously reported.	('modulates', 'Reg', (13, 22))	('JQ1', 'Var', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
375364	26908627	It is of interest that in this Matrigel assay JQ1 significantly reduced angiogenesis, whereas in the tumor experiments there was no decreased vascularization at day 7, but a significant decrease from control levels by day 14.	('JQ1', 'Var', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('reduced', 'NegReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('angiogenesis', 'CPA', (72, 84))	('decrease', 'NegReg', (186, 194))
375366	26908627	Furthermore, despite the reduced vascularity, JQ1 did not cause a decrease in KI67 staining in tumor tissue from rhabdomyosarcoma xenografts (Supplemental Figure 6), or Ewing sarcoma xenografts (Supplemental Figure 7), again suggesting that its antitumor activity is a consequence of effects on angiogenesis.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (169, 182))	('tumor', 'Disease', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('reduced', 'NegReg', (25, 32))	('JQ1', 'Var', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('KI67', 'Protein', (78, 82))	('vascularity', 'MPA', (33, 44))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (113, 129))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('staining', 'MPA', (83, 91))	('decrease', 'NegReg', (66, 74))	('tumor', 'Disease', (95, 100))	('Ewing sarcoma xenografts', 'Disease', 'MESH:C563168', (169, 193))	('rhabdomyosarcoma xenografts', 'Disease', 'MESH:D012208', (113, 140))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('rhabdomyosarcoma xenografts', 'Disease', (113, 140))	('Ewing sarcoma xenografts', 'Disease', (169, 193))
375367	26908627	JQ1 treatment reduced HUVEC tube formation at 0.5 muM, whereas significant inhibition of proliferation required a higher concentration (2 muM); JQ1 (at 3 muM) also reduced invasion of endothelial cells.	('proliferation', 'CPA', (89, 102))	('reduced', 'NegReg', (14, 21))	('invasion of endothelial cells', 'CPA', (172, 201))	('muM', 'Gene', '56925', (138, 141))	('inhibition', 'NegReg', (75, 85))	('muM', 'Gene', '56925', (50, 53))	('muM', 'Gene', (138, 141))	('JQ1', 'Var', (144, 147))	('muM', 'Gene', '56925', (154, 157))	('reduced', 'NegReg', (164, 171))	('muM', 'Gene', (50, 53))	('HUVEC tube formation', 'CPA', (22, 42))	('muM', 'Gene', (154, 157))
375376	26908627	Exactly how JQ1 suppresses angiogenesis remains to be determined, although BRD4 is a positive regulatory component of P-TEFb and an inhibitor of P-TEFb suppresses angiogenesis.	('angiogenesis', 'CPA', (163, 175))	('suppresses', 'NegReg', (152, 162))	('suppresses', 'NegReg', (16, 26))	('BRD4', 'Gene', (75, 79))	('P-TEFb', 'Disease', 'MESH:C000656865', (145, 151))	('P-TEFb', 'Disease', 'MESH:C000656865', (118, 124))	('P-TEFb', 'Disease', (145, 151))	('P-TEFb', 'Disease', (118, 124))	('angiogenesis', 'CPA', (27, 39))	('inhibitor', 'Var', (132, 141))	('BRD4', 'Gene', '23476', (75, 79))
375378	26908627	In summary, our results indicate that in sarcoma xenograft models of childhood cancer, JQ1 significantly suppresses tumor progression, but does not induce tumor regression.	('sarcoma', 'Disease', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (116, 121))	('JQ1', 'Var', (87, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('suppresses', 'NegReg', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
375425	25364412	Phase II studies of single agents and combinations of drugs have documented the efficacy of methotrexate (MTX), doxorubicin (DXR) and cisplatin (CDDP) in advanced osteosarcoma, leading to randomized studies confirming the efficacy of adjuvant chemotherapy.	('DXR', 'Chemical', 'MESH:D004317', (125, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('osteosarcoma', 'Disease', (163, 175))	('CDDP', 'Chemical', 'MESH:D002945', (145, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (163, 175))	('osteosarcoma', 'Disease', 'MESH:D012516', (163, 175))	('methotrexate', 'Chemical', 'MESH:D008727', (92, 104))	('MTX', 'Chemical', 'MESH:D008727', (106, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('doxorubicin', 'Var', (112, 123))
375477	26299493	An understanding of these unique subtypes has allowed us to develop new diagnostic studies based on their associated genetic mutations (e.g., FISH for gene translocations or immunohistochemistry for aberrant protein expression as in Table 1), improving diagnosis, and in some instances leading to targeted therapies currently in clinical trials (e.g., imatinib for inhibition of activated c-Kit mutation in gastrointestinal stromal tumors).	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (432, 437))	('tumors', 'Phenotype', 'HP:0002664', (432, 438))	('gastrointestinal stromal tumors', 'Disease', (407, 438))	('imatinib', 'Chemical', 'MESH:D000068877', (352, 360))	('mutation', 'Var', (395, 403))	('c-Kit', 'Gene', (389, 394))	('c-Kit', 'Gene', '3815', (389, 394))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (407, 438))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (407, 438))	('inhibition', 'NegReg', (365, 375))
375483	26299493	Hereditary syndromes predispose patients to developing STS, particularly Li-Fraumeni syndrome (p53 mutation associated with malignant fibrous histiocytoma [MFH] and myxofibrosarcoma), Gardner's syndrome (APC mutation associated with polyposis and desmoid tumor) and neurofibromatosis (NF1 mutation associated malignant peripheral nerve sheath tumors [MPNST]).	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (73, 93))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('neurofibromatosis', 'Disease', (266, 283))	('polyposis', 'Disease', (233, 242))	('p53', 'Gene', '7157', (95, 98))	('polyposis', 'Disease', 'MESH:D011125', (233, 242))	("Gardner's syndrome", 'Disease', 'MESH:D005736', (184, 202))	('NF1', 'Gene', (285, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	("Gardner's syndrome", 'Disease', (184, 202))	('myxofibrosarcoma', 'Disease', 'None', (165, 181))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (309, 349))	('mutation', 'Var', (99, 107))	('p53', 'Gene', (95, 98))	('sheath tumors', 'Disease', (336, 349))	('desmoid tumor', 'Disease', 'MESH:C535944', (247, 260))	('APC', 'Disease', 'MESH:D011125', (204, 207))	('APC', 'Disease', (204, 207))	('desmoid tumor', 'Phenotype', 'HP:0100245', (247, 260))	('sheath tumors', 'Disease', 'MESH:D010524', (336, 349))	('associated', 'Reg', (108, 118))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (266, 283))	('malignant fibrous histiocytoma', 'Disease', (124, 154))	('myxofibrosarcoma', 'Disease', (165, 181))	('patients', 'Species', '9606', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('histiocytoma', 'Phenotype', 'HP:0012315', (142, 154))	('Li-Fraumeni syndrome', 'Disease', (73, 93))	('neurofibromatosis', 'Disease', 'MESH:C537392', (266, 283))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('desmoid tumor', 'Disease', (247, 260))	('NF1', 'Gene', '4763', (285, 288))
375517	26299493	Again, local recurrence was reduced in patients treated with brachytherapy (89% 5 year actuarial local control rates as compared to 66% in those managed with surgery alone, p=0.04), but no difference in distant recurrence (76 vs 83%, respectively; p=0.60) or disease specific survival (84 vs81%; p=0.65) were observed.	('reduced', 'NegReg', (28, 35))	('local recurrence', 'CPA', (7, 23))	('patients', 'Species', '9606', (39, 47))	('local control', 'CPA', (97, 110))	('brachytherapy', 'Var', (61, 74))
375538	26299493	For example, in a retrospective review of 356 patients with large, high-grade STSs, patients with >10cm, high-grade tumors who were treated with neoadjuvant doxorubicin and ifosfamide had improved disease specific survival at three years as compared to those patients who did not receive therapy (83% versus 62%, respectively).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (259, 267))	('patients', 'Species', '9606', (84, 92))	('disease specific survival', 'CPA', (197, 222))	('doxorubicin', 'Chemical', 'MESH:D004317', (157, 168))	('ifosfamide', 'Chemical', 'MESH:D007069', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('STSs', 'Phenotype', 'HP:0030448', (78, 82))	('high-grade', 'Var', (105, 115))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('improved', 'PosReg', (188, 196))
375568	26299493	Liposarcomas are almost always associated with abnormal appearing fat, which appears associated with an infiltrative process and in the context of dedifferentiated tumors have one or more solid, enhancing masses.	('sarcomas', 'Phenotype', 'HP:0100242', (4, 12))	('abnormal appearing', 'Var', (47, 65))	('Liposarcomas', 'Phenotype', 'HP:0012034', (0, 12))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('Liposarcoma', 'Phenotype', 'HP:0012034', (0, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Liposarcomas', 'Disease', 'MESH:D008080', (0, 12))	('Liposarcomas', 'Disease', (0, 12))	('associated', 'Reg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('associated', 'Reg', (85, 95))
375597	26299493	One such event, copy number loss on chromosome 19 is associated with rapid recurrence and death from disease.	('copy number loss', 'Var', (16, 32))	('associated', 'Reg', (53, 63))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', (90, 95))
375603	26299493	Well- and dedifferentiate liposarcoma specifically is characterized by amplification of the chromosome 12 genes CDK4 and MDM2.	('liposarcoma', 'Disease', (26, 37))	('amplification', 'Var', (71, 84))	('CDK4', 'Gene', (112, 116))	('liposarcoma', 'Disease', 'MESH:D008080', (26, 37))	('liposarcoma', 'Phenotype', 'HP:0012034', (26, 37))	('CDK4', 'Gene', '1019', (112, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('MDM2', 'Gene', '4193', (121, 125))	('MDM2', 'Gene', (121, 125))
375604	26299493	Inhibitors of MDM2 have been examined in clinical trials and are associated with significant rates of grade 3 toxicities and few responses.	('toxicities', 'Disease', (110, 120))	('Inhibitors', 'Var', (0, 10))	('MDM2', 'Gene', '4193', (14, 18))	('MDM2', 'Gene', (14, 18))	('toxicities', 'Disease', 'MESH:D064420', (110, 120))
375605	26299493	CDK4 inhibitors may trigger response and prolong progression free survival by over four months.	('progression free survival', 'CPA', (49, 74))	('trigger', 'PosReg', (20, 27))	('inhibitors', 'Var', (5, 15))	('CDK4', 'Gene', (0, 4))	('response', 'CPA', (28, 36))	('CDK4', 'Gene', '1019', (0, 4))	('prolong', 'PosReg', (41, 48))
375665	33618582	This diagnosis was corroborated by immunohistochemistry markers (ie, the positivity of D33 and NSE and negativity of h-CD and S100).	('D33', 'Protein', (87, 90))	('h-CD', 'Gene', (117, 121))	('NSE', 'Gene', (95, 98))	('S100', 'Gene', (126, 130))	('h-CD', 'Gene', '1732', (117, 121))	('positivity', 'Var', (73, 83))	('NSE', 'Gene', '2026', (95, 98))	('negativity', 'NegReg', (103, 113))
375784	32076024	uPAR sections were treated similarly except that epitope retrieval was performed using PT link and a low-pH Envision FLEX target retrieval solution (Agilent, Santa Clara, United States) and visualization was done with Envision anti mouse (K4001, Agilent) and 3,3 diaminobenzidine tetrahydrochloride (Agilent).	('uPAR', 'Gene', (0, 4))	('K4001', 'Var', (239, 244))	('uPAR', 'Gene', '5329', (0, 4))	('3,3 diaminobenzidine tetrahydrochloride', 'Chemical', '-', (259, 298))
375933	31434953	As TP53 mutations are relatively rare (<10%) in EW, we compared gene sequences of the patient's sample and of the PDX, because TP53 alterations can arise during the adaptation to in vitro culture of human sarcoma cells, resulting in a much higher proportion of cell lines harboring TP53 mutations than actual human tumors.	('TP53', 'Gene', '7157', (3, 7))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('alterations', 'Var', (132, 143))	('sarcoma', 'Disease', (205, 212))	('mutations', 'Var', (287, 296))	('TP53', 'Gene', '7157', (127, 131))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('EW', 'Phenotype', 'HP:0012254', (48, 50))	('human', 'Species', '9606', (199, 204))	('human', 'Species', '9606', (309, 314))	('harboring', 'Reg', (272, 281))	('TP53', 'Gene', (282, 286))	('patient', 'Species', '9606', (86, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumors', 'Disease', (315, 321))	('TP53', 'Gene', (3, 7))	('TP53', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (282, 286))	('tumors', 'Disease', 'MESH:D009369', (315, 321))
375934	31434953	The results showed that de novo TP53 mutations did not arise in EW PDX (Supplementary Table 2), further confirming that PDX reliably reproduce the molecular features of the original tumor.	('TP53', 'Gene', '7157', (32, 36))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (32, 36))	('EW', 'Phenotype', 'HP:0012254', (64, 66))	('original tumor', 'Disease', (173, 187))	('original tumor', 'Disease', 'MESH:D009369', (173, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
375971	31434953	Our results suggest that the addition of the anti-CD99 treatment could be beneficial when irinotecan alone is less effective, possibly depending on tumor growth rate.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('anti-CD99', 'Var', (45, 54))	('irinotecan', 'Chemical', 'MESH:D000077146', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
376010	31151427	Tumor cells were negative for actin, desmin, CD34, CD117, S100P, EMA and panCK immunomarkers.	('desmin', 'Gene', '1674', (37, 43))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('S100P', 'Var', (58, 63))	('CD117', 'Gene', '3815', (51, 56))	('CD117', 'Gene', (51, 56))	('S100P', 'SUBSTITUTION', 'None', (58, 63))	('CD34', 'Gene', '947', (45, 49))	('desmin', 'Gene', (37, 43))	('CD34', 'Gene', (45, 49))
376079	29751751	Synovial sarcoma is a mesenchymal spindle cell tumor which displays variable epithelial differentiation and has a specific chromosomal translocation t(X; 18) (p11; q11), which results from the fusion of the SYT gene on chromosome 18 to exon 5 of either SSX1 or SSX2 genes on chromosome X.	('SSX2', 'Gene', (261, 265))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('SS', 'Phenotype', 'HP:0012570', (253, 255))	('SSX1', 'Gene', (253, 257))	('SYT', 'Gene', (207, 210))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('sarcoma', 'Disease', (9, 16))	('SS', 'Phenotype', 'HP:0012570', (261, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SYT', 'Gene', '6760', (207, 210))	('SSX2', 'Gene', '6757', (261, 265))	('fusion', 'Var', (193, 199))	('tumor', 'Disease', (47, 52))	('SSX1', 'Gene', '6756', (253, 257))
376101	29751751	This might have explained our negative results, when trying to identify the translocations, since our RT-PCR was only designed to detect SYT/SSX1 and SYT/SSX2 fusion gene variants.	('SYT', 'Gene', '6760', (137, 140))	('SSX2', 'Gene', '6757', (154, 158))	('SS', 'Phenotype', 'HP:0012570', (154, 156))	('SSX1', 'Gene', '6756', (141, 145))	('SYT', 'Gene', (150, 153))	('SS', 'Phenotype', 'HP:0012570', (141, 143))	('SYT', 'Gene', (137, 140))	('SSX2', 'Gene', (154, 158))	('SYT', 'Gene', '6760', (150, 153))	('SSX1', 'Gene', (141, 145))	('variants', 'Var', (171, 179))
376113	29751751	In another study by Ladanyi et al., the SYT-SSX2 fusion transcript had a significantly longer metastasis-free survival.	('SS', 'Phenotype', 'HP:0012570', (44, 46))	('fusion transcript', 'Var', (49, 66))	('SYT', 'Gene', (40, 43))	('metastasis-free survival', 'CPA', (94, 118))	('SSX2', 'Gene', (44, 48))	('SYT', 'Gene', '6760', (40, 43))	('longer', 'PosReg', (87, 93))	('SSX2', 'Gene', '6757', (44, 48))
376146	27120803	Drugs specifically targeting the product of its driver translocation are currently unavailable, in part because the SS18-SSX oncoprotein functions via aberrant interactions within multiprotein complexes.	('aberrant', 'Var', (151, 159))	('SSX', 'Gene', '6757', (121, 124))	('interactions', 'Interaction', (160, 172))	('SSX', 'Gene', (121, 124))	('multiprotein complexes', 'Protein', (180, 202))
376150	27120803	The chromosomal translocation t(X;18)(p11.2;q11.2) is the main cytogenetic event in synovial sarcoma and results in the fusion of the BAF complex member SS18 with one of three highly homologous transcriptional repressor genes, SSX1, SSX2 or SSX4.	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 50))	('BAF', 'Gene', (134, 137))	('SSX1', 'Gene', (227, 231))	('SS18', 'Gene', (153, 157))	('fusion', 'Var', (120, 126))	('synovial sarcoma', 'Disease', (84, 100))	('results in', 'Reg', (105, 115))	('SSX1', 'Gene', '6756', (227, 231))	('SSX2', 'Gene', '6757', (233, 237))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (84, 100))	('synovial sarcoma', 'Disease', 'MESH:D013584', (84, 100))	('SSX4', 'Gene', '6759', (241, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('BAF', 'Gene', '8815', (134, 137))	('SSX2', 'Gene', (233, 237))	('SSX4', 'Gene', (241, 245))
376154	27120803	The fusion of SSX to SS18 also recruits interacting proteins involved in epigenetic regulation, including transducin-like enhancer of split 1 (TLE1), activating transcription factor 2 (ATF2), members of the polycomb group and histone deacetylases (HDAC).	('histone deacetylases', 'Gene', '9734', (226, 246))	('HDAC', 'Gene', (248, 252))	('TLE1', 'Gene', '7088', (143, 147))	('proteins', 'Protein', (52, 60))	('ATF2', 'Gene', '1386', (185, 189))	('HDAC', 'Gene', '9734', (248, 252))	('transducin-like enhancer of split 1', 'Gene', '7088', (106, 141))	('activating transcription factor 2', 'Gene', (150, 183))	('fusion', 'Var', (4, 10))	('histone deacetylases', 'Gene', (226, 246))	('SSX', 'Gene', '6757', (14, 17))	('transducin-like enhancer of split 1', 'Gene', (106, 141))	('SS18', 'Gene', (21, 25))	('recruits', 'PosReg', (31, 39))	('TLE1', 'Gene', (143, 147))	('ATF2', 'Gene', (185, 189))	('SSX', 'Gene', (14, 17))	('activating transcription factor 2', 'Gene', '1386', (150, 183))
376159	27120803	When this association is disrupted by specific knockdown of TLE1, ATF2 or SS18-SSX, synovial sarcoma cell lines are observed to undergo apoptosis, indicating this complex association is important for tumor cell survival.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('ATF2', 'Gene', (66, 70))	('TLE1', 'Gene', '7088', (60, 64))	('synovial sarcoma', 'Disease', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('ATF2', 'Gene', '1386', (66, 70))	('apoptosis', 'CPA', (136, 145))	('tumor', 'Disease', (200, 205))	('knockdown', 'Var', (47, 56))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (84, 100))	('TLE1', 'Gene', (60, 64))	('synovial sarcoma', 'Disease', 'MESH:D013584', (84, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('SSX', 'Gene', (79, 82))	('SSX', 'Gene', '6757', (79, 82))
376184	27120803	To investigate if the SS18-SSX/TLE1 complex disruption induced by HDAC inhibitors can be detected in situ using the PLA method, SYO-1 synovial sarcoma cells were treated at IC50 doses with the class I HDAC inhibitors FK288 (romidepsin), MS275 (entinostat), SAHA (vorinostat) or the pan-HDAC inhibitor SB939 (pracinostat), as well as nexturastat A (a cytoplasmic class IIb HDAC6 inhibitor).	('HDAC', 'Gene', (201, 205))	('HDAC', 'Gene', '9734', (66, 70))	('entinostat', 'Chemical', 'MESH:C118739', (244, 254))	('SB939', 'Gene', (301, 306))	('HDAC6', 'Gene', (372, 377))	('MS275', 'Chemical', 'MESH:C118739', (237, 242))	('vorinostat', 'Chemical', 'MESH:D000077337', (263, 273))	('SSX', 'Gene', '6757', (27, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('HDAC', 'Gene', (66, 70))	('HDAC', 'Gene', '9734', (372, 376))	('HDAC', 'Gene', '9734', (286, 290))	('SSX', 'Gene', (27, 30))	('TLE1', 'Gene', (31, 35))	('HDAC', 'Gene', (372, 376))	('SYO-1 synovial sarcoma', 'Disease', (128, 150))	('HDAC', 'Gene', (286, 290))	('HDAC6', 'Gene', '10013', (372, 377))	('FK288', 'Var', (217, 222))	('pracinostat', 'Chemical', 'MESH:C557525', (308, 319))	('nexturastat A', 'Chemical', 'MESH:C577944', (333, 346))	('FK288', 'Chemical', '-', (217, 222))	('HDAC', 'Gene', '9734', (201, 205))	('SYO-1 synovial sarcoma', 'Disease', 'MESH:D013584', (128, 150))	('TLE1', 'Gene', '7088', (31, 35))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (134, 150))
376187	27120803	HDAC6 inhibition had minimal effect on SS18-SSX/TLE1 co-localization (Figure 4A-4C), supporting class I HDAC inhibition as being required for disruption of this complex.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', (104, 108))	('TLE1', 'Gene', (48, 52))	('HDAC', 'Gene', '9734', (0, 4))	('HDAC6', 'Gene', (0, 5))	('SSX', 'Gene', (44, 47))	('HDAC', 'Gene', '9734', (104, 108))	('HDAC6', 'Gene', '10013', (0, 5))	('SSX', 'Gene', '6757', (44, 47))	('TLE1', 'Gene', '7088', (48, 52))	('co-localization', 'MPA', (53, 68))	('inhibition', 'Var', (6, 16))
376191	27120803	SYO-1 cells were exposed to IC50 doses of the HDAC inhibitors FK228, MS-275, SAHA, SB939, ITF2357 (givinostat), JNJ-26481585 (quisinostat), LAQ824 (dacinostat), PCI-24781 (abexinostat), as well as doxorubicin (DNA intercalator) and PI-103 (PI3K inhibitor).	('PCI-24781', 'Chemical', 'MESH:C512352', (161, 170))	('doxorubicin', 'MPA', (197, 208))	('LAQ824', 'Var', (140, 146))	('PCI-24781', 'Gene', (161, 170))	('abexinostat', 'Chemical', 'MESH:C512352', (172, 183))	('givinostat', 'Chemical', 'MESH:C575255', (99, 109))	('HDAC', 'Gene', '9734', (46, 50))	('MS-275', 'Chemical', 'MESH:C118739', (69, 75))	('SB939', 'Gene', (83, 88))	('doxorubicin', 'Chemical', 'MESH:D004317', (197, 208))	('HDAC', 'Gene', (46, 50))	('ITF2357', 'Var', (90, 97))	('LAQ824', 'Chemical', 'MESH:C477361', (140, 146))	('SYO-1', 'Gene', '55027', (0, 5))	('dacinostat', 'Chemical', '-', (148, 158))	('PI-103', 'Chemical', 'MESH:C522973', (232, 238))	('SYO-1', 'Gene', (0, 5))	('JNJ-26481585', 'Chemical', 'MESH:C541788', (112, 124))	('JNJ-26481585', 'Var', (112, 124))	('quisinostat', 'Chemical', 'MESH:C541788', (126, 137))	('FK228', 'Chemical', 'MESH:C087123', (62, 67))
376197	27120803	Compound SXT1596 effectively disrupts the interaction between SS18-SSX and TLE1, as confirmed by PLA and immunoprecipitation (Figure 5D-5F).	('SSX', 'Gene', (67, 70))	('SSX', 'Gene', '6757', (67, 70))	('TLE1', 'Gene', '7088', (75, 79))	('interaction', 'Interaction', (42, 53))	('SXT1596', 'Var', (9, 16))	('TLE1', 'Gene', (75, 79))	('disrupts', 'NegReg', (29, 37))
376198	27120803	Treatment of SYO-1 cells with SXT1596 resulted in significantly decreased cell viability (Figure 6A) and increased apoptosis (Figure 6B) that correlated with the decrease in SS18-SSX/TLE1 co-localization signal (Figure 6C-6D).	('SYO-1', 'Gene', (13, 18))	('TLE1', 'Gene', '7088', (183, 187))	('TLE1', 'Gene', (183, 187))	('SYO-1', 'Gene', '55027', (13, 18))	('SSX', 'Gene', '6757', (179, 182))	('SXT1596', 'Var', (30, 37))	('SSX', 'Gene', (179, 182))	('increased', 'PosReg', (105, 114))	('apoptosis', 'CPA', (115, 124))	('decrease', 'NegReg', (162, 170))	('cell viability', 'CPA', (74, 88))	('decreased', 'NegReg', (64, 73))
376200	27120803	Similar to class I HDAC inhibitors, the compound SXT1596 reactivates EGR1 transcription and protein expression (Figure 6F-6G).	('reactivates', 'NegReg', (57, 68))	('EGR1', 'Gene', (69, 73))	('SXT1596', 'Var', (49, 56))	('EGR1', 'Gene', '1958', (69, 73))	('HDAC', 'Gene', (19, 23))	('HDAC', 'Gene', '9734', (19, 23))	('protein expression', 'MPA', (92, 110))	('transcription', 'MPA', (74, 87))
376211	27120803	Whether the compound directly inhibits the SS18-SSX/TLE1 interaction domain or disrupts the complex by a secondary mechanism is currently unknown, but the structure of SXT1596 indicates that it is likely a covalent protein inhibitor, not expected to be well tolerated until further pharmacologic optimization steps are carried out.	('TLE1', 'Gene', (52, 56))	('TLE1', 'Gene', '7088', (52, 56))	('inhibits', 'NegReg', (30, 38))	('SSX', 'Gene', '6757', (48, 51))	('SSX', 'Gene', (48, 51))	('SXT1596', 'Var', (168, 175))
376249	27120803	shRNA-mediated knockdown of SS18-SSX was induced by the addition of doxycycline (Clontech).	('Clontech', 'Chemical', '-', (81, 89))	('knockdown', 'Var', (15, 24))	('SSX', 'Gene', (33, 36))	('SSX', 'Gene', '6757', (33, 36))	('doxycycline', 'Chemical', 'MESH:D004318', (68, 79))
376261	26499495	Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and disruption of Cdkn2a.	('sarcoma growth', 'Disease', 'MESH:D006130', (148, 162))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('aspartate', 'Chemical', 'MESH:D001224', (77, 86))	('inhibitory', 'NegReg', (127, 137))	('sarcomas', 'Disease', (203, 211))	('sarcoma growth', 'Disease', (148, 162))	('asparagine', 'Chemical', 'MESH:D001216', (92, 102))	('asparagine synthetase', 'Gene', '27053', (13, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Cdkn2a', 'Gene', '12578', (258, 264))	('mouse', 'Species', '10090', (197, 202))	('disruption', 'Var', (244, 254))	('Cdkn2a', 'Gene', (258, 264))	('Silencing', 'Var', (0, 9))	('asparagine synthetase', 'Gene', (13, 34))	('asparagine', 'Chemical', 'MESH:D001216', (13, 23))	('sarcomas', 'Disease', 'MESH:D012509', (203, 211))
376262	26499495	ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis.	('sarcoma', 'Disease', (34, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('mouse', 'Species', '10090', (18, 23))	('human', 'Species', '9606', (28, 33))	('new polypeptide synthesis', 'MPA', (105, 130))	('silencing', 'Var', (5, 14))	('reduced', 'NegReg', (53, 60))	('S phase cells', 'CPA', (79, 92))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('impeded', 'NegReg', (97, 104))
376264	26499495	Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo.	('tumor', 'Disease', (251, 256))	('inhibited', 'NegReg', (92, 101))	('sarcoma', 'Disease', (118, 125))	('genetic silencing', 'Var', (147, 164))	('amino sulfoximine 5', 'Chemical', '-', (50, 69))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('asparagine', 'Chemical', 'MESH:D001216', (230, 240))	('human', 'Species', '9606', (112, 117))	('mouse', 'Species', '10090', (102, 107))	('sarcoma growth', 'Disease', 'MESH:D006130', (118, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcoma growth', 'Disease', (118, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('inhibited', 'NegReg', (241, 250))	('AS5', 'Chemical', '-', (71, 74))	('ASNS', 'Gene', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('asparagine', 'Chemical', 'MESH:D001216', (6, 16))	('depletion of plasma asparagine', 'Phenotype', 'HP:0500157', (210, 240))	('mouse', 'Species', '10090', (176, 181))	('sarcoma', 'Disease', 'MESH:D012509', (182, 189))	('sarcoma', 'Disease', (182, 189))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
376270	26499495	Many sarcomas have a mutation in a gene that encodes a protein called Ras.	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('mutation', 'Var', (21, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('sarcomas', 'Disease', (5, 13))
376273	26499495	These genes were also hyperactive in human sarcoma cells and may promote the growth of sarcomas carrying mutant forms of Ras.	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('Ras', 'Gene', (121, 124))	('growth', 'MPA', (77, 83))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('mutant forms', 'Var', (105, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcomas', 'Disease', (87, 95))	('promote', 'PosReg', (65, 72))	('hyperactive', 'PosReg', (22, 33))	('human', 'Species', '9606', (37, 42))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
376274	26499495	- including some of the same researchers involved in the earlier work - show that targeting one of these hyperactive genes can slow sarcoma growth.	('targeting', 'Var', (82, 91))	('slow', 'NegReg', (127, 131))	('sarcoma growth', 'Disease', (132, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma growth', 'Disease', 'MESH:D006130', (132, 146))
376278	26499495	Further experiments showed that reducing the amount of asparagine in human and mouse sarcoma cells slowed down the growth of these cells.	('mouse', 'Species', '10090', (79, 84))	('asparagine', 'Chemical', 'MESH:D001216', (55, 65))	('human', 'Species', '9606', (69, 74))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('sarcoma', 'Disease', (85, 92))	('reducing', 'Var', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('slowed down', 'NegReg', (99, 110))	('growth of these cells', 'CPA', (115, 136))
376280	26499495	's findings suggest that drugs that alter the availability of asparagine in the body might also be useful to treat sarcomas with mutant forms of Ras.	('asparagine', 'Chemical', 'MESH:D001216', (62, 72))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('sarcomas', 'Disease', (115, 123))	('mutant', 'Var', (129, 135))
376284	26499495	Many tumors carry complex karyotypes with variable genetic changes; others express specific oncogenic mutations or exclusive chromosomal translocations within a relatively simple karyotype.	('express', 'Reg', (75, 82))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Disease', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutations', 'Var', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
376292	26499495	The strongest inhibitory effect on sarcoma cell proliferation was observed after silencing of asparagine synthetase (ASNS), the enzyme that catalyzes cellular synthesis of the non-essential amino acid asparagine.	('sarcoma', 'Disease', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('asparagine synthetase', 'Gene', (94, 115))	('inhibitory', 'NegReg', (14, 24))	('silencing', 'Var', (81, 90))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('amino acid asparagine', 'Chemical', '-', (190, 211))	('asparagine synthetase', 'Gene', '27053', (94, 115))
376296	26499495	The myogenic differentiation status of the Ras-driven sarcomas generated in this system depends largely on the cell type transduced, also known as the "cell-of-origin": Kras; p16p19null satellite cells typically gave rise to RMS, whereas the identical oncogenetic lesions introduced into fibroadipogenic precursors within the MFA cell pool almost always produced sarcomas lacking myogenic differentiation features (non-myogenic sarcomas, NMS) (Figure 1:figure supplement 1).	('sarcomas', 'Disease', (428, 436))	('NMS', 'Disease', 'MESH:D009459', (438, 441))	('RMS', 'CPA', (225, 228))	('produced', 'Reg', (354, 362))	('NMS', 'Disease', (438, 441))	('Kras; p16p19null', 'Var', (169, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (428, 435))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('sarcomas', 'Disease', 'MESH:D012509', (428, 436))	('gave rise', 'Reg', (212, 221))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcomas', 'Disease', 'MESH:D012509', (363, 371))	('sarcomas', 'Phenotype', 'HP:0100242', (428, 436))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (363, 371))	('sarcoma', 'Phenotype', 'HP:0100242', (363, 370))	('sarcomas', 'Disease', (363, 371))	('sarcomas', 'Disease', (54, 62))
376297	26499495	We previously showed that Kras;p16p19nullmouse sarcomas from each of these cellular origins recapitulate transcriptional profiles across the entire spectrum of human RMS and used this information to identify 141 genes of potential significance for sarcoma growth.	('rev', 'Gene', (4, 7))	('sarcomas', 'Disease', (47, 55))	('sarcoma growth', 'Disease', (248, 262))	('transcriptional profiles', 'MPA', (105, 129))	('mouse', 'Species', '10090', (41, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('Kras;p16p19nullmouse', 'Var', (26, 46))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcoma growth', 'Disease', 'MESH:D006130', (248, 262))	('rev', 'Gene', '19714', (4, 7))	('human', 'Species', '9606', (160, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
376301	26499495	As shRNA mediated silencing of Kras (G12v)-IRES-GFP, the driver oncogene used to initiate the mouse sarcomas, markedly inhibits the growth of Kras;p16p19nullsarcoma cells (Figure 2A-B, Figure 2:figure supplement 1A-B), shRNAs directed against either GFP or KRAS served as positive controls in this screen and showed clear growth-inhibitory effects (Figure 1C-D, 1H-I).	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('silencing', 'Var', (18, 27))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Disease', (100, 108))	('Kras;p16p19nullsarcoma', 'Disease', 'None', (142, 164))	('growth', 'CPA', (132, 138))	('mouse', 'Species', '10090', (94, 99))	('1H', 'Chemical', '-', (362, 364))	('Kras;p16p19nullsarcoma', 'Disease', (142, 164))	('inhibits', 'NegReg', (119, 127))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
376305	26499495	In both RMS and NMS cells, silencing of ASNS (Asparagine Synthetase) produced by far the strongest anti-proliferative effect (p<0.0001, q<0.01, 4-5 of 5 shRNAs with FDR<30%; Figure 1D,I and Supplementary files 5-6).	('Asparagine Synthetase', 'Gene', (46, 67))	('ASNS', 'Gene', (40, 44))	('silencing', 'Var', (27, 36))	('NMS', 'Disease', (16, 19))	('NMS', 'Disease', 'MESH:D009459', (16, 19))	('anti-proliferative effect', 'MPA', (99, 124))	('Asparagine Synthetase', 'Gene', '440', (46, 67))
376306	26499495	ASNS silencing reduced the growth of Kras;p16p19nullRMS and NMS cells to 30.16% and 6.69% of the average of control RMS and NMS cells, respectively.	('silencing reduced', 'NegReg', (5, 22))	('NMS', 'Disease', 'MESH:D009459', (124, 127))	('Kras;p16p19nullRMS', 'Var', (37, 55))	('NMS', 'Disease', (60, 63))	('NMS', 'Disease', 'MESH:D009459', (60, 63))	('growth', 'MPA', (27, 33))	('ASNS', 'Gene', (0, 4))	('NMS', 'Disease', (124, 127))
376309	26499495	Supplementation of the culture media with 100 mg/L asparagine reversed the growth inhibition observed in shASNS-infected Kras;p16p19null RMS (Figure 2A-2B) and NMS (Figure 2:figure supplement 1A-1B) cells.	('rev', 'Gene', (62, 65))	('asparagine', 'Chemical', 'MESH:D001216', (51, 61))	('growth', 'MPA', (75, 81))	('NMS', 'Disease', 'MESH:D009459', (160, 163))	('NMS', 'Disease', (160, 163))	('shASNS', 'Chemical', '-', (105, 111))	('rev', 'Gene', '19714', (62, 65))	('p16p19null', 'Var', (126, 136))
376314	26499495	Moreover, Asns silencing reduced the percentage of BrdU + cells in S phase (p<0.001, Figure 2E-2F).	('reduced', 'NegReg', (25, 32))	('Asns', 'Protein', (10, 14))	('BrdU', 'Chemical', 'MESH:D001973', (51, 55))	('silencing', 'Var', (15, 24))	('S phase', 'CPA', (67, 74))
376318	26499495	Rapidly proliferating shLUC-infected Kras;p16p19null RMS cells exhibited strong OP-puromycin staining, indicating brisk polypeptide synthesis (Figure 2G, middle panels).	('OP-puromycin staining', 'MPA', (80, 101))	('OP-puromycin', 'Chemical', '-', (80, 92))	('polypeptide synthesis', 'MPA', (120, 141))	('p16p19null', 'Var', (42, 52))
376321	26499495	Similar effects of ASNS silencing on apoptosis, cell cycle and synthesis of nascent peptide chains were observed in Kras;p16p19null NMS cells (Figure 2:figure supplement 1).	('synthesis of nascent peptide chains', 'MPA', (63, 98))	('NMS', 'Disease', (132, 135))	('apoptosis', 'CPA', (37, 46))	('cell cycle', 'CPA', (48, 58))	('ASNS', 'Gene', (19, 23))	('silencing', 'NegReg', (24, 33))	('Kras;p16p19null', 'Var', (116, 131))	('NMS', 'Disease', 'MESH:D009459', (132, 135))
376326	26499495	ShRNA-mediated knockdown of ASNS in Rh30 cells (Figure 3A) reduced proliferation (p<0.001; Figure 3B-C), increased the percentage of apoptotic cells (p<0.01; Figure 3D-E), reduced the percentage of cells in S phase (p<0.001; Figure 3F-G) and impeded nascent polypeptide synthesis (Figure 3H).	('Rh30', 'Gene', '6007', (36, 40))	('reduced', 'NegReg', (172, 179))	('reduced', 'NegReg', (59, 66))	('knockdown', 'Var', (15, 24))	('proliferation', 'CPA', (67, 80))	('increased', 'PosReg', (105, 114))	('Rh30', 'Gene', (36, 40))	('cells', 'CPA', (198, 203))	('impeded', 'NegReg', (242, 249))	('nascent polypeptide synthesis', 'MPA', (250, 279))
376327	26499495	The effects of ASNS silencing on Rh30 growth and peptide synthesis were reversed by asparagine supplementation (Figure 3B-H).	('ASNS', 'Gene', (15, 19))	('asparagine', 'Chemical', 'MESH:D001216', (84, 94))	('Rh30', 'Gene', '6007', (33, 37))	('rev', 'Gene', '19714', (72, 75))	('rev', 'Gene', (72, 75))	('Rh30', 'Gene', (33, 37))	('peptide synthesis', 'MPA', (49, 66))	('silencing', 'Var', (20, 29))
376332	26499495	For asparaginase, EC50 concentrations were estimated at 0.2-0.5 IU/ml in mouse Kras;p16p19null sarcoma cells, 0.8-0.9 IU/ml in human HT1080, Rh30 and Rh41 cells and 6 IU/ml in human RD cells (Figure 4A-B).	('human', 'Species', '9606', (127, 132))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('p16p19null', 'Var', (84, 94))	('Rh30', 'Gene', (141, 145))	('human', 'Species', '9606', (176, 181))	('HT1080', 'CellLine', 'CVCL:0317', (133, 139))	('mouse', 'Species', '10090', (73, 78))	('sarcoma', 'Disease', (95, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('Rh30', 'Gene', '6007', (141, 145))
376346	26499495	Serum asparagine levels were reduced 13-fold in asparaginase-treated mice (0.53 mg/L (4 muM) versus 6.87 mg/L (52 muM) in untreated mice, p<0.001; Figure 5D and Supplementary file 7).	('asparagine', 'Chemical', 'MESH:D001216', (6, 16))	('muM', 'Gene', (88, 91))	('muM', 'Gene', '56925', (114, 117))	('mice', 'Species', '10090', (69, 73))	('reduced', 'NegReg', (29, 36))	('mice', 'Species', '10090', (132, 136))	('muM', 'Gene', '56925', (88, 91))	('muM', 'Gene', (114, 117))	('Serum asparagine levels', 'MPA', (0, 23))	('asparaginase-treated', 'Var', (48, 68))
376347	26499495	Daily exposure to asparaginase did not change the latency of shLUC-tumors (p = 0.5; Figure 5B); however, asparaginase treatment significantly prolonged tumor latency in mice implanted with shASNS-RMS cells (p<0.001; Figure 5B).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('prolonged', 'PosReg', (142, 151))	('shLUC-tumors', 'Disease', (61, 73))	('mice', 'Species', '10090', (169, 173))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('shLUC-tumors', 'Disease', 'MESH:D009369', (61, 73))	('asparaginase', 'Var', (105, 117))	('shASNS', 'Chemical', '-', (189, 195))
376358	26499495	Moreover, ASNS inhibition significantly slowed mouse sarcoma growth in vivo only when combined with depletion of plasma asparagine, likely reflecting the ability of systemic asparagine in the tumor environment to replenish intracellular asparagine availability after ASNS inhibition.	('sarcoma growth', 'Disease', 'MESH:D006130', (53, 67))	('tumor', 'Disease', (192, 197))	('slowed', 'NegReg', (40, 46))	('sarcoma growth', 'Disease', (53, 67))	('ASNS', 'Gene', (10, 14))	('asparagine', 'Chemical', 'MESH:D001216', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('depletion of plasma asparagine', 'Phenotype', 'HP:0500157', (100, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('asparagine', 'Chemical', 'MESH:D001216', (237, 247))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('asparagine', 'Chemical', 'MESH:D001216', (174, 184))	('inhibition', 'Var', (15, 25))	('mouse', 'Species', '10090', (47, 52))	('depletion', 'MPA', (100, 109))
376369	26499495	However, aspartate carries reducing equivalents in the malate-aspartate shuttle, and increased aspartate levels after ASNS knockdown might be predicted to benefit the redox state of sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('reducing', 'NegReg', (27, 35))	('increased aspartate', 'Phenotype', 'HP:0500159', (85, 104))	('aspartate', 'Var', (9, 18))	('aspartate', 'Chemical', 'MESH:D001224', (95, 104))	('benefit', 'PosReg', (155, 162))	('aspartate levels', 'MPA', (95, 111))	('redox state', 'MPA', (167, 178))	('sarcoma', 'Disease', 'MESH:D012509', (182, 189))	('aspartate', 'Chemical', 'MESH:D001224', (9, 18))	('increased', 'PosReg', (85, 94))	('aspartate', 'Chemical', 'MESH:D001224', (62, 71))	('equivalents in the malate-aspartate shuttle', 'MPA', (36, 79))	('malate', 'Chemical', 'MESH:C030298', (55, 61))	('sarcoma', 'Disease', (182, 189))
376381	26499495	However, in our screen, silencing of PSAT1, PHGDH or BCAT1 did not inhibit sarcoma cell growth (Supplementary files 5-6), suggesting that these biosynthetic pathways may be of lesser importance for the sarcomatous malignancies studied here.	('sarcoma cell growth', 'Disease', (75, 94))	('BCAT1', 'Gene', (53, 58))	('sarcomatous malignancies', 'Disease', (202, 226))	('inhibit', 'NegReg', (67, 74))	('PSAT1', 'Gene', '29968', (37, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('PSAT1', 'Gene', (37, 42))	('sarcomatous malignancies', 'Disease', 'MESH:D018316', (202, 226))	('PHGDH', 'Gene', (44, 49))	('sarcomatous malignancies', 'Phenotype', 'HP:0100242', (202, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('BCAT1', 'Gene', '586', (53, 58))	('sarcoma cell growth', 'Disease', 'MESH:D006130', (75, 94))	('silencing', 'Var', (24, 33))	('PHGDH', 'Gene', '26227', (44, 49))
376384	26499495	Similarly, upregulation of ASNS in response to amino acid restriction, such as plasma asparagine depletion by treatment with asparaginase, is part of a normal physiological adaptation response to counteract nutrient deprivation.	('plasma asparagine depletion', 'MPA', (79, 106))	('asparagine', 'Chemical', 'MESH:D001216', (86, 96))	('asparaginase', 'Var', (125, 137))	('treatment', 'Var', (110, 119))	('upregulation', 'PosReg', (11, 23))	('ASNS', 'MPA', (27, 31))
376386	26499495	Increased Asns mRNA expression in Kras;p16p19null mouse sarcomas as compared to normal muscle could occur in response to amino acid and glucose deprivation in rapidly growing sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('glucose deprivation', 'Disease', 'MESH:D012892', (136, 155))	('Asns mRNA expression', 'MPA', (10, 30))	('sarcomas', 'Disease', (175, 183))	('mouse', 'Species', '10090', (50, 55))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('glucose deprivation', 'Disease', (136, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcomas', 'Disease', (56, 64))	('sarcomas', 'Disease', 'MESH:D012509', (175, 183))	('Kras;p16p19null', 'Var', (34, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (175, 183))
376396	26499495	Primary Kras;p16p19null mouse sarcomas were induced by ex-vivo transduction of freshly sorted Cdkn2a-/- (p16p19null) mouse skeletal muscle precursor cells (CD45-CD11b-TER119-Sca1-CXCR4+ beta1integrin+) or Sca1+ fibroadipogenic precursor cells CD45-CD11b-TER119-Sca1+) with pGIPZ-Kras (G12V)-IRES-GFP lentivirus followed by intramuscular transplantation of Kras-expressing, p16p19null cells into the cardiotoxin-preinjured gastrocnemius muscles of 1- to 3-months old NOD/SCID mice, as previously described.	('mouse', 'Species', '10090', (24, 29))	('CD11b', 'Gene', (248, 253))	('rev', 'Gene', (485, 488))	('mice', 'Species', '10090', (475, 479))	('Cdkn2a', 'Gene', (94, 100))	('mouse', 'Species', '10090', (117, 122))	('CXCR4', 'Gene', '12767', (179, 184))	('SCID', 'Disease', 'MESH:D053632', (470, 474))	('sarcomas', 'Disease', 'MESH:D012509', (30, 38))	('CXCR4', 'Gene', (179, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('p16p19null', 'Var', (373, 383))	('CD45', 'Gene', '19264', (156, 160))	('sarcomas', 'Disease', (30, 38))	('NOD', 'Gene', '1822', (466, 469))	('CD45', 'Gene', '19264', (243, 247))	('SCID', 'Disease', (470, 474))	('NOD', 'Gene', (466, 469))	('rev', 'Gene', '19714', (485, 488))	('CD11b', 'Gene', '16409', (161, 166))	('G12V', 'Mutation', 'rs121913529', (285, 289))	('CD11b', 'Gene', '16409', (248, 253))	('CD45', 'Gene', (156, 160))	('CD45', 'Gene', (243, 247))	('CD11b', 'Gene', (161, 166))	('Cdkn2a', 'Gene', '12578', (94, 100))
376397	26499495	Secondary Kras;p16p19null mouse sarcomas were generated by implanting 100 Kras;p16p19null mouse RMS or NMS cells into the cardiotoxin-preinjured gastrocnemius muscles of 1- to 3-months old NOD/SCID mice.	('SCID', 'Disease', (193, 197))	('NMS', 'Disease', (103, 106))	('NOD', 'Gene', (189, 192))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('mouse', 'Species', '10090', (90, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Kras;p16p19null', 'Var', (74, 89))	('mice', 'Species', '10090', (198, 202))	('NOD', 'Gene', '1822', (189, 192))	('sarcomas', 'Disease', (32, 40))	('mouse', 'Species', '10090', (26, 31))	('NMS', 'Disease', 'MESH:D009459', (103, 106))	('SCID', 'Disease', 'MESH:D053632', (193, 197))
376401	26499495	C57BL6, NOD/CB17-Prkdcscid/J (NOD/SCID) and p16p19nullmice (B6.129 background) mice were obtained from Jackson Laboratory and the National Institutes of Health/Mouse Models of Human Cancer Consortium, respectively.	('NOD', 'Gene', '1822', (30, 33))	('Cancer', 'Disease', (182, 188))	('mice', 'Species', '10090', (79, 83))	('p16p19nullmice', 'Var', (44, 58))	('Human', 'Species', '9606', (176, 181))	('SCID', 'Disease', 'MESH:D053632', (34, 38))	('NOD', 'Gene', (8, 11))	('Cancer', 'Disease', 'MESH:D009369', (182, 188))	('SCID', 'Disease', (34, 38))	('NOD', 'Gene', '1822', (8, 11))	('Mouse', 'Species', '10090', (160, 165))	('Cancer', 'Phenotype', 'HP:0002664', (182, 188))	('NOD', 'Gene', (30, 33))	('mice', 'Species', '10090', (54, 58))	('BL6', 'CellLine', 'CVCL:M564', (3, 6))
376409	26499495	The screen was performed using the Kras;p16p19null RMS line T14R and the Kras;p16p19null NMS line Sca1-01.	('NMS', 'Disease', 'MESH:D009459', (89, 92))	('T14R', 'Var', (60, 64))	('T14R', 'SUBSTITUTION', 'None', (60, 64))	('NMS', 'Disease', (89, 92))
376424	26499495	Human sarcoma sections were stained for ASNS (1 in 100, HPA029318, Sigma; human brain served as positive and muscle as negative control tissue).	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Human', 'Species', '9606', (0, 5))	('HPA029318', 'Var', (56, 65))	('sarcoma', 'Disease', 'MESH:D012509', (6, 13))	('human', 'Species', '9606', (74, 79))	('sarcoma', 'Disease', (6, 13))
376442	26499495	Annexin V staining was performed according to the manufacturer's instructions using Annexin V-APC (550474, BD Biosciences, Franklin Lakes, NJ) and PI.	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('550474', 'Var', (99, 105))	('Annexin V', 'Gene', '308', (84, 93))	('Annexin V', 'Gene', (84, 93))
376462	26499495	It further shows a decrease in cell proliferation, increase in cell death and decrease of polypeptide synthesis after ASNS silencing in the model cells and human RMS cell line, effects that can be reversed by addition of exogenous asparagine.	('human', 'Species', '9606', (156, 161))	('decrease', 'NegReg', (19, 27))	('decrease', 'NegReg', (78, 86))	('ASNS', 'Gene', (118, 122))	('rev', 'Gene', '19714', (197, 200))	('cell proliferation', 'CPA', (31, 49))	('rev', 'Gene', (197, 200))	('asparagine', 'Chemical', 'MESH:D001216', (231, 241))	('polypeptide synthesis', 'MPA', (90, 111))	('cell death', 'CPA', (63, 73))	('silencing', 'Var', (123, 132))
376485	26499495	However, in our screen, silencing of PSAT1, PHGDH or BCAT1 did not result in growth inhibition, suggesting that sarcoma cells show lesser dependence on these pathways.	('BCAT1', 'Gene', (53, 58))	('PSAT1', 'Gene', '29968', (37, 42))	('PSAT1', 'Gene', (37, 42))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('PHGDH', 'Gene', (44, 49))	('BCAT1', 'Gene', '586', (53, 58))	('sarcoma', 'Disease', (112, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('silencing', 'Var', (24, 33))	('PHGDH', 'Gene', '26227', (44, 49))
376487	26499495	We also included a new series of experiments documenting the effects of increasing concentrations of asparagine on the growth of shASNS and sh-LUC-transduced mouse Kras;p16p19null RMS and NMS cells.	('mouse', 'Species', '10090', (158, 163))	('p16p19null', 'Var', (169, 179))	('asparagine', 'Chemical', 'MESH:D001216', (101, 111))	('NMS', 'Disease', (188, 191))	('NMS', 'Disease', 'MESH:D009459', (188, 191))	('shASNS', 'Chemical', '-', (129, 135))
376493	26499495	As noted by the reviewers, ASNS inhibition or exogenous Asparaginase treatment should result in increased aspartate and glutamine, as well as decreased glutamate levels.	('glutamate levels', 'MPA', (152, 168))	('increased', 'PosReg', (96, 105))	('decreased glutamate levels', 'Phenotype', 'HP:0500150', (142, 168))	('exogenous', 'Var', (46, 55))	('aspartate', 'Chemical', 'MESH:D001224', (106, 115))	('decreased', 'NegReg', (142, 151))	('rev', 'Gene', '19714', (16, 19))	('rev', 'Gene', (16, 19))	('glutamate', 'Chemical', 'MESH:D018698', (152, 161))	('increased aspartate', 'Phenotype', 'HP:0500159', (96, 115))	('glutamine', 'Chemical', 'MESH:D005973', (120, 129))
376497	26499495	Aspartate, on the other hand, carries reducing equivalents in the malate-aspartate shuttle (Chen et al., 2013), and increased aspartate levels after ASNS knockdown conceivably would benefit the redox state of sarcoma cells.	('increased aspartate', 'Phenotype', 'HP:0500159', (116, 135))	('benefit', 'PosReg', (182, 189))	('redox state', 'MPA', (194, 205))	('reducing', 'NegReg', (38, 46))	('aspartate', 'Chemical', 'MESH:D001224', (73, 82))	('sarcoma', 'Disease', 'MESH:D012509', (209, 216))	('aspartate', 'Chemical', 'MESH:D001224', (126, 135))	('knockdown', 'Var', (154, 163))	('sarcoma', 'Disease', (209, 216))	('malate', 'Chemical', 'MESH:C030298', (66, 72))	('increased', 'PosReg', (116, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('Aspartate', 'Chemical', 'MESH:D001224', (0, 9))	('aspartate levels', 'MPA', (126, 142))	('malate-aspartate shuttle', 'MPA', (66, 90))	('ASNS', 'Gene', (149, 153))
376498	26499495	Nonetheless, we recognize that disruption of Gln/Glu metabolism may represent an additional mechanism by which modulation of asparagine availability disrupts sarcoma cell growth.	('sarcoma cell growth', 'Disease', 'MESH:D006130', (158, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('disrupts sarcoma', 'Disease', 'MESH:D019958', (149, 165))	('asparagine', 'Chemical', 'MESH:D001216', (125, 135))	('sarcoma cell growth', 'Disease', (158, 177))	('Glu', 'Chemical', 'MESH:D018698', (49, 52))	('modulation', 'Var', (111, 121))	('Gln/Glu metabolism', 'MPA', (45, 63))	('disruption', 'Var', (31, 41))	('disrupts sarcoma', 'Disease', (149, 165))	('Gln', 'Chemical', 'MESH:D005973', (45, 48))
376500	26499495	We also demonstrated increased expression of Glutaminase transcripts in Kras;p16p19null sarcoma cells compared to normal mouse skeletal muscle (see Figure 2-figure supplement 3 and the aforementioned paragraph), which, as noted above, may counterbalance glutamate reduction due to ASNS inhibition.	('Glutaminase', 'Gene', '14660', (45, 56))	('increased', 'PosReg', (21, 30))	('Glutaminase', 'Gene', (45, 56))	('Kras;p16p19null', 'Var', (72, 87))	('glutamate', 'Chemical', 'MESH:D018698', (254, 263))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('mouse', 'Species', '10090', (121, 126))	('expression', 'MPA', (31, 41))	('glutamate reduction', 'Phenotype', 'HP:0500150', (254, 273))	('sarcoma', 'Disease', (88, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
376501	26499495	In our experiments, ASNS silencing in sarcoma cells did not impede sarcoma growth in vivo unless systemic asparagine was depleted by treatment with asparaginase.	('silencing', 'Var', (25, 34))	('sarcoma growth', 'Disease', 'MESH:D006130', (67, 81))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('sarcoma', 'Disease', (38, 45))	('ASNS', 'Protein', (20, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('sarcoma', 'Disease', (67, 74))	('sarcoma growth', 'Disease', (67, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('impede', 'NegReg', (60, 66))	('asparagine', 'Chemical', 'MESH:D001216', (106, 116))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))
376503	26499495	Nevertheless, our data support the notion that exogenous asparagine in the cell environment restores intracellular asparagine availability after ASNS silencing.	('asparagine', 'Chemical', 'MESH:D001216', (115, 125))	('intracellular asparagine availability', 'MPA', (101, 138))	('restores', 'PosReg', (92, 100))	('asparagine', 'Chemical', 'MESH:D001216', (57, 67))	('exogenous', 'Var', (47, 56))
376508	26499495	Recently published data revealed that, surprisingly, asparagine supplementation suppressed cell death in glutamine-deprived cells (although it did not restore TCA anaplerosis and proliferation) (Huang et al., 2014).	('cell death', 'CPA', (91, 101))	('rev', 'Gene', (24, 27))	('asparagine', 'Chemical', 'MESH:D001216', (53, 63))	('TCA', 'Chemical', 'MESH:D014238', (159, 162))	('glutamine', 'Chemical', 'MESH:D005973', (105, 114))	('asparagine', 'Var', (53, 63))	('suppressed', 'NegReg', (80, 90))	('rev', 'Gene', '19714', (24, 27))
376509	26499495	Thus, Asparagine appears to promote cellular adaptation to metabolic stress such as glutamine depletion.	('Asparagine', 'Chemical', 'MESH:D001216', (6, 16))	('glutamine', 'Chemical', 'MESH:D005973', (84, 93))	('Asparagine', 'Var', (6, 16))	('promote', 'PosReg', (28, 35))	('cellular adaptation', 'CPA', (36, 55))	('glutamine depletion', 'MPA', (84, 103))
376516	26295810	We mapped the interaction between PLCgamma1, PLCgamma2 and their individual domains with two K15 alleles, P and M. We found that the PLCgamma2 cSH2 domain, by binding to K15P, can be used as dominant negative inhibitor of the K15P-PLCgamma1 interaction, K15P-dependent PLCgamma1 phosphorylation, NFAT-dependent promoter activation and the increased invasiveness and angiogenic properties of KSHV infected endothelial cells.	('activation', 'PosReg', (320, 330))	('K15P', 'Var', (254, 258))	('K15P', 'Var', (226, 230))	('phospho', 'Chemical', 'MESH:D004099', (279, 286))	('PLCgamma2', 'Gene', (45, 54))	('K15P', 'SUBSTITUTION', 'None', (226, 230))	('K15P', 'SUBSTITUTION', 'None', (254, 258))	('PLCgamma2', 'Gene', '5336', (133, 142))	('phosphorylation', 'MPA', (279, 294))	('K15P', 'SUBSTITUTION', 'None', (170, 174))	('K15P', 'Var', (170, 174))	('PLCgamma2', 'Gene', (133, 142))	('cSH2', 'Gene', '1443', (143, 147))	('angiogenic properties of', 'CPA', (366, 390))	('PLCgamma2', 'Gene', '5336', (45, 54))	('increased', 'PosReg', (339, 348))	('cSH2', 'Gene', (143, 147))
376517	26295810	We increased the binding of the PLCgamma2 cSH2 domain for K15P by substituting two amino acids, thereby creating an improved dominant negative inhibitor of the K15P-dependent PLCgamma1 activation.	('increased', 'PosReg', (3, 12))	('cSH2', 'Gene', '1443', (42, 46))	('K15P', 'Var', (58, 62))	('binding', 'Interaction', (17, 24))	('cSH2', 'Gene', (42, 46))	('PLCgamma2', 'Gene', '5336', (32, 41))	('K15P', 'SUBSTITUTION', 'None', (58, 62))	('K15P', 'Var', (160, 164))	('PLCgamma2', 'Gene', (32, 41))	('K15P', 'SUBSTITUTION', 'None', (160, 164))	('substituting', 'Var', (66, 78))
376522	26295810	Moreover, the PCLgamma2 cSH2 domain, when overexpressed in KSHV infected endothelial cells, reduces the angiogenesis and invasiveness induced by the virus.	('invasiveness', 'CPA', (121, 133))	('cSH2', 'Gene', (24, 28))	('cSH2', 'Gene', '1443', (24, 28))	('angiogenesis', 'CPA', (104, 116))	('reduces', 'NegReg', (92, 99))	('PCLgamma2', 'Var', (14, 23))
376531	26295810	For both K15P and M a mRNA comprising all eight exons is the most strongly expressed transcript and encodes a protein of 12 predicted transmembrane domains and a cytoplasmic tail involved in signalling.	('K15P', 'SUBSTITUTION', 'None', (9, 13))	('encodes', 'Reg', (100, 107))	('K15P', 'Var', (9, 13))
376532	26295810	Although K15P and M share as little as 33% of amino acid sequence homology, the cytoplasmic tail of both K15 alleles contains a putative src homology -3 (SH3) (PLPP) and two SH2 (YASIL, YEEVL) binding sites (Fig 1A, upper panel).	('K15', 'Gene', (105, 108))	('K15P', 'SUBSTITUTION', 'None', (9, 13))	('binding', 'Interaction', (193, 200))	('K15P', 'Var', (9, 13))
376533	26295810	Previous studies reported that both K15 alleles activate NF-kappaB and the Ras/MAPK signalling.	('NF-kappaB', 'Gene', (57, 66))	('activate', 'PosReg', (48, 56))	('Ras/MAPK signalling', 'Pathway', (75, 94))	('K15', 'Var', (36, 39))	('NF-kappaB', 'Gene', '4790', (57, 66))
376534	26295810	Microarray studies revealed that K15 upregulates the expression of genes involved in angiogenesis and cell migration, including, among others, COX2 and an NFAT-dependent upregulation of DSCR1.	('rat', 'Species', '10116', (110, 113))	('COX2', 'Gene', (143, 147))	('upregulation', 'PosReg', (170, 182))	('upregulates', 'PosReg', (37, 48))	('expression', 'Species', '29278', (53, 63))	('DSCR1', 'Gene', (186, 191))	('expression', 'MPA', (53, 63))	('cell migration', 'CPA', (102, 116))	('K15', 'Var', (33, 36))
376535	26295810	This process involves the K15P-dependent recruitment of phospholipase C gamma1 (PLCgamma1) and its phosphorylation on tyrosine 783, the successive activation of the calcineurin/NFAT pathway and the downstream upregulation of DSCR1.	('K15P', 'SUBSTITUTION', 'None', (26, 30))	('PLCgamma1', 'Gene', (80, 89))	('tyrosine', 'Chemical', 'MESH:D014443', (118, 126))	('phospho', 'Chemical', 'MESH:D004099', (56, 63))	('recruitment', 'PosReg', (41, 52))	('DSCR1', 'Gene', (225, 230))	('phospholipase C gamma1', 'Gene', (56, 78))	('phospho', 'Chemical', 'MESH:D004099', (99, 106))	('calcineurin/NFAT pathway', 'Pathway', (165, 189))	('upregulation', 'PosReg', (209, 221))	('activation', 'PosReg', (147, 157))	('phosphorylation on tyrosine 783', 'MPA', (99, 130))	('phospholipase C gamma1', 'Gene', '5335', (56, 78))	('K15P', 'Var', (26, 30))
376542	26295810	We also show that the overexpression of an isolated SH2 domain, derived from PLCgamma2, can disrupt the K15P-PLCgamma1 interaction and can inhibit K15-dependent downstream signalling and thereby the increased invasiveness and angiogenic properties of KSHV infected endothelial cells.	('interaction', 'Interaction', (119, 130))	('overexpression', 'PosReg', (22, 36))	('expression', 'Species', '29278', (26, 36))	('angiogenic properties', 'CPA', (226, 247))	('K15P', 'Var', (104, 108))	('inhibit', 'NegReg', (139, 146))	('PLCgamma2', 'Gene', '5336', (77, 86))	('K15P', 'SUBSTITUTION', 'None', (104, 108))	('K15-dependent downstream signalling', 'MPA', (147, 182))	('PLCgamma2', 'Gene', (77, 86))	('disrupt', 'NegReg', (92, 99))	('invasiveness', 'CPA', (209, 221))	('increased', 'PosReg', (199, 208))
376543	26295810	Previously reported microarray experiments have shown that K15 increases the expression of genes involved in inflammation and cell migration such as chemokines and MMPs.	('increases', 'PosReg', (63, 72))	('expression', 'MPA', (77, 87))	('K15', 'Var', (59, 62))	('inflammation', 'Disease', 'MESH:D007249', (109, 121))	('inflammation', 'Disease', (109, 121))	('rat', 'Species', '10116', (134, 137))	('expression', 'Species', '29278', (77, 87))	('MMPs', 'Disease', (164, 168))	('cell migration', 'CPA', (126, 140))
376544	26295810	Moreover, we and others had suggested that K15 expression increased the invasiveness of endothelial cells.	('invasiveness of endothelial cells', 'CPA', (72, 105))	('K15 expression', 'Var', (43, 57))	('increased', 'PosReg', (58, 67))	('expression', 'Species', '29278', (47, 57))
376545	26295810	This is illustrated in Fig 1B and S1A Fig, which compare the invasiveness of K15-transduced immortalized endothelial cells (HuAR2T) to that of cells transduced with the control vector.	('K15-transduced', 'Var', (77, 91))	('invasiveness', 'CPA', (61, 73))	('rat', 'Species', '10116', (14, 17))
376547	26295810	Furthermore, reduced invasiveness was also observed in HEK 293 stably harbouring a recombinant KSHV genome lacking K15 (KSHV BAC36 DeltaK15) as compared to cells harbouring KSHV wt genome (KSHV BAC36) (S2 Fig).	('HEK 293', 'CellLine', 'CVCL:0045', (55, 62))	('K15', 'MPA', (115, 118))	('DeltaK15', 'Var', (131, 139))	('lacking', 'NegReg', (107, 114))	('invasiveness', 'CPA', (21, 33))	('reduced', 'NegReg', (13, 20))	('DeltaK15', 'DELETION', 'None', (131, 139))
376550	26295810	Therefore, we conclude that K15 contributes to KSHV-induced invasiveness and that this process is mediated, at least in part, by PLCgamma1 and its downstream effectors GIT1, betaPIX and cdc42.	('GIT1', 'Gene', (168, 172))	('betaPIX', 'Gene', '8874', (174, 181))	('PLCgamma1', 'Gene', (129, 138))	('betaPIX', 'Gene', (174, 181))	('KSHV-induced', 'Gene', (47, 59))	('K15', 'Var', (28, 31))	('invasiveness', 'CPA', (60, 72))	('cdc42', 'Gene', '998', (186, 191))	('cdc42', 'Gene', (186, 191))	('GIT1', 'Gene', '28964', (168, 172))
376557	26295810	Similarly to what we observed in latently infected HuAR2T (Fig 2A-2C), in lytically induced cultures, we also observed partial co-localisation of phosphorylated PLCgamma1 and K15 (Fig 3B).	('K15', 'Var', (175, 178))	('phospho', 'Chemical', 'MESH:D004099', (146, 153))	('co-localisation', 'Interaction', (127, 142))	('PLCgamma1', 'Protein', (161, 170))
376566	26295810	Since it has been previously shown that GIT1 forms a stable complex with betaPIX and that these proteins serve as a scaffold for the assembly of pro-migratory cytoplasmic protein complexes induced by activated PLCgamma1, K15 might recruit these proteins to trigger virus-induced cellular invasiveness.	('virus-induced cellular invasiveness', 'CPA', (265, 300))	('PLCgamma1', 'Protein', (210, 219))	('rat', 'Species', '10116', (152, 155))	('GIT1', 'Gene', '28964', (40, 44))	('GIT1', 'Gene', (40, 44))	('activated', 'Var', (200, 209))	('betaPIX', 'Gene', '8874', (73, 80))	('betaPIX', 'Gene', (73, 80))	('K15', 'Var', (221, 224))
376567	26295810	Previously, we showed that the C-terminal SH2 binding motif (YEEV) and SH3 binding motif (PPLP) of K15P (Fig 1A) both contribute to the interaction with PLCgamma1.	('contribute', 'Reg', (118, 128))	('PLCgamma1', 'Protein', (153, 162))	('K15P', 'SUBSTITUTION', 'None', (99, 103))	('interaction', 'Interaction', (136, 147))	('K15P', 'Var', (99, 103))
376570	26295810	In particular, an arginine within the binding pocket is highly conserved in human SH2 domains and provides nearly half of the ligand binding energy.	('ligand', 'MPA', (126, 132))	('arginine', 'Var', (18, 26))	('human', 'Species', '9606', (76, 81))	('arginine', 'Chemical', 'MESH:D001120', (18, 26))
376571	26295810	To investigate the potential role of the two PLCgamma1 SH2 domains in the interaction with K15, we mutated the conserved arginine residues within both the n and c SH2 domains (R586L and R694L, respectively; see Figs 1A and 4A) and tested these PLCgamma1mutants for binding to both the K15P and M variants, after co-transfection with K15 expressing vectors into HEK293T cells.	('R694L', 'Mutation', 'rs1336595726', (186, 191))	('binding', 'Interaction', (265, 272))	('tested', 'Reg', (231, 237))	('R586L', 'Mutation', 'rs750791519', (176, 181))	('K15P', 'Var', (285, 289))	('R694L', 'Var', (186, 191))	('K15P', 'SUBSTITUTION', 'None', (285, 289))	('arginine', 'Chemical', 'MESH:D001120', (121, 129))	('R586L', 'Var', (176, 181))	('HEK293T', 'CellLine', 'CVCL:0063', (361, 368))
376572	26295810	While mutation of the nSH2 domain (R586L) moderately decreased the binding to K15P, mutation of the cSH2 domain (R694L) had a stronger effect on this interaction (Fig 4B).	('R694L', 'Var', (113, 118))	('R586L', 'Var', (35, 40))	('rat', 'Species', '10116', (46, 49))	('nSH2', 'Gene', (22, 26))	('cSH2', 'Gene', (100, 104))	('R586L', 'Mutation', 'rs750791519', (35, 40))	('R694L', 'Mutation', 'rs1336595726', (113, 118))	('decreased', 'NegReg', (53, 62))	('binding', 'Interaction', (67, 74))	('K15P', 'Var', (78, 82))	('K15P', 'SUBSTITUTION', 'None', (78, 82))	('cSH2', 'Gene', '1443', (100, 104))
376573	26295810	In the case of K15M, only the mutant of the nSH2 domain of PLCgamma1 (R586L) showed a reduced binding (Fig 4C).	('K15M', 'Var', (15, 19))	('reduced', 'NegReg', (86, 93))	('R586L', 'Mutation', 'rs750791519', (70, 75))	('binding', 'Interaction', (94, 101))	('R586L', 'Var', (70, 75))	('K15M', 'SUBSTITUTION', 'None', (15, 19))
376574	26295810	These results indicate that between K15P and K15M there is a subtle difference with regard to how they interact with PLCgamma1.	('interact', 'Interaction', (103, 111))	('K15M', 'Var', (45, 49))	('K15M', 'SUBSTITUTION', 'None', (45, 49))	('K15P', 'Var', (36, 40))	('K15P', 'SUBSTITUTION', 'None', (36, 40))
376575	26295810	While the N-terminal SH2 domain of PLCgamma1 seems to be involved in the interaction with both K15P and K15M, the cSH2 domain is only important for the binding to K15P.	('K15P', 'Var', (95, 99))	('K15P', 'SUBSTITUTION', 'None', (95, 99))	('interaction', 'Interaction', (73, 84))	('cSH2', 'Gene', '1443', (114, 118))	('K15M', 'SUBSTITUTION', 'None', (104, 108))	('binding', 'Interaction', (152, 159))	('K15P', 'Var', (163, 167))	('K15M', 'Var', (104, 108))	('cSH2', 'Gene', (114, 118))	('K15P', 'SUBSTITUTION', 'None', (163, 167))	('involved', 'Reg', (57, 65))
376578	26295810	To this end, we performed a GST pulldown assay with a fusion protein of GST and the K15P cytoplasmic domain (aa 347-489) bound to glutathione beads and a lysate of HEK293T cells that had been transiently transfected with plasmid expressing PLCgamma2 or individual PLCgamma2 domains.	('PLCgamma2', 'Gene', (240, 249))	('glutathione', 'Chemical', 'MESH:D005978', (130, 141))	('PLCgamma2', 'Gene', (264, 273))	('GST', 'Gene', (72, 75))	('HEK293T', 'CellLine', 'CVCL:0063', (164, 171))	('bound', 'Interaction', (121, 126))	('K15P', 'Var', (84, 88))	('PLCgamma2', 'Gene', '5336', (240, 249))	('glutathione beads', 'Protein', (130, 147))	('PLCgamma2', 'Gene', '5336', (264, 273))	('K15P', 'SUBSTITUTION', 'None', (84, 88))
376579	26295810	Although we could not observe an interaction between the K15P cytoplasmic domain and the full length PLCgamma2 protein (Fig 5A, left panel), the PLCgamma2 cSH2 domain, in isolation, did bind to K15P (Fig 5A, right panel).	('K15P', 'SUBSTITUTION', 'None', (57, 61))	('cSH2', 'Gene', '1443', (155, 159))	('PLCgamma2', 'Gene', '5336', (145, 154))	('bind', 'Interaction', (186, 190))	('PLCgamma2', 'Gene', (145, 154))	('cSH2', 'Gene', (155, 159))	('PLCgamma2', 'Gene', (101, 110))	('K15P', 'Var', (57, 61))	('K15P', 'Var', (194, 198))	('K15P', 'SUBSTITUTION', 'None', (194, 198))	('PLCgamma2', 'Gene', '5336', (101, 110))
376582	26295810	We first characterized the interaction between K15P and the isolated PLCgamma2 cSH2 domain in more detail.	('K15P', 'SUBSTITUTION', 'None', (47, 51))	('PLCgamma2', 'Gene', (69, 78))	('cSH2', 'Gene', (79, 83))	('interaction', 'Interaction', (27, 38))	('cSH2', 'Gene', '1443', (79, 83))	('K15P', 'Var', (47, 51))	('PLCgamma2', 'Gene', '5336', (69, 78))
376584	26295810	Fig 5B shows that the K15P YF mutant does not associate with the PLCgamma2 cSH2 domain.	('K15P', 'SUBSTITUTION', 'None', (22, 26))	('PLCgamma2', 'Gene', (65, 74))	('associate', 'Interaction', (46, 55))	('cSH2', 'Gene', '1443', (75, 79))	('PLCgamma2', 'Gene', '5336', (65, 74))	('K15P', 'Var', (22, 26))	('cSH2', 'Gene', (75, 79))
376585	26295810	We also mutated the conserved arginine (R672L) (Fig 1A, bottom panel) within the PLCgamma2 cSH2 domain.	('cSH2', 'Gene', (91, 95))	('arginine', 'Chemical', 'MESH:D001120', (30, 38))	('PLCgamma2', 'Gene', '5336', (81, 90))	('R672L', 'Var', (40, 45))	('cSH2', 'Gene', '1443', (91, 95))	('PLCgamma2', 'Gene', (81, 90))	('R672L', 'Mutation', 'p.R672L', (40, 45))
376586	26295810	Fig 5C shows that this mutation impairs binding to K15P.	('binding', 'Interaction', (40, 47))	('impairs', 'NegReg', (32, 39))	('K15P', 'SUBSTITUTION', 'None', (51, 55))	('K15P', 'Var', (51, 55))
376587	26295810	Therefore, the interaction between the PLCgamma2 cSH2 and K15P involves the Y481 of K15 and R672 of the PLCgamma2 cSH2 domain.	('K15', 'Gene', (84, 87))	('cSH2', 'Gene', (49, 53))	('K15P', 'Var', (58, 62))	('PLCgamma2', 'Gene', '5336', (39, 48))	('cSH2', 'Gene', '1443', (114, 118))	('R672', 'Var', (92, 96))	('PLCgamma2', 'Gene', (104, 113))	('K15P', 'SUBSTITUTION', 'None', (58, 62))	('cSH2', 'Gene', (114, 118))	('interaction', 'Interaction', (15, 26))	('PLCgamma2', 'Gene', (39, 48))	('Y481', 'Var', (76, 80))	('cSH2', 'Gene', '1443', (49, 53))	('PLCgamma2', 'Gene', '5336', (104, 113))
376589	26295810	The authors obtained this superbinder (SB) SH2 domain by mutating specific amino acids (T181V; S186A; K204L) within the Fyn SH2 domain.	('S186A', 'Mutation', 'p.S186A', (95, 100))	('T181V; S186A; K204L', 'Var', (88, 107))	('Fyn', 'Gene', '2534', (120, 123))	('SB', 'Chemical', '-', (39, 41))	('Fyn', 'Gene', (120, 123))	('mutating', 'Var', (57, 65))	('T181V', 'Mutation', 'p.T181V', (88, 93))	('K204L', 'Mutation', 'p.K204L', (102, 107))
376590	26295810	As both sequence and structure of SH2 domains are highly conserved, we identified and mutated the corresponding amino acids in the isolated PLCgamma2 cSH2 domain (Fig 5D) in order to obtain a SB mutant.	('PLCgamma2', 'Gene', (140, 149))	('cSH2', 'Gene', (150, 154))	('mutated', 'Var', (86, 93))	('PLCgamma2', 'Gene', '5336', (140, 149))	('cSH2', 'Gene', '1443', (150, 154))	('SB', 'Chemical', '-', (192, 194))
376592	26295810	We therefore mutated only two residues, S677 and R695 to valine and leucine, respectively.	('R695', 'Var', (49, 53))	('valine', 'Chemical', 'MESH:D014633', (57, 63))	('leucine', 'Chemical', 'MESH:D007930', (68, 75))	('S677', 'Var', (40, 44))
376593	26295810	Subsequently, we tested the ability of K15P to associate with the PLCgamma2 cSH2 S677V/R695L mutant (from now on called superbinder, SB) by co-immunoprecipitation (Fig 5E).	('associate', 'Interaction', (47, 56))	('K15P', 'SUBSTITUTION', 'None', (39, 43))	('cSH2', 'Gene', '1443', (76, 80))	('PLCgamma2', 'Gene', (66, 75))	('tested', 'Reg', (17, 23))	('S677V', 'SUBSTITUTION', 'None', (81, 86))	('S677V', 'Var', (81, 86))	('cSH2', 'Gene', (76, 80))	('R695L', 'Mutation', 'p.R695L', (87, 92))	('SB', 'Chemical', '-', (133, 135))	('PLCgamma2', 'Gene', '5336', (66, 75))	('K15P', 'Var', (39, 43))
376594	26295810	K15 was precipitated more efficiently with the SB mutant than with the wt cSH2 domain (Fig 5E).	('cSH2', 'Gene', '1443', (74, 78))	('SB', 'Chemical', '-', (47, 49))	('cSH2', 'Gene', (74, 78))	('mutant', 'Var', (50, 56))
376596	26295810	The K15P cytoplasmic tail fused to GST bound more efficiently to the SB than to either of the single mutants (S677V and R695L) of the cSH2 domain (Fig 5F).	('S677V', 'Mutation', 'p.S677V', (110, 115))	('cSH2', 'Gene', (134, 138))	('K15P', 'Var', (4, 8))	('SB', 'Chemical', '-', (69, 71))	('S677V', 'Var', (110, 115))	('R695L', 'Mutation', 'p.R695L', (120, 125))	('efficiently', 'PosReg', (50, 61))	('K15P', 'SUBSTITUTION', 'None', (4, 8))	('R695L', 'Var', (120, 125))	('bound', 'Interaction', (39, 44))	('cSH2', 'Gene', '1443', (134, 138))
376597	26295810	that the properties of the SB mutant are the result of a synergistic effect obtained by mutating multiple residues in the SH2 domain.	('mutant', 'Var', (30, 36))	('SB', 'Chemical', '-', (27, 29))	('mutating', 'Var', (88, 96))
376598	26295810	To confirm that the cytoplasmic domain of K15 binds directly to the PLCgamma2 cSH2 domain or its SB mutant, we used surface plasmon resonance (SPR) to measure the interaction of purified, prokaryotically expressed GST-K15P and the PLCgamma2 cSH2 wt and SB domains, as described in Materials and Methods.	('PLCgamma2', 'Gene', (68, 77))	('cSH2', 'Gene', '1443', (241, 245))	('PLCgamma2', 'Gene', '5336', (231, 240))	('binds', 'Interaction', (46, 51))	('interaction', 'Interaction', (163, 174))	('cSH2', 'Gene', (241, 245))	('SB', 'Chemical', '-', (97, 99))	('cSH2', 'Gene', '1443', (78, 82))	('PLCgamma2', 'Gene', (231, 240))	('SB', 'Chemical', '-', (253, 255))	('PLCgamma2', 'Gene', '5336', (68, 77))	('cSH2', 'Gene', (78, 82))	('K15P', 'Var', (218, 222))	('K15P', 'SUBSTITUTION', 'None', (218, 222))
376599	26295810	We obtained equilibrium dissociation constants (KD) of 5.8 10-9 for PLCgamma2 cSH2 wt, and 3.8 10-9 for the SB mutant This result shows that the interaction of K15 with the PLCgamma2 cSH2 domain is of high affinity, in the nanomolar range, even though in this experiment K15, having been expressed in bacteria, was not phosphorylated on Y489.	('PLCgamma2', 'Gene', (68, 77))	('cSH2', 'Gene', '1443', (183, 187))	('SB', 'Chemical', '-', (108, 110))	('cSH2', 'Gene', (183, 187))	('mutant', 'Var', (111, 117))	('PLCgamma2', 'Gene', '5336', (173, 182))	('cSH2', 'Gene', '1443', (78, 82))	('interaction', 'Interaction', (145, 156))	('PLCgamma2', 'Gene', '5336', (68, 77))	('PLCgamma2', 'Gene', (173, 182))	('cSH2', 'Gene', (78, 82))	('phospho', 'Chemical', 'MESH:D004099', (319, 326))
376601	26295810	Since the cSH2 domain of PLCgamma1 has been shown to contact the phosphorylated Y783 in PLCgamma1, thereby mediating an intramolecular interaction required for the activation of this protein, we also investigated if the isolated PLCgamma2 cSH2 would interact with PLCgamma1.	('Y783', 'Var', (80, 84))	('PLCgamma2', 'Gene', '5336', (229, 238))	('phospho', 'Chemical', 'MESH:D004099', (65, 72))	('cSH2', 'Gene', (10, 14))	('PLCgamma1', 'Gene', (88, 97))	('cSH2', 'Gene', '1443', (239, 243))	('PLCgamma2', 'Gene', (229, 238))	('mediating', 'Reg', (107, 116))	('cSH2', 'Gene', (239, 243))	('cSH2', 'Gene', '1443', (10, 14))
376607	26295810	Moreover, as shown above, K15 co-localizes with PLCgamma1, GIT1, betaPIX and these proteins contribute to KSHV-mediated invasiveness (Figs 1, 2 and 3).	('K15', 'Var', (26, 29))	('GIT1', 'Gene', '28964', (59, 63))	('GIT1', 'Gene', (59, 63))	('contribute', 'Reg', (92, 102))	('betaPIX', 'Gene', '8874', (65, 72))	('betaPIX', 'Gene', (65, 72))	('invasiveness', 'CPA', (120, 132))	('KSHV-mediated', 'Gene', (106, 119))
376611	26295810	In addition, the presence of the isolated PLCgamma2 cSH2 domain reduced in a dose-dependent manner K15-mediated PLCgamma1 phosphorylation levels in HeLa cells, as well as in primary HUVECs (Fig 6B).	('HeLa', 'CellLine', 'CVCL:0030', (148, 152))	('phospho', 'Chemical', 'MESH:D004099', (122, 129))	('cSH2', 'Gene', '1443', (52, 56))	('PLCgamma2', 'Gene', (42, 51))	('cSH2', 'Gene', (52, 56))	('reduced', 'NegReg', (64, 71))	('presence', 'Var', (17, 25))	('PLCgamma2', 'Gene', '5336', (42, 51))	('K15-mediated PLCgamma1 phosphorylation levels', 'MPA', (99, 144))
376615	26295810	K15 mediates the activation of several cellular signalling cascades, including the NF-kappaB pathway.	('K15', 'Var', (0, 3))	('NF-kappaB', 'Gene', '4790', (83, 92))	('activation', 'PosReg', (17, 27))	('cellular signalling cascades', 'Pathway', (39, 67))	('NF-kappaB', 'Gene', (83, 92))
376616	26295810	We previously showed that the activation of NF-kappaB by K15 occurs via a region in the K15 cytoplasmic tail located close to the last transmembrane domain.	('K15', 'Var', (57, 60))	('NF-kappaB', 'Gene', '4790', (44, 53))	('K15', 'Gene', (88, 91))	('activation', 'PosReg', (30, 40))	('NF-kappaB', 'Gene', (44, 53))
376619	26295810	Furthermore, we tested the effect of the SB (S677V/R695L) and the R672L mutants of the PLCgamma2 cSH2 domain on the K15-mediated NFAT- as well as NF-kappaB activation (Fig 6E and 6F).	('S677V', 'Var', (45, 50))	('tested', 'Reg', (16, 22))	('PLCgamma2', 'Gene', (87, 96))	('K15-mediated NFAT-', 'MPA', (116, 134))	('activation', 'PosReg', (156, 166))	('R672L', 'Mutation', 'p.R672L', (66, 71))	('cSH2', 'Gene', '1443', (97, 101))	('S677V', 'SUBSTITUTION', 'None', (45, 50))	('cSH2', 'Gene', (97, 101))	('NF-kappaB', 'Gene', '4790', (146, 155))	('R695L', 'Mutation', 'p.R695L', (51, 56))	('PLCgamma2', 'Gene', '5336', (87, 96))	('R672L', 'Var', (66, 71))	('NF-kappaB', 'Gene', (146, 155))	('SB', 'Chemical', '-', (41, 43))
376620	26295810	While the SB showed a stronger effect than the PLCgamma2 cSH2 wt, the R672L mutant had no effect on the ability of K15 to activate NFAT-dependent transcription (Fig 6E).	('activate', 'PosReg', (122, 130))	('PLCgamma2', 'Gene', '5336', (47, 56))	('NFAT-dependent transcription', 'MPA', (131, 159))	('R672L', 'Mutation', 'p.R672L', (70, 75))	('cSH2', 'Gene', '1443', (57, 61))	('PLCgamma2', 'Gene', (47, 56))	('cSH2', 'Gene', (57, 61))	('R672L', 'Var', (70, 75))	('SB', 'Chemical', '-', (10, 12))
376621	26295810	In contrast, neither the SB nor the R672L mutant had any effect on the ability of K15 to activate an NF-kappaB-dependent promoter (Fig 6F).	('SB', 'Chemical', '-', (25, 27))	('activate', 'PosReg', (89, 97))	('R672L', 'Var', (36, 41))	('NF-kappaB', 'Gene', '4790', (101, 110))	('NF-kappaB', 'Gene', (101, 110))	('R672L', 'Mutation', 'p.R672L', (36, 41))
376624	26295810	As described above, the other K15 allele, K15M, also binds to PLCgamma1 via the PLCgamma1 nSH2 domain but differs subtly from K15P, whose binding to PLCgamma1 appears to involve additionally the PLCgamma1 cSH2 domain (Fig 4C).	('cSH2', 'Gene', '1443', (205, 209))	('K15P', 'Var', (126, 130))	('K15P', 'SUBSTITUTION', 'None', (126, 130))	('cSH2', 'Gene', (205, 209))	('binding', 'Interaction', (138, 145))	('K15M', 'Var', (42, 46))	('K15M', 'SUBSTITUTION', 'None', (42, 46))	('binds', 'Interaction', (53, 58))	('PLCgamma1', 'Gene', (62, 71))
376625	26295810	Similar to K15P, K15M can also activate NFAT-dependent promoters.	('activate', 'PosReg', (31, 39))	('K15M', 'SUBSTITUTION', 'None', (17, 21))	('NFAT-dependent promoters', 'MPA', (40, 64))	('K15M', 'Var', (17, 21))	('K15P', 'Var', (11, 15))	('K15P', 'SUBSTITUTION', 'None', (11, 15))
376626	26295810	Therefore we investigated the effect of the PLCgamma2 cSH2 domain on K15M-mediated NFAT-dependent transcriptional activation (Fig 7A).	('PLCgamma2', 'Gene', '5336', (44, 53))	('cSH2', 'Gene', '1443', (54, 58))	('K15M', 'SUBSTITUTION', 'None', (69, 73))	('K15M', 'Var', (69, 73))	('cSH2', 'Gene', (54, 58))	('PLCgamma2', 'Gene', (44, 53))
376627	26295810	Irrespective of the amount of transfected PLCgamma2 cSH2 plasmid, we did not detect any significant difference in K15M-mediated NFAT-dependent activation, although in the same assay a dose dependent inhibitory effect was observed for K15P.	('K15P', 'Var', (234, 238))	('cSH2', 'Gene', '1443', (52, 56))	('PLCgamma2', 'Gene', (42, 51))	('cSH2', 'Gene', (52, 56))	('K15P', 'SUBSTITUTION', 'None', (234, 238))	('PLCgamma2', 'Gene', '5336', (42, 51))	('K15M', 'Var', (114, 118))	('K15M', 'SUBSTITUTION', 'None', (114, 118))
376628	26295810	Consequently, we decided to test the ability of K15M to bind the isolated PLCgamma2 cSH2 domain but could not detect any association between these two proteins (Fig 7B).	('bind', 'Interaction', (56, 60))	('PLCgamma2', 'Gene', '5336', (74, 83))	('cSH2', 'Gene', '1443', (84, 88))	('K15M', 'Var', (48, 52))	('K15M', 'SUBSTITUTION', 'None', (48, 52))	('PLCgamma2', 'Gene', (74, 83))	('cSH2', 'Gene', (84, 88))
376629	26295810	Furthermore, we tested whether the expression of the PLCgamma2 cSH2 SB could affect K15M-triggered activation of an NFAT-dependent promoter.	('K15M', 'SUBSTITUTION', 'None', (84, 88))	('tested', 'Reg', (16, 22))	('cSH2', 'Gene', (63, 67))	('expression', 'Species', '29278', (35, 45))	('PLCgamma2', 'Gene', '5336', (53, 62))	('affect', 'Reg', (77, 83))	('SB', 'Chemical', '-', (68, 70))	('PLCgamma2', 'Gene', (53, 62))	('cSH2', 'Gene', '1443', (63, 67))	('K15M', 'Var', (84, 88))
376630	26295810	To this end, we compared the ability of both K15M and P to activate NFAT signalling in the presence of the wt or SB PLCgamma2 cSH2 domain.	('cSH2', 'Gene', (126, 130))	('K15M', 'Var', (45, 49))	('activate', 'PosReg', (59, 67))	('NFAT', 'MPA', (68, 72))	('PLCgamma2', 'Gene', '5336', (116, 125))	('K15M', 'SUBSTITUTION', 'None', (45, 49))	('SB', 'Chemical', '-', (113, 115))	('cSH2', 'Gene', '1443', (126, 130))	('PLCgamma2', 'Gene', (116, 125))
376631	26295810	While the presence of both wt and SB PLCgamma2 cSH2 domain reduced K15P-dependent NFAT activation, neither of these two proteins affected the ability of K15M to activate the NFAT-dependent promoter (Fig 7C).	('reduced', 'NegReg', (59, 66))	('K15P', 'SUBSTITUTION', 'None', (67, 71))	('NFAT-dependent promoter', 'MPA', (174, 197))	('PLCgamma2', 'Gene', '5336', (37, 46))	('cSH2', 'Gene', '1443', (47, 51))	('PLCgamma2', 'Gene', (37, 46))	('SB', 'Chemical', '-', (34, 36))	('cSH2', 'Gene', (47, 51))	('K15P', 'Var', (67, 71))	('K15M', 'Var', (153, 157))	('K15M', 'SUBSTITUTION', 'None', (153, 157))
376632	26295810	To explore whether the PLCgamma2 cSH2 domain SB would interact with K15M, we also tested the binding of the wt and the SB cSH2 domain to K15M in a co-immunoprecipitation assay (Fig 7D).	('SB', 'Chemical', '-', (45, 47))	('K15M', 'SUBSTITUTION', 'None', (68, 72))	('K15M', 'Var', (137, 141))	('K15M', 'Var', (68, 72))	('K15M', 'SUBSTITUTION', 'None', (137, 141))	('cSH2', 'Gene', '1443', (33, 37))	('PLCgamma2', 'Gene', '5336', (23, 32))	('binding', 'Interaction', (93, 100))	('tested', 'Reg', (82, 88))	('PLCgamma2', 'Gene', (23, 32))	('cSH2', 'Gene', (33, 37))	('cSH2', 'Gene', '1443', (122, 126))	('SB', 'Chemical', '-', (119, 121))	('cSH2', 'Gene', (122, 126))
376633	26295810	While the PLCgamma2 cSH2 SB domain, as expected, showed increased binding to K15P, it failed, as did the wt cSH2 domain, to interact with K15M (Fig 7D).	('SB', 'Chemical', '-', (25, 27))	('K15P', 'SUBSTITUTION', 'None', (77, 81))	('PLCgamma2', 'Gene', (10, 19))	('cSH2', 'Gene', (20, 24))	('increased', 'PosReg', (56, 65))	('cSH2', 'Gene', (108, 112))	('binding', 'Interaction', (66, 73))	('PLCgamma2', 'Gene', '5336', (10, 19))	('K15M', 'Var', (138, 142))	('K15M', 'SUBSTITUTION', 'None', (138, 142))	('K15P', 'Var', (77, 81))	('cSH2', 'Gene', '1443', (20, 24))	('cSH2', 'Gene', '1443', (108, 112))
376634	26295810	Therefore, while the PLCgamma2 cSH2 domain binds K15P and thereby blocks K15P-dependent NFAT signalling, it does not bind K15M and, consequently, has no influence on the K15M-mediated activation of NFAT-dependent transcription.	('NFAT-dependent', 'MPA', (198, 212))	('cSH2', 'Gene', '1443', (31, 35))	('PLCgamma2', 'Gene', (21, 30))	('PLCgamma2', 'Gene', '5336', (21, 30))	('K15P', 'Var', (49, 53))	('K15M', 'Var', (122, 126))	('cSH2', 'Gene', (31, 35))	('K15P', 'Var', (73, 77))	('K15M', 'SUBSTITUTION', 'None', (122, 126))	('K15P', 'SUBSTITUTION', 'None', (49, 53))	('blocks', 'NegReg', (66, 72))	('K15P', 'SUBSTITUTION', 'None', (73, 77))	('K15M', 'SUBSTITUTION', 'None', (170, 174))	('K15M', 'Var', (170, 174))
376635	26295810	Mutations that increase the ability of the PLCgamma2 cSH2 domain to interact with K15P do not confer binding to K15M.	('K15M', 'Var', (112, 116))	('K15P', 'SUBSTITUTION', 'None', (82, 86))	('K15M', 'SUBSTITUTION', 'None', (112, 116))	('PLCgamma2', 'Gene', '5336', (43, 52))	('Mutations', 'Var', (0, 9))	('cSH2', 'Gene', '1443', (53, 57))	('binding', 'Interaction', (101, 108))	('cSH2', 'Gene', (53, 57))	('PLCgamma2', 'Gene', (43, 52))	('interact', 'Interaction', (68, 76))	('K15P', 'Var', (82, 86))
376638	26295810	As a first step, we performed an invasion assay using immortalized endothelial cells (HuAR2T) that had been transduced with a retroviral vector for K15P and a lentiviral vector for the PLCgamma2 cSH2 domain.	('PLCgamma2', 'Gene', (185, 194))	('cSH2', 'Gene', (195, 199))	('K15P', 'Var', (148, 152))	('K15P', 'SUBSTITUTION', 'None', (148, 152))	('PLCgamma2', 'Gene', '5336', (185, 194))	('cSH2', 'Gene', '1443', (195, 199))
376639	26295810	We observed that the presence of the PLCgamma2 cSH2 domain significantly reduced K15-mediated invasiveness (Fig 8A and S3A Fig).	('reduced', 'NegReg', (73, 80))	('PLCgamma2', 'Gene', '5336', (37, 46))	('K15-mediated invasiveness', 'CPA', (81, 106))	('cSH2', 'Gene', '1443', (47, 51))	('PLCgamma2', 'Gene', (37, 46))	('presence', 'Var', (21, 29))	('cSH2', 'Gene', (47, 51))
376642	26295810	We have previously shown that K15 triggers angiogenesis via PLCgamma1 and subsequent NFAT activation and that the PLCgamma2 cSH2 domain can reduce the level of NFAT activation in the case of the K15P allele (Fig 6B, 6C and 6E and Fig 7A).	('NFAT activation', 'MPA', (85, 100))	('K15P', 'Var', (195, 199))	('cSH2', 'Gene', '1443', (124, 128))	('PLCgamma2', 'Gene', '5336', (114, 123))	('reduce', 'NegReg', (140, 146))	('K15P', 'SUBSTITUTION', 'None', (195, 199))	('angiogenesis', 'CPA', (43, 55))	('cSH2', 'Gene', (124, 128))	('PLCgamma1', 'Gene', (60, 69))	('PLCgamma2', 'Gene', (114, 123))	('NFAT activation', 'MPA', (160, 175))	('K15', 'Var', (30, 33))
376643	26295810	As a next step, we tested whether we could measure a reduction in K15-dependent angiogenic tube formation in primary endothelial cells (HUVEC) after the transduction with a lentivirus expressing the PLCgamma2 cSH2 domain and a retroviral vector for K15P (Fig 8C).	('K15P', 'SUBSTITUTION', 'None', (249, 253))	('PLCgamma2', 'Gene', (199, 208))	('cSH2', 'Gene', (209, 213))	('K15-dependent angiogenic tube formation', 'CPA', (66, 105))	('reduction', 'NegReg', (53, 62))	('K15P', 'Var', (249, 253))	('cSH2', 'Gene', '1443', (209, 213))	('PLCgamma2', 'Gene', '5336', (199, 208))
376644	26295810	Indeed, in the presence of the PLCgamma2 cSH2 domain, the increased formation of angiogenic tubes, which we previously showed to be induced by K15P, was significantly reduced (Fig 8C compare lanes 1 and 2, and S3C Fig).	('cSH2', 'Gene', (41, 45))	('formation of angiogenic tubes', 'CPA', (68, 97))	('increased', 'PosReg', (58, 67))	('PLCgamma2', 'Gene', (31, 40))	('K15P', 'SUBSTITUTION', 'None', (143, 147))	('cSH2', 'Gene', '1443', (41, 45))	('reduced', 'NegReg', (167, 174))	('PLCgamma2', 'Gene', '5336', (31, 40))	('K15P', 'Var', (143, 147))
376650	26295810	Therefore, we conclude that the isolated PLCgamma2 cSH2 domain impaired both the increased invasiveness and angiogenesis observed in endothelial cells infected with a KSHV strain carrying the K15P allele.	('K15P', 'Var', (192, 196))	('K15P', 'SUBSTITUTION', 'None', (192, 196))	('cSH2', 'Gene', (51, 55))	('cSH2', 'Gene', '1443', (51, 55))	('PLCgamma2', 'Gene', (41, 50))	('invasiveness', 'CPA', (91, 103))	('PLCgamma2', 'Gene', '5336', (41, 50))	('increased', 'PosReg', (81, 90))	('angiogenesis', 'CPA', (108, 120))	('impaired', 'NegReg', (63, 71))	('domain', 'Var', (56, 62))
376651	26295810	Aberrant angiogenesis and cell migration represent important features in the pathogenesis of KS.	('cell migration', 'CPA', (26, 40))	('Aberrant', 'Var', (0, 8))	('rat', 'Species', '10116', (34, 37))
376652	26295810	In the present study, we demonstrate that K15 also triggers migration and invasiveness of KSHV infected endothelial cells in a PLCgamma1-GIT1-betaPIX-cdc42-dependent manner (Fig 1D and 1E).	('invasiveness of KSHV infected', 'Disease', (74, 103))	('cdc42', 'Gene', '998', (150, 155))	('rat', 'Species', '10116', (32, 35))	('cdc42', 'Gene', (150, 155))	('invasiveness of KSHV infected', 'Disease', 'MESH:C537372', (74, 103))	('GIT1', 'Gene', '28964', (137, 141))	('K15', 'Var', (42, 45))	('triggers', 'Reg', (51, 59))	('migration', 'CPA', (60, 69))	('betaPIX', 'Gene', '8874', (142, 149))	('rat', 'Species', '10116', (63, 66))	('GIT1', 'Gene', (137, 141))	('betaPIX', 'Gene', (142, 149))
376655	26295810	Moreover, co-immunoprecipitation of PLCgamma1 in virus infected endothelial cells showed the presence of a complex formed by K15, PLCgamma1, GIT1, and cdc42 (Fig 3D and 3E).	('complex', 'Interaction', (107, 114))	('GIT1', 'Gene', '28964', (141, 145))	('GIT1', 'Gene', (141, 145))	('PLCgamma1', 'Gene', (36, 45))	('PLCgamma1', 'Gene', (130, 139))	('cdc42', 'Gene', '998', (151, 156))	('K15', 'Var', (125, 128))	('cdc42', 'Gene', (151, 156))
376656	26295810	Since several studies reported previously that betaPIX and GIT1 form a stable complex in endothelial cells, we hypothesize that K15 recruits a complex formed by PLCgamma1, betaPIX, GIT1 and cdc42, which is then responsible for the increased invasiveness of KSHV infected endothelial cells that are either latent or show a restricted viral gene expression pattern.	('GIT1', 'Gene', (181, 185))	('GIT1', 'Gene', (59, 63))	('invasiveness of KSHV infected', 'Disease', 'MESH:C537372', (241, 270))	('betaPIX', 'Gene', '8874', (47, 54))	('increased', 'PosReg', (231, 240))	('expression', 'Species', '29278', (344, 354))	('betaPIX', 'Gene', (47, 54))	('K15', 'Var', (128, 131))	('betaPIX', 'Gene', '8874', (172, 179))	('GIT1', 'Gene', '28964', (181, 185))	('invasiveness of KSHV infected', 'Disease', (241, 270))	('betaPIX', 'Gene', (172, 179))	('cdc42', 'Gene', '998', (190, 195))	('GIT1', 'Gene', '28964', (59, 63))	('cdc42', 'Gene', (190, 195))
376661	26295810	Similar to RTKs, both the M and P variants of K15 associate with the nSH2 domain of PLCgamma1, since mutation of the conserved R586 in PLCgamma1 responsible for contacting the phosphorylated tyrosine in the SH2 binding site of the interacting protein, decreases the affinity of both K15 variants for PLCgamma1 (Fig 4).	('PLCgamma1', 'Gene', (135, 144))	('K15', 'Gene', (283, 286))	('phospho', 'Chemical', 'MESH:D004099', (176, 183))	('tyrosine', 'Chemical', 'MESH:D014443', (191, 199))	('PLCgamma1', 'Enzyme', (300, 309))	('R586', 'Var', (127, 131))	('decreases', 'NegReg', (252, 261))	('mutation', 'Var', (101, 109))	('variants', 'Var', (287, 295))	('affinity', 'MPA', (266, 274))
376662	26295810	However, in the case of K15P, but not of K15M, mutation of a similar arginine (R694) in the PLCgamma1 cSH2 domain reduced this interaction more significantly.	('R694', 'Var', (79, 83))	('K15P', 'Var', (24, 28))	('reduced', 'NegReg', (114, 121))	('K15M', 'SUBSTITUTION', 'None', (41, 45))	('mutation', 'Var', (47, 55))	('K15P', 'SUBSTITUTION', 'None', (24, 28))	('K15M', 'Var', (41, 45))	('arginine', 'Chemical', 'MESH:D001120', (69, 77))	('cSH2', 'Gene', '1443', (102, 106))	('interaction', 'MPA', (127, 138))	('cSH2', 'Gene', (102, 106))
376663	26295810	Since the PLCgamma1 cSH2 domain is involved in an intramolecular interaction with the phosphorylated Y783 (Fig 4A,), one interpretation of our observation could be that a change in the PLCgamma1 conformation, resulting from a loss of the intramolecular interaction between Y783 and the cSH2 domain, could dramatically affect the affinity for K15P.	('conformation', 'MPA', (195, 207))	('K15P', 'Var', (342, 346))	('phospho', 'Chemical', 'MESH:D004099', (86, 93))	('change', 'Reg', (171, 177))	('cSH2', 'Gene', (20, 24))	('K15P', 'SUBSTITUTION', 'None', (342, 346))	('cSH2', 'Gene', '1443', (20, 24))	('Y783', 'Var', (273, 277))	('cSH2', 'Gene', '1443', (286, 290))	('involved', 'Reg', (35, 43))	('affect', 'Reg', (318, 324))	('cSH2', 'Gene', (286, 290))	('affinity', 'Interaction', (329, 337))	('loss', 'NegReg', (226, 230))	('intramolecular interaction', 'Interaction', (238, 264))
376664	26295810	However, we also found that the cSH2 domain of PLCgamma2 directly binds to the YEEV motif of K15P (but not K15M) (Figs 5A-5C, 7B and 7D).	('binds', 'Interaction', (66, 71))	('PLCgamma2', 'Gene', '5336', (47, 56))	('cSH2', 'Gene', '1443', (32, 36))	('K15P', 'Var', (93, 97))	('cSH2', 'Gene', (32, 36))	('K15P', 'SUBSTITUTION', 'None', (93, 97))	('K15M', 'SUBSTITUTION', 'None', (107, 111))	('PLCgamma2', 'Gene', (47, 56))	('K15M', 'Var', (107, 111))
376665	26295810	By analogy, we postulate that the PLCgamma1 cSH2 domain can also directly interact with K15P.	('K15P', 'SUBSTITUTION', 'None', (88, 92))	('interact', 'Interaction', (74, 82))	('cSH2', 'Gene', '1443', (44, 48))	('cSH2', 'Gene', (44, 48))	('K15P', 'Var', (88, 92))
376666	26295810	In view of the importance of the cSH2 domain for the enzymatic activation of PLCgamma1, we speculate that the recruitment of this domain by K15P could explain the constitutive activation of PLCgamma1 induced by K15P.	('K15P', 'Var', (140, 144))	('cSH2', 'Gene', '1443', (33, 37))	('K15P', 'SUBSTITUTION', 'None', (140, 144))	('PLCgamma1', 'Enzyme', (190, 199))	('recruitment', 'PosReg', (110, 121))	('K15P', 'Var', (211, 215))	('cSH2', 'Gene', (33, 37))	('activation', 'PosReg', (176, 186))	('K15P', 'SUBSTITUTION', 'None', (211, 215))
376667	26295810	We previously reported that a mutation of either the tyrosine residue in the K15P YEEV motif or the proline residues in the K15P SH3 binding motif (PPLP), reduced the interaction with PLCgamma1 and that both mutations together abolished it completely.	('interaction', 'Interaction', (167, 178))	('K15P', 'SUBSTITUTION', 'None', (77, 81))	('reduced', 'NegReg', (155, 162))	('abolished', 'NegReg', (227, 236))	('mutation', 'Var', (30, 38))	('K15P', 'Var', (124, 128))	('tyrosine', 'Chemical', 'MESH:D014443', (53, 61))	('proline', 'Chemical', 'MESH:D011392', (100, 107))	('K15P', 'SUBSTITUTION', 'None', (124, 128))	('K15P', 'Var', (77, 81))	('PLCgamma1', 'Protein', (184, 193))
376669	26295810	We have previously shown that the commercially available PLCgamma1 inhibitor, U73122, blocks K15-dependent NFAT activation.	('U73122', 'Chemical', 'MESH:C060229', (78, 84))	('blocks', 'NegReg', (86, 92))	('U73122', 'Var', (78, 84))	('K15-dependent NFAT activation', 'MPA', (93, 122))
376670	26295810	Others had already shown, as evidence of an involvement of PLCgamma1 in cell motility, that a dominant negative fragment of PLCgamma1 can impair the migration and invasiveness of cancer cells in vivo.	('PLCgamma1', 'Gene', (124, 133))	('rat', 'Species', '10116', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('invasiveness of cancer', 'Disease', (163, 185))	('negative', 'NegReg', (103, 111))	('fragment', 'Var', (112, 120))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (163, 185))	('impair', 'NegReg', (138, 144))
376671	26295810	Based on the observation that the isolated cSH2 domain of PLCgamma2 interacts with the YEEV motif of K15P (Fig 5B) and that this interaction involves R672 of the PLCgamma2 cSH2 domain (Fig 5C), we explored whether the PLCgamma2 cSH2 domain could act as a dominant negative inhibitor of the K15P-PLCgamma1 interaction.	('PLCgamma2', 'Gene', '5336', (162, 171))	('PLCgamma2', 'Gene', (58, 67))	('cSH2', 'Gene', (172, 176))	('cSH2', 'Gene', '1443', (228, 232))	('PLCgamma2', 'Gene', '5336', (218, 227))	('PLCgamma2', 'Gene', (162, 171))	('cSH2', 'Gene', '1443', (43, 47))	('K15P', 'Var', (101, 105))	('R672', 'Var', (150, 154))	('PLCgamma2', 'Gene', (218, 227))	('cSH2', 'Gene', (228, 232))	('interacts', 'Interaction', (68, 77))	('K15P', 'SUBSTITUTION', 'None', (101, 105))	('cSH2', 'Gene', (43, 47))	('K15P', 'SUBSTITUTION', 'None', (290, 294))	('PLCgamma2', 'Gene', '5336', (58, 67))	('K15P', 'Var', (290, 294))	('cSH2', 'Gene', '1443', (172, 176))
376672	26295810	We showed that the PLCgamma2 cSH2 domain can compete with PLCgamma1, GIT1 and cdc42 for the binding to K15 (Fig 6A), releasing these factors from the complex and thereby decreasing the levels of PLCgamma1 phosphorylation (Fig 6B) as well as the NFAT-dependent promoter activation (Fig 6C) induced by K15.	('GIT1', 'Gene', '28964', (69, 73))	('levels', 'MPA', (185, 191))	('cdc42', 'Gene', (78, 83))	('GIT1', 'Gene', (69, 73))	('decreasing', 'NegReg', (170, 180))	('releasing', 'PosReg', (117, 126))	('PLCgamma1 phosphorylation', 'MPA', (195, 220))	('cSH2', 'Gene', '1443', (29, 33))	('phospho', 'Chemical', 'MESH:D004099', (205, 212))	('PLCgamma2', 'Gene', '5336', (19, 28))	('PLCgamma2', 'Gene', (19, 28))	('cSH2', 'Gene', (29, 33))	('NFAT-dependent promoter activation', 'MPA', (245, 279))	('K15', 'Var', (300, 303))	('cdc42', 'Gene', '998', (78, 83))
376674	26295810	In line with these data, the K15-dependent phosphorylation of PLCgamma1 on Y783 in endothelial cells could be efficiently inhibited by overexpressing the PLCgamma2 cSH2 domain (Fig 6B).	('PLCgamma2', 'Gene', (154, 163))	('cSH2', 'Gene', (164, 168))	('phospho', 'Chemical', 'MESH:D004099', (43, 50))	('inhibited', 'NegReg', (122, 131))	('overexpressing', 'PosReg', (135, 149))	('Y783', 'Var', (75, 79))	('PLCgamma2', 'Gene', '5336', (154, 163))	('cSH2', 'Gene', '1443', (164, 168))	('K15-dependent phosphorylation', 'MPA', (29, 58))	('PLCgamma1', 'Gene', (62, 71))
376675	26295810	Activation of NFAT signalling by K15M, which binds PLCgamma1 through its nSH2 domain (Fig 4B), and does not associate with the PLCgamma2 cSH2 domain (Fig 7B and 7D), could not be significantly inhibited by overexpressing the PLCgamma2 cSH2 domain (Fig 7A and 7C), thus suggesting that the inhibitory effect of the PLCgamma2 cSH2 domain on K15P is due to its ability to interact with the latter, and not due to an indirect effect on other cellular proteins.	('PLCgamma2', 'Gene', '5336', (225, 234))	('PLCgamma2', 'Gene', (127, 136))	('K15P', 'Var', (339, 343))	('cSH2', 'Gene', '1443', (324, 328))	('PLCgamma2', 'Gene', '5336', (314, 323))	('K15P', 'SUBSTITUTION', 'None', (339, 343))	('cSH2', 'Gene', '1443', (235, 239))	('PLCgamma2', 'Gene', (225, 234))	('cSH2', 'Gene', (235, 239))	('interact', 'Interaction', (369, 377))	('cSH2', 'Gene', (324, 328))	('PLCgamma2', 'Gene', (314, 323))	('PLCgamma2', 'Gene', '5336', (127, 136))	('cSH2', 'Gene', '1443', (137, 141))	('K15M', 'SUBSTITUTION', 'None', (33, 37))	('NFAT signalling', 'MPA', (14, 29))	('cSH2', 'Gene', (137, 141))	('K15M', 'Var', (33, 37))
376676	26295810	Apart from binding to the phosphate moiety, which provides half of the ligand binding energy, SH2 domains also contact their cognate binding sites through additional residues in their binding pocket, which confer increased affinity and specificity.	('SH2', 'Gene', (94, 97))	('increased', 'PosReg', (213, 222))	('residues', 'Var', (166, 174))	('phosphate', 'Chemical', 'MESH:D010710', (26, 35))	('binding', 'Interaction', (184, 191))	('affinity', 'MPA', (223, 231))
376677	26295810	We therefore hypothesize that different residues in the K15P and M SH2 binding sites, involved in contacting the phosphotyrosine-binding pocket allow K15P, but not M, to associate with the PLCgamma2 cSH2 domain.	('K15P', 'Var', (150, 154))	('cSH2', 'Gene', '1443', (199, 203))	('PLCgamma2', 'Gene', (189, 198))	('cSH2', 'Gene', (199, 203))	('K15P', 'SUBSTITUTION', 'None', (150, 154))	('K15P', 'Var', (56, 60))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (113, 128))	('PLCgamma2', 'Gene', '5336', (189, 198))	('K15P', 'SUBSTITUTION', 'None', (56, 60))	('associate', 'Interaction', (170, 179))
376678	26295810	A recent report showed that the affinity of SH2 domains for their ligands can be increased by altering amino acids which flank the binding pocket for the residues surrounding the phosphorylated tyrosine in the corresponding SH2 binding site.	('altering', 'Var', (94, 102))	('phospho', 'Chemical', 'MESH:D004099', (179, 186))	('tyrosine', 'Chemical', 'MESH:D014443', (194, 202))	('increased', 'PosReg', (81, 90))	('affinity', 'MPA', (32, 40))
376679	26295810	We therefore explored if the dominant negative effect of the PLCgamma2 cSH2 domain on the K15P-PLCgamma1 complex could be enhanced by strengthening its binding to K15P.	('PLCgamma2', 'Gene', '5336', (61, 70))	('K15P', 'SUBSTITUTION', 'None', (90, 94))	('strengthening', 'PosReg', (134, 147))	('cSH2', 'Gene', '1443', (71, 75))	('binding', 'Interaction', (152, 159))	('K15P', 'Var', (90, 94))	('K15P', 'Var', (163, 167))	('PLCgamma2', 'Gene', (61, 70))	('cSH2', 'Gene', (71, 75))	('K15P', 'SUBSTITUTION', 'None', (163, 167))
376680	26295810	We found (Figs 5D-5F, 6E and 6F) that altering two residues, S677V and R695L, achieves this objective and that the resulting PLCgamma2 SB mutant (S677V/R695L) shows an increased ability to inhibit the K15-dependent activation of NFAT, but not of NF-kappaB, thus demonstrating the specificity for the K15-dependent recruitment and activation of NFAT.	('increased', 'PosReg', (168, 177))	('NF-kappaB', 'Gene', '4790', (246, 255))	('SB', 'Chemical', '-', (135, 137))	('K15-dependent activation', 'MPA', (201, 225))	('R695L', 'Mutation', 'p.R695L', (71, 76))	('S677V', 'Var', (146, 151))	('NF-kappaB', 'Gene', (246, 255))	('S677V', 'Mutation', 'p.S677V', (61, 66))	('PLCgamma2', 'Gene', (125, 134))	('S677V', 'SUBSTITUTION', 'None', (61, 66))	('S677V', 'Var', (61, 66))	('S677V', 'SUBSTITUTION', 'None', (146, 151))	('rat', 'Species', '10116', (269, 272))	('R695L', 'Mutation', 'p.R695L', (152, 157))	('S677V', 'Mutation', 'p.S677V', (146, 151))	('PLCgamma2', 'Gene', '5336', (125, 134))	('inhibit', 'NegReg', (189, 196))
376684	26295810	Since tyrosine phosphorylation (on the SH2 binding site) increases the affinity for the SH2 domain on the order of 100 fold, a possible interpretation of our results is that the K15 fusion protein used in our SPR assay was not phosphorylated and we therefore failed to observe an increased affinity of the SB domain when using recombinant proteins, in contrast to the results obtained when we analysed the binding of PLCgamma2 cSH2 wt and SB domains in lysates of transfected cells (Figs 5E, 5F, 7B and 7D).	('tyrosine', 'Chemical', 'MESH:D014443', (6, 14))	('phospho', 'Chemical', 'MESH:D004099', (227, 234))	('SB', 'Chemical', '-', (306, 308))	('tyrosine phosphorylation', 'Var', (6, 30))	('PLCgamma2', 'Gene', '5336', (417, 426))	('affinity', 'MPA', (71, 79))	('cSH2', 'Gene', '1443', (427, 431))	('phospho', 'Chemical', 'MESH:D004099', (15, 22))	('increases', 'PosReg', (57, 66))	('PLCgamma2', 'Gene', (417, 426))	('cSH2', 'Gene', (427, 431))	('SB', 'Chemical', '-', (439, 441))
376688	26295810	In fact, the observation that K15 overexpression alone can induce invasiveness (Fig 1B and 1C) whereas in KSHV infected endothelial cells, the contribution of K15 the increased invasiveness only becomes measurable if there are lytic cells present in the culture (Fig 1D and 1E), suggests that, when expressed in its physiological context from the viral genome, K15 is necessary, but not sufficient, for KSHV-induced invasiveness and angiogenesis.	('expression', 'Species', '29278', (38, 48))	('K15', 'Var', (30, 33))	('invasiveness', 'CPA', (66, 78))	('overexpression', 'PosReg', (34, 48))
376690	26295810	We identified the isolated cSH2 domain of PLCgamma2, as well as its SB derivative, as dominant negative inhibitors of K15P-dependent NFAT signalling and the resulting increased invasiveness and angiogenesis of endothelial cells infected with a KSHV strain carrying the K15P allele.	('K15P', 'SUBSTITUTION', 'None', (118, 122))	('cSH2', 'Gene', (27, 31))	('negative inhibitors', 'NegReg', (95, 114))	('PLCgamma2', 'Gene', (42, 51))	('angiogenesis', 'CPA', (194, 206))	('invasiveness', 'CPA', (177, 189))	('K15P', 'Var', (269, 273))	('increased', 'PosReg', (167, 176))	('PLCgamma2', 'Gene', '5336', (42, 51))	('cSH2', 'Gene', '1443', (27, 31))	('K15P', 'Var', (118, 122))	('SB', 'Chemical', '-', (68, 70))	('K15P', 'SUBSTITUTION', 'None', (269, 273))
376691	26295810	Although we have so far only been able to antagonize the recruitment of PLCgamma1 by K15P, and not by its other allele, K15M, our results may provide the foundation for a search for dominant negative protein fragment-based inhibitors or small molecules which will also target K15M and help to mitigate some of the pathogenic features of KSHV in infected endothelial cells.	('PLCgamma1', 'Gene', (72, 81))	('K15M', 'SUBSTITUTION', 'None', (120, 124))	('K15P', 'SUBSTITUTION', 'None', (85, 89))	('K15M', 'Var', (120, 124))	('recruitment', 'MPA', (57, 68))	('K15M', 'SUBSTITUTION', 'None', (276, 280))	('K15M', 'Var', (276, 280))	('K15P', 'Var', (85, 89))
376693	26295810	GST-K15 contains a synthetic K15P cytoplasmic tail (aa 347-489)(sK15P), with a nucleotide sequence optimized for prokaryotic expression (GENEART GmbH).	('synthetic', 'Species', '2005392', (19, 28))	('expression', 'Species', '29278', (125, 135))	('K15P', 'Var', (65, 69))	('K15P', 'SUBSTITUTION', 'None', (65, 69))	('K15P', 'Var', (29, 33))	('K15P', 'SUBSTITUTION', 'None', (29, 33))
376697	26295810	PLCgamma1 R586L and PLCgamma1 R694L were generated by site-directed mutagenesis of PLCgamma1 wt using the following primers: F 5'-CTTCCTCGTGCTAGAGAGTGA-3'; R 5'-CTCACTCTCTAGCACGAGGAA-3'; F 5'-CCTTCCTGGTGCTGAAGCGGAATGAACCC-3'; R5'-GGGTTCCTTCCGCTTCAGCACCAGGAAGG-3', respectively.	('R586L', 'Mutation', 'rs750791519', (10, 15))	('R694L', 'Mutation', 'rs1336595726', (30, 35))	('mutagenesis', 'Var', (68, 79))	('PLCgamma1', 'Gene', (83, 92))	('rat', 'Species', '10116', (45, 48))
376698	26295810	PLCgamma2 cSH2 R672L was generated by site-directed mutagenesis of PLCgamma2 cSH2 using the primers F 5'-CTTCCTGATCCTGAAGCGAGAGGG-3' and R 5'- CCCTCTCGCTTCAGGATCAGGAAG-3'.	('R672L', 'Var', (15, 20))	('cSH2', 'Gene', (10, 14))	('PLCgamma2', 'Gene', '5336', (67, 76))	('mutagenesis', 'Var', (52, 63))	('rat', 'Species', '10116', (29, 32))	('PLCgamma2', 'Gene', '5336', (0, 9))	('cSH2', 'Gene', '1443', (77, 81))	('R672L', 'Mutation', 'p.R672L', (15, 20))	('PLCgamma2', 'Gene', (67, 76))	('cSH2', 'Gene', (77, 81))	('cSH2', 'Gene', '1443', (10, 14))	('PLCgamma2', 'Gene', (0, 9))
376699	26295810	PLCgamma2 cSH2 S677V was generated by site directed mutagenesis of PLCgamma2 cSH2 wt using the primers:F 5`-CATAGGAGTCGACCCCCTCTC-3`and R5`-GACAGGGGGTCGACTCCTATG-3`.	('cSH2', 'Gene', (10, 14))	('S677V', 'Mutation', 'p.S677V', (15, 20))	('PLCgamma2', 'Gene', '5336', (67, 76))	('mutagenesis', 'Var', (52, 63))	('rat', 'Species', '10116', (29, 32))	('PLCgamma2', 'Gene', '5336', (0, 9))	('cSH2', 'Gene', '1443', (77, 81))	('PLCgamma2', 'Gene', (67, 76))	('cSH2', 'Gene', (77, 81))	('cSH2', 'Gene', '1443', (10, 14))	('PLCgamma2', 'Gene', (0, 9))
376700	26295810	PLCgamma2 cSH2 R695L was generated by site directed mutagenesis of PLCgamma2 cSH2 wt using the primers:F5`-AAAGCATTGTCTCATCAACCG-3`; and R5`-CGGTTGATGAGACAATGCTTT-3`.	('R695L', 'Mutation', 'p.R695L', (15, 20))	('cSH2', 'Gene', (10, 14))	('PLCgamma2', 'Gene', '5336', (67, 76))	('mutagenesis', 'Var', (52, 63))	('rat', 'Species', '10116', (29, 32))	('PLCgamma2', 'Gene', '5336', (0, 9))	('cSH2', 'Gene', '1443', (77, 81))	('PLCgamma2', 'Gene', (67, 76))	('cSH2', 'Gene', (77, 81))	('cSH2', 'Gene', '1443', (10, 14))	('PLCgamma2', 'Gene', (0, 9))
376701	26295810	To generate the PLCgamma2 cSH2 S677V/R695L (SB) mutant, the S677V mutant was amplified using the R695L primers.	('R695L', 'Mutation', 'p.R695L', (37, 42))	('S677V', 'Mutation', 'p.S677V', (31, 36))	('S677V/R695L', 'Var', (31, 42))	('S677V', 'Mutation', 'p.S677V', (60, 65))	('PLCgamma2', 'Gene', '5336', (16, 25))	('SB', 'Chemical', '-', (44, 46))	('rat', 'Species', '10116', (7, 10))	('S677V', 'Var', (60, 65))	('cSH2', 'Gene', '1443', (26, 30))	('PLCgamma2', 'Gene', (16, 25))	('R695L', 'Mutation', 'p.R695L', (97, 102))	('S677V/R', 'Mutation', 'p.S677V,R', (31, 38))	('cSH2', 'Gene', (26, 30))
376705	26295810	HEK293 stably infected with KSHV BAC36 wt or DeltaK15 have been previously described.	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('KSHV BAC36', 'Gene', (28, 38))	('DeltaK15', 'Var', (45, 53))
376709	26295810	The following siRNAs (siGenome SMART pool) were purchased from Dharmacon, Thermo Scientific: control (non-targeting siRNA pool 2 D-001206-14-20), siPLCgamma1 (M-003559-01), sibetaPIX (M-009616-00), siGIT1 (M-020565-02) and siRNA against KSHV K15 protein targeting exon 8 (CAACCACCUUGGCAAUAAU).	('GIT1', 'Gene', '28964', (200, 204))	('GIT1', 'Gene', (200, 204))	('M-009616-00', 'Var', (184, 195))	('betaPIX', 'Gene', '8874', (175, 182))	('M-003559-01', 'Var', (159, 170))	('betaPIX', 'Gene', (175, 182))	('M-020565-02', 'Var', (206, 217))
376710	26295810	For retrovirus production, HEK293T were transfected using the calcium phosphate method with either pSF91-K15-IRES or pSF91-IRES vector, together with the packaging plasmids pM57DAW (gag/pol) and pRD114 envelope protein.	('pSF91-IRES', 'Var', (117, 127))	('calcium phosphate', 'Chemical', 'MESH:C020243', (62, 79))	('pSF91-K15-IRES', 'Var', (99, 113))	('pM57DAW', 'Var', (173, 180))	('HEK293T', 'CellLine', 'CVCL:0063', (27, 34))
376712	26295810	For transduction, cells were transduced with the indicated lenti- or retrovirus in the presence of 5 mug/ml of polybrene and centrifuged for 30 min at 450g.	('lenti-', 'Var', (59, 65))	('retrovirus', 'Protein', (69, 79))	('polybrene', 'Chemical', 'MESH:D006583', (111, 120))
376730	26295810	Antibodies from tissue culture supernatant recognizing K15 were detected with HRP conjugated mouse mAbs against the rat IgG isotypes (TIB173 IgG2a, TIB174 IgG2b, TIB170 IgG1 all from ATCC, R-2c IgG2c homemade), thus avoiding mAbs of IgM class.	('TIB173', 'Var', (134, 140))	('TIB170', 'Var', (162, 168))	('mouse', 'Species', '10090', (93, 98))	('IgG2b', 'Gene', '16016', (155, 160))	('IgG1', 'Gene', (169, 173))	('TIB174', 'Var', (148, 154))	('rat', 'Species', '10116', (116, 119))	('IgG2b', 'Gene', (155, 160))	('IgG1', 'Gene', '16017', (169, 173))
376740	26295810	Alternatively, uninfected HEK293 cells, or HEK293 cells stably harbouring KSHV BAC36 wt or a DeltaK15 mutant, were plated on a 6-well plate at a density of 6X105 cells per well and the lytic cycle was induced twenty-four hours later.	('mutant', 'Var', (102, 108))	('HEK293', 'CellLine', 'CVCL:0045', (26, 32))	('HEK293', 'CellLine', 'CVCL:0045', (43, 49))	('KSHV BAC36', 'Gene', (74, 84))	('DeltaK15 mutant', 'Var', (93, 108))	('lytic cycle', 'CPA', (185, 196))
376755	26295810	For binding assays, purified recombinant His-tagged wild type and mutant PLCgamma2 cSH2 domains were injected at different concentrations in HBS-EP buffer (10 mM Hepes, 150 mM, NaCl, 3 mM EDTA, 0.005% (vol/vol) surfactant P20, pH 7.4) at a flow rate of 10 mul/min.	('P20', 'Gene', '51673', (222, 225))	('P20', 'Gene', (222, 225))	('His', 'Chemical', 'MESH:D006639', (41, 44))	('NaCl', 'Chemical', 'MESH:D012965', (177, 181))	('PLCgamma2', 'Gene', (73, 82))	('cSH2', 'Gene', (83, 87))	('rat', 'Species', '10116', (245, 248))	('mutant', 'Var', (66, 72))	('Hepes', 'Chemical', 'MESH:D006531', (162, 167))	('rat', 'Species', '10116', (130, 133))	('EDTA', 'Chemical', 'MESH:D004492', (188, 192))	('PLCgamma2', 'Gene', '5336', (73, 82))	('cSH2', 'Gene', '1443', (83, 87))
376771	21826516	Radiation therapy increases the risk of developing a second malignancy in the irradiated field.	('malignancy', 'Disease', (60, 70))	('Radiation', 'Var', (0, 9))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))
376819	21826516	Heritable retinoblastoma and osteosarcoma were found to be associated in some cases with the deletion of the 13q14 locus of the RB-1 gene.	('RB', 'Phenotype', 'HP:0009919', (128, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('retinoblastoma', 'Gene', (10, 24))	('deletion of', 'Var', (93, 104))	('retinoblastoma', 'Gene', '5925', (10, 24))	('RB-1', 'Gene', '5925', (128, 132))	('associated', 'Reg', (59, 69))	('RB-1', 'Gene', (128, 132))	('retinoblastoma', 'Phenotype', 'HP:0009919', (10, 24))	('osteosarcoma', 'Disease', (29, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))
376829	21826516	Patients with the genetic form of retinoblastoma are also at higher risk.	('retinoblastoma', 'Gene', (34, 48))	('retinoblastoma', 'Gene', '5925', (34, 48))	('retinoblastoma', 'Phenotype', 'HP:0009919', (34, 48))	('Patients', 'Species', '9606', (0, 8))	('genetic', 'Var', (18, 25))
376842	31481761	Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('correlated', 'Reg', (86, 96))	('patients', 'Species', '9606', (67, 75))	('type I IFN signature', 'MPA', (121, 141))	('anti-PD-1', 'Var', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
376844	31481761	The understanding that immune responses are routinely generated against tumor-specific neoantigens resulting from cancer-associated mutations and commonly suppressed by immunosuppressive tumor microenvironments (TME) has led to the development of effective immunotherapies aimed at provoking immune control against tumor progression.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (169, 192))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('immunosuppressive tumor', 'Disease', (169, 192))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (315, 320))	('cancer', 'Disease', (114, 120))
376853	31481761	A subset of melanoma patients who progressed despite an initial response to therapy with pembrolizumab, which targets PD-1, displayed either loss-of-function mutations in Janus kinases JAK1 or JAK2, leading to reduced sensitivity to the anti-proliferative effects of IFNs, decreased phosphorylation of STAT1, or a truncating mutation in the gene beta2 microglobulin, resulting in defective antigen presentation due to prevention of folding and transport of MHC class I molecules to the cell surface for T cell recognition of tumor cells.	('JAK2', 'Gene', (193, 197))	('reduced', 'NegReg', (210, 217))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('patients', 'Species', '9606', (21, 29))	('antigen presentation', 'MPA', (390, 410))	('MHC', 'Protein', (457, 460))	('phosphorylation', 'MPA', (283, 298))	('mutations', 'Var', (158, 167))	('transport', 'MPA', (444, 453))	('truncating mutation', 'Var', (314, 333))	('tumor', 'Disease', (525, 530))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('defective', 'NegReg', (380, 389))	('tumor', 'Disease', 'MESH:D009369', (525, 530))	('tumor', 'Phenotype', 'HP:0002664', (525, 530))	('prevention', 'NegReg', (418, 428))	('decreased', 'NegReg', (273, 282))	('loss-of-function', 'NegReg', (141, 157))	('JAK1', 'Gene', (185, 189))	('folding', 'MPA', (432, 439))	('PD-1', 'Gene', (118, 122))
376857	31481761	A chronic PD-1 blockade progressively induced IFNgamma and IFNbeta transcription in the TME, with both IFNs in turn triggering PD-L1 and NOS2 expression on both tumor cells and leukocytes.	('blockade', 'Var', (15, 23))	('IFNgamma', 'Gene', (46, 54))	('triggering', 'Reg', (116, 126))	('induced', 'PosReg', (38, 45))	('PD-1', 'Gene', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('IFNbeta transcription', 'Disease', 'OMIM:602482', (59, 80))	('PD-L1', 'Gene', (127, 132))	('NOS2', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('expression', 'MPA', (142, 152))	('tumor', 'Disease', (161, 166))	('PD-L1', 'Gene', '60533', (127, 132))	('IFNbeta transcription', 'Disease', (59, 80))
376860	31481761	While PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, reducing NOS2 with L-NAME or a genetic knockout improved long-term tumor control by PD-1 blockade in several tumor models.	('L-NAME', 'Chemical', 'None', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('reducing', 'NegReg', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (138, 143))	('genetic knockout', 'Var', (102, 118))	('tumor', 'Disease', (180, 185))	('PD-1', 'Gene', (155, 159))	('PD-L1', 'Gene', (6, 11))	('NOS2', 'MPA', (80, 84))	('improved', 'PosReg', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('PD-L1', 'Gene', '60533', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
376865	31481761	While the MCA205WT sarcoma remained sensitive to 4 doses of PD-1 blockade over 12 days (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('MCA205WT', 'Var', (10, 18))	('sarcoma', 'Disease', (19, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('PD-1', 'Gene', (60, 64))
376866	31481761	S1b), hosts bearing MCA205OVA and MC38 colon cancers were eventually resistant as initial treatments slightly reduced their tumor growth kinetics (Fig.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('reduced', 'NegReg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('MCA205OVA', 'Var', (20, 29))	('tumor', 'Disease', (124, 129))	('MC38', 'Var', (34, 38))	('colon cancers', 'Disease', (39, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('colon cancers', 'Phenotype', 'HP:0003003', (39, 52))	('colon cancers', 'Disease', 'MESH:D015179', (39, 52))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
376880	31481761	In fact, two MCA205 clones,19-14 and 19-37, produced by nucleo-transfection with specific zinc finger nucleases (ZFN) causing targeted deletion of the Ifnar1 gene were implanted into Ifnar1 wild-type mice.	('deletion', 'Var', (135, 143))	('Ifnar1', 'Gene', '15975', (183, 189))	('Ifnar1', 'Gene', (151, 157))	('mice', 'Species', '10090', (200, 204))	('Ifnar1', 'Gene', '15975', (151, 157))	('Ifnar1', 'Gene', (183, 189))
376908	31481761	However, at the protein level, flow cytometry analyses performed after 4 injections of mAb revealed two-fold higher NOS2 expression in CD11c+ as well as F4/80+/Gr1- fractions of CD45+ tumor infiltrating cells from anti-PD-1-treated mice compared with isotype-treated controls (Fig.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('CD11c+', 'Var', (135, 141))	('CD45', 'Gene', '19264', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('higher', 'PosReg', (109, 115))	('expression', 'MPA', (121, 131))	('tumor', 'Disease', (184, 189))	('NOS2', 'Gene', (116, 120))	('CD45', 'Gene', (178, 182))	('mice', 'Species', '10090', (232, 236))
376909	31481761	In addition, the CD45- fraction from MCA205WT tumors in vivo also expressed higher levels of Nos2 at later stages of PD-1 blockade (Fig.	('levels', 'MPA', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('higher', 'PosReg', (76, 82))	('CD45', 'Gene', '19264', (17, 21))	('Nos2', 'MPA', (93, 97))	('tumors', 'Disease', (46, 52))	('CD45', 'Gene', (17, 21))	('MCA205WT', 'Var', (37, 45))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
376920	31481761	To a lesser extent, L-NAME also improved anti-PD-1 efficacy in MC38-bearing mice (Fig.	('L-NAME', 'Var', (20, 26))	('improved', 'PosReg', (32, 40))	('mice', 'Species', '10090', (76, 80))	('L-NAME', 'Chemical', 'None', (20, 26))	('anti-PD-1', 'MPA', (41, 50))
376921	31481761	Flow cytometric analyses of TILs revealed that L-NAME combined with an anti-PD-1 blockade tended to decrease tumor-infiltrating CD4+FOXP3+ regulatory T cells, and significantly increased the CD8+/CD4+FOXP3+ ratio in MCA205WT tumors (Fig.	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CD4', 'Gene', '12504', (128, 131))	('decrease', 'NegReg', (100, 108))	('FOXP3', 'Gene', (132, 137))	('L-NAME', 'Chemical', 'None', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('CD4', 'Gene', (196, 199))	('MCA205WT', 'Var', (216, 224))	('FOXP3', 'Gene', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CD4', 'Gene', '12504', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('increased', 'PosReg', (177, 186))	('FOXP3', 'Gene', '20371', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('anti-PD-1', 'Gene', (71, 80))	('CD4', 'Gene', (128, 131))	('FOXP3', 'Gene', '20371', (200, 205))	('tumors', 'Disease', (225, 231))	('tumor', 'Disease', (109, 114))
376924	31481761	Altogether, IFNAR signaling in leukocytes led to deleterious Nos2 expression contributing to progressive resistance to PD-1 blockade.	('IFNAR', 'Gene', '15975', (12, 17))	('expression', 'MPA', (66, 76))	('Nos2', 'Gene', (61, 65))	('deleterious', 'Var', (49, 60))	('IFNAR', 'Gene', (12, 17))
376943	31481761	In addition, two case reports described melanoma patients who initially responded to anti-PD-1 mAb but exhibited a late relapse attributed to loss-of-function mutations in JAK1 or JAK2.	('responded', 'MPA', (72, 81))	('JAK2', 'Gene', (180, 184))	('mutations', 'Var', (159, 168))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('loss-of-function', 'NegReg', (142, 158))	('patients', 'Species', '9606', (49, 57))	('JAK1', 'Gene', (172, 176))	('anti-PD-1', 'Gene', (85, 94))
376947	31481761	The copy number loss in IFN pathway genes (such as Ifngr1, Irf1, Jak2, and Ifngr2), or the amplification of crucial IFNgamma pathway inhibitors, including SOCS1 and PIAS4 and loss-of-function mutations in JAK1/JAK2 represent paradigms of primary and/or acquired resistance mechanisms to ICB.	('IFN pathway genes', 'Gene', (24, 41))	('loss-of-function', 'NegReg', (175, 191))	('Ifngr2', 'Gene', (75, 81))	('PIAS4', 'Gene', '59004', (165, 170))	('SOCS1', 'Gene', (155, 160))	('JAK1/JAK2', 'Gene', (205, 214))	('PIAS4', 'Gene', (165, 170))	('Irf1', 'Gene', '16362', (59, 63))	('Ifngr1', 'Gene', '15979', (51, 57))	('Ifngr2', 'Gene', '15980', (75, 81))	('loss', 'NegReg', (16, 20))	('Jak2', 'Gene', '16452', (65, 69))	('copy number', 'Var', (4, 15))	('SOCS1', 'Gene', '12703', (155, 160))	('Jak2', 'Gene', (65, 69))	('Irf1', 'Gene', (59, 63))	('mutations', 'Var', (192, 201))	('Ifngr1', 'Gene', (51, 57))
376952	31481761	NO acts at cell autonomous levels such as DNA damage, oncogene activation, inhibition of DNA repair enzymes, and tumor suppressor genes, modulation of apoptosis and metastases.	('tumor', 'Disease', (113, 118))	('DNA repair', 'Gene', (89, 99))	('inhibition', 'Var', (75, 85))	('oncogene', 'Gene', (54, 62))	('metastases', 'Disease', 'MESH:D009362', (165, 175))	('modulation', 'Reg', (137, 147))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('DNA', 'Disease', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('apoptosis', 'CPA', (151, 160))	('metastases', 'Disease', (165, 175))	('activation', 'PosReg', (63, 73))
376955	31481761	NO mediates the nitration of tyrosine residues in multiple proteins, thereby lessening the Th1 gene signature in M1 macrophages.	('tyrosine', 'Chemical', 'None', (29, 37))	('lessening', 'NegReg', (77, 86))	('Th1', 'Gene', '57314', (91, 94))	('Th1', 'Gene', (91, 94))	('nitration', 'Var', (16, 25))
376961	31481761	Supporting this notion, type I IFN-induced NOS2 in macrophages reduced intracellular accumulation of Leishmania major while favoring infection with Mycobacterium tuberculosis.	('Mycobacterium tuberculosis', 'Disease', (148, 174))	('favoring', 'PosReg', (124, 132))	('reduced', 'NegReg', (63, 70))	('NOS2', 'Var', (43, 47))	('Leishmania major', 'Species', '5664', (101, 117))	('intracellular accumulation of Leishmania major', 'MPA', (71, 117))
376965	31481761	The main mode of action of L-NAME was its capacity to activate DC and to reduce Treg accumulation in tumor beds, thereby increasing the CD8+/FOXP3 ratio in the context of a long-term PD-1 blockade.	('FOXP3', 'Gene', '20371', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('FOXP3', 'Gene', (141, 146))	('increasing', 'PosReg', (121, 131))	('L-NAME', 'Var', (27, 33))	('activate', 'PosReg', (54, 62))	('reduce', 'NegReg', (73, 79))	('L-NAME', 'Chemical', 'None', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
376975	31481761	The right flank of mice was subcutaneously (s.c.) injected with 0.8 x 106 cells for MCA205WT and 1 x 106 cells for MCA205OVA, MC38 and AT3.	('MCA205OVA', 'Var', (115, 124))	('AT3', 'Gene', (135, 138))	('AT3', 'Gene', '11608', (135, 138))	('MCA205WT', 'Var', (84, 92))	('mice', 'Species', '10090', (19, 23))
377002	31481761	Expression of beta2 m (Mm00437762_m1), Ppia (Mm02342429_g1), Ifnbeta1 (Mm00439552_s1), Nos2 (Mm00440502_m1), Nos1 (Mm01208059_m1), Nos3 (Mm00435217_m1), Arg1 (Mm00475988_m1), Isg15 (Mm01705338_s1), Mx1 (Mm01218004_m1), and Pdl1 (Mm0045054_m1) (all from Life Technologies) was analyzed with the TaqMan  Gene Expression Assay using the Universal Master Mix II on a StepOnePlus  Real-Time PCR System (Life Technologies).	('StepOnePlus', 'Disease', 'None', (363, 374))	('beta2 m', 'Gene', '12010', (14, 21))	('Isg15', 'Gene', '100038882', (175, 180))	('Nos1', 'Gene', '18125', (109, 113))	('Arg1', 'Gene', (153, 157))	('Ppia', 'Gene', '268373', (39, 43))	('Ppia', 'Gene', (39, 43))	('Nos3', 'Gene', (131, 135))	('Mm00435217_m1', 'Var', (137, 150))	('Nos3', 'Gene', '18127', (131, 135))	('StepOnePlus', 'Disease', (363, 374))	('Mm00440502_m1', 'Var', (93, 106))	('Pdl1', 'Gene', '60533', (223, 227))	('Nos1', 'Gene', (109, 113))	('Mm00475988_m1', 'Var', (159, 172))	('beta2 m', 'Gene', (14, 21))	('Mm00437762_m1', 'Var', (23, 36))	('Pdl1', 'Gene', (223, 227))	('Isg15', 'Gene', (175, 180))	('Mm01208059_m1', 'Var', (115, 128))	('Arg1', 'Gene', '11846', (153, 157))	('Mm01705338_s1', 'Var', (182, 195))
377015	31481761	Expression of beta2 M (Hs00187842_m1), NOS2 (Hs01075529_m1), NOS3 (Hs01574665_m1) and PDL1 (Hs00204257_m1) (all from Life Technologies) were analyzed with TaqMan  Gene Expression Assay using the Universal Master Mix II.	('NOS3', 'Gene', '18127', (61, 65))	('PDL1', 'Gene', '60533', (86, 90))	('Hs01574665_m1', 'Var', (67, 80))	('Hs01075529_m1', 'Var', (45, 58))	('Hs00187842_m1', 'Var', (23, 36))	('NOS3', 'Gene', (61, 65))	('beta2 M', 'Gene', (14, 21))	('Hs00204257_m1', 'Var', (92, 105))	('PDL1', 'Gene', (86, 90))	('beta2 M', 'Gene', '12010', (14, 21))
377045	30864973	However, a subset of adult renal sarcomas which overexpress BCOR are negative for BCOR genetic alterations, including BCOR gene fusions or BCOR-internal tandem duplication, and thus remain unclassified.	('renal sarcomas', 'Phenotype', 'HP:0008663', (27, 41))	('BCOR', 'Gene', (139, 143))	('BCOR', 'Gene', (118, 122))	('BCOR', 'Gene', (60, 64))	('negative', 'NegReg', (69, 77))	('adult renal sarcomas', 'Disease', (21, 41))	('BCOR', 'Gene', '54880', (118, 122))	('BCOR', 'Gene', (82, 86))	('overexpress', 'PosReg', (48, 59))	('BCOR', 'Gene', '54880', (139, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('BCOR', 'Gene', '54880', (60, 64))	('gene fusions', 'Var', (123, 135))	('adult renal sarcomas', 'Disease', 'MESH:D007674', (21, 41))	('BCOR', 'Gene', '54880', (82, 86))
377060	30864973	Genetic alterations underlying CCSK have been delineated in the past decade.	('CCSK', 'Phenotype', 'HP:0006770', (31, 35))	('Genetic alterations', 'Var', (0, 19))	('CCSK', 'Disease', (31, 35))	('CCSK', 'Chemical', '-', (31, 35))
377061	30864973	The majority (>90%) of CCSK harbor internal tandem duplications (ITD) in the last exon of the BCOR (Bcl6 interacting co-repressor) gene.	('BCOR', 'Gene', (94, 98))	('Bcl6 interacting co-repressor', 'Gene', '54880', (100, 129))	('CCSK', 'Chemical', '-', (23, 27))	('BCOR', 'Gene', '54880', (94, 98))	('Bcl6 interacting co-repressor', 'Gene', (100, 129))	('CCSK', 'Disease', (23, 27))	('internal tandem duplications', 'Var', (35, 63))	('CCSK', 'Phenotype', 'HP:0006770', (23, 27))
377063	30864973	A third subset of CCSK harbor a YWHAE-NUTM2B gene fusion resulting from a t(10;17)(q22.3;p13.3) translocation which is identical to that seen in high grade endometrial stromal sarcoma.	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (156, 183))	('CCSK', 'Disease', (18, 22))	('translocation', 'Var', (96, 109))	('t(10;17)(q22.3;p13.3)', 'STRUCTURAL_ABNORMALITY', 'None', (74, 95))	('YWHAE', 'Gene', '7531', (32, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('NUTM2B', 'Gene', '729262', (38, 44))	('CCSK', 'Chemical', '-', (18, 22))	('CCSK', 'Phenotype', 'HP:0006770', (18, 22))	('YWHAE', 'Gene', (32, 37))	('endometrial stromal sarcoma', 'Disease', (156, 183))	('resulting from', 'Reg', (57, 71))	('NUTM2B', 'Gene', (38, 44))
377068	30864973	RNA sequencing (RNA-Seq) then demonstrated the characteristic NAB2-STAT6 gene fusion supporting the diagnosis of malignant solitary fibrous tumor (SFT), a previously unrecognized mimic of CCSK.	('fusion', 'Var', (78, 84))	('malignant solitary fibrous tumor', 'Disease', 'MESH:D054364', (113, 145))	('malignant solitary fibrous tumor', 'Disease', (113, 145))	('STAT6', 'Gene', (67, 72))	('NAB2', 'Gene', '4665', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('STAT6', 'Gene', '6778', (67, 72))	('CCSK', 'Chemical', '-', (188, 192))	('NAB2', 'Gene', (62, 66))	('CCSK', 'Phenotype', 'HP:0006770', (188, 192))
377102	30864973	The diagnosis was retrospectively established in each case following RNA sequencing, which demonstrated the characteristic NAB2-STAT6 gene fusion of solitary fibrous tumor.	('NAB2', 'Gene', '4665', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('fibrous tumor', 'Disease', (158, 171))	('STAT6', 'Gene', (128, 133))	('NAB2', 'Gene', (123, 127))	('STAT6', 'Gene', '6778', (128, 133))	('fibrous tumor', 'Disease', 'MESH:D054364', (158, 171))	('gene fusion', 'Var', (134, 145))
377109	30864973	Finally, we identified frequent BCOR immunoreactivity in a separate cohort of extrarenal SFT.	('BCOR', 'Gene', (32, 36))	('BCOR', 'Gene', '54880', (32, 36))	('extrarenal SFT', 'Disease', (78, 92))	('immunoreactivity', 'Var', (37, 53))
377121	30864973	By RNA sequencing all five renal/perirenal SFTs demonstrated gene fusions involving NAB2 exon 6/7-STAT6 exons 16/17, which is one of the less common transcript variants, often associated with younger patients, deep seated soft tissue sites, malignant histology and aggressive clinical behavior.	('patients', 'Species', '9606', (200, 208))	('associated', 'Reg', (176, 186))	('NAB2', 'Gene', (84, 88))	('STAT6', 'Gene', (98, 103))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (265, 293))	('gene fusions', 'Var', (61, 73))	('STAT6', 'Gene', '6778', (98, 103))	('malignant', 'Disease', (241, 250))	('NAB2', 'Gene', '4665', (84, 88))
377128	30864973	However, these neoplasms are easily distinguished genetically; synovial sarcomas harbor SS18-SSX1/2 fusions, which are not found in SFT, and lack the NAB2-STAT6 gene fusion of SFT.	('fusions', 'Var', (100, 107))	('neoplasms', 'Phenotype', 'HP:0002664', (15, 24))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (63, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('STAT6', 'Gene', (155, 160))	('NAB2', 'Gene', '4665', (150, 154))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (63, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('neoplasms', 'Disease', (15, 24))	('SSX1/2', 'Gene', (93, 99))	('STAT6', 'Gene', '6778', (155, 160))	('neoplasm', 'Phenotype', 'HP:0002664', (15, 23))	('neoplasms', 'Disease', 'MESH:D009369', (15, 24))	('synovial sarcomas', 'Disease', 'MESH:D013584', (63, 80))	('synovial sarcomas', 'Disease', (63, 80))	('SSX1/2', 'Gene', '6756;6757', (93, 99))	('NAB2', 'Gene', (150, 154))
377149	30967943	Furthermore, the relative biological effectiveness (RBE) in the tumor region is higher for heavy ions than for photons.	('heavy ions', 'Var', (91, 101))	('tumor', 'Disease', (64, 69))	('higher', 'PosReg', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
377203	30967943	Thus, irradiation of the gastrointestinal tract around the tumor has a risk for fistula formation.	('gastrointestinal tract', 'Disease', 'MESH:D004067', (25, 47))	('tumor', 'Disease', (59, 64))	('irradiation', 'Var', (6, 17))	('fistula', 'Disease', 'MESH:D005402', (80, 87))	('fistula', 'Disease', (80, 87))	('gastrointestinal tract', 'Disease', (25, 47))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
377256	30898996	The tissue-specific expression pattern of miRNAs is important for the precise regulation of cell differentiation and tissue development, and alterations in these processes are involved in the pathogenesis of cancer.	('cancer', 'Disease', (208, 214))	('alterations', 'Var', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('involved', 'Reg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
377281	30898996	Among the 33 miRNAs, miR-4488, miR-1908-3p, miR-1292-3p, miR-6088, and miR-4492 were excluded because specific primers for these sequences could not be obtained.	('miR-1908-3p', 'Var', (31, 42))	('miR-4492', 'Gene', '100616376', (71, 79))	('miR-4488', 'Gene', (21, 29))	('miR-6088', 'Gene', '102464836', (57, 65))	('miR-6088', 'Gene', (57, 65))	('miR-4492', 'Gene', (71, 79))	('miR-1292-3p', 'Var', (44, 55))	('miR-4488', 'Gene', '100616470', (21, 29))
377286	30898996	For example, Index I was calculated using two miRNAs with the following formula: (0.90 x miR-4736) + (0.55 x miR-6836-3p) - 11.3.	('miR-4736', 'Gene', (89, 97))	('miR-4736', 'Gene', '100616220', (89, 97))	('0.90', 'Var', (82, 86))
377319	30898996	Index VI, which exhibited the ability to diagnose sarcoma accurately, was calculated based on the levels of seven serum miRNAs: miR-4736, miR-6836-3p, miR-4281, miR-762, miR-658, miR-4649-5p, and miR-4665-3p.	('miR-6836-3p', 'Var', (138, 149))	('miR-658', 'Gene', '724028', (170, 177))	('miR-762', 'Gene', '100313837', (161, 168))	('miR-4281', 'Gene', (151, 159))	('miR-4736', 'Gene', '100616220', (128, 136))	('miR-658', 'Gene', (170, 177))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('miR-4281', 'Gene', '100422962', (151, 159))	('miR-4665-3p', 'Var', (196, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('miR-4736', 'Gene', (128, 136))	('miR-762', 'Gene', (161, 168))	('miR-4649-5p', 'Var', (179, 190))
377362	30898996	To normalize the signals among microarrays, three preselected internal control miRNAs (miR-149-3p, miR-2861, and miR-4463), which had been stably detected in more than 500 serum samples, were used.	('miR-4463', 'Gene', '100616389', (113, 121))	('miR-4463', 'Gene', (113, 121))	('miR-2861', 'Gene', '100422910', (99, 107))	('miR-149-3p', 'Var', (87, 97))	('miR-2861', 'Gene', (99, 107))
377365	30898996	The expression levels were normalized against the average signal of miR-149-3p, miR-2861, and miR-4463.	('miR-4463', 'Gene', '100616389', (94, 102))	('miR-4463', 'Gene', (94, 102))	('miR-2861', 'Gene', '100422910', (80, 88))	('miR-2861', 'Gene', (80, 88))	('miR-149-3p', 'Var', (68, 78))
377366	30898996	Only 28 of the 33 candidate miRNAs were analyzed because miScript PCR primers for miR-4488, miR-1908-3p, miR-1292-3p, miR-6088, and miR-4492 were not commercially available.	('miR-6088', 'Gene', (118, 126))	('miR-4492', 'Gene', (132, 140))	('miR-6088', 'Gene', '102464836', (118, 126))	('miR-4488', 'Gene', (82, 90))	('miR-1908-3p', 'Var', (92, 103))	('miR-4488', 'Gene', '100616470', (82, 90))	('miR-1292-3p', 'Var', (105, 116))	('miR-4492', 'Gene', '100616376', (132, 140))
377385	29490653	A 71-year-old woman was diagnosed as having breast cancer (left breast, invasive lobular carcinoma, T4cN3cM1, Stage IV) in September 2014 and was treated with endocrine therapy (exemestane 25 mg/day).	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (81, 98))	('lobular carcinoma', 'Disease', (81, 98))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('T4cN3cM1', 'Var', (100, 108))	('woman', 'Species', '9606', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('exemestane', 'Chemical', 'MESH:C056516', (178, 188))	('lobular carcinoma', 'Disease', 'MESH:D018275', (81, 98))
377391	29490653	We diagnosed her as having right renal pelvic cancer (cT3N0M0) and right renal cell cancer (cT1aN0M0).	('cT1aN0M0', 'Var', (92, 100))	('right renal pelvic cancer', 'Phenotype', 'HP:0006762', (27, 52))	('right renal cell cancer', 'Disease', 'MESH:C538614', (67, 90))	('right renal pelvic cancer', 'Disease', (27, 52))	('right renal pelvic cancer', 'Disease', 'MESH:D007680', (27, 52))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('renal cell cancer', 'Phenotype', 'HP:0005584', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('right renal cell cancer', 'Disease', (67, 90))
377406	29490653	We thus diagnosed right pelvic cancer (urothelial carcinoma, G2 > G3, pT3) and renal capsule metastasis.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('right pelvic cancer', 'Disease', (18, 37))	('urothelial carcinoma', 'Disease', (39, 59))	('renal capsule metastasis', 'Disease', (79, 103))	('right pelvic cancer', 'Disease', 'MESH:D010386', (18, 37))	('pT3', 'Gene', '7694', (70, 73))	('pT3', 'Gene', (70, 73))	('G2 > G3', 'Var', (61, 68))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (39, 59))
377434	28576884	Mdm2 is required for survival and growth of p53-deficient cancer cells p53 deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent.	('Mdm2', 'Gene', '17246', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('prevents', 'NegReg', (84, 92))	('Mdm2', 'Gene', '17246', (0, 4))	('p53-deficient cancer', 'Disease', (44, 64))	('deletion', 'Var', (75, 83))	('Mdm2', 'Gene', (143, 147))	('Mdm2', 'Gene', '17246', (191, 195))	('p53', 'Gene', (71, 74))	('Mdm2', 'Gene', (0, 4))	('p53-deficient cancer', 'Disease', 'MESH:D009369', (44, 64))	('embryonic lethality', 'Disease', 'MESH:D020964', (97, 116))	('embryonic lethality', 'Disease', (97, 116))	('Mdm2', 'Gene', (191, 195))
377435	28576884	Deletion of Mdm2 in T cell lymphomas or sarcomas lacking p53 induced apoptosis and G2 cell cycle arrest, prolonging survival of mice with these tumors.	('tumors', 'Disease', (144, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('apoptosis', 'CPA', (69, 78))	('cell lymphoma', 'Phenotype', 'HP:0012191', (22, 35))	('Mdm2', 'Gene', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('T cell lymphomas', 'Disease', (20, 36))	('Deletion', 'Var', (0, 8))	('survival', 'CPA', (116, 124))	('G2 cell cycle arrest', 'CPA', (83, 103))	('lymphomas', 'Phenotype', 'HP:0002665', (27, 36))	('mice', 'Species', '10090', (128, 132))	('prolonging', 'PosReg', (105, 115))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('T cell lymphomas', 'Disease', 'MESH:D016399', (20, 36))	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (27, 35))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (20, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('sarcomas', 'Disease', (40, 48))
377436	28576884	Additionally, Mdm2 deletion differed from blocking Mdm2 interaction with p53 family members, as Nutlin-3 induced G1 arrest but did not activate apoptosis in p53-/- sarcoma cells.	('deletion', 'Var', (19, 27))	('G1 arrest', 'MPA', (113, 122))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('Mdm2', 'Gene', (14, 18))	('Nutlin-3', 'Chemical', 'MESH:C482205', (96, 104))	('Nutlin-3', 'MPA', (96, 104))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
377437	28576884	Moreover, our results suggest that p73 compensates for loss of p53 and that targeting Mdm2 in p53-deficient cancers has therapeutic potential.	('loss', 'NegReg', (55, 59))	('p73', 'Var', (35, 38))	('p53-deficient cancers', 'Disease', 'MESH:D009369', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('p53-deficient cancers', 'Disease', (94, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Mdm2', 'Gene', (86, 90))	('p53', 'Protein', (63, 66))
377439	28576884	During development in mice, global Mdm2 deletion results in embryonic lethality, which is rescued with accompanying p53 deletion, genetically establishing Mdm2 regulation of p53.	('results in', 'Reg', (49, 59))	('embryonic lethality', 'Disease', 'MESH:D020964', (60, 79))	('embryonic lethality', 'Disease', (60, 79))	('deletion', 'Var', (40, 48))	('deletion', 'Var', (120, 128))	('Mdm2', 'Gene', (35, 39))	('mice', 'Species', '10090', (22, 26))	('p53', 'Gene', (116, 119))
377440	28576884	Induced Mdm2 deletion in adult mice resulted in abnormalities in multiple tissues, (e.g., spleen, liver, and kidney), which were not evident when performed on a p53-null background.	('deletion', 'Var', (13, 21))	('mice', 'Species', '10090', (31, 35))	('Mdm2', 'Gene', (8, 12))	('abnormalities', 'MPA', (48, 61))
377442	28576884	Furthermore, the rate of tumor development was analogous between Mdm2-/-p53-/- and p53-/- mice.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('mice', 'Species', '10090', (90, 94))	('Mdm2-/-p53-/-', 'Var', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
377446	28576884	p73, a p53 family member, is rarely mutated in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('p73', 'Var', (0, 3))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('human', 'Species', '9606', (47, 52))
377449	28576884	Since Mdm2 loss in the context of p53 inactivation could hold therapeutic promise and has not been thoroughly examined outside of development, we utilized a conditional Mdm2 deletion mouse model to determine the effect of Mdm2 loss on p53-/- cells.	('Mdm2', 'Gene', (169, 173))	('loss', 'NegReg', (227, 231))	('Mdm2', 'Gene', (222, 226))	('deletion', 'Var', (174, 182))	('mouse', 'Species', '10090', (183, 188))	('Mdm2', 'Gene', (6, 10))
377451	28576884	Immortalized adult mouse fibroblasts were similarly affected by Mdm2 deletion.	('Mdm2', 'Gene', (64, 68))	('mouse', 'Species', '10090', (19, 24))	('deletion', 'Var', (69, 77))
377452	28576884	Therefore, targeting Mdm2 directly may offer therapeutic potential for cancers that have deleted p53 by activating p73.	('p73', 'MPA', (115, 118))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('p53', 'Gene', (97, 100))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('activating', 'PosReg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('deleted', 'Var', (89, 96))
377454	28576884	Ear punches to derive fibroblasts or tumors (T-cell lymphoma and sarcoma) that developed in Mdm2fl/flp53-/- mice were harvested and placed in short-term culture (see Supplementary Information).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('cell lymphoma', 'Phenotype', 'HP:0012191', (47, 60))	('sarcoma', 'Disease', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (45, 60))	('tumors', 'Disease', (37, 43))	('T-cell lymphoma', 'Disease', (45, 60))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (45, 60))	('lymphoma', 'Phenotype', 'HP:0002665', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('Mdm2fl/flp53-/-', 'Var', (92, 107))
377462	28576884	Proliferation determined by MTS (492nm; Promega) or MTT (562nm; Sigma) assays (quadruplicate), as we previously reported,.	('562nm', 'Var', (57, 62))	('Proliferation', 'CPA', (0, 13))	('MTT', 'Chemical', 'MESH:C070243', (52, 55))
377466	28576884	Antibodies used include: Mdm2 (2A10, Calbiochem), cleaved Caspase-3 (D175) and cleaved PARP (Asp214) from Cell Signaling, p73 (EP436Y, Abcam), and beta-actin (Sigma).	('beta-actin (Sigma)', 'Gene', '11461', (147, 165))	('cleaved Caspase-3', 'Gene', (50, 67))	('cleaved', 'Var', (79, 86))	('cleaved Caspase-3', 'Gene', '12367', (50, 67))	('beta-actin (Sigma', 'Gene', (147, 164))	('PARP', 'Gene', (87, 91))	('PARP', 'Gene', '11545', (87, 91))	('Asp214', 'Chemical', '-', (93, 99))
377467	28576884	PCR genotyping was also used to confirm the T-cell lymphoma, sarcoma, and fibroblasts evaluated were p53-null (Supplementary Fig.	('sarcoma', 'Disease', (61, 68))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (44, 59))	('T-cell lymphoma', 'Disease', (44, 59))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (44, 59))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('cell lymphoma', 'Phenotype', 'HP:0012191', (46, 59))	('lymphoma', 'Phenotype', 'HP:0002665', (51, 59))	('p53-null', 'Var', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
377472	28576884	Previous studies showed cell death from loss of Mdm2 during development is rescued by p53 deletion, indicating cells can survive without Mdm2 if p53 is also absent.	('deletion', 'Var', (90, 98))	('death', 'Disease', 'MESH:D003643', (29, 34))	('death', 'Disease', (29, 34))	('p53', 'Gene', (86, 89))
377473	28576884	Additionally, since many human cancers delete p53, we sought to determine whether Mdm2 loss in p53-null malignant cells would affect their growth and/or survival.	('loss', 'NegReg', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('p53', 'Gene', (46, 49))	('delete', 'Var', (39, 45))	('growth', 'CPA', (139, 145))	('Mdm2', 'Gene', (82, 86))	('human', 'Species', '9606', (25, 30))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('affect', 'Reg', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Disease', (31, 38))	('survival', 'CPA', (153, 161))
377474	28576884	We generated p53-null mice homozygous for the conditional Mdm2 knockout.	('knockout', 'Var', (63, 71))	('mice', 'Species', '10090', (22, 26))	('Mdm2', 'Gene', (58, 62))
377479	28576884	Surprisingly, p53-null lymphoma cells with CreERT2-mediated Mdm2 deletion showed reduced proliferation compared to vehicle control treated lymphoma cells (Fig.	('proliferation', 'CPA', (89, 102))	('lymphoma', 'Disease', 'MESH:D008223', (139, 147))	('lymphoma', 'Disease', 'MESH:D008223', (23, 31))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('Mdm2', 'Gene', (60, 64))	('lymphoma', 'Phenotype', 'HP:0002665', (23, 31))	('lymphoma', 'Disease', (23, 31))	('reduced', 'NegReg', (81, 88))	('lymphoma', 'Disease', (139, 147))	('deletion', 'Var', (65, 73))
377481	28576884	Within 12 hours of CreERT2 activation, the percentage of cells with fragmented (sub-G1) DNA and that were Annexin-V positive was significantly higher in those that deleted Mdm2, and these differences increased over 48 hours (Fig.	('deleted', 'Var', (164, 171))	('Annexin-V', 'Gene', '11747', (106, 115))	('Annexin-V', 'Gene', (106, 115))	('higher', 'PosReg', (143, 149))	('Mdm2', 'Gene', (172, 176))	('CreERT2', 'Gene', (19, 26))
377484	28576884	Interestingly, there were significantly more cells in the G2/M phase of the cell cycle 12 hours following CreERT2 activation in the Mdm2fl/flp53-/- lymphoma cells, indicating cell cycle arrest may be occurring (Fig.	('cells in', 'CPA', (45, 53))	('activation', 'PosReg', (114, 124))	('more', 'PosReg', (40, 44))	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('CreERT2', 'Gene', (106, 113))	('Mdm2fl/flp53-/-', 'Var', (132, 147))	('lymphoma', 'Disease', (148, 156))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (175, 192))	('G2/M phase of the cell cycle', 'CPA', (58, 86))	('lymphoma', 'Disease', 'MESH:D008223', (148, 156))	('cell cycle', 'CPA', (175, 185))
377486	28576884	Our data indicate Mdm2 deletion in p53-/- T-cell lymphoma inhibits growth and survival by initiating a G2 cell cycle arrest and apoptosis.	('deletion', 'Var', (23, 31))	('inhibits', 'NegReg', (58, 66))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (42, 57))	('T-cell lymphoma', 'Disease', (42, 57))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (42, 57))	('G2 cell cycle arrest', 'CPA', (103, 123))	('initiating', 'Reg', (90, 100))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (106, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))	('Mdm2', 'Gene', (18, 22))	('apoptosis', 'CPA', (128, 137))	('cell lymphoma', 'Phenotype', 'HP:0012191', (44, 57))
377487	28576884	To test the reproducibility of our results and determine whether the apoptosis and cell cycle arrest observed following Mdm2 deletion was specific to p53-/- T-cell lymphoma, we evaluated a different p53-null cancer.	('cancer', 'Disease', (208, 214))	('cell cycle arrest', 'CPA', (83, 100))	('Mdm2', 'Gene', (120, 124))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (157, 172))	('cell lymphoma', 'Phenotype', 'HP:0012191', (159, 172))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('T-cell lymphoma', 'Disease', (157, 172))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('apoptosis', 'CPA', (69, 78))	('lymphoma', 'Phenotype', 'HP:0002665', (164, 172))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('deletion', 'Var', (125, 133))
377490	28576884	Consistent with this, the Mdm2-deleted sarcoma cells showed reduced cell number (Fig.	('cell number', 'CPA', (68, 79))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('Mdm2-deleted', 'Var', (26, 38))	('reduced', 'NegReg', (60, 67))	('sarcoma', 'Disease', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))
377493	28576884	Thus, apoptosis of the sarcoma cells was occurring upon Mdm2 deletion.	('deletion', 'Var', (61, 69))	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('sarcoma', 'Disease', (23, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('Mdm2', 'Gene', (56, 60))
377495	28576884	Analysis of phosphorylated histone H3 showed no difference in the percentage of cells in M phase between control and CreERT2 activated sarcomas, indicating the increase of cells in G2/M is likely due to a G2 cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (208, 225))	('sarcomas', 'Disease', 'MESH:D012509', (135, 143))	('increase', 'PosReg', (160, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('G2/M', 'Var', (181, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('sarcomas', 'Disease', (135, 143))
377496	28576884	Therefore, when Mdm2 was deleted in either p53-/- sarcoma or lymphoma cells, growth and survival are greatly diminished by a combination of apoptosis and G2 cell cycle arrest.	('G2 cell cycle arrest', 'CPA', (154, 174))	('Mdm2', 'Gene', (16, 20))	('diminished', 'NegReg', (109, 119))	('lymphoma', 'Disease', 'MESH:D008223', (61, 69))	('deleted', 'Var', (25, 32))	('apoptosis', 'CPA', (140, 149))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (157, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('lymphoma', 'Disease', (61, 69))
377497	28576884	To test whether Mdm2 deletion would impact p53-null tumor growth in vivo, we injected CreERT2 expressing Mdm2fl/flp53-/- T-cell lymphoma cells subcutaneously into nude mice.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cell lymphoma', 'Phenotype', 'HP:0012191', (123, 136))	('impact', 'Reg', (36, 42))	('nude mice', 'Species', '10090', (163, 172))	('Mdm2', 'Gene', (16, 20))	('tumor', 'Disease', (52, 57))	('deletion', 'Var', (21, 29))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (121, 136))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (121, 136))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('T-cell lymphoma', 'Disease', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
377507	28576884	Therefore, deletion of Mdm2 in p53-/- lymphoma in vivo causes an increase in cells in G2/M and apoptosis, dramatically diminishing their growth and prolonging survival of the mice.	('increase', 'PosReg', (65, 73))	('mice', 'Species', '10090', (175, 179))	('Mdm2', 'Gene', (23, 27))	('cells in G2/M', 'CPA', (77, 90))	('lymphoma', 'Disease', (38, 46))	('apoptosis', 'CPA', (95, 104))	('growth', 'MPA', (137, 143))	('prolonging', 'PosReg', (148, 158))	('survival', 'CPA', (159, 167))	('lymphoma', 'Disease', 'MESH:D008223', (38, 46))	('lymphoma', 'Phenotype', 'HP:0002665', (38, 46))	('deletion', 'Var', (11, 19))	('diminishing', 'NegReg', (119, 130))
377508	28576884	We next evaluated Mdm2 deletion in Mdm2fl/flp53-/- sarcoma cells in vivo.	('sarcoma', 'Disease', (51, 58))	('deletion', 'Var', (23, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('Mdm2', 'Gene', (18, 22))
377509	28576884	CreERT2 expressing Mdm2fl/flp53-/- sarcoma cells were injected subcutaneously into nude mice and tamoxifen or corn oil vehicle control was administered.	('corn', 'Species', '4577', (110, 114))	('sarcoma', 'Disease', (35, 42))	('CreERT2', 'Gene', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('Mdm2fl/flp53-/-', 'Var', (19, 34))	('tamoxifen', 'Chemical', 'MESH:D013629', (97, 106))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('nude mice', 'Species', '10090', (83, 92))
377510	28576884	Survival was significantly extended in mice administered tamoxifen to induce Mdm2 deletion (Fig.	('tamoxifen', 'Chemical', 'MESH:D013629', (57, 66))	('Mdm2', 'Gene', (77, 81))	('Survival', 'CPA', (0, 8))	('deletion', 'Var', (82, 90))	('extended', 'PosReg', (27, 35))	('mice', 'Species', '10090', (39, 43))
377513	28576884	In mice that received tamoxifen to delete Mdm2, there were significantly more sarcoma cells that were Annexin-V positive (Fig.	('delete', 'Var', (35, 41))	('tamoxifen', 'Chemical', 'MESH:D013629', (22, 31))	('mice', 'Species', '10090', (3, 7))	('Annexin-V', 'Gene', (102, 111))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('Annexin-V', 'Gene', '11747', (102, 111))	('sarcoma', 'Disease', (78, 85))	('Mdm2', 'Gene', (42, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))
377515	28576884	However, the sarcoma tumors that developed in the mice receiving tamoxifen in Figure 4A retained Mdm2 (Fig.	('sarcoma tumors', 'Disease', 'MESH:D012509', (13, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Mdm2', 'Var', (97, 101))	('tamoxifen', 'Chemical', 'MESH:D013629', (65, 74))	('mice', 'Species', '10090', (50, 54))	('sarcoma tumors', 'Disease', (13, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
377516	28576884	Our data show that similar to p53-null lymphoma, loss of Mdm2 in p53-/- sarcoma cells induces apoptosis and significantly inhibits tumor cell growth in vitro and in vivo.	('lymphoma', 'Disease', (39, 47))	('sarcoma', 'Disease', (72, 79))	('lymphoma', 'Disease', 'MESH:D008223', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('inhibits', 'NegReg', (122, 130))	('Mdm2', 'Gene', (57, 61))	('loss', 'Var', (49, 53))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('induces', 'Reg', (86, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('tumor', 'Disease', (131, 136))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('apoptosis', 'CPA', (94, 103))
377518	28576884	To determine whether the effects of Mdm2 loss extended to non-cancerous cells, we evaluated deletion of Mdm2 in p53-/- adult mouse fibroblasts.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mouse', 'Species', '10090', (125, 130))	('deletion', 'Var', (92, 100))	('Mdm2', 'Gene', (104, 108))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
377520	28576884	Interestingly, as with the cancer cells, the immortalized p53-null fibroblasts had increased cell numbers in G2 after Mdm2 deletion (Fig.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cell numbers in G2', 'CPA', (93, 111))	('increased', 'PosReg', (83, 92))	('deletion', 'Var', (123, 131))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('Mdm2', 'Gene', (118, 122))
377521	28576884	Following CreERT2 activation to delete Mdm2 in the lymphoma cells, the pro-apoptotic Bcl-2 family members, Bax and Puma, were significantly elevated, whereas Noxa, also a pro-apoptotic Bcl-2 family member remained undetectable (Fig.	('Bcl-2', 'Gene', '12043', (185, 190))	('Mdm2', 'Gene', (39, 43))	('delete', 'Var', (32, 38))	('lymphoma', 'Disease', (51, 59))	('Bax', 'Gene', '12028', (107, 110))	('lymphoma', 'Disease', 'MESH:D008223', (51, 59))	('Puma', 'MPA', (115, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (51, 59))	('elevated', 'PosReg', (140, 148))	('Bcl-2', 'Gene', (85, 90))	('Bcl-2', 'Gene', '12043', (85, 90))	('Bax', 'Gene', (107, 110))	('Bcl-2', 'Gene', (185, 190))
377522	28576884	Mdm2 deletion in p53-/- sarcoma significantly elevated levels of Bax, Noxa, Puma, and p21 (Fig.	('deletion', 'Var', (5, 13))	('elevated', 'PosReg', (46, 54))	('sarcoma', 'Disease', (24, 31))	('Noxa', 'MPA', (70, 74))	('Bax', 'Gene', '12028', (65, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('p21', 'MPA', (86, 89))	('Mdm2', 'Gene', (0, 4))	('Puma', 'MPA', (76, 80))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('Bax', 'Gene', (65, 68))
377523	28576884	Our data show Mdm2 deletion in p53-/- lymphoma, sarcoma, and pre-cancerous fibroblasts decreased growth and survival, consistent with the upregulation of pro-apoptotic and cell cycle arrest genes known to be transcriptionally regulated by p53.	('upregulation', 'PosReg', (138, 150))	('decreased growth', 'Phenotype', 'HP:0001510', (87, 103))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (172, 189))	('decreased', 'NegReg', (87, 96))	('lymphoma', 'Disease', (38, 46))	('deletion', 'Var', (19, 27))	('sarcoma', 'Disease', (48, 55))	('cell cycle', 'CPA', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('Mdm2', 'Gene', (14, 18))	('lymphoma', 'Disease', 'MESH:D008223', (38, 46))	('lymphoma', 'Phenotype', 'HP:0002665', (38, 46))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('sarcoma', 'Disease', 'MESH:D012509', (48, 55))
377524	28576884	Following CreERT2 activation to delete Mdm2 in the sarcoma cells (Fig.	('sarcoma', 'Disease', (51, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('Mdm2', 'Gene', (39, 43))	('delete', 'Var', (32, 38))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))
377525	28576884	Additionally, after CreERT2 activation, cleaved PARP was absent in the sarcoma cells with p73 knockdown, but present in the non-targeting shRNA controls (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('cleaved', 'MPA', (40, 47))	('p73 knockdown', 'Var', (90, 103))	('PARP', 'Gene', (48, 52))	('PARP', 'Gene', '11545', (48, 52))	('sarcoma', 'Disease', (71, 78))	('absent', 'NegReg', (57, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))
377526	28576884	Evaluation of Bax, Noxa, Puma, and p21 mRNA levels showed that following p73 knockdown, Mdm2 deletion did not increase these mRNA, whereas the cells with non-targeting shRNA were upregulated (Fig.	('Bax', 'Gene', '12028', (14, 17))	('Mdm2', 'Gene', (88, 92))	('upregulated', 'PosReg', (179, 190))	('Bax', 'Gene', (14, 17))	('deletion', 'Var', (93, 101))
377528	28576884	We evaluated Nutlin-3 treatment of Mdm2fl/fp53-/- sarcoma cells to determine whether the effects of inhibiting Mdm2 interaction with p53 family members pharmacologically were analogous to deleting Mdm2.	('deleting', 'Var', (188, 196))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('Nutlin-3', 'Chemical', 'MESH:C482205', (13, 21))	('sarcoma', 'Disease', (50, 57))	('inhibiting', 'NegReg', (100, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('Mdm2', 'Gene', (111, 115))	('interaction', 'Interaction', (116, 127))
377540	28576884	In contrast, 14-3-3-sigma, Gadd45a, and p21 were significantly increased following deletion of Mdm2 (Fig.	('increased', 'PosReg', (63, 72))	('p21', 'MPA', (40, 43))	('Gadd45a', 'Gene', '13197', (27, 34))	('Gadd45a', 'Gene', (27, 34))	('Mdm2', 'Gene', (95, 99))	('14-3-3-sigma', 'MPA', (13, 25))	('deletion', 'Var', (83, 91))
377541	28576884	Our results indicate Mdm2 deletion in p53-/- cells inhibits proliferation and induces apoptosis, which is distinct from blocking Mdm2 from binding p53 family members with Nutlin-3, leading to increased levels of Mdm2 and cell cycle arrest.	('levels of Mdm2', 'MPA', (202, 216))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (221, 238))	('induces', 'Reg', (78, 85))	('inhibits', 'NegReg', (51, 59))	('Mdm2', 'Gene', (21, 25))	('deletion', 'Var', (26, 34))	('Nutlin-3', 'Chemical', 'MESH:C482205', (171, 179))	('cell cycle arrest', 'CPA', (221, 238))	('proliferation', 'CPA', (60, 73))	('apoptosis', 'CPA', (86, 95))	('increased', 'PosReg', (192, 201))
377542	28576884	While inhibiting Mdm2 interaction with p53 family members in p53 wild-type containing tumors is being clinically pursued, evidence indicates that resistance develops through p53 inactivation.	('inactivation', 'Var', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('p53', 'Gene', (174, 177))
377543	28576884	Additionally, many human cancers present with p53 deletions.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('p53', 'Gene', (46, 49))	('present', 'Reg', (33, 40))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('human', 'Species', '9606', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('deletions', 'Var', (50, 59))
377544	28576884	Therefore, better treatment options are needed for patients with p53-null cancers.	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('p53-null', 'Var', (65, 73))	('cancers', 'Disease', (74, 81))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
377549	28576884	Numerous studies show that when wild-type p53 is present, loss of Mdm2 induces a p53-dependent death, leading to the belief that Mdm2 is unnecessary if p53 is inactivated.	('death', 'Disease', 'MESH:D003643', (95, 100))	('loss', 'Var', (58, 62))	('death', 'Disease', (95, 100))	('Mdm2', 'Gene', (66, 70))	('induces', 'Reg', (71, 78))
377550	28576884	This was not just evident in primary cell culture, as our in vivo experiments showed that while Mdm2 protein was lost initially after receiving tamoxifen to activate CreERT2 and delete Mdm2, Mdm2 was detectable at levels similar to vehicle treated controls in the tumors that ultimately emerged.	('lost', 'NegReg', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('activate', 'PosReg', (157, 165))	('tamoxifen', 'Chemical', 'MESH:D013629', (144, 153))	('protein', 'Protein', (101, 108))	('Mdm2', 'Gene', (96, 100))	('CreERT2', 'Gene', (166, 173))	('tumors', 'Disease', (264, 270))	('Mdm2', 'Gene', (185, 189))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('delete', 'Var', (178, 184))
377553	28576884	These results are in contrast to an in vivo study showing induced deletion of Mdm2 in multiple tissues of p53-/- mice did not cause tissue defects or lethality of the mice.	('mice', 'Species', '10090', (113, 117))	('Mdm2', 'Gene', (78, 82))	('mice', 'Species', '10090', (167, 171))	('deletion', 'Var', (66, 74))
377556	28576884	p73 is rarely inactivated in human cancers, in contrast with the high frequency of p53 mutation or deletion.	('p73', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('human', 'Species', '9606', (29, 34))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
377560	28576884	Here, we show that Mdm2 loss induces apoptosis and G2 cell cycle arrest in p53-null cancer cells and that loss of p73 was sufficient to rescue these effects, indicating that p73 mediates the negative consequences of Mdm2 deletion when p53 is absent.	('deletion', 'Var', (221, 229))	('Mdm2', 'Gene', (19, 23))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('apoptosis', 'CPA', (37, 46))	('cancer', 'Disease', (84, 90))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('Mdm2', 'Gene', (216, 220))	('G2 cell cycle arrest', 'CPA', (51, 71))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('loss', 'NegReg', (24, 28))	('loss', 'Var', (106, 110))
377561	28576884	Our data indicate p73 functionally replaced p53 in p53-null cancer cells and mature fibroblasts and consequently, p73 was stabilized and activated upon Mdm2 deletion.	('Mdm2', 'Gene', (152, 156))	('p73', 'Var', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('deletion', 'Var', (157, 165))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
377565	28576884	Consistent with this report, we observed the standard 10muM of Nutlin-3 as well as 20muM had no effect, but 30muM induced a G1 cell cycle arrest of p53-null sarcoma cells.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (127, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('G1 cell cycle arrest', 'CPA', (124, 144))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('30muM', 'Var', (108, 113))	('Nutlin-3', 'Chemical', 'MESH:C482205', (63, 71))	('induced', 'Reg', (114, 121))	('sarcoma', 'Disease', (157, 164))
377566	28576884	In contrast to blocking p53 family members from binding Mdm2, Mdm2 deletion induced a G2 arrest and apoptosis in p53-null cancer cells, indicating different mechanisms or different target genes involved.	('cancer', 'Disease', (122, 128))	('deletion', 'Var', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Mdm2', 'Gene', (62, 66))	('G2 arrest', 'CPA', (86, 95))	('apoptosis', 'CPA', (100, 109))	('induced', 'Reg', (76, 83))
377567	28576884	We detected differences in the target genes induced by Nutlin-3 and Mdm2 deletion that explain these different outcomes.	('Nutlin-3', 'Gene', (55, 63))	('deletion', 'Var', (73, 81))	('Nutlin-3', 'Chemical', 'MESH:C482205', (55, 63))	('Mdm2', 'Gene', (68, 72))
377601	28346375	Non-PEGylated liposome (NPL) is a unique drug-delivery system that came as a breakthrough in cancer therapy by offering the benefits of PEGylated-liposome while eliminating the side effects associated with PEG such as hand-foot syndrome (HFS).	('cancer', 'Disease', (93, 99))	('hand-foot syndrome', 'Disease', (218, 236))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (218, 236))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('HFS', 'Disease', 'MESH:D057770', (238, 241))	('PEGylated-liposome', 'Var', (136, 154))	('PEG', 'Chemical', 'MESH:D011092', (136, 139))	('PEG', 'Chemical', 'MESH:D011092', (4, 7))	('eliminating', 'NegReg', (161, 172))	('HFS', 'Disease', (238, 241))	('PEG', 'Chemical', 'MESH:D011092', (206, 209))
377603	28346375	NPLD not only reduces the cardiac toxicity associated with DOX, but also the dose-limiting toxicity linked with the use of Doxil , such as HFS.	('NPLD', 'Var', (0, 4))	('DOX', 'Chemical', 'MESH:D004317', (59, 62))	('HFS', 'Disease', (139, 142))	('reduces', 'NegReg', (14, 21))	('Doxil', 'Chemical', 'MESH:C506643', (123, 128))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))	('toxicity', 'Disease', (34, 42))	('cardiac toxicity', 'Disease', 'MESH:D066126', (26, 42))	('cardiac toxicity', 'Disease', (26, 42))	('toxicity', 'Disease', 'MESH:D064420', (91, 99))	('toxicity', 'Disease', (91, 99))	('HFS', 'Disease', 'MESH:D057770', (139, 142))
377682	28346375	The study demonstrated reduced myelosuppression and gastrointestinal adverse effects due to Myocet  as compared with free DOX.	('DOX', 'Chemical', 'MESH:D004317', (122, 125))	('gastrointestinal adverse', 'Disease', (52, 76))	('Myocet', 'Var', (92, 98))	('gastrointestinal adverse', 'Disease', 'MESH:D005767', (52, 76))	('free', 'Chemical', '-', (117, 121))	('myelosuppression', 'Disease', 'MESH:D001855', (31, 47))	('myelosuppression', 'Disease', (31, 47))	('reduced', 'NegReg', (23, 30))
377693	28346375	The anti-osteosarcoma effects produced by MFT in vivo are due to an immune response against osteosarcoma lung metastases, even though the drug showed no cytotoxicity towards normal or tumour cells in vitro.	('osteosarcoma', 'Disease', 'MESH:D012516', (92, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('cytotoxicity', 'Disease', 'MESH:D064420', (153, 165))	('osteosarcoma lung metastases', 'Disease', 'MESH:D009362', (92, 120))	('osteosarcoma', 'Phenotype', 'HP:0002669', (92, 104))	('MFT', 'Chemical', 'MESH:C037144', (42, 45))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcoma lung metastases', 'Disease', (92, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumour', 'Disease', (184, 190))	('osteosarcoma', 'Disease', (9, 21))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('osteosarcoma', 'Disease', (92, 104))	('MFT', 'Var', (42, 45))	('cytotoxicity', 'Disease', (153, 165))
377696	28346375	The results showed that single MFT at a single 4 mg dose can be safely given to healthy adult volunteers and that pharmacokinetic variability is less for MFT [the coefficient of variation (% CV) in both the AUC and the maximal concentration (Cmax) was less than 30%].	('less', 'NegReg', (145, 149))	('AUC', 'MPA', (207, 210))	('MFT', 'Chemical', 'MESH:C037144', (31, 34))	('MFT', 'Var', (154, 157))	('pharmacokinetic variability', 'MPA', (114, 141))	('MFT', 'Chemical', 'MESH:C037144', (154, 157))
377720	28346375	In another study patients who consumed fluorouracil/leucovorin with Onivyde  had an average delay of 3.1 months in the amount of time required for tumour progression compared with 1.5 months for those who consumed either fluorouracil or leucovorin.	('fluorouracil', 'Chemical', 'MESH:D005472', (221, 233))	('Onivyde', 'Chemical', 'MESH:D000077146', (68, 75))	('leucovorin', 'Chemical', 'MESH:D002955', (237, 247))	('fluorouracil', 'Chemical', 'MESH:D005472', (39, 51))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('leucovorin', 'Chemical', 'MESH:D002955', (52, 62))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('patients', 'Species', '9606', (17, 25))	('tumour', 'Disease', (147, 153))	('fluorouracil/leucovorin', 'Var', (39, 62))
377768	28346375	Biodistribution studies for liposomal VPF and aqueous VPF showed slightly higher accumulation of VPF in tumour tissue with liposomal VPF than with aqueous VPF.	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('VPF', 'Protein', (97, 100))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('liposomal', 'Var', (123, 132))	('tumour', 'Disease', (104, 110))	('accumulation', 'PosReg', (81, 93))
377795	28346375	A phase II multi-centre clinical trial confirmed the 7-fold increase in tmax in the liposomal bupivacaine group compared with the plain bupivacaine group, which was attributed to the sustained release of liposomal bupivacaine.	('tmax', 'MPA', (72, 76))	('liposomal bupivacaine', 'Var', (84, 105))	('increase', 'PosReg', (60, 68))	('bupivacaine', 'Chemical', 'MESH:D002045', (94, 105))	('bupivacaine', 'Chemical', 'MESH:D002045', (214, 225))	('bupivacaine', 'Chemical', 'MESH:D002045', (136, 147))
377822	28346375	Transave Inc. got merged with Insmed Inc. in 2010 and the combined company filed for its orphan status with FDA and European Medicines Agency in 2011 for lung infections due to non-TB Mycobacteria (NTM).	('lung infections', 'Disease', 'MESH:D008171', (154, 169))	('lung infections', 'Disease', (154, 169))	('non-TB', 'Var', (177, 183))	('lung infections', 'Phenotype', 'HP:0006532', (154, 169))
377852	28346375	Upon administration of T4N5 lotion, T4-bacteriophage endonuclease V, a DNA repair enzyme, makes its entry into dermal cells.	('entry into dermal', 'MPA', (100, 117))	('bacteriophage', 'Species', '38018', (39, 52))	('T4-bacteriophage', 'Var', (36, 52))
377853	28346375	T4N5 then enters cell nuclei, where it attaches and incises pyrimidine dimers, which leads to catalysis of the first step of the cellular excision repair pathway.	('leads to', 'Reg', (85, 93))	('T4N5', 'Var', (0, 4))	('pyrimidine', 'Chemical', 'MESH:C030986', (60, 70))	('pyrimidine dimers', 'MPA', (60, 77))	('attaches', 'Interaction', (39, 47))	('incises', 'NegReg', (52, 59))	('catalysis', 'MPA', (94, 103))
377873	28346375	The addition of MSPC to the composition accelerates drug release by a slight reduction in the transition temperature of DPPC, while DSPE-PEG-2000 enhances the circulation time of liposomes.	('enhances', 'PosReg', (146, 154))	('accelerates', 'PosReg', (40, 51))	('DSPE-PEG-2000', 'Var', (132, 145))	('DSPE-PEG-2000', 'Chemical', '-', (132, 145))	('transition temperature of DPPC', 'MPA', (94, 124))	('reduction', 'NegReg', (77, 86))	('drug release', 'MPA', (52, 64))	('MSPC', 'Chemical', '-', (16, 20))	('circulation time of liposomes', 'MPA', (159, 188))	('DPPC', 'Chemical', 'MESH:D015060', (120, 124))
377891	28346375	Lipoplatin  has considerably reduced the adverse effects associated with CPT including renal toxicity, peripheral neuropathy, ototoxicity and myelotoxicity.	('Lipoplatin', 'Var', (0, 10))	('renal toxicity', 'Disease', 'MESH:D007674', (87, 101))	('reduced', 'NegReg', (29, 36))	('peripheral neuropathy', 'Disease', (103, 124))	('CPT', 'Chemical', 'MESH:D002945', (73, 76))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (103, 124))	('ototoxicity and myelotoxicity', 'Disease', 'MESH:D006311', (126, 155))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (103, 124))	('renal toxicity', 'Disease', (87, 101))
377931	28346375	CKD-602 is a semi-synthetic analogue of camptothecin, which, when encapsulated into liposomes, increased the AUC 50-fold compared to non-liposomal CKD-602.	('AUC', 'MPA', (109, 112))	('increased', 'PosReg', (95, 104))	('camptothecin', 'Chemical', 'MESH:D002166', (40, 52))	('CKD-602', 'Var', (0, 7))
377934	28346375	S-CKD602, presently under phase II trial investigation, exhibited an interesting property of greater distribution in fat compared to muscle tissue, which varies according to the body composition of a patient.	('distribution in fat', 'MPA', (101, 120))	('greater', 'PosReg', (93, 100))	('patient', 'Species', '9606', (200, 207))	('S-CKD602', 'Var', (0, 8))
377969	28346375	Overexpression of the Grb2 protein and amplification of the GRB2 gene have been reported in human cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('GRB2', 'Gene', (60, 64))	('amplification', 'Var', (39, 52))	('Grb2', 'Gene', '2885', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('GRB2', 'Gene', '2885', (60, 64))	('human', 'Species', '9606', (92, 97))	('Grb2', 'Gene', (22, 26))
377983	28346375	Other products currently in phase I/II include PLK1 siRNA (TKM-080301) indicated for neuroendocrine tumours, PKN3 siRNA (Atu027) for pancreatic cancer and DOX (2B3-101) for solid tumours.	('PKN3', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('DOX', 'Chemical', 'MESH:D004317', (155, 158))	('solid tumours', 'Disease', 'MESH:D009369', (173, 186))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('PLK1', 'Gene', (47, 51))	('solid tumours', 'Disease', (173, 186))	('pancreatic cancer', 'Disease', (133, 150))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('neuroendocrine tumours', 'Disease', 'MESH:D018358', (85, 107))	('PLK1', 'Gene', '5347', (47, 51))	('PKN3', 'Gene', '29941', (109, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (133, 150))	('neuroendocrine tumours', 'Disease', (85, 107))	('TKM-080301', 'Var', (59, 69))
377984	28346375	TKM 080301 is a stable nucleic acid lipid particle (SNALP)-encapsulated siRNA targeting PLK1.	('PLK1', 'Gene', '5347', (88, 92))	('TKM 080301', 'Var', (0, 10))	('PLK1', 'Gene', (88, 92))	('lipid', 'Chemical', 'MESH:D008055', (36, 41))
377986	28346375	Inhibition of PLK1 expression prevents tumour cell growth and thereby inhibits cancer cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Disease', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('inhibits', 'NegReg', (70, 78))	('prevents', 'NegReg', (30, 38))	('Inhibition', 'Var', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('PLK1', 'Gene', (14, 18))	('PLK1', 'Gene', '5347', (14, 18))
377995	28346375	This product is developed based on glutathione PEGylation, where glutathione enhances the delivery of encapsulated moiety across the BBB.	('enhances', 'PosReg', (77, 85))	('glutathione', 'Chemical', 'MESH:D005978', (65, 76))	('glutathione', 'Chemical', 'MESH:D005978', (35, 46))	('delivery of encapsulated moiety across the BBB', 'MPA', (90, 136))	('PEG', 'Chemical', 'MESH:D011092', (47, 50))	('glutathione', 'Var', (65, 76))
378007	27486986	Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death.	('Sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('p53', 'Gene', (16, 19))	('cancers', 'Disease', (84, 91))	('Sarcomas', 'Disease', (50, 58))	('p53', 'Gene', '7157', (16, 19))	('Sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('Bone Sarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('Bone Sarcomas', 'Phenotype', 'HP:0002669', (45, 58))	('mutated', 'Var', (34, 41))
378008	27486986	Here, we demonstrate for the first time that TAp73beta, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'.	("Sarcomas'", 'Disease', 'MESH:D012509', (131, 140))	("Sarcomas'", 'Disease', (131, 140))	('Sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('implicated', 'Reg', (81, 91))	('TAp73beta', 'Chemical', '-', (45, 54))	('Cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('Bone Sarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('Bone Sarcomas', 'Phenotype', 'HP:0002669', (126, 139))	('TAp73beta', 'Var', (45, 54))	('Sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
378017	27486986	In 85% of the cases, Ewing Sarcoma is outlined by the chromosomal translocations t(11;22)(q24;12), giving rise to the chimeric transcription factor EWS-Fli1, whose the oncogenic features are well documented.	('Sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('Fli1', 'Gene', (152, 156))	('EWS', 'Gene', '2130', (148, 151))	('EWS', 'Gene', (148, 151))	('t(11', 'Var', (81, 85))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('Ewing Sarcoma', 'Disease', (21, 34))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (21, 34))	('Fli1', 'Gene', '2313', (152, 156))
378029	27486986	It is thus noteworthy that the expression of P73 modulates chemosensitivity of several cancer types.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('P73', 'Gene', '7161', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('modulates', 'Reg', (49, 58))	('P73', 'Gene', (45, 48))	('expression', 'Var', (31, 41))
378035	27486986	Additionally, we also demonstrated that through modulating the expression of TAp73beta, the miR-193a-5p was a key component of an endogenous Cisplatin-chemoresistance mechanism.	('TAp73beta', 'Var', (77, 86))	('modulating', 'Reg', (48, 58))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('expression', 'MPA', (63, 73))	('TAp73beta', 'Chemical', '-', (77, 86))	('Cisplatin', 'Chemical', 'MESH:D002945', (141, 150))
378037	27486986	We observed that inhibiting TAp73beta reduces the caspase activity and increases both the clonogenic features and the cell's Cisplatin-resistance.	('Cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('caspase', 'Enzyme', (50, 57))	('activity', 'MPA', (58, 66))	('inhibiting', 'Var', (17, 27))	('reduces', 'NegReg', (38, 45))	('TAp73beta', 'Chemical', '-', (28, 37))	('clonogenic features', 'CPA', (90, 109))	('increases', 'PosReg', (71, 80))	('TAp73beta', 'Protein', (28, 37))	('Cisplatin-resistance', 'MPA', (125, 145))
378040	27486986	To directly assess the relevance of studying the TAp73beta/miR-193a-5p axis in the drugs-resistance mechanisms of Bone Sarcomas, we first evaluated the expression of TAp73beta at mRNA level and the miR-193a-5p's expression in seven Osteosarcoma cell lines and in seven Ewing Sarcoma cell lines (Figure 1a, 1b).	('miR', 'Gene', (198, 201))	('Osteosarcoma', 'Disease', (232, 244))	('miR', 'Gene', '220972', (59, 62))	('Osteosarcoma', 'Disease', 'MESH:D012516', (232, 244))	('Sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('Sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('miR', 'Gene', (59, 62))	('Ewing Sarcoma', 'Disease', (269, 282))	('Bone Sarcoma', 'Phenotype', 'HP:0002669', (114, 126))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (269, 282))	('Sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (232, 244))	('TAp73beta', 'Chemical', '-', (166, 175))	('TAp73beta', 'Chemical', '-', (49, 58))	('Sarcomas', 'Disease', (119, 127))	('TAp73beta', 'Var', (166, 175))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (269, 282))	('miR', 'Gene', '220972', (198, 201))	('Bone Sarcomas', 'Phenotype', 'HP:0002669', (114, 127))	('Sarcomas', 'Disease', 'MESH:D012509', (119, 127))
378042	27486986	All the cell lines express TAp73beta except the CAL-72 one, potentially because it is the only Osteosarcoma cell line of our panel displaying a wild-type and functional p53 status (Figure 1a, Supp.	('p53', 'Gene', (169, 172))	('p53', 'Gene', '7157', (169, 172))	('TAp73beta', 'Chemical', '-', (27, 36))	('Osteosarcoma', 'Disease', (95, 107))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (95, 107))	('TAp73beta', 'Var', (27, 36))	('Osteosarcoma', 'Disease', 'MESH:D012516', (95, 107))
378052	27486986	A statistically significant correlation was found between the GI50 and the miR-193a-5p expression level in all the cell lines, reinforcing the hypothesis of the miR-193a-5p's involvement in the Cisplatin-chemoresistance in such model (Figure 1f).	('miR', 'Gene', '220972', (75, 78))	('significant correlation', 'Reg', (16, 39))	('miR', 'Gene', (75, 78))	('expression level', 'MPA', (87, 103))	('Cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('Cisplatin-chemoresistance', 'CPA', (194, 219))	('miR', 'Gene', '220972', (161, 164))	('miR', 'Gene', (161, 164))	('GI50', 'Var', (62, 66))	('involvement', 'Reg', (175, 186))
378053	27486986	In addition, a non-significant higher global average GI50 is observed in the Osteosarcoma compared with the Ewing Sarcoma cells (Figure 1g).	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('Sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('Osteosarcoma', 'Disease', (77, 89))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('Osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('Ewing Sarcoma', 'Disease', (108, 121))	('higher', 'PosReg', (31, 37))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('GI50', 'Var', (53, 57))
378058	27486986	In the RDES cells, we can notice that the Cisplatin induces a down-regulation of the miR-193a-5p from about 82% compared with the non-treated control cells.	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('down-regulation', 'NegReg', (62, 77))	('Cisplatin', 'Var', (42, 51))	('Cisplatin', 'Chemical', 'MESH:D002945', (42, 51))
378071	27486986	These two cell lines display a non-functional p53 protein, weakly express both TAp73beta and the miR-193a-5p and exhibit the same intermediate Cisplatin sensitivity as shown by their equivalent GI50 (Figure 1 and Supp.	('non-functional', 'MPA', (31, 45))	('p53', 'Gene', (46, 49))	('TAp73beta', 'Chemical', '-', (79, 88))	('Cisplatin sensitivity', 'MPA', (143, 164))	('TAp73beta', 'Var', (79, 88))	('p53', 'Gene', '7157', (46, 49))	('Cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))
378081	27486986	Taking together, these results argue for the anti-apoptotic role of the miR-193a-5p, through its TAp73beta's targeting capabilities and strongly support its implication in the Cisplatin-chemoresistance in this model.	('miR', 'Gene', (72, 75))	('TAp73beta', 'Chemical', '-', (97, 106))	('targeting capabilities', 'MPA', (109, 131))	('TAp73beta', 'Var', (97, 106))	('anti-apoptotic', 'CPA', (45, 59))	('miR', 'Gene', '220972', (72, 75))	('Cisplatin', 'Chemical', 'MESH:D002945', (176, 185))
378085	27486986	The efficiency of the transfection was validated by qRT-PCR, as the expression of TAp73beta was about five thousand times more elevated in the TAp73beta-transfected cells than in the control ones (Figure 5a left panel).	('TAp73beta-transfected', 'Var', (143, 164))	('TAp73beta', 'Chemical', '-', (143, 152))	('expression', 'MPA', (68, 78))	('TAp73beta', 'Gene', (82, 91))	('elevated', 'PosReg', (127, 135))	('TAp73beta', 'Chemical', '-', (82, 91))
378087	27486986	Moreover, increasing the expression of TAp73beta markedly improve the Cisplatin-induced caspase 3/7 activity (Figure 5c).	('TAp73beta', 'Var', (39, 48))	('Cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('improve', 'PosReg', (58, 65))	('expression', 'MPA', (25, 35))	('Cisplatin-induced', 'MPA', (70, 87))	('caspase 3', 'Gene', (88, 97))	('caspase 3', 'Gene', '836', (88, 97))	('increasing', 'PosReg', (10, 20))	('TAp73beta', 'Chemical', '-', (39, 48))
378106	27486986	Interestingly, we have highlighted that this mechanism occurs both in Osteosarcoma and Ewing Sarcoma, even if the global expression levels of TAp73beta and the miRNA-193a-5p are lower in Ewing Sarcoma (Figure 1a, 1b).	('miR', 'Gene', (160, 163))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('Ewing Sarcoma', 'Disease', (187, 200))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (187, 200))	('lower', 'NegReg', (178, 183))	('Sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('TAp73beta', 'Chemical', '-', (142, 151))	('global expression levels', 'MPA', (114, 138))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (87, 100))	('Sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('Osteosarcoma and Ewing Sarcoma', 'Disease', 'MESH:C563168', (70, 100))	('TAp73beta', 'Var', (142, 151))	('Ewing Sarcoma', 'Disease', (87, 100))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (87, 100))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (187, 200))	('miR', 'Gene', '220972', (160, 163))
378108	27486986	In addition, this difference could also be supported by the fact that human bone marrow mesenchymal stem cells, which are the cells of origin of Ewing Sarcoma, display a silenced-expression of the p73 gene through the hypermethylation of its promoter.	('Sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('silenced-expression', 'NegReg', (170, 189))	('human', 'Species', '9606', (70, 75))	('p73', 'Gene', '7161', (197, 200))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (145, 158))	('p73', 'Gene', (197, 200))	('hypermethylation', 'Var', (218, 234))	('Ewing Sarcoma', 'Disease', (145, 158))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (145, 158))
378114	27486986	As a consequence, the expression of the pro-apoptotic factor TAp73beta and two of its target-genes, p21 and MDM2 are increased (Figure 2 and Supp.	('p21', 'Gene', (100, 103))	('increased', 'PosReg', (117, 126))	('p21', 'Gene', '644914', (100, 103))	('MDM2', 'Gene', '4193', (108, 112))	('TAp73beta', 'Chemical', '-', (61, 70))	('MDM2', 'Gene', (108, 112))	('expression', 'MPA', (22, 32))	('TAp73beta', 'Var', (61, 70))
378115	27486986	Our results are in accordance with a previous work, demonstrating that increasing TAp73beta's expression leads to a rapid and robust up-regulation of p21 in the SaOS2 Osteosarcoma cell line.	('p21', 'Gene', '644914', (150, 153))	('increasing', 'PosReg', (71, 81))	('TAp73beta', 'Var', (82, 91))	('Osteosarcoma', 'Disease', (167, 179))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (167, 179))	('up-regulation', 'PosReg', (133, 146))	('p21', 'Gene', (150, 153))	('Osteosarcoma', 'Disease', 'MESH:D012516', (167, 179))	('TAp73beta', 'Chemical', '-', (82, 91))
378116	27486986	Through overexpression and knockdown experiments, we found that TAp73beta is implicated in the regulation of both the caspase 3/7 activity and the clonogenic capabilities of the Bone Sarcoma cells.	('TAp73beta', 'Chemical', '-', (64, 73))	('TAp73beta', 'Var', (64, 73))	('implicated', 'Reg', (77, 87))	('caspase 3', 'Gene', (118, 127))	('Sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('Bone Sarcoma', 'Phenotype', 'HP:0002669', (178, 190))	('caspase 3', 'Gene', '836', (118, 127))	('clonogenic capabilities of', 'CPA', (147, 173))	('Sarcoma', 'Disease', (183, 190))	('Sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('activity', 'MPA', (130, 138))
378117	27486986	Thus, such involvement in these cellular processes functionally confers to TAp73beta a mediator role in the Cisplatin-induced apoptosis of the Bone Sarcomas.	('TAp73beta', 'Chemical', '-', (75, 84))	('Cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('Sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('TAp73beta', 'Var', (75, 84))	('Sarcomas', 'Disease', (148, 156))	('Sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Bone Sarcomas', 'Phenotype', 'HP:0002669', (143, 156))	('Sarcomas', 'Disease', 'MESH:D012509', (148, 156))	('Bone Sarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('involvement', 'Reg', (11, 22))
378170	31382485	Other aspects of the viral replication cycle, such as DNA replication and viral protein expression, appeared unaffected by UL7 and UL103 mutations.	('DNA replication', 'MPA', (54, 69))	('mutations', 'Var', (137, 146))	('viral protein expression', 'MPA', (74, 98))	('UL7', 'Gene', (123, 126))	('UL103', 'Gene', (131, 136))	('UL103', 'Gene', '3077559', (131, 136))
378171	31382485	Additionally, in alpha- and beta-herpesviruses UL7 and UL103 are consistently found in the tegument, leading to the classification of their homologs as tegument proteins, although the data for gamma-herpesviral virions are less clear.	('UL103', 'Gene', '3077559', (55, 60))	('herpesvirus', 'Species', '39059', (33, 44))	('UL7', 'Var', (47, 50))	('UL103', 'Gene', (55, 60))
378178	31382485	Interestingly, we found that ORF42 mutations reduced the levels of several proteins, including late proteins involved in virion formation.	('reduced', 'NegReg', (45, 52))	('ORF42', 'Gene', (29, 34))	('ORF42', 'Gene', '4961440', (29, 34))	('levels of several proteins', 'MPA', (57, 83))	('mutations', 'Var', (35, 44))
378184	31382485	pCDNA4/TO-ORF42-Flag (used for subcloning ORF42), pCDNA4/TO-C-terminal-Flag, and pJP1_Zeo were kind gifts by Dr. Glaunsinger.	('ORF42', 'Gene', (10, 15))	('ORF42', 'Gene', '4961440', (42, 47))	('ORF42', 'Gene', '4961440', (10, 15))	('pCDNA4/TO-C-terminal-Flag', 'Var', (50, 75))	('ORF42', 'Gene', (42, 47))
378197	31382485	The fragment to carry out the BAC recombination was generated by fusing the 3' end of ORF42 and the Flag sequence to the 5' end of the Kan cassette.	('ORF42', 'Gene', (86, 91))	('ORF42', 'Gene', '4961440', (86, 91))	('fusing', 'Var', (65, 71))
378261	31382485	This mutation should abolish expression of full-length ORF42.	('abolish', 'NegReg', (21, 28))	('ORF42', 'Gene', (55, 60))	('ORF42', 'Gene', '4961440', (55, 60))	('expression', 'MPA', (29, 39))	('mutation', 'Var', (5, 13))
378263	31382485	The sequence alteration we introduced generates a synonymous mutation in the coding sequence of ORF43 (at Valine 585), which overlaps with the 5' end of the ORF42 coding sequence and is not expected to affect ORF43 expression and activity (Figure 1A).	('Valine', 'Chemical', 'MESH:D014633', (106, 112))	('ORF43', 'Gene', (209, 214))	('ORF43', 'Gene', '4961497', (96, 101))	('alteration', 'Var', (13, 23))	('ORF43', 'Gene', (96, 101))	('activity', 'MPA', (230, 238))	('ORF42', 'Gene', (157, 162))	('ORF42', 'Gene', '4961440', (157, 162))	('affect', 'Reg', (202, 208))	('ORF43', 'Gene', '4961497', (209, 214))	('expression', 'MPA', (215, 225))
378264	31382485	We also generated a revertant BAC, ORF42REV, in which the ORF42PTC was mutated back to the wild-type sequence, in order to confirm that the recombineering had not compromised the integrity of the rest of the BAC.	('ORF42', 'Gene', (58, 63))	('ORF42', 'Gene', '4961440', (58, 63))	('ORF42', 'Gene', (35, 40))	('mutated', 'Var', (71, 78))	('ORF42', 'Gene', '4961440', (35, 40))
378272	31382485	To conclusively determine that any observed phenotype really reflected the effect of the ORF42 mutation, rather than variability between cell lines, we decided to include two separate WT KSHV-infected cell lines as reference for most of our experiments.	('KS', 'Phenotype', 'HP:0100726', (187, 189))	('WT KSHV-infected', 'Disease', (184, 200))	('WT KSHV-infected', 'Disease', 'MESH:C537372', (184, 200))	('ORF42', 'Gene', (89, 94))	('ORF42', 'Gene', '4961440', (89, 94))	('mutation', 'Var', (95, 103))
378276	31382485	Since the fold change in ORF57 levels is similar in all infected cells, we conclude that loss of full-length ORF42 did not compromise reactivation of the lytic cycle from latency, and that ORF42 is dispensable for KSHV reactivation from latency.	('loss', 'Var', (89, 93))	('ORF42', 'Gene', '4961440', (189, 194))	('ORF57', 'Gene', '4961525', (25, 30))	('KS', 'Phenotype', 'HP:0100726', (214, 216))	('ORF57', 'Gene', (25, 30))	('KSHV', 'Species', '37296', (214, 218))	('lytic cycle', 'CPA', (154, 165))	('ORF42', 'Gene', (109, 114))	('ORF42', 'Gene', (189, 194))	('ORF42', 'Gene', '4961440', (109, 114))
378288	31382485	In order to confirm the inhibitory effect of the ORF42PTC mutation on viral replication, we examined the ability of full-length ORF42 express from a transgene to complement the KSHV ORF42PTC virus and restore efficient viral production.	('ORF42', 'Gene', (182, 187))	('ORF42', 'Gene', (49, 54))	('ORF42', 'Gene', '4961440', (182, 187))	('ORF42', 'Gene', (128, 133))	('mutation', 'Var', (58, 66))	('ORF42', 'Gene', '4961440', (49, 54))	('ORF42', 'Gene', '4961440', (128, 133))	('restore', 'PosReg', (201, 208))	('KS', 'Phenotype', 'HP:0100726', (177, 179))	('KSHV', 'Species', '37296', (177, 181))	('viral production', 'MPA', (219, 235))
378290	31382485	Rescue of the viral protein in trans is increasingly common in studies of KSHV mutants, to control for potential differences among the stable latently infected lines.	('KSHV', 'Species', '37296', (74, 78))	('KS', 'Phenotype', 'HP:0100726', (74, 76))	('mutants', 'Var', (79, 86))	('KSHV', 'Gene', (74, 78))
378294	31382485	The fact that complementing ORF42 in trans rescues viral production confirms that the virus production defect observed in the ORF42PTC virus is due to a loss of function effect of our ORF42 mutation.	('mutation', 'Var', (190, 198))	('virus production', 'MPA', (86, 102))	('ORF42', 'Gene', '4961440', (126, 131))	('ORF42', 'Gene', (28, 33))	('ORF42', 'Gene', '4961440', (28, 33))	('viral', 'MPA', (51, 56))	('ORF42', 'Gene', (184, 189))	('defect', 'NegReg', (103, 109))	('ORF42', 'Gene', '4961440', (184, 189))	('ORF42', 'Gene', (126, 131))	('loss of function', 'NegReg', (153, 169))
378296	31382485	This result suggests that the C-terminal tag may reduce ORF42 activity, similarly to what has been reported for the cytomegalovirus ORF42 homolog UL103, or alter ORF42 production from the transgene.	('ORF42', 'Gene', (56, 61))	('alter', 'Reg', (156, 161))	('ORF42', 'Gene', (162, 167))	('activity', 'MPA', (62, 70))	('ORF42', 'Gene', (132, 137))	('ORF42', 'Gene', '4961440', (56, 61))	('ORF42', 'Gene', '4961440', (162, 167))	('ORF42', 'Gene', '4961440', (132, 137))	('UL103', 'Gene', (146, 151))	('C-terminal tag', 'Var', (30, 44))	('reduce', 'NegReg', (49, 55))	('UL103', 'Gene', '3077559', (146, 151))
378304	31382485	In particular, DNA replication was not reduced in ORF42PTC-infected cells, suggesting that loss of full-length ORF42 does not impact DNA replication (Figure 2E).	('ORF42', 'Gene', (111, 116))	('DNA replication', 'MPA', (133, 148))	('ORF42', 'Gene', '4961440', (111, 116))	('ORF42', 'Gene', (50, 55))	('loss', 'Var', (91, 95))	('ORF42', 'Gene', '4961440', (50, 55))
378305	31382485	There was an apparent increase in DNA replication in all transgene-rescued cells relative to the KSHV WT-infected cells, although the differences were not statistically significant.	('DNA replication', 'CPA', (34, 49))	('KSHV', 'Species', '37296', (97, 101))	('transgene-rescued', 'Var', (57, 74))	('increase', 'PosReg', (22, 30))	('KS', 'Phenotype', 'HP:0100726', (97, 99))
378308	31382485	Because ORF42 homologs are tegument proteins that could be involved in early stages of de novo infection, loss of full-length ORF42 could reduce particle production, particle infectivity, or both.	('ORF42', 'Gene', '4961440', (126, 131))	('infection', 'Disease', 'MESH:D007239', (95, 104))	('reduce', 'NegReg', (138, 144))	('infection', 'Disease', (95, 104))	('ORF42', 'Gene', (8, 13))	('ORF42', 'Gene', (126, 131))	('particle production', 'CPA', (145, 164))	('ORF42', 'Gene', '4961440', (8, 13))	('loss', 'Var', (106, 110))	('particle infectivity', 'CPA', (166, 186))
378309	31382485	We found that the changes in viral particles mirrored those in infectious titers: KSHV ORF42PTC-infected cells produced lower levels of cell-free viral particles, estimated from viral DNA in the supernatant, and complementation of ORF42 expression in trans abrogated this defect (Figure 2F).	('lower', 'NegReg', (120, 125))	('ORF42', 'Gene', (87, 92))	('complementation', 'Var', (212, 227))	('ORF42', 'Gene', '4961440', (87, 92))	('ORF42', 'Gene', (231, 236))	('ORF42', 'Gene', '4961440', (231, 236))	('KSHV', 'Species', '37296', (82, 86))	('KS', 'Phenotype', 'HP:0100726', (82, 84))	('levels of cell-free viral particles', 'MPA', (126, 161))	('KSHV', 'Var', (82, 86))
378312	31382485	However, we cannot exclude that loss of full-length ORF42 may also impact infectivity in other target cell types, for example more relevant cell types such as endothelial and B cells, especially since we found that ORF42 is present in virions (see Section 3.3).	('impact', 'Reg', (67, 73))	('ORF42', 'Gene', (52, 57))	('infectivity', 'MPA', (74, 85))	('ORF42', 'Gene', '4961440', (52, 57))	('ORF42', 'Gene', (215, 220))	('loss', 'Var', (32, 36))	('ORF42', 'Gene', '4961440', (215, 220))
378314	31382485	The most convincing evidence is that in the absence of PRV UL7, nucleocapsid formation, nuclear egress and budding of capsids into the Golgi appeared normal by electron microscopy, but the release of virions from the cell was severely inhibited.	('budding of capsids into the', 'CPA', (107, 134))	('release of virions from the', 'MPA', (189, 216))	('inhibited', 'NegReg', (235, 244))	('absence', 'Var', (44, 51))	('PRV UL7', 'Gene', (55, 62))	('nucleocapsid formation', 'CPA', (64, 86))	('PRV', 'Species', '10345', (55, 58))	('nuclear egress', 'CPA', (88, 102))
378317	31382485	Based on these results, it is unclear whether virion release is affected by ORF42 mutations.	('virion release', 'MPA', (46, 60))	('mutations', 'Var', (82, 91))	('ORF42', 'Gene', (76, 81))	('ORF42', 'Gene', '4961440', (76, 81))
378319	31382485	Collectively, our initial characterization of the ORF42 mutant KSHV reveals that full-length ORF42 is essential for wild-type levels of virion production but does not affect reactivation of the lytic cycle or viral DNA replication.	('ORF42', 'Gene', (93, 98))	('KSHV', 'Species', '37296', (63, 67))	('ORF42', 'Gene', '4961440', (93, 98))	('mutant', 'Var', (56, 62))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('ORF42', 'Gene', (50, 55))	('ORF42', 'Gene', '4961440', (50, 55))
378320	31382485	To characterize the localization and the temporal expression of ORF42 in the context of the lytic replication cycle, we also made a KSHV BAC16 variant that expresses a C-terminally Flag-tagged version of ORF42 from the viral genome (KSHV ORF42-Flag) (Figure 3A).	('KS', 'Phenotype', 'HP:0100726', (233, 235))	('KSHV BAC16', 'Gene', (132, 142))	('KSHV', 'Species', '37296', (233, 237))	('ORF42', 'Gene', (204, 209))	('KSHV', 'Species', '37296', (132, 136))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('variant', 'Var', (143, 150))	('ORF42', 'Gene', (238, 243))	('ORF42', 'Gene', '4961440', (204, 209))	('ORF42', 'Gene', '4961440', (238, 243))	('ORF42', 'Gene', (64, 69))	('ORF42', 'Gene', '4961440', (64, 69))
378328	31382485	This is important to note, because the organization of the ORF42 genomic locus and the presence of in-frame methionines at position 59 and 62 of ORF42 would potentially allow for the production of additional shorter isoforms of ORF42, for example from the ORF43/ORF42 bicistronic transcript that is used to produce ORF43.	('ORF42', 'Gene', (262, 267))	('presence', 'Var', (87, 95))	('ORF43', 'Gene', (256, 261))	('ORF43', 'Gene', (315, 320))	('ORF42', 'Gene', '4961440', (228, 233))	('ORF42', 'Gene', (145, 150))	('methionines', 'Chemical', 'MESH:D008715', (108, 119))	('ORF42', 'Gene', '4961440', (145, 150))	('ORF42', 'Gene', '4961440', (262, 267))	('ORF42', 'Gene', '4961440', (59, 64))	('ORF42', 'Gene', (228, 233))	('ORF43', 'Gene', '4961497', (256, 261))	('ORF43', 'Gene', '4961497', (315, 320))	('ORF42', 'Gene', (59, 64))
378329	31382485	However, the absence of additional bands in the Western blot suggests that shorter isoforms are not produced at any appreciable rate, at least in the absence of any mutations in the ORF42 coding sequence.	('ORF42', 'Gene', '4961440', (182, 187))	('ORF42', 'Gene', (182, 187))	('mutations', 'Var', (165, 174))
378348	31382485	At Day 6, we again found that, while almost all the proteins tested were produced at lower levels in cells infected with KSHV ORF42PTC, there was a more dramatic effect on the late proteins K8.1, ORF26 and ORF33 (Figure 4A,B, Table 2).	('ORF42', 'Gene', '4961440', (126, 131))	('KS', 'Phenotype', 'HP:0100726', (121, 123))	('KSHV', 'Species', '37296', (121, 125))	('K8.1', 'Var', (190, 194))	('ORF33', 'Gene', '4961502', (206, 211))	('ORF42', 'Gene', (126, 131))	('ORF33', 'Gene', (206, 211))	('ORF26', 'Gene', (196, 201))
378349	31382485	Complementation of ORF42 in trans restored high levels of all viral proteins (Figure 4A,B, Table 2).	('Complementation', 'Var', (0, 15))	('ORF42', 'Gene', (19, 24))	('ORF42', 'Gene', '4961440', (19, 24))
378350	31382485	However, levels of all proteins tested (except ORF52) were on average lower in empty vector transduced cells than ORF42-complemented cells (Figure 4A,B, Table 2).	('ORF42', 'Gene', (114, 119))	('lower', 'NegReg', (70, 75))	('ORF42', 'Gene', '4961440', (114, 119))	('empty vector transduced', 'Var', (79, 102))	('proteins', 'Protein', (23, 31))	('ORF52', 'Gene', '4961496', (47, 52))	('ORF52', 'Gene', (47, 52))	('levels of', 'MPA', (9, 18))
378353	31382485	The change in protein levels was unexpected because no change in viral protein levels has been reported for other herpesviruses carrying mutations in the ORF42 homologs.	('mutations', 'Var', (137, 146))	('herpesvirus', 'Species', '39059', (114, 125))	('ORF42', 'Gene', '4961440', (154, 159))	('ORF42', 'Gene', (154, 159))
378355	31382485	Based on our characterization of ORF57 induction and viral DNA replication in the mutant virus (Figure 1D and Figure 2C-E), we can also exclude that the alteration in protein levels is a secondary effect of early defects in reactivation and viral DNA replication.	('induction', 'PosReg', (39, 48))	('protein levels', 'MPA', (167, 181))	('ORF57', 'Gene', '4961525', (33, 38))	('ORF57', 'Gene', (33, 38))	('mutant', 'Var', (82, 88))
378359	31382485	At Day 4 post-induction, we found that the protein levels of K8.1 were significantly reduced in the absence of ORF42, while there was no significant difference in the RNA levels (Figure 5A).	('RNA levels', 'MPA', (167, 177))	('K8.1', 'Gene', (61, 65))	('ORF42', 'Gene', (111, 116))	('protein levels', 'MPA', (43, 57))	('ORF42', 'Gene', '4961440', (111, 116))	('reduced', 'NegReg', (85, 92))	('absence', 'Var', (100, 107))
378362	31382485	Therefore, while there was some difference between the two targets, the overall effects followed a similar trend: only protein levels were decreased in the absence of ORF42 at Day 4, whereas at Day 6 RNA levels were also reduced, but the magnitude of the change was smaller.	('absence', 'Var', (156, 163))	('protein levels', 'MPA', (119, 133))	('decreased', 'NegReg', (139, 148))	('reduced', 'NegReg', (221, 228))	('ORF42', 'Gene', (167, 172))	('RNA levels', 'MPA', (200, 210))	('ORF42', 'Gene', '4961440', (167, 172))
378371	31382485	The median fluorescence intensity of KSHV lytically-infected cells was 10% lower in the absence of ORF42, suggesting that in the presence of ORF42 total protein production is elevated by 10% (Figure 6A,B).	('lower', 'NegReg', (75, 80))	('ORF42', 'Gene', '4961440', (99, 104))	('ORF42', 'Gene', (141, 146))	('total protein production', 'MPA', (147, 171))	('fluorescence intensity', 'MPA', (11, 33))	('ORF42', 'Gene', '4961440', (141, 146))	('presence', 'Var', (129, 137))	('elevated', 'PosReg', (175, 183))	('KS', 'Phenotype', 'HP:0100726', (37, 39))	('KSHV', 'Species', '37296', (37, 41))	('ORF42', 'Gene', (99, 104))
378373	31382485	Nevertheless, this small but consistent change indicates that the presence of ORF42 promoted the synthesis of new proteins in infected cells.	('promoted', 'PosReg', (84, 92))	('presence', 'Var', (66, 74))	('synthesis of new proteins', 'MPA', (97, 122))	('ORF42', 'Gene', (78, 83))	('ORF42', 'Gene', '4961440', (78, 83))
378383	31382485	Because we introduced an early nonsense mutation in the ORF42PTC mutant virus and we do not have an ORF42 antibody, we cannot exclude the possibility that truncated shorter forms of the protein are still produced in KSHV ORF42PTC-infected cells from later in-frame methionines.	('mutation', 'Var', (40, 48))	('ORF42', 'Gene', (56, 61))	('methionines', 'Chemical', 'MESH:D008715', (265, 276))	('KS', 'Phenotype', 'HP:0100726', (216, 218))	('ORF42', 'Gene', (100, 105))	('ORF42', 'Gene', '4961440', (100, 105))	('mutant', 'Var', (65, 71))	('ORF42', 'Gene', (221, 226))	('ORF42', 'Gene', '4961440', (221, 226))	('ORF42', 'Gene', '4961440', (56, 61))	('KSHV', 'Species', '37296', (216, 220))
378412	31382485	Unfortunately, currently there are no systems to reconstitute and study KSHV mutants in the context of the lytic cycle in endothelial and B cells.	('KSHV', 'Gene', (72, 76))	('mutants', 'Var', (77, 84))	('KSHV', 'Species', '37296', (72, 76))	('KS', 'Phenotype', 'HP:0100726', (72, 74))
378416	31382485	We propose that ORF42 has a function in promoting viral protein production because loss of full-length ORF42 reduced the levels of viral proteins (Figure 4 and Figure 5, Table 2).	('ORF42', 'Gene', (103, 108))	('loss', 'Var', (83, 87))	('ORF42', 'Gene', '4961440', (103, 108))	('levels of viral proteins', 'MPA', (121, 145))	('ORF42', 'Gene', (16, 21))	('viral protein production', 'MPA', (50, 74))	('reduced', 'NegReg', (109, 116))	('ORF42', 'Gene', '4961440', (16, 21))	('promoting', 'PosReg', (40, 49))
378417	31382485	As transcriptional induction of early genes and viral DNA replication were normal in KSHV ORF42PTC infected cells (Figure 1C and Figure 2C-E), the change in viral protein levels is unlikely to be a secondary effect of earlier problems in the replication cycle.	('viral DNA replication', 'MPA', (48, 69))	('ORF42', 'Gene', (90, 95))	('ORF42', 'Gene', '4961440', (90, 95))	('viral', 'MPA', (157, 162))	('transcriptional induction', 'MPA', (3, 28))	('KS', 'Phenotype', 'HP:0100726', (85, 87))	('KSHV', 'Species', '37296', (85, 89))	('KSHV', 'Var', (85, 89))
378418	31382485	We favor a post-transcriptional effect of ORF42 activity on gene expression, because loss of full-length ORF42 had only modest and delayed effects on RNA levels for the two late genes we tested (Figure 5A-D).	('loss', 'Var', (85, 89))	('ORF42', 'Gene', '4961440', (42, 47))	('RNA levels', 'MPA', (150, 160))	('ORF42', 'Gene', (42, 47))	('ORF42', 'Gene', (105, 110))	('ORF42', 'Gene', '4961440', (105, 110))
378434	30818224	Upon inactivation of HDAC2, this acetylation creates a structural signal in the lysine-rich domain of MDM2 to prevent the recognition and degradation of its downstream substrate, MCL-1 ubiquitin ligase E3 (MULE).	('MULE', 'Gene', (206, 210))	('degradation', 'MPA', (138, 149))	('lysine', 'Chemical', 'MESH:D008239', (80, 86))	('rat', 'Species', '10116', (173, 176))	('MDM2', 'Gene', '4193', (102, 106))	('MDM2', 'Gene', (102, 106))	('structural', 'MPA', (55, 65))	('HDAC2', 'Gene', (21, 26))	('HDAC2', 'Gene', '3066', (21, 26))	('prevent', 'NegReg', (110, 117))	('MCL-1', 'MPA', (179, 184))	('inactivation', 'Var', (5, 17))	('recognition', 'MPA', (122, 133))	('MULE', 'Gene', '10075', (206, 210))
378440	30818224	However, synovial sarcoma displays variable degrees of epithelial differentiation and contains a unique chromosomal translocation t(X; 18), which most commonly fuses the SS18 gene with SSX1 or SSX2.	('synovial sarcoma', 'Disease', (9, 25))	('SS18', 'Gene', (170, 174))	('SSX2', 'Gene', (193, 197))	('SSX1', 'Gene', '6756', (185, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('fuses', 'Var', (160, 165))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (9, 25))	('synovial sarcoma', 'Disease', 'MESH:D013584', (9, 25))	('SSX1', 'Gene', (185, 189))	('SSX2', 'Gene', '6757', (193, 197))
378448	30818224	In the present study, we propose an additional, transcription-independent mechanism whereby HDAC inhibition facilitates proteasomal degradation of the SS18-SSX fusion protein.	('inhibition', 'Var', (97, 107))	('SSX', 'Gene', (156, 159))	('SSX', 'Gene', '6757', (156, 159))	('facilitates', 'PosReg', (108, 119))	('HDAC', 'Gene', (92, 96))	('HDAC', 'Gene', '9734', (92, 96))	('proteasomal degradation', 'MPA', (120, 143))
378458	30818224	We also tested this in SS18-SSX1-associated synovial sarcoma cells (Yamato-SS) and found that treatment with the HDAC inhibitors FK228 and SB939 led to a marked reduction of SS18-SSX protein levels, coupled with impaired tumor cell growth (Figures 1D and 1E).	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (44, 60))	('HDAC', 'Gene', (113, 117))	('SSX', 'Gene', '6757', (179, 182))	('SSX', 'Gene', '6757', (28, 31))	('FK228', 'Chemical', 'MESH:C087123', (129, 134))	('SSX1', 'Gene', '6756', (28, 32))	('SB939', 'Chemical', 'MESH:C557525', (139, 144))	('reduction', 'NegReg', (161, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('SSX', 'Gene', (179, 182))	('SSX1', 'Gene', (28, 32))	('SSX', 'Gene', (28, 31))	('impaired tumor', 'Disease', (212, 226))	('SB939', 'Var', (139, 144))	('impaired tumor', 'Disease', 'MESH:D015417', (212, 226))	('synovial sarcoma', 'Disease', (44, 60))	('FK228', 'Var', (129, 134))	('HDAC', 'Gene', '9734', (113, 117))	('synovial sarcoma', 'Disease', 'MESH:D013584', (44, 60))
378467	30818224	Given the fact that MULE neither binds wild-type SS18 nor does its deletion affect SS18 protein expression (Figures S2E and S2F), we reasoned that the C-terminal SSXRD may play an indispensable role for SS18-SSX recognition by MULE E3 ligase.	('affect', 'Reg', (76, 82))	('SSX', 'Gene', (162, 165))	('MULE', 'Gene', (20, 24))	('MULE', 'Gene', '10075', (227, 231))	('SSX', 'Gene', (208, 211))	('SSX', 'Gene', '6757', (208, 211))	('MULE', 'Gene', (227, 231))	('deletion', 'Var', (67, 75))	('expression', 'MPA', (96, 106))	('protein', 'Protein', (88, 95))	('SS18', 'Gene', (83, 87))	('SSX', 'Gene', '6757', (162, 165))	('MULE', 'Gene', '10075', (20, 24))
378474	30818224	However, among four lysines, only mutating K23 to arginine (K23R) effectively blocked SS18-SSX ubiquitination (Figure 3E).	('SSX', 'Gene', (91, 94))	('K23', 'Var', (43, 46))	('SSX', 'Gene', '6757', (91, 94))	('blocked', 'NegReg', (78, 85))	('arginine', 'Chemical', 'MESH:D001120', (50, 58))	('K23R', 'Var', (60, 64))	('K23R', 'SUBSTITUTION', 'None', (60, 64))	('K23', 'Chemical', '-', (60, 63))	('mutating K23', 'Var', (34, 46))	('K23', 'Chemical', '-', (43, 46))	('lysines', 'Chemical', 'MESH:D008239', (20, 27))
378478	30818224	In SYO-1 cells, SS18-SSX levels fell after addition of FK228 and SB939.	('SYO-1', 'Gene', (3, 8))	('SB939', 'Chemical', 'MESH:C557525', (65, 70))	('FK228', 'Var', (55, 60))	('SSX', 'Gene', (21, 24))	('SSX', 'Gene', '6757', (21, 24))	('SB939', 'Var', (65, 70))	('fell', 'NegReg', (32, 36))	('FK228', 'Chemical', 'MESH:C087123', (55, 60))	('SYO-1', 'Gene', '55027', (3, 8))
378480	30818224	More importantly, removal of MULE reduced the sensitivity of SYO-1 cells to HDAC inhibitors (Figures 4F and 4G).	('reduced', 'NegReg', (34, 41))	('HDAC', 'Gene', (76, 80))	('removal', 'Var', (18, 25))	('MULE', 'Gene', '10075', (29, 33))	('HDAC', 'Gene', '9734', (76, 80))	('SYO-1', 'Gene', '55027', (61, 66))	('MULE', 'Gene', (29, 33))	('SYO-1', 'Gene', (61, 66))	('sensitivity', 'MPA', (46, 57))
378492	30818224	This effect seems independent of the p53 tumor suppressor, a key target of MDM2, because SYO-1 cells express wild-type p53, but Yamato-SS cells harbor a mutant p53 (R273C).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('R273C', 'Mutation', 'rs121913343', (165, 170))	('R273C', 'Var', (165, 170))	('MDM2', 'Gene', '4193', (75, 79))	('MDM2', 'Gene', (75, 79))	('p53', 'Gene', '7157', (119, 122))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('p53', 'Gene', (37, 40))	('SYO-1', 'Gene', '55027', (89, 94))	('p53', 'Gene', '7157', (37, 40))	('p53', 'Gene', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('SYO-1', 'Gene', (89, 94))
378493	30818224	Consistent with this view, depletion of endogenous p53 failed to rescue SYO-1 cells from MDM2 knockdown (Figures S4G-S4I).	('p53', 'Gene', (51, 54))	('knockdown', 'Var', (94, 103))	('p53', 'Gene', '7157', (51, 54))	('SYO-1', 'Gene', '55027', (72, 77))	('SYO-1', 'Gene', (72, 77))	('MDM2', 'Gene', '4193', (89, 93))	('MDM2', 'Gene', (89, 93))	('depletion', 'MPA', (27, 36))
378495	30818224	Notably, this action could be reversed by the addition of FK228 and SB939, which suppressed MDM2 binding to MULE (Figure 5E).	('SB939', 'Chemical', 'MESH:C557525', (68, 73))	('suppressed', 'NegReg', (81, 91))	('FK228', 'Var', (58, 63))	('MDM2', 'Gene', '4193', (92, 96))	('MULE', 'Gene', (108, 112))	('MULE', 'Gene', '10075', (108, 112))	('MDM2', 'Gene', (92, 96))	('binding', 'Interaction', (97, 104))	('FK228', 'Chemical', 'MESH:C087123', (58, 63))	('SB939', 'Var', (68, 73))
378497	30818224	In addition, we found that the response of SYO-1 cells to FK228 and SB939 treatment, similar to MDM2 knockdown, remained unaffected after p53 deletion (Figures S4L-S4N), further supporting the notion that HDAC-inhibitor-induced anticancer action relies largely on MDM2 regulation of MULE, rather than p53, in synovial sarcoma.	('p53', 'Gene', (138, 141))	('cancer', 'Disease', (232, 238))	('p53', 'Gene', '7157', (301, 304))	('MULE', 'Gene', '10075', (283, 287))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('deletion', 'Var', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (318, 325))	('p53', 'Gene', (301, 304))	('HDAC', 'Gene', '9734', (205, 209))	('MDM2', 'Gene', (96, 100))	('synovial sarcoma', 'Disease', (309, 325))	('SYO-1', 'Gene', '55027', (43, 48))	('FK228', 'Chemical', 'MESH:C087123', (58, 63))	('SYO-1', 'Gene', (43, 48))	('MDM2', 'Gene', (264, 268))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('SB939', 'Chemical', 'MESH:C557525', (68, 73))	('synovial sarcoma', 'Disease', 'MESH:D013584', (309, 325))	('HDAC', 'Gene', (205, 209))	('MDM2', 'Gene', '4193', (96, 100))	('MDM2', 'Gene', '4193', (264, 268))	('rat', 'Species', '10116', (289, 292))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (309, 325))	('p53', 'Gene', '7157', (138, 141))	('MULE', 'Gene', (283, 287))
378499	30818224	Recently, it has been discovered that acetylation of the lysine-rich domain (KRD) can remove its positive charge and interrupt its association with the negatively charged acidic domain.	('negatively charged acidic domain', 'MPA', (152, 184))	('positive charge', 'MPA', (97, 112))	('lysine', 'Chemical', 'MESH:D008239', (57, 63))	('remove', 'NegReg', (86, 92))	('interrupt', 'NegReg', (117, 126))	('association', 'Interaction', (131, 142))	('acetylation', 'Var', (38, 49))
378500	30818224	Indeed, there does exist a lysine-rich stretch (amino acids 460-476) in the MDM2 protein, whereas MULE has an acidic domain between the residues 2425 and 2469.	('amino acids 460-476', 'Var', (48, 67))	('lysine', 'Chemical', 'MESH:D008239', (27, 33))	('lysine-rich stretch', 'MPA', (27, 46))	('MULE', 'Gene', '10075', (98, 102))	('MDM2', 'Gene', '4193', (76, 80))	('MULE', 'Gene', (98, 102))	('MDM2', 'Gene', (76, 80))
378505	30818224	Point mutation analysis identified two acetylated lysines, K469 and K470, responsible for the release of MDM2 from MULE (Figures 6F, 6G, S5I, and S5J).	('MDM2', 'Gene', '4193', (105, 109))	('MDM2', 'Gene', (105, 109))	('K470', 'Var', (68, 72))	('MULE', 'Gene', '10075', (115, 119))	('K470', 'Chemical', '-', (68, 72))	('MULE', 'Gene', (115, 119))	('lysines', 'Chemical', 'MESH:D008239', (50, 57))	('S5I', 'Mutation', 'p.S5I', (137, 140))	('K469', 'Chemical', '-', (59, 63))	('K469', 'Var', (59, 63))	('release', 'MPA', (94, 101))
378506	30818224	In line with this observation, K469 and K470 appeared to be the most effective sites of MDM2 acetylation after FK228 addition (Figure S5H).	('MDM2', 'Gene', '4193', (88, 92))	('MDM2', 'Gene', (88, 92))	('K470', 'Var', (40, 44))	('K470', 'Chemical', '-', (40, 44))	('K469', 'Chemical', '-', (31, 35))	('S5H', 'Mutation', 'p.S5H', (134, 137))	('FK228', 'Chemical', 'MESH:C087123', (111, 116))	('acetylation', 'MPA', (93, 104))	('K469', 'Var', (31, 35))
378507	30818224	To further test this idea, we generated another MDM2 mutation in which the K469 and K470 residues were substituted to glutamine.	('K469', 'Chemical', '-', (75, 79))	('K470 residues', 'Var', (84, 97))	('glutamine', 'Chemical', 'MESH:D005973', (118, 127))	('K470', 'Chemical', '-', (84, 88))	('K469', 'Var', (75, 79))	('MDM2', 'Gene', '4193', (48, 52))	('MDM2', 'Gene', (48, 52))	('rat', 'Species', '10116', (34, 37))
378508	30818224	This acetylation-mimicked mutation resulted in a dramatic loss of the MDM2-MULE interaction even without HDAC inhibitor treatment (Figures 6H and 6I).	('loss', 'NegReg', (58, 62))	('mutation', 'Var', (26, 34))	('HDAC', 'Gene', (105, 109))	('HDAC', 'Gene', '9734', (105, 109))	('MULE', 'Gene', '10075', (75, 79))	('MDM2', 'Gene', '4193', (70, 74))	('MULE', 'Gene', (75, 79))	('MDM2', 'Gene', (70, 74))
378509	30818224	Intriguingly, Moshe Oren and colleagues reported that acetylation of the neighboring lysines K466 and K467 impairs MDM2's E3 ligase activity.	('K467 impairs MDM2', 'Disease', (102, 119))	("K467 impairs MDM2's", 'Disease', 'MESH:D009422', (102, 121))	('activity', 'MPA', (132, 140))	('acetylation', 'MPA', (54, 65))	('K466', 'Chemical', '-', (93, 97))	('K466', 'Var', (93, 97))	('lysines', 'Chemical', 'MESH:D008239', (85, 92))	('E3 ligase', 'Enzyme', (122, 131))
378510	30818224	However, a similar defect was not found when mimicking the acetylation of K469 and K470 (Figure S5K).	('K470', 'Chemical', '-', (83, 87))	('K470', 'Var', (83, 87))	('K469', 'Chemical', '-', (74, 78))	('K469', 'Var', (74, 78))
378513	30818224	We focused on two highly homologous members, HDAC1 and HDAC2, because they are most abundantly expressed in synovial sarcoma cells (Figure 7A), and because the compound FK228 mainly inhibits HDAC1/2 activity.	('HDAC1', 'Gene', (191, 196))	('activity', 'MPA', (199, 207))	('FK228', 'Chemical', 'MESH:C087123', (169, 174))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (108, 124))	('HDAC1', 'Gene', '3065', (45, 50))	('inhibits', 'NegReg', (182, 190))	('synovial sarcoma', 'Disease', 'MESH:D013584', (108, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('HDAC1', 'Gene', '3065', (191, 196))	('FK228', 'Var', (169, 174))	('HDAC2', 'Gene', (55, 60))	('synovial sarcoma', 'Disease', (108, 124))	('HDAC1', 'Gene', (45, 50))	('HDAC2', 'Gene', '3066', (55, 60))
378516	30818224	Moreover, the amount of SS18-SSX protein (but not mRNA) was drastically reduced upon HDAC2 knockdown (Figures 7C, S6F, and S6H), similar to the results obtained in MDM2-knockdown cells.	('reduced', 'NegReg', (72, 79))	('S6H', 'Mutation', 'p.S6H', (123, 126))	('SSX', 'Gene', '6757', (29, 32))	('SSX', 'Gene', (29, 32))	('HDAC2', 'Gene', (85, 90))	('HDAC2', 'Gene', '3066', (85, 90))	('knockdown', 'Var', (91, 100))	('MDM2', 'Gene', '4193', (164, 168))	('MDM2', 'Gene', (164, 168))
378608	30030906	Kepka et al6 mentioned that LC rates at 5 years were 51, 45, and 9% for tumors <5 cm, 5-10 cm, and >10 cm, respectively.	('5-10 cm', 'Var', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))
378642	29354796	In the remainder of cases, most tumors harbor a fusion of the EWSR1 gene with a different member of the E-26 Transformation Specific (ETS) family of transcription factors .	('EWSR1', 'Gene', (62, 67))	('EWS', 'Phenotype', 'HP:0012254', (62, 65))	('fusion', 'Var', (48, 54))	('EWSR1', 'Gene', '2130', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
378650	29354796	Additionally, the presence of the EWSR1-FLI1 translocation in a rare subset of small-cell OS further complicates diagnostics .	('EWSR1', 'Gene', (34, 39))	('small-cell OS', 'Disease', (79, 92))	('translocation', 'Var', (45, 58))	('EWSR1', 'Gene', '2130', (34, 39))	('FLI1', 'Gene', (40, 44))	('presence', 'Reg', (18, 26))	('FLI1', 'Gene', '2313', (40, 44))	('EWS', 'Phenotype', 'HP:0012254', (34, 37))	('OS', 'Phenotype', 'HP:0002669', (90, 92))
378658	29354796	EWS were screened by histology and the diagnosis confirmed with the presence of an EWSR1 rearrangement by FISH.	('EWS', 'Phenotype', 'HP:0012254', (83, 86))	('EWS', 'Gene', '2130', (83, 86))	('EWS', 'Gene', (83, 86))	('EWSR1', 'Gene', (83, 88))	('rearrangement', 'Var', (89, 102))	('EWSR1', 'Gene', '2130', (83, 88))	('EWS', 'Phenotype', 'HP:0012254', (0, 3))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
378673	29354796	For EWS, two probes (cg21242508 and cg06516502) are located on chromosome 22q, approximately 1Mb away from EWSR1 within a tetratricopeptide repeat domain TTC28.	('TTC28', 'Gene', (154, 159))	('EWS', 'Gene', '2130', (107, 110))	('EWSR1', 'Gene', (107, 112))	('EWS', 'Gene', (107, 110))	('cg06516502', 'Var', (36, 46))	('EWSR1', 'Gene', '2130', (107, 112))	('EWS', 'Phenotype', 'HP:0012254', (4, 7))	('cg21242508', 'Var', (21, 31))	('TTC28', 'Gene', '23331', (154, 159))	('EWS', 'Gene', '2130', (4, 7))	('EWS', 'Gene', (4, 7))	('EWS', 'Phenotype', 'HP:0012254', (107, 110))
378682	29354796	While the expression of FLI1 was similar to other samples in the cohort, we noted a striking overexpression of ETV1 (70 Transcripts / kb * million) and EWSR1 (200 Transcripts / kb * million) compared to the other OS samples in the dataset (Figure 1C).	('FLI1', 'Gene', '2313', (24, 28))	('FLI1', 'Gene', (24, 28))	('EWS', 'Phenotype', 'HP:0012254', (152, 155))	('EWSR1', 'Gene', (152, 157))	('overexpression', 'PosReg', (93, 107))	('ETV1', 'Gene', (111, 115))	('OS', 'Phenotype', 'HP:0002669', (213, 215))	('EWSR1', 'Gene', '2130', (152, 157))	('ETV1', 'Gene', '2115', (111, 115))	('200', 'Var', (159, 162))
378684	29354796	We hypothesized that the tumor harbored a EWSR1/ETV1 rearrangement consistent with EWS, however after manually curating the transcript sequence reads, there was no evidence of an ETV1 fusion; suggesting an alternative mechanism leading to ETV1 upregulation.	('EWSR1', 'Gene', (42, 47))	('EWS', 'Phenotype', 'HP:0012254', (83, 86))	('EWS', 'Gene', '2130', (83, 86))	('EWS', 'Gene', (83, 86))	('ETV1', 'Gene', (179, 183))	('ETV1', 'Gene', '2115', (239, 243))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('EWSR1', 'Gene', '2130', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('ETV1', 'Gene', (48, 52))	('ETV1', 'Gene', '2115', (179, 183))	('ETV1', 'Gene', '2115', (48, 52))	('EWS', 'Gene', '2130', (42, 45))	('ETV1', 'Gene', (239, 243))	('EWS', 'Phenotype', 'HP:0012254', (42, 45))	('rearrangement', 'Var', (53, 66))	('EWS', 'Gene', (42, 45))
378691	29354796	FISH testing using dual-color break-apart probe showed a rearrangement involving SS18 (SYT) (88.0% of cells, data not shown), raising the concern that the tumor may represent SS.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('SYT', 'Gene', (87, 90))	('SS', 'Phenotype', 'HP:0012570', (81, 83))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('SYT', 'Gene', '6760', (87, 90))	('SS', 'Phenotype', 'HP:0012570', (175, 177))	('rearrangement', 'Var', (57, 70))
378696	29354796	Moreover, it indicates robustness of methylation based sarcoma classifier not only in de novo, but also in radiation-induced OS.	('methylation', 'Var', (37, 48))	('sarcoma', 'Disease', (55, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('OS', 'Phenotype', 'HP:0002669', (125, 127))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))
378704	29354796	Targeted DNA (MSK-IMPACT) and RNA (Archer FusionPlex, ArcherDX, Inc.) was non-diagnostic, but revealed a genomically unstable tumor with numerous mutations, which would be unusual for translocation-driven sarcomas such as EWS.	('mutations', 'Var', (146, 155))	('sarcomas', 'Disease', 'MESH:D012509', (205, 213))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('EWS', 'Phenotype', 'HP:0012254', (222, 225))	('sarcomas', 'Phenotype', 'HP:0100242', (205, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('EWS', 'Gene', '2130', (222, 225))	('EWS', 'Gene', (222, 225))	('sarcomas', 'Disease', (205, 213))	('tumor', 'Disease', (126, 131))
378722	29354796	Methylation also provides novel insights into sarcomabiology, for example OS appears to be characterized by a consistently hypomethylated strip along chromosome 1q43, among other features.	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('OS', 'Phenotype', 'HP:0002669', (74, 76))	('sarcoma', 'Disease', (46, 53))	('hypomethylated', 'Var', (123, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
378832	24959052	In addition, pressure on the nerves can cause pain, facial paralysis, deafness and blindness depending on the location of involvement.	('pressure', 'Var', (13, 21))	('blindness', 'Disease', (83, 92))	('deafness', 'Disease', 'MESH:D003638', (70, 78))	('cause', 'Reg', (40, 45))	('blindness', 'Disease', 'MESH:D001766', (83, 92))	('pain', 'Phenotype', 'HP:0012531', (46, 50))	('deafness', 'Phenotype', 'HP:0000365', (70, 78))	('pain', 'Disease', 'MESH:D010146', (46, 50))	('blindness', 'Phenotype', 'HP:0000618', (83, 92))	('pain', 'Disease', (46, 50))	('paralysis', 'Phenotype', 'HP:0003470', (59, 68))	('deafness', 'Disease', (70, 78))	('facial paralysis', 'Disease', (52, 68))	('facial paralysis', 'Phenotype', 'HP:0007209', (52, 68))	('facial paralysis', 'Disease', 'MESH:D010243', (52, 68))
378847	24959052	They concluded that immunohistochemical panel including CD43, lysozyme, MPO, CD68 or CD163, CD117, CD3 and CD20 can successfully identify vast majority of MS variants in formalin-fixed paraffin-embedded tissue sections.	('lysozyme', 'Gene', '4069', (62, 70))	('CD43', 'Gene', (56, 60))	('formalin', 'Chemical', 'MESH:D005557', (170, 178))	('CD68', 'Gene', '968', (77, 81))	('paraffin', 'Chemical', 'MESH:D010232', (185, 193))	('variants', 'Var', (158, 166))	('CD163', 'Gene', '9332', (85, 90))	('CD163', 'Gene', (85, 90))	('MPO', 'Gene', (72, 75))	('CD20', 'Gene', '54474', (107, 111))	('CD68', 'Gene', (77, 81))	('CD117', 'Gene', '3815', (92, 97))	('CD20', 'Gene', (107, 111))	('CD43', 'Gene', '6693', (56, 60))	('CD117', 'Gene', (92, 97))	('MPO', 'Gene', '4353', (72, 75))	('lysozyme', 'Gene', (62, 70))
378873	33680459	The most frequent one is Ewing sarcoma, which is characterized by EWS RNA binding protein 1 (EWSR1)-erythroblast transformation-specific (ETS) gene fusions, and others without theses fusions are called 'Ewing-like sarcomas'.	('fusions', 'Var', (148, 155))	("'Ewing-like sarcomas", 'Phenotype', 'HP:0012254', (202, 222))	('Ewing-like sarcomas', 'Disease', (203, 222))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (203, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('EWSR1', 'Gene', (93, 98))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (203, 222))	('EWSR1', 'Gene', '2130', (93, 98))	('Ewing sarcoma', 'Disease', (25, 38))	('EWS RNA binding protein 1', 'Gene', '2130', (66, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (214, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (25, 38))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (203, 222))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (25, 38))	('EWS RNA binding protein 1', 'Gene', (66, 91))
378875	33680459	In CIC-rearranged sarcoma, CIC is fused to double homeobox 4 (DUX4) with either t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation, which are associated with oncogenesis, tumor development, and metastatic capability.	('CIC-rearranged sarcoma', 'Disease', (3, 25))	('CIC', 'Gene', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('t(4;19)(q35;q13.1)', 'STRUCTURAL_ABNORMALITY', 'None', (80, 98))	('associated', 'Reg', (147, 157))	('t(4;19)(q35;q13.1', 'Var', (80, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('DUX4', 'Gene', (62, 66))	('tumor', 'Disease', (176, 181))	('CIC', 'Gene', '23152', (3, 6))	('DUX4', 'Gene', '100288687', (62, 66))	('double homeobox 4', 'Gene', '100288687', (43, 60))	('CIC-rearranged sarcoma', 'Disease', 'MESH:D012509', (3, 25))	('t(10;19)(q26.3;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (102, 121))	('CIC', 'Gene', '23152', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('CIC', 'Gene', (3, 6))	('double homeobox 4', 'Gene', (43, 60))
378950	32573957	Further research is necessary to evaluate the impact of germline mutations in patients with sarcoma, and sarcomas with evidence of hypermutation.	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('patients', 'Species', '9606', (78, 86))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('sarcomas', 'Disease', 'MESH:D012509', (105, 113))	('sarcoma', 'Disease', (105, 112))	('sarcoma', 'Disease', (92, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('sarcomas', 'Disease', (105, 113))	('germline mutations', 'Var', (56, 74))
379004	32573957	Approximately one third of sarcomas are defined by a recurrent genetic alteration [2].	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcomas', 'Disease', (27, 35))	('genetic alteration', 'Var', (63, 81))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))
379005	32573957	Specifically, amplification of MDM2, which characterises both well-differentiated and dedifferentiated liposarcoma [8] and parosteal osteosarcoma [9] and is routinely detected by FISH, were not called by the Canvas algorithm for copy number variant calling.	('liposarcoma', 'Phenotype', 'HP:0012034', (103, 114))	('liposarcoma', 'Disease', 'MESH:D008080', (103, 114))	('well-differentiated', 'Disease', (62, 81))	('parosteal osteosarcoma', 'Disease', 'MESH:D012516', (123, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('parosteal osteosarcoma', 'Disease', (123, 145))	('MDM2', 'Gene', '4193', (31, 35))	('liposarcoma', 'Disease', (103, 114))	('MDM2', 'Gene', (31, 35))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))	('amplification', 'Var', (14, 27))
379006	32573957	SS18 rearrangements were only detected if the fusion partner was SSX1 but not if SSX2 [11] (Table 4).	('SSX2', 'Gene', '6757', (81, 85))	('SS18', 'Gene', '6760', (0, 4))	('SSX1', 'Gene', '6756', (65, 69))	('SSX2', 'Gene', (81, 85))	('SSX1', 'Gene', (65, 69))	('SS18', 'Gene', (0, 4))	('rearrangements', 'Var', (5, 19))
379010	32573957	A second MPNST was reclassified as fibrosarcomatous transformation of a dermatofibrosarcoma protuberans on discovery of the characteristic COL1A1-PDGFB fusion [14].	('fibrosarcomatous', 'Disease', (35, 51))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (72, 103))	('PDGFB', 'Gene', (146, 151))	('COL1A1', 'Gene', (139, 145))	('COL1A1', 'Gene', '1277', (139, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('dermatofibrosarcoma protuberans', 'Disease', (72, 103))	('MPNST', 'Phenotype', 'HP:0100697', (9, 14))	('fusion', 'Var', (152, 158))	('dermatofibrosarcoma protuberans on discovery', 'Phenotype', 'HP:0030447', (72, 116))	('fibrosarcomatous', 'Disease', 'MESH:D018223', (35, 51))	('PDGFB', 'Gene', '5155', (146, 151))
379012	32573957	Two chondrosarcomas reported as secondary to osteochondroma, peripheral subtype, were reclassified as central following detection of somatic IDH1/2 variants [16].	('osteochondroma', 'Disease', 'MESH:D015831', (45, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('chondrosarcomas', 'Disease', 'MESH:D002813', (4, 19))	('IDH1/2', 'Gene', '3417;3418', (141, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('osteochondroma', 'Disease', (45, 59))	('chondrosarcomas', 'Disease', (4, 19))	('variants', 'Var', (148, 156))	('osteochondroma', 'Phenotype', 'HP:0030431', (45, 59))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (4, 18))	('IDH1/2', 'Gene', (141, 147))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (4, 19))
379014	32573957	Domain 2 variants are cancer-related alterations as defined by the Cancer Gene Census [19].	('Domain 2', 'Gene', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('variants', 'Var', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Cancer', 'Disease', (67, 73))
379015	32573957	An alteration in a domain 1 gene was detected in approximately 55% of cases, including cases of chondrosarcoma, myxofibrosarcoma, and osteosarcoma, which are among the most common sarcoma subtypes submitted for WGS (see supplementary material, Table S1).	('chondrosarcoma, myxofibrosarcoma', 'Disease', 'MESH:D002813', (96, 128))	('osteosarcoma', 'Disease', (134, 146))	('osteosarcoma', 'Disease', 'MESH:D012516', (134, 146))	('sarcoma', 'Disease', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('detected', 'Reg', (37, 45))	('sarcoma', 'Disease', 'MESH:D012509', (180, 187))	('sarcoma', 'Disease', (180, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('alteration', 'Var', (3, 13))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (96, 110))	('osteosarcoma', 'Phenotype', 'HP:0002669', (134, 146))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('sarcoma', 'Disease', (139, 146))	('domain 1 gene', 'Gene', (19, 32))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))	('sarcoma', 'Disease', (121, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))
379023	32573957	Tier 1 variants are considered to be pathogenic or likely pathogenic variants for the patient's enrolled cancer type.	('pathogenic', 'Reg', (37, 47))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('variants', 'Var', (7, 15))	('patient', 'Species', '9606', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
379024	32573957	Tier 3 includes rare variants reported in genes in a broader set of cancer susceptibility panels not currently associated with sarcoma, e.g.	('variants', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('cancer', 'Disease', (68, 74))	('sarcoma', 'Disease', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
379031	32573957	As a result, we discussed selected paediatric patients with variants classified as being of 'uncertain pathogenic significance' [23] including two children with germline alterations in SQSTM1 and TSC2 (see supplementary material, Table S1).	('SQSTM1', 'Gene', '8878', (185, 191))	('patients', 'Species', '9606', (46, 54))	('variants', 'Var', (60, 68))	('children', 'Species', '9606', (147, 155))	('SQSTM1', 'Gene', (185, 191))	('TSC2', 'Gene', '7249', (196, 200))	('TSC2', 'Gene', (196, 200))
379039	32573957	Although over 50% of our patients had an alteration in domain 1, only a minority were found in a gene that is associated with an approved clinical therapy or that can be used as a prognostic biomarker [29].	('alteration', 'Var', (41, 51))	('patients', 'Species', '9606', (25, 33))	('domain 1', 'Gene', (55, 63))
379040	32573957	The majority of these variants occurred in TP53 and ATRX, which have potential clinical significance and are associated with open early phase clinical trials [30] but remain for the moment non-actionable for patients with sarcoma.	('patients', 'Species', '9606', (208, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('sarcoma', 'Disease', 'MESH:D012509', (222, 229))	('ATRX', 'Gene', (52, 56))	('sarcoma', 'Disease', (222, 229))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('occurred', 'Reg', (31, 39))	('variants', 'Var', (22, 30))	('ATRX', 'Gene', '546', (52, 56))
379043	32573957	For patients with active disease, it was disappointing that only a single clinical trial was open to the recruitment of patients with sarcoma and that this was limited to surgically untreatable chondrosarcomas with somatic IDH1 mutations [31].	('sarcoma', 'Disease', 'MESH:D012509', (201, 208))	('chondrosarcomas', 'Disease', (194, 209))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (201, 209))	('mutations', 'Var', (228, 237))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (194, 208))	('sarcoma', 'Disease', (201, 208))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (194, 209))	('patients', 'Species', '9606', (120, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('sarcoma', 'Disease', (134, 141))	('patients', 'Species', '9606', (4, 12))	('IDH1', 'Gene', (223, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('chondrosarcomas', 'Disease', 'MESH:D002813', (194, 209))	('IDH1', 'Gene', '3417', (223, 227))
379046	32573957	In particular, patients with sarcoma with a high mutational burden should be included in the relevant immune checkpoint blockage clinical trials going forward.	('patients', 'Species', '9606', (15, 23))	('mutational', 'Var', (49, 59))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('sarcoma', 'Disease', (29, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))
379050	32573957	However, this may change as new therapeutic agents continue to be identified, such as for patients with sarcomas harbouring NTRK fusion genes [33], or in cases where melanoma has been misclassified as a MPNST [34].	('NTRK', 'Gene', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('sarcomas', 'Disease', 'MESH:D012509', (104, 112))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('sarcomas', 'Disease', (104, 112))	('MPNST', 'Phenotype', 'HP:0100697', (203, 208))	('fusion genes', 'Var', (129, 141))	('patients', 'Species', '9606', (90, 98))
379076	31915413	Among patients who received chemotherapy, doxorubicin and cisplatin were significantly associated with improved PFS but not OS.	('cisplatin', 'Var', (58, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('doxorubicin', 'Var', (42, 53))	('improved', 'PosReg', (103, 111))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('PFS', 'Disease', (112, 115))
379086	31915413	Of the 6 patients who received neoadjuvant chemotherapy, one had 80% tumor necrosis after MAP, one had 70% necrosis following AP, and another two both had 30% necrosis after the treatment of MAP or methotrexate with IE.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('necrosis', 'Disease', (159, 167))	('necrosis', 'Disease', (107, 115))	('necrosis', 'Disease', 'MESH:D009336', (75, 83))	('necrosis', 'Disease', 'MESH:D009336', (159, 167))	('MAP', 'Var', (90, 93))	('necrosis', 'Disease', 'MESH:D009336', (107, 115))	('tumor', 'CPA', (69, 74))	('necrosis', 'Disease', (75, 83))
379134	27673450	Furthermore, ASPL-TFE3 expression in mesenchymal stem cells resulted in a significant up-regulation of proinflammatory cytokines associated with senescence-associated secretory phenotype (SASP).	('up-regulation', 'PosReg', (86, 99))	('ASPL-TFE3', 'Var', (13, 22))	('senescence-associated secretory phenotype', 'Disease', (145, 186))	('SASP', 'Gene', (188, 192))	('SASP', 'Gene', '7295', (188, 192))	('proinflammatory cytokines', 'MPA', (103, 128))
379135	27673450	These results show that ASPL-TFE3 regulates cell cycle progression and induces cellular senescence by up-regulating p21 expression.	('p21', 'Gene', (116, 119))	('expression', 'MPA', (120, 130))	('up-regulating', 'PosReg', (102, 115))	('regulates', 'Reg', (34, 43))	('ASPL-TFE3', 'Var', (24, 33))	('cellular senescence', 'CPA', (79, 98))	('p21', 'Gene', '1026', (116, 119))	('cell cycle progression', 'CPA', (44, 66))	('induces', 'PosReg', (71, 78))
379136	27673450	In addition, our data suggest a potential mechanism by which ASPL-TFE3-induced senescence may play a role in tumorigenesis by inducing SASP, which could promote the protumorigenic microenvironment.	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('SASP', 'Gene', (135, 139))	('SASP', 'Gene', '7295', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('ASPL-TFE3-induced', 'Var', (61, 78))	('senescence', 'CPA', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('promote', 'PosReg', (153, 160))	('inducing', 'PosReg', (126, 134))	('tumor', 'Disease', (109, 114))
379139	27673450	Moreover, almost all cases of ASPS have the unbalanced recurrent chromosomal translocation der(17)t(X;17)(p11;q25), which results in generation of the ASPL-TFE3 (also known as ASPSCR1-TFE3) fusion gene.	('ASPS', 'Disease', (176, 180))	('ASPS', 'Disease', 'MESH:D018234', (176, 180))	('ASPS', 'Phenotype', 'HP:0012218', (176, 180))	('der(17)t(X;17)(p11;q25', 'Var', (91, 113))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (55, 90))	('ASPSCR1', 'Gene', '79058', (176, 183))	('der(17)t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (91, 114))	('results in', 'Reg', (122, 132))	('ASPS', 'Disease', (30, 34))	('ASPS', 'Disease', 'MESH:D018234', (30, 34))	('ASPS', 'Phenotype', 'HP:0012218', (30, 34))	('ASPSCR1', 'Gene', (176, 183))	('ASPL-TFE3', 'Protein', (151, 160))
379141	27673450	In a subset of renal cell carcinomas with the translocation Xp11.2, TFE3 fuses with PRCC, CLTC, PSF, NonO, PARP14, LUC7L3, KHSRP, and DVL2, resulting in the expression of PRCC-TFE3, CLTC-TFE3, PSF-TFE3, NonO-TFE3, PARP14-TFE3, LUC7L3-TFE3, KHSRP-TFE3, and DVL2-TFE3 fusion oncogenes, respectively.	('PSF', 'Gene', '3490', (193, 196))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (15, 36))	('NonO', 'Gene', (101, 105))	('KHSRP', 'Gene', (240, 245))	('KHSRP', 'Gene', (123, 128))	('PSF', 'Gene', (193, 196))	('p11', 'Gene', '6281', (61, 64))	('NonO', 'Gene', '4841', (101, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('DVL2', 'Gene', (256, 260))	('PSF', 'Gene', '3490', (96, 99))	('PARP14', 'Gene', (214, 220))	('CLTC', 'Gene', '1213', (90, 94))	('PRCC', 'Gene', (84, 88))	('DVL2', 'Gene', '1856', (134, 138))	('NonO', 'Gene', (203, 207))	('PSF', 'Gene', (96, 99))	('p11', 'Gene', (61, 64))	('PRCC', 'Gene', (171, 175))	('PARP14', 'Gene', '54625', (107, 113))	('NonO', 'Gene', '4841', (203, 207))	('DVL2', 'Gene', (134, 138))	('KHSRP', 'Gene', '8570', (240, 245))	('KHSRP', 'Gene', '8570', (123, 128))	('CLTC', 'Gene', (90, 94))	('LUC7L3', 'Gene', (227, 233))	('LUC7L3', 'Gene', '51747', (227, 233))	('LUC7L3', 'Gene', '51747', (115, 121))	('PARP14', 'Gene', (107, 113))	('LUC7L3', 'Gene', (115, 121))	('PRCC', 'Gene', '5546', (84, 88))	('CLTC', 'Gene', '1213', (182, 186))	('PRCC', 'Gene', '5546', (171, 175))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (15, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (15, 35))	('renal cell carcinomas', 'Disease', (15, 36))	('PARP14', 'Gene', '54625', (214, 220))	('translocation', 'Var', (46, 59))	('DVL2', 'Gene', '1856', (256, 260))	('CLTC', 'Gene', (182, 186))	('TFE3', 'Var', (68, 72))
379145	27673450	ASPL-TFE3 functions as an aberrant transcriptional factor and induces the inappropriate up-regulation of various molecules that contribute to the pathogenesis and progression of ASPS.	('ASPL-TFE3', 'Var', (0, 9))	('induces', 'Reg', (62, 69))	('up-regulation', 'PosReg', (88, 101))	('ASPS', 'Disease', 'MESH:D018234', (178, 182))	('ASPS', 'Disease', (178, 182))	('ASPS', 'Phenotype', 'HP:0012218', (178, 182))
379148	27673450	Because TFE3 plays roles in the regulation of cell growth, we hypothesized that ASPL-TFE3 may affect the proliferation of tumor cells by inducing inappropriate expression of cell cycle regulatory proteins.	('expression', 'MPA', (160, 170))	('affect', 'Reg', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('proliferation', 'CPA', (105, 118))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('inducing', 'Reg', (137, 145))	('tumor', 'Disease', (122, 127))	('ASPL-TFE3', 'Var', (80, 89))
379149	27673450	In this paper, we report that ASPL-TFE3 affected the cell cycle machinery by the direct transcriptional up-regulation of p21.	('affected', 'Reg', (40, 48))	('p21', 'Gene', '1026', (121, 124))	('up-regulation', 'PosReg', (104, 117))	('ASPL-TFE3', 'Var', (30, 39))	('cell cycle machinery', 'CPA', (53, 73))	('p21', 'Gene', (121, 124))
379150	27673450	In addition, we reveal that the expression of ASPL-TFE3 in mesenchymal stem cells (MSCs) induced p21-mediated cellular senescence and increased the mRNA level of proinflammatory cytokines.	('ASPL-TFE3', 'Gene', (46, 55))	('p21', 'Gene', '1026', (97, 100))	('expression', 'Var', (32, 42))	('mRNA level of proinflammatory cytokines', 'MPA', (148, 187))	('p21', 'Gene', (97, 100))	('increased', 'PosReg', (134, 143))	('induced', 'PosReg', (89, 96))
379183	27673450	Fluorescence-activated cell sorting (FACS) analysis revealed that ASPL-TFE3 expression resulted in an increase in the population of cells in the G0/G1 phase, with a concomitant decrease in the number of cells in the S phase (Figure 1C), suggesting that ASPL-TFE3 induces growth arrest in 293 cells.	('decrease', 'NegReg', (177, 185))	('ASPL-TFE3 expression', 'Var', (66, 86))	('growth arrest', 'Disease', 'MESH:D006323', (271, 284))	('growth arrest', 'Disease', (271, 284))	('increase', 'PosReg', (102, 110))	('growth arrest', 'Phenotype', 'HP:0001510', (271, 284))	('expression', 'Var', (76, 86))
379189	27673450	To further confirm ASPL-TFE3-induced up-regulation of p21, we transiently transfected HeLa cells with ASPL-TFE3 and subsequently observed an increase in p21 protein expression (Figure 2B).	('HeLa', 'CellLine', 'CVCL:0030', (86, 90))	('increase', 'PosReg', (141, 149))	('ASPL-TFE3', 'Var', (102, 111))	('p21', 'Gene', '1026', (153, 156))	('p21', 'Gene', '1026', (54, 57))	('up-regulation', 'PosReg', (37, 50))	('p21', 'Gene', (153, 156))	('p21', 'Gene', (54, 57))
379191	27673450	Because the ASPL-TFE3 fusion oncoprotein functions as an aberrant transcription factor, we investigated whether ASPL-TFE3 activates the p21 gene promoter using luciferase reporter assays of the full-length human p21 promoter.	('p21', 'Gene', (136, 139))	('p21', 'Gene', (212, 215))	('ASPL-TFE3', 'Var', (112, 121))	('human', 'Species', '9606', (206, 211))	('activates', 'PosReg', (122, 131))	('p21', 'Gene', '1026', (136, 139))	('p21', 'Gene', '1026', (212, 215))
379219	27673450	Here, we demonstrate a novel mechanism by which ASPL-TFE3 regulates cell cycle progression and induces cellular senescence by directly up-regulating p21 expression.	('cell cycle progression', 'CPA', (68, 90))	('p21', 'Gene', '1026', (149, 152))	('up-regulating', 'PosReg', (135, 148))	('p21', 'Gene', (149, 152))	('regulates', 'Reg', (58, 67))	('ASPL-TFE3', 'Var', (48, 57))	('cellular senescence', 'CPA', (103, 122))	('expression', 'MPA', (153, 163))	('induces', 'PosReg', (95, 102))
379224	27673450	By luciferase and ChIP assays, we provided evidence that ASPL-TFE3 directly interacts with the p21 promoter region and activates it.	('interacts', 'Interaction', (76, 85))	('ASPL-TFE3', 'Var', (57, 66))	('p21', 'Gene', '1026', (95, 98))	('p21', 'Gene', (95, 98))	('activates', 'PosReg', (119, 128))
379229	27673450	Our data revealed that ASPL-TFE3 expression in MSCs induced some hallmarks of OIS, including the induction of SA-beta-gal activity and increased p21 expression.	('p21', 'Gene', '1026', (145, 148))	('SA-beta', 'Gene', '9467', (110, 117))	('SA-beta', 'Gene', (110, 117))	('p21', 'Gene', (145, 148))	('ASPL-TFE3 expression', 'Var', (23, 43))	('increased', 'PosReg', (135, 144))	('expression', 'MPA', (149, 159))	('OIS', 'Disease', (78, 81))	('induced', 'Reg', (52, 59))	('beta-gal', 'Chemical', '-', (113, 121))
379231	27673450	Given that ASPL-TFE3 activated the p21 promoter in p53-deficient Kato III cells, ASPL-TFE3 appears to induce senescence in a p53-independent manner.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('induce', 'Reg', (102, 108))	('p21', 'Gene', (35, 38))	('p53', 'Gene', (125, 128))	('ASPL-TFE3', 'Var', (81, 90))	('p53', 'Gene', '7157', (125, 128))	('p21', 'Gene', '1026', (35, 38))	('senescence', 'MPA', (109, 119))
379236	27673450	Our data demonstrate that ASPL-TFE3 expression in MSCs induced cellular senescence, while ASPL-TFE3 expression in 293 cells resulted in growth arrest but failed to induce senescence.	('ASPL-TFE3 expression', 'Var', (26, 46))	('growth arrest', 'Disease', (136, 149))	('growth arrest', 'Disease', 'MESH:D006323', (136, 149))	('cellular senescence', 'CPA', (63, 82))	('growth arrest', 'Phenotype', 'HP:0001510', (136, 149))	('induced', 'Reg', (55, 62))
379237	27673450	This notion is further supported by evidence that despite harboring the same fusion gene, ASPS is cathepsin K positive, while ASPL-TFE3-positive renal cell carcinoma is cathepsin K negative.	('ASPS', 'Disease', (90, 94))	('cathepsin K', 'Gene', (98, 109))	('ASPS', 'Disease', 'MESH:D018234', (90, 94))	('cathepsin K', 'Gene', '1513', (98, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('renal cell carcinoma', 'Disease', (145, 165))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (145, 165))	('fusion gene', 'Var', (77, 88))	('positive', 'Reg', (110, 118))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 165))	('cathepsin K', 'Gene', (169, 180))	('cathepsin K', 'Gene', '1513', (169, 180))	('ASPS', 'Phenotype', 'HP:0012218', (90, 94))
379239	27673450	reported that ASPL-TFE3 expression alone, without an additional oncogenic event, is sufficient for invasive sarcomagenesis in mice.	('mice', 'Species', '10090', (126, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('ASPL-TFE3', 'Var', (14, 23))	('invasive sarcomagenesis', 'Disease', (99, 122))	('invasive sarcomagenesis', 'Disease', 'MESH:D009362', (99, 122))
379246	27673450	Our data revealed that ASPL-TFE3-induced senescence in MSCs was accompanied by an increase in the expression of SASP-associated proinflammatory cytokines.	('ASPL-TFE3-induced', 'Var', (23, 40))	('increase', 'PosReg', (82, 90))	('senescence', 'CPA', (41, 51))	('SASP', 'Gene', '7295', (112, 116))	('SASP', 'Gene', (112, 116))	('expression', 'MPA', (98, 108))
379249	27673450	In conclusion, we demonstrate that p21 is a novel transcriptional target of ASPL-TFE3 oncoprotein, and that ASPL-TFE3 affects cell cycle machinery and induces cellular senescence by up-regulating p21 expression.	('p21', 'Gene', (196, 199))	('affects', 'Reg', (118, 125))	('induces', 'PosReg', (151, 158))	('up-regulating', 'PosReg', (182, 195))	('p21', 'Gene', (35, 38))	('cell cycle machinery', 'CPA', (126, 146))	('expression', 'MPA', (200, 210))	('ASPL-TFE3', 'Var', (108, 117))	('cellular senescence', 'CPA', (159, 178))	('p21', 'Gene', '1026', (196, 199))	('p21', 'Gene', '1026', (35, 38))
379250	27673450	Furthermore, the present work provides a potential mechanism by which ASPL-TFE3-induced senescent cells may promote a protumorigenic microenvironment by secreting proinflammatory cytokines.	('ASPL-TFE3-induced', 'Var', (70, 87))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('promote', 'PosReg', (108, 115))	('secreting proinflammatory cytokines', 'MPA', (153, 188))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
379473	32467817	SMARCB1/INI mutations have become a defining characteristic for not only MRT, but also any neoplasm with a disposition for rhabdoid cytomorphology .	('INI', 'Gene', '84844', (8, 11))	('MRT', 'Disease', (73, 76))	('mutations', 'Var', (12, 21))	('neoplasm', 'Disease', 'MESH:D009369', (91, 99))	('neoplasm', 'Disease', (91, 99))	('SMARCB1', 'Gene', '6598', (0, 7))	('neoplasm', 'Phenotype', 'HP:0002664', (91, 99))	('SMARCB1', 'Gene', (0, 7))	('INI', 'Gene', (8, 11))
379502	32467817	IHC can be used to identify inactivation of SMARCB1/INI1 and thereby support the diagnosis of malignant extrarenal rhabdoid tumors in adults.	('malignant extrarenal rhabdoid tumors', 'Disease', (94, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('malignant extrarenal rhabdoid tumors', 'Disease', 'MESH:D018335', (94, 130))	('SMARCB1', 'Gene', '6598', (44, 51))	('SMARCB1', 'Gene', (44, 51))	('inactivation', 'Var', (28, 40))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('INI1', 'Gene', '6598', (52, 56))	('INI1', 'Gene', (52, 56))
379507	32467817	Thus, FISH for NR4A3 rearrangement can be performed to help differentiate between the two neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (90, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (90, 98))	('neoplasms', 'Disease', 'MESH:D009369', (90, 99))	('rearrangement', 'Var', (21, 34))	('neoplasms', 'Disease', (90, 99))	('NR4A3', 'Gene', '8013', (15, 20))	('NR4A3', 'Gene', (15, 20))
379511	32467817	Regarding the location of the patient's soft tissue neoplasm, loss of SMARCB1/INI1 expression is not a feature of dedifferentiated liposarcoma, a tumor that frequently involves the paratesticular region.	('liposarcoma', 'Disease', (131, 142))	('patient', 'Species', '9606', (30, 37))	('loss', 'Var', (62, 66))	('INI1', 'Gene', '6598', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('INI1', 'Gene', (78, 82))	('neoplasm', 'Disease', (52, 60))	('tumor', 'Disease', (146, 151))	('liposarcoma', 'Phenotype', 'HP:0012034', (131, 142))	('neoplasm', 'Disease', 'MESH:D009369', (52, 60))	('liposarcoma', 'Disease', 'MESH:D008080', (131, 142))	('neoplasm', 'Phenotype', 'HP:0002664', (52, 60))	('SMARCB1', 'Gene', '6598', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('SMARCB1', 'Gene', (70, 77))	('soft tissue neoplasm', 'Phenotype', 'HP:0031459', (40, 60))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
379519	32467817	IHC can help elucidate the inactivation of SMARCB1/INI1 and thereby support the diagnosis of malignant extrarenal rhabdoid tumors in adults.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('inactivation', 'Var', (27, 39))	('malignant extrarenal rhabdoid tumors', 'Disease', (93, 129))	('malignant extrarenal rhabdoid tumors', 'Disease', 'MESH:D018335', (93, 129))	('INI1', 'Gene', (51, 55))	('SMARCB1', 'Gene', '6598', (43, 50))	('INI1', 'Gene', '6598', (51, 55))	('SMARCB1', 'Gene', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
379634	31998420	More interestingly, a study revealed that the high level of serum CRP was significantly correlated with PD-L1 (programmed death-ligand 1) positivity in patients with non-small-cell lung cancer.	('serum', 'MPA', (60, 65))	('high level of serum CRP', 'Phenotype', 'HP:0011227', (46, 69))	('correlated', 'Reg', (88, 98))	('PD-L1', 'Gene', '29126', (104, 109))	('non-small-cell lung cancer', 'Disease', (166, 192))	('programmed death-ligand 1', 'Gene', (111, 136))	('programmed death-ligand 1', 'Gene', '29126', (111, 136))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (166, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('positivity', 'Var', (138, 148))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (170, 192))	('CRP', 'Protein', (66, 69))	('PD-L1', 'Gene', (104, 109))
379637	29133752	Proportion of Uterine Malignant Tumors in Patients with Laparoscopic Myomectomy: A National Multicenter Study in China The Food and Drug Administration recently announced that the use of morcellation may cause fibroids or pelvic dissemination and metastasis of uterine sarcoma; therefore, the use of morcellation is limited in the USA.	('Tumors', 'Phenotype', 'HP:0002664', (32, 38))	('morcellation', 'Var', (187, 199))	('sarcoma', 'Disease', (269, 276))	('Uterine Malignant Tumors', 'Phenotype', 'HP:0010784', (14, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	('Malignant Tumors', 'Disease', (22, 38))	('pelvic dissemination', 'CPA', (222, 242))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (261, 276))	('Patients', 'Species', '9606', (42, 50))	('sarcoma', 'Disease', 'MESH:D012509', (269, 276))	('fibroids', 'CPA', (210, 218))	('cause', 'Reg', (204, 209))	('metastasis', 'CPA', (247, 257))	('Malignant Tumors', 'Disease', 'MESH:D018198', (22, 38))
379650	29133752	Furthermore, previous studies reported that power morcellation had a risk of dispersing missed fragments all over the pelvic cavity, which can negatively affect patient prognosis and cause a range of complications.	('power morcellation', 'Var', (44, 62))	('patient', 'Species', '9606', (161, 168))	('affect', 'Reg', (154, 160))	('cause', 'Reg', (183, 188))	('dispersing', 'MPA', (77, 87))
379654	29133752	According to the International Classification of Diseases (ICD)-10 disease code, the primary diagnosis code is D25 (myoma).	('myoma', 'Disease', (116, 121))	('D25', 'Var', (111, 114))	('myoma', 'Disease', 'MESH:D009214', (116, 121))
379721	26535983	This component was highlighted on examination at low microscopic power by strong CD10 positivity.	('CD10', 'Gene', '4311', (81, 85))	('CD10', 'Gene', (81, 85))	('positivity', 'Var', (86, 96))
379963	31423173	In addition, previous literature on the pulmonary metastasis of low-grade ESS was reviewed by searching the PubMed database for pulmonary metastases of low-grade endometrial stromal sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (162, 189))	('low-grade', 'Var', (152, 161))	('pulmonary metastases', 'Disease', 'MESH:D009362', (128, 148))	('pulmonary metastases', 'Disease', (128, 148))	('endometrial stromal sarcoma', 'Disease', (162, 189))
380007	31423173	Of the 36 patients with pulmonary metastases of low-grade ESS, dyspnea was experienced by 9 patients (25.0%), chest pain was reported by 8 patients (22.2%), pneumothorax was identified in 7 patients (19.4%), coughing was experienced by 6 patients (16.7%), hemoptysis was presented by 2 patients (5.6%) and 18 patients (50%) were asymptomatic.	('dyspnea', 'Disease', 'MESH:D004417', (63, 70))	('patients', 'Species', '9606', (190, 198))	('hemoptysis', 'Phenotype', 'HP:0002105', (256, 266))	('pulmonary metastases', 'Disease', (24, 44))	('pneumothorax', 'Disease', (157, 169))	('hemoptysis', 'Disease', (256, 266))	('patients', 'Species', '9606', (92, 100))	('coughing', 'Disease', (208, 216))	('dyspnea', 'Phenotype', 'HP:0002094', (63, 70))	('chest pain', 'Disease', 'MESH:D002637', (110, 120))	('chest pain', 'Disease', (110, 120))	('coughing', 'Phenotype', 'HP:0012735', (208, 216))	('low-grade', 'Var', (48, 57))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (10, 18))	('pneumothorax', 'Phenotype', 'HP:0002107', (157, 169))	('patients', 'Species', '9606', (238, 246))	('pulmonary metastases', 'Disease', 'MESH:D009362', (24, 44))	('chest pain', 'Phenotype', 'HP:0100749', (110, 120))	('pain', 'Phenotype', 'HP:0012531', (116, 120))	('patients', 'Species', '9606', (309, 317))	('dyspnea', 'Disease', (63, 70))	('patients', 'Species', '9606', (286, 294))
380055	31423173	In conclusion, the present study reports a case of pulmonary metastatic low-grade ESS that simultaneously presented as cystic and solitary nodular lesions.	('low-grade', 'Var', (72, 81))	('solitary nodular lesions', 'Disease', 'MESH:D020518', (130, 154))	('solitary nodular lesions', 'Disease', (130, 154))
380060	31209257	T-cell receptor gene therapy targeting melanoma-associated antigen-A4 by silencing of endogenous TCR inhibits tumor growth in mice and human Genetically engineered T cells expressing a T-cell receptor (TCR) are powerful tools for cancer treatment and have shown significant clinical effects in sarcoma patients.	('TCR', 'Gene', '328483', (202, 205))	('mice', 'Species', '10090', (126, 130))	('endogenous', 'MPA', (86, 96))	('T-cell receptor', 'Gene', '328483', (0, 15))	('melanoma-associated antigen', 'Gene', (39, 66))	('melanoma-associated antigen', 'Gene', '57730', (39, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (294, 301))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('TCR', 'Gene', (97, 100))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('TCR', 'Gene', '328483', (97, 100))	('T-cell receptor', 'Gene', (185, 200))	('inhibits', 'NegReg', (101, 109))	('cancer', 'Disease', (230, 236))	('T-cell receptor', 'Gene', '6962', (185, 200))	('si', 'Chemical', 'MESH:D012825', (262, 264))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('T-cell receptor', 'Gene', (0, 15))	('T-cell receptor', 'Gene', '6962', (0, 15))	('silencing', 'Var', (73, 82))	('tumor', 'Disease', (110, 115))	('sarcoma', 'Disease', 'MESH:D012509', (294, 301))	('si', 'Chemical', 'MESH:D012825', (178, 180))	('T-cell receptor', 'Gene', '328483', (185, 200))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('sarcoma', 'Disease', (294, 301))	('patients', 'Species', '9606', (302, 310))	('TCR', 'Gene', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
380061	31209257	However, mismatch of the introduced TCR alpha/beta chains with endogenous TCR may impair the expression of transduced TCR, resulting in an insufficient antitumor capacity of modified T cells.	('TCR alpha', 'Gene', '28755', (36, 45))	('impair', 'NegReg', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('TCR', 'Gene', (118, 121))	('TCR alpha', 'Gene', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('insufficient', 'NegReg', (139, 151))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', (156, 161))	('mismatch', 'Var', (9, 17))
380074	31209257	In contrast, TCR-T cells recognize fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules and display good clinical effects in the treatment of solid tumors.	('bound', 'Interaction', (68, 73))	('solid tumors', 'Disease', 'MESH:D009369', (180, 192))	('solid tumors', 'Disease', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('antigen', 'Protein', (48, 55))	('fragments', 'Var', (35, 44))
380093	31209257	Next, we introduced the gene-modified T cells into NOD-SCID mice bearing tumors with or without HLA-A2402 to assess its in vivo antitumor capacity.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('NOD', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('HLA-A', 'Gene', '3105', (96, 101))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (132, 137))	('tumors', 'Disease', (73, 79))	('HLA-A', 'Gene', (96, 101))	('gene-modified', 'Var', (24, 37))	('mice', 'Species', '10090', (60, 64))	('NOD', 'Gene', '1822', (51, 54))
380147	31209257	The results showed cell surface MAGE-A4-specific TCR expression was much higher in si-TCR cells than in control NGMCs (Fig.	('si-TCR cells', 'Var', (83, 95))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('NGMCs', 'Chemical', '-', (112, 117))	('TCR', 'Gene', (49, 52))	('higher', 'PosReg', (73, 79))
380149	31209257	After cocultured for 4 h, the cell killing effect observed on KE4 was significant increased in si-TCR cells than in NGMCs, while there was no significant difference between the killing effect on QG56 (Fig.	('KE4', 'Var', (62, 65))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('QG56', 'CellLine', 'CVCL:6943', (195, 199))	('si-TCR', 'Var', (95, 101))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('cell killing effect', 'CPA', (30, 49))	('increased', 'PosReg', (82, 91))	('NGMCs', 'Chemical', '-', (116, 121))
380152	31209257	The number of spots developed in GMCs after peptide-specific stimulation was significantly higher than that in NGMCs following the same stimulation (Fig.	('higher', 'PosReg', (91, 97))	('GMCs', 'Chemical', '-', (112, 116))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('NGMCs', 'Chemical', '-', (111, 116))	('peptide-specific stimulation', 'Var', (44, 72))	('GMCs', 'Chemical', '-', (33, 37))
380157	31209257	Eight-week-old female NOD-SCID immunodeficient mice were inoculated subcutaneously with KE4 (1 x 107 cells/mouse) and QG56 (1 x 106 cells/mouse) into the right flank of mice.	('1 x 107', 'Var', (93, 100))	('mouse', 'Species', '10090', (107, 112))	('mouse', 'Species', '10090', (138, 143))	('NOD-SCID immunodeficient', 'Disease', (22, 46))	('mice', 'Species', '10090', (169, 173))	('NOD-SCID immunodeficient', 'Disease', 'MESH:D020191', (22, 46))	('mice', 'Species', '10090', (47, 51))	('QG56', 'CellLine', 'CVCL:6943', (118, 122))
380158	31209257	After inoculation with tumor cells, mice were randomly divided into three groups and administered three different treatments: normal saline group (NS), NGMC group, and si-TCR GMC group.	('NGMC', 'Chemical', '-', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('GMC', 'Chemical', '-', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('si-TCR', 'Var', (168, 174))	('si', 'Chemical', 'MESH:D012825', (168, 170))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Disease', (23, 28))	('GMC', 'Chemical', '-', (175, 178))
380162	31209257	Compared to the NS group and NGMC group, si-TCR GMCs transferred into KE4 tumor-bearing mice inhibited tumor growth specifically, while this effect was not observed in QG56 tumor-bearing mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('NGMC', 'Chemical', '-', (29, 33))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('mice', 'Species', '10090', (187, 191))	('QG56', 'CellLine', 'CVCL:6943', (168, 172))	('tumor', 'Disease', (74, 79))	('si-TCR', 'Var', (41, 47))	('GMCs', 'Chemical', '-', (48, 52))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('mice', 'Species', '10090', (88, 92))	('inhibited', 'NegReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
380188	31209257	NOD-SCID mice inoculated with human tumor cell lines expressing both MAGE-A4 and HLA-A*2402 exhibited decreased tumor growth after si-TCR T cell treatment.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('human', 'Species', '9606', (30, 35))	('HLA-A', 'Gene', '3105', (81, 86))	('NOD', 'Gene', (0, 3))	('MAGE-A4', 'Var', (69, 76))	('decreased', 'NegReg', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('HLA-A', 'Gene', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NOD', 'Gene', '1822', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mice', 'Species', '10090', (9, 13))	('tumor', 'Disease', (112, 117))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('tumor', 'Disease', (36, 41))
380194	31209257	However, one problem associated with introduction of exogenous TCR is the mismatch with endogenous TCR, which leads to T cell recognition of normal tissues expressing unknown antigens to cause tissue damage.	('leads to', 'Reg', (110, 118))	('mismatch', 'Var', (74, 82))	('si', 'Chemical', 'MESH:D012825', (162, 164))
380199	31209257	We manufactured large numbers of gene-modified T cells and performed in vitro and in vivo detection of anti-tumor activity.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('gene-modified', 'Var', (33, 46))	('tumor', 'Disease', (108, 113))
380202	31209257	Tetramer assay showed the cell surface MAGE-A4-specific TCR expression was much higher in si-TCR cells than in control NGMCs and cytotoxic assay indicated the specific cell killing effect toward MAGE-A4+, HLA-A*2402+ cell lines.	('si', 'Chemical', 'MESH:D012825', (90, 92))	('HLA-A', 'Gene', (205, 210))	('TCR', 'Gene', (56, 59))	('MAGE-A4-specific TCR', 'Gene', (39, 59))	('si-TCR cells', 'Var', (90, 102))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('cell killing effect', 'CPA', (168, 187))	('higher', 'PosReg', (80, 86))	('NGMCs', 'Chemical', '-', (119, 124))	('HLA-A', 'Gene', '3105', (205, 210))
380204	31209257	For in vivo experiment, we observed the general state and response of NOD-SCID mice infused with si-TCR T cells, no adverse reactions or side effects were detected.	('NOD', 'Gene', '1822', (70, 73))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('NOD', 'Gene', (70, 73))	('mice', 'Species', '10090', (79, 83))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('si-TCR T cells', 'Var', (97, 111))
380205	31209257	After infusion, the growth of KE4 tumors (MAGE-A4+, HLA-A*2402+) was specifically inhibited, while the tumor size of QG56 tumors (MAGE-A4+, HLA-A*2402-) was not changed, indicating that the modified T cells specifically killed their HLA matching KE4 tumors.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('growth', 'MPA', (20, 26))	('HLA-A', 'Gene', (140, 145))	('HLA-A', 'Gene', (52, 57))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', (122, 127))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('tumor', 'Disease', (34, 39))	('inhibited', 'NegReg', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('QG56', 'CellLine', 'CVCL:6943', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('HLA-A', 'Gene', '3105', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (103, 108))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('HLA-A', 'Gene', '3105', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', (34, 40))	('MAGE-A4+', 'Var', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (250, 256))
380211	31209257	Clinical evidence for a patient also suggested that si-TCR T cell therapy may attribute to maintaining a CR status.	('CR', 'Chemical', '-', (56, 58))	('patient', 'Species', '9606', (24, 31))	('CR status', 'MPA', (105, 114))	('CR', 'Chemical', '-', (105, 107))	('si-TCR', 'Var', (52, 58))	('si', 'Chemical', 'MESH:D012825', (52, 54))
380212	31209257	Our data suggest the adoptive cell therapy with human lymphocytes engineered to express MAGE-A4 si-TCR is a promising strategy to treat patients with MAGE-A4 expressing tumors.	('MAGE-A4', 'Gene', (88, 95))	('human', 'Species', '9606', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('patients', 'Species', '9606', (136, 144))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('si-TCR', 'Var', (96, 102))	('tumors', 'Disease', (169, 175))	('si', 'Chemical', 'MESH:D012825', (96, 98))
380219	29610390	Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (MDM2, CDK4, and YEATS2) and adipocytic differentiation factors (HMGA2 and CPM).	('rearrangements', 'Var', (81, 95))	('liposarcomas', 'Phenotype', 'HP:0012034', (15, 27))	('WD', 'Disease', 'MESH:D006527', (5, 7))	('CPM', 'Gene', '1368', (204, 207))	('liposarcoma', 'Phenotype', 'HP:0012034', (15, 26))	('Chr 12q', 'Gene', (99, 106))	('DD liposarcomas', 'Disease', 'MESH:D008080', (12, 27))	('DD liposarcomas', 'Disease', (12, 27))	('MDM2', 'Gene', (130, 134))	('CPM', 'Gene', (204, 207))	('HMGA2', 'Gene', (194, 199))	('MDM2', 'Gene', '4193', (130, 134))	('encode', 'Reg', (112, 118))	('CDK4', 'Gene', (136, 140))	('YEATS2', 'Gene', '55689', (146, 152))	('CDK4', 'Gene', '1019', (136, 140))	('YEATS2', 'Gene', (146, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('HMGA2', 'Gene', '8091', (194, 199))
380224	29610390	DD tumors had higher numbers of somatic copy-number losses, amplifications involving Chr 12q, and fusion transcripts than WD tumors.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('fusion transcripts', 'Var', (98, 116))	('amplifications', 'Var', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('DD tumors', 'Disease', 'MESH:D009369', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('DD tumors', 'Disease', (0, 9))	('Chr', 'Gene', (85, 88))	('WD tumors', 'Disease', 'MESH:D006527', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('WD tumors', 'Disease', (122, 131))
380231	29610390	Myxoid liposarcomas are characterized by a disease-defining translocation DDIT3 with FUS or EWSR1, whereas pleomorphic liposarcomas show complex karyotypes, often alongside TP53 mutations.	('Myxoid liposarcomas', 'Phenotype', 'HP:0012268', (0, 19))	('EWSR1', 'Gene', (92, 97))	('DDIT3', 'Gene', '1649', (74, 79))	('Myxoid liposarcomas', 'Disease', (0, 19))	('liposarcomas', 'Phenotype', 'HP:0012034', (7, 19))	('translocation', 'Var', (60, 73))	('TP53', 'Gene', (173, 177))	('pleomorphic liposarcomas', 'Disease', (107, 131))	('DDIT3', 'Gene', (74, 79))	('FUS', 'Gene', (85, 88))	('TP53', 'Gene', '7157', (173, 177))	('Myxoid liposarcomas', 'Disease', 'MESH:D018208', (0, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('EWSR1', 'Gene', '2130', (92, 97))	('liposarcomas', 'Phenotype', 'HP:0012034', (119, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (107, 131))	('FUS', 'Gene', '2521', (85, 88))	('liposarcoma', 'Phenotype', 'HP:0012034', (119, 130))	('liposarcoma', 'Phenotype', 'HP:0012034', (7, 18))
380241	29610390	In addition, both of these tumors harbor amplified segments from Chr 12q that form the basis of ring or rod neochromosomes, the origins of which are unknown.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('amplified', 'Var', (41, 50))	('ring or rod neochromosomes', 'Disease', (96, 122))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))
380251	29610390	Furthermore, only one known cancer gene, NAV3, with a nonsynonymous mutation was common in both WD and DD tumors from patient DWN3 (uc001syp.3, p.R2241Q, variant allele frequencies of 0.77 and 0.80 in WD and DD tumors, respectively).	('WD', 'Disease', 'MESH:D006527', (201, 203))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('DD tumors', 'Disease', 'MESH:D009369', (208, 217))	('NAV3', 'Gene', (41, 45))	('NAV3', 'Gene', '89795', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('p.R2241Q', 'Var', (144, 152))	('DD tumors', 'Disease', (208, 217))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('patient', 'Species', '9606', (118, 125))	('WD', 'Disease', 'MESH:D006527', (96, 98))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('p.R2241Q', 'Mutation', 'rs201015374', (144, 152))	('DD tumors', 'Disease', (103, 112))	('cancer', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('DD tumors', 'Disease', 'MESH:D009369', (103, 112))
380256	29610390	Recurrent copy-number amplifications were observed in Chromosomes 1q, 5p, 6q, and 12q that were recapitulated as focal amplifications in both tumor types (Fig.	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('copy-number amplifications', 'Var', (10, 36))
380257	29610390	As a note, the reported recurrent Chr 1p32 amplification in c-JUN was present in 3 of 17 samples (DWN6-DD, DWN7-DD, and FF7-WD).	('c-JUN', 'Gene', '3725', (60, 65))	('amplification', 'MPA', (43, 56))	('DD', 'Chemical', '-', (112, 114))	('c-JUN', 'Gene', (60, 65))	('DWN6-DD', 'Var', (98, 105))	('FF7-WD', 'Disease', 'MESH:D006527', (120, 126))	('DD', 'Chemical', '-', (103, 105))	('DWN7-DD', 'Var', (107, 114))	('FF7-WD', 'Disease', (120, 126))
380258	29610390	In addition, loss of TP53 was found in one sample (DWN3-DD), and three patients had TERT amplification (DWN2-WD, DWN2-DD, DWN10-DD, and FF7-DD) in Chr 5p.	('TP53', 'Gene', (21, 25))	('FF7-DD', 'Var', (136, 142))	('DD', 'Chemical', '-', (140, 142))	('patients', 'Species', '9606', (71, 79))	('DWN2-DD', 'Var', (113, 120))	('DWN2-WD', 'Disease', (104, 111))	('DD', 'Chemical', '-', (56, 58))	('DWN2-WD', 'Disease', 'MESH:D006527', (104, 111))	('loss', 'NegReg', (13, 17))	('DWN10-DD', 'Var', (122, 130))	('DD', 'Chemical', '-', (128, 130))	('DD', 'Chemical', '-', (118, 120))	('TP53', 'Gene', '7157', (21, 25))
380261	29610390	In general, deletions were more abundant in DD than in WD tumors (P = 0.025 for deleted genes; P = 0.14 for amplified genes) (Fig.	('deletions', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('DD', 'Chemical', '-', (44, 46))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('WD tumors', 'Disease', 'MESH:D006527', (55, 64))	('WD tumors', 'Disease', (55, 64))
380266	29610390	Next, we used a pathway-level approach to identify enrichments of somatic copy-number changes in WD or DD tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('copy-number changes', 'Var', (74, 93))	('DD tumors', 'Disease', (103, 112))	('DD tumors', 'Disease', 'MESH:D009369', (103, 112))	('WD', 'Disease', 'MESH:D006527', (97, 99))
380268	29610390	There, we found that immune-related pathways scored higher in copy-number losses in DD than in WD samples that are also differentially expressed between these two subtypes in our data (Fig.	('immune-related pathways', 'Pathway', (21, 44))	('copy-number', 'Var', (62, 73))	('WD', 'Disease', 'MESH:D006527', (95, 97))	('losses', 'NegReg', (74, 80))	('higher', 'PosReg', (52, 58))	('DD', 'Chemical', '-', (84, 86))
380276	29610390	This unique data set provided the opportunity to study whether copy-number alterations in each paired set of matched tumors would impact gene expression differences between WD and DD tumor groups.	('WD', 'Disease', 'MESH:D006527', (173, 175))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('DD tumor', 'Disease', (180, 188))	('gene expression differences', 'MPA', (137, 164))	('impact', 'Reg', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('copy-number alterations', 'Var', (63, 86))	('DD tumor', 'Disease', 'MESH:D009369', (180, 188))
380288	29610390	PTEN is a DD-specific loss in three DD samples (DWN3-DD, DWN5-DD, and DWN7-DD) and its expression is lower in these samples when compared to their matched WD tumor (data not shown).	('DWN3-DD', 'Var', (48, 55))	('DD', 'Chemical', '-', (36, 38))	('WD tumor', 'Disease', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('DD', 'Chemical', '-', (62, 64))	('DWN7-DD', 'Var', (70, 77))	('lower', 'NegReg', (101, 106))	('expression', 'MPA', (87, 97))	('loss', 'NegReg', (22, 26))	('DD', 'Chemical', '-', (10, 12))	('DD', 'Chemical', '-', (53, 55))	('PTEN', 'Gene', (0, 4))	('WD tumor', 'Disease', 'MESH:D006527', (155, 163))	('DD', 'Chemical', '-', (75, 77))	('PTEN', 'Gene', '5728', (0, 4))	('DWN5-DD', 'Var', (57, 64))
380289	29610390	Immune-related pathways are both enriched by copy-number losses specifically in DD samples and are significantly down-regulated in DD samples compared to WD samples (Supplemental Table 4A,B).	('down-regulated', 'NegReg', (113, 127))	('copy-number losses', 'Var', (45, 63))	('WD', 'Disease', 'MESH:D006527', (154, 156))	('DD', 'Chemical', '-', (131, 133))	('DD', 'Chemical', '-', (80, 82))	('Immune-related pathways', 'Pathway', (0, 23))
380299	29610390	Fusions involving carboxypeptidase M (CPM) on Chr 12q were also more prevalent in DD tumors than in WD tumors.	('carboxypeptidase M', 'Gene', (18, 36))	('Fusions', 'Var', (0, 7))	('WD tumors', 'Disease', 'MESH:D006527', (100, 109))	('carboxypeptidase M', 'Gene', '1368', (18, 36))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('DD tumors', 'Disease', (82, 91))	('DD tumors', 'Disease', 'MESH:D009369', (82, 91))	('CPM', 'Gene', (38, 41))	('WD tumors', 'Disease', (100, 109))	('CPM', 'Gene', '1368', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('prevalent', 'Reg', (69, 78))
380300	29610390	These rearrangements would cause truncated transcripts of CPM to be depressed, which follows the significantly lower levels of CPM found in DD tumors when compared to WD tumors (P = 0.01; log2 of fold change = 1.77).	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('CPM', 'Gene', (127, 130))	('rearrangements', 'Var', (6, 20))	('CPM', 'Gene', (58, 61))	('truncated transcripts', 'MPA', (33, 54))	('depressed', 'Disease', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('CPM', 'Gene', '1368', (127, 130))	('WD tumors', 'Disease', 'MESH:D006527', (167, 176))	('CPM', 'Gene', '1368', (58, 61))	('depressed', 'Disease', 'MESH:D000275', (68, 77))	('DD tumors', 'Disease', (140, 149))	('DD tumors', 'Disease', 'MESH:D009369', (140, 149))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('WD tumors', 'Disease', (167, 176))
380304	29610390	First, the existence of shared point mutations between WD and DD components indicate that they were derivatives from a common ancestral clone as these shared events are rare in independent tumors from two individuals.	('DD', 'Chemical', '-', (62, 64))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Disease', (189, 195))	('point mutations', 'Var', (31, 46))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('WD', 'Disease', 'MESH:D006527', (55, 57))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
380306	29610390	This suggests that although the point mutations accumulated at a similar rate in each tumor type, the large proportion of tumor-specific point mutations indicates an early and continual divergence.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('point mutations', 'Var', (137, 152))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (122, 127))
380307	29610390	Copy-number alterations (especially amplified Chr 12q) may be responsible for determining the initiation of malignancy because there were no clear drivers in the somatic point mutations.	('malignancy', 'Disease', 'MESH:D009369', (108, 118))	('malignancy', 'Disease', (108, 118))	('amplified', 'Var', (36, 45))	('Chr 12q', 'Gene', (46, 53))
380308	29610390	First, gains from Chr 12 are highest in magnitude in matched WD and DD liposarcomas, are 100% recurrent across all patients, and are accompanied by coamplifications of Chr 6q23 and Chr 1p32, both of which harbor known oncogenes.	('DD liposarcomas', 'Disease', 'MESH:D008080', (68, 83))	('patients', 'Species', '9606', (115, 123))	('WD', 'Disease', 'MESH:D006527', (61, 63))	('Chr 6q23', 'Gene', (168, 176))	('liposarcoma', 'Phenotype', 'HP:0012034', (71, 82))	('liposarcomas', 'Phenotype', 'HP:0012034', (71, 83))	('coamplifications', 'Var', (148, 164))	('DD liposarcomas', 'Disease', (68, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('Chr 12', 'Gene', (18, 24))	('Chr', 'Gene', (181, 184))
380310	29610390	Because the number of copy-number losses and fusions was higher in DD than in WD tumors, we infer that DD tumors have undergone more cycles of breakage-fusion-bridge than their matched WD tumors.	('WD tumors', 'Disease', (185, 194))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('higher', 'PosReg', (57, 63))	('WD tumors', 'Disease', 'MESH:D006527', (185, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('DD', 'Chemical', '-', (103, 105))	('WD tumors', 'Disease', 'MESH:D006527', (78, 87))	('copy-number losses', 'Var', (22, 40))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('WD tumors', 'Disease', (78, 87))	('DD tumors', 'Disease', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('fusions', 'Var', (45, 52))	('DD tumors', 'Disease', 'MESH:D009369', (103, 112))	('DD', 'Chemical', '-', (67, 69))
380311	29610390	This would be consistent with the high number of amplifications and overexpression of CDK4 and MDM2 from Chr 12q in DD tumors when compared to WD tumors that would contribute to the rapid cell division and thus increased breakage-fusion-bridge events experienced by DD tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('CDK4', 'Gene', (86, 90))	('DD tumors', 'Disease', 'MESH:D009369', (116, 125))	('MDM2', 'Gene', '4193', (95, 99))	('amplifications', 'Var', (49, 63))	('increased breakage', 'Phenotype', 'HP:0040012', (211, 229))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('DD tumors', 'Disease', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('CDK4', 'Gene', '1019', (86, 90))	('DD tumors', 'Disease', 'MESH:D009369', (266, 275))	('breakage-fusion-bridge events', 'CPA', (221, 250))	('DD tumors', 'Disease', (266, 275))	('increased', 'PosReg', (211, 220))	('overexpression', 'PosReg', (68, 82))	('WD tumors', 'Disease', 'MESH:D006527', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('WD tumors', 'Disease', (143, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('MDM2', 'Gene', (95, 99))
380314	29610390	Rearrangements disrupting the coding regions of both HMGA2 and CPM occurred significantly more frequently in DD than in their matched WD samples.	('Rearrangements', 'Var', (0, 14))	('DD', 'Chemical', '-', (109, 111))	('HMGA2', 'Gene', (53, 58))	('WD', 'Disease', 'MESH:D006527', (134, 136))	('CPM', 'Gene', (63, 66))	('CPM', 'Gene', '1368', (63, 66))	('HMGA2', 'Gene', '8091', (53, 58))
380315	29610390	The Cancer Genome Atlas sarcoma (TCGA SARC) set also revealed that out of all the sarcoma subtypes characterized, only DD liposarcomas have fusions involving HMGA2 (there are no WD liposarcomas in this data set).	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('sarcoma', 'Disease', (24, 31))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('liposarcomas', 'Phenotype', 'HP:0012034', (181, 193))	('WD liposarcomas', 'Disease', (178, 193))	('HMGA2', 'Gene', (158, 163))	('liposarcoma', 'Phenotype', 'HP:0012034', (181, 192))	('sarcoma', 'Disease', (126, 133))	('WD liposarcomas', 'Disease', 'MESH:D006527', (178, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('fusions', 'Var', (140, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('liposarcomas', 'Phenotype', 'HP:0012034', (122, 134))	('HMGA2', 'Gene', '8091', (158, 163))	('sarcoma', 'Disease', (82, 89))	('liposarcoma', 'Phenotype', 'HP:0012034', (122, 133))	('sarcoma', 'Disease', 'MESH:D012509', (185, 192))	('sarcoma', 'Disease', (185, 192))	('DD liposarcomas', 'Disease', 'MESH:D008080', (119, 134))	('Cancer Genome Atlas sarcoma', 'Disease', 'MESH:D009369', (4, 31))	('DD liposarcomas', 'Disease', (119, 134))	('Cancer Genome Atlas sarcoma', 'Disease', (4, 31))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
380317	29610390	Several studies also showed that in DD liposarcoma, rearrangements of HMGA2 to distant or extrachromosomal regions result in the loss of Let-7 miRNA binding sites within the 3'-untranslated regions (3' UTRs).	('rearrangements', 'Var', (52, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('loss', 'NegReg', (129, 133))	('HMGA2', 'Gene', '8091', (70, 75))	('liposarcoma', 'Phenotype', 'HP:0012034', (39, 50))	('DD liposarcoma', 'Disease', (36, 50))	('HMGA2', 'Gene', (70, 75))	('Let-7', 'Gene', (137, 142))	('DD liposarcoma', 'Disease', 'MESH:D008080', (36, 50))
380326	29610390	Methylation of CEBPA and KLF14 promoters was reported to alter their gene expression in DD more than WD liposarcoma, but we did not observe these expression differences in our samples (Supplemental Fig.	('liposarcoma', 'Phenotype', 'HP:0012034', (104, 115))	('CEBPA', 'Gene', (15, 20))	('alter', 'Reg', (57, 62))	('DD', 'Chemical', '-', (88, 90))	('Methylation', 'Var', (0, 11))	('CEBPA', 'Gene', '1050', (15, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('KLF14', 'Gene', (25, 30))	('KLF14', 'Gene', '136259', (25, 30))	('gene expression', 'MPA', (69, 84))	('WD liposarcoma', 'Disease', (101, 115))	('WD liposarcoma', 'Disease', 'MESH:D006527', (101, 115))	('DD more', 'Disease', (88, 95))
380327	29610390	In addition, enriched H3K9me3 methylation of the transcription factor, KLF6, appears to result in lower expression in DD liposarcomas when compared to WD liposarcomas.	('liposarcomas', 'Phenotype', 'HP:0012034', (121, 133))	('WD liposarcomas', 'Disease', 'MESH:D006527', (151, 166))	('KLF6', 'Gene', '1316', (71, 75))	('liposarcomas', 'Phenotype', 'HP:0012034', (154, 166))	('H3K9me3 methylation', 'Var', (22, 41))	('WD liposarcomas', 'Disease', (151, 166))	('expression', 'MPA', (104, 114))	('KLF6', 'Gene', (71, 75))	('DD liposarcomas', 'Disease', 'MESH:D008080', (118, 133))	('liposarcoma', 'Phenotype', 'HP:0012034', (154, 165))	('liposarcoma', 'Phenotype', 'HP:0012034', (121, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('lower', 'NegReg', (98, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('DD liposarcomas', 'Disease', (118, 133))
380334	29610390	Future studies are needed to investigate the putative mechanisms of HMGA2 that may reveal therapeutic implications in combining inhibitors of CDK4/MDM2 and HMGA2 in DD liposarcoma.	('CDK4', 'Gene', '1019', (142, 146))	('HMGA2', 'Gene', '8091', (156, 161))	('DD liposarcoma', 'Disease', (165, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('MDM2', 'Gene', '4193', (147, 151))	('DD liposarcoma', 'Disease', 'MESH:D008080', (165, 179))	('HMGA2', 'Gene', (156, 161))	('MDM2', 'Gene', (147, 151))	('HMGA2', 'Gene', '8091', (68, 73))	('HMGA2', 'Gene', (68, 73))	('inhibitors', 'Var', (128, 138))	('CDK4', 'Gene', (142, 146))	('liposarcoma', 'Phenotype', 'HP:0012034', (168, 179))
380343	29610390	Only frozen samples were used in the mutation analysis because the variants in the FFPE samples were largely derived from nonreproducible C > T/G > A sequencing artifacts that were caused by the formalin fixation, and true positives were indistinguishable (Supplemental Fig.	('C > T/G > A', 'Var', (138, 149))	('variants', 'Var', (67, 75))	('formalin', 'Chemical', 'MESH:D005557', (195, 203))
380349	29610390	To identify whether the copy number of genes within a pathway were differentially altered between WD and DD tumors, an enrichment score of copy-number alteration was derived for a pathway in a sample, which is odds ratio for the ratio of genes with copy-number alterations in a pathway versus the ratio of genes with copy-number changes among all genes.	('WD', 'Disease', 'MESH:D006527', (98, 100))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('DD tumors', 'Disease', 'MESH:D009369', (105, 114))	('DD tumors', 'Disease', (105, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('copy-number alterations', 'Var', (249, 272))	('altered', 'Reg', (82, 89))
380351	29610390	An integration analysis was performed to integrate copy-number and gene expression data in order to identify pathways in which changes in somatic copy number were correlated with differential gene expression changes between WD and DD samples.	('differential gene expression changes', 'MPA', (179, 215))	('DD', 'Chemical', '-', (231, 233))	('changes', 'Var', (127, 134))	('WD', 'Disease', 'MESH:D006527', (224, 226))
380356	29610390	Pathways with significant combined P-values (P < 0.05) would have significant difference in both copy-number alterations and gene expression between WD and DD samples.	('copy-number alterations', 'Var', (97, 120))	('WD', 'Disease', 'MESH:D006527', (149, 151))	('DD', 'Chemical', '-', (156, 158))	('difference', 'Reg', (78, 88))
380366	29610390	Funding sources include Amshwand Foundation, QuadW Foundation, and Lemuel Allen Jr. to the Sarcoma Oncology Group as well as a Cancer Prevention Research Institute (R120501 to P.A.F., Summer Internship to A.A.), Welch Foundation's Robert A. Welch Distinguished University Chair Award (G-0040 to P.A.F.	('Sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('Sarcoma', 'Disease', (91, 98))	('Oncology', 'Phenotype', 'HP:0002664', (99, 107))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('G-0040', 'Var', (285, 291))
380442	29118572	The DSC curves for physical mixture of MTX, PLGA, and PEG4000 (Figure 3D) and MTX-loaded implants (Figure 3E) showed a thermal behavior similar to that identified for pure MTX and the polymers.	('MTX', 'Chemical', 'MESH:D008727', (39, 42))	('PEG4000', 'Var', (54, 61))	('PEG4000', 'Chemical', 'MESH:C000595214', (54, 61))	('polymers', 'Chemical', 'MESH:D011108', (184, 192))	('MTX', 'Chemical', 'MESH:D008727', (78, 81))	('MTX', 'Chemical', 'MESH:D008727', (172, 175))	('DSC', 'MPA', (4, 7))
380443	29118572	FTIR spectra analysis of MTX, PLGA, PEG4000, physical mixture of MTX, PLGA, and PEG4000, and MTX-loaded implants revealed characteristic absorption bands at different frequencies (Figure 4).	('MTX', 'Chemical', 'MESH:D008727', (93, 96))	('PEG4000', 'Chemical', 'MESH:C000595214', (80, 87))	('MTX', 'Chemical', 'MESH:D008727', (25, 28))	('PEG4000', 'Var', (80, 87))	('PEG4000', 'Chemical', 'MESH:C000595214', (36, 43))	('absorption bands', 'MPA', (137, 153))	('MTX', 'Chemical', 'MESH:D008727', (65, 68))
380445	29118572	Typical infrared absorption bands observed in PLGA (Figure 4B) and PEG4000 (Figure 4C) were detected in the spectra of physical mixture of MTX, PLGA, and PEG4000 (Figure 4D) and MTX-loaded implants (Figure 4E).	('MTX', 'Chemical', 'MESH:D008727', (139, 142))	('PEG4000', 'Var', (67, 74))	('PEG4000', 'Chemical', 'MESH:C000595214', (67, 74))	('MTX', 'Chemical', 'MESH:D008727', (178, 181))	('PEG4000', 'Chemical', 'MESH:C000595214', (154, 161))	('PEG4000', 'Var', (154, 161))
380474	29118572	PEG has been widely used as a drug carrier and addition of PEG can facilitate the dissolution and increase the release rate of the drug from implants by promoting the water diffusion into the implants.	('water', 'Chemical', 'MESH:D014867', (167, 172))	('PEG', 'Var', (59, 62))	('facilitate', 'PosReg', (67, 77))	('increase', 'PosReg', (98, 106))	('release rate', 'MPA', (111, 123))	('promoting', 'PosReg', (153, 162))	('PEG', 'Chemical', '-', (59, 62))	('PEG', 'Chemical', '-', (0, 3))	('water diffusion into', 'MPA', (167, 187))	('dissolution', 'MPA', (82, 93))
380507	22645714	Distinctions are made between cell surface antigens that can be targeted in an MHC independent manner using antibodies, antibody derivatives, or chimeric antigen receptors versus intracellular antigens which must be targeted with MHC restricted T cell therapies.	('chimeric', 'Var', (145, 153))	('MHC', 'Gene', '3107', (79, 82))	('MHC', 'Gene', (230, 233))	('MHC', 'Gene', (79, 82))	('MHC', 'Gene', '3107', (230, 233))
380511	22645714	This strategy has yielded some impressive results, including the development of ABL inhibitors for chronic myeloid leukemia (Cortes et al.,), KIT inhibitors for gastrointestinal stromal tumor, and BRAF inhibitors for melanoma (Dhomen and Marais,; Ribas and Flaherty,).	('inhibitors', 'Var', (84, 94))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (99, 123))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('chronic myeloid leukemia', 'Disease', (99, 123))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (99, 123))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('ABL', 'Gene', '25', (80, 83))	('BRAF', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (197, 201))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (161, 191))	('ABL', 'Gene', (80, 83))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (161, 191))	('gastrointestinal stromal tumor', 'Disease', (161, 191))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (107, 123))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanoma', 'Disease', (217, 225))
380522	22645714	Despite these challenges, the likelihood that immunogenic epitopes are present in any individual cancer increases with an increase in mutation frequency.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Disease', (97, 103))	('mutation frequency', 'Var', (134, 152))
380523	22645714	Carcinomas are estimated to carry, on average, 7-10 unique, novel mutations capable of being recognized by the immune system (Segal et al.,).	('mutations', 'Var', (66, 75))	('Carcinomas', 'Disease', (0, 10))	('Carcinomas', 'Disease', 'MESH:D002277', (0, 10))	('Carcinomas', 'Phenotype', 'HP:0030731', (0, 10))
380548	22645714	Of four patients who suffered a relapse following blinatumomab, two were in sanctuary sites (testis, brain), and two relapsed with CD19- ALL, suggesting that tissue penetration and the development of antigen negative variants could pose a challenge for monotherapy with this agent (Topp et al.,).	('CD19', 'Gene', (131, 135))	('blinatumomab', 'Chemical', 'MESH:C510808', (50, 62))	('CD19', 'Gene', '930', (131, 135))	('blinatumomab', 'Var', (50, 62))	('patients', 'Species', '9606', (8, 16))
380555	22645714	Two pediatric studies are currently using anti-CD19 CARs to treat ALL (NCT00840853 and NCT01430390).	('CAR', 'Gene', '653108', (52, 55))	('CD19', 'Gene', (47, 51))	('CD19', 'Gene', '930', (47, 51))	('CAR', 'Gene', (52, 55))	('NCT00840853', 'Var', (71, 82))	('NCT01430390', 'Var', (87, 98))
380577	22645714	(Jeha et al.,; Piccaluga et al.,) Interestingly though, recent data suggests that CD20 may be upregulated on ALL blasts after induction chemotherapy or with steroids, providing rationale for renewed efforts at the immunotherapeutic targeting of CD20 in pediatric ALL (Gaipa et al.,; Dworzak et al.,; NCT01363128; and NCT01279707).	('NCT01363128', 'Var', (300, 311))	('CD20', 'Gene', (82, 86))	('CD20', 'Gene', '931', (82, 86))	('steroids', 'Chemical', 'MESH:D013256', (157, 165))	('NCT01279707', 'Var', (317, 328))	('upregulated', 'PosReg', (94, 105))	('CD20', 'Gene', (245, 249))	('CD20', 'Gene', '931', (245, 249))
380590	22645714	To that end, CARs targeting CD30 are currently under study (NCT01192464; NCT01316146), but results have not yet been reported.	('CD30', 'Gene', '943', (28, 32))	('CAR', 'Gene', (13, 16))	('NCT01316146', 'Var', (73, 84))	('CAR', 'Gene', '653108', (13, 16))	('NCT01192464; NCT01316146', 'Var', (60, 84))	('CD30', 'Gene', (28, 32))
380609	22645714	Mouse models of malignancy originally identified CD8+ T cell clones specific for VEGFR2-derived peptides that could inhibit tumor angiogenesis and growth (Dong et al.,; Suzuki et al.,).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('growth', 'CPA', (147, 153))	('VEGFR2-derived', 'Gene', (81, 95))	('tumor', 'Disease', (124, 129))	('malignancy', 'Disease', 'MESH:D009369', (16, 26))	('peptides', 'Var', (96, 104))	('inhibit', 'NegReg', (116, 123))	('Mouse', 'Species', '10090', (0, 5))	('malignancy', 'Disease', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
380626	22645714	A mutant, constitutively activated form of the epidermal growth factor receptor, EGFRvIII, is overexpressed on the surface of approximately 20% of adult and pediatric gliomas (Heimberger et al.,; Bax et al.,).	('pediatric gliomas', 'Disease', 'MESH:D005910', (157, 174))	('epidermal growth factor receptor', 'Gene', (47, 79))	('epidermal growth factor receptor', 'Gene', '1956', (47, 79))	('pediatric gliomas', 'Disease', (157, 174))	('overexpressed', 'PosReg', (94, 107))	('mutant', 'Var', (2, 8))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
380629	22645714	Fibroblast growth factors play myriad roles in cell signaling, growth and differentiation, and mutations or alterations in this system have been described in a number of malignancies (Olsen et al.,; Wesche et al.,).	('malignancies', 'Disease', (170, 182))	('alterations', 'Var', (108, 119))	('described', 'Reg', (145, 154))	('malignancies', 'Disease', 'MESH:D009369', (170, 182))	('mutations', 'Var', (95, 104))
380630	22645714	Antibodies to fibroblast growth factor receptor 3 (FGFR3) are currently undergoing trials in multiple myeloma (NCT00866138).	('Antibodies', 'Var', (0, 10))	('FGFR3', 'Gene', '2261', (51, 56))	('multiple myeloma', 'Phenotype', 'HP:0006775', (93, 109))	('fibroblast growth factor receptor 3', 'Gene', (14, 49))	('multiple myeloma', 'Disease', 'MESH:D009101', (93, 109))	('multiple myeloma', 'Disease', (93, 109))	('FGFR3', 'Gene', (51, 56))	('fibroblast growth factor receptor 3', 'Gene', '2261', (14, 49))
380631	22645714	FGFR4 is a new target identified in pediatric solid tumors that is overexpressed by nearly all rhabdomyosarcomas with activating point-mutations observed in more aggressive disease (Taylor et al.,; Paulson et al.,) and with limited expression on normal myocytes.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (95, 112))	('solid tumors', 'Disease', 'MESH:D009369', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('activating', 'PosReg', (118, 128))	('aggressive disease', 'Disease', 'MESH:D001523', (162, 180))	('point-mutations', 'Var', (129, 144))	('solid tumors', 'Disease', (46, 58))	('FGFR4', 'Gene', '2264', (0, 5))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (95, 112))	('FGFR4', 'Gene', (0, 5))	('aggressive disease', 'Disease', (162, 180))	('rhabdomyosarcomas', 'Disease', (95, 112))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (95, 111))
380636	22645714	Clinical studies are currently underway using radioconjugated 8H9 for treatment of intraperitoneal desmoplastic small round cell tumor (NCT01099644) as well as for leptomeningeal spread of 8H9 binding tumors (NCT00089245).	('8H9', 'Chemical', '-', (189, 192))	('intraperitoneal desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (83, 134))	('NCT01099644', 'Var', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('8H9', 'Chemical', '-', (62, 65))	('leptomeningeal spread', 'CPA', (164, 185))
380647	22645714	Several small, non-randomized studies have demonstrated WT1 specific immunity following peptide based vaccination and in some cases this was associated with evidence for anti-leukemic activity.	('peptide based', 'Var', (88, 101))	('leukemic', 'Disease', (175, 183))	('WT1', 'Gene', '7490', (56, 59))	('WT1', 'Gene', (56, 59))	('leukemic', 'Disease', 'MESH:D007938', (175, 183))
380744	20687934	The gross specimen consisted of a centrally necrotic, peripherally viable appearing, heterogenous gray to pink-yellow friable suprarenal mass, 17.0 x 6.0 x 6.0 cm, 2974 grams, completely effacing the adrenal gland (Fig.	('2974', 'Var', (164, 168))	('necrotic', 'Disease', (44, 52))	('effacing', 'NegReg', (187, 195))	('necrotic', 'Disease', 'MESH:D009336', (44, 52))
380795	20687934	Malignant peripheral nerve sheet tumor with rhabdomyoblastic elements (Triton tumor) can be excluded by morphology as well as negativity of Melan-A, synaptophysin, and calretinin and positivity of S-100.	('synaptophysin', 'Gene', (149, 162))	('Malignant peripheral nerve sheet tumor', 'Disease', (0, 38))	('synaptophysin', 'Gene', '6855', (149, 162))	('Malignant peripheral nerve sheet tumor', 'Disease', 'MESH:D010524', (0, 38))	('negativity', 'Var', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('calretinin', 'Gene', '794', (168, 178))	('Malignant peripheral nerve', 'Phenotype', 'HP:0100697', (0, 26))	('positivity', 'Var', (183, 193))	('S-100', 'Protein', (197, 202))	('Triton tumor', 'Disease', 'MESH:D009369', (71, 83))	('Melan-A', 'Gene', (140, 147))	('Melan-A', 'Gene', '2315', (140, 147))	('calretinin', 'Gene', (168, 178))	('Triton tumor', 'Disease', (71, 83))
380797	20687934	This can be distinguished from an adrenocortical tumor by positivity for other melanocytic makers such as S-100, HMB-45, tyrosinase and negativity of calretinin, synaptophysin and inhibin.	('inhibin', 'Protein', (180, 187))	('synaptophysin', 'Gene', '6855', (162, 175))	('tyrosinase', 'Gene', '7299', (121, 131))	('calretinin', 'Gene', '794', (150, 160))	('HMB-45', 'Gene', (113, 119))	('positivity', 'Var', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('negativity', 'Var', (136, 146))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (34, 54))	('tyrosinase', 'Gene', (121, 131))	('calretinin', 'Gene', (150, 160))	('adrenocortical tumor', 'Disease', (34, 54))	('synaptophysin', 'Gene', (162, 175))
380812	33467570	In 1982, the first description of an NTRK1 gene fusion in a colon cancer sample was published.	('gene fusion', 'Var', (43, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (60, 72))	('colon cancer', 'Disease', 'MESH:D015179', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colon cancer', 'Disease', (60, 72))	('NTRK1', 'Gene', (37, 42))
380814	33467570	Subsequently ETV6-NTRK3 gene fusions were found to be canonical in secretory breast carcinoma and secretory carcinoma of salivary gland.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('breast carcinoma', 'Disease', 'MESH:D001943', (77, 93))	('fusions', 'Var', (29, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinoma of salivary gland', 'Phenotype', 'HP:0100684', (108, 135))	('breast carcinoma', 'Phenotype', 'HP:0003002', (77, 93))	('secretory carcinoma of salivary gland', 'Disease', (98, 135))	('ETV6-NTRK3', 'Gene', (13, 23))	('breast carcinoma', 'Disease', (77, 93))
380817	33467570	It was studied in: Patients with metastatic solid tumours, regardless of NTRK gene fusion/alteration status, including mutations, fusions, and amplifications were included in the Phase I dose escalation trial.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('amplifications', 'Var', (143, 157))	('metastatic solid tumours', 'Disease', (33, 57))	('Patients', 'Species', '9606', (19, 27))	('fusions', 'Var', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (119, 128))	('NTRK', 'Gene', (73, 77))
380842	33467570	We recommend reflex testing for NTRK gene fusions in all RAS/BRAF wildtype, MSI-high/dMMR CRC tumours.	('dMMR CRC tumours', 'Disease', 'MESH:D015179', (85, 101))	('dMMR CRC tumours', 'Disease', (85, 101))	('NTRK', 'Gene', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('fusions', 'Var', (42, 49))
380843	33467570	In two studies, 86% and 89% of patients with TRK fusion-positive CRC were deficient in MLH1/ PMS2 as a result of MLH1 promoter hypermethylation.	('deficient', 'NegReg', (74, 83))	('PMS2', 'Gene', '5395', (93, 97))	('MLH1', 'Gene', '4292', (113, 117))	('MLH1', 'Gene', (113, 117))	('PMS2', 'Gene', (93, 97))	('MLH1', 'Gene', '4292', (87, 91))	('MLH1', 'Gene', (87, 91))	('CRC', 'Disease', (65, 68))	('hypermethylation', 'Var', (127, 143))
380853	33467570	Ideally, non-squamous patients (estimated at 70-75% of locally advanced/metastatic patients/year in Canada) would receive IHC testing for PD-L1 and molecular testing including EGFR mutations; gene fusions involving ALK, ROS1, NRG1, NTRK1-3, and RET; and other genes with known oncogenic drivers (e.g., BRAF (V600x), ERBB2 exon 20, KRAS, and MET (exon 14 skipping, mutation, or amplification)) (Figure 3).	('ALK', 'Gene', (215, 218))	('KRAS', 'Gene', (331, 335))	('ROS1', 'Gene', (220, 224))	('NRG1', 'Gene', (226, 230))	('KRAS', 'Gene', '3845', (331, 335))	('mutation', 'Var', (364, 372))	('MET', 'Gene', '79811', (341, 344))	('EGFR', 'Gene', (176, 180))	('mutations', 'Var', (181, 190))	('ERBB2', 'Gene', (316, 321))	('MET', 'Gene', (341, 344))	('NTRK1-3', 'Gene', (232, 239))	('ERBB2', 'Gene', '2064', (316, 321))
380858	33467570	According to a recent review of TRK fusion-positive mesenchymal tumours, the morphological characteristics indicative of a higher probability of harbouring an NTRK gene fusion were inflammatory myofibroblastic tumour-like, fibrosarcoma/malignant peripheral nerve sheath tumour-like, or lipofibromatosis-like morphological patterns, particularly if combined with S100 and CD34 co-expression.	('myofibroblastic tumour', 'Disease', 'MESH:D009369', (194, 216))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('NTRK', 'Gene', (159, 163))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('fibrosarcoma/malignant peripheral nerve sheath tumour', 'Disease', 'MESH:D018319', (223, 276))	('myofibroblastic tumour', 'Phenotype', 'HP:0020135', (194, 216))	('S100', 'Gene', '6271', (362, 366))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (223, 235))	('malignant peripheral nerve sheath tumour', 'Phenotype', 'HP:0100697', (236, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('S100', 'Gene', (362, 366))	('lipofibromatosis', 'Disease', (286, 302))	('lipofibromatosis', 'Disease', 'None', (286, 302))	('fusion', 'Var', (169, 175))	('myofibroblastic tumour', 'Disease', (194, 216))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))
380860	33467570	The majority of GISTs harbour activating KIT or PDGFRA mutations.	('PDGFRA', 'Gene', '5156', (48, 54))	('PDGFRA', 'Gene', (48, 54))	('mutations', 'Var', (55, 64))	('KIT', 'Gene', '3815', (41, 44))	('KIT', 'Gene', (41, 44))
380861	33467570	However, 15% of cases are KIT/PDGFRA wildtype, and most are associated with deficiency in the succinate dehydrogenase (SDH) enzyme or a BRAF mutation.	('SDH', 'Gene', (119, 122))	('succinate dehydrogenase', 'Gene', '6390', (94, 117))	('BRAF', 'Gene', (136, 140))	('succinate dehydrogenase', 'Gene', (94, 117))	('SDH', 'Gene', '6390', (119, 122))	('deficiency', 'NegReg', (76, 86))	('mutation', 'Var', (141, 149))	('associated', 'Reg', (60, 70))
380863	33467570	Patients with wildtype GIST are less responsive to imatinib and may be less responsive to sunitinib and regorafenib (the conventional treatments for KIT/PDGFRA mutated GIST), and thus there is an urgent need for effective treatments.	('less', 'NegReg', (32, 36))	('imatinib', 'Chemical', 'MESH:D000068877', (51, 59))	('wildtype', 'Var', (14, 22))	('responsive to', 'MPA', (76, 89))	('less', 'NegReg', (71, 75))	('responsive to imatinib', 'MPA', (37, 59))	('regorafenib', 'Chemical', 'MESH:C559147', (104, 115))
380875	33467570	Papillary thyroid carcinomas have an intermediate frequency (5-25%) of NTRK gene fusions, and most other tumour types have a low (<5%) frequency.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('NTRK', 'Gene', (71, 75))	('gene fusions', 'Var', (76, 88))	('Papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (0, 28))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (10, 28))	('Papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (0, 28))	('Papillary thyroid carcinomas', 'Disease', (0, 28))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (10, 27))
380879	33435156	The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer Cancer is a global health concern, and the prognosis of patients with cancer is associated with metastasis.	('Cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (169, 175))	('Cancer', 'Disease', (92, 98))	('Cancer', 'Disease', 'MESH:D009369', (99, 105))	('Cancer', 'Disease', (99, 105))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Noncoding', 'Var', (12, 21))	('Anchorage-Independent Growth', 'CPA', (60, 88))	('patients', 'Species', '9606', (155, 163))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
380901	33435156	Also, knockdown of Beclin-1 (BECN1), a mediator of autophagy, attenuates anoikis resistance, thereby inhibiting the spheroid formation of cancer cells under anchorage-independent conditions.	('Beclin-1', 'Gene', (19, 27))	('BECN1', 'Gene', (29, 34))	('cancer', 'Disease', (138, 144))	('Beclin-1', 'Gene', '8678', (19, 27))	('attenuates', 'NegReg', (62, 72))	('BECN1', 'Gene', '8678', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('knockdown', 'Var', (6, 15))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('anoikis resistance', 'CPA', (73, 91))	('inhibiting', 'NegReg', (101, 111))
380903	33435156	Inhibition of FAK using genetic and pharmacological approaches weakens anoikis resistance as well as metastasis.	('weakens', 'NegReg', (63, 70))	('anoikis resistance', 'CPA', (71, 89))	('FAK', 'Gene', '5747', (14, 17))	('metastasis', 'CPA', (101, 111))	('Inhibition', 'Var', (0, 10))	('FAK', 'Gene', (14, 17))
380912	33435156	A recent study also demonstrated that high expression of miR-21-5p is associated with poor overall survival and lymph node metastasis in patients with esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('high expression', 'Var', (38, 53))	('lymph node metastasis', 'CPA', (112, 133))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('rat', 'Species', '10116', (27, 30))	('expression', 'Species', '29278', (43, 53))	('overall survival', 'CPA', (91, 107))	('miR-21-5p', 'Gene', (57, 66))	('miR-21-5p', 'Gene', '406997', (57, 66))	('poor', 'NegReg', (86, 90))
380914	33435156	It was also found that the overexpression or knockdown of miR-21-5p promotes or impedes liver metastases in vivo, respectively.	('liver metastases', 'Disease', 'MESH:D009362', (88, 104))	('impedes', 'NegReg', (80, 87))	('miR-21-5p', 'Gene', (58, 67))	('promotes', 'PosReg', (68, 76))	('miR-21-5p', 'Gene', '406997', (58, 67))	('expression', 'Species', '29278', (31, 41))	('liver metastases', 'Disease', (88, 104))	('overexpression', 'PosReg', (27, 41))	('knockdown', 'Var', (45, 54))
380915	33435156	In retinoblastoma, PTEN is also targeted by miR-25-3p (a member of the miR-106b-25 cluster), thereby activating PI3K/Akt signaling and anchorage-independent cell growth.	('miR-25-3p', 'Chemical', '-', (44, 53))	('miR-25-3p', 'Var', (44, 53))	('Akt', 'Gene', (117, 120))	('miR-106', 'Gene', (71, 78))	('retinoblastoma', 'Phenotype', 'HP:0009919', (3, 17))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('miR-106', 'Gene', '406899', (71, 78))	('anchorage-independent cell growth', 'CPA', (135, 168))	('Akt', 'Gene', '207', (117, 120))	('activating', 'PosReg', (101, 111))	('retinoblastoma', 'Disease', 'MESH:D012175', (3, 17))	('retinoblastoma', 'Disease', (3, 17))
380916	33435156	Knockdown of miR-25-3p increases the expression of cleaved caspase-3 as well as the induction of apoptosis in vitro.	('caspase-3', 'Gene', '836', (59, 68))	('miR-25-3p', 'Var', (13, 22))	('expression', 'Species', '29278', (37, 47))	('cleaved', 'MPA', (51, 58))	('caspase-3', 'Gene', (59, 68))	('expression', 'MPA', (37, 47))	('increases', 'PosReg', (23, 32))	('apoptosis', 'CPA', (97, 106))	('miR-25-3p', 'Chemical', '-', (13, 22))
380917	33435156	Moreover, it was observed that miR-25-3p accelerates cancer growth, which can be abolished by PTEN restoration or PI3K inhibition in vivo (Figure 1 and Table 1).	('PTEN', 'Gene', (94, 98))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('PTEN', 'Gene', '5728', (94, 98))	('miR-25-3p', 'Chemical', '-', (31, 40))	('miR-25-3p', 'Var', (31, 40))	('rat', 'Species', '10116', (47, 50))	('accelerates', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('rat', 'Species', '10116', (104, 107))
380921	33435156	The relationship between miR-141-3p and metastasis has been explored in cancer.	('cancer', 'Disease', (72, 78))	('miR-141-3p', 'Chemical', '-', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('miR-141-3p', 'Var', (25, 35))
380922	33435156	For example, exosomal miR-141-3p derived from prostate cancer cells activates osteogenesis, thus facilitating the bone metastasis of prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('prostate cancer', 'Disease', (46, 61))	('facilitating', 'PosReg', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('bone metastasis of prostate cancer', 'Disease', 'MESH:D011471', (114, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('osteogenesis', 'Disease', (78, 90))	('osteogenesis', 'Disease', 'MESH:D010013', (78, 90))	('exosomal', 'Var', (13, 21))	('miR-141-3p', 'Chemical', '-', (22, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (46, 61))	('activates', 'PosReg', (68, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))	('bone metastasis of prostate cancer', 'Disease', (114, 148))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))
380924	33435156	In addition, miR-141-3p is overexpressed in ovarian cancer tissues, and this miRNA can augment anchorage-independent cell growth and anoikis resistance by suppressing the expression of Kruppel-like factor 12 (KLF12), which interferes with Sp1-activated transcription of the survivin gene.	('expression', 'MPA', (171, 181))	('miR-141-3p', 'Chemical', '-', (13, 23))	('KLF12', 'Gene', '11278', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (44, 58))	('anoikis resistance', 'CPA', (133, 151))	('augment', 'PosReg', (87, 94))	('survivin gene', 'Gene', (274, 287))	('KLF12', 'Gene', (209, 214))	('suppressing', 'NegReg', (155, 166))	('ovarian cancer', 'Disease', (44, 58))	('miR-141-3p', 'Var', (13, 23))	('anchorage-independent cell growth', 'CPA', (95, 128))	('expression', 'Species', '29278', (171, 181))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))
380925	33435156	It was also observed that miR-141-3p stimulates the growth of metastatic ovarian cancer cells in vivo (Figure 1 and Table 1).	('metastatic ovarian cancer', 'Disease', 'MESH:D018223', (62, 87))	('miR-141-3p', 'Var', (26, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('miR-141-3p', 'Chemical', '-', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('metastatic ovarian cancer', 'Disease', (62, 87))	('stimulates', 'PosReg', (37, 47))
380932	33435156	In that study, it was also denoted that human papillomavirus E6/E7 oncoproteins increase the level of miR-146-3p, which targets HPGD and supports the anchorage-independent growth of cancer cells (Figure 1 and Table 1).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('anchorage-independent growth', 'CPA', (150, 178))	('supports', 'PosReg', (137, 145))	('increase', 'PosReg', (80, 88))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('miR-146-3p', 'Var', (102, 112))	('cancer', 'Disease', (182, 188))	('E6/E7', 'Var', (61, 66))	('human papillomavirus', 'Species', '10566', (40, 60))
380934	33435156	The knockdown of miR-186-5p attenuates anchorage-independent growth, along with a decrease in Akt activity.	('anchorage-independent growth', 'CPA', (39, 67))	('attenuates', 'NegReg', (28, 38))	('Akt', 'Gene', (94, 97))	('decrease', 'NegReg', (82, 90))	('miR-186', 'Gene', '406962', (17, 24))	('Akt', 'Gene', '207', (94, 97))	('miR-186', 'Gene', (17, 24))	('knockdown', 'Var', (4, 13))
380956	33435156	Anchorage-independent cell growth resulted from the knockdown of NFKB2 can be reversed by miR-494 inhibition, supporting that miR-494 undeviatingly promotes cancer progression (Figure 1 and Table 1).	('miR-494', 'Gene', '574452', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('miR-494', 'Gene', (126, 133))	('miR-494', 'Gene', '574452', (90, 97))	('miR-494', 'Gene', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('NFKB2', 'Gene', (65, 70))	('cancer', 'Disease', (157, 163))	('promotes', 'PosReg', (148, 156))	('knockdown', 'Var', (52, 61))
380957	33435156	Screening of miRNAs identified that miR-645 is one of the upregulated miRNAs in colorectal cancer tissues.	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('upregulated', 'PosReg', (58, 69))	('miR-645', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))
380960	33435156	In line with this, another study also denoted that miR-645 facilitates liver metastasis of colorectal cancer in a mouse xenograft model (Figure 1 and Table 1).	('miR-645', 'Var', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('metastasis of colorectal cancer', 'Disease', 'MESH:D015179', (77, 108))	('facilitates', 'PosReg', (59, 70))	('rectal cancer', 'Phenotype', 'HP:0100743', (95, 108))	('metastasis of colorectal cancer', 'Disease', (77, 108))	('mouse', 'Species', '10090', (114, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('liver metastasis', 'Disease', 'MESH:D009362', (71, 87))	('liver metastasis', 'Disease', (71, 87))
380961	33435156	Several studies demonstrated that miR-27-3p promotes and suppresses the metastasis of pancreatic cancer and hepatocellular carcinoma, respectively, suggesting the dual role of this miRNA in a cellular context-dependent manner.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (108, 132))	('promotes', 'PosReg', (44, 52))	('metastasis', 'CPA', (72, 82))	('hepatocellular carcinoma', 'Disease', (108, 132))	('suppresses', 'NegReg', (57, 67))	('miR-27-3p', 'Var', (34, 43))	('pancreatic cancer', 'Disease', (86, 103))	('miR-27-3p', 'Chemical', '-', (34, 43))	('rat', 'Species', '10116', (23, 26))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (108, 132))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
380962	33435156	Another study showed that the anchorage-independent growth of osteosarcoma cells is accelerated by miR-27-3p, whose expression is upregulated in cancer cells in comparison with normal osteocyte cells.	('cancer', 'Disease', (145, 151))	('upregulated', 'PosReg', (130, 141))	('expression', 'MPA', (116, 126))	('miR-27-3p', 'Var', (99, 108))	('miR-27-3p', 'Chemical', '-', (99, 108))	('accelerated', 'PosReg', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('osteosarcoma', 'Phenotype', 'HP:0002669', (62, 74))	('osteosarcoma', 'Disease', (62, 74))	('osteosarcoma', 'Disease', 'MESH:D012516', (62, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('expression', 'Species', '29278', (116, 126))	('rat', 'Species', '10116', (90, 93))
380963	33435156	A further study on the mechanism of miR-27-3p indicated that G1-S cell cycle progression is promoted by miR-27-3p that targets the inhibitor of growth family member 5 (ING5).	('miR-27-3p', 'Chemical', '-', (36, 45))	('inhibitor of growth family member 5', 'Gene', (131, 166))	('ING5', 'Gene', (168, 172))	('promoted', 'PosReg', (92, 100))	('inhibitor of growth family member 5', 'Gene', '84289', (131, 166))	('miR-27-3p', 'Var', (104, 113))	('G1-S cell cycle progression', 'CPA', (61, 88))	('miR-27-3p', 'Chemical', '-', (104, 113))	('ING5', 'Gene', '84289', (168, 172))
380967	33435156	Additional evidence showed that miR-141-3p expression is repressed by tumor protein P63 alpha containing the transactivation domain (TAp63alpha), leading to a reduction of CCND1.	('reduction', 'NegReg', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CCND1', 'Gene', '595', (172, 177))	('tumor', 'Disease', (70, 75))	('miR-141-3p', 'Var', (32, 42))	('miR-141-3p', 'Chemical', '-', (32, 42))	('expression', 'Species', '29278', (43, 53))	('CCND1', 'Gene', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
380968	33435156	Besides, TAp63alpha diminishes in vitro anchorage-independent growth and in vivo tumorigenic growth of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('TAp63alpha', 'Var', (9, 19))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('bladder cancer', 'Disease', (103, 117))	('diminishes', 'NegReg', (20, 30))
380969	33435156	TAp63alpha and CCND1 are considered to suppress metastasis and anoikis, respectively.	('CCND1', 'Gene', (15, 20))	('anoikis', 'CPA', (63, 70))	('TAp63alpha', 'Var', (0, 10))	('suppress', 'NegReg', (39, 47))	('CCND1', 'Gene', '595', (15, 20))	('metastasis', 'CPA', (48, 58))
380970	33435156	The TAp63alpha/miR-141-3p/AUF1/CCND1 axis can support the finding that TAp63alpha inhibits cancer metastasis and that miR-141-3p serves as an anoikis-resistant factor in cancer (also see Section 2.1.2) (Figure 1 and Table 1).	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer metastasis', 'Disease', (91, 108))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('2.1', 'Gene', (195, 198))	('TAp63alpha', 'Var', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer metastasis', 'Disease', 'MESH:D009362', (91, 108))	('miR-141-3p', 'Var', (118, 128))	('miR-141-3p', 'Chemical', '-', (15, 25))	('CCND1', 'Gene', '595', (31, 36))	('inhibits', 'NegReg', (82, 90))	('CCND1', 'Gene', (31, 36))	('cancer', 'Disease', (91, 97))	('AUF1', 'Gene', (26, 30))	('2.1', 'Gene', '6700', (195, 198))	('miR-141-3p', 'Chemical', '-', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AUF1', 'Gene', '3184', (26, 30))
380984	33435156	It was also denoted that miR-1288-3p is upregulated in glioblastoma tissues and cell lines compared to normal brain tissues and astrocyte cells, respectively.	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))	('miR-1288-3p', 'Var', (25, 36))	('glioblastoma', 'Disease', (55, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))	('upregulated', 'PosReg', (40, 51))	('miR-1288-3p', 'Chemical', '-', (25, 36))
380985	33435156	Ectopic expression of miR-1288-3p boosts the anchorage-independent growth of glioblastoma cells by targeting CYLD (Figure 1 and Table 1).	('CYLD', 'Gene', '1540', (109, 113))	('boosts', 'PosReg', (34, 40))	('glioblastoma', 'Disease', (77, 89))	('targeting', 'Reg', (99, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('expression', 'Species', '29278', (8, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('miR-1288-3p', 'Chemical', '-', (22, 33))	('CYLD', 'Gene', (109, 113))	('miR-1288-3p', 'Var', (22, 33))
380987	33435156	Additionally, a recent study found that the overexpression or knockdown of miR-362-3p increases or decreases the anchorage-independent growth of hepatocellular carcinoma cells, respectively, through targeting TOB2.	('decreases', 'NegReg', (99, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('miR-362-3p', 'Var', (75, 85))	('miR-362-3p', 'Chemical', '-', (75, 85))	('expression', 'Species', '29278', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('anchorage-independent growth', 'CPA', (113, 141))	('hepatocellular carcinoma', 'Disease', (145, 169))	('increases', 'PosReg', (86, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('targeting', 'Reg', (199, 208))	('overexpression', 'PosReg', (44, 58))	('TOB2', 'Gene', (209, 213))	('TOB2', 'Gene', '10766', (209, 213))
380990	33435156	It was illustrated that miR-376c-3p augments the anchorage-independent growth of gastric cancer cells via repressing AT-rich interactive domain-containing protein 4A (ARID4A, also called RBP-1), which negatively regulates E2F-mediated transcription (Figure 1 and Table 1).	('augments', 'PosReg', (36, 44))	('RBP-1', 'Gene', '5947', (187, 192))	('miR-376c-3p', 'Chemical', '-', (24, 35))	('AT-rich interactive domain-containing protein 4A', 'Gene', (117, 165))	('RBP-1', 'Gene', (187, 192))	('AT-rich interactive domain-containing protein 4A', 'Gene', '5926', (117, 165))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('ARID4A', 'Gene', '5926', (167, 173))	('gastric cancer', 'Disease', (81, 95))	('miR-376c-3p', 'Var', (24, 35))	('anchorage-independent growth', 'CPA', (49, 77))	('rat', 'Species', '10116', (13, 16))	('repressing', 'PosReg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ARID4A', 'Gene', (167, 173))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
380991	33435156	Additionally, miR-376c-3p was validated to promote metastasis of hepatocellular carcinoma cells in vivo.	('metastasis', 'CPA', (51, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('hepatocellular carcinoma', 'Disease', (65, 89))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (65, 89))	('promote', 'PosReg', (43, 50))	('miR-376c-3p', 'Chemical', '-', (14, 25))	('miR-376c-3p', 'Var', (14, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))
380993	33435156	Functional experiments showed that the anchorage-independent growth ability of cancer cells is enhanced by overexpressing either miR-527 or miR-760, in company with an increase in CCND1 levels (Figure 1 and Table 1).	('increase', 'PosReg', (168, 176))	('miR-7', 'Gene', '10859', (140, 145))	('overexpressing', 'PosReg', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CCND1', 'Gene', '595', (180, 185))	('miR-527', 'Var', (129, 136))	('anchorage-independent growth ability', 'CPA', (39, 75))	('miR-7', 'Gene', (140, 145))	('enhanced', 'PosReg', (95, 103))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('CCND1', 'Gene', (180, 185))
380997	33435156	Recent investigations showed that APC is directly regulated by miR-582-5p and miR-3607 in colorectal and lung cancer, respectively.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('miR-3607', 'Gene', '100500805', (78, 86))	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (90, 116))	('regulated', 'Reg', (50, 59))	('miR-3607', 'Gene', (78, 86))	('APC', 'Phenotype', 'HP:0005227', (34, 37))	('APC', 'Disease', 'MESH:D011125', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('APC', 'Disease', (34, 37))	('miR-582-5p', 'Var', (63, 73))
381000	33435156	Recently, it was reported that the inhibition of miR-766-5p blocks cell proliferation, invasion, and survival of SW480 colorectal cancer cells.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('blocks', 'NegReg', (60, 66))	('miR-766', 'Gene', '768218', (49, 56))	('SW480', 'CellLine', 'CVCL:0546', (113, 118))	('miR-766', 'Gene', (49, 56))	('colorectal cancer', 'Disease', (119, 136))	('rat', 'Species', '10116', (79, 82))	('inhibition', 'Var', (35, 45))	('rectal cancer', 'Phenotype', 'HP:0100743', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('invasion', 'CPA', (87, 95))	('survival', 'CPA', (101, 109))	('cell proliferation', 'CPA', (67, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))
381011	33435156	The expression of miR-10b is transcriptionally activated by BRAFV600E-mediated upregulation of Twist family BHLH transcription factor 1 (TWIST1) in melanoma cells.	('TWIST1', 'Gene', (137, 143))	('BRAFV600E-mediated', 'Var', (60, 78))	('TWIST1', 'Gene', '7291', (137, 143))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('expression', 'Species', '29278', (4, 14))	('activated', 'PosReg', (47, 56))	('expression', 'MPA', (4, 14))	('miR-10b', 'Gene', '406903', (18, 25))	('upregulation', 'PosReg', (79, 91))	('BRAFV600E', 'Mutation', 'rs113488022', (60, 69))	('miR-10b', 'Gene', (18, 25))
381013	33435156	The levels of both miR-139-5p and miR-483-5p are upregulated in adrenocortical cancer tissues and inversely correlated with the overall survival of patients.	('patients', 'Species', '9606', (148, 156))	('correlated', 'Reg', (108, 118))	('inversely', 'NegReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR-139-5p', 'Var', (19, 29))	('adrenocortical cancer', 'Disease', (64, 85))	('upregulated', 'PosReg', (49, 60))	('miR-483', 'Gene', '619552', (34, 41))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (64, 85))	('miR-483', 'Gene', (34, 41))
381015	33435156	Evidence provided indicated that miR-139-5p and miR-483-5p target N-Myc downstream-regulated gene 4 (NDRG4) and NDRG2, respectively, and that overexpression of either NDRG4 or NDRG2 inhibits the invasive capacity of cancer cells (Figure 1 and Table 1).	('overexpression', 'PosReg', (142, 156))	('cancer', 'Disease', (216, 222))	('NDRG4', 'Gene', (101, 106))	('inhibits', 'NegReg', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('N-Myc downstream-regulated gene 4', 'Gene', (66, 99))	('NDRG2', 'Gene', '57447', (176, 181))	('miR-483', 'Gene', (48, 55))	('NDRG4', 'Gene', '65009', (167, 172))	('NDRG2', 'Gene', '57447', (112, 117))	('expression', 'Species', '29278', (146, 156))	('N-Myc downstream-regulated gene 4', 'Gene', '65009', (66, 99))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('miR-483', 'Gene', '619552', (48, 55))	('miR-139-5p', 'Var', (33, 43))	('NDRG4', 'Gene', (167, 172))	('NDRG2', 'Gene', (176, 181))	('NDRG2', 'Gene', (112, 117))	('NDRG4', 'Gene', '65009', (101, 106))
381019	33435156	For example, CPEB2A and CPEB2B act as a tumor suppressor and an oncogene, respectively, and a high CPEB2B/CPEB2A ratio leads to anoikis resistance and metastasis of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('CPEB2', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('CPEB2', 'Gene', '132864', (13, 18))	('leads to', 'Reg', (119, 127))	('CPEB2', 'Gene', (99, 104))	('CPEB2', 'Gene', (106, 111))	('CPEB2', 'Gene', '132864', (99, 104))	('CPEB2', 'Gene', '132864', (106, 111))	('anoikis resistance', 'CPA', (128, 146))	('high', 'Var', (94, 98))	('CPEB2', 'Gene', (24, 29))	('metastasis of breast cancer', 'Disease', (151, 178))	('tumor', 'Disease', (40, 45))	('CPEB2', 'Gene', '132864', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('metastasis of breast cancer', 'Disease', 'MESH:D001943', (151, 178))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('rat', 'Species', '10116', (113, 116))
381021	33435156	Further, both miR-526b-5p and miR-655-3p were identified to directly target CPEB2, suggesting a possibility that these miRNAs can serve as anoikis-resistant factors (Figure 1 and Table 1), even though more investigation on the effect of these miRNAs especially on the regulation of CPEB2B/CPEB2A ratio is warranted.	('CPEB2', 'Gene', '132864', (282, 287))	('rat', 'Species', '10116', (296, 299))	('CPEB2', 'Gene', '132864', (76, 81))	('CPEB2', 'Gene', '132864', (289, 294))	('CPEB2', 'Gene', (289, 294))	('CPEB2', 'Gene', (282, 287))	('miR-526b-5p', 'Var', (14, 25))	('CPEB2', 'Gene', (76, 81))	('miR-655-3p', 'Var', (30, 40))
381022	33435156	Deep sequencing analysis of GRSF1-bound miRNAs identified that miR-G-10 is one of the most abundant miRNAs in cervical cancer.	('miR-G-10', 'Var', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('abundant', 'Reg', (91, 99))	('GRSF1', 'Gene', '2926', (28, 33))	('miR-G-10', 'Chemical', '-', (63, 71))	('GRSF1', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
381023	33435156	A further investigation on the molecular mechanism of miR-G-10 indicated that the malignant phenotypes of cancer cells, such as EMT and anoikis resistance, are promoted by miR-G-10 that increases the expression of phosphatidylinositol 3-kinase regulatory subunit gamma (PIK3R3), an upstream activator of NF-kappaB.	('promoted', 'PosReg', (160, 168))	('NF-kappaB', 'Gene', (304, 313))	('anoikis resistance', 'CPA', (136, 154))	('miR-G-10', 'Var', (172, 180))	('PIK3R3', 'Gene', (270, 276))	('EMT', 'CPA', (128, 131))	('miR-G-10', 'Chemical', '-', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('increases', 'PosReg', (186, 195))	('expression', 'Species', '29278', (200, 210))	('cancer', 'Disease', (106, 112))	('expression', 'MPA', (200, 210))	('miR-G-10', 'Chemical', '-', (172, 180))	('NF-kappaB', 'Gene', '4790', (304, 313))	('PIK3R3', 'Gene', '8503', (270, 276))
381024	33435156	Indeed, lung metastasis of cervical cancer is accelerated by miR-G-10 in vivo (Figure 1 and Table 1).	('lung metastasis', 'CPA', (8, 23))	('rat', 'Species', '10116', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('accelerated', 'PosReg', (46, 57))	('cancer', 'Disease', (36, 42))	('miR-G-10', 'Chemical', '-', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('miR-G-10', 'Var', (61, 69))
381032	33435156	Tumor-suppressive miR-22-3p is underexpressed in rhabdomyosarcoma tissues, and the reconstitution of miR-22-3p was observed to induce apoptosis and subdue anchorage-independent growth of cancer cells.	('subdue', 'NegReg', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('miR-22-3p', 'Gene', '407008', (18, 27))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-22-3p', 'Gene', '407008', (101, 110))	('induce', 'PosReg', (127, 133))	('cancer', 'Disease', (187, 193))	('apoptosis', 'CPA', (134, 143))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (49, 65))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (49, 65))	('miR-22-3p', 'Gene', (18, 27))	('rhabdomyosarcoma', 'Disease', (49, 65))	('reconstitution', 'Var', (83, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('miR-22-3p', 'Gene', (101, 110))
381034	33435156	Huntingtin-interacting protein 1-related (HIP1R) is involved in the encouragement of cell survival via stabilizing receptor tyrosine kinases; therefore, loss-of-function mutants of HIP1R are able to induce cell death.	('Huntingtin-interacting protein 1-related', 'Gene', (0, 40))	('HIP1R', 'Gene', '9026', (181, 186))	('HIP1R', 'Gene', (42, 47))	('HIP1R', 'Gene', (181, 186))	('HIP1R', 'Gene', '9026', (42, 47))	('mutants', 'Var', (170, 177))	('cell death', 'CPA', (206, 216))	('loss-of-function', 'NegReg', (153, 169))	('Huntingtin-interacting protein 1-related', 'Gene', '9026', (0, 40))
381039	33435156	Additional studies provided evidence that miR-30-5p and miR-33a target MTA1 and METTL3, respectively, hence contributing to attenuated anchorage-independent growth of cancer cells (Figure 2 and Table 2).	('miR-30-5p', 'Var', (42, 51))	('miR-33a', 'Gene', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('miR-33a', 'Gene', '407039', (56, 63))	('cancer', 'Disease', (167, 173))	('MTA1', 'Gene', (71, 75))	('attenuated', 'NegReg', (124, 134))	('METTL3', 'Gene', '56339', (80, 86))	('MTA1', 'Gene', '9112', (71, 75))	('METTL3', 'Gene', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('miR-30-5p', 'Chemical', '-', (42, 51))
381041	33435156	Knockdown of ME1 increases the level of reactive oxygen species (ROS), leading to the inhibition of cell growth and the induction of anoikis.	('anoikis', 'CPA', (133, 140))	('cell growth', 'CPA', (100, 111))	('increases', 'PosReg', (17, 26))	('Knockdown', 'Var', (0, 9))	('level of reactive oxygen species', 'MPA', (31, 63))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (40, 63))	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('ME1', 'Gene', (13, 16))	('ME1', 'Gene', '4199', (13, 16))	('induction', 'Reg', (120, 129))	('inhibition', 'NegReg', (86, 96))
381042	33435156	In the case of miR-30-5p, this miRNA also targets ME1, promotes apoptosis, and attenuates the anchorage-independent growth of colorectal cancer cells (Figure 2 and Table 2).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('attenuates', 'NegReg', (79, 89))	('miR-30-5p', 'Chemical', '-', (15, 24))	('colorectal cancer', 'Disease', (126, 143))	('rectal cancer', 'Phenotype', 'HP:0100743', (130, 143))	('apoptosis', 'CPA', (64, 73))	('ME1', 'Gene', (50, 53))	('promotes', 'PosReg', (55, 63))	('miR-30-5p', 'Var', (15, 24))	('ME1', 'Gene', '4199', (50, 53))	('anchorage-independent growth', 'CPA', (94, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('targets', 'Reg', (42, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
381043	33435156	The expression of miR-133-3p is downregulated in prostate cancer and further reduced in metastatic prostate cancer, suggesting that miR-133-3p may affect cellular events/signaling associated with metastasis.	('miR-133-3p', 'Gene', (18, 28))	('downregulated', 'NegReg', (32, 45))	('miR-133-3p', 'Chemical', '-', (18, 28))	('cellular events/signaling', 'MPA', (154, 179))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('expression', 'Species', '29278', (4, 14))	('miR-133-3p', 'Var', (132, 142))	('miR-133-3p', 'Chemical', '-', (132, 142))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('expression', 'MPA', (4, 14))	('prostate cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('reduced', 'NegReg', (77, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('prostate cancer', 'Disease', (49, 64))	('affect', 'Reg', (147, 153))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
381044	33435156	Investigations of miR-133-3p in relation to anoikis and metastasis showed that this miRNA diminishes the level of anti-apoptotic factors (e.g., BCL-2) and the activity of PI3K/Akt signaling via targeting multiple genes (e.g., EGFR), eventually alleviating anoikis resistance and bone metastasis of prostate cancer (Figure 2 and Table 2).	('targeting', 'Reg', (194, 203))	('miR-133-3p', 'Var', (18, 28))	('BCL-2', 'Gene', '596', (144, 149))	('miR-133-3p', 'Chemical', '-', (18, 28))	('activity', 'MPA', (159, 167))	('bone metastasis of prostate cancer', 'Disease', 'MESH:D011471', (279, 313))	('anoikis resistance', 'CPA', (256, 274))	('Akt', 'Gene', (176, 179))	('prostate cancer', 'Phenotype', 'HP:0012125', (298, 313))	('BCL-2', 'Gene', (144, 149))	('diminishes', 'NegReg', (90, 100))	('level of anti-apoptotic factors', 'MPA', (105, 136))	('Akt', 'Gene', '207', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('bone metastasis of prostate cancer', 'Disease', (279, 313))	('EGFR', 'Gene', '1956', (226, 230))	('alleviating', 'NegReg', (244, 255))	('EGFR', 'Gene', (226, 230))
381046	33435156	The silencing of SESN2 leads to anoikis in vitro and restricts distant metastasis in vivo.	('anoikis', 'Disease', (32, 39))	('SESN2', 'Gene', (17, 22))	('leads to', 'Reg', (23, 31))	('SESN2', 'Gene', '83667', (17, 22))	('restricts', 'NegReg', (53, 62))	('distant metastasis', 'CPA', (63, 81))	('silencing', 'Var', (4, 13))
381061	33435156	Ectopic expression of miR-451 facilitates anoikis induction, and the overexpression of Ras-related protein Rab-14 (RAB14), a target of miR-451, substantially abrogates the effect of miR-451 on anoikis.	('overexpression', 'PosReg', (69, 83))	('RAB14', 'Gene', (115, 120))	('miR-451', 'Gene', '574411', (135, 142))	('anoikis induction', 'CPA', (42, 59))	('RAB14', 'Gene', '51552', (115, 120))	('expression', 'Species', '29278', (73, 83))	('Ectopic expression', 'Var', (0, 18))	('miR-451', 'Gene', '574411', (182, 189))	('miR-451', 'Gene', (135, 142))	('expression', 'Species', '29278', (8, 18))	('miR-451', 'Gene', (22, 29))	('anoikis', 'CPA', (193, 200))	('abrogates', 'NegReg', (158, 167))	('facilitates', 'PosReg', (30, 41))	('miR-451', 'Gene', (182, 189))	('miR-451', 'Gene', '574411', (22, 29))
381064	33435156	Liver metastasis of colorectal cancer is restrained by miR-487b-3p that inhibits the KRAS/Akt signaling pathway.	('restrained', 'NegReg', (41, 51))	('miR-487b-3p', 'Var', (55, 66))	('Akt', 'Gene', (90, 93))	('-487b', 'Chemical', '-', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('inhibits', 'NegReg', (72, 80))	('Liver metastasis of colorectal cancer', 'Disease', (0, 37))	('rectal cancer', 'Phenotype', 'HP:0100743', (24, 37))	('Akt', 'Gene', '207', (90, 93))	('Liver metastasis of colorectal cancer', 'Disease', 'MESH:D015179', (0, 37))
381065	33435156	In another study, miR-487b-3p was also demonstrated to dampen colorectal cancer tumorigenesis by diminishing anchorage-independent growth and Akt activity.	('Akt', 'Gene', (142, 145))	('-487b', 'Chemical', '-', (21, 26))	('dampen', 'NegReg', (55, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('anchorage-independent growth', 'CPA', (109, 137))	('rat', 'Species', '10116', (46, 49))	('miR-487b-3p', 'Var', (18, 29))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('diminishing', 'NegReg', (97, 108))	('tumor', 'Disease', (80, 85))	('colorectal cancer', 'Disease', (62, 79))	('Akt', 'Gene', '207', (142, 145))	('rectal cancer', 'Phenotype', 'HP:0100743', (66, 79))
381066	33435156	In this study, glutamate metabotropic receptor 3 (GRM3) was confirmed as a target gene of miR-487b-3p.	('glutamate metabotropic receptor 3', 'Gene', (15, 48))	('-487b', 'Chemical', '-', (93, 98))	('GRM3', 'Gene', '2913', (50, 54))	('GRM3', 'Gene', (50, 54))	('glutamate metabotropic receptor 3', 'Gene', '2913', (15, 48))	('miR-487b-3p', 'Var', (90, 101))
381081	33435156	Lately, it was also demonstrated that the knockdown of LGALS1 reduces anchorage-independent growth and lung metastasis of hepatocellular carcinoma cells.	('LGALS1', 'Gene', '3956', (55, 61))	('reduces', 'NegReg', (62, 69))	('lung metastasis of hepatocellular carcinoma', 'Disease', (103, 146))	('LGALS1', 'Gene', (55, 61))	('anchorage-independent growth', 'CPA', (70, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('rat', 'Species', '10116', (27, 30))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (122, 146))	('lung metastasis of hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 146))	('knockdown', 'Var', (42, 51))
381085	33435156	As stated in Section 3.1.4, miR-133-3p serves as an anoikis-promoting factor by targeting, for example, EGFR.	('EGFR', 'Gene', (104, 108))	('miR-133-3p', 'Chemical', '-', (28, 38))	('miR-133-3p', 'Var', (28, 38))	('targeting', 'Reg', (80, 89))	('EGFR', 'Gene', '1956', (104, 108))
381087	33435156	Indeed, it was reported that miR-133-3p suppresses EMT, eventually restricting anoikis resistance, anchorage-independent growth, and lung metastasis of esophageal cancer cells (Figure 2 and Table 2).	('EMT', 'CPA', (51, 54))	('anchorage-independent growth', 'CPA', (99, 127))	('miR-133-3p', 'Var', (29, 39))	('miR-133-3p', 'Chemical', '-', (29, 39))	('lung metastasis', 'CPA', (133, 148))	('suppresses', 'NegReg', (40, 50))	('restricting', 'NegReg', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('anoikis resistance', 'CPA', (79, 97))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
381094	33435156	The silencing of SET reduces the level of EMT markers such as vimentin (VIM) and represses the migration and invasion of cancer cells.	('VIM', 'Gene', (72, 75))	('level of EMT markers', 'MPA', (33, 53))	('represses', 'NegReg', (81, 90))	('vimentin', 'Gene', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('SET', 'Gene', (17, 20))	('rat', 'Species', '10116', (98, 101))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('VIM', 'Gene', '7431', (72, 75))	('vimentin', 'Gene', '7431', (62, 70))	('cancer', 'Disease', (121, 127))	('silencing', 'Var', (4, 13))	('reduces', 'NegReg', (21, 28))
381096	33435156	Moreover, SET is targeted by miR-199-5p, which is downregulated in colorectal cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rectal cancer', 'Phenotype', 'HP:0100743', (71, 84))	('miR-199-5p', 'Var', (29, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('downregulated', 'NegReg', (50, 63))	('colorectal cancer', 'Disease', (67, 84))
381097	33435156	These results suggest that low miR-199-5p expression is one of the causes of high SET levels in colorectal cancer and that miR-199-5p can negatively modulate anchorage-independent growth via targeting SET (Figure 2 and Table 2).	('high SET levels', 'MPA', (77, 92))	('modulate', 'Reg', (149, 157))	('expression', 'Species', '29278', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('anchorage-independent growth', 'CPA', (158, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('low', 'NegReg', (27, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))	('colorectal cancer', 'Disease', (96, 113))	('miR-199-5p', 'Var', (123, 133))	('rectal cancer', 'Phenotype', 'HP:0100743', (100, 113))	('miR-199-5p expression', 'MPA', (31, 52))
381100	33435156	A recent study further demonstrated that TDO2 is targeted by miR-200 in breast cancer and that the overexpression of TDO2 brings about enhanced anchorage-independent growth, suggesting that miR-200 can inhibit anchorage-independent cell growth through repressing EMT process mediated by the TDO2/kynurenine/AHR signaling (Figure 2 and Table 2).	('TDO2', 'Gene', (117, 121))	('AHR', 'Gene', (307, 310))	('TDO2', 'Gene', '6999', (41, 45))	('TDO2', 'Gene', (291, 295))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('miR-200', 'Var', (190, 197))	('rat', 'Species', '10116', (30, 33))	('kynurenine', 'Chemical', 'MESH:D007737', (296, 306))	('enhanced', 'PosReg', (135, 143))	('TDO2', 'Gene', (41, 45))	('AHR', 'Gene', '196', (307, 310))	('anchorage-independent cell growth', 'CPA', (210, 243))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TDO2', 'Gene', '6999', (117, 121))	('inhibit', 'NegReg', (202, 209))	('EMT process', 'CPA', (263, 274))	('expression', 'Species', '29278', (103, 113))	('TDO2', 'Gene', '6999', (291, 295))	('repressing', 'NegReg', (252, 262))	('anchorage-independent growth', 'CPA', (144, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
381104	33435156	In addition, the knockdown of XIAP attenuates anchorage-independent cell growth, suggesting that the anchorage-independent growth of bladder cancer can be modulated by the XIAP/miR-200/EGFR/EMT axis (see Section 3.3.2 for EGFR/EMT relationship) (Figure 2 and Table 2).	('anchorage-independent growth', 'CPA', (101, 129))	('XIAP', 'Gene', '331', (30, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('XIAP', 'Gene', (172, 176))	('EGFR', 'Gene', (185, 189))	('attenuates', 'NegReg', (35, 45))	('XIAP', 'Gene', '331', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('anchorage-independent cell growth', 'CPA', (46, 79))	('EGFR', 'Gene', '1956', (222, 226))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('knockdown', 'Var', (17, 26))	('XIAP', 'Gene', (30, 34))	('EGFR', 'Gene', (222, 226))	('modulated', 'Reg', (155, 164))	('EGFR', 'Gene', '1956', (185, 189))
381105	33435156	Accumulating evidence reveals that miR-204-5p hinders EMT, stemness, invasion, and metastasis in multiple types of cancer.	('miR-204-5p', 'Var', (35, 45))	('cancer', 'Disease', (115, 121))	('metastasis', 'CPA', (83, 93))	('hinders', 'NegReg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('stemness', 'CPA', (59, 67))	('invasion', 'CPA', (69, 77))	('EMT', 'CPA', (54, 57))	('miR-204-5p', 'Chemical', '-', (35, 45))
381106	33435156	In gastric cancer, low levels of miR-204-5p are correlated with lymph node metastasis, and this miRNA negatively regulates C-X-C motif chemokine receptor 4 (CXCR4), which can provoke metastasis by blocking anoikis.	('provoke', 'PosReg', (175, 182))	('C-X-C motif chemokine receptor 4', 'Gene', '7852', (123, 155))	('miR-204-5p', 'Chemical', '-', (33, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('CXCR4', 'Gene', '7852', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('anoikis', 'CPA', (206, 213))	('miR-204-5p', 'Var', (33, 43))	('metastasis', 'CPA', (183, 193))	('regulates', 'Reg', (113, 122))	('lymph node metastasis', 'CPA', (64, 85))	('CXCR4', 'Gene', (157, 162))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('negatively', 'NegReg', (102, 112))	('C-X-C motif chemokine receptor 4', 'Gene', (123, 155))
381107	33435156	Also, miR-204-5p interrupts EMT process by targeting POU class 2 homeobox 1 (POU2F1, also called OCT1), which is proposed to protect cells from anoikis.	('POU2F1', 'Gene', '5451', (77, 83))	('targeting', 'Reg', (43, 52))	('POU class 2 homeobox 1', 'Gene', '5451', (53, 75))	('OCT1', 'Gene', (97, 101))	('OCT1', 'Gene', '5451', (97, 101))	('miR-204-5p', 'Chemical', '-', (6, 16))	('POU2F1', 'Gene', (77, 83))	('POU class 2 homeobox 1', 'Gene', (53, 75))	('miR-204-5p', 'Var', (6, 16))
381108	33435156	Further, there is consistent evidence that miR-204-5p negatively regulates EMT process and dampens anoikis resistance in gastric cancer.	('EMT process', 'CPA', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('anoikis resistance', 'CPA', (99, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('miR-204-5p', 'Chemical', '-', (43, 53))	('miR-204-5p', 'Var', (43, 53))	('dampens', 'NegReg', (91, 98))	('regulates', 'Reg', (65, 74))	('negatively', 'NegReg', (54, 64))	('gastric cancer', 'Disease', (121, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
381109	33435156	In this study, sirtuin 1 (SIRT1) was validated as a target of miR-204-5p.	('SIRT1', 'Gene', '23411', (26, 31))	('SIRT1', 'Gene', (26, 31))	('miR-204-5p', 'Var', (62, 72))	('sirtuin 1', 'Gene', '23411', (15, 24))	('miR-204-5p', 'Chemical', '-', (62, 72))	('sirtuin 1', 'Gene', (15, 24))
381111	33435156	Therefore, it is feasible that miR-204-5p acts as an anoikis-promoting miRNA by regulating CXCR4, OCT1, etcetera, rather than SIRT1, in gastric cancer (Figure 2 and Table 2).	('CXCR4', 'Gene', '7852', (91, 96))	('OCT1', 'Gene', (98, 102))	('rat', 'Species', '10116', (114, 117))	('OCT1', 'Gene', '5451', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('miR-204-5p', 'Chemical', '-', (31, 41))	('SIRT1', 'Gene', '23411', (126, 131))	('CXCR4', 'Gene', (91, 96))	('gastric cancer', 'Disease', (136, 150))	('etcetera', 'MPA', (104, 112))	('SIRT1', 'Gene', (126, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('regulating', 'Reg', (80, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('miR-204-5p', 'Var', (31, 41))
381114	33435156	In addition, it was found that UBE2C knockdown leads to the reduction of anchorage-independent growth of rectal carcinoma cells and that UBE2C is targeted by miR-381, suggesting that miR-381 can modulate anchorage-independent growth partly via UBE2C.	('rectal carcinoma', 'Disease', (105, 121))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (105, 121))	('UBE2C', 'Gene', '11065', (137, 142))	('UBE2C', 'Gene', '11065', (244, 249))	('UBE2C', 'Gene', (137, 142))	('knockdown', 'Var', (37, 46))	('UBE2C', 'Gene', '11065', (31, 36))	('UBE2C', 'Gene', (244, 249))	('miR-381', 'Gene', '494330', (183, 190))	('UBE2C', 'Gene', (31, 36))	('reduction', 'NegReg', (60, 69))	('miR-381', 'Gene', (158, 165))	('rectal carcinoma', 'Disease', 'MESH:D012004', (105, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('modulate', 'Reg', (195, 203))	('miR-381', 'Gene', '494330', (158, 165))	('miR-381', 'Gene', (183, 190))	('anchorage-independent growth', 'CPA', (204, 232))
381120	33435156	Further tests showed that the restoration of miR-450 forcefully increases the rate of anoikis in vitro and cancer growth in vivo (Figure 2 and Table 2).	('anoikis', 'CPA', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rat', 'Species', '10116', (78, 81))	('miR-450', 'Chemical', '-', (45, 52))	('miR-450', 'Protein', (45, 52))	('restoration', 'Var', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('rat', 'Species', '10116', (35, 38))	('cancer', 'Disease', (107, 113))	('increases', 'PosReg', (64, 73))
381127	33435156	In pancreatic cancer, miR-29-3p sensitizes cancer cells to gemcitabine and diminishes the ability of cancer cells to grow under anchorage-independent conditions.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('pancreatic cancer', 'Disease', (3, 20))	('miR-29-3p', 'Chemical', '-', (22, 31))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (43, 49))	('sensitizes', 'Reg', (32, 42))	('gemcitabine', 'Chemical', 'MESH:C056507', (59, 70))	('miR-29-3p', 'Var', (22, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('diminishes', 'NegReg', (75, 85))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
381128	33435156	The mechanism underlying these tumor-suppressive activities of miR-29-3p involves the downregulation of autophagy-related 9A (ATG9A) and transcription factor EB (TFEB), which control the trafficking of autophagosome and lysosomal function.	('autophagy-related 9A', 'Gene', (104, 124))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('ATG9A', 'Gene', (126, 131))	('miR-29-3p', 'Chemical', '-', (63, 72))	('downregulation', 'NegReg', (86, 100))	('ATG9A', 'Gene', '79065', (126, 131))	('TFEB', 'Gene', '7942', (162, 166))	('miR-29-3p', 'Var', (63, 72))	('autophagy-related 9A', 'Gene', '79065', (104, 124))	('TFEB', 'Gene', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
381129	33435156	Therefore, the overexpression of miR-29-3p causes the impairment of autophagic flux resulting from the blockage of autophagosome-lysosome fusion (Figure 2 and Table 2).	('overexpression', 'PosReg', (15, 29))	('miR-29-3p', 'Var', (33, 42))	('miR-29-3p', 'Chemical', '-', (33, 42))	('autophagic flux', 'CPA', (68, 83))	('autophagosome-lysosome fusion', 'CPA', (115, 144))	('impairment', 'NegReg', (54, 64))	('blockage', 'NegReg', (103, 111))	('expression', 'Species', '29278', (19, 29))
381130	33435156	Several studies have highlighted the role of miR-30-5p in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (58, 82))	('miR-30-5p', 'Var', (45, 54))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('miR-30-5p', 'Chemical', '-', (45, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
381131	33435156	For instance, through targeting SNAI1, miR-30-5p impedes EMT.	('targeting', 'Reg', (22, 31))	('miR-30-5p', 'Chemical', '-', (39, 48))	('SNAI1', 'Gene', '6615', (32, 37))	('SNAI1', 'Gene', (32, 37))	('impedes', 'NegReg', (49, 56))	('miR-30-5p', 'Var', (39, 48))	('EMT', 'CPA', (57, 60))
381132	33435156	In addition, miR-30-5p induces apoptotic cell death and retards proliferation, as well as invasion.	('induces', 'Reg', (23, 30))	('retards proliferation', 'Disease', (56, 77))	('miR-30-5p', 'Var', (13, 22))	('apoptotic cell death', 'CPA', (31, 51))	('retards proliferation', 'Disease', 'MESH:C565054', (56, 77))	('miR-30-5p', 'Chemical', '-', (13, 22))	('invasion', 'CPA', (90, 98))
381133	33435156	Moreover, it has been recently demystified that miR-30-5p abates anoikis resistance and lung metastasis in hepatocellular carcinoma cells through targeting autophagy-inducing factors, namely, ATG5 and BECN1 (Figure 2 and Table 2).	('abates', 'NegReg', (58, 64))	('miR-30-5p', 'Var', (48, 57))	('ATG5', 'Gene', (192, 196))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (107, 131))	('BECN1', 'Gene', (201, 206))	('hepatocellular carcinoma', 'Disease', (107, 131))	('lung metastasis', 'CPA', (88, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (107, 131))	('targeting', 'Reg', (146, 155))	('ATG5', 'Gene', '9474', (192, 196))	('BECN1', 'Gene', '8678', (201, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('anoikis resistance', 'CPA', (65, 83))	('miR-30-5p', 'Chemical', '-', (48, 57))
381134	33435156	These findings suggest the therapeutic benefit of miR-30-5p overexpression for hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('hepatocellular carcinoma', 'Disease', (79, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('miR-30-5p', 'Var', (50, 59))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))	('expression', 'Species', '29278', (64, 74))	('miR-30-5p', 'Chemical', '-', (50, 59))
381135	33435156	The expression of miR-204-5p is epigenetically silenced in medulloblastoma, and low levels of this miRNA are correlated with the dismal prognosis of patients.	('miR-204-5p', 'Var', (18, 28))	('miR-204-5p', 'Chemical', '-', (18, 28))	('patients', 'Species', '9606', (149, 157))	('expression', 'Species', '29278', (4, 14))	('expression', 'MPA', (4, 14))	('medulloblastoma', 'Disease', 'MESH:D008527', (59, 74))	('correlated', 'Reg', (109, 119))	('medulloblastoma', 'Phenotype', 'HP:0002885', (59, 74))	('silenced', 'NegReg', (47, 55))	('medulloblastoma', 'Disease', (59, 74))
381136	33435156	The evaluation of miR-204-5p activity denoted that miR-204-5p reduces the number of cells growing anchorage-independently, at least in part owing to its capability to inhibit autophagy via targeting microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B, also called LC3B) (Figure 2 and Table 2).	('LC3B', 'Gene', (257, 261))	('miR-204-5p', 'Chemical', '-', (18, 28))	('reduces', 'NegReg', (62, 69))	('LC3B', 'Gene', (275, 279))	('microtubule-associated proteins 1A/1B light chain 3B', 'Gene', '81631', (199, 251))	('autophagy', 'CPA', (175, 184))	('MAP1LC3B', 'Gene', (253, 261))	('number of cells growing anchorage-independently', 'CPA', (74, 121))	('inhibit', 'NegReg', (167, 174))	('MAP1LC3B', 'Gene', '81631', (253, 261))	('LC3B', 'Gene', '81631', (257, 261))	('LC3B', 'Gene', '81631', (275, 279))	('miR-204-5p', 'Chemical', '-', (51, 61))	('miR-204-5p', 'Var', (51, 61))
381137	33435156	In hepatocellular carcinoma, miR-26-5p has been perceived to suppress metastasis by regulating several cellular events, such as apoptosis and EMT.	('metastasis', 'CPA', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('miR-26-5p', 'Var', (29, 38))	('miR-26-5p', 'Chemical', '-', (29, 38))	('EMT', 'CPA', (142, 145))	('suppress', 'NegReg', (61, 69))	('regulating', 'Reg', (84, 94))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('apoptosis', 'CPA', (128, 137))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
381138	33435156	Moreover, miR-26-5p stimulates the anoikis of hepatocellular carcinoma cells by directly suppressing ITGA5.	('anoikis of hepatocellular carcinoma', 'Disease', (35, 70))	('suppressing', 'NegReg', (89, 100))	('ITGA5', 'Gene', (101, 106))	('stimulates', 'PosReg', (20, 30))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('miR-26-5p', 'Var', (10, 19))	('miR-26-5p', 'Chemical', '-', (10, 19))	('ITGA5', 'Gene', '3678', (101, 106))	('anoikis of hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 70))
381139	33435156	These observations demonstrate that miR-26-5p is a bona fide metastasis-suppressing miRNA in hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (93, 117))	('miR-26-5p', 'Chemical', '-', (36, 45))	('hepatocellular carcinoma', 'Disease', (93, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (93, 117))	('rat', 'Species', '10116', (26, 29))	('miR-26-5p', 'Var', (36, 45))
381141	33435156	In that study, it was also shown that ITGA3 levels are positively correlated with poor prognosis of patients with colorectal cancer and that knockdown of ITGA3 augments anoikis induction and reduces metastasis.	('rectal cancer', 'Phenotype', 'HP:0100743', (118, 131))	('knockdown', 'Var', (141, 150))	('ITGA3', 'Gene', (38, 43))	('augments', 'PosReg', (160, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('ITGA3', 'Gene', '3675', (154, 159))	('ITGA3', 'Gene', '3675', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('patients', 'Species', '9606', (100, 108))	('reduces', 'NegReg', (191, 198))	('metastasis', 'CPA', (199, 209))	('anoikis induction', 'CPA', (169, 186))	('colorectal cancer', 'Disease', (114, 131))	('ITGA3', 'Gene', (154, 159))
381142	33435156	Moreover, anoikis resistance is attenuated by the overexpression of miR-363-3p, which is downregulated in papillary thyroid carcinoma.	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (106, 133))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (116, 133))	('overexpression', 'PosReg', (50, 64))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (106, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('miR-363-3p', 'Var', (68, 78))	('downregulated', 'NegReg', (89, 102))	('anoikis resistance', 'CPA', (10, 28))	('attenuated', 'NegReg', (32, 42))	('papillary thyroid carcinoma', 'Disease', (106, 133))	('expression', 'Species', '29278', (54, 64))
381153	33435156	LncRNA-ANRIL knockdown increases miR-203a levels and abates the expression of several cellular factors, such as BCL-2, CDK2, c-Myc, and Akt.	('CDK2', 'Gene', (119, 123))	('BCL-2', 'Gene', (112, 117))	('expression', 'MPA', (64, 74))	('c-Myc', 'Gene', '4609', (125, 130))	('ANRIL', 'Gene', '100048912', (7, 12))	('ncRNA', 'Gene', '220202', (1, 6))	('increases', 'PosReg', (23, 32))	('c-Myc', 'Gene', (125, 130))	('miR-203', 'Gene', (33, 40))	('Akt', 'Gene', '207', (136, 139))	('miR-203', 'Gene', '406986', (33, 40))	('abates', 'NegReg', (53, 59))	('ANRIL', 'Gene', (7, 12))	('BCL-2', 'Gene', '596', (112, 117))	('Akt', 'Gene', (136, 139))	('knockdown', 'Var', (13, 22))	('ncRNA', 'Gene', (1, 6))	('expression', 'Species', '29278', (64, 74))
381154	33435156	The knockdown of miR-203a partially reverses the effect of lncRNA-ANRIL silencing, certainly indicating that the ability of lncRNA-ANRIL to regulate anoikis is mediated by miR-203a (Figure 3 and Table 3).	('ANRIL', 'Gene', (131, 136))	('anoikis', 'Disease', (149, 156))	('ncRNA', 'Gene', '220202', (125, 130))	('ncRNA', 'Gene', (60, 65))	('miR-203', 'Gene', '406986', (172, 179))	('ANRIL', 'Gene', '100048912', (66, 71))	('ANRIL', 'Gene', '100048912', (131, 136))	('miR-203', 'Gene', (17, 24))	('ncRNA', 'Gene', (125, 130))	('ncRNA', 'Gene', '220202', (60, 65))	('miR-203', 'Gene', '406986', (17, 24))	('miR-203', 'Gene', (172, 179))	('knockdown', 'Var', (4, 13))	('ANRIL', 'Gene', (66, 71))
381173	33435156	Also, it was demonstrated that lncRNA-MEG3 impedes the metastasis of gastric cancer, at least partly via sponging miR-21.	('MEG3', 'Gene', '55384', (38, 42))	('miR-21', 'Gene', '406991', (114, 120))	('gastric cancer', 'Disease', (69, 83))	('ncRNA', 'Gene', (32, 37))	('metastasis', 'CPA', (55, 65))	('impedes', 'NegReg', (43, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('ncRNA', 'Gene', '220202', (32, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('sponging', 'Var', (105, 113))	('miR-21', 'Gene', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rat', 'Species', '10116', (20, 23))	('MEG3', 'Gene', (38, 42))
381176	33435156	Ectopic expression of lncRNA-MEG3 brings about the retarded growth of cancer cells in the absence of anchorage.	('ncRNA', 'Gene', (23, 28))	('MEG3', 'Gene', (29, 33))	('retarded growth', 'Phenotype', 'HP:0001510', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Ectopic expression', 'Var', (0, 18))	('ncRNA', 'Gene', '220202', (23, 28))	('expression', 'Species', '29278', (8, 18))	('MEG3', 'Gene', '55384', (29, 33))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
381177	33435156	The expression of lncRNA-MEG3 can be derepressed by miR-29-3p that negatively regulates the levels of DNA Methyltransferase 1 (DNMT1) and DNMT3B.	('regulates', 'Reg', (78, 87))	('DNMT3B', 'Gene', (138, 144))	('levels of', 'MPA', (92, 101))	('DNMT3B', 'Gene', '1789', (138, 144))	('ncRNA', 'Gene', (19, 24))	('expression', 'Species', '29278', (4, 14))	('ncRNA', 'Gene', '220202', (19, 24))	('expression', 'MPA', (4, 14))	('miR-29-3p', 'Chemical', '-', (52, 61))	('negatively', 'NegReg', (67, 77))	('MEG3', 'Gene', (25, 29))	('miR-29-3p', 'Var', (52, 61))	('MEG3', 'Gene', '55384', (25, 29))
381178	33435156	These findings suggest that miR-29-3p can modulate anchorage-independent growth by affecting lncRNA levels and autophagy processes (see Section 3.4.1) (Figure 3 and Table 3).	('ncRNA', 'Gene', '220202', (94, 99))	('miR-29-3p', 'Chemical', '-', (28, 37))	('affecting', 'Reg', (83, 92))	('miR-29-3p', 'Var', (28, 37))	('anchorage-independent growth', 'CPA', (51, 79))	('autophagy processes', 'CPA', (111, 130))	('modulate', 'Reg', (42, 50))	('ncRNA', 'Gene', (94, 99))
381181	33435156	Further, it was shown that the knockdown of lncRNA-MEG3 abrogates TGF-beta-induced EMT marker levels.	('abrogates', 'NegReg', (56, 65))	('ncRNA', 'Gene', '220202', (45, 50))	('TGF-beta', 'Gene', (66, 74))	('MEG3', 'Gene', '55384', (51, 55))	('MEG3', 'Gene', (51, 55))	('TGF-beta', 'Gene', '7039', (66, 74))	('ncRNA', 'Gene', (45, 50))	('knockdown', 'Var', (31, 40))
381189	33435156	In lung cancer, miR-218 is actuated following the lncRNA-SNHG12 knockdown, causing the suppression of migration, invasion, and the level of EMT-related factors, such as SNAI2 and ZEB2.	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('level', 'MPA', (131, 136))	('migration', 'CPA', (102, 111))	('SNAI2', 'Gene', '6591', (169, 174))	('invasion', 'CPA', (113, 121))	('suppression', 'NegReg', (87, 98))	('ZEB2', 'Gene', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('miR-21', 'Gene', (16, 22))	('ncRNA', 'Gene', (51, 56))	('SNAI2', 'Gene', (169, 174))	('lung cancer', 'Disease', (3, 14))	('ncRNA', 'Gene', '220202', (51, 56))	('ZEB2', 'Gene', '9839', (179, 183))	('miR-21', 'Gene', '406991', (16, 22))	('SNHG12', 'Gene', (57, 63))	('rat', 'Species', '10116', (105, 108))	('SNHG12', 'Gene', '85028', (57, 63))	('knockdown', 'Var', (64, 73))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
381190	33435156	Also, the knockdown of lncRNA-SNHG12 inactivates Wnt/beta-catenin signaling and decreases CCND1 expression, eventually limiting the metastasis of thyroid cancer in vivo.	('CCND1', 'Gene', '595', (90, 95))	('SNHG12', 'Gene', (30, 36))	('limiting', 'NegReg', (119, 127))	('CCND1', 'Gene', (90, 95))	('thyroid cancer', 'Disease', (146, 160))	('expression', 'MPA', (96, 106))	('inactivates', 'NegReg', (37, 48))	('knockdown', 'Var', (10, 19))	('SNHG12', 'Gene', '85028', (30, 36))	('metastasis', 'CPA', (132, 142))	('beta-catenin', 'Gene', (53, 65))	('ncRNA', 'Gene', (24, 29))	('thyroid cancer', 'Disease', 'MESH:D013964', (146, 160))	('beta-catenin', 'Gene', '1499', (53, 65))	('ncRNA', 'Gene', '220202', (24, 29))	('expression', 'Species', '29278', (96, 106))	('thyroid cancer', 'Phenotype', 'HP:0002890', (146, 160))	('decreases', 'NegReg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
381195	33435156	The silencing of lncRNA-TINCR suppresses the cell survival, migration, invasion, anchorage-independent growth, and in vivo growth of breast cancer cells (Figure 3 and Table 3).	('breast cancer', 'Disease', (133, 146))	('anchorage-independent growth', 'CPA', (81, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('cell survival', 'CPA', (45, 58))	('suppresses', 'NegReg', (30, 40))	('invasion', 'CPA', (71, 79))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('migration', 'CPA', (60, 69))	('ncRNA', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('rat', 'Species', '10116', (63, 66))	('ncRNA', 'Gene', '220202', (18, 23))	('silencing', 'Var', (4, 13))
381207	33435156	EVs secreted from gemcitabine-resistant cells contain miR-222-3p, and this miRNA confers anoikis resistance in EV-receiving cells.	('miR-222-3p', 'Var', (54, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (18, 29))	('anoikis resistance', 'CPA', (89, 107))
381270	30109285	Prospective studies indicated that the detection of HHV-8 could predict the development of Kaposi's sarcoma in asymptomatic subjects (Whitby et al., 1995 dan Moore et al., 1996).	('HHV-8', 'Species', '37296', (52, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (91, 107))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (91, 107))	('men', 'Species', '9606', (83, 86))	('detection', 'Var', (39, 48))	("Kaposi's sarcoma", 'Disease', (91, 107))	('HHV-8', 'Gene', (52, 57))
381273	30109285	The presence of HHV-8 infection in HIV-positive patients is possibly related to the risk of developing opportunistic diseases, including Kaposi's sarcoma (classic, AIDS-related KS, endemic and iatrogenic) and other proliferative diseases, such as primary effusion lymphoma and multicentric Castleman disease.	('primary effusion lymphoma', 'Disease', (247, 272))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (247, 272))	('opportunistic diseases', 'Disease', (103, 125))	('AIDS', 'Disease', 'MESH:D000163', (164, 168))	('opportunistic diseases', 'Disease', 'MESH:D009894', (103, 125))	('lymphoma', 'Phenotype', 'HP:0002665', (264, 272))	('related', 'Reg', (69, 76))	('HHV-8 infection in HIV-positive', 'Disease', (16, 47))	('multicentric Castleman disease', 'Disease', (277, 307))	('HHV-8 infection in HIV-positive', 'Disease', 'MESH:D015658', (16, 47))	('KS', 'Chemical', 'MESH:D011188', (177, 179))	('AIDS', 'Disease', (164, 168))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (137, 153))	('presence', 'Var', (4, 12))	('multicentric Castleman disease', 'Disease', 'MESH:C537372', (277, 307))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (247, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (137, 153))	("Kaposi's sarcoma", 'Disease', (137, 153))	('patients', 'Species', '9606', (48, 56))
381275	30109285	Various tests have detected HHV-8 antibodies in the majority of asymptomatic individuals with increased tumor risk, including HIV-positive homosexual men (Martin et al., 1998), adults from Italy and various regions of sub-Saharan Africa (Sitas et al., 1999; Calabro et al., 1998), and some low risk people, such as blood donors from the UK, USA, and Jamaica (Simpson et al., 1996; Engels et al., 1999).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('people', 'Species', '9606', (299, 305))	('tumor', 'Disease', (104, 109))	('antibodies', 'Var', (34, 44))	('detected', 'Reg', (19, 27))	('men', 'Species', '9606', (150, 153))	('HHV-8', 'Gene', (28, 33))	('HIV', 'Species', '12721', (126, 129))	('HHV-8', 'Species', '37296', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
381319	30018812	Multiple examples in the choice of systemic treatments were highlighted at the meeting, such as the peculiar activity of taxanes and gemcitabine in angiosarcoma and m-TOR inhibitors in malignant perivascular epithelioid cell tumours (PEComas), which are often associated with a disruption in the m-TOR pathway.	('gemcitabine', 'Chemical', 'MESH:C056507', (133, 144))	('angiosarcoma', 'Disease', 'MESH:D006394', (148, 160))	('angiosarcoma', 'Disease', (148, 160))	('taxanes', 'Chemical', 'MESH:D043823', (121, 128))	('inhibitors', 'Var', (171, 181))	('PEComas', 'Disease', (234, 241))	('TOR', 'Gene', '6097', (167, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('PEComas', 'Disease', 'MESH:D054973', (234, 241))	('epithelioid cell tumours', 'Disease', 'MESH:D054973', (208, 232))	('angiosarcoma', 'Phenotype', 'HP:0200058', (148, 160))	('TOR', 'Gene', '6097', (298, 301))	('activity', 'MPA', (109, 117))	('epithelioid cell tumours', 'Disease', (208, 232))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('TOR', 'Gene', (167, 170))	('TOR', 'Gene', (298, 301))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))
381321	30018812	DFSP is an STS subtype in the skin with a translocation, t(17;22)(q22;q13), that leads to the fusion of collagen type 1alpha1 (COL1A1) and platelet-derived growth factor B (PDGFB).	('leads to', 'Reg', (81, 89))	('DFSP', 'Disease', (0, 4))	('collagen type 1alpha1', 'Gene', (104, 125))	('PDGFB', 'Gene', '5155', (173, 178))	('platelet-derived growth factor B', 'Gene', (139, 171))	('PDGFB', 'Gene', (173, 178))	('DFSP', 'Disease', 'MESH:D018223', (0, 4))	('platelet-derived growth factor B', 'Gene', '5155', (139, 171))	('collagen type 1alpha1', 'Gene', '1277', (104, 125))	('fusion', 'Var', (94, 100))	('COL1A1', 'Gene', '1277', (127, 133))	('COL1A1', 'Gene', (127, 133))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (57, 74))
381336	30018812	M. Gounder described how gene silencing through DNA hypermethylation at promoter and/or enhancer regions, mutation or post-translational modification of histones and deregulation of chromatin remodelling complexes are epigenetic mechanisms of oncogenicity across many different sarcoma types.	('chromatin', 'Protein', (182, 191))	('sarcoma', 'Disease', (278, 285))	('histones', 'Protein', (153, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (278, 285))	('mutation', 'Var', (106, 114))	('deregulation', 'Var', (166, 178))	('DNA hypermethylation', 'Var', (48, 68))	('gene', 'MPA', (25, 29))	('sarcoma', 'Disease', 'MESH:D012509', (278, 285))
381337	30018812	Such epigenetic deregulation can result in the upregulation of oncogenes or the silencing of genes with tumour suppressor or cellular differentiation programming functions.	('epigenetic deregulation', 'Var', (5, 28))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('silencing', 'MPA', (80, 89))	('upregulation', 'PosReg', (47, 59))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour', 'Disease', (104, 110))	('oncogenes', 'Protein', (63, 72))
381338	30018812	Recurrent mutational deregulation of the SWI-SNF chromatin-remodelling complex is crucial to the development of certain STS subtypes such as epithelioid sarcoma, malignant rhabdoid tumour, synovial sarcoma and a subset of chordomas.	('SWI-SNF', 'Gene', (41, 48))	('chordomas', 'Disease', (222, 231))	('synovial sarcoma', 'Disease', 'MESH:D013584', (189, 205))	('epithelioid sarcoma', 'Disease', (141, 160))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('chordomas', 'Disease', 'MESH:D002817', (222, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('malignant rhabdoid tumour', 'Disease', 'MESH:C563738', (162, 187))	('synovial sarcoma', 'Disease', (189, 205))	('malignant rhabdoid tumour', 'Disease', (162, 187))	('mutational deregulation', 'Var', (10, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (141, 160))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (189, 205))
381339	30018812	For example, a Cancer Genome Atlas study identified a subset of dedifferentiated liposarcoma with a hypermethylated genome that is associated with worse survival compared with hypomethylated tumours of the same subtype.	('Cancer', 'Disease', 'MESH:D009369', (15, 21))	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (64, 92))	('worse', 'NegReg', (147, 152))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('dedifferentiated liposarcoma', 'Disease', (64, 92))	('hypomethylated tumours', 'Disease', (176, 198))	('liposarcoma', 'Phenotype', 'HP:0012034', (81, 92))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('hypomethylated tumours', 'Disease', 'MESH:D009369', (176, 198))	('hypermethylated', 'Var', (100, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('Cancer', 'Disease', (15, 21))
381340	30018812	EZH2 inhibitors have been associated with dramatic responses in tumours with deficient expression of the SWI-SNF member protein INI1.	('deficient', 'NegReg', (77, 86))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('inhibitors', 'Var', (5, 15))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('expression', 'MPA', (87, 97))	('INI1', 'Gene', '6598', (128, 132))	('INI1', 'Gene', (128, 132))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
381353	30018812	Similarly, an analysis of the mutational and copy number profiles of 587 patients with STS found that 93% had at least one actionable mutation, copy number alteration and/or fusion gene.	('copy number alteration', 'Var', (144, 166))	('fusion gene', 'Var', (174, 185))	('patients', 'Species', '9606', (73, 81))
381427	23858317	It is important to remember that endosalpingiosis is positive for B72.3 and also shows nuclear estrogen receptor (ER) and progesteron receptor (PR) positivity.	('positive', 'Reg', (53, 61))	('B72.3', 'Var', (66, 71))	('ER', 'Gene', '2099', (114, 116))	('endosalpingiosis', 'Disease', (33, 49))	('endosalpingiosis', 'Disease', 'MESH:C537064', (33, 49))	('estrogen receptor', 'Gene', (95, 112))	('estrogen receptor', 'Gene', '2099', (95, 112))	('nuclear', 'Protein', (87, 94))
381467	23858317	Low grade serous carcinomas are indolent tumors, and mutations of Kirsten rat sarcoma (KRAS) and vRaf murine sarcoma viral oncogene homolog B1BRAF can be found in the majority of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('sarcoma viral', 'Disease', (109, 122))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('tumors', 'Disease', (185, 191))	('tumors', 'Disease', (41, 47))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('sarcoma', 'Disease', (78, 85))	('sarcoma', 'Disease', (109, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('serous carcinomas', 'Disease', 'MESH:D018284', (10, 27))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('murine', 'Species', '10090', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('B1BRAF', 'Gene', (140, 146))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('serous carcinomas', 'Disease', (10, 27))	('rat', 'Species', '10116', (74, 77))	('sarcoma viral', 'Disease', 'MESH:D001102', (109, 122))
381480	23858317	At the molecular level, these tumors demonstrate chromosomal instability and tumor protein 53(TP53) mutations.	('mutations', 'Var', (100, 109))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumor protein 53', 'Gene', '7157', (77, 93))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('rat', 'Species', '10116', (44, 47))	('tumor protein 53', 'Gene', (77, 93))	('chromosomal', 'MPA', (49, 60))	('chromosomal instability', 'Phenotype', 'HP:0040012', (49, 72))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
381481	23858317	Peritoneal washings tend to be highly cellular, have larger tissue fragments (sometimes with over 30 cells) with complex architecture, crowded and disorganized cell arrangements, marked nuclear atypia, pleomorphism, macronucleoli and mitoses when compared with low grade serous tumors.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('pleomorphism', 'Var', (202, 214))	('men', 'Species', '9606', (71, 74))	('serous tumors', 'Disease', 'MESH:D018284', (271, 284))	('serous tumors', 'Disease', (271, 284))	('mitoses', 'CPA', (234, 241))	('men', 'Species', '9606', (172, 175))
381483	23858317	Most serous carcinomas are immunoreactive for Wilm's tumor 1 (WT1), CA-125 and PAX8 [Figure 10].	('serous carcinomas', 'Disease', (5, 22))	("Wilm's tumor 1", 'Gene', '7490', (46, 60))	('WT1', 'Gene', '7490', (62, 65))	('PAX8', 'Gene', '7849', (79, 83))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (46, 58))	('WT1', 'Gene', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('PAX8', 'Gene', (79, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	("Wilm's tumor 1", 'Gene', (46, 60))	('CA-125', 'Var', (68, 74))	('serous carcinomas', 'Disease', 'MESH:D018284', (5, 22))
381495	23858317	With that possibility in mind, Landon et al., studied the utility of peritoneal washing for detecting occult primary peritoneal carcinoma in 117 patients with breast cancer 1 (BRCA-1 or BRCA2 mutations.	('patients', 'Species', '9606', (145, 153))	('BRCA-1', 'Gene', (176, 182))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('BRCA-1', 'Gene', '672', (176, 182))	('primary peritoneal carcinoma', 'Phenotype', 'HP:0030406', (109, 137))	('BRCA2', 'Gene', (186, 191))	('carcinoma', 'Disease', 'MESH:D002277', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('carcinoma', 'Disease', (128, 137))	('BRCA2', 'Gene', '675', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (192, 201))
381507	23858317	TP53 mutations have been reported in these tumors, which is only rarely seen in uterine or ovarian MMMT.	('TP53', 'Gene', '7157', (0, 4))	('reported', 'Reg', (25, 33))	('TP53', 'Gene', (0, 4))	('ovarian MMMT', 'Disease', (91, 103))	('mutations', 'Var', (5, 14))	('ovarian MMMT', 'Disease', 'MESH:D010051', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
381520	23858317	Deleted in pancretic cancer (DPC4) or SMAD4 can be a helpful immunostain, since it is positive in ovarian mucinous tumors and negative in approximately 50% of pancreatic tumors.	('pancretic cancer', 'Phenotype', 'HP:0002894', (11, 27))	('Deleted', 'Var', (0, 7))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (159, 176))	('SMAD4', 'Gene', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian mucinous tumors', 'Disease', (98, 121))	('pancretic cancer', 'Disease', 'MESH:D009369', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pancreatic tumors', 'Disease', 'MESH:D010190', (159, 176))	('SMAD4', 'Gene', '4089', (38, 43))	('ovarian mucinous tumors', 'Disease', 'MESH:D010051', (98, 121))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('pancreatic tumors', 'Disease', (159, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('DPC4', 'Gene', (29, 33))	('ovarian mucinous tumors', 'Phenotype', 'HP:0031494', (98, 121))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('positive', 'Reg', (86, 94))	('DPC4', 'Gene', '4089', (29, 33))	('pancretic cancer', 'Disease', (11, 27))
381552	23858317	The Call-Exner bodies in fluid appear as small clusters of cells in a rosette pattern with a central hyaline globule that stains green or blue on Pap stain or pink on Diff-Quik.	('Pap', 'Gene', (146, 149))	('stains', 'Var', (122, 128))	('rosette', 'Phenotype', 'HP:0031925', (70, 77))	('hyaline globule', 'Phenotype', 'HP:0025115', (101, 116))	('Pap', 'Gene', '10914', (146, 149))
381569	23858317	Immunostains for epithelial markers (e.g., B72.3 and BerEP4) help detect and/or confirm the presence of endometrial carcinoma in washings, but will not distinguish these cell groups from benign epithelial entities such as endosalpingiosis.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (104, 125))	('endometrial carcinoma', 'Disease', (104, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('endosalpingiosis', 'Disease', (222, 238))	('endosalpingiosis', 'Disease', 'MESH:C537064', (222, 238))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (104, 125))	('B72.3', 'Var', (43, 48))
381602	23858317	At the molecular level neurofibromatosis 2 (NF2) gene alterations have been associated with this tumor.	('NF2', 'Gene', '4771', (44, 47))	('fibroma', 'Phenotype', 'HP:0010614', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('neurofibromatosis 2', 'Gene', '4771', (23, 42))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (23, 40))	('tumor', 'Disease', (97, 102))	('associated', 'Reg', (76, 86))	('NF2', 'Gene', (44, 47))	('alterations', 'Var', (54, 65))	('rat', 'Species', '10116', (58, 61))	('neurofibromatosis 2', 'Gene', (23, 42))
381623	23858317	Although several immunostains have been reported to support a diagnosis of malignant mesothelioma (e.g., epithelial membrane antigen (EMA), glucose transporter-1(GLUT-1), and X-linked inhibitor of apoptosis protein), detection of a homozygous deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene (p16) on chromosome 9p21 by fluorescence in situ hybridization appears to show the most promising results as a marker for malignancy in mesothelial proliferations.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (75, 97))	('CDKN2A', 'Gene', (297, 303))	('p16', 'Gene', (311, 314))	('EMA', 'Gene', (134, 137))	('malignancy', 'Disease', 'MESH:D009369', (432, 442))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (259, 295))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (259, 295))	('CDKN2A', 'Gene', '1029', (297, 303))	('malignancy', 'Disease', (432, 442))	('GLUT-1', 'Gene', '6513', (162, 168))	('EMA', 'Gene', '4582', (134, 137))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (75, 97))	('deletion', 'Var', (243, 251))	('GLUT-1', 'Gene', (162, 168))	('rat', 'Species', '10116', (465, 468))	('p16', 'Gene', '1029', (311, 314))	('malignant mesothelioma', 'Disease', (75, 97))
381649	23858317	DSRCT also exhibits a reciprocal translocation t (11;22) resulting in fusion of the Ewing sarcoma 1 (EWS1) gene on chromosome 22 and WT1 on chromosome 11.	('Ewing sarcoma', 'Disease', (84, 97))	('WT1', 'Gene', (133, 136))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('fusion', 'Var', (70, 76))	('EWS1', 'Gene', (101, 105))	('WT1', 'Gene', '7490', (133, 136))
381674	23626551	The percentage of malignant PGLs is higher if related to SDH B (SDH-B) gene mutations.	('higher', 'PosReg', (36, 42))	('mutations', 'Var', (76, 85))	('SDH B', 'Gene', '6390', (57, 62))	('PGLs', 'Phenotype', 'HP:0002668', (28, 32))	('SDH-B', 'Gene', '6390', (64, 69))	('PGL', 'Phenotype', 'HP:0002668', (28, 31))	('SDH-B', 'Gene', (64, 69))	('SDH B', 'Gene', (57, 62))
381676	23626551	The most widely therapeutic approaches utilized are 131I-metaiodobenzylguanidine (MIBG) or a combination of cyclophosphamide, vincristine and dacarbazine, with comparable rates of response and toxicity, but no standard of care is established for patients with metastatic PGLs.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (108, 124))	('131I-metaiodobenzylguanidine', 'Var', (52, 80))	('MIBG', 'Chemical', '-', (82, 86))	('131I-metaiodobenzylguanidine', 'Chemical', '-', (52, 80))	('patients', 'Species', '9606', (246, 254))	('PGLs', 'Phenotype', 'HP:0002668', (271, 275))	('vincristine', 'Chemical', 'MESH:D014750', (126, 137))	('PGL', 'Phenotype', 'HP:0002668', (271, 274))	('toxicity', 'Disease', 'MESH:D064420', (193, 201))	('dacarbazine', 'Chemical', 'MESH:D003606', (142, 153))	('toxicity', 'Disease', (193, 201))
381685	23626551	Meanwhile, genetic testing was performed and fluorescence in situ hybridization analysis, using the LSI EWSR1 break-apart probe, revealed the translocation 22q12 for the EWSR1 gene, translocation characteristic of Ewing's sarcoma/pPNET, confirming diagnosis.	('EWSR1', 'Gene', (104, 109))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (214, 229))	('EWSR1', 'Gene', (170, 175))	("Ewing's sarcoma", 'Disease', (214, 229))	('pPNET', 'Phenotype', 'HP:0030067', (230, 235))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (214, 229))	('EWSR1', 'Gene', '2130', (170, 175))	('EWSR1', 'Gene', '2130', (104, 109))	('translocation 22q12', 'Var', (142, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
381689	23626551	The control CT scan showed a volume reduction of the lesion D9-D10 and the appearance of a solid new lesion with compression of the right-side profile of VI and VIII hepatic segments attributable to recurrent disease (fig.	('VIII', 'Gene', '1351', (161, 165))	('D9-D10', 'Var', (60, 66))	('compression', 'NegReg', (113, 124))	('reduction', 'NegReg', (36, 45))	('VIII', 'Gene', (161, 165))
381701	23626551	Simultaneously, genetic tests were performed: DNA sequencing showed an SDH-B mutation, characteristic of familial PGL syndrome 4.	('SDH-B', 'Gene', '6390', (71, 76))	('mutation', 'Var', (77, 85))	('familial PGL syndrome', 'Disease', (105, 126))	('SDH-B', 'Gene', (71, 76))	('familial PGL syndrome', 'Disease', 'MESH:D010235', (105, 126))	('PGL', 'Phenotype', 'HP:0002668', (114, 117))
381719	23626551	These data and the evidence, in preclinical models, that blocking VEGFR-2 leads to suppression of Ewing's sarcoma tumor growth and tumor vessel formation, indicate the VEGF pathway is an important therapeutic target.	('VEGF', 'Gene', (66, 70))	('VEGFR-2', 'Gene', '3791', (66, 73))	('blocking', 'Var', (57, 65))	("Ewing's sarcoma tumor", 'Disease', (98, 119))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('suppression', 'NegReg', (83, 94))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	("Ewing's sarcoma tumor", 'Disease', 'MESH:C563168', (98, 119))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (98, 113))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('VEGF', 'Gene', '7422', (168, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('VEGF', 'Gene', '7422', (66, 70))	('VEGFR-2', 'Gene', (66, 73))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (131, 136))	('VEGF', 'Gene', (168, 172))
381720	23626551	Also, the translocation t(11;22) is common in ESFT and produces the chimeric EWS/Fli-1 fusion gene found in 85% of patients with ESFT.	('patients', 'Species', '9606', (115, 123))	('EWS', 'Gene', '2130', (77, 80))	('EWS', 'Gene', (77, 80))	('translocation t', 'Var', (10, 25))	('ESFT', 'Disease', (46, 50))	('Fli-1', 'Gene', (81, 86))	('Fli-1', 'Gene', '2313', (81, 86))	('ESFT', 'Disease', (129, 133))
381722	23626551	Our pPNET patient treated with sunitinib, carrying the translocation 22q12 for the EWSR1 gene, showed a significant radiological response with the almost complete necrosis of the perihepatic metastatic lesion (a typical radiological response of some targeted agents) and a progression-free survival of 9 months.	('necrosis of the perihepatic metastatic lesion', 'Disease', (163, 208))	('EWSR1', 'Gene', (83, 88))	('necrosis of the perihepatic metastatic lesion', 'Disease', 'MESH:C537936', (163, 208))	('sunitinib', 'Chemical', 'MESH:D000077210', (31, 40))	('EWSR1', 'Gene', '2130', (83, 88))	('patient', 'Species', '9606', (10, 17))	('pPNET', 'Phenotype', 'HP:0030067', (4, 9))	('translocation 22q12', 'Var', (55, 74))
381726	23626551	This state of pseudo-hypoxia is functionally analogous to defects in the VHL protein in renal cell carcinoma, where antiangiogenic therapy and sunitinib are effective.	('sunitinib', 'Chemical', 'MESH:D000077210', (143, 152))	('renal cell carcinoma', 'Disease', (88, 108))	('hypoxia', 'Disease', 'MESH:D000860', (21, 28))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (88, 108))	('VHL', 'Disease', 'MESH:D006623', (73, 76))	('hypoxia', 'Disease', (21, 28))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (88, 108))	('VHL', 'Disease', (73, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('defects', 'Var', (58, 65))
381728	23626551	Similarly our patient, with SDH-B mutation, reported a clinical benefit with pain disappearance, an evident PET response and a progression-free survival of 36 weeks, confirming this treatment as very interesting in this setting of patients.	('patients', 'Species', '9606', (231, 239))	('mutation', 'Var', (34, 42))	('PET response', 'CPA', (108, 120))	('pain', 'Phenotype', 'HP:0012531', (77, 81))	('SDH-B', 'Gene', '6390', (28, 33))	('patient', 'Species', '9606', (14, 21))	('pain', 'Disease', 'MESH:D010146', (77, 81))	('pain', 'Disease', (77, 81))	('benefit', 'PosReg', (64, 71))	('patient', 'Species', '9606', (231, 238))	('SDH-B', 'Gene', (28, 33))
381768	33680274	In the present case, the tumor was very large, 10 cm in diameter at the largest point, and was hyperintense on T2-weighted images and hypointense on T1-weighted, with central necrosis.	('hypointense', 'Var', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('necrosis', 'Disease', 'MESH:D009336', (175, 183))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('necrosis', 'Disease', (175, 183))
381856	32977357	Two patients with T3N0M0 SCC of maxillary sinus and T2N0M0 ACC of nasal cavity received PRT to 70 and 66 Gy (RBE) in 35 and 30 fractions, respectively.	('PRT', 'Chemical', '-', (88, 91))	('T3N0M0 SCC', 'Var', (18, 28))	('SCC of maxillary', 'Phenotype', 'HP:0430028', (25, 41))	('patients', 'Species', '9606', (4, 12))	('T2N0M0 ACC', 'Var', (52, 62))
381857	32977357	Four patients achieved R0 resection of SCC or adenocarcinoma received CIRT to 60 Gy (RBE) in 20 fractions.	('adenocarcinoma', 'Disease', (46, 60))	('SCC', 'Disease', (39, 42))	('patients', 'Species', '9606', (5, 13))	('adenocarcinoma', 'Disease', 'MESH:D000230', (46, 60))	('CIRT', 'Var', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
381858	32977357	The remaining 66 patients with gross disease or R1 resection who received CIRT to 63-73.5 Gy (RBE) in 18-21 fractions to the CTV-G for gross tumors and surgical bed, and 54-63 Gy (RBE) in 18-21 fractions for CTVs of the high-risk region using simultaneous integrated boost technique.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('patients', 'Species', '9606', (17, 25))	('CIRT', 'Var', (74, 78))
381886	32977357	One additional patient who received PRT to 66 Gy (RBE) in 30 fractions gradually progress to grade 3 xerostomia after completion of treatment.	('PRT to 66 Gy', 'Var', (36, 48))	('patient', 'Species', '9606', (15, 22))	('xerostomia', 'Disease', (101, 111))	('PRT', 'Chemical', '-', (36, 39))	('xerostomia', 'Phenotype', 'HP:0000217', (101, 111))	('xerostomia', 'Disease', 'MESH:D014987', (101, 111))
381910	32977357	In a retrospective study of 39 unresectable SNM patients (excluding sarcoma) with N0M0 disease treated with proton therapy, the 3-year PFS and OS rates of 49.1% and 59.3% were reported, respectively.	('N0M0', 'Var', (82, 86))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('SNM', 'Chemical', '-', (44, 47))	('sarcoma', 'Disease', (68, 75))	('patients', 'Species', '9606', (48, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
381944	29900093	EWS-FLI1 expression in NIH-3T3 fibroblasts has a profound impact on the phenotype, resulting in the cytoskeleton and adhesive capacity disorganization (EF cells).	('expression', 'Var', (9, 19))	('FLI1', 'Gene', (4, 8))	('NIH-3T3', 'CellLine', 'CVCL:0594', (23, 30))	('cytoskeleton', 'MPA', (100, 112))	('T3 fibroblasts', 'CellLine', 'CVCL:0594', (28, 42))	('FLI1', 'Gene', '14247', (4, 8))	('impact', 'Reg', (58, 64))	('EWS', 'Gene', '14030', (0, 3))	('adhesive capacity disorganization', 'CPA', (117, 150))	('EWS', 'Gene', (0, 3))
381955	29900093	Fusion of EWS to FLI1 gene yields an oncoprotein EWS-FLI1.	('EWS', 'Gene', (49, 52))	('Fusion', 'Var', (0, 6))	('FLI1', 'Gene', '14247', (53, 57))	('FLI1', 'Gene', '14247', (17, 21))	('EWS', 'Gene', '14030', (10, 13))	('FLI1', 'Gene', (17, 21))	('EWS', 'Gene', '14030', (49, 52))	('FLI1', 'Gene', (53, 57))	('EWS', 'Gene', (10, 13))
381958	29900093	These NIH-3T3 fibroblasts were stably transformed by the transduction of EWS-FLI1 fusion gene, giving birth to the so-called EF cell line.	('transduction', 'Var', (57, 69))	('EWS', 'Gene', (73, 76))	('NIH-3T3', 'CellLine', 'CVCL:0594', (6, 13))	('FLI1', 'Gene', '14247', (77, 81))	('giving birth', 'Reg', (95, 107))	('T3 fibroblasts', 'CellLine', 'CVCL:0594', (11, 25))	('FLI1', 'Gene', (77, 81))	('EWS', 'Gene', '14030', (73, 76))
381959	29900093	EWS-FLI1 expression has a profound impact on cell phenotype as it is causing a loss of their cytoskeleton organization and adhesive capacity.	('loss', 'NegReg', (79, 83))	('adhesive capacity', 'CPA', (123, 140))	('FLI1', 'Gene', (4, 8))	('expression', 'Var', (9, 19))	('FLI1', 'Gene', '14247', (4, 8))	('EWS', 'Gene', '14030', (0, 3))	('impact', 'Reg', (35, 41))	('cytoskeleton organization', 'CPA', (93, 118))	('EWS', 'Gene', (0, 3))
381972	29900093	Both the biotin tag and the photoactivable probe will not be of interest for the present work but these modifications have required a biological validation to ensure that photo(R/W)9 behaved similarly to (R/W)9, in particular regarding the actin remodeling activity.	('actin remodeling activity', 'CPA', (240, 265))	('biotin', 'Chemical', 'MESH:D001710', (9, 15))	('photo(R/W)9', 'Var', (171, 182))
381992	29900093	3T3 and EF cells were cultured in Dulbecco s modified Eagle s medium supplemented with 10% newborn calf serum (Invitrogen), penicillin (100,000 IU/l), and streptomycin (100,000 IU/l) (PAA Laboratories) and selected with 25 mug/ml puromycin (Sigma).	('Dulbecco s modified Eagle s medium', 'Chemical', '-', (34, 68))	('calf', 'Species', '9913', (99, 103))	('penicillin', 'Chemical', 'MESH:D010406', (124, 134))	('PAA', 'Chemical', '-', (184, 187))	('100,000 IU/l', 'Var', (169, 181))	('puromycin', 'Chemical', 'MESH:D011691', (230, 239))	('streptomycin', 'Chemical', 'MESH:D013307', (155, 167))	('100,000 IU/l', 'Var', (136, 148))
382005	29900093	However it should be noted that this higher cytotoxicity can very likely be explained by a much higher internalization capacity, about six times more efficient for photo(R/W)9 compared to (R/W)9 ( 3 pmol versus  0.5 pmol, respectively at 5 muM extracellular concentration) (Fig.	('cytotoxicity', 'Disease', (44, 56))	('internalization capacity', 'MPA', (103, 127))	('photo(R/W)9', 'Var', (164, 175))	('cytotoxicity', 'Disease', 'MESH:D064420', (44, 56))	('higher', 'PosReg', (96, 102))	('more', 'PosReg', (145, 149))
382027	29900093	Expression level modifications of proteins involved in oxidation-reduction processes are a common feature for tumoral cells.	('modifications', 'Var', (17, 30))	('Expression level', 'MPA', (0, 16))	('tumor', 'Disease', (110, 115))	('proteins', 'Protein', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
382036	29900093	Consequently this comparison of tumoral EF with non-tumoral 3T3 cells indicates that the oncogenic transformation induced by the presence of the fusion protein EWS-FLI1 is leading to a significant decrease of several key actin binding proteins.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('EWS', 'Gene', '14030', (160, 163))	('oncogenic transformation', 'CPA', (89, 113))	('tumor', 'Disease', (52, 57))	('several key actin', 'MPA', (209, 226))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('EWS', 'Gene', (160, 163))	('presence', 'Var', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('FLI1', 'Gene', '14247', (164, 168))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('decrease', 'NegReg', (197, 205))	('FLI1', 'Gene', (164, 168))
382088	28060130	Cytogenetic evaluation identified an EWSR1 rearrangement and confirmed a diagnosis of ES.	('rearrangement', 'Var', (43, 56))	('EWSR1', 'Gene', (37, 42))	('EWSR1', 'Gene', '2130', (37, 42))	('ES', 'Phenotype', 'HP:0012254', (86, 88))
382097	28060130	An EWSR1-FLI1 fusion was identified on the original ES tumor biopsy, while the intracardiac tumor revealed two silent somatic mutations, an intronic mutation of MRE11A and a synonymous mutation of AMER1.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('intronic mutation', 'Var', (140, 157))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('EWSR1', 'Gene', '2130', (3, 8))	('FLI1', 'Gene', '2313', (9, 13))	('cardiac tumor', 'Phenotype', 'HP:0100544', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('AMER1', 'Gene', (197, 202))	('EWSR1', 'Gene', (3, 8))	('MRE11A', 'Gene', '4361', (161, 167))	('cardiac tumor', 'Disease', (84, 97))	('AMER1', 'Gene', '139285', (197, 202))	('ES', 'Phenotype', 'HP:0012254', (52, 54))	('cardiac tumor', 'Disease', 'MESH:D006338', (84, 97))	('FLI1', 'Gene', (9, 13))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (92, 97))	('MRE11A', 'Gene', (161, 167))
382098	28060130	After his first three cycles of chemotherapy, the patient was enrolled on an ongoing study evaluating the utility of identifying genomic EWSR1 fusions from plasma-derived DNA as a potential biomarker for subclinical disease.	('EWSR1', 'Gene', (137, 142))	('EWSR1', 'Gene', '2130', (137, 142))	('patient', 'Species', '9606', (50, 57))	('fusions', 'Var', (143, 150))
382102	28060130	Furthermore, an additional extensive interrogation of germline TP53 mutations was also negative.	('mutations', 'Var', (68, 77))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))
382103	28060130	Given the limited differential for a cardiac tumor, notably, no mutations or copy number alterations in the TSC1 or TSC2 genes were detected and the young man did not exhibit any stigmata of tuberous sclerosis.	('TSC2', 'Gene', (116, 120))	('TSC1', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('stigmata of tuberous sclerosis', 'Disease', 'MESH:D014402', (179, 209))	('cardiac tumor', 'Disease', 'MESH:D006338', (37, 50))	('stigmata of tuberous sclerosis', 'Disease', (179, 209))	('TSC1', 'Gene', '7248', (108, 112))	('cardiac tumor', 'Disease', (37, 50))	('TSC2', 'Gene', '7249', (116, 120))	('man', 'Species', '9606', (155, 158))	('cardiac tumor', 'Phenotype', 'HP:0100544', (37, 50))	('copy number alterations', 'Var', (77, 100))
382109	28060130	Ultimately, despite a negative targeted evaluation of germline variants with known associations with cancer, it is possible that an uninterrogated gene aberration is responsible for the development of multiple malignancies in this patient.	('responsible', 'Reg', (166, 177))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('multiple malignancies', 'Disease', 'MESH:D009369', (201, 222))	('multiple malignancies', 'Disease', (201, 222))	('cancer', 'Disease', (101, 107))	('variants', 'Var', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patient', 'Species', '9606', (231, 238))
382116	28060130	Our group has recently demonstrated that EWSR1 fusions can be detected via blood droplet digital PCR in 11/11 ES patients, 7 of which were able to be detected at relapse.	('EWSR1', 'Gene', (41, 46))	('patients', 'Species', '9606', (113, 121))	('ES', 'Phenotype', 'HP:0012254', (110, 112))	('fusions', 'Var', (47, 54))	('EWSR1', 'Gene', '2130', (41, 46))
382189	22439931	Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis.	('target gene expression', 'MPA', (92, 114))	('growth suppression', 'CPA', (127, 145))	('apoptosis', 'CPA', (150, 159))	('HDAC', 'Gene', (68, 72))	('HDAC', 'Gene', '9734', (68, 72))	('rescues', 'PosReg', (84, 91))	('Disruption', 'Var', (0, 10))
382190	22439931	Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (117, 133))	('synovial sarcoma', 'Disease', 'MESH:D013584', (117, 133))	('synovial sarcoma', 'Disease', (117, 133))	('transcriptional', 'MPA', (68, 83))	('ATF2', 'Gene', (63, 67))	('aberrant', 'Var', (54, 62))
382195	22439931	Almost all synovial sarcomas carry a demonstrable, pathognomonic t(X;18) reciprocal translocation fusing SS18 to an SSX gene.	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (11, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('SS18', 'Gene', (105, 109))	('SSX', 'Gene', '6757', (116, 119))	('SSX', 'Gene', (116, 119))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (11, 28))	('synovial sarcomas', 'Disease', 'MESH:D013584', (11, 28))	('synovial sarcomas', 'Disease', (11, 28))	('fusing', 'Var', (98, 104))
382219	22439931	Similar to SS18-SSX2 knockdown, both ATF2 and TLE1 silencing reduces synovial sarcoma cell growth (Figure 2A and Figure S2C) and impairs the ability of human and mouse tumor cells to form colonies (Figure 2B and Figure S2D).	('silencing', 'Var', (51, 60))	('synovial sarcoma', 'Disease', 'MESH:D013584', (69, 85))	('SSX2', 'Gene', '6757', (16, 20))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (69, 85))	('tumor', 'Disease', (168, 173))	('impairs', 'NegReg', (129, 136))	('TLE1', 'Gene', (46, 50))	('mouse', 'Species', '10090', (162, 167))	('SSX2', 'Gene', (16, 20))	('human', 'Species', '9606', (152, 157))	('ATF2', 'Gene', (37, 41))	('synovial sarcoma', 'Disease', (69, 85))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('reduces', 'NegReg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
382220	22439931	These knockdown cells appear to undergo apoptosis since depletion of either ATF2 or TLE1 induces an enrichment in the Annexin-V+ fraction (Figure 2C) and also stimulates Caspase-3 activation (Figure S2E).	('Annexin-V', 'Gene', (118, 127))	('induces', 'Reg', (89, 96))	('ATF2', 'Gene', (76, 80))	('Annexin-V', 'Gene', '308', (118, 127))	('Caspase-3', 'Gene', (170, 179))	('TLE1', 'Gene', (84, 88))	('enrichment', 'MPA', (100, 110))	('activation', 'MPA', (180, 190))	('Caspase-3', 'Gene', '836', (170, 179))	('stimulates', 'PosReg', (159, 169))	('depletion', 'Var', (56, 65))
382225	22439931	To further confirm binding specificity, HEK293 cell lines stably expressing Myc-tagged SS18, SS18-SSX2, or empty vector were generated (Figure S3A).	('SS18', 'Var', (87, 91))	('HEK293', 'CellLine', 'CVCL:0045', (40, 46))	('SSX2', 'Gene', '6757', (98, 102))	('rat', 'Species', '10116', (129, 132))	('SSX2', 'Gene', (98, 102))	('Myc', 'Gene', '4609', (76, 79))	('Myc', 'Gene', (76, 79))
382231	22439931	To address which domains of SS18-SSX are responsible for ATF2 and TLE1 binding, we next generated SS18-SSX2 deletion mutants (Figure 3E and Figure S3E) and performed reciprocal IP using the antibodies specific to Myc-tag, ATF2, and TLE1 in HEK293 cells.	('Myc', 'Gene', (213, 216))	('SSX', 'Gene', (33, 36))	('Myc', 'Gene', '4609', (213, 216))	('mutants', 'Var', (117, 124))	('SSX', 'Gene', '6757', (33, 36))	('rat', 'Species', '10116', (92, 95))	('SSX2', 'Gene', '6757', (103, 107))	('HEK293', 'CellLine', 'CVCL:0045', (240, 246))	('SSX', 'Gene', (103, 106))	('SSX', 'Gene', '6757', (103, 106))	('deletion mutants', 'Var', (108, 124))	('SSX2', 'Gene', (103, 107))
382238	22439931	Immunohistochemical and immunofluorescent analysis of ATF2 in patient synovial sarcoma specimens and SYO-1 cells, respectively, shows that ATF2 is predominantly located in the nucleus (Figures 4B and 4C).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (70, 86))	('SYO-1', 'Gene', '55027', (101, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('synovial sarcoma', 'Disease', 'MESH:D013584', (70, 86))	('SYO-1', 'Gene', (101, 106))	('ATF2', 'Gene', (54, 58))	('patient', 'Species', '9606', (62, 69))	('synovial sarcoma', 'Disease', (70, 86))	('ATF2', 'Var', (139, 143))
382249	22439931	ChIP analyses reveal that loss of ATF2 significantly compromises the association of SS18-SSX2 and TLE1 with target gene promoters (Figure 6A).	('compromises', 'NegReg', (53, 64))	('loss', 'Var', (26, 30))	('SSX2', 'Gene', '6757', (89, 93))	('association', 'Interaction', (69, 80))	('TLE1', 'Gene', (98, 102))	('SSX2', 'Gene', (89, 93))	('ATF2', 'Gene', (34, 38))
382253	22439931	To confirm the specificity of this effect, wild-type (wt) or dominant-negative (dn) ATF2 was transfected into HEK293 cells in the presence or absence of the fusion protein SS18-SSX2.	('dominant-negative', 'Var', (61, 78))	('SSX2', 'Gene', '6757', (177, 181))	('ATF2', 'Gene', (84, 88))	('SSX2', 'Gene', (177, 181))	('HEK293', 'CellLine', 'CVCL:0045', (110, 116))
382259	22439931	To assess whether TLE1 influences SS18-SSX transcriptional activity, TLE1 was knocked down in synovial sarcoma cells.	('TLE1', 'Gene', (69, 73))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (94, 110))	('SSX', 'Gene', '6757', (39, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('SSX', 'Gene', (39, 42))	('knocked', 'Var', (78, 85))	('synovial sarcoma', 'Disease', 'MESH:D013584', (94, 110))	('synovial sarcoma', 'Disease', (94, 110))
382261	22439931	The specificity of this effect was further confirmed by showing that TLE1 depletion only induces EGR1 and ATF3 transcription in HEK293 cells in the presence of Myc-SS18-SSX2 (Figures S6A and S6B).	('Myc', 'Gene', (160, 163))	('depletion', 'Var', (74, 83))	('induces', 'Reg', (89, 96))	('EGR1', 'Gene', (97, 101))	('SSX2', 'Gene', (169, 173))	('ATF3', 'Gene', '467', (106, 110))	('transcription', 'MPA', (111, 124))	('EGR1', 'Gene', '1958', (97, 101))	('ATF3', 'Gene', (106, 110))	('Myc', 'Gene', '4609', (160, 163))	('HEK293', 'CellLine', 'CVCL:0045', (128, 134))	('SSX2', 'Gene', '6757', (169, 173))
382264	22439931	TLE1 knockdown in SYO-1 cells results in a pronounced reduction in H3K27me3 levels at the same EGR1 and ATF3 promoter regions occupied by SS18-SSX, whereas the levels of trimethylated histone H3 at lysine 4 (H3K4me3), used as controls, are unchanged (Figure 7C).	('SYO-1', 'Gene', (18, 23))	('SYO-1', 'Gene', '55027', (18, 23))	('H3K27me3 levels', 'MPA', (67, 82))	('EGR1', 'Gene', '1958', (95, 99))	('knockdown', 'Var', (5, 14))	('reduction', 'NegReg', (54, 63))	('lysine', 'Chemical', 'MESH:D008239', (198, 204))	('SSX', 'Gene', (143, 146))	('SSX', 'Gene', '6757', (143, 146))	('ATF3', 'Gene', '467', (104, 108))	('EGR1', 'Gene', (95, 99))	('TLE1', 'Gene', (0, 4))	('ATF3', 'Gene', (104, 108))
382265	22439931	Given that H3K27me3 is a hallmark of PcG-dependent gene silencing, we asked whether TLE1 serves to link the PcG complex to SS18-SSX, thereby promoting repression of target genes.	('SSX', 'Gene', '6757', (128, 131))	('repression', 'MPA', (151, 161))	('promoting', 'PosReg', (141, 150))	('H3K27me3', 'Var', (11, 19))	('SSX', 'Gene', (128, 131))	('silencing', 'NegReg', (56, 65))
382275	22439931	Indeed, it has been shown that repression of HDAC activity by small-molecule inhibitors can effectively suppress synovial sarcoma by reversing SS18-SSX-mediated epigenetic silencing.	('reversing', 'NegReg', (133, 142))	('synovial sarcoma', 'Disease', (113, 129))	('suppress', 'NegReg', (104, 112))	('SSX', 'Gene', (148, 151))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (113, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('synovial sarcoma', 'Disease', 'MESH:D013584', (113, 129))	('epigenetic', 'Var', (161, 171))	('HDAC', 'Gene', '9734', (45, 49))	('HDAC', 'Gene', (45, 49))	('repression', 'NegReg', (31, 41))	('SSX', 'Gene', '6757', (148, 151))
382276	22439931	To further examine the importance of HDAC proteins in regulating SS18-SSX activity, HDAC1 (identified as a core SS18-SSX complex subunit, Figure S1C) was knocked down.	('SSX', 'Gene', (70, 73))	('knocked down', 'Var', (154, 166))	('HDAC', 'Gene', (84, 88))	('HDAC', 'Gene', (37, 41))	('HDAC', 'Gene', '9734', (84, 88))	('HDAC', 'Gene', '9734', (37, 41))	('SSX', 'Gene', (117, 120))	('SSX', 'Gene', '6757', (117, 120))	('SSX', 'Gene', '6757', (70, 73))
382277	22439931	Similar to the published effects of HDAC inhibitors, depletion of HDAC1 from SYO-1 cells results in EGR1 reactivation (Figure S7A), and is also associated with decreased cell growth and increased cell death (Figures S7B and S7C).	('EGR1', 'Gene', (100, 104))	('depletion', 'Var', (53, 62))	('HDAC', 'Gene', (66, 70))	('cell growth', 'CPA', (170, 181))	('reactivation', 'MPA', (105, 117))	('HDAC', 'Gene', '9734', (66, 70))	('EGR1', 'Gene', '1958', (100, 104))	('increased', 'PosReg', (186, 195))	('HDAC', 'Gene', (36, 40))	('cell death', 'CPA', (196, 206))	('HDAC', 'Gene', '9734', (36, 40))	('SYO-1', 'Gene', '55027', (77, 82))	('decreased', 'NegReg', (160, 169))	('SYO-1', 'Gene', (77, 82))
382288	22439931	Taken together, these findings suggest that HDAC inhibitors derepress SS18-SSX target genes, at least in part through disrupting the recruitment of TLE1 and its associated HDAC/PcG proteins to the SS18-SSX complex, thus leading to loss of the repressive H3K27me3 mark and restored gene expression.	('disrupting', 'NegReg', (118, 128))	('SSX', 'Gene', '6757', (75, 78))	('HDAC', 'Gene', (172, 176))	('SSX', 'Gene', (75, 78))	('gene expression', 'MPA', (281, 296))	('HDAC', 'Gene', '9734', (172, 176))	('repressive', 'MPA', (243, 253))	('loss', 'NegReg', (231, 235))	('restored', 'PosReg', (272, 280))	('HDAC', 'Gene', (44, 48))	('recruitment', 'MPA', (133, 144))	('SSX', 'Gene', '6757', (202, 205))	('H3K27me3 mark', 'Protein', (254, 267))	('HDAC', 'Gene', '9734', (44, 48))	('SSX', 'Gene', (202, 205))	('derepress', 'Var', (60, 69))
382292	22439931	In this study, we identify a core SS18-SSX transcriptional complex that is required for epigenetic silencing of tumor suppressor genes in synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (138, 154))	('synovial sarcoma', 'Disease', 'MESH:D013584', (138, 154))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('SSX', 'Gene', '6757', (39, 42))	('SSX', 'Gene', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('synovial sarcoma', 'Disease', (138, 154))	('tumor', 'Disease', (112, 117))	('epigenetic silencing', 'Var', (88, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
382299	22439931	Putative ATF2 inactivating mutations in lung cancer have been identified, and in melanoma increased ATF2 cytoplasmic localization is associated with reduced tumorgenic potential and a better prognosis.	('inactivating mutations', 'Var', (14, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('increased', 'PosReg', (90, 99))	('lung cancer', 'Disease', (40, 51))	('ATF2', 'Gene', (9, 13))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('cytoplasmic localization', 'MPA', (105, 129))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('reduced tumorgenic', 'Disease', (149, 167))	('reduced tumorgenic', 'Disease', 'MESH:D015354', (149, 167))	('ATF2', 'Gene', (100, 104))
382302	22439931	In a skin cancer model in mice, deletion of Atf2 was sufficient to increase the appearance of precancerous lesions.	('precancerous lesions', 'Disease', (94, 114))	('deletion', 'Var', (32, 40))	('skin cancer', 'Disease', (5, 16))	('skin cancer', 'Disease', 'MESH:D012878', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('increase', 'PosReg', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Atf2', 'Gene', (44, 48))	('Atf2', 'Gene', '11909', (44, 48))	('precancerous lesions', 'Disease', 'MESH:D011230', (94, 114))	('skin cancer', 'Phenotype', 'HP:0008069', (5, 16))	('mice', 'Species', '10090', (26, 30))
382303	22439931	However, in this model loss of ATF2 appears to promote tumorgenesis and is unlikely involved in initation.	('ATF2', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumorgenesis', 'Disease', (55, 67))	('promote', 'PosReg', (47, 54))	('tumorgenesis', 'Disease', 'None', (55, 67))	('loss', 'Var', (23, 27))
382309	22439931	In this regard, TLE1 appears to function in a dominant-negative manner on ATF2-mediated transactivation, by mediating HDAC/PcG-directed gene silencing of ATF2 targets.	('ATF2-mediated', 'Gene', (74, 87))	('gene', 'Var', (136, 140))	('HDAC', 'Gene', (118, 122))	('transactivation', 'MPA', (88, 103))	('TLE1', 'Gene', (16, 20))	('HDAC', 'Gene', '9734', (118, 122))
382315	22439931	In support of this concept, TLE1 depletion similarly results in diminished H3K27me3 signals and elevated transcript levels for ATF2/SS18-SSX target genes.	('TLE1', 'Gene', (28, 32))	('depletion', 'Var', (33, 42))	('H3K27me3', 'Protein', (75, 83))	('diminished', 'NegReg', (64, 74))	('transcript levels', 'MPA', (105, 122))	('SSX', 'Gene', (137, 140))	('SSX', 'Gene', '6757', (137, 140))	('elevated', 'PosReg', (96, 104))
382318	22439931	This information provides a biological rationale for including synovial sarcoma in clinical trials of HDAC inhibitors (NCT01112384, NCT00918489, NCT00878800) and a framework for identifying therapeutic strategies to treat this deadly disease.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (63, 79))	('synovial sarcoma', 'Disease', 'MESH:D013584', (63, 79))	('NCT01112384', 'Var', (119, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('NCT00878800', 'Var', (145, 156))	('rat', 'Species', '10116', (204, 207))	('rat', 'Species', '10116', (39, 42))	('synovial sarcoma', 'Disease', (63, 79))	('HDAC', 'Gene', (102, 106))	('HDAC', 'Gene', '9734', (102, 106))	('NCT00918489', 'Var', (132, 143))
382325	22439931	To define the domains within SS18-SSX2 that interact with ATF2 and TLE1, variants missing the SNH or QPGY domain of SS18 and the SSXRD domain of SSX2 were generated via gene synthesis (Integrated DNA Technologies) and sub-cloned as EcoR1 - Not1 fragments into the mammalian expression vector pcDNA4/myc-HisA (Life Technologies).	('myc', 'Gene', (299, 302))	('SSX', 'Gene', '6757', (145, 148))	('variants', 'Var', (73, 81))	('rat', 'Species', '10116', (190, 193))	('SSX', 'Gene', '6757', (129, 132))	('SSX', 'Gene', '6757', (34, 37))	('SSX', 'Gene', (145, 148))	('Not1', 'Gene', (240, 244))	('SSX', 'Gene', (129, 132))	('SSX', 'Gene', (34, 37))	('SSX2', 'Gene', (34, 38))	('mammalian', 'Species', '9606', (264, 273))	('SSX2', 'Gene', (145, 149))	('Not1', 'Gene', '23019', (240, 244))	('SSX2', 'Gene', '6757', (34, 38))	('SS18', 'Gene', (116, 120))	('myc', 'Gene', '4609', (299, 302))	('SSX2', 'Gene', '6757', (145, 149))	('rat', 'Species', '10116', (159, 162))
382359	22439931	The wild-type and mutant ATF/CRE competitor probes were obtained from Santa Cruz Biotechnology.	('ATF', 'Gene', (25, 28))	('mutant', 'Var', (18, 24))	('ATF', 'Gene', '2668', (25, 28))
382362	22439931	SYO-1 cells were subcultured in 24-well plates, and transfected with the wild-type or mutant human ATF3 promoter-firefly luciferase reporter plasmid together with renilla luciferase expression vector.	('ATF3', 'Gene', '467', (99, 103))	('mutant', 'Var', (86, 92))	('human', 'Species', '9606', (93, 98))	('SYO-1', 'Gene', '55027', (0, 5))	('ATF3', 'Gene', (99, 103))	('SYO-1', 'Gene', (0, 5))
382381	23027341	A critical factor in each of these processes is the intracellular concentration of beta-catenin, a multi-functional protein that acts in the Wnt signalling pathway to modulate transcription of specific target genes; beta-catenin is at the centre of the Wnt pathway and is the key arm of Wnt signalling.	('beta-catenin', 'Var', (216, 228))	('Wnt', 'Chemical', '-', (253, 256))	('Wnt', 'Chemical', '-', (287, 290))	('modulate', 'Reg', (167, 175))	('Wnt', 'Chemical', '-', (141, 144))
382389	23027341	Deregulation and constitutive activation of the Wnt/beta-catenin pathway have been seen to lead to various forms of cancer.	('lead to', 'Reg', (91, 98))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('activation', 'PosReg', (30, 40))	('Wnt', 'Chemical', '-', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Wnt/beta-catenin pathway', 'Pathway', (48, 72))
382390	23027341	It has been noted that if any of the four proteins in the degradation complex (GSK3-beta, axin, APC, and beta-TrCP/Slimb) is mutated, uncontrolled intracellular concentrations of beta-catenin almost always lead to cancer.	('GSK3-beta', 'Gene', (79, 88))	('cancer', 'Disease', (214, 220))	('beta-TrCP', 'Gene', '8945', (105, 114))	('mutated', 'Var', (125, 132))	('APC', 'Gene', (96, 99))	('axin', 'Gene', '8312', (90, 94))	('APC', 'Phenotype', 'HP:0005227', (96, 99))	('axin', 'Gene', (90, 94))	('lead to', 'Reg', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('APC', 'Gene', '324', (96, 99))	('GSK3-beta', 'Gene', '2932', (79, 88))	('beta-TrCP', 'Gene', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
382391	23027341	Previous works have shown that CTNNB1, the beta-catenin gene, APC and axin are frequently mutated in different types of human epithelial cancers as well as in colorectal, gastric, liver and pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CTNNB1', 'Gene', '1499', (31, 37))	('human', 'Species', '9606', (120, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (190, 207))	('colorectal', 'Disease', (159, 169))	('gastric', 'Disease', (171, 178))	('mutated', 'Var', (90, 97))	('epithelial cancers', 'Disease', 'MESH:D000077216', (126, 144))	('axin', 'Gene', '8312', (70, 74))	('APC', 'Gene', (62, 65))	('liver and pancreatic cancer', 'Disease', 'MESH:D010190', (180, 207))	('APC', 'Phenotype', 'HP:0005227', (62, 65))	('APC', 'Gene', '324', (62, 65))	('axin', 'Gene', (70, 74))	('CTNNB1', 'Gene', (31, 37))	('epithelial cancers', 'Disease', (126, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))
382409	23027341	Colon adenocarcinoma carrying a beta-catenin mutation was used as the positive control.	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (0, 20))	('Colon adenocarcinoma', 'Disease', (0, 20))	('mutation', 'Var', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
382426	23027341	Wnt signalling via beta-catenin has been seen to play a role in early proliferation and differentiation of human connective tissue progenitor cells, and beta-catenin deregulation has been implicated in the inherited predisposition to fibromatosis and in the pathogenesis of sporadic desmoid-type fibromatosis.	('desmoid-type fibromatosis', 'Disease', (283, 308))	('beta-catenin', 'Protein', (153, 165))	('human', 'Species', '9606', (107, 112))	('fibromatosis', 'Disease', (234, 246))	('fibromatosis', 'Disease', (296, 308))	('deregulation', 'Var', (166, 178))	('Wnt', 'Chemical', '-', (0, 3))	('implicated', 'Reg', (188, 198))	('desmoid-type fibromatosis', 'Disease', 'MESH:C535944', (283, 308))	('fibromatosis', 'Disease', 'MESH:D005350', (234, 246))	('fibromatosis', 'Disease', 'MESH:D005350', (296, 308))
382427	23027341	Nuclear immunoreactivity for beta-catenin is a useful adjunct to the diagnosis of adult desmoid-type fibromatosis, many types of which exhibit mutations in the APC/beta-catenin (Wnt) pathway.	('APC', 'Gene', '324', (160, 163))	('Wnt', 'Chemical', '-', (178, 181))	('desmoid-type fibromatosis', 'Disease', (88, 113))	('APC', 'Phenotype', 'HP:0005227', (160, 163))	('APC', 'Gene', (160, 163))	('desmoid-type fibromatosis', 'Disease', 'MESH:C535944', (88, 113))	('mutations', 'Var', (143, 152))
382429	23027341	Sequencing of CTNNB1 exon 3 disclosed the presence of one of three specific mutation types of CTNNB1 (41A, 45F, and 45P) in 85% of desmoid tumour cases.	('45P', 'Var', (116, 119))	('CTNNB1', 'Gene', '1499', (94, 100))	('desmoid tumour', 'Phenotype', 'HP:0100245', (131, 145))	('CTNNB1', 'Gene', '1499', (14, 20))	('41A', 'Var', (102, 105))	('presence', 'Reg', (42, 50))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('CTNNB1', 'Gene', (14, 20))	('desmoid tumour', 'Disease', 'MESH:C535944', (131, 145))	('desmoid tumour', 'Disease', (131, 145))	('CTNNB1', 'Gene', (94, 100))
382450	23027341	Finally, our findings suggest that the differential diagnosis of infantile fibromatosis from low-grade fibrosarcoma can be achieved according to the flow-chart reported in Figure 2: nuclear beta-catenin positivity in >25% of tumour cells is suggestive of fibromatosis, and strong nuclear staining in >50% of cells is highly suggestive of fibromatosis; CTNNB1 mutation analysis is mandatory when nuclear staining is between 10% and 50%; finally, nuclear staining in <=10% of cells favours a diagnosis of low-grade fibrosarcoma.	('infantile fibromatosis', 'Disease', 'MESH:D005350', (65, 87))	('CTNNB1', 'Gene', '1499', (352, 358))	('infantile fibromatosis', 'Phenotype', 'HP:0025197', (65, 87))	('fibromatosis', 'Disease', (75, 87))	('fibromatosis', 'Disease', 'MESH:D005350', (338, 350))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (103, 115))	('nuclear', 'Var', (445, 452))	('fibromatosis', 'Disease', (255, 267))	('infantile fibromatosis', 'Disease', (65, 87))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (513, 525))	('CTNNB1', 'Gene', (352, 358))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('fibrosarcoma', 'Disease', 'MESH:D005354', (103, 115))	('tumour', 'Disease', (225, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('fibromatosis', 'Disease', 'MESH:D005350', (75, 87))	('fibrosarcoma', 'Disease', (103, 115))	('fibromatosis', 'Disease', 'MESH:D005350', (255, 267))	('fibrosarcoma', 'Disease', 'MESH:D005354', (513, 525))	('fibromatosis', 'Disease', (338, 350))	('fibrosarcoma', 'Disease', (513, 525))	('sarcoma', 'Phenotype', 'HP:0100242', (518, 525))
382557	30786888	Pre-operative diagnosis was made with a percutaneous biopsy including molecular analysis which demonstrated MDM2 amplification.	('MDM2', 'Gene', (108, 112))	('amplification', 'Var', (113, 126))	('MDM2', 'Gene', '4193', (108, 112))
382558	30786888	We describe a simultaneous anterior and posterior approach, including the ligation of the posterior trunk of the internal iliac artery, to reduce intra-operative blood loss and devascularise the tumour.	('devascularise', 'NegReg', (177, 190))	('intra-operative blood loss', 'Disease', 'MESH:D006473', (146, 172))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('ligation', 'Var', (74, 82))	('tumour', 'Disease', (195, 201))	('reduce', 'NegReg', (139, 145))	('intra-operative blood loss', 'Disease', (146, 172))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
382568	30786888	However, deviations from guidelines and inadequate management of these patients remain common and thus considerably impact on patients' survival.	('patients', 'Species', '9606', (71, 79))	('deviations', 'Var', (9, 19))	('impact', 'Reg', (116, 122))	('patients', 'Species', '9606', (126, 134))
382585	30786888	Samples were analysed by a pathologist from the Reseau de Reference en Pathologie des Sarcomes des tissus mous et des visceres group, and revealed a well-differentiated liposarcoma with amplification of MDM2 on the fluorescent in situ hybridisation (FISH).	('amplification', 'Var', (186, 199))	('liposarcoma', 'Phenotype', 'HP:0012034', (169, 180))	('liposarcoma', 'Disease', 'MESH:D008080', (169, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('MDM2', 'Gene', '4193', (203, 207))	('MDM2', 'Gene', (203, 207))	('liposarcoma', 'Disease', (169, 180))
382607	30786888	The ligation of the internal iliac artery exposes the patient to a rectal ischemia or buttock claudication.	('patient', 'Species', '9606', (54, 61))	('ischemia', 'Disease', (74, 82))	('buttock claudication', 'Disease', 'MESH:D007383', (86, 106))	('ischemia', 'Disease', 'MESH:D007511', (74, 82))	('ligation', 'Var', (4, 12))	('buttock claudication', 'Disease', (86, 106))	('rectal', 'Disease', (67, 73))
382618	30786888	However, in the case of malignant tumours, such as in our case, debulking the retroperitoneal portion of the tumour risks tumour contamination and therefore we advocate an expansion osteotomy if needed to deliver the tumour.	('tumour risks tumour', 'Disease', (109, 128))	('deliver the tumour', 'Disease', 'MESH:D009369', (205, 223))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('debulking', 'Var', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('deliver the tumour', 'Disease', (205, 223))	('malignant tumours', 'Disease', 'MESH:D009369', (24, 41))	('malignant tumours', 'Disease', (24, 41))	('tumour risks tumour', 'Disease', 'MESH:D009369', (109, 128))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
382661	29269639	Furthermore, fluorescence in situ hybridization (FISH) studies demonstrated rearrangement of the Ewing's sarcoma breakpoint region 1 (EWSR1) gene on chromosome 22 (Fig.	('EWSR1', 'Gene', '2130', (134, 139))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (97, 112))	("Ewing's sarcoma", 'Disease', (97, 112))	('rearrangement', 'Var', (76, 89))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (97, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('EWSR1', 'Gene', (134, 139))
382685	29269639	In general, MRI studies of Ewing's sarcoma show isointensity to hyperintensity on T1-weighted images and hyperintensity on T2-weighted images.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (27, 42))	("Ewing's sarcoma", 'Disease', (27, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('T1-weighted images', 'MPA', (82, 100))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (27, 42))	('hyperintensity', 'Var', (105, 119))	('hyperintensity', 'MPA', (64, 78))
383004	27525088	2B), CD1a, CD3, and CD79a and negative for EMA, CK, CD23, CD34, HMB-45, CD30, MPO, and lysozyme.	('CD34', 'Gene', (58, 62))	('CD23', 'Gene', '2208', (52, 56))	('CD30', 'Gene', (72, 76))	('CD1a', 'Gene', (5, 9))	('MPO', 'Gene', '4353', (78, 81))	('CD30', 'Gene', '943', (72, 76))	('CD23', 'Gene', (52, 56))	('CD79a', 'Gene', '973', (20, 25))	('CD79a', 'Gene', (20, 25))	('CD34', 'Gene', '947', (58, 62))	('CD1a', 'Gene', '909', (5, 9))	('MPO', 'Gene', (78, 81))	('CD3', 'Var', (11, 14))
383064	26425616	Allopurinol decreases the new uric acid concentration, which further reduces the obstructive uropathy in patients who are at high risk for TLS.	('patients', 'Species', '9606', (105, 113))	('Allopurinol', 'Var', (0, 11))	('obstructive uropathy', 'Disease', (81, 101))	('uric acid', 'Chemical', 'MESH:D014527', (30, 39))	('obstructive uropathy', 'Disease', 'MESH:C536483', (81, 101))	('reduces', 'NegReg', (69, 76))	('decreases', 'NegReg', (12, 21))	('Allopurinol', 'Chemical', 'MESH:D000493', (0, 11))
383065	26425616	Allopurinol increases the serum xanthine and hypoxanthine levels in the serum, which could lead to acute renal failure by forming xanthine crystals in the renal tubules.	('lead to', 'Reg', (91, 98))	('xanthine', 'Chemical', 'MESH:D019820', (49, 57))	('acute renal failure', 'Disease', 'MESH:D058186', (99, 118))	('forming', 'Reg', (122, 129))	('Allopurinol', 'Var', (0, 11))	('xanthine crystals', 'Phenotype', 'HP:0000804', (130, 147))	('hypoxanthine', 'Chemical', 'MESH:D019271', (45, 57))	('xanthine', 'Chemical', 'MESH:D019820', (32, 40))	('acute renal failure', 'Phenotype', 'HP:0001919', (99, 118))	('renal failure', 'Phenotype', 'HP:0000083', (105, 118))	('increases', 'PosReg', (12, 21))	('acute renal failure', 'Disease', (99, 118))	('xanthine', 'Chemical', 'MESH:D019820', (130, 138))	('Allopurinol', 'Chemical', 'MESH:D000493', (0, 11))
383077	24946937	This sarcoma is defined by t(12;22)(q13;q12) translocation, which leads to the fusion of Ewing sarcoma gene (EWS) to activating transcription factor 1 (ATF1) gene, producing a chimeric EWS-ATF1 fusion gene.	('EWS', 'Gene', '2130', (109, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('chimeric', 'MPA', (176, 184))	('ATF1', 'Gene', '466', (152, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('EWS', 'Gene', (185, 188))	('ATF1', 'Gene', (189, 193))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('sarcoma', 'Disease', (5, 12))	('activating transcription factor 1', 'Gene', (117, 150))	('ATF1', 'Gene', '466', (189, 193))	('EWS', 'Gene', (109, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (27, 44))	('Ewing sarcoma gene', 'Gene', '2130', (89, 107))	('EWS', 'Gene', '2130', (185, 188))	('Ewing sarcoma gene', 'Gene', (89, 107))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('ATF1', 'Gene', (152, 156))	('fusion', 'Var', (79, 85))	('activating transcription factor 1', 'Gene', '466', (117, 150))	('sarcoma', 'Disease', (95, 102))
383087	24946937	Cytogenetic analysis of CCS has detected the presence of clonal chromosomal translocation, t(12;22)(q13;q12), and identified the fusion of the ATF1 and EWS, resulting in the EWS-ATF1 fusion gene.	('ATF1', 'Gene', '466', (143, 147))	('fusion', 'Var', (129, 135))	('ATF1', 'Gene', (178, 182))	('EWS', 'Gene', '2130', (152, 155))	('EWS', 'Gene', (152, 155))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (91, 108))	('ATF1', 'Gene', '466', (178, 182))	('EWS', 'Gene', '2130', (174, 177))	('EWS', 'Gene', (174, 177))	('ATF1', 'Gene', (143, 147))
383125	24946937	The primary antibodies used were anti-Ki67 (M7240; Dako, Glostrup, Denmark), anti-S100 (IR50461; Dako), anti-HMB45 (N1545; Dako), and anti-Melan-A (IR633; Dako).	('Melan-A', 'Gene', (139, 146))	('N1545;', 'Var', (116, 122))	('Melan-A', 'Gene', '2315', (139, 146))	('anti-HMB45 (N1545', 'Var', (104, 121))	('IR50461', 'Var', (88, 95))	('M7240', 'Var', (44, 49))
383148	24946937	Interestingly, pazopanib inhibited autophosphorylation of c-MET in a dose-dependent manner, whereas total c-MET remained constant (Figure 4B).	('pazopanib', 'Var', (15, 24))	('c-MET', 'Gene', '4233', (106, 111))	('c-MET', 'Gene', '4233', (58, 63))	('c-MET', 'Gene', (106, 111))	('inhibited', 'NegReg', (25, 34))	('autophosphorylation', 'MPA', (35, 54))	('pazopanib', 'Chemical', 'MESH:C516667', (15, 24))	('c-MET', 'Gene', (58, 63))
383151	24946937	In addition, silencing of c-MET expression by siRNA significantly suppressed the growth of Hewga-CCS cells (Figure 4D, E).	('c-MET', 'Gene', '4233', (26, 31))	('suppressed', 'NegReg', (66, 76))	('c-MET', 'Gene', (26, 31))	('growth', 'CPA', (81, 87))	('silencing', 'Var', (13, 22))
383153	24946937	We found that pazopanib inhibited Asra-Eps cell growth in vitro and autophosphorylation of c-MET in a dose-dependent manner (data not shown).	('c-MET', 'Gene', '4233', (91, 96))	('autophosphorylation', 'MPA', (68, 87))	('pazopanib', 'Chemical', 'MESH:C516667', (14, 23))	('inhibited', 'NegReg', (24, 33))	('c-MET', 'Gene', (91, 96))	('Asra-Eps cell growth', 'CPA', (34, 54))	('pazopanib', 'Var', (14, 23))	('Asra-Eps', 'Chemical', '-', (34, 42))
383162	24946937	Consistent with the in vitro data, TUNEL assays on tumor sections from treated and control mice showed no significant differences, but Ki-67 staining was significantly decreased in the pazopanib-treated group (Figures 6B-D).	('Ki-67', 'Gene', '17345', (135, 140))	('mice', 'Species', '10090', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('decreased', 'NegReg', (168, 177))	('pazopanib', 'Chemical', 'MESH:C516667', (185, 194))	('tumor', 'Disease', (51, 56))	('Ki-67', 'Gene', (135, 140))	('pazopanib-treated', 'Var', (185, 202))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
383163	24946937	We also investigated c-MET activation in Hewga-CCS tumor tissues and found that pazopanib inhibited c-MET phosphorylation in Hewga-CCS xenografts (Figure 6E, Additional file 7: Figure S5).	('Hewga-CCS', 'Disease', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('c-MET', 'Gene', '4233', (21, 26))	('c-MET', 'Gene', '4233', (100, 105))	('pazopanib', 'Chemical', 'MESH:C516667', (80, 89))	('pazopanib', 'Var', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('inhibited', 'NegReg', (90, 99))	('c-MET', 'Gene', (21, 26))	('c-MET', 'Gene', (100, 105))
383178	24946937	However, there have only been a few reports that have demonstrated the molecular mechanism by which pazopanib inhibits the growth of a variety of tumors.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('inhibits', 'NegReg', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('pazopanib', 'Chemical', 'MESH:C516667', (100, 109))	('tumors', 'Disease', (146, 152))	('pazopanib', 'Var', (100, 109))
383179	24946937	Kumar used a cell-free assay system to show kinase activity of pazopanib and found that pazopanib had an IC50 value of 6 mumol/L for inhibiting c-MET activity.	('mum', 'Gene', (121, 124))	('inhibiting', 'NegReg', (133, 143))	('c-MET', 'Gene', '4233', (144, 149))	('pazopanib', 'Var', (88, 97))	('pazopanib', 'Chemical', 'MESH:C516667', (88, 97))	('pazopanib', 'Chemical', 'MESH:C516667', (63, 72))	('c-MET', 'Gene', (144, 149))	('mum', 'Gene', '56925', (121, 124))
383181	24946937	Podar demonstrated that pazopanib inhibited multiple myeloma cell growth in vitro by inhibiting VEGF signaling at IC50 values of 10-30 mumol/L.	('mum', 'Gene', '56925', (135, 138))	('myeloma', 'Disease', (53, 60))	('myeloma', 'Disease', 'MESH:D009101', (53, 60))	('inhibiting', 'NegReg', (85, 95))	('pazopanib', 'Chemical', 'MESH:C516667', (24, 33))	('mum', 'Gene', (135, 138))	('inhibited', 'NegReg', (34, 43))	('VEGF', 'Gene', '7422', (96, 100))	('multiple myeloma', 'Phenotype', 'HP:0006775', (44, 60))	('pazopanib', 'Var', (24, 33))	('VEGF', 'Gene', (96, 100))
383182	24946937	Paesler demonstrated that pazopanib abrogated the survival of chronic lymphocytic leukemia cells at an IC50 of 32.7 mumol/L through VEGF pathway suppression.	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (62, 90))	('pazopanib', 'Chemical', 'MESH:C516667', (26, 35))	('VEGF', 'Gene', (132, 136))	('suppression', 'NegReg', (145, 156))	('lymphocytic leukemia', 'Disease', (70, 90))	('pazopanib', 'Var', (26, 35))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (70, 90))	('mum', 'Gene', '56925', (116, 119))	('VEGF', 'Gene', '7422', (132, 136))	('abrogated', 'NegReg', (36, 45))	('mum', 'Gene', (116, 119))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))
383198	30281149	All tumours lacked hotspot mutations in IDH1/2 132 or 172 codons, thereby excluding the diagnosis of dedifferentiated chondrosarcoma.	('mutations', 'Var', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('IDH1/2', 'Gene', (40, 46))	('chondrosarcoma', 'Disease', 'MESH:D002813', (118, 132))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('chondrosarcoma', 'Disease', (118, 132))	('hotspot', 'MPA', (19, 26))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (118, 132))	('IDH1/2', 'Gene', '3417;3418', (40, 46))	('tumours', 'Disease', (4, 11))
383200	30281149	Moreover, recurrent mutations in histone chromatin remodelling genes, including H3F3A, ATRX and DOT1L, were identified in 5/14 samples (36%), highlighting the potential role of deregulated chromatin remodelling pathways in UPSb tumourigenesis.	('DOT1L', 'Gene', '84444', (96, 101))	('UPSb tumour', 'Disease', 'MESH:D009369', (223, 234))	('identified', 'Reg', (108, 118))	('UPSb tumour', 'Disease', (223, 234))	('ATRX', 'Gene', (87, 91))	('H3F3A', 'Gene', '3020', (80, 85))	('DOT1L', 'Gene', (96, 101))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('H3F3A', 'Gene', (80, 85))	('ATRX', 'Gene', '546', (87, 91))	('mutations', 'Var', (20, 29))
383201	30281149	The majority of recurrent mutations in chromatin remodelling genes identified here are reported in COSMIC, including the H3F3A G35 and K36 hotspot residues.	('K36', 'Gene', (135, 138))	('H3F3A', 'Gene', '3020', (121, 126))	('mutations', 'Var', (26, 35))	('H3F3A', 'Gene', (121, 126))	('K36', 'Gene', '8689', (135, 138))
383206	30281149	To our knowledge, this study represents the first comprehensive WES and RNA-Seq analysis of UPSb tumours revealing novel protein-coding recurrent gene mutations, gene fusions and identifying a potential UPSb molecular biomarker, thereby broadening the understanding of the pathogenic mechanisms and highlighting the possibility of developing novel targeted therapeutics.	('UPSb tumours', 'Disease', (92, 104))	('UPSb tumours', 'Disease', 'MESH:D009369', (92, 104))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('mutations', 'Var', (151, 160))
383213	30281149	Previous studies have reported low frequency of TP53 mutations, MDM2 amplification, and various genomic gains and losses, including CDKN2A, RB1 and TP53.	('CDKN2A', 'Gene', (132, 138))	('TP53', 'Gene', '7157', (48, 52))	('genomic gains', 'CPA', (96, 109))	('MDM2', 'Gene', '4193', (64, 68))	('CDKN2A', 'Gene', '1029', (132, 138))	('losses', 'NegReg', (114, 120))	('MDM2', 'Gene', (64, 68))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('TP53', 'Gene', (48, 52))	('RB1', 'Gene', '5925', (140, 143))	('mutations', 'Var', (53, 62))	('RB1', 'Gene', (140, 143))
383232	30281149	All four TP53 somatic missense substitutions (R158H, V216M, Y236C C242G) are described 'somatic' in COSMIC database and predicted deleterious by two independent in silico tools (supplementary material, Table S2).	('R158H', 'Mutation', 'rs587782144', (46, 51))	('C242G', 'SUBSTITUTION', 'None', (66, 71))	('Y236C', 'Var', (60, 65))	('Y236C', 'SUBSTITUTION', 'None', (60, 65))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('C242G', 'Var', (66, 71))	('V216M', 'Var', (53, 58))	('V216M', 'Mutation', 'rs730882025', (53, 58))	('R158H', 'Var', (46, 51))
383233	30281149	The V216M missense substitution has been reported previously in a UPSb tumour with a progressive disease behaviour.	('V216M', 'Mutation', 'rs730882025', (4, 9))	('UPSb tumour', 'Disease', 'MESH:D009369', (66, 77))	('V216M missense', 'Var', (4, 18))	('UPSb tumour', 'Disease', (66, 77))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))
383234	30281149	In addition to mutations in TP53 gene, which participates in the integrity of histone remodelling complexes, recurrent somatic mutations in histone remodelling genes including H3F3A, ATRX and DOT1L were detected in 5/14 (36%) samples, suggesting a potential role of defective chromatin remodelling genes in UPSb tumourigenesis (Figure 2 B-D, supplementary material, Table S2).	('TP53', 'Gene', '7157', (28, 32))	('tumour', 'Phenotype', 'HP:0002664', (312, 318))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (15, 24))	('DOT1L', 'Gene', '84444', (192, 197))	('H3F3A', 'Gene', '3020', (176, 181))	('DOT1L', 'Gene', (192, 197))	('ATRX', 'Gene', (183, 187))	('UPSb tumour', 'Disease', 'MESH:D009369', (307, 318))	('H3F3A', 'Gene', (176, 181))	('ATRX', 'Gene', '546', (183, 187))	('mutations', 'Var', (127, 136))	('UPSb tumour', 'Disease', (307, 318))
383235	30281149	Somatic G34V missense substitution and V35_K36insL in-frame insertion in the previously known H3F3A hotspot residues were identified in two UPSb tumours.	('K36insL', 'Mutation', 'c.36insK,L', (43, 50))	('V35_K36insL', 'Var', (39, 50))	('G34V missense substitution', 'Var', (8, 34))	('UPSb tumours', 'Disease', 'MESH:D009369', (140, 152))	('H3F3A', 'Gene', '3020', (94, 99))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('UPSb tumours', 'Disease', (140, 152))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('G34V', 'Mutation', 'p.G34V', (8, 12))	('H3F3A', 'Gene', (94, 99))
383236	30281149	Mutations in ATRX and DOT1L were missense substitutions.	('DOT1L', 'Gene', (22, 27))	('ATRX', 'Gene', (13, 17))	('ATRX', 'Gene', '546', (13, 17))	('Mutations', 'Var', (0, 9))	('DOT1L', 'Gene', '84444', (22, 27))	('missense substitutions', 'Var', (33, 55))
383237	30281149	One ATRX mutation, E351V, is reported somatic in COSMIC database.	('E351V', 'Mutation', 'p.E351V', (19, 24))	('ATRX', 'Gene', (4, 8))	('E351V', 'Var', (19, 24))	('ATRX', 'Gene', '546', (4, 8))
383238	30281149	We identified two mutations in DOT1L, G307V and Q595H occurring in Histone-lysine N-methyltransferase catalytic DOT1 domain and STAT1 binding motifs, respectively.	('DOT1L', 'Gene', '84444', (31, 36))	('G307V', 'Var', (38, 43))	('DOT1', 'Gene', (31, 35))	('G307V', 'Mutation', 'p.G307V', (38, 43))	('Q595H', 'Var', (48, 53))	('lysine', 'Chemical', 'MESH:D008239', (75, 81))	('STAT1', 'Gene', (128, 133))	('DOT1', 'Gene', '84444', (112, 116))	('DOT1', 'Gene', (112, 116))	('DOT1L', 'Gene', (31, 36))	('STAT1', 'Gene', '6772', (128, 133))	('Q595H', 'Mutation', 'p.Q595H', (48, 53))	('DOT1', 'Gene', '84444', (31, 35))
383245	30281149	We also found somatic CNV losses in RB1 in 5/10 (50%) cases, gains and losses in VGLL3 and CDKN2A, losses in YAP1 as well as loss and gain in CCNE1 (supplementary material, Table S3), genes that been previously implicated in UPSst.	('loss', 'NegReg', (125, 129))	('VGLL3', 'Gene', '389136', (81, 86))	('UPSst', 'Disease', (225, 230))	('CDKN2A', 'Gene', (91, 97))	('YAP1', 'Gene', '10413', (109, 113))	('losses', 'NegReg', (26, 32))	('losses', 'NegReg', (71, 77))	('RB1', 'Gene', (36, 39))	('CDKN2A', 'Gene', '1029', (91, 97))	('CCNE1', 'Gene', '898', (142, 147))	('VGLL3', 'Gene', (81, 86))	('losses', 'Var', (99, 105))	('YAP1', 'Gene', (109, 113))	('RB1', 'Gene', '5925', (36, 39))	('CCNE1', 'Gene', (142, 147))	('gain', 'PosReg', (134, 138))
383272	30281149	In 36% of the tumours, we identified mutations in chromatin remodelling genes (H3F3A, ATRX, DOT1L) which have not been previously described in the UPSb subtype.	('ATRX', 'Gene', '546', (86, 90))	('DOT1L', 'Gene', (92, 97))	('H3F3A', 'Gene', '3020', (79, 84))	('DOT1L', 'Gene', '84444', (92, 97))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('mutations', 'Var', (37, 46))	('H3F3A', 'Gene', (79, 84))	('ATRX', 'Gene', (86, 90))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))
383273	30281149	A significant co-occurrence of G34 H3F3A mutation with ATRX/DAXX and TP53 mutations has been observed in nearly 100% of glioblastoma tumours.	('glioblastoma tumours', 'Disease', 'MESH:D005909', (120, 140))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('glioblastoma tumours', 'Disease', (120, 140))	('TP53', 'Gene', '7157', (69, 73))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('TP53', 'Gene', (69, 73))	('ATRX', 'Gene', (55, 59))	('H3F3A', 'Gene', '3020', (35, 40))	('DAXX', 'Gene', '1616', (60, 64))	('G34', 'Var', (31, 34))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('ATRX', 'Gene', '546', (55, 59))	('H3F3A', 'Gene', (35, 40))	('DAXX', 'Gene', (60, 64))
383274	30281149	Notably, no correlation of H3F3A mutations was observed in UPSb tumours harbouring TP53, ATRX or DOT1L mutations.	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (103, 112))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('DOT1L', 'Gene', '84444', (97, 102))	('ATRX', 'Gene', (89, 93))	('H3F3A', 'Gene', '3020', (27, 32))	('TP53', 'Gene', (83, 87))	('UPSb tumours', 'Disease', 'MESH:D009369', (59, 71))	('H3F3A', 'Gene', (27, 32))	('ATRX', 'Gene', '546', (89, 93))	('UPSb tumours', 'Disease', (59, 71))	('DOT1L', 'Gene', (97, 102))
383276	30281149	Deep deletions in RB1 and CDKN2A has been identified recently in 16% and 20% of UPSst, respectively; whereas high-level amplifications were present in VGLL3, YAP1 and CCNE1 in 11%, 3% and 10% of UPSst.	('VGLL3', 'Gene', (151, 156))	('RB1', 'Gene', (18, 21))	('YAP1', 'Gene', (158, 162))	('CDKN2A', 'Gene', (26, 32))	('UPSst', 'Disease', (80, 85))	('CCNE1', 'Gene', (167, 172))	('CCNE1', 'Gene', '898', (167, 172))	('YAP1', 'Gene', '10413', (158, 162))	('CDKN2A', 'Gene', '1029', (26, 32))	('RB1', 'Gene', '5925', (18, 21))	('VGLL3', 'Gene', '389136', (151, 156))	('Deep deletions', 'Var', (0, 14))
383277	30281149	Heterozygous R132 and R172 hotspot point mutations in IDH1 and IDH2, respectively, are commonly present in 61-87% of chondrosarcoma cases, including dedifferentiated chondrosarcoma; by contrast, these changes are absent in 222 osteosarcoma samples.	('R172', 'Var', (22, 26))	('IDH2', 'Gene', '3418', (63, 67))	('chondrosarcoma', 'Disease', (117, 131))	('chondrosarcoma', 'Disease', 'MESH:D002813', (117, 131))	('IDH1', 'Gene', (54, 58))	('chondrosarcoma', 'Disease', 'MESH:D002813', (166, 180))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (166, 180))	('osteosarcoma', 'Disease', (227, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('chondrosarcoma', 'Disease', (166, 180))	('osteosarcoma', 'Phenotype', 'HP:0002669', (227, 239))	('osteosarcoma', 'Disease', 'MESH:D012516', (227, 239))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (117, 131))	('IDH1', 'Gene', '3417', (54, 58))	('R132', 'Var', (13, 17))	('IDH2', 'Gene', (63, 67))
383278	30281149	In an earlier study by Chen et al., we investigated the IDH1/2 mutation status in the 14 UPSb tumours used in this study and found no R132 and R172 mutations in any tumour, ruling out a diagnosis of dedifferentiated chondrosarcoma.	('tumour', 'Disease', (94, 100))	('chondrosarcoma', 'Disease', (216, 230))	('R172 mutations', 'Var', (143, 157))	('chondrosarcoma', 'Disease', 'MESH:D002813', (216, 230))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('IDH1/2', 'Gene', '3417;3418', (56, 62))	('UPSb tumours', 'Disease', (89, 101))	('UPSb tumours', 'Disease', 'MESH:D009369', (89, 101))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (216, 230))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumour', 'Disease', (165, 171))	('R132', 'Var', (134, 138))	('IDH1/2', 'Gene', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
383281	30281149	The TP53 gene is the most frequently mutated gene in various human cancers and 90% of TP53 mutations are missense changes with potential gain-of-function characteristics.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('TP53', 'Gene', (4, 8))	('gain-of-function', 'PosReg', (137, 153))	('TP53', 'Gene', '7157', (86, 90))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('TP53', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (91, 100))	('human', 'Species', '9606', (61, 66))	('TP53', 'Gene', '7157', (4, 8))	('missense changes', 'Var', (105, 121))
383282	30281149	Previously, TP53 mutations were identified in 22% of UPSb tumours by conventional PCR and Sanger sequencing.	('UPSb tumours', 'Disease', 'MESH:D009369', (53, 65))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('UPSb tumours', 'Disease', (53, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
383283	30281149	In this study, using massive-parallel sequencing for the first time on this tumour subtype, four TP53 missense mutations (R158H, COSMIC ID: COSM1640853; V216M, COSM10667; Y236C, COSM10731; C242G, COSM3717645), all occurring in the DNA-binding domain of p53 protein (Figure 2A), were identified.	('TP53', 'Gene', '7157', (97, 101))	('COSM3717645', 'Var', (196, 207))	('C242G', 'Mutation', 'rs587778720', (189, 194))	('R158H', 'Var', (122, 127))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('C242G', 'Var', (189, 194))	('R158H', 'Mutation', 'rs587782144', (122, 127))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))	('Y236C', 'Mutation', 'rs730882026', (171, 176))	('p53', 'Gene', '7157', (253, 256))	('V216M', 'Var', (153, 158))	('COSM10667', 'Var', (160, 169))	('Y236C', 'Var', (171, 176))	('TP53', 'Gene', (97, 101))	('p53', 'Gene', (253, 256))	('COSM10731', 'Var', (178, 187))	('COSM1640853; V216M', 'Var', (140, 158))	('V216M', 'Mutation', 'rs730882025', (153, 158))
383284	30281149	Mutations in the p53 DNA-binding domain can reduce the protein's binding specificity to DNA sequence motifs in p53-regulated genes.	('reduce', 'NegReg', (44, 50))	('binding', 'Interaction', (65, 72))	('p53', 'Gene', (111, 114))	('protein', 'Protein', (55, 62))	('p53', 'Gene', '7157', (111, 114))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
383285	30281149	The R158H, V216M and Y236C mutations are reported among the 50 most common somatic missense mutations in TP53, highlighting their potential pathological role in tumourigenesis.	('Y236C', 'Mutation', 'rs730882026', (21, 26))	('V216M', 'Var', (11, 16))	('R158H', 'Var', (4, 9))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('Y236C', 'Var', (21, 26))	('R158H', 'Mutation', 'rs587782144', (4, 9))	('V216M', 'Mutation', 'rs730882025', (11, 16))	('tumour', 'Disease', (161, 167))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))
383286	30281149	We could not find significant differences in the total number of mutations in samples harbouring TP53 mutations (n=4) comparing to the remaining samples (n=10).	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('TP53', 'Gene', '7157', (97, 101))
383287	30281149	Correlations between TP53 mutations and clinical implications are difficult to establish due to the clinical heterogeneity of the patients and small sample size; hence, additional investigations to elucidate their prognostic information are required.	('TP53', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('patients', 'Species', '9606', (130, 138))	('TP53', 'Gene', '7157', (21, 25))
383288	30281149	Recurrent mutations in H3F3A, ATRX and DOT1L were detected in 5/14 tumours.	('DOT1L', 'Gene', (39, 44))	('H3F3A', 'Gene', (23, 28))	('ATRX', 'Gene', (30, 34))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('H3F3A', 'Gene', '3020', (23, 28))	('DOT1L', 'Gene', '84444', (39, 44))	('detected', 'Reg', (50, 58))	('ATRX', 'Gene', '546', (30, 34))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (10, 19))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
383289	30281149	Highly specific cancer-driving hotspot mutations in H3F3A (G34) and H3F3B (K36) were identified in 92% of giant cell tumours of the bone and 95% of chondroblastoma cases, respectively.	('H3F3B', 'Gene', '3021', (68, 73))	('H3F3B', 'Gene', (68, 73))	('chondroblastoma', 'Disease', (148, 163))	('tumours of the bone', 'Phenotype', 'HP:0010622', (117, 136))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (39, 48))	('giant cell tumours of the bone', 'Phenotype', 'HP:0011847', (106, 136))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('K36', 'Gene', '8689', (75, 78))	('H3F3A', 'Gene', '3020', (52, 57))	('chondroblastoma', 'Disease', 'MESH:D002804', (148, 163))	('tumours', 'Disease', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('K36', 'Gene', (75, 78))	('chondroblastoma', 'Phenotype', 'HP:0030432', (148, 163))	('H3F3A', 'Gene', (52, 57))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('tumours', 'Disease', 'MESH:D009369', (117, 124))
383290	30281149	In this study, we identified recurrent somatic mutations (G34V, COSM502595 and V35_K36insL, COSM5574356) in H3F3A affecting the previously reported amino acid residues (Figure 2B).	('G34V', 'Mutation', 'p.G34V', (58, 62))	('COSM502595', 'Var', (64, 74))	('COSM5574356', 'Var', (92, 103))	('K36insL', 'Mutation', 'c.36insK,L', (83, 90))	('H3F3A', 'Gene', '3020', (108, 113))	('amino acid residues', 'MPA', (148, 167))	('V35_K36insL', 'Var', (79, 90))	('G34V', 'Var', (58, 62))	('H3F3A', 'Gene', (108, 113))	('affecting', 'Reg', (114, 123))
383292	30281149	Histone 3.3 lysine to methionine substitution (K36M) reduces the methylation of lysine residue through inhibition of SET domain-containing enzymes.	('lysine', 'Chemical', 'MESH:D008239', (80, 86))	('K36M', 'Mutation', 'p.K36M', (47, 51))	('inhibition', 'NegReg', (103, 113))	('K36M', 'Var', (47, 51))	('lysine', 'Chemical', 'MESH:D008239', (12, 18))	('3 lysine to methionine', 'Mutation', 'p.K3M', (10, 32))	('reduces', 'NegReg', (53, 60))	('methylation of lysine residue', 'MPA', (65, 94))	('SET domain-containing enzymes', 'Enzyme', (117, 146))
383293	30281149	This reduction of methylation at K36 was also observed in cell lines carrying the G34V substitution.	('G34V', 'Mutation', 'p.G34V', (82, 86))	('K36', 'Gene', '8689', (33, 36))	('reduction', 'NegReg', (5, 14))	('G34V', 'Var', (82, 86))	('K36', 'Gene', (33, 36))
383295	30281149	H3F3A/H3F3B driver mutations were described in giant cell tumour of the bone and chondroblastoma which are considered benign tumours or benign but locally aggressive tumours, respectively as well as in malignant giant cell tumour of the bone.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('H3F3A', 'Gene', '3020', (0, 5))	('tumour', 'Disease', (166, 172))	('aggressive tumours', 'Disease', 'MESH:D009369', (155, 173))	('tumour of the bone', 'Phenotype', 'HP:0010622', (58, 76))	('giant cell tumour of the bone', 'Phenotype', 'HP:0011847', (47, 76))	('giant cell tumour of the bone', 'Phenotype', 'HP:0011847', (212, 241))	('chondroblastoma', 'Phenotype', 'HP:0030432', (81, 96))	('malignant giant cell tumour', 'Disease', 'MESH:D009369', (202, 229))	('H3F3A', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('aggressive tumours', 'Disease', (155, 173))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour of the bone', 'Phenotype', 'HP:0010622', (223, 241))	('tumour', 'Disease', (58, 64))	('chondroblastoma', 'Disease', (81, 96))	('malignant giant cell tumour', 'Disease', (202, 229))	('H3F3B', 'Gene', (6, 11))	('tumours', 'Disease', (166, 173))	('H3F3B', 'Gene', '3021', (6, 11))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('tumour', 'Disease', (223, 229))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('tumours', 'Disease', 'MESH:D009369', (166, 173))	('tumours', 'Disease', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (19, 28))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumour', 'Disease', (125, 131))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('chondroblastoma', 'Disease', 'MESH:D002804', (81, 96))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
383296	30281149	identified H3F3A G34 substitutions in 13/385 (3.37%) of primary malignant bone tumours, classified as either osteosarcoma or malignant giant cell tumour of bone.	('substitutions', 'Var', (21, 34))	('tumour of bone', 'Phenotype', 'HP:0010622', (146, 160))	('malignant bone tumours', 'Disease', (64, 86))	('H3F3A', 'Gene', '3020', (11, 16))	('giant cell tumour of bone', 'Phenotype', 'HP:0011847', (135, 160))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('malignant bone tumours', 'Disease', 'MESH:D001859', (64, 86))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('H3F3A', 'Gene', (11, 16))	('osteosarcoma or malignant giant cell tumour', 'Disease', 'MESH:D012516', (109, 152))	('osteosarcoma', 'Phenotype', 'HP:0002669', (109, 121))	('osteosarcoma or malignant giant cell tumour', 'Disease', (109, 152))	('G34 substitutions', 'Var', (17, 34))
383297	30281149	In this study, we report recurrent H3F3A alterations in 2/14 (14.3%) UPSb tumours, a higher percentage than in previously reported malignant tumours, with the caveat of a smaller cohort size.	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('malignant tumours', 'Disease', (131, 148))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('H3F3A', 'Gene', '3020', (35, 40))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('malignant tumours', 'Disease', 'MESH:D009369', (131, 148))	('UPSb tumours', 'Disease', 'MESH:D009369', (69, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('H3F3A', 'Gene', (35, 40))	('UPSb tumours', 'Disease', (69, 81))	('alterations', 'Var', (41, 52))
383298	30281149	Hence, the possibility of a malignant phenotype or evolution should be considered in tumours harbouring H3F3A alterations.	('alterations', 'Var', (110, 121))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('H3F3A', 'Gene', '3020', (104, 109))	('tumours', 'Disease', (85, 92))	('H3F3A', 'Gene', (104, 109))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
383302	30281149	Dysfunction ATRX/DAXX is associated with the alternative lengthening of telomeres (ALT), a phenomenon observed in 10-15% of cancers of mesenchymal origin (e.g.	('DAXX', 'Gene', (17, 21))	('Dysfunction', 'Var', (0, 11))	('ATRX', 'Gene', '546', (12, 16))	('ATRX', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DAXX', 'Gene', '1616', (17, 21))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
383303	30281149	In this study, we identified two missense mutations in ATRX: S2109I and E351V (COSMIC ID: COSM6608613) occurring in the Helicase/ adenosine triphosphatase (ATPase) conserved C-terminus and Enhancer zeste homologue 2 (EZH2) interacting region of the ATRX protein, respectively (Figure 2C).	('ATRX', 'Gene', '546', (249, 253))	('EZH2', 'Gene', (217, 221))	('EZH2', 'Gene', '2146', (217, 221))	('ATRX', 'Gene', (55, 59))	('S2109I', 'Var', (61, 67))	('Helicase', 'Gene', '164045', (120, 128))	('Helicase', 'Gene', (120, 128))	('E351V', 'Var', (72, 77))	('adenosine', 'Chemical', 'MESH:D000241', (130, 139))	('E351V', 'Mutation', 'p.E351V', (72, 77))	('ATP', 'Chemical', 'MESH:D000255', (156, 159))	('ATRX', 'Gene', '546', (55, 59))	('S2109I', 'Mutation', 'p.S2109I', (61, 67))	('ATRX', 'Gene', (249, 253))
383306	30281149	Although further studies are required, mutations in these two functionally important domains can disrupt ATRX protein function, affecting the integrity of the chromatin structure.	('ATRX', 'Gene', '546', (105, 109))	('integrity of the chromatin structure', 'MPA', (142, 178))	('mutations', 'Var', (39, 48))	('disrupt', 'NegReg', (97, 104))	('function', 'MPA', (118, 126))	('ATRX', 'Gene', (105, 109))	('affecting', 'Reg', (128, 137))
383315	30281149	Rearrangements involving CLTC-PTRH2-VMP1 locus have been observed in multiple tumour types, including glioblastoma, lung cancer, breast cancer and leukaemias.	('VMP1', 'Gene', (36, 40))	('VMP1', 'Gene', '81671', (36, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('glioblastoma', 'Disease', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('observed', 'Reg', (57, 65))	('CLTC', 'Gene', '1213', (25, 29))	('tumour', 'Disease', (78, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('leukaemias', 'Disease', (147, 157))	('PTRH2', 'Gene', '51651', (30, 35))	('CLTC', 'Gene', (25, 29))	('PTRH2', 'Gene', (30, 35))	('Rearrangements', 'Var', (0, 14))	('lung cancer', 'Disease', (116, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('leukaemias', 'Disease', 'MESH:D007938', (147, 157))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('breast cancer', 'Disease', (129, 142))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
383319	30281149	suggested, the rearrangement involving CLTC-PTRH2-VMP1 and the CLTC-VMP1 gene fusion being out-of-frame are indicative of a disruption of the tumour suppressor activity.	('VMP1', 'Gene', (50, 54))	('PTRH2', 'Gene', (44, 49))	('tumour', 'Disease', (142, 148))	('VMP1', 'Gene', (68, 72))	('VMP1', 'Gene', '81671', (50, 54))	('VMP1', 'Gene', '81671', (68, 72))	('CLTC', 'Gene', '1213', (39, 43))	('CLTC', 'Gene', (39, 43))	('CLTC', 'Gene', '1213', (63, 67))	('PTRH2', 'Gene', '51651', (44, 49))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('rearrangement', 'Var', (15, 28))	('CLTC', 'Gene', (63, 67))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
383322	30281149	Since the 5' transcription regulatory apparatus of both FARP1 and STK24 is retained, theoretically, both sense (FARP1) and antisense (STK24) genes can start transcription that extends into the other gene partner, or vice versa.	('FARP1', 'Gene', (56, 61))	('FARP1', 'Gene', '10160', (56, 61))	('start', 'Reg', (151, 156))	('STK24', 'Gene', (134, 139))	('STK24', 'Gene', '8428', (134, 139))	('FARP1', 'Gene', (112, 117))	('FARP1', 'Gene', '10160', (112, 117))	('STK24', 'Gene', '8428', (66, 71))	('antisense', 'Var', (123, 132))	('STK24', 'Gene', (66, 71))
383323	30281149	Gene fusions involving FARP1 have been reported in multiple cancers, including lung adenocarcinoma, breast adenocarcinoma and lower grade glioma (http://www.tumorfusions.org).	('FARP1', 'Gene', (23, 28))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('breast adenocarcinoma', 'Disease', 'MESH:D001943', (100, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('glioma', 'Disease', (138, 144))	('breast adenocarcinoma', 'Disease', (100, 121))	('Gene fusions', 'Var', (0, 12))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (100, 121))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('FARP1', 'Gene', '10160', (23, 28))	('reported', 'Reg', (39, 47))	('lung adenocarcinoma', 'Disease', (79, 98))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
383330	30281149	The use of kinase inhibitors in tumours harbouring kinase-related gene fusions can improve tumour prognosis and patient outcome.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Disease', (32, 39))	('patient', 'Species', '9606', (112, 119))	('gene fusions', 'Var', (66, 78))	('tumour', 'Disease', (32, 38))	('tumour', 'Disease', (91, 97))	('improve', 'PosReg', (83, 90))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
383331	30281149	For example, the efficacy of using ALK inhibitors in advanced non-small-cell lung cancer with ALK rearrangement is evident in clinical trials.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ALK', 'Gene', '238', (35, 38))	('ALK', 'Gene', '238', (94, 97))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (62, 88))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (66, 88))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('ALK', 'Gene', (35, 38))	('ALK', 'Gene', (94, 97))	('lung cancer', 'Disease', (77, 88))	('rearrangement', 'Var', (98, 111))
383333	30281149	Although further detailed investigations are required, STK24-selective inhibitors are potential cancer therapeutics in tumours harbouring STK24 rearrangements.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('rearrangements', 'Var', (144, 158))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (119, 126))	('tumours', 'Disease', (119, 126))	('STK24', 'Gene', '8428', (138, 143))	('STK24', 'Gene', '8428', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('STK24', 'Gene', (138, 143))	('STK24', 'Gene', (55, 60))	('cancer', 'Disease', (96, 102))
383347	30281149	We identified novel recurrent gene mutations in multiple cancer-related genes, including chromatin remodelling genes, that are reported in UPSb tumours for the first time.	('UPSb tumours', 'Disease', (139, 151))	('UPSb tumours', 'Disease', 'MESH:D009369', (139, 151))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (57, 63))	('chromatin remodelling genes', 'Gene', (89, 116))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (35, 44))
383355	32793503	Gene alterations and elevated expression of VGLL1-3 were observed in various types of tumors, and VGLL1-3 have been shown to possess tumorigenic functions.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('expression', 'MPA', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (86, 91))	('observed', 'Reg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('elevated', 'PosReg', (21, 29))	('alterations', 'Var', (5, 16))	('VGLL1-3', 'Gene', '51442;245806;389136', (44, 51))	('VGLL1-3', 'Gene', (44, 51))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('VGLL1-3', 'Gene', '51442;245806;389136', (98, 105))	('VGLL1-3', 'Gene', (98, 105))
383365	32793503	Studies so far have revealed that the dysregulation of TEAD activity causes tumorigenesis.	('dysregulation', 'Var', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
383369	32793503	YAP/TAZ-TEAD complex promotes the expression of genes involved in cell growth, and disruption in the Hippo pathway causes aberrant activation of this complex and thereby induces tumor development.	('YAP/TAZ', 'Gene', '10413;6901', (0, 7))	('activation', 'PosReg', (131, 141))	('tumor', 'Disease', (178, 183))	('Hippo', 'Gene', '37247', (101, 106))	('expression', 'MPA', (34, 44))	('Hippo', 'Gene', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('YAP/TAZ', 'Gene', (0, 7))	('induces', 'Reg', (170, 177))	('disruption', 'Var', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
383377	32793503	Importantly, anchorage-independent growth or IGFBP5 expression was not induced by stable expression of the VGLL1 mutant lacking TEAD-binding ability, suggesting that VGLL1 depends on TEAD for its oncogenic activity.	('lacking', 'NegReg', (120, 127))	('VGLL1', 'Gene', (107, 112))	('VGLL1', 'Gene', (166, 171))	('anchorage-independent growth', 'CPA', (13, 41))	('VGLL1', 'Gene', '51442', (107, 112))	('VGLL1', 'Gene', '51442', (166, 171))	('IGFBP5', 'Gene', '3488', (45, 51))	('IGFBP5', 'Gene', (45, 51))	('mutant', 'Var', (113, 119))
383378	32793503	Recently, EWSR1-VGLL1 fusion genes were found in a soft tissue malignant myoepithelial tumor and a pediatric neuroepithelial neoplasm.	('malignant myoepithelial tumor', 'Disease', (63, 92))	('EWSR1', 'Gene', (10, 15))	('malignant myoepithelial tumor', 'Disease', 'MESH:D009208', (63, 92))	('neuroepithelial neoplasm', 'Disease', 'MESH:D018302', (109, 133))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('neuroepithelial neoplasm', 'Disease', (109, 133))	('neuroepithelial neoplasm', 'Phenotype', 'HP:0030063', (109, 133))	('EWSR1', 'Gene', '2130', (10, 15))	('VGLL1', 'Gene', (16, 21))	('found', 'Reg', (40, 45))	('neoplasm', 'Phenotype', 'HP:0002664', (125, 133))	('VGLL1', 'Gene', '51442', (16, 21))	('fusion genes', 'Var', (22, 34))
383383	32793503	It has been suggested that the modulation of estrogen receptor (ER) is involved in increased VGLL1 expression.	('expression', 'MPA', (99, 109))	('modulation', 'Var', (31, 41))	('increased', 'PosReg', (83, 92))	('estrogen receptor', 'Gene', (45, 62))	('VGLL1', 'Gene', (93, 98))	('estrogen receptor', 'Gene', '2099', (45, 62))	('VGLL1', 'Gene', '51442', (93, 98))	('increased VGLL1 expression', 'Phenotype', 'HP:0030269', (83, 109))	('ER', 'Gene', '2099', (64, 66))
383387	32793503	The knockdown of VGLL1 reduced viral early gene expression in human cervical keratinocytes and cervical cancer cell lines.	('VGLL1', 'Gene', '51442', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('human', 'Species', '9606', (62, 67))	('viral', 'Protein', (31, 36))	('reduced', 'NegReg', (23, 30))	('knockdown', 'Var', (4, 13))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('VGLL1', 'Gene', (17, 22))
383389	32793503	The introduction of HPV16 and HPV18 whole-genomes into primary human keratinocytes increased VGLL1 expression.	('expression', 'MPA', (99, 109))	('increased', 'PosReg', (83, 92))	('human', 'Species', '9606', (63, 68))	('HPV', 'Species', '10566', (20, 23))	('VGLL1', 'Gene', (93, 98))	('HPV18', 'Gene', (30, 35))	('HPV16', 'Species', '333760', (20, 25))	('VGLL1', 'Gene', '51442', (93, 98))	('HPV16', 'Var', (20, 25))	('HPV', 'Species', '10566', (30, 33))	('increased VGLL1 expression', 'Phenotype', 'HP:0030269', (83, 109))
383405	32793503	Similarly to VGLL2, VGLL3 gene alterations were identified in sarcoma.	('alterations', 'Var', (31, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('VGLL3', 'Gene', (20, 25))	('sarcoma', 'Disease', (62, 69))
383408	32793503	Recent deep sequencing of myxoinflammatory fibroblastic sarcoma demonstrated that VGLL3 amplification is a highly recurrent feature of this type of sarcoma.	('myxoinflammatory fibroblastic sarcoma', 'Disease', (26, 63))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('myxoinflammatory fibroblastic sarcoma', 'Disease', 'MESH:D012509', (26, 63))	('amplification', 'Var', (88, 101))	('sarcoma', 'Disease', (148, 155))	('sarcoma', 'Disease', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('VGLL3', 'Gene', (82, 87))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))
383410	32793503	VGLL3-high gastric tumor showed the activation of the MAPK, JAK-STAT, and WNT pathways together with enhanced immune infiltrates.	('immune infiltrates', 'CPA', (110, 128))	('gastric tumor', 'Disease', 'MESH:D013274', (11, 24))	('gastric tumor', 'Phenotype', 'HP:0006753', (11, 24))	('STAT', 'Gene', (64, 68))	('activation', 'PosReg', (36, 46))	('VGLL3-high', 'Var', (0, 10))	('STAT', 'Gene', '6774;20848', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MAPK', 'Pathway', (54, 58))	('enhanced', 'PosReg', (101, 109))	('gastric tumor', 'Disease', (11, 24))	('WNT pathways', 'Pathway', (74, 86))
383425	32793503	The tumor-suppressing role of VGLL4 was first observed in the transposon Sleeping Beauty-mediated mutagenesis in murine Kras-driven pancreatic adenocarcinoma models.	('tumor', 'Disease', (4, 9))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (132, 157))	('Kras', 'Gene', (120, 124))	('Kras', 'Gene', '16653', (120, 124))	('pancreatic adenocarcinoma', 'Disease', (132, 157))	('murine', 'Species', '10090', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('transposon', 'Var', (62, 72))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (132, 157))	('mutagenesis', 'Var', (98, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
383426	32793503	The reduction in VGLL4 expression was observed in human lung tumor, and VGLL4 expression repressed the proliferation of lung tumor cells via the suppression of TEAD transcriptional activities.	('VGLL4', 'Gene', (72, 77))	('proliferation', 'CPA', (103, 116))	('suppression', 'NegReg', (145, 156))	('lung tumor', 'Phenotype', 'HP:0100526', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('expression', 'Var', (78, 88))	('lung tumor', 'Disease', 'MESH:D008175', (120, 130))	('TEAD transcriptional activities', 'MPA', (160, 191))	('lung tumor', 'Disease', (120, 130))	('lung tumor', 'Phenotype', 'HP:0100526', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('repressed', 'NegReg', (89, 98))	('human', 'Species', '9606', (50, 55))	('lung tumor', 'Disease', 'MESH:D008175', (56, 66))	('lung tumor', 'Disease', (56, 66))
383431	32793503	VGLL4 repressed the proliferation of breast tumor cells via the inhibition of YAP-mediated gene induction, and high expression of VGLL4 correlated with poor prognosis of breast tumor patients.	('breast tumor', 'Phenotype', 'HP:0100013', (170, 182))	('breast tumor', 'Phenotype', 'HP:0100013', (37, 49))	('breast tumor', 'Disease', 'MESH:D001943', (170, 182))	('breast tumor', 'Disease', 'MESH:D001943', (37, 49))	('YAP', 'Gene', '10413', (78, 81))	('inhibition', 'NegReg', (64, 74))	('VGLL4', 'Gene', (130, 135))	('breast tumor', 'Disease', (170, 182))	('breast tumor', 'Disease', (37, 49))	('correlated', 'Reg', (136, 146))	('patients', 'Species', '9606', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('YAP', 'Gene', (78, 81))	('high', 'Var', (111, 115))
383432	32793503	Although the tumor-suppressing roles of VGLL4 mostly depend on competition with YAP for TEAD binding, VGLL4 also acts as a tumor suppressor in a YAP-independent manner.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (123, 128))	('YAP', 'Gene', '10413', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('YAP', 'Gene', (145, 148))	('binding', 'Interaction', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('YAP', 'Gene', (80, 83))	('TEAD', 'Protein', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('VGLL4', 'Var', (102, 107))	('YAP', 'Gene', '10413', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
383436	32793503	STAT3, a transcription factor in JAK-STAT signaling, was another target of VGLL4, and binding of VGLL4 to STAT3 repressed its transcriptional activity and cell growth in triple-negative breast cancer.	('transcriptional activity', 'MPA', (126, 150))	('STAT', 'Gene', '6774;20848', (106, 110))	('STAT3', 'Gene', '6774', (0, 5))	('STAT', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('STAT', 'Gene', '6774;20848', (0, 4))	('STAT', 'Gene', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('breast cancer', 'Disease', (186, 199))	('STAT3', 'Gene', (106, 111))	('binding', 'Var', (86, 93))	('cell growth', 'CPA', (155, 166))	('VGLL4', 'Gene', (97, 102))	('STAT', 'Gene', '6774;20848', (37, 41))	('STAT', 'Gene', (37, 41))	('repressed', 'NegReg', (112, 121))	('STAT3', 'Gene', '6774', (106, 111))	('STAT3', 'Gene', (0, 5))
383447	32793503	Ubiquitin-specific protease 11 (USP11) deubiquitinated and stabilized VGLL4 proteins, and the inactivation of USP11 was suggested to be involved in the destabilization of VGLL4 in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('USP11', 'Gene', '8237', (32, 37))	('deubiquitinated', 'MPA', (39, 54))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('destabilization', 'MPA', (152, 167))	('Ubiquitin-specific protease 11', 'Gene', (0, 30))	('tumor', 'Disease', (180, 185))	('Ubiquitin-specific protease 11', 'Gene', '8237', (0, 30))	('stabilized', 'MPA', (59, 69))	('USP11', 'Gene', (110, 115))	('inactivation', 'Var', (94, 106))	('USP11', 'Gene', '8237', (110, 115))	('USP11', 'Gene', (32, 37))	('VGLL4 proteins', 'Protein', (70, 84))
383454	32793503	VGLL1 dysregulation was detected in various types of tumor; however, gene alterations in VGLL2 and VGLL3 were observed specifically in sarcoma.	('observed', 'Reg', (110, 118))	('VGLL1', 'Gene', '51442', (0, 5))	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('VGLL1', 'Gene', (0, 5))	('VGLL2', 'Gene', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sarcoma', 'Disease', (135, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('tumor', 'Disease', (53, 58))	('VGLL3', 'Gene', (99, 104))	('gene alterations', 'Var', (69, 85))
383455	32793503	The inactivation of VGLL4 is involved in various types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('inactivation', 'Var', (4, 16))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('VGLL4', 'Protein', (20, 25))	('involved', 'Reg', (29, 37))
383457	32793503	Therefore, the transfer of VGLL4 into tumor cells may be an effective therapeutic method.	('transfer', 'Var', (15, 23))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('VGLL4', 'Protein', (27, 32))
383458	32793503	Actually, adenovirus-mediated transfer of VGLL4 into hepatocellular carcinoma cells selectively killed the tumor cells through cell cycle arrest and apoptosis induction.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('arrest', 'Disease', 'MESH:D006323', (138, 144))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (53, 77))	('arrest', 'Disease', (138, 144))	('transfer', 'Var', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('hepatocellular carcinoma', 'Disease', (53, 77))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 77))	('apoptosis induction', 'CPA', (149, 168))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (127, 144))	('VGLL4', 'Gene', (42, 47))	('adenovirus', 'Species', '10508', (10, 20))
383478	30550483	Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas.	('aberrant', 'Var', (119, 127))	('clear cell carcinomas', 'Disease', (145, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('Napsin A', 'Gene', (39, 47))	('Napsin A', 'Gene', '9476', (39, 47))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (145, 166))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('expression', 'MPA', (105, 115))
383499	30550483	Nearly every case harbors a TP53 mutation, which is associated with aberrant immunohistochemical expression of p53.	('TP53', 'Gene', '7157', (28, 32))	('mutation', 'Var', (33, 41))	('TP53', 'Gene', (28, 32))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))
383522	30550483	ARID1A is a tumor suppressor gene mutated in ~50% of ovarian endometrioid and clear cell carcinomas, as well as a significant percentage of the corresponding uterine tumors, resulting in loss of immunoexpression of its protein product, BAF250a.	('loss', 'NegReg', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('BAF250a', 'Gene', (236, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (12, 17))	('immunoexpression', 'MPA', (195, 211))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumors', 'Disease', (166, 172))	('ovarian endometrioid', 'Disease', (53, 73))	('tumor', 'Disease', (166, 171))	('clear cell carcinomas', 'Disease', (78, 99))	('ovarian endometrioid', 'Disease', 'MESH:D016889', (53, 73))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('ARID1A', 'Gene', (0, 6))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (78, 99))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('BAF250a', 'Gene', '8289', (236, 243))	('uterine tumors', 'Phenotype', 'HP:0010784', (158, 172))	('mutated', 'Var', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('ARID1A', 'Gene', '8289', (0, 6))
383524	30550483	Aberrant p53 expression was found in 18% of grade 3 endometrioid carcinoma compared with 78% of serous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('Aberrant', 'Var', (0, 8))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('expression', 'MPA', (13, 23))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (52, 74))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (52, 74))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('serous carcinomas', 'Disease', 'MESH:D018284', (96, 113))	('serous carcinomas', 'Disease', (96, 113))	('found', 'Reg', (28, 33))	('endometrioid carcinoma', 'Disease', (52, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
383547	30550483	Insufficient evidence is available to support the use of vimentin, Ki-67, HNF1B, WT1 and IMP2, and monoclonal carcinoembryonic antigen may be safely omitted from the antibody panel.	('WT1', 'Gene', (81, 84))	('HNF1B', 'Gene', '6928', (74, 79))	('monoclonal carcinoembryonic', 'Disease', 'MESH:D010265', (99, 126))	('monoclonal carcinoembryonic', 'Disease', (99, 126))	('IMP2', 'Gene', '10644', (89, 93))	('HNF1B', 'Gene', (74, 79))	('IMP2', 'Gene', (89, 93))	('vimentin', 'Gene', '7431', (57, 65))	('vimentin', 'Gene', (57, 65))	('WT1', 'Gene', '7490', (81, 84))	('Ki-67', 'Var', (67, 72))
383578	30550483	Aberrant mutation-type p53 immunohistochemical expression is seen in up to one third of otherwise typical clear cell carcinomas (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('clear cell carcinomas', 'Disease', (106, 127))	('Aberrant mutation-type', 'Var', (0, 22))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (106, 127))
383580	30550483	Nevertheless, p53 immunohistochemistry can still provide useful information, as wild-type p53 staining minimizes the probability that the tumor is a true serous carcinoma, and mutation-type p53 expression is an adverse prognostic factor in histotypically ambiguous tumors.	('p53', 'Gene', (90, 93))	('tumor', 'Disease', (138, 143))	('serous carcinoma', 'Disease', (154, 170))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('minimizes', 'NegReg', (103, 112))	('tumor', 'Disease', (265, 270))	('p53', 'Gene', '7157', (190, 193))	('ambiguous tumors', 'Disease', (255, 271))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('serous carcinoma', 'Disease', 'MESH:D018284', (154, 170))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('mutation-type', 'Var', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (90, 93))	('ambiguous tumors', 'Disease', 'MESH:D012734', (255, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
383582	30550483	At the molecular level, ~14% of morphologically and immunophenotypically characteristic clear cell carcinomas display a profile of mutations (mutations in TP53 and PPP2R1A; wild-type PTEN, CTNNB1, and ARID1A) typically seen in serous carcinoma.	('mutations', 'Var', (142, 151))	('CTNNB1', 'Gene', '1499', (189, 195))	('PTEN', 'Gene', (183, 187))	('TP53', 'Gene', '7157', (155, 159))	('PTEN', 'Gene', '5728', (183, 187))	('serous carcinoma', 'Disease', 'MESH:D018284', (227, 243))	('clear cell carcinomas', 'Disease', (88, 109))	('PPP2R1A', 'Gene', '5518', (164, 171))	('TP53', 'Gene', (155, 159))	('CTNNB1', 'Gene', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('ARID1A', 'Gene', '8289', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('ARID1A', 'Gene', (201, 207))	('PPP2R1A', 'Gene', (164, 171))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (88, 109))	('serous carcinoma', 'Disease', (227, 243))
383586	30550483	Similarly, the diagnostic value of AMACR (alpha-methylacyl-coenzyme-A racemase or p504s), which has been reported to be frequently positive in clear cell carcinoma, requires further study.	('AMACR', 'Gene', '23600', (35, 40))	('AMACR', 'Gene', (35, 40))	('clear cell carcinoma', 'Disease', (143, 163))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (143, 163))	('p504s', 'Var', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
383625	30550483	The frequency of aberrant mutation-type p53 staining in these cases (36%) is comparable with that reported in conventional clear cell carcinoma (33%-38%), and substantially less than that expected in serous carcinoma.	('clear cell carcinoma', 'Disease', 'MESH:C538614', (123, 143))	('clear cell carcinoma', 'Disease', (123, 143))	('serous carcinoma', 'Disease', (200, 216))	('serous carcinoma', 'Disease', 'MESH:D018284', (200, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('p53', 'Gene', (40, 43))	('aberrant mutation-type', 'Var', (17, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('p53', 'Gene', '7157', (40, 43))
383658	30550483	Rare cases with germline DNA MMR gene mutations diagnostic of Lynch syndrome have been reported.	('mutations', 'Var', (38, 47))	('Lynch syndrome', 'Disease', 'MESH:D003123', (62, 76))	('Lynch syndrome', 'Disease', (62, 76))
383659	30550483	Possible mechanisms underlying the transition from differentiated to undifferentiated carcinoma include the acquisition of mutations in SMARCA4, ARID1B, CTNNB1, PPP2R1A or TP53 .	('PPP2R1A', 'Gene', (161, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('PPP2R1A', 'Gene', '5518', (161, 168))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('undifferentiated carcinoma', 'Disease', (69, 95))	('ARID1B', 'Gene', (145, 151))	('CTNNB1', 'Gene', '1499', (153, 159))	('SMARCA4', 'Gene', '6597', (136, 143))	('ARID1B', 'Gene', '57492', (145, 151))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (69, 95))	('CTNNB1', 'Gene', (153, 159))	('mutations', 'Var', (123, 132))	('differentiated', 'Disease', (51, 65))	('SMARCA4', 'Gene', (136, 143))
383680	30550483	Loss of BRG1 and/or INI1 expression has been reported in undifferentiated carcinoma and the undifferentiated component of dedifferentiated carcinomas; loss of another subunit of the SWI/SNF complex, BAF250a (the protein product of ARID1A) is common in both low-grade and high-grade endometrial carcinomas.	('BAF250a', 'Gene', (199, 206))	('undifferentiated carcinoma and the undifferentiated component of dedifferentiated carcinomas', 'Disease', 'MESH:D002277', (57, 149))	('INI1', 'Gene', (20, 24))	('INI1', 'Gene', '6598', (20, 24))	('endometrial carcinomas', 'Disease', (282, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (282, 303))	('carcinomas', 'Phenotype', 'HP:0030731', (294, 304))	('ARID1A', 'Gene', (231, 237))	('BAF250a', 'Gene', '8289', (199, 206))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (282, 304))	('BRG1', 'Gene', '6597', (8, 12))	('ARID1A', 'Gene', '8289', (231, 237))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (282, 304))	('BRG1', 'Gene', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('low-grade', 'Disease', (257, 266))	('loss', 'Var', (151, 155))
383708	30550483	A recent large-scale molecular genetic analysis of uterine carcinosarcomas by the Cancer Genome Atlas revealed extensive copy-number alterations and highly recurrent somatic mutations, most frequently in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS.	('carcinosarcomas', 'Disease', (59, 74))	('PPP2R1A', 'Gene', '5518', (224, 231))	('PIK3CA', 'Gene', '5290', (216, 222))	('TP53', 'Gene', (204, 208))	('PTEN', 'Gene', (210, 214))	('PPP2R1A', 'Gene', (224, 231))	('FBXW7', 'Gene', '55294', (233, 238))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PTEN', 'Gene', '5728', (210, 214))	('PIK3CA', 'Gene', (216, 222))	('Cancer', 'Disease', (82, 88))	('TP53', 'Gene', '7157', (204, 208))	('carcinosarcomas', 'Disease', 'MESH:D002296', (59, 74))	('KRAS', 'Gene', '3845', (244, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('copy-number alterations', 'Var', (121, 144))	('FBXW7', 'Gene', (233, 238))	('KRAS', 'Gene', (244, 248))
383781	29854498	When matched for cytogenetics and age, isolated MS was associated with improved event-free survival and overall survival on standard AML therapy.	('overall survival', 'CPA', (104, 120))	('AML', 'Disease', 'MESH:D015470', (133, 136))	('isolated MS', 'Var', (39, 50))	('AML', 'Phenotype', 'HP:0004808', (133, 136))	('event-free survival', 'CPA', (80, 99))	('AML', 'Disease', (133, 136))	('improved', 'PosReg', (71, 79))
383808	29197420	The tumor cells had a high index of Ki67.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('Ki67', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Ki67', 'Chemical', '-', (36, 40))
383833	21793187	Evaluation of Polymorphisms in EWSR1 and Risk of Ewing Sarcoma: A Report from the Childhood Cancer Survivor Study Ewing sarcoma is a malignant bone tumor characterized by a high frequency of somatic EWSR1 translocations.	('EWSR1', 'Gene', (31, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (114, 127))	('bone tumor', 'Phenotype', 'HP:0010622', (143, 153))	('Ewing Sarcoma', 'Disease', (49, 62))	('malignant bone tumor', 'Disease', (133, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('EWSR1', 'Gene', '2130', (199, 204))	('Sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('malignant bone tumor', 'Disease', 'MESH:D001859', (133, 153))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('Ewing sarcoma', 'Disease', (114, 127))	('translocations', 'Var', (205, 219))	('EWSR1', 'Gene', '2130', (31, 36))	('Polymorphisms', 'Var', (14, 27))	('EWSR1', 'Gene', (199, 204))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))
383837	21793187	One SNP in EWSR1 (rs2857461) showed a low level of statistical association with the diagnosis of Ewing sarcoma compared to Wilms tumor.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (97, 110))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (97, 110))	('EWSR1', 'Gene', (11, 16))	('rs2857461', 'Var', (18, 27))	('Wilms tumor', 'Disease', 'MESH:D009396', (123, 134))	('Wilms tumor', 'Phenotype', 'HP:0002667', (123, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('EWSR1', 'Gene', '2130', (11, 16))	('Ewing sarcoma', 'Disease', (97, 110))	('Wilms tumor', 'Disease', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('rs2857461', 'Mutation', 'rs2857461', (18, 27))
383838	21793187	The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 was 3.57 (95% confidence interval 0.79 - 21.7; p = 0.07).	('Ewing sarcoma', 'Disease', (26, 39))	('rs2857461', 'Var', (96, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('people', 'Species', '9606', (43, 49))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('rs2857461', 'Mutation', 'rs2857461', (96, 105))
383839	21793187	No other SNPs or variations in intron 7 of EWSR1 were associated with Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('variations', 'Var', (17, 27))	('Ewing sarcoma', 'Disease', (70, 83))	('EWSR1', 'Gene', (43, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (70, 83))	('associated', 'Reg', (54, 64))	('EWSR1', 'Gene', '2130', (43, 48))
383841	21793187	Variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('EWSR1', 'Gene', '2130', (14, 19))	('Variations', 'Var', (0, 10))	('Ewing sarcoma', 'Disease', (94, 107))	('associated', 'Reg', (61, 71))	('EWSR1', 'Gene', (14, 19))
383846	21793187	Approximately 95% of Ewing sarcoma tumors harbor characteristic gene translocations involving the EWSR1 gene.	('EWSR1', 'Gene', '2130', (98, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('Ewing sarcoma tumors', 'Disease', (21, 41))	('gene translocations', 'Var', (64, 83))	('EWSR1', 'Gene', (98, 103))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (21, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))
383848	21793187	These fusion oncogenes are felt to play a critical role in the pathogenesis of these tumors and the formation of these translocations may be the precipitating event in the formation of these tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('translocations', 'Var', (119, 133))	('tumors', 'Disease', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
383853	21793187	We conducted a candidate gene study to attempt to identify other genetic variations that might impact susceptibility to developing Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (131, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (131, 144))	('impact', 'Reg', (95, 101))	('variations', 'Var', (73, 83))	('Ewing sarcoma', 'Disease', (131, 144))
383872	21793187	First, we selected single nucleotide polymorphisms (SNPs) of interest in the EWSR1 gene locus.	('single nucleotide polymorphisms', 'Var', (19, 50))	('EWSR1', 'Gene', (77, 82))	('EWSR1', 'Gene', '2130', (77, 82))
383877	21793187	We therefore also sequenced the entirety of intron 7 to identify possible novel variations that might be associated with the diagnosis of Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (138, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('Ewing sarcoma', 'Disease', (138, 151))	('variations', 'Var', (80, 90))	('associated', 'Reg', (105, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (138, 151))
383883	21793187	As the evaluation of variations in EWSR1 between white and African-American populations was a planned descriptive secondary aim, no statistical comparisons were performed with these data.	('EWSR1', 'Gene', (35, 40))	('EWSR1', 'Gene', '2130', (35, 40))	('variations', 'Var', (21, 31))
383884	21793187	Four SNPs (rs72547438, rs72547439, rs72547473, and rs72547475) showed no variability between groups.	('rs72547439', 'Var', (23, 33))	('rs72547473', 'Mutation', 'rs72547473', (35, 45))	('rs72547438', 'Mutation', 'rs72547438', (11, 21))	('rs72547473', 'Var', (35, 45))	('rs72547475', 'Mutation', 'rs72547475', (51, 61))	('rs72547475', 'Var', (51, 61))	('rs72547439', 'Mutation', 'rs72547439', (23, 33))	('rs72547438', 'Var', (11, 21))
383885	21793187	Two additional SNPs (rs58047811 and rs72547484) showed minor allele frequencies <= 1.5% across the whole study population (0.8% and 1.5%, respectively).	('rs72547484', 'Mutation', 'rs72547484', (36, 46))	('rs58047811', 'Mutation', 'rs58047811', (21, 31))	('rs72547484', 'Var', (36, 46))	('rs58047811', 'Var', (21, 31))
383886	21793187	These six SNPs comprised the entire group of additional non-tagged but validated SNPs that were selected to enrich for SNPs specifically in the EWSR1 breakpoint region.	('SNPs', 'Var', (119, 123))	('EWSR1', 'Gene', (144, 149))	('EWSR1', 'Gene', '2130', (144, 149))
383890	21793187	The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 (intron 1) was 3.57 (95% confidence interval 0.79 - 21.7; p = 0.07).	('Ewing sarcoma', 'Disease', (26, 39))	('rs2857461', 'Var', (96, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('people', 'Species', '9606', (43, 49))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('rs2857461', 'Mutation', 'rs2857461', (96, 105))
383891	21793187	The minor allele frequency at rs2857461 was 5.2% in patients with Ewing sarcoma compared to 1.5% in patients with Wilms tumor.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (66, 79))	('Wilms tumor', 'Disease', (114, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('Ewing sarcoma', 'Disease', (66, 79))	('rs2857461', 'Mutation', 'rs2857461', (30, 39))	('patients', 'Species', '9606', (100, 108))	('Wilms tumor', 'Phenotype', 'HP:0002667', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('rs2857461', 'Var', (30, 39))	('Wilms tumor', 'Disease', 'MESH:D009396', (114, 125))	('patients', 'Species', '9606', (52, 60))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (66, 79))
383898	21793187	In order to better understand racial differences at the EWSR1 locus, we also evaluated variations in our group of 15 SNPs across EWSR1 in white cases with Ewing sarcoma and African-American controls (Table III).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (155, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('EWSR1', 'Gene', (56, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('EWSR1', 'Gene', '2130', (56, 61))	('variations', 'Var', (87, 97))	('EWSR1', 'Gene', (129, 134))	('Ewing sarcoma', 'Disease', (155, 168))	('EWSR1', 'Gene', '2130', (129, 134))
383905	21793187	Given a possible central role for EWSR1 somatic translocation in the pathogenesis of this disease, we focused our efforts on evaluating variation across this gene as a potential risk factor for developing Ewing sarcoma.	('EWSR1', 'Gene', (34, 39))	('variation', 'Var', (136, 145))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (205, 218))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (205, 218))	('EWSR1', 'Gene', '2130', (34, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('Ewing sarcoma', 'Disease', (205, 218))
383906	21793187	We hypothesized that patients with Ewing sarcoma have germline genetic variants in EWSR1 that predispose to somatic translocation at this locus.	('predispose to', 'Reg', (94, 107))	('variants', 'Var', (71, 79))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('EWSR1', 'Gene', (83, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('somatic translocation', 'Disease', (108, 129))	('EWSR1', 'Gene', '2130', (83, 88))	('patients', 'Species', '9606', (21, 29))	('Ewing sarcoma', 'Disease', (35, 48))
383907	21793187	While one EWSR1 SNP (rs2857461) located in intron 1 was present at higher rates in patients with Ewing sarcoma compared to controls, there was only a low level of statistical evidence for this association.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (97, 110))	('EWSR1', 'Gene', (10, 15))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (97, 110))	('rs2857461', 'Var', (21, 30))	('EWSR1', 'Gene', '2130', (10, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('Ewing sarcoma', 'Disease', (97, 110))	('rs2857461', 'Mutation', 'rs2857461', (21, 30))	('patients', 'Species', '9606', (83, 91))
383909	21793187	Therefore, even if this variation is associated with an increased risk of Ewing sarcoma, the majority of patients with Ewing sarcoma did not have this variant.	('patients', 'Species', '9606', (105, 113))	('variation', 'Var', (24, 33))	('Ewing sarcoma', 'Disease', (119, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (74, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (74, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (119, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (119, 132))	('Ewing sarcoma', 'Disease', (74, 87))
383913	21793187	It is not clear if these variants simply reflect expected racial differences or whether these variants are associated with a lower risk of Ewing sarcoma.	('variants', 'Var', (25, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (139, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (139, 152))	('variants', 'Var', (94, 102))	('Ewing sarcoma', 'Disease', (139, 152))
383914	21793187	Future studies may focus specifically on comparing Alu repeat sequences in white patients with Ewing sarcoma and in white controls without Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (139, 152))	('Ewing sarcoma', 'Disease', (95, 108))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (139, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('patients', 'Species', '9606', (81, 89))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (95, 108))	('Alu repeat sequences', 'Var', (51, 71))	('Ewing sarcoma', 'Disease', (139, 152))
383917	21793187	Given that intron 7 of EWSR1 is the most common site of translocation in Ewing sarcoma, our strategy also included full sequencing of this entire intron.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (73, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('translocation', 'Var', (56, 69))	('EWSR1', 'Gene', (23, 28))	('Ewing sarcoma', 'Disease', (73, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (73, 86))	('EWSR1', 'Gene', '2130', (23, 28))	('common', 'Reg', (41, 47))
383923	21793187	While it is possible that these patients harbor germline EWSR1 variants at a rate different from race-matched controls, at least two points argue against this possibility.	('patients', 'Species', '9606', (32, 40))	('EWSR1', 'Gene', (57, 62))	('EWSR1', 'Gene', '2130', (57, 62))	('variants', 'Var', (63, 71))
383925	21793187	In conclusion, variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (109, 122))	('EWSR1', 'Gene', (29, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('associated', 'Reg', (76, 86))	('variations', 'Var', (15, 25))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('EWSR1', 'Gene', '2130', (29, 34))
383962	21331156	Small-molecule inhibitors of tyrosine kinase receptors have been used in the treatment of GISTs, dermatofibrosarcoma protuberans, chronic myelogenous leukemia, and others, demonstrating great therapeutic potential.	('dermatofibrosarcoma protuberans', 'Disease', (97, 128))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (130, 158))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (138, 158))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (130, 158))	('GISTs', 'Phenotype', 'HP:0100723', (90, 95))	('Small-molecule inhibitors', 'Var', (0, 25))	('GISTs', 'Disease', (90, 95))	('chronic myelogenous leukemia', 'Disease', (130, 158))	('inhibitors', 'Var', (15, 25))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (104, 116))
384019	31615436	Two months after discontinuation of pegylated liposomal doxorubicin, he died as a result of wasting and cachexia caused by recurrent sepsis and advanced KS.	('cachexia', 'Disease', (104, 112))	('wasting', 'Disease', (92, 99))	('sepsis', 'Phenotype', 'HP:0100806', (133, 139))	('sepsis', 'Disease', (133, 139))	('pegylated', 'Var', (36, 45))	('cachexia', 'Phenotype', 'HP:0004326', (104, 112))	('sepsis', 'Disease', 'MESH:D018805', (133, 139))	('KS', 'Phenotype', 'HP:0100726', (153, 155))	('KS', 'Disease', 'MESH:D012514', (153, 155))	('doxorubicin', 'Chemical', 'MESH:D004317', (56, 67))	('cachexia', 'Disease', 'MESH:D002100', (104, 112))
384031	31615436	Pegylation of liposomal doxorubicin reduces uptake by reticuloendothelial system (liver or spleen), and therefore maintains high blood concentrations of the drug.	('maintains', 'Reg', (114, 123))	('Pegylation', 'Var', (0, 10))	('high blood concentrations', 'MPA', (124, 149))	('doxorubicin', 'Chemical', 'MESH:D004317', (24, 35))	('reduces', 'NegReg', (36, 43))
384032	31615436	In a study of 509 women with metastatic breast cancer, cardiac toxicity (defined by declining LVEF) during treatment and follow up was less frequently associated with pegylated liposomal doxorubicin than with conventional doxorubicin; cardiotoxicity developed in 4% versus 19% of cases, cardiotoxicity with signs and symptoms of CHF in 0% versus 4% of cases, and cardiotoxicity without signs and symptoms of CHF in 4% versus 15% of cases, respectively.	('cardiotoxicity', 'Disease', (287, 301))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('cardiotoxicity', 'Disease', 'MESH:D066126', (287, 301))	('CHF', 'Disease', 'MESH:D006333', (329, 332))	('CHF', 'Disease', 'MESH:D006333', (408, 411))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('CHF', 'Phenotype', 'HP:0001635', (329, 332))	('CHF', 'Phenotype', 'HP:0001635', (408, 411))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('men', 'Species', '9606', (112, 115))	('cardiotoxicity', 'Disease', (363, 377))	('doxorubicin', 'Chemical', 'MESH:D004317', (222, 233))	('doxorubicin', 'Chemical', 'MESH:D004317', (187, 198))	('cardiotoxicity', 'Disease', 'MESH:D066126', (363, 377))	('CHF', 'Disease', (329, 332))	('CHF', 'Disease', (408, 411))	('pegylated liposomal', 'Var', (167, 186))	('cardiotoxicity', 'Disease', (235, 249))	('cardiac toxicity', 'Disease', 'MESH:D066126', (55, 71))	('cardiac toxicity', 'Disease', (55, 71))	('cardiotoxicity', 'Disease', 'MESH:D066126', (235, 249))	('women', 'Species', '9606', (18, 23))	('men', 'Species', '9606', (20, 23))
384033	31615436	Several trials and case reports of breast and gynecological cancer have shown that patients treated with pegylated liposomal doxorubicin showed no signs or symptoms of CHF, even when they received a cumulative dose of pegylated liposomal doxorubicin > 1000 mg/m2.	('CHF', 'Disease', 'MESH:D006333', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('breast', 'Disease', (35, 41))	('CHF', 'Phenotype', 'HP:0001635', (168, 171))	('cancer', 'Disease', (60, 66))	('doxorubicin', 'Chemical', 'MESH:D004317', (238, 249))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('patients', 'Species', '9606', (83, 91))	('pegylated liposomal', 'Var', (105, 124))	('doxorubicin', 'Chemical', 'MESH:D004317', (125, 136))	('breast', 'Disease', 'MESH:D061325', (35, 41))	('CHF', 'Disease', (168, 171))
384169	24707262	It is a mesenchymal tumor with varied epithelial differentiation and is frequently associated with a translocation between chromosomes X and 18.	('translocation', 'Var', (101, 114))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('associated', 'Reg', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
384173	24707262	A 26-year-old Caucasian female, G2P1, at 21 weeks' gestation with no other significant medical history presented to a community hospital with a dry cough and right-sided pleuritic chest pain, which radiated to her right shoulder.	('dry cough', 'Disease', (144, 153))	('pleuritic chest pain', 'Disease', 'MESH:D002637', (170, 190))	('pleuritic chest pain', 'Disease', (170, 190))	('pain', 'Phenotype', 'HP:0012531', (186, 190))	('dry cough', 'Disease', 'MESH:D003371', (144, 153))	('chest pain', 'Phenotype', 'HP:0100749', (180, 190))	('G2P1', 'Var', (32, 36))	('pleuritic chest', 'Phenotype', 'HP:0002102', (170, 185))	('dry cough', 'Phenotype', 'HP:0031246', (144, 153))	('cough', 'Phenotype', 'HP:0012735', (148, 153))
384224	23527175	We further demonstrate that re-expression of SPRY1, a repressed target of BCL11B, limits the transformation capacity of Ewing sarcoma cells.	('SPRY1', 'Gene', '10252', (45, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('SPRY1', 'Gene', (45, 50))	('Ewing sarcoma', 'Disease', (120, 133))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (120, 133))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (120, 133))	('limits', 'NegReg', (82, 88))	('re-expression', 'Var', (28, 41))
384245	23527175	In addition, mouse models of both TLX1 driven T-ALL and gamma-ray induced thymic lymphomas had spontaneous deletions and mutations in Bcl11b .	('mouse', 'Species', '10090', (13, 18))	('lymphomas', 'Phenotype', 'HP:0002665', (81, 90))	('mutations', 'Var', (121, 130))	('TLX1', 'Gene', '21908', (34, 38))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('Bcl11b', 'Gene', (134, 140))	('deletions', 'Var', (107, 116))	('lymphomas', 'Disease', (81, 90))	('TLX1', 'Gene', (34, 38))	('lymphomas', 'Disease', 'MESH:D008223', (81, 90))	('T-ALL', 'Phenotype', 'HP:0006727', (46, 51))
384254	23527175	Small interfering RNA (siRNA) transfections (siBCL11B: A673 6.25 nM and TC71 25 nM; siNCOR1: A673 25 nM) were carried out according the manufacturer's instructions (ThermoFisher).	('TC71', 'Var', (72, 76))	('TC71', 'CellLine', 'CVCL:2213', (72, 76))	('A673 6.25 nM', 'Var', (55, 67))	('NCOR1', 'Gene', '9611', (86, 91))	('NCOR1', 'Gene', (86, 91))
384256	23527175	Endpoint was dictated by the ability to see colonies on control plate (approximately 2-4 weeks; e.g., A673 form colonies faster than TC71), and was internally consistent for all experiments.	('TC71', 'CellLine', 'CVCL:2213', (133, 137))	('A673', 'Var', (102, 106))	('colonies', 'CPA', (112, 120))
384279	23527175	Of the 118 genes repressed by BCL11B, 55 genes were also repressed by EWS/FLI (p = 2.55x10-24; Figure 3B).	('FLI', 'Gene', (74, 77))	('FLI', 'Gene', '2314', (74, 77))	('BCL11B', 'Var', (30, 36))
384288	23527175	We then validated the results from the EWS/FLI microarray by knocking down EWS/FLI in A673 cells and again observing an increased expression of these four genes (Figure 4B).	('expression', 'MPA', (130, 140))	('FLI', 'Gene', (43, 46))	('FLI', 'Gene', '2314', (79, 82))	('FLI', 'Gene', (79, 82))	('knocking down', 'Var', (61, 74))	('increased', 'PosReg', (120, 129))	('FLI', 'Gene', '2314', (43, 46))
384294	23527175	We tested the necessity of these three co-repressors in BCL11B-mediated repression in Ewing sarcoma cells by shRNA knock-down for chomodomain helicase DNA binding protein 4 (CHD4), the core component of the NuRD complex, or chemical inhibitors targeting SUV39H1 or SIRT1.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (86, 99))	('SUV39H1', 'Gene', '6839', (254, 261))	('CHD4', 'Gene', '1108', (174, 178))	('chomodomain helicase DNA binding protein 4', 'Gene', '1108', (130, 172))	('tested', 'Reg', (3, 9))	('SIRT1', 'Gene', (265, 270))	('Ewing sarcoma', 'Disease', (86, 99))	('chomodomain helicase DNA binding protein 4', 'Gene', (130, 172))	('knock-down', 'Var', (115, 125))	('CHD4', 'Gene', (174, 178))	('SIRT1', 'Gene', '23411', (265, 270))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('BCL11B-mediated', 'Gene', (56, 71))	('SUV39H1', 'Gene', (254, 261))
384298	23527175	In contrast to SIRT1 and SUV39H1, we found that targeting of the core NuRD component CHD4, using a retroviral shRNA in A673 cells, increased expression of NCEH1, SPRY1, ADORA1, and TGFBR1 (Figure 5A), while levels of BCL11B were unchanged.	('SIRT1', 'Gene', '23411', (15, 20))	('SPRY1', 'Gene', '10252', (162, 167))	('SUV39H1', 'Gene', '6839', (25, 32))	('NCEH1', 'Gene', '57552', (155, 160))	('SPRY1', 'Gene', (162, 167))	('increased', 'PosReg', (131, 140))	('SIRT1', 'Gene', (15, 20))	('CHD4', 'Gene', '1108', (85, 89))	('NCEH1', 'Gene', (155, 160))	('TGFBR1', 'Gene', (181, 187))	('ADORA1', 'Gene', '134', (169, 175))	('ADORA1', 'Gene', (169, 175))	('expression', 'MPA', (141, 151))	('CHD4', 'Gene', (85, 89))	('TGFBR1', 'Gene', '7046', (181, 187))	('targeting', 'Var', (48, 57))	('SUV39H1', 'Gene', (25, 32))
384303	23527175	It must be noted that HCI-2509 also decreased the expression of BCL11B at this dose (Figure 5C), rendering interpretation of this result difficult.	('BCL11B', 'Gene', (64, 70))	('HCI-2509', 'Var', (22, 30))	('HCI-2509', 'Chemical', '-', (22, 30))	('expression', 'MPA', (50, 60))	('decreased', 'NegReg', (36, 45))
384305	23527175	Knock-down of NCOR1 had no effect on the BCL11B repressed genes (Figure S1C).	('NCOR1', 'Gene', '9611', (14, 19))	('NCOR1', 'Gene', (14, 19))	('Knock-down', 'Var', (0, 10))	('BCL11B repressed genes', 'Gene', (41, 63))
384315	23527175	The dramatic decrease in BCL11B expression levels with EWS/FLI knock-down suggests that BCL11B is not normally expressed in the Ewing sarcoma cell of origin.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('FLI', 'Gene', '2314', (59, 62))	('decrease', 'NegReg', (13, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('knock-down', 'Var', (63, 73))	('FLI', 'Gene', (59, 62))	('BCL11B expression levels', 'MPA', (25, 49))	('Ewing sarcoma', 'Disease', (128, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
384319	23527175	There are however variant ETS sites in BCL11B's promoter/enhancer region that may allow for EWS/FLI binding and warrant further investigation.	('FLI', 'Gene', '2314', (96, 99))	('binding', 'Interaction', (100, 107))	('FLI', 'Gene', (96, 99))	('BCL11B', 'Gene', (39, 45))	('allow', 'Reg', (82, 87))	('variant', 'Var', (18, 25))
384322	23527175	Mutations or deletions of the BCL11B gene are found in 9-16% of human T-ALL where it is thought to be a haploinsufficient tumor suppressor.	('human', 'Species', '9606', (64, 69))	('BCL11B', 'Gene', (30, 36))	('human T-ALL', 'Disease', (64, 75))	('deletions', 'Var', (13, 22))	('T-ALL', 'Phenotype', 'HP:0006727', (70, 75))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (104, 127))	('haploinsufficient tumor', 'Disease', (104, 127))	('found', 'Reg', (46, 51))
384323	23527175	Loss of one allele via the involvement of BCL11B in translocations in this malignancy as well as distinct mutations often found in the zinc finger region may contribute to the oncogenic process in part by preventing differentiation.	('translocations', 'Var', (52, 66))	('differentiation', 'CPA', (216, 231))	('BCL11B', 'Gene', (42, 48))	('preventing', 'NegReg', (205, 215))	('contribute', 'Reg', (158, 168))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('malignancy', 'Disease', (75, 85))
384324	23527175	Moreover in a mouse model of thymic lymphoma, spontaneous homozygous deletions and point mutations occurred in Bcl11b.	('Bcl11b', 'Gene', (111, 117))	('mouse', 'Species', '10090', (14, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (36, 44))	('deletions', 'Var', (69, 78))	('point mutations', 'Var', (83, 98))	('lymphoma', 'Disease', (36, 44))	('lymphoma', 'Disease', 'MESH:D008223', (36, 44))
384325	23527175	This group also found that ectopic expression of Bcl11b in HeLa cells suppressed cell growth.	('Bcl11b', 'Gene', (49, 55))	('cell growth', 'CPA', (81, 92))	('suppressed', 'NegReg', (70, 80))	('HeLa', 'CellLine', 'CVCL:0030', (59, 63))	('ectopic expression', 'Var', (27, 45))
384328	23527175	For example, BCL11B has been implicated in cell cycle progression by directly repressing the cell cycle inhibitors p21WAF1 and p57KIP2 in microglial cells and SK-N-MC (which were originally characterized as a neuroblastoma cell line, but are in fact a Ewing cell line) cells, respectively.	('neuroblastoma', 'Phenotype', 'HP:0003006', (209, 222))	('BCL11B', 'Gene', (13, 19))	('p57KIP2', 'Gene', (127, 134))	('p21WAF1', 'Var', (115, 122))	('SK-N-MC', 'CellLine', 'CVCL:0530', (159, 166))	('neuroblastoma', 'Disease', 'MESH:D009447', (209, 222))	('cell cycle', 'Gene', (93, 103))	('repressing', 'NegReg', (78, 88))	('neuroblastoma', 'Disease', (209, 222))	('p57KIP2', 'Gene', '1028', (127, 134))
384338	23527175	The mechanism for HCI-2509 is unclear due to the fact that BCL11B levels are also somewhat reduced.	('HCI-2509', 'Chemical', '-', (18, 26))	('reduced', 'NegReg', (91, 98))	('HCI-2509', 'Var', (18, 26))	('BCL11B levels', 'MPA', (59, 72))
384341	23527175	We have shown that the re-expression of the BCL11B repressed gene, SPRY1, reduces the transformation potential of Ewing sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('re-expression', 'Var', (23, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (114, 127))	('SPRY1', 'Gene', '10252', (67, 72))	('SPRY1', 'Gene', (67, 72))	('Ewing sarcoma', 'Disease', (114, 127))	('reduces', 'NegReg', (74, 81))
384344	23527175	Spry1 is also known to inhibit phospholipase C (PLC) activation, and during Xenopus mesoderm development, Xtsprouty inhibits the PLC pathway while still allowing for RAS/ERK signaling.	('Spry1', 'Gene', '100192368', (0, 5))	('Spry1', 'Gene', (0, 5))	('allowing', 'Reg', (153, 161))	('PLC pathway', 'Pathway', (129, 140))	('Xtsprouty', 'Var', (106, 115))	('inhibit', 'NegReg', (23, 30))	('ERK', 'Gene', (170, 173))	('Xenopus', 'Species', '8355', (76, 83))	('phospholipase C', 'Enzyme', (31, 46))	('ERK', 'Gene', '5595;5594;5595', (170, 173))	('inhibits', 'NegReg', (116, 124))
384348	23527175	Here we have shown the aberrant expression of BCL11B in Ewing sarcoma cell lines represses a subset of the EWS/FLI repressed gene signature and contributes to the transformed phenotype.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('aberrant', 'Var', (23, 31))	('BCL11B', 'Gene', (46, 52))	('contributes', 'Reg', (144, 155))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('Ewing sarcoma', 'Disease', (56, 69))	('FLI', 'Gene', '2314', (111, 114))	('transformed', 'MPA', (163, 174))	('FLI', 'Gene', (111, 114))	('represses', 'NegReg', (81, 90))
384400	32911724	Univariate analysis revealed that DFS was significantly influenced by advanced stage (III/IV) of sarcoma, subtype of leiomyosarcoma, high mitotic index, preoperative high NLR, and preoperative high PLR.	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (117, 131))	('sarcoma', 'Disease', (124, 131))	('high PLR', 'Var', (193, 201))	('high', 'Var', (133, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('DFS', 'MPA', (34, 37))	('sarcoma', 'Disease', (97, 104))	('leiomyosarcoma', 'Disease', (117, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (117, 131))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('high', 'Var', (166, 170))	('influenced', 'Reg', (56, 66))
384401	32911724	Univariate analysis revealed that advanced stage (III/IV), subtype of leiomyosarcoma, high mitotic index, nuclear atypia, and preoperative high NLR were significant factors associated with OS.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (70, 84))	('nuclear atypia', 'CPA', (106, 120))	('associated', 'Reg', (173, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('leiomyosarcoma', 'Disease', (70, 84))	('high', 'Var', (86, 90))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (70, 84))
384410	32911724	Patients with old age, advanced stage, high tumor grade, and high mitotic index have been found to have worse prognosis.	('high', 'Var', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
384422	32911724	In the area of gynecological cancer, several studies have reported that high NLR is associated with OS and DFS in patients with ovarian, endometrial, or cervical cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (162, 168))	('NLR', 'Gene', (77, 80))	('ovarian', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('ovarian', 'Disease', 'MESH:D010049', (128, 135))	('endometrial', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('associated', 'Reg', (84, 94))	('DFS', 'Disease', (107, 110))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('high', 'Var', (72, 76))
384436	32911724	Our data also showed that high NLR was significantly associated with worse DFS and worse OS of not only advanced stage patients, but also patients with stage I uterine sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (160, 175))	('high', 'Var', (26, 30))	('patients', 'Species', '9606', (119, 127))	('NLR', 'Gene', (31, 34))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('patients', 'Species', '9606', (138, 146))	('sarcoma', 'Disease', (168, 175))	('DFS', 'MPA', (75, 78))
384441	32911724	Our findings suggested that patients in the early stage with high NLR ratio should be considered as having a high risk of poor prognosis.	('patients', 'Species', '9606', (28, 36))	('high', 'Var', (61, 65))	('NLR', 'MPA', (66, 69))
384501	32082998	Subgroup analytical studies illustrated that PLR had significant prognostic effect for OS and DFS in most subgroups, while the mixed treatment group on OS and DFS Caucasian ethnicity group had no significant prognostic value (Table 4).	('PLR', 'Var', (45, 48))	('OS', 'Chemical', '-', (87, 89))	('DFS', 'Disease', (94, 97))	('OS', 'Chemical', '-', (152, 154))
384549	32082998	However, most high scores are caused by abnormalities in CRP.	('caused by', 'Reg', (30, 39))	('CRP', 'Gene', '1401', (57, 60))	('CRP', 'Gene', (57, 60))	('abnormalities', 'Var', (40, 53))
384562	32082998	Our research shows that hematological markers are one of the important prognostic indicators for patients affected by high-grade STS and patients with the STS being located in the extremity.	('STS', 'Disease', (155, 158))	('STS', 'Disease', 'MESH:D012509', (155, 158))	('patients', 'Species', '9606', (137, 145))	('high-grade', 'Var', (118, 128))	('STS', 'Phenotype', 'HP:0030448', (129, 132))	('STS', 'Disease', (129, 132))	('STS', 'Phenotype', 'HP:0030448', (155, 158))	('STS', 'Disease', 'MESH:D012509', (129, 132))	('patients', 'Species', '9606', (97, 105))
384593	30228850	An extensive genetic workup including a STAT workup for pathogenic variants of 9 genes associated with increased risk for breast cancer were all negative, including TP53 which has been linked to several malignancies including sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('TP53', 'Gene', (165, 169))	('linked', 'Reg', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('sarcomas', 'Disease', (226, 234))	('malignancies', 'Disease', 'MESH:D009369', (203, 215))	('TP53', 'Gene', '7157', (165, 169))	('malignancies', 'Disease', (203, 215))	('sarcomas', 'Disease', 'MESH:D012509', (226, 234))	('variants', 'Var', (67, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (226, 234))
384595	30228850	A variant of uncertain significance in the FLCN tumor suppressor gene was identified, which has been associated with increased risk of some clear cell RCC and colon cancers, but it is unclear whether this variant was the cause of this patient's condition.	('patient', 'Species', '9606', (235, 242))	('colon cancers', 'Disease', (159, 172))	('tumor', 'Disease', (48, 53))	('variant', 'Var', (2, 9))	('FLCN', 'Gene', '201163', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('colon cancers', 'Phenotype', 'HP:0003003', (159, 172))	('colon cancers', 'Disease', 'MESH:D015179', (159, 172))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('associated', 'Reg', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('RCC', 'Disease', (151, 154))	('FLCN', 'Gene', (43, 47))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
384603	30228850	A case series of five PPS's, reports misdiagnosis by FNA in two cases, with one case correctly diagnosed by intraoral open biopsy.	('FNA', 'Gene', (53, 56))	('misdiagnosis', 'Var', (37, 49))	('PPS', 'Chemical', '-', (22, 25))
384652	30158830	Mutations in proteins and/or aberrant proteins expressed by tumor cells and the "neoantigens" they generate are the primary targets for T-cell-mediated destruction.	('proteins', 'Protein', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('proteins', 'Protein', (13, 21))
384673	30158830	For example, approximately 13% of angiosarcomas manifest mutation frequencies of more than 20 per Mb.	('mutation', 'Var', (57, 65))	('angiosarcomas', 'Disease', (34, 47))	('angiosarcoma', 'Phenotype', 'HP:0200058', (34, 46))	('angiosarcomas', 'Phenotype', 'HP:0200058', (34, 47))	('angiosarcomas', 'Disease', 'MESH:D006394', (34, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))
384674	30158830	It should be noted that tumor microsatellite instability, which is an indication for treatment with PD-1 inhibitors because of the associated increase in mutations, is not considered to play a major role in soft tissue sarcoma tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (207, 226))	('increase', 'PosReg', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', (24, 29))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (207, 226))	('PD-1', 'Gene', (100, 104))	('soft tissue sarcoma', 'Disease', (207, 226))	('mutations', 'MPA', (154, 163))	('microsatellite', 'Var', (30, 44))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
384683	30158830	In some studies, including studies of patients with GIST, angiosarcoma, leiomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma, the presence of TILs has been associated with improved prognosis.	('presence', 'Var', (152, 160))	('TILs', 'Gene', (164, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('patients', 'Species', '9606', (38, 46))	('angiosarcoma', 'Disease', 'MESH:D006394', (58, 70))	('synovial sarcoma', 'Disease', (88, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('angiosarcoma', 'Phenotype', 'HP:0200058', (58, 70))	('GIST', 'Phenotype', 'HP:0100723', (52, 56))	('synovial sarcoma', 'Disease', 'MESH:D013584', (88, 104))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (72, 86))	('angiosarcoma', 'Disease', (58, 70))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (72, 86))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (110, 146))	('improved', 'PosReg', (194, 202))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (88, 104))	('undifferentiated pleomorphic sarcoma', 'Disease', (110, 146))	('leiomyosarcoma', 'Disease', (72, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))
384685	30158830	In several cancer types, CD3+ and CD8+ TILs have been most strongly associated with improved survival.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CD8', 'Gene', (34, 37))	('survival', 'CPA', (93, 101))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('improved', 'PosReg', (84, 92))	('CD8', 'Gene', '925', (34, 37))	('CD3+', 'Var', (25, 29))	('cancer', 'Disease', (11, 17))
384713	30158830	Activity was significantly enhanced when combining anti-PD-1 antibody with antibody against the coinhibitory receptor, LAG-3.	('enhanced', 'PosReg', (27, 35))	('anti-PD-1', 'Var', (51, 60))	('LAG-3', 'Gene', (119, 124))	('Activity', 'MPA', (0, 8))	('LAG-3', 'Gene', '3902', (119, 124))	('combining', 'Interaction', (41, 50))
384728	30158830	The expression of transforming growth factor (TGF) beta, a cytokine that inhibits antitumor immunity by several mechanisms, has been associated with a poorer survival in soft tissue sarcoma.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (170, 189))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('tumor', 'Disease', (86, 91))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (170, 189))	('poorer', 'NegReg', (151, 157))	('inhibits', 'NegReg', (73, 81))	('soft tissue sarcoma', 'Disease', (170, 189))	('expression', 'Var', (4, 14))	('transforming growth factor (TGF) beta', 'Gene', '7040', (18, 55))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('associated', 'Reg', (133, 143))
384734	30158830	They identified PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.	('reduced', 'NegReg', (35, 42))	('PTEN', 'Gene', (16, 20))	('PTEN', 'Gene', '5728', (16, 20))	('expression', 'MPA', (43, 53))	('mutations', 'Var', (21, 30))
384774	30158830	Sarcomas manifest a high frequency of p53 mutations and functional p53 inactivation.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('inactivation', 'NegReg', (71, 83))	('mutations', 'Var', (42, 51))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
384776	30158830	ONCOS-102 is an adenovirus with an engineered capsid for enhanced cancer cell transduction and a deletion in the E1A gene, which also promotes proliferation, that binds the tumor suppressor, the retinoblastoma protein (Rb), rendering the viral replication to cells that lack Rb, also commonly observed in soft tissue sarcoma.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('E1A', 'Gene', (113, 116))	('promotes', 'PosReg', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('enhanced', 'PosReg', (57, 65))	('retinoblastoma', 'Gene', '5925', (195, 209))	('retinoblastoma', 'Phenotype', 'HP:0009919', (195, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (317, 324))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('deletion', 'Var', (97, 105))	('retinoblastoma', 'Gene', (195, 209))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (305, 324))	('viral replication', 'MPA', (238, 255))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (305, 324))	('tumor', 'Disease', (173, 178))	('soft tissue sarcoma', 'Disease', (305, 324))	('proliferation', 'CPA', (143, 156))	('cancer', 'Disease', (66, 72))
384777	30158830	Because deletion of the RL1 gene and the gamma134.5 gene, respectively, both which encode virulence factors and the herpes virus vectors HSV1716 and HSV-1 M002, is unable to replicate in nondividing cells, and preferentially infect, replicate in, and lyse rapidly dividing cells such as tumor cells.	('infect', 'CPA', (225, 231))	('preferentially', 'PosReg', (210, 224))	('RL1', 'Gene', '2703396', (24, 27))	('HSV-1', 'Species', '10298', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('replicate in', 'CPA', (233, 245))	('tumor', 'Disease', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('lyse', 'CPA', (251, 255))	('RL1', 'Gene', (24, 27))	('deletion', 'Var', (8, 16))
384783	30158830	Neutralizing antibodies are highly prevalent and can reduce the efficacy of repeat injections although how antivector immunity influences the clinical or biologic response of intratumoral virotherapy is not known.	('reduce', 'NegReg', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('efficacy', 'MPA', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('influences', 'Reg', (127, 137))	('tumor', 'Disease', (180, 185))	('Neutralizing antibodies', 'Var', (0, 23))
384791	30158830	A freeze-stored allogeneic DC preparation, known as INTOVAX, in which DC derived from blood of healthy donors with GM-CSF and IL-4 are 17 activated with toll-like receptor (TLR) 7/8 agonist R848and TLR3 agonist Poly I:C, and human recombinant interferon gamma is under investigation.	('Poly I:C', 'Chemical', 'MESH:D011070', (211, 219))	('TLR3', 'Gene', '7098', (198, 202))	('TLR', 'Gene', (173, 176))	('interferon gamma', 'Gene', '3458', (243, 259))	('IL-4', 'Gene', (126, 130))	('GM-CSF', 'Gene', '1437', (115, 121))	('TLR', 'Gene', '7098;54106', (173, 176))	('human', 'Species', '9606', (225, 230))	('IL-4', 'Gene', '3565', (126, 130))	('TLR3', 'Gene', (198, 202))	('TLR', 'Gene', (198, 201))	('GM-CSF', 'Gene', (115, 121))	('R848and', 'Var', (190, 197))	('TLR', 'Gene', '7098;54106', (198, 201))	('interferon gamma', 'Gene', (243, 259))
384804	30158830	The sequential intratumoral and intramuscular injections of the synthetic PAMP, polyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose (Poly-ICLC), has been reported to be active in sarcoma.	('synthetic', 'Species', '32630', (64, 73))	('sarcoma', 'Disease', 'MESH:D012509', (193, 200))	('Poly-ICLC', 'Chemical', '-', (147, 156))	('active', 'MPA', (183, 189))	('sarcoma', 'Disease', (193, 200))	('polyinosinic-polycytidylic', 'Var', (80, 106))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('polyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose', 'Chemical', '-', (80, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
384845	29942495	Currently available immunosuppressive agents influence different anticancer pathways and mammalian target of rapamycin (mTOR) inhibitors have been reported to have a decreased cancer risk compared with alternative immunosuppressive therapies.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mTOR', 'Gene', '2475', (120, 124))	('inhibitors', 'Var', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mammalian target of rapamycin', 'Gene', '2475', (89, 118))	('mammalian target of rapamycin', 'Gene', (89, 118))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('decreased', 'NegReg', (166, 175))	('influence', 'Reg', (45, 54))	('mTOR', 'Gene', (120, 124))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (69, 75))
384847	29942495	While some studies have suggested an association between antibody induction and cancer after transplantation, others have failed to demonstrate this association.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('antibody', 'Var', (57, 65))	('cancer', 'Disease', (80, 86))
384882	29942495	Regarding outcome, early donor-transmitted cancer (diagnosed <=6 weeks of transplantation) was associated with a better outcome compared with late donor-transmitted cancer; 5-year survival was 83% for kidney recipients with donor-transmitted cancer compared with 93% for recipients without donor-transmitted cancer (P = 0.077).	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (43, 49))	('donor-transmitted', 'Var', (224, 241))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('cancer', 'Disease', (308, 314))	('donor', 'Species', '9606', (290, 295))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('donor', 'Species', '9606', (147, 152))	('donor', 'Species', '9606', (25, 30))	('donor', 'Species', '9606', (224, 229))
384912	29942495	More than 50% of PTLD cases are EBV related, and EBV mismatch between donor and recipient (an EBV-negative receptor engrafted with an EBV-positive donor) is associated with a 20-fold increased risk for PTLD.	('EBV', 'Species', '10376', (49, 52))	('EBV', 'Species', '10376', (94, 97))	('PTLD', 'Disease', (17, 21))	('PTLD', 'Disease', (202, 206))	('EBV', 'Species', '10376', (32, 35))	('PTLD', 'Disease', 'MESH:D008232', (17, 21))	('PTLD', 'Disease', 'MESH:D008232', (202, 206))	('EBV', 'Species', '10376', (134, 137))	('donor', 'Species', '9606', (147, 152))	('donor', 'Species', '9606', (70, 75))	('mismatch', 'Var', (53, 61))
384941	29942495	As both CD4+ and CD8+ T cells are crucial in adaptive antiviral immunity, depletion of both populations of T cells with T cell-depleting antibodies would increase the susceptibility of individuals to a higher risk of virus-associated diseases.	('depletion', 'Var', (74, 83))	('CD8', 'Gene', (17, 20))	('CD4', 'Gene', (8, 11))	('CD8', 'Gene', '925', (17, 20))	('virus-associated diseases', 'Disease', (217, 242))	('CD4', 'Gene', '920', (8, 11))	('susceptibility', 'MPA', (167, 181))	('increase', 'PosReg', (154, 162))
384944	29942495	The immunosuppressive potency of OKT3 is greater than that of polyclonal lymphocyte-depleting agents and the use of OKT3 has clearly been associated with an increase in lymphoma risk.	('lymphoma', 'Disease', 'MESH:D008223', (169, 177))	('OKT3', 'Gene', (116, 120))	('lymphoma', 'Phenotype', 'HP:0002665', (169, 177))	('use', 'Var', (109, 112))	('associated', 'Reg', (138, 148))	('lymphoma', 'Disease', (169, 177))
384952	29942495	Also, a study of the SRTR and the United States Renal Data System databases reported similar results (70% increased risk of PTLD in renal transplant recipients receiving monoclonal and/or polyclonal T cell-depleting antibodies as induction therapy).	('PTLD', 'Disease', 'MESH:D008232', (124, 128))	('PTLD', 'Disease', (124, 128))	('monoclonal', 'Var', (170, 180))
384959	29942495	evaluated the rate of PTLD in recipients of kidney or heart allografts and pointed to the importance of antiviral prophylaxis, as in this study; the absence of antiviral prophylaxis was the greatest risk factor for the development of PTLD rather than the use of induction therapy.	('PTLD', 'Disease', (22, 26))	('PTLD', 'Disease', 'MESH:D008232', (22, 26))	('PTLD', 'Disease', (234, 238))	('PTLD', 'Disease', 'MESH:D008232', (234, 238))	('absence', 'Var', (149, 156))
384962	29942495	In a recent observation study, rATG was associated with a decreased risk of adverse outcomes (including mortality) compared with alemtuzumab and basiliximab as induction therapy.	('decreased', 'NegReg', (58, 67))	('alemtuzumab', 'Chemical', 'MESH:D000074323', (129, 140))	('adverse outcomes', 'MPA', (76, 92))	('basiliximab', 'Chemical', 'MESH:D000077552', (145, 156))	('rATG', 'Var', (31, 35))
384966	29942495	Calcineurin inhibitors: In kidney transplant recipients, both cyclosporine and tacrolimus are associated with an increased risk of malignancy.	('cyclosporine', 'Var', (62, 74))	('cyclosporine', 'Chemical', 'MESH:D016572', (62, 74))	('malignancy', 'Disease', 'MESH:D009369', (131, 141))	('tacrolimus', 'Chemical', 'MESH:D016559', (79, 89))	('malignancy', 'Disease', (131, 141))
384967	29942495	In a French prospective randomized study involving 231 renal allograft recipients, low-dose (75-125 ng/mL) cyclosporine was associated with a lower incidence of secondary cancers (particularly skin cancers) compared with normal-dose (150-250 ng/mL) cyclosporine at a median of 66 months follow-up.	('secondary cancers', 'Disease', 'MESH:D009369', (161, 178))	('cyclosporine', 'Var', (107, 119))	('cyclosporine', 'Chemical', 'MESH:D016572', (107, 119))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('skin cancers', 'Disease', 'MESH:D012878', (193, 205))	('secondary cancers', 'Disease', (161, 178))	('lower', 'NegReg', (142, 147))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cyclosporine', 'Chemical', 'MESH:D016572', (249, 261))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('skin cancer', 'Phenotype', 'HP:0008069', (193, 204))	('skin cancers', 'Phenotype', 'HP:0008069', (193, 205))	('skin cancers', 'Disease', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
384971	29942495	An analysis of the CTS demonstrated that cyclosporine did not confer added risk for the development of NHL compared with azathioprine/steroid treatment, whereas treatment with FK506 increased the risk approximately 2-fold.	('steroid', 'Chemical', 'MESH:D013256', (134, 141))	('cyclosporine', 'Chemical', 'MESH:D016572', (41, 53))	('azathioprine', 'Chemical', 'MESH:D001379', (121, 133))	('FK506', 'Chemical', 'MESH:D016559', (176, 181))	('NHL', 'Disease', (103, 106))	('NHL', 'Disease', 'MESH:D008228', (103, 106))	('FK506', 'Var', (176, 181))	('NHL', 'Phenotype', 'HP:0012539', (103, 106))
384973	29942495	Furthermore, azathioprine is associated with the development of myelodysplastic syndrome.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (64, 88))	('azathioprine', 'Chemical', 'MESH:D001379', (13, 25))	('associated', 'Reg', (29, 39))	('azathioprine', 'Var', (13, 25))	('myelodysplastic syndrome', 'Disease', (64, 88))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (64, 88))
384975	29942495	An SRTR analysis reported that the introduction of mycophenolate mofetil was associated with the greatest decrease in relative risk for the development of PTLD.	('PTLD', 'Disease', 'MESH:D008232', (155, 159))	('decrease', 'NegReg', (106, 114))	('mycophenolate mofetil', 'Chemical', 'MESH:D009173', (51, 72))	('mycophenolate', 'Var', (51, 64))	('PTLD', 'Disease', (155, 159))
384979	29942495	In humans, evidence suggests that sirolimus may confer a decreased risk of malignancy compared with other immunosuppressive medications.	('humans', 'Species', '9606', (3, 9))	('decreased', 'NegReg', (57, 66))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('sirolimus', 'Var', (34, 43))	('malignancy', 'Disease', (75, 85))	('sirolimus', 'Chemical', 'MESH:D020123', (34, 43))
384981	29942495	In the TUMORAPA study, where patients with a history of squamous cell carcinoma were studied, conversion to sirolimus significantly reduced the risk for relapse when compared with those who were maintained on calcineurin inhibitor-based therapy.	('patients', 'Species', '9606', (29, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('calcineurin inhibitor', 'Gene', (209, 230))	('squamous cell carcinoma', 'Disease', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('sirolimus', 'Chemical', 'MESH:D020123', (108, 117))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 79))	('reduced', 'NegReg', (132, 139))	('calcineurin inhibitor', 'Gene', '23523', (209, 230))	('conversion', 'Var', (94, 104))
384986	29942495	The incidence of prostate cancer was higher during sirolimus use (hazard ratio 1.86), while the incidence of other cancers was similar or lower, with a 26% decrease in overall cancer incidence excluding prostate carcinoma (hazard ratio 0.74).	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('prostate carcinoma', 'Disease', 'MESH:D011472', (203, 221))	('cancer', 'Disease', (26, 32))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('decrease', 'NegReg', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (17, 32))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (203, 221))	('prostate cancer', 'Phenotype', 'HP:0012125', (17, 32))	('higher', 'PosReg', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('prostate cancer', 'Disease', (17, 32))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('prostate carcinoma', 'Disease', (203, 221))	('sirolimus', 'Var', (51, 60))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('sirolimus', 'Chemical', 'MESH:D020123', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (176, 182))
384989	29942495	In the meta-analysis of Knoll et al., including 21 randomized controlled trials with patient-level data from 5876 patients, it was demonstrated that sirolimus was associated with a 40% reduction in malignancy risk and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls.	('patient', 'Species', '9606', (85, 92))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('sirolimus', 'Var', (149, 158))	('skin cancer', 'Phenotype', 'HP:0008069', (262, 273))	('sirolimus', 'Chemical', 'MESH:D020123', (149, 158))	('patient', 'Species', '9606', (114, 121))	('reduction', 'NegReg', (224, 233))	('malignancy', 'Disease', 'MESH:D009369', (198, 208))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (249, 273))	('malignancy', 'Disease', (198, 208))	('reduction', 'NegReg', (185, 194))	('non-melanoma skin cancer', 'Disease', (249, 273))	('patients', 'Species', '9606', (114, 122))
385030	29942495	Moreover, cancer-related mortality rates are also higher in solid organ transplant recipients compared with the general population.	('higher', 'PosReg', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('solid organ transplant', 'Var', (60, 82))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
385042	29795990	Multivariate analysis revealed that age under 40 years, localized stage, low grade, surgical treatment, and first primary tumor were associated with improved OS, and decade of diagnosis, stage, grade, and surgery were independent predictors of CSS.	('CSS', 'Chemical', '-', (244, 247))	('low grade', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('improved', 'PosReg', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CSS', 'Disease', (244, 247))	('OS', 'Chemical', '-', (158, 160))	('tumor', 'Disease', (122, 127))
385057	29795990	All primary tumors that originated in the short bones were identified using the lesion number C40.1 (short bones of upper limb and associated joints) and C40.3 (short bones of lower limb and associated joints).	('short bones', 'Phenotype', 'HP:0003026', (161, 172))	('short bone', 'Phenotype', 'HP:0003026', (161, 171))	('lower limb', 'Phenotype', 'HP:0006385', (176, 186))	('short bones', 'Phenotype', 'HP:0003026', (42, 53))	('C40.3', 'Var', (154, 159))	('short bones of lower limb', 'Phenotype', 'HP:0009816', (161, 186))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('short bones', 'Phenotype', 'HP:0003026', (101, 112))	('short bone', 'Phenotype', 'HP:0003026', (101, 111))	('tumors', 'Disease', (12, 18))	('C40.1', 'Var', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('short bones of upper limb', 'Phenotype', 'HP:0009824', (101, 126))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('short bone', 'Phenotype', 'HP:0003026', (42, 52))
385058	29795990	The International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) was then used to identify patients with chondrosarcoma (ICD-O-3 codes 9180, 9220, 9221, 9231, 9240, 9242, and 9243), Ewing sarcoma (ICD-O-3 code 9260), and osteosarcoma (ICD-O-3 codes 9180-9187 and 9192-9195).	('9240', 'Var', (175, 179))	('chondrosarcoma', 'Disease', (121, 135))	('osteosarcoma', 'Disease', (237, 249))	('chondrosarcoma', 'Disease', 'MESH:D002813', (121, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (198, 211))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (198, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('osteosarcoma', 'Phenotype', 'HP:0002669', (237, 249))	('osteosarcoma', 'Disease', 'MESH:D012516', (237, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('Oncology', 'Phenotype', 'HP:0002664', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (121, 135))	('Ewing sarcoma', 'Disease', (198, 211))	('9231', 'Var', (169, 173))	('patients', 'Species', '9606', (107, 115))
385199	29443776	The primers used for the detection of hsa-miR-141_1, hsa-miR-1915-5p, and U6 were from the Hs_miR-141_1 miScript Primer Assay (MS00003501, Qiagen), hs_miR-1915-5p_1 miScript Primer Assay (MS00042238,Qiagen), and the Hs_RNU6 miScript Primer Assay (MS00033740, Qiagen).	('MS00003501', 'Var', (127, 137))	('miR-141', 'Gene', '406933', (42, 49))	('MS00033740', 'Var', (247, 257))	('miR-1915', 'Gene', (57, 65))	('miR-141', 'Gene', '406933', (94, 101))	('miR-1915', 'Gene', (151, 159))	('miR-1915', 'Gene', '100302129', (57, 65))	('MS00042238', 'Var', (188, 198))	('miR-141', 'Gene', (42, 49))	('miR-1915', 'Gene', '100302129', (151, 159))	('miR-141', 'Gene', (94, 101))
385233	29443776	The identification of dysregulated miRNAs in normal Uyghur and Han skin samples has opened up new possibilities for the diagnosis of certain cancers.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('dysregulated', 'Var', (22, 34))	('cancers', 'Disease', (141, 148))
385265	29443776	Therefore, we speculate that the dysregulated expression of the above miRNAs may be markers of susceptibility to Kaposi sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (113, 127))	('Kaposi sarcoma', 'Disease', (113, 127))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (113, 127))	('dysregulated', 'Var', (33, 45))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('expression', 'MPA', (46, 56))
385295	29484066	However, multiple metastases in other segments of the liver and in the mesentery were observed 48 months after RFA.	('metastases', 'Disease', 'MESH:D009362', (18, 28))	('RFA', 'Var', (111, 114))	('metastases', 'Disease', (18, 28))
385432	24156028	While few studies focused on the age-related biological and molecular differences of RMS, the cell of origin of RMS was investigated in recent works such as the European Pediatric Soft Tissue Sarcoma Study Group showing that the patient outcomes and gene expression signatures of fusion-negative ARMSs were very similar to those of ERMSs, and may help better understand the relationship between outcome and histological subtype.	('RMS', 'Phenotype', 'HP:0002859', (333, 336))	('RMS', 'Phenotype', 'HP:0002859', (85, 88))	('RMS', 'Phenotype', 'HP:0002859', (112, 115))	('ARMS', 'Disease', 'None', (296, 300))	('fusion-negative', 'Var', (280, 295))	('Sarcoma', 'Disease', (192, 199))	('Sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('RMS', 'Phenotype', 'HP:0002859', (297, 300))	('Soft Tissue Sarcoma', 'Phenotype', 'HP:0030448', (180, 199))	('Sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('ARMS', 'Disease', (296, 300))	('patient', 'Species', '9606', (229, 236))
385490	33643904	Molecular analysis was also performed retrospectively in the study and found that expressions of beta-catenin and insulin like growth factor 1 receptor were associated with inferior disease-specific survival.	('inferior', 'NegReg', (173, 181))	('beta-catenin', 'Gene', (97, 109))	('insulin like growth factor 1 receptor', 'Gene', '3480', (114, 151))	('expressions', 'Var', (82, 93))	('insulin like growth factor 1 receptor', 'Gene', (114, 151))	('disease-specific survival', 'CPA', (182, 207))	('beta-catenin', 'Gene', '1499', (97, 109))
385501	33643904	Beside surgical intervention, irradiation to head and neck region also carry the risk of injury to carotid body.	('irradiation', 'Var', (30, 41))	('injury', 'Disease', (89, 95))	('injury', 'Disease', 'MESH:D014947', (89, 95))
385575	22572725	Coexpression of HGF and its receptor c-MET has been shown to significantly correlate with larger tumor size, higher proliferation index, and poor prognosis in synovial sarcomas.	('synovial sarcomas', 'Disease', (159, 176))	('HGF', 'Gene', '3082', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (159, 175))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('higher', 'PosReg', (109, 115))	('c-MET', 'Gene', (37, 42))	('tumor', 'Disease', (97, 102))	('HGF', 'Gene', (16, 19))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (159, 176))	('c-MET', 'Gene', '4233', (37, 42))	('Coexpression', 'Var', (0, 12))	('synovial sarcomas', 'Disease', 'MESH:D013584', (159, 176))
385577	22572725	Clinical studies evaluating hypoxia within tumors reveal not only amplification of HGF signaling but also activation of transcription of the MET proto-oncogene, and promotion of invasive growth.	('amplification', 'Var', (66, 79))	('transcription', 'MPA', (120, 133))	('invasive growth', 'CPA', (178, 193))	('MET proto-oncogene', 'Gene', (141, 159))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('hypoxia within tumors', 'Disease', 'MESH:D000860', (28, 49))	('HGF', 'Gene', (83, 86))	('HGF', 'Gene', '3082', (83, 86))	('promotion', 'PosReg', (165, 174))	('hypoxia within tumors', 'Disease', (28, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('activation', 'PosReg', (106, 116))
385584	22572725	In-vitro inhibition of PI3K enzymatic activity resulted in decreases in phosphorylated AKT, mTOR, GSK-3beta expression and increased apoptosis and inhibition of cellular proliferation.	('increased', 'PosReg', (123, 132))	('decreases', 'NegReg', (59, 68))	('phosphorylated', 'MPA', (72, 86))	('AKT', 'Gene', (87, 90))	('apoptosis', 'CPA', (133, 142))	('GSK-3beta', 'Gene', '2931', (98, 107))	('cellular proliferation', 'CPA', (161, 183))	('mTOR', 'Gene', (92, 96))	('mTOR', 'Gene', '2475', (92, 96))	('GSK-3beta', 'Gene', (98, 107))	('expression', 'MPA', (108, 118))	('inhibition', 'NegReg', (147, 157))	('AKT', 'Gene', '207', (87, 90))	('PI3K', 'Var', (23, 27))
385632	32189908	The pathogenesis of GCT can be attributed to the mutations in the histone H3.3-protein encoding H3F3A gene.	('H3F3A', 'Gene', (96, 101))	('GCT', 'Disease', (20, 23))	('H3F3A', 'Gene', '3020', (96, 101))	('mutations', 'Var', (49, 58))
385633	32189908	Specifically, GCRO may show a mutation of the H3K27 me3 (the trimethylatedlysine residue at position 27 in the protein histone H3) mutation.	('H3K27', 'Protein', (46, 51))	('mutation', 'Var', (30, 38))	('GCRO', 'Chemical', '-', (14, 18))	('trimethylatedlysine', 'Chemical', '-', (61, 80))	('mutation', 'Var', (131, 139))
385634	32189908	GCRO has also been reported to originate from previous low-grade osteosarcoma with amplification of the MDM2 and CDK4 genes.	('GCRO', 'Disease', (0, 4))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('GCRO', 'Chemical', '-', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('CDK4', 'Gene', (113, 117))	('CDK4', 'Gene', '1019', (113, 117))	('MDM2', 'Gene', '4193', (104, 108))	('MDM2', 'Gene', (104, 108))	('amplification', 'Var', (83, 96))
385656	32189908	However, on meticulous examination of the slides, the presence of irregular tumor osteoids in a lace-like pattern was noted, with pleomorphic osteoblasts showing pronounced nuclear hyperchromatism and pleomorphism, thereby ruling out the possibility of a GCT and corroborating to the findings of GCRO.	('irregular tumor osteoids', 'Phenotype', 'HP:0025027', (66, 90))	('irregular tumor osteoids', 'Disease', 'MESH:D008599', (66, 90))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('hyperchromatism', 'Disease', (181, 196))	('GCRO', 'Chemical', '-', (296, 300))	('irregular tumor osteoids', 'Disease', (66, 90))	('hyperchromatism', 'Disease', '-', (181, 196))	('pleomorphism', 'Var', (201, 213))	('pleomorphic osteoblasts', 'CPA', (130, 153))
385773	31521180	The second group of tumor antigens involves chromosome/gene mutations in cancer cells.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('chromosome/gene mutations', 'Var', (44, 69))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
385774	31521180	These mutations can lead to the expression of truncated proteins, fusion proteins, or neoantigens that are unique to cancer cells, such as beta-catenin S37F in melanoma, alpha-actinin-4 K122N in lung cancer, heat shock protein 70 kilodalton-2 (hsp70-2) F293I in renal cancer, Kirsten rat sarcoma viral oncogene (K-ras) G12D in colon cancer, myeloid differentiation primary response 88 (MYD88) L265P in hairy cell leukemia, and B cell receptor-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) fusion protein in chronic myeloid leukemia.	('K122N', 'Var', (186, 191))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('alpha-actinin-4', 'Gene', (170, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('leukemia', 'Disease', 'MESH:D007938', (413, 421))	('BCR', 'Gene', '613', (493, 496))	('sarcoma viral', 'Disease', 'MESH:D001102', (288, 301))	('alpha-actinin-4', 'Gene', '63836', (170, 185))	('leukemia', 'Disease', (413, 421))	('renal cancer', 'Disease', 'MESH:D007680', (262, 274))	('heat shock protein 70 kilodalton-2', 'Gene', '24472', (208, 242))	('beta-catenin', 'Gene', '84353', (139, 151))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('hsp70-2', 'Gene', '24472', (244, 251))	('colon cancer', 'Phenotype', 'HP:0003003', (327, 339))	('heat shock protein 70 kilodalton-2', 'Gene', (208, 242))	('sarcoma viral', 'Disease', (288, 301))	('myeloid leukemia', 'Disease', (528, 544))	('L265P', 'SUBSTITUTION', 'None', (393, 398))	('murine', 'Species', '10090', (451, 457))	('MYD88', 'Gene', '301059', (386, 391))	('L265P', 'Var', (393, 398))	('rat', 'Species', '10116', (284, 287))	('ABL', 'Gene', '25', (497, 500))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (402, 421))	('cancer', 'Disease', (333, 339))	('BCR', 'Gene', (493, 496))	('K-ras', 'Gene', (312, 317))	('hsp70-2', 'Gene', (244, 251))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('shock', 'Phenotype', 'HP:0031273', (213, 218))	('leukemia', 'Phenotype', 'HP:0001909', (458, 466))	('mutations', 'Var', (6, 15))	('colon cancer', 'Disease', 'MESH:D015179', (327, 339))	('G12D', 'Mutation', 'rs121913529', (319, 323))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('myeloid leukemia', 'Disease', 'MESH:D007951', (528, 544))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (528, 544))	('lung cancer', 'Disease', (195, 206))	('K-ras', 'Gene', '24525', (312, 317))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('leukemia', 'Phenotype', 'HP:0001909', (536, 544))	('F293I', 'SUBSTITUTION', 'None', (253, 258))	('ABL', 'Gene', (497, 500))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (520, 544))	('leukemia', 'Disease', (458, 466))	('K122N', 'SUBSTITUTION', 'None', (186, 191))	('leukemia', 'Disease', 'MESH:D007938', (458, 466))	('cancer', 'Disease', (268, 274))	('colon cancer', 'Disease', (327, 339))	('renal cancer', 'Disease', (262, 274))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('hairy cell leukemia', 'Disease', (402, 421))	('F293I', 'Var', (253, 258))	('beta-catenin', 'Gene', (139, 151))	('S37F', 'Mutation', 'rs121913403', (152, 156))	('leukemia', 'Disease', 'MESH:D007938', (536, 544))	('renal cancer', 'Phenotype', 'HP:0009726', (262, 274))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('leukemia', 'Phenotype', 'HP:0001909', (413, 421))	('MYD88', 'Gene', (386, 391))	('leukemia', 'Disease', (536, 544))	('BL', 'Phenotype', 'HP:0030080', (498, 500))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('cancer', 'Disease', (200, 206))
385776	31521180	However, some types of cancer have a high burden of genetic mutations, whereas other types of cancers may not; in addition, many genetic mutations are unique to the tumor cells of individual patients.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('patients', 'Species', '9606', (191, 199))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancers', 'Disease', (94, 101))	('tumor', 'Disease', (165, 170))
385789	31521180	Similar results have been found in mouse cells transformed with simian virus antigen (SV40), murine cytomegalovirus (MCMV) pp89 (168-176) peptides, vesicular stomatic virus (VSV), and EBV.	('pp89', 'Var', (123, 127))	('MCMV', 'Species', '10366', (117, 121))	('murine cytomegalovirus', 'Species', '10366', (93, 115))	('vesicular stomatic virus', 'Disease', 'MESH:D054243', (148, 172))	('EBV', 'Species', '10376', (184, 187))	('mouse', 'Species', '10090', (35, 40))	('vesicular stomatic virus', 'Disease', (148, 172))
385808	31521180	A functional study of Fab-Hyb3 found that the mutated TCR-like CAR-T mediated better recognition of the antigen on the tumor cell surface, indicating that the affinity of TCR-like antibodies dramatically affected the killing ability of the antibodies.	('affected', 'Reg', (204, 212))	('killing ability', 'CPA', (217, 232))	('tumor', 'Disease', (119, 124))	('better', 'PosReg', (78, 84))	('-like CAR', 'Phenotype', 'HP:0010806', (57, 66))	('CAR-T', 'Gene', (63, 68))	('mutated', 'Var', (46, 53))	('recognition', 'MPA', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CAR-T', 'Gene', '9607', (63, 68))	('Fab', 'Chemical', '-', (22, 25))
385814	31521180	Moreover, 3.2G1 antibody mediated CDC and ADCC against the human breast carcinoma MDA-MB-231 cell line in vitro and inhibited tumor implantation and growth in nude mice.	('human', 'Species', '9606', (59, 64))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (82, 92))	('nude mice', 'Species', '10090', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('3.2G1', 'Var', (10, 15))	('inhibited', 'NegReg', (116, 125))	('breast carcinoma', 'Disease', 'MESH:D001943', (65, 81))	('breast carcinoma', 'Disease', (65, 81))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ADCC', 'CPA', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CDC', 'CPA', (34, 37))	('breast carcinoma', 'Phenotype', 'HP:0003002', (65, 81))	('tumor', 'Disease', (126, 131))
385882	31521180	TCR-like antibody therapy, however, does not depend on the existence of tumor antigen-specific T cells in the patient's body and can activate the normal immune cells to target the tumor cells through ADCC, CDC, or ADCP.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CDC', 'Var', (206, 209))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (72, 77))	('ADCC', 'Var', (200, 204))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('patient', 'Species', '9606', (110, 117))	('ADCP', 'Var', (214, 218))	('activate', 'PosReg', (133, 141))
385903	31521180	ABL Abelson murine leukemia viral oncogene homolog 1 ADC Antibody-drug conjugate ADCC Antibody-dependent cellular cytotoxicity Adcetris Brentuximab vedotin, abti-CD30 antibody-drug conjugate ADCP Antibody-dependent cellular phagocytosis APCs Antigen-presenting cells ATL Adult T cell leukemia BCR B cell receptor BiTEs Bi-specific T cell engaging antibodies BL Burkitt's lymphoma BP Basic protein from myelin C1q Complement component 1q CAR Chimeric antigen receptor CAR-T Chimeric antigen receptor T cells CD19 Cluster of differentiation 19 CD20 Cluster of differentiation 20 CD3 zeta CD3 zeta CDC Complement-dependent cytotoxicity CEA Carcinoembryonic antigen CMV Cytomegalovirus CTLA-4 Cytotoxic T-lymphocyte-associated protein-4 DT Diphtheria toxin E5 Papillomavirus E5 antigen E6 Papillomavirus E6 antigen E7 Papillomavirus E7 antigen EBNA Epstein-Barr nuclear antigen EbV Epstein-Barr virus ER Endoplasmic reticulum F293I Phenylalanine mutated to isoleucine at 293 position Fab Fragment antigen-binding FC Fragment crystallizable region FcgammaR IIalpha Fc gamma receptor II alpha FcgammaR Fc gamma receptor FDA US Food and Drug Administration G12D Glycine mutated to aspartic acid at 12 position H chain Immunoglobulin heavy chain HA Viral hemagglutinin HBV Hepatitis B virus HBX Hepatitis B virus X protein HCC Hepatocellular carcinoma HCV Hepatitis C virus HER2 Human epidermal growth factor receptor 2 HIV Human immunodeficiency virus HIV.Gag Group-specific antigen from HIV HIV-Pol468 Pol reading frame 468 from HIV HLA Human leukocyte antigen HPV Human papillomavirus hsp70-2 Heat shock protein 70-2 hTERT Telomerase reverse transcriptase HTLV Human T cell leukemia-lymphoma virus I-As Mouse MHC allele IFN-gamma Interferon gamma JNK C-Jun N-terminal kinases K122N Lysine mutated to asparagine at 122 position Kadcyla Ado-trastuzumab emtansine, anti-HER2 antibody-drug conjugate Keytruda Pembrolizumab, anti-PD-1 Kras Kirsten rat sarcoma virus oncogene KS Kaposi's sarcoma KSHV Kaposi sarcoma-associated herpesvirus Kymriah Tisagenlecleucel, anti-CD19 CAR-T cells L chain Immunoglobulin light chain L265P Leucine mutated to proline at 265 position LANA Virus latency-associated nuclear antigen from KSHV LMP1 Latent membrane protein 1 LMP2 Latent membrane protein 2 mAb Monoclonal antibody MAC Membrane attack complex MAGE Melanoma-associated antigen MART Melanoma antigen recognized by T cells MCC Merkel cell carcinoma MCMV Murine cytomegalovirus MHC Major histocompatibility complex MYD88 Myeloid differentiation primary response 88 Mylotarg Gemtuzumab ozogamicin, anti-CD33 antibody-drug conjugate NHL Non-Hodgkin's lymphoma NK Natural killer NP Nucleoprotein NPC Nasopharyngeal carcinoma NS3 Virus nonstructural protein 3 from HCV NS5A Virus nonstructural protein 5A from HCV NYESO-1 New York esophageal squamous cell carcinoma-1 Opdivo Nivolumab, anti-PD-1 OVA Ovalbumin PD-1 Programmed cell death receptor-1 PEL Primary effusion lymphoma PP65 CMV PP65 antigen PRAME Preferentially expressed antigen in melanoma S37F Serine mutated to phenylalanine at 37 position scFv Single-chain fragment variable SSX Synovial sarcoma X SV40 Simian virus 40 TARP TCR gamma alternate reading frame protein Tax The viral transactivator TCR T cell receptor TNFalpha Tumor necrosis factor alpha TP53 Tumor protein p53 vFLIP Virus FLICE/caspase-8-inhibitory protein from KSHV vGPCR Virus active G protein-coupled receptor homolog from KSHV VH Heavy chain variable vIRF-1 Virus IFN-inducible factor from KSHV VL Light chain variable VSV Vesicular stomatic virus WT-1 Wilms tumor gene-1 Yervoy Ipilimumab, anti-CTLA-4 JW and QH designed the study.	('NS5', 'Gene', '5894', (2748, 2751))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (1900, 1913))	('sarcoma', 'Disease', 'MESH:D012509', (1942, 1949))	('Mouse', 'Species', '10090', (1698, 1703))	('Melanoma', 'Disease', (2335, 2343))	('NYESO-1', 'Gene', '246100', (2793, 2800))	('cytotoxicity', 'Disease', 'MESH:D064420', (114, 126))	('HCV', 'Species', '11103', (2744, 2747))	('Hepatitis C', 'Disease', 'MESH:D006526', (1348, 1359))	('KSHV', 'Species', '37296', (1985, 1989))	('CD19', 'Gene', '930', (2059, 2063))	('rat sarcoma virus', 'Species', '11848', (1938, 1955))	('Papillomavirus', 'Disease', 'MESH:D030361', (814, 828))	('S37F', 'Mutation', 'rs121913403', (3030, 3034))	('Nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (2680, 2704))	('KS', 'Phenotype', 'HP:0100726', (2211, 2213))	('carcinoma', 'Disease', 'MESH:D002277', (2695, 2704))	('carcinoma', 'Disease', (2835, 2844))	('Gemtuzumab', 'Chemical', 'MESH:C406061', (2557, 2567))	('Primary effusion lymphoma', 'Disease', 'MESH:D054685', (2931, 2956))	('herpesvirus', 'Species', '39059', (2016, 2027))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (878, 896))	("Burkitt's lymphoma", 'Disease', (361, 379))	('KSHV', 'Species', '37296', (3434, 3438))	('EBNA', 'Chemical', '-', (840, 844))	('Wilms tumor', 'Disease', 'MESH:D009396', (3565, 3576))	('New York esophageal squamous cell carcinoma-1', 'Gene', (2801, 2846))	('Chimeric antigen receptor', 'Gene', (441, 466))	('NHL', 'Disease', 'MESH:D008228', (2614, 2617))	('BCR', 'Gene', '613', (293, 296))	('hTERT', 'Gene', (1612, 1617))	('Human', 'Species', '9606', (1656, 1661))	('F293I', 'SUBSTITUTION', 'None', (922, 927))	('melanoma', 'Disease', (3021, 3029))	('HCC', 'Phenotype', 'HP:0001402', (1315, 1318))	('papillomavirus', 'Disease', 'MESH:D030361', (1565, 1579))	('CD33', 'Gene', '945', (2585, 2589))	('leukemia', 'Disease', 'MESH:D007938', (284, 292))	('G12D', 'Mutation', 'rs121913529', (1150, 1154))	('HER2', 'Gene', '2064', (1862, 1866))	('CTLA-4', 'Gene', '1493', (682, 688))	('Ado-trastuzumab emtansine', 'Chemical', 'MESH:C550911', (1830, 1855))	('Cytotoxic', 'Disease', (689, 698))	('KSHV', 'Species', '37296', (2211, 2215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (2821, 2844))	('lymphoma', 'Phenotype', 'HP:0002665', (371, 379))	('HCV', 'Species', '11103', (2789, 2792))	('carcinoma', 'Phenotype', 'HP:0030731', (2695, 2704))	('Melanoma', 'Disease', 'MESH:D008545', (2368, 2376))	('scFv', 'Gene', '652070', (3082, 3086))	('Cytotoxic', 'Disease', 'MESH:D064420', (689, 698))	('hsp70-2', 'Gene', '24472', (1580, 1587))	('Vesicular stomatic', 'Disease', 'MESH:D054243', (3535, 3553))	('sarcoma', 'Phenotype', 'HP:0100242', (3131, 3138))	('CD20', 'Chemical', '-', (542, 546))	('necrosis', 'Disease', (3273, 3281))	('rat', 'Species', '10116', (1938, 1941))	('CD19', 'Gene', (2059, 2063))	('immunodeficiency', 'Phenotype', 'HP:0002721', (1422, 1438))	('leukemia', 'Phenotype', 'HP:0001909', (1669, 1677))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (1319, 1343))	('CTLA-4', 'Gene', '1493', (3608, 3614))	('leukemia-lymphoma virus', 'Disease', (1669, 1692))	('hsp70-2', 'Gene', (1580, 1587))	('carcinoma', 'Disease', (2423, 2432))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (1990, 2004))	('SSX', 'Gene', (3118, 3121))	('NS5', 'Gene', (2748, 2751))	('Glycine mutated to aspartic acid at 12', 'Mutation', 'rs121913529', (1155, 1193))	('lymphoma', 'Phenotype', 'HP:0002665', (2948, 2956))	('Leucine mutated to proline at 265', 'Mutation', 'rs387907272', (2117, 2150))	('Epstein-Barr virus', 'Disease', (878, 896))	('rat', 'Species', '10116', (1143, 1146))	('CAR-T', 'Gene', '9607', (2064, 2069))	('carcinoma', 'Phenotype', 'HP:0030731', (2835, 2844))	('Melanoma', 'Phenotype', 'HP:0002861', (2368, 2376))	('KS', 'Phenotype', 'HP:0100726', (3370, 3372))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (361, 379))	('Papillomavirus', 'Disease', (785, 799))	('Hepatitis', 'Phenotype', 'HP:0012115', (1348, 1357))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (1968, 1984))	('CAR-T', 'Gene', '9607', (467, 472))	('sarcoma', 'Phenotype', 'HP:0100242', (1977, 1984))	("Non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (2618, 2640))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (2622, 2640))	('carcinoma', 'Disease', 'MESH:D002277', (2423, 2432))	('Human', 'Species', '9606', (1371, 1376))	('HCC', 'Gene', '619501', (1315, 1318))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (2411, 2432))	('sarcoma', 'Disease', (3131, 3138))	('TNFalpha', 'Gene', '7124', (3258, 3266))	('Tumor', 'Phenotype', 'HP:0002664', (3267, 3272))	('leukemia', 'Disease', (284, 292))	('PEL', 'Phenotype', 'HP:0030069', (2927, 2930))	('HCC', 'Gene', (1315, 1318))	('carcinoma', 'Disease', 'MESH:D002277', (1334, 1343))	('murine', 'Species', '10090', (12, 18))	('immunodeficiency', 'Disease', 'MESH:D007153', (1422, 1438))	('L265P', 'SUBSTITUTION', 'None', (2111, 2116))	('Fc gamma receptor', 'Gene', (1096, 1113))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (1990, 2004))	('CTLA-4', 'Gene', (682, 688))	('necrosis', 'Disease', 'MESH:D009336', (3273, 3281))	('TARP', 'Gene', '445347', (3162, 3166))	('KSHV', 'Species', '37296', (3502, 3506))	('CAR-T', 'Gene', (2064, 2069))	('Hepatocellular carcinoma', 'Disease', (1319, 1343))	('MCMV', 'Species', '10366', (2433, 2437))	('Melanoma', 'Disease', 'MESH:D008545', (2335, 2343))	('Hepatitis B virus', 'Species', '10407', (1287, 1304))	('leukemia', 'Phenotype', 'HP:0001909', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (1997, 2004))	('Papillomavirus', 'Disease', (756, 770))	('Papillomavirus', 'Disease', 'MESH:D030361', (785, 799))	('ozogamicin', 'Chemical', '-', (2568, 2578))	('Kaposi sarcoma', 'Disease', (1990, 2004))	('lymphoma', 'Phenotype', 'HP:0002665', (2632, 2640))	('sarcoma', 'Disease', 'MESH:D012509', (1977, 1984))	('carcinoma', 'Phenotype', 'HP:0030731', (2423, 2432))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (3122, 3138))	('New York esophageal squamous cell carcinoma-1', 'Gene', '246100', (2801, 2846))	('CD19', 'Gene', '930', (507, 511))	('Melanoma', 'Disease', (2368, 2376))	('HBX', 'Gene', (1283, 1286))	('CTLA-4', 'Gene', (3608, 3614))	('sarcoma', 'Disease', (1977, 1984))	('melanoma', 'Disease', 'MESH:D008545', (3021, 3029))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (1968, 1984))	('Fab', 'Chemical', '-', (980, 983))	('HBV', 'Species', '10407', (1261, 1264))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (1319, 1343))	('MYD88', 'Gene', '301059', (2498, 2503))	("Non-Hodgkin's lymphoma", 'Disease', (2618, 2640))	('KS', 'Phenotype', 'HP:0100726', (3434, 3436))	('hTERT', 'Gene', '7015', (1612, 1617))	('carcinoma', 'Phenotype', 'HP:0030731', (1334, 1343))	('Chimeric antigen receptor', 'Gene', '9970', (441, 466))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (361, 379))	('carcinoma', 'Disease', (1334, 1343))	('leukemia', 'Phenotype', 'HP:0001909', (284, 292))	('cytotoxicity', 'Disease', (620, 632))	('tumor', 'Phenotype', 'HP:0002664', (3571, 3576))	('Chimeric antigen receptor', 'Gene', '9970', (473, 498))	('HIV', 'Species', '12721', (1445, 1448))	("Kaposi's sarcoma", 'Disease', (1968, 1984))	('Hepatitis C', 'Disease', (1348, 1359))	('K122N', 'Var', (1771, 1776))	('cytotoxicity', 'Disease', 'MESH:D064420', (620, 632))	('TCR gamma alternate reading frame protein', 'Gene', (3167, 3208))	('sarcoma', 'Phenotype', 'HP:0100242', (1942, 1949))	('OVA', 'Gene', (2875, 2878))	('sarcoma', 'Disease', 'MESH:D012509', (1997, 2004))	('HIV', 'Species', '12721', (1523, 1526))	('sarcoma', 'Disease', 'MESH:D012509', (3131, 3138))	('LMP2', 'Gene', (2247, 2251))	('Papillomavirus', 'Disease', 'MESH:D030361', (756, 770))	('Phenylalanine mutated to isoleucine at 293', 'Mutation', 'p.F293I', (928, 970))	('melanoma', 'Phenotype', 'HP:0002861', (3021, 3029))	('BL', 'Phenotype', 'HP:0030080', (358, 360))	('T cell leukemia', 'Phenotype', 'HP:0005517', (277, 292))	('sarcoma', 'Disease', (1997, 2004))	('NPC', 'Phenotype', 'HP:0100630', (2676, 2679))	('NS3', 'Gene', (2705, 2708))	('HER2', 'Gene', (1366, 1370))	('HIV', 'Species', '12721', (1481, 1484))	('F293I', 'Var', (922, 927))	('CD19', 'Gene', (507, 511))	('PRAME', 'Gene', '23532', (2979, 2984))	('PRAME', 'Gene', (2979, 2984))	('L265P', 'Var', (2111, 2116))	('scFv', 'Gene', (3082, 3086))	('Hepatitis', 'Phenotype', 'HP:0012115', (1265, 1274))	('HCV', 'Species', '11103', (1344, 1347))	('Merkel cell carcinoma', 'Disease', (2411, 2432))	('papillomavirus', 'Disease', (1565, 1579))	('NYESO-1', 'Gene', (2793, 2800))	('TP53', 'Gene', (3295, 3299))	('C1q', 'Gene', (409, 412))	('LMP1', 'Gene', (2216, 2220))	('HPV', 'Species', '10566', (1555, 1558))	('lymphoma', 'Phenotype', 'HP:0002665', (1678, 1686))	('TNFalpha', 'Gene', (3258, 3266))	('CAR-T', 'Gene', (467, 472))	('C1q', 'Gene', '712', (409, 412))	('leukemia', 'Disease', 'MESH:D007938', (19, 27))	('ABL', 'Gene', '25', (0, 3))	('Primary effusion lymphoma', 'Phenotype', 'HP:0030069', (2931, 2956))	('CD30', 'Gene', (162, 166))	('NHL', 'Disease', (2614, 2617))	('leukemia', 'Disease', (1669, 1677))	('Fc gamma receptor', 'Gene', (1060, 1077))	('sarcoma', 'Disease', (1942, 1949))	('leukemia', 'Disease', 'MESH:D007938', (1669, 1677))	('KS', 'Phenotype', 'HP:0100726', (1965, 1967))	('HIV', 'Species', '12721', (1485, 1488))	('HER2', 'Gene', '2064', (1366, 1370))	('Hepatitis', 'Phenotype', 'HP:0012115', (1287, 1296))	('OVA', 'Gene', '282665', (2875, 2878))	('TP53', 'Gene', '7157', (3295, 3299))	('leukemia-lymphoma virus', 'Disease', 'MESH:D015459', (1669, 1692))	('TARP', 'Gene', (3162, 3166))	('LMP1', 'Gene', '9260', (2216, 2220))	('Vesicular stomatic', 'Disease', (3535, 3553))	('ABL', 'Gene', (0, 3))	('Hepatitis B virus', 'Species', '10407', (1265, 1282))	('Melanoma', 'Phenotype', 'HP:0002861', (2335, 2343))	('Primary effusion lymphoma', 'Disease', (2931, 2956))	('TCR gamma alternate reading frame protein', 'Gene', '445347', (3167, 3208))	('CD30', 'Gene', '943', (162, 166))	('HIV', 'Species', '12721', (1412, 1415))	('CEA', 'Gene', '1048', (633, 636))	('NS3', 'Gene', '3845', (2705, 2708))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (3591, 3601))	('Human', 'Species', '9606', (1531, 1536))	('Fc gamma receptor', 'Gene', '2209', (1096, 1113))	('KSHV', 'Species', '37296', (3370, 3374))	('Tumor', 'Phenotype', 'HP:0002664', (3300, 3305))	('Chimeric antigen receptor', 'Gene', (473, 498))	('immunodeficiency', 'Disease', (1422, 1438))	('HBX', 'Gene', '944566', (1283, 1286))	('BL', 'Phenotype', 'HP:0030080', (1, 3))	('CD33', 'Gene', (2585, 2589))	('Papillomavirus', 'Disease', (814, 828))	('Lysine mutated to asparagine at 122', 'Mutation', 'p.K122N', (1777, 1812))	('Wilms tumor', 'Phenotype', 'HP:0002667', (3565, 3576))	('SSX', 'Gene', '727837', (3118, 3121))	('BCR', 'Gene', (293, 296))	('carcinoma', 'Disease', 'MESH:D002277', (2835, 2844))	('KS', 'Phenotype', 'HP:0100726', (1985, 1987))	('MYD88', 'Gene', (2498, 2503))	('Human', 'Species', '9606', (1416, 1421))	('T cell leukemia', 'Phenotype', 'HP:0005517', (1662, 1677))	('shock', 'Phenotype', 'HP:0031273', (1593, 1598))	('carcinoma', 'Disease', (2695, 2704))	('Fc gamma receptor', 'Gene', '2209', (1060, 1077))	('Serine mutated to phenylalanine at 37', 'Mutation', 'rs121913403', (3035, 3072))	('Wilms tumor', 'Disease', (3565, 3576))	('CEA', 'Gene', (633, 636))	('LMP2', 'Gene', '17494212', (2247, 2251))	('Human', 'Species', '9606', (1559, 1564))	('cytotoxicity', 'Disease', (114, 126))	('K122N', 'SUBSTITUTION', 'None', (1771, 1776))	('HER2', 'Gene', (1862, 1866))	('leukemia', 'Disease', (19, 27))
385940	31011321	As for the mutational state, the percentage of BRCA1/2 mutations was 52%.	('BRCA1/2', 'Gene', (47, 54))	('BRCA1/2', 'Gene', '672;675', (47, 54))	('mutations', 'Var', (55, 64))
385942	31011321	The patients with an NF1 mutation have a lower 5-year survival: only 77.1%, compared to those who do not have a documented NF1 mutation.	('mutation', 'Var', (25, 33))	('lower', 'NegReg', (41, 46))	('NF1', 'Gene', '4763', (123, 126))	('NF1', 'Gene', (123, 126))	('NF1', 'Gene', (21, 24))	('patients', 'Species', '9606', (4, 12))	('NF1', 'Gene', '4763', (21, 24))
385948	31011321	The most common mutation present in the NF1 gene is deletion.	('NF1', 'Gene', '4763', (40, 43))	('NF1', 'Gene', (40, 43))	('deletion', 'Var', (52, 60))
385950	31011321	It has been proposed that haplodeficiency rather than total deficiency of neurofibromin is important for the development of neurofibromas in NF1.	('neurofibroma', 'Phenotype', 'HP:0001067', (124, 136))	('neurofibromas', 'Phenotype', 'HP:0001067', (124, 137))	('haplodeficiency', 'Var', (26, 41))	('neurofibromin', 'Gene', '4763', (74, 87))	('neurofibromas', 'Disease', (124, 137))	('neurofibromin', 'Gene', (74, 87))	('NF1', 'Gene', (141, 144))	('neurofibromas', 'Disease', 'MESH:D009455', (124, 137))	('NF1', 'Gene', '4763', (141, 144))
385952	31011321	Deleterious NF1 pathogenic variants were identified in women.	('women', 'Species', '9606', (55, 60))	('variants', 'Var', (27, 35))	('NF1', 'Gene', '4763', (12, 15))	('NF1', 'Gene', (12, 15))
385953	31011321	In some cases, the haplodeficiency of NF1 could complete the inexpression of neurofibromin by following the model of the double hit proposed by Knudson.	('neurofibromin', 'Gene', (77, 90))	('haplodeficiency', 'Var', (19, 34))	('neurofibromin', 'Gene', '4763', (77, 90))	('inexpression of', 'MPA', (61, 76))	('NF1', 'Gene', (38, 41))	('NF1', 'Gene', '4763', (38, 41))
385955	31011321	Each tumor had a distinct genomic profile with mutually exclusive mutations in different genes.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (5, 10))
385956	31011321	Somatic NF1 mutation in the Schwann cells may trigger the formation of a neurofibroma.	('NF1', 'Gene', (8, 11))	('NF1', 'Gene', '4763', (8, 11))	('trigger', 'Reg', (46, 53))	('neurofibroma', 'Disease', (73, 85))	('neurofibroma', 'Disease', 'MESH:D009455', (73, 85))	('neurofibroma', 'Phenotype', 'HP:0001067', (73, 85))	('mutation', 'Var', (12, 20))
385957	31011321	NF1 aberrations can potentially lead to activation of the Ras, MAP kinase, and PI3K-mTOR pathways, resulting in proliferation of tumor cells.	('Ras', 'Chemical', 'MESH:D011883', (58, 61))	('aberrations', 'Var', (4, 15))	('NF1', 'Gene', '4763', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mTOR', 'Gene', '2475', (84, 88))	('Ras', 'Pathway', (58, 61))	('activation', 'PosReg', (40, 50))	('MAP kinase', 'Pathway', (63, 73))	('mTOR', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NF1', 'Gene', (0, 3))	('tumor', 'Disease', (129, 134))	('proliferation', 'CPA', (112, 125))
385959	31011321	The patient had a metastatic mass of the primary colon cancer, but the challenge was related to attributing another mutation apart from NF1 to the development of a second neoplasm that could not be identified in both cases.	('neoplasm', 'Disease', 'MESH:D009369', (171, 179))	('neoplasm', 'Phenotype', 'HP:0002664', (171, 179))	('mutation', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patient', 'Species', '9606', (4, 11))	('colon cancer', 'Phenotype', 'HP:0003003', (49, 61))	('NF1', 'Gene', (136, 139))	('colon cancer', 'Disease', 'MESH:D015179', (49, 61))	('NF1', 'Gene', '4763', (136, 139))	('colon cancer', 'Disease', (49, 61))	('neoplasm', 'Disease', (171, 179))
385968	27735950	Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs.	('human', 'Species', '9606', (143, 148))	('apoptosis', 'CPA', (113, 122))	('growth arrest', 'Disease', (95, 108))	('mouse', 'Species', '10090', (182, 187))	('ES', 'Phenotype', 'HP:0012254', (149, 151))	('growth arrest', 'Disease', 'MESH:D006323', (95, 108))	('growth arrest', 'Phenotype', 'HP:0001510', (95, 108))	('knockdown', 'Var', (14, 23))	('Cdk4', 'Gene', (35, 39))	('Mcl1', 'Gene', (27, 31))
385971	27735950	The malignancy is caused by fusion of chromosome 11 and 22 creating the EWS/FLI1 (EF) transcription factor.	('malignancy', 'Disease', 'MESH:D009369', (4, 14))	('fusion', 'Var', (28, 34))	('EWS', 'Gene', (72, 75))	('malignancy', 'Disease', (4, 14))	('FLI1', 'Gene', (76, 80))	('caused by', 'Reg', (18, 27))	('FLI1', 'Gene', '14247', (76, 80))	('EWS', 'Gene', '14030', (72, 75))
385975	27735950	Tumor formation was influenced by positional effects of lentiviral vector integration into cancer-associated gene loci, but a unified hotspot integration was not reported.	('Tumor formation', 'CPA', (0, 15))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('influenced', 'Reg', (20, 30))	('lentiviral vector integration', 'Var', (56, 85))	('integration', 'Var', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
385978	27735950	Compound cross with p53-deficient mice (Prx1Cre-mediated p53 deletion) synergized in osteosarcoma formation.	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('mice', 'Species', '10090', (34, 38))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('deletion', 'Var', (61, 69))	('Prx1', 'Gene', (40, 44))	('Prx1', 'Gene', '18933', (40, 44))	('p53', 'Gene', (57, 60))
385990	27735950	EF expression caused developmental abnormalities such as endochondral bone formation arrest, starting at E10.5 up to postnatal day P1 (Figure 1).	('EF expression', 'Var', (0, 13))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (21, 48))	('developmental abnormalities', 'Disease', (21, 48))	('endochondral bone formation arrest', 'CPA', (57, 91))	('developmental abnormalities', 'Disease', 'MESH:D006130', (21, 48))
385991	27735950	EF-expressing embryos or newborns displayed gross malformations in limb development that became apparent at E12.5.	('limb development', 'CPA', (67, 83))	('EF-expressing', 'Var', (0, 13))	('malformations in limb', 'Phenotype', 'HP:0040064', (50, 71))	('malformations', 'Disease', 'MESH:D000014', (50, 63))	('malformations', 'Disease', (50, 63))
385995	27735950	Mutant mice were born at normal Mendelian ratios (n=174 EFPrx1 versus n=161 wt controls were analyzed; Figure 1c).	('Mutant', 'Var', (0, 6))	('Prx1', 'Gene', '18933', (58, 62))	('Prx1', 'Gene', (58, 62))	('mice', 'Species', '10090', (7, 11))
385996	27735950	All mutant embryos analyzed showed condensed cartilaginous elements instead of long bone formation.	('cartilaginous', 'Disease', (45, 58))	('cartilaginous', 'Disease', 'MESH:D015831', (45, 58))	('mutant', 'Var', (4, 10))	('long bone formation', 'CPA', (79, 98))
385998	27735950	In line, all mutant embryos showed absence of hypertrophic and mature chondrocytes or osteoblasts as confirmed by RNA in situ hybridization for bone lineage markers.	('mutant', 'Var', (13, 19))	('hypertrophic', 'Disease', (46, 58))	('absence', 'NegReg', (35, 42))	('hypertrophic', 'Disease', 'MESH:D006984', (46, 58))
386001	27735950	EF+ embryos at different embryonic stages (E14.5, E16.5 and P1) showed a severe reduction of mature chondrocytes in mutant limbs, as measured by dimethylmethylene blue staining, which reflects sulphated glycosaminglycane content (Figure 2a; Supplementary Figure 3b).	('E16.5', 'Var', (50, 55))	('glycosaminglycane', 'Chemical', '-', (203, 220))	('reduction', 'NegReg', (80, 89))	('dimethylmethylene blue', 'Chemical', 'MESH:C435946', (145, 167))	('mature chondrocytes', 'CPA', (93, 112))	('mutant', 'Var', (116, 122))
386004	27735950	RUNX2, OSTERIX, DLX5, pSMAD4, SMAD1/5, SMAD7 and beta-CATENIN were found diminished at all embryonic stages in EFPrx1 transgenic limbs (Figures 2a and b; Supplementary Figure 4), whereas SMAD7 expression at birth was comparable with wt expression levels.	('SMAD7', 'Gene', '17131', (39, 44))	('SMAD1/5', 'Gene', (30, 37))	('SMAD', 'Gene', (30, 34))	('beta-CATENIN', 'Gene', (49, 61))	('beta-CATENIN', 'Gene', '12387', (49, 61))	('SMAD7', 'Gene', (187, 192))	('DLX5', 'Gene', (16, 20))	('RUNX2', 'Gene', (0, 5))	('OSTERIX', 'Gene', (7, 14))	('Prx1', 'Gene', '18933', (113, 117))	('Prx1', 'Gene', (113, 117))	('SMAD1/5', 'Gene', '17125;17129', (30, 37))	('SMAD7', 'Gene', '17131', (187, 192))	('SMAD', 'Gene', '17125;17128;17129;17131', (39, 43))	('diminished', 'NegReg', (73, 83))	('SMAD', 'Gene', '17125;17128;17129;17131', (23, 27))	('transgenic', 'Var', (118, 128))	('SMAD', 'Gene', '17125;17128;17129;17131', (187, 191))	('SMAD7', 'Gene', (39, 44))	('DLX5', 'Gene', '13395', (16, 20))	('RUNX2', 'Gene', '12393', (0, 5))	('SMAD', 'Gene', '17125;17128;17129;17131', (30, 34))	('SMAD', 'Gene', (39, 43))	('transgenic', 'Species', '10090', (118, 128))	('SMAD', 'Gene', (23, 27))	('OSTERIX', 'Gene', '170574', (7, 14))	('SMAD', 'Gene', (187, 191))
386006	27735950	DLX5 as a TGF-beta-induced protein was downregulated in mutant limbs compared with controls (Figures 2a and b; Supplementary Figure 4).	('DLX5', 'Gene', '13395', (0, 4))	('TGF-beta', 'Gene', (10, 18))	('DLX5', 'Gene', (0, 4))	('mutant', 'Var', (56, 62))	('TGF-beta', 'Gene', '21803', (10, 18))	('downregulated', 'NegReg', (39, 52))
386007	27735950	The proliferation rate of EF-mutant chondrocytes was not significantly changed, as measured by Ki67 staining.	('Ki67', 'Gene', (95, 99))	('EF-mutant', 'Var', (26, 35))	('Ki67', 'Gene', '17345', (95, 99))
386008	27735950	Of note, nuclear P21 (CDKN1A), a known senescence marker often lost or mutated in human cancer was induced at E14.5, but suppressed from E16.5 on in EF-mutant limbs.	('cancer', 'Disease', (88, 94))	('CDKN1A', 'Gene', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('P21', 'Gene', '1026', (17, 20))	('CDKN1A', 'Gene', '1026', (22, 28))	('suppressed', 'NegReg', (121, 131))	('P21', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('induced', 'PosReg', (99, 106))	('human', 'Species', '9606', (82, 87))	('E14.5', 'Var', (110, 115))
386009	27735950	Moreover, cyclin D1 expression was slightly decreased throughout development of EFPrx1 transgenic limbs, whereas its expression was diminished at birth (Figures 3a-c; Supplementary Figure 5).	('transgenic', 'Species', '10090', (87, 97))	('expression', 'MPA', (20, 30))	('transgenic', 'Var', (87, 97))	('cyclin D1', 'Gene', '12443', (10, 19))	('Prx1', 'Gene', '18933', (82, 86))	('cyclin D1', 'Gene', (10, 19))	('Prx1', 'Gene', (82, 86))	('decreased', 'NegReg', (44, 53))
386039	27735950	We next examined whether on a transcriptomic level ES correlates better with the EFPrx1MSCL+Mcl1 transplant model than other human sarcomas using a comprehensive set of microarray data for different human sarcomas.	('ES', 'Phenotype', 'HP:0012254', (51, 53))	('human', 'Species', '9606', (199, 204))	('sarcomas', 'Disease', 'MESH:D012509', (205, 213))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('human', 'Species', '9606', (125, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (205, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('EFPrx1MSCL+Mcl1', 'Var', (81, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('sarcomas', 'Disease', (131, 139))	('sarcomas', 'Disease', (205, 213))
386046	27735950	RB expression was lower, but pS780-RB expression was higher and CDK6 expression was also higher.	('higher', 'PosReg', (53, 59))	('CDK6', 'Gene', (64, 68))	('expression', 'MPA', (38, 48))	('pS780-RB', 'Var', (29, 37))	('lower', 'NegReg', (18, 23))	('RB', 'Chemical', 'MESH:D012413', (0, 2))	('expression', 'MPA', (69, 79))	('RB expression', 'MPA', (0, 13))	('higher', 'PosReg', (89, 95))	('CDK6', 'Gene', '12571', (64, 68))	('RB', 'Chemical', 'MESH:D012413', (35, 37))
386047	27735950	Furthermore, sarcoma cells isolated from EFPrx1MSCL+Mcl1 tumors and recultivated displayed changed expression, most notable for upregulated p53, MCL1 and CDK6 expression.	('expression', 'MPA', (99, 109))	('EFPrx1MSCL+Mcl1', 'Var', (41, 56))	('changed', 'Reg', (91, 98))	('CDK6', 'Gene', (154, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('expression', 'MPA', (159, 169))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('sarcoma', 'Disease', 'MESH:D012509', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('sarcoma', 'Disease', (13, 20))	('CDK6', 'Gene', '12571', (154, 158))	('p53', 'Gene', (140, 143))	('upregulated', 'PosReg', (128, 139))	('MCL1', 'Gene', (145, 149))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
386050	27735950	P19ARF and P16Ink4A were expressed lower in EFPrx1MSCL+Mcl1 tumor-derived cells and P53 expression was significantly enhanced in EFPrx1MSCL or even expressed/activated higher upon MCL1 transduction before transplant (Figure 5h).	('MSCL', 'Gene', (135, 139))	('MSCL', 'Gene', '50880', (50, 54))	('P16Ink4A', 'Gene', '1029', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('P16Ink4A', 'Gene', (11, 19))	('enhanced', 'PosReg', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('P19ARF', 'Var', (0, 6))	('tumor', 'Disease', (60, 65))	('expression', 'MPA', (88, 98))	('MSCL', 'Gene', (50, 54))	('MSCL', 'Gene', '50880', (135, 139))	('P53', 'Gene', (84, 87))
386052	27735950	Upon siRNA-mediated knockdown of Mcl1 or Cdk4 in Ewing-like mouse as well as in ES cell lines TC252 and SK-N-MC we could demonstrate that both genes are important for ES cell growth and survival (Figure 6).	('ES', 'Phenotype', 'HP:0012254', (80, 82))	('SK-N-MC', 'CellLine', 'CVCL:0530', (104, 111))	('Mcl1', 'Gene', (33, 37))	('Cdk4', 'Gene', (41, 45))	('TC252', 'CellLine', 'CVCL:S866', (94, 99))	('ES', 'Phenotype', 'HP:0012254', (167, 169))	('knockdown', 'Var', (20, 29))	('mouse', 'Species', '10090', (60, 65))
386053	27735950	Mechanistically, we observed a slightly lower expression of pS780-RB after downregulation of Mcl1 or Cdk4, whereas total RB levels were increased, indicating that Mcl1 and Cdk4 downregulation resulted in blocked proliferation (Figure 6a,Supplementary Figure 7i).	('downregulation', 'NegReg', (177, 191))	('downregulation', 'NegReg', (75, 89))	('Cdk4', 'Gene', (101, 105))	('Mcl1', 'Gene', (93, 97))	('pS780-RB', 'Var', (60, 68))	('RB levels', 'MPA', (121, 130))	('RB', 'Chemical', 'MESH:D012413', (66, 68))	('Cdk4', 'Gene', (172, 176))	('RB', 'Chemical', 'MESH:D012413', (121, 123))	('blocked proliferation', 'CPA', (204, 225))	('increased', 'PosReg', (136, 145))	('expression', 'MPA', (46, 56))	('lower', 'NegReg', (40, 45))
386070	27735950	We noted deregulated WNT; HEDGEHOG, BMP and TGF-beta pathways that culminated into skeletal development defects.	('deregulated', 'Var', (9, 20))	('WNT; HEDGEHOG', 'Pathway', (21, 34))	('TGF-beta', 'Gene', '21803', (44, 52))	('culminated into', 'Reg', (67, 82))	('TGF-beta', 'Gene', (44, 52))	('skeletal development defects', 'CPA', (83, 111))
386071	27735950	Polydactyly was associated with elevated hedgehog signaling and Gli1 expression known to be EF-dependent.	('hedgehog signaling', 'Pathway', (41, 59))	('elevated', 'PosReg', (32, 40))	('Gli1', 'Gene', '14632', (64, 68))	('expression', 'MPA', (69, 79))	('Polydactyly', 'Phenotype', 'HP:0010442', (0, 11))	('Gli1', 'Gene', (64, 68))	('Polydactyly', 'Var', (0, 11))
386090	27735950	INK4A proteins are frequently lost owing to homozygous deletion or p53 mutations, both prominent in patients with ES.	('homozygous deletion', 'Var', (44, 63))	('lost', 'NegReg', (30, 34))	('p53', 'Gene', (67, 70))	('ES', 'Phenotype', 'HP:0012254', (114, 116))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (100, 108))	('INK4A proteins', 'Protein', (0, 14))
386092	27735950	It was shown that MCL1 and cell cycle progression are interconnected and more MCL1 expression accelerated the cancer cell cycle progression.	('MCL1', 'Gene', (78, 82))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('accelerated', 'PosReg', (94, 105))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('expression', 'Var', (83, 93))
386093	27735950	Here, we found that MCL1 knockdown led to a G1 cell cycle arrest by decreasing CYCLIN D1, CDK4/6 and by increasing P27 expression.	('expression', 'MPA', (119, 129))	('P27', 'Gene', '3429', (115, 118))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('MCL1', 'Gene', (20, 24))	('decreasing', 'NegReg', (68, 78))	('CDK4/6', 'MPA', (90, 96))	('CYCLIN D1', 'MPA', (79, 88))	('P27', 'Gene', (115, 118))	('increasing', 'PosReg', (104, 114))	('knockdown', 'Var', (25, 34))	('G1 cell cycle arrest', 'CPA', (44, 64))
386097	27735950	Our study displays mechanistic insights how the high apoptosis induced through EF-induced Caspase-3 mRNA and protein expression can be overcome to promote sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (155, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('promote', 'PosReg', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('mRNA and', 'MPA', (100, 108))	('sarcomas', 'Disease', (155, 163))	('Caspase-3', 'Gene', (90, 99))	('EF-induced', 'Var', (79, 89))	('Caspase-3', 'Gene', '12367', (90, 99))
386101	27735950	Cells were cultivated for inhibitor Palbociclib (PD-0332991) HCl in a dose-response cellular viability assay, incubated for 24 h (Selleckchem, Houston, TX, USA) with doses: 0, 0.3, 0.5, 1, 2, 5 and 7 muM followed by viability counting using trypan blue.	('PD-0332991', 'Var', (49, 59))	('muM', 'Gene', (200, 203))	('muM', 'Gene', '56925', (200, 203))	('HCl', 'Chemical', '-', (61, 64))	('PD-0332991', 'Chemical', 'MESH:C500026', (49, 59))	('Palbociclib', 'Chemical', 'MESH:C500026', (36, 47))	('trypan blue', 'Chemical', 'MESH:D014343', (241, 252))
386117	31711514	In recent years, numerous studies have reported that abnormal m6A modification causes aberrant expression of important viral genes.	('causes', 'Reg', (79, 85))	('abnormal', 'Var', (53, 61))	('m6A', 'Gene', (62, 65))	('aberrant expression of', 'MPA', (86, 108))	('m6A', 'Gene', '56339', (62, 65))
386124	31711514	Furthermore, it has been found that m6A modification mostly occur at RRACH motif (R = A or G, H = A, C, or U), and m6A sites are significantly clustered around transcription start sites, exonic regions flanking splicing sites, stop codons, 5'untranslated region (5'UTR) and 3'untranslated region (3'UTR).	('modification', 'Var', (40, 52))	('m6A', 'Gene', (36, 39))	('m6A', 'Gene', (115, 118))	('m6A', 'Gene', '56339', (36, 39))	('m6A', 'Gene', '56339', (115, 118))	('occur', 'Reg', (60, 65))
386137	31711514	Moreover, knockdown of RBM15 caused a significant reduction of m6A deposition on mRNAs.	('m6A', 'Gene', (63, 66))	('RBM15', 'Gene', (23, 28))	('reduction', 'NegReg', (50, 59))	('m6A', 'Gene', '56339', (63, 66))	('knockdown', 'Var', (10, 19))	('RBM15', 'Gene', '64783', (23, 28))
386147	31711514	Furthermore, ALKBH5 significantly regulated the nuclear RNA export, metabolism and gene expression, indicating that reversible m6A modification on RNA has broad biological effects.	('m6A', 'Gene', '56339', (127, 130))	('nuclear RNA export', 'MPA', (48, 66))	('regulated', 'Reg', (34, 43))	('ALKBH5', 'Gene', '54890', (13, 19))	('gene expression', 'MPA', (83, 98))	('metabolism', 'MPA', (68, 78))	('ALKBH5', 'Gene', (13, 19))	('m6A', 'Gene', (127, 130))	('modification', 'Var', (131, 143))
386159	31711514	Currently, it is known that deregulation of m6A modification is associated with diseases caused by pathogenic viruses.	('associated', 'Reg', (64, 74))	('m6A', 'Gene', '56339', (44, 47))	('deregulation', 'Var', (28, 40))	('m6A', 'Gene', (44, 47))
386161	31711514	In recent years, numerous studies have revealed that m6A modification regulates viral life cycles and m6A modification in pathogenic viruses is increasingly being investigated.	('modification', 'Var', (57, 69))	('m6A', 'Gene', (53, 56))	('m6A', 'Gene', (102, 105))	('regulates', 'Reg', (70, 79))	('viral life cycles', 'CPA', (80, 97))	('m6A', 'Gene', '56339', (53, 56))	('m6A', 'Gene', '56339', (102, 105))
386162	31711514	Other scholars have revealed that m6A modification influences the expression of key genes involved in the viral life.	('m6A', 'Gene', '56339', (34, 37))	('influences', 'Reg', (51, 61))	('expression', 'MPA', (66, 76))	('modification', 'Var', (38, 50))	('m6A', 'Gene', (34, 37))
386170	31711514	reported the presence of m6A modification on HIV-1 RNA, and characterized the molecular features, topology and function of the viral-host RNA m6A during CD4+T cell infection.	('m6A', 'Gene', (142, 145))	('m6A', 'Gene', '56339', (25, 28))	('modification', 'Var', (29, 41))	('HIV-1', 'Species', '11676', (45, 50))	('m6A', 'Gene', '56339', (142, 145))	('m6A', 'Gene', (25, 28))
386173	31711514	Knockdown of METTL3/14 suppressed virus replication, while knocking down of ALKBH5 produced opposite results.	('ALKBH5', 'Gene', (76, 82))	('suppressed', 'NegReg', (23, 33))	('METTL3', 'Gene', (13, 19))	('METTL3', 'Gene', '56339', (13, 19))	('virus replication', 'MPA', (34, 51))	('ALKBH5', 'Gene', '54890', (76, 82))	('knocking down', 'Var', (59, 72))
386191	31711514	found that EV71 RNA also contains m6A modification in the coding region of VP, 3D and 2C.	('EV71', 'Var', (11, 15))	('EV71', 'Species', '39054', (11, 15))	('m6A', 'Gene', (34, 37))	('m6A', 'Gene', '56339', (34, 37))
386194	31711514	Similarly, mutation in m6A modification sites were found to decrease the production of EV71 progeny virus and protein expression in the infectious clones.	('decrease', 'NegReg', (60, 68))	('production of', 'MPA', (73, 86))	('protein expression', 'MPA', (110, 128))	('EV71', 'Species', '39054', (87, 91))	('EV71', 'Protein', (87, 91))	('m6A', 'Gene', (23, 26))	('mutation', 'Var', (11, 19))	('m6A', 'Gene', '56339', (23, 26))
386195	31711514	Moreover, METTL3 silencing decreased the virus titers and RNA copies, but knockdown of FTO produced opposite results.	('RNA copies', 'MPA', (58, 68))	('virus titers', 'MPA', (41, 53))	('decreased', 'NegReg', (27, 36))	('METTL3', 'Gene', '56339', (10, 16))	('METTL3', 'Gene', (10, 16))	('FTO', 'Gene', '79068', (87, 90))	('silencing', 'Var', (17, 26))	('FTO', 'Gene', (87, 90))
386205	31711514	reported that m6A modification affected the viral replication and gene expression of IAV.	('m6A', 'Gene', (14, 17))	('IAV', 'Species', '11320', (85, 88))	('viral replication', 'MPA', (44, 61))	('affected', 'Reg', (31, 39))	('m6A', 'Gene', '56339', (14, 17))	('modification', 'Var', (18, 30))	('IAV', 'Disease', (85, 88))	('gene expression', 'MPA', (66, 81))
386222	31711514	On the other hand, knockdown of FTO moderately increased viral lytic replication.	('FTO', 'Gene', (32, 35))	('knockdown', 'Var', (19, 28))	('viral lytic replication', 'CPA', (57, 80))	('FTO', 'Gene', '79068', (32, 35))	('increased', 'PosReg', (47, 56))
386225	31711514	Moreover, the expression of RTA increased the modification level of m6A, further inducing the splicing of pre-mRNA.	('expression', 'Var', (14, 24))	('modification level', 'MPA', (46, 64))	('m6A', 'Gene', (68, 71))	('m6A', 'Gene', '56339', (68, 71))	('RTA', 'Gene', (28, 31))	('increased', 'PosReg', (32, 41))	('splicing of pre-mRNA', 'MPA', (94, 114))	('inducing', 'Reg', (81, 89))
386230	31711514	They also revealed that m6A modification regulated the expression of ORF50 in iSLK.219 cells, and YTHDF2 deletion impaired the transcription of ORF50.	('m6A', 'Gene', (24, 27))	('deletion', 'Var', (105, 113))	('transcription', 'MPA', (127, 140))	('m6A', 'Gene', '56339', (24, 27))	('expression', 'MPA', (55, 65))	('YTHDF2', 'Gene', (98, 104))	('ORF50', 'Gene', (144, 149))	('ORF50', 'Gene', (69, 74))	('impaired', 'NegReg', (114, 122))
386232	31711514	Moreover, YTHDF2 in m6Am negatively affected lytic replication by decaying transcripts of KSHV.	('negatively', 'NegReg', (25, 35))	('m6A', 'Gene', '56339', (20, 23))	('YTHDF2', 'Var', (10, 16))	('lytic replication', 'CPA', (45, 62))	('KSHV', 'Species', '37296', (90, 94))	('decaying', 'NegReg', (66, 74))	('KS', 'Phenotype', 'HP:0100726', (90, 92))	('KSHV', 'Gene', (90, 94))	('m6A', 'Gene', (20, 23))	('affected', 'Reg', (36, 44))
386233	31711514	These observations illustrate that YTHDC1 and YTHDF2 might be involved in KSHV lifecycle, suggesting that the regulation of ORF50 expression through m6A modification could be a new research direction into the mechanisms of KSHV infections.	('modification', 'Var', (153, 165))	('m6A', 'Gene', '56339', (149, 152))	('ORF50', 'Gene', (124, 129))	('YTHDC1', 'Gene', (35, 41))	('KSHV infections', 'Disease', 'MESH:C537372', (223, 238))	('KSHV', 'Species', '37296', (223, 227))	('KS', 'Phenotype', 'HP:0100726', (223, 225))	('involved', 'Reg', (62, 70))	('YTHDC1', 'Gene', '91746', (35, 41))	('KSHV infections', 'Disease', (223, 238))	('KSHV', 'Species', '37296', (74, 78))	('KS', 'Phenotype', 'HP:0100726', (74, 76))	('m6A', 'Gene', (149, 152))
386235	31711514	HBV infection causes chronic hepatitis and increases the risk of developing cirrhosis and hepatocellular carcinoma.	('HBV', 'Disease', (0, 3))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (21, 38))	('HBV', 'Disease', 'MESH:D006509', (0, 3))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('hepatocellular carcinoma', 'Disease', (90, 114))	('cirrhosis', 'Disease', (76, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('hepatitis', 'Phenotype', 'HP:0012115', (29, 38))	('causes', 'Reg', (14, 20))	('hepatitis', 'Disease', (29, 38))	('infection', 'Var', (4, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cirrhosis', 'Phenotype', 'HP:0001394', (76, 85))	('cirrhosis', 'Disease', 'MESH:D005355', (76, 85))	('hepatitis', 'Disease', 'MESH:D056486', (29, 38))
386236	31711514	Recently, researchers have demonstrated that the life cycle of HBV is influenced by m6A modification that can affect the expression of viral oncoprotein and the reverse transcription of pre-genomic RNA (pgRNA).	('HBV', 'Disease', (63, 66))	('modification', 'Var', (88, 100))	('HBV', 'Disease', 'MESH:D006509', (63, 66))	('affect', 'Reg', (110, 116))	('expression', 'MPA', (121, 131))	('influenced', 'Reg', (70, 80))	('m6A', 'Gene', (84, 87))	('m6A', 'Gene', '56339', (84, 87))	('oncoprotein', 'Protein', (141, 152))	('viral oncoprotein', 'Protein', (135, 152))	('reverse transcription', 'MPA', (161, 182))
386238	31711514	Knock down of METTL3 and METTL14 increased the expression of HBc, HBs and the half-life of pgRNA, similar to YTHDF2 and YTHDF3.	('METTL14', 'Gene', (25, 32))	('pgRNA', 'Protein', (91, 96))	('HBc', 'Gene', '85348', (61, 64))	('METTL14', 'Gene', '57721', (25, 32))	('expression', 'MPA', (47, 57))	('METTL3', 'Gene', '56339', (14, 20))	('METTL3', 'Gene', (14, 20))	('increased', 'PosReg', (33, 42))	('half-life', 'MPA', (78, 87))	('HBs', 'Gene', (66, 69))	('Knock down', 'Var', (0, 10))	('HBc', 'Gene', (61, 64))
386249	31711514	found that knockdown of METTL3 inhibited the transcription of SOCS2 mRNA.	('METTL3', 'Gene', (24, 30))	('SOCS2', 'Gene', (62, 67))	('SOCS2', 'Gene', '8835', (62, 67))	('transcription', 'MPA', (45, 58))	('mRNA', 'Gene', (68, 72))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (11, 20))	('METTL3', 'Gene', '56339', (24, 30))
386263	31711514	A recent study revealed that m6A methylation participates in the oncogenesis of cervical cancer.	('methylation', 'Var', (33, 44))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('m6A', 'Gene', (29, 32))	('cancer', 'Disease', (89, 95))	('participates', 'Reg', (45, 57))	('m6A', 'Gene', '56339', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
386266	31711514	Moreover, for patients with cervical cancer, the disease-free survival (DFS) and overall survival (OS) were significantly higher in patients with high m6A level than those with low m6A level, indicating that the level of m6A methylation could be a prognostic marker of cervical cancer.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cervical', 'Disease', (28, 36))	('m6A', 'Gene', '56339', (221, 224))	('m6A', 'Gene', (151, 154))	('cancer', 'Disease', (278, 284))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (132, 140))	('m6A', 'Gene', '56339', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('m6A', 'Gene', (221, 224))	('m6A', 'Gene', (181, 184))	('cancer', 'Disease', (37, 43))	('higher', 'PosReg', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('high', 'Var', (146, 150))	('disease-free survival', 'CPA', (49, 70))	('overall survival', 'CPA', (81, 97))	('m6A', 'Gene', '56339', (151, 154))
386278	31711514	Like other virus, ZIKV viral-RNA is also modified at adenosines by writers and erasers; and perturbation of ZIKV m6A affects the replication efficiency and viral titer of ZIKV.	('ZIKV', 'Species', '64320', (171, 175))	('viral titer', 'CPA', (156, 167))	('ZIKV', 'Species', '64320', (18, 22))	('ZIKV', 'Species', '64320', (108, 112))	('adenosines', 'Chemical', 'MESH:D000241', (53, 63))	('perturbation', 'Var', (92, 104))	('m6A', 'Gene', (113, 116))	('replication efficiency', 'CPA', (129, 151))	('m6A', 'Gene', '56339', (113, 116))	('affects', 'Reg', (117, 124))
386281	31711514	Compared to YTHDF1 and YTHDF3, YTHDF2 has the greatest effect on ZIKV replication, RNA expression and stability of viral RNA.	('YTHDF1', 'Gene', '54915', (12, 18))	('ZIKV', 'Species', '64320', (65, 69))	('YTHDF2', 'Var', (31, 37))	('stability of viral RNA', 'CPA', (102, 124))	('YTHDF1', 'Gene', (12, 18))	('RNA expression', 'MPA', (83, 97))	('ZIKV replication', 'MPA', (65, 81))
386288	31711514	In addition, they demonstrated that overexpression of YTHDF2 significantly enhanced the replication of SV40, and mutation of YTHDF2 inhibited the replication of SV40.	('SV40', 'Gene', (103, 107))	('inhibited', 'NegReg', (132, 141))	('mutation', 'Var', (113, 121))	('replication', 'MPA', (88, 99))	('enhanced', 'PosReg', (75, 83))	('YTHDF2', 'Gene', (54, 60))	('SV40', 'Species', '1891767', (161, 165))	('YTHDF2', 'Gene', (125, 131))	('replication', 'MPA', (146, 157))	('SV40', 'Species', '1891767', (103, 107))
386300	31711514	EBV latent antigens are the major contributors to EBV-associated malignancies, and low expression of EBV latent antigens attenuates the EBV-mediated tumorigenesis.	('EBV', 'Disease', 'MESH:D020031', (50, 53))	('EBV', 'Disease', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('EBV', 'Disease', (50, 53))	('attenuates', 'NegReg', (121, 131))	('low expression', 'Var', (83, 97))	('EBV', 'Disease', 'MESH:D020031', (136, 139))	('EBV', 'Disease', 'MESH:D020031', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('EBV', 'Disease', (136, 139))	('EBV', 'Disease', (0, 3))	('tumor', 'Disease', (149, 154))	('EBV', 'Disease', 'MESH:D020031', (101, 104))
386305	31711514	The emergence of posttranscriptional modification of RNAs, especially the methylation of RNAs, has triggered several investigations into the role of such modifications on gene expression, cell behaviors, and physiological conditions in many species, including humans.	('methylation', 'Var', (74, 85))	('RNAs', 'Gene', (89, 93))	('RNAs', 'Gene', (53, 57))	('humans', 'Species', '9606', (260, 266))
386308	31711514	Emerging evidence indicates that aberrant expression of proteins related to m6A modification is associated with the development of various cancers, such as acute myeloid leukemia, lung cancer, and hepatocellular carcinoma.	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('associated', 'Reg', (96, 106))	('expression', 'MPA', (42, 52))	('cancers', 'Disease', (139, 146))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (197, 221))	('aberrant', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('hepatocellular carcinoma', 'Disease', (197, 221))	('lung cancer', 'Disease', (180, 191))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('acute myeloid leukemia', 'Disease', (156, 178))	('m6A', 'Gene', '56339', (76, 79))	('leukemia', 'Phenotype', 'HP:0001909', (170, 178))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (162, 178))	('modification', 'Var', (80, 92))	('m6A', 'Gene', (76, 79))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('proteins', 'Protein', (56, 64))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (197, 221))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (156, 178))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (156, 178))
386312	31711514	Thus, inhibition of m6A modification may be a potential therapy for virus induced diseases.	('m6A', 'Gene', (20, 23))	('m6A', 'Gene', '56339', (20, 23))	('inhibition', 'Var', (6, 16))
386409	27115504	Discard the ring and place the TE-tumor in a well of 6-well plate with medium at 37 C in a humidified incubator containing 5% CO2 during 2 weeks.	('TE-tumor', 'Disease', (31, 39))	('CO2', 'Chemical', '-', (126, 129))	('Discard', 'Var', (0, 7))	('TE-tumor', 'Disease', 'MESH:D009369', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
386426	25045413	PNET/EWS characteristically expresses fusion of the EWSR1 gene (22q12) with a member of the ETS gene family, including FLI1 (11q24), ERG (21q22), ETV1 (7p22), ETV4 (17q12), and FEV (2q36).	('EWSR1', 'Gene', (52, 57))	('fusion', 'Var', (38, 44))	('EWS', 'Gene', '2130', (52, 55))	('EWS', 'Gene', (52, 55))	('EWS', 'Gene', '2130', (5, 8))	('EWS', 'Gene', (5, 8))	('ETV4', 'Gene', (159, 163))	('ETV1', 'Gene', (146, 150))	('EWSR1', 'Gene', '2130', (52, 57))	('ETV1', 'Gene', '2115', (146, 150))	('FLI1', 'Gene', (119, 123))	('ERG', 'Gene', '2078', (133, 136))	('FLI1', 'Gene', '2313', (119, 123))	('ERG', 'Gene', (133, 136))	('ETV4', 'Gene', '2118', (159, 163))
386463	25045413	Chromosomal translocation (EWS-FLI1 gene) of chromosome t(11,22) (q24;q12) is a characteristic and unique feature of PNET/EWS, leading to oncogenesis.	('FLI1', 'Gene', (31, 35))	('EWS', 'Gene', '2130', (122, 125))	('FLI1', 'Gene', '2313', (31, 35))	('q24;q12', 'Var', (66, 73))	('Chromosomal translocation', 'Var', (0, 25))	('oncogenesis', 'CPA', (138, 149))	('leading to', 'Reg', (127, 137))	('EWS', 'Gene', '2130', (27, 30))	('EWS', 'Gene', (27, 30))	('EWS', 'Gene', (122, 125))
386464	25045413	In addition, cPNETs have increased expression of MYCN or MYCC genes and polysomies of chromosomes 2 and 8, which may in part account for their more aggressive behavior.	('MYCC', 'Gene', '4609', (57, 61))	('increased', 'PosReg', (25, 34))	('aggressive behavior', 'Phenotype', 'HP:0000718', (148, 167))	('MYCC', 'Gene', (57, 61))	('MYCN', 'Gene', (49, 53))	('expression', 'MPA', (35, 45))	('MYCN', 'Gene', '4613', (49, 53))	('polysomies', 'Var', (72, 82))
386482	25045413	This treatment could potentially have led to unrecognized mutations predisposing her to a second malignancy.	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('mutations', 'Var', (58, 67))	('malignancy', 'Disease', (97, 107))
386488	25045413	Those individuals with Li-Fraumeni syndrome with germline p53 mutations have an increased risk for breast cancer and sarcoma.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('sarcoma', 'Disease', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('germline', 'Var', (49, 57))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (23, 43))	('p53', 'Gene', (58, 61))	('Li-Fraumeni syndrome', 'Disease', (23, 43))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('mutations', 'Var', (62, 71))	('p53', 'Gene', '7157', (58, 61))
386489	25045413	One study of 525 patients, of which 91 were identified as having germline p53 mutations, showed a 35% incidence of breast cancer and a 26% incidence of sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('sarcoma', 'Disease', (152, 159))	('germline', 'Var', (65, 73))	('mutations', 'Var', (78, 87))	('p53', 'Gene', (74, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('patients', 'Species', '9606', (17, 25))	('p53', 'Gene', '7157', (74, 77))	('breast cancer', 'Disease', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
386493	25045413	Radon has been associated with an increased risk of lung malignancy, although there is no known association with sarcoma.	('lung malignancy', 'Phenotype', 'HP:0100526', (52, 67))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('lung malignancy', 'Disease', (52, 67))	('lung malignancy', 'Disease', 'MESH:D009369', (52, 67))	('sarcoma', 'Disease', (113, 120))	('Radon', 'Var', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
386525	21496258	According to the clinical information, histopathological features, and immunoprofiles, it was a case of malignant mesenchymoma, and the AJCC sarcoma staging was pT2bN0M0, stage III.	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('malignant mesenchymoma', 'Disease', (104, 126))	('AJCC sarcoma', 'Disease', (136, 148))	('malignant mesenchymoma', 'Disease', 'MESH:C535700', (104, 126))	('AJCC sarcoma', 'Disease', 'MESH:D012509', (136, 148))	('pT2bN0M0', 'Var', (161, 169))
386544	21496258	Chemotherapy and radiotherapy were ineffective for the soft parts of the sarcoma, including the malignant mesenchymoma, but the efficacy of chemotherapy with doxorubicin plus ifosfamide and cyclophosphamide, vincristine, doxorubicin, and dacarbazine has recently been reported.	('doxorubicin', 'Chemical', 'MESH:D004317', (158, 169))	('sarcoma', 'Disease', (73, 80))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (190, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('malignant mesenchymoma', 'Disease', (96, 118))	('doxorubicin', 'Chemical', 'MESH:D004317', (221, 232))	('malignant mesenchymoma', 'Disease', 'MESH:C535700', (96, 118))	('doxorubicin', 'Var', (158, 169))	('dacarbazine', 'Chemical', 'MESH:D003606', (238, 249))	('vincristine', 'Chemical', 'MESH:D014750', (208, 219))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))	('ifosfamide', 'Chemical', 'MESH:D007069', (175, 185))
386604	20831829	Accordingly, in the multivariate model only age 70+ HR 4.49 (95% CI: 1.78-11.3) and radicality HR 4.39 (95% CI: 1.80-10.7) remained significant predictors of death.	('radicality HR', 'Var', (84, 97))	('death', 'Disease', 'MESH:D003643', (158, 163))	('death', 'Disease', (158, 163))
386634	31311607	In contrast with pediatric sarcomas, adult malignancies are predisposed to increased mutational loads, while oncogenic gene fusions are commonly detected in pediatric sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('pediatric sarcomas', 'Disease', (17, 35))	('pediatric sarcomas', 'Disease', (157, 175))	('malignancies', 'Disease', (43, 55))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (17, 35))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (157, 175))	('mutational loads', 'Var', (85, 101))	('malignancies', 'Disease', 'MESH:D009369', (43, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (167, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
386667	31311607	For example, blockade of either the PD-1/PD-L1 or CTLA-4 axis results in expansion of distinct populations of otherwise exhausted intratumoral CD8+ T cells; CTLA-4 blockade also induces expansion of ICOS+ Th1-like cells.	('CTLA-4', 'Gene', (157, 163))	('OS', 'Phenotype', 'HP:0002669', (201, 203))	('Th1', 'Gene', '51497', (205, 208))	('CTLA-4', 'Gene', '1493', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('blockade', 'Var', (13, 21))	('CD8', 'Gene', (143, 146))	('tumor', 'Disease', (135, 140))	('CD8', 'Gene', '925', (143, 146))	('CTLA-4', 'Gene', '1493', (157, 163))	('Th1', 'Gene', (205, 208))	('CTLA-4', 'Gene', (50, 56))	('ICOS', 'Gene', (199, 203))	('expansion', 'PosReg', (73, 82))	('ICOS', 'Gene', '29851', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
386669	31311607	In addition to the distinct cell populations present within tumors, immune checkpoint expression on myeloid and tumor cells can suppress anti-tumor immunity.	('immune checkpoint', 'Var', (68, 85))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('suppress', 'NegReg', (128, 136))
386674	31311607	MicroRNA-140 in the OS microenvironment has been shown to decrease PD-L1 expression, myeloid-derived suppressor cells, and regulatory T cells and increase CD8+ lymphocytes.	('increase', 'PosReg', (146, 154))	('PD-L1', 'Gene', (67, 72))	('decrease PD', 'Phenotype', 'HP:0032198', (58, 69))	('myeloid-derived suppressor cells', 'CPA', (85, 117))	('decrease', 'NegReg', (58, 66))	('expression', 'MPA', (73, 83))	('CD8', 'Gene', (155, 158))	('OS', 'Phenotype', 'HP:0002669', (20, 22))	('CD8', 'Gene', '925', (155, 158))	('regulatory T cells', 'CPA', (123, 141))	('MicroRNA-140', 'Var', (0, 12))
386715	31311607	Although (as discussed) the number of mutations is limited, some sarcomas like Ewing's have conserved EWSR1-FLI1 fusions (present in 85% of patients) that may be amenable to immunotherapeutic targeting.	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('EWSR1', 'Gene', '2130', (102, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('fusions', 'Var', (113, 120))	('sarcomas', 'Disease', (65, 73))	("Ewing's", 'Disease', 'MESH:C563168', (79, 86))	('EWS', 'Phenotype', 'HP:0012254', (102, 105))	('patients', 'Species', '9606', (140, 148))	('EWSR1', 'Gene', (102, 107))	('Ewing', 'Disease', (79, 84))
386717	31311607	Other promising EWS-FLI1 inhibitors include lysine-specific demethylase 1 (LSD1), a demethylating protein that interacts with EWS-FLI1 to mitigate tumor suppression, and lurbinectedin, a trabectedin analog that inactivates EWS-FLI1 by redistributing its oncoprotein within the nucleus, that has shown preclinical efficacy in murine models, particularly in combination with the cytotoxic alkaloid irinotecan.	('mitigate', 'NegReg', (138, 146))	('EWS-FLI1', 'Gene', (16, 24))	('murine', 'Species', '10090', (325, 331))	('LSD1', 'Gene', '99982', (75, 79))	('tumor', 'Disease', (147, 152))	('inactivates', 'NegReg', (211, 222))	('interacts', 'Var', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('lysine-specific demethylase 1', 'Gene', '99982', (44, 73))	('redistributing', 'PosReg', (235, 249))	('EWS', 'Phenotype', 'HP:0012254', (16, 19))	('LSD1', 'Gene', (75, 79))	('EWS', 'Phenotype', 'HP:0012254', (223, 226))	('irinotecan', 'Chemical', 'MESH:D000077146', (396, 406))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('lysine-specific demethylase 1', 'Gene', (44, 73))	('EWS-FLI1', 'Gene', (223, 231))	('oncoprotein', 'Protein', (254, 265))	('EWS', 'Phenotype', 'HP:0012254', (126, 129))
386743	31311607	The survival was extended in patients receiving the vaccine compared to the patients in a contemporaneous control group.	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (76, 84))	('extended', 'PosReg', (17, 25))	('vaccine', 'Var', (52, 59))	('survival', 'MPA', (4, 12))
386750	31311607	Viral vaccines have demonstrated promise in early trials, including one patient with an impressive regression of metastatic recurrent SS after treatment with a DC-targeted lentivirus LV305.	('patient', 'Species', '9606', (72, 79))	('metastatic recurrent SS', 'Disease', (113, 136))	('LV305', 'Var', (183, 188))	('SS', 'Phenotype', 'HP:0012570', (134, 136))
386763	31311607	The presentation of endogenous antigen on MHC-I, including tumor-specific antigens encoded by mutations in intracellular proteins, enables the recognition of virtually any peptide, endogenous or exogenous, by CTLs in an MHC-restricted manner.	('tumor', 'Disease', (59, 64))	('mutations', 'Var', (94, 103))	('recognition', 'MPA', (143, 154))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('MHC-I', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
386776	31311607	Mutations in adult malignancies resulting from missense changes in cancer cells lead to new epitopes that sensitize endogenous immunity for rescue by immune checkpoint inhibitors.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('malignancies', 'Disease', (19, 31))	('cancer', 'Disease', (67, 73))	('missense changes', 'Var', (47, 63))	('epitopes', 'MPA', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))
386799	29091716	This may provide unique perspective on the role of non-coding DNA in cancer susceptibility and therapeutic development.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('non-coding', 'Var', (51, 61))	('cancer', 'Disease', (69, 75))
386808	29091716	How polymorphisms of GGAA-microsatellites in Ewing sarcoma affect EWS/FLI binding and transcriptional regulation across the genome, however, remains unclear.	('affect', 'Reg', (59, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('polymorphisms', 'Var', (4, 17))	('Ewing sarcoma', 'Disease', (45, 58))	('transcriptional regulation', 'MPA', (86, 112))	('GGAA-microsatellites', 'Gene', (21, 41))	('binding', 'Interaction', (74, 81))	('FLI', 'Gene', '2314', (70, 73))	('FLI', 'Gene', (70, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('EWS', 'Gene', '2130', (66, 69))	('EWS', 'Gene', (66, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 58))
386814	29091716	Once described, we then computationally link bound microsatellites to adjacent EWS/FLI regulated genes.	('EWS', 'Gene', '2130', (79, 82))	('EWS', 'Gene', (79, 82))	('microsatellites', 'Var', (51, 66))	('FLI', 'Gene', '2314', (83, 86))	('FLI', 'Gene', (83, 86))
386867	29091716	In the previous section, we established the global correlation between microsatellite motif number and EWS/FLI binding intensities.	('EWS', 'Gene', '2130', (103, 106))	('EWS', 'Gene', (103, 106))	('FLI', 'Gene', '2314', (107, 110))	('microsatellite motif', 'Var', (71, 91))	('FLI', 'Gene', (107, 110))
386871	29091716	Prior analysis of these regions, however, has primarily focused on microsatellites located within about 5kb of associated EWS/FLI target promoters.	('FLI', 'Gene', '2314', (126, 129))	('FLI', 'Gene', (126, 129))	('microsatellites', 'Var', (67, 82))	('EWS', 'Gene', '2130', (122, 125))	('EWS', 'Gene', (122, 125))
386872	29091716	We therefore separately evaluated EWS/FLI activated and repressed targets associated with microsatellites both near (within 5kb) and distal (greater than 5kb) to the TSS of these genes.	('EWS', 'Gene', (34, 37))	('microsatellites', 'Var', (90, 105))	('FLI', 'Gene', '2314', (38, 41))	('FLI', 'Gene', (38, 41))	('EWS', 'Gene', '2130', (34, 37))
386903	29091716	Increased EWS/FLI binding enrichment is also shown to be positively correlated with total number of motifs (r = 0.22, p = 3.0x10-6) at these microsatellites (S10A Fig).	('S10A', 'Var', (158, 162))	('FLI', 'Gene', '2314', (14, 17))	('S10A', 'SUBSTITUTION', 'None', (158, 162))	('FLI', 'Gene', (14, 17))	('EWS', 'Gene', '2130', (10, 13))	('EWS', 'Gene', (10, 13))
386904	29091716	We found, however, there is no significant correlation between EWS/FLI binding and expression of repressed genes more than 5kb from their associated microsatellite (r = -0.05, p = 0.33) (S10B Fig).	('EWS', 'Gene', '2130', (63, 66))	('EWS', 'Gene', (63, 66))	('S10B', 'Var', (187, 191))	('S10B', 'SUBSTITUTION', 'None', (187, 191))	('FLI', 'Gene', '2314', (67, 70))	('expression', 'MPA', (83, 93))	('FLI', 'Gene', (67, 70))
386916	29091716	The present genome-wide analysis provides further support for length-dependency of EWS/FLI responsiveness near activated, promoter-like and enhancer-like microsatellites.	('EWS', 'Gene', '2130', (83, 86))	('EWS', 'Gene', (83, 86))	('FLI', 'Gene', '2314', (87, 90))	('microsatellites', 'Var', (154, 169))	('FLI', 'Gene', (87, 90))
386919	29091716	The association of EWS/FLI-bound microsatellites with only activated genes supports a likely molecular mechanistic difference in transcriptional modulation of EWS/FLI up vs. down-regulated targets.	('EWS', 'Gene', '2130', (159, 162))	('FLI', 'Gene', (23, 26))	('EWS', 'Gene', (159, 162))	('EWS', 'Gene', '2130', (19, 22))	('EWS', 'Gene', (19, 22))	('FLI', 'Gene', '2314', (163, 166))	('microsatellites', 'Var', (33, 48))	('FLI', 'Gene', (163, 166))	('FLI', 'Gene', '2314', (23, 26))
386934	29091716	Although minimal, due to few microsatellites longer than 20 consecutive repeats across the genome, our overall data nevertheless suggests that microsatellites with numbers of GGAA-motifs greater than the "sweet-spot" are not associated with EWS/FLI-mediated differential gene expression.	('FLI', 'Gene', (245, 248))	('associated', 'Reg', (225, 235))	('FLI', 'Gene', '2314', (245, 248))	('EWS', 'Gene', '2130', (241, 244))	('EWS', 'Gene', (241, 244))	('microsatellites', 'Var', (143, 158))
386938	29091716	To evaluate the appropriateness of using the human reference genome, we selected a number of our favorite EWS/FLI activated genes, amplified the associated GGAA-microsatellites, and sequenced these regions.	('amplified', 'Var', (131, 140))	('human', 'Species', '9606', (45, 50))	('FLI', 'Gene', '2314', (110, 113))	('EWS', 'Gene', '2130', (106, 109))	('EWS', 'Gene', (106, 109))	('FLI', 'Gene', (110, 113))
387019	28046107	Notably, changes in miR-210 were correlated with changes in homeobox A1 (HOXA1), a well-described target of miR-210, and CLUH, a regulator of mitochondrial biogenesis, among others.	('miR-210', 'Gene', '406992', (20, 27))	('CLUH', 'Gene', (121, 125))	('changes', 'Var', (9, 16))	('miR-210', 'Gene', '406992', (108, 115))	('homeobox A1', 'Gene', (60, 71))	('HOXA1', 'Gene', (73, 78))	('CLUH', 'Gene', '23277', (121, 125))	('homeobox A1', 'Gene', '3198', (60, 71))	('HOXA1', 'Gene', '3198', (73, 78))	('changes', 'Reg', (49, 56))	('miR-210', 'Gene', (108, 115))	('miR-210', 'Gene', (20, 27))
387037	28046107	In addition, the results demonstrate that while the hypoxic response comprises a substantial portion of the changes in cellular gene expression induced by KSHV, KSHV induces a number of other changes in gene expression unrelated to hypoxia.	('KSHV', 'Species', '37296', (161, 165))	('KSHV', 'Var', (161, 165))	('hypoxia', 'Disease', (232, 239))	('KS', 'Phenotype', 'HP:0100726', (161, 163))	('rat', 'Species', '10116', (32, 35))	('KS', 'Phenotype', 'HP:0100726', (155, 157))	('KSHV', 'Species', '37296', (155, 159))	('cellular gene expression', 'MPA', (119, 143))	('changes', 'Reg', (108, 115))	('KSHV', 'Gene', (155, 159))	('hypoxia', 'Disease', 'MESH:D000860', (232, 239))
387098	28046107	Note that after transient transfection with miRNA mimics or antisense inhibitors, the majority of transfected RNA is vesicular and is therefore not accessible for loading into Argonaute.	('vesicular', 'MPA', (117, 126))	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('antisense', 'Var', (60, 69))
387102	28046107	ISCU was found significantly down-regulated after transfection of miR-210 mimics and after exposure to hypoxia (NT control, mimic-ctrl, and anti-ctrl).	('hypoxia', 'Disease', (103, 110))	('ISCU', 'Gene', '23479', (0, 4))	('mimics', 'Var', (74, 80))	('miR-210', 'Gene', '406992', (66, 73))	('miR-210', 'Gene', (66, 73))	('down-regulated', 'NegReg', (29, 43))	('ISCU', 'Gene', (0, 4))	('transfection', 'Var', (50, 62))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))
387152	28046107	The systems and pathways that are induced by hypoxia include glycolysis and glucose uptake, growth factor signaling, immortalization, resistance to apoptosis, angiogenesis, and genetic instability.	('immortalization', 'CPA', (117, 132))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('glucose', 'CPA', (76, 83))	('glycolysis', 'MPA', (61, 71))	('growth', 'CPA', (92, 98))	('hypoxia', 'Disease', (45, 52))	('angiogenesis', 'CPA', (159, 171))	('hypoxia', 'Disease', 'MESH:D000860', (45, 52))	('genetic', 'Var', (177, 184))
387153	28046107	It is notable that KSHV has such an effect on hypoxia-related genes, and raises the question as to what evolutionary advantage it provides the virus.	('hypoxia', 'Disease', 'MESH:D000860', (46, 53))	('hypoxia', 'Disease', (46, 53))	('KSHV', 'Species', '37296', (19, 23))	('effect', 'Reg', (36, 42))	('KSHV', 'Var', (19, 23))	('KS', 'Phenotype', 'HP:0100726', (19, 21))
387169	28046107	To further explore whether there was substantial overlap in the cellular response to KSHV infection and to hypoxia in systems that were biologically more similar to KS, we used published datasets to analyze gene changes in HUVECs and in KS lesions, and found evidence in these systems as well.	('KS lesions', 'Disease', 'MESH:D051437', (237, 247))	('KS', 'Phenotype', 'HP:0100726', (237, 239))	('KS', 'Phenotype', 'HP:0100726', (165, 167))	('KS', 'Phenotype', 'HP:0100726', (85, 87))	('KSHV infection', 'Disease', 'MESH:C537372', (85, 99))	('changes', 'Var', (212, 219))	('KS lesions', 'Disease', (237, 247))	('KSHV infection', 'Disease', (85, 99))	('hypoxia', 'Disease', (107, 114))	('hypoxia', 'Disease', 'MESH:D000860', (107, 114))
387184	28046107	An important target of miR-210 is ISCU, a mitochondrial iron sulfur scaffold protein involved in cellular metabolism, and as seen here, changes in ISCU are consistent with its regulation by miR-210 in KSHV-infected cells (Fig 4C).	('KSHV-infected', 'Disease', 'MESH:C537372', (201, 214))	('ISCU', 'Gene', '23479', (147, 151))	('ISCU', 'Gene', '23479', (34, 38))	('iron sulfur', 'Chemical', '-', (56, 67))	('changes', 'Var', (136, 143))	('miR-210', 'Gene', (190, 197))	('miR-210', 'Gene', (23, 30))	('miR-210', 'Gene', '406992', (190, 197))	('miR-210', 'Gene', '406992', (23, 30))	('KS', 'Phenotype', 'HP:0100726', (201, 203))	('KSHV-infected', 'Disease', (201, 214))	('ISCU', 'Gene', (147, 151))	('ISCU', 'Gene', (34, 38))
387186	28046107	Such changes could help promote the Warburg effect that has been described in KSHV-infected cells and favors their cell growth and survival.	('KS', 'Phenotype', 'HP:0100726', (78, 80))	('KSHV-infected', 'Disease', (78, 91))	('changes', 'Var', (5, 12))	('cell growth', 'CPA', (115, 126))	('KSHV-infected', 'Disease', 'MESH:C537372', (78, 91))	('Warburg effect', 'CPA', (36, 50))	('promote', 'PosReg', (24, 31))	('favors', 'PosReg', (102, 108))
387196	28046107	Interestingly, while GLUT1 is up-regulated in endothelial cells acutely infected by KSHV, it has recently been reported to be down-regulated in acutely infected rat mesenchymal cells.	('down-regulated', 'NegReg', (126, 140))	('GLUT1', 'Gene', (21, 26))	('GLUT1', 'Gene', '6513', (21, 26))	('KS', 'Phenotype', 'HP:0100726', (84, 86))	('rat', 'Species', '10116', (161, 164))	('KSHV', 'Var', (84, 88))	('KSHV', 'Species', '37296', (84, 88))	('up-regulated', 'PosReg', (30, 42))
387238	28046107	All samples were stored at -80 C. For miRNA expression, stem-loop qPCR was performed using TaqMan Universal master mix (Applied Biosystems) and the following microRNA assays: 000512 for miR-210-3p, 197204 for miR-K12-1-5p, 197192 for miR-K12-2-5p, 008316 for miR-K12-3-5p, 197240 for miR-K12-4-3p, 008459 for miR-K12-6-3p, 241994 for miR-K12-8-3p, 008504 for miR-K12-10a-3p, and 008562 for miR-K12-11-3p.	('miR', 'Gene', '220972', (259, 262))	('miR', 'Gene', (284, 287))	('miR', 'Gene', '220972', (209, 212))	('008562', 'Var', (379, 385))	('miR', 'Gene', '220972', (234, 237))	('miR', 'Gene', (38, 41))	('miR', 'Gene', '220972', (186, 189))	('miR', 'Gene', (259, 262))	('miR', 'Gene', (209, 212))	('miR-210', 'Gene', '406992', (186, 193))	('miR', 'Gene', (234, 237))	('miR', 'Gene', '220972', (334, 337))	('197204', 'Var', (198, 204))	('miR', 'Gene', '220972', (359, 362))	('miR', 'Gene', (186, 189))	('miR', 'Gene', '220972', (390, 393))	('miR-210', 'Gene', (186, 193))	('241994', 'Var', (323, 329))	('miR', 'Gene', '220972', (309, 312))	('008504', 'Var', (348, 354))	('miR', 'Gene', (334, 337))	('miR', 'Gene', (359, 362))	('197192', 'Var', (223, 229))	('miR', 'Gene', '220972', (284, 287))	('miR', 'Gene', (390, 393))	('197240', 'Var', (273, 279))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (309, 312))	('008459', 'Var', (298, 304))
387313	25501082	According to the American Joint Committee on Cancer criterion, the tumor size was categorized as <=5 cm (T1) or >5 cm (T2) and <=8 cm (T1) or >8 cm (T2) for soft-tissue and bone tumors, respectively.	('tumor', 'Disease', (178, 183))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('soft-tissue', 'CPA', (157, 168))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', (45, 51))	('bone tumors', 'Disease', (173, 184))	('bone tumors', 'Disease', 'MESH:D001859', (173, 184))	('>5 cm', 'Var', (112, 117))	('<=8 cm', 'Var', (127, 133))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('bone tumors', 'Phenotype', 'HP:0010622', (173, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
387370	25984907	miRNAs are known to be involved in a wide array of biological processes including cell differentiation, development, cell death, homeostasis, and fine-tuning their regulation and their aberrant expression have been shown to be strongly correlated to STS pathogenesis.	('STS', 'Phenotype', 'HP:0030448', (250, 253))	('aberrant', 'Var', (185, 193))	('miR', 'Gene', '220972', (0, 3))	('correlated', 'Reg', (236, 246))	('miR', 'Gene', (0, 3))	('expression', 'MPA', (194, 204))	('regulation', 'MPA', (164, 174))	('involved', 'Reg', (23, 31))
387447	25984907	Comparative genomic hybridization (CGH) studies on copy number in dedifferentiated and pleomorphic liposarcomas have revealed gain in copy number of oncogenes, notably ESR1 (Estrogen receptor 1), a receptor in estrogen signaling.	('gain', 'PosReg', (126, 130))	('liposarcomas', 'Phenotype', 'HP:0012034', (99, 111))	('Estrogen receptor 1', 'Gene', '2099', (174, 193))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (87, 111))	('copy number', 'MPA', (134, 145))	('ESR1', 'Gene', (168, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('liposarcoma', 'Phenotype', 'HP:0012034', (99, 110))	('copy', 'Var', (51, 55))	('Estrogen receptor 1', 'Gene', (174, 193))	('pleomorphic liposarcomas', 'Disease', (87, 111))	('dedifferentiated', 'Disease', (66, 82))	('ESR1', 'Gene', '2099', (168, 172))
387473	25984907	We retrieved primary high grade STS gene expression profile (GSE21122) of Affymetrix's platform (Human Genome U133A technology) and miRNA expression profile (GSE36982) of Illumina platform from Gene expression omnibus database (GEO).	('STS', 'Phenotype', 'HP:0030448', (32, 35))	('GSE21122', 'Var', (61, 69))	('Human', 'Species', '9606', (97, 102))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (132, 135))
387537	25231134	While the majority of LGFMS cases are characterized by a FUS-CREB3L1 fusion, both FUS-CREB3L2 and EWSR1-CREB3L1 fusions were recently demonstrated in a small number of LGFMS and SEF/LGFMS hybrid tumors.	('CREB3L1', 'Gene', (104, 111))	('tumors', 'Disease', (195, 201))	('EWSR1', 'Gene', '2130', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('LGFMS', 'Disease', (22, 27))	('LGFMS', 'Disease', (168, 173))	('CREB3L1', 'Gene', (61, 68))	('EWSR1', 'Gene', (98, 103))	('CREB3L1', 'Gene', '90993', (61, 68))	('fusion', 'Var', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('CREB3L1', 'Gene', '90993', (104, 111))
387538	25231134	In contrast, recent studies pointed out that SEF harbor frequent EWSR1 rearrangements, with only a minority of cases showing FUS-CREB3L2 fusions.	('EWSR1', 'Gene', (65, 70))	('EWSR1', 'Gene', '2130', (65, 70))	('rearrangements', 'Var', (71, 85))
387541	25231134	The majority (90%) of pure SEF cases showed EWSR1 gene rearrangements by FISH with only one case exhibiting FUS rearrangement.	('EWSR1', 'Gene', '2130', (44, 49))	('rearrangements', 'Var', (55, 69))	('EWSR1', 'Gene', (44, 49))
387542	25231134	Of the 9 EWSR1 positive cases, 6 cases harbored CREB3L1 break-apart, two had CREB3L2 rearrangement (a previously unreported finding) and one lacked evidence of CREB3L1/2 abnormalities.	('rearrangement', 'Var', (85, 98))	('CREB3L1', 'Gene', '90993', (48, 55))	('break-apart', 'Var', (56, 67))	('CREB3L1', 'Gene', '90993', (160, 167))	('EWSR1', 'Gene', (9, 14))	('CREB3L1', 'Gene', (160, 167))	('EWSR1', 'Gene', '2130', (9, 14))	('CREB3L1', 'Gene', (48, 55))
387544	25231134	These results further demarcate a relative cytogenetic dichotomy between pure SEF, often characterized by EWSR1 rearrangements, and hybrid SEF/LGFMS, harboring FUS-CREB3L2 fusion; the latter group recapitulating the genotype of LGFMS.	('EWSR1', 'Gene', (106, 111))	('rearrangements', 'Var', (112, 126))	('EWSR1', 'Gene', '2130', (106, 111))
387550	25231134	The majority of LGFMS exhibit the characteristic t(7;16)(q33;p11) translocation resulting in FUS-CREB3L2 fusion, with rare reported cases harboring a t(11;16)(p11;p11) secondary to a FUS-CREB3L1 fusion.	('t(7;16)(q33;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 65))	('CREB3L1', 'Gene', (187, 194))	('t(7;16)(q33;p11) translocation', 'Var', (49, 79))	('LGFMS', 'Gene', (16, 21))	('translocation', 'Var', (66, 79))	('CREB3L1', 'Gene', '90993', (187, 194))	('FUS-CREB3L2', 'Disease', (93, 104))	('resulting in', 'Reg', (80, 92))	('t(11;16)(p11;p11', 'Var', (150, 166))	('t(11;16)(p11;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (150, 167))
387552	25231134	In contrast, in a series of 22 morphologically pure SEFs, FUS gene rearrangements were found in only 2 cases (9%), after extensive sampling of the tumors to rule out the presence of a LGFMS component.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('FUS gene', 'Gene', (58, 66))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('rearrangements', 'Var', (67, 81))	('found', 'Reg', (87, 92))
387553	25231134	In addition to the rare FUS-CREB3L1 variant, EWSR1-CRE3BL1 fusions were also described in two LGFMS cases and in a small number of tumors with SEF/LGFMS hybrid morphology.	('CREB3L1', 'Gene', '90993', (28, 35))	('EWSR1', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('EWSR1', 'Gene', '2130', (45, 50))	('BL1', 'CellLine', 'CVCL:3454', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('fusions', 'Var', (59, 66))	('CREB3L1', 'Gene', (28, 35))	('LGFMS', 'Disease', (94, 99))
387599	25231134	The overwhelming majority of pure SEF cases (9/10, 90%) showed EWSR1 rearrangements.	('rearrangements', 'Var', (69, 83))	('EWSR1', 'Gene', '2130', (63, 68))	('EWSR1', 'Gene', (63, 68))	('pure SEF', 'Disease', (29, 37))
387600	25231134	Six out of nine examples of the EWSR1-rearranged lesions exhibited CREB3L1 gene break-apart by FISH (Figures 1G,H), two cases revealed a CREB3L2 rearrangements (one case by FISH, Figure 1I and the other by RNAseq, see below) and the remaining case lacked abnormalities in both genes.	('CREB3L1', 'Gene', '90993', (67, 74))	('CREB3L1', 'Gene', (67, 74))	('rearrangements', 'Var', (145, 159))	('revealed', 'Reg', (126, 134))	('break-apart', 'NegReg', (80, 91))	('EWSR1', 'Gene', (32, 37))	('CREB3L2', 'Gene', (137, 144))	('EWSR1', 'Gene', '2130', (32, 37))
387602	25231134	The only SEF case investigated by RNAseq (SEF 3) was selected due to a positive EWSR1 rearrangement result, but negative FISH results for both CREB3L1/2 gene abnormalities.	('EWSR1', 'Gene', (80, 85))	('rearrangement', 'Var', (86, 99))	('result', 'Reg', (100, 106))	('CREB3L1', 'Gene', (143, 150))	('CREB3L1', 'Gene', '90993', (143, 150))	('EWSR1', 'Gene', '2130', (80, 85))
387617	25231134	Fluorescence in situ hybridization (FISH) analysis using custom break-apart probes interrogating the EWSR1, FUS, CREB3L1 and CREB3L2 loci revealed that a great majority of the pure SEF tumors (83%) exhibited rearrangements of EWSR1, which was accompanied by CREB3L1 break-apart in all except two cases, showing an EWSR1-CREB3L2 fusion instead.	('CREB3L1', 'Gene', '90993', (258, 265))	('EWSR1', 'Gene', '2130', (101, 106))	('EWSR1', 'Gene', '2130', (226, 231))	('EWSR1', 'Gene', (101, 106))	('EWSR1', 'Gene', (314, 319))	('SEF tumors', 'Disease', (181, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('CREB3L1', 'Gene', (113, 120))	('SEF tumors', 'Disease', 'MESH:D009369', (181, 191))	('exhibited', 'Reg', (198, 207))	('CREB3L1', 'Gene', '90993', (113, 120))	('rearrangements', 'Var', (208, 222))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('EWSR1', 'Gene', (226, 231))	('EWSR1', 'Gene', '2130', (314, 319))	('CREB3L1', 'Gene', (258, 265))
387620	25231134	Since a moderate amount of spindling was also present in 60% of the EWSR1 rearranged tumors, we concluded that probably there is no correlation between the presence of spindle cell component and the type of rearrangement in an otherwise typical SEF.	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('EWSR1', 'Gene', '2130', (68, 73))	('rearranged', 'Var', (74, 84))	('tumors', 'Disease', (85, 91))	('EWSR1', 'Gene', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
387621	25231134	The presence of EWSR1 rearrangements in SEF was first recognized by Doyle et al.	('rearrangements', 'Var', (22, 36))	('EWSR1', 'Gene', '2130', (16, 21))	('EWSR1', 'Gene', (16, 21))
387623	25231134	composed of a total of 15 cases of both morphologically "pure" SEFs (10 cases) and SEF/LGFMS hybrid tumors (5 cases) explored the prevalence of EWSR1, FUS, CREB3L1 and CREB3L2 rearrangements in this group of tumors with a combination of RT-PCR and FISH techniques in an effort to better characterize the shared pathogenesis between SEF and LGFMS.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CREB3L2', 'Gene', (168, 175))	('EWSR1', 'Gene', '2130', (144, 149))	('CREB3L1', 'Gene', '90993', (156, 163))	('CREB3L1', 'Gene', (156, 163))	('rearrangements', 'Var', (176, 190))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('EWSR1', 'Gene', (144, 149))
387624	25231134	Their results show a bona fide recurrent EWSR1-CREB3L1 fusion/rearrangement by either RT-PCR or FISH in four of their SEF cases (4/10), while the remainder SEF cases (6/10) revealed either loss of 3' EWSR1 locus (3/10), an altogether hemizygous deletion of EWSR1 (2/10) or a negative FISH and RT-PCR result for all loci (EWSR1, FUS and CREB3L1/2) in one case (1/10).	('EWSR1', 'Gene', (257, 262))	('EWSR1', 'Gene', (41, 46))	('EWSR1', 'Gene', '2130', (321, 326))	('deletion', 'Var', (245, 253))	('EWSR1', 'Gene', (200, 205))	('EWSR1', 'Gene', '2130', (257, 262))	('CREB3L1', 'Gene', '90993', (336, 343))	('EWSR1', 'Gene', (321, 326))	('EWSR1', 'Gene', '2130', (41, 46))	('CREB3L1', 'Gene', (336, 343))	('CREB3L1', 'Gene', '90993', (47, 54))	('CREB3L1', 'Gene', (47, 54))	('EWSR1', 'Gene', '2130', (200, 205))	('loss', 'NegReg', (189, 193))
387626	25231134	Additionally, 5/7 SEF interrogated cases were positive for CREB3L1 rearrangements by FISH and two were negative.	('rearrangements', 'Var', (67, 81))	('CREB3L1', 'Gene', '90993', (59, 66))	('positive', 'Reg', (46, 54))	('CREB3L1', 'Gene', (59, 66))
387629	25231134	Overall, our results are quite similar; especially with regards to EWSR1 rearrangements/aberrations predominantly identified in pure SEF cases (9 of the 10 cases), while the hybrid SEF/LGFMS lesions were exclusively characterized by FUS-CREB3L2 fusion transcripts by RT-PCR.	('EWSR1', 'Gene', '2130', (67, 72))	('EWSR1', 'Gene', (67, 72))	('FUS-CREB3L2', 'Protein', (233, 244))	('fusion transcripts', 'Var', (245, 263))
387630	25231134	The soft tissue tumors that harbor aberrations involving EWSR1 rearrangements are legion.	('aberrations', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('rearrangements', 'Var', (63, 77))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (4, 21))	('soft tissue tumors', 'Disease', (4, 22))	('EWSR1', 'Gene', (57, 62))	('soft tissue tumors', 'Disease', 'MESH:D012983', (4, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (4, 22))	('EWSR1', 'Gene', '2130', (57, 62))
387634	25231134	This similarity in function between EWSR1 and FUS is evidenced by the plethora of soft tissue tumors that can interchangeably exhibit fusions involving EWSR1 and FUS, namely angiomatoid fibrous histiocytoma, myxoid liposarcoma and Ewing sarcoma.	('plethora', 'Phenotype', 'HP:0001050', (70, 78))	('EWSR1', 'Gene', '2130', (36, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (231, 244))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (231, 244))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (82, 99))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (174, 206))	('EWSR1', 'Gene', '2130', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (208, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('angiomatoid fibrous histiocytoma', 'Disease', (174, 206))	('myxoid liposarcoma', 'Disease', (208, 226))	('histiocytoma', 'Phenotype', 'HP:0012315', (194, 206))	('soft tissue tumors', 'Disease', (82, 100))	('EWSR1', 'Gene', (36, 41))	('Ewing sarcoma', 'Disease', (231, 244))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (82, 100))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (208, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('EWSR1', 'Gene', (152, 157))	('soft tissue tumors', 'Disease', 'MESH:D012983', (82, 100))	('fusions', 'Var', (134, 141))	('liposarcoma', 'Phenotype', 'HP:0012034', (215, 226))
387647	25231134	In selected cases the distinction of SEF from both myoepithelial tumors and SBRCTs is further complicated if one were solely rely on the presence of EWSR1 rearrangement, without interrogating the CREB3L1/2 status and/or immunohistochemistry for MUC4.	('EWSR1', 'Gene', '2130', (149, 154))	('EWSR1', 'Gene', (149, 154))	('myoepithelial tumors', 'Disease', (51, 71))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (51, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('MUC4', 'Gene', (245, 249))	('rearrangement', 'Var', (155, 168))	('CREB3L1', 'Gene', '90993', (196, 203))	('CREB3L1', 'Gene', (196, 203))	('MUC4', 'Gene', '140474', (245, 249))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
387659	23959089	In paraffin-embedded specimens, expression of the following molecular markers was detected: CD10 (27/36), vimentin (37/38), HHF35 (3/32), S-100 (0/25), desmin (2/29), CD117 (0/23), CD34 (2/24), alpha-inhibin (0/17), CK (1/34), CD99 (4/9), smooth muscle actin (5/25), EMA (0/7), estrogen receptor (13/16) and progesterone receptor (13/16).	('CD99', 'Gene', '4267', (227, 231))	('CD10', 'Gene', (92, 96))	('S-100', 'Var', (138, 143))	('CD34', 'Gene', '947', (181, 185))	('vimentin', 'Gene', '7431', (106, 114))	('CD117', 'Gene', (167, 172))	('vimentin', 'Gene', (106, 114))	('desmin', 'Gene', '1674', (152, 158))	('estrogen receptor', 'Gene', '2099', (278, 295))	('smooth muscle actin', 'Protein', (239, 258))	('alpha-inhibin', 'Protein', (194, 207))	('CD34', 'Gene', (181, 185))	('(13/16) and progesterone receptor', 'Gene', '5241', (296, 329))	('estrogen receptor', 'Gene', (278, 295))	('CD10', 'Gene', '4311', (92, 96))	('CD99', 'Gene', (227, 231))	('desmin', 'Gene', (152, 158))	('13/16) and progesterone receptor', 'Gene', (297, 329))	('CD117', 'Gene', '3815', (167, 172))	('HHF35', 'Gene', (124, 129))
387686	23959089	In our study, the group of ESS cases expressed CD10, vimentin, HHF35, desmin, CD34, CK, CD99, smooth muscle actin, estrogen receptor, and progesterone receptor.	('CD99', 'Gene', (88, 92))	('CD34', 'Protein', (78, 82))	('vimentin', 'Protein', (53, 61))	('HHF35', 'Gene', (63, 68))	('ESS', 'Disease', (27, 30))	('desmin', 'Protein', (70, 76))	('expressed', 'Reg', (37, 46))	('CD10', 'Var', (47, 51))	('smooth muscle actin, estrogen receptor, and progesterone receptor', 'Gene', '5241', (94, 159))
387752	31402605	Diaphyseal malignancies with MSS >=10 may contraindicate DBR for increased chances of reconstructive failure.	('DBR', 'Disease', (57, 60))	('DBR', 'Chemical', '-', (57, 60))	('Diaphyseal malignancies', 'Disease', (0, 23))	('MSS >=10', 'Var', (29, 37))	('Diaphyseal malignancies', 'Disease', 'MESH:D009369', (0, 23))
387842	31402605	The current study demonstrates that MSS may yield favorable performance in predicting reconstructive failures of replanted tumor-bearing autografts; cases exhibiting MSS >=10 are exposed to >=22.7% likelihood of fractures, although several procedures including bone grafting and cement may augment the rigidity of devitalized grafts.	('MSS', 'Gene', (166, 169))	('tumor', 'Disease', (123, 128))	('fractures', 'Disease', (212, 221))	('rigidity', 'Phenotype', 'HP:0002063', (302, 310))	('rigidity', 'Disease', (302, 310))	('>=10', 'Var', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('fractures', 'Disease', 'MESH:D050723', (212, 221))	('rigidity', 'Disease', 'MESH:D009127', (302, 310))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
387856	31402605	MSS >= 10 may contraindicate DBR, and in such situations other procedures are advisable.	('DBR', 'Disease', (29, 32))	('DBR', 'Chemical', '-', (29, 32))	('MSS >= 10', 'Var', (0, 9))
387953	20981248	For instance, many are encoded by multigene families, can be epigenetically regulated in expression level with drugs such as 5-aza-2'-deoxycytidine, and many have unknown functionality yet appear to play some role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (125, 147))	('role', 'Reg', (209, 213))	('epigenetically regulated', 'Var', (61, 85))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('play', 'Reg', (199, 203))
387968	20981248	Some members of this family can become fused to the SS18 protein in synovial sarcoma (SS) through gene translocations, which is how these proteins were first identified.	('synovial sarcoma', 'Disease', (68, 84))	('fused', 'Reg', (39, 44))	('gene translocations', 'Var', (98, 117))	('SS', 'Phenotype', 'HP:0012570', (52, 54))	('SS', 'Phenotype', 'HP:0012570', (86, 88))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (68, 84))	('synovial sarcoma', 'Disease', 'MESH:D013584', (68, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
387972	20981248	The SSX gene family was first identified through cytogenetic studies of synovial sarcoma (SS) in which approximately 70% of both biphasic and monophasic SS tumor types were found to contain the same characteristic chromosomal translocation event t(X;18)(p11.2;q11.2).	('SS tumor', 'Disease', 'MESH:D009369', (153, 161))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (72, 88))	('synovial sarcoma', 'Disease', 'MESH:D013584', (72, 88))	('t(X;18)(p11.2;q11.2', 'Var', (246, 265))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (246, 266))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('SSX', 'Gene', '6757', (4, 7))	('SS', 'Phenotype', 'HP:0012570', (90, 92))	('SS', 'Phenotype', 'HP:0012570', (4, 6))	('SSX', 'Gene', (4, 7))	('SS', 'Phenotype', 'HP:0012570', (153, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('synovial sarcoma', 'Disease', (72, 88))	('SS tumor', 'Disease', (153, 161))
388003	20981248	From these sequencing studies, the authors confirmed that all members share conserved exon/intron junctions, exon sizes, and most introns, with a few exceptions for alternative splice isoforms (i.e., SSX2, SSX4, SSX5 and SSX7).	('SSX7', 'Gene', (221, 225))	('SSX5', 'Gene', (212, 216))	('SSX5', 'Gene', '6758', (212, 216))	('SSX7', 'Gene', '280658', (221, 225))	('SS', 'Phenotype', 'HP:0012570', (212, 214))	('SS', 'Phenotype', 'HP:0012570', (206, 208))	('SSX4', 'Var', (206, 210))	('SS', 'Phenotype', 'HP:0012570', (200, 202))	('SS', 'Phenotype', 'HP:0012570', (221, 223))	('SSX2', 'Var', (200, 204))
388049	20981248	Creating a series of FLAG- or VSV-tagged deletion mutants, they showed that the N-terminal amino acids 51 to 90 of SS18 are responsible for its nuclear localization, even though this region does not contain an NLS, whereas SSX nuclear targeting was dependent on the last 34 C-terminal amino acids (SSXRD).	('responsible', 'Reg', (124, 135))	('SSX', 'Gene', (223, 226))	('SS', 'Phenotype', 'HP:0012570', (298, 300))	('SS18', 'Gene', (115, 119))	('SS', 'Phenotype', 'HP:0012570', (115, 117))	('SSX', 'Gene', '6757', (298, 301))	('SS', 'Phenotype', 'HP:0012570', (223, 225))	('SSX', 'Gene', (298, 301))	('deletion mutants', 'Var', (41, 57))	('mutants', 'Var', (50, 57))	('SSX', 'Gene', '6757', (223, 226))	('nuclear localization', 'MPA', (144, 164))
388051	20981248	to be the dominant SSX NLS, was confirmed by amino acid substitutions to play a role in nuclear targeting.	('SSX', 'Gene', '6757', (19, 22))	('SS', 'Phenotype', 'HP:0012570', (19, 21))	('SSX', 'Gene', (19, 22))	('amino acid substitutions', 'Var', (45, 69))
388052	20981248	However, knockout of NLS3 resulted in both cytoplasmic and nuclear staining suggesting that SSX may use additional, nonbasic amino acid residues for nuclear targeting.	('knockout', 'Var', (9, 17))	('SS', 'Phenotype', 'HP:0012570', (92, 94))	('SSX', 'Gene', '6757', (92, 95))	('SSX', 'Gene', (92, 95))	('resulted', 'Reg', (26, 34))	('NLS3', 'Gene', (21, 25))
388060	20981248	However, in the Soulez paper, toroidal-like structures were observed in 2C4 cells transfected with SS18 or SS18-SSX1/2, and two prominent foci were observed in the cells transfected with SS18-SSX1/2 or SSX1/2.	('SS', 'Phenotype', 'HP:0012570', (112, 114))	('SS', 'Phenotype', 'HP:0012570', (187, 189))	('SS', 'Phenotype', 'HP:0012570', (99, 101))	('SSX1/2', 'Gene', (202, 208))	('SSX1/2', 'Gene', (192, 198))	('SSX1/2', 'Gene', '6756;6757', (192, 198))	('SSX1/2', 'Gene', '6756;6757', (202, 208))	('SS', 'Phenotype', 'HP:0012570', (192, 194))	('SS18', 'Var', (99, 103))	('toroidal-like structures', 'CPA', (30, 54))	('SS', 'Phenotype', 'HP:0012570', (107, 109))	('SSX1/2', 'Gene', (112, 118))	('SSX1/2', 'Gene', '6756;6757', (112, 118))
388063	20981248	Specifically, SS18-SSX2 was found to localize to sites of RING1 expression in all cells examined, and SS18-SSX1 and SS18-SSX2 colocalized to sites of endogenous BMI-1 expression (both members of the PcG complex).	('RING1', 'Gene', '6015', (58, 63))	('SS', 'Phenotype', 'HP:0012570', (116, 118))	('SS', 'Phenotype', 'HP:0012570', (19, 21))	('dog', 'Species', '9615', (152, 155))	('SS', 'Phenotype', 'HP:0012570', (102, 104))	('PcG', 'Gene', (199, 202))	('PcG', 'Gene', '40358', (199, 202))	('RING1', 'Gene', (58, 63))	('SS18-SSX1', 'Var', (102, 111))	('SS', 'Phenotype', 'HP:0012570', (14, 16))	('BMI-1', 'Gene', (161, 166))	('SS', 'Phenotype', 'HP:0012570', (107, 109))
388067	20981248	PcG knockout experiments and overexpression studies have shown that PcG genes are associated with proliferation of progenitor cells in the murine haematopoietic system, with BMI-1 overexpression leading to lymphoma development.	('murine', 'Species', '10090', (139, 145))	('associated with', 'Reg', (82, 97))	('PcG', 'Gene', (68, 71))	('lymphoma', 'Disease', (206, 214))	('rat', 'Species', '10116', (105, 108))	('PcG', 'Gene', (0, 3))	('PcG', 'Gene', '40358', (68, 71))	('PcG', 'Gene', '40358', (0, 3))	('lymphoma', 'Disease', 'MESH:D008223', (206, 214))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('leading to', 'Reg', (195, 205))	('genes', 'Var', (72, 77))	('BMI-1', 'Gene', (174, 179))	('overexpression', 'PosReg', (180, 194))
388069	20981248	Like SSX proteins, many PcG complex members lack DNA-binding domains and are believed to exert their repressive functions through epigenetic regulation of chromatin structure via protein-protein interactions.	('repressive functions', 'MPA', (101, 121))	('SS', 'Phenotype', 'HP:0012570', (5, 7))	('protein-protein', 'Protein', (179, 194))	('SSX', 'Gene', '6757', (5, 8))	('PcG', 'Gene', (24, 27))	('SSX', 'Gene', (5, 8))	('epigenetic', 'Var', (130, 140))	('PcG', 'Gene', '40358', (24, 27))	('DNA-binding', 'Protein', (49, 60))	('lack', 'NegReg', (44, 48))
388079	20981248	The two different-sized clones were found to be alternative splices of RAB3IP, and were designated RAB3IP alpha and RAB3IP gamma, with RAB3IP alpha encoding a predicted 51 kDa protein 460 amino acids long, which is analogous to Rabin3 in rats.	('RAB3IP', 'Var', (135, 141))	('rats', 'Species', '10116', (238, 242))	('RAB3IP', 'Gene', (71, 77))
388091	20981248	Microarray data has demonstrated lower expression of SSX2IP in AML patients with t(8;21) translocation, while higher expression of SSX2IP was associated with the t(15;17) translocation.	('translocation', 'Var', (89, 102))	('SS', 'Phenotype', 'HP:0012570', (53, 55))	('AML', 'Disease', (63, 66))	('patients', 'Species', '9606', (67, 75))	('expression', 'MPA', (117, 127))	('SS', 'Phenotype', 'HP:0012570', (131, 133))	('rat', 'Species', '10116', (27, 30))	('expression', 'MPA', (39, 49))	('AML', 'Disease', 'MESH:D015470', (63, 66))	('lower', 'NegReg', (33, 38))	('AML', 'Phenotype', 'HP:0004808', (63, 66))
388103	20981248	Interestingly, in similar assays it was found that SSX2 alone actually had an inhibitory effect on CGA activation, which indicates that SS18-SSX2 and SSX2 have opposite activities of transcriptional regulation in SS.	('SS', 'Phenotype', 'HP:0012570', (141, 143))	('SS', 'Phenotype', 'HP:0012570', (150, 152))	('SS', 'Phenotype', 'HP:0012570', (136, 138))	('SS', 'Phenotype', 'HP:0012570', (213, 215))	('CGA', 'Gene', '1113', (99, 102))	('SS18-SSX2', 'Var', (136, 145))	('SS', 'Phenotype', 'HP:0012570', (51, 53))	('CGA', 'Gene', (99, 102))	('activation', 'PosReg', (103, 113))
388116	20981248	Direct associations between SSX and these proteins were not observed from coimmunoprecipitation studies, however it was found that when melanoma cell line DFW (known to express SSX) was knocked out for SSX expression, DFW cells had 40% decreased ability to migrate in soft agar compared to SSX+ DFW cells, and this reduction was accompanied by a decrease in MMP2 expression.	('SSX', 'Gene', '6757', (290, 293))	('SSX', 'Gene', '6757', (202, 205))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('SSX', 'Gene', '6757', (28, 31))	('melanoma', 'Disease', (136, 144))	('SSX', 'Gene', '6757', (177, 180))	('decrease', 'NegReg', (346, 354))	('SSX', 'Gene', (290, 293))	('DFW', 'Chemical', '-', (218, 221))	('MMP2', 'Gene', (358, 362))	('rat', 'Species', '10116', (260, 263))	('SSX', 'Gene', (202, 205))	('SSX', 'Gene', (28, 31))	('SSX', 'Gene', (177, 180))	('knocked out', 'Var', (186, 197))	('DFW', 'Chemical', '-', (295, 298))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('MMP2', 'Gene', '4313', (358, 362))	('decreased', 'NegReg', (236, 245))	('agar', 'Chemical', 'MESH:D000362', (273, 277))	('expression', 'MPA', (363, 373))	('SS', 'Phenotype', 'HP:0012570', (290, 292))	('DFW', 'Chemical', '-', (155, 158))	('SS', 'Phenotype', 'HP:0012570', (202, 204))	('SS', 'Phenotype', 'HP:0012570', (28, 30))	('SS', 'Phenotype', 'HP:0012570', (177, 179))
388125	20981248	Constitutive genome-wide demethylation has been demonstrated in spermatogonia cells where SSX proteins are normally expressed, and interestingly, these same global demethylation patterns have been observed in tumor tissue and tumor cell lines and are associated with the reactivation of silenced genes.	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('demethylation', 'Var', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('SS', 'Phenotype', 'HP:0012570', (90, 92))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('SSX', 'Gene', '6757', (90, 93))	('rat', 'Species', '10116', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('SSX', 'Gene', (90, 93))	('tumor', 'Disease', (226, 231))
388144	20981248	In addition to MM, SSX2 expression in prostate cancer has been reported by our group to be associated with advanced-stage prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (122, 137))	('SS', 'Phenotype', 'HP:0012570', (19, 21))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('SSX2', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('prostate cancer', 'Disease', (38, 53))	('prostate cancer', 'Disease', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('expression', 'Var', (24, 34))	('associated', 'Reg', (91, 101))
388154	20981248	Specifically, RT-PCR showed that SSX mRNA expression was clearly induced in BLM cells and increased in K562 cells with 5-aza-dc treatment, while SSX protein expression was found by immunofluorescence staining in 9-13% of all treated cells.	('5-aza-dc', 'Var', (119, 127))	('mRNA expression', 'MPA', (37, 52))	('SSX', 'Gene', (33, 36))	('BLM', 'CellLine', 'CVCL:7035', (76, 79))	('increased', 'PosReg', (90, 99))	('SSX', 'Gene', '6757', (33, 36))	('induced', 'PosReg', (65, 72))	('5-aza-dc', 'Chemical', 'MESH:D000077209', (119, 127))	('K562', 'CellLine', 'CVCL:0004', (103, 107))	('SSX', 'Gene', '6757', (145, 148))	('SS', 'Phenotype', 'HP:0012570', (145, 147))	('SSX', 'Gene', (145, 148))	('SS', 'Phenotype', 'HP:0012570', (33, 35))
388156	20981248	SSX expression has also been shown to be upregulated with 5-aza-dc in bladder cancer cell lines that are SSX-negative prior to treatment, and SSX2 has been shown to be inducible with 5-aza-dc in mesothelioma.	('mesothelioma', 'Disease', (195, 207))	('SS', 'Phenotype', 'HP:0012570', (105, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (195, 207))	('SSX', 'Gene', '6757', (105, 108))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SS', 'Phenotype', 'HP:0012570', (142, 144))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('bladder cancer', 'Disease', (70, 84))	('SSX', 'Gene', (105, 108))	('upregulated', 'PosReg', (41, 52))	('5-aza-dc', 'Var', (58, 66))	('SSX', 'Gene', '6757', (0, 3))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('SSX', 'Gene', (142, 145))	('SSX', 'Gene', '6757', (142, 145))	('SSX', 'Gene', (0, 3))	('5-aza-dc', 'Chemical', 'MESH:D000077209', (58, 66))	('5-aza-dc', 'Chemical', 'MESH:D000077209', (183, 191))
388160	20981248	it was shown that upregulation of SSX expression in melanoma cell clones with 5-aza-dc treatment was directly correlated with promoter demethylation patterns.	('upregulation', 'PosReg', (18, 30))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('promoter demethylation', 'MPA', (126, 148))	('expression', 'MPA', (38, 48))	('5-aza-dc', 'Chemical', 'MESH:D000077209', (78, 86))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('SS', 'Phenotype', 'HP:0012570', (34, 36))	('SSX', 'Gene', '6757', (34, 37))	('SSX', 'Gene', (34, 37))	('5-aza-dc', 'Var', (78, 86))
388171	20981248	The digested products were analyzed by mass spectrometry, which identified 12 peptides that were processed from the proteasome: SSX2p5-13, p7-15, p15-24, p16-24, p40-49, p41-49, p50-59, p53-61, p57-65, p58-67, p59-67, and p103-111.	('p57', 'Gene', (194, 197))	('SSX2p5-13', 'Var', (128, 137))	('p16-24', 'Var', (154, 160))	('p40-49', 'Var', (162, 168))	('p7-15', 'Var', (139, 144))	('p15-24', 'Var', (146, 152))	('p59', 'Gene', (210, 213))	('p59', 'Gene', '352990', (210, 213))	('p50', 'Gene', (178, 181))	('p41', 'Gene', '2035', (170, 173))	('p53', 'Gene', (186, 189))	('p53', 'Gene', '7157', (186, 189))	('p41', 'Gene', (170, 173))	('p58-67', 'Var', (202, 208))	('p50', 'Gene', '958', (178, 181))	('p57', 'Gene', '1028', (194, 197))	('SS', 'Phenotype', 'HP:0012570', (128, 130))	('p103-111', 'Var', (222, 230))
388175	20981248	It was also shown that SSX2p41-49 CD8+ T cells (CTL clone LAU 50 E2.4) could lyse peptide-pulsed T2 cells and HLA-A2+ melanoma cell lines.	('T2', 'CellLine', 'CVCL:0042', (97, 99))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('SSX2p41-49', 'Var', (23, 33))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('SS', 'Phenotype', 'HP:0012570', (23, 25))	('CD8', 'Gene', (34, 37))	('lyse peptide-pulsed', 'MPA', (77, 96))	('CD8', 'Gene', '925', (34, 37))	('HLA-A', 'Gene', '3105', (110, 115))	('HLA-A', 'Gene', (110, 115))
388176	20981248	Interestingly, when this clone was incubated with COS7 cells transfected with plasmids encoding HLA-A2 and SSX2 or SSX4, high levels of IFNgamma secretion and lysis were observed by the clone with SSX2-transfected cells but not SSX4-transfected cells.	('SSX2', 'Gene', (107, 111))	('SSX2-transfected', 'Var', (197, 213))	('IFNgamma', 'Gene', (136, 144))	('lysis', 'CPA', (159, 164))	('HLA-A', 'Gene', '3105', (96, 101))	('HLA-A', 'Gene', (96, 101))	('IFNgamma', 'Gene', '3458', (136, 144))	('SS', 'Phenotype', 'HP:0012570', (228, 230))	('SS', 'Phenotype', 'HP:0012570', (107, 109))	('SS', 'Phenotype', 'HP:0012570', (115, 117))	('SS', 'Phenotype', 'HP:0012570', (197, 199))	('COS7', 'CellLine', 'CVCL:0224', (50, 54))
388198	20981248	PBMCs from seven breast cancer patients and eleven healthy donors were evaluated for reactivity to peptides p41-49 and p103-111, and p167-175, which had all been predicted from the peptide-binding algorithm to have affinity for HLA-A2.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('HLA-A', 'Gene', (228, 233))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('p41', 'Gene', '2035', (108, 111))	('affinity', 'Interaction', (215, 223))	('breast cancer', 'Disease', (17, 30))	('p41', 'Gene', (108, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('p167-175', 'Var', (133, 141))	('patients', 'Species', '9606', (31, 39))	('donor', 'Species', '9606', (59, 64))	('reactivity', 'MPA', (85, 95))	('HLA-A', 'Gene', '3105', (228, 233))	('p103-111', 'Var', (119, 127))
388199	20981248	They found that 5/7 (71%) of the HLA-A2+ breast cancer patients and 6/11 (55%) of the HLAA2+ healthy controls had T cells that were reactive to SSX2 peptide p103-111 by IFNgamma-ELISPOT assay.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('HLA-A', 'Gene', (33, 38))	('HLA', 'Gene', '3115', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('IFNgamma', 'Gene', '3458', (169, 177))	('breast cancer', 'Disease', (41, 54))	('IFNgamma', 'Gene', (169, 177))	('SS', 'Phenotype', 'HP:0012570', (144, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('HLA', 'Gene', (33, 36))	('SSX2', 'Var', (144, 148))	('HLA', 'Gene', '3115', (86, 89))	('patients', 'Species', '9606', (55, 63))	('HLA-A', 'Gene', '3105', (33, 38))	('HLA', 'Gene', (86, 89))
388201	20981248	SSX2 p103-111 was also shown to be a naturally presented SSX2 epitope by the recognition of SSX2+ SK-MEL-37 melanoma cell line and transfected COS7 cells by p103-11 peptide-specific CD8+ T cells (Table 3).	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('SS', 'Phenotype', 'HP:0012570', (57, 59))	('SSX2+', 'Var', (92, 97))	('SS', 'Phenotype', 'HP:0012570', (92, 94))	('COS7', 'CellLine', 'CVCL:0224', (143, 147))	('CD8', 'Gene', (182, 185))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SSX2', 'Gene', (57, 61))	('CD8', 'Gene', '925', (182, 185))	('SK-MEL-37', 'CellLine', 'CVCL:3878', (98, 107))	('p103-111', 'Var', (5, 13))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
388202	20981248	Also, SSX2 p103-111-specific T cells could lyse peptide-pulsed target cells in cytotoxicity assays.	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('lyse', 'CPA', (43, 47))	('cytotoxicity', 'Disease', (79, 91))	('SSX2', 'Var', (6, 10))	('SS', 'Phenotype', 'HP:0012570', (6, 8))
388204	20981248	Rentzsch and colleagues found that PBMCs from one out of ten primary breast cancer patients exposed to SSX2-p103-111 significantly increased their mRNA expression of IFNgamma by QT-RTPCR analysis.	('SSX2-p103-111', 'Var', (103, 116))	('IFNgamma', 'Gene', (166, 174))	('increased', 'PosReg', (131, 140))	('IFNgamma', 'Gene', '3458', (166, 174))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mRNA expression', 'MPA', (147, 162))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('SS', 'Phenotype', 'HP:0012570', (103, 105))	('patients', 'Species', '9606', (83, 91))
388205	20981248	We have also recently identified SSX2 p103-111 as an SSX2 epitope using HLA-A2 transgenic mice immunized with a genetic vaccine encoding SSX2, and further identified that p103-111-specific CTL can lyse HLA-A2-expressing prostate tumor cells (Smith, manuscript submitted).	('transgenic mice', 'Species', '10090', (79, 94))	('SS', 'Phenotype', 'HP:0012570', (53, 55))	('CTL', 'Gene', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('HLA-A', 'Gene', '3105', (202, 207))	('prostate tumor', 'Disease', 'MESH:D011471', (220, 234))	('lyse', 'CPA', (197, 201))	('SS', 'Phenotype', 'HP:0012570', (33, 35))	('SS', 'Phenotype', 'HP:0012570', (137, 139))	('HLA-A', 'Gene', '3105', (72, 77))	('p103-111-specific', 'Var', (171, 188))	('HLA-A', 'Gene', (202, 207))	('HLA-A', 'Gene', (72, 77))	('prostate tumor', 'Disease', (220, 234))	('prostate tumor', 'Phenotype', 'HP:0100787', (220, 234))
388206	20981248	Not only has the endogenous processing and presentation of SSX2 peptide p103-111 been demonstrated by reactivity of p103-111-specific CTL for SSX2-expressing tumor cells, it has also recently been shown that this peptide epitope is directly presented on the surface of cancer cells.	('tumor', 'Disease', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('dog', 'Species', '9615', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('SS', 'Phenotype', 'HP:0012570', (59, 61))	('p103-111-specific', 'Var', (116, 133))	('SS', 'Phenotype', 'HP:0012570', (142, 144))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('rat', 'Species', '10116', (93, 96))
388208	20981248	generated SSX2 p103-111-specific Fab antibodies that specifically recognized and bound to this peptide in the context of HLA-A2.	('bound', 'Interaction', (81, 86))	('Fab', 'Gene', '2187', (33, 36))	('p103-111-specific', 'Var', (15, 32))	('Fab', 'Gene', (33, 36))	('HLA-A', 'Gene', '3105', (121, 126))	('SS', 'Phenotype', 'HP:0012570', (10, 12))	('rat', 'Species', '10116', (4, 7))	('HLA-A', 'Gene', (121, 126))	('SSX2', 'Gene', (10, 14))
388220	20981248	Using the SYFPEITHI algorithm, p45-59 was ranked as the 2nd highest predicted HLA-DR-binding peptide for SSX2, whereas this peptide ranked 3rd, 13th, and 2nd for SSX1, SSX4, and SSX5, respectively.	('SSX2', 'Var', (105, 109))	('SS', 'Phenotype', 'HP:0012570', (105, 107))	('p45', 'Gene', '4778', (31, 34))	('HLA', 'Gene', '3115', (78, 81))	('SS', 'Phenotype', 'HP:0012570', (178, 180))	('p45', 'Gene', (31, 34))	('HLA', 'Gene', (78, 81))	('SS', 'Phenotype', 'HP:0012570', (168, 170))	('SSX5', 'Gene', (178, 182))	('SSX5', 'Gene', '6758', (178, 182))	('SS', 'Phenotype', 'HP:0012570', (162, 164))
388223	20981248	Contrary to what was found for the class II peptide p19-34, T cells recognized epitope p45-59 on both antigen-loaded DCs as well as HLA-DR+ tumor cells.	('HLA', 'Gene', (132, 135))	('epitope', 'Var', (79, 86))	('p19', 'Gene', (52, 55))	('p45', 'Gene', '4778', (87, 90))	('p45', 'Gene', (87, 90))	('p19', 'Gene', '1032', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HLA', 'Gene', '3115', (132, 135))	('tumor', 'Disease', (140, 145))
388224	20981248	This peptide was also described by Neumann and colleagues in which p45-59 was found to be restricted to HLA-DRB1 subtypes *0701, *1101, *1302 and B3*0301, and it was demonstrated that p45-59 CD4+ T cell responses could be induced in 3/6 of breast cancer patients and 1/5 of healthy controls.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('rat', 'Species', '10116', (173, 176))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('breast cancer', 'Disease', (240, 253))	('HLA-DRB1', 'Gene', '3123', (104, 112))	('*1101', 'Var', (129, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('CD4', 'Gene', (191, 194))	('B3*0301', 'Var', (146, 153))	('p45', 'Gene', '4778', (184, 187))	('p45', 'Gene', (67, 70))	('p45', 'Gene', '4778', (67, 70))	('*1302', 'Var', (136, 141))	('HLA-DRB1', 'Gene', (104, 112))	('CD4', 'Gene', '920', (191, 194))	('p45', 'Gene', (184, 187))	('patients', 'Species', '9606', (254, 262))
388230	20981248	Cross reactivity of SSX2 p37-51-specific CD4+ T cells was observed for SSX4 and SSX5 but not SSX1 or SSX3 p37-51 peptides in an IFNgamma peptide titration ELISA assay.	('p37', 'Gene', (25, 28))	('p37', 'Gene', (106, 109))	('SSX4', 'Var', (71, 75))	('SSX3', 'Gene', '10214', (101, 105))	('SS', 'Phenotype', 'HP:0012570', (80, 82))	('SSX3', 'Gene', (101, 105))	('SSX5', 'Gene', '6758', (80, 84))	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('p37', 'Gene', '926', (106, 109))	('p37', 'Gene', '926', (25, 28))	('SSX5', 'Gene', (80, 84))	('rat', 'Species', '10116', (148, 151))	('CD4', 'Gene', '920', (41, 44))	('SS', 'Phenotype', 'HP:0012570', (20, 22))	('SS', 'Phenotype', 'HP:0012570', (101, 103))	('SS', 'Phenotype', 'HP:0012570', (93, 95))	('IFNgamma', 'Gene', '3458', (128, 136))	('IFNgamma', 'Gene', (128, 136))	('CD4', 'Gene', (41, 44))
388241	20981248	Using peptide prediction algorithms He and colleagues identified SSX p57-65 and p99-107 as shared epitopes between family members SSX1-9.	('SS', 'Phenotype', 'HP:0012570', (130, 132))	('p57', 'Gene', '1028', (69, 72))	('SSX', 'Gene', '6757', (65, 68))	('SSX', 'Gene', '6757', (130, 133))	('p57', 'Gene', (69, 72))	('p99-107', 'Var', (80, 87))	('SSX', 'Gene', (130, 133))	('SS', 'Phenotype', 'HP:0012570', (65, 67))	('SSX', 'Gene', (65, 68))	('SSX1-9', 'Gene', (130, 136))	('SSX1-9', 'Gene', '6756;6757;10214;6759;6758;280657;280658;280659;280660', (130, 136))
388243	20981248	Using T2 binding assays with four altered p57-65 peptides specific to SSX1-9, it was shown that altered peptide P4 (AMTKLGFNV), which is encoded by SSX6 and SSX8, had the greatest in vitro binding affinity for HLA-A2, and this affinity was stable at low peptide concentrations.	('altered', 'Var', (96, 103))	('T2', 'CellLine', 'CVCL:0042', (6, 8))	('SSX8', 'Gene', (157, 161))	('SSX1-9', 'Gene', (70, 76))	('p57', 'Gene', '1028', (42, 45))	('SSX1-9', 'Gene', '6756;6757;10214;6759;6758;280657;280658;280659;280660', (70, 76))	('SSX8', 'Gene', '280659', (157, 161))	('SS', 'Phenotype', 'HP:0012570', (157, 159))	('low peptide concentrations', 'Phenotype', 'HP:0030795', (250, 276))	('p57', 'Gene', (42, 45))	('HLA-A', 'Gene', '3105', (210, 215))	('SS', 'Phenotype', 'HP:0012570', (70, 72))	('SS', 'Phenotype', 'HP:0012570', (148, 150))	('rat', 'Species', '10116', (269, 272))	('binding affinity', 'Interaction', (189, 205))	('HLA-A', 'Gene', (210, 215))	('SSX6', 'Gene', '280657', (148, 152))	('SSX6', 'Gene', (148, 152))
388244	20981248	All four altered p57-65 peptides were shown to elicit peptide-specific CTL from the PBMCs of healthy HLA-A*0201 individuals, however P4-specific CTL showed the greatest lysis and IFNgamma secretion when incubated with peptide-pulsed target cells.	('HLA-A', 'Gene', '3105', (101, 106))	('elicit', 'Reg', (47, 53))	('p57', 'Gene', '1028', (17, 20))	('P4-specific', 'Var', (133, 144))	('p57', 'Gene', (17, 20))	('IFNgamma', 'Gene', (179, 187))	('lysis', 'MPA', (169, 174))	('peptide-specific CTL', 'MPA', (54, 74))	('HLA-A', 'Gene', (101, 106))	('IFNgamma', 'Gene', '3458', (179, 187))
388272	28589056	The translocation of the EWSR1 gene on to chromosome 22p12 next to the FLI1 gene usually results in upregulation of insulin-like growth factor 1 which plays a role in cellular proliferation.	('translocation', 'Var', (4, 17))	('insulin-like growth factor 1', 'Gene', (116, 144))	('EWSR1', 'Gene', (25, 30))	('insulin-like growth factor 1', 'Gene', '3479', (116, 144))	('EWSR1', 'Gene', '2130', (25, 30))	('FLI1', 'Gene', (71, 75))	('FLI1', 'Gene', '2313', (71, 75))	('upregulation', 'PosReg', (100, 112))
388291	28589056	FISH demonstrated EWSR1 rearrangement without SYT rearrangement, confirming extraosseous Ewing sarcoma.	('EWSR1', 'Gene', (18, 23))	('rearrangement', 'Var', (24, 37))	('EWSR1', 'Gene', '2130', (18, 23))	('Ewing sarcoma', 'Disease', (89, 102))	('extraosseous Ewing', 'Disease', (76, 94))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('extraosseous Ewing', 'Disease', 'MESH:C563168', (76, 94))
388341	26677338	Tumor markers (CA199, CA125, CEA) and complete biochemical panel including lactose dehydrogenase and uric acid were all in the normal range.	('CA125', 'Gene', '94025', (22, 27))	('lactose dehydrogenase', 'MPA', (75, 96))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CA199', 'Var', (15, 20))	('CA125', 'Gene', (22, 27))	('CA199', 'Chemical', '-', (15, 20))	('CEA', 'Gene', (29, 32))	('CEA', 'Gene', '1084', (29, 32))	('uric acid', 'MPA', (101, 110))	('uric acid', 'Chemical', 'MESH:D014527', (101, 110))
388363	26677338	Yamauchi and Yasuda analyzed 74 patients with non-leukemic MS using a literature search on Medline (including two patients in their institute), and found that the non-leukemic period after the diagnosis of granulocytic sarcoma was significantly longer in the patients who received systemic chemotherapy than those who received surgical resection or irradiation (12 months versus 3 months versus 6 months), this study also revealed that in the patients treated with chemotherapeutic agents containing cytosine arabinoside and anthracycline, the period of progression to acute leukemia was significantly longer than in those who were treated with regimens used in lymphomas.	('lymphomas', 'Disease', (662, 671))	('acute leukemia', 'Disease', 'MESH:D015470', (569, 583))	('non-leukemic', 'Disease', (163, 175))	('patients', 'Species', '9606', (443, 451))	('cytosine arabinoside', 'Var', (500, 520))	('acute leukemia', 'Phenotype', 'HP:0002488', (569, 583))	('non-leukemic MS', 'Disease', (46, 61))	('patients', 'Species', '9606', (259, 267))	('patients', 'Species', '9606', (114, 122))	('lymphomas', 'Disease', 'MESH:D008223', (662, 671))	('anthracycline', 'Var', (525, 538))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('granulocytic sarcoma', 'Disease', (206, 226))	('non-leukemic', 'Disease', 'MESH:D007938', (46, 58))	('lymphomas', 'Phenotype', 'HP:0002665', (662, 671))	('leukemia', 'Phenotype', 'HP:0001909', (575, 583))	('non-leukemic MS', 'Disease', 'MESH:D009103', (46, 61))	('acute leukemia', 'Disease', (569, 583))	('non-leukemic', 'Disease', 'MESH:D007938', (163, 175))	('patients', 'Species', '9606', (32, 40))	('cytosine arabinoside', 'Chemical', 'MESH:D003561', (500, 520))	('lymphoma', 'Phenotype', 'HP:0002665', (662, 670))	('granulocytic sarcoma', 'Disease', 'MESH:D023981', (206, 226))	('non-leukemic', 'Disease', (46, 58))
388408	22937421	Vimentin positivity and smooth muscle actin, desmin, epithelial membrane antigen, CD 45, CD 30, and CD 3 negativity as in our case made the final diagnosis.	('Vimentin', 'Gene', '7431', (0, 8))	('desmin', 'Gene', (45, 51))	('CD 30', 'Gene', (89, 94))	('negativity', 'NegReg', (105, 115))	('positivity', 'Var', (9, 19))	('desmin', 'Gene', '1674', (45, 51))	('smooth muscle actin', 'Protein', (24, 43))	('epithelial membrane antigen, CD 45', 'Gene', '5788', (53, 87))	('CD 30', 'Gene', '943', (89, 94))	('Vimentin', 'Gene', (0, 8))
388411	22310819	However, in a subset of patients, dysregulated immune response after initiation of ART leads to the phenomenon of immune reconstitution inflammatory syndrome (IRIS).	('dysregulated', 'Var', (34, 46))	('ART', 'Chemical', '-', (83, 86))	('dysregulated immune response', 'Phenotype', 'HP:0002958', (34, 62))	('immune reconstitution inflammatory syndrome', 'Disease', (114, 157))	('patients', 'Species', '9606', (24, 32))
388461	22310819	Cytomegalovirus (CMV)-IRIS frequently carry HLA-B44 and an ancestral haplotype HLA-A2, B44, DR4.	('HLA-B44', 'Var', (44, 51))	('Cytomegalovirus', 'Disease', (0, 15))	('Cytomegalovirus', 'Disease', 'MESH:D003586', (0, 15))	('DR4', 'Gene', (92, 95))	('CM', 'Phenotype', 'HP:0032160', (17, 19))	('DR4', 'Gene', '3126', (92, 95))
388550	22310819	Interruption of ART may place a patient at risk for additional opportunistic infections, and the IRIS may recur when ART is reintroduced.	('opportunistic infections', 'Phenotype', 'HP:0031690', (63, 87))	('Interruption', 'Var', (0, 12))	('opportunistic infection', 'Phenotype', 'HP:0031690', (63, 86))	('ART', 'Chemical', '-', (117, 120))	('ART', 'Chemical', '-', (16, 19))	('opportunistic infections', 'Disease', (63, 87))	('patient', 'Species', '9606', (32, 39))	('opportunistic infections', 'Disease', 'MESH:D009894', (63, 87))
388571	32579783	ALT alanine aminotransferase AST aspartate aminotransferase ASPS alveolar soft part sarcoma CCS clear cell sarcoma Choi Choi criteria CR complete response CT computed tomography ES epithelioid sarcoma JMOG Japanese Musculoskeletal Oncology Group OS overall survival PD progressive disease PFS progression-free survival PR partial response SD stable disease Alveolar soft part sarcoma, ES, and CCS have different genetic backgrounds of ASPL-TFE3 translocation, 1  inactivation of INI1, 2  and EWSR1-ATF1 translocation, 3  respectively, and primarily affect young adults.	('Oncology', 'Phenotype', 'HP:0002664', (231, 239))	('TFE3', 'Gene', '7030', (440, 444))	('INI1', 'Gene', (479, 483))	('INI1', 'Gene', '6598', (479, 483))	('ASPL', 'Gene', '79058', (435, 439))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (96, 114))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (65, 91))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (74, 91))	('ATF1', 'Gene', (498, 502))	('sarcoma', 'Disease', (84, 91))	('EWSR1', 'Gene', '2130', (492, 497))	('ASPS', 'Gene', (60, 64))	('Alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (357, 383))	('AST', 'Gene', '26503', (29, 32))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))	('sarcoma', 'Disease', 'MESH:D012509', (376, 383))	('sarcoma', 'Disease', 'MESH:D012509', (193, 200))	('sarcoma', 'Disease', (376, 383))	('sarcoma', 'Disease', (107, 114))	('ATF1', 'Gene', '466', (498, 502))	('inactivation', 'Var', (463, 475))	('sarcoma', 'Disease', (193, 200))	('CR', 'Chemical', 'MESH:D002857', (134, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (366, 383))	('PR', 'Gene', '140738', (319, 321))	('clear cell sarcoma', 'Disease', (96, 114))	('ASPS', 'Gene', '79058', (60, 64))	('EWSR1', 'Gene', (492, 497))	('ASPS', 'Phenotype', 'HP:0012218', (60, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (376, 383))	('ASPL', 'Gene', (435, 439))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('TFE3', 'Gene', (440, 444))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('AST', 'Gene', (29, 32))
388686	32579783	This patient had no further problems, but caution is needed because pazopanib causes bleeding and inhibits wound healing due to its inhibition of vascular endothelial growth factor.	('patient', 'Species', '9606', (5, 12))	('inhibition', 'NegReg', (132, 142))	('pazopanib', 'Chemical', 'MESH:C516667', (68, 77))	('wound healing', 'CPA', (107, 120))	('bleeding', 'Disease', 'MESH:D006470', (85, 93))	('pazopanib', 'Var', (68, 77))	('vascular endothelial growth factor', 'Gene', (146, 180))	('bleeding', 'Disease', (85, 93))	('inhibits', 'NegReg', (98, 106))	('causes', 'PosReg', (78, 84))	('vascular endothelial growth factor', 'Gene', '7422', (146, 180))
388740	28587971	In 90% of all cases of CCS polymerase chain reaction and fluorescence in situ hybridisation can detach the translocation (t[12; 22] [q13;q12]) or a resultant EWSR1-ATF1 fusion gene unique for CCS.	('ATF1', 'Gene', (164, 168))	('EWSR1', 'Gene', '2130', (158, 163))	('detach', 'NegReg', (96, 102))	('t[12; 22] [q13;q12]', 'Var', (122, 141))	('CCS', 'Disease', (23, 26))	('ATF1', 'Gene', '466', (164, 168))	('EWSR1', 'Gene', (158, 163))
388770	25826368	As the genesis of most childhood cancers seems to come from disruptions of normal early development, they accumulate fewer mutations than adult tumors.	('tumors', 'Disease', (144, 150))	('come from', 'Reg', (50, 59))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('disruptions', 'Var', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('childhood cancers', 'Disease', 'MESH:C536928', (23, 40))	('childhood cancers', 'Disease', (23, 40))
388771	25826368	On the other hand, it appears that development of pediatric tumors rely heavily on epigenetic modifications.	('pediatric tumors', 'Disease', 'MESH:D063766', (50, 66))	('pediatric tumors', 'Disease', (50, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('epigenetic modifications', 'Var', (83, 107))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
388868	25826368	Again, no association could be found between the presence of specific mutations in a cancer cell line and its ability to be sensitized by the RasGAP-derived peptide.	('mutations', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('RasGAP', 'Gene', '5921', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('RasGAP', 'Gene', (142, 148))
388879	25826368	Alternatively, passage in different medium may induce differential epigenetic modifications or mutations that impact on the sensitivities of the NB1-FBS and NB1-NBM cell lines toward the RasGAP-derived peptide.	('NB1', 'Gene', '57126', (157, 160))	('NB1', 'Gene', (157, 160))	('NB1', 'Gene', '57126', (145, 148))	('NBM', 'Chemical', '-', (161, 164))	('RasGAP', 'Gene', '5921', (187, 193))	('RasGAP', 'Gene', (187, 193))	('NB1', 'Gene', (145, 148))	('epigenetic modifications', 'Var', (67, 91))	('mutations', 'Var', (95, 104))	('sensitivities', 'MPA', (124, 137))	('induce', 'Reg', (47, 53))	('impact', 'Reg', (110, 116))
388913	23901138	For example, deletion of A20 in mice abrogates homeostatic inhibition of NF-kappaB, resulting in systemic inflammation and severe cachexia, and mutations in A20 are associated with the constitutive activation of NF-kappaB in B cell lymphomas.	('cachexia', 'Phenotype', 'HP:0004326', (130, 138))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (225, 241))	('abrogates', 'NegReg', (37, 46))	('A20', 'Gene', (157, 160))	('cachexia', 'Disease', (130, 138))	('mutations', 'Var', (144, 153))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (225, 240))	('lymphoma', 'Phenotype', 'HP:0002665', (232, 240))	('B cell lymphomas', 'Disease', 'MESH:D016393', (225, 241))	('deletion', 'Var', (13, 21))	('inflammation', 'Disease', 'MESH:D007249', (106, 118))	('NF-kappaB', 'Protein', (73, 82))	('activation', 'PosReg', (198, 208))	('associated', 'Reg', (165, 175))	('mice', 'Species', '10090', (32, 36))	('A20', 'Gene', (25, 28))	('inflammation', 'Disease', (106, 118))	('resulting in', 'Reg', (84, 96))	('lymphomas', 'Phenotype', 'HP:0002665', (232, 241))	('cachexia', 'Disease', 'MESH:D002100', (130, 138))	('homeostatic inhibition', 'MPA', (47, 69))	('B cell lymphomas', 'Disease', (225, 241))
388916	23901138	Increased NF-kappaB signaling in these tumors epigenetically suppresses the expression of the microRNA (miRNA) miR-29 through the Polycomb repressor complex PRC2, causing RMS cells to become less differentiated.	('tumors', 'Disease', (39, 45))	('epigenetically', 'Var', (46, 60))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('RMS', 'Phenotype', 'HP:0002859', (171, 174))	('suppresses', 'NegReg', (61, 71))	('causing', 'Reg', (163, 170))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('less differentiated', 'CPA', (191, 210))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('expression', 'MPA', (76, 86))	('RMS', 'Disease', (171, 174))	('miR', 'Gene', '220972', (104, 107))	('miR', 'Gene', (104, 107))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))	('NF-kappaB signaling', 'MPA', (10, 29))
388929	23901138	Because K63-linked ubiquitination of RIP1 is removed by A20, we examined its correlation with the abundance of A20 in sarcoma cells compared with normal counterparts.	('sarcoma', 'Disease', (118, 125))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))	('RIP1', 'Gene', (37, 41))	('K63-linked', 'Var', (8, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('A20', 'Var', (56, 59))	('removed', 'NegReg', (45, 52))
388937	23901138	As expected, RIP1 knockdown in Rh30 and U2OS cells decreased the transcriptional activity of an NF-kappaB reporter (Fig.	('knockdown', 'Var', (18, 27))	('transcriptional activity', 'MPA', (65, 89))	('Rh30', 'Gene', (31, 35))	('decreased', 'NegReg', (51, 60))	('RIP1', 'Gene', (13, 17))	('U2OS', 'CellLine', 'CVCL:0042', (40, 44))	('Rh30', 'Gene', '6007', (31, 35))
388945	23901138	Reduced A20 mRNA can result from mutations in the A20 gene, including exons 2 and 5, such as those found in large B cell lymphomas (:); however, we did not find similar mutations in these exons or in the UTRs of the gene in six confirmed sarcoma cases compared with the A20 gene sequence in two commercially sourced normal human DNA samples (fig.	('A20 mRNA', 'MPA', (8, 16))	('sarcoma', 'Disease', (238, 245))	('A20', 'Gene', (50, 53))	('Reduced', 'NegReg', (0, 7))	('mutations', 'Var', (33, 42))	('human', 'Species', '9606', (323, 328))	('lymphomas', 'Phenotype', 'HP:0002665', (121, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('B cell lymphomas', 'Disease', 'MESH:D016393', (114, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('B cell lymphomas', 'Disease', (114, 130))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('large B cell', 'Phenotype', 'HP:0005404', (108, 120))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (114, 130))	('sarcoma', 'Disease', 'MESH:D012509', (238, 245))
388956	23901138	Pearson association analysis of the abundance of miR-29 or miR-125 with A20 mRNA revealed a positive correlation between A20 and miR-29 and a negative correlation between A20 and miR-125, although the latter was not statistically significant (fig.	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', (129, 132))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', (59, 62))	('miR', 'Gene', (179, 182))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('A20', 'Var', (121, 124))
388966	23901138	In addition, mutating either the miR-29 binding sites in the A20 3'UTR or the seed sequence in miR-29 also increased the activity of the A20 3'UTR reporter in Rh30 (Fig.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('Rh30', 'Gene', '6007', (159, 163))	('miR', 'Gene', (95, 98))	('miR', 'Gene', '220972', (95, 98))	('activity', 'MPA', (121, 129))	('increased', 'PosReg', (107, 116))	('Rh30', 'Gene', (159, 163))	('mutating', 'Var', (13, 21))
388979	23901138	Ectopic expression of RIP1 in Rh30 and U2OS cells significantly enhanced the activity of a wild-type, but not a mutated, NF-kappaB reporter (Fig.	('Rh30', 'Gene', (30, 34))	('Ectopic expression', 'Var', (0, 18))	('Rh30', 'Gene', '6007', (30, 34))	('RIP1', 'Gene', (22, 26))	('activity', 'MPA', (77, 85))	('U2OS', 'CellLine', 'CVCL:0042', (39, 43))	('enhanced', 'PosReg', (64, 72))
388980	23901138	This activity was inhibited by overexpression of either miR-29 or A20 (Fig.	('A20', 'Var', (66, 69))	('activity', 'MPA', (5, 13))	('miR', 'Gene', '220972', (56, 59))	('inhibited', 'NegReg', (18, 27))	('miR', 'Gene', (56, 59))
388981	23901138	However, the activity of the NF-kappaB reporter was not inhibited when miR-29 was overexpressed in the presence of an siRNA targeting A20 (Fig.	('miR', 'Gene', (71, 74))	('miR', 'Gene', '220972', (71, 74))	('A20', 'Var', (134, 137))	('activity', 'MPA', (13, 21))
388985	23901138	However, the miR-29-mediated induction of myogenic differentiation markers depended on A20 because exogenous expression of miR-29 in the presence of siRNA-mediated A20 knockdown was less effective at inducing myogenic genes in Rh30 cells (Fig.	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('Rh30', 'Gene', (227, 231))	('inducing', 'Reg', (200, 208))	('myogenic genes', 'Gene', (209, 223))	('Rh30', 'Gene', '6007', (227, 231))	('knockdown', 'Var', (168, 177))
389001	23901138	Compared with cells transfected with a nontargeted control siRNA, HuR knockdown increased the abundance of both A20 mRNA and protein (Fig.	('A20', 'Protein', (112, 115))	('HuR', 'Gene', (66, 69))	('knockdown', 'Var', (70, 79))	('HuR', 'Gene', '1994', (66, 69))	('increased', 'PosReg', (80, 89))	('abundance', 'MPA', (94, 103))	('protein', 'Protein', (125, 132))
389010	23901138	5G, lane 2), and its binding was diminished either in extracts from cells in which endogenous HuR was knocked down (Fig.	('diminished', 'NegReg', (33, 43))	('binding', 'Interaction', (21, 28))	('HuR', 'Gene', (94, 97))	('HuR', 'Gene', '1994', (94, 97))	('endogenous', 'MPA', (83, 93))	('knocked', 'Var', (102, 109))
389012	23901138	Likewise, a miR-29 oligomer that contained a mutated HuR binding site (5'-AUUU-3' to 5'-ACCC-3'; Fig.	('HuR', 'Gene', (53, 56))	('HuR', 'Gene', '1994', (53, 56))	('miR', 'Gene', '220972', (12, 15))	('mutated', 'Var', (45, 52))	('miR', 'Gene', (12, 15))
389025	23901138	HuR knockdown in the absence of miR-29 overexpression also stimulated A20 reporter activity (Fig.	('miR', 'Gene', (32, 35))	('HuR', 'Gene', '1994', (0, 3))	('A20 reporter activity', 'MPA', (70, 91))	('HuR', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))	('stimulated', 'PosReg', (59, 69))	('miR', 'Gene', '220972', (32, 35))
389026	23901138	However, neither overexpression of miR-29 that contained a mutation within the HuR binding site (Fig.	('HuR', 'Gene', '1994', (79, 82))	('HuR', 'Gene', (79, 82))	('miR', 'Gene', '220972', (35, 38))	('mutation', 'Var', (59, 67))	('miR', 'Gene', (35, 38))
389031	23901138	We transfected sarcoma cells with plasmids containing wild-type pre-miR-29 or one of the three pre-miR-29 mutants in which HuR binding sites within the precursor sequence of miR-29 were mutated (fig.	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (68, 71))	('miR', 'Gene', (99, 102))	('miR', 'Gene', '220972', (174, 177))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('miR', 'Gene', (174, 177))	('mutated', 'Var', (186, 193))	('sarcoma', 'Disease', (15, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('HuR', 'Gene', (123, 126))	('HuR', 'Gene', '1994', (123, 126))
389033	23901138	Amplification of the bottom strand revealed that HuR interacted with the wild-type miR-29 precursor, but this interaction was strongly reduced when a mutation was introduced into the AUUU binding site (mut 2) (Fig.	('HuR', 'Gene', '1994', (49, 52))	('HuR', 'Gene', (49, 52))	('mutation', 'Var', (150, 158))	('interaction', 'Interaction', (110, 121))	('interacted', 'Interaction', (53, 63))	('reduced', 'NegReg', (135, 142))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))
389034	23901138	Unexpectedly, we observed a similar reduction in HuR binding when amplifying the upper strand of precursor miR-29 containing a mutation in the GUUU binding site (mut 1).	('HuR', 'Gene', '1994', (49, 52))	('HuR', 'Gene', (49, 52))	('reduction', 'NegReg', (36, 45))	('GUUU', 'Chemical', '-', (143, 147))	('mutation in', 'Var', (127, 138))	('miR', 'Gene', '220972', (107, 110))	('miR', 'Gene', (107, 110))
389037	23901138	Compared to the vector control, expression of wild-type precursor miR-29 increased the abundance of A20 in sarcoma cells, but none of the miR-29 HuR binding site mutants increased A20 to the same extent (Fig.	('increased', 'PosReg', (73, 82))	('abundance', 'MPA', (87, 96))	('HuR', 'Gene', (145, 148))	('HuR', 'Gene', '1994', (145, 148))	('mutants', 'Var', (162, 169))	('sarcoma', 'Disease', (107, 114))	('A20', 'Protein', (100, 103))	('miR', 'Gene', (66, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', (138, 141))	('miR', 'Gene', '220972', (66, 69))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))
389045	23901138	Knocking down HuR reduced the amount of miR-125 that immunoprecipitated with Ago2 (fig.	('miR', 'Gene', '220972', (40, 43))	('Knocking down', 'Var', (0, 13))	('HuR', 'Gene', (14, 17))	('miR', 'Gene', (40, 43))	('HuR', 'Gene', '1994', (14, 17))	('reduced', 'NegReg', (18, 25))	('Ago2', 'Gene', '27161', (77, 81))	('amount', 'MPA', (30, 36))	('Ago2', 'Gene', (77, 81))
389050	23901138	Results showed that in Rh30 cells, A20 mRNA immunoprecipitated with Ago2, but this interaction was decreased by silencing HuR (Fig.	('decreased', 'NegReg', (99, 108))	('Rh30', 'Gene', '6007', (23, 27))	('Ago2', 'Gene', '27161', (68, 72))	('silencing', 'Var', (112, 121))	('Rh30', 'Gene', (23, 27))	('Ago2', 'Gene', (68, 72))	('HuR', 'Gene', (122, 125))	('HuR', 'Gene', '1994', (122, 125))
389055	23901138	6B), which was consistent with the ability of the miR-29 mutants to reduce A20 abundance (Fig.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('reduce', 'NegReg', (68, 74))	('A20 abundance', 'MPA', (75, 88))	('mutants', 'Var', (57, 64))
389063	23901138	Our findings reveal, at least in sarcomas, a novel mechanism explaining A20 mRNA decay involving the ability of HuR to interact with an Ago2 complex in the absence of miR-29.	('miR', 'Gene', '220972', (167, 170))	('miR', 'Gene', (167, 170))	('HuR', 'Gene', '1994', (112, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcomas', 'Disease', 'MESH:D012509', (33, 41))	('Ago2', 'Gene', '27161', (136, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('A20', 'Var', (72, 75))	('HuR', 'Gene', (112, 115))	('interact', 'Interaction', (119, 127))	('sarcomas', 'Disease', (33, 41))	('Ago2', 'Gene', (136, 140))
389072	23901138	If this is the case, then constitutive NF-kappaB activation in sarcomas resulting from the loss of A20 is also likely to participate in the regulatory circuit described above, leading to increased expression of HuR.	('activation', 'PosReg', (49, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcomas', 'Disease', (63, 71))	('NF-kappaB', 'Protein', (39, 48))	('A20', 'Gene', (99, 102))	('HuR', 'Gene', (211, 214))	('HuR', 'Gene', '1994', (211, 214))	('increased', 'PosReg', (187, 196))	('loss', 'Var', (91, 95))	('expression', 'MPA', (197, 207))	('sarcomas', 'Disease', 'MESH:D012509', (63, 71))	('participate', 'Reg', (121, 132))
389076	23901138	Although A20 mRNA contains miR-29 binding sites in its 3'UTR, A20 mRNA stability does not seem to be regulated directly by miR-29 because mutating these sites or mutating the seed sequence within mature miR-29 had no effect on the activity of an A20 reporter construct.	('mutating', 'Var', (138, 146))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('mutating', 'Var', (162, 170))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('miR', 'Gene', (203, 206))	('miR', 'Gene', '220972', (203, 206))	('activity', 'MPA', (231, 239))
389093	23901138	Mutations in predicted miR-29 and miR-125 binding sites within the A20 3'UTR were produced with a second generation QuikChange Site-Directed Mutagenesis Kit (Agilent Technologies).	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('Mutations', 'Var', (0, 9))
389095	23901138	BR756443) and 3'UTR (NM_006290) of the A20 gene were analyzed in sarcoma cases by direct Sanger sequencing.	('sarcoma', 'Disease', (65, 72))	('NM_006290', 'Var', (21, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('BR756443', 'Var', (0, 8))	('A20', 'Gene', (39, 42))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))
389131	23901138	For RMSAs, 32P-labeled miR-29 wild-type (5'-uagcaccauuugaaauca-gug-3') and mutant (5'-uagcaccaCCCgaaaucagug-3') probes were generated (mutated sites are shown as capitalized letters).	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('RMS', 'Phenotype', 'HP:0002859', (4, 7))	('mutant', 'Var', (75, 81))	('32P', 'Chemical', 'MESH:C000615311', (11, 14))
389149	23365673	Chromosomal translocation in these tumors produces fusion oncogenes of the EWS/ETS class, with EWS/FLI1 being by far the most common.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('Chromosomal translocation', 'Var', (0, 25))	('produces', 'Reg', (42, 50))	('EWS/ETS', 'Disease', (75, 82))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
389154	23365673	FOXM1 expression is enhanced by EWS/FLI1, though, unlike other tumor systems, it is not driven by expression of the EWS/FLI1 target GLI1.	('GLI1', 'Gene', '2735', (132, 136))	('tumor', 'Disease', (63, 68))	('enhanced', 'PosReg', (20, 28))	('GLI1', 'Gene', (132, 136))	('expression', 'MPA', (6, 16))	('EWS/FLI1', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('FOXM1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
389163	23365673	The prototype rearrangement between chromosomes 11 and 22 produces an EWS/FLI1 fusion which is found in over 85% of Ewing tumors.	('Ewing tumors', 'Disease', 'MESH:C563168', (116, 128))	('rearrangement', 'Var', (14, 27))	('fusion', 'Var', (79, 85))	('Ewing tumors', 'Phenotype', 'HP:0012254', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('EWS/FLI1', 'Gene', (70, 78))	('Ewing tumors', 'Disease', (116, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('Ewing tumor', 'Phenotype', 'HP:0012254', (116, 127))
389205	23365673	We conclude that while FOXM1 is activated by EWS/FLI1, it is not in the subset of EWS/FLI1 targets that are deregulated via GLI1 deregulation.	('GLI1', 'Gene', '2735', (124, 128))	('activated', 'PosReg', (32, 41))	('GLI1', 'Gene', (124, 128))	('FOXM1', 'Gene', (23, 28))	('deregulation', 'Var', (129, 141))
389224	23365673	Indeed many modulators of FOXM1 have been described, including E2F, ERK, HIF-1, and AKT, so the potential for indirect upregulation is significant.	('HIF-1', 'Gene', '3091', (73, 78))	('E2F', 'Var', (63, 66))	('AKT', 'Gene', '207', (84, 87))	('ERK', 'Gene', '5594', (68, 71))	('HIF-1', 'Gene', (73, 78))	('FOXM1', 'Gene', (26, 31))	('AKT', 'Gene', (84, 87))	('ERK', 'Gene', (68, 71))
389286	23019529	Endometrial cancer risk has been previously associated with several host factors, including high body mass index, nulliparity or low parity, early age at first birth, history of type 2 diabetes mellitus (non-insulin dependent), and family history of cancer, particularly endometrial cancer.	('endometrial cancer', 'Disease', (271, 289))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('endometrial cancer', 'Disease', 'MESH:D016889', (271, 289))	('Endometrial cancer', 'Disease', 'MESH:D016889', (0, 18))	('type 2 diabetes mellitus', 'Disease', (178, 202))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (178, 202))	('insulin', 'Gene', '3630', (208, 215))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (185, 202))	('cancer', 'Disease', (283, 289))	('Endometrial cancer', 'Disease', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('nulliparity', 'Var', (114, 125))	('associated', 'Reg', (44, 54))	('insulin', 'Gene', (208, 215))	('endometrial cancer', 'Phenotype', 'HP:0012114', (271, 289))	('cancer', 'Disease', (12, 18))	('Endometrial cancer', 'Phenotype', 'HP:0012114', (0, 18))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
389308	23019529	Besides these risk factors, having a family history of the disease increases risk, as does being a carrier of mutations in BRCA1/BRCA2 genes, or being affected by hereditary non-polyposis colorectal cancer syndrome.	('BRCA1', 'Gene', '672', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (110, 119))	('BRCA2', 'Gene', (129, 134))	('BRCA1', 'Gene', (123, 128))	('affected', 'Reg', (151, 159))	('BRCA2', 'Gene', '675', (129, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('hereditary non-polyposis colorectal cancer syndrome', 'Disease', 'MESH:D015179', (163, 214))
389334	23019529	The available human evidence considered by the IARC Working Group to classify tetrachloroethylene as probably carcinogenic to the cervix uteri comes from 3 cohort studies.	('tetrachloroethylene', 'Chemical', 'MESH:D013750', (78, 97))	('human', 'Species', '9606', (14, 19))	('tetrachloroethylene', 'Var', (78, 97))	('cervix uteri', 'Phenotype', 'HP:0000139', (130, 142))	('carcinogenic', 'Disease', 'MESH:D063646', (110, 122))	('carcinogenic', 'Disease', (110, 122))
389336	23019529	Since the publication of the IARC Monograph, updates of the 2 cohorts of dry cleaners confirmed the increased risk of cervical cancer with exposure to tetrachloroethylene, with excess risks of 60% (standardized mortality ratio [SMR] 1.6, 95% confidence interval [CI] 1.0-2.3, based on 27 deaths) and 95% (SMR 1.95, 95% CI 1.00-3.40).	('cervical cancer', 'Disease', (118, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('death', 'Disease', 'MESH:D003643', (288, 293))	('death', 'Disease', (288, 293))	('tetrachloroethylene', 'Chemical', 'MESH:D013750', (151, 170))	('tetrachloroethylene', 'Var', (151, 170))	('cervical cancer', 'Disease', 'MESH:D002583', (118, 133))
389345	23019529	A Finnish record-linkage study reported excess risks of cervical cancer of about 20 to 40% with exposures to aliphatic and alicyclic, aromatic, and chlorinated hydrocarbon solvents.	('aliphatic', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('hydrocarbon', 'Chemical', 'MESH:D006838', (160, 171))	('cervical cancer', 'Disease', (56, 71))	('cervical cancer', 'Disease', 'MESH:D002583', (56, 71))
389387	23019529	In summary, if occupational exposures to X-radiation or gamma-radiation do confer an increased risk of ovarian cancer, their overall impact is likely to be limited compared to other risk factors.	('X-radiation', 'Disease', 'MESH:D004194', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gamma-radiation', 'Var', (56, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('X-radiation', 'Disease', (41, 52))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('ovarian cancer', 'Disease', (103, 117))
389451	33121123	Classification of tumors according to their immune phenotype can help predict responses to immune checkpoint inhibitors (ICIs), such as anti-programmed cell death 1 (PD-1) inhibitors, pembrolizumab, and nivolumab.	('pembrolizumab', 'Chemical', 'MESH:C582435', (184, 197))	('inhibitors', 'Var', (172, 182))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('nivolumab', 'Chemical', 'MESH:D000077594', (203, 212))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('PD-1', 'Gene', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
389520	33121123	However, TILs may have the potential to improve the clinical outcome in patients treated with molecular targeted drugs and ICIs.	('TIL', 'Gene', (9, 12))	('molecular targeted', 'Var', (94, 112))	('TIL', 'Gene', '7096', (9, 12))	('clinical', 'MPA', (52, 60))	('improve', 'PosReg', (40, 47))	('patients', 'Species', '9606', (72, 80))
389526	33121123	The CheckMate 025, KEYNOTE-426, JAVELIN Renal 101, CheckMate 214, BTCRC-GU14-003, and IMmotion151 trials investigated the association between PD-L1 expression in tumor cells and prognosis as a subgroup analysis, and these trials showed that high PD-L1 expression was associated with a treatment benefit for ICIs.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('PD-L1', 'Gene', (246, 251))	('tumor', 'Disease', (162, 167))	('men', 'Species', '9606', (290, 293))	('ICIs', 'Disease', (307, 311))	('expression', 'MPA', (252, 262))	('high', 'Var', (241, 245))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
389527	33121123	Interestingly, CheckMate 214 revealed that high expression of PD-L1 had a high rate of mortality in patients who received sunitinib.	('high expression', 'Var', (43, 58))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('patients', 'Species', '9606', (100, 108))	('PD-L1', 'Gene', (62, 67))	('mortality', 'Disease', (87, 96))	('sunitinib', 'Chemical', 'MESH:D000077210', (122, 131))
389538	33121123	demonstrated that ADT induced abundant T cell infiltration in both benign glands and tumor tissues in human prostates.	('tumor', 'Disease', (85, 90))	('T cell infiltration', 'CPA', (39, 58))	('ADT', 'Chemical', '-', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ADT', 'Var', (18, 21))	('human', 'Species', '9606', (102, 107))
389550	33121123	Response duration was 4.4 months in patients with an ATM mutation and more than 21.8 months in patients with a BRCA2 mutation.	('BRCA2', 'Gene', (111, 116))	('ATM', 'Gene', '472', (53, 56))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (95, 103))	('ATM', 'Gene', (53, 56))	('BRCA2', 'Gene', '675', (111, 116))	('mutation', 'Var', (117, 125))
389594	33121123	However, neither PD-L1 positivity nor increased tumour-infiltrating lymphocyte score correlated with progression-free survival of longer than 6 months or achieving a partial response.	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('PD-L1', 'Gene', (17, 22))	('positivity', 'Var', (23, 33))
389605	33121123	Early data showed the presence of TILs in UC was associated with a favorable prognosis.	('TIL', 'Gene', '7096', (34, 37))	('TIL', 'Gene', (34, 37))	('presence', 'Var', (22, 30))
389686	32627957	DH82Ond pi cells exhibited an increased percentage of round cells starting at 3 days post-seeding accompanied by a decrease of the others 3 morphological phenotypes (triangle, cigar and slender) as shown in Figure S4.	('triangle', 'CPA', (166, 174))	('cigar', 'CPA', (176, 181))	('round cells', 'CPA', (54, 65))	('decrease', 'NegReg', (115, 123))	('DH82Ond', 'Var', (0, 7))	('DH82Ond pi', 'Chemical', '-', (0, 10))
389687	32627957	From 5 to 7 days post-seeding, round cells predominated among DH82Ond pi cells.	('DH82Ond pi', 'Chemical', '-', (62, 72))	('DH82Ond', 'Var', (62, 69))	('round cells', 'CPA', (31, 42))
389692	32627957	Immunofluorescence of DH82Ond pi cells displayed an increased number of cells expressing beta-catenin (Figure 1A-C; mean = 33%; median = 32%; range: 28%-34%) compared to non-infected controls (mean = 18%; median = 17%; range: 12%-29%).	('DH82Ond', 'Var', (22, 29))	('non-infected', 'Disease', (170, 182))	('DH82Ond pi', 'Chemical', '-', (22, 32))	('beta-catenin', 'Protein', (89, 101))	('non-infected', 'Disease', 'MESH:D007239', (170, 182))
389696	32627957	On the other hand, DH82Ond pi cells exhibited an increased focal cytoplasmic E-cadherin expression compared to non-infected controls, despite not reaching statistical significance (P = .0846).	('non-infected', 'Disease', (111, 123))	('increased', 'PosReg', (49, 58))	('focal cytoplasmic', 'MPA', (59, 76))	('DH82Ond pi', 'Var', (19, 29))	('non-infected', 'Disease', 'MESH:D007239', (111, 123))	('DH82Ond pi', 'Chemical', '-', (19, 29))
389699	32627957	Immunolabelling for cytokeratin 8 (Figure 1K-M) lacked a significant difference (P = .0688) in the percentage of positive cells between DH82Ond pi (mean = 45%; median = 49%; range: 38%-50%) and non-infected controls (mean = 33%; median = 33%; range: 28%-39%).	('non-infected', 'Disease', (194, 206))	('DH82Ond pi', 'Chemical', '-', (136, 146))	('cytokeratin 8', 'Gene', (20, 33))	('non-infected', 'Disease', 'MESH:D007239', (194, 206))	('DH82Ond pi', 'Var', (136, 146))	('cytokeratin 8', 'Gene', '3856', (20, 33))
389701	32627957	However, DH82Ond pi cells displayed a significantly (P < .0001) higher 'membranous to cytoplasmic' expression of this protein compared to non-infected controls (Figure 1O), while the diffuse cytoplasmic localization did not reach statistical significance (P = 0,8340).	("'membranous to cytoplasmic' expression", 'MPA', (71, 109))	('non-infected', 'Disease', (138, 150))	('DH82Ond pi', 'Var', (9, 19))	('DH82Ond pi', 'Chemical', '-', (9, 19))	('higher', 'PosReg', (64, 70))	('non-infected', 'Disease', 'MESH:D007239', (138, 150))
389709	32627957	DH82Ond pi cells contained a significantly higher amount of E-cadherin (P = .0192) compared to non-infected controls (Figure 3B).	('non-infected', 'Disease', 'MESH:D007239', (95, 107))	('higher', 'PosReg', (43, 49))	('E-cadherin', 'Protein', (60, 70))	('non-infected', 'Disease', (95, 107))	('DH82Ond pi', 'Var', (0, 10))	('DH82Ond pi', 'Chemical', '-', (0, 10))
389710	32627957	In addition, a similar higher amount of cytokeratin 8 expression was observed in DH82Ond pi cells compared to non-infected controls (P = .0376).	('expression', 'MPA', (54, 64))	('non-infected', 'Disease', (110, 122))	('higher', 'PosReg', (23, 29))	('cytokeratin 8', 'Gene', (40, 53))	('non-infected', 'Disease', 'MESH:D007239', (110, 122))	('DH82Ond pi', 'Var', (81, 91))	('DH82Ond pi', 'Chemical', '-', (81, 91))	('cytokeratin 8', 'Gene', '3856', (40, 53))
389711	32627957	The beta-catenin expression was higher in DH82Ond pi compared to non-infected DH82 cells (Figure 3B) although this increase did not reach statistical significance (P = .0956).	('DH82Ond pi', 'Chemical', '-', (42, 52))	('non-infected', 'Disease', (65, 77))	('beta-catenin', 'Protein', (4, 16))	('higher', 'PosReg', (32, 38))	('expression', 'MPA', (17, 27))	('DH82', 'Chemical', '-', (42, 46))	('non-infected', 'Disease', 'MESH:D007239', (65, 77))	('DH82', 'Chemical', '-', (78, 82))	('DH82Ond pi', 'Var', (42, 52))
389715	32627957	On the other hand, in DH82Ond pi cells this protein was predominantly expressed in cells with a round morphology, which were significantly more abundant (P = .0156) compared to the same phenotype among non-infected cells.	('non-infected', 'Disease', (202, 214))	('non-infected', 'Disease', 'MESH:D007239', (202, 214))	('DH82Ond', 'Var', (22, 29))	('DH82Ond pi', 'Chemical', '-', (22, 32))	('more abundant', 'PosReg', (139, 152))
389722	32627957	In contrast, a significantly (P = .0035) higher percentage of DH82Ond pi cells showed a focal cytoplasmic expression of vimentin compared to non-infected controls.	('DH82Ond pi', 'Chemical', '-', (62, 72))	('non-infected', 'Disease', (141, 153))	('higher', 'PosReg', (41, 47))	('non-infected', 'Disease', 'MESH:D007239', (141, 153))	('vimentin', 'Protein', (120, 128))	('DH82Ond', 'Var', (62, 69))
389724	32627957	Similar to non-infected cells with a round morphology, DH82Ond pi cells often displayed a focal immunoreactivity not expanding to the cell membrane (Figure 5D-F).	('DH82Ond', 'Var', (55, 62))	('non-infected', 'Disease', (11, 23))	('DH82Ond pi', 'Chemical', '-', (55, 65))	('non-infected', 'Disease', 'MESH:D007239', (11, 23))
389727	32627957	Among the selected gene symbols, 38 were differentially expressed between DH82Ond pi cells and non-infected controls.	('non-infected', 'Disease', 'MESH:D007239', (95, 107))	('differentially', 'Reg', (41, 55))	('DH82Ond', 'Var', (74, 81))	('DH82Ond pi', 'Chemical', '-', (74, 84))	('non-infected', 'Disease', (95, 107))
389728	32627957	Among the epithelial markers previously investigated, only cytokeratin 8 gene symbol was up-regulated in DH82Ond pi cells.	('cytokeratin 8', 'Gene', '3856', (59, 72))	('DH82Ond pi', 'Var', (105, 115))	('DH82Ond pi', 'Chemical', '-', (105, 115))	('cytokeratin 8', 'Gene', (59, 72))	('up-regulated', 'PosReg', (89, 101))
389739	32627957	After 6 hours, no significant differences (P = .1161) were found in the percentage of wound closure in non-infected DH82 compared to DH82Ond pi cells.	('DH82', 'Chemical', '-', (116, 120))	('non-infected', 'Disease', (103, 115))	('non-infected', 'Disease', 'MESH:D007239', (103, 115))	('DH82', 'Var', (116, 120))	('DH82Ond pi', 'Chemical', '-', (133, 143))	('wound closure', 'CPA', (86, 99))	('DH82', 'Chemical', '-', (133, 137))
389741	32627957	On the contrary, DH82Ond pi cells maintained an arrangement in a monolayer, associated with a weak tendency to move towards the scratch.	('DH82Ond pi', 'Chemical', '-', (17, 27))	('arrangement', 'CPA', (48, 59))	('DH82Ond', 'Var', (17, 24))
389745	32627957	After 144 hours, both non-infected DH82 and DH82Ond pi cells showed clear signs of cellular necrosis characterized by cell shrinkage and by the accumulation of abundant cellular debris within each well.	('necrosis', 'Disease', 'MESH:D009336', (92, 100))	('non-infected', 'Disease', 'MESH:D007239', (22, 34))	('cell shrinkage', 'CPA', (118, 132))	('DH82Ond', 'Var', (44, 51))	('DH82', 'Chemical', '-', (35, 39))	('DH82Ond pi', 'Chemical', '-', (44, 54))	('necrosis', 'Disease', (92, 100))	('non-infected', 'Disease', (22, 34))	('DH82', 'Chemical', '-', (44, 48))
389749	32627957	In the present study, as detected with immunofluorescence and confirmed by immunoblotting, E-cadherin was significantly over-expressed in DH82Ond pi cells compared to non-infected controls.	('non-infected', 'Disease', 'MESH:D007239', (167, 179))	('DH82Ond', 'Var', (138, 145))	('DH82Ond pi', 'Chemical', '-', (138, 148))	('E-cadherin', 'Protein', (91, 101))	('non-infected', 'Disease', (167, 179))	('over-expressed', 'PosReg', (120, 134))
389750	32627957	This observation was further substantiated by an increased protein expression of cytokeratin 8 in DH82Ond pi compared to non-infected DH82 cells.	('DH82', 'Chemical', '-', (98, 102))	('DH82', 'Chemical', '-', (134, 138))	('increased', 'PosReg', (49, 58))	('non-infected', 'Disease', (121, 133))	('DH82Ond pi', 'Var', (98, 108))	('protein expression', 'MPA', (59, 77))	('cytokeratin 8', 'Gene', (81, 94))	('DH82Ond pi', 'Chemical', '-', (98, 108))	('non-infected', 'Disease', 'MESH:D007239', (121, 133))	('cytokeratin 8', 'Gene', '3856', (81, 94))
389757	32627957	31  In the current study, DH82Ond pi cells showed a significant down-regulation of the myoferlin gene (MYOF) compared to non-infected DH82 cells.	('DH82', 'Chemical', '-', (26, 30))	('DH82', 'Chemical', '-', (134, 138))	('MYOF', 'Gene', '607472', (103, 107))	('non-infected', 'Disease', (121, 133))	('down-regulation', 'NegReg', (64, 79))	('myoferlin', 'Gene', '607472', (87, 96))	('DH82Ond', 'Var', (26, 33))	('DH82Ond pi', 'Chemical', '-', (26, 36))	('non-infected', 'Disease', 'MESH:D007239', (121, 133))	('myoferlin', 'Gene', (87, 96))	('MYOF', 'Gene', (103, 107))
389764	32627957	However, at the protein level, DH82Ond pi cells displayed an increased E-cadherin protein expression while a high expression of N-cadherin was present only at the mRNA level.	('DH82Ond pi', 'Var', (31, 41))	('DH82Ond pi', 'Chemical', '-', (31, 41))	('N-cadherin', 'Gene', (128, 138))	('increased', 'PosReg', (61, 70))	('E-cadherin protein', 'Protein', (71, 89))	('N-cadherin', 'Gene', '1000', (128, 138))
389771	32627957	Notably, non-infected DH82 cells were characterized by a significantly more frequent cytoplasmic expression of cytokeratin 8, which was focally arranged around the nucleus and the Golgi apparatus, whereas DH82Ond pi cells showed a pronounced expression of variably sized aggregates of this protein within the cytoplasm and intermingled with the cell membrane.	('cytoplasmic', 'MPA', (85, 96))	('more', 'PosReg', (71, 75))	('cytokeratin 8', 'Gene', '3856', (111, 124))	('DH82Ond', 'Var', (205, 212))	('DH82', 'Chemical', '-', (205, 209))	('DH82Ond pi', 'Chemical', '-', (205, 215))	('non-infected', 'Disease', (9, 21))	('non-infected', 'Disease', 'MESH:D007239', (9, 21))	('DH82', 'Chemical', '-', (22, 26))	('cytokeratin 8', 'Gene', (111, 124))
389773	32627957	Indeed, as already reported, a knockdown of cytokeratin 8 and 18 in neoplastic epithelial cells was associated with a significantly increased cancer cell motility and invasiveness.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('increased', 'PosReg', (132, 141))	('cytokeratin 8', 'Gene', (44, 57))	('invasiveness', 'CPA', (167, 179))	('cytokeratin 8', 'Gene', '3856', (44, 57))	('knockdown', 'Var', (31, 40))	('cancer', 'Disease', (142, 148))
389775	32627957	39  Similar results were obtained in the present study, which revealed an up-regulation of cytokeratin 8 within DH82Ond pi cells compared to non-infected controls The observation of cytokeratin 8 mainly in a 'membranous to cytoplasmic' localization in DH82Ond pi cells might be one factor leading to the reduced cell motility observed in the scratch and in the invasion assay.	('non-infected', 'Disease', 'MESH:D007239', (141, 153))	('up-regulation', 'PosReg', (74, 87))	('non-infected', 'Disease', (141, 153))	('cytokeratin 8', 'Gene', '3856', (182, 195))	('DH82Ond pi', 'Chemical', '-', (252, 262))	('cytokeratin 8', 'Gene', (91, 104))	('DH82Ond', 'Var', (252, 259))	('DH82Ond pi', 'Chemical', '-', (112, 122))	('cytokeratin 8', 'Gene', (182, 195))	('reduced', 'NegReg', (304, 311))	('invasion assay', 'CPA', (361, 375))	('cytokeratin 8', 'Gene', '3856', (91, 104))	('cell motility', 'CPA', (312, 325))
389777	32627957	40  This might be correlated with the more homogeneous round cellular shape of DH82Ond pi cultures compared to non-infected controls, with the latter characterized by a more pleomorphic phenotype.	('non-infected', 'Disease', (111, 123))	('non-infected', 'Disease', 'MESH:D007239', (111, 123))	('DH82Ond pi', 'Chemical', '-', (79, 89))	('DH82Ond', 'Var', (79, 86))
389779	32627957	However, DH82Ond pi and non-infected DH82 cells showed a higher number of positive round and spindle cells, respectively.	('non-infected', 'Disease', (24, 36))	('DH82Ond pi', 'Chemical', '-', (9, 19))	('non-infected', 'Disease', 'MESH:D007239', (24, 36))	('DH82Ond', 'Var', (9, 16))	('DH82', 'Chemical', '-', (9, 13))	('DH82', 'Chemical', '-', (37, 41))
389780	32627957	This finding was mirrored by the fact that DH82Ond pi and non-infected DH82 cells showed a more frequent focal and diffuse cytoplasmic distribution of vimentin, respectively, which was confirmed by 3D reconstructions.	('non-infected', 'Disease', (58, 70))	('DH82', 'Chemical', '-', (43, 47))	('non-infected', 'Disease', 'MESH:D007239', (58, 70))	('DH82Ond pi', 'Chemical', '-', (43, 53))	('vimentin', 'Protein', (151, 159))	('DH82Ond', 'Var', (43, 50))	('DH82', 'Chemical', '-', (71, 75))
389785	32627957	Additionally, CDV-driven MET seems to affect invasiveness and cell motility in vitro, most likely based on a rearrangement of cytoskeletal intermediate filaments.	('CDV', 'Species', '11232', (14, 17))	('cell motility', 'CPA', (62, 75))	('MET', 'Var', (25, 28))	('invasiveness', 'CPA', (45, 57))	('affect', 'Reg', (38, 44))	('rearrangement', 'Reg', (109, 122))
389817	32079176	Significant associations were found between the isokinetic dynamometer and the following self-reported outcomes: (1) TESS, (2) MFI-20 General fatigue, (3) MFI-20 Physical fatigue, (4) MFI-20 Reduced activity, and (5) MFI-20 Reduced motivation.	('TESS', 'Disease', (117, 121))	('activity', 'MPA', (199, 207))	('Reduced motivation', 'Phenotype', 'HP:0000745', (224, 242))	('fatigue', 'Phenotype', 'HP:0012378', (171, 178))	('Physical fatigue', 'Disease', (162, 178))	('Physical fatigue', 'Disease', 'MESH:D005221', (162, 178))	('fatigue', 'Disease', 'MESH:D005221', (142, 149))	('fatigue', 'Disease', (171, 178))	('motivation', 'MPA', (232, 242))	('fatigue', 'Disease', (142, 149))	('MFI-20', 'Gene', (127, 133))	('fatigue', 'Disease', 'MESH:D005221', (171, 178))	('Reduced', 'NegReg', (224, 231))	('fatigue', 'Phenotype', 'HP:0012378', (142, 149))	('MFI-20', 'Gene', (155, 161))	('Reduced', 'NegReg', (191, 198))	('MFI-20', 'Var', (184, 190))
389818	32079176	Significant associations were also found between the 10-MWT and the following self-reported outcomes: (1) TESS, (2) MSTS, (3) MFI-20 General fatigue, (4) MFI-20 Physical fatigue, and (5) MFI-20 Reduced activity (Table 6).	('fatigue', 'Disease', 'MESH:D005221', (141, 148))	('Reduced', 'NegReg', (194, 201))	('MSTS', 'Disease', (116, 120))	('fatigue', 'Disease', (141, 148))	('fatigue', 'Phenotype', 'HP:0012378', (170, 177))	('MFI-20', 'Gene', (126, 132))	('MFI-20', 'Var', (154, 160))	('fatigue', 'Disease', 'MESH:D005221', (170, 177))	('fatigue', 'Phenotype', 'HP:0012378', (141, 148))	('fatigue', 'Disease', (170, 177))	('STS', 'Phenotype', 'HP:0030448', (117, 120))	('TESS', 'Disease', (106, 110))	('Physical fatigue', 'Disease', 'MESH:D005221', (161, 177))	('activity', 'MPA', (202, 210))	('Physical fatigue', 'Disease', (161, 177))
389820	32079176	Lastly, significant associations were found between the 6-MWT and the following self-reported outcomes: (1) HADS-Depression, (2) MFI-20 General fatigue, (3) MFI-20 Physical fatigue, and (4) MFI-20 Reduced motivation.	('MFI-20', 'Var', (190, 196))	('fatigue', 'Disease', (144, 151))	('fatigue', 'Disease', 'MESH:D005221', (144, 151))	('fatigue', 'Disease', 'MESH:D005221', (173, 180))	('MFI-20', 'Var', (129, 135))	('Reduced motivation', 'Phenotype', 'HP:0000745', (197, 215))	('fatigue', 'Phenotype', 'HP:0012378', (144, 151))	('fatigue', 'Disease', (173, 180))	('Depression', 'Phenotype', 'HP:0000716', (113, 123))	('MFI-20', 'Var', (157, 163))	('fatigue', 'Phenotype', 'HP:0012378', (173, 180))	('Physical fatigue', 'Disease', 'MESH:D005221', (164, 180))	('HADS-Depression', 'Disease', (108, 123))	('motivation', 'CPA', (205, 215))	('Physical fatigue', 'Disease', (164, 180))	('Reduced', 'NegReg', (197, 204))
389869	32079176	Patient exclusion criteria were (1) previous arthroplasty in a unilaterally affected extremity; (2) poor general condition defined as presence of severe cardiopulmonary diseases (DI519 and DJ894); (3) recurrence of the disease during the study period in, which case patients were excluded from the time of recurrence.	('patients', 'Species', '9606', (266, 274))	('cardiopulmonary diseases', 'Disease', (153, 177))	('DJ894)', 'Var', (189, 195))	('cardiopulmonary diseases', 'Disease', 'MESH:D006323', (153, 177))	('DI519', 'Var', (179, 184))	('Patient', 'Species', '9606', (0, 7))
389901	29140881	PDGFB Rearrangements in Dermatofibrosarcoma Protuberans of the Vulva: A Study of 11 Cases Including Myxoid and Fibrosarcomatous Variants Dermatofibrosarcoma protuberans (DFSP) is a low grade fibroblastic sarcoma that tends to arise in young to middle age adults and involve the trunk and proximal extremities.	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('Rearrangements', 'Var', (6, 20))	('sarcoma', 'Disease', (149, 156))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (144, 156))	('PDGFB', 'Gene', (0, 5))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (31, 43))	('Dermatofibrosarcoma protuberans', 'Disease', (137, 168))	('sarcoma', 'Disease', 'MESH:D012509', (204, 211))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('sarcoma', 'Disease', (204, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('sarcoma', 'Disease', (36, 43))	('sarcoma', 'Disease', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('PDGFB', 'Gene', '5155', (0, 5))	('DFSP', 'Disease', (170, 174))	('DFSP', 'Disease', 'None', (170, 174))	('Dermatofibrosarcoma protuberans', 'Disease', 'None', (137, 168))	('Dermatofibrosarcoma Protuberans', 'Disease', (24, 55))	('Dermatofibrosarcoma Protuberans', 'Disease', 'None', (24, 55))
389908	29140881	Nine of 11 tumors (82%) had rearrangement of PDGFB by fluorescence in situ hybridization.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('PDGFB', 'Gene', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('rearrangement', 'Var', (28, 41))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('PDGFB', 'Gene', '5155', (45, 50))
389913	29140881	The high frequency of PDGFB rearrangement in vulvar DFSP provides a useful exploit in diagnostically challenging cases and genetic evidence of probable clinical response to targeted therapeutics in cases of locally advanced or metastatic vulvar DFSP.	('PDGFB', 'Gene', '5155', (22, 27))	('DFSP', 'Disease', 'None', (52, 56))	('rearrangement', 'Var', (28, 41))	('DFSP', 'Disease', (52, 56))	('PDGFB', 'Gene', (22, 27))	('DFSP', 'Disease', (245, 249))	('DFSP', 'Disease', 'None', (245, 249))
389921	29140881	Most examples of classic DFSP and its variants have a unique underlying unbalanced chromosomal translocation, t(17;22)(q22;q13), that generates a supernumerary ring chromosome containing a COL1A1-PDGFB gene fusion.	('COL1A1', 'Gene', '1277', (189, 195))	('DFSP', 'Disease', (25, 29))	('COL1A1', 'Gene', (189, 195))	('PDGFB', 'Gene', (196, 201))	('DFSP', 'Disease', 'None', (25, 29))	('variants', 'Var', (38, 46))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (110, 127))	('PDGFB', 'Gene', '5155', (196, 201))	('generates', 'Reg', (134, 143))
389925	29140881	Studies of extra-vulvar DFSP indicate that their characteristic t(17;22)(q22;q13) or resulting fusion transcript can be detected in a majority of tumors.	('t(17;22)(q22;q13', 'Var', (64, 80))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('DFSP', 'Disease', (24, 28))	('DFSP', 'Disease', 'None', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('fusion transcript', 'MPA', (95, 112))	('tumors', 'Disease', (146, 152))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (64, 81))	('extra-vulvar', 'Disease', (11, 23))
389927	29140881	To better understand the frequency of PDGFB rearrangement in vulvar DFSP and its variants, we evaluated a series of tumors by FISH.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('rearrangement', 'Var', (44, 57))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('PDGFB', 'Gene', '5155', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('DFSP', 'Disease', (68, 72))	('DFSP', 'Disease', 'None', (68, 72))	('PDGFB', 'Gene', (38, 43))
389933	29140881	Immunoreactivity was scored by percentage of tumor cell expression: 0 (negative); 1+ (1% to 33%); 2+ (34% to 66%); 3+ (67% to 100%) and intensity: weak (W), heterogeneous (H) or strong (S).	('tumor', 'Disease', (45, 50))	('heterogeneous', 'Var', (157, 170))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))
389963	29140881	Nine of 11 tumors (82%) demonstrated rearrangement of PDGFB (Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('PDGFB', 'Gene', '5155', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('PDGFB', 'Gene', (54, 59))	('rearrangement', 'Var', (37, 50))
390000	29140881	However, in one patient with metastasis and a fibrosarcomatous tumor with t(17;22)(q22;q13), in addition to other complex karyotypic changes, had only a partial response with disease progression 7 months later.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (46, 58))	('fibrosarcomatous tumor', 'Disease', 'MESH:D018223', (46, 68))	('fibrosarcomatous tumor', 'Disease', (46, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('patient', 'Species', '9606', (16, 23))	('t(17;22)(q22;q13', 'Var', (74, 90))
390005	29140881	By FISH, our rate of PDGFB rearrangement was 82% or 9 of 11 cases, inclusive of variants and high grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('rearrangement', 'Var', (27, 40))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('PDGFB', 'Gene', '5155', (21, 26))	('PDGFB', 'Gene', (21, 26))
390031	29140881	PDGFB rearrangement is present and detectable by FISH in a majority of tumors that arise in the vulva, including variants and high grade tumors.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('rearrangement', 'Var', (6, 19))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('PDGFB', 'Gene', '5155', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('variants', 'Disease', (113, 121))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('PDGFB', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
390032	29140881	These data support evaluation of COL1A1-PDGFB fusion transcript in diagnostically difficult cases in addition to providing genetic evidence of probable clinical response to targeted therapeutics in cases of locally advanced or metastatic vulvar DFSP.	('COL1A1', 'Gene', (33, 39))	('PDGFB', 'Gene', '5155', (40, 45))	('COL1A1', 'Gene', '1277', (33, 39))	('DFSP', 'Disease', (245, 249))	('PDGFB', 'Gene', (40, 45))	('DFSP', 'Disease', 'None', (245, 249))	('fusion', 'Var', (46, 52))
390352	33919049	Presence of MDI was also significantly associated with longer treatment delay (p = 0.006) and longer duration of unscheduled hospitalization (p = 0.001).	('MDI', 'Gene', (12, 15))	('associated', 'Reg', (39, 49))	('Presence', 'Var', (0, 8))	('MDI', 'Chemical', '-', (12, 15))
390408	33349267	Previous studies revealed that local recurrence rates were not higher in primary advanced STS tumors treated with TM-ILP and subsequent resection of the residual tumor than those treated by a combination of radiation therapy and surgery.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('TM-ILP', 'Chemical', '-', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('TM-ILP', 'Var', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (94, 99))	('local recurrence', 'CPA', (31, 47))	('STS tumors', 'Disease', 'MESH:D016114', (90, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('STS tumors', 'Disease', (90, 100))
390411	33349267	The aim of this study was to compare the oncological outcome parameters (manifestation of local recurrence or distant metastasis) of patients treated for recurrent high-grade soft tissue sarcoma of the extremities with a combination of TM-ILP and subsequent tumor-resection to a group of patients treated with standard therapy (tumor resection without TM-ILP).	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('distant metastasis', 'CPA', (110, 128))	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('tumor', 'Disease', (258, 263))	('patients', 'Species', '9606', (288, 296))	('TM-ILP', 'Var', (236, 242))	('patients', 'Species', '9606', (133, 141))	('TM-ILP', 'Chemical', '-', (352, 358))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('TM-ILP', 'Chemical', '-', (236, 242))	('sarcoma', 'Disease', (187, 194))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (175, 194))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', (328, 333))
390437	33349267	Although patients treated with TM-ILP had significantly more non-resectable tumors (50% vs. 29%, p = 0.008), and there was no statistically significant difference in terms of resection margins (p = 0.898), type of surgery (p = 0.531), and perioperative radiation therapy (p = 0.202) between the TM-ILP and standard groups (Table 2).	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('TM-ILP', 'Chemical', '-', (295, 301))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('TM-ILP', 'Var', (31, 37))	('TM-ILP', 'Chemical', '-', (31, 37))
390448	33349267	This novel study sought to exclusively compare locally recurrent soft tissue extremity sarcoma treated by TM-ILP and subsequent resection of the residual tumor to a group of comparable tumors treated by standard surgical therapy without the use of TM-ILP.	('tumor', 'Disease', (185, 190))	('TM-ILP', 'Chemical', '-', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('sarcoma', 'Disease', (87, 94))	('tumors', 'Disease', (185, 191))	('soft tissue extremity sarcoma', 'Phenotype', 'HP:0030448', (65, 94))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('TM-ILP', 'Chemical', '-', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('TM-ILP', 'Var', (106, 112))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))	('tumor', 'Disease', (154, 159))
390453	33349267	Most surprisingly, we observed quite the opposite: the local recurrence-free survival was significantly higher in the TM-ILP group compared to the standard group.	('TM-ILP', 'Var', (118, 124))	('higher', 'PosReg', (104, 110))	('local recurrence-free survival', 'CPA', (55, 85))	('TM-ILP', 'Chemical', '-', (118, 124))
390502	27257447	Immunohistochemistry is positive for Bcl-2 protein in approximately 79% of cases, and cytogenetic analysis demonstrates a characteristic chromosomal translocation t(x;18)(p11;q110) in 90% of cases.	('Bcl-2', 'Gene', '596', (37, 42))	('t(x;18)(p11;q110)', 'STRUCTURAL_ABNORMALITY', 'None', (163, 180))	('t(x;18)(p11;q110', 'Var', (163, 179))	('Bcl-2', 'Gene', (37, 42))
390705	32391124	Nevertheless, despite the close association between KS and immune dysfunction, it remains unclear whether TIIC are a critical component in KS pathogenesis, and whether their absence, presence, or dysregulation could serve as a prognostic biomarker of KS disease progression or control.	('dysregulation', 'Var', (196, 209))	('KS disease', 'Disease', 'MESH:D003141', (251, 261))	('KS disease', 'Disease', (251, 261))
390724	32391124	CxCL-9 was examined instead of CxCL-10 and -11 because it was upregulated the most in KS lesions vs controls skin at false discovery rate (FDR) < 5%.	('lesions', 'Var', (89, 96))	('CxCL-10', 'Gene', (31, 38))	('CxCL-9', 'Gene', (0, 6))	('CxCL-9', 'Gene', '4283', (0, 6))	('CxCL-10', 'Gene', '3627', (31, 38))	('upregulated', 'PosReg', (62, 73))
390776	32391124	KSHV is known to induce hypoxic metabolic derangements through HIF-1 expression.	('induce', 'Reg', (17, 23))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('hypoxic', 'Disease', (24, 31))	('hypoxic', 'Disease', 'MESH:D000860', (24, 31))	('HIF-1', 'Gene', '3091', (63, 68))	('metabolic derangements', 'Phenotype', 'HP:0001939', (32, 54))	('HIF-1', 'Gene', (63, 68))
390825	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))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('genetic alterations', 'Var', (62, 81))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('response to therapy', 'MPA', (118, 137))
390826	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))
390828	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))
390834	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))
390836	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))
390839	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))
390840	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))
390842	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))
390857	30442178	To address the question of how mutational differences between two classes affect protein expressions in more than one histotype in the same way, we performed a cross-cancer effect analysis.	('mutational', 'Var', (31, 41))	('affect', 'Reg', (74, 80))	('protein expressions', 'MPA', (81, 100))	('cross-cancer', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cross-cancer', 'Disease', 'MESH:C537866', (160, 172))
390872	30442178	At this point, it is unclear whether the reason for this inconsistency between genetic and protein profiles is the differential translation of genetic profiles into protein levels in different cancer types, or organ- and tissue-specific protein base levels that are modulated by mutations:or a combination of both.	('ran', 'Gene', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('ran', 'Gene', '5901', (129, 132))	('mutations', 'Var', (279, 288))	('cancer', 'Disease', (193, 199))	('modulated', 'Reg', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
390886	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))
390898	30442178	The least pronounced but still significant class discriminability is achieved for classes C12 and C5 in breast cancer (sdis = - 0.31, p = 4.4e-3; srand = - 8.0e-5).	('ran', 'Gene', (147, 150))	('sdis', 'Chemical', '-', (119, 123))	('ran', 'Gene', '5901', (147, 150))	('C12', 'Var', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
390917	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))
390920	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))	('glioma', 'Disease', (126, 132))	('ran', 'Gene', (236, 239))	('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))
390943	30442178	Using the same approach as above, we are systematically evaluating all major actionable somatic mutations and copy number alterations against which drugs are approved for clinical use or which are currently tested in clinical trials with respect to their effects on proteins across cancers.	('cancers', 'Disease', (282, 289))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('copy number alterations', 'Var', (110, 133))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('mutations', 'Var', (96, 105))
390948	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))
390950	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))
390953	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', 'MPA', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
390954	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))
390955	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))
390956	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))
390960	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))
390962	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))	('Cyclin_B1', 'Gene', '891', (176, 185))	('Syk', 'Gene', '6850', (269, 272))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('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))
390964	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))
390966	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))
390967	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))
390968	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))
390978	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))
390983	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))
390984	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))
390987	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))
390988	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))
390989	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))
390990	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))
390991	30442178	E-Cadherin, beta-Catenin, HER2, Ku80, PTEN, IRS1, and 53BP1 are increased among cases having one or more specific FGF3 mutation.	('53BP1', 'Gene', (54, 59))	('beta-Catenin', 'Gene', '1499', (12, 24))	('FGF3', 'Gene', (114, 118))	('mutation', 'Var', (119, 127))	('PTEN', 'Gene', '5728', (38, 42))	('Ku80', 'Gene', '7520', (32, 36))	('53BP1', 'Gene', '7158', (54, 59))	('Ku80', 'Gene', (32, 36))	('HER2', 'Gene', (26, 30))	('E-Cadherin', 'Gene', (0, 10))	('FGF3', 'Gene', '2248', (114, 118))	('IRS1', 'Gene', '3667', (44, 48))	('IRS1', 'Gene', (44, 48))	('HER2', 'Gene', '2064', (26, 30))	('increased', 'PosReg', (64, 73))	('E-Cadherin', 'Gene', '999', (0, 10))	('PTEN', 'Gene', (38, 42))	('beta-Catenin', 'Gene', (12, 24))
390992	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))	('IDH1', 'Gene', '3417', (0, 4))	('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))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (33, 55))	('IDH1', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', (57, 75))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
390993	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))
390995	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))	('Caveolin-1', 'Gene', '857', (51, 61))	('EGFR', 'Gene', '1956', (104, 108))	('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))
390996	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))
390997	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))
390998	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))
390999	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))	('Fibronectin', 'Gene', (150, 161))	('c-Kit', 'Gene', (205, 210))	('sdis', 'Chemical', '-', (75, 79))	('expression levels', 'MPA', (233, 250))	('E-Cadherin', 'Gene', '999', (135, 145))	('c-Kit', 'Gene', '3815', (205, 210))	('decreased', 'NegReg', (125, 134))	('Syk', 'Gene', '6850', (229, 232))	('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))
391001	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))	('NRAS', 'Gene', '4893', (5, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('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))
391002	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))
391005	30442178	For melanoma (sdis = - 0.16; p = 1.0e-3; and = 5.2e-6) E-Cadherin, Caveolin-1, and c-Kit expression levels are decreased for mutated cases, and MAPK_pT202_Y204 is increased.	('E-Cadherin', 'Gene', '999', (55, 65))	('Caveolin-1', 'Gene', (67, 77))	('MAPK_pT202_Y204', 'Var', (144, 159))	('mutated', 'Var', (125, 132))	('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))
391006	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))	('mutated', 'Var', (107, 114))	('ran', 'Gene', (48, 51))	('ran', 'Gene', '5901', (48, 51))	('Fibronectin', 'Gene', '2335', (79, 90))	('decreased', 'NegReg', (94, 103))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (4, 21))	('Fibronectin', 'Gene', (79, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (4, 21))	('thyroid carcinoma', 'Disease', (4, 21))
391007	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))
391008	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))
391009	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))
391010	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).	('ran', 'Gene', '5901', (150, 153))	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('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))
391011	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))
391014	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.	('glioma', 'Disease', (115, 121))	('tumor', 'Disease', (251, 256))	('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))
391017	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))
391019	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))
391021	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))
391023	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))	('HER2', 'Gene', (284, 288))	('GATA3', 'Gene', (225, 230))	('ER-alpha', 'Gene', (177, 185))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('mutations', 'Var', (43, 52))	('ER-alpha', 'Gene', '2099', (177, 185))	('Breast cancer', 'Disease', (0, 13))	('Fibronectin', 'Gene', (204, 215))
391027	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))
391028	30442178	Moreover, even for a given cancer, clinical response to therapy targeting a specific mutation strongly varies, which is likely due to the modulatory influence of the usually high mutational complexity in tumors.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('varies', 'Reg', (103, 109))	('mutation', 'Var', (85, 93))	('cancer', 'Disease', (27, 33))	('tumors', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
391033	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))
391038	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))
391042	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))
391046	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))
391053	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))
391067	29309807	The discovery of NAB2-STAT6 rearrangement in nearly 100% of SFTs and as a result consistent immunohistochemical expression of STAT6 has greatly enhanced diagnostic accuracy of this neoplasm in recent years.	('neoplasm', 'Disease', (181, 189))	('SFTs', 'Disease', (60, 64))	('neoplasm', 'Phenotype', 'HP:0002664', (181, 189))	('NAB2', 'Gene', '4665', (17, 21))	('enhanced', 'PosReg', (144, 152))	('rearrangement', 'Var', (28, 41))	('neoplasm', 'Disease', 'MESH:D009369', (181, 189))	('NAB2', 'Gene', (17, 21))
391072	29309807	In both cases, CD34 and STAT6 were positive in tumor cells and molecular studies demonstrated the presence of NAB2-STAT6 fusion, confirming the diagnosis.	('fusion', 'Var', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('NAB2', 'Gene', '4665', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('NAB2', 'Gene', (110, 114))
391088	29309807	Targeted RNA sequencing, using the MSK - Solid Fusion assay, detected an in-frame fusion between NAB2 Exon 6 (NM_005967) and STAT6 Exon 16 (NM_001178078) (Fig.	('MSK', 'Gene', '150094', (35, 38))	('MSK', 'Gene', (35, 38))	('NAB2', 'Gene', (97, 101))	('NAB2', 'Gene', '4665', (97, 101))	('NM_005967', 'Var', (110, 119))	('NM_001178078', 'Var', (140, 152))
391095	29309807	2D), CD56 and CD117 (focal), and negative for DOG-1, desmin, myogenin and TTF-1.	('CD117', 'Var', (14, 19))	('TTF-1', 'Gene', '608462', (74, 79))	('DOG', 'Species', '9615', (46, 49))	('TTF-1', 'Gene', (74, 79))	('myogenin', 'Gene', '490224', (61, 69))	('CD56', 'Var', (5, 9))	('myogenin', 'Gene', (61, 69))
391108	29309807	The fusion was an in-frame fusion between NAB2 Exon 6 (NM_005967) and STAT6 Exon 15 (NM_001178081) (Fig.	('NAB2', 'Gene', '4665', (42, 46))	('NAB2', 'Gene', (42, 46))	('NM_005967', 'Var', (55, 64))	('NM_001178081', 'Var', (85, 97))
391111	29309807	The biologic behavior of this tumor has remained unpredictable and SFTs with increased mitoses (>4/10HPFs), hypercellularity, pleomorphism, tumor necrosis, and/or infiltrative margins have been reported to behave in a more aggressive manner.	('mitoses', 'CPA', (87, 94))	('hypercellularity', 'Var', (108, 124))	('tumor necrosis', 'Disease', (140, 154))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('pleomorphism', 'Var', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('man', 'Species', '9606', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('increased', 'PosReg', (77, 86))	('tumor necrosis', 'Disease', 'MESH:D009336', (140, 154))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (140, 145))
391129	29309807	Multiple variants of NAB2-STAT6 fusion have been reported in SFT, however, their prognostic significance is not well established.	('variants', 'Var', (9, 17))	('reported', 'Reg', (49, 57))	('NAB2', 'Gene', '4665', (21, 25))	('SFT', 'Disease', (61, 64))	('NAB2', 'Gene', (21, 25))
391160	29163353	Diagnosis of Ewing sarcoma/primitive neuroectodermal tumor was made based on either a core needle biopsy or surgical specimen, and the reports confirmed that six out of seven patients displayed EWSR1 mutation on fluorescence in situ hybridization.	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (37, 58))	('neuroectodermal tumor', 'Disease', (37, 58))	('Ewing sarcoma', 'Disease', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('EWSR1', 'Gene', (194, 199))	('patients', 'Species', '9606', (175, 183))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (37, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))	('EWSR1', 'Gene', '2130', (194, 199))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (27, 58))	('mutation', 'Var', (200, 208))
391170	29163353	Laboratory markers:TSH, T3, T4, LDH were in reference range, respectively: TSH 0.64 muU/ml (0.34-0.94), fT3 4.9 pmol/l (2.63-5.7), fT4 14.28 pmol/l (9.01-19.05), LDH 201 U/l (125-220) with CEA and calcitonin being negative.	('CEA', 'Gene', '5670', (189, 192))	('fT4', 'Chemical', '-', (131, 134))	('TSH', 'Chemical', '-', (19, 22))	('TSH', 'Chemical', '-', (75, 78))	('fT4', 'Var', (131, 134))	('CEA', 'Gene', (189, 192))
391173	29163353	Mutation in EWSR1 was confirmed using the FISH (fluorescence in situ hybridization) method.	('Mutation', 'Var', (0, 8))	('EWSR1', 'Gene', (12, 17))	('EWSR1', 'Gene', '2130', (12, 17))
391299	24252471	We thus found that the double positivity for CD34 and ALDH1 was highly specific for the diagnosis of SFT, with a specificity and positive predictive value of 100%.	('SFT', 'Disease', (101, 104))	('double positivity', 'Var', (23, 40))	('CD34', 'Gene', '947', (45, 49))	('ALDH1', 'Gene', (54, 59))	('CD34', 'Gene', (45, 49))	('ALDH1', 'Gene', '216', (54, 59))
391333	24252471	In addition to its diagnostic interest, high ALDH1 expression in SFT and HPC also has therapeutic implications.	('high', 'Var', (40, 44))	('SFT', 'Disease', (65, 68))	('ALDH1', 'Gene', (45, 50))	('ALDH1', 'Gene', '216', (45, 50))	('HPC', 'Disease', 'MESH:C537262', (73, 76))	('HPC', 'Disease', (73, 76))	('expression', 'MPA', (51, 61))
391337	24252471	Recently, two different teams identified recurrent NAB2-STAT6 gene fusions on chromosome 12q13 in Solitary Fibrous Tumours of various locations.	('Solitary Fibrous Tumours', 'Disease', 'MESH:D054364', (98, 122))	('STAT6', 'Gene', (56, 61))	('Tumours', 'Phenotype', 'HP:0002664', (115, 122))	('fusions', 'Var', (67, 74))	('NAB2', 'Gene', '4665', (51, 55))	('STAT6', 'Gene', '6778', (56, 61))	('Solitary Fibrous Tumours', 'Disease', (98, 122))	('NAB2', 'Gene', (51, 55))
391338	24252471	identified a NAB2-STAT6 gene fusion in a hepatic metastasis of a malignant meningeal SFT by integrative sequencing.	('STAT6', 'Gene', (18, 23))	('NAB2', 'Gene', '4665', (13, 17))	('STAT6', 'Gene', '6778', (18, 23))	('NAB2', 'Gene', (13, 17))	('hepatic metastasis', 'MPA', (41, 59))	('fusion', 'Var', (29, 35))
391376	24252471	Automate IHC was performed using a Ventana automate (Benchmark XT, Ventana Medical Systems SA, Illkirch, France) and the two following antibodies: ALDH1 (clone 44/ALDH, immunogen Human ALDH1 aa.	('Human', 'Species', '9606', (179, 184))	('ALDH1', 'Gene', '216', (185, 190))	('ALDH1', 'Gene', '216', (147, 152))	('clone', 'Var', (154, 159))	('ALDH1', 'Gene', (185, 190))	('ALDH1', 'Gene', (147, 152))
391618	31820302	Our recently published data indicated that cyclic NGR peptide with daunorubicin connected via chemo selective ligation (oxime bond formation) can have significant antitumor activity in vitro.	('cyclic', 'Var', (43, 49))	('peptide', 'Chemical', 'MESH:D010455', (54, 61))	('daunorubicin', 'Chemical', 'MESH:D003630', (67, 79))	('oxime', 'Chemical', 'MESH:D010091', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
391623	31820302	In addition, conjugate 2 with Nle instead of Lys in the cycle provided significantly higher efficiency on both cell lines, which is supported by cellular uptake studies where conjugate 2 entered the cells more efficiently than 1, especially at lower concentrations.	('Lys', 'Chemical', 'MESH:D008239', (45, 48))	('higher', 'PosReg', (85, 91))	('conjugate', 'Var', (13, 22))	('efficiency', 'MPA', (92, 102))	('Nle', 'Var', (30, 33))
391661	31820302	High inhibition of tumor weight (45.7%) was obtained in the treatment with conjugate 2, though the decrease was not significant.	('conjugate', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('inhibition', 'NegReg', (5, 15))	('tumor', 'Disease', (19, 24))
391677	30275026	Primary undifferentiated pleomorphic cardiac sarcoma with MDM2 amplification presenting as acute left-sided heart failure Primary cardiac tumours are a rare clinical entity that can present with myriad of non-specific cardiopulmonary symptoms.	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('heart failure', 'Phenotype', 'HP:0001635', (108, 121))	('heart failure', 'Disease', 'MESH:D006333', (108, 121))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('Primary cardiac tumours', 'Disease', (122, 145))	('Primary undifferentiated pleomorphic cardiac sarcoma', 'Disease', 'MESH:D002277', (0, 52))	('MDM2', 'Gene', '4193', (58, 62))	('Primary cardiac tumours', 'Disease', 'MESH:D006338', (122, 145))	('left-sided heart failure', 'Phenotype', 'HP:0005162', (97, 121))	('heart failure', 'Disease', (108, 121))	('MDM2', 'Gene', (58, 62))	('amplification', 'Var', (63, 76))	('cardiac sarcoma', 'Phenotype', 'HP:0031350', (37, 52))
391704	30275026	Furthermore, fluorescence in situ hybridisation (FISH) molecular analysis demonstrated amplification of the murine double minute 2 (MDM2) oncogene, supporting the diagnosis of undifferentiated sarcoma (figure 5).	('murine double minute 2', 'Gene', (108, 130))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (176, 200))	('undifferentiated sarcoma', 'Disease', (176, 200))	('murine double minute 2', 'Gene', '17246', (108, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('MDM2', 'Gene', (132, 136))	('amplification', 'Var', (87, 100))
391728	30275026	The term cardiac intimal sarcoma was used in reference to previous studies that showed the majority of pulmonary artery intimal sarcomas displayed MDM2 amplification.	('MDM2 amplification', 'Var', (147, 165))	('sarcoma', 'Disease', (25, 32))	('sarcoma', 'Disease', 'MESH:D012509', (128, 135))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcoma', 'Disease', (128, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomas', 'Disease', (128, 136))	('pulmonary artery intimal sarcomas', 'Phenotype', 'HP:0005312', (103, 136))	('sarcoma', 'Disease', 'MESH:D012509', (25, 32))
391735	30275026	A recent retrospective review of 124 cases showed that complete resection increased median survival by 7 months (11.2 vs 18.2 months), compared with non-resected patients.	('increased', 'PosReg', (74, 83))	('patients', 'Species', '9606', (162, 170))	('median survival', 'MPA', (84, 99))	('complete resection', 'Var', (55, 73))
391777	26788276	These studies have shown UESL to be associated with inac-tivation of the TP53 gene through the loss of heterozygosity and pathogenic mutation of the remaining allele leading to over expression.	('mutation', 'Var', (133, 141))	('TP53', 'Gene', '7157', (73, 77))	('over expression', 'MPA', (177, 192))	('TP53', 'Gene', (73, 77))	('loss of', 'NegReg', (95, 102))
391795	23300809	PI3K Inhibition Enhances Doxorubicin-Induced Apoptosis in Sarcoma Cells We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX).	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('Sarcoma', 'Disease', (58, 65))	('doxorubicin', 'Chemical', 'MESH:D004317', (140, 151))	('Sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('Enhances', 'PosReg', (16, 24))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('Doxorubicin-Induced', 'MPA', (25, 44))	('DOX', 'Chemical', 'MESH:D004317', (153, 156))	('Doxorubicin', 'Chemical', 'MESH:D004317', (25, 36))	('PI3K Inhibition', 'Var', (0, 15))	('sarcoma', 'Disease', (123, 130))	('Sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
391796	23300809	We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis.	('enhances', 'PosReg', (50, 58))	('sarcoma', 'Disease', (90, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('DOX', 'Chemical', 'MESH:D004317', (128, 131))	('interacts', 'Reg', (113, 122))	('DOX', 'Chemical', 'MESH:D004317', (75, 78))	('efficacy', 'MPA', (63, 71))	('PI103', 'Var', (44, 49))	('PI103', 'Chemical', 'MESH:C522973', (44, 49))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
391797	23300809	PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation.	('MRP1', 'Gene', (43, 47))	('expression', 'MPA', (20, 30))	('decreased', 'NegReg', (6, 15))	('MDR1', 'Gene', (34, 38))	('DOX', 'Chemical', 'MESH:D004317', (67, 70))	('DOX accumulation', 'MPA', (67, 83))	('MRP1', 'Gene', '4363', (43, 47))	('MDR1', 'Gene', '5243', (34, 38))	('resulted in', 'Reg', (55, 66))	('PI103', 'Var', (0, 5))	('PI103', 'Chemical', 'MESH:C522973', (0, 5))
391799	23300809	Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3.	('activated', 'PosReg', (53, 62))	('DOX', 'Chemical', 'MESH:D004317', (38, 41))	('Bax', 'Gene', '581', (63, 66))	('PI103', 'Chemical', 'MESH:C522973', (47, 52))	('Bax', 'Gene', (63, 66))	('caspase 3', 'Pathway', (109, 118))	('PI103', 'Var', (47, 52))	('mitochondrial apoptosis pathway', 'Pathway', (72, 103))
391801	23300809	Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('inhibition', 'Var', (170, 180))	('DOX-induced proapoptotic effects', 'MPA', (201, 233))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('DOX', 'Chemical', 'MESH:D004317', (201, 204))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('GDC-0941', 'Chemical', 'MESH:C532162', (126, 134))	('PI3K', 'Gene', (184, 188))	('sarcoma', 'Disease', (237, 244))	('tumor', 'Disease', (61, 66))	('improve', 'PosReg', (193, 200))
391809	23300809	Chemotherapy of sarcomas frequently involves anthracyclines, which are topoisomerase II (TOP2) inhibitors, in combination with other cytostatic drugs.	('sarcomas', 'Disease', (16, 24))	('anthracyclines', 'Var', (45, 59))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('anthracyclines', 'Chemical', 'MESH:D018943', (45, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))
391819	23300809	All these drugs have been shown to sensitize other tumor entities to antitumoral effects of TOP2A inhibitors, purportedly by increasing TOP2A expression levels.	('TOP2A', 'Gene', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('inhibitors', 'Var', (98, 108))	('expression levels', 'MPA', (142, 159))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (51, 56))	('TOP2A', 'Gene', '7153', (92, 97))	('tumor', 'Disease', (73, 78))	('TOP2A', 'Gene', '7153', (136, 141))	('TOP2A', 'Gene', (92, 97))	('increasing', 'PosReg', (125, 135))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('sensitize', 'Reg', (35, 44))
391822	23300809	Our present study was prompted by the observation that PI103 interacts with DOX in the induction of apoptosis and in activation of caspase 3 in 3 different sarcoma cell lines.	('sarcoma', 'Disease', 'MESH:D012509', (156, 163))	('PI103', 'Var', (55, 60))	('sarcoma', 'Disease', (156, 163))	('PI103', 'Chemical', 'MESH:C522973', (55, 60))	('DOX', 'Chemical', 'MESH:D004317', (76, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('activation', 'PosReg', (117, 127))	('caspase', 'Enzyme', (131, 138))	('apoptosis', 'CPA', (100, 109))
391866	23300809	Whereas treatment of the cells with 5-Aza (5 microM) and VPA (2 mM) significantly induced the proliferation rate of the cells, bortezomib (10 nM) and PI103 (1 microM) significantly reduced it.	('reduced', 'NegReg', (181, 188))	('5-Aza', 'Chemical', 'MESH:D001374', (36, 41))	('VPA', 'Chemical', 'MESH:D014635', (57, 60))	('proliferation rate', 'CPA', (94, 112))	('bortezomib', 'Chemical', 'MESH:D000069286', (127, 137))	('PI103', 'Var', (150, 155))	('PI103', 'Chemical', 'MESH:C522973', (150, 155))	('induced', 'PosReg', (82, 89))
391871	23300809	The enhancement by PI103 was of borderline significance (P<0.08).	('enhancement', 'PosReg', (4, 15))	('PI103', 'Var', (19, 24))	('PI103', 'Chemical', 'MESH:C522973', (19, 24))
391872	23300809	DOX-related apoptosis was also enhanced by both pioglitazone and PI103, as indicated by the significant increase of Annexin V-positive cells.	('increase', 'PosReg', (104, 112))	('pioglitazone', 'Chemical', 'MESH:D000077205', (48, 60))	('Annexin V', 'Gene', (116, 125))	('PI103', 'Var', (65, 70))	('DOX', 'Chemical', 'MESH:D004317', (0, 3))	('enhanced', 'PosReg', (31, 39))	('PI103', 'Chemical', 'MESH:C522973', (65, 70))	('Annexin V', 'Gene', '308', (116, 125))	('apoptosis', 'CPA', (12, 21))
391873	23300809	In addition, PI103 was able to enhance DOX-mediated induction of caspase 3/7 activity.	('PI103', 'Chemical', 'MESH:C522973', (13, 18))	('DOX-mediated induction', 'MPA', (39, 61))	('enhance', 'PosReg', (31, 38))	('caspase', 'Enzyme', (65, 72))	('activity', 'MPA', (77, 85))	('DOX', 'Chemical', 'MESH:D004317', (39, 42))	('PI103', 'Var', (13, 18))
391874	23300809	In summary, the dual PI3K/mTOR inhibitor PI103 significantly affected 2 of the measured parameters of apoptotic cell death when combined with DOX, i.e.	('DOX', 'Chemical', 'MESH:D004317', (142, 145))	('PI103', 'Chemical', 'MESH:C522973', (41, 46))	('affected', 'Reg', (61, 69))	('PI103', 'Var', (41, 46))
391878	23300809	We first assessed whether the dual PI3K/mTOR inhibitor PI103 blocks PI3K/Akt/mTOR signaling in the cell lines examined by assessing phosphorylation of Akt and S6 ribosomal protein taken as surrogate readouts for the activity of PI3K and mTOR, respectively.	('Akt', 'Gene', (73, 76))	('blocks', 'NegReg', (61, 67))	('Akt', 'Gene', '207', (73, 76))	('PI103', 'Var', (55, 60))	('Akt', 'Gene', '207', (151, 154))	('PI103', 'Chemical', 'MESH:C522973', (55, 60))	('phosphorylation', 'MPA', (132, 147))	('Akt', 'Gene', (151, 154))
391879	23300809	This is evidenced by phosphorylation of Akt and S6, which was efficiently decreased by PI103 (Figure 1A).	('PI103', 'Chemical', 'MESH:C522973', (87, 92))	('Akt', 'Gene', '207', (40, 43))	('PI103', 'Var', (87, 92))	('phosphorylation', 'MPA', (21, 36))	('Akt', 'Gene', (40, 43))	('decreased', 'NegReg', (74, 83))
391880	23300809	Treatment with 3 microM PI103 almost completely inhibited Akt phosphorylation in all 3 cell lines.	('PI103', 'Chemical', 'MESH:C522973', (24, 29))	('PI103', 'Var', (24, 29))	('Akt', 'Gene', '207', (58, 61))	('inhibited', 'NegReg', (48, 57))	('Akt', 'Gene', (58, 61))
391881	23300809	Besides dephosphorylation of S6 we also observed a decrease in the total amount of S6 after incubation with PI103.	('PI103', 'Var', (108, 113))	('amount', 'MPA', (73, 79))	('PI103', 'Chemical', 'MESH:C522973', (108, 113))	('decrease', 'NegReg', (51, 59))	('dephosphorylation', 'MPA', (8, 25))
391886	23300809	Both DOX and PI103 alone consistently reduced cell proliferation in all 3 sarcoma cell lines (Figure 1B).	('DOX', 'Chemical', 'MESH:D004317', (5, 8))	('PI103', 'Chemical', 'MESH:C522973', (13, 18))	('reduced', 'NegReg', (38, 45))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('sarcoma', 'Disease', (74, 81))	('cell proliferation', 'CPA', (46, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('PI103', 'Var', (13, 18))
391888	23300809	A calculation of the CI in RD and HT1080 cells revealed that PI103 synergistically cooperated with DOX to inhibit proliferation (CI = 0.769 and CI = 0.766, respectively).	('DOX', 'Chemical', 'MESH:D004317', (99, 102))	('inhibit', 'NegReg', (106, 113))	('proliferation', 'CPA', (114, 127))	('PI103', 'Chemical', 'MESH:C522973', (61, 66))	('PI103', 'Var', (61, 66))
391895	23300809	Together these data demonstrated that the combined treatment with PI103 and DOX results in enhancement of apoptosis of sarcoma cells.	('PI103', 'Var', (66, 71))	('PI103', 'Chemical', 'MESH:C522973', (66, 71))	('apoptosis', 'CPA', (106, 115))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('enhancement', 'PosReg', (91, 102))	('DOX', 'Chemical', 'MESH:D004317', (76, 79))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))
391898	23300809	Based on these observations we hypothesized that inhibition of PI3K/Akt activity decreases the expression of MDR1 and MRP1, leading to DOX accumulation in the tumor cells.	('MDR1', 'Gene', (109, 113))	('MDR1', 'Gene', '5243', (109, 113))	('Akt', 'Gene', '207', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('MRP1', 'Gene', '4363', (118, 122))	('inhibition', 'Var', (49, 59))	('tumor', 'Disease', (159, 164))	('DOX', 'Chemical', 'MESH:D004317', (135, 138))	('DOX accumulation', 'MPA', (135, 151))	('Akt', 'Gene', (68, 71))	('MRP1', 'Gene', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('decreases', 'NegReg', (81, 90))	('expression', 'MPA', (95, 105))
391903	23300809	As shown in Figure 2B, PI103 resulted in a 60% decrease in the transcription of both MDR1 and MRP1 mRNA (Figure 2B; left and middle panel).	('transcription', 'MPA', (63, 76))	('MRP1', 'Gene', '4363', (94, 98))	('decrease', 'NegReg', (47, 55))	('MDR1', 'Gene', (85, 89))	('MDR1', 'Gene', '5243', (85, 89))	('PI103', 'Chemical', 'MESH:C522973', (23, 28))	('PI103', 'Var', (23, 28))	('MRP1', 'Gene', (94, 98))
391904	23300809	The PI103-mediated decrease in MRP1 expression was confirmed on the protein level (Figure 2B; right panel).	('PI103', 'Chemical', 'MESH:C522973', (4, 9))	('decrease', 'NegReg', (19, 27))	('MRP1', 'Gene', '4363', (31, 35))	('MRP1', 'Gene', (31, 35))	('PI103-mediated', 'Var', (4, 18))	('expression', 'MPA', (36, 46))
391906	23300809	We next investigated if the PI103-associated DOX accumulation was responsible for the combined effects of the drugs on apoptosis.	('PI103-associated', 'Var', (28, 44))	('DOX', 'Chemical', 'MESH:D004317', (45, 48))	('PI103', 'Chemical', 'MESH:C522973', (28, 33))	('DOX accumulation', 'MPA', (45, 61))
391911	23300809	We also analyzed if an additional 12-hours pretreatment with PI103 enhanced sensitization of sarcoma cells to DOX-induced anticancer effects.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('sensitization', 'MPA', (76, 89))	('sarcoma', 'Disease', (93, 100))	('DOX', 'Chemical', 'MESH:D004317', (110, 113))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('PI103', 'Chemical', 'MESH:C522973', (61, 66))	('PI103', 'Var', (61, 66))	('enhanced', 'PosReg', (67, 75))
391914	23300809	This was not only evident by a stronger antiproliferative effect (Figure S3A; for HT1080 and TP5014 cells see Figure S3B and S3C), but also by a further increase of Annexin V-positive cells (approximately 5-fold compared to the control; see Figure 2E, left panel) when compared to the increase of Annexin V positive cells after the 24-hours co-incubation (approximately 3.5-fold compared to the control; see Figure 2C, left panel).	('Annexin V', 'Gene', '308', (165, 174))	('Annexin V', 'Gene', (165, 174))	('antiproliferative effect', 'CPA', (40, 64))	('increase', 'PosReg', (153, 161))	('TP5014', 'Var', (93, 99))	('Annexin V', 'Gene', '308', (297, 306))	('Annexin V', 'Gene', (297, 306))
391915	23300809	However, the preincubation with PI103 did not result in a further increase in DOX accumulation (Figure 2E, right panel).	('DOX accumulation', 'MPA', (78, 94))	('PI103', 'Chemical', 'MESH:C522973', (32, 37))	('DOX', 'Chemical', 'MESH:D004317', (78, 81))	('PI103', 'Var', (32, 37))
391916	23300809	Together, these data indicated that the enhancement of DOX-induced apoptosis by PI103 cannot solely be explained by PI103-associated DOX accumulation.	('DOX-induced apoptosis', 'CPA', (55, 76))	('DOX', 'Chemical', 'MESH:D004317', (55, 58))	('PI103', 'Var', (80, 85))	('enhancement', 'PosReg', (40, 51))	('PI103', 'Chemical', 'MESH:C522973', (80, 85))	('DOX', 'Chemical', 'MESH:D004317', (133, 136))	('PI103', 'Chemical', 'MESH:C522973', (116, 121))
391917	23300809	PI103 has been recently reported to cooperate with DOX to shift the ratio of pro- and antiapoptotic Bcl-2 proteins finally resulting in activation of the proapoptotic protein Bax.	('Bax', 'Gene', '581', (175, 178))	('Bcl-2', 'Gene', (100, 105))	('DOX', 'Chemical', 'MESH:D004317', (51, 54))	('Bcl-2', 'Gene', '596', (100, 105))	('ratio of', 'MPA', (68, 76))	('Bax', 'Gene', (175, 178))	('activation', 'PosReg', (136, 146))	('PI103', 'Var', (0, 5))	('PI103', 'Chemical', 'MESH:C522973', (0, 5))
391920	23300809	We first investigated the effect of PI103 and DOX on Bax activation by immunoprecipitation of protein lysates with anti-Bax antibody 6A7 and subsequent analysis by western blotting using BaxNT antibody as previously described.	('Bax', 'Gene', (187, 190))	('Bax', 'Gene', (53, 56))	('Bax', 'Gene', '581', (187, 190))	('Bax', 'Gene', (120, 123))	('DOX', 'Chemical', 'MESH:D004317', (46, 49))	('Bax', 'Gene', '581', (53, 56))	('PI103', 'Var', (36, 41))	('PI103', 'Chemical', 'MESH:C522973', (36, 41))	('Bax', 'Gene', '581', (120, 123))
391924	23300809	As revealed by Western Blot analysis, DOX did not alter Bax activity, whereas PI103 marginally changed the conformation of Bax.	('Bax', 'Gene', (56, 59))	('Bax', 'Gene', '581', (123, 126))	('DOX', 'Chemical', 'MESH:D004317', (38, 41))	('conformation', 'MPA', (107, 119))	('Bax', 'Gene', '581', (56, 59))	('Bax', 'Gene', (123, 126))	('changed', 'Reg', (95, 102))	('PI103', 'Var', (78, 83))	('activity', 'MPA', (60, 68))	('PI103', 'Chemical', 'MESH:C522973', (78, 83))
391928	23300809	Whereas monotherapy with PI103 had a moderate effect on cytochrome c release, the combination with DOX strongly enhanced this effect (Figure 3B).	('enhanced', 'PosReg', (112, 120))	('PI103', 'Var', (25, 30))	('cytochrome c', 'Gene', (56, 68))	('PI103', 'Chemical', 'MESH:C522973', (25, 30))	('cytochrome c', 'Gene', '54205', (56, 68))	('DOX', 'Chemical', 'MESH:D004317', (99, 102))
391929	23300809	Together these data demonstrate that the combined effect of PI103 plus DOX involves Bax activation and cytochrome c release.	('cytochrome c', 'Gene', (103, 115))	('activation', 'PosReg', (88, 98))	('Bax', 'Gene', (84, 87))	('cytochrome c', 'Gene', '54205', (103, 115))	('DOX', 'Chemical', 'MESH:D004317', (71, 74))	('PI103', 'Var', (60, 65))	('Bax', 'Gene', '581', (84, 87))	('PI103', 'Chemical', 'MESH:C522973', (60, 65))
391930	23300809	Next, we investigated to what extent the combined proapoptotic effects of PI103 plus DOX were mediated by mTOR or by PI3K.	('proapoptotic', 'MPA', (50, 62))	('DOX', 'Chemical', 'MESH:D004317', (85, 88))	('PI103', 'Var', (74, 79))	('PI103', 'Chemical', 'MESH:C522973', (74, 79))
391936	23300809	In contrast, LY294002 significantly increased DOX-induced apoptosis as revealed by Annexin V labeling (Figure 4A right panel) and by increased caspase activity (Figure 4B right panel).	('caspase', 'Gene', '841', (143, 150))	('Annexin V', 'Gene', '308', (83, 92))	('Annexin V', 'Gene', (83, 92))	('caspase', 'Gene', (143, 150))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('increased', 'PosReg', (36, 45))	('DOX', 'Chemical', 'MESH:D004317', (46, 49))	('LY294002', 'Var', (13, 21))	('increased', 'PosReg', (133, 142))	('activity', 'MPA', (151, 159))
391939	23300809	The solubility of PI103 is limited and the compound is metabolized extensively.	('PI103', 'Chemical', 'MESH:C522973', (18, 23))	('solubility', 'MPA', (4, 14))	('PI103', 'Var', (18, 23))
391941	23300809	In comparison to PI103, GDC-0941 is much more PI3K-specific, whereas its effect on mTOR is negligible.	('GDC-0941', 'Var', (24, 32))	('PI103', 'Chemical', 'MESH:C522973', (17, 22))	('GDC-0941', 'Chemical', 'MESH:C532162', (24, 32))	('PI3K-specific', 'Disease', (46, 59))
391946	23300809	Compared to the continuous low-dose application of DOX, GDC-0941 had a more pronounced effect on tumor growth inhibition.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('GDC-0941', 'Var', (56, 64))	('DOX', 'Chemical', 'MESH:D004317', (51, 54))	('GDC-0941', 'Chemical', 'MESH:C532162', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))
391947	23300809	In fact, GDC-0941 completely stopped tumor growth after 7 days of treatment (Figure 5A; Table S2).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('GDC-0941', 'Chemical', 'MESH:C532162', (9, 17))	('GDC-0941', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('stopped', 'NegReg', (29, 36))
391952	23300809	Although immunohistochemical analysis of paraffin-embedded tumor sections did not reveal any significant difference in TUNEL positive cells (data not shown), the combination increased the percentage of cells positive for active caspase 3 when compared to application of either DOX or GDC-0941 alone (Figure 5B).	('DOX', 'Chemical', 'MESH:D004317', (277, 280))	('paraffin', 'Chemical', 'MESH:D010232', (41, 49))	('tumor', 'Disease', (59, 64))	('GDC-0941', 'Chemical', 'MESH:C532162', (284, 292))	('combination', 'Var', (162, 173))	('active', 'MPA', (221, 227))	('caspase', 'Protein', (228, 235))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('increased', 'PosReg', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
391953	23300809	These data demonstrated that the combination therapy consisting of DOX plus GDC-0941 elevates caspase 3 activity in vivo.	('elevates', 'PosReg', (85, 93))	('GDC-0941', 'Var', (76, 84))	('activity', 'MPA', (104, 112))	('GDC-0941', 'Chemical', 'MESH:C532162', (76, 84))	('DOX', 'Chemical', 'MESH:D004317', (67, 70))	('caspase', 'Enzyme', (94, 101))
391966	23300809	pretreatment of the cells with the drugs; application of the drugs at a higher dose; combination with lower or higher DOX concentrations), we focused on PI103, which simultaneously enhanced DOX-induced proliferation inhibition, induction of apoptosis, and activation of caspase 3 in all three sarcoma- and RMS-derived cell lines investigated.	('caspase', 'Enzyme', (270, 277))	('sarcoma', 'Disease', (293, 300))	('enhanced', 'PosReg', (181, 189))	('PI103', 'Var', (153, 158))	('activation', 'PosReg', (256, 266))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('PI103', 'Chemical', 'MESH:C522973', (153, 158))	('DOX', 'Chemical', 'MESH:D004317', (118, 121))	('apoptosis', 'CPA', (241, 250))	('RMS', 'Phenotype', 'HP:0002859', (306, 309))	('DOX-induced', 'MPA', (190, 201))	('DOX', 'Chemical', 'MESH:D004317', (190, 193))	('sarcoma', 'Disease', 'MESH:D012509', (293, 300))
391969	23300809	Among these are ridaforolimus and DOX (NCT00288431), or temsirolimus plus pegylated liposomal DOX in resistant solid malignancies or recurrent sarcoma (NCT00703170; NCT00949325).	('NCT00703170;', 'Var', (152, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('DOX', 'Chemical', 'MESH:D004317', (34, 37))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('DOX', 'Chemical', 'MESH:D004317', (94, 97))	('sarcoma', 'Disease', (143, 150))	('sarcoma', 'Disease', 'MESH:D012509', (143, 150))	('malignancies', 'Disease', (117, 129))	('NCT00288431', 'Var', (39, 50))
391970	23300809	However, pure mTOR inhibition (alone or in combination with other cytostatics) should be carefully reconsidered, because inhibition of mTOR results in activation of Akt in some tumor entities including RMS (this study, see Figure 4).	('RMS', 'Disease', (202, 205))	('RMS', 'Phenotype', 'HP:0002859', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mTOR', 'Gene', (135, 139))	('inhibition', 'Var', (121, 131))	('Akt', 'Gene', '207', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('activation', 'PosReg', (151, 161))	('Akt', 'Gene', (165, 168))
391975	23300809	Our results now show that the PI103-mediated sensitization of sarcoma cells to DOX treatment also involves activation of Bax, cytochrome c release, and activation of caspase 3.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('cytochrome c', 'Gene', '54205', (126, 138))	('activation', 'PosReg', (152, 162))	('DOX', 'Chemical', 'MESH:D004317', (79, 82))	('PI103', 'Chemical', 'MESH:C522973', (30, 35))	('sarcoma', 'Disease', (62, 69))	('Bax', 'Gene', '581', (121, 124))	('PI103-mediated', 'Var', (30, 44))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('caspase', 'Enzyme', (166, 173))	('Bax', 'Gene', (121, 124))	('cytochrome c', 'Gene', (126, 138))	('activation', 'PosReg', (107, 117))
391977	23300809	In neuroblastoma, the cooperative proapoptotic effect of DOX and PI103 resulted in upregulation of Noxa and Bim, which correlated with increased Bax/Bak conformational change, loss of mitochondrial membrane potential, cytochrome c release, caspase activation, and caspase-dependent apoptosis.	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('Bax', 'Gene', '581', (145, 148))	('neuroblastoma', 'Disease', 'MESH:D009447', (3, 16))	('mitochondrial membrane potential', 'MPA', (184, 216))	('Bim', 'Gene', '10018', (108, 111))	('Bak', 'Gene', (149, 152))	('cytochrome c', 'Gene', (218, 230))	('Bim', 'Gene', (108, 111))	('caspase', 'Gene', (240, 247))	('caspase', 'Gene', (264, 271))	('DOX', 'Chemical', 'MESH:D004317', (57, 60))	('activation', 'PosReg', (248, 258))	('PI103', 'Var', (65, 70))	('loss', 'NegReg', (176, 180))	('Noxa', 'Gene', '5366', (99, 103))	('Bak', 'Gene', '578', (149, 152))	('upregulation', 'PosReg', (83, 95))	('caspase', 'Gene', '841', (240, 247))	('PI103', 'Chemical', 'MESH:C522973', (65, 70))	('caspase', 'Gene', '841', (264, 271))	('Noxa', 'Gene', (99, 103))	('increased', 'PosReg', (135, 144))	('neuroblastoma', 'Disease', (3, 16))	('Bax', 'Gene', (145, 148))	('cytochrome c', 'Gene', '54205', (218, 230))
391979	23300809	These data suggest that the molecular mechanism resulting in PI103-mediated sensitization of sarcoma to DOX is similar to the chemosensitization of neuroblastoma and glioblastoma and involves the activation of several proteins of the mitochondrial apoptosis pathway.	('sensitization', 'MPA', (76, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('neuroblastoma', 'Phenotype', 'HP:0003006', (148, 161))	('PI103-mediated', 'Var', (61, 75))	('sarcoma', 'Disease', (93, 100))	('DOX', 'Chemical', 'MESH:D004317', (104, 107))	('neuroblastoma and glioblastoma', 'Disease', 'MESH:D005909', (148, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('activation', 'PosReg', (196, 206))	('PI103', 'Chemical', 'MESH:C522973', (61, 66))	('proteins', 'Protein', (218, 226))	('mitochondrial apoptosis pathway', 'Pathway', (234, 265))
391980	23300809	Since the reason for the combined effect of PI103 and DOX on the mitochondrial apoptosis pathway activation is still unknown, we addressed several questions: First, we wanted to know whether PI103-mediated inhibition of PI3K/Akt activity may decrease the expression of MDR1 and MRP1, ultimately resulting in accumulation of DOX in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('PI103-mediated', 'Var', (191, 205))	('MRP1', 'Gene', (278, 282))	('PI103', 'Chemical', 'MESH:C522973', (191, 196))	('decrease', 'NegReg', (242, 250))	('inhibition', 'NegReg', (206, 216))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('activity', 'MPA', (229, 237))	('expression', 'MPA', (255, 265))	('DOX', 'MPA', (324, 327))	('MDR1', 'Gene', '5243', (269, 273))	('DOX', 'Chemical', 'MESH:D004317', (324, 327))	('Akt', 'Gene', (225, 228))	('DOX', 'Chemical', 'MESH:D004317', (54, 57))	('accumulation', 'PosReg', (308, 320))	('PI103', 'Chemical', 'MESH:C522973', (44, 49))	('MRP1', 'Gene', '4363', (278, 282))	('Akt', 'Gene', '207', (225, 228))	('tumor', 'Disease', (331, 336))	('MDR1', 'Gene', (269, 273))
391987	23300809	Indeed, the in vivo experiments demonstrated that the combination of GDC-0941 plus DOX significantly increased the numbers of caspase 3 positive cells.	('increased', 'PosReg', (101, 110))	('caspase', 'Protein', (126, 133))	('DOX', 'Chemical', 'MESH:D004317', (83, 86))	('GDC-0941', 'Var', (69, 77))	('GDC-0941', 'Chemical', 'MESH:C532162', (69, 77))
391988	23300809	This indicates that PI3K inhibition in combination with DOX increases proapoptotic events also in vivo.	('DOX', 'Chemical', 'MESH:D004317', (56, 59))	('proapoptotic events', 'MPA', (70, 89))	('PI3K', 'Pathway', (20, 24))	('inhibition', 'Var', (25, 35))	('increases', 'PosReg', (60, 69))
391997	31308696	WDL/DDL are thought to represent the broad spectrum of one disease, as they are both associated with the amplification in the chromosomal 12q13-15 region that causes MDM2 and CDK4 overexpression, the most useful predictor for liposarcoma diagnosis.	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('amplification', 'Var', (105, 118))	('MDM2', 'Disease', (166, 170))	('liposarcoma', 'Disease', (226, 237))	('causes', 'Reg', (159, 165))	('CDK4', 'Gene', (175, 179))	('liposarcoma', 'Disease', 'MESH:D008080', (226, 237))	('liposarcoma', 'Phenotype', 'HP:0012034', (226, 237))	('WDL/DDL', 'Disease', (0, 7))	('overexpression', 'PosReg', (180, 194))
391998	31308696	In comparison to WDL, DDL contains additional genetic abnormalities, principally coamplifications of 1p32 and 6q23, that increase recurrence and metastatic rate.	('rat', 'Species', '10116', (156, 159))	('coamplifications', 'Var', (81, 97))	('increase', 'PosReg', (121, 129))	('1p32', 'Gene', (101, 105))	('DDL', 'Gene', (22, 25))	('recurrence', 'CPA', (130, 140))	('metastatic rate', 'CPA', (145, 160))	('6q23', 'Gene', (110, 114))	('genetic abnormalities', 'Disease', 'MESH:D030342', (46, 67))	('WDL', 'Gene', (17, 20))	('DDL', 'Gene', '18998', (22, 25))	('WDL', 'Gene', '12319', (17, 20))	('genetic abnormalities', 'Disease', (46, 67))
392011	31308696	DDL variants are more predisposed to metastasize, while ALT/WDL subtypes do not metastasize without dedifferentiation.	('variants', 'Var', (4, 12))	('DDL', 'Gene', (0, 3))	('WDL', 'Gene', (60, 63))	('DDL', 'Gene', '18998', (0, 3))	('metastasize', 'CPA', (37, 48))	('WDL', 'Gene', '12319', (60, 63))
392019	31308696	Unsurprisingly, WDL shows high expression of genes associated with lipid metabolism and adipocytic differentiation, while DDL is characterized by upregulation of genes involved in proliferation and DNA repair as a result of additional genetic abnormalities, including losses, fusion transcripts, and amplifications.	('lipid', 'Chemical', 'MESH:D008055', (67, 72))	('rat', 'Species', '10116', (187, 190))	('genetic abnormalities', 'Disease', (235, 256))	('losses', 'Var', (268, 274))	('upregulation', 'PosReg', (146, 158))	('WDL', 'Gene', (16, 19))	('DDL', 'Gene', (122, 125))	('WDL', 'Gene', '12319', (16, 19))	('DDL', 'Gene', '18998', (122, 125))	('expression', 'MPA', (31, 41))	('amplifications', 'Var', (300, 314))	('adipocytic differentiation', 'CPA', (88, 114))	('genetic abnormalities', 'Disease', 'MESH:D030342', (235, 256))	('fusion transcripts', 'Var', (276, 294))
392021	31308696	Over the last years, novel gene amplifications (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R), deletions at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1), and chromosome 13q14.2 (MIR15A, MIR16-1), and recurrent mutations in members of PI3KCA, PTEN, WNT, ERBB, MAPK, and JAK-STAT pathways have been detected in DDL.	('MIR15A', 'Gene', '387174', (192, 198))	('ARID1A', 'Gene', (130, 136))	('ERBB', 'Gene', (267, 271))	('ARID1A', 'Gene', '93760', (130, 136))	('IGF1R', 'Gene', '16001', (87, 92))	('MAPK', 'Gene', (273, 277))	('CHEK1', 'Gene', '12649', (160, 165))	('CPM', 'Gene', (69, 72))	('ERBB3', 'Gene', '13867', (80, 85))	('CPM', 'Gene', '70574', (69, 72))	('IGF2', 'Gene', (74, 78))	('DDL', 'Gene', '18998', (323, 326))	('ERBB3', 'Gene', (80, 85))	('ERBB', 'Gene', '13649', (80, 84))	('IGF1R', 'Gene', (87, 92))	('DDL', 'Gene', (323, 326))	('CHEK1', 'Gene', (160, 165))	('JAK-STAT pathways', 'Pathway', (283, 300))	('MIR15A', 'Gene', (192, 198))	('WNT', 'Pathway', (262, 265))	('PI3KCA', 'Gene', (248, 254))	('PTEN', 'Gene', (256, 260))	('ATM', 'Gene', (155, 158))	('ERBB', 'Gene', '13649', (267, 271))	('ERBB', 'Gene', (80, 84))	('MIR16-1', 'Gene', (200, 207))	('deletions', 'Var', (95, 104))	('MIR16-1', 'Gene', '387134', (200, 207))	('IGF2', 'Gene', '16002', (74, 78))	('ATM', 'Gene', '11920', (155, 158))	('mutations', 'Var', (224, 233))
392022	31308696	Finally, an important role for epigenetic mechanisms in the dedifferentiation process is emerging, since CEBPalpha methylation was found in 24% of the DDL and CDKN2A gene promoter hypermethylation was observed in DDL but not in recurrent WDL.	('methylation', 'Var', (115, 126))	('found', 'Reg', (131, 136))	('CEBPalpha', 'Gene', (105, 114))	('DDL', 'Gene', '18998', (213, 216))	('WDL', 'Gene', (238, 241))	('DDL', 'Gene', (213, 216))	('DDL', 'Gene', '18998', (151, 154))	('WDL', 'Gene', '12319', (238, 241))	('DDL', 'Gene', (151, 154))	('CDKN2A', 'Gene', '12578', (159, 165))	('CDKN2A', 'Gene', (159, 165))
392034	31308696	The PDX models generated from surgical specimens maintain the tumor microenvironment present in the human host and the genetic features associated to intratumor heterogeneity, including gene expression profile, copy number variants, and treatment susceptibility.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('rat', 'Species', '10116', (153, 156))	('tumor', 'Disease', (62, 67))	('human', 'Species', '9606', (100, 105))	('tumor', 'Disease', (155, 160))	('rat', 'Species', '10116', (19, 22))	('copy number variants', 'Var', (211, 231))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
392035	31308696	However, it should be advised that one recent study has reported that PDX models of varied tumor types develop mutations with serial passages that diverge from those observed in the patients.	('mutations', 'Var', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('develop', 'Reg', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Disease', (91, 96))
392047	31308696	In a PDX model established from a tumor specimen of a man presenting a high-grade DDL of the mesentery, genome sequencing showed MDM2/CDK4 coamplification and mutation on JAK2.	('man', 'Species', '9606', (54, 57))	('DDL', 'Gene', '18998', (82, 85))	('MDM2/CDK4', 'Gene', (129, 138))	('tumor', 'Disease', (34, 39))	('JAK2', 'Gene', '3717', (171, 175))	('DDL', 'Gene', (82, 85))	('JAK2', 'Gene', (171, 175))	('mutation', 'Var', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('coamplification', 'Var', (139, 154))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
392048	31308696	Though, a limited clinical benefit was observed for the patient receiving Cdk4 inhibitor (P1446A-05) and further supplementation with Jak2 inhibitor (ruxolitinib).	('P1446A', 'Mutation', 'p.P1446A', (90, 96))	('ruxolitinib', 'Chemical', 'MESH:C540383', (150, 161))	('P1446A-05', 'Var', (90, 99))	('Jak2', 'Gene', (134, 138))	('Jak2', 'Gene', '3717', (134, 138))	('Cdk4 inhibitor', 'Protein', (74, 88))	('patient', 'Species', '9606', (56, 63))
392052	31308696	In two bilaterally transplanted PDX models, treatment with ALGP-doxo, that is converted to doxorubicin by peptidases present in tumor cells and/or tumor microenvironment, showed a significantly higher antiproliferative effect compared to doxorubicin.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('higher', 'PosReg', (194, 200))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('antiproliferative effect', 'CPA', (201, 225))	('doxorubicin', 'Chemical', 'MESH:D004317', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('rat', 'Species', '10116', (212, 215))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (128, 133))	('ALGP-doxo', 'Var', (59, 68))	('ALGP-doxo', 'Chemical', 'MESH:C000627546', (59, 68))	('doxorubicin', 'Chemical', 'MESH:D004317', (238, 249))
392055	31308696	The overactivation of Akt pathway in WDL/DDL frequently occurs because of the loss of PTEN or the presence of activating mutations in the PI3K gene (E542K and H1047R amino acid substitutions).	('PTEN', 'Protein', (86, 90))	('H1047R amino acid substitutions', 'Var', (159, 190))	('Akt', 'Gene', '11651', (22, 25))	('E542K', 'Var', (149, 154))	('overactivation', 'PosReg', (4, 18))	('Akt', 'Gene', (22, 25))	('H1047R', 'Mutation', 'rs121913279', (159, 165))	('loss', 'NegReg', (78, 82))	('E542K', 'Mutation', 'rs121913273', (149, 154))	('activating', 'PosReg', (110, 120))	('WDL/DDL', 'Disease', (37, 44))	('PI3K', 'Gene', (138, 142))
392060	31308696	In CDX tumors, concomitant inhibition of the PI3K/Akt/mTOR and Mdm2 pathway, mediated by BEZ-235 and RG7388 compounds, promoted a significant reduction of tumor growth.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('reduction', 'NegReg', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (7, 12))	('CDX tumors', 'Disease', (3, 13))	('Mdm2', 'Gene', '17246', (63, 67))	('Akt', 'Gene', '11651', (50, 53))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Disease', (155, 160))	('Akt', 'Gene', (50, 53))	('BEZ-235', 'Chemical', 'MESH:C531198', (89, 96))	('CDX tumors', 'Disease', 'MESH:D009369', (3, 13))	('Mdm2', 'Gene', (63, 67))	('RG7388', 'Var', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('inhibition', 'NegReg', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
392061	31308696	Reduced tumor growth and metastatic rate of CDX tumors were also reported upon knockdown of AXL, a member of the TAM family that signals through PI3K/Akt/mTOR and Mapk pathways and whose inhibition represents a promising avenue for the treatment of a wide number of cancers.	('Akt', 'Gene', '11651', (150, 153))	('metastatic rate', 'CPA', (25, 40))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('AXL', 'Gene', (92, 95))	('CDX tumors', 'Disease', (44, 54))	('tumor', 'Disease', (48, 53))	('inhibition', 'NegReg', (187, 197))	('Mapk pathways', 'Pathway', (163, 176))	('rat', 'Species', '10116', (36, 39))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Disease', (8, 13))	('AXL', 'Gene', '26362', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('knockdown', 'Var', (79, 88))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancers', 'Disease', (266, 273))	('CDX tumors', 'Disease', 'MESH:D009369', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('Akt', 'Gene', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
392064	31308696	Consistent with this, treatment with a novel Met inhibitor (EMD1214063) was reported to abrogate tumor growth in CDX models.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CDX', 'Chemical', '-', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('abrogate', 'NegReg', (88, 96))	('tumor', 'Disease', (97, 102))	('EMD1214063', 'Var', (60, 70))
392077	31308696	On the other side, miR-25-3p and miR-92a-3p are secreted by liposarcoma cells through extracellular vesicles and may be useful as potential disease biomarkers.	('liposarcoma', 'Disease', (60, 71))	('miR-92a-3p', 'Var', (33, 43))	('liposarcoma', 'Phenotype', 'HP:0012034', (60, 71))	('liposarcoma', 'Disease', 'MESH:D008080', (60, 71))	('miR-25-3p', 'Var', (19, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))
392079	31308696	Consistent with these results, miR-155 knockdown in CDX tumors delayed tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('knockdown', 'Var', (39, 48))	('miR-155', 'Gene', '387173', (31, 38))	('CDX tumors delayed tumor', 'Disease', 'MESH:D009369', (52, 76))	('miR-155', 'Gene', (31, 38))	('CDX tumors delayed tumor', 'Disease', (52, 76))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))
392088	31308696	Furthermore, it must be mentioned that cell transdifferentiation processes are possible, as it has been observed that the aberrant activation of the Shh signaling in mature adipocytes is sufficient to convert them into myogenic tumor cells.	('activation', 'PosReg', (131, 141))	('convert', 'Reg', (201, 208))	('Shh', 'Gene', '20423', (149, 152))	('aberrant', 'Var', (122, 130))	('myogenic tumor', 'Disease', (219, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('Shh', 'Gene', (149, 152))	('myogenic tumor', 'Disease', 'MESH:D009369', (219, 233))
392089	31308696	As depicted in Figure 2, four transgenic animal models developing liposarcoma have been generated through gene manipulation in mesenchymal cell progenitors or adipocytes, as described below.	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('gene manipulation', 'Var', (106, 123))	('rat', 'Species', '10116', (92, 95))	('liposarcoma', 'Disease', (66, 77))	('transgenic', 'Species', '10090', (30, 40))	('liposarcoma', 'Disease', 'MESH:D008080', (66, 77))	('man', 'Species', '9606', (111, 114))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))
392090	31308696	Oncogenic gene mutations in receptors (FGFR, EGFR) or transducers (KRAS, PI3K) commonly elicit deregulation of PI3K/Akt/mTOR pathway, as analogously observed in liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (161, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('FGFR', 'Gene', (39, 43))	('EGFR', 'Gene', (45, 49))	('EGFR', 'Gene', '13649', (45, 49))	('liposarcoma', 'Disease', 'MESH:D008080', (161, 172))	('mutations', 'Var', (15, 24))	('liposarcoma', 'Disease', (161, 172))	('KRAS', 'Gene', (67, 71))	('KRAS', 'Gene', '16653', (67, 71))	('deregulation', 'MPA', (95, 107))	('Akt', 'Gene', '11651', (116, 119))	('Akt', 'Gene', (116, 119))	('elicit', 'Reg', (88, 94))
392097	31308696	Mice with activated Notch1 exhibited a lipodystrophy phenotype in the pre-neoplastic state, characterized by hepatic steatosis, hyperglycemia, and severe insulin resistance.	('lipodystrophy', 'Disease', (39, 52))	('hyperglycemia', 'Disease', (128, 141))	('activated', 'Var', (10, 19))	('Notch1', 'Gene', '18128', (20, 26))	('insulin resistance', 'MPA', (154, 172))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (109, 126))	('exhibited', 'Reg', (27, 36))	('hepatic steatosis', 'Disease', (109, 126))	('neoplastic state', 'Phenotype', 'HP:0002664', (74, 90))	('hyperglycemia', 'Phenotype', 'HP:0003074', (128, 141))	('lipodystrophy', 'Phenotype', 'HP:0009125', (39, 52))	('insulin resistance', 'Phenotype', 'HP:0000855', (154, 172))	('Mice', 'Species', '10090', (0, 4))	('hepatic steatosis', 'Disease', 'MESH:D005234', (109, 126))	('hyperglycemia', 'Disease', 'MESH:D006943', (128, 141))	('Notch1', 'Gene', (20, 26))	('lipodystrophy', 'Disease', 'MESH:D008060', (39, 52))
392099	31308696	A selective Notch inhibitor (LY3039478) was recently tested in a phase 1a/b trial showing a modest clinical activity and a safety profile towards several sarcomas, including liposarcoma.	('sarcomas', 'Phenotype', 'HP:0100242', (154, 162))	('LY3039478', 'Chemical', '-', (29, 38))	('sarcomas', 'Disease', (154, 162))	('liposarcoma', 'Phenotype', 'HP:0012034', (174, 185))	('liposarcoma', 'Disease', (174, 185))	('liposarcoma', 'Disease', 'MESH:D008080', (174, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('LY3039478', 'Var', (29, 38))	('sarcomas', 'Disease', 'MESH:D012509', (154, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
392111	31308696	Of note, deletion of PNPLA2 is reported in WDL and sarcoma, and deletions of the chromosome 19p13 region containing LIPE are frequent in DDL and correlate with poor prognosis.	('sarcoma', 'Disease', (51, 58))	('deletion', 'Var', (9, 17))	('DDL', 'Gene', (137, 140))	('DDL', 'Gene', '18998', (137, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('deletions', 'Var', (64, 73))	('WDL', 'Gene', (43, 46))	('PNPLA2', 'Gene', (21, 27))	('WDL', 'Gene', '12319', (43, 46))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))
392182	29912603	They found genetic alterations in 6 patients and a liposarcoma in 1 patient.	('liposarcoma', 'Phenotype', 'HP:0012034', (51, 62))	('liposarcoma', 'Disease', 'MESH:D008080', (51, 62))	('genetic alterations', 'Var', (11, 30))	('patients', 'Species', '9606', (36, 44))	('patient', 'Species', '9606', (68, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('liposarcoma', 'Disease', (51, 62))	('patient', 'Species', '9606', (36, 43))
392196	29912603	Some studies have reported higher melanoma incidence in patients treated with non-MoM implants than in the general population (Nyren et al., Olsen et al., Visuri et al.)	('patients', 'Species', '9606', (56, 64))	('higher', 'PosReg', (27, 33))	('non-MoM', 'Var', (78, 85))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('MoM', 'Chemical', '-', (82, 85))
392267	28196946	Note that tumour size is given in centimetre, implying that a 'k' cm change in size multiplies the hazard by HRk.	('HRk', 'Gene', '8739', (109, 112))	("'k' cm", 'Var', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('HRk', 'Gene', (109, 112))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('tumour', 'Disease', (10, 16))
392291	28196946	The probability of occupying the state 'DM/Death without LR' (red area) decreases slightly for patient A (upper panels) as margins increase, while for patient B (middle panels), the probability remains almost the same for the first two margin scenarios and even increases for a margin wider than 2 mm.	('DM', 'Disease', 'MESH:D009223', (40, 42))	('margins', 'Var', (123, 130))	('patient', 'Species', '9606', (95, 102))	('decreases', 'NegReg', (72, 81))	('increase', 'PosReg', (131, 139))	('patient', 'Species', '9606', (151, 158))
392425	31598348	Until recently, the genetic profile of histiocytic sarcoma was not clearly defined; some studies have reported BRAF mutations, including V600E, which suggests that BRAF-target therapy could be promising.	('V600E', 'Mutation', 'p.V600E', (137, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('BRAF', 'Gene', '673', (164, 168))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (39, 58))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (164, 168))	('V600E', 'Var', (137, 142))	('BRAF', 'Gene', (111, 115))	('histiocytic sarcoma', 'Disease', (39, 58))
392426	31598348	BRAF V600E IHC was performed in our case, and the result was negative.	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Mutation', 'p.V600E', (5, 10))	('BRAF', 'Gene', (0, 4))
392652	30288129	In these studies, flow cytometry was used to prove that bispecific eBAT was more potent in binding and killing sarcoma cells than either of its monospecific counterparts targeting only EGFR or only urokinase receptor.	('bispecific', 'Var', (56, 66))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('EGFR', 'Gene', (185, 189))	('eBAT', 'Chemical', '-', (67, 71))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('binding', 'Interaction', (91, 98))	('killing', 'CPA', (103, 110))	('eBAT', 'Gene', (67, 71))	('EGFR', 'Gene', '1956', (185, 189))
392668	30288129	Bispecificity was associated with improved specificity and cytotoxicity when a BLT was compared with its monospecific counterparts, targeting a single distinct receptor.	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('improved', 'PosReg', (34, 42))	('specificity', 'MPA', (43, 54))	('cytotoxicity', 'Disease', (59, 71))	('Bispecificity', 'Var', (0, 13))
392722	30288129	As predicted, eBAT, EGFKDEL, and ATFKDEL did not have any specific binding affinity to the cells as shown in Figure 2C and D and there was no effect on cell proliferation in Figure 3C and D. CD3CD3KDEL also exhibited negligible cytotoxic effects on cell proliferation as a non EGFR- and uPAR-targeting negative control.	('uPAR', 'Gene', (287, 291))	('ATFKDEL', 'Chemical', '-', (33, 40))	('cytotoxic effects', 'CPA', (228, 245))	('CD3CD3KDEL', 'Var', (191, 201))	('EGFR', 'Gene', '1956', (277, 281))	('uPAR', 'Gene', '5329', (287, 291))	('cell proliferation', 'CPA', (249, 267))	('eBAT', 'Chemical', '-', (14, 18))	('EGFR', 'Gene', (277, 281))
392826	25363179	Well-differentiated and small cancers (grades 1 and 2) are usually limited to prostate, whereas the massive cancers (4 cm3<) or with low grade differentiation (grades 4 and 5) in most cases have extended to the regional lymph node or bone or have metastasized.	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('prostate', 'Disease', (78, 86))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('small cancers', 'Disease', 'MESH:D055752', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('metastasized', 'CPA', (247, 259))	('small cancers', 'Disease', (24, 37))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('4 cm3<', 'Var', (117, 123))
392876	25363179	Studies now show that at least in the short term, cryotherapy can cause negative surgical biopsy of the prostate after treatment and low PSA serum or undetectable.	('men', 'Species', '9606', (124, 127))	('cryotherapy', 'Var', (50, 61))	('negative', 'NegReg', (72, 80))	('PSA', 'Gene', (137, 140))	('PSA', 'Gene', '354', (137, 140))
392910	25363179	The most common Gleason scoring is in patients with 5-7 score, so prostate cancer is in its moderate differentiation.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('common', 'Reg', (9, 15))	('prostate cancer', 'Disease', (66, 81))	('patients', 'Species', '9606', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('5-7 score', 'Var', (52, 61))
392963	25126127	Contrast enhanced computed tomography (CECT) revealed destruction of C1, C2 vertebra (moth eaten appearance) with associated enhancing soft tissue component extending into the extradural, paravertebral space, and foramen magnum, pushing the medulla to the right, and the internal carotid artery and internal jugular vein antero-laterally [Figure 1].	('pushing', 'PosReg', (229, 236))	('enhancing', 'PosReg', (125, 134))	('C2 vertebra', 'Disease', (73, 84))	('soft tissue component', 'CPA', (135, 156))	('C2 vertebra', 'Disease', 'OMIM:217000', (73, 84))	('destruction', 'Var', (54, 65))
393053	24701226	The participation of changes in GTP-ases such as HRAS (chromosome 11), KRAS (chromosome 12) and RB1 (chromosome 13) in sarcoma pathology was found.	('HRAS', 'Gene', (49, 53))	('RB1', 'Gene', '5925', (96, 99))	('sarcoma pathology', 'Disease', 'MESH:D012509', (119, 136))	('sarcoma pathology', 'Disease', (119, 136))	('KRAS', 'Gene', (71, 75))	('changes', 'Var', (21, 28))	('KRAS', 'Gene', '3845', (71, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('GTP', 'Chemical', 'MESH:D006160', (32, 35))	('RB1', 'Gene', (96, 99))	('HRAS', 'Gene', '3265', (49, 53))
393141	24701226	Molecular analysis helped to determine the presence of aberrations within the 19q13 locus, which promoted the creation of more frequent recurrences and metastases in patients with MFH.	('aberrations', 'Var', (55, 66))	('more', 'PosReg', (122, 126))	('metastases', 'Disease', (152, 162))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('patients', 'Species', '9606', (166, 174))	('19q13', 'Gene', (78, 83))
393214	24701226	In the case of anthracycline resistance, sorafenib or trabectedin can be used in soft tissue sarcomas (STS).	('sorafenib', 'Chemical', 'MESH:D000077157', (41, 50))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (81, 100))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (81, 101))	('anthracycline', 'Chemical', 'MESH:D018943', (15, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('anthracycline', 'Var', (15, 28))	('trabectedin', 'Chemical', 'MESH:D000077606', (54, 65))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (81, 101))	('soft tissue sarcomas', 'Disease', (81, 101))	('STS', 'Phenotype', 'HP:0030448', (103, 106))
393381	20566784	Fatty infiltration (either microscopic or macroscopic) will also dilute the choline concentration, because choline is expected to be present only in the aqueous phase.	('Fatty infiltration', 'Var', (0, 18))	('choline', 'Chemical', 'MESH:D002794', (76, 83))	('choline', 'Chemical', 'MESH:D002794', (107, 114))	('dilute', 'NegReg', (65, 71))	('choline concentration', 'MPA', (76, 97))
393388	20566784	Also, over the 3-year period of recruitment for this study, errors in acquisition as a result of limited experience with MRS may have contributed to the non-diagnostic rate that was observed.	('MRS', 'Disease', (121, 124))	('acquisition', 'MPA', (70, 81))	('MRS', 'Disease', 'MESH:D008556', (121, 124))	('non-diagnostic', 'MPA', (153, 167))	('errors', 'Var', (60, 66))
393414	33567506	An early phase trial using hexaminolevulinate photosensitizer in bladder cancer was found to have serious adverse effects of hematuria and irritative bladder/urgency syndrome related to PDT but was ultimately concluded to be tolerable after dose adjustment.	('bladder cancer', 'Disease', (65, 79))	('hematuria', 'Phenotype', 'HP:0000790', (125, 134))	('hexaminolevulinate', 'Chemical', 'MESH:C419924', (27, 45))	('urgency syndrome', 'Phenotype', 'HP:0000012', (158, 174))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('irritative bladder', 'Disease', 'MESH:D001745', (139, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('hematuria', 'Disease', (125, 134))	('irritative bladder', 'Disease', (139, 157))	('hematuria', 'Disease', 'MESH:D006417', (125, 134))	('PDT', 'Var', (186, 189))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
393438	33567506	With regards to healthy muscle and bone, likely to undergo unintended PDT treatment if soft tissue sarcoma is treated, studies in the dental and orthopedic fields have shown low dose PDT to be a stimulus for growth and repair, reiterating the possibility for healthy tissues to repair themselves.	('soft', 'Gene', (87, 91))	('repair', 'CPA', (219, 225))	('soft', 'Gene', '25886', (87, 91))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('growth', 'CPA', (208, 214))	('PDT', 'Var', (183, 186))	('sarcoma', 'Disease', (99, 106))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (87, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
393461	33567506	This suggests that when appropriately activated, the upstream Hippo pathway kinases demonstrate tumor suppressor effects, whereas dysregulation within the pathway contributes to oncogenic potential by activation of TAZ and YAP.	('activation', 'PosReg', (201, 211))	('oncogenic potential', 'CPA', (178, 197))	('dysregulation', 'Var', (130, 143))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TAZ', 'CPA', (215, 218))	('tumor', 'Disease', (96, 101))	('Hippo', 'Gene', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Hippo', 'Gene', '37247', (62, 67))
393465	33567506	In vitro studies show that targeting the YAP/TEAD complex with verteporfin reduces anchorage independent growth in soft agar treatment with verteporfin in two different in vivo models of hepatomegaly, either induced by YAP overexpression or NF2 inactivation (negative regulator of YAP), showed considerable reduction in liver overgrowth.	('NF2', 'Gene', (241, 244))	('hepatomegaly', 'Disease', 'MESH:D006529', (187, 199))	('reduction', 'NegReg', (307, 316))	('hepatomegaly', 'Disease', (187, 199))	('agar', 'Chemical', 'MESH:D000362', (120, 124))	('liver overgrowth', 'Disease', 'MESH:D017093', (320, 336))	('NF2', 'Gene', '4771', (241, 244))	('soft', 'Gene', (115, 119))	('soft', 'Gene', '25886', (115, 119))	('verteporfin', 'Chemical', 'MESH:D000077362', (140, 151))	('liver overgrowth', 'Disease', (320, 336))	('verteporfin', 'Chemical', 'MESH:D000077362', (63, 74))	('reduces', 'NegReg', (75, 82))	('hepatomegaly', 'Phenotype', 'HP:0002240', (187, 199))	('inactivation', 'Var', (245, 257))	('overgrowth', 'Phenotype', 'HP:0001548', (326, 336))
393472	33567506	described a molecular based mechanism of YAP/TAZ activation in synovial sarcoma that involves IGF-II/IGF-1R signaling loop, which leads to aberrant LATS1 and MOB1.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (63, 79))	('synovial sarcoma', 'Disease', 'MESH:D013584', (63, 79))	('MOB1', 'Gene', (158, 162))	('leads to', 'Reg', (130, 138))	('IGF-1R', 'Gene', '3480', (101, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('MOB1', 'Gene', '55233', (158, 162))	('IGF-1R', 'Gene', (101, 107))	('IGF-II', 'Gene', '3481', (94, 100))	('IGF-II', 'Gene', (94, 100))	('synovial sarcoma', 'Disease', (63, 79))	('LATS1', 'Gene', (148, 153))	('aberrant', 'Var', (139, 147))	('LATS1', 'Gene', '9113', (148, 153))
393482	33567506	Red (wavelength = 600-750 nm) and infrared light (wavelength = 750-800 nm) best penetrate tissues, up to 5 mm in depth, but that may not be sufficient for large volumetric cancers, such as sarcoma.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('sarcoma', 'Disease', (189, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('wavelength = 750-800 nm', 'Var', (50, 73))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))
393486	33567506	Overall, results indicated that implanting multiple microLights and operating them for 1-2 h can achieve cytotoxicity levels comparable to clinically reported cases using external light sources.	('cytotoxicity', 'Disease', 'MESH:D064420', (105, 117))	('implanting', 'Var', (32, 42))	('cytotoxicity', 'Disease', (105, 117))
393582	27238092	The overall rate of chronic pain in the patient cohort was 13% (13/101) with 23% (5/22) of those with MWCs experiencing chronic pain as opposed to 10% (8/79) of patients without MWCs.	('patient', 'Species', '9606', (40, 47))	('pain', 'Phenotype', 'HP:0012531', (128, 132))	('patient', 'Species', '9606', (161, 168))	('chronic pain', 'Disease', 'MESH:D059350', (120, 132))	('MWCs', 'Var', (102, 106))	('chronic pain', 'Phenotype', 'HP:0012532', (120, 132))	('chronic pain', 'Phenotype', 'HP:0012532', (20, 32))	('patients', 'Species', '9606', (161, 169))	('pain', 'Phenotype', 'HP:0012531', (28, 32))	('chronic pain', 'Disease', 'MESH:D059350', (20, 32))	('chronic pain', 'Disease', (120, 132))	('chronic pain', 'Disease', (20, 32))
393585	27238092	Although the rate of chronic edema was higher in patients with MWCs 27% (6/22) compared to those without MWCs (20%, 16/79), the presence of a MWC did not predict for chronic edema (OR 1.48, 95% CI 0.5-4.4, P = 0.482).	('edema', 'Disease', (174, 179))	('edema', 'Disease', 'MESH:D004487', (29, 34))	('edema', 'Phenotype', 'HP:0000969', (29, 34))	('patients', 'Species', '9606', (49, 57))	('edema', 'Disease', 'MESH:D004487', (174, 179))	('edema', 'Disease', (29, 34))	('edema', 'Phenotype', 'HP:0000969', (174, 179))	('MWCs', 'Var', (63, 67))
393641	32268008	Doses to the lung, heart, and liver for all patients are substantially lower with the 3DPT and IMPT plans than those of IMRT plans.	('patients', 'Species', '9606', (44, 52))	('IMPT plans', 'Var', (95, 105))	('3DPT', 'Var', (86, 90))	('Doses', 'MPA', (0, 5))	('lower', 'NegReg', (71, 76))
393686	32268008	where, D5% is the minimum dose received by 5% volume of the target, D95% is the minimum dose received by 95% volume of the target, and Dp is the prescription dose.	('Dp', 'Chemical', 'MESH:D004176', (135, 137))	('D5%', 'Var', (7, 10))	('D95%', 'Var', (68, 72))
393692	32268008	For heart dose, patient A, B, C and D IMRT plans had either mean dose or V25 Gy(RBE) exceeded the threshold values.	('patient', 'Species', '9606', (16, 23))	('heart', 'MPA', (4, 9))	('V25 Gy', 'Var', (73, 79))	('mean dose', 'MPA', (60, 69))
393693	32268008	For patient D, 3DCPT plan rendered the lowest dose volume parameter values compared to those of IMPT plans.	('3DCPT plan', 'Var', (15, 25))	('dose volume parameter values', 'MPA', (46, 74))	('patient', 'Species', '9606', (4, 11))	('lowest', 'NegReg', (39, 45))
393697	32268008	However, IMPT plans with apertures have the integrated dose lower than those of 3DCPT plans and it can be as low as one quarter of those of IMRT plans for some patients.	('apertures', 'Var', (25, 34))	('integrated dose', 'MPA', (44, 59))	('patients', 'Species', '9606', (160, 168))	('lower', 'NegReg', (60, 65))
393712	32268008	However, four of six patients of IMPT_UN had slightly higher integral dose than those of 3DCPT.	('patients', 'Species', '9606', (21, 29))	('IMPT_UN', 'Var', (33, 40))	('higher', 'PosReg', (54, 60))	('integral dose', 'MPA', (61, 74))
393717	32268008	For patients E and F, there was about 40% reduction of integral dose of IMPT_DN_A compared to 3DCPT.	('reduction', 'NegReg', (42, 51))	('IMPT_DN_A', 'Var', (72, 81))	('integral dose', 'MPA', (55, 68))	('patients', 'Species', '9606', (4, 12))
393718	32268008	Similarly, for OARs, IMPT_DN_A showed the lowest doses and integral doses of all four plans.	('IMPT_DN_A', 'Var', (21, 30))	('lowest', 'NegReg', (42, 48))	('doses', 'MPA', (49, 54))	('OAR', 'Gene', '4936', (15, 18))	('integral doses', 'MPA', (59, 73))	('OAR', 'Gene', (15, 18))
393732	28148901	C/EBPbeta-1 promotes transformation and chemoresistance in Ewing sarcoma cells CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized.	('CEBPB', 'Gene', '1051', (79, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('Ewing sarcoma', 'Disease', (59, 72))	('CEBPB', 'Gene', (216, 221))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('Ewing sarcoma', 'Disease', (105, 118))	('C/EBPbeta', 'Gene', (0, 9))	('C/EBPbeta', 'Gene', '1051', (0, 9))	('gain', 'PosReg', (97, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('CEBPB', 'Gene', (79, 84))	('tumors', 'Disease', (197, 203))	('transformation', 'CPA', (21, 35))	('copy number', 'Var', (85, 96))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))	('CEBPB', 'Gene', '1051', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('chemoresistance', 'CPA', (40, 55))
393741	28148901	Ewing sarcoma is defined by a translocation of the EWSR1 gene to one of the ETS transcription factor family members, most commonly FLI1.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', (51, 56))	('Ewing sarcoma', 'Disease', (0, 13))	('FLI1', 'Gene', (131, 135))	('EWSR1', 'Gene', '2130', (51, 56))	('FLI1', 'Gene', '2313', (131, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('translocation', 'Var', (30, 43))
393742	28148901	EWS-FLI1 binds with high affinity to GGAA microsatellite repeats within the promoter regions of its target genes.	('binds', 'Interaction', (9, 14))	('microsatellite repeats', 'Var', (42, 64))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('EWS-FLI1', 'Gene', (0, 8))
393745	28148901	In our Utah cohort, chromosome 20q showed trisomy in 15% (N = 6/40) of tumors.	('trisomy', 'Var', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
393750	28148901	Recent genomic landscape of Ewing sarcoma publications support our observation of trisomy in chromosome 20q in approximately 15% of Ewing sarcoma tumors, suggesting that a copy number gain in this region may confer a survival disadvantage for these patients.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (132, 145))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (132, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('survival disadvantage', 'CPA', (217, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('patients', 'Species', '9606', (249, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Ewing sarcoma publications', 'Disease', 'MESH:C563168', (28, 54))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('Ewing sarcoma tumors', 'Disease', (132, 152))	('Ewing sarcoma publications', 'Disease', (28, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))	('trisomy in chromosome', 'Var', (82, 103))	('copy number gain', 'Var', (172, 188))
393757	28148901	C/EBPbeta is a transcriptional regulator of aldehyde dehydrogenase 1A1 (ALDH1A1), a member of a family of detoxifying enzymes responsible for oxidizing aldehydes, in breast cancer cells.	('ALDH1A1', 'Gene', (72, 79))	('C/EBPbeta', 'Var', (0, 9))	('aldehyde dehydrogenase 1A1', 'Gene', '216', (44, 70))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('ALDH1A1', 'Gene', '216', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('aldehydes', 'Chemical', 'MESH:D000447', (152, 161))	('aldehyde dehydrogenase 1A1', 'Gene', (44, 70))
393761	28148901	Our data suggest that high levels of C/EBPbeta lead to increased transformation, increased ALDH1A1 expression and activity, and chemotherapy resistance.	('C/EBPbeta', 'Var', (37, 46))	('expression', 'MPA', (99, 109))	('ALDH1A1', 'Gene', '216', (91, 98))	('transformation', 'CPA', (65, 79))	('activity', 'MPA', (114, 122))	('increased', 'PosReg', (55, 64))	('chemotherapy resistance', 'CPA', (128, 151))	('ALDH1A1', 'Gene', (91, 98))	('increased', 'PosReg', (81, 90))
393767	28148901	We used the same dataset (GSE1825) to evaluate expression of all five genes within the focal region of high copy gain in the Ewing sarcoma samples compared to neuroblastoma samples.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('neuroblastoma', 'Disease', (159, 172))	('neuroblastoma', 'Disease', 'MESH:D009447', (159, 172))	('GSE1825', 'Chemical', '-', (26, 33))	('neuroblastoma', 'Phenotype', 'HP:0003006', (159, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Ewing sarcoma', 'Disease', (125, 138))	('high copy gain', 'Var', (103, 117))	('expression', 'MPA', (47, 57))
393777	28148901	Treatment with this shRNA led to a significant decrease in EWS-FLI1 protein and mRNA expression, as well as knockdown of protein and mRNA expression of all three C/EBPbeta isoforms and NR0B1, a known target of EWS-FLI1 (Figure 2A, 2B).	('protein', 'MPA', (121, 128))	('knockdown', 'Var', (108, 117))	('EWS-FLI1', 'Gene', '2130;2313', (59, 67))	('mRNA expression', 'MPA', (133, 148))	('decrease', 'NegReg', (47, 55))	('NR0B1', 'Gene', '190', (185, 190))	('protein', 'MPA', (68, 75))	('EWS-FLI1', 'Gene', (210, 218))	('EWS-FLI1', 'Gene', (59, 67))	('NR0B1', 'Gene', (185, 190))	('mRNA expression', 'MPA', (80, 95))	('EWS-FLI1', 'Gene', '2130;2313', (210, 218))
393781	28148901	This is supported by publicly available EWS-FLI1 knockdown data in additional Ewing sarcoma cell lines (Supplementary Figure 1A, 1B).	('knockdown', 'Var', (49, 58))	('EWS-FLI1', 'Gene', (40, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('EWS-FLI1', 'Gene', '2130;2313', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('Ewing sarcoma', 'Disease', (78, 91))
393786	28148901	Additionally, we measured no difference in cell viability over time with CEBPB knockdown and rescue, or after 72 hours following overexpression of the different C/EBPbeta isoforms (Figure 3C, 3D).	('knockdown', 'Var', (79, 88))	('CEBPB', 'Gene', (73, 78))	('CEBPB', 'Gene', '1051', (73, 78))
393790	28148901	Conversely, there was a decrease in colony formation with knockdown of CEBPB expression compared to treatment with a non-targeting shRNA control (GFP) (Figure 4B-4D; Supplementary Figure 2A).	('colony formation', 'CPA', (36, 52))	('CEBPB', 'Gene', (71, 76))	('decrease', 'NegReg', (24, 32))	('CEBPB', 'Gene', '1051', (71, 76))	('knockdown', 'Var', (58, 67))
393791	28148901	The colony-formation phenotype was rescued with overexpression of C/EBPbeta-1 and C/EBPbeta-2 following knockdown (Figure 4B-4D), suggesting that C/EBPbeta-1 and C/EBPbeta-2 expression increases transformation of Ewing sarcoma cells.	('increases', 'PosReg', (185, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('C/EBPbeta-2', 'Gene', (162, 173))	('Ewing sarcoma', 'Disease', (213, 226))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (213, 226))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (213, 226))	('C/EBPbeta-1', 'Var', (146, 157))	('transformation', 'CPA', (195, 209))
393792	28148901	We explored potential downstream targets of C/EBPbeta by microarray in four Ewing sarcoma cell lines (A673, CHLA9, CHLA10, TC252) harboring altered C/EBPbeta-1 expression: C/EBPbeta lentiviral knockdown; C/EBPbeta-1 retroviral overexpression; C/EBPbeta-1 rescue by lentiviral knockdown followed by retroviral overexpression; empty vector and non-targeting shRNA control treatment; and untreated cells (Supplementary Figure 3A, 3C).	('altered', 'Reg', (140, 147))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('knockdown', 'Var', (276, 285))	('C/EBPbeta-1', 'Gene', (243, 254))	('TC252', 'CellLine', 'CVCL:S866', (123, 128))	('CHLA10', 'CellLine', 'CVCL:6583', (115, 121))	('Ewing sarcoma', 'Disease', (76, 89))	('C/EBPbeta-1', 'Gene', (148, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('CHLA9', 'CellLine', 'CVCL:M150', (108, 113))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (76, 89))
393797	28148901	To validate the array data, ALDH1A1 protein expression was measured by Western blot in Ewing sarcoma cell lines with C/EBPbeta-1 depletion, rescue, and overexpression.	('ALDH1A1', 'Gene', (28, 35))	('overexpression', 'PosReg', (152, 166))	('depletion', 'Var', (129, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('ALDH1A1', 'Gene', '216', (28, 35))	('C/EBPbeta-1', 'Var', (117, 128))	('Ewing sarcoma', 'Disease', (87, 100))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (87, 100))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (87, 100))
393798	28148901	We observed an increase in ALDH1A1 protein expression with C/EBPbeta-1 overexpression and a decrease in ALDH1A1 protein expression with C/EBPbeta-1 knockdown (Figure 5B).	('ALDH1A1', 'Gene', (27, 34))	('ALDH1A1', 'Gene', (104, 111))	('decrease', 'NegReg', (92, 100))	('increase', 'PosReg', (15, 23))	('ALDH1A1', 'Gene', '216', (27, 34))	('protein expression', 'MPA', (35, 53))	('C/EBPbeta-1', 'Gene', (59, 70))	('ALDH1A1', 'Gene', '216', (104, 111))	('overexpression', 'Var', (71, 85))	('protein expression', 'MPA', (112, 130))
393805	28148901	When C/EBPbeta-1 was knocked down in Ewing sarcoma cells, there was a decrease in ALDH activity; and ALDH activity increased with rescued expression of C/EBPbeta-1 (Figure 6C; Supplementary Figure 4).	('ALDH activity', 'MPA', (101, 114))	('C/EBPbeta-1', 'Gene', (152, 163))	('Ewing sarcoma', 'Disease', (37, 50))	('ALDH activity', 'MPA', (82, 95))	('knocked down', 'Var', (21, 33))	('increased', 'PosReg', (115, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (37, 50))	('decrease', 'NegReg', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
393808	28148901	Cells grown in normal, attachment-dependent conditions, overexpressing either C/EBPbeta-1 or C/EBPbeta-2, had significantly increased viability after 48 hours of doxorubicin treatment compared to control cells (empty vector) and C/EBPbeta-3 overexpressing cells (P < 0.05) (Figure 7A; Supplementary Figure 5A).	('C/EBPbeta-1', 'Var', (78, 89))	('C/EBPbeta-2', 'Var', (93, 104))	('increased', 'PosReg', (124, 133))	('doxorubicin', 'Chemical', 'MESH:D004317', (162, 173))	('viability', 'CPA', (134, 143))
393810	28148901	These results suggest that Ewing sarcoma cells with increased expression of C/EBPbeta-1 or C/EBPbeta-2 are more chemoresistant than cells without.	('increased', 'PosReg', (52, 61))	('chemoresistant', 'CPA', (112, 126))	('expression', 'MPA', (62, 72))	('Ewing sarcoma', 'Disease', (27, 40))	('C/EBPbeta-2', 'Var', (91, 102))	('C/EBPbeta-1', 'Gene', (76, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (27, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (27, 40))
393812	28148901	Overexpression of C/EBPbeta-1 and C/EBPbeta-2 resulted in significant increases in cellular transformation as measured by colony formation in soft agar.	('agar', 'Chemical', 'MESH:D000362', (147, 151))	('increases', 'PosReg', (70, 79))	('C/EBPbeta-2', 'Gene', (34, 45))	('colony formation in soft agar', 'CPA', (122, 151))	('C/EBPbeta-1', 'Var', (18, 29))	('cellular transformation', 'CPA', (83, 106))
393813	28148901	Interestingly, in breast cancer, C/EBPbeta-2 is the isoform capable of transforming normal mammary epithelial cells.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('C/EBPbeta-2', 'Var', (33, 44))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))
393814	28148901	In Ewing sarcoma cells, both C/EBPbeta-1 and C/EBPbeta-2 increase transformation, yet the increase in colony formation is consistently greater with overexpression of C/EBPbeta-1 compared to C/EBPbeta-2.	('C/EBPbeta-1', 'Var', (29, 40))	('C/EBPbeta-1', 'Var', (166, 177))	('transformation', 'CPA', (66, 80))	('increase', 'PosReg', (90, 98))	('Ewing sarcoma', 'Disease', (3, 16))	('colony formation', 'CPA', (102, 118))	('increase', 'PosReg', (57, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('greater', 'PosReg', (135, 142))	('C/EBPbeta-2', 'Var', (45, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))
393818	28148901	However, even if the amount of C/EBPbeta expressed in our transduced cell lines was greater than that of patient tumors, knockdown of C/EBPbeta expression significantly decreased colony formation and increased chemosensitivity, further supporting a critical role for this gene in Ewing sarcoma transformation and growth.	('knockdown', 'Var', (121, 130))	('patient', 'Species', '9606', (105, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (280, 293))	('chemosensitivity', 'CPA', (210, 226))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('increased', 'PosReg', (200, 209))	('Ewing sarcoma transformation', 'Disease', (280, 308))	('sarcoma', 'Phenotype', 'HP:0100242', (286, 293))	('colony formation', 'CPA', (179, 195))	('decreased', 'NegReg', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('C/EBPbeta', 'Gene', (134, 143))	('Ewing sarcoma transformation', 'Disease', 'MESH:C563168', (280, 308))
393821	28148901	In breast cancer cell lines, C/EBPbeta-2 has been shown to regulate ALDH1A1 expression.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('ALDH1A1', 'Gene', '216', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('C/EBPbeta-2', 'Var', (29, 40))	('regulate', 'Reg', (59, 67))	('expression', 'MPA', (76, 86))	('ALDH1A1', 'Gene', (68, 75))
393825	28148901	Furthermore, overexpression of C/EBPbeta-1 and C/EBPbeta-2 render Ewing sarcoma cells more resistant to doxorubicin.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (66, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('Ewing sarcoma', 'Disease', (66, 79))	('overexpression', 'PosReg', (13, 27))	('C/EBPbeta-1', 'Var', (31, 42))	('C/EBPbeta-2', 'Var', (47, 58))	('more', 'PosReg', (86, 90))	('doxorubicin', 'Chemical', 'MESH:D004317', (104, 115))	('resistant to doxorubicin', 'MPA', (91, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (66, 79))
393827	28148901	Taken together, these results support the oncogenic role of C/EBPbeta-1 in Ewing sarcoma.	('Ewing sarcoma', 'Disease', (75, 88))	('C/EBPbeta-1', 'Var', (60, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
393828	28148901	The increase in cellular transformation and growth with C/EBPbeta-1 overexpression in cell lines may explain the poor outcome of patients previously reported to have CEBPB copy number gain.	('CEBPB', 'Gene', (166, 171))	('patients', 'Species', '9606', (129, 137))	('CEBPB', 'Gene', '1051', (166, 171))	('cellular transformation', 'CPA', (16, 39))	('copy number', 'Var', (172, 183))	('gain', 'PosReg', (184, 188))	('growth', 'CPA', (44, 50))	('increase', 'PosReg', (4, 12))
393840	28148901	Five CEBPB MISSION shRNA Plasmid DNA (Sigma) clones were used in knockdown experiments (TRCN0000007440, TRCN0000007441, TRCN0000007442, TRCN0000007443, TRCN0000007444).	('TRCN0000007443', 'Var', (136, 150))	('TRCN0000007444', 'Var', (152, 166))	('CEBPB', 'Gene', (5, 10))	('CEBPB', 'Gene', '1051', (5, 10))	('TRCN0000007440, TRCN0000007441, TRCN0000007442', 'Disease', 'None', (88, 134))
393848	28148901	The following primer/probes were used: EWS-FLI1 Hs03024807_ft, CEBPB Hs00270923_s1, GAPDH Hu GAPDH 4310884E-1003044, and ALDH1A1 Hs00946916_m1 (all from Applied Biosystems).	('Hs00270923_s1', 'Var', (69, 82))	('GAPDH', 'Gene', '2597', (93, 98))	('4310884E-1003044', 'Var', (99, 115))	('GAPDH', 'Gene', (93, 98))	('EWS-FLI1', 'Gene', (39, 47))	('ALDH1A1', 'Gene', (121, 128))	('EWS-FLI1', 'Gene', '2130;2313', (39, 47))	('Hs03024807_ft', 'Var', (48, 61))	('GAPDH', 'Gene', '2597', (84, 89))	('GAPDH', 'Gene', (84, 89))	('Hs00946916_m1', 'Var', (129, 142))	('ALDH1A1', 'Gene', '216', (121, 128))	('CEBPB', 'Gene', (63, 68))	('CEBPB', 'Gene', '1051', (63, 68))
393869	26952093	We therefore examined if BEZ235 and BKM120, two selective compounds in these pathways, would inhibit leiomyosarcoma growth in vitro.	('inhibit', 'NegReg', (93, 100))	('BKM120', 'Chemical', 'MESH:C571178', (36, 42))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (101, 115))	('leiomyosarcoma growth', 'Disease', (101, 122))	('BEZ235', 'Var', (25, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('BEZ235', 'Chemical', 'MESH:C531198', (25, 31))	('BKM120', 'Var', (36, 42))	('leiomyosarcoma growth', 'Disease', 'MESH:D007890', (101, 122))
393874	26952093	BEZ235 treated xenografts (n = 8) demonstrated a decrease in tumor volume of 42 % whereas combining BEZ235 with Dox (n = 8) decreased tumor volume 68 % compared to vehicle alone.	('BEZ235', 'Var', (100, 106))	('BEZ235', 'Chemical', 'MESH:C531198', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('decrease', 'NegReg', (49, 57))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Dox', 'Chemical', 'MESH:D004317', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (134, 139))
393877	26952093	They can be broadly classified in two groups: those containing simple karyotypic defects including recurrent translocations or those with complex cytogenetic lesions characterised by multiple altered genes, such as leiomyosarcoma (LMS).	('leiomyosarcoma', 'Disease', (215, 229))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (215, 229))	('translocations', 'Var', (109, 123))	('LMS', 'Phenotype', 'HP:0100243', (231, 234))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (215, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
393878	26952093	LMS accounts for 11 % of soft tissue sarcomas (STS) and although its genetic basis is not fully characterized, common genetic abnormalities include loss of function mutations in p53 or PTEN and activating mutations in the PI3K/AKT/mTOR pathways.	('STS', 'Phenotype', 'HP:0030448', (47, 50))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (25, 44))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (25, 45))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('mTOR', 'Gene', (231, 235))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('mutations', 'Var', (165, 174))	('genetic abnormalities', 'Disease', 'MESH:D030342', (118, 139))	('PTEN', 'Gene', (185, 189))	('sarcomas', 'Disease', (37, 45))	('genetic abnormalities', 'Disease', (118, 139))	('mTOR', 'Gene', '2475', (231, 235))	('activating', 'PosReg', (194, 204))	('p53', 'Gene', '7157', (178, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('LMS', 'Disease', (0, 3))	('LMS', 'Phenotype', 'HP:0100243', (0, 3))	('loss of function', 'NegReg', (148, 164))	('p53', 'Gene', (178, 181))
393883	26952093	Another commonly used regimen is gemcitabine (900 mg/m2 day 1 and 8) and docetaxel (100 mg/m2 day 8), which has response rates ranging from 27 to 53 % in uterine and non-uterine leiomyosarcoma.	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (170, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('docetaxel', 'Chemical', 'MESH:D000077143', (73, 82))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (178, 192))	('leiomyosarcoma', 'Disease', (178, 192))	('gemcitabine', 'Chemical', 'MESH:C056507', (33, 44))	('900 mg/m2', 'Var', (46, 55))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (178, 192))
393892	26952093	Furthermore, we discovered that BEZ235, a dual PI3K/mTOR inhibitor, significantly inhibited LMS growth in vivo.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('LMS growth', 'CPA', (92, 102))	('inhibited', 'NegReg', (82, 91))	('BEZ235', 'Var', (32, 38))	('LMS', 'Phenotype', 'HP:0100243', (92, 95))	('BEZ235', 'Chemical', 'MESH:C531198', (32, 38))
393913	26952093	Immunoblots were performed with the following antibodies: p-AKTS473, total AKT, p-S6KT389, total S6K, p-4EBP1T37/46, total 4EBP1, PARP-1, all from Cell Signaling Technology (Denver, US), and tubulin [clone DM1A] (Sigma, St. Louis, USA).	('4EBP1', 'Gene', (123, 128))	('S6K', 'Mutation', 'p.S6K', (97, 100))	('p-S6KT389', 'Var', (80, 89))	('4EBP1', 'Gene', '1978', (104, 109))	('4EBP1', 'Gene', (104, 109))	('S6K', 'Mutation', 'p.S6K', (82, 85))	('PARP-1', 'Gene', (130, 136))	('PARP-1', 'Gene', '142', (130, 136))	('4EBP1', 'Gene', '1978', (123, 128))	('p-AKTS473', 'Var', (58, 67))
393926	26952093	Xenograft tumors were stained for desmin (Dako), SMA [clone 1A4] (Dako), Ki-67 [clone SP6] (ThermoScientific), TUNEL (Roche, TdT) and p-AKTS473 (Cell Signaling Technology) at 1:100.	('desmin', 'Gene', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('SP6', 'Gene', '80320', (86, 89))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('desmin', 'Gene', '1674', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('TdT', 'Gene', (125, 128))	('p-AKTS473', 'Var', (134, 143))	('TdT', 'Gene', '1791', (125, 128))	('SP6', 'Gene', (86, 89))
393935	26952093	BKM120 inhibits PI3K only and is somewhat less potent (EC50 = 800.0 and 513.2 nM in SKLMS1 and STS39, respectively).	('BKM120', 'Var', (0, 6))	('LMS', 'Phenotype', 'HP:0100243', (86, 89))	('inhibits', 'NegReg', (7, 15))	('PI3K', 'Pathway', (16, 20))	('STS', 'Phenotype', 'HP:0030448', (95, 98))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('SKLMS1', 'CellLine', 'CVCL:0628', (84, 90))
393936	26952093	We next analysed our cell lines to determine if they had any common mutations in the PI3K/mTOR axis.	('mutations', 'Var', (68, 77))	('mTOR', 'Gene', '2475', (90, 94))	('mTOR', 'Gene', (90, 94))
393937	26952093	Since mutations in the p85 subunit of PI3K are a common mechanism of PI3K pathway activation in sarcomas, we sequenced both cell lines but did not identify activating mutations (data not shown).	('p85', 'Gene', (23, 26))	('PI3K pathway', 'Pathway', (69, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('sarcomas', 'Disease', (96, 104))	('activation', 'PosReg', (82, 92))	('PI3K', 'Gene', (38, 42))	('p85', 'Gene', '5296', (23, 26))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))	('mutations', 'Var', (6, 15))
393941	26952093	To determine if the PI3K/AKT/mTOR pathways are selectively inhibited in LMS cells, we treated both cell lines with BEZ235 or BKM120 for 72 h with five different doses (0-1000 nM).	('BKM120', 'Var', (125, 131))	('inhibited', 'NegReg', (59, 68))	('mTOR', 'Gene', (29, 33))	('LMS', 'Phenotype', 'HP:0100243', (72, 75))	('mTOR', 'Gene', '2475', (29, 33))	('BKM120', 'Chemical', 'MESH:C571178', (125, 131))	('BEZ235', 'Chemical', 'MESH:C531198', (115, 121))
393944	26952093	BKM120-treated cells demonstrated decreased levels of p-AKTS473 but not p-4EBP1T37/46 at a 500-1000 nM dose (Fig.	('4EBP1', 'Gene', '1978', (74, 79))	('p-AKTS473', 'Var', (54, 63))	('decreased', 'NegReg', (34, 43))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('4EBP1', 'Gene', (74, 79))
393945	26952093	These data suggest that BEZ235 treatment in LMS cells inhibits downstream effectors of the PI3K and mTOR pathways and BKM120 treatment results in inhibition of PI3K pathway targets in both LMS cell lines as expected.	('mTOR', 'Gene', '2475', (100, 104))	('downstream effectors', 'MPA', (63, 83))	('BEZ235', 'Chemical', 'MESH:C531198', (24, 30))	('LMS', 'Phenotype', 'HP:0100243', (44, 47))	('inhibition', 'NegReg', (146, 156))	('LMS', 'Phenotype', 'HP:0100243', (189, 192))	('BKM120', 'Var', (118, 124))	('inhibits', 'NegReg', (54, 62))	('PI3K pathway targets', 'Pathway', (160, 180))	('BKM120', 'Chemical', 'MESH:C571178', (118, 124))	('mTOR', 'Gene', (100, 104))	('BEZ235', 'Var', (24, 30))
393953	26952093	The combination of BKM120 and Dox resulted in an additive effects only (range of CI around 1.0) and thus was not pursued further in our in vivo studies (Additional file 1: Table S2).	('additive effects', 'MPA', (49, 65))	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('Dox', 'Chemical', 'MESH:D004317', (30, 33))	('BKM120', 'Var', (19, 25))
393954	26952093	We further investigated the capacity of BEZ235 and Dox to inhibit downstream effectors of PI3K/mTOR pathways, alone and in combination.	('Dox', 'Chemical', 'MESH:D004317', (51, 54))	('BEZ235', 'Var', (40, 46))	('inhibit', 'NegReg', (58, 65))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('BEZ235', 'Chemical', 'MESH:C531198', (40, 46))
393957	26952093	Treatment of STS39 cells with BEZ235 at 60 nM caused a reduction in phosphorylation of AKTS473, with no change in the downstream effector p-4EBP1T37/46.	('BEZ235 at', 'Var', (30, 39))	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('phosphorylation', 'MPA', (68, 83))	('reduction', 'NegReg', (55, 64))	('STS', 'Phenotype', 'HP:0030448', (13, 16))	('AKTS473', 'Protein', (87, 94))	('4EBP1', 'Gene', '1978', (140, 145))	('4EBP1', 'Gene', (140, 145))
393958	26952093	As expected, increasing the dosage of BEZ235 to 500 nM dramatically decreased phosphorylation of AKTS473 and abolished the phosphorylation of 4EBP1T37/46.	('decreased', 'NegReg', (68, 77))	('phosphorylation', 'MPA', (78, 93))	('phosphorylation', 'MPA', (123, 138))	('BEZ235', 'Var', (38, 44))	('4EBP1', 'Gene', (142, 147))	('BEZ235', 'Chemical', 'MESH:C531198', (38, 44))	('AKTS473', 'Protein', (97, 104))	('4EBP1', 'Gene', '1978', (142, 147))	('abolished', 'NegReg', (109, 118))
393963	26952093	This cell population was increased with BEZ235 and Dox combination treatment for 72 h (15.3 and 9.6 % respectively for early and late apoptotic cells in SKLMS1, p < 0.01; 8 and 8.2 % respectively for early and late apoptotic cells in STS39, p < 0.01) suggesting that combination treatment may inhibit LMS survival via apoptosis.	('BEZ235', 'Chemical', 'MESH:C531198', (40, 46))	('Dox', 'Chemical', 'MESH:D004317', (51, 54))	('apoptosis', 'CPA', (318, 327))	('LMS', 'Phenotype', 'HP:0100243', (155, 158))	('SKLMS1', 'CellLine', 'CVCL:0628', (153, 159))	('LMS', 'Phenotype', 'HP:0100243', (301, 304))	('STS', 'Phenotype', 'HP:0030448', (234, 237))	('LMS survival', 'CPA', (301, 313))	('BEZ235', 'Var', (40, 46))	('inhibit', 'NegReg', (293, 300))
393964	26952093	Furthermore, PARP-1 levels, a marker of apoptosis, were increased at concentrations of 500 nM BEZ235 and with BEZ235 and Dox combination treatment as compared to controls by immunoblot (data not shown).	('Dox', 'Chemical', 'MESH:D004317', (121, 124))	('increased', 'PosReg', (56, 65))	('BEZ235', 'Var', (94, 100))	('BEZ235', 'Chemical', 'MESH:C531198', (110, 116))	('BEZ235', 'Chemical', 'MESH:C531198', (94, 100))	('PARP-1', 'Gene', (13, 19))	('PARP-1', 'Gene', '142', (13, 19))
393971	26952093	Overall, tumor growth was inhibited by 50 % following administration of BEZ235 alone, which was further reduced by 71 % by combination therapy compared to vehicle only (Fig.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('inhibited', 'NegReg', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('BEZ235', 'Chemical', 'MESH:C531198', (72, 78))	('BEZ235', 'Var', (72, 78))	('tumor', 'Disease', (9, 14))
393974	26952093	Treatment with BEZ235 alone or in combination with Dox showed decreased in p-AKTS473 levels when compared with vehicle and Dox controls (Fig.	('Dox', 'Chemical', 'MESH:D004317', (51, 54))	('decreased', 'NegReg', (62, 71))	('Dox', 'Chemical', 'MESH:D004317', (123, 126))	('BEZ235', 'Var', (15, 21))	('p-AKTS473 levels', 'MPA', (75, 91))	('BEZ235', 'Chemical', 'MESH:C531198', (15, 21))
393975	26952093	Thus, dual treatment Dox and BEZ235 is more effective in inhibiting LMS tumor growth in vivo compared to single agent therapy.	('inhibiting', 'NegReg', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('LMS tumor', 'Disease', (68, 77))	('BEZ235', 'Var', (29, 35))	('BEZ235', 'Chemical', 'MESH:C531198', (29, 35))	('LMS tumor', 'Disease', 'MESH:C535903', (68, 77))	('LMS', 'Phenotype', 'HP:0100243', (68, 71))	('Dox', 'Chemical', 'MESH:D004317', (21, 24))
393981	26952093	Therefore, two compounds that showed favourable selectivity profiles and were in clinical trials at the time of our study initiation, BEZ235 (a dual PI3K and mTOR inhibitor) and BKM120 (PI3K inhibitor) were chosen for further assessment.	('BEZ235', 'Chemical', 'MESH:C531198', (134, 140))	('BKM120', 'Chemical', 'MESH:C571178', (178, 184))	('mTOR', 'Gene', (158, 162))	('BKM120', 'Var', (178, 184))	('mTOR', 'Gene', '2475', (158, 162))
393982	26952093	BEZ235 and BKM120 have shown efficacy in many types of cancer, such as breast cancer with activating PI3K mutations, ovarian cancer, pancreatic cancer, rhabdomyosarcoma, hepatocellular carcinoma, undifferentiated pleomorphic sarcoma (UPS) in cell lines and/or animal models.	('undifferentiated pleomorphic sarcoma', 'Disease', (196, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', (144, 150))	('pancreatic cancer', 'Disease', (133, 150))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Disease', (71, 84))	('rhabdomyosarcoma', 'Disease', (152, 168))	('BKM120', 'Var', (11, 17))	('UPS', 'Disease', (234, 237))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (170, 194))	('cancer', 'Disease', (125, 131))	('UPS', 'Disease', 'MESH:D017118', (234, 237))	('cancer', 'Disease', (55, 61))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (152, 168))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (78, 84))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 194))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (152, 168))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pancreatic cancer', 'Disease', 'MESH:D010190', (133, 150))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (196, 232))	('PI3K', 'Gene', (101, 105))	('BKM120', 'Chemical', 'MESH:C571178', (11, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('activating', 'PosReg', (90, 100))	('hepatocellular carcinoma', 'Disease', (170, 194))	('mutations', 'Var', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('ovarian cancer', 'Disease', (117, 131))
393984	26952093	Dysregulated PI3K/AKT/mTOR signalling has been implicated in tumor progression and metastasis in multiple cancers of epithelial origin and recent data has begun to elucidate that these signalling pathways may be critical in STS.	('metastasis in multiple cancers', 'Disease', (83, 113))	('implicated', 'Reg', (47, 57))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mTOR', 'Gene', '2475', (22, 26))	('Dysregulated', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mTOR', 'Gene', (22, 26))	('metastasis in multiple cancers', 'Disease', 'MESH:D009362', (83, 113))	('STS', 'Phenotype', 'HP:0030448', (224, 227))	('tumor', 'Disease', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
393986	26952093	Also zebrafish expressing constitutively active AKTSer473 in mesenchymal progenitors resulted in the development of well-differentiated liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('liposarcoma', 'Disease', (136, 147))	('resulted in', 'Reg', (85, 96))	('liposarcoma', 'Disease', 'MESH:D008080', (136, 147))	('AKTSer473', 'Var', (48, 57))	('liposarcoma', 'Phenotype', 'HP:0012034', (136, 147))	('zebrafish', 'Species', '7955', (5, 14))
393987	26952093	Furthermore, mutations in the PI3K receptor are frequently seen in myxoid round cell liposarcoma.	('seen', 'Reg', (59, 63))	('myxoid round cell liposarcoma', 'Disease', 'MESH:D018208', (67, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('PI3K', 'Gene', (30, 34))	('myxoid round cell liposarcoma', 'Disease', (67, 96))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('mutations', 'Var', (13, 22))
393999	26952093	Although single agent Dox did not significantly inhibit tumor growth compared to control animals, administration of BEZ235 alone or in combination with Dox resulted in significant reduction in tumor volume.	('BEZ235', 'Chemical', 'MESH:C531198', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('reduction', 'NegReg', (180, 189))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (56, 61))	('Dox', 'Chemical', 'MESH:D004317', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('Dox', 'Chemical', 'MESH:D004317', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('BEZ235', 'Var', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
394001	26952093	In summary, we demonstrate that inhibition of the PI3K and mTOR pathways impairs LMS growth in vitro and in vivo.	('inhibition', 'Var', (32, 42))	('PI3K', 'Pathway', (50, 54))	('LMS growth', 'CPA', (81, 91))	('impairs', 'NegReg', (73, 80))	('LMS', 'Phenotype', 'HP:0100243', (81, 84))	('mTOR', 'Gene', '2475', (59, 63))	('mTOR', 'Gene', (59, 63))
394002	26952093	Also, we describe that the use of PI3K and mTOR inhibitors may have a synergistic effect with doxorubicin, standard chemotherapy for this disease.	('PI3K', 'Var', (34, 38))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))	('doxorubicin', 'Chemical', 'MESH:D004317', (94, 105))
394019	24038812	PARP-1, the primary member of the PARP family, binds to both single and double strand DNA breaks.	('single', 'Var', (61, 67))	('double strand DNA', 'Var', (72, 89))	('PARP-1', 'Gene', '142', (0, 6))	('PARP', 'Gene', (0, 4))	('PARP', 'Gene', (34, 38))	('binds', 'Interaction', (47, 52))	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', '142', (34, 38))	('PARP-1', 'Gene', (0, 6))
394020	24038812	Inhibition of PARP-1, results in persistent single strand DNA breaks leading to stalled replication forks and double strand DNA breaks.	('stalled replication forks', 'CPA', (80, 105))	('double strand', 'CPA', (110, 123))	('PARP-1', 'Gene', (14, 20))	('PARP-1', 'Gene', '142', (14, 20))	('single strand DNA breaks', 'MPA', (44, 68))	('Inhibition', 'Var', (0, 10))
394021	24038812	PARP-1 inhibition in cells with innately dysfunctional DNA repair mechanisms, such as BRCA-1 or BRCA-2 deficient cells, results in DNA damage that leads to cell cycle arrest and apoptosis.	('BRCA-1', 'Gene', (86, 92))	('PARP-1', 'Gene', '142', (0, 6))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (156, 173))	('BRCA-1', 'Gene', '672', (86, 92))	('DNA damage', 'MPA', (131, 141))	('BRCA-2', 'Gene', (96, 102))	('apoptosis', 'CPA', (178, 187))	('inhibition', 'Var', (7, 17))	('arrest', 'Disease', 'MESH:D006323', (167, 173))	('BRCA-2', 'Gene', '675', (96, 102))	('arrest', 'Disease', (167, 173))	('PARP-1', 'Gene', (0, 6))
394025	24038812	DNA repair mutations, deletions or epigenetic modifications in mesenchymal or neuroectodermal tumors provide the rationale for evaluation of PARP inhibitors in childhood malignancies.	('malignancies', 'Disease', (170, 182))	('mesenchymal', 'Disease', (63, 74))	('mutations', 'Var', (11, 20))	('deletions', 'Var', (22, 31))	('PARP', 'Gene', '142', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('DNA repair', 'Gene', (0, 10))	('epigenetic modifications', 'Var', (35, 59))	('PARP', 'Gene', (141, 145))	('malignancies', 'Disease', 'MESH:D009369', (170, 182))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (78, 100))	('neuroectodermal tumors', 'Disease', (78, 100))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (78, 100))
394026	24038812	PARP inhibition may potentiate the activity of DNA damaging agents such as alkylating agents, topoisomerase inhibitors, and radiation therapy, which are the cornerstones of treatment for childhood cancers.	('activity', 'MPA', (35, 43))	('potentiate', 'PosReg', (20, 30))	('inhibition', 'Var', (5, 15))	('PARP', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('DNA', 'MPA', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('childhood cancers', 'Disease', 'MESH:C536928', (187, 204))	('childhood cancers', 'Disease', (187, 204))	('PARP', 'Gene', '142', (0, 4))
394028	24038812	PARP inhibitors enhance the efficacy of temozolomide and topotecan in preclinical models of pediatric leukemia, neuroblastoma, and medulloblastoma.	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', (0, 4))	('neuroblastoma', 'Disease', 'MESH:D009447', (112, 125))	('inhibitors', 'Var', (5, 15))	('pediatric leukemia', 'Disease', 'MESH:D063766', (92, 110))	('pediatric leukemia', 'Disease', (92, 110))	('neuroblastoma', 'Disease', (112, 125))	('enhance', 'PosReg', (16, 23))	('medulloblastoma', 'Disease', 'MESH:D008527', (131, 146))	('topotecan', 'Chemical', 'MESH:D019772', (57, 66))	('medulloblastoma', 'Phenotype', 'HP:0002885', (131, 146))	('efficacy', 'MPA', (28, 36))	('neuroblastoma', 'Phenotype', 'HP:0003006', (112, 125))	('temozolomide', 'Chemical', 'MESH:D000077204', (40, 52))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))	('medulloblastoma', 'Disease', (131, 146))
394060	24038812	Drugs, drug combinations, or vehicle control were added to achieve final concentrations: olaparib (0.02-100microM), irinotecan (0.0005-100microM), SN38 (4x10-5 -0.2microM), melphalan (0.06-200microM), doxorubicin (0.0003-0.6microM), carboplatin (0.02-200microM), vincristine (2-10-5 -0.1microM).	('vincristine', 'Chemical', 'MESH:D014750', (263, 274))	('SN38', 'Var', (147, 151))	('0.02-200microM', 'Var', (246, 260))	('0.0005-100microM', 'Var', (128, 144))	('melphalan', 'Chemical', 'MESH:D008558', (173, 182))	('olaparib', 'Chemical', 'MESH:C531550', (89, 97))	('irinotecan', 'Chemical', 'MESH:D000077146', (116, 126))	('carboplatin', 'Chemical', 'MESH:D016190', (233, 244))	('0.0003-0.6microM', 'Var', (214, 230))	('SN38', 'Chemical', 'MESH:D000077146', (147, 151))	('0.06-200microM', 'Var', (184, 198))	('doxorubicin', 'Chemical', 'MESH:D004317', (201, 212))	('0.02-100microM', 'Var', (99, 113))
394093	24038812	In the combination of olaparib with the camptothecin, irinotecan and its active metabolite SN38, the median (range) CI was 0.4 (0.06-1.0) and 0.2 (0.04-0.7), respectively (Figure 2).	('olaparib', 'Chemical', 'MESH:C531550', (22, 30))	('SN38', 'Var', (91, 95))	('irinotecan', 'Chemical', 'MESH:D000077146', (54, 64))	('SN38', 'Chemical', 'MESH:D000077146', (91, 95))	('combination', 'Interaction', (7, 18))	('camptothecin', 'Chemical', 'MESH:D002166', (40, 52))
394195	31309284	Additionally, a distinct small subset of PEComas harboring rearrangements of the TFE3 (Xp11) gene locus has been identified.	('PEComas', 'Disease', (41, 48))	('rearrangements', 'Var', (59, 73))	('TFE3', 'Gene', (81, 85))	('PEComas', 'Disease', 'MESH:D054973', (41, 48))	('TFE3', 'Gene', '7030', (81, 85))
394206	31309284	Additionally, a distinct small subset of PEComas harboring rearrangements of the TFE3(Xp11) gene locus have been identified.	('PEComas', 'Disease', (41, 48))	('rearrangements', 'Var', (59, 73))	('TFE3', 'Gene', (81, 85))	('PEComas', 'Disease', 'MESH:D054973', (41, 48))	('TFE3', 'Gene', '7030', (81, 85))
394207	31309284	The PEComas of this group exhibit distinctive morphological features known from other TFE3 rearranged tumors such as Xp11-translocation renal cell cancer and alveolar soft part sarcoma, including an alveolar growth pattern and an epithelioid cytomorphology.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Xp11-translocation', 'Var', (117, 135))	('PEComas', 'Disease', 'MESH:D054973', (4, 11))	('renal cell cancer', 'Disease', 'MESH:C538614', (136, 153))	('alveolar soft part sarcoma', 'Disease', (158, 184))	('renal cell cancer', 'Disease', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('renal cell cancer', 'Phenotype', 'HP:0005584', (136, 153))	('PEComas', 'Disease', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('alveolar growth pattern', 'CPA', (199, 222))	('tumors', 'Disease', (102, 108))	('alveolar growth pattern', 'Phenotype', 'HP:0009085', (199, 222))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (167, 184))	('TFE3', 'Gene', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (158, 184))	('TFE3', 'Gene', '7030', (86, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (158, 184))
394223	31309284	In a multigene panel analysis (Human Actionable Solid Tumor Panel kit, Qiagen, Venlo, The Netherlands) only a pathogenic TP53 mutation in exon 5, but no other mutations especially no melanoma-associated mutations, could be detected.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('pathogenic', 'Reg', (110, 120))	('melanoma', 'Disease', (183, 191))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('Human', 'Species', '9606', (31, 36))	('mutation in', 'Var', (126, 137))	('Tumor', 'Phenotype', 'HP:0002664', (54, 59))
394247	31309284	In order to verify the immunohistochemical results and to possibly unveil the binding partner, we performed RNA-sequencing (TrueSight RNA Fusion Panel, Illumina, San Diego, CA, USA), which disclosed an extremely rare NONO-TFE3 fusion.	('TFE3', 'Gene', (222, 226))	('fusion', 'Var', (227, 233))	('TFE3', 'Gene', '7030', (222, 226))	('NONO', 'Gene', (217, 221))	('NONO', 'Gene', '4841', (217, 221))
394286	31309284	In addition, as in our first case, the molecular detection of a TP53 mutation could also be used to predict malignant behavior.	('mutation', 'Var', (69, 77))	('TP53', 'Gene', '7157', (64, 68))	('malignant behavior', 'CPA', (108, 126))	('TP53', 'Gene', (64, 68))
394310	31309284	In difficult cases, immunolabeling for more than one melanocytic marker and the demonstration of TSC2 mutations/alterations or TFE3 translocations might be helpful to differentiate PEComa from aberrant HMB-45-positive leiomyosarcoma.	('PEComa', 'Disease', 'MESH:D054973', (181, 187))	('leiomyosarcoma', 'Disease', (218, 232))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (218, 232))	('translocations', 'Var', (132, 146))	('TFE3', 'Gene', (127, 131))	('mutations/alterations', 'Var', (102, 123))	('TSC2', 'Gene', '7249', (97, 101))	('TSC2', 'Gene', (97, 101))	('PEComa', 'Disease', (181, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (218, 232))	('TFE3', 'Gene', '7030', (127, 131))
394321	31309284	A few years later, the authors also found that a distinctive subtype of PEComa harbors TFE3 gene fusions.	('TFE3', 'Gene', '7030', (87, 91))	('PEComa', 'Disease', 'MESH:D054973', (72, 78))	('PEComa', 'Disease', (72, 78))	('gene fusions', 'Var', (92, 104))	('TFE3', 'Gene', (87, 91))
394332	31309284	It appears that the combination of genetic findings in the TSC1/TSC2 complex and staining of the mTOR signaling pathway may predict response to mTOR inhibitors.	('predict', 'Reg', (124, 131))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('TSC1', 'Gene', '7248', (59, 63))	('genetic', 'Var', (35, 42))	('mTOR', 'Gene', (144, 148))	('TSC2', 'Gene', '7249', (64, 68))	('TSC1', 'Gene', (59, 63))	('TSC2', 'Gene', (64, 68))	('mTOR', 'Gene', '2475', (144, 148))
394340	31309284	Two molecular subtypes of PEComas have been identified: The first subtype is defined by a loss of TSC1/2, while the second subgroup harbors TFE3 rearrangements.	('loss', 'NegReg', (90, 94))	('PEComas', 'Disease', 'MESH:D054973', (26, 33))	('rearrangements', 'Var', (145, 159))	('TSC1/2', 'Gene', '7248;7249', (98, 104))	('TFE3', 'Gene', (140, 144))	('TSC1/2', 'Gene', (98, 104))	('PEComas', 'Disease', (26, 33))	('TFE3', 'Gene', '7030', (140, 144))
394345	32012890	Combined Inhibition of Epigenetic Readers and Transcription Initiation Targets the EWS-ETS Transcriptional Program in Ewing Sarcoma Background: Previously, we used inhibitors blocking BET bromodomain binding proteins (BRDs) in Ewing sarcoma (EwS) and observed that long term treatment resulted in the development of resistance.	('Ewing Sarcoma', 'Disease', (118, 131))	('EWS', 'Gene', '2130', (83, 86))	('EWS', 'Gene', (83, 86))	('BRDs', 'Gene', (218, 222))	('BET', 'Gene', '92737', (184, 187))	('P', 'Chemical', 'MESH:D010758', (144, 145))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (227, 240))	('Sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('EwS', 'Phenotype', 'HP:0012254', (242, 245))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('BET', 'Gene', (184, 187))	('P', 'Chemical', 'MESH:D010758', (107, 108))	('Ewing sarcoma', 'Gene', '2130', (227, 240))	('Ewing sarcoma', 'Gene', (227, 240))	('inhibitors', 'Var', (164, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (118, 131))	('resistance', 'MPA', (316, 326))
394353	32012890	EwS is defined by specific balanced chromosomal EWSR1/ETS translocations that give rise to oncogenic chimeric proteins, the most common being EWS-FLI1 as a consequence of the t(11;22)(q24;q12) translocation.	('EWSR1', 'Gene', (48, 53))	('EwS', 'Disease', (0, 3))	('t(11;22)(q24;q12', 'Var', (175, 191))	('EWS-FLI1', 'Gene', '2130;2313', (142, 150))	('consequence', 'Reg', (156, 167))	('EwS', 'Phenotype', 'HP:0012254', (0, 3))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (175, 192))	('give rise', 'Reg', (78, 87))	('EWSR1', 'Gene', '2130', (48, 53))	('EWS-FLI1', 'Gene', (142, 150))	('oncogenic chimeric proteins', 'MPA', (91, 118))
394356	32012890	Specific inhibitors of BET proteins such as I-BET151 or JQ1 result in the displacement of BRDs from chromatin and inhibition of transcription at key genes such as BCL2, MYC, and CDK6, and induce growth arrest and differentiation of cancer cells.	('cancer', 'Disease', (232, 238))	('MYC', 'Gene', (169, 172))	('growth arrest', 'Disease', (195, 208))	('BCL2', 'Gene', '596', (163, 167))	('CDK6', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('transcription', 'MPA', (128, 141))	('JQ1', 'Var', (56, 59))	('BET', 'Gene', '92737', (46, 49))	('BET', 'Gene', '92737', (23, 26))	('BCL2', 'Gene', (163, 167))	('displacement', 'MPA', (74, 86))	('MYC', 'Gene', '4609', (169, 172))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('BRDs', 'Gene', (90, 94))	('growth arrest', 'Phenotype', 'HP:0001510', (195, 208))	('differentiation', 'CPA', (213, 228))	('induce', 'Reg', (188, 194))	('inhibition', 'NegReg', (114, 124))	('BET', 'Gene', (46, 49))	('growth arrest', 'Disease', 'MESH:D006323', (195, 208))	('BET', 'Gene', (23, 26))	('CDK6', 'Gene', '1021', (178, 182))
394363	32012890	P-TEFb phosphorylates RNA Pol II C-terminal domain and promotes transcription elongation.	('P', 'Chemical', 'MESH:D010758', (26, 27))	('P-TEFb', 'Var', (0, 6))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('transcription elongation', 'CPA', (64, 88))	('promotes', 'PosReg', (55, 63))	('TEFb', 'Chemical', '-', (2, 6))
394368	32012890	Treatment of EwS cells with CDK9i induced a rapid down-regulation of EWS-FLI1 expression and reduced contact-dependent growth, as previously observed for BRD inhibition.	('contact-dependent growth', 'CPA', (101, 125))	('EWS-FLI1', 'Gene', '2130;2313', (69, 77))	('expression', 'MPA', (78, 88))	('reduced', 'NegReg', (93, 100))	('down-regulation', 'NegReg', (50, 65))	('EWS-FLI1', 'Gene', (69, 77))	('EwS', 'Phenotype', 'HP:0012254', (13, 16))	('CDK9i', 'Var', (28, 33))
394369	32012890	However, combined treatment of EwS with BRD and CDK9 inhibitors in vitro and in a preclinical mouse model in vivo overall was more effective than individual drug application.	('inhibitors', 'Var', (53, 63))	('combined', 'Interaction', (9, 17))	('mouse', 'Species', '10090', (94, 99))	('BRD', 'Gene', (40, 43))	('CDK9', 'Gene', (48, 52))	('EwS', 'Phenotype', 'HP:0012254', (31, 34))
394370	32012890	Previously, we demonstrated that EwS are susceptible to treatment with epigenetic inhibitors, such as JQ1, blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program.	('P', 'Chemical', 'MESH:D010758', (0, 1))	('blocking', 'NegReg', (107, 115))	('EwS', 'Phenotype', 'HP:0012254', (33, 36))	('BET', 'Gene', '92737', (116, 119))	('BET', 'Gene', (116, 119))	('epigenetic inhibitors', 'Var', (71, 92))
394378	32012890	However, densitometry of repeated Western blotting of CoIPs demonstrated only enrichment of p-CDK9 in the precipitate although EWS-FLI1 was clearly present (Figure S1B).	('EWS-FLI1', 'Gene', '2130;2313', (127, 135))	('P', 'Chemical', 'MESH:D010758', (57, 58))	('EWS-FLI1', 'Gene', (127, 135))	('p-CDK9', 'Var', (92, 98))
394386	32012890	However, treatment of JQ1 resistant cells with CDKI-73 revealed that these cells were still sensitive to CDK9i and confirmed a BET bromodomain independent mechanism in EwS (Figure 2B, A673r, SKNMCr).	('SKNMC', 'Chemical', '-', (191, 196))	('A673r', 'Var', (184, 189))	('BET', 'Gene', '92737', (127, 130))	('BET', 'Gene', (127, 130))	('EwS', 'Phenotype', 'HP:0012254', (168, 171))	('EwS', 'Disease', (168, 171))
394410	32012890	In SKNMC tumors, CDKI-73 induced the highest level of cleaved caspase 3 compared to the treatment with either JQ1 or its combination with CDKI-73 (Figure S5B,C), suggesting additional mechanisms influencing tumor growth.	('S5B', 'Gene', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cleaved caspase 3', 'MPA', (54, 71))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('SKNMC', 'Disease', (3, 8))	('CDKI-73', 'Var', (17, 24))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (9, 14))	('tumors', 'Disease', (9, 15))	('tumor', 'Disease', (207, 212))	('SKNMC', 'Chemical', '-', (3, 8))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('S5B', 'Gene', '5711', (154, 157))
394413	32012890	Inhibition of BRD4 by JQ1, dBET, or iBET significantly blocked proliferation and in vivo tumor growth of different EwS lines and strikingly resulted in a strong down-regulation of the EWS-FLI1 mediated transcription program (Becker-Dettling, data not shown).	('dBET', 'Gene', (27, 31))	('proliferation', 'CPA', (63, 76))	('EWS-FLI1', 'Gene', (184, 192))	('JQ1', 'Var', (22, 25))	('EWS-FLI1', 'Gene', '2130;2313', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('EwS', 'Phenotype', 'HP:0012254', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('iBET', 'Chemical', '-', (36, 40))	('dBET', 'Gene', '46236', (27, 31))	('Becker-Dettling', 'Disease', 'MESH:D009224', (225, 240))	('BRD4', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('Becker-Dettling', 'Disease', (225, 240))	('down-regulation', 'NegReg', (161, 176))	('blocked', 'NegReg', (55, 62))	('tumor', 'Disease', (89, 94))
394423	32012890	Active P-TEFb was identified by GSEA to activate E2F3 target genes in EwS necessary for the G1 to S phase transition affecting DNA replication and mitotic activity, which was further validated by GSEA leading-edge analysis providing a potential rationale for the observed disturbed G2/M phase of EwS cells following CDK9 inhibition.	('P-TEFb', 'Var', (7, 13))	('EwS', 'Phenotype', 'HP:0012254', (70, 73))	('E2F3', 'Gene', '1871', (49, 53))	('EwS', 'Phenotype', 'HP:0012254', (296, 299))	('GSEA', 'Chemical', '-', (32, 36))	('mitotic activity', 'CPA', (147, 163))	('G2/M', 'CPA', (282, 286))	('P', 'Chemical', 'MESH:D010758', (7, 8))	('TEFb', 'Chemical', '-', (9, 13))	('DNA replication', 'MPA', (127, 142))	('GSEA', 'Chemical', '-', (196, 200))	('activate', 'PosReg', (40, 48))	('E2F3', 'Gene', (49, 53))
394427	32012890	The diminished synergistic activity against SKNMC cells in vivo might be related to known functional mutations in the RB pathway or overall functional heterogenicity, as demonstrated by GO analysis presumably affecting the efficacy of CDK9 inhibition.	('mutations', 'Var', (101, 110))	('synergistic activity', 'MPA', (15, 35))	('affecting', 'Reg', (209, 218))	('SKNMC', 'Chemical', '-', (44, 49))	('diminished', 'NegReg', (4, 14))	('RB pathway', 'Pathway', (118, 128))
394429	32012890	Targeting both BRD4 and CDK9 complements affected functional differences of genes identified in EwS; thus, co-targeting BRDs and P-TEFb can be developed as an effective strategy for preventing or overcoming the drug resistance to JQ1.	('drug resistance', 'Phenotype', 'HP:0020174', (211, 226))	('P', 'Chemical', 'MESH:D010758', (129, 130))	('BRDs', 'Gene', (120, 124))	('functional differences', 'MPA', (50, 72))	('TEFb', 'Chemical', '-', (131, 135))	('affected', 'Reg', (41, 49))	('drug', 'MPA', (211, 215))	('EwS', 'Phenotype', 'HP:0012254', (96, 99))	('P-TEFb', 'Var', (129, 135))
394460	32012890	Once the tumor was palpable, mice were divided randomly into four groups and treated either with 50 mg/kg body weight JQ1, CDKI-73, or JQ1 in combination with CDKI-73, or solvent controls.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('JQ1', 'Var', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('JQ1', 'Gene', (118, 121))	('tumor', 'Disease', (9, 14))	('mice', 'Species', '10090', (29, 33))	('CDKI-73', 'Gene', (123, 130))
394475	32012890	Translocation driven tumors such as EwS are very sensitive to combined treatment with inhibitors targeting transcriptional elongation.	('Translocation', 'Var', (0, 13))	('EwS', 'Phenotype', 'HP:0012254', (36, 39))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('EwS', 'Disease', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
394477	32012890	The following are available online at , Supplementary information; Figure S1: The BRD4, CDK9 expression axis and its influence on cell cycle and proliferation; Figure S2: Influence of CDK9 inhibition on transcriptional regulation and cell cycle progression, Figure S3: GO Analysis of differentially regulated genes, Figure S4: Influence of CDK9 inhibition on the regulation of apoptosis, Figure S5: Combined targeting of CDK9 and BRD4 of SKNMC tumors results in the inhibition of proliferation and tumor growth, Figure S6: Whole Western blots with molecular weight markers and densitometry of individual Western blot figures, Figure S7: Western blots used for densitometry in Figure S1B.	('tumor', 'Phenotype', 'HP:0002664', (498, 503))	('tumor', 'Disease', 'MESH:D009369', (444, 449))	('tumors', 'Disease', 'MESH:D009369', (444, 450))	('tumor', 'Disease', (498, 503))	('SKNMC', 'Chemical', '-', (438, 443))	('inhibition', 'NegReg', (466, 476))	('BRD4', 'Gene', (430, 434))	('tumor', 'Phenotype', 'HP:0002664', (444, 449))	('targeting', 'Var', (408, 417))	('proliferation', 'CPA', (480, 493))	('tumors', 'Disease', (444, 450))	('tumor', 'Disease', (444, 449))	('tumor', 'Disease', 'MESH:D009369', (498, 503))	('tumors', 'Phenotype', 'HP:0002664', (444, 450))	('CDK9', 'Gene', (421, 425))
394478	32012890	T.H., B.W.S., C.P., H.-Y.Y., K.S., S.F., S.W., W.W. and G.H.S.R.	('H.-Y.Y.', 'Var', (20, 27))	('G.H.S.R', 'Var', (56, 63))	('K.S.', 'Var', (29, 33))	('S.F.', 'Var', (35, 39))	('C.P.', 'Var', (14, 18))	('W.W.', 'Var', (47, 51))	('S.W.', 'Var', (41, 45))	('P', 'Chemical', 'MESH:D010758', (16, 17))
394497	29440930	Figure 1 shows the chemical structures of eribulin (C40H59NO11) from halichondrin B (C60H86O19), a compound isolated from a natural marine sponge.	('C60H86O19', 'Chemical', '-', (85, 94))	('halichondrin B', 'Chemical', 'MESH:C070519', (69, 83))	('C60H86O19', 'Var', (85, 94))	('C40H59NO11', 'Chemical', '-', (52, 62))	('eribulin', 'Chemical', 'MESH:C490954', (42, 50))	('C40H59NO11', 'Var', (52, 62))
394510	29440930	Eribulin causes mitotic arrest prior to BCL-2 and BCL-xL phosphorylation, MCL-1 downregulation, and onset of apoptosis.	('BCL-2', 'Gene', (40, 45))	('apoptosis', 'CPA', (109, 118))	('MCL-1', 'Gene', '4170', (74, 79))	('BCL-xL', 'Gene', '598', (50, 56))	('MCL-1', 'Gene', (74, 79))	('BCL-2', 'Gene', '596', (40, 45))	('BCL-xL', 'Gene', (50, 56))	('Eribulin', 'Var', (0, 8))	('mitotic arrest', 'Disease', (16, 30))	('mitotic arrest', 'Disease', 'MESH:D006323', (16, 30))	('downregulation', 'NegReg', (80, 94))
394525	29440930	The results show that eribulin had an effect on gene expression in signaling pathways related to angiogenesis and EMT in the tumor stroma and reduced the degree of hypoxia.	('angiogenesis', 'CPA', (97, 109))	('eribulin', 'Var', (22, 30))	('eribulin', 'Chemical', 'MESH:C490954', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('reduced', 'NegReg', (142, 149))	('hypoxia', 'Disease', (164, 171))	('hypoxia', 'Disease', 'MESH:D000860', (164, 171))	('tumor stroma', 'Disease', 'MESH:D009369', (125, 137))	('gene expression', 'MPA', (48, 63))	('tumor stroma', 'Disease', (125, 137))	('signaling pathways', 'Pathway', (67, 85))	('effect', 'Reg', (38, 44))
394542	29440930	There are two additional important mechanisms of resistance: induction of P-glycoprotein encoded by multidrug resistance protein 1 gene and mutations of beta-tubulin.	('multidrug resistance protein 1', 'Gene', '5243', (100, 130))	('beta-tubulin', 'Protein', (153, 165))	('multidrug resistance protein 1', 'Gene', (100, 130))	('P-glycoprotein', 'Gene', '5243', (74, 88))	('P-glycoprotein', 'Gene', (74, 88))	('mutations', 'Var', (140, 149))	('drug resistance', 'Phenotype', 'HP:0020174', (105, 120))
394718	28381750	Several investigators have reported that pulmonary artery sarcoma has amplification of the PDGFRalpha gene and constitutive activation of the PDGFRalpha protein.	('pulmonary artery sarcoma', 'Disease', (41, 65))	('activation', 'PosReg', (124, 134))	('pulmonary artery sarcoma', 'Disease', 'MESH:D000071079', (41, 65))	('PDGFRalpha', 'Gene', '5156', (142, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('PDGFRalpha', 'Gene', (142, 152))	('PDGFRalpha', 'Gene', '5156', (91, 101))	('amplification', 'Var', (70, 83))	('PDGFRalpha', 'Gene', (91, 101))
394974	23477833	Several lines of evidence have suggested that IGF-1R signalling is crucial to the biological changes in Ewing's sarcoma and that targeting IGF-1R can inhibit tumour growth.	('IGF-1R', 'Gene', (139, 145))	('IGF-1R', 'Gene', '3480', (139, 145))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('targeting', 'Var', (129, 138))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (104, 119))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('IGF-1R', 'Gene', '3480', (46, 52))	('inhibit', 'NegReg', (150, 157))	('IGF-1R', 'Gene', (46, 52))	("Ewing's sarcoma", 'Disease', (104, 119))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (104, 119))	('tumour', 'Disease', (158, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
394979	23477833	However, IGF-1R inhibition suppresses mTOR-induced Akt activation and sensitises tumour cells to mTOR inhibitors.	('IGF-1R', 'Gene', (9, 15))	('Akt', 'Gene', (51, 54))	('mTOR', 'Gene', '2475', (97, 101))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('mTOR', 'Gene', (97, 101))	('sensitises tumour', 'Disease', 'MESH:D009369', (70, 87))	('Akt', 'Gene', '207', (51, 54))	('suppresses', 'NegReg', (27, 37))	('sensitises tumour', 'Disease', (70, 87))	('mTOR', 'Gene', (38, 42))	('mTOR', 'Gene', '2475', (38, 42))	('IGF-1R', 'Gene', '3480', (9, 15))	('inhibition', 'Var', (16, 26))
394980	23477833	Pretreatment of rhabdomyosarcoma cell lines with the IGF-1R antibody h7C10 resulted in blockade of rapamycin-induced Akt activation and in an enhanced antiproliferative effect compared with either drug alone.	('rhabdomyosarcoma', 'Disease', (16, 32))	('IGF-1R', 'Gene', '3480', (53, 59))	('h7C10', 'Var', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('IGF-1R', 'Gene', (53, 59))	('Akt', 'Gene', (117, 120))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (16, 32))	('blockade', 'NegReg', (87, 95))	('rapamycin', 'Chemical', 'MESH:D020123', (99, 108))	('enhanced', 'PosReg', (142, 150))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (16, 32))	('Akt', 'Gene', '207', (117, 120))	('antiproliferative effect', 'CPA', (151, 175))	('activation', 'PosReg', (121, 131))
394981	23477833	The IGF-1R antibody R1507 similarly enhanced the effect of rapamycin by downregulating IGF-1R and blocking the reactivation of phosphorylated Akt (p-Akt) in a broad range of sarcoma cell lines.	('R1507', 'Var', (20, 25))	('Akt', 'Gene', (142, 145))	('IGF-1R', 'Gene', '3480', (4, 10))	('IGF-1R', 'Gene', (87, 93))	('Akt', 'Gene', (149, 152))	('downregulating', 'NegReg', (72, 86))	('IGF-1R', 'Gene', '3480', (87, 93))	('reactivation', 'MPA', (111, 123))	('sarcoma', 'Disease', 'MESH:D012509', (174, 181))	('Akt', 'Gene', '207', (149, 152))	('rapamycin', 'Chemical', 'MESH:D020123', (59, 68))	('Akt', 'Gene', '207', (142, 145))	('sarcoma', 'Disease', (174, 181))	('blocking', 'NegReg', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('IGF-1R', 'Gene', (4, 10))	('enhanced', 'PosReg', (36, 44))
395083	23477833	Pappo and colleagues suggested that the moderate clinical benefit noted with the IGF-1R antibody R1507 as a single drug in the treatment of Ewing's sarcoma could have been because of under dosing of the drug.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (140, 155))	('IGF-1R', 'Gene', '3480', (81, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('IGF-1R', 'Gene', (81, 87))	('R1507', 'Var', (97, 102))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (140, 155))	("Ewing's sarcoma", 'Disease', (140, 155))
395095	23477833	With R1507 alone in Ewing's sarcoma, median PFS was 5.7 weeks, the RECIST response rate was 10%, and median overall survival was 7.6 months.	("Ewing's sarcoma", 'Disease', (20, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (20, 35))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (20, 35))	('R1507 alone', 'Var', (5, 16))
395136	22778956	Unique mutations have been associated with certain soft tissue sarcomas, but their etiologies remain unknown.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (51, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('soft tissue sarcomas', 'Disease', (51, 71))	('associated', 'Reg', (27, 37))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (51, 71))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (51, 70))	('mutations', 'Var', (7, 16))
395147	22778956	Genetic alterations such as recurrent chromosomal translocations and genetic deregulations have been reported in soft tissue sarcomas.	('genetic deregulations', 'Var', (69, 90))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (113, 133))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (113, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (113, 133))	('soft tissue sarcomas', 'Disease', (113, 133))	('chromosomal translocations', 'Var', (38, 64))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (28, 63))
395148	22778956	For example, chimeric genes have been reported in Ewing sarcoma, alveolar rhabdomyosarcoma (RMS), desmoplastic small round cell tumor, clear cell sarcoma (CCS), myxoid/round cell liposarcoma, myxoid chondrosarcoma, synovial sarcoma, alveolar soft part sarcoma (ASPS), and fibromyxoid sarcoma.	('myxoid chondrosarcoma', 'Disease', (192, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('liposarcoma', 'Disease', (179, 190))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (161, 190))	('Ewing sarcoma', 'Disease', (50, 63))	('synovial sarcoma', 'Disease', (215, 231))	('ASPS', 'Gene', (261, 265))	('alveolar rhabdomyosarcoma', 'Disease', (65, 90))	('RMS', 'Phenotype', 'HP:0002859', (92, 95))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (233, 259))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (135, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (199, 213))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (242, 259))	('fibromyxoid sarcoma', 'Disease', (272, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('synovial sarcoma', 'Disease', 'MESH:D013584', (215, 231))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (74, 90))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (233, 259))	('liposarcoma', 'Phenotype', 'HP:0012034', (179, 190))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (65, 90))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (215, 231))	('ASPS', 'Gene', '79058', (261, 265))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (65, 90))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (98, 133))	('liposarcoma', 'Disease', 'MESH:D008080', (179, 190))	('desmoplastic small round cell tumor', 'Disease', (98, 133))	('alveolar soft part sarcoma', 'Disease', (233, 259))	('chimeric genes', 'Var', (13, 27))	('ASPS', 'Phenotype', 'HP:0012218', (261, 265))	('clear cell sarcoma', 'Disease', (135, 153))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (50, 63))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (50, 63))	('reported', 'Reg', (38, 46))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (272, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (192, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))
395149	22778956	Some soft tissue sarcomas depend on genetic deregulation of kinase signaling pathways, including inflammatory myofibroblastic tumor, congenital fibrosarcoma, dermatofibrosarcoma protuberans, giant cell tumor of the tendon sheath, and gastrointestinal stromal tumor (GIST).	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (234, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('kinase signaling pathways', 'Pathway', (60, 85))	('giant cell tumor', 'Disease', 'MESH:D005870', (191, 207))	('myofibroblastic tumor', 'Disease', (110, 131))	('gastrointestinal stromal tumor', 'Disease', (234, 264))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (144, 156))	('congenital fibrosarcoma', 'Disease', (133, 156))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (110, 131))	('myofibroblastic tumor', 'Disease', 'MESH:D009369', (110, 131))	('GIST', 'Phenotype', 'HP:0100723', (266, 270))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('congenital fibrosarcoma', 'Disease', 'MESH:D005354', (133, 156))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (165, 177))	('deregulation', 'Var', (44, 56))	('giant cell tumor', 'Disease', (191, 207))	('dermatofibrosarcoma protuberans', 'Disease', (158, 189))	('soft tissue sarcomas', 'Disease', (5, 25))	('giant cell tumor', 'Phenotype', 'HP:0011847', (191, 207))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (5, 25))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (5, 24))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (234, 264))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (5, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (158, 189))
395150	22778956	Unique genetic alterations have diagnostic and prognostic value and provide a clue for therapeutic targets, for example, a small molecule directed against tyrosine kinase reduced metastasis after surgical resection in GIST.	('tyrosine', 'Chemical', 'MESH:D014443', (155, 163))	('GIST', 'Phenotype', 'HP:0100723', (218, 222))	('alterations', 'Var', (15, 26))	('metastasis', 'CPA', (179, 189))	('reduced', 'NegReg', (171, 178))
395166	22778956	Unique genetic alterations have been reported in certain tumors, but molecular histological backgrounds have not been defined for most tumors and differential diagnosis is often difficult.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('reported', 'Reg', (37, 45))	('genetic alterations', 'Var', (7, 26))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
395185	22778956	It emerges from the interstitial cells of Cajal and is characterized by the presence of gain-of-function mutations in c-kit or platelet-derived growth factor receptor.	('c-kit', 'Gene', '3815', (118, 123))	('mutations', 'Var', (105, 114))	('gain-of-function', 'PosReg', (88, 104))	('c-kit', 'Gene', (118, 123))
395229	22778956	Murine fibroblast cells coexpressing P3F and simian virus 40 large-T antigen exhibited malignant features such as anchorage-independent growth and colony formation.	('P3F', 'Var', (37, 40))	('anchorage-independent growth', 'CPA', (114, 142))	('colony formation', 'CPA', (147, 163))	('Murine fibroblast', 'CellLine', 'CVCL:0594', (0, 17))	('simian virus 40', 'Species', '1891767', (45, 60))
395231	22778956	Specific phosphorylated forms of Akt, eIF4G, 4EBP1, and p70S6 were associated with survival of patients with RMS.	('Akt', 'Gene', '207', (33, 36))	('patients', 'Species', '9606', (95, 103))	('4EBP1', 'Gene', (45, 50))	('p70S6', 'Var', (56, 61))	('Akt', 'Gene', (33, 36))	('associated with', 'Reg', (67, 82))	('RMS', 'Disease', (109, 112))	('eIF4G', 'Var', (38, 43))	('RMS', 'Phenotype', 'HP:0002859', (109, 112))
395271	22778956	The antigens that most frequently reacted with patient plasma samples were ORF38, a myristoylated tegument protein, and ORF73, LANA.	('patient', 'Species', '9606', (47, 54))	('LANA', 'Gene', (127, 131))	('LANA', 'Gene', '4961527', (127, 131))	('ORF73', 'Var', (120, 125))	('ORF38', 'Var', (75, 80))
395389	22778956	Synovial sarcoma is characterized by the presence of a fusion of the SYT gene with either SSX1 or SSX2, as a consequence of a chromosomal translocation.	('SSX1', 'Gene', (90, 94))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('SSX2', 'Gene', '6757', (98, 102))	('SYT', 'Gene', '6760', (69, 72))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('SSX2', 'Gene', (98, 102))	('SSX1', 'Gene', '6756', (90, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('fusion', 'Var', (55, 61))	('SYT', 'Gene', (69, 72))
395434	22778956	In tumors where pathogenic gene alterations were identified, a focused approach using MS and antibodies appeared to be effective for surveying the results of such aberrations, while many proteins associated with aberrant gene products were identified by MS and Y2H.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('alterations', 'Var', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
395440	22778956	In the case of sarcomas with a homogeneous molecular etiology, such as those with common fusion genes or mutations, the use of a small number of samples during the initial stage could be compromised in a subsequent extensive validation study.	('fusion genes', 'Var', (89, 101))	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('mutations', 'Var', (105, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('sarcomas', 'Disease', (15, 23))
395492	33552942	In patients with macroscopically complete resection, a major improvement in disease-specific and total survivals was observed relative to cases where only incomplete surgery or re-irradiation had been carried out.	('disease-specific', 'CPA', (76, 92))	('total survivals', 'CPA', (97, 112))	('macroscopically complete resection', 'Var', (17, 51))	('improvement', 'PosReg', (61, 72))	('patients', 'Species', '9606', (3, 11))
395521	33552942	retrospectively analyzed 27,714 NPC patients from December 1998 to September 2012, and a total of 69 patients (0.25%) were found who had RIS in the head and neck after RT for NPC.	('patients', 'Species', '9606', (101, 109))	('NPC', 'Gene', '4864', (175, 178))	('patients', 'Species', '9606', (36, 44))	('NPC', 'Gene', (32, 35))	('NPC', 'Gene', '4864', (32, 35))	('RIS', 'Var', (137, 140))	('NPC', 'Gene', (175, 178))
395567	31965673	Fortunately, a significant number of soft tissue tumors, in particular those with monomorphic round cell, spindle cell or epithelioid morphology, harbor recurrent gene translocations, which are often tumor-specific.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('soft tissue tumors', 'Disease', (37, 55))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (37, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('soft tissue tumors', 'Disease', 'MESH:D012983', (37, 55))	('tumor', 'Disease', (200, 205))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (37, 55))	('gene translocations', 'Var', (163, 182))
395590	31965673	In both studies, specific fusion genes were detected in all cases of Ewing sarcoma (n = 28), synovial sarcoma (n = 19), myxoid liposarcoma (n = 12), alveolar rhabdomyosarcoma (n = 10), and desmoplastic small round cell tumor (n = 5).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (93, 109))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (158, 174))	('detected', 'Reg', (44, 52))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (149, 174))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (149, 174))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (120, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('myxoid liposarcoma', 'Disease', (120, 138))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (69, 82))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (69, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (189, 224))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (120, 138))	('desmoplastic small round cell tumor', 'Disease', (189, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('synovial sarcoma', 'Disease', (93, 109))	('fusion genes', 'Var', (26, 38))	('alveolar rhabdomyosarcoma', 'Disease', (149, 174))	('synovial sarcoma', 'Disease', 'MESH:D013584', (93, 109))	('Ewing sarcoma', 'Disease', (69, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('liposarcoma', 'Phenotype', 'HP:0012034', (127, 138))
395680	29619120	As VEGF promotes many aspects including an increase in the number of vessels and structural abnormalities, variation in caliber, a non-hierarchical network, lack of smooth muscle cells, disturbed pericapillary architecture, and incomplete vessel walls can be seen in non-physiological tumor angiogenesis.	('non-hierarchical network', 'CPA', (131, 155))	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('incomplete vessel walls', 'CPA', (228, 251))	('VEGF', 'Gene', '7422', (3, 7))	('structural abnormalities', 'Disease', (81, 105))	('tumor', 'Disease', (285, 290))	('disturbed', 'Reg', (186, 195))	('pericapillary architecture', 'CPA', (196, 222))	('variation', 'Var', (107, 116))	('increase', 'PosReg', (43, 51))	('caliber', 'CPA', (120, 127))	('VEGF', 'Gene', (3, 7))	('structural abnormalities', 'Disease', 'MESH:C566527', (81, 105))	('lack', 'NegReg', (157, 161))
395681	29619120	US can easily and non-invasively detect such abnormalities in angiogenesis in the tumor, and therefore, it is broadly applied for distinguishing malignant soft-tissue tumors from benign lesions.	('soft-tissue tumors', 'Disease', 'MESH:D012983', (155, 173))	('abnormalities', 'Var', (45, 58))	('soft-tissue tumors', 'Disease', (155, 173))	('soft-tissue tumors', 'Phenotype', 'HP:0031459', (155, 173))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('soft-tissue tumor', 'Phenotype', 'HP:0031459', (155, 172))	('tumor', 'Disease', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', (167, 172))	('angiogenesis', 'CPA', (62, 74))
395770	28464838	The most common alteration carried by ESS is the t (7;17) (p15;q21) translocation, which results in JAZF1-SUZ12 gene fusion (also known as JJAZ1).	('JAZF1', 'Gene', '221895', (100, 105))	('SUZ12', 'Gene', (106, 111))	('JJAZ1', 'Gene', '23512', (139, 144))	('results in', 'Reg', (89, 99))	('JJAZ1', 'Gene', (139, 144))	('JAZF1', 'Gene', (100, 105))	('SUZ12', 'Gene', '23512', (106, 111))	('t (7;17) (p15;q21', 'Var', (49, 66))
395793	25657424	The patient was severely immunosuppressed with CD4 lymphocyte counts 79/mm3, plasma HIV viral load 395722 IU/ml, and HCV viral load was 21900 IU/ml.	('CD4', 'Gene', '920', (47, 50))	('395722 IU/ml', 'Var', (99, 111))	('patient', 'Species', '9606', (4, 11))	('CD4', 'Gene', (47, 50))
395961	24111893	The effective use of immunohistochemistry specifically assesses the differential diagnostic possibilities, and the use of a small 'universal' panel is suggested here: CD34, desmin, EMA, keratin cocktail AE1/AE3, S100 protein and SMA.	('desmin', 'Gene', '1674', (173, 179))	('EMA', 'Gene', (181, 184))	('S100', 'Gene', (212, 216))	('CD34', 'Var', (167, 171))	('S100', 'Gene', '6271', (212, 216))	('EMA', 'Gene', '4582', (181, 184))	('desmin', 'Gene', (173, 179))	('AE1/AE3', 'Gene', (203, 210))	('AE1/AE3', 'Gene', '6521;6508', (203, 210))
396053	24111893	Another pitfall is the presence of CD31 in platelets and thrombi from where the antigen can be adsorbed onto the surface of tumour cells, potentially simulating antigen expression.	('antigen expression', 'MPA', (161, 179))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('simulating', 'Reg', (150, 160))	('CD31', 'Var', (35, 39))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('tumour', 'Disease', (124, 130))
396069	24111893	A classical example of pathological KIT activation by gain-of-function mutation occurs in GISTs, most of which have these mutations.	('gain-of-function', 'PosReg', (54, 70))	('KIT', 'Gene', '3815', (36, 39))	('mutation', 'Var', (71, 79))	('KIT', 'Gene', (36, 39))	('activation', 'PosReg', (40, 50))
396080	24111893	A small subset of GIST that especially include some PDGFRA mutant gastric GISTs can be KIT-negative or only focally positive (Figure 4).	('PDGFRA', 'Gene', (52, 58))	('KIT', 'Gene', (87, 90))	('PDGFRA', 'Gene', '5156', (52, 58))	('mutant', 'Var', (59, 65))	('KIT', 'Gene', '3815', (87, 90))
396085	24111893	It is especially useful in KIT-negative gastric GISTs, many of which are PDG-FRA-mutant tumours: such mutants still appear strongly positive for DOG1.	('mutants', 'Var', (102, 109))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('PDG', 'Gene', (73, 76))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('KIT', 'Gene', '3815', (27, 30))	('DOG1', 'Gene', '55107', (145, 149))	('tumours', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('positive', 'Reg', (132, 140))	('DOG1', 'Gene', (145, 149))	('KIT', 'Gene', (27, 30))	('PDG', 'Gene', '26227', (73, 76))
396095	24111893	Desmin positivity is detectable in a great majority of smooth muscle tumours.	('detectable', 'Reg', (21, 31))	('Desmin positivity', 'Phenotype', 'HP:0100300', (0, 17))	('positivity', 'Var', (7, 17))	('smooth muscle tumours', 'Disease', (55, 76))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('Desmin', 'Gene', '1674', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('smooth muscle tumours', 'Disease', 'MESH:D018235', (55, 76))	('Desmin', 'Gene', (0, 6))
396139	24111893	Conversely, widespread positivity for keratins more probably suggests metastatic carcinoma or mesothelioma.	('carcinoma or mesothelioma', 'Disease', 'MESH:D008654', (81, 106))	('keratins', 'Protein', (38, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinoma or mesothelioma', 'Disease', (81, 106))	('positivity', 'Var', (23, 33))
396403	28725344	Cytogenetics revealed a complex abnormal karyotype including t(12;22)(q13;q12) and fluorescence in situ hybridization (FISH) demonstrated an EWSR1 gene rearrangement, collectively diagnostic of CCS.	('CCS', 'Disease', (194, 197))	('t(12;22)(', 'Var', (61, 70))	('EWSR1', 'Gene', (141, 146))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (61, 78))	('EWSR1', 'Gene', '2130', (141, 146))
396404	28725344	Genomic profiling with a 405 gene panel (Foundation Medicine, Inc., Cambridge, MA) demonstrated an EWSR1-ATF1 fusion characteristic of CCS; a frameshift mutation of ARID1A, a tumor suppressor gene frequently mutated in desmoplastic melanoma; and a low estimated tumor mutation burden of 2 mutations per megabase.	('CCS', 'Disease', (135, 138))	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('ATF1', 'Gene', '466', (105, 109))	('frameshift mutation', 'Var', (142, 161))	('EWSR1', 'Gene', '2130', (99, 104))	('ARID1A', 'Gene', '8289', (165, 171))	('tumor', 'Disease', (262, 267))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('ARID1A', 'Gene', (165, 171))	('ATF1', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('desmoplastic melanoma', 'Disease', (219, 240))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('EWSR1', 'Gene', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (219, 240))
396418	28725344	Desmoplastic melanomas with spindle cell morphology and sarcoma-like clinical behavior also frequently harbor inactivating NF1 mutations.	('sarcoma', 'Disease', (56, 63))	('Desmoplastic melanomas', 'Disease', (0, 22))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('NF1', 'Gene', '4763', (123, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('NF1', 'Gene', (123, 126))	('Desmoplastic melanomas', 'Disease', 'MESH:D008545', (0, 22))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('mutations', 'Var', (127, 136))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))	('inactivating', 'Var', (110, 122))
396443	26166537	Examples of routinely used positron-emitting isotopes are 11C, 13N, 15O, 18F, 44Sc, 62Cu, 64Cu, 68Ga, 72As, 74As, 76Br, 82Rb, 86Y, 89Zr, and 124I .	('72As', 'Var', (102, 106))	('18F', 'Var', (73, 76))	('74As', 'Var', (108, 112))	('15O', 'Var', (68, 71))	('86Y', 'Var', (126, 129))	('82Rb', 'Var', (120, 124))	('44Sc', 'Var', (78, 82))	('76Br', 'Var', (114, 118))	('64Cu', 'Var', (90, 94))	('68Ga', 'Var', (96, 100))	('89Zr', 'Var', (131, 135))	('62Cu', 'Var', (84, 88))	('11C', 'Chemical', 'MESH:C000615233', (58, 61))
396457	26166537	The biodistribution of the constructs was evaluated in nude mice bearing human U87MG tumors, and as exemplified in Figure 3D, the obtained PET images clearly demonstrated a difference in tumor uptake for RGD-targeted vs. non-targeted nanoparticles.	('tumor', 'Disease', (85, 90))	('nude mice', 'Species', '10090', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('human', 'Species', '9606', (73, 78))	('tumor', 'Disease', (187, 192))	('RGD-targeted', 'Var', (204, 216))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('U87MG', 'CellLine', 'CVCL:0022', (79, 84))	('rat', 'Species', '10116', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
396470	26166537	For nanomedicine research, besides 64Cu (t1/2 = 13 h), radionuclides such as 89Zr, 72/74As and 124I are therefore of particular interest .	('radionuclides', 'Chemical', 'MESH:D011868', (55, 68))	('124I', 'Var', (95, 99))	('72/74As', 'Var', (83, 90))	('89Zr', 'Var', (77, 81))
396479	26166537	Figure 4C), 89Zr-DNP primarily accumulated in liver and spleen, but also showed prominent localization in macrophages in plaques in the aortic root of atherogenic ApoE-/- mice.	('89Zr-DNP', 'Chemical', '-', (12, 20))	('89Zr-DNP', 'Var', (12, 20))	('mice', 'Species', '10090', (171, 175))	('aortic root', 'Phenotype', 'HP:0002616', (136, 147))	('ApoE', 'Gene', (163, 167))	('ApoE', 'Gene', '11816', (163, 167))
396482	26166537	Prototypic examples of radio-isotopes used in SPECT are 99mTc, 111In, 123I and 201TI.	('111In', 'Chemical', 'MESH:C000615551', (63, 68))	('201TI', 'Var', (79, 84))	('111In', 'Var', (63, 68))	('99mTc', 'Var', (56, 61))	('123I', 'Var', (70, 74))
396489	26166537	Both the transaxial and the coronal images obtained in these analyses demonstrated that RFA is able to substantially increase the tumor accumulation of radiolabeled liposomal doxorubicin (likely both by direct (i.e.	('increase', 'PosReg', (117, 125))	('rat', 'Species', '10116', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('doxorubicin', 'Chemical', 'MESH:D004317', (175, 186))	('RFA', 'Var', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
396493	26166537	As shown in the right panels in Figure 5B, in case of non-targeted G5-PAMAM-dendrimers, the vast majority of the administered dose accumulated in organs of the mononuclear phagocytic system (MPS), such as liver and spleen.	('G5-PAMAM-dendrimers', 'Var', (67, 86))	('MPS', 'Disease', (191, 194))	('G5-PAMAM', 'Chemical', '-', (67, 75))	('MPS', 'Disease', 'MESH:D009084', (191, 194))
396542	26166537	On day 1 p.i., there is a considerable decrease in signal intensity in case of both NP-MTX and NP-MTX-CTX, indicating accumulation of the probes in the tumor.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('NP-MTX', 'Chemical', '-', (95, 101))	('NP-MTX-CTX', 'Var', (95, 105))	('decrease', 'NegReg', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('NP-MTX-CTX', 'Chemical', '-', (95, 105))	('tumor', 'Disease', (152, 157))	('signal intensity', 'MPA', (51, 67))	('accumulation', 'PosReg', (118, 130))	('NP-MTX', 'Chemical', '-', (84, 90))
396568	26166537	The first formulation contained Gd-HPDO3A, and was used to visualize differences in (sub-) cellular localization and content release using T1 and T2 contrast.	('content', 'MPA', (117, 124))	('Gd-HPDO3A', 'Chemical', 'MESH:C062402', (32, 41))	('Gd-HPDO3A', 'Var', (32, 41))
396574	26166537	In the actual experiments, they injected both liposomal formulations, containing Gd-HPDO3A and Tm-DOTMA, directly into B16 melanoma tumors in mice, and acquired T1-weighted images (for Gd-HPDO3A), saturation transfer maps (for Tm-DOTMA) and T2 maps (for both) at several different time points post intratumoral injection.	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('rat', 'Species', '10116', (301, 304))	('tumor', 'Disease', (132, 137))	('saturation transfer maps', 'MPA', (197, 221))	('B16', 'CellLine', 'CVCL:N540', (119, 122))	('T2 maps', 'MPA', (241, 248))	('Gd-HPDO3A', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('Gd-HPDO3A', 'Chemical', 'MESH:C062402', (185, 194))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (303, 308))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma tumors', 'Disease', 'MESH:D008545', (123, 138))	('T1-weighted', 'MPA', (161, 172))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('Gd-HPDO3A', 'Chemical', 'MESH:C062402', (81, 90))	('rat', 'Species', '10116', (201, 204))	('mice', 'Species', '10090', (142, 146))	('melanoma tumors', 'Disease', (123, 138))
396612	26166537	From these longitudinal studies, as shown in Figure 10A, it was concluded that in case of RGD-HDL, active targeting to tumor vasculature was evident from 30 min p.i.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('RGD-HDL', 'Var', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
396622	26166537	Figure 3D), mesoporous silica particles (MSN) were loaded with the NIRF ZW800, and upon the injection of ZW800-MSN into the footpad of mice bearing metastatic 4T1 tumors, 2D FRI was performed at several times points post i.v.	('ZW800-MSN', 'Var', (105, 114))	('NIRF', 'Chemical', '-', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('mice', 'Species', '10090', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('silica', 'Chemical', 'MESH:D012822', (23, 29))
396638	26166537	To provide proof-of-principle for this, analogous to the efforts mentioned above, pHPMA-Dy750 was administered to CT26 tumor-bearing mice, CT and FMT scans were performed at several different time points p.i., and the CT images were subsequently fused with the respective FMT signals, to obtain fused CT-FMT images.	('tumor', 'Disease', (119, 124))	('mice', 'Species', '10090', (133, 137))	('Dy750', 'Chemical', '-', (88, 93))	('CT-FMT', 'Chemical', '-', (301, 307))	('pHPMA-Dy750', 'Var', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CT26', 'CellLine', 'CVCL:7254', (114, 118))
396639	26166537	In line with the kinetics of EPR-mediated tumor targeting, the tumor accumulation of pHPMA-Dy750 was very low at 1 h p.i., but very prominent at 72 h (as shown by the circles in the left panel of Figure 11C).	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (42, 47))	('11C', 'Chemical', 'MESH:C000615233', (203, 206))	('pHPMA-Dy750', 'Var', (85, 96))	('low', 'NegReg', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Dy750', 'Chemical', '-', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
396659	26166537	The efficacy and specificity of gene silencing were analyzed at 48 h p.i., showing that MN-NIRF-siGFP substantially suppressed GFP expression in GFP-transfected tumors, but did not affect RFP-transfected tumors (lower left panels in Figure 12B).	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('suppressed', 'NegReg', (116, 126))	('tumors', 'Disease', (161, 167))	('NIRF', 'Chemical', '-', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('GFP', 'Protein', (127, 130))	('MN-NIRF-siGFP', 'Var', (88, 101))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('RFP-transfected tumors', 'Disease', (188, 210))	('expression', 'MPA', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('RFP-transfected tumors', 'Disease', 'MESH:D009369', (188, 210))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('MN', 'CellLine', 'CVCL:U508', (88, 90))
396660	26166537	These findings were validated using ex vivo OI, confirming not only significant tumor accumulation of MN-NIRF-siGFP (independent of tumor type; right panels in Figure 12A), but also effective and selective GFP silencing (dependent of tumor type; right panels in Figure 12B).	('MN', 'CellLine', 'CVCL:U508', (102, 104))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('NIRF', 'Chemical', '-', (105, 109))	('GFP', 'MPA', (206, 209))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (80, 85))	('MN-NIRF-siGFP', 'Var', (102, 115))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('silencing', 'NegReg', (210, 219))
396663	26166537	Effective transfection of (tumor) cells with luciferase enables the local activation of luciferin (which is co-injected intraperitoneally), generating a luminescent signal which can be sensitively detected using BLI-based OI.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('luciferase', 'Gene', (45, 55))	('luciferin', 'Enzyme', (88, 97))	('tumor', 'Disease', (27, 32))	('activation', 'PosReg', (74, 84))	('luminescent signal', 'MPA', (153, 171))	('transfection', 'Var', (10, 22))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('rat', 'Species', '10116', (144, 147))
396666	26166537	injected L-PEI resulted in very high transgene expression levels in the lungs of mice, whereas the luminescent signal generated in tumors was relatively low.	('L-PEI', 'Var', (9, 14))	('mice', 'Species', '10090', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('transgene expression levels', 'MPA', (37, 64))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('rat', 'Species', '10116', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
396667	26166537	G5-PAMAM-dendrimers, on the other hand, resulted in much lower levels of off-target gene expression in the lung, and in much higher levels of gene expression in tumors.	('levels', 'MPA', (63, 69))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('G5-PAMAM', 'Chemical', '-', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('G5-PAMAM-dendrimers', 'Var', (0, 19))	('levels of gene expression', 'MPA', (132, 157))	('higher', 'PosReg', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('lower', 'NegReg', (57, 62))
396694	26166537	Upon US-mediated MB oscillation and destruction, acoustic forces and microjets are generated, resulting in the loosening of the endothelial lining and/or the permeation of cellular membranes, thereby facilitating the transport of drugs (and contrast agents) from the intravascular compartment into the interstitial and/or intracellular compartment.	('facilitating', 'PosReg', (200, 212))	('permeation', 'MPA', (158, 168))	('loosening', 'CPA', (111, 120))	('destruction', 'Var', (36, 47))	('transport of drugs', 'MPA', (217, 235))	('rat', 'Species', '10116', (87, 90))
396774	33489215	Presence of a CD99 + small round blue cell tumor and detection of an EWSR1 rearrangement at 22q12 in 84% of cells via FISH testing are consistent with diagnosis of recurrent Ewing's sarcoma.	('CD99', 'Gene', '4267', (14, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('EWSR1', 'Gene', (69, 74))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (174, 189))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('rearrangement at', 'Var', (75, 91))	('EWSR1', 'Gene', '2130', (69, 74))	('CD99', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (174, 189))	('tumor', 'Disease', (43, 48))	("Ewing's sarcoma", 'Disease', (174, 189))
396786	33489215	Studies have shown that the t(11;22)(q24;q12) translocation is found in about 85% of Ewing's sarcoma, which leads to an EWS/FLI1 fusion gene but more studies have to be done to further understand the significance.	("Ewing's sarcoma", 'Disease', (85, 100))	('fusion', 'Var', (129, 135))	('FLI1', 'Gene', '2313', (124, 128))	('FLI1', 'Gene', (124, 128))	('t(11;22)(q24;q12', 'Var', (28, 44))	('leads to', 'Reg', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (28, 45))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (85, 100))	('EWS', 'Gene', '2130', (120, 123))	('EWS', 'Gene', (120, 123))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (85, 100))
396824	29623567	Fluorescence in situ hybridization (FISH) analysis identified rearrangement of EWSR1 (22q12) gene and targeted next generation sequencing revealed characteristic EWSR1 - ATF1 fusion.	('EWSR1', 'Gene', (79, 84))	('fusion', 'Var', (175, 181))	('EWSR1', 'Gene', (162, 167))	('EWSR1', 'Gene', '2130', (79, 84))	('rearrangement', 'Var', (62, 75))	('ATF1', 'Gene', (170, 174))	('ATF1', 'Gene', '466', (170, 174))	('EWSR1', 'Gene', '2130', (162, 167))
396830	29623567	The small intestine proximal to the lesion was fluid-filled and dilated, consistent with obstruction.	('obstruction', 'Disease', 'MESH:D000402', (89, 100))	('obstruction', 'Disease', (89, 100))	('lesion', 'Var', (36, 42))
396838	29623567	Fluorescence in situ hybridization (FISH) analysis detected rearrangement of EWSR1 (22q12) gene in 82% of the cells (Fig.	('rearrangement', 'Var', (60, 73))	('EWSR1', 'Gene', (77, 82))	('EWSR1', 'Gene', '2130', (77, 82))
396852	29623567	More importantly, most CCSLGTs have been found to harbor EWSR1-CREB1 fusions or EWSR1-ATF1 fusions, the latter are also associated with conventional clear cell sarcoma of soft tissue.	('CREB1', 'Gene', (63, 68))	('clear cell sarcoma', 'Disease', (149, 167))	('associated', 'Reg', (120, 130))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (149, 167))	('EWSR1', 'Gene', (80, 85))	('fusions', 'Var', (91, 98))	('ATF1', 'Gene', (86, 90))	('CREB1', 'Gene', '1385', (63, 68))	('ATF1', 'Gene', '466', (86, 90))	('EWSR1', 'Gene', (57, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('CCSLGTs', 'Disease', (23, 30))	('EWSR1', 'Gene', '2130', (80, 85))	('EWSR1', 'Gene', '2130', (57, 62))	('fusions', 'Var', (69, 76))
396857	29623567	These two tumors are distinct entities at genetic level as CCSLGT are characterized by EWSR1 rearrangements, in contrast malignant melanomas usually have BRAF mutations.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('malignant melanomas', 'Disease', 'MESH:D008545', (121, 140))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('CCSLGT', 'Disease', (59, 65))	('EWSR1', 'Gene', (87, 92))	('malignant melanomas', 'Disease', (121, 140))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('rearrangements', 'Var', (93, 107))	('BRAF', 'Gene', '673', (154, 158))	('EWSR1', 'Gene', '2130', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('BRAF', 'Gene', (154, 158))	('malignant melanomas', 'Phenotype', 'HP:0002861', (121, 140))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))
396860	29623567	Other differential diagnoses including poorly differentiated neuroendocrine carcinoma (no cytokeratin and neuroendocrine marker expression), gastrointestinal stromal tumor (no CD117, DOG-1 expression), leiomyosarcoma (no smooth muscle marker expression), synovial sarcoma (no cytokeratin or CD99 expression), and malignant peripheral nerve sheet tumor (no diffuse and strong S100 expression) were also ruled out based on the results of additional immunohistochemical work-up.	('gastrointestinal stromal tumor', 'Disease', (141, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('CD117', 'Gene', (176, 181))	('synovial sarcoma', 'Disease', (255, 271))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (61, 85))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (202, 216))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (202, 216))	('synovial sarcoma', 'Disease', 'MESH:D013584', (255, 271))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (61, 85))	('CD99', 'Gene', '609832', (291, 295))	('malignant peripheral nerve', 'Phenotype', 'HP:0100697', (313, 339))	('no', 'Var', (173, 175))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('S100', 'Gene', (375, 379))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (255, 271))	('S100', 'Gene', '6271', (375, 379))	('tumor', 'Disease', (166, 171))	('leiomyosarcoma', 'Disease', (202, 216))	('neuroendocrine carcinoma', 'Disease', (61, 85))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (141, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('CD117', 'Gene', '3815', (176, 181))	('CD99', 'Gene', (291, 295))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (141, 171))	('tumor', 'Disease', (346, 351))
396862	29623567	Moreover, FISH analysis revealed characteristic EWSR1 rearrangement in our case, confirming the diagnosis of CCSLGT.	('EWSR1', 'Gene', (48, 53))	('CCSLGT', 'Disease', (109, 115))	('rearrangement', 'Var', (54, 67))	('EWSR1', 'Gene', '2130', (48, 53))
396890	31200868	While Helicobacter pylori is associated with developing MALT lymphoma in the stomach, no conclusive organism has been identified for pulmonary MALT lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('Helicobacter pylori', 'Species', '210', (6, 25))	('MALT lymphoma', 'Disease', 'MESH:D018442', (56, 69))	('pulmonary MALT lymphoma', 'Phenotype', 'HP:0011953', (133, 156))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('pulmonary MALT lymphoma', 'Disease', 'MESH:D018442', (133, 156))	('pulmonary MALT lymphoma', 'Disease', (133, 156))	('MALT lymphoma', 'Disease', (56, 69))	('MALT lymphoma', 'Disease', 'MESH:D018442', (143, 156))	('Helicobacter pylori', 'Var', (6, 25))	('associated with', 'Reg', (29, 44))
396895	31200868	Possible mechanisms for developing lymphoma include antigenic stimulation and underlying genetic causes, such as translocations.	('lymphoma', 'Disease', (35, 43))	('lymphoma', 'Disease', 'MESH:D008223', (35, 43))	('translocations', 'Var', (113, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (35, 43))
397079	29463038	Presence of TERT Promoter Mutations is a Secondary Event and Associates with Elongated Telomere Length in Myxoid Liposarcomas The occurrence of TERT promoter mutations has been well described in soft tissue sarcomas (STS).	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (195, 215))	('Elongated', 'PosReg', (77, 86))	('Myxoid Liposarcomas', 'Disease', (106, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('Liposarcomas', 'Phenotype', 'HP:0012034', (113, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('Mutations', 'Var', (26, 35))	('Elongated Telomere Length', 'Phenotype', 'HP:0031413', (77, 102))	('Myxoid Liposarcomas', 'Phenotype', 'HP:0012268', (106, 125))	('TERT', 'Gene', (12, 16))	('TERT', 'Gene', '7015', (12, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (195, 214))	('STS', 'Phenotype', 'HP:0030448', (217, 220))	('soft tissue sarcomas', 'Disease', (195, 215))	('TERT', 'Gene', (144, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (207, 215))	('TERT', 'Gene', '7015', (144, 148))	('Myxoid Liposarcomas', 'Disease', 'MESH:D018208', (106, 125))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (195, 215))	('Telomere Length', 'MPA', (87, 102))
397080	29463038	We analyzed 116 patient samples diagnosed with 22 distinct histological subtypes of bone and STS for the occurrence of TERT promoter mutations by Sanger sequencing.	('STS', 'Phenotype', 'HP:0030448', (93, 96))	('TERT', 'Gene', (119, 123))	('TERT', 'Gene', '7015', (119, 123))	('mutations', 'Var', (133, 142))	('patient', 'Species', '9606', (16, 23))
397082	29463038	Except for one chondrosarcoma case harboring a C250T mutation, all other mutations were detected at location C228T.	('C250T', 'Var', (47, 52))	('C250T', 'Mutation', 'c.250C>T', (47, 52))	('chondrosarcoma', 'Disease', 'MESH:D002813', (15, 29))	('C228T', 'Mutation', 'rs779695088', (109, 114))	('chondrosarcoma', 'Disease', (15, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (15, 29))
397085	29463038	Based on the frequency of TERT promoter mutations and the elongated telomere length in mutated compared to wildtype MLS, we hypothesize that occurrence of TERT promoter mutations has a pivotal role in the disease progression as a secondary genetic event at a time when tumor cells face the need for telomere elongation to allow further proliferation.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('TERT', 'Gene', (26, 30))	('MLS', 'Disease', 'MESH:C537466', (116, 119))	('mutations', 'Var', (169, 178))	('MLS', 'Disease', (116, 119))	('MLS', 'Phenotype', 'HP:0012268', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('TERT', 'Gene', '7015', (26, 30))	('tumor', 'Disease', (269, 274))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', '7015', (155, 159))	('elongated telomere length', 'Phenotype', 'HP:0031413', (58, 83))
397090	29463038	Recently, two highly recurrent mutations in the promoter region of TERT (c.-124 C>T and c.-146 C>T), also called C228T and C250T, respectively were described in 71% of all melanomas.	('TERT', 'Gene', (67, 71))	('described', 'Reg', (148, 157))	('TERT', 'Gene', '7015', (67, 71))	('melanomas', 'Disease', 'MESH:D008545', (172, 181))	('C250T', 'Var', (123, 128))	('c.-146 C>T', 'Mutation', 'c.-146C>T', (88, 98))	('C250T', 'Mutation', 'c.250C>T', (123, 128))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('c.-146 C>T', 'Var', (88, 98))	('melanomas', 'Disease', (172, 181))	('c.-124 C>T', 'Mutation', 'rs1242535815', (73, 83))	('C228T', 'Mutation', 'rs779695088', (113, 118))	('C228T', 'Var', (113, 118))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))
397091	29463038	In follow up studies, these mutations were reported to be, overall, the most prevalent somatic point mutations being present at varying frequencies in over 50 different types of cancers.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Disease', (178, 185))	('mutations', 'Var', (28, 37))	('point', 'Var', (95, 100))
397092	29463038	Of note, both the C228T and the C250T mutation are typically heterozygous, mutually exclusive, and both create the identical 11bp sequence (i.e., "CCCGGAAGGGG") that has substantial similarity to an ETS binding motif representing a de-novo binding site for an activating ETS family transcription factor.	('C250T', 'Mutation', 'c.250C>T', (32, 37))	('C228T', 'Var', (18, 23))	('C228T', 'Mutation', 'rs779695088', (18, 23))	('C250T', 'Var', (32, 37))
397093	29463038	Both mutations activate TERT promoter activity and TERT gene transcription functionally resulting in in vitro telomere elongation.	('TERT', 'Gene', (51, 55))	('TERT', 'Gene', (24, 28))	('telomere elongation', 'CPA', (110, 129))	('mutations', 'Var', (5, 14))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', '7015', (24, 28))	('activate', 'PosReg', (15, 23))	('transcription', 'MPA', (61, 74))	('resulting in', 'Reg', (88, 100))
397095	29463038	Genomic alterations including chromosomal translocations, DNA copy number variations and the presence of typical genetic aberrations are hallmarks of certain subtypes of sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (170, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('DNA copy number variations', 'Var', (58, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('chromosomal', 'CPA', (30, 41))	('sarcomas', 'Disease', (170, 178))
397097	29463038	In 95% of the cases, MLSs share the reciprocal translocation t(12;16)(q13; p11).	('MLS', 'Disease', (21, 24))	('MLS', 'Disease', 'MESH:C537466', (21, 24))	('t(12;16)(q13; p11', 'Var', (61, 78))	('MLS', 'Phenotype', 'HP:0012268', (21, 24))
397103	29463038	Based on the oncogenic potential and respective mouse models, the occurrence of t(12;16)(q13; p11) translocation is generally expected to be the first event in sarcoma initiation in MLS.	('MLS', 'Disease', 'MESH:C537466', (182, 185))	('sarcoma initiation', 'Disease', (160, 178))	('MLS', 'Disease', (182, 185))	('mouse', 'Species', '10090', (48, 53))	('MLS', 'Phenotype', 'HP:0012268', (182, 185))	('sarcoma initiation', 'Disease', 'MESH:D012509', (160, 178))	('t(12', 'Var', (80, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))
397105	29463038	These include the introduction of telomere length as a prognosis marker in Ewig sarcoma, the association of telomere length of peripheral blood leukocytes with increased risk for soft tissue sarcoma, telomere length in complex and simple karyotype sarcomas, assessment of ALT in sarcoma, mosaicism of telomere maintenance mechanisms in sarcomas and the frequency of TERT promoter mutations in sarcomas.	('soft tissue sarcoma', 'Disease', (179, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('sarcoma', 'Disease', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('sarcoma', 'Disease', 'MESH:D012509', (393, 400))	('sarcoma', 'Disease', (393, 400))	('Ewig sarcoma', 'Disease', (75, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcomas', 'Disease', 'MESH:D012509', (393, 401))	('sarcomas', 'Phenotype', 'HP:0100242', (393, 401))	('sarcoma', 'Disease', 'MESH:D012509', (336, 343))	('sarcomas', 'Disease', 'MESH:D012509', (336, 344))	('sarcoma', 'Disease', 'MESH:D012509', (279, 286))	('sarcoma', 'Disease', (336, 343))	('mosaicism', 'Var', (288, 297))	('sarcoma', 'Disease', 'MESH:D012509', (248, 255))	('sarcomas', 'Disease', (393, 401))	('sarcomas', 'Phenotype', 'HP:0100242', (336, 344))	('sarcomas', 'Disease', 'MESH:D012509', (248, 256))	('sarcoma', 'Disease', (279, 286))	('TERT', 'Gene', (366, 370))	('sarcomas', 'Phenotype', 'HP:0100242', (248, 256))	('sarcomas', 'Disease', (336, 344))	('sarcoma', 'Disease', 'MESH:D012509', (191, 198))	('sarcoma', 'Disease', (248, 255))	('sarcoma', 'Disease', (191, 198))	('TERT', 'Gene', '7015', (366, 370))	('Ewig sarcoma', 'Phenotype', 'HP:0012254', (75, 87))	('sarcomas', 'Disease', (248, 256))	('Ewig sarcoma', 'Disease', 'MESH:D012509', (75, 87))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (179, 198))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (179, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))
397107	29463038	The aim of our study was first to investigate the prevalence of TERT promoter mutations in the different sarcoma subtypes and second to analyze the relation between presence of TERT promoter mutations and telomere lengths in a specific subtype of sarcomas, the MLSs.	('TERT', 'Gene', (64, 68))	('TERT', 'Gene', '7015', (64, 68))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (105, 121))	('sarcomas', 'Disease', (247, 255))	('TERT', 'Gene', '7015', (177, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('MLS', 'Disease', 'MESH:C537466', (261, 264))	('sarcoma subtypes', 'Disease', (105, 121))	('MLS', 'Disease', (261, 264))	('mutations', 'Var', (78, 87))	('MLS', 'Phenotype', 'HP:0012268', (261, 264))	('sarcomas', 'Disease', 'MESH:D012509', (247, 255))	('sarcomas', 'Phenotype', 'HP:0100242', (247, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (247, 254))	('TERT', 'Gene', (177, 181))
397108	29463038	First, we analyzed for the incidence of TERT promoter mutations in 116 bone and STS tumors of 22 different subtypes (Table 1).	('TERT', 'Gene', '7015', (40, 44))	('STS', 'Phenotype', 'HP:0030448', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutations', 'Var', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('TERT', 'Gene', (40, 44))
397109	29463038	We found mutations in 11/116 patients (9.5%), namely in four cases of MLS, one solitary fibrous tumor (SFT), two malignant fibrous histiocytomas (MFH) or undifferentiated pleomorphic sarcoma (UPS), one pleomorphic sarcoma, one poorly differentiated sarcoma NOS and two chondrosarcomas (Figure 1; Table 2).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('sarcoma', 'Disease', 'MESH:D012509', (214, 221))	('mutations', 'Var', (9, 18))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (171, 190))	('sarcoma', 'Disease', 'MESH:D012509', (276, 283))	('fibrous tumor', 'Disease', 'MESH:D054364', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('sarcoma', 'Disease', (276, 283))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (202, 221))	('sarcomas', 'Phenotype', 'HP:0100242', (276, 284))	('sarcoma', 'Disease', (214, 221))	('chondrosarcomas', 'Disease', (269, 284))	('undifferentiated pleomorphic sarcoma', 'Disease', (154, 190))	('patients', 'Species', '9606', (29, 37))	('fibrous tumor', 'Disease', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('pleomorphic sarcoma', 'Disease', (202, 221))	('sarcoma', 'Disease', 'MESH:D012509', (249, 256))	('sarcoma', 'Disease', (249, 256))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (269, 283))	('MLS', 'Phenotype', 'HP:0012268', (70, 73))	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (269, 284))	('sarcoma', 'Disease', (183, 190))	('chondrosarcomas', 'Disease', 'MESH:D002813', (269, 284))	('MLS', 'Disease', 'MESH:C537466', (70, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('MLS', 'Disease', (70, 73))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (154, 190))
397110	29463038	Of note, 10 out of 11 (91%) mutations found were C228T and only in one patient with chondrosarcoma we observed a TERT promoter mutation at position C250T (Table 3).	('TERT', 'Gene', '7015', (113, 117))	('C228T', 'Var', (49, 54))	('C228T', 'Mutation', 'rs779695088', (49, 54))	('chondrosarcoma', 'Disease', 'MESH:D002813', (84, 98))	('chondrosarcoma', 'Disease', (84, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('C250T', 'Mutation', 'c.250C>T', (148, 153))	('patient', 'Species', '9606', (71, 78))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (84, 98))	('TERT', 'Gene', (113, 117))
397114	29463038	Patients with histopathological G1 grading/well-differentiated tumors showed significant higher percentage of TERT promoter mutations (5/21, 24%) compared to patients with G2-3 grading/poor differentiation (6/92, 7%, p = 0.030, see Table 2).	('mutations', 'Var', (124, 133))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Patients', 'Species', '9606', (0, 8))	('TERT', 'Gene', (110, 114))	('tumors', 'Disease', (63, 69))	('TERT', 'Gene', '7015', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
397119	29463038	Interestingly, telomere length of MLS samples with TERT promoter mutations was found to be significantly less shortened (8.10 +- 0.50 kb; n = 4) compared to the telomere length of wildtype tumors (6.61 +- 1.06 kb; n = 5; p < 0.037) (Figure 2A-C).	('MLS', 'Disease', 'MESH:C537466', (34, 37))	('MLS', 'Disease', (34, 37))	('TERT', 'Gene', (51, 55))	('MLS', 'Phenotype', 'HP:0012268', (34, 37))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('wildtype tumors', 'Disease', (180, 195))	('TERT', 'Gene', '7015', (51, 55))	('less shortened', 'NegReg', (105, 119))	('telomere length', 'CPA', (15, 30))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('wildtype tumors', 'Disease', 'MESH:D009369', (180, 195))	('mutations', 'Var', (65, 74))
397123	29463038	We report the prevalence of TERT promoter mutations (overall incidence near to 9.5%) to vary widely among different bone and STS subtypes (ranging from 0-44%), with the highest mutation frequency found within MLS subgroup (44% harboring a C228T mutation at the promoter region of the TERT gene).	('MLS', 'Disease', 'MESH:C537466', (209, 212))	('to 9', 'Species', '1214577', (76, 80))	('MLS', 'Disease', (209, 212))	('TERT', 'Gene', (284, 288))	('TERT', 'Gene', '7015', (284, 288))	('STS', 'Phenotype', 'HP:0030448', (125, 128))	('MLS', 'Phenotype', 'HP:0012268', (209, 212))	('C228T', 'Mutation', 'rs779695088', (239, 244))	('TERT', 'Gene', (28, 32))	('C228T', 'Var', (239, 244))	('TERT', 'Gene', '7015', (28, 32))	('mutations', 'Var', (42, 51))
397124	29463038	The two existing mutations C228T and C250T were found to be mutually exclusive in every case.	('C228T', 'Mutation', 'rs779695088', (27, 32))	('C228T', 'Var', (27, 32))	('C250T', 'Var', (37, 42))	('C250T', 'Mutation', 'c.250C>T', (37, 42))
397125	29463038	Our results add value to previous studies on smaller cohorts or limited number of sarcoma subtypes, as those same hotspot mutations have also previously been characterized as recurrent in MLS but rather uncommon in other subtypes (Table 1).	('MLS', 'Disease', 'MESH:C537466', (188, 191))	('MLS', 'Disease', (188, 191))	('MLS', 'Phenotype', 'HP:0012268', (188, 191))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (82, 98))	('sarcoma subtypes', 'Disease', (82, 98))	('mutations', 'Var', (122, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
397127	29463038	Of note, the C228T is the predominant mutation found in our sarcoma cohort similar to the results of previous studies.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('C228T', 'Mutation', 'rs779695088', (13, 18))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('C228T', 'Var', (13, 18))
397128	29463038	Yet, we describe the first case of a C250T TERT promoter mutation in a chondrosarcoma, after Killela et al.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (71, 85))	('TERT', 'Gene', (43, 47))	('TERT', 'Gene', '7015', (43, 47))	('chondrosarcoma', 'Disease', (71, 85))	('chondrosarcoma', 'Disease', 'MESH:D002813', (71, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('C250T', 'Var', (37, 42))	('C250T', 'Mutation', 'c.250C>T', (37, 42))
397129	29463038	TERT promoter mutations occur mainly in tumors that are derived from tissues with low rates of self-renewal.	('occur', 'Reg', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', (40, 46))
397131	29463038	The high frequency of TERT promoter mutations in just two nucleotide positions strongly suggests a possible role as drivers, i.e., primary or secondary events in tumor pathogenesis.	('TERT', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('TERT', 'Gene', '7015', (22, 26))	('tumor', 'Disease', (162, 167))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
397132	29463038	have indeed shown that TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by critical telomere shortening without additional tumor-selected mutations.	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('telomere shortening', 'Phenotype', 'HP:0031413', (120, 139))	('tumor', 'Disease', (159, 164))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
397133	29463038	In addition, some studies suggest TERT promoter mutations are among the earliest genetic events in bladder cancer, thyroid carcinoma, cutaneous melanoma, basal cell and squamous cell carcinoma and oligodendroglioma.	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 192))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('cutaneous melanoma', 'Disease', (134, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (134, 152))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (115, 132))	('mutations', 'Var', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('thyroid carcinoma', 'Disease', (115, 132))	('squamous cell carcinoma', 'Disease', (169, 192))	('TERT', 'Gene', (34, 38))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (115, 132))	('TERT', 'Gene', '7015', (34, 38))	('oligodendroglioma', 'Disease', 'MESH:D009837', (197, 214))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('bladder cancer', 'Disease', (99, 113))	('oligodendroglioma', 'Disease', (197, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
397136	29463038	Therefore, we used MLS as an ideal model to study telomere lenght in sarcoma as this sarcoma subtype is not only characterized by a typical initial oncogenic driver translocation, i.e., the t(12;16)(q13; p11), but also by a substantially higher incidence of TERT promoter mutations compared to other sarcomas subtypes.	('MLS', 'Disease', (19, 22))	('t(12;16)(q13; p11', 'Var', (190, 207))	('sarcoma', 'Disease', 'MESH:D012509', (300, 307))	('sarcomas', 'Disease', 'MESH:D012509', (300, 308))	('MLS', 'Phenotype', 'HP:0012268', (19, 22))	('sarcoma', 'Disease', (69, 76))	('sarcoma', 'Disease', (300, 307))	('sarcomas', 'Phenotype', 'HP:0100242', (300, 308))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (300, 307))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('TERT', 'Gene', (258, 262))	('sarcomas', 'Disease', (300, 308))	('TERT', 'Gene', '7015', (258, 262))	('sarcoma', 'Disease', (85, 92))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('MLS', 'Disease', 'MESH:C537466', (19, 22))
397137	29463038	Our telomere analysis on MLS histopathological slides revealed significantly less shortened telomeres in MLS with TERT promoter mutations compared to wildtype tumors after age matching.	('MLS', 'Phenotype', 'HP:0012268', (105, 108))	('wildtype tumors', 'Disease', 'MESH:D009369', (150, 165))	('TERT', 'Gene', '7015', (114, 118))	('MLS', 'Disease', 'MESH:C537466', (25, 28))	('mutations', 'Var', (128, 137))	('MLS', 'Disease', (25, 28))	('MLS', 'Phenotype', 'HP:0012268', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('less shortened', 'NegReg', (77, 91))	('shortened telomeres', 'Phenotype', 'HP:0031413', (82, 101))	('MLS', 'Disease', 'MESH:C537466', (105, 108))	('MLS', 'Disease', (105, 108))	('wildtype tumors', 'Disease', (150, 165))	('TERT', 'Gene', (114, 118))
397138	29463038	Of note, the telomere length of wildtype tumor was close to the range where telomeres become critically short (known to be near 3-5 kb) as e.g., similar to the telomere length of patients with dyskeratosis congenita, a disease characterized by mutations within the telomerase complex.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('dyskeratosis congenita', 'Disease', (193, 215))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (193, 215))	('patients', 'Species', '9606', (179, 187))	('mutations', 'Var', (244, 253))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
397140	29463038	One explanation for our observations might be the upregulation of telomerase activity by frequently occurring TERT promoter mutations leading to telomere elongation/maintenance in TERT promoter-mutated tumors.	('mutations', 'Var', (124, 133))	('telomere', 'MPA', (145, 153))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('upregulation', 'PosReg', (50, 62))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('activity', 'MPA', (77, 85))	('TERT', 'Gene', (180, 184))	('TERT', 'Gene', '7015', (180, 184))	('telomerase', 'Enzyme', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
397144	29463038	However, the high incidence of TERT promoter mutations in MLS implies that C/EBP has no major role in telomerase regulation and telomere maintenance.	('C/EBP', 'Gene', (75, 80))	('mutations', 'Var', (45, 54))	('MLS', 'Disease', 'MESH:C537466', (58, 61))	('MLS', 'Disease', (58, 61))	('MLS', 'Phenotype', 'HP:0012268', (58, 61))	('C/EBP', 'Gene', '1050', (75, 80))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))
397149	29463038	Based on our experimental data, we propose that the acquisition of TERT promoter mutations is a secondary event in disease progression of MLS required to protect MLS cells from growth arrest due to replication-induced critically short telomeres (see proposed model in Figure S2) Although is it evident that TERT promoter mutation status and telomere regulation is variable and complex among different cancers types, particularly due to the variety related to tumor cell origin, tumor subtype, our proposed model is further substantiated by others studies.	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('MLS', 'Disease', 'MESH:C537466', (138, 141))	('growth arrest', 'Phenotype', 'HP:0001510', (177, 190))	('MLS', 'Disease', (138, 141))	('MLS', 'Disease', 'MESH:C537466', (162, 165))	('MLS', 'Disease', (162, 165))	('TERT', 'Gene', (307, 311))	('mutations', 'Var', (81, 90))	('TERT', 'Gene', '7015', (307, 311))	('growth arrest', 'Disease', 'MESH:D006323', (177, 190))	('tumor', 'Disease', (478, 483))	('cancers', 'Disease', 'MESH:D009369', (401, 408))	('tumor', 'Disease', 'MESH:D009369', (478, 483))	('TERT', 'Gene', (67, 71))	('growth arrest', 'Disease', (177, 190))	('TERT', 'Gene', '7015', (67, 71))	('tumor', 'Disease', (459, 464))	('cancer', 'Phenotype', 'HP:0002664', (401, 407))	('tumor', 'Phenotype', 'HP:0002664', (478, 483))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('cancers', 'Phenotype', 'HP:0002664', (401, 408))	('short telomeres', 'Phenotype', 'HP:0031413', (229, 244))	('cancers', 'Disease', (401, 408))	('MLS', 'Phenotype', 'HP:0012268', (138, 141))	('MLS', 'Phenotype', 'HP:0012268', (162, 165))
397150	29463038	In follicular and atypical thyroid adenoma as well as gliomas, TERT promoter mutations lead to significantly increased telomerase activity explaining longer telomeres observed in our cohort of mutated MLS.	('atypical thyroid adenoma', 'Phenotype', 'HP:0011778', (18, 42))	('longer', 'PosReg', (150, 156))	('thyroid adenoma', 'Disease', (27, 42))	('follicular', 'Disease', (3, 13))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('MLS', 'Phenotype', 'HP:0012268', (201, 204))	('TERT', 'Gene', (63, 67))	('mutations', 'Var', (77, 86))	('telomerase activity', 'MPA', (119, 138))	('MLS', 'Disease', (201, 204))	('thyroid adenoma', 'Disease', 'MESH:D013964', (27, 42))	('TERT', 'Gene', '7015', (63, 67))	('MLS', 'Disease', 'MESH:C537466', (201, 204))	('increased', 'PosReg', (109, 118))	('thyroid adenoma', 'Phenotype', 'HP:0000854', (27, 42))	('atypical thyroid', 'Phenotype', 'HP:0100028', (18, 34))
397152	29463038	TERT promoter mutations alone have been linked with worse prognosis in various tumor entities such as melanoma, glioblastoma multiforme, medulloblastoma, urogenital cancer, laryngeal tumors, and with larger tumors and lymph node metastasis in the case of conventional papillary thyroid carcinomas.	('papillary thyroid carcinomas', 'Disease', (268, 296))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (268, 296))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('urogenital cancer', 'Disease', (154, 171))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (278, 296))	('tumors', 'Disease', (207, 213))	('laryngeal tumors', 'Disease', 'MESH:D007822', (173, 189))	('tumors', 'Disease', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('carcinomas', 'Phenotype', 'HP:0030731', (286, 296))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (268, 296))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('laryngeal tumors', 'Disease', (173, 189))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (173, 189))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (207, 212))	('glioblastoma multiforme', 'Disease', (112, 135))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('medulloblastoma', 'Disease', 'MESH:D008527', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('medulloblastoma', 'Phenotype', 'HP:0002885', (137, 152))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (112, 135))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('medulloblastoma', 'Disease', (137, 152))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('urogenital cancer', 'Disease', 'MESH:D014565', (154, 171))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (278, 295))
397154	29463038	Based on the role of TERT promoter mutations in other tumor entities and the perception that its occurrence is a secondary event in MLS, it is tempting to see clinical similarities between MLS and e.g., gliomas.	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('TERT', 'Gene', (21, 25))	('MLS', 'Disease', 'MESH:C537466', (189, 192))	('MLS', 'Disease', (189, 192))	('TERT', 'Gene', '7015', (21, 25))	('MLS', 'Phenotype', 'HP:0012268', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('MLS', 'Disease', 'MESH:C537466', (132, 135))	('MLS', 'Disease', (132, 135))	('tumor', 'Disease', (54, 59))	('MLS', 'Phenotype', 'HP:0012268', (132, 135))	('gliomas', 'Disease', (203, 210))	('mutations', 'Var', (35, 44))
397156	29463038	In summary, we observed that in a subset of MLS patients, TERT promoter mutations likely occur as a secondary event in a setting of critically short telomere length, most likely reflecting a compensatory mechanism that allows telomeres to elongate/maintain.	('MLS', 'Disease', (44, 47))	('occur', 'Reg', (89, 94))	('mutations', 'Var', (72, 81))	('MLS', 'Phenotype', 'HP:0012268', (44, 47))	('TERT', 'Gene', (58, 62))	('short telomere length', 'Phenotype', 'HP:0031413', (143, 164))	('TERT', 'Gene', '7015', (58, 62))	('patients', 'Species', '9606', (48, 56))	('MLS', 'Disease', 'MESH:C537466', (44, 47))
397165	29463038	Briefly, 150 ng of DNA template in a total volume of 50 microL were used, 2.5 U/reaction Taq Biotherm DNA polymerase (Genecraft, Koln, Germany) were used and cycling conditions included initial denaturation at 94  C for 120 s, followed by 35 cycles with denaturation at 94  C for 60 s, annealing at 60  C for 30 s and extension at 72  C for 30 s. PCR primers amplifying a fragment of the hTERT promoter region containing the sites of the c.-124 C>T (C228T) and c.-146 C>T (C250T) mutations were used to screen for mutations.	('c.-146 C>T', 'Mutation', 'c.-146C>T', (461, 471))	('hTERT', 'Gene', (388, 393))	('C250T', 'Mutation', 'c.250C>T', (473, 478))	('c.-124 C>T (C228T', 'Var', (438, 455))	('C228T', 'Mutation', 'rs779695088', (450, 455))	('c.-146 C>T (C250T', 'Var', (461, 478))	('c.-124 C>T', 'Mutation', 'rs1242535815', (438, 448))	('hTERT', 'Gene', '7015', (388, 393))
397180	26430669	Electronic morcellation during laparoscopic surgery in women with LGESS can result in iatrogenic intraabdominal dissemination and a poorer prognosis.	('women', 'Species', '9606', (55, 60))	('iatrogenic intraabdominal dissemination', 'Disease', 'MESH:D007049', (86, 125))	('Electronic morcellation', 'Var', (0, 23))	('result in', 'Reg', (76, 85))	('iatrogenic intraabdominal dissemination', 'Disease', (86, 125))
397191	26430669	Although CT and PET-CT showed no evidence of a metastatic tumor, we still recommended surgical reexploration due to the fact that electronic morcellation during surgery may have caused abdominopelvic dissemination of tumor cells.	('electronic morcellation', 'Var', (130, 153))	('caused', 'Reg', (178, 184))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('abdominopelvic dissemination of tumor', 'Disease', 'MESH:D009103', (185, 222))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('abdominopelvic dissemination of tumor', 'Disease', (185, 222))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (217, 222))
397298	20606682	SU5402, PD98059, LY294002, U-73122, a Rac1 inhibitor (NSC23766), and rapamycin were purchased from Calbiochem (San Diego, CA, USA).	('PD98059', 'Chemical', 'MESH:C093973', (8, 15))	('LY294002', 'Var', (17, 25))	('U-73122', 'Chemical', 'MESH:C060229', (27, 34))	('SU5402', 'Chemical', 'MESH:C105686', (0, 6))	('LY294002', 'Chemical', 'MESH:C085911', (17, 25))	('Rac1', 'Gene', (38, 42))	('Rac1', 'Gene', '5879', (38, 42))	('SU5402', 'Var', (0, 6))	('PD98059', 'Var', (8, 15))	('rapamycin', 'Chemical', 'MESH:D020123', (69, 78))
397363	20606682	The wound-healing assay (Figure 2D) and chemotaxis assay (Figure 2E) both showed that bFGF-induced motility of RD-ES cells was significantly suppressed by SU5402, confirming that the receptor kinase activity of FGFR was required for bFGF-induced motility of RD-ES cells.	('FGF', 'Gene', '2247', (87, 90))	('FGF', 'Gene', (211, 214))	('FGF', 'Gene', '2247', (234, 237))	('wound-healing', 'CPA', (4, 17))	('bFGF', 'Gene', '2247', (233, 237))	('FGF', 'Gene', '2247', (211, 214))	('SU5402', 'Chemical', 'MESH:C105686', (155, 161))	('bFGF', 'Gene', (233, 237))	('FGF', 'Gene', (234, 237))	('bFGF', 'Gene', '2247', (86, 90))	('suppressed', 'NegReg', (141, 151))	('bFGF', 'Gene', (86, 90))	('SU5402', 'Var', (155, 161))	('FGF', 'Gene', (87, 90))
397364	20606682	As SU5402 only weakly inhibits tyrosine phosphorylation of the PDGF receptor, PDGF-BB-induced chemotaxis, but not chemokinesis, was also inhibited (Figure 2D and E).	('tyrosine', 'Chemical', 'MESH:D014443', (31, 39))	('SU5402', 'Chemical', 'MESH:C105686', (3, 9))	('chemokinesis', 'Disease', 'None', (114, 126))	('inhibited', 'NegReg', (137, 146))	('tyrosine phosphorylation', 'MPA', (31, 55))	('chemotaxis', 'CPA', (94, 104))	('chemokinesis', 'Disease', (114, 126))	('SU5402', 'Var', (3, 9))	('PDGF-BB-induced', 'Gene', (78, 93))	('inhibits', 'NegReg', (22, 30))
397370	20606682	In contrast, the expression of tyrosine-phosphorylated FGFR1, in most cases, was only detected on the vascular endothelium and the subset of stromal cells within the bone marrow (Figure 3E).	('FGFR1', 'Gene', (55, 60))	('tyrosine', 'Chemical', 'MESH:D014443', (31, 39))	('tyrosine-phosphorylated', 'Var', (31, 54))	('FGFR1', 'Gene', '2260', (55, 60))
397386	20606682	To identify the dominant signalling pathway downstream of FGFRs that was required for bFGF-induced cell motility, we used various pharmacological inhibitors, including LY294002 for PI3K, PD98059 for MEK/ERK, and U-73122 for PLCgamma.	('U-73122', 'Chemical', 'MESH:C060229', (212, 219))	('LY294002', 'Var', (168, 176))	('FGF', 'Gene', '2247', (87, 90))	('PD98059', 'Chemical', 'MESH:C093973', (187, 194))	('LY294002', 'Chemical', 'MESH:C085911', (168, 176))	('MEK', 'Gene', (199, 202))	('U-73122', 'Var', (212, 219))	('MEK', 'Gene', '5609', (199, 202))	('FGF', 'Gene', '2247', (58, 61))	('FGF', 'Gene', (58, 61))	('bFGF', 'Gene', '2247', (86, 90))	('ERK', 'Gene', '5594', (203, 206))	('bFGF', 'Gene', (86, 90))	('PD98059', 'Var', (187, 194))	('FGF', 'Gene', (87, 90))	('ERK', 'Gene', (203, 206))
397387	20606682	LY294002, but not PD98059 and U-73122, remarkably attenuated bFGF-induced chemotaxis of RD-ES cells (Figure 5).	('LY294002', 'Var', (0, 8))	('bFGF', 'Gene', (61, 65))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('U-73122', 'Chemical', 'MESH:C060229', (30, 37))	('attenuated', 'NegReg', (50, 60))	('PD98059', 'Chemical', 'MESH:C093973', (18, 25))	('bFGF', 'Gene', '2247', (61, 65))
397389	20606682	A wound-healing assay confirmed that LY294002 also significantly suppressed bFGF-induced chemokinesis (% wound closure; control: 14.7+-8.9%, bFGF+DMSO: 74.9+-8.0%, LY294002: 9.3+-3.5%).	('chemokinesis', 'Disease', (89, 101))	('LY294002', 'Var', (164, 172))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('bFGF', 'Gene', '2247', (141, 145))	('suppressed', 'NegReg', (65, 75))	('LY294002', 'Chemical', 'MESH:C085911', (164, 172))	('LY294002', 'Var', (37, 45))	('bFGF', 'Gene', (141, 145))	('bFGF', 'Gene', '2247', (76, 80))	('DMSO', 'Chemical', 'MESH:D004121', (146, 150))	('bFGF', 'Gene', (76, 80))	('chemokinesis', 'Disease', 'None', (89, 101))
397398	20606682	Rac1, a small GTP-binding protein, acts as a downstream modulator of PI3K-induced cell polarisation and lamellipodia formation in leukocytes.	('PI3K-induced', 'Var', (69, 81))	('Rac1', 'Gene', '5879', (0, 4))	('GTP', 'Chemical', 'MESH:D006160', (14, 17))	('lamellipodia formation', 'CPA', (104, 126))	('Rac1', 'Gene', (0, 4))	('cell polarisation', 'CPA', (82, 99))
397404	20606682	Importantly, LY294002 inhibited Rac1 activation upon bFGF stimulation, indicating that Rac1 acts as a downstream modulator of the FGFR/PI3K pathway (Figure 7A).	('Rac1', 'Gene', (32, 36))	('inhibited', 'NegReg', (22, 31))	('bFGF', 'Gene', (53, 57))	('FGF', 'Gene', (54, 57))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('FGF', 'Gene', (130, 133))	('FGF', 'Gene', '2247', (54, 57))	('Rac1', 'Gene', '5879', (87, 91))	('FGF', 'Gene', '2247', (130, 133))	('LY294002', 'Var', (13, 21))	('bFGF', 'Gene', '2247', (53, 57))	('Rac1', 'Gene', (87, 91))	('activation', 'MPA', (37, 47))	('Rac1', 'Gene', '5879', (32, 36))
397452	20606682	In corneal epithelial cells, bFGF induces a change in cell morphology from a polygonal to fibroblastic shape and a reorganisation of the actin cytoskeleton through PI3K.	('cell morphology', 'CPA', (54, 69))	('bFGF', 'Gene', (29, 33))	('change', 'Reg', (44, 50))	('reorganisation', 'MPA', (115, 129))	('PI3K', 'Var', (164, 168))	('bFGF', 'Gene', '2247', (29, 33))
397455	20606682	Recently, a direct and/or indirect link of the activation of PI3K and Rho GTPases, including Rac1, has been shown, and we indicated that PI3K enhanced Rac1 activation in response to bFGF.	('bFGF', 'Gene', '2247', (182, 186))	('Rac1', 'Gene', (151, 155))	('GTP', 'Chemical', 'MESH:D006160', (74, 77))	('Rac1', 'Gene', '5879', (151, 155))	('enhanced', 'PosReg', (142, 150))	('bFGF', 'Gene', (182, 186))	('Rac1', 'Gene', '5879', (93, 97))	('activation', 'MPA', (156, 166))	('Rac1', 'Gene', (93, 97))	('PI3K', 'Var', (137, 141))
397469	33488267	Survey of Paediatric Oncologists and Pathologists regarding Their Views and Experiences with Variant Translocations in Ewing and Ewing-Like Sarcoma: A Report of the Children's Oncology Group Advances in molecular diagnostics have identified subsets of Ewing and Ewing-like sarcomas driven by variant translocations with unique biology.	('Children', 'Species', '9606', (165, 173))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (262, 280))	('Oncology', 'Phenotype', 'HP:0002664', (176, 184))	('variant translocations', 'Var', (292, 314))	('driven by', 'Reg', (282, 291))	('sarcomas', 'Phenotype', 'HP:0100242', (273, 281))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('Sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('Ewing and Ewing-Like Sarcoma', 'Disease', 'MESH:C563168', (119, 147))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (262, 281))	('Ewing-Like Sarcoma', 'Phenotype', 'HP:0012254', (129, 147))	('Ewing and Ewing-like sarcomas', 'Disease', 'MESH:C563168', (252, 281))
397476	33488267	Chromosomal rearrangements are the defining molecular feature for a number of sarcomas.	('sarcomas', 'Disease', (78, 86))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('Chromosomal rearrangements', 'Var', (0, 26))
397482	33488267	In addition, over the last decade, two new histological variants of Ewing sarcoma have been described that result from either a t(4; 19) (q35; q13) or a t(10; 19) (q35; q13) translocation or chromosome X paracentric inversion to generate CIC-DUX4 or BCOR-CCNB3 fusion proteins, respectively.	('CIC', 'Gene', '23152', (238, 241))	('BCOR', 'Gene', '54880', (250, 254))	('CIC', 'Gene', (238, 241))	('CCNB3', 'Gene', (255, 260))	('Ewing sarcoma', 'Disease', (68, 81))	('chromosome X paracentric inversion', 'CPA', (191, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('t(4; 19) (q35; q13', 'Var', (128, 146))	('BCOR', 'Gene', (250, 254))	('DUX4', 'Gene', (242, 246))	('CCNB3', 'Gene', '85417', (255, 260))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (68, 81))	('result from', 'Reg', (107, 118))	('DUX4', 'Gene', '100288687', (242, 246))
397485	33488267	Although some studies showed substantial differences in clinical behaviour between tumours with typical Ewing sarcoma translocations and those with rarer rearrangements, the numbers of cases are too small to reach any convincing conclusion.	('tumours', 'Disease', (83, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (104, 117))	('translocations', 'Var', (118, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (104, 117))	('differences', 'Reg', (41, 52))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('Ewing sarcoma', 'Disease', (104, 117))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
397491	33488267	The goal of this study is to better understand oncologists and pathologists' views on the classifications and management of variant chromosomal rearrangements previously reported in small round cell tumours resembling Ewing sarcoma.	('Ewing sarcoma', 'Disease', (218, 231))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('variant chromosomal rearrangements', 'Var', (124, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (218, 231))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (218, 231))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumours', 'Disease', (199, 206))
397493	33488267	Herein, we performed an international survey of oncologists and pathologists' regarding their current approach to classification and identification of variant translocations and how they would stratify these rare variant translocations on future Ewing sarcoma clinical trials.	('Ewing sarcoma', 'Disease', (246, 259))	('variant translocations', 'Var', (151, 173))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (246, 259))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (246, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))
397495	33488267	The survey items were developed with a desire to obtain providers' opinions on the designation and eligibility to be enrolled on a Ewing sarcoma clinical trial based on a list of variant translocations that have been reported in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (131, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (131, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (229, 242))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (229, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('Ewing sarcoma', 'Disease', (131, 144))	('Ewing sarcoma', 'Disease', (229, 242))	('variant translocations', 'Var', (179, 201))
397502	33488267	The primary objective of this study was how paediatric oncologists and pathologists would classify variant chromosomal rearrangement previously reported in small round cell tumours resembling Ewing sarcoma histology.	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('variant chromosomal rearrangement', 'Var', (99, 132))	('tumours', 'Disease', (173, 180))	('Ewing sarcoma', 'Disease', (192, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (192, 205))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (192, 205))
397506	33488267	There was near consensus regarding the classification of the canonical EWSR1-FLI1 translocation with greater than 95% of respondents classifying this as Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (153, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('EWSR1', 'Gene', (71, 76))	('FLI1', 'Gene', (77, 81))	('FLI1', 'Gene', '2313', (77, 81))	('translocation', 'Var', (82, 95))	('EWSR1', 'Gene', '2130', (71, 76))	('Ewing sarcoma', 'Disease', (153, 166))
397513	33488267	The data showed a similar lack of consensus as to how the presence of a given translocation should influence inclusion in a Ewing sarcoma clinical trial (Figure 3).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (124, 137))	('presence', 'Var', (58, 66))	('influence', 'Reg', (99, 108))	('Ewing sarcoma', 'Disease', (124, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (124, 137))
397525	33488267	Novel molecular alterations in patients presenting with tumours that histologically represent Ewing sarcoma, but lack the canonical EWSR1-ETS gene family translocation, have challenged how we approach diagnosis and classification of these tumours.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Phenotype', 'HP:0002664', (239, 246))	('tumours', 'Disease', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('alterations', 'Var', (16, 27))	('tumours', 'Disease', 'MESH:D009369', (239, 246))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('EWSR1', 'Gene', (132, 137))	('tumours', 'Disease', (239, 246))	('patients', 'Species', '9606', (31, 39))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('Ewing sarcoma', 'Disease', (94, 107))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('EWSR1', 'Gene', '2130', (132, 137))
397529	33488267	This survey of 141 pathologists and oncologists revealed that while there was a consensus that tumours with EWSR1-ETS gene family translocations should be considered Ewing sarcoma, there is a lack of consensus regarding how to classify rare Ewing sarcoma variants, EWSR1+ with non-ETS partner sarcomas, and both CIC and BCOR sarcomas.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (241, 254))	('sarcomas', 'Disease', 'MESH:D012509', (293, 301))	('CIC', 'Gene', '23152', (312, 315))	('sarcomas', 'Phenotype', 'HP:0100242', (293, 301))	('BCOR', 'Gene', '54880', (320, 324))	('sarcomas', 'Disease', (293, 301))	('EWSR1', 'Gene', '2130', (265, 270))	('sarcoma', 'Phenotype', 'HP:0100242', (325, 332))	('partner sarcomas', 'Disease', (285, 301))	('partner sarcomas', 'Disease', 'MESH:D012509', (285, 301))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (166, 179))	('BCOR', 'Gene', (320, 324))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (166, 179))	('variants', 'Var', (255, 263))	('EWSR1', 'Gene', (108, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('Ewing sarcoma', 'Disease', (241, 254))	('tumours', 'Disease', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('EWSR1', 'Gene', (265, 270))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('CIC', 'Gene', (312, 315))	('Ewing sarcoma', 'Disease', (166, 179))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('sarcomas', 'Disease', 'MESH:D012509', (325, 333))	('EWSR1', 'Gene', '2130', (108, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (325, 333))	('sarcomas', 'Disease', (325, 333))	('sarcoma', 'Phenotype', 'HP:0100242', (247, 254))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (241, 254))
397545	33488267	Survival for patients with BCOR-CCNB3 rearrangements is similar to Ewing sarcoma, with reported 5-year survival rates of 72% and 76.5% in two small cases series.	('BCOR', 'Gene', '54880', (27, 31))	('CCNB3', 'Gene', '85417', (32, 37))	('rearrangements', 'Var', (38, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('patients', 'Species', '9606', (13, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('CCNB3', 'Gene', (32, 37))	('BCOR', 'Gene', (27, 31))	('Ewing sarcoma', 'Disease', (67, 80))
397547	33488267	Patients with tumours harbouring this fusion have a particularly aggressive disease course, with a 5-year overall survival of 43%, compared to 77% in a matched Ewing sarcoma group.	('aggressive disease', 'Disease', (65, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (160, 173))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (160, 173))	('fusion', 'Var', (38, 44))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('aggressive disease', 'Disease', 'MESH:D001523', (65, 83))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('Ewing sarcoma', 'Disease', (160, 173))	('tumours', 'Disease', (14, 21))
397548	33488267	While it is clear that those with BCOR-CCNB3 fusions benefit from Ewing-type therapy, patients with CIC-DUX4 fusions have worse outcomes and may benefit from alternative treatment approaches.	('CIC', 'Gene', (100, 103))	('BCOR', 'Gene', '54880', (34, 38))	('CIC', 'Gene', '23152', (100, 103))	('CCNB3', 'Gene', '85417', (39, 44))	('DUX4', 'Gene', (104, 108))	('DUX4', 'Gene', '100288687', (104, 108))	('CCNB3', 'Gene', (39, 44))	('benefit', 'PosReg', (53, 60))	('benefit', 'Reg', (145, 152))	('BCOR', 'Gene', (34, 38))	('fusions', 'Var', (45, 52))	('patients', 'Species', '9606', (86, 94))
397562	33488267	In translocation-positive sarcomas, the consensus is that the biology of the tumour is defined by the underlying translocation and resulting fusion protein.	('sarcomas', 'Disease', (26, 34))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('translocation-positive', 'Var', (3, 25))	('sarcomas', 'Disease', 'MESH:D012509', (26, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
397696	29942746	To our knowledge this case is the first case of M. nonliquefaciens causing SCJ septic arthritis in an asymptomatic immunocompetent patient.	('SCJ septic arthritis', 'Disease', (75, 95))	('causing', 'Reg', (67, 74))	('arthritis', 'Phenotype', 'HP:0001369', (86, 95))	('septic arthritis', 'Phenotype', 'HP:0003095', (79, 95))	('SCJ septic arthritis', 'Disease', 'MESH:D001170', (75, 95))	('patient', 'Species', '9606', (131, 138))	('M. nonliquefaciens', 'Species', '478', (48, 66))	('M. nonliquefaciens', 'Var', (48, 66))
397710	27895047	Conversely, immortalized cell lines undergo a phenotypic, epigenetic and sometimes genetic drift from the early matching tumor, maintaining only part of their pathologically relevant properties.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('genetic', 'Var', (83, 90))	('epigenetic', 'Var', (58, 68))	('matching tumor', 'Disease', 'MESH:D009369', (112, 126))	('matching tumor', 'Disease', (112, 126))
397728	27895047	Chromosomal amplification of the 12q13-15 region, including the MDM2 and CDK4 genes, is the hallmark genetic change in these diseases.	('CDK4', 'Gene', '1019', (73, 77))	('MDM2', 'Gene', '4193', (64, 68))	('MDM2', 'Gene', (64, 68))	('Chromosomal amplification', 'Var', (0, 25))	('CDK4', 'Gene', (73, 77))
397729	27895047	Amplification of MDM2 occurs in almost all DDLPS cases and detection by fluorescence in situ hybridization is widely used as a diagnostic tool.	('occurs', 'Reg', (22, 28))	('Amplification', 'Var', (0, 13))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))	('DDLPS', 'Disease', (43, 48))
397740	27895047	The percentage of cells harboring MDM2 amplification in monolayer cultures was significantly lower than that of cells cultured on collagen-based scaffolds, i.e.	('amplification', 'Var', (39, 52))	('lower', 'NegReg', (93, 98))	('MDM2', 'Gene', '4193', (34, 38))	('MDM2', 'Gene', (34, 38))
397770	27895047	While the cytotoxicity was similar, epirubicin plus ifosfamide induced a higher apoptotic cell death compared to trabectedin, which is also known to exert its effect by the arrest of the cell cycle.	('epirubicin', 'Var', (36, 46))	('death', 'Disease', 'MESH:D003643', (95, 100))	('death', 'Disease', (95, 100))	('ifosfamide', 'Chemical', 'MESH:D007069', (52, 62))	('cytotoxicity', 'Disease', (10, 22))	('epirubicin', 'Chemical', 'MESH:D015251', (36, 46))	('trabectedin', 'Chemical', 'MESH:D000077606', (113, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (10, 22))
397792	27895047	Cancer cells were positive for MDM2 amplification and desmin, with focal actin expression, and negative for miogenin.	('desmin', 'Protein', (54, 60))	('expression', 'MPA', (79, 89))	('focal', 'MPA', (67, 72))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('amplification', 'Var', (36, 49))	('positive', 'Reg', (18, 26))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('MDM2', 'Gene', '4193', (31, 35))	('MDM2', 'Gene', (31, 35))
397970	31743843	As myxoid and round cell tumors share the same cytogenetic abnormalities, namely the translocation t (12; 16) (q13; p11) leading to the fusion of the genes DDIT3 and FUS with the generation of a hybrid protein FUS/DDIT3, some authors consider both lesions as a continuum of the same disease.	('myxoid', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('fusion', 'Var', (136, 142))	('FUS', 'Gene', (166, 169))	('tumors', 'Disease', (25, 31))	('p11', 'Gene', '8909', (116, 119))	('p11', 'Gene', (116, 119))	('FUS', 'Gene', '2521', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('DDIT3', 'Gene', (214, 219))	('DDIT3', 'Gene', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('DDIT3', 'Gene', '1649', (214, 219))	('DDIT3', 'Gene', '1649', (156, 161))	('FUS', 'Gene', (210, 213))	('FUS', 'Gene', '2521', (210, 213))
397980	31743843	Among such therapies are CDK4 inhibitors in well- and dedifferentiated liposarcoma (WD/DDLS) and trabectedin, which prevents FUS-DDIT3 binding to DNA, in (M/RCLS).	('WD', 'Disease', 'MESH:D006527', (84, 86))	('FUS', 'Gene', '2521', (125, 128))	('FUS', 'Gene', (125, 128))	('liposarcoma', 'Phenotype', 'HP:0012034', (71, 82))	('liposarcoma', 'Disease', 'MESH:D008080', (71, 82))	('inhibitors', 'Var', (30, 40))	('DDIT3', 'Gene', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('CDK4', 'Gene', (25, 29))	('binding', 'Interaction', (135, 142))	('DDIT3', 'Gene', '1649', (129, 134))	('CDK4', 'Gene', '1019', (25, 29))	('liposarcoma', 'Disease', (71, 82))
398043	30602058	The univariable Cox model HR estimate for LR after S+RT versus surgery only was 0.53 (95% CI, 0.33-0.86; P = .009) without adjustment and 0.70 (95% CI, 0.36-1.39; Wald test P = .312) with IPTW adjustment.	('Cox', 'Gene', '1351', (16, 19))	('S+RT', 'Var', (51, 55))	('IPTW', 'Chemical', '-', (188, 192))	('Cox', 'Gene', (16, 19))
398065	30602058	The RT prognostic effect on DM was not found to be statistically significant either before or after IPTW adjustment; the univariable Cox model HR estimate of S+RT versus surgery only was 0.70 (95% CI, 0.36-1.36; P = .296) without adjustment and 1.30 (95% CI, 0.25-6.67; Wald test P = .750) with IPTW adjustment.	('Cox', 'Gene', '1351', (133, 136))	('Cox', 'Gene', (133, 136))	('S+RT', 'Var', (158, 162))	('DM', 'Disease', 'MESH:D009223', (28, 30))	('IPTW', 'Chemical', '-', (295, 299))	('IPTW', 'Chemical', '-', (100, 104))
398074	30602058	The RT effect on OS was not found to be statistically significant after IPTW adjustment; the univariable Cox model HR estimate for S+RT versus surgery only was 0.50 (95% CI, 0.29-0.84; P = .009) without adjustment and 0.72 (95% CI, 0.22-2.30; Wald test P = .576) with IPTW adjustment.	('Cox', 'Gene', (105, 108))	('IPTW', 'Chemical', '-', (268, 272))	('S+RT', 'Var', (131, 135))	('IPTW', 'Chemical', '-', (72, 76))	('Cox', 'Gene', '1351', (105, 108))
398263	29046139	However, positivity for myogenin identifies the neoplasm as an RMS.	('myogenin', 'Protein', (24, 32))	('neoplasm', 'Disease', (48, 56))	('neoplasm', 'Disease', 'MESH:D009369', (48, 56))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('RMS', 'Phenotype', 'HP:0002859', (63, 66))	('positivity', 'Var', (9, 19))
398269	29046139	This strain has a null mutation of the gene for dysferlin, a protein in skeletal muscle that is thought to be involved in the repair of damage to the muscle fiber plasma membrane.	('null mutation', 'Var', (18, 31))	('dysferlin', 'Gene', '26903', (48, 57))	('dysferlin', 'Gene', (48, 57))
398271	29046139	Several mouse models of embryonic or pleomorphic RMS have been produced through deactivation of Trp53 or creation of mutant Trp53 alleles; in some models the modified Trp53 works in concert with other genes, in particular KRas.	('Trp53', 'Gene', '22059', (124, 129))	('deactivation', 'Var', (80, 92))	('Trp53', 'Gene', '22059', (167, 172))	('Trp53', 'Gene', (96, 101))	('mutant', 'Var', (117, 123))	('KRas', 'Gene', (222, 226))	('embryonic', 'Disease', 'MESH:D009373', (24, 33))	('RMS', 'Phenotype', 'HP:0002859', (49, 52))	('Trp53', 'Gene', (124, 129))	('KRas', 'Gene', '16653', (222, 226))	('modified', 'Var', (158, 166))	('Trp53', 'Gene', '22059', (96, 101))	('Trp53', 'Gene', (167, 172))	('mouse', 'Species', '10090', (8, 13))	('embryonic', 'Disease', (24, 33))
398302	29046139	Furthermore, the authors considered the high prevalence of staining for smooth muscle actin in the group of neoplasms to be indicative of its nonspecificity for smooth muscle neoplasms.	('staining', 'Var', (59, 67))	('neoplasms', 'Disease', (175, 184))	('neoplasm', 'Phenotype', 'HP:0002664', (175, 183))	('neoplasm', 'Phenotype', 'HP:0002664', (108, 116))	('neoplasms', 'Disease', 'MESH:D009369', (108, 117))	('neoplasms', 'Disease', (108, 117))	('neoplasms', 'Phenotype', 'HP:0002664', (175, 184))	('muscle neoplasms', 'Disease', 'MESH:D009217', (168, 184))	('muscle neoplasms', 'Disease', (168, 184))	('smooth muscle actin', 'Protein', (72, 91))	('neoplasms', 'Phenotype', 'HP:0002664', (108, 117))	('neoplasms', 'Disease', 'MESH:D009369', (175, 184))
398308	29046139	Sarcomas occur in Trp53+/- mice without the presence of a microchip, and sarcomas associated with microchips may also occur in non-genetically modified mice and in rats.	('Trp53', 'Gene', (18, 23))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('mice', 'Species', '10090', (27, 31))	('microchips', 'Var', (98, 108))	('rats', 'Species', '10116', (164, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('Trp53', 'Gene', '22059', (18, 23))	('sarcomas', 'Disease', (73, 81))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('mice', 'Species', '10090', (152, 156))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
398309	29046139	However, sarcomas occurring in association with a microchip in non-genetically modified mice generally occur at a low incidence and with a latent period longer than in Trp53+/- mice.	('Trp53', 'Gene', (168, 173))	('microchip', 'Var', (50, 59))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('Trp53', 'Gene', '22059', (168, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcomas', 'Disease', (9, 17))	('mice', 'Species', '10090', (177, 181))	('mice', 'Species', '10090', (88, 92))
398313	29046139	However,, in a review of available literature, found reports of a large variety of genetic alterations in RMS, and other genetic abnormalities have been reported in a variety of soft tissue neoplasms.	('soft tissue neoplasms', 'Disease', 'MESH:D012983', (178, 199))	('RMS', 'Disease', (106, 109))	('genetic alterations', 'Var', (83, 102))	('RMS', 'Phenotype', 'HP:0002859', (106, 109))	('soft tissue neoplasms', 'Disease', (178, 199))	('soft tissue neoplasms', 'Phenotype', 'HP:0031459', (178, 199))	('rat', 'Species', '10116', (95, 98))	('rat', 'Species', '10116', (39, 42))	('genetic abnormalities', 'Disease', 'MESH:D030342', (121, 142))	('reported', 'Reg', (153, 161))	('genetic abnormalities', 'Disease', (121, 142))	('neoplasm', 'Phenotype', 'HP:0002664', (190, 198))	('neoplasms', 'Phenotype', 'HP:0002664', (190, 199))
398314	29046139	Since the cellular markers identified by IHC represent products of activated genes, it is possible to speculate that alterations to gene function in a neoplastic cell may allow expression of genes and the consequent production of cellular markers not found in the normal tissue.	('alterations', 'Var', (117, 128))	('expression', 'MPA', (177, 187))	('allow', 'Reg', (171, 176))	('rat', 'Species', '10116', (121, 124))
398492	25221796	When the analysis was restricted to patients receiving prior zidovudine, survival was improved in the liposomal daunorubicin group as compared to the ABV group (p=0.26; individual level data not provided).	('survival', 'MPA', (73, 81))	('patients', 'Species', '9606', (36, 44))	('daunorubicin', 'Chemical', 'MESH:D003630', (112, 124))	('zidovudine', 'Chemical', 'MESH:D015215', (61, 71))	('improved', 'PosReg', (86, 94))	('ABV', 'Chemical', 'MESH:C036986', (150, 153))	('liposomal', 'Var', (102, 111))
398493	25221796	Nine out of 116 participants had progressive disease in the liposomal daunorubicin group, compared to 11 participants out of 111 in the ABV group(RR 0.78; 95% CI 0.34 to 1.82) (Analysis 6.1).	('liposomal', 'Var', (60, 69))	('ABV', 'Chemical', 'MESH:C036986', (136, 139))	('progressive disease', 'Disease', (33, 52))	('daunorubicin', 'Chemical', 'MESH:D003630', (70, 82))	('participants', 'Species', '9606', (105, 117))	('participants', 'Species', '9606', (16, 28))
398510	25221796	Progression Five participants in the bleomycin group had progressive disease compared to none in the ABV group (RR 11; 95% CI 0.67 to 179.29) (Analysis 8.2).	('RR 1', 'Gene', (112, 116))	('ABV', 'Chemical', 'MESH:C036986', (101, 104))	('participants', 'Species', '9606', (17, 29))	('RR 1', 'Gene', '6240', (112, 116))	('progressive disease', 'Disease', (57, 76))	('bleomycin', 'Var', (37, 46))	('bleomycin', 'Chemical', 'MESH:D001761', (37, 46))
398524	25221796	In the previous version of this Cochrane review, two large randomised trials (total of 499 T0 and T1 Kaposi's sarcoma patients) were pooled:, comparing pegylated liposomal doxorubicin (PLD) to doxorubicin, bleomycin and vincristine (ABV), and, comparing PLD to bleomycin and vincristine.	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (101, 117))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (101, 117))	("Kaposi's sarcoma", 'Disease', (101, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('bleomycin', 'Chemical', 'MESH:D001761', (261, 270))	('bleomycin', 'Chemical', 'MESH:D001761', (206, 215))	('patients', 'Species', '9606', (118, 126))	('doxorubicin', 'Chemical', 'MESH:D004317', (172, 183))	('vincristine', 'Chemical', 'MESH:D014750', (220, 231))	('vincristine', 'Chemical', 'MESH:D014750', (275, 286))	('ABV', 'Chemical', 'MESH:C036986', (233, 236))	('pegylated', 'Var', (152, 161))	('doxorubicin', 'Chemical', 'MESH:D004317', (193, 204))
398537	25221796	Liposomal doxorubicin also showed a significant survival time benefit.	('survival time', 'CPA', (48, 61))	('benefit', 'PosReg', (62, 69))	('doxorubicin', 'Chemical', 'MESH:D004317', (10, 21))	('Liposomal', 'Var', (0, 9))
398583	33505574	Positive nuclear staining to HHV8 is highly specific and simplifies diagnosis.	('Positive', 'Var', (0, 8))	('HHV8', 'Species', '37296', (29, 33))	('HHV8', 'Gene', (29, 33))
398594	33505574	Further research on targeted therapies for HHV-8 inhibition is needed, as it may provide a promising treatment for KS.	('inhibition', 'Var', (49, 59))	('HHV-8', 'Species', '37296', (43, 48))	('KS', 'Phenotype', 'HP:0100726', (115, 117))	('HHV-8', 'Gene', (43, 48))
398599	30899417	Many attempts have been made to map distinct functions to specific features of the EWS domain, but described deletion mutants are either fully active or completely "dead" and other approaches have been limited by the repetitive and disordered nature of the EWS domain.	('repetitive and disordered nature', 'Phenotype', 'HP:0000733', (217, 249))	('disordered', 'Disease', 'MESH:D030342', (232, 242))	('disordered', 'Disease', (232, 242))	('deletion mutants', 'Var', (109, 125))
398601	30899417	Using transcriptomic and phenotypic anchorage-independent growth profiles of other EWS/FLI mutants coupled with reported EWS/FLI localization data, we have mapped the critical structure-function requirements of the EWS domain for EWS/FLI-mediated oncogenesis.	('FLI', 'Gene', '2314', (234, 237))	('FLI', 'Gene', '2314', (87, 90))	('FLI', 'Gene', (234, 237))	('FLI', 'Gene', '2314', (125, 128))	('mutants', 'Var', (91, 98))	('FLI', 'Gene', (87, 90))	('FLI', 'Gene', (125, 128))
398616	30899417	In this model, mutating a small number of tyrosines minimally impacts function, while changing a majority of tyrosine residues dramatically reduces intermolecular interactions.	('reduces', 'NegReg', (140, 147))	('tyrosines', 'Chemical', 'MESH:D014443', (42, 51))	('mutating', 'Var', (15, 23))	('tyrosine', 'Chemical', 'MESH:D014443', (109, 117))	('function', 'MPA', (70, 78))	('intermolecular interactions', 'MPA', (148, 175))	('tyrosine', 'Chemical', 'MESH:D014443', (42, 50))
398617	30899417	Other models of EWS domain function focus on the importance of tyrosine residues in driving intramolecular interactions, resulting in local phase separation or EWS polymerization.	('tyrosine', 'Chemical', 'MESH:D014443', (63, 71))	('local phase separation', 'MPA', (134, 156))	('tyrosine residues', 'Var', (63, 80))	('EWS polymerization', 'MPA', (160, 178))
398620	30899417	A minimal transforming transcriptional signature has not been established and whether SYGQ-FLI mutants recapitulate EWS/FLI activity at repressed and non-microsatellite targets remains untested.	('FLI', 'Gene', (91, 94))	('FLI', 'Gene', '2314', (120, 123))	('FLI', 'Gene', (120, 123))	('mutants', 'Var', (95, 102))	('FLI', 'Gene', '2314', (91, 94))
398622	30899417	In this study we turned to a mutant of EWS/FLI called DAF, which contains Y to A mutations in the first 17 DHRs of the EWS domain (Figure 1A,).	('DHR', 'Chemical', '-', (107, 110))	('FLI', 'Gene', '2314', (43, 46))	('mutations in', 'Var', (81, 93))	('FLI', 'Gene', (43, 46))
398623	30899417	While these mutations resulted in a transcriptionally "dead" EWS domain (when fused to ATF), the DAF mutant contains an intact SYGQ2 domain that we hypothesized would confer activity at GGAA-repeats.	('ATF', 'Gene', '2668', (87, 90))	('ATF', 'Gene', (87, 90))	('mutations', 'Var', (12, 21))	('mutant', 'Var', (101, 107))	('activity', 'MPA', (174, 182))
398630	30899417	We use the A673 Ewing sarcoma cell line for these experiments, as it is the only cell line to reliably proliferate following depletion of EWS/FLI and subsequent rescue, in our experience.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('FLI', 'Gene', '2314', (142, 145))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (16, 29))	('A673', 'CellLine', 'CVCL:0080', (11, 15))	('depletion', 'Var', (125, 134))	('FLI', 'Gene', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('Ewing sarcoma', 'Disease', (16, 29))
398650	30899417	We next compared the transcriptional activity of other EWS/FLI mutants to "full" rescue with WT-EF.	('FLI', 'Gene', '2314', (59, 62))	('FLI', 'Gene', (59, 62))	('mutants', 'Var', (63, 70))
398662	30899417	Differences in the relationship between EWS/FLI binding and subsequent gene regulation were observed between genes with promoter-like proximal (< 5 kb from transcription start) microsatellites and distant enhancer-like (> 5 kb from transcription start) microsatellites.	('FLI', 'Gene', '2314', (44, 47))	('FLI', 'Gene', (44, 47))	('microsatellites', 'Var', (177, 192))
398665	30899417	However, DAF showed limited activity from isolated microsatellites and failed to rescue NKX2-2.	('NKX2-2', 'Gene', '4821', (88, 94))	('NKX2-2', 'Gene', (88, 94))	('microsatellites', 'Var', (51, 66))	('activity', 'MPA', (28, 36))
398673	30899417	For genes repressed by EWS/FLI-bound microsatellites, WT-EF similarly showed ~75% rescue and good correlation with endo-EF function (r = 0.83 and r = 0.80 for distal and proximal, respectively) with a slightly decreased degree of rescue (slope = 0.62 and 0.52 for distal and proximal, respectively), suggesting gene repression is a phenotype less amenable to rescue (Supplementary Figure 6).	('correlation', 'Interaction', (98, 109))	('FLI', 'Gene', '2314', (27, 30))	('microsatellites', 'Var', (37, 52))	('FLI', 'Gene', (27, 30))
398678	30899417	Taken together transcriptomic profiling of DAF showed 1) that DAF most recapitulated WT-EF activity at genes directly activated by EWS/FLI-bound microsatellites, 2) that DAF partially rescues activation from both distal and proximal microsatellites, 3) DAF shows weak activity from all other EWS/FLI-bound elements, and 4) the global transcriptional profile for a given mutant is a functional extension of genes regulated directly by EWS/FLI.	('FLI', 'Gene', (135, 138))	('activation', 'MPA', (192, 202))	('FLI', 'Gene', '2314', (296, 299))	('FLI', 'Gene', (296, 299))	('FLI', 'Gene', '2314', (135, 138))	('mutant', 'Var', (370, 376))	('FLI', 'Gene', '2314', (438, 441))	('FLI', 'Gene', (438, 441))
398680	30899417	To better understand which transcriptional functions are required for oncongenic phenotypes, we profiled the transcriptome of a "minimal fully functional" EWS/FLI deletion mutant, mut9, and its corresponding DAF mutant (Figure 5A).	('FLI', 'Gene', (159, 162))	('deletion mutant', 'Var', (163, 178))	('FLI', 'Gene', '2314', (159, 162))
398687	30899417	However, the reduced overall number of tyrosine residues leads to a reduced ability to interact with co-regulators at non-microsatellite loci, resulting in only ~25% transcriptional activity at these targets.	('only', 'NegReg', (156, 160))	('interact', 'Interaction', (87, 95))	('tyrosine residues', 'Var', (39, 56))	('tyrosine', 'Chemical', 'MESH:D014443', (39, 47))	('transcriptional activity', 'MPA', (166, 190))	('reduced', 'NegReg', (68, 75))	('ability', 'MPA', (76, 83))
398691	30899417	Transcriptomic profiling showed DAF is a partially functional EWS/FLI mutant, representing the first EWS/FLI variant reported to possess partial function.	('FLI', 'Gene', (105, 108))	('mutant', 'Var', (70, 76))	('FLI', 'Gene', '2314', (66, 69))	('FLI', 'Gene', (66, 69))	('FLI', 'Gene', '2314', (105, 108))
398697	30899417	Contrary to our early prediction that the DAF mutations may impair function specifically at enhancer-like motifs, DAF activated a similar proportion of WT-EF-activated microsatellites, regardless of distance to the target gene, suggesting other local factors determine the functional activity of DAF, as seen in our initial NR0B1 promoter vs. isolated microsatellite reporter assay.	('impair', 'NegReg', (60, 66))	('mutations', 'Var', (46, 55))	('NR0B1', 'Gene', (324, 329))	('NR0B1', 'Gene', '190', (324, 329))	('function', 'MPA', (67, 75))
398698	30899417	The data presented here support repression from GGAA-repeats as a bona fide EWS/FLI function.	('repression', 'Var', (32, 42))	('FLI', 'Gene', (80, 83))	('FLI', 'Gene', '2314', (80, 83))	('GGAA-repeats', 'Gene', (48, 60))
398703	30899417	activating vs. repressive) interact with different EWS/FLI-bound microsatellites.	('microsatellites', 'Var', (65, 80))	('FLI', 'Gene', '2314', (55, 58))	('FLI', 'Gene', (55, 58))
398705	30899417	Non-microsatellite EWS/FLI targets also showed interesting patterns of rescue in this study.	('FLI', 'Gene', '2314', (23, 26))	('Non-microsatellite', 'Var', (0, 18))	('FLI', 'Gene', (23, 26))
398706	30899417	Mut9 activity at these loci was only half that of EWS/FLI, and DAF regulated a similar number of genes as mut9, but often acted in the wrong direction.	('FLI', 'Gene', '2314', (54, 57))	('mut9', 'Var', (106, 110))	('FLI', 'Gene', (54, 57))
398717	30899417	Regardless of whether CRC transcription factors are involved in Ewing sarcoma, transforming mutants were better able to alter the transcriptional landscape through activation of multiple transcription factors involved in varied developmental pathways.	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('alter', 'Reg', (120, 125))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (64, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (64, 77))	('activation', 'PosReg', (164, 174))	('mutants', 'Var', (92, 99))	('transcriptional landscape', 'MPA', (130, 155))	('Ewing sarcoma', 'Disease', (64, 77))
398718	30899417	The data presented herein suggest the differential activity of structural EWS/FLI mutants at EWS/FLI response elements is, in part, determined by the ability of such mutants to interact with other local regulatory factors.	('activity', 'MPA', (51, 59))	('FLI', 'Gene', '2314', (78, 81))	('FLI', 'Gene', (78, 81))	('interact', 'Interaction', (177, 185))	('FLI', 'Gene', '2314', (97, 100))	('mutants', 'Var', (82, 89))	('FLI', 'Gene', (97, 100))
398723	30899417	These cells possess a V600E mutated BRAF, however, RNAi-mediated depletion of BRAF or treatment with vemurafenib shows limited impact on cell behavior.	('BRAF', 'Gene', (36, 40))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', (78, 82))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('vemurafenib', 'Chemical', 'MESH:D000077484', (101, 112))	('V600E', 'Var', (22, 27))	('BRAF', 'Gene', '673', (36, 40))
398729	30899417	The DAF and mut9-DAF constructs were subcloned into the Murine Stem Cell Virus (pMSCV) backbone (with hyrgomycin resistance) by inserting gene blocks (IDT gBlocks) containing the appropriate tyrosine mutations between the NotI site after the 3X-FLAG tag and the BamHI site in the EWS domain of the 3X-FLAG EWS/FLI vector.	('FLI', 'Gene', (310, 313))	('tyrosine mutations', 'Var', (191, 209))	('tyrosine', 'Chemical', 'MESH:D014443', (191, 199))	('Murine Stem Cell Virus', 'Species', '258023', (56, 78))	('FLI', 'Gene', '2314', (310, 313))	('hyrgomycin', 'Chemical', '-', (102, 112))
398742	30899417	These data have also been deposited in NCBI's Sequencing Read Archive through SRA accession numbers SRP168620 and SRP168621.	('SRP168621', 'Var', (114, 123))	('SRP168620', 'Var', (100, 109))	('SRA', 'Gene', (78, 81))	('SRA', 'Gene', '10307', (78, 81))
398761	25767667	The tumor cells were expressing diffusely HMB-45, Melan-A but not expressing PS100, Cytokeratin, EMA, Desmin (Figure 2).	('tumor', 'Disease', (4, 9))	('Melan-A', 'Gene', (50, 57))	('diffusely HMB-45', 'Var', (32, 48))	('EMA', 'Gene', (97, 100))	('Desmin', 'Gene', '1674', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Desmin', 'Gene', (102, 108))	('EMA', 'Gene', '4582', (97, 100))
398773	25767667	Unlike melanomas, most CCS tumors are characterized by a recurrent chromosomal translocation, t (12; 22), resulting in fusion of the EWS gene on 22q12 with the ATF1 gene on 12q13.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('CCS tumors', 'Disease', 'MESH:D009369', (23, 33))	('fusion', 'Var', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('melanomas', 'Disease', (7, 16))	('CCS tumors', 'Disease', (23, 33))	('ATF1', 'Gene', (160, 164))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (57, 92))	('EWS', 'Gene', '2130', (133, 136))	('EWS', 'Gene', (133, 136))	('ATF1', 'Gene', '466', (160, 164))	('melanomas', 'Disease', 'MESH:D008545', (7, 16))	('melanomas', 'Phenotype', 'HP:0002861', (7, 16))
398774	25767667	Several fusion transcript types have been described, with a predominance of type 1 fusing exon 8 of EWS with exon 4 of ATF1 and type 2 fusing exon 7 of EWS with exon 5 of ATF1.	('ATF1', 'Gene', '466', (119, 123))	('exon 4', 'Var', (109, 115))	('ATF1', 'Gene', '466', (171, 175))	('EWS', 'Gene', '2130', (152, 155))	('EWS', 'Gene', (152, 155))	('EWS', 'Gene', '2130', (100, 103))	('ATF1', 'Gene', (119, 123))	('ATF1', 'Gene', (171, 175))	('EWS', 'Gene', (100, 103))
398795	25268941	Critical for diagnostic confirmation, ASPS typically demonstrates a der(17) t(X; 17)(p11.2; q25.3) translocation between ASPSCR1 (17q25.3) and TFE3 (Xp11.2) .	('p11', 'Gene', (85, 88))	('der(17) t(', 'Var', (68, 78))	('ASPSCR1', 'Gene', '79058', (121, 128))	('ASPS', 'Gene', (121, 125))	('ASPS', 'Gene', '79058', (38, 42))	('p11', 'Gene', '6281', (150, 153))	('TFE3', 'Gene', (143, 147))	('p11', 'Gene', '6281', (85, 88))	('ASPS', 'Phenotype', 'HP:0012218', (38, 42))	('ASPS', 'Gene', '79058', (121, 125))	('TFE3', 'Gene', '7030', (143, 147))	('ASPSCR1', 'Gene', (121, 128))	('ASPS', 'Gene', (38, 42))	('ASPS', 'Phenotype', 'HP:0012218', (121, 125))	('p11', 'Gene', (150, 153))
398842	25268941	FISH studies demonstrated a rearrangement of the TFE3 locus in 84.5% of 200 interphase cells analyzed using the two- and three-color probe sets as well as an ASPSCR1-TFE3 fusion in 93.0% of 100 interphase cells examined (Figure 3A, 3B, and 3C, respectively).	('ASPSCR1', 'Gene', (158, 165))	('TFE3', 'Gene', '7030', (49, 53))	('rearrangement', 'Var', (28, 41))	('TFE3', 'Gene', '7030', (166, 170))	('ASPS', 'Phenotype', 'HP:0012218', (158, 162))	('ASPSCR1', 'Gene', '79058', (158, 165))	('TFE3', 'Gene', (49, 53))	('TFE3', 'Gene', (166, 170))
398884	25268941	As such, CD68 positivity in ASPS may be of diagnostic importance in isolated cases, particularly if the clinical presentation is unusual and there are few other positive markers on a broad-spectrum immunohistochemical panel (both features of the present report).	('ASPS', 'Gene', (28, 32))	('CD68', 'Gene', (9, 13))	('ASPS', 'Gene', '79058', (28, 32))	('positivity', 'Var', (14, 24))	('CD68', 'Gene', '968', (9, 13))	('ASPS', 'Phenotype', 'HP:0012218', (28, 32))
398892	25268941	In this setting, immunoreactivity for HMB-45 and/or microphthalmia-associated transcription factor (MiTF) in tumor cells would be consistent with PEComa and exclude a diagnosis of metastatic ASPS .	('PEComa', 'Disease', (146, 152))	('microphthalmia-associated transcription factor', 'Gene', '4286', (52, 98))	('ASPS', 'Phenotype', 'HP:0012218', (191, 195))	('ASPS', 'Gene', (191, 195))	('PEComa', 'Disease', 'MESH:D054973', (146, 152))	('immunoreactivity', 'Var', (17, 33))	('HMB-45', 'Gene', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MiTF', 'Gene', (100, 104))	('microphthalmia-associated transcription factor', 'Gene', (52, 98))	('ASPS', 'Gene', '79058', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MiTF', 'Gene', '4286', (100, 104))	('microphthalmia', 'Phenotype', 'HP:0000568', (52, 66))	('tumor', 'Disease', (109, 114))
398987	33268763	In a retrospective study from the U.S., IRIS was more common in those with PJP at the time of cART initiation (28%) than in those with Mycobacterium avium complex (MAC) infection (4%).	('Mycobacterium avium complex (MAC)', 'Species', '120793', (135, 168))	('infection', 'Disease', (169, 178))	('IRIS', 'Disease', (40, 44))	('common', 'Reg', (54, 60))	('infection', 'Disease', 'MESH:D007239', (169, 178))	('PJP', 'Var', (75, 78))	('cART', 'Chemical', '-', (94, 98))
399008	33268763	Patients with KICS have higher mortality rates than those with MCD, and clinical deterioration and death can occur rapidly, as seen in our patient.	('mortality', 'Disease', (31, 40))	('KICS', 'Var', (14, 18))	('MCD', 'Disease', 'MESH:D012514', (63, 66))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('MCD', 'Disease', (63, 66))	('Patients', 'Species', '9606', (0, 8))	('mortality', 'Disease', 'MESH:D003643', (31, 40))	('patient', 'Species', '9606', (139, 146))	('KICS', 'Chemical', '-', (14, 18))
399066	28440953	Patient ineligibility included prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody, or other antibody or drug specifically targeting T cell costimulation or immune checkpoint pathways, active autoimmune disease, active brain metastasis or leptomeningeal disease, or required systemic glucocorticoid-replacement therapy (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.	('PD-1', 'Gene', '5133', (60, 64))	('active brain metastasis', 'Disease', 'MESH:D009362', (275, 298))	('anti-PD-L1', 'Var', (66, 76))	('anti-cytotoxic T lymphocyte antigen-4', 'Gene', (90, 127))	('autoimmune disease', 'Phenotype', 'HP:0002960', (255, 273))	('active brain metastasis', 'Disease', (275, 298))	('anti-PD-L2', 'Var', (78, 88))	('CTLA-4', 'Gene', '1493', (129, 135))	('autoimmune disease', 'Disease', (255, 273))	('leptomeningeal disease', 'Disease', 'MESH:D008577', (302, 324))	('anti-cytotoxic T lymphocyte antigen-4', 'Gene', '1493', (90, 127))	('autoimmune disease', 'Disease', 'MESH:D001327', (255, 273))	('CTLA-4', 'Gene', (129, 135))	('leptomeningeal disease', 'Disease', (302, 324))	('Patient', 'Species', '9606', (0, 7))	('PD-1', 'Gene', (60, 64))
399101	28440953	Anti-PD-1/PD-L1 inhibition has shown unprecedented clinical activity and durable responses across a variety of solid tumors, including previously considered "low-immunogenic" tumors such as non-small cell lung cancer and bladder carcinoma.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (194, 216))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (190, 216))	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('solid tumors', 'Disease', (111, 123))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (221, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('bladder carcinoma', 'Disease', 'MESH:D001749', (221, 238))	('inhibition', 'Var', (16, 26))	('non-small cell lung cancer', 'Disease', (190, 216))	('bladder carcinoma', 'Disease', (221, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('low-immunogenic" tumors', 'Disease', (158, 181))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (190, 216))	('low-immunogenic" tumors', 'Disease', 'MESH:D009800', (158, 181))	('PD-1', 'Gene', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('PD-1', 'Gene', '5133', (5, 9))
399107	28440953	Hopefully, a more comprehensive recognition of these immunogenic mutations in specific cancer types, including ULMS, would allow for better patient selection and outcome in response to anti-PD-1 therapy.	('cancer', 'Disease', (87, 93))	('ULMS', 'Disease', (111, 115))	('patient', 'Species', '9606', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PD-1', 'Gene', (190, 194))	('ULMS', 'Phenotype', 'HP:0002891', (111, 115))	('PD-1', 'Gene', '5133', (190, 194))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('mutations', 'Var', (65, 74))
399179	26234681	Furthermore, mechanistic studies revealed that Pax7 can promote sarcoma metastasis in vivo through MyoD-dependent regulation of pro-metastatic miR-182.	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('Pax7', 'Var', (47, 51))	('MyoD-dependent regulation of', 'MPA', (99, 127))	('sarcoma metastasis', 'Disease', 'MESH:D009362', (64, 82))	('sarcoma metastasis', 'Disease', (64, 82))	('promote', 'PosReg', (56, 63))
399183	26234681	Many of the somatic mutations necessary for metastasis of epithelial tumors are present within distinct subclones of the primary tumor which ultimately give rise to distant metastases.	('metastasis of epithelial tumors', 'Disease', (44, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('metastases', 'Disease', (173, 183))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('metastasis of epithelial tumors', 'Disease', 'MESH:D009362', (44, 75))	('give rise to', 'Reg', (152, 164))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('mutations', 'Var', (20, 29))
399184	26234681	In some cases, the risk of metastasis correlates with changes in the genomic sequence, copy number, or gene expression of the primary tumor.	('copy number', 'Var', (87, 98))	('gene', 'MPA', (103, 107))	('changes', 'Reg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('metastasis', 'CPA', (27, 37))	('tumor', 'Disease', (134, 139))
399191	26234681	UPS tumors are characterized by complex karyotypes reflecting genomic instability and often harbor inactivating mutations in the p53 tumor-suppressor pathway.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('UPS tumors', 'Disease', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('inactivating mutations', 'Var', (99, 121))	('UPS tumors', 'Disease', 'MESH:D017118', (0, 10))
399194	26234681	We recently used genetically engineered mice to delete or overexpress miR-182 in primary mouse sarcomas.	('delete', 'Var', (48, 54))	('overexpress', 'PosReg', (58, 69))	('sarcomas', 'Disease', 'MESH:D012509', (95, 103))	('miR-182', 'Gene', (70, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('mice', 'Species', '10090', (40, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('sarcomas', 'Disease', (95, 103))	('mouse', 'Species', '10090', (89, 94))
399202	26234681	Sarcomas develop after intramuscular delivery of an adenovirus that expresses Cre (Ad-Cre) into compound mutant mice with conditional mutations in both oncogenic Kras (LSL-KrasG12D) and mutant p53 (p53flox/flox), which we refer to as KP mice.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('LSL-KrasG12D', 'Gene', '16653', (168, 180))	('p53', 'Gene', (193, 196))	('LSL-KrasG12D', 'Gene', (168, 180))	('mutant', 'Var', (186, 192))	('mice', 'Species', '10090', (237, 241))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('mice', 'Species', '10090', (112, 116))	('mutations', 'Var', (134, 143))	('Kras', 'Gene', (162, 166))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
399204	26234681	Although the available genomic data suggest that human UPS may often arise in the absence of Kras and p53 mutations, in the related soft tissue sarcoma rhabdomyosarcoma, where more comprehensive genomic data are available, mutations of Ras and p53 commonly occur.	('p53', 'Gene', (244, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('absence', 'NegReg', (82, 89))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (132, 151))	('occur', 'Reg', (257, 262))	('human', 'Species', '9606', (49, 54))	('sarcoma rhabdomyosarcoma', 'Disease', 'MESH:D012208', (144, 168))	('Ras', 'Gene', (236, 239))	('sarcoma rhabdomyosarcoma', 'Disease', (144, 168))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (152, 168))	('mutations', 'Var', (106, 115))	('p53', 'Gene', (102, 105))	('Kras', 'Gene', (93, 97))	('mutations', 'Var', (223, 232))	('human UPS', 'Disease', (49, 58))
399222	26234681	Interestingly, the expression of miR-182 by RT-PCR was similar in the lung metastasis compared to the matched primary tumor, but Pax7/MyoD-positive primary tumors (n=5) did not maintain the expression of these factors (Supplemental Figure 1).	('primary tumors', 'Disease', 'MESH:D009369', (148, 162))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (118, 123))	('primary tumors', 'Disease', (148, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('miR-182', 'Var', (33, 40))
399229	26234681	In cells derived from primary mouse sarcomas from KP mice (Ctrl), siRNA-mediated knockdown of MyoD decreased miR-182 transcript levels (Figure 2E-F and Supplemental Figure 3E).	('decreased', 'NegReg', (99, 108))	('mice', 'Species', '10090', (53, 57))	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('knockdown', 'Var', (81, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('miR-182 transcript levels', 'MPA', (109, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('MyoD', 'Gene', (94, 98))	('sarcomas', 'Disease', (36, 44))	('mouse', 'Species', '10090', (30, 35))
399232	26234681	While knockdown of MyoD blunted migration/invasion in control sarcoma cells, overexpression of miR-182 was sufficient to maintain invasion across the transwell membrane.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('MyoD', 'Gene', (19, 23))	('miR-182', 'Gene', (95, 102))	('invasion', 'MPA', (130, 138))	('migration/invasion', 'CPA', (32, 50))	('blunted', 'NegReg', (24, 31))	('maintain', 'PosReg', (121, 129))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('knockdown', 'Var', (6, 15))	('sarcoma', 'Disease', (62, 69))
399238	26234681	Second, Pax7 is known to directly bind to and activate the MyoD promoter and displays stronger transcriptional activation properties than Pax3 in C2C12 cells.	('C2C12', 'CellLine', 'CVCL:0188', (146, 151))	('Pax3', 'Gene', (138, 142))	('Pax7', 'Var', (8, 12))	('transcriptional activation', 'MPA', (95, 121))	('activate', 'PosReg', (46, 54))	('MyoD promoter', 'Protein', (59, 72))	('stronger', 'PosReg', (86, 94))	('bind', 'Interaction', (34, 38))	('Pax3', 'Gene', '18505', (138, 142))
399244	26234681	To determine if Pax7 expression could influence metastatic phenotypes in our mouse model similar to MyoD, we overexpressed Pax7 in KP sarcoma cell lines, which induced miR-182 expression (Figure 3D).	('miR-182', 'Var', (168, 175))	('induced', 'Reg', (160, 167))	('influence', 'Reg', (38, 47))	('expression', 'MPA', (176, 186))	('mouse', 'Species', '10090', (77, 82))	('Pax7', 'Gene', (123, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('KP sarcoma', 'Disease', 'MESH:D012509', (131, 141))	('metastatic', 'CPA', (48, 58))	('KP sarcoma', 'Disease', (131, 141))
399245	26234681	As a control, we overexpressed Pax7 in sarcoma cells derived from miR-182flox/flox; LSL-KrasG12D; p53flox/flox mice that lack expression of miR-182 (KO cells).	('miR-182flox/flox', 'Var', (66, 82))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('mice', 'Species', '10090', (111, 115))	('LSL-KrasG12D', 'Gene', (84, 96))	('LSL-KrasG12D', 'Gene', '16653', (84, 96))	('sarcoma', 'Disease', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))
399247	26234681	In tandem, we knocked down Pax7 in sarcoma cells derived from mice with conditional overexpression of miR-182.	('miR-182', 'Var', (102, 109))	('overexpression', 'PosReg', (84, 98))	('sarcoma', 'Disease', (35, 42))	('knocked', 'Reg', (14, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('mice', 'Species', '10090', (62, 66))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('Pax7', 'Gene', (27, 31))
399250	26234681	We next tested the role of Pax7 in modulating miR-182 levels, MyoD expression, and metastatic phenotypes through siRNA knockdown of Pax7 in two KP sarcoma cell lines.	('tested', 'Reg', (8, 14))	('MyoD expression', 'MPA', (62, 77))	('Pax7', 'Gene', (132, 136))	('KP sarcoma', 'Disease', 'MESH:D012509', (144, 154))	('KP sarcoma', 'Disease', (144, 154))	('modulating', 'Reg', (35, 45))	('knockdown', 'Var', (119, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('miR-182 levels', 'MPA', (46, 60))
399252	26234681	To further define the role of Pax7 in miR-182-mediated sarcoma metastasis, we generated stable mouse sarcoma cell lines that express either Flag-tagged Pax7 or a Flag-alone control vector.	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('sarcoma', 'Disease', (55, 62))	('Pax7', 'Gene', (152, 156))	('sarcoma metastasis', 'Disease', 'MESH:D009362', (55, 73))	('sarcoma metastasis', 'Disease', (55, 73))	('sarcoma', 'Disease', (101, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('Flag-tagged', 'Var', (140, 151))	('mouse', 'Species', '10090', (95, 100))
399253	26234681	We used two cell lines derived from primary sarcomas resulting from Ad-Cre injection into mice that were LSL-KrasG12D; p53flox/flox (KP cells) or LSL-KrasG12D; Ink4a/Arfflox/flox (KI cells).	('LSL-KrasG12D', 'Gene', (146, 158))	('primary sarcomas', 'Disease', 'MESH:D012509', (36, 52))	('primary sarcomas', 'Disease', (36, 52))	('LSL-KrasG12D', 'Gene', (105, 117))	('LSL-KrasG12D', 'Gene', '16653', (146, 158))	('Ink4a/Arf', 'Gene', '12578', (160, 169))	('mice', 'Species', '10090', (90, 94))	('LSL-KrasG12D', 'Gene', '16653', (105, 117))	('p53flox/flox', 'Var', (119, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('Ink4a/Arf', 'Gene', (160, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))
399256	26234681	Lungs from mice receiving the Pax7-expressing cells showed increased metastatic lung area (Supplemental Figure 4I-J).	('mice', 'Species', '10090', (11, 15))	('Pax7-expressing', 'Var', (30, 45))	('metastatic lung area', 'CPA', (69, 89))	('increased', 'PosReg', (59, 68))
399257	26234681	Taken together, these data show that Pax7 expression can induce metastatic phenotypes in sarcoma cells in vivo.	('Pax7 expression', 'Var', (37, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('induce', 'PosReg', (57, 63))	('metastatic', 'CPA', (64, 74))
399258	26234681	To further explore the Pax7/miR182 relationship in metastasis, we performed an orthotopic allograft amputation experiment using sarcoma cells that expressed Pax7 or Flag-alone with or without an anti-miR-182 sponge (n=9-10 mice per cell line; Figure 5A).	('sarcoma', 'Disease', 'MESH:D012509', (128, 135))	('miR182', 'Gene', (28, 34))	('sarcoma', 'Disease', (128, 135))	('mice', 'Species', '10090', (223, 227))	('miR182', 'Gene', '387177', (28, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Pax7', 'Var', (157, 161))
399264	26234681	These results suggest a model where Pax7-dependent metastasis requires miR-182 for sarcoma metastasis in vivo (Figure 5F).	('sarcoma metastasis', 'Disease', 'MESH:D009362', (83, 101))	('miR-182', 'Var', (71, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma metastasis', 'Disease', (83, 101))
399270	26234681	Expression of Pax7 and MyoD correlated with miR-182 levels in both mouse and human sarcoma samples.	('sarcoma', 'Disease', (83, 90))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('MyoD', 'Protein', (23, 27))	('mouse', 'Species', '10090', (67, 72))	('miR-182', 'Var', (44, 51))	('Pax7', 'Gene', (14, 18))	('human', 'Species', '9606', (77, 82))
399310	25165418	50 ancillary molecular tests were performed, 33 for aiding diagnosis and 17 mutational analyses for gastrointestinal stromal tumour to guide therapy.	('mutational', 'Var', (76, 86))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('gastrointestinal stromal tumour', 'Disease', (100, 131))	('gastrointestinal stromal tumour', 'Disease', 'MESH:D046152', (100, 131))
399336	32630797	Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination.	('fits', 'Disease', 'MESH:D012640', (73, 77))	('IGF-1R', 'Gene', '3480', (81, 87))	('mTOR', 'Gene', '2475', (114, 118))	('IGF-1R', 'Gene', (81, 87))	('mTOR', 'Gene', (114, 118))	('fits', 'Disease', (73, 77))	('IGF-1R', 'Gene', '3480', (107, 113))	('antibodies', 'Var', (88, 98))	('IGF-1R', 'Gene', (107, 113))
399338	32630797	Results: Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, p = 0.042).	('IGF-1R', 'Gene', (80, 86))	('IGF-1R', 'Gene', '3480', (194, 200))	('improvement', 'PosReg', (145, 156))	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('IGF-1R', 'Gene', (194, 200))	('IGF-1R/mTORi', 'Gene', '3480', (194, 206))	('ES', 'Phenotype', 'HP:0012254', (18, 20))	('antibodies', 'Var', (87, 97))	('patients', 'Species', '9606', (21, 29))	('PFS', 'MPA', (160, 163))	('IGF-1R', 'Gene', '3480', (80, 86))	('Cancer', 'Disease', (53, 59))	('IGF-1R/mTORi', 'Gene', (194, 206))
399354	32630797	Around the same time, derepression of IRS-1:immediately downstream of IGF-1R:was described as a potent mechanism used by cancer cells to quickly evade single-agent mTORi.	('IGF-1R', 'Gene', (70, 76))	('IRS-1', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('derepression', 'Var', (22, 34))	('mTORi', 'Chemical', '-', (164, 169))	('evade', 'NegReg', (145, 150))	('IRS-1', 'Gene', '3667', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('IGF-1R', 'Gene', '3480', (70, 76))
399384	32630797	The usefulness of early 18F-FDG PET imaging:obtained just 8 days (range 8-14 days) after beginning R1507 IGF-1R mAb treatment:has been shown by Sarcoma Alliance for Research and Collaboration (SARC) investigators to predict a 6-week response, PFS, and OS.	('Sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('IGF-1R', 'Gene', '3480', (105, 111))	('IGF-1R', 'Gene', (105, 111))	('Sarcoma', 'Disease', (144, 151))	('18F-FDG', 'Chemical', 'MESH:D019788', (24, 31))	('PFS', 'Disease', (243, 246))	('Sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('R1507', 'Var', (99, 104))
399411	32630797	Notably, the absence of detectable pretreatment pIGF-1R was predictive of RECIST response (p = 0.0128) and clinical benefit (p = 0.0377).	('clinical benefit', 'CPA', (107, 123))	('absence', 'Var', (13, 20))	('RECIST response', 'CPA', (74, 89))	('pIGF', 'Gene', '5281', (48, 52))	('pIGF', 'Gene', (48, 52))	('IGF-1R', 'Gene', '3480', (49, 55))	('IGF-1R', 'Gene', (49, 55))
399437	32630797	As future mechanistic studies explore why low or absent pIGF-1R expression was associated with a higher response rate, it is essential to note that our IHC analysis used a mAb against the pIGF-1R tyrosine 1161 residue because it outperformed other phospho-targeted Abs (ones targeting tyrosine 950 and 1131/1135/1136) (Figure S6).	('outperformed', 'PosReg', (229, 241))	('IGF-1R', 'Gene', (189, 195))	('tyrosine', 'Chemical', 'MESH:D014443', (285, 293))	('pIGF', 'Gene', '5281', (188, 192))	('pIGF', 'Gene', (188, 192))	('IGF-1R', 'Gene', '3480', (57, 63))	('tyrosine 950', 'Var', (285, 297))	('absent', 'NegReg', (49, 55))	('IGF-1R', 'Gene', (57, 63))	('tyrosine', 'Chemical', 'MESH:D014443', (196, 204))	('pIGF', 'Gene', '5281', (56, 60))	('tyrosine 1161', 'Var', (196, 209))	('low', 'Var', (42, 45))	('IGF-1R', 'Gene', '3480', (189, 195))	('pIGF', 'Gene', (56, 60))
399477	32630797	The primary antibodies IGF-IR (sc-713, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and pIGF-IRY1161 (ab39398, Abcam, Cambridge, MA, USA) diluted in blocking buffer (1:150 for IGF-IR and 1:75 for pIGF-IRY1161) were added for overnight incubation at 4  C. Subsequently, the slides were washed three times for 5 min and incubated with secondary antibody EnVision+ Dual Link (K406311, Dako, Carpentaria, CA, USA) for 30 min.	('IGF-IR', 'Gene', (91, 97))	('pIGF', 'Gene', '5281', (198, 202))	('pIGF', 'Gene', (198, 202))	('IGF-IR', 'Gene', (23, 29))	('K406311', 'Var', (375, 382))	('IGF-IR', 'Gene', (199, 205))	('IGF-IR', 'Gene', '3480', (91, 97))	('IGF-IR and 1', 'Gene', '3480;3479', (178, 190))	('IGF-IR', 'Gene', (178, 184))	('IGF-IR', 'Gene', '3480', (23, 29))	('IGF-IR', 'Gene', '3480', (199, 205))	('IGF-IR', 'Gene', '3480', (178, 184))	('pIGF', 'Gene', (90, 94))	('pIGF', 'Gene', '5281', (90, 94))
399488	32630797	This work was supported in part by the National Cancer Institute through grants R01-CA180279-01 and R01-CA151533, the National Institutes of Health through MD Anderson's Cancer Center Support Grant (CA16672), and with the generous philanthropic support provided by the Wells Alliance, Faris Virani Foundation, and Gaylord Foundation.	('R01-CA151533', 'Var', (100, 112))	('Cancer', 'Disease', 'MESH:D009369', (170, 176))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('R01-CA180279-01', 'Var', (80, 95))	('Cancer', 'Disease', (48, 54))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Cancer', 'Disease', (170, 176))
399521	32457880	The biologically effective dose (BED) conversion factor applied to the PTV was alpha/beta = 10 Gy/fraction; for the OARs, it was alpha/beta = 3 Gy for 2 Gy/fraction.	('alpha/beta =', 'Var', (79, 91))	('PTV', 'Chemical', '-', (71, 74))	('alpha/beta = 3', 'Var', (129, 143))
399714	25611008	Among children, only antibodies to PfAMA-1 were significantly associated with KSHV seropositivity, (P < 0.0001).	('KS', 'Phenotype', 'HP:0100726', (78, 80))	('KSHV seropositivity', 'Disease', (78, 97))	('PfAMA-1', 'Gene', (35, 42))	('associated', 'Reg', (62, 72))	('antibodies', 'Var', (21, 31))	('KSHV', 'Species', '37296', (78, 82))	('children', 'Species', '9606', (6, 14))
399715	25611008	In both mothers and children, anti-ORF73 antibodies were more strongly associated with malaria antibodies than anti-K8.1 antibodies.	('malaria', 'Disease', (87, 94))	('ORF73', 'Gene', (35, 40))	('antibodies', 'Var', (41, 51))	('malaria', 'Disease', 'MESH:D008288', (87, 94))	('ORF73', 'Gene', '4961527', (35, 40))	('children', 'Species', '9606', (20, 28))	('associated', 'Reg', (71, 81))
399745	25611008	Individuals with antibodies to either ORF73 or K8.1 were considered to be KSHV seropositive, and individuals with antibodies to neither ORF73 nor K8.1 were considered to be KSHV seronegative.	('ORF73', 'Gene', (38, 43))	('ORF73', 'Gene', '4961527', (136, 141))	('KSHV', 'Disease', (74, 78))	('ORF73', 'Gene', '4961527', (38, 43))	('antibodies', 'Var', (17, 27))	('KS', 'Phenotype', 'HP:0100726', (173, 175))	('KSHV', 'Species', '37296', (173, 177))	('KSHV', 'Species', '37296', (74, 78))	('K8.1', 'Var', (47, 51))	('ORF73', 'Gene', (136, 141))	('KS', 'Phenotype', 'HP:0100726', (74, 76))
399749	25611008	Tables 1 and 2 show crude and adjusted associations between KSHV seropositivity, socio-demographic factors and other clinical factors among mothers and children, respectively.	('KSHV', 'Gene', (60, 64))	('children', 'Species', '9606', (152, 160))	('seropositivity', 'Var', (65, 79))	('KSHV', 'Species', '37296', (60, 64))	('KS', 'Phenotype', 'HP:0100726', (60, 62))
399750	25611008	Household socioeconomic status and location were independently associated with KSHV seropositivity both in the mothers and in the children.	('seropositivity', 'Var', (84, 98))	('KSHV', 'Species', '37296', (79, 83))	('associated', 'Reg', (63, 73))	('KS', 'Phenotype', 'HP:0100726', (79, 81))	('KSHV', 'Gene', (79, 83))	('children', 'Species', '9606', (130, 138))
399751	25611008	Age was crudely associated with KSHV seropositivity (P = 0.01) among mothers, but the association was lost when we adjusted for household socio-economic status and location.	('seropositivity', 'Var', (37, 51))	('KSHV', 'Species', '37296', (32, 36))	('KS', 'Phenotype', 'HP:0100726', (32, 34))	('associated', 'Reg', (16, 26))	('KSHV', 'Gene', (32, 36))
399755	25611008	Among children, malaria antibodies to PfAMA-1 were strongly associated with KSHV seropositivity.	('PfAMA-1', 'Gene', (38, 45))	('malaria', 'Disease', (16, 23))	('antibodies', 'Var', (24, 34))	('KSHV', 'Species', '37296', (76, 80))	('KSHV seropositivity', 'Disease', (76, 95))	('KS', 'Phenotype', 'HP:0100726', (76, 78))	('children', 'Species', '9606', (6, 14))	('malaria', 'Disease', 'MESH:D008288', (16, 23))	('associated', 'Reg', (60, 70))
399756	25611008	The odds of being KSHV seropositive among children with high PfAMA-1 antibody titres, compared to those with low PfAMA-1 antibody titres, were 1.59 (P = 0.02) (Table 4).	('children', 'Species', '9606', (42, 50))	('KSHV', 'Species', '37296', (18, 22))	('KS', 'Phenotype', 'HP:0100726', (18, 20))	('PfAMA-1', 'Gene', (61, 68))	('high', 'Var', (56, 60))
399759	25611008	Among mothers, the association between malaria antibodies and the presence of ORF73 seropositivity was stronger than the association between malaria antibodies and K8.1 seropositivity (Table 5).	('malaria', 'Disease', (141, 148))	('malaria', 'Disease', 'MESH:D008288', (39, 46))	('ORF73', 'Gene', '4961527', (78, 83))	('presence', 'Var', (66, 74))	('malaria', 'Disease', 'MESH:D008288', (141, 148))	('malaria', 'Disease', (39, 46))	('stronger', 'PosReg', (103, 111))	('ORF73', 'Gene', (78, 83))
399765	25611008	Its major findings are as follows: (1) KSHV seropositivity was strongly associated with malaria antibodies to both PfMSP-1 and PfAMA-1 in the mothers.	('malaria', 'Disease', 'MESH:D008288', (88, 95))	('KSHV', 'Gene', (39, 43))	('PfMSP-1', 'Gene', (115, 122))	('seropositivity', 'Var', (44, 58))	('associated', 'Reg', (72, 82))	('KS', 'Phenotype', 'HP:0100726', (39, 41))	('malaria', 'Disease', (88, 95))	('KSHV', 'Species', '37296', (39, 43))	('PfAMA-1', 'Gene', (127, 134))
399766	25611008	(2) In the children, KSHV seropositivity was highly associated with malaria antibody titres to PfAMA-1 but not PfMSP-1.	('children', 'Species', '9606', (11, 19))	('KS', 'Phenotype', 'HP:0100726', (21, 23))	('malaria antibody titres', 'Disease', (68, 91))	('malaria antibody titres', 'Disease', 'MESH:D008288', (68, 91))	('seropositivity', 'Var', (26, 40))	('KSHV', 'Gene', (21, 25))	('associated', 'Reg', (52, 62))	('PfAMA-1', 'Gene', (95, 102))	('KSHV', 'Species', '37296', (21, 25))
399768	25611008	Kaposi's sarcoma-associated herpes virus seropositivity was strongly associated with both malaria antibodies in the mothers.	('malaria', 'Disease', (90, 97))	('herpes virus seropositivity', 'Phenotype', 'HP:0005353', (28, 55))	('seropositivity', 'Var', (41, 55))	('associated', 'Reg', (69, 79))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (0, 16))	('malaria', 'Disease', 'MESH:D008288', (90, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (0, 16))	("Kaposi's sarcoma", 'Disease', (0, 16))
399777	25611008	We have previously shown that asymptomatic malaria parasitaemia is associated with KSHV seropositivity.	('seropositivity', 'Var', (88, 102))	('KSHV', 'Species', '37296', (83, 87))	('malaria parasitaemia', 'Disease', (43, 63))	('malaria parasitaemia', 'Disease', 'MESH:D008288', (43, 63))	('KS', 'Phenotype', 'HP:0100726', (83, 85))	('KSHV', 'Gene', (83, 87))	('associated', 'Reg', (67, 77))
399783	25611008	Unlike in the mothers, we observed that KSHV seropositivity is associated with antibodies to PfAMA-1 but not PfMSP-1 in the children.	('children', 'Species', '9606', (124, 132))	('PfAMA-1', 'Gene', (93, 100))	('associated', 'Reg', (63, 73))	('antibodies', 'Var', (79, 89))	('KSHV', 'Species', '37296', (40, 44))	('KS', 'Phenotype', 'HP:0100726', (40, 42))	('KSHV', 'Gene', (40, 44))
399840	25802527	On MRI imaging the mass may appear hypo-, iso-, or hyperintense on T1 and hypo or hyperintense on T2.	('hyperintense', 'Var', (82, 94))	('hyperintense', 'Var', (51, 63))	('hypo', 'Disease', (35, 39))	('hypo', 'Disease', (74, 78))	('hypo', 'Disease', 'MESH:D052456', (35, 39))	('iso-', 'Var', (42, 46))	('hypo', 'Disease', 'MESH:D052456', (74, 78))
399910	24187593	A bone marrow aspiration and cytogenetics were suggestive of acute myeloid leukaemia with t(8;21)(q22;q22).	('aspiration', 'Phenotype', 'HP:0002835', (14, 24))	('t(8;21)(q22;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (90, 106))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (67, 84))	('acute myeloid leukaemia', 'Disease', (61, 84))	('t(8;21)(q22;q22', 'Var', (90, 105))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (61, 84))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (61, 84))
399927	24187593	Its incidence is increased in AML with t(8; 21) (q22;q22), FAB M4/M5 sub-types, infantile leukaemia and allogenic stem cell transplantation.	('increased', 'PosReg', (17, 26))	('FAB', 'Gene', '2187', (59, 62))	('AML', 'Disease', 'MESH:D015470', (30, 33))	('leukaemia', 'Disease', (90, 99))	('FAB', 'Gene', (59, 62))	('t(8; 21) (q22;q22', 'Var', (39, 56))	('AML', 'Disease', (30, 33))	('incidence', 'MPA', (4, 13))	('leukaemia', 'Disease', 'MESH:D007938', (90, 99))
399946	24187593	Recent systematic fluorescence in situ hybridisation analysis on granulocytic sarcoma samples detected several chromosomal aberrations, including monosomy 7, trisomy 4, trisomy 8, trisomy 11, del(5q), and del(20q).	('trisomy', 'Disease', (158, 165))	('del(20q', 'Var', (205, 212))	('granulocytic sarcoma', 'Disease', (65, 85))	('del(5q', 'Var', (192, 198))	('trisomy 8', 'Var', (169, 178))	('monosomy 7', 'Disease', (146, 156))	('granulocytic sarcoma', 'Disease', 'MESH:D023981', (65, 85))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (111, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('trisomy 11', 'Var', (180, 190))
399972	32558385	The inclusion criteria were as follows: (i) the International Classification of Diseases (ICD) code O-3 morphology 8930/3 or 8931/3; (ii) SEER site recodes of ICD-O-3 included the corpus uteri/uterus not specified; (iii) active follow-up to ensure reliable patient status; (iv) ESS as the only or first primary tumor that was confirmed by histology.	('8931/3', 'Var', (125, 131))	('not specified', 'Species', '32644', (200, 213))	('patient', 'Species', '9606', (257, 264))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('Classification of Diseases', 'Disease', 'MESH:D008310', (62, 88))	('Classification of Diseases', 'Disease', (62, 88))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('tumor', 'Disease', (311, 316))	('ESS', 'Disease', (278, 281))
400061	32368542	The positivity for P53 could be a reflection of anaplasia.	('P53', 'Gene', '7157', (19, 22))	('anaplasia', 'Disease', (48, 57))	('positivity', 'Var', (4, 14))	('P53', 'Gene', (19, 22))
400073	32368542	Positivity for CD56 was nonspecific for Wilms tumor.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Wilms tumor', 'Disease', 'MESH:D009396', (40, 51))	('Wilms tumor', 'Disease', (40, 51))	('Wilms tumor', 'Phenotype', 'HP:0002667', (40, 51))	('CD56', 'Gene', '4684', (15, 19))	('Positivity', 'Var', (0, 10))	('CD56', 'Gene', (15, 19))
400120	31312520	In the presence of post-surgical change after IE, visualizing areas within the surgical bed that show similar imaging appearances on MRI to the original tumour is highly suggestive of residual disease.	('residual disease', 'Disease', (184, 200))	('original tumour', 'Disease', (144, 159))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('original tumour', 'Disease', 'MESH:D009369', (144, 159))	('change', 'Var', (33, 39))
400194	31118781	Alveolar soft part sarcoma (ASPS) is a rare, mostly chemo-resistant soft tissue sarcoma (STS) subtype characterized by the unbalanced translocation t(X; 17) (p11.2; q25.3), which results in the ASPACR1-TFE3 fusion gene.	('TFE3', 'Gene', '7030', (202, 206))	('ASPS', 'Gene', (28, 32))	('Alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (0, 26))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('t(X; 17) (p11.2', 'Var', (148, 163))	('ASPS', 'Gene', '79058', (28, 32))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (68, 87))	('sarcoma', 'Disease', (80, 87))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (9, 26))	('Alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (0, 26))	('results in', 'Reg', (179, 189))	('Alveolar soft part sarcoma', 'Disease', (0, 26))	('TFE3', 'Gene', (202, 206))	('sarcoma', 'Disease', (19, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('CR', 'Chemical', '-', (198, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))
400270	31118781	For example, MET gene expression was not assessed Third, although apatinib is known as a specific VEGFR-2 inhibitor, there remains a question whether apatinib also suppresses the activity of other factors such as EGF, PDGFRalpha/beta, Aurora-B, Ret, c-FMS, and c-Kit.	('apatinib', 'Chemical', 'MESH:C553458', (66, 74))	('EGF', 'Gene', (213, 216))	('EGF', 'Gene', '1950', (99, 102))	('c-Kit', 'Gene', (261, 266))	('c-FMS', 'Gene', (250, 255))	('apatinib', 'Var', (150, 158))	('VEGFR-2', 'Gene', '3791', (98, 105))	('apatinib', 'Chemical', 'MESH:C553458', (150, 158))	('Ret', 'Gene', (245, 248))	('EGF', 'Gene', (99, 102))	('Aurora-B', 'Gene', (235, 243))	('EGF', 'Gene', '1950', (213, 216))	('Ret', 'Gene', '5979', (245, 248))	('activity', 'MPA', (179, 187))	('VEGFR-2', 'Gene', (98, 105))	('PDGFRalpha/beta', 'Gene', '5156;5159', (218, 233))	('Aurora-B', 'Gene', '9212', (235, 243))	('suppresses', 'NegReg', (164, 174))	('PDGFRalpha/beta', 'Gene', (218, 233))	('c-FMS', 'Gene', '1436', (250, 255))	('c-Kit', 'Gene', '3815', (261, 266))
400284	29956493	In a multivariate analysis of the retrospective study, independent prognostic factors for OS were A-RMS, R0 resection, and adjuvant radiotherapy (RT).	('OS', 'Chemical', '-', (90, 92))	('RMS', 'Phenotype', 'HP:0002859', (100, 103))	('A-RMS', 'Disease', (98, 103))	('R0 resection', 'Var', (105, 117))
400312	29956493	Lymph nodes (LN) and/or metastases were statistically more frequently noted in A-RMS (30/55, 54%) compared with E-RMS (7/33, 21%) or P-RMS (9/69, 13%) (P = 0.001).	('metastases', 'Disease', 'MESH:D009362', (24, 34))	('RMS', 'Phenotype', 'HP:0002859', (135, 138))	('Lymph nodes', 'CPA', (0, 11))	('RMS', 'Phenotype', 'HP:0002859', (114, 117))	('A-RMS', 'Var', (79, 84))	('metastases', 'Disease', (24, 34))	('RMS', 'Phenotype', 'HP:0002859', (81, 84))
400313	29956493	Only metastases other than LN were observed in 22 of 157 (14%) patients with 13 of 22 (59%) patients with A-RMS, two of 22 (9%) patients with E-RMS, and seven of 22 (32%) patients with P-RMS.	('patients', 'Species', '9606', (92, 100))	('RMS', 'Phenotype', 'HP:0002859', (108, 111))	('patients', 'Species', '9606', (171, 179))	('RMS', 'Phenotype', 'HP:0002859', (187, 190))	('RMS', 'Phenotype', 'HP:0002859', (144, 147))	('metastases', 'Disease', (5, 15))	('A-RMS', 'Var', (106, 111))	('patients', 'Species', '9606', (63, 71))	('metastases', 'Disease', 'MESH:D009362', (5, 15))	('patients', 'Species', '9606', (128, 136))
400321	29956493	In total, 83 patients who received chemotherapy had localized RMS with the following subtype RMS: 24 of 25 (96%) for A-RMS, 22 of 26 (84%) for E-RMS, and 37 of 60 (62%) for P-RMS (P = 0.002).	('RMS', 'Phenotype', 'HP:0002859', (175, 178))	('RMS', 'Phenotype', 'HP:0002859', (119, 122))	('RMS', 'Phenotype', 'HP:0002859', (62, 65))	('patients', 'Species', '9606', (13, 21))	('localized RMS', 'Disease', (52, 65))	('RMS', 'Phenotype', 'HP:0002859', (145, 148))	('RMS', 'Phenotype', 'HP:0002859', (93, 96))	('E-RMS', 'Var', (143, 148))	('A-RMS', 'Var', (117, 122))
400322	29956493	Patients with A-RMS, E-RMS, and P-RMS received CT for 53 of 55 (96%), 29 of 33 (88%), and 45 of 69 (62%) patients, respectively (P = 0.0001).	('patients', 'Species', '9606', (105, 113))	('RMS', 'Phenotype', 'HP:0002859', (34, 37))	('Patients', 'Species', '9606', (0, 8))	('E-RMS', 'Var', (21, 26))	('RMS', 'Phenotype', 'HP:0002859', (16, 19))	('A-RMS', 'Var', (14, 19))	('P-RMS', 'Var', (32, 37))	('RMS', 'Phenotype', 'HP:0002859', (23, 26))
400323	29956493	Among 122 patients with a known administered regimen, PP was used for 27 of 51 (53%) with A-RMS, 20 of 29 (69%) with E-RMS, and five of 42 (12%) patients with P-RMS (P = 0.0001).	('patients', 'Species', '9606', (145, 153))	('RMS', 'Phenotype', 'HP:0002859', (119, 122))	('men', 'Species', '9606', (49, 52))	('A-RMS', 'Var', (90, 95))	('RMS', 'Phenotype', 'HP:0002859', (92, 95))	('RMS', 'Phenotype', 'HP:0002859', (161, 164))	('patients', 'Species', '9606', (10, 18))	('E-RMS', 'Var', (117, 122))
400336	29956493	Median OS was 16 (range: 2-227), 33 (range = 1-337), and 51 months (range = 1-297) for A-RMS, P-RMS, and E-RMS, respectively.	('OS', 'Chemical', '-', (7, 9))	('RMS', 'Phenotype', 'HP:0002859', (89, 92))	('E-RMS', 'Var', (105, 110))	('RMS', 'Phenotype', 'HP:0002859', (96, 99))	('RMS', 'Phenotype', 'HP:0002859', (107, 110))	('P-RMS', 'Var', (94, 99))	('A-RMS', 'Var', (87, 92))
400337	29956493	In patients with localized disease, median OS was 24, 42, and 66 months for A-RMS, P-RMS, and E-RMS, respectively.	('RMS', 'Phenotype', 'HP:0002859', (85, 88))	('RMS', 'Phenotype', 'HP:0002859', (78, 81))	('P-RMS', 'Var', (83, 88))	('RMS', 'Phenotype', 'HP:0002859', (96, 99))	('patients', 'Species', '9606', (3, 11))	('OS', 'Chemical', '-', (43, 45))	('A-RMS', 'Disease', (76, 81))	('E-RMS', 'Var', (94, 99))
400338	29956493	In patients with metastatic disease at diagnosis, median OS was 9, 13, and 28 months for A-RMS, P-RMS, and E-RMS, respectively.	('P-RMS', 'Disease', (96, 101))	('RMS', 'Phenotype', 'HP:0002859', (98, 101))	('A-RMS', 'Disease', (89, 94))	('OS', 'Chemical', '-', (57, 59))	('patients', 'Species', '9606', (3, 11))	('E-RMS', 'Var', (107, 112))	('RMS', 'Phenotype', 'HP:0002859', (91, 94))	('RMS', 'Phenotype', 'HP:0002859', (109, 112))
400370	29956493	The positive impact of PP for A-RMS and E-RMS on OS is also reported by MSKCC and MDA experience 14, 15 and Ferrari who described better survival with administration of chemotherapy per current guidelines for pediatric RMS 11.	('better', 'PosReg', (130, 136))	('E-RMS', 'Var', (40, 45))	('OS', 'Chemical', '-', (49, 51))	('RMS', 'Phenotype', 'HP:0002859', (219, 222))	('RMS', 'Phenotype', 'HP:0002859', (42, 45))	('A-RMS', 'Var', (30, 35))	('RMS', 'Phenotype', 'HP:0002859', (32, 35))
400382	29956493	Why are adult patients with A-RMS and E-RMS at higher risk of relapse than children affected with the same disease?	('RMS', 'Phenotype', 'HP:0002859', (30, 33))	('E-RMS', 'Var', (38, 43))	('children', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (14, 22))	('A-RMS', 'Var', (28, 33))	('RMS', 'Phenotype', 'HP:0002859', (40, 43))
400483	29202127	Furthermore, it was determined that a high BMI at diagnosis was associated with a reduced overall survival in pediatric osteosarcoma subjects.	('osteosarcoma', 'Disease', (120, 132))	('osteosarcoma', 'Disease', 'MESH:D012516', (120, 132))	('high', 'Var', (38, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('reduced', 'NegReg', (82, 89))	('osteosarcoma', 'Phenotype', 'HP:0002669', (120, 132))	('overall survival', 'MPA', (90, 106))
400529	29202127	Interestingly, there were no detectable differences in any of the aforementioned analytes tested in our healthy control group when stratified by BMI, suggesting that alterations in sCD40L and EGF occur only in the presence of combined overweight or obesity and sarcoma growth.	('sarcoma growth', 'Disease', (261, 275))	('obesity', 'Disease', 'MESH:D009765', (249, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('CD40L', 'Gene', (182, 187))	('obesity', 'Disease', (249, 256))	('alterations', 'Var', (166, 177))	('EGF', 'Gene', (192, 195))	('overweight', 'Phenotype', 'HP:0025502', (235, 245))	('sarcoma growth', 'Disease', 'MESH:D006130', (261, 275))	('obesity', 'Phenotype', 'HP:0001513', (249, 256))	('CD40L', 'Gene', '959', (182, 187))
400576	29202127	Prior studies in other tumor models have described CCL4 expression as being either tumor promoting or being host protective and associated with prolonged survival.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('survival', 'CPA', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('host protective', 'CPA', (108, 123))	('CCL4', 'Gene', '6351', (51, 55))	('tumor', 'Disease', (23, 28))	('expression', 'Var', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('CCL4', 'Gene', (51, 55))
400586	29202127	HB-EGF has been identified previously as a potential biomarker in certain subtypes of sarcoma, and high levels of HB-EGF transcripts have been correlated with decreased overall survival.	('sarcoma', 'Disease', (86, 93))	('HB-EGF', 'Gene', '1839', (114, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('HB-EGF', 'Gene', (0, 6))	('overall', 'MPA', (169, 176))	('high', 'Var', (99, 103))	('decreased', 'NegReg', (159, 168))	('sarcoma', 'Disease', 'MESH:D012509', (86, 93))	('HB-EGF', 'Gene', (114, 120))	('HB-EGF', 'Gene', '1839', (0, 6))
400587	29202127	EGF is expressed in soft-tissue sarcomas, and initial studies into EGFR blockade plus chemotherapy have shown decreased tumor growth both in vitro and in a mouse model of fibrosarcoma, but EGFR levels may contribute to starvation- and chemotherapeutic-resistance in osteosarcoma.	('contribute', 'Reg', (205, 215))	('fibrosarcoma', 'Disease', (171, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('EGFR', 'Gene', (67, 71))	('osteosarcoma', 'Disease', 'MESH:D012516', (266, 278))	('osteosarcoma', 'Disease', (266, 278))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (20, 39))	('tumor', 'Disease', (120, 125))	('decreased', 'NegReg', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (171, 183))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (20, 40))	('blockade', 'Var', (72, 80))	('osteosarcoma', 'Phenotype', 'HP:0002669', (266, 278))	('mouse', 'Species', '10090', (156, 161))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('fibrosarcoma', 'Disease', 'MESH:D005354', (171, 183))	('sarcomas', 'Disease', (32, 40))
400633	26429980	Finally, activated IGF-1R is thought to promote cellular motility through activation of IRS2, which acts to alter integrin expression through poorly understood mechanisms involving the small G protein RHOA, focal adhesion kinase (FAK), and Rho-kinase (ROCK).	('promote', 'PosReg', (40, 47))	('IRS2', 'Gene', '8660', (88, 92))	('RHOA', 'Gene', (201, 205))	('IGF-1R', 'Gene', '3480', (19, 25))	('IGF-1R', 'Gene', (19, 25))	('FAK', 'Gene', '5747', (230, 233))	('activation', 'PosReg', (74, 84))	('cellular motility', 'CPA', (48, 65))	('activated', 'Var', (9, 18))	('FAK', 'Gene', (230, 233))	('integrin expression', 'MPA', (114, 133))	('IRS2', 'Gene', (88, 92))	('alter', 'Reg', (108, 113))	('RHOA', 'Gene', '387', (201, 205))
400638	26429980	Furthermore, IGF-1R pathway dysregulation acts as an oncogenic signal in the context of both initial tumorigenesis and resistance to cytotoxic and targeted anticancer therapies.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('dysregulation', 'Var', (28, 41))	('IGF-1R', 'Gene', '3480', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('IGF-1R', 'Gene', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
400649	26429980	To date, the most widely tested combination strategy involves the use of IGF-1R antibodies with MTOR allosteric inhibitors, such as temsirolimus or ridaforolimus.	('MTOR', 'Gene', '2475', (96, 100))	('IGF-1R', 'Gene', (73, 79))	('temsirolimus', 'Chemical', 'MESH:C401859', (132, 144))	('ridaforolimus', 'Chemical', 'MESH:C515074', (148, 161))	('MTOR', 'Gene', (96, 100))	('antibodies', 'Var', (80, 90))	('IGF-1R', 'Gene', '3480', (73, 79))
400671	26429980	The serious adverse events that were observed more commonly in patients receiving figitumumab compared to chemotherapy alone included pneumonia (6% vs 4%), hyperglycemia (3% vs <1%), asthenia (3% vs 1%), and dehydration (4% vs 1%).	('figitumumab', 'Chemical', 'MESH:C525021', (82, 93))	('asthenia', 'Disease', (183, 191))	('hyperglycemia', 'Disease', (156, 169))	('asthenia', 'Phenotype', 'HP:0025406', (183, 191))	('dehydration', 'Disease', 'MESH:D003681', (208, 219))	('dehydration', 'Disease', (208, 219))	('pneumonia', 'Phenotype', 'HP:0002090', (134, 143))	('hyperglycemia', 'Phenotype', 'HP:0003074', (156, 169))	('patients', 'Species', '9606', (63, 71))	('pneumonia', 'Disease', (134, 143))	('pneumonia', 'Disease', 'MESH:D011014', (134, 143))	('hyperglycemia', 'Disease', 'MESH:D006943', (156, 169))	('figitumumab', 'Var', (82, 93))	('asthenia', 'Disease', 'MESH:D001247', (183, 191))	('dehydration', 'Phenotype', 'HP:0001944', (208, 219))
400674	26429980	Importantly, in this study less than 5% of patients had an EGFR mutation, as it was proposed that based on preclinical models IGF-1R and EGFR crosstalk was a key mechanism of tumorigenesis and resistance to isolated EGFR inhibition in patients with NSCLC independent of EGFR mutation status.	('EGFR', 'Gene', (59, 63))	('resistance', 'CPA', (193, 203))	('EGFR', 'Gene', (137, 141))	('EGFR', 'Gene', (216, 220))	('patients', 'Species', '9606', (235, 243))	('IGF-1R', 'Gene', (126, 132))	('IGF-1R', 'Gene', '3480', (126, 132))	('NSCLC', 'Disease', 'MESH:D002289', (249, 254))	('EGFR', 'Gene', (270, 274))	('EGFR', 'Gene', '1956', (59, 63))	('tumor', 'Disease', (175, 180))	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (43, 51))	('NSCLC', 'Disease', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('EGFR', 'Gene', '1956', (137, 141))	('EGFR', 'Gene', '1956', (216, 220))	('EGFR', 'Gene', '1956', (270, 274))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
400678	26429980	Recently completed phase II trials have evaluated OSI-906 combination therapies with paclitaxel in patients with recurrent ovarian cancer (NCT00889382) and with erlotinib in patients with metastatic EGFR mutant NSCLC (NCT01221077).	('ovarian cancer', 'Phenotype', 'HP:0100615', (123, 137))	('EGFR', 'Gene', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ovarian cancer', 'Disease', 'MESH:D010051', (123, 137))	('patients', 'Species', '9606', (174, 182))	('mutant', 'Var', (204, 210))	('patients', 'Species', '9606', (99, 107))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (113, 137))	('NSCLC', 'Disease', (211, 216))	('ovarian cancer', 'Disease', (123, 137))	('erlotinib', 'Chemical', 'MESH:D000069347', (161, 170))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('paclitaxel', 'Chemical', 'MESH:D017239', (85, 95))	('OSI-906', 'Chemical', 'MESH:C551528', (50, 57))	('EGFR', 'Gene', '1956', (199, 203))
400887	23340972	One example previously mentioned involves evanescently coupling light from illuminated glass slides into the nanoparticles to excite them as opposed to a broadband source.	('men', 'Species', '9606', (23, 26))	('evanescently', 'Var', (42, 54))	('excite', 'PosReg', (126, 132))
400921	31892977	HMGA2 expression products can regulate transcription through DNA structural modification and cross-linking with other enhanceosome proteins, which are normally expressed during embryonic development instead of normal somatic cells.	('HMGA2', 'Gene', '8091', (0, 5))	('DNA', 'MPA', (61, 64))	('regulate', 'Reg', (30, 38))	('HMGA2', 'Gene', (0, 5))	('structural modification', 'Var', (65, 88))	('cross-linking', 'Var', (93, 106))	('transcription', 'MPA', (39, 52))
400922	31892977	However, for WDL/DDL, MDM2 amplification is accompanied by HMGA2 dysregulation, presenting its oncogenic property.	('MDM2', 'Gene', '4193', (22, 26))	('MDM2', 'Gene', (22, 26))	('HMGA2', 'Gene', '8091', (59, 64))	('dysregulation', 'Var', (65, 78))	('HMGA2', 'Gene', (59, 64))	('WDL/DDL', 'Disease', (13, 20))	('amplification', 'Var', (27, 40))
400928	31892977	The difference is that DDL has additional genetic changes, especially co-amplification of genes in chromosome 6q23 and 1p32 regions, such as JUN and ASK1/MAP3K5.	('co-amplification', 'Var', (70, 86))	('MAP3K5', 'Gene', '4217', (154, 160))	('MAP3K5', 'Gene', (154, 160))	('ASK1', 'Gene', '4217', (149, 153))	('ASK1', 'Gene', (149, 153))
400938	31892977	The most prominent cytogenetic feature of MRCL is that about 95% of cases have specific t(12;16)(q13;p11) chromosomal translocation, which produces FUS-DDIT3 fusion protein (also known as TLS-CHOP fusion protein), while about 5% of cases have t(12;22) (q13;q12) chromosomal translocation, producing EWSR1-DDIT3 fusion protein.	('EWSR1', 'Gene', (299, 304))	('FUS', 'Gene', (148, 151))	('chromosomal translocation', 'Var', (106, 131))	('DDIT3', 'Gene', (152, 157))	('MRCL', 'Phenotype', 'HP:0012268', (42, 46))	('FUS', 'Gene', '2521', (148, 151))	('CHOP', 'Gene', '1649', (192, 196))	('t(12;16)(', 'Var', (88, 97))	('DDIT3', 'Gene', '1649', (152, 157))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (88, 105))	('DDIT3', 'Gene', '1649', (305, 310))	('DDIT3', 'Gene', (305, 310))	('EWSR1', 'Gene', '2130', (299, 304))	('CHOP', 'Gene', (192, 196))	('TLS', 'Gene', (188, 191))	('TLS', 'Gene', '2521', (188, 191))
400943	31892977	Interestingly, for most of MRCL, TP53 is not mutated and can produce functionally normal p53, and once this gene is mutated, the invasive ability of MRCL will also be strengthened.	('strengthened', 'PosReg', (167, 179))	('MRCL', 'Phenotype', 'HP:0012268', (27, 31))	('TP53', 'Gene', '7157', (33, 37))	('MRCL', 'Phenotype', 'HP:0012268', (149, 153))	('invasive ability', 'CPA', (129, 145))	('p53', 'Gene', (89, 92))	('TP53', 'Gene', (33, 37))	('p53', 'Gene', '7157', (89, 92))	('mutated', 'Var', (116, 123))
400945	31892977	used gene expression profiling, immunohistochemistry, biochemical analysis, and other techniques to study two groups of samples containing only MLS and RCL, respectively, and found that in this process, the silence of the DLK1-DIO3 genomic region at 14q32 resulted in the over-expression of genes such as YY1/C-MYC/HDAC2 that promoted rapid cell cycle progression.	('DLK1', 'Gene', '8788', (222, 226))	('DLK1', 'Gene', (222, 226))	('YY1', 'Gene', (305, 308))	('HDAC2', 'Gene', (315, 320))	('HDAC2', 'Gene', '3066', (315, 320))	('C-MYC', 'Gene', (309, 314))	('promoted', 'PosReg', (326, 334))	('DIO3', 'Gene', '1735', (227, 231))	('rapid cell cycle progression', 'CPA', (335, 363))	('silence', 'Var', (207, 214))	('MLS', 'Phenotype', 'HP:0012268', (144, 147))	('DIO3', 'Gene', (227, 231))	('YY1', 'Gene', '7528', (305, 308))	('C-MYC', 'Gene', '4609', (309, 314))	('over-expression', 'PosReg', (272, 287))
400952	31892977	The cytogenetic feature of PLS is complex aneuploid karyotypes with complex genomic amplification and deletions.	('aneuploid', 'Disease', 'MESH:D000782', (42, 51))	('deletions', 'Var', (102, 111))	('PLS', 'Disease', 'MESH:D010214', (27, 30))	('aneuploid', 'Disease', (42, 51))	('PLS', 'Disease', (27, 30))
400953	31892977	found mutations in genes such as TP53, RB1 and NF1 in PLS by DNA sequencing, while Ghadimi et al.	('RB1', 'Gene', '5925', (39, 42))	('PLS', 'Disease', 'MESH:D010214', (54, 57))	('TP53', 'Gene', '7157', (33, 37))	('NF1', 'Gene', (47, 50))	('RB1', 'Gene', (39, 42))	('NF1', 'Gene', '4763', (47, 50))	('PLS', 'Disease', (54, 57))	('TP53', 'Gene', (33, 37))	('mutations', 'Var', (6, 15))
400954	31892977	found many biomarkers, such as peroxisome proliferator-activated receptor gamma (PPAR-gamma), VEGF, survivin protein, B-cell leukemia 2 and matrix metalloproteinase 2, were over-expressed in PLS; in addition, they observed the presence of high-frequency deletion of retinoblastoma protein and high-frequency gene mutation of TP53 (about 60%) in PLS.	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (31, 79))	('TP53', 'Gene', (325, 329))	('VEGF', 'Gene', (94, 98))	('retinoblastoma', 'Disease', 'MESH:D012175', (266, 280))	('peroxisome proliferator-activated receptor gamma', 'Gene', (31, 79))	('deletion', 'Var', (254, 262))	('PPAR-gamma', 'Gene', '5468', (81, 91))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('PLS', 'Disease', 'MESH:D010214', (345, 348))	('TP53', 'Gene', '7157', (325, 329))	('retinoblastoma', 'Phenotype', 'HP:0009919', (266, 280))	('PLS', 'Disease', (345, 348))	('retinoblastoma', 'Disease', (266, 280))	('leukemia', 'Disease', 'MESH:D007938', (125, 133))	('leukemia', 'Disease', (125, 133))	('PPAR-gamma', 'Gene', (81, 91))	('PLS', 'Disease', 'MESH:D010214', (191, 194))	('high-frequency gene mutation', 'Var', (293, 321))	('over-expressed', 'PosReg', (173, 187))	('PLS', 'Disease', (191, 194))	('VEGF', 'Gene', '7422', (94, 98))
400974	31892977	Similarly, one patient with DDL received PR in a phase I clinical trial of DS-3032b for WDL/DDL.	('patient', 'Species', '9606', (15, 22))	('DS-3032b', 'Var', (75, 83))	('WDL/DDL', 'Disease', (88, 95))
400976	31892977	It is worth mentioning that although both MDM2 and CDK4 have corresponding targeted inhibitors for clinical trials, in vitro experiments have shown that the cytotoxicity of the two drugs against sarcoma cell lines is mutually antagonistic.	('inhibitors', 'Var', (84, 94))	('sarcoma', 'Disease', (195, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('cytotoxicity', 'Disease', (157, 169))	('MDM2', 'Gene', '4193', (42, 46))	('MDM2', 'Gene', (42, 46))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('CDK4', 'Gene', (51, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (157, 169))	('CDK4', 'Gene', '1019', (51, 55))
400977	31892977	Therefore, careful consideration must be given to the combination of CDK4 and MDM2 inhibitors to treat WDL/DDL.	('CDK4', 'Gene', '1019', (69, 73))	('MDM2', 'Gene', '4193', (78, 82))	('WDL/DDL', 'Disease', (103, 110))	('MDM2', 'Gene', (78, 82))	('CDK4', 'Gene', (69, 73))	('inhibitors', 'Var', (83, 93))
400979	31892977	In vitro and in vivo experiments have shown that pan-FGFR inhibitor LY2874455 has clinical value in the treatment of DDL for FRS2 amplification.	('FRS2', 'Gene', (125, 129))	('DDL', 'Disease', (117, 120))	('LY2874455', 'Var', (68, 77))	('LY2874455', 'Chemical', 'MESH:C570663', (68, 77))	('FRS2', 'Gene', '10818', (125, 129))
400980	31892977	In addition, methylation of C/EBPalpha is found in 24% of DDL while demethylation pharmacotherapy can restore the expression of C/EBPalpha in DDL cells so as to inhibit the proliferation of DDL cells in vitro experiment as well as promote apoptosis and slow down the tumor growth in vivo .	('C/EBPalpha', 'Gene', '1050', (128, 138))	('apoptosis', 'CPA', (239, 248))	('promote', 'PosReg', (231, 238))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('methylation', 'Var', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('C/EBPalpha', 'Gene', (28, 38))	('proliferation', 'CPA', (173, 186))	('tumor', 'Disease', (267, 272))	('expression', 'MPA', (114, 124))	('slow down', 'NegReg', (253, 262))	('inhibit', 'NegReg', (161, 168))	('C/EBPalpha', 'Gene', '1050', (28, 38))	('C/EBPalpha', 'Gene', (128, 138))
400984	31892977	Studies have shown that PD-L1 is highly expressed in DDL cell lines, and patients with the PD-L1 expression >=1% have a significant decrease in recurrence-free survival (P = 0.027) and overall survival (P = 0.017).	('overall survival', 'CPA', (185, 201))	('>=1%', 'Var', (108, 112))	('PD-L1', 'Gene', (91, 96))	('PD-L1', 'Gene', '29126', (91, 96))	('PD-L1', 'Gene', (24, 29))	('recurrence-free survival', 'CPA', (144, 168))	('patients', 'Species', '9606', (73, 81))	('decrease', 'NegReg', (132, 140))	('PD-L1', 'Gene', '29126', (24, 29))
401004	31892977	found that miR-143 was highly expressed in normal adipocytes, while the expression was down-regulated in WDL, and if the expression was further down-regulated, the WDL could develop to DDL; in addition, recovery of miR-143 expression in DDL could inhibit its proliferation and induce apoptosis.	('miR-143', 'Gene', '406935', (215, 222))	('apoptosis', 'CPA', (284, 293))	('miR-143', 'Gene', (215, 222))	('down-regulated', 'NegReg', (87, 101))	('miR-143', 'Gene', '406935', (11, 18))	('proliferation', 'CPA', (259, 272))	('inhibit', 'NegReg', (247, 254))	('miR-143', 'Gene', (11, 18))	('induce', 'Reg', (277, 283))	('recovery', 'Var', (203, 211))
401014	31892977	Exosomes-derived miR-25-3p and miR-92a-3p were found in liposarcoma, which could accelerate the proliferation, invasion, and metastasis of liposarcoma by stimulating the secretion of pro-inflammatory cytokine IL-6; in addition, these miRNAs could effectively distinguish patients with liposarcoma from healthy individuals and had the possibility of becoming a new non-invasive biomarker, so as to be used for early diagnosis of liposarcoma, evaluation of efficacy and prognosis.	('accelerate', 'PosReg', (81, 91))	('liposarcoma', 'Phenotype', 'HP:0012034', (285, 296))	('liposarcoma', 'Phenotype', 'HP:0012034', (56, 67))	('proliferation', 'CPA', (96, 109))	('liposarcoma', 'Phenotype', 'HP:0012034', (428, 439))	('liposarcoma', 'Disease', (139, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('liposarcoma', 'Disease', 'MESH:D008080', (285, 296))	('metastasis', 'CPA', (125, 135))	('liposarcoma', 'Disease', 'MESH:D008080', (56, 67))	('liposarcoma', 'Disease', 'MESH:D008080', (428, 439))	('IL-6', 'Gene', '3569', (209, 213))	('stimulating', 'PosReg', (154, 165))	('liposarcoma', 'Phenotype', 'HP:0012034', (139, 150))	('IL-6', 'Gene', (209, 213))	('patients', 'Species', '9606', (271, 279))	('liposarcoma', 'Disease', (285, 296))	('secretion', 'MPA', (170, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('liposarcoma', 'Disease', (56, 67))	('invasion', 'CPA', (111, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (432, 439))	('liposarcoma', 'Disease', (428, 439))	('miR-92a-3p', 'Var', (31, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (289, 296))	('liposarcoma', 'Disease', 'MESH:D008080', (139, 150))
401022	29563856	Introducing anti-miR-181c into ES cell lines resulted in an increased expression of FAS2.	('ES', 'Phenotype', 'HP:0012254', (31, 33))	('anti-miR-181c', 'Var', (12, 25))	('expression', 'MPA', (70, 80))	('FAS', 'Chemical', 'MESH:C038178', (84, 87))	('FAS2', 'Protein', (84, 88))	('increased', 'PosReg', (60, 69))
401024	29563856	These results suggest that unregulated expression of miR-181c could contribute to ES by targeting FAS.	('targeting', 'Reg', (88, 97))	('FAS', 'Disease', (98, 101))	('unregulated', 'Var', (27, 38))	('contribute', 'Reg', (68, 78))	('miR-181c', 'Var', (53, 61))	('ES', 'Phenotype', 'HP:0012254', (82, 84))	('FAS', 'Chemical', 'MESH:C038178', (98, 101))
401037	29563856	The results showed that the expression of miR-181c was increased in all five ES cell lines, whereas that of FAS was repressed in all five ES cell lines.	('miR-181c', 'Var', (42, 50))	('FAS', 'Chemical', 'MESH:C038178', (108, 111))	('ES', 'Phenotype', 'HP:0012254', (138, 140))	('increased', 'PosReg', (55, 64))	('expression', 'MPA', (28, 38))	('ES', 'Phenotype', 'HP:0012254', (77, 79))
401039	29563856	The aim of our study is to evaluate whether the expression of FAS is repressed by miR-181c and the pathway could play a role in malignancy in ES cells.	('malignancy', 'Disease', 'MESH:D009369', (128, 138))	('play', 'Reg', (113, 117))	('ES', 'Phenotype', 'HP:0012254', (142, 144))	('malignancy', 'Disease', (128, 138))	('miR-181c', 'Var', (82, 90))	('role', 'Reg', (120, 124))	('FAS', 'Chemical', 'MESH:C038178', (62, 65))
401049	29563856	Antibodies produced in rabbits for FAS (#8023), caspase 3 (#9662), cleaved caspase 3 (#9661), caspase 7 (#9492), cleaved caspase 7 (#9491), caspase 8 (#4790), cleaved caspase 8 (#9496), PAR/poly (ADP-ribose) polymerase (PARP) (#9542), cleaved PARP (#9541) and beta-Actin (#4970) were purchased from Cell Signaling Technology (Tokyo, Japan).	('#9661', 'Var', (86, 91))	('FAS', 'Chemical', 'MESH:C038178', (35, 38))	('#9542', 'Var', (227, 232))	('#4790', 'Var', (151, 156))	('#9541', 'Var', (249, 254))	('PARP', 'Gene', (243, 247))	('#9662', 'Var', (59, 64))	('rabbits', 'Species', '9986', (23, 30))	('#9491', 'Var', (132, 137))	('#9492', 'Var', (105, 110))	('PARP', 'Gene', (220, 224))	('PARP', 'Gene', '142', (243, 247))	('PARP', 'Gene', '142', (220, 224))	('#8023', 'Var', (40, 45))	('#9496', 'Var', (178, 183))	('#4970', 'Var', (272, 277))
401060	29563856	The results of the database analyses suggested that FAS was the strongest target of miR-181c.	('FAS', 'Chemical', 'MESH:C038178', (52, 55))	('FAS', 'Disease', (52, 55))	('miR-181c', 'Var', (84, 92))
401069	29563856	The proteins on the gel were transferred onto PVDF membrane, and reacted with anti-FAS (#8023), caspase 3 (#9662), cleaved caspase 3 (#9661), caspase 7 (#9492), cleaved caspase 7 (#9491), caspase 8 (#4790), cleaved caspase 8 (#9496), PAR/poly (ADP-ribose) polymerase (PARP) (#9542), cleaved PARP (#9541) and beta-Actin (#4970) were purchased from Cell Signaling Technology (Tokyo, Japan).	('#9491', 'Var', (180, 185))	('#4790', 'Var', (199, 204))	('FAS', 'Chemical', 'MESH:C038178', (83, 86))	('PARP', 'Gene', '142', (268, 272))	('#9542', 'Var', (275, 280))	('PARP', 'Gene', (291, 295))	('#9541', 'Var', (297, 302))	('#9492', 'Var', (153, 158))	('#4970', 'Var', (320, 325))	('#9662', 'Var', (107, 112))	('#8023', 'Var', (88, 93))	('PARP', 'Gene', (268, 272))	('PARP', 'Gene', '142', (291, 295))	('#9661', 'Var', (134, 139))	('#9496', 'Var', (226, 231))
401083	29563856	2a) suggesting the influence of miR-181c to FAS mRNA via association with 3'UTR of the mRNA.	('influence', 'Reg', (19, 28))	("3'UTR of the mRNA", 'MPA', (74, 91))	('miR-181c', 'Var', (32, 40))	('FAS', 'Chemical', 'MESH:C038178', (44, 47))	('association', 'Interaction', (57, 68))	('FAS', 'Disease', (44, 47))
401084	29563856	Therefore, we examined the effects of miR-181c on the expression of FAS in ES cells by the transfection of miR-181c and a mutated miR-181c into SK-ES-1 cells.	('miR-181c', 'Var', (107, 115))	('miR-181c', 'Gene', (130, 138))	('ES', 'Phenotype', 'HP:0012254', (75, 77))	('SK-ES-1', 'CellLine', 'CVCL:0627', (144, 151))	('FAS', 'Chemical', 'MESH:C038178', (68, 71))	('mutated', 'Var', (122, 129))	('ES', 'Phenotype', 'HP:0012254', (147, 149))
401085	29563856	In this experiment, de novo mRNA transcription was blocked using actinomycin D (10 mug/ml), an inhibitor of mRNA transcription, since we attempted to determine whether FAS mRNA stability would be affected by miR-181c.	('FAS', 'Chemical', 'MESH:C038178', (168, 171))	('miR-181c', 'Var', (208, 216))	('actinomycin D', 'Chemical', 'MESH:D003609', (65, 78))	('affected', 'Reg', (196, 204))
401086	29563856	Using a microRNA mutant oligonucleotide method instead of the luciferase method, we have provided evidence that the microRNA in question disrupts and/or interferes with expression of the target mRNA.	('disrupts', 'NegReg', (137, 145))	('oligonucleotide', 'Chemical', 'MESH:D009841', (24, 39))	('microRNA', 'Var', (116, 124))	('interferes', 'NegReg', (153, 163))	('expression', 'MPA', (169, 179))
401087	29563856	2b) and significantly decreased FAS expression by 0.43 +- 0.23 folds at mRNA level after the transfection with miR-181c oligonucleotide (Fig.	('oligonucleotide', 'Chemical', 'MESH:D009841', (120, 135))	('FAS', 'Chemical', 'MESH:C038178', (32, 35))	('miR-181c oligonucleotide', 'Var', (111, 135))	('FAS', 'Protein', (32, 35))	('decreased', 'NegReg', (22, 31))
401089	29563856	The results suggested that the stability of FAS mRNA was inhibited by miR-181c in ES cell lines.	('inhibited', 'NegReg', (57, 66))	('miR-181c', 'Var', (70, 78))	('stability of FAS mRNA', 'CPA', (31, 52))	('FAS', 'Chemical', 'MESH:C038178', (44, 47))	('ES', 'Phenotype', 'HP:0012254', (82, 84))
401091	29563856	In anti-miR-181c transfected cells, the levels of FAS protein remarkably elevated in comparison with untreated or control oligonucleotide-treated cells (Fig.	('levels of', 'MPA', (40, 49))	('oligonucleotide', 'Chemical', 'MESH:D009841', (122, 137))	('FAS', 'Chemical', 'MESH:C038178', (50, 53))	('FAS', 'Protein', (50, 53))	('anti-miR-181c transfected', 'Var', (3, 28))	('elevated', 'PosReg', (73, 81))	('transfected', 'Var', (17, 28))
401092	29563856	The level of FAS protein expression in the cells transfected with anti-miR-181c (20 nM) was up-regulated to 2.34-fold of that in the control cells (p < 0.01) (Fig.	('anti-miR-181c', 'Var', (66, 79))	('FAS', 'Chemical', 'MESH:C038178', (13, 16))	('FAS protein', 'Protein', (13, 24))	('up-regulated', 'PosReg', (92, 104))
401096	29563856	Since the introduction of anti-miR-181c lead to the increase in the expression of FAS, we also investigated the effects of anti-miR-181c on the growth of ES cells.	('expression', 'MPA', (68, 78))	('increase', 'PosReg', (52, 60))	('anti-miR-181c', 'Var', (26, 39))	('FAS', 'Chemical', 'MESH:C038178', (82, 85))	('FAS', 'Protein', (82, 85))	('ES', 'Phenotype', 'HP:0012254', (154, 156))
401097	29563856	Compared to negative control-miRNA-transfected cells (118.5 +- 13.9 x 105 cells), anti-miR-181c (20 nM) transfected SK-ES-1 cells showed a significant decrease in the cell number (78.1 +- 11.9 x 105 cells) at 48 h after transfection (p = 0.0083).	('anti-miR-181c', 'Var', (82, 95))	('cell number', 'CPA', (167, 178))	('decrease', 'NegReg', (151, 159))	('SK-ES-1', 'CellLine', 'CVCL:0627', (116, 123))	('ES', 'Phenotype', 'HP:0012254', (119, 121))
401098	29563856	Treatment with anti-miR-181c (40 nM) also inhibited the proliferation of SK-ES-1 cells (72.1 +- 22.5 x 105 cells) compared to in negative control-miRNA-transfected cells (112.7 +- 17.5 x 105 cells) (p = 0.031).	('ES', 'Phenotype', 'HP:0012254', (76, 78))	('proliferation', 'CPA', (56, 69))	('inhibited', 'NegReg', (42, 51))	('anti-miR-181c', 'Var', (15, 28))	('SK-ES-1', 'CellLine', 'CVCL:0627', (73, 80))
401099	29563856	The cell growth of SK-ES-1 (62.5 +- 14.9 x 105 cells) was inhibited by the transfection of anti-miR-181c (80 nM) as determined by cell counting in comparison with negative control-miRNA transfected cells (93.1 +- 14.6 x 105 cells) (p = 0.044) (Fig.	('SK-ES-1', 'CellLine', 'CVCL:0627', (19, 26))	('transfection', 'Var', (75, 87))	('ES', 'Phenotype', 'HP:0012254', (22, 24))	('inhibited', 'NegReg', (58, 67))	('cell growth', 'CPA', (4, 15))
401105	29563856	FACS analysis revealed that the number of SK-ES-1 cells transfected with anti-miR-181c (6.2 +- 1.2%) or FAS vector (7.7 +- 1.1%) in sub-G1 phase was significantly higher than that in untreated (0.5 +- 0.4%) and negative control (0.8 +- 0.2%) transfected cells.	('ES', 'Phenotype', 'HP:0012254', (45, 47))	('FAS', 'Chemical', 'MESH:C038178', (104, 107))	('sub-G1 phase', 'CPA', (132, 144))	('SK-ES-1', 'CellLine', 'CVCL:0627', (42, 49))	('anti-miR-181c', 'Var', (73, 86))	('higher', 'PosReg', (163, 169))
401106	29563856	The results indicated that anti-miR-181c and FAS might have no effect on the cell cycle progression of ES cells.	('ES', 'Phenotype', 'HP:0012254', (103, 105))	('anti-miR-181c', 'Var', (27, 40))	('cell cycle progression', 'CPA', (77, 99))	('FAS', 'Chemical', 'MESH:C038178', (45, 48))
401107	29563856	Double staining with Annexin V-FITC and PI further demonstrated the induction of apoptosis in SK-ES-1 cells transfected with anti-miR-181c or FAS vector compared with untreated and negative control transfected cells (Fig.	('FAS', 'Chemical', 'MESH:C038178', (142, 145))	('Annexin V', 'Gene', '308', (21, 30))	('Annexin V', 'Gene', (21, 30))	('apoptosis', 'CPA', (81, 90))	('ES', 'Phenotype', 'HP:0012254', (97, 99))	('anti-miR-181c', 'Var', (125, 138))	('SK-ES-1', 'CellLine', 'CVCL:0627', (94, 101))
401108	29563856	The anti-miR-181c and FAS vector transfected groups had increased sub-G1 fraction compared to the untreated and control-miR groups, indicating that apoptosis had been induced.	('sub-G1 fraction', 'CPA', (66, 81))	('anti-miR-181c', 'Var', (4, 17))	('FAS', 'Chemical', 'MESH:C038178', (22, 25))	('increased', 'PosReg', (56, 65))
401111	29563856	SK-ES-1 cells that were transfected with anti-miR-181c or FAS expression vector showed the increase in expression of FAS, and cleaved caspase 3, 7, and 8 (Fig.	('FAS', 'Chemical', 'MESH:C038178', (117, 120))	('FAS', 'Protein', (117, 120))	('expression', 'MPA', (103, 113))	('anti-miR-181c', 'Var', (41, 54))	('increase', 'PosReg', (91, 99))	('cleaved', 'MPA', (126, 133))	('SK-ES-1', 'CellLine', 'CVCL:0627', (0, 7))	('ES', 'Phenotype', 'HP:0012254', (3, 5))	('FAS', 'Chemical', 'MESH:C038178', (58, 61))	('caspase', 'Protein', (134, 141))
401112	29563856	FAS expression in SK-ES-1 cells was increased transfected with the anti-miR-181c (288 +- 2.9%) and FAS vector (303 +- 3.1%) compared to in control cells (100%).	('SK-ES-1', 'CellLine', 'CVCL:0627', (18, 25))	('anti-miR-181c', 'Var', (67, 80))	('expression', 'MPA', (4, 14))	('increased', 'PosReg', (36, 45))	('FAS', 'Chemical', 'MESH:C038178', (99, 102))	('FAS', 'Gene', (0, 3))	('ES', 'Phenotype', 'HP:0012254', (21, 23))	('FAS', 'Chemical', 'MESH:C038178', (0, 3))
401113	29563856	When SK-ES-1 cells were transfected with the anti-miR-181c, the expression of cleaved PARP (342 +- 14.1%), cleaved caspase 3 (372 +- 12.2%), cleaved caspase 7 (321 +- 5.95%) and cleaved caspase 8 (315 +- 3.24%) was dramatically increased compared to in untreated SE-ES-1 cells (100%).	('expression', 'MPA', (64, 74))	('SK-ES-1', 'CellLine', 'CVCL:0627', (5, 12))	('PARP', 'Gene', '142', (86, 90))	('ES-1', 'CellLine', 'CVCL:1198', (266, 270))	('ES', 'Phenotype', 'HP:0012254', (8, 10))	('ES-1', 'CellLine', 'CVCL:1198', (8, 12))	('cleaved', 'MPA', (178, 185))	('cleaved', 'MPA', (78, 85))	('ES', 'Phenotype', 'HP:0012254', (266, 268))	('increased', 'PosReg', (228, 237))	('PARP', 'Gene', (86, 90))	('anti-miR-181c', 'Var', (45, 58))	('cleaved', 'MPA', (141, 148))	('cleaved', 'MPA', (107, 114))	('caspase', 'Gene', (115, 122))
401115	29563856	The introduction of anti-miR-181c into SKES1 cells resulted in the decreased growth of subcutaneous xenografted tumors in nude mice (Fig.	('ES', 'Phenotype', 'HP:0012254', (41, 43))	('decreased growth', 'Phenotype', 'HP:0001510', (67, 83))	('growth', 'MPA', (77, 83))	('tumors', 'Disease', (112, 118))	('nude mice', 'Species', '10090', (122, 131))	('anti-miR-181c', 'Var', (20, 33))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('SKES1', 'CellLine', 'CVCL:B526', (39, 44))	('decreased', 'NegReg', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
401116	29563856	The size of tumors in mice inoculated with anti-miR-181c-transfected SK-ES-1 cells (466.5 +- 28.1 cells/mm3) or FAS vector-transfected cells (385.5 +- 16.9 cells/mm3) was significantly smaller than that with untreated (1165.8 +- 74.1 cells/mm3) and NC-miRNA-transfected cells (1021.2 +- 54.7 cells/mm3).	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('smaller', 'NegReg', (185, 192))	('anti-miR-181c-transfected', 'Var', (43, 68))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('FAS', 'Chemical', 'MESH:C038178', (112, 115))	('SK-ES-1', 'CellLine', 'CVCL:0627', (69, 76))	('mice', 'Species', '10090', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('ES', 'Phenotype', 'HP:0012254', (72, 74))
401117	29563856	Immunohistochemical studies revealed that the expression of FAS and cleaved caspase 3 in the xenografted tumors was inhibited by the transfection with anti-miR-181c and FAS expression vector (Fig.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('inhibited', 'NegReg', (116, 125))	('FAS', 'Chemical', 'MESH:C038178', (169, 172))	('caspase 3', 'Gene', (76, 85))	('cleaved', 'MPA', (68, 75))	('FAS', 'Gene', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('FAS', 'Chemical', 'MESH:C038178', (60, 63))	('anti-miR-181c', 'Var', (151, 164))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('expression', 'MPA', (46, 56))
401118	29563856	The number of cells positive for FAS expression was significantly increased in mice inoculated with anti-miR-181c (199 +- 21.8 cells/mm2) or FAS expression vector transfected cells (230.7 +- 45.7 cells/mm2) than that with untreated (65.6 +- 10.6 cells/mm2) or control-miR transfected cells (93.8 +- 16.8 cells/mm2) (p < 0.01).	('FAS', 'Chemical', 'MESH:C038178', (141, 144))	('increased', 'PosReg', (66, 75))	('mice', 'Species', '10090', (79, 83))	('FAS', 'Chemical', 'MESH:C038178', (33, 36))	('FAS', 'Gene', (33, 36))	('expression', 'MPA', (37, 47))	('anti-miR-181c', 'Var', (100, 113))	('FAS', 'Gene', (141, 144))
401119	29563856	The number of cleaved caspase 3 expressing cells was significantly increased in mice inoculated with anti-miR-181c (170.9 +- 22.2 cells/mm2) or FAS vector (169.3 +- 37.4 cells/mm2) transfected cells than that with untreated (44.1 +- 3.6 cells/mm2) or control-miR transfected cells (49.7 +- 13.3 cells/mm2) (p < 0.01) (Fig.	('transfected', 'Var', (181, 192))	('FAS', 'Chemical', 'MESH:C038178', (144, 147))	('increased', 'PosReg', (67, 76))	('mice', 'Species', '10090', (80, 84))	('cleaved', 'MPA', (14, 21))	('anti-miR-181c', 'Var', (101, 114))	('caspase 3', 'Protein', (22, 31))
401123	29563856	Furthermore, sequence analysis suggested possible association of miR-181c with 3'UTR of FAS.	('association', 'Interaction', (50, 61))	('miR-181c', 'Var', (65, 73))	('FAS', 'Chemical', 'MESH:C038178', (88, 91))	("3'UTR of FAS", 'Disease', (79, 91))
401127	29563856	Although miR-181c might influence the expression of many genes, we focused on FAS as the target of miR-181c in ES cells.	('expression', 'MPA', (38, 48))	('ES', 'Phenotype', 'HP:0012254', (111, 113))	('influence', 'Reg', (24, 33))	('miR-181c', 'Var', (99, 107))	('FAS', 'Chemical', 'MESH:C038178', (78, 81))
401129	29563856	Analysis using several algorithms, such as BLAST and TargetScan, further suggested that FAS was a putative target of miR-181c.	('FAS', 'Disease', (88, 91))	('FAS', 'Chemical', 'MESH:C038178', (88, 91))	('miR-181c', 'Var', (117, 125))
401132	29563856	Therefore, we hypothesized that an elevation in miR-181c results in inhibition of FAS mRNA expression, and we investigated our hypothesis.	('miR-181c', 'Var', (48, 56))	('FAS', 'Chemical', 'MESH:C038178', (82, 85))	('inhibition', 'NegReg', (68, 78))	('FAS', 'Protein', (82, 85))	('elevation', 'PosReg', (35, 44))
401133	29563856	Therefore, we analyzed the possibility that miR-181c might play an anti-cancer regulatory role in ES cells by targeting FAS.	('FAS', 'Disease', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('FAS', 'Chemical', 'MESH:C038178', (120, 123))	('miR-181c', 'Var', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('targeting', 'Reg', (110, 119))	('ES', 'Phenotype', 'HP:0012254', (98, 100))	('cancer', 'Disease', (72, 78))
401135	29563856	Therefore, miR-181c may have affected FAS mRNA directly at least in part.	('miR-181c', 'Var', (11, 19))	('affected', 'Reg', (29, 37))	('FAS', 'Chemical', 'MESH:C038178', (38, 41))	('FAS', 'Disease', (38, 41))
401137	29563856	Forced expression of miR-181c resulted in the repression of FAS protein, indicating that miR-181c might function as an oncogene in ES cells.	('miR-181c', 'Gene', (21, 29))	('repression', 'NegReg', (46, 56))	('ES', 'Phenotype', 'HP:0012254', (131, 133))	('FAS', 'Chemical', 'MESH:C038178', (60, 63))	('miR-181c', 'Var', (89, 97))	('FAS protein', 'Protein', (60, 71))
401138	29563856	Our results are the first evidence that suggest that the same miR-181c mediated regulatory mechanism of FAS expression might exist in ES cells.	('miR-181c', 'Var', (62, 70))	('FAS', 'Gene', (104, 107))	('ES', 'Phenotype', 'HP:0012254', (134, 136))	('FAS', 'Chemical', 'MESH:C038178', (104, 107))
401139	29563856	Transfection of anti-miR-181c or FAS expression vector into SKES1 cells resulted in the increase of sub G1 fraction but did not influence the proportion between G1/G0, S and G2/M phases.	('ES', 'Phenotype', 'HP:0012254', (62, 64))	('anti-miR-181c', 'Var', (16, 29))	('increase', 'PosReg', (88, 96))	('FAS', 'Chemical', 'MESH:C038178', (33, 36))	('sub G1 fraction', 'MPA', (100, 115))	('SKES1', 'CellLine', 'CVCL:B526', (60, 65))
401140	29563856	Thus, we can infer that the upregulation of FAS, resulting from transfection of anti-miR-181c or FAS expression vector, induced apoptosis of ES cells.	('transfection', 'Var', (64, 76))	('ES', 'Phenotype', 'HP:0012254', (141, 143))	('FAS', 'Chemical', 'MESH:C038178', (97, 100))	('FAS', 'Chemical', 'MESH:C038178', (44, 47))	('FAS', 'Gene', (44, 47))	('anti-miR-181c', 'Var', (80, 93))	('apoptosis', 'CPA', (128, 137))	('upregulation', 'PosReg', (28, 40))
401143	29563856	The receptor ligation followed by binding with Fas-associated death domain protein leads to the recruitment of caspase-8, resulting in the cleavage and activation of caspase-8 and downstream caspases.	('caspases', 'Gene', '841', (191, 199))	('cleavage', 'MPA', (139, 147))	('activation', 'PosReg', (152, 162))	('binding', 'Interaction', (34, 41))	('caspase-8', 'Gene', (111, 120))	('caspase-8', 'Gene', (166, 175))	('ligation', 'Var', (13, 21))	('caspase-8', 'Gene', '841', (166, 175))	('caspase-8', 'Gene', '841', (111, 120))	('recruitment', 'MPA', (96, 107))	('caspases', 'Gene', (191, 199))
401145	29563856	Our results show that transfection with anti-miR-181c and FAS expression vector enhances caspase-8, and caspase 3/7 activity, and increases cleaved PARP expression levels.	('enhances', 'PosReg', (80, 88))	('caspase-8', 'Gene', '841', (89, 98))	('PARP', 'Gene', '142', (148, 152))	('anti-miR-181c', 'Var', (40, 53))	('activity', 'MPA', (116, 124))	('PARP', 'Gene', (148, 152))	('caspase', 'Enzyme', (104, 111))	('FAS', 'Chemical', 'MESH:C038178', (58, 61))	('increases', 'PosReg', (130, 139))	('caspase-8', 'Gene', (89, 98))
401148	29563856	The present study indicates the inverse correlation of miR-181c and FAS in ES cells for the first time.	('FAS', 'Chemical', 'MESH:C038178', (68, 71))	('ES', 'Phenotype', 'HP:0012254', (75, 77))	('FAS', 'Disease', (68, 71))	('miR-181c', 'Var', (55, 63))
401149	29563856	We show that miR-181c regulates FAS and the FAS-mediated apoptosis pathway by directly downregulating FAS expression.	('downregulating', 'NegReg', (87, 101))	('regulates', 'Reg', (22, 31))	('expression', 'MPA', (106, 116))	('FAS', 'Chemical', 'MESH:C038178', (32, 35))	('FAS', 'Chemical', 'MESH:C038178', (44, 47))	('miR-181c', 'Var', (13, 21))	('FAS', 'Chemical', 'MESH:C038178', (102, 105))	('FAS-mediated apoptosis pathway', 'Pathway', (44, 74))	('FAS', 'Disease', (32, 35))	('FAS', 'Protein', (102, 105))
401150	29563856	These results suggest that miR-181c is a regulator of FAS mediated apoptosis in Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (80, 95))	("Ewing's sarcoma", 'Disease', (80, 95))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (80, 95))	('FAS', 'Chemical', 'MESH:C038178', (54, 57))	('miR-181c', 'Var', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
401213	33552988	DICER1 Syndrome and Cancer Predisposition: From a Rare Pediatric Tumor to Lifetime Risk DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1 gene.	('DICER1', 'Gene', '23405', (196, 202))	('DICER1', 'Gene', (0, 6))	('caused by', 'Reg', (170, 179))	('DICER1', 'Gene', '23405', (0, 6))	('hereditary cancer', 'Disease', 'MESH:D009369', (148, 165))	('Tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('DICER1', 'Gene', (88, 94))	('Cancer', 'Disease', 'MESH:D009369', (20, 26))	('hereditary cancer', 'Disease', (148, 165))	('variants', 'Var', (180, 188))	('DICER1', 'Gene', '23405', (88, 94))	('DICER1', 'Gene', (196, 202))
401215	33552988	DICER1 variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome.	('DICER1', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor of the lung', 'Phenotype', 'HP:0100526', (121, 138))	('PPB', 'Phenotype', 'HP:0100528', (98, 101))	('children', 'Species', '9606', (166, 174))	('variants', 'Var', (7, 15))	('familial pleuropulmonary blastoma', 'Disease', (63, 96))	('malignant tumor', 'Disease', (111, 126))	('malignant tumor', 'Disease', 'MESH:D009369', (111, 126))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (72, 96))	('familial pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (63, 96))	('associated', 'Reg', (26, 36))
401217	33552988	DICER1 syndrome is a cancer-predisposing disorder caused by pathogenic variants in the DICER1 gene (OMIM 606241), which are known to confer a lifetime risks for a variety of neoplastic and dysplastic lesions.	('variants', 'Var', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('DICER1 syndrome', 'Disease', (0, 15))	('caused by', 'Reg', (50, 59))	('DICER1', 'Gene', (87, 93))	('dysplastic lesions', 'Disease', 'MESH:D004416', (189, 207))	('cancer-predisposing disorder', 'Disease', (21, 49))	('dysplastic lesions', 'Disease', (189, 207))	('cancer-predisposing disorder', 'Disease', 'MESH:C566426', (21, 49))
401218	33552988	Germline DICER1 variants have been detected in individuals affected with familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years.	('children', 'Species', '9606', (176, 184))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (82, 106))	('tumor of the lung', 'Phenotype', 'HP:0100526', (131, 148))	('DICER1', 'Gene', (9, 15))	('malignant tumor', 'Disease', 'MESH:D009369', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('familial pleuropulmonary blastoma', 'Disease', (73, 106))	('PPB', 'Phenotype', 'HP:0100528', (108, 111))	('variants', 'Var', (16, 24))	('familial pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (73, 106))	('malignant tumor', 'Disease', (121, 136))
401220	33552988	A study on 207 carriers of DICER1 pathogenic variants reported that the risk to develop a neoplasm is 5.3% before the age of 10 years and of 31.5% before the age of 60, while in the American general population is estimated to be respectively 0.17 and 6.57%.	('DICER1', 'Gene', (27, 33))	('neoplasm', 'Disease', (90, 98))	('variants', 'Var', (45, 53))	('neoplasm', 'Phenotype', 'HP:0002664', (90, 98))	('neoplasm', 'Disease', 'MESH:D009369', (90, 98))
401225	33552988	In most syndrome's neoplasms a biallelic pathogenic variant in DICER1 has been detected: usually a germline loss-of-function pathogenic variant in one allele and a tumor-specific somatic hotspot variant in the second allele.	('tumor', 'Disease', (164, 169))	('neoplasms', 'Phenotype', 'HP:0002664', (19, 28))	('DICER1', 'Gene', (63, 69))	('variant', 'Var', (136, 143))	('loss-of-function', 'NegReg', (108, 124))	('neoplasms', 'Disease', 'MESH:D009369', (19, 28))	('neoplasms', 'Disease', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('neoplasm', 'Phenotype', 'HP:0002664', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
401226	33552988	Several studies have shown that "monoallelic DICER1 inactivation promotes tumorigenesis, whereas biallelic loss is inhibitory, and although inactivation of one DICER1 allele is the initiating event in DICER1 syndrome", leading "to dysregulation of miRNA levels, other events must be required for cancer to occur ".	('inactivation', 'Var', (140, 152))	('dysregulation', 'MPA', (231, 244))	('DICER1', 'Gene', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('miRNA levels', 'MPA', (248, 260))	('inactivation', 'Var', (52, 64))	('promotes', 'PosReg', (65, 73))	('tumor', 'Disease', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Disease', (296, 302))
401227	33552988	Only one third of DICER1 carriers present a neoplasm during the life, hinting that multiple additional events are required.	('DICER1', 'Gene', (18, 24))	('neoplasm', 'Disease', (44, 52))	('neoplasm', 'Phenotype', 'HP:0002664', (44, 52))	('carriers', 'Var', (25, 33))	('neoplasm', 'Disease', 'MESH:D009369', (44, 52))
401229	33552988	Complete loss of Dicer is incompatible with life, while somatic mosaic mutations in the RNase IIIb domain have been associated with a more serious form of DICER1 syndrome, named GLOW syndrome from Global developmental delay, Lung cysts, Overgrowth, and Wilms tumor.	('mosaic mutations', 'Var', (64, 80))	('associated with', 'Reg', (116, 131))	('DICER1 syndrome', 'Disease', (155, 170))	('Wilms tumor', 'Disease', (253, 264))	('Global developmental delay', 'Disease', 'MESH:D001037', (197, 223))	('Global developmental delay', 'Disease', (197, 223))	('RNase IIIb', 'Gene', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('GLOW syndrome', 'Disease', (178, 191))	('Wilms tumor', 'Disease', 'MESH:D009396', (253, 264))	('Overgrowth', 'Disease', (237, 247))	('Lung cysts', 'Disease', (225, 235))	('Lung cysts', 'Disease', 'MESH:D008171', (225, 235))	('Overgrowth', 'Phenotype', 'HP:0001548', (237, 247))	('Wilms tumor', 'Phenotype', 'HP:0002667', (253, 264))	('Dicer', 'Gene', '23405', (17, 22))	('Lung cysts', 'Phenotype', 'HP:0032445', (225, 235))	('Dicer', 'Gene', (17, 22))	('Global developmental delay', 'Phenotype', 'HP:0001263', (197, 223))
401230	33552988	Functional evidence links the hotspot mutations in the RNAse IIIb domain to specific dysregulation of certain miRNAs leading to activation of the PI3K/AKT/mTOR pathway.	('activation', 'PosReg', (128, 138))	('AKT', 'Gene', (151, 154))	('mTOR', 'Gene', '2475', (155, 159))	('mTOR', 'Gene', (155, 159))	('miRNAs', 'MPA', (110, 116))	('dysregulation', 'MPA', (85, 98))	('AKT', 'Gene', '207', (151, 154))	('mutations', 'Var', (38, 47))	('RNAse', 'Protein', (55, 60))
401231	33552988	This mechanistic link to the PI3K/AKT/mTOR pathway may explain the fact that GLOW syndrome shares some clinical features with other conditions characterized by somatic gain-of-function mutations of genes of this pathway, such as lung cysts, reported in Proteus syndrome, and segmental overgrowth, a prominent feature of PROS.	('segmental overgrowth', 'Disease', (275, 295))	('AKT', 'Gene', (34, 37))	('Proteus syndrome', 'Disease', (253, 269))	('Proteus syndrome', 'Disease', 'MESH:D016715', (253, 269))	('lung cysts', 'Phenotype', 'HP:0032445', (229, 239))	('lung cysts', 'Disease', 'MESH:D008171', (229, 239))	('overgrowth', 'Phenotype', 'HP:0001548', (285, 295))	('AKT', 'Gene', '207', (34, 37))	('gain-of-function', 'PosReg', (168, 184))	('GLOW syndrome', 'Disease', (77, 90))	('mutations', 'Var', (185, 194))	('lung cyst', 'Phenotype', 'HP:0032445', (229, 238))	('mTOR', 'Gene', (38, 42))	('mTOR', 'Gene', '2475', (38, 42))	('lung cysts', 'Disease', (229, 239))
401232	33552988	The recurrent involvement of specific organs (lungs, thyroid, kidneys, ovaries) in presence of DICER1 alterations may lead to infer that the effects of miRNAs on gene expression are tissue-specific.	('ovaries', 'Disease', 'MESH:D010051', (71, 78))	('alterations', 'Var', (102, 113))	('ovaries', 'Disease', (71, 78))	('DICER1', 'Gene', (95, 101))
401234	33552988	Individuals carrying germline loss-of-function mutations may present clinical features in few sites (0-2) of their body, while patients with mosaic "hotspot" mutations are more prone to manifestations in multiple site.	('patients', 'Species', '9606', (127, 135))	('loss-of-function', 'NegReg', (30, 46))	('mutations', 'Var', (47, 56))
401237	33552988	recently published the first quantitative analysis of site-specific neoplasm risk, analyzing the standardized incidence ratios of 207 individuals carrying DICER1 variants, selected combining data from three large cohorts of patients.	('neoplasm', 'Disease', 'MESH:D009369', (68, 76))	('DICER1', 'Gene', (155, 161))	('variants', 'Var', (162, 170))	('patients', 'Species', '9606', (224, 232))	('neoplasm', 'Disease', (68, 76))	('neoplasm', 'Phenotype', 'HP:0002664', (68, 76))
401242	33552988	Cystic PPB is reported to be common in carriers of DICER1 variants, and only a limited number of cases had a type II II or III PPB progression.	('DICER1', 'Gene', (51, 57))	('variants', 'Var', (58, 66))	('Cystic PPB', 'Disease', (0, 10))	('PPB', 'Phenotype', 'HP:0100528', (127, 130))	('Cystic PPB', 'Disease', 'MESH:C537516', (0, 10))	('PPB', 'Phenotype', 'HP:0100528', (7, 10))	('type II II', 'Disease', 'MESH:D016532', (109, 119))	('type II II', 'Disease', (109, 119))
401245	33552988	Indeed, in more than 70% of CPAM, a wait and see strategy is addressed; in this cases a DICER1 variants should always be considered in order to identify promptly with a strict follow-up and genetic screening patients at risk of more aggressive PBB.	('patients', 'Species', '9606', (208, 216))	('DICER1', 'Gene', (88, 94))	('variants', 'Var', (95, 103))
401248	33552988	MNG is common in individuals with DICER1 pathogenic variants, as reported by Khan et al.. Germline DICER1 mutations have been reported in children with both MNG or familial MNG.	('MNG', 'Phenotype', 'HP:0005987', (157, 160))	('children', 'Species', '9606', (138, 146))	('MNG', 'Phenotype', 'HP:0005987', (0, 3))	('MNG', 'Disease', (157, 160))	('familial MNG', 'Disease', (164, 176))	('MNG', 'Phenotype', 'HP:0005987', (173, 176))	('mutations', 'Var', (106, 115))	('DICER1', 'Gene', (99, 105))	('reported', 'Reg', (126, 134))
401251	33552988	Recent reports enumerate anaplastic sarcoma of the kidney in DICER1 syndrome, correlating the germline DICER1 mutations with the development of these tumors, and postulate that they may arise from pre-existing pediatric cystic nephromas.	('cystic nephromas', 'Disease', 'MESH:D018201', (220, 236))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('DICER1', 'Gene', (103, 109))	('sarcoma of the kidney', 'Disease', (36, 57))	('mutations', 'Var', (110, 119))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cystic nephromas', 'Disease', (220, 236))	('sarcoma of the kidney', 'Disease', 'MESH:D012509', (36, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (36, 57))
401254	33552988	Unlike PPB, the age range of increased risk for genital tract tumors is wide (2 to 40 years), even if some data suggest that ovarian SLCTs arising in patients carrying DICER1 variants occur mostly in the second decade.	('variants', 'Var', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('ovarian SLCTs', 'Disease', 'MESH:D010049', (125, 138))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('patients', 'Species', '9606', (150, 158))	('ovarian SLCTs', 'Disease', (125, 138))	('SLCT', 'Phenotype', 'HP:0100619', (133, 137))	('PPB', 'Phenotype', 'HP:0100528', (7, 10))	('genital tract tumors', 'Phenotype', 'HP:0010787', (48, 68))	('DICER1', 'Gene', (168, 174))
401257	33552988	The prognosis of ovarian SLCT is generally favorable, but a recent report indicates that somatic DICER1 variants SLCTs may be linked to a higher relapse risk than others.	('ovarian SLCT', 'Disease', (17, 29))	('ovarian SLCT', 'Disease', 'MESH:D010049', (17, 29))	('variants', 'Var', (104, 112))	('DICER1', 'Gene', (97, 103))	('SLCT', 'Phenotype', 'HP:0100619', (113, 117))	('SLCT', 'Phenotype', 'HP:0100619', (25, 29))	('relapse', 'CPA', (145, 152))
401261	33552988	Poorly differentiated ovarian sarcoma, retiform SLCT, and primitive neuroectodermal tumor (PNET) of the cervix have also been reported in individuals with possible germline DICER1 variants.	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (68, 89))	('SLCT', 'Phenotype', 'HP:0100619', (48, 52))	('ovarian sarcoma', 'Disease', 'MESH:D012509', (22, 37))	('neuroectodermal tumor', 'Disease', (68, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('retiform SLCT', 'Disease', (39, 52))	('DICER1', 'Gene', (173, 179))	('variants', 'Var', (180, 188))	('ovarian sarcoma', 'Disease', (22, 37))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (58, 89))	('PNET', 'Phenotype', 'HP:0030065', (91, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (68, 89))
401267	33552988	Moreover, somatic DROSHA and DGCR8 mutations, both related to the Dicer miRNA-regulating pathway, have been recently documented in pineoblastomas, in addition to germline and somatic DICER1 mutations, indicating that pineoblastoma development is influenced by disturbances of miRNA processes.	('Dicer', 'Gene', (66, 71))	('pineoblastoma', 'Phenotype', 'HP:0030408', (131, 144))	('DGCR8', 'Gene', (29, 34))	('pineoblastoma', 'Disease', (131, 144))	('pineoblastoma', 'Disease', 'MESH:D010871', (217, 230))	('pineoblastomas', 'Disease', (131, 145))	('DGCR8', 'Gene', '54487', (29, 34))	('DROSHA', 'Gene', '29102', (18, 24))	('pineoblastomas', 'Disease', 'MESH:D010871', (131, 145))	('pineoblastoma', 'Phenotype', 'HP:0030408', (217, 230))	('pineoblastoma', 'Disease', 'MESH:D010871', (131, 144))	('documented', 'Reg', (117, 127))	('pineoblastoma', 'Disease', (217, 230))	('DROSHA', 'Gene', (18, 24))	('Dicer', 'Gene', '23405', (66, 71))	('mutations', 'Var', (35, 44))
401268	33552988	Other brain tumors associated to DICER1 alterations have also been reported but their genetic association has not been clearly demonstrated.	('associated', 'Reg', (19, 29))	('alterations', 'Var', (40, 51))	('brain tumors', 'Disease', 'MESH:D001932', (6, 18))	('DICER1', 'Gene', (33, 39))	('brain tumors', 'Phenotype', 'HP:0030692', (6, 18))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('brain tumors', 'Disease', (6, 18))
401273	33552988	Heterozygosis is the most common condition through DICER1 syndrome's patients, where commonly a germline loss-of-function gene variant (nonsense, frameshift, or splice-affected) generates a truncated protein.	('DICER1 syndrome', 'Disease', (51, 66))	('frameshift', 'Var', (146, 156))	('truncated protein', 'MPA', (190, 207))	('patients', 'Species', '9606', (69, 77))	('loss-of-function', 'NegReg', (105, 121))
401277	33552988	Although risks of malignancy are elevated, most patients with pathogenic germline DICER1 variants live healthy lives.	('variants', 'Var', (89, 97))	('malignancy', 'Disease', 'MESH:D009369', (18, 28))	('malignancy', 'Disease', (18, 28))	('DICER1', 'Gene', (82, 88))	('patients', 'Species', '9606', (48, 56))
401278	33552988	Indeed, a tumor occurs in 19,3% of the patients who carry germline pathogenic variation by the age of 50 years old and the neoplastic risk rises with age, especially in females, that are exposed to the risk to present with gynecologic neoplasms.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('patients', 'Species', '9606', (39, 47))	('neoplasms', 'Phenotype', 'HP:0002664', (235, 244))	('tumor', 'Disease', (10, 15))	('neoplasm', 'Phenotype', 'HP:0002664', (235, 243))	('neoplasms', 'Disease', 'MESH:D009369', (235, 244))	('neoplasms', 'Disease', (235, 244))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('variation', 'Var', (78, 87))
401285	33552988	Despite patients affected by biallelic DICER1 mutations may not benefit from this treatment, metformin will be may proposed to patients with a single allele alteration, to try to augment DICER1 protein production and compensate the deficit, preventing the oncogenetic cascade.	('mutations', 'Var', (46, 55))	('augment', 'NegReg', (179, 186))	('DICER1', 'Gene', (39, 45))	('DICER1 protein production', 'MPA', (187, 212))	('oncogenetic', 'CPA', (256, 267))	('patients', 'Species', '9606', (127, 135))	('metformin', 'Chemical', 'MESH:D008687', (93, 102))	('patients', 'Species', '9606', (8, 16))
401286	33552988	DICER1 syndrome is a rare condition caused by germline variants of DICER1; the occurrence of a second somatic tissue-specific mutation leads to different phenotypes ranging from benign lesions to malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('DICER1 syndrome', 'Disease', (0, 15))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('malignant tumors', 'Disease', (196, 212))	('germline variants', 'Var', (46, 63))	('DICER1', 'Gene', (67, 73))	('malignant tumors', 'Disease', 'MESH:D009369', (196, 212))	('caused', 'Reg', (36, 42))	('leads to', 'Reg', (135, 143))
401287	33552988	Screening for DICER1 variants should be performed in all patients with PPB and considered in few benign lesions and malignant tumors.	('variants', 'Var', (21, 29))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('PPB', 'Phenotype', 'HP:0100528', (71, 74))	('PPB', 'Disease', (71, 74))	('patients', 'Species', '9606', (57, 65))	('DICER1', 'Gene', (14, 20))	('malignant tumors', 'Disease', (116, 132))	('malignant tumors', 'Disease', 'MESH:D009369', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
401290	30276917	Triggered by a few index cases with monomorphic cytomorphology and distinctive stromal and perivascular hyalinization, immunopositivity for S100 and CD34, and RAF1 and NTRK1 fusions, the authors undertook a systematic review of tumors with similar features.	('RAF1', 'Gene', (159, 163))	('NTRK1', 'Gene', (168, 173))	('RAF1', 'Gene', '5894', (159, 163))	('S100', 'Gene', '6285', (140, 144))	('CD34', 'Gene', (149, 153))	('S100', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('fusions', 'Var', (174, 181))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('NTRK1', 'Gene', '4914', (168, 173))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('CD34', 'Gene', '947', (149, 153))
401293	30276917	A total of 25 cases (15 adults and 10 children) with kinase fusions were identified, including 8 cases involving RAF1, 2 BRAF, 14 NTRK1, and 1 NTRK2 gene rearrangements.	('BRAF', 'Gene', (121, 125))	('NTRK2', 'Gene', '4915', (143, 148))	('RAF1', 'Gene', (113, 117))	('RAF1', 'Gene', '5894', (113, 117))	('fusions', 'Var', (60, 67))	('NTRK1', 'Gene', '4914', (130, 135))	('NTRK2', 'Gene', (143, 148))	('NTRK1', 'Gene', (130, 135))	('BRAF', 'Gene', '673', (121, 125))	('children', 'Species', '9606', (38, 46))
401301	30276917	Recurrent fusions involving genes encoding receptor tyrosine or cytoplasmic kinases have been described in distinct soft tissue tumors with spindle cell morphology and fibroblastic or neural differentiation.	('fibroblastic', 'CPA', (168, 180))	('described', 'Reg', (94, 103))	('spindle cell', 'Disease', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (116, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (116, 134))	('tyrosine', 'Chemical', 'None', (52, 60))	('fusions', 'Var', (10, 17))
401309	30276917	Prompted by detection of RAF1 and NTRK1 fusions in a group of tumors with monomorphic cytomorphology and co-expression of S100 and CD34, somewhat reminiscent of low-grade malignant peripheral nerve sheath tumors (MPNST), we mined our pathology department and consultation files at the contributing institutions for additional similar cases.	('CD34', 'Gene', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('NTRK1', 'Gene', '4914', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('S100', 'Gene', '6285', (122, 126))	('NTRK1', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('S100', 'Gene', (122, 126))	('tumors', 'Disease', (62, 68))	('RAF1', 'Gene', '5894', (25, 29))	('MPNST', 'Phenotype', 'HP:0100697', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))	('CD34', 'Gene', '947', (131, 135))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('RAF1', 'Gene', (25, 29))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (171, 211))	('sheath tumors', 'Disease', 'MESH:D018317', (198, 211))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('fusions', 'Var', (40, 47))	('sheath tumors', 'Disease', (198, 211))
401311	30276917	The study was triggered by 2 index cases with RAF1 or NTRK1 fusions which showed similar morphologic features and an identical immunoprofile of S100 and CD34 positivity.	('CD34', 'Gene', (153, 157))	('CD34', 'Gene', '947', (153, 157))	('S100', 'Gene', '6285', (144, 148))	('NTRK1', 'Gene', '4914', (54, 59))	('fusions', 'Var', (60, 67))	('RAF1', 'Gene', '5894', (46, 50))	('S100', 'Gene', (144, 148))	('NTRK1', 'Gene', (54, 59))	('RAF1', 'Gene', (46, 50))
401316	30276917	Prototypical high-grade sarcomas or high-grade MPNSTs with high mitotic count, geographic areas of necrosis, and loss of H3K27me3 were excluded, as were MPNST cases associated with NF1 or previous radiation.	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('MPNST', 'Phenotype', 'HP:0100697', (47, 52))	('associated', 'Reg', (165, 175))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcomas', 'Disease', (24, 32))	('necrosis', 'Disease', 'MESH:D009336', (99, 107))	('loss', 'Var', (113, 117))	('H3K27me3', 'Protein', (121, 129))	('NF1', 'Gene', (181, 184))	('NF1', 'Gene', '4763', (181, 184))	('necrosis', 'Disease', (99, 107))	('MPNST', 'Phenotype', 'HP:0100697', (153, 158))
401319	30276917	In tumors with NTRK-related fusions, IHC staining for TrkA (NTRK1) was performed on 12 of the 14 NTRK1-rearranged tumors, mostly in retrospect after the identification of the positive results by FISH/RNA sequencing.	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('NTRK1', 'Gene', '4914', (60, 65))	('TRK', 'Gene', (61, 64))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('NTRK1', 'Gene', (60, 65))	('NTRK1', 'Gene', '4914', (97, 102))	('TrkA', 'Gene', '4914', (54, 58))	('TRK', 'Gene', (98, 101))	('NTRK1', 'Gene', (97, 102))	('TRK', 'Gene', '4914', (61, 64))	('fusions', 'Var', (28, 35))	('TRK', 'Gene', (16, 19))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('TRK', 'Gene', '4914', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('TRK', 'Gene', '4914', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (3, 9))	('TrkA', 'Gene', (54, 58))	('tumors', 'Disease', (114, 120))
401320	30276917	We used a commercially available TrkA rabbit monoclonal antibody, clone EP1058Y (Abcam, Cambridge, MA) at a dilution of 1:1500.	('EP1058Y', 'Var', (72, 79))	('TrkA', 'Gene', '4914', (33, 37))	('rabbit', 'Species', '9986', (38, 44))	('TrkA', 'Gene', (33, 37))
401339	30276917	Six RAF1/BRAF rearranged tumors had pure low-grade morphology with low cellularity and abundant collagenous stroma, and a low mitotic count (1-2 MF/10 HPFs) and lacked necrosis.	('necrosis', 'Disease', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('BRAF', 'Gene', (9, 13))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('low', 'NegReg', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('RAF1', 'Gene', (4, 8))	('necrosis', 'Disease', 'MESH:D009336', (168, 176))	('RAF1', 'Gene', '5894', (4, 8))	('mitotic count', 'CPA', (126, 139))	('rearranged', 'Var', (14, 24))	('BRAF', 'Gene', '673', (9, 13))
401355	30276917	There were 14 tumors with NTRK1 rearrangements and one with NTRK2-related fusion (Table 1).	('NTRK1', 'Gene', '4914', (26, 31))	('NTRK2', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('rearrangements', 'Var', (32, 46))	('NTRK2', 'Gene', '4915', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('NTRK1', 'Gene', (26, 31))
401365	30276917	At the other end of the spectrum, three NTRK1 rearranged spindle cell sarcomas were composed of cellular fascicular areas, with >10 MF/10 HPFs and lacked necrosis, which would correspond to an intermediate histo-logic grade category.	('rearranged', 'Var', (46, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('NTRK1', 'Gene', '4914', (40, 45))	('necrosis', 'Disease', 'MESH:D009336', (154, 162))	('spindle cell sarcomas', 'Disease', (57, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('spindle cell sarcomas', 'Disease', 'MESH:D012509', (57, 78))	('necrosis', 'Disease', (154, 162))	('NTRK1', 'Gene', (40, 45))
401379	30276917	Microscopically, the tumor had a similar morphologic appearance to all the other kinase fusion variants, of a low cellularity spindle cell tumor with a haphazard growth pattern, composed of mostly uniform cytomorphology and scattered plumper cells with enlarged and multilobated nuclei with smudgy chromatin.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('variants', 'Var', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
401383	30276917	This is the first report of RAF1 gene fusions in soft tissue tumors.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (49, 67))	('RAF1', 'Gene', '5894', (28, 32))	('RAF1', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('gene fusions', 'Var', (33, 45))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (49, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
401385	30276917	Isolated examples of RAF1 fusions have been reported in various epithelial malignancies, such as prostate, breast, thyroid, and pancreas, as well as in a group of pediatric low-grade gliomas.	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('gliomas', 'Disease', (183, 190))	('breast', 'Disease', (107, 113))	('gliomas', 'Disease', 'MESH:D005910', (183, 190))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('fusions', 'Var', (26, 33))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (64, 87))	('malignancies', 'Disease', (75, 87))	('pancreas', 'Disease', (128, 136))	('RAF1', 'Gene', (21, 25))	('RAF1', 'Gene', '5894', (21, 25))	('thyroid', 'Disease', (115, 122))	('reported', 'Reg', (44, 52))	('prostate', 'Disease', (97, 105))
401387	30276917	In addition, BRAF gene rearrangements have been described recently in a subset of spindle cell sarcomas, morphologically resembling infantile fibrosarcomas.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (142, 154))	('infantile fibrosarcomas', 'Disease', (132, 155))	('described', 'Reg', (48, 57))	('BRAF', 'Gene', '673', (13, 17))	('spindle cell sarcomas', 'Disease', (82, 103))	('BRAF', 'Gene', (13, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('rearrangements', 'Var', (23, 37))	('spindle cell sarcomas', 'Disease', 'MESH:D012509', (82, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('infantile fibrosarcomas', 'Disease', 'MESH:D005354', (132, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
401392	30276917	Other established examples of recurrent kinase gene rearrangements in spindle cell tumors are ETV6-NTRK3 fusions in infantile fibrosarcomas (IFS), sarcomas that typically present at birth or in the first 2 years of life.	('spindle cell tumors', 'Disease', (70, 89))	('IFS', 'Disease', (141, 144))	('ETV6', 'Gene', (94, 98))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (126, 138))	('sarcomas', 'Disease', 'MESH:D012509', (147, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('infantile fibrosarcomas', 'Disease', 'MESH:D005354', (116, 139))	('sarcomas', 'Disease', (147, 155))	('rearrangements', 'Var', (52, 66))	('fusions', 'Var', (105, 112))	('IFS', 'Disease', 'MESH:D005354', (141, 144))	('sarcomas', 'Disease', 'MESH:D012509', (131, 139))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('NTRK3', 'Gene', '4916', (99, 104))	('sarcomas', 'Disease', (131, 139))	('spindle cell tumors', 'Disease', 'MESH:D002277', (70, 89))	('NTRK3', 'Gene', (99, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('infantile fibrosarcomas', 'Disease', (116, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('ETV6', 'Gene', '2120', (94, 98))
401393	30276917	Moreover, recurrent variant NTRK1 fusions have been detected in the so-called lipofibromatosis-like neural tumors, which is another group of pediatric and young adult lesions, that, by immunohistochemistry (IHC), often co-express CD34 and S100 (but not SOX10), suggesting neural differentiation.	('NTRK1', 'Gene', (28, 33))	('S100', 'Gene', (239, 243))	('lipofibromatosis-like neural tumors', 'Disease', 'MESH:C536408', (78, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SOX10', 'Gene', (253, 258))	('SOX10', 'Gene', '6663', (253, 258))	('detected', 'Reg', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('co-express', 'Reg', (219, 229))	('lipofibromatosis-like neural tumors', 'Disease', (78, 113))	('CD34', 'Gene', (230, 234))	('CD34', 'Gene', '947', (230, 234))	('variant NTRK1', 'CellLine', 'CVCL:7204', (20, 33))	('S100', 'Gene', '6285', (239, 243))	('fusions', 'Var', (34, 41))	('variant', 'Var', (20, 27))
401401	30276917	A STRN-NTRK2 fusion variant was reported in one pediatric patient with soft tissue sarcoma, although the exact morphologic features remain unclear.	('NTRK2', 'Gene', '4915', (7, 12))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (71, 90))	('sarcoma', 'Disease', (83, 90))	('patient', 'Species', '9606', (58, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('NTRK2', 'Gene', (7, 12))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('variant', 'Var', (20, 27))
401420	30276917	BRAF fusions have also been reported in IFS-like sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('IFS', 'Disease', (40, 43))	('fusions', 'Var', (5, 12))	('sarcomas', 'Disease', (49, 57))	('IFS', 'Disease', 'MESH:D005354', (40, 43))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))
401422	30276917	Fascicular spindle cell sarcomas with NTRK1 rearrangements and similar fibrosarcoma-like morphology have been described in soft tissue and uterus in previous publications from our group.	('NTRK1', 'Gene', (38, 43))	('fibrosarcoma', 'Disease', (71, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('Fascicular spindle cell sarcomas', 'Disease', 'MESH:D012509', (0, 32))	('NTRK1', 'Gene', '4914', (38, 43))	('fibrosarcoma', 'Disease', 'MESH:D005354', (71, 83))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (71, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Fascicular spindle cell sarcomas', 'Disease', (0, 32))	('rearrangements', 'Var', (44, 58))
401428	30276917	Other bland fibroblastic spindle cell tumors with collagen bands and perivascular collagen deposits and diffuse CD34 expression include cellular angiofibroma, mammary-type myofibroblastoma, and spindle cell lipoma, three tumors which are histogenetically related, as they all have abnormalities in 13q14, leading to loss of Rb1.	('spindle cell lipoma', 'Disease', (194, 213))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('loss', 'NegReg', (316, 320))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('Rb1', 'Gene', (324, 327))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('angiofibroma', 'Disease', (145, 157))	('tumors', 'Disease', (38, 44))	('CD34', 'Gene', (112, 116))	('lipoma', 'Phenotype', 'HP:0012032', (207, 213))	('abnormalities', 'Var', (281, 294))	('spindle cell tumors', 'Disease', 'MESH:D002277', (25, 44))	('tumors', 'Disease', (221, 227))	('spindle cell lipoma', 'Disease', 'MESH:D002277', (194, 213))	('angiofibroma', 'Disease', 'MESH:D018322', (145, 157))	('myofibroblastoma', 'Disease', 'MESH:D009379', (172, 188))	('cellular angiofibroma', 'Phenotype', 'HP:0010615', (136, 157))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('spindle cell tumors', 'Disease', (25, 44))	('CD34', 'Gene', '947', (112, 116))	('Rb1', 'Gene', '5925', (324, 327))	('myofibroblastoma', 'Disease', (172, 188))
401431	30276917	In this respect, two recent clinical studies demonstrated promising sensitivity of various malignancies with TRK fusions to Larotrectinib, a highly selective small molecule TRK inhibitor.	('TRK', 'Gene', '4914', (173, 176))	('malignancies', 'Disease', (91, 103))	('fusions', 'Var', (113, 120))	('TRK', 'Gene', (109, 112))	('TRK', 'Gene', '4914', (109, 112))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('TRK', 'Gene', (173, 176))
401436	30276917	In conclusion, we describe a series of spindle cell tumors resembling low- to intermediate-grade MPNST, occurring in both children and young adults, in various anatomic sites (including bone, soft tissue, and viscera) and harboring recurrent gene fusions in various kinases, such as RAF1, BRAF, NTRK1, and NTRK2.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('children', 'Species', '9606', (122, 130))	('RAF1', 'Gene', (283, 287))	('RAF1', 'Gene', '5894', (283, 287))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('spindle cell tumors', 'Disease', 'MESH:D002277', (39, 58))	('NTRK2', 'Gene', '4915', (306, 311))	('NTRK1', 'Gene', '4914', (295, 300))	('gene fusions', 'Var', (242, 254))	('spindle cell tumors', 'Disease', (39, 58))	('BRAF', 'Gene', '673', (289, 293))	('MPNST', 'Phenotype', 'HP:0100697', (97, 102))	('NTRK1', 'Gene', (295, 300))	('NTRK2', 'Gene', (306, 311))	('BRAF', 'Gene', (289, 293))
401437	30276917	Regardless of the different fusion variants, most tumors showed a monomorphic spindle cell histology, patternless growth, and distinctive band-like stromal hyalinization and perivascular collagen rings.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('variants', 'Var', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
401438	30276917	Our findings suggest that these kinase fusions may define a novel tumor entity with RAF1, BRAF, and NTRK1/2 fusions.	('BRAF', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('RAF1', 'Gene', (84, 88))	('RAF1', 'Gene', '5894', (84, 88))	('NTRK1/2', 'Gene', '4914;4915', (100, 107))	('tumor', 'Disease', (66, 71))	('fusions', 'Var', (39, 46))	('BRAF', 'Gene', '673', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('NTRK1/2', 'Gene', (100, 107))	('fusions', 'Var', (108, 115))
401441	30276917	Our results add this novel subtype to the growing list of soft tissue tumors characterized by oncogenic kinase activation through gene fusions.	('activation', 'PosReg', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (58, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (58, 75))	('gene fusions', 'Var', (130, 142))
401442	30276917	Furthermore, NTRK1 immunohistochemistry appears to be a sensitive method to select this subset of tumors with NTRK1 gene rearrangements.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('NTRK1', 'Gene', (110, 115))	('NTRK1', 'Gene', '4914', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NTRK1', 'Gene', '4914', (110, 115))	('NTRK1', 'Gene', (13, 18))	('gene rearrangements', 'Var', (116, 135))
401580	29441101	Several successful strategies have been described (Table 3), and high rates of tumor regression have been reported using different energy sources (Cobalt-60, low-energy electrons, superficial X-rays).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('Cobalt-60', 'Chemical', 'MESH:C000615395', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('rays', 'Species', '255564', (194, 198))	('low-energy', 'Var', (158, 168))
401603	21127723	This procedure also lacks in precision, leading to discrepancies at the host-allograft junctions and increased risks of osteosynthesis failure and nonunion.	('discrepancies', 'Var', (51, 64))	('osteosynthesis failure', 'Disease', (120, 142))	('nonunion', 'CPA', (147, 155))	('leading to', 'Reg', (40, 50))	('osteosynthesis failure', 'Disease', 'MESH:D017093', (120, 142))
401696	30256525	We used the original SEER record to identify a patient's cancer type (NHL, HL, ALL, or sarcoma), age at diagnosis (15-19, 20-24, 25-29, 30-34, 35-39 years), sex, marital status (married, other), race/ethnicity (non-Hispanic (NH)-White, NH Black, Hispanic, NH Asian, American Indian/Alaskan Native), and health insurance at diagnosis (private, public, no insurance/unknown).	('cancer', 'Disease', (57, 63))	('sarcoma', 'Disease', (87, 94))	('HL', 'Disease', 'MESH:D006689', (71, 73))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('NHL', 'Phenotype', 'HP:0012539', (70, 73))	('NHL', 'Disease', 'MESH:D008228', (70, 73))	('NH Black', 'Chemical', 'MESH:C041779', (236, 244))	('NH', 'Chemical', 'MESH:D000641', (225, 227))	('NH', 'Chemical', 'MESH:D000641', (256, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('ALL', 'Phenotype', 'HP:0006721', (79, 82))	('HL', 'Phenotype', 'HP:0012189', (71, 73))	('HL', 'Disease', 'MESH:D006689', (75, 77))	('patient', 'Species', '9606', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('NH', 'Chemical', 'MESH:D000641', (70, 72))	('NH', 'Chemical', 'MESH:D000641', (236, 238))	('non-Hispanic', 'Var', (211, 223))	('NHL', 'Disease', (70, 73))	('HL', 'Phenotype', 'HP:0012189', (75, 77))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
401804	31221668	Development of mouse models of angiosarcoma driven by p53 Angiosarcomas are a rare group of tumours which have poor prognosis and limited treatment options.	('angiosarcoma', 'Disease', (31, 43))	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('Angiosarcomas', 'Disease', (58, 71))	('angiosarcoma', 'Phenotype', 'HP:0200058', (31, 43))	('p53', 'Var', (54, 57))	('Angiosarcomas', 'Disease', 'MESH:D006394', (58, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('Angiosarcomas', 'Phenotype', 'HP:0200058', (58, 71))	('tumours', 'Disease', (92, 99))	('angiosarcoma', 'Disease', 'MESH:D006394', (31, 43))	('mouse', 'Species', '10090', (15, 20))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))
401805	31221668	Here, we describe the development of an autochthonous mouse model of angiosarcoma driven by loss of p53 in VE-cadherin-expressing endothelial cells.	('VE-cadherin', 'Gene', (107, 118))	('angiosarcoma', 'Disease', (69, 81))	('VE-cadherin', 'Gene', '12562', (107, 118))	('angiosarcoma', 'Phenotype', 'HP:0200058', (69, 81))	('loss', 'Var', (92, 96))	('angiosarcoma', 'Disease', 'MESH:D006394', (69, 81))	('mouse', 'Species', '10090', (54, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('p53', 'Gene', (100, 103))
401806	31221668	Using Cdh5-Cre to drive recombination in adult endothelial cells, mice developed angiosarcomas with 100% penetrance upon homozygous deletion of Trp53 with a median lifespan of 325 days.	('angiosarcoma', 'Phenotype', 'HP:0200058', (81, 93))	('deletion', 'Var', (132, 140))	('angiosarcomas', 'Disease', (81, 94))	('Trp53', 'Gene', (144, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('angiosarcomas', 'Disease', 'MESH:D006394', (81, 94))	('mice', 'Species', '10090', (66, 70))	('angiosarcomas', 'Phenotype', 'HP:0200058', (81, 94))
401807	31221668	In contrast, expression of the R172H mutant p53 resulted in formation of thymic lymphomas with a more rapid onset (median lifespan 151 days).	('R172H', 'Var', (31, 36))	('lymphoma', 'Phenotype', 'HP:0002665', (80, 88))	('R172H', 'Mutation', 'rs755944376', (31, 36))	('thymic lymphomas', 'Disease', (73, 89))	('p53', 'Gene', (44, 47))	('lymphomas', 'Phenotype', 'HP:0002665', (80, 89))	('thymic lymphomas', 'Disease', 'MESH:D013953', (73, 89))
401810	31221668	Upon deletion of Trp53 in Pdgfrb-Cre-expressing mice (Pdgfrb-Cre, Trp53fl/fl mice), 65% developed lymphomas and 21% developed pleomorphic undifferentiated soft tissue sarcomas.	('sarcomas', 'Disease', (167, 175))	('Trp53', 'Gene', (17, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('pleomorphic undifferentiated soft tissue sarcoma', 'Disease', (126, 174))	('pleomorphic undifferentiated soft tissue sarcoma', 'Disease', 'MESH:D012509', (126, 174))	('Pdgfrb', 'Gene', '18596', (26, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('developed', 'Reg', (116, 125))	('mice', 'Species', '10090', (77, 81))	('Pdgfrb', 'Gene', (26, 32))	('lymphomas', 'Disease', 'MESH:D008223', (98, 107))	('lymphomas', 'Phenotype', 'HP:0002665', (98, 107))	('deletion', 'Var', (5, 13))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (155, 174))	('Pdgfrb', 'Gene', '18596', (54, 60))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (155, 175))	('Pdgfrb', 'Gene', (54, 60))	('mice', 'Species', '10090', (48, 52))	('lymphomas', 'Disease', (98, 107))	('developed', 'PosReg', (88, 97))	('sarcomas', 'Disease', 'MESH:D012509', (167, 175))	('sarcomas', 'Phenotype', 'HP:0100242', (167, 175))
401812	31221668	In contrast, 75% of Pdgfrb-Cre, Trp53R172H/R172H mice developed angiosarcomas, with 60% of these mice also developing lymphomas.	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('angiosarcomas', 'Disease', 'MESH:D006394', (64, 77))	('angiosarcomas', 'Phenotype', 'HP:0200058', (64, 77))	('lymphomas', 'Disease', (118, 127))	('Pdgfrb', 'Gene', (20, 26))	('R172H', 'Mutation', 'rs755944376', (37, 42))	('mice', 'Species', '10090', (49, 53))	('mice', 'Species', '10090', (97, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('lymphomas', 'Disease', 'MESH:D008223', (118, 127))	('R172H', 'Mutation', 'rs755944376', (43, 48))	('Trp53R172H/R172H', 'Var', (32, 48))	('developing', 'Reg', (107, 117))	('lymphomas', 'Phenotype', 'HP:0002665', (118, 127))	('angiosarcoma', 'Phenotype', 'HP:0200058', (64, 76))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('angiosarcomas', 'Disease', (64, 77))	('Pdgfrb', 'Gene', '18596', (20, 26))
401813	31221668	The median lifespan of the Pdgfrb-Cre, Trp53R172H/R172H mice was 151 days.	('Pdgfrb', 'Gene', '18596', (27, 33))	('R172H', 'Mutation', 'rs755944376', (50, 55))	('mice', 'Species', '10090', (56, 60))	('Pdgfrb', 'Gene', (27, 33))	('R172H', 'Mutation', 'rs755944376', (44, 49))	('Trp53R172H/R172H', 'Var', (39, 55))
401816	31221668	Editor's choice: Deletion of p53, rather than mutation, in endothelial cells leads to reliable angiosarcoma generation, which, along with establishment of a transplantation model, provides a novel approach for testing potential new therapeutics.	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('angiosarcoma', 'Disease', 'MESH:D006394', (95, 107))	('p53', 'Gene', (29, 32))	('rat', 'Species', '10116', (112, 115))	('angiosarcoma', 'Disease', (95, 107))	('rat', 'Species', '10116', (34, 37))	('Deletion', 'Var', (17, 25))	('angiosarcoma', 'Phenotype', 'HP:0200058', (95, 107))
401823	31221668	Mutations in TP53 (which encodes p53) have been reported in human angiosarcomas, with incidences of between 4% and 52% reported in different studies.	('TP53', 'Gene', (13, 17))	('angiosarcoma', 'Phenotype', 'HP:0200058', (66, 78))	('reported', 'Reg', (48, 56))	('angiosarcomas', 'Disease', (66, 79))	('Mutations', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('angiosarcomas', 'Phenotype', 'HP:0200058', (66, 79))	('angiosarcomas', 'Disease', 'MESH:D006394', (66, 79))	('human', 'Species', '9606', (60, 65))
401824	31221668	In addition, mice with germline deletion of Trp53 which are predisposed to the development of lymphoma develop angiosarcomas in significant numbers.	('mice', 'Species', '10090', (13, 17))	('lymphoma', 'Disease', 'MESH:D008223', (94, 102))	('lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('angiosarcomas', 'Disease', (111, 124))	('angiosarcoma', 'Phenotype', 'HP:0200058', (111, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('angiosarcomas', 'Disease', 'MESH:D006394', (111, 124))	('lymphoma', 'Disease', (94, 102))	('germline deletion', 'Var', (23, 40))	('angiosarcomas', 'Phenotype', 'HP:0200058', (111, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('Trp53', 'Gene', (44, 49))
401831	31221668	It is widely accepted that mutant forms of p53 can exert dominant negative or gain-of-function effects that contribute to tumour development beyond that seen following loss of the wild-type p53 protein alone.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('mutant', 'Var', (27, 33))	('gain-of-function', 'PosReg', (78, 94))	('tumour', 'Disease', (122, 128))	('negative', 'NegReg', (66, 74))	('p53', 'Gene', (43, 46))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
401832	31221668	Individuals with Li-Fraumeni syndrome carry inherited mutations in TP53 and are predisposed to tumour development, including sarcomas.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('mutations', 'Var', (54, 63))	('predisposed', 'Reg', (80, 91))	('sarcomas', 'Disease', 'MESH:D012509', (125, 133))	('tumour', 'Disease', (95, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('sarcomas', 'Disease', (125, 133))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (17, 37))	('TP53', 'Gene', (67, 71))	('Li-Fraumeni syndrome', 'Disease', (17, 37))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
401833	31221668	In mouse models of Li-Fraumeni syndrome, expression of Trp53R172H, which corresponds to the TP53R175H hotspot mutation in human tumours, in mice leads to the development of predominantly lymphomas, but a small percentage of these mice also develop angiosarcomas.	('human', 'Species', '9606', (122, 127))	('predominantly lymphomas', 'Disease', (173, 196))	('leads to', 'Reg', (145, 153))	('angiosarcomas', 'Phenotype', 'HP:0200058', (248, 261))	('sarcomas', 'Phenotype', 'HP:0100242', (253, 261))	('tumours', 'Disease', (128, 135))	('mice', 'Species', '10090', (140, 144))	('angiosarcoma', 'Phenotype', 'HP:0200058', (248, 260))	('angiosarcomas', 'Disease', (248, 261))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('lymphomas', 'Phenotype', 'HP:0002665', (187, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('R172H', 'Mutation', 'rs755944376', (60, 65))	('expression', 'Var', (41, 51))	('Li-Fraumeni syndrome', 'Disease', (19, 39))	('lymphoma', 'Phenotype', 'HP:0002665', (187, 195))	('mouse', 'Species', '10090', (3, 8))	('predominantly lymphomas', 'Disease', 'MESH:C563709', (173, 196))	('mice', 'Species', '10090', (230, 234))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (19, 39))	('Trp53R172H', 'Var', (55, 65))	('angiosarcomas', 'Disease', 'MESH:D006394', (248, 261))
401835	31221668	Experimental cohorts consisted of mice expressing either one (Pdgfrb-Cre, Trp53R172H/+) (n=16) or two (Pdgfrb-Cre, Trp53R172H/R172H) (n=28) mutant Trp53R172H alleles, or loss of both Trp53 alleles (Pdgfrb-Cre, Trp53fl/fl) (n=14).	('R172H', 'Mutation', 'rs755944376', (152, 157))	('mice', 'Species', '10090', (34, 38))	('Pdgfrb', 'Gene', '18596', (62, 68))	('Pdgfrb', 'Gene', '18596', (103, 109))	('Trp53R172H/R172H', 'Var', (115, 131))	('Trp53R172H', 'Gene', (147, 157))	('Pdgfrb', 'Gene', '18596', (198, 204))	('Pdgfrb', 'Gene', (62, 68))	('R172H', 'Mutation', 'rs755944376', (79, 84))	('Pdgfrb', 'Gene', (103, 109))	('R172H', 'Mutation', 'rs755944376', (120, 125))	('R172H', 'Mutation', 'rs755944376', (126, 131))	('Pdgfrb', 'Gene', (198, 204))
401836	31221668	The median lifespan of the Pdgfrb-Cre, Trp53R172H/R172H mice was 93 days compared to >365 days for the Pdgfrb-Cre, Trp53R172H/+ mice and 189.5 days for the Pdgfrb-Cre, Trp53fl/fl mice (Fig.	('Pdgfrb', 'Gene', (156, 162))	('Pdgfrb', 'Gene', (103, 109))	('mice', 'Species', '10090', (179, 183))	('Pdgfrb', 'Gene', '18596', (27, 33))	('Pdgfrb', 'Gene', '18596', (103, 109))	('R172H', 'Mutation', 'rs755944376', (50, 55))	('mice', 'Species', '10090', (128, 132))	('mice', 'Species', '10090', (56, 60))	('Pdgfrb', 'Gene', (27, 33))	('R172H', 'Mutation', 'rs755944376', (44, 49))	('Pdgfrb', 'Gene', '18596', (156, 162))	('Trp53R172H/R172H', 'Var', (39, 55))	('R172H', 'Mutation', 'rs755944376', (120, 125))
401837	31221668	The deaths of all Pdgfrb-Cre, Trp53R172H/R172H mice were due to tumour formation, in contrast to the Pdgfrb-Cre, Trp53R172H/+ cohort in which only 2/16 mice were culled owing to tumour formation.	('R172H', 'Mutation', 'rs755944376', (35, 40))	('R172H', 'Mutation', 'rs755944376', (41, 46))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('Pdgfrb', 'Gene', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('R172H', 'Mutation', 'rs755944376', (118, 123))	('tumour', 'Disease', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('Pdgfrb', 'Gene', '18596', (18, 24))	('Pdgfrb', 'Gene', '18596', (101, 107))	('tumour', 'Disease', (178, 184))	('mice', 'Species', '10090', (152, 156))	('Pdgfrb', 'Gene', (18, 24))	('mice', 'Species', '10090', (47, 51))	('Trp53R172H/R172H', 'Var', (30, 46))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
401838	31221668	In the Pdgfrb-Cre, Trp53fl/fl cohort, 12/14 mice were culled owing to tumour formation.	('Pdgfrb', 'Gene', '18596', (7, 13))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('Pdgfrb', 'Gene', (7, 13))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))	('mice', 'Species', '10090', (44, 48))	('Trp53fl/fl', 'Var', (19, 29))
401840	31221668	In the Pdgfrb-Cre, Trp53R172H/R172H cohort, 75% (n=21/28) of the mice developed angiosarcomas.	('angiosarcomas', 'Phenotype', 'HP:0200058', (80, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('Pdgfrb', 'Gene', '18596', (7, 13))	('mice', 'Species', '10090', (65, 69))	('developed', 'PosReg', (70, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('angiosarcoma', 'Phenotype', 'HP:0200058', (80, 92))	('Pdgfrb', 'Gene', (7, 13))	('angiosarcomas', 'Disease', (80, 93))	('R172H', 'Mutation', 'rs755944376', (30, 35))	('Trp53R172H/R172H', 'Var', (19, 35))	('R172H', 'Mutation', 'rs755944376', (24, 29))	('angiosarcomas', 'Disease', 'MESH:D006394', (80, 93))
401842	31221668	The remaining Pdgfrb-Cre, Trp53R172H/R172H mice developed either lymphomas (n=5/28) or teratomas (n=2/28) (Fig.	('mice', 'Species', '10090', (43, 47))	('lymphomas', 'Disease', 'MESH:D008223', (65, 74))	('R172H', 'Mutation', 'rs755944376', (31, 36))	('developed', 'PosReg', (48, 57))	('Pdgfrb', 'Gene', '18596', (14, 20))	('teratomas', 'Phenotype', 'HP:0009792', (87, 96))	('R172H', 'Mutation', 'rs755944376', (37, 42))	('lymphomas', 'Phenotype', 'HP:0002665', (65, 74))	('teratomas', 'Disease', (87, 96))	('teratomas', 'Disease', 'MESH:D013724', (87, 96))	('Trp53R172H/R172H', 'Var', (26, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (65, 73))	('Pdgfrb', 'Gene', (14, 20))	('lymphomas', 'Disease', (65, 74))
401846	31221668	The two Pdgfrb-Cre, Trp53R172H/+ mice culled owing to tumour formation had developed lymphomas.	('lymphomas', 'Phenotype', 'HP:0002665', (85, 94))	('R172H', 'Mutation', 'rs755944376', (25, 30))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('lymphomas', 'Disease', 'MESH:D008223', (85, 94))	('tumour', 'Disease', (54, 60))	('Pdgfrb', 'Gene', '18596', (8, 14))	('lymphoma', 'Phenotype', 'HP:0002665', (85, 93))	('mice', 'Species', '10090', (33, 37))	('lymphomas', 'Disease', (85, 94))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('Pdgfrb', 'Gene', (8, 14))	('Trp53R172H/+', 'Var', (20, 32))
401847	31221668	At autopsy, following culling of the asymptomatic Pdgfrb-Cre, Trp53R172H/+ mice at 1 year, three were found to have developed lymphomas and one was found to have adenocarcinoma in the lung.	('Pdgfrb', 'Gene', (50, 56))	('mice', 'Species', '10090', (75, 79))	('lymphomas', 'Phenotype', 'HP:0002665', (126, 135))	('adenocarcinoma in the lung', 'Disease', 'MESH:D000077192', (162, 188))	('Trp53R172H/+', 'Var', (62, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('R172H', 'Mutation', 'rs755944376', (67, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (126, 134))	('Pdgfrb', 'Gene', '18596', (50, 56))	('lymphomas', 'Disease', (126, 135))	('adenocarcinoma in the lung', 'Disease', (162, 188))	('developed', 'PosReg', (116, 125))	('lymphomas', 'Disease', 'MESH:D008223', (126, 135))
401854	31221668	2E) in keeping with the stabilization of mutant p53 that is often seen in human tumours expressing mutant p53.	('p53', 'Gene', (48, 51))	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('mutant', 'Var', (41, 47))	('tumours', 'Disease', (80, 87))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('human', 'Species', '9606', (74, 79))	('mutant', 'Var', (99, 105))	('p53', 'Gene', (106, 109))
401857	31221668	Immunohistochemistry showed no expression of p53, confirming the homozygous deletion of p53 in the Pdgfrb-Cre, Trp53fl/fl mice , and strong expression of PDGFR-beta by the tumour cells .	('deletion', 'Var', (76, 84))	('mice', 'Species', '10090', (122, 126))	('PDGFR-beta', 'Gene', '18596', (154, 164))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('PDGFR-beta', 'Gene', (154, 164))	('expression', 'MPA', (140, 150))	('Pdgfrb', 'Gene', (99, 105))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('p53', 'Gene', (88, 91))	('tumour', 'Disease', (172, 178))	('Pdgfrb', 'Gene', '18596', (99, 105))
401862	31221668	3A), a tissue in which a number of angiosarcomas arose in the Pdgfrb-Cre, Trp53R172H/R172H mice.	('mice', 'Species', '10090', (91, 95))	('angiosarcomas', 'Phenotype', 'HP:0200058', (35, 48))	('Pdgfrb', 'Gene', '18596', (62, 68))	('angiosarcoma', 'Phenotype', 'HP:0200058', (35, 47))	('Pdgfrb', 'Gene', (62, 68))	('angiosarcomas', 'Disease', (35, 48))	('Trp53R172H/R172H', 'Var', (74, 90))	('R172H', 'Mutation', 'rs755944376', (85, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('R172H', 'Mutation', 'rs755944376', (79, 84))	('angiosarcomas', 'Disease', 'MESH:D006394', (35, 48))
401867	31221668	To determine whether we could promote more efficient generation of angiosarcomas, we directly induced expression of mutant p53 or loss of p53 in adult endothelial cells using Cdh5-CreERT2 mice, in which Cre recombinase is driven by Cdh5.	('mice', 'Species', '10090', (188, 192))	('angiosarcomas', 'Disease', 'MESH:D006394', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('angiosarcomas', 'Phenotype', 'HP:0200058', (67, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('rat', 'Species', '10116', (57, 60))	('p53', 'Gene', (123, 126))	('angiosarcoma', 'Phenotype', 'HP:0200058', (67, 79))	('loss', 'NegReg', (130, 134))	('mutant', 'Var', (116, 122))	('induced', 'Reg', (94, 101))	('angiosarcomas', 'Disease', (67, 80))
401869	31221668	Experimental cohorts consisted of mice expressing either one (Cdh5-CreERT2, Trp53R172H/+) (n=15) or two (Cdh5-CreERT2, Trp53R172H/R172H) (n=8) mutant Trp53R172H alleles, or loss of one (Cdh5-CreERT2, Trp53fl/+) (n=9) or both (Cdh5-CreERT2, Trp53fl/fl) (n=13) Trp53 alleles.	('R172H', 'Mutation', 'rs755944376', (155, 160))	('mice', 'Species', '10090', (34, 38))	('R172H', 'Mutation', 'rs755944376', (124, 129))	('Trp53R172H', 'Gene', (150, 160))	('R172H', 'Mutation', 'rs755944376', (81, 86))	('R172H', 'Mutation', 'rs755944376', (130, 135))	('Trp53R172H/R172H', 'Var', (119, 135))
401872	31221668	In the Cdh5-CreERT2, Trp53R172H/+ cohort, 2/16 mice developed tumours; all other mice were asymptomatic and sacrificed at 1 year (Fig.	('Trp53R172H/+', 'Var', (21, 33))	('mice', 'Species', '10090', (81, 85))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('mice', 'Species', '10090', (47, 51))	('tumours', 'Disease', (62, 69))
401873	31221668	The median lifespan of Cdh5-CreERT2, Trp53fl/fl mice was 325 days (range 224-407) (Fig.	('Cdh5-CreERT2', 'Var', (23, 35))	('Trp53fl/fl', 'Var', (37, 47))	('mice', 'Species', '10090', (48, 52))
401875	31221668	All Cdh5-CreERT2, Trp53fl/+ and Cdh5-CreERT2 mice were asymptomatic at 12 months of age and culled with no evidence of tumour formation upon autopsy.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('mice', 'Species', '10090', (45, 49))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Disease', (119, 125))	('Cdh5-CreERT2', 'Var', (32, 44))	('Trp53fl/+', 'Var', (18, 27))	('Cdh5-CreERT2', 'Var', (4, 16))
401876	31221668	In the Cdh5-CreERT2, Trp53R172H/R172H cohort, 7/8 mice developed thymic lymphomas, with evidence of thymic hyperplasia in the remaining mouse, but none developed angiosarcomas (Fig.	('R172H', 'Mutation', 'rs755944376', (32, 37))	('angiosarcoma', 'Phenotype', 'HP:0200058', (162, 174))	('angiosarcomas', 'Disease', (162, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('thymic hyperplasia', 'Disease', (100, 118))	('thymic hyperplasia', 'Phenotype', 'HP:0010516', (100, 118))	('thymic lymphomas', 'Disease', (65, 81))	('developed', 'PosReg', (55, 64))	('mice', 'Species', '10090', (50, 54))	('angiosarcomas', 'Phenotype', 'HP:0200058', (162, 175))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))	('Trp53R172H/R172H', 'Var', (21, 37))	('angiosarcomas', 'Disease', 'MESH:D006394', (162, 175))	('lymphomas', 'Phenotype', 'HP:0002665', (72, 81))	('thymic hyperplasia', 'Disease', 'MESH:D013952', (100, 118))	('R172H', 'Mutation', 'rs755944376', (26, 31))	('mouse', 'Species', '10090', (136, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (167, 175))	('thymic lymphomas', 'Disease', 'MESH:D013953', (65, 81))
401879	31221668	In the Cdh5-CreERT2, Trp53R172H/+ mice, two developed tumours: one a thymic lymphoma and the other an angiosarcoma (Fig.	('lymphoma', 'Disease', 'MESH:D008223', (76, 84))	('Trp53R172H/+', 'Var', (21, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (76, 84))	('mice', 'Species', '10090', (34, 38))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('angiosarcoma', 'Disease', 'MESH:D006394', (102, 114))	('R172H', 'Mutation', 'rs755944376', (26, 31))	('lymphoma', 'Disease', (76, 84))	('angiosarcoma', 'Disease', (102, 114))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('angiosarcoma', 'Phenotype', 'HP:0200058', (102, 114))
401881	31221668	Thus, the predominant tumour type driven by Trp53R172H in the Cdh5-CreERT2 mice was lymphoma, in contrast to the angiosarcomas that developed in the Pdgfrb-Cre, Trp53R172H/R172H mice.	('R172H', 'Mutation', 'rs755944376', (49, 54))	('R172H', 'Mutation', 'rs755944376', (166, 171))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('angiosarcomas', 'Disease', 'MESH:D006394', (113, 126))	('angiosarcoma', 'Phenotype', 'HP:0200058', (113, 125))	('lymphoma', 'Disease', (84, 92))	('Trp53R172H', 'Var', (44, 54))	('lymphoma', 'Disease', 'MESH:D008223', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('angiosarcomas', 'Phenotype', 'HP:0200058', (113, 126))	('tumour type', 'Disease', 'MESH:D009369', (22, 33))	('mice', 'Species', '10090', (75, 79))	('R172H', 'Mutation', 'rs755944376', (172, 177))	('angiosarcomas', 'Disease', (113, 126))	('mice', 'Species', '10090', (178, 182))	('Pdgfrb', 'Gene', '18596', (149, 155))	('Pdgfrb', 'Gene', (149, 155))	('tumour type', 'Disease', (22, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
401882	31221668	Within the Cdh5-CreERT2, Trp53fl/fl cohort all mice developed angiosarcomas (13/13), many with multiple tumours that developed in a range of anatomical locations (Table 2) (Fig.	('Trp53fl/fl', 'Var', (25, 35))	('multiple tumours', 'Disease', 'MESH:D009369', (95, 111))	('developed', 'PosReg', (52, 61))	('angiosarcomas', 'Disease', (62, 75))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('angiosarcoma', 'Phenotype', 'HP:0200058', (62, 74))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('angiosarcomas', 'Disease', 'MESH:D006394', (62, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('angiosarcomas', 'Phenotype', 'HP:0200058', (62, 75))	('multiple tumours', 'Disease', (95, 111))	('mice', 'Species', '10090', (47, 51))
401883	31221668	The Cdh5-CreERT2, Trp53fl/+ mice had no detectable tumours upon sacrifice.	('mice', 'Species', '10090', (28, 32))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('tumours', 'Disease', (51, 58))	('Cdh5-CreERT2', 'Var', (4, 16))
401899	31221668	We generated cell lines from four angiosarcomas that developed in the Pdgfrb-Cre, Trp53R172H/R172H mice.	('R172H', 'Mutation', 'rs755944376', (93, 98))	('mice', 'Species', '10090', (99, 103))	('angiosarcomas', 'Disease', (34, 47))	('angiosarcoma', 'Phenotype', 'HP:0200058', (34, 46))	('Pdgfrb', 'Gene', '18596', (70, 76))	('angiosarcomas', 'Phenotype', 'HP:0200058', (34, 47))	('angiosarcomas', 'Disease', 'MESH:D006394', (34, 47))	('rat', 'Species', '10116', (7, 10))	('Pdgfrb', 'Gene', (70, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('Trp53R172H/R172H', 'Var', (82, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('R172H', 'Mutation', 'rs755944376', (87, 92))
401900	31221668	As with the spontaneous tumours, the cell lines all expressed p53 (Fig.	('tumours', 'Disease', (24, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('expressed', 'Reg', (52, 61))	('p53', 'Var', (62, 65))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))
401902	31221668	Upon re-implantation of the cell lines into the flanks of mice, two of the lines from the Pdgfrb-Cre, Trp53R172H/R172H mice developed tumours, with morphological features of undifferentiated pleomorphic sarcomas (Fig.	('R172H', 'Mutation', 'rs755944376', (107, 112))	('mice', 'Species', '10090', (119, 123))	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('tumours', 'Disease', 'MESH:D009369', (134, 141))	('Pdgfrb', 'Gene', '18596', (90, 96))	('developed', 'PosReg', (124, 133))	('tumours', 'Disease', (134, 141))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (174, 211))	('undifferentiated pleomorphic sarcomas', 'Disease', (174, 211))	('mice', 'Species', '10090', (58, 62))	('R172H', 'Mutation', 'rs755944376', (113, 118))	('Pdgfrb', 'Gene', (90, 96))	('Trp53R172H/R172H', 'Var', (102, 118))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
401909	31221668	We have generated two mouse models of angiosarcoma driven by deregulation of p53.	('rat', 'Species', '10116', (12, 15))	('angiosarcoma', 'Phenotype', 'HP:0200058', (38, 50))	('angiosarcoma', 'Disease', 'MESH:D006394', (38, 50))	('p53', 'Gene', (77, 80))	('driven by', 'Reg', (51, 60))	('mouse', 'Species', '10090', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('angiosarcoma', 'Disease', (38, 50))	('deregulation', 'Var', (61, 73))
401911	31221668	This resulted in 75% of Pdgfrb-Cre, Trp53R172H/R172H mice developing angiosarcomas, which is higher than the 62% reported when Tie2-Cre mice were crossed to Trp53 floxed mice.	('Pdgfrb', 'Gene', '18596', (24, 30))	('mice', 'Species', '10090', (136, 140))	('R172H', 'Mutation', 'rs755944376', (41, 46))	('developing', 'PosReg', (58, 68))	('angiosarcomas', 'Disease', (69, 82))	('Tie2', 'Gene', '21687', (127, 131))	('angiosarcoma', 'Phenotype', 'HP:0200058', (69, 81))	('Pdgfrb', 'Gene', (24, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('R172H', 'Mutation', 'rs755944376', (47, 52))	('Trp53R172H/R172H', 'Var', (36, 52))	('mice', 'Species', '10090', (170, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('angiosarcomas', 'Disease', 'MESH:D006394', (69, 82))	('Tie2', 'Gene', (127, 131))	('angiosarcomas', 'Phenotype', 'HP:0200058', (69, 82))	('mice', 'Species', '10090', (53, 57))
401912	31221668	Interestingly, we saw no angiosarcomas in the Pdgfrb-Cre, p53fl/fl mice suggesting that the Trp53R172H mutant is exerting a gain-of-function activity that is required for angiosarcoma development when Pdgfrb cells are targeted.	('angiosarcoma', 'Phenotype', 'HP:0200058', (171, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('Pdgfrb', 'Gene', '18596', (201, 207))	('angiosarcoma', 'Disease', 'MESH:D006394', (25, 37))	('angiosarcoma', 'Disease', (171, 183))	('gain-of-function', 'PosReg', (124, 140))	('angiosarcomas', 'Disease', 'MESH:D006394', (25, 38))	('Pdgfrb', 'Gene', (201, 207))	('angiosarcoma', 'Phenotype', 'HP:0200058', (25, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('angiosarcomas', 'Phenotype', 'HP:0200058', (25, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('mice', 'Species', '10090', (67, 71))	('angiosarcoma', 'Disease', (25, 37))	('angiosarcomas', 'Disease', (25, 38))	('Pdgfrb', 'Gene', '18596', (46, 52))	('Pdgfrb', 'Gene', (46, 52))	('R172H', 'Mutation', 'rs755944376', (97, 102))	('angiosarcoma', 'Disease', 'MESH:D006394', (171, 183))	('Trp53R172H', 'Var', (92, 102))
401913	31221668	The development of angiosarcomas in a small percentage of mice in a model of Li-Fraumeni syndrome that expresses Trp53R172H supports the specific involvement of mutant p53 in the development of angiosarcoma.	('angiosarcoma', 'Disease', 'MESH:D006394', (194, 206))	('angiosarcoma', 'Disease', 'MESH:D006394', (19, 31))	('angiosarcomas', 'Phenotype', 'HP:0200058', (19, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('angiosarcoma', 'Phenotype', 'HP:0200058', (194, 206))	('angiosarcoma', 'Phenotype', 'HP:0200058', (19, 31))	('angiosarcomas', 'Disease', (19, 32))	('p53', 'Gene', (168, 171))	('mutant', 'Var', (161, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('angiosarcoma', 'Disease', (194, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('R172H', 'Mutation', 'rs755944376', (118, 123))	('angiosarcoma', 'Disease', (19, 31))	('Li-Fraumeni syndrome', 'Disease', (77, 97))	('Trp53R172H', 'Var', (113, 123))	('mice', 'Species', '10090', (58, 62))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (77, 97))	('angiosarcomas', 'Disease', 'MESH:D006394', (19, 32))
401914	31221668	Analysis of Pdgfrb-Cre mice has shown that recombination occurs in a number of cell types during development, including endothelial and mural cells, so it is not possible to define the cell of origin in the angiosarcomas that developed in the Pdgfrb-Cre, Trp53R172H/R172H mice.	('sarcomas', 'Phenotype', 'HP:0100242', (212, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('Trp53R172H/R172H', 'Var', (255, 271))	('Pdgfrb', 'Gene', (12, 18))	('Pdgfrb', 'Gene', (243, 249))	('mice', 'Species', '10090', (272, 276))	('angiosarcomas', 'Disease', (207, 220))	('R172H', 'Mutation', 'rs755944376', (260, 265))	('R172H', 'Mutation', 'rs755944376', (266, 271))	('Pdgfrb', 'Gene', '18596', (12, 18))	('angiosarcoma', 'Phenotype', 'HP:0200058', (207, 219))	('angiosarcomas', 'Phenotype', 'HP:0200058', (207, 220))	('angiosarcomas', 'Disease', 'MESH:D006394', (207, 220))	('Pdgfrb', 'Gene', '18596', (243, 249))	('mice', 'Species', '10090', (23, 27))
401919	31221668	Interestingly, we found that loss of p53 in the Pdgfrb-Cre mice gave rise to undifferentiated sarcomas that expressed PDGFR-beta, albeit with a reduced efficiency and increased latency compared to that observed by Sato and colleagues.	('reduced', 'NegReg', (144, 151))	('mice', 'Species', '10090', (59, 63))	('Pdgfrb', 'Gene', '18596', (48, 54))	('rise to undifferentiated sarcomas', 'Disease', (69, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('rise to undifferentiated sarcomas', 'Disease', 'MESH:D002277', (69, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('increased', 'PosReg', (167, 176))	('loss', 'Var', (29, 33))	('Pdgfrb', 'Gene', (48, 54))	('p53', 'Gene', (37, 40))	('PDGFR-beta', 'Gene', (118, 128))	('PDGFR-beta', 'Gene', '18596', (118, 128))
401921	31221668	In the future, use of a conditional Pdgfrb-iCreERT2 mouse that allows specific deletion of Trp53 in the adult, in which Pdgfrb expression is restricted to pericytes, will allow further evaluation of the role of distinct mesenchymal cell lineages to the development of different sarcoma subtypes.	('Pdgfrb', 'Gene', (36, 42))	('sarcoma', 'Disease', (278, 285))	('mouse', 'Species', '10090', (52, 57))	('Pdgfrb', 'Gene', (120, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (278, 285))	('sarcoma', 'Disease', 'MESH:D012509', (278, 285))	('Trp53', 'Gene', (91, 96))	('Pdgfrb', 'Gene', '18596', (36, 42))	('deletion', 'Var', (79, 87))	('Pdgfrb', 'Gene', '18596', (120, 126))
401923	31221668	Surprisingly, all Cdh5-CreERT2, Trp53R172H/R172H mice developed lymphomas.	('lymphomas', 'Phenotype', 'HP:0002665', (64, 73))	('lymphoma', 'Phenotype', 'HP:0002665', (64, 72))	('R172H', 'Mutation', 'rs755944376', (37, 42))	('mice', 'Species', '10090', (49, 53))	('developed', 'PosReg', (54, 63))	('Cdh5-CreERT2', 'Gene', (18, 30))	('R172H', 'Mutation', 'rs755944376', (43, 48))	('Trp53R172H/R172H', 'Var', (32, 48))	('lymphomas', 'Disease', (64, 73))	('lymphomas', 'Disease', 'MESH:D008223', (64, 73))
401925	31221668	Combined with the propensity of mutant p53 to drive lymphomagenesis, this appears to be sufficient to drive development of lymphomas in the Cdh5-CreERT2, Trp53R172H/R172H mice.	('lymphoma', 'Disease', (123, 131))	('R172H', 'Mutation', 'rs755944376', (159, 164))	('lymphomas', 'Phenotype', 'HP:0002665', (123, 132))	('mice', 'Species', '10090', (171, 175))	('lymphoma', 'Disease', 'MESH:D008223', (123, 131))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('lymphoma', 'Phenotype', 'HP:0002665', (52, 60))	('lymphoma', 'Disease', (52, 60))	('mutant', 'Var', (32, 38))	('p53', 'Gene', (39, 42))	('R172H', 'Mutation', 'rs755944376', (165, 170))	('lymphoma', 'Disease', 'MESH:D008223', (52, 60))	('lymphomas', 'Disease', 'MESH:D008223', (123, 132))	('lymphomas', 'Disease', (123, 132))
401926	31221668	However, all of the Cdh5-CreERT2, Trp53fl/fl mice developed angiosarcomas, with no lymphomas detected.	('lymphomas', 'Disease', (83, 92))	('lymphomas', 'Disease', 'MESH:D008223', (83, 92))	('angiosarcomas', 'Disease', 'MESH:D006394', (60, 73))	('Cdh5-CreERT2', 'Var', (20, 32))	('mice', 'Species', '10090', (45, 49))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	('angiosarcomas', 'Phenotype', 'HP:0200058', (60, 73))	('lymphomas', 'Phenotype', 'HP:0002665', (83, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('developed', 'PosReg', (50, 59))	('angiosarcoma', 'Phenotype', 'HP:0200058', (60, 72))	('angiosarcomas', 'Disease', (60, 73))	('Trp53fl/fl', 'Var', (34, 44))
401927	31221668	The enrichment of genes associated with p53 in the differentially expressed genes between the tumours that develop in the two models indicates that, as expected, the gain-of-function Trp53R172H mutant drives expression of a different set of genes to those seen in the Cdh5-CreERT2, Trp53fl/fl mice to initiate angiosarcoma development.	('tumours', 'Disease', (94, 101))	('angiosarcoma', 'Disease', 'MESH:D006394', (310, 322))	('angiosarcoma', 'Disease', (310, 322))	('mutant', 'Var', (194, 200))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('mice', 'Species', '10090', (293, 297))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('expression', 'MPA', (208, 218))	('Trp53R172H mutant', 'Var', (183, 200))	('angiosarcoma', 'Phenotype', 'HP:0200058', (310, 322))	('sarcoma', 'Phenotype', 'HP:0100242', (315, 322))	('R172H', 'Mutation', 'rs755944376', (188, 193))	('gain-of-function', 'PosReg', (166, 182))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
401933	31221668	In this study, loss of Trp53 alone did not result in the development of angiosarcomas.	('Trp53', 'Protein', (23, 28))	('angiosarcoma', 'Phenotype', 'HP:0200058', (72, 84))	('angiosarcomas', 'Disease', (72, 85))	('loss', 'Var', (15, 19))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('angiosarcomas', 'Phenotype', 'HP:0200058', (72, 85))	('angiosarcomas', 'Disease', 'MESH:D006394', (72, 85))
401935	31221668	Taken together with the distinctive spectrum of tumours seen upon deletion of Tsc1, this suggests that targeting distinct populations of endothelial cells in mice in combination with differential pathway activation impacts on the type and site of vascular tumour development.	('tumours', 'Disease', (48, 55))	('Tsc1', 'Gene', (78, 82))	('impacts', 'Reg', (215, 222))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('mice', 'Species', '10090', (158, 162))	('Tsc1', 'Gene', '64930', (78, 82))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('vascular tumour', 'Disease', (247, 262))	('type', 'CPA', (230, 234))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('vascular tumour', 'Phenotype', 'HP:0100742', (247, 262))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('deletion', 'Var', (66, 74))	('vascular tumour', 'Disease', 'MESH:D019043', (247, 262))
401937	31221668	Interestingly, conditional triple knock-out of FOXO1/3/4 in mice results in development of thymic lymphomas and vascular lesions, predominantly haemangiomas, in a number of tissues, with only 9% progressing to angiosarcomas, although there is no reported role for Myc in this model.	('vascular lesions', 'Disease', (112, 128))	('angiosarcomas', 'Phenotype', 'HP:0200058', (210, 223))	('haemangiomas', 'Disease', 'None', (144, 156))	('FOXO1', 'Gene', (47, 52))	('vascular lesions', 'Disease', 'MESH:D000783', (112, 128))	('FOXO1', 'Gene', '56458', (47, 52))	('angiosarcoma', 'Phenotype', 'HP:0200058', (210, 222))	('angiosarcomas', 'Disease', (210, 223))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('thymic lymphomas', 'Disease', 'MESH:D013953', (91, 107))	('knock-out', 'Var', (34, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('haemangiomas', 'Disease', (144, 156))	('mice', 'Species', '10090', (60, 64))	('angiosarcomas', 'Disease', 'MESH:D006394', (210, 223))	('lymphomas', 'Phenotype', 'HP:0002665', (98, 107))	('thymic lymphomas', 'Disease', (91, 107))
401947	31221668	Knockout of p53 in alymphocytic Rag2-/-;Il2rg-/- mice leads to a high frequency of angiosarcomas (over 65%), with only sporadic formation of lymphomas.	('lymphoma', 'Phenotype', 'HP:0002665', (141, 149))	('lymphomas', 'Disease', (141, 150))	('lymphomas', 'Disease', 'MESH:D008223', (141, 150))	('angiosarcomas', 'Disease', (83, 96))	('angiosarcoma', 'Phenotype', 'HP:0200058', (83, 95))	('lymphomas', 'Phenotype', 'HP:0002665', (141, 150))	('mice', 'Species', '10090', (49, 53))	('p53', 'Gene', (12, 15))	('Rag2', 'Gene', '19374', (32, 36))	('Knockout', 'Var', (0, 8))	('angiosarcomas', 'Phenotype', 'HP:0200058', (83, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('angiosarcomas', 'Disease', 'MESH:D006394', (83, 96))	('Rag2', 'Gene', (32, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
401949	31221668	A recent report has shown that use of a lentiviral vector-based system to introduce oncogenic HrasG12V in combination with loss of Cdkn2a via intravenous injection into immune competent mice resulted in the formation of angiosarcomas.	('Cdkn2a', 'Gene', (131, 137))	('angiosarcomas', 'Disease', (220, 233))	('angiosarcoma', 'Phenotype', 'HP:0200058', (220, 232))	('HrasG12V', 'Gene', (94, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (225, 233))	('angiosarcomas', 'Disease', 'MESH:D006394', (220, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('mice', 'Species', '10090', (186, 190))	('angiosarcomas', 'Phenotype', 'HP:0200058', (220, 233))	('loss', 'Var', (123, 127))	('resulted in', 'Reg', (191, 202))	('Cdkn2a', 'Gene', '12578', (131, 137))
401951	31221668	To overcome these issues, we generated cell lines from angiosarcomas that developed in the Pdgfrb-Cre, Trp53R172H/R172H and Cdh5-CreERT2, Trp53fl/fl mice, in an attempt to generate syngeneic mouse models of angiosarcoma.	('rat', 'Species', '10116', (176, 179))	('Pdgfrb', 'Gene', (91, 97))	('rat', 'Species', '10116', (33, 36))	('mice', 'Species', '10090', (149, 153))	('mouse', 'Species', '10090', (191, 196))	('angiosarcoma', 'Disease', 'MESH:D006394', (207, 219))	('Trp53R172H/R172H', 'Var', (103, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('angiosarcoma', 'Phenotype', 'HP:0200058', (207, 219))	('angiosarcoma', 'Disease', 'MESH:D006394', (55, 67))	('angiosarcomas', 'Disease', 'MESH:D006394', (55, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('angiosarcoma', 'Disease', (207, 219))	('R172H', 'Mutation', 'rs755944376', (108, 113))	('angiosarcoma', 'Phenotype', 'HP:0200058', (55, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('angiosarcoma', 'Disease', (55, 67))	('angiosarcomas', 'Phenotype', 'HP:0200058', (55, 68))	('R172H', 'Mutation', 'rs755944376', (114, 119))	('angiosarcomas', 'Disease', (55, 68))	('Pdgfrb', 'Gene', '18596', (91, 97))
401957	31221668	Taken together, our data indicate that deleting p53 in endothelial cells in the adult mouse is the most effective way to generate angiosarcomas.	('angiosarcomas', 'Disease', (130, 143))	('rat', 'Species', '10116', (125, 128))	('p53', 'Gene', (48, 51))	('deleting', 'Var', (39, 47))	('angiosarcomas', 'Disease', 'MESH:D006394', (130, 143))	('mouse', 'Species', '10090', (86, 91))	('angiosarcomas', 'Phenotype', 'HP:0200058', (130, 143))	('angiosarcoma', 'Phenotype', 'HP:0200058', (130, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('generate', 'Reg', (121, 129))
401959	31221668	The development of lymphomas in the Cdh5-CreERT2, Trp53R172H/R172H mice supports a strong selection for angiosarcoma formation following loss of p53 in contrast to expression of the gain-of-function mutant p53.	('R172H', 'Mutation', 'rs755944376', (55, 60))	('angiosarcoma', 'Disease', (104, 116))	('p53', 'Gene', (145, 148))	('angiosarcoma', 'Phenotype', 'HP:0200058', (104, 116))	('lymphoma', 'Phenotype', 'HP:0002665', (19, 27))	('lymphomas', 'Disease', (19, 28))	('lymphomas', 'Disease', 'MESH:D008223', (19, 28))	('R172H', 'Mutation', 'rs755944376', (61, 66))	('lymphomas', 'Phenotype', 'HP:0002665', (19, 28))	('loss', 'Var', (137, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('angiosarcoma', 'Disease', 'MESH:D006394', (104, 116))	('mice', 'Species', '10090', (67, 71))
401962	31221668	Mice expressing Cre under the control of the Pdgfrb promoter (Pdgfrb-Cre) or in the inducible control of the Cdh5 promotor (Cdh5-CreERT2) were crossed to mice expressing either a mutant p53R172H or floxed p53 allele to give experimental cohorts on a mixed background, segregating for C57BL/6J and S129 genomes.	('Pdgfrb', 'Gene', '18596', (45, 51))	('Pdgfrb', 'Gene', '18596', (62, 68))	('mice', 'Species', '10090', (154, 158))	('Pdgfrb', 'Gene', (45, 51))	('Pdgfrb', 'Gene', (62, 68))	('Mice', 'Species', '10090', (0, 4))	('p53R172H', 'Var', (186, 194))	('mutant p53R172H', 'Var', (179, 194))
401963	31221668	The mutant p53 allele is preceded by a STOP cassette, flanked by loxP sites, such that upon activation of Cre recombinase the STOP cassette is excised and the mutant p53R172H is expressed, whereas in the floxed p53 mice activation of Cre deletes exons 2-10, resulting in a loss of p53.	('p53', 'MPA', (281, 284))	('R172H', 'Mutation', 'rs755944376', (169, 174))	('p53R172H', 'Var', (166, 174))	('loss', 'NegReg', (273, 277))	('mice', 'Species', '10090', (215, 219))	('deletes', 'NegReg', (238, 245))
401977	31221668	Tumours from Pdgfrb-Cre, p53R172H/R172H mice were freshly processed by rinsing in PBS and then mincing to ~1 mm3 pieces using two scalpels.	('Pdgfrb', 'Gene', '18596', (13, 19))	('p53R172H/R172H', 'Var', (25, 39))	('PBS', 'Chemical', 'MESH:D007854', (82, 85))	('Pdgfrb', 'Gene', (13, 19))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('R172H', 'Mutation', 'rs755944376', (34, 39))	('mice', 'Species', '10090', (40, 44))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('R172H', 'Mutation', 'rs755944376', (28, 33))
401980	31221668	Tumours from Cdh5-CreERT2, Trp53fl/fl mice were manually minced using scalpels and left undisturbed for 5-7 days before transferring to flasks when confluent.	('mice', 'Species', '10090', (38, 42))	('Trp53fl/fl', 'Var', (27, 37))	('Cdh5-CreERT2', 'Gene', (13, 25))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
401986	31221668	RNA prepared from angiosarcomas that developed in the Pdgfrb-Cre, p53R172H/R172H and Cdh5-CreERT2, Trp53fl/fl mice was analyzed using the NanoString PanCancer Pathways panel (represents 750 cancer associated genes) on the NanoString nCounter DX platform as per the manufacturer's instructions.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('R172H', 'Mutation', 'rs755944376', (69, 74))	('p53R172H/R172H', 'Var', (66, 80))	('Pdgfrb', 'Gene', (54, 60))	('angiosarcoma', 'Phenotype', 'HP:0200058', (18, 30))	('angiosarcomas', 'Disease', (18, 31))	('mice', 'Species', '10090', (110, 114))	('R172H', 'Mutation', 'rs755944376', (75, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('angiosarcomas', 'Disease', 'MESH:D006394', (18, 31))	('Pdgfrb', 'Gene', '18596', (54, 60))	('angiosarcomas', 'Phenotype', 'HP:0200058', (18, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))
401989	31221668	Following standard nCounter normalisation, differentially expressed genes were identified using Student's t-tests (P<0.05) between the angiosarcomas derived from the Pdgfrb-Cre, p53R172H/R172H and Cdh5-CreERT2, Trp53fl/fl mice and relative to the normal endothelial cells.	('p53R172H/R172H', 'Var', (178, 192))	('Pdgfrb', 'Gene', (166, 172))	('mice', 'Species', '10090', (222, 226))	('angiosarcomas', 'Disease', 'MESH:D006394', (135, 148))	('angiosarcomas', 'Phenotype', 'HP:0200058', (135, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('R172H', 'Mutation', 'rs755944376', (187, 192))	('angiosarcoma', 'Phenotype', 'HP:0200058', (135, 147))	('angiosarcomas', 'Disease', (135, 148))	('Pdgfrb', 'Gene', '18596', (166, 172))	('R172H', 'Mutation', 'rs755944376', (181, 186))
401996	28587364	15d-PGJ2 inhibited cell growth and increased apoptosis.	('inhibited', 'NegReg', (9, 18))	('increased', 'PosReg', (35, 44))	('15d-PGJ2', 'Var', (0, 8))	('cell growth', 'CPA', (19, 30))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (0, 8))	('apoptosis', 'CPA', (45, 54))
402010	28587364	Previous studies have shown that 15d-PGJ2 significantly inhibits cell growth and induces apoptosis in cancer cells, indicating it as a potential cancer treatment.	('cancer', 'Disease', (145, 151))	('cell growth', 'CPA', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('apoptosis', 'CPA', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('inhibits', 'NegReg', (56, 64))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (33, 41))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('15d-PGJ2', 'Var', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('induces', 'Reg', (81, 88))
402011	28587364	15d-PGJ2 induces a variety of cellular responses including activation of mitogen-activated protein kinase (MAPK), modulation of Cox-2, inhibition of vascular smooth muscle cell proliferation and upregulation of antioxidant response genes.	('antioxidant', 'Gene', (211, 222))	('inhibition', 'NegReg', (135, 145))	('15d-PGJ2', 'Var', (0, 8))	('Cox-2', 'Gene', '5743', (128, 133))	('vascular smooth muscle cell proliferation', 'CPA', (149, 190))	('Cox-2', 'Gene', (128, 133))	('modulation', 'MPA', (114, 124))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (0, 8))	('upregulation', 'PosReg', (195, 207))	('activation', 'PosReg', (59, 69))
402014	28587364	Peroxisome proliferator-activated receptors (PPAR) omicron, beta and gamma are nuclear hormone receptors that regulate a multitude of downstream metabolic processes.	('Peroxisome proliferator-activated receptors', 'Gene', (0, 43))	('Peroxisome proliferator-activated receptors', 'Gene', '5465', (0, 43))	('omicron', 'Var', (51, 58))	('PPAR', 'Gene', '5465', (45, 49))	('PPAR', 'Gene', (45, 49))	('regulate', 'Reg', (110, 118))
402029	28587364	MEK and phospho-MEK (ser217/221) antibodies were purchased from Santa Cruz Biotechnology, Inc., and SRC, phospho-SRC (tyr416), ERK, phospho-ERK (tyr204), AKT, phospho-AKT and beta-actin antibodies were purchased from Cell Signaling Technology, Inc. (Beverly, MA, USA).	('AKT', 'Gene', (167, 170))	('MEK', 'Gene', (0, 3))	('SRC', 'Gene', (113, 116))	('beta-actin', 'Gene', '728378', (175, 185))	('tyr204', 'Chemical', '-', (145, 151))	('ERK', 'Gene', (140, 143))	('tyr416', 'Chemical', '-', (118, 124))	('ERK', 'Gene', '5594', (127, 130))	('AKT', 'Gene', '207', (167, 170))	('AKT', 'Gene', (154, 157))	('SRC', 'Gene', '6714', (100, 103))	('beta-actin', 'Gene', (175, 185))	('ser217', 'Chemical', '-', (21, 27))	('SA', 'Chemical', 'MESH:C012546', (264, 266))	('ERK', 'Gene', (127, 130))	('SRC', 'Gene', (100, 103))	('MEK', 'Gene', '5609', (16, 19))	('tyr416', 'Var', (118, 124))	('SRC', 'Gene', '6714', (113, 116))	('AKT', 'Gene', '207', (154, 157))	('MEK', 'Gene', '5609', (0, 3))	('ERK', 'Gene', '5594', (140, 143))	('MEK', 'Gene', (16, 19))
402044	28587364	Together our results showed that 15d-PGJ2 significantly inhibited the growth of all three uterine sarcoma cell lines in a dose- and time-dependent manner.	('growth', 'CPA', (70, 76))	('uterine sarcoma', 'Disease', 'MESH:D012509', (90, 105))	('uterine sarcoma', 'Disease', (90, 105))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (33, 41))	('15d-PGJ2', 'Var', (33, 41))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (90, 105))	('inhibited', 'NegReg', (56, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
402048	28587364	These studies indicated that 15d-PGJ2 exerts a cytotoxic effect, inhibiting uterine sarcoma cell growth.	('15d-PGJ2', 'Chemical', 'MESH:C097240', (29, 37))	('uterine sarcoma', 'Disease', 'MESH:D012509', (76, 91))	('uterine sarcoma', 'Disease', (76, 91))	('inhibiting', 'NegReg', (65, 75))	('15d-PGJ2', 'Var', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (76, 91))
402050	28587364	Other reports demonstrated that 15-d-PGJ2 induced ERK activation.	('ERK', 'Gene', '5594', (50, 53))	('ERK', 'Gene', (50, 53))	('15-d-PGJ2', 'Var', (32, 41))	('activation', 'PosReg', (54, 64))	('15-d-PGJ2', 'Chemical', 'MESH:C477819', (32, 41))
402055	28587364	The western blot results showed that phosphorylation of AKT was decreased by 15d-PGJ2 in uterine sarcoma cells, indicating that 15d-PGJ2 represses the AKT pathway.	('AKT', 'Gene', (151, 154))	('AKT', 'Gene', '207', (56, 59))	('uterine sarcoma', 'Disease', (89, 104))	('phosphorylation', 'MPA', (37, 52))	('uterine sarcoma', 'Disease', 'MESH:D012509', (89, 104))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (89, 104))	('AKT', 'Gene', (56, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (77, 85))	('AKT', 'Gene', '207', (151, 154))	('represses', 'NegReg', (137, 146))	('15d-PGJ2', 'Var', (77, 85))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (128, 136))	('decreased', 'NegReg', (64, 73))
402062	28587364	The CI was 0.489,0.36428 and 0.36301 in the MES-SA cell, MES-SA/DX5 and SKN cell line, indicating that combined PGJ2 and dasatinib generates synergistic effect (Table I).	('synergistic effect', 'MPA', (141, 159))	('0.36301', 'Var', (29, 36))	('MES-SA', 'Chemical', '-', (57, 63))	('PGJ2', 'Chemical', 'MESH:C037112', (112, 116))	('dasatinib', 'Chemical', 'MESH:D000069439', (121, 130))	('MES-SA', 'Chemical', '-', (44, 50))
402065	28587364	PPAR-gamma is targeted by endogenous ligands such as Delta12.15 prostaglandin J2 and functions as a transcriptional factor in vivo.	('PPAR-gamma', 'Gene', '5468', (0, 10))	('prostaglandin J2', 'Chemical', 'MESH:C037112', (64, 80))	('PPAR-gamma', 'Gene', (0, 10))	('Delta12.15', 'Var', (53, 63))
402070	28587364	The present study shows that 15d-PGJ2 induced downregulation of the AKT pathway with subsequent apoptosis.	('downregulation', 'NegReg', (46, 60))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (29, 37))	('AKT', 'Gene', '207', (68, 71))	('15d-PGJ2', 'Var', (29, 37))	('AKT', 'Gene', (68, 71))
402073	28587364	Our results showed that 15d-PGJ2 inhibited phosphorylation of AKT and also promoted phosphorylation of MAPK.	('AKT', 'Gene', (62, 65))	('phosphorylation', 'MPA', (43, 58))	('inhibited', 'NegReg', (33, 42))	('15d-PGJ2', 'Var', (24, 32))	('promoted', 'PosReg', (75, 83))	('AKT', 'Gene', '207', (62, 65))	('MAPK', 'Protein', (103, 107))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (24, 32))	('phosphorylation', 'MPA', (84, 99))
402074	28587364	Because of its activation of MAPK, the anti-tumor effects of 15d-PGJ2 are limited.	('activation', 'PosReg', (15, 25))	('MAPK', 'Pathway', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('15d-PGJ2', 'Var', (61, 69))
402080	28587364	Activation of these pathways may limit the antiproliferative effects of 15d-PGJ2, and thus the addition of molecular-targeted agents with PGJ2 may help to suppress these growth pathways.	('15d-PGJ2', 'Chemical', 'MESH:C097240', (72, 80))	('PGJ2', 'Gene', (138, 142))	('PGJ2', 'Chemical', 'MESH:C037112', (76, 80))	('PGJ2', 'Chemical', 'MESH:C037112', (138, 142))	('growth pathways', 'Pathway', (170, 185))	('15d-PGJ2', 'Var', (72, 80))	('antiproliferative effects', 'CPA', (43, 68))	('limit', 'NegReg', (33, 38))	('suppress', 'NegReg', (155, 163))
402087	28587364	These results showed that inhibition of SRC has sustained effects on the MAPK cascade and AKT in uterine sarcoma.	('effects', 'Reg', (58, 65))	('SRC', 'Gene', '6714', (40, 43))	('AKT', 'Gene', (90, 93))	('inhibition', 'Var', (26, 36))	('SRC', 'Gene', (40, 43))	('uterine sarcoma', 'Disease', 'MESH:D012509', (97, 112))	('uterine sarcoma', 'Disease', (97, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (97, 112))	('AKT', 'Gene', '207', (90, 93))	('MAPK cascade', 'Pathway', (73, 85))
402089	28587364	The MAPK pathway is activated by 15d-PGJ2 treatment, and combined treatment with 15d-PGJ2 and dasatinib suppresses both the AKT and MAPK pathways, leading to synergistic antiproliferative effects.	('suppresses', 'NegReg', (104, 114))	('antiproliferative effects', 'CPA', (170, 195))	('AKT', 'Gene', '207', (124, 127))	('AKT', 'Gene', (124, 127))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (33, 41))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (81, 89))	('MAPK pathways', 'Pathway', (132, 145))	('dasatinib', 'Chemical', 'MESH:D000069439', (94, 103))	('MAPK pathway', 'Pathway', (4, 16))	('15d-PGJ2', 'Var', (81, 89))
402091	28587364	Treatment with 15d-PGJ2 combined with dasatinib produced a synergistic effect by negatively regulating both AKT and MAPK pathways.	('AKT', 'Gene', '207', (108, 111))	('MAPK pathways', 'Pathway', (116, 129))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (15, 23))	('dasatinib', 'Chemical', 'MESH:D000069439', (38, 47))	('AKT', 'Gene', (108, 111))	('15d-PGJ2', 'Var', (15, 23))	('negatively', 'NegReg', (81, 91))
402175	23224828	Recent data have demonstrated that radiation-induced angiosarcomas are characterized by a consistent amplification of the c-MYC oncogene, which is less often observed in sporadic lesions.	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('angiosarcomas', 'Disease', 'MESH:D006394', (53, 66))	('amplification', 'Var', (101, 114))	('angiosarcomas', 'Phenotype', 'HP:0200058', (53, 66))	('c-MYC', 'Gene', '4609', (122, 127))	('c-MYC', 'Gene', (122, 127))	('angiosarcoma', 'Phenotype', 'HP:0200058', (53, 65))	('angiosarcomas', 'Disease', (53, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
402182	23224828	Angiosarcoma is a multifocal disease characterized by microsatellite lesions that may comprise occult sarcoma spread beyond apparent R0 margins, as noted in other sarcoma subtypes; hence, the significance of negative surgical margins is unclear, highlighting that surgery alone may not eradicate all disease.	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('sarcoma', 'Disease', (163, 170))	('Angiosarcoma', 'Disease', (0, 12))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('microsatellite lesions', 'Var', (54, 76))	('Angiosarcoma', 'Disease', 'MESH:D006394', (0, 12))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (0, 12))	('multifocal disease', 'Disease', (18, 36))	('sarcoma', 'Disease', (5, 12))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('multifocal disease', 'Disease', 'None', (18, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
402269	31426131	Meanwhile, the presence of calcification in a lung nodule reduces the risk of lung cancer.	('lung cancer', 'Disease', (78, 89))	('reduces', 'NegReg', (58, 65))	('calcification', 'Disease', 'MESH:D002114', (27, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('calcification', 'Disease', (27, 40))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('presence', 'Var', (15, 23))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))
402297	31426131	Genetically, fluorescence in situ hybridization analysis using a SS18 break-apart probe disclosed a rearrangement of the SS18 gene (Fig.	('SS18', 'Gene', (121, 125))	('SS18', 'Gene', '6760', (65, 69))	('rearrangement', 'Var', (100, 113))	('SS18', 'Gene', '6760', (121, 125))	('SS18', 'Gene', (65, 69))
402418	31231939	Particle therapy is the superior technology used to treat the base of skull chordoma, chondrosarcoma, and other deeply located head and neck tumors, especially those within the vicinity of vulnerable tissues.27, 33 Furthermore, CIRT represents a high-LET radiation, and the value of relative biological effectiveness (RBE) of CIRT is 3 ~ 5 (which is greater than proton or photon therapy), depending on the tumor or tissue type as well as the end point of study.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('CIRT', 'Chemical', '-', (228, 232))	('neck tumors', 'Disease', 'MESH:D006258', (136, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('chordoma', 'Phenotype', 'HP:0010762', (76, 84))	('chordoma', 'Disease', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('chondrosarcoma', 'Disease', (86, 100))	('chondrosarcoma', 'Disease', 'MESH:D002813', (86, 100))	('tumor', 'Disease', (407, 412))	('tumor', 'Disease', 'MESH:D009369', (407, 412))	('CIRT', 'Chemical', '-', (326, 330))	('head and neck tumors', 'Phenotype', 'HP:0012288', (127, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('neck tumors', 'Disease', (136, 147))	('CIRT', 'Var', (228, 232))	('chordoma', 'Disease', 'MESH:D002817', (76, 84))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (86, 100))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (407, 412))
402427	31231939	In 79 patients with base of skull chondrosarcomas, treated with CIRT to 60GyE (3 GyE/fraction), the 3-year LC and OS rates of 95.9% and 96.1% were reported.	('CIRT to 60GyE', 'Var', (64, 77))	('chondrosarcomas', 'Disease', 'MESH:D002813', (34, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('CIRT', 'Chemical', '-', (64, 68))	('chondrosarcomas', 'Disease', (34, 49))	('OS', 'Chemical', '-', (114, 116))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (34, 48))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (34, 49))	('patients', 'Species', '9606', (6, 14))
402466	26937486	Previous studies found that inactivation of SMARCB1/IN1 played a crucial role in tumorigenesis of ES and immunochemistry studies revealed that 85 to 93% of cases have inactivated SMARCB1/IN1 .	('inactivated', 'NegReg', (167, 178))	('SMARCB1', 'Gene', '6598', (44, 51))	('SMARCB1', 'Gene', (44, 51))	('inactivation', 'Var', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SMARCB1', 'Gene', '6598', (179, 186))	('SMARCB1', 'Gene', (179, 186))	('tumor', 'Disease', (81, 86))
402641	24453964	Similar observations were recently reported in genome-wide analyses of polyadenylation sites in PEL cells infected with KSHV.	('KSHV', 'Gene', (120, 124))	('PEL', 'Phenotype', 'HP:0030069', (96, 99))	('KSHV', 'Species', '37296', (120, 124))	('polyadenylation', 'Var', (71, 86))
402657	24453964	Our data support the existence of canonical splice donor and acceptor sites in the new predicted junction (Figure S6A), which give rise to a novel splice variant of ORF57 in which the truncation of a second exon results in the accumulation of ribosomes on a previously uncharacterized third exon (Figure 5A,B).	('ORF57', 'Gene', '4961525', (165, 170))	('ribosomes on', 'MPA', (243, 255))	('ORF57', 'Gene', (165, 170))	('truncation', 'Var', (184, 194))	('accumulation', 'PosReg', (227, 239))	('donor', 'Species', '9606', (51, 56))
402660	24453964	Interestingly, the stop codon of ORF57A (position 83464) is located downstream of the canonical polyA cleavage site in ORF57 (position 83453), suggesting the presence of a transcript with an extended 3' end.	('polyA', 'Chemical', 'MESH:D011061', (96, 101))	('position 83464', 'Var', (41, 55))	('ORF57', 'Gene', '4961525', (119, 124))	('position 83453', 'Var', (126, 140))	('ORF57', 'Gene', (119, 124))	('ORF57', 'Gene', '4961525', (33, 38))	('ORF57', 'Gene', (33, 38))
402670	24453964	In addition to investigating the mechanisms of regulation and the activity of ADAR during lytic infection, it would be of great interest to ascertain the biological impact of the A638T substitution in RTA.	('A638T', 'Mutation', 'c.638A>T', (179, 184))	('infection', 'Disease', (96, 105))	('infection', 'Disease', 'MESH:D007239', (96, 105))	('ADAR', 'Gene', '103', (78, 82))	('A638T', 'Var', (179, 184))	('ADAR', 'Gene', (78, 82))
402673	24453964	ORF70, ORF K6, ORF54, ORF62 and Kaposin exhibit a remarkable accumulation of initiating ribosomes on multiple in-frame translation start sites, strongly arguing in favor of the presence of at least two protein variants for each one of these ORFs (Figure 5F, Tables 1 and 2, Table S6, Figure S8, File S1 and data not shown).	('ORF62', 'Var', (22, 27))	('ORF70', 'Var', (0, 5))	('initiating ribosomes', 'MPA', (77, 97))	('ORF54', 'Gene', '4961459', (15, 20))	('ORF K6', 'Var', (7, 13))	('ORF54', 'Gene', (15, 20))	('accumulation', 'PosReg', (61, 73))
402690	24453964	Both of these uORFs inhibit the expression of ORF35, as their deletion promotes accumulation of this protein.	('expression', 'MPA', (32, 42))	('promotes', 'PosReg', (71, 79))	('ORF35', 'Gene', '4961512', (46, 51))	('inhibit', 'NegReg', (20, 27))	('deletion', 'Var', (62, 70))	('accumulation', 'MPA', (80, 92))	('ORF35', 'Gene', (46, 51))
402700	24453964	Most importantly, this study provides tangible evidence derived from experimental data, as opposed to in silico prediction approaches, of the mechanisms employed by herpesviruses to widen the coding capacity of their genome through the use of diverse strategies including splicing, mRNA recoding, and alternative start codon usage.	('splicing', 'Var', (272, 280))	('widen', 'PosReg', (182, 187))	('coding capacity', 'MPA', (192, 207))	('herpesvirus', 'Species', '39059', (165, 176))	('mRNA', 'Var', (282, 286))
402753	24453964	Two previously reported and two novel splice junctions had low or no TopHat score, but were included in the annotations due to their detection in multiple samples and high HMMSplicer score (ORFK1/ORF4, ORF70, ORF46/47, and Kaposin).	('ORF46', 'Gene', '4961472', (209, 214))	('ORF46', 'Gene', (209, 214))	('ORF70', 'Var', (202, 207))
402766	24453964	The following files are included: GQ994935 sequence, KSHV2.0 location, mRNA_dox8h_minus, mRNA_dox8h_plus, mRNA_dox24h_minus, mRNA_dox24h_plus, mRNA_dox48h_minus, mRNA_dox48h_plus, mRNA_dox72h_minus, mRNA_dox72h_plus, fp_dox8h_minus, fp_dox8h_plus, fp_dox24h_minus, fp_dox24h_plus, fp_dox48h_minus, fp_dox48h_plus, fp_dox72h_minus, fp_dox72h_plus, fp_harr_dox48h_minus, fp_harr_dox48h_plus, fp_harr_dox72h_minus, fp_harr_dox72h_plus	('fp_dox72h_minus', 'Var', (314, 329))	('fp_dox72h_plus', 'Var', (331, 345))	('fp_harr_dox48h_plus', 'Var', (369, 388))	('fp_harr_dox48h_minus', 'Var', (347, 367))	('KSHV', 'Species', '37296', (53, 57))	('fp_harr_dox72h_minus', 'Var', (390, 410))
402955	32394150	Results Average percentage change on PROMs was similar for patients in both arms of the trial with no statistically significant differences between treatment and placebo groups (EQ-5D, p = 0.98; EQ-5D VAS, p = 0.88; SF-36, p = 0.94, GQL-15, p = 0.66; GAL-9, p = 0.87).	('EQ-5D', 'Var', (195, 200))	('GAL-9', 'Gene', '3965', (251, 256))	('men', 'Species', '9606', (153, 156))	('patients', 'Species', '9606', (59, 67))	('GAL-9', 'Gene', (251, 256))
403120	32394150	post-LDKT had significantly lower 1 -year DCGS (94.5% vs. 98.4%, log rank p=0.04).	('post-LDKT', 'Var', (0, 9))	('lower', 'NegReg', (28, 33))	('DCGS', 'Chemical', '-', (42, 46))	('DCGS', 'CPA', (42, 46))
403175	29138631	In addition, detailed analyses including determination of tumor margin, histologic variant, cellularity, number of mitoses, presence of tumor necrosis, grade, immunohistochemical features (including S100, p53, and MIB-1, a marker for cell proliferation), and fluorescence in situ hybridization (FISH) studies were performed for copy number alterations of 10 known tumor suppressor and oncogenes, including TOPO2A amplification on provided samples (see Table S3).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor necrosis', 'Disease', (136, 150))	('copy number alterations', 'Var', (328, 351))	('amplification', 'Var', (413, 426))	('necrosis', 'Disease', (142, 150))	('MIB-1', 'Gene', '57534', (214, 219))	('p53', 'Gene', (205, 208))	('TOPO2A', 'Gene', (406, 412))	('p53', 'Gene', '7157', (205, 208))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('necrosis', 'Disease', 'MESH:D009336', (142, 150))	('tumor necrosis', 'Disease', 'MESH:D009336', (136, 150))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('MIB-1', 'Gene', (214, 219))
403258	29468609	After obtaining Institutional Review Board approval, the NCDB Participant User File for sarcoma was queried for patients age 18 or older with trunk or extremity tumors treated between January 1, 2004 and December 31, 2013, using the International Classification of Disease for Oncology (3rd ed) topography codes C471, C472, C476, C491, C492, and C496.	('Oncology', 'Phenotype', 'HP:0002664', (277, 285))	('C471', 'Var', (312, 316))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('C496', 'Var', (346, 350))	('Participant', 'Species', '9606', (62, 73))	('C491', 'Var', (330, 334))	('C472', 'Var', (318, 322))	('patients', 'Species', '9606', (112, 120))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('C476', 'Var', (324, 328))	('extremity tumors', 'Disease', 'MESH:D009369', (151, 167))	('extremity tumors', 'Phenotype', 'HP:0009763', (151, 167))	('C492', 'Var', (336, 340))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('sarcoma', 'Disease', (88, 95))	('extremity tumors', 'Disease', (151, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
403276	29468609	On multivariate analysis amongst patients with localized disease (M0; n = 23,579), older age, race, positive margin status, lymph node positive disease (N1), and high grade were associated with poorer OS, whereas radiation therapy was protective (Table 3).	('lymph node positive disease', 'Disease', 'MESH:D000072717', (124, 151))	('localized disease', 'Disease', (47, 64))	('localized disease', 'Disease', 'MESH:D012594', (47, 64))	('patients', 'Species', '9606', (33, 41))	('lymph node positive disease', 'Disease', (124, 151))	('high grade', 'Var', (162, 172))	('positive margin status', 'Var', (100, 122))
403278	29468609	For patients with metastatic disease (n = 2,565) older age, increasing T stage, nodal disease, and high grade tumors correlated with decreased OS on multivariate analyses, although the overall impact was less than for those with localized disease.	('T stage', 'CPA', (71, 78))	('nodal disease', 'Disease', 'MESH:D013611', (80, 93))	('high grade', 'Var', (99, 109))	('nodal disease', 'Disease', (80, 93))	('localized disease', 'Disease', 'MESH:D012594', (229, 246))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (4, 12))	('metastatic disease', 'Disease', (18, 36))	('localized disease', 'Disease', (229, 246))	('decreased', 'NegReg', (133, 142))
403318	22157934	This latter 9-year old had a DICER1 germline mutation.	('germline mutation', 'Var', (36, 53))	('DICER1', 'Gene', (29, 35))	('DICER1', 'Gene', '23405', (29, 35))
403385	22157934	Additional studies were performed in this child and she was found to have a germline DICER1 mutation, c5104CST, which she had inherited from her mother.	('c5104CST', 'Var', (102, 110))	('DICER1', 'Gene', (85, 91))	('DICER1', 'Gene', '23405', (85, 91))	('child', 'Species', '9606', (42, 47))
403434	22157934	A germline mutation in DICER1 has recently been identified in a linkage analysis of four families with an inherited predisposition to pleuropulmonary blastoma.	('DICER1', 'Gene', '23405', (23, 29))	('germline mutation', 'Var', (2, 19))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (134, 158))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (134, 158))	('DICER1', 'Gene', (23, 29))	('pleuropulmonary blastoma', 'Disease', (134, 158))
403448	22157934	The cambium layer with its relationship to the overlying epithelium reflects the perturbation or disruption in the normal epithelial-stromal interaction as a consequence of a loss-of-function mutation of DICER1.	('loss-of-function', 'NegReg', (175, 191))	('DICER1', 'Gene', (204, 210))	('mutation', 'Var', (192, 200))	('disruption', 'NegReg', (97, 107))	('DICER1', 'Gene', '23405', (204, 210))
403519	26156022	In most series, favourable, small, low grade tumors tended to be treated with surgery alone, whereas unfavourable tumors with incomplete resections were more likely to receive additional radiation therapy.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('low grade', 'Var', (35, 44))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
403552	26156022	Although we could not establish any dose-effect relationship in our series due to the small number of patients, we continue to use our margin-dependent dose concept, attempting 60 Gy after resection with free margins, 66 Gy in cases with microscopic residual disease and 70-72 Gy if gross residual disease is present using the dose constraints for organs at risk established in head and neck cancer.	('head and neck cancer', 'Phenotype', 'HP:0012288', (378, 398))	('patients', 'Species', '9606', (102, 110))	('Gy', 'Chemical', 'MESH:C022013', (277, 279))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('neck cancer', 'Disease', 'MESH:D006258', (387, 398))	('Gy', 'Chemical', 'MESH:C022013', (180, 182))	('neck cancer', 'Disease', (387, 398))	('microscopic', 'Var', (238, 249))	('Gy', 'Chemical', 'MESH:C022013', (221, 223))
403559	24481001	DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years.	('DICER1', 'Gene', (0, 6))	('DICER1', 'Gene', (70, 76))	('DICER1', 'Gene', '23405', (0, 6))	('cystic nephroma of the kidney', 'Disease', (111, 140))	('DICER1', 'Gene', '23405', (70, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('cystic nephroma', 'Disease', (30, 45))	('DICER1-renal sarcoma', 'Disease', 'MESH:D007674', (70, 90))	('cystic nephroma of the kidney', 'Disease', 'MESH:D052177', (111, 140))	('renal sarcoma', 'Phenotype', 'HP:0008663', (77, 90))	('cystic nephroma', 'Disease', 'MESH:D018201', (111, 126))	('DICER1-renal sarcoma', 'Disease', (70, 90))	('cystic nephroma', 'Disease', 'MESH:D018201', (30, 45))	('mutations', 'Var', (7, 16))
403563	24481001	Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma.	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (326, 350))	('sarcoma', 'Disease', (229, 236))	('nephroblastomas', 'Disease', 'MESH:D009396', (106, 121))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (177, 201))	('nephroblastoma', 'Phenotype', 'HP:0002667', (106, 120))	('nephroblastomas', 'Disease', (106, 121))	('cystic nephroma', 'Disease', 'MESH:D018201', (51, 66))	('mutations', 'Var', (23, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('cystic nephromas', 'Disease', 'MESH:D018201', (51, 67))	('cystic nephroma', 'Disease', (248, 263))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (326, 350))	('III pleuropulmonary blastoma', 'Disease', (322, 350))	('nephroblastomas', 'Phenotype', 'HP:0002667', (106, 121))	('III pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (322, 350))	('cystic nephroma', 'Disease', 'MESH:D018201', (248, 263))	('cystic nephromas', 'Disease', (51, 67))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (177, 201))	('pleuropulmonary blastoma', 'Disease', (177, 201))	('DICER1', 'Gene', (16, 22))
403564	24481001	The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma.	('cystic nephroma', 'Disease', (116, 131))	('cystic nephroma', 'Disease', 'MESH:D018201', (116, 131))	('mutations', 'Var', (56, 65))	('DICER1', 'Gene', (49, 55))
403565	24481001	Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain.	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (29, 53))	('DICER1', 'Gene', (67, 73))	('missense mutation', 'Var', (105, 122))	('loss of function', 'NegReg', (74, 90))	('cystic nephroma and pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (9, 53))
403572	24481001	Using linkage analysis, Hill and associates detected heterozygous germline loss-of-function mutations of the miRNA processing gene DICER1 in 11 pleuropulmonary blastoma families; one of the individuals in this initial linkage study had a cystic nephroma.	('cystic nephroma', 'Disease', (238, 253))	('loss-of-function', 'NegReg', (75, 91))	('DICER1', 'Gene', (131, 137))	('mutations', 'Var', (92, 101))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (144, 168))	('cystic nephroma', 'Disease', 'MESH:D018201', (238, 253))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (144, 168))	('pleuropulmonary blastoma', 'Disease', (144, 168))
403573	24481001	Subsequent analyses demonstrate that 80/122 (65.5%) children with pleuropulmonary blastoma have heterozygous germline loss-of-function DICER1 mutations (unpublished data).	('mutations', 'Var', (142, 151))	('pleuropulmonary blastoma', 'Disease', (66, 90))	('children', 'Species', '9606', (52, 60))	('DICER1', 'Gene', (135, 141))	('loss-of-function', 'NegReg', (118, 134))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (66, 90))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (66, 90))
403575	24481001	Analysis of pleuropulmonary blastoma tumor tissue identified deleterious somatic missense mutations in the second (normal) DICER1 allele involving very specific regions or 'hotspots' in the RNase IIIb domain.	('missense mutations', 'Var', (81, 99))	('pleuropulmonary blastoma tumor', 'Disease', 'MESH:C537516', (12, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('pleuropulmonary blastoma tumor', 'Disease', (12, 42))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (12, 36))	('DICER1', 'Gene', (123, 129))
403576	24481001	These RNase IIIb mutations, or second 'hits', lead to defective cleavage of the mature miRNA from the 5p arm of the miRNA hairpin, resulting in tumor-specific loss of the major subset of miRNAs in the tumors.	('defective', 'NegReg', (54, 63))	('cleavage', 'MPA', (64, 72))	('tumor', 'Disease', (144, 149))	('major subset of miRNAs in', 'MPA', (171, 196))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('loss', 'NegReg', (159, 163))	('RNase IIIb', 'Gene', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutations', 'Var', (17, 26))
403577	24481001	These missense mutations appear to occur very early in tumorigenesis with subsequent genetic events involving p53 function and RAS pathway activation contributing to pleuropulmonary blastoma tumor progression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('contributing to', 'Reg', (150, 165))	('p53', 'Gene', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('activation', 'PosReg', (139, 149))	('pleuropulmonary blastoma tumor', 'Disease', 'MESH:C537516', (166, 196))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('p53', 'Gene', '7157', (110, 113))	('RAS pathway', 'Pathway', (127, 138))	('missense mutations', 'Var', (6, 24))	('tumor', 'Disease', (55, 60))	('pleuropulmonary blastoma tumor', 'Disease', (166, 196))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (166, 190))
403580	24481001	The present report documents our findings of DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas that were selected independently of a familial association with pleuropulmonary blastoma and also includes a clinicopathologic review of 34 individuals with cystic nephroma from the Registry.	('mutations', 'Var', (52, 61))	('cystic nephromas', 'Disease', (80, 96))	('cystic nephroma', 'Disease', 'MESH:D018201', (308, 323))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (215, 239))	('DICER1', 'Gene', (45, 51))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (215, 239))	('nephroblastomas', 'Disease', 'MESH:D009396', (135, 150))	('cystic nephromas', 'Disease', 'MESH:D018201', (80, 96))	('nephroblastoma', 'Phenotype', 'HP:0002667', (135, 149))	('pleuropulmonary blastoma', 'Disease', (215, 239))	('cystic nephroma', 'Disease', (308, 323))	('cystic nephroma', 'Disease', 'MESH:D018201', (80, 95))	('nephroblastomas', 'Disease', (135, 150))	('nephroblastomas', 'Phenotype', 'HP:0002667', (135, 150))
403590	24481001	SIFT was used to assess the potential significance of predicted novel amino-acid substitutions outside of the hotspot regions http://sift-dna.org.	('SIFT', 'Disease', 'None', (0, 4))	('SIFT', 'Disease', (0, 4))	('amino-acid substitutions', 'Var', (70, 94))
403601	24481001	Allelic loss of function DICER1 mutations were seen in 14/20 (70%) cystic nephromas and 0/6 (0%) cystic partially differentiated nephroblastomas, respectively.	('nephroblastomas', 'Disease', (129, 144))	('nephroblastomas', 'Phenotype', 'HP:0002667', (129, 144))	('cystic nephromas', 'Disease', (67, 83))	('DICER1', 'Gene', (25, 31))	('nephroblastoma', 'Phenotype', 'HP:0002667', (129, 143))	('cystic nephromas', 'Disease', 'MESH:D018201', (67, 83))	('nephroblastomas', 'Disease', 'MESH:D009396', (129, 144))	('mutations', 'Var', (32, 41))	('loss of function', 'NegReg', (8, 24))
403602	24481001	The loss of function mutations included nine insertion-deletions with frameshifts, four nonsense mutations and one c.2437-1G>A substitution involving the canonical splice site of intron 18-exon19.	('loss of function', 'NegReg', (4, 20))	('frameshifts', 'Var', (70, 81))	('c.2437-1G>A', 'Mutation', 'c.2437-1G>A', (115, 126))	('insertion-deletions', 'Var', (45, 64))	('c.2437-1G>A', 'Var', (115, 126))	('mutations', 'Var', (21, 30))
403603	24481001	Each of these mutations result in premature truncation of the DICER1 protein (deleterious truncating mutations) An additional loss of function variant in one of the cystic nephromas was three bases proximal to the intron 25-exon 26 junction c.5527+3A>G (intron 25) (Table 1).	('c.5527+3A>G', 'Mutation', 'c.5527+3A>G', (241, 252))	('truncation', 'MPA', (44, 54))	('loss of function', 'NegReg', (126, 142))	('c.5527+3A>G', 'Var', (241, 252))	('protein', 'Protein', (69, 76))	('cystic nephromas', 'Disease', (165, 181))	('cystic nephromas', 'Disease', 'MESH:D018201', (165, 181))	('mutations', 'Var', (14, 23))	('DICER1', 'Gene', (62, 68))
403604	24481001	(However, the majority (80%) of loss of function mutations are germline in the pleuropulmonary blastoma).	('mutations', 'Var', (49, 58))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (79, 103))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (79, 103))	('loss of function', 'NegReg', (32, 48))	('pleuropulmonary blastoma', 'Disease', (79, 103))
403605	24481001	Deleterious missense DICER1 mutations affecting one of the six amino-acid hotspots were seen in 18/20 (90%) cystic nephromas and 0/6 cystic partially differentiated nephroblastomas, respectively (Fisher exact test two-tailed P=0.0001).	('DICER1', 'Gene', (21, 27))	('cystic nephromas', 'Disease', 'MESH:D018201', (108, 124))	('nephroblastomas', 'Disease', (165, 180))	('nephroblastomas', 'Phenotype', 'HP:0002667', (165, 180))	('nephroblastomas', 'Disease', 'MESH:D009396', (165, 180))	('missense', 'Var', (12, 20))	('nephroblastoma', 'Phenotype', 'HP:0002667', (165, 179))	('cystic nephromas', 'Disease', (108, 124))	('mutations', 'Var', (28, 37))
403606	24481001	One truncating mutation had a low frequency of 15%, which may indicate either loss of this allele in the tumor was the second event (this tumor also had 38% allele frequency hotspot) or the truncating mutation in this allele was accompanied by duplication of the hotspot missense mutant allele (see below).	('truncating mutation', 'Var', (190, 209))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
403607	24481001	The allele frequencies for hotspot missense mutations were widely variable ranging from 1 to 53% (median 23%), which likely reflects the variability in mesenchymal content of each sampled tissue, as it would be unexpected in a cystic nephroma sample to have 100% tumor cellularity given the commonplace presence of inflammatory cells, fibroblasts and normal renal parenchyma.	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('renal parenchyma', 'Disease', 'MESH:D007674', (358, 374))	('cystic nephroma', 'Disease', 'MESH:D018201', (227, 242))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (263, 268))	('missense mutations', 'Var', (35, 53))	('cystic nephroma', 'Disease', (227, 242))	('renal parenchyma', 'Disease', (358, 374))
403608	24481001	Thus, in the one case of cystic nephroma with 53% hotspot allele frequency, it is likely that there has been gain of the hotspot missense allele, which has been described in pleuropulmonary blastoma.	('gain', 'PosReg', (109, 113))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (174, 198))	('cystic nephroma', 'Disease', 'MESH:D018201', (25, 40))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (174, 198))	('pleuropulmonary blastoma', 'Disease', (174, 198))	('cystic nephroma', 'Disease', (25, 40))	('missense', 'Var', (129, 137))
403611	24481001	In this group, 18 patients had DICER1 testing performed and 13/18 (72%) had a loss of function (truncating) germline mutation.	('germline mutation', 'Var', (108, 125))	('patients', 'Species', '9606', (18, 26))	('loss of function', 'NegReg', (78, 94))
403620	24481001	Of note, the mother with Wilms tumor in childhood did not have a DICER1 mutation, whereas her child with pleuropulmonary blastoma inherited her germline truncating DICER1 mutation from the paternal side.	('pleuropulmonary blastoma inherited', 'Disease', 'MESH:C537516', (105, 139))	('child', 'Species', '9606', (94, 99))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (105, 129))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('DICER1', 'Gene', (65, 71))	('mutation', 'Var', (171, 179))	('child', 'Species', '9606', (40, 45))	('Wilms tumor', 'Disease', 'MESH:D009396', (25, 36))	('Wilms tumor', 'Phenotype', 'HP:0002667', (25, 36))	('mutation', 'Var', (72, 80))	('Wilms tumor', 'Disease', (25, 36))	('DICER1', 'Gene', (164, 170))	('pleuropulmonary blastoma inherited', 'Disease', (105, 139))
403623	24481001	Next generation sequencing on formalin-fixed, paraffin-embedded tissue from the pleuropulmonary blastoma in this child identified a germline loss of function DICER1 mutation (c.1732dupA; p.Thr578Asnfs*6) and a somatic missense mutation (p.E1813D).	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (80, 104))	('c.1732dupA', 'Mutation', 'rs1131691193', (175, 185))	('p.Thr578Asnfs*6', 'FRAMESHIFT', 'None', (187, 202))	('p.E1813D', 'Mutation', 'p.E1813D', (237, 245))	('pleuropulmonary blastoma', 'Disease', (80, 104))	('paraffin', 'Chemical', 'MESH:D010232', (46, 54))	('DICER1', 'Gene', (158, 164))	('formalin', 'Chemical', 'MESH:D005557', (30, 38))	('child', 'Species', '9606', (113, 118))	('p.Thr578Asnfs*6', 'Var', (187, 202))	('loss of function', 'NegReg', (141, 157))	('p.E1813D', 'Var', (237, 245))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (80, 104))
403624	24481001	Similar analysis of tissue from the Wilms tumor detected the loss of function DICER1 mutation c.1732dupA but did not identify a missense mutation in a common hotspot region.	('Wilms tumor', 'Disease', 'MESH:D009396', (36, 47))	('Wilms tumor', 'Phenotype', 'HP:0002667', (36, 47))	('loss of function', 'NegReg', (61, 77))	('Wilms tumor', 'Disease', (36, 47))	('c.1732dupA', 'Var', (94, 104))	('DICER1', 'Gene', (78, 84))	('c.1732dupA', 'Mutation', 'rs1131691193', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
403633	24481001	Mutation analysis was performed on frozen tumor tissue and showed DICER1 nonsense mutation in exon 14 (c.2233C>T; p. Arg745*) and a missense hotspot mutation (c.5437G>A; p.Glu1813Lys).	('c.2233C>T', 'Mutation', 'rs1060503584', (103, 112))	('tumor', 'Disease', (42, 47))	('p.Glu1813Lys', 'Mutation', 'p.E1813K', (170, 182))	('DICER1', 'Gene', (66, 72))	('c.5437G>A; p.Glu1813Lys', 'Var', (159, 182))	('p. Arg745*', 'Mutation', 'rs1060503584', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('c.5437G>A', 'Mutation', 'c.5437G>A', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('c.2233C>T; p. Arg745*', 'Var', (103, 124))
403634	24481001	There was also a TP53 mutation in exon 7 (c.731G>A; p.G244D) affecting the transactivational domain and predicted to be deleterious by SIFT.	('c.731G>A', 'Mutation', 'rs371409680', (42, 50))	('affecting', 'Reg', (61, 70))	('p.G244D', 'Mutation', 'rs985033810', (52, 59))	('SIFT', 'Disease', (135, 139))	('c.731G>A; p.G244D', 'Var', (42, 59))	('transactivational domain', 'MPA', (75, 99))	('TP53', 'Gene', '7157', (17, 21))	('SIFT', 'Disease', 'None', (135, 139))	('p.G244D', 'Var', (52, 59))	('TP53', 'Gene', (17, 21))
403635	24481001	The TP53 variant allele frequency was 97% suggesting loss of the wild-type allele.	('variant', 'Var', (9, 16))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
403636	24481001	Cytogenetics showed a complex karyotype with multiple numerical and structural abnormalities including allelic loss of chromosome 17.	('allelic loss of', 'Var', (103, 118))	('structural abnormalities', 'Disease', (68, 92))	('structural abnormalities', 'Disease', 'MESH:C566527', (68, 92))
403642	24481001	DICER1 sequencing on both germline DNA and formalin-fixed, paraffin-embedded tissue did not identify either a deleterious loss of function mutation or a hotspot somatic missense mutation.	('formalin', 'Chemical', 'MESH:D005557', (43, 51))	('loss of function', 'NegReg', (122, 138))	('mutation', 'Var', (139, 147))	('paraffin', 'Chemical', 'MESH:D010232', (59, 67))
403645	24481001	DICER1 testing on formalin-fixed, paraffin-embedded tumor tissue identified a c.5427G>A; G1809R somatic missense mutation.	('c.5427G>A', 'Mutation', 'c.5427G>A', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('paraffin', 'Chemical', 'MESH:D010232', (34, 42))	('tumor', 'Disease', (52, 57))	('c.5427G>A; G1809R', 'Var', (78, 95))	('formalin', 'Chemical', 'MESH:D005557', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('G1809R', 'Mutation', 'p.G1809R', (89, 95))
403655	24481001	Mouse models with conditional biallelic DICER1 ablation in distal lung epithelium and ureteric bud epithelium have recapitulated the human phenotype of cystic (type I) pleuropulmonary blastoma and cystic nephroma, respectively.	('cystic (type I) pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (152, 192))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (168, 192))	('cystic nephroma', 'Disease', (197, 212))	('human', 'Species', '9606', (133, 138))	('ablation', 'Var', (47, 55))	('Mouse', 'Species', '10090', (0, 5))	('DICER1', 'Gene', (40, 46))	('cystic nephroma', 'Disease', 'MESH:D018201', (197, 212))
403660	24481001	It was our premise that a DICER1 cystic nephroma may have a sarcomatous counterpart like pleuropulmonary blastoma.	('sarcomatous', 'Disease', 'MESH:D018316', (60, 71))	('DICER1', 'Var', (26, 32))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (89, 113))	('cystic nephroma', 'Disease', (33, 48))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (89, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('sarcomatous', 'Disease', (60, 71))	('pleuropulmonary blastoma', 'Disease', (89, 113))	('cystic nephroma', 'Disease', 'MESH:D018201', (33, 48))
403672	24481001	Recently, a potential relationship between DICER1 mutations and Wilms tumor has been suggested.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations', 'Var', (50, 59))	('Wilms tumor', 'Disease', 'MESH:D009396', (64, 75))	('Wilms tumor', 'Phenotype', 'HP:0002667', (64, 75))	('Wilms tumor', 'Disease', (64, 75))	('DICER1', 'Gene', (43, 49))
403674	24481001	However, unlike pleuropulmonary blastoma, familial Wilms tumor is quite uncommon (only 1-2% of all cases) and has been linked to mutations/deletions in WT1 (11p13), FWT1 (17q12) and FWT2 (19q13) but not 14q 32.13 where DICER1 is located.	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (16, 40))	('FWT2', 'Gene', (182, 186))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (16, 40))	('familial Wilms tumor', 'Disease', (42, 62))	('FWT1', 'Gene', (165, 169))	('pleuropulmonary blastoma', 'Disease', (16, 40))	('mutations/deletions', 'Var', (129, 148))	('WT1', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('familial Wilms tumor', 'Disease', 'MESH:D009396', (42, 62))	('WT1', 'Gene', '7490', (152, 155))	('WT1', 'Gene', '7490', (166, 169))	('Wilms tumor', 'Phenotype', 'HP:0002667', (51, 62))	('WT1', 'Gene', (152, 155))	('linked', 'Reg', (119, 125))	('FWT1', 'Gene', '8151', (165, 169))
403675	24481001	Three studies to date have reported results on DICER1 testing in individuals with Wilms tumor; one of these found no DICER1 mutations in the germline DNA from 50 patients.	('patients', 'Species', '9606', (162, 170))	('DICER1', 'Gene', (117, 123))	('mutations', 'Var', (124, 133))	('Wilms tumor', 'Disease', 'MESH:D009396', (82, 93))	('Wilms tumor', 'Phenotype', 'HP:0002667', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Wilms tumor', 'Disease', (82, 93))
403676	24481001	The second study identified a truncating mutation in DICER1 in germline DNA from 1 (0.4%) of 243 patients with Wilms tumor.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Wilms tumor', 'Disease', (111, 122))	('Wilms tumor', 'Disease', 'MESH:D009396', (111, 122))	('truncating mutation', 'Var', (30, 49))	('DICER1', 'Gene', (53, 59))	('Wilms tumor', 'Phenotype', 'HP:0002667', (111, 122))	('patients', 'Species', '9606', (97, 105))
403678	24481001	Wu and colleagues performed whole gene DICER1 sequencing on tumor tissue from 120 sporadic Wilms tumor and targeted sequencing of the RNase IIIa and IIIb domains on 71 formalin-fixed, paraffin-embedded Wilms tumors; five missense or deleterious mutations in four Wilms tumors (2.6%) were identified.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('Wilms tumor', 'Phenotype', 'HP:0002667', (91, 102))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('Wilms tumor', 'Phenotype', 'HP:0002667', (202, 213))	('tumor', 'Disease', (60, 65))	('Wilms tumors', 'Disease', 'MESH:D009396', (263, 275))	('Wilms tumors', 'Phenotype', 'HP:0002667', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('Wilms tumor', 'Disease', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Wilms tumor', 'Disease', 'MESH:D009396', (263, 274))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (208, 213))	('formalin', 'Chemical', 'MESH:D005557', (168, 176))	('Wilms tumors', 'Disease', (202, 214))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Wilms tumor', 'Phenotype', 'HP:0002667', (263, 274))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('Wilms tumors', 'Phenotype', 'HP:0002667', (263, 275))	('paraffin', 'Chemical', 'MESH:D010232', (184, 192))	('missense', 'Var', (221, 229))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('Wilms tumor', 'Disease', 'MESH:D009396', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Wilms tumors', 'Disease', 'MESH:D009396', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (269, 274))	('Wilms tumors', 'Disease', (263, 275))	('Wilms tumor', 'Disease', 'MESH:D009396', (202, 213))
403679	24481001	Upon closer review, only one of these four Wilms tumor had detectable biallelic DICER1 variants; this case (case N) had two somatic mutations in trans involving the RNase IIIb domain (c.5438A>G and c.5452G>A); c.5438 A>G affects a common hotspot amino acid E1813G seen in pleuropulmonary blastoma and cystic nephroma.	('c.5438 A>G', 'Mutation', 'c.5438A>G', (210, 220))	('c.5438 A>G', 'Var', (210, 220))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('DICER1', 'Gene', (80, 86))	('c.5452G>A', 'Mutation', 'c.5452G>A', (198, 207))	('cystic nephroma', 'Disease', (301, 316))	('Wilms tumor', 'Disease', (43, 54))	('Wilms tumor', 'Disease', 'MESH:D009396', (43, 54))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (272, 296))	('Wilms tumor', 'Phenotype', 'HP:0002667', (43, 54))	('E1813G', 'Mutation', 'p.E1813G', (257, 263))	('c.5438A>G', 'Var', (184, 193))	('c.5438A>G', 'Mutation', 'c.5438A>G', (184, 193))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (272, 296))	('E1813G', 'Var', (257, 263))	('cystic nephroma', 'Disease', 'MESH:D018201', (301, 316))	('pleuropulmonary blastoma', 'Disease', (272, 296))	('affects', 'Reg', (221, 228))
403681	24481001	The other three cases described contained a benign change p.I110V (case X), a single 5330T>A; p.L1777H involving RNase IIIb domain (case M), and a germline missense single-nucleotide polymorphism c.2614G>A;p.A872T (rs149242330; MAF 0.009) in a patient with biallelic WT gene deletion/mutation and WAGR syndrome (case C).	('rs149242330;', 'Var', (215, 227))	('p.A872T', 'Mutation', 'rs149242330', (206, 213))	('WAGR syndrome', 'Disease', 'MESH:D017624', (297, 310))	('WAGR syndrome', 'Disease', (297, 310))	('c.2614G>A', 'Mutation', 'rs149242330', (196, 205))	('p.I110V', 'Var', (58, 65))	('rs149242330', 'Mutation', 'rs149242330', (215, 226))	('patient', 'Species', '9606', (244, 251))	('5330T>A', 'Mutation', 'g.5330T>A', (85, 92))	('p.L1777H', 'Mutation', 'p.L1777H', (94, 102))	('MAF', 'Gene', '4094', (228, 231))	('c.2614G>A', 'Var', (196, 205))	('MAF', 'Gene', (228, 231))	('p.I110V', 'Mutation', 'p.I110V', (58, 65))
403682	24481001	It would be difficult to ascertain if the heterozygous DICER1 mutation was additive to the WT1 gene abnormalities in the development of this Wilms tumor in this child.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('DICER1', 'Gene', (55, 61))	('Wilms tumor', 'Disease', 'MESH:D009396', (141, 152))	('child', 'Species', '9606', (161, 166))	('WT1 gene abnormalities', 'Disease', 'MESH:D009396', (91, 113))	('mutation', 'Var', (62, 70))	('Wilms tumor', 'Phenotype', 'HP:0002667', (141, 152))	('Wilms tumor', 'Disease', (141, 152))	('WT1 gene abnormalities', 'Disease', (91, 113))
403684	24481001	One family member with a Wilms tumor did not have a DICER1 mutation, whereas her child with pleuropulmonary blastoma inherited the germline DICER1 mutation from the paternal side.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (92, 116))	('mutation', 'Var', (147, 155))	('Wilms tumor', 'Disease', 'MESH:D009396', (25, 36))	('child', 'Species', '9606', (81, 86))	('Wilms tumor', 'Phenotype', 'HP:0002667', (25, 36))	('Wilms tumor', 'Disease', (25, 36))	('DICER1', 'Gene', (140, 146))	('pleuropulmonary blastoma inherited', 'Disease', (92, 126))	('pleuropulmonary blastoma inherited', 'Disease', 'MESH:C537516', (92, 126))
403685	24481001	This case highlights the need for caution in presuming that all examples of a particular neoplasm within a pleuropulmonary blastoma family are necessarily attributable to DICER1 mutations.	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (107, 131))	('pleuropulmonary blastoma', 'Disease', (107, 131))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('particular neoplasm', 'Disease', (78, 97))	('attributable', 'Reg', (155, 167))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (107, 131))	('DICER1', 'Gene', (171, 177))	('mutations', 'Var', (178, 187))	('particular neoplasm', 'Disease', 'MESH:D009369', (78, 97))
403687	24481001	Sequencing of this tumor identified the germline loss of function mutation, but hotspot missense mutations were not identified despite adequate coverage of those regions.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('loss of function', 'NegReg', (49, 65))	('mutation', 'Var', (66, 74))	('tumor', 'Disease', (19, 24))
403691	24481001	It is notable that only two in five Wilms tumors with loss of function DICER1 mutations also had somatic RNase IIIb mutations.	('Wilms tumor', 'Phenotype', 'HP:0002667', (36, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('Wilms tumors', 'Phenotype', 'HP:0002667', (36, 48))	('mutations', 'Var', (78, 87))	('Wilms tumors', 'Disease', (36, 48))	('mutations', 'Var', (116, 125))	('DICER1', 'Gene', (71, 77))	('Wilms tumors', 'Disease', 'MESH:D009396', (36, 48))	('loss of function', 'NegReg', (54, 70))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('RNase IIIb', 'Protein', (105, 115))
403692	24481001	Additional studies in this area are necessary to obtain a full understanding of the role of DICER1 mutations in the development of Wilms tumor.	('Wilms tumor', 'Disease', 'MESH:D009396', (131, 142))	('Wilms tumor', 'Disease', (131, 142))	('Wilms tumor', 'Phenotype', 'HP:0002667', (131, 142))	('mutations', 'Var', (99, 108))	('DICER1', 'Gene', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
403694	24481001	The genetic analyses presented here confirm that DICER1 mutations have a major genetic role in the pathogenesis of cystic nephroma in children.	('mutations', 'Var', (56, 65))	('DICER1', 'Gene', (49, 55))	('cystic nephroma', 'Disease', (115, 130))	('cystic nephroma', 'Disease', 'MESH:D018201', (115, 130))	('children', 'Species', '9606', (134, 142))
403695	24481001	Further, cystic nephroma and pleuropulmonary blastoma have a similar DICER1 truncating and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain.	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (29, 53))	('DICER1', 'Gene', (69, 75))	('missense mutation', 'Var', (101, 118))	('cystic nephroma and pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (9, 53))	("'hotspot'", 'PosReg', (91, 100))	('truncating', 'MPA', (76, 86))
403702	24481001	The presence of cystic neprhoma or renal sarcoma in a child or young adult should alert the clinician to the possibility of a germline mutation in DICER1 and the associated risk for pleuropulmonary blastoma and other associated conditions in the proband and/or family members.	('DICER1', 'Gene', (147, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('child', 'Species', '9606', (54, 59))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (182, 206))	('renal sarcoma', 'Phenotype', 'HP:0008663', (35, 48))	('germline mutation', 'Var', (126, 143))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (182, 206))	('cystic neprhoma or renal sarcoma', 'Disease', 'MESH:D052177', (16, 48))	('cystic neprhoma or renal sarcoma', 'Disease', (16, 48))	('pleuropulmonary blastoma', 'Disease', (182, 206))
403704	24481001	Similarly, children diagnosed with pleuropulmonary blastoma or DICER1 mutation should have serial periodic ultrasound evaluations of the kidneys as cystic nephroma may grow rapidly and early intervention may limit the damage to normal renal parenchyma.	('children', 'Species', '9606', (11, 19))	('cystic nephroma', 'Disease', 'MESH:D018201', (148, 163))	('renal parenchyma', 'Disease', (235, 251))	('DICER1', 'Gene', (63, 69))	('cystic nephroma', 'Disease', (148, 163))	('renal parenchyma', 'Disease', 'MESH:D007674', (235, 251))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (35, 59))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (35, 59))	('mutation', 'Var', (70, 78))	('limit', 'NegReg', (208, 213))	('pleuropulmonary blastoma', 'Disease', (35, 59))
403713	31173362	The median duration of treatment exposure was higher in the trabectedin arm compared with the dacarbazine arm (4 vs 2 cycles), as was the proportion of patients receiving an extended number of therapy courses (>=6 cycles: 42% vs 22%).	('dacarbazine', 'Chemical', 'MESH:D003606', (94, 105))	('trabectedin', 'Var', (60, 71))	('patients', 'Species', '9606', (152, 160))	('higher', 'PosReg', (46, 52))
403744	31173362	Demographics with mild imbalances (>=5% frequency difference in trabectedin vs dacarbazine) were age >=65 years (24% vs 19%), body mass index >=30 (41% vs 36%), and female sex (68% vs 73%), which reflected the increased proportion of patients with uterine LMS histology (51% vs 62%) randomized to dacarbazine.	('imbalances', 'Phenotype', 'HP:0002172', (23, 33))	('>=30', 'Var', (142, 146))	('dacarbazine', 'Chemical', 'MESH:D003606', (297, 308))	('LMS', 'Disease', (256, 259))	('patients', 'Species', '9606', (234, 242))	('LMS', 'Phenotype', 'HP:0100243', (256, 259))	('dacarbazine', 'Chemical', 'MESH:D003606', (79, 90))	('LMS', 'Disease', 'MESH:D007890', (256, 259))
403761	31173362	Although post-study anticancer therapies were used at similar rates in both treatment arms, improved disease control observed in patients treated with trabectedin resulted in a correspondingly prolonged time to starting any post-study anticancer therapy in the trabectedin arm compared with the dacarbazine arm (median 6.8 vs 3.5 months; HR, 0.53; 95% CI, 0.43, 0.65; P < .001) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('trabectedin', 'Var', (151, 162))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('disease', 'Disease', (101, 108))	('dacarbazine', 'Chemical', 'MESH:D003606', (295, 306))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', (239, 245))	('prolonged', 'PosReg', (193, 202))	('improved', 'PosReg', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
403778	31173362	The reported PFS results of the randomized phase 3 ET743-SAR-3007 trial directly demonstrated the superior disease control of trabectedin over dacarbazine, confirming the results of the phase 2 STS-201 study15 and historical comparisons that led to its initial approval in most countries outside the United States.19 The corresponding safety profiles of trabectedin and dacarbazine, observed in ET743-SAR-3007, were consistent with the safety profiles of both agents, with serious adverse events of grade 3-4 severity in the trabectedin arm characterized by transient elevations in hepatic transaminases and hematological toxicities.	('ET743-SAR-3007', 'Var', (395, 409))	('hematological toxicities', 'Disease', (608, 632))	('hematological toxicities', 'Disease', 'MESH:D006402', (608, 632))	('STS', 'Phenotype', 'HP:0030448', (194, 197))	('dacarbazine', 'Chemical', 'MESH:D003606', (370, 381))	('dacarbazine', 'Chemical', 'MESH:D003606', (143, 154))	('STS', 'Disease', (194, 197))	('STS', 'Disease', 'MESH:D012509', (194, 197))	('elevations', 'PosReg', (568, 578))	('hepatic transaminases', 'MPA', (582, 603))
403809	30918253	Diagnosis of fusion genes using targeted RNA sequencing Fusion genes are a major cause of cancer.	('cause', 'Reg', (81, 86))	('fusion genes', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Fusion genes', 'Var', (56, 68))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
403811	30918253	Next, we analyse a clinical patient cohort and improve the overall fusion gene diagnostic rate from 63% with conventional approaches to 76% with targeted RNAseq while demonstrating high concordance for patient samples with previous diagnoses.	('improve', 'PosReg', (47, 54))	('patient', 'Species', '9606', (202, 209))	('clinical', 'Species', '191496', (19, 27))	('fusion gene diagnostic', 'Var', (67, 89))	('patient', 'Species', '9606', (28, 35))
403815	30918253	Fusion genes play a causal role in tumorigenesis, accounting for ~20% of human cancer morbidity.	('Fusion genes', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('human', 'Species', '9606', (73, 78))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumorigenesis', 'CPA', (35, 48))
403817	30918253	Accordingly, the rapid and accurate identification of fusion genes can characterise and stratify cancer diagnoses.	('fusion', 'Var', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
403819	30918253	Fusion gene diagnosis can also predict prognosis, patient survival and treatment response.	('predict', 'Reg', (31, 38))	('prognosis', 'CPA', (39, 48))	('Fusion gene', 'Var', (0, 11))	('patient survival', 'CPA', (50, 66))	('patient', 'Species', '9606', (50, 57))
403820	30918253	As a result, false-negative results attributed to non-tested or novel fusion genes and isoforms are a leading cause of misdiagnosis of haematological cancers.	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('haematological cancers', 'Disease', (135, 157))	('fusion genes', 'Var', (70, 82))	('haematological cancers', 'Disease', 'MESH:D009369', (135, 157))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
403821	30918253	However, due to the sheer size of the transcriptome, RNAseq suffers from poor sensitivity for detecting fusion genes that are lowly expressed or diluted by accompanying non-cancerous cells within a sample.	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('fusion', 'Var', (104, 110))	('cancerous', 'Disease', (173, 182))	('cancerous', 'Disease', 'MESH:D009369', (173, 182))
403824	30918253	We show that in a cohort of clinical patient samples, targeted RNAseq increases the diagnostic rate from 63 to 76% compared to FISH and RT-PCR methods.	('clinical', 'Species', '191496', (28, 36))	('patient', 'Species', '9606', (37, 44))	('diagnostic', 'MPA', (84, 94))	('increases', 'PosReg', (70, 79))	('targeted RNAseq', 'Var', (54, 69))	('RNAseq', 'Var', (63, 69))
403839	30918253	In both cases, targeted RNAseq not only confirmed the previously identified ROS1 and ALK rearrangements, but also ascertained both the fusion gene partners (EZR and EML4, respectively) and the precise fusion junction locations (Fig.	('EZR', 'Gene', '7430', (157, 160))	('ALK', 'Gene', (85, 88))	('EML4', 'Gene', (165, 169))	('EML4', 'Gene', '27436', (165, 169))	('ROS1', 'Gene', (76, 80))	('ALK', 'Gene', '238', (85, 88))	('EZR', 'Gene', (157, 160))	('ROS1', 'Gene', '6098', (76, 80))	('rearrangements', 'Var', (89, 103))
403843	30918253	Across the total cohort of 72 clinical patient samples, targeted RNAseq detected fusion genes in 55 samples (76%), a subset of which were validated by Sanger sequencing (Fig.	('fusion genes', 'Var', (81, 93))	('detected', 'Reg', (72, 80))	('clinical', 'Species', '191496', (30, 38))	('patient', 'Species', '9606', (39, 46))
403848	30918253	Of the 20 prostate cancer samples within the cohort, we confirmed all 10 (100%) samples previously diagnosed by RT-PCR and found fusion genes in an additional four samples (Fig.	('prostate cancer', 'Disease', 'MESH:D011471', (10, 25))	('prostate cancer', 'Phenotype', 'HP:0012125', (10, 25))	('prostate cancer', 'Disease', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('fusion genes', 'Var', (129, 141))
403850	30918253	In addition, we identified a novel fusion gene in one sarcoma sample lacking a previous molecular diagnosis (Fig.	('sarcoma', 'Disease', (54, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('fusion gene', 'Var', (35, 46))
403853	30918253	Of the 15 acute myeloid leukaemia (AML) samples analysed, we confirmed previously reported fusion genes in 1 out of 2 (50%) samples and identified a novel gene in the other sample with a previously reported fusion gene.	('AML', 'Disease', (35, 38))	('AML', 'Disease', 'MESH:D015470', (35, 38))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (16, 33))	('myeloid leukaemia', 'Disease', 'MESH:D007938', (16, 33))	('fusion genes', 'Var', (91, 103))	('myeloid leukaemia', 'Disease', (16, 33))
403854	30918253	We confirmed previously detected fusion genes in all three (100%) chronic myeloid leukaemia (CML) samples and identified fusion genes in 1 CML sample where prior testing identified no fusion genes and one sample with no analysis history available.	('CML', 'Disease', (139, 142))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (74, 91))	('myeloid leukaemia', 'Disease', 'MESH:D007938', (74, 91))	('CML', 'Disease', 'MESH:D015464', (93, 96))	('myeloid leukaemia', 'Disease', (74, 91))	('CML', 'Disease', 'MESH:D015464', (139, 142))	('fusion', 'Var', (33, 39))	('CML', 'Disease', (93, 96))
403856	30918253	Finally, we detected a novel fusion gene in one uncategorised blood cancer sample.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('fusion gene', 'Var', (29, 40))	('blood cancer', 'Disease', (62, 74))	('blood cancer', 'Disease', 'MESH:D009369', (62, 74))	('blood cancer', 'Phenotype', 'HP:0001909', (62, 74))
403874	30918253	As deregulated V(D)J recombination can create fusion genes involving IG/TCR receptor loci in a range of blood cancers, our blood panel targeted the V, J and C exons at these loci (Fig.	('blood cancer', 'Phenotype', 'HP:0001909', (104, 116))	('deregulated', 'Var', (3, 14))	('blood cancers', 'Disease', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('IG/TCR receptor', 'Gene', (69, 84))	('blood cancers', 'Phenotype', 'HP:0001909', (104, 117))	('blood cancers', 'Disease', 'MESH:D009369', (104, 117))	('fusion genes', 'Var', (46, 58))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))
403883	30918253	Chromosomal translocations that generate fusion genes are a major cause of cancer, and their accurate diagnosis is critical to effective treatment.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('Chromosomal translocations', 'Var', (0, 26))	('fusion genes', 'Var', (41, 53))	('cancer', 'Disease', (75, 81))	('cause', 'Reg', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
403995	24489925	Moreover, the invasion assay demonstrated that batimastat decreased the invasion of SCLs (Figure 6B), and the three-dimensional culture showed that it prevented these cells from organizing themselves into aligned tube-like structures (Figures 5C, 5D).	('batimastat', 'Var', (47, 57))	('decreased', 'NegReg', (58, 67))	('prevented', 'NegReg', (151, 160))	('batimastat', 'Chemical', 'MESH:C080985', (47, 57))	('invasion of SCLs', 'CPA', (72, 88))	('organizing themselves into', 'CPA', (178, 204))
404100	22588017	A total of 68 different chromosome bands were involved in structural rearrangements; two-thirds of these were near-centromeric (p11-q11; 26 bands) or terminal (19 bands) chromosome bands.	('p11-q11;', 'Var', (128, 136))	('involved', 'Reg', (46, 54))	('men', 'Species', '9606', (78, 81))
404101	22588017	The only breakpoints which were recurrent in, and restricted to, a particular morphologic subtype were 14p11 in UPS and 16p13 in myoepithelioma-like sarcomas.	('myoepithelioma-like sarcomas', 'Disease', (129, 157))	('UPS', 'Disease', (112, 115))	('16p13', 'Var', (120, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('myoepithelioma-like sarcomas', 'Disease', 'MESH:D009208', (129, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('14p11', 'Var', (103, 108))
404103	22588017	Only one balanced translocation, a t(8;9)(q22;p24) in a myoepithelioma-like sarcoma, was found.	('t(8;9)(q22;p24', 'Var', (35, 49))	('myoepithelioma-like sarcoma', 'Disease', 'MESH:D009208', (56, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('myoepithelioma-like sarcoma', 'Disease', (56, 83))	('t(8;9)(q22;p24)', 'STRUCTURAL_ABNORMALITY', 'None', (35, 50))
404105	22588017	Interphase FISH analysis for rearrangement of the EWSR1 and FUS loci was successfully performed in two of the three cases of myoepithelioma-like sarcoma.	('men', 'Species', '9606', (38, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('myoepithelioma-like sarcoma', 'Disease', 'MESH:D009208', (125, 152))	('EWSR1', 'Gene', (50, 55))	('rearrangement', 'Var', (29, 42))	('myoepithelioma-like sarcoma', 'Disease', (125, 152))
404107	22588017	The results indicated a different pattern of chromosomal imbalances compared to that in high-grade osteosarcomas, fibrosarcomas of bone, and soft tissue MFHs.	('osteosarcomas', 'Disease', (99, 112))	('imbalances', 'Phenotype', 'HP:0002172', (57, 67))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (114, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('osteosarcomas', 'Phenotype', 'HP:0002669', (99, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('fibrosarcomas', 'Disease', 'MESH:D005354', (114, 127))	('osteosarcomas', 'Disease', 'MESH:D012516', (99, 112))	('chromosomal imbalances', 'Var', (45, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('fibrosarcomas', 'Disease', (114, 127))	('osteosarcoma', 'Phenotype', 'HP:0002669', (99, 111))
404110	22588017	The present study included too few cases of each subtype to allow any meaningful comparison between the new morphologic subgroups; until more cases have been analyzed, the finding of two recurrent breakpoints in UPS (14p11) and myoepithelioma-like sarcoma (16p13) should be considered chance findings.	('myoepithelioma-like sarcoma', 'Disease', (228, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('myoepithelioma-like sarcoma', 'Disease', 'MESH:D009208', (228, 255))	('UPS (14p11', 'Var', (212, 222))
404112	22588017	Antonescu and co-workers recently showed that gene fusions involving the EWSR1 gene are common in myoepithelial tumors of soft tissue and bone.	('myoepithelial tumors', 'Disease', 'MESH:D009208', (98, 118))	('myoepithelial tumors', 'Disease', (98, 118))	('common', 'Reg', (88, 94))	('EWSR1', 'Gene', (73, 78))	('gene fusions', 'Var', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
404113	22588017	An EWSR1/POU5F1, EWSR1/PBX1 or EWSR1/ZNF444 fusion gene, or a rearrangement of the EWSR1 gene with unknown fusion partner, was detected in close to half of the soft tissue lesions, and in four out of five bone tumors.	('bone tumor', 'Phenotype', 'HP:0010622', (205, 215))	('EWSR1', 'Gene', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('rearrangement', 'Var', (62, 75))	('soft tissue lesions', 'CPA', (160, 179))	('men', 'Species', '9606', (71, 74))	('EWSR1/PBX1', 'Gene', (17, 27))	('EWSR1/ZNF444', 'Gene', (31, 43))	('bone tumors', 'Disease', (205, 216))	('bone tumors', 'Disease', 'MESH:D001859', (205, 216))	('bone tumors', 'Phenotype', 'HP:0010622', (205, 216))	('EWSR1/POU5F1', 'Gene', (3, 15))	('detected', 'Reg', (127, 135))
404165	31762864	A large Finnish study demonstrated that RIS in all treated parts of the body with prior radiation led to development of malignancy in approximately 0.05% of all treated patients.	('patients', 'Species', '9606', (169, 177))	('RIS', 'Var', (40, 43))	('malignancy', 'Disease', (120, 130))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))
404177	23432728	A CALL TO ARMS: TARGETING THE PAX3-FOXO1 GENE IN ALVEOLAR RHABDOMYOSARCOMA* Expression of fusion oncoproteins generated by recurrent chromosomal translocations represents a major tumorigenic mechanism characteristic of multiple cancers, including one-third of all sarcomas.	('CALL TO ARMS', 'Disease', 'None', (2, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('multiple cancers', 'Disease', (219, 235))	('CALL TO ARMS', 'Disease', (2, 14))	('RHABDOMYOSARCOMA', 'Phenotype', 'HP:0002859', (58, 74))	('ALVEOLAR RHABDOMYOSARCOMA', 'Phenotype', 'HP:0006779', (49, 74))	('PAX3', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('PAX3', 'Gene', '5077', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('FOXO1', 'Gene', '2308', (35, 40))	('chromosomal translocations', 'Var', (133, 159))	('sarcomas', 'Disease', 'MESH:D012509', (264, 272))	('multiple cancers', 'Disease', 'MESH:D009369', (219, 235))	('sarcomas', 'Phenotype', 'HP:0100242', (264, 272))	('sarcomas', 'Disease', (264, 272))	('FOXO1', 'Gene', (35, 40))	('tumor', 'Disease', (179, 184))
404187	23432728	Tumors classified in the second category often arise de novo and harbor chromosomal translocations .	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chromosomal translocations', 'Var', (72, 98))
404188	23432728	Although non-random translocations are generally rare in solid tumors, they are associated with about one-third of all sarcomas .	('non-random translocations', 'Var', (9, 34))	('sarcomas', 'Disease', (119, 127))	('solid tumors', 'Disease', (57, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('associated', 'Reg', (80, 90))	('solid tumors', 'Disease', 'MESH:D009369', (57, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
404189	23432728	Indeed, recurrent translocations have been identified in 19 sarcoma subtypes .	('translocations', 'Var', (18, 32))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))
404190	23432728	In Ewing's sarcoma, for example, the common t(11;22)(q24;q12) translocation creates the EWSR1-FLI1 fusion transcription factor .	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (3, 18))	("Ewing's sarcoma", 'Disease', (3, 18))	('t(11', 'Var', (44, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (44, 61))	('FLI1', 'Gene', (94, 98))	('FLI1', 'Gene', '2313', (94, 98))	('EWSR1', 'Gene', (88, 93))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (3, 18))	('EWSR1', 'Gene', '2130', (88, 93))
404192	23432728	Studies of recurrent chromosomal translocations and their associated fusion genes have contributed much to sarcoma research from both basic biology and clinical perspectives.	('chromosomal translocations', 'Var', (21, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('sarcoma', 'Disease', (107, 114))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))
404204	23432728	In contrast to 11p15.5 allelic loss and point mutations that occur frequently in ERMS , recurrent chromosomal translocations characterize 70-80% of ARMS tumors .	('ARMS tumors', 'Disease', 'MESH:D009369', (148, 159))	('point mutations', 'Var', (40, 55))	('ERMS', 'Disease', (81, 85))	('ARMS tumors', 'Disease', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))
404205	23432728	Two specific translocations are unique to ARMS tumors: the majority of ARMS cases harbor the common translocation, t(2;13)(q35;q14), whereas a smaller subset of ARMS harbor a variant translocation, t(1; 13)(p36;q14) .	('p36', 'Gene', '51251', (207, 210))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (115, 131))	('ARMS tumors', 'Disease', (42, 53))	('p36', 'Gene', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('ARMS tumors', 'Disease', 'MESH:D009369', (42, 53))	('t(2;13)(q35;q14', 'Var', (115, 130))
404208	23432728	In rare cases, alternative translocations, such as t(2;2)(p23;q35) and t(2;8)(q35;q13), result in fusion of PAX3 to nuclear receptor coactivator genes NCOA1 and NCOA2, respectively .	('NCOA1', 'Gene', (151, 156))	('fusion', 'Var', (98, 104))	('result in', 'Reg', (88, 97))	('NCOA2', 'Gene', (161, 166))	('NCOA2', 'Gene', '10499', (161, 166))	('PAX3', 'Gene', (108, 112))	('t(2;2)(p23;q35', 'Var', (51, 65))	('t(2;2)(p23;q35)', 'STRUCTURAL_ABNORMALITY', 'None', (51, 66))	('t(2;8)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (71, 86))	('NCOA1', 'Gene', '8648', (151, 156))	('t(2;8)(q35;q13', 'Var', (71, 85))
404209	23432728	The PAX-FOXO1 fusion products have altered expression, subcellular localization, and function, compared to wild-type PAX3, PAX7, or FOXO1.	('PAX', 'Gene', '19303', (117, 120))	('altered', 'Reg', (35, 42))	('PAX', 'Gene', (4, 7))	('function', 'MPA', (85, 93))	('PAX', 'Gene', (117, 120))	('subcellular localization', 'MPA', (55, 79))	('fusion', 'Var', (14, 20))	('PAX', 'Gene', '19303', (123, 126))	('PAX', 'Gene', '19303', (4, 7))	('expression', 'MPA', (43, 53))	('PAX', 'Gene', (123, 126))
404214	23432728	In fact, high expression levels of PAX3-FOXO1, comparable to endogenous fusion expression levels in human ARMS tumor cells, were found to be anti-proliferative in immortalized murine cell lines.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('human', 'Species', '9606', (100, 105))	('PAX3-FOXO1', 'Var', (35, 45))	('expression', 'MPA', (14, 24))	('ARMS tumor', 'Disease', (106, 116))	('ARMS tumor', 'Disease', 'MESH:D009369', (106, 116))	('anti-proliferative', 'CPA', (141, 159))	('murine', 'Species', '10090', (176, 182))
404217	23432728	Similarly, p53 inactivation was required in PAX3-FOXO1-expressing murine mesenchymal stem cells to elicit ARMS-like tumor formation when injected into immunocompromised mice .	('elicit', 'Reg', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mice', 'Species', '10090', (169, 173))	('murine', 'Species', '10090', (66, 72))	('tumor', 'Disease', (116, 121))	('inactivation', 'Var', (15, 27))
404218	23432728	Human skeletal muscle myoblasts stably expressing PAX3-FOXO1 can produce ARMS-like tumors after addition of TERT and MYCN and loss of CDKN2A .In studies of a mouse model using a conditional PAX3-FOXO1 knock-in allele, ARMS formed at low frequency, but addition of conditional Trp53 or Cdkn2a inactivation increased ARMS tumor incidence, providing further evidence that the PAX3-FOXO1 fusion requires accompanying genetic lesions for ARMS pathogenesis  Although PAX3-FOXO1 and PAX7-FOXO1 are virtually indistinguishable in structure ,PAX3-FOXO1 expression portends an especially unfavorable outcome relative to PAX7-FOXO1 .	('Human', 'Species', '9606', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mouse', 'Species', '10090', (158, 163))	('ARMS tumor', 'Disease', 'MESH:D009369', (315, 325))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('CDKN2A', 'Gene', (134, 140))	('PAX3-FOXO1', 'Var', (533, 543))	('tumors', 'Disease', (83, 89))	('Trp53', 'Gene', (276, 281))	('ARMS tumor', 'Disease', (315, 325))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('CDKN2A', 'Gene', '1029', (134, 140))	('TERT', 'Gene', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('TERT', 'Gene', '7015', (108, 112))	('Cdkn2a', 'Gene', '12578', (285, 291))	('Trp53', 'Gene', '22059', (276, 281))	('Cdkn2a', 'Gene', (285, 291))
404222	23432728	Antisense oligonucleotide- or siRNA-mediated depletion of PAX3-FOXO1 induced apoptosis, suggesting that the fusion protein is essential in cell viability .	('PAX3-FOXO1', 'Gene', (58, 68))	('oligonucleotide', 'Chemical', 'MESH:D009841', (10, 25))	('apoptosis', 'CPA', (77, 86))	('depletion', 'Var', (45, 54))	('Antisense oligonucleotide-', 'Var', (0, 26))	('induced', 'Reg', (69, 76))
404223	23432728	The anti-tumor effects of PAX3-FOXO1 depletion provide proof of principle for therapeutic strategies designed to abrogate PAX3-FOXO1 expression.	('expression', 'MPA', (133, 143))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('depletion', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('PAX3-FOXO1', 'Gene', (26, 36))	('PAX3-FOXO1', 'Gene', (122, 132))
404224	23432728	Despite existing limitations that impede full clinical translation of antisense therapeutics , antisense oligonucleotide-mediated depletion of PAX3-FOXO1 is a potential therapeutic alternative.	('oligonucleotide', 'Chemical', 'MESH:D009841', (105, 120))	('antisense oligonucleotide-mediated depletion', 'Var', (95, 139))	('PAX3-FOXO1', 'Gene', (143, 153))
404225	23432728	In a related study, antisense oligodeoxynucleotide treatment against EWSR1-FLI1 in Ewing's sarcoma induced tumor regression .	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (83, 98))	('antisense oligodeoxynucleotide treatment', 'Var', (20, 60))	('EWSR1', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	("Ewing's sarcoma", 'Disease', (83, 98))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (30, 50))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (83, 98))	('EWSR1', 'Gene', '2130', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('FLI1', 'Gene', (75, 79))	('FLI1', 'Gene', '2313', (75, 79))
404229	23432728	Interestingly, the sensitivity of ARMS cells to camptothecin appeared to depend not on topoisomerase I, but on the transcriptional activity of PAX3-FOXO1, as ectopic expression of PAX3-FOXO1 in ERMS cells increases sensitivity to campothecin .	('campothecin', 'Chemical', '-', (230, 241))	('sensitivity to campothecin', 'MPA', (215, 241))	('camptothecin', 'Chemical', 'MESH:D002166', (48, 60))	('PAX3-FOXO1', 'Var', (180, 190))	('increases', 'PosReg', (205, 214))
404235	23432728	While multiple serine/threonine kinases, such as members of the AGC protein kinase family , CDK1 , CDK2, CK1, and DYRK1 have been reported to phosphorylate FOXO1 at various sites, AKT is regarded as the primary kinase involved in phosphorylation-dependent modulation of FOXO1 subcellular localization and consequent transcriptional activity  FOXO1 harbors three evolutionarily conserved AKT phosphorylation sites located at threonine 24, serine 256, and serine 319  Upon activation, AKT translocates to the nucleus and directly phosphorylates FOXO1 .	('CDK1', 'Gene', '983', (92, 96))	('FOXO1', 'Gene', (342, 347))	('CDK1', 'Gene', (92, 96))	('serine', 'Chemical', 'MESH:D012694', (454, 460))	('FOXO1', 'Gene', (543, 548))	('serine', 'Chemical', 'MESH:D012694', (438, 444))	('serine 319', 'Var', (454, 464))	('CK1', 'Species', '2498238', (105, 108))	('serine', 'Chemical', 'MESH:D012694', (15, 21))
404236	23432728	Using a FOXO1 mutant in which threonine 24 was replaced by alanine but serines 256 and 319 were unaltered, studies demonstrated that the presence of these two AKT phosphorylation sites matching those preserved in the PAX3-FOXO1 chimera are sufficient for AKT-mediated cytoplasmic sequestration and inhibition of FOXO1 transcriptional activity  A promising prediction was derived: if serine 256 and serine 319 in the FOXO1 portion of PAX3- FOXO1 were phosphorylated by AKT, then PAX3-FOXO1 should be relocalized to the cytoplasm, thereby quelling its ability to aberrantly transactivate target gene expression.	('aberrantly', 'MPA', (561, 571))	('serines', 'Chemical', 'MESH:D012694', (71, 78))	('serine', 'Chemical', 'MESH:D012694', (398, 404))	('mutant', 'Var', (14, 20))	('threonine 24 was replaced by alanine', 'Mutation', 'rs1262334323', (30, 66))	('serine', 'Chemical', 'MESH:D012694', (383, 389))	('ability', 'MPA', (550, 557))	('serine', 'Chemical', 'MESH:D012694', (71, 77))	('quelling', 'NegReg', (537, 545))
404237	23432728	In HEK293T and NIH 3T3 cells, transfection of PAX3-FOXO1 or a form with the two serines mutated, with or without constitutively active AKT, showed no effect on PAX3-FOXO1 nuclear localization or transcriptional activity .	('serines', 'Chemical', 'MESH:D012694', (80, 87))	('transfection', 'Var', (30, 42))	('transcriptional activity', 'MPA', (195, 219))	('NIH 3T3', 'CellLine', 'CVCL:0594', (15, 22))	('HEK293T', 'CellLine', 'CVCL:0063', (3, 10))	('PAX3-FOXO1', 'Gene', (46, 56))	('nuclear localization', 'MPA', (171, 191))	('PAX3-FOXO1', 'Protein', (160, 170))
404238	23432728	A recent study using murine cell lines derived from conditional PAX3-FOXO1 knock-in mice and cultured in low serum provided evidence that PAX3-FOXO1 can be phosphorylated by hyperactivated AKT in this setting .	('PAX3-FOXO1', 'Var', (138, 148))	('AKT', 'Pathway', (189, 192))	('hyperactivated', 'PosReg', (174, 188))	('PAX3-FOXO1', 'Gene', (64, 74))	('murine', 'Species', '10090', (21, 27))	('mice', 'Species', '10090', (84, 88))
404243	23432728	In vitro and in vivo studies of murine primary myoblasts revealed serine 201, serine 205, and serine 209 as the only sites of phosphorylation in wild-type PAX3, and all three serine residues are retained in the oncogenic PAX3-FOXO1 fusion .	('serine', 'Chemical', 'MESH:D012694', (78, 84))	('murine', 'Species', '10090', (32, 38))	('serine', 'Chemical', 'MESH:D012694', (66, 72))	('phosphorylation', 'MPA', (126, 141))	('serine', 'Chemical', 'MESH:D012694', (94, 100))	('serine 209', 'Var', (94, 104))	('serine', 'Chemical', 'MESH:D012694', (175, 181))
404247	23432728	Serine 201 phosphorylation subsequently promotes serine 205 dephosphorylation, as evidenced by the absence of PAX3 species exhibiting simultaneous phosphorylation at serines 201 and 205.	('serine', 'Chemical', 'MESH:D012694', (49, 55))	('Serine 201', 'Var', (0, 10))	('serine', 'Chemical', 'MESH:D012694', (166, 172))	('Serine', 'Chemical', 'MESH:D012694', (0, 6))	('serine 205 dephosphorylation', 'MPA', (49, 77))	('serines', 'Chemical', 'MESH:D012694', (166, 173))	('promotes', 'PosReg', (40, 48))
404249	23432728	Experiments in mouse primary myoblasts and human ARMS cell lines indicate that the oncogenic PAX3-FOXO1 fusion is phosphorylated by CK2 at serine 205 followed by GSK3beta-driven phosphorylation at serine 201.	('GSK3beta', 'Gene', (162, 170))	('GSK3beta', 'Gene', '2932', (162, 170))	('serine', 'Var', (139, 145))	('PAX3-FOXO1', 'Gene', (93, 103))	('serine', 'Chemical', 'MESH:D012694', (139, 145))	('mouse', 'Species', '10090', (15, 20))	('human', 'Species', '9606', (43, 48))	('serine', 'Chemical', 'MESH:D012694', (197, 203))
404256	23432728	It should be noted that simultaneous mutation of all six serines to phosphorylation-mimicking aspartate residues was required to overcome PKC412 inhibition but was not sufficient to rescue complete transcriptional activity of PAX3-FOXO1 , suggesting that PKC412 inhibits fusion protein transactivation potential by mechanisms beyond these six phosphorylation events.	('fusion protein', 'Protein', (271, 285))	('inhibits', 'NegReg', (262, 270))	('mutation', 'Var', (37, 45))	('PKC', 'Gene', '112476', (255, 258))	('serines', 'Chemical', 'MESH:D012694', (57, 64))	('PKC', 'Gene', (138, 141))	('PKC', 'Gene', '112476', (138, 141))	('aspartate', 'Chemical', 'MESH:D001224', (94, 103))	('PKC', 'Gene', (255, 258))
404257	23432728	Despite concerns of potential toxicity from off-target effects, this study demonstrates that small- molecule-mediated modulation of PAX3-FOXO1 post-transcriptional modifications, namely phosphorylation, is a promising approach for ARMS treatment.	('toxicity', 'Disease', 'MESH:D064420', (30, 38))	('phosphorylation', 'Var', (186, 201))	('toxicity', 'Disease', (30, 38))	('PAX3-FOXO1', 'Gene', (132, 142))	('modulation', 'Var', (118, 128))
404269	23432728	Analysis of primary RMS tumors revealed a strong correlation of high FGFR4 expression with PAX3-FOXO1-positive ARMS , advanced clinical stage, and lower overall survival .	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('high', 'Var', (64, 68))	('FGFR4', 'Gene', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('lower', 'NegReg', (147, 152))	('overall survival', 'CPA', (153, 169))	('RMS tumors', 'Disease', (20, 30))	('expression', 'MPA', (75, 85))	('RMS tumors', 'Disease', 'MESH:D009369', (20, 30))
404270	23432728	In addition, activating mutations in the tyrosine kinase domain of FGFR4 were found in 7.5% of RMS tumors (mostly ERMS) , and transduction of murine RMS772 cells with two of these FGFR4 mutants resulted in elevated proliferation, invasion, and metastatic capacity relative to wild-type FGFR4-transduced cells in vitro and in vivo .	('murine', 'Species', '10090', (142, 148))	('ERMS', 'Disease', (114, 118))	('activating', 'PosReg', (13, 23))	('FGFR4', 'Gene', (180, 185))	('mutants', 'Var', (186, 193))	('metastatic capacity', 'CPA', (244, 263))	('RMS tumors', 'Disease', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('invasion', 'CPA', (230, 238))	('elevated', 'PosReg', (206, 214))	('FGFR4', 'Gene', (67, 72))	('RMS tumors', 'Disease', 'MESH:D009369', (95, 105))	('mutations', 'Var', (24, 33))	('RMS772', 'CellLine', 'CVCL:S121', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
404271	23432728	Recent findings in primary mouse myoblasts demonstrated that ectopic expression of a constitutively active FGFR4 mutant, but not wild-type FGFR4, is sufficient to contribute to ARMS tumorigenesis .	('FGFR4', 'Gene', (107, 112))	('ARMS tumor', 'Disease', (177, 187))	('ARMS tumor', 'Disease', 'MESH:D009369', (177, 187))	('mouse', 'Species', '10090', (27, 32))	('mutant', 'Var', (113, 119))	('contribute', 'Reg', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
404273	23432728	In a very promising finding in vitro, FGFR4 mutant-expressing RMS772 cells exhibited enhanced sensitivity to FGFR inhibitor PD173074, as apoptotic cell death was higher in RMS772 cells transduced with FGFR4 mutants compared to those expressing wild-type FGFR4 .	('higher', 'PosReg', (162, 168))	('enhanced', 'PosReg', (85, 93))	('apoptotic cell death', 'CPA', (137, 157))	('sensitivity', 'MPA', (94, 105))	('mutants', 'Var', (207, 214))	('RMS772', 'CellLine', 'CVCL:S121', (62, 68))	('FGFR4', 'Gene', (201, 206))	('PD173074', 'Chemical', 'MESH:C115711', (124, 132))	('RMS772', 'CellLine', 'CVCL:S121', (172, 178))	('mutant-expressing', 'Var', (44, 61))	('FGFR4', 'Gene', (38, 43))
404274	23432728	PD173074 also attenuated cell proliferation of ARMS and ERMS cell lines overexpressing wild-type FGFR; therefore, FGFR mutations are not required for pharmacologic efficacy of PD173074 in vitro .	('PD173074', 'Var', (0, 8))	('attenuated', 'NegReg', (14, 24))	('PD173074', 'Chemical', 'MESH:C115711', (0, 8))	('cell proliferation', 'CPA', (25, 43))	('PD173074', 'Chemical', 'MESH:C115711', (176, 184))
404275	23432728	In the in vivo setting, however, the small-molecule inhibitor was found to have a narrow therapeutic window and high toxicity, eliminating PD173074 as a viable option in ARMS therapy .	('toxicity', 'Disease', (117, 125))	('PD173074', 'Chemical', 'MESH:C115711', (139, 147))	('PD173074', 'Var', (139, 147))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))
404278	23432728	Other small-molecule inhibitors targeting FGFRs, including AZD4547 and AZ12908010, have already been developed and are undergoing preclinical and clinical evaluation  Moreover, neutralizing or high-affinity monoclonal antibodies against FGFR4 have been generated, and strategies to target FGF19:the ligand of FGFR4:are under investigation .	('FGFR4', 'Gene', (237, 242))	('AZD4547', 'Var', (59, 66))	('FGFRs', 'Gene', (42, 47))	('AZD4547', 'Chemical', 'MESH:C572463', (59, 66))	('AZ12908010', 'Var', (71, 81))	('FGF19', 'Gene', (289, 294))	('FGF19', 'Gene', '9965', (289, 294))	('AZ12908010', 'Chemical', '-', (71, 81))
404280	23432728	Collectively, the cellular responses evoked by MET have been referred to as "invasive growth,"  a program that, if dysregulated, can have profound tumorigenic and metastatic consequences.	('MET', 'Var', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
404281	23432728	Amplification of MET, gain-of-function mutations, and transcriptional upregulation are mechanisms leading to MET overexpression and/or activation, which has been reported in a myriad of human primary tumors .	('gain-of-function', 'PosReg', (22, 38))	('activation', 'PosReg', (135, 145))	('upregulation', 'PosReg', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('overexpression', 'PosReg', (113, 127))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('mutations', 'Var', (39, 48))	('human', 'Species', '9606', (186, 191))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('MET', 'Disease', (109, 112))
404283	23432728	Additionally, MET amplification was found in non-small cell lung cancers with acquired resistance to erlotinib or gefitinib, two epidermal growth factor receptor inhibitors .	('erlotinib', 'Chemical', 'MESH:D000069347', (101, 110))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (45, 72))	('lung cancers', 'Phenotype', 'HP:0100526', (60, 72))	('MET amplification', 'Var', (14, 31))	('found', 'Reg', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (45, 72))	('gefitinib', 'Chemical', 'MESH:D000077156', (114, 123))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (49, 72))	('non-small cell lung cancers', 'Disease', (45, 72))
404286	23432728	In glioblastoma, osteosarcoma, breast carcinoma, and RMS , expression of HGF has been proposed to aberrantly activate MET through an autocrine loop .	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('osteosarcoma', 'Disease', (17, 29))	('breast carcinoma', 'Disease', (31, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (17, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('breast carcinoma', 'Disease', 'MESH:D001943', (31, 47))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))	('HGF', 'Gene', (73, 76))	('activate', 'PosReg', (109, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('expression', 'Var', (59, 69))	('breast carcinoma', 'Phenotype', 'HP:0003002', (31, 47))	('HGF', 'Gene', '3082', (73, 76))	('MET', 'MPA', (118, 121))
404287	23432728	Importantly, both ARMS and ERMS tumors demonstrated oncogene addiction to MET, as MET depletion abrogated proliferation, invasiveness, survival, and anchorage-independent growth in vitro and arrested tumor growth in vivo  Therefore, both RMS subtypes:in addition to the multitude of cancer types described above:could potentially benefit from MET-directed therapies.	('anchorage-independent growth', 'CPA', (149, 177))	('invasiveness', 'CPA', (121, 133))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('arrested tumor', 'Disease', 'MESH:D006323', (191, 205))	('arrested tumor', 'Disease', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Disease', (283, 289))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ERMS tumors', 'Disease', (27, 38))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('survival', 'CPA', (135, 143))	('proliferation', 'CPA', (106, 119))	('depletion abrogated', 'NegReg', (86, 105))	('MET', 'Var', (82, 85))	('ERMS tumors', 'Disease', 'MESH:D009369', (27, 38))
404288	23432728	The sheer variety of compounds and strategies designed to antagonize MET holds much promise: HGF antagonists to block interaction of MET with its ligand, HGF and MET neutralizing antibodies to interfere with HGF-MET binding and to downregulate MET, MET decoys to sequester HGF and obstruct receptor dimerization, and small-molecule inhibitors to impair catalytic activity .	('HGF', 'Gene', (154, 157))	('HGF', 'Gene', '3082', (273, 276))	('interaction', 'Interaction', (118, 129))	('catalytic activity', 'MPA', (353, 371))	('obstruct', 'NegReg', (281, 289))	('impair', 'NegReg', (346, 352))	('HGF', 'Gene', (273, 276))	('HGF', 'Gene', '3082', (208, 211))	('MET', 'MPA', (244, 247))	('sequester', 'MPA', (263, 272))	('HGF', 'Gene', (208, 211))	('binding', 'Interaction', (216, 223))	('small-molecule inhibitors', 'Var', (317, 342))	('HGF', 'Gene', '3082', (93, 96))	('interfere', 'NegReg', (193, 202))	('downregulate', 'NegReg', (231, 243))	('HGF', 'Gene', '3082', (154, 157))	('receptor', 'Protein', (290, 298))	('HGF', 'Gene', (93, 96))
404291	23432728	MYCN is a basic helix-loop-helix/leucine zipper transcription factor that is expressed predominantly in neuronal tissues during embryogenesis  Following heterodimerization with MAX, MYCN activates transcription of target genes, such as TERT, ODC, MDM2, and IGF1R .	('ODC', 'Gene', (242, 245))	('TERT', 'Gene', (236, 240))	('TERT', 'Gene', '7015', (236, 240))	('MDM2', 'Gene', '4193', (247, 251))	('MDM2', 'Gene', (247, 251))	('activates', 'PosReg', (187, 196))	('ODC', 'Gene', '4953', (242, 245))	('IGF1R', 'Gene', (257, 262))	('IGF1R', 'Gene', '3480', (257, 262))	('transcription', 'MPA', (197, 210))	('MYCN', 'Var', (182, 186))
404293	23432728	Aberrant expression of MYCN as a result of MYCN amplification, however, has been detected in several malignancies, including neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma, anaplastic large cell lymphoma, and small cell lung carcinoma .	('cell lymphoma', 'Disease', (204, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('glioblastoma', 'Disease', 'MESH:D005909', (140, 152))	('expression', 'MPA', (9, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (209, 217))	('cell lymphoma', 'Phenotype', 'HP:0012191', (204, 217))	('cell lymphoma', 'Disease', 'MESH:D016399', (204, 217))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (187, 217))	('small cell lung carcinoma', 'Disease', (223, 248))	('retinoblastoma', 'Phenotype', 'HP:0009919', (171, 185))	('glioblastoma', 'Disease', (140, 152))	('retinoblastoma', 'Disease', (171, 185))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (223, 248))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('MYCN', 'Gene', (43, 47))	('medulloblastoma', 'Disease', 'MESH:D008527', (154, 169))	('neuroblastoma', 'Disease', (125, 138))	('medulloblastoma', 'Phenotype', 'HP:0002885', (154, 169))	('neuroblastoma', 'Phenotype', 'HP:0003006', (125, 138))	('medulloblastoma', 'Disease', (154, 169))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('detected', 'Reg', (81, 89))	('neuroblastoma', 'Disease', 'MESH:D009447', (125, 138))	('amplification', 'Var', (48, 61))	('malignancies', 'Disease', (101, 113))	('retinoblastoma', 'Disease', 'MESH:D012175', (171, 185))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (223, 248))	('MYCN', 'Gene', (23, 27))
404294	23432728	MYCN amplification is perhaps best known in neuroblastoma, in which it clearly correlates with poor outcome .	('MYCN', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('neuroblastoma', 'Disease', 'MESH:D009447', (44, 57))	('neuroblastoma', 'Disease', (44, 57))	('neuroblastoma', 'Phenotype', 'HP:0003006', (44, 57))
404297	23432728	High MYCN expression levels significantly correlated with PAX3/7-FOXO1 -positive ARMS tumors and poorer clinical outcome for ARMS patients .	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('PAX3/7-FOXO1', 'Var', (58, 70))	('High MYCN expression levels', 'MPA', (0, 27))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('patients', 'Species', '9606', (130, 138))	('ARMS tumors', 'Disease', 'MESH:D009369', (81, 92))	('correlated', 'Reg', (42, 52))	('ARMS tumors', 'Disease', (81, 92))
404301	23432728	Although recurrent chromosomal translocations are uncommon in solid tumors, they are characteristic of approximately one-third of all sarcomas .	('sarcomas', 'Disease', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('chromosomal translocations', 'Var', (19, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('solid tumors', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))
404319	23432728	The majority of recurrent chromosomal translocations in sarcomas generate oncogenic chimeric transcription factors, which aberrantly transactivate target gene expression.	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('chromosomal translocations', 'Var', (26, 52))	('transactivate', 'Reg', (133, 146))	('sarcomas', 'Disease', (56, 64))
404321	23432728	Therefore, an important additional approach is to exploit downstream targets in these translocation-associated sarcomas that are also applicable to more common cancer categories.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('sarcomas', 'Disease', 'MESH:D012509', (111, 119))	('cancer', 'Disease', (160, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcomas', 'Disease', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('translocation-associated', 'Var', (86, 110))
404326	30394881	Of the 6,427 patients identified, 9% had tumors <=5 cm (n=580), 19.4% 5<x<=10cm (n=1,246), 20.2% 10<x<=15cm (n=1,298) and 47.4% >15cm (n=3,045).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('10<x<=15cm', 'Var', (97, 107))	('5<x<=10cm', 'Var', (70, 79))
404327	30394881	With the 8th edition, stage II patients (G2/3 <=5cm) have a similar OS to stage IIIA patients (G2/3 5cm<x<=10cm), and patients with larger tumors (stage IIIB, G2/3>10cm) show a decrease in OS.	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (31, 39))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('G2/3 <=5cm', 'Var', (41, 51))	('patients', 'Species', '9606', (118, 126))
404368	30394881	For patients with metastatic disease (n = 749) increasing age, male sex, government insurance status, treatment at a non-academic facility, and high grade tumors were associated with poorer OS, whereas selection for surgery was associated with better OS (Supplemental Table 2).	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('high grade', 'Var', (144, 154))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('patients', 'Species', '9606', (4, 12))
404379	30394881	was unable to identify an association between tumor size and OS when using tumor size either as a continuous variable or dichotomized at various cutpoints, including 20 cm, 10 cm, as well as the AJCC 7th edition cutpoint of 5 cm.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('10 cm', 'Var', (173, 178))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
404445	28243188	These include monosomy 7, trisomy 8, MLL rearrangement, inv(16), trisomy 4, monosomy 16, 16q-, 5q-, 20q- and trisomy 11.	('MLL', 'Gene', (37, 40))	('monosomy 16', 'Var', (76, 87))	('inv', 'Disease', (56, 59))	('trisomy 4', 'Disease', (65, 74))	('5q-', 'Var', (95, 98))	('monosomy 7', 'Disease', (14, 24))	('trisomy 8', 'Disease', (26, 35))	('20q-', 'Disease', (100, 104))	('16q-', 'Disease', (89, 93))	('trisomy', 'Disease', (109, 116))	('MLL', 'Gene', '4297', (37, 40))
404456	27627705	In contrast, the association of EWSR1 chimeric fusion genes with leukemia has rarely been reported.	('leukemia', 'Phenotype', 'HP:0001909', (65, 73))	('leukemia', 'Disease', 'MESH:D007938', (65, 73))	('leukemia', 'Disease', (65, 73))	('EWSR1', 'Gene', (32, 37))	('chimeric fusion genes', 'Var', (38, 59))
404457	27627705	We identified a novel EWSR1-associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality.	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (84, 100))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (78, 100))	('p13', 'Gene', '440926', (131, 134))	('acute myeloid leukemia', 'Disease', (78, 100))	('p13', 'Gene', (131, 134))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (78, 100))	('patient', 'Species', '9606', (65, 72))	('EWSR1-associated', 'Gene', (22, 38))	('chimeric fusion gene', 'Var', (39, 59))
404465	27627705	In vitro studies suggest that a disruption of senescence or DNA damage responses, both associated with the tumor barrier, may play a critical role in the tumorigenic effects of EWSR1/ETS.13, 14 In addition, the tumor phenotype is determined by the cell type expressing EWSR1/ETS.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('EWSR1/ETS', 'Var', (269, 278))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('ETS', 'Chemical', '-', (275, 278))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('ETS', 'Chemical', '-', (183, 186))	('DNA damage responses', 'MPA', (60, 80))	('senescence', 'MPA', (46, 56))	('tumor', 'Disease', (154, 159))
404467	27627705	Intriguingly, EWSR1/FLI1 can direct partial neuroectodermal differentiation of primary mesenchymal stem cells.15 However, EWSR1/ETS is rarely associated with leukemia,16, 17 thus preventing hematopoietic lineage analysis in clinical specimens.	('hematopoietic lineage analysis', 'CPA', (190, 220))	('leukemia', 'Disease', (158, 166))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('leukemia', 'Disease', 'MESH:D007938', (158, 166))	('preventing', 'NegReg', (179, 189))	('ETS', 'Chemical', '-', (128, 131))	('EWSR1/ETS', 'Var', (122, 131))
404504	27627705	He was diagnosed with low blast-count AML immunologically positive for CD7, CD33, CD34, CD45dull, CD61, CD99 and CD117 (c-kit) but negative for the sarcoma markers desmin, MyoD1, myogenin, neuron-specific enolase (NSE) and paired box gene 5 (PAX5).	('PAX5', 'Gene', (242, 246))	('CD117', 'Gene', '3815', (113, 118))	('paired box gene 5', 'Gene', (223, 240))	('CD34', 'Gene', (82, 86))	('CD99', 'Gene', (104, 108))	('MyoD1', 'Gene', '4654', (172, 177))	('CD7', 'Gene', (71, 74))	('NSE', 'Gene', '2026', (214, 217))	('PAX5', 'Gene', '5079', (242, 246))	('CD117', 'Gene', (113, 118))	('myogenin', 'Gene', (179, 187))	('desmin', 'Gene', (164, 170))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('CD99', 'Gene', '4267', (104, 108))	('sarcoma', 'Disease', (148, 155))	('NSE', 'Gene', (214, 217))	('CD61', 'Gene', (98, 102))	('CD61', 'Gene', '3690', (98, 102))	('c-kit', 'Gene', (120, 125))	('neuron-specific enolase', 'Gene', (189, 212))	('CD34', 'Gene', '947', (82, 86))	('myogenin', 'Gene', '4656', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('desmin', 'Gene', '1674', (164, 170))	('AML', 'Disease', 'MESH:D015470', (38, 41))	('neuron-specific enolase', 'Gene', '2026', (189, 212))	('AML', 'Disease', (38, 41))	('CD33', 'Gene', '945', (76, 80))	('CD33', 'Gene', (76, 80))	('MyoD1', 'Gene', (172, 177))	('paired box gene 5', 'Gene', '5079', (223, 240))	('CD7', 'Gene', '924', (71, 74))	('CD45dull', 'Var', (88, 96))	('c-kit', 'Gene', '3815', (120, 125))
404510	27627705	Chromosomal G-banding analysis using leukemic cell revealed translocation between 22q12 and 11p13 in leukemia cells (Fig.	('translocation between 22q12', 'Var', (60, 87))	('leukemic', 'Disease', (37, 45))	('p13', 'Gene', (94, 97))	('leukemic', 'Disease', 'MESH:D007938', (37, 45))	('leukemia', 'Disease', (101, 109))	('p13', 'Gene', '440926', (94, 97))	('leukemia', 'Disease', 'MESH:D007938', (101, 109))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))
404520	27627705	Instead, mutation of CASP9, a central player in common apoptosis pathways, was identified (Data S1).	('mutation', 'Var', (9, 17))	('CASP9', 'Gene', (21, 26))	('CASP9', 'Gene', '842', (21, 26))
404521	27627705	Analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID) revealed several patterns of tumor-specific gene alterations.	('alterations', 'Var', (136, 147))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))
404535	27627705	Therefore, we investigated whether the transduction of EWSR1/ELF5 induces apoptosis or cellular senescence in NIH3T3 cells.	('apoptosis', 'CPA', (74, 83))	('induces', 'Reg', (66, 73))	('EWSR1/ELF5', 'Gene', (55, 65))	('NIH3T3', 'CellLine', 'CVCL:0594', (110, 116))	('cellular senescence', 'CPA', (87, 106))	('transduction', 'Var', (39, 51))
404536	27627705	In addition, SA-beta-gal staining was enhanced in EWSR1/ELF5 transduced NIH3T3 cells (Fig.	('transduced', 'Var', (61, 71))	('enhanced', 'PosReg', (38, 46))	('SA-beta-gal', 'Protein', (13, 24))	('NIH3T3', 'CellLine', 'CVCL:0594', (72, 78))	('SA', 'Chemical', '-', (13, 15))	('EWSR1/ELF5', 'Gene', (50, 60))	('beta-gal', 'Chemical', '-', (16, 24))
404542	27627705	The EWSR1/FLI1 fusion transcript was reported to inhibit p21 activity.32, 33, 34 To determine whether EWSR1/ELF5 also suppresses p21 expression, EWSR1/ELF5 was transduced into p53-competent U2OS cells.	('suppresses', 'NegReg', (118, 128))	('p21 expression', 'MPA', (129, 143))	('EWSR1/ELF5', 'Var', (102, 112))	('U2OS', 'CellLine', 'CVCL:0042', (190, 194))	('expression', 'Species', '29278', (133, 143))
404543	27627705	Intriguingly, EWSR1/ELF5 stimulated the baseline expression of p53 and p21, compared to MOCK-transduced U2OS cells (Fig.	('EWSR1/ELF5', 'Var', (14, 24))	('baseline expression', 'MPA', (40, 59))	('p21', 'Var', (71, 74))	('expression', 'Species', '29278', (49, 59))	('U2OS', 'CellLine', 'CVCL:0042', (104, 108))	('stimulated', 'PosReg', (25, 35))	('p53', 'Protein', (63, 66))
404547	27627705	p21 reporter promoter activity induced by p53 transfection was attenuated by EWSR1/ELF5 expression.	('p53', 'Gene', (42, 45))	('p21 reporter promoter activity', 'MPA', (0, 30))	('attenuated', 'NegReg', (63, 73))	('expression', 'Species', '29278', (88, 98))	('transfection', 'Var', (46, 58))
404558	27627705	This might also be the case in our experiments, because retroviral transduction did not induce leukemia even after 12 months in our model.	('retroviral transduction', 'Var', (56, 79))	('leukemia', 'Disease', (95, 103))	('leukemia', 'Disease', 'MESH:D007938', (95, 103))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))
404561	27627705	The ETS transcription factor family is a diverse group of proteins cooperating with other factors to regulate a wide range of cellular processes, such as proliferation, differentiation, apoptosis and senescence; members also possess oncogenic or tumor suppressive activities.38 Chromosomal translocations involving ETS family members are associated with several forms of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('ETS', 'Chemical', '-', (315, 318))	('human', 'Species', '9606', (371, 376))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('cancers', 'Disease', 'MESH:D009369', (377, 384))	('ETS', 'Chemical', '-', (4, 7))	('associated', 'Reg', (338, 348))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('ETS', 'Gene', (315, 318))	('cancers', 'Phenotype', 'HP:0002664', (377, 384))	('Chromosomal translocations', 'Var', (278, 304))	('tumor', 'Disease', (246, 251))	('cancers', 'Disease', (377, 384))
404567	27627705	Further study is needed to show whether ELF5 aberrantly expressed by a chimeric protein may induce tumorigenesis, or this fusion may play a role in malignant transformation in the hematopoietic system.	('tumor', 'Disease', (99, 104))	('malignant transformation', 'CPA', (148, 172))	('play', 'Reg', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('role', 'Reg', (140, 144))	('ELF5', 'Gene', (40, 44))	('induce', 'PosReg', (92, 98))	('aberrantly expressed', 'Var', (45, 65))
404568	27627705	In this study we demonstrated that the novel EWSR1/ELF5 fusion gene disrupts the p53/p21-dependent pathway, similar to the case of sarcoma genesis induced by other members of the EWSR1/ETS family.	('sarcoma genesis', 'Disease', 'MESH:D012509', (131, 146))	('disrupts', 'NegReg', (68, 76))	('EWSR1/ELF5', 'Gene', (45, 55))	('p53/p21-dependent pathway', 'Pathway', (81, 106))	('sarcoma genesis', 'Disease', (131, 146))	('ETS', 'Chemical', '-', (185, 188))	('fusion', 'Var', (56, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))
404569	27627705	In most primary cells, the ectopic expression of EWSR1/ETS leads to cell cycle arrest or apoptosis, whereas an inhibition of p53 activity may rescue the cells from EWSR1/ETS-induced toxicity and facilitate tumorigenesis.13, 14 This observation suggests that the p53/p21-dependent pathway plays an important role in the prevention of tumorigenesis by EWSR1/ETS.	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('tumor', 'Disease', (333, 338))	('ETS', 'Chemical', '-', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('expression', 'Species', '29278', (35, 45))	('tumor', 'Disease', (206, 211))	('toxicity', 'Disease', 'MESH:D064420', (182, 190))	('ETS', 'Chemical', '-', (356, 359))	('toxicity', 'Disease', (182, 190))	('arrest', 'Disease', (79, 85))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('ETS', 'Chemical', '-', (55, 58))	('EWSR1/ETS', 'Var', (350, 359))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
404572	27627705	The activity of the p21 promoter is negatively regulated by the EWSR1/FLI1 fusion protein through ETS-binding sites located within the promoter region of p21.32 In addition, EWSR1/FLI1 interacted with the cotransactivator of p300 and suppressed its histone acetyltransferase activity.	('EWSR1/FLI1', 'Var', (174, 184))	('p300', 'Gene', '2033', (225, 229))	('activity', 'MPA', (275, 283))	('ETS', 'Chemical', '-', (98, 101))	('suppressed', 'NegReg', (234, 244))	('histone acetyltransferase', 'Enzyme', (249, 274))	('negatively', 'NegReg', (36, 46))	('p300', 'Gene', (225, 229))	('activity', 'MPA', (4, 12))	('interacted', 'Interaction', (185, 195))
404618	25812660	Other translocations leading to the fusion of the EWS gene with one of several members of the ETS family of transcription factors have subsequently been identified, including t(21,22)(q22;q21) in 10%-15% of cases and t(7;22), t(17; 22) and t(2;22) in less than 1% of cases.	('t(7;22', 'Var', (217, 223))	('EWS', 'Gene', (50, 53))	('EWS', 'Gene', '2130', (50, 53))
404623	25812660	However, due to the presence of the t(11;22) translocation in other tumor types such as desmoplastic small round cell tumor, FISH results should be interpreted in light of the morphology and immunohistochemical profile.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('translocation', 'Var', (45, 58))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (118, 123))	('t(11;22', 'Gene', (36, 43))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (88, 123))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('desmoplastic small round cell tumor', 'Disease', (88, 123))
404763	25239186	The relative mortality method relies on internal comparability between the cohort of interest (soft tissue sarcoma patients) and the general comparison cohort, and violation of this can result in possible bias.	('patients', 'Species', '9606', (115, 123))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (95, 114))	('soft tissue sarcoma', 'Disease', (95, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (95, 114))	('result', 'Reg', (186, 192))	('violation', 'Var', (164, 173))
404846	33489055	Additional genomic findings included MDM2 amplification, BCL7A rearrangement, FRS2 amplification, and NCOR2 rearrangement.	('NCOR2', 'Gene', (102, 107))	('MDM2', 'Gene', '4193', (37, 41))	('rearrangement', 'Var', (63, 76))	('FRS2', 'Gene', '10818', (78, 82))	('MDM2', 'Gene', (37, 41))	('FRS2', 'Gene', (78, 82))	('NCOR2', 'Gene', '9612', (102, 107))	('amplification', 'Var', (42, 55))	('BCL7A', 'Gene', '605', (57, 62))	('amplification', 'Var', (83, 96))	('BCL7A', 'Gene', (57, 62))
404873	33489055	Additionally, small molecule inhibitors of MDM2 have shown promising activity, including a recently reported trial of milademetan which showed a median progression-free survival of 6.3 months in liposarcoma patients.	('small', 'Var', (14, 19))	('patients', 'Species', '9606', (207, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('activity', 'MPA', (69, 77))	('milademetan', 'Chemical', '-', (118, 129))	('MDM2', 'Gene', '4193', (43, 47))	('MDM2', 'Gene', (43, 47))	('liposarcoma', 'Disease', (195, 206))	('liposarcoma', 'Phenotype', 'HP:0012034', (195, 206))	('liposarcoma', 'Disease', 'MESH:D008080', (195, 206))
404893	31573951	In addition to physical functioning, patients receiving treatment for a high-grade bone sarcoma also show significantly poorer social functioning.	('high-grade', 'Var', (72, 82))	('patients', 'Species', '9606', (37, 45))	('social functioning', 'CPA', (127, 145))	('bone sarcoma', 'Disease', (83, 95))	('poorer social functioning', 'Phenotype', 'HP:0000735', (120, 145))	('bone sarcoma', 'Disease', 'MESH:D012509', (83, 95))	('bone sarcoma', 'Phenotype', 'HP:0002669', (83, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('poorer', 'NegReg', (120, 126))
404903	31573951	Therefore, the investigators compromised on the use of 1 questionnaire for adults (>=16 years; European Organization for Research and Treatment of Cancer:Quality of Life-Core Questionnaire C30 [EORTC-QLQ-C30]) and 2 age-adapted questionnaires for pediatric patients (self-report and parallelized proxy report): Pediatric Quality of Life Questionnaire (PEDQoL) in Central Europe and Scandinavia and Pediatric Quality of Life Inventory (PedsQL) in North America and EOI-related countries (eg, United Kingdom or Belgium).	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('C30', 'Var', (189, 192))	('Cancer', 'Disease', (147, 153))	('Cancer', 'Disease', 'MESH:D009369', (147, 153))	('patients', 'Species', '9606', (257, 265))
404983	23255526	AEWS1031 is the current Children's Oncology Group (COG) study of localized Ewing sarcoma.	('Ewing sarcoma', 'Disease', (75, 88))	('Children', 'Species', '9606', (24, 32))	('AEWS1031', 'Var', (0, 8))	('COG', 'Chemical', '-', (51, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('Oncology', 'Phenotype', 'HP:0002664', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
405010	23255526	For instance, D9602 and ARST0331 tested whether RT could be eliminated in female patients with tumors of the vagina; this approach resulted in an unacceptable local failure rate.	('local failure', 'CPA', (159, 172))	('tested', 'Reg', (33, 39))	('tumors of the vagina', 'Phenotype', 'HP:0100650', (95, 115))	('patients', 'Species', '9606', (81, 89))	('tumors of the vagina', 'Disease', (95, 115))	('ARST0331', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('D9602', 'Var', (14, 19))	('tumors of the vagina', 'Disease', 'MESH:D014625', (95, 115))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
405036	23255526	They supported randomized trials comparing chemotherapy alone with combined-modality therapy in patients with Hodgkin lymphoma who experienced complete response to induction chemotherapy found that combined-modality therapy is associated with superior EFS; no significant difference in OS was detected.	('EFS', 'MPA', (252, 255))	('Hodgkin lymphoma', 'Disease', (110, 126))	('superior', 'PosReg', (243, 251))	('combined-modality therapy', 'Var', (198, 223))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (110, 126))	('patients', 'Species', '9606', (96, 104))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (110, 126))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))
405054	23255526	Unfortunately, irradiation is associated with an increased risk for late mortality; development of second malignancies; endocrine, pulmonary, and cardiac dysfunction; growth abnormalities; and other various chronic health conditions.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('cardiac dysfunction', 'Disease', (146, 165))	('late mortality', 'CPA', (68, 82))	('malignancies', 'Disease', (106, 118))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (146, 165))	('growth abnormalities', 'Phenotype', 'HP:0001507', (167, 187))	('endocrine', 'Disease', (120, 129))	('growth abnormalities', 'Disease', (167, 187))	('irradiation', 'Var', (15, 26))	('growth abnormalities', 'Disease', 'MESH:D006130', (167, 187))	('pulmonary', 'Disease', (131, 140))
405285	31844962	However, GBCAs can be associated with side effects, such as nephrogenic systemic fibrosis (NSF) in patients with renal failure and gadolinium (Gd) deposition in the brain after repetitive administration.	('GBCAs', 'Chemical', '-', (9, 14))	('nephrogenic systemic fibrosis', 'Disease', (60, 89))	('nephrogenic systemic fibrosis', 'Disease', 'MESH:D054989', (60, 89))	('renal failure', 'Disease', 'MESH:D051437', (113, 126))	('renal failure', 'Disease', (113, 126))	('patients', 'Species', '9606', (99, 107))	('gadolinium', 'Chemical', 'MESH:D005682', (131, 141))	('renal failure', 'Phenotype', 'HP:0000083', (113, 126))	('GBCAs', 'Var', (9, 14))	('associated', 'Reg', (22, 32))	('Gd', 'Chemical', 'MESH:D005682', (143, 145))
405349	31844962	However, FMX-MRI improved delineation of tumour deposits in the bone marrow (see Figure 4), liver (see Figure 5) and vessels (see Figure 6).	('improved', 'PosReg', (17, 25))	('tumour deposits', 'Disease', (41, 56))	('tumour deposits', 'Disease', 'MESH:D009369', (41, 56))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('FMX', 'Chemical', 'MESH:D052203', (9, 12))	('FMX-MRI', 'Var', (9, 16))
405357	31844962	However, the reported reader confidence for evaluation of presence or absence of a tumour thrombus was significantly higher on FMX-MRI compared to Gd-MRI (0.62 vs 0.20; p<0.001) and the confidence for evaluation of involvement of the neurovascular bundle was significantly higher on FMX-MRI compared to Gd-MRI (0.76 vs 0.52; p<0.001; see Table 5).	('neurovascular bundle', 'Disease', 'MESH:D013901', (234, 254))	('FMX', 'Chemical', 'MESH:D052203', (127, 130))	('higher', 'PosReg', (273, 279))	('FMX-MRI', 'Var', (127, 134))	('Gd', 'Chemical', 'MESH:D005682', (147, 149))	('tumour thrombus', 'Disease', (83, 98))	('Gd', 'Chemical', 'MESH:D005682', (303, 305))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour thrombus', 'Disease', 'MESH:D013927', (83, 98))	('neurovascular bundle', 'Disease', (234, 254))	('higher', 'PosReg', (117, 123))	('FMX-MRI', 'Var', (283, 290))	('FMX', 'Chemical', 'MESH:D052203', (283, 286))
405359	31844962	The tumour T1-enhancement was significantly more hyperintense on Gd-MRI compared to FMX-MRI scans.	('more', 'PosReg', (44, 48))	('Gd-MRI', 'Var', (65, 71))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('Gd', 'Chemical', 'MESH:D005682', (65, 67))	('hyperintense', 'MPA', (49, 61))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('FMX', 'Chemical', 'MESH:D052203', (84, 87))
405361	31844962	FMX-MRI scans provided improved tumour-to-liver contrast and improved tumour-to-vessel contrast compared to Gd-MRI scans, which facilitated the detection of vascular involvement and tumour thrombi.	('improved', 'PosReg', (61, 69))	('facilitated', 'PosReg', (128, 139))	('vascular involvement', 'CPA', (157, 177))	('FMX', 'Chemical', 'MESH:D052203', (0, 3))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('FMX-MRI', 'Var', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', (32, 38))	('tumour thrombi', 'Disease', 'MESH:D009369', (182, 196))	('Gd', 'Chemical', 'MESH:D005682', (108, 110))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumour thrombi', 'Disease', (182, 196))	('improved', 'PosReg', (23, 31))	('tumour', 'Disease', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', (70, 76))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
405365	31844962	found different enhancement patterns of malignant brain tumours with FMX- and Gd-enhanced MRI: Ferumoxytol-enhanced MRI demonstrated enhancement of growing tumours but not pseudoprogression, while Gd-MRI showed enhancement of both pathologies.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('Ferumoxytol-enhanced', 'Var', (95, 115))	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('FMX', 'Chemical', 'MESH:D052203', (69, 72))	('tumours', 'Disease', (156, 163))	('brain tumours', 'Phenotype', 'HP:0030692', (50, 63))	('malignant brain tumours', 'Disease', 'MESH:D001932', (40, 63))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('malignant brain tumours', 'Disease', (40, 63))	('Gd', 'Chemical', 'MESH:D005682', (197, 199))	('Ferumoxytol', 'Chemical', 'MESH:D052203', (95, 106))	('enhancement', 'PosReg', (133, 144))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('Gd', 'Chemical', 'MESH:D005682', (78, 80))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))
405375	31844962	Ferumoxytol is phagocytosed by bone marrow cells and thereby improves the tumour-to-bone marrow contrast compared to unenhanced T2-weighted scans.	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('Ferumoxytol', 'Chemical', 'MESH:D052203', (0, 11))	('tumour', 'Disease', (74, 80))	('improves', 'PosReg', (61, 69))	('Ferumoxytol', 'Var', (0, 11))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
405383	31844962	Our data showed significantly improved vessel and tumour thrombus delineation on FMX-MRI.	('tumour thrombus delineation', 'Disease', 'MESH:D013927', (50, 77))	('FMX', 'Chemical', 'MESH:D052203', (81, 84))	('tumour thrombus delineation', 'Disease', (50, 77))	('FMX-MRI', 'Var', (81, 88))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('improved', 'PosReg', (30, 38))
405393	31844962	bSSFP Balanced steady state free precession CNR Contrast-to-noise ratio COG Children's oncology group DSRCT Desmoplastic small round cell tumour FDA U.S. food and drug administration FMX Ferumoxytol FMX-MRI Ferumoxytol-enhanced MRI scan-protocol GBCAs Gadolinium-based contrast agents Gd Gadolinium Gd-MRI Gadolinium-enhanced MRI scan-protocol GIST Gastrointestinal stroma tumour IND Investigational new drug MPNST Malignant peripheral nerve sheath tumour MRI Magnetic resonance imaging NSF Nephrogenic systemic fibrosis SNR Signal-to-noise ratio T1-LAVA T1-liver acquisition with volume acceleration T1-SE T1-weighted spin echo sequence T2-FSE T2-weighted fast spin echo sequence TAM Tumour-associated macrophages In contrast to gadolinium, ferumoxytol does not bear the risk of a nephrogenic systemic fibrosis in patients with an impaired kidney function or brain deposition after repetitive administration.	('TAM', 'Chemical', '-', (681, 684))	('Gadolinium', 'Chemical', 'MESH:D005682', (306, 316))	('Nephrogenic systemic fibrosis', 'Disease', (491, 520))	('Malignant peripheral nerve sheath', 'Phenotype', 'HP:0100697', (415, 448))	('Children', 'Species', '9606', (76, 84))	('Malignant peripheral nerve sheath tumour', 'Disease', (415, 455))	('FS', 'Disease', 'MESH:D018223', (641, 643))	('Malignant peripheral nerve sheath tumour', 'Disease', 'MESH:D018319', (415, 455))	('gadolinium', 'Chemical', 'MESH:D005682', (730, 740))	('tumour', 'Phenotype', 'HP:0002664', (449, 455))	('patients', 'Species', '9606', (815, 823))	('tumour', 'Disease', 'MESH:D009369', (449, 455))	('GBCAs', 'Chemical', '-', (246, 251))	('spin', 'Gene', '10927', (619, 623))	('Ferumoxytol', 'Chemical', 'MESH:D052203', (207, 218))	('FMX', 'Chemical', 'MESH:D052203', (183, 186))	('tumour', 'Disease', (449, 455))	('nephrogenic systemic fibrosis', 'Disease', (782, 811))	('impaired kidney function', 'Disease', (832, 856))	('Nephrogenic systemic fibrosis', 'Disease', 'MESH:D054989', (491, 520))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('Gadolinium', 'Chemical', 'MESH:D005682', (288, 298))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('Gastrointestinal stroma tumour', 'Disease', (349, 379))	('spin', 'Gene', (619, 623))	('tumour', 'Disease', (138, 144))	('Gastrointestinal stroma tumour', 'Phenotype', 'HP:0100723', (349, 379))	('FMX', 'Chemical', 'MESH:D052203', (199, 202))	('Gd', 'Chemical', 'MESH:D005682', (285, 287))	('T1-LAVA', 'Gene', '921', (547, 554))	('spin', 'Gene', '10927', (662, 666))	('nephrogenic systemic fibrosis', 'Disease', 'MESH:D054989', (782, 811))	('impaired kidney function', 'Disease', 'MESH:D007674', (832, 856))	('oncology', 'Phenotype', 'HP:0002664', (87, 95))	('T1-LAVA', 'Gene', (547, 554))	('ferumoxytol', 'Var', (742, 753))	('Tumour', 'Phenotype', 'HP:0002664', (685, 691))	('tumour', 'Phenotype', 'HP:0002664', (373, 379))	('spin', 'Gene', (662, 666))	('Gd', 'Chemical', 'MESH:D005682', (299, 301))	('Ferumoxytol', 'Chemical', 'MESH:D052203', (187, 198))	('Gadolinium', 'Chemical', 'MESH:D005682', (252, 262))	('tumour', 'Disease', 'MESH:D009369', (373, 379))	('Gadolinium-based contrast agents', 'Chemical', '-', (252, 284))	('tumour', 'Disease', (373, 379))	('Gastrointestinal stroma tumour', 'Disease', 'MESH:D004067', (349, 379))	('ferumoxytol', 'Chemical', 'MESH:D052203', (742, 753))	('COG', 'Chemical', '-', (72, 75))
405449	23193489	PBS tends to be negative for estrogen receptor, progesterone receptor, and Her2 mutations therefore making hormone therapy ineffective as an adjuvant.	('progesterone receptor', 'Gene', (48, 69))	('negative', 'NegReg', (16, 24))	('mutations', 'Var', (80, 89))	('progesterone receptor', 'Gene', '5241', (48, 69))	('estrogen', 'Protein', (29, 37))	('Her2', 'Gene', (75, 79))	('Her2', 'Gene', '2064', (75, 79))
405462	23193489	Pathologic state is IIA and TNM grading of pT2pN0pMX.	('TNM', 'Gene', '10178', (28, 31))	('pT2pN0pMX', 'Var', (43, 52))	('TNM', 'Gene', (28, 31))
405482	21284868	There is however no universal agreement and at least one series reported that in selected patients with retroperitoneal liposarcomas, partial resection can prolong survival and provide palliation.	('retroperitoneal liposarcomas', 'Disease', 'MESH:C538370', (104, 132))	('liposarcoma', 'Phenotype', 'HP:0012034', (120, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('retroperitoneal liposarcomas', 'Phenotype', 'HP:0006729', (104, 132))	('prolong', 'PosReg', (156, 163))	('survival', 'CPA', (164, 172))	('partial resection', 'Var', (134, 151))	('liposarcomas', 'Phenotype', 'HP:0012034', (120, 132))	('retroperitoneal liposarcomas', 'Disease', (104, 132))	('patients', 'Species', '9606', (90, 98))
405536	21284868	It been reported recently that well differentiated liposarcomas and de-differentiated liposarcomas have different biological behaviors, in de-differentiated tumors, they tend to present as a recurrence more often, require multi-organ resection more frequently and has a shorter disease free interval when compared to well differentiated subtypes.	('liposarcoma', 'Phenotype', 'HP:0012034', (86, 97))	('liposarcomas', 'Disease', (86, 98))	('liposarcoma', 'Phenotype', 'HP:0012034', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('de-differentiated', 'Var', (139, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Disease', (157, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('liposarcomas', 'Disease', 'MESH:D008080', (51, 63))	('liposarcomas', 'Phenotype', 'HP:0012034', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('liposarcomas', 'Phenotype', 'HP:0012034', (86, 98))	('liposarcomas', 'Disease', 'MESH:D008080', (86, 98))	('liposarcomas', 'Disease', (51, 63))
405564	32010431	The role of ctDNA is now well established in the clinical decision in certain alterations and tumors, such as the epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer and the v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer.	('v-Ki-ras2', 'Var', (201, 210))	('sarcoma', 'Disease', (223, 230))	('colorectal cancer', 'Disease', (273, 290))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (170, 192))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (166, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutation', 'Var', (154, 162))	('epidermal growth factor receptor', 'Gene', '24329', (114, 146))	('tumors', 'Disease', (94, 100))	('KRAS', 'Gene', (255, 259))	('colorectal cancer', 'Phenotype', 'HP:0003003', (273, 290))	('non-small cell lung cancer', 'Disease', (166, 192))	('mutation', 'Var', (261, 269))	('epidermal growth factor receptor', 'Gene', (114, 146))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('EGFR', 'Gene', (148, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (273, 290))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (166, 192))	('sarcoma', 'Disease', 'MESH:D012509', (223, 230))
405575	32010431	ddPCR is a highly sensitive (EGFR exon 19 deletion, 82%; EGFR L858R mutation, 74%) and quantitative approach that allows for the longitudinal monitoring of treatment response.	('L858R', 'Mutation', 'rs121434568', (62, 67))	('deletion', 'Var', (42, 50))	('men', 'Species', '9606', (161, 164))	('L858R', 'Var', (62, 67))
405579	32010431	Overall, 75% of patients with NSCLC harbor potentially actionable genomic aberrations in ctDNA, although concordance with tissue is suboptimal (specificity, 63.5%).	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('genomic aberrations', 'Var', (66, 85))	('patients', 'Species', '9606', (16, 24))	('ctDNA', 'Disease', (89, 94))	('actionable', 'Reg', (55, 65))	('NSCLC', 'Disease', (30, 35))
405580	32010431	Tumor NGS can help monitor tumor dynamics and detect acquired ALK resistance mutations in crizotinib-resistant patients.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (27, 32))	('ALK', 'Gene', (62, 65))	('mutations', 'Var', (77, 86))	('ALK', 'Gene', '238', (62, 65))	('crizotinib', 'Chemical', 'MESH:C551994', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patients', 'Species', '9606', (111, 119))
405582	32010431	Plasma genotyping is widely used as a screening test for detection of the EGFR T790M resistance mutation, with tumor biopsy needed only if the result is negative.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('T790M', 'Mutation', 'rs121434569', (79, 84))	('T790M', 'Var', (79, 84))	('EGFR', 'Gene', (74, 78))
405585	32010431	In 323 patients with NSCLC, the addition of ctDNA analysis to tissue NGS analysis increased the identification of driver alterations and resulted in an 85.7% rate of objective response or stable disease.	('alterations', 'Var', (121, 132))	('NSCLC', 'Disease', (21, 26))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('driver', 'MPA', (114, 120))	('objective response', 'CPA', (166, 184))	('identification', 'MPA', (96, 110))	('increased', 'PosReg', (82, 91))	('patients', 'Species', '9606', (7, 15))
405596	32010431	The allele frequencies of the mutations increased with tumor burden and preceded radiologic evidence of tumor recurrence by 6 months.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (30, 39))	('increased', 'PosReg', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
405600	32010431	ctDNA analysis is used to detect and monitor HER2 copy numbers in patients with gastric cancer.	('gastric cancer', 'Disease', (80, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('copy numbers', 'Var', (50, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('HER2', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HER2', 'Gene', '2064', (45, 49))	('patients', 'Species', '9606', (66, 74))
405603	32010431	HER2 positivity by ctDNA analysis was associated with significantly shorter OS compared to HER2 negativity.	('positivity', 'Var', (5, 15))	('HER2', 'Gene', (91, 95))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (91, 95))	('HER2', 'Gene', '2064', (0, 4))	('shorter', 'NegReg', (68, 75))
405604	32010431	In late-stage gastric cancer, ctDNA mutations were associated with poor prognosis.	('gastric cancer', 'Disease', 'MESH:D013274', (14, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (14, 28))	('mutations', 'Var', (36, 45))	('ctDNA', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('gastric cancer', 'Disease', (14, 28))
405605	32010431	In a multiple-parallel cohort, ctDNA-guided plasma-based digital sequencing in patients with metastatic solid tumors, including gastric cancer, identified somatic alterations in 78% of the 76 patients with gastric cancer, and 33% of these 76 patients had targetable alterations.	('gastric cancer', 'Disease', (128, 142))	('alterations', 'Var', (163, 174))	('patients', 'Species', '9606', (242, 250))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('gastric cancer', 'Disease', 'MESH:D013274', (128, 142))	('patients', 'Species', '9606', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('patients', 'Species', '9606', (79, 87))	('gastric cancer', 'Disease', (206, 220))	('gastric cancer', 'Disease', 'MESH:D013274', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
405607	32010431	In a prospective study of 106 patient samples of CRC, ctDNA analysis of KRAS and BRAF mutational status was compared to the analysis of tumor tissue.	('patient', 'Species', '9606', (30, 37))	('KRAS', 'Gene', (72, 76))	('mutational status', 'Var', (86, 103))	('BRAF', 'Gene', '673', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('CRC', 'Disease', 'MESH:D015179', (49, 52))	('BRAF', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('CRC', 'Disease', (49, 52))
405608	32010431	The specificity and sensitivity of ctDNA were both 100% for BRAF V600E mutation and were 98% and 92%, respectively, for KRAS point mutations.	('BRAF', 'Gene', (60, 64))	('KRAS point', 'Var', (120, 130))	('V600E', 'Mutation', 'rs113488022', (65, 70))	('BRAF', 'Gene', '673', (60, 64))
405618	32010431	In a prospective analysis in 26 patients with pancreatic (n = 18) or biliary (n = 8) cancer, tumor sequencing using a 54-gene panel failed in 9 patients (35%), and of the remaining 17 patients, 90.3% of the mutations detected in the tumor biopsies were also detected using ctDNA.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('detected', 'Reg', (258, 266))	('pancreatic', 'Disease', 'MESH:D010195', (46, 56))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Disease', (233, 238))	('pancreatic', 'Disease', (46, 56))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (207, 216))	('biliary', 'Disease', (69, 76))	('patients', 'Species', '9606', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
405619	32010431	In pancreatic cancer, high ctDNA levels of KRAS and/or other mutations have been associated with poor progression-free survival (PFS) and/or OS.	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (61, 70))	('KRAS', 'Gene', (43, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('progression-free survival', 'CPA', (102, 127))	('poor', 'NegReg', (97, 101))
405621	32010431	In a prospective study in advanced pancreatic cancer, ctDNA was analyzed for KRAS mutations using blood samples collected prior to gemcitabine or FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) treatment and monthly during treatment (median follow-up, 3.7 months).	('irinotecan', 'Chemical', 'MESH:C051890', (187, 197))	('leucovorin', 'Chemical', 'MESH:D002955', (203, 213))	('pancreatic cancer', 'Disease', 'MESH:D010190', (35, 52))	('pancreatic cancer', 'Disease', (35, 52))	('mutations', 'Var', (82, 91))	('KRAS', 'Gene', (77, 81))	('men', 'Species', '9606', (249, 252))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (158, 172))	('oxaliplatin', 'Chemical', 'MESH:C030110', (174, 185))	('gemcitabine', 'Chemical', 'MESH:C056507', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 52))	('men', 'Species', '9606', (220, 223))
405622	32010431	Disease progression was more frequent in patients with ctDNA-identified KRAS mutations at baseline compared to KRAS-mutant-negative patients (9/10 vs. 1/4; p = 0.01).	('KRAS', 'Gene', (72, 76))	('patients', 'Species', '9606', (41, 49))	('Disease', 'Disease', (0, 7))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (132, 140))
405624	32010431	In other studies, ctDNA analysis detected mutations in up to 48% of patients, and these mutations were associated with shorter OS.	('patients', 'Species', '9606', (68, 76))	('mutations', 'Var', (42, 51))	('shorter OS', 'Disease', (119, 129))
405625	32010431	In another study, ctDNA analysis (ddPCR for rare KRAS mutations) detected mutations in 31% of 105 patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy.	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('mutations', 'Var', (74, 83))	('pancreatic ductal adenocarcinoma', 'Disease', (112, 144))	('patients', 'Species', '9606', (98, 106))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (112, 144))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (112, 144))
405626	32010431	Detectable ctDNA KRAS mutations were associated with shorter OS compared to patients without mutations (13.6 months vs. 27.6 months; p < 0.0001).	('patients', 'Species', '9606', (76, 84))	('shorter', 'NegReg', (53, 60))	('mutations', 'Var', (22, 31))	('ctDNA KRAS', 'Gene', (11, 21))
405628	32010431	These mutations were strongly correlated with shorter OS compared to OS of patients with undetectable mutations (6.5 vs. 19.0 months; p < 0.001).	('shorter', 'NegReg', (46, 53))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (6, 15))
405630	32010431	ctDNA analysis of pre- and post-operative plasma samples and tumor tissue (n = 42) using PCR-based SafeSeqS assays to identify KRAS mutation (codons 12, 13, and 61) identified RAS mutations in 90.5% of tumor samples and in 62.2% of 37 pre-operative and 37.1% of 35 post-operative plasma samples.	('mutations', 'Var', (180, 189))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('KRAS', 'Gene', (127, 131))	('RAS', 'Gene', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
405634	32010431	ctDNA variant allele frequency (VAF) was significantly correlated with tumor load and PFS, and the mutational profile changed after chemotherapy in 36% of patients.	('correlated', 'Reg', (55, 65))	('PFS', 'Disease', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('changed', 'Reg', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ctDNA', 'Gene', (0, 5))	('variant', 'Var', (6, 13))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Disease', (71, 76))
405636	32010431	In patients who underwent hepatectomy or liver transplantation, disease recurrence and extrahepatic metastases were more frequent in those with mutations detected by ctDNA analysis vs. others (p = 0.01 and 0.04, respectively) and ctDNA was an independent factor predicting invasion of the portal vein (odds ratio = 6.10).	('ctDNA', 'Gene', (166, 171))	('disease recurrence', 'CPA', (64, 82))	('extrahepatic metastases', 'Disease', (87, 110))	('extrahepatic metastases', 'Disease', 'MESH:D009362', (87, 110))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (144, 153))
405637	32010431	In other studies, hotspot mutations in the TERT, CTNNB1, and TP53 genes detected in the plasma of patients with HCC were associated with vascular invasion and likely predicted a shorter recurrence-free survival time.	('shorter', 'NegReg', (178, 185))	('CTNNB1', 'Gene', '1499', (49, 55))	('TERT', 'Gene', (43, 47))	('vascular invasion', 'Disease', (137, 154))	('TERT', 'Gene', '7015', (43, 47))	('associated with', 'Reg', (121, 136))	('HCC', 'Disease', 'MESH:D006528', (112, 115))	('patients', 'Species', '9606', (98, 106))	('HCC', 'Disease', (112, 115))	('mutations', 'Var', (26, 35))	('CTNNB1', 'Gene', (49, 55))	('recurrence-free survival time', 'CPA', (186, 215))	('vascular invasion', 'Disease', 'MESH:D019043', (137, 154))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
405639	32010431	In patients with early-stage breast cancer, PIK3CA mutations have been identified presurgically in ctDNA with high sensitivity (93.3%) and specificity (100%).	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('PIK3CA', 'Gene', '5290', (44, 50))	('patients', 'Species', '9606', (3, 11))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('ctDNA', 'Disease', (99, 104))	('identified', 'Reg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
405640	32010431	In a retrospective analysis, the concordance between tissue DNA and ctDNA (digital sequencing of plasma-derived DNA) was robust in PIK3CA mutation and ERBB2 amplification analyses (Cohen's kappa = 0.64 and 0.77, respectively) but poor in TP53 mutation and EGFR amplification analyses (Cohen's kappa = 0.18 and 0.33, respectively).	('PIK3CA', 'Gene', '5290', (131, 137))	('TP53', 'Gene', '7157', (238, 242))	('ERBB2', 'Gene', (151, 156))	('mutation', 'Var', (138, 146))	('PIK3CA', 'Gene', (131, 137))	('poor', 'NegReg', (230, 234))	('ERBB2', 'Gene', '2064', (151, 156))	('TP53', 'Gene', (238, 242))
405641	32010431	In another study, TP53 and PIK3CA mutant allele frequencies were associated with response to therapy and PFS.	('TP53', 'Gene', '7157', (18, 22))	('PIK3CA', 'Gene', (27, 33))	('PFS', 'Disease', (105, 108))	('TP53', 'Gene', (18, 22))	('response', 'Disease', (81, 89))	('associated', 'Reg', (65, 75))	('PIK3CA', 'Gene', '5290', (27, 33))	('mutant', 'Var', (34, 40))
405642	32010431	When PCR and targeted exome sequencing were used to detect the hotspot AKT1 E17K mutation in two cohorts of patients with advanced metastatic breast cancer (MBC), the concordance rates between tissue and blood samples were 98% and 97.1%.	('AKT1', 'Gene', '207', (71, 75))	('E17K', 'Mutation', 'rs121434592', (76, 80))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('E17K', 'Var', (76, 80))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('patients', 'Species', '9606', (108, 116))	('AKT1', 'Gene', (71, 75))
405644	32010431	In the BOLERO-2 study, PIK3CA mutations by ctDNA analysis were associated with efficacy of everolimus.	('PIK3CA', 'Gene', (23, 29))	('everolimus', 'Chemical', 'MESH:C107135', (91, 101))	('associated', 'Reg', (63, 73))	('PIK3CA', 'Gene', '5290', (23, 29))	('mutations', 'Var', (30, 39))	('efficacy', 'MPA', (79, 87))
405645	32010431	In the BELLE-3 study, patients progressing on or after mTOR inhibition and endocrine therapy with PIK3CA mutations (detected by ctDNA or tissue DNA analysis; concordance, 80%) had significantly longer PFS in the buparlisib plus fulvestrant arm compared to the fulvestrant arm.	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (55, 59))	('fulvestrant', 'Chemical', 'MESH:C070081', (228, 239))	('PIK3CA', 'Gene', (98, 104))	('patients', 'Species', '9606', (22, 30))	('PIK3CA', 'Gene', '5290', (98, 104))	('fulvestrant', 'Chemical', 'MESH:C070081', (260, 271))	('mutations', 'Var', (105, 114))	('PFS', 'MPA', (201, 204))	('longer', 'PosReg', (194, 200))
405646	32010431	In patients with HER2-positive breast cancer treated with an anti-HER1/HER2 tyrosine kinase inhibitor, ctDNA analysis for HER2 amplification was associated with disease progression (4/6, 66.7%), whereas TP53 mutations (3/6, 50%) and PI3K/mTOR pathway alterations (3/6, 50.0%) were associated with disease resistance.	('mutations', 'Var', (208, 217))	('associated with', 'Reg', (145, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('alterations', 'Reg', (251, 262))	('tyrosine', 'Chemical', 'None', (76, 84))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (17, 44))	('TP53', 'Gene', (203, 207))	('HER2', 'Gene', (17, 21))	('HER2', 'Gene', '2064', (71, 75))	('HER2', 'Gene', (122, 126))	('HER2-positive breast cancer', 'Disease', (17, 44))	('HER1', 'Gene', (66, 70))	('disease progression', 'CPA', (161, 180))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('mTOR', 'Gene', (238, 242))	('patients', 'Species', '9606', (3, 11))	('TP53', 'Gene', '7157', (203, 207))	('HER1', 'Gene', '1956', (66, 70))	('HER2', 'Gene', (71, 75))	('mTOR', 'Gene', '2475', (238, 242))	('HER2', 'Gene', '2064', (17, 21))	('HER2', 'Gene', '2064', (122, 126))
405653	32010431	ESR1 mutations were detected in 56.4% (22/39) of patients who had disease progression 6.7 months (median) prior to clinical progression.	('ESR1', 'Gene', (0, 4))	('ESR1', 'Gene', '2099', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (49, 57))
405654	32010431	On the basis of detection of ESR1 mutations in primary breast cancer using ctDNA analysis at a very low allele frequency, in contrast to a high allele frequency in metastases, it is plausible that in some tumors rare ESR1-mutant clones may be enriched by endocrine therapy.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('metastases', 'Disease', 'MESH:D009362', (164, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('ESR1', 'Gene', (217, 221))	('ESR1', 'Gene', '2099', (29, 33))	('tumors', 'Disease', (205, 211))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('metastases', 'Disease', (164, 174))	('breast cancer', 'Disease', (55, 68))	('ESR1', 'Gene', (29, 33))	('ESR1', 'Gene', '2099', (217, 221))	('mutations', 'Var', (34, 43))
405657	32010431	In patients with high-grade serous ovarian carcinoma who received standard-of-care therapy, p53 alterations identified using ctDNA analysis at baseline were correlated with volume of disease, and a decrease in TP53 mutant allele fraction <=60% after 1 cycle of chemotherapy was associated with shorter time to disease progression.	('decrease', 'NegReg', (198, 206))	('alterations', 'Var', (96, 107))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (35, 52))	('ovarian carcinoma', 'Disease', (35, 52))	('TP53', 'Gene', (210, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('p53', 'Gene', (92, 95))	('patients', 'Species', '9606', (3, 11))	('mutant', 'Var', (215, 221))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (35, 52))	('p53', 'Gene', '7157', (92, 95))	('TP53', 'Gene', '7157', (210, 214))
405658	32010431	In patients with gynecologic cancer (n = 44), ctDNA analysis using ddPCR detected alterations in 93.8% of patients, and detected cancer in 6 patients, 7 months prior to radiologic evidence on CT imaging studies.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gynecologic cancer', 'Disease', (17, 35))	('cancer', 'Disease', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (106, 114))	('alterations', 'Var', (82, 93))	('detected', 'Reg', (120, 128))	('patients', 'Species', '9606', (141, 149))
405660	32010431	Plasma DNA analysis for detection of chromosomal instability using copy-number alterations in patients with an adnexal mass (n = 68) and in healthy individuals (n = 44) improved detection of malignancy (AUC = 0.89) compared to serum CA-125 (AUC = 0.78) or the RMI (risk of malignancy) index (composite of serum CA 125 level, ultrasound scan result and menopausal status) (AUC = 0.81).	('malignancy', 'Disease', 'MESH:D009369', (273, 283))	('patients', 'Species', '9606', (94, 102))	('chromosomal instability', 'Phenotype', 'HP:0040012', (37, 60))	('CA 125', 'Gene', '94025', (311, 317))	('detection', 'MPA', (178, 187))	('malignancy', 'Disease', (191, 201))	('men', 'Species', '9606', (352, 355))	('CA 125', 'Gene', (311, 317))	('CA-125', 'Chemical', 'MESH:D018394', (233, 239))	('malignancy', 'Disease', 'MESH:D009369', (191, 201))	('improved', 'PosReg', (169, 177))	('copy-number alterations', 'Var', (67, 90))	('malignancy', 'Disease', (273, 283))	('menopausal status', 'Phenotype', 'HP:0008209', (352, 369))
405668	32010431	Aberrations in the androgen receptor (AR) gene by ctDNA analysis have been correlated with resistance to enzalutamide and abiraterone treatment and AR amplification was more common in patients whose disease progressed on enzalutamide compared to abiraterone or other agents (p = 0.02).	('androgen receptor', 'Gene', '367', (19, 36))	('AR', 'Gene', '367', (148, 150))	('abiraterone', 'Chemical', 'MESH:C089740', (246, 257))	('patients', 'Species', '9606', (184, 192))	('abiraterone', 'Chemical', 'MESH:C089740', (122, 133))	('enzalutamide', 'Chemical', 'MESH:C540278', (221, 233))	('correlated', 'Reg', (75, 85))	('androgen receptor', 'Gene', (19, 36))	('men', 'Species', '9606', (139, 142))	('AR', 'Gene', '367', (38, 40))	('enzalutamide', 'Chemical', 'MESH:C540278', (105, 117))	('common', 'Reg', (174, 180))	('Aberrations', 'Var', (0, 11))	('resistance to enzalutamide', 'MPA', (91, 117))	('amplification', 'Var', (151, 164))
405669	32010431	Targeted NGS covering all AR coding bases using plasma from patients treated with abiraterone (control, patients' normal circulating DNA) identified AR copy numbers in 82.5% (80/97) of patients and demonstrated that 45% of tumors had AR gain or T878A or L702H changes before abiraterone treatment, which were associated with shorter PFS and OS.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('T878A', 'Var', (245, 250))	('AR', 'Gene', '367', (234, 236))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('AR', 'Gene', '367', (26, 28))	('patients', 'Species', '9606', (60, 68))	('abiraterone', 'Chemical', 'MESH:C089740', (275, 286))	('L702H', 'Var', (254, 259))	('men', 'Species', '9606', (292, 295))	('patients', 'Species', '9606', (185, 193))	('patients', 'Species', '9606', (104, 112))	('T878A', 'Mutation', 'rs137852578', (245, 250))	('AR', 'Gene', '367', (149, 151))	('abiraterone', 'Chemical', 'MESH:C089740', (82, 93))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('L702H', 'Mutation', 'rs864622007', (254, 259))	('gain', 'PosReg', (237, 241))	('PFS', 'Disease', (333, 336))
405675	32010431	Total serum ctDNA levels and CpG island methylation of RASSF1A and VHL were shown to support the diagnosis of renal cell carcinoma (RCC) and VHL methylation indicates clear cell RCC.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('methylation', 'Var', (40, 51))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (110, 130))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('RCC', 'Disease', 'MESH:D002292', (132, 135))	('RCC', 'Disease', (132, 135))	('VHL', 'Disease', 'MESH:D006623', (141, 144))	('RASSF1A', 'Gene', (55, 62))	('VHL', 'Disease', (141, 144))	('RCC', 'Disease', 'MESH:D002292', (178, 181))	('RCC', 'Disease', (178, 181))	('RASSF1A', 'Gene', '11186', (55, 62))	('VHL', 'Disease', 'MESH:D006623', (67, 70))	('methylation', 'Var', (145, 156))	('VHL', 'Disease', (67, 70))	('renal cell carcinoma', 'Disease', (110, 130))
405681	32010431	In another study, 36% (129/363) of patients with non-muscle-invasive bladder cancer and 11% (44/403) of patients with muscle-invasive bladder cancer who underwent radical cystectomy had >=1 FGFR3 or PIK3CA mutations and high ctDNA levels were associated with disease progression.	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (118, 148))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (53, 83))	('FGFR3', 'Gene', '2261', (190, 195))	('PIK3CA', 'Gene', '5290', (199, 205))	('disease progression', 'Disease', (259, 278))	('non-muscle-invasive bladder cancer', 'Disease', (49, 83))	('patients', 'Species', '9606', (35, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))	('muscle-invasive bladder cancer', 'Disease', (118, 148))	('mutations', 'Var', (206, 215))	('PIK3CA', 'Gene', (199, 205))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (49, 76))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (104, 112))	('associated', 'Reg', (243, 253))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('invasive bladder', 'Phenotype', 'HP:0100645', (125, 141))	('FGFR3', 'Gene', (190, 195))	('non-muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (49, 83))	('invasive bladder', 'Phenotype', 'HP:0100645', (60, 76))
405683	32010431	In patients with metastatic melanoma, identification of BRAF mutations in ctDNA has been associated with higher disease burden and worse prognosis and may precede clinical evidence of disease progression.	('melanoma', 'Disease', (28, 36))	('higher', 'PosReg', (105, 111))	('BRAF', 'Gene', '673', (56, 60))	('ctDNA', 'Gene', (74, 79))	('mutations', 'Var', (61, 70))	('disease burden', 'MPA', (112, 126))	('patients', 'Species', '9606', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('BRAF', 'Gene', (56, 60))
405684	32010431	In patients with unresectable advanced-stage metastatic melanoma, BRAF and NRAS mutations identified in ctDNA analysis at baseline and during treatment with targeted therapy against BRAF or immunotherapy have been associated with larger tumors, increased LDH levels, and brain metastases.	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('NRAS', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutations', 'Var', (80, 89))	('melanoma', 'Disease', (56, 64))	('tumors', 'Disease', (237, 243))	('LDH levels', 'MPA', (255, 265))	('BRAF', 'Gene', '673', (182, 186))	('metastases', 'Disease', 'MESH:D009362', (277, 287))	('BRAF', 'Gene', (182, 186))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('metastases', 'Disease', (277, 287))	('patients', 'Species', '9606', (3, 11))	('NRAS', 'Gene', '4893', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('increased', 'PosReg', (245, 254))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))	('men', 'Species', '9606', (147, 150))
405685	32010431	Other investigators found that in this setting, the presence of BRAF mutations in ctDNA analysis was associated with a higher number of metastatic sites, higher serum LDH levels or S100 protein concentration, and shorter OS.	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (64, 68))	('higher', 'PosReg', (154, 160))	('S100', 'Gene', (181, 185))	('higher', 'PosReg', (119, 125))	('ctDNA', 'Gene', (82, 87))	('serum LDH levels', 'MPA', (161, 177))	('S100', 'Gene', '6271', (181, 185))
405688	32010431	In patients with BRAF V600E/V600K-positive tumors enrolled in 4 different studies of dabrafenib or trametinib, ctDNA analysis identified BRAF V600E and BRAF V600K mutations in 76% and 81% of 732 patients, respectively.	('BRAF', 'Gene', (152, 156))	('V600E', 'Var', (142, 147))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('V600K', 'Mutation', 'rs121913227', (28, 33))	('V600E', 'SUBSTITUTION', 'None', (142, 147))	('patients', 'Species', '9606', (195, 203))	('V600E', 'Var', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('trametinib', 'Chemical', 'MESH:C560077', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('patients', 'Species', '9606', (3, 11))	('dabrafenib', 'Chemical', 'MESH:C561627', (85, 95))	('V600E', 'SUBSTITUTION', 'None', (22, 27))	('tumors', 'Disease', (43, 49))	('V600E', 'Mutation', 'rs113488022', (142, 147))	('BRAF', 'Gene', '673', (17, 21))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (152, 156))	('V600K', 'Mutation', 'rs121913227', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
405689	32010431	Patients with undetectable ctDNA BRAF mutations at baseline had higher rates of response, PFS, and OS than those with ctDNA BRAF mutations.	('BRAF', 'Gene', '673', (33, 37))	('response', 'MPA', (80, 88))	('PFS', 'Disease', (90, 93))	('higher', 'PosReg', (64, 70))	('BRAF', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (124, 128))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (38, 47))	('BRAF', 'Gene', (124, 128))
405690	32010431	Circulating BRAF mutations have been identified in some patients prior to clinical evidence of disease progression.	('patients', 'Species', '9606', (56, 64))	('BRAF', 'Gene', '673', (12, 16))	('mutations', 'Var', (17, 26))	('BRAF', 'Gene', (12, 16))
405691	32010431	In patients with melanoma who received adoptive transfer of activated autologous TILs, ctDNA analysis for BRAF V600E (n = 48, 388 serum samples) demonstrated a strong correlation between an early peak of circulating V600E mutation and objective response.	('BRAF', 'Gene', '673', (106, 110))	('V600E', 'Mutation', 'rs113488022', (216, 221))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('BRAF', 'Gene', (106, 110))	('melanoma', 'Disease', (17, 25))	('patients', 'Species', '9606', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('V600E', 'Var', (216, 221))	('objective response', 'CPA', (235, 253))	('V600E', 'Mutation', 'rs113488022', (111, 116))
405695	32010431	In the post-surgical setting, ctDNA analysis of BRAF and NRAS mutations predicted OS in 161 patients with high-risk stage II/III melanoma who underwent surgical resection followed by adjuvant bevacizumab for 1 year.	('NRAS', 'Gene', '4893', (57, 61))	('predicted', 'Reg', (72, 81))	('NRAS', 'Gene', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('patients', 'Species', '9606', (92, 100))	('III melanoma', 'Disease', (125, 137))	('III melanoma', 'Disease', 'MESH:D008545', (125, 137))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('mutations', 'Var', (62, 71))
405704	32010431	In patients with localized or metastatic Ewing sarcoma (EWS), copy numbers of the EWSR1 fusion sequence in plasma were associated with tumor volume.	('Ewing sarcoma', 'Disease', 'MESH:D012512', (41, 54))	('EWS', 'Gene', '2130', (56, 59))	('EWS', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Ewing sarcoma', 'Disease', (41, 54))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('localized', 'Disease', (17, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (41, 54))	('patients', 'Species', '9606', (3, 11))	('EWS', 'Gene', '2130', (82, 85))	('EWS', 'Gene', (82, 85))	('EWSR1', 'Gene', (82, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('copy numbers', 'Var', (62, 74))	('EWSR1', 'Gene', '2130', (82, 87))	('associated', 'Reg', (119, 129))
405710	32010431	In patients with gastrointestinal stromal tumors (GIST), ctDNA harboring CKIT or PDGFRA was used as a tumor-specific biomarker and the amount of mutant-free circulating DNA was correlated with disease course.	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (17, 48))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (17, 48))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (42, 47))	('CKIT', 'Gene', (73, 77))	('correlated', 'Reg', (177, 187))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('GIST', 'Disease', (50, 54))	('CKIT', 'Gene', '3815', (73, 77))	('mutant-free', 'Var', (145, 156))	('gastrointestinal stromal tumors', 'Disease', (17, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('GIST', 'Disease', 'MESH:D046152', (50, 54))	('patients', 'Species', '9606', (3, 11))	('PDGFRA', 'Gene', (81, 87))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('PDGFRA', 'Gene', '5156', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (102, 107))
405711	32010431	In patients with TKI-refractory GIST treated with dovitinib, genotyping of the KIT gene in exon 17 of serum ctDNA using beads, emulsions, amplification, and magnetics assays identified mutations associated with disease resistance.	('disease resistance', 'Disease', (211, 229))	('associated with', 'Reg', (195, 210))	('GIST', 'Disease', 'MESH:D046152', (32, 36))	('patients', 'Species', '9606', (3, 11))	('GIST', 'Disease', (32, 36))	('KIT', 'Gene', '3815', (79, 82))	('mutations', 'Var', (185, 194))	('KIT', 'Gene', (79, 82))
405712	32010431	Other investigators suggested that detection of secondary C-KIT mutations in ctDNA may improve the selection of targeted agents.	('C-KIT', 'Gene', '3815', (58, 63))	('improve', 'PosReg', (87, 94))	('mutations', 'Var', (64, 73))	('C-KIT', 'Gene', (58, 63))
405715	32010431	In patients with glioblastoma multiforme (GBM), ctDNA analysis identified the EGFRvIII deletion in 3 of 13 patients, which was correlated with tumor tissue analysis.	('tumor', 'Disease', (143, 148))	('GBM', 'Disease', (42, 45))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (17, 40))	('glioblastoma multiforme', 'Disease', (17, 40))	('GBM', 'Disease', 'MESH:D005909', (42, 45))	('EGFRvIII', 'Gene', (78, 86))	('patients', 'Species', '9606', (3, 11))	('glioblastoma', 'Phenotype', 'HP:0012174', (17, 29))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('deletion', 'Var', (87, 95))	('patients', 'Species', '9606', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
405720	32010431	In patients with glioma, the IDH1 R132H mutation was identified in plasma with a specificity of 100% and sensitivity related to the tumor volume and contrast enhancement, suggesting that it may help in the diagnosis of patients not amenable to biopsy.	('men', 'Species', '9606', (165, 168))	('R132H', 'Mutation', 'rs121913500', (34, 39))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('IDH1', 'Gene', (29, 33))	('help', 'Reg', (194, 198))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('IDH1', 'Gene', '3417', (29, 33))	('tumor', 'Disease', (132, 137))	('patients', 'Species', '9606', (3, 11))	('glioma', 'Disease', (17, 23))	('patients', 'Species', '9606', (219, 227))	('men', 'Species', '9606', (233, 236))	('R132H', 'Var', (34, 39))
405721	32010431	In patients with classical Hodgkin lymphoma, an XPO1 mutation detected using ctDNA analysis at the end of treatment was associated with a tendency toward shorter PFS compared to patients without the mutation, suggesting that plasma ctDNA may be clinically useful for the noninvasive management of this disease.	('mutation', 'Var', (53, 61))	('Hodgkin lymphoma', 'Disease', (27, 43))	('men', 'Species', '9606', (111, 114))	('men', 'Species', '9606', (289, 292))	('patients', 'Species', '9606', (178, 186))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (27, 43))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (27, 43))	('patients', 'Species', '9606', (3, 11))	('XPO1', 'Gene', '7514', (48, 52))	('XPO1', 'Gene', (48, 52))	('PFS', 'MPA', (162, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (35, 43))	('shorter', 'NegReg', (154, 161))
405729	32010431	Overall, 88% of patients with MYD88 L265P in tissue had an identifiable L265P variant in their ctDNA and OS was not significantly correlated with mutations detected in ctDNA.	('L265P', 'Mutation', 'rs387907272', (36, 41))	('L265P', 'Var', (72, 77))	('patients', 'Species', '9606', (16, 24))	('L265P', 'Var', (36, 41))	('L265P', 'Mutation', 'rs387907272', (72, 77))	('MYD88', 'Gene', '4615', (30, 35))	('MYD88', 'Gene', (30, 35))
405731	32010431	In an analysis of 105 patients using the Sequenom MassArray System and OncoCarta panel for somatic mutations, the ctDNA concentration was 3 times higher in patients with advanced cancer compared to healthy volunteers.	('higher', 'PosReg', (146, 152))	('patients', 'Species', '9606', (156, 164))	('ctDNA concentration', 'MPA', (114, 133))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (99, 108))
405732	32010431	Although the concordance between matched ctDNA and archival tumor tissue was high for selected 'hot-spot' mutations (KRAS, BRAF, PIK3CA), some differences were noted between archival tumor and ctDNA.	('PIK3CA', 'Gene', (129, 135))	('concordance', 'MPA', (13, 24))	('KRAS', 'Var', (117, 121))	('BRAF', 'Gene', (123, 127))	('archival tumor', 'Disease', 'MESH:D009369', (174, 188))	('BRAF', 'Gene', '673', (123, 127))	('PIK3CA', 'Gene', '5290', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('archival tumor', 'Disease', 'MESH:D009369', (51, 65))	('archival tumor', 'Disease', (174, 188))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('archival tumor', 'Disease', (51, 65))
405735	32010431	These rates were 91%, 99%, 83%, and 91% for BRAF, EGFR, KRAS, and PIK3CA mutations, respectively.	('BRAF', 'Gene', '673', (44, 48))	('KRAS', 'Gene', (56, 60))	('BRAF', 'Gene', (44, 48))	('PIK3CA', 'Gene', (66, 72))	('EGFR', 'Gene', (50, 54))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutations', 'Var', (73, 82))
405736	32010431	Patients with >1% of KRAS mutant ctDNA had shorter OS compared to those with <=1% of KRAS mutant ctDNA (4.8 vs. 7.3 months, p = 0.008).	('Patients', 'Species', '9606', (0, 8))	('KRAS mutant', 'Var', (21, 32))	('shorter', 'NegReg', (43, 50))
405737	32010431	Patients with >1% of mutant ctDNA (BRAF, EGFR, KRAS, or PIK3CA) had shorter OS compared to those with <=1% of mutant ctDNA (5.5 vs. 9.8 months, p = 0.001).	('BRAF', 'Gene', (35, 39))	('mutant', 'Var', (21, 27))	('PIK3CA', 'Gene', '5290', (56, 62))	('PIK3CA', 'Gene', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('ctDNA', 'Gene', (28, 33))	('BRAF', 'Gene', '673', (35, 39))
405742	32010431	In metastatic CRC (n = 206), ctDNA analysis for KRAS mutation was associated with high sensitivity (87.2%) and specificity (99.2%).	('CRC', 'Disease', 'MESH:D015179', (14, 17))	('KRAS', 'Gene', (48, 52))	('mutation', 'Var', (53, 61))	('CRC', 'Disease', (14, 17))
405743	32010431	ctDNA analysis to assess resistance mechanisms to anti-EGFR treatment in patients with CRC demonstrated that 96% (23/24) of patients developed >=1 mutation in genes involved in the mitogen-activated protein kinase pathway.	('CRC', 'Disease', (87, 90))	('developed', 'Reg', (133, 142))	('men', 'Species', '9606', (65, 68))	('mutation', 'Var', (147, 155))	('CRC', 'Disease', 'MESH:D015179', (87, 90))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (124, 132))
405744	32010431	In a study of clonal evolution, exome sequencing of ctDNA using serial plasma from 6 patients with breast, ovarian, or lung cancer demonstrated that emergence of resistance was associated with increased mutant allele fractions, and an activating PIK3CA mutation was noted after treatment with paclitaxel.	('activating', 'PosReg', (235, 245))	('mutant', 'Var', (203, 209))	('PIK3CA', 'Gene', '5290', (246, 252))	('mutation', 'Var', (253, 261))	('breast, ovarian, or lung cancer', 'Disease', 'MESH:D061325', (99, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('paclitaxel', 'Chemical', 'MESH:D017239', (293, 303))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (85, 93))	('increased', 'PosReg', (193, 202))	('men', 'Species', '9606', (283, 286))	('PIK3CA', 'Gene', (246, 252))
405746	32010431	Other investigators used NGS to analyze 54 genes and copy number variants in three genes (EGFR, ERBB2 and MET) on ctDNA of patients with various tumor types.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('MET', 'Gene', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', (145, 150))	('EGFR', 'Gene', (90, 94))	('ERBB2', 'Gene', (96, 101))	('ERBB2', 'Gene', '2064', (96, 101))	('copy number variants', 'Var', (53, 73))
405757	32010431	The discordance between ctDNA analysis and tumor tissue genomic analysis is attributed, at least in part, to biologic and technical differences in detection of alterations between DNA shed by the tumor in the circulatory system and DNA in tumor tissue.	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('alterations', 'Var', (160, 171))	('tumor in the circulatory system', 'Phenotype', 'HP:0100006', (196, 227))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
405778	28619757	Deregulation of the cell cycle is one of the hallmarks of cancer, and may be a reasonable target for the development of new therapies in sarcoma.	('cell cycle', 'CPA', (20, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Deregulation', 'Var', (0, 12))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('sarcoma', 'Disease', (137, 144))
405788	28619757	High expression of CDK4 has also been associated with a poor prognosis in these patients.	('patients', 'Species', '9606', (80, 88))	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('CDK4', 'Gene', (19, 23))	('CDK4', 'Gene', '1019', (19, 23))
405793	28619757	One such G2/M target, Wee1 kinase, is a key regulator of the G2/M checkpoint, through inhibitory phosphorylation of CDK1, preventing progression of cells with DNA damage into mitosis.	('preventing', 'NegReg', (122, 132))	('CDK1', 'Gene', '983', (116, 120))	('progression', 'MPA', (133, 144))	('CDK1', 'Gene', (116, 120))	('mitosis', 'Disease', (175, 182))	('Wee1', 'Gene', (22, 26))	('mitosis', 'Disease', 'None', (175, 182))	('inhibitory', 'Var', (86, 96))	('Wee1', 'Gene', '7465', (22, 26))
405795	28619757	In this report, we tested the hypothesis that palbociclib-induced G1 arrest and subsequent release primes the cells to respond to agents that are active maximally in S/G2 phase such as Wee1 kinase inhibitors.	('Wee1', 'Gene', (185, 189))	('tested', 'Reg', (19, 25))	('S/G2', 'Var', (166, 170))	('Wee1', 'Gene', '7465', (185, 189))	('S/G2', 'SUBSTITUTION', 'None', (166, 170))	('respond', 'MPA', (119, 126))	('palbociclib', 'Chemical', 'MESH:C500026', (46, 57))	('G1 arrest', 'CPA', (66, 75))
405808	28619757	The Rb shRNAs used were V3LHS_340825 and V3LHS_340827 (Dharmacon) and the non-targeting control was Cat#- RHS 4346, sense sequence-CTCGCTTGGGCGAGAGTAA (Open Biosystems).	('V3LHS_340827', 'Var', (41, 53))	('Rb', 'Gene', '5925', (4, 6))	('V3LHS_340825', 'Var', (24, 36))
405841	28619757	Since CDK4/6 inhibitors have been shown to be largely cytostatic due to causing G1 cell cycle arrest, in aggressive malignancies such as sarcomas, combination treatments with other agents are likely needed for significant tumor response.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('causing', 'Reg', (72, 79))	('aggressive malignancies', 'Disease', (105, 128))	('sarcomas', 'Disease', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('inhibitors', 'Var', (13, 23))	('aggressive malignancies', 'Disease', 'MESH:D009369', (105, 128))	('sarcomas', 'Disease', 'MESH:D012509', (137, 145))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('G1 cell cycle arrest', 'CPA', (80, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('CDK4/6', 'Gene', (6, 12))
405842	28619757	We hypothesized that inducing a reversible G1 arrest with CDK4/6 inhibitors, then allowing recovery and re-entry into the cell cycle, may prime cells for sensitivity to agents that preferentially act during S or G2 phase, such as DNA damaging chemotherapy or Wee1 kinase inhibitors.	('inducing', 'Reg', (21, 29))	('recovery', 'MPA', (91, 99))	('Wee1', 'Gene', '7465', (259, 263))	('Wee1', 'Gene', (259, 263))	('inhibitors', 'Var', (65, 75))	('CDK4/6', 'Gene', (58, 64))
405845	28619757	It is well-established that palbociclib induces a G1 arrest with concomitant S phase reduction in many cancer cell lines by continuous inhibition of CDK4/6 over several population doubling times.	('S phase', 'MPA', (77, 84))	('inhibition', 'NegReg', (135, 145))	('G1 arrest', 'MPA', (50, 59))	('induces', 'Reg', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CDK4/6', 'Protein', (149, 155))	('palbociclib', 'Chemical', 'MESH:C500026', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('reduction', 'NegReg', (85, 94))	('cancer', 'Disease', (103, 109))	('palbociclib', 'Var', (28, 39))
405858	28619757	To determine the requirement for Rb in mediating G1 arrest, we also examined the cell cycle profiles following 6 days of treatment, and found that Rb knockdown cells had moderately less G1 arrest than the control cells (Figure 3E).	('G1 arrest', 'CPA', (186, 195))	('knockdown', 'Var', (150, 159))	('less', 'NegReg', (181, 185))	('Rb', 'Gene', '5925', (147, 149))	('Rb', 'Gene', '5925', (33, 35))
405862	28619757	Combination treatment with palbociclib followed by doxorubicin (Figure 4A) and palbociclib followed by AZD1775 (Figure 4B) resulted in synergistic activity of the combination in SK-LMS1 and HT-1080 cells, but not in Rb-deficient RD and SaOS2 cells (compare blue to red bars in Figure 4A and 4B).	('synergistic activity', 'MPA', (135, 155))	('palbociclib', 'Chemical', 'MESH:C500026', (27, 38))	('palbociclib', 'Chemical', 'MESH:C500026', (79, 90))	('AZD1775', 'Var', (103, 110))	('HT-1080', 'CellLine', 'CVCL:0317', (190, 197))	('AZD1775', 'Chemical', 'MESH:C549567', (103, 110))	('SK-LMS1', 'CellLine', 'CVCL:0628', (178, 185))	('palbociclib', 'Var', (79, 90))	('Rb', 'Gene', '5925', (216, 218))	('doxorubicin', 'Chemical', 'MESH:D004317', (51, 62))
405867	28619757	We treated the Rb shRNA SK-LMS1 cells with the combination of palbociclib and AZD1775 and results showed that once Rb is knocked down, the combination treatment did not result in synergistic activity (Supplemental Figure 4).	('AZD1775', 'Chemical', 'MESH:C549567', (78, 85))	('palbociclib', 'Chemical', 'MESH:C500026', (62, 73))	('Rb', 'Gene', '5925', (115, 117))	('Rb', 'Gene', '5925', (15, 17))	('synergistic activity', 'MPA', (179, 199))	('knocked down', 'Var', (121, 133))	('SK-LMS1', 'CellLine', 'CVCL:0628', (24, 31))
405891	28619757	These in vivo studies with cell line xenografts suggest that sequential treatment with palbociclib, followed by a period of recovery and then treatment with AZD1775 leads to synergistic inhibition of tumor growth.	('AZD1775', 'Var', (157, 164))	('AZD1775', 'Chemical', 'MESH:C549567', (157, 164))	('inhibition', 'NegReg', (186, 196))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('palbociclib', 'Chemical', 'MESH:C500026', (87, 98))	('tumor growth', 'Disease', (200, 212))	('tumor growth', 'Disease', 'MESH:D006130', (200, 212))
405908	28619757	This sequential regimen synchronizes cells in vitro and in vivo to accumulate in G1 phase by treatment with a selective CDK4/6 inhibitor, followed by a period of recovery that allows cells to re-enter the cell cycle where they are more sensitive to subsequent treatment with agents that are active in S phase such as doxorubicin or AZD1775.	('AZD1775', 'Var', (332, 339))	('AZD1775', 'Chemical', 'MESH:C549567', (332, 339))	('CDK4/6', 'Gene', (120, 126))	('cell cycle', 'CPA', (205, 215))	('doxorubicin', 'Chemical', 'MESH:D004317', (317, 328))
405912	28619757	Beyond direct hyperactivation of this growth-promoting pathway through amplification of kinases such as CDK4 in liposarcoma and rhabdomyosarcoma, cyclin D1 may be overexpressed in various subtypes due to oncogenic activation by several transcription factors.	('cyclin D1', 'Gene', (146, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('amplification', 'Var', (71, 84))	('overexpressed', 'PosReg', (163, 176))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (128, 144))	('liposarcoma', 'Phenotype', 'HP:0012034', (112, 123))	('liposarcoma and rhabdomyosarcoma', 'Disease', 'MESH:D012208', (112, 144))	('CDK4', 'Gene', (104, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('cyclin D1', 'Gene', '595', (146, 155))	('CDK4', 'Gene', '1019', (104, 108))
405913	28619757	For example, in synovial sarcoma the histology-defining fusion chromosome (X;18) creating fusions such as SS18-SSX, results in nuclear expression of beta-catenin leading to upregulation of cyclin D1.	('SSX', 'Gene', (111, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (16, 32))	('upregulation', 'PosReg', (173, 185))	('beta-catenin', 'Gene', (149, 161))	('nuclear expression', 'MPA', (127, 145))	('SSX', 'Gene', '727837', (111, 114))	('synovial sarcoma', 'Disease', 'MESH:D013584', (16, 32))	('beta-catenin', 'Gene', '1499', (149, 161))	('fusions', 'Var', (90, 97))	('synovial sarcoma', 'Disease', (16, 32))	('cyclin D1', 'Gene', (189, 198))	('cyclin D1', 'Gene', '595', (189, 198))
405920	28619757	Our work strongly implicates Rb as a biomarker for CDK4/6 inhibitor combinations, similar to data from other cancer types such as breast cancer and glioblastoma.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('breast cancer', 'Disease', (130, 143))	('Rb', 'Gene', '5925', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('combinations', 'Var', (68, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('glioblastoma', 'Disease', (148, 160))	('implicates', 'Reg', (18, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (148, 160))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
405921	28619757	The frequency of Rb positivity within sarcoma appears to differ among histologic subtypes, and not be universally expressed in any subtype.	('positivity', 'Var', (20, 30))	('sarcoma', 'Disease', (38, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('differ', 'Reg', (57, 63))	('Rb', 'Gene', '5925', (17, 19))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))
405924	28619757	Osteosarcoma, the most common childhood sarcoma, also may be a good candidate for this therapy, as 50% are Rb positive, and p16 is frequently hypermethylated.	('p16', 'Gene', '1029', (124, 127))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('sarcoma', 'Disease', (40, 47))	('Osteosarcoma', 'Disease', (0, 12))	('p16', 'Gene', (124, 127))	('sarcoma', 'Disease', (5, 12))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('hypermethylated', 'Var', (142, 157))	('Rb', 'Gene', '5925', (107, 109))
405927	28619757	In one preclinical study using a different CDK4/6 inhibitor (LEE011), CDK4 amplification in rhabdomyosarcoma was shown to be a biomarker of resistance due to inability to activate the G1 checkpoint and induce G1 arrest.	('CDK4', 'Gene', '1019', (70, 74))	('CDK4', 'Gene', (70, 74))	('induce', 'Reg', (202, 208))	('LEE011', 'Chemical', 'MESH:C000589651', (61, 67))	('rhabdomyosarcoma', 'Disease', (92, 108))	('CDK4', 'Gene', (43, 47))	('G1 arrest', 'CPA', (209, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('amplification', 'Var', (75, 88))	('CDK4', 'Gene', '1019', (43, 47))	('inability', 'NegReg', (158, 167))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (92, 108))	('G1 checkpoint', 'Pathway', (184, 197))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (92, 108))
405928	28619757	However, another recent study showed that in other soft tissue sarcomas (cell lines and PDXs), those with high levels of CDK4 were more sensitive compared to low-expressing tumors.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (51, 71))	('high levels', 'Var', (106, 117))	('CDK4', 'Gene', '1019', (121, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('soft tissue sarcomas', 'Disease', (51, 71))	('sensitive', 'MPA', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (51, 71))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (51, 70))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('CDK4', 'Gene', (121, 125))
405930	28619757	In mice it has recently been shown that CDK4/6 inhibition protected normal intestinal epithelium from radiation-induced damage, through the inhibition of radiation-induced p53 activation.	('inhibition', 'Var', (47, 57))	('mice', 'Species', '10090', (3, 7))	('CDK4/6', 'Protein', (40, 46))	('inhibition', 'NegReg', (140, 150))	('p53', 'Protein', (172, 175))	('activation', 'PosReg', (176, 186))
405933	28619757	Indeed, in a large screen of PDX models, LEE011 (Novartis CDK4/6 inhibitor) synergized with several different signal transduction pathway targeting agents, based on the premise that targeting a single pathway more potently leads to more resistance.	('LEE011', 'Chemical', 'MESH:C000589651', (41, 47))	('LEE011', 'Var', (41, 47))	('resistance', 'MPA', (237, 247))	('leads to', 'Reg', (223, 231))
405937	28619757	Our group has previously identified that CDK1/2 inhibition prior to doxorubicin selectively targets triple-negative breast cancer cells for DNA-damage-induced cell death in a mutant p53-dependent manner, through CDK1-mediated inhibition of DNA repair.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('doxorubicin', 'Chemical', 'MESH:D004317', (68, 79))	('CDK1', 'Gene', '983', (212, 216))	('p53-dependent', 'Gene', (182, 195))	('CDK1', 'Gene', (212, 216))	('CDK1', 'Gene', '983', (41, 45))	('CDK1', 'Gene', (41, 45))	('DNA repair', 'Enzyme', (240, 250))	('inhibition', 'NegReg', (226, 236))	('inhibition', 'NegReg', (48, 58))	('mutant', 'Var', (175, 181))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
405984	29046788	Certain sarcoma cases that may occur in the sinonasal tracts harbor MDM2 amplifications in alveolar rhabdomyosarcoma (11%), anaplastic embryonal rhabdomyosarcoma (14%), leiomyosarcoma, malignant peripheral nerve sheath tumors (20%), synovial sarcoma (33%), pleomorphic liposarcoma (33%) and myxofibrosarcoma (33%).	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (185, 225))	('liposarcoma', 'Phenotype', 'HP:0012034', (269, 280))	('sarcoma', 'Disease', (300, 307))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (100, 116))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('MDM2', 'Gene', (68, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('amplifications', 'Var', (73, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (233, 249))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (295, 307))	('sarcoma', 'Disease', (109, 116))	('alveolar rhabdomyosarcoma', 'Disease', (91, 116))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (185, 225))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (169, 183))	('sarcoma', 'Disease', 'MESH:D012509', (242, 249))	('pleomorphic liposarcoma', 'Disease', (257, 280))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (135, 161))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('sarcoma', 'Disease', (242, 249))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (169, 183))	('malignant peripheral nerve sheath tumors', 'Disease', (185, 225))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (154, 161))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (91, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('myxofibrosarcoma', 'Disease', 'None', (291, 307))	('embryonal rhabdomyosarcoma', 'Disease', (135, 161))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (91, 116))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (257, 280))	('sarcoma', 'Disease', 'MESH:D012509', (273, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('sarcoma', 'Disease', (273, 280))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (145, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('leiomyosarcoma', 'Disease', (169, 183))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (135, 161))	('synovial sarcoma', 'Disease', (233, 249))	('sarcoma', 'Disease', (176, 183))	('sarcoma', 'Disease', (8, 15))	('sarcoma', 'Disease', 'MESH:D012509', (300, 307))	('synovial sarcoma', 'Disease', 'MESH:D013584', (233, 249))	('myxofibrosarcoma', 'Disease', (291, 307))
406052	28684728	In general, CK5/6 and p63 are markers of squamous cell carcinoma, whereas SP-A and TTF-1 are markers of adenocarcinoma.	('p63', 'Gene', '8626', (22, 25))	('squamous cell carcinoma', 'Disease', (41, 64))	('TTF', 'Gene', '399', (83, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('p63', 'Gene', (22, 25))	('TTF', 'Gene', (83, 86))	('adenocarcinoma', 'Disease', (104, 118))	('CK5/6', 'Var', (12, 17))	('SP-A', 'Gene', (74, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (104, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
406062	28684728	In a study by Ro et al., a tumor size of >5 cm, a clinical stage of >I, metastasis, associated genetic mutation (K-Ras or p53 mutation), and lymph node involvement significantly shortened patient survival.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('metastasis', 'CPA', (72, 82))	('shortened', 'NegReg', (178, 187))	('patient', 'Species', '9606', (188, 195))	('tumor', 'Disease', (27, 32))	('men', 'Species', '9606', (159, 162))	('p53', 'Gene', '7157', (122, 125))	('K-Ras', 'Var', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patient survival', 'CPA', (188, 204))	('p53', 'Gene', (122, 125))
406151	24986479	Interphase FISH was performed using a WWTR1-CAMTA1 fusion probe (BACs RP11-1120, RP11-980).	('CAMTA1', 'Gene', (44, 50))	('RP11-980', 'Var', (81, 89))	('CAMTA1', 'Gene', '23261', (44, 50))	('WWTR1', 'Gene', (38, 43))	('WWTR1', 'Gene', '25937', (38, 43))
406156	24986479	The cDNA was tested by the reverse transcription-polymerase chain reaction (RT-PCR) for the HMBS (hydroxymethylbilase synthase) housekeeping gene using the primers forw150 5'-TGCCAGAGAAGAGTGTGGTG-3', rev150 5'-ATGATGGCACTGAACTCCTG-3', forw250 5'- CTGGTAACGGCAATGCGGCT-3', rev250 5'- TTCTTCTCCAGGGCATGTTC-3'.	('HMBS', 'Gene', '3145', (92, 96))	('hydroxymethylbilase synthase', 'Gene', (98, 126))	('hydroxymethylbilase synthase', 'Gene', '3145', (98, 126))	("rev250 5'- TTCTTCTCCAGGGCATGTTC-3", 'Var', (272, 305))	('HMBS', 'Gene', (92, 96))
406202	24986479	Several fusion-transcript variants for WWTR1-CAMTA1 were found: exon 4-exon 8 in 13 cases (Figure 8), exon 4-exon 9 in 7 cases and exon 3-exon 9 in 3 cases.	('CAMTA1', 'Gene', '23261', (45, 51))	('exon 4-exon 8', 'Var', (64, 77))	('WWTR1', 'Gene', (39, 44))	('exon 4-exon 9', 'Var', (102, 115))	('WWTR1', 'Gene', '25937', (39, 44))	('CAMTA1', 'Gene', (45, 51))	('exon 3-exon', 'Var', (131, 142))
406204	24986479	Similar to other translocation associated tumors, the t (1;3)(p36;q23-25) or t(11;X)(q13;p11) translocations are seemingly early causative events in EHE oncogenesis which initiate a novel transcription program in cells with endothelial properties.	('translocations', 'Var', (94, 108))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('p36', 'Gene', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('p36', 'Gene', '51251', (62, 65))	('t(11;X)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (77, 93))	('EHE', 'Phenotype', 'HP:0032060', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
406218	24986479	Interestingly, these 2 cases involved adolescents/young adults in concert with the finding of young age reported by Antonescu et al.. TFE3 rearrangements are also present in alveolar soft part sarcoma, certain pediatric renal cancers and a subset of PEComas.	('PEComas', 'Disease', 'MESH:D054973', (250, 257))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (174, 200))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (183, 200))	('TFE3', 'Gene', (134, 138))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('pediatric renal cancers', 'Disease', (210, 233))	('present', 'Reg', (163, 170))	('rearrangements', 'Var', (139, 153))	('PEComas', 'Disease', (250, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (174, 200))	('TFE3', 'Gene', '7030', (134, 138))	('alveolar soft part sarcoma', 'Disease', (174, 200))	('pediatric renal cancers', 'Disease', 'MESH:D007680', (210, 233))
406242	24986479	EWSR1 and PLAG rearrangements are characteristic genetic changes in myoepithelial tumors.	('PLAG', 'Gene', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (68, 88))	('EWSR1', 'Gene', '2130', (0, 5))	('myoepithelial tumors', 'Disease', (68, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('rearrangements', 'Var', (15, 29))	('EWSR1', 'Gene', (0, 5))
406246	24986479	NR4A3 rearrangement is a pathognomonic genetic aberration.	('NR4A3', 'Gene', '8013', (0, 5))	('rearrangement', 'Var', (6, 19))	('NR4A3', 'Gene', (0, 5))
406337	24204583	Comparatively, various OIs exhibited a higher prevalence in patients with CD4 fewer than 200cells/ul (p<0.05).	('OIs', 'Phenotype', 'HP:0031690', (23, 26))	('fewer than 200cells/ul', 'Var', (78, 100))	('patients', 'Species', '9606', (60, 68))	('CD4', 'Gene', (74, 77))	('OIs', 'Disease', (23, 26))	('CD4', 'Gene', '920', (74, 77))
406390	24204583	Most of CMV infection, especially CMV related end-organ diseases, occurred in HIV-infected patients with immune suppression, typically in those with CD4 count less than 50cells/ul.	('CMV infection', 'Disease', (8, 21))	('occurred', 'Reg', (66, 74))	('HIV-infected', 'Disease', 'MESH:D015658', (78, 90))	('CMV infection', 'Disease', 'MESH:D007239', (8, 21))	('patients', 'Species', '9606', (91, 99))	('CD4', 'Gene', (149, 152))	('less than 50cells/ul', 'Var', (159, 179))	('CD4', 'Gene', '920', (149, 152))	('HIV-infected', 'Disease', (78, 90))
406397	24204583	We found that penicilliosis was mainly diagnosed in patients from southern or southwestern China, and most cases of penicilliosis were observed in patients who had CD4 cell counts less than 100cells/ul(mean CD4 cell counts was 49.1cells/ul), This will increase the awareness of physicians to establish diagnosis and perform treatment of penicilliosis in patients with less than 100cells/ul from southern or southwestern China.	('CD4', 'Gene', '920', (164, 167))	('penicilliosis', 'Disease', (337, 350))	('penicilliosis', 'Disease', (14, 27))	('penicilliosis', 'Disease', 'MESH:C000656865', (116, 129))	('patients', 'Species', '9606', (147, 155))	('CD4', 'Gene', (207, 210))	('penicilliosis', 'Disease', (116, 129))	('penicilliosis', 'Disease', 'MESH:C000656865', (14, 27))	('less', 'Var', (180, 184))	('men', 'Species', '9606', (329, 332))	('patients', 'Species', '9606', (354, 362))	('CD4', 'Gene', '920', (207, 210))	('penicilliosis', 'Disease', 'MESH:C000656865', (337, 350))	('patients', 'Species', '9606', (52, 60))	('CD4', 'Gene', (164, 167))
406401	24204583	In this study, PCP was diagnosed based on characteristic clinical presentation, thin-section computerized tomography scan and histopathological demonstration pneumocystis jirovecii in BALF, but not on elevated serum (1,3)-ss-D-glucan while other fungal infection was diagnosed based on systemic symptoms and (1,3)-ss-D-Glucan >100pg/ml.	('pneumocystis jirovecii', 'Species', '42068', (158, 180))	('(1,3)-ss-D-glucan', 'Chemical', '-', (216, 233))	('(1,3)-ss-D-Glucan', 'Chemical', '-', (308, 325))	('fungal infection', 'Disease', 'MESH:D009181', (246, 262))	('PCP', 'Phenotype', 'HP:0020102', (15, 18))	('PCP', 'Disease', (15, 18))	('pneumocystis', 'Var', (158, 170))	('fungal infection', 'Disease', (246, 262))
406482	20602757	Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor- and N-methyl-D-aspartate (NMDA) receptor-mediated EPSCs evoked by focal stimulation were also enhanced in cancer-bearing mice.	('AMPA', 'Chemical', 'MESH:D018350', (58, 62))	('mice', 'Species', '10090', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Cs', 'Chemical', 'MESH:D002586', (127, 129))	('NMDA', 'Chemical', 'MESH:D016202', (100, 104))	('enhanced', 'PosReg', (168, 176))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('focal', 'Var', (140, 145))	('cancer', 'Disease', (180, 186))
406491	20602757	Implantation of cancer cells within the femur or tibia induces ongoing pain-related behaviors such as licking and flinching of the ipsilateral hind limb following bone destruction associated with injuries of the primary afferent fibers innervating the cancer-bearing bones.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (252, 258))	('licking', 'CPA', (102, 109))	('induces', 'PosReg', (55, 62))	('cancer', 'Disease', (16, 22))	('pain', 'Phenotype', 'HP:0012531', (71, 75))	('pain', 'Disease', 'MESH:D010146', (71, 75))	('pain', 'Disease', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('ongoing pain', 'Phenotype', 'HP:0012532', (63, 75))	('bone destruction', 'Phenotype', 'HP:0002797', (163, 179))	('injuries', 'Var', (196, 204))
406568	20602757	An increased astrogliosis in the spinal cord segments of T10-S1 has been also shown in mice bearing cancer in the femur.	('increased', 'PosReg', (3, 12))	('gliosis', 'Phenotype', 'HP:0002171', (18, 25))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('T10-S1', 'Var', (57, 63))	('gliosis', 'Disease', 'MESH:D005911', (18, 25))	('mice', 'Species', '10090', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('gliosis', 'Disease', (18, 25))	('increased astrogliosis', 'Phenotype', 'HP:0002446', (3, 25))
406580	20602757	Such changes in subunit composition of AMPA receptors are known to alter the kinetics of the synaptic currents.	('alter', 'Reg', (67, 72))	('AMPA', 'Protein', (39, 43))	('changes', 'Var', (5, 12))	('kinetics of', 'MPA', (77, 88))	('synaptic currents', 'MPA', (93, 110))	('AMPA', 'Chemical', 'MESH:D018350', (39, 43))
406585	20602757	Previous studies have shown that changes in spinal NMDA receptors are involved in the development of bone cancer pain.	('bone cancer pain', 'Disease', 'MESH:D001859', (101, 117))	('bone cancer pain', 'Disease', (101, 117))	('bone cancer pain', 'Phenotype', 'HP:0002653', (101, 117))	('changes', 'Var', (33, 40))	('NMDA', 'Chemical', 'MESH:D016202', (51, 55))	('pain', 'Phenotype', 'HP:0012531', (113, 117))	('involved', 'Reg', (70, 78))	('spinal NMDA receptors', 'Protein', (44, 65))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
406641	32770123	EWSR1/FUS-CREB Fusions Define a Distinctive Malignant Epithelioid Neoplasm with Predilection for Mesothelial-Lined Cavities Gene fusions constitute pivotal driver mutations often encoding aberrant chimeric transcription factors.	('Malignant Epithelioid Neoplasm', 'Disease', (44, 74))	('EWSR1', 'Gene', '2130', (0, 5))	('CREB', 'Gene', (10, 14))	('fusions', 'Var', (129, 136))	('FUS', 'Gene', (6, 9))	('CREB', 'Gene', '1385', (10, 14))	('EWSR1', 'Gene', (0, 5))	('Neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('FUS', 'Gene', '2521', (6, 9))	('Malignant Epithelioid Neoplasm', 'Disease', 'MESH:D009369', (44, 74))
406643	32770123	One such remarkable example of chromosomal translocation promiscuity is represented by fusions between EWSR1 or FUS with genes encoding for CREB-transcription factors family (ATF1, CREB1 and CREM), driving the pathogenesis of various tumor types spanning mesenchymal, neuroectodermal, and epithelial lineages.	('ATF1', 'Gene', (175, 179))	('pathogenesis', 'Reg', (210, 222))	('fusions', 'Var', (87, 94))	('tumor', 'Disease', (234, 239))	('driving', 'Reg', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('CREB1', 'Gene', (181, 186))	('ATF1', 'Gene', '466', (175, 179))	('CREB', 'Gene', (181, 185))	('EWSR1', 'Gene', '2130', (103, 108))	('FUS', 'Gene', (112, 115))	('CREB1', 'Gene', '1385', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('CREB', 'Gene', (140, 144))	('CREM', 'Gene', (191, 195))	('CREB', 'Gene', '1385', (181, 185))	('FUS', 'Gene', '2521', (112, 115))	('EWSR1', 'Gene', (103, 108))	('CREM', 'Gene', '1390', (191, 195))	('CREB', 'Gene', '1385', (140, 144))
406688	32770123	Other pertinent negative stains included P40, P63, SF1, and S100.	('SF1', 'Gene', (51, 54))	('P40', 'Var', (41, 44))	('S100', 'Gene', '6271', (60, 64))	('SF1', 'Gene', '7536', (51, 54))	('P63', 'Var', (46, 49))	('S100', 'Gene', (60, 64))
406695	32770123	The rest of the cases were tested by FISH and showed gene rearrangements for EWSR1, FUS and CREM genes.	('FUS', 'Gene', (84, 87))	('FUS', 'Gene', '2521', (84, 87))	('gene rearrangements', 'Var', (53, 72))	('EWSR1', 'Gene', (77, 82))	('CREM', 'Gene', '1390', (92, 96))	('CREM', 'Gene', (92, 96))	('EWSR1', 'Gene', '2130', (77, 82))
406716	32770123	Most AFH show variable positivity for desmin, EMA, and CD99 in about half of the cases, but are consistently negative for cytokeratins.	('EMA', 'Gene', '4582', (46, 49))	('desmin', 'Gene', (38, 44))	('CD99', 'Gene', '4267', (55, 59))	('CD99', 'Gene', (55, 59))	('desmin', 'Gene', '1674', (38, 44))	('EMA', 'Gene', (46, 49))	('positivity', 'Var', (23, 33))
406717	32770123	AFH harbor mostly EWSR1-CREB1 fusions, though rare cases with EWSR1-ATF1 or FUS-ATF1 fusion have been reported.	('CREB1', 'Gene', (24, 29))	('EWSR1', 'Gene', (18, 23))	('FUS-ATF1', 'Gene', '466;2521', (76, 84))	('EWSR1', 'Gene', (62, 67))	('EWSR1', 'Gene', '2130', (18, 23))	('ATF1', 'Gene', (80, 84))	('fusions', 'Var', (30, 37))	('EWSR1', 'Gene', '2130', (62, 67))	('ATF1', 'Gene', '466', (80, 84))	('ATF1', 'Gene', (68, 72))	('CREB1', 'Gene', '1385', (24, 29))	('FUS-ATF1', 'Gene', (76, 84))	('ATF1', 'Gene', '466', (68, 72))
406720	32770123	Moreover, our group has reported recently on a small subset of epithelioid mesothelioma occurring in young adults harboring EWSR1/FUS-ATF1 fusions.	('EWSR1', 'Gene', (124, 129))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('FUS-ATF1', 'Gene', (130, 138))	('fusions', 'Var', (139, 146))	('EWSR1', 'Gene', '2130', (124, 129))	('FUS-ATF1', 'Gene', '466;2521', (130, 138))	('mesothelioma', 'Disease', (75, 87))
406726	32770123	Only one case of myoepithelial tumor of soft tissue was so far reported with an EWSR1-ATF1 fusion; however, that case had a well-documented myoepithelial immunophenotype.	('fusion', 'Var', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('myoepithelial tumor', 'Disease', 'MESH:D009208', (17, 36))	('EWSR1', 'Gene', (80, 85))	('ATF1', 'Gene', (86, 90))	('ATF1', 'Gene', '466', (86, 90))	('EWSR1', 'Gene', '2130', (80, 85))	('myoepithelial tumor', 'Disease', (17, 36))
406731	32770123	However, these tumors consistently show positivity for S100 protein, while none of the cases in the present cohort showed expression for this marker.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('S100', 'Gene', (55, 59))	('S100', 'Gene', '6271', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('positivity', 'Var', (40, 50))
406738	32770123	Similar to fusions encompassing other CREB family members, CREM-related fusions are evolving as promiscuous abnormalities, spanning the pathogenesis of a number of tumor entities, of different cell lineages.	('tumor', 'Disease', (164, 169))	('CREM', 'Gene', '1390', (59, 63))	('CREM', 'Gene', (59, 63))	('CREB', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('CREB', 'Gene', '1385', (38, 42))	('fusions', 'Var', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
406740	32770123	However, a recent report has described 3 cases of myxoid AFH harboring EWSR1-CREM fusions.	('fusions', 'Var', (82, 89))	('myxoid', 'Disease', (50, 56))	('EWSR1', 'Gene', (71, 76))	('CREM', 'Gene', '1390', (77, 81))	('EWSR1', 'Gene', '2130', (71, 76))	('CREM', 'Gene', (77, 81))
406758	31970591	However, entity-defining fusion oncogenes acting as the main oncogenic driver mutations are frequently found in pediatric bone and soft-tissue sarcomas such as Ewing sarcoma (EWSR1-FLI1), alveolar rhabdomyosarcoma (PAX3/7-FOXO1), and synovial sarcoma (SS18-SSX1/2/4).	('SSX1/2/4', 'Gene', (257, 265))	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (160, 173))	('sarcomas', 'Disease', (143, 151))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (188, 213))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (234, 250))	('SS18', 'Gene', '6760', (252, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('mutations', 'Var', (78, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('Ewing sarcoma', 'Gene', (160, 173))	('SSX1/2/4', 'Gene', '6756;6757;6759', (257, 265))	('alveolar rhabdomyosarcoma', 'Disease', (188, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('Ewing sarcoma', 'Gene', '2130', (160, 173))	('bone and', 'Disease', (122, 130))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (131, 151))	('SS18', 'Gene', (252, 256))	('synovial sarcoma', 'Disease', (234, 250))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (197, 213))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (188, 213))	('sarcomas', 'Disease', 'MESH:D012509', (143, 151))	('synovial sarcoma', 'Disease', 'MESH:D013584', (234, 250))
406762	31970591	In cancer entities with high numbers of somatic mutations, the vast majority of gene fusions are supposed passenger mutations, i.e., byproducts of spontaneous genomic rearrangements, which accumulate progressively over time.	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('gene fusions', 'Var', (80, 92))	('cancer', 'Disease', (3, 9))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
406763	31970591	However, in oligo-mutated childhood cancers, such as EwS, fusion genes are acquired early in tumorigenesis either through balanced chromosomal translocations or through a complex, but well-orchestrated, genomic rearrangement called chromoplexy.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('tumor', 'Disease', (93, 98))	('EwS', 'Phenotype', 'HP:0012254', (53, 56))	('EwS', 'Disease', (53, 56))	('balanced chromosomal translocations', 'Var', (122, 157))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
406764	31970591	Once the respective fusion has occurred, oligo-mutated cancer cells show a strong oncogene addiction toward their disease-defining fusion oncogene (e.g., EWSR1-FLI1 in EwS, PAX3/7-FOXO1 in alveolar rhabdomyosarcoma (ARMS) and SS18-SSX1/2/4 in synovial sarcoma (SS)) in terms of tumor progression and metastasis.	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (189, 214))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (189, 214))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (243, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('SS', 'Disease', 'MESH:D013584', (231, 233))	('ARMS', 'Disease', 'MESH:D018232', (216, 220))	('metastasis', 'CPA', (300, 310))	('SS18', 'Gene', '6760', (226, 230))	('SS', 'Disease', 'MESH:D013584', (261, 263))	('SSX1/2/4', 'Gene', (231, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('PAX3/7-FOXO1', 'Var', (173, 185))	('cancer', 'Disease', (55, 61))	('ARMS', 'Phenotype', 'HP:0006779', (216, 220))	('tumor', 'Disease', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('alveolar rhabdomyosarcoma', 'Disease', (189, 214))	('synovial sarcoma', 'Disease', (243, 259))	('SS', 'Disease', 'MESH:D013584', (226, 228))	('SS18', 'Gene', (226, 230))	('ARMS', 'Disease', (216, 220))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (198, 214))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('EwS', 'Phenotype', 'HP:0012254', (168, 171))	('synovial sarcoma', 'Disease', 'MESH:D013584', (243, 259))	('SSX1/2/4', 'Gene', '6756;6757;6759', (231, 239))
406769	31970591	Notably, germline variants of GGAA-mSats that affect the repeat length have recently been reported to contribute to EwS susceptibility and tumor progression in EwS.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('GGAA-mSats', 'Gene', (30, 40))	('variants', 'Var', (18, 26))	('EwS', 'Phenotype', 'HP:0012254', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('contribute', 'Reg', (102, 112))	('repeat length', 'MPA', (57, 70))	('EwS', 'Phenotype', 'HP:0012254', (116, 119))	('EwS', 'Disease', (116, 119))
406772	31970591	Approximately two thirds of ARMS harbor a fusion oncogene, whereas one third is fusion oncogene negative.	('ARMS', 'Phenotype', 'HP:0006779', (28, 32))	('ARMS', 'Disease', 'MESH:D018232', (28, 32))	('fusion', 'Var', (42, 48))	('ARMS', 'Disease', (28, 32))
406775	31970591	While PAX3- and PAX7-FOXO1-positive ARMS have the same prognosis in their localized states, PAX3-FOXO1-positive tumors show a more aggressive phenotype once they have metastasized.	('PAX7', 'Gene', (16, 20))	('ARMS', 'Disease', (36, 40))	('ARMS', 'Disease', 'MESH:D018232', (36, 40))	('PAX7', 'Gene', '5081', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PAX3-FOXO1-positive', 'Var', (92, 111))	('ARMS', 'Phenotype', 'HP:0006779', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
406781	31970591	Subsequently, the altered BAF complex binds broad polycomb domains, opposes PRC-mediated repression of gene sets, and activates transcription of a SS-specific gene signature.	('opposes', 'NegReg', (68, 75))	('SS', 'Disease', 'MESH:D013584', (147, 149))	('altered', 'Var', (18, 25))	('activates', 'PosReg', (118, 127))	('BAF', 'Gene', '8815', (26, 29))	('transcription', 'MPA', (128, 141))	('broad polycomb domains', 'Protein', (44, 66))	('BAF', 'Gene', (26, 29))	('binds', 'Interaction', (38, 43))
406785	31970591	Besides monogenic disorders, malignant tumors driven by a single-driver mutation represent favorable future indications for the therapeutic use of CRISPR-CAS9.	('malignant tumors', 'Disease', 'MESH:D009369', (29, 45))	('single-driver mutation', 'Var', (58, 80))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('malignant tumors', 'Disease', (29, 45))
406786	31970591	Among them, tumors harboring a fusion oncogene constitute excellent candidates for oligonucleotide-based treatment strategies due to the sequence specificity of their breakpoint region.	('oligonucleotide', 'Chemical', 'MESH:D009841', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('fusion', 'Var', (31, 37))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
406790	31970591	In a human myoblast model, the CRISPR-CAS9 mediated knockout of PAX3-FOXO1 abrogated colony formation in vitro.	('knockout', 'Var', (52, 60))	('colony formation in vitro', 'CPA', (85, 110))	('abrogated', 'NegReg', (75, 84))	('human', 'Species', '9606', (5, 10))	('PAX3-FOXO1', 'Gene', (64, 74))
406791	31970591	Another elegant strategy was pursued by Johnson et al., who deleted the GGAA-mSat regulating the expression of NR0B1 using CRISPR-CAS9 and thereby impaired the proliferation and oncogenic transformation of EwS cell lines.	('GGAA-mSat', 'Gene', (72, 81))	('oncogenic transformation', 'CPA', (178, 202))	('NR0B1', 'Gene', (111, 116))	('proliferation', 'CPA', (160, 173))	('NR0B1', 'Gene', '190', (111, 116))	('impaired', 'NegReg', (147, 155))	('deleted', 'Var', (60, 67))	('EwS', 'Phenotype', 'HP:0012254', (206, 209))
406794	31970591	Epigenomic alterations are common in cancer and have become therapeutically accessible by the advent of epigenome-modifying drugs such as HDAC inhibitors.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('HDAC', 'Gene', (138, 142))	('HDAC', 'Gene', '9734', (138, 142))	('cancer', 'Disease', (37, 43))	('Epigenomic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
406800	31970591	Indeed, knockdown of fusion oncoproteins in EwS, ARMS, and SS consistently causes G0/G1 cell cycle arrest and cell death in vitro, which supports the potential therapeutic usefulness of this approach.	('ARMS', 'Disease', (49, 53))	('causes', 'Reg', (75, 81))	('ARMS', 'Disease', 'MESH:D018232', (49, 53))	('SS', 'Disease', 'MESH:D013584', (59, 61))	('knockdown', 'Var', (8, 17))	('ARMS', 'Phenotype', 'HP:0006779', (49, 53))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('EwS', 'Phenotype', 'HP:0012254', (44, 47))	('arrest', 'Disease', 'MESH:D006323', (99, 105))	('cell death', 'CPA', (110, 120))	('arrest', 'Disease', (99, 105))
406812	31970591	EWSR1-FLI1 was found to modulate the splicing machinery by interacting with RNA polymerase II, non-fused (wild type) EWSR1, and YB1, creating atypical mRNA isoforms.	('creating', 'Reg', (133, 141))	('EWSR1', 'Gene', (117, 122))	('splicing machinery', 'MPA', (37, 55))	('non-fused', 'Var', (95, 104))	('YB1', 'Gene', (128, 131))	('interacting', 'Interaction', (59, 70))	('YB1', 'Gene', '4904', (128, 131))	('mRNA isoforms', 'MPA', (151, 164))	('EWSR1-FLI1', 'Gene', (0, 10))	('RNA', 'Protein', (76, 79))	('modulate', 'Reg', (24, 32))
406814	31970591	Increased VEGF165/VEGF189 ratio by alternative splicing has been reported to be caused by EWSR1-FLI1 inhibition of CAPER-alpha (RBM39), which confers a more neoangiogenic phenotype to EwS by recruiting bone marrow-derived progenitor cells in a murine xenograft model.	('EWSR1-FLI1', 'Gene', (90, 100))	('alternative splicing', 'Var', (35, 55))	('inhibition', 'NegReg', (101, 111))	('murine', 'Species', '10090', (244, 250))	('EwS', 'Phenotype', 'HP:0012254', (184, 187))	('CAPER-alpha', 'Gene', (115, 126))	('Increased', 'PosReg', (0, 9))	('neoangiogenic', 'CPA', (157, 170))	('CAPER-alpha', 'Gene', '9584', (115, 126))	('more', 'PosReg', (152, 156))	('VEGF165/VEGF189', 'Gene', (10, 25))
406816	31970591	Wild-type EWSR1 has been shown to alternatively splice the transmembrane domain coding exon of FAS/CD95 receptor.	('FAS', 'Chemical', 'MESH:C038178', (95, 98))	('CD95', 'Gene', '355', (99, 103))	('CD95', 'Gene', (99, 103))	('alternatively splice', 'Var', (34, 54))
406819	31970591	Moreover, EWSR1-FLI1 reduces the elongation speed of RNA polymerase II on CCND1 leading to preferential alternative splicing of the D1b isoform, which has a higher oncogenic potential than the D1a isoform.	('oncogenic potential', 'CPA', (164, 183))	('RNA polymerase II', 'Enzyme', (53, 70))	('CCND1', 'Gene', (74, 79))	('elongation speed', 'MPA', (33, 49))	('preferential', 'PosReg', (91, 103))	('CCND1', 'Gene', '595', (74, 79))	('EWSR1-FLI1', 'Var', (10, 20))	('alternative splicing', 'MPA', (104, 124))	('reduces', 'NegReg', (21, 28))
406822	31970591	ARID1A-L generated by alternative splicing in EwS cells plays an important role in tumor growth and promotes the stability of EWSR1-FLI1.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('stability', 'MPA', (113, 122))	('alternative splicing', 'Var', (22, 42))	('EwS', 'Phenotype', 'HP:0012254', (46, 49))	('ARID1A', 'Gene', '8289', (0, 6))	('tumor', 'Disease', (83, 88))	('promotes', 'PosReg', (100, 108))	('ARID1A', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
406823	31970591	Evidence indicating a direct association of fusion oncoproteins with alternative splicing in SS and ARMS is still missing.	('ARMS', 'Disease', 'MESH:D018232', (100, 104))	('ARMS', 'Phenotype', 'HP:0006779', (100, 104))	('SS', 'Disease', 'MESH:D013584', (93, 95))	('alternative splicing', 'Var', (69, 89))	('ARMS', 'Disease', (100, 104))
406832	31970591	Inhibition of PLK1 with the small molecule BI 2536 causes increased proteasomal degradation of PAX3-FOXO1 and tumor regression in a xenograft mouse model, an effect that could be reproduced in a different study using the PLK1 inhibitor Volasertib.	('increased', 'PosReg', (58, 67))	('mouse', 'Species', '10090', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('BI 2536', 'Chemical', 'MESH:C518477', (43, 50))	('BI 2536', 'Var', (43, 50))	('Inhibition', 'Var', (0, 10))	('proteasomal degradation', 'MPA', (68, 91))	('PLK1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
406833	31970591	Furthermore, multiple studies have shown PAX3-FOXO1 to be a substrate of GSK3beta, inhibition of which reduces transcriptional activity of the fusion protein and proliferation of tumor cells in a PAX3-FOXO1 dependent manner.	('GSK3beta', 'Gene', (73, 81))	('GSK3beta', 'Gene', '2931', (73, 81))	('proliferation', 'CPA', (162, 175))	('reduces', 'NegReg', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('transcriptional activity', 'MPA', (111, 135))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('inhibition', 'Var', (83, 93))	('fusion protein', 'Protein', (143, 157))	('tumor', 'Disease', (179, 184))
406834	31970591	Additionally, PAX3-FOXO1 is phosphorylated by cyclin-dependent kinase 4 (CDK4) in the ARMS cell line RH30 and inhibition of CDK4 by facsaplysin reduces the transcriptional activity and increases its cytoplasmatic levels, indicating redistribution.	('increases', 'PosReg', (185, 194))	('ARMS', 'Disease', (86, 90))	('CDK4', 'Gene', '1019', (73, 77))	('CDK4', 'Gene', '1019', (124, 128))	('reduces', 'NegReg', (144, 151))	('cyclin-dependent kinase 4', 'Gene', '1019', (46, 71))	('cyclin-dependent kinase 4', 'Gene', (46, 71))	('cytoplasmatic levels', 'MPA', (199, 219))	('ARMS', 'Disease', 'MESH:D018232', (86, 90))	('ARMS', 'Phenotype', 'HP:0006779', (86, 90))	('transcriptional activity', 'MPA', (156, 180))	('inhibition', 'Var', (110, 120))	('CDK4', 'Gene', (73, 77))	('CDK4', 'Gene', (124, 128))
406841	31970591	Depletion of USP19 was shown to decrease EWSR1-FLI1 expression levels, but neither the expression of wild-type of EWSR1 nor FLI1, and to reduce tumor growth in vitro and in vivo indicating a potential therapeutic value for USP19 inhibition.	('USP19', 'Gene', '10869', (13, 18))	('tumor', 'Disease', (144, 149))	('USP19', 'Gene', (223, 228))	('USP19', 'Gene', '10869', (223, 228))	('expression levels', 'MPA', (52, 69))	('reduce', 'NegReg', (137, 143))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('USP19', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('decrease', 'NegReg', (32, 40))	('EWSR1-FLI1', 'Gene', (41, 51))
406845	31970591	have recently shown that SS18-SSX is ubiquitinated and thereby marked for degradation by the MCL-1 ubiquitin ligase E3 (MULE) at the lysine K23 of SS18, which is not a known ubiquitination site in wild-type SS18.	('SS18', 'Gene', '6760', (147, 151))	('SS18', 'Gene', '6760', (25, 29))	('SS18', 'Gene', (207, 211))	('SSX', 'Gene', '6757', (30, 33))	('MULE', 'Species', '319699', (120, 124))	('SSX', 'Gene', (30, 33))	('degradation', 'MPA', (74, 85))	('SS18', 'Gene', '6760', (207, 211))	('ubiquitinated', 'MPA', (37, 50))	('SS18', 'Gene', (147, 151))	('SS18', 'Gene', (25, 29))	('lysine K23', 'Var', (133, 143))	('lysine', 'Chemical', 'MESH:D008239', (133, 139))
406853	31970591	For EWSR1-FLI1, it was shown that a modified 9-mer peptide of the fusion site (YLNPSVDS) was able to induce a robust immune response in vitro and in vivo facilitating prolonged survival of xenograft-bearing mice after treatment with YLNPSVDS-specific cytotoxic T lymphocytes (CTLs).	('modified', 'Var', (36, 44))	('YLNPSVDS', 'Chemical', '-', (79, 87))	('mice', 'Species', '10090', (207, 211))	('induce', 'PosReg', (101, 107))	('EWSR1-FLI1', 'Gene', (4, 14))	('prolonged survival', 'CPA', (167, 185))	('YLNPSVDS', 'Chemical', '-', (233, 241))
406855	31970591	For instance, two highly similar peptides of the PAX3-FOXO1 breakpoint region showed strikingly different results depending on the HLA alleles used in the respective study: The RS10 peptide (SPQNSIRHNL) was able to induce highly effective CTLs in HLA-B7+ donor peripheral blood mononuclear cells and allowed killing of HLA-B7+ ARMS cells.	('donor', 'Species', '9606', (255, 260))	('ARMS', 'Disease', (327, 331))	('CTLs', 'CPA', (239, 243))	('RS10', 'Var', (177, 181))	('ARMS', 'Disease', 'MESH:D018232', (327, 331))	('ARMS', 'Phenotype', 'HP:0006779', (327, 331))	('RS10', 'Chemical', '-', (177, 181))	('induce', 'PosReg', (215, 221))
406860	31970591	For instance, it has been shown that EWSR1-FLI1, but not wild-type EWSR1, directly binds RNA helicase A and reduces helicase activity.	('helicase', 'Protein', (116, 124))	('EWSR1-FLI1', 'Var', (37, 47))	('RNA helicase A', 'Gene', (89, 103))	('binds', 'Interaction', (83, 88))	('activity', 'MPA', (125, 133))	('RNA helicase A', 'Gene', '1660', (89, 103))	('reduces', 'NegReg', (108, 115))
406863	31970591	Mutations in p53 have been found in as little as 5-7% of EwS; however, even in wild-type sarcomas, p53 function seems to be compromised in analogy to other fusion-positive malignancies such as fusion-driven leukemia.	('p53', 'Gene', (99, 102))	('sarcomas', 'Disease', (89, 97))	('p53', 'Gene', (13, 16))	('malignancies', 'Disease', 'MESH:D009369', (172, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('function', 'MPA', (103, 111))	('compromised', 'NegReg', (124, 135))	('Mutations', 'Var', (0, 9))	('EwS', 'Phenotype', 'HP:0012254', (57, 60))	('leukemia', 'Disease', (207, 215))	('p53', 'Gene', '7157', (99, 102))	('EwS', 'Disease', (57, 60))	('malignancies', 'Disease', (172, 184))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('leukemia', 'Phenotype', 'HP:0001909', (207, 215))	('leukemia', 'Disease', 'MESH:D007938', (207, 215))	('p53', 'Gene', '7157', (13, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
406880	31970591	As fusion-driven sarcomas are characterized by the paucity of other genetic mutations and due to the functions of their disease-defining oncogenes, epigenetic dysregulation plays an important role in the maintenance of their phenotype.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcomas', 'Disease', (17, 25))	('epigenetic dysregulation', 'Var', (148, 172))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
406881	31970591	Hence, epigenetic modulators, which are increasingly becoming of interest in other malignancies as well, are major potential targets in EwS, SS and ARMS.	('EwS', 'Disease', (136, 139))	('epigenetic modulators', 'Var', (7, 28))	('ARMS', 'Disease', (148, 152))	('SS', 'Disease', 'MESH:D013584', (141, 143))	('ARMS', 'Disease', 'MESH:D018232', (148, 152))	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('ARMS', 'Phenotype', 'HP:0006779', (148, 152))	('EwS', 'Phenotype', 'HP:0012254', (136, 139))	('malignancies', 'Disease', (83, 95))
406883	31970591	Indeed, in preclinical models of EwS, HDAC inhibitors have been shown to induce apoptosis, promote differentiation, and reduce tumor growth in xenograft experiments.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HDAC', 'Gene', '9734', (38, 42))	('inhibitors', 'Var', (43, 53))	('promote', 'PosReg', (91, 98))	('reduce', 'NegReg', (120, 126))	('tumor', 'Disease', (127, 132))	('EwS', 'Phenotype', 'HP:0012254', (33, 36))	('induce', 'PosReg', (73, 79))	('differentiation', 'CPA', (99, 114))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('apoptosis', 'CPA', (80, 89))	('HDAC', 'Gene', (38, 42))
406896	31970591	In SS cells, inhibition of EZH2 with the small molecule EPZ005687 has been shown to impair proliferation and migration.	('SS', 'Disease', 'MESH:D013584', (3, 5))	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('inhibition', 'Var', (13, 23))	('impair', 'NegReg', (84, 90))
406905	31970591	Inhibition or targeted degradation of BRD9 induced downregulation of oncogenic programs and reduced growth of SS xenografts.	('targeted degradation', 'Var', (14, 34))	('SS', 'Disease', 'MESH:D013584', (110, 112))	('BRD9', 'Gene', '65980', (38, 42))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (92, 99))	('downregulation', 'NegReg', (51, 65))	('oncogenic programs', 'CPA', (69, 87))	('BRD9', 'Gene', (38, 42))
406907	31970591	Malignant transformation and maintenance of tumorigenesis in EwS, SS, and ARMS depend on the expression of their specific fusion proteins to the extent that their deletion results in cell death.	('deletion', 'Var', (163, 171))	('SS', 'Disease', 'MESH:D013584', (66, 68))	('ARMS', 'Disease', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('ARMS', 'Disease', 'MESH:D018232', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ARMS', 'Phenotype', 'HP:0006779', (74, 78))	('Malignant transformation', 'CPA', (0, 24))	('EwS', 'Phenotype', 'HP:0012254', (61, 64))	('results in', 'Reg', (172, 182))	('tumor', 'Disease', (44, 49))
163020	31970591	Tumorigenesis in translocation-driven tumors is critically mediated via the IGF-1R signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('Tumorigenesis', 'CPA', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mediated', 'Reg', (59, 67))	('translocation-driven', 'Var', (17, 37))	('IGF-1R', 'Gene', (76, 82))	('IGF-1R', 'Gene', '3480', (76, 82))
406910	31970591	In SS, the translocation induces the expression of IGF2, which is also required for tumor growth in vivo, while its immune targeting inhibits tumor growth and metastasis formation in ARMS.	('ARMS', 'Disease', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('ARMS', 'Disease', 'MESH:D018232', (183, 187))	('SS', 'Disease', 'MESH:D013584', (3, 5))	('ARMS', 'Phenotype', 'HP:0006779', (183, 187))	('tumor', 'Disease', (142, 147))	('induces', 'Reg', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('translocation', 'Var', (11, 24))	('tumor', 'Disease', (84, 89))	('IGF2', 'Gene', '3481', (51, 55))	('expression', 'MPA', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('IGF2', 'Gene', (51, 55))	('inhibits', 'NegReg', (133, 141))
406919	31970591	In fact, the A673 EwS cell has a constitutively activating mutation in BRAF.	('EwS', 'Phenotype', 'HP:0012254', (18, 21))	('BRAF', 'Gene', '673', (71, 75))	('activating', 'PosReg', (48, 58))	('BRAF', 'Gene', (71, 75))	('mutation', 'Var', (59, 67))
406921	31970591	Besides, pharmacological treatment with FGFR inhibitor PD-173074 yielded a decrease in tumorigenic features in preclinical studies.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('decrease', 'NegReg', (75, 83))	('inhibitor PD-173074', 'Var', (45, 64))	('tumor', 'Disease', (87, 92))	('FGFR', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('PD-173074', 'Chemical', 'MESH:C115711', (55, 64))	('PD-173074', 'Var', (55, 64))
406927	31970591	Notably, due to the high expression of FGFR4, the inhibitor PD-173074 has shown similar preclinical promising effects in ARMS as in EwS.	('EwS', 'Phenotype', 'HP:0012254', (132, 135))	('PD-173074', 'Var', (60, 69))	('PD-173074', 'Chemical', 'MESH:C115711', (60, 69))	('ARMS', 'Disease', 'MESH:D018232', (121, 125))	('ARMS', 'Phenotype', 'HP:0006779', (121, 125))	('FGFR4', 'Gene', '2264', (39, 44))	('FGFR4', 'Gene', (39, 44))	('ARMS', 'Disease', (121, 125))
406930	31970591	Inhibitory targeting of GLI1/2 using GANT-61 leads to a blockage of tumor growth in vivo, and its effect was shown to be synergistic with commonly used chemotherapeutic drugs for ARMS such as temsirolimus or vincristine.	('tumor', 'Disease', (68, 73))	('blockage', 'NegReg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('GANT-61', 'Gene', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('GLI1/2', 'Gene', '2735;2736', (24, 30))	('temsirolimus', 'Chemical', 'MESH:C401859', (192, 204))	('Inhibitory', 'Var', (0, 10))	('ARMS', 'Disease', (179, 183))	('GLI1/2', 'Gene', (24, 30))	('vincristine', 'Chemical', 'MESH:D014750', (208, 219))	('ARMS', 'Disease', 'MESH:D018232', (179, 183))	('ARMS', 'Phenotype', 'HP:0006779', (179, 183))
406934	31970591	GLI1 was also shown to be upregulated in EwS and driven by the translocation, and therefore, therapeutic approaches using ATO have been attempted with promising preclinical results.	('GLI1', 'Gene', (0, 4))	('translocation', 'Var', (63, 76))	('upregulated', 'PosReg', (26, 37))	('ATO', 'Chemical', 'MESH:D000077237', (122, 125))	('GLI1', 'Gene', '2735', (0, 4))	('EwS', 'Phenotype', 'HP:0012254', (41, 44))	('EwS', 'Disease', (41, 44))
406941	31970591	Additionally, SS patients have been enrolled in a results-pending trial to test an antibody against the Wnt receptor FZD10 (NCT01469975).	('FZD10', 'Gene', (117, 122))	('FZD10', 'Gene', '11211', (117, 122))	('NCT01469975', 'Var', (124, 135))	('SS', 'Disease', 'MESH:D013584', (14, 16))	('patients', 'Species', '9606', (17, 25))
406943	31970591	So far, WNT974-a modulator of the Wnt pathway at PORCN level-showed a significant delay in formation of metastasis in vivo.	('WNT974-a', 'Var', (8, 16))	('formation of metastasis', 'CPA', (91, 114))	('PORCN', 'Gene', (49, 54))	('PORCN', 'Gene', '64840', (49, 54))	('delay', 'NegReg', (82, 87))
406983	25791363	Trabectedin was decreased by one level for grade >=3 nausea or vomiting despite adequate prophylaxis, grade <=1 nonosseous alkaline phosphatase elevation, grade >=3 transaminase elevation with recovery to grade <=1 or conjugated bilirubin greater than upper limit of normal, or any other grade >=3 nonhematologic toxicity.	('conjugated bilirubin', 'MPA', (218, 238))	('vomiting', 'Phenotype', 'HP:0002013', (63, 71))	('bilirubin', 'Chemical', 'MESH:D001663', (229, 238))	('vomiting', 'Disease', (63, 71))	('nausea or vomiting', 'Phenotype', 'HP:0002017', (53, 71))	('elevation', 'PosReg', (178, 187))	('grade >=3', 'Var', (155, 164))	('nausea', 'Phenotype', 'HP:0002018', (53, 59))	('decreased', 'NegReg', (16, 25))	('elevation', 'PosReg', (144, 153))	('grade <=1', 'Var', (102, 111))	('toxicity', 'Disease', 'MESH:D064420', (313, 321))	('nausea', 'Disease', (53, 59))	('transaminase', 'MPA', (165, 177))	('nonosseous alkaline phosphatase', 'MPA', (112, 143))	('Trabectedin', 'Chemical', 'MESH:D000077606', (0, 11))	('alkaline phosphatase elevation', 'Phenotype', 'HP:0003155', (123, 153))	('toxicity', 'Disease', (313, 321))	('transaminase elevation', 'Phenotype', 'HP:0002910', (165, 187))	('vomiting', 'Disease', 'MESH:D014839', (63, 71))	('nausea', 'Disease', 'MESH:D009325', (53, 59))
406986	25791363	Dose-limiting toxicity (DLT) was defined as >=1 of the following in cycle 1: ANC < 500 muL for >5 days or with fever or sepsis; platelet count <25 000 muL; any grade 3/4 nonhematologic toxicity except nausea or vomiting despite appropriate prophylaxis; grade 3 transaminitis lasting >1 week; or cycle delay >3 weeks.	('sepsis', 'Phenotype', 'HP:0100806', (120, 126))	('sepsis', 'Disease', 'MESH:D018805', (120, 126))	('toxicity', 'Disease', (185, 193))	('nausea', 'Disease', (201, 207))	('fever', 'Phenotype', 'HP:0001945', (111, 116))	('ANC', 'Var', (77, 80))	('muL', 'Gene', '4591', (151, 154))	('sepsis', 'Disease', (120, 126))	('vomiting', 'Disease', 'MESH:D014839', (211, 219))	('<25 000', 'Var', (143, 150))	('toxicity', 'Disease', 'MESH:D064420', (14, 22))	('muL', 'Gene', '4591', (87, 90))	('nausea', 'Disease', 'MESH:D009325', (201, 207))	('vomiting', 'Phenotype', 'HP:0002013', (211, 219))	('vomiting', 'Disease', (211, 219))	('toxicity', 'Disease', (14, 22))	('nausea or vomiting', 'Phenotype', 'HP:0002017', (201, 219))	('toxicity', 'Disease', 'MESH:D064420', (185, 193))	('muL', 'Gene', (151, 154))	('nausea', 'Phenotype', 'HP:0002018', (201, 207))	('muL', 'Gene', (87, 90))	('fever', 'Disease', 'MESH:D005334', (111, 116))	('fever', 'Disease', (111, 116))
407114	26039627	Genome-wide expression analysis of the effects of NFYB knockdown on E2F1-mediated transcription identified a large group of genes that are co-regulated by E2F1 and NFYB.	('E2F1 and NFYB', 'Gene', '1869;4801', (155, 168))	('knockdown', 'Var', (55, 64))	('NFYB', 'Gene', (50, 54))
407115	26039627	Bioinformatic analysis suggests that deregulation of these NFY-dependent E2F1 target genes might play a role in sarcomagenesis as well as drug resistance.	('role', 'Reg', (104, 108))	('E2F1', 'Gene', (73, 77))	('play', 'Reg', (97, 101))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('drug resistance', 'CPA', (138, 153))	('drug resistance', 'Phenotype', 'HP:0020174', (138, 153))	('sarcoma', 'Disease', (112, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('deregulation', 'Var', (37, 49))
407117	26039627	Genetic lesions in the Rb tumor suppressor pathway lead to unrestrained E2F activity and deregulated cell proliferation that are critical to the development of numerous cancers.	('unrestrained', 'MPA', (59, 71))	('numerous cancers', 'Disease', 'MESH:D009369', (160, 176))	('E2F', 'Enzyme', (72, 75))	('activity', 'MPA', (76, 84))	('numerous cancers', 'Disease', (160, 176))	('Rb tumor', 'Disease', 'MESH:D009369', (23, 31))	('Rb tumor', 'Disease', (23, 31))	('deregulated cell proliferation', 'CPA', (89, 119))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lead to', 'Reg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('Genetic lesions', 'Var', (0, 15))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
407118	26039627	Among the three activator E2Fs, E2F1-E2F3, E2F1 is unique in its ability to induce apoptosis as well as proliferation.	('proliferation', 'CPA', (104, 117))	('E2F1', 'Var', (43, 47))	('induce', 'PosReg', (76, 82))	('E2F1-E2F3', 'CellLine', 'CVCL:L875', (32, 41))	('E2F1-E2F3', 'Var', (32, 41))	('apoptosis', 'CPA', (83, 92))	('E2Fs', 'Var', (26, 30))
407121	26039627	Together, these studies suggest an important role of E2F1 deregulation in cancer as well as the therapeutic potential to harness the apoptotic activity of E2F1 for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('deregulation', 'Var', (58, 70))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (164, 170))	('E2F1', 'Gene', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
407122	26039627	We and others have previously demonstrated that E2F1 induces numerous other transcription factors, some of which cooperate with E2F1 during induction of target genes, such as the cooperation with FOXO1/3 to induce apoptotic genes.	('FOXO1', 'Gene', (196, 201))	('FOXO1', 'Gene', '2308', (196, 201))	('E2F1', 'Var', (48, 52))	('induce', 'PosReg', (207, 213))	('apoptotic genes', 'Gene', (214, 229))	('induces', 'Reg', (53, 60))
407123	26039627	In contrast, E2F1 induces TopBP1, which binds to E2F1 and specifically represses its apoptotic activity.	('E2F1', 'Var', (49, 53))	('E2F1', 'Var', (13, 17))	('TopBP1', 'Gene', '11073', (26, 32))	('apoptotic activity', 'CPA', (85, 103))	('binds', 'Interaction', (40, 45))	('represses', 'NegReg', (71, 80))	('TopBP1', 'Gene', (26, 32))
407127	26039627	Paradoxically, ectopic expression of NFYA was recently shown to induce apoptosis through upregulation of E2F1.	('ectopic expression', 'Var', (15, 33))	('induce', 'PosReg', (64, 70))	('apoptosis', 'CPA', (71, 80))	('E2F1', 'Gene', (105, 109))	('NFYA', 'Gene', (37, 41))	('upregulation', 'PosReg', (89, 101))	('NFYA', 'Gene', '4800', (37, 41))
407137	26039627	NFYB (GPH1017391(-)01A), SFRP1 (GPH1026162 (+)01A), PRKCZ (GPH1000044(-)01A), FOLH1 (GPH1016343(-)01A), and IGX1A (GPH100001C(-)01A) EpiTect ChIP primers were obtained from Qiagen.	('FOLH1', 'Gene', '2346', (78, 83))	('PRKCZ', 'Gene', (52, 57))	('SFRP1', 'Gene', '6422', (25, 30))	('GPH1016343', 'Var', (85, 95))	('GPH1017391', 'Var', (6, 16))	('PRKCZ', 'Gene', '5590', (52, 57))	('FOLH1', 'Gene', (78, 83))	('GPH1026162', 'Var', (32, 42))	('SFRP1', 'Gene', (25, 30))
407148	26039627	We found that the knockdown of E2F1 in U2OS cells resulted in small but statistically significant downregulation of NFYB mRNA levels (A in S1 Fig).	('E2F1', 'Var', (31, 35))	('U2OS', 'CellLine', 'CVCL:0042', (39, 43))	('downregulation', 'NegReg', (98, 112))	('NFYB', 'Gene', (116, 120))
407150	26039627	Since Rb is a negative upstream regulator of E2Fs, inactivation of Rb is expected to result in the upregulation of endogenous E2F target genes.	('Rb', 'Gene', '5925', (67, 69))	('inactivation', 'Var', (51, 63))	('endogenous', 'MPA', (115, 125))	('upregulation', 'PosReg', (99, 111))	('Rb', 'Gene', '5925', (6, 8))
407151	26039627	As demonstrated in B in S1 Fig, NFYB expression was significantly higher in Rb knockout compared to wild-type villi to support the concept that E2F activation upregulates NFYB.	('NFYB', 'Gene', (32, 36))	('higher', 'PosReg', (66, 72))	('knockout', 'Var', (79, 87))	('expression', 'MPA', (37, 47))	('Rb', 'Gene', '5925', (76, 78))	('upregulates', 'PosReg', (159, 170))
407155	26039627	As expression of these genes is affected by NFYB knockdown and given that E2F1 directly targets NFYB, these genes represent the broad spectrum of genes directly or indirectly targeted by E2F1 and NFYB.	('knockdown', 'Var', (49, 58))	('NFYB', 'Gene', (44, 48))	('expression', 'MPA', (3, 13))	('NFYB', 'Gene', (96, 100))	('E2F1 and NFYB', 'Gene', '1869;4801', (187, 200))	('affected', 'Reg', (32, 40))
407156	26039627	For example, within cluster 2 (expression reduced by NFYB knockdown), the levels of API5, an inhibitor of E2F1-mediated apoptosis, and of MALT1, a paracaspase that promotes activation of NF-kappaB signaling was reduced following NFYB knockdown.	('NF-kappaB signaling', 'Pathway', (187, 206))	('MALT1', 'Gene', '10892', (138, 143))	('MALT1', 'Gene', (138, 143))	('NFYB', 'Gene', (229, 233))	('NFYB', 'Gene', (53, 57))	('API5', 'Gene', '8539', (84, 88))	('reduced', 'NegReg', (211, 218))	('levels', 'MPA', (74, 80))	('knockdown', 'Var', (234, 243))	('API5', 'Gene', (84, 88))	('knockdown', 'Var', (58, 67))
407157	26039627	Within cluster 4 (genes induced by E2F1 and further increased by NFYB knockdown) is SIVA1, apoptosis inducing factor, a proapoptotic gene that plays an important role in CD27-mediated apoptosis and is known to be induced by E2F1.	('CD27', 'Gene', '939', (170, 174))	('CD27', 'Gene', (170, 174))	('knockdown', 'Var', (70, 79))	('SIVA1', 'Gene', (84, 89))	('SIVA1', 'Gene', '10572', (84, 89))	('NFYB', 'Gene', (65, 69))	('E2F1', 'Var', (35, 39))
407159	26039627	Focused analysis of the genes positively regulated by both E2F1 and NFYB identified 148 genes whose expression is induced at least two fold by E2F1 activation and significantly lower (p<0.05) following NFYB knockdown at a ratio of 1:1.2 compared to control (S2 Table).	('lower', 'NegReg', (177, 182))	('activation', 'PosReg', (148, 158))	('E2F1 and NFYB', 'Gene', '1869;4801', (59, 72))	('knockdown', 'Var', (207, 216))	('NFYB', 'Gene', (202, 206))	('induced', 'PosReg', (114, 121))	('expression', 'MPA', (100, 110))	('E2F1', 'Gene', (143, 147))
407160	26039627	To further validate these genes that may be co-regulated by E2F1 and NFYB, we used real-time RT-PCR to measure the expression of those genes in which the effect of NFYB knockdown on expression levels was most significant.	('knockdown', 'Var', (169, 178))	('E2F1 and NFYB', 'Gene', '1869;4801', (60, 73))	('NFYB', 'Gene', (164, 168))
407172	26039627	To determine whether this association is specific for the E2F1/NFYB signature, we compared the results to those signatures generated using the Oncomine determined concept "Up-regulated genes in human osteosarcoma cell line (U2OS) expressing E2F1 compared to U2OS controls - Literature-defined Concepts" (E2F1 signature).	('U2OS', 'CellLine', 'CVCL:0042', (224, 228))	('U2OS', 'CellLine', 'CVCL:0042', (258, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('human', 'Species', '9606', (194, 199))	('osteosarcoma', 'Disease', (200, 212))	('E2F1', 'Var', (241, 245))	('osteosarcoma', 'Phenotype', 'HP:0002669', (200, 212))	('Oncomine', 'Chemical', '-', (143, 151))	('osteosarcoma', 'Disease', 'MESH:D012516', (200, 212))	('Up-regulated', 'PosReg', (172, 184))
407174	26039627	Similarly, an NFYB signature in which the top 145 genes that were most strongly downregulated by NFYB knockdown irrespective of E2F1 showed only one dataset in which the signature significantly associates with a concept overexpressed in cancer and one in which it associates with a concept underexpressed in cancer.	('overexpressed', 'PosReg', (220, 233))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('associates', 'Reg', (194, 204))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('knockdown', 'Var', (102, 111))	('cancer', 'Disease', (308, 314))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('downregulated', 'NegReg', (80, 93))	('cancer', 'Disease', (237, 243))	('NFYB', 'Gene', (97, 101))
407181	26039627	Furthermore, genome-wide analyses identified enrichment for both NF-Y and E2F binding sites in a large cluster of genes upregulated following p53 inactivation in an in-vitro transformation system.	('inactivation', 'Var', (146, 158))	('upregulated', 'PosReg', (120, 131))	('p53', 'Gene', '7157', (142, 145))	('p53', 'Gene', (142, 145))
407188	26039627	A recent study has shown that E2F1 is transcriptionally induced by ectopic NFYA expression and that NFYA binds to the E2F1 promoter.	('ectopic', 'Var', (67, 74))	('NFYA', 'Gene', '4800', (75, 79))	('NFYA', 'Gene', '4800', (100, 104))	('induced', 'PosReg', (56, 63))	('NFYA', 'Gene', (75, 79))	('E2F1', 'Gene', (30, 34))	('binds', 'Interaction', (105, 110))	('NFYA', 'Gene', (100, 104))	('expression', 'Var', (80, 90))
407191	26039627	API5, an apoptosis inhibitor, is down-regulated while SIVA1, an apoptosis-inducing factor, is upregulated following NFYB knockdown.	('knockdown', 'Var', (121, 130))	('SIVA1', 'Gene', '10572', (54, 59))	('API5', 'Gene', (0, 4))	('NFYB', 'Gene', (116, 120))	('upregulated', 'PosReg', (94, 105))	('API5', 'Gene', '8539', (0, 4))	('down-regulated', 'NegReg', (33, 47))	('SIVA1', 'Gene', (54, 59))
407301	24778572	It has been demonstrated that mice with impaired function of CD8+ CTLs, CD4+ Th1 helper T cells, or NK cells have increased incidence of tumors.	('mice', 'Species', '10090', (30, 34))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('increased', 'PosReg', (114, 123))	('CTLs', 'Gene', (66, 70))	('CD4+', 'Var', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
407326	24778572	Tissue microarrays were constructed and immunohistochemistry was used to evaluate multiple white blood cells that play a role in the immune system these including CD3+ (T cell coreceptor), CD4+, CD8+, CD20+ (expressed on B cell surface, which plays a role in B cell activation), and CD45+ lymphocytes (lymphocyte common antigen, which plays a role in T cell activation) in tumors.	('CD45', 'Gene', '5788', (283, 287))	('tumors', 'Disease', (373, 379))	('tumors', 'Disease', 'MESH:D009369', (373, 379))	('CD4+', 'Var', (189, 193))	('tumors', 'Phenotype', 'HP:0002664', (373, 379))	('CD45', 'Gene', (283, 287))	('CD8', 'Gene', (195, 198))	('CD8', 'Gene', '925', (195, 198))	('CD20', 'Gene', (201, 205))	('CD20', 'Gene', '931', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))
407332	24778572	In the 21 osteosarcoma patients, expression of MHC I was associated with improved overall and event-free survival.	('expression', 'Var', (33, 43))	('patients', 'Species', '9606', (23, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (10, 22))	('osteosarcoma', 'Disease', (10, 22))	('osteosarcoma', 'Disease', 'MESH:D012516', (10, 22))	('overall', 'CPA', (82, 89))	('improved', 'PosReg', (73, 81))	('MHC', 'Gene', (47, 50))	('event-free survival', 'CPA', (94, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('MHC', 'Gene', '3107', (47, 50))
407398	24778572	There is a phase Ib/II study of ipilimumab with dasatinib for patients with soft tissue sarcoma with an expansion of GIST (NCT01643278).	('GIST', 'Gene', (117, 121))	('soft tissue sarcoma', 'Disease', (76, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('dasatinib', 'Chemical', 'MESH:D000069439', (48, 57))	('ipilimumab', 'Chemical', 'MESH:D000074324', (32, 42))	('patients', 'Species', '9606', (62, 70))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (76, 95))	('expansion', 'Var', (104, 113))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (76, 95))
407405	24778572	Among patients that received combination therapy, responses were seen both in patients with PDL-1 expression (6/13) or those without PDL-1 expression (9/22).	('PDL-1', 'Gene', '29126', (92, 97))	('PDL-1', 'Gene', (133, 138))	('PDL-1', 'Gene', (92, 97))	('expression', 'Var', (98, 108))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (6, 14))	('PDL-1', 'Gene', '29126', (133, 138))
407457	24778572	Yet, we have since learned that anti-PD-1 antibodies have led to durable and effective responses in lung cancers.	('lung cancers', 'Disease', (100, 112))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancers', 'Disease', 'MESH:D008175', (100, 112))	('antibodies', 'Var', (42, 52))	('lung cancers', 'Phenotype', 'HP:0100526', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('anti-PD-1', 'Gene', (32, 41))
407484	30697075	Lastly, a 14-3-3 oncoprotein was identified through whole transcriptome sequencing, caused by the fusion of YWHAE (14-3-3epsilon) with NUTM2A/B.	('YWHAE (14-3-3epsilon', 'Gene', '7531', (108, 128))	('NUTM2A/B', 'Gene', '728118;729262', (135, 143))	('fusion', 'Var', (98, 104))	('caused by', 'Reg', (84, 93))	('NUTM2A/B', 'Gene', (135, 143))
407539	30697075	The results of the present study suggested that the minimum value of CA125 and endometriosis were independent risk factors for PFS.	('endometriosis', 'Disease', 'MESH:D004715', (79, 92))	('CA125', 'Gene', '94025', (69, 74))	('minimum value', 'Var', (52, 65))	('endometriosis', 'Disease', (79, 92))	('endometriosis', 'Phenotype', 'HP:0030127', (79, 92))	('PFS', 'Disease', (127, 130))	('CA125', 'Gene', (69, 74))
407542	30697075	BCOR immunohistochemistry is positive in only half of the tumors harboring BCOR rearrangements.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('BCOR', 'Gene', '54880', (0, 4))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('rearrangements', 'Var', (80, 94))	('BCOR', 'Gene', (75, 79))	('BCOR', 'Gene', '54880', (75, 79))	('BCOR', 'Gene', (0, 4))
407558	30697075	In addition, women with HG-ESS and no surgical node evaluation had significantly decreased survival.	('decreased', 'NegReg', (81, 90))	('women', 'Species', '9606', (13, 18))	('HG-ESS', 'Var', (24, 30))	('survival', 'MPA', (91, 99))
407618	23750284	In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies.	('malignancies', 'Disease', (204, 216))	('LOX-PP', 'Gene', '4015', (127, 133))	('LOX-PP', 'Gene', (127, 133))	('participates', 'Reg', (72, 84))	('LOX', 'Gene', (63, 66))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('deregulation', 'Var', (43, 55))	('Ewing sarcoma', 'Disease', (88, 101))
407625	23750284	The most common of these translocations, observed in approximately 85% of the cases, is t(11;22) that fuse the EWS gene to the FLI1 transcription factor resulting in the EWS/FLI1 fusion protein.	('FLI1', 'Gene', '2313', (174, 178))	('FLI1', 'Gene', (174, 178))	('fuse', 'Var', (102, 106))	('EWS', 'Gene', '2130', (111, 114))	('EWS', 'Gene', (111, 114))	('EWS', 'Gene', (170, 173))	('EWS', 'Gene', '2130', (170, 173))	('FLI1', 'Gene', '2313', (127, 131))	('FLI1', 'Gene', (127, 131))
407637	23750284	The role of the propeptide has been, however, much less studied, although recent reports suggest that LOX propeptide acts as a tumor suppressor in several contexts.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('propeptide', 'Chemical', '-', (106, 116))	('tumor', 'Disease', (127, 132))	('LOX', 'Var', (102, 105))	('propeptide', 'Chemical', '-', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
407647	23750284	Time-course experiments confirmed that LOX is a gene downregulated by EWS/FLI1, since LOX mRNA levels were significantly upregulated upon EWS/FLI1 knockdown in the A673 Ewing sarcoma cell line (Figure 1A).	('EWS', 'Gene', '2130', (138, 141))	('EWS', 'Gene', (138, 141))	('EWS', 'Gene', '2130', (70, 73))	('EWS', 'Gene', (70, 73))	('FLI1', 'Gene', (142, 146))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (169, 182))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (169, 182))	('FLI1', 'Gene', '2313', (142, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('LOX mRNA levels', 'MPA', (86, 101))	('upregulated', 'PosReg', (121, 132))	('FLI1', 'Gene', '2313', (74, 78))	('FLI1', 'Gene', (74, 78))	('knockdown', 'Var', (147, 156))	('Ewing sarcoma', 'Disease', (169, 182))
407648	23750284	However, EWS/FLI1 knockdown produced a dramatic increase in LOX protein levels confirming that EWS/FLI1 downregulates LOX expression in these cells.	('knockdown', 'Var', (18, 27))	('FLI1', 'Gene', '2313', (99, 103))	('EWS', 'Gene', '2130', (9, 12))	('EWS', 'Gene', (9, 12))	('EWS', 'Gene', '2130', (95, 98))	('EWS', 'Gene', (95, 98))	('LOX protein levels', 'MPA', (60, 78))	('downregulates', 'NegReg', (104, 117))	('FLI1', 'Gene', '2313', (13, 17))	('FLI1', 'Gene', (99, 103))	('FLI1', 'Gene', (13, 17))	('increase', 'PosReg', (48, 56))
407664	23750284	We thus genetically modified the A673 Ewing sarcoma cell line to express LOX proenzyme (A673/TR/preLOX, aminoacides 1-415), its catalytic domain (A673/TR/LOXenz, aminoacides 166-415) and the LOX propeptide (A673/TR/LOX-PP, aminoacides 1-179) in an attempt to characterize the specific contribution of full-length LOX and of each one of the LOX-derived fragments to Ewing sarcoma tumorigenesis (Figure 3A).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (365, 378))	('sarcoma', 'Phenotype', 'HP:0100242', (371, 378))	('tumor', 'Disease', 'MESH:D009369', (379, 384))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (365, 378))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('preLOX', 'Chemical', '-', (96, 102))	('A673/TR/LOXenz', 'Var', (146, 160))	('Ewing sarcoma', 'Disease', (38, 51))	('tumor', 'Disease', (379, 384))	('LOX-PP', 'Gene', '4015', (215, 221))	('LOX-PP', 'Gene', (215, 221))	('A673/TR/preLOX', 'Var', (88, 102))	('LOXenz', 'Chemical', '-', (154, 160))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('Ewing sarcoma', 'Disease', (365, 378))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))	('propeptide', 'Chemical', '-', (195, 205))
407666	23750284	As shown in Figure 3B, preLOX, LOXenz and LOX-PP mRNAs were induced upon doxycycline stimulation in the A673/TR/preLOX, A673/TR/LOXenz and A673/TR/LOX-PP Ewing cells respectively.	('LOX-PP', 'Gene', (42, 48))	('doxycycline', 'Chemical', 'MESH:D004318', (73, 84))	('LOXenz', 'Chemical', '-', (31, 37))	('LOX-PP', 'Gene', '4015', (147, 153))	('LOX-PP', 'Gene', (147, 153))	('A673/TR/preLOX', 'Var', (104, 118))	('LOXenz', 'Chemical', '-', (128, 134))	('preLOX', 'Chemical', '-', (112, 118))	('A673/TR/LOXenz', 'Var', (120, 134))	('preLOX', 'Chemical', '-', (23, 29))	('LOX-PP', 'Gene', '4015', (42, 48))
407695	23750284	Following, we analysed the effect of preLOX, LOX-PP and LOXenz on cell migration and the ability to grow in an anchorage-independent manner.	('LOXenz', 'Chemical', '-', (56, 62))	('LOX-PP', 'Gene', '4015', (45, 51))	('LOX-PP', 'Gene', (45, 51))	('cell migration', 'CPA', (66, 80))	('LOXenz', 'Var', (56, 62))	('rat', 'Species', '10116', (74, 77))	('preLOX', 'Chemical', '-', (37, 43))
407696	23750284	In Figure 5A are shown the effects of preLOX, LOX-PP and LOXenz on cell migration through porous membranes in response to serum.	('preLOX', 'Chemical', '-', (38, 44))	('rat', 'Species', '10116', (75, 78))	('cell migration through', 'CPA', (67, 89))	('LOXenz', 'Chemical', '-', (57, 63))	('LOX-PP', 'Gene', '4015', (46, 52))	('LOX-PP', 'Gene', (46, 52))	('LOXenz', 'Var', (57, 63))
407705	23750284	Mice were injected subcutaneously with A673/TR/empty or A673/TR/LOX-PP and each group of animals was split into two groups of treatment, one of which was given doxycycline in the drinking water to induce the expression of the corresponding protein.	('doxycycline', 'Chemical', 'MESH:D004318', (160, 171))	('water', 'Chemical', 'MESH:D014867', (188, 193))	('A673/TR/empty', 'Var', (39, 52))	('expression', 'MPA', (208, 218))	('Mice', 'Species', '10090', (0, 4))	('LOX-PP', 'Gene', '4015', (64, 70))	('LOX-PP', 'Gene', (64, 70))
407706	23750284	As expected, animals injected with A673/TR/empty cells produced tumors both in the absence and in the presence of doxycycline in the drinking water.	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('A673/TR/empty', 'Var', (35, 48))	('doxycycline', 'Chemical', 'MESH:D004318', (114, 125))	('water', 'Chemical', 'MESH:D014867', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
407739	23750284	In addition, we also showed that DNA methylation can be involved in the repression of LOX gene in A673 cells, although we did not demonstrate if this was an indirect or a direct mechanism.	('methylation', 'Var', (37, 48))	('repression', 'MPA', (72, 82))	('rat', 'Species', '10116', (137, 140))	('LOX gene', 'Gene', (86, 94))	('involved', 'Reg', (56, 64))
407752	23750284	reported that normal rat kidney fibroblasts (NRK-49F) in which LOX mRNA was knocked down by antisense lysyl oxidase showed loose attachment to the plate and anchorage-independent growth and were highly tumorigenic in nude mice.	('knocked', 'Var', (76, 83))	('tumor', 'Disease', (202, 207))	('anchorage-independent growth', 'CPA', (157, 185))	('rat', 'Species', '10116', (21, 24))	('nude mice', 'Species', '10090', (217, 226))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('loose', 'NegReg', (123, 128))	('NRK-49', 'CellLine', 'CVCL:2144', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
407798	23750284	Anti-FLI1 antibody (# 554267) was purchased from BD Pharmingen (San Diego, CA, USA), anti-LOX (# L4794) and anti-tubulin (# T9026) from Sigma-Aldrich, anti-V5 (# R960-25) from Invitrogen, anti-P-Erk (P-Tyr 204, # sc-7383) from Santa Cruz Biotechnology (Santa Cruz, CA, USA), anti-Akt (# 9272), anti-P-Akt (P-Ser 473, # 9271) and anti-Erk (# 9102) from Cell Signalling (Boston, MA, USA).	('Erk', 'Gene', (334, 337))	('P-Ser 473', 'Var', (306, 315))	('Erk', 'Gene', '5594', (195, 198))	('Tyr', 'Chemical', 'MESH:D014443', (202, 205))	('# T9026', 'Var', (122, 129))	('Erk', 'Gene', '5594', (334, 337))	('FLI1', 'Gene', (5, 9))	('FLI1', 'Gene', '2313', (5, 9))	('Ser', 'Chemical', 'MESH:D012694', (308, 311))	('Erk', 'Gene', (195, 198))	('# 9272', 'Var', (285, 291))	('# L4794', 'Var', (95, 102))
407876	28732326	Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs.	('sensitize', 'Reg', (70, 79))	('increase', 'PosReg', (132, 140))	('treatment responses', 'CPA', (141, 160))	('sarcomas', 'Disease', 'MESH:D012509', (80, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcomas', 'Disease', (80, 88))	('HDIs', 'Var', (52, 56))
407899	28732326	Acetylation removes the positive charge on the histones, thereby decreasing the interaction of the N terminus of histones with the negatively charged phosphate groups of DNA.	('Acetylation', 'Var', (0, 11))	('interaction', 'Interaction', (80, 91))	('histones', 'Protein', (113, 121))	('phosphate', 'Chemical', 'MESH:D010710', (150, 159))	('decreasing', 'NegReg', (65, 75))	('removes', 'NegReg', (12, 19))	('positive charge', 'MPA', (24, 39))
407900	28732326	Thus, acetylation of histones is known to increase the expression of genes, leading to gene expression in the multiple pathways involved in proliferation, migration, angiogenesis and differentiation.	('angiogenesis', 'CPA', (166, 178))	('proliferation', 'CPA', (140, 153))	('migration', 'CPA', (155, 164))	('acetylation', 'Var', (6, 17))	('differentiation', 'CPA', (183, 198))	('expression', 'MPA', (55, 65))	('histones', 'Protein', (21, 29))	('rat', 'Species', '10116', (147, 150))	('rat', 'Species', '10116', (158, 161))	('gene expression', 'MPA', (87, 102))	('leading to', 'Reg', (76, 86))	('increase', 'PosReg', (42, 50))
407945	28732326	For example, HDI trichostatin A promoted p53-p300 interaction and recruitment of p53 Lys-382 to promoter regions of its target genes p21 and PUMA, consequently upregulating their expression in Ewing sarcoma cells .	('promoted', 'PosReg', (32, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (193, 206))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (193, 206))	('Lys-382', 'Var', (85, 92))	('p53', 'Gene', (81, 84))	('p53', 'Gene', (41, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('sarcoma cells', 'Disease', 'MESH:D012509', (199, 212))	('p21', 'Gene', (133, 136))	('upregulating', 'PosReg', (160, 172))	('Ewing sarcoma', 'Disease', (193, 206))	('p300', 'Gene', (45, 49))	('p300', 'Gene', '2033', (45, 49))	('trichostatin A', 'Chemical', 'MESH:C012589', (17, 31))	('Lys', 'Chemical', 'MESH:D008239', (85, 88))	('sarcoma cells', 'Disease', (199, 212))	('expression', 'MPA', (179, 189))	('p21', 'Gene', '1026', (133, 136))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', '7157', (41, 44))
407961	28732326	HDI, romidepsin, reversed SS18-SSX-mediated polycomb silencing of EGR1 in synovial sarcoma .	('SS18', 'Gene', '6760', (26, 30))	('EGR1', 'Gene', (66, 70))	('synovial sarcoma', 'Disease', (74, 90))	('SSX', 'Gene', '727837', (31, 34))	('silencing', 'NegReg', (53, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('SS18', 'Gene', (26, 30))	('EGR1', 'Gene', '1958', (66, 70))	('polycomb', 'Var', (44, 52))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (74, 90))	('synovial sarcoma', 'Disease', 'MESH:D013584', (74, 90))	('SSX', 'Gene', (31, 34))
407973	28732326	Some sarcoma cells exhibit a phenotype resistant to death receptor-mediated apoptosis by expressing c-FLIP.	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('c-FLIP', 'Var', (100, 106))	('sarcoma cells', 'Disease', (5, 18))	('sarcoma cells', 'Disease', 'MESH:D012509', (5, 18))
407982	28732326	In uterine sarcoma, vorinostat induced immediate apoptotic cell death as supported by upregulation of caspase-9 as well as activation of caspases-3, caspases-7 and PARP cleavage .	('caspase', 'Gene', '841;842', (102, 109))	('caspase-9', 'Gene', (102, 111))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (3, 18))	('activation', 'PosReg', (123, 133))	('PARP', 'Gene', '142', (164, 168))	('vorinostat', 'Var', (20, 30))	('caspase', 'Gene', (137, 144))	('PARP', 'Gene', (164, 168))	('apoptotic cell death', 'CPA', (49, 69))	('sarcoma', 'Disease', 'MESH:D012509', (11, 18))	('caspase', 'Gene', '841;842', (137, 144))	('sarcoma', 'Disease', (11, 18))	('upregulation', 'PosReg', (86, 98))	('caspase', 'Gene', (149, 156))	('vorinostat', 'Chemical', 'MESH:D000077337', (20, 30))	('caspase-9', 'Gene', '842', (102, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('caspase', 'Gene', (102, 109))	('caspase', 'Gene', '841;842', (149, 156))
407985	28732326	EGR1 reactivation by HDIs promoted cell death in sarcoma by PTEN tumor suppressor .	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('EGR1', 'Gene', '1958', (0, 4))	('tumor', 'Disease', (65, 70))	('reactivation', 'Var', (5, 17))	('promoted', 'PosReg', (26, 34))	('PTEN', 'Gene', (60, 64))	('PTEN', 'Gene', '5728', (60, 64))	('cell death', 'CPA', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('EGR1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('sarcoma', 'Disease', (49, 56))
407988	28732326	In addition, HDI trichostatin A significantly inhibited the human osteosarcoma cells growth and promoted apoptosis in a dose-dependent manner through p53 signaling pathway activation .	('apoptosis', 'CPA', (105, 114))	('osteosarcoma', 'Disease', (66, 78))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('p53', 'Gene', (150, 153))	('trichostatin A', 'Chemical', 'MESH:C012589', (17, 31))	('promoted', 'PosReg', (96, 104))	('p53', 'Gene', '7157', (150, 153))	('sarcoma cells', 'Disease', (71, 84))	('osteosarcoma', 'Disease', 'MESH:D012516', (66, 78))	('sarcoma cells', 'Disease', 'MESH:D012509', (71, 84))	('activation', 'PosReg', (172, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('inhibited', 'NegReg', (46, 55))	('HDI', 'Var', (13, 16))	('human', 'Species', '9606', (60, 65))
407995	28732326	Two new HDIs, PCI-34051 and PCI-48012, specifically inhibited the activity of HDAC 8 leading to marked S-phase cell cycle arrest in human malignant peripheral nerve sheath tumors cells .	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('HDAC 8', 'Gene', (78, 84))	('sheath tumors', 'Disease', 'MESH:D010524', (165, 178))	('activity', 'MPA', (66, 74))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (138, 178))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('HDAC 8', 'Gene', '55869', (78, 84))	('PCI-48012', 'Var', (28, 37))	('inhibited', 'NegReg', (52, 61))	('human', 'Species', '9606', (132, 137))	('sheath tumors', 'Disease', (165, 178))	('PCI-34051', 'Var', (14, 23))	('arrest', 'Disease', (122, 128))
408009	28732326	Overexpression of gelatinase A, also known as MMP-2, is associated with pulmonary metastasis and related to the prognosis of osteosarcoma .	('gelatinase', 'Protein', (18, 28))	('MMP-2', 'Gene', '4313', (46, 51))	('related to', 'Reg', (97, 107))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('pulmonary metastasis', 'Disease', (72, 92))	('osteosarcoma', 'Disease', (125, 137))	('MMP-2', 'Gene', (46, 51))	('associated with', 'Reg', (56, 71))	('Overexpression', 'Var', (0, 14))	('osteosarcoma', 'Disease', 'MESH:D012516', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (72, 92))
408016	28732326	Furthermore, in rat chondrosarcoma cells, vorinostat induces autophagy-associated cell death which was confirmed by the detection of autophagosome-specific protein and specific ultrastructural morphology in the cytoplasm .	('chondrosarcoma', 'Disease', 'MESH:D002813', (20, 34))	('vorinostat', 'Chemical', 'MESH:D000077337', (42, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('vorinostat', 'Var', (42, 52))	('induces', 'Reg', (53, 60))	('rat', 'Species', '10116', (16, 19))	('sarcoma cells', 'Disease', (27, 40))	('sarcoma cells', 'Disease', 'MESH:D012509', (27, 40))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (20, 34))	('autophagy-associated cell death', 'CPA', (61, 92))	('chondrosarcoma', 'Disease', (20, 34))
408029	28732326	Epigenetic treatment with trichostatin A or vorinostat can reduce the expressing of Notch1 and EphrinB1 in embryonal rhabdomyosarcoma cells .	('embryonal rhabdomyosarcoma', 'Disease', (107, 133))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (107, 133))	('sarcoma cells', 'Disease', (126, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcoma cells', 'Disease', 'MESH:D012509', (126, 139))	('EphrinB1', 'Gene', '1947', (95, 103))	('Notch1', 'Gene', (84, 90))	('trichostatin A', 'Chemical', 'MESH:C012589', (26, 40))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (117, 133))	('reduce', 'NegReg', (59, 65))	('Epigenetic treatment', 'Var', (0, 20))	('Notch1', 'Gene', '4851', (84, 90))	('expressing', 'MPA', (70, 80))	('vorinostat', 'Chemical', 'MESH:D000077337', (44, 54))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (107, 133))	('EphrinB1', 'Gene', (95, 103))
408034	28732326	Heavy ion radiotherapy has been shown certain therapeutic advantages including potentially reducing undesirable side-effects, lower risk of secondary malignancies and improvement of clinical outcome and quality of life when compared with conventional photon radiotherapy.	('Heavy ion', 'Var', (0, 9))	('malignancies', 'Disease', (150, 162))	('clinical', 'MPA', (182, 190))	('undesirable', 'MPA', (100, 111))	('improvement', 'PosReg', (167, 178))	('reducing', 'NegReg', (91, 99))	('malignancies', 'Disease', 'MESH:D009369', (150, 162))
408041	28732326	Vorinostat enhances cytotoxicity of temozolomide by downregulating cyclin D1 to induce G0/G1 cell cycle arrest and promoting apoptosis by cleavage of caspase-3 and PARP in Ewing sarcoma cells.	('sarcoma cells', 'Disease', 'MESH:D012509', (178, 191))	('cyclin D1', 'Gene', '595', (67, 76))	('Ewing sarcoma', 'Disease', (172, 185))	('apoptosis', 'CPA', (125, 134))	('PARP', 'Gene', '142', (164, 168))	('enhances', 'PosReg', (11, 19))	('arrest', 'Disease', 'MESH:D006323', (104, 110))	('caspase-3', 'Gene', '836', (150, 159))	('downregulating', 'NegReg', (52, 66))	('promoting', 'PosReg', (115, 124))	('cleavage', 'Var', (138, 146))	('PARP', 'Gene', (164, 168))	('caspase-3', 'Gene', (150, 159))	('induce', 'PosReg', (80, 86))	('sarcoma cells', 'Disease', (178, 191))	('Vorinostat', 'Chemical', 'MESH:D000077337', (0, 10))	('temozolomide', 'Chemical', 'MESH:D000077204', (36, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (172, 185))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (172, 185))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('cytotoxicity', 'Disease', (20, 32))	('arrest', 'Disease', (104, 110))	('cyclin D1', 'Gene', (67, 76))	('cytotoxicity', 'Disease', 'MESH:D064420', (20, 32))
408047	28732326	Some sarcomas are with chromatin translocations resulting in abnormal fusion proteins like Ewing sarcomas, synovial sarcoma, and embryonal rhabdomyosarcoma.	('synovial sarcoma', 'Disease', 'MESH:D013584', (107, 123))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (129, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (91, 105))	('fusion proteins', 'MPA', (70, 85))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (107, 123))	('Ewing sarcomas', 'Disease', (91, 105))	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (91, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('embryonal rhabdomyosarcoma', 'Disease', (129, 155))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (139, 155))	('sarcomas', 'Disease', (5, 13))	('abnormal', 'Var', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (129, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcomas', 'Disease', (97, 105))	('synovial sarcoma', 'Disease', (107, 123))
408048	28732326	The fact was that these sarcomas with fusion oncogenes are more sensitive to HDIs treatment than sarcomas lacking known translocations.	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcomas', 'Disease', (24, 32))	('sensitive', 'MPA', (64, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (97, 105))	('fusion oncogenes', 'Var', (38, 54))
408051	28732326	The most effective tumor growth inhibition in vitro was observed with doxorubicin and the HDI vorinostat.	('doxorubicin', 'Var', (70, 81))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('vorinostat', 'Chemical', 'MESH:D000077337', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('doxorubicin', 'Chemical', 'MESH:D004317', (70, 81))
408064	28732326	In vivo, treatment of xenografted mice carrying sarcomas with pazopanib and valproic acid results in a greater than additive reduction in tumor volume compared with single treatment with either drug .	('reduction', 'NegReg', (125, 134))	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('mice', 'Species', '10090', (34, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('tumor', 'Disease', (138, 143))	('pazopanib', 'Chemical', 'MESH:C516667', (62, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('sarcomas', 'Disease', (48, 56))	('valproic acid', 'Chemical', 'MESH:D014635', (76, 89))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('pazopanib', 'Var', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
408066	28732326	Deregulation of epigenetic silencing by histone acetylation and DNA hyper-methylation might play a fundamental role in the etiology of uterine sarcomas .	('epigenetic', 'MPA', (16, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcomas', 'Disease', (143, 151))	('Deregulation', 'Var', (0, 12))	('histone', 'Protein', (40, 47))	('DNA', 'MPA', (64, 67))	('sarcomas', 'Disease', 'MESH:D012509', (143, 151))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (135, 150))
408069	28732326	Combination of 5-aza-dC and entinostat shows marked synergy, and is correlated with significant reactivation of the expression of two tumor suppressor genes, E-cadherin and tumor suppressor lung cancer-1 .	('reactivation', 'PosReg', (96, 108))	('expression', 'MPA', (116, 126))	('entinostat', 'Gene', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (173, 178))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('5-aza-dC', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lung cancer', 'Disease', (190, 201))	('E-cadherin', 'Protein', (158, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('tumor', 'Disease', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
408071	28732326	For example, in a study that adopted heterozygous Ptch knockout mice, 5-aza-dC and HDI valproic acid combination therapy reactivates wild-type Ptch expression by reducing methylation of the Ptch promoter and induction of histone hyperacetylation, effectively preventing rhabdomyosarcoma formation .	('rhabdomyosarcoma', 'Disease', (270, 286))	('methylation', 'MPA', (171, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (270, 286))	('preventing', 'NegReg', (259, 269))	('Ptch', 'Protein', (190, 194))	('valproic acid', 'Chemical', 'MESH:D014635', (87, 100))	('reactivates', 'Var', (121, 132))	('induction', 'Reg', (208, 217))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (70, 78))	('reducing', 'NegReg', (162, 170))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (270, 286))	('histone hyperacetylation', 'MPA', (221, 245))	('mice', 'Species', '10090', (64, 68))
408072	28732326	Recent studies have indicated that HDIs can augment NK cell immunotherapy of sarcomas (Table 3).	('HDIs', 'Var', (35, 39))	('augment', 'PosReg', (44, 51))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('NK cell immunotherapy', 'CPA', (52, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))
408090	28732326	In a phase II trial, eligible patients with recurrent or metastatic translocation-associated sarcoma were treated with SB939.	('sarcoma', 'Disease', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('SB939', 'Var', (119, 124))	('patients', 'Species', '9606', (30, 38))	('SB939', 'Chemical', 'MESH:C557525', (119, 124))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
408122	28732326	It is also suggested that other epigenetic modulators can lead to resistance to HDIs in sarcomas.	('sarcomas', 'Disease', (88, 96))	('epigenetic', 'Var', (32, 42))	('lead to', 'Reg', (58, 65))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('resistance', 'MPA', (66, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
408130	28732326	What's more, evidences from preclinical studies showed that HDIs can not only sensitize sarcomas to radiotherapy and chemotherapy, but also increase the treatment efficacy when combine chemotherapeutic drugs or other targeted drugs in sarcomas.	('sarcomas', 'Disease', (88, 96))	('HDIs', 'Var', (60, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('sensitize', 'Reg', (78, 87))	('sarcomas', 'Disease', 'MESH:D012509', (235, 243))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (235, 243))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('increase', 'PosReg', (140, 148))	('treatment efficacy', 'CPA', (153, 171))	('sarcomas', 'Disease', (235, 243))
408133	28732326	Another challenge is that sarcomas have diverse subtypes and genetic alterations involve oncogenic somatic mutations in some subtypes and chromosomal translocations in other subtypes.	('sarcomas', 'Disease', (26, 34))	('sarcomas', 'Disease', 'MESH:D012509', (26, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('chromosomal translocations', 'Var', (138, 164))	('rat', 'Species', '10116', (73, 76))
408134	28732326	In some context, sarcomas with chromosomal translocations can be more sensitive to HDI treatment than sarcomas lacking known translocations.	('sarcomas', 'Disease', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcomas', 'Disease', (17, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))	('sarcomas', 'Disease', 'MESH:D012509', (102, 110))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('sensitive', 'MPA', (70, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('chromosomal translocations', 'Var', (31, 57))
408143	23324546	A population-based study of Kaposi Sarcoma-associated herpesvirus seropositivity in Uganda using principal components analysis Kaposi sarcoma-associated herpesvirus (KSHV) seropositivity is associated with sexual, environmental, and socioeconomic exposures.	('herpesvirus', 'Species', '39059', (153, 164))	('Sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('herpesvirus', 'Species', '39059', (54, 65))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (127, 141))	('KSHV', 'Species', '37296', (166, 170))	('Kaposi Sarcoma', 'Phenotype', 'HP:0100726', (28, 42))	('men', 'Species', '9606', (221, 224))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (127, 141))	('KS', 'Phenotype', 'HP:0100726', (166, 168))	('Kaposi sarcoma', 'Disease', (127, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('seropositivity', 'Var', (172, 186))	('Kaposi Sarcoma', 'Disease', (28, 42))	('associated', 'Reg', (190, 200))	('herpesvirus seropositivity', 'Phenotype', 'HP:0005353', (54, 80))	('KSHV', 'Gene', (166, 170))	('Kaposi Sarcoma', 'Disease', 'MESH:D012514', (28, 42))
408149	23324546	In crude analysis, KSHV seropositivity was associated with the Knowledge (ptrend = 0.012) and Socioeconomic components (ptrend = 0.0001), but not with the Sexual-behavioral component (ptrend = 0.066).	('KSHV', 'Gene', (19, 23))	('associated', 'Interaction', (43, 53))	('seropositivity', 'Var', (24, 38))	('KSHV', 'Species', '37296', (19, 23))	('KS', 'Phenotype', 'HP:0100726', (19, 21))
408150	23324546	KSHV seropositivity was associated with the Socioeconomic PC (ptrend = 0.037), but not with the Sexual-behavioral and Knowledge PCs, in the models including PCs, age, gender and geographic region.	('KSHV', 'Species', '37296', (0, 4))	('associated', 'Reg', (24, 34))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('PCs', 'Chemical', '-', (128, 131))	('Socioeconomic PC', 'Disease', (44, 60))	('seropositivity', 'Var', (5, 19))	('KSHV', 'Gene', (0, 4))	('PCs', 'Chemical', '-', (157, 160))
408160	23324546	KSHV seropositivity has been positively associated with some sexual risk factors such as number of marital unions and number of children born in some studies, but not with other sexual risk factors such as ever had other STIs in other studies.	('KSHV', 'Species', '37296', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('children', 'Species', '9606', (128, 136))	('associated', 'Interaction', (40, 50))	('seropositivity', 'Var', (5, 19))	('KSHV', 'Gene', (0, 4))
408162	23324546	We previously showed statistically significant positive association between KSHV seropositivity and male gender, increasing age, low or no formal education, and residence in a KS endemic geographical area in Uganda, using data from a nationally representative population-based sample of adults in Uganda.	('KS', 'Phenotype', 'HP:0100726', (176, 178))	('seropositivity', 'Var', (81, 95))	('positive', 'PosReg', (47, 55))	('KS', 'Phenotype', 'HP:0100726', (76, 78))	('KSHV', 'Species', '37296', (76, 80))	('KSHV', 'Gene', (76, 80))
408163	23324546	In a follow-up analysis of the same subjects, KSHV seropositivity was positively associated with number of marital unions, number of children born, and inversely associated with having ever used a condom, possibly implicating sexual transmission.	('KSHV', 'Species', '37296', (46, 50))	('children', 'Species', '9606', (133, 141))	('seropositivity', 'Var', (51, 65))	('KS', 'Phenotype', 'HP:0100726', (46, 48))	('inversely', 'NegReg', (152, 161))	('KSHV', 'Gene', (46, 50))
408170	23324546	In unadjusted analyses (Table 2), KHSV seropositivity was significantly associated with Socioeconomic (ptrend = 0.0001) and Knowledge (ptrend = 0.012) PCs, but it was not associated with the Sexual behavioral PC (ptrend = 0.07).	('seropositivity', 'Var', (39, 53))	('KHSV', 'Gene', (34, 38))	('Socioeconomic', 'Disease', (88, 101))	('PCs', 'Chemical', '-', (151, 154))	('behavioral PC', 'Phenotype', 'HP:0000708', (198, 211))	('Sexual behavior', 'Phenotype', 'HP:0030214', (191, 206))	('associated', 'Interaction', (72, 82))	('KHSV', 'Chemical', '-', (34, 38))	('PCs', 'Disease', (151, 154))
408172	23324546	The association of KSHV seropositivity with the Socioeconomic (ptrend = 0.002) and Knowledge (ptrend = 0.018) PCs remained significant when we adjusted for age, sex and geographical area of residence.	('KSHV', 'Gene', (19, 23))	('association', 'Interaction', (4, 15))	('PCs', 'Chemical', '-', (110, 113))	('seropositivity', 'Var', (24, 38))	('KSHV', 'Species', '37296', (19, 23))	('KS', 'Phenotype', 'HP:0100726', (19, 21))
408174	23324546	KSHV seropositivity was significantly associated with the Socioeconomic PC, but not with Knowledge PC when the PCs were entered into a multivariable model that also included age, sex, and geographical region (ptrend =0.038).	('KSHV', 'Species', '37296', (0, 4))	('associated', 'Reg', (38, 48))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('seropositivity', 'Var', (5, 19))	('PCs', 'Chemical', '-', (111, 114))	('KSHV', 'Gene', (0, 4))	('Socioeconomic PC', 'Disease', (58, 74))
408176	23324546	We found that in Uganda, where KSHV is highly endemic, KSHV seropositivity was inversely associated with high factor scores on the Socioeconomic and Knowledge PCs, but not with Sexual behavioral PC.	('behavioral PC', 'Phenotype', 'HP:0000708', (184, 197))	('KSHV', 'Species', '37296', (55, 59))	('KS', 'Phenotype', 'HP:0100726', (31, 33))	('KSHV', 'Species', '37296', (31, 35))	('PCs', 'Chemical', '-', (159, 162))	('seropositivity', 'Var', (60, 74))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('associated', 'Interaction', (89, 99))	('Sexual behavior', 'Phenotype', 'HP:0030214', (177, 192))	('KSHV', 'Gene', (55, 59))
408179	23324546	In that study, KSHV seropositivity was inversely associated with low factor scores of maternal and environmental factors, which are surrogates for socioeconomic status.	('seropositivity', 'Var', (20, 34))	('KSHV', 'Species', '37296', (15, 19))	('low', 'NegReg', (65, 68))	('KS', 'Phenotype', 'HP:0100726', (15, 17))	('KSHV', 'Gene', (15, 19))	('men', 'Species', '9606', (106, 109))
408184	23324546	Our study found a marginal association between the Sexual behavior PC and KSHV seropositivity in crude analyses, but the association disappeared after adjusting for the other PCs, suggesting that the association detected with sexual variables may be due to confounding by other poorly understood socioeconomic factors.	('PCs', 'Chemical', '-', (175, 178))	('KSHV', 'Gene', (74, 78))	('Sexual behavior', 'Phenotype', 'HP:0030214', (51, 66))	('Sexual', 'Disease', (51, 57))	('seropositivity', 'Var', (79, 93))	('KSHV', 'Species', '37296', (74, 78))	('KS', 'Phenotype', 'HP:0100726', (74, 76))
408187	23324546	For example, de Sanjose and colleagues observed significant variation in KSHV seroprevalence from 3.8% in Spain to 46% in Nigeria among women participating in a large international study conducted by the International Agency for Research on Cancer.	('KSHV', 'Species', '37296', (73, 77))	('Cancer', 'Disease', (241, 247))	('women', 'Species', '9606', (136, 141))	('KS', 'Phenotype', 'HP:0100726', (73, 75))	('Cancer', 'Disease', 'MESH:D009369', (241, 247))	('Cancer', 'Phenotype', 'HP:0002664', (241, 247))	('seroprevalence', 'Var', (78, 92))	('KSHV', 'Gene', (73, 77))	('Spain', 'Disease', (106, 111))	('Nigeria', 'Disease', (122, 129))
408188	23324546	KSHV seropositivity is lower in wealthier countries in Africa, such as South Africa, and higher in poorer countries, such as Uganda.	('KSHV', 'Species', '37296', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('seropositivity', 'Var', (5, 19))	('KSHV', 'Gene', (0, 4))	('higher', 'PosReg', (89, 95))	('lower', 'NegReg', (23, 28))
408196	23324546	For instance, some sexual behavioral variables such as ever used condom from the last sex intercourse or number of children born were found to be associated with KSHV seropositivity, but PCA does not reveal this association.	('associated', 'Interaction', (146, 156))	('seropositivity', 'Var', (167, 181))	('KSHV', 'Species', '37296', (162, 166))	('children', 'Species', '9606', (115, 123))	('behavioral variables', 'Phenotype', 'HP:0000708', (26, 46))	('sexual behavior', 'Phenotype', 'HP:0030214', (19, 34))	('KS', 'Phenotype', 'HP:0100726', (162, 164))	('KSHV', 'Gene', (162, 166))	('sex intercourse', 'Phenotype', 'HP:0030214', (86, 101))
408198	23324546	To summarize, we report a significant association between low socioeconomic status and KSHV seropositivity.	('seropositivity', 'Var', (92, 106))	('KSHV', 'Species', '37296', (87, 91))	('KSHV', 'Disease', (87, 91))	('KS', 'Phenotype', 'HP:0100726', (87, 89))
408217	23324546	Because age, gender, and geographic region were previously shown to be significantly associated with KSHV seropositivity, they were excluded from the PCA.	('seropositivity', 'Var', (106, 120))	('KSHV', 'Species', '37296', (101, 105))	('KS', 'Phenotype', 'HP:0100726', (101, 103))	('KSHV', 'Gene', (101, 105))	('associated', 'Reg', (85, 95))
408232	23329308	Molecular detection and targeting of EWSR1 fusion transcripts in soft tissue tumors Soft tissue tumors are a heterogeneous group of tumors, traditionally classified according to morphology and histogenesis.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Soft tissue tumors', 'Phenotype', 'HP:0031459', (84, 102))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (65, 83))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('EWSR1', 'Gene', (37, 42))	('tumors', 'Disease', (132, 138))	('fusion', 'Var', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('EWSR1', 'Gene', '2130', (37, 42))
408251	23329308	It lies on a fragment flanked on the centromeric side, by the translocation breakpoint in acute lymphoblastic leukemia-associated t(4;11)(q21;q23) and on the telomeric side in Ewing sarcoma-associated t(11;22)(q24;q12) breakpoint.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (176, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (176, 189))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (90, 118))	('acute lymphoblastic leukemia', 'Disease', (90, 118))	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('t(4;11)(q21;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (130, 146))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (96, 118))	('Ewing sarcoma', 'Disease', (176, 189))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (90, 118))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (201, 218))	('t(4;11)(q21;q23', 'Var', (130, 145))
408253	23329308	The fusion transcript EWSR1/FLI1, as well as many other chimeric proteins, interferes with several molecular pathways, influencing the development and progression of this tumor.	('development', 'CPA', (135, 146))	('molecular pathways', 'Pathway', (99, 117))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('fusion', 'Var', (4, 10))	('interferes', 'NegReg', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('EWSR1/FLI1', 'Gene', (22, 32))	('influencing', 'Reg', (119, 130))
408256	23329308	EWSR1/FLI1 also determines an upregulation of GLI, altering the molecular pathways associated with it.	('GLI', 'Gene', (46, 49))	('EWSR1/FLI1', 'Var', (0, 10))	('molecular pathways', 'Pathway', (64, 82))	('altering', 'Reg', (51, 59))	('GLI', 'Gene', '2735', (46, 49))	('upregulation', 'PosReg', (30, 42))
408261	23329308	The chromosomal translocation t(21;22)(q22;q12) has been described in approximately 10 % of Ewing's sarcoma tumors.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (92, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	("Ewing's sarcoma tumors", 'Disease', 'MESH:C563168', (92, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 47))	('t(21;22)(q22;q12', 'Var', (30, 46))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	("Ewing's sarcoma tumors", 'Disease', (92, 114))
408281	23329308	identified this type of translocation in tumor tissue derived from an undifferentiated sarcoma from the pelvic bone.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('translocation', 'Var', (24, 37))	('tumor', 'Disease', (41, 46))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
408282	23329308	Recently, using small-interfering RNA, the fundamental role of EWS-POU5F1 in tumorigenesis and tumor cell maintenance and its importance in the development and progression of sarcomas has been proved.	('POU5F1', 'Gene', '5460', (67, 73))	('small-interfering', 'Var', (16, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('sarcomas', 'Disease', (175, 183))	('POU5F1', 'Gene', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('sarcomas', 'Disease', 'MESH:D012509', (175, 183))	('tumor', 'Disease', (77, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (175, 183))	('tumor', 'Disease', (95, 100))
408295	23329308	Deregulation of Patz1 has been described in colorectal cancer and in testicular tumors.	('described', 'Reg', (31, 40))	('colorectal cancer', 'Disease', (44, 61))	('Deregulation', 'Var', (0, 12))	('testicular tumors', 'Disease', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('testicular tumors', 'Disease', 'MESH:D013736', (69, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('testicular tumors', 'Phenotype', 'HP:0010788', (69, 86))	('Patz1', 'Gene', (16, 21))	('Patz1', 'Gene', '23598', (16, 21))
408298	23329308	The chimeric transcript has been described in small round cell tumor with multidirectional differentiation rather than pPNET.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('chimeric', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (63, 68))
408305	23329308	Finally, the most recent studies have shown the presence of EWSR1-ATF1 fusion gene in a myoepithelial tumor and in endobronchial pulmonary angiomatoid fibrous histiocytoma.	('myoepithelial tumor', 'Disease', 'MESH:D009208', (88, 107))	('endobronchial pulmonary angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (115, 171))	('fusion gene', 'Var', (71, 82))	('ATF1', 'Gene', (66, 70))	('ATF1', 'Gene', '466', (66, 70))	('presence', 'Reg', (48, 56))	('myoepithelial tumor', 'Disease', (88, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('histiocytoma', 'Phenotype', 'HP:0012315', (159, 171))
408309	23329308	Activation of CREB by phosphorylation has been implicated in the survival of mammalian cells and has been mainly involved in neuronal development.	('CREB', 'Gene', (14, 18))	('phosphorylation', 'Var', (22, 37))	('implicated', 'Reg', (47, 57))	('mammalian', 'Species', '9606', (77, 86))	('CREB', 'Gene', '1385', (14, 18))	('Activation', 'PosReg', (0, 10))	('involved', 'Reg', (113, 121))
408324	23329308	Deregulation of this gene has been described in several cancer cell lines, while a fusion transcript with EWSR1 has been detected in a panel of cancer cell lines of a small round cell sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (184, 191))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('sarcoma', 'Disease', (184, 191))	('cancer', 'Disease', (144, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('EWSR1', 'Gene', (106, 111))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
408338	23329308	have developed a four-color FISH, with CREB1 proximal probe RP11-167C7 and ATF1 proximal probe RP11-189H16 labeled by nick translation with Cy5, and CREB1 distal probes G248P81788B12 and G248P89268A6 and ATF1 distal probe RP11-407N8 labeled with Cy3.	('ATF1', 'Gene', '466', (75, 79))	('CREB1', 'Gene', '1385', (149, 154))	('Cy3', 'Chemical', '-', (246, 249))	('G248P81788B12', 'Var', (169, 182))	('RP11-189H16', 'Var', (95, 106))	('CREB1', 'Gene', '1385', (39, 44))	('G248P89268A6', 'Var', (187, 199))	('CREB1', 'Gene', (149, 154))	('CREB1', 'Gene', (39, 44))	('ATF1', 'Gene', (204, 208))	('Cy5', 'Chemical', 'MESH:C085321', (140, 143))	('RP11-167C7', 'Var', (60, 70))	('ATF1', 'Gene', (75, 79))	('ATF1', 'Gene', '466', (204, 208))
408342	23329308	Different systems based on q RT-PCR have been developed for the detection of fusion transcripts in soft tumors, in particular for synovial sarcoma with Syt translocation.	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('fusion transcripts', 'Var', (77, 95))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('synovial sarcoma', 'Disease', (130, 146))	('synovial sarcoma', 'Disease', 'MESH:D013584', (130, 146))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('soft tumors', 'Disease', 'MESH:C562950', (99, 110))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (130, 146))	('Syt', 'Gene', '6760', (152, 155))	('Syt', 'Gene', (152, 155))	('soft tumors', 'Disease', (99, 110))
408344	23329308	There are few information about the use of western blotting for the detection of translocations in soft tissue tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('soft tissue tumors', 'Disease', (99, 117))	('soft tissue tumors', 'Disease', 'MESH:D012983', (99, 117))	('translocations', 'Var', (81, 95))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (99, 117))
408347	23329308	The identification of specific fusion transcripts, including several variants of spicing of EWSR1 gene could help in establishing new biotechnological systems to block their aberrant activity in cancer cells.	('aberrant', 'MPA', (174, 182))	('variants', 'Var', (69, 77))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('EWSR1', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
408361	23329308	The loss of PKC-B causes apoptosis in Ewing sarcoma cells and reduces tumor growth in animal model.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('reduces', 'NegReg', (62, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('tumor', 'Disease', (70, 75))	('Ewing sarcoma', 'Disease', (38, 51))	('PKC-B', 'Gene', (12, 17))	('apoptosis', 'CPA', (25, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('PKC-B', 'Gene', '5579', (12, 17))	('loss', 'Var', (4, 8))
408370	22084725	High expression of complement component 5 (C5) correlated with better event-free (P = 0.01) and overall survival (P = 0.004) in a dose-dependent manner.	('overall survival', 'CPA', (96, 112))	('High', 'Var', (0, 4))	('component 5', 'Gene', '727', (30, 41))	('C5', 'Gene', (43, 45))	('better', 'PosReg', (63, 69))	('component 5', 'Gene', (30, 41))
408406	22084725	The survival analysis showed that high expression of IL8, also known as CXCL8, associates with unfavourable survival in classical Ewing sarcoma of bone.	('high expression', 'Var', (34, 49))	('CXCL8', 'Gene', '3576', (72, 77))	('IL8', 'Gene', (53, 56))	('CXCL8', 'Gene', (72, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (130, 143))	('classical Ewing sarcoma of bone', 'Disease', (120, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))
408409	22084725	One should bear in mind, however, that mutations in JAK1 resulting in its constitutive activation have been suggested to be the initial defects in several human cancers and inhibition of JAK1 has been shown to induce apoptosis and to reduce tumour cell invasion in colorectal cancer cells.	('activation', 'PosReg', (87, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (265, 282))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('JAK1', 'Gene', (187, 191))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('colorectal cancer', 'Phenotype', 'HP:0003003', (265, 282))	('induce', 'PosReg', (210, 216))	('mutations', 'Var', (39, 48))	('apoptosis', 'CPA', (217, 226))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('reduce', 'NegReg', (234, 240))	('colorectal cancer', 'Disease', (265, 282))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('JAK1', 'Gene', (52, 56))	('tumour cell invasion', 'CPA', (241, 261))	('inhibition', 'Var', (173, 183))	('constitutive', 'MPA', (74, 86))
408441	33305494	Being female and of older age, and having increased tumor invasion, non-total resection, recurrence and metastasis, and the dedifferentiated histological subtype were demonstrated to independently reduce the survival of patients with chordoma 5 .	('increased', 'PosReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('reduce', 'NegReg', (197, 203))	('chordoma', 'Phenotype', 'HP:0010762', (234, 242))	('tumor', 'Disease', (52, 57))	('metastasis', 'CPA', (104, 114))	('chordoma', 'Gene', '121775', (234, 242))	('survival', 'MPA', (208, 216))	('age', 'Gene', '5973', (26, 29))	('patients', 'Species', '9606', (220, 228))	('chordoma', 'Gene', (234, 242))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('non-total', 'Var', (68, 77))	('age', 'Gene', (26, 29))
408612	25091619	Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that binds to the same site on beta tubulin as paclitaxel and, in preclinical models, appears to be a more potent polymerizer of tubulin than paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (210, 220))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))	('epothilone B', 'Chemical', 'MESH:C093788', (55, 67))	('binds', 'Interaction', (73, 78))	('Ixabepilone', 'Chemical', 'MESH:C430592', (0, 11))	('potent polymerizer', 'MPA', (175, 193))	('BMS-247550', 'Var', (13, 23))
408615	25091619	In addition, specific mutations in the ss-tubulin binding sites associated with resistance to paclitaxel were not associated with resistance to ixabepilone in preclinical models, suggesting that this epothilone might be associated with enhanced clinical activity compared to paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (275, 285))	('clinical activity', 'MPA', (245, 262))	('paclitaxel', 'Chemical', 'MESH:D017239', (94, 104))	('epothilone', 'Chemical', 'MESH:D034261', (200, 210))	('ixabepilone', 'Chemical', 'MESH:C430592', (144, 155))	('mutations', 'Var', (22, 31))	('ss-tubulin', 'Protein', (39, 49))	('enhanced', 'PosReg', (236, 244))
408616	25091619	Ixabepilone has demonstrated antitumor activity in both taxane sensitive and taxane refractory cancer cell lines and tumors, including those overexpressing multidrug resistance (MDR) and those with mutations in the beta tubulin gene.	('taxane', 'Chemical', 'MESH:C080625', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('multidrug resistance', 'MPA', (156, 176))	('beta tubulin', 'Gene', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('overexpressing', 'PosReg', (141, 155))	('cancer', 'Disease', (95, 101))	('tumors', 'Disease', (117, 123))	('mutations', 'Var', (198, 207))	('taxane', 'Chemical', 'MESH:C080625', (77, 83))	('tumor', 'Disease', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('Ixabepilone', 'Chemical', 'MESH:C430592', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
408629	25091619	Patients were required to have GOG performance status of 0-2, and adequate bone marrow function (absolute neutrophil count (ANC) >=1500/mul, and platelets >=100,000/mul); renal function (creatinine <=1.5 x institutional upper limit of normal); hepatic function (bilirubin <=1.5 x institutional upper limit of normal, and SGOT and alkaline phosphatase <=2.5 x institutional upper limit of normal); and neurologic function (baseline neuropathy (sensory and motor) <= Common Toxicity Criteria grade 1).	('neuropathy', 'Phenotype', 'HP:0009830', (431, 441))	('Toxicity Criteria', 'Disease', 'MESH:D064420', (472, 489))	('renal function', 'CPA', (171, 185))	('Toxicity Criteria', 'Disease', (472, 489))	('bilirubin', 'Chemical', 'MESH:D001663', (262, 271))	('neuropathy', 'Disease', (431, 441))	('>=1500/mul', 'Var', (129, 139))	('bone marrow function', 'CPA', (75, 95))	('Patients', 'Species', '9606', (0, 8))	('neuropathy', 'Disease', 'MESH:D009422', (431, 441))
408639	25091619	Patients received day one treatment of each cycle provided the ANC was >=1500/mul and platelet count >=100,000/mul.	('>=1500/mul', 'Var', (71, 81))	('Patients', 'Species', '9606', (0, 8))	('ANC', 'MPA', (63, 66))
408676	25091619	Unfortunately, the responses seen in endometrial cancer in GOG-129P and in taxane resistant breast cancer were not seen in the setting of uterine leiomyosarcoma.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('leiomyosarcoma', 'Disease', (146, 160))	('breast cancer', 'Disease', (92, 105))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (146, 160))	('GOG-129P', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (146, 160))	('taxane', 'Chemical', 'MESH:C080625', (75, 81))	('endometrial cancer', 'Disease', (37, 55))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (138, 160))	('endometrial cancer', 'Disease', 'MESH:D016889', (37, 55))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
408681	25091619	One Phase III randomized double blind placebo controlled study in patients with metastatic and recurrent soft tissue sarcoma demonstrated a survival advantage for pazopanib over placebo, with an increase in PFS of 4.6 months vs 1.6 months (HR: 0.31, 95%CI: 0.24-0.40; p < 0.0001) and an increase in OS of 12.5 months vs 10.7 months with placebo (HR: 0.86, 95%CI: 0.67-1.1; p = 0.25).	('pazopanib', 'Var', (163, 172))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (105, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (105, 124))	('soft tissue sarcoma', 'Disease', (105, 124))	('pazopanib', 'Chemical', 'MESH:C516667', (163, 172))	('PFS', 'MPA', (207, 210))	('increase', 'PosReg', (195, 203))	('patients', 'Species', '9606', (66, 74))
408714	22894735	All lesions were nodular stage KS lesions and, when epidermal changes were analyzed, hyperkeratosis was detected in 100% of the cases, serum exudation into the keratin layer in 64%, intraepidermal splitting in 84%, subepidermal splitting in16%, ulceration in 10%, papillomatous changes in 10%, and a rise in pigmentation on the basal membrane in 5%.	('hyperkeratosis', 'Disease', 'MESH:D017488', (85, 99))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (85, 99))	('KS', 'Phenotype', 'HP:0100726', (31, 33))	('subepidermal splitting', 'CPA', (215, 237))	('rise', 'PosReg', (300, 304))	('hyperkeratosis', 'Disease', (85, 99))	('ulcer', 'Disease', 'MESH:D014456', (245, 250))	('subepidermal splitting in16', 'Phenotype', 'HP:0003341', (215, 242))	('intraepidermal splitting', 'Phenotype', 'HP:0003341', (182, 206))	('papillomatous', 'Disease', 'MESH:D058066', (264, 277))	('ulcer', 'Disease', (245, 250))	('intraepidermal', 'Var', (182, 196))	('papillomatous', 'Disease', (264, 277))	('serum exudation into the', 'MPA', (135, 159))	('pigmentation', 'MPA', (308, 320))
408721	22894735	The lesion cells of all KS cases showed various degrees of CD31, CD34, D2-40 (cytoplasmic), and HHV-8 (LNA-1) (nuclear) immunoreactivities.	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('D2-40', 'Var', (71, 76))	('CD31', 'Gene', (59, 63))	('CD34', 'Gene', '947', (65, 69))	('CD34', 'Gene', (65, 69))	('HHV-8', 'Gene', (96, 101))	('HHV-8', 'Species', '37296', (96, 101))	('CD31', 'Gene', '5175', (59, 63))
408722	22894735	The non-neoplastic lymphatic endothelium, lymphangioma-like channels, proliferative capillaries, and spindle cells were reactive with D2-40, whereas the non-neoplastic blood vessels and thick-walled, mature vascular structures were non-reactive.	('lymphangioma', 'Disease', 'MESH:D008202', (42, 54))	('lymphangioma', 'Phenotype', 'HP:0100764', (42, 54))	('neoplastic blood vessels', 'Phenotype', 'HP:0100742', (157, 181))	('lymphangioma', 'Disease', (42, 54))	('D2-40', 'Var', (134, 139))
408771	20543980	Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose.	('tumor', 'Disease', (25, 30))	('pS6RP/S6RP', 'Var', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
408802	20543980	Studies done in preparation for this trial showed that components of the mTOR pathway, mTOR, p-S6, p-4EBP1 are expressed in canine osteosarcoma cell lines and primary tumors (data not shown).	('mTOR', 'Gene', (87, 91))	('canine', 'Species', '9615', (124, 130))	('p-S6', 'Var', (93, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('osteosarcoma', 'Phenotype', 'HP:0002669', (131, 143))	('primary tumors', 'Disease', (159, 173))	('primary tumors', 'Disease', 'MESH:D009369', (159, 173))	('osteosarcoma', 'Disease', (131, 143))	('mTOR pathway', 'Pathway', (73, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('p-4EBP1', 'Var', (99, 106))
408839	20543980	Rapamycin led to >2-fold inhibition of tumoral p/t-S6RP (S240/S244) in 8/10 dogs ( Figure 4A  ., p = 0.039).	('tumoral', 'Disease', (39, 46))	('tumoral', 'Disease', 'MESH:D009369', (39, 46))	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('p/t-S6RP (S240/S244', 'Var', (47, 66))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('dogs', 'Species', '9615', (76, 80))	('inhibition', 'NegReg', (25, 35))	('S240/S244', 'Var', (57, 66))
408843	20543980	There was no relationship observed between pharmacokinetic parameters (AUC0-48hr, trough concentration, or Cmax) and decrease in pS6RP/t-S6RP in PBMC or tumor (data not shown).	('Cmax', 'MPA', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('pS6RP/t-S6RP', 'MPA', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('decrease', 'NegReg', (117, 125))	('trough concentration', 'MPA', (82, 102))	('AUC0-48hr', 'Var', (71, 80))
408890	20543980	The antibodies against AKT and p-AKT (Ser473), S6RP and p-S6RP, and actin were obtained from Cell Signaling.	('AKT', 'Gene', '207', (23, 26))	('AKT', 'Gene', '207', (33, 36))	('AKT', 'Gene', (23, 26))	('p-S6RP', 'Var', (56, 62))	('Ser473', 'Var', (38, 44))	('AKT', 'Gene', (33, 36))	('Ser473', 'Chemical', '-', (38, 44))
408937	20543980	For quantitative analysis of phospho-proteins, duplex t/p-AKT (S473) and duplex t/p-S6RP (S240/S244) were obtained from MSD, used following manufacturer's instructions, and read with Sector Imager 2400 (MSD).	('MSD', 'Disease', (203, 206))	('AKT', 'Gene', (58, 61))	('MSD', 'Disease', (120, 123))	('MSD', 'Disease', 'MESH:D052517', (120, 123))	('MSD', 'Disease', 'MESH:D052517', (203, 206))	('AKT', 'Gene', '207', (58, 61))	('S240/S244', 'Var', (90, 99))	('S473', 'Var', (63, 67))
408942	33332735	Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor Rhabdoid tumor (RT) is a pediatric cancer characterized by the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex.	('differentiation', 'CPA', (47, 62))	('cancer', 'Disease', (116, 122))	('SMARCB1', 'Gene', (160, 167))	('promoter reprogramming', 'CPA', (20, 42))	('inactivation', 'Var', (144, 156))	('rhabdoid tumor', 'Disease', (66, 80))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Mithramycin', 'Chemical', 'MESH:D008926', (0, 11))	('Rhabdoid tumor', 'Disease', (81, 95))	('Rhabdoid tumor', 'Disease', 'MESH:D018335', (81, 95))
408945	33332735	The sensitivity of MMA and EC8042 was superior to traditional DNA damaging agents and linked to the causative mutation of the tumor, SMARCB1 deletion.	('EC8042', 'Chemical', 'MESH:C576677', (27, 33))	('deletion', 'Var', (141, 149))	('EC8042', 'Var', (27, 33))	('linked', 'Reg', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('SMARCB1', 'Gene', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
408947	33332735	Importantly, a single 3-day infusion of EC8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice.	('regressions', 'NegReg', (63, 74))	('H3K27me3', 'Protein', (123, 131))	('EC8042', 'Var', (40, 46))	('cellular differentiation', 'CPA', (137, 161))	('mice', 'Species', '10090', (219, 223))	('RT xenografts', 'CPA', (78, 91))	('EC8042', 'Chemical', 'MESH:C576677', (40, 46))
408948	33332735	EC8042 is identified as an inhibitor of oncogenic SWI/SNF and a promising therapeutic candidate for rhabdoid tumor.	('EC8042', 'Chemical', 'MESH:C576677', (0, 6))	('EC8042', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (100, 114))	('rhabdoid tumor', 'Disease', (100, 114))
408951	33332735	Rhabdoid tumor is a pediatric cancer that is most commonly characterized by biallelic deletion in SMARCB1 of the SWI/SNF chromatin remodeling complex.	('Rhabdoid tumor', 'Disease', (0, 14))	('biallelic deletion', 'Var', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('SMARCB1', 'Gene', (98, 105))	('Rhabdoid tumor', 'Disease', 'MESH:D018335', (0, 14))
408952	33332735	This mutation creates a dependence of this cancer on residual SWI/SNF activity.	('dependence', 'Reg', (24, 34))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (5, 13))
408953	33332735	In this report, we identify EC8042 as an inhibitor of SMARCB1-deficient SWI/SNF and explore the therapeutic development of this compound from a mechanistic and translational perspective.	('EC8042', 'Chemical', 'MESH:C576677', (28, 34))	('EC8042', 'Var', (28, 34))	('SMARCB1-deficient', 'Gene', (54, 71))
408954	33332735	Inhibition of SMARCB1-deficient SWI/SNF triggers an epigenetic switch to cause differentiation of rhabdoid tumor mouse xenografts into bone.	('rhabdoid tumor', 'Disease', 'MESH:D018335', (98, 112))	('differentiation', 'CPA', (79, 94))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('epigenetic switch', 'MPA', (52, 69))	('triggers', 'Reg', (40, 48))	('rhabdoid tumor', 'Disease', (98, 112))	('SWI/SNF', 'Gene', (32, 39))	('Inhibition', 'Var', (0, 10))	('mouse', 'Species', '10090', (113, 118))	('cause', 'Reg', (73, 78))
408974	33332735	We show mithramycin displaces SWI/SNF from chromatin to cause focal chromatin remodeling, loss of CTCF accessibility to restore PRC2 activity and H3K27me3.	('CTCF', 'Gene', (98, 102))	('accessibility', 'MPA', (103, 116))	('displaces', 'NegReg', (20, 29))	('loss', 'NegReg', (90, 94))	('restore', 'PosReg', (120, 127))	('CTCF', 'Gene', '10664', (98, 102))	('cause', 'Reg', (56, 61))	('H3K27me3', 'Protein', (146, 154))	('mithramycin', 'Var', (8, 19))	('mithramycin', 'Chemical', 'MESH:D008926', (8, 19))	('PRC2 activity', 'MPA', (128, 141))
408975	33332735	These effects trigger epigenetic reprogramming that favors promoters to block numerous oncogenic pathways associated with rhabdoid tumor and induce differentiation of the tumor cells into benign mesenchymal tissue both in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (122, 136))	('block', 'NegReg', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('induce', 'Reg', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('rhabdoid tumor', 'Disease', (122, 136))	('differentiation', 'CPA', (148, 163))	('tumor', 'Disease', (131, 136))	('effects', 'Var', (6, 13))	('oncogenic pathways', 'Pathway', (87, 105))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('promoters', 'Var', (59, 68))
408977	33332735	Because of the favorable toxicity profile of EC8042 (Osgood et al, 2016), these results establish EC8042 as a new clinical candidate for rhabdoid tumor patients.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('EC8042', 'Var', (98, 104))	('toxicity', 'Disease', 'MESH:D064420', (25, 33))	('toxicity', 'Disease', (25, 33))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (137, 151))	('rhabdoid tumor', 'Disease', (137, 151))	('EC8042', 'Chemical', 'MESH:C576677', (98, 104))	('EC8042', 'Chemical', 'MESH:C576677', (45, 51))	('patients', 'Species', '9606', (152, 160))
408987	33332735	Three RT cell lines (BT12, CHLA266, and G401) were 70-fold, four-fold, and 100-fold more resistant to three broadly active chemotherapy agents, etoposide, doxorubicin, and SN38 (the active metabolite of irinotecan) than Ewing sarcoma cells (Fig 1C).	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('resistant', 'MPA', (89, 98))	('SN38', 'Var', (172, 176))	('CHLA266', 'CellLine', 'CVCL:M149', (27, 34))	('Ewing sarcoma', 'Disease', (220, 233))	('etoposide', 'Chemical', 'MESH:D005047', (144, 153))	('irinotecan', 'Chemical', 'MESH:D000077146', (203, 213))	('doxorubicin', 'Chemical', 'MESH:D004317', (155, 166))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (220, 233))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (220, 233))	('BT12', 'CellLine', 'CVCL:M155', (21, 25))	('SN38', 'Chemical', 'MESH:D000077146', (172, 176))
409004	33332735	Importantly, EC8042 is 20-40 times less toxic than mithramycin in multiple species (Osgood et al, 2016).	('less', 'NegReg', (35, 39))	('EC8042', 'Var', (13, 19))	('mithramycin', 'Chemical', 'MESH:D008926', (51, 62))	('EC8042', 'Chemical', 'MESH:C576677', (13, 19))	('toxic', 'MPA', (40, 45))
409005	33332735	EC8042 required a concentration of 750 nM to induce any appreciable DNA damage in only one of two RT cell lines.	('EC8042', 'Chemical', 'MESH:C576677', (0, 6))	('DNA damage', 'MPA', (68, 78))	('EC8042', 'Var', (0, 6))
409008	33332735	Instead, with prolonged exposure, EC8042 arrested cellular proliferation and induced what appeared to be mesenchymal differentiation with the accumulation of lipid and migration of the nucleus to the cell periphery in a subset of cells, similar to mithramycin (Fig 2E and G).	('mesenchymal differentiation', 'CPA', (105, 132))	('lipid', 'Chemical', 'MESH:D008055', (158, 163))	('induced', 'Reg', (77, 84))	('EC8042', 'Var', (34, 40))	('arrested', 'NegReg', (41, 49))	('accumulation of lipid', 'MPA', (142, 163))	('cellular proliferation', 'CPA', (50, 72))	('EC8042', 'Chemical', 'MESH:C576677', (34, 40))	('mithramycin', 'Chemical', 'MESH:D008926', (248, 259))	('migration of the nucleus to the cell periphery', 'CPA', (168, 214))
409011	33332735	While DNA damage occurs at relatively high concentrations of mithramycin and EC8042, the observed phenotype of cellular differentiation at sub-IC50 concentrations likely reflects fundamental biology of the disease, particularly with prolonged exposure to the less toxic analogue EC8042.	('EC8042', 'Chemical', 'MESH:C576677', (279, 285))	('mithramycin', 'Chemical', 'MESH:D008926', (61, 72))	('EC8042', 'Chemical', 'MESH:C576677', (77, 83))	('cellular differentiation', 'CPA', (111, 135))	('EC8042', 'Var', (77, 83))
409024	33332735	These effects were dependent on deletion of SMARCB1 as complementation using a doxycycline inducible SMARCB1 eliminated the dose dependent accumulation of H3K27me3 seen with mithramycin exposure in G401 cells (Fig 3I).	('deletion', 'Var', (32, 40))	('doxycycline', 'Chemical', 'MESH:D004318', (79, 90))	('eliminated', 'NegReg', (109, 119))	('mithramycin', 'Chemical', 'MESH:D008926', (174, 185))	('SMARCB1', 'Gene', (44, 51))	('H3K27me3', 'Protein', (155, 163))	('accumulation', 'PosReg', (139, 151))
409025	33332735	In order to link mithramycin-mediated eviction of SWI/SNF binding and accumulation of H3K27me3 to the described cellular hypersensitivity of rhabdoid tumor, we next examined the importance of SMARCB1 deletion to these effects.	('deletion', 'Var', (200, 208))	('hypersensitivity', 'Disease', 'MESH:D004342', (121, 137))	('cellular hypersensitivity', 'Phenotype', 'HP:0100326', (112, 137))	('mithramycin', 'Chemical', 'MESH:D008926', (17, 28))	('hypersensitivity', 'Disease', (121, 137))	('SMARCB1', 'Gene', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (141, 155))	('rhabdoid tumor', 'Disease', (141, 155))
409027	33332735	Further, complementation of these cells with the same inducible SMARCB1 that eliminated H3K27me3 accumulation (see Fig 3I) led to the inability of mithramycin to compete SMARCE1, a subunit of the canonical SWI/SNF complex, off chromatin consistent with the need for the deletion for this activity (Fig 4B).	('eliminated', 'NegReg', (77, 87))	('SMARCE1', 'Gene', '6605', (170, 177))	('inability', 'Disease', (134, 143))	('mithramycin', 'Chemical', 'MESH:D008926', (147, 158))	('SMARCB1', 'Gene', (64, 71))	('inability', 'Disease', 'MESH:D007319', (134, 143))	('complementation', 'Var', (9, 24))	('H3K27me3', 'Protein', (88, 96))	('SMARCE1', 'Gene', (170, 177))
409029	33332735	In order to further link the mechanism of the suppression of cellular proliferation to the accumulation of H3K27me3, we silenced EZH2, the catalytic subunit of PRC2 responsible for H3K27me3, and evaluated the impact on mithramycin sensitivity.	('silenced', 'Var', (120, 128))	('mithramycin', 'Chemical', 'MESH:D008926', (219, 230))	('cellular proliferation', 'CPA', (61, 83))	('EZH2', 'Gene', '2146', (129, 133))	('EZH2', 'Gene', (129, 133))
409030	33332735	Silencing of EZH2 with either siRNA or with the small molecule inhibitor, tazemetostat, in BT12 made the cells less sensitive to the drug shifting the IC50 almost 2-fold from 20 to 37 nM (Figs EV2, 4).	('IC50', 'MPA', (151, 155))	('EZH2', 'Gene', (13, 17))	('EZH2', 'Gene', '2146', (13, 17))	('tazemetostat', 'Chemical', 'MESH:C000593333', (74, 86))	('BT12', 'CellLine', 'CVCL:M155', (91, 95))	('Silencing', 'Var', (0, 9))	('less', 'NegReg', (111, 115))
409031	33332735	Conversely, silencing of SMARCB1 in U2OS cells to genocopy SMARCB1-deleted rhabdoid tumor increases the sensitivity of the cells to mithramycin almost 2-fold from 202 to 120 nM (Figs 4F and EV2E).	('rhabdoid tumor', 'Disease', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('increases', 'PosReg', (90, 99))	('SMARCB1-deleted', 'Gene', (59, 74))	('silencing', 'Var', (12, 21))	('sensitivity', 'MPA', (104, 115))	('U2OS', 'CellLine', 'CVCL:0042', (36, 40))	('mithramycin', 'Chemical', 'MESH:D008926', (132, 143))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (75, 89))
409032	33332735	Further, the deletion of SMARCB1 in U2OS cells triggered an increase in H3K37me3 that was not otherwise evident with the SMARCB1 wild-type complex (Fig 4G).	('increase', 'PosReg', (60, 68))	('deletion', 'Var', (13, 21))	('U2OS', 'CellLine', 'CVCL:0042', (36, 40))	('SMARCB1', 'Gene', (25, 32))	('H3K37me3', 'Protein', (72, 80))
409040	33332735	Further, silencing of subunits of SWI/SNF, SMARCC1, and SMARCA4 also caused a loss of expression of SP1 (Fig EV3B).	('SWI/SNF', 'Gene', (34, 41))	('silencing', 'Var', (9, 18))	('SMARCC1', 'Gene', (43, 50))	('expression', 'MPA', (86, 96))	('SMARCA4', 'Gene', (56, 63))	('loss', 'NegReg', (78, 82))	('SMARCA4', 'Gene', '6597', (56, 63))	('SP1', 'Gene', (100, 103))
409043	33332735	Importantly, these pathways have been linked to aberrant SMARCB1-deficient SWI/SNF activity in rhabdoid tumor (Chakravadhanula et al, 2015; Johann et al, 2016; Torchia et al, 2016).	('linked', 'Reg', (38, 44))	('activity', 'MPA', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (95, 109))	('rhabdoid tumor', 'Disease', (95, 109))	('aberrant', 'Var', (48, 56))	('SMARCB1-deficient SWI/SNF', 'Gene', (57, 82))	('SWI/SNF', 'Gene', (75, 82))
409055	33332735	It is notable, the peaks in BMP1 as well as multiple other genes overlapped with published ATAC-seq peaks that were gained following SMARCB1 complementation in rhabdoid tumor cells (Fig EV4) (Weissmiller et al, 2019).	('rhabdoid tumor', 'Disease', 'MESH:D018335', (160, 174))	('AT', 'Disease', 'None', (91, 93))	('rhabdoid tumor', 'Disease', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('complementation', 'Var', (141, 156))	('SMARCB1', 'Gene', (133, 140))	('BMP1', 'Gene', '649', (28, 32))	('BMP1', 'Gene', (28, 32))
409067	33332735	However, several mice were cured of their disease with a single 3-day infusion of EC8042 and never showed tumor recurrence 140 days after treatment (Fig 7C).	('EC8042', 'Var', (82, 88))	('mice', 'Species', '10090', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('EC8042', 'Chemical', 'MESH:C576677', (82, 88))	('tumor', 'Disease', (106, 111))
409068	33332735	The effects occurred with limited toxicity, and importantly, the total amount of EC8042 administered was six times less than the amount of EC8042 administered in a previous study in Ewing sarcoma (Osgood et al, 2016).	('EC8042', 'Var', (81, 87))	('less', 'NegReg', (115, 119))	('EC8042', 'Chemical', 'MESH:C576677', (139, 145))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))	('toxicity', 'Disease', (34, 42))	('Ewing sarcoma', 'Disease', (182, 195))	('EC8042', 'Chemical', 'MESH:C576677', (81, 87))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))
409070	33332735	Importantly, EC8042 drove the combined apoptotic and differentiation phenotype by the described mechanism of action.	('EC8042', 'Chemical', 'MESH:C576677', (13, 19))	('EC8042', 'Var', (13, 19))	('apoptotic', 'CPA', (39, 48))
409072	33332735	The presence of osteoblasts and embedded osteocytes in the trabecular architecture provides further support for EC8042 inducing osteogenesis (Fig EV5D).	('osteogenesis', 'Disease', (128, 140))	('osteogenesis', 'Disease', 'MESH:D010013', (128, 140))	('osteoblasts', 'CPA', (16, 27))	('EC8042', 'Chemical', 'MESH:C576677', (112, 118))	('EC8042', 'Var', (112, 118))	('inducing', 'Reg', (119, 127))
409076	33332735	Nevertheless, this phenotype leads to a significant increase in survival of mice bearing the rhabdoid tumor xenografts treated with EC8042.	('survival', 'CPA', (64, 72))	('increase', 'PosReg', (52, 60))	('EC8042', 'Chemical', 'MESH:C576677', (132, 138))	('mice', 'Species', '10090', (76, 80))	('EC8042', 'Var', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (93, 107))	('rhabdoid tumor', 'Disease', (93, 107))
409078	33332735	We show that mithramycin and EC8042 drive a differentiation phenotype in vitro and in vivo and link the activity to the defining molecular feature of this tumor, dysregulated SWI/SNF.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mithramycin', 'Chemical', 'MESH:D008926', (13, 24))	('EC8042', 'Chemical', 'MESH:C576677', (29, 35))	('tumor', 'Disease', (155, 160))	('EC8042', 'Var', (29, 35))	('differentiation', 'MPA', (44, 59))
409080	33332735	However, it is also known that SMARCB1 deletion leads to a redistribution of SWI/SNF in the genome, with a higher percentage of ncSWI/SNF, colocalized with SMARCA4, favoring proximal promoters and CTCF sites (Alver et al, 2017; Nakayama et al, 2017; Michel et al, 2018; Erkek et al, 2019; Wang et al, 2019).	('CTCF', 'Gene', '10664', (197, 201))	('redistribution', 'MPA', (59, 73))	('deletion', 'Var', (39, 47))	('CTCF', 'Gene', (197, 201))	('SMARCA4', 'Gene', (156, 163))	('SMARCB1', 'Gene', (31, 38))	('SMARCA4', 'Gene', '6597', (156, 163))
409084	33332735	It is tempting to speculate that the effect of mithramycin-mediated displacement of SWI/SNF can be generalized to the 20% of all human cancer characterized by mutated or dysregulated SWI/SNF, though more research is needed to explore this hypothesis.	('cancer', 'Disease', (135, 141))	('mutated', 'Var', (159, 166))	('mithramycin', 'Chemical', 'MESH:D008926', (47, 58))	('dysregulated', 'Var', (170, 182))	('SWI/SNF', 'Gene', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('SWI/SNF', 'Gene', (84, 91))	('human', 'Species', '9606', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
409087	33332735	We demonstrate that the activity of EC8042 and mithramycin in RT is dependent on this increase in H3K27me3 and can be antagonized by inhibiting EZH2 expression or activity.	('increase', 'PosReg', (86, 94))	('activity', 'MPA', (24, 32))	('H3K27me3', 'Protein', (98, 106))	('inhibiting', 'NegReg', (133, 143))	('EZH2', 'Gene', (144, 148))	('mithramycin', 'Chemical', 'MESH:D008926', (47, 58))	('EZH2', 'Gene', '2146', (144, 148))	('EC8042', 'Chemical', 'MESH:C576677', (36, 42))	('activity', 'MPA', (163, 171))	('expression', 'MPA', (149, 159))	('EC8042', 'Var', (36, 42))
409090	33332735	Our data show a strong schedule dependence of these tumors for both mithramycin and EC8042.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mithramycin', 'Chemical', 'MESH:D008926', (68, 79))	('EC8042', 'Chemical', 'MESH:C576677', (84, 90))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('EC8042', 'Var', (84, 90))
409095	33332735	Consistent with these observations, we show a dramatic suppression of tumor growth of every mouse in the cohort with a single 3-day infusion of the EC8042.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('suppression', 'NegReg', (55, 66))	('EC8042', 'Chemical', 'MESH:C576677', (148, 154))	('tumor', 'Disease', (70, 75))	('EC8042', 'Var', (148, 154))	('mouse', 'Species', '10090', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
409102	33332735	However, the suppression of SP1 activity is likely not an important mechanism of the drug in rhabdoid tumor as silencing of SP1 had no effect on cellular proliferation.	('SP1', 'Gene', (124, 127))	('silencing', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (93, 107))	('rhabdoid tumor', 'Disease', (93, 107))
409104	33332735	Further, recognition of these mechanisms should aid in the identification of analogues more selective for SP1 vs. SWI/SNF vs. EWS-FLI1.	('FLI1', 'Gene', (130, 134))	('SP1', 'Var', (106, 109))	('EWS', 'Gene', (126, 129))	('FLI1', 'Gene', '2313', (130, 134))	('EWS', 'Gene', '2130', (126, 129))
409107	33332735	We show that RT cells are hypersensitive to mithramycin and link the activity to the fundamental genetic lesion of the tumor, SMARCB1 deletion, and consequential aberrant SWI/SNF activity.	('activity', 'MPA', (179, 187))	('tumor', 'Disease', (119, 124))	('mithramycin', 'Chemical', 'MESH:D008926', (44, 55))	('deletion', 'Var', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('SMARCB1', 'Gene', (126, 133))	('SWI/SNF', 'CPA', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
409127	33332735	10 microg solubilized chromatin was immunoprecipitated with 1 microg mouse IgG and 1 microg H3K27me3 (Abcam); 2 microg rabbit IgG and 2 microg SMARCC1 (Cell Signaling); 1 microg rabbit IgG; and 1 microg H3K27ac (Active Motif).	('H3K27ac', 'Var', (203, 210))	('mouse', 'Species', '10090', (69, 74))	('H3K27me3', 'Var', (92, 100))
409181	26351324	Chromosomal translocations occur in about one-third of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('Chromosomal translocations', 'Var', (0, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('occur', 'Reg', (27, 32))	('sarcomas', 'Disease', (55, 63))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))
409184	26351324	Approximately 30% of mesenchymal tumors carry a specific translocation with an otherwise relatively simple karyotype.	('mesenchymal tumors', 'Disease', 'MESH:C535700', (21, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mesenchymal tumors', 'Disease', (21, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('translocation', 'Var', (57, 70))
409223	26351324	Pairwise Pearson correlations between the negative log10 IC50 and log2 gene or miRNA expression are presented.	('log10 IC50', 'Var', (51, 61))	('negative', 'NegReg', (42, 50))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('log2 gene', 'Gene', (66, 75))
409244	26351324	Among the MEK inhibitors, trametinib (NSC758246) in combination with dabrafenib (BRAF inhibitor) is approved for treatment of mutant B-Raf melanoma, selumetinib (NSC764042) is in Phase III trial (NCT01933932, NCT01843062, NCT01974752) and refametinib (NSC765866) is in Phase II trial (NCT02168777, NCT01915589, NCT01915602).	('B-Raf', 'Gene', '673', (133, 138))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('NSC765866', 'Var', (252, 261))	('NSC764042', 'Var', (162, 171))	('NCT01974752', 'Var', (222, 233))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('mutant', 'Var', (126, 132))	('B-Raf', 'Gene', (133, 138))	('NCT01933932', 'Var', (196, 207))	('MEK', 'Gene', '5609', (10, 13))	('NCT01915602', 'Var', (311, 322))	('trametinib', 'Chemical', 'MESH:C560077', (26, 36))	('NCT01915589', 'Var', (298, 309))	('NCT02168777', 'Var', (285, 296))	('selumetinib', 'Chemical', 'MESH:C517975', (149, 160))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('MEK', 'Gene', (10, 13))
409251	26351324	The BET bromodomain inhibitors JQ1 (NSC764043) and I-BET-151 (NSC767599) are shown in Figure 5A.	('BET', 'Gene', '92737', (53, 56))	('BET', 'Gene', '92737', (4, 7))	('BET', 'Gene', (53, 56))	('NSC764043', 'Var', (36, 45))	('NSC767599', 'Var', (62, 71))	('BET', 'Gene', (4, 7))
409277	26351324	The A-673 Ewing sarcoma line was exceptionally responsive to three kinase inhibitors, saracatinib (NSC758872), ZM-336372 (NSC756654) and WZ-4002 (NSC755927).	('NSC756654', 'Var', (122, 131))	('saracatinib', 'Chemical', 'MESH:C515233', (86, 97))	('Ewing sarcoma', 'Disease', (10, 23))	('responsive', 'MPA', (47, 57))	('WZ-4002', 'Chemical', 'MESH:C571455', (137, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('ZM-336372', 'Chemical', 'MESH:C121825', (111, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (10, 23))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (10, 23))	('NSC758872', 'Var', (99, 108))
409297	26351324	MiR-9-5p expression was positively correlated (r = 0.59) with sensitivity to linsitinib while the expression of miRs 100-5p, 222-3p, 125b-5p, 22-3p and 21-5p were negatively correlated.	('MiR-9-5p', 'Gene', (0, 8))	('222-3p', 'Var', (125, 131))	('linsitinib', 'Chemical', 'MESH:C551528', (77, 87))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('125b-5p', 'Var', (133, 140))	('sensitivity to linsitinib', 'MPA', (62, 87))	('MiR-9-5p', 'Gene', '407052', (0, 8))
409306	26351324	Among the sensitive lines, the HT-1080 fibrosarcoma and the rhabdomyosarcoma lines RD and Rh36 express mutant RAS.	('mutant', 'Var', (103, 109))	('HT-1080 fibrosarcoma and the rhabdomyosarcoma lines RD', 'Disease', 'MESH:D005354', (31, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('RAS', 'Gene', (110, 113))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (39, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (60, 76))
409311	26351324	The MEK inhibitor PD-0325901 is in clinical trial for adolescent and adults with neurofibromatosis type-1 (NF1), a genetic disease with a predisposition for patients to rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (169, 185))	('NF1', 'Gene', '4763', (107, 110))	('PD-0325901', 'Chemical', 'MESH:C506614', (18, 28))	('neurofibromatosis type-1', 'Gene', '4763', (81, 105))	('MEK', 'Gene', (4, 7))	('MEK', 'Gene', '5609', (4, 7))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (169, 185))	('patients', 'Species', '9606', (157, 165))	('PD-0325901', 'Var', (18, 28))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (81, 98))	('genetic disease', 'Disease', (115, 130))	('neurofibromatosis type-1', 'Gene', (81, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('genetic disease', 'Disease', 'MESH:D030342', (115, 130))	('rhabdomyosarcoma', 'Disease', (169, 185))	('NF1', 'Gene', (107, 110))
409320	26351324	Bromodomain inhibitors are in Phase 1 clinical trial in hematological malignancies, NUT (nuclear protein in testis) midline carcinoma, lymphoma and advanced solid tumors (ClinicalTrials.gov Identifiers NCT01713582, NCT01587703, NCT01949883, and NCT01987362).	('solid tumors', 'Disease', (157, 169))	('NUT', 'Gene', (84, 87))	('hematological malignancies', 'Disease', (56, 82))	('solid tumors', 'Disease', 'MESH:D009369', (157, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('NCT01949883', 'Var', (228, 239))	('midline carcinoma', 'Disease', (116, 133))	('lymphoma', 'Phenotype', 'HP:0002665', (135, 143))	('NCT01587703', 'Var', (215, 226))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('hematological malignancies', 'Disease', 'MESH:D019337', (56, 82))	('midline carcinoma', 'Disease', 'MESH:D009436', (116, 133))	('NCT01987362', 'Var', (245, 256))	('NCT01713582', 'Var', (202, 213))	('hematological malignancies', 'Phenotype', 'HP:0004377', (56, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('lymphoma', 'Disease', (135, 143))	('NUT', 'Gene', '256646', (84, 87))	('lymphoma', 'Disease', 'MESH:D008223', (135, 143))
409332	26351324	In the sarcoma panel, high miR-150 was associated with sensitivity to talazoparib (Figure 6).	('talazoparib', 'Chemical', 'MESH:C586365', (70, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('high', 'Var', (22, 26))	('sensitivity to', 'MPA', (55, 69))	('sarcoma', 'Disease', 'MESH:D012509', (7, 14))	('miR-150', 'Gene', (27, 34))	('associated', 'Reg', (39, 49))	('miR-150', 'Gene', '406942', (27, 34))	('sarcoma', 'Disease', (7, 14))
409333	26351324	Talazoparib is in active clinical trials including Phase 2 trials (ClinicalTrials.gov Identifiers NCT02116777, NCT02049593, NCT01286987, NCT01989546, NCT02127151, NCT01945775 and NCT02034916).	('NCT02049593', 'Var', (111, 122))	('NCT01989546', 'Var', (137, 148))	('Talazoparib', 'Chemical', 'MESH:C586365', (0, 11))	('NCT02034916', 'Var', (179, 190))	('NCT02127151', 'Var', (150, 161))	('NCT01945775', 'Var', (163, 174))	('NCT01286987', 'Var', (124, 135))	('NCT02116777', 'Var', (98, 109))
409338	26351324	High miR-204 is associated with slower tumor growth in malignant peripheral nerve sheath tumors and cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (55, 95))	('slower', 'NegReg', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('miR-204', 'Gene', (5, 12))	('High', 'Var', (0, 4))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('cholangiocarcinoma', 'Disease', (100, 118))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (55, 95))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('malignant peripheral nerve sheath tumors', 'Disease', (55, 95))	('tumor', 'Disease', (39, 44))	('miR-204', 'Gene', '406987', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
409404	23761860	One such indirect possibility might lie in the epigenetic control of gene expression which seems to play a major role also in sarcomas, as discussed during the conference.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcomas', 'Disease', (126, 134))	('epigenetic control', 'Var', (47, 65))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))
409409	23761860	Interestingly, inhibition of CB1 was found to abrogate lung metastasis in a xenograft mouse model (G. Grosveld, Memphis, TN, USA).	('CB1', 'Gene', '12801', (29, 32))	('abrogate', 'NegReg', (46, 54))	('mouse', 'Species', '10090', (86, 91))	('lung metastasis', 'Disease', (55, 70))	('CB1', 'Gene', (29, 32))	('inhibition', 'Var', (15, 25))	('lung metastasis', 'Disease', 'MESH:D009362', (55, 70))
409410	23761860	Finally, S. Hettmer (Boston, MA, USA) reported on a promising in vitro system that allows transformation of primary satellite cells by specific oncogenes such as RAS together with deletion of CDKN2A, thereby creating a defined RMS tumorigenicity model.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('deletion', 'Var', (180, 188))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('CDKN2A', 'Gene', '12578', (192, 198))	('RMS', 'Phenotype', 'HP:0002859', (227, 230))	('tumor', 'Disease', (231, 236))	('CDKN2A', 'Gene', (192, 198))
409426	23761860	Along similar lines, blockade of survivin might enhance sensitivity to therapeutic T cells (K. Simon-Keller, Mannheim, Germany).	('survivin', 'Gene', '11799', (33, 41))	('blockade', 'Var', (21, 29))	('enhance', 'PosReg', (48, 55))	('sensitivity to therapeutic T cells', 'MPA', (56, 90))	('survivin', 'Gene', (33, 41))
409427	23761860	Ectopic expression of PAX3/FOXO1 was able to induce expression of myogenin but not myoD.	('myogenin', 'Gene', (66, 74))	('induce', 'PosReg', (45, 51))	('PAX3', 'Gene', (22, 26))	('Ectopic expression', 'Var', (0, 18))	('myogenin', 'Gene', '17928', (66, 74))	('expression', 'MPA', (52, 62))	('PAX3', 'Gene', '18505', (22, 26))	('FOXO1', 'Gene', (27, 32))	('FOXO1', 'Gene', '56458', (27, 32))
409441	23761860	These included a CRKL/Yes axis (L. Helman, Bethesda, MD, USA), targeting of c-Met by a small-molecule inhibitor (S.J.	('CRKL', 'Gene', (17, 21))	('c-Met', 'Gene', (76, 81))	('CRKL', 'Gene', '12929', (17, 21))	('targeting', 'Var', (63, 72))	('c-Met', 'Gene', '17295', (76, 81))
409444	23761860	A new and exciting area of research is represented by the newly discovered ALK mutations that occur in RMS and which can be targeted by small-molecule inhibitors (Y. Versleijen-Jonkers, Nijmegen, Netherlands).	('ALK', 'Gene', (75, 78))	('RMS', 'Disease', (103, 106))	('RMS', 'Phenotype', 'HP:0002859', (103, 106))	('ALK', 'Gene', '11682', (75, 78))	('mutations', 'Var', (79, 88))
409447	23761860	Furthermore, inhibition of the IGF1R resulted in suppression of sarcoma growth.	('suppression', 'NegReg', (49, 60))	('sarcoma growth', 'Disease', 'MESH:D006130', (64, 78))	('IGF1R', 'Gene', '16001', (31, 36))	('inhibition', 'Var', (13, 23))	('sarcoma growth', 'Disease', (64, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('IGF1R', 'Gene', (31, 36))
409455	23761860	Since fusion TF are often the only genetic abnormality present at high frequency in these tumors, they are hypothesized to be one of the tumor-initiating events and might represent important therapeutic targets.	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('fusion', 'Var', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
409475	31872312	In this regard, the principle behind the SUVratio concept, which is used in several approaches, e.g., PERCIST, the visual Deauville criteria or a quantitative extension of the Deauville scale referred to as qPET, has been proposed for the assessment of tumour response to therapy by 18F-FDG PET/CT in paediatric HL patients.	('visual Deauville criteria', 'Disease', (115, 140))	('HL', 'Disease', 'MESH:D006689', (312, 314))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('18F-FDG PET/CT', 'Var', (283, 297))	('tumour', 'Disease', (253, 259))	('patients', 'Species', '9606', (315, 323))	('18F-FDG', 'Chemical', 'MESH:C554683', (283, 290))	('visual Deauville criteria', 'Disease', 'MESH:D014786', (115, 140))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('HL', 'Phenotype', 'HP:0012189', (312, 314))
409552	31872312	Butylscopolamine, on the other hand, reduces artefacts coming from bowel peristalsis, thus also improving the accuracy of abdominal 18F-FDG PET reporting.	('artefacts coming from bowel peristalsis', 'MPA', (45, 84))	('Butylscopolamine', 'Var', (0, 16))	('18F-FDG', 'Chemical', 'MESH:C554683', (132, 139))	('improving', 'PosReg', (96, 105))	('reduces', 'NegReg', (37, 44))	('Butylscopolamine', 'Chemical', 'MESH:D002086', (0, 16))
409579	31824805	We included only patients with primary site codes of C471, C472, C476, C478, C479, C491, C492, C496, C498, and C499, corresponding to the ICD-O-3 codes included for trunk/extremity STS via the American Joint Committee on Cancer (AJCC), 8th edition (n = 55,469).	('STS', 'Disease', (181, 184))	('C496', 'Chemical', 'MESH:C513461', (95, 99))	('C498', 'Var', (101, 105))	('C499', 'Var', (111, 115))	('C496', 'Var', (95, 99))	('STS', 'Disease', 'MESH:D012509', (181, 184))	('C476', 'Chemical', 'MESH:C047119', (65, 69))	('C491', 'Chemical', 'MESH:C107116', (83, 87))	('C471', 'Var', (53, 57))	('C476', 'Var', (65, 69))	('C491', 'Var', (83, 87))	('C479', 'Chemical', 'MESH:C000596309', (77, 81))	('C472', 'Chemical', 'MESH:C007525', (59, 63))	('C472', 'Var', (59, 63))	('C492', 'Var', (89, 93))	('O-3', 'Chemical', 'MESH:D013481', (142, 145))	('C478', 'Chemical', 'MESH:C017971', (71, 75))	('patients', 'Species', '9606', (17, 25))	('Cancer', 'Phenotype', 'HP:0002664', (221, 227))	('C492', 'Chemical', 'MESH:C006100', (89, 93))	('C471', 'Chemical', 'MESH:C432083', (53, 57))	('C478', 'Var', (71, 75))	('C479', 'Var', (77, 81))
409580	31824805	Other exclusion criteria included distant metastatic disease (n = 8,979), lack of pathologic nodal evaluation (n = 29.684), unknown or discrepant grade (n = 3,231), discordant nodal status and stage group (n = 7), and any patients receiving neoadjuvant therapy or if receipt of neoadjuvant therapy was unknown (n = 2,837).	('nodal', 'Gene', (176, 181))	('discordant', 'Var', (165, 175))	('nodal', 'Gene', '4838', (93, 98))	('distant metastatic disease', 'CPA', (34, 60))	('nodal', 'Gene', '4838', (176, 181))	('patients', 'Species', '9606', (222, 230))	('nodal', 'Gene', (93, 98))
409604	31824805	In 1987, a cohort study of 323 patients showed that high-grade, rhabdomyosarcoma histology, and epithelioid histology were associated with LNM.	('associated', 'Reg', (123, 133))	('high-grade', 'Var', (52, 62))	('epithelioid', 'Disease', (96, 107))	('rhabdomyosarcoma', 'Disease', (64, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (64, 80))	('LNM', 'Disease', (139, 142))	('patients', 'Species', '9606', (31, 39))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (64, 80))
409625	29531545	Differentiating and Categorizing of Liposarcoma and Synovial Sarcoma Neoplasms by Fluorescence in Situ Hybridization Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumors of mesenchymal origin and various cytogenetic abnormalities ranging from distinct genomic rearrangements, such as chromosomal translocations and amplifications, to more intricate rearrangements involving multiple chromosomes.	('genetic abnormalities', 'Disease', (239, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Liposarcoma and Synovial Sarcoma Neoplasms', 'Disease', 'MESH:D013584', (36, 78))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('Soft tissue sarcomas', 'Phenotype', 'HP:0030448', (117, 137))	('Liposarcoma', 'Phenotype', 'HP:0012034', (36, 47))	('amplifications', 'Var', (346, 360))	('STS', 'Phenotype', 'HP:0030448', (139, 142))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (52, 68))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('Sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('tumors', 'Disease', (194, 200))	('sarcomas', 'Disease', (129, 137))	('Neoplasms', 'Phenotype', 'HP:0002664', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('genetic abnormalities', 'Disease', 'MESH:D030342', (239, 260))
409626	29531545	The current study aimed at investigating the usefulness of FISH, as a diagnostic ancillary aid, to detect cytogenetic abnormalities such as MDM2 (murine double minute 2) amplification and CHOP(C/EBP homologous protein) rearrangement in liposarcoma, as well as SYT (synaptotagmin) rearrangement in synovial sarcoma.	('murine', 'Species', '10090', (146, 152))	('amplification', 'Var', (170, 183))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (297, 313))	('rearrangement', 'Var', (219, 232))	('SYT', 'Gene', '6857', (260, 263))	('liposarcoma', 'Disease', (236, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('liposarcoma', 'Phenotype', 'HP:0012034', (236, 247))	('SYT', 'Gene', (260, 263))	('MDM2', 'Gene', '4193', (140, 144))	('synovial sarcoma', 'Disease', 'MESH:D013584', (297, 313))	('MDM2', 'Gene', (140, 144))	('liposarcoma', 'Disease', 'MESH:D008080', (236, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (306, 313))	('rearrangement', 'Var', (280, 293))	('genetic abnormalities', 'Disease', 'MESH:D030342', (110, 131))	('synovial sarcoma', 'Disease', (297, 313))	('genetic abnormalities', 'Disease', (110, 131))
409627	29531545	The FISH technique was used to analyze 17 specimens of liposarcoma for MDM2 amplification and CHOP rearrangement, and 10 specimens of synovial sarcoma for SYT rearrangement.	('liposarcoma', 'Disease', 'MESH:D008080', (55, 66))	('SYT', 'Gene', (155, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('liposarcoma', 'Phenotype', 'HP:0012034', (55, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('rearrangement', 'Var', (99, 112))	('MDM2', 'Gene', '4193', (71, 75))	('synovial sarcoma', 'Disease', 'MESH:D013584', (134, 150))	('MDM2', 'Gene', (71, 75))	('synovial sarcoma', 'Disease', (134, 150))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (134, 150))	('SYT', 'Gene', '6857', (155, 158))	('liposarcoma', 'Disease', (55, 66))	('amplification', 'Var', (76, 89))
409646	29531545	Lioposarcomas and synovial sarcomas, similar to many types of soft tissue sarcomas, are associated with specific genetic alterations such as translocations and amplifications, which are helpful to diagnose individual cases.	('Lioposarcomas and synovial sarcomas', 'Disease', 'MESH:D013584', (0, 35))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (18, 35))	('amplifications', 'Var', (160, 174))	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('sarcomas', 'Disease', (5, 13))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (18, 34))	('translocations', 'Var', (141, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcomas', 'Disease', (27, 35))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('sarcomas', 'Disease', (74, 82))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (62, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('associated', 'Reg', (88, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
409653	29531545	The translocation fuses SYT gene from chromosome 18 to either of the two highly homologous genes at Xp11, SSX1 or SSX2, or in less than 1% of SSX4 cases.	('SYT', 'Gene', (24, 27))	('SS', 'Phenotype', 'HP:0100242', (114, 116))	('translocation fuses', 'Var', (4, 23))	('SSX2', 'Gene', (114, 118))	('SS', 'Phenotype', 'HP:0100242', (106, 108))	('SSX1', 'Gene', (106, 110))	('SYT', 'Gene', '6857', (24, 27))	('fuses', 'Var', (18, 23))	('SS', 'Phenotype', 'HP:0100242', (142, 144))
409655	29531545	Regarding liposarcomas and synovial sarcomas, FISH is commonly used to detectMDM2 amplification and CHOP rearrangement in liposarcomas and SYT rearrangement in synovial sarcomas.	('MDM2', 'Gene', (77, 81))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (27, 44))	('SYT', 'Gene', (139, 142))	('synovial sarcomas', 'Disease', (27, 44))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (27, 43))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (160, 177))	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('synovial sarcomas', 'Disease', (160, 177))	('sarcomas', 'Phenotype', 'HP:0100242', (14, 22))	('CHOP rearrangement in liposarcomas', 'Disease', (100, 134))	('MDM2', 'Gene', '4193', (77, 81))	('amplification', 'Var', (82, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('synovial sarcomas', 'Disease', 'MESH:D013584', (27, 44))	('synovial sarcomas', 'Disease', 'MESH:D013584', (160, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('SYT', 'Gene', '6857', (139, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('liposarcomas', 'Phenotype', 'HP:0012034', (122, 134))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (160, 176))	('liposarcomas', 'Phenotype', 'HP:0012034', (10, 22))	('liposarcomas and synovial sarcomas', 'Disease', 'MESH:D013584', (10, 44))	('liposarcoma', 'Phenotype', 'HP:0012034', (122, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('liposarcoma', 'Phenotype', 'HP:0012034', (10, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('CHOP rearrangement in liposarcomas', 'Disease', 'MESH:D008080', (100, 134))
409656	29531545	The current study used the FISH technique as an ancillary tool to detect MDM2 amplification and CHOP rearrangement in liposarcomas and SYT rearrangement in synovial sarcomas, aiming at differentiating liposarcoma and synovial sarcoma subtypes from other morphologically similar sarcomas and benign conditions.	('SYT', 'Gene', '6857', (135, 138))	('sarcomas', 'Disease', 'MESH:D012509', (278, 286))	('liposarcoma', 'Phenotype', 'HP:0012034', (118, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (278, 286))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (156, 172))	('sarcomas', 'Disease', (278, 286))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (226, 242))	('synovial sarcoma', 'Disease', (217, 233))	('sarcoma subtypes', 'Disease', (226, 242))	('rearrangement', 'Var', (139, 152))	('liposarcoma', 'Disease', (201, 212))	('sarcomas', 'Disease', 'MESH:D012509', (165, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('liposarcoma', 'Disease', 'MESH:D008080', (118, 129))	('synovial sarcoma', 'Disease', 'MESH:D013584', (217, 233))	('sarcomas', 'Disease', (165, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (278, 285))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('MDM2', 'Gene', (73, 77))	('CHOP rearrangement in liposarcomas', 'Disease', 'MESH:D008080', (96, 130))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (217, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('SYT', 'Gene', (135, 138))	('liposarcoma', 'Phenotype', 'HP:0012034', (201, 212))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (156, 173))	('MDM2', 'Gene', '4193', (73, 77))	('sarcomas', 'Disease', 'MESH:D012509', (122, 130))	('liposarcoma', 'Disease', (118, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('synovial sarcomas', 'Disease', (156, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('CHOP rearrangement in liposarcomas', 'Disease', (96, 130))	('sarcomas', 'Disease', (122, 130))	('liposarcoma', 'Disease', 'MESH:D008080', (201, 212))	('synovial sarcoma', 'Disease', 'MESH:D013584', (156, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('liposarcomas', 'Phenotype', 'HP:0012034', (118, 130))	('synovial sarcomas', 'Disease', 'MESH:D013584', (156, 173))
409677	29531545	MDM2 amplification was observed in seven cases (41.2%) and CHOP rearrangement in two cases (11.8%).	('amplification', 'Var', (5, 18))	('MDM2', 'Gene', '4193', (0, 4))	('observed', 'Reg', (23, 31))	('MDM2', 'Gene', (0, 4))
409685	29531545	Currently, it is estimated that about 30% of sarcomas harbor specific chromosomal abnormalities such as chromosomal translocations and amplifications result in fusion genes; this provides a useful tool for diagnosis and offers novel and potential targets for future therapeutic approaches.	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('chromosomal translocations', 'Var', (104, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcomas', 'Disease', (45, 53))	('chromosomal abnormalities', 'Disease', (70, 95))	('amplifications', 'Var', (135, 149))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (70, 95))	('fusion genes', 'Var', (160, 172))
409686	29531545	Various molecular genetic abnormalities are detected in 12q in different subtypes of liposarcoma including t(12;16)(q13;p11), or t(12;22)(q13;q12) translocations, which lead to fusion of transcription factor gene CHOP (DDIT3) (a negative regulator of adipocyte differentiation) with TLS (FUS) or EWS genes in at least 95% of MLS cases, as well as amplification of 12q13-15 encompassing MDM2 and CDK4 genes in well-differentiated and dedifferentiated liposarcomas.	('amplification', 'Var', (347, 360))	('EWS', 'Gene', (296, 299))	('sarcoma', 'Phenotype', 'HP:0100242', (454, 461))	('TLS', 'Gene', (283, 286))	('liposarcoma', 'Phenotype', 'HP:0012034', (85, 96))	('liposarcomas', 'Phenotype', 'HP:0012034', (450, 462))	('MDM2', 'Gene', '4193', (386, 390))	('liposarcoma', 'Phenotype', 'HP:0012034', (450, 461))	('MLS', 'Phenotype', 'HP:0012268', (325, 328))	('liposarcoma', 'Disease', 'MESH:D008080', (85, 96))	('MLS', 'Disease', 'MESH:C537466', (325, 328))	('liposarcomas', 'Disease', (450, 462))	('fusion', 'Var', (177, 183))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (107, 124))	('MLS', 'Disease', (325, 328))	('liposarcoma', 'Disease', 'MESH:D008080', (450, 461))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (129, 146))	('liposarcoma', 'Disease', (85, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (454, 462))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('genetic abnormalities', 'Disease', 'MESH:D030342', (18, 39))	('liposarcoma', 'Disease', (450, 461))	('CDK4', 'Gene', (395, 399))	('liposarcomas', 'Disease', 'MESH:D008080', (450, 462))	('genetic abnormalities', 'Disease', (18, 39))	('translocations', 'Var', (147, 161))	('MDM2', 'Gene', (386, 390))
409687	29531545	A specific t(X;18)(p11.2;q11.2) translocation resulting in fusion of genes between SYT, on chromosome 18, and SSX1, SSX2, or rarely SSX4 on chromosome X is detectable in 90% of synovial sarcomas.	('SS', 'Phenotype', 'HP:0100242', (116, 118))	('SYT', 'Gene', (83, 86))	('synovial sarcomas', 'Disease', 'MESH:D013584', (177, 194))	('synovial sarcomas', 'Disease', (177, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('fusion', 'Var', (59, 65))	('SS', 'Phenotype', 'HP:0100242', (110, 112))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (177, 193))	('SYT', 'Gene', '6857', (83, 86))	('SS', 'Phenotype', 'HP:0100242', (132, 134))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (177, 194))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (11, 31))
409690	29531545	Specific genetic abnormalities of various sarcoma subtypes, including gene translocation and amplification, can be detected with high sensitivity by FISH.	('amplification', 'Var', (93, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('genetic abnormalities of various sarcoma subtypes', 'Disease', 'MESH:D030342', (9, 58))	('gene translocation', 'Var', (70, 88))	('genetic abnormalities of various sarcoma subtypes', 'Disease', (9, 58))
409691	29531545	Recent studies showed that FISH is more specific and sensitive than quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC)to detectMDM2 amplification and CHOP rearrangement in liposarcomas and SYT rearrangement in synovial sarcomas.	('MDM2', 'Gene', (153, 157))	('SYT', 'Gene', '6857', (215, 218))	('CHOP rearrangement in liposarcomas', 'Disease', 'MESH:D008080', (176, 210))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (236, 253))	('sarcomas', 'Phenotype', 'HP:0100242', (202, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('liposarcomas', 'Phenotype', 'HP:0012034', (198, 210))	('synovial sarcomas', 'Disease', 'MESH:D013584', (236, 253))	('CHOP rearrangement in liposarcomas', 'Disease', (176, 210))	('synovial sarcomas', 'Disease', (236, 253))	('SYT', 'Gene', (215, 218))	('sarcomas', 'Phenotype', 'HP:0100242', (245, 253))	('amplification', 'Var', (158, 171))	('liposarcoma', 'Phenotype', 'HP:0012034', (198, 209))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (236, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('MDM2', 'Gene', '4193', (153, 157))
409705	29531545	The current study results showed that patients with liposarcoma and amplification of MDM2had a high rate of recurrence (47%), and patients with CHOP rearrangement had no recurrence after treatment.	('liposarcoma', 'Phenotype', 'HP:0012034', (52, 63))	('liposarcoma', 'Disease', 'MESH:D008080', (52, 63))	('MDM2', 'Gene', '4193', (85, 89))	('MDM2', 'Gene', (85, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (38, 46))	('liposarcoma', 'Disease', (52, 63))	('amplification', 'Var', (68, 81))
409713	28399901	We hypothesized that PARP-1 inhibition is able to perpetuate trabectedin-induced DNA damage.	('PARP-1', 'Gene', '142', (21, 27))	('trabectedin-induced DNA damage', 'Disease', (61, 91))	('inhibition', 'Var', (28, 38))	('trabectedin', 'Chemical', 'MESH:D000077606', (61, 72))	('PARP-1', 'Gene', (21, 27))
409727	28399901	Indeed, trabectedin adducts have been suggested to induce a trapping of NER factors, which result in increased levels of cytotoxic DNA damage.	('trapping', 'MPA', (60, 68))	('increased', 'PosReg', (101, 110))	('trabectedin', 'Chemical', 'MESH:D000077606', (8, 19))	('induce', 'Reg', (51, 57))	('adducts', 'Var', (20, 27))	('levels of cytotoxic DNA damage', 'MPA', (111, 141))	('NER factors', 'Protein', (72, 83))
409732	28399901	PARP-1 recognizes and binds to sites of single-strand DNA breaks (SSBs).	('PARP-1', 'Gene', '142', (0, 6))	('binds', 'Interaction', (22, 27))	('single-strand DNA', 'Var', (40, 57))	('PARP-1', 'Gene', (0, 6))
409787	28399901	2, the combination of trabectedin (Et-743) and rucaparib induced significantly higher levels of gamma-H2AX expression only in two cell lines IB115 and IB111 cell lines.	('levels', 'MPA', (86, 92))	('rucaparib', 'Chemical', 'MESH:C531549', (47, 56))	('trabectedin', 'Chemical', 'MESH:D000077606', (22, 33))	('gamma-H2AX', 'Chemical', '-', (96, 106))	('Et-743', 'Chemical', 'MESH:D000077606', (35, 41))	('gamma-H2AX expression', 'MPA', (96, 117))	('Et-743', 'Var', (35, 41))	('higher', 'PosReg', (79, 85))	('rucaparib', 'Gene', (47, 56))
409805	28399901	For instance, it is well known that loss of BRCA-1 or BRCA-2 leads to sensitivity to PARP1 inhibition, resulting in apoptosis.	('BRCA-2', 'Gene', '675', (54, 60))	('apoptosis', 'CPA', (116, 125))	('loss', 'Var', (36, 40))	('sensitivity', 'MPA', (70, 81))	('BRCA-1', 'Gene', (44, 50))	('PARP1', 'Gene', '142', (85, 90))	('BRCA-1', 'Gene', '672', (44, 50))	('PARP1', 'Gene', (85, 90))	('BRCA-2', 'Gene', (54, 60))
409815	28399901	We have also reported that BRCA1 genotype status was predictive of trabectedin efficacy in patients with advanced STS.	('BRCA1', 'Gene', '672', (27, 32))	('patients', 'Species', '9606', (91, 99))	('genotype', 'Var', (33, 41))	('trabectedin efficacy', 'CPA', (67, 87))	('trabectedin', 'Chemical', 'MESH:D000077606', (67, 78))	('BRCA1', 'Gene', (27, 32))	('predictive', 'Reg', (53, 63))	('STS', 'Phenotype', 'HP:0030448', (114, 117))
409825	25614743	Following total tumor resection, histological and molecular examination revealed Ewing sarcoma with rearranged EWSR-1 gene.	('Ewing sarcoma', 'Disease', (81, 94))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('EWSR-1', 'Gene', '2130', (111, 117))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('EWSR-1', 'Gene', (111, 117))	('tumor', 'Disease', (16, 21))	('revealed', 'Reg', (72, 80))	('rearranged', 'Var', (100, 110))
409848	25614743	Molecular analysis demonstrated a break in the EWSR-1 gene on chromosome 22q12 using FISH (fluorescence in situ hybridization) technique (Figure 2(f), arrows) consistent with a diagnosis of Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('EWSR-1', 'Gene', '2130', (47, 53))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (190, 203))	('EWSR-1', 'Gene', (47, 53))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (190, 203))	('break', 'Var', (34, 39))	('Ewing sarcoma', 'Disease', (190, 203))
409860	25614743	Mutations in the EWSR-1 gene (Ewing sarcoma breakpoint region 1, 22q12.2) are known to cause ESFT as well as other mesenchymal tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('EWSR-1', 'Gene', '2130', (17, 23))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (30, 63))	('cause', 'Reg', (87, 92))	('ESFT', 'Disease', (93, 97))	('Ewing sarcoma breakpoint region 1', 'Gene', (30, 63))	('Mutations', 'Var', (0, 9))	('EWSR-1', 'Gene', (17, 23))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (115, 133))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (30, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('mesenchymal tumors', 'Disease', (115, 133))
409862	25614743	Rearrangements within the EWSR-1 gene are characteristic for tumors of ESFT.	('EWSR-1', 'Gene', '2130', (26, 32))	('tumors', 'Disease', (61, 67))	('Rearrangements', 'Var', (0, 14))	('EWSR-1', 'Gene', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('ESFT', 'Disease', (71, 75))
409870	23741982	The modulation of apoptosis by oncogenic viruses Transforming viruses can change a normal cell into a cancer cell during their normal life cycle.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('change', 'Reg', (74, 80))	('viruses', 'Var', (62, 69))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
409877	23741982	The deregulation of apoptosis has been implicated in the etiology of diverse diseases, including cancer.	('deregulation', 'Var', (4, 16))	('apoptosis', 'Protein', (20, 29))	('cancer', 'Disease', (97, 103))	('implicated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
409890	23741982	It is now indisputable that cervical cancer, penile cancer, some oropharyngeal cancers and other cancers of the anogenital tract are caused by certain strains of HPV.	('penile cancer', 'Disease', (45, 58))	('penile cancer', 'Disease', 'MESH:D004414', (45, 58))	('strains', 'Var', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('oropharyngeal cancers', 'Disease', (65, 86))	('HPV', 'Species', '10566', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers of the anogenital tract', 'Phenotype', 'HP:0007379', (97, 128))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('caused by', 'Reg', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('HPV', 'Gene', (162, 165))	('cervical cancer', 'Disease', 'MESH:D002583', (28, 43))	('cervical cancer', 'Disease', (28, 43))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('oropharyngeal cancers', 'Disease', 'MESH:D009959', (65, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
409910	23741982	In the cytosol, a complex known as the apoptosome is formed through the binding of Apoptotic Protease Activation Factor 1 (Apaf-1), procaspase 9, and cytochrome c. The oligomerization of Apaf-1 activates caspase 9, which, in turn, induces the proteolytic cleavage of other substrates involved in cell death (Figure 1).	('cytochrome c', 'Gene', '54205', (150, 162))	('rat', 'Species', '10116', (278, 281))	('caspase 9', 'Gene', '842', (204, 213))	('proteolytic cleavage of', 'MPA', (243, 266))	('caspase 9', 'Gene', (204, 213))	('Apoptotic Protease Activation Factor 1', 'Gene', '317', (83, 121))	('Apaf-1', 'Gene', '317', (187, 193))	('Apaf-1', 'Gene', (187, 193))	('activates', 'PosReg', (194, 203))	('Apoptotic Protease Activation Factor 1', 'Gene', (83, 121))	('oligomerization', 'Var', (168, 183))	('Apaf-1', 'Gene', '317', (123, 129))	('cytochrome c', 'Gene', (150, 162))	('caspase 9', 'Gene', (135, 144))	('caspase 9', 'Gene', '842', (135, 144))	('induces', 'Reg', (231, 238))	('Apaf-1', 'Gene', (123, 129))
409948	23741982	Moreover, E7 has been shown to sensitize JD3 mouse lymphoma cells to IFN-alpha-induced apoptosis, the co-expression of E7 and p21 induces apoptosis in U2OS osteosarcoma cells, and the overexpression of E7 in genital-derived keratinocytes induces spontaneous cell death and sensitizes the cells to TNF-mediated apoptosis.	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('co-expression', 'Var', (102, 115))	('osteosarcoma', 'Disease', (156, 168))	('TNF', 'Gene', '7124', (297, 300))	('osteosarcoma', 'Disease', 'MESH:D012516', (156, 168))	('U2OS', 'CellLine', 'CVCL:0042', (151, 155))	('lymphoma', 'Disease', (51, 59))	('lymphoma', 'Disease', 'MESH:D008223', (51, 59))	('apoptosis', 'CPA', (138, 147))	('IFN-alpha', 'Gene', '111654', (69, 78))	('overexpression', 'PosReg', (184, 198))	('induces', 'Reg', (130, 137))	('p21', 'Gene', (126, 129))	('mouse', 'Species', '10090', (45, 50))	('rat', 'Species', '10116', (226, 229))	('osteosarcoma', 'Phenotype', 'HP:0002669', (156, 168))	('sensitize', 'Reg', (31, 40))	('IFN-alpha', 'Gene', (69, 78))	('sensitizes', 'Reg', (273, 283))	('TNF', 'Gene', (297, 300))	('lymphoma', 'Phenotype', 'HP:0002665', (51, 59))	('spontaneous cell death', 'CPA', (246, 268))
409950	23741982	In another study, it was reported that the expression of E7 in fibroblasts delayed Fas-mediated apoptosis and prevented TNF-mediated apoptosis by suppressing caspase-8 activation.	('caspase-8', 'Gene', (158, 167))	('Fas-mediated apoptosis', 'CPA', (83, 105))	('caspase-8', 'Gene', '841', (158, 167))	('TNF', 'Gene', '7124', (120, 123))	('activation', 'MPA', (168, 178))	('expression', 'Var', (43, 53))	('prevented', 'NegReg', (110, 119))	('suppressing', 'NegReg', (146, 157))	('delayed', 'NegReg', (75, 82))	('Fas', 'Chemical', 'MESH:C038178', (83, 86))	('TNF', 'Gene', (120, 123))
409983	23741982	Because E2 is expressed in the intermediate differentiated layers of the HPV infected lesions, it is possible that in vivo, the modulation of caspase 8 by E2 might play a role in the formation of warts, via an as yet unknown mechanism.	('caspase 8', 'Gene', (142, 151))	('modulation', 'Var', (128, 138))	('HPV infected lesions', 'Disease', 'MESH:D030361', (73, 93))	('warts', 'Phenotype', 'HP:0200043', (196, 201))	('play', 'Reg', (164, 168))	('HPV infected lesions', 'Disease', (73, 93))	('warts', 'Disease', (196, 201))	('role', 'Reg', (171, 175))	('caspase 8', 'Gene', '841', (142, 151))
409994	23741982	In contrast, after 10 years of infection, HBV only induces chronic cirrhosis in a small percentage of patients (5-10%), while the percentage of patients who develop this disease as a consequence of HCV infection is 55-60%.	('cirrhosis', 'Phenotype', 'HP:0001394', (67, 76))	('HCV infection', 'Disease', (198, 211))	('patients', 'Species', '9606', (102, 110))	('infection', 'Disease', (31, 40))	('induces', 'Reg', (51, 58))	('HBV', 'Var', (42, 45))	('infection', 'Disease', (202, 211))	('HBV', 'Species', '10407', (42, 45))	('patients', 'Species', '9606', (144, 152))	('HCV infection', 'Disease', 'MESH:D006526', (198, 211))	('infection', 'Disease', 'MESH:D007239', (202, 211))	('infection', 'Disease', 'MESH:D007239', (31, 40))	('chronic cirrhosis', 'Disease', 'MESH:D005355', (59, 76))	('chronic cirrhosis', 'Disease', (59, 76))
410034	23741982	The pX region contains four open reading frames (ORFs), that encode the accessory proteins (p12I, p13II, p30II), the posttranscriptional regulator REX (ORF III) and the transactivator Tax (ORF IV).	('p13', 'Gene', '440926', (98, 101))	('p30II', 'Var', (105, 110))	('p12', 'Gene', '56655', (92, 95))	('p13', 'Gene', (98, 101))	('p12', 'Gene', (92, 95))
410057	23741982	Even though the virus can be eliminated from BL cells in culture through continuous passages, the direct elimination of EBV from these cells induces apoptosis.	('apoptosis', 'CPA', (149, 158))	('EBV', 'Gene', (120, 123))	('BL', 'Phenotype', 'HP:0030080', (45, 47))	('induces', 'Reg', (141, 148))	('EBV', 'Species', '10376', (120, 123))	('elimination', 'Var', (105, 116))
410096	23741982	It also associates with different host cell proteins, including chromatin-associated proteins, which are involved in the epigenetic silencing of TGFbeta expression.	('TGFbeta', 'Gene', '7040', (145, 152))	('epigenetic', 'Var', (121, 131))	('TGFbeta', 'Gene', (145, 152))	('associates', 'Interaction', (8, 18))
410108	23741982	The target of miR-K5 is the Bcl2 associated factor, BCLAF1, which promotes apoptosis.	('miR-K5', 'Var', (14, 20))	('apoptosis', 'CPA', (75, 84))	('promotes', 'PosReg', (66, 74))	('BCLAF1', 'Gene', '9774', (52, 58))	('BCLAF1', 'Gene', (52, 58))
410110	23741982	The aberrant expression of the ORF50 protein is required for the initiation of the lytic phase and the expression of many KSHV-encoded lytic genes, such as K1, K3, and K5; viral macrophage inflammatory proteins (vMIPs); K12; viral G-protein-coupled receptor (vGPCR); viral dihydrofolate reductase (vDHFR); DNA replication factors; and thymidylate synthase.	('KS', 'Phenotype', 'HP:0100726', (122, 124))	('thymidylate synthase', 'Gene', (335, 355))	('vDHFR', 'Gene', (298, 303))	('KSHV-encoded', 'Gene', (122, 134))	('thymidylate synthase', 'Gene', '4961481', (335, 355))	('vGPCR', 'Gene', (259, 264))	('KSHV', 'Species', '37296', (122, 126))	('K12', 'Var', (220, 223))	('ORF50', 'Gene', '4961526', (31, 36))	('ORF50', 'Gene', (31, 36))
410137	33725983	The translocations lead to a juxtaposition of Ewing sarcoma genes on chromosome 22 and a Fms-like tyrosine kinase 1 gene on chromosome 11, and production of a chimeric protein with a transcription capability [Fig.	('translocations', 'Var', (4, 18))	('lead to', 'Reg', (19, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (46, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('Fms-like tyrosine kinase 1', 'Gene', '2321', (89, 115))	('juxtaposition', 'Reg', (29, 42))	('Ewing sarcoma', 'Disease', (46, 59))	('transcription', 'MPA', (183, 196))	('Fms-like tyrosine kinase 1', 'Gene', (89, 115))
410152	33725983	The assessment of the primary tumor showed a t11/22 translocation, the cytogenetic assessment of the bone marrow was negative.	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (30, 35))	('t11/22', 'Var', (45, 51))
410189	33725983	As a consequence, a young patient's quality-of-life was considerably impaired due to the amputation of the penis which could unfortunately be avoided.	('patient', 'Species', '9606', (26, 33))	('quality-of-life', 'CPA', (36, 51))	('impaired', 'NegReg', (69, 77))	('amputation', 'Var', (89, 99))
410202	33293370	Induced cells expressing EWSR1/FLI1 displayed an increased incidence of aberrant localization of Aurora B, and greater levels of aneuploidy, compared with noninduced cells.	('Aurora B', 'Protein', (97, 105))	('EWSR1/FLI1', 'Var', (25, 35))	('aneuploidy', 'Disease', 'MESH:D000782', (129, 139))	('aberrant localization', 'MPA', (72, 93))	('aneuploidy', 'Disease', (129, 139))
410204	33293370	In contrast, the phosphomimetic mutant EWSR1/FLI1-T79D (Thr to aspartic acid (Asp)) retained the high activity as wild-type EWSR1/FLI1.	('Asp', 'Gene', (78, 81))	('aspartic acid', 'Chemical', 'MESH:D001224', (63, 76))	('T79D', 'SUBSTITUTION', 'None', (50, 54))	('Thr', 'Chemical', 'MESH:D013912', (56, 59))	('activity', 'MPA', (102, 110))	('T79D', 'Var', (50, 54))	('Asp', 'Gene', '259266', (78, 81))
410205	33293370	Together, these findings suggest that phosphorylation of EWSR1/FLI1 at Thr 79 promotes the colocalization of EWSR1/FLI1 and Aurora B on the chromosomes during prophase and metaphase and, in addition, impairs the localization of Aurora B during anaphase, leading to induction of aneuploidy.	('EWSR1/FLI1', 'Gene', (57, 67))	('promotes', 'PosReg', (78, 86))	('EWSR1/FLI1', 'Gene', (109, 119))	('localization', 'MPA', (212, 224))	('Aurora', 'Protein', (228, 234))	('aneuploidy', 'Disease', (278, 288))	('Thr', 'Chemical', 'MESH:D013912', (71, 74))	('aneuploidy', 'Disease', 'MESH:D000782', (278, 288))	('phosphorylation', 'Var', (38, 53))	('colocalization', 'MPA', (91, 105))	('impairs', 'NegReg', (200, 207))
410209	33293370	Subsequent studies demonstrated that 85% of Ewing sarcoma patients have tumors that express the EWSR1/FLI1 fusion gene, while the remaining patients have tumors that express fusion genes composed of EWSR1 and other ETS transcription factors (ETV1, ETV4, ERG, and FEV1).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ERG', 'Gene', '2078', (254, 257))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('fusion', 'Var', (107, 113))	('tumors', 'Disease', (72, 78))	('ETV4', 'Gene', '2118', (248, 252))	('ETV1', 'Gene', (242, 246))	('Ewing sarcoma', 'Disease', (44, 57))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('EWSR1/FLI1', 'Gene', (96, 106))	('patients', 'Species', '9606', (140, 148))	('ETV1', 'Gene', '2115', (242, 246))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('patients', 'Species', '9606', (58, 66))	('EWSR1', 'Gene', (199, 204))	('tumors', 'Disease', (154, 160))	('ETV4', 'Gene', (248, 252))	('ERG', 'Gene', (254, 257))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (44, 57))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (44, 57))
410210	33293370	The reported effects of EWSR1 fusion protein expression include: 1) altered epigenetic status due to aberrant recruitment of the chromatin remodeling complex, and 2) aberrant expression of target genes in Ewing sarcoma cells.	('EWSR1', 'Gene', (24, 29))	('expression', 'MPA', (175, 185))	('recruitment', 'MPA', (110, 121))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (205, 218))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (205, 218))	('epigenetic status', 'MPA', (76, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('aberrant', 'Var', (166, 174))	('fusion protein', 'Protein', (30, 44))	('Ewing sarcoma', 'Disease', (205, 218))	('altered', 'Reg', (68, 75))
410213	33293370	For example, mutations in STAG2 have been identified in 17% of patients, mutations in CDKN2A were found in 12% of patients, and mutations in TP53 were found in 7% of patients.	('identified', 'Reg', (42, 52))	('CDKN2A', 'Gene', '1029', (86, 92))	('found', 'Reg', (98, 103))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('patients', 'Species', '9606', (166, 174))	('STAG2', 'Gene', '10735', (26, 31))	('patients', 'Species', '9606', (63, 71))	('STAG2', 'Gene', (26, 31))	('CDKN2A', 'Gene', (86, 92))	('mutations', 'Var', (13, 22))	('mutations', 'Var', (73, 82))	('patients', 'Species', '9606', (114, 122))
410218	33293370	We previously demonstrated that EWSR1/FLI1 impairs the recruitment of the key mitotic regulator Aurora B kinase to the midzone, (the network of antiparallel microtubules and midzone proteins located between segregating chromosomes during anaphase).	('Aurora B kinase', 'Enzyme', (96, 111))	('recruitment', 'MPA', (55, 66))	('impairs', 'NegReg', (43, 50))	('midzone', 'Chemical', '-', (119, 126))	('midzone', 'Chemical', '-', (174, 181))	('EWSR1/FLI1', 'Var', (32, 42))
410224	33293370	Surprisingly, substitution of amino acid T79 of EWSR1/FLI1 with alanine abolished the ability of the cells to induce these phenotypes, whereas expression of EWSR1/FLI1-T79D (containing the phosphomimetic substitution of Asp for Thr 79) retained the high activity as wild-type EWSR1/FLI1.	('activity', 'MPA', (254, 262))	('abolished', 'NegReg', (72, 81))	('EWSR1/FLI1', 'Gene', (48, 58))	('Asp for Thr 79', 'SUBSTITUTION', 'None', (220, 234))	('T79D', 'Var', (168, 172))	('Asp for Thr 79', 'Var', (220, 234))	('substitution', 'Var', (14, 26))	('alanine', 'Chemical', 'MESH:D000409', (64, 71))	('T79D', 'SUBSTITUTION', 'None', (168, 172))
410233	33293370	The substitution constructs had a Thr to Ala substitution (T79A) or a Thr to Asp substitution (T79D; phosphomimetic mutation).	('Asp', 'Gene', (77, 80))	('T79D', 'Var', (95, 99))	('Thr', 'Chemical', 'MESH:D013912', (34, 37))	('T79A', 'SUBSTITUTION', 'None', (59, 63))	('T79A', 'Var', (59, 63))	('T79D', 'SUBSTITUTION', 'None', (95, 99))	('Ala', 'Chemical', 'MESH:D000409', (41, 44))	('Asp', 'Gene', '259266', (77, 80))	('Thr', 'Chemical', 'MESH:D013912', (70, 73))
410234	33293370	Using these three DNA constructs, we established stable Tet-on cell lines by integrating EWSR1/FLI1, EWSR1/FLI1-T79A, and EWSR1/FLI1-T79D transgenes (each with an mCherry tag) into the safe-harbor AAVS1 locus of DLD-1 cells using CRISPR/Cas9 technology (Fig.	('T79D', 'Var', (133, 137))	('AAVS1', 'Gene', '17', (197, 202))	('T79A', 'SUBSTITUTION', 'None', (112, 116))	('T79A', 'Var', (112, 116))	('Tet', 'Chemical', 'MESH:C010349', (56, 59))	('T79D', 'SUBSTITUTION', 'None', (133, 137))	('AAVS1', 'Gene', (197, 202))	('EWSR1/FLI1', 'Var', (89, 99))
410237	33293370	Expression of EWSR1/FLI1, EWSR1/FLI1-T79A, and EWSR1/FLI1-T79D was verified in induced cells by western blot using an anti-FLI1 antibody and by immunocytochemistry using antibodies against the mCherry tags (Fig.	('T79A', 'Var', (37, 41))	('T79D', 'Var', (58, 62))	('T79D', 'SUBSTITUTION', 'None', (58, 62))	('T79A', 'SUBSTITUTION', 'None', (37, 41))
410246	33293370	(Note that DLD-1 cells do not express detectable levels of endogenous FLI1, thus the antibody specifically recognizes both EWSR1/FLI1 and EWSR1/FLI1-T79A).	('T79A', 'SUBSTITUTION', 'None', (149, 153))	('T79A', 'Var', (149, 153))	('EWSR1/FLI1', 'Var', (123, 133))
410247	33293370	Consistent with the observations using immunocytochemistry, the FLI1 signal appears in the chromosome fraction in Dox treated cells expressing EWSR1/FLI1, and there is virtually no signal in this fraction for the EWSR1/FLI1-T79A (Dox+) sample (Fig.	('Dox', 'Chemical', 'MESH:D004318', (230, 233))	('Dox', 'Chemical', 'MESH:D004318', (114, 117))	('T79A', 'SUBSTITUTION', 'None', (224, 228))	('T79A', 'Var', (224, 228))	('FLI1', 'Gene', (64, 68))	('EWSR1/FLI1', 'Var', (143, 153))
410248	33293370	Quantification of the band intensity for the EWSR1/FLI1 and EWSR1/FLI1-T79A signals in the chromosome fractions obtained from three experiments revealed that the intensity of the EWSR1/FLI1-T79A signal was significantly lower than that of EWSR1/FLI1 (defined as 1.0) (Fig.	('T79A', 'Var', (190, 194))	('T79A', 'SUBSTITUTION', 'None', (71, 75))	('T79A', 'Var', (71, 75))	('lower', 'NegReg', (220, 225))	('intensity', 'MPA', (162, 171))	('T79A', 'SUBSTITUTION', 'None', (190, 194))
410249	33293370	Note that the expression level of the EWSR1/FLI1-T79A is higher than that of EWSR1/FLI1 (Fig.	('higher', 'PosReg', (57, 63))	('expression level', 'MPA', (14, 30))	('T79A', 'SUBSTITUTION', 'None', (49, 53))	('T79A', 'Var', (49, 53))
410250	33293370	2C whole-cell lysate); however, the localization of EWSR1/FLI1-T79A on the chromosome was significantly lower than that of EWSR1/FLI1.	('T79A', 'SUBSTITUTION', 'None', (63, 67))	('lower', 'NegReg', (104, 109))	('localization', 'MPA', (36, 48))	('T79A', 'Var', (63, 67))
410251	33293370	Therefore, the result suggests that the localization of the EWSR1/FLI1 on the chromosome is not regulated by the level of the protein, but the residue Thr 79 is required for EWSR1/FLI1 to localize to chromosomes during mitosis.	('Thr', 'Chemical', 'MESH:D013912', (151, 154))	('Thr 79', 'Var', (151, 157))	('EWSR1/FLI1', 'Gene', (174, 184))
410255	33293370	3A, top row, far-right panel) in EWSR1/FLI1 expressing cells compared with cells expressing EWSR1/FLI1-T79A (Fig.	('T79A', 'Var', (103, 107))	('EWSR1/FLI1', 'Gene', (33, 43))	('T79A', 'SUBSTITUTION', 'None', (103, 107))
410256	33293370	Dox-treated cells expressing EWSR1/FLI1 (n = 11 cells) show a significantly higher correlation of localization than cells expressing EWSR1/FLI1-T79A (n = 12 cells) (Fig.	('Dox', 'Chemical', 'MESH:D004318', (0, 3))	('correlation', 'MPA', (83, 94))	('T79A', 'Var', (144, 148))	('EWSR1/FLI1', 'Var', (29, 39))	('T79A', 'SUBSTITUTION', 'None', (144, 148))	('higher', 'PosReg', (76, 82))	('localization', 'MPA', (98, 110))
410261	33293370	In Dox-induced cells expressing EWSR1/FLI1, the percentage of cells displaying aberrant Aurora B localization was significantly higher (49 +- 4%) compared with that observed in noninduced (Dox-) cells (37 +- 6%, p < 0.05) (Fig.	('higher', 'PosReg', (128, 134))	('Dox', 'Chemical', 'MESH:D004318', (189, 192))	('Aurora B', 'Protein', (88, 96))	('EWSR1/FLI1', 'Var', (32, 42))	('Dox', 'Chemical', 'MESH:D004318', (3, 6))
410263	33293370	The EWSR1/FLI1-T79A expression did not affect the symmetric distribution of Aurora B signal along the midline (Fig.	('T79A', 'Var', (15, 19))	('T79A', 'SUBSTITUTION', 'None', (15, 19))	('Aurora B signal', 'MPA', (76, 91))
410264	33293370	The EWSR1/FLI1-T79A expressing cells did not display a significant change in their incidence of Aurora B mislocalization (33 +- 2%) compared with that observed in noninduced cells (32 +- 4%, p > 0.05) (Fig.	('Aurora B', 'Protein', (96, 104))	('T79A', 'Var', (15, 19))	('T79A', 'SUBSTITUTION', 'None', (15, 19))
410265	33293370	These results suggest that amino acid Thr 79 of EWSR1/FLI1 is critical to induce mislocalization of Aurora B at the midzone during anaphase.	('mislocalization', 'MPA', (81, 96))	('EWSR1/FLI1', 'Gene', (48, 58))	('midzone', 'Chemical', '-', (116, 123))	('Thr', 'Chemical', 'MESH:D013912', (38, 41))	('Aurora B', 'Protein', (100, 108))	('induce', 'Reg', (74, 80))	('amino acid Thr', 'Var', (27, 41))
410267	33293370	Because the doubling time of DLD-1 cell is approximately 20 h, and the maximum induction of EWSR1/FLI1 by doxycycline takes approximately 20 h, the stable DLD-1 cell lines were treated with Dox or left untreated for 48 h to assess whether the EWSR1/FLI1 induces aneuploidy after one cell cycle (Fig.	('aneuploidy', 'Disease', (262, 272))	('aneuploidy', 'Disease', 'MESH:D000782', (262, 272))	('induces', 'Reg', (254, 261))	('Dox', 'Chemical', 'MESH:D004318', (190, 193))	('EWSR1/FLI1', 'Var', (243, 253))	('doxycycline', 'Chemical', 'MESH:D004318', (106, 117))	('EWSR1/FLI1', 'Gene', (92, 102))
410271	33293370	The majority of cells in the EWSR1/FLI1 (Dox-) sample, the EWSR1/FLI1-T79A (Dox-) sample, and the EWSR1/FLI1-T79A (Dox+) sample had 46 chromosomes (Fig.	('T79A', 'Var', (70, 74))	('Dox', 'Chemical', 'MESH:D004318', (41, 44))	('T79A', 'SUBSTITUTION', 'None', (109, 113))	('T79A', 'Var', (109, 113))	('Dox', 'Chemical', 'MESH:D004318', (76, 79))	('Dox', 'Chemical', 'MESH:D004318', (115, 118))	('T79A', 'SUBSTITUTION', 'None', (70, 74))
410274	33293370	The characterization of the EWSR1/FLI1-T79A cell line suggested that residue Thr 79 of EWSR1/FLI1 plays a critical role in the regulation of Aurora B during metaphase and anaphase and in the induction of aneuploidy.	('T79A', 'Var', (39, 43))	('Aurora B', 'Protein', (141, 149))	('aneuploidy', 'Disease', (204, 214))	('Thr', 'Chemical', 'MESH:D013912', (77, 80))	('T79A', 'SUBSTITUTION', 'None', (39, 43))	('plays', 'Reg', (98, 103))	('aneuploidy', 'Disease', 'MESH:D000782', (204, 214))	('regulation', 'MPA', (127, 137))	('EWSR1/FLI1', 'Gene', (87, 97))
410276	33293370	To address this, we analyzed the phosphomimetic EWSR1/FLI1-T79D mutant line, which has a Thr to Asp substitution at residue 79, and compared its activity with that of EWSR1/FLI1.	('Thr to Asp substitution at residue 79', 'SUBSTITUTION', 'None', (89, 126))	('T79D', 'SUBSTITUTION', 'None', (59, 63))	('Thr to Asp substitution at residue 79', 'Var', (89, 126))	('T79D', 'Var', (59, 63))
410279	33293370	Similar to EWSR1/FLI1, majority of the EWSR1/FLI1-T79D-mCherry expressing cells displayed strong mCherry signals on the chromosomes during all mitotic stages (Fig.	('mCherry signals on the', 'MPA', (97, 119))	('T79D', 'Var', (50, 54))	('T79D', 'SUBSTITUTION', 'None', (50, 54))
410280	33293370	We further analyzed the localization of EWSR1/FLI1-T79D in biochemically fractionated cytoplasm and chromosome samples using the same protocol used in the experiments shown in Figure 2, C and D. Consistent with the result obtained by immunocytochemistry, both EWSR1/FLI1 and EWSR1/FLI1-T79D signal are present in the chromosome fraction in Dox-treated cells (Fig.	('T79D', 'SUBSTITUTION', 'None', (286, 290))	('T79D', 'Var', (51, 55))	('T79D', 'Var', (286, 290))	('EWSR1/FLI1', 'Var', (260, 270))	('Dox', 'Chemical', 'MESH:D004318', (340, 343))	('T79D', 'SUBSTITUTION', 'None', (51, 55))
410281	33293370	Interestingly, quantification of the band intensity for the EWSR1/FLI1 and EWSR1/FLI1-T79D signals in the chromosome fractions revealed that the signal intensity for EWSR1/FLI1-T79D was significantly higher than that of EWSR1/FLI1 (defined as 1.0) (Fig.	('T79D', 'Var', (177, 181))	('T79D', 'SUBSTITUTION', 'None', (86, 90))	('T79D', 'SUBSTITUTION', 'None', (177, 181))	('signal', 'MPA', (145, 151))	('T79D', 'Var', (86, 90))	('higher', 'PosReg', (200, 206))
410282	33293370	Despite the higher expression level of the EWSR1/FLI1-T79A and EWSR1/FLI1-T79D than EWSR1/FLI1 (Figs.	('T79D', 'Var', (74, 78))	('higher', 'PosReg', (12, 18))	('T79A', 'SUBSTITUTION', 'None', (54, 58))	('T79A', 'Var', (54, 58))	('expression level', 'MPA', (19, 35))	('T79D', 'SUBSTITUTION', 'None', (74, 78))
410283	33293370	2C and 6C whole cell lysate), the localization of EWSR1/FLI1-T79A on the chromosome was significantly lower than that of EWSR1/FLI1.	('lower', 'NegReg', (102, 107))	('T79A', 'SUBSTITUTION', 'None', (61, 65))	('localization', 'MPA', (34, 46))	('T79A', 'Var', (61, 65))
410288	33293370	In contrast to the results shown in Figure 3 with T79A mutant, there was a significant increase in the Pearson Coefficient between EWSR1/FLI1 (n = 10 cells) and EWSR1/FLI1-T79D (n = 10 cells) (p < 0.01) (Fig.	('T79D', 'SUBSTITUTION', 'None', (172, 176))	('T79A', 'SUBSTITUTION', 'None', (50, 54))	('increase', 'PosReg', (87, 95))	('EWSR1/FLI1', 'Var', (131, 141))	('Pearson Coefficient', 'MPA', (103, 122))	('T79D', 'Var', (172, 176))	('T79A', 'Var', (50, 54))
410289	33293370	There was higher level of colocalization between EWSR1/FLI1-T79D and Aurora B compared with that of EWSR1/FLI1 and Aurora B.	('colocalization', 'MPA', (26, 40))	('T79D', 'SUBSTITUTION', 'None', (60, 64))	('T79D', 'Var', (60, 64))	('Aurora B', 'Disease', (69, 77))
410291	33293370	Because EWSR1/FLI1-T79A lacks the ability to localize Aurora B to the midzone, we investigated the effect of phosphorylation of EWSR1/FLI1 residue T79 on Aurora B localization using stable cell lines with the phosphomimetic mutant EWSR1/FLI1-T79D.	('T79A', 'SUBSTITUTION', 'None', (19, 23))	('T79A', 'Var', (19, 23))	('T79D', 'SUBSTITUTION', 'None', (242, 246))	('midzone', 'Chemical', '-', (70, 77))	('T79D', 'Var', (242, 246))
410292	33293370	DLD1 cells expressing EWSR1/FLI1 (Dox+) and EWSR1/FLI1-T79D (Dox+) (and untreated controls) were subjected to immunocytochemistry using anti-mCherry and anti-Aurora B antibodies.	('T79D', 'SUBSTITUTION', 'None', (55, 59))	('Dox', 'Chemical', 'MESH:D004318', (34, 37))	('T79D', 'Var', (55, 59))	('EWSR1/FLI1', 'Var', (22, 32))	('Dox', 'Chemical', 'MESH:D004318', (61, 64))
410293	33293370	Cells expressing either EWSR1/FLI1 or EWSR1/FLI1-T79D displayed a greater incidence of aberrant Aurora B localization than uninduced (Dox-) cells (Fig.	('EWSR1/FLI1', 'Var', (24, 34))	('T79D', 'SUBSTITUTION', 'None', (49, 53))	('T79D', 'Var', (49, 53))	('aberrant Aurora B', 'CPA', (87, 104))	('Dox', 'Chemical', 'MESH:D004318', (134, 137))
410296	33293370	Cells expressing the phosphomimetic EWSR1/FLI1-T79D also displayed a significant increase in their incidence of Aurora B mislocalization (57.3 +- 6.1 %) compared with that observed in noninduced cells (31.3 +- 2.3 %, p < 0.01) (Fig.	('T79D', 'Var', (47, 51))	('phosphomimetic', 'Var', (21, 35))	('T79D', 'SUBSTITUTION', 'None', (47, 51))	('increase', 'PosReg', (81, 89))	('Aurora', 'Disease', (112, 118))
410297	33293370	Moreover, there was no significant difference between the incidence of aberrant Aurora B localization in EWSR1/FLI1-expressing cells and EWSR1/FLI1-T79D-expressing cells (p > 0.05, nonsignificant).	('T79D', 'SUBSTITUTION', 'None', (148, 152))	('localization', 'MPA', (89, 101))	('T79D', 'Var', (148, 152))	('Aurora B', 'Protein', (80, 88))
410298	33293370	These results suggest that phosphorylation of the Thr 79 residue of EWSR1/FLI1 is critical for the EWSR1/FLI1-induced mislocalization of Aurora B at the midzone during anaphase.	('Thr', 'Chemical', 'MESH:D013912', (50, 53))	('EWSR1/FLI1', 'Gene', (68, 78))	('Aurora B', 'Protein', (137, 145))	('mislocalization', 'MPA', (118, 133))	('EWSR1/FLI1-induced', 'Var', (99, 117))	('midzone', 'Chemical', '-', (153, 160))
410299	33293370	To address whether phosphorylation of EWSR1/FLI1 at Thr 79 is a critical modification required for the induction of aneuploidy in cells expressing EWSR1/FLI1, chromosome spread experiments were performed on Dox-treated cells expressing EWSR1/FLI1 and EWSR1/FLI1-T79D (Fig.	('aneuploidy', 'Disease', 'MESH:D000782', (116, 126))	('EWSR1/FLI1', 'Var', (147, 157))	('T79D', 'SUBSTITUTION', 'None', (262, 266))	('Dox', 'Chemical', 'MESH:D004318', (207, 210))	('T79D', 'Var', (262, 266))	('EWSR1/FLI1', 'Var', (236, 246))	('aneuploidy', 'Disease', (116, 126))	('Thr', 'Chemical', 'MESH:D013912', (52, 55))
410300	33293370	Consistent with the results shown in Figure 5, cells expressing EWSR1/FLI1 had a higher incidence of aberrant numbers of chromosomes (76.7 +- 11.7 %) than Dox negative cells (35.7 +- 2.3 %, p < 0.01) that don't express the fusion protein.	('aberrant numbers of chromosomes', 'CPA', (101, 132))	('EWSR1/FLI1', 'Var', (64, 74))	('Dox', 'Chemical', 'MESH:D004318', (155, 158))
410301	33293370	Surprisingly, Dox+ cells expressing EWSR1/FLI1-T79D also displayed a higher incidence of aberrant numbers of chromosomes (70.3 +- 6.0 %) compared with Dox negative cells (43.3 +- 2.1 %, p < 0.01), and there was no significant difference in the incidence of cells containing aberrant chromosome numbers between cells expressing EWSR1/FLI1 and cells expressing the phosphomimetic mutant EWSR1/FLI1-T79D (Fig.	('T79D', 'Var', (47, 51))	('Dox', 'Chemical', 'MESH:D004318', (14, 17))	('T79D', 'SUBSTITUTION', 'None', (396, 400))	('EWSR1/FLI1', 'Var', (327, 337))	('aberrant numbers of chromosomes', 'CPA', (89, 120))	('T79D', 'SUBSTITUTION', 'None', (47, 51))	('T79D', 'Var', (396, 400))	('Dox', 'Chemical', 'MESH:D004318', (151, 154))
410302	33293370	The number of chromosomes per cell in cells expressing EWSR1/FLI1 and cells expressing EWSR1/FLI1-T79D are shown in Figure 9C.	('EWSR1/FLI1', 'Var', (55, 65))	('T79D', 'SUBSTITUTION', 'None', (98, 102))	('T79D', 'Var', (98, 102))
410305	33293370	The conversion of a single amino acid at residue 79 of EWSR1/FLI1 from Thr to Ala was sufficient to abolish the induction of the phenotypes described above.	('Thr', 'Chemical', 'MESH:D013912', (71, 74))	('conversion of', 'Var', (4, 17))	('abolish', 'NegReg', (100, 107))	('Ala', 'Chemical', 'MESH:D000409', (78, 81))	('EWSR1/FLI1', 'Gene', (55, 65))
410306	33293370	In contrast, the substitution of amino acid 79 of EWSR1/FLI1 from Thr to Asp did not abolish the induction of the phenotypes described above.	('EWSR1/FLI1', 'Gene', (50, 60))	('substitution of amino acid', 'Var', (17, 43))	('Asp', 'Gene', '259266', (73, 76))	('Thr', 'Chemical', 'MESH:D013912', (66, 69))	('abolish', 'NegReg', (85, 92))	('Asp', 'Gene', (73, 76))
410313	33293370	Our previous report demonstrated that knockdown of OGA (the enzyme that removes O-GlcNAc from proteins) in HeLa cells resulted in increased levels of O-GlcNAcylation of EWSR1 as well as aberrant localization of EWSR1 during metaphase.	('localization', 'MPA', (195, 207))	('HeLa', 'CellLine', 'CVCL:0030', (107, 111))	('OGA', 'Gene', (51, 54))	('O-GlcNAc', 'Chemical', '-', (80, 88))	('levels of O-GlcNAcylation', 'MPA', (140, 165))	('EWSR1', 'Gene', (169, 174))	('EWSR1', 'Gene', (211, 216))	('O-GlcNAc', 'Chemical', '-', (150, 158))	('OGA', 'Gene', '10724', (51, 54))	('increased', 'PosReg', (130, 139))	('knockdown', 'Var', (38, 47))
410315	33293370	With our demonstration of the importance of T79 in the induction of aneuploidy, the EWSR1/FLI1-T79A and EWSR1/FLI1-T79D mutants that we developed may provide an important tool for dissecting the disease.	('aneuploidy', 'Disease', 'MESH:D000782', (68, 78))	('T79D', 'SUBSTITUTION', 'None', (115, 119))	('T79A', 'Var', (95, 99))	('T79A', 'SUBSTITUTION', 'None', (95, 99))	('T79D', 'Var', (115, 119))	('aneuploidy', 'Disease', (68, 78))
410316	33293370	Interestingly, numerous proteins are known to alternatively undergo both O-GlcNAcylation and phosphorylation at the same Thr residue, and the phenotypes of the cells expressing those modified proteins are altered by the posttranslational modification (PTM).	('posttranslational modification', 'Var', (220, 250))	('altered', 'Reg', (205, 212))	('Thr', 'Chemical', 'MESH:D013912', (121, 124))	('O-GlcNAc', 'Chemical', '-', (73, 81))	('O-GlcNAcylation', 'MPA', (73, 88))
410317	33293370	Therefore, it is possible that EWSR1-T79 and EWSR1/FLI1-T79 undergo both phosphorylation and O-GlcNAcylation and that the phosphorylation of EWSR1/FLI1 is the dominant PTM critical for the induction of mitotic dysfunction.	('undergo', 'Reg', (60, 67))	('mitotic dysfunction', 'Disease', 'MESH:D004314', (202, 221))	('mitotic dysfunction', 'Disease', (202, 221))	('EWSR1-T79', 'Var', (31, 40))	('EWSR1/FLI1-T79', 'Var', (45, 59))	('EWSR1/FLI1', 'Gene', (141, 151))	('O-GlcNAcylation', 'MPA', (93, 108))	('phosphorylation', 'MPA', (73, 88))	('O-GlcNAc', 'Chemical', '-', (93, 101))
410321	33293370	Given the critical importance of amino acid T79 in the function of EWSR1/FLI1, utilizing the amino acid residue-substituted EWSR1/FLI1-T79A and EWSR1/FLI1-T79D constructs will further improve our understanding of the molecular pathogenesis of the disease.	('T79A', 'SUBSTITUTION', 'None', (135, 139))	('T79A', 'Var', (135, 139))	('T79D', 'SUBSTITUTION', 'None', (155, 159))	('T79D', 'Var', (155, 159))
410322	33293370	For example, because EWSR1/FLI1-T79A does not localize to chromosomes during early mitosis, we can determine if this molecule lacks the ability to interact with EWSR1 and/or Aurora B. Alternatively, EWSR1/FLI1-T79A may form dimers with EWSR1 or Aurora B, but may not be capable of localizing to chromosomes, indicating that localization is mediated by an additional unknown mechanism.	('dimers', 'Interaction', (224, 230))	('T79A', 'SUBSTITUTION', 'None', (32, 36))	('T79A', 'Var', (32, 36))	('form', 'Reg', (219, 223))	('T79A', 'SUBSTITUTION', 'None', (210, 214))	('T79A', 'Var', (210, 214))
410323	33293370	Conversely, it is possible that the EWSR1/FLI1-T79D has an opposite activity compared with EWSR1/FLI1-T79A.	('T79A', 'Var', (102, 106))	('T79D', 'SUBSTITUTION', 'None', (47, 51))	('T79D', 'Var', (47, 51))	('T79A', 'SUBSTITUTION', 'None', (102, 106))
410325	33293370	Future studies will be required to elucidate the mechanism for the enrichment of aneuploidy of specific chromosomes (e.g., the high incidence (~50%) of trisomy of chromosome 8) observed in Ewing sarcoma cells.	('aneuploidy', 'Disease', 'MESH:D000782', (81, 91))	('trisomy of chromosome', 'Var', (152, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('Ewing sarcoma', 'Disease', (189, 202))	('aneuploidy', 'Disease', (81, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (189, 202))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (189, 202))
410326	33293370	Our results suggested that phosphorylation of Thr 79 of EWSR1/FLI1 promotes the induction of aneuploidy, and the daughter cells of cells expressing EWSR1/FLI1 or EWSR1/FLI1-T79D displayed a wide range of chromosome numbers (Fig.	('T79D', 'Var', (173, 177))	('promotes', 'PosReg', (67, 75))	('aneuploidy', 'Disease', (93, 103))	('chromosome numbers', 'CPA', (204, 222))	('phosphorylation', 'MPA', (27, 42))	('EWSR1/FLI1', 'Var', (148, 158))	('EWSR1/FLI1', 'Gene', (56, 66))	('T79D', 'SUBSTITUTION', 'None', (173, 177))	('aneuploidy', 'Disease', 'MESH:D000782', (93, 103))	('induction', 'MPA', (80, 89))	('Thr', 'Chemical', 'MESH:D013912', (46, 49))
410334	33293370	Utilizing the EWSR1/FLI1-T79A and EWSR1/FLI1-T79D mutant constructs as well as constructs involving EWSR1-T79A and EWSR1-T79D fused to other genes will enable us to understand the role of phosphorylation in various disease phenotypes.	('T79D', 'SUBSTITUTION', 'None', (121, 125))	('T79A', 'SUBSTITUTION', 'None', (106, 110))	('T79A', 'Var', (106, 110))	('T79D', 'Var', (45, 49))	('T79A', 'SUBSTITUTION', 'None', (25, 29))	('T79A', 'Var', (25, 29))	('T79D', 'Var', (121, 125))	('T79D', 'SUBSTITUTION', 'None', (45, 49))
410335	33293370	Because various types of sarcomas express fusion genes that have N terminus of EWSR1 including Thr 79, this study has the potential to reveal a universal mechanism for the pathogenesis underlying all EWSR1 fusion protein-expressing sarcomas.	('EWSR1', 'Gene', (79, 84))	('Thr', 'Chemical', 'MESH:D013912', (95, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('EWSR1', 'Gene', (200, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('N terminus', 'Var', (65, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))	('sarcomas', 'Disease', 'MESH:D012509', (232, 240))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (232, 240))	('sarcomas', 'Disease', (232, 240))
410337	33293370	EWSR1/FLI1-T79A:F (5'- CCCACTGGTTATACTGCTCCAACTGCCCCCC -3') EWSR1/FLI1-T79A:R (5'- GGGGGGCAGTTGGAGCAGTATAACCAGTGGG -3').	('T79A', 'Var', (11, 15))	('T79A', 'Var', (71, 75))	('T79A', 'SUBSTITUTION', 'None', (11, 15))	('T79A', 'SUBSTITUTION', 'None', (71, 75))
410338	33293370	hEWS/FLI1-T79D:F: 5'-CCCACTGGTTATACTgatCCAACTGCCCCC-3' hEWS/FLI1-T79D:R:5'-GGGGGCAGTTGGatcAGTATAACCAGTGGG-3' Human pSG5-2xFLAG-EWSR1/FLI1-T79A and pSG5-2xFLAG-EWSR1/FLI1-T79D was constructed from the plasmid pSG5-2xFLAG-EWSR1/FLI1 following the manufacturer's protocol (QuickChange II Site-Directed Mutagenesis Kit, #200524, Agilent Technologies), using the primers: MluI hEWS:F (5'-GATACGCGTATGGCTGCCACGGATTAC-3') NotI nostp hsEF:R (5'-CTGCGGCCGCGTAGTAGCTGCCTAAGTG-3') Then, the hEWSR1/FLI1, hEWSR1/FLI1-T79A, and hEWSR1/FLI1-T79D genes are amplified by PCR from pSG5-2xFLAG-EWSR1/FLI1, pSG5-2xFLAG-EWSR1/FLI1-T79A, and hEWSR1/FLI1-T79D respectively, using the following primers that contain a linker with MluI and NotI sites.	('hEWS', 'Gene', (372, 376))	('pSG5', 'Gene', '5673', (564, 568))	('hEWS', 'Gene', (55, 59))	('T79D', 'SUBSTITUTION', 'None', (170, 174))	('hEWSR1', 'Gene', '2130', (515, 521))	('pSG5', 'Gene', '5673', (588, 592))	('pSG5', 'Gene', '5673', (208, 212))	('T79D', 'SUBSTITUTION', 'None', (527, 531))	('T79A', 'SUBSTITUTION', 'None', (138, 142))	('T79A', 'Var', (138, 142))	('T79D', 'SUBSTITUTION', 'None', (65, 69))	('T79D', 'SUBSTITUTION', 'None', (10, 14))	('T79D', 'Var', (633, 637))	('hEWSR1', 'Gene', (480, 486))	('pSG5', 'Gene', (147, 151))	('hEWS', 'Gene', '2130', (55, 59))	('pSG5', 'Gene', (115, 119))	('hEWSR1', 'Gene', '2130', (480, 486))	('T79D', 'Var', (170, 174))	('hEWSR1', 'Gene', (493, 499))	('Human', 'Species', '9606', (109, 114))	('T79D', 'Var', (527, 531))	('pSG5', 'Gene', (564, 568))	('hEWS', 'Gene', '2130', (480, 484))	('pSG5', 'Gene', (588, 592))	('hEWSR1', 'Gene', (621, 627))	('T79D', 'Var', (65, 69))	('T79A', 'Var', (611, 615))	('T79D', 'Var', (10, 14))	('hEWS', 'Gene', (480, 484))	('hEWSR1', 'Gene', '2130', (493, 499))	('hEWS', 'Gene', '2130', (621, 625))	('T79A', 'SUBSTITUTION', 'None', (611, 615))	('hEWS', 'Gene', (621, 625))	('pSG5', 'Gene', (208, 212))	('hEWS', 'Gene', '2130', (372, 376))	('pSG5', 'Gene', '5673', (147, 151))	('hEWSR1', 'Gene', '2130', (621, 627))	('hEWS', 'Gene', '2130', (493, 497))	('pSG5', 'Gene', '5673', (115, 119))	('hEWS', 'Gene', (493, 497))	('T79D', 'SUBSTITUTION', 'None', (633, 637))	('T79A', 'SUBSTITUTION', 'None', (505, 509))	('T79A', 'Var', (505, 509))	('hEWS', 'Gene', '2130', (515, 519))	('hEWS', 'Gene', '2130', (0, 4))	('hEWSR1', 'Gene', (515, 521))	('hEWS', 'Gene', (515, 519))	('hEWS', 'Gene', (0, 4))
410340	33293370	Finally, the DNA transgenes of EWSR1/FLI1, EWSR1/FLI1-T79A, or EWSR1/FLI1-T79D and mCherry were ligated into the MluI and SalI sites of the newly modified pMK243 plasmid.	('T79A', 'Var', (54, 58))	('T79A', 'SUBSTITUTION', 'None', (54, 58))	('T79D', 'Var', (74, 78))	('T79D', 'SUBSTITUTION', 'None', (74, 78))
410341	33293370	The mutations were introduced in PAM sequences on the homology arms.	('mutations', 'Var', (4, 13))	('PAM', 'Gene', '5066', (33, 36))	('PAM', 'Gene', (33, 36))
410345	33293370	In addition, 24 clones were isolated from EWSR1/FLI1-T79D transfected cells, and six clones expressed the transgene.	('T79D', 'Var', (53, 57))	('expressed', 'Reg', (92, 101))	('T79D', 'SUBSTITUTION', 'None', (53, 57))
410347	33293370	The expression of EWSR1/FLI1, EWSR1/FLI1-T79A, and EWSR1/FLI1-T79D was induced in the DLD-1 cells by treatment with 1ug/ml Doxycycline (Dox) for 20 h. All cells used in this study were passaged less than 20 times.	('Dox', 'Chemical', 'MESH:D004318', (136, 139))	('T79D', 'SUBSTITUTION', 'None', (62, 66))	('T79A', 'Var', (41, 45))	('T79D', 'Var', (62, 66))	('T79A', 'SUBSTITUTION', 'None', (41, 45))	('Dox', 'Chemical', 'MESH:D004318', (123, 126))	('Doxycycline', 'Chemical', 'MESH:D004318', (123, 134))
410425	31915327	The dysregulation of fibulin-2 has been revealed as a potential therapeutic target in the development of cancer such as breast cancer, NPC, Kaposi's sarcoma, brain cancer, etc.	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('brain cancer', 'Disease', 'MESH:D001932', (158, 170))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('fibulin-2', 'Gene', '14115', (21, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('cancer', 'Disease', (127, 133))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (140, 156))	('C', 'Chemical', 'MESH:D002244', (137, 138))	('brain cancer', 'Disease', (158, 170))	('fibulin-2', 'Gene', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (164, 170))	("Kaposi's sarcoma", 'Disease', (140, 156))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (140, 156))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('NPC', 'Phenotype', 'HP:0100630', (135, 138))	('brain cancer', 'Phenotype', 'HP:0030692', (158, 170))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('NPC', 'Disease', (135, 138))
410430	31915327	revealed that the expression of fibulin-2 is overexpressed in lung adenocarcinoma cell lines, which was obtained from the co-expression of mutant K-ras and p53 mice (KP mice).	('K-ras', 'Gene', (146, 151))	('K-ras', 'Gene', '16653', (146, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('fibulin-2', 'Gene', '14115', (32, 41))	('overexpressed', 'PosReg', (45, 58))	('p53', 'Gene', (156, 159))	('fibulin-2', 'Gene', (32, 41))	('mutant', 'Var', (139, 145))	('mice', 'Species', '10090', (160, 164))	('mice', 'Species', '10090', (169, 173))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (62, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('p53', 'Gene', '22060', (156, 159))	('lung adenocarcinoma', 'Disease', (62, 81))
410431	31915327	Furthermore, they showed that the co-expression of mutant K-ras and p53 cells (KP cells) can express mucoprotein 4 (MUC4), in which it was noted that the nidogen-like domain of MUC4 binds to fibulin-2, and that this relationship would promote the breaching of BM integrity, contributing to the spreading of pancreatic cancer cells.	('fibulin-2', 'Gene', '14115', (191, 200))	('binds', 'Interaction', (182, 187))	('p53', 'Gene', '22060', (68, 71))	('contributing to', 'Reg', (274, 289))	('promote', 'PosReg', (235, 242))	('pancreatic cancer', 'Disease', 'MESH:D010190', (307, 324))	('breaching', 'CPA', (247, 256))	('spreading', 'CPA', (294, 303))	('mutant', 'Var', (51, 57))	('pancreatic cancer', 'Disease', (307, 324))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('fibulin-2', 'Gene', (191, 200))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (307, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('p53', 'Gene', (68, 71))	('K-ras', 'Gene', '16653', (58, 63))	('C', 'Chemical', 'MESH:D002244', (179, 180))	('K-ras', 'Gene', (58, 63))
410434	31915327	discovered that the deficiency of fibulin-2 resulted in the increase in lysyl oxidase-like 2 (Loxl2) expression and the reduction in lysyl oxidase-like 4 (Loxl4) expression by stably transfecting Fbln2 shRNA into 344SQ cells.	('lysyl oxidase-like 2', 'Gene', (72, 92))	('Fbln2', 'Var', (196, 201))	('fibulin-2', 'Gene', (34, 43))	('N', 'Chemical', 'MESH:D009584', (205, 206))	('deficiency', 'Var', (20, 30))	('lysyl oxidase-like 4', 'Gene', (133, 153))	('Loxl4', 'Gene', '67573', (155, 160))	('Loxl2', 'Gene', '94352', (94, 99))	('fibulin-2', 'Gene', '14115', (34, 43))	('lysyl oxidase-like 4', 'Gene', '67573', (133, 153))	('increase', 'PosReg', (60, 68))	('reduction', 'NegReg', (120, 129))	('expression', 'MPA', (162, 172))	('lysyl oxidase-like 2', 'Gene', '94352', (72, 92))	('Loxl2', 'Gene', (94, 99))	('expression', 'MPA', (101, 111))	('Loxl4', 'Gene', (155, 160))
410441	31915327	In an in vivo study, mice implanted with MiaPaCa-MUC4 PC cells that express MUC4 were detected to metastasize to the liver, while liver metastasis was not observed in the MiaPaCa-MUC4-NIDODelta group, which was expressed in MiaPaCa PC cells as lacking the endogenous MUC4 protein.	('N', 'Chemical', 'MESH:D009584', (184, 185))	('mice', 'Species', '10090', (21, 25))	('C', 'Chemical', 'MESH:D002244', (176, 177))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('C', 'Chemical', 'MESH:D002244', (269, 270))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('MiaPaCa', 'CellLine', 'CVCL:0428', (171, 178))	('C', 'Chemical', 'MESH:D002244', (229, 230))	('MiaPaCa', 'CellLine', 'CVCL:0428', (224, 231))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('MUC4', 'Var', (76, 80))	('MiaPaCa', 'CellLine', 'CVCL:0428', (41, 48))	('metastasize', 'CPA', (98, 109))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('MiaPaCa PC', 'CellLine', 'CVCL:0428', (224, 234))	('C', 'Chemical', 'MESH:D002244', (181, 182))	('MiaPaCa-MUC4 PC', 'CellLine', 'CVCL:0428', (41, 56))	('C', 'Chemical', 'MESH:D002244', (233, 234))
410448	31915327	revealed that the knockdown of fibulin-2 in immortalized/transformed keratinocyte cells reduced cell invasion.	('knockdown', 'Var', (18, 27))	('cell invasion', 'CPA', (96, 109))	('fibulin-2', 'Gene', '14115', (31, 40))	('reduced', 'NegReg', (88, 95))	('fibulin-2', 'Gene', (31, 40))
410482	31915327	The knockdown of VEGF and matrix metallopeptidase (MMP)-2 expression has been found to contribute to angiogenesis inhibition.	('matrix metallopeptidase (MMP)-2', 'Gene', '17390', (26, 57))	('VEGF', 'Gene', '22339', (17, 21))	('angiogenesis inhibition', 'CPA', (101, 124))	('VEGF', 'Gene', (17, 21))	('knockdown', 'Var', (4, 13))
410483	31915327	In Fbln2S transfectants, angiogenesis-related genes, and VEGF-165 and VEGF-189 are downregulated.	('VEGF', 'Gene', '22339', (57, 61))	('VEGF', 'Gene', (70, 74))	('Fbln2S', 'Gene', (3, 9))	('transfectants', 'Var', (10, 23))	('downregulated', 'NegReg', (83, 96))	('VEGF', 'Gene', (57, 61))	('VEGF', 'Gene', '22339', (70, 74))	('angiogenesis-related genes', 'Gene', (25, 51))
410486	31915327	Hence, these ensures that the decrease in MMP-2 and VEGF may provide an explanation to the function of Fbln2S in cancer progression.	('VEGF', 'Gene', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('MMP-2', 'Gene', (42, 47))	('decrease', 'NegReg', (30, 38))	('MMP-2', 'Gene', '17390', (42, 47))	('Fbln2S', 'Var', (103, 109))	('cancer', 'Disease', (113, 119))	('VEGF', 'Gene', '22339', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
410504	31915327	Unexpectedly, they found that the loss of fibulin-2 can improve the survival of mice after MI by attenuating ventricular dysfunction.	('ventricular dysfunction', 'Phenotype', 'HP:0005162', (109, 132))	('loss', 'Var', (34, 38))	('survival', 'CPA', (68, 76))	('attenuating', 'NegReg', (97, 108))	('ventricular dysfunction', 'Disease', 'MESH:D018754', (109, 132))	('MI', 'Phenotype', 'HP:0001658', (91, 93))	('fibulin-2', 'Gene', '14115', (42, 51))	('mice', 'Species', '10090', (80, 84))	('improve', 'PosReg', (56, 63))	('ventricular dysfunction', 'Disease', (109, 132))	('fibulin-2', 'Gene', (42, 51))
410514	31915327	Fibulin-2 is associated with arterial stiffness, and different levels of fibulin-2 and variations in the Fbln2 gene (rs3732666 and rs1061376) may account for the development of hypertension.	('fibulin-2', 'Gene', (73, 82))	('account', 'Reg', (146, 153))	('Fibulin-2', 'Gene', '14115', (0, 9))	('hypertension', 'Disease', (177, 189))	('rs3732666', 'Var', (117, 126))	('hypertension', 'Phenotype', 'HP:0000822', (177, 189))	('Fbln2', 'Gene', (105, 110))	('fibulin-2', 'Gene', '14115', (73, 82))	('rs3732666', 'Mutation', 'rs3732666', (117, 126))	('rs1061376', 'Mutation', 'rs1061376', (131, 140))	('arterial stiffness', 'MPA', (29, 47))	('hypertension', 'Disease', 'MESH:D006973', (177, 189))	('Fibulin-2', 'Gene', (0, 9))	('rs1061376', 'Var', (131, 140))
410627	31413752	The high expression of SR-B1 was significantly associated with age (p = 0.001) and sarcoma phenotypes (p = 0.000).	('SR-B1', 'Gene', (23, 28))	('sarcoma', 'Disease', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('high', 'Var', (4, 8))	('associated', 'Reg', (47, 57))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))
410678	24274261	In addition, molecular testing for BRAF exon 15, was negative for the V600E mutation.	('BRAF', 'Gene', (35, 39))	('BRAF', 'Gene', '673', (35, 39))	('V600E', 'Var', (70, 75))	('V600E', 'Mutation', 'rs113488022', (70, 75))
410679	24274261	Although the primary site could not be discerned with certainty, assuming that the leg mass is the primary tumor yielded a stage of T4bN3M1a.	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('T4bN3M1a', 'Var', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))
410688	24274261	Abnormal growth of melanocytes in MM is due to activation of the mitogen-activated protein kinase (MAPK) via various mechanisms such as N-RAS or BRAF mutations.	('BRAF', 'Gene', (145, 149))	('Abnormal growth of melanocytes', 'Phenotype', 'HP:0002861', (0, 30))	('activation', 'PosReg', (47, 57))	('N-RAS', 'Gene', (136, 141))	('Abnormal growth', 'Phenotype', 'HP:0001507', (0, 15))	('mutations', 'Var', (150, 159))	('N-RAS', 'Gene', '4893', (136, 141))	('BRAF', 'Gene', '673', (145, 149))
410695	24274261	Furthermore, recent biomarker research has shown that high MCM3 expression is a sign of poor prognosis that correlates with reduced RBM3 expression.	('MCM3', 'Gene', '4172', (59, 63))	('expression', 'MPA', (64, 74))	('expression', 'MPA', (137, 147))	('reduced', 'NegReg', (124, 131))	('high', 'Var', (54, 58))	('RBM3', 'Gene', '5935', (132, 136))	('RBM3', 'Gene', (132, 136))	('MCM3', 'Gene', (59, 63))
410704	24274261	The two are often difficult to differentiate because 70-90% of clear cell sarcomas express melanin due to fusion of the EWS and ATF1 genes from chromosomes 22q12 and 12q13 respectively.	('sarcomas', 'Disease', (74, 82))	('melanin', 'Chemical', 'MESH:D008543', (91, 98))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (63, 81))	('fusion', 'Var', (106, 112))	('melanin', 'Protein', (91, 98))	('ATF1', 'Gene', (128, 132))	('ATF1', 'Gene', '466', (128, 132))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('express', 'Reg', (83, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('EWS', 'Gene', '2130', (120, 123))	('EWS', 'Gene', (120, 123))	('clear cell sarcoma', 'Disease', (63, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
410707	24274261	Also, diagnosis of malignant melanoma can be made if a BRAF mutation is found.	('mutation', 'Var', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('malignant melanoma', 'Phenotype', 'HP:0002861', (19, 37))	('BRAF', 'Gene', '673', (55, 59))	('malignant melanoma', 'Disease', 'MESH:D008545', (19, 37))	('malignant melanoma', 'Disease', (19, 37))	('BRAF', 'Gene', (55, 59))
410708	24274261	This case was particularly difficult to diagnose due to the lack of V600E BRAF mutation and negative EWS rearrangement, either of which could have greatly clarified the diagnosis.	('V600E', 'Var', (68, 73))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('EWS', 'Gene', '2130', (101, 104))	('EWS', 'Gene', (101, 104))	('V600E', 'Mutation', 'rs113488022', (68, 73))
410766	21733164	FGF2 did not correlate with the clinical variables while low FGFR-1 expression correlated with small tumor size (low expression; < 50 mm 44%, 50-100 mm 34%, > 100 mm 22%, P = 0.005).	('< 50 mm', 'Var', (129, 136))	('small tumor', 'Disease', 'MESH:D058405', (95, 106))	('expression', 'MPA', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('low', 'NegReg', (57, 60))	('FGFR-1', 'Gene', (61, 67))	('small tumor', 'Disease', (95, 106))	('FGFR-1', 'Gene', '2260', (61, 67))	('clinical', 'Species', '191496', (32, 40))	('50-100 mm', 'Var', (142, 151))
410769	21733164	High expression of FGF 2 was significantly (P = 0.048) associated with a poor prognosis.	('associated', 'Reg', (55, 65))	('FGF 2', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('FGF 2', 'Gene', '2247', (19, 24))
410770	21733164	Russian nationality (P = 0.002), high malignancy grade (P = 0.015), metastasis at diagnosis (P < 0.001) and high FGF2 expression (P = 0.024, HR = 2.203, 95% CI 1.11-4.38) were significant independent negative indicators of DSS.	('FGF2', 'Gene', (113, 117))	('high malignancy', 'Disease', (33, 48))	('high malignancy', 'Disease', 'MESH:D009369', (33, 48))	('metastasis', 'CPA', (68, 78))	('high', 'Var', (108, 112))	('DSS', 'Gene', (223, 226))	('expression', 'MPA', (118, 128))	('DSS', 'Gene', '5376', (223, 226))
410772	21733164	In the multivariate analyses, high expression of FGF2 & PDGF-B was, when compared to low expression, a significant independent prognostic indicator of poor DSS (HR = 6.0, 95% CI = 1.966-18.132, P = 0.002).	('FGF2 &', 'Gene', (49, 55))	('DSS', 'Gene', (156, 159))	('DSS', 'Gene', '5376', (156, 159))	('high expression', 'Var', (30, 45))	('of poor', 'Disease', (148, 155))
410779	21733164	We found high FGF2 expression in tumor to be a significant independent negative prognostic marker in non-GIST STS patients with wide resection margins.	('expression', 'MPA', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('FGF2', 'Gene', (14, 18))	('non-GIST STS', 'Disease', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('negative', 'NegReg', (71, 79))	('tumor', 'Disease', (33, 38))	('patients', 'Species', '9606', (114, 122))	('high', 'Var', (9, 13))
410785	21733164	In our cohort, patients who expressed high intensity staining of PDGF-B and FGF2 had HR's of 3.9 or 2.2, respectively, in comparison to those expressing low intensity staining.	('FGF2', 'Gene', (76, 80))	('patients', 'Species', '9606', (15, 23))	('PDGF-B', 'Gene', (65, 71))	('high intensity staining', 'Var', (38, 61))
410787	21733164	Previously, we found non-GIST STS patients with wide resection margins expressing high intensity VEGFR-3 staining to have a HR of 2.0 compared to those with low intensity staining.	('high intensity', 'Var', (82, 96))	('patients', 'Species', '9606', (34, 42))	('VEGFR-3', 'Gene', (97, 104))
410844	30559557	A finding of intralesional fat significantly shortens the list of differential diagnoses, narrowing it down to only lesions with distinct biological behavior, such as liposarcoma, teratoma, and extramedullary hematopoiesis.	('hematopoiesis', 'Disease', (209, 222))	('liposarcoma', 'Disease', (167, 178))	('extramedullary hematopoiesis', 'Phenotype', 'HP:0001978', (194, 222))	('teratoma', 'Phenotype', 'HP:0009792', (180, 188))	('teratoma', 'Disease', 'MESH:D013724', (180, 188))	('fat', 'Gene', (27, 30))	('hematopoiesis', 'Disease', 'MESH:C536227', (209, 222))	('intralesional', 'Var', (13, 26))	('fat', 'Gene', '2195', (27, 30))	('liposarcoma', 'Disease', 'MESH:D008080', (167, 178))	('teratoma', 'Disease', (180, 188))	('liposarcoma', 'Phenotype', 'HP:0012034', (167, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))
410871	30559557	It is characterized by mutations in the c-kit gene, being histologically similar to a gastrointestinal stromal tumor.	('c-kit', 'Gene', '3815', (40, 45))	('gastrointestinal stromal tumor', 'Disease', (86, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (86, 116))	('mutations', 'Var', (23, 32))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (86, 116))	('c-kit', 'Gene', (40, 45))
410958	29531804	Until now most disease models using iPS cells have focused on diseases caused by mutations in a single gene, with early disease onset, and often with high penetrance, such as Fragile X syndrome and Familial dysautonomia, both monogenic Mendelian diseases, as well as chromosomal diseases such as Down's syndrome.	('Fragile X syndrome', 'Disease', (175, 193))	('Familial dysautonomia', 'Disease', (198, 219))	('Mendelian diseases', 'Disease', 'MESH:D030342', (236, 254))	('Mendelian diseases', 'Disease', (236, 254))	('caused by', 'Reg', (71, 80))	("'s syndrome", 'Disease', 'MESH:D010300', (300, 311))	('iPS', 'Chemical', '-', (36, 39))	('Fragile X syndrome', 'Disease', 'MESH:D005600', (175, 193))	('dysautonomia', 'Phenotype', 'HP:0012332', (207, 219))	('mutations', 'Var', (81, 90))	('Familial dysautonomia', 'Disease', 'MESH:D004402', (198, 219))	("'s syndrome", 'Disease', (300, 311))
410970	29531804	So far, two different ways for reprogramming somatic cells to pluripotency have been described, by somatic cell nuclear transfer ((SCNT) implantation of a somatic nucleus cell into a enucleated oocyte) or by using ectopic expression of TFs to produce iPS cells (Fig.	('TFs', 'Gene', (236, 239))	('ectopic expression', 'Var', (214, 232))	('iPS', 'Chemical', '-', (251, 254))
410987	29531804	Cancer is not solely driven by genetic defects, extensive research has identified epigenetic changes in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('epigenetic changes', 'Var', (82, 100))	('genetic defects', 'Disease', 'MESH:D030342', (31, 46))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic defects', 'Disease', (31, 46))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
411000	29531804	These findings suggest that epigenetic processes associated with iPS cell reprogramming may also drive cancer development and that this genetic transformation is reversible.	('epigenetic processes', 'Var', (28, 48))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('iPS', 'Chemical', '-', (65, 68))	('drive', 'PosReg', (97, 102))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
411005	29531804	Using this approach, iPS cells have been generated to model breast cancer (BRCA1 mutation) and Li Fraumeni syndrome (LFS; p53 mutation).	('breast cancer', 'Disease', (60, 73))	('BRCA1', 'Gene', (75, 80))	('iPS', 'Chemical', '-', (21, 24))	('p53', 'Gene', '7157', (122, 125))	('mutation', 'Var', (81, 89))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (95, 115))	('Li Fraumeni syndrome', 'Disease', (95, 115))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA1', 'Gene', '672', (75, 80))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('p53', 'Gene', (122, 125))
411006	29531804	The tumor suppressors BRCA1/2 play an important role in DNA repair, and mutations in BRCA1/2 are found in familial as well as sporadic breast cancers.	('tumor', 'Disease', (4, 9))	('found', 'Reg', (97, 102))	('mutations', 'Var', (72, 81))	('familial', 'Disease', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('BRCA1/2', 'Gene', (22, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('BRCA1/2', 'Gene', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('breast cancers', 'Disease', 'MESH:D001943', (135, 149))	('breast cancers', 'Disease', (135, 149))	('BRCA1/2', 'Gene', '672;675', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('BRCA1/2', 'Gene', '672;675', (85, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
411008	29531804	As an example, BRCA1 mutation in a single allele has been found to promote genomic instability in human cells but not in murine cells.	('mutation', 'Var', (21, 29))	('BRCA1', 'Gene', '672', (15, 20))	('genomic instability', 'CPA', (75, 94))	('murine', 'Species', '10090', (121, 127))	('BRCA1', 'Gene', (15, 20))	('human', 'Species', '9606', (98, 103))	('promote', 'PosReg', (67, 74))
411009	29531804	Therefore, iPS cell lines from a BRCA1-carrier with a 5382insC mutation, predicted to be high risk for breast and ovarian cancer, were successfully generated.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (103, 128))	('iPS', 'Chemical', '-', (11, 14))	('5382insC', 'Mutation', 'c.5382insC', (54, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('BRCA1', 'Gene', '672', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('5382insC', 'Var', (54, 62))	('BRCA1', 'Gene', (33, 38))
411011	29531804	LFS is an autosomal dominant syndrome caused by mutations in the p53 tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('p53', 'Gene', (65, 68))	('autosomal dominant syndrome', 'Disease', (10, 37))	('p53', 'Gene', '7157', (65, 68))	('LFS', 'Disease', (0, 3))	('tumor', 'Disease', (69, 74))	('caused by', 'Reg', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('mutations', 'Var', (48, 57))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (10, 37))
411013	29531804	Non-cancerous fibroblasts from LFS patients with a germline p53 mutation (G245D), also commonly found in sporadic tumors, were reprogrammed into iPS cells.	('G245D', 'Var', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('sporadic tumors', 'Disease', (105, 120))	('iPS', 'Chemical', '-', (145, 148))	('Non-cancerous', 'Disease', (0, 13))	('p53', 'Gene', (60, 63))	('Non-cancerous', 'Disease', 'MESH:D009369', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('patients', 'Species', '9606', (35, 43))	('sporadic tumors', 'Disease', 'MESH:D009369', (105, 120))	('p53', 'Gene', '7157', (60, 63))	('G245D', 'Mutation', 'rs121912656', (74, 79))
411016	29531804	Moreover, they found impaired expression of the imprinted H19 gene in LFS-derived OB and more interestingly, restoration of H19 expression improved OB differentiation.	('H19', 'Gene', (58, 61))	('expression', 'MPA', (30, 40))	('H19', 'Gene', '283120', (58, 61))	('H19', 'Gene', '283120', (124, 127))	('H19', 'Gene', (124, 127))	('OB', 'Disease', 'MESH:D009765', (148, 150))	('improved', 'PosReg', (139, 147))	('impaired', 'NegReg', (21, 29))	('expression', 'MPA', (128, 138))	('restoration', 'Var', (109, 120))	('OB', 'Disease', 'MESH:D009765', (82, 84))
411021	29531804	Importantly, the majority of these genes are also mutated in sporadic cancers; therefore, generating iPS cells from non-cancerous somatic cells carrying HNPCC-germline mutations would be the perfect alternative for studying not only colon cancer but also the contribution of these genes to other type of cancers.	('sporadic cancers', 'Disease', 'MESH:D009369', (61, 77))	('cancers', 'Phenotype', 'HP:0002664', (304, 311))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', (304, 310))	('cancers', 'Disease', (304, 311))	('colon cancer', 'Phenotype', 'HP:0003003', (233, 245))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('mutations', 'Var', (168, 177))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('sporadic cancers', 'Disease', (61, 77))	('HNPCC', 'Disease', 'None', (153, 158))	('HNPCC', 'Disease', (153, 158))	('cancer', 'Disease', (239, 245))	('iPS', 'Chemical', '-', (101, 104))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('colon cancer', 'Disease', 'MESH:D015179', (233, 245))	('cancers', 'Disease', (70, 77))	('cancer', 'Disease', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancers', 'Disease', 'MESH:D009369', (304, 311))	('colon cancer', 'Disease', (233, 245))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
411025	29531804	For these reasons, several strategies have been developed for increasing the cellular age of iPS cells, including adding chemical compounds that accelerate differentiation and maturation, transfections of genes that accelerate terminal differentiation, or promote overall aging by increasing genomic instability (progeria accelerated cellular aging in vitro).	('genes', 'Gene', (205, 210))	('transfections', 'Var', (188, 201))	('increasing', 'PosReg', (281, 291))	('promote', 'PosReg', (256, 263))	('accelerate', 'PosReg', (216, 226))	('iPS', 'Chemical', '-', (93, 96))	('genomic instability', 'MPA', (292, 311))	('increasing', 'PosReg', (62, 72))	('accelerate', 'PosReg', (145, 155))	('terminal differentiation', 'CPA', (227, 251))
411033	29531804	We suggest that reprogramming somatic non-cancerous cells from patients carrying cancer-predisposing germline mutations will generate new childhood cancer models and treatment options, and add valuable information of onset and development of childhood cancers.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('childhood cancers', 'Disease', 'MESH:C536928', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('patients', 'Species', '9606', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('childhood cancers', 'Disease', (242, 259))
411051	29531804	JMLL is initiated by deregulation of cytokine receptor signaling that causes enhanced myelopoiesis.	('deregulation', 'Var', (21, 33))	('enhanced', 'PosReg', (77, 85))	('cytokine receptor signaling', 'MPA', (37, 64))	('MLL', 'Gene', '4297', (1, 4))	('MLL', 'Gene', (1, 4))
411052	29531804	generated iPS cells from malignant cells from two JMLL patients with somatic heterozygous missense mutations in PTPN11, which encodes SHP-2, a non-receptor tyrosine phosphatase.	('PTPN11', 'Gene', (112, 118))	('iPS', 'Chemical', '-', (10, 13))	('MLL', 'Gene', '4297', (51, 54))	('SHP-2', 'Gene', '5781', (134, 139))	('MLL', 'Gene', (51, 54))	('missense mutations', 'Var', (90, 108))	('patients', 'Species', '9606', (55, 63))	('PTPN11', 'Gene', '5781', (112, 118))	('SHP-2', 'Gene', (134, 139))
411055	29531804	Translocations at chromosome 11q23 involving the MLL gene is a frequent event in pediatric ALL and AML, and have been associated with an intermediate to poor outcome.	('Translocations', 'Var', (0, 14))	('AML', 'Disease', 'MESH:D015470', (99, 102))	('MLL', 'Gene', '4297', (49, 52))	('MLL', 'Gene', (49, 52))	('AML', 'Disease', (99, 102))	('ALL', 'Disease', (91, 94))
411056	29531804	Recently it was reported that primary blasts from AML patients with MLL rearrangements could be reprogrammed into iPS cells.	('MLL', 'Gene', (68, 71))	('MLL', 'Gene', '4297', (68, 71))	('AML', 'Disease', 'MESH:D015470', (50, 53))	('patients', 'Species', '9606', (54, 62))	('rearrangements', 'Var', (72, 86))	('iPS', 'Chemical', '-', (114, 117))	('AML', 'Disease', (50, 53))
411060	29531804	were able to show similarities by mimicking hematopoiesis to myelodysplastic syndrome and AML by introducing or correcting mutations using CRISPR-Cas9.	('AML', 'Disease', (90, 93))	('hematopoiesis to myelodysplastic syndrome', 'Disease', 'MESH:D009190', (44, 85))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (61, 85))	('AML', 'Disease', 'MESH:D015470', (90, 93))	('correcting', 'Reg', (112, 122))	('hematopoiesis to myelodysplastic syndrome', 'Disease', (44, 85))	('mutations', 'Var', (123, 132))
411066	29531804	Germline mutations in SHH pathway components, PTCH1, SMO and SUFU predispose to different pathologies that include higher risk of MB.	('Germline mutations', 'Var', (0, 18))	('predispose', 'Reg', (66, 76))	('SHH', 'Gene', '6469', (22, 25))	('PTCH1', 'Gene', '5727', (46, 51))	('SUFU', 'Gene', '51684', (61, 65))	('SHH', 'Gene', (22, 25))	('PTCH1', 'Gene', (46, 51))	('SMO', 'Gene', (53, 56))	('SMO', 'Gene', '6608', (53, 56))	('SUFU', 'Gene', (61, 65))	('MB', 'Phenotype', 'HP:0002885', (130, 132))
411067	29531804	Gorlin syndrome or nevoid basal cell carcinoma (NBCCS) is a hereditary disease caused by mutations in the PTCH1 gene.	('Gorlin syndrome', 'Disease', 'MESH:D001478', (0, 15))	('nevoid basal cell carcinoma', 'Disease', (19, 46))	('BCC', 'Phenotype', 'HP:0002671', (49, 52))	('nevoid basal cell carcinoma', 'Disease', 'MESH:D001478', (19, 46))	('PTCH1', 'Gene', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('NB', 'Phenotype', 'HP:0003006', (48, 50))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (26, 46))	('mutations', 'Var', (89, 98))	('PTCH1', 'Gene', '5727', (106, 111))	('Gorlin syndrome', 'Disease', (0, 15))	('caused by', 'Reg', (79, 88))	('hereditary disease', 'Disease', 'MESH:D030342', (60, 78))	('hereditary disease', 'Disease', (60, 78))
411069	29531804	Germline SUFU mutations also lead to infant desmoplastic MB and children develop similar symptoms as Gorlin patients.	('lead to', 'Reg', (29, 36))	('SUFU', 'Gene', (9, 13))	('children', 'Species', '9606', (64, 72))	('desmoplastic MB', 'Disease', 'MESH:D018220', (44, 59))	('desmoplastic MB', 'Disease', (44, 59))	('patients', 'Species', '9606', (108, 116))	('infant', 'Species', '9606', (37, 43))	('mutations', 'Var', (14, 23))	('MB', 'Phenotype', 'HP:0002885', (57, 59))	('SUFU', 'Gene', '51684', (9, 13))
411070	29531804	Mutations in the APC gene are associated with familial adenomatous polyposis and Turcot syndrome.	('associated', 'Reg', (30, 40))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (55, 76))	('APC', 'Gene', (17, 20))	('APC', 'Gene', '324', (17, 20))	('Turcot syndrome', 'Disease', 'MESH:C536928', (81, 96))	('Mutations', 'Var', (0, 9))	('familial adenomatous polyposis', 'Disease', (46, 76))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (46, 76))	('Turcot syndrome', 'Disease', (81, 96))
411072	29531804	Modeling human MB using iPS cells from patients with MB-associated syndromes carrying any of these germline mutations could give new insights in how SHH and WNT signaling pathways contribute to MB and as well as initiation of other cancers with the same mutations.	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('WNT signaling pathways', 'Pathway', (157, 179))	('patients', 'Species', '9606', (39, 47))	('SHH', 'Gene', (149, 152))	('initiation of other cancers', 'Disease', (212, 239))	('mutations', 'Var', (108, 117))	('iPS', 'Chemical', '-', (24, 27))	('MB', 'Phenotype', 'HP:0002885', (15, 17))	('human', 'Species', '9606', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('initiation of other cancers', 'Disease', 'MESH:D009369', (212, 239))	('SHH', 'Gene', '6469', (149, 152))	('MB', 'Phenotype', 'HP:0002885', (53, 55))	('contribute', 'Reg', (180, 190))	('MB', 'Phenotype', 'HP:0002885', (194, 196))
411077	29531804	Most typical genetic aberrations found in sporadic NB are copy-number alterations; MYCN amplifications, gain of chromosomes 11q, and 17q, and loss of 1p36, as well as different point mutations.	('17q', 'CPA', (133, 136))	('loss', 'NegReg', (142, 146))	('gain', 'PosReg', (104, 108))	('copy-number alterations', 'Var', (58, 81))	('MYCN', 'Gene', (83, 87))	('MYCN', 'Gene', '4613', (83, 87))	('NB', 'Phenotype', 'HP:0003006', (51, 53))	('1p36', 'Protein', (150, 154))	('amplifications', 'Var', (88, 102))
411078	29531804	Although rare, germline mutations in anaplastic lymphoma kinase (ALK) and PHOX2B have been found in hereditary NB.	('PHOX2B', 'Gene', '8929', (74, 80))	('ALK', 'Gene', '238', (65, 68))	('anaplastic lymphoma kinase', 'Gene', (37, 63))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (37, 56))	('found', 'Reg', (91, 96))	('hereditary NB', 'Disease', (100, 113))	('ALK', 'Gene', (65, 68))	('hereditary NB', 'Disease', 'MESH:D009386', (100, 113))	('PHOX2B', 'Gene', (74, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (48, 56))	('anaplastic lymphoma kinase', 'Gene', '238', (37, 63))	('NB', 'Phenotype', 'HP:0003006', (111, 113))	('germline mutations', 'Var', (15, 33))
411081	29531804	ALK alterations have been described in multiple human cancers, most frequently translocations resulting in ALK fusion proteins in anaplastic large cell lymphoma, inflammatory myofibroblastic tumors and non-small cell lung cancers.	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (202, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('translocations', 'Var', (79, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (152, 160))	('cell lymphoma', 'Phenotype', 'HP:0012191', (147, 160))	('alterations', 'Var', (4, 15))	('ALK', 'Gene', '238', (107, 110))	('human', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancers', 'Phenotype', 'HP:0100526', (217, 229))	('non-small cell lung cancers', 'Disease', (202, 229))	('ALK', 'Gene', (107, 110))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (162, 197))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (175, 197))	('cancers', 'Disease', (54, 61))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (202, 228))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (202, 229))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('lymphoma', 'Disease', (152, 160))	('lymphoma', 'Disease', 'MESH:D008223', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (206, 228))	('ALK', 'Gene', '238', (0, 3))	('inflammatory myofibroblastic tumors', 'Disease', (162, 197))	('ALK', 'Gene', (0, 3))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (206, 229))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))
411082	29531804	Identification of activating ALK point mutation in familial and sporadic NB opened up new possibilities for using targeted therapy such as Tyrosine kinase inhibitors.	('ALK', 'Gene', (29, 32))	('activating', 'PosReg', (18, 28))	('point mutation', 'Var', (33, 47))	('ALK', 'Gene', '238', (29, 32))	('NB', 'Phenotype', 'HP:0003006', (73, 75))
411087	29531804	Several germline mutations have been shown to predispose to pediatric sarcoma development, including mutations in p53, PMS2, RET, RB1, and PALB2.	('PALB2', 'Gene', (139, 144))	('mutations', 'Var', (101, 110))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('RB1', 'Gene', '5925', (130, 133))	('PMS2', 'Gene', '5395', (119, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('predispose', 'Reg', (46, 56))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (60, 77))	('RET', 'Gene', (125, 128))	('RET', 'Gene', '5979', (125, 128))	('pediatric sarcoma', 'Disease', (60, 77))	('RB1', 'Gene', (130, 133))	('PMS2', 'Gene', (119, 123))	('PALB2', 'Gene', '79728', (139, 144))
411089	29531804	The majority of EWS tumors carry the t(11;22)(q24;q12) chromosomal translocation generating the EWS-FLI1 fusion protein, a promiscuous TF that activates pro-oncogenic programs.	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (37, 54))	('EWS', 'Gene', '2130', (96, 99))	('EWS', 'Gene', (96, 99))	('tumors', 'Disease', (20, 26))	('FLI1', 'Gene', '2313', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('FLI1', 'Gene', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('EWS', 'Phenotype', 'HP:0012254', (16, 19))	('EWS', 'Gene', '2130', (16, 19))	('EWS', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('EWS', 'Phenotype', 'HP:0012254', (96, 99))	('t(11;22)(q24;q12', 'Var', (37, 53))
411095	29531804	As proof of principle, with help of CRISPR/Cas9, mutations can be introduced or corrected and their effect on tumor development studied.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
411109	28881742	Together, these findings demonstrate that eribulin induces cell death via the intrinsic pathway of apoptosis in ES cells, both alone at cytotoxic concentrations and in combination with BI 6727 at subtoxic concentrations.	('BI 6727', 'Chemical', 'MESH:C541363', (185, 192))	('eribulin', 'Var', (42, 50))	('intrinsic pathway of apoptosis', 'Pathway', (78, 108))	('cell death', 'CPA', (59, 69))	('ES', 'Phenotype', 'HP:0012254', (112, 114))
411119	28881742	We recently reported that PLK1 inhibitors such as BI 6727 provide a new strategy to chemosensitize ES cells and demonstrated that BI 6727 synergizes with VCR to trigger apoptosis in ES cells.	('apoptosis', 'CPA', (169, 178))	('ES', 'Phenotype', 'HP:0012254', (99, 101))	('BI 6727', 'Var', (130, 137))	('ES', 'Phenotype', 'HP:0012254', (182, 184))	('PLK1', 'Gene', (26, 30))	('BI 6727', 'Chemical', 'MESH:C541363', (50, 57))	('PLK1', 'Gene', '5347', (26, 30))	('BI 6727', 'Chemical', 'MESH:C541363', (130, 137))
411124	28881742	Preclinical evaluation by the Pediatric Preclinical Testing Program (PPTP) has recently shown that eribulin exerts higher antineoplastic activity in ES xenografts than VCR, a classical microtubule-interfering drug that is part of first-line chemotherapy protocols for ES.	('eribulin', 'Var', (99, 107))	('ES', 'Phenotype', 'HP:0012254', (268, 270))	('ES', 'Phenotype', 'HP:0012254', (149, 151))	('antineoplastic activity', 'MPA', (122, 145))	('higher', 'PosReg', (115, 121))	('PPTP', 'Chemical', '-', (69, 73))
411142	28881742	Notably, eribulin alone at high doses as well as eribulin/BI 6727 co-treatment significantly increased caspase-3/7 activity in both tested ES cell lines compared to their untreated controls or the treatment with either agent alone (Supplementary Figure 1).	('BI 6727', 'Chemical', 'MESH:C541363', (58, 65))	('eribulin/BI', 'Var', (49, 60))	('increased', 'PosReg', (93, 102))	('ES', 'Phenotype', 'HP:0012254', (139, 141))	('activity', 'MPA', (115, 123))	('caspase-3/7', 'Enzyme', (103, 114))
411148	28881742	Also, eribulin and BI 6727 cooperated to cause histone H3 phosphorylation compared to treatment with either drug alone at 9 and 12 hours (Figure 3H).	('histone H3 phosphorylation', 'MPA', (47, 73))	('BI 6727', 'Var', (19, 26))	('BI 6727', 'Chemical', 'MESH:C541363', (19, 26))	('cause', 'Reg', (41, 46))
411162	28881742	It has been reported that inactivation of antiapoptotic BCL-2 family proteins shifts the balance towards apoptosis resulting in the activation of BAX or BAK, two proapoptotic proteins of the BCL-2 family.	('inactivation', 'Var', (26, 38))	('activation', 'PosReg', (132, 142))	('shifts', 'Reg', (78, 84))	('BAK', 'Gene', (153, 156))	('BCL-2', 'Gene', (56, 61))	('BAX', 'Gene', (146, 149))	('BAK', 'Gene', '578', (153, 156))
411176	28881742	Fourth, genetic evidence using BCL-2 overexpression emphasizes the importance of BCL-2 inactivation following mitotic arrest and the central role of the mitochondrial apoptosis pathway.	('mitotic arrest', 'Disease', (110, 124))	('BCL-2', 'Gene', (81, 86))	('mitotic arrest', 'Disease', 'MESH:D006323', (110, 124))	('inactivation', 'Var', (87, 99))
411177	28881742	Post-translational modifications of antiapoptotic BCL-2 family members during prolonged mitotic arrest either via phosphorylation (in case of BCL-2 and BCL-xL) or via phosphorylation, ubiquitination and subsequent proteasomal degradation (in case of MCL-1) have previously been reported to result in inhibition of their antiapoptotic function.	('mitotic arrest', 'Disease', 'MESH:D006323', (88, 102))	('BCL-2', 'Gene', (50, 55))	('antiapoptotic function', 'MPA', (320, 342))	('Post-translational modifications', 'Var', (0, 32))	('proteasomal degradation', 'MPA', (214, 237))	('phosphorylation', 'Var', (167, 182))	('ubiquitination', 'MPA', (184, 198))	('phosphorylation', 'MPA', (114, 129))	('mitotic arrest', 'Disease', (88, 102))	('inhibition', 'NegReg', (300, 310))
411178	28881742	Our findings showing that eribulin single as well as eribulin/BI 6727 co-treatment cause mitotic arrest prior to BCL-2 and BCL-xL phosphorylation, MCL-1 downregulation and the onset of apoptosis support the conclusion that these antiapoptotic BCL-2 family proteins become inactivated by phosphorylation during prolonged mitotic arrest.	('mitotic arrest', 'Disease', (89, 103))	('BI 6727', 'Chemical', 'MESH:C541363', (62, 69))	('co-treatment', 'Var', (70, 82))	('mitotic arrest', 'Disease', 'MESH:D006323', (89, 103))	('BCL-xL phosphorylation', 'MPA', (123, 145))	('mitotic arrest', 'Disease', (320, 334))	('eribulin/BI', 'Var', (53, 64))	('mitotic arrest', 'Disease', 'MESH:D006323', (320, 334))	('MCL-1', 'MPA', (147, 152))	('downregulation', 'NegReg', (153, 167))
411182	28881742	Caspase-8 has been reported to be epigenetically silenced in some ES cell lines.	('epigenetically silenced', 'Var', (34, 57))	('Caspase-8', 'Gene', '841', (0, 9))	('ES', 'Phenotype', 'HP:0012254', (66, 68))	('Caspase-8', 'Gene', (0, 9))
411188	28881742	In addition to in vitro studies, we demonstrated in in vivo models of RMS and NB that the PLK1 inhibitor BI 2536 cooperates with VCR or eribulin, respectively, to significantly suppress tumor growth compared to either drug alone.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('NB', 'Phenotype', 'HP:0003006', (78, 80))	('PLK1', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('BI', 'Chemical', 'MESH:D001729', (105, 107))	('BI 2536', 'Var', (105, 112))	('RMS', 'Disease', (70, 73))	('tumor', 'Disease', (186, 191))	('suppress', 'NegReg', (177, 185))	('PLK1', 'Gene', '5347', (90, 94))	('RMS', 'Phenotype', 'HP:0002859', (70, 73))
411189	28881742	Of note, we did not detect additive toxicity of BI 6727 and VCR in a human xenograft mouse model of RMS, pointing to some tumor selectivity.	('mouse', 'Species', '10090', (85, 90))	('RMS', 'Phenotype', 'HP:0002859', (100, 103))	('human', 'Species', '9606', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('BI 6727', 'Chemical', 'MESH:C541363', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('toxicity', 'Disease', 'MESH:D064420', (36, 44))	('toxicity', 'Disease', (36, 44))	('BI 6727', 'Var', (48, 55))	('tumor', 'Disease', (122, 127))
411192	28881742	Additionally, a recent phase III clinical trial showed that eribulin improves the overall survival of patients with advanced or metastatic soft-tissue sarcomas compared to dacarbazine treatment.	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (139, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcomas', 'Disease', (151, 159))	('patients', 'Species', '9606', (102, 110))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (139, 158))	('dacarbazine', 'Chemical', 'MESH:D003606', (172, 183))	('improves', 'PosReg', (69, 77))	('overall survival', 'MPA', (82, 98))	('eribulin', 'Var', (60, 68))
411197	28881742	In contrast, eribulin is associated with a comparatively low incidence of severe peripheral neuropathy, which has been linked to eribulin's different mode of microtubule binding and action as compared to other microtubule-targeting drugs.	('peripheral neuropathy', 'Disease', 'MESH:D010523', (81, 102))	('eribulin', 'Var', (13, 21))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (81, 102))	('peripheral neuropathy', 'Disease', (81, 102))
411339	24255838	One retrospective cohort study that included 97 patients in various stages of uterine sarcoma who received different treatment modalities, including surgery, chemotherapy and radiation therapy, indicated that patients with ER-positive uterine sarcoma have a median overall survival of 36 months, while ER negative demonstrated a median overall survival of 16 months (Ioffe et al.).	('sarcoma', 'Disease', (86, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (78, 93))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (235, 250))	('sarcoma', 'Disease', 'MESH:D012509', (243, 250))	('patients', 'Species', '9606', (209, 217))	('sarcoma', 'Disease', 'MESH:D012509', (86, 93))	('sarcoma', 'Disease', (243, 250))	('ER-positive', 'Var', (223, 234))	('patients', 'Species', '9606', (48, 56))	('men', 'Species', '9606', (122, 125))
411365	21681092	Although there was no significant difference between the groups in overall survival at 12 months, the overall response rate (complete and partial) at month 12 was significantly higher in the chemotherapy arm (66%) than in the HAART-only arm (39%), p=0.005, and time to response was 2.7 times faster in the chemotherapy arm.	('ART', 'Chemical', '-', (228, 231))	('higher', 'PosReg', (177, 183))	('response', 'MPA', (110, 118))	('chemotherapy', 'Var', (191, 203))
411426	21533183	Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas.	('Dmd', 'Gene', '13405', (57, 60))	('liposarcomas', 'Phenotype', 'HP:0012034', (213, 225))	('Capn3', 'Gene', (68, 73))	('mixed rhabdomyo-', 'Disease', (183, 199))	('mice', 'Species', '10090', (163, 167))	('Dysf', 'Gene', '26903', (62, 66))	('liposarcomas', 'Disease', (213, 225))	('fibro-', 'Disease', (201, 207))	('lead to', 'Reg', (82, 89))	('malignant tumors', 'Disease', 'MESH:D018198', (143, 159))	('muscular dystrophy', 'Disease', (31, 49))	('muscular dystrophy', 'Disease', 'MESH:D009136', (31, 49))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('Dysf', 'Gene', (62, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('sarcomas', 'Phenotype', 'HP:0100242', (217, 225))	('Capn3', 'Gene', '12335', (68, 73))	('malignant tumors', 'Disease', (143, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (31, 49))	('Dmd', 'Gene', (57, 60))	('liposarcomas', 'Disease', 'MESH:D008080', (213, 225))	('liposarcoma', 'Phenotype', 'HP:0012034', (213, 224))	('mutations', 'Var', (18, 27))
411429	21533183	Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage.	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Met', 'Gene', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('losses', 'NegReg', (114, 120))	('DNA damage', 'CPA', (254, 264))	('Nf1', 'Gene', (151, 154))	('tumor', 'Disease', (124, 129))	('amplification', 'Var', (157, 170))	('MD sarcomas', 'Disease', 'MESH:D012509', (46, 57))	('Cdkn2a', 'Gene', (143, 149))	('MD sarcomas', 'Disease', (46, 57))
411431	21533183	Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies.	('affected', 'Reg', (89, 97))	('human', 'Species', '9606', (52, 57))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (58, 76))	('aneusomies', 'Disease', (200, 210))	('patients', 'Species', '9606', (77, 85))	('muscular dystrophy', 'Disease', (58, 76))	('muscular dystrophy', 'Disease', 'MESH:D009136', (58, 76))	('DNA', 'Var', (143, 146))
411436	21533183	Collectively, these tumors are characterized by profound genomic instability such as DNA damage, recurring mutations in cancer genes, and aberrant chromosome copy numbers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('mutations', 'Var', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('DNA damage', 'Disease', (85, 95))	('aberrant', 'Var', (138, 146))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
411438	21533183	Moreover, we discovered corresponding genomic lesions also in skeletal muscles from human MD patients, as well as stem cells cultured thereof, and show that genomic instability precedes muscle degeneration in MDs.	('muscle degeneration', 'Disease', 'MESH:D009135', (186, 205))	('muscle degeneration', 'Disease', (186, 205))	('genomic instability', 'Var', (157, 176))	('MDs', 'Phenotype', 'HP:0003560', (209, 212))	('human', 'Species', '9606', (84, 89))	('muscle degeneration', 'Phenotype', 'HP:0003202', (186, 205))	('patients', 'Species', '9606', (93, 101))
411443	21533183	Most MDs are caused by gene mutations that lead to absence or dysfunction of structurally and/or functionally important molecules of the muscle fiber.	('absence or dysfunction', 'Disease', 'MESH:D004832', (51, 73))	('MDs', 'Disease', (5, 8))	('absence or dysfunction', 'Disease', (51, 73))	('MDs', 'Phenotype', 'HP:0003560', (5, 8))	('caused by', 'Reg', (13, 22))	('mutations', 'Var', (28, 37))
411446	21533183	Mutations in several glycosyltransferase-encoding genes, such as the fukutin related protein (FKRP) or LARGE lead to defective glycosylation of the alpha-subunit of DG.	('fukutin related protein', 'Gene', '243853', (69, 92))	('fukutin related protein', 'Gene', (69, 92))	('FKRP', 'Gene', (94, 98))	('DG', 'Gene', '13138', (165, 167))	('glycosylation', 'MPA', (127, 140))	('Mutations', 'Var', (0, 9))	('defective', 'NegReg', (117, 126))
411450	21533183	An inbred mutation in the murine dysferlin (Dysf) gene makes the SJL-mouse a naturally occurring animal model for the human dysferlinopathies.	('Dysf', 'Gene', '26903', (44, 48))	('murine', 'Species', '10090', (26, 32))	('mouse', 'Species', '10090', (69, 74))	('dysferlinopathies', 'Disease', (124, 141))	('dysferlinopathies', 'Disease', 'MESH:C537995', (124, 141))	('Dysf', 'Gene', (44, 48))	('mutation', 'Var', (10, 18))	('human', 'Species', '9606', (118, 123))
411451	21533183	Mutations of the CAPN3 gene encoding the muscle-specific calcium-activated neutral protease calpain-3, a proteolytic switch in muscle remodeling, cause LGMD2A, a MD with a wide clinical spectrum.	('CAPN3', 'Gene', (17, 22))	('LGMD', 'Disease', 'None', (152, 156))	('Mutations', 'Var', (0, 9))	('cause', 'Reg', (146, 151))	('LGMD', 'Disease', (152, 156))
411456	21533183	Therefore we extended our studies to other dystrophin mutations, mouse strains, and even to other MD-mouse models for the most frequent MDs in humans, like dysferlin, calpain-3 and Large, respectively.	('mouse', 'Species', '10090', (65, 70))	('mutations', 'Var', (54, 63))	('mouse', 'Species', '10090', (101, 106))	('humans', 'Species', '9606', (143, 149))	('MDs', 'Phenotype', 'HP:0003560', (136, 139))	('dystrophin', 'Gene', (43, 53))
411460	21533183	Collectively, these data strongly support an unprecedented general link between muscular dystrophy and cancer, driven by the accumulation of DNA damage, chromosome copy number aberrations, and finally the origin of cell clones harboring cancer-like mutations in dystrophic muscle tissue.	('DNA damage', 'MPA', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('mutations', 'Var', (249, 258))	('dystrophic muscle', 'Disease', (262, 279))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('accumulation', 'PosReg', (125, 137))	('dystrophic muscle', 'Disease', 'MESH:D009136', (262, 279))	('muscular dystrophy', 'Disease', (80, 98))	('cancer', 'Disease', (237, 243))	('muscular dystrophy', 'Disease', 'MESH:D009136', (80, 98))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (80, 98))	('cancer', 'Disease', (103, 109))	('chromosome copy number aberrations', 'Var', (153, 187))
411464	21533183	In our colony of another dystrophin-deficient mouse line, mdx-3Cv, which lacks both the muscle 427 kDa and non-muscle 71 kDa dystrophin isoforms due to a mutation at the intron-exon 66 junction, we observed the spontaneous occurrence of skeletal muscle-derived tumors indistinguishable from those observed in C57BL/10-mdx mice.	('mdx', 'Gene', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('mutation', 'Var', (154, 162))	('tumors', 'Disease', (261, 267))	('mouse', 'Species', '10090', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('mdx', 'Gene', '13405', (318, 321))	('mdx', 'Gene', (318, 321))	('mdx', 'Gene', '13405', (58, 61))	('mice', 'Species', '10090', (322, 326))
411471	21533183	In order to learn whether other MD-genes, which are not directly related to dystrophin, might also suppress tumor formation, we studied mice lacking dysferlin (DysfSJL mutation; Dysf -/-), calpain-3 (Capn3 -/-; knockout), or Large (Largemyd mutation; Large -/-).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('mice', 'Species', '10090', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Dysf', 'Gene', (160, 164))	('Capn3', 'Gene', (200, 205))	('tumor', 'Disease', (108, 113))	('lacking', 'NegReg', (141, 148))	('Dysf', 'Gene', '26903', (178, 182))	('mutation', 'Var', (168, 176))	('Capn3', 'Gene', '12335', (200, 205))	('calpain-3', 'Protein', (189, 198))	('Dysf', 'Gene', (178, 182))	('Dysf', 'Gene', '26903', (160, 164))
411473	21533183	Also for Dysf -/- mice a strain-dependent effect with respect to mean age of sarcoma-onset was detected, which was more than 100 days later (~755 d) when the mutation was bred on a mixed C57BL/10 x B6C3Fe background, whereas the sarcoma incidence remained unchanged (22%).	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('Dysf', 'Gene', (9, 13))	('sarcoma-onset', 'Disease', (77, 90))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('mice', 'Species', '10090', (18, 22))	('mutation', 'Var', (158, 166))	('sarcoma', 'Disease', (229, 236))	('sarcoma', 'Disease', (77, 84))	('sarcoma-onset', 'Disease', 'MESH:D012509', (77, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('Dysf', 'Gene', '26903', (9, 13))
411492	21533183	The unifying characteristics of all LS-cells were positivity for lipid staining by Sudan Black (Figure 1H) and, moreover, immunoreactivity for Cdk4 (a human LS biomarker) (Figure 1K).	('lipid staining', 'MPA', (65, 79))	('Cdk4', 'Protein', (143, 147))	('lipid', 'Chemical', 'MESH:D008055', (65, 70))	('human', 'Species', '9606', (151, 156))	('LS', 'Phenotype', 'HP:0012034', (36, 38))	('positivity', 'Var', (50, 60))	('LS', 'Phenotype', 'HP:0012034', (157, 159))
411497	21533183	DNA extracted from solid tumors from Dmd -/- or Dysf -/- mice was subjected to an arrayCGH-based screen (n = 8), which revealed that the majority of Dmd -/- tumors were characterized by multiple segmental chromosomal changes, chromosome number aberrations, and amplification of loci harboring the Met (encoding the Met proto oncogene hepatocyte growth factor receptor) or Jun oncogene, while tumors from Dysf -/- mice typically displayed less genomic instability (Figure 2A).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('Dysf', 'Gene', '26903', (48, 52))	('Dmd', 'Gene', '13405', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (392, 398))	('Dysf', 'Gene', '26903', (404, 408))	('multiple segmental chromosomal changes', 'Phenotype', 'HP:0040012', (186, 224))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('Dmd', 'Gene', (37, 40))	('solid tumors', 'Disease', (19, 31))	('Dmd', 'Gene', '13405', (37, 40))	('Dysf', 'Gene', (48, 52))	('Met', 'Var', (297, 300))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('Dysf', 'Gene', (404, 408))	('tumors', 'Disease', (157, 163))	('mice', 'Species', '10090', (413, 417))	('tumors', 'Phenotype', 'HP:0002664', (392, 398))	('men', 'Species', '9606', (198, 201))	('mice', 'Species', '10090', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('solid tumors', 'Disease', 'MESH:D009369', (19, 31))	('tumors', 'Disease', (392, 398))	('amplification', 'Var', (261, 274))	('Dmd', 'Gene', (149, 152))
411498	21533183	Frequent disruption of the tumor suppressor loci Cdkn2a, encoding p16INK4a and p19ARF, Nf1, encoding neurofibromin 1, and Trp53, together with whole chromosome 8 and/or 15 gains represented key non-random alterations of sarcomas in both MD models.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('tumor', 'Disease', (27, 32))	('sarcomas', 'Disease', (220, 228))	('p19ARF', 'Var', (79, 85))	('Nf1', 'Gene', (87, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (220, 228))	('sarcomas', 'Disease', 'MESH:D012509', (220, 228))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('disruption', 'Var', (9, 19))	('Trp53', 'Gene', (122, 127))	('Cdkn2a', 'Gene', (49, 55))
411509	21533183	More than 50% of the measured chromosome 8/15 ratios were consistent with gains throughout the tumor, implying the presence of trisomies in more than 90% of tumor cells.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('chromosome', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (95, 100))
411510	21533183	This suggested that together with losses at Cdkn2a and Nf1 loci the recurrent duplications of these chromosomes belong to early events in sarcoma development.	('sarcoma', 'Disease', (138, 145))	('duplications', 'Var', (78, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('men', 'Species', '9606', (153, 156))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))
411513	21533183	We found elevated levels of chromosome 8 and/or 15 in ~30% of muscles from MD-mice but never in wild-type mice (Figure 3B).	('elevated', 'PosReg', (9, 17))	('MD-mice', 'Var', (75, 82))	('mice', 'Species', '10090', (106, 110))	('levels', 'MPA', (18, 24))	('mice', 'Species', '10090', (78, 82))
411514	21533183	Also occasional copy number aberrations of the Cdkn2a, Nf1, Met and Jun genes were detected in dystrophic muscles (~12%).	('dystrophic muscles', 'Disease', (95, 113))	('detected', 'Reg', (83, 91))	('Nf1', 'Gene', (55, 58))	('Cdkn2a', 'Gene', (47, 53))	('copy number aberrations', 'Var', (16, 39))	('Met', 'Gene', (60, 63))	('dystrophic muscles', 'Disease', 'MESH:D009136', (95, 113))	('Jun', 'Gene', (68, 71))
411522	21533183	In contrast to normal cells, myoblasts from DMD and LGMD2B patients frequently harbored tetrasomies of chromosome 19 (13-27%; Figure 4B).	('DMD', 'Disease', (44, 47))	('myoblasts', 'CPA', (29, 38))	('LGMD2B', 'Gene', '8291', (52, 58))	('harbored', 'Reg', (79, 87))	('tetrasomies', 'Var', (88, 99))	('patients', 'Species', '9606', (59, 67))	('LGMD2B', 'Gene', (52, 58))	('DMD', 'Disease', 'MESH:D020388', (44, 47))
411524	21533183	DNA content analyses by FACS profiling of propidium iodide-stained cells revealed that myoblasts from DMD and LGMD2B patients contained abnormally high proportions of nuclei with aberrant DNA-content, indicated by prominent G0+ peaks (Figure 4E).	('propidium iodide', 'Chemical', 'MESH:D011419', (42, 58))	('DMD', 'Disease', 'MESH:D020388', (102, 105))	('LGMD2B', 'Gene', (110, 116))	('DMD', 'Disease', (102, 105))	('aberrant', 'Var', (179, 187))	('G0+ peaks', 'MPA', (224, 233))	('LGMD2B', 'Gene', '8291', (110, 116))	('myoblasts', 'CPA', (87, 96))	('patients', 'Species', '9606', (117, 125))	('DNA-content', 'MPA', (188, 199))
411527	21533183	We detected tri- and/or tetrasomies of chromosomes 2 and/or 19 in ~5-12% of the nuclei isolated from DMD muscle (n = 4) (Figure 4F).	('tetrasomies', 'Var', (24, 35))	('tri-', 'Var', (12, 16))	('DMD', 'Disease', 'MESH:D020388', (101, 104))	('DMD', 'Disease', (101, 104))	('detected', 'Reg', (3, 11))
411528	21533183	Similarly, aberrant chromosome 2 and 19 counts were detectable in muscle biopsies from patients with LGMD2A (n = 3, CAPN3 mutations), LGMD2I (n = 3, FKRP mutations), as well as LGMD2B (n = 1, DYSF mutations) (Figure 4G).	('detectable', 'Reg', (52, 62))	('LGMD2B', 'Gene', (177, 183))	('CAPN3', 'Gene', (116, 121))	('LGMD', 'Disease', (134, 138))	('LGMD', 'Disease', 'None', (101, 105))	('aberrant', 'Var', (11, 19))	('mutations', 'Var', (122, 131))	('LGMD', 'Disease', (101, 105))	('LGMD2B', 'Gene', '8291', (177, 183))	('LGMD', 'Disease', 'None', (177, 181))	('patients', 'Species', '9606', (87, 95))	('LGMD', 'Disease', (177, 181))	('LGMD', 'Disease', 'None', (134, 138))
411530	21533183	Generally, poly-/aneusomic nuclei further displayed features like enlargement, more irregular shape, and micronucleus formation, when compared to disomic nuclei.	('enlargement', 'Disease', (66, 77))	('micronucleus formation', 'CPA', (105, 127))	('poly-/aneusomic', 'Var', (11, 26))	('enlargement', 'Disease', 'MESH:D006529', (66, 77))
411532	21533183	In order to learn if the degree of aneusomies correlates with the disease progression of muscular dystrophies, we also studied fetal muscle obtained during autopsy of aborted fetuses with prenatal diagnosis of DMD or MDC1C.	('MDC1C', 'Var', (217, 222))	('DMD', 'Disease', 'MESH:D020388', (210, 213))	('DMD', 'Disease', (210, 213))	('muscular dystrophies', 'Phenotype', 'HP:0003560', (89, 109))	('muscular dystrophies', 'Disease', 'MESH:D009136', (89, 109))	('muscular dystrophies', 'Disease', (89, 109))
411537	21533183	When analyzing muscle tissue from Dmd -/- mice, pronounced activation of the two major DNA damage response pathways was observed, characterized by high expression of Ser1981-posphorylated ATM (p-ATM, ataxia-telangiectasia mutated kinase) and Ser428-posphorylated ATR (p-ATR, ATM and Rad3-related), and of their downstream signaling targets Chk1 and Chk2 (not shown).	('ATM', 'Gene', '11920', (195, 198))	('Chk1', 'Gene', (340, 344))	('Ser428-posphorylated', 'Var', (242, 262))	('activation', 'PosReg', (59, 69))	('AT', 'Disease', 'None', (263, 265))	('Chk2', 'Gene', '50883', (349, 353))	('Chk1', 'Gene', '12649', (340, 344))	('telangiectasia', 'Phenotype', 'HP:0001009', (207, 221))	('ataxia', 'Phenotype', 'HP:0001251', (200, 206))	('ataxia-telangiectasia', 'Disease', (200, 221))	('AT', 'Disease', 'None', (270, 272))	('Ser1981-posphorylated', 'Var', (166, 187))	('mice', 'Species', '10090', (42, 46))	('ATM', 'Gene', (188, 191))	('Chk2', 'Gene', (349, 353))	('ATM', 'Gene', (275, 278))	('Dmd', 'Gene', (34, 37))	('Ser428', 'Chemical', '-', (242, 248))	('ATM', 'Gene', '11920', (188, 191))	('AT', 'Disease', 'None', (188, 190))	('Dmd', 'Gene', '13405', (34, 37))	('Ser1981', 'Chemical', '-', (166, 173))	('ATM', 'Gene', '11920', (275, 278))	('AT', 'Disease', 'None', (195, 197))	('ATM', 'Gene', (195, 198))	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (200, 221))	('AT', 'Disease', 'None', (275, 277))	('DNA damage response pathways', 'Pathway', (87, 115))
411550	21533183	Our work further shows for the first time that also mice lacking dystrophin due to other mutations than mdx and on different genetic backgrounds are prone to develop age-related STS.	('lacking', 'NegReg', (57, 64))	('dystrophin', 'Protein', (65, 75))	('mdx', 'Gene', '13405', (104, 107))	('mdx', 'Gene', (104, 107))	('mice', 'Species', '10090', (52, 56))	('STS', 'Phenotype', 'HP:0030448', (178, 181))	('mutations', 'Var', (89, 98))	('develop', 'PosReg', (158, 165))
411560	21533183	We found that strain backgrounds with C57BL/6 proportions obviously exerted protective effects with regard to tumor latency and that tumor penetrance was lower in Dmd -/- mice on C3H or BALB/c backgrounds compared to C57BL/10.	('lower', 'NegReg', (154, 159))	('Dmd', 'Gene', (163, 166))	('mice', 'Species', '10090', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('Dmd', 'Gene', '13405', (163, 166))	('C57BL/6 proportions', 'Var', (38, 57))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
411561	21533183	In line with our observation, C57BL/6 is known for its resistance to Ptch1+/--induced rhabdomyosarcomas.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (86, 102))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (86, 103))	('rhabdomyosarcomas', 'Disease', (86, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('Ptch1', 'Gene', '19206', (69, 74))	('C57BL/6', 'Var', (30, 37))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (86, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('Ptch1', 'Gene', (69, 74))
411562	21533183	Genetic background also clearly influenced tumor gender specificity in Dmd  - mice (male preference in BALB/c, female in C3H) and tumor site predilection in Dysf -/- mice (~60% abdominal wall tumors in C57BL/10 x B6C3Fe compared to ~20% in C57BL/10).	('tumors', 'Disease', (192, 198))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (130, 135))	('influenced', 'Reg', (32, 42))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('Dysf', 'Gene', '26903', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', (192, 197))	('C57BL/10 x B6C3Fe', 'Var', (202, 219))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('Dysf', 'Gene', (157, 161))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('Dmd', 'Gene', (71, 74))	('mice', 'Species', '10090', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('Dmd', 'Gene', '13405', (71, 74))	('mice', 'Species', '10090', (78, 82))
411567	21533183	Notably, in melanoma cell lines dystrophin knock-down enhanced migration and invasion, whereas re-expression attenuated migration and induced a senescent phenotype, fully in line with a tumor suppressor role of dystrophin.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('dystrophin', 'Gene', (32, 42))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('senescent', 'MPA', (144, 153))	('induced', 'Reg', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('invasion', 'CPA', (77, 85))	('tumor', 'Disease', (186, 191))	('migration', 'CPA', (120, 129))	('migration', 'CPA', (63, 72))	('enhanced', 'PosReg', (54, 62))	('knock-down', 'Var', (43, 53))	('attenuated', 'NegReg', (109, 119))
411569	21533183	Notably, aberrations of the DG have been associated with several types of human cancer, suggesting a potential role also in tumorigenesis.	('human', 'Species', '9606', (74, 79))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('DG', 'Gene', '13138', (28, 30))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (124, 129))	('aberrations', 'Var', (9, 20))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
411570	21533183	In particular, a tumor suppressor function has been suggested for laminin-binding glycans on alpha-dystroglycan, whose loss can be caused by silencing of the LARGE gene in several metastatic epithelial cell lines.	('silencing', 'Var', (141, 150))	('tumor', 'Disease', (17, 22))	('laminin-binding glycans', 'Protein', (66, 89))	('dystroglycan', 'Gene', '13138', (99, 111))	('dystroglycan', 'Gene', (99, 111))	('glycans', 'Chemical', 'MESH:D011134', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
411574	21533183	The pivotal p53 and retinoblastoma (RB) cell cycle control pathways were frequently incapacitated by the disruption of the Cdkn2a locus, which encodes two different tumor suppressors, the Cdk4 kinase inhibitor p16INK4a and the Mdm2-p53 regulator p19ARF, both of which play an important role in the development and progression of many human cancer types.	('incapacitated', 'NegReg', (84, 97))	('retinoblastoma', 'Gene', '5925', (20, 34))	('disruption', 'Var', (105, 115))	('RB', 'Phenotype', 'HP:0009919', (36, 38))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('retinoblastoma', 'Gene', (20, 34))	('retinoblastoma', 'Phenotype', 'HP:0009919', (20, 34))	('human', 'Species', '9606', (334, 339))	('men', 'Species', '9606', (305, 308))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('p53', 'Pathway', (12, 15))	('cancer', 'Disease', 'MESH:D009369', (340, 346))	('Cdkn2a', 'Gene', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', (340, 346))	('tumor', 'Disease', (165, 170))
411575	21533183	Deletions at Trp53 and Nf1 loci established a genetic link to human soft-tissue sarcomas, which are characterized by frequent p53 mutations, as well as to syndromes associated with increased RMS incidence due to germ-line disruption of these tumor suppressor genes (Li-Fraumeni, TP53; Neurofibromatosis type I, NF1).	('TP53', 'Gene', '7157', (279, 283))	('disruption', 'Var', (222, 232))	('soft-tissue sarcomas', 'Disease', (68, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('RMS', 'Disease', (191, 194))	('tumor', 'Disease', (242, 247))	('Nf1', 'Gene', (23, 26))	('Neurofibromatosis type I', 'Disease', 'MESH:C537392', (285, 309))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (68, 87))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('Li-Fraumeni', 'Disease', (266, 277))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (68, 88))	('Trp53', 'Gene', (13, 18))	('human', 'Species', '9606', (62, 67))	('Neurofibromatosis type I', 'Disease', (285, 309))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (68, 88))	('TP53', 'Gene', (279, 283))	('NF1', 'Gene', '4763', (311, 314))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (266, 277))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (285, 302))	('RMS', 'Phenotype', 'HP:0002859', (191, 194))	('p53', 'Gene', (126, 129))	('NF1', 'Gene', (311, 314))	('mutations', 'Var', (130, 139))	('Deletions', 'Var', (0, 9))
411576	21533183	More recently, human myxofibrosarcoma and pleomorphic liposarcomas were shown to frequently harbor NF1 mutations.	('mutations', 'Var', (103, 112))	('myxofibrosarcoma and pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (21, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('liposarcomas', 'Phenotype', 'HP:0012034', (54, 66))	('NF1', 'Gene', (99, 102))	('liposarcoma', 'Phenotype', 'HP:0012034', (54, 65))	('NF1', 'Gene', '4763', (99, 102))	('human', 'Species', '9606', (15, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (25, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
411577	21533183	Thus, the disruption of Nf1 in sarcomas from MD-mice parallels specific - non myogenic - subtypes of human soft-tissue sarcomas and suggests a more general role for Nf1-lesions in the genesis of mesenchymal cancers.	('sarcomas', 'Disease', (119, 127))	('Nf1', 'Gene', (24, 27))	('sarcomas', 'Disease', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('soft-tissue sarcomas', 'Disease', (107, 127))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (107, 126))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (107, 127))	('mesenchymal cancers', 'Disease', (195, 214))	('human', 'Species', '9606', (101, 106))	('mesenchymal cancers', 'Disease', 'MESH:C535700', (195, 214))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (107, 127))	('mice', 'Species', '10090', (48, 52))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('disruption', 'Var', (10, 20))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
411578	21533183	A high fraction of sarcomas from MD-mice harbored amplifications of the Met or Jun oncogenes.	('Jun oncogenes', 'Gene', (79, 92))	('Met', 'Gene', (72, 75))	('sarcomas', 'Disease', 'MESH:D012509', (19, 27))	('mice', 'Species', '10090', (36, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('sarcomas', 'Disease', (19, 27))	('amplifications', 'Var', (50, 64))
411579	21533183	The Met oncogene amplification constitutes a critical path to aberrant activation of the Hgf/c-Met axis, which is known to promote tumorigenesis and to be involved in the progression and spread of multiple human cancers.	('Met oncogene', 'Gene', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('c-Met', 'Gene', (93, 98))	('human', 'Species', '9606', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('activation', 'PosReg', (71, 81))	('c-Met', 'Gene', '4233', (93, 98))	('promote', 'PosReg', (123, 130))	('Hgf', 'Gene', '3082', (89, 92))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('tumor', 'Disease', (131, 136))	('involved', 'Reg', (155, 163))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('amplification', 'Var', (17, 30))	('cancers', 'Disease', (212, 219))	('Hgf', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
411580	21533183	Amplification of the JUN oncogene has been reported in human liposarcomas, in sound accordance with herein discovered frequent Jun amplification in MD mixed sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('Amplification', 'Var', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('sarcomas', 'Disease', (157, 165))	('JUN oncogene', 'Gene', '3725', (21, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('sarcomas', 'Disease', (65, 73))	('human', 'Species', '9606', (55, 60))	('liposarcomas', 'Disease', 'MESH:D008080', (61, 73))	('liposarcomas', 'Phenotype', 'HP:0012034', (61, 73))	('JUN oncogene', 'Gene', (21, 33))	('liposarcoma', 'Phenotype', 'HP:0012034', (61, 72))	('sarcomas', 'Disease', 'MESH:D012509', (157, 165))	('liposarcomas', 'Disease', (61, 73))
411592	21533183	We focused on DMD and LGMDs caused by DYSF, CAPN3, or FKRP mutations, representing the most frequent MDs, and found that all of them are associated with somatic aneuploidy and widespread DNA damage in skeletal muscle tissue in vivo.	('LGMD', 'Disease', (22, 26))	('MDs', 'Phenotype', 'HP:0003560', (101, 104))	('associated with', 'Reg', (137, 152))	('DMD', 'Disease', 'MESH:D020388', (14, 17))	('somatic aneuploidy', 'Disease', 'MESH:D000782', (153, 171))	('somatic aneuploidy', 'Disease', (153, 171))	('DMD', 'Disease', (14, 17))	('mutations', 'Var', (59, 68))	('DYSF', 'Gene', (38, 42))	('FKRP', 'Gene', (54, 58))	('MDs', 'Phenotype', 'HP:0003560', (24, 27))	('LGMD', 'Disease', 'None', (22, 26))	('CAPN3', 'Gene', (44, 49))
411595	21533183	In contrast, high levels of DSBs were already evident in fetal muscle from DMD and MDC1C individuals and in muscle biopsies from DMD infants (<1 year), which suggested that DNA damage precedes the clinical manifestation and therefore cannot be solely related to replication stress.	('DMD', 'Disease', (75, 78))	('DMD', 'Disease', 'MESH:D020388', (129, 132))	('DMD', 'Disease', (129, 132))	('infants', 'Species', '9606', (133, 140))	('MDC1C', 'Var', (83, 88))	('DSBs', 'Chemical', 'MESH:C007563', (28, 32))	('DMD', 'Disease', 'MESH:D020388', (75, 78))
411597	21533183	Genomic instability has been reported in laminopathy-based premature ageing, a condition caused by mutations in lamin A/C, notably another MD-related molecule.	('laminopathy-based premature ageing', 'Disease', (41, 75))	('lamin A/C', 'Gene', '16905', (112, 121))	('premature ageing', 'Phenotype', 'HP:0007495', (59, 75))	('lamin A/C', 'Gene', (112, 121))	('caused by', 'Reg', (89, 98))	('mutations', 'Var', (99, 108))	('reported', 'Reg', (29, 37))
411601	21533183	Unrepaired DNA damage activates cellular senescence and could therefore be also associated with the known generalized diminished replicative capacity of DMD myoblasts, contributing to the progressive exhaustion of the muscle's regenerative potential.	('DMD', 'Disease', (153, 156))	('regenerative potential', 'CPA', (227, 249))	('replicative', 'MPA', (129, 140))	('exhaustion', 'PosReg', (200, 210))	('progressive exhaustion', 'Phenotype', 'HP:0012432', (188, 210))	('activates', 'PosReg', (22, 31))	('DMD', 'Disease', 'MESH:D020388', (153, 156))	('damage', 'Var', (15, 21))	('diminished', 'NegReg', (118, 128))	('cellular senescence', 'CPA', (32, 51))
411605	21533183	But it is interesting to note that it is also not fully understood why loss of dystrophin causes a fatal MD in humans while only a mild myopathy in mice.	('myopathy', 'Phenotype', 'HP:0003198', (136, 144))	('myopathy', 'Disease', (136, 144))	('mice', 'Species', '10090', (148, 152))	('dystrophin', 'Gene', (79, 89))	('loss', 'Var', (71, 75))	('myopathy', 'Disease', 'MESH:D009135', (136, 144))	('fatal MD', 'Disease', (99, 107))	('humans', 'Species', '9606', (111, 117))
411606	21533183	Also, Dysf -/- and Capn3 -/- deficient mice are largely spared the severe symptoms of the patients with LGMD due to defects in these two genes.	('spared', 'NegReg', (56, 62))	('LGMD', 'Disease', 'None', (104, 108))	('mice', 'Species', '10090', (39, 43))	('Capn3', 'Gene', '12335', (19, 24))	('Dysf', 'Gene', '26903', (6, 10))	('LGMD', 'Disease', (104, 108))	('Capn3', 'Gene', (19, 24))	('defects', 'Var', (116, 123))	('patients', 'Species', '9606', (90, 98))	('Dysf', 'Gene', (6, 10))
411614	21533183	Muscle biopsy samples used in this study were from a total of n = 6 different DMD patients: M2006 (age at muscle biopsy: 9 m; DMD gene mutation: c.3053_3087del), M2008 (11 m; c.8669-1G>T), M1633 (6 a; c.858T>G p.Tyr286X), M1994 (7a; unknown DMD mutation), M1895 (8 a; dup_ex3-7), M1959 (15 a; del_ex17), and two samples from aborted fetuses with DMD.	('M1633 (6 a; c.858T>G p.Tyr286X', 'Var', (189, 219))	('DMD', 'Disease', 'MESH:D020388', (346, 349))	('DMD', 'Disease', (78, 81))	('DMD', 'Disease', (126, 129))	('DMD', 'Disease', (346, 349))	('DMD', 'Disease', (241, 244))	('c.8669-1G>T', 'Mutation', 'c.8669-1G>T', (175, 186))	('DMD', 'Disease', 'MESH:D020388', (126, 129))	('DMD', 'Disease', 'MESH:D020388', (241, 244))	('patients', 'Species', '9606', (82, 90))	('c.3053_3087del', 'Mutation', 'c.3053_3087del', (145, 159))	('c.3053_3087del', 'Var', (145, 159))	('c.858T>G', 'Mutation', 'rs753987509', (201, 209))	('p.Tyr286X', 'Mutation', 'rs886042875', (210, 219))	('DMD', 'Disease', 'MESH:D020388', (78, 81))
411616	21533183	LGMD2I patients (n = 3) had a confirmed diagnosis by FKRP gene sequencing: M1787 (10 a; c.854A>C p.Glu285Ala), M2190 (28 a; c.826C>A, p.Leu276Ile), M2166 (prenatal; c. [962C>A]+[1086C>G] p.Ala321Glu + p.Asp362Glu).	('p.Leu276Ile', 'Mutation', 'rs28937900', (134, 145))	('LGMD', 'Disease', 'None', (0, 4))	('LGMD', 'Disease', (0, 4))	('p.Glu285Ala', 'Mutation', 'rs963039919', (97, 108))	('p.Leu276Ile', 'Var', (134, 145))	('1086C>G', 'Mutation', 'c.1086C>G', (178, 185))	('c.826C>A', 'Mutation', 'rs28937900', (124, 132))	('c.854A>C', 'Mutation', 'rs963039919', (88, 96))	('p.Asp362Glu', 'Mutation', 'p.D362E', (201, 212))	('p.Ala321Glu', 'Mutation', 'rs745882222', (187, 198))	('962C>A', 'SUBSTITUTION', 'None', (169, 175))	('962C>A', 'Var', (169, 175))	('patients', 'Species', '9606', (7, 15))
411617	21533183	LGMD2B in one patient was confirmed by reduced dysferlin reactivity in IH and WB, and DYSF gene sequencing: M2057 (62 a, c.509C>A p.Ala170Glu).	('LGMD2B', 'Gene', '8291', (0, 6))	('p.Ala170Glu', 'Mutation', 'rs34999029', (130, 141))	('c.509C>A', 'Mutation', 'rs34999029', (121, 129))	('c.509C>A p.Ala170Glu', 'Var', (121, 141))	('patient', 'Species', '9606', (14, 21))	('reduced', 'NegReg', (39, 46))	('dysferlin reactivity', 'MPA', (47, 67))	('LGMD2B', 'Gene', (0, 6))
411620	21533183	DMD: "Essen 88/07" (14 a, del45_50); "72/05" (7 a, dup_ex8-29); "Essen 8/02" (4 a, del_ex51-55); "166/00" (6 a, 2bp-deletion in exon 6); LGMD2B: "90/01" (36 a, female, c. [638C>T]+ [5249delG]); "176/01" (32 a, male, c. [2367C>A]+ [5979dupA]); "362/03" (male, 33 a, c. [exon 5 p.Pro134Leu]+ [5022delT]); controls: "363/07" (21a, male); "179/07" (21a, female).	('DMD', 'Disease', 'MESH:D020388', (0, 3))	('5022delT', 'Mutation', 'c.5022delT', (291, 299))	('5979dupA', 'Mutation', 'rs398123799', (231, 239))	('5249delG', 'Mutation', 'c.5249delG', (182, 190))	('638C>T', 'Var', (172, 178))	('DMD', 'Disease', (0, 3))	('p.Pro134Leu', 'Mutation', 'rs773837400', (276, 287))	('2367C>A', 'Var', (220, 227))	('638C>T', 'SUBSTITUTION', 'None', (172, 178))	('LGMD2B', 'Gene', (137, 143))	('2367C>A', 'SUBSTITUTION', 'None', (220, 227))	('LGMD2B', 'Gene', '8291', (137, 143))
411629	21533183	The Dmdmdx C57BL/10 (mdx), Dmdmdx-3cv C57BL/6 (mdx-3cv), SJL Dysfim (SJL-Dysf), and B6C3Fe Largemyd (myd) mice were originally obtained from The Jackson Laboratory (Bar Harbor, ME).	('mice', 'Species', '10090', (106, 110))	('Dysf', 'Gene', '26903', (61, 65))	('C57BL/6', 'Var', (38, 45))	('mdx', 'Gene', (7, 10))	('mdx', 'Gene', '13405', (47, 50))	('mdx', 'Gene', '13405', (30, 33))	('mdx', 'Gene', (30, 33))	('Dysf', 'Gene', (61, 65))	('mdx', 'Gene', '13405', (7, 10))	('mdx', 'Gene', '13405', (21, 24))	('Dysf', 'Gene', '26903', (73, 77))	('mdx', 'Gene', (47, 50))	('Dysf', 'Gene', (73, 77))	('mdx', 'Gene', (21, 24))
411630	21533183	To study dystrophin deficiency on other strains, we inbred the Dmdmdx mutation to C3H and BALB/c (>20 consecutive backcross generations; residual heterozygosity <0.01).	('dystrophin deficiency', 'Disease', (9, 30))	('dystrophin deficiency', 'Phenotype', 'HP:0030098', (9, 30))	('Dmdmdx', 'Gene', (63, 69))	('dystrophin deficiency', 'Disease', 'MESH:D020388', (9, 30))	('mutation', 'Var', (70, 78))
411632	21533183	Further, we inbred the SJL-Dysf mutation onto the C57BL/10 background, where a prolonged life span compared to SJL was observed, which enabled us to study late-onset stages of dysferlin-deficiency.	('dysferlin-deficiency', 'Disease', 'MESH:D007153', (176, 196))	('dysferlin-deficiency', 'Disease', (176, 196))	('Dysf', 'Gene', '26903', (27, 31))	('Dysf', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))
411637	21533183	In all cases, Large+/- heterozygosity had no influence on tumorigenesis and conferred no overt additional phenotype with regard to muscle pathology.	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Large+/- heterozygosity', 'Var', (14, 37))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
411650	21533183	Primary antibodies used in this study were as follows: Myogenin (Santa Cruz Biotechnology, CA; sc-576), Myf-5 (sc-302), desmin (Millipore, Billerica, MA, MAB3430), Cdk4 (sc-260), PCNA (sc-7907), p27 (sc-776), p-Ser1981-ATM (Cell Signaling Technology, Danvers, MA; #4526), phopsho-Ser428-ATR (#2853), p-Ser296-Chk1 (#2349), p-Thr68-Chk2 (#2661), p-Ser139-Histone H2A.X (#9718).	('Chk2', 'Gene', (331, 335))	('Myogenin', 'Gene', (55, 63))	('Chk1', 'Gene', '12649', (309, 313))	('Ser428', 'Chemical', '-', (280, 286))	('ATM', 'Gene', '11920', (219, 222))	('Ser1981', 'Chemical', '-', (211, 218))	('AT', 'Disease', 'None', (287, 289))	('Myf-5', 'Gene', (104, 109))	('#2853', 'Var', (292, 297))	('PCNA', 'Gene', '18538', (179, 183))	('#2349', 'Var', (315, 320))	('p27', 'Gene', (195, 198))	('Chk2', 'Gene', '50883', (331, 335))	('Ser139', 'Chemical', '-', (347, 353))	('desmin', 'Gene', '13346', (120, 126))	('desmin', 'Gene', (120, 126))	('p-Ser139-Histone', 'Var', (345, 361))	('Myogenin', 'Gene', '17928', (55, 63))	('PCNA', 'Gene', (179, 183))	('Myf-5', 'Gene', '17877', (104, 109))	('Chk1', 'Gene', (309, 313))	('ATM', 'Gene', (219, 222))	('AT', 'Disease', 'None', (219, 221))	('p27', 'Gene', '12576', (195, 198))
411663	21533183	Deletions at the Cdkn2a (chr 4) and Nf1 (chr 11) loci were measured using a quantitative real-time PCR (qRT-PCR) SybrGreen assay (DeltaCt method), involving separate amplification of target genes and an internal reference (Lig3).	('Lig3', 'Gene', '16882', (223, 227))	('Lig3', 'Gene', (223, 227))	('Cdkn2a', 'Gene', (17, 23))	('Nf1', 'Gene', (36, 39))	('Deletions', 'Var', (0, 9))
411665	21533183	To screen for Nf1 deletions in other tumors, two different exons (23 and 56) were chosen as qRT-PCR targets.	('Nf1', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('deletions', 'Var', (18, 27))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
411666	21533183	Primer sequences were as follows: Cdkn2a_f: GTA GCA GCT CTT CTG CTC AAC TAC; Cdkn2a_r AAT ATC GCA CGA TGT CTT GAT GT; Nf1_I22_f TGA TGA AGT AGT TTG CCA TTG TTT; Nf1_E23_r TTG CCA TCA TGA CTT CAA CTA ACT; Nf1_I55_f CTC TCG CTC TTC ATT TCA TCT TCT; Nf1_E56_r GCC ATA AGC CAT TAA AAC CAA AAC.	('AT', 'Disease', 'None', (111, 113))	('Nf1_E56_r', 'Var', (247, 256))	('AT', 'Disease', 'None', (270, 272))	('AAT', 'Gene', (86, 89))	('AAT', 'Gene', '20701', (86, 89))	('AT', 'Disease', 'None', (230, 232))	('AT', 'Disease', 'None', (261, 263))	('AT', 'Disease', 'None', (87, 89))	('AT', 'Disease', 'None', (90, 92))
411776	30897294	For example, Beck et al29 found that the recurrence rate of patients with postoperative progestogen was lower than those with surgery alone in stage I (14.3% vs 38.5%), as well as all stages (33% vs 50%).	('postoperative', 'Var', (74, 87))	('lower', 'NegReg', (104, 109))	('patients', 'Species', '9606', (60, 68))	('recurrence', 'MPA', (41, 51))
411919	28747130	There was a significant association between CT attenuation of psoas muscle and tumor recurrence (Table 2 and Fig.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('CT attenuation', 'Var', (44, 58))	('tumor', 'Disease', (79, 84))
411938	28747130	Two large multicenter studies demonstrated increased all-cause mortality in patients with high CT attenuation of abdominal adipose tissue, independent of known risk factors, such as age, smoking, or co-morbidities.	('patients', 'Species', '9606', (76, 84))	('high CT', 'Var', (90, 97))	('attenuation', 'NegReg', (98, 109))	('all-cause mortality', 'MPA', (53, 72))	('increased', 'PosReg', (43, 52))
411939	28747130	A study in patients with bone and soft tissue sarcomas undergoing a variety of therapies has demonstrated a positive association between mortality and high CT attenuation of abdominal SAT and low attenuation of psoas muscle, independent of known risk factors, such as age, BMI, co-morbidities, tumor stage and grade.	('tumor', 'Disease', (294, 299))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (34, 54))	('soft tissue sarcomas', 'Disease', (34, 54))	('abdominal SAT', 'Disease', 'MESH:D015746', (174, 187))	('high', 'Var', (151, 155))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (34, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (34, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('abdominal SAT', 'Disease', (174, 187))	('patients', 'Species', '9606', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))
411940	28747130	In our study, focusing on patients with soft tissue sarcomas of the extremities treated with a standard regimen, radiation therapy and surgery, high abdominal SAT and low psoas muscle attenuation were positive predictors of tumor recurrence, independent of tumor size, stage, radiation dose and other risk factors.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('high', 'Var', (144, 148))	('soft tissue sarcomas', 'Disease', (40, 60))	('abdominal SAT', 'Disease', 'MESH:D015746', (149, 162))	('tumor', 'Disease', (257, 262))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (40, 60))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (40, 59))	('sarcomas of the extremities', 'Disease', (52, 79))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (40, 60))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('tumor', 'Disease', (224, 229))	('sarcomas of the extremities', 'Disease', 'MESH:D012509', (52, 79))	('low', 'Var', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('men', 'Species', '9606', (108, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('abdominal SAT', 'Disease', (149, 162))	('patients', 'Species', '9606', (26, 34))
411952	28747130	Interestingly, a study in mice has shown that ablation of adipocyte lipase results in preservation of skeletal muscle, suggesting that the breakdown of fat in cancer precedes that of skeletal muscle and that the breakdown of adipocytes affects the breakdown of muscle.	('breakdown of fat', 'MPA', (139, 155))	('ablation', 'Var', (46, 54))	('affects', 'Reg', (236, 243))	('cancer', 'Disease', (159, 165))	('breakdown of muscle', 'MPA', (248, 267))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('mice', 'Species', '10090', (26, 30))
411963	28747986	Tumor size and volume were lower in H-Cis-treated mice than in L-Cis-treated mice in all three ICR stocks with no significant differences among stocks.	('mice', 'Species', '10090', (77, 81))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('H-Cis-treated', 'Var', (36, 49))	('lower', 'NegReg', (27, 32))	('H-Cis', 'Chemical', '-', (36, 41))	('stocks', 'Species', '3724', (99, 105))	('stocks', 'Species', '3724', (144, 150))	('mice', 'Species', '10090', (50, 54))	('L-Cis', 'Chemical', '-', (63, 68))
411964	28747986	There was a significant enhancement of the necrotizing areas in the histological structures in the L-Cis- and H-Cis-treated groups relative to that in the untreated group.	('enhancement', 'PosReg', (24, 35))	('L-Cis-', 'Var', (99, 105))	('H-Cis', 'Chemical', '-', (110, 115))	('necrotizing areas in the histological structures', 'CPA', (43, 91))	('H-Cis-treated', 'Var', (110, 123))	('L-Cis', 'Chemical', '-', (99, 104))
412002	28747986	The size decrease was greater in the L-Cis and H-Cis-treated groups than that in the Vehicle-treated group.	('H-Cis-treated', 'Var', (47, 60))	('H-Cis', 'Chemical', '-', (47, 52))	('L-Cis', 'Var', (37, 42))	('L-Cis', 'Chemical', '-', (37, 42))	('size', 'MPA', (4, 8))	('decrease', 'NegReg', (9, 17))
412004	28747986	Furthermore, tumor volumes collected from Sarcoma 180 tumor-bearing ICR mice were smaller in the L-Cis- and H-Cis-treated groups than in the Vehicle-treated group.	('L-Cis-', 'Var', (97, 103))	('tumor', 'Disease', (13, 18))	('smaller', 'NegReg', (82, 89))	('H-Cis', 'Chemical', '-', (108, 113))	('Sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Sarcoma 180 tumor', 'Disease', (42, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('L-Cis', 'Chemical', '-', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Disease', (54, 59))	('Sarcoma 180 tumor', 'Disease', 'MESH:D012510', (42, 59))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
412010	28747986	In the L-Cis- and H-Cis-treated groups, the necrotizing area and the number of dead cells were significantly greater than those in the Vehicle-treated group.	('H-Cis', 'Chemical', '-', (18, 23))	('L-Cis', 'Chemical', '-', (7, 12))	('L-Cis-', 'Var', (7, 13))	('necrotizing area', 'CPA', (44, 60))	('H-Cis-treated', 'Var', (18, 31))	('greater', 'PosReg', (109, 116))
412018	28747986	Specifically, high BUN levels were detected in B:ICR mice treated with both L-Cis and H-Cis and in Korl:ICR mice treated with H-Cis compared with A:ICR mice (Figure 4B).	('mice', 'Species', '10090', (53, 57))	('high BUN', 'Phenotype', 'HP:0003138', (14, 22))	('L-Cis', 'Var', (76, 81))	('mice', 'Species', '10090', (108, 112))	('H-Cis', 'Chemical', '-', (126, 131))	('L-Cis', 'Chemical', '-', (76, 81))	('mice', 'Species', '10090', (152, 156))	('BUN', 'Phenotype', 'HP:0003138', (19, 22))	('high', 'PosReg', (14, 18))	('BUN levels', 'MPA', (19, 29))	('H-Cis', 'Chemical', '-', (86, 91))	('H-Cis', 'Var', (86, 91))
412024	28747986	The results presented in this report provide the first evidence that Korl:ICR, A:ICR, and B:ICR mice show similar responses to tumor development after the injection of Sarcoma 180 cells and that Cis has similar antitumor activity among the three ICR stocks, although additional research is needed to quantify stock-based effects fully.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Disease', (127, 132))	('stocks', 'Species', '3724', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('Sarcoma', 'Disease', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('tumor', 'Disease', (215, 220))	('Cis', 'Var', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
412049	26541413	In a multivariate analysis, PFS was superior for patients receiving sirolimus compared to other TTs (Hazard Ratio (HR) = 2.7, 95 % CI [1.05-7.1]).	('sirolimus', 'Var', (68, 77))	('PFS', 'MPA', (28, 31))	('patients', 'Species', '9606', (49, 57))	('sirolimus', 'Chemical', 'MESH:D020123', (68, 77))	('TTs', 'Chemical', '-', (96, 99))
412113	26541413	In a multivariate analysis, PFS seemed superior for patients receiving sirolimus compared to other TTs.	('PFS', 'MPA', (28, 31))	('TTs', 'Chemical', '-', (99, 102))	('sirolimus', 'Var', (71, 80))	('sirolimus', 'Chemical', 'MESH:D020123', (71, 80))	('patients', 'Species', '9606', (52, 60))
412199	29718861	A 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography (18F-FDG-PET) scan showed accumulation of 18F in the right liver (S6), the eleventh thoracic vertebra, and the right ilium.	('vertebra', 'Disease', (172, 180))	('vertebra', 'Disease', 'MESH:C562952', (172, 180))	('18F', 'Var', (121, 124))	('2-deoxy-2-[fluorine-18] fluoro-D-glucose', 'Chemical', '-', (2, 42))
412299	27594909	Li Fraumeni is associated with germline mutations in p53.	('associated', 'Reg', (15, 25))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('germline mutations', 'Var', (31, 49))	('Li Fraumeni', 'Disease', (0, 11))
412381	26265619	Thus, we hypothesized that mixed HSP/Ps may deliver more specific tumor antigens and so exhibit greater efficacy.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('HSP', 'Gene', '7190', (33, 36))	('tumor', 'Disease', (66, 71))	('mixed', 'Var', (27, 32))	('Ps', 'Chemical', 'MESH:D010758', (37, 39))	('HSP', 'Gene', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('efficacy', 'MPA', (104, 112))
412441	26265619	To explore the specificity of mHSP/P vaccine, three mice were vaccinated with the MCA207 mHSP/P, and the MCA207 tumor was rejected.	('P', 'Chemical', 'MESH:D010758', (92, 93))	('mice', 'Species', '10090', (52, 56))	('MCA207 tumor', 'Disease', 'MESH:D009369', (105, 117))	('P', 'Chemical', 'MESH:D010758', (35, 36))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('MCA207', 'Var', (82, 88))	('P', 'Chemical', 'MESH:D010758', (33, 34))	('MCA207 tumor', 'Disease', (105, 117))	('P', 'Chemical', 'MESH:D010758', (94, 95))	('mHSP', 'Chemical', '-', (30, 34))	('mHSP', 'Chemical', '-', (89, 93))
412449	26265619	Numbers of CD8+ cells and NK cells were elevated following S180 mHSP/P treatment in BALB/C mice, as determined using flow cytometry analysis.	('mice', 'Species', '10090', (91, 95))	('elevated', 'PosReg', (40, 48))	('NK cells', 'CPA', (26, 34))	('S180 mHSP/P treatment', 'Var', (59, 80))	('P', 'Chemical', 'MESH:D010758', (69, 70))	('mHSP', 'Chemical', '-', (64, 68))	('CD8+ cells', 'CPA', (11, 21))	('P', 'Chemical', 'MESH:D010758', (67, 68))
412455	26265619	Upon stimulation with ConA and mHSP/Ps, the mean IFN-gamma level in mHSP/P-immunized mice was 246.6 +- 7.45/106 cells, higher than that of wild-type (180 +- 3.082/106 cells, P < 0.05) and tumor-bearing (121.3 +- 1.00/106, P < 0.01) mice [Figure 6].	('tumor', 'Disease', (188, 193))	('mice', 'Species', '10090', (85, 89))	('P', 'Chemical', 'MESH:D010758', (71, 72))	('mHSP', 'Chemical', '-', (31, 35))	('P', 'Chemical', 'MESH:D010758', (34, 35))	('P', 'Chemical', 'MESH:D010758', (174, 175))	('IFN-gamma', 'Gene', (49, 58))	('higher', 'PosReg', (119, 125))	('Ps', 'Chemical', 'MESH:D010758', (36, 38))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mHSP/P-immunized', 'Var', (68, 84))	('mHSP', 'Chemical', '-', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('IFN-gamma', 'Gene', '15978', (49, 58))	('P', 'Chemical', 'MESH:D010758', (73, 74))	('P', 'Chemical', 'MESH:D010758', (36, 37))	('P', 'Chemical', 'MESH:D010758', (222, 223))	('mice', 'Species', '10090', (232, 236))
412456	26265619	The level of IFN-gamma from splenocytes stimulated with ConA alone was significantly higher in mHSP/P-immunized than in untreated tumor-bearing mice and wild-type mice.	('IFN-gamma', 'Gene', (13, 22))	('P', 'Chemical', 'MESH:D010758', (98, 99))	('higher', 'PosReg', (85, 91))	('mice', 'Species', '10090', (144, 148))	('IFN-gamma', 'Gene', '15978', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mHSP/P-immunized', 'Var', (95, 111))	('P', 'Chemical', 'MESH:D010758', (100, 101))	('mice', 'Species', '10090', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mHSP', 'Chemical', '-', (95, 99))	('tumor', 'Disease', (130, 135))
412457	26265619	Cytotoxic T-lymphocyte generated by mixture of heat shock protein/peptide were capable of killing target cells To assess the functional effector properties of CTLs generated by mHSP/P, we performed in vitro cytotoxicity assays of T-lymphocytes isolated from mice vaccinated with S180 mHSP/Ps.	('P', 'Chemical', 'MESH:D010758', (287, 288))	('shock', 'Phenotype', 'HP:0031273', (52, 57))	('Ps', 'Chemical', 'MESH:D010758', (289, 291))	('P', 'Chemical', 'MESH:D010758', (182, 183))	('S180 mHSP/Ps', 'Var', (279, 291))	('cytotoxicity', 'Disease', 'MESH:D064420', (207, 219))	('Cytotoxic', 'Disease', 'MESH:D064420', (0, 9))	('mice', 'Species', '10090', (258, 262))	('P', 'Chemical', 'MESH:D010758', (180, 181))	('mHSP', 'Chemical', '-', (284, 288))	('mHSP', 'Chemical', '-', (177, 181))	('Cytotoxic', 'Disease', (0, 9))	('P', 'Chemical', 'MESH:D010758', (289, 290))	('cytotoxicity', 'Disease', (207, 219))
412460	26265619	In addition, T-lymphocytes isolated from liver or muscle of wild-type mice vaccinated with mHSP/Ps did not kill the S180 sarcoma cells; all cytolytic ratios were lower than 1%.	('Ps', 'Chemical', 'MESH:D010758', (96, 98))	('sarcoma', 'Disease', (121, 128))	('mHSP/Ps', 'Var', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('lower', 'NegReg', (162, 167))	('mice', 'Species', '10090', (70, 74))	('mHSP', 'Chemical', '-', (91, 95))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))
412469	26265619	mHSP/P vaccination induced an antitumor immune response and significantly inhibited S180 and MCA207 tumor growth in mice, and significantly prolonged their survival.	('mice', 'Species', '10090', (116, 120))	('inhibited', 'NegReg', (74, 83))	('mHSP', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (34, 39))	('P', 'Chemical', 'MESH:D010758', (3, 4))	('prolonged', 'PosReg', (140, 149))	('MCA207 tumor', 'Disease', 'MESH:D009369', (93, 105))	('tumor', 'Disease', (100, 105))	('mHSP/P', 'Var', (0, 6))	('MCA207 tumor', 'Disease', (93, 105))	('survival', 'CPA', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('P', 'Chemical', 'MESH:D010758', (5, 6))	('S180', 'CPA', (84, 88))
412479	26265619	This may explain why use of multiple mHSP/Ps results in greater antitumor effects compared to use of single HSP70, HSP60 alone, although the differences between mHSP/P and HSP70 or HSP60 were not significant.	('tumor', 'Disease', (68, 73))	('P', 'Chemical', 'MESH:D010758', (40, 41))	('P', 'Chemical', 'MESH:D010758', (174, 175))	('P', 'Chemical', 'MESH:D010758', (164, 165))	('P', 'Chemical', 'MESH:D010758', (42, 43))	('P', 'Chemical', 'MESH:D010758', (117, 118))	('greater', 'PosReg', (56, 63))	('P', 'Chemical', 'MESH:D010758', (166, 167))	('mHSP/Ps', 'Var', (37, 44))	('mHSP', 'Chemical', '-', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('P', 'Chemical', 'MESH:D010758', (110, 111))	('P', 'Chemical', 'MESH:D010758', (183, 184))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mHSP', 'Chemical', '-', (161, 165))	('Ps', 'Chemical', 'MESH:D010758', (42, 44))
412480	26265619	In addition, mHSP/Ps isolated from MCA207 cells were more effective than those isolated from S180 cells, possibly because S180 is more aggressive than MCA207.	('MCA207', 'Var', (35, 41))	('S180', 'Var', (122, 126))	('Ps', 'Chemical', 'MESH:D010758', (18, 20))	('mHSP', 'Chemical', '-', (13, 17))
412481	26265619	In the S180 model, metastasis of the tumor to lung occurred in 90% of the mice, compared to 0% in the MCA207 model.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('S180', 'Var', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mice', 'Species', '10090', (74, 78))
412492	26265619	We found that the number of NK cells and the INF-gamma level were elevated in mHSP/P-treated mice, which increased the frequency of IFN-gamma-producing cells and IFN-gamma-secreting NK cells.	('P', 'Chemical', 'MESH:D010758', (81, 82))	('mHSP/P-treated', 'Var', (78, 92))	('IFN-gamma', 'Gene', (162, 171))	('P', 'Chemical', 'MESH:D010758', (83, 84))	('mHSP', 'Chemical', '-', (78, 82))	('IFN-gamma', 'Gene', (132, 141))	('mice', 'Species', '10090', (93, 97))	('IFN-gamma', 'Gene', '15978', (162, 171))	('increased', 'PosReg', (105, 114))	('INF-gamma level', 'MPA', (45, 60))	('IFN-gamma', 'Gene', '15978', (132, 141))	('elevated', 'PosReg', (66, 74))
412517	25202342	Additionally, pre-clinical and clinical studies have shown that PDT treatment of a tumor can enhance systemic anti-tumor immunity and surveillance.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('surveillance', 'CPA', (134, 146))	('PDT', 'Var', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (115, 120))	('enhance', 'PosReg', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
412522	25202342	As DNA damage is less in PDT-treated cells compared with those irradiated by other means, it is a great benefit that PDT does not appear to be carcinogenic when compared with chemotherapy or radiation therapy.	('PDT-treated', 'Var', (25, 36))	('carcinogenic', 'Disease', 'MESH:D063646', (143, 155))	('carcinogenic', 'Disease', (143, 155))	('less', 'NegReg', (17, 21))	('DNA damage', 'MPA', (3, 13))
412555	25202342	Kusuzaki et al also showed that local tumor recurrence was significantly inhibited (23%) in a group treated with curettage under fluorovisualization and AO-PDT, compared with the control group (80%) treated with curettage alone under ordinary light.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('AO', 'Chemical', 'MESH:D000165', (153, 155))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('inhibited', 'NegReg', (73, 82))	('AO-PDT', 'Var', (153, 159))
412575	25202342	Unfiltered xenon light was determined as the light source for AO-PDT, and PDT was shown to enhance the cytocidal effect of AO-PDT in the mouse osteosarcoma cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('AO', 'Chemical', 'MESH:D000165', (62, 64))	('osteosarcoma', 'Disease', (143, 155))	('osteosarcoma', 'Disease', 'MESH:D012516', (143, 155))	('mouse', 'Species', '10090', (137, 142))	('AO-PDT', 'Var', (123, 129))	('cytocidal', 'CPA', (103, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('AO', 'Chemical', 'MESH:D000165', (123, 125))	('xenon', 'Chemical', 'MESH:D014978', (11, 16))	('enhance', 'PosReg', (91, 98))	('PDT', 'Var', (74, 77))
412577	25202342	Kusuzaki et al (60) discovered that AO-PDT has a strong cytocidal effect, not only on chemosensitive mouse osteosarcoma cells, but also on multidrug-resistant mouse osteosarcoma cells.	('AO-PDT', 'Var', (36, 42))	('osteosarcoma', 'Disease', (165, 177))	('osteosarcoma', 'Phenotype', 'HP:0002669', (165, 177))	('AO', 'Chemical', 'MESH:D000165', (36, 38))	('mouse', 'Species', '10090', (159, 164))	('osteosarcoma', 'Disease', 'MESH:D012516', (165, 177))	('mouse', 'Species', '10090', (101, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('osteosarcoma', 'Disease', (107, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (107, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('cytocidal effect', 'CPA', (56, 72))
412583	25202342	It was also suggested that AO-PDT would prevent primary osteosarcoma metastasis to the lung.	('primary osteosarcoma metastasis to the lung', 'Disease', (48, 91))	('primary osteosarcoma metastasis to the lung', 'Disease', 'MESH:D009362', (48, 91))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('AO-PDT', 'Var', (27, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('AO', 'Chemical', 'MESH:D000165', (27, 29))	('prevent', 'NegReg', (40, 47))
412585	25202342	Kusuzaki et al performed a clinical trial with six cases of SS to analyze the use of AO-PDT, and concluded that AO-PDT with 5 Gy irradiation may be an excellent novel therapeutic modality, together with reduction surgery, to salvage limb function in SS involving major nerves and vessels or bones.	('AO-PDT', 'Var', (112, 118))	('AO', 'Chemical', 'MESH:D000165', (112, 114))	('limb function', 'CPA', (233, 246))	('AO', 'Chemical', 'MESH:D000165', (85, 87))
412620	24966711	Li-Fraumeni syndrome has been linked to germline mutations (de novo or inherited) of the tumor suppressor gene for p53.	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('germline mutations', 'Var', (40, 58))	('p53', 'Gene', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('linked', 'Reg', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
412629	24966711	This was mainly observed in aged dystrophic mice, suggesting that cumulative deoxyribonucleic acid damage - over time, together with paracrine signals - could direct the muscle cells and their progenitors toward tumor formation.	('muscle cells', 'CPA', (170, 182))	('tumor', 'Disease', (212, 217))	('dystrophic', 'Disease', 'MESH:D020388', (33, 43))	('deoxyribonucleic', 'Protein', (77, 93))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('dystrophic', 'Disease', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('mice', 'Species', '10090', (44, 48))	('damage', 'Var', (99, 105))	('direct', 'PosReg', (159, 165))
412634	24966711	In ERMS, the LOH results in loss of the maternal IGF2 allele and duplication of the paternal allele, resulting in the overexpression of IGF2.	('overexpression', 'PosReg', (118, 132))	('RMS', 'Phenotype', 'HP:0002859', (4, 7))	('IGF2', 'Gene', '3481', (136, 140))	('loss', 'NegReg', (28, 32))	('IGF2', 'Gene', '3481', (49, 53))	('duplication', 'Var', (65, 76))	('IGF2', 'Gene', (136, 140))	('IGF2', 'Gene', (49, 53))
412639	24966711	Thus, fusion gene status may play a role as a factor in risk stratification in RMS, irrespective of histology.	('RMS', 'Disease', (79, 82))	('rat', 'Species', '10116', (63, 66))	('fusion gene', 'Var', (6, 17))	('RMS', 'Phenotype', 'HP:0002859', (79, 82))
412641	24966711	RMS cell lines showed a high frequency of mutations in p53 (up to 60%), but a lower frequency was observed in tumors (up to 30%).	('p53', 'Gene', (55, 58))	('RMS', 'Phenotype', 'HP:0002859', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('mutations', 'Var', (42, 51))
412642	24966711	Mutations in CDKN2A have been found in all RMS cell lines but only 25% of RMS primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('RMS primary tumors', 'Disease', 'MESH:D009369', (74, 92))	('found', 'Reg', (30, 35))	('CDKN2A', 'Gene', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Mutations', 'Var', (0, 9))	('RMS primary tumors', 'Disease', (74, 92))	('CDKN2A', 'Gene', '1029', (13, 19))	('RMS', 'Phenotype', 'HP:0002859', (74, 77))	('RMS', 'Phenotype', 'HP:0002859', (43, 46))
412650	24966711	Another study suggested that ERMS and the undifferentiated pleomorphic sarcoma form a continuum, with mutant p53, Ptch1, or Rb1 in satellite cells, giving rise to undifferentiated sarcoma and ERMS originating from myoblasts that express satellite cells markers.	('Rb1', 'Gene', '5925', (124, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('ERMS', 'Disease', (29, 33))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (42, 78))	('sarcoma', 'Disease', 'MESH:D012509', (180, 187))	('sarcoma', 'Disease', (180, 187))	('RMS', 'Phenotype', 'HP:0002859', (193, 196))	('Rb1', 'Gene', (124, 127))	('Ptch1', 'Gene', (114, 119))	('undifferentiated pleomorphic sarcoma', 'Disease', (42, 78))	('ERMS', 'Disease', (192, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('p53', 'Gene', (109, 112))	('mutant', 'Var', (102, 108))	('Ptch1', 'Gene', '5727', (114, 119))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('giving rise to', 'Reg', (148, 162))	('sarcoma', 'Disease', (71, 78))	('RMS', 'Phenotype', 'HP:0002859', (30, 33))
412679	24966711	With regards to molecular markers, the presence of PAX3/FOXO1 fusion has been proposed by one study as a molecular prognostic marker of poor outcome in patients with nonmetastatic ARMS.	('RMS', 'Phenotype', 'HP:0002859', (181, 184))	('fusion', 'Var', (62, 68))	('presence', 'Var', (39, 47))	('PAX3', 'Gene', '5077', (51, 55))	('PAX3', 'Gene', (51, 55))	('FOXO1', 'Gene', (56, 61))	('FOXO1', 'Gene', '2308', (56, 61))	('nonmetastatic ARMS', 'Disease', (166, 184))	('patients', 'Species', '9606', (152, 160))
412737	24966711	Alkylating agents like cyclophosphamide and ifosfamide have been linked to secondary malignancies and have shown a dose-dependent effect on testicular function and fertility.	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('linked', 'Reg', (65, 71))	('testicular function', 'CPA', (140, 159))	('fertility', 'CPA', (164, 173))	('malignancies', 'Disease', (85, 97))	('effect', 'Reg', (130, 136))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (23, 39))	('cyclophosphamide', 'Var', (23, 39))	('ifosfamide', 'Chemical', 'MESH:D007069', (44, 54))
412769	33889459	Worst outcomes are often associated with male gender, proximal rather than distal lesions, late age at presentation, tumours larger than 2 cm across, vascular invasion, necrosis and high mitotic index.	('necrosis', 'Disease', 'MESH:D009336', (169, 177))	('tumours', 'Disease', (117, 124))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('necrosis', 'Disease', (169, 177))	('high', 'Var', (182, 186))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('vascular invasion', 'CPA', (150, 167))	('tumours', 'Disease', 'MESH:D009369', (117, 124))
412779	33889459	The immuno-histochemistry was diffusely positive for epithelial membrane antigen (EMA), cytokeratin 8 and vimentin; it was focally positive for cytokeratin 19, smooth muscle actin, CD34 and integrase interactor 1 (INI-1); and it was negative for myogenin, p63, desmin, cytokeratin 7, cytokeratin 5/6, cytokeratin 14, CD117, Melan-A, HMB-45, S100, Factor 13A and CD68 (Figure 4).	('Melan-A', 'Gene', '2315', (324, 331))	('cytokeratin 7', 'Gene', '3855', (269, 282))	('cytokeratin 7', 'Gene', (269, 282))	('CD117', 'Gene', '3815', (317, 322))	('p63', 'Gene', '8626', (256, 259))	('desmin', 'Gene', (261, 267))	('cytokeratin 19', 'Gene', '3880', (144, 158))	('vimentin', 'Gene', '7431', (106, 114))	('Melan-A', 'Gene', (324, 331))	('integrase interactor 1', 'Gene', (190, 212))	('vimentin', 'Gene', (106, 114))	('myogenin', 'Gene', '4656', (246, 254))	('S100, Factor 13A', 'Gene', '6271', (341, 357))	('CD117', 'Gene', (317, 322))	('cytokeratin 8', 'Gene', '3856', (88, 101))	('desmin', 'Gene', '1674', (261, 267))	('integrase interactor 1', 'Gene', '6598', (190, 212))	('cytokeratin 8', 'Gene', (88, 101))	('cytokeratin 5/6', 'Gene', (284, 299))	('INI-1', 'Gene', '6598', (214, 219))	('cytokeratin 14', 'Gene', (301, 315))	('CD34', 'Var', (181, 185))	('INI-1', 'Gene', (214, 219))	('cytokeratin 5/6', 'Gene', '3852', (284, 299))	('cytokeratin 19', 'Gene', (144, 158))	('cytokeratin 14', 'Gene', '3861', (301, 315))	('myogenin', 'Gene', (246, 254))	('p63', 'Gene', (256, 259))
412828	31150156	CBX2 is a functional target of miRNA let-7a and acts as a tumor promoter in osteosarcoma Osteosarcoma is the most common type of primary malignant tumor of skeletal with poor prognosis in children and adolescents.	('malignant tumor of skeletal', 'Phenotype', 'HP:0010622', (137, 164))	('miRNA let-7a', 'Var', (31, 43))	('Osteosarcoma', 'Disease', (89, 101))	('Osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (147, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('CBX2', 'Gene', '84733', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('osteosarcoma', 'Disease', (76, 88))	('osteosarcoma', 'Disease', 'MESH:D012516', (76, 88))	('CBX2', 'Gene', (0, 4))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('children', 'Species', '9606', (188, 196))	('malignant tumor', 'Disease', (137, 152))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('malignant tumor', 'Disease', 'MESH:D018198', (137, 152))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
412833	31150156	We found that CBX2 is dramatically upregulated in osteosarcoma tissues and high CBX2 expression was correlated with metastasis, recurrence, and chemotherapy response, as well as unfavorable prognosis in patients with osteosarcoma.	('expression', 'MPA', (85, 95))	('osteosarcoma tissues', 'Disease', (50, 70))	('osteosarcoma', 'Disease', (217, 229))	('osteosarcoma tissues', 'Disease', 'MESH:D012516', (50, 70))	('high', 'Var', (75, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('osteosarcoma', 'Phenotype', 'HP:0002669', (217, 229))	('osteosarcoma', 'Disease', 'MESH:D012516', (50, 62))	('osteosarcoma', 'Disease', 'MESH:D012516', (217, 229))	('patients', 'Species', '9606', (203, 211))	('upregulated', 'PosReg', (35, 46))	('osteosarcoma', 'Disease', (50, 62))	('metastasis', 'CPA', (116, 126))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('CBX2', 'Gene', (14, 18))	('correlated', 'Reg', (100, 110))	('CBX2', 'Gene', (80, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
412835	31150156	Further experiments revealed that CBX2 knockdown significantly impeded osteosarcoma cell proliferation and invasion ability in vitro, and suppressed the tumor growth in tumor xenografts model.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('knockdown', 'Var', (39, 48))	('invasion ability in vitro', 'CPA', (107, 132))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('osteosarcoma cell', 'Disease', 'MESH:D012516', (71, 88))	('CBX2', 'Gene', (34, 38))	('impeded', 'NegReg', (63, 70))	('tumor', 'Disease', (169, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('suppressed', 'NegReg', (138, 148))	('osteosarcoma cell', 'Disease', (71, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))
412843	31150156	Here we report that CBX2 is markedly upregulated in osteosarcoma and high CBX2 expression predicts poor clinical outcomes in osteosarcoma.	('upregulated', 'PosReg', (37, 48))	('expression', 'MPA', (79, 89))	('CBX2', 'Gene', (74, 78))	('osteosarcoma', 'Disease', (52, 64))	('osteosarcoma', 'Phenotype', 'HP:0002669', (52, 64))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('CBX2', 'Gene', (20, 24))	('osteosarcoma', 'Disease', (125, 137))	('osteosarcoma', 'Disease', 'MESH:D012516', (52, 64))	('high', 'Var', (69, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
412845	31150156	We further revealed the marked positive association between high CBX2 expression and the activation of DNA replication and cell cycle pathway in TCGA sarcoma cohort, indicating that CBX2 may play oncogenic role in osteosarcoma progression through regulating DNA replication and cell cycle.	('osteosarcoma', 'Disease', 'MESH:D012516', (214, 226))	('cell cycle', 'CPA', (278, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('sarcoma cohort', 'Disease', (150, 164))	('high', 'Var', (60, 64))	('DNA replication', 'CPA', (258, 273))	('cell cycle pathway', 'Pathway', (123, 141))	('DNA replication', 'CPA', (103, 118))	('expression', 'MPA', (70, 80))	('regulating', 'Reg', (247, 257))	('activation', 'PosReg', (89, 99))	('CBX2', 'Gene', (182, 186))	('sarcoma cohort', 'Disease', 'MESH:D012509', (150, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('osteosarcoma', 'Disease', (214, 226))	('CBX2', 'Gene', (65, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (214, 226))
412886	31150156	Next, cell counting kit-8 (CCK-8) assays were conducted to assess the influence of CBX2 silencing on osteosarcoma cell proliferation.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('osteosarcoma cell', 'Disease', 'MESH:D012516', (101, 118))	('osteosarcoma cell', 'Disease', (101, 118))	('silencing', 'Var', (88, 97))	('osteosarcoma', 'Phenotype', 'HP:0002669', (101, 113))	('CBX2', 'Gene', (83, 87))
412887	31150156	Furthermore, we found that CBX2 silencing could significantly decrease EdU incorporation rate in osteosarcoma cells via EdU incorporation assays (Figure 3E).	('osteosarcoma cell', 'Disease', 'MESH:D012516', (97, 114))	('CBX2', 'Gene', (27, 31))	('osteosarcoma cell', 'Disease', (97, 114))	('silencing', 'Var', (32, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('decrease', 'NegReg', (62, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('EdU incorporation rate', 'CPA', (71, 93))
412888	31150156	Moreover, we examined whether CBX2 knockdown could influence the invasion ability of osteosarcoma cells by Matrigel invasion assay.	('knockdown', 'Var', (35, 44))	('osteosarcoma cell', 'Disease', (85, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('invasion ability of', 'CPA', (65, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('CBX2', 'Gene', (30, 34))	('influence', 'Reg', (51, 60))	('osteosarcoma cell', 'Disease', 'MESH:D012516', (85, 102))
412892	31150156	Consistently, the average tumor luciferase activity and tumor weight were significantly decreased after CBX2 knockdown (Figure 4C,D).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('knockdown', 'Var', (109, 118))	('CBX2', 'Gene', (104, 108))	('activity', 'MPA', (43, 51))	('decreased', 'NegReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
412893	31150156	In addition, CBX2 and ki-67 were assessed using IHC analysis in xenograft tumor tissues and results revealed that both CBX2 and Ki-67 staining intensities were markedly decreased in the tumors from the sh-CBX2 group (Figure 4E-G).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('sh-CBX2', 'Var', (202, 209))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('staining intensities', 'MPA', (134, 154))	('CBX2', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (186, 191))	('tumors', 'Disease', (186, 192))	('tumor', 'Disease', (74, 79))	('Ki-67', 'Gene', (128, 133))	('decreased', 'NegReg', (169, 178))	('tumors', 'Disease', 'MESH:D009369', (186, 192))
412895	31150156	Previous studies have revealed that numerous miRNAs are dysregulated and contributed to the initiation and development of the osteosarcoma; we hypothesized that miRNA might be involved in the mechanism of CBX2 dysregulation in osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('osteosarcoma', 'Disease', (126, 138))	('osteosarcoma', 'Disease', (227, 239))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('osteosarcoma', 'Phenotype', 'HP:0002669', (227, 239))	('osteosarcoma', 'Disease', 'MESH:D012516', (227, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('involved', 'Reg', (176, 184))	('dysregulation', 'Var', (210, 223))
412896	31150156	According to the comprehensive analysis results, miRNA let-7a, a well-known tumor suppressor, was chosen for further validation.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('miRNA', 'Var', (49, 54))	('let-7a', 'Chemical', '-', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
412900	31150156	Additionally, we transfected let-7a mimics into well5 and 143B cells and qPCR results showed that CBX2 was downregulated in well5 and 143B cells treated with let-7a mimics (Figure 5C).	('let-7a', 'Chemical', '-', (29, 35))	('CBX2', 'Gene', (98, 102))	('let-7a', 'Var', (158, 164))	('downregulated', 'NegReg', (107, 120))	('let-7a', 'Chemical', '-', (158, 164))
412918	31150156	Consistent with this notion, invasive ability of osteosarcoma cell was dramatically suppressed following CBX2 knockdown.	('knockdown', 'Var', (110, 119))	('osteosarcoma cell', 'Disease', (49, 66))	('CBX2', 'Gene', (105, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (49, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('osteosarcoma cell', 'Disease', 'MESH:D012516', (49, 66))	('suppressed', 'NegReg', (84, 94))
412923	31150156	let-7a is proven to be a significantly decreased miRNA in different tumors.	('let-7a', 'Chemical', '-', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Disease', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('miRNA', 'MPA', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('decreased', 'NegReg', (39, 48))	('let-7a', 'Var', (0, 6))
412924	31150156	As a tumor suppressor miRNA, let-7a was found to be downregulated in osteosarcoma tissues than in the normal bone tissues,18 and let-7a could suppress the cancer cell proliferation through inhibiting it's downstream oncogenes such as RAS, CCR7, E2F2, and CCDN2.7, 27, 28 Here, we show that let-7a targets CBX2 as well and represses its expression.	('CCR7', 'Gene', (239, 243))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('let-7a', 'Chemical', '-', (29, 35))	('inhibiting', 'NegReg', (189, 199))	('osteosarcoma tissues', 'Disease', 'MESH:D012516', (69, 89))	('represses', 'NegReg', (322, 331))	('osteosarcoma tissues', 'Disease', (69, 89))	('CCR7', 'Gene', '1236', (239, 243))	('let-7a', 'Gene', (290, 296))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('expression', 'MPA', (336, 346))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CBX2', 'Gene', (305, 309))	('let-7a', 'Chemical', '-', (290, 296))	('suppress', 'NegReg', (142, 150))	('E2F2', 'Gene', (245, 249))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('E2F2', 'Gene', '1870', (245, 249))	('let-7a', 'Var', (129, 135))	('cancer', 'Disease', (155, 161))	('let-7a', 'Chemical', '-', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('downregulated', 'NegReg', (52, 65))	('let-7a', 'Gene', (29, 35))	('tumor', 'Disease', (5, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
413018	26457233	Refractory myeloid sarcoma with a FIP1L1-PDGFRA rearrangement detected by clinical high throughput somatic sequencing Next generation sequencing (NGS) is increasingly being used clinically to characterize the molecular alterations found in patients' tumors.	('PDGFRA', 'Gene', (41, 47))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (11, 26))	('PDGFRA', 'Gene', '5156', (41, 47))	('rearrangement', 'Var', (48, 61))	('FIP1L1', 'Gene', '81608', (34, 40))	('FIP1L1', 'Gene', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('myeloid sarcoma', 'Disease', (11, 26))	('patients', 'Species', '9606', (240, 248))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))
413020	26457233	Our clinical NGS assay detected an unanticipated FIP1L1-PDGFRA rearrangement in his tumor.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('rearrangement', 'Var', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('PDGFRA', 'Gene', '5156', (56, 62))	('PDGFRA', 'Gene', (56, 62))	('tumor', 'Disease', (84, 89))	('FIP1L1', 'Gene', '81608', (49, 55))	('FIP1L1', 'Gene', (49, 55))
413022	26457233	As cancer therapeutics increasingly target molecular alterations, testing for somatic changes in cancer is becoming an integral part of pathology evaluations.	('molecular', 'Var', (43, 52))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
413023	26457233	While these somatic alterations may only be present in a small subset of a given tumor type, patients with these genetic changes often show dramatic responses when treated with targeted agents.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('patients', 'Species', '9606', (93, 101))	('tumor', 'Disease', (81, 86))	('genetic changes', 'Var', (113, 128))
413026	26457233	Moreover, these gene panels for somatic testing can identify unexpected genetic changes in cancer types not generally associated with a given somatic alteration.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('genetic changes', 'Var', (72, 87))
413027	26457233	At the Center for Advanced Molecular Diagnostics (CAMD) at Brigham and Women's Hospital, a targeted next generation sequencing assay (OncoPanel) is performed in a Clinical Laboratory Improvement Amendments-certified laboratory to detect somatic mutations, copy number variations, and structural variants across 300 cancer-associated genes.	('detect', 'Reg', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('CAMD', 'Disease', (50, 54))	('cancer', 'Disease', (315, 321))	('copy number variations', 'Var', (256, 278))	('CAMD', 'Disease', 'None', (50, 54))	('structural variants', 'Var', (284, 303))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('Women', 'Species', '9606', (71, 76))
413036	26457233	A biopsy of a left neck lymph node was performed and flow cytometry found that 10 % of the cells were phenotypically were positive for CD34, CD45(dim), HLA-DR, CD56, CD34, and myeloid markers CD13, CD33, and CD117, and negative for TdT, CD11b, CD15, and other monocytic, B and T lymphoid markers, consistent with myeloblasts.	('CD34', 'Gene', '947', (166, 170))	('CD13', 'Gene', '290', (192, 196))	('CD117', 'Gene', (208, 213))	('CD33', 'Gene', '945', (198, 202))	('TdT', 'Gene', '1791', (232, 235))	('CD33', 'Gene', (198, 202))	('CD34', 'Gene', (166, 170))	('CD11b', 'Gene', (237, 242))	('CD11b', 'Gene', '3684', (237, 242))	('CD34', 'Gene', (135, 139))	('CD15', 'Gene', (244, 248))	('CD13', 'Gene', (192, 196))	('CD56', 'Gene', (160, 164))	('HLA-DR', 'Var', (152, 158))	('CD45', 'Gene', (141, 145))	('CD56', 'Gene', '4684', (160, 164))	('CD117', 'Gene', '3815', (208, 213))	('CD45', 'Gene', '5788', (141, 145))	('TdT', 'Gene', (232, 235))	('CD15', 'Gene', '2526', (244, 248))	('CD34', 'Gene', '947', (135, 139))
413037	26457233	Cytogenetics showed trisomy 8, and a diagnosis of myeloid sarcoma was rendered.	('myeloid sarcoma', 'Disease', (50, 65))	('showed', 'Reg', (13, 19))	('trisomy 8', 'Var', (20, 29))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (50, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
413045	26457233	Targeted next generation sequence analysis by OncoPanel detected 6 heterozygous single nucleotide variants or small insertions/deletions, including KRAS c.38G>A p.G13D, ARID1B c.165_177CCAGCAGCAGCAG>C p.QQQQ68del, EPHA7 c.2042G>A p.C681Y, FANCA c.2712G>C p.Q904H, GATA4 c.124C>A p.P42T, and MSH6 c.359T>C p.I120T.	('c.359T>C', 'Mutation', 'rs587781275', (296, 304))	('p.QQQQ68del', 'Mutation', 'p.68delQQQQ', (201, 212))	('FANCA', 'Gene', '2175', (239, 244))	('c.165_177CCAGCAGCAGCAG>C', 'Mutation', 'c.165_177CCAGCAGCAGCAG>C', (176, 200))	('GATA4', 'Gene', (264, 269))	('p.C681Y', 'Mutation', 'rs771918424', (230, 237))	('p.P42T', 'Mutation', 'rs34014629', (279, 285))	('EPHA7', 'Gene', '2045', (214, 219))	('FANCA', 'Gene', (239, 244))	('c.124C>A', 'Mutation', 'rs980252090', (270, 278))	('c.2042G>A', 'Mutation', 'rs771918424', (220, 229))	('c.38G>A', 'Mutation', 'rs750214622', (153, 160))	('MSH6', 'Gene', (291, 295))	('c.124C>A p.P42T', 'Var', (270, 285))	('MSH6', 'Gene', '2956', (291, 295))	('c.165_177CCAGCAGCAGCAG', 'Var', (176, 198))	('p.G13D', 'Mutation', 'rs750214622', (161, 167))	('p.I120T', 'Mutation', 'rs775971872', (305, 312))	('GATA4', 'Gene', '2626', (264, 269))	('p.Q904H', 'Mutation', 'rs945821823', (255, 262))	('c.359T>C p.I120T', 'Var', (296, 312))	('ARID1B', 'Gene', (169, 175))	('c.2712G>C p.Q904H', 'Var', (245, 262))	('ARID1B', 'Gene', '57492', (169, 175))	('EPHA7', 'Gene', (214, 219))	('c.2712G>C', 'Mutation', 'rs945821823', (245, 254))
413046	26457233	Copy number analysis from Oncopanel confirmed cytogenetic findings that the patient's myeloid sarcoma contained trisomy 8.	('myeloid sarcoma', 'Disease', 'MESH:D023981', (86, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('myeloid sarcoma', 'Disease', (86, 101))	('patient', 'Species', '9606', (76, 83))	('trisomy', 'Var', (112, 119))
413050	26457233	In this assay, FIP1L1-PDGFRA fusion is indicated by isolated deletion of LNX with retention of the flanking SCFD2 and PDGFRA probes.	('FIP1L1', 'Gene', '81608', (15, 21))	('SCFD2', 'Gene', '152579', (108, 113))	('FIP1L1', 'Gene', (15, 21))	('LNX', 'Gene', '84708', (73, 76))	('deletion', 'Var', (61, 69))	('PDGFRA', 'Gene', (118, 124))	('SCFD2', 'Gene', (108, 113))	('PDGFRA', 'Gene', '5156', (118, 124))	('PDGFRA', 'Gene', '5156', (22, 28))	('PDGFRA', 'Gene', (22, 28))	('LNX', 'Gene', (73, 76))
413052	26457233	Moreover, the cells with a detected FIP1L1-PDGFRA rearrangement also contained trisomy 8, which was a previously demonstrated marker of this patient's myeloid sarcoma.	('FIP1L1', 'Gene', (36, 42))	('FIP1L1', 'Gene', '81608', (36, 42))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (151, 166))	('trisomy', 'Var', (79, 86))	('myeloid sarcoma', 'Disease', (151, 166))	('patient', 'Species', '9606', (141, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('PDGFRA', 'Gene', (43, 49))	('contained', 'Reg', (69, 78))	('rearrangement', 'Var', (50, 63))	('PDGFRA', 'Gene', '5156', (43, 49))
413059	26457233	The finding of a FIP1L1-PDGFRA rearrangement in a patient with refractory myeloid sarcoma was an unexpected finding only discovered because of clinical gene panel testing that is performed on all malignancies presenting to our institution.	('PDGFRA', 'Gene', '5156', (24, 30))	('myeloid sarcoma', 'Disease', (74, 89))	('PDGFRA', 'Gene', (24, 30))	('malignancies', 'Disease', 'MESH:D009369', (196, 208))	('rearrangement', 'Var', (31, 44))	('FIP1L1', 'Gene', '81608', (17, 23))	('FIP1L1', 'Gene', (17, 23))	('malignancies', 'Disease', (196, 208))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (74, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('patient', 'Species', '9606', (50, 57))
413064	26457233	The FIP1L1-PDGFRA fusion results in a constitutively activated tyrosine kinase and, in hematopoietic cells, results in growth factor-independent growth.	('tyrosine', 'Enzyme', (63, 71))	('results in', 'Reg', (108, 118))	('PDGFRA', 'Gene', (11, 17))	('PDGFRA', 'Gene', '5156', (11, 17))	('FIP1L1', 'Gene', (4, 10))	('fusion', 'Var', (18, 24))	('FIP1L1', 'Gene', '81608', (4, 10))	('growth factor-independent', 'CPA', (119, 144))	('constitutively', 'MPA', (38, 52))
413068	26457233	The diagnosis of acute myeloid leukemia or myeloid sarcoma with a FIP1L1-PDGFRA rearrangement is extremely rare, with only a handful of case reports in the literature.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (23, 39))	('leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('myeloid sarcoma', 'Disease', (43, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('PDGFRA', 'Gene', (73, 79))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (17, 39))	('PDGFRA', 'Gene', '5156', (73, 79))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (43, 58))	('acute myeloid leukemia', 'Disease', (17, 39))	('rearrangement', 'Var', (80, 93))	('FIP1L1', 'Gene', '81608', (66, 72))	('FIP1L1', 'Gene', (66, 72))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (17, 39))
413069	26457233	The largest case series of patients with AML and a FIP1L1-PDGFRA rearrangement consists of 5 patients, all of whom achieved complete molecular remission with imatinib.	('PDGFRA', 'Gene', (58, 64))	('patients', 'Species', '9606', (93, 101))	('PDGFRA', 'Gene', '5156', (58, 64))	('rearrangement', 'Var', (65, 78))	('patients', 'Species', '9606', (27, 35))	('AML', 'Disease', 'MESH:D015470', (41, 44))	('FIP1L1', 'Gene', '81608', (51, 57))	('FIP1L1', 'Gene', (51, 57))	('AML', 'Disease', (41, 44))	('imatinib', 'Chemical', 'MESH:D000068877', (158, 166))
413070	26457233	All of the patients described had histories of peripheral eosinophilia, which prompted targeted testing for the FIP1L1-PDGFRA rearrangement, since this rearrangement is cryptic and cannot be detected by conventional karyotype.	('PDGFRA', 'Gene', '5156', (119, 125))	('FIP1L1', 'Gene', (112, 118))	('rearrangement', 'Var', (126, 139))	('FIP1L1', 'Gene', '81608', (112, 118))	('peripheral eosinophilia', 'Disease', 'MESH:D004802', (47, 70))	('eosinophilia', 'Phenotype', 'HP:0001880', (58, 70))	('peripheral eosinophilia', 'Disease', (47, 70))	('patients', 'Species', '9606', (11, 19))	('PDGFRA', 'Gene', (119, 125))
413074	26457233	As the number of therapeutics targeting specific genetic alterations increases and the use of gene panel testing for somatic changes expands, this scenario of unanticipated findings dramatically affecting a patient's clinical course is bound to be repeated to the benefit of cancer patients.	('affecting', 'Reg', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('alterations', 'Var', (57, 68))	('patient', 'Species', '9606', (282, 289))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('patient', 'Species', '9606', (207, 214))	('patients', 'Species', '9606', (282, 290))	('cancer', 'Disease', (275, 281))
413111	24213130	Many sarcoma subtypes harbor attractive targets for immune-mediated strategies due to the presence of specific epitopes, either based on cell of origin or alterations of gene products, leading to ongoing enthusiasm for this technique.	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('alterations', 'Var', (155, 166))	('sarcoma subtypes', 'Disease', (5, 21))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (5, 21))
413120	24213130	Inhibitory cell surface components on infiltrating lymphocytes, such as PD-1 and CTLA-4 have been determined, with their presence resulting in CTL suppression.	('CTL', 'MPA', (143, 146))	('presence', 'Var', (121, 129))	('CTLA-4', 'Gene', '1493', (81, 87))	('PD', 'Disease', 'MESH:D010300', (72, 74))	('CTLA-4', 'Gene', (81, 87))	('suppression', 'NegReg', (147, 158))
413137	24213130	L-MTP-PE was chosen for its utility as a monocyte/macrophage activator, with downstream activation of other components of the immune response.	('L-MTP-PE', 'Var', (0, 8))	('activation', 'PosReg', (88, 98))	('L-MTP-PE', 'Chemical', '-', (0, 8))
413140	24213130	Unfortunately, for patients with metastatic disease, L-MTP-PE did not achieve a statistically significant improvement in outcome.	('metastatic disease', 'Disease', (33, 51))	('L-MTP-PE', 'Var', (53, 61))	('patients', 'Species', '9606', (19, 27))	('L-MTP-PE', 'Chemical', '-', (53, 61))
413186	23936488	These included deletions of the tumor suppressor genes CDKN2A/B, RB1 and PTEN .	('PTEN', 'Gene', (73, 77))	('RB1', 'Gene', (65, 68))	('deletions', 'Var', (15, 24))	('PTEN', 'Gene', '403832', (73, 77))	('CDKN2A/B', 'Gene', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('RB1', 'Gene', '476915', (65, 68))	('CDKN2A/B', 'Gene', '100271861;481563', (55, 63))	('tumor', 'Disease', (32, 37))
413188	23936488	Another study concluded that deregulation of the expression of the glycation end products (Receptor for Advanced Glycation Endproducts; RAGE) and the high mobility group box1 protein (HMGB1) potentially have a major effect on the progression of malignant histiocytic disorders.	('effect', 'Reg', (216, 222))	('glycation end products', 'MPA', (67, 89))	('RAGE', 'Gene', (136, 140))	('high mobility group box1', 'Gene', (150, 174))	('malignant histiocytic disorders', 'Disease', (245, 276))	('malignant histiocytic disorders', 'Disease', 'MESH:D015620', (245, 276))	('RAGE', 'Gene', '403168', (136, 140))	('expression', 'MPA', (49, 59))	('high mobility group box1', 'Gene', '403170', (150, 174))	('HMGB1', 'Gene', (184, 189))	('deregulation', 'Var', (29, 41))	('HMGB1', 'Gene', '403170', (184, 189))
413263	30697061	ES is a fusion-associated malignancy with recurrent translocations between EWSR1 and members of the ETS family of transcription factors, most commonly FLI1.	('FLI1', 'Gene', '2313', (151, 155))	('EWSR1', 'Gene', '2130', (75, 80))	('FLI1', 'Gene', (151, 155))	('translocations', 'Var', (52, 66))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('EWSR1', 'Gene', (75, 80))	('malignancy', 'Disease', 'MESH:D009369', (26, 36))	('malignancy', 'Disease', (26, 36))
413265	30697061	Recurrent oncogenic mutations have been noted, however, in several tumor suppressors including STAG2 (15%-22%), TP53 (6%-7%), and CDKN2A (12%-28%).	('CDKN2A', 'Gene', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('CDKN2A', 'Gene', '1029', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('STAG2', 'Gene', (95, 100))	('TP53', 'Gene', '7157', (112, 116))	('tumor', 'Disease', (67, 72))	('STAG2', 'Gene', '10735', (95, 100))	('mutations', 'Var', (20, 29))	('TP53', 'Gene', (112, 116))
413267	30697061	A large case-control study of 1,162 patients with a variety of sarcoma subtypes found a high burden of likely pathogenic germline alterations in sarcoma patients relative to a control population with variants in TP53, ATM, ATR, BRCA2, and ERCC2 being commonly represented.	('pathogenic', 'Reg', (110, 120))	('sarcoma', 'Disease', (63, 70))	('ATM', 'Gene', (218, 221))	('ATR', 'Gene', (223, 226))	('ERCC2', 'Gene', (239, 244))	('patients', 'Species', '9606', (36, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('ERCC2', 'Gene', '2068', (239, 244))	('variants', 'Var', (200, 208))	('TP53', 'Gene', '7157', (212, 216))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('sarcoma', 'Disease', (145, 152))	('BRCA2', 'Gene', (228, 233))	('ATR', 'Gene', '545', (223, 226))	('ATM', 'Gene', '472', (218, 221))	('patients', 'Species', '9606', (153, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('BRCA2', 'Gene', '675', (228, 233))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('TP53', 'Gene', (212, 216))
413268	30697061	Focusing on the ES population, a germline sequencing study utilizing whole-genome or whole-exome sequencing in 175 patients with ES identified pathogenic or likely pathogenic mutations in 13.1% of patients, with significant enrichment in genes involved in hereditary breast cancer and DNA repair pathways.	('breast cancer', 'Phenotype', 'HP:0003002', (267, 280))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (197, 205))	('DNA repair pathways', 'Pathway', (285, 304))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (256, 280))	('ES', 'Phenotype', 'HP:0012254', (16, 18))	('mutations', 'Var', (175, 184))	('ES', 'Phenotype', 'HP:0012254', (129, 131))	('pathogenic', 'Reg', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('pathogenic', 'Reg', (143, 153))	('hereditary breast cancer', 'Disease', (256, 280))
413270	30697061	Germline alterations in more common cancers such as ovarian, breast, and colon have led to personalized medicine strategies unique to the individual's cancer biology.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('colon', 'Disease', 'MESH:D015179', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('led to', 'Reg', (84, 90))	('ovarian', 'Disease', (52, 59))	('cancers', 'Disease', (36, 43))	('cancer', 'Disease', (36, 42))	('alterations', 'Var', (9, 20))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('ovarian', 'Disease', 'MESH:D010051', (52, 59))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('colon', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast', 'Disease', (61, 67))
413285	30697061	Since the IGF-1R pathway is deregulated by the EWSR1-FLI1 translocation, it has come under the spotlight as a potential target for therapy.	('EWSR1', 'Gene', '2130', (47, 52))	('deregulated', 'Reg', (28, 39))	('translocation', 'Var', (58, 71))	('FLI1', 'Gene', '2313', (53, 57))	('EWSR1', 'Gene', (47, 52))	('FLI1', 'Gene', (53, 57))	('IGF-1R', 'Gene', '3480', (10, 16))	('IGF-1R', 'Gene', (10, 16))
413297	30697061	In both in vitro and in vivo disease models, inhibition of LSD1 leads to a reversal of the EWS-FLI1 transcriptional profile and shows significant single-agent activity.	('LSD1', 'Gene', '23028', (59, 63))	('transcriptional profile', 'MPA', (100, 123))	('EWS', 'Gene', '2130', (91, 94))	('EWS', 'Gene', (91, 94))	('inhibition', 'Var', (45, 55))	('FLI1', 'Gene', (95, 99))	('LSD1', 'Gene', (59, 63))	('reversal', 'Reg', (75, 83))	('FLI1', 'Gene', '2313', (95, 99))
413306	30697061	Of the three most highly recurrent mutations in STAG2, CDKN2A, and TP53, there are conflicting data at present on the prognostic utility of these findings.	('CDKN2A', 'Gene', '1029', (55, 61))	('STAG2', 'Gene', '10735', (48, 53))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('CDKN2A', 'Gene', (55, 61))	('STAG2', 'Gene', (48, 53))	('mutations', 'Var', (35, 44))
413307	30697061	Initial landscape genomics studies suggested that STAG2 mutation, particularly the combination of STAG2 and TP53 mutations, is a poor prognostic indicator; however, this finding was not confirmed in a follow-up study using an independent cohort.	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('STAG2', 'Gene', (98, 103))	('mutations', 'Var', (113, 122))	('STAG2', 'Gene', '10735', (50, 55))	('STAG2', 'Gene', (50, 55))	('STAG2', 'Gene', '10735', (98, 103))
413308	30697061	Similarly, there are conflicting studies regarding whether CDKN2A deletion is associated with poor prognosis.	('CDKN2A', 'Gene', (59, 65))	('deletion', 'Var', (66, 74))	('CDKN2A', 'Gene', '1029', (59, 65))
413310	30697061	Several efforts utilizing RT-PCR methodology have shown the ability to detect fusion transcript in the peripheral blood or bone marrow of patients with both localized and metastatic disease.	('detect', 'Reg', (71, 77))	('fusion', 'Var', (78, 84))	('patients', 'Species', '9606', (138, 146))
413319	30477180	Cereus jamacaru D.C. Hydroalcoholic Extract Promotes Anti-Cytotoxic and Antitumor Activity Cereus jamacaru D.C. (mandacaru) is a cactus used as food and in the traditional medicine.	('Cereus jamacaru D.C.', 'Var', (91, 111))	('Cytotoxic', 'Disease', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Cereus jamacaru', 'Species', '1574107', (91, 106))	('Cytotoxic', 'Disease', 'MESH:D064420', (58, 67))	('Antitumor Activity', 'CPA', (72, 90))	('Promotes', 'PosReg', (44, 52))	('Cereus jamacaru', 'Species', '1574107', (0, 15))
413324	30477180	Following in vivo assays, C. jamacaru promoted tumor reduction (86.07% of tumor inhibition), without inducing mutagenic or cytotoxic damage on mice blood cells.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('reduction', 'NegReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('C. jamacaru', 'Var', (26, 37))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('jamacaru', 'Species', '1586200', (29, 37))	('tumor', 'Disease', (47, 52))	('mice', 'Species', '10090', (143, 147))
413352	30477180	The cells were cultured with C. jamacaru extract for 24 h or 48 h. In order to allow the evaluation of the anti-cytotoxicity, human lymphocytes were treated with C. jamacaru extract more cisplatin following the protocols of pre-treatment, simultaneous treatment and post-treatment.	('human', 'Species', '9606', (126, 131))	('cisplatin', 'MPA', (187, 196))	('cytotoxicity', 'Disease', (112, 124))	('C. jamacaru', 'Var', (162, 173))	('jamacaru', 'Species', '1586200', (165, 173))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('jamacaru', 'Species', '1586200', (32, 40))
413514	29898687	Antibodies were utilized with the following dilution: PD-L1 (1:100), CD3 (1:100), CD20 (1:400), CD68 (1:3000), CD163 (1:200), CD57 (1:100), CD56 (1:400).	('CD68', 'Gene', '968', (96, 100))	('CD20', 'Gene', '54474', (82, 86))	('CD20', 'Gene', (82, 86))	('1:100', 'Var', (132, 137))	('1:3000', 'Var', (102, 108))	('CD56', 'Gene', (140, 144))	('CD57', 'Gene', (126, 130))	('CD163', 'Gene', '9332', (111, 116))	('CD57', 'Gene', '27087', (126, 130))	('CD163', 'Gene', (111, 116))	('CD56', 'Gene', '4684', (140, 144))	('CD68', 'Gene', (96, 100))
413525	29898687	Of the 15 RMS displaying PDL1 expression 5 RMS scored IC3, 8 RMS had IC2 and only one RMS showing occasional PD-L1 expression in single immune cells outside the tumor burden (IC1).	('IC1', 'Gene', '105259599', (175, 178))	('RMS', 'Phenotype', 'HP:0002859', (61, 64))	('PDL1', 'Gene', '29126', (25, 29))	('RMS', 'Phenotype', 'HP:0002859', (10, 13))	('RMS', 'Phenotype', 'HP:0002859', (86, 89))	('expression', 'Var', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('IC1', 'Gene', (175, 178))	('PDL1', 'Gene', (25, 29))	('IC2', 'Gene', (69, 72))	('IC2', 'Gene', '1781', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('IC3', 'Disease', (54, 57))	('tumor', 'Disease', (161, 166))	('RMS', 'Phenotype', 'HP:0002859', (43, 46))
413540	29898687	Moreover, RMS18, RMS22 and RMS24 were all ERMS tissues obtained at diagnosis, while RMS19, RMS23 and RMS25 were their corresponding tumor progression post several lines of treatment (possible cycle treatments: Vincristine and Irinotecan, Vinorelbine and Endoxan, Ifosfamide/Doxorubicina/Actinomicina and Ciclofosfamide/ Doxorubicina/ Vincristina).	('Ifosfamide', 'Chemical', 'MESH:D007069', (263, 273))	('Vinorelbine', 'Chemical', 'MESH:D000077235', (238, 249))	('tumor', 'Disease', (132, 137))	('RMS19', 'Var', (84, 89))	('Irinotecan', 'Chemical', 'MESH:D000077146', (226, 236))	('RMS', 'Phenotype', 'HP:0002859', (84, 87))	('Ciclofosfamide', 'Chemical', 'MESH:D003520', (304, 318))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('RMS', 'Phenotype', 'HP:0002859', (27, 30))	('Endoxan', 'Chemical', 'MESH:D003520', (254, 261))	('RMS2', 'Gene', (101, 105))	('Doxorubicina', 'Chemical', 'MESH:D004317', (274, 286))	('Vincristine', 'Chemical', 'MESH:D014750', (210, 221))	('RMS', 'Phenotype', 'HP:0002859', (43, 46))	('RMS2', 'Gene', (27, 31))	('RMS18', 'Var', (10, 15))	('RMS2', 'Gene', '5081', (101, 105))	('RMS', 'Phenotype', 'HP:0002859', (17, 20))	('Actinomicina', 'Chemical', '-', (287, 299))	('RMS', 'Phenotype', 'HP:0002859', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Vincristina', 'Chemical', 'MESH:D014750', (334, 345))	('RMS2', 'Gene', '5081', (27, 31))	('RMS2', 'Gene', (91, 95))	('RMS2', 'Gene', (17, 21))	('RMS2', 'Gene', '5081', (91, 95))	('Doxorubicina', 'Chemical', 'MESH:D004317', (320, 332))	('RMS2', 'Gene', '5081', (17, 21))
413547	29898687	Current studies have pointed out that high expression of PD-L1 in tumor cells is associated with poor prognosis in NSCLC, ovarian cancer and kidney cancer, melanoma, renal cancer, Hodgkin lymphoma and bone and soft tissue sarcoma.	('ovarian cancer', 'Disease', 'MESH:D010051', (122, 136))	('soft tissue sarcoma', 'Disease', (210, 229))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('PD-L1', 'Gene', (57, 62))	('renal cancer', 'Disease', 'MESH:D007680', (166, 178))	('tumor', 'Disease', (66, 71))	('ovarian cancer', 'Disease', (122, 136))	('high', 'Var', (38, 42))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('Hodgkin lymphoma', 'Disease', (180, 196))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('NSCLC', 'Disease', (115, 120))	('kidney cancer', 'Disease', 'MESH:D007680', (141, 154))	('lymphoma', 'Phenotype', 'HP:0002665', (188, 196))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (180, 196))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (180, 196))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('renal cancer', 'Disease', (166, 178))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('kidney cancer', 'Phenotype', 'HP:0009726', (141, 154))	('renal cancer', 'Phenotype', 'HP:0009726', (166, 178))	('kidney cancer', 'Disease', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (210, 229))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (210, 229))
413570	28101017	HPV proteins (mainly E6 and E7) seem to act synergistically with ultraviolet (UV) radiation in reducing the defensive mechanisms of keratinocyte apoptosis after UV damage.	('HPV', 'Species', '10566', (0, 3))	('E7', 'Var', (28, 30))	('defensive mechanisms of keratinocyte apoptosis', 'CPA', (108, 154))	('reducing', 'NegReg', (95, 103))
413586	28101017	HPV proteins (mainly E6 and E7) seem to act synergistically with UV radiation in reducing the defensive mechanisms of keratinocyte apoptosis after UV damage.	('reducing', 'NegReg', (81, 89))	('E7', 'Var', (28, 30))	('defensive mechanisms of keratinocyte apoptosis', 'CPA', (94, 140))	('HPV', 'Species', '10566', (0, 3))
413599	28101017	In addition, the subject reported severe allergic contact dermatitis of the hands and feet, with positive patch tests to several components (perfume mix, p-fenylenediamine, and Sudan yellow color).	('p-fenylenediamine', 'Chemical', '-', (154, 171))	('dermatitis', 'Phenotype', 'HP:0011123', (58, 68))	('contact dermatitis', 'Phenotype', 'HP:0032282', (50, 68))	('p-fenylenediamine', 'Var', (154, 171))	('dermatitis', 'Disease', 'MESH:D003872', (58, 68))	('dermatitis', 'Disease', (58, 68))
413620	23598961	Desktop Transcriptome Sequencing From Archival Tissue to Identify Clinically Relevant Translocations Somatic mutations, often translocations or single nucleotide variations, are pathognomonic for certain types of cancers and are increasingly of clinical importance for diagnosis and prediction of response to therapy.	('pathognomonic', 'Reg', (178, 191))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('single nucleotide variations', 'Var', (144, 172))	('clinical', 'Species', '191496', (245, 253))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('translocations', 'Var', (126, 140))	('cancers', 'Disease', (213, 220))	('Translocations', 'Var', (86, 100))
413622	23598961	Genome-wide or transcriptome-wide high-throughput sequencing (HTS) of clinical samples offers an opportunity to evaluate for all clinically significant mutations with a single test.	('evaluate', 'Reg', (112, 120))	('mutations', 'Var', (152, 161))	('clinical samples', 'Species', '191496', (70, 86))	('clinical', 'Species', '191496', (70, 78))	('clinical', 'Species', '191496', (129, 137))
413623	23598961	In this study, we demonstrate, as a proof of principle, that translocations in sarcomas can be diagnosed from formalin-fixed paraffin-embedded (FFPE) tissue with desktop HTS.	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Disease', (79, 87))	('paraffin', 'Chemical', 'MESH:D010232', (125, 133))	('translocations', 'Var', (61, 75))	('formalin', 'Chemical', 'MESH:D005557', (110, 118))
413632	23598961	The vast majority of clinically relevant nucleic acid variations (mutations, fusions, etc.)	('mutations', 'Var', (66, 75))	('nucleic acid variations', 'Var', (41, 64))	('clinical', 'Species', '191496', (21, 29))	('fusions', 'Var', (77, 84))
413640	23598961	In this study we focus on gene fusions and sarcomas because of the pathognomonic translocations that characterize many of these cancers, the clinical utility of identifying these translocations, and the resultant battery of molecular tests that have been created to achieve this end.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('clinical', 'Species', '191496', (141, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gene fusions', 'Var', (26, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcomas', 'Disease', (43, 51))
413641	23598961	In the past 2 decades, fusions involving over 60 different genes have been described as characteristic molecular events in 19 sarcomas (COSMIC database, November 15, 2011).	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('fusions', 'Var', (23, 30))	('19 sarcomas', 'Disease', 'MESH:D012509', (123, 134))	('19 sarcomas', 'Disease', (123, 134))
413642	23598961	Currently in the clinical setting, translocations in sarcomas are diagnosed by FISH or reverse transcriptase PCR (RT-PCR).	('translocations', 'Var', (35, 49))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcomas', 'Disease', (53, 61))	('clinical', 'Species', '191496', (17, 25))
413663	23598961	High-quality reads were aligned to the 83 genes involved in known translocations and mutations in sarcomas (the "sarcomatome") according to the COSMIC database (date November 15, 2011).	('sarcomas', 'Disease', (98, 106))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcoma', 'Disease', (113, 120))	('mutations', 'Var', (85, 94))	('sarcomas', 'Disease', 'MESH:D012509', (98, 106))	('sarcoma', 'Disease', (98, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
413666	23598961	The 3 synovial sarcomas showed the most robust sequencing evidence for the pathognomonic translocation, t(x;18)(p11.2;q11.2), on the desktop platform using FFPE material with the number of breakpoint spanning reads ranging from 8 to 16 in the 3 cases.	('synovial sarcomas', 'Phenotype', 'HP:0012570', (6, 23))	('synovial sarcomas', 'Disease', 'MESH:D013584', (6, 23))	('synovial sarcomas', 'Disease', (6, 23))	('t(x', 'Var', (104, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('t(x;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (104, 124))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (6, 22))
413670	23598961	Although this particular fusion has not been described, the fusion involved COL1A1, which is the most highly expressed gene in the sarcomatome.	('fusion', 'Var', (60, 66))	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('sarcoma', 'Disease', (131, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('COL1A1', 'Gene', (76, 82))
413695	23598961	Potential sources of false positives include the generation of true chimeric reads as the result of aberrant hybridization during library preparation, the combination of HTS errors that generate new sequences that could map to other genes, and mapping errors that place the read at the wrong location because of sequence homology between 2 genes.	('HTS errors', 'Disease', (170, 180))	('HTS errors', 'Disease', 'MESH:C537160', (170, 180))	('errors', 'Var', (252, 258))
413703	23598961	With the ever increasing number of known and clinically important mutations in cancer, it may become prohibitive to maintain validated FISH assays for each translocation and additional molecular assays for other types of mutations.	('mutations', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('clinical', 'Species', '191496', (45, 53))
413739	24282374	A confidence interval of <0.1 is represented as +++++ and indicates strong synergism by this method.	('synergism', 'Interaction', (75, 84))	('as +++++', 'Chemical', 'MESH:D001151', (45, 53))	('+++++', 'Var', (48, 53))
413781	24282374	MK-2206 is an allosteric inhibitor of the AKT kinase family of proteins (at nanomolar levels) without additional kinase inhibitory activity in a panel of 256 kinases.	('MK-2206', 'Chemical', 'MESH:C548887', (0, 7))	('AKT', 'Gene', (42, 45))	('AKT', 'Gene', '207', (42, 45))	('MK-2206', 'Var', (0, 7))
413792	24282374	The concurrent treatment of dasatinib with either MK-2206 or triciribine resulted in more than additive activity, and caspase 3/7 activation was also readily detected, indicating that effects on viability are at least partially mediated through apoptosis (Figure 3).	('caspase 3', 'Gene', (118, 127))	('dasatinib', 'Chemical', 'MESH:D000069439', (28, 37))	('MK-2206', 'Var', (50, 57))	('caspase 3', 'Gene', '836', (118, 127))	('MK-2206', 'Chemical', 'MESH:C548887', (50, 57))	('triciribine', 'Chemical', 'MESH:C023764', (61, 72))	('additive activity', 'MPA', (95, 112))
413857	33203900	A particular genomic mutational signature explains the majority of mutations in the studied XP-C leukemias and sarcomas.	('XP-C leukemia', 'Disease', 'MESH:C567886', (92, 105))	('leukemias and sarcomas', 'Disease', 'MESH:D012509', (97, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('mutations', 'Var', (67, 76))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('XP-C leukemia', 'Disease', (92, 105))	('leukemias', 'Phenotype', 'HP:0001909', (97, 106))
413863	33203900	XP-C cancers contained somatic copy number aberrations (SCNAs) and mutations which are characteristic for corresponding types of sporadic malignancies: mutations in TP53 and deletions of chromosomes 5 and 7 in leukemia, biallelic loss of CDKN2A in breast cancer and highly unstable genome of rhabdomyosarcoma (Supplementary Table 1).	('XP-C cancers', 'Disease', (0, 12))	('TP53', 'Gene', (165, 169))	('mutations', 'Var', (152, 161))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (292, 308))	('sarcoma', 'Phenotype', 'HP:0100242', (301, 308))	('C', 'Chemical', 'MESH:D002244', (3, 4))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('XP-C cancers', 'Disease', 'MESH:C567886', (0, 12))	('TP53', 'Gene', '7157', (165, 169))	('CDKN2A', 'Gene', (238, 244))	('leukemia', 'Phenotype', 'HP:0001909', (210, 218))	('C', 'Chemical', 'MESH:D002244', (238, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('loss', 'NegReg', (230, 234))	('rhabdomyosarcoma', 'Disease', (292, 308))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('CDKN2A', 'Gene', '1029', (238, 244))	('leukemia', 'Disease', (210, 218))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('leukemia', 'Disease', 'MESH:D007938', (210, 218))	('breast cancer', 'Disease', 'MESH:D001943', (248, 261))	('deletions', 'Var', (174, 183))	('breast cancer', 'Disease', (248, 261))	('malignancies', 'Disease', (138, 150))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (292, 308))
413864	33203900	We compared frequency of TP53 mutations and common chromosomal aberrations (5q and 7q deletions) between XP-C leukemia and adult de novo acute myeloid leukemia cohort (AML); and found that TP53 was mutated significantly more often in our dataset (5/6 cases and 15/200 cases for XP-C and sporadic AML respectively, P = 2.963e-05, odds ratio = 58.66, 95% CI = 6.04-2872.04; Fisher's exact test, two-sided).	('AML', 'Disease', (296, 299))	('leukemia', 'Phenotype', 'HP:0001909', (151, 159))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (143, 159))	('TP53', 'Gene', (189, 193))	('C', 'Chemical', 'MESH:D002244', (108, 109))	('XP-C leukemia', 'Disease', (105, 118))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (51, 74))	('AML', 'Disease', 'MESH:D015470', (168, 171))	('mutated', 'Var', (198, 205))	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('C', 'Chemical', 'MESH:D002244', (281, 282))	('AML', 'Disease', (168, 171))	('XP-C leukemia', 'Disease', 'MESH:C567886', (105, 118))	('C', 'Chemical', 'MESH:D002244', (353, 354))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (137, 159))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (137, 159))	('TP53', 'Gene', '7157', (189, 193))	('TP53', 'Gene', (25, 29))	('acute myeloid leukemia', 'Disease', (137, 159))	('AML', 'Disease', 'MESH:D015470', (296, 299))	('TP53', 'Gene', '7157', (25, 29))
413865	33203900	Together with significantly higher proportions of 5q and 7q deletions in XP-C leukemia (P = 1.024e-06 for 5q and P = 0.002985 for 7q deletions, Fisher's exact test, two-sided), this may indicate that the studied leukemia cases are close to TP53 mutated with complex karyotype subgroup according to Papaemmanuil et al.. We identified 14.5-31.2 (mean 24.6)-fold increase in the number of somatic mutations in XP-C leukemia samples relative to the sporadic myeloid neoplasms (Mann-Whitney U test, two-sided, P = 5.8e-05) and the absence of such an effect for XP-C sarcomas (Fig.	('TP53', 'Gene', '7157', (240, 244))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (454, 471))	('sporadic myeloid neoplasms', 'Disease', (445, 471))	('leukemia', 'Phenotype', 'HP:0001909', (212, 220))	('leukemia', 'Phenotype', 'HP:0001909', (78, 86))	('XP-C leukemia', 'Disease', (73, 86))	('leukemia', 'Phenotype', 'HP:0001909', (412, 420))	('sarcomas', 'Phenotype', 'HP:0100242', (561, 569))	('XP-C leukemia', 'Disease', (407, 420))	('XP-C leukemia', 'Disease', 'MESH:C567886', (73, 86))	('XP-C leukemia', 'Disease', 'MESH:C567886', (407, 420))	('leukemia', 'Disease', (78, 86))	('leukemia', 'Disease', 'MESH:D007938', (212, 220))	('leukemia', 'Disease', 'MESH:D007938', (78, 86))	('TP53', 'Gene', (240, 244))	('leukemia', 'Disease', (212, 220))	('neoplasms', 'Phenotype', 'HP:0002664', (462, 471))	('leukemia', 'Disease', (412, 420))	('leukemia', 'Disease', 'MESH:D007938', (412, 420))	('sarcoma', 'Phenotype', 'HP:0100242', (561, 568))	('mutations', 'Var', (394, 403))	('increase', 'PosReg', (360, 368))	('sporadic myeloid neoplasms', 'Disease', 'MESH:D009369', (445, 471))	('XP-C sarcomas', 'Disease', (556, 569))	('XP-C sarcomas', 'Disease', 'MESH:C567886', (556, 569))
413869	33203900	The mutational patterns of indels were dominated by single nucleotide deletions of C:G and T:A bases in homopolymer stretches and dinucleotide deletions in repeats (Supplementary Fig.	('dinucleotide', 'Chemical', 'MESH:D015226', (130, 142))	('T:A', 'Gene', (91, 94))	('C:G', 'Gene', (83, 86))	('single nucleotide deletions', 'Var', (52, 79))	('dinucleotide deletions', 'Var', (130, 152))	('C', 'Chemical', 'MESH:D002244', (83, 84))
413872	33203900	2a, b) and one of them, Signature "C" explained on average 83.1% of mutations in the XP-C samples (57% in breast sarcoma, 88.9% in rhabdomyosarcoma and 84.1-88.7% in leukemia) while in sporadic tumors only small contribution (average 9.7%, range 0-34.3%) of signature "C" was observed (Fig.	('breast sarcoma', 'Disease', (106, 120))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (131, 147))	('XP-C', 'Gene', (85, 89))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (131, 147))	('leukemia', 'Disease', 'MESH:D007938', (166, 174))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('leukemia', 'Disease', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', (194, 200))	('breast sarcoma', 'Disease', 'MESH:D001943', (106, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('C', 'Chemical', 'MESH:D002244', (269, 270))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('mutations', 'Var', (68, 77))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('rhabdomyosarcoma', 'Disease', (131, 147))
413875	33203900	At the same time the Signature "C" was different from Signature 8 by strong transcriptional asymmetry, increased mutations from C and decreased mutations from T (1.24- and 1.43-fold respectively) specifically in excess of VpCpT > D and NpCpT > T (where V designates A,C,T and D-A,G,T; Fig.	('decreased', 'NegReg', (134, 143))	('C', 'Chemical', 'MESH:D002244', (268, 269))	('C', 'Chemical', 'MESH:D002244', (224, 225))	('D-A', 'Var', (276, 279))	('NpCpT > T', 'Var', (236, 245))	('C', 'Chemical', 'MESH:D002244', (128, 129))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('C', 'Chemical', 'MESH:D002244', (238, 239))	('mutations', 'Var', (113, 122))	('VpCpT > D', 'Var', (222, 231))	('mutations', 'Var', (144, 153))
413878	33203900	Indeed, transcriptional strand bias in XP-C was strong and highly significant for all six classes of nucleotide substitutions grouped by the reference and mutated nucleotide, while in tissue-matched sporadic cancers it was weak or absent (Fig.	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('transcriptional', 'MPA', (8, 23))	('cancers', 'Disease', (208, 215))	('nucleotide substitutions', 'Var', (101, 125))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('significant', 'Reg', (66, 77))
413880	33203900	These effects could be explained by either excess of mutations from damaged pyrimidines or decrease of mutations from damaged purines on the transcribed (noncoding) strand.	('excess', 'PosReg', (43, 49))	('pyrimidines', 'Var', (76, 87))	('pyrimidines', 'Chemical', 'MESH:D011743', (76, 87))	('mutations', 'Var', (53, 62))	('mutations', 'MPA', (103, 112))	('purines', 'Chemical', 'MESH:D011687', (126, 133))	('damaged pyrimidines', 'Var', (68, 87))	('decrease', 'NegReg', (91, 99))
413888	33203900	In line with that, we observed no difference between mutations from purines on untranscribed strand and intergenic regions at different replication times, while signature of repair of mutations from purines on transcribed strand was observed and was the strongest in early-replicating regions which are usually associated with active gene transcription (Fig.	('mutations', 'Var', (184, 193))	('strongest', 'Reg', (254, 263))	('purines', 'Chemical', 'MESH:D011687', (68, 75))	('mutations', 'Var', (53, 62))	('purines', 'Chemical', 'MESH:D011687', (199, 206))
413889	33203900	Similarly to SBS, transcriptional bias in DBS and ID indicated that the primary damage is on purine bases, specifically in CpC > ApD and single nucleotide deletion of C:G nucleotides (Fig.	('C', 'Chemical', 'MESH:D002244', (125, 126))	('purine', 'Chemical', 'MESH:C030985', (93, 99))	('single nucleotide deletion', 'Var', (137, 163))	('CpC > ApD', 'Disease', (123, 132))	('purine bases', 'MPA', (93, 105))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('C', 'Chemical', 'MESH:D002244', (123, 124))
413893	33203900	In diploid genome regions of XP-C leukemia 0.3% of SBS formed 140 short clusters with distance between mutations inferior to 16 bp and mean of 7 bp (Fig.	('XP-C leukemia', 'Disease', 'MESH:C567886', (29, 42))	('mutations', 'Var', (103, 112))	('XP-C leukemia', 'Disease', (29, 42))	('leukemia', 'Phenotype', 'HP:0001909', (34, 42))
413894	33203900	These results are compatible with the hypothesis of the existence of bulky DNA lesions that enter the S-phase and get bypassed by error-prone translesion DNA synthesis polymerases in XPC-deficient cells, while in XPC-proficient cells majority of these lesions may be repaired prior to replication in error-free manner.	('XPC-deficient', 'Disease', (183, 196))	('lesions', 'Var', (79, 86))	('XPC-deficient', 'Disease', 'MESH:C567886', (183, 196))
413895	33203900	Due to the absence of GG-NER we expected to observe strong difference in terms of mutation rates between transcribed and untranscribed strands, particularly in open chromatin and early-replicating regions known to be actively transcribed while we expected no difference between untranscribed strand of genes and intergenic regions in heterochromatic regions.	('GG-NER', 'Gene', (22, 28))	('absence', 'Var', (11, 18))	('GG-NER', 'Chemical', '-', (22, 28))
413896	33203900	In XP-C leukemia mutation load in regions of open chromatin was strongly depleted in early-replicating regions and regions with active histone marks (H3K27ac (2.83-fold), H3K36me3 (8.45-fold), H3K4me1 (2.72-fold)) for transcribed strands of genes (Fig.	('H3K36me3', 'Var', (171, 179))	('XP-C leukemia', 'Disease', 'MESH:C567886', (3, 16))	('mutation', 'Var', (17, 25))	('H3K4me1', 'Var', (193, 200))	('leukemia', 'Phenotype', 'HP:0001909', (8, 16))	('depleted', 'NegReg', (73, 81))	('H3K27ac', 'Var', (150, 157))	('XP-C leukemia', 'Disease', (3, 16))
413899	33203900	The analysis revealed more homogeneous mutation load across the different states in XP-C leukemia in comparison with sporadic leukemia as well as elevated mutation rates in heterochromatic regions relative to genic and regulatory elements (Supplementary Fig.	('mutation', 'Var', (39, 47))	('mutation rates', 'MPA', (155, 169))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('sporadic leukemia', 'Disease', (117, 134))	('XP-C leukemia', 'Disease', (84, 97))	('sporadic leukemia', 'Disease', 'MESH:D007938', (117, 134))	('elevated', 'PosReg', (146, 154))	('XP-C leukemia', 'Disease', 'MESH:C567886', (84, 97))
413901	33203900	All cSCC tumors, independently of XP-C mutational status presented the typical UV-light induced signature (C > T mutations at YpC sites (where Y designates C or T), 85.6%, Supplementary Fig.	('C', 'Chemical', 'MESH:D002244', (107, 108))	('C', 'Chemical', 'MESH:D002244', (7, 8))	('cSCC tumors', 'Disease', 'MESH:D009369', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('C', 'Chemical', 'MESH:D002244', (128, 129))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (113, 122))	('C', 'Chemical', 'MESH:D002244', (156, 157))	('cSCC tumors', 'Disease', (4, 15))	('C', 'Chemical', 'MESH:D002244', (6, 7))
413903	33203900	However, in XP-C cSCCs there was remarkably more pronounced decrease of mutations from pyrimidines on the transcribed strand relative to untrascribed strand and intergenic regions, as well as much stronger transcriptional bias in highly expressed genes (Supplementary Fig.	('transcriptional bias', 'MPA', (206, 226))	('stronger', 'PosReg', (197, 205))	('decrease', 'NegReg', (60, 68))	('mutations', 'Var', (72, 81))	('pyrimidines', 'Chemical', 'MESH:D011743', (87, 98))	('highly expressed genes', 'MPA', (230, 252))
413907	33203900	On average 75% of mutations occurred before SCNAs suggesting that they may have accumulated in progenitor cells before tumorigenesis or early in tumor development (Wilcoxon signed-rank test, two-sided, P = 0.03906; Fig.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('C', 'Chemical', 'MESH:D002244', (45, 46))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mutations', 'Var', (18, 27))
413908	33203900	Therefore, the observed mutational burden and signature in XP-C tumor genomes may partially represent mutagenesis associated with lesion accumulation during the lifetime of normal body cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('XP-C tumor', 'Disease', 'MESH:C567886', (59, 69))	('XP-C tumor', 'Disease', (59, 69))	('mutational', 'Var', (24, 34))
413910	33203900	Our results are in line with recent reports in human and mice showing that attenuated NER at germinal level is associated with increased risk of lymphoma and sarcoma.	('mice', 'Species', '10090', (57, 61))	('attenuated', 'Var', (75, 85))	('sarcoma', 'Disease', 'MESH:D012509', (158, 165))	('sarcoma', 'Disease', (158, 165))	('lymphoma', 'Disease', (145, 153))	('human', 'Species', '9606', (47, 52))	('lymphoma', 'Disease', 'MESH:D008223', (145, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))
413913	33203900	Our work provides evidence that COSMIC Signature 8 is likely to result from mutagenesis associated with bulky lesions primarily repaired by NER and can be considered as a marker of attenuated NER function.	('result', 'Reg', (64, 70))	('mutagenesis', 'Var', (76, 87))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('COSMIC', 'Gene', (32, 38))
413914	33203900	The studied patients were diagnosed as XP-C at early age (median: 3 years) and were well protected from environmental mutagens during their life; therefore, the observed mutagenesis could be caused by endogenous genotoxins which DNA lesions are almost fully repaired in XPC-proficient cells (Fig.	('patients', 'Species', '9606', (12, 20))	('caused', 'Reg', (191, 197))	('mutagenesis', 'Var', (170, 181))
413925	33203900	DNA from solid tumors (SA002T2 and SA007T3) was extracted from FFPE blocks after examination and dissection by a pathologist.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('SA002T2', 'Var', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('SA007T3', 'Var', (35, 42))	('tumors', 'Disease', (15, 21))
413938	33203900	To avoid contamination of true variants by FFPE sequencing artifacts, we used more stringent criteria for breast sarcoma (SA007T3) and rhabdomyosarcoma (SA002T2) samples which included at least 2 and 1 reads from each strand and minimal VAF equal to 0.3 and 0.4 for breast cancer and rhabdomyosarcoma samples respectively.	('rhabdomyosarcoma', 'Disease', (135, 151))	('breast cancer', 'Disease', (266, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (135, 151))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (284, 300))	('rhabdomyosarcoma', 'Disease', (284, 300))	('breast sarcoma', 'Disease', (106, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('SA002T2', 'Var', (153, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('SA007T3', 'Var', (122, 129))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (135, 151))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (284, 300))	('breast sarcoma', 'Disease', 'MESH:D001943', (106, 120))
413947	33203900	The function computed inequality between mutations from pyrimidines (C > A,T,G; T > A,C,G) to mutations from purines (G > A,C,T; A > C,G,T) for genes located on the sense and antisense strands of DNA relative to the reference human genome.	('mutations', 'Var', (41, 50))	('human', 'Species', '9606', (226, 231))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('C > A', 'Var', (69, 74))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('purines', 'Chemical', 'MESH:D011687', (109, 116))	('pyrimidines', 'Chemical', 'MESH:D011743', (56, 67))	('C', 'Chemical', 'MESH:D002244', (133, 134))
413949	33203900	To compute tissue-specific TRB between genes expressed at low and high level, we used RPKM values of RNA-seq from Epigenetic Roadmap Project (E028 for breast sarcoma, E050 for leukemia, E100 for rhabdomyosarcoma).	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (195, 211))	('E100', 'Var', (186, 190))	('breast sarcoma', 'Disease', 'MESH:D001943', (151, 165))	('rhabdomyosarcoma', 'Disease', (195, 211))	('breast sarcoma', 'Disease', (151, 165))	('E028', 'Var', (142, 146))	('leukemia', 'Disease', (176, 184))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (195, 211))	('leukemia', 'Disease', 'MESH:D007938', (176, 184))	('leukemia', 'Phenotype', 'HP:0001909', (176, 184))	('E050', 'Var', (167, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
413952	33203900	Following the hypothesis that majority of mutations were caused by purine DNA lesions, we were able to compute strand-specific mutation densities around transcription start sites (TSSs).	('caused', 'Reg', (57, 63))	('purine', 'Chemical', 'MESH:C030985', (67, 73))	('mutations', 'Var', (42, 51))
413958	33203900	We developed a mathematical model of the Monte Carlo method for random mutations generation based on the following statements: (1) positions of mutations are random and uniformly distributed along the genome; (2) random positions are selected from the same set of genomic intervals as original somatic mutations; (3) the number and nucleotide context spectrum of randomly generated mutations exactly matches somatic mutations in the corresponding sample.	('C', 'Chemical', 'MESH:D002244', (47, 48))	('mutations', 'Var', (144, 153))	('mutations', 'Var', (382, 391))
414002	33109665	In other cancers and chronic diseases, lengthening of total interval was associated with decreased HRQoL.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('lengthening', 'Var', (39, 50))	('decreased HRQoL', 'Disease', (89, 104))	('chronic diseases', 'Disease', 'MESH:D002908', (21, 37))	('chronic diseases', 'Disease', (21, 37))	('decreased HRQoL', 'Disease', 'MESH:D002303', (89, 104))
414016	33109665	Inclusion criteria are: (1) aged >=18 years; (2) new histological diagnosis of sarcoma as confirmed by a sarcoma histopathologist (according to the International Statistical Classification Of Diseases And Related Health Problems, 10th revision, German Modification (ICD-10-GM) codes C40 and C41 for bone sarcoma and C49 for soft-tissue sarcoma); (3) able to communicate in English or Dutch and to complete questionnaires themselves; (4) mental capacity to provide informed consent and participate in the study (as determined by the healthcare professional) and (5) diagnosed at or referred to one of the participating hospitals.	('C49', 'Var', (316, 319))	('sarcoma', 'Disease', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('bone sarcoma', 'Disease', (299, 311))	('C40', 'Gene', '55571', (283, 286))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('sarcoma', 'Disease', 'MESH:D012509', (304, 311))	('C40', 'Gene', (283, 286))	('sarcoma', 'Disease', (105, 112))	('sarcoma', 'Disease', 'MESH:D012509', (336, 343))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))	('sarcoma', 'Disease', (304, 311))	('sarcoma', 'Disease', (336, 343))	('C41', 'Var', (291, 294))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('bone sarcoma', 'Phenotype', 'HP:0002669', (299, 311))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))	('bone sarcoma', 'Disease', 'MESH:D012509', (299, 311))
414017	33109665	Exclusion criteria are: (1) too ill to complete questionnaires (according to treating physician:patients who experience symptoms are still eligible); (2) desmoid fibromatosis and gastrointestinal stromal tumours due to the different nature of the diseases (ICD-10-GM codes C15-20, C26, C48 and C80).	('C48', 'Gene', '55755', (286, 289))	('desmoid fibromatosis', 'Disease', (154, 174))	('C15', 'Gene', '51316', (273, 276))	('desmoid fibromatosis', 'Phenotype', 'HP:0100245', (154, 174))	('C80', 'Var', (294, 297))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (179, 211))	('C48', 'Gene', (286, 289))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('gastrointestinal stromal tumours', 'Disease', (179, 211))	('desmoid fibromatosis', 'Disease', 'MESH:D018222', (154, 174))	('C26', 'Var', (281, 284))	('patients', 'Species', '9606', (96, 104))	('C15', 'Gene', (273, 276))	('C26', 'CellLine', 'CVCL:0240', (281, 284))	('tumours', 'Phenotype', 'HP:0002664', (204, 211))
414109	32917245	Accumulating evidence has indicated the existence of a multistep aggregation of additional mutations of multiple tumour suppressors, cell cycle dysfunctions, and signalling regulation genes, resulting in signalling cascade disorders and receptor tyrosine kinase amplification.	('receptor tyrosine kinase', 'Gene', (237, 261))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('receptor tyrosine kinase', 'Gene', '5979', (237, 261))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('signalling cascade disorders', 'MPA', (204, 232))	('tumour', 'Disease', (113, 119))	('mutations', 'Var', (91, 100))
414117	32917245	This work was supported by the National Natural Science Foundation of China (81700070 to Siying Ren), the Natural Science Foundation of Hunan Province (2019JJ30038 to Siying Ren) and the Hunan Province Health Department Research Fund (B2018-0541 to Siying Ren).	('Ren', 'Gene', (174, 177))	('Ren', 'Gene', '5972', (256, 259))	('Ren', 'Gene', '5972', (174, 177))	('Ren', 'Gene', (96, 99))	('Ren', 'Gene', '5972', (96, 99))	('81700070', 'Var', (77, 85))	('Ren', 'Gene', (256, 259))
414128	32257479	A major marker for Ewing sarcoma is the presence of t(11;22) chromosomal translocation.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (19, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (19, 32))	('t(11', 'Var', (52, 56))	('Ewing sarcoma', 'Disease', (19, 32))
414187	31992690	Either the PARPi olaparib or the PARP1 catalytic mutation (E988K) did not impair the repression of PARP1 on the FoxO1 expression.	('E988K', 'Var', (59, 64))	('impair', 'NegReg', (74, 80))	('PARP', 'Gene', '142', (11, 15))	('PARP', 'Gene', (99, 103))	('FoxO1', 'Gene', (112, 117))	('PARP', 'Gene', (33, 37))	('E988K', 'Mutation', 'p.E988K', (59, 64))	('PARP', 'Gene', '142', (33, 37))	('PARP', 'Gene', '142', (99, 103))	('PARP', 'Gene', (11, 15))	('repression', 'MPA', (85, 95))	('expression', 'MPA', (118, 128))
414201	31992690	To investigate the transcriptional regulation by PARP1, we used cellular models generated from Ewing sarcoma RD-ES and SK-ES-1 cells by knocking out the PARP1 gene, denoted as RD/KO1, RD/KO2, SK/KO1, and SK/KO2.	('Ewing sarcoma RD', 'Disease', 'MESH:D012512', (95, 111))	('SK-ES-1', 'CellLine', 'CVCL:0627', (119, 126))	('PARP1', 'Gene', (153, 158))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('Ewing sarcoma RD', 'Disease', (95, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('knocking out', 'Var', (136, 148))
414214	31992690	In addition, PARP1 reconstitution led to no (IkappaBalpha or NF-kappaB1) or only weak (TNFAIP3) changes at the protein levels (Fig.	('PARP1', 'Gene', (13, 18))	('IkappaBalpha', 'Gene', (45, 57))	('TNFAIP3', 'Gene', (87, 94))	('reconstitution', 'Var', (19, 33))	('NF-kappaB1', 'Gene', (61, 71))	('NF-kappaB1', 'Gene', '4790', (61, 71))	('IkappaBalpha', 'Gene', '4792', (45, 57))	('TNFAIP3', 'Gene', '7128', (87, 94))
414221	31992690	4e) revealed that PARP1 bound to the biotin-labeled FoxO1-L-B (Lane 3) and FoxO1-R-B (Lane 6) much more than the control (Lane 9).	('FoxO1-L-B', 'Gene', (52, 61))	('bound', 'Interaction', (24, 29))	('FoxO1-R-B', 'Var', (75, 84))	('biotin', 'Chemical', 'MESH:D001710', (37, 43))	('PARP1', 'Gene', (18, 23))
414225	31992690	E988K has no poly(ADP-ribose) polymerase activity but keeps the mono-ADP-ribosyl-transferase activity.	('E988K', 'Var', (0, 5))	('poly(ADP-ribose) polymerase', 'Gene', '142', (13, 40))	('poly(ADP-ribose) polymerase', 'Gene', (13, 40))	('E988K', 'Mutation', 'p.E988K', (0, 5))	('mono-ADP-ribosyl', 'Chemical', 'MESH:C024857', (64, 80))	('mono-ADP-ribosyl-transferase activity', 'MPA', (64, 101))
414226	31992690	The expression of E988K in RD-ES/KO1 cells led to apparent decreases in FoxO1 mRNA and protein levels (Fig.	('FoxO1', 'Gene', (72, 77))	('E988K', 'Var', (18, 23))	('decreases', 'NegReg', (59, 68))	('E988K', 'Mutation', 'p.E988K', (18, 23))
414324	30299262	The morcellation resulted in a tissue spill on various intraabdominal organs such as ovaries, liver, and omentum, and it did not matter which surgical technique (vaginal, laparoscopic or open) was used.	('morcellation', 'Var', (4, 16))	('resulted in', 'Reg', (17, 28))	('ovaries', 'Disease', (85, 92))	('ovaries', 'Disease', 'MESH:D010051', (85, 92))
414362	25644184	Sequencing of 740 mutation hotspots revealed no mutations in UACC-SARC1 nor in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('UACC-SARC1', 'Gene', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mutations', 'Var', (48, 57))
414437	25644184	Two cellular concentrations were prepared of both the wild type and GFP/ Luciferase tagged cells for mouse modeling, 5x105 (low dose) and 5x106 (high dose) cells, which were subcutaneously injected into ten 6-week old female NOD/SCID gamma mice.	('SCID', 'Gene', '19090', (229, 233))	('mice', 'Species', '10090', (240, 244))	('SCID', 'Gene', (229, 233))	('mouse', 'Species', '10090', (101, 106))	('5x105', 'Var', (117, 122))	('5x106', 'Var', (138, 143))
414466	25644184	The >2N spindle-cell sarcoma karyotype is as follows: 48-57,XX,add(1)(p36.1)x2,del(1)(q25),del(2)(p21p23),add(3)(p13),del(3)(q21),-5, del(6)(q21),+7,del(7)(q22q36),+9,+9,add(9)(p24),add(11)(q21),add(13)(p12),add(13)(q34), del(13)(q12q22)x2,+14,add(15)(p10),add(15)(p12),add(15)(q26),+19,+19,hsr(19)(q13.4)x2, del(20)(q11.2),-21,+22,add(22)(q13),+1-4mar[cp7] Extra copies of whole chromosomes 7, 9, 14, 19, and 22, and losses of chromosomes 5 and 21 were noted.	('p36', 'Gene', (70, 73))	('p24', 'Gene', '13088', (177, 180))	('p10', 'Gene', '20194', (252, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('p12', 'Gene', '69745', (203, 206))	('p12', 'Gene', '69745', (265, 268))	('p10', 'Gene', (252, 255))	('p12', 'Gene', (203, 206))	('p12', 'Gene', (265, 268))	('p36', 'Gene', '12306', (70, 73))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('losses', 'NegReg', (418, 424))	('p24', 'Gene', (177, 180))	('add(22)(q13', 'Var', (332, 343))	('del(13', 'Var', (222, 228))	('sarcoma', 'Disease', (21, 28))
414470	25644184	Although UACC-SARC1 was genetically similar to its tumor of origin, more probes were affected by changes in copy number in the cell line - the majority of these being losses.	('changes', 'Var', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('affected', 'Reg', (85, 93))	('copy number', 'Var', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
414483	25644184	Mutant p53 was 1% positive for each.	('Mutant', 'Var', (0, 6))	('p53', 'Gene', '22060', (7, 10))	('p53', 'Gene', (7, 10))
414516	25644184	Mutant p53 protein is a common IHC finding in primary MFH sarcomas; however, its role in RIS is less clear.	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('protein', 'Protein', (11, 18))	('p53', 'Gene', '22060', (7, 10))	('RIS', 'Chemical', '-', (89, 92))	('MFH sarcomas', 'Disease', (54, 66))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('MFH sarcomas', 'Disease', 'MESH:D012509', (54, 66))
414519	25644184	Moreover, our Ampliseq surveys for 87 distinct p53 mutations were negative in both the tumor of origin and UACC-SARC1.	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('p53', 'Gene', '22060', (47, 50))	('UACC-SARC1', 'Disease', (107, 117))	('tumor', 'Disease', (87, 92))	('negative', 'NegReg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('p53', 'Gene', (47, 50))
414520	25644184	Validation IHC/ICC showed no evidence of mutant p53, PTEN or RB1, which supported our Next Generation Sequencing results.	('p53', 'Gene', (48, 51))	('mutant', 'Var', (41, 47))	('PTEN', 'Gene', '19211', (53, 57))	('RB1', 'Gene', '19645', (61, 64))	('p53', 'Gene', '22060', (48, 51))	('PTEN', 'Gene', (53, 57))	('RB1', 'Gene', (61, 64))
414521	25644184	In primary STS with complex genomics, PTEN and RB1 deletions have been reported to be prevalent.	('prevalent', 'Reg', (86, 95))	('RB1', 'Gene', '19645', (47, 50))	('primary STS', 'Disease', (3, 14))	('deletions', 'Var', (51, 60))	('PTEN', 'Gene', '19211', (38, 42))	('RB1', 'Gene', (47, 50))	('PTEN', 'Gene', (38, 42))
414527	25644184	Sequencing of 740 mutation hotspots across 46 oncogenes and tumor suppressor genes using the Ion Ampliseq Cancer panel revealed no mutations or indels in UACC-SARC1 cells nor in the tumor of origin, which rules out the possibility of aberrant PTEN or RB1 protein.	('mutations', 'Var', (131, 140))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('RB1', 'Gene', '19645', (251, 254))	('PTEN', 'Gene', '19211', (243, 247))	('PTEN', 'Gene', (243, 247))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('indels', 'Var', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (60, 65))	('RB1', 'Gene', (251, 254))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
414538	25644184	Recently, Wang et al showed that the side population (putative stem cells) from undifferentiated pleomorphic sarcomas displayed activation of the Hedgehog and Notch signaling pathways and that inhibition of these pathways reduced the proportion of side population cells present.	('activation', 'PosReg', (128, 138))	('inhibition', 'Var', (193, 203))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (80, 117))	('undifferentiated pleomorphic sarcomas', 'Disease', (80, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('Notch signaling pathways', 'Pathway', (159, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('reduced', 'NegReg', (222, 229))
414540	25644184	While UACC-SARC1 could produce tumors in SCID mice, this was much more robustly demonstrated in more immunodeficient mouse models (NOD-SCID IL2R gamma chain knockout mice).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('SCID', 'Gene', (41, 45))	('SCID', 'Gene', (135, 139))	('SCID', 'Gene', '19090', (135, 139))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('mouse', 'Species', '10090', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mice', 'Species', '10090', (46, 50))	('mice', 'Species', '10090', (166, 170))	('SCID', 'Gene', '19090', (41, 45))	('immunodeficient', 'Disease', 'MESH:D007153', (101, 116))	('UACC-SARC1', 'Var', (6, 16))	('immunodeficient', 'Disease', (101, 116))
414553	23637631	Breakpoint Analysis of Transcriptional and Genomic Profiles Uncovers Novel Gene Fusions Spanning Multiple Human Cancer Types Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies.	('mesenchymal malignancies', 'Disease', (231, 255))	('mesenchymal malignancies', 'Disease', 'MESH:C535700', (231, 255))	('Human', 'Species', '9606', (106, 111))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (164, 184))	('fusions', 'Var', (130, 137))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (156, 184))	('BCR/ABL1', 'Gene', '613;25', (144, 152))	('BCR/ABL1', 'Gene', (144, 152))	('leukemia', 'Phenotype', 'HP:0001909', (176, 184))	('chronic myelogenous leukemia', 'Disease', (156, 184))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (156, 184))	('hematologic', 'Disease', (215, 226))
414554	23637631	The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('prostate and lung cancers', 'Disease', 'MESH:D011471', (38, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('malignancies', 'Disease', (126, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('lung cancers', 'Phenotype', 'HP:0100526', (51, 63))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('gene fusions', 'Var', (22, 34))
414555	23637631	Mining data from 974 diverse cancer samples, we identified 198 candidate fusions involving annotated cancer genes.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('fusions', 'Var', (73, 80))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
414560	23637631	Taken together, we provide a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('fusion', 'Var', (124, 130))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
414568	23637631	Some are also good drug targets (including rearrangements of ROS1, RAF1, and CDK6 kinases), with clear implications for therapy.	('ROS1', 'Gene', (61, 65))	('RAF1', 'Gene', (67, 71))	('RAF1', 'Gene', '5894', (67, 71))	('ROS1', 'Gene', '6098', (61, 65))	('CDK6 kinases', 'Enzyme', (77, 89))	('rearrangements', 'Var', (43, 57))
414569	23637631	During cancer development and progression, chromosomal rearrangements frequently lead to the juxtaposition of two previously separate genes.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('lead to', 'Reg', (81, 88))	('juxtaposition', 'MPA', (93, 106))	('chromosomal rearrangements', 'Var', (43, 69))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
414572	23637631	Pathogenic gene fusions characterize many hematological and mesenchymal neoplasms.	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (60, 81))	('gene fusions', 'Var', (11, 23))	('Pathogenic', 'Reg', (0, 10))	('neoplasm', 'Phenotype', 'HP:0002664', (72, 80))	('mesenchymal neoplasms', 'Disease', (60, 81))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))
414575	23637631	Gene fusions frequently represent markers for specific cancer subtypes.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Gene fusions', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (55, 61))
414576	23637631	For example, chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome and the resulting BCR/ABL1 gene fusion, while acute promyelocytic leukemia (APL) is characterized by RARA rearrangement.	('chronic myelogenous leukemia', 'Disease', (13, 41))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (13, 41))	('APL', 'Disease', 'MESH:D015473', (172, 175))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (142, 170))	('CML', 'Disease', (43, 46))	('BCR/ABL1', 'Gene', '613;25', (114, 122))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (21, 41))	('CML', 'Phenotype', 'HP:0005506', (43, 46))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (13, 41))	('APL', 'Disease', (172, 175))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (142, 170))	('RARA', 'Gene', '5914', (197, 201))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('fusion', 'Var', (128, 134))	('BCR/ABL1', 'Gene', (114, 122))	('acute promyelocytic leukemia', 'Disease', (142, 170))	('APL', 'Phenotype', 'HP:0004836', (172, 175))	('leukemia', 'Phenotype', 'HP:0001909', (33, 41))	('RARA', 'Gene', (197, 201))	('CML', 'Disease', 'MESH:D015464', (43, 46))
414580	23637631	Similarly, oncogenic rearrangements of the RAF kinases, RAF1 and BRAF, have been found in various cancers including pilocytic astrocytoma, melanoma, gastric cancer, and prostate cancer.	('RAF', 'Gene', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('prostate cancer', 'Disease', 'MESH:D011471', (169, 184))	('prostate cancer', 'Phenotype', 'HP:0012125', (169, 184))	('cancers', 'Disease', (98, 105))	('RAF', 'Gene', (43, 46))	('gastric cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Disease', (169, 184))	('RAF', 'Gene', '22882', (56, 59))	('found', 'Reg', (81, 86))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (116, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('pilocytic astrocytoma', 'Disease', (116, 137))	('rearrangements', 'Var', (21, 35))	('RAF', 'Gene', (56, 59))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('RAF1', 'Gene', '5894', (56, 60))	('RAF', 'Gene', '22882', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('astrocytoma', 'Phenotype', 'HP:0009592', (126, 137))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('BRAF', 'Gene', '673', (65, 69))	('RAF', 'Gene', '22882', (43, 46))	('BRAF', 'Gene', (65, 69))	('RAF1', 'Gene', (56, 60))
414582	23637631	Next-generation genomic and transcriptome sequencing have been used to discover novel gene rearrangements in prostate cancer, lung cancer, colon cancer, and melanoma.	('prostate cancer', 'Disease', (109, 124))	('colon cancer', 'Disease', 'MESH:D015179', (139, 151))	('colon cancer', 'Disease', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))	('rearrangements', 'Var', (91, 105))	('colon cancer', 'Phenotype', 'HP:0003003', (139, 151))
414585	23637631	In the modern era of cancer genomics, a major goal will be to mine these large datasets for the discovery of novel pathogenic alterations that drive oncogenesis.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('oncogenesis', 'CPA', (149, 160))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('alterations', 'Var', (126, 137))
414597	23637631	We then screened for copy number changes disrupting those genes of the Cancer Gene Census.	('screened', 'Reg', (8, 16))	('Cancer', 'Disease', (71, 77))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('copy number changes', 'Var', (21, 40))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
414601	23637631	Many of these candidates also corresponded to known gene fusions, including EWSR1/FLI1 in Ewing sarcoma and ABL1 rearrangements in several leukemia samples (Figure S5).	('leukemia', 'Disease', (139, 147))	('ABL1', 'Gene', '25', (108, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('ABL1', 'Gene', (108, 112))	('Ewing sarcoma', 'Disease', (90, 103))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('FLI1', 'Gene', '2313', (82, 86))	('leukemia', 'Disease', 'MESH:D007938', (139, 147))	('rearrangements', 'Var', (113, 127))	('FLI1', 'Gene', (82, 86))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 103))
414614	23637631	Ewing sarcoma) harbor pathognomonic gene fusions, no such alterations have been discovered to date in angiosarcoma, a rare but aggressive endothelial neoplasm.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('neoplasm', 'Disease', 'MESH:D009369', (150, 158))	('neoplasm', 'Phenotype', 'HP:0002664', (150, 158))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('Ewing sarcoma', 'Disease', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('angiosarcoma', 'Disease', 'MESH:D006394', (102, 114))	('gene fusions', 'Var', (36, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('angiosarcoma', 'Disease', (102, 114))	('neoplasm', 'Disease', (150, 158))	('angiosarcoma', 'Phenotype', 'HP:0200058', (102, 114))
414615	23637631	By 5' rapid amplification of cDNA ends (5' RACE), we uncovered a novel CEP85L/ROS1 rearrangement in AS1 (Figure 2B, 2C).	('ROS1', 'Gene', (78, 82))	('ROS1', 'Gene', '6098', (78, 82))	('rearrangement', 'Var', (83, 96))	('CEP85L', 'Gene', (71, 77))	('CEP85L', 'Gene', '387119', (71, 77))	('AS1', 'Gene', '5729', (100, 103))	('AS1', 'Gene', (100, 103))
414618	23637631	CEP85L was recently discovered to be the 5' partner of a rearrangement involving PDGFRB in a patient with precursor T-ALL and an associated myeloproliferative neoplasm.	('CEP85L', 'Gene', (0, 6))	('CEP85L', 'Gene', '387119', (0, 6))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (140, 167))	('neoplasm', 'Phenotype', 'HP:0002664', (159, 167))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (140, 167))	('patient', 'Species', '9606', (93, 100))	('myeloproliferative neoplasm', 'Disease', (140, 167))	('PDGFRB', 'Gene', '5159', (81, 87))	('rearrangement', 'Var', (57, 70))	('PDGFRB', 'Gene', (81, 87))
414622	23637631	FISH analysis confirmed genomic rearrangement with amplification of ROS1 (Figure 2D).	('ROS1', 'Gene', '6098', (68, 72))	('ROS1', 'Gene', (68, 72))	('amplification', 'Var', (51, 64))
414623	23637631	To determine whether ROS1 rearrangements recurred in angiosarcomas or other sarcoma subtypes, we performed the break-apart FISH assay on two tissue microarrays (TMA) containing 280 specimens representing 36 diverse sarcoma and soft tissue tumor diagnoses (Table S3).	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (76, 92))	('sarcoma subtypes', 'Disease', (76, 92))	('ROS1', 'Gene', (21, 25))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('tumor', 'Disease', (239, 244))	('sarcoma', 'Disease', (58, 65))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('angiosarcomas', 'Disease', 'MESH:D006394', (53, 66))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('angiosarcomas', 'Phenotype', 'HP:0200058', (53, 66))	('sarcoma', 'Disease', 'MESH:D012509', (215, 222))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('sarcoma', 'Disease', (215, 222))	('ROS1', 'Gene', '6098', (21, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (227, 244))	('angiosarcoma', 'Phenotype', 'HP:0200058', (53, 65))	('rearrangements', 'Var', (26, 40))	('angiosarcomas', 'Disease', (53, 66))
414625	23637631	Of 33 evaluable angiosarcoma and 20 epithelioid hemangioendothelioma (EHE; a related diagnosis) cases, one EHE case (EHE10) exhibited rearrangement at the ROS1 locus (Figure 2D).	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('rearrangement', 'Var', (134, 147))	('angiosarcoma', 'Disease', (16, 28))	('exhibited', 'Reg', (124, 133))	('ROS1', 'Gene', (155, 159))	('epithelioid hemangioendothelioma', 'Disease', (36, 68))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (36, 68))	('angiosarcoma', 'Phenotype', 'HP:0200058', (16, 28))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (36, 68))	('ROS1', 'Gene', '6098', (155, 159))	('EHE', 'Phenotype', 'HP:0032060', (107, 110))	('EHE', 'Phenotype', 'HP:0032060', (117, 120))	('EHE', 'Phenotype', 'HP:0032060', (70, 73))	('angiosarcoma', 'Disease', 'MESH:D006394', (16, 28))
414626	23637631	Thus, in all we observed ROS1 rearrangement in 1 of 34 (~3%) angiosarcomas and 1 of 20 (5%) EHE cases.	('angiosarcoma', 'Phenotype', 'HP:0200058', (61, 73))	('rearrangement', 'Var', (30, 43))	('angiosarcomas', 'Disease', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('EHE', 'Phenotype', 'HP:0032060', (92, 95))	('ROS1', 'Gene', (25, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('angiosarcomas', 'Disease', 'MESH:D006394', (61, 74))	('ROS1', 'Gene', '6098', (25, 29))	('observed', 'Reg', (16, 24))	('angiosarcomas', 'Phenotype', 'HP:0200058', (61, 74))
414635	23637631	Our DBA results suggested that SLC1A2 rearrangements occur in cancer types other than gastric carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('rearrangements', 'Var', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SLC1A2', 'Gene', (31, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('DBA', 'Chemical', '-', (4, 7))	('SLC1A2', 'Gene', '6506', (31, 37))	('occur', 'Reg', (53, 58))	('gastric carcinomas', 'Disease', 'MESH:D013274', (86, 104))	('gastric carcinomas', 'Disease', (86, 104))
414636	23637631	In addition to detecting a known SLC1A2 rearrangement in the gastric cancer cell line SNU-16, DBA identified breakpoints disrupting SLC1A2 in the colon cancer cell line SNU-C1 and in a pancreatic cancer xenograft (247) (Figure 3A and Table S2).	('SLC1A2', 'Gene', (33, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (185, 202))	('colon cancer', 'Disease', 'MESH:D015179', (146, 158))	('DBA', 'Chemical', '-', (94, 97))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('SLC1A2', 'Gene', '6506', (132, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (185, 202))	('colon cancer', 'Disease', (146, 158))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('pancreatic cancer', 'Disease', (185, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('breakpoints', 'Var', (109, 120))	('SLC1A2', 'Gene', '6506', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('SLC1A2', 'Gene', (132, 138))	('disrupting', 'NegReg', (121, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))
414641	23637631	Analogous to TMPRSS2/ERG in prostate cancer, the SLC1A2 fusion in gastric cancer is thought to be driven by strong expression of its 5' partner, CD44 .	('CD44', 'Gene', (145, 149))	('ERG', 'Gene', (21, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('ERG', 'Gene', '2078', (21, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('TMPRSS2', 'Gene', (13, 20))	('SLC1A2', 'Gene', (49, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('fusion', 'Var', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('TMPRSS2', 'Gene', '7113', (13, 20))	('prostate cancer', 'Disease', (28, 43))	('CD44', 'Gene', '960', (145, 149))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('SLC1A2', 'Gene', '6506', (49, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
414645	23637631	Attempts to characterize the oncogenic contribution of APIP/SLC1A2 by RNA interference (RNAi)-mediated knockdown were met with technical difficulties in efficiently transfecting the suspension line SNU-C1 (data not shown).	('SLC1A2', 'Gene', (60, 66))	('APIP', 'Gene', (55, 59))	('APIP', 'Gene', '51074', (55, 59))	('SLC1A2', 'Gene', '6506', (60, 66))	('knockdown', 'Var', (103, 112))
414647	23637631	Recurrent rearrangements of the RAF kinases, RAF1 and BRAF, were recently reported in a small fraction of prostate cancers, gastric cancers, and melanomas.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('rearrangements', 'Var', (10, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('RAF1', 'Gene', (45, 49))	('RAF', 'Gene', '22882', (32, 35))	('reported', 'Reg', (74, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('RAF', 'Gene', '22882', (55, 58))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('melanomas', 'Disease', 'MESH:D008545', (145, 154))	('prostate cancers', 'Phenotype', 'HP:0012125', (106, 122))	('RAF', 'Gene', (32, 35))	('prostate cancers', 'Disease', (106, 122))	('melanomas', 'Disease', (145, 154))	('RAF', 'Gene', '22882', (45, 48))	('RAF', 'Gene', (55, 58))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('RAF', 'Gene', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('RAF1', 'Gene', '5894', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gastric cancers', 'Disease', 'MESH:D013274', (124, 139))	('gastric cancers', 'Disease', (124, 139))	('gastric cancers', 'Phenotype', 'HP:0012126', (124, 139))	('prostate cancers', 'Disease', 'MESH:D011471', (106, 122))
414648	23637631	Here, DBA identified candidate rearrangements of RAF1 in lung cancer (DMS-153), pancreatic cancer (PL5), anaplastic astrocytoma (D538-MG), and osteosarcoma (CAL-72) (Figure 4A and Table S2), and candidate rearrangements of BRAF in gastric cancer (NCI-N87), breast cancer (HCC38), and glioblastoma (D397-MG) (Table S2).	('glioblastoma', 'Phenotype', 'HP:0012174', (284, 296))	('astrocytoma', 'Phenotype', 'HP:0009592', (116, 127))	('gastric cancer', 'Disease', (231, 245))	('anaplastic astrocytoma', 'Disease', (105, 127))	('pancreatic cancer', 'Disease', (80, 97))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('BRAF', 'Gene', '673', (223, 227))	('BRAF', 'Gene', (223, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('rearrangements', 'Var', (31, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (231, 245))	('RAF1', 'Gene', '5894', (49, 53))	('rearrangements', 'Var', (205, 219))	('DBA', 'Chemical', '-', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (105, 127))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('gastric cancer', 'Phenotype', 'HP:0012126', (231, 245))	('RAF1', 'Gene', (49, 53))	('lung cancer', 'Disease', (57, 68))	('osteosarcoma', 'Disease', (143, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (284, 296))	('osteosarcoma', 'Disease', 'MESH:D012516', (143, 155))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('breast cancer', 'Disease', (257, 270))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('glioblastoma', 'Disease', (284, 296))
414660	23637631	We identified BRAF rearrangement in one of the 104 samples (~1%) (Figure 4G) but no additional RAF1 rearrangements.	('RAF1', 'Gene', '5894', (95, 99))	('RAF1', 'Gene', (95, 99))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))	('rearrangement', 'Var', (19, 32))
414661	23637631	Taken together, our findings are consistent with RAF kinase fusions occurring in a small subset of pancreatic cancers, where they possibly substitute for KRAS mutations.	('KRAS', 'Gene', '3845', (154, 158))	('RAF', 'Gene', '22882', (49, 52))	('RAF', 'Gene', (49, 52))	('pancreatic cancers', 'Disease', (99, 117))	('occurring', 'Reg', (68, 77))	('fusions', 'Var', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic cancers', 'Disease', 'MESH:D010190', (99, 117))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (99, 117))	('KRAS', 'Gene', (154, 158))
414662	23637631	Rearrangements of the RNA binding protein, EWSR1, characterize various malignancies including Ewing sarcoma (EWSR1/ETS), desmoplastic small round cell tumor (EWSR1/WT1), and some acute lymphoblastic leukemias (EWSR1/ZNF384).	('WT1', 'Gene', '7490', (164, 167))	('acute lymphoblastic leukemias', 'Disease', (179, 208))	('leukemia', 'Phenotype', 'HP:0001909', (199, 207))	('ZNF384', 'Gene', '171017', (216, 222))	('characterize', 'Reg', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('EWSR1', 'Gene', (43, 48))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (179, 207))	('Rearrangements', 'Var', (0, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('malignancies', 'Disease', (71, 83))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (185, 207))	('lymphoblastic leukemias', 'Phenotype', 'HP:0005526', (185, 208))	('acute lymphoblastic leukemias', 'Disease', 'MESH:D054198', (179, 208))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (121, 156))	('WT1', 'Gene', (164, 167))	('ZNF384', 'Gene', (216, 222))	('desmoplastic small round cell tumor', 'Disease', (121, 156))	('acute lymphoblastic leukemias', 'Phenotype', 'HP:0006721', (179, 208))	('leukemias', 'Phenotype', 'HP:0001909', (199, 208))	('Ewing sarcoma', 'Disease', (94, 107))
414664	23637631	As EWSR1 gene fusions had not previously been described in cutaneous melanoma, we prioritized CHL-1 and SH4 for further evaluation.	('cutaneous melanoma', 'Disease', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('fusions', 'Var', (14, 21))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('EWSR1', 'Gene', (3, 8))
414668	23637631	Cyclin-dependent kinase 6 (CDK6) encodes a regulator of G1/S cell-cycle progression and has been found rearranged in B-cell lymphoma (IGK/CDK6), chronic lymphocytic leukemia (IGL/CDK6, IGH/CDK6, IGK/CDK6), and acute lymphoblastic leukemia (CDK6/MLL).	('leukemia', 'Phenotype', 'HP:0001909', (230, 238))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (117, 132))	('cell lymphoma', 'Phenotype', 'HP:0012191', (119, 132))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (145, 173))	('IGK', 'Gene', (134, 137))	('rearranged', 'Var', (103, 113))	('IGH', 'Gene', '3492', (185, 188))	('B-cell lymphoma', 'Disease', (117, 132))	('leukemia', 'Phenotype', 'HP:0001909', (165, 173))	('acute lymphoblastic leukemia', 'Disease', (210, 238))	('IGK', 'Gene', (195, 198))	('IGK', 'Gene', '50802', (134, 137))	('Cyclin-dependent kinase 6', 'Gene', (0, 25))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (210, 238))	('MLL', 'Gene', (245, 248))	('MLL', 'Gene', '4297', (245, 248))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (210, 238))	('IGL', 'Gene', (175, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))	('IGK', 'Gene', '50802', (195, 198))	('IGH', 'Gene', (185, 188))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (117, 132))	('IGL', 'Gene', '3535', (175, 178))	('CDK6', 'Gene', (27, 31))	('Cyclin-dependent kinase 6', 'Gene', '1021', (0, 25))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (145, 173))	('chronic lymphocytic leukemia', 'Disease', (145, 173))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (216, 238))
414676	23637631	Gene fusions involving clathrin heavy chain (CLTC) have been described in various leukemias (CLTC/ALK) and in renal cell carcinoma (CLTC/TFE3).	('CLTC', 'Gene', (132, 136))	('CLTC', 'Gene', (93, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('TFE3', 'Gene', (137, 141))	('described', 'Reg', (61, 70))	('TFE3', 'Gene', '7030', (137, 141))	('clathrin heavy chain', 'Gene', (23, 43))	('Gene fusions', 'Var', (0, 12))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (110, 130))	('ALK', 'Gene', '238', (98, 101))	('leukemias', 'Disease', 'MESH:D007938', (82, 91))	('ALK', 'Gene', (98, 101))	('leukemias', 'Phenotype', 'HP:0001909', (82, 91))	('CLTC', 'Gene', '1213', (45, 49))	('CLTC', 'Gene', '1213', (132, 136))	('CLTC', 'Gene', '1213', (93, 97))	('renal cell carcinoma', 'Disease', (110, 130))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('leukemias', 'Disease', (82, 91))	('CLTC', 'Gene', (45, 49))	('clathrin heavy chain', 'Gene', '1213', (23, 43))
414677	23637631	DBA suggested that CLTC rearrangements might be more widespread in human malignancies (Table S2).	('DBA', 'Chemical', '-', (0, 3))	('rearrangements', 'Var', (24, 38))	('CLTC', 'Gene', (19, 23))	('malignancies', 'Disease', 'MESH:D009369', (73, 85))	('human', 'Species', '9606', (67, 72))	('malignancies', 'Disease', (73, 85))	('CLTC', 'Gene', '1213', (19, 23))
414678	23637631	Copy-number transitions within cytoband 17q23.1 occurred as focal deletions that involved three neighboring genes, CLTC, PTRH2, and VMP1 (also called TMEM49).	('PTRH2', 'Gene', '51651', (121, 126))	('TMEM49', 'Gene', '81671', (150, 156))	('CLTC', 'Gene', (115, 119))	('PTRH2', 'Gene', (121, 126))	('TMEM49', 'Gene', (150, 156))	('deletions', 'Var', (66, 75))	('VMP1', 'Gene', (132, 136))	('VMP1', 'Gene', '81671', (132, 136))	('CLTC', 'Gene', '1213', (115, 119))
414679	23637631	We selected to further evaluate two breast cancer cell lines, BT-549 and HCC1954, with deletions spanning CLTC-VMP1 (Figure 7A).	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('HCC1954', 'CellLine', 'CVCL:1259', (73, 80))	('BT-549', 'CellLine', 'CVCL:1092', (62, 68))	('CLTC', 'Gene', '1213', (106, 110))	('CLTC', 'Gene', (106, 110))	('deletions', 'Var', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('VMP1', 'Gene', (111, 115))	('VMP1', 'Gene', '81671', (111, 115))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
414681	23637631	Notably, both CLTC/VMP1 fusions were predicted to be out of frame.	('CLTC', 'Gene', '1213', (14, 18))	('VMP1', 'Gene', '81671', (19, 23))	('CLTC', 'Gene', (14, 18))	('fusions', 'Var', (24, 31))	('VMP1', 'Gene', (19, 23))
414682	23637631	A recent study also identified the CLTC/VMP1 fusion in BT-549; our findings now demonstrate this to be a recurrent rearrangement in breast cancer.	('CLTC', 'Gene', (35, 39))	('VMP1', 'Gene', (40, 44))	('fusion', 'Var', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BT-549', 'CellLine', 'CVCL:1092', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('VMP1', 'Gene', '81671', (40, 44))	('CLTC', 'Gene', '1213', (35, 39))
414683	23637631	A similar deletion pattern occurred in other malignancies, including glioblastoma, neuroblastoma, lung cancer, bladder cancer, thyroid cancer, melanoma, leukemia, and others (Figure 7D).	('thyroid cancer', 'Disease', 'MESH:D013964', (127, 141))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('glioblastoma', 'Disease', (69, 81))	('leukemia', 'Disease', (153, 161))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('leukemia', 'Disease', 'MESH:D007938', (153, 161))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('thyroid cancer', 'Phenotype', 'HP:0002890', (127, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))	('bladder cancer', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('malignancies', 'Disease', 'MESH:D009369', (45, 57))	('malignancies', 'Disease', (45, 57))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('thyroid cancer', 'Disease', (127, 141))	('neuroblastoma', 'Disease', (83, 96))	('neuroblastoma', 'Phenotype', 'HP:0003006', (83, 96))	('lung cancer', 'Disease', (98, 109))	('neuroblastoma', 'Disease', 'MESH:D009447', (83, 96))	('deletion', 'Var', (10, 18))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('occurred', 'Reg', (27, 35))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))
414684	23637631	Across all these samples, the minimum common region of deletion appeared to include only PTRH2 and VMP1.	('PTRH2', 'Gene', (89, 94))	('VMP1', 'Gene', (99, 103))	('VMP1', 'Gene', '81671', (99, 103))	('PTRH2', 'Gene', '51651', (89, 94))	('deletion', 'Var', (55, 63))
414687	23637631	Approximately 20-30% of glioblastoma tumors harbor a constitutively active rearrangement of EGFR, called EGFRvIII, but glioblastoma derived cell lines typically lose EGFR amplification and EGFRvIII expression.	('EGFR', 'Gene', '1956', (166, 170))	('glioblastoma tumors', 'Disease', (24, 43))	('EGFR', 'Gene', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('lose', 'NegReg', (161, 165))	('rearrangement', 'Var', (75, 88))	('EGFR', 'Gene', '1956', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('EGFR', 'Gene', '1956', (92, 96))	('expression', 'MPA', (198, 208))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (24, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', (166, 170))	('glioblastoma', 'Disease', 'MESH:D005909', (24, 36))	('glioblastoma', 'Disease', (119, 131))	('amplification', 'MPA', (171, 184))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('EGFR', 'Gene', (189, 193))	('glioblastoma', 'Disease', (24, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (24, 36))	('EGFR', 'Gene', (92, 96))
414693	23637631	The FIP1L1/PDGFRA fusion is a hallmark of chronic eosinophilic leukemia and has been studied extensively in EOL-1 cells, but other cell line models are lacking.	('PDGFRA', 'Gene', (11, 17))	('PDGFRA', 'Gene', '5156', (11, 17))	('leukemia', 'Phenotype', 'HP:0001909', (63, 71))	('hallmark of chronic eosinophilic leukemia', 'Disease', (30, 71))	('fusion', 'Var', (18, 24))	('FIP1L1', 'Gene', '81608', (4, 10))	('FIP1L1', 'Gene', (4, 10))	('hallmark of chronic eosinophilic leukemia', 'Disease', 'MESH:D004802', (30, 71))
414697	23637631	We discovered novel gene rearrangements in diverse human cancer types, including fusions of ROS1, SLC1A2, RAF1, EWSR1, CDK6, and CLTC.	('ROS1', 'Gene', (92, 96))	('CLTC', 'Gene', '1213', (129, 133))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('SLC1A2', 'Gene', (98, 104))	('CDK6', 'Gene', (119, 123))	('ROS1', 'Gene', '6098', (92, 96))	('cancer', 'Disease', (57, 63))	('CLTC', 'Gene', (129, 133))	('fusions', 'Var', (81, 88))	('RAF1', 'Gene', (106, 110))	('human', 'Species', '9606', (51, 56))	('RAF1', 'Gene', '5894', (106, 110))	('EWSR1', 'Gene', (112, 117))	('SLC1A2', 'Gene', '6506', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
414699	23637631	By FISH analysis, ROS1 rearrangements appear to be infrequent in angiosarcoma (and in another endothelial-derived tumor, epithelioid hemangioendothelioma).	('angiosarcoma', 'Disease', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('epithelioid hemangioendothelioma', 'Disease', (121, 153))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('angiosarcoma', 'Phenotype', 'HP:0200058', (65, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (121, 153))	('tumor', 'Disease', (114, 119))	('ROS1', 'Gene', (18, 22))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (121, 153))	('rearrangements', 'Var', (23, 37))	('angiosarcoma', 'Disease', 'MESH:D006394', (65, 77))	('ROS1', 'Gene', '6098', (18, 22))
414704	23637631	In this regard, we note that ROS1 tyrosine kinase is sensitive to the existing ALK small-molecule inhibitor, crizotinib, and indeed a single patient's non-small cell lung cancer harboring a ROS1 fusion was found to be responsive.	('ALK', 'Gene', '238', (79, 82))	('ROS1', 'Gene', '6098', (29, 33))	('fusion', 'Var', (195, 201))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (151, 177))	('patient', 'Species', '9606', (141, 148))	('tyrosine kinase', 'Gene', (34, 49))	('crizotinib', 'Chemical', 'MESH:D000077547', (109, 119))	('ALK', 'Gene', (79, 82))	('ROS1', 'Gene', (190, 194))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (151, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('ROS1', 'Gene', '6098', (190, 194))	('tyrosine kinase', 'Gene', '7294', (34, 49))	('non-small cell lung cancer', 'Disease', (151, 177))	('ROS1', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (155, 177))
414705	23637631	Intriguingly, single nucleotide polymorphism (SNP) variants in ROS1 have been associated with increased risk of vascular diseases, including coronary artery disease and stroke.	('stroke', 'Disease', (169, 175))	('associated', 'Reg', (78, 88))	('stroke', 'Disease', 'MESH:D020521', (169, 175))	('single nucleotide polymorphism', 'Var', (14, 44))	('ROS1', 'Gene', (63, 67))	('coronary artery disease', 'Disease', 'MESH:D003324', (141, 164))	('vascular diseases', 'Disease', (112, 129))	('ROS1', 'Gene', '6098', (63, 67))	('stroke', 'Phenotype', 'HP:0001297', (169, 175))	('coronary artery disease', 'Disease', (141, 164))	('vascular diseases', 'Disease', 'MESH:D000783', (112, 129))
414707	23637631	Our findings also demonstrate a more widespread role of SLC1A2 rearrangements in human malignancies.	('SLC1A2', 'Gene', '6506', (56, 62))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('rearrangements', 'Var', (63, 77))	('SLC1A2', 'Gene', (56, 62))	('human', 'Species', '9606', (81, 86))	('malignancies', 'Disease', (87, 99))
414710	23637631	Notably, while most oncogenic gene fusions encode protein kinases and transcription factors, SLC1A2 fusions appear to define a new class of rearrangement targeting metabolism-related genes.	('fusions', 'Var', (100, 107))	('SLC1A2', 'Gene', '6506', (93, 99))	('metabolism-related', 'MPA', (164, 182))	('encode', 'Reg', (43, 49))	('SLC1A2', 'Gene', (93, 99))
414712	23637631	SLC1A2 fusions therefore also represent potential therapeutic targets in gastric and now colon cancer.	('SLC1A2', 'Gene', (0, 6))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('gastric', 'Disease', (73, 80))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('fusions', 'Var', (7, 14))	('colon cancer', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('SLC1A2', 'Gene', '6506', (0, 6))
414714	23637631	Our analysis also uncovered RAF1 rearrangements in pancreatic cancer and in anaplastic astrocytoma.	('anaplastic astrocytoma', 'Disease', (76, 98))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('pancreatic cancer', 'Disease', (51, 68))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('rearrangements', 'Var', (33, 47))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (76, 98))	('RAF1', 'Gene', (28, 32))	('RAF1', 'Gene', '5894', (28, 32))	('astrocytoma', 'Phenotype', 'HP:0009592', (87, 98))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))
414716	23637631	On a cautionary note, most pilocytic astrocytomas (a distinct diagnosis, but related to anaplastic astrocytoma) carry RAF1 or BRAF rearrangements; thus it is possible that the D538-MG cell line (harboring BCL6/RAF1) was actually derived from a misdiagnosed pilocytic astrocytoma.	('astrocytoma', 'Phenotype', 'HP:0009592', (267, 278))	('astrocytoma', 'Phenotype', 'HP:0009592', (37, 48))	('RAF1', 'Gene', '5894', (118, 122))	('anaplastic astrocytoma', 'Disease', (88, 110))	('BCL6', 'Gene', (205, 209))	('RAF1', 'Gene', '5894', (210, 214))	('RAF1', 'Gene', (118, 122))	('RAF1', 'Gene', (210, 214))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (88, 110))	('BCL6', 'Gene', '604', (205, 209))	('pilocytic astrocytomas', 'Disease', (27, 49))	('rearrangements', 'Var', (131, 145))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (257, 278))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (27, 48))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (27, 49))	('pilocytic astrocytoma', 'Disease', (257, 278))	('astrocytoma', 'Phenotype', 'HP:0009592', (99, 110))
414718	23637631	Our findings extend the spectrum of cancer types harboring RAF kinase rearrangements, and underscore the importance of the RAS-RAF-MAPK signaling pathway in these additional malignancies.	('RAF', 'Gene', '22882', (59, 62))	('RAF', 'Gene', (59, 62))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('malignancies', 'Disease', (174, 186))	('cancer', 'Disease', (36, 42))	('rearrangements', 'Var', (70, 84))	('MAPK', 'Gene', '5594', (131, 135))	('MAPK', 'Gene', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('RAF', 'Gene', (127, 130))	('malignancies', 'Disease', 'MESH:D009369', (174, 186))	('RAF', 'Gene', '22882', (127, 130))
414719	23637631	In pancreatic cancer, pathway activation typically occurs by mutation of KRAS, but in uncommon KRAS-wildtype tumors, RAF kinase fusions may provide an alternative route.	('KRAS', 'Gene', '3845', (95, 99))	('KRAS', 'Gene', (73, 77))	('pancreatic cancer', 'Disease', (3, 20))	('KRAS', 'Gene', '3845', (73, 77))	('RAF', 'Gene', '22882', (117, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('mutation', 'Var', (61, 69))	('pathway activation', 'PosReg', (22, 40))	('RAF', 'Gene', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('KRAS-wildtype tumors', 'Disease', 'MESH:D009369', (95, 115))	('KRAS', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('KRAS-wildtype tumors', 'Disease', (95, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
414720	23637631	Though RAF kinase fusions are uncommon, they nonetheless have therapeutic implications for this deadly malignancy.	('RAF', 'Gene', (7, 10))	('malignancy', 'Disease', 'MESH:D009369', (103, 113))	('fusions', 'Var', (18, 25))	('malignancy', 'Disease', (103, 113))	('RAF', 'Gene', '22882', (7, 10))
414724	23637631	found rearrangements of RAF kinase genomic loci by FISH in rare cases of melanoma, but no specific RAF kinase gene fusion was identified.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('rearrangements', 'Var', (6, 20))	('RAF', 'Gene', '22882', (24, 27))	('RAF', 'Gene', (24, 27))	('RAF', 'Gene', '22882', (99, 102))	('RAF', 'Gene', (99, 102))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
414726	23637631	EWSR1 rearrangements in Ewing's sarcoma have recently been shown to confer sensitivity to PARP-1 inhibition.	('PARP-1', 'Gene', (90, 96))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (24, 39))	('rearrangements', 'Var', (6, 20))	('PARP-1', 'Gene', '142', (90, 96))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (24, 39))	("Ewing's sarcoma", 'Disease', (24, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('EWSR1', 'Gene', (0, 5))	('sensitivity', 'MPA', (75, 86))
414732	23637631	Lastly our breakpoint analysis uncovered recurrent deletions and rearrangements of the CLTC-PTRH2-VMP1 locus, evident in diverse tumor types, including glioblastoma, neuroblastoma, lung cancer, breast cancer, bladder cancer, thyroid cancer, melanoma, and leukemias.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('melanoma', 'Disease', (241, 249))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('bladder cancer', 'Phenotype', 'HP:0009725', (209, 223))	('rearrangements', 'Var', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Disease', (129, 134))	('leukemias', 'Disease', (255, 264))	('neuroblastoma', 'Disease', (166, 179))	('VMP1', 'Gene', (98, 102))	('VMP1', 'Gene', '81671', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('PTRH2', 'Gene', '51651', (92, 97))	('lung cancer', 'Disease', (181, 192))	('neuroblastoma', 'Phenotype', 'HP:0003006', (166, 179))	('thyroid cancer', 'Disease', (225, 239))	('deletions', 'Var', (51, 60))	('CLTC', 'Gene', '1213', (87, 91))	('glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('PTRH2', 'Gene', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('neuroblastoma', 'Disease', 'MESH:D009447', (166, 179))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('thyroid cancer', 'Disease', 'MESH:D013964', (225, 239))	('glioblastoma', 'Disease', (152, 164))	('breast cancer', 'Disease', (194, 207))	('CLTC', 'Gene', (87, 91))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('leukemia', 'Phenotype', 'HP:0001909', (255, 263))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('leukemias', 'Disease', 'MESH:D007938', (255, 264))	('thyroid cancer', 'Phenotype', 'HP:0002890', (225, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('bladder cancer', 'Disease', 'MESH:D001749', (209, 223))	('bladder cancer', 'Disease', (209, 223))	('leukemias', 'Phenotype', 'HP:0001909', (255, 264))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
414733	23637631	In breast cancer, we discovered two CLTC-VMP1 fusions; however, both were out-of-frame.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('CLTC', 'Gene', (36, 40))	('breast cancer', 'Disease', (3, 16))	('fusions', 'Var', (46, 53))	('VMP1', 'Gene', '81671', (41, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('VMP1', 'Gene', (41, 45))	('CLTC', 'Gene', '1213', (36, 40))
414736	23637631	The results of these experiments highlight the pathogenic roles of these alterations in their corresponding cancer types.	('alterations', 'Var', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
414741	23637631	In particular, recurrent gene fusions appear to occur at low frequency in many cancer types, and therefore these existing very large sample sets should empower their discovery.	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('gene fusions', 'Var', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
414742	23637631	While here we have applied breakpoint analysis to discover rearrangements of known cancer genes as part of novel fusions and in novel cancer types, our approach should be extendable to discover pathogenic fusion genes not previously linked to malignancy.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rearrangements', 'Var', (59, 73))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('malignancy', 'Disease', 'MESH:D009369', (243, 253))	('malignancy', 'Disease', (243, 253))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
414743	23637631	In summary, breakpoint analysis uncovered several novel gene rearrangements spanning multiple human cancer types.	('rearrangements', 'Var', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('human', 'Species', '9606', (94, 99))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
414745	23637631	Several of these fusions represent druggable targets or potential markers for sensitivity to specific anti-cancer treatments with therapeutic implications for the corresponding cancer types.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('fusions', 'Var', (17, 24))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (107, 113))
414750	23637631	Briefly, 10 microg of sample total RNA and 1 microg of reference mRNA (pooled from 11 diverse cell lines) were differentially labeled with Cy5 and Cy3, respectively, and co-hybridized to the microarray.	('Cy3', 'Var', (147, 150))	('Cy3', 'Chemical', '-', (147, 150))	('Cy5', 'Chemical', 'MESH:C085321', (139, 142))	('Cy5', 'Var', (139, 142))
414762	23637631	For example, breakpoints disrupting ABL1 kinase must comprise either amplification of the 3' end or deletion of the 5' end of the gene, since ABL1 is the 3' partner in known oncogenic rearrangements such as BCR/ABL1.	('ABL1', 'Gene', '25', (142, 146))	('BCR/ABL1', 'Gene', (207, 215))	('ABL1', 'Gene', (142, 146))	('ABL1', 'Gene', '25', (36, 40))	('ABL1', 'Gene', '25', (211, 215))	('ABL1', 'Gene', (211, 215))	('ABL1', 'Gene', (36, 40))	('BCR/ABL1', 'Gene', '613;25', (207, 215))	('deletion', 'Var', (100, 108))	('amplification', 'Var', (69, 82))
414769	23637631	Cell lines were propagated in RPMI-1640 supplemented with 10% fetal bovine serum (FBS), except for VCaP (DMEM with 10% FBS), D-538MG (Richter's zinc option medium (Invitrogen) with 10% FBS), and SK-ES-1 (McCoy's 5A Medium with 15% FBS).	('FBS', 'Disease', (185, 188))	('FBS', 'Disease', 'MESH:D005198', (231, 234))	('D-538MG', 'Var', (125, 132))	("Richter's zinc option medium", 'Chemical', '-', (134, 162))	('FBS', 'Disease', 'MESH:D005198', (119, 122))	('bovine', 'Species', '9913', (68, 74))	('D-538MG', 'Chemical', '-', (125, 132))	('FBS', 'Disease', 'MESH:D005198', (82, 85))	('RPMI-1640', 'Chemical', '-', (30, 39))	('VCaP', 'CellLine', 'CVCL:2235', (99, 103))	('FBS', 'Disease', (231, 234))	('FBS', 'Disease', 'MESH:D005198', (185, 188))	('DMEM', 'Chemical', '-', (105, 109))	('FBS', 'Disease', (119, 122))	('SK-ES-1', 'CellLine', 'CVCL:0627', (195, 202))	('FBS', 'Disease', (82, 85))	("McCoy's 5A Medium", 'Chemical', 'MESH:C113109', (204, 221))
414783	23637631	Locus-specific BACs encompassing ROS1 (CTD-2174H19 telomeric, RP11-605K7 centromeric), RAF1 (RP11-586C12 telomeric, RP11-767C1 centromeric), and BRAF (RP11-364M15 telomeric, RP11-597I24 centromeric) were labeled with Cy5-dUTP (telomeric probes) or Cy3-dUTP (centromeric probes).	('RP11', 'Gene', (62, 66))	('BRAF', 'Gene', (145, 149))	('RP11', 'Gene', (93, 97))	('Cy5-dUTP', 'Var', (217, 225))	('RP11', 'Gene', (116, 120))	('Cy3-dUTP', 'Var', (248, 256))	('RP11', 'Gene', '26121', (151, 155))	('Cy3-dUTP', 'Chemical', 'MESH:C088941', (248, 256))	('Cy5-dUTP', 'Chemical', 'MESH:C088942', (217, 225))	('ROS1', 'Gene', '6098', (33, 37))	('RP11', 'Gene', '26121', (174, 178))	('RP11', 'Gene', '26121', (62, 66))	('RP11', 'Gene', '26121', (93, 97))	('RAF1', 'Gene', '5894', (87, 91))	('RP11', 'Gene', (151, 155))	('RP11', 'Gene', '26121', (116, 120))	('RAF1', 'Gene', (87, 91))	('RP11', 'Gene', (174, 178))	('ROS1', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (145, 149))
414839	26847678	A negative or positive expression classification was assigned to markers (Ki67, Cyclin D1, p53, AXL, c-kit, pEGFR, IGF-1R, PTEN, pS6RP, and p4EBP1) with low median expression (0-30% of cells positive for stain); samples were considered positive if >= 10% of cells were stained.	('negative', 'NegReg', (2, 10))	('Cyclin D1', 'Gene', (80, 89))	('IGF-1R', 'Gene', (115, 121))	('p4EBP1', 'Var', (140, 146))	('pEGFR', 'Gene', (108, 113))	('c-kit', 'Gene', (101, 106))	('p53', 'Gene', (91, 94))	('AXL', 'Gene', '558', (96, 99))	('p53', 'Gene', '7157', (91, 94))	('c-kit', 'Gene', '3815', (101, 106))	('pS6RP', 'Gene', (129, 134))	('PTEN', 'Gene', (123, 127))	('Cyclin D1', 'Gene', '595', (80, 89))	('PTEN', 'Gene', '5728', (123, 127))	('IGF-1R', 'Gene', '3480', (115, 121))	('AXL', 'Gene', (96, 99))	('expression', 'MPA', (23, 33))
414855	26847678	Univariate analysis of clinical factors for DSS resulted in the identification of age < 61 years at diagnosis, tumor size < 10 cm, margin-negative resection and sporadic tumors were associated with improved DSS (Table 3; Fig.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('margin-negative', 'Var', (131, 146))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('sporadic tumors', 'Disease', 'MESH:D009369', (161, 176))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (170, 175))	('improved', 'PosReg', (198, 206))	('< 10', 'Var', (122, 126))	('DSS', 'Chemical', '-', (207, 210))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('sporadic tumors', 'Disease', (161, 176))	('DSS', 'MPA', (207, 210))	('DSS', 'Chemical', '-', (44, 47))
414858	26847678	Although not statistically significant, we observed that tumors expressing high levels of cyclin D were associated with a better survival (5-year DSS 78% versus 58%, p = 0.060).	('better', 'PosReg', (122, 128))	('survival', 'MPA', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('DSS', 'Chemical', '-', (146, 149))	('high levels', 'Var', (75, 86))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('cyclin D', 'Protein', (90, 98))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
414882	26847678	Overexpression of AXL has been associated with worse prognosis in many cancer types, including Ewing's and osteosarcoma.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('AXL', 'Gene', (18, 21))	('cancer', 'Disease', (71, 77))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('AXL', 'Gene', '558', (18, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	("Ewing's and osteosarcoma", 'Disease', 'MESH:C563168', (95, 119))
414997	26689374	MyoD1 & Myogenin are often negative in pleomorphic RMS41.	('MyoD1', 'Gene', (0, 5))	('in pleomorphic', 'Var', (36, 50))	('MyoD1', 'Gene', '4654', (0, 5))	('Myogenin', 'Gene', (8, 16))	('Myogenin', 'Gene', '4656', (8, 16))	('RMS', 'Phenotype', 'HP:0002859', (51, 54))	('often', 'NegReg', (21, 26))
415059	26366542	In addition, dissection of arteries and veins from abutting tumors can threaten their integrity, and formal vascular resection is sometimes necessary to prevent inadvertent venotomy or arteriotomy even in the absence of true invasion.	('dissection', 'Var', (13, 23))	('dissection of arteries', 'Phenotype', 'HP:0005294', (13, 35))	('integrity', 'MPA', (86, 95))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('threaten', 'NegReg', (71, 79))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
415075	24886914	The Two Main Forms of Histiocytic Sarcoma in the Predisposed Flatcoated Retriever Dog Display Variation in Gene Expression Examination of gene functions in specific tumor types improves insight in tumorigenesis and helps design better treatments.	('Sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('Histiocytic Sarcoma', 'Disease', (22, 41))	('improves', 'PosReg', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('Gene Expression', 'MPA', (107, 122))	('Variation', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Dog', 'Species', '9615', (82, 85))	('Histiocytic Sarcoma', 'Disease', 'MESH:D054747', (22, 41))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', (165, 170))
415109	24886914	As a result, C6, S100A12, S100A8, PHYH and IGJ were up-regulated and TKTL1, CLEC12A, CD9, CCL5 and ASPN were down-regulated in VHS compared to STHS.	('ASPN', 'Gene', (99, 103))	('PHYH', 'Gene', (34, 38))	('S100A8', 'Gene', (26, 32))	('up-regulated', 'PosReg', (52, 64))	('down-regulated', 'NegReg', (109, 123))	('TKTL1', 'Gene', (69, 74))	('IGJ', 'Gene', (43, 46))	('S100A12', 'Var', (17, 24))	('S100A8', 'Gene', '490461', (26, 32))	('C6', 'Gene', '479348', (13, 15))	('TKTL1', 'Gene', '481083', (69, 74))	('STHS', 'Phenotype', 'HP:0030448', (143, 147))	('ASPN', 'Gene', '610685', (99, 103))	('IGJ', 'Gene', '475166', (43, 46))
415126	24886914	At present, a straight forward hypothesis on the functional consequences of the variation in C6 expression in the different forms of HS is not easily postulated but it might be associated with a reaction of the innate immune system to the neoplasm and not a direct effect of the neoplastic cell population.	('neoplasm', 'Phenotype', 'HP:0002664', (239, 247))	('C6', 'Gene', '479348', (93, 95))	('neoplasm', 'Disease', (239, 247))	('variation', 'Var', (80, 89))	('associated', 'Reg', (177, 187))	('neoplasm', 'Disease', 'MESH:D009369', (239, 247))
415147	31595101	Since then, several Phase I and II clinical trials have been reported (or are ongoing) using these fluorescent antibodies for resection of head and neck (NTC01987375), glioma (NTC02855086), and pancreatic (NTC03384238) cancers.	('NTC03384238', 'Var', (206, 217))	('pancreatic', 'Disease', (194, 204))	('NTC02855086', 'Chemical', 'MESH:C527538', (176, 187))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('NTC01987375', 'Var', (154, 165))	('NTC02855086', 'Var', (176, 187))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancers', 'Disease', (219, 226))	('glioma', 'Disease', (168, 174))	('NTC01987375', 'Chemical', 'MESH:C527538', (154, 165))	('pancreatic', 'Disease', 'MESH:D010195', (194, 204))	('NTC03384238', 'Chemical', 'MESH:C527538', (206, 217))
415222	27317788	Therefore, partial or total quadriceps resection for soft-tissue sarcoma in the anterior compartment of the thigh can reduce knee extension strength and decrease post-operative function.	('men', 'Species', '9606', (96, 99))	('knee extension strength', 'CPA', (125, 148))	('sarcoma', 'Disease', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('partial', 'Var', (11, 18))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (53, 72))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('reduce knee extension', 'Phenotype', 'HP:0003066', (118, 139))	('reduce', 'NegReg', (118, 124))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (57, 72))	('post-operative', 'MPA', (162, 176))	('decrease', 'NegReg', (153, 161))
415271	27317788	Resection of four muscles or the femoral nerve increases risk of bone fracture from falling and decreases functional evaluation scores.	('decreases', 'NegReg', (96, 105))	('Resection', 'Var', (0, 9))	('functional', 'MPA', (106, 116))	('falling', 'Phenotype', 'HP:0002527', (84, 91))	('bone fracture', 'Disease', 'MESH:D050723', (65, 78))	('bone fracture', 'Phenotype', 'HP:0020110', (65, 78))	('bone fracture', 'Disease', (65, 78))
415289	22754201	There is a relation between chromosomal aberrations andendometrial sarcomas.	('endometrial sarcoma', 'Disease', 'MESH:D018203', (55, 74))	('endometrial sarcoma', 'Disease', (55, 74))	('chromosomal aberrations', 'Var', (28, 51))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (28, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('sarcomas', 'Disease', (67, 75))
415290	22754201	Chromosomal deletion on 7p was the most common finding (55.6%) in ESS and may play a role in tumor development and progression.	('Chromosomal deletion on', 'Var', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('play', 'Reg', (78, 82))	('ESS', 'Disease', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
415323	22754201	In multivariate analysis, older patients (age more than 50 years), black race, advanced stage, lack of primary surgery, nodal metastasis, high mitotic count more than 5 per 10 high-power fields, CD10 negative or low expression and lack of estrogen and progesterone receptors were independent prognostic factors for poor survival.	('CD10', 'Gene', '4311', (195, 199))	('patients', 'Species', '9606', (32, 40))	('CD10', 'Gene', (195, 199))	('expression', 'MPA', (216, 226))	('estrogen', 'Protein', (239, 247))	('low', 'NegReg', (212, 215))	('progesterone receptor', 'Gene', (252, 273))	('negative', 'NegReg', (200, 208))	('progesterone receptor', 'Gene', '5241', (252, 273))	('high', 'Var', (138, 142))
415336	22754201	Estrogen deprivation is most specifically achieved using inhibitors that block the last stage in the biosynthetic sequence, that is, the conversion of androgens to estrogens by the aromatase enzyme.	('conversion', 'MPA', (137, 147))	('aromatase', 'Gene', (181, 190))	('inhibitors', 'Var', (57, 67))	('aromatase', 'Gene', '1588', (181, 190))
415368	27955733	Detection of an EWSR1-WT1 rearrangement and selective WT1 carboxy-terminus immunoreactivity (characteristic of DSRCT) or dual immunoreactivity for the WT1 amino-terminus and carboxy-terminus (characteristic of WT) remain the most discriminating diagnostic tools.	('rearrangement', 'Var', (26, 39))	('EWSR1', 'Gene', '2130', (16, 21))	('WT1', 'Gene', '7490', (151, 154))	('EWS', 'Phenotype', 'HP:0012254', (16, 19))	('WT1', 'Gene', (151, 154))	('EWSR1', 'Gene', (16, 21))	('WT1', 'Gene', '7490', (22, 25))	('WT1', 'Gene', '7490', (54, 57))	('WT1', 'Gene', (22, 25))	('WT1', 'Gene', (54, 57))
415402	27955733	A phase 1 clinical trial of HIPEC in pediatric patients has demonstrated safety of HIPEC in children using cisplatin (Figure 4); the maximum tolerated dose was 100mg/m2 with a dose-limiting toxicity of grade 3 renal failure.	('100mg/m2', 'Var', (160, 168))	('renal failure', 'Phenotype', 'HP:0000083', (210, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('patients', 'Species', '9606', (47, 55))	('renal failure', 'Disease', 'MESH:D051437', (210, 223))	('children', 'Species', '9606', (92, 100))	('toxicity', 'Disease', 'MESH:D064420', (190, 198))	('toxicity', 'Disease', (190, 198))	('renal failure', 'Disease', (210, 223))
415490	32082316	However, modulation of ligand expression in order to avoid NK cell detection is a well-known strategy employed by tumors to escape immune recognition.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('modulation', 'Var', (9, 19))	('ligand', 'Protein', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))
415525	32082316	The ability of WT, DNAM-1, and NKG2D modified NK-92 cells to produce IFNgamma and TNFalpha upon 4 h of co-culture of 200,000 NK-92 cells with 200,000 primary sarcoma explant lines or the cell line Saos-2, was assessed by intracellular cytokine staining using the BD cytofix/cytoperm kit according to the manufacturer's instructions.	('NKG2D', 'Gene', '22914', (31, 36))	('DNAM-1', 'Gene', (19, 25))	('modified', 'Var', (37, 45))	('TNFalpha', 'Gene', '7124', (82, 90))	('NKG2D', 'Gene', (31, 36))	('sarcoma', 'Disease', 'MESH:D012509', (158, 165))	('DNAM-1', 'Gene', '10666', (19, 25))	('IFNgamma', 'Gene', (69, 77))	('sarcoma', 'Disease', (158, 165))	('IFNgamma', 'Gene', '3458', (69, 77))	('TNFalpha', 'Gene', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
415587	32082316	We also observed strong involvement of DNAM-1-mediated anti-tumor responses with 6 independent in vitro propagated sarcoma explants (HTT15, HTT53, HTT55, HTT73, HTT79, and HTT82) and 5 healthy donor PBMCs (Figure S5).	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('DNAM-1', 'Gene', '10666', (39, 45))	('sarcoma', 'Disease', (115, 122))	('donor', 'Species', '9606', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('HTT55', 'Var', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MC', 'Chemical', 'MESH:D008748', (201, 203))	('tumor', 'Disease', (60, 65))	('HTT73', 'Var', (154, 159))	('DNAM-1', 'Gene', (39, 45))
415598	32082316	Likewise, the blocking of DNAM-1 and NKG2D on NK-92 cells prior to co-incubation with targets, caused the respective responses of DNAM-1+ and NKG2D+ GM NK-92 cells to decrease to background levels when tested against Saos-2 and U-2 OS sarcoma cell lines (Figures 4B,D).	('DNAM-1', 'Gene', (26, 32))	('NKG2D', 'Gene', '22914', (142, 147))	('DNAM-1', 'Gene', (130, 136))	('responses', 'MPA', (117, 126))	('OS sarcoma', 'Disease', (232, 242))	('decrease', 'NegReg', (167, 175))	('NKG2D', 'Gene', (142, 147))	('DNAM-1', 'Gene', '10666', (26, 32))	('DNAM-1', 'Gene', '10666', (130, 136))	('NKG2D', 'Gene', '22914', (37, 42))	('blocking', 'Var', (14, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('OS sarcoma', 'Disease', 'MESH:C567932', (232, 242))	('GM', 'Chemical', '-', (149, 151))	('NKG2D', 'Gene', (37, 42))	('U-2 OS', 'CellLine', 'CVCL:0042', (228, 234))
415643	32082316	Clinical trials using T cell receptor (TCR) modified T cells seem to focus on NY-ESO-I on subtypes of sarcomas, such as liposarcoma and synovial sarcoma (NCT03450122, NCT01477021, NCT01343043, NCT03399448) while applications of Chimeric Antigen Receptor (CAR) technology in sarcoma include HER2 (NCT00902044), EGFR (NCT03618381), CD44v6 and GD2 directed CARs.	('HER2', 'Gene', (290, 294))	('EGFR', 'Gene', '1956', (310, 314))	('CD4', 'Gene', '920', (330, 333))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('liposarcoma', 'Disease', 'MESH:D008080', (120, 131))	('sarcomas', 'Disease', 'MESH:D012509', (102, 110))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcomas', 'Disease', (102, 110))	('TCR', 'Gene', '6962', (39, 42))	('CD4', 'Gene', (330, 333))	('sarcoma', 'Disease', (124, 131))	('liposarcoma', 'Phenotype', 'HP:0012034', (120, 131))	('synovial sarcoma', 'Disease', (136, 152))	('sarcoma', 'Disease', 'MESH:D012509', (274, 281))	('CAR', 'Gene', (255, 258))	('CAR', 'Gene', '9970', (255, 258))	('sarcoma', 'Disease', (274, 281))	('NCT01343043', 'Var', (180, 191))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('synovial sarcoma', 'Disease', 'MESH:D013584', (136, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcoma', 'Disease', (145, 152))	('NCT01477021', 'Var', (167, 178))	('NCT00902044', 'Var', (296, 307))	('Chimeric Antigen Receptor', 'Gene', '9970', (228, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('Chimeric Antigen Receptor', 'Gene', (228, 253))	('liposarcoma', 'Disease', (120, 131))	('HER2', 'Gene', '2064', (290, 294))	('TCR', 'Gene', (39, 42))	('EGFR', 'Gene', (310, 314))	('NCT03618381', 'Var', (316, 327))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (136, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('NCT03399448', 'Var', (193, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('CAR', 'Gene', (354, 357))	('CAR', 'Gene', '9970', (354, 357))	('NCT03450122', 'Var', (154, 165))	('T cell receptor', 'Gene', (22, 37))	('T cell receptor', 'Gene', '6962', (22, 37))
415645	32082316	While NK cells are one of the promising candidates in the development of advanced cancer immunotherapies, very few clinical trials are currently exploring NK cells as a therapeutic option for sarcomas and none are exclusively designed to be sarcoma-specific (NCT02100891, NCT01875601).	('NCT02100891', 'Var', (259, 270))	('sarcomas', 'Disease', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (241, 248))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('sarcomas', 'Disease', 'MESH:D012509', (192, 200))	('sarcoma', 'Disease', 'MESH:D012509', (241, 248))	('sarcoma', 'Disease', (192, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('sarcoma', 'Disease', (241, 248))
415676	32082316	Thus, it is possible to argue that the co-triggering of DNAM-1 and NKG2D may result in the enhancement of these signals but also has the risk of the two signals stumbling upon a bottleneck of either ligand engagement or signaling intermediates that dictates the amount of activation possible.	('co-triggering', 'Var', (39, 52))	('NKG2D', 'Gene', '22914', (67, 72))	('enhancement', 'PosReg', (91, 102))	('DNAM-1', 'Gene', (56, 62))	('NKG2D', 'Gene', (67, 72))	('DNAM-1', 'Gene', '10666', (56, 62))
415800	31289572	MicroRNA-410-3p upregulation suppresses proliferation, invasion and migration, and promotes apoptosis in rhabdomyosarcoma cells Rhabdomyosarcoma (RMS) is one of the most common types of soft tissue sarcoma in children; however, the pathogenesis of RMS is unclear.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (186, 205))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (186, 205))	('rhabdomyosarcoma', 'Disease', (105, 121))	('soft tissue sarcoma', 'Disease', (186, 205))	('children', 'Species', '9606', (209, 217))	('MicroRNA-410-3p upregulation', 'Var', (0, 28))	('proliferation', 'CPA', (40, 53))	('apoptosis', 'CPA', (92, 101))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (105, 121))	('Rhabdomyosarcoma', 'Disease', (128, 144))	('promotes', 'PosReg', (83, 91))	('RMS', 'Phenotype', 'HP:0002859', (146, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (105, 121))	('RMS', 'Phenotype', 'HP:0002859', (248, 251))	('invasion', 'CPA', (55, 63))	('suppresses', 'NegReg', (29, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (128, 144))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (128, 144))
415814	31289572	This includes miR-21, miR-183, miR-372 and miR-373, which serve as oncogenes, and let-7, miR-124 and miR-200a, which serve as tumor suppressor genes.	('miR-21', 'Gene', '406991', (14, 20))	('miR-372', 'Gene', (31, 38))	('miR-373', 'Gene', '442918', (43, 50))	('let-7', 'Var', (82, 87))	('miR-200a', 'Gene', (101, 109))	('miR', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('miR', 'Gene', (101, 104))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', '220972', (89, 92))	('miR-21', 'Gene', (14, 20))	('miR-372', 'Gene', '442917', (31, 38))	('miR', 'Gene', (43, 46))	('miR', 'Gene', (89, 92))	('miR-183', 'Gene', '406959', (22, 29))	('miR', 'Gene', '220972', (31, 34))	('miR-200a', 'Gene', '406983', (101, 109))	('tumor', 'Disease', (126, 131))	('miR', 'Gene', '220972', (22, 25))	('miR-183', 'Gene', (22, 29))	('miR-373', 'Gene', (43, 50))	('miR', 'Gene', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (22, 25))	('miR', 'Gene', '220972', (101, 104))
415855	31289572	The cBioPortal for Cancer Genomics  was used to evaluate the survival analysis of miR-410-3p copy number alterations (CNAs) in the sarcoma data from TCGA, and was employed for exploring, visualizing and analyzing multidimensional cancer genomics data from TCGA.	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer', 'Disease', (19, 25))	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('sarcoma', 'Disease', (131, 138))	('miR-410', 'Gene', (82, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('copy number alterations', 'Var', (93, 116))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('miR-410', 'Gene', '574434', (82, 89))
415882	31289572	Therefore, changes of miR-410-3p may serve as tumor regulatory factors in patients.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Disease', (46, 51))	('miR-410', 'Gene', (22, 29))	('changes', 'Var', (11, 18))	('miR-410', 'Gene', '574434', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
415902	31289572	Exogenous miR-410-3p expression promoted the expression of apoptotic proteins, including bax, cleaved-caspase 3, cleaved PARP and p53, and inhibited the expression of Bcl-2 protein (Fig.	('miR-410', 'Gene', (10, 17))	('promoted', 'PosReg', (32, 40))	('p53', 'Gene', (130, 133))	('PARP', 'Gene', '142', (121, 125))	('cleaved-caspase', 'MPA', (94, 109))	('miR-410', 'Gene', '574434', (10, 17))	('apoptotic proteins', 'Gene', (59, 77))	('p53', 'Gene', '7157', (130, 133))	('expression', 'MPA', (45, 55))	('cleaved', 'Var', (113, 120))	('expression', 'MPA', (153, 163))	('PARP', 'Gene', (121, 125))	('Bcl-2 protein', 'Protein', (167, 180))	('bax', 'Gene', (89, 92))	('inhibited', 'NegReg', (139, 148))
415909	31289572	The cBioPortal for Cancer Genomics revealed that the miR-410 alterations may act as regulatory factors of sarcoma in patients.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer', 'Disease', (19, 25))	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('miR-410', 'Gene', (53, 60))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('miR-410', 'Gene', '574434', (53, 60))	('alterations', 'Var', (61, 72))	('patients', 'Species', '9606', (117, 125))	('sarcoma', 'Disease', (106, 113))
415915	31289572	A number of studies have reported that sarcoma aggressiveness is associated with key factors of the phenotypic plasticity of tumors, including Snail, of which high expression was associated with reduced DFS of patients with sarcoma, and ZEB1, which is upregulated in patients with metastasized osteosarcoma compared with those without metastasis.	('reduced', 'NegReg', (195, 202))	('sarcoma aggressiveness', 'Disease', (39, 61))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('sarcoma', 'Disease', (39, 46))	('ZEB1', 'Gene', (237, 241))	('osteosarcoma', 'Phenotype', 'HP:0002669', (294, 306))	('sarcoma', 'Disease', 'MESH:D012509', (299, 306))	('sarcoma', 'Disease', (299, 306))	('patients', 'Species', '9606', (267, 275))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('Snail', 'Gene', '6615', (143, 148))	('high expression', 'Var', (159, 174))	('patients', 'Species', '9606', (210, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('aggressiveness', 'Phenotype', 'HP:0000718', (47, 61))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('DFS', 'MPA', (203, 206))	('sarcoma', 'Disease', 'MESH:D012509', (224, 231))	('ZEB1', 'Gene', '6935', (237, 241))	('osteosarcoma', 'Disease', 'MESH:D012516', (294, 306))	('osteosarcoma', 'Disease', (294, 306))	('sarcoma', 'Disease', (224, 231))	('Snail', 'Gene', (143, 148))	('sarcoma aggressiveness', 'Disease', 'MESH:D012509', (39, 61))	('upregulated', 'PosReg', (252, 263))
415923	31289572	miR-27a overexpression has been demonstrated to promote RMS cell proliferation by directly targeting retinoic acid alpha receptor and retinoic X receptor alpha.	('miR-27a', 'Gene', '407018', (0, 7))	('targeting', 'Reg', (91, 100))	('RMS', 'Phenotype', 'HP:0002859', (56, 59))	('retinoic X receptor alpha', 'Protein', (134, 159))	('overexpression', 'Var', (8, 22))	('retinoic acid alpha receptor', 'Protein', (101, 129))	('miR-27a', 'Gene', (0, 7))	('promote', 'PosReg', (48, 55))	('RMS cell proliferation', 'CPA', (56, 78))
415926	31289572	Therefore, growing evidence suggests that the aberrant expression of miRNAs serves important roles in diverse biological processes, including development, differentiation, growth and metabolism.	('differentiation', 'CPA', (155, 170))	('metabolism', 'CPA', (183, 193))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('roles', 'Reg', (93, 98))	('serves', 'Reg', (76, 82))	('aberrant expression', 'Var', (46, 65))	('growth', 'CPA', (172, 178))
415931	31289572	Furthermore, exogenous miR-410-3p expression was revealed to induce apoptosis and inhibit proliferation by enhancing the expression of pro-apoptotic proteins, and suppress RMS cell invasion and migration by regulating the EMT process.	('induce', 'PosReg', (61, 67))	('regulating', 'Reg', (207, 217))	('EMT process', 'CPA', (222, 233))	('proliferation', 'CPA', (90, 103))	('suppress', 'NegReg', (163, 171))	('RMS', 'Phenotype', 'HP:0002859', (172, 175))	('apoptosis', 'CPA', (68, 77))	('inhibit', 'NegReg', (82, 89))	('expression of', 'MPA', (121, 134))	('miR-410', 'Gene', (23, 30))	('enhancing', 'PosReg', (107, 116))	('miR-410', 'Gene', '574434', (23, 30))	('exogenous', 'Var', (13, 22))
415950	29487589	In melanoma, HERV-K expression is suggested to be an early event in tumorigenesis, seemingly enhancing the pathological process of tumor formation.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('HERV-K', 'Protein', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('expression', 'Var', (20, 30))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('enhancing', 'PosReg', (93, 102))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('HERV-K', 'Species', '45617', (13, 19))
415978	29487589	Expression analyses for BCL2 mRNA, miR-203 and miR-210, HIF-1alpha mRNA and miR-199a were carried out as previously described.	('HIF-1alpha', 'Gene', (56, 66))	('miR-210', 'Var', (47, 54))	('HIF-1alpha', 'Gene', '3091', (56, 66))	('miR-199a', 'Var', (76, 84))	('miR-203', 'Var', (35, 42))
416015	29487589	Other groups demonstrated upregulation of the HERV-W expression in neuroblastoma cell lines due to hypoxic conditions or upregulation of the HERV-E expression in renal cell carcinomas due to inactivation of the von Hippel-Lindau factor and subsequent stabilization of the oxygen sensor protein HIF-1alpha.	('HERV-W', 'Species', '87786', (46, 52))	('neuroblastoma', 'Disease', 'MESH:D009447', (67, 80))	('upregulation', 'PosReg', (121, 133))	('HERV-W', 'Gene', (46, 52))	('upregulation', 'PosReg', (26, 38))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (162, 183))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (211, 228))	('hypoxic conditions', 'Disease', (99, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('renal cell carcinomas', 'Disease', (162, 183))	('HERV-E', 'Gene', (141, 147))	('HERV', 'Species', '11827', (46, 50))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (162, 183))	('oxygen', 'Chemical', 'MESH:D010100', (272, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('HIF-1alpha', 'Gene', '3091', (294, 304))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('HERV', 'Species', '11827', (141, 145))	('inactivation', 'Var', (191, 203))	('hypoxic conditions', 'Disease', 'MESH:D009135', (99, 117))	('neuroblastoma', 'Disease', (67, 80))	('von Hippel-Lindau', 'Disease', (211, 228))	('neuroblastoma', 'Phenotype', 'HP:0003006', (67, 80))	('expression', 'MPA', (148, 158))	('HIF-1alpha', 'Gene', (294, 304))
416018	29487589	Furthermore, HERV-K and HERV-F expression were both significantly correlated to the mRNA expression of H2A.Bbd, a histone A2 variant encoded on the X chromosome, which is found to be associated with the nucleosomes of transcriptionally active genomic regions.	('variant', 'Var', (125, 132))	('HERV', 'Species', '11827', (13, 17))	('H2A.Bbd', 'Gene', '474381', (103, 110))	('HERV', 'Species', '11827', (24, 28))	('H2A.Bbd', 'Gene', (103, 110))	('HERV-K', 'Species', '45617', (13, 19))
416025	29487589	Additionally, hypomethylation and subsequent HERV induction was also demonstrated in ovarian carcinoma, and specifically the extent HERV-K hypomethylation was associated with a poor prognosis and therapy resistance in ovarian carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (218, 235))	('HERV', 'Species', '11827', (45, 49))	('patients', 'Species', '9606', (236, 244))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (218, 235))	('HERV', 'Protein', (45, 49))	('HERV-K', 'Species', '45617', (132, 138))	('ovarian carcinoma', 'Disease', (218, 235))	('HERV-K', 'Gene', (132, 138))	('HERV', 'Species', '11827', (132, 136))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (85, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (85, 102))	('ovarian carcinoma', 'Disease', (85, 102))	('hypomethylation', 'Var', (139, 154))
416036	26528855	Palbociclib is also active in vivo against sarcomas displaying high levels of CDK4 but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a.	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('sarcomas', 'Disease', (99, 107))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('CDK4', 'Var', (78, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcomas', 'Disease', 'MESH:D012509', (99, 107))	('sarcomas', 'Disease', (43, 51))
416037	26528855	The analysis of tumors growing after palbociclib showed a clear decrease in the CDK4 levels, indicating that clonal selection occurred in these treated tumors.	('decrease', 'NegReg', (64, 72))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('palbociclib', 'Var', (37, 48))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('CDK4 levels', 'MPA', (80, 91))	('tumors', 'Disease', (152, 158))	('tumors', 'Disease', (16, 22))	('palbociclib', 'Chemical', 'MESH:C500026', (37, 48))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
416043	26528855	Sarcomas are usually grouped in two broad categories according to molecular genetics: sarcomas harboring a diploid or nearly diploid karyotype and simple genetic driver alterations, such as Ewing's sarcoma, or sarcomas with a complex and imbalanced karyotype, such as osteosarcoma.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('osteosarcoma', 'Disease', (268, 280))	('osteosarcoma', 'Disease', 'MESH:D012516', (268, 280))	("Ewing's sarcoma", 'Disease', (190, 205))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('alterations', 'Var', (169, 180))	('sarcomas', 'Disease', 'MESH:D012509', (86, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('sarcomas', 'Disease', (86, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('sarcomas', 'Disease', 'MESH:D012509', (210, 218))	('sarcomas', 'Phenotype', 'HP:0100242', (210, 218))	('sarcomas', 'Disease', (210, 218))	('osteosarcoma', 'Phenotype', 'HP:0002669', (268, 280))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (190, 205))	('Sarcomas', 'Disease', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (190, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))
416053	26528855	Those findings support the hypothesis that widely diverse sarcoma tumors may share a dependence on a particular kinase and that inhibiting this kinase may, therefore, be expected to be effective for all histological subtypes that are positive for this biomarker.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('sarcoma tumors', 'Disease', 'MESH:D012509', (58, 72))	('inhibiting', 'Var', (128, 138))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('sarcoma tumors', 'Disease', (58, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
416054	26528855	Aberrant regulation of the cell cycle is a hallmark of cancer, and multiple mechanisms contribute to the deregulation of the G1-to-S checkpoint.	('G1-to-S', 'CPA', (125, 132))	('regulation', 'MPA', (9, 19))	('Aberrant', 'Var', (0, 8))	('deregulation', 'MPA', (105, 117))	('cell cycle', 'CPA', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('hallmark of cancer', 'Disease', (43, 61))	('hallmark of cancer', 'Disease', 'MESH:D009369', (43, 61))
416055	26528855	These mechanisms include amplification or mutation of the CDK4 and CDK6 genes, amplification of the genes encoding D-type cyclins and deletion or silencing of the CDKN2A/B gene, which encodes for the INK4 inhibitors p16ink4a and p15ink4b.	('CDK6', 'Gene', (67, 71))	('CDKN2A/B', 'Gene', '1029;1030', (163, 171))	('amplification', 'PosReg', (25, 38))	('CDK6', 'Gene', '1021', (67, 71))	('p15ink4b', 'Gene', '1030', (229, 237))	('mutation', 'Var', (42, 50))	('deletion', 'Var', (134, 142))	('CDKN2A/B', 'Gene', (163, 171))	('INK4', 'Gene', '1029', (200, 204))	('INK4', 'Gene', (200, 204))	('amplification', 'Var', (79, 92))	('CDK4', 'Gene', (58, 62))	('silencing', 'NegReg', (146, 155))	('p15ink4b', 'Gene', (229, 237))
416060	26528855	Additionally, mice expressing a mutant form of cyclin D1 that binds to, but does not activate, CDK4 are resistant to erbB2-induced tumorigenesis.	('binds', 'Interaction', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mice', 'Species', '10090', (14, 18))	('resistant', 'NegReg', (104, 113))	('tumor', 'Disease', (131, 136))	('mutant', 'Var', (32, 38))
416061	26528855	The ablation of CDK4 using siRNA in erbB2-induced mammary tumor cells eliminates their oncogenic properties.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('oncogenic properties', 'CPA', (87, 107))	('CDK4', 'Gene', (16, 20))	('ablation', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('eliminates', 'NegReg', (70, 80))
416062	26528855	The loss of CDK4 has also been implicated in the inability of KRasG12-induced lung tumors and c-Myc-induced skin tumors to develop.	('skin tumors', 'Phenotype', 'HP:0008069', (108, 119))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('skin tumors', 'Disease', (108, 119))	('c-Myc', 'Gene', '4609', (94, 99))	('lung tumors', 'Disease', (78, 89))	('CDK4', 'Gene', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('lung tumors', 'Phenotype', 'HP:0100526', (78, 89))	('c-Myc', 'Gene', (94, 99))	('KRasG12-induced', 'Gene', (62, 77))	('skin tumors', 'Disease', 'MESH:D012878', (108, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('lung tumors', 'Disease', 'MESH:D008175', (78, 89))	('loss', 'Var', (4, 8))
416066	26528855	Palbociclib (PD0332991) is the first highly selective inhibitor of CDK4/6 to be tested and approved in humans for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as an initial endocrine-based therapy for metastatic disease.	('women', 'Species', '9606', (184, 189))	('epidermal growth factor receptor 2', 'Gene', '2064', (233, 267))	('letrozole', 'Chemical', 'MESH:D000077289', (138, 147))	('ER', 'Gene', '2099', (214, 216))	('ER', 'Gene', '2099', (270, 272))	('breast cancer', 'Phenotype', 'HP:0003002', (293, 306))	('PD0332991', 'Var', (13, 22))	('estrogen receptor', 'Gene', (195, 212))	('human', 'Species', '9606', (103, 108))	('epidermal growth factor receptor 2', 'Gene', (233, 267))	('CDK4/6', 'Gene', '1019;1021', (67, 73))	('breast cancer', 'Disease', (293, 306))	('breast cancer', 'Disease', 'MESH:D001943', (293, 306))	('CDK4/6', 'Gene', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('estrogen receptor', 'Gene', '2099', (195, 212))	('human', 'Species', '9606', (227, 232))	('humans', 'Species', '9606', (103, 109))	('PD0332991', 'Chemical', 'MESH:C500026', (13, 22))
416071	26528855	In different cancer models, treatment with PD0332991 not only exerts a cytostatic effect but also induces either the senescence or the apoptotic cell death of tumoral cells.	('apoptotic cell death', 'CPA', (135, 155))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('induces', 'Reg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PD0332991', 'Chemical', 'MESH:C500026', (43, 52))	('cancer', 'Disease', (13, 19))	('tumor', 'Disease', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cytostatic effect', 'CPA', (71, 88))	('senescence', 'CPA', (117, 127))	('PD0332991', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
416081	26528855	We found that in all cell lines tested, palbociclib induced growth arrest at Go/G1 based on the detection of markers of cellular senescence (Figure 1).	('palbociclib', 'Var', (40, 51))	('growth arrest', 'Disease', 'MESH:D006323', (60, 73))	('growth arrest', 'Disease', (60, 73))	('growth arrest at Go', 'Phenotype', 'HP:0031164', (60, 79))	('growth arrest', 'Phenotype', 'HP:0001510', (60, 73))	('palbociclib', 'Chemical', 'MESH:C500026', (40, 51))
416092	26528855	Because it has been reported that CDK4R24C, an active mutant of CDK4, is present in human tumors (athough not reported in sarcomas) and cannot be inhibited by members of the INK4 family, we decided to overexpress this mutant in these sarcoma cells (Figure 2B) in order to gain insight on palbociclib mechanism by exploring the effect of CDK4R24C on its cellular response.	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('R24C', 'Mutation', 'rs11547328', (341, 345))	('overexpress', 'PosReg', (201, 212))	('R24C', 'Mutation', 'rs11547328', (38, 42))	('INK4', 'Gene', '1029', (174, 178))	('gain', 'PosReg', (272, 276))	('sarcoma', 'Disease', 'MESH:D012509', (234, 241))	('palbociclib', 'Chemical', 'MESH:C500026', (288, 299))	('sarcoma', 'Disease', (234, 241))	('INK4', 'Gene', (174, 178))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('human', 'Species', '9606', (84, 89))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('sarcomas', 'Disease', 'MESH:D012509', (122, 130))	('sarcoma', 'Disease', (122, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('sarcomas', 'Disease', (122, 130))	('CDK4R24C', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
416093	26528855	An increased sensitivity to palbociclib was observed in cells overexpressing wild type CDK4, whereas the overexpression of the CDK4R24C mutant increased the resistance of both sarcoma cell lines to palbociclib (Figure 2C).	('increased', 'PosReg', (3, 12))	('increased', 'PosReg', (143, 152))	('sensitivity', 'MPA', (13, 24))	('CDK4R24C', 'Var', (127, 135))	('sarcoma cell lines', 'Disease', 'MESH:D012509', (176, 194))	('sarcoma cell lines', 'Disease', (176, 194))	('palbociclib', 'Chemical', 'MESH:C500026', (28, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('resistance', 'MPA', (157, 167))	('palbociclib', 'Chemical', 'MESH:C500026', (198, 209))	('CDK4', 'Gene', (87, 91))
416106	26528855	Whereas some PDXs such as S11, S14 and S23 displayed a clear decrease in proliferation, others such as S29, did not show any effect of to palbociclib administration on KI67 expression (Figure 5A).	('decrease', 'NegReg', (61, 69))	('KI67', 'Gene', (168, 172))	('S11', 'Var', (26, 29))	('proliferation', 'CPA', (73, 86))	('palbociclib', 'Chemical', 'MESH:C500026', (138, 149))	('S23', 'Var', (39, 42))	('S14', 'Var', (31, 34))	('KI67', 'Gene', '17345', (168, 172))
416109	26528855	We can appreciate that palbociclib induces a decrease in all cell cycle related proteins, with a clear effect on pRb phosporylation in all models, either responding or not responding, as well as CDK4, confirming the activity of palbociclib in all models.	('palbociclib', 'Var', (23, 34))	('pRb', 'Gene', '5925', (113, 116))	('palbociclib', 'Chemical', 'MESH:C500026', (228, 239))	('decrease', 'NegReg', (45, 53))	('pRb', 'Gene', (113, 116))	('cell', 'Protein', (61, 65))	('palbociclib', 'Chemical', 'MESH:C500026', (23, 34))
416112	26528855	The tumors expressing high CDK4 levels (S11 and S16) responded to the drug (figure 6).	('S11', 'Var', (40, 43))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('S16', 'Var', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('responded to the drug', 'MPA', (53, 74))
416115	26528855	However, the two tumors expressing high p16ink4a and normal CDK4 levels, (S23 and S27), showed some initial response to the CDK4 inhibitor, but after ending the treatment, tumor growth recovered to an even faster rate than that of the untreated tumors, and the survival of the treated mice was very similar to that of the untreated controls (Figure 6).	('tumor', 'Disease', (172, 177))	('tumors', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('high p16ink4a', 'Var', (35, 48))	('faster', 'PosReg', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (245, 250))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('response', 'MPA', (108, 116))	('p16ink4a', 'Var', (40, 48))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('mice', 'Species', '10090', (285, 289))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
416120	26528855	These data agree with the in vitro cellular data, suggesting that tumors expressing high CDK4 levels respond more strongly to palbociclib.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('palbociclib', 'Chemical', 'MESH:C500026', (126, 137))	('strongly', 'PosReg', (114, 122))	('high', 'Var', (84, 88))	('respond', 'MPA', (101, 108))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('CDK4', 'Gene', (89, 93))
416129	26528855	Similarly, we did not detect any association of the p16ink4a, cyclin D1 or CDK2 levels with the re-growth of treated tumors (Figure 7).	('CDK2', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('CDK2', 'Gene', '1017', (75, 79))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('p16ink4a', 'Var', (52, 60))	('cyclin D1', 'MPA', (62, 71))
416133	26528855	Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEE011, and LY2835219.	('LEE011', 'Chemical', 'MESH:C000589651', (92, 98))	('PD0332991', 'Chemical', 'MESH:C500026', (80, 89))	('CDK4', 'Protein', (21, 25))	('PD0332991', 'Var', (80, 89))	('LEE011', 'Var', (92, 98))	('palbociclib', 'Chemical', 'MESH:C500026', (67, 78))	('LY2835219', 'Var', (104, 113))	('LY2835219', 'Chemical', 'MESH:C000590451', (104, 113))
416134	26528855	CDK4 inhibitors display in vitro activity against a broad range of cancers and antitumor activity in patients with breast cancer, lymphoma, sarcoma, and other tumors.	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('patients', 'Species', '9606', (101, 109))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('sarcoma', 'Disease', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('lymphoma', 'Disease', (130, 138))	('lymphoma', 'Disease', 'MESH:D008223', (130, 138))	('tumor', 'Disease', (159, 164))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('CDK4', 'Gene', (0, 4))	('breast cancer', 'Disease', (115, 128))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('cancers', 'Disease', (67, 74))	('inhibitors', 'Var', (5, 15))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
416136	26528855	Treating these sarcoma tumors with the CDK4 inhibitor palbociclib revealed that tumors expressing high levels of CDK4 mRNA, but not those expressing low CDK4 and high p16INK4a levels, responded to palbociclib.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('sarcoma tumors', 'Disease', (15, 29))	('p16INK4a', 'Gene', (167, 175))	('CDK4', 'Var', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('palbociclib', 'Chemical', 'MESH:C500026', (197, 208))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('responded to', 'MPA', (184, 196))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('sarcoma tumors', 'Disease', 'MESH:D012509', (15, 29))	('p16INK4a', 'Gene', '1029', (167, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('palbociclib', 'Chemical', 'MESH:C500026', (54, 65))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
416137	26528855	On the other hand, we have found that CDK4-R24C mutant increases resistance to the drug.	('increases', 'PosReg', (55, 64))	('resistance to the drug', 'MPA', (65, 87))	('R24C', 'Mutation', 'rs11547328', (43, 47))	('CDK4-R24C mutant', 'Var', (38, 54))
416138	26528855	Since the only known phenotype associated to the R24C mutation is the insensitivity to Ink4 inhibitors the mechanistic basis of this result is unclear.	('insensitivity to', 'MPA', (70, 86))	('Ink4', 'Gene', '1029', (87, 91))	('Ink4', 'Gene', (87, 91))	('R24C', 'Mutation', 'rs11547328', (49, 53))	('R24C', 'Var', (49, 53))
416140	26528855	It is possible that mutation in R24C of CDK4 slightly disturbs the ATP-binding pocket providing lower affinity of palbociclib for mutant CDK4, thus rendering this protein more resistant to its inhibition.	('CDK4', 'Gene', (40, 44))	('ATP-binding pocket', 'MPA', (67, 85))	('resistant', 'MPA', (176, 185))	('lower', 'NegReg', (96, 101))	('affinity', 'MPA', (102, 110))	('mutation', 'Var', (20, 28))	('more', 'PosReg', (171, 175))	('palbociclib', 'Chemical', 'MESH:C500026', (114, 125))	('CDK4', 'Gene', (137, 141))	('ATP', 'Chemical', 'MESH:D000255', (67, 70))	('R24C', 'Mutation', 'rs11547328', (32, 36))	('mutant', 'Var', (130, 136))	('disturbs', 'NegReg', (54, 62))
416145	26528855	In our hands, in vivo studies suggest that high levels of p16ink4a are a marker of poor response to palbociclib, even in the presence of active pRb in the tumors as demonstrated by its phosphorylation as diverse sites (Figure 7).	('palbociclib', 'Chemical', 'MESH:C500026', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('p16ink4a', 'Var', (58, 66))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('pRb', 'Gene', (144, 147))	('pRb', 'Gene', '5925', (144, 147))
416146	26528855	Whereas two sarcomas expressing high CDK4 levels responded (S11 and S16), the two sarcomas expressing high p16INK4a and normal CDK4 levels showed a poor response and early recovery from treatment.	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('p16INK4a', 'Gene', '1029', (107, 115))	('S11', 'Var', (60, 63))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('S16', 'Var', (68, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('sarcomas', 'Disease', 'MESH:D012509', (82, 90))	('sarcomas', 'Disease', (12, 20))	('p16INK4a', 'Gene', (107, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcomas', 'Disease', (82, 90))
416149	26528855	It is also possible that under possible limiting molecular conditions (normal CDK4 medium/low cyclin D and low p16INK4a), the response is worse than under conditions of the complete absence of p16INK4a.	('cyclin D', 'Protein', (94, 102))	('p16INK4a', 'Gene', '1029', (111, 119))	('p16INK4a', 'Gene', '1029', (193, 201))	('CDK4', 'Var', (78, 82))	('p16INK4a', 'Gene', (111, 119))	('medium/low', 'NegReg', (83, 93))	('p16INK4a', 'Gene', (193, 201))	('low', 'Var', (107, 110))
416152	26528855	In line with the results of the responsive MPNST-S14 sample, it is worth mentioning that MPNSTs are sensitive to sorafenib, probably due to the inhibition of MEK and ERK, the suppression of cyclin D1, and the hypophosphorylation of pRb at CDK4-specific sites, resulting in cell cycle arrest.	('MEK', 'Gene', (158, 161))	('hypophosphorylation', 'Var', (209, 228))	('ERK', 'Gene', '5594', (166, 169))	('MEK', 'Gene', '5609', (158, 161))	('pRb', 'Gene', '5925', (232, 235))	('ERK', 'Gene', (166, 169))	('pRb', 'Gene', (232, 235))	('cyclin D1', 'Protein', (190, 199))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (273, 290))	('inhibition', 'NegReg', (144, 154))	('sorafenib', 'Chemical', 'MESH:D000077157', (113, 122))	('cell cycle arrest', 'CPA', (273, 290))	('suppression', 'NegReg', (175, 186))
416162	26528855	Increased CDK4 activity due to activating mutations, gene amplification, or the inhibition of CDK4-inhibitory signals via the silencing of p16INK4a has been suggested as a tumor-initiating and/or tumor-promoting event in different tumor types.	('inhibition', 'NegReg', (80, 90))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('silencing', 'Var', (126, 135))	('CDK4', 'Enzyme', (10, 14))	('activity', 'MPA', (15, 23))	('tumor', 'Disease', (231, 236))	('activating', 'PosReg', (31, 41))	('gene amplification', 'Var', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('p16INK4a', 'Gene', (139, 147))	('Increased', 'PosReg', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('CDK4-inhibitory signals', 'MPA', (94, 117))	('p16INK4a', 'Gene', '1029', (139, 147))	('mutations', 'Var', (42, 51))
416163	26528855	The amplification of CDK4, located on chromosome 12q13-14, has been reported in sarcomas, glioblastomas and breast cancers.	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('glioblastomas', 'Disease', (90, 103))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('sarcomas', 'Disease', 'MESH:D012509', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('CDK4', 'Gene', (21, 25))	('amplification', 'Var', (4, 17))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('glioblastomas', 'Phenotype', 'HP:0012174', (90, 103))	('breast cancers', 'Disease', (108, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('reported', 'Reg', (68, 76))	('sarcomas', 'Disease', (80, 88))	('glioblastomas', 'Disease', 'MESH:D005909', (90, 103))
416164	26528855	Activating CDK4 mutations have been reported in melanoma.	('melanoma', 'Disease', (48, 56))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (16, 25))	('CDK4', 'Gene', (11, 15))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
416165	26528855	Based on the accumulating evidence that CDK4 gene alterations are associated with the proliferation of different tumor types, CDK4 inhibitors are currently being studied in clinical trials.	('tumor', 'Disease', (113, 118))	('associated', 'Reg', (66, 76))	('alterations', 'Var', (50, 61))	('CDK4 gene', 'Gene', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
416166	26528855	Activating CDK4 mutations are less frequently reported in tumors than CDK4 gene amplification, and not reported in sarcoma tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('sarcoma tumors', 'Disease', (115, 129))	('Activating', 'PosReg', (0, 10))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (16, 25))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('sarcoma tumors', 'Disease', 'MESH:D012509', (115, 129))	('CDK4', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
416167	26528855	Our data suggest that tumors carrying these mutants may not be suitable for treatment with palbociclib.	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutants', 'Var', (44, 51))	('palbociclib', 'Chemical', 'MESH:C500026', (91, 102))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
416168	26528855	The amplification of chromosome 12q13-15 has been well documented in different sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Disease', (79, 87))	('amplification', 'Var', (4, 17))
416172	26528855	CDK4 amplification is correlated with a significantly poorer progression-free survival (PFS) and disease-free survival of liposarcoma.	('poorer', 'NegReg', (54, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Disease', (122, 133))	('CDK4', 'Gene', (0, 4))	('liposarcoma', 'Phenotype', 'HP:0012034', (122, 133))	('liposarcoma', 'Disease', 'MESH:D008080', (122, 133))	('progression-free survival', 'CPA', (61, 86))
416173	26528855	Furthermore, in a small number of MPNSTs, or neurosarcomas, CDK4 gene amplification and subsequent increased CDK4 expression are significant predictors of poor patient survival.	('CDK4', 'Gene', (109, 113))	('gene amplification', 'Var', (65, 83))	('CDK4', 'Gene', (60, 64))	('neurosarcomas', 'Disease', 'None', (45, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('neurosarcomas', 'Disease', (45, 58))	('increased', 'PosReg', (99, 108))	('expression', 'MPA', (114, 124))	('patient', 'Species', '9606', (160, 167))	('amplification', 'Var', (70, 83))
416174	26528855	Very little is known about whether genomic alterations in CDK4 can predict the tumor response to CDK inhibitors.	('tumor', 'Disease', (79, 84))	('genomic alterations', 'Var', (35, 54))	('predict', 'Reg', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('CDK4', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
416175	26528855	No completed study has demonstrated that activating CDK4 mutations affect the sensitivity of tumors or tumor cells to CDK inhibitors independently of 12q13-15 amplification.	('CDK4', 'Gene', (52, 56))	('sensitivity', 'MPA', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors or tumor', 'Disease', 'MESH:D009369', (93, 108))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('activating', 'PosReg', (41, 51))	('affect', 'Reg', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (57, 66))	('tumors or tumor', 'Disease', (93, 108))
416176	26528855	Preclinical and clinical studies of liposarcoma suggested that the amplification of CDK4 may predict an increased response to CDK4 inhibitors.	('response', 'MPA', (114, 122))	('liposarcoma', 'Disease', (36, 47))	('increased', 'PosReg', (104, 113))	('CDK4', 'Gene', (84, 88))	('amplification', 'Var', (67, 80))	('liposarcoma', 'Phenotype', 'HP:0012034', (36, 47))	('liposarcoma', 'Disease', 'MESH:D008080', (36, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
416177	26528855	However, CDK4 amplification or overexpression predicted either CDK inhibitor resistance or showed no association with the drug response in tumor models of glioblastoma and melanoma.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CDK4', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (155, 180))	('predicted', 'Reg', (46, 55))	('CDK inhibitor resistance', 'MPA', (63, 87))	('overexpression', 'PosReg', (31, 45))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('amplification', 'Var', (14, 27))
416178	26528855	There are ongoing trials designed to test the utility of CDK4 genomic alterations in predicting the tumor response to CDK inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('genomic alterations', 'Var', (62, 81))	('tumor', 'Disease', (100, 105))	('CDK4', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
416182	26528855	Alternatively, indirectly supporting the data suggesting CDK4 inhibition as suitable therapeutic strategy for sarcoma, in a phase 1 clinical trial, flavopiridol and doxorubicin combination therapy resulted in a disease control rate of 67% in progressive non-chemotherapy-responsive liposarcoma with likely CDK4 amplification.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('CDK4', 'Gene', (306, 310))	('sarcoma', 'Disease', 'MESH:D012509', (286, 293))	('liposarcoma', 'Disease', 'MESH:D008080', (282, 293))	('liposarcoma', 'Phenotype', 'HP:0012034', (282, 293))	('sarcoma', 'Disease', (110, 117))	('sarcoma', 'Disease', (286, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (286, 293))	('amplification', 'Var', (311, 324))	('flavopiridol', 'Chemical', 'MESH:C077990', (148, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (165, 176))	('liposarcoma', 'Disease', (282, 293))
416184	26528855	In vivo sarcoma xenografts harboring CDK4 amplification also show significant responses to flavopiridol either as a single agent or in combination with doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (152, 163))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('CDK4', 'Gene', (37, 41))	('sarcoma', 'Disease', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('flavopiridol', 'Chemical', 'MESH:C077990', (91, 103))	('responses to flavopiridol', 'MPA', (78, 103))	('amplification', 'Var', (42, 55))
416186	26528855	Additionally, our results suggest that high levels of p16ink4a may indicate a poor effect of these drugs on the tumor.	('tumor', 'Disease', (112, 117))	('p16ink4a', 'Var', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))
416187	26528855	Additionally, we show that tumors harboring active mutant CDK4R24C may respond poorly to palbociclib but may be suitable targets for other CDK4 inhibitors such as flavopiridol.	('palbociclib', 'Chemical', 'MESH:C500026', (89, 100))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutant', 'Var', (51, 57))	('flavopiridol', 'Chemical', 'MESH:C077990', (163, 175))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('CDK4R24C', 'Gene', (58, 66))
416231	26528855	Subconfluent AW and AX cells were transfected using the Lipofectamine method (Effectene, Qiagen) with 0.4 mug of the empty mammalian expression plasmid pCMV6-neo or pCMV6-neo containing either the wild type CDK4 gene (Origene) or the R24C mutant CDK4 gene.	('Lipofectamine', 'Chemical', 'MESH:C086724', (56, 69))	('R24C', 'Mutation', 'rs11547328', (234, 238))	('CDK4', 'Gene', (246, 250))	('-neo', 'Chemical', '-', (157, 161))	('mammalian', 'Species', '9606', (123, 132))	('-neo', 'Chemical', '-', (170, 174))	('R24C mutant', 'Var', (234, 245))
416325	26021553	Mammary tumors can be induced in rats by administering dimethylbenzanthracene, N-methyl-N-nitrosourea (MNU), or N-ethyl-N-nitrosourea (ENU).	('N-methyl-N-nitrosourea', 'Chemical', 'MESH:D008770', (79, 101))	('dimethylbenzanthracene', 'Chemical', 'MESH:D015127', (55, 77))	('MNU', 'Chemical', 'MESH:D008770', (103, 106))	('N-methyl-N-nitrosourea', 'Var', (79, 101))	('N-ethyl-N-nitrosourea', 'Var', (112, 133))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (112, 133))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('rats', 'Species', '10116', (33, 37))	('ENU', 'Chemical', 'MESH:D005038', (135, 138))
416390	26021553	The MATLyLu subline was developed from a 22-month-old inbred Copenhagen rat and can produce osteolytic or osteoblastic (variant R3327) bone metastases after tail vein, intracardiac, or intraosseous injection.	('rat', 'Species', '10116', (72, 75))	('variant R3327', 'Var', (120, 133))	('osteolytic or osteoblastic', 'Disease', 'MESH:D030981', (92, 118))	('produce', 'PosReg', (84, 91))	('bone metastases', 'Disease', 'MESH:D009362', (135, 150))	('bone metastases', 'Disease', (135, 150))	('osteolytic or osteoblastic', 'Disease', (92, 118))
416396	26021553	While tail vein, intracardiac, intraosseous, and orthotopic routes of administration have been investigated, orthotopic implantation better recapitulates the metastatic behavior of lung cancers compared with other injection routes.	('orthotopic implantation', 'Var', (109, 132))	('lung cancers', 'Disease', (181, 193))	('recapitulates', 'NegReg', (140, 153))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('rat', 'Species', '10116', (78, 81))	('lung cancers', 'Disease', 'MESH:D008175', (181, 193))	('lung cancers', 'Phenotype', 'HP:0100526', (181, 193))	('metastatic behavior', 'CPA', (158, 177))
416456	26021553	Imbalance of the RANKL/OPG ratio was suggested as the critical event for osteoclastogenesis in HNSCC.	('Imbalance', 'Var', (0, 9))	('OPG', 'Gene', '4982', (23, 26))	('SCC', 'Gene', '6317', (97, 100))	('osteoclastogenesis', 'Disease', 'None', (73, 91))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('SCC', 'Gene', (97, 100))	('osteoclastogenesis', 'Disease', (73, 91))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('rat', 'Species', '10116', (27, 30))	('RANKL', 'Gene', '8600', (17, 22))	('RANKL', 'Gene', (17, 22))	('OPG', 'Gene', (23, 26))
416487	26021553	Similar to humans, high PTHrP expression has been found in feline oral SCC (OSCC) and is often associated with increased bone invasion and osteoclastogenesis in vivo and in vitro.	('high', 'Var', (19, 23))	('expression', 'MPA', (30, 40))	('increased', 'PosReg', (111, 120))	('PTHrP', 'Gene', (24, 29))	('osteoclastogenesis', 'Disease', 'None', (139, 157))	('osteoclastogenesis', 'Disease', (139, 157))	('bone invasion', 'CPA', (121, 134))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', (77, 80))	('humans', 'Species', '9606', (11, 17))	('associated with', 'Reg', (95, 110))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))	('SCC', 'Gene', '6317', (71, 74))	('SCC', 'Gene', '6317', (77, 80))
416527	26021553	In addition, a mouse model of Burkitt lymphoma was created by a Myc mutation.	('Myc', 'Gene', (64, 67))	('Myc', 'Gene', '17869', (64, 67))	('mutation', 'Var', (68, 76))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (30, 46))	('Burkitt lymphoma', 'Disease', (30, 46))	('mouse', 'Species', '10090', (15, 20))	('lymphoma', 'Phenotype', 'HP:0002665', (38, 46))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (30, 46))
416553	26021553	Similarly, metastases to the lungs and other organs developed in all mice injected with the C-643-Luc2, THJ-16T-Luc2, FTC-133-Luc2, FTC- 236-Luc2, and FTC-238-Luc2 sublines.	('FTC- 236-Luc2', 'Var', (132, 145))	('metastases to the lung', 'Disease', 'MESH:D009362', (11, 33))	('mice', 'Species', '10090', (69, 73))	('metastases to the lung', 'Disease', (11, 33))	('C-643-Luc2', 'Var', (92, 102))
416580	26263384	TPM proteins are divided in two groups according to their molecular weight: the low molecular weight (LMW) TPM (MW<30kDa) and the high molecular weight (HMW) TPM (MW>30KDa).	('HMW', 'Gene', (153, 156))	('HMW', 'Gene', '57587', (153, 156))	('MW<30kDa', 'Var', (112, 120))
416600	26263384	Human embryonic kidney (HEK)-293 cells and human cell line SLK infected with recombinant r.KSHV.219 (SLKK) were routinely cultured in Dulbecco's modified Eagle's medium at 4.5 g/L glucose supplemented with 10% fetal bovine serum and 1x ampicillin/streptomycin glutamine solution (Gibco).	('Human', 'Species', '9606', (0, 5))	('embryonic kidney', 'Disease', (6, 22))	('SLK', 'Gene', '9748', (101, 104))	('glucose', 'Chemical', 'MESH:D005947', (180, 187))	('human', 'Species', '9606', (43, 48))	('SLK', 'Gene', (101, 104))	('streptomycin glutamine', 'Chemical', '-', (247, 269))	('men', 'Species', '9606', (194, 197))	('bovine', 'Species', '9913', (216, 222))	('ampicillin', 'Chemical', 'MESH:D000667', (236, 246))	('r.KSHV.219', 'Var', (89, 99))	('embryonic kidney', 'Disease', 'MESH:D007674', (6, 22))	('KS', 'Phenotype', 'HP:0100726', (91, 93))	('HEK)-293 cells', 'CellLine', 'CVCL:0045', (24, 38))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (134, 168))	('SLK', 'Gene', '9748', (59, 62))	('KSHV', 'Species', '37296', (91, 95))	('SLK', 'Gene', (59, 62))
416632	26263384	SLK cells latently infected with BAC16 mutants of KSHV were provided by Rolf Renne and were maintained in DMEM with 10% FBS, 250 mug/mL G418, 1.2 mg/ml HygB, 1 mug/mL Puromycin.	('KSHV', 'Gene', (50, 54))	('G418', 'Chemical', 'MESH:C010680', (136, 140))	('Puromycin', 'Chemical', 'MESH:D011691', (167, 176))	('FBS', 'Disease', 'MESH:D005198', (120, 123))	('KSHV', 'Species', '37296', (50, 54))	('SLK', 'Gene', '9748', (0, 3))	('mutants', 'Var', (39, 46))	('BAC16 mutants', 'Var', (33, 46))	('KS', 'Phenotype', 'HP:0100726', (50, 52))	('DMEM', 'Chemical', '-', (106, 110))	('SLK', 'Gene', (0, 3))	('FBS', 'Disease', (120, 123))
416648	26263384	Thus far, two high molecular weight (HMW) variants were identified in HUVECs, Tmskalpha1 and TM3.	('TM3', 'Gene', '7170', (93, 96))	('HMW', 'Gene', '57587', (37, 40))	('TM3', 'Gene', (93, 96))	('variants', 'Var', (42, 50))	('HMW', 'Gene', (37, 40))
416653	26263384	To identify which TPM1 variants were repressed in the context of KSHV infection, we infected HUVECs with KSHV and harvested the cells at 3 and 7 days post-infection (dpi).	('KSHV infection', 'Disease', (65, 79))	('KSHV', 'Species', '37296', (65, 69))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('KSHV', 'Species', '37296', (105, 109))	('TPM1', 'Gene', (18, 22))	('variants', 'Var', (23, 31))	('KSHV infection', 'Disease', 'MESH:C537372', (65, 79))	('dpi', 'Chemical', '-', (166, 169))	('KS', 'Phenotype', 'HP:0100726', (105, 107))
416657	26263384	HMW-TPM1 proteins are also expressed at lower levels in limited fresh lung biopsies infected by KSHV compare with the LANA-negative lung samples (Fig 1G).	('LANA', 'Gene', (118, 122))	('KSHV', 'Var', (96, 100))	('KSHV', 'Species', '37296', (96, 100))	('HMW-TPM1', 'Gene', (0, 8))	('LANA', 'Gene', '4961527', (118, 122))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('proteins', 'Protein', (9, 17))	('lower', 'NegReg', (40, 45))
416665	26263384	We mutated the luciferase reporter carrying exon-13 by changing three nucleotides in the region recognized by the seed of miR-K5 (pLuc-Exon13mut, Fig 2B).	('luciferase', 'Enzyme', (15, 25))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (122, 125))	('changing', 'Reg', (55, 63))	('mutated', 'Var', (3, 10))
416667	26263384	In contrast, miR-K5 mimics had no effect on luciferase activity of the mutated reporter.	('activity', 'MPA', (55, 63))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('luciferase', 'Enzyme', (44, 54))	('mutated', 'Var', (71, 78))
416669	26263384	Inhibition of the luciferase activity of the reporter carrying the wild type exon-13 is rescued when the binding site of miR-K5 is mutated (Fig 2D).	('mutated', 'Var', (131, 138))	('activity', 'MPA', (29, 37))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('luciferase', 'Enzyme', (18, 28))
416671	26263384	Rescue of luciferase activity by mutating the miR-K5 binding site on the luciferase reporter or by quenching miR-K5 mimics with a "sponge" vector demonstrated the specificity of miR-K5 for the 3'UTR of Tmskalpha1.	('miR', 'Gene', (46, 49))	('miR', 'Gene', '220972', (109, 112))	('miR', 'Gene', (109, 112))	('miR', 'Gene', '220972', (178, 181))	('luciferase', 'Enzyme', (10, 20))	('miR', 'Gene', (178, 181))	('quenching', 'NegReg', (99, 108))	('mutating', 'Var', (33, 41))	('activity', 'MPA', (21, 29))	('miR', 'Gene', '220972', (46, 49))
416677	26263384	Whereas miR-K2 does not target the 3'UTRs of HMW-TPM1, miR-K2 mimics decreased the protein level of HMW-TPM1s expressed in HUVECs.	('protein level', 'MPA', (83, 96))	('mimics', 'Var', (62, 68))	('decreased', 'NegReg', (69, 78))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('miR', 'Gene', '220972', (8, 11))	('miR', 'Gene', (8, 11))
416684	26263384	However, the expression of Tmskalpha1 and TM3 was significantly higher in infected cells in the presence of LNA inhibitors of miR-K2, compared with the LNA negative control inhibitor (Fig 3C).	('TM3', 'Gene', '7170', (42, 45))	('TM3', 'Gene', (42, 45))	('inhibitors', 'Var', (112, 122))	('expression', 'MPA', (13, 23))	('higher', 'PosReg', (64, 70))	('miR', 'Gene', (126, 129))	('miR', 'Gene', '220972', (126, 129))	('Tmskalpha1', 'Gene', (27, 37))
416690	26263384	In these assays, de-repression was observed for Tmskalpha1 when miR-K5 was deleted (Fig 3E-3G).	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('de-repression', 'NegReg', (17, 30))	('Tmskalpha1', 'Gene', (48, 58))	('deleted', 'Var', (75, 82))
416691	26263384	Additionally, Tmskalpha1 and TM3 levels increased when miR-K2 is deleted.	('deleted', 'Var', (65, 72))	('TM3', 'Gene', '7170', (29, 32))	('TM3', 'Gene', (29, 32))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('increased', 'PosReg', (40, 49))
416704	26263384	Knock-down of hnRNP-H1 expression led to a decrease in exon-3 transcript, consistent with the TPM1 isoform expression pattern induced by miR-K2.	('decrease', 'NegReg', (43, 51))	('hnRNP-H1', 'Gene', '3187', (14, 22))	('miR', 'Gene', '220972', (137, 140))	('exon-3 transcript', 'MPA', (55, 72))	('miR', 'Gene', (137, 140))	('Knock-down', 'Var', (0, 10))	('hnRNP-H1', 'Gene', (14, 22))
416707	26263384	To investigate a possible targeting of hnRNP-H1 3'UTR by miR-K2, we cloned the putative wild-type (K2BS wt) or mutated (K2BS mut) miR-K2 binding sequences from the hnRNP-H1 3'UTR into a luciferase reporter (Fig 4B).	('hnRNP-H1', 'Gene', (39, 47))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('K2BS', 'Var', (120, 124))	('hnRNP-H1', 'Gene', (164, 172))	('miR', 'Gene', (130, 133))	('miR', 'Gene', '220972', (130, 133))	('hnRNP-H1', 'Gene', '3187', (39, 47))	('hnRNP-H1', 'Gene', '3187', (164, 172))
416724	26263384	As expected, si-Exon15 decreased the protein levels of TM3 and TM5 because exon-15 encodes the 3'UTR of these mRNAs.	('TM3', 'Gene', (55, 58))	('TM5', 'Gene', '7170', (63, 66))	('protein levels', 'MPA', (37, 51))	('TM5', 'Gene', (63, 66))	('si-Exon15', 'Var', (13, 22))	('decreased', 'NegReg', (23, 32))	('TM3', 'Gene', '7170', (55, 58))
416726	26263384	Unexpectedly, si-Exon12 also down-regulated TM3 protein levels.	('down-regulated', 'NegReg', (29, 43))	('TM3', 'Gene', '7170', (44, 47))	('si-Exon12', 'Var', (14, 23))	('TM3', 'Gene', (44, 47))
416727	26263384	The miRNA target prediction program, miRanda, predicted a binding site for si-Exon12 in the exon-3 of TPM1, suggesting that si-Exon12 may also target TM3 mRNA using imperfect complementarity.	('miR', 'Gene', '220972', (37, 40))	('binding', 'Interaction', (58, 65))	('si-Exon12', 'Var', (75, 84))	('miR', 'Gene', (37, 40))	('TPM1', 'Gene', (102, 106))	('miR', 'Gene', (4, 7))	('TM3', 'Gene', (150, 153))	('miR', 'Gene', '220972', (4, 7))	('TM3', 'Gene', '7170', (150, 153))	('si-Exon12', 'Var', (124, 133))	('men', 'Species', '9606', (181, 184))
416729	26263384	Consequently, by targeting both HMW-TPM1 isoforms expressed in HUVECs like miR-K2 and KSHV de novo infection, si-Exon12 is a valuable tool to mimic the effect of miR-K2 and KSHV infection on TPM1 isoforms in endothelial cells.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('KSHV infection', 'Disease', 'MESH:C537372', (173, 187))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('KSHV', 'Species', '37296', (86, 90))	('KSHV infection', 'Disease', (173, 187))	('KS', 'Phenotype', 'HP:0100726', (173, 175))	('KSHV', 'Species', '37296', (173, 177))	('si-Exon12', 'Var', (110, 119))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
416736	26263384	Therefore, we performed basement membrane matrix extract tube formation assays with HUVECs previously transfected with miR-K2 or miR-K5 or with siRNAs targeting exon 15 or exon 12 (si-Exon15, si-Exon12).	('miR', 'Gene', '220972', (129, 132))	('men', 'Species', '9606', (28, 31))	('miR', 'Gene', (129, 132))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (119, 122))	('si-Exon12', 'Var', (192, 201))
416738	26263384	Because miR-K2 and si-Exon15 both repress TM3, it is possible that the down-regulation of TM3 enhances tube formation.	('TM3', 'Gene', '7170', (42, 45))	('enhances', 'PosReg', (94, 102))	('TM3', 'Gene', (42, 45))	('TM3', 'Gene', '7170', (90, 93))	('TM3', 'Gene', (90, 93))	('tube formation', 'CPA', (103, 117))	('repress', 'NegReg', (34, 41))	('down-regulation', 'NegReg', (71, 86))	('si-Exon15', 'Var', (19, 28))	('miR', 'Gene', '220972', (8, 11))	('miR', 'Gene', (8, 11))
416740	26263384	TM3 and Tmskalpha1 protein levels were reduced in HUVECs transfected with si-Exon12.	('TM3', 'Gene', '7170', (0, 3))	('TM3', 'Gene', (0, 3))	('si-Exon12', 'Var', (74, 83))	('reduced', 'NegReg', (39, 46))
416741	26263384	Remarkably, these cells formed longer tube structures, with more segments and branch points as cells knocked-down for TM3 by miR-K2 does and developed large nodes as cells knocked-down for Tmskalpha1 by miR-K5 does.	('knocked-down', 'Var', (101, 113))	('TM3', 'Gene', '7170', (118, 121))	('TM3', 'Gene', (118, 121))	('miR', 'Gene', '220972', (203, 206))	('miR', 'Gene', (203, 206))	('branch points', 'CPA', (78, 91))	('miR', 'Gene', '220972', (125, 128))	('men', 'Species', '9606', (68, 71))	('miR', 'Gene', (125, 128))
416754	26263384	KSHV miR-K10a reduces expression of a luciferase reporter carrying exon-15.	('miR', 'Gene', '220972', (5, 8))	('KSHV', 'Species', '37296', (0, 4))	('miR', 'Gene', (5, 8))	('KSHV', 'Var', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('reduces', 'NegReg', (14, 21))	('luciferase reporter', 'Enzyme', (38, 57))	('expression', 'MPA', (22, 32))
416755	26263384	Additionally, transfection of miR-K10a represses TM5 in HUVEC.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('TM5', 'Gene', '7170', (49, 52))	('transfection', 'Var', (14, 26))	('represses', 'NegReg', (39, 48))	('TM5', 'Gene', (49, 52))
416767	26263384	Free of their contacts, endothelial cells undergo anoikis, but ectopic expression of the KSHV protein vFLIP diminished this effect.	('KS', 'Phenotype', 'HP:0100726', (89, 91))	('KSHV', 'Species', '37296', (89, 93))	('vFLIP', 'Gene', (102, 107))	('anoikis', 'CPA', (50, 57))	('ectopic expression', 'Var', (63, 81))
416769	26263384	In cancer cells, down-regulation of HMW-TPM1 expression could be the result of activation of the Ras/Raf/MEK/ERK pathway, or DNA methylation of TPM1 promoter, or over-expression of the onco-microR-21.	('methylation', 'Var', (129, 140))	('ERK', 'Gene', '2048', (109, 112))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('over-expression', 'PosReg', (162, 177))	('TPM1', 'Gene', (144, 148))	('expression', 'MPA', (45, 55))	('cancer', 'Disease', (3, 9))	('ERK', 'Gene', (109, 112))	('Raf', 'Gene', '22882', (101, 104))	('activation', 'PosReg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('MEK', 'Gene', (105, 108))	('down-regulation', 'NegReg', (17, 32))	('MEK', 'Gene', '5609', (105, 108))	('HMW-TPM1', 'Gene', (36, 44))	('Raf', 'Gene', (101, 104))
416776	26263384	More recently it has been reported that KSHV reduces the protein expression of another anti-angiogenic factor, Delta-like 4 (DLL4), by promoting the expression of specific host miRNAs.	('DLL4', 'Gene', '54567', (125, 129))	('reduces', 'NegReg', (45, 52))	('promoting', 'PosReg', (135, 144))	('KSHV', 'Species', '37296', (40, 44))	('miR', 'Gene', '220972', (177, 180))	('DLL4', 'Gene', (125, 129))	('expression', 'MPA', (149, 159))	('KSHV', 'Var', (40, 44))	('miR', 'Gene', (177, 180))	('KS', 'Phenotype', 'HP:0100726', (40, 42))	('protein expression', 'MPA', (57, 75))
416787	26263384	It seems that KSHV induces a drastic remodeling of the actin filaments.	('KSHV', 'Species', '37296', (14, 18))	('actin', 'Protein', (55, 60))	('men', 'Species', '9606', (65, 68))	('KSHV', 'Var', (14, 18))	('KS', 'Phenotype', 'HP:0100726', (14, 16))
416796	23858101	NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition Soft-tissue sarcomas are a heterogeneous group of tumors arising from connective tissue.	('NF1', 'Gene', '18015', (0, 3))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (44, 63))	('NF1', 'Gene', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (44, 63))	('MEK', 'Gene', (80, 83))	('Soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (95, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('soft-tissue sarcoma', 'Disease', (44, 63))	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('sarcomas', 'Disease', (107, 115))	('deletion', 'Var', (4, 12))	('tumors arising from connective tissue', 'Phenotype', 'HP:0100242', (145, 182))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('MEK', 'Gene', '17242', (80, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))
416797	23858101	Recently, mutations in the neurofibromin 1 (NF1) tumor suppressor gene were identified in multiple subtypes of human soft-tissue sarcomas.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (117, 136))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('NF1', 'Gene', (44, 47))	('identified', 'Reg', (76, 86))	('neurofibromin 1', 'Gene', (27, 42))	('tumor', 'Disease', (49, 54))	('human', 'Species', '9606', (111, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('neurofibromin 1', 'Gene', '4763', (27, 42))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('mutations', 'Var', (10, 19))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (117, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcomas', 'Disease', (129, 137))
416804	23858101	We also examined the effects of MEK inhibition on the native tumor stroma and find that PD325901 decreases VEGFalpha expression in tumor cells with a corresponding decrease in microvessel density.	('PD325901', 'Chemical', 'MESH:C506614', (88, 96))	('tumor stroma', 'Disease', 'MESH:D009369', (61, 73))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor stroma', 'Disease', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('expression', 'MPA', (117, 127))	('decreases', 'NegReg', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (131, 136))	('PD325901', 'Var', (88, 96))	('microvessel', 'MPA', (176, 187))	('VEGFalpha', 'Gene', (107, 116))	('decrease', 'NegReg', (164, 172))	('VEGFalpha', 'Gene', '22339', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
416806	23858101	These studies suggest that MEK inhibitors should be further explored as potential sarcoma therapies in patients with tumors containing NF1 deletion.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('deletion', 'Var', (139, 147))	('NF1', 'Gene', (135, 138))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('sarcoma', 'Disease', (82, 89))	('patients', 'Species', '9606', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
416809	23858101	Recent genomic studies have identified novel mutations in a diverse spectrum of human soft tissue sarcomas that may reveal new molecular targets for therapy.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (86, 106))	('mutations', 'Var', (45, 54))	('sarcomas', 'Disease', (98, 106))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (86, 105))	('human', 'Species', '9606', (80, 85))	('sarcomas', 'Disease', 'MESH:D012509', (98, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
416811	23858101	Although the loss of NF1 is well-characterized in malignant peripheral nerve sheath tumors (MPNSTs), NF1 mutations in other soft-tissue sarcomas have only been recently identified.	('peripheral nerve sheath tumors', 'Disease', 'MESH:D010524', (60, 90))	('peripheral nerve sheath tumors', 'Disease', (60, 90))	('NF1', 'Gene', (101, 104))	('sarcomas', 'Disease', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (124, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (50, 89))	('NF1', 'Gene', (21, 24))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (50, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (124, 144))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('loss', 'Var', (13, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))
416812	23858101	Using genomic sequencing and copy number analysis, NF1 mutations were identified in myxofibrosarcoma (10.5%, n = 4/38) and pleomorphic liposarcoma (8%, n = 2/24).	('identified', 'Reg', (70, 80))	('mutations', 'Var', (55, 64))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (123, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('liposarcoma', 'Phenotype', 'HP:0012034', (135, 146))	('NF1', 'Gene', (51, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('myxofibrosarcoma', 'Disease', (84, 100))	('pleomorphic liposarcoma', 'Disease', (123, 146))	('myxofibrosarcoma', 'Disease', 'None', (84, 100))
416813	23858101	Similar studies have identified genomic loss of the NF1 locus in 15% of pediatric embryonal rhabdomyosarcomas (n = 4/26).	('NF1', 'Gene', (52, 55))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (92, 109))	('pediatric embryonal rhabdomyosarcomas', 'Disease', 'MESH:D018233', (72, 109))	('pediatric embryonal rhabdomyosarcomas', 'Disease', (72, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('genomic loss', 'Var', (32, 44))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (92, 108))	('embryonal rhabdomyosarcomas', 'Phenotype', 'HP:0006743', (82, 109))
416814	23858101	The identification of novel mutations in sarcomas with complex karyotypes provides new opportunities to model human sarcomas and to investigate new therapies for this difficult to treat disease.	('sarcomas', 'Disease', (116, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('human', 'Species', '9606', (110, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcomas', 'Disease', 'MESH:D012509', (116, 124))	('mutations', 'Var', (28, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
416815	23858101	In addition to identifying NF1 mutations in spontaneous sarcomas in the general population, patients with Neurofibromatosis Type 1 (NF1) are at increased risk for developing aggressive soft-tissue sarcomas.	('mutations', 'Var', (31, 40))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (185, 204))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (185, 205))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('sarcomas', 'Disease', 'MESH:D012509', (197, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('patients', 'Species', '9606', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (106, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (197, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('NF1', 'Gene', (27, 30))	('sarcomas', 'Disease', (56, 64))	('sarcomas', 'Disease', (197, 205))
416817	23858101	NF1 patients are also at risk for developing non-neurogenic sarcomas, including rhabdomyosarcoma (RMS) and undifferentiated pleomorphic sarcoma (UPS), with a 3-6% lifetime risk.	('sarcomas', 'Disease', (60, 68))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (80, 96))	('rhabdomyosarcoma', 'Disease', (80, 96))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (107, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('undifferentiated pleomorphic sarcoma', 'Disease', (107, 143))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (80, 96))	('patients', 'Species', '9606', (4, 12))	('NF1', 'Var', (0, 3))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))
416818	23858101	Most malignant NF1-deleted tumors have inactivation of either p53 or Ink4a/Arf tumor suppressor genes, with over 50% of MPNSTs expressing wild-type p53 and homozygous deletion of Ink4a/Arf.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (27, 32))	('inactivation', 'Var', (39, 51))	('Ink4a/Arf', 'Gene', (179, 188))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('NF1-deleted', 'Gene', (15, 26))	('p53', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
416819	23858101	Deletion of NF1 alone is not sufficient to cause high-grade sarcomas, as tissue-specific deletion of NF1 with either Krox20-Cre or Dhh-Cre results in neurofibromas.	('sarcomas', 'Disease', (60, 68))	('Krox20', 'Gene', '13654', (117, 123))	('results in', 'Reg', (139, 149))	('Dhh', 'Gene', (131, 134))	('NF1', 'Gene', (101, 104))	('cause', 'Reg', (43, 48))	('neurofibromas', 'Disease', (150, 163))	('Dhh', 'Gene', '13363', (131, 134))	('neurofibromas', 'Phenotype', 'HP:0001067', (150, 163))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('deletion', 'Var', (89, 97))	('neurofibromas', 'Disease', 'MESH:D009455', (150, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('Krox20', 'Gene', (117, 123))	('neurofibroma', 'Phenotype', 'HP:0001067', (150, 162))	('Deletion', 'Var', (0, 8))
416820	23858101	Similarly, deletion of either Ink4a or Arf alone is not sufficient for formation of neurofibromas or MPNSTs on an NF1 heterozygous background from either NF1 +/-; Ink4a -/- mice or NF1 +/-; Arf -/- mice.	('Ink4a', 'Gene', (163, 168))	('neurofibromas', 'Disease', (84, 97))	('Arf', 'Gene', (39, 42))	('Ink4a', 'Gene', (30, 35))	('neurofibromas', 'Disease', 'MESH:D009455', (84, 97))	('neurofibromas', 'Phenotype', 'HP:0001067', (84, 97))	('neurofibroma', 'Phenotype', 'HP:0001067', (84, 96))	('Ink4a', 'Gene', '12578', (163, 168))	('mice', 'Species', '10090', (198, 202))	('deletion', 'Var', (11, 19))	('mice', 'Species', '10090', (173, 177))	('Ink4a', 'Gene', '12578', (30, 35))
416822	23858101	Deletion of both Ink4a and Arf in an NF1 heterozygous background (NF1 +/-; Ink4a/Arf -/) generated sporadic MPNSTs in 26% of mice.	('Ink4a', 'Gene', '12578', (17, 22))	('Ink4a', 'Gene', (75, 80))	('mice', 'Species', '10090', (125, 129))	('Ink4a', 'Gene', (17, 22))	('Arf', 'Gene', (27, 30))	('Ink4a', 'Gene', '12578', (75, 80))	('Deletion', 'Var', (0, 8))
416824	23858101	Despite the prevalence of NF1 mutations in soft-tissue sarcomas, the role of NF1 in the development of soft-tissue sarcomas, particularly in the background of wild-type p53 alleles, has not been fully explored in a primary mouse model of soft-tissue sarcoma.	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('mouse', 'Species', '10090', (223, 228))	('sarcoma', 'Disease', (55, 62))	('sarcomas', 'Disease', (55, 63))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (103, 123))	('sarcoma', 'Disease', 'MESH:D012509', (250, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcoma', 'Disease', (250, 257))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (43, 62))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('sarcoma', 'Disease', (115, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (238, 257))	('mutations', 'Var', (30, 39))	('sarcomas', 'Disease', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (43, 63))	('NF1', 'Gene', (26, 29))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (103, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))
416825	23858101	Therefore, we designed a study to test if deletion of both NF1 and Ink4a/Arf could generate high-grade soft-tissue sarcomas in an NF1 wild-type background.	('Ink4a/Arf', 'Gene', (67, 76))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (103, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (103, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('NF1', 'Gene', (59, 62))	('sarcomas', 'Disease', (115, 123))	('deletion', 'Var', (42, 50))	('generate', 'Reg', (83, 91))
416829	23858101	Using Cre-loxP technology, tumors are initiated through Cre-mediated deletion of conditional NF1 and Ink4a/Arf floxed alleles (NF1flox/flox; Ink4a/Arf flox/flox).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('Ink4a/Arf', 'Gene', (101, 110))	('deletion', 'Var', (69, 77))	('conditional NF1', 'Gene', (81, 96))
416832	23858101	We have identified MAPK inhibition as a promising therapy that slows the growth of primary mouse sarcomas through effects on tumor cell growth and the surrounding vasculature.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('effects', 'Reg', (114, 121))	('growth', 'CPA', (73, 79))	('tumor', 'Disease', (125, 130))	('inhibition', 'Var', (24, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (97, 105))	('MAPK', 'Gene', (19, 23))	('mouse', 'Species', '10090', (91, 96))	('slows', 'NegReg', (63, 68))
416836	23858101	Tumors were generated by injection of Adenovirus-expressing Cre recombinase (Ad-Cre; University of Iowa, Vector core) into the lower left leg of NF1flox/flox; Ink4a/Arfflox/flox compound mutant mice as previously described.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutant', 'Var', (187, 193))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (194, 198))
416861	23858101	Cells were washed once with cold PBS (Sigma) and lysed for 10 minutes on ice with RIPA buffer (Sigma), supplemented with phosphatase inhibitors (Sigma, P5726 and P0044).	('P5726', 'Var', (152, 157))	('PBS', 'Disease', 'MESH:D011535', (33, 36))	('PBS', 'Disease', (33, 36))	('RIPA buffer', 'Chemical', '-', (82, 93))	('Sigma', 'Var', (145, 150))	('P0044', 'Var', (162, 167))
416863	23858101	As NF1 mutations have been recently detected in a variety of human soft-tissue sarcoma subtypes, we sought to determine if loss of NF1 and the tumor suppressor Ink4a/Arf was sufficient to generate soft-tissue sarcomas in a p53- and NF1-wild type background.	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (67, 86))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (197, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('loss', 'Var', (123, 127))	('mutations', 'Var', (7, 16))	('NF1', 'Gene', (3, 6))	('generate', 'Reg', (188, 196))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (79, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('sarcomas', 'Disease', 'MESH:D012509', (209, 217))	('human', 'Species', '9606', (61, 66))	('sarcoma subtypes', 'Disease', (79, 95))	('NF1', 'Gene', (131, 134))	('sarcomas', 'Phenotype', 'HP:0100242', (209, 217))	('tumor', 'Disease', (143, 148))	('sarcomas', 'Disease', (209, 217))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (197, 216))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
416865	23858101	Therefore, we generated mice with conditional mutations in both NF1 and Ink4a/Arf (NF1flox/flox; Ink4a/Arfflox/flox).	('NF1', 'Gene', (64, 67))	('Ink4a/Arf', 'Gene', (72, 81))	('mutations', 'Var', (46, 55))	('mice', 'Species', '10090', (24, 28))
416879	23858101	Both RMS and UPS occur in patients with neurofibromatosis type 1, and NF1 mutations have been identified in these sarcoma subtypes.	('sarcoma subtypes', 'Disease', (114, 130))	('neurofibromatosis type 1', 'Gene', (40, 64))	('neurofibromatosis type 1', 'Gene', '4763', (40, 64))	('identified', 'Reg', (94, 104))	('mutations', 'Var', (74, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('patients', 'Species', '9606', (26, 34))	('neurofibroma', 'Phenotype', 'HP:0001067', (40, 52))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (40, 57))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (114, 130))	('NF1', 'Gene', (70, 73))
416895	23858101	The identification of NF1 mutations in myogenic sarcoma provides a new foundation for preclinical studies examining targeted therapies for soft-tissue sarcomas.	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (139, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('NF1', 'Gene', (22, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcomas', 'Disease', (151, 159))	('myogenic sarcoma', 'Disease', (39, 55))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (139, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('mutations', 'Var', (26, 35))	('myogenic sarcoma', 'Disease', 'MESH:D012509', (39, 55))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))
416898	23858101	We treated the cells with the MEK inhibitor PD325901 and observed decreases in colony-forming units and cell proliferation following exposure to the drug (Figure 3A and Supplemental Figure 3A).	('PD325901', 'Chemical', 'MESH:C506614', (44, 52))	('decreases', 'NegReg', (66, 75))	('cell proliferation', 'CPA', (104, 122))	('PD325901', 'Var', (44, 52))	('colony-forming units', 'CPA', (79, 99))
416899	23858101	Similar results were seen when cells were treated with PD325901 prior to seeding for colony formation to account for cell-cell interaction signals and growth factors that are usually present in sub-confluent conditions and in the tumor microenvironment (Supplemental Figure 3B).	('tumor', 'Disease', (230, 235))	('PD325901', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('PD325901', 'Chemical', 'MESH:C506614', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
416900	23858101	Western blot analysis of 1863 cells treated with PD325901 for 4 hours showed a decrease in phosphorylation of ERK (Figure 3B), with corresponding changes in phospho-S6 and phospho-AKT levels (Supplemental Figure 4).	('changes', 'Reg', (146, 153))	('phosphorylation', 'MPA', (91, 106))	('PD325901', 'Var', (49, 57))	('phospho-S6', 'MPA', (157, 167))	('ERK', 'Protein', (110, 113))	('decrease', 'NegReg', (79, 87))	('PD325901', 'Chemical', 'MESH:C506614', (49, 57))	('phospho-AKT levels', 'MPA', (172, 190))
416901	23858101	To extend these studies to the primary mouse model of NF1-deleted myogenic sarcoma, we compared mice receiving PD325901 treatment (n=8) to mice receiving vehicle alone (n=5).	('myogenic sarcoma', 'Disease', 'MESH:D012509', (66, 82))	('mice', 'Species', '10090', (96, 100))	('PD325901', 'Var', (111, 119))	('myogenic sarcoma', 'Disease', (66, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('mice', 'Species', '10090', (139, 143))	('mouse', 'Species', '10090', (39, 44))	('PD325901', 'Chemical', 'MESH:C506614', (111, 119))
416906	23858101	As predicted, treatment with PD325901 delayed tumor growth in a majority of the mice, with a partial response rate of 75% (Figure 3C).	('PD325901', 'Chemical', 'MESH:C506614', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('delayed', 'NegReg', (38, 45))	('tumor', 'Disease', (46, 51))	('PD325901', 'Var', (29, 37))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
416908	23858101	The range of treatment response for individual tumors during PD325901 exposure is similar to the individual tumor-to-tumor heterogeneity observed in Ki67 and CD31 staining (Figure 2).	('tumors', 'Disease', (47, 53))	('Ki67', 'Gene', (149, 153))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor-to-tumor', 'Disease', 'MESH:D009369', (108, 122))	('PD325901', 'Chemical', 'MESH:C506614', (61, 69))	('CD31', 'Gene', '18613', (158, 162))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('Ki67', 'Gene', '17345', (149, 153))	('CD31', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor-to-tumor', 'Disease', (108, 122))	('PD325901', 'Var', (61, 69))
416911	23858101	These results show that MEK inhibition slows growth of NF1-deleted rhabdomyosarcoma and undifferentiated pleomorphic sarcoma, as the histologies for each of these high-grade sarcoma subtype were evenly distributed between vehicle treated, responders, and non-responding tumors.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (67, 83))	('MEK', 'Gene', (24, 27))	('growth', 'MPA', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (67, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('sarcoma subtype', 'Disease', 'MESH:D012509', (174, 189))	('tumors', 'Disease', (270, 276))	('sarcoma subtype', 'Disease', (174, 189))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (88, 124))	('slows', 'NegReg', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('undifferentiated pleomorphic sarcoma', 'Disease', (88, 124))	('rhabdomyosarcoma', 'Disease', (67, 83))	('NF1-deleted', 'Gene', (55, 66))	('inhibition', 'Var', (28, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('slows growth', 'Phenotype', 'HP:0001510', (39, 51))
416916	23858101	Tumors that responded to PD325901 treatment exhibit a significant decrease in levels of cyclin D1 mRNA (p<0.05), supporting previous reports that suggest inhibition of the cell cycle contributes to the decrease in tumor cell proliferation observed with this agent (Figure 4C).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('cell cycle', 'CPA', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('cyclin D1', 'Gene', (88, 97))	('decrease', 'NegReg', (202, 210))	('Tumors', 'Disease', (0, 6))	('PD325901', 'Chemical', 'MESH:C506614', (25, 33))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (214, 219))	('decrease', 'NegReg', (66, 74))	('PD325901', 'Var', (25, 33))	('cyclin D1', 'Gene', '12443', (88, 97))
416918	23858101	Taken together, these data suggest that PD325901 inhibits NF1-deleted sarcomas through cytostatic, but not cytotoxic, mechanisms.	('NF1-deleted', 'Gene', (58, 69))	('PD325901', 'Chemical', 'MESH:C506614', (40, 48))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('inhibits', 'NegReg', (49, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))	('PD325901', 'Var', (40, 48))
416919	23858101	Very recently, others have used PD325901 to treat neurofibromatosis-associated diseases, and treatment of a primary neurofibroma model with PD325901 resulted in decreased proliferation as measured by Ki67 staining, but not an increase in apoptosis.	('neurofibromatosis', 'Disease', (50, 67))	('PD325901', 'Chemical', 'MESH:C506614', (32, 40))	('Ki67', 'Gene', (200, 204))	('decreased', 'NegReg', (161, 170))	('neurofibroma', 'Phenotype', 'HP:0001067', (116, 128))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (50, 67))	('PD325901', 'Chemical', 'MESH:C506614', (140, 148))	('neurofibroma', 'Phenotype', 'HP:0001067', (50, 62))	('neurofibromatosis', 'Disease', 'MESH:C537392', (50, 67))	('Ki67', 'Gene', '17345', (200, 204))	('neurofibroma', 'Disease', (50, 62))	('neurofibroma', 'Disease', 'MESH:D009455', (50, 62))	('neurofibroma', 'Disease', (116, 128))	('proliferation', 'CPA', (171, 184))	('PD325901', 'Var', (140, 148))	('neurofibroma', 'Disease', 'MESH:D009455', (116, 128))
416922	23858101	Recently, the MEK inhibitor PD325901 was shown to inhibit angiogenesis and VEGF signaling in xenografted tumor models of RCC and lung cancer.	('PD325901', 'Var', (28, 36))	('lung cancer', 'Disease', (129, 140))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('VEGF', 'Gene', '22339', (75, 79))	('RCC', 'Disease', (121, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('inhibit', 'NegReg', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('angiogenesis', 'CPA', (58, 70))	('VEGF', 'Gene', (75, 79))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('PD325901', 'Chemical', 'MESH:C506614', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (105, 110))
416926	23858101	In our NF1-deleted sarcomas, toluidine blue staining demonstrates that tumors treated with either vehicle-alone or PD325901 have similar levels of mast cell infiltration (Figure 5A).	('PD325901', 'Chemical', 'MESH:C506614', (115, 123))	('mast cell', 'CPA', (147, 156))	('toluidine blue', 'Chemical', 'MESH:D014048', (29, 43))	('PD325901', 'Var', (115, 123))	('sarcomas', 'Disease', 'MESH:D012509', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('tumors', 'Disease', (71, 77))	('sarcomas', 'Disease', (19, 27))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
416927	23858101	In contrast, MEK inhibition results in a significant decrease in CD31+ microvessel density (p=0.010, Figure 5B).	('decrease', 'NegReg', (53, 61))	('MEK', 'Enzyme', (13, 16))	('inhibition', 'Var', (17, 27))	('CD31', 'Gene', '18613', (65, 69))	('CD31', 'Gene', (65, 69))
416934	23858101	Therefore, decreased levels of Angpt2, VEGF 120, and VEGF 165 mRNA suggest a potential mechanism for the decreased vascularity seen with PD325901 exposure.	('Angpt2', 'Gene', '11601', (31, 37))	('VEGF', 'Gene', '22339', (39, 43))	('PD325901', 'Chemical', 'MESH:C506614', (137, 145))	('VEGF', 'Gene', '22339', (53, 57))	('decreased', 'NegReg', (11, 20))	('VEGF', 'Gene', (53, 57))	('VEGF', 'Gene', (39, 43))	('PD325901', 'Var', (137, 145))	('vascularity', 'CPA', (115, 126))	('Angpt2', 'Gene', (31, 37))	('decreased', 'NegReg', (105, 114))
416935	23858101	To determine if the change in angiogenic genes following PD325901 treatment was primarily through action on the tumor cells or on tumor stroma, we treated NF1-deficient sarcoma cells with PD325901.	('NF1-deficient sarcoma', 'Disease', (155, 176))	('tumor', 'Disease', (112, 117))	('PD325901', 'Chemical', 'MESH:C506614', (188, 196))	('PD325901', 'Chemical', 'MESH:C506614', (57, 65))	('tumor stroma', 'Disease', 'MESH:D009369', (130, 142))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor stroma', 'Disease', (130, 142))	('PD325901', 'Var', (188, 196))	('angiogenic genes', 'Gene', (30, 46))	('NF1-deficient sarcoma', 'Disease', 'MESH:C537392', (155, 176))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PD325901', 'Var', (57, 65))	('tumor', 'Disease', (130, 135))
416937	23858101	However, levels of Angiopoeitin 2 remain unchanged in the PD325901-treated tumor cells.	('PD325901-treated', 'Var', (58, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PD325901', 'Chemical', 'MESH:C506614', (58, 66))	('tumor', 'Disease', (75, 80))	('levels of', 'MPA', (9, 18))
416939	23858101	To determine if the decreased levels in VEGF 120, VEGF 165, and Angiopoeitin 2 mRNA in the primary tumors correspond to decreased VEGFalpha signaling in vivo, we performed immunofluoresence for pVEGFR-2 in the primary tumors treated with PD325901 (Figure 5D).	('VEGFalpha', 'Gene', (130, 139))	('VEGFR-2', 'Gene', '16542', (195, 202))	('primary tumors', 'Disease', (210, 224))	('VEGF', 'Gene', (195, 199))	('primary tumors', 'Disease', 'MESH:D009369', (91, 105))	('Angiopoeitin 2', 'Gene', (64, 78))	('decreased', 'NegReg', (120, 129))	('VEGF', 'Gene', (50, 54))	('VEGF', 'Gene', '22339', (195, 199))	('primary tumors', 'Disease', 'MESH:D009369', (210, 224))	('VEGF', 'Gene', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('levels', 'MPA', (30, 36))	('PD325901', 'Chemical', 'MESH:C506614', (238, 246))	('VEGF', 'Gene', '22339', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('VEGF', 'Gene', '22339', (130, 134))	('VEGF', 'Gene', (40, 44))	('VEGFR-2', 'Gene', (195, 202))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('VEGF', 'Gene', '22339', (40, 44))	('decreased', 'NegReg', (20, 29))	('PD325901', 'Var', (238, 246))	('primary tumors', 'Disease', (91, 105))	('VEGFalpha', 'Gene', '22339', (130, 139))
416943	23858101	These data suggest that in addition to decreasing proliferation of tumor cells, MEK inhibition has important effects on the surrounding tumor microenvironment by blocking angiogenesis and decreasing tumor microvessel density.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('blocking', 'NegReg', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decreasing', 'NegReg', (188, 198))	('angiogenesis', 'CPA', (171, 183))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('MEK', 'Gene', (80, 83))	('inhibition', 'Var', (84, 94))	('tumor', 'Disease', (136, 141))
416944	23858101	Taken together, these preclinical data suggest that the MEK inhibitor PD325901 may be a useful therapy for patients with NF1-deficient sarcomas.	('NF1-deficient sarcomas', 'Disease', 'MESH:C537392', (121, 143))	('NF1-deficient sarcomas', 'Disease', (121, 143))	('PD325901', 'Var', (70, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('PD325901', 'Chemical', 'MESH:C506614', (70, 78))	('patients', 'Species', '9606', (107, 115))
416946	23858101	This primary mouse model can be used to study the tumor biology and therapeutic response of sarcomas with NF1 mutation.	('mouse', 'Species', '10090', (13, 18))	('sarcomas', 'Disease', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('NF1', 'Gene', (106, 109))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('mutation', 'Var', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('tumor', 'Disease', (50, 55))
416947	23858101	Using temporally and spatially controlled conditional gene deletion, we have determined that inactivation of NF1 and Ink4a/Arf in the tumor cells is sufficient to initiate both myogenic and MPNST-like sarcomas in mice with a wild-type stroma.	('initiate', 'PosReg', (163, 171))	('mice', 'Species', '10090', (213, 217))	('sarcomas', 'Disease', 'MESH:D012509', (201, 209))	('NF1', 'Gene', (109, 112))	('myogenic', 'CPA', (177, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (201, 209))	('inactivation', 'Var', (93, 105))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('Ink4a/Arf', 'Gene', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('sarcomas', 'Disease', (201, 209))	('tumor', 'Disease', (134, 139))
416949	23858101	Histopathological analysis shows the spectrum of sarcomas that develop in this model are similar to sarcomas with NF1 deletion in the patient population.	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Disease', (100, 108))	('sarcomas', 'Disease', (49, 57))	('deletion', 'Var', (118, 126))	('NF1', 'Gene', (114, 117))	('sarcomas', 'Disease', 'MESH:D012509', (49, 57))	('patient', 'Species', '9606', (134, 141))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))
416950	23858101	By initiating sarcomas through deletion of NF1 and Ink4a/Arf, these mice model the ~50% of NF1-deleted sarcomas with wild-type p53 and complement the existing models of p53-deleted NF1 mutant sarcomas for therapeutic studies.	('mice', 'Species', '10090', (68, 72))	('sarcomas', 'Disease', 'MESH:D012509', (14, 22))	('sarcomas', 'Disease', (192, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (14, 22))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('initiating', 'Reg', (3, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('NF1', 'Gene', (43, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomas', 'Disease', (103, 111))	('sarcomas', 'Disease', (14, 22))	('deletion', 'Var', (31, 39))	('sarcomas', 'Disease', 'MESH:D012509', (192, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
416951	23858101	In this model, tumor growth is delayed by the MEK inhibitor PD325901, which is accompanied by a decrease in tumor cell proliferation but does not increase cellular apoptosis.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PD325901', 'Chemical', 'MESH:C506614', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (108, 113))	('decrease', 'NegReg', (96, 104))	('delayed', 'NegReg', (31, 38))	('PD325901', 'Var', (60, 68))	('tumor', 'Disease', (15, 20))	('increase cellular apoptosis', 'Phenotype', 'HP:0030887', (146, 173))
416953	23858101	PD325901 treatment decreases microvessel density, at least partially through a decrease in expression of proangiogenic genes, such as VEGF 120, VEGF 165 and Angiopoeitin 2.	('Angiopoeitin 2', 'Gene', (157, 171))	('PD325901', 'Var', (0, 8))	('expression', 'MPA', (91, 101))	('VEGF', 'Gene', '22339', (144, 148))	('VEGF', 'Gene', '22339', (134, 138))	('decrease', 'NegReg', (79, 87))	('PD325901', 'Chemical', 'MESH:C506614', (0, 8))	('microvessel density', 'CPA', (29, 48))	('decreases', 'NegReg', (19, 28))	('VEGF', 'Gene', (134, 138))	('VEGF', 'Gene', (144, 148))
416955	23858101	Several recent studies have also reported encouraging results using MEK inhibition to treat other neurofibromin-deficient disorders in mice.	('neurofibromin', 'Gene', (98, 111))	('deficient disorders', 'Disease', 'MESH:D030342', (112, 131))	('deficient disorders', 'Disease', (112, 131))	('inhibition', 'Var', (72, 82))	('mice', 'Species', '10090', (135, 139))	('MEK', 'Protein', (68, 71))	('neurofibromin', 'Gene', '18015', (98, 111))
416970	23858101	Finally, the effect of PD325901 on the tumor stroma of non-responders was not well-defined, as changes in the levels of mast cells and microvessel density were varied.	('PD325901', 'Chemical', 'MESH:C506614', (23, 31))	('tumor stroma', 'Disease', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PD325901', 'Var', (23, 31))	('tumor stroma', 'Disease', 'MESH:D009369', (39, 51))
416973	23858101	Our results support a model in which PD325901 targets both the tumor cell itself and results in secondary effects on the tumor vasculature.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('PD325901', 'Chemical', 'MESH:C506614', (37, 45))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PD325901', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('effects', 'Reg', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
416974	23858101	Following MEK inhibition, the sarcoma cell decreases both cyclin D1 and VEGFalpha mRNA levels.	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('MEK', 'Gene', (10, 13))	('cyclin D1', 'Gene', '12443', (58, 67))	('VEGFalpha', 'Gene', '22339', (72, 81))	('sarcoma', 'Disease', (30, 37))	('VEGFalpha', 'Gene', (72, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('decreases', 'NegReg', (43, 52))	('inhibition', 'Var', (14, 24))	('cyclin D1', 'Gene', (58, 67))
416979	23858101	Alternatively, it is also possible that PD325901 could have direct effects on the tumor endothelial cells, which has been reported in vitro.	('PD325901', 'Chemical', 'MESH:C506614', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('effects', 'Reg', (67, 74))	('PD325901', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
416982	23858101	We have used this model to assess the efficacy of PD325901 and to investigate its mechanism of action in a primary tumor model.	('PD325901', 'Chemical', 'MESH:C506614', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('PD325901', 'Var', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
417057	33591953	Mutations in other genes such as TP53, EED, SUZ12, and CDKN2A are required for malignant transformation to MPNST.	('CDKN2A', 'Gene', '1029', (55, 61))	('SUZ12', 'Gene', (44, 49))	('EED', 'Gene', (39, 42))	('TP53', 'Gene', '7157', (33, 37))	('Mutations', 'Var', (0, 9))	('PN', 'Phenotype', 'HP:0009732', (108, 110))	('MPNST', 'Phenotype', 'HP:0100697', (107, 112))	('TP53', 'Gene', (33, 37))	('PN', 'Gene', '79650', (108, 110))	('SUZ12', 'Gene', '23512', (44, 49))	('CDKN2A', 'Gene', (55, 61))	('EED', 'Gene', '8726', (39, 42))
417074	33591953	As expected based on prior genomic studies, TP53 mutations occurred in 12.5% (1 of 8 pairs) and SUZ12 mutations in 62.5% (5 of 8 pairs) of patients.	('SUZ12', 'Gene', '23512', (96, 101))	('mutations', 'Var', (49, 58))	('patients', 'Species', '9606', (139, 147))	('SUZ12', 'Gene', (96, 101))	('mutations', 'Var', (102, 111))	('TP53', 'Gene', '7157', (44, 48))	('occurred', 'Reg', (59, 67))	('TP53', 'Gene', (44, 48))
417075	33591953	Immunostaining revealed that H3K27me3 was absent, consistent with SUZ12 mutations that we observed in these samples (Supplemental Figure 1B).	('absent', 'NegReg', (42, 48))	('mutations', 'Var', (72, 81))	('SUZ12', 'Gene', '23512', (66, 71))	('SUZ12', 'Gene', (66, 71))	('H3K27me3', 'Protein', (29, 37))
417076	33591953	The other 25% (2 of 8 pairs) had mutations in other cancer-related pathways, such as DNA repair genes.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('DNA repair genes', 'Gene', (85, 101))	('mutations', 'Var', (33, 42))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
417078	33591953	Interestingly, some variants showed a VAF difference, likely representing variants found predominantly in either the parental tumor or the PDX, suggesting that some clonal selection occurs upon engraftment (Supplemental Figure 2).	('variants', 'Var', (20, 28))	('parental tumor', 'Disease', 'MESH:D063129', (117, 131))	('parental tumor', 'Disease', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('VAF', 'MPA', (38, 41))
417079	33591953	Engraftment-related selection is also illustrated by the fact that some genes were found to have somatic variants in the PDX but not in the parental tumor (Figure 1A), with a median correlation coefficient of 0.474 (range, 0.014-0.791).	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('PDX', 'Gene', (121, 124))	('variants', 'Var', (105, 113))	('parental tumor', 'Disease', (140, 154))	('parental tumor', 'Disease', 'MESH:D063129', (140, 154))
417089	33591953	As expected, all PDX exhibited a Chr8q gain in all or a high percentage of the tumor cells (Figure 2C and Supplemental Figure 5).	('tumor', 'Disease', (79, 84))	('Chr8q', 'Var', (33, 38))	('PDX', 'Disease', (17, 20))	('gain', 'PosReg', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
417095	33591953	Our results specifically support Chr8q gain and suggest that Chr8q gain may be important for high-grade transformation into MPNST.	('Chr8q', 'Var', (33, 38))	('Chr8q', 'Var', (61, 66))	('PN', 'Phenotype', 'HP:0009732', (125, 127))	('gain', 'PosReg', (39, 43))	('PN', 'Gene', '79650', (125, 127))	('MPNST', 'Phenotype', 'HP:0100697', (124, 129))
417098	33591953	Chr8 alterations are implicated in multiple malignancies, including translocations involving MYC in Burkitt lymphoma.	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (100, 116))	('malignancies', 'Disease', (44, 56))	('Chr8', 'Gene', (0, 4))	('MYC', 'Gene', (93, 96))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (100, 116))	('Burkitt lymphoma', 'Disease', (100, 116))	('alterations', 'Var', (5, 16))	('translocations', 'Var', (68, 82))	('implicated', 'Reg', (21, 31))	('lymphoma', 'Phenotype', 'HP:0002665', (108, 116))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))	('MYC', 'Gene', '4609', (93, 96))
417099	33591953	Additionally, certain solid tumors show extra copies of Chr8, such as desmoid fibromatosis and lipoblastoma.	('extra copies', 'Var', (40, 52))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('desmoid fibromatosis', 'Disease', 'MESH:D018222', (70, 90))	('Chr8', 'Gene', (56, 60))	('lipoblastoma', 'Disease', 'MESH:D062689', (95, 107))	('lipoblastoma', 'Disease', (95, 107))	('desmoid fibromatosis', 'Disease', (70, 90))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('desmoid fibromatosis', 'Phenotype', 'HP:0100245', (70, 90))
417100	33591953	There are increasing data showing that chromosomal gains can contribute to cancer pathogenesis, in addition to amplification of specific genes or chromosomal rearrangements.	('contribute', 'Reg', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('chromosomal gains', 'Var', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
417117	33591953	Finally, using the cancer genome atlas database, we analyzed the correlation between Chr8q gain and OS, and we found that Chr8q gain was associated with inferior OS in 2 soft-tissue sarcomas data sets (Figure 5A; P = 0.0013, P = 0.0129, logrank).	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (170, 190))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('sarcomas', 'Disease', (182, 190))	('cancer', 'Disease', (19, 25))	('gain', 'PosReg', (128, 132))	('inferior OS', 'Disease', (153, 164))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (170, 189))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Chr8q', 'Var', (122, 127))
417119	33591953	As every MPNST examined in our analysis demonstrated Chr8q gain, this association may be, at least in part, accountable for the poor survival seen in MPNST patients.	('patients', 'Species', '9606', (156, 164))	('MPNST', 'Phenotype', 'HP:0100697', (150, 155))	('PN', 'Phenotype', 'HP:0009732', (151, 153))	('PN', 'Phenotype', 'HP:0009732', (10, 12))	('Chr8q', 'Var', (53, 58))	('PN', 'Gene', '79650', (151, 153))	('PN', 'Gene', '79650', (10, 12))	('MPNST', 'Phenotype', 'HP:0100697', (9, 14))	('gain', 'PosReg', (59, 63))
417126	33591953	TP53 mutations occurred in 12.5% (1 of 8 pairs), SUZ12 mutations in 62.5% (5 of 8 pairs), and the other 25% (2 of 8 pairs) had mutations in other cancer-related pathways, such as DNA repair genes.	('cancer', 'Disease', (146, 152))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('mutations', 'Var', (55, 64))	('SUZ12', 'Gene', '23512', (49, 54))	('mutations', 'Var', (5, 14))	('SUZ12', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutations', 'Reg', (127, 136))
417129	33591953	Sarcomas are, in general, more copy-number aberrant than other cancers, and MPNST in particular are highly copy-number aberrant.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('PN', 'Phenotype', 'HP:0009732', (77, 79))	('PN', 'Gene', '79650', (77, 79))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('copy-number aberrant', 'Var', (31, 51))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('MPNST', 'Phenotype', 'HP:0100697', (76, 81))	('cancers', 'Disease', (63, 70))	('Sarcomas', 'Disease', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
417130	33591953	Our data illustrate the difference in copy-number variants between benign precursor lesions and the high-grade sarcoma after malignant transformation.	('copy-number variants', 'Var', (38, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))
417134	33591953	Third, copy-number variation analysis highlighted a significant gain in Chr8 in NF1-MPNST, while PN did not demonstrate this finding.	('MPNST', 'Phenotype', 'HP:0100697', (84, 89))	('PN', 'Gene', '79650', (97, 99))	('copy-number', 'Var', (7, 18))	('PN', 'Phenotype', 'HP:0009732', (85, 87))	('PN', 'Gene', '79650', (85, 87))	('Chr8', 'Gene', (72, 76))	('gain', 'PosReg', (64, 68))	('PN', 'Phenotype', 'HP:0009732', (97, 99))
417136	33591953	Our results specifically support 8q gain, an arm that encompasses several key cancer-related genes that may be important for MPNST transformation.	('PN', 'Phenotype', 'HP:0009732', (126, 128))	('PN', 'Gene', '79650', (126, 128))	('cancer', 'Disease', (78, 84))	('8q gain', 'Var', (33, 40))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('MPNST', 'Phenotype', 'HP:0100697', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
417140	33591953	This finding suggests that there is a preceding event that triggers the tumor to become aneuploid but that Chr8q gain likely confers a competitive advantage to the tumor and, thus, is selected early on.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (164, 169))	('Chr8q', 'Var', (107, 112))	('aneuploid', 'Disease', (88, 97))	('competitive advantage', 'CPA', (135, 156))	('tumor', 'Disease', (72, 77))	('gain', 'PosReg', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('aneuploid', 'Disease', 'MESH:D000782', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
417242	23898988	heart disease; (4) risk for a disease caused by many genes which usually have a lower impact on health for which there is treatment as well as lifestyle changes which can modify the risk e.g.	('heart disease', 'Disease', 'MESH:D006331', (0, 13))	('genes', 'Var', (53, 58))	('men', 'Species', '9606', (127, 130))	('heart disease', 'Disease', (0, 13))
417331	31081028	Overall, the characteristics of patients operated in a NETSARC center were less favorable, with a higher proportion of patients with large tumors (P < 0.001), grade 3, retroperitoneal, UPS histology and a lower proportion of patients with tumors of intermediate malignancy (all P < 0.001).	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('patients', 'Species', '9606', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('patients', 'Species', '9606', (225, 233))	('malignancy', 'Disease', (262, 272))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('retroperitoneal', 'Disease', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('grade 3', 'Var', (159, 166))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('malignancy', 'Disease', 'MESH:D009369', (262, 272))
417461	30684969	Final pathology revealed a grade 3, pT2bN0M0 undifferentiated sarcoma with epithelioid morphology.	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('pT2bN0M0', 'Var', (36, 44))	('sarcoma', 'Disease', (62, 69))
417497	30084838	One patient with clinical signs of extensive MC activation was treated with antagonists of MC pro-inflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions.	('antagonists', 'Var', (76, 87))	('AIDS-KS lesions', 'Disease', 'MESH:D000163', (174, 189))	('patient', 'Species', '9606', (4, 11))	('regression', 'NegReg', (160, 170))	('AIDS-KS lesions', 'Disease', (174, 189))
417629	30084838	Significant increases were also observed in N-methylhistamine levels in KS patients, 1578 +- 333.10 vs. 723.10+-114.10 vs. 101.10+-31.96 pg/ml, p<0.001, mean +- SEM.	('N-methylhistamine levels', 'MPA', (44, 68))	('patients', 'Species', '9606', (75, 83))	('N-methylhistamine', 'Chemical', 'MESH:C048140', (44, 61))	('increases', 'PosReg', (12, 21))	('1578 +- 333.10', 'Var', (85, 99))
417675	30084838	LTB4 is a potent chemoattractant for immature MCs and bone marrow derived MC progenitors and PGE2 induces the release of CCL2 and VEGF.	('VEGF', 'Gene', '7422', (130, 134))	('CCL2', 'Gene', '6347', (121, 125))	('LTB4', 'Chemical', 'MESH:D007975', (0, 4))	('induces', 'Reg', (98, 105))	('CCL2', 'Gene', (121, 125))	('VEGF', 'Gene', (130, 134))	('LTB4', 'Var', (0, 4))	('PGE2', 'Chemical', 'MESH:D015232', (93, 97))	('PGE2', 'Gene', (93, 97))
417676	30084838	Thus, infection with KSHV may induce MC chemotaxis to the developing lesions via both direct viral gene expression and by induction of potent chemotactic signals (Figure 5B).	('induction', 'Reg', (122, 131))	('KSHV', 'Gene', (21, 25))	('infection', 'Var', (6, 15))	('MC chemotaxis to the developing lesions', 'CPA', (37, 76))	('KSHV', 'Species', '37296', (21, 25))	('induce', 'Reg', (30, 36))
417710	30084838	However, our study results suggest that modulation of MC activity could potently alter KS tumorigenesis irrespective of a significant immunological and virological response to ARVs.	('alter', 'Reg', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('modulation', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
417712	30084838	Thus, modifying MC activation may represent a therapeutic strategy amenable for use in KS-prevalent, resource-constrained settings like sub-Saharan Africa.	('modifying', 'Var', (6, 15))	('men', 'Species', '9606', (68, 71))	('KS-prevalent', 'Disease', (87, 99))	('MC activation', 'Gene', (16, 29))
417713	30084838	Inflammation is a key driver of oncogenesis and modulation of inflammation in the tumor microenvironment is emerging as a viable therapeutic approach.	('inflammation', 'Disease', 'MESH:D007249', (62, 74))	('inflammation', 'Disease', (62, 74))	('men', 'Species', '9606', (100, 103))	('modulation', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
417740	29749998	Endogenous peroxidase activity was quenched with 3% H2O2, followed by heat-induced antigen retrieval in a microwave at 95 C with citrate buffer at pH 6.0.	('H2O2', 'Chemical', 'MESH:D006861', (52, 56))	('H2O2', 'Var', (52, 56))	('3% H2O2', 'Var', (49, 56))	('quenched', 'NegReg', (35, 43))	('Endogenous', 'MPA', (0, 10))	('citrate', 'Chemical', 'MESH:D019343', (129, 136))	('activity', 'MPA', (22, 30))
417763	27050758	ES tumors also have common translocations involving chromosome 22, most notably t(11;22)(q24;q12).	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('ES tumors', 'Disease', 'MESH:C563168', (0, 9))	('ES tumors', 'Disease', (0, 9))	('t(11;22)(q24;q12', 'Var', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (80, 97))
417806	27050758	FISH studies showed a rearrangement of the ESWR1 locus, consistent with ES.	('ES', 'Chemical', 'MESH:D004540', (72, 74))	('ES', 'Chemical', 'MESH:D004540', (43, 45))	('ESWR1', 'Gene', (43, 48))	('rearrangement', 'Var', (22, 35))
417919	23412658	Single intramuscular mIL-12 gene electrotransfer potentiated the cell kill by electrochemotherapy by 3.2 log, resulting in a 23% increase in tumor cures as well as prolonged specific tumor growth delay of the remaining tumors (Figures 2,3).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('electrotransfer', 'Var', (33, 48))	('cell kill', 'CPA', (65, 74))	('mIL-12', 'Gene', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('mIL-12', 'Chemical', '-', (21, 27))	('growth delay', 'Phenotype', 'HP:0001510', (189, 201))	('potentiated', 'PosReg', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('prolonged', 'PosReg', (164, 173))	('tumor growth delay', 'Disease', (183, 201))	('increase', 'PosReg', (129, 137))	('tumor', 'Disease', (183, 188))	('tumor growth delay', 'Disease', 'MESH:D006130', (183, 201))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', (141, 146))
417922	23412658	Multiple intramuscular mIL-12 gene electrotransfer resulted in an earlier onset of complete responses (9.0 +- 0.7 days) than a single intramuscular mIL-12 gene electrotransfer (12.0 +- 0.0 days).	('mIL-12', 'Chemical', '-', (148, 154))	('mIL-12', 'Chemical', '-', (23, 29))	('electrotransfer', 'Var', (35, 50))	('mIL-12', 'Gene', (23, 29))
417925	23412658	Electrochemotherapy resulted in a cell kill of 1.5 and 1.9 log in immunocompetent and immunodeficient SCID mice, respectively (Figure 3, Table 3).	('Electrochemotherapy', 'Var', (0, 19))	('cell kill', 'CPA', (34, 43))	('mice', 'Species', '10090', (107, 111))	('immunodeficient SCID', 'Disease', 'MESH:D053632', (86, 106))	('immunodeficient SCID', 'Disease', (86, 106))
417927	23412658	In immunocompetent mice, single intramuscular mIL-12 gene electrotransfer increased the cell kill by 1.5 log, resulting in 22% of tumor cures and a prolongation of a specific tumor growth delay.	('mIL-12', 'Chemical', '-', (46, 52))	('cell kill', 'CPA', (88, 97))	('tumor', 'Disease', (175, 180))	('mIL-12', 'Gene', (46, 52))	('tumor growth delay', 'Disease', 'MESH:D006130', (175, 193))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('gene electrotransfer', 'Var', (53, 73))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('increased', 'PosReg', (74, 83))	('growth delay', 'Phenotype', 'HP:0001510', (181, 193))	('tumor growth delay', 'Disease', (175, 193))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (130, 135))	('mice', 'Species', '10090', (19, 23))	('prolongation', 'PosReg', (148, 160))
417928	23412658	In SCID mice, the log cell kill by electrochemotherapy was not increased even after multiple intramuscular mIL-12 gene electrotransfer, resulting also in zero cure rate and having no effect on the specific tumor growth delay.	('tumor growth delay', 'Disease', (206, 224))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('growth delay', 'Phenotype', 'HP:0001510', (212, 224))	('zero', 'NegReg', (154, 158))	('SCID', 'Disease', (3, 7))	('mIL-12', 'Chemical', '-', (107, 113))	('mice', 'Species', '10090', (8, 12))	('gene', 'Var', (114, 118))	('SCID', 'Disease', 'MESH:D053632', (3, 7))	('tumor growth delay', 'Disease', 'MESH:D006130', (206, 224))	('mIL-12', 'Gene', (107, 113))	('cure rate', 'CPA', (159, 168))
417932	23412658	Adjuvant intramuscular mIL-12 gene electrotransfer increased the tumor response of both tumor models growing in immunocompetent mice to approximately the same degree: the log cell kill by 3.2 and 1.5, the specific tumor growth delay by a factor of 1.8-2, and the tumor cure rate by approximately 20% in SA-1 and TS/A, respectively.	('mIL-12', 'Gene', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('SA-1', 'Gene', (303, 307))	('tumor', 'Disease', (65, 70))	('mIL-12', 'Chemical', '-', (23, 29))	('growth delay', 'Phenotype', 'HP:0001510', (220, 232))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('increased', 'PosReg', (51, 60))	('tumor growth delay', 'Disease', (214, 232))	('SA-1', 'Gene', '20842', (303, 307))	('mice', 'Species', '10090', (128, 132))	('log cell kill', 'CPA', (171, 184))	('tumor', 'Disease', (214, 219))	('tumor growth delay', 'Disease', 'MESH:D006130', (214, 232))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('electrotransfer', 'Var', (35, 50))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
417953	23412658	Furthermore, electropermeabilization of cells increases the cytotoxicity of the drug, in our case cisplatin, and may result in a similar cell kill in vitro of two differently chemosensitive cell lines, indicating that the SA-1 cells are resistant to cisplatin mainly due to the membrane-related mechanism.	('SA-1', 'Gene', '20842', (222, 226))	('cytotoxicity', 'Disease', (60, 72))	('increases', 'PosReg', (46, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))	('SA-1', 'Gene', (222, 226))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (250, 259))	('electropermeabilization', 'Var', (13, 36))	('result in', 'Reg', (117, 126))
417955	23412658	The in vitro data on tumor cells do not predict the result of in vivo electrochemotherapy because of its dependence on other factors; first being the degree of tumor perfusion, which may influence drug delivery to the tumors, and electrochemotherapy might also result in a vascular-disrupting effect, and the second being controlled by physical factors, e.g., electric field distribution and electrical properties of the tissue for electropermeabilization of cells in the tumors, namely tumor and stromal cells.	('tumor', 'Disease', (21, 26))	('drug delivery', 'MPA', (197, 210))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (472, 477))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', (487, 492))	('tumor', 'Disease', 'MESH:D009369', (472, 477))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (487, 492))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Phenotype', 'HP:0002664', (472, 478))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (487, 492))	('tumors', 'Disease', (472, 478))	('tumor', 'Disease', (160, 165))	('tumors', 'Disease', (218, 224))	('influence', 'Reg', (187, 196))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('electrochemotherapy', 'Var', (230, 249))	('vascular-disrupting effect', 'CPA', (273, 299))	('tumors', 'Disease', 'MESH:D009369', (472, 478))	('result in', 'Reg', (261, 270))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
417956	23412658	Some reports have indicated that the disruption of tumor cells by electrochemotherapy can induce the immune response of the organism, which was demonstrated after electrochemotherapy with bleomycin on the SA-1 tumor model, the same model as used in the present study.	('immune response', 'CPA', (101, 116))	('bleomycin', 'Chemical', 'MESH:D001761', (188, 197))	('disruption', 'Var', (37, 47))	('SA-1', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (210, 215))	('electrochemotherapy', 'Var', (66, 85))	('induce', 'Reg', (90, 96))	('SA-1', 'Gene', '20842', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
417960	23412658	The specific tumor growth delay increased by a factor of 1.8-2, indicating that the adjuvant intramuscular mIL-12 gene electrotransfer increases direct tumor cell kill achieved by electrochemotherapy, in addition to increasing the tumor cure rate.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('growth delay', 'Phenotype', 'HP:0001510', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('increases', 'PosReg', (135, 144))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', (231, 236))	('tumor growth delay', 'Disease', 'MESH:D006130', (13, 31))	('electrotransfer', 'Var', (119, 134))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mIL-12', 'Chemical', '-', (107, 113))	('increasing', 'PosReg', (216, 226))	('tumor growth delay', 'Disease', (13, 31))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mIL-12', 'Gene', (107, 113))
417969	22185227	Here, we target 71 kb of mutational hotspots in 42 cancer genes.	('mutational', 'Var', (25, 35))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
417970	22185227	We evaluate UDT-Seq true sensitivity and specificity (> 94% and > 99%, respectively) for low prevalence mutations in a mixing experiment and demonstrate its utility using six tumor samples.	('tumor', 'Disease', (175, 180))	('mutations', 'Var', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('UDT-Seq', 'Gene', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('UDT-Seq', 'Chemical', '-', (12, 19))
417972	22185227	The number of somatic tumor mutations with potential utility for predicting treatment response is rapidly growing due to increasing numbers of targeted therapies.	('somatic tumor', 'Disease', (14, 27))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('somatic tumor', 'Disease', 'MESH:C563610', (14, 27))
417976	22185227	As molecular subtyping has emerged, molecularly defined trials have been restricted to common DNA alterations (for example, Imatinib and KIT gene mutations in gastro-intestinal stromal tumors) or uncommon alterations in very common tumors (for example, Erlotinib and EGFR-L858R in non-small cell lung cancer).	('tumors', 'Disease', (185, 191))	('EGFR-L858R', 'Var', (267, 277))	('cell lung cancer', 'Disease', 'MESH:D008175', (291, 307))	('lung cancer', 'Phenotype', 'HP:0100526', (296, 307))	('Erlotinib', 'Chemical', 'MESH:D000069347', (253, 262))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('cell lung cancer', 'Disease', (291, 307))	('Imatinib', 'MPA', (124, 132))	('L858R', 'Mutation', 'rs121434568', (272, 277))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (281, 307))	('Imatinib', 'Chemical', 'MESH:D000068877', (124, 132))	('KIT gene', 'Gene', (137, 145))	('gastro-intestinal stromal tumors', 'Disease', (159, 191))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('gastro-intestinal stromal tumors', 'Disease', 'MESH:D046152', (159, 191))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (285, 307))	('mutations', 'Var', (146, 155))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('gastro-intestinal stromal tumors', 'Phenotype', 'HP:0100723', (159, 191))	('Erlotinib', 'Disease', (253, 262))	('tumors', 'Disease', (232, 238))
417977	22185227	The identification of an increasing number of somatic tumor mutations common across cancers arising from different tissues has begun to encourage molecularly defined clinical trials in which subjects with cancers from a number of differing sites of origin are eligible.	('somatic tumor', 'Disease', (46, 59))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('clinical', 'Species', '191496', (166, 174))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (205, 212))	('cancers', 'Disease', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('somatic tumor', 'Disease', 'MESH:C563610', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('mutations', 'Var', (60, 69))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
417979	22185227	Somatic mutations can affect key domains of cancer genes.	('key domains', 'MPA', (29, 40))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('affect', 'Reg', (22, 28))	('Somatic mutations', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
417980	22185227	These mutations, associated with cancer progression and resistance to therapy, exist in restricted regions of the genome, termed mutational hotspots.	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
417981	22185227	While most available clinical assays interrogate one or only a few commonly mutated loci in cancers, two published clinical assays, SNaPShot and OncoMap, respectively target 38 mutations in 8 genes by single base extension assays and approximately 400 mutations in 33 genes by mass spectrometry.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('mutations', 'Var', (177, 186))	('clinical', 'Species', '191496', (115, 123))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('clinical', 'Species', '191496', (21, 29))
417983	22185227	Massively parallel sequencing enables the analysis of independent, clonal, DNA molecules and has been used early on to digitally measure the presence of low prevalence mutations in complex DNA mixtures or in EGFR exons of heterogeneous tumor DNA samples.	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (236, 241))	('mutations', 'Var', (168, 177))
417984	22185227	Constant improvements of the massively parallel sequencing technology offer the opportunity to revise the balance between breadth and depth of such assays and identify a wide variety of potentially actionable DNA changes in a patient's tumor.	('patient', 'Species', '9606', (226, 233))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('changes', 'Var', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (236, 241))
417985	22185227	Broad assays like whole genome and whole exome sequencing have been used to discover new cancer mutations, or study clonal selection in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mutations', 'Var', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
417994	22185227	This facilitates the sensitive and specific detection of low prevalence mutations in the tumor samples.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
417996	22185227	An unsupervised clustering analysis (Materials and methods) led to the identification of cancer hotspots in 42 cancer genes (Table S1 in Additional file 2), which contain 53% (5,271/9,935) of all mutations and 87% (67,440/77,052) of all COSMIC database valid entries (substitutions or small indels with reported genomic location).	('substitutions', 'Var', (268, 281))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
418000	22185227	We sequenced 71.1 kb of cancer mutational hotspots in DNA samples from a primary colon adenocarcinoma with its matching xenograft, a breast primary carcinoma with its matching xenograft, an ovarian carcinoma xenograft, a sarcoma xenograft (Materials and methods) and the matching germline DNA derived from all four patients' blood.	('mutational', 'Var', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('sarcoma', 'Disease', 'MESH:D012509', (221, 228))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (190, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cancer', 'Disease', (24, 30))	('sarcoma', 'Disease', (221, 228))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('breast primary carcinoma', 'Disease', (133, 157))	('patients', 'Species', '9606', (315, 323))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('colon adenocarcinoma', 'Disease', (81, 101))	('ovarian carcinoma xenograft', 'Disease', 'MESH:D010051', (190, 217))	('ovarian carcinoma xenograft', 'Disease', (190, 217))	('breast primary carcinoma', 'Disease', 'MESH:D001943', (133, 157))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (81, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
418005	22185227	We considered all variants in a cancer sample that passed statistical assessment (Materials and methods) as potential somatic mutations.	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('variants', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
418007	22185227	In the colon primary sample, UDT-Seq identified ten somatic mutations (Figure 2, Table 1; Table S8 in Additional file 2) of which eight are shared with the xenograft sample and two are present only in the tumor.	('UDT-Seq', 'Chemical', '-', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('mutations', 'Var', (60, 69))
418008	22185227	Of note, KRAS-G12D has a high prevalence (35%); this cancer driver mutation is present in 40% of colorectal cancers and is associated with anti-EGFR therapy resistance.	('G12D', 'Mutation', 'rs121913529', (14, 18))	('associated with', 'Reg', (123, 138))	('colorectal cancers', 'Disease', (97, 115))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('KRAS-G12D', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colorectal cancers', 'Disease', 'MESH:D015179', (97, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
418009	22185227	Interestingly, two common APC inactivating mutations (APC-R405X and APC-R283X), both frequent mutations in colorectal cancer, are present at different prevalence (25% and 49%, respectively), suggesting that they occur in different cell populations.	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('APC-R405X', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('R283X', 'Mutation', 'p.R283X', (72, 77))	('R405X', 'Mutation', 'p.R405X', (58, 63))	('colorectal cancer', 'Disease', (107, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('APC-R283X', 'Var', (68, 77))
418010	22185227	Examination of the primary specific mutations (BRAF-intron and KIT-R49C) shows that neither of them has evidence of presence in the xenograft (Figure 2).	('KIT-R49C', 'Var', (63, 71))	('BRAF-intron', 'Var', (47, 58))	('R49C', 'Mutation', 'rs759250095', (67, 71))
418013	22185227	Both STK11-R304W and APC-R283X show significant and similar prevalence differences in the primary (22 to 23%) and xenograft (49%), suggesting that they may be present in the same populations of cells, and were selected for in the xenograft.	('R283X', 'Mutation', 'p.R283X', (25, 30))	('STK11-R304W', 'Var', (5, 16))	('APC-R283X', 'Var', (21, 30))	('R304W', 'Mutation', 'rs786201090', (11, 16))
418014	22185227	In the primary breast cancer sample, we identified a single somatic mutation (HRAS-G12V) by UDT-Seq (Table 1; Table S8 in Additional file 2).	('G12V', 'Mutation', 'rs104894230', (83, 87))	('UDT-Seq', 'Chemical', '-', (92, 99))	('HRAS-G12V', 'Var', (78, 87))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
418015	22185227	HRAS-G12V (prevalence 51%) is a common activating mutation in bladder cancer, and its role in breast cancer has not been described.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('G12V', 'Mutation', 'rs104894230', (5, 9))	('HRAS-G12V', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
418016	22185227	HRAS-G12V is homologous to the KRAS-G12D mutation and similarly may be important in the development of resistance to tyrosine kinase targeting agents.	('KRAS-G12D', 'Var', (31, 40))	('G12D', 'Mutation', 'rs121913529', (36, 40))	('G12V', 'Mutation', 'rs104894230', (5, 9))	('HRAS-G12V', 'Var', (0, 9))
418028	22185227	We then applied WGA to the breast cancer xenograft sample and performed a UDT-Seq assay, observing the HRAS-G12V mutation at 49%, in agreement with the prevalence observed without WGA (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('G12V', 'Mutation', 'rs104894230', (108, 112))	('UDT-Seq', 'Chemical', '-', (74, 81))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('HRAS-G12V', 'Var', (103, 112))
418033	22185227	We have shown that this approach can comprehensively detect low prevalence mutations by screening 71,081 DNA positions located in cancer mutational hotspots.	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
418034	22185227	The sensitivity of the assay down to mutations present at 5% prevalence permits detection of mutations in heterogeneous or poor quality samples with rare mutated clones, low cellularity, or contamination with stroma or immune cell infiltration, all of which are commonly seen in clinical samples.	('detection', 'Reg', (80, 89))	('clinical samples', 'Species', '191496', (279, 295))	('stroma', 'Disease', (209, 215))	('mutations', 'Var', (93, 102))	('stroma', 'Disease', 'None', (209, 215))
418040	22185227	Lastly, similar to other approaches, UDT-Seq can also be used to establish a personalized molecular signature of tumor driver and/or passenger mutations that can be used to monitor for recurrence or response in circulating DNA in plasma or urine by more sensitive methods.	('tumor', 'Disease', (113, 118))	('UDT-Seq', 'Chemical', '-', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutations', 'Var', (143, 152))
418044	22185227	The COSMIC database has some redundancy due to over-ascertainment of particular genes or cancer types; 96% of the mutations were observed less than 5 times and 2% were observed more than 100 times.	('mutations', 'Var', (114, 123))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
418045	22185227	Based on this clustering analysis, we chose 42 cancer genes (Table S1 in Additional file 2), which contain 53% (5271/9935) of all mutations and 87% (67,440/77,052) of all COSMIC (v44) valid entries (substitutions or small indels with reported genomic location).	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('COSMIC (v44', 'Gene', (171, 182))	('cancer', 'Disease', (47, 53))	('mutations', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('substitutions', 'Var', (199, 212))
418048	22185227	The four Coriell Institute DNA samples (NA12156, NA12878, NA18507, and NA19240) were quantified in triplicate using Nanodrop and each sample was diluted at a low concentration (approximately 5 ng/mul), which was re-measured in triplicate by Nanodrop (Agilent Technologies Santa Clara CA, USA).	('NA19240', 'Var', (71, 78))	('Agilent Technologies Santa Clara CA', 'Disease', (251, 286))	('NA18507', 'Var', (58, 65))	('NA12156', 'Var', (40, 47))	('NA12878', 'Var', (49, 56))	('Agilent Technologies Santa Clara CA', 'Disease', 'None', (251, 286))
418068	22185227	We considered all variants in a cancer sample that passed the statistical assessment described above as potential somatic mutations.	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('variants', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
418073	22185227	After removing these exogenous mutations, there were 1, 11, and 1 high confidence somatic mutations in the breast, colon, and ovarian xenograft samples, respectively.	('mutations', 'Var', (31, 40))	('mutations', 'Var', (90, 99))	('ovarian xenograft', 'Disease', (126, 143))	('ovarian xenograft', 'Disease', 'MESH:D010051', (126, 143))
418104	30987007	The inorganic core very often consists of magnetite and maghemite (Fe3O4, gamma-Fe2O3), the most common forms.	('gamma-Fe2O3', 'Chemical', '-', (74, 85))	('maghemite', 'Chemical', 'MESH:C000499', (56, 65))	('Fe3O4', 'Chemical', '-', (67, 72))	('Fe3O4', 'Var', (67, 72))	('gamma-Fe2O3', 'Var', (74, 85))	('magnetite', 'Chemical', 'MESH:D052203', (42, 51))
418108	30987007	PEG confers hydrophilicity, increasing their solubility in water, and also prevents MNP aggregation and non-specific binding with other molecules.	('hydrophilicity', 'MPA', (12, 26))	('PEG', 'Var', (0, 3))	('prevents', 'NegReg', (75, 83))	('MNP', 'Gene', '107502', (84, 87))	('MNP', 'Gene', (84, 87))	('water', 'Chemical', 'MESH:D014867', (59, 64))	('increasing', 'PosReg', (28, 38))	('non-specific', 'MPA', (104, 116))	('PEG', 'Chemical', 'MESH:D011092', (0, 3))	('solubility in water', 'MPA', (45, 64))
418165	30987007	To ensure an effective functionalization, the stability of the MNPs was confirmed by TEM (Figure 1a) and the variations of their net charge due to replacing some carboxylic groups by GT/bmGT were analyzed by agarose electrophoresis (Figure 1b).	('TEM', 'Gene', '64103', (85, 88))	('carboxylic groups', 'MPA', (162, 179))	('agarose', 'Chemical', 'MESH:D012685', (208, 215))	('GT', 'Chemical', 'MESH:D005912', (188, 190))	('MNP', 'Gene', (63, 66))	('TEM', 'Gene', (85, 88))	('MNP', 'Gene', '107502', (63, 66))	('GT', 'Chemical', 'MESH:D005912', (183, 185))	('net charge', 'MPA', (129, 139))	('replacing', 'Var', (147, 156))
418191	30987007	In contrast, incorporation of PEG into GT-NPs completely abrogated the anti-tumor effect of GT-MNPs.	('incorporation', 'Var', (13, 26))	('MNP', 'Gene', '107502', (95, 98))	('GT', 'Chemical', 'MESH:D005912', (92, 94))	('tumor', 'Disease', (76, 81))	('MNP', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('PEG', 'Chemical', 'MESH:D011092', (30, 33))	('abrogated', 'NegReg', (57, 66))	('NP', 'Chemical', 'MESH:D009405', (42, 44))	('NP', 'Chemical', 'MESH:D009405', (96, 98))	('rat', 'Species', '10116', (20, 23))	('GT', 'Chemical', 'MESH:D005912', (39, 41))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
418193	30987007	Our results agree with previous findings indicating that PEGylation modifies the size of the particle and prevents intracellular delivery.	('PEGylation', 'Var', (57, 67))	('intracellular delivery', 'MPA', (115, 137))	('modifies', 'Reg', (68, 76))	('prevents', 'NegReg', (106, 114))	('size of the particle', 'MPA', (81, 101))	('PEG', 'Chemical', 'MESH:D011092', (57, 60))
418201	30987007	Notably, PEG almost completely abrogated the uptake of MNPs.	('abrogated', 'NegReg', (31, 40))	('PEG', 'Chemical', 'MESH:D011092', (9, 12))	('uptake', 'MPA', (45, 51))	('MNP', 'Gene', '107502', (55, 58))	('PEG', 'Var', (9, 12))	('MNP', 'Gene', (55, 58))
418223	30987007	In contrast, MNPs functionalized with GT/bmGT without glucose were located in white vacuole-like structures indicating an effect of glucose not only on the level of internalization, but in addition, in the uptake route.	('GT', 'Chemical', 'MESH:D005912', (43, 45))	('glucose', 'Chemical', 'MESH:D005947', (132, 139))	('internalization', 'MPA', (165, 180))	('glucose', 'Chemical', 'MESH:D005947', (54, 61))	('MNP', 'Gene', '107502', (13, 16))	('GT', 'Chemical', 'MESH:D005912', (38, 40))	('MNP', 'Gene', (13, 16))	('effect', 'Reg', (122, 128))	('GT/bmGT', 'Var', (38, 45))	('uptake', 'MPA', (206, 212))
418224	30987007	Notable, free MNPs were located in similar structures confirming that in this type of cells the presence of GT or bmGT do not affect intracellular MNP delivery, which seems to be modulated by glucose.	('MNP', 'Gene', (14, 17))	('presence', 'Var', (96, 104))	('GT', 'Chemical', 'MESH:D005912', (116, 118))	('GT', 'Chemical', 'MESH:D005912', (108, 110))	('glucose', 'Chemical', 'MESH:D005947', (192, 199))	('MNP', 'Gene', '107502', (147, 150))	('MNP', 'Gene', (147, 150))	('MNP', 'Gene', '107502', (14, 17))	('bmGT', 'Gene', (114, 118))
418234	30453386	Doxorubicin-induced heart failure in cancer patients: A cohort study based on the Korean National Health Insurance Database Doxorubicin is a typical anticancer drug that causes cardiomyopathy and heart failure (HF).	('Doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('heart failure', 'Phenotype', 'HP:0001635', (20, 33))	('heart failure', 'Disease', 'MESH:D006333', (20, 33))	('heart failure', 'Disease', 'MESH:D006333', (196, 209))	('cardiomyopathy', 'Disease', (177, 191))	('heart failure', 'Phenotype', 'HP:0001635', (196, 209))	('patients', 'Species', '9606', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (37, 43))	('heart failure', 'Disease', (196, 209))	('heart failure', 'Disease', (20, 33))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (177, 191))	('cardiomyopathy', 'Disease', 'MESH:D009202', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('HF', 'Phenotype', 'HP:0001635', (211, 213))	('Doxorubicin', 'Var', (124, 135))
418261	30453386	Patients were assigned to the HR group if they experienced cardiomyopathy due to drugs and other external agents (I42.7), cardiomyopathy (I42), other cardiomyopathies (I42.8), unspecified cardiomyopathy (I42.9), HF (I50), congestive HF (I50.0), congestive HF with systolic dysfunction (I50.04), other and unspecified congestive HF (I50.08), LV failure (I50.1), and unspecified HF (I50.9).	('congestive HF', 'Disease', (222, 235))	('HF', 'Phenotype', 'HP:0001635', (256, 258))	('cardiomyopathy', 'Disease', (122, 136))	('HF', 'Phenotype', 'HP:0001635', (328, 330))	('cardiomyopathy', 'Disease', (59, 73))	('I42.9', 'Var', (204, 209))	('cardiomyopathy', 'Disease', 'MESH:D009202', (188, 202))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (188, 202))	('I50.04', 'Var', (286, 292))	('unspecified', 'Species', '32644', (305, 316))	('cardiomyopathies', 'Phenotype', 'HP:0001638', (150, 166))	('Patients', 'Species', '9606', (0, 8))	('cardiomyopathy', 'Disease', 'MESH:D009202', (122, 136))	('systolic dysfunction', 'Disease', (264, 284))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (122, 136))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (59, 73))	('cardiomyopathy', 'Disease', 'MESH:D009202', (59, 73))	('cardiomyopathies', 'Disease', 'MESH:D009202', (150, 166))	('HF', 'Phenotype', 'HP:0001635', (212, 214))	('LV failure', 'Disease', (341, 351))	('unspecified', 'Species', '32644', (176, 187))	('cardiomyopathies', 'Disease', (150, 166))	('I50.08', 'Var', (332, 338))	('congestive HF', 'Disease', 'MESH:D002311', (317, 330))	('systolic dysfunction', 'Disease', 'MESH:D006331', (264, 284))	('cardiomyopathy', 'Disease', (188, 202))	('congestive HF', 'Disease', 'MESH:D002311', (245, 258))	('HF', 'Phenotype', 'HP:0001635', (233, 235))	('congestive HF', 'Disease', (317, 330))	('systolic dysfunction', 'Phenotype', 'HP:0006673', (264, 284))	('congestive HF', 'Disease', 'MESH:D002311', (222, 235))	('HF', 'Phenotype', 'HP:0001635', (377, 379))	('unspecified', 'Species', '32644', (365, 376))	('LV failure', 'Disease', 'MESH:C535509', (341, 351))	('congestive HF', 'Disease', (245, 258))
418262	30453386	Other diseases were classified and defined according to ICD-10: I10, I11, I12, and I13 for hypertension; E10, E11, E13, and E14 for diabetes mellitus; E78 for dyslipidemia; and I20, I21, I22, I23, I24, and I25 for coronary artery disease.	('I10', 'Var', (64, 67))	('I11', 'Var', (69, 72))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (132, 149))	('hypertension', 'Disease', (91, 103))	('E78', 'Var', (151, 154))	('I23', 'Var', (192, 195))	('I24', 'Var', (197, 200))	('coronary artery disease', 'Disease', 'MESH:D003324', (214, 237))	('E14', 'Gene', (124, 127))	('coronary artery disease', 'Disease', (214, 237))	('hypertension', 'Phenotype', 'HP:0000822', (91, 103))	('I20', 'Var', (177, 180))	('diabetes mellitus', 'Disease', (132, 149))	('E11', 'Var', (110, 113))	('dyslipidemia', 'Disease', 'MESH:D050171', (159, 171))	('I21', 'Var', (182, 185))	('E14', 'Gene', '4863', (124, 127))	('I25', 'Var', (206, 209))	('E13', 'Var', (115, 118))	('I13', 'Var', (83, 86))	('E10', 'Var', (105, 108))	('I22', 'Var', (187, 190))	('diabetes mellitus', 'Disease', 'MESH:D003920', (132, 149))	('hypertension', 'Disease', 'MESH:D006973', (91, 103))	('dyslipidemia', 'Phenotype', 'HP:0003119', (159, 171))	('dyslipidemia', 'Disease', (159, 171))
418263	30453386	The subjects were divided by cancer disease codes: C50 for breast cancer; C81, C82, C83, C85, C86, C91, and C92 for hematologic malignancy; C54, C55, and C56 for gynecologic malignancy; and C40, C41, and C49 for sarcoma.	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('C40', 'Gene', '55571', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('C85', 'Var', (89, 92))	('C91', 'Var', (99, 102))	('malignancy', 'Disease', (128, 138))	('cancer disease', 'Disease', (29, 43))	('C92', 'Var', (108, 111))	('sarcoma', 'Disease', 'MESH:D012509', (212, 219))	('sarcoma', 'Disease', (212, 219))	('C83', 'Var', (84, 87))	('C50', 'Var', (51, 54))	('C40', 'Gene', (190, 193))	('malignancy', 'Disease', (174, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('C49', 'Var', (204, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('C81', 'Var', (74, 77))	('C86', 'Var', (94, 97))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('hematologic malignancy', 'Disease', 'MESH:D019337', (116, 138))	('breast cancer', 'Disease', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('C54', 'Var', (140, 143))	('hematologic malignancy', 'Phenotype', 'HP:0004377', (116, 138))	('C82', 'Gene', (79, 82))	('C56', 'Var', (154, 157))	('hematologic malignancy', 'Disease', (116, 138))	('cancer disease', 'Disease', 'MESH:D009369', (29, 43))	('malignancy', 'Disease', 'MESH:D009369', (128, 138))	('C55', 'Var', (145, 148))	('C41', 'Var', (195, 198))	('C82', 'Gene', '732', (79, 82))
418291	30453386	The 8-year survival rate was 76% in breast cancer patients with doxorubicin-induced HF and 80% in breast cancer patients without doxorubicin-induced HF (P < 0.001).	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (36, 49))	('breast cancer', 'Disease', (98, 111))	('patients', 'Species', '9606', (50, 58))	('doxorubicin-induced', 'Var', (64, 83))	('doxorubicin', 'Chemical', 'MESH:D004317', (64, 75))	('doxorubicin', 'Chemical', 'MESH:D004317', (129, 140))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HF', 'Phenotype', 'HP:0001635', (149, 151))	('HF', 'Phenotype', 'HP:0001635', (84, 86))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
418293	30453386	The 8-year survival rate was 65% in breast cancer patients with doxorubicin-induced HF and 70% in breast cancer patients without doxorubicin-induced HF (P < 0.001) (Figure 3).	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (36, 49))	('breast cancer', 'Disease', (98, 111))	('patients', 'Species', '9606', (50, 58))	('doxorubicin-induced', 'Var', (64, 83))	('doxorubicin', 'Chemical', 'MESH:D004317', (64, 75))	('doxorubicin', 'Chemical', 'MESH:D004317', (129, 140))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HF', 'Phenotype', 'HP:0001635', (149, 151))	('HF', 'Phenotype', 'HP:0001635', (84, 86))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
418323	30453386	Doxorubicin-induced HF also reduces quality of life by causing dyspnea, fatigue, and related symptoms in cancer survivors.3, 27 Therefore, prevention and early diagnosis and treatment of doxorubicin-induced HF can both increase patient survival and improve quality of life for cancer survivors.	('dyspnea', 'Disease', 'MESH:D004417', (63, 70))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('doxorubicin-induced', 'Var', (187, 206))	('HF', 'Phenotype', 'HP:0001635', (207, 209))	('fatigue', 'Disease', 'MESH:D005221', (72, 79))	('cancer', 'Disease', (277, 283))	('quality of life', 'CPA', (257, 272))	('dyspnea', 'Phenotype', 'HP:0002094', (63, 70))	('increase', 'PosReg', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('patient', 'Species', '9606', (228, 235))	('HF', 'Phenotype', 'HP:0001635', (20, 22))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('doxorubicin', 'Chemical', 'MESH:D004317', (187, 198))	('improve', 'PosReg', (249, 256))	('fatigue', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('fatigue', 'Phenotype', 'HP:0012378', (72, 79))	('patient survival', 'CPA', (228, 244))	('dyspnea', 'Disease', (63, 70))
418333	30542624	Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating certain gene transcriptions.	('participate', 'Reg', (108, 119))	('cancers', 'Disease', (79, 86))	('activating', 'PosReg', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Dysregulation', 'Var', (0, 13))	('invasion', 'CPA', (123, 131))	('facilitates', 'PosReg', (45, 56))	('gene transcriptions', 'MPA', (169, 188))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
418348	30542624	ETS protein functional activity is modulated by post-translational modification and interaction with other nuclear proteins.	('post-translational modification', 'Var', (48, 79))	('ETS protein', 'Protein', (0, 11))	('ETS', 'Chemical', '-', (0, 3))	('interaction', 'Interaction', (84, 95))	('modulated', 'Reg', (35, 44))	('functional activity', 'MPA', (12, 31))
418349	30542624	The importance of ETS genes in human carcinogenesis is supported by the observations that ETS genes have altered expression patterns, amplified, deleted mutated, and most importantly are located at translocation breakpoints in human leukemias and solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('carcinogenesis', 'Disease', 'MESH:D063646', (37, 51))	('solid tumors', 'Disease', (247, 259))	('ETS genes', 'Gene', (90, 99))	('leukemias', 'Disease', 'MESH:D007938', (233, 242))	('carcinogenesis', 'Disease', (37, 51))	('leukemia', 'Phenotype', 'HP:0001909', (233, 241))	('deleted', 'Var', (145, 152))	('human', 'Species', '9606', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('expression patterns', 'MPA', (113, 132))	('human', 'Species', '9606', (31, 36))	('solid tumors', 'Disease', 'MESH:D009369', (247, 259))	('ETS', 'Chemical', '-', (90, 93))	('ETS', 'Chemical', '-', (18, 21))	('leukemias', 'Phenotype', 'HP:0001909', (233, 242))	('altered', 'Reg', (105, 112))	('leukemias', 'Disease', (233, 242))
418351	30542624	Aberrant expression of ETS1 and 2 proteins results in the altered regulation of their target response genes, which was recently reviewed.	('altered', 'Reg', (58, 65))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (9, 19))	('ETS1 and 2', 'Gene', '2113;2114', (23, 33))	('regulation', 'MPA', (66, 76))
418361	30542624	The ETS family gene often fuses with other genes as a result of translocation.	('translocation', 'Var', (64, 77))	('fuses', 'Reg', (26, 31))	('ETS', 'Chemical', '-', (4, 7))	('ETS family', 'Gene', (4, 14))
418363	30542624	In solid tumors, the ERG gene is activated by translocation in Ewing sarcoma with EWS:ERG translocation t(11;22)(q24,q22) and EWS:FLI1 translocation t(21,22)(q22,q12) (Fli1 belongs to ERG family of proteins; ref.	('activated', 'PosReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Fli1', 'Gene', (168, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('solid tumors', 'Disease', (3, 15))	('translocation', 'Var', (46, 59))	('Ewing sarcoma', 'Disease', (63, 76))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('Fli1', 'Gene', '2313', (168, 172))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('solid tumors', 'Disease', 'MESH:D009369', (3, 15))	('ERG gene', 'Gene', (21, 29))
418370	30542624	ERG2 differs from ERG1 by a splicing event that causes a frameshift, resulting in an additional 99 amino acids at the N terminus.	('ERG1', 'Gene', '3757', (18, 22))	('ERG2', 'Gene', '81033', (0, 4))	('causes', 'Reg', (48, 54))	('frameshift', 'Var', (57, 67))	('ERG1', 'Gene', (18, 22))	('ERG2', 'Gene', (0, 4))
418373	30542624	RT-PCR analysis of 6 ERG variants showed variable expression in placenta and most human cell lines examined.	('variants', 'Var', (25, 33))	('ERG', 'Gene', (21, 24))	('expression', 'MPA', (50, 60))	('human', 'Species', '9606', (82, 87))
418374	30542624	demonstrated that in human myeloid leukemia with t(16;21)(p11;q22), the TLS/FUS gene on chromosome 16 was fused with ERG gene on chromosome 21.	('myeloid leukemia', 'Disease', (27, 43))	('FUS', 'Gene', (76, 79))	('t(16;21)(p11;q22', 'Var', (49, 65))	('TLS', 'Gene', (72, 75))	('FUS', 'Gene', '2521', (76, 79))	('TLS', 'Gene', '2521', (72, 75))	('t(16;21)(p11;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 66))	('human', 'Species', '9606', (21, 26))	('leukemia', 'Phenotype', 'HP:0001909', (35, 43))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (27, 43))	('myeloid leukemia', 'Disease', 'MESH:D007951', (27, 43))
418380	30542624	EWS and related peripheral primitive neuro-ectodermal tumors show a t(11;22)(q24,q22) translocation (present in 85% of Ewing's sarcoma; EWS-FLI1 fusion; 28) or a t(21,22)(q22,q12) (EWS-ERG fusion) that is associated with hybrid transcripts of the EWS gene with the FLI1 or ERG gene.	('neuro-ectodermal tumors', 'Disease', 'MESH:C536203', (37, 60))	('t(21,22)(q22,q12', 'Var', (162, 178))	('neuro-ectodermal tumors', 'Disease', (37, 60))	('EWS-FLI1', 'Gene', (136, 144))	('EWS-FLI1', 'Gene', '2130;2313', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (119, 134))	("Ewing's sarcoma", 'Disease', (119, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (119, 134))
418390	30542624	siRNA-mediated depletion of DAX1 in EWS-FLI1 cell lines results in growth arrest and inhibition of tumor formation in immunodeficient mice.	('depletion', 'Var', (15, 24))	('tumor', 'Disease', (99, 104))	('EWS-FLI1', 'Gene', (36, 44))	('mice', 'Species', '10090', (134, 138))	('growth arrest', 'Disease', 'MESH:D006323', (67, 80))	('growth arrest', 'Disease', (67, 80))	('EWS-FLI1', 'Gene', '2130;2313', (36, 44))	('inhibition', 'NegReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (67, 80))	('immunodeficient', 'Disease', 'MESH:D007153', (118, 133))	('immunodeficient', 'Disease', (118, 133))	('DAX1', 'Gene', (28, 32))
418397	30542624	Loss of tumor suppressor genes, such as p53 or Ink4a/ARF, greatly accelerate tumorigenesis in EWS-FLI1-transgenic mice, and studies have shown that loss of p16Ink4a stabilizes EWS-FLI1 expression and cooperates with EWS-FLI1-mediated transformation.	('expression', 'MPA', (185, 195))	('EWS-FLI1', 'Gene', '2130;2313', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Ink4a/ARF', 'Gene', '12578', (47, 56))	('EWS-FLI1', 'Gene', (94, 102))	('transgenic mice', 'Species', '10090', (103, 118))	('loss', 'Var', (148, 152))	('p53', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('EWS-FLI1', 'Gene', '2130;2313', (94, 102))	('EWS-FLI1', 'Gene', (216, 224))	('stabilizes', 'PosReg', (165, 175))	('tumor', 'Disease', (8, 13))	('p16Ink4a', 'Var', (156, 164))	('Ink4a/ARF', 'Gene', (47, 56))	('EWS-FLI1', 'Gene', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('accelerate', 'PosReg', (66, 76))	('EWS-FLI1', 'Gene', '2130;2313', (216, 224))	('tumor', 'Disease', (77, 82))
418407	30542624	When crossed with Mx1-Cre mice (interferon-inducible the most commonly used "deleter strain" in experimental hematology that is interferon-inducible; 79), activation of EWS-FLI1 resulted in the rapid development of myeloid/erythroid leukemia characterized by expansion of primitive mononuclear cells causing hepatosplenomegaly, severe anemia, and death.	('expansion', 'PosReg', (259, 268))	('causing', 'Reg', (300, 307))	('hepatosplenomegaly', 'Disease', (308, 326))	('EWS-FLI1', 'Gene', '2130;2313', (169, 177))	('anemia', 'Disease', (335, 341))	('hepatosplenomegaly', 'Disease', 'MESH:C535727', (308, 326))	('Mx1', 'Gene', '17857', (18, 21))	('hepatosplenomegaly', 'Phenotype', 'HP:0001433', (308, 326))	('men', 'Species', '9606', (207, 210))	('death', 'Disease', (347, 352))	('anemia', 'Disease', 'MESH:D000740', (335, 341))	('myeloid/erythroid leukemia', 'Disease', (215, 241))	('men', 'Species', '9606', (102, 105))	('mice', 'Species', '10090', (26, 30))	('Mx1', 'Gene', (18, 21))	('EWS-FLI1', 'Gene', (169, 177))	('myeloid/erythroid leukemia', 'Disease', 'MESH:D007951', (215, 241))	('leukemia', 'Phenotype', 'HP:0001909', (233, 241))	('death', 'Disease', 'MESH:D003643', (347, 352))	('activation', 'Var', (155, 165))	('anemia', 'Phenotype', 'HP:0001903', (335, 341))
418413	30542624	Under the condition of p53 deletion, EWS-FLI1 accelerated the formation of sarcomas from a median time of 50 to 21 weeks, with poorly differentiated phenotype.	('sarcomas', 'Disease', (75, 83))	('accelerated', 'PosReg', (46, 57))	('EWS-FLI1', 'Gene', (37, 45))	('deletion', 'Var', (27, 35))	('EWS-FLI1', 'Gene', '2130;2313', (37, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('p53', 'Gene', (23, 26))	('sarcomas', 'Disease', 'MESH:D012509', (75, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
418419	30542624	They demonstrated that 23 of 29 PCa samples (79%) had rearrangements in ERG or ETV1 by FISH.	('men', 'Species', '9606', (63, 66))	('rearrangements', 'Var', (54, 68))	('ETV1', 'Gene', (79, 83))	('ERG', 'Gene', (72, 75))	('ETV1', 'Gene', '2115', (79, 83))	('PCa', 'Disease', (32, 35))
418422	30542624	found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2.	('inhibiting', 'NegReg', (60, 70))	('expression', 'MPA', (74, 84))	('EZH2', 'Gene', (222, 226))	('androgen receptor', 'Gene', '367', (24, 41))	('binding', 'Interaction', (86, 93))	('AR', 'Gene', '367', (71, 73))	('activity', 'MPA', (115, 123))	('AR', 'Gene', '367', (43, 45))	('AR', 'Gene', '367', (112, 114))	('inducing', 'Reg', (129, 137))	('ERG', 'Var', (11, 14))	('repressive epigenetic programs', 'MPA', (138, 168))	('androgen receptor', 'Gene', (24, 41))	('EZH2', 'Gene', '2146', (222, 226))	('disrupts', 'NegReg', (15, 23))	('activation', 'PosReg', (180, 190))	('inhibiting', 'NegReg', (101, 111))
418425	30542624	ERG knockdown in VCaP cells (PCa cell line established from a vertebral metastatic lesion) induced a transcriptional program consistent with prostate differentiation.	('prostate differentiation', 'Disease', (141, 165))	('ERG', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))	('induced', 'Reg', (91, 98))	('VCaP', 'CellLine', 'CVCL:2235', (17, 21))	('transcriptional program', 'MPA', (101, 124))
418427	30542624	reported that aberrant expression of ERG is a progression event in prostate tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('aberrant expression', 'Var', (14, 33))	('ERG', 'Gene', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
418428	30542624	Interestingly, PCa specimens containing the TMPRSS2-ERG rearrangement were significantly enriched for loss of the tumor suppressor PTEN, consistent with the report by King et al..	('men', 'Species', '9606', (24, 27))	('loss of the tumor', 'Disease', (102, 119))	('PTEN', 'Gene', (131, 135))	('men', 'Species', '9606', (65, 68))	('loss of the tumor', 'Disease', 'MESH:D009369', (102, 119))	('PTEN', 'Gene', '5728', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('rearrangement', 'Var', (56, 69))	('TMPRSS2-ERG', 'Gene', (44, 55))
418441	30542624	Thus, loss of PTEN and the presence of the TMPRSS2-ERG gene fusion are events significantly associated with PCa.	('loss', 'NegReg', (6, 10))	('PTEN', 'Gene', (14, 18))	('PTEN', 'Gene', '5728', (14, 18))	('PCa', 'Disease', (108, 111))	('associated', 'Reg', (92, 102))	('presence', 'Var', (27, 35))	('TMPRSS2-ERG', 'Gene', (43, 54))
418442	30542624	proposed the hypothesis that PCa development might be driven initially by PTEN hemizygous loss that caused high grade PIN lesions, which leads to genomic instability, chromosomal rearrangement, and progression to cancer.	('genomic instability', 'MPA', (146, 165))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('caused', 'Reg', (100, 106))	('chromosomal rearrangement', 'Var', (167, 192))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('PTEN', 'Gene', (74, 78))	('PTEN', 'Gene', '5728', (74, 78))	('men', 'Species', '9606', (40, 43))	('cancer', 'Disease', (213, 219))	('PCa', 'Disease', (29, 32))	('men', 'Species', '9606', (188, 191))	('leads to', 'Reg', (137, 145))
418444	30542624	HDAC1 upregulation is common in PCa, and was found to be increased in tumors with ERG rearrangement.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('HDAC1', 'Gene', (0, 5))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('ERG rearrangement', 'Var', (82, 99))	('men', 'Species', '9606', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('increased', 'PosReg', (57, 66))	('HDAC1', 'Gene', '3065', (0, 5))	('upregulation', 'PosReg', (6, 18))	('PCa', 'Disease', (32, 35))
418450	30542624	reported that patients with two or more copies of the TMPRSS2-ERG fusion gene due to the interstitial deletion had worse survival rates than patients without TMPRSS2-ERG rearrangement.	('survival rates', 'CPA', (121, 135))	('men', 'Species', '9606', (179, 182))	('TMPRSS2-ERG fusion', 'Gene', (54, 72))	('deletion', 'Var', (102, 110))	('worse', 'NegReg', (115, 120))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (141, 149))
418451	30542624	This is consistent with the view that ERG overexpression is responsible for driving cancer progression, and that the 2.8 Mb deletion (containing genes with tumor suppressor activity) may contribute to the oncogenic potential of the TMPRSS2-ERG fusion product.	('contribute', 'Reg', (187, 197))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('deletion', 'Var', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', (156, 161))	('oncogenic potential', 'CPA', (205, 224))
418452	30542624	They identified a subset of tumors manifesting stem-like signatures together with p53 and PTEN inactivation, which had very poor survival outcome; a second group characterized by the TMPRSS2-ERG fusion with poor survival outcome, composed of 18% of the tumors in the dataset.	('tumors', 'Disease', (253, 259))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('tumors', 'Disease', (28, 34))	('PTEN', 'Gene', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('PTEN', 'Gene', '5728', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('p53', 'Var', (82, 85))	('inactivation', 'Var', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
418458	30542624	In clinical tumor specimens, the overexpression of ERG was associated with the rearrangement.	('overexpression', 'PosReg', (33, 47))	('ERG', 'Protein', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('rearrangement', 'Var', (79, 92))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('men', 'Species', '9606', (23, 26))	('men', 'Species', '9606', (88, 91))	('tumor', 'Disease', (12, 17))
418459	30542624	Fifty of 150 (33%) of the prostatectomy specimens and 28 of 76 (37%) of the hormone-refractory PCa on tissue microarrays carried the TMPRSS2-ERG rearrangement.	('TMPRSS2-ERG rearrangement', 'Var', (133, 158))	('carried', 'Reg', (121, 128))	('men', 'Species', '9606', (45, 48))	('men', 'Species', '9606', (154, 157))
418462	30542624	analyzed TMPRSS2-ERG gene rearrangement status by fluorescence in situ hybridization in 521 cases of clinically localized surgically treated PCa with 95 months of median follow-up.	('rearrangement', 'Var', (26, 39))	('men', 'Species', '9606', (35, 38))	('PCa', 'Disease', (141, 144))	('TMPRSS2-ERG', 'Gene', (9, 20))
418463	30542624	42% of primary tumors and 40% of metastases had rearrangements.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('rearrangements', 'Var', (48, 62))	('metastases', 'Disease', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('men', 'Species', '9606', (57, 60))	('tumors', 'Disease', (15, 21))
418464	30542624	Rearrangement alone was associated with lower grade, but not with stage, biochemical recurrence, metastases, or survival.	('Rearrangement', 'Var', (0, 13))	('metastases', 'Disease', (97, 107))	('men', 'Species', '9606', (9, 12))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('lower', 'NegReg', (40, 45))
418465	30542624	They reported that a subgroup of cancers with chromosomal number instability (CNI) and rearrangement by deletion, with two or more copies of the deleted locus, tended to be more clinically aggressive.	('clinically aggressive', 'CPA', (178, 199))	('men', 'Species', '9606', (96, 99))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('rearrangement', 'Var', (87, 100))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('chromosomal number instability', 'Var', (46, 76))	('deletion', 'Var', (104, 112))
418468	30542624	In this context, the association of greater probability of tumor progression with increased copy number of the ERG gene formed without fusion is not surprising given the previous evidence supporting aneuploidy as a negative prognostic indicator in PCa.	('tumor', 'Disease', (59, 64))	('aneuploidy', 'Disease', 'MESH:D000782', (199, 209))	('copy number', 'Var', (92, 103))	('PCa', 'Disease', (248, 251))	('ERG', 'Gene', (111, 114))	('increased', 'PosReg', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('aneuploidy', 'Disease', (199, 209))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
418473	30542624	In pediatric B-cell ALL, the most frequent chromosomal lesion is t(12;21)(p13;q22), which results in the fusion of ETV6/RUNX1 (E/R fusion; also known as TEL/AML1) fusion gene [; Fig.	('AML1', 'Gene', '861', (157, 161))	('fusion', 'Var', (105, 111))	('frequent chromosomal lesion', 'Phenotype', 'HP:0040012', (34, 61))	('TEL', 'Gene', '2120', (153, 156))	('ETV6', 'Gene', (115, 119))	('AML1', 'Gene', (157, 161))	('t(12;21)(p13;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (65, 82))	('TEL', 'Gene', (153, 156))	('RUNX1', 'Gene', (120, 125))	('RUNX1', 'Gene', '861', (120, 125))	('ETV6', 'Gene', '2120', (115, 119))	('results in', 'Reg', (90, 100))
418478	30542624	Early studies addressing secondary genetic changes have focused on the deletion of the non-rearranged ETV6 allele which is a tumor suppressor by dimerizing with E/R to reduce its transforming activity.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('ETV6', 'Gene', '2120', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('deletion', 'Var', (71, 79))	('tumor', 'Disease', (125, 130))	('reduce', 'NegReg', (168, 174))	('transforming activity', 'CPA', (179, 200))	('ETV6', 'Gene', (102, 106))
418480	30542624	Moreover, ~20% of t(12;21) (+) patients have additional genetic change in ETV6 or RUNX1.	('ETV6', 'Gene', '2120', (74, 78))	('genetic change', 'Var', (56, 70))	('RUNX1', 'Gene', (82, 87))	('t(12;21', 'Gene', (18, 25))	('ETV6', 'Gene', (74, 78))	('RUNX1', 'Gene', '861', (82, 87))	('patients', 'Species', '9606', (31, 39))
418482	30542624	As predicted, deletion of 12p (39%) was the most common abnormality resulting in the loss of wild type ETV6 allele (138).	('ETV6', 'Gene', '2120', (103, 107))	('deletion of', 'Var', (14, 25))	('ETV6', 'Gene', (103, 107))	('loss', 'NegReg', (85, 89))
418483	30542624	The 9p deletion containing the INK4b/ARF/INK4a locus (139-141) can be seen in up to 25% of E/R(+) patients, and the B-cell differentiation regulator PAX5 (126, 142).	('ARF', 'Gene', (37, 40))	('INK4b', 'Gene', (31, 36))	('INK4b', 'Gene', '1030', (31, 36))	('patients', 'Species', '9606', (98, 106))	('INK4a', 'Gene', '1029', (41, 46))	('PAX5', 'Gene', '5079', (149, 153))	('INK4a', 'Gene', (41, 46))	('139-141', 'Var', (54, 61))	('ARF', 'Gene', '12578', (37, 40))	('PAX5', 'Gene', (149, 153))
418484	30542624	CDKN2a/b, ETV6, PAX5, deletions, chromosome 6q loss, and chromosome 16 gain are probably among the earliest genetic aberrations in E/R(+) ALL.	('chromosome 6q', 'Gene', (33, 46))	('ETV6', 'Gene', (10, 14))	('deletions', 'Var', (22, 31))	('chromosome 16', 'Gene', (57, 70))	('PAX5', 'Gene', (16, 20))	('PAX5', 'Gene', '5079', (16, 20))	('CDKN2a', 'Gene', '1029', (0, 6))	('CDKN2a', 'Gene', (0, 6))	('ETV6', 'Gene', '2120', (10, 14))	('loss', 'NegReg', (47, 51))	('gain', 'PosReg', (71, 75))
418485	30542624	addressed the issue by conducting a shRNA-mediated knock-down (KD) of the E/R fusion gene and investigated the consequences with two E/R(+) leukemic cell lines.	('E/R', 'Gene', (74, 77))	('leukemic', 'Disease', 'MESH:D007938', (140, 148))	('leukemic', 'Disease', (140, 148))	('knock-down', 'Var', (51, 61))
418487	30542624	The results suggest that the E/R chimeric protein accelerates tumorigenesis by up-regulating genes involved in cell proliferation without sending signals to the PI3K-AKT-mTOR pathway.	('accelerates', 'PosReg', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('AKT', 'Gene', '207', (166, 169))	('mTOR', 'Gene', (170, 174))	('tumor', 'Disease', (62, 67))	('mTOR', 'Gene', '2475', (170, 174))	('E/R chimeric', 'Var', (29, 41))	('AKT', 'Gene', (166, 169))	('genes', 'Gene', (93, 98))	('up-regulating', 'PosReg', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
418501	30542624	In conclusion, the relapse clones of E/R(+) leukemia originate from those exist at initial presentation.	('leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('leukemia', 'Disease', 'MESH:D007938', (44, 52))	('E/R(+', 'Var', (37, 42))	('leukemia', 'Disease', (44, 52))
418503	30542624	They identified recurrent, mainly non-overlapping deletions associated with glucocorticoid-mediated apoptosis targeting the Bcl2 modifying factor (BMF), glucocorticoid receptor NR3C1, and components of the mismatch repair pathways.	('NR3C1', 'Gene', '2908', (177, 182))	('Bcl2 modifying factor', 'Gene', '90427', (124, 145))	('BMF', 'Gene', (147, 150))	('deletions', 'Var', (50, 59))	('Bcl2 modifying factor', 'Gene', (124, 145))	('BMF', 'Gene', '90427', (147, 150))	('NR3C1', 'Gene', (177, 182))	('associated', 'Reg', (60, 70))	('glucocorticoid-mediated', 'Disease', (76, 99))
418504	30542624	Fluorescence in situ hybridization demonstrated that BMF deletions, NR3C1 and mismatch repair alterations became more common at relapse.	('deletions', 'Var', (57, 66))	('NR3C1', 'Gene', '2908', (68, 73))	('BMF', 'Gene', (53, 56))	('NR3C1', 'Gene', (68, 73))	('mismatch repair', 'MPA', (78, 93))	('BMF', 'Gene', '90427', (53, 56))
418505	30542624	performed a long-term, follow-up retrospective study to address the outcome of patients with E/R(+) leukemia relapses.	('leukemia', 'Disease', 'MESH:D007938', (100, 108))	('leukemia', 'Disease', (100, 108))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('E/R(+', 'Var', (93, 98))	('patients', 'Species', '9606', (79, 87))
418507	30542624	Overall, they found an excellent outcome for patients with E/R(+) leukemia relapses that occurred more than 36 months after diagnosis.	('E/R(+', 'Var', (59, 64))	('leukemia', 'Disease', (66, 74))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))	('leukemia', 'Disease', 'MESH:D007938', (66, 74))	('patients', 'Species', '9606', (45, 53))
418511	30542624	ETS proteins are frequently activated in human cancers by translocation.	('translocation', 'Var', (58, 71))	('ETS proteins', 'Protein', (0, 12))	('human', 'Species', '9606', (41, 46))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('ETS', 'Chemical', '-', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('activated', 'PosReg', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
418512	30542624	To make GEMM for EWS, the EWS-FLI1 fusion transcripts express exclusively in mesenchymal stem cells to avoid its expression in hematological tissues.	('EWS-FLI1', 'Gene', (26, 34))	('fusion', 'Var', (35, 41))	('EWS-FLI1', 'Gene', '2130;2313', (26, 34))
418513	30542624	When crossed with interferon -inducible Mx1-Cre mice, activation of EWS-FLI1 resulted in the rapid development of myeloid/erythroid leukemia characterized by expansion of mononuclear cells causing hepatosplenomegaly, severe anemia, and death.	('death', 'Disease', 'MESH:D003643', (236, 241))	('anemia', 'Phenotype', 'HP:0001903', (224, 230))	('hepatosplenomegaly', 'Disease', 'MESH:C535727', (197, 215))	('anemia', 'Disease', (224, 230))	('men', 'Species', '9606', (106, 109))	('hepatosplenomegaly', 'Phenotype', 'HP:0001433', (197, 215))	('myeloid/erythroid leukemia', 'Disease', (114, 140))	('Mx1', 'Gene', '17857', (40, 43))	('EWS-FLI1', 'Gene', (68, 76))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('myeloid/erythroid leukemia', 'Disease', 'MESH:D007951', (114, 140))	('death', 'Disease', (236, 241))	('EWS-FLI1', 'Gene', '2130;2313', (68, 76))	('anemia', 'Disease', 'MESH:D000740', (224, 230))	('activation', 'Var', (54, 64))	('mice', 'Species', '10090', (48, 52))	('Mx1', 'Gene', (40, 43))	('expansion', 'PosReg', (158, 167))	('hepatosplenomegaly', 'Disease', (197, 215))
418516	30542624	The disease is accelerated in p16Ink4a-null mice but not Arf-null mice suggesting the critical role of p16INK4a in Ewing's sarcoma.	('p16Ink4a-null', 'Var', (30, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('p16INK4a', 'Gene', '12578', (103, 111))	('accelerated', 'PosReg', (15, 26))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (115, 130))	('mice', 'Species', '10090', (66, 70))	("Ewing's sarcoma", 'Disease', (115, 130))	('Arf', 'Gene', (57, 60))	('Arf', 'Gene', '12578', (57, 60))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (115, 130))	('p16INK4a', 'Gene', (103, 111))	('mice', 'Species', '10090', (44, 48))
418519	30542624	In pediatric B-cell ALL, the translocation involving ETV6 and RUNX1 are very common.	('ETV6', 'Gene', '2120', (53, 57))	('RUNX1', 'Gene', '861', (62, 67))	('translocation', 'Var', (29, 42))	('ETV6', 'Gene', (53, 57))	('RUNX1', 'Gene', (62, 67))
418520	30542624	CDKN2a/b, ETV6, PAX5, deletions, -6q, and +16 are among the earliest genetic aberrations in E/R(+) ALL; they are secondary events that contribute to the leukemic disease.	('ETV6', 'Gene', (10, 14))	('deletions', 'Var', (22, 31))	('PAX5', 'Gene', (16, 20))	('PAX5', 'Gene', '5079', (16, 20))	('CDKN2a', 'Gene', (0, 6))	('leukemic disease', 'Disease', 'MESH:D007938', (153, 169))	('ETV6', 'Gene', '2120', (10, 14))	('leukemic disease', 'Disease', (153, 169))	('CDKN2a', 'Gene', '1029', (0, 6))	('contribute', 'Reg', (135, 145))
418544	29238756	The final tumor size was noted from the final histopathologic report of the specimen and was categorized on the basis of the largest diameter being either >=20 cm, between 10 and 20 cm, or <10 cm.	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('>=20 cm', 'Var', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
418651	25917851	A staging positron emission tomography/CT was performed but did not reveal any distant metastases, indicating T2N2aM0 disease according to American Joint Committee on Cancer staging criteria for head and neck pharyngeal cancer.	('Cancer', 'Phenotype', 'HP:0002664', (167, 173))	('metastases', 'Disease', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('T2N2aM0', 'Var', (110, 117))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (209, 226))	('cancer', 'Disease', (220, 226))
418708	25917851	A study of 14 FDCS cases and 188 cases of 15 different types of spindle-cell tumors found clusterin positivity to have a sensitivity of 100% and a specificity of 93%.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('clusterin', 'Gene', '1191', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('clusterin', 'Gene', (90, 99))	('positivity', 'Var', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
418760	33794573	Patients' reported complete response rates were significantly higher in the 20 Gy per 5 fractions treatment arm (p = 0.042; OR = 1.75; 95% CI, 1.1-2.7).	('20 Gy', 'Var', (76, 81))	('men', 'Species', '9606', (103, 106))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (62, 68))	('complete response', 'CPA', (19, 36))
418844	31719101	The previously developed R package, LFSPRO, is capable of estimating the risk of an individual being a TP53 mutation carrier.	('TP53', 'Gene', '7157', (103, 107))	('TP53', 'Gene', (103, 107))	('mutation', 'Var', (108, 116))
418853	31719101	LFS is known to be associated with deleterious germ-line mutations in the TP53 tumor suppressor gene.	('tumor', 'Disease', (79, 84))	('LFS', 'Disease', (0, 3))	('TP53', 'Gene', '7157', (74, 78))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('TP53', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
418854	31719101	It is crucial to accurately estimate the penetrance of TP53 mutations in order to provide better clinical management to the individuals at high risk of LFS.	('mutations', 'Var', (60, 69))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))	('LFS', 'Disease', (152, 155))
418855	31719101	Due to the wide spectrum of LFS cancers, it is likely that specific TP53 mutations have different effects for different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('LFS cancers', 'Disease', 'MESH:D016864', (28, 39))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', (120, 126))	('LFS cancers', 'Disease', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('effects', 'Reg', (98, 105))	('mutations', 'Var', (73, 82))
418858	31719101	It is necessary to estimate a cancer-specific penetrance in order to not only reveal the cancer-specific effect of the TP53 mutations but also improve the risk prediction performance by accommodating more detailed disease histories.	('mutations', 'Var', (124, 133))	('risk prediction', 'MPA', (155, 170))	('cancer', 'Disease', (30, 36))	('improve', 'PosReg', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', (89, 95))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
418866	31719101	We hereby provide a new set of cancer-specific penetrance estimates for individuals with different TP53 mutation status, sex and age.	('TP53', 'Gene', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('mutation', 'Var', (104, 112))	('TP53', 'Gene', '7157', (99, 103))	('cancer', 'Disease', (31, 37))
418877	31719101	The high-risk families in the training cohort were identified by those pedigrees that differentiated the most in linkage and segregation analysis from the general population and chosen to be tested for a TP53 mutation.	('TP53', 'Gene', '7157', (204, 208))	('TP53', 'Gene', (204, 208))	('mutation', 'Var', (209, 217))
418879	31719101	If a TP53 mutation was identified, all first-degree relatives of the proband and any other family member with an increased risk of carrying the mutation were offered TP53 testing.	('TP53', 'Gene', '7157', (166, 170))	('mutation', 'Var', (10, 18))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (166, 170))	('TP53', 'Gene', (5, 9))
418882	31719101	For the MDACC pediatric sarcoma cohort, which began collecting data in the 1980's, blood samples tested for a germline TP53 mutation were compared to the available literature for a suggestion of pathogenicity.	('sarcoma', 'Disease', (24, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('mutation', 'Var', (124, 132))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
162185	31719101	If the mutation had not been reported then available family data was used to observe if direct transmission of the same TP53 mutation was present and if cancers segregated as established LFS phenotypes.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('mutation', 'Var', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
418885	31719101	As large proportions of genotype-observed individuals are probands, who have excessively high risk for a TP53 mutation, we excluded probands in the validation study in order to mitigate this bias.	('TP53', 'Gene', '7157', (105, 109))	('mutation', 'Var', (110, 118))	('TP53', 'Gene', (105, 109))
418892	31719101	The study includes individuals meeting the classic LFS or Birch's LFL criteria, having a pathogenic germline TP53 mutation or a first- or second-degree relative with a mutation, or having a personal history of choroid plexus carcinoma, adrenocortical carcinoma, or at least 3 primary cancers .	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (236, 260))	('choroid plexus carcinoma', 'Disease', (210, 234))	('cancers', 'Disease', 'MESH:D009369', (284, 291))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (210, 234))	('cancers', 'Disease', (284, 291))	('adrenocortical carcinoma', 'Disease', (236, 260))	('TP53', 'Gene', '7157', (109, 113))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (210, 234))	('pathogenic', 'Reg', (89, 99))	('TP53', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('mutation', 'Var', (114, 122))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (236, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
418909	31719101	Define T = mink Tk and D = k. If the the kth event observed, then the cancer-specific penetrance qk(t) is  where G denotes the TP53 mutation status coded as 1 for mutation and 0 for wildtype, and X is sex coded as 1 for male and 2 for female.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mink', 'Species', '9666', (11, 15))	('mutation', 'Var', (163, 171))	('TP53', 'Gene', '7157', (127, 131))	('cancer', 'Disease', (70, 76))	('TP53', 'Gene', (127, 131))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
162197	31719101	The mutation prevalence for pathogenic TP53 mutations was specified as 0.0006 for LFSPRO, which was derived in our previous study.	('LFSPRO', 'Disease', (82, 88))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
418921	31719101	Figures 1 shows the five sex-specific, cancer-specific penetrance estimates for breast cancer, sarcoma, and other cancers combined, respectively, for TP53 mutation carriers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('TP53', 'Gene', (150, 154))	('cancers', 'Disease', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('cancer', 'Disease', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('TP53', 'Gene', '7157', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutation carriers', 'Var', (155, 172))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('sarcoma', 'Disease', (95, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', (114, 120))
418925	31719101	Risk of breast cancer greatly increases between 20 and 40 years of age for female TP53 mutation carriers (Figure 1).	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('TP53', 'Gene', (82, 86))	('increases', 'PosReg', (30, 39))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('TP53', 'Gene', '7157', (82, 86))	('mutation', 'Var', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))
418928	31719101	Through the head-to-head comparison, we observed that the female TP53 mutation carrier has excessively high probability of developing breast cancer before 25, which is not the case for BRCA1/2 (Figure 2).	('TP53', 'Gene', '7157', (65, 69))	('breast cancer', 'Disease', (134, 147))	('TP53', 'Gene', (65, 69))	('BRCA1/2', 'Gene', '672;675', (185, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutation', 'Var', (70, 78))	('BRCA1/2', 'Gene', (185, 192))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
418929	31719101	Therefore, we provide quantitative evidence for a very early-onset breast cancer being regarded as a clinical evidence of mutations in TP53.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('TP53', 'Gene', '7157', (135, 139))	('mutations', 'Var', (122, 131))	('TP53', 'Gene', (135, 139))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
418934	31719101	The other-cancer-combined penetrance for TP53 carriers is noticeably different that the wild-type individuals.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('different', 'Reg', (69, 78))	('carriers', 'Var', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
418936	31719101	Interestingly, the penetrance of death before cancer for TP53 carriers was different than that of non-carriers and of the general population SEER estimates which was used for validation purposes.	('death', 'Disease', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('carriers', 'Var', (62, 70))	('death', 'Disease', 'MESH:D003643', (33, 38))
418945	31719101	The AUCs are 0.914 (95% CI: 0.872, 0.957) for breast cancer, 0.748 (95% CI: 0.678, 0.818) for sarcoma, and 0.805 (95% CI: 0.745, 0.865) for other cancers.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('sarcoma', 'Disease', (94, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('0.748', 'Var', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
418951	31719101	Our final penetrance estimates for specific cancer types are age-of-diagnosis-dependent and vary with cancer type, sex and TP53 mutation status.	('vary', 'Reg', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('TP53', 'Gene', '7157', (123, 127))	('mutation', 'Var', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('TP53', 'Gene', (123, 127))
418952	31719101	Based on the new penetrance estimates, we observed the risk for breast cancer is higher than that from BRCA1/2 mutations before age 25.	('mutations', 'Var', (111, 120))	('BRCA1/2', 'Gene', (103, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('BRCA1/2', 'Gene', '672;675', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
418959	31719101	With a 90% lifetime risk of cancer in TP53 mutation carriers, and a near 100% risk of cancer for female TP53 mutation carriers by age 70, patients that have tested positive for a germline mutation are constantly on alert for when a cancer diagnosis will occur.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('patients', 'Species', '9606', (138, 146))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (232, 238))	('mutation', 'Var', (43, 51))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', '7157', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', (86, 92))	('mutation', 'Var', (109, 117))
418960	31719101	Our goal is for LFSPRO is be used as a tool for genetics counselors and clinicians that work with TP53 mutation carriers to provide more information to their patients during their screening visits.	('mutation', 'Var', (103, 111))	('patients', 'Species', '9606', (158, 166))	('TP53', 'Gene', '7157', (98, 102))	('TP53', 'Gene', (98, 102))
418965	31719101	It is hypothesized that the different point mutations in TP53 contribute to different effects of LFS.	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('LFS', 'Disease', (97, 100))	('point mutations', 'Var', (38, 53))
418968	31719101	In summary, we provide cancer-specific penetrance estimates of TP53 mutation carriers with improved resolution that allows us to utilize the cancer type information.	('TP53', 'Gene', '7157', (63, 67))	('mutation', 'Var', (68, 76))	('TP53', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (141, 147))
419047	28877062	Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle cell Sarcomas - Expanding the Genetic Spectrum of Tumors with Overlapping Features with Infantile Fibrosarcoma Infantile fibrosarcomas (IFS) represent a distinct group of soft tissue tumors occurring in patients under two years of age and most commonly involving the extremities.	('Tumors', 'Disease', (111, 117))	('Sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (182, 194))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('soft tissue tumors', 'Disease', (232, 250))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (232, 249))	('IFS', 'Chemical', '-', (197, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('Fibrosarcoma', 'Phenotype', 'HP:0100244', (159, 171))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (232, 250))	('Tumors', 'Disease', 'MESH:D009369', (111, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('fibrosarcomas', 'Disease', 'MESH:D005354', (182, 195))	('Sarcomas', 'Disease', (66, 74))	('Fibrosarcoma', 'Disease', (159, 171))	('soft tissue tumors', 'Disease', 'MESH:D012983', (232, 250))	('Fibrosarcoma', 'Disease', 'MESH:D005354', (159, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('patients', 'Species', '9606', (264, 272))	('fibrosarcomas', 'Disease', (182, 195))	('Sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('Tumors', 'Phenotype', 'HP:0002664', (111, 117))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('Gene Fusions', 'Var', (15, 27))
419048	28877062	Most IFS show recurrent ETV6-NTRK3 gene fusions, sensitivity to chemotherapy, and an overall favorable clinical outcome.	('fusions', 'Var', (40, 47))	('ETV6', 'Gene', (24, 28))	('IFS', 'Chemical', '-', (5, 8))	('ETV6', 'Gene', '2120', (24, 28))
419050	28877062	This study was triggered by the identification of a novel SEPT7-BRAF fusion in an unclassified retroperitoneal spindle cell sarcoma in a 16 year-old female by targeted RNA sequencing.	('SEPT7', 'Gene', '989', (58, 63))	('BRAF', 'Gene', '673', (64, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('SEPT7', 'Gene', (58, 63))	('BRAF', 'Gene', (64, 68))	('retroperitoneal spindle cell sarcoma', 'Disease', (95, 131))	('fusion', 'Var', (69, 75))	('retroperitoneal spindle cell sarcoma', 'Disease', 'MESH:D012509', (95, 131))
419051	28877062	FISH screening of nine additional tumors with similar phenotype and lacking ETV6-NTRK3 identified four additional cases with BRAF gene rearrangements in the pelvic cavity (n=2), paraspinal region (n=1), and thigh (n=1) of young children (0-3 years old).	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('ETV6', 'Gene', (76, 80))	('rearrangements', 'Var', (135, 149))	('BRAF', 'Gene', '673', (125, 129))	('children', 'Species', '9606', (228, 236))	('ETV6', 'Gene', '2120', (76, 80))	('BRAF', 'Gene', (125, 129))
419054	28877062	Our findings of recurrent BRAF gene rearrangements in tumors showing morphologic overlap with IFS expand the genetic spectrum of fusion-positive spindle cell sarcomas, to include unusual presentations, such as older children and adolescents and predilection for axial location, thereby opening new opportunities for kinase-targeted therapeutic intervention.	('spindle cell sarcomas', 'Disease', (145, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('BRAF', 'Gene', '673', (26, 30))	('IFS', 'Chemical', '-', (94, 97))	('BRAF', 'Gene', (26, 30))	('spindle cell sarcomas', 'Disease', 'MESH:D012509', (145, 166))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('rearrangements', 'Var', (36, 50))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))	('children', 'Species', '9606', (216, 224))
419075	28877062	Other cases were screened by FISH for BRAF, NTRK3, and NTRK1 gene abnormalities.	('NTRK3', 'Gene', (44, 49))	('abnormalities', 'Var', (66, 79))	('NTRK1', 'Gene', (55, 60))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (38, 42))	('NTRK1', 'Gene', '4914', (55, 60))
419077	28877062	The BAC representing SEPT7 (RP11-1011L9) covered part of the gene and its centromeric region.	('SEPT7', 'Gene', (21, 26))	('RP11-1011L9', 'Var', (28, 39))	('SEPT7', 'Gene', '989', (21, 26))
419082	28877062	Targeted RNA sequencing identified a SEPT7-BRAF fusion candidate in the index case.	('SEPT7', 'Gene', (37, 42))	('BRAF', 'Gene', '673', (43, 47))	('fusion', 'Var', (48, 54))	('BRAF', 'Gene', (43, 47))	('SEPT7', 'Gene', '989', (37, 42))
419083	28877062	The fusion resulted from a pericentric inversion of chromosome 7, leading to an in-frame fusion of exon 11 of SEPT7 (7p14.2) to exon 11 of BRAF (7q34), as confirmed by RT-PCR (Fig.	('BRAF', 'Gene', (139, 143))	('SEPT7', 'Gene', '989', (110, 115))	('fusion', 'Var', (89, 95))	('SEPT7', 'Gene', (110, 115))	('BRAF', 'Gene', '673', (139, 143))
419090	28877062	FISH screening for BRAF gene abnormalities identified 4 additional cases positive for rearrangements (cases #2-5, Supplementary Fig.	('BRAF gene abnormalities', 'Disease', (19, 42))	('rearrangements', 'Var', (86, 100))	('BRAF gene abnormalities', 'Disease', 'MESH:D025063', (19, 42))
419096	28877062	Unlike ETV6-NTRK3 rearranged infantile fibrosarcomas, which frequently involve extremities, only 1 of the BRAF rearranged cases occurred in the extremity, presenting as a congenital mass in the thigh, extending into pelvis (case #5).	('infantile fibrosarcoma', 'Disease', (29, 51))	('ETV6', 'Gene', (7, 11))	('congenital mass', 'Disease', (171, 186))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (29, 51))	('BRAF', 'Gene', '673', (106, 110))	('ETV6', 'Gene', '2120', (7, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (39, 51))	('BRAF', 'Gene', (106, 110))	('fibrosarcomas', 'Disease', 'MESH:D005354', (39, 52))	('fibrosarcomas', 'Disease', (39, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('rearranged', 'Var', (111, 121))
419105	28877062	Fusion FISH assay for SEPT7-BRAF fusion was negative in case #2, while non-contributory in case #3 due to a deletion of the telomeric signal of BRAF.	('BRAF', 'Gene', '673', (28, 32))	('telomeric signal', 'MPA', (124, 140))	('SEPT7', 'Gene', '989', (22, 27))	('BRAF', 'Gene', '673', (144, 148))	('BRAF', 'Gene', (144, 148))	('BRAF', 'Gene', (28, 32))	('deletion', 'Var', (108, 116))	('SEPT7', 'Gene', (22, 27))
419108	28877062	This breakpoint was identical to the only other reported IFS tumor with EML4-NTRK3 fusion occurring in an upper extremity of a 9 month-old boy.	('boy', 'Species', '9606', (139, 142))	('IFS tumor', 'Disease', (57, 66))	('IFS tumor', 'Disease', 'MESH:D049912', (57, 66))	('EML4-NTRK3', 'Gene', (72, 82))	('fusion', 'Var', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))
419114	28877062	RT-PCR confirmed the fusion of exon 6 of TPM3 with exon 9 of NTRK1, which preserves the C-terminal kinase domain of NTRK1, similar to the other 2 IFS cases with NTRK1 fusions reported in the literature, although the fusion partners and exact breakpoint of NTRK1 is variable, with SQSTM1 exon 2 - NTRK1 exon 10 and LMNA exon 10 - NTRK1 exon 12, resepctively.	('TPM3', 'Gene', '7170', (41, 45))	('NTRK1', 'Gene', '4914', (161, 166))	('fusion', 'Var', (21, 27))	('SQSTM1', 'Gene', '8878', (280, 286))	('NTRK1', 'Gene', '4914', (329, 334))	('NTRK1', 'Gene', (161, 166))	('NTRK1', 'Gene', (329, 334))	('NTRK1', 'Gene', '4914', (296, 301))	('NTRK1', 'Gene', (296, 301))	('LMNA', 'Gene', '4000', (314, 318))	('NTRK1', 'Gene', '4914', (256, 261))	('TPM3', 'Gene', (41, 45))	('NTRK1', 'Gene', (256, 261))	('C-terminal kinase domain', 'MPA', (88, 112))	('IFS', 'Chemical', '-', (146, 149))	('SQSTM1', 'Gene', (280, 286))	('NTRK1', 'Gene', '4914', (116, 121))	('NTRK1', 'Gene', '4914', (61, 66))	('NTRK1', 'Gene', (61, 66))	('LMNA', 'Gene', (314, 318))	('NTRK1', 'Gene', (116, 121))
419115	28877062	Further FISH testing confirmed rearrangement of NTRK1 as well as fusion with TPM3 (Fig.	('NTRK1', 'Gene', (48, 53))	('rearrangement', 'Var', (31, 44))	('TPM3', 'Gene', (77, 81))	('fusion', 'Var', (65, 71))	('NTRK1', 'Gene', '4914', (48, 53))	('TPM3', 'Gene', '7170', (77, 81))
419123	28877062	Our combined approach, using RNA sequencing for fusion gene discovery and FISH screening, revealed recurrent BRAF gene rearrangements in 5 cases of spindle cell sarcomas, morphologically akin to IFS, occurring within the abdominal cavity, paraspinal region, and thigh of children, ranging from 0 to 16 year-old.	('spindle cell sarcomas', 'Disease', (148, 169))	('BRAF', 'Gene', '673', (109, 113))	('BRAF', 'Gene', (109, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('spindle cell sarcomas', 'Disease', 'MESH:D012509', (148, 169))	('IFS', 'Chemical', '-', (195, 198))	('children', 'Species', '9606', (271, 279))	('rearrangements', 'Var', (119, 133))
419126	28877062	Furthermore, 3 BRAF rearranged tumors occurred within the abdominal cavity (one retroperitoneum, two pelvic).	('BRAF', 'Gene', '673', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BRAF', 'Gene', (15, 19))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('rearranged', 'Var', (20, 30))	('occurred', 'Reg', (38, 46))
419134	28877062	Regardless of their fusion status the IFS/CMN showed distinctive mRNA and protein expression profiles and by unsupervised hierarchical clustering the fusion-negative IFS/CMN clustered together with ETV6-NTRK3-positive IFS/CMN, compared to other soft tissue tumors in the same dataset.	('CMN', 'Phenotype', 'HP:0100881', (42, 45))	('IFS', 'Chemical', '-', (166, 169))	('soft tissue tumors', 'Disease', (245, 263))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('soft tissue tumors', 'Disease', 'MESH:D012983', (245, 263))	('IFS/CMN', 'Disease', (166, 173))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (245, 262))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('fusion-negative', 'Var', (150, 165))	('CMN', 'Phenotype', 'HP:0100881', (170, 173))	('IFS', 'Chemical', '-', (218, 221))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (245, 263))	('ETV6', 'Gene', (198, 202))	('CMN', 'Phenotype', 'HP:0100881', (222, 225))	('IFS', 'Chemical', '-', (38, 41))	('ETV6', 'Gene', '2120', (198, 202))
419136	28877062	BRAF related fusions have been reported in various tumors including gliomas, carcinomas, and melanocytic neoplasms through either intra- or inter-chromosomal translocations.	('fusions', 'Var', (13, 20))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('BRAF', 'Gene', '673', (0, 4))	('gliomas', 'Disease', (68, 75))	('BRAF', 'Gene', (0, 4))	('carcinomas', 'Disease', (77, 87))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('neoplasm', 'Phenotype', 'HP:0002664', (105, 113))	('reported', 'Reg', (31, 39))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (93, 114))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (93, 114))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('melanocytic neoplasms', 'Disease', (93, 114))	('carcinomas', 'Disease', 'MESH:D002277', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))
419137	28877062	Among soft tissue tumors, BRAF gene rearrangements were only recently reported in a subset of myxoinflammatory fibroblastic sarcomas, a clinically and morphologically distinct tumor type, characterized by superficial acral location and composed of alternating myxoid and solid areas, with a histiocytoid phenotype and Reed-Sternberg-like tumor cells.	('BRAF', 'Gene', '673', (26, 30))	('tumor', 'Disease', (338, 343))	('BRAF', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('sarcomas', 'Disease', 'MESH:D012509', (124, 132))	('tumor', 'Disease', (18, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('tumor', 'Disease', (176, 181))	('sarcomas', 'Disease', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('soft tissue tumors', 'Disease', (6, 24))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (6, 23))	('rearrangements', 'Var', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (6, 24))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('reported', 'Reg', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('soft tissue tumors', 'Disease', 'MESH:D012983', (6, 24))
419141	28877062	With the recent advent of next generation sequencing, a handful of IFS and related pediatric spindle cell sarcoma cases have been reported to harbor alternative gene fusions, either NTRK3 fused to different 5' partner genes, or other kinases, such as NTRK1 and MET.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('spindle cell sarcoma', 'Disease', (93, 113))	('IFS', 'Chemical', '-', (67, 70))	('NTRK1', 'Gene', (251, 256))	('NTRK3', 'Gene', (182, 187))	('NTRK1', 'Gene', '4914', (251, 256))	('fused', 'Var', (188, 193))	('spindle cell sarcoma', 'Disease', 'MESH:D012509', (93, 113))
419147	28877062	Two additional IFS cases identified by targeted DNA and RNA sequencing at Foundation Medicine harbored SQSTM1-NTRK1 and LMNA-NTRK1 fusion transcripts, respectively, although no histologic description or images were provided.	('NTRK1', 'Gene', '4914', (125, 130))	('IFS', 'Chemical', '-', (15, 18))	('LMNA', 'Gene', (120, 124))	('NTRK1', 'Gene', (125, 130))	('NTRK1', 'Gene', (110, 115))	('LMNA', 'Gene', '4000', (120, 124))	('NTRK1', 'Gene', '4914', (110, 115))	('SQSTM1', 'Gene', (103, 109))	('fusion transcripts', 'Var', (131, 149))	('harbored', 'Reg', (94, 102))	('SQSTM1', 'Gene', '8878', (103, 109))
419150	28877062	Although the exonic composition of the 3 IFS cases with NTRK1 fusions is slightly variable, including exon 9 (our case, TPM3-NTRK1), exon 10 (SQSTM1-NTRK1), or exon 12 (LMNA-NTRK1), they all retain the full-length coding sequence of the tyrosine kinase domain of NTRK1 (exons 13-17).	('TPM3', 'Gene', '7170', (120, 124))	('NTRK1', 'Gene', '4914', (125, 130))	('NTRK1', 'Gene', (174, 179))	('SQSTM1', 'Gene', (142, 148))	('NTRK1', 'Gene', '4914', (149, 154))	('SQSTM1', 'Gene', '8878', (142, 148))	('NTRK1', 'Gene', (56, 61))	('NTRK1', 'Gene', '4914', (263, 268))	('LMNA', 'Gene', '4000', (169, 173))	('NTRK1', 'Gene', (125, 130))	('NTRK1', 'Gene', (263, 268))	('NTRK1', 'Gene', (149, 154))	('TPM3', 'Gene', (120, 124))	('NTRK1', 'Gene', '4914', (174, 179))	('fusions', 'Var', (62, 69))	('NTRK1', 'Gene', '4914', (56, 61))	('IFS', 'Chemical', '-', (41, 44))	('LMNA', 'Gene', (169, 173))
419151	28877062	Furthermore, NTRK1-related gene fusions, including an identical TPM3-NTRK1 fusion, were identified in two distinct soft tissue tumor types, including lipofibromatosis-like neural tumors and a group of spindle cell sarcomas with prominent myopericytic/haemangiopericytic pattern.	('soft tissue tumor', 'Phenotype', 'HP:0031459', (115, 132))	('lipofibromatosis-like neural tumors', 'Disease', (150, 185))	('identified', 'Reg', (88, 98))	('spindle cell sarcomas', 'Disease', 'MESH:D012509', (201, 222))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (214, 222))	('TPM3', 'Gene', '7170', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('spindle cell sarcomas', 'Disease', (201, 222))	('TPM3', 'Gene', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('lipofibromatosis-like neural tumors', 'Disease', 'MESH:C536149', (150, 185))	('NTRK1', 'Gene', '4914', (69, 74))	('fusions', 'Var', (32, 39))	('NTRK1', 'Gene', (69, 74))	('tumor', 'Disease', (127, 132))	('NTRK1', 'Gene', '4914', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('NTRK1', 'Gene', (13, 18))	('tumor', 'Disease', (179, 184))
419154	28877062	More recently, our group identified a novel TFG-MET gene fusion by RNA sequencing in a retroperitoneal spindle cell sarcoma in a 4 month-old female showing strong S100 protein expression suggestive of neural features.	('retroperitoneal spindle cell sarcoma', 'Disease', (87, 123))	('TFG', 'Gene', (44, 47))	('S100', 'Gene', '6285', (163, 167))	('TFG', 'Gene', '10342', (44, 47))	('retroperitoneal spindle cell sarcoma', 'Disease', 'MESH:D012509', (87, 123))	('fusion', 'Var', (57, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('S100', 'Gene', (163, 167))
419157	28877062	Another member of the septin gene family, SEPT9, was previously reported in a case of T-cell prolymphocytic leukemia with SEPT9-ABL1 fusion, which was resistant to both imatinib and dasatinib therapy.	('ABL1', 'Gene', '25', (128, 132))	('SEPT9', 'Gene', '10801', (122, 127))	('T-cell prolymphocytic leukemia', 'Disease', 'MESH:D015461', (86, 116))	('fusion', 'Var', (133, 139))	('SEPT9', 'Gene', '10801', (42, 47))	('imatinib', 'Chemical', 'MESH:D000068877', (169, 177))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('ABL1', 'Gene', (128, 132))	('dasatinib', 'Chemical', 'MESH:D000069439', (182, 191))	('SEPT9', 'Gene', (122, 127))	('SEPT9', 'Gene', (42, 47))	('T-cell prolymphocytic leukemia', 'Disease', (86, 116))	('reported', 'Reg', (64, 72))
419158	28877062	Additionally, other members of the septin family, including SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11, were involved as 3' partners in hematological malignancies with MLL-SEPTIN genes fusions.	('SEPT5', 'Gene', '5413', (67, 72))	('MLL', 'Gene', '4297', (164, 167))	('SEPT9', 'Gene', '10801', (81, 86))	('MLL', 'Gene', (164, 167))	('hematological malignancies', 'Phenotype', 'HP:0004377', (132, 158))	('SEPT9', 'Gene', (81, 86))	('SEPT11', 'Gene', '55752', (92, 98))	('SEPT6', 'Gene', '23157', (74, 79))	('SEPT5', 'Gene', (67, 72))	('SEPT2', 'Gene', (60, 65))	('SEPT2', 'Gene', '4735', (60, 65))	('SEPT6', 'Gene', (74, 79))	('involved', 'Reg', (105, 113))	('fusions', 'Var', (181, 188))	('hematological malignancies', 'Disease', (132, 158))	('SEPT11', 'Gene', (92, 98))	('hematological malignancies', 'Disease', 'MESH:D019337', (132, 158))
419160	28877062	We also describe a 2nd case of IFS with EML4-NTRK3 fusion and a 3rd example of IFS with NTRK1 fusion, with a previously unreported gene partner in this tumor type, TPM3.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('NTRK1', 'Gene', '4914', (88, 93))	('EML4-NTRK3', 'Gene', (40, 50))	('TPM3', 'Gene', '7170', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('fusion', 'Var', (51, 57))	('TPM3', 'Gene', (164, 168))	('NTRK1', 'Gene', (88, 93))	('IFS', 'Chemical', '-', (31, 34))	('IFS', 'Chemical', '-', (79, 82))
419161	28877062	These findings bring further foundation to an increasing number of primitive sarcomas of childhood driven by oncogenically activated kinases through gene fusions, with critical therapeutic implications.	('driven by', 'Reg', (99, 108))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('gene fusions', 'Var', (149, 161))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))
419163	28877062	Therefore, in the setting of pediatric tumors with infantile fibrosarcoma-like phenotype, the molecular work-up should ideally include testing for abnormalities in other kinases, such as BRAF, NTRK1, MET, etc, if the tumor lacks the canonical ETV6-NTRK3 fusion.	('testing', 'Reg', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('abnormalities', 'Var', (147, 160))	('MET', 'Gene', (200, 203))	('tumor', 'Disease', (217, 222))	('NTRK1', 'Gene', '4914', (193, 198))	('NTRK1', 'Gene', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('BRAF', 'Gene', '673', (187, 191))	('BRAF', 'Gene', (187, 191))	('pediatric tumors', 'Disease', 'MESH:D063766', (29, 45))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (243, 260))	('pediatric tumors', 'Disease', (29, 45))	('ETV6-NTRK3 fusion', 'Gene', (243, 260))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (61, 73))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('infantile fibrosarcoma', 'Disease', (51, 73))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('infantile fibrosarcoma', 'Disease', 'MESH:D005354', (51, 73))
419165	28877062	Larger series of pediatric spindle cell sarcomas characterized by gene fusions across various kinases will also provide insight on their shared morphologic and clinical features, as well as their responses to targeted therapy.	('spindle cell sarcomas', 'Disease', (27, 48))	('gene fusions', 'Var', (66, 78))	('spindle cell sarcomas', 'Disease', 'MESH:D012509', (27, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
419170	28395901	In multivariable analyses, leiomyosarcoma histologic subtype (p=0.007), primary tumor size <=10 cm (p=0.006), increasing time from primary tumor resection to development of metastases (p<0.001), solitary lung metastasis (p=0.001), and minimally invasive resection (p=0.023) were associated with lower hazard of death.	('solitary lung metastasis', 'Disease', 'MESH:D009362', (195, 219))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (27, 41))	('death', 'Disease', 'MESH:D003643', (311, 316))	('death', 'Disease', (311, 316))	('solitary lung metastasis', 'Disease', (195, 219))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('metastases', 'Disease', (173, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('primary tumor', 'Disease', (72, 85))	('primary tumor', 'Disease', (131, 144))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('primary tumor', 'Disease', 'MESH:D009369', (72, 85))	('primary tumor', 'Disease', 'MESH:D009369', (131, 144))	('leiomyosarcoma', 'Disease', (27, 41))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (27, 41))	('<=10', 'Var', (91, 95))
419245	28395901	Low-grade primary tumors were also associated with better survival (p<0.001).	('Low-grade', 'Var', (0, 9))	('primary tumor', 'Disease', 'MESH:D009369', (10, 23))	('better', 'PosReg', (51, 57))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('primary tumor', 'Disease', (10, 23))
419260	28395901	Similarly, R0 resection was associated with a survival benefit of 8 months in terms of median survival, compared with R1/R2 resection (33.8 months [95% CI, 30.8-39.2] vs 25.4 months [95% CI, 16.5-31.5]; p=0.003).	('R1/R2', 'Gene', (118, 123))	('R1/R2', 'Gene', '910;6241', (118, 123))	('R0 resection', 'Var', (11, 23))
419276	28395901	Minimally invasive resection (HR=0.73 [95% CI, 0.56-0.96]; p=0.023) was additionally associated with a reduced risk of death.	('Minimally invasive resection', 'Var', (0, 28))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))
419291	28395901	Furthermore, we have identified positive prognostic factors, including leiomyosarcoma histologic subtype, primary tumor size <=10 cm, DFI >=1 year, absence of synchronous extrapulmonary metastases or local recurrence, and singular pulmonary metastasis.	('leiomyosarcoma', 'Disease', (71, 85))	('primary tumor', 'Disease', 'MESH:D009369', (106, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('synchronous extrapulmonary metastases', 'Disease', (159, 196))	('local', 'CPA', (200, 205))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (231, 251))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('<=10', 'Var', (125, 129))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (71, 85))	('synchronous extrapulmonary metastases', 'Disease', 'MESH:D009362', (159, 196))	('pulmonary metastasis', 'Disease', (231, 251))	('primary tumor', 'Disease', (106, 119))
419308	28395901	Currently, the existing literature on STS suggests that failure to perform PM predicts worse survival.	('failure', 'Var', (56, 63))	('worse', 'NegReg', (87, 92))	('STS', 'Phenotype', 'HP:0030448', (38, 41))	('PM', 'Chemical', '-', (75, 77))
419320	28395901	Additional therapies aimed at the insulin growth factor and mTOR pathways, as well as at mutations in ALK or MET, are undergoing clinical trials.	('MET', 'Gene', (109, 112))	('ALK', 'Gene', (102, 105))	('mTOR', 'Gene', '2475', (60, 64))	('mTOR', 'Gene', (60, 64))	('mutations', 'Var', (89, 98))	('ALK', 'Gene', '238', (102, 105))
419347	33936075	After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNgamma as well as granule associated proteins, resulting in potent target cell lysis.	('IFNgamma', 'Gene', '3458', (242, 250))	('IFNgamma', 'Gene', (242, 250))	('NKG2D-CD3', 'Gene', (121, 130))	('NKG2DL', 'Gene', (26, 32))	('NKG2D-CD16', 'Var', (106, 116))	('NKG2D-CD3', 'Gene', '22914', (121, 130))	('NKG2DL', 'Gene', '3821', (26, 32))	('STS', 'Phenotype', 'HP:0030448', (64, 67))	('degranulation', 'MPA', (211, 224))	('secretion', 'MPA', (229, 238))
419349	33936075	Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.	('STS', 'Phenotype', 'HP:0030448', (78, 81))	('NKG2D-CD3', 'Gene', (39, 48))	('NKG2D-CD16', 'Var', (53, 63))	('NKG2D-CD3', 'Gene', '22914', (39, 48))	('BFP', 'Chemical', '-', (64, 67))
419353	33936075	Complex karyotypes, typically associated with a worse clinical prognosis are frequently related to PTEN, RB1, BRCA2, PIK3CA or APC mutations.	('mutations', 'Var', (131, 140))	('APC', 'Gene', (127, 130))	('BRCA2', 'Gene', (110, 115))	('related', 'Reg', (88, 95))	('PIK3CA', 'Gene', (117, 123))	('APC', 'Gene', '324', (127, 130))	('BRCA2', 'Gene', '675', (110, 115))	('RB1', 'Gene', (105, 108))	('PIK3CA', 'Gene', '5290', (117, 123))	('PTEN', 'Gene', (99, 103))	('PTEN', 'Gene', '5728', (99, 103))	('RB1', 'Gene', '5925', (105, 108))
419368	33936075	NKG2D-CD16 and NKG2D-CD3 BFP were previously shown to induce potent lysis of acute myeloid leukemia cells.	('lysis', 'MPA', (68, 73))	('NKG2D-CD3 BFP', 'Gene', '22914', (15, 28))	('NKG2D-CD16', 'Var', (0, 10))	('acute myeloid leukemia', 'Disease', (77, 99))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (83, 99))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (77, 99))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (77, 99))	('NKG2D-CD3 BFP', 'Gene', (15, 28))
419369	33936075	Considering the reported expression of NKG2DL in STS, our NKG2D-CD16 and NKG2D-CD3 BFPs might offer a new promising approach in sarcoma treatment.	('NKG2D-CD3 BFP', 'Gene', '22914', (73, 86))	('sarcoma', 'Disease', 'MESH:D012509', (128, 135))	('NKG2DL', 'Gene', (39, 45))	('NKG2D-CD16', 'Var', (58, 68))	('sarcoma', 'Disease', (128, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('NKG2DL', 'Gene', '3821', (39, 45))	('NKG2D-CD3 BFP', 'Gene', (73, 86))	('STS', 'Phenotype', 'HP:0030448', (49, 52))
419370	33936075	In the present study we provide preclinical evidence that an effective treatment with NKG2D-CD16 and NKG2D-CD3 BFPs might be possible even in heavily pretreated STS patients.	('NKG2D-CD3 BFP', 'Gene', '22914', (101, 114))	('NKG2D-CD16', 'Var', (86, 96))	('STS', 'Phenotype', 'HP:0030448', (161, 164))	('patients', 'Species', '9606', (165, 173))	('NKG2D-CD3 BFP', 'Gene', (101, 114))
419394	33936075	PBMC subsets of sarcoma patients and healthy control donors were identified by counterstaining with CD3-APC/Fire750, CD4-Pacific Blue, CD8-BV605, CD14-BV785, CD16-APC, CD19-FITC, CD56-PeCy7 and HLA-DR-BV650 (BioLegend).	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('CD8', 'Gene', '925', (135, 138))	('CD14-BV785', 'Var', (146, 156))	('CD3', 'Gene', (100, 103))	('FITC', 'Chemical', 'MESH:D016650', (173, 177))	('Pacific Blue', 'Chemical', '-', (121, 133))	('CD4', 'Gene', (117, 120))	('sarcoma', 'Disease', (16, 23))	('CD4', 'Gene', '920', (117, 120))	('APC', 'Gene', (104, 107))	('APC', 'Gene', (163, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('CD3', 'Gene', '28134', (100, 103))	('APC', 'Gene', '324', (104, 107))	('patients', 'Species', '9606', (24, 32))	('CD8', 'Gene', (135, 138))	('APC', 'Gene', '324', (163, 166))
419427	33936075	PBMC of healthy donors were incubated with RD-ES and SW1353 cells in the presence or absence of NKG2D-CD16 and NKG2D-CD3 BFP.	('NKG2D-CD3 BFP', 'Gene', '22914', (111, 124))	('NKG2D-CD3 BFP', 'Gene', (111, 124))	('NKG2D-CD16', 'Var', (96, 106))	('SW1353', 'CellLine', 'CVCL:0543', (53, 59))
419428	33936075	We observed a significant increase of CD16+ cells interacting with sarcoma cells when treated with NKG2D-CD16 in three independent experiments and two different cell lines (RD-ES: p<0.0001, SW1353: p<0.0001,  Figures 3A ,  S2A ).	('NKG2D-CD16', 'Var', (99, 109))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('CD16+ cells', 'CPA', (38, 49))	('SW1353', 'CellLine', 'CVCL:0543', (190, 196))	('sarcoma', 'Disease', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('increase', 'PosReg', (26, 34))
419432	33936075	Flow cytometry analysis of CD69 on NK and T cells revealed that both constructs significantly induced activation upon treatment with NKG2D-CD16 and NKG2D-CD3, respectively (NK cells: p=0.009, CD4: p=0.0001, CD8: p=0.0009,  Figure 4A ).	('NKG2D-CD16', 'Var', (133, 143))	('CD8', 'Gene', '925', (207, 210))	('CD4', 'Gene', '920', (192, 195))	('NKG2D-CD3', 'Gene', (148, 157))	('NKG2D-CD3', 'Gene', '22914', (148, 157))	('activation', 'PosReg', (102, 112))	('CD8', 'Gene', (207, 210))	('CD4', 'Gene', (192, 195))
419433	33936075	In line, determination of CD107a upregulation confirmed that NKG2D-CD16 and NKG2D-CD3 potently induced degranulation of NK and T cells, respectively (NK cells: p<0.0001, CD4: p<0.0001, CD8: p<0.0001,  Figure 4B ).	('CD107a', 'Gene', (26, 32))	('NKG2D-CD3', 'Gene', (76, 85))	('CD107a', 'Gene', '3916', (26, 32))	('degranulation', 'MPA', (103, 116))	('CD8', 'Gene', (185, 188))	('CD4', 'Gene', (170, 173))	('NKG2D-CD3', 'Gene', '22914', (76, 85))	('CD8', 'Gene', '925', (185, 188))	('CD4', 'Gene', '920', (170, 173))	('NKG2D-CD16', 'Var', (61, 71))
419435	33936075	Furthermore there was a tendency to increased Granzyme A and Granulysin secretion after NKG2D-CD16 treatment ( Figure 4C ).	('Granzyme A', 'Gene', (46, 56))	('Granzyme A', 'Gene', '3001', (46, 56))	('Granulysin', 'Gene', '10578', (61, 71))	('increased', 'PosReg', (36, 45))	('NKG2D-CD16', 'Var', (88, 98))	('Granulysin', 'Gene', (61, 71))
419441	33936075	Interestingly, a bright staining for Perforin could be detected after 1 h and 3 h of treatment with NKG2D-CD16 and NKG2D-CD3, respectively ( Figures 4F ,  S4  ).	('NKG2D-CD3', 'Gene', '22914', (115, 124))	('NKG2D-CD3', 'Gene', (115, 124))	('Perforin', 'Protein', (37, 45))	('NKG2D-CD16', 'Var', (100, 110))
419449	33936075	To determine whether NKG2D-CD3 and NKG2D-CD16 could stimulate effector cells of pretreated STS patients in a similar manner as in healthy donors, we employed an experimental setting independent of target cell binding.	('NKG2D-CD3', 'Gene', (21, 30))	('NKG2D-CD3', 'Gene', '22914', (21, 30))	('patients', 'Species', '9606', (95, 103))	('STS', 'Phenotype', 'HP:0030448', (91, 94))	('NKG2D-CD16', 'Var', (35, 45))	('effector cells', 'CPA', (62, 76))	('stimulate', 'PosReg', (52, 61))
419451	33936075	Although NK cells of STS patients showed slightly decreased CD69 expression after treatment with NKG2D-CD16 compared to healthy donors ( Figure 5F ), this trend did not reach statistical significance (p=0.15).	('CD69', 'Gene', (60, 64))	('decreased CD69 expression', 'Phenotype', 'HP:0031268', (50, 75))	('decreased', 'NegReg', (50, 59))	('expression', 'MPA', (65, 75))	('patients', 'Species', '9606', (25, 33))	('NKG2D-CD16', 'Var', (97, 107))	('STS', 'Phenotype', 'HP:0030448', (21, 24))
419457	33936075	As NKG2D-CD3 and NKG2D-CD16 stimulate T cells and NK cells which differ with regard to efficacy of effector function over time, we performed cytotoxicity assays after various incubation times using different suitable experimental systems.	('NKG2D-CD3', 'Gene', '22914', (3, 12))	('cytotoxicity', 'Disease', 'MESH:D064420', (141, 153))	('NKG2D-CD16', 'Var', (17, 27))	('cytotoxicity', 'Disease', (141, 153))	('NKG2D-CD3', 'Gene', (3, 12))
419458	33936075	Europium based short-term cytotoxicity assays showed a potent target cell lysis by treatment with NKG2D-CD16 after 2 h, whereas no significant effect was observed with NKG2D-CD3 ( Figures 6A ,  S6A ).	('NKG2D-CD3', 'Gene', (168, 177))	('cytotoxicity', 'Disease', (26, 38))	('NKG2D-CD3', 'Gene', '22914', (168, 177))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('target cell lysis', 'CPA', (62, 79))	('NKG2D-CD16', 'Var', (98, 108))
419471	33936075	Remarkably, we observed a highly effective tumor cell lysis using NKG2D-CD16 BFP.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('NKG2D-CD16', 'Var', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('BFP', 'Chemical', '-', (77, 80))
419473	33936075	Even more important, NKG2D-CD16 overcomes several drawbacks of mAbs with conventional Fc-parts like binding to inhibitory FcgammaR, which may decrease immunostimulatory potential, or FcgammaR expressed on non-cytotoxic cells (e.g., platelets and B cells) and FcgammaR that do not trigger cytotoxicity (e.g.	('cytotoxicity', 'Disease', (288, 300))	('NKG2D-CD16', 'Var', (21, 31))	('decrease', 'NegReg', (142, 150))	('immunostimulatory potential', 'MPA', (151, 178))	('cytotoxicity', 'Disease', 'MESH:D064420', (288, 300))
419480	33936075	When comparing the therapeutic potential of NKG2D-CD16 and NKG2D-CD3 in STS, it is important to note that NKG2D-CD16 showed most potent cytotoxicity after short time points.	('NKG2D-CD3', 'Gene', '22914', (59, 68))	('STS', 'Phenotype', 'HP:0030448', (72, 75))	('NKG2D-CD16', 'Var', (106, 116))	('cytotoxicity', 'Disease', (136, 148))	('cytotoxicity', 'Disease', 'MESH:D064420', (136, 148))	('NKG2D-CD3', 'Gene', (59, 68))
419487	33936075	Furthermore it has been reported that glycosylation of MICA enhanced complex formation with NKG2D.	('MICA', 'Gene', (55, 59))	('MICA', 'Gene', '100507436', (55, 59))	('glycosylation', 'Var', (38, 51))	('complex', 'Interaction', (69, 76))	('enhanced', 'PosReg', (60, 68))
419489	33936075	by targeting NKG2D-L with chimeric antigen receptor T (CAR-T) cells (NKR-2) (NCT03018405), (CYAD-02) (NCT04167696).	('NCT03018405', 'Var', (77, 88))	('NCT04167696', 'Var', (102, 113))	('CA', 'Gene', '12310', (55, 57))
419492	33936075	Our finding that PBMCs from STS patients receiving poly-chemotherapy showed profound NK and T cell activation after stimulation with NKG2D-CD16 indicates that combinatorial therapy might be promising.	('NKG2D-CD16', 'Var', (133, 143))	('patients', 'Species', '9606', (32, 40))	('activation', 'PosReg', (99, 109))	('STS', 'Phenotype', 'HP:0030448', (28, 31))	('T cell', 'CPA', (92, 98))
419497	33936075	In conclusion, NKG2D-CD16 and NKG2D-CD3 BFP showed powerful anti-sarcoma effects in a preclinical setting.	('sarcoma', 'Disease', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('NKG2D-CD3 BFP', 'Gene', (30, 43))	('NKG2D-CD16', 'Var', (15, 25))	('NKG2D-CD3 BFP', 'Gene', '22914', (30, 43))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))
419532	32900797	As a result, CSPG4 immuno-targeting selectively inhibits neoangiogenesis in the tumor microenvironment, thus contributing to the elimination of the vasculature that supports tumor growth.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('inhibits', 'NegReg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('immuno-targeting', 'Var', (19, 35))	('neoangiogenesis in the', 'CPA', (57, 79))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('CSPG4', 'Gene', (13, 18))
419599	32900797	In these models, when the tumor volume was approximatively 20 mm3, mice received two infusions (on day 0 and day +4) of 3x106 CSPG4-CAR.CIK or unmodified NTD.CIK.	('NTD.CIK', 'Gene', '80199', (154, 161))	('NTD.CIK', 'Gene', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('CAR', 'Gene', (132, 135))	('3x106', 'Var', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('mice', 'Species', '10090', (67, 71))	('CAR', 'Gene', '19674', (132, 135))
419654	32900797	The antitumor activity of CSPG4-CAR.CIK was also verified in additional experiments in which we reduced the initial tumor burden (~20 mm3) for both HT1080 and S172 tumors (Suppl.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('HT1080', 'Gene', (148, 154))	('tumors', 'Disease', (164, 170))	('CAR', 'Gene', '19674', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('S172', 'Var', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (8, 13))	('CAR', 'Gene', (32, 35))	('tumor', 'Disease', (116, 121))	('HT1080', 'CellLine', 'CVCL:0317', (148, 154))	('reduced', 'NegReg', (96, 103))
419659	32900797	Here, we report that CSPG4 is a clinically relevant target in STS and that CSPG4 expression can be efficiently exploited to eliminate STS tumors by redirecting the specificity of CIK through CAR engineering.	('CAR', 'Gene', '19674', (191, 194))	('eliminate', 'NegReg', (124, 133))	('redirecting', 'Var', (148, 159))	('CSPG4', 'Gene', (75, 80))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('CAR', 'Gene', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
419763	31175328	Histone H3K27 Dimethyl Loss is Highly Specific for Malignant Peripheral Nerve Sheath Tumor and Distinguishes True PRC2 Loss from Isolated H3K27 Trimethyl Loss Malignant peripheral nerve sheath tumors contain loss of histone H3K27 trimethylation (H3K27me3) due to driver mutations affecting the polycomb repressive complex 2 (PRC2).	('Malignant Peripheral Nerve Sheath Tumor', 'Disease', 'MESH:D009442', (51, 90))	('K27', 'Gene', '342574', (140, 143))	('K27', 'Gene', '342574', (226, 229))	('Malignant peripheral nerve sheath tumors', 'Disease', (159, 199))	('PRC2', 'Gene', (325, 329))	('mutations', 'Var', (270, 279))	('Malignant Peripheral Nerve Sheath Tumor', 'Phenotype', 'HP:0100697', (51, 90))	('K27', 'Gene', '342574', (10, 13))	('K27', 'Gene', (226, 229))	('K27', 'Gene', (140, 143))	('K27', 'Gene', '342574', (248, 251))	('Tumor', 'Phenotype', 'HP:0002664', (85, 90))	('loss', 'NegReg', (208, 212))	('Malignant Peripheral Nerve Sheath Tumor', 'Disease', (51, 90))	('Dimethyl', 'Chemical', 'MESH:C032720', (14, 22))	('K27', 'Gene', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('K27', 'Gene', (248, 251))	('Trimethyl', 'Chemical', 'MESH:C003715', (144, 153))	('Malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D009442', (159, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (159, 198))	('Malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (159, 199))
419766	31175328	Since these tumors lose H3K27me3 through mechanisms distinct from PRC2 loss, we set out to determine whether loss of dimethylation of H3K27, which is also catalyzed by PRC2, might be a more specific marker of PRC2 loss and malignant peripheral nerve sheath tumor.	('K27', 'Gene', '342574', (26, 29))	('K27', 'Gene', (26, 29))	('lose', 'NegReg', (19, 23))	('dimethylation', 'MPA', (117, 130))	('malignant peripheral nerve sheath tumor', 'Disease', (223, 262))	('K27', 'Gene', '342574', (136, 139))	('loss', 'Var', (109, 113))	('K27', 'Gene', (136, 139))	('loss', 'NegReg', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D009442', (223, 262))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('PRC2', 'Gene', (209, 213))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (223, 262))
419777	31175328	The relatively recent finding of recurrent loss-of-function alterations in components of the polycomb repressive complex 2 (PRC2) provided hope for a new immunohistochemical marker rooted in the molecular biology of the tumor.	('loss-of-function', 'NegReg', (43, 59))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('PRC2', 'Gene', (124, 128))	('tumor', 'Disease', (220, 225))	('alterations', 'Var', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
419816	31175328	This peptide contains two lysine residues that can be post-translationally modified (lysine 27 and lysine 36).	('lysine', 'Chemical', 'MESH:C114808', (26, 32))	('lysine', 'Chemical', 'MESH:C114808', (85, 91))	('lysine', 'Chemical', 'MESH:C114808', (99, 105))	('lysine 27', 'Var', (85, 94))	('lysine 36', 'Var', (99, 108))
419860	31175328	Since prior reports had also posited a link between NRAS mutation and H3K27me3 loss in melanoma, we ensured that our cohort contained roughly equal numbers of BRAF-mutant and NRAS-mutant melanomas.	('NRAS', 'Gene', (52, 56))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanomas', 'Disease', 'MESH:D008545', (187, 196))	('BRAF', 'Gene', '673', (159, 163))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanomas', 'Disease', (187, 196))	('melanoma', 'Disease', (87, 95))	('BRAF', 'Gene', (159, 163))	('NRAS', 'Gene', (175, 179))	('mutation', 'Var', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('NRAS', 'Gene', '4893', (52, 56))	('melanomas', 'Phenotype', 'HP:0002861', (187, 196))	('K27', 'Gene', '342574', (72, 75))	('loss', 'NegReg', (79, 83))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('NRAS', 'Gene', '4893', (175, 179))	('K27', 'Gene', (72, 75))
419862	31175328	We also failed to observe any difference in staining between melanomas with driver BRAF mutations and NRAS mutations.	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('mutations', 'Var', (88, 97))	('melanomas', 'Disease', 'MESH:D008545', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('NRAS', 'Gene', (102, 106))	('BRAF', 'Gene', '673', (83, 87))	('NRAS', 'Gene', '4893', (102, 106))	('BRAF', 'Gene', (83, 87))	('melanomas', 'Disease', (61, 70))
419871	31175328	In contrast, H3K27me2 H-scores more effectively segregated tumors into binary 'positive' and 'negative' categories (Figure 6).	('H3K27me2 H', 'Chemical', 'MESH:C033990', (13, 23))	('H3K27me2', 'Var', (13, 21))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
419884	31175328	While it was initially thought to be a specific marker for malignant peripheral nerve sheath tumor, there is an increasing awareness that some degree of loss of H3K27me3 is a relatively common event across diverse tumor types.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (59, 98))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('loss', 'Var', (153, 157))	('malignant peripheral nerve sheath tumor', 'Disease', (59, 98))	('tumor', 'Disease', (214, 219))	('K27', 'Gene', '342574', (163, 166))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D009442', (59, 98))	('K27', 'Gene', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
419890	31175328	In H3K27M-mutant glioma, H3K27me3 loss occurs because the mutant histone potently inhibits PRC2 activity via an interaction with the EZH2 subunit.	('mutant', 'Var', (58, 64))	('EZH2', 'Gene', (133, 137))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('K27', 'Gene', '342574', (5, 8))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('PRC2 activity', 'MPA', (91, 104))	('K27', 'Gene', (5, 8))	('K27', 'Gene', '342574', (27, 30))	('inhibits', 'NegReg', (82, 90))	('K27', 'Gene', (27, 30))	('histone', 'Protein', (65, 72))	('glioma', 'Disease', (17, 23))	('loss', 'NegReg', (34, 38))	('K27M', 'Mutation', 'p.K27M', (5, 9))	('interaction', 'Interaction', (112, 123))	('EZH2', 'Gene', '2146', (133, 137))
419891	31175328	In posterior fossa ependymoma, loss of H3K27me3 appears to be related to mutations in or overexpression of CXorf67, an uncharacterized gene whose protein product physically interacts with PRC2.	('CXorf67', 'Gene', (107, 114))	('loss', 'Var', (31, 35))	('K27', 'Gene', '342574', (41, 44))	('ependymoma', 'Phenotype', 'HP:0002888', (19, 29))	('overexpression', 'PosReg', (89, 103))	('K27', 'Gene', (41, 44))	('related', 'Reg', (62, 69))	('ependymoma', 'Disease', 'MESH:D004806', (19, 29))	('ependymoma', 'Disease', (19, 29))	('mutations in', 'Var', (73, 85))	('CXorf67', 'Gene', '340602', (107, 114))
419901	31175328	Of the 4 melanomas that lost H3K27me3, 3 were NRAS-mutant, leading some to suggest that NRAS mutation might create selective pressure for H3K27me3 loss.	('NRAS', 'Gene', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('K27', 'Gene', '342574', (140, 143))	('NRAS', 'Gene', (88, 92))	('lost', 'NegReg', (24, 28))	('melanomas', 'Disease', 'MESH:D008545', (9, 18))	('mutation', 'Var', (93, 101))	('K27', 'Gene', '342574', (31, 34))	('NRAS', 'Gene', '4893', (46, 50))	('NRAS', 'Gene', '4893', (88, 92))	('K27', 'Gene', (140, 143))	('loss', 'NegReg', (147, 151))	('K27', 'Gene', (31, 34))	('melanomas', 'Disease', (9, 18))
419911	31175328	In both K27M gliomas and malignant peripheral nerve sheath tumors, sensitivity to HDAC inhibitors and related compounds that dysregulate transcription are linked to polycomb dysfunction.	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (25, 65))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D009442', (25, 65))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (25, 64))	('linked', 'Reg', (155, 161))	('K27M', 'Var', (8, 12))	('polycomb dysfunction', 'Disease', 'MESH:D012735', (165, 185))	('malignant peripheral nerve sheath tumors', 'Disease', (25, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('gliomas', 'Disease', (13, 20))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('K27M', 'Mutation', 'p.K27M', (8, 12))	('polycomb dysfunction', 'Disease', (165, 185))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('transcription', 'MPA', (137, 150))
419937	30935419	More aggressive treatment strategies are adopted because under-interpretation of uterine sarcomas might delay necessary treatment and, hence, worsen the prognosis.	('sarcomas', 'Disease', (89, 97))	('uterine', 'Disease', (81, 88))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (81, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('worsen', 'Reg', (142, 148))	('prognosis', 'MPA', (153, 162))	('delay', 'NegReg', (104, 109))	('under-interpretation', 'Var', (57, 77))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
420017	29209034	Inhibitors of homomeric TRPC4 channels were weak inhibitors of the Icat and EA-induced cytotoxicity whereas a potent inhibitor of TRPC4/C1 channels (Pico145) strongly inhibited Icat and cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('inhibited', 'NegReg', (167, 176))	('Pico145', 'Chemical', '-', (149, 156))	('cytotoxicity', 'Disease', 'MESH:D064420', (186, 198))	('EA', 'Chemical', 'MESH:C534971', (76, 78))	('cytotoxicity', 'Disease', (87, 99))	('Pico145', 'Var', (149, 156))	('Icat', 'CPA', (67, 71))	('Icat', 'CPA', (177, 181))	('cytotoxicity', 'Disease', (186, 198))
420018	29209034	Depletion of TRPC1 converted Icat into a current with biophysical and pharmacological properties of homomeric TRPC4 channels and depletion of TRPC1 or TRPC4 suppressed the cytotoxicity of EA.	('Icat', 'MPA', (29, 33))	('EA', 'Chemical', 'MESH:C534971', (188, 190))	('cytotoxicity', 'Disease', 'MESH:D064420', (172, 184))	('depletion', 'Var', (129, 138))	('suppressed', 'NegReg', (157, 167))	('TRPC1', 'Gene', '7220', (13, 18))	('TRPC1', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('TRPC1', 'Gene', '7220', (142, 147))	('TRPC1', 'Gene', (142, 147))	('cytotoxicity', 'Disease', (172, 184))	('TRPC4', 'Gene', (151, 156))
420019	29209034	A Na+/K+-ATPase inhibitor (ouabain) potentiated EA-induced cytotoxicity and direct Na+ loading by gramicidin-A caused Pico145-resistant cytotoxicity in the absence of EA.	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('EA', 'Chemical', 'MESH:C534971', (48, 50))	('potentiated', 'PosReg', (36, 47))	('cytotoxicity', 'Disease', (136, 148))	('Pico145', 'Chemical', '-', (118, 125))	('Na+', 'Var', (83, 86))	('cytotoxicity', 'Disease', (59, 71))	('EA-induced', 'Disease', (48, 58))	('ouabain', 'Chemical', 'MESH:D010042', (27, 34))	('cytotoxicity', 'Disease', 'MESH:D064420', (136, 148))	('ATP', 'Chemical', 'MESH:D000255', (9, 12))	('EA', 'Chemical', 'MESH:C534971', (167, 169))
420030	29209034	However we recently reported that Pico145 is a powerful tool as a potent and selective inhibitor against heteromeric TRPC4/C1 and TRPC5/C1 as well as homometic TRPC4 and TRPC5.	('TRPC5/C1', 'Gene', (130, 138))	('TRPC5', 'Gene', '7224', (130, 135))	('heteromeric TRPC4/C1', 'Protein', (105, 125))	('TRPC5/C1', 'Gene', '7224', (130, 138))	('TRPC5', 'Gene', (170, 175))	('Pico145', 'Var', (34, 41))	('TRPC5', 'Gene', (130, 135))	('Pico145', 'Chemical', '-', (34, 41))	('TRPC5', 'Gene', '7224', (170, 175))
420038	29209034	Although among eight different types of cells employed, HaCaT, OUMS, HEK, and SW982 cells expressed TRPC4 mRNA transcripts more abundantly than IMR32, Caco2, A549, and PC3 cells, only SW982 cells significantly responded to 30 nM EA in Ca2+-measuring studies (0.57 +- 0.04 DeltaF340/F380, six independent experiments, supplementary Fig.	('PC3', 'Gene', '3853', (168, 171))	('HEK', 'CellLine', 'CVCL:M624', (69, 72))	('SW982', 'CellLine', 'CVCL:1734', (184, 189))	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('SW982', 'CellLine', 'CVCL:1734', (78, 83))	('responded to 30 nM EA', 'MPA', (210, 231))	('Caco2', 'Chemical', '-', (151, 156))	('PC3', 'Gene', (168, 171))	('DeltaF340', 'Var', (272, 281))	('DeltaF340', 'DELETION', 'None', (272, 281))	('Ca2+', 'Chemical', 'MESH:D000069285', (235, 239))	('HaCaT', 'CellLine', 'CVCL:0038', (56, 61))	('EA', 'Chemical', 'MESH:C534971', (229, 231))	('TRPC4', 'Gene', (100, 105))
420052	29209034	However, it is not determined yet that EA can also activate channels with homomeric TRPC4alpha and heteromeric TRPC1 and TRPC4alpha (TRPC4alpha/C1).	('homomeric', 'Var', (74, 83))	('TRPC4alpha', 'Protein', (84, 94))	('heteromeric', 'Var', (99, 110))	('activate', 'PosReg', (51, 59))	('TRPC4alpha', 'Var', (121, 131))	('TRPC1', 'Gene', '7220', (111, 116))	('EA', 'Chemical', 'MESH:C534971', (39, 41))	('TRPC1', 'Gene', (111, 116))
420055	29209034	When 100 nM EA was applied to homomeric TRPC4alpha and heteromeric TRPC4alpha/C1 in whole-cell and excised outside-out patch configurations, the large amplitude of Icat was activated in which the current-voltage relationship (I-V) had a typical chair- and ladle-shape, respectively (Fig.	('TRPC4alpha', 'Var', (40, 50))	('activated', 'PosReg', (173, 182))	('homomeric', 'Var', (30, 39))	('Icat', 'MPA', (164, 168))	('EA', 'Chemical', 'MESH:C534971', (12, 14))	('TRPC4alpha/C1', 'Gene', (67, 80))	('heteromeric', 'Var', (55, 66))
420061	29209034	4a and b, 5 muM ML204 effectively inhibited homomeric TRPC4alpha, whereas it was much less effective against heteromeric TRPC4alpha/C1 (Fig.	('inhibited', 'NegReg', (34, 43))	('muM', 'Gene', '56925', (12, 15))	('ML204', 'Chemical', 'MESH:C567966', (16, 21))	('homomeric TRPC4alpha', 'Protein', (44, 64))	('muM', 'Gene', (12, 15))	('ML204', 'Var', (16, 21))
420078	29209034	In contrast, when SW982 cells were treated with si-TRPC4, 100 nM EA failed to activate Icat (Fig.	('si-TRPC4', 'Var', (48, 56))	('EA', 'Chemical', 'MESH:C534971', (65, 67))	('SW982', 'CellLine', 'CVCL:1734', (18, 23))	('Icat', 'MPA', (87, 91))
420080	29209034	We also examined effects of EA on cell-viability of SW982 cells in which either TRPC1 or TRPC4 was knocked-down by si-RNAs (Fig.	('knocked-down', 'NegReg', (99, 111))	('si-RNAs', 'Var', (115, 122))	('EA', 'Chemical', 'MESH:C534971', (28, 30))	('TRPC4', 'Gene', (89, 94))	('SW982', 'CellLine', 'CVCL:1734', (52, 57))	('TRPC1', 'Gene', '7220', (80, 85))	('TRPC1', 'Gene', (80, 85))
420082	29209034	In contrast, in SW982 cells treated with si-TRPC4, EA-induced cell-death was abolished (Fig.	('SW982', 'CellLine', 'CVCL:1734', (16, 21))	('abolished', 'NegReg', (77, 86))	('EA', 'Chemical', 'MESH:C534971', (51, 53))	('si-TRPC4', 'Var', (41, 49))	('cell-death', 'CPA', (62, 72))
420087	29209034	Pretreatment of SW982 cells with Pico145 between 0.1 and 10 nM in the absence of EA had little effect on the cell-viability (Fig.	('SW982', 'CellLine', 'CVCL:1734', (16, 21))	('cell-viability', 'CPA', (109, 123))	('Pico145', 'Chemical', '-', (33, 40))	('Pico145 between', 'Var', (33, 48))	('EA', 'Chemical', 'MESH:C534971', (81, 83))
420101	29209034	Biophysical, pharmacological, gene expression knocking-down and Na+ loading studies suggested that EA-induced cell-death is due to Na+ loading into cells via sustained activation of heteromeric TRPC4/C1 channels which is insufficiently compensated by Na+/K+-ATPase activity.	('cell-death', 'CPA', (110, 120))	('insufficiently', 'Disease', 'MESH:D000309', (221, 235))	('insufficiently', 'Disease', (221, 235))	('EA-induced', 'Disease', (99, 109))	('ATP', 'Chemical', 'MESH:D000255', (258, 261))	('Na+', 'Var', (131, 134))	('heteromeric TRPC4/C1', 'Protein', (182, 202))	('activation', 'PosReg', (168, 178))	('EA', 'Chemical', 'MESH:C534971', (99, 101))
420133	29209034	Excess Na+ loading may deplete cellular ATP by forcing Na+/K+-ATPase into overdrive and inhibit a Na+-dependent amino acid transporter (system ASC transporter 2 (ASCT2)) by reducing Na+ gradient.	('Na+-dependent amino acid transporter', 'MPA', (98, 134))	('ATP', 'Chemical', 'MESH:D000255', (40, 43))	('ASCT2', 'Gene', '6510', (162, 167))	('ASC transporter 2', 'Gene', '6510', (143, 160))	('ATP', 'Chemical', 'MESH:D000255', (62, 65))	('inhibit', 'NegReg', (88, 95))	('deplete', 'NegReg', (23, 30))	('Na+ gradient', 'MPA', (182, 194))	('ASC transporter 2', 'Gene', (143, 160))	('Na+/K+-ATPase', 'Var', (55, 68))	('reducing', 'NegReg', (173, 181))	('ASCT2', 'Gene', (162, 167))
420146	29209034	Pico145 was dissolved in 100% DMSO to make 10 muM stoc.	('Pico145', 'Var', (0, 7))	('DMSO', 'Chemical', 'MESH:D004121', (30, 34))	('muM', 'Gene', '56925', (46, 49))	('muM', 'Gene', (46, 49))	('Pico145', 'Chemical', '-', (0, 7))
420166	29209034	Cells were seeded onto 24-well plates 24 h prior to WST-1 measurements (1 x 104 SW982, 1 x 104 HaCaT, 4 x 104 Caco2, 5 x 103 A549, and 1 x 104 PC3 cells).	('PC3', 'Gene', '3853', (143, 146))	('SW982', 'CellLine', 'CVCL:1734', (80, 85))	('HaCaT', 'Var', (95, 100))	('A549', 'CellLine', 'CVCL:0023', (125, 129))	('HaCaT', 'CellLine', 'CVCL:0038', (95, 100))	('PC3', 'Gene', (143, 146))	('Caco2', 'Chemical', '-', (110, 115))
420351	27931230	The median PFS and OS of patients with G900/D70 were 7.2 months (0.4-32.5 months) and 13.7 months (0.6-32.5 months), respectively, whereas those with >G900/D70 were 3.3 months (0.3-54.6 months) and 6.3 months (1.6-54.6 months), respectively.	('PFS', 'CPA', (11, 14))	('patients', 'Species', '9606', (25, 33))	('G900/D70', 'Var', (39, 47))	('OS', 'Chemical', '-', (19, 21))
420387	27931230	On the other hand, GD regimen is also known to have the risk of interstitial pneumonitis.	('interstitial pneumonitis', 'Disease', (64, 88))	('GD', 'Chemical', '-', (19, 21))	('GD regimen', 'Var', (19, 29))	('interstitial pneumonitis', 'Phenotype', 'HP:0006515', (64, 88))	('interstitial pneumonitis', 'Disease', 'MESH:D011014', (64, 88))
420407	27931230	RR and survival in the patients treated with G900/D70 were better than those with >G900/D70.	('patients', 'Species', '9606', (23, 31))	('better', 'PosReg', (59, 65))	('G900/D70', 'Var', (45, 53))	('survival', 'CPA', (7, 15))
420410	27931230	For instance, neutropenia and decrease in platelet were observed in 83.3 and 38.9% of the patients in G900/D70 group, whereas those in >G900/D70 group were 96.9 and 62.5%, respectively.	('neutropenia', 'Disease', (14, 25))	('G900/D70', 'Var', (102, 110))	('decrease', 'NegReg', (30, 38))	('neutropenia', 'Disease', 'MESH:D009503', (14, 25))	('neutropenia', 'Phenotype', 'HP:0001875', (14, 25))	('patients', 'Species', '9606', (90, 98))	('platelet', 'MPA', (42, 50))
420411	27931230	Thus, it is possible that the higher incidence of adverse events in >G900/D70 group might associate with the inferior outcome because of discontinuation or dose reduction of GD.	('>G900/D70', 'Var', (68, 77))	('GD', 'Chemical', '-', (174, 176))	('discontinuation', 'NegReg', (137, 152))
420413	27931230	Thus, such doses around G900/D100 might be too high for the patients with BSTS.	('patients', 'Species', '9606', (60, 68))	('STS', 'Phenotype', 'HP:0030448', (75, 78))	('BSTS', 'Disease', (74, 78))	('BS', 'Phenotype', 'HP:0002669', (74, 76))	('G900/D100', 'Var', (24, 33))
420414	27931230	Since the number of chemotherapy-naive patients was larger in G900/D70 group (50.0% of the patients) than that in >G900/D70 group (31.3%), there is a possibility that more drug-resistant tumors were included in the latter group, which might lead to the lower response to GD.	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (39, 47))	('response', 'MPA', (259, 267))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('G900/D70', 'Var', (62, 70))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('GD', 'Chemical', '-', (271, 273))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
420482	22143203	It is well documented that the risk of LR is significantly higher for high grade tumors.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('high grade', 'Var', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
420620	21352555	The proportions of natural killer cells, CD8+, and interferon-gamma-secreting cells were all increased in the immune group, and tumor-specific cytotoxic T lymphocyte activity was increased.	('interferon-gamma', 'Gene', (51, 67))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('immune', 'Var', (110, 116))	('increased', 'PosReg', (93, 102))	('CD8+', 'CPA', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('interferon-gamma', 'Gene', '15978', (51, 67))	('tumor', 'Disease', (128, 133))	('natural killer cells', 'CPA', (19, 39))	('increased', 'PosReg', (179, 188))
420635	21352555	As an alternative to selecting a single antigen for tumor vaccine development, random mutations in cancer cells generate antigens unique to an individual.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('antigens', 'MPA', (121, 129))	('tumor', 'Disease', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('random mutations', 'Var', (79, 95))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
420649	21352555	In experimental tumor models, recombinant IL-12 has demonstrated marked antitumor effects through mechanisms of both innate and adaptive immunity.	('IL-1', 'Gene', (42, 46))	('recombinant', 'Var', (30, 41))	('IL-1', 'Gene', '111343', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
420684	21352555	Three days after the combined therapy of mHSP/Ps and CY plus IL-12, all mice were killed, and blood and spleen samples were collected.	('mice', 'Species', '10090', (72, 76))	('CY', 'Chemical', 'MESH:D003520', (53, 55))	('IL-1', 'Gene', '111343', (61, 65))	('mHSP/Ps', 'Var', (41, 48))	('IL-1', 'Gene', (61, 65))
420687	21352555	Lactate dehydrogenase assay was used to assess in vitro tumor-specific CTL response to immunization with mHSP/Ps or mHSP/Ps and CY plus IL-12.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('mHSP/Ps', 'Var', (105, 112))	('CY', 'Chemical', 'MESH:D003520', (128, 130))	('mHSP/Ps', 'Var', (116, 123))	('IL-1', 'Gene', '111343', (136, 140))	('IL-1', 'Gene', (136, 140))
420711	21352555	Treatment with mHSP/Ps increased the proportion of CD8+ T cells to 9.1 5% at about the same time of tumor establishment (day 26), With mHSP/Ps plus CY plus IL-12 treatment, the CD8+ population was higher (9.21 +- 1.45%) than that in mHSP/P-treated mice and untreated tumor-bearing mice.	('mHSP/', 'Chemical', '-', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mice', 'Species', '10090', (281, 285))	('mHSP/', 'Chemical', '-', (15, 20))	('CD8+ population', 'CPA', (177, 192))	('higher', 'PosReg', (197, 203))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('to 9', 'Species', '1214577', (64, 68))	('mHSP/Ps', 'Var', (135, 142))	('IL-1', 'Gene', '111343', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('mice', 'Species', '10090', (248, 252))	('IL-1', 'Gene', (156, 160))	('CY', 'Chemical', 'MESH:D003520', (148, 150))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mHSP/', 'Chemical', '-', (233, 238))
420716	21352555	This ratio was increased to 4.98% with mHSP/Ps alone and was even greater with mHSP/Ps plus CY plus IL-12 (5.72%).	('IL-1', 'Gene', '111343', (100, 104))	('IL-1', 'Gene', (100, 104))	('CY', 'Chemical', 'MESH:D003520', (92, 94))	('mHSP/Ps', 'Var', (79, 86))
420717	21352555	To determine whether vaccination with mHSP/Ps results in increased number of antigen-specific Th1 cells and IFN-gamma-producing NK cells, the number of IFN-gamma-secreting splenocytes was determined by an in vitro assay of IFN-gamma ELISPOT.	('IFN-gamma', 'Gene', (223, 232))	('IFN-gamma', 'Gene', (152, 161))	('IFN-gamma', 'Gene', (108, 117))	('IFN-gamma', 'Gene', '15978', (223, 232))	('IFN-gamma', 'Gene', '15978', (108, 117))	('IFN-gamma', 'Gene', '15978', (152, 161))	('mHSP/Ps', 'Var', (38, 45))
420719	21352555	Under both stimulation conditions, splenocytes from mice treated with both mHSP/Ps alone and mHSP/Ps plus CY plus IL-12 showed an increased number of IFN-gamma-producing cells, with the later treatment giving the higher number.	('CY', 'Chemical', 'MESH:D003520', (106, 108))	('mHSP/Ps', 'Var', (93, 100))	('IFN-gamma', 'Gene', '15978', (150, 159))	('IL-1', 'Gene', '111343', (114, 118))	('mice', 'Species', '10090', (52, 56))	('IL-1', 'Gene', (114, 118))	('increased', 'PosReg', (130, 139))	('IFN-gamma', 'Gene', (150, 159))
420720	21352555	The number of IFN-gamma elicited by mHSP/P+Cy+IL12 vaccination was significantly higher than that of tumor bearing mice and naive mice, P < 0.05.	('mice', 'Species', '10090', (130, 134))	('IFN-gamma', 'Gene', (14, 23))	('higher', 'PosReg', (81, 87))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Cy', 'Chemical', 'MESH:D003545', (43, 45))	('IFN-gamma', 'Gene', '15978', (14, 23))	('mHSP/', 'Chemical', '-', (36, 41))	('mice', 'Species', '10090', (115, 119))	('mHSP/P+Cy+IL12 vaccination', 'Var', (36, 62))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
420722	21352555	Target cells (S180) pulsed with effector splenocyte cells from mice treated with mHSP/Ps were killed to some extent by CTLs, an amount higher than in those pulsed with splenocytes from naive mice or tumor-bearing mice not treated with mHSP/Ps (Figure 5).	('tumor', 'Disease', (199, 204))	('CTLs', 'Gene', (119, 123))	('mice', 'Species', '10090', (213, 217))	('mice', 'Species', '10090', (63, 67))	('mHSP/Ps', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('mice', 'Species', '10090', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('higher', 'PosReg', (135, 141))
420723	21352555	The cytolysis percentage of mHSP/P+Cy+IL12 vaccine was significantly higher than that of mHSP/Ps vaccine and naive mice, P < 0.05, and that of tumor bearing mice, P < 0.01.	('mHSP/P+Cy+IL12 vaccine', 'Var', (28, 50))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (143, 148))	('mice', 'Species', '10090', (157, 161))	('cytolysis', 'MPA', (4, 13))	('mHSP/', 'Chemical', '-', (89, 94))	('mHSP/', 'Chemical', '-', (28, 33))	('mice', 'Species', '10090', (115, 119))	('Cy', 'Chemical', 'MESH:D003545', (35, 37))	('higher', 'PosReg', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
420736	21352555	Also, we compared the mHSP/p of S180 against rabbit liver cancer cell line vx2, and the cytolysis effect was lower than 10%, [data not shown].	('lower', 'NegReg', (109, 114))	('rabbit liver cancer', 'Disease', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cytolysis effect', 'MPA', (88, 104))	('mHSP/p', 'Var', (22, 28))	('mHSP/', 'Chemical', '-', (22, 27))	('rabbit liver cancer', 'Disease', 'MESH:D006528', (45, 64))	('liver cancer', 'Phenotype', 'HP:0002896', (52, 64))
420737	21352555	In addition, we found that the mice vaccinated with mHSP/P of MCA207 were protected only against MCA207 but not S180 in vivo.	('MCA207', 'Var', (97, 103))	('mHSP/P of', 'Var', (52, 61))	('mice', 'Species', '10090', (31, 35))	('mHSP/', 'Chemical', '-', (52, 57))	('MCA207', 'Gene', (62, 68))
420741	21352555	However, with mHSP/Ps and CY alone or with mHSP/Ps and IL-12 alone, the antitumor efficacy was not improved.	('IL-1', 'Gene', (55, 59))	('IL-1', 'Gene', '111343', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CY', 'Chemical', 'MESH:D003520', (26, 28))	('mHSP/Ps', 'Var', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
420742	21352555	Our results suggested that one potential mechanism of mHSP/Ps and CY plus IL-12 in augmenting therapeutic immunotherapy strategies was that mHSP/P immunization activated the antitumor immunization, and at the same time, also induced the T-cell tolerance directed toward tumor-associated antigens and limited the repertoire of functional tumor-reactive T cells.	('CY', 'Chemical', 'MESH:D003520', (66, 68))	('tumor', 'Disease', (337, 342))	('limited', 'NegReg', (300, 307))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('activated', 'PosReg', (160, 169))	('T-cell tolerance directed', 'CPA', (237, 262))	('IL-1', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (270, 275))	('mHSP/P', 'Var', (140, 146))	('mHSP/', 'Chemical', '-', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('IL-1', 'Gene', '111343', (74, 78))	('induced', 'PosReg', (225, 232))	('mHSP/', 'Chemical', '-', (140, 145))
420755	21352555	Our data showed that inflammatory cells infiltrated tumors with mHSP/P vaccination and that a preexisting antitumor immune response was elicited, which was required for an effective IL-12 response for tumor rejection.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('IL-1', 'Gene', '111343', (182, 186))	('mHSP/P vaccination', 'Var', (64, 82))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('IL-1', 'Gene', (182, 186))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('mHSP/', 'Chemical', '-', (64, 69))
420966	30264519	Although the incidence of NETs was also significantly increased, the increase did not affect the overall increase in pancreatic cancer significantly due to the relatively lower percentage.	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('pancreatic cancer', 'Disease', (117, 134))	('NETs', 'Phenotype', 'HP:0100634', (26, 30))	('increased', 'PosReg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('NETs', 'Var', (26, 30))
421028	30003157	Chemical shifts were reported in delta values utilizing tetramethylsilane as an internal standard with the number of protons, multiplicities (s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet, dd-double doublet) and coupling constants (J) in Hz (Hertz) in 1H NMR.	('in 1H', 'Gene', (259, 264))	('tetramethylsilane', 'Chemical', 'MESH:C073196', (56, 73))	('q-quartet', 'Var', (175, 184))	('t-triplet', 'Var', (164, 173))	('in 1H', 'Gene', '16314', (259, 264))	('d-doublet', 'Var', (153, 162))	('coupling', 'MPA', (222, 230))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('m-multiplet', 'Var', (186, 197))
421116	30003157	It was observed that SK-25 caused an apoptotic induction to 30.33 % was observed on treatment at 20 muM as compared with the control sample.	('SK-25', 'Var', (21, 26))	('SK-25', 'Chemical', '-', (21, 26))	('apoptotic induction', 'CPA', (37, 56))
421117	30003157	A report of extensive investigations on chalcones shows that the presence of two aryl nuclei increases the anti-tumour prospectives.	('aryl nuclei', 'Protein', (81, 92))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('increases', 'PosReg', (93, 102))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('chalcones', 'Chemical', 'MESH:D047188', (40, 49))	('presence', 'Var', (65, 73))
421119	30003157	The remarkable anti-cancer potential of pyrimidine/ones, as evidenced by the number of research articles further motivated us to utilise it as a constraint for attaining a rigid arrangement of the two aromatic rings.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('pyrimidine', 'Chemical', 'MESH:C030986', (40, 50))	('pyrimidine/ones', 'Var', (40, 55))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))
421136	30003157	brain-blood partition coefficient, aqueous solubility, serum protein binding, number of likely metabolic reactions, Caco-2 cell permeability, solvent accessible surface area, blockage of human-ether-a-go-go potassium ion (HERG K+) channels and the total volume of the molecule enclosed by the solvent accessible surface area, beside the usual Lipinski descriptors (molecular weight, MW, the n-octanol-water partition coefficient, log P, number of H-bond donors and acceptors, HBD and HBA).	('HBD', 'Gene', (476, 479))	('HERG', 'Gene', (222, 226))	('water', 'Chemical', 'MESH:D014867', (401, 406))	('Caco-2', 'CellLine', 'CVCL:0025', (116, 122))	('HERG', 'Gene', '3757', (222, 226))	('aq', 'Chemical', '-', (35, 37))	('human', 'Species', '9606', (187, 192))	('HBD', 'Gene', '100187828', (476, 479))	('blockage', 'Var', (175, 183))
421166	28887457	Alteration in gene expression is a known mechanism of cancer pain in which microRNAs (miRNAs), a class of non-coding regulatory RNAs, play a crucial role.	('Alteration', 'Var', (0, 10))	('cancer pain', 'Disease', 'MESH:D000072716', (54, 65))	('pain', 'Phenotype', 'HP:0012531', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer pain', 'Disease', (54, 65))
421172	28887457	Finally, miR-124 was also down-regulated in the cerebrospinal fluid of cancer patients who developed pain, suggesting that miR-124 could be an efficient analgesic drug to treat cancer pain patients.	('cancer', 'Disease', (177, 183))	('cancer pain', 'Disease', (177, 188))	('pain', 'Disease', (184, 188))	('pain', 'Disease', 'MESH:D010146', (101, 105))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('patients', 'Species', '9606', (189, 197))	('pain', 'Phenotype', 'HP:0012531', (184, 188))	('cancer pain', 'Disease', 'MESH:D000072716', (177, 188))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('miR-124', 'Var', (123, 130))	('pain', 'Disease', 'MESH:D010146', (184, 188))	('pain', 'Disease', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('pain', 'Phenotype', 'HP:0012531', (101, 105))	('miR-124', 'Gene', (9, 16))	('down-regulated', 'NegReg', (26, 40))
421193	28887457	In this report combining genome-wide screening, in silico analyses, a behavioral study in a cancer pain mouse model and investigation of patients' samples, we demonstrate the clinical potential of miR-124 as a cancer-pain analgesic.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer-pain', 'Disease', (210, 221))	('cancer pain', 'Disease', 'MESH:D000072716', (92, 103))	('cancer-pain', 'Disease', 'MESH:D000072716', (210, 221))	('mouse', 'Species', '10090', (104, 109))	('patients', 'Species', '9606', (137, 145))	('cancer pain', 'Disease', (92, 103))	('pain', 'Phenotype', 'HP:0012531', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('miR-124', 'Var', (197, 204))	('pain', 'Phenotype', 'HP:0012531', (217, 221))
421238	28887457	To confirm the relevance of Synpo regulation in the context of bone-cancer pain, we tested whether a modification of Synpo expression has an impact on pain perception.	('pain', 'Disease', (151, 155))	('Synpo', 'Gene', (117, 122))	('tested', 'Reg', (84, 90))	('bone-cancer pain', 'Disease', 'MESH:D001859', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bone-cancer', 'Phenotype', 'HP:0010622', (63, 74))	('Synpo', 'Gene', '104027', (117, 122))	('Synpo', 'Gene', '104027', (28, 33))	('pain', 'Phenotype', 'HP:0012531', (75, 79))	('impact', 'Reg', (141, 147))	('pain', 'Phenotype', 'HP:0012531', (151, 155))	('pain', 'Disease', 'MESH:D010146', (151, 155))	('pain', 'Disease', (75, 79))	('Synpo', 'Gene', (28, 33))	('pain', 'Disease', 'MESH:D010146', (75, 79))	('modification', 'Var', (101, 113))	('bone-cancer pain', 'Disease', (63, 79))
421247	28887457	As expected, RT-qPCR analysis of spinal cord tissue at day 14 showed a significant up-regulation of miR-124 in miR-124-injected mice when compared to Cel-miR-67-injected animals (Figs 5A, +113.50%, P < 0.05, Mann-Whitney).	('up-regulation', 'PosReg', (83, 96))	('miR-124-injected', 'Var', (111, 127))	('miR-67', 'Gene', (154, 160))	('miR-124', 'Gene', (100, 107))	('miR-67', 'Gene', '259740', (154, 160))	('mice', 'Species', '10090', (128, 132))
421253	28887457	In contrast, intrathecal administration of miR-124 alleviated nociceptive behavior since the weight borne by miR-124-injected mice was not significantly altered until day 9 of the experiment (Fig.	('miR-124', 'Var', (43, 50))	('alleviated', 'NegReg', (51, 61))	('nociceptive behavior', 'MPA', (62, 82))	('mice', 'Species', '10090', (126, 130))
421256	28887457	However, these results suggest that miR-124 regulates Synpo expression in the spinal cord of mice and plays a causal role in bone-cancer pain.	('expression', 'MPA', (60, 70))	('bone-cancer pain', 'Disease', 'MESH:D001859', (125, 141))	('Synpo', 'Gene', '104027', (54, 59))	('bone-cancer pain', 'Disease', (125, 141))	('regulates', 'Reg', (44, 53))	('Synpo', 'Gene', (54, 59))	('pain', 'Phenotype', 'HP:0012531', (137, 141))	('mice', 'Species', '10090', (93, 97))	('bone-cancer', 'Phenotype', 'HP:0010622', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('plays', 'Reg', (102, 107))	('miR-124', 'Var', (36, 43))
421257	28887457	These effects are solely due to the analgesic effect of miR-124 and not to its anti-tumor effect.	('analgesic', 'CPA', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('miR-124', 'Var', (56, 63))
421271	28887457	Specific Clcn3 knock-down in DRG neurons confirmed its crucial role in tumor-induced mechanical hypersensitivity.	('hypersensitivity', 'Disease', (96, 112))	('hypersensitivity', 'Disease', 'MESH:D004342', (96, 112))	('Clcn3', 'Gene', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Clcn3', 'Gene', '12725', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('knock-down', 'Var', (15, 25))	('tumor', 'Disease', (71, 76))
421273	28887457	We previously showed in neuropathic pain condition that miRNA regulation in spinal cord neurons can have a strong impact on hyperalgesia and allodynia.	('miRNA regulation', 'Var', (56, 72))	('impact', 'Reg', (114, 120))	('neuropathic pain', 'Disease', (24, 40))	('pain', 'Phenotype', 'HP:0012531', (36, 40))	('hyperalgesia', 'Disease', 'MESH:D006930', (124, 136))	('hyperalgesia', 'Disease', (124, 136))	('allodynia', 'Phenotype', 'HP:0012533', (141, 150))	('allodynia', 'Disease', (141, 150))	('neuropathic pain', 'Disease', 'MESH:D009437', (24, 40))	('hyperalgesia', 'Phenotype', 'HP:0031005', (124, 136))	('allodynia', 'Disease', 'MESH:D006930', (141, 150))
421281	28887457	Therefore, we needed to reduce the number of candidates so we screened the miRNA-mRNA pairs to find miRNAs that could regulate multiple mRNAs implicated in pain perception and finally selected miR-124.	('pain', 'Phenotype', 'HP:0012531', (156, 160))	('pain', 'Disease', 'MESH:D010146', (156, 160))	('pain', 'Disease', (156, 160))	('regulate', 'Reg', (118, 126))	('miR-124', 'Var', (193, 200))
421282	28887457	The first criterion for choosing miR-124 is that it is one of the most regulated miRNAs in bone-cancer-pain conditions.	('miR-124', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('bone-cancer-pain', 'Disease', (91, 107))	('bone-cancer-pain', 'Disease', 'MESH:D001859', (91, 107))	('pain', 'Phenotype', 'HP:0012531', (103, 107))	('bone-cancer', 'Phenotype', 'HP:0010622', (91, 102))
421284	28887457	In addition, miR-124 is linked to cancer mechanisms since it has been identified as a tumor suppressor miRNA in osteosarcoma cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('osteosarcoma', 'Phenotype', 'HP:0002669', (112, 124))	('osteosarcoma', 'Disease', 'MESH:D012516', (112, 124))	('miR-124', 'Var', (13, 20))	('tumor', 'Disease', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('osteosarcoma', 'Disease', (112, 124))
421285	28887457	Indeed, miR-124 supplementation reduced tumor cell migration and invasion.	('supplementation', 'Var', (16, 31))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('reduced', 'NegReg', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('miR-124', 'Gene', (8, 15))
421303	28887457	The protective effect of miR-124 injections against the onset of cancer pain suggests its clinical potential as a preventive analgesic.	('cancer pain', 'Disease', (65, 76))	('pain', 'Phenotype', 'HP:0012531', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('miR-124', 'Gene', (25, 32))	('cancer pain', 'Disease', 'MESH:D000072716', (65, 76))	('injections', 'Var', (33, 43))
421307	28887457	Indeed, previous studies have demonstrated the beneficial effect of miR-124 supplementation on tumor aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (101, 115))	('miR-124', 'Gene', (68, 75))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (95, 115))	('beneficial', 'PosReg', (47, 57))	('supplementation', 'Var', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor aggressiveness', 'Disease', (95, 115))
421308	28887457	Thus, miR-124 could have both an anti-tumoral effect on bone cancer and an analgesic effect on bone-cancer pain.	('pain', 'Phenotype', 'HP:0012531', (107, 111))	('tumor', 'Disease', (38, 43))	('bone cancer', 'Disease', 'MESH:D001859', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('bone cancer', 'Disease', (56, 67))	('analgesic', 'CPA', (75, 84))	('miR-124', 'Var', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('bone-cancer pain', 'Disease', (95, 111))	('bone-cancer pain', 'Disease', 'MESH:D001859', (95, 111))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('bone-cancer', 'Phenotype', 'HP:0010622', (95, 106))
421327	28887457	Briefly, results were normalized using the DeltaDeltaCp method with multiple reference genes (U6, RNU1A1, miR-191-5p and miR-423-5p).	('miR-191-5p', 'Var', (106, 116))	('RNU1A1', 'Gene', '19842', (98, 104))	('RNU1A1', 'Gene', (98, 104))	('miR-423-5p', 'Var', (121, 131))
421332	28887457	For the assay, 50ng of candidate gene Renilla reporter or mutated form were co-transfected with 750ng of either pcDNA3.1 plasmid expressing miR-124 or empty pcDNA3.1 plasmid, and Firefly control plasmid (pGL3, Promega) into HEK-293T cells.	('HEK-293T', 'CellLine', 'CVCL:0063', (224, 232))	('miR-124', 'Var', (140, 147))	('pGL3', 'Gene', '6391', (204, 208))	('pGL3', 'Gene', (204, 208))
421337	28887457	Sections were incubated for 72 hours at 4  C with anti-synaptopodin (1/250; Synaptic Systems) and anti-GFP (1/500; AveLabs).	('synaptopodin', 'Gene', (55, 67))	('synaptopodin', 'Gene', '104027', (55, 67))	('anti-GFP', 'Var', (98, 106))
421345	28887457	designed and performed experiments, data acquisition, analysis and interpretation of data; MB and TLL performed experiments; S.E., M.J.L.G., M.L.	('M.J.L.G.', 'Var', (131, 139))	('TLL', 'Gene', '21892', (98, 101))	('S.E.', 'Var', (125, 129))	('TLL', 'Gene', (98, 101))
421429	25915942	MicroRNA-27a Contributes to Rhabdomyosarcoma Cell Proliferation by Suppressing RARA and RXRA Rhabdomyosarcomas (RMS) are rare but very aggressive childhood tumors that arise as a consequence of a regulatory disruption in the growth and differentiation pathways of myogenic precursor cells.	('27a', 'Species', '1412829', (9, 12))	('very aggressive childhood tumors', 'Disease', 'MESH:D000326', (130, 162))	('MicroRNA-27a', 'Var', (0, 12))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('RARA', 'Disease', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (93, 109))	('Suppressing', 'NegReg', (67, 78))	('Rhabdomyosarcomas', 'Disease', 'MESH:D012208', (93, 110))	('very aggressive childhood tumors', 'Disease', (130, 162))	('Rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (28, 44))	('Rhabdomyosarcoma Cell', 'Disease', (28, 49))	('Rhabdomyosarcoma Cell', 'Disease', 'MESH:D012208', (28, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('RMS', 'Phenotype', 'HP:0002859', (112, 115))	('Rhabdomyosarcomas', 'Disease', (93, 110))
421434	25915942	Sixteen miRNAs whose expression discriminates between translocation-positive ARMS and negative RMS were identified.	('translocation-positive', 'Var', (54, 76))	('RMS', 'Phenotype', 'HP:0002859', (78, 81))	('miR', 'Gene', '220972', (8, 11))	('miR', 'Gene', (8, 11))	('RMS', 'Phenotype', 'HP:0002859', (95, 98))
421466	25915942	A recent work conducted in patients with metastatic and recurrent gastric cancer reported that high miR-27a expression is correlated with a significantly worse overall survival.	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('high', 'Var', (95, 99))	('miR-27a', 'Gene', '407018', (100, 107))	('overall survival', 'MPA', (160, 176))	('patients', 'Species', '9606', (27, 35))	('expression', 'MPA', (108, 118))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('worse', 'NegReg', (154, 159))	('miR-27a', 'Gene', (100, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
421469	25915942	The present study found that translocation-positive ARMS and translocation-negative RMS cell lines are characterized by different miRNA expression signatures that could be used to stratify RMS patients.	('patients', 'Species', '9606', (193, 201))	('RMS', 'Disease', (189, 192))	('RMS', 'Phenotype', 'HP:0002859', (189, 192))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (130, 133))	('rat', 'Species', '10116', (182, 185))	('RMS', 'Phenotype', 'HP:0002859', (84, 87))	('RMS', 'Phenotype', 'HP:0002859', (53, 56))	('translocation-positive', 'Var', (29, 51))
421475	25915942	Pre-miRNA negative control (ID 4464058), Anti-miRNA negative control (ID 4464077), miRNA precursors and inhibitors hsa-miR-27a (MIMAT0000084) and hsa-miR-23a (MIMAT0000078) were provided by Ambion (Ambion-Life Technologies, Carlsbad, CA).	('miR', 'Gene', (46, 49))	('miR', 'Gene', '220972', (150, 153))	('miR', 'Gene', (150, 153))	('miR-23a', 'Gene', '407010', (150, 157))	('ID 4464058', 'Var', (28, 38))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (119, 122))	('miR', 'Gene', (4, 7))	('miR-23a', 'Gene', (150, 157))	('MIMAT0000084', 'Var', (128, 140))	('miR-27a', 'Gene', (119, 126))	('miR', 'Gene', '220972', (4, 7))	('miR', 'Gene', '220972', (46, 49))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('ID 4464077', 'Var', (70, 80))	('miR-27a', 'Gene', '407018', (119, 126))
421485	25915942	Two replicates of each experiment were performed using different microarray slides in which sample and reference RNAs, labeled either with Cy3 or Cy5 fluorochromes, were crossed in both combinations (dye-swapping procedure) (Fig 1A).	('Cy3', 'Chemical', '-', (139, 142))	('Cy3', 'Var', (139, 142))	('Cy5', 'Chemical', 'MESH:C085321', (146, 149))	('Cy5 fluorochromes', 'Var', (146, 163))
421488	25915942	The amine-modified miRNAs were then cleaned up and coupled to NHS-ester modified Cy5 or Cy3 dyes (GE Healthcare, Little Chalfont, UK).	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('Cy5', 'Chemical', 'MESH:C085321', (81, 84))	('Cy3', 'Chemical', '-', (88, 91))	('amine', 'Chemical', 'MESH:D000588', (4, 9))	('Cy3', 'Var', (88, 91))	('NHS-ester', 'Chemical', '-', (62, 71))
421515	25915942	When indicated, the 3'-UTRs were mutagenized at the miR-27a recognition site/s using the QuickChange Multi Site- Directed Mutagenesis kit (Stratagene-Agilent Technologies, Palo Alto, CA) following the manufacturer's instructions.	('miR-27a', 'Gene', '407018', (52, 59))	('mutagenized', 'Var', (33, 44))	('miR-27a', 'Gene', (52, 59))	('rat', 'Species', '10116', (141, 144))
421517	25915942	About 8x104 293T cells were plated in 24-well plates and were co-transfected with 50 ng of the pmirGLO dual-luciferase (Promega) constructs containing the wild type or mutant/deleted 3'-UTRs of the indicated miR-27a potential target genes and 50 nM of pre-miR-27a or miRNA Precursor Molecules-Negative Control (all from Ambion-Life Technologies), using Lipofectamine2000 (Invitrogen-Life Technologies).	('miR', 'Gene', '220972', (267, 270))	('miR', 'Gene', (208, 211))	('miR', 'Gene', (267, 270))	('miR', 'Gene', (256, 259))	('miR', 'Gene', '220972', (256, 259))	('miR-27a', 'Gene', (256, 263))	('miR-27a', 'Gene', (208, 215))	('Lipofectamine', 'Chemical', 'MESH:C086724', (353, 366))	('miR-27a', 'Gene', '407018', (208, 215))	('293T', 'CellLine', 'CVCL:0063', (12, 16))	('miR-27a', 'Gene', '407018', (256, 263))	('mutant/deleted', 'Var', (168, 182))	('miR', 'Gene', '220972', (208, 211))
421523	25915942	The SAM two-class analysis identified 16 miRNAs which discriminated between translocation-positive and negative RMS cell lines (Fig 1B).	('translocation-positive', 'Var', (76, 98))	('miR', 'Gene', '220972', (41, 44))	('RMS', 'Phenotype', 'HP:0002859', (112, 115))	('miR', 'Gene', (41, 44))
421525	25915942	This result is in agreement with previous transcriptome studies that demonstrated that ERMS and ARMS have different expression signatures and that the presence of PAX3/FOXO1 translocation confers a particular molecular signature to RMS samples.	('PAX3', 'Gene', (163, 167))	('rat', 'Species', '10116', (76, 79))	('FOXO1', 'Gene', '2308', (168, 173))	('RMS', 'Disease', (232, 235))	('FOXO1', 'Gene', (168, 173))	('RMS', 'Phenotype', 'HP:0002859', (97, 100))	('RMS', 'Phenotype', 'HP:0002859', (232, 235))	('presence', 'Var', (151, 159))	('RMS', 'Phenotype', 'HP:0002859', (88, 91))	('PAX3', 'Gene', '5077', (163, 167))
421531	25915942	A t-test was performed to identify differentially expressed miRNAs between translocation-positive ARMS and translocation-negative RMS.	('translocation-positive', 'Var', (75, 97))	('RMS', 'Phenotype', 'HP:0002859', (99, 102))	('miR', 'Gene', '220972', (60, 63))	('RMS', 'Phenotype', 'HP:0002859', (130, 133))	('miR', 'Gene', (60, 63))
421533	25915942	MiR-27a showed a significant up-regulation in translocation-positive ARMS versus ERMS patients suggesting that it plays a different role in the pathogenesis of translocation-positive and -negative RMS tumors.	('translocation-positive', 'Var', (160, 182))	('MiR-27a', 'Gene', '407018', (0, 7))	('up-regulation', 'PosReg', (29, 42))	('RMS tumors', 'Disease', (197, 207))	('RMS', 'Phenotype', 'HP:0002859', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('MiR-27a', 'Gene', (0, 7))	('RMS tumors', 'Disease', 'MESH:D009369', (197, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('RMS', 'Phenotype', 'HP:0002859', (82, 85))	('RMS', 'Phenotype', 'HP:0002859', (197, 200))	('translocation-positive', 'Var', (46, 68))	('patients', 'Species', '9606', (86, 94))
421540	25915942	To confirm these results, we transiently induced the knockdown of miR-27a and miR-23a in RH4, which is the ARMS cell line with high endogenous expression levels of both miRNAs, and we evaluated cell cycle progression and cell motility respectively.	('RH4', 'Gene', '6007', (89, 92))	('miR-27a', 'Gene', '407018', (66, 73))	('miR', 'Gene', '220972', (78, 81))	('knockdown', 'Var', (53, 62))	('miR', 'Gene', (78, 81))	('miR-23a', 'Gene', '407010', (78, 85))	('miR-23a', 'Gene', (78, 85))	('miR', 'Gene', (66, 69))	('cell cycle progression', 'CPA', (194, 216))	('miR', 'Gene', (169, 172))	('evaluated', 'Reg', (184, 193))	('miR', 'Gene', '220972', (66, 69))	('induced', 'Reg', (41, 48))	('RMS', 'Phenotype', 'HP:0002859', (108, 111))	('miR-27a', 'Gene', (66, 73))	('RH4', 'Gene', (89, 92))	('miR', 'Gene', '220972', (169, 172))	('cell motility', 'CPA', (221, 234))
421541	25915942	We observed a decrease in the G0/G1 phase in cells treated with miR-27a inhibitors as well as a reduced motility of cells after transfection with miR-23a inhibitors with respect to controls (Fig 3C and 3D).	('miR-27a', 'Gene', '407018', (64, 71))	('miR-23a', 'Gene', '407010', (146, 153))	('miR-23a', 'Gene', (146, 153))	('inhibitors', 'Var', (154, 164))	('motility of cells', 'CPA', (104, 121))	('miR-27a', 'Gene', (64, 71))	('decrease', 'NegReg', (14, 22))	('G0/G1 phase', 'CPA', (30, 41))	('inhibitors', 'Var', (72, 82))	('reduced', 'NegReg', (96, 103))
421547	25915942	Direct modulation by miR-27a of its targets was confirmed by performing luciferase assays in miR-27a-overexpressing or control 293T cells transfected with reporter vectors containing wild type or mutated 3'-UTRs.	('miR-27a', 'Gene', (93, 100))	('miR-27a', 'Gene', '407018', (21, 28))	('miR-27a', 'Gene', '407018', (93, 100))	('miR-27a', 'Gene', (21, 28))	('mutated', 'Var', (196, 203))	('293T', 'CellLine', 'CVCL:0063', (127, 131))
421554	25915942	We prepared a series of luciferase constructs in which one or both miR-27a binding sites were mutated in four contiguous positions in order to demonstrate the real interaction between miR-27a and RARA (Fig 5C).	('interaction', 'Interaction', (164, 175))	('mutated', 'Var', (94, 101))	('miR-27a', 'Gene', (184, 191))	('miR-27a', 'Gene', (67, 74))	('rat', 'Species', '10116', (150, 153))	('miR-27a', 'Gene', '407018', (67, 74))	('miR-27a', 'Gene', '407018', (184, 191))
421555	25915942	The luciferase reporter assays in 293T cells demonstrated that the mutated binding sites abrogated the negative effect of overexpressed miR-27a on RARA 3'-UTR (Fig 5D), indicating a specific, direct regulation of miR-27a at both RARA 3'-UTR binding sites.	('rat', 'Species', '10116', (52, 55))	('miR-27a', 'Gene', '407018', (213, 220))	('293T', 'CellLine', 'CVCL:0063', (34, 38))	('miR-27a', 'Gene', (136, 143))	('mutated', 'Var', (67, 74))	('abrogated', 'NegReg', (89, 98))	('miR-27a', 'Gene', (213, 220))	('miR-27a', 'Gene', '407018', (136, 143))	('binding', 'Interaction', (75, 82))	('negative effect', 'MPA', (103, 118))
421558	25915942	Luciferase assays also revealed a 20% reduction in luciferase expression driven by the 3'-UTRs of RXRA, an effect that was abrogated by point mutations in the miR-27a interacting region of the 3'-UTR of RXRA (Fig 5F and 5G).	('RA', 'Chemical', 'MESH:D014212', (205, 207))	('point mutations', 'Var', (136, 151))	('expression', 'MPA', (62, 72))	('miR-27a', 'Gene', '407018', (159, 166))	('RA', 'Chemical', 'MESH:D014212', (100, 102))	('reduction', 'NegReg', (38, 47))	('luciferase', 'Enzyme', (51, 61))	('abrogated', 'NegReg', (123, 132))	('miR-27a', 'Gene', (159, 166))
421560	25915942	Our previous studies on the human RMS transcriptome have, in fact, indicated that the PAX/FOXO1 fusion gene gives a particular expression signature to ARMS.	('human', 'Species', '9606', (28, 33))	('RMS', 'Phenotype', 'HP:0002859', (34, 37))	('expression signature', 'MPA', (127, 147))	('fusion', 'Var', (96, 102))	('RMS', 'Phenotype', 'HP:0002859', (152, 155))	('FOXO1', 'Gene', '2308', (90, 95))	('ARMS', 'Disease', (151, 155))	('FOXO1', 'Gene', (90, 95))
421564	25915942	The study outlined here set out to analyze miRNAs expression profiles in human rhabdomyosarcoma cell lines in which a set of 16 miRNAs able to discriminate translocation-positive ARMS from translocation-negative RMS were identified.	('translocation-positive', 'Var', (156, 178))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('RMS', 'Phenotype', 'HP:0002859', (212, 215))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (79, 95))	('human', 'Species', '9606', (73, 78))	('RMS', 'Phenotype', 'HP:0002859', (180, 183))	('miR', 'Gene', '220972', (128, 131))	('miR', 'Gene', (128, 131))	('rhabdomyosarcoma', 'Disease', (79, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (79, 95))
421566	25915942	Out of the 50 sarcoma subtypes contained in S-MED, we used the microarray data of 42 RMS tissue samples to evaluate the differences in expression patterns between translocation-positive ARMS and translocation-negative RMS.	('RMS', 'Phenotype', 'HP:0002859', (85, 88))	('sarcoma', 'Disease', (14, 21))	('translocation-positive', 'Var', (163, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('RMS', 'Phenotype', 'HP:0002859', (187, 190))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))	('RMS', 'Phenotype', 'HP:0002859', (218, 221))
421567	25915942	Interestingly, it was found that about 50% of discriminating miRNAs in RMS cells obtained in these experiments were also confirmed in RMS patients (FDR<0.1), and miR-27a was one of the most over-expressed in translocation-positive ARMS with respect to translocation-negative RMS.	('RMS', 'Phenotype', 'HP:0002859', (134, 137))	('miR-27a', 'Gene', (162, 169))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('RMS', 'Phenotype', 'HP:0002859', (275, 278))	('over-expressed', 'PosReg', (190, 204))	('miR-27a', 'Gene', '407018', (162, 169))	('RMS', 'Phenotype', 'HP:0002859', (232, 235))	('translocation-positive', 'Var', (208, 230))	('RMS', 'Phenotype', 'HP:0002859', (71, 74))	('miR', 'Gene', '220972', (162, 165))	('patients', 'Species', '9606', (138, 146))	('miR', 'Gene', (162, 165))
421572	25915942	Some have hypothesized that the overexpression of miR-27a affects cell cycle progression by interacting with the tumor suppressor FBW7 that regulates ubiquitylation and turnover of the FBW7 target cyclin E. Inhibition of miR-27a was, moreover, found to suppress the growth, colony formation, and migration of pancreatic cancer cells by targeting Spry2.	('tumor', 'Disease', (113, 118))	('pancreatic cancer', 'Disease', (309, 326))	('Inhibition', 'Var', (207, 217))	('miR-27a', 'Gene', (221, 228))	('targeting', 'Reg', (336, 345))	('pancreatic cancer', 'Disease', 'MESH:D010190', (309, 326))	('miR-27a', 'Gene', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('colony formation', 'CPA', (274, 290))	('suppress', 'NegReg', (253, 261))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (309, 326))	('miR-27a', 'Gene', '407018', (221, 228))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('growth', 'CPA', (266, 272))	('miR-27a', 'Gene', '407018', (50, 57))	('Spry2', 'Gene', (346, 351))	('rat', 'Species', '10116', (299, 302))
421593	25915942	In fact, silencing miR-27a to decrease its abnormal over-expression in RMS cell lines could restore normal retinoic acid receptor expression and improve the response to retinoic acid treatment.	('restore', 'PosReg', (92, 99))	('retinoic acid', 'Chemical', 'MESH:D014212', (169, 182))	('silencing', 'Var', (9, 18))	('miR-27a', 'Gene', (19, 26))	('improve', 'PosReg', (145, 152))	('normal retinoic acid receptor expression', 'MPA', (100, 140))	('retinoic acid', 'Chemical', 'MESH:D014212', (107, 120))	('response to retinoic acid treatment', 'MPA', (157, 192))	('miR-27a', 'Gene', '407018', (19, 26))	('RMS', 'Phenotype', 'HP:0002859', (71, 74))	('over-expression', 'MPA', (52, 67))
421605	23637977	We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs) in 279 participants from a clinical trial of adjuvant imatinib mesylate.	('PDGFRA', 'Gene', (41, 47))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (175, 192))	('PDGFRA', 'Gene', '5156', (41, 47))	('deletions', 'Var', (69, 78))	('participants', 'Species', '9606', (128, 140))	('single nucleotide polymorphisms', 'Var', (82, 113))	('mutations', 'Var', (48, 57))
421606	23637977	Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci.	('GIST tumors', 'Disease', 'MESH:D046152', (242, 253))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('mutations', 'Var', (201, 210))	('PDGFRA', 'Gene', '5156', (226, 232))	('GIST tumors', 'Disease', (242, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('KIT', 'Gene', (218, 221))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PDGFRA', 'Gene', (226, 232))
421607	23637977	As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response.	('men', 'Species', '9606', (49, 52))	('variants', 'Var', (147, 155))	('sarcomas', 'Disease', 'MESH:D012509', (124, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('linked', 'Reg', (114, 120))	('sarcomas', 'Disease', (124, 132))	('dioxin', 'Chemical', 'MESH:D004147', (204, 210))	('dioxin', 'Chemical', 'MESH:D004147', (77, 83))
421608	23637977	We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each variant and 7 categories of tumor mutation using logistic regression.	('variant', 'Var', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))
421610	23637977	Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836) and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836).	('rs1056836', 'Var', (270, 279))	('rs1056836', 'Mutation', 'rs1056836', (270, 279))	('CYP1B1', 'Gene', '1545', (124, 130))	('associated', 'Reg', (145, 155))	('SNPs', 'Var', (116, 120))	('rs1800440', 'Var', (332, 341))	('rs1056836', 'Var', (376, 385))	('rs2855658', 'Var', (226, 235))	('CYP1B1', 'Gene', (124, 130))	('rs2855658', 'Mutation', 'rs2855658', (226, 235))	('men', 'Species', '9606', (85, 88))	('rs1800440', 'Mutation', 'rs1800440', (332, 341))	('rs1056836', 'Mutation', 'rs1056836', (376, 385))
421612	23637977	Other potential risk variants included GSTM1, RAD23B and ERCC2.	('variants', 'Var', (21, 29))	('GSTM1', 'Gene', '2944', (39, 44))	('RAD23B', 'Gene', (46, 52))	('GSTM1', 'Gene', (39, 44))	('ERCC2', 'Gene', '2068', (57, 62))	('RAD23B', 'Gene', '5887', (46, 52))	('ERCC2', 'Gene', (57, 62))
421618	23637977	In approximately 75% of GISTs, this CD117 overexpression is attributable to a gain-in-function mutation in the tyrosine kinase domain of KIT.	('gain-in-function', 'PosReg', (78, 94))	('mutation', 'Var', (95, 103))	('overexpression', 'PosReg', (42, 56))	('KIT', 'Gene', (137, 140))	('CD117', 'Gene', '3815', (36, 41))	('CD117', 'Gene', (36, 41))
421619	23637977	Once mutated, KIT may encode tyrosine kinase receptors in which the tyrosine kinase domain can be activated in the absence of stem cell factor signaling, thereby stimulating excess, unregulated proliferation of the host tumor cells.	('tyrosine kinase domain', 'MPA', (68, 90))	('KIT', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('activated', 'PosReg', (98, 107))	('host tumor', 'Disease', 'MESH:D006086', (215, 225))	('mutated', 'Var', (5, 12))	('stimulating', 'PosReg', (162, 173))	('host tumor', 'Disease', (215, 225))
421620	23637977	Another 10-15% of GISTs have mutations in the PDGFRA gene, another tyrosine kinase receptor encoding gene.	('PDGFRA', 'Gene', '5156', (46, 52))	('mutations', 'Var', (29, 38))	('PDGFRA', 'Gene', (46, 52))
421621	23637977	Primary GIST-related KIT and PDGFRA mutations have been well characterized.	('PDGFRA', 'Gene', '5156', (29, 35))	('PDGFRA', 'Gene', (29, 35))	('mutations', 'Var', (36, 45))
421622	23637977	Results from 3 population-based studies in Switzerland, Norway and France suggest that 50-60% of all GISTs have mutations in KIT exon 11, 5-10% in KIT exon 9, 3% in KIT exon 13, 1% in KIT exon 17, 2-5% in PDGFRA exon 12 and 2-6% in PDGFRA exon 18.	('KIT exon 11', 'Gene', (125, 136))	('mutations', 'Var', (112, 121))	('PDGFRA', 'Gene', (232, 238))	('PDGFRA', 'Gene', (205, 211))	('PDGFRA', 'Gene', '5156', (232, 238))	('PDGFRA', 'Gene', '5156', (205, 211))	('KIT exon 13', 'Gene', (165, 176))
421623	23637977	Most GISTs with primary KIT or PDGFRA mutations respond to treatment with imatinib mesylate (STI571, Gleevec , Novartis Pharmaceuticals, Basel, Switzerland), an inhibitor of the KIT and PDGFRA tyrosine kinase.	('PDGFRA', 'Gene', (31, 37))	('PDGFRA', 'Gene', (186, 192))	('PDGFRA', 'Gene', '5156', (31, 37))	('STI571', 'Chemical', 'MESH:D000068877', (93, 99))	('PDGFRA', 'Gene', '5156', (186, 192))	('respond', 'Reg', (48, 55))	('men', 'Species', '9606', (64, 67))	('mutations', 'Var', (38, 47))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (74, 91))	('KIT', 'Gene', (24, 27))
421624	23637977	Imatinib is more effective in patients with mutations in KIT exon 11 than in patients with no tumor mutations (wild type) or exon 9 mutations.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('KIT exon 11', 'Gene', (57, 68))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (30, 38))	('mutations', 'Var', (44, 53))	('effective', 'MPA', (17, 26))
421626	23637977	This acquired resistance may be attributable to the development of secondary KIT mutations in residual tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('KIT', 'Gene', (77, 80))	('mutations', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('men', 'Species', '9606', (59, 62))
421627	23637977	While some KIT and PDGFRA germline mutations have been identified among families with multiple GIST cases and a few studies have identified single nucleotide polymorphisms (SNPs) associated with soft tissue sarcoma incidence (MDM2 ), survival (AhR ), or specific translocations common in some types of soft tissue sarcoma (XPG/ERCC5 ), no studies have looked for inherited genetic risk factors for sporadic GISTs.	('ERCC5', 'Gene', (327, 332))	('translocations', 'Var', (263, 277))	('survival', 'Disease', (234, 242))	('MDM2', 'Gene', (226, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (302, 321))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (302, 321))	('KIT', 'Gene', (11, 14))	('AhR', 'Gene', '196', (244, 247))	('soft tissue sarcoma', 'Disease', (302, 321))	('XPG', 'Gene', '2073', (323, 326))	('MDM2', 'Gene', '4193', (226, 230))	('associated', 'Reg', (179, 189))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (195, 214))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (195, 214))	('PDGFRA', 'Gene', (19, 25))	('soft tissue sarcoma', 'Disease', (195, 214))	('PDGFRA', 'Gene', '5156', (19, 25))	('AhR', 'Gene', (244, 247))	('ERCC5', 'Gene', '2073', (327, 332))	('sarcoma', 'Phenotype', 'HP:0100242', (314, 321))	('XPG', 'Gene', (323, 326))	('single nucleotide polymorphisms', 'Var', (140, 171))	('mutations', 'Var', (35, 44))
421630	23637977	Given these constraints, we decided to investigate the role of inherited genetic polymorphisms in GIST development by conducting a case-only analysis of the association between tumor mutation type (mutations in KIT exon 11, KIT exon 9, PDGFRA, or wild type) and 225 variants in 39 candidate genes using tumor and blood samples collected during a phase III clinical trial of adjuvant imatinib.	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('association', 'Interaction', (157, 168))	('men', 'Species', '9606', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', (303, 308))	('mutations', 'Var', (198, 207))	('imatinib', 'Chemical', 'MESH:D000068877', (383, 391))	('KIT exon 11', 'Gene', (211, 222))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('PDGFRA', 'Gene', '5156', (236, 242))	('KIT exon 9', 'Gene', (224, 234))	('PDGFRA', 'Gene', (236, 242))	('tumor', 'Disease', (177, 182))
421632	23637977	These include associations between GSTM1-null genotype and TP53 transversion mutations among bladder cancer patients, and certain functional polymorphisms in XPD and G:C T:A TP53 mutations among lung cancer patients.	('TP53', 'Gene', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('patients', 'Species', '9606', (108, 116))	('TP53', 'Gene', (59, 63))	('TP53', 'Gene', '7157', (174, 178))	('GSTM1', 'Gene', (35, 40))	('XPD', 'Gene', '2068', (158, 161))	('lung cancer', 'Disease', (195, 206))	('transversion mutations', 'Var', (64, 86))	('mutations', 'Var', (179, 188))	('TP53', 'Gene', '7157', (59, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))	('associations', 'Interaction', (14, 26))	('patients', 'Species', '9606', (207, 215))	('bladder cancer', 'Disease', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('GSTM1', 'Gene', '2944', (35, 40))	('XPD', 'Gene', (158, 161))
421633	23637977	Similarly, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may be mutational signatures that are causally linked to specific mutagens or susceptibility loci.	('GIST tumors', 'Disease', (100, 111))	('KIT', 'Gene', (76, 79))	('PDGFRA', 'Gene', '5156', (84, 90))	('PDGFRA', 'Gene', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutations', 'Var', (59, 68))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('GIST tumors', 'Disease', 'MESH:D046152', (100, 111))
421635	23637977	We included genes related to dioxin, phenoxyherbicide, insecticide, vinyl chloride, and radiation response, as well as variants in the previously identified AhR, MDM2, and ERCC5 genes.	('ERCC5', 'Gene', '2073', (172, 177))	('MDM2', 'Gene', '4193', (162, 166))	('MDM2', 'Gene', (162, 166))	('vinyl chloride', 'Chemical', 'MESH:D014752', (68, 82))	('dioxin', 'Chemical', 'MESH:D004147', (29, 35))	('AhR', 'Gene', (157, 160))	('AhR', 'Gene', '196', (157, 160))	('phenoxyherbicide', 'Chemical', '-', (37, 53))	('variants', 'Var', (119, 127))	('ERCC5', 'Gene', (172, 177))
421637	23637977	Additionally, we selected several DNA repair genes (ERCC2, RAD23B, XPA, and XPC) in the same DNA repair pathway as ERCC5, as polymorphisms in these nucleotide excision repair genes can affect individual sensitivity to carcinogen-induced DNA damage.	('affect', 'Reg', (185, 191))	('XPC', 'Gene', (76, 79))	('sensitivity to carcinogen-induced DNA damage', 'MPA', (203, 247))	('ERCC2', 'Gene', (52, 57))	('XPA', 'Gene', (67, 70))	('ERCC5', 'Gene', '2073', (115, 120))	('XPA', 'Gene', '7507', (67, 70))	('XPC', 'Gene', '7508', (76, 79))	('RAD23B', 'Gene', '5887', (59, 65))	('polymorphisms', 'Var', (125, 138))	('RAD23B', 'Gene', (59, 65))	('ERCC2', 'Gene', '2068', (52, 57))	('ERCC5', 'Gene', (115, 120))
421641	23637977	This genetic ancillary study includes the first 333 Z9001 participants who provided a blood sample and consented in writing to unspecified future research using their blood and tumor tissue samples.	('unspecified', 'Species', '32644', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('participants', 'Species', '9606', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Z9001', 'Var', (52, 57))	('tumor', 'Disease', (177, 182))
421647	23637977	Deletions in GSTM1 and GSTT1 were detected using multiplex PCR utilizing sets of target specific and housekeeping gene specific primers.	('GSTT1', 'Gene', (23, 28))	('GSTT1', 'Gene', '2952', (23, 28))	('GSTM1', 'Gene', '2944', (13, 18))	('GSTM1', 'Gene', (13, 18))	('Deletions', 'Var', (0, 9))
421649	23637977	Tumors without exon 11 mutations were then subjected to PCR analysis using primers for KIT exon 9, 13, 14 and 17 and PDGFRA exon 12 and 18.	('PDGFRA', 'Gene', (117, 123))	('PDGFRA', 'Gene', '5156', (117, 123))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (23, 32))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
421651	23637977	non-codon 557-8) KIT exon 11 deletion, iii) a KIT exon 11 insertion, iv) A KIT exon 11 point mutation, v) a KIT exon 9, exon 13, exon 14, or exon 17 mutation, vi) a PDGFRA exon 18 or 12 mutation, and vii) no KIT or PDGFRA mutation (wild type).	('deletion', 'Var', (29, 37))	('KIT exon 11', 'Gene', (17, 28))	('PDGFRA', 'Gene', '5156', (165, 171))	('PDGFRA', 'Gene', (165, 171))	('insertion', 'Var', (58, 67))	('KIT exon 11', 'Gene', (46, 57))	('PDGFRA', 'Gene', '5156', (215, 221))	('PDGFRA', 'Gene', (215, 221))	('KIT exon 11', 'Gene', (75, 86))
421660	23637977	70% of evaluated tumors had exon 11 KIT mutations, 10% had PDGFRA mutations and 13% had no identified KIT or PDGFRA mutations.	('mutations', 'Var', (66, 75))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('exon 11', 'Var', (28, 35))	('tumors', 'Disease', (17, 23))	('PDGFRA', 'Gene', '5156', (59, 65))	('PDGFRA', 'Gene', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('KIT', 'Gene', (36, 39))	('mutations', 'Var', (40, 49))	('PDGFRA', 'Gene', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('PDGFRA', 'Gene', '5156', (109, 115))
421661	23637977	Non-white participants were younger, on average (53.0 years vs. 59.0 years), and more likely to have stomach tumors (74% vs. 64%) and exon 11 KIT mutations (84% vs. 67%).	('stomach tumors', 'Disease', (101, 115))	('exon 11 KIT mutations', 'Var', (134, 155))	('stomach tumors', 'Phenotype', 'HP:0006753', (101, 115))	('participants', 'Species', '9606', (10, 22))	('stomach tumors', 'Disease', 'MESH:D013274', (101, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
421664	23637977	Notable discrepancies included SNPs on several aldehyde dehydrogenase genes, ALDH1A3, ALDH1A2, ALDH1L1 and ALDH1L2, and two DNA repair genes, ERCC2 and XPC.	('ERCC2', 'Gene', '2068', (142, 147))	('ALDH1L2', 'Gene', (107, 114))	('ALDH1A2', 'Gene', '8854', (86, 93))	('ALDH1L2', 'Gene', '160428', (107, 114))	('XPC', 'Gene', (152, 155))	('SNPs', 'Var', (31, 35))	('ALDH1A3', 'Gene', '220', (77, 84))	('ERCC2', 'Gene', (142, 147))	('ALDH1A2', 'Gene', (86, 93))	('XPC', 'Gene', '7508', (152, 155))	('ALDH1L1', 'Gene', (95, 102))	('ALDH1L1', 'Gene', '10840', (95, 102))	('ALDH1A3', 'Gene', (77, 84))
421665	23637977	Most notably, minor alleles at CYP1B1 rs1056836 and rs2855658 were positively associated with a deletion at KIT exon 11 codons 557-8 (OR = 1.81, 95% CI: 1.21-2.71 and OR = 1.91, 95% CI: 1.27-2.86, respectively), while variation in another CYP1B1 SNP, rs1800440, was positively associated with wild type tumors (OR = 2.65, 95% CI: 1.48-4.76).	('rs1800440', 'Mutation', 'rs1800440', (251, 260))	('associated', 'Reg', (78, 88))	('CYP1B1', 'Gene', (239, 245))	('type tumors', 'Disease', (298, 309))	('KIT exon', 'Gene', (108, 116))	('rs2855658', 'Var', (52, 61))	('rs1056836', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('CYP1B1', 'Gene', (31, 37))	('CYP1B1', 'Gene', '1545', (31, 37))	('rs1056836', 'Mutation', 'rs1056836', (38, 47))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('deletion', 'Var', (96, 104))	('rs2855658', 'Mutation', 'rs2855658', (52, 61))	('CYP1B1', 'Gene', '1545', (239, 245))	('rs1800440', 'Var', (251, 260))	('type tumors', 'Disease', 'MESH:D009369', (298, 309))
421667	23637977	Minor alleles in two RAD23B SNPs, rs7041137 and rs1805329, were more common among tumors with KIT exon 9, 13, or 14 mutations (ORrs7041136 = 3.05, 95% CI: 1.52-6.12 and ORrs1805329 = 3.24, 95% CI: 1.48-7.11) than tumors without such mutations.	('rs1805329', 'Mutation', 'rs1805329', (171, 180))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumors', 'Disease', (213, 219))	('common', 'Reg', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('rs1805329', 'Var', (48, 57))	('RAD23B', 'Gene', '5887', (21, 27))	('RAD23B', 'Gene', (21, 27))	('rs7041137', 'Mutation', 'rs7041137', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('ORrs7041136', 'Var', (127, 138))	('rs1805329', 'Mutation', 'rs1805329', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ORrs1805329 =', 'Var', (169, 182))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('rs7041137', 'Var', (34, 43))	('KIT exon 9', 'Gene', (94, 104))
421668	23637977	The rare form of a third RAD23B SNP, rs1805334, was also positively associated with non- exon 11 KIT mutations (OR = 2.45, 95% CI: 1.16-5.14).	('associated', 'Reg', (68, 78))	('rs1805334', 'Var', (37, 46))	('RAD23B', 'Gene', '5887', (25, 31))	('non- exon 11 KIT mutations', 'Var', (84, 110))	('rs1805334', 'Mutation', 'rs1805334', (37, 46))	('RAD23B', 'Gene', (25, 31))
421669	23637977	rs50872 in ERCC2 was the strongest risk factor for KIT exon 11 insertion mutations (OR = 2.68, 95% CI: 1.43-5.04) and the rare variant of rs3815029 in GSTM1 was inversely associated with non-codon 557-8 KIT exon 11 deletions (OR = 0.43, 95% CI: 0.25,0.75).	('GSTM1', 'Gene', (151, 156))	('rs50872', 'Var', (0, 7))	('ERCC2', 'Gene', (11, 16))	('KIT exon 11', 'Gene', (51, 62))	('insertion mutations', 'Var', (63, 82))	('rs3815029', 'Var', (138, 147))	('rs50872', 'Mutation', 'rs50872', (0, 7))	('GSTM1', 'Gene', '2944', (151, 156))	('ERCC2', 'Gene', '2068', (11, 16))	('rs3815029', 'Mutation', 'rs3815029', (138, 147))	('mutations', 'Var', (73, 82))
421670	23637977	Based on the above evidence that at least one variant in CYP1B1, RAD23B, ERCC2, or GSTM1 was associated with one or more GIST mutation types at p<0.005, we provided a detailed evaluation of the estimated effects for all of the variants in these four key genes (Table 3).	('variant', 'Var', (46, 53))	('ERCC2', 'Gene', '2068', (73, 78))	('associated', 'Reg', (93, 103))	('ERCC2', 'Gene', (73, 78))	('GSTM1', 'Gene', '2944', (83, 88))	('RAD23B', 'Gene', '5887', (65, 71))	('CYP1B1', 'Gene', (57, 63))	('CYP1B1', 'Gene', '1545', (57, 63))	('RAD23B', 'Gene', (65, 71))	('GSTM1', 'Gene', (83, 88))
421671	23637977	This table includes results for rs4646755 in ALDH1L1 and rs3731149 in XPC, the strongest risk factors for PDGFRA mutations and KIT exon 11 point mutations, respectively, both of which had p-values of 0.02.	('XPC', 'Gene', (70, 73))	('ALDH1L1', 'Gene', (45, 52))	('PDGFRA', 'Gene', '5156', (106, 112))	('ALDH1L1', 'Gene', '10840', (45, 52))	('rs3731149', 'Var', (57, 66))	('rs3731149', 'Mutation', 'rs3731149', (57, 66))	('rs4646755', 'Mutation', 'rs4646755', (32, 41))	('XPC', 'Gene', '7508', (70, 73))	('mutations', 'Var', (113, 122))	('PDGFRA', 'Gene', (106, 112))	('rs4646755', 'Var', (32, 41))
421672	23637977	These patterns were preserved in the gene-level SKAT analysis (Figure 1, Table 4, and Table S3), with CYP1B1 again associated with KIT exon 11 codon 557-8 deletions and wild type tumors (p = 0.002 and 0.003, respectively); strong associations between RAD23B and KIT exon 9, 13 or 14 mutations (p = 0.002); and GSTM1 and non-codon 557-8 KIT exon 11 deletions (p = 0.01).	('CYP1B1', 'Gene', '1545', (102, 108))	('CYP1B1', 'Gene', (102, 108))	('GSTM1', 'Gene', (310, 315))	('codon 557-8 deletions', 'Var', (143, 164))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('RAD23B', 'Gene', '5887', (251, 257))	('associated', 'Reg', (115, 125))	('KIT exon 9', 'Gene', (262, 272))	('KIT exon 11', 'Gene', (131, 142))	('SKAT', 'Disease', (48, 52))	('RAD23B', 'Gene', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('SKAT', 'Disease', 'None', (48, 52))	('type tumors', 'Disease', 'MESH:D009369', (174, 185))	('GSTM1', 'Gene', '2944', (310, 315))	('type tumors', 'Disease', (174, 185))	('KIT exon 11', 'Gene', (336, 347))	('associations', 'Interaction', (230, 242))
421674	23637977	As for the other three possible tumor subtypes, ALDH2 was associated with KIT exon 11 insertions (p = 0.03) and the null GSTT1 genotype was associated with PDGFRA-mutated tumors (p = 0.04).	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('KIT exon 11', 'Gene', (74, 85))	('GSTT1', 'Gene', '2952', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('PDGFRA', 'Gene', (156, 162))	('ALDH2', 'Gene', (48, 53))	('PDGFRA', 'Gene', '5156', (156, 162))	('GSTT1', 'Gene', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('associated', 'Reg', (140, 150))	('tumor', 'Disease', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('associated', 'Reg', (58, 68))	('ALDH2', 'Gene', '217', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('insertions', 'Var', (86, 96))	('tumor', 'Disease', (171, 176))
421675	23637977	Although the effect estimates were very imprecise, the associations between the rare alleles of CYP1B1 SNPs rs1056836 and rs2855658 and KIT exon 11 codon 557-8 deletions were even stronger when the analysis was limited to small intestinal tumors (ORrs1056836 = 5.18, 95% CI: 2.07, 12.95 and ORrs2855658 = 5.17, 95% CI: 2.05, 13.03).	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('ORrs2855658', 'Var', (291, 302))	('intestinal tumors', 'Disease', (228, 245))	('associations', 'Interaction', (55, 67))	('rs2855658', 'Mutation', 'rs2855658', (293, 302))	('intestinal tumors', 'Disease', 'MESH:D007414', (228, 245))	('rs2855658', 'Mutation', 'rs2855658', (122, 131))	('CYP1B1', 'Gene', (96, 102))	('CYP1B1', 'Gene', '1545', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('rs2855658', 'Var', (122, 131))	('rs1056836', 'Var', (108, 117))	('rs1056836', 'Mutation', 'rs1056836', (108, 117))	('stronger', 'PosReg', (180, 188))	('rs1056836', 'Mutation', 'rs1056836', (249, 258))	('small intestinal tumors', 'Phenotype', 'HP:0100833', (222, 245))
421683	23637977	The rare allele of rs1800440, another missense mutation, was also associated with lung and head and neck cancer, with no reported association with breast or colorectal cancer.	('neck cancer', 'Disease', (100, 111))	('lung', 'Disease', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('rs1800440', 'Var', (19, 28))	('rs1800440', 'Mutation', 'rs1800440', (19, 28))	('associated', 'Reg', (66, 76))	('breast or colorectal cancer', 'Disease', 'MESH:D015179', (147, 174))	('breast or colorectal cancer', 'Disease', (147, 174))	('head and neck cancer', 'Phenotype', 'HP:0012288', (91, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))	('neck cancer', 'Disease', 'MESH:D006258', (100, 111))
421685	23637977	The remaining CYP1B1 SNP, rs2855658, is located in a seed microRNA region, but has no previously established links to cancer.	('cancer', 'Disease', (118, 124))	('rs2855658', 'Mutation', 'rs2855658', (26, 35))	('rs2855658', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CYP1B1', 'Gene', (14, 20))	('CYP1B1', 'Gene', '1545', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
421686	23637977	Although there is little evidence of a link between cancer and the specific RAD23B, ERCC2, and GSTM1 variants identified here, previous studies have observed associations between one or more types of cancer and other variants on these three genes.	('associations', 'Interaction', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('ERCC2', 'Gene', '2068', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('GSTM1', 'Gene', '2944', (95, 100))	('variants', 'Var', (101, 109))	('ERCC2', 'Gene', (84, 89))	('GSTM1', 'Gene', (95, 100))	('RAD23B', 'Gene', '5887', (76, 82))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('RAD23B', 'Gene', (76, 82))	('cancer', 'Disease', (200, 206))
421687	23637977	For example, SNPs in RAD23B have been linked to esophageal and bladder cancers and one SNP near RAD23B was strongly associated with breast cancer in a genome-wide association study.	('linked', 'Reg', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('bladder cancers', 'Phenotype', 'HP:0009725', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('SNPs', 'Var', (13, 17))	('RAD23B', 'Gene', '5887', (21, 27))	('RAD23B', 'Gene', '5887', (96, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('RAD23B', 'Gene', (21, 27))	('esophageal and bladder cancers', 'Disease', 'MESH:D001749', (48, 78))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('RAD23B', 'Gene', (96, 102))	('associated', 'Reg', (116, 126))
421688	23637977	ERCC2 has also been linked to bladder cancer and a large meta-analysis completed in 2006 reported statistically significant associations between ERCC2 SNPs and skin, breast and lung cancer.	('ERCC2', 'Gene', '2068', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('skin', 'Disease', (160, 164))	('significant associations', 'Reg', (112, 136))	('ERCC2', 'Gene', (145, 150))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('breast and lung cancer', 'Disease', 'MESH:D001943', (166, 188))	('SNPs', 'Var', (151, 155))	('ERCC2', 'Gene', '2068', (0, 5))	('ERCC2', 'Gene', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))	('linked', 'Reg', (20, 26))
421690	23637977	Like the seed microRNA and missense mutation SNPs in CYP1B1 that were strongly associated with tumor mutations in the present study, some of the identified RAD23B and ERCC2 SNPs also have potentially functional roles.	('associated', 'Reg', (79, 89))	('RAD23B', 'Gene', (156, 162))	('missense mutation', 'Var', (27, 44))	('RAD23B', 'Gene', '5887', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('ERCC2', 'Gene', '2068', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CYP1B1', 'Gene', '1545', (53, 59))	('CYP1B1', 'Gene', (53, 59))	('tumor', 'Disease', (95, 100))	('ERCC2', 'Gene', (167, 172))
421691	23637977	For example, rs13181 on ERCC2 is a missense mutation, as is rs1805329 on RAD23B.	('rs1805329', 'Mutation', 'rs1805329', (60, 69))	('ERCC2', 'Gene', (24, 29))	('RAD23B', 'Gene', (73, 79))	('rs13181', 'Mutation', 'rs13181', (13, 20))	('rs13181', 'Var', (13, 20))	('ERCC2', 'Gene', '2068', (24, 29))	('RAD23B', 'Gene', '5887', (73, 79))	('rs1805329', 'Var', (60, 69))
421692	23637977	Additionally, RAD23B's rs1805330 is a splice site mutation and rs10868 and rs1805334 are located on transcription binding sites.	('RAD23B', 'Gene', (14, 20))	('rs10868', 'Var', (63, 70))	('rs1805330', 'Var', (23, 32))	('rs1805334', 'Var', (75, 84))	('rs10868', 'Mutation', 'rs10868', (63, 70))	('RAD23B', 'Gene', '5887', (14, 20))	('rs1805330', 'Mutation', 'rs1805330', (23, 32))	('rs1805334', 'Mutation', 'rs1805334', (75, 84))
421695	23637977	In previous studies, GSTM1 deletions have been linked to osteosarcoma incidence and recurrence, with a non-statistically significant positive association with soft tissue sarcoma mortality.	('osteosarcoma', 'Phenotype', 'HP:0002669', (57, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('soft tissue sarcoma', 'Disease', (159, 178))	('osteosarcoma', 'Disease', 'MESH:D012516', (57, 69))	('GSTM1', 'Gene', '2944', (21, 26))	('deletions', 'Var', (27, 36))	('linked', 'Reg', (47, 53))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (159, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (159, 178))	('GSTM1', 'Gene', (21, 26))	('osteosarcoma', 'Disease', (57, 69))
421696	23637977	Other studies of GSTM1 deletions have identified positive associations between the null genotype and a variety of cancers, included oral, colorectal, cervical, and bladder.	('colorectal', 'Disease', (138, 148))	('deletions', 'Var', (23, 32))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cervical', 'Disease', (150, 158))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('positive', 'PosReg', (49, 57))	('bladder', 'Disease', (164, 171))	('GSTM1', 'Gene', '2944', (17, 22))	('colorectal', 'Disease', 'MESH:D015179', (138, 148))	('GSTM1', 'Gene', (17, 22))	('oral', 'Disease', (132, 136))
421699	23637977	Outcome misclassification is also a potential concern, as tumors with KIT exon 11 mutations were not assessed for other KIT or PDGFRA mutations and we did not test for PDGFRA exon 14 mutations in any tumors.	('PDGFRA', 'Gene', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('PDGFRA', 'Gene', (127, 133))	('PDGFRA', 'Gene', '5156', (168, 174))	('tumors', 'Disease', (58, 64))	('KIT exon 11', 'Gene', (70, 81))	('PDGFRA', 'Gene', '5156', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('mutations', 'Var', (82, 91))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))
421702	23637977	In this small, yet novel, case-only study of genetic risk factors for GIST tumor subtypes we identified several variants in CYP1B1, RAD23B, GSTM1, and ERCC2 that we believe are worthy of further investigation.	('RAD23B', 'Gene', (132, 138))	('GSTM1', 'Gene', '2944', (140, 145))	('CYP1B1', 'Gene', '1545', (124, 130))	('ERCC2', 'Gene', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CYP1B1', 'Gene', (124, 130))	('GSTM1', 'Gene', (140, 145))	('RAD23B', 'Gene', '5887', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ERCC2', 'Gene', '2068', (151, 156))	('tumor', 'Disease', (75, 80))	('variants', 'Var', (112, 120))
421729	31551374	Several studies comparing patients who undergo an amputation or limb sparing surgery have shown no differences in quality-of-life scores; however, there are also reports of patients who had an amputation having poorer health-related quality of life scores compared with patients who had other types of surgery.	('patients', 'Species', '9606', (270, 278))	('patients', 'Species', '9606', (173, 181))	('amputation', 'Var', (193, 203))	('patients', 'Species', '9606', (26, 34))	('health-related quality of life scores', 'MPA', (218, 255))	('poorer', 'NegReg', (211, 217))
421730	31551374	The inconsistent results are also shown in studies that report that patients who had amputations had poorer mental health but better feelings of self-worth compared with patients who had other type of surgery.	('patients', 'Species', '9606', (170, 178))	('feelings of self-worth', 'MPA', (133, 155))	('better', 'PosReg', (126, 132))	('mental health', 'CPA', (108, 121))	('patients', 'Species', '9606', (68, 76))	('poorer', 'NegReg', (101, 107))	('amputations', 'Var', (85, 96))
421765	31551374	After lower limb amputation, as well as mobility being severely affected, patients needed to relearn activities of daily living, including going to the toilet, taking a shower and walking.	('lower limb', 'Phenotype', 'HP:0006385', (6, 16))	('walking', 'CPA', (180, 187))	('patients', 'Species', '9606', (74, 82))	('amputation', 'Var', (17, 27))	('activities of daily living', 'Phenotype', 'HP:0031058', (101, 127))
421866	29018115	Analysis of the cytokine and chemokine milieu following KSHV infection of monocytes revealed that KSHV induces interleukins 1alpha, 1beta, and 6, all of which have been implicated in KS development.	('KSHV infection', 'Disease', (56, 70))	('KS', 'Phenotype', 'HP:0100726', (98, 100))	('KS', 'Phenotype', 'HP:0100726', (56, 58))	('induces', 'PosReg', (103, 110))	('men', 'Species', '9606', (193, 196))	('KSHV', 'Species', '37296', (56, 60))	('KS', 'Phenotype', 'HP:0100726', (183, 185))	('interleukins 1alpha', 'MPA', (111, 130))	('KSHV infection', 'Disease', 'MESH:C537372', (56, 70))	('KSHV', 'Species', '37296', (98, 102))	('KSHV', 'Var', (98, 102))	('1beta', 'MPA', (132, 137))
421873	29018115	Although reconstitution of the host immune system via highly active antiretroviral therapy (HAART) in AIDS-KS or change of immunosuppressive regimens in iatrogenic KS often leads to clinical regression of KS, an improper immune response in immune reconstitution inflammatory syndrome (IRIS) during HAART-initiated repopulation of CD4+ T cells can lead to KS lesion progression.	('AIDS-KS', 'Disease', 'MESH:D000163', (102, 109))	('men', 'Species', '9606', (145, 148))	('inflammatory syndrome', 'Disease', 'MESH:D007249', (262, 283))	('KS', 'Phenotype', 'HP:0100726', (355, 357))	('KS', 'Phenotype', 'HP:0100726', (107, 109))	('KS lesion', 'Disease', 'MESH:D051437', (355, 364))	('AIDS-KS', 'Disease', (102, 109))	('KS', 'Phenotype', 'HP:0100726', (205, 207))	('inflammatory syndrome', 'Disease', (262, 283))	('lead to', 'Reg', (347, 354))	('KS lesion', 'Disease', (355, 364))	('improper', 'Var', (212, 220))	('KS', 'Phenotype', 'HP:0100726', (164, 166))
421885	29018115	Cytokine involvement is suggested by the high dependency of KS spindle cells in vitro on cytokines for growth, exposure to these required cytokines in vitro induces a morphological shift to the classic spindle KS shape in endothelial cells, and high levels of proinflammatory cytokines including interleukin 1alpha (IL-1alpha), IL-1beta, and IL-6 are found within the KS tumor microenvironment.	('KS tumor', 'Disease', (368, 376))	('men', 'Species', '9606', (389, 392))	('induces', 'Reg', (157, 164))	('KS', 'Phenotype', 'HP:0100726', (210, 212))	('IL-1beta', 'Gene', (328, 336))	('IL-1beta', 'Gene', '3553', (328, 336))	('KS', 'Phenotype', 'HP:0100726', (368, 370))	('men', 'Species', '9606', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('morphological shift', 'CPA', (167, 186))	('exposure', 'Var', (111, 119))	('KS', 'Phenotype', 'HP:0100726', (60, 62))	('KS tumor', 'Disease', 'MESH:D009369', (368, 376))
421890	29018115	KS is the most common AIDS-defining cancer and coinfection of monocytes with KSHV and HIV leads to higher HIV replication.	('HIV replication', 'MPA', (106, 121))	('AIDS', 'Disease', (22, 26))	('KSHV', 'Gene', (77, 81))	('higher', 'PosReg', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('AIDS', 'Disease', 'MESH:D000163', (22, 26))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('coinfection', 'Var', (47, 58))	('KS', 'Phenotype', 'HP:0100726', (77, 79))	('KSHV', 'Species', '37296', (77, 81))
421915	29018115	We consistently observed an increase in PD-L1 protein expression in CD14-positive cells compared to mock-infected cells from all donors (Table 1).	('donor', 'Species', '9606', (129, 134))	('PD-L1', 'Gene', (40, 45))	('CD14-positive', 'Var', (68, 81))	('PD-L1', 'Gene', '29126', (40, 45))	('increase', 'PosReg', (28, 36))
421960	29018115	Finally, KSHV increases IP-10 at each time point (Table 2), which correlates with our previous report that KSHV can activate Toll-like receptor 3 (TLR3), resulting in the induction of IP-10 downstream of TLR3 signaling.	('TLR3', 'Gene', (147, 151))	('activate', 'PosReg', (116, 124))	('KS', 'Phenotype', 'HP:0100726', (107, 109))	('KSHV', 'Species', '37296', (107, 111))	('KSHV', 'Var', (107, 111))	('induction', 'MPA', (171, 180))	('IP-10 downstream of TLR3 signaling', 'MPA', (184, 218))	('KSHV', 'Species', '37296', (9, 13))	('KSHV', 'Var', (9, 13))	('KS', 'Phenotype', 'HP:0100726', (9, 11))
421966	29018115	Together these data suggest that KSHV induces an immune response in cells and one of the potential mechanisms that KSHV may utilize to decrease immune responses is through upregulation of the immunomodulatory protein PD-L1.	('PD-L1', 'Gene', '29126', (217, 222))	('upregulation', 'PosReg', (172, 184))	('immune responses', 'MPA', (144, 160))	('KSHV', 'Species', '37296', (115, 119))	('KSHV', 'Var', (115, 119))	('KS', 'Phenotype', 'HP:0100726', (33, 35))	('KSHV', 'Species', '37296', (33, 37))	('KSHV', 'Var', (33, 37))	('KS', 'Phenotype', 'HP:0100726', (115, 117))	('PD-L1', 'Gene', (217, 222))	('decrease immune responses', 'Phenotype', 'HP:0002721', (135, 160))	('immune', 'MPA', (49, 55))
421981	29018115	We report that KSHV induces an overall proinflammatory cytokine milieu including IL-1alpha, IL-1beta, and IL-6, which have all been reported to be important for KSHV-derived malignancies.	('KSHV', 'Species', '37296', (161, 165))	('IL-1alpha', 'MPA', (81, 90))	('KS', 'Phenotype', 'HP:0100726', (161, 163))	('IL-1beta', 'Gene', (92, 100))	('malignancies', 'Disease', (174, 186))	('proinflammatory cytokine milieu', 'MPA', (39, 70))	('induces', 'Reg', (20, 27))	('IL-1beta', 'Gene', '3553', (92, 100))	('KSHV', 'Species', '37296', (15, 19))	('KSHV', 'Var', (15, 19))	('KS', 'Phenotype', 'HP:0100726', (15, 17))	('malignancies', 'Disease', 'MESH:D009369', (174, 186))
421989	29018115	iSLK.219 cells were maintained in Dulbecco modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS) (Cellgro), 1% penicillin and streptomycin (Pen-Strep), G418 (250 mug/ml), hygromycin (400 mug/ml), and puromycin (10 mug/ml).	('streptomycin', 'Chemical', 'MESH:D013307', (148, 160))	('hygromycin', 'Chemical', 'MESH:C026273', (193, 203))	('FBS', 'Disease', (114, 117))	('G418', 'Chemical', 'MESH:C010680', (174, 178))	('DMEM', 'Chemical', '-', (66, 70))	('penicillin', 'Chemical', 'MESH:D010406', (133, 143))	('bovine', 'Species', '9913', (100, 106))	('Pen-Strep', 'Chemical', '-', (162, 171))	('FBS', 'Disease', 'MESH:D005198', (114, 117))	('puromycin', 'Chemical', 'MESH:D011691', (222, 231))	('Dulbecco modified Eagle medium', 'Chemical', '-', (34, 64))	('men', 'Species', '9606', (78, 81))	('250 mug/ml', 'Var', (180, 190))
422028	25774118	Survival of patients with a LMS is strongly associated with the number of mitoses per 10 high power fields (x100 magnification): 1-4, 98 %; 5-9, 42 %; >=10, 15 %.	('associated', 'Reg', (44, 54))	('patients', 'Species', '9606', (12, 20))	('LMS', 'Disease', (28, 31))	('LMS', 'Phenotype', 'HP:0100243', (28, 31))	('mitoses', 'Var', (74, 81))
422093	25774118	Not only electromechanical power morcellation is associated with the risk of upstaging but also other 'manipulations' of the sarcomatous tumour, such as myomectomy by laparotomy, subtotal hysterectomy and hysteroscopic resection of submucous fibroids, may affect survival suggesting upstaging.	('upstaging', 'CPA', (283, 292))	('sarcomatous tumour', 'Disease', 'MESH:D018316', (125, 143))	('upstaging', 'Disease', (77, 86))	('electromechanical power morcellation', 'Var', (9, 45))	('sarcomatous tumour', 'Disease', (125, 143))	('sarcomatous tumour', 'Phenotype', 'HP:0100242', (125, 143))	('survival', 'MPA', (263, 271))	('affect', 'Reg', (256, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
422136	25242356	Further, chemotherapy induces peripheral neuropathy giving rise to cancer related pain.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (30, 51))	('cancer', 'Disease', (67, 73))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (30, 51))	('peripheral neuropathy', 'Disease', (30, 51))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('chemotherapy', 'Var', (9, 21))	('pain', 'Phenotype', 'HP:0012531', (82, 86))	('pain', 'Disease', 'MESH:D010146', (82, 86))	('pain', 'Disease', (82, 86))
422144	25242356	Deletion of this receptor results in inhibiting experimental inflammatory hyperalgesia and neurogenic inflammation pain.	('neurogenic inflammation pain', 'Disease', (91, 119))	('hyperalgesia', 'Disease', 'MESH:D006930', (74, 86))	('hyperalgesia', 'Disease', (74, 86))	('pain', 'Phenotype', 'HP:0012531', (115, 119))	('inhibiting', 'NegReg', (37, 47))	('hyperalgesia', 'Phenotype', 'HP:0031005', (74, 86))	('neurogenic inflammation pain', 'Disease', 'MESH:D020078', (91, 119))	('Deletion', 'Var', (0, 8))
422160	25242356	Here, we report that FKI not only decreased the size of the tumor, but also decreased hyperalgesia induced by sarcoma as well as TRPV1 and ERK phosphorylation.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('FKI', 'Var', (21, 24))	('TRPV1', 'Protein', (129, 134))	('sarcoma', 'Disease', (110, 117))	('hyperalgesia', 'Phenotype', 'HP:0031005', (86, 98))	('decreased', 'NegReg', (34, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('phosphorylation', 'MPA', (143, 158))	('ERK', 'Gene', (139, 142))	('decreased', 'NegReg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ERK', 'Gene', '26413', (139, 142))	('hyperalgesia', 'Disease', 'MESH:D006930', (86, 98))	('FKI', 'Chemical', '-', (21, 24))	('tumor', 'Disease', (60, 65))	('hyperalgesia', 'Disease', (86, 98))
422161	25242356	Anti-mouse antibodies to p-ERK (4370), T-ERK (9102), p-38 (4511p), p-NFkb (3033p), p-MEK (9154), T-AKT (9272), p-AKT (9275), p-BAD (4366) and GAPDH (2118) were purchased from Cell Signaling (Boston, MA).	('p-ERK', 'Gene', (25, 30))	('ERK', 'Gene', (41, 44))	('mouse', 'Species', '10090', (5, 10))	('GAPDH', 'Gene', '14433', (142, 147))	('p-38 (4511p', 'Var', (53, 64))	('GAPDH', 'Gene', (142, 147))	('p-ERK', 'Gene', '13666', (25, 30))	('AKT', 'Gene', '11651', (99, 102))	('AKT', 'Gene', '11651', (113, 116))	('AKT', 'Gene', (113, 116))	('MEK', 'Gene', '17242', (85, 88))	('AKT', 'Gene', (99, 102))	('ERK', 'Gene', '26413', (41, 44))	('ERK', 'Gene', '26413', (27, 30))	('p-NFkb (3033p', 'Var', (67, 80))	('ERK', 'Gene', (27, 30))	('MEK', 'Gene', (85, 88))
422196	25242356	The proliferation of S-180 sarcoma cells was markedly inhibited by FKI as compared with the other cell lines (Fig.	('sarcoma', 'Disease', (27, 34))	('inhibited', 'NegReg', (54, 63))	('proliferation', 'CPA', (4, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('FKI', 'Chemical', '-', (67, 70))	('FKI', 'Var', (67, 70))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))
422234	25242356	In contrast to the increase in phosphorylation, total TRPV1 levels were not changed by FKI (Fig.	('FKI', 'Chemical', '-', (87, 90))	('TRPV1', 'Protein', (54, 59))	('FKI', 'Var', (87, 90))
422242	25242356	Further, FKI inhibits inflammatory cytokine production in mice.	('inflammatory cytokine production', 'MPA', (22, 54))	('FKI', 'Chemical', '-', (9, 12))	('mice', 'Species', '10090', (58, 62))	('FKI', 'Var', (9, 12))	('inhibits', 'NegReg', (13, 21))
422244	25242356	FKI also inhibited capsaicin-TRPV1-induced ERK phosphorylation in both TRPV1 transfected HEK cells and cultured spinal cord cells.	('inhibited', 'NegReg', (9, 18))	('TRPV1', 'Gene', (71, 76))	('HEK', 'CellLine', 'CVCL:M624', (89, 92))	('ERK', 'Gene', (43, 46))	('capsaicin-TRPV1-induced', 'Protein', (19, 42))	('capsaicin', 'Chemical', 'MESH:D002211', (19, 28))	('ERK', 'Gene', '26413', (43, 46))	('FKI', 'Chemical', '-', (0, 3))	('transfected', 'Var', (77, 88))
422245	25242356	Thus, FKI inhibited both tumor growth and tumor-induced hyperalgesia in part by inhibiting tumor-induced inflammation and the TRPV1-ERK pathway.	('FKI', 'Var', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor-induced hyperalgesia', 'Disease', 'MESH:D006930', (42, 68))	('ERK', 'Gene', (132, 135))	('tumor-induced hyperalgesia', 'Disease', (42, 68))	('tumor', 'Disease', (91, 96))	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('inhibited', 'NegReg', (10, 19))	('ERK', 'Gene', '26413', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('FKI', 'Chemical', '-', (6, 9))	('hyperalgesia', 'Phenotype', 'HP:0031005', (56, 68))	('tumor', 'Disease', (25, 30))	('inflammation', 'Disease', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('inhibiting', 'NegReg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
422251	25242356	They observed reduced phosphorylation of both Akt and ERK when cell lines were given U0126, a MEK inhibitor, and PI103 a PI3K/mTor inhibitor.	('MEK', 'Gene', '17242', (94, 97))	('reduced', 'NegReg', (14, 21))	('Akt', 'Gene', '11651', (46, 49))	('U0126', 'Var', (85, 90))	('Akt', 'Gene', (46, 49))	('MEK', 'Gene', (94, 97))	('ERK', 'Gene', (54, 57))	('U0126', 'Chemical', 'MESH:C113580', (85, 90))	('mTor', 'Gene', '56717', (126, 130))	('ERK', 'Gene', '26413', (54, 57))	('mTor', 'Gene', (126, 130))	('phosphorylation', 'MPA', (22, 37))	('PI103', 'Var', (113, 118))
422263	25242356	Pharmaceutical inhibitors of TRPV1 resulted in hyperthermia.	('TRPV1', 'Gene', (29, 34))	('hyperthermia', 'Disease', 'MESH:D005334', (47, 59))	('hyperthermia', 'Phenotype', 'HP:0001945', (47, 59))	('hyperthermia', 'Disease', (47, 59))	('inhibitors', 'Var', (15, 25))
422264	25242356	Opioids by cross talking with both the TRPV1 signal cascade and cytokine or chemokine receptors signal cascades reduce pain sensation at the cost of immune competence.	('reduce pain sensation', 'Phenotype', 'HP:0007328', (112, 133))	('TRPV1', 'Gene', (39, 44))	('reduce', 'NegReg', (112, 118))	('pain', 'Phenotype', 'HP:0012531', (119, 123))	('pain', 'Disease', 'MESH:D010146', (119, 123))	('cross talking', 'Var', (11, 24))	('pain', 'Disease', (119, 123))
422285	24810959	demonstrated that WT1 represses the splice factor kinase SRPK1, whose target, SRSF1, directly regulates the splicing of VEGF, specifically the utilization of either exon 8a or exon 8b in the mature mRNA.	('regulates', 'Reg', (94, 103))	('SRSF1', 'Gene', (78, 83))	('exon 8b', 'Var', (176, 183))	('rat', 'Species', '10116', (7, 10))	('VEGF', 'Gene', (120, 124))	('exon 8a', 'Var', (165, 172))	('splicing', 'MPA', (108, 116))	('SRPK1', 'Gene', (57, 62))	('utilization', 'MPA', (143, 154))
422302	24810959	Vessels in tumors arising from SKWT1A cells are slender, tortuous, and highly branched (Figure 2A) whereas those in tumors arising from SKWT1D cells are wide and long, with few branches, but readily apparent vascular sprouts and filopodial extensions (Figure 2A).	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('SKWT1A', 'Var', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
422305	24810959	Silencing of WT1 resulted in significantly less CD31-positive area in MHHshRNA tumors (0.48+-0.075%) compared with MHHNC tumors (7.4+-2.2%; p=0.006; Figure 2C).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('CD31-positive area', 'MPA', (48, 66))	('MHHNC tumors', 'Disease', 'MESH:D009369', (115, 127))	('MHHNC tumors', 'Disease', (115, 127))	('WT1', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('less', 'NegReg', (43, 47))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Silencing', 'Var', (0, 9))	('MHHshRNA', 'Disease', (70, 78))
422306	24810959	Interestingly, there were no morphologic differences in the vessels seen in tumors arising from MHHshRNA cells compared with tumors arising from MHHNC cells.	('MHHshRNA', 'Var', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
422307	24810959	Thus, in these Ewing sarcoma xenografts, modulating WT1 expression has a significant effect on the extent of tumor vasculature, and in conditions that alter the relative expression of isoforms, vascular morphology is also affected.	('Ewing sarcoma xenografts', 'Disease', (15, 39))	('vascular morphology', 'CPA', (194, 213))	('affected', 'Reg', (222, 230))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (15, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('Ewing sarcoma xenografts', 'Disease', 'MESH:C563168', (15, 39))	('expression', 'Species', '29278', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('effect', 'Reg', (85, 91))	('expression', 'Species', '29278', (170, 180))	('modulating', 'Var', (41, 51))	('WT1', 'Gene', (52, 55))	('tumor', 'Disease', (109, 114))
422309	24810959	Vessels in tumors derived from SKWT1A cells are slender and highly branched, whereas vessels in tumors derived from SKWT1D cells are wider, with less branching (Figure 2A).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('SKWT1A', 'Var', (31, 37))
422310	24810959	VEGF, the major factor regulating tumor vascularity, is subject to alternate splicing, resulting in expression of a variety of splice variants which can induce different vascular morphologies.	('splice variants', 'Var', (127, 142))	('tumor', 'Disease', (34, 39))	('expression', 'Species', '29278', (100, 110))	('induce', 'Reg', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('resulting', 'Reg', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
422318	24810959	Of the 90 genes on the array, 18 genes were decreased in expression by 50% or more upon silencing of WT1 (Figure 4A).	('expression', 'MPA', (57, 67))	('expression', 'Species', '29278', (57, 67))	('silencing', 'Var', (88, 97))	('decreased', 'NegReg', (44, 53))
422325	24810959	SKWT1A and SKWT1D tumors have significantly more WT1, VEGF, MMP9, Ang1, and Tie2, as assessed by immunohistochemistry than did SKNC tumors (Figure 5).	('SKWT1D tumors', 'Disease', (11, 24))	('more', 'PosReg', (44, 48))	('MMP9', 'Gene', '4318', (60, 64))	('SKWT1A', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('WT1', 'CPA', (49, 52))	('SKNC tumors', 'Disease', 'MESH:D009369', (127, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('VEGF', 'CPA', (54, 58))	('SKNC tumors', 'Disease', (127, 138))	('SKWT1D tumors', 'Disease', 'MESH:D009369', (11, 24))	('MMP9', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
422340	24810959	Tumor growth was substantially diminished by knockdown of WT1 expression.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('expression', 'Species', '29278', (62, 72))	('diminished', 'NegReg', (31, 41))	('Tumor growth', 'CPA', (0, 12))	('knockdown', 'Var', (45, 54))
422364	24810959	In a Ewing sarcoma xenograft model, we found that tumors which express high levels of WT1 demonstrate increased angiogenesis, while suppression of WT1 dramatically diminishes angiogenesis.	('rat', 'Species', '10116', (97, 100))	('diminishes', 'NegReg', (164, 174))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (5, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (5, 18))	('angiogenesis', 'CPA', (112, 124))	('WT1', 'Gene', (86, 89))	('high levels', 'Var', (71, 82))	('angiogenesis', 'CPA', (175, 187))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('increased', 'PosReg', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('Ewing sarcoma', 'Disease', (5, 18))
422371	24810959	There are several lines of evidence that support a role for WT1 in regulating tumor angiogenesis: 1) WT1 expression has been demonstrated in tumor endothelial cells in a wide variety of common tumors as well as in tumors derived from endothelial cells, such as Kaposi sarcoma and angiosarcoma; 2) our work and work from other labs has demonstrated that WT1 directly regulates the expression of VEGF, the major cytokine regulating blood vessel growth; 3) WT1 expression can be regulated by hypoxia, and we have shown that knocking down WT1 expression with shRNA diminishes the HIF-1-mediated response to hypoxia, suggesting a functional role for WT1 in the response to hypoxia.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('angiosarcoma', 'Disease', 'MESH:D006394', (280, 292))	('hypoxia', 'Disease', 'MESH:D000860', (489, 496))	('rat', 'Species', '10116', (342, 345))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('expression', 'Species', '29278', (458, 468))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('angiosarcoma', 'Phenotype', 'HP:0200058', (280, 292))	('hypoxia', 'Disease', (668, 675))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('angiosarcoma', 'Disease', (280, 292))	('diminishes', 'NegReg', (561, 571))	('tumor', 'Disease', (193, 198))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (261, 275))	('hypoxia', 'Disease', (603, 610))	('hypoxia', 'Disease', 'MESH:D000860', (668, 675))	('rat', 'Species', '10116', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('expression', 'Species', '29278', (105, 115))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', (78, 83))	('Kaposi sarcoma', 'Disease', (261, 275))	('knocking down', 'Var', (521, 534))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('hypoxia', 'Disease', (489, 496))	('hypoxia', 'Disease', 'MESH:D000860', (603, 610))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (141, 146))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (261, 275))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('tumors', 'Disease', (193, 199))	('expression', 'Species', '29278', (380, 390))	('expression', 'Species', '29278', (539, 549))	('WT1', 'Gene', (535, 538))	('shRNA', 'Gene', (555, 560))
422379	24810959	Further support for this hypothesis comes from our angiogenesis array experiments, which demonstrate that suppression of WT1 in Ewing sarcoma cells reduces expression of a significant number of pro-angiogenic genes.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('expression of a', 'MPA', (156, 171))	('reduces', 'NegReg', (148, 155))	('expression', 'Species', '29278', (156, 166))	('rat', 'Species', '10116', (96, 99))	('suppression', 'Var', (106, 117))	('Ewing sarcoma', 'Disease', (128, 141))	('WT1', 'Gene', (121, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
422384	24810959	Vessels in tumors expressing exclusively WT1A are slender, tortuous, and highly branched, whereas those found in tumors expressing exclusively WT1D are wide and long, with few branches, but readily apparent vascular sprouts and filopodial extensions.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('WT1A', 'Var', (41, 45))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
422386	24810959	Alternative splicing of the VEGF mRNA results in the expression of multiple different protein isoforms with distinct biological properties.	('Alternative splicing', 'Var', (0, 20))	('expression', 'Species', '29278', (53, 63))	('results in', 'Reg', (38, 48))	('expression', 'MPA', (53, 63))
422392	24810959	Our work clearly shows that, in the context of Ewing sarcoma, WT1 is pro-angiogenic.	('Ewing sarcoma', 'Disease', (47, 60))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (47, 60))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (47, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('pro-angiogenic', 'CPA', (69, 83))	('WT1', 'Var', (62, 65))
422420	24810959	QPCR Primers for WT1 (PPH00254A), MMP9 (PPH00152E), and beta-2-microglobulin (PPH01094E) were obtained from SABiosciences (Frederick, MD).	('MMP9', 'Gene', '4318', (34, 38))	('MMP9', 'Gene', (34, 38))	('PPH00152E', 'Var', (40, 49))	('PPH00254A', 'Var', (22, 31))	('PPH01094E', 'Var', (78, 87))
422512	33509178	Development and validation of prognostic markers in sarcomas base on a multi-omics analysis In sarcomas, the DNA copy number and DNA methylation exhibit genomic aberrations.	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('methylation', 'Var', (133, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcomas', 'Disease', 'MESH:D012509', (95, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('sarcomas', 'Disease', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('sarcomas', 'Disease', (95, 103))
422519	33509178	Four molecular subtypes (iC1, iC2, iC3, and iC4) with different prognostic significances were identified by multiomics cluster analysis, specifically, iC2 had the worst prognosis and iC4 indicated an immune-enhancing state.	('iC2', 'Gene', (30, 33))	('iC2', 'Gene', (151, 154))	('iC2', 'Gene', '1781', (30, 33))	('iC1', 'Gene', (25, 28))	('iC2', 'Gene', '1781', (151, 154))	('iC4', 'Var', (183, 186))	('iC1', 'Gene', '105259599', (25, 28))
422523	33509178	In addition, the number of silent/nonsilent mutations and neoantigens in iC2 subtype were significantly more than those in iC1/iC3/iC4 subtype, and the same trend was also observed in CNV Gain/Loss.	('neoantigens', 'Var', (58, 69))	('iC1', 'Gene', (123, 126))	('Gain/Loss', 'PosReg', (188, 197))	('iC1', 'Gene', '105259599', (123, 126))	('iC2', 'Gene', (73, 76))	('iC2', 'Gene', '1781', (73, 76))	('silent/nonsilent mutations', 'Var', (27, 53))
422533	33509178	Genomic variations caused by the abnormalities of DNA copy numbers (CNVs) and single nucleotide mutations (SNPs) could lead to tumor development.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('lead to', 'Reg', (119, 126))	('abnormalities', 'Var', (33, 46))	('single nucleotide mutations', 'Var', (78, 105))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('DNA', 'Gene', (50, 53))
422534	33509178	Moreover, epigenetic regulation of DNA methylation on cancer genome also plays a key role in heterogeneous cancer behaviors.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('DNA', 'Gene', (35, 38))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('heterogeneous', 'MPA', (93, 106))	('epigenetic regulation', 'Var', (10, 31))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (107, 113))
422536	33509178	Transcription disorders resulted from copy number changes are potential driving events in sarcoma progression.	('Transcription disorders', 'Disease', (0, 23))	('sarcoma', 'Disease', (90, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('copy number changes', 'Var', (38, 57))	('resulted', 'Reg', (24, 32))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
422537	33509178	In addition, studies of DNA methylation profiles suggested that epigenetic regulation has important biological and clinical significance in sarcoma progression.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('sarcoma', 'Disease', (140, 147))	('epigenetic regulation', 'Var', (64, 85))
422539	33509178	Studies found that the abnormalities of DNA copy number and DNA methylation have important effects on the progression of sarcomas, and the two may also have co-regulatory effects.	('sarcomas', 'Disease', 'MESH:D012509', (121, 129))	('methylation', 'Var', (64, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('progression', 'CPA', (106, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('abnormalities', 'Var', (23, 36))	('sarcomas', 'Disease', (121, 129))	('effects', 'Reg', (91, 98))	('DNA', 'Gene', (40, 43))	('DNA', 'Gene', (60, 63))
422543	33509178	Moreover, further systematic analysis was conducted to identify novel mutations with the potential to serve as therapeutic targets or biomarkers for distinguishing sarcoma subtypes.	('mutations', 'Var', (70, 79))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))
422588	33509178	After analyzing the correlation between gene expression, methylation, and CNV, we found that DEGs were high-expressed in demethylated samples (Fig.	('DEGs', 'Gene', (93, 97))	('demethylated', 'Var', (121, 133))	('DEGs', 'Gene', '8560', (93, 97))	('high-expressed', 'PosReg', (103, 117))
422589	33509178	6c), but this was not observed in CNV, suggesting that the effect of methylation on the expressions of DEGs was stronger than CNV.	('expressions', 'MPA', (88, 99))	('stronger', 'PosReg', (112, 120))	('DEGs', 'Gene', (103, 107))	('methylation', 'Var', (69, 80))	('DEGs', 'Gene', '8560', (103, 107))
422595	33509178	Correspondingly, high-expressed ENO1 was associated with worse prognosis recorded in TCGA and GSE21050 (Fig.	('GSE21050', 'Var', (94, 102))	('high-expressed', 'Var', (17, 31))	('ENO1', 'Gene', (32, 36))	('ENO1', 'Gene', '2023', (32, 36))
422598	33509178	By analyzing the mutant spectrum differences, we found that the number of silent/nonsilent mutations and neoantigens in the iC2 subtype was significantly higher than that in iC1/iC3/iC4 subtype (Fig.	('iC1', 'Gene', (174, 177))	('higher', 'PosReg', (154, 160))	('silent/nonsilent mutations', 'Var', (74, 100))	('iC2', 'Gene', (124, 127))	('iC1', 'Gene', '105259599', (174, 177))	('iC2', 'Gene', '1781', (124, 127))
422599	33509178	These results indicated that genomic instability had an important impact on the prognosis of sarcoma because subtypes with high mutation rate and high CNV were related to worse prognosis.	('high CNV', 'Var', (146, 154))	('sarcoma', 'Disease', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('impact', 'Reg', (66, 72))	('high mutation', 'Var', (123, 136))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
422606	33509178	Study indicated that high-expressed AMPD2 is correlated with poor prognosis of UPS.	('AMPD2', 'Gene', (36, 41))	('UPS', 'Disease', (79, 82))	('AMPD2', 'Gene', '271', (36, 41))	('high-expressed', 'Var', (21, 35))
422608	33509178	In our study, both high-expressed ENO1 and low-expressed APBB1IP were predictive of a poor sarcoma prognosis, suggesting that the three potential prognostic markers were closely associated with known genetic markers.	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('high-expressed', 'Var', (19, 33))	('low-expressed', 'NegReg', (43, 56))	('sarcoma', 'Disease', (91, 98))	('APBB1IP', 'Gene', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('ENO1', 'Gene', '2023', (34, 38))	('ENO1', 'Gene', (34, 38))
422612	33509178	Genomic instability, which is a hallmark of malignancy, could lead to DNA copy number changes in most cancer types.	('malignancy', 'Disease', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('DNA', 'Gene', (70, 73))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('lead to', 'Reg', (62, 69))	('Genomic instability', 'Var', (0, 19))	('malignancy', 'Disease', 'MESH:D009369', (44, 54))
422613	33509178	In viral infection and alcohol-related liver cancer, amplification of the common chromosome 8q24 copy number could cause high expression of the oncogene c-myc, indicating that the development of some liver cancers may be c-myc-dependent.	('liver cancer', 'Disease', (39, 51))	('amplification', 'Var', (53, 66))	('c-myc', 'Gene', (221, 226))	('liver cancers', 'Disease', 'MESH:D006528', (200, 213))	('alcohol', 'Chemical', 'MESH:D000438', (23, 30))	('liver cancers', 'Phenotype', 'HP:0002896', (200, 213))	('liver cancer', 'Disease', 'MESH:D006528', (200, 212))	('c-myc', 'Gene', '4609', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('viral infection', 'Disease', (3, 18))	('c-myc', 'Gene', '4609', (221, 226))	('liver cancer', 'Phenotype', 'HP:0002896', (200, 212))	('cause', 'Reg', (115, 120))	('liver cancers', 'Disease', (200, 213))	('viral infection', 'Disease', 'MESH:D001102', (3, 18))	('liver cancer', 'Disease', 'MESH:D006528', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('c-myc', 'Gene', (153, 158))	('high expression', 'MPA', (121, 136))	('liver cancer', 'Phenotype', 'HP:0002896', (39, 51))
422614	33509178	In addition to copy number abnormalities, DNA methylation is an important regulator of gene transcription and one of the most widely studied epigenetic modifications.	('DNA', 'Var', (42, 45))	('number abnormalities', 'Disease', (20, 40))	('number abnormalities', 'Disease', 'MESH:D007674', (20, 40))
422615	33509178	Hypermethylation of tumor suppressor gene CpG island is commonly detected in tumors and is largely tumor-specific.	('tumors', 'Disease', (77, 83))	('detected', 'Reg', (65, 73))	('tumor', 'Disease', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('CpG island', 'Protein', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (20, 25))
422616	33509178	For example, hypermethylation of the BRCA1 gene CpG island mainly occurs in breast and ovarian cancer, while hypermethylation of the hMLH1 gene is commonly found in colon, stomach and endometrial cancers.	('endometrial cancers', 'Disease', 'MESH:D016889', (184, 203))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (76, 101))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('hMLH1', 'Gene', '4292', (133, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('colon', 'Disease', (165, 170))	('found', 'Reg', (156, 161))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('occurs', 'Reg', (66, 72))	('stomach', 'Disease', (172, 179))	('BRCA1', 'Gene', '672', (37, 42))	('hypermethylation', 'Var', (109, 125))	('hMLH1', 'Gene', (133, 138))	('hypermethylation', 'Var', (13, 29))	('endometrial cancers', 'Disease', (184, 203))	('BRCA1', 'Gene', (37, 42))
422623	33509178	In our study, there were also significant differences in the immune microenvironment of the four molecular subtypes, but the iC4 subtype with the optimal prognosis showed higher scores of the six immune cells than the other subtypes, especially, its scores of lymphocyte infiltration, IFN gamma response and TGF beta response were significantly higher than the other subtypes.	('lymphocyte', 'CPA', (260, 270))	('IFN gamma', 'Gene', (285, 294))	('higher', 'PosReg', (171, 177))	('TGF beta', 'Gene', (308, 316))	('IFN gamma', 'Gene', '3458', (285, 294))	('TGF beta', 'Gene', '7039', (308, 316))	('higher', 'PosReg', (345, 351))	('iC4', 'Var', (125, 128))
422628	33509178	found significantly downregulated expression of ENO1 in NSCLC compared with normal tissues, and indicated that low-expressed ENO1 may suggest a favorable prognosis.	('ENO1', 'Gene', (125, 129))	('ENO1', 'Gene', '2023', (125, 129))	('ENO1', 'Gene', (48, 52))	('expression', 'MPA', (34, 44))	('NSCLC', 'Disease', (56, 61))	('downregulated', 'NegReg', (20, 33))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('low-expressed', 'Var', (111, 124))	('ENO1', 'Gene', '2023', (48, 52))
422635	33509178	APBB1IP is alternatively known as RIAM, silencing RIAM in melanoma cells leads to the inhibition of tumor growth and hinders metastasis in a mouse xenograft model combined with immunodeficiency.	('hinders', 'NegReg', (117, 124))	('RIAM', 'Gene', (34, 38))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('metastasis', 'CPA', (125, 135))	('tumor', 'Disease', (100, 105))	('melanoma', 'Disease', (58, 66))	('RIAM', 'Gene', '54518', (34, 38))	('mouse', 'Species', '10090', (141, 146))	('RIAM', 'Gene', (50, 54))	('immunodeficiency', 'Phenotype', 'HP:0002721', (177, 193))	('silencing', 'Var', (40, 49))	('immunodeficiency', 'Disease', (177, 193))	('immunodeficiency', 'Disease', 'MESH:D007153', (177, 193))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('RIAM', 'Gene', '54518', (50, 54))	('inhibition', 'NegReg', (86, 96))
422637	33509178	In summary, in this study, we analyzed the possible pathogenesis of sarcomas through multi-omics analysis of genomics, epigenomics, and transcriptomics, and discovered that DNA CNV and methylation play important roles in sarcomas.	('sarcomas', 'Disease', (68, 76))	('sarcomas', 'Disease', 'MESH:D012509', (221, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (221, 229))	('roles', 'Reg', (212, 217))	('methylation', 'Var', (185, 196))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('sarcomas', 'Disease', (221, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
422726	32084139	Breakthrough advances using inhibitors of PD-1, PD-L1, and CTLA-4 and chimeric antigen receptor (CAR) T cells have clearly identified immunotherapy as the future of clinical oncology.	('CTLA-4', 'Gene', (59, 65))	('oncology', 'Phenotype', 'HP:0002664', (174, 182))	('PD-1', 'Gene', (42, 46))	('PD-L1', 'Gene', '484186', (48, 53))	('inhibitors', 'Var', (28, 38))	('PD-L1', 'Gene', (48, 53))	('clinical', 'Species', '191496', (165, 173))
422749	32084139	This is particularly relevant in the context of tumor MHC-I expression where MHC-I+ tumor cells elicit greater antigen-specific CD8+ T cell responses and MHC-I loss is a well-established mechanism of tumor immune evasion.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('loss', 'NegReg', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('MHC-I', 'Gene', (154, 159))	('tumor', 'Disease', (200, 205))	('greater', 'PosReg', (103, 110))	('tumor', 'Disease', (84, 89))	('MHC-I+', 'Var', (77, 83))	('CD8', 'Gene', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CD8', 'Gene', '925', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
422759	32084139	(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Robert Cantor and colleagues have previously shown that radiation therapy sensitizes tumor cells, including osteosarcoma to NK cell-mediated cytoctoxicity.	('toxicity', 'Disease', 'MESH:D064420', (236, 244))	('toxicity', 'Disease', (236, 244))	('tumor', 'Disease', (175, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('osteosarcoma', 'Phenotype', 'HP:0002669', (198, 210))	('radiation therapy', 'Var', (146, 163))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('sensitizes', 'Reg', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('osteosarcoma', 'Disease', (198, 210))	('osteosarcoma', 'Disease', 'MESH:D012516', (198, 210))
422799	32084139	However, we completely agree with the reviewer that this is an important area for future study in dog immunotherapy as these haplotypes have clearly been shown to influence CD8 T cell and NK cell effector function in human immunotherapy studies.	('influence', 'Reg', (163, 172))	('haplotypes', 'Var', (125, 135))	('CD8', 'Gene', '925', (173, 176))	('human', 'Species', '9606', (217, 222))	('dog', 'Species', '9615', (98, 101))	('CD8', 'Gene', (173, 176))
422848	29333027	The Ewing's family of tumors is associated with translocation t (11; 22) (q24; q12) in 85% of cases.	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('translocation t (11; 22) (q24; q12', 'Var', (48, 82))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
422883	24285434	The most common abnormality is PHF1 gene rearrangement (80%), being present in benign, atypical and malignant lesions, with fusion to EP400 in 44% of cases.	('EP400', 'Gene', (134, 139))	('rearrangement', 'Var', (41, 54))	('PHF1', 'Gene', (31, 35))	('PHF1', 'Gene', '5252', (31, 35))	('EP400', 'Gene', '57634', (134, 139))
422884	24285434	ZC3H7B-BCOR and MEAF6-PHF1 fusions occurred predominantly in S100 protein-negative and malignant OFMT.	('PHF1', 'Gene', (22, 26))	('BCOR', 'Gene', (7, 11))	('PHF1', 'Gene', '5252', (22, 26))	('BCOR', 'Gene', '54880', (7, 11))	('MEAF6', 'Gene', '64769', (16, 21))	('S100 protein-negative', 'Protein', (61, 82))	('ZC3H7B', 'Gene', (0, 6))	('MEAF6', 'Gene', (16, 21))	('ZC3H7B', 'Gene', '23264', (0, 6))	('fusions', 'Var', (27, 34))	('occurred', 'Reg', (35, 43))
422919	24285434	FusionSeq identified a ZC3H7B-BCOR fusion as the top candidate in OFMT1, a malignant OFMT (Figs.	('BCOR', 'Gene', '54880', (30, 34))	('OFMT1', 'Disease', (66, 71))	('ZC3H7B', 'Gene', '23264', (23, 29))	('BCOR', 'Gene', (30, 34))	('fusion', 'Var', (35, 41))	('ZC3H7B', 'Gene', (23, 29))
422920	24285434	Alignment of the reads suggested a fusion of ZC3H7B exon 10 with exon 7 of BCOR, fusion transcript sequence, which was then confirmed by RT-PCR (Fig.	('ZC3H7B', 'Gene', (45, 51))	('fusion', 'Var', (35, 41))	('BCOR', 'Gene', (75, 79))	('ZC3H7B', 'Gene', '23264', (45, 51))	('BCOR', 'Gene', '54880', (75, 79))
422921	24285434	Furthermore, FISH analysis using a fusion-assay showed rearrangements in both ZC3H7B and BCOR genes (Fig.	('BCOR', 'Gene', '54880', (89, 93))	('ZC3H7B', 'Gene', (78, 84))	('ZC3H7B', 'Gene', '23264', (78, 84))	('rearrangements', 'Var', (55, 69))	('BCOR', 'Gene', (89, 93))
422923	24285434	Remaining PHF1-negative cases were tested for BCOR gene abnormalities by FISH and one additional case was identified, OFMT2 (Table 1); however this lacked a break-apart signal in ZC3H7B.	('PHF1', 'Gene', (10, 14))	('BCOR', 'Gene', (46, 50))	('abnormalities', 'Var', (56, 69))	('ZC3H7B', 'Gene', (179, 185))	('PHF1', 'Gene', '5252', (10, 14))	('BCOR', 'Gene', '54880', (46, 50))	('lacked', 'NegReg', (148, 154))	('ZC3H7B', 'Gene', '23264', (179, 185))
422925	24285434	Alignment of the reads suggested a fusion of MEAF6 exon 5 with exon 2 of PHF1, which was confirmed by RT-PCR (Fig.	('MEAF6', 'Gene', (45, 50))	('PHF1', 'Gene', (73, 77))	('PHF1', 'Gene', '5252', (73, 77))	('fusion', 'Var', (35, 41))	('MEAF6', 'Gene', '64769', (45, 50))
422929	24285434	Two additional cases were positive for a MEAF6-PHF1 fusion (Fig 4, Table 1).	('PHF1', 'Gene', (47, 51))	('PHF1', 'Gene', '5252', (47, 51))	('fusion', 'Var', (52, 58))	('MEAF6', 'Gene', '64769', (41, 46))	('MEAF6', 'Gene', (41, 46))
422933	24285434	PHF1 gene rearrangements were identified in 31/39 cases (80%).	('rearrangements', 'Var', (10, 24))	('PHF1', 'Gene', '5252', (0, 4))	('PHF1', 'Gene', (0, 4))
422935	24285434	As EPC1 and JAZF1 have been described as additional gene partners involved in PHF1 fusions in ESS, we hypothesized that similar gene fusions may be implicated in OFMT with PHF1 gene rearrangements.	('JAZF1', 'Gene', (12, 17))	('PHF1', 'Gene', '5252', (78, 82))	('PHF1', 'Gene', (172, 176))	('involved', 'Reg', (66, 74))	('PHF1', 'Gene', '5252', (172, 176))	('PHF1', 'Gene', (78, 82))	('ESS', 'Disease', (94, 97))	('fusions', 'Var', (83, 90))
422951	24285434	Gebre-Medhin et al recently identified the presence of PHF1 gene rearrangements on 6p21 in more than half of the OFMT lesions tested, with higher incidence in benign lesions (4/4) compared to malignant OFTs (1/6).	('PHF1', 'Gene', '5252', (55, 59))	('PHF1', 'Gene', (55, 59))	('rearrangements', 'Var', (65, 79))
422954	24285434	Furthermore, a very recent study screening a larger cohort of 41 OFMTs confirmed the incidence of PHF1 gene rearrangements by FISH at nearly 50%, including roughly similar percentages of typical, atypical, and malignant tumors.	('PHF1', 'Gene', (98, 102))	('PHF1', 'Gene', '5252', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('rearrangements', 'Var', (108, 122))	('malignant tumors', 'Disease', (210, 226))	('malignant tumors', 'Disease', 'MESH:D018198', (210, 226))
422955	24285434	The recurrent PHF1 abnormalities identified in both typical and malignant OFMTs suggest a shared pathogenesis for these lesions and suggest the utility of FISH testing for PHF1 gene rearrangements when diagnosing morphologically challenging cases.	('PHF1', 'Gene', (14, 18))	('rearrangements', 'Var', (182, 196))	('PHF1', 'Gene', (172, 176))	('abnormalities', 'Var', (19, 32))	('PHF1', 'Gene', '5252', (14, 18))	('PHF1', 'Gene', '5252', (172, 176))
422958	24285434	RNA sequencing, followed by FusionSeq data analysis, in one of the index cases (OFMT1) showed the presence of a t(X;22)(p11;q13) translocation resulting in a ZC3H7B-BCOR fusion.	('ZC3H7B', 'Gene', (158, 164))	('BCOR', 'Gene', '54880', (165, 169))	('t(X;22)(p11;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 128))	('ZC3H7B', 'Gene', '23264', (158, 164))	('t(X;22)(p11;q13', 'Var', (112, 127))	('BCOR', 'Gene', (165, 169))
422960	24285434	Interestingly of the three patients with available karyotypes in the study of Gebre-Medhin et al, two cases that were positive for PHF1 gene rearrangements but negative for EP400 by FISH, showed an Xp11 locus abnormality, either involving a standard translocation with 6p, or in a three-way exchange with chromosomes 6 and 7.	('rearrangements', 'Var', (141, 155))	('EP400', 'Gene', '57634', (173, 178))	('patients', 'Species', '9606', (27, 35))	('EP400', 'Gene', (173, 178))	('PHF1', 'Gene', (131, 135))	('involving', 'Reg', (229, 238))	('PHF1', 'Gene', '5252', (131, 135))	('Xp11', 'Var', (198, 202))
422962	24285434	BCOR gene rearrangements have recently been described in a subset of small blue round cell tumors, as the 5' fusion partner to CCNB3 (encoding the testis-specific cyclin B3, which induces oncogenic activation of the CCNB3 protein.	('protein', 'Protein', (222, 229))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('BCOR', 'Gene', '54880', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('activation', 'PosReg', (198, 208))	('rearrangements', 'Var', (10, 24))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('BCOR', 'Gene', (0, 4))	('CCNB3', 'Gene', (127, 132))
422963	24285434	In contrast, in the OFMT setting, BCOR, encoding for BCL6 co-repressor, is the 3' partner in the fusion with ZC3H7B, resulting in BCOR mRNA expression, suggesting a different mechanism of oncogenesis.	('mRNA expression', 'MPA', (135, 150))	('BCOR', 'Gene', '54880', (34, 38))	('ZC3H7B', 'Gene', '23264', (109, 115))	('BCOR', 'Gene', (130, 134))	('fusion', 'Var', (97, 103))	('BCOR', 'Gene', (34, 38))	('BCOR', 'Gene', '54880', (130, 134))	('ZC3H7B', 'Gene', (109, 115))
422965	24285434	PHF1 rearrangements have previously been associated with endometrial stromal sarcoma (ESS), in that context being fused with either JAZF1 or EPC1.	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (57, 84))	('associated', 'Reg', (41, 51))	('PHF1', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('PHF1', 'Gene', '5252', (0, 4))	('endometrial stromal sarcoma', 'Disease', (57, 84))	('rearrangements', 'Var', (5, 19))
422966	24285434	The JAZF1-PHF1 and EPC1-PHF1 fusions account for a minority (9%) of ESS cases and have not been detected in benign endometrial stromal nodules.	('PHF1', 'Gene', (10, 14))	('PHF1', 'Gene', (24, 28))	('fusions', 'Var', (29, 36))	('PHF1', 'Gene', '5252', (24, 28))	('PHF1', 'Gene', '5252', (10, 14))	('ESS', 'Disease', (68, 71))
422969	24285434	Furthermore, similar with ESS pathogenesis, it appears that translocation genes involved in acetylation (MEAF6, EPC1) and methylation (PHF1) have a role in the neoplastic development of OFMT.	('OFMT', 'Disease', (186, 190))	('role', 'Reg', (148, 152))	('acetylation', 'MPA', (92, 103))	('MEAF6', 'Gene', (105, 110))	('PHF1', 'Gene', (135, 139))	('MEAF6', 'Gene', '64769', (105, 110))	('PHF1', 'Gene', '5252', (135, 139))	('neoplastic development', 'CPA', (160, 182))	('translocation', 'Var', (60, 73))
422975	24285434	With these additional gene fusions, the majority (85%) of OFMTs with classic morphologic appearances demonstrated recurrent gene rearrangements, regardless of the degree of malignancy, presence of ossification or immunoprofile, which can therefore be used as molecular markers in challenging cases.	('gene rearrangements', 'Var', (124, 143))	('malignancy', 'Disease', 'MESH:D009369', (173, 183))	('malignancy', 'Disease', (173, 183))
422976	24285434	ZC3H7B-BCOR, MEAF6-PHF1 and EPC1-PHF1 fusions occurred predominantly in S100 protein-negative and malignant OFMT.	('BCOR', 'Gene', (7, 11))	('PHF1', 'Gene', '5252', (19, 23))	('BCOR', 'Gene', '54880', (7, 11))	('ZC3H7B', 'Gene', (0, 6))	('occurred', 'Reg', (46, 54))	('PHF1', 'Gene', (19, 23))	('PHF1', 'Gene', '5252', (33, 37))	('MEAF6', 'Gene', '64769', (13, 18))	('ZC3H7B', 'Gene', '23264', (0, 6))	('malignant OFMT', 'CPA', (98, 112))	('MEAF6', 'Gene', (13, 18))	('PHF1', 'Gene', (33, 37))	('S100 protein-negative', 'Protein', (72, 93))	('fusions', 'Var', (38, 45))
423012	23582396	Molecular studies carried this burden by convincingly showing that patients with Merkel cell polyomavirus and Merkel cell carcinoma undergo stepwise molecular changes that include loss of immune surveillance, clonal viral integration into the host genome, and mutation to the virus itself.	('immune surveillance', 'CPA', (188, 207))	('patients', 'Species', '9606', (67, 75))	('loss', 'NegReg', (180, 184))	('mutation', 'Var', (260, 268))	('Merkel cell polyomavirus', 'Species', '493803', (81, 105))	('clonal viral integration', 'CPA', (209, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (110, 131))	('Merkel cell carcinoma', 'Disease', (110, 131))
423013	23582396	The possibility that cancers can arise from mutations to a commensal virus rather than the host cell could fundamentally change our searches for the causes of human cancers.	('men', 'Species', '9606', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('change', 'Reg', (121, 127))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('mutations', 'Var', (44, 53))	('cancers', 'Disease', (21, 28))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('men', 'Species', '9606', (112, 115))	('cancers', 'Disease', (165, 172))	('arise', 'Reg', (33, 38))
423261	32846908	Multi-agent chemotherapy was associated with improved OS in several subgroups, including patients with larger tumors (>5 cm), those treated at high-volume centers, or those who received radiation.	('Multi-agent', 'Var', (0, 11))	('improved', 'PosReg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('patients', 'Species', '9606', (89, 97))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))
423279	32846908	Consistent with prior meta-analyses, a Cox proportional hazards model demonstrated decreased OS survival associated with single-agent chemotherapy use when compared to no chemotherapy (HR 1.49; 95% CI 1.06-2.10).	('HR 1.49', 'Disease', 'OMIM:617237', (185, 192))	('decreased', 'NegReg', (83, 92))	('HR 1.49', 'Disease', (185, 192))	('single-agent chemotherapy use', 'Var', (121, 150))
423286	32846908	Of note, younger patients were not more likely to benefit from multi-agent chemotherapy; in fact, we observed that for patients >=70 years of age and for African American patients, multi-agent chemotherapy was associated with improved survival.	('improved', 'PosReg', (226, 234))	('multi-agent chemotherapy', 'Var', (181, 205))	('patients', 'Species', '9606', (119, 127))	('patients', 'Species', '9606', (171, 179))	('survival', 'MPA', (235, 243))	('patients', 'Species', '9606', (17, 25))
423329	32846908	As a result that our data suggested that single-agent chemotherapy was associated with decreased OS, we excluded these patients from our analysis of the association between neoadjuvant versus adjuvant chemotherapy use and survival (Figure 1).	('patients', 'Species', '9606', (119, 127))	('single-agent chemotherapy', 'Var', (41, 66))	('decreased', 'NegReg', (87, 96))
423349	32846908	; formal analysis, D.S.G., R.v.D., N.J.J., B.J.D., M.A.E., S.D.N., B.C., J.E.S., A.S.S., F.C.E., and A.K.	('J.E.S.', 'Var', (73, 79))	('F.C.E.', 'Var', (89, 95))	('B.C.', 'Var', (67, 71))	('M.A.E.', 'Var', (51, 57))	('J.E.S', 'CellLine', 'CVCL:0355', (73, 78))
423415	25329465	Unexpectedly, lysosomal targeting also blocked cell growth and reduced the invasive potential of rhabdomyosarcoma CSC, even at very low doses of omeprazole (10 and 50 microM, respectively).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('rhabdomyosarcoma CSC', 'Disease', (97, 117))	('reduced', 'NegReg', (63, 70))	('lysosomal', 'Var', (14, 23))	('blocked', 'NegReg', (39, 46))	('omeprazole', 'Chemical', 'MESH:D009853', (145, 155))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (97, 113))	('rhabdomyosarcoma CSC', 'Disease', 'MESH:D012208', (97, 117))	('cell growth', 'CPA', (47, 58))	('invasive potential', 'CPA', (75, 93))
423430	25329465	In fact, accumulation of basic drugs into acidic vesicles, or their neutralization through acidification of the extracellular environment is an effective mechanism of chemoresistance and may facilitate tumor invasion.	('tumor', 'Disease', (202, 207))	('accumulation', 'PosReg', (9, 21))	('facilitate', 'PosReg', (191, 201))	('basic', 'Var', (25, 30))	('chemoresistance', 'CPA', (167, 182))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('acidification', 'MPA', (91, 104))	('neutralization', 'MPA', (68, 82))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
423446	25329465	The expression of mRNA for OCT3/4 (NM_002701.4), NANOG (NM_024865.2), MDR1 (AF016535.1), ATPase V0c (NM_001101.2), matrix metalloproteinase (MMP) 9 (NM_004994.2), and CXC chemokine receptor-4 (CXCR4) (NM_001008540.1) was evaluated using a Light Cycler instrument (Roche Diagnostics), amplifying 1 microg of cDNA, and the Universal Probe Library (Roche Applied Science).	('MDR1', 'Gene', '5243', (70, 74))	('ATPase', 'Gene', '1769', (89, 95))	('OCT3/4', 'Gene', '5460', (27, 33))	('NM_024865.2', 'Var', (56, 67))	('ATPase', 'Gene', (89, 95))	('CXCR4', 'Gene', (193, 198))	('NANOG', 'Gene', '79923', (49, 54))	('OCT3/4', 'Gene', (27, 33))	('CXC chemokine receptor-4', 'Gene', '7852', (167, 191))	('NM_002701.4', 'Var', (35, 46))	('matrix metalloproteinase (MMP) 9', 'Gene', '4318', (115, 147))	('NM_001101.2', 'Var', (101, 112))	('CXC chemokine receptor-4', 'Gene', (167, 191))	('MDR1', 'Gene', (70, 74))	('NANOG', 'Gene', (49, 54))	('NM_001008540.1', 'Var', (201, 215))	('AF016535.1', 'Var', (76, 86))	('CXCR4', 'Gene', '7852', (193, 198))
423466	25329465	To characterize the profile of AO emission spectra, the red band contribution (R%) within the whole emission spectrum was calculated as follows: R% = 100I 655/(I 655/I 530) where I 655 and I 530 are the green (520-540 nm) and the red (645-665 nm) integrated emission intensities, respectively.	('I 655', 'Var', (179, 184))	('I 530', 'Var', (189, 194))	('AO', 'Chemical', 'MESH:D000165', (31, 33))
423489	25329465	After 24 h, the reduction of mRNA level for the V0c ATPase was verified by Real Time PCR, as previously described.	('ATPase', 'Gene', '1769', (52, 58))	('V0c', 'Var', (48, 51))	('reduction', 'NegReg', (16, 25))	('ATPase', 'Gene', (52, 58))	('mRNA level', 'MPA', (29, 39))
423506	25329465	MDR1 mRNA (Figure 2D; p = 0.0339 MG-63-DXR100 vs RD and p = 0.0253 MG-63-DXR100 vs spheres) and P-glycoprotein (Figure 2E) were both undetectable in rhabdospheres and native RD cells, suggesting the existence of a different mechanism for the reduced sensitivity to DXR in these cells.	('P-glycoprotein', 'Gene', '5243', (96, 110))	('P-glycoprotein', 'Gene', (96, 110))	('MDR1', 'Gene', (0, 4))	('MDR1', 'Gene', '5243', (0, 4))	('p = 0.0253 MG-63-DXR100', 'Var', (56, 79))
423517	25329465	On the other hand, treatment with OME 100 microM induced a significantly increased in the number of cells in G0-G1 phase, with a corresponding decrease in the S phase (Figure 4E; p = 0.0163).	('increased', 'PosReg', (73, 82))	('decrease', 'NegReg', (143, 151))	('OME', 'Chemical', 'MESH:D009853', (34, 37))	('S phase', 'CPA', (159, 166))	('OME 100 microM', 'Var', (34, 48))
423527	25329465	This result suggests that inhibition of V-ATPase induces an increase of intracellular DXR, in turn, leading to an increase of its nuclear concentration and cytotoxicity.	('intracellular DXR', 'MPA', (72, 89))	('cytotoxicity', 'Disease', (156, 168))	('increase', 'PosReg', (114, 122))	('V-ATPase', 'Gene', '1769', (40, 48))	('inhibition', 'Var', (26, 36))	('cytotoxicity', 'Disease', 'MESH:D064420', (156, 168))	('increase', 'PosReg', (60, 68))	('nuclear concentration', 'MPA', (130, 151))	('V-ATPase', 'Gene', (40, 48))
423550	25329465	An aberrant ion pumping mediated by proton transporters may be responsible not only for an increased lysosomal acidity, but also for an altered pH gradient across the plasma membrane that can, in turn, obstacle the DXR intracellular uptake also by an alternative mechanism, the alteration of the surface pressure and permeability of the cytoplasmic membrane, like elegantly demonstrated by other authors.	('surface pressure', 'MPA', (296, 312))	('aberrant', 'Var', (3, 11))	('lysosomal acidity', 'MPA', (101, 118))	('DXR intracellular uptake', 'MPA', (215, 239))	('obstacle', 'Reg', (202, 210))	('ion pumping', 'MPA', (12, 23))	('permeability', 'MPA', (317, 329))	('increased', 'PosReg', (91, 100))	('altered', 'Reg', (136, 143))	('pH', 'Gene', '5250', (144, 146))
423598	33889298	Hippo pathway dysregulation is an important impetus for uncontrolled cell growth or neoplasia.	('Hippo', 'Gene', (0, 5))	('neoplasia', 'Disease', (84, 93))	('dysregulation', 'Var', (14, 27))	('neoplasia', 'Phenotype', 'HP:0002664', (84, 93))	('Hippo', 'Gene', '37247', (0, 5))	('neoplasia', 'Disease', 'MESH:D009369', (84, 93))
423602	33889298	In epithelioid hemangioendothelioma (EHE), a vascular sarcoma, a WWTR1-CAMTA1 gene fusion encodes a constitutively activated form of TAZ (TAZ-CAMTA1 fusion protein) that activates a TAZ-like transcriptional program.	('vascular sarcoma', 'Disease', 'MESH:D012509', (45, 61))	('WWTR1', 'Gene', '25937', (65, 70))	('EHE', 'Phenotype', 'HP:0032060', (37, 40))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (3, 35))	('CAMTA1', 'Gene', (71, 77))	('activates', 'PosReg', (170, 179))	('hemangioendothelioma', 'Disease', 'MESH:D006390', (15, 35))	('CAMTA1', 'Gene', '23261', (142, 148))	('vascular sarcoma', 'Disease', (45, 61))	('CAMTA1', 'Gene', '23261', (71, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('fusion', 'Var', (83, 89))	('WWTR1', 'Gene', (65, 70))	('hemangioendothelioma', 'Disease', (15, 35))	('CAMTA1', 'Gene', (142, 148))	('TAZ-like transcriptional program', 'Pathway', (182, 214))
423606	33889298	Alterations of the p53 pathway are among the most frequent aberrations observed in human cancers, including sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('Alterations', 'Var', (0, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('human', 'Species', '9606', (83, 88))	('sarcomas', 'Disease', (108, 116))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('p53 pathway', 'Pathway', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
423608	33889298	Individuals with Li-Fraumeni syndrome (LFS) have inherited mutations in TP53 and are prone to the development of multiple tumor types at an early age.	('LFS', 'Disease', (39, 42))	('TP53', 'Gene', '7157', (72, 76))	('LFS', 'Disease', 'MESH:D016864', (39, 42))	('multiple tumor', 'Disease', (113, 127))	('TP53', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutations', 'Var', (59, 68))	('multiple tumor', 'Disease', 'MESH:D009369', (113, 127))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (17, 37))	('prone', 'Reg', (85, 90))	('Li-Fraumeni syndrome', 'Disease', (17, 37))
423610	33889298	Alterations in the p53 pathway also appear to confer a metastatic advantage with regard to sarcomas and thus a poor overall survival and prognosis.	('metastatic advantage', 'CPA', (55, 75))	('Alterations', 'Var', (0, 11))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('p53 pathway', 'Pathway', (19, 30))	('sarcomas', 'Disease', (91, 99))
423612	33889298	As such, the amplification of the MDM2 gene region in several sarcomas including well-differentiated liposarcoma/dedifferentiated liposarcoma, parosteal and low-grade central osteosarcoma, and intimal sarcomas represents an effective mechanism of p53 inactivation.	('amplification', 'Var', (13, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcomas', 'Disease', 'MESH:D012509', (62, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (175, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('liposarcoma', 'Phenotype', 'HP:0012034', (101, 112))	('liposarcoma/dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (101, 141))	('MDM2', 'Gene', (34, 38))	('sarcomas', 'Disease', (62, 70))	('liposarcoma', 'Phenotype', 'HP:0012034', (130, 141))	('sarcomas', 'Disease', 'MESH:D012509', (201, 209))	('sarcomas', 'Phenotype', 'HP:0100242', (201, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('sarcomas', 'Disease', (201, 209))	('inactivation', 'NegReg', (251, 263))	('osteosarcoma', 'Disease', (175, 187))	('osteosarcoma', 'Disease', 'MESH:D012516', (175, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('liposarcoma/dedifferentiated liposarcoma', 'Disease', (101, 141))
423616	33889298	In pancreatic neuroendocrine tumors, RABL6A activates Akt signaling through PP2A inactivation and drives G1 to S phase progression via inactivation of the retinoblastoma (RB1) tumor suppressor.	('G1 to S phase', 'MPA', (105, 118))	('drives', 'PosReg', (98, 104))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (14, 35))	('Akt', 'Gene', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('PP2A', 'Gene', (76, 80))	('RABL6A', 'Var', (37, 43))	('Akt', 'Gene', '207', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('retinoblastoma', 'Phenotype', 'HP:0009919', (155, 169))	('inactivation', 'NegReg', (81, 93))	('RABL6A', 'Chemical', '-', (37, 43))	('inactivation', 'NegReg', (135, 147))	('activates', 'PosReg', (44, 53))	('retinoblastoma (RB1) tumor suppressor', 'Gene', '5925', (155, 192))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (3, 35))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PP2A', 'Gene', '5524', (76, 80))	('pancreatic neuroendocrine tumors', 'Disease', (3, 35))
423626	33889298	Strong detection of p53 in tumors typically correlates with TP53 genetic mutations that impair MDM2-mediated degradation of the protein.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('MDM2-mediated degradation of the protein', 'MPA', (95, 135))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('TP53', 'Gene', '7157', (60, 64))	('genetic mutations', 'Var', (65, 82))	('impair', 'NegReg', (88, 94))	('TP53', 'Gene', (60, 64))
423655	33889298	RABL6A had a slightly higher hazard ratio (HR = 1.51; p = 0.0028) than TAZ by univariate analysis and was the only protein that independently predicted poorer metastasis free survival by multivariate analysis (HR = 1.42; p = 0.0350) (Figure 4B).	('higher', 'PosReg', (22, 28))	('metastasis free survival', 'CPA', (159, 183))	('RABL6A', 'Var', (0, 6))	('RABL6A', 'Chemical', '-', (0, 6))	('poorer', 'NegReg', (152, 158))
423658	33889298	A log-rank test comparing the highest and lowest tertiles of RABL6A expression (Figure 4D) demonstrated that high RABL6A expression portended a poorer prognosis in sarcomas compared to those with low RABL6A expression (p = 0.03).	('RABL6A', 'Chemical', '-', (114, 120))	('RABL6A', 'Gene', (114, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('high', 'Var', (109, 113))	('RABL6A', 'Chemical', '-', (200, 206))	('RABL6A', 'Chemical', '-', (61, 67))	('sarcomas', 'Disease', (164, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('sarcomas', 'Disease', 'MESH:D012509', (164, 172))
423664	33889298	These analyses continued to show positive associations between RABL6A and p53 (coef = 0.27; p = 0.0120) and RABL6A with YAP (coef = 0.33; p = 0.0003), indicating an association of these proteins independent of the expression levels of the other biomarkers.	('associations', 'Interaction', (42, 54))	('RABL6A', 'Gene', (108, 114))	('p53', 'Gene', (74, 77))	('YAP', 'Gene', '10413', (120, 123))	('RABL6A', 'Var', (63, 69))	('YAP', 'Gene', (120, 123))	('RABL6A', 'Chemical', '-', (63, 69))	('RABL6A', 'Chemical', '-', (108, 114))
423668	33889298	In this way, the correlation analysis suggests RABL6A represents a previously unappreciated link between YAP and TAZ.	('RABL6A', 'Var', (47, 53))	('YAP', 'Gene', (105, 108))	('YAP', 'Gene', '10413', (105, 108))	('RABL6A', 'Chemical', '-', (47, 53))
423669	33889298	RABL6A is positively correlated with dysregulated p53 (likely including mutated p53 in clinical samples with the highest H-scores) but is known to inhibit the function of the wild-type tumor suppressor, as such the relationship between the two proteins is indicated by an inhibitory sign.	('tumor', 'Disease', (185, 190))	('correlated', 'Interaction', (21, 31))	('function', 'MPA', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('inhibit', 'NegReg', (147, 154))	('RABL6A', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('RABL6A', 'Chemical', '-', (0, 6))	('dysregulated', 'MPA', (37, 49))
423676	33889298	Consistent with its p53-independent mechanism, MA242 inhibited sarcoma cell lines regardless of whether p53 was wild type or null (Figure 6B).	('inhibited', 'NegReg', (53, 62))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('MA242', 'Var', (47, 52))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))
423694	33889298	Additional studies are needed to evaluate how inactivation of p53 cooperates with TAZ and YAP activation in sarcoma tumor progression.	('sarcoma tumor', 'Disease', 'MESH:D012509', (108, 121))	('sarcoma tumor', 'Disease', (108, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('YAP', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inactivation', 'Var', (46, 58))	('p53', 'Gene', (62, 65))	('YAP', 'Gene', '10413', (90, 93))
423697	33889298	One of the questions the above findings raise is whether TAZ/YAP activation, inactivation of p53, and activation of MDM2 are entirely stochastic events or mechanistically linked.	('p53', 'Gene', (93, 96))	('MDM2', 'Gene', (116, 120))	('YAP', 'Gene', '10413', (61, 64))	('YAP', 'Gene', (61, 64))	('inactivation', 'Var', (77, 89))
423861	26425600	Thrombophilia workup revealed a homozygous mutation of A1298C MTHFR by polymerase chain reaction.	('Thrombophilia', 'Disease', (0, 13))	('Thrombophilia', 'Phenotype', 'HP:0100724', (0, 13))	('MTHFR', 'Gene', '4524', (62, 67))	('revealed', 'Reg', (21, 29))	('A1298C', 'Mutation', 'rs1801131', (55, 61))	('MTHFR', 'Gene', (62, 67))	('Thrombophilia', 'Disease', 'MESH:D019851', (0, 13))	('A1298C', 'Var', (55, 61))
423883	26425600	The genetic instability and the abnormal DNA methylation induced by these mutations could contribute to the genesis of this type of sarcoma.	('sarcoma', 'Disease', (132, 139))	('mutations', 'Var', (74, 83))	('DNA methylation', 'MPA', (41, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('genetic', 'MPA', (4, 11))	('contribute', 'Reg', (90, 100))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
423895	24847440	Investigation revealed haemoglobin 9 gm.%, total leukocyte count 8200 cells/mm cu with 70% polymorphs and 26% lymphocytes.	('revealed', 'Reg', (14, 22))	('cu', 'Chemical', 'MESH:D003300', (79, 81))	('polymorphs', 'MPA', (91, 101))	('haemoglobin', 'Var', (23, 34))
423907	24847440	This family of tumors share common cytogenetic and molecular changes which involve the translocation of Ewing's sarcoma gene on chromosome 22 (22q12) onto chromosome 11 (11q24).	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('translocation', 'Var', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	("Ewing's sarcoma gene", 'Gene', (104, 124))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (104, 119))	('cu', 'Chemical', 'MESH:D003300', (55, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
423915	20933505	EWS-Fli1 knockdown increased expression of genes such as DKK1 and p57 that are known to be repressed by EWS-Fli1 fusion protein.	('DKK1', 'Gene', '22943', (57, 61))	('DKK1', 'Gene', (57, 61))	('EWS-Fli1', 'Gene', (104, 112))	('knockdown', 'Var', (9, 18))	('p57', 'Gene', '1028', (66, 69))	('EWS-Fli1', 'Gene', '2130', (104, 112))	('p57', 'Gene', (66, 69))	('increased', 'PosReg', (19, 28))	('EWS-Fli1', 'Gene', '2130', (0, 8))	('expression', 'MPA', (29, 39))	('EWS-Fli1', 'Gene', (0, 8))
423917	20933505	To better understand how EWS-Fli1 affects FOXO1 expression, we have established a doxycycline-inducible siRNA system to achieve stable and reversible knockdown of EWS-Fli1 in Ewing's sarcoma cells.	("Ewing's sarcoma", 'Disease', (175, 190))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (175, 190))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (175, 190))	('EWS-Fli1', 'Gene', (163, 171))	('EWS-Fli1', 'Gene', '2130', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('FOXO1', 'Gene', (42, 47))	('knockdown', 'Var', (150, 159))	('doxycycline', 'Chemical', 'MESH:D004318', (82, 93))	('EWS-Fli1', 'Gene', '2130', (25, 33))	('EWS-Fli1', 'Gene', (25, 33))
423918	20933505	Here we show that FOXO1 expression in Ewing's cells has an inverse relationship with EWS-Fli1 protein level, and FOXO1 promoter activity is increased after doxycycline-induced EWS-Fli1 knockdown.	('EWS-Fli1', 'Gene', '2130', (176, 184))	('EWS-Fli1', 'Gene', (176, 184))	('FOXO1', 'Gene', (113, 118))	('doxycycline', 'Chemical', 'MESH:D004318', (156, 167))	('protein level', 'MPA', (94, 107))	('FOXO1', 'Gene', (18, 23))	('promoter activity', 'MPA', (119, 136))	('knockdown', 'Var', (185, 194))	('increased', 'PosReg', (140, 149))	('EWS-Fli1', 'Gene', '2130', (85, 93))	('EWS-Fli1', 'Gene', (85, 93))
423922	20933505	This translocation results in a chimeric transcript encoding the N-terminal domain of the RNA-binding protein EWS and the DNA-binding domain of the ETS family transcription factor Fli1.	('RNA-binding protein EWS', 'Gene', (90, 113))	('RNA-binding protein EWS', 'Gene', '2130', (90, 113))	('chimeric', 'Var', (32, 40))	('results in', 'Reg', (19, 29))
423923	20933505	The resultant EWS-Fli1 chimeric fusion protein is known to affect both gene transcription and RNA splicing.	('affect', 'Reg', (59, 65))	('EWS-Fli1', 'Gene', '2130', (14, 22))	('EWS-Fli1', 'Gene', (14, 22))	('chimeric', 'Var', (23, 31))	('RNA splicing', 'MPA', (94, 106))	('gene transcription', 'MPA', (71, 89))
423926	20933505	To study how EWS-Fli1 influences gene expression in the genetic background of Ewing's sarcoma, we and others have examined the effects of EWS-Fli1 knockdown by siRNA in actual Ewing's cell lines.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (78, 93))	('actual Ewing', 'Disease', (169, 181))	('EWS-Fli1', 'Gene', '2130', (138, 146))	('EWS-Fli1', 'Gene', (138, 146))	("Ewing's sarcoma", 'Disease', (78, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('actual Ewing', 'Disease', 'MESH:C563168', (169, 181))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (78, 93))	('EWS-Fli1', 'Gene', '2130', (13, 21))	('EWS-Fli1', 'Gene', (13, 21))	('knockdown', 'Var', (147, 156))	('influences', 'Reg', (22, 32))
423927	20933505	We previously found that knockdown of EWS-Fli1 in Ewing's cells leads to growth arrest and reduced invasiveness.	('growth arrest', 'Phenotype', 'HP:0001510', (73, 86))	('arrest', 'Disease', 'MESH:D006323', (80, 86))	('EWS-Fli1', 'Gene', '2130', (38, 46))	('invasiveness', 'CPA', (99, 111))	('arrest', 'Disease', (80, 86))	('reduced', 'NegReg', (91, 98))	('knockdown', 'Var', (25, 34))	('EWS-Fli1', 'Gene', (38, 46))
423933	20933505	Using this inducible siRNA system in Ewing's sarcoma cells, we have found that doxycycline-induced siRNA knockdown of EWS-Fli1 in Ewing's sarcoma cells is accompanied by an increase in FOXO1 expression and a decrease in proliferation.	('proliferation', 'CPA', (220, 233))	('doxycycline', 'Chemical', 'MESH:D004318', (79, 90))	('EWS-Fli1', 'Gene', (118, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('EWS-Fli1', 'Gene', '2130', (118, 126))	('FOXO1', 'Gene', (185, 190))	('knockdown', 'Var', (105, 114))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (37, 52))	('increase', 'PosReg', (173, 181))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (130, 145))	("Ewing's sarcoma", 'Disease', (130, 145))	('expression', 'MPA', (191, 201))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (37, 52))	('decrease', 'NegReg', (208, 216))	("Ewing's sarcoma", 'Disease', (37, 52))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (130, 145))
423959	20933505	To this end, we were able to achieve a specific siRNA knockdown of EWS-Fli1 in SK-ES Ewing's sarcoma cells, whereas a non-specific siRNA against the firefly luciferase gene had no effect on EWS-Fli1 expression (Fig.	("Ewing's sarcoma", 'Disease', (85, 100))	('knockdown', 'Var', (54, 63))	('EWS-Fli1', 'Gene', '2130', (190, 198))	('EWS-Fli1', 'Gene', (190, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (85, 100))	('EWS-Fli1', 'Gene', '2130', (67, 75))	('EWS-Fli1', 'Gene', (67, 75))	('SK-ES', 'CellLine', 'CVCL:0627', (79, 84))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (85, 100))
423961	20933505	After comparison of the microarray data, we identified a set of genes that are significantly affected by EWS-Fli1 knockdown in these transfected Ewing's sarcoma cells (Fig.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (145, 160))	("Ewing's sarcoma", 'Disease', (145, 160))	('knockdown', 'Var', (114, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (145, 160))	('EWS-Fli1', 'Gene', '2130', (105, 113))	('EWS-Fli1', 'Gene', (105, 113))	('affected', 'Reg', (93, 101))
423965	20933505	One of the genes in our list that were found to be up-regulated by EWS-Fli1 knockdown but have not been reported previously is FOXO1, a member of the Forkhead box family of transcription factors.	('up-regulated', 'PosReg', (51, 63))	('knockdown', 'Var', (76, 85))	('FOXO1', 'Gene', (127, 132))	('EWS-Fli1', 'Gene', '2130', (67, 75))	('EWS-Fli1', 'Gene', (67, 75))
423971	20933505	In the absence of doxycycline, these G418-resistant cells do not express GFP or siRNA, and EWS-Fli1 level in Ewing's sarcoma cells remained constant.	('doxycycline', 'Chemical', 'MESH:D004318', (18, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (109, 124))	('EWS-Fli1', 'Gene', '2130', (91, 99))	('EWS-Fli1', 'Gene', (91, 99))	('G418-resistant', 'Var', (37, 51))	("Ewing's sarcoma", 'Disease', (109, 124))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (109, 124))	('G418', 'Chemical', 'MESH:C010680', (37, 41))
423974	20933505	This pSLIK vector system has wide applicability since we were able to obtain efficient siRNA knockdown of EWS-Fli1 in other Ewing cell lines such as RD-ES and SK-ES cells (Fig.	('knockdown', 'Var', (93, 102))	('SK-ES', 'CellLine', 'CVCL:0627', (159, 164))	('EWS-Fli1', 'Gene', (106, 114))	('EWS-Fli1', 'Gene', '2130', (106, 114))
423977	20933505	Doxycycline-induced specific siRNA knockdown of EWS-Fli1 also inhibited proliferation of Ewing's cells, whereas doxycyclin-induction of siRNA against luciferase did not have such an inhibitory effect (Fig.	('knockdown', 'Var', (35, 44))	('EWS-Fli1', 'Gene', '2130', (48, 56))	('EWS-Fli1', 'Gene', (48, 56))	('proliferation', 'CPA', (72, 85))	('doxycyclin', 'Chemical', 'MESH:D004318', (112, 122))	('inhibited', 'NegReg', (62, 71))	('Doxycycline', 'Chemical', 'MESH:D004318', (0, 11))
423980	20933505	To confirm that the FOXO1 gene is indeed up-regulated after siRNA knockdown of EWS-Fli1, we carried out RT-PCR analysis of FOXO1 mRNA in three Ewing's cell lines before and after doxycycline addition to the culture medium.	('up-regulated', 'PosReg', (41, 53))	('EWS-Fli1', 'Gene', '2130', (79, 87))	('EWS-Fli1', 'Gene', (79, 87))	('doxycycline', 'Chemical', 'MESH:D004318', (179, 190))	('FOXO1', 'Gene', (123, 128))	('FOXO1 gene', 'Gene', (20, 30))	('knockdown', 'Var', (66, 75))
423981	20933505	3A, doxycycline-induced siRNA knockdown of EWS-Fli1 in these Ewing cell lines led to an increase in FOXO1 mRNA.	('increase', 'PosReg', (88, 96))	('knockdown', 'Var', (30, 39))	('EWS-Fli1', 'Gene', '2130', (43, 51))	('EWS-Fli1', 'Gene', (43, 51))	('doxycycline', 'Chemical', 'MESH:D004318', (4, 15))	('FOXO1 mRNA', 'MPA', (100, 110))
423984	20933505	To further confirm that up-regulation of FOXO1 after EWS-Fli1 knockdown is a specific event related to changes in EWS-Fli1 but not an artifact due to the presence of doxycycline in the culture medium, we tested its expression in control A673 Ewing's cells expressing an siRNA against luciferase.	('tested', 'Reg', (204, 210))	('EWS-Fli1', 'Gene', '2130', (114, 122))	('EWS-Fli1', 'Gene', (114, 122))	('doxycycline', 'Chemical', 'MESH:D004318', (166, 177))	('FOXO1', 'Gene', (41, 46))	('EWS-Fli1', 'Gene', '2130', (53, 61))	('EWS-Fli1', 'Gene', (53, 61))	('up-regulation', 'PosReg', (24, 37))	('knockdown', 'Var', (62, 71))
423987	20933505	We found that doxycycline induction of EWS-Fli1 knockdown resulted in an increase in luciferase activity in A673 cells transfected with pGL3-hFOXO1-952 but not in A673 cells trasnfected with pGL3-hFOXO1-286, suggesting that EWS-Fli1 repression of the FOXO1 gene is mediated through an element between -952 to -286 of the FOXO1 promoter region (Fig.	('doxycycline', 'Chemical', 'MESH:D004318', (14, 25))	('activity', 'MPA', (96, 104))	('hFOXO1', 'Gene', '2308', (196, 202))	('hFOXO1', 'Gene', (196, 202))	('EWS-Fli1', 'Gene', (224, 232))	('pGL3', 'Gene', (191, 195))	('luciferase', 'Enzyme', (85, 95))	('pGL3', 'Gene', '6391', (191, 195))	('EWS-Fli1', 'Gene', '2130', (39, 47))	('pGL3', 'Gene', (136, 140))	('pGL3', 'Gene', '6391', (136, 140))	('FOXO1', 'Gene', (251, 256))	('EWS-Fli1', 'Gene', (39, 47))	('knockdown', 'Var', (48, 57))	('FOXO1', 'Gene', (321, 326))	('hFOXO1', 'Gene', '2308', (141, 147))	('increase', 'PosReg', (73, 81))	('hFOXO1', 'Gene', (141, 147))	('EWS-Fli1', 'Gene', '2130', (224, 232))
423989	20933505	In addition, less DNA was recovered by the anti-Fli1 antibody from A673 cells with doxycycline-induced siRNA knockdown of EWS-Fli1 (compare lanes 5 and 6).	('less', 'NegReg', (13, 17))	('knockdown', 'Var', (109, 118))	('DNA', 'MPA', (18, 21))	('EWS-Fli1', 'Gene', '2130', (122, 130))	('EWS-Fli1', 'Gene', (122, 130))	('doxycycline', 'Chemical', 'MESH:D004318', (83, 94))
423992	20933505	However, siRNA knockdown via adenoviral vector is irreversible and fresh infection has to be carried out for each new experiment.	('knockdown', 'Var', (15, 24))	('fresh infection', 'Disease', 'MESH:D007239', (67, 82))	('fresh infection', 'Disease', (67, 82))
423993	20933505	In this study, we have established a conditional lentiviral siRNA system to reversibly knockdown EWS-Fli1 in several Ewing cell lines.	('knockdown', 'Var', (87, 96))	('EWS-Fli1', 'Gene', '2130', (97, 105))	('EWS-Fli1', 'Gene', (97, 105))
423994	20933505	This doxycycline inducible siRNA system offers at least two advantages: first, those Ewing cell lines that are difficult to transfect can now be subjected to siRNA knockdown since the lentivirus will infect all Ewing cells, and the infected cells can be selected by their resistance to G418; second, siRNA knockdown of EWS-Fli1 in infected Ewing cells can now be turned on by addition of doxycycline to the culture medium and turned off by its withdrawal.	('knockdown', 'Var', (306, 315))	('doxycycline', 'MPA', (388, 399))	('infected Ewing', 'Disease', 'MESH:C563168', (331, 345))	('G418', 'Chemical', 'MESH:C010680', (286, 290))	('doxycycline', 'Chemical', 'MESH:D004318', (5, 16))	('doxycycline', 'Chemical', 'MESH:D004318', (388, 399))	('infected Ewing', 'Disease', (331, 345))	('EWS-Fli1', 'Gene', '2130', (319, 327))	('EWS-Fli1', 'Gene', (319, 327))
423997	20933505	Genetic deletion of FOXO1 results in modest neoplastic phenotype in a lineage-restricted manner, suggesting its role as a potential tumor suppressor in certain cell types.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('FOXO1', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Genetic deletion', 'Var', (0, 16))	('tumor', 'Disease', (132, 137))	('neoplastic phenotype', 'MPA', (44, 64))
423998	20933505	Loss of FOXO1 through chromosomal deletion was shown to promote androgen-independent prostate cancers.	('FOXO1', 'Gene', (8, 13))	('prostate cancers', 'Disease', 'MESH:D011471', (85, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('chromosomal deletion', 'Var', (22, 42))	('prostate cancers', 'Phenotype', 'HP:0012125', (85, 101))	('Loss', 'NegReg', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('prostate cancers', 'Disease', (85, 101))	('promote', 'PosReg', (56, 63))
424001	20933505	From our studies shown here and reported previously, EWS-Fli1 knockdown has been associated with activation of the S-phase repressor pRb, cell cycle arrest, decreased expression of cyclin D and increased expression of FOXO1.	('FOXO1', 'Gene', (218, 223))	('activation', 'PosReg', (97, 107))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (138, 155))	('cyclin', 'Gene', '5111', (181, 187))	('arrest', 'Disease', (149, 155))	('increased', 'PosReg', (194, 203))	('pRb', 'Gene', '5925', (133, 136))	('cyclin', 'Gene', (181, 187))	('EWS-Fli1', 'Gene', (53, 61))	('pRb', 'Gene', (133, 136))	('EWS-Fli1', 'Gene', '2130', (53, 61))	('expression', 'MPA', (204, 214))	('decreased', 'NegReg', (157, 166))	('expression', 'MPA', (167, 177))	('knockdown', 'Var', (62, 71))
424024	20610196	Their inactivation, through various mechanisms, permits the dysregulated growth of cancer cells.	('permits', 'PosReg', (48, 55))	('inactivation', 'Var', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
424025	20610196	Cancer cells carry DNA that has point mutations; viral insertions; or chromosomal or gene amplifications, deletions, or rearrangements.	('rearrangements', 'Var', (120, 134))	('deletions', 'Var', (106, 115))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('point mutations', 'Var', (32, 47))
424028	20610196	Specific tumors occur earlier and are more often bilateral (in paired organs) when they result from germline mutations than when they result from sporadic or somatic alterations.	('Specific', 'Disease', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('germline mutations', 'Var', (100, 118))	('result', 'Reg', (88, 94))	('bilateral', 'Disease', (49, 58))
424034	20610196	Many pediatric cancers, specifically hematologic malignancies and soft-tissue neoplasms, have recurrent, nonrandom abnormalities in chromosomal structure, typically chromosomal translocations (Table 3).	('pediatric cancers', 'Disease', 'MESH:D009369', (5, 22))	('pediatric cancers', 'Disease', (5, 22))	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('hematologic malignancies', 'Disease', 'MESH:D019337', (37, 61))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('soft-tissue neoplasms', 'Phenotype', 'HP:0031459', (66, 87))	('hematologic malignancies', 'Disease', (37, 61))	('neoplasms', 'Disease', (78, 87))	('neoplasms', 'Disease', 'MESH:D009369', (78, 87))	('chromosomal translocations', 'Var', (165, 191))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
424036	20610196	For example, in Ewing sarcoma the consequence of the t(11;22)(q24;q12) translocation is a fusion of EWS, a transcription factor gene on chromosome 22, and FLI-1, a gene encoding a member of the ETS family of transcription factors on chromosome 11.	('FLI-1', 'Gene', '2313', (155, 160))	('t(11', 'Var', (53, 57))	('FLI-1', 'Gene', (155, 160))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('EWS', 'Gene', '2130', (100, 103))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (16, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 70))	('Ewing sarcoma', 'Disease', (16, 29))	('EWS', 'Gene', (100, 103))
424040	20610196	Alveolar rhabdomyosarcomas have characteristic translocations between the long arm of chromosome 2 (75% of cases) or the short arm of chromosome 1 (10% of cases) and the long arm of chromosome 13.	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (9, 26))	('Alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (0, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('translocations', 'Var', (47, 61))	('Alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (0, 26))	('Alveolar rhabdomyosarcomas', 'Disease', (0, 26))	('short arm', 'Phenotype', 'HP:0009824', (121, 130))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (9, 25))
424050	20610196	This consistency suggests that MYCN amplification is an early event in the pathogenesis of neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (91, 104))	('MYCN', 'Gene', (31, 35))	('amplification', 'Var', (36, 49))	('MYCN', 'Gene', '4613', (31, 35))	('neuroblastoma', 'Disease', (91, 104))	('neuroblastoma', 'Phenotype', 'HP:0003006', (91, 104))
424051	20610196	Because, gene amplification is usually associated with advanced stages of disease, rapid tumor progression, and poor outcome, it is a powerful prognostic indicator.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('gene amplification', 'Var', (9, 27))	('associated', 'Reg', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
424056	20610196	In addition, heritable cancer-associated changes in the p53 tumor suppressor gene occur in families with Li-Fraumeni syndrome, an autosomal dominant predisposition for rhabdomyosarcoma, other soft tissue and bone sarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinomas.	('tumor', 'Disease', (258, 263))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (270, 295))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('brain tumors', 'Disease', (252, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('adrenocortical carcinomas', 'Disease', (270, 295))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('soft tissue', 'Disease', (192, 203))	('bone sarcomas', 'Disease', 'MESH:D001847', (208, 221))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('sarcomas', 'Phenotype', 'HP:0100242', (213, 221))	('bone sarcomas', 'Disease', (208, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('p53', 'Gene', '7157', (56, 59))	('bone sarcomas', 'Phenotype', 'HP:0002669', (208, 221))	('breast cancer', 'Disease', (237, 250))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (270, 294))	('rhabdomyosarcoma', 'Disease', (168, 184))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (270, 295))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('p53', 'Gene', (56, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (285, 295))	('cancer', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('changes', 'Var', (41, 48))	('Li-Fraumeni syndrome', 'Disease', (105, 125))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (223, 250))	('cancer', 'Disease', (244, 250))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (168, 184))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('brain tumors', 'Disease', 'MESH:D001932', (252, 264))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (105, 125))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (168, 184))	('brain tumors', 'Phenotype', 'HP:0030692', (252, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('soft tissue and bone sarcomas', 'Phenotype', 'HP:0030448', (192, 221))
424059	20610196	For example, early karyotype analyses of neuroblastoma-derived cell lines found frequent deletion of the short arm of chromosome 1.	('short arm', 'Phenotype', 'HP:0009824', (105, 114))	('neuroblastoma', 'Disease', 'MESH:D009447', (41, 54))	('deletion', 'Var', (89, 97))	('neuroblastoma', 'Disease', (41, 54))	('neuroblastoma', 'Phenotype', 'HP:0003006', (41, 54))
424061	20610196	Deletion of genetic material in tumors suggests the presence (and subsequent loss) of a tumor suppressor gene, but a specific tumor suppressor gene has yet to be identified on chromosome 1p, although CHD5 has recently emerged as a strong candidate in neuroblastoma.	('CHD5', 'Gene', '26038', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('loss', 'NegReg', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (32, 38))	('tumor', 'Disease', (88, 93))	('Deletion', 'Var', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CHD5', 'Gene', (200, 204))	('tumor', 'Disease', (32, 37))	('neuroblastoma', 'Disease', (251, 264))	('tumor', 'Disease', (126, 131))	('neuroblastoma', 'Phenotype', 'HP:0003006', (251, 264))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('neuroblastoma', 'Disease', 'MESH:D009447', (251, 264))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
424065	20610196	However, recent data have suggested that LOH at chromosome 1p or 11q (unbalanced), is independently associated with decreased progression-free survival in patients with low-and intermediate-risk disease.	('progression-free survival', 'CPA', (126, 151))	('LOH at chromosome 1p', 'Var', (41, 61))	('decreased', 'NegReg', (116, 125))	('patients', 'Species', '9606', (155, 163))
424067	20610196	Chromosomal deletion also occurs commonly in Wilms tumor.	('Wilms tumor', 'Disease', 'MESH:D009396', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Chromosomal deletion', 'Var', (0, 20))	('Wilms tumor', 'Phenotype', 'HP:0002667', (45, 56))	('Wilms tumor', 'Disease', (45, 56))
424068	20610196	The recently concluded NWTS-5 trial, a single-arm therapeutic trial designed to evaluate the prognostic value of certain biologic markers in Wilms tumor, demonstrated that LOH for genetic material on chromosome 1p and 16q in stage I and II favorable histology Wilms tumor was associated with a poorer prognosis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('Wilms tumor', 'Phenotype', 'HP:0002667', (260, 271))	('Wilms tumor', 'Disease', 'MESH:D009396', (260, 271))	('Wilms tumor', 'Disease', (260, 271))	('Wilms tumor', 'Disease', 'MESH:D009396', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('Wilms tumor', 'Phenotype', 'HP:0002667', (141, 152))	('LOH for genetic material', 'Var', (172, 196))	('Wilms tumor', 'Disease', (141, 152))
424075	20610196	However, both abnormal hypo- and hypermethylation states exist in human tumors, resulting in both dysregulated expression and silencing, respectively, of affected genes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('human', 'Species', '9606', (66, 71))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('dysregulated expression', 'MPA', (98, 121))	('hypermethylation', 'Var', (33, 49))	('silencing', 'NegReg', (126, 135))
424077	20610196	For example, promoter methylation resulting in silencing of caspase 8, a protein involved in apoptosis, likely contributes to the pathogenesis of MYCN-amplified neuroblastoma, as well as Ewing sarcoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (161, 174))	('Ewing sarcoma', 'Disease', (187, 200))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (187, 200))	('MYCN', 'Gene', (146, 150))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (187, 200))	('silencing', 'NegReg', (47, 56))	('neuroblastoma', 'Disease', 'MESH:D009447', (161, 174))	('MYCN', 'Gene', '4613', (146, 150))	('promoter methylation', 'Var', (13, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('neuroblastoma', 'Disease', (161, 174))	('caspase 8', 'Gene', '841', (60, 69))	('contributes', 'Reg', (111, 122))	('caspase 8', 'Gene', (60, 69))
424081	20610196	Constitutional genetic abnormalities present in all cells of the body that are hereditary (i.e., passed from parent to child) or nonhereditary (i.e., de novo mutations in the sperm or oocyte before fertilization) contribute to an estimated 10% to 15% of pediatric cancers.	('genetic abnormalities', 'Disease', (15, 36))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('pediatric cancers', 'Disease', (254, 271))	('pediatric cancers', 'Disease', 'MESH:D009369', (254, 271))	('child', 'Species', '9606', (119, 124))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('mutations', 'Var', (158, 167))	('genetic abnormalities', 'Disease', 'MESH:D030342', (15, 36))
424082	20610196	Constitutional chromosomal abnormalities are the result of an abnormal number or structural rearrangement of the normal 46 chromosomes and may be associated with a predisposition to cancer.	('Constitutional chromosomal abnormalities', 'Disease', (0, 40))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('abnormal', 'Var', (62, 70))	('Constitutional chromosomal abnormalities', 'Disease', 'MESH:D005878', (0, 40))	('structural rearrangement', 'CPA', (81, 105))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('associated', 'Reg', (146, 156))
424083	20610196	Examples of chromosomal abnormalities resulting in a predisposition to certain types of childhood cancers include the predisposition to leukemia seen with trisomy 21 (Down syndrome) and to germ cell tumors with Klinefelter syndrome (47XXY).	('Klinefelter syndrome', 'Disease', (211, 231))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('leukemia', 'Disease', (136, 144))	('trisomy 21', 'Var', (155, 165))	('leukemia', 'Disease', 'MESH:D007938', (136, 144))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('germ cell tumors', 'Phenotype', 'HP:0100728', (189, 205))	('germ cell tumors', 'Disease', 'MESH:D009373', (189, 205))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (12, 37))	('Klinefelter syndrome', 'Disease', 'MESH:D007713', (211, 231))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('childhood cancers', 'Disease', 'MESH:C536928', (88, 105))	('childhood cancers', 'Disease', (88, 105))	('chromosomal abnormalities', 'Disease', (12, 37))	('germ cell tumors', 'Disease', (189, 205))
424088	20610196	Constitutional deletions from chromosome 11p13 are consistent in children with WAGR syndrome and also occur in approximately 35% of children with sporadic Wilms tumor.	('Constitutional deletions', 'Var', (0, 24))	('children', 'Species', '9606', (65, 73))	('children', 'Species', '9606', (132, 140))	('Wilms tumor', 'Disease', 'MESH:D009396', (155, 166))	('Wilms tumor', 'Phenotype', 'HP:0002667', (155, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('WAGR syndrome', 'Disease', 'MESH:D017624', (79, 92))	('WAGR syndrome', 'Disease', (79, 92))	('Wilms tumor', 'Disease', (155, 166))
424092	20610196	Denys-Drash syndrome, which is characterized by a very high risk of Wilms tumor, pseudohermaphroditism, and mesangeal sclerosis leading to early renal failure, is associated with germline mutations in the DNA-binding domain of WT1.	('renal failure', 'Disease', (145, 158))	('mesangeal sclerosis', 'Disease', (108, 127))	('Denys-Drash syndrome', 'Disease', 'MESH:D030321', (0, 20))	('mesangeal sclerosis', 'Disease', 'MESH:D012598', (108, 127))	('renal failure', 'Disease', 'MESH:D051437', (145, 158))	('Denys-Drash syndrome', 'Disease', (0, 20))	('renal failure', 'Phenotype', 'HP:0000083', (145, 158))	('Wilms tumor', 'Disease', (68, 79))	('germline mutations in the', 'Var', (179, 204))	('Wilms tumor', 'Disease', 'MESH:D009396', (68, 79))	('WT1', 'Gene', '7490', (227, 230))	('associated', 'Reg', (163, 173))	('Wilms tumor', 'Phenotype', 'HP:0002667', (68, 79))	('WT1', 'Gene', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('pseudohermaphroditism', 'Disease', 'MESH:D012734', (81, 102))	('pseudohermaphroditism', 'Disease', (81, 102))	('mesangeal sclerosis', 'Phenotype', 'HP:0001967', (108, 127))
424093	20610196	The mutated WT1 protein appears to function by a dominant negative effect.	('mutated', 'Var', (4, 11))	('WT1', 'Gene', '7490', (12, 15))	('negative', 'NegReg', (58, 66))	('WT1', 'Gene', (12, 15))
424097	20610196	Loss of heterozygosity at this locus has also been described in patients with Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth syndrome characterized by numerous growth abnormalities as well as predisposition to a variety of malignancies, including Wilms tumor.	('BWS', 'Disease', 'MESH:D001506', (107, 110))	('BWS', 'Disease', (107, 110))	('Wilms tumor', 'Disease', 'MESH:D009396', (259, 270))	('Loss of heterozygosity', 'Var', (0, 22))	('numerous growth abnormalities', 'Disease', (163, 192))	('numerous growth abnormalities', 'Disease', 'MESH:D006130', (163, 192))	('patients', 'Species', '9606', (64, 72))	('overgrowth', 'Phenotype', 'HP:0001548', (126, 136))	('malignancies', 'Disease', (235, 247))	('Wilms tumor', 'Disease', (259, 270))	('Wilms tumor', 'Phenotype', 'HP:0002667', (259, 270))	('Beckwith-Wiedemann syndrome', 'Disease', (78, 105))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('growth abnormalities', 'Phenotype', 'HP:0001507', (172, 192))	('congenital overgrowth syndrome', 'Disease', 'MESH:C537340', (115, 145))	('malignancies', 'Disease', 'MESH:D009369', (235, 247))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (78, 105))	('congenital overgrowth syndrome', 'Disease', (115, 145))
424099	20610196	The NF1 protein normally inhibits the proto-oncogene RAS, but in patients with NF1, mutation of one copy of the gene combined with deletion of the other permits uncontrolled RAS pathway activation.	('activation', 'PosReg', (186, 196))	('deletion', 'Var', (131, 139))	('RAS pathway', 'Pathway', (174, 185))	('NF1', 'Gene', (4, 7))	('patients', 'Species', '9606', (65, 73))	('NF1', 'Gene', '4763', (4, 7))	('NF1', 'Gene', (79, 82))	('NF1', 'Gene', '4763', (79, 82))	('mutation', 'Var', (84, 92))
424101	20610196	An inherited predisposition to pediatric cancers is also associated with Li-Fraumeni syndrome (which results from inactivating mutations of the p53 gene and in which patients are at risk of osteosarcoma, rhabdomyosarcoma, adrenocortical carcinoma, and brain tumors, among other tumors), familial retinoblastoma (which results from inactivating mutations of the RB gene and in which patients are at risk of osteosarcoma as well as retinoblastoma), familial adenomatous polyposis, and multiple endocrine neoplasia syndromes.	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (456, 477))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('multiple endocrine neoplasia syndromes', 'Disease', (483, 521))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (73, 93))	('tumors', 'Disease', (278, 284))	('familial adenomatous polyposis', 'Disease', (447, 477))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (204, 220))	('adrenocortical carcinoma', 'Disease', (222, 246))	('brain tumors', 'Disease', (252, 264))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (447, 477))	('multiple endocrine neoplasia syndromes', 'Disease', 'MESH:D009377', (483, 521))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('pediatric cancers', 'Disease', 'MESH:D009369', (31, 48))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (204, 220))	('osteosarcoma', 'Phenotype', 'HP:0002669', (406, 418))	('retinoblastoma', 'Disease', 'MESH:D012175', (296, 310))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('p53', 'Gene', '7157', (144, 147))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('neoplasia', 'Phenotype', 'HP:0002664', (502, 511))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('patients', 'Species', '9606', (166, 174))	('osteosarcoma', 'Disease', 'MESH:D012516', (190, 202))	('osteosarcoma', 'Phenotype', 'HP:0002669', (190, 202))	('results', 'Reg', (318, 325))	('retinoblastoma', 'Disease', 'MESH:D012175', (430, 444))	('p53', 'Gene', (144, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (411, 418))	('tumors', 'Disease', (258, 264))	('osteosarcoma', 'Disease', (406, 418))	('retinoblastoma', 'Phenotype', 'HP:0009919', (296, 310))	('familial retinoblastoma', 'Disease', 'MESH:D012175', (287, 310))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (222, 246))	('osteosarcoma', 'Disease', 'MESH:D012516', (406, 418))	('patients', 'Species', '9606', (382, 390))	('retinoblastoma', 'Disease', (296, 310))	('rhabdomyosarcoma', 'Disease', (204, 220))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (492, 511))	('inactivating mutations', 'Var', (331, 353))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('Li-Fraumeni syndrome', 'Disease', (73, 93))	('brain tumors', 'Disease', 'MESH:D001932', (252, 264))	('familial retinoblastoma', 'Disease', (287, 310))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('brain tumors', 'Phenotype', 'HP:0030692', (252, 264))	('retinoblastoma', 'Phenotype', 'HP:0009919', (430, 444))	('osteosarcoma', 'Disease', (190, 202))	('pediatric cancers', 'Disease', (31, 48))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (222, 246))	('retinoblastoma', 'Disease', (430, 444))	('associated', 'Reg', (57, 67))
424102	20610196	Recently, the germline mutation associated with hereditary neuroblastoma has been identified - activating mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) oncogene on the long arm of chromosome 2 (2p23).	('neuroblastoma', 'Phenotype', 'HP:0003006', (59, 72))	('anaplastic lymphoma kinase', 'Gene', (153, 179))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (153, 172))	('hereditary neuroblastoma', 'Disease', (48, 72))	('ALK', 'Gene', (181, 184))	('anaplastic lymphoma kinase', 'Gene', '238', (153, 179))	('mutations in', 'Var', (106, 118))	('lymphoma', 'Phenotype', 'HP:0002665', (164, 172))	('hereditary neuroblastoma', 'Disease', 'MESH:D009447', (48, 72))	('activating', 'PosReg', (95, 105))	('ALK', 'Gene', '238', (181, 184))
424104	20610196	Finally, the same group has also shown that inherited copy number variation at chromosome 1q21.1 is associated with neuroblastoma, implicating a neuroblastoma breakpoint family gene in early neuroblastoma genesis.	('copy number variation', 'Var', (54, 75))	('neuroblastoma', 'Disease', (145, 158))	('neuroblastoma', 'Disease', 'MESH:D009447', (191, 204))	('neuroblastoma', 'Disease', 'MESH:D009447', (116, 129))	('associated', 'Reg', (100, 110))	('neuroblastoma', 'Disease', (116, 129))	('neuroblastoma', 'Disease', (191, 204))	('neuroblastoma', 'Phenotype', 'HP:0003006', (145, 158))	('neuroblastoma', 'Phenotype', 'HP:0003006', (191, 204))	('neuroblastoma genesis', 'Disease', 'MESH:D009447', (191, 212))	('neuroblastoma', 'Phenotype', 'HP:0003006', (116, 129))	('neuroblastoma', 'Disease', 'MESH:D009447', (145, 158))	('neuroblastoma genesis', 'Disease', (191, 212))
424107	20610196	Demonstration of tumor-specific translocations by cytogenetics, FISH, and RT-PCR confirms histopathologic diagnoses.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (17, 22))	('translocations', 'Var', (32, 46))
424277	23775410	Thus, the small proportion of patients with N1M0 disease have a DSS intermediate to those with localized disease and overt metastatic disease, with the implication that they represent a unique class of patient for staging purposes, inferior to G3T2 (N0M0) primaries but superior to patients with overt M1 disease.	('localized disease', 'Disease', (95, 112))	('patient', 'Species', '9606', (30, 37))	('N1M0 disease', 'Var', (44, 56))	('localized disease', 'Disease', 'MESH:D012594', (95, 112))	('patient', 'Species', '9606', (202, 209))	('patients', 'Species', '9606', (30, 38))	('patient', 'Species', '9606', (282, 289))	('patients', 'Species', '9606', (282, 290))	('DSS', 'Chemical', '-', (64, 67))
424278	23775410	This is borne out in the multivariate analysis, in which nodal disease is significantly worse than no metastatic disease, and N0M1 metastatic disease is significantly worse than N1M0 disease (Table 1).	('nodal disease', 'Disease', (57, 70))	('nodal disease', 'Disease', 'MESH:D013611', (57, 70))	('N0M1', 'Var', (126, 130))
424279	23775410	In other words, N1M0 patients have outcomes intermediate to what are presently defined as AJCC version 7 stages III and IV disease.	('patients', 'Species', '9606', (21, 29))	('IV disease', 'Disease', 'MESH:D020432', (120, 130))	('N1M0', 'Var', (16, 20))	('IV disease', 'Disease', (120, 130))	('stages III', 'Disease', (105, 115))
424281	23775410	As an example of the importance of histology, patients with dedifferentiated liposarcoma of the extremity have superior overall survival than those with pleomorphic sarcoma, even though both are G3 by FNCLCC (Figure 4B).	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('patients', 'Species', '9606', (46, 54))	('superior', 'PosReg', (111, 119))	('liposarcoma', 'Disease', (77, 88))	('pleomorphic sarcoma', 'Disease', (153, 172))	('liposarcoma', 'Disease', 'MESH:D008080', (77, 88))	('liposarcoma', 'Phenotype', 'HP:0012034', (77, 88))	('overall survival', 'MPA', (120, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (153, 172))	('dedifferentiated', 'Var', (60, 76))
424286	23775410	Refinements included in AJCC version 7 should help improve staging, in particular, the consistent use of FNCLCC grade and N1M0 disease as a separate tumor entity.	('FNCLCC', 'Disease', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('N1M0', 'Var', (122, 126))
424335	24348744	These individuals will then present for medical attention at a higher rate phi 2 > phi 1.	('phi', 'Var', (75, 78))	('phi 1', 'Gene', '26472', (83, 88))	('phi 1', 'Gene', (83, 88))
424341	24348744	Full-blown AIDS individuals A can also develop KS at rate epsilon 3 > epsilon 2 > epsilon 1 due to weakened immune systems.	('weakened immune systems', 'Phenotype', 'HP:0002721', (99, 122))	('AIDS', 'Disease', 'MESH:D000163', (11, 15))	('AIDS', 'Disease', (11, 15))	('epsilon', 'Var', (58, 65))	('KS', 'Phenotype', 'HP:0100726', (47, 49))
424404	32911853	In all cases of R0 resections, we grouped the patients into four categories:margins of <1 mm, 1-5 mm, >5 mm, or >10 mm.	('patients', 'Species', '9606', (46, 54))	('>5 mm', 'Var', (102, 107))	('1-5 mm', 'Var', (94, 100))
424443	32911853	Using the UICC R + 1 mm, an LR of 12% was seen in R0 + 1 resected patients vs. 36.9% in R1 patients after 5 years.	('R0 + 1 resected', 'Var', (50, 65))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (66, 74))	('R + 1', 'Var', (15, 20))
424473	32968711	We demonstrate that Set2Gaussian improves gene set member identification, accurately stratifies tumors, and finds concise gene sets for gene set enrichment analysis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('improves', 'PosReg', (33, 41))	('Set2Gaussian', 'Chemical', '-', (20, 32))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('gene set member identification', 'MPA', (42, 72))	('Set2Gaussian', 'Var', (20, 32))
424481	32968711	We demonstrate that Set2Gaussian significantly improves gene set member identification in three large-scale gene set collections.	('Set2Gaussian', 'Var', (20, 32))	('improves', 'PosReg', (47, 55))	('gene set member identification', 'MPA', (56, 86))	('Set2Gaussian', 'Chemical', '-', (20, 32))
424490	32968711	For example, In Reactome, at the medium set [11-30], Set2Gaussian obtained an AUPRC of 0.48, outperforming mean (0.42), weighted mean (0.40), and max (0.22).	('Set2Gaussian', 'Chemical', '-', (53, 65))	('AUPRC', 'MPA', (78, 83))	('outperforming', 'NegReg', (93, 106))	('Set2Gaussian', 'Var', (53, 65))
424491	32968711	For example, Set2Gaussian obtained 36% improvement on large sets [31-1000] versus 21% improvement on small sets [3-10] in comparison to mean on MSigDB.	('Set2Gaussian', 'Var', (13, 25))	('improvement', 'PosReg', (39, 50))	('Set2Gaussian', 'Chemical', '-', (13, 25))
424492	32968711	By adopting a covariance matrix to model uncertainty, Set2Gaussian is able to model this diversity and thus substantially improves gene set identification performance.	('improves', 'PosReg', (122, 130))	('Set2Gaussian', 'Var', (54, 66))	('gene set identification', 'MPA', (131, 154))	('ovarian', 'Disease', 'MESH:D010049', (15, 22))	('ovarian', 'Disease', (15, 22))	('Set2Gaussian', 'Chemical', '-', (54, 66))
424513	32968711	We attributed Set2Gaussian's superior performance against comparison approaches to its projection of mutation profiles as low-dimensional Gaussian distributions, thus obtaining more accurate similarity between tumors.	('similarity', 'MPA', (191, 201))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('Set2Gaussian', 'Chemical', '-', (14, 26))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('Set2Gaussian', 'Var', (14, 26))
424516	32968711	The subtype with a larger NEFM-subnetwork mutation rate tends to have worse survival in comparison to other subtypes.	('worse', 'NegReg', (70, 75))	('survival', 'MPA', (76, 84))	('NEFM', 'Gene', '4741', (26, 30))	('NEFM', 'Gene', (26, 30))	('mutation', 'Var', (42, 50))
424536	32968711	For all cell lines, Set2Gaussian enriched for more gene sets in comparison to Standard.	('Set2Gaussian', 'Var', (20, 32))	('more', 'PosReg', (46, 50))	('gene sets', 'MPA', (51, 60))	('Set2Gaussian', 'Chemical', '-', (20, 32))
424538	32968711	In addition to increasing the number of enriched gene sets, Set2Gaussian-filtered previously defined gene sets also substantially enhanced the enrichment analysis computational speed in comparison to all previously defined gene sets (almost 65-fold).	('enrichment analysis', 'MPA', (143, 162))	('enhanced', 'PosReg', (130, 138))	('Set2Gaussian', 'Chemical', '-', (60, 72))	('Set2Gaussian-filtered', 'Var', (60, 81))
424541	32968711	Our analysis of 11,892 gene sets indicates that Set2Gaussian is able to accurately recover gene set members, thus substantially reducing noise in experimentally derived gene sets.	('noise', 'MPA', (137, 142))	('reducing', 'NegReg', (128, 136))	('Set2Gaussian', 'Var', (48, 60))	('Set2Gaussian', 'Chemical', '-', (48, 60))
424544	32968711	Set2Gaussian allows us to stratify tumors into biologically meaningful subtypes and obtain an unrecognized NEFM-subnetwork, whereas none of the compared methods is able to achieve.	('NEFM', 'Gene', '4741', (107, 111))	('NEFM', 'Gene', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Set2Gaussian', 'Chemical', '-', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('Set2Gaussian', 'Var', (0, 12))
424580	32968711	We excluded tumors with less than 10 mutations, leaving a total of 237 tumors with 10,618 mutations in 15,108 genes.	('mutations', 'Var', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
424586	32968711	Here, we asked whether Set2Gaussian could enhance tumor stratification accuracy and identify the underlying driver subnetworks.	('enhance', 'PosReg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Set2Gaussian', 'Var', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Set2Gaussian', 'Chemical', '-', (23, 35))	('tumor', 'Disease', (50, 55))
424594	32968711	Mutation Load clustered tumors according to the number of mutations in each tumor.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Disease', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
424627	32138169	Phosphorylation at Thr288 in its catalytic domain triggers its kinase activity.	('triggers', 'Reg', (50, 58))	('Thr288', 'Var', (19, 25))	('Phosphorylation', 'MPA', (0, 15))	('Thr288', 'Chemical', '-', (19, 25))	('kinase activity', 'MPA', (63, 78))
424648	32138169	A gain at AURKA locus for IB105, IB111, IB112, IB116, IB119, LPS78 and LPS80 was detected.	('AURKA', 'Gene', (10, 15))	('LPS80', 'Var', (71, 76))	('IB111', 'Var', (33, 38))	('IB105', 'Chemical', '-', (26, 31))	('LPS80', 'Chemical', '-', (71, 76))	('IB116', 'Var', (47, 52))	('IB111', 'Chemical', '-', (33, 38))	('LPS78', 'Chemical', '-', (61, 66))	('IB119', 'Var', (54, 59))	('IB112', 'Gene', (40, 45))	('AURKA', 'Gene', '6790', (10, 15))	('gain', 'PosReg', (2, 6))	('IB105', 'Gene', (26, 31))
424650	32138169	AURKB amplification was absent in IB105, IB115, IB116, IB119 and LPS80.	('IB105', 'Var', (34, 39))	('amplification', 'MPA', (6, 19))	('AURKB', 'Gene', (0, 5))	('IB105', 'Chemical', '-', (34, 39))	('LPS80', 'Chemical', '-', (65, 70))	('IB115', 'Chemical', '-', (41, 46))	('AURKB', 'Gene', '9212', (0, 5))	('absent', 'NegReg', (24, 30))
424652	32138169	Tumour cell lines exhibited higher expression level of Aurora kinase mRNAs by more than 300-fold in IB105, IB112, IB116, and LPS80 compared to commercial standard skeletal muscle.	('Aurora kinase mRNAs', 'Enzyme', (55, 74))	('expression level', 'MPA', (35, 51))	('IB105', 'Var', (100, 105))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (28, 34))	('IB105', 'Chemical', '-', (100, 105))	('LPS80', 'Chemical', '-', (125, 130))	('IB112', 'Var', (107, 112))
424654	32138169	Only IB111 presented a moderate AURKA expression of 2.5 more than the standard RNA.	('IB111', 'Chemical', '-', (5, 10))	('IB111', 'Var', (5, 10))	('AURKA', 'Gene', '6790', (32, 37))	('AURKA', 'Gene', (32, 37))
424660	32138169	High levels of AURKB were detected in LPS78, LPS80, IB105, IB112, IB119, and MFH152.	('AURKB', 'Gene', (15, 20))	('MFH152', 'Chemical', '-', (77, 83))	('LPS78', 'Var', (38, 43))	('AURKB', 'Gene', '9212', (15, 20))	('LPS80', 'Chemical', '-', (45, 50))	('LPS80', 'Var', (45, 50))	('IB105', 'Chemical', '-', (52, 57))	('LPS78', 'Chemical', '-', (38, 43))
424676	32138169	For LPS78, AMG 900 reduced clonogenicity from 10% of the IC50, and a higher concentration did not lead to a higher reduction.	('clonogenicity', 'MPA', (27, 40))	('LPS78', 'Var', (4, 9))	('AMG 900', 'Chemical', 'MESH:C555658', (11, 18))	('reduced', 'NegReg', (19, 26))	('AMG 900', 'Var', (11, 18))	('LPS78', 'Chemical', '-', (4, 9))
424681	32138169	LPS78 showed the strongest apoptosis level of 4.26-fold with AMG 900 and 2.36-fold with doxorubicin (Figure 5C).	('doxorubicin', 'Chemical', 'MESH:D004317', (88, 99))	('LPS78', 'Var', (0, 5))	('AMG 900', 'Chemical', 'MESH:C555658', (61, 68))	('LPS78', 'Chemical', '-', (0, 5))	('apoptosis', 'MPA', (27, 36))
424692	32138169	The same effect was observed using RNAi or drug treatment, the doxorubicin induced the strongest diminution of 4 times the control condition.	('doxorubicin', 'Chemical', 'MESH:D004317', (63, 74))	('doxorubicin', 'Var', (63, 74))	('diminution', 'NegReg', (97, 107))
424694	32138169	Doxorubicin had no effect on IB115, but increased the percentage of cells in S phase for IB111 or LPS78.	('LPS78', 'Var', (98, 103))	('LPS78', 'Chemical', '-', (98, 103))	('IB111', 'Chemical', '-', (89, 94))	('increased', 'PosReg', (40, 49))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('IB115', 'Chemical', '-', (29, 34))
424703	32138169	LPS78 AMG 900-induced polyploidy is correlated to an increase of nucleus size (Figure 6B).	('AMG 900', 'Chemical', 'MESH:C555658', (6, 13))	('increase', 'PosReg', (53, 61))	('nucleus size', 'CPA', (65, 77))	('polyploidy', 'Disease', (22, 32))	('LPS78', 'Chemical', '-', (0, 5))	('LPS78 AMG 900-induced', 'Var', (0, 21))	('polyploidy', 'Disease', 'MESH:D011123', (22, 32))
424710	32138169	AKT1, AKT2, AKT3, pKC, CAMK and CDK1, CDK2 were activated in response to AMG 900, while some CDK members and two MAPK family members were inhibited.	('AKT1', 'Gene', (0, 4))	('AMG 900', 'Chemical', 'MESH:C555658', (73, 80))	('AMG', 'Var', (73, 76))	('CDK', 'Gene', (32, 35))	('pKC', 'Gene', (18, 21))	('AKT3', 'Gene', '10000', (12, 16))	('CDK', 'Gene', '983;1017;1019', (32, 35))	('CAMK', 'Gene', (23, 27))	('CDK1', 'Gene', (32, 36))	('CDK1', 'Gene', '983', (32, 36))	('CAMK', 'Gene', '818', (23, 27))	('AKT3', 'Gene', (12, 16))	('CDK2', 'Gene', '1017', (38, 42))	('CDK', 'Gene', (38, 41))	('pKC', 'Gene', '112476', (18, 21))	('activated', 'PosReg', (48, 57))	('AKT2', 'Gene', '208', (6, 10))	('CDK', 'Gene', (93, 96))	('AKT1', 'Gene', '207', (0, 4))	('CDK2', 'Gene', (38, 42))	('CDK', 'Gene', '983;1017;1019', (38, 41))	('CDK', 'Gene', '983;1017;1019', (93, 96))	('AKT2', 'Gene', (6, 10))
424738	32138169	We did not observe significant modification of the proliferation index, Ki67, with AMG 900 while clonogenic proliferation was decreased even with low AMG 900 concentration (Figure 5A).	('decreased', 'NegReg', (126, 135))	('clonogenic proliferation', 'CPA', (97, 121))	('AMG 900', 'Chemical', 'MESH:C555658', (150, 157))	('AMG 900', 'Chemical', 'MESH:C555658', (83, 90))	('AMG 900', 'Var', (83, 90))
424739	32138169	In cell-cycle, LPS78 and IB115 shown less than 10% cells in G0/SubG1 phase, suggesting that Ki67 is expressed in more than 90% of cells in other cell cycle phases without any treatment (Figure 6A).	('LPS78', 'Var', (15, 20))	('LPS78', 'Chemical', '-', (15, 20))	('IB115', 'Var', (25, 30))	('IB115', 'Chemical', '-', (25, 30))
424741	32138169	Inhibition of AURKA by RNA interference or alisertib in normal fibroblast-like or epithelial ovarian cancer cells induces a reduction of the migration process.	('reduction', 'NegReg', (124, 133))	('AURKA', 'Gene', (14, 19))	('RNA interference', 'MPA', (23, 39))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (82, 107))	('alisertib', 'Chemical', 'MESH:C550258', (43, 52))	('epithelial ovarian cancer', 'Disease', (82, 107))	('Inhibition', 'Var', (0, 10))	('migration process', 'CPA', (141, 158))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (82, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('AURKA', 'Gene', '6790', (14, 19))
424755	32138169	ERK1/2 are mostly known to induce survival signal, and under specific conditions, ERK phosphorylation is able induce apoptosis, whereas Phospho-p38 is known to be mainly involved in apoptosis (for review, see).	('p38', 'Gene', (144, 147))	('ERK1/2', 'Gene', (0, 6))	('ERK1/2', 'Gene', '5595;5594', (0, 6))	('survival signal', 'CPA', (34, 49))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', '5594', (82, 85))	('induce', 'Reg', (110, 116))	('p38', 'Gene', '5594', (144, 147))	('ERK', 'Gene', (82, 85))	('apoptosis', 'CPA', (117, 126))	('ERK', 'Gene', (0, 3))	('phosphorylation', 'Var', (86, 101))
424771	32138169	These findings suggest a possible competition between AMG 900 and doxorubicin in some tumours because of their genetic alterations resulting in drug bypasses/resistance.	('AMG 900', 'Chemical', 'MESH:C555658', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('resulting in', 'Reg', (131, 143))	('drug bypasses/resistance', 'MPA', (144, 168))	('alterations', 'Var', (119, 130))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))
424776	32138169	The inhibition of ERK activity by AMG 900 could explain this antagonist effect, whereas no similar effect was observed in the resistant and ERK active IB111.	('IB111', 'Chemical', '-', (151, 156))	('ERK', 'Gene', (18, 21))	('inhibition', 'NegReg', (4, 14))	('ERK', 'Gene', '5594', (140, 143))	('AMG', 'Var', (34, 37))	('AMG 900', 'Chemical', 'MESH:C555658', (34, 41))	('activity', 'MPA', (22, 30))	('ERK', 'Gene', '5594', (18, 21))	('ERK', 'Gene', (140, 143))
424957	32391141	Real-world experience with doxorubicin and olaratumab in soft tissue sarcomas in England and Northern Ireland A randomised phase II trial demonstrated that the addition of olaratumab to doxorubicin significantly increased overall survival (OS) in patients with advanced soft tissue sarcomas (STS) compared to doxorubicin alone.	('doxorubicin', 'Chemical', 'MESH:D004317', (186, 197))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (57, 76))	('soft tissue sarcomas', 'Disease', (270, 290))	('soft tissue sarcomas', 'Disease', (57, 77))	('sarcomas', 'Disease', 'MESH:D012509', (69, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (270, 290))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (270, 289))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (57, 77))	('sarcomas', 'Disease', (69, 77))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (270, 290))	('overall survival', 'MPA', (222, 238))	('doxorubicin', 'Chemical', 'MESH:D004317', (309, 320))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (57, 77))	('olaratumab', 'Chemical', 'MESH:C000589393', (172, 182))	('sarcomas', 'Disease', 'MESH:D012509', (282, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('olaratumab', 'Chemical', 'MESH:C000589393', (43, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (282, 290))	('sarcomas', 'Disease', (282, 290))	('patients', 'Species', '9606', (247, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('doxorubicin', 'Chemical', 'MESH:D004317', (27, 38))	('olaratumab', 'Var', (172, 182))	('increased', 'PosReg', (212, 221))
425105	31376222	The results showed that positive/high ezrin expression was significantly associated with poor prognosis in patients with bone and soft tissue sarcomas, which was consistent with the results of previous analyses in patients with solid cancers 20.	('expression', 'MPA', (44, 54))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (130, 149))	('patients', 'Species', '9606', (214, 222))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (130, 150))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (130, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('ezrin', 'Gene', '7430', (38, 43))	('ezrin', 'Gene', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('cancers', 'Disease', (234, 241))	('soft tissue sarcomas', 'Disease', (130, 150))	('cancers', 'Disease', 'MESH:D009369', (234, 241))	('patients', 'Species', '9606', (107, 115))	('positive/high', 'Var', (24, 37))
425150	31360726	When illuminated by blue light (466.5 nm), or exposed to low-dose (1-5 Gy) X-ray irradiation, acridine orange is cytotoxic through the generation of singlet oxygen (1O2).	('acridine', 'Var', (94, 102))	('singlet oxygen', 'MPA', (149, 163))	('acridine orange', 'Chemical', 'MESH:D000165', (94, 109))	('1O2', 'Chemical', '-', (165, 168))	('singlet oxygen', 'Chemical', 'MESH:D026082', (149, 163))	('cytotoxic', 'CPA', (113, 122))
425309	32493854	In our case, histological findings revealed spindle-shaped cell proliferation and positivity for smooth muscle actin, while other markers, such as CD31, CD34, and desmin, were negative.	('smooth muscle actin', 'Protein', (97, 116))	('CD34', 'Gene', (153, 157))	('CD31', 'Gene', '5175', (147, 151))	('CD34', 'Gene', '947', (153, 157))	('positivity', 'Var', (82, 92))	('desmin', 'Gene', (163, 169))	('CD31', 'Gene', (147, 151))	('desmin', 'Gene', '1674', (163, 169))	('spindle-shaped cell proliferation', 'CPA', (44, 77))
425353	30855438	It should also be noted that the genetic mutations in the Langerhans cell-specific marker langerin are associated with a lack of Birbeck granules and can also complicate diagnosis.	('Birbeck granules', 'MPA', (129, 145))	('associated', 'Reg', (103, 113))	('genetic mutations', 'Var', (33, 50))	('lack', 'NegReg', (121, 125))	('Lan', 'Gene', '9993', (58, 61))	('langerin', 'Gene', (90, 98))	('langerin', 'Gene', '50489', (90, 98))	('Lan', 'Gene', (58, 61))	('complicate', 'Reg', (159, 169))
425379	28179300	Activation of STAT3 and its target genes can induce cell-cycle progression, immune evasion, angiogenesis, antiapoptotic effects, tumor invasion and metastasis.	('STAT3', 'Gene', (14, 19))	('antiapoptotic effects', 'MPA', (106, 127))	('angiogenesis', 'CPA', (92, 104))	('induce', 'PosReg', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('metastasis', 'CPA', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cell-cycle progression', 'CPA', (52, 74))	('Activation', 'Var', (0, 10))	('immune evasion', 'MPA', (76, 90))	('tumor', 'Disease', (129, 134))
425421	28179300	As seen in Figure 1, STAT3 siRNA transfection of cells reduced viability among under the same oxygen concentrations, indicating the effectiveness of siRNA.	('reduced', 'NegReg', (55, 62))	('viability', 'MPA', (63, 72))	('transfection', 'Var', (33, 45))	('oxygen', 'Chemical', 'MESH:D010100', (94, 100))
425422	28179300	However, STAT3 siRNA more significantly reduced cell viability under normoxic conditons than hypoxic conditions.	('cell viability', 'CPA', (48, 62))	('hypoxic conditions', 'Disease', (93, 111))	('reduced', 'NegReg', (40, 47))	('STAT3 siRNA', 'Var', (9, 20))	('hypoxic conditions', 'Disease', 'MESH:D009135', (93, 111))
425423	28179300	These results indicate that hypoxic conditions might allow greater cell survival under treatment with STAT3 inhibitors or STAT3 siRNA.	('hypoxic conditions', 'Disease', (28, 46))	('STAT3', 'Var', (122, 127))	('hypoxic conditions', 'Disease', 'MESH:D009135', (28, 46))	('cell survival', 'CPA', (67, 80))	('STAT3', 'Gene', (102, 107))
425431	28179300	LY5 significantly inhibited colony-forming ability in all cancer cell lines even at 1.0 muM under 21% O2 (Figure 3).	('muM', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colony-forming ability in', 'CPA', (28, 53))	('LY5', 'Chemical', '-', (0, 3))	('LY5', 'Var', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('inhibited', 'NegReg', (18, 27))	('O2', 'Chemical', 'MESH:D010100', (102, 104))	('muM', 'Gene', '56925', (88, 91))	('cancer', 'Disease', (58, 64))
425438	28179300	From the results shown in Figure 4, it can be clearly seen that P-STAT3 levels in cells were higher with LLL12 in 1% O2 compared with those cultured in 21% O2.	('higher', 'PosReg', (93, 99))	('O2', 'Chemical', 'MESH:D010100', (156, 158))	('LLL12', 'Var', (105, 110))	('O2', 'Chemical', 'MESH:D010100', (117, 119))	('P-STAT3 levels', 'MPA', (64, 78))
425461	28179300	Inhibition of STAT3 caused increased expression of P-AKT and PERK under normoxic, but not under hypoxic conditions.	('STAT3', 'Gene', (14, 19))	('increased', 'PosReg', (27, 36))	('hypoxic conditions', 'Disease', (96, 114))	('AKT', 'Gene', '207', (53, 56))	('ERK', 'Gene', '5594', (62, 65))	('Inhibition', 'Var', (0, 10))	('hypoxic conditions', 'Disease', 'MESH:D009135', (96, 114))	('expression', 'MPA', (37, 47))	('AKT', 'Gene', (53, 56))	('ERK', 'Gene', (62, 65))
425738	33741020	PET-CT suggested that FDG metabolism inhomogeneity increased in the mass in the right atrium.	('increased', 'PosReg', (51, 60))	('inhomogeneity', 'Var', (37, 50))	('mass in the right atrium', 'MPA', (68, 92))	('FDG', 'Chemical', 'MESH:D019788', (22, 25))
425804	32881892	Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (93, 106))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (107, 120))	('EwS', 'Gene', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('aggressive solid tumor', 'Disease', (138, 160))	('aggressive solid tumor', 'Disease', 'MESH:D009369', (138, 160))	('EWSR1', 'Gene', '2130', (237, 242))	('Low-frequency variation', 'Var', (0, 23))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (93, 106))	('Ewing sarcoma', 'Disease', (93, 106))	('Ewing sarcoma', 'Disease', (107, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (107, 120))	('EwS', 'Gene', '2130', (122, 125))	('EWSR1', 'Gene', (237, 242))
425806	32881892	We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).	('variation', 'Var', (59, 68))	('EwS', 'Gene', '2130', (106, 109))	('EwS', 'Gene', (106, 109))	('EwS', 'Gene', '2130', (72, 75))	('EwS', 'Gene', (72, 75))	('EwS', 'Gene', '2130', (153, 156))	('EwS', 'Gene', (153, 156))
425807	32881892	We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5x10-8) and located near previously reported common susceptibility loci.	('EwS', 'Gene', (112, 115))	('rs2296730', 'Mutation', 'rs2296730', (58, 67))	('associated', 'Reg', (96, 106))	('rs112837127', 'Mutation', 'rs112837127', (42, 53))	('rs112837127', 'Var', (42, 53))	('EwS', 'Gene', '2130', (112, 115))	('rs2296730', 'Var', (58, 67))
425815	32881892	A defining feature of EwS tumors is the somatically acquired translocation between EWSR1 (22q12) and a member of the ETS transcription factor family, most commonly FLI1 (11q24) (85% of cases).	('translocation', 'Var', (61, 74))	('FLI1', 'Gene', '2313', (164, 168))	('EWSR1', 'Gene', (83, 88))	('EwS tumors', 'Disease', 'MESH:C563168', (22, 32))	('EWSR1', 'Gene', '2130', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('EwS tumors', 'Disease', (22, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('FLI1', 'Gene', (164, 168))
425817	32881892	The presence of EwS EWSR1-ETS fusions provides a molecularly distinct phenotype for genomic characterization, despite small case sample sizes.	('EWSR1', 'Gene', '2130', (20, 25))	('EwS', 'Gene', '2130', (16, 19))	('fusions', 'Var', (30, 37))	('EwS', 'Gene', (16, 19))	('EWSR1', 'Gene', (20, 25))
425818	32881892	Previous genome-wide association studies (GWAS) have identified 6 common genetic susceptibility loci associated with EwS risk (1p36.22, 6p25.1, 10q21, 15q15, 20p11.22 and 20p11.23).	('1p36.22', 'Var', (127, 134))	('EwS', 'Gene', '2130', (117, 120))	('10q21', 'Var', (144, 149))	('6p25.1', 'Var', (136, 142))	('20p11.22', 'Var', (158, 166))	('EwS', 'Gene', (117, 120))	('15q15', 'Var', (151, 156))
425819	32881892	Effect estimates for variants at these loci exhibit elevated odds ratios (OR > 1.7), which is high for cancer GWAS and striking in light of the rarity of EwS in familial cancer predisposition syndromes.	('variants', 'Var', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('EwS', 'Gene', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (170, 176))	('familial cancer', 'Disease', (161, 176))	('familial cancer', 'Disease', 'MESH:D009369', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('EwS', 'Gene', '2130', (154, 157))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
425823	32881892	The high locus-to-case discovery ratio of previous EwS GWAS and large effect sizes of common EwS susceptibility loci led our group to revisit whether current series of EwS cases would be sufficient to detect associations between rare or low-frequency variants and EwS risk.	('EwS', 'Gene', '2130', (51, 54))	('EwS', 'Gene', (168, 171))	('variants', 'Var', (251, 259))	('EwS', 'Gene', '2130', (264, 267))	('EwS', 'Gene', '2130', (93, 96))	('EwS', 'Gene', (51, 54))	('EwS', 'Gene', (93, 96))	('EwS', 'Gene', (264, 267))	('associations', 'Interaction', (208, 220))	('EwS', 'Gene', '2130', (168, 171))
425824	32881892	We systematically scanned across the genome for well-imputed, low-frequency variants associated with EwS susceptibility in the largest collection of genotyped EwS cases to date (733 EwS cases and 1,346 controls).	('EwS', 'Gene', (182, 185))	('EwS', 'Gene', '2130', (159, 162))	('EwS', 'Gene', (159, 162))	('EwS', 'Gene', '2130', (101, 104))	('variants', 'Var', (76, 84))	('EwS', 'Gene', (101, 104))	('EwS', 'Gene', '2130', (182, 185))
425834	32881892	Imputed genotypes for the three EwS-associated low-frequency or rare variants (rs78119607, rs112837127, rs2296730) were validated by allele-specific TaqMan assay (Thermo Fisher Scientific) at CGR following standard manufacturer protocols.	('rs2296730', 'Var', (104, 113))	('rs2296730', 'Mutation', 'rs2296730', (104, 113))	('EwS', 'Gene', '2130', (32, 35))	('rs112837127', 'Var', (91, 102))	('EwS', 'Gene', (32, 35))	('rs78119607', 'Mutation', 'rs78119607', (79, 89))	('rs112837127', 'Mutation', 'rs112837127', (91, 102))	('rs78119607', 'Var', (79, 89))
425836	32881892	Our analysis identified evidence for associations of three putative low frequency (MAF < 0.05) imputed variants associated with EwS risk, which we advanced to validation studies described below.	('EwS', 'Gene', '2130', (128, 131))	('variants', 'Var', (103, 111))	('EwS', 'Gene', (128, 131))	('associations', 'Interaction', (37, 49))	('associated', 'Reg', (112, 122))
425837	32881892	The variants were located at 1q23.3, 20p11.23, and 20p11.22 (Table 1, Fig 1 and S1 Fig) and tagged by rs78119607, rs112837127, and rs2296730, respectively.	('rs2296730', 'Var', (131, 140))	('rs2296730', 'Mutation', 'rs2296730', (131, 140))	('rs112837127', 'Mutation', 'rs112837127', (114, 125))	('rs112837127', 'Var', (114, 125))	('rs78119607', 'Mutation', 'rs78119607', (102, 112))	('rs78119607', 'Var', (102, 112))
425838	32881892	The MAF among controls of European ancestry ranged from 0.001 for rs78119607 to 0.046 for rs2296730 with minor allele effect sizes ranging from 0.18 to 16.64 (Table 2).	('rs2296730', 'Var', (90, 99))	('rs78119607', 'Mutation', 'rs78119607', (66, 76))	('rs78119607', 'Var', (66, 76))	('rs2296730', 'Mutation', 'rs2296730', (90, 99))
425839	32881892	The odds ratio for the minor A allele of rs112837127 suggested a potentially protective effect (OR = 0.18) indicating that in some instances low-frequency variation could reduce susceptibility to EwS.	('susceptibility', 'MPA', (178, 192))	('rs112837127', 'Mutation', 'rs112837127', (41, 52))	('reduce', 'NegReg', (171, 177))	('rs112837127', 'Var', (41, 52))	('EwS', 'Gene', (196, 199))	('EwS', 'Gene', '2130', (196, 199))
425841	32881892	As shown in S2 Fig, we were able to replicate the imputed genotypes for rs112837127 and rs2296730 with 98.46% and 100% concordance rate.	('rs2296730', 'Var', (88, 97))	('rs112837127', 'Var', (72, 83))	('rs112837127', 'Mutation', 'rs112837127', (72, 83))	('rs2296730', 'Mutation', 'rs2296730', (88, 97))
425843	32881892	The two validated low frequency variants, rs112837127 and rs2296730, associated with EwS on chromosome 20 are in proximity to two previously identified EwS common susceptibility variants, rs6106336 and rs6047482.	('rs2296730', 'Mutation', 'rs2296730', (58, 67))	('EwS', 'Gene', '2130', (152, 155))	('rs112837127', 'Mutation', 'rs112837127', (42, 53))	('rs112837127', 'Var', (42, 53))	('rs6106336', 'Var', (188, 197))	('rs6106336', 'Mutation', 'rs6106336', (188, 197))	('rs6047482', 'Mutation', 'rs6047482', (202, 211))	('rs6047482', 'Var', (202, 211))	('EwS', 'Gene', '2130', (85, 88))	('EwS', 'Gene', (152, 155))	('EwS', 'Gene', (85, 88))	('rs2296730', 'Var', (58, 67))
425844	32881892	rs112837127 did not display evidence for LD with either the nearby common variant (R2EUR rs6106336 = 0.005, R2EUR rs6047482 = 0.023) or the other low-frequency variant (R2EUR rs2296730 = 0.003).	('rs6047482', 'Mutation', 'rs6047482', (114, 123))	('rs112837127', 'Var', (0, 11))	('R2EUR', 'Var', (108, 113))	('rs112837127', 'Mutation', 'rs112837127', (0, 11))	('rs6106336', 'Mutation', 'rs6106336', (89, 98))	('rs2296730', 'Mutation', 'rs2296730', (175, 184))
425845	32881892	However, rs2296730 displayed evidence for moderate levels of LD with the common rs6106336 variant (R2EUR = 0.311), but not the common rs6047482 variant (R2EUR = 0.006).	('rs2296730', 'Var', (9, 18))	('rs6047482', 'Mutation', 'rs6047482', (134, 143))	('rs2296730', 'Mutation', 'rs2296730', (9, 18))	('rs6106336', 'Mutation', 'rs6106336', (80, 89))	('rs6106336', 'Var', (80, 89))
425846	32881892	Estimates of D', a measure of allelic transmission, suggest the two associated low-frequency variants (rs112837127 and rs2296730) are transmitted on haplotypes of the common rs6106336 variant (S3 Fig), with the minor A allele of rs112837127 being transmitted with the major T allele of rs6106336 (D'EUR = 1.0) and the minor G allele of rs2296730 being transmitted with the minor G allele of the rs6106336 (D'EUR = 0.772).	('rs6106336', 'Mutation', 'rs6106336', (395, 404))	('rs6106336', 'Var', (174, 183))	('rs6106336', 'Mutation', 'rs6106336', (174, 183))	('rs2296730', 'Var', (336, 345))	('rs112837127', 'Var', (103, 114))	('rs112837127', 'Mutation', 'rs112837127', (103, 114))	('rs6106336', 'Mutation', 'rs6106336', (286, 295))	('rs2296730', 'Var', (119, 128))	('rs112837127', 'Mutation', 'rs112837127', (229, 240))	('rs112837127', 'Var', (229, 240))	('rs2296730', 'Mutation', 'rs2296730', (119, 128))	('rs6106336', 'Var', (286, 295))	('rs2296730', 'Mutation', 'rs2296730', (336, 345))
425847	32881892	To further test if the two low-frequency variants tagged independent EwS association signals, odds ratios and P-values for the association with EwS were calculated with and without conditioning on the neighboring common variants.	('variants', 'Var', (41, 49))	('EwS', 'Gene', '2130', (69, 72))	('EwS', 'Gene', (144, 147))	('EwS', 'Gene', (69, 72))	('EwS', 'Gene', '2130', (144, 147))
425848	32881892	Conditional analyses indicated that rs112837127 was statistically associated with EwS (OR = 0.20, 95%CI = 0.09-0.40, P-value = 5.84x10-8; Table 2) independent from neighboring common variants.	('EwS', 'Gene', (82, 85))	('associated', 'Reg', (66, 76))	('EwS', 'Gene', '2130', (82, 85))	('rs112837127', 'Mutation', 'rs112837127', (36, 47))	('rs112837127', 'Var', (36, 47))
425849	32881892	As in the R2 analyses, the low-frequency rs22966730 variant demonstrated evidence for a correlation with the common rs6106336 variant as observed in the attenuated odds ratio estimate and increase in p-value in the conditional analysis (OR = 1.61, 95%CI = 1.16-2.24, P-value = 3.50x10-3; Table 2).	('p-value', 'MPA', (200, 207))	('rs22966730', 'Mutation', 'rs22966730', (41, 51))	('rs6106336', 'Mutation', 'rs6106336', (116, 125))	('rs22966730', 'Var', (41, 51))
425850	32881892	Finally, we examined potential interaction between rs2296730 and rs6106336 (p = 0.568), rs2296730 and rs6047482 (p = 0.319), as well as rs6106336 and rs112837127 (p = 0.538) and found no significant evidence for SNP-SNP interactions.	('rs2296730', 'Var', (51, 60))	('rs6047482', 'Mutation', 'rs6047482', (102, 111))	('rs2296730', 'Mutation', 'rs2296730', (51, 60))	('interaction', 'Interaction', (31, 42))	('rs2296730', 'Var', (88, 97))	('rs6106336', 'Var', (136, 145))	('rs6106336', 'Mutation', 'rs6106336', (136, 145))	('rs6047482', 'Var', (102, 111))	('rs6106336', 'Var', (65, 74))	('rs6106336', 'Mutation', 'rs6106336', (65, 74))	('rs2296730', 'Mutation', 'rs2296730', (88, 97))	('rs112837127', 'Mutation', 'rs112837127', (150, 161))	('rs112837127', 'Var', (150, 161))
425851	32881892	We report an analysis of well-imputed low-frequency variants based on common genotyped variants in a large EwS case series to investigate the contribution of low-frequency variants to the underlying genetic architecture of EwS susceptibility.	('EwS', 'Gene', '2130', (223, 226))	('EwS', 'Gene', '2130', (107, 110))	('EwS', 'Gene', (223, 226))	('variants', 'Var', (52, 60))	('EwS', 'Gene', (107, 110))
425852	32881892	We found evidence for associations of two low-frequency variants (rs112837127 and rs22966730) with EwS risk, and one of the variants, rs112837127, demonstrated an association independent of a nearby common germline susceptibility variant.	('rs112837127', 'Var', (134, 145))	('rs112837127', 'Var', (66, 77))	('rs112837127', 'Mutation', 'rs112837127', (66, 77))	('rs22966730', 'Var', (82, 92))	('EwS', 'Gene', '2130', (99, 102))	('associations', 'Interaction', (22, 34))	('EwS', 'Gene', (99, 102))	('rs22966730', 'Mutation', 'rs22966730', (82, 92))	('rs112837127', 'Mutation', 'rs112837127', (134, 145))
425853	32881892	Our findings suggest that in addition to common germline susceptibility variants, low-frequency variants are important for genetic susceptibility to EwS.	('EwS', 'Gene', (149, 152))	('EwS', 'Gene', '2130', (149, 152))	('variants', 'Var', (96, 104))
425856	32881892	SNPs in the vitamin D receptor gene have also been linked to decreased risk in prostate cancer in African American men and rs1866074 near the thymine DNA glycosylase gene were reported to be correlated with lower colorectal cancer risk.	('rs1866074', 'Var', (123, 132))	('men', 'Species', '9606', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('decreased risk in prostate', 'Phenotype', 'HP:0008687', (61, 87))	('colorectal cancer', 'Disease', 'MESH:D015179', (213, 230))	('vitamin D receptor', 'Gene', (12, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('colorectal cancer', 'Disease', (213, 230))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('thymine DNA glycosylase', 'Gene', '6996', (142, 165))	('decreased', 'NegReg', (61, 70))	('prostate cancer', 'Disease', (79, 94))	('vitamin D receptor', 'Gene', '7421', (12, 30))	('lower', 'NegReg', (207, 212))	('SNPs', 'Var', (0, 4))	('thymine DNA glycosylase', 'Gene', (142, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (213, 230))	('rs1866074', 'Mutation', 'rs1866074', (123, 132))
425860	32881892	Whether the minor allele of rs112837127 tags a haplotype with modified LINC00237 expression remains to be investigated.	('LINC00237', 'Gene', '101180898', (71, 80))	('rs112837127', 'Mutation', 'rs112837127', (28, 39))	('rs112837127', 'Var', (28, 39))	('LINC00237', 'Gene', (71, 80))
425863	32881892	These synthetic associations may be of particular importance for EwS susceptibility as it is plausible common, low-frequency and rare variation at GGAA microsatellites may interact to impact binding of EWSR1-FLI1 fusion oncoproteins and alter regulation of downstream genes in core EwS regulatory pathways.	('EwS', 'Gene', '2130', (65, 68))	('EWSR1', 'Gene', (202, 207))	('variation', 'Var', (134, 143))	('GGAA', 'Gene', (147, 151))	('EwS', 'Gene', '2130', (282, 285))	('fusion oncoproteins', 'Protein', (213, 232))	('EwS', 'Gene', (65, 68))	('alter', 'Reg', (237, 242))	('FLI1', 'Gene', (208, 212))	('interact', 'Reg', (172, 180))	('EWSR1', 'Gene', '2130', (202, 207))	('EwS', 'Gene', (282, 285))	('regulation', 'MPA', (243, 253))	('binding', 'Interaction', (191, 198))	('FLI1', 'Gene', '2313', (208, 212))	('impact', 'Reg', (184, 190))
425864	32881892	In the case of EwS, common variant associations may highlight important EwS germline susceptibility regions where low-frequency and rare variation have important roles altering EwS risk.	('EwS', 'Gene', '2130', (177, 180))	('EwS', 'Gene', '2130', (72, 75))	('EwS', 'Gene', '2130', (15, 18))	('EwS', 'Gene', (72, 75))	('EwS', 'Gene', (177, 180))	('variant', 'Var', (27, 34))	('EwS', 'Gene', (15, 18))
425865	32881892	A limitation of our study is the lack of validation in an independent cohort as well as a lack of regional EwS sequencing of the relevant region to identify potential causal variants which can be functionally examined through in vitro experiments.	('variants', 'Var', (174, 182))	('EwS', 'Gene', '2130', (107, 110))	('men', 'Species', '9606', (241, 244))	('EwS', 'Gene', (107, 110))
425868	32881892	15 May 2020  PONE-D-20-05330 Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma PLOS ONE Dear Dr. Machiela, Thank you for submitting your manuscript to PLOS ONE.	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (122, 135))	('PONE-D-20-05330', 'Chemical', '-', (13, 28))	('Ewing sarcoma PLOS', 'Disease', (122, 140))	('Low-frequency variation', 'Var', (29, 52))
425885	32881892	The authors identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5x10 -8).	('EwS', 'Gene', '2130', (121, 124))	('rs2296730', 'Var', (67, 76))	('rs112837127', 'Var', (51, 62))	('EwS', 'Gene', (121, 124))	('rs112837127', 'Mutation', 'rs112837127', (51, 62))	('rs2296730', 'Mutation', 'rs2296730', (67, 76))	('associated', 'Reg', (105, 115))
425887	32881892	Reviewer #2: The author utilized imputed genotype data from several studies and identified two rare variants that may be associated with EwS.	('EwS', 'Gene', '2130', (137, 140))	('EwS', 'Gene', (137, 140))	('associated', 'Reg', (121, 131))	('variants', 'Var', (100, 108))
425894	32881892	We agree with Reviewer #1 that it would be of interest to investigate clinical indices associated with Ewing sarcoma with these two reported variants (rs112837127 and rs2296730) to better understand potential clinical relationships.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (103, 116))	('rs112837127', 'Mutation', 'rs112837127', (151, 162))	('rs112837127', 'Var', (151, 162))	('rs2296730', 'Var', (167, 176))	('Ewing sarcoma', 'Disease', (103, 116))	('rs2296730', 'Mutation', 'rs2296730', (167, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))
425903	32881892	Furthermore, the resulting independent associations of low-frequency variants rs112837127 and rs2296730 near the known Ewing sarcoma chromosome 20 susceptibility locus adds to the evidence that this region is important for Ewing sarcoma susceptibility and suggests that common and low-frequency germline variation interact in this region to impact Ewing sarcoma risk.	('rs2296730', 'Var', (94, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (348, 361))	('rs2296730', 'Mutation', 'rs2296730', (94, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (354, 361))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (119, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('impact', 'Reg', (341, 347))	('Ewing sarcoma', 'Disease', (348, 361))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (223, 236))	('rs112837127', 'Mutation', 'rs112837127', (78, 89))	('rs112837127', 'Var', (78, 89))
425911	32881892	We thank Reviewer #3's insight and performed logistic regression using Ewing sarcoma diagnosis as outcome, and the SNPs of interest as predictors to test potential interaction between rs2296730 and rs6106336 (p=0.568), rs2296730 and rs6047482 (p=0.319), as well as rs6106336 and rs112837127 (p = 0.538).	('rs6106336', 'Mutation', 'rs6106336', (198, 207))	('interaction', 'Interaction', (164, 175))	('rs2296730', 'Mutation', 'rs2296730', (219, 228))	('rs6106336', 'Var', (198, 207))	('rs2296730', 'Var', (184, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('rs112837127', 'Mutation', 'rs112837127', (279, 290))	('rs112837127', 'Var', (279, 290))	('rs2296730', 'Mutation', 'rs2296730', (184, 193))	('rs6106336', 'Mutation', 'rs6106336', (265, 274))	('rs6047482', 'Mutation', 'rs6047482', (233, 242))	('rs6047482', 'Var', (233, 242))	('rs2296730', 'Var', (219, 228))	('rs6106336', 'Var', (265, 274))
425912	32881892	-- Methods "Finally, we examined potential interaction between rs2296730 and rs6106336 (p=0.568), rs2296730 and rs6047482 (p=0.319), as well as rs6106336 and rs112837127 (p = 0.538) and found no significant evidence for SNP-SNP interactions."	('rs6106336', 'Mutation', 'rs6106336', (77, 86))	('rs112837127', 'Mutation', 'rs112837127', (158, 169))	('rs2296730', 'Mutation', 'rs2296730', (63, 72))	('rs6106336', 'Var', (77, 86))	('rs6106336', 'Mutation', 'rs6106336', (144, 153))	('rs6047482', 'Mutation', 'rs6047482', (112, 121))	('rs6047482', 'Var', (112, 121))	('rs2296730', 'Var', (98, 107))	('rs6106336', 'Var', (144, 153))	('rs2296730', 'Mutation', 'rs2296730', (98, 107))	('rs2296730', 'Var', (63, 72))	('rs112837127', 'Var', (158, 169))	('interaction', 'Interaction', (43, 54))
425913	32881892	4 Aug 2020  Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma PONE-D-20-05330R1 Dear Dr. Machiela, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.	('Low-frequency variation', 'Var', (12, 35))	('men', 'Species', '9606', (354, 357))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('PONE-D-20-05330', 'Chemical', '-', (119, 134))	('Ewing sarcoma', 'Disease', (105, 118))
426120	27082603	The scope included the following (Figure 3): tumor cells presented as a spindle shape and were woven in a vortex arrangement; cell pleomorphism was apparent, and the mitotic count could be determined easily; patchy necrosis was observed in the area; and immunohistochemistry showed CD21 (+), CD23 (+), CD117 (-), S-100 (-), Desmin (-), CD34 (-), SMA (-), DOG-1 (-), Ki-67(40%), CK (-), CgA (-), Syn (-), and EBER (-).	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('DOG', 'Species', '9615', (355, 358))	('Desmin', 'Gene', (324, 330))	('CD21', 'Gene', (282, 286))	('tumor', 'Disease', (45, 50))	('CD34', 'Gene', '415130', (336, 340))	('CD34', 'Gene', (336, 340))	('necrosis', 'Disease', (215, 223))	('CD23', 'Gene', (292, 296))	('S-100', 'Var', (313, 318))	('Desmin', 'Gene', '497091', (324, 330))	('CD21', 'Gene', '1380', (282, 286))	('CD117 (-', 'Var', (302, 310))	('CD23', 'Gene', '2208', (292, 296))	('necrosis', 'Disease', 'MESH:D009336', (215, 223))	('men', 'Species', '9606', (120, 123))
426168	22374332	The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose escalation clinical trial Dysregulated cyclin-dependent kinases (CDKs) are important to the growth of some sarcomas.	('Dysregulated', 'Var', (189, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('flavopiridol', 'Chemical', 'MESH:C077990', (38, 50))	('CDKs', 'Gene', '1017;1019;1021;1025', (228, 232))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))	('sarcomas', 'Disease', (96, 104))	('sarcomas', 'Disease', 'MESH:D012509', (270, 278))	('sarcomas', 'Phenotype', 'HP:0100242', (270, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (270, 277))	('doxorubicin', 'Chemical', 'MESH:D004317', (63, 74))	('sarcomas', 'Disease', (270, 278))	('CDKs', 'Gene', (228, 232))
426191	22374332	This defect in DNA repair then sensitizes tumor cells to p53-dependent induction of apoptosis by irinotecan.	('sensitizes', 'Reg', (31, 41))	('irinotecan', 'Chemical', 'MESH:D000077146', (97, 107))	('tumor', 'Disease', (42, 47))	('defect', 'Var', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('p53', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('p53', 'Gene', '7157', (57, 60))
426210	22374332	PVDF membranes were blocked with 5% nonfat dried milk in PBS buffer containing 0.1% Tween-20 (PBST) for 1 hour and probed with antibodies for full length and cleaved PARP (Santa Cruz Biotechnology) and tubulin (Cell Signaling).	('PVDF', 'Chemical', 'MESH:C024865', (0, 4))	('PBS', 'Chemical', 'MESH:D007854', (57, 60))	('PARP', 'Gene', '1302', (166, 170))	('tubulin', 'Protein', (202, 209))	('Tween-20', 'Chemical', 'MESH:D011136', (84, 92))	('PBS', 'Chemical', 'MESH:D007854', (94, 97))	('PARP', 'Gene', (166, 170))	('cleaved', 'Var', (158, 165))
426258	22374332	As shown in Figure 1A, colony formation assays revealed that in comparison to doxorubicin or flavopiridol alone, observable colonies decreased significantly with all the combinations tested.	('doxorubicin', 'Chemical', 'MESH:D004317', (78, 89))	('flavopiridol', 'Chemical', 'MESH:C077990', (93, 105))	('combinations', 'Var', (170, 182))	('decreased', 'NegReg', (133, 142))
426268	22374332	These data were consistent with prior observations that dedifferentiated liposarcoma cell lines, with amplified CDK4, are highly sensitive to flavopiridol (data not shown) as well as the clinical observation that dedifferentiated liposarcomas are generally resistant to doxorubicin.	('sensitive', 'MPA', (129, 138))	('liposarcoma', 'Disease', 'MESH:D008080', (73, 84))	('liposarcoma', 'Phenotype', 'HP:0012034', (73, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('doxorubicin', 'Chemical', 'MESH:D004317', (270, 281))	('flavopiridol', 'Chemical', 'MESH:C077990', (142, 154))	('CDK4', 'Gene', (112, 116))	('liposarcoma', 'Disease', (230, 241))	('liposarcomas', 'Disease', 'MESH:D008080', (230, 242))	('liposarcomas', 'Phenotype', 'HP:0012034', (230, 242))	('sarcomas', 'Phenotype', 'HP:0100242', (234, 242))	('liposarcoma', 'Disease', (73, 84))	('CDK4', 'Gene', '1019', (112, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('liposarcomas', 'Disease', (230, 242))	('amplified', 'Var', (102, 111))	('liposarcoma', 'Phenotype', 'HP:0012034', (230, 241))	('liposarcoma', 'Disease', 'MESH:D008080', (230, 241))
426324	22374332	Preclinically, we documented in MPNST cells that flavopiridol potentiates doxorubicin, when compared to single agents alone.	('flavopiridol', 'Var', (49, 61))	('MPNST', 'Phenotype', 'HP:0100697', (32, 37))	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('flavopiridol', 'Chemical', 'MESH:C077990', (49, 61))	('men', 'Species', '9606', (22, 25))	('doxorubicin', 'MPA', (74, 85))	('potentiates', 'PosReg', (62, 73))
426325	22374332	Further, we demonstrated that flavopiridol is active in vivo both as a single agent and in combination with doxorubicin in liposarcoma xenograft with amplified CDK4.	('CDK4', 'Gene', (160, 164))	('liposarcoma', 'Disease', (123, 134))	('CDK4', 'Gene', '1019', (160, 164))	('amplified', 'Var', (150, 159))	('liposarcoma', 'Disease', 'MESH:D008080', (123, 134))	('liposarcoma', 'Phenotype', 'HP:0012034', (123, 134))	('flavopiridol', 'Chemical', 'MESH:C077990', (30, 42))	('doxorubicin', 'Chemical', 'MESH:D004317', (108, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
426344	22374332	Notably, in this study, the PFS12weeks and PFS24weeks compare favorably to these reference standards and suggest that this regimen may be worth further exploration in this patient population.	('patient', 'Species', '9606', (172, 179))	('PFS12weeks', 'Var', (28, 38))	('PFS24weeks', 'Var', (43, 53))	('men', 'Species', '9606', (127, 130))
426345	22374332	While the benefit of flavopiridol based therapy in the treatment of WD and DD liposarcoma could be hypothesized to be a function of its CDK4 amplification, other sarcoma types are not as clearly linked to dysregulated apoptosis.	('amplification', 'Var', (141, 154))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('sarcoma', 'Disease', (162, 169))	('WD', 'Disease', 'MESH:D006527', (68, 70))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('CDK4', 'Gene', (136, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('CDK4', 'Gene', '1019', (136, 140))	('liposarcoma', 'Phenotype', 'HP:0012034', (78, 89))	('DD liposarcoma', 'Disease', (75, 89))	('men', 'Species', '9606', (60, 63))	('sarcoma', 'Disease', (82, 89))	('DD liposarcoma', 'Disease', 'MESH:D008080', (75, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('flavopiridol', 'Chemical', 'MESH:C077990', (21, 33))
426402	27733900	High nuclear expression of proteasome activator complex subunit 1 predicts poor survival in soft tissue leiomyosarcomas Previous studies on high grade sarcomas using mass spectrometry imaging showed proteasome activator complex subunit 1 (PSME1) to be associated with poor survival in soft tissue sarcoma patients.	('leiomyosarcomas', 'Disease', (104, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('sarcomas', 'Disease', (151, 159))	('sarcomas', 'Disease', 'MESH:D012509', (111, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('sarcoma', 'Disease', (111, 118))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (104, 119))	('sarcomas', 'Disease', (111, 119))	('proteasome activator complex subunit 1', 'Gene', (27, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('High', 'Var', (0, 4))	('sarcoma', 'Disease', 'MESH:D012509', (297, 304))	('sarcoma', 'Disease', (297, 304))	('poor', 'NegReg', (75, 79))	('PSME1', 'Gene', (239, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('soft tissue leiomyosarcomas', 'Phenotype', 'HP:0030448', (92, 119))	('proteasome activator complex subunit 1', 'Gene', '5720', (27, 65))	('proteasome activator complex subunit 1', 'Gene', (199, 237))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (285, 304))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (104, 118))	('PSME1', 'Gene', '5720', (239, 244))	('patients', 'Species', '9606', (305, 313))	('sarcoma', 'Phenotype', 'HP:0100242', (297, 304))	('proteasome activator complex subunit 1', 'Gene', '5720', (199, 237))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (104, 119))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('sarcoma', 'Disease', (151, 158))
426408	27733900	In leiomyosarcomas, high expression was associated with overall poor survival (p = 0.034), decreased metastasis-free survival (p = 0.002) and lower event-free survival (p = 0.007).	('sarcomas', 'Phenotype', 'HP:0100242', (10, 18))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (3, 18))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (3, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('poor', 'NegReg', (64, 68))	('lower', 'NegReg', (142, 147))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (3, 17))	('leiomyosarcomas', 'Disease', (3, 18))	('high', 'Var', (20, 24))	('event-free survival', 'CPA', (148, 167))	('metastasis-free survival', 'CPA', (101, 125))	('decreased', 'NegReg', (91, 100))
426410	27733900	High expression of PSME1 is associated with poor metastasis-free survival in soft tissue leiomyosarcoma patients, and might be used as an independent prognostic biomarker.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('High expression', 'Var', (0, 15))	('leiomyosarcoma', 'Disease', (89, 103))	('poor', 'NegReg', (44, 48))	('metastasis-free survival', 'CPA', (49, 73))	('PSME1', 'Gene', '5720', (19, 24))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (89, 103))	('PSME1', 'Gene', (19, 24))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (89, 103))	('patients', 'Species', '9606', (104, 112))
426459	27733900	High PSME1 expression was associated with poor overall survival (p = 0.034), decreased metastasis-free survival (p = 0.002) and lower event-free survival (p = 0.007) (Fig.	('event-free survival', 'CPA', (134, 153))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('PSME1', 'Gene', '5720', (5, 10))	('metastasis-free survival', 'CPA', (87, 111))	('PSME1', 'Gene', (5, 10))	('lower', 'NegReg', (128, 133))	('overall survival', 'CPA', (47, 63))	('poor', 'NegReg', (42, 46))	('decreased', 'NegReg', (77, 86))
426460	27733900	Using multivariable Cox Regression analyses including clinically relevant co-factors such as histological grade, age and gender, we showed that high nuclear expression of PSME1 was independently associated with metastasis-free survival (p = 0.03) (Table 1).	('associated', 'Reg', (195, 205))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('high', 'Var', (144, 148))	('metastasis-free survival', 'CPA', (211, 235))	('PSME1', 'Gene', (171, 176))	('PSME1', 'Gene', '5720', (171, 176))
426484	27733900	Moreover, high nuclear expression of PSME1 was significantly associated to poor outcome (overall survival, metastasis-free survival and event-free survival) in leiomyosarcoma patients, although the patient cohort is rather small (n = 34).	('leiomyosarcoma', 'Disease', (160, 174))	('patient', 'Species', '9606', (198, 205))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (160, 174))	('patient', 'Species', '9606', (175, 182))	('PSME1', 'Gene', (37, 42))	('high nuclear', 'Var', (10, 22))	('PSME1', 'Gene', '5720', (37, 42))	('metastasis-free survival', 'CPA', (107, 131))	('patients', 'Species', '9606', (175, 183))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (160, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
426487	27733900	Moreover, high nuclear PSME1 expression was found to be an independent predictor of metastasis-free survival in leiomyosarcoma patients.	('leiomyosarcoma', 'Disease', (112, 126))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (112, 126))	('PSME1', 'Gene', (23, 28))	('high nuclear', 'Var', (10, 22))	('PSME1', 'Gene', '5720', (23, 28))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (112, 126))	('patients', 'Species', '9606', (127, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('expression', 'MPA', (29, 39))	('metastasis-free survival', 'CPA', (84, 108))
426490	27733900	Our results showed that high nuclear expression of proteasome activator complex subunit 1 is an independent poor prognostic factor in leiomyosarcomas, which suggests that the proteasome could be exploited as a possible novel target for the treatment of leiomyosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (260, 268))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (134, 149))	('proteasome activator complex subunit 1', 'Gene', (51, 89))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (253, 268))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (253, 268))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (253, 267))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (134, 148))	('leiomyosarcomas', 'Disease', (134, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('leiomyosarcomas', 'Disease', (253, 268))	('high', 'Var', (24, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('proteasome activator complex subunit 1', 'Gene', '5720', (51, 89))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (134, 149))
426502	29904746	Molecular analysis using a break-apart probe revealed a Ewing sarcoma breakpoint region 1 (EWSR1) gene translocation in 100% of 300 interphase nuclei that, upon examination, confirmed Ewing's sarcoma or PNET that was staged as T1b/N0/M0.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('confirmed', 'Reg', (174, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('translocation', 'Var', (103, 116))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (184, 199))	("Ewing's sarcoma", 'Disease', (184, 199))	('EWSR1', 'Gene', (91, 96))	('Ewing sarcoma breakpoint region 1', 'Gene', (56, 89))	('PNET', 'Disease', (203, 207))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (56, 89))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (184, 199))	('EWSR1', 'Gene', '2130', (91, 96))
426519	29904746	EFTs are characterized by translocations of the EWSR1 gene on chromosome 22q12.	('EWSR1', 'Gene', (48, 53))	('EWSR1', 'Gene', '2130', (48, 53))	('EFTs', 'Disease', (0, 4))	('translocations', 'Var', (26, 40))
426520	29904746	In 85% to 90% of EFT cases, a recurrent chromosomal translocation, t(11;22)(q24;q12), fuses the 5' portion of the EWSR1 gene on chromosome 22 to the 3' portion of the FLI1 gene on chromosome 11.	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (30, 65))	('EWSR1', 'Gene', (114, 119))	('EWSR1', 'Gene', '2130', (114, 119))	('FLI1', 'Gene', (167, 171))	('fuses', 'Var', (86, 91))	('FLI1', 'Gene', '2313', (167, 171))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (67, 84))
426609	28975018	Tumor DNA sequencing of 236 genes by FoundationOne panel found truncating mutations in PTEN and missense mutations in RET and TP53.	('truncating', 'MPA', (63, 73))	('PTEN', 'Gene', (87, 91))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PTEN', 'Gene', '5728', (87, 91))	('TP53', 'Gene', (126, 130))	('RET', 'Gene', '5979', (118, 121))	('missense mutations', 'Var', (96, 114))	('TP53', 'Gene', '7157', (126, 130))	('RET', 'Gene', (118, 121))
426614	28975018	A clonal truncating mutation in the CLTCL1 gene, which stabilizes the mitotic spindle, was likely a driver mutation of tumorigenesis and could explain the extensive copy number aberrations (CNAs) and genomic rearrangements in the tumor including a chr15/chr17 local chromothripsis resulted in 6 expressed fusion genes.	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (119, 124))	('CLTCL1', 'Gene', '8218', (36, 42))	('mutation', 'Var', (20, 28))	('expressed', 'MPA', (295, 304))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('CLTCL1', 'Gene', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
426616	28975018	Missense mutations in ATM and splice-site mutation in VEGFR1 were also detected in addition to the TP53 missense mutation reported by FoundationOne.	('TP53', 'Gene', (99, 103))	('ATM', 'Gene', (22, 25))	('ATM', 'Gene', '472', (22, 25))	('VEGFR1', 'Gene', '2321', (54, 60))	('TP53', 'Gene', '7157', (99, 103))	('VEGFR1', 'Gene', (54, 60))	('Missense mutations', 'Var', (0, 18))
426623	28975018	The exome sequencing identified 81 somatic mutations (Supplementary Table S1) in tumor but not in blood or adjacent normal tissues, giving a mutation rate of 1.2 per million base-pairs (Mbp) compared to the average rate of 0.41 per Mbp in papillary thyroid cancer.	('papillary thyroid cancer', 'Disease', (239, 263))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (239, 263))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (239, 263))	('thyroid cancer', 'Phenotype', 'HP:0002890', (249, 263))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
426625	28975018	In addition, the FoundationOne Panel didn't report mutations in CLTCL1, VEGFR1, or ATM, which are of particular interests due to their established roles in cancer (Table 1, Supplementary Figure 2A-D).	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('VEGFR1', 'Gene', '2321', (72, 78))	('ATM', 'Gene', '472', (83, 86))	('VEGFR1', 'Gene', (72, 78))	('CLTCL1', 'Gene', '8218', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ATM', 'Gene', (83, 86))	('CLTCL1', 'Gene', (64, 70))
426626	28975018	The clonal heterozygous truncating mutation L433* in CLTCL1 was found in tumor exome sequencing and was consequently validated by Sanger sequencing (data not shown).	('L433*', 'SUBSTITUTION', 'None', (44, 49))	('CLTCL1', 'Gene', '8218', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('L433*', 'Var', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CLTCL1', 'Gene', (53, 59))	('tumor', 'Disease', (73, 78))
426627	28975018	While majority of the mutations detected in the tumor were subclonal [alternative allele concentrations (AAC)<0.4], the CLTC1 mutation with AAC of 0.63 is clearly clonal (Table 1; Supplementary Figure 3A) and happened early during tumorigenesis as a potentially driver events.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('CLTC1', 'Gene', (120, 125))	('mutation', 'Var', (126, 134))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
426628	28975018	CLTCL1 is involved in stabilization of the mitotic spindle and the mutation L433* truncated the VPS functional domain leading to faulty assembly of clathrin complex in tumor (Supplementary Figure 3B-C).	('faulty', 'NegReg', (129, 135))	('CLTCL1', 'Gene', (0, 6))	('tumor', 'Disease', (168, 173))	('VPS', 'Protein', (96, 99))	('CLTCL1', 'Gene', '8218', (0, 6))	('L433*', 'Var', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('L433*', 'SUBSTITUTION', 'None', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
426629	28975018	The subclonal splice site mutation (AAC=0.22) in VEGFR1 detected in the exome located at an intronic splice-site 3bp from the exon boundary led to intron retention in expressed mRNA (Supplementary Figures 2D and 4) which consequently introduced an early stop codon in the kinase domain of VEGFR1.	('VEGFR1', 'Gene', '2321', (49, 55))	('mutation', 'Var', (26, 34))	('VEGFR1', 'Gene', '2321', (289, 295))	('introduced', 'Reg', (234, 244))	('VEGFR1', 'Gene', (49, 55))	('VEGFR1', 'Gene', (289, 295))	('intron retention', 'MPA', (147, 163))	('led to', 'Reg', (140, 146))
426631	28975018	In addition, subclonal missense mutations were identified in ATM (ACC=0.3; Supplementary Figure 2C) and TP53 (ACC=0.11; Supplementary Figure 2B) genes by both exome and RNA sequencing.	('missense mutations', 'Var', (23, 41))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('ATM', 'Gene', (61, 64))	('ATM', 'Gene', '472', (61, 64))
426638	28975018	Phosphorylation of SHC4 at the conserved tyrosine induces Ras and MAPK up-regulation.	('Ras', 'Protein', (58, 61))	('SHC4', 'Gene', (19, 23))	('Phosphorylation', 'Var', (0, 15))	('MAPK', 'Gene', (66, 70))	('up-regulation', 'PosReg', (71, 84))	('SHC4', 'Gene', '399694', (19, 23))	('tyrosine', 'Chemical', 'MESH:D014443', (41, 49))
426640	28975018	The first 18 exons of BPTF fused into the middle of exon 21 of WDR72 which introduced an early stop codon with the loss of the second PHD zinc finger and Bromo domains in BPTF (Figure 3).	('WDR72', 'Gene', (63, 68))	('loss', 'NegReg', (115, 119))	('BPTF', 'Gene', (22, 26))	('Bromo domains', 'Var', (154, 167))	('BPTF', 'Gene', '2186', (22, 26))	('BPTF', 'Gene', (171, 175))	('WDR72', 'Gene', '256764', (63, 68))	('BPTF', 'Gene', '2186', (171, 175))
426643	28975018	Our comprehensive genomic profiling of the tumor, tumor adjacent normal and patient germline DNA identified additional site mutations not reported by and large genomic rearrangements not targeted by the FoundationOne Panel.	('mutations', 'Var', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patient', 'Species', '9606', (76, 83))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (50, 55))
426644	28975018	Specifically we detected mutations in CLTCL1, ATM and VEGFR1 in addition to the TP53 mutations reported by FoundationOne.	('ATM', 'Gene', (46, 49))	('mutations', 'Var', (25, 34))	('CLTCL1', 'Gene', (38, 44))	('TP53', 'Gene', '7157', (80, 84))	('ATM', 'Gene', '472', (46, 49))	('TP53', 'Gene', (80, 84))	('CLTCL1', 'Gene', '8218', (38, 44))	('VEGFR1', 'Gene', '2321', (54, 60))	('VEGFR1', 'Gene', (54, 60))
426645	28975018	The fusion gene of HDGFRP3 SHC4 led to the overexpression of a potential oncogene, SHC4, and the fusion between BPTF WDR72 resulted in the truncation of BPTF functional domains involved in chromatin remodeling.	('BPTF', 'Gene', (153, 157))	('SHC4', 'Gene', '399694', (27, 31))	('BPTF', 'Gene', '2186', (153, 157))	('WDR72', 'Gene', (117, 122))	('SHC4', 'Gene', '399694', (83, 87))	('overexpression', 'PosReg', (43, 57))	('BPTF', 'Gene', '2186', (112, 116))	('fusion', 'Var', (4, 10))	('BPTF', 'Gene', (112, 116))	('SHC4', 'Gene', (27, 31))	('fusion', 'Var', (97, 103))	('WDR72', 'Gene', '256764', (117, 122))	('HDGFRP3', 'Gene', '50810', (19, 26))	('HDGFRP3', 'Gene', (19, 26))	('SHC4', 'Gene', (83, 87))	('truncation', 'MPA', (139, 149))
426646	28975018	The most intriguing discovery from this study was the HDGFRP3 SHC4 fusion which resulted in a 200-fold overexpression of the oncogene SHC4, a member of the Src family.	('Src', 'Gene', '6714', (156, 159))	('SHC4', 'Gene', '399694', (134, 138))	('SHC4', 'Gene', '399694', (62, 66))	('SHC4', 'Gene', (134, 138))	('HDGFRP3', 'Gene', (54, 61))	('overexpression', 'PosReg', (103, 117))	('HDGFRP3', 'Gene', '50810', (54, 61))	('SHC4', 'Gene', (62, 66))	('Src', 'Gene', (156, 159))	('fusion', 'Var', (67, 73))
426649	28356770	Breast cancer in patients with Li-Fraumeni syndrome - a case-series study and review of literature Li-Fraumeni Syndrome (LFS) is a rare disease with autosomal dominant inheritance linked to germline mutations of tumor suppressor gene TP53.	('Li-Fraumeni Syndrome', 'Disease', (99, 119))	('TP53', 'Gene', '7157', (234, 238))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('TP53', 'Gene', (234, 238))	('germline mutations', 'Var', (190, 208))	('Li-Fraumeni syndrome', 'Disease', (31, 51))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('linked', 'Reg', (180, 186))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('LFS', 'Disease', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('patients', 'Species', '9606', (17, 25))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (31, 51))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (99, 119))	('Breast cancer', 'Disease', (0, 13))	('tumor', 'Disease', (212, 217))	('LFS', 'Disease', 'MESH:D016864', (121, 124))
426665	28356770	Only 5%-10% of breast cancer cases are associated with hereditary syndromes, with BRCA1/2 mutations being the most commonly found.	('BRCA1', 'Gene', (82, 87))	('mutations', 'Var', (90, 99))	('hereditary syndromes', 'Disease', 'MESH:D009386', (55, 75))	('hereditary syndromes', 'Disease', (55, 75))	('associated', 'Reg', (39, 49))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('BRCA1', 'Gene', '672', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
426666	28356770	Li-Fraumeni syndrome (LFS) is a rare, highly penetrant, and autosomal dominant syndrome that occurs due to the germline mutation in the TP53 gene, which encodes the tumor suppressor protein p53.	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('LFS', 'Disease', 'MESH:D016864', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (60, 87))	('due', 'Reg', (100, 103))	('autosomal dominant syndrome', 'Disease', (60, 87))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('LFS', 'Disease', (22, 25))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))	('germline mutation', 'Var', (111, 128))	('tumor', 'Disease', (165, 170))
426668	28356770	Missense mutations in the DNA-binding domain of the TP53 gene destroy the ability of the p53 protein to bind to its target DNA sequences, leading to not only loss of tumor suppressor function, but also gain of novel pro-oncogenic functions with different TP53 hotspot mutations exhibiting gain-of-function effects which may affect the age onset of certain cancers in LFS.	('gain', 'PosReg', (202, 206))	('LFS', 'Disease', (367, 370))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('affect', 'Reg', (324, 330))	('cancers', 'Disease', 'MESH:D009369', (356, 363))	('LFS', 'Disease', 'MESH:D016864', (367, 370))	('bind', 'Interaction', (104, 108))	('ability', 'MPA', (74, 81))	('TP53', 'Gene', (52, 56))	('gain-of-function', 'PosReg', (289, 305))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('TP53', 'Gene', (255, 259))	('mutations', 'Var', (268, 277))	('tumor', 'Disease', (166, 171))	('pro-oncogenic functions', 'CPA', (216, 239))	('cancers', 'Phenotype', 'HP:0002664', (356, 363))	('cancers', 'Disease', (356, 363))	('destroy', 'NegReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('TP53', 'Gene', '7157', (255, 259))	('TP53', 'Gene', '7157', (52, 56))	('loss', 'NegReg', (158, 162))	('Missense mutations', 'Var', (0, 18))
426669	28356770	As a consequence of abnormal cell cycle regulation, about 50% of TP53 mutation carriers develop cancer before age 30 years, with a cumulative lifetime risk up to 70% in men and 100% in women.	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('men', 'Species', '9606', (169, 172))	('men', 'Species', '9606', (187, 190))	('mutation', 'Var', (70, 78))	('women', 'Species', '9606', (185, 190))	('abnormal cell cycle', 'Phenotype', 'HP:0011018', (20, 39))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('develop', 'PosReg', (88, 95))	('cancer', 'Disease', (96, 102))
426672	28356770	In 1990, TP53 mutations were identified in 5 families with LFS, and TP53 germline mutation is considered the hallmark of LFS; however, genetic TP53 modifiers have also been implicated in LFS.	('TP53', 'Gene', (143, 147))	('LFS', 'Disease', 'MESH:D016864', (59, 62))	('LFS', 'Disease', 'MESH:D016864', (187, 190))	('implicated', 'Reg', (173, 183))	('LFS', 'Disease', (59, 62))	('LFS', 'Disease', (121, 124))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('LFS', 'Disease', (187, 190))	('TP53', 'Gene', '7157', (143, 147))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('mutations', 'Var', (14, 23))	('LFS', 'Disease', 'MESH:D016864', (121, 124))
426675	28356770	These findings suggest that DLL may play a role in cancer immune surveillance, and DLL4 dysregulation - such as in LFS - can contribute to widespread tumorigenesis.	('DLL4', 'Gene', '54567', (83, 87))	('LFS', 'Disease', 'MESH:D016864', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('DLL4', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('LFS', 'Disease', (115, 118))	('contribute', 'Reg', (125, 135))	('DLL', 'Protein', (28, 31))	('cancer', 'Disease', (51, 57))	('tumor', 'Disease', (150, 155))	('dysregulation', 'Var', (88, 101))
426678	28356770	Moreover, Chompret criteria also included individuals at risk of carrying germline mutation in TP53 independently of family history (Table 1).	('germline mutation', 'Var', (74, 91))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
426679	28356770	LFS criteria are used in clinical practice to identify individuals with high risk who would benefit from TP53 mutation testing.	('LFS', 'Disease', (0, 3))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('LFS', 'Disease', 'MESH:D016864', (0, 3))	('mutation testing', 'Var', (110, 126))
426680	28356770	TP53 germline mutations can be identified in 70% of families who meet the classic LFS criteria and 40% of those families meeting the LFL criteria; furthermore, the frequency of de novo mutations in TP53 is ~7%-20%.	('TP53', 'Gene', (198, 202))	('TP53', 'Gene', '7157', (0, 4))	('LFS', 'Disease', (82, 85))	('TP53', 'Gene', (0, 4))	('LFL', 'Disease', (133, 136))	('LFS', 'Disease', 'MESH:D016864', (82, 85))	('TP53', 'Gene', '7157', (198, 202))	('LFL', 'Disease', 'MESH:D016864', (133, 136))	('mutations', 'Var', (185, 194))
426681	28356770	In addition, the combination of Chompret with classic criteria achieves the highest sensitivity (95%) to identify patients with TP53 mutations.	('TP53', 'Gene', '7157', (128, 132))	('patients', 'Species', '9606', (114, 122))	('TP53', 'Gene', (128, 132))	('mutations', 'Var', (133, 142))
426692	28356770	She underwent genetic counseling with BreastNext analysis and she was found to be heterogeneous for the p.R248W (c.742C>t) pathogenic mutation in the TP53 gene, consistent with the diagnosis LFS.	('TP53', 'Gene', (150, 154))	('c.742C>t', 'Mutation', 'rs121912651', (113, 121))	('p.R248W', 'Mutation', 'rs121912651', (104, 111))	('LFS', 'Disease', 'MESH:D016864', (191, 194))	('pathogenic', 'Reg', (123, 133))	('LFS', 'Disease', (191, 194))	('TP53', 'Gene', '7157', (150, 154))	('p.R248W (c.742C>t', 'Var', (104, 121))
426694	28356770	Surgical pathology specimen revealed ypT1bN0 breast cancer.	('men', 'Species', '9606', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('ypT1bN0', 'Var', (37, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))
426697	28356770	Her 4-year-old son was recently diagnosed with a left temporal high-grade neuroepithelial tumor, which required surgical resection; his genetic testing revealed the same deleterious TP53 mutation as mother.	('neuroepithelial tumor', 'Disease', (74, 95))	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (74, 95))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (74, 95))	('mutation', 'Var', (187, 195))
426700	28356770	She was evaluated for inherited mutations and was found to be heterozygous for pathogenic mutation in p.T155N (c.464C>A) variant in TP53 gene, consistent with a diagnosis of LFS.	('p.T155N', 'Mutation', 'rs786202752', (102, 109))	('LFS', 'Disease', (174, 177))	('c.464C>A', 'Mutation', 'rs786202752', (111, 119))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('LFS', 'Disease', 'MESH:D016864', (174, 177))	('pathogenic', 'Reg', (79, 89))	('p.T155N (c.464C>A', 'Var', (102, 119))
426709	28356770	The patient finally agreed to have genetic counseling, and BreastNext analysis found a heterozygous 5'UTR_3'UTR pathogenic mutation in the TP53 gene, consistent with the diagnosis of LFS.	('LFS', 'Disease', 'MESH:D016864', (183, 186))	('mutation', 'Var', (123, 131))	('patient', 'Species', '9606', (4, 11))	('TP53', 'Gene', '7157', (139, 143))	('LFS', 'Disease', (183, 186))	('TP53', 'Gene', (139, 143))
426712	28356770	Cytogenetics revealed 5q deletion and monosomy 7, diagnosis consistent with myelodysplastic syndrome (MDS-RAEB).	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (76, 100))	('5q deletion', 'Var', (22, 33))	('MDS-RAEB', 'Disease', (102, 110))	('revealed', 'Reg', (13, 21))	('monosomy 7', 'Var', (38, 48))	('myelodysplastic syndrome', 'Disease', (76, 100))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (76, 100))	('MDS-RAEB', 'Disease', 'MESH:D000754', (102, 110))
426718	28356770	She was referred for genetic counseling and was found to have a p.H193R TP53 pathogenic mutation compatible with LFS.	('LFS', 'Disease', (113, 116))	('TP53', 'Gene', '7157', (72, 76))	('p.H193R', 'Var', (64, 71))	('LFS', 'Disease', 'MESH:D016864', (113, 116))	('TP53', 'Gene', (72, 76))	('p.H193R', 'Mutation', 'rs786201838', (64, 71))
426725	28356770	In adults, breast cancer is the most common cancer among female patients with LFS, which is present in up to 79% of affected TP53 mutation carriers, followed by STS (27% of mutation carriers).	('LFS', 'Disease', (78, 81))	('patients', 'Species', '9606', (64, 72))	('TP53', 'Gene', '7157', (125, 129))	('mutation', 'Var', (130, 138))	('cancer', 'Disease', (44, 50))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('TP53', 'Gene', (125, 129))	('breast cancer', 'Disease', (11, 24))	('LFS', 'Disease', 'MESH:D016864', (78, 81))	('STS', 'Phenotype', 'HP:0030448', (161, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
426726	28356770	A study revealed that none of the 59 male patients with TP53 mutations were found to have breast cancer, suggesting a correlation of breast cancer risk only for females.	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('TP53', 'Gene', '7157', (56, 60))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('TP53', 'Gene', (56, 60))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('patients', 'Species', '9606', (42, 50))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
426744	28356770	Moreover, literature suggests that patients with germline TP53 mutations have limited response to pre- or postoperative chemotherapy.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('germline', 'Var', (49, 57))	('patients', 'Species', '9606', (35, 43))
426745	28356770	Alkylating agents and anthracyclines induce p53-dependent apoptosis; therefore, their effect in patients with TP53 mutations might not be optimal, leading to treatment resistance.	('mutations', 'Var', (115, 124))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('anthracyclines', 'Chemical', 'MESH:D018943', (22, 36))	('men', 'Species', '9606', (163, 166))	('patients', 'Species', '9606', (96, 104))	('treatment', 'MPA', (158, 167))	('leading to', 'Reg', (147, 157))
426747	28356770	Loss of cell cycle arrest due to p53 deficiency may allow cells to undergo S phase with more effective mitosis, thus making paclitaxel a potential better chemotherapy option for these patients.	('more', 'PosReg', (88, 92))	('mitosis', 'Disease', 'None', (103, 110))	('patients', 'Species', '9606', (184, 192))	('paclitaxel', 'Chemical', 'MESH:D017239', (124, 134))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (8, 25))	('Loss', 'NegReg', (0, 4))	('p53', 'Gene', (33, 36))	('cell cycle arrest', 'CPA', (8, 25))	('S phase', 'CPA', (75, 82))	('deficiency', 'Var', (37, 47))	('mitosis', 'Disease', (103, 110))
426772	28356770	Other studies are currently evaluating different screening strategies, such as the LIFESCREEN French project (NCT01464086), the SIGNIFY trial in the UK (NCT01737255), US NIH (NCT01443468), Dana-Farber Cancer Institute study (NCT02950987), and the Australian surveillance study in multiorgan cancer prone syndromes (ACTRN12613000987763).	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('NCT01464086', 'Var', (110, 121))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('NCT01443468', 'Var', (175, 186))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('Cancer', 'Disease', (201, 207))
426933	32257847	The patient's platelet count normalized after surgical intervention: 13900/mm3 on postoperative day one (POD1) and 16300/mm3 on POD2.	('platelet count', 'MPA', (14, 28))	('patient', 'Species', '9606', (4, 11))	('16300/mm3', 'Var', (115, 124))
426944	32257847	Some genetic aberrations have been variably detected in cases of HS, among which BRAF (present in up to 70% of cases), HRAS, and BRAF gene fusion are the most frequently linked.	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('BRAF', 'Gene', '673', (81, 85))	('linked', 'Reg', (170, 176))	('BRAF', 'Gene', (81, 85))	('HRAS', 'Gene', '3265', (119, 123))	('HRAS', 'Gene', (119, 123))	('gene fusion', 'Var', (134, 145))
426954	32257847	HS commonly presents as multiple hypointense T1 and hyperintense T2 lesions on MRI, which can also be found in cases of splenic neoplasm such as splenic lymphoma, hemagiomatosis, or angiosarcoma.	('hyperintense T2', 'Var', (52, 67))	('angiosarcoma', 'Phenotype', 'HP:0200058', (182, 194))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('neoplasm', 'Phenotype', 'HP:0002664', (128, 136))	('splenic lymphoma', 'Disease', (145, 161))	('angiosarcoma', 'Disease', 'MESH:D006394', (182, 194))	('splenic lymphoma', 'Disease', 'MESH:D013158', (145, 161))	('splenic neoplasm', 'Disease', 'MESH:D013160', (120, 136))	('hemagiomatosis', 'Disease', (163, 177))	('splenic neoplasm', 'Disease', (120, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('hemagiomatosis', 'Disease', 'None', (163, 177))	('angiosarcoma', 'Disease', (182, 194))
427046	25318087	This therapy was prescribed significantly more often for STSs that were greater than or equal to 5 cm (p = 0.02), high grade (p = 0.01) and deep (p = 0.01) and that had distant metastases (p = 0.01).	('metastases', 'Disease', 'MESH:D009362', (177, 187))	('high grade', 'Var', (114, 124))	('metastases', 'Disease', (177, 187))
427057	25318087	However, after performing the multivariate analysis, we verified that patients undergoing Pex had an 8.17 times higher risk of developing distant metastases compared with the Unpex group (p = 0.03).	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('patients', 'Species', '9606', (70, 78))	('metastases', 'Disease', (146, 156))	('Pex', 'Var', (90, 93))
427084	25318087	Unexpectedly, after adjustment for other variables, the group that underwent Pex showed a greater risk of distant lesions (p = 0.03), with an odds ratio of 8.17 (95% CI: 0.81 to 29), and was approximately eight times more likely to develop distant metastases compared with the Unpex group.	('metastases', 'Disease', (248, 258))	('Pex', 'Var', (77, 80))	('metastases', 'Disease', 'MESH:D009362', (248, 258))	('develop', 'PosReg', (232, 239))	('distant lesions', 'CPA', (106, 121))
427086	25318087	There was no relationship between distant metastasis and local recurrence (p = 0.088) during follow-up, as reported by Gustafson et al.. For Lewis et al., whose study included a total of 1,092 individuals and was conducted at MSKCC, those patients who underwent Pex (70%) showed worse 5-year survival than did the Unpex group (88%) (p = 0.005), suggesting that re-resection, or margin amplification, is a predictor of improved survival and the occurrence of distant metastases.	('patients', 'Species', '9606', (239, 247))	('margin amplification', 'Var', (378, 398))	('metastases', 'Disease', (466, 476))	('metastases', 'Disease', 'MESH:D009362', (466, 476))	('improved', 'PosReg', (418, 426))
427090	25318087	The Pex group had a higher risk of distant metastasis in this series, whereas the Unpex group had a high rate of residual cancer.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('Pex', 'Var', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('distant metastasis', 'CPA', (35, 53))
427209	21731656	Since toxoplasmosis is strongly associated with HIV infection, many codes related to HIV complications and opportunistic infections appear: "287.5 Leukocytopenia," "799.4 Cachexia," "112.84 Candidal esophagitis," "078.5 Cytomegaloviral disease."	('opportunistic infections', 'Disease', 'MESH:D009894', (107, 131))	('HIV infection', 'Disease', (48, 61))	('Leukocytopenia', 'Disease', 'MESH:D007970', (147, 161))	('Cachexia', 'Disease', 'MESH:D002100', (171, 179))	('associated', 'Reg', (32, 42))	('Cachexia', 'Phenotype', 'HP:0004326', (171, 179))	('opportunistic infections', 'Disease', (107, 131))	('HIV complications', 'Disease', 'MESH:D015658', (85, 102))	('Cytomegaloviral disease', 'Disease', 'MESH:D017726', (220, 243))	('Candidal esophagitis', 'Disease', 'MESH:D004941', (190, 210))	('opportunistic infection', 'Phenotype', 'HP:0031690', (107, 130))	('opportunistic infections', 'Phenotype', 'HP:0031690', (107, 131))	('esophagitis', 'Phenotype', 'HP:0100633', (199, 210))	('HIV infection', 'Disease', 'MESH:D015658', (48, 61))	('Candidal esophagitis', 'Disease', (190, 210))	('HIV complications', 'Disease', (85, 102))	('Cytomegaloviral disease', 'Disease', (220, 243))	('Cachexia', 'Disease', (171, 179))	('Leukocytopenia', 'Disease', (147, 161))	('toxoplasmosis', 'Disease', (6, 19))	('799.4', 'Var', (165, 170))	('toxoplasmosis', 'Disease', 'MESH:D014123', (6, 19))
427237	21731656	For those codes to be statistically significant associations with the case disease, the case cohort would have to have even larger counts of patients with the same ICD-9-CM codes; or the control cohort would have to be larger with the same proportion of patients with the same ICD-9-CM codes.	('associations', 'Interaction', (48, 60))	('patients', 'Species', '9606', (254, 262))	('patients', 'Species', '9606', (141, 149))	('codes', 'Var', (10, 15))
427302	20725831	Multiplanar reconstructions and the automatic tailoring of machine settings according to the volume of the patient have led to a substantial reduction of radiation dose compared to the former single-slice scanners but it is still not zero.	('radiation dose', 'MPA', (154, 168))	('patient', 'Species', '9606', (107, 114))	('reduction', 'NegReg', (141, 150))	('Multiplanar', 'Var', (0, 11))
427316	20725831	However, distant metastases (M-stage) were much better appreciated by PET-CT compared to MRI, CT or bone scintigraphy.	('metastases', 'Disease', 'MESH:D009362', (17, 27))	('PET-CT', 'Var', (70, 76))	('metastases', 'Disease', (17, 27))
427332	20725831	In one of our patients we noticed abnormal enhancement of the thickened CN V-2 within the foramen rotundum at diagnosis.	('V-2', 'Gene', (75, 78))	('enhancement', 'PosReg', (43, 54))	('thickened', 'Var', (62, 71))	('V-2', 'Gene', '6983', (75, 78))	('patients', 'Species', '9606', (14, 22))
427487	31543780	Among 22 so called infant URCS and 7 primitive myxoid mesenchymal tumors of infancy, they individualized a group sharing the same genetic profiles as the CCSK, but harbouring either an YWHAE-NUTM2B fusion (2 cases) or a tandem internal duplication of BCOR (15 cases).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('infant URCS', 'Disease', (19, 30))	('BCOR', 'Gene', '54880', (251, 255))	('YWHAE', 'Gene', (185, 190))	('NUTM2B', 'Gene', (191, 197))	('tandem internal duplication', 'Var', (220, 247))	('NUTM2B', 'Gene', '729262', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('myxoid mesenchymal tumors', 'Disease', 'MESH:C535700', (47, 72))	('BCOR', 'Gene', (251, 255))	('YWHAE', 'Gene', '7531', (185, 190))	('myxoid mesenchymal tumors', 'Disease', (47, 72))	('infant', 'Species', '9606', (19, 25))
427490	31543780	Both BCOR internal duplication and YWHAE-NUTM2B fusion harbor an overexpression of BCOR that might be the oncogenesis starting point.	('YWHAE', 'Gene', '7531', (35, 40))	('internal duplication', 'Var', (10, 30))	('BCOR', 'Gene', '54880', (83, 87))	('YWHAE', 'Gene', (35, 40))	('BCOR', 'Gene', (5, 9))	('NUTM2B', 'Gene', '729262', (41, 47))	('BCOR', 'Gene', '54880', (5, 9))	('overexpression', 'PosReg', (65, 79))	('BCOR', 'Gene', (83, 87))	('NUTM2B', 'Gene', (41, 47))
427491	31543780	The exact mechanism remains to be understood but internal tandem duplication located at the C terminal of BCOR may affect the conformation of BCOR protein and interfere with PCGF1 binding.	('BCOR', 'Gene', '54880', (106, 110))	('interfere', 'NegReg', (159, 168))	('BCOR', 'Gene', (142, 146))	('affect', 'Reg', (115, 121))	('BCOR', 'Gene', '54880', (142, 146))	('internal tandem duplication', 'Var', (49, 76))	('PCGF1', 'Gene', (174, 179))	('PCGF1', 'Gene', '84759', (174, 179))	('BCOR', 'Gene', (106, 110))	('binding', 'Interaction', (180, 187))	('conformation', 'MPA', (126, 138))
427492	31543780	This BCOR complex modification could affect gene transcription through an epigenetic mechanism.	('gene transcription', 'MPA', (44, 62))	('epigenetic', 'MPA', (74, 84))	('affect', 'Reg', (37, 43))	('BCOR', 'Gene', (5, 9))	('modification', 'Var', (18, 30))	('BCOR', 'Gene', '54880', (5, 9))
427523	28841687	Soft tissue sarcomas are broadly classified as either tumors with simple karyotypes, which are defined by characteristic chromosomal translocations or gene amplifications and few other cytogenetic alterations, or those with complex karyotypes containing multiple cytogenetic alterations.	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('Soft tissue sarcoma', 'Phenotype', 'HP:0030448', (0, 19))	('Soft tissue sarcomas', 'Phenotype', 'HP:0030448', (0, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('sarcomas', 'Disease', (12, 20))	('gene amplifications', 'Var', (151, 170))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Disease', (54, 60))
427525	28841687	One of the most common genetic alterations in sarcomas with complex karyotypes is tumor protein 53 (TP53) inactivation, either via somatic mutation, deletion, or alterations in TP53 pathway genes such as CDKN2A and MDM2.	('deletion', 'Var', (149, 157))	('MDM2', 'Gene', (215, 219))	('alterations', 'Var', (162, 173))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('TP53', 'Gene', (100, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('MDM2', 'Gene', '17246', (215, 219))	('tumor protein 53', 'Gene', '22059', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TP53 pathway genes', 'Gene', (177, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('tumor protein 53', 'Gene', (82, 98))	('sarcomas', 'Disease', (46, 54))	('CDKN2A', 'Gene', '12578', (204, 210))	('inactivation', 'NegReg', (106, 118))	('CDKN2A', 'Gene', (204, 210))
427526	28841687	Loss of p53 is known to cause global genetic instability and promote additional pro-tumorigenic mutations due to its critical role in regulating DNA repair, cell cycle, programmed cell death, and cellular senescence.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('p53', 'Gene', (8, 11))	('regulating', 'Reg', (134, 144))	('global', 'MPA', (30, 36))	('cell cycle', 'CPA', (157, 167))	('cause', 'Reg', (24, 29))	('cellular senescence', 'CPA', (196, 215))	('promote', 'PosReg', (61, 68))	('p53', 'Gene', '22059', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('programmed cell', 'CPA', (169, 184))	('DNA repair', 'MPA', (145, 155))	('Loss', 'Var', (0, 4))	('mutations', 'Var', (96, 105))
427527	28841687	TP53 appears to play a particularly important role in sarcomagenesis; 25-30% of tumors that develop in patients with germline TP53 mutations (patients with Li-Fraumeni syndrome) are sarcomas, specifically soft tissue sarcomas and osteosarcomas.	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('TP53', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('sarcoma', 'Disease', (54, 61))	('tumors', 'Disease', (80, 86))	('patients', 'Species', '9606', (142, 150))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('sarcomas', 'Disease', (182, 190))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('osteosarcomas', 'Disease', 'MESH:D012516', (230, 243))	('sarcoma', 'Disease', 'MESH:D012509', (217, 224))	('sarcomas', 'Disease', 'MESH:D012509', (235, 243))	('Li-Fraumeni syndrome', 'Disease', (156, 176))	('sarcoma', 'Disease', (235, 242))	('soft tissue sarcomas', 'Disease', (205, 225))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (235, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcoma', 'Disease', (217, 224))	('sarcomas', 'Disease', (235, 243))	('osteosarcomas', 'Disease', (230, 243))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (205, 225))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (205, 224))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (156, 176))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (205, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('sarcomas', 'Disease', 'MESH:D012509', (217, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('mutations', 'Var', (131, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (217, 225))	('osteosarcomas', 'Phenotype', 'HP:0002669', (230, 243))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('sarcomas', 'Disease', (217, 225))	('sarcoma', 'Disease', 'MESH:D012509', (182, 189))	('patients', 'Species', '9606', (103, 111))	('sarcoma', 'Disease', (182, 189))
427533	28841687	In this study, we sought to characterize the role of concurrent Trp53 and Pten deletion in a mouse model of sarcoma.	('Pten', 'Gene', (74, 78))	('sarcoma', 'Disease', (108, 115))	('mouse', 'Species', '10090', (93, 98))	('Pten', 'Gene', '19211', (74, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('Trp53', 'Gene', '22059', (64, 69))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('deletion', 'Var', (79, 87))	('Trp53', 'Gene', (64, 69))
427538	28841687	Development of this model supplies a new tool for following sarcomagenesis driven by inactivation of Trp53 and Pten, providing opportunities to better understand tumor initiation and progression.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('inactivation', 'Var', (85, 97))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('tumor initiation', 'Disease', 'MESH:D009369', (162, 178))	('Trp53', 'Gene', (101, 106))	('tumor initiation', 'Disease', (162, 178))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('Pten', 'Gene', (111, 115))	('Trp53', 'Gene', '22059', (101, 106))	('Pten', 'Gene', '19211', (111, 115))
427540	28841687	Researchers have also developed genetic models of sarcoma focusing on either global or tissue-specific gene loss to promote tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('gene', 'Var', (103, 107))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('tumor', 'Disease', (124, 129))	('sarcoma', 'Disease', (50, 57))	('promote', 'PosReg', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
427545	28841687	A model of high-grade sarcoma with myofibroblastic differentiation based on intramuscular adenoviral-Cre injection into Trp53/Kras conditional mutant transgenic mice was described by Kirsch et al..	('mutant', 'Var', (143, 149))	('Trp53', 'Gene', '22059', (120, 125))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('Kras', 'Gene', '16653', (126, 130))	('Kras', 'Gene', (126, 130))	('transgenic mice', 'Species', '10090', (150, 165))	('sarcoma', 'Disease', (22, 29))	('Trp53', 'Gene', (120, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))
427546	28841687	In this study, adenovirus (Ad) containing a Cre recombinase expression vector was injected into the extremity muscles of transgenic mice, resulting in knock-out of Trp53 and activation of oncogenic mutant Kras (LSL-KRasG12D Trp53flox/flox).	('Trp53', 'Gene', (164, 169))	('Kras', 'Gene', '16653', (205, 209))	('Trp53', 'Gene', (224, 229))	('Trp53', 'Gene', '22059', (224, 229))	('Trp53', 'Gene', '22059', (164, 169))	('transgenic mice', 'Species', '10090', (121, 136))	('activation', 'PosReg', (174, 184))	('knock-out', 'Var', (151, 160))	('expression', 'Species', '29278', (60, 70))	('Kras', 'Gene', (205, 209))
427552	28841687	The metastatic potential of UPS to the lung in the LSL-KRasG12D Trp53flox/flox model appears to be at least in part driven by mir-182 expression.	('driven by', 'Reg', (116, 125))	('expression', 'Species', '29278', (134, 144))	('mir-182', 'Var', (126, 133))	('Trp53', 'Gene', '22059', (64, 69))	('metastatic potential', 'CPA', (4, 24))	('Trp53', 'Gene', (64, 69))
427556	28841687	BLI allows for real-time, longitudinal imaging of allelic recombination and transgene expression, and when tracked over time serves as a marker for tumor formation and growth.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('expression', 'Species', '29278', (86, 96))	('tumor', 'Disease', (148, 153))	('transgene', 'Var', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
427563	28841687	The C57BL/6J-Tyrc-2J/J ROSA26 LSL-Luc Ptenfl/fl are on an albino C57BL/6J background.	('ROSA26', 'Gene', '14910', (23, 29))	('C57BL/6J-Tyrc-2J/J', 'Var', (4, 22))	('ROSA26', 'Gene', (23, 29))	('Pten', 'Gene', (38, 42))	('Pten', 'Gene', '19211', (38, 42))	('Tyrc', 'Chemical', '-', (13, 17))
427597	28841687	Dilutions utilized for immunohistochemistry are as follows pan-cytokeratin (1:1600), S100 protein (1:4000), SMA (1:2000), desmin (1:50), myogenin (1:50), phospho-AKT (1:50), PTEN (1:50), CD45 (1:100), and PD-L1 (1:50).	('1:4000', 'Var', (99, 105))	('AKT', 'Gene', '11651', (162, 165))	('CD45', 'Gene', (187, 191))	('PD-L1', 'Gene', (205, 210))	('CD45', 'Gene', '19264', (187, 191))	('S100', 'Gene', (85, 89))	('desmin', 'Gene', '13346', (122, 128))	('AKT', 'Gene', (162, 165))	('PD-L1', 'Gene', '60533', (205, 210))	('myogenin', 'Gene', (137, 145))	('1:50', 'Var', (130, 134))	('S100', 'Gene', '20193', (85, 89))	('myogenin', 'Gene', '17928', (137, 145))	('desmin', 'Gene', (122, 128))
427604	28841687	Four tumor classes were considered for each type of tumor: TP53 mutant only, PTEN mutant only, TP53 and PTEN mutated, or TP53 and PTEN wild type.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutant only', 'Var', (82, 93))	('TP53', 'Gene', (59, 63))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('PTEN', 'Gene', (77, 81))	('mutated', 'Var', (109, 116))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('PTEN', 'Gene', (104, 108))	('TP53', 'Gene', (95, 99))	('mutant only', 'Var', (64, 75))
427606	28841687	In this study we examined the consequence of temporally and spatially controlled Trp53 and Pten deletion by somatic Cre recombinase expression on sarcoma formation.	('Trp53', 'Gene', '22059', (81, 86))	('sarcoma', 'Disease', (146, 153))	('Pten', 'Gene', (91, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Pten', 'Gene', '19211', (91, 95))	('expression', 'Species', '29278', (132, 142))	('deletion', 'Var', (96, 104))	('Trp53', 'Gene', (81, 86))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
427607	28841687	Review of the TCGA database indicates that co-mutation of TP53 and PTEN occurs more frequently (66.7%; n = 21) in UPS as compared to all other soft tissue sarcomas (43.4%; n = 221) (Chi-squared = 28.108, df = 3, p<0.0001), indicating that this combination of mutations is frequently observed in human UPS.	('human', 'Species', '9606', (295, 300))	('TP53', 'Gene', (58, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (143, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('UPS', 'Disease', (114, 117))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (143, 163))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (143, 162))	('PTEN', 'Gene', (67, 71))	('co-mutation', 'Var', (43, 54))	('soft tissue sarcomas', 'Disease', (143, 163))
427616	28841687	Mice injected with Ad CMV-Cre via SQ or IM administration showed a robust and reproducible increase in whole-body BLI signal, with a substantial increase in BLI signal within the first week, likely representing viral infection and initial recombination events; this was followed by a steady increase in luciferase expression at the site of injection over subsequent weeks as depicted by BLI signal at weeks 1, 9, and 17 across five representative mice from each cohort (Fig 2A).	('Ad CMV-Cre', 'Var', (19, 29))	('mice', 'Species', '10090', (447, 451))	('increase', 'PosReg', (145, 153))	('increase', 'PosReg', (91, 99))	('expression', 'Species', '29278', (314, 324))	('viral infection', 'Disease', 'MESH:D001102', (211, 226))	('increase', 'PosReg', (291, 299))	('expression', 'MPA', (314, 324))	('Mice', 'Species', '10090', (0, 4))	('BLI signal', 'MPA', (157, 167))	('viral infection', 'Disease', (211, 226))	('luciferase', 'Enzyme', (303, 313))
427619	28841687	Importantly, 100% of Trp53/Pten mice injected with Ad CMV-Cre demonstrated luciferase expression by BLI at the site of injection, whereas all mice injected with the control virus Ad CMV-eGFP exhibited only background levels of bioluminescence signal for the duration of the study (Fig 2C).	('Trp53', 'Gene', (21, 26))	('Ad CMV-Cre', 'Var', (51, 61))	('expression', 'Species', '29278', (86, 96))	('luciferase', 'Enzyme', (75, 85))	('expression', 'MPA', (86, 96))	('Trp53', 'Gene', '22059', (21, 26))	('mice', 'Species', '10090', (142, 146))	('mice', 'Species', '10090', (32, 36))	('Pten', 'Gene', (27, 31))	('Pten', 'Gene', '19211', (27, 31))
427641	28841687	These data highlight some major clinical differences between primary tumors in the SQ- and IM-injected Ad CMV-Cre Trp53/Pten mice, including more fixed and invasive tumors, longer latency to a palpable tumor, and greater morbidity in the IM group compared to SQ.	('primary tumors', 'Disease', 'MESH:D009369', (61, 75))	('mice', 'Species', '10090', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('invasive tumors', 'Disease', (156, 171))	('Ad CMV-Cre', 'Var', (103, 113))	('tumor', 'Disease', (202, 207))	('invasive tumors', 'Disease', 'MESH:D009369', (156, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('fixed', 'CPA', (146, 151))	('morbidity', 'CPA', (221, 230))	('Pten', 'Gene', (120, 124))	('Pten', 'Gene', '19211', (120, 124))	('primary tumors', 'Disease', (61, 75))	('Trp53', 'Gene', '22059', (114, 119))	('more', 'PosReg', (141, 145))	('tumor', 'Disease', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Trp53', 'Gene', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
427664	28841687	Herein we describe a new mouse model for UPS that incorporates viral Cre-mediated deletion of Pten/Trp53 and BLI capability.	('Pten', 'Gene', (94, 98))	('Pten', 'Gene', '19211', (94, 98))	('Trp53', 'Gene', '22059', (99, 104))	('mouse', 'Species', '10090', (25, 30))	('deletion', 'Var', (82, 90))	('Trp53', 'Gene', (99, 104))
427671	28841687	Although tumors arising in SQ and IM locations were histologically and immunohistochemically similar, IM adenoviral injection resulted in greater systemic dissemination and unanticipated infection of Ad-Cre, a phenomenon which may need to be taken into account during experimental design.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('greater', 'PosReg', (138, 145))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('systemic dissemination', 'CPA', (146, 168))	('adenoviral injection', 'Var', (105, 125))	('infection', 'Disease', (187, 196))	('infection', 'Disease', 'MESH:D007239', (187, 196))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
427685	28841687	Our Trp53fl/flPtenfl/fl model demonstrates that homozygous inactivation of both Trp53 and Pten in either SQ tissue or in skeletal muscle promotes sarcomagenesis.	('Pten', 'Gene', '19211', (90, 94))	('Trp53', 'Gene', (4, 9))	('promotes', 'PosReg', (137, 145))	('Pten', 'Gene', '19211', (14, 18))	('inactivation', 'Var', (59, 71))	('Trp53', 'Gene', '22059', (4, 9))	('sarcoma', 'Disease', (146, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Trp53', 'Gene', (80, 85))	('Pten', 'Gene', (14, 18))	('Trp53', 'Gene', '22059', (80, 85))	('Pten', 'Gene', (90, 94))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
427693	28841687	In conclusion, we have developed a novel mouse model of UPS, which is driven by Ad-Cre recombinase mediated inactivation of Trp53 and Pten in either SQ tissue or skeletal muscle.	('mouse', 'Species', '10090', (41, 46))	('inactivation', 'Var', (108, 120))	('Trp53', 'Gene', (124, 129))	('Pten', 'Gene', (134, 138))	('Pten', 'Gene', '19211', (134, 138))	('UPS', 'Disease', (56, 59))	('Trp53', 'Gene', '22059', (124, 129))
427695	28841687	Further facilitating the observation of the tumor is concurrent expression of luciferase following inactivation of Trp53 and Pten, providing the ability to use BLI to track allelic recombination, tumor formation, and tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (196, 201))	('Pten', 'Gene', '19211', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('Trp53', 'Gene', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('expression', 'Species', '29278', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Pten', 'Gene', (125, 129))	('tumor', 'Disease', (44, 49))	('Trp53', 'Gene', '22059', (115, 120))	('inactivation', 'Var', (99, 111))
427798	23874201	Exosomes derived from serum of three independent KSHV-positive TIVE L1 xenograft tumor mice and PEL fluid contained KSHV miR-K2 (Figure 2I).	('KSHV', 'Var', (116, 120))	('xenograft tumor', 'Disease', (71, 86))	('KSHV', 'Species', '37296', (49, 53))	('mice', 'Species', '10090', (87, 91))	('xenograft tumor', 'Disease', 'MESH:D009369', (71, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('miR', 'Gene', '220972', (121, 124))	('KSHV', 'Species', '37296', (116, 120))	('miR', 'Gene', (121, 124))
427834	23874201	We found KSHV DNA in both exosomal and free supernatant fractions of plasma and pleural fluid (Figure 3D,E).	('KSHV', 'Species', '37296', (9, 13))	('pleural', 'Disease', 'MESH:D010995', (80, 87))	('KSHV', 'Var', (9, 13))	('pleural fluid', 'Phenotype', 'HP:0002202', (80, 93))	('pleural', 'Disease', (80, 87))
427909	23874201	In our clinical and mouse model samples, levels of the miR-17-92 and miR-106b/25 clusters were induced in exosomes derived from KSHV-associated mouse serum, primary human pleural fluid and KS biopsies compared with control exosomes (Figure 5B, C).	('human', 'Species', '9606', (165, 170))	('mouse', 'Species', '10090', (144, 149))	('pleural', 'Disease', (171, 178))	('miR-106b/25', 'Gene', (69, 80))	('miR-17-92', 'Var', (55, 64))	('clinical', 'Species', '191496', (7, 15))	('KSHV', 'Species', '37296', (128, 132))	('pleural fluid', 'Phenotype', 'HP:0002202', (171, 184))	('pleural', 'Disease', 'MESH:D010995', (171, 178))	('induced', 'PosReg', (95, 102))	('mouse', 'Species', '10090', (20, 25))
427954	23874201	Since Annexin V can bind PS on the surface, annexin blocking of exosomes has been previously used as a means of inhibiting exosome fusion and transfer of exosomal contents.	('Annexin V', 'Gene', '308', (6, 15))	('exosome fusion', 'MPA', (123, 137))	('PS', 'Chemical', 'MESH:D010718', (25, 27))	('Annexin V', 'Gene', (6, 15))	('transfer of exosomal contents', 'MPA', (142, 171))	('annexin', 'Var', (44, 51))	('bind', 'Interaction', (20, 24))	('inhibiting', 'NegReg', (112, 122))
428249	31522190	However, the 10-year survival rate dropped to 41%, and the 5-year survival rate was 70% for tumor size <=5 cm, 46.8% for tumor size >5 cm and 48.9% and 32% at 10 years, respectively.	('<=5 cm', 'Var', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('dropped', 'NegReg', (35, 42))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
428250	31522190	According to tumor size, disease-specific survivals were 86.2% for tumor size <=3 cm and 42.8% for tumor size >3 cm at 5 years and 80.9% for tumor size <=3 cm and 26.4% for tumor size >3 cm at 10 years, respectively.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (99, 104))	('<=3', 'Var', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
428280	26861456	In the PCR cohort, RT-PCR on blood or BM samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations.	('patients', 'Species', '9606', (64, 72))	('FLI1', 'Gene', (111, 115))	('FLI1', 'Gene', '2313', (111, 115))	('translocations', 'Var', (116, 130))	('EWSR1', 'Gene', (105, 110))	('negative', 'NegReg', (91, 99))	('EWSR1', 'Gene', '2130', (105, 110))
428283	26861456	In the PCR cohort, 19.6% (44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or BM.	('EWSR1', 'Gene', '2130', (67, 72))	('FLI1', 'Gene', '2313', (73, 77))	('FLI1', 'Gene', (73, 77))	('EWSR1', 'Gene', (67, 72))	('patients', 'Species', '9606', (34, 42))	('translocation', 'Var', (78, 91))
428290	26861456	Occult ES cells can be detected in the peripheral blood (PB) and in bone marrow (BM) using a polymerase chain reaction (PCR) assay to detect EWSR1 fusion transcripts characteristic of this tumor.	('tumor', 'Disease', (189, 194))	('EWSR1', 'Gene', (141, 146))	('fusion transcripts', 'Var', (147, 165))	('EWSR1', 'Gene', '2130', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
428291	26861456	PCR studies have shown that approximately 20-43% of patients with newly diagnosed Ewing sarcoma have detectable EWSR1 fusion transcripts in their PB and/or BM.	('Ewing sarcoma', 'Disease', (82, 95))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (82, 95))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('EWSR1', 'Gene', (112, 117))	('fusion transcripts', 'Var', (118, 136))	('EWSR1', 'Gene', '2130', (112, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('patients', 'Species', '9606', (52, 60))
428296	26861456	Some PCR-based studies have shown that detectable EWSR1 fusion transcripts in the PB and/or BM at diagnosis is an adverse prognostic factor.	('EWSR1', 'Gene', (50, 55))	('EWSR1', 'Gene', '2130', (50, 55))	('fusion transcripts', 'Var', (56, 74))
428298	26861456	Monoclonal antibodies against IGF-1R have resulted in objective clinical responses in patients with ES and this class of agents is being evaluated in newly diagnosed patients with metastatic ES.	('IGF-1R', 'Gene', '3480', (30, 36))	('IGF-1R', 'Gene', (30, 36))	('patients', 'Species', '9606', (166, 174))	('Monoclonal antibodies', 'Var', (0, 21))	('patients', 'Species', '9606', (86, 94))
428358	26861456	In the PCR cohort, 19.6% (44/225) of patients were "positive" for any EWSR1/FLI1 translocation by RT-PCR in either blood and/or BM.	('translocation', 'Var', (81, 94))	('EWSR1', 'Gene', (70, 75))	('patients', 'Species', '9606', (37, 45))	('FLI1', 'Gene', '2313', (76, 80))	('FLI1', 'Gene', (76, 80))	('EWSR1', 'Gene', '2130', (70, 75))	('positive', 'Reg', (52, 60))
428385	26861456	CD90 (Thy-1) is expressed on human hematopoietic progenitor cells as well as on ES cells, and its use may have increased their positivity rate.	('CD90', 'Gene', (0, 4))	('increased', 'PosReg', (111, 120))	('use', 'Var', (98, 101))	('Thy-1', 'Gene', (6, 11))	('Thy-1', 'Gene', '7070', (6, 11))	('human', 'Species', '9606', (29, 34))	('CD90', 'Gene', '7070', (0, 4))	('positivity', 'MPA', (127, 137))
428400	26861456	As a result of our work, this novel pharmacodynamic assay has been incorporated in an ongoing COG clinical trial using an IGF-1R inhibitor plus standard chemotherapy in patients with newly diagnosed metastatic ES (NCT02306161).	('patients', 'Species', '9606', (169, 177))	('IGF-1R', 'Gene', '3480', (122, 128))	('IGF-1R', 'Gene', (122, 128))	('COG', 'Chemical', '-', (94, 97))	('NCT02306161', 'Var', (214, 225))	('metastatic ES', 'Disease', (199, 212))
428459	25699170	SS18 gene region rearrangement was demonstrated in all cases.	('SS18', 'Gene', (0, 4))	('rearrangement', 'Var', (17, 30))	('SS18', 'Gene', '6760', (0, 4))	('SS', 'Phenotype', 'HP:0012570', (0, 2))
428509	25699170	However gastrointestinal clear cell sarcomas are usually negative for epithelial markers and show rearrangement of the EWSR1 gene.	('negative', 'NegReg', (57, 65))	('EWSR1', 'Gene', '2130', (119, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('gastrointestinal clear cell sarcomas', 'Disease', 'MESH:D018227', (8, 44))	('rearrangement', 'Var', (98, 111))	('EWSR1', 'Gene', (119, 124))	('gastrointestinal clear cell sarcomas', 'Disease', (8, 44))
428515	25699170	In this setting, demonstration of rearrangement of SSX18 or EWSR1 is crucial for differentiating respectively PDSS from Ewing Sarcoma/PNET.	('Sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('SS', 'Phenotype', 'HP:0012570', (112, 114))	('EWSR1', 'Gene', '2130', (60, 65))	('rearrangement', 'Var', (34, 47))	('SSX1', 'Gene', '6756', (51, 55))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (120, 133))	('Ewing Sarcoma', 'Disease', (120, 133))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (120, 133))	('SSX1', 'Gene', (51, 55))	('EWSR1', 'Gene', (60, 65))	('PD', 'Disease', 'MESH:D010300', (110, 112))	('SS', 'Phenotype', 'HP:0012570', (51, 53))
428516	25699170	Also it should be remembered that CD99 positivity in synovial sarcomas does not feature the typical crisp membrane staining most often observed in Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (147, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('synovial sarcomas', 'Disease', 'MESH:D013584', (53, 70))	('synovial sarcomas', 'Disease', (53, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (147, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('CD99', 'Gene', (34, 38))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (53, 69))	('positivity', 'Var', (39, 49))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (147, 162))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (53, 70))
428517	25699170	Cytogenetically, all SS variants are characterized by the reciprocal translocation t(X;18)(p11.2;q11.2), which leads, at molecular level, to the fusion between the synovial sarcoma translocation gene on chromosome 18 (SS18) and one of the synovial sarcoma X breakpoint (SSX) genes on chromosome X: SSX1, SSX2 and rarely with SSX4.	('synovial sarcoma', 'Disease', 'MESH:D013584', (164, 180))	('SS', 'Phenotype', 'HP:0012570', (304, 306))	('SSX4', 'Gene', (325, 329))	('SSX', 'Gene', '6757', (298, 301))	('SS18', 'Gene', (218, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (248, 255))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (164, 180))	('SSX1', 'Gene', '6756', (298, 302))	('SS', 'Phenotype', 'HP:0012570', (270, 272))	('SSX', 'Gene', '6757', (304, 307))	('SSX4', 'Gene', '6759', (325, 329))	('SSX1', 'Gene', (298, 302))	('SSX', 'Gene', (298, 301))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('synovial sarcoma', 'Disease', 'MESH:D013584', (239, 255))	('SS18', 'Gene', '6760', (218, 222))	('synovial sarcoma X breakpoint', 'Gene', (239, 268))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (83, 103))	('variants', 'Var', (24, 32))	('SSX', 'Gene', (304, 307))	('SSX', 'Gene', '6757', (325, 328))	('SSX', 'Gene', '6757', (270, 273))	('SSX2', 'Gene', (304, 308))	('synovial sarcoma X breakpoint', 'Gene', '6757', (239, 268))	('SS', 'Phenotype', 'HP:0012570', (21, 23))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (239, 255))	('SS', 'Phenotype', 'HP:0012570', (218, 220))	('SSX2', 'Gene', '6757', (304, 308))	('SSX', 'Gene', (325, 328))	('SS', 'Phenotype', 'HP:0012570', (298, 300))	('SSX', 'Gene', (270, 273))	('synovial sarcoma', 'Disease', (164, 180))
428861	28933787	We additionally confirmed that GA induces cytoprotective autophagy in sarcoma cells via IRE1alpha-JNK/c-jun cascade activation, and that inhibition of autophagy or the JNK pathway increases GA-induced inhibitory effects and apoptosis on sarcoma cells.	('sarcoma', 'Disease', (70, 77))	('c-jun', 'Gene', '3725', (102, 107))	('c-jun', 'Gene', (102, 107))	('IRE1alpha', 'Gene', (88, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('cytoprotective autophagy', 'CPA', (42, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('autophagy', 'CPA', (151, 160))	('GA', 'Chemical', 'MESH:C119129', (190, 192))	('inhibition', 'Var', (137, 147))	('GA', 'Chemical', 'MESH:C119129', (31, 33))	('apoptosis', 'CPA', (224, 233))	('IRE1alpha', 'Gene', '2081', (88, 97))	('increases', 'PosReg', (180, 189))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('activation', 'PosReg', (116, 126))	('inhibitory effects', 'CPA', (201, 219))	('JNK', 'Gene', (98, 101))	('JNK', 'Gene', (168, 171))	('JNK', 'Gene', '5599', (98, 101))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('sarcoma', 'Disease', (237, 244))	('JNK', 'Gene', '5599', (168, 171))
428886	28933787	As expected, we observed a moderate inhibitory effect for z-IETD-fmk and z-LEHD-fmk in GA-induced apoptosis; z-VAD-fmk demonstrated a more potent inhibitory effect (Figure 2f).	('inhibitory', 'NegReg', (36, 46))	('apoptosis', 'CPA', (98, 107))	('z-IETD-fmk', 'Chemical', 'MESH:C403753', (58, 68))	('z-VAD-fmk', 'Var', (109, 118))	('GA', 'Chemical', 'MESH:C119129', (87, 89))	('z-LEHD-fmk', 'Chemical', 'MESH:C403754', (73, 83))	('z-VAD-fmk', 'Chemical', 'MESH:C096713', (109, 118))	('GA-induced', 'Disease', (87, 97))	('z-LEHD-fmk', 'Var', (73, 83))
428897	28933787	The JNK/c-jun pathway plays a pivotal role in autophagy, and activation of JNK/c-jun induces autophagy under diverse conditions.	('induces', 'Reg', (85, 92))	('autophagy', 'CPA', (93, 102))	('c-jun', 'Gene', '3725', (79, 84))	('JNK', 'Gene', (75, 78))	('c-jun', 'Gene', (79, 84))	('JNK', 'Gene', (4, 7))	('JNK', 'Gene', '5599', (75, 78))	('activation', 'Var', (61, 71))	('c-jun', 'Gene', '3725', (8, 13))	('c-jun', 'Gene', (8, 13))	('JNK', 'Gene', '5599', (4, 7))
428901	28933787	As shown in Figure 4b, GA-activated JNK and c-jun levels were decreased following pretreatment with SP600125 (10 muM, 1 h).	('muM', 'Gene', (113, 116))	('JNK', 'Gene', (36, 39))	('decreased', 'NegReg', (62, 71))	('c-jun', 'Gene', '3725', (44, 49))	('c-jun', 'Gene', (44, 49))	('JNK', 'Gene', '5599', (36, 39))	('SP600125', 'Chemical', 'MESH:C432165', (100, 108))	('muM', 'Gene', '56925', (113, 116))	('GA', 'Chemical', 'MESH:C119129', (23, 25))	('SP600125', 'Var', (100, 108))
428902	28933787	In addition, induction of autophagy markers such as LC3-II, ATG5, and Beclin-1 was also reversed following SP600125 treatment.	('SP600125', 'Var', (107, 115))	('LC3', 'Gene', '84557', (52, 55))	('ATG5', 'Gene', '9474', (60, 64))	('LC3', 'Gene', (52, 55))	('Beclin-1', 'Gene', (70, 78))	('ATG5', 'Gene', (60, 64))	('Beclin-1', 'Gene', '8678', (70, 78))	('SP600125', 'Chemical', 'MESH:C432165', (107, 115))
428910	28933787	IRE1alpha knockdown by siRNA decreased GA-induced autophagy, as evidenced by decreased LC3-II expression (Figures 5b and c).	('GA-induced', 'Disease', (39, 49))	('IRE1alpha', 'Gene', (0, 9))	('IRE1alpha', 'Gene', '2081', (0, 9))	('LC3', 'Gene', '84557', (87, 90))	('LC3', 'Gene', (87, 90))	('GA', 'Chemical', 'MESH:C119129', (39, 41))	('decreased', 'NegReg', (29, 38))	('expression', 'MPA', (94, 104))	('knockdown', 'Var', (10, 19))	('decreased', 'NegReg', (77, 86))
428913	28933787	However, JNK knockdown, as well as inhibition of the JNK/c-jun pathway by SP600125, increased GA-induced ER stress in HOS and HT1080 cells (Figures 6a-d, Supplementary Figure S4) that may be attributed to inhibition of GA-induced autophagy.	('c-jun', 'Gene', (57, 62))	('GA', 'Chemical', 'MESH:C119129', (219, 221))	('SP600125', 'Chemical', 'MESH:C432165', (74, 82))	('JNK', 'Gene', (9, 12))	('c-jun', 'Gene', '3725', (57, 62))	('GA', 'Chemical', 'MESH:C119129', (94, 96))	('JNK', 'Gene', (53, 56))	('SP600125', 'Var', (74, 82))	('HT1080', 'CellLine', 'CVCL:0317', (126, 132))	('JNK', 'Gene', '5599', (9, 12))	('increased', 'PosReg', (84, 93))	('JNK', 'Gene', '5599', (53, 56))	('knockdown', 'Var', (13, 22))	('inhibition', 'NegReg', (35, 45))
428915	28933787	These results indicated that GA induces autophagy in HOS and HT1080 cells via the IRE1alpha-JNK/c-jun pathway, and that inhibition of JNK/c-jun or autophagy increases GA-induced ER stress.	('autophagy', 'CPA', (147, 156))	('inhibition', 'Var', (120, 130))	('GA', 'Chemical', 'MESH:C119129', (167, 169))	('HT1080', 'CellLine', 'CVCL:0317', (61, 67))	('c-jun', 'Gene', (138, 143))	('GA', 'Chemical', 'MESH:C119129', (29, 31))	('c-jun', 'Gene', '3725', (96, 101))	('JNK', 'Gene', (92, 95))	('c-jun', 'Gene', (96, 101))	('autophagy', 'CPA', (40, 49))	('ER stress', 'MPA', (178, 187))	('JNK', 'Gene', (134, 137))	('JNK', 'Gene', '5599', (92, 95))	('c-jun', 'Gene', '3725', (138, 143))	('increases', 'PosReg', (157, 166))	('IRE1alpha', 'Gene', (82, 91))	('IRE1alpha', 'Gene', '2081', (82, 91))	('JNK', 'Gene', '5599', (134, 137))
428924	28933787	Furthermore, both autophagy inhibition and JNK knockdown enhanced the level of apoptosis-related proteins following GA treatment (Figures 7a and d).	('level of apoptosis-related proteins', 'MPA', (70, 105))	('JNK', 'Gene', (43, 46))	('knockdown', 'Var', (47, 56))	('autophagy inhibition', 'CPA', (18, 38))	('GA', 'Chemical', 'MESH:C119129', (116, 118))	('JNK', 'Gene', '5599', (43, 46))	('enhanced', 'PosReg', (57, 65))
428950	28933787	Our study demonstrated that GA treatment led to remarkable increases in JNK phosphorylation in sarcoma cells that could, in turn, be reversed by treatment with the JNK inhibitor, SP600125, or with siRNA targeting IRE1.	('IRE1', 'Gene', '2081', (213, 217))	('JNK', 'Gene', (72, 75))	('IRE1', 'Gene', (213, 217))	('GA', 'Chemical', 'MESH:C119129', (28, 30))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('JNK', 'Gene', '5599', (72, 75))	('JNK', 'Gene', (164, 167))	('sarcoma', 'Disease', (95, 102))	('SP600125', 'Var', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('SP600125', 'Chemical', 'MESH:C432165', (179, 187))	('JNK', 'Gene', '5599', (164, 167))	('increases', 'PosReg', (59, 68))
428954	28933787	The cytotoxic effects of gefitinib against glioma cells mainly involve cell death through autophagy; however, in lung cancer cells, autophagy induced by gefitinib exerts a cytoprotective effect.	('lung cancer', 'Disease', (113, 124))	('gefitinib', 'Var', (153, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('gefitinib', 'Chemical', 'MESH:D000077156', (25, 34))	('autophagy', 'CPA', (90, 99))	('glioma', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('autophagy', 'CPA', (132, 141))	('cytoprotective effect', 'CPA', (172, 193))	('gefitinib', 'Chemical', 'MESH:D000077156', (153, 162))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
428957	28933787	However, IRE1alpha knockdown failed to elicit an increase in GA-induced cell apoptosis (Supplementary Figure S2) that may be attributed to the activation of both autophagy and apoptosis by IRE1alpha.	('autophagy', 'CPA', (162, 171))	('knockdown', 'Var', (19, 28))	('IRE1alpha', 'Gene', (189, 198))	('IRE1alpha', 'Gene', '2081', (189, 198))	('GA', 'Chemical', 'MESH:C119129', (61, 63))	('activation', 'PosReg', (143, 153))	('cell apoptosis', 'CPA', (72, 86))	('apoptosis', 'CPA', (176, 185))	('IRE1alpha', 'Gene', (9, 18))	('IRE1alpha', 'Gene', '2081', (9, 18))
429010	28933787	Then, slides were blocked in 10% normal goat serum for 15 min, followed by incubation with p-JNK, and cleaved caspase-3 at 4  C overnight in a moist chamber.	('JNK', 'Gene', (93, 96))	('goat', 'Species', '9925', (40, 44))	('caspase-3', 'Protein', (110, 119))	('JNK', 'Gene', '5599', (93, 96))	('cleaved', 'Var', (102, 109))
429077	28105325	Dedifferentiated liposarcoma is molecularly similar to WDLS/ALT with amplicons in 12q12-15 despite its inherent more-aggressive biological activity.	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('amplicons in 12q12-15', 'Var', (69, 90))	('liposarcoma', 'Disease', (17, 28))	('liposarcoma', 'Disease', 'MESH:D008080', (17, 28))	('liposarcoma', 'Phenotype', 'HP:0012034', (17, 28))
429079	28105325	MRCL is characterized by a recurring unique chromosome rearrangement, t(12;16)(q13;p11), resulting in a TLS-CHOP fusion oncoprotein that is present in 95% of cases.	('TLS-CHOP', 'Disease', 'None', (104, 112))	('t(12;16)(q13;p11', 'Var', (70, 86))	('TLS-CHOP', 'Disease', (104, 112))	('MRCL', 'Disease', 'None', (0, 4))	('MRCL', 'Disease', (0, 4))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (70, 87))
429082	28105325	The most common mutations seen are found in p53 .	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('mutations', 'Var', (16, 25))
429118	28105325	Additionally, nelfinavir, a protease inhibitor used in HIV treatment and thought to contribute to treatment-related lipodystrophy through alteration of SREBP-1, a transcriptional regulator expressed in liposarcoma, has been the subject of a clinical trial.	('SREBP-1', 'Gene', (152, 159))	('SREBP-1', 'Gene', '6720', (152, 159))	('lipodystrophy', 'Disease', (116, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('lipodystrophy', 'Phenotype', 'HP:0009125', (116, 129))	('nelfinavir', 'Chemical', 'MESH:D019888', (14, 24))	('liposarcoma', 'Disease', (202, 213))	('alteration', 'Var', (138, 148))	('liposarcoma', 'Disease', 'MESH:D008080', (202, 213))	('liposarcoma', 'Phenotype', 'HP:0012034', (202, 213))
429135	22928012	Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells.	('SW-1353', 'Var', (77, 84))	('doxorubicin', 'Chemical', 'MESH:D004317', (156, 167))	('higher', 'PosReg', (92, 98))	('ALDH1', 'Gene', (200, 205))	('epirubicin', 'Chemical', 'MESH:D015251', (169, 179))	('epirubicin', 'MPA', (169, 179))	('ALDH1', 'Gene', '216', (200, 205))	('cisplatin', 'Chemical', '-', (185, 194))	('SW-1353', 'CellLine', 'CVCL:0543', (77, 84))	('resistance', 'MPA', (99, 109))	('ALDH1', 'Gene', (47, 52))	('ALDH1', 'Gene', '216', (47, 52))	('SW-982', 'CellLine', 'CVCL:1734', (66, 72))
429136	22928012	This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells.	('sarcoma', 'Disease', (42, 49))	('ABC transporter', 'Gene', '9429', (241, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('activity', 'MPA', (73, 81))	('expression', 'MPA', (227, 237))	('ALDH1', 'Gene', (67, 72))	('increased', 'PosReg', (191, 200))	('higher', 'PosReg', (164, 170))	('colony forming', 'CPA', (201, 215))	('proliferation rate', 'CPA', (171, 189))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('high', 'Var', (62, 66))	('ALDH1', 'Gene', '216', (67, 72))	('ABC transporter', 'Gene', (241, 256))	('increased', 'PosReg', (217, 226))
429214	22928012	The proliferation rate and clonogenicity of SW-684, SW-982, and SW-1353 ALDH1high cells in vitro were significantly higher than that of ALDH1low cells, consistent with the characteristics of the high ALDH1 activity phenotype in other cancer cells, which may indicate that ALDH1high cells from sarcoma are partially responsible for tumor metastasis and recurrence and should be focused during the cancer therapy.	('ALDH1', 'Gene', '216', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (396, 402))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('SW-982', 'Var', (52, 58))	('clonogenicity', 'CPA', (27, 40))	('sarcoma', 'Disease', (293, 300))	('ALDH1', 'Gene', '216', (72, 77))	('ALDH1', 'Gene', (272, 277))	('tumor metastasis', 'Disease', (331, 347))	('proliferation rate', 'CPA', (4, 22))	('higher', 'PosReg', (116, 122))	('ALDH1', 'Gene', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('ALDH1', 'Gene', (136, 141))	('SW-1353 ALDH1', 'CellLine', 'CVCL:0543', (64, 77))	('SW-982', 'CellLine', 'CVCL:1734', (52, 58))	('ALDH1', 'Gene', (72, 77))	('cancer', 'Disease', (396, 402))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('SW-684', 'Var', (44, 50))	('ALDH1', 'Gene', '216', (272, 277))	('SW-684', 'CellLine', 'CVCL:1726', (44, 50))	('ALDH1', 'Gene', '216', (200, 205))	('tumor metastasis', 'Disease', 'MESH:D009362', (331, 347))	('cancer', 'Disease', (234, 240))	('sarcoma', 'Disease', 'MESH:D012509', (293, 300))
429226	22928012	ALDH1high cells of SW-982 and SW-1353 showed significantly lower sensitivity to both doxorubicin and epirubicin compared with ALDH1low cells.	('ALDH1', 'Gene', '216', (0, 5))	('SW-1353', 'Var', (30, 37))	('sensitivity to', 'MPA', (65, 79))	('doxorubicin', 'Chemical', 'MESH:D004317', (85, 96))	('lower', 'NegReg', (59, 64))	('SW-1353', 'CellLine', 'CVCL:0543', (30, 37))	('epirubicin', 'Chemical', 'MESH:D015251', (101, 111))	('SW-982', 'CellLine', 'CVCL:1734', (19, 25))	('ALDH1', 'Gene', (0, 5))	('ALDH1', 'Gene', (126, 131))	('SW-982', 'Var', (19, 25))	('ALDH1', 'Gene', '216', (126, 131))
429244	33373921	A pathognomonic chromosomal translocation generating SYT-SSX fusion transcripts genetically characterize SS and the detection of this translocation leads to the diagnosis of SS.	('SS', 'Phenotype', 'HP:0012570', (57, 59))	('SS', 'Phenotype', 'HP:0012570', (105, 107))	('SS', 'Phenotype', 'HP:0012570', (174, 176))	('detection', 'Var', (116, 125))	('SSX', 'Gene', '6757', (57, 60))	('SSX', 'Gene', (57, 60))	('SYT', 'Gene', (53, 56))	('leads to', 'Reg', (148, 156))	('SYT', 'Gene', '6760', (53, 56))
429338	32204536	Interestingly, TRIM28 mutations have been associated with a specific subset of purely epithelial WTs.	('WT', 'Phenotype', 'HP:0002667', (97, 99))	('TRIM28', 'Gene', '10155', (15, 21))	('associated with', 'Reg', (42, 57))	('purely epithelial WTs', 'Disease', (79, 100))	('TRIM28', 'Gene', (15, 21))	('mutations', 'Var', (22, 31))
429339	32204536	Type 1 PRCCs show MET alterations in 81%, and 25% of type 2 PRCCs harbor CDKN2A genomic abnormalities.	('PRCC', 'Gene', (60, 64))	('PRCC', 'Gene', '5546', (7, 11))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('CDKN2A', 'Gene', '1029', (73, 79))	('PRCC', 'Gene', (7, 11))	('alterations', 'Var', (22, 33))	('PRCC', 'Gene', '5546', (60, 64))	('CDKN2A', 'Gene', (73, 79))
429354	32204536	Interestingly, in these spindle cell areas, immunoreactivity for markers normally seen in the original tumor type is often lost, whereas most cases show abnormal p53 immunoreactivity suggestive of a TP53 mutation.	('mutation', 'Var', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('lost', 'NegReg', (123, 127))	('p53', 'Gene', (162, 165))	('TP53', 'Gene', (199, 203))	('immunoreactivity for markers', 'MPA', (44, 72))	('tumor', 'Disease', (103, 108))	('p53', 'Gene', '7157', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('TP53', 'Gene', '7157', (199, 203))
429361	32204536	The majority of MSTs are BRAFV600E (~65%) and CD34 positive (Figure 2), while the other tumors are usually negative.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('BRAFV600E', 'Var', (25, 34))	('BRAFV600E', 'Mutation', 'rs113488022', (25, 34))	('CD34', 'Gene', (46, 50))	('MSTs', 'Disease', (16, 20))	('positive', 'Reg', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('CD34', 'Gene', '947', (46, 50))
429367	32204536	The recently reported EGFR-ITDs rearrangements in all CMN types, together with the previously known t(12;15) (ETV6-NTRK3 translocation) in cellular CMNs help to confirm the diagnosis of CMN.	('NTRK3', 'Gene', '4916', (115, 120))	('CMN', 'Phenotype', 'HP:0100881', (148, 151))	('ETV6', 'Gene', (110, 114))	('CMN', 'Phenotype', 'HP:0100881', (54, 57))	('NTRK3', 'Gene', (115, 120))	('CMN', 'Disease', (186, 189))	('CMN', 'Phenotype', 'HP:0100881', (186, 189))	('ETV6', 'Gene', '2120', (110, 114))	('rearrangements', 'Var', (32, 46))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
429369	32204536	A PCR study on 22 CMNs (including 10 cellular CMNs) showed no BRAF V600e mutations.	('CMN', 'Phenotype', 'HP:0100881', (18, 21))	('CMN', 'Phenotype', 'HP:0100881', (46, 49))	('BRAF', 'Gene', (62, 66))	('BRAF', 'Gene', '673', (62, 66))	('V600e mutations', 'Var', (67, 82))
429370	32204536	In one study 2 out of 3 cellular CMN which showed no ETV6 translocation, showed different rearrangements in the BRAF oncogene on WGS.	('ETV6', 'Gene', '2120', (53, 57))	('BRAF', 'Gene', '673', (112, 116))	('BRAF', 'Gene', (112, 116))	('rearrangements', 'Var', (90, 104))	('CMN', 'Phenotype', 'HP:0100881', (33, 36))	('ETV6', 'Gene', (53, 57))
429371	32204536	The diagnosis of synovial sarcoma can be established by demonstrating the characteristic translocation t(X;18)(p11.2;q11.2), present in >90% of cases.	('t(X;18)(p11.2;q11.2', 'Var', (103, 122))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (103, 123))	('synovial sarcoma', 'Disease', (17, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (17, 33))	('synovial sarcoma', 'Disease', 'MESH:D013584', (17, 33))
429385	32204536	Two newly described sarcomas, very rarely seen in children in the kidney, are the CIC-DUX4 translocation sarcoma and the BCOR-CCNB3 translocation sarcomas.	('BCOR', 'Gene', (121, 125))	('CIC-DUX4 translocation sarcoma', 'Disease', (82, 112))	('CCNB3', 'Gene', '85417', (126, 131))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('sarcomas', 'Disease', (20, 28))	('BCOR', 'Gene', '54880', (121, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('children', 'Species', '9606', (50, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcomas', 'Disease', (146, 154))	('CCNB3', 'Gene', (126, 131))	('translocation', 'Var', (132, 145))	('CIC-DUX4 translocation sarcoma', 'Disease', 'MESH:D014178', (82, 112))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
429402	32204536	MRTKs are characterized by inactivating mutations in the chromatin-remodeling complex members INI1 (also referred to as SMARCB1; 95%) or SMARCA4 (5%), or show deletions of 22q11 (on which INI1 is located).	('SMARCA4', 'Gene', (137, 144))	('INI1', 'Gene', (188, 192))	('SMARCA4', 'Gene', '6597', (137, 144))	('inactivating mutations', 'Var', (27, 49))	('INI1', 'Gene', '6598', (188, 192))	('SMARCB1', 'Gene', (120, 127))	('SMARCB1', 'Gene', '6598', (120, 127))	('deletions', 'Var', (159, 168))	('INI1', 'Gene', (94, 98))	('INI1', 'Gene', '6598', (94, 98))
429403	32204536	Therefore, sequencing of INI1 and SMARCA4 is helpful in establishing a diagnosis of MRTK.	('sequencing', 'Var', (11, 21))	('MRTK', 'Disease', (84, 88))	('SMARCA4', 'Gene', (34, 41))	('SMARCA4', 'Gene', '6597', (34, 41))	('INI1', 'Gene', (25, 29))	('INI1', 'Gene', '6598', (25, 29))
429404	32204536	Notably, when patients with a MRTK have a synchronous or metachronous rhabdoid tumor affecting other organs (including the central nervous system, referred to as Atypical Teratoid/Rhabdoid Tumor (AT/RT)), it is highly suggestive of the rhabdoid tumor predisposition syndrome.	('Tumor', 'Phenotype', 'HP:0002664', (189, 194))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (236, 250))	('synchronous or metachronous rhabdoid tumor', 'Disease', 'MESH:D018335', (42, 84))	('affecting', 'Reg', (85, 94))	('rhabdoid tumor', 'Disease', (236, 250))	('synchronous or metachronous rhabdoid tumor', 'Disease', (42, 84))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('MRTK', 'Var', (30, 34))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (70, 84))	('Rhabdoid Tumor', 'Disease', 'MESH:D018335', (180, 194))	('Rhabdoid Tumor', 'Disease', (180, 194))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
429406	32204536	In contrast, EWS show a wide variety of translocations involving the EWS gene (Table 5 and Table 7), most commonly t(11;22)(q24;q12) resulting in the EWS-FLI1 fusion.	('FLI1', 'Gene', (154, 158))	('EWS', 'Gene', '2130', (69, 72))	('EWS', 'Gene', (69, 72))	('EWS', 'Phenotype', 'HP:0012254', (150, 153))	('EWS', 'Gene', '2130', (150, 153))	('EWS', 'Gene', (150, 153))	('t(11;22)(q24;q12', 'Var', (115, 131))	('FLI1', 'Gene', '2313', (154, 158))	('EWS', 'Phenotype', 'HP:0012254', (13, 16))	('EWS', 'Gene', '2130', (13, 16))	('EWS', 'Gene', (13, 16))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (115, 132))	('EWS', 'Phenotype', 'HP:0012254', (69, 72))	('resulting in', 'Reg', (133, 145))
429407	32204536	In EWS-negative round cell sarcomas, CIC-DUX4 gene fusion (resulting from either t(4;19) or t(10;19)), is the most common genetic abnormality detected.	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcomas', 'Disease', (27, 35))	('DUX4', 'Gene', (41, 45))	('DUX4', 'Gene', '100288687', (41, 45))	('common', 'Reg', (115, 121))	('EWS', 'Phenotype', 'HP:0012254', (3, 6))	('EWS', 'Gene', '2130', (3, 6))	('EWS', 'Gene', (3, 6))	('t(10;19', 'Var', (92, 99))	('t(4;19', 'Var', (81, 87))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))
429408	32204536	The remainder includes BCOR-CCNB3 translocation sarcomas, harboring the same translocation reported in some CCSKs, suggesting that they might be in the same spectrum.	('translocation', 'Var', (34, 47))	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('CCNB3', 'Gene', '85417', (28, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('sarcomas', 'Disease', (48, 56))	('BCOR', 'Gene', (23, 27))	('CCSKs', 'Chemical', '-', (108, 113))	('CCSK', 'Phenotype', 'HP:0006770', (108, 112))	('BCOR', 'Gene', '54880', (23, 27))	('CCNB3', 'Gene', (28, 33))
429411	32204536	Furthermore, approximately 50% of MAFs carry the BRAF V600E mutation, although rare WTs may also harbor a BRAF mutation.	('WT', 'Phenotype', 'HP:0002667', (84, 86))	('MAFs', 'Disease', (34, 38))	('BRAF', 'Gene', '673', (106, 110))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('BRAF', 'Gene', (106, 110))	('BRAF', 'Gene', '673', (49, 53))	('V600E', 'Var', (54, 59))	('BRAF', 'Gene', (49, 53))
429421	32204536	The focused use of ancillary techniques will likely result in fewer unclassified cases, and lead to an increase in children diagnosed with germline mutations.	('fewer', 'NegReg', (62, 67))	('unclassified cases', 'MPA', (68, 86))	('germline mutations', 'Var', (139, 157))	('children', 'Species', '9606', (115, 123))
429516	25977825	It is remarkable that, despite partial HLA mismatch, the leukemic clone proliferated in both recipients.	('leukemic', 'Disease', 'MESH:D007938', (57, 65))	('HLA', 'Protein', (39, 42))	('leukemic', 'Disease', (57, 65))	('partial', 'Var', (31, 38))
429520	25977825	It is plausible that a similar phenomenon occurred in these two recipients, whereby genomic instability of the transplanted leukemic clones resulted in decreased expression of mismatched HLA allowing leukemic cells to escape from alloreactive recipient T cells and proliferate.	('leukemic', 'Disease', 'MESH:D007938', (124, 132))	('proliferate', 'CPA', (265, 276))	('HLA', 'Protein', (187, 190))	('leukemic', 'Disease', 'MESH:D007938', (200, 208))	('mismatched', 'Var', (176, 186))	('decreased', 'NegReg', (152, 161))	('expression', 'MPA', (162, 172))	('leukemic', 'Disease', (124, 132))	('leukemic', 'Disease', (200, 208))	('escape', 'CPA', (218, 224))
429587	21394230	The most common markers used, with varying degrees of success, to identify TSC in adult tumors include CD133, CD44, CD24, CD90, CD34, CD117, CD20, side population (SP) (ability to exclude Hoechst dye), and aldehyde dehydrogenase 1 (ALDH1).	('TSC', 'Gene', '7248', (75, 78))	('CD20', 'Gene', '931', (141, 145))	('CD117', 'Gene', '3815', (134, 139))	('CD34', 'Gene', (128, 132))	('TSC', 'Gene', (75, 78))	('aldehyde dehydrogenase 1', 'Gene', (206, 230))	('CD44', 'Gene', '960', (110, 114))	('CD24', 'Gene', (116, 120))	('ALDH1', 'Gene', (232, 237))	('CD133', 'Var', (103, 108))	('CD44', 'Gene', (110, 114))	('CD90', 'Gene', (122, 126))	('aldehyde dehydrogenase 1', 'Gene', '216', (206, 230))	('CD117', 'Gene', (134, 139))	('Hoechst dye', 'Chemical', '-', (188, 199))	('CD90', 'Gene', '7070', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('SP', 'Chemical', '-', (164, 166))	('CD34', 'Gene', '947', (128, 132))	('adult tumors', 'Disease', (82, 94))	('CD24', 'Gene', '100133941', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ALDH1', 'Gene', '216', (232, 237))	('CD20', 'Gene', (141, 145))	('adult tumors', 'Disease', 'MESH:C538052', (82, 94))
429594	21394230	purified CD133+ medulloblastoma (MB) TSC from patients' tumors based on several functional criteria including a marked capacity for proliferation, a propensity for self-renewal, and capacity for asymmetric differentiation.	('patients', 'Species', '9606', (46, 54))	('asymmetric differentiation', 'CPA', (195, 221))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TSC', 'Gene', (37, 40))	('TSC', 'Gene', '7248', (37, 40))	('medulloblastoma', 'Disease', (16, 31))	('self-renewal', 'CPA', (164, 176))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('MB', 'Phenotype', 'HP:0002885', (33, 35))	('CD133+', 'Var', (9, 15))	('medulloblastoma', 'Disease', 'MESH:D008527', (16, 31))	('medulloblastoma', 'Phenotype', 'HP:0002885', (16, 31))
429602	21394230	After the discovery of CD133+ pediatric brain TSC, many investigators began examining the utility of CD133 as a TSC marker in a wide variety of other pediatric solid tumors including retinoblastoma, neuroblastoma, malignant melanoma, and renal tumors.	('CD133+', 'Var', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('retinoblastoma', 'Disease', (183, 197))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('neuroblastoma', 'Disease', (199, 212))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (150, 172))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('neuroblastoma', 'Phenotype', 'HP:0003006', (199, 212))	('neuroblastoma', 'Disease', 'MESH:D009447', (199, 212))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('TSC', 'Gene', (46, 49))	('malignant melanoma', 'Phenotype', 'HP:0002861', (214, 232))	('pediatric solid tumors', 'Disease', (150, 172))	('malignant melanoma', 'Disease', 'MESH:D008545', (214, 232))	('renal tumors', 'Disease', (238, 250))	('TSC', 'Gene', '7248', (112, 115))	('retinoblastoma', 'Disease', 'MESH:D012175', (183, 197))	('TSC', 'Gene', '7248', (46, 49))	('renal tumors', 'Disease', 'MESH:D007674', (238, 250))	('TSC', 'Gene', (112, 115))	('renal tumors', 'Phenotype', 'HP:0009726', (238, 250))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('malignant melanoma', 'Disease', (214, 232))	('retinoblastoma', 'Phenotype', 'HP:0009919', (183, 197))
429614	21394230	first identified CD133+ cells in osteosarcoma with stem-like features including the ability to form tumor spheres, high proliferation rate, cell cycle detection in the G2/M phase, positivity for the nuclear protein Ki-67 which is associated with cellular proliferation, SP profile and expression of ATP-binding cassette (ABC) transporters which have been implicated in chemotherapy drug resistance.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ATP-binding cassette', 'Gene', (299, 319))	('ATP-binding cassette', 'Gene', '10058', (299, 319))	('tumor', 'Disease', (100, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('positivity', 'Var', (180, 190))	('ABC', 'Gene', (321, 324))	('drug resistance', 'Phenotype', 'HP:0020174', (382, 397))	('Ki-67', 'Gene', (215, 220))	('SP', 'Chemical', '-', (270, 272))	('osteosarcoma', 'Phenotype', 'HP:0002669', (33, 45))	('osteosarcoma', 'Disease', (33, 45))	('osteosarcoma', 'Disease', 'MESH:D012516', (33, 45))	('ABC', 'Gene', '10058', (321, 324))
429624	21394230	This may partially explain why several studies in adult cancers including colon, lung and brain have demonstrated that CD133- tumor cells can initiate tumors and why both CD133+ and CD133- DAOY MB cells displayed equivalent stem-like frequencies.	('adult cancers', 'Disease', 'MESH:C535836', (50, 63))	('CD133+', 'Var', (171, 177))	('MB', 'Phenotype', 'HP:0002885', (194, 196))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('colon', 'Disease', 'MESH:D015179', (74, 79))	('tumor', 'Disease', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('DAOY MB', 'CellLine', 'CVCL:1167', (189, 196))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('colon', 'Disease', (74, 79))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('adult cancers', 'Disease', (50, 63))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', (126, 131))
429670	21394230	Dysregulation of the Wnt pathways has been implicated in tumor formation, proliferation, and maintenance.	('Wnt pathways', 'Pathway', (21, 33))	('Dysregulation', 'Var', (0, 13))	('implicated', 'Reg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('proliferation', 'CPA', (74, 87))	('tumor', 'Disease', (57, 62))
429674	21394230	An earlier study found that deleting Patched gene, an antagonist of SHH, in mouse multipotent stem cells led to the expansion of the stem cell population and growth of the granule neuron precursors derived from the stem cells resulting in rapid tumor formation with 100% of the animals dying from MB by four weeks of age.	('Patched gene', 'Gene', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('stem cell population', 'CPA', (133, 153))	('mouse', 'Species', '10090', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('expansion', 'PosReg', (116, 125))	('deleting', 'Var', (28, 36))	('tumor', 'Disease', (245, 250))	('MB', 'Phenotype', 'HP:0002885', (297, 299))	('growth', 'CPA', (158, 164))
429676	21394230	Cells which expressed CD133 were more resistant to cyclopamine inhibition suggesting a potential mechanism of CD133+ TSC treatment resistance.	('TSC', 'Gene', (117, 120))	('cyclopamine', 'Chemical', 'MESH:C000541', (51, 62))	('CD133', 'Var', (22, 27))	('TSC', 'Gene', '7248', (117, 120))
429683	21394230	CD133+ neuroblastoma cells formed tumorspheres more efficiently than CD133- cells, and the tumorspheres were more resistant to doxorubicin than bulk cells.	('tumors', 'Disease', (91, 97))	('neuroblastoma', 'Disease', (7, 20))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('neuroblastoma', 'Phenotype', 'HP:0003006', (7, 20))	('doxorubicin', 'Chemical', 'MESH:D004317', (127, 138))	('CD133+', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (7, 20))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
429695	21394230	Activated phosphorylation of the checkpoint proteins ATM, Rad17, Chk1 and Chk2 were significantly higher in the CD133+ fraction, and relative radioresistance of the CD133+ cells was reversible with the pharmacologic inhibition of Chk1 and Chk2.	('CD133+', 'Var', (112, 118))	('Rad17', 'Gene', '5884', (58, 63))	('Chk2', 'Gene', '11200', (74, 78))	('Chk2', 'Gene', '11200', (239, 243))	('Chk2', 'Gene', (74, 78))	('ATM', 'Gene', (53, 56))	('Chk2', 'Gene', (239, 243))	('Chk1', 'Gene', (230, 234))	('Chk1', 'Gene', '1111', (65, 69))	('Chk1', 'Gene', (65, 69))	('CD133+', 'Var', (165, 171))	('higher', 'PosReg', (98, 104))	('Chk1', 'Gene', '1111', (230, 234))	('radioresistance', 'CPA', (142, 157))	('Rad17', 'Gene', (58, 63))	('Activated phosphorylation', 'MPA', (0, 25))	('ATM', 'Gene', '472', (53, 56))
429718	21394230	Oncolytic viruses typically work in two main ways: as a direct, targeted attack by containing mutations that cause the virus to spare normal cells but infect tumor cells that then die and release infectious virus to neighboring tumor cells, or by expressing therapeutic foreign gene products that either directly or indirectly lead to cell death.	('lead to', 'Reg', (327, 334))	('tumor', 'Disease', (158, 163))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('infect tumor', 'Disease', (151, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('infect tumor', 'Disease', 'MESH:D009369', (151, 163))
429826	29075423	The final diagnosis was of oral myeloid sarcoma associated with acute promyelocytic leukemia with t(15;17).	('t(15;17', 'Var', (98, 105))	('associated', 'Reg', (48, 58))	('acute promyelocytic leukemia', 'Disease', (64, 92))	('oral myeloid sarcoma', 'Disease', (27, 47))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (64, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (64, 92))	('oral myeloid sarcoma', 'Disease', 'MESH:D023981', (27, 47))	('leukemia', 'Phenotype', 'HP:0001909', (84, 92))
429839	29075423	By immunohistochemis-try, tumor cells were intensely positive for myeloperoxidase (dilution 1:5000, polyclonal, Dako, Carpinteria, CA, USA) and CD99 (dilution 1:100, clone 12e7, Dako, Carpinteria, CA, USA), and negative for CD20 (dilution 1:1000, clone L26, Dako, Carpinteria, CA, USA), CD3 (dilution 1:500, polyclonal, Dako, Carpinteria, CA, USA), CD34 (dilution 1:50, clone QBEnd10, Dako, Carpinteria, CA, USA), and TdT (dilution 1:50, polyclonal, Dako, Carpinteria, CA, USA).	('positive', 'Reg', (53, 61))	('TdT', 'Gene', '1791', (418, 421))	('CD3', 'Gene', (287, 290))	('myeloperoxidase', 'Gene', (66, 81))	('myeloperoxidase', 'Gene', '4353', (66, 81))	('CD20', 'Gene', '54474', (224, 228))	('CD99', 'Gene', (144, 148))	('CD20', 'Gene', (224, 228))	('CD34', 'Gene', (349, 353))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('dilution 1:50', 'Var', (355, 368))	('CD34', 'Gene', '947', (349, 353))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('TdT', 'Gene', (418, 421))	('CD99', 'Gene', '4267', (144, 148))
429842	29075423	The final diagnosis of the oral lesion was myeloid sarcoma associated with acute promyelocytic leukemia with t(15;17).	('oral lesion', 'Phenotype', 'HP:0100649', (27, 38))	('oral lesion', 'Disease', (27, 38))	('myeloid sarcoma', 'Disease', (43, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('acute promyelocytic leukemia', 'Disease', (75, 103))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (75, 103))	('associated', 'Reg', (59, 69))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (75, 103))	('t(15;17', 'Var', (109, 116))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (43, 58))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('oral lesion', 'Disease', 'MESH:D020820', (27, 38))
429921	27446625	The SYT gene (Chr 18) fuses with SSX1 (Chr X) to form biphasic tumour while fusion with SSX2 leads to monophasic tumour.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('SYT', 'Gene', '6760', (4, 7))	('SSX2', 'Gene', '6757', (88, 92))	('SSX1', 'Gene', (33, 37))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('biphasic tumour', 'Disease', (54, 69))	('SSX2', 'Gene', (88, 92))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', (113, 119))	('fusion', 'Var', (76, 82))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('biphasic tumour', 'Disease', 'MESH:D009369', (54, 69))	('SSX1', 'Gene', '6756', (33, 37))	('SYT', 'Gene', (4, 7))	('tumour', 'Disease', (63, 69))
429942	30505422	Canonical Wnt/beta-catenin signaling activation in soft-tissue sarcomas: A comparative study of synovial sarcoma and leiomyosarcoma Previous studies have shown that aberrant activation of the Wnt/beta-catenin pathway is associated with many malignant neoplasms.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('neoplasm', 'Phenotype', 'HP:0002664', (251, 259))	('sarcomas', 'Disease', (63, 71))	('synovial sarcoma', 'Disease', (96, 112))	('malignant neoplasms', 'Disease', 'MESH:D009369', (241, 260))	('leiomyosarcoma', 'Disease', (117, 131))	('malignant neoplasms', 'Disease', (241, 260))	('neoplasms', 'Phenotype', 'HP:0002664', (251, 260))	('synovial sarcoma', 'Disease', 'MESH:D013584', (96, 112))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (51, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (96, 112))	('beta-catenin', 'Gene', (196, 208))	('beta-catenin', 'Gene', (14, 26))	('beta-catenin', 'Gene', '1499', (196, 208))	('beta-catenin', 'Gene', '1499', (14, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('aberrant', 'Var', (165, 173))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (51, 71))	('activation', 'PosReg', (174, 184))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (117, 131))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (117, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('sarcomas', 'Disease', 'MESH:D012509', (63, 71))
429952	30505422	While targeting the constituents of this pathway might be effective in the treatment of synovial sarcomas, it is not likely to be an effective strategy in the treatment of leiomyosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('synovial sarcomas', 'Disease', 'MESH:D013584', (88, 105))	('synovial sarcomas', 'Disease', (88, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (172, 187))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (88, 104))	('targeting', 'Var', (6, 15))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (172, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (172, 186))	('leiomyosarcomas', 'Disease', (172, 187))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (88, 105))
429957	30505422	The dawn of the molecular era of medicine in the 1990s and early 2000s led to the realization that various aberrancies in the canonical Wnt pathway are associated with certain types of malignancies.	('aberrancies', 'Var', (107, 118))	('canonical Wnt pathway', 'Pathway', (126, 147))	('malignancies', 'Disease', 'MESH:D009369', (185, 197))	('malignancies', 'Disease', (185, 197))	('associated', 'Reg', (152, 162))
429958	30505422	One of the first genetic alterations to be associated with cancer was mutation of the APC gene in patients with the hereditary colorectal cancer syndrome familial adenomatous polyposis (FAP).	('familial adenomatous polyposis', 'Disease', (154, 184))	('cancer', 'Disease', (138, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (163, 184))	('APC', 'Phenotype', 'HP:0005227', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('hereditary colorectal cancer syndrome', 'Disease', 'MESH:D015179', (116, 153))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (154, 184))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('APC', 'Gene', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('FAP', 'Disease', 'MESH:C567782', (186, 189))	('patients', 'Species', '9606', (98, 106))	('FAP', 'Disease', (186, 189))	('hereditary colorectal cancer syndrome', 'Disease', (116, 153))	('APC', 'Gene', '324', (86, 89))	('mutation', 'Var', (70, 78))	('cancer', 'Disease', (59, 65))
429960	30505422	Since then, many different types of malignancies have been associated with genetic alterations leading to aberrancies in the canonical Wnt/beta-catenin pathway: some hepatocellular carcinomas, pancreatic carcinomas, adrenocortical carcinomas, melanomas, and several others.	('melanomas', 'Disease', (243, 252))	('adrenocortical carcinomas', 'Disease', (216, 241))	('pancreatic carcinomas', 'Disease', (193, 214))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (216, 241))	('melanomas', 'Phenotype', 'HP:0002861', (243, 252))	('leading to', 'Reg', (95, 105))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (166, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (166, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('hepatocellular carcinomas', 'Disease', (166, 191))	('aberrancies', 'Var', (106, 117))	('malignancies', 'Disease', 'MESH:D009369', (36, 48))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (193, 214))	('malignancies', 'Disease', (36, 48))	('associated', 'Reg', (59, 69))	('beta-catenin', 'Gene', (139, 151))	('genetic alterations', 'Var', (75, 94))	('melanomas', 'Disease', 'MESH:D008545', (243, 252))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (216, 241))	('beta-catenin', 'Gene', '1499', (139, 151))
429961	30505422	The majority of previously described malignancies associated with aberrancies in the canonical Wnt pathway are carcinomas (i.e.	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('malignancies', 'Disease', (37, 49))	('carcinomas', 'Disease', 'MESH:D002277', (111, 121))	('canonical Wnt pathway', 'Pathway', (85, 106))	('carcinomas', 'Disease', (111, 121))	('aberrancies', 'Var', (66, 77))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))
429963	30505422	However, several expression-profiling studies have demonstrated a link between upregulation of the Wnt/beta-catenin pathway and the tumorigenesis of synovial sarcoma, a malignant mesenchymal spindle cell neoplasm characterized by the reciprocal translocation t(X;18) (p11;q11) with fusion of SS18 (SYT) to SSX1, SSX2, or (rarely) SSX4.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (149, 165))	('SS18', 'Gene', '6760', (292, 296))	('t(X', 'Var', (259, 262))	('tumor', 'Disease', (132, 137))	('neoplasm', 'Phenotype', 'HP:0002664', (204, 212))	('SSX4', 'Gene', (330, 334))	('upregulation', 'PosReg', (79, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('SYT', 'Gene', '6760', (298, 301))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('beta-catenin', 'Gene', (103, 115))	('beta-catenin', 'Gene', '1499', (103, 115))	('SSX1', 'Gene', '6756', (306, 310))	('SSX4', 'Gene', '6759', (330, 334))	('SSX1', 'Gene', (306, 310))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('SSX2', 'Gene', (312, 316))	('neoplasm', 'Disease', 'MESH:D009369', (204, 212))	('SS18', 'Gene', (292, 296))	('synovial sarcoma', 'Disease', (149, 165))	('SSX2', 'Gene', '6757', (312, 316))	('synovial sarcoma', 'Disease', 'MESH:D013584', (149, 165))	('neoplasm', 'Disease', (204, 212))	('SYT', 'Gene', (298, 301))
429982	30505422	After peroxidase blocking, LEF1 rabbit monoclonal antibody (EPR2029Y, Abcam, Cambridge, MA) was applied at a dilution of 1:250 at room temperature for 60 min.	('rabbit', 'Species', '9986', (32, 38))	('EPR2029Y', 'Var', (60, 68))	('LEF1', 'Gene', '51176', (27, 31))	('LEF1', 'Gene', (27, 31))
430017	30505422	The detection of such alterations can supplement histomorphologic impressions in making a diagnosis, potentially provide critical information regarding prognosis and anticipated clinical behavior of certain malignancies, identify tumorigenic mechanisms that can be targeted by molecular therapies for use in clinical trials, and/or play a crucial role in monitoring minimal residual disease by molecular methods in patients who are undergoing therapy.	('tumor', 'Disease', (230, 235))	('malignancies', 'Disease', (207, 219))	('alterations', 'Var', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('patients', 'Species', '9606', (415, 423))	('malignancies', 'Disease', 'MESH:D009369', (207, 219))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
430019	30505422	One such example is the association of aberrant Wnt/beta-catenin signaling in the pathogenesis of synovial sarcoma, a piece of information which may hopefully lead to the discovery of effective molecular therapies for patients with synovial sarcoma in the not too distant future.	('sarcoma', 'Phenotype', 'HP:0100242', (241, 248))	('beta-catenin', 'Gene', (52, 64))	('synovial sarcoma', 'Disease', (232, 248))	('association', 'Interaction', (24, 35))	('patients', 'Species', '9606', (218, 226))	('synovial sarcoma', 'Disease', (98, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (232, 248))	('beta-catenin', 'Gene', '1499', (52, 64))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (98, 114))	('synovial sarcoma', 'Disease', 'MESH:D013584', (98, 114))	('synovial sarcoma', 'Disease', 'MESH:D013584', (232, 248))	('aberrant', 'Var', (39, 47))
430237	26957498	Histopathologic classification of soft tissue sarcoma has become more accurate over the past 10 years due to advances in immunohistochemistry (newly developed antibodies) and molecular biology (FISH and PCR detecting newly discovered gene translocations which are more or less histotype specific).	('soft tissue sarcoma', 'Disease', (34, 53))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (34, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (34, 53))	('gene translocations', 'Var', (234, 253))
430288	26793543	Following his PSA in 2011, his local urologist performed a transrectal prostate biopsy, which revealed patchy fascicular spindle cell proliferation with CD34 positivity and negative PR, actin, desmin, and pankeratin on immunohistochemistry.	('patchy fascicular', 'Disease', (103, 120))	('positivity', 'Var', (158, 168))	('CD34', 'Gene', (153, 157))	('PSA', 'Gene', '354', (14, 17))	('CD34', 'Gene', '947', (153, 157))	('PSA', 'Gene', (14, 17))	('desmin', 'Gene', '1674', (193, 199))	('patchy fascicular', 'Disease', 'MESH:C531609', (103, 120))	('actin', 'Protein', (186, 191))	('desmin', 'Gene', (193, 199))	('negative', 'NegReg', (173, 181))
430363	24076008	In a mouse model of CIBP, ARRY-470 attenuates spontaneous and evoked pain behaviors compared to untreated animals.	('ARRY-470', 'Var', (26, 34))	('CIBP', 'Chemical', '-', (20, 24))	('attenuates', 'NegReg', (35, 45))	('pain behaviors', 'Disease', (69, 83))	('mouse', 'Species', '10090', (5, 10))	('pain behaviors', 'Disease', 'MESH:D013001', (69, 83))	('pain', 'Phenotype', 'HP:0012531', (69, 73))
430364	24076008	ARRY-470 can also effectively diminish nerve fiber sprouting and neuroma formation in the periosteum.	('neuroma', 'Phenotype', 'HP:0030430', (65, 72))	('neuroma', 'Disease', (65, 72))	('diminish', 'NegReg', (30, 38))	('nerve fiber sprouting', 'CPA', (39, 60))	('neuroma', 'Disease', 'MESH:D009463', (65, 72))	('ARRY-470', 'Var', (0, 8))
430372	24076008	This provides evidence that NGF/TrkA signaling over other neurotrophin subtypes may be more important in cancer pain Recent studies on BDNF have demonstrated a role in the induction and maintenance of behavioral hypersensitivity in a rat model of CIBP by BDNF modulating the NMDA subunit 1 (NR1) at the level of the spinal cord and DRG.	('hypersensitivity in', 'Disease', 'MESH:D004342', (212, 231))	('rat', 'Species', '10116', (152, 155))	('cancer pain', 'Disease', 'MESH:D000072716', (105, 116))	('BDNF', 'Var', (255, 259))	('NMDA', 'Chemical', 'MESH:D016202', (275, 279))	('cancer pain', 'Disease', (105, 116))	('pain', 'Phenotype', 'HP:0012531', (112, 116))	('NR1', 'Gene', (291, 294))	('rat', 'Species', '10116', (234, 237))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CIBP', 'Chemical', '-', (247, 251))	('modulating', 'Reg', (260, 270))	('hypersensitivity in', 'Disease', (212, 231))
430375	24076008	Besides the prototypical cancer cells, containing oncogenic and tumor suppressor mutations characterizing cancer, there are cancer stem cells, pericytes, cancer-associated fibroblast, stem and progenitor cells of the tumor stroma, and immune pro-inflammatory cells.	('cancer', 'Disease', (106, 112))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumor stroma', 'Disease', (217, 229))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor stroma', 'Disease', 'MESH:D009369', (217, 229))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (64, 69))	('cancer', 'Disease', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
430389	24076008	In human osteoclasts in vitro, biomolecular and functional experiments showed that resiniferatoxin (RTX), a selective TRPV1 receptor agonist, increased the expression and activity of the osteoclast biomarkers, TRAP and cathepsin K. Capsazepine has been shown to inhibit osteoclastic bone resorption, osteoblast activity and bone formation.	('resiniferatoxin', 'Chemical', 'MESH:C024353', (83, 98))	('bone resorption', 'Phenotype', 'HP:0002797', (283, 298))	('osteoblast activity', 'CPA', (300, 319))	('TRAP', 'Gene', (210, 214))	('Capsazepine', 'Var', (232, 243))	('Capsazepine', 'Chemical', 'MESH:C071423', (232, 243))	('osteoclastic bone', 'Disease', 'MESH:D001862', (270, 287))	('bone formation', 'CPA', (324, 338))	('human', 'Species', '9606', (3, 8))	('RTX', 'Chemical', 'MESH:C024353', (100, 103))	('osteoclastic bone', 'Disease', (270, 287))	('TRAP', 'Gene', '100187907', (210, 214))	('inhibit', 'NegReg', (262, 269))
430390	24076008	Inhibition of TRPV1 also protects against ovariectomy induced bone loss in mice.	('bone loss', 'Phenotype', 'HP:0002797', (62, 71))	('mice', 'Species', '10090', (75, 79))	('bone loss', 'Disease', (62, 71))	('bone loss', 'Disease', 'MESH:D016301', (62, 71))	('TRPV1', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('ovariectomy induced', 'Disease', (42, 61))
430391	24076008	This implies pharmacological blockade of TRPV1 may interfere with osteoclastogenesis, reducing one source of extracellular proton production and ensuing pain.	('pharmacological blockade', 'Var', (13, 37))	('one source of extracellular proton production', 'MPA', (95, 140))	('osteoclastogenesis', 'CPA', (66, 84))	('pain', 'Phenotype', 'HP:0012531', (153, 157))	('pain', 'Disease', 'MESH:D010146', (153, 157))	('pain', 'Disease', (153, 157))	('reducing', 'NegReg', (86, 94))	('TRPV1', 'Gene', (41, 46))	('interfere', 'NegReg', (51, 60))
430395	24076008	JNJ-17203212 is a selective, potent antagonist of both rodent and human TRPV1, with an IC50 value of 38+-10 nM was used in a murine bone cancer model.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bone cancer', 'Disease', (132, 143))	('human', 'Species', '9606', (66, 71))	('JNJ-17203212', 'Chemical', 'MESH:C500065', (0, 12))	('TRPV1', 'Protein', (72, 77))	('murine', 'Species', '10090', (125, 131))	('bone cancer', 'Disease', 'MESH:D001859', (132, 143))	('JNJ-17203212', 'Var', (0, 12))
430403	24076008	In a rat model of CIBP, VPC32183, an LPA1 receptor antagonist, attenuated mechanical allodynia and thermal hyperalgesia, suggesting release of LPA from cancer cells and cross-talk between LPA1 and TRPV1 in CIBP.	('hyperalgesia', 'Phenotype', 'HP:0031005', (107, 119))	('VPC32183', 'Chemical', 'MESH:C529824', (24, 32))	('LPA1', 'Protein', (188, 192))	('LPA', 'Chemical', 'MESH:C032881', (37, 40))	('release', 'MPA', (132, 139))	('cancer', 'Disease', (152, 158))	('CIBP', 'Chemical', '-', (18, 22))	('LPA', 'MPA', (143, 146))	('TRPV1', 'Gene', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('CIBP', 'Chemical', '-', (206, 210))	('attenuated mechanical allodynia', 'Disease', 'MESH:D006930', (63, 94))	('rat', 'Species', '10116', (5, 8))	('LPA', 'Chemical', 'MESH:C032881', (143, 146))	('hyperalgesia', 'Disease', 'MESH:D006930', (107, 119))	('VPC32183', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('allodynia', 'Phenotype', 'HP:0012533', (85, 94))	('hyperalgesia', 'Disease', (107, 119))	('LPA', 'Chemical', 'MESH:C032881', (188, 191))	('attenuated mechanical allodynia', 'Disease', (63, 94))	('cross-talk', 'Reg', (169, 179))
430417	24076008	demonstrated injection of acetic acid to SNL rats evoked an increase in spontaneous pain and mechanical allodynia compared to sham animals, providing evidence that ASIC3 is associated with hyperalgesia in response to an acidic stimulus in this neuropathic pain model.	('response to an acidic stimulus', 'MPA', (205, 235))	('ASIC3', 'Var', (164, 169))	('pain', 'Disease', 'MESH:D010146', (84, 88))	('rat', 'Species', '10116', (7, 10))	('pain', 'Disease', (256, 260))	('increase', 'PosReg', (60, 68))	('pain', 'Phenotype', 'HP:0012531', (256, 260))	('hyperalgesia', 'Disease', 'MESH:D006930', (189, 201))	('neuropathic pain', 'Disease', 'MESH:D009437', (244, 260))	('allodynia', 'Phenotype', 'HP:0012533', (104, 113))	('mechanical allodynia', 'Disease', 'MESH:D006930', (93, 113))	('rat', 'Species', '10116', (45, 48))	('spontaneous pain', 'Phenotype', 'HP:0010833', (72, 88))	('mechanical allodynia', 'Disease', (93, 113))	('pain', 'Disease', (84, 88))	('hyperalgesia', 'Disease', (189, 201))	('pain', 'Disease', 'MESH:D010146', (256, 260))	('hyperalgesia', 'Phenotype', 'HP:0031005', (189, 201))	('acetic acid', 'Chemical', 'MESH:D019342', (26, 37))	('neuropathic pain', 'Disease', (244, 260))	('rats', 'Species', '10116', (45, 49))	('pain', 'Phenotype', 'HP:0012531', (84, 88))
430419	24076008	These studies suggest ASIC3 modulation contributes to maintenance and generation of acute inflammatory and chronic neuropathic pain.	('modulation', 'Var', (28, 38))	('rat', 'Species', '10116', (74, 77))	('neuropathic pain', 'Disease', (115, 131))	('pain', 'Phenotype', 'HP:0012531', (127, 131))	('neuropathic pain', 'Disease', 'MESH:D009437', (115, 131))	('acute inflammatory', 'Disease', (84, 102))
430438	24076008	Hence, intrathecal injection of a neutralizing antibody against CX3CR1 reduced mechanical allodynia in cancer-induced rats with further studies suggesting a CX3CR1 mediated pain through microglia and p38 mitogen-activated protein kinase (MAPK) activation in the spinal cord.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('p38 mitogen-activated protein kinase', 'Gene', (200, 236))	('rat', 'Species', '10116', (118, 121))	('CX3CR1', 'Var', (157, 163))	('pain', 'Phenotype', 'HP:0012531', (173, 177))	('rat', 'Species', '10116', (10, 13))	('pain', 'Disease', 'MESH:D010146', (173, 177))	('mechanical allodynia', 'Disease', 'MESH:D006930', (79, 99))	('reduced', 'NegReg', (71, 78))	('microglia', 'CPA', (186, 195))	('pain', 'Disease', (173, 177))	('allodynia', 'Phenotype', 'HP:0012533', (90, 99))	('p38 mitogen-activated protein kinase', 'Gene', '81649', (200, 236))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('mechanical allodynia', 'Disease', (79, 99))	('rats', 'Species', '10116', (118, 122))	('activation', 'PosReg', (244, 254))
430461	24076008	The viability of breast cancer lines MCF-7, T47D and 4T1 is promoted by the uptake of NO precursor, L-arginine, and its conversion to nitric oxide.	('uptake', 'MPA', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('viability', 'CPA', (4, 13))	('promoted', 'PosReg', (60, 68))	('breast cancer', 'Disease', (17, 30))	('L-arginine', 'Var', (100, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('conversion', 'MPA', (120, 130))	('nitric oxide', 'Chemical', 'MESH:D009569', (134, 146))	('T47D', 'CellLine', 'CVCL:0553', (44, 48))	('L-arginine', 'Chemical', 'MESH:D001120', (100, 110))	('MCF-7', 'CellLine', 'CVCL:0031', (37, 42))
430463	24076008	Furthermore, in human breast cancer tumors, aberrant iNOS expression and production of NO is thought to activate oncogenic pathways, select for mutant tumor suppressor loss, induce stem cell-like tumor characteristics and promote tumor viability.	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('mutant', 'Var', (144, 150))	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('human', 'Species', '9606', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (230, 235))	('induce', 'PosReg', (174, 180))	('promote', 'PosReg', (222, 229))	('oncogenic pathways', 'Pathway', (113, 131))	('activate', 'PosReg', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('aberrant', 'Var', (44, 52))	('breast cancer tumors', 'Disease', 'MESH:D001943', (22, 42))	('loss', 'NegReg', (168, 172))	('tumor', 'Disease', (151, 156))	('breast cancer tumors', 'Disease', (22, 42))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('iNOS', 'Protein', (53, 57))
430464	24076008	Because NO diffuses easily from its site of release, primary afferent neurons innervating the bone-tumor microenvironment are vulnerable to reaction with NO and subsequent nitration events.	('nitration', 'Var', (172, 181))	('bone-tumor', 'Phenotype', 'HP:0010622', (94, 104))	('bone-tumor', 'Disease', (94, 104))	('rat', 'Species', '10116', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('bone-tumor', 'Disease', 'MESH:D001859', (94, 104))
430467	24076008	Accordingly, NMDA antagonists have demonstrated efficacy in preclinical models of pain associated with nitration events and in a model of CIBP.	('nitration events', 'Var', (103, 119))	('NMDA', 'Chemical', 'MESH:D016202', (13, 17))	('CIBP', 'Chemical', '-', (138, 142))	('pain', 'Phenotype', 'HP:0012531', (82, 86))	('rat', 'Species', '10116', (106, 109))	('pain', 'Disease', 'MESH:D010146', (82, 86))	('NMDA', 'Gene', (13, 17))	('pain', 'Disease', (82, 86))	('rat', 'Species', '10116', (42, 45))
430468	24076008	It has also been posited that nitration of glutamate recycling mechanisms may contribute to enhanced glutamatergic neurotransmission in the bone-tumor microenvironment: the nitration of glutamate transporters including GLT-1 and GLAST reduces uptake of glutamate, which may lead prolonged synaptic glutamate concentrations.	('rat', 'Species', '10116', (176, 179))	('bone-tumor', 'Disease', 'MESH:D001859', (140, 150))	('rat', 'Species', '10116', (33, 36))	('synaptic glutamate concentrations', 'MPA', (289, 322))	('prolonged', 'PosReg', (279, 288))	('nitration', 'Var', (173, 182))	('GLAST', 'Gene', '20512', (229, 234))	('glutamate', 'Chemical', 'MESH:D018698', (253, 262))	('rat', 'Species', '10116', (315, 318))	('glutamate', 'Chemical', 'MESH:D018698', (101, 110))	('GLAST', 'Gene', (229, 234))	('GLT-1', 'Gene', (219, 224))	('bone-tumor', 'Disease', (140, 150))	('uptake of glutamate', 'MPA', (243, 262))	('GLT-1', 'Gene', '20511', (219, 224))	('glutamate', 'Chemical', 'MESH:D018698', (186, 195))	('bone-tumor', 'Phenotype', 'HP:0010622', (140, 150))	('glutamate', 'Chemical', 'MESH:D018698', (43, 52))	('enhanced', 'PosReg', (92, 100))	('glutamate', 'Chemical', 'MESH:D018698', (298, 307))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('glutamate', 'Protein', (186, 195))	('reduces', 'NegReg', (235, 242))	('glutamatergic neurotransmission', 'MPA', (101, 132))
430469	24076008	Understanding mechanisms of nitration-mediated enhancements in glutamatergic transmission in the context of CIBP models is an on-going effort that requires research attention.	('nitration-mediated', 'Var', (28, 46))	('CIBP', 'Chemical', '-', (108, 112))	('glutamate', 'Chemical', 'MESH:D018698', (63, 72))	('enhancements', 'PosReg', (47, 59))	('glutamatergic transmission', 'MPA', (63, 89))	('rat', 'Species', '10116', (31, 34))
430520	28794805	For less fit patients, in whom the risks of toxicity outweigh the benefits of AI combination chemotherapy, alternatives may include single-agent doxorubicin, single-agent ifosfamide, or liposomal doxorubicin (Doxil).	('AI', 'Chemical', '-', (78, 80))	('liposomal', 'Var', (186, 195))	('patients', 'Species', '9606', (13, 21))	('Doxil', 'Chemical', '-', (209, 214))	('doxorubicin', 'Chemical', 'MESH:D004317', (196, 207))	('doxorubicin', 'Chemical', 'MESH:D004317', (145, 156))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('ifosfamide', 'Chemical', 'MESH:D007069', (171, 181))	('toxicity', 'Disease', (44, 52))
430569	28794805	ORR was marginally higher for anthracycline-based regimens in the first line, 26% compared with 22% among GD-treated patients.	('ORR', 'MPA', (0, 3))	('GD', 'Chemical', '-', (106, 108))	('anthracycline-based', 'Var', (30, 49))	('anthracycline', 'Chemical', 'MESH:D018943', (30, 43))	('patients', 'Species', '9606', (117, 125))
430579	28794805	Unlike other alkylating agents which target the DNA major groove, trabectedin binds and alkylates the minor groove, bending towards the major groove, disrupting the late S-phase and G2 phase, and induces p-53-independent apoptosis.	('trabectedin', 'Gene', (66, 77))	('disrupting', 'NegReg', (150, 160))	('p-53', 'Gene', '7157', (204, 208))	('induces', 'Reg', (196, 203))	('trabectedin', 'Chemical', 'MESH:D000077606', (66, 77))	('alkylates', 'Var', (88, 97))	('p-53', 'Gene', (204, 208))	('G2 phase', 'CPA', (182, 190))
430594	28794805	At 6 months, 37% of patients treated with trabectedin were progression free, compared with 14% of patients treated with dacarbazine.	('trabectedin', 'Chemical', 'MESH:D000077606', (42, 53))	('progression free', 'CPA', (59, 75))	('trabectedin', 'Var', (42, 53))	('dacarbazine', 'Chemical', 'MESH:D003606', (120, 131))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (20, 28))
430618	28794805	Among LMS, SS and other sarcomas, the PFR12w rates were 44%, 49% and 39%, respectively.	('LMS', 'Phenotype', 'HP:0100243', (6, 9))	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcomas', 'Disease', (24, 32))	('SS', 'Phenotype', 'HP:0012570', (11, 13))	('LMS', 'Disease', (6, 9))	('PFR12w', 'Var', (38, 44))
430623	28794805	Pazopanib improved median PFS; 4.6 months versus 1.6 months (HR 0.31, 95% CI 0.24-0.40, p < 0.001), compared with placebo.	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('improved', 'PosReg', (10, 18))	('Pazopanib', 'Var', (0, 9))	('PFS', 'MPA', (26, 29))
430624	28794805	Similar to the phase II study, rates of PR were very low (6% versus 0%), but rates of SD were higher for pazopanib, 67% versus 38%, compared with placebo.	('PR', 'Chemical', '-', (40, 42))	('pazopanib', 'Chemical', 'MESH:C516667', (105, 114))	('SD', 'Disease', 'MESH:D029461', (86, 88))	('pazopanib', 'Var', (105, 114))	('higher', 'PosReg', (94, 100))
430627	28794805	Questionnaire-based, health-related quality of life (HRQoL) was not improved with pazopanib, although this did not correlate with significantly worse overall health status.	('pazopanib', 'Chemical', 'MESH:C516667', (82, 91))	('pazopanib', 'Var', (82, 91))	('health-related quality of life', 'CPA', (21, 51))
430629	28794805	TP53 mutations may predict response to pazopanib, but further investigation is need to validate this, as well as other biomarkers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('predict', 'Reg', (19, 26))	('response', 'MPA', (27, 35))	('pazopanib', 'Chemical', 'MESH:C516667', (39, 48))
430644	28794805	Eribulin also remodels the tumor vasculature, and reverses the epithelial-mesenchymal transition.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('epithelial-mesenchymal transition', 'CPA', (63, 96))	('remodels', 'Reg', (14, 22))	('reverses', 'NegReg', (50, 58))	('Eribulin', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
430648	28794805	At the primary endpoint, 46.9% of LPS patients and 31.6% of LMS patients were progression free at 12 weeks, while among SS and other sarcomas, PFR12w was 21% and 19%, respectively.	('sarcomas', 'Disease', (133, 141))	('patients', 'Species', '9606', (64, 72))	('LPS', 'Disease', 'MESH:C536528', (34, 37))	('SS', 'Phenotype', 'HP:0012570', (120, 122))	('LMS', 'Phenotype', 'HP:0100243', (60, 63))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('LPS', 'Phenotype', 'HP:0012034', (34, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('patients', 'Species', '9606', (38, 46))	('PFR12w', 'Var', (143, 149))	('LPS', 'Disease', (34, 37))
430653	28794805	At the primary endpoint, patients with LPS or LMS histology had a PFR12w of 60% compared with 31% in other sarcomas and 51% overall.	('LPS', 'Disease', 'MESH:C536528', (39, 42))	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('PFR12w', 'Var', (66, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('LMS', 'Disease', (46, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('LPS', 'Disease', (39, 42))	('LMS', 'Phenotype', 'HP:0100243', (46, 49))	('sarcomas', 'Disease', (107, 115))	('patients', 'Species', '9606', (25, 33))	('LPS', 'Phenotype', 'HP:0012034', (39, 42))
430657	28794805	Eribulin significantly improved median OS; 13.5 months versus 11.5 months, compared with dacarbazine (HR 0.77, 95% CI 0.62-0.95; p = 0.0169).	('median OS', 'MPA', (32, 41))	('dacarbazine', 'Chemical', 'MESH:D003606', (89, 100))	('OS', 'Chemical', '-', (39, 41))	('improved', 'PosReg', (23, 31))	('Eribulin', 'Var', (0, 8))
430663	28794805	Similar findings occurred in a breast cancer study, where eribulin resulted in improved OS, but not PFS, compared with other cytotoxic therapy.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('improved', 'PosReg', (79, 87))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('eribulin', 'Var', (58, 66))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('OS', 'Chemical', '-', (88, 90))
430673	28794805	PDGFR amplification and activating mutations have also been found in gliomas and gastrointestinal stromal tumor (GIST).	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (81, 111))	('activating', 'PosReg', (24, 34))	('found', 'Reg', (60, 65))	('PDGFR', 'Gene', (0, 5))	('PDGFR', 'Gene', '5159', (0, 5))	('gliomas and gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (69, 111))	('amplification', 'Var', (6, 19))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('GIST', 'Phenotype', 'HP:0100723', (113, 117))
430708	28794805	PD-1 positivity and PD-L1 expression in STS have been correlated with poor prognosis, advanced stage, higher histologic grade, distant metastasis, and degree of tumor differentiation and necrosis.	('expression', 'MPA', (26, 36))	('necrosis', 'Disease', 'MESH:D009336', (187, 195))	('positivity', 'Var', (5, 15))	('PD-1', 'Gene', (0, 4))	('poor prognosis', 'CPA', (70, 84))	('STS', 'Phenotype', 'HP:0030448', (40, 43))	('PD-1', 'Gene', '5133', (0, 4))	('necrosis', 'Disease', (187, 195))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('PD-L1', 'Gene', '29126', (20, 25))	('PD-L1', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('distant metastasis', 'CPA', (127, 145))	('tumor', 'Disease', (161, 166))
430787	28114920	These analyses include fluorescence in situ hybridization (FISH) to detect the rearrangement of EWSR1 or FUS and reverse transcription-polymerase chain reaction (RT-PCR) to elucidate EWSR1-CREB1, EWSR1-ATF1, or FUS-ATF1 fusion transcripts.	('EWSR1', 'Gene', (196, 201))	('CREB1', 'Gene', (189, 194))	('EWSR1', 'Gene', (96, 101))	('EWSR1', 'Gene', '2130', (196, 201))	('rearrangement', 'Var', (79, 92))	('EWSR1', 'Gene', (183, 188))	('EWSR1', 'Gene', '2130', (96, 101))	('CREB1', 'Gene', '1385', (189, 194))	('EWSR1', 'Gene', '2130', (183, 188))
430788	28114920	reported that 76% of assessed AFH were shown by FISH to harbor EWSR1 rearrangement.	('rearrangement', 'Var', (69, 82))	('EWSR1', 'Gene', '2130', (63, 68))	('EWSR1', 'Gene', (63, 68))
430789	28114920	The detection of EWSR1 rearrangement by FISH was indeed helpful for reaching the correct diagnosis in our series, including five cases (cases 2-6) to which incorrect labeling was assigned initially.	('EWSR1', 'Gene', '2130', (17, 22))	('rearrangement', 'Var', (23, 36))	('EWSR1', 'Gene', (17, 22))
430790	28114920	In addition, CREB1 gene rearrangement further supported the diagnoses in 2 cases (cases 3 and 6) that showed unexpected aggressive courses.	('rearrangement', 'Var', (24, 37))	('CREB1', 'Gene', '1385', (13, 18))	('CREB1', 'Gene', (13, 18))	('supported', 'Reg', (46, 55))
430796	28114920	Notably, the diagnosis of AFH in both of these aggressive cases was confirmed by FISH on a molecular level for the presence of rearrangements of both EWSR1 and CREB1.	('rearrangements', 'Var', (127, 141))	('EWSR1', 'Gene', '2130', (150, 155))	('CREB1', 'Gene', '1385', (160, 165))	('CREB1', 'Gene', (160, 165))	('EWSR1', 'Gene', (150, 155))
430805	28114920	Interestingly, these pleomorphic tumor cells harbored an increased (up to 12 copies) number of rearranged EWSR1 genes in contrast to a signal copy in non-pleomorphic areas.	('pleomorphic tumor', 'Disease', (21, 38))	('EWSR1', 'Gene', '2130', (106, 111))	('rearranged', 'Var', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('increased', 'PosReg', (57, 66))	('EWSR1', 'Gene', (106, 111))	('pleomorphic tumor', 'Disease', 'MESH:C538229', (21, 38))
430820	26967056	Since, MAPK pathways are crucial for the every aspect of cell survival and growth, any irregularities may impose cancerous properties to cells, like independence from proliferation signals, infinite replicative potential, capability to invade and metastasize, attract and endure angiogenesis for nutrient supply, evasion of apoptosis, attainment of drug resistance and evasion of oncogene induced senescence.	('drug resistance', 'CPA', (349, 364))	('irregularities', 'Var', (87, 101))	('attract', 'CPA', (260, 267))	('cancerous', 'Disease', 'MESH:D009369', (113, 122))	('drug resistance', 'Phenotype', 'HP:0020174', (349, 364))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('rat', 'Species', '10116', (174, 177))	('cancerous', 'Disease', (113, 122))	('evasion', 'CPA', (313, 320))	('infinite replicative potential', 'CPA', (190, 220))	('apoptosis', 'CPA', (324, 333))	('oncogene induced senescence', 'CPA', (380, 407))	('evasion', 'CPA', (369, 376))	('impose', 'Reg', (106, 112))
430846	26967056	In CML, auto-phosphorylation of tyrosine 177 on BCR-ABL fusion protein provides a docking site for the adapter molecule, growth factor receptor-bound protein 2 (GRB-2).	('CML', 'Disease', 'MESH:D015464', (3, 6))	('tyrosine 177', 'Var', (32, 44))	('auto-phosphorylation', 'MPA', (8, 28))	('docking', 'Interaction', (82, 89))	('GRB-2', 'Gene', '2885', (161, 166))	('GRB-2', 'Gene', (161, 166))	('growth factor receptor-bound protein 2', 'Gene', '2885', (121, 159))	('CML', 'Phenotype', 'HP:0005506', (3, 6))	('tyrosine', 'Chemical', 'MESH:D014443', (32, 40))	('BCR-ABL', 'Gene', '25', (48, 55))	('CML', 'Disease', (3, 6))	('growth factor receptor-bound protein 2', 'Gene', (121, 159))	('BCR-ABL', 'Gene', (48, 55))
430855	26967056	Most of the patients with CML possess breakpoints in intron 1 or 2 of the ABL gene and in the main breakpoint cluster region (M-bcr) of the BCR gene, either amongst exons 13 and 14 (b2), or else 14 and 15 (b3).	('BCR', 'Gene', '613', (140, 143))	('CML', 'Disease', 'MESH:D015464', (26, 29))	('bcr', 'Gene', '613', (128, 131))	('patients', 'Species', '9606', (12, 20))	('CML', 'Phenotype', 'HP:0005506', (26, 29))	('CML', 'Disease', (26, 29))	('breakpoints', 'Var', (38, 49))	('ABL', 'Gene', '25', (74, 77))	('ABL', 'Gene', (74, 77))	('bcr', 'Gene', (128, 131))	('BCR', 'Gene', (140, 143))
430952	26967056	The N-terminal end of SOS1 encodes a Dbl homology (Dbl) and Pleckstrin homology (PH) duo that exchanges GTP for GDP on RAS.	('exchanges', 'Var', (94, 103))	('Dbl', 'Gene', '4168', (37, 40))	('GTP for GDP on RAS', 'MPA', (104, 122))	('GTP', 'Chemical', 'MESH:D006160', (104, 107))	('Dbl', 'Gene', (37, 40))	('SOS1', 'Gene', (22, 26))	('Dbl', 'Gene', '4168', (51, 54))	('SOS1', 'Gene', '6654', (22, 26))	('Pleckstrin', 'Gene', (60, 70))	('Dbl', 'Gene', (51, 54))	('Pleckstrin', 'Gene', '5341', (60, 70))	('GDP', 'Chemical', 'MESH:D006153', (112, 115))
430979	26967056	Moreover, it was found that the expression level of K-RAS was significantly higher in K562 cells compared to normal blood samples.	('K562', 'Var', (86, 90))	('K-RAS', 'Gene', '3845', (52, 57))	('expression level', 'MPA', (32, 48))	('K-RAS', 'Gene', (52, 57))	('K562', 'CellLine', 'CVCL:0004', (86, 90))	('higher', 'PosReg', (76, 82))
431003	26967056	It is well known that regulation of both RAS and RAF is crucial for the proper maintenance of cell proliferation, as activating mutations in these genes lead to oncogenesis.	('RAF', 'Gene', '22882', (49, 52))	('mutations', 'Var', (128, 137))	('RAF', 'Gene', (49, 52))	('oncogenesis', 'CPA', (161, 172))	('rat', 'Species', '10116', (106, 109))	('lead to', 'Reg', (153, 160))
431036	26738797	Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('LUM015', 'Chemical', '-', (25, 31))	('LUM015', 'Chemical', '-', (111, 117))	('lysine', 'Chemical', 'MESH:D008239', (85, 91))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('rat', 'Species', '10116', (100, 103))	('rat', 'Species', '10116', (14, 17))	('LUM015', 'Var', (111, 117))
431076	26738797	After 6 hours, tumors resected from mice injected with LUM015 had a significantly higher proportion of Cy5+ fluorescent cells compared to control animals given saline (Fig.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('higher', 'PosReg', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('LUM015', 'Chemical', '-', (55, 61))	('Cy5+ fluorescent cells', 'MPA', (103, 125))	('mice', 'Species', '10090', (36, 40))	('Cy5+', 'Chemical', 'MESH:C085321', (103, 107))	('saline', 'Chemical', 'MESH:D012965', (160, 166))	('LUM015', 'Var', (55, 61))	('tumors', 'Disease', (15, 21))
431101	26738797	Tumor fluorescence in the first six humans imaged at 30 hours was lower than fluorescence measured in mice at 6 hours, but in both mice and humans, absolute tumor fluorescence was significantly higher when measured 6 hours after LUM015 administration compared to 30 hours (Fig.	('mice', 'Species', '10090', (102, 106))	('higher', 'PosReg', (194, 200))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('LUM015', 'Var', (229, 235))	('absolute tumor', 'Disease', 'MESH:D009369', (148, 162))	('humans', 'Species', '9606', (36, 42))	('rat', 'Species', '10116', (244, 247))	('humans', 'Species', '9606', (140, 146))	('mice', 'Species', '10090', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('absolute tumor', 'Disease', (148, 162))	('LUM015', 'Chemical', '-', (229, 235))
431105	26738797	To determine if preoperative administration of LUM015 results in tumor-specific fluorescence, we compared the absolute fluorescence in the tumor with the absolute fluorescence in adjacent normal tissue from all patients (Table 1), except for patient 10.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('patients', 'Species', '9606', (211, 219))	('tumor', 'Disease', (65, 70))	('rat', 'Species', '10116', (22, 25))	('LUM015', 'Var', (47, 53))	('rat', 'Species', '10116', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('results', 'Reg', (54, 61))	('patient', 'Species', '9606', (242, 249))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('patient', 'Species', '9606', (211, 218))	('LUM015', 'Chemical', '-', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
431127	26738797	To image tumors with a probe that does not require protease activation, we injected STS-bearing mice with either LUM015 or LUM033, a constitutively active fluorescent imaging probe identical to fragment 2 (also from Lumicell Inc.).	('LUM015', 'Chemical', '-', (113, 119))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('STS', 'Phenotype', 'HP:0030448', (84, 87))	('tumors', 'Disease', (9, 15))	('LUM033', 'Var', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('mice', 'Species', '10090', (218, 222))
431128	26738797	Six hours after injection, resected tumors had a tumor/normal fluorescence ratio twofold higher for LUM015 than for LUM033 (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('rat', 'Species', '10116', (75, 78))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('LUM015', 'Chemical', '-', (100, 106))	('higher', 'PosReg', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumor', 'Disease', (36, 41))	('LUM015', 'Var', (100, 106))
431137	26738797	These results for PEG staining, together with the quantification of LUM015 and its metabolites, suggest that tumor-selective distribution of LUM015 may serve to delineate the tumor margin while protease activation intensifies the contrast between tumor and normal tissue types for intraoperative imaging.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('PEG', 'Chemical', 'MESH:D011092', (18, 21))	('tumor', 'Disease', (175, 180))	('rat', 'Species', '10116', (289, 292))	('LUM015', 'Chemical', '-', (68, 74))	('tumor', 'Disease', (247, 252))	('intensifies', 'PosReg', (214, 225))	('LUM015', 'Chemical', '-', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('contrast', 'MPA', (230, 238))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('LUM015', 'Var', (141, 147))	('tumor', 'Disease', (109, 114))
431165	26738797	We have shown that LUM015 is safe for use in humans and generates tumor-specific fluorescence.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('generates', 'Reg', (56, 65))	('tumor', 'Disease', (66, 71))	('LUM015', 'Var', (19, 25))	('humans', 'Species', '9606', (45, 51))	('rat', 'Species', '10116', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('LUM015', 'Chemical', '-', (19, 25))
431190	26738797	Mice were administered LUM015 or LUM033 via tail vein injection when tumors reached about 1000 mm3 (4 to 5 mm in diameter).	('LUM033', 'Var', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('Mice', 'Species', '10090', (0, 4))	('LUM015', 'Chemical', '-', (23, 29))
431199	26738797	Genomic PCR analysis to show recombination of the mutant Kras allele was performed with the following primers: (i) 5'-GTCTTTCCCCAGCACAGTGC-3'; (ii) 5'-CTCTTGCCTACGCCACCAGCTC-3'; (iii) 5'-AGCTAGCCACCATGGCTTGAGTAAGTCTGCA-3'.	('Kras', 'Gene', (57, 61))	('Kras', 'Gene', '3845', (57, 61))	('mutant', 'Var', (50, 56))
431226	33937231	B cells, MDSC, and other cells in the MM microenvironment can facilitate its migration and proliferation by secreting a variety of cytokines; targeted intervention of tumor microenvironment B cells has significant efficacy in MM treatment.	('MDS', 'Disease', (9, 12))	('targeted', 'Var', (142, 150))	('MDS', 'Disease', 'MESH:D009190', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('migration', 'CPA', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('proliferation', 'CPA', (91, 104))	('tumor', 'Disease', (167, 172))
431359	32115569	Interphase FISH analysis revealed that 91% of the cells in the sample had a gain-of-function mutation in the MDM2 gene (primer signal), which is often seen in liposarcomas that are either well-differentiated or de-differentiated (Histology slides Figure 5A, 5B).	('MDM2', 'Gene', (109, 113))	('liposarcoma', 'Phenotype', 'HP:0012034', (159, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (163, 171))	('liposarcomas', 'Phenotype', 'HP:0012034', (159, 171))	('liposarcomas', 'Disease', 'MESH:D008080', (159, 171))	('mutation', 'Var', (93, 101))	('gain-of-function', 'PosReg', (76, 92))	('liposarcomas', 'Disease', (159, 171))
431375	32115569	This is in line with the surgical literature, in which liposarcomas are noted to have a 3-fold higher risk of local recurrence compared with other histologies and to recur more often as the de-differentiated subtype compared to the well-differentiated.	('liposarcoma', 'Phenotype', 'HP:0012034', (55, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('de-differentiated', 'Var', (190, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('local recurrence', 'CPA', (110, 126))	('liposarcomas', 'Phenotype', 'HP:0012034', (55, 67))	('liposarcomas', 'Disease', 'MESH:D008080', (55, 67))	('liposarcomas', 'Disease', (55, 67))
431527	31016339	Bone lesions were more likely to be false-negative on 18F-FDG PET-CT if hematopoietic bone marrow extension was widespread and active (p = 0.001), during or after (neo)-adjuvant treatment (p = 0.001) or when the lesion was smaller than 10 mm (p < 0.001).	('Bone lesions', 'CPA', (0, 12))	('18F-FDG', 'Chemical', 'MESH:D019788', (54, 61))	('18F-FDG', 'Var', (54, 61))	('hematopoietic bone marrow extension', 'Disease', (72, 107))	('hematopoietic bone marrow extension', 'Disease', 'MESH:D001855', (72, 107))
431529	31016339	Poor contrast between metastases and active hematopoietic bone marrow, chemotherapeutic treatment, and/or small size significantly decrease the diagnostic yield of 18F-FDG PET-CT, but not of MRI.	('18F-FDG', 'Chemical', 'MESH:D019788', (164, 171))	('metastases', 'Disease', (22, 32))	('diagnostic yield', 'MPA', (144, 160))	('metastases', 'Disease', 'MESH:D009362', (22, 32))	('decrease', 'NegReg', (131, 139))	('18F-FDG', 'Var', (164, 171))
431540	31016339	Literature comparing the two modalities for skeletal metastases in other cancers shows conflicting results, with some researchers suggesting superiority for 18F-FDG PET-CT and others for MRI.	('cancers', 'Disease', (73, 80))	('metastases', 'Disease', (53, 63))	('18F-FDG', 'Chemical', 'MESH:D019788', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('metastases', 'Disease', 'MESH:D009362', (53, 63))	('18F-FDG', 'Var', (157, 164))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
431573	31016339	Additionally, if osseous lesions showed no 18F-FDG uptake we evaluated whether these lesions were visible on the low-dose CT of the 18F-FDG PET-CT, using MRI as guidance.	('osseous lesions', 'Disease', (17, 32))	('18F-FDG', 'Chemical', 'MESH:D019788', (43, 50))	('18F-FDG', 'Var', (132, 139))	('18F-FDG', 'Chemical', 'MESH:D019788', (132, 139))	('osseous lesions', 'Disease', 'MESH:C537508', (17, 32))
431630	31016339	The question is what can explain the difference between 18F-FDG PET-CT, which is based on the glucose metabolism within the tumor, and MRI, which is based on the morphology of the metastases in bone marrow.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('18F-FDG', 'Var', (56, 63))	('metastases', 'Disease', 'MESH:D009362', (180, 190))	('glucose metabolism within the tumor', 'Disease', (94, 129))	('18F-FDG', 'Chemical', 'MESH:D019788', (56, 63))	('glucose metabolism within the tumor', 'Disease', 'MESH:D044882', (94, 129))	('metastases', 'Disease', (180, 190))
431769	29466296	In this study, a vanadium (IV) complex with the flavonoid chrysin displayed better effect than cis-platinum in osteosarcoma spheroids, because VOchrys altered the shape of spheroids and decreased their viability.	('shape of spheroids', 'CPA', (163, 181))	('altered', 'Reg', (151, 158))	('osteosarcoma spheroids', 'Disease', 'MESH:D012516', (111, 133))	('VOchrys', 'Var', (143, 150))	('osteosarcoma spheroids', 'Disease', (111, 133))	('viability', 'CPA', (202, 211))	('cis-platinum', 'Chemical', 'MESH:D002945', (95, 107))	('decreased', 'NegReg', (186, 195))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('flavonoid', 'Chemical', 'MESH:D005419', (48, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
431777	29466296	Interestingly, larger spheroids were more sensitive to TH-302 (multicellular resistance index (MCRI) = 7.7) than smaller hypoxic spheroids (MCRI = 9.1).	('TH-302', 'Chemical', 'MESH:C552526', (55, 61))	('sensitive', 'MPA', (42, 51))	('TH-302', 'Var', (55, 61))
431802	26965049	Silencing of CAPZB inhibited the growth, invasion and migration of the EpiS cells.	('inhibited', 'NegReg', (19, 28))	('CAPZB', 'Gene', '832', (13, 18))	('growth', 'CPA', (33, 39))	('CAPZB', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))
431804	26965049	Furthermore, silencing of CAPZB resulted in a decreased expression of INI1 proteins in the INI1-positive EpiS cells, whereas the induction of INI1 in the INI1-deficient EpiS cells resulted in an increased CAPZB mRNA expression.	('mRNA expression', 'MPA', (211, 226))	('CAPZB', 'Gene', '832', (205, 210))	('INI1', 'Gene', '6598', (70, 74))	('CAPZB', 'Gene', '832', (26, 31))	('INI1', 'Gene', '6598', (91, 95))	('INI1', 'Gene', '6598', (154, 158))	('INI1', 'Gene', (91, 95))	('CAPZB', 'Gene', (205, 210))	('INI1', 'Gene', (154, 158))	('INI1', 'Gene', (70, 74))	('expression', 'MPA', (56, 66))	('decreased', 'NegReg', (46, 55))	('CAPZB', 'Gene', (26, 31))	('INI1', 'Gene', '6598', (142, 146))	('increased', 'PosReg', (195, 204))	('INI1', 'Gene', (142, 146))	('silencing', 'Var', (13, 22))
431809	26965049	Although the molecular pathogenesis of EpiS remains unknown, deletion of the SMARCB1/INI1 tumor-suppressor gene (INI1) was recently reported in cases of proximal-type EpiS and subsequently in cases of distal-type EpiS.	('tumor-suppressor', 'Gene', (90, 106))	('INI1', 'Gene', '6598', (113, 117))	('proximal-type', 'Disease', (153, 166))	('SMARCB1', 'Gene', '6598', (77, 84))	('INI1', 'Gene', (113, 117))	('deletion', 'Var', (61, 69))	('SMARCB1', 'Gene', (77, 84))	('reported', 'Reg', (132, 140))	('INI1', 'Gene', (85, 89))	('INI1', 'Gene', '6598', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor-suppressor', 'Gene', '7248', (90, 106))
431810	26965049	Loss of the INI1 expression is observed in approximately 80-90 % of distal and proximal EpiS patients, and INI1 genetic inactivation is considered to be responsible for tumorigenesis in cases of EpiS.	('INI1', 'Gene', (12, 16))	('genetic inactivation', 'Var', (112, 132))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('INI1', 'Gene', '6598', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Loss', 'NegReg', (0, 4))	('tumor', 'Disease', (169, 174))	('INI1', 'Gene', (107, 111))	('INI1', 'Gene', '6598', (107, 111))	('patients', 'Species', '9606', (93, 101))	('distal', 'Disease', (68, 74))
431821	26965049	In the current study, in order to elucidate the functions of CAPZB in EpiS, we performed functional assays using gene silencing of CAPZB in EpiS cell lines.	('CAPZB', 'Gene', '832', (61, 66))	('gene silencing', 'Var', (113, 127))	('CAPZB', 'Gene', (131, 136))	('EpiS', 'Disease', (70, 74))	('CAPZB', 'Gene', (61, 66))	('CAPZB', 'Gene', '832', (131, 136))
431838	26965049	VAESBJ cells have a deletion of the INI1 gene and show the loss of the INI1 protein expression, whereas ESX cells exhibit the INI1 protein expression.	('INI1', 'Gene', (36, 40))	('INI1', 'Gene', (71, 75))	('INI1', 'Gene', '6598', (71, 75))	('ESX', 'Gene', '1999', (104, 107))	('protein', 'Protein', (76, 83))	('INI1', 'Gene', (126, 130))	('deletion', 'Var', (20, 28))	('INI1', 'Gene', '6598', (126, 130))	('loss', 'NegReg', (59, 63))	('INI1', 'Gene', '6598', (36, 40))	('ESX', 'Gene', (104, 107))
431864	26965049	Following gene silencing of CAPZB by the two siRNAs in both EpiS cell lines, we performed in vitro assays consisting of cell proliferation, invasion and scratch assays.	('scratch assays', 'CPA', (153, 167))	('invasion', 'CPA', (140, 148))	('CAPZB', 'Gene', '832', (28, 33))	('CAPZB', 'Gene', (28, 33))	('gene silencing', 'Var', (10, 24))
431865	26965049	In the cell proliferation assays, knockdown of CAPZB significantly decreased the rate of cell growth at 96 h after transfection in both the VAESBJ and ESX cells (Fig.	('rate', 'MPA', (81, 85))	('CAPZB', 'Gene', '832', (47, 52))	('knockdown', 'Var', (34, 43))	('CAPZB', 'Gene', (47, 52))	('ESX', 'Gene', (151, 154))	('decreased', 'NegReg', (67, 76))	('ESX', 'Gene', '1999', (151, 154))
431867	26965049	In the scratch assays, silencing of CAPZB in the VAESBJ cells significantly suppressed cell migration compared to that observed in the control cells (Fig.	('CAPZB', 'Gene', '832', (36, 41))	('cell migration', 'CPA', (87, 101))	('silencing', 'Var', (23, 32))	('suppressed', 'NegReg', (76, 86))	('CAPZB', 'Gene', (36, 41))
431869	26965049	Next, we performed a proteomics approach using i-TRAQ assays with the CAPZB siRNA-transfected EpiS cells in order to determine the differences in the protein expression profile according to the knockdown of CAPZB in EpiS.	('CAPZB', 'Gene', (70, 75))	('CAPZB', 'Gene', '832', (207, 212))	('knockdown', 'Var', (194, 203))	('CAPZB', 'Gene', (207, 212))	('CAPZB', 'Gene', '832', (70, 75))
431875	26965049	In the ESX cell line (without the loss of INI1), gene silencing of CAPZB led to a decrease in the expression level of INI1 (Fig.	('INI1', 'Gene', '6598', (118, 122))	('CAPZB', 'Gene', '832', (67, 72))	('INI1', 'Gene', (118, 122))	('decrease', 'NegReg', (82, 90))	('CAPZB', 'Gene', (67, 72))	('gene silencing', 'Var', (49, 63))	('INI1', 'Gene', (42, 46))	('expression level', 'MPA', (98, 114))	('INI1', 'Gene', '6598', (42, 46))	('ESX', 'Gene', (7, 10))	('ESX', 'Gene', '1999', (7, 10))
431894	26965049	Therefore, we performed a proteomics study to examine changes in the protein expression profiles according to the knockdown of CAPZB.	('protein expression profiles', 'MPA', (69, 96))	('knockdown', 'Var', (114, 123))	('CAPZB', 'Gene', (127, 132))	('CAPZB', 'Gene', '832', (127, 132))
431895	26965049	Protein profiles differentially expressed based on the knockdown of CAPZB included MX1 and BCCIP as upregulated proteins and CD44 and FLNB as downregulated proteins.	('CD44', 'Gene', (125, 129))	('knockdown', 'Var', (55, 64))	('FLNB', 'Gene', '2317', (134, 138))	('FLNB', 'Gene', (134, 138))	('CAPZB', 'Gene', '832', (68, 73))	('downregulated', 'NegReg', (142, 155))	('BCCIP', 'Gene', (91, 96))	('upregulated', 'PosReg', (100, 111))	('CAPZB', 'Gene', (68, 73))	('MX1', 'Gene', (83, 86))	('CD44', 'Gene', '960', (125, 129))	('BCCIP', 'Gene', '56647', (91, 96))	('MX1', 'Gene', '4599', (83, 86))
431910	26965049	Consequently, silencing of CAPZB definitively suppressed cell proliferation in the setting of EpiS, although, surprisingly, the expression levels of INI1, which possesses a tumor suppressor function, were decreased in the ESX cells.	('INI1', 'Gene', (149, 153))	('silencing', 'Var', (14, 23))	('INI1', 'Gene', '6598', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('expression levels', 'MPA', (128, 145))	('ESX', 'Gene', (222, 225))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('decreased', 'NegReg', (205, 214))	('CAPZB', 'Gene', '832', (27, 32))	('ESX', 'Gene', '1999', (222, 225))	('cell proliferation', 'CPA', (57, 75))	('CAPZB', 'Gene', (27, 32))	('suppressed', 'NegReg', (46, 56))
431911	26965049	On the other hand, the induction of INI1 in the INI1-negative EpiS cells (VAESBJ cells) definitively suppressed cell growth.	('INI1', 'Gene', (36, 40))	('INI1', 'Gene', '6598', (36, 40))	('cell growth', 'CPA', (112, 123))	('INI1', 'Gene', (48, 52))	('INI1', 'Gene', '6598', (48, 52))	('induction', 'Var', (23, 32))	('suppressed', 'NegReg', (101, 111))
431929	25880253	CCS, initially named malignant melanoma of soft parts, are molecularly characterized in most cases by a specific translocation, t(12;22)(q13;q12), which results in fusion of the Ewing's sarcoma gene, EWS, with the cyclic AMP (cAMP) regulated transcription factor, ATF1, a member of the cAMP-responsive element binding protein (CREB) family.	('melanoma of soft parts', 'Disease', (31, 53))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (178, 193))	('fusion', 'Var', (164, 170))	('ATF1', 'Gene', '466', (264, 268))	('cAMP-responsive element binding protein', 'Gene', '1385', (286, 325))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('CREB', 'Gene', '1385', (327, 331))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (178, 193))	('cAMP-responsive element binding protein', 'Gene', (286, 325))	('EWS', 'Gene', (200, 203))	('malignant melanoma', 'Disease', (21, 39))	('cAMP', 'Chemical', 'MESH:D000242', (286, 290))	("Ewing's sarcoma", 'Disease', (178, 193))	('cyclic AMP', 'Chemical', 'MESH:D000242', (214, 224))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (128, 145))	('malignant melanoma', 'Phenotype', 'HP:0002861', (21, 39))	('ATF1', 'Gene', (264, 268))	('cAMP', 'Chemical', 'MESH:D000242', (226, 230))	('melanoma of soft parts', 'Disease', 'MESH:D018227', (31, 53))	('malignant melanoma', 'Disease', 'MESH:D008545', (21, 39))	('EWS', 'Gene', '2130', (200, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('CREB', 'Gene', (327, 331))
431934	25880253	Moreover, BRAF activating mutations have been occasionally detected in both EWS-ATF1 positive and negative CCS.	('mutations', 'Var', (26, 35))	('BRAF', 'Gene', '673', (10, 14))	('BRAF', 'Gene', (10, 14))	('EWS-ATF1', 'Gene', '466;2130', (76, 84))	('EWS-ATF1', 'Gene', (76, 84))
431961	25880253	The in vivo generation of the MART-1 loss antigen variant paralleled the presence of anti-MART-1 systemic immunity in the blood of this CCS patient.	('MART-1', 'Gene', '2315', (90, 96))	('MART-1', 'Gene', (90, 96))	('rat', 'Species', '10116', (16, 19))	('variant', 'Var', (50, 57))	('patient', 'Species', '9606', (140, 147))	('MART-1', 'Gene', '2315', (30, 36))	('MART-1', 'Gene', (30, 36))
431967	25880253	The anti-MART-1 systemic immunity in post-sunitinib CCS patients was associated with low frequency of circulating immunosuppressive CD14+CD11b+HLADRneg/low monocytic myeloid-derived suppressor cells (mMDSCs), a population expanded in cancer patients, including melanoma.	('patients', 'Species', '9606', (56, 64))	('CD11b', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('MART-1', 'Gene', '2315', (9, 15))	('MART-1', 'Gene', (9, 15))	('sunitinib', 'Chemical', 'MESH:D000077210', (42, 51))	('CD14', 'Gene', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('post-sunitinib', 'Var', (37, 51))	('CD14', 'Gene', '929', (132, 136))	('cancer', 'Disease', (234, 240))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('patients', 'Species', '9606', (241, 249))	('melanoma', 'Disease', (261, 269))	('CD11b', 'Gene', '3684', (137, 142))
431977	25880253	The in vivo generation of MART-1 loss variant was associated to a CD3 + CD8+ T cell infiltration and to the presence of areas of pathologic regression, thus suggesting the in vivo occurrence of MART1-specific response.	('MART1', 'Gene', (194, 199))	('rat', 'Species', '10116', (16, 19))	('loss', 'NegReg', (33, 37))	('MART-1', 'Gene', '2315', (26, 32))	('MART-1', 'Gene', (26, 32))	('MART1', 'Gene', '2315', (194, 199))	('CD8', 'Gene', (72, 75))	('variant', 'Var', (38, 45))	('CD8', 'Gene', '925', (72, 75))	('rat', 'Species', '10116', (90, 93))
431988	25880253	In conclusion, this case shed light on immune-similarities between CCS and melanoma, and indicates that manipulation of the immune response in this STS subtype likely evokes antigen-specific response.	('evokes', 'Reg', (167, 173))	('STS', 'Phenotype', 'HP:0030448', (148, 151))	('antigen-specific response', 'MPA', (174, 199))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('manipulation', 'Var', (104, 116))	('CCS', 'Disease', (67, 70))
431997	25880253	The monoclonal antibodies used were directed against the following antigens: anti-S100, anti-Melan-A/MART-1, anti-HMB-45/gp100, anti-CD8 (DAKO) and anti-CD3 (Novocastra).	('gp100', 'Gene', '6490', (121, 126))	('CD8', 'Gene', (133, 136))	('Melan-A', 'Gene', '2315', (93, 100))	('CD8', 'Gene', '925', (133, 136))	('anti-S100', 'Var', (77, 86))	('MART-1', 'Gene', (101, 107))	('anti-CD3', 'Var', (148, 156))	('MART-1', 'Gene', '2315', (101, 107))	('gp100', 'Gene', (121, 126))	('Melan-A', 'Gene', (93, 100))
432002	25880253	For surface staining, after treatment with FcR Blocking Reagent (Miltenyi, Bergisch-Gladbach, Germany), cells were incubated with the following antibodies for 30 minutes at 4 C :APCH7-conjugated anti-CD4, PE-Cy7-conjugated anti-CD25 (for detecting Treg); APCH7 conjugated anti-CD14, PE-Cy7-conjugated anti-CD11b, PE-conjugated anti-HLADR (for detecting mMDSC).	('CD25', 'Gene', (228, 232))	('PE-Cy7', 'Chemical', '-', (205, 211))	('CD14', 'Gene', '929', (277, 281))	('CD11b', 'Gene', '3684', (306, 311))	('CD11b', 'Gene', (306, 311))	('PE-', 'Chemical', '-', (313, 316))	('CD4', 'Gene', (200, 203))	('CD25', 'Gene', '3559', (228, 232))	('PE-Cy7-conjugated', 'Var', (283, 300))	('PE-', 'Chemical', '-', (205, 208))	('PE-Cy7', 'Chemical', '-', (283, 289))	('CD4', 'Gene', '920', (200, 203))	('PE-', 'Chemical', '-', (283, 286))	('CD14', 'Gene', (277, 281))
432047	22933997	Fluorescence in situ hybridization (FISH) testing confirmed rearrangement involving the EWSR1(22q12) gene region as detected by break-apart signals (fig.	('rearrangement', 'Var', (60, 73))	('EWSR1', 'Gene', (88, 93))	('EWSR1', 'Gene', '2130', (88, 93))
432065	22933997	In this case, the diagnosis of PNET was made following confirmation of CD99 immunostaining and presence of the11;22 EWS-FLI1 chromosomal translocation.	('CD99', 'Gene', (71, 75))	('PNET', 'Disease', (31, 35))	('EWS-FLI1', 'Gene', (116, 124))	('the11;22', 'Var', (107, 115))	('CD99', 'Gene', '4267', (71, 75))
432067	22933997	The most common result is fusion of EWS with FLI1 - a member of the ETS gene family on chromosome 11q24 which is homologous to murine Friend's leukemia.	('fusion', 'Var', (26, 32))	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('FLI1 -', 'Gene', (45, 51))	("Friend's leukemia", 'Disease', 'MESH:D007938', (134, 151))	("Friend's leukemia", 'Disease', (134, 151))	('murine', 'Species', '10090', (127, 133))
432068	22933997	This fusion results in the characteristic t(11;22)(q24;q12) chromosomal translocation and ETS transcription factor which is present in up to 80% of such cases.	('ETS', 'MPA', (90, 93))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (42, 59))	('results in', 'Reg', (12, 22))	('t(11', 'Var', (42, 46))
432080	22933997	Inhibitors of vascular endothelial growth factor (VEGF) have also been considered as a potential therapy for Ewing's sarcomas.	('VEGF', 'Gene', (50, 54))	('vascular endothelial growth factor', 'Gene', (14, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	("Ewing's sarcomas", 'Disease', (109, 125))	('Inhibitors', 'Var', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (109, 125))	('vascular endothelial growth factor', 'Gene', '7422', (14, 48))	('VEGF', 'Gene', '7422', (50, 54))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (109, 124))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (109, 125))
432311	28400352	The inadvertent morcellation of an undiagnosed uterine sarcoma can cause upstaging of a cancer and worsen the prognosis of the patient.	('cause', 'Reg', (67, 72))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('worsen', 'Reg', (99, 105))	('morcellation', 'Var', (16, 28))	('sarcoma', 'Disease', (55, 62))	('patient', 'Species', '9606', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (47, 62))	('prognosis', 'MPA', (110, 119))	('upstaging', 'MPA', (73, 82))	('inadvertent', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))
432334	28400352	Furthermore, immunohistochemical assays for ERs, PRs, and p53 showed the following results: ER (+++), PR (+++) and p53 (-).	('ER (+++', 'Var', (92, 99))	('p53', 'Gene', '7157', (115, 118))	('p53', 'Gene', (115, 118))	('PR (+++', 'Var', (102, 109))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
432372	28400352	concluded that open power morcellation was associated with a 3- and 4-fold increase in overall and intra-abdominal recurrence of ULMS, respectively, as well as a 2.5-fold decrease in overall survival compared with patients whose tumors were removed intact.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('intra-abdominal recurrence', 'CPA', (99, 125))	('patients', 'Species', '9606', (214, 222))	('decrease', 'NegReg', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('overall', 'MPA', (183, 190))	('ULMS', 'Disease', (129, 133))	('open power morcellation', 'Var', (15, 38))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('increase', 'PosReg', (75, 83))	('tumors', 'Disease', (229, 235))	('ULMS', 'Phenotype', 'HP:0002891', (129, 133))
432382	26580448	Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.	('patient', 'Species', '9606', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patient', 'Species', '9606', (83, 90))	('improve', 'PosReg', (32, 39))	('tumor', 'Disease', (61, 66))	('mutations', 'Var', (18, 27))
432385	26580448	The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
432387	26580448	Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('persons', 'Species', '9606', (147, 154))	('autism', 'Disease', (219, 225))	('participants', 'Species', '9606', (199, 211))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('autism', 'Disease', 'MESH:D001321', (219, 225))	('autism', 'Phenotype', 'HP:0000717', (219, 225))
432389	26580448	A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('protein-truncating mutations', 'Var', (38, 66))	('tumor', 'Disease', (70, 75))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
432390	26580448	Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutation', 'Var', (39, 47))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('patients', 'Species', '9606', (10, 18))
432391	26580448	Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', (109, 115))	('identified', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('children', 'Species', '9606', (79, 87))
432393	26580448	The frequency of germline mutations in cancer-predisposition genes in children and adolescents with cancer and the implications of such mutations are largely unknown.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('children', 'Species', '9606', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('germline mutations', 'Var', (17, 35))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
432394	26580448	To better determine the contribution of germline predisposition mutations to childhood cancer, we used next-generation sequencing, including whole-genome and whole-exome sequencing, to analyze the genomes of 1120 children and adolescents with cancer.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('childhood cancer', 'Disease', 'MESH:C536928', (77, 93))	('childhood cancer', 'Disease', (77, 93))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('children', 'Species', '9606', (213, 221))
432395	26580448	We describe the prevalence and spectrum of germline variants among 565 cancer-associated genes, with an emphasis on the analysis of 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (71, 77))	('variants', 'Var', (52, 60))	('associated', 'Reg', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
432396	26580448	We also reviewed records of patients with mutations and those without mutations in these 60 genes for information on family history of cancer.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('patients', 'Species', '9606', (28, 36))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
432399	26580448	To verify predictions of aberrant splicing caused by variants affecting splice junctions, we sequenced the RNA transcripts extracted from 522 samples of tumor tissue obtained from 522 patients.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('splice junctions', 'MPA', (72, 88))	('variants', 'Var', (53, 61))
432406	26580448	The first category included genes that have been associated with autosomal dominant cancer-predisposition syndromes, and it consisted of 49 classical genes (including 23 genes from the ACMG gene list) and 11 genes that have been implicated in genetic syndromes associated with RAS mutations (sometimes called RASopathies; these include the cardiofaciocutaneous syndrome, Costello's syndrome [also called the faciocutaneoskeletal syndrome], Noonan's syndrome, and the multiple lentigines syndrome).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('RASopathies', 'Disease', (309, 320))	('associated', 'Reg', (49, 59))	('multiple lentigines syndrome', 'Disease', 'MESH:D044542', (467, 495))	('faciocutaneoskeletal syndrome', 'Disease', 'MESH:D056685', (408, 437))	('RAS', 'Gene', (277, 280))	('cardiofaciocutaneous syndrome', 'Disease', 'MESH:C535579', (340, 369))	("Costello's syndrome", 'Disease', 'MESH:D056685', (371, 390))	('multiple lentigines syndrome', 'Disease', (467, 495))	("Noonan's syndrome", 'Disease', (440, 457))	('cancer', 'Disease', (84, 90))	('multiple lentigines', 'Phenotype', 'HP:0001003', (467, 486))	('genetic syndrome', 'Disease', (243, 259))	('RASopathies', 'Disease', 'None', (309, 320))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	("Noonan's syndrome", 'Disease', 'MESH:D009634', (440, 457))	('cardiofaciocutaneous syndrome', 'Disease', (340, 369))	('mutations', 'Var', (281, 290))	('faciocutaneoskeletal syndrome', 'Disease', (408, 437))	('genetic syndrome', 'Disease', 'MESH:D030342', (243, 259))	("Costello's syndrome", 'Disease', (371, 390))
432409	26580448	Variants detected in the 89 genes that have been associated with autosomal dominant or autosomal recessive cancer-predisposition syndromes were reviewed by a multidisciplinary panel for classification and reporting.	('autosomal recessive cancer', 'Disease', (87, 113))	('Variants', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('autosomal dominant', 'Disease', (65, 83))	('autosomal recessive cancer', 'Disease', 'MESH:D009369', (87, 113))
432412	26580448	Our analyses of the genes in these three categories focused on known hotspot-activating mutations in genes encoding kinases and on truncation mutations in genes encoding tumor-suppressor proteins and in other cancer genes.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('truncation mutations', 'Var', (131, 151))	('tumor', 'Disease', (170, 175))	('cancer', 'Disease', (209, 215))	('hotspot-activating', 'PosReg', (69, 87))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
432418	26580448	In the 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes, we identified 633 nonsilent germline variants, of which 78 (12%) were deemed to be pathogenic, 17 (3%) probably pathogenic, 226 (36%) of uncertain significance, 273 (43%) probably benign, and 39 (6%) benign (Table S4A in Supplementary Appendix 2).	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('variants', 'Var', (136, 144))	('cancer', 'Disease', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))
432421	26580448	One patient (Patient HGG111) with cafe au lait spots and a high-grade glioma had 2 distinct PMS2 truncation mutations, which indicated a diagnosis of biallelic mismatch-repair deficiency that was corroborated by the somatic hypermutation observed in the genome of the high-grade glioma.	('PMS2', 'Gene', '5395', (92, 96))	('glioma', 'Disease', (279, 285))	('glioma', 'Disease', (70, 76))	('truncation mutations', 'Var', (97, 117))	('glioma', 'Disease', 'MESH:D005910', (279, 285))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('patient', 'Species', '9606', (4, 11))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (279, 285))	('cafe au lait spots', 'Phenotype', 'HP:0000957', (34, 52))	('Patient', 'Species', '9606', (13, 20))	('PMS2', 'Gene', (92, 96))	('indicated', 'Reg', (125, 134))
432422	26580448	The most common cancer types that were associated with germline TP53 mutations included adrenocortical tumors (in 27 of 39 patients [69%]), hypodiploid acute lymphoblastic leukemia (in 9 of 47 [19%]), and choroid plexus carcinoma (in 1 of 4 [25%]) : findings that were consistent with those in previous reports.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('hypodiploid acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (140, 180))	('adrenocortical tumors', 'Disease', (88, 109))	('TP53', 'Gene', '7157', (64, 68))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (158, 180))	('hypodiploid acute lymphoblastic leukemia', 'Disease', (140, 180))	('cancer', 'Disease', (16, 22))	('choroid plexus carcinoma', 'Disease', (205, 229))	('patients', 'Species', '9606', (123, 131))	('germline', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('mutations', 'Var', (69, 78))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (205, 229))	('TP53', 'Gene', (64, 68))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (88, 109))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (152, 180))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (205, 229))
432424	26580448	One patient with retinoblastoma had a mosaic RB1 mutation, and three patients with hypodiploid acute lymphoblastic leukemia had a mosaic TP53 mutation (Table S4A in Supplementary Appendix 2).	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (101, 123))	('RB1', 'Gene', (45, 48))	('retinoblastoma', 'Phenotype', 'HP:0009919', (17, 31))	('mosaic', 'Var', (38, 44))	('RB1', 'Gene', '5925', (45, 48))	('mutation', 'Var', (49, 57))	('patients', 'Species', '9606', (69, 77))	('hypodiploid acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (83, 123))	('patient', 'Species', '9606', (4, 11))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (95, 123))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('TP53', 'Gene', '7157', (137, 141))	('hypodiploid acute lymphoblastic leukemia', 'Disease', (83, 123))	('mutation', 'Var', (142, 150))	('patient', 'Species', '9606', (69, 76))	('retinoblastoma', 'Disease', 'MESH:D012175', (17, 31))	('retinoblastoma', 'Disease', (17, 31))	('TP53', 'Gene', (137, 141))
432425	26580448	The mutant allele fraction in matching tumor specimens ranged from 0.76 to 0.90, a finding that is consistent with the presence of a second hit within the tumors.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mutant', 'Var', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('tumor', 'Disease', (39, 44))
432427	26580448	In the first control data set, from the 1000 Genomes Project, we identified 11 pathogenic or probably pathogenic mutations in the 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes; mutations were found in APC (in one person), BRCA1 (in one), BRCA2 (in four), MSH6 (in one), SDHA (in one), SDHB (in one), and TP53 (in two) (Table S6 in Supplementary Appendix 1).	('APC', 'Disease', (246, 249))	('mutations', 'Var', (113, 122))	('SDHB', 'Gene', '6390', (330, 334))	('TP53', 'Gene', '7157', (349, 353))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('MSH6', 'Gene', (300, 304))	('mutations', 'Var', (222, 231))	('MSH6', 'Gene', '2956', (300, 304))	('SDHB', 'Gene', (330, 334))	('BRCA2', 'Gene', (283, 288))	('associated', 'Reg', (154, 164))	('person', 'Species', '9606', (258, 264))	('TP53', 'Gene', (349, 353))	('SDHA', 'Gene', (315, 319))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('BRCA1', 'Gene', '672', (267, 272))	('SDHA', 'Gene', '6389', (315, 319))	('BRCA2', 'Gene', '675', (283, 288))	('APC', 'Disease', 'MESH:D011125', (246, 249))	('BRCA1', 'Gene', (267, 272))
432431	26580448	Combining data from this single patient, who had ataxia telangiectasia caused by biallelic mutations in ATM (Fig.	('telangiectasia', 'Phenotype', 'HP:0001009', (56, 70))	('patient', 'Species', '9606', (32, 39))	('biallelic mutations', 'Var', (81, 100))	('ATM', 'Gene', '472', (104, 107))	('caused by', 'Reg', (71, 80))	('ataxia', 'Phenotype', 'HP:0001251', (49, 55))	('ataxia telangiectasia', 'Disease', (49, 70))	('ATM', 'Gene', (104, 107))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (49, 70))
432432	26580448	S4 in Supplementary Appendix 1), with data from the 94 patients who had pathogenic mutations in the 60 autosomal dominant cancer-predisposition genes, we observed an 8.5% prevalence (95 of 1120 patients) of germline mutations that were pathogenic or probably pathogenic in the sample we analyzed.	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (194, 202))	('germline mutations', 'Var', (207, 225))	('pathogenic', 'Reg', (236, 246))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('patients', 'Species', '9606', (55, 63))
432433	26580448	A total of 61 of the 93 patients (66%) with monoallelic germline mutations had a second hit within the tumor genome (Table S4 in Supplementary Appendix 2), as shown by loss of heterozygosity (in 57 patients) or mutational inactivation of the second allele (in 4).	('loss', 'NegReg', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('patients', 'Species', '9606', (198, 206))	('heterozygosity', 'MPA', (176, 190))	('tumor', 'Disease', (103, 108))	('mutational', 'Var', (211, 221))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
432435	26580448	S5 and S6 in Supplementary Appendix 1) The prevalence of germline mutations that were pathogenic or probably pathogenic was greatest among patients with non-CNS solid tumors (48 of 287 patients [16.7%]), followed by those with CNS tumors (21 of 245 [8.6%], including the patient with biallelic loss of ATM) or leukemia (26 of 588 [4.4%]) (Fig.	('mutations', 'Var', (66, 75))	('ATM', 'Gene', '472', (302, 305))	('germline', 'Gene', (57, 65))	('patient', 'Species', '9606', (271, 278))	('patient', 'Species', '9606', (185, 192))	('leukemia', 'Phenotype', 'HP:0001909', (310, 318))	('CNS tumor', 'Phenotype', 'HP:0100006', (227, 236))	('leukemia', 'Disease', 'MESH:D007938', (310, 318))	('leukemia', 'Disease', (310, 318))	('ATM', 'Gene', (302, 305))	('patients', 'Species', '9606', (139, 147))	('loss', 'NegReg', (294, 298))	('patients', 'Species', '9606', (185, 193))	('CNS tumors', 'Disease', 'MESH:D009369', (227, 237))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('CNS tumors', 'Disease', (227, 237))	('non-CNS solid tumors', 'Disease', (153, 173))	('non-CNS solid tumors', 'Disease', 'MESH:D009369', (153, 173))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('patient', 'Species', '9606', (139, 146))
432437	26580448	The histologic subtypes of CNS tumor that were most often associated with germline mutations included choroid plexus carcinoma (in 1 of 4 patients [25%]), medulloblastoma (in 5 of 37 [13.5%]), high-grade glioma (in 9 of 99 [9.1%]), low-grade glioma (in 3 of 38 [7.9%]), and ependymoma (in 4 of 67 [6.0%]).	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (102, 126))	('glioma', 'Disease', (242, 248))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('medulloblastoma', 'Disease', 'MESH:D008527', (155, 170))	('ependymoma', 'Disease', (274, 284))	('medulloblastoma', 'Phenotype', 'HP:0002885', (155, 170))	('choroid plexus carcinoma', 'Disease', (102, 126))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('patients', 'Species', '9606', (138, 146))	('medulloblastoma', 'Disease', (155, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ependymoma', 'Phenotype', 'HP:0002888', (274, 284))	('CNS tumor', 'Phenotype', 'HP:0100006', (27, 36))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (102, 126))	('mutations', 'Var', (83, 92))	('associated', 'Reg', (58, 68))	('glioma', 'Disease', (204, 210))	('tumor', 'Disease', (31, 36))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('ependymoma', 'Disease', 'MESH:D004806', (274, 284))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
432440	26580448	The known associations included the association of TP53 mutations with classic Li-Fraumeni syndrome-associated component cancers such as rhabdomyosarcomas, osteosarcomas, adrenocortical tumors, CNS tumors, and leukemia; NF1 mutations with CNS tumors; RB1 mutations with retinoblastoma and osteosarcoma; and ALK mutations with neuroblastoma (Fig.	('Li-Fraumeni syndrome-associated component cancers', 'Disease', 'MESH:D016864', (79, 128))	('retinoblastoma', 'Phenotype', 'HP:0009919', (270, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (137, 154))	('ALK', 'Gene', '238', (307, 310))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('neuroblastoma', 'Disease', (326, 339))	('osteosarcomas', 'Phenotype', 'HP:0002669', (156, 169))	('mutations', 'Var', (311, 320))	('ALK', 'Gene', (307, 310))	('RB1', 'Gene', (251, 254))	('NF1', 'Gene', '4763', (220, 223))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (171, 192))	('mutations', 'Var', (255, 264))	('neuroblastoma', 'Phenotype', 'HP:0003006', (326, 339))	('sarcoma', 'Phenotype', 'HP:0100242', (294, 301))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('associations', 'Interaction', (10, 22))	('neuroblastoma', 'Disease', 'MESH:D009447', (326, 339))	('CNS tumors', 'Disease', 'MESH:D009369', (239, 249))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('CNS tumors', 'Disease', (239, 249))	('NF1', 'Gene', (220, 223))	('association', 'Interaction', (36, 47))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (137, 153))	('CNS tumor', 'Phenotype', 'HP:0100006', (194, 203))	('Li-Fraumeni syndrome-associated component cancers', 'Disease', (79, 128))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('RB1', 'Gene', '5925', (251, 254))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('leukemia', 'Phenotype', 'HP:0001909', (210, 218))	('adrenocortical tumors', 'Disease', (171, 192))	('retinoblastoma and osteosarcoma', 'Disease', 'MESH:C566714', (270, 301))	('osteosarcoma', 'Phenotype', 'HP:0002669', (156, 168))	('osteosarcomas', 'Disease', 'MESH:D012516', (156, 169))	('TP53', 'Gene', '7157', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('CNS tumor', 'Phenotype', 'HP:0100006', (239, 248))	('CNS tumors', 'Disease', (194, 204))	('CNS tumors', 'Disease', 'MESH:D009369', (194, 204))	('leukemia', 'Disease', (210, 218))	('osteosarcoma', 'Phenotype', 'HP:0002669', (289, 301))	('leukemia', 'Disease', 'MESH:D007938', (210, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('osteosarcomas', 'Disease', (156, 169))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('mutations', 'Var', (224, 233))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (137, 154))	('rhabdomyosarcomas', 'Disease', (137, 154))
432441	26580448	New associations included the association of germline TP53, PMS2, and RET mutations with Ewing's sarcoma; APC and SDHB mutations with neuroblastoma; and a variety of mutations (APC, VHL, CDH1, PTCH1, or SDHA) with leukemia.	('VHL', 'Disease', 'MESH:D006623', (182, 185))	('SDHB', 'Gene', (114, 118))	('CDH1', 'Gene', '999', (187, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leukemia', 'Phenotype', 'HP:0001909', (214, 222))	('PMS2', 'Gene', (60, 64))	('association', 'Interaction', (30, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (89, 104))	('CDH1', 'Gene', (187, 191))	('SDHA', 'Gene', '6389', (203, 207))	('TP53', 'Gene', '7157', (54, 58))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (89, 104))	('neuroblastoma', 'Disease', (134, 147))	('mutations', 'Var', (119, 128))	('leukemia', 'Disease', 'MESH:D007938', (214, 222))	('neuroblastoma', 'Phenotype', 'HP:0003006', (134, 147))	('leukemia', 'Disease', (214, 222))	('RET', 'Gene', '5979', (70, 73))	('VHL', 'Disease', (182, 185))	('neuroblastoma', 'Disease', 'MESH:D009447', (134, 147))	('PTCH1', 'Gene', '5727', (193, 198))	('APC', 'Disease', 'MESH:D011125', (177, 180))	("Ewing's sarcoma", 'Disease', (89, 104))	('APC', 'Disease', (177, 180))	('PMS2', 'Gene', '5395', (60, 64))	('SDHA', 'Gene', (203, 207))	('SDHB', 'Gene', '6390', (114, 118))	('APC', 'Disease', 'MESH:D011125', (106, 109))	('mutations', 'Var', (74, 83))	('APC', 'Disease', (106, 109))	('TP53', 'Gene', (54, 58))	('PTCH1', 'Gene', (193, 198))	('RET', 'Gene', (70, 73))	('associations', 'Interaction', (4, 16))
432442	26580448	A total of eight children had germline mutations in the adult-onset cancer-predisposition genes BRCA1, BRCA2, and PALB2.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PALB2', 'Gene', (114, 119))	('BRCA2', 'Gene', '675', (103, 108))	('BRCA1', 'Gene', '672', (96, 101))	('children', 'Species', '9606', (17, 25))	('germline mutations', 'Var', (30, 48))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('BRCA1', 'Gene', (96, 101))	('cancer', 'Disease', (68, 74))	('BRCA2', 'Gene', (103, 108))	('PALB2', 'Gene', '79728', (114, 119))
432444	26580448	Although biallelic mutations of BRCA1/2 and PALB2 are known to cause Fanconi's anemia, there were no germline mutations or deletions involving the second alleles of these genes in any of the affected patients.	('patients', 'Species', '9606', (200, 208))	('cause', 'Reg', (63, 68))	('BRCA1/2', 'Gene', (32, 39))	('PALB2', 'Gene', '79728', (44, 49))	("Fanconi's anemia", 'Disease', (69, 85))	('anemia', 'Phenotype', 'HP:0001903', (79, 85))	('PALB2', 'Gene', (44, 49))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (69, 85))	('BRCA1/2', 'Gene', '672;675', (32, 39))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (69, 85))	('biallelic mutations', 'Var', (9, 28))
432448	26580448	Of these 2 patients, 1 had an adrenocortical tumor tested for TP53 (TP53 p.I332F in Patient ACT001) and 1 had retinoblastoma that was tested for RB1 (mosaic RB1 p.R445* in Patient RB002); both lesions were identified by means of the next-generation sequencing approaches used in this study.	('adrenocortical tumor', 'Disease', 'MESH:D018268', (30, 50))	('TP53', 'Gene', (62, 66))	('retinoblastoma', 'Phenotype', 'HP:0009919', (110, 124))	('TP53', 'Gene', (68, 72))	('Patient', 'Species', '9606', (172, 179))	('RB1', 'Gene', (157, 160))	('retinoblastoma', 'Disease', (110, 124))	('Patient', 'Species', '9606', (84, 91))	('p.R445*', 'Var', (161, 168))	('RB1', 'Gene', (145, 148))	('RB1', 'Gene', '5925', (157, 160))	('TP53', 'Gene', '7157', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mosaic', 'Var', (150, 156))	('p.R445*', 'Mutation', 'p.R445*', (161, 168))	('p.I332F', 'Mutation', 'p.I332F', (73, 80))	('TP53', 'Gene', '7157', (68, 72))	('patients', 'Species', '9606', (11, 19))	('p.I332F', 'Var', (73, 80))	('retinoblastoma', 'Disease', 'MESH:D012175', (110, 124))	('RB1', 'Gene', '5925', (145, 148))	('adrenocortical tumor', 'Disease', (30, 50))
432450	26580448	Furthermore, among these 23 patients, only 13 (57%) had a history that was consistent with the underlying genetic syndrome, including 8 patients with TP53 mutations (and thus the Li-Fraumeni syndrome), 2 with APC mutations (familial adenomatous polyposis), 2 with BRCA2 mutations (hereditary breast and ovarian cancer; the pedigrees are shown in Fig.	('TP53', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (233, 254))	('genetic syndrome', 'Disease', 'MESH:D030342', (106, 122))	('BRCA2', 'Gene', '675', (264, 269))	('mutations', 'Var', (270, 279))	('familial adenomatous polyposis', 'Disease', (224, 254))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (224, 254))	('TP53', 'Gene', '7157', (150, 154))	('patients', 'Species', '9606', (28, 36))	('APC', 'Disease', 'MESH:D011125', (209, 212))	('Li-Fraumeni syndrome', 'Disease', (179, 199))	('APC', 'Disease', (209, 212))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (179, 199))	('mutations', 'Var', (155, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (303, 317))	('patients', 'Species', '9606', (136, 144))	('genetic syndrome', 'Disease', (106, 122))	('BRCA2', 'Gene', (264, 269))	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (281, 317))
432451	26580448	S8 in Supplementary Appendix 1), and 1 with PMS2 mutations (hereditary nonpolyposis colorectal cancer, also known as the Lynch syndrome).	('PMS2', 'Gene', '5395', (44, 48))	('Lynch syndrome', 'Disease', (121, 135))	('mutations', 'Var', (49, 58))	('nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (71, 101))	('Lynch syndrome', 'Disease', 'MESH:D003123', (121, 135))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (60, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hereditary nonpolyposis colorectal cancer', 'Disease', (60, 101))	('PMS2', 'Gene', (44, 48))
432455	26580448	These included 114 heterozygous truncation mutations, in 109 patients, that involved tumor-suppressor genes, tyrosine kinase genes, or other cancer genes (Fig.	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('truncation mutations', 'Var', (32, 52))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (141, 147))
432457	26580448	A total of 18 patients who did not have pathogenic mutations in genes that have been associated with cancer-predisposition syndromes had protein-truncating mutations in tumor-suppressor genes.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Disease', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (169, 174))	('patients', 'Species', '9606', (14, 22))	('protein-truncating mutations', 'Var', (137, 165))
432458	26580448	Two known hotspots of somatic activating mutations in EGFR, T790 and H773, were identified once each in the germline of 2 patients with leukemia (Fig.	('activating', 'PosReg', (30, 40))	('T790', 'Var', (60, 64))	('leukemia', 'Disease', (136, 144))	('leukemia', 'Disease', 'MESH:D007938', (136, 144))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('H773', 'Var', (69, 73))	('patients', 'Species', '9606', (122, 130))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))
432460	26580448	First, we included mutations that were pathogenic or probably pathogenic in 60 genes that have been associated with clinically relevant autosomal dominant cancer-predisposition syndromes, and we did not include other genes that, when mutated, may contribute toward a patient's susceptibility to cancer.	('patient', 'Species', '9606', (267, 274))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (295, 301))	('pathogenic', 'Reg', (39, 49))	('mutations', 'Var', (19, 28))	('associated', 'Reg', (100, 110))	('contribute', 'Reg', (247, 257))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
432462	26580448	Moreover, 109 children (9.7%) had germline-truncating mutations in other cancer-associated genes, although non-hotspot missense mutations in these genes were not fully characterized, some of which may eventually be considered to be cancer-susceptibility genes.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('children', 'Species', '9606', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('germline-truncating mutations', 'Var', (34, 63))
432463	26580448	Second, among the 226 variants of uncertain significance that were identified in the 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes, 119 (52.7%) were predicted to be deleterious by at least two computational methods, and some of these could, in fact, confer susceptibility to cancer.	('associated', 'Reg', (109, 119))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('susceptibility', 'Reg', (302, 316))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('variants', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (320, 326))
432464	26580448	Finally, as we learn more about how certain genetic alterations (e.g., structural variations, changes in noncoding regions, and epigenetic modifications) influence cellular function, new cancer-predisposing lesions in these and other newly discovered cancer-associated genes will be identified.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (187, 193))	('influence', 'Reg', (154, 163))	('epigenetic modifications', 'Var', (128, 152))	('cellular function', 'MPA', (164, 181))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('structural', 'MPA', (71, 81))	('cancer', 'Disease', (251, 257))
432465	26580448	We found several unexpected germline mutations in patients with Ewing's sarcoma, neuroblastoma, osteosarcoma, or leukemia.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (64, 79))	('osteosarcoma', 'Disease', (96, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('patients', 'Species', '9606', (50, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (96, 108))	('neuroblastoma', 'Disease', 'MESH:D009447', (81, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (96, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('neuroblastoma', 'Disease', (81, 94))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (64, 79))	('germline mutations', 'Var', (28, 46))	('leukemia', 'Phenotype', 'HP:0001909', (113, 121))	('neuroblastoma', 'Phenotype', 'HP:0003006', (81, 94))	("Ewing's sarcoma", 'Disease', (64, 79))	('leukemia', 'Disease', (113, 121))	('leukemia', 'Disease', 'MESH:D007938', (113, 121))
432471	26580448	described a high prevalence of childhood cancer in families with germline BRCA2 mutations, and Brooks et al.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (80, 89))	('BRCA2', 'Gene', (74, 79))	('germline', 'Var', (65, 73))	('BRCA2', 'Gene', '675', (74, 79))	('childhood cancer', 'Disease', 'MESH:C536928', (31, 47))	('childhood cancer', 'Disease', (31, 47))
432472	26580448	reported 20 cases of pediatric cancer among 379 families, members of which had a mutation in either BRCA1 or BRCA2.	('pediatric cancer', 'Disease', 'MESH:D009369', (21, 37))	('BRCA1', 'Gene', '672', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mutation', 'Var', (81, 89))	('BRCA1', 'Gene', (100, 105))	('BRCA2', 'Gene', (109, 114))	('pediatric cancer', 'Disease', (21, 37))	('BRCA2', 'Gene', '675', (109, 114))
432473	26580448	These reports suggest that pathogenic mutations in BRCA1 and BRCA2 are more common in pediatric cancer than has been recognized previously and that they potentially underpin a broader spectrum of cancer phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('common', 'Reg', (76, 82))	('BRCA2', 'Gene', '675', (61, 66))	('pediatric cancer', 'Disease', 'MESH:D009369', (86, 102))	('BRCA1', 'Gene', '672', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('BRCA2', 'Gene', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('BRCA1', 'Gene', (51, 56))	('pediatric cancer', 'Disease', (86, 102))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (38, 47))	('underpin', 'Reg', (165, 173))	('cancer', 'Disease', (96, 102))
432475	26580448	However, only 40% of our patients with germline mutations that were pathogenic or probably pathogenic and that could be evaluated had a family history of cancer.	('germline mutations', 'Var', (39, 57))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
432482	26580448	Observation of pathogenic mutations in the controls may indicate uncharacterized cancer phenotypes in the people enrolled, rather than refuting the pathogenicity of these mutations in cancer predisposition (Tables S6 and S7 in Supplementary Appendix 1).	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('people', 'Species', '9606', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
432483	26580448	Moreover, by adjusting for the distribution of cancer subtypes observed in the SEER program and by applying previously reported mutation frequencies for those not included in this study, we predicted an overall mutation prevalence of 7.3 to 9.8% in the SEER pediatric cancer population (Table S10 in Supplementary Appendix 2).	('cancer', 'Disease', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('pediatric cancer', 'Disease', 'MESH:D009369', (258, 274))	('to 9', 'Species', '1214577', (238, 242))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('pediatric cancer', 'Disease', (258, 274))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('mutation', 'Var', (211, 219))
432484	26580448	Second, we did not study the parents or relatives of the patients in our cohort and hence could not assess whether variants were new or segregated with a cancer phenotype among family members.	('patients', 'Species', '9606', (57, 65))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('variants', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
432487	26580448	Additional family, epidemiologic, and functional studies are warranted to better understand the cancer risks associated with each of these variants.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('variants', 'Var', (139, 147))
432488	26580448	In conclusion, germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer who participated in this study.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (37, 43))	('children', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('identified', 'Reg', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('germline mutations', 'Var', (15, 33))
432493	26237416	Pazopanib tended to reduce the tumor volume compared to the untreated mice, but there was no significant difference (p = 0.115).	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('tumor', 'Disease', (31, 36))	('reduce', 'NegReg', (20, 26))	('mice', 'Species', '10090', (70, 74))	('Pazopanib', 'Var', (0, 9))
432496	26237416	These results suggest tumor-targeting S. typhimurium A1-R is a promising treatment for chemo-resistant soft-tissue sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('sarcoma', 'Disease', (115, 122))	('S. typhimurium', 'Var', (38, 52))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (103, 122))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('tumor', 'Disease', (22, 27))	('S. typhimurium', 'Species', '90371', (38, 52))
432511	26237416	In the present study, we report the efficacy of S. typhimurium A1-R against a human patient chemo-resistant sarcoma growing in nude mice.	('S. typhimurium', 'Species', '90371', (48, 62))	('sarcoma', 'Disease', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('S. typhimurium', 'Var', (48, 62))	('nude mice', 'Species', '10090', (127, 136))	('human', 'Species', '9606', (78, 83))	('patient', 'Species', '9606', (84, 91))
432530	26237416	Resected sarcoma specimens from mice treated with S. typhimurium A1-R were embedded with optimal cutting temperature (OCT) compound (Tissue-Tek; Sakura Finetek Europe BV, Zoeterwude, Netherlands) and preserved in liquid nitrogen.	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('sarcoma', 'Disease', (9, 16))	('S. typhimurium', 'Species', '90371', (50, 64))	('nitrogen', 'Chemical', 'MESH:D009584', (220, 228))	('mice', 'Species', '10090', (32, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('S. typhimurium A1-R', 'Var', (50, 69))
432538	26237416	Pazopanib tended to reduce the tumor volume compared to the untreated mice, but there was not a significant difference (p = 0.115).	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('tumor', 'Disease', (31, 36))	('reduce', 'NegReg', (20, 26))	('mice', 'Species', '10090', (70, 74))	('Pazopanib', 'Var', (0, 9))
432544	26237416	Tumors treated with S. typhimurium A1-R consisted of 2 components; one was a viable-like component and the other one was a necrotic component.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('S. typhimurium', 'Var', (20, 34))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('S. typhimurium', 'Species', '90371', (20, 34))	('necrotic component', 'Disease', (123, 141))	('necrotic component', 'Disease', 'MESH:C562869', (123, 141))
432552	26237416	We have recently shown that quiescent cancer cells are sensitive to S. typhimurium A1-R. S. typhimurium A1-R, unlike C. novyi-NT, is a facultative anaerobe and can be administered systemically such as in the present study (i.p.	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('S. typhimurium', 'Var', (89, 103))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('C. novyi-NT', 'Species', '386415', (117, 128))	('S. typhimurium', 'Species', '90371', (89, 103))	('S. typhimurium', 'Species', '90371', (68, 82))
432555	26237416	The results of the present study indicate tumor-targeting S. typhimurium A1-R is a promising treatment for soft-tissue sarcomas.	('arg', 'Chemical', 'MESH:D001120', (49, 52))	('sarcomas', 'Disease', (119, 127))	('tumor', 'Disease', (42, 47))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (107, 126))	('S. typhimurium', 'Var', (58, 72))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (107, 127))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('S. typhimurium', 'Species', '90371', (58, 72))
432669	32718998	Both sarcoma subtypes have complex karyotypes and harbor similar genetic alterations, including inactivation of a canonical tumor suppressor (TRP53 or CDKN2A) and activation of the Ras pathway, usually through loss of the Ras GAP neurofibromin (NF1).	('TRP53', 'Gene', '22059', (142, 147))	('activation', 'PosReg', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('inactivation', 'NegReg', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('sarcoma', 'Disease', 'MESH:D012509', (5, 12))	('TRP53', 'Gene', (142, 147))	('NF1', 'Gene', (245, 248))	('tumor', 'Disease', (124, 129))	('CDKN2A', 'Gene', '12578', (151, 157))	('Ras pathway', 'Pathway', (181, 192))	('CDKN2A', 'Gene', (151, 157))	('sarcoma', 'Disease', (5, 12))	('NF1', 'Gene', '18015', (245, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('loss', 'Var', (210, 214))
432686	32718998	We demonstrated that Ad-Cre injection into the sciatic nerve of Nf1 Flox/Flox; Cdkn2a Flox/Flox mice (NC mice) generates MPNSTs at the site of injection within 3-4 months, while injection into the gastrocnemius muscle of NC mice generates UPS tumors within 7-9 months.	('MPNSTs', 'MPA', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('mice', 'Species', '10090', (96, 100))	('Flox/Flox', 'Var', (86, 95))	('mice', 'Species', '10090', (224, 228))	('Cdkn2a Flox/Flox', 'Var', (79, 95))	('UPS tumors', 'Disease', 'MESH:D017118', (239, 249))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('UPS tumors', 'Disease', (239, 249))
432692	32718998	Dysregulation of the PI3K/AKT/mTOR signaling axis is common across multiple sarcoma types and correlates with poor response to treatment.	('mTOR', 'Gene', '56717', (30, 34))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('Dysregulation', 'Var', (0, 13))	('AKT', 'Gene', '11651', (26, 29))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('AKT', 'Gene', (26, 29))	('mTOR', 'Gene', (30, 34))
432693	32718998	Both IHC and gene expression studies have shown that PTEN expression can be lost in patient samples of aggressive MPNST and UPS through DNA methylation or copy number loss.	('expression', 'MPA', (58, 68))	('aggressive MPNST', 'Disease', (103, 119))	('DNA methylation', 'Var', (136, 151))	('PTEN', 'Gene', (53, 57))	('lost', 'NegReg', (76, 80))	('copy number loss', 'Var', (155, 171))	('patient', 'Species', '9606', (84, 91))
432694	32718998	Data from multiple groups demonstrate that combining Pten deletion with loss of either p53 or Nf1 can generate several distinct types of STS in genetically-engineered mice, including leiomyosarcoma, UPS or MPNST.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (183, 197))	('loss', 'NegReg', (72, 76))	('p53', 'Gene', (87, 90))	('Pten', 'Gene', (53, 57))	('UPS', 'Disease', (199, 202))	('p53', 'Gene', '22059', (87, 90))	('generate', 'Reg', (102, 110))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (183, 197))	('Nf1', 'Gene', (94, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('deletion', 'Var', (58, 66))	('mice', 'Species', '10090', (167, 171))	('leiomyosarcoma', 'Disease', (183, 197))
432695	32718998	For example, high-grade peripheral nerve sheath tumors were generated in PtenFlox/Flox; Nf1Flox/Flox mice with Schwann cell-specific expression of Cre recombinase.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('sheath tumors', 'Disease', 'MESH:D010524', (41, 54))	('mice', 'Species', '10090', (101, 105))	('sheath tumors', 'Disease', (41, 54))	('PtenFlox/Flox', 'Var', (73, 86))
432697	32718998	Based on these data, we hypothesized that introducing somatic Pten loss into the NC mouse models would accelerate tumor development to enhance the feasibility of longitudinal preclinical studies.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('accelerate', 'PosReg', (103, 113))	('tumor', 'Disease', (114, 119))	('mouse', 'Species', '10090', (84, 89))	('loss', 'Var', (67, 71))	('Pten', 'Gene', (62, 66))	('enhance', 'PosReg', (135, 142))
432699	32718998	To determine if CP-nanoparticle-based chemotherapy is a promising therapeutic approach for STS, we tested the efficacy of CP-nanoparticle doxorubicin (CP-Dox) in MPNST and UPS mouse models containing identical tumor-initiating mutations.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('CP', 'Gene', '1356', (16, 18))	('tested', 'Reg', (99, 105))	('mouse', 'Species', '10090', (176, 181))	('tumor', 'Disease', (210, 215))	('CP', 'Gene', '1356', (122, 124))	('CP-Dox', 'Chemical', '-', (151, 157))	('doxorubicin', 'Chemical', 'MESH:D004317', (138, 149))	('CP', 'Gene', '1356', (151, 153))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('mutations', 'Var', (227, 236))
432702	32718998	We observed improved biodistribution in MPNSTs treated with CP-Dox, but not in CP-Dox-treated UPS tumors.	('UPS tumors', 'Disease', 'MESH:D017118', (94, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('CP-Dox', 'Chemical', '-', (60, 66))	('CP-Dox', 'Var', (60, 66))	('biodistribution', 'MPA', (21, 36))	('improved', 'PosReg', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('UPS tumors', 'Disease', (94, 104))	('CP-Dox', 'Chemical', '-', (79, 85))
432747	32718998	To generate primary mouse models of STS to undertake preclinical therapeutic studies of CP-nanoparticle-based chemotherapy in MPNSTs and UPS tumors, we chose to accelerate tumorigenesis in the previously described NC model by introducing Pten loss-of-function mutations.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('loss-of-function', 'NegReg', (243, 259))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Pten', 'Gene', (238, 242))	('UPS tumors', 'Disease', 'MESH:D017118', (137, 147))	('UPS tumors', 'Disease', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (172, 177))	('accelerate', 'PosReg', (161, 171))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (141, 146))	('CP', 'Gene', '1356', (88, 90))	('mutations', 'Var', (260, 269))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('mouse', 'Species', '10090', (20, 25))
432754	32718998	To use Cre/loxP to induce MPNSTs with deletion of Pten, we injected the sciatic nerve of PtenFlox/Flox; NC mice with Ad-Cre to delete Pten, Nf1, and Cdkn2a in the nerve sheath.	('Pten', 'Gene', (50, 54))	('Cdkn2a', 'Gene', (149, 155))	('Nf1', 'Gene', (140, 143))	('Pten', 'Gene', (134, 138))	('mice', 'Species', '10090', (107, 111))	('deletion', 'Var', (38, 46))	('delete', 'Var', (127, 133))
432757	32718998	To utilize CRISPR/Cas9 technology to mutate Pten in the NC MPNST model, we generated mice with a Cre-activatable Cas9 (Rosa26-LSL-Cas9) and floxed Nf1 and Cdkn2a alleles (Rosa26-LSL-Cas9; Nf1Flox/Flox; Cdkn2aFlox/Flox, referred to as LSL-Cas9; NC mice).	('mice', 'Species', '10090', (85, 89))	('Cdkn2aFlox/Flox', 'Var', (202, 217))	('mice', 'Species', '10090', (247, 251))	('Rosa26', 'Gene', '14910', (171, 177))	('Nf1Flox/Flox; Cdkn2aFlox/Flox', 'Var', (188, 217))	('Rosa26', 'Gene', '14910', (119, 125))	('Rosa26', 'Gene', (171, 177))	('Rosa26', 'Gene', (119, 125))
432758	32718998	Ad-Cre injection into these mice activates Cas9 expression by deletion of the upstream floxed STOP cassette, as well as deleting the floxed genes Nf1 and Cdkn2a.	('mice', 'Species', '10090', (28, 32))	('expression', 'MPA', (48, 58))	('activates', 'PosReg', (33, 42))	('Cas9', 'Gene', (43, 47))	('Cdkn2a', 'Gene', (154, 160))	('Nf1', 'Gene', (146, 149))	('deleting', 'NegReg', (120, 128))	('deletion', 'Var', (62, 70))
432760	32718998	When LSL-Cas9; NC mice are injected in the sciatic nerve with Ad-Cre + gPten, Nf1/Cdkn2a-null tumors develop that express Cas9 targeting Pten disruption (Figure 1B).	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mice', 'Species', '10090', (18, 22))	('Cas9 targeting', 'Var', (122, 136))	('Pten', 'Protein', (137, 141))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
432762	32718998	LSL-Cas9; NC mice injected with Ad-Cre + sgPten develop tumors more quickly than control mice injected with Ad-Cre + sgTom (52 vs 93 days), similar to results seen with the Cre/loxP approach in Figure 1A.	('Ad-Cre + sgPten', 'Var', (32, 47))	('mice', 'Species', '10090', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('sgTom', 'Chemical', '-', (117, 122))	('mice', 'Species', '10090', (89, 93))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
432763	32718998	To confirm Pten disruption in CRISPR/Cas9-initiated tumors, we performed indel pattern analysis on tumor-derived cell lines (Figure 1C).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (99, 104))	('disruption', 'Var', (16, 26))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Pten', 'Gene', (11, 15))
432764	32718998	This method examines the frequency and location of insertions and deletions within individual tumors generated by CRISPR/Cas9 targeting.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('deletions', 'Var', (66, 75))	('tumors', 'Disease', (94, 100))	('insertions', 'Var', (51, 61))
432766	32718998	While deletion of Pten in the Cre/loxP model does not alter tumor growth kinetics, Pten mutation in the CRISPR/Cas9 model appears to accelerate the time required for MPNSTs to triple in volume (Figure 1D).	('mutation', 'Var', (88, 96))	('accelerate', 'PosReg', (133, 143))	('time', 'MPA', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('deletion', 'Var', (6, 14))	('Pten', 'Gene', (18, 22))	('tumor', 'Disease', (60, 65))	('Pten', 'Gene', (83, 87))
432768	32718998	Taken together, these data are consistent with other studies of Pten deletion in nerve sheath tumors, and provide robust new spatially- and temporally- restricted mouse models for preclinical studies of MPNST.	('sheath tumors', 'Disease', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Pten', 'Gene', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('mouse', 'Species', '10090', (163, 168))	('sheath tumors', 'Disease', 'MESH:D010524', (87, 100))	('deletion', 'Var', (69, 77))
432770	32718998	We and others have shown that the PI3K pathway plays an important role in UPS, and we hypothesized that Pten deletion would accelerate tumor formation in the NC model.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('deletion', 'Var', (109, 117))	('tumor', 'Disease', (135, 140))	('accelerate', 'PosReg', (124, 134))	('Pten', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
432771	32718998	Using Cre/loxP technology, injection of Ad-Cre into the gastrocnemius muscle of NC or PtenFlox/+; NC mice generates tumors with an average latency of 138 and 129 days, respectively.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('Ad-Cre', 'Var', (40, 46))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
432772	32718998	A similar phenotype is observed using the CRISPR/Cas9 model in LSL-Cas9; NC mice, where injection of Ad-Cre + gPten generates tumors in an average of 78 days, but only 2 of 12 LSL-Cas9; NC mice injected with the negative control sgRNA (Ad-Cre + sgTom) developed tumors after 5-8 months (Figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('Ad-Cre', 'Var', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('mice', 'Species', '10090', (189, 193))	('tumors', 'Disease', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('sgTom', 'Chemical', '-', (245, 250))	('mice', 'Species', '10090', (76, 80))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
432773	32718998	This is longer than the time required for tumorigenesis in Cre/loxP-driven NC mice with wildtype Pten, suggesting that Pten deletion may play a larger role in tumorigenesis for mice with constitutive Cas9 expression.	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Pten', 'Gene', (119, 123))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mice', 'Species', '10090', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('deletion', 'Var', (124, 132))	('mice', 'Species', '10090', (78, 82))
432774	32718998	Indel pattern analysis shows that cell lines from CRISPR/Cas9-generated UPS tumors have a wide range of indels within Pten, including one tumor-derived cell line with a large deletion greater than 50 base pairs (Figure 2C).	('Pten', 'Gene', (118, 122))	('tumor', 'Disease', (138, 143))	('UPS tumors', 'Disease', (72, 82))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('indels', 'Var', (104, 110))	('UPS tumors', 'Disease', 'MESH:D017118', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
432776	32718998	Similar to observations in the MPNST model, deletion of Pten in Cre/loxP-generated UPS tumors does not alter tumor proliferation, while mutation of Pten via CRISPR/Cas9 technology appears to accelerate UPS growth kinetics in comparison to PtenFlox/+; NC and NC models (Figure 2D).	('UPS tumors', 'Disease', 'MESH:D017118', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutation', 'Var', (136, 144))	('deletion', 'Var', (44, 52))	('tumor', 'Disease', (87, 92))	('accelerate', 'PosReg', (191, 201))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('UPS growth kinetics', 'MPA', (202, 221))	('UPS tumors', 'Disease', (83, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Pten', 'Gene', (56, 60))	('Pten', 'Gene', (148, 152))	('tumor', 'Disease', (109, 114))
432777	32718998	While it is interesting that deletion of Pten via CRISPR/Cas9 technology appears to accelerate tumor growth in both UPS and MPNST models, this phenotype requires further validation in a larger cohort of mice.	('deletion', 'Var', (29, 37))	('mice', 'Species', '10090', (203, 207))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('Pten', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('accelerate', 'PosReg', (84, 94))	('tumor', 'Disease', (95, 100))
432778	32718998	Taken together, these data show that Pten deletion can accelerate tumor initiation in mouse models of two distinct sarcoma subtypes, and that CRISPR/Cas9 approaches to mutate Pten can accelerate sarcoma development similar to Cre/loxP-mediated deletion.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('sarcoma', 'Disease', (195, 202))	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('tumor', 'Disease', (66, 71))	('sarcoma', 'Disease', (115, 122))	('Pten', 'Gene', (37, 41))	('mutate', 'Var', (168, 174))	('mouse', 'Species', '10090', (86, 91))	('Pten', 'Gene', (175, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('accelerate', 'PosReg', (55, 65))	('accelerate', 'PosReg', (184, 194))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('deletion', 'Var', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
432779	32718998	Disruption of Pten results in pAKT elevation, which can drive cell proliferation and survival.	('AKT', 'Gene', (31, 34))	('survival', 'CPA', (85, 93))	('cell proliferation', 'CPA', (62, 80))	('pAKT elevation', 'Phenotype', 'HP:0031597', (30, 44))	('Pten', 'Gene', (14, 18))	('AKT', 'Gene', '11651', (31, 34))	('Disruption', 'Var', (0, 10))
432780	32718998	In addition, PI3K signaling can modulate cross-talk with the MAPK/ERK and mTOR/S6 pathways.	('PI3K', 'Var', (13, 17))	('MAPK', 'Gene', (61, 65))	('modulate', 'Reg', (32, 40))	('ERK', 'Gene', '26413', (66, 69))	('cross-talk', 'MPA', (41, 51))	('MAPK', 'Gene', '26413', (61, 65))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '56717', (74, 78))	('ERK', 'Gene', (66, 69))	('S6', 'Chemical', 'MESH:C012008', (79, 81))
432782	32718998	To assess PI3K-pathway activation in the Pten/Nf1/Cdkn2a-null sarcoma models, we used western blots of tumor-derived cell lines to examine three frequently activated signaling nodes in the PI3K pathway: phospho-AKT, phospho-S6 and phospho-ERK.	('S6', 'Chemical', 'MESH:C012008', (224, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('PI3K pathway', 'Pathway', (189, 201))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('AKT', 'Gene', '11651', (211, 214))	('tumor', 'Disease', (103, 108))	('phospho', 'Chemical', '-', (231, 238))	('AKT', 'Gene', (211, 214))	('ERK', 'Gene', (239, 242))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('phospho', 'Chemical', '-', (216, 223))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('ERK', 'Gene', '26413', (239, 242))	('phospho-S6', 'Var', (216, 226))	('sarcoma', 'Disease', (62, 69))	('phospho', 'Chemical', '-', (203, 210))
432783	32718998	In MPNSTs, Pten deletion elevates phospho-AKT levels in cells derived from both Cre/loxP and CRISPR/Cas9 models (Figure 3A).	('elevates', 'PosReg', (25, 33))	('AKT', 'Gene', (42, 45))	('deletion', 'Var', (16, 24))	('phospho', 'Chemical', '-', (34, 41))	('Pten', 'Gene', (11, 15))	('AKT', 'Gene', '11651', (42, 45))
432785	32718998	Moderate levels of phospho-ERK are observed in cell lines from MPNSTs by western blot, but we are unable to detect further induction of phospho-ERK with Pten deletion.	('Pten', 'Gene', (153, 157))	('ERK', 'Gene', '26413', (144, 147))	('ERK', 'Gene', (144, 147))	('phospho', 'Chemical', '-', (136, 143))	('phospho', 'Chemical', '-', (19, 26))	('deletion', 'Var', (158, 166))	('ERK', 'Gene', '26413', (27, 30))	('ERK', 'Gene', (27, 30))
432787	32718998	Western blot analyses show that deletion of Pten upregulates phospho-AKT levels in UPS-derived cell lines generated by both Cre/loxP and CRISPR/Cas9 approaches (Figure 3B).	('deletion', 'Var', (32, 40))	('AKT', 'Gene', (69, 72))	('Pten', 'Gene', (44, 48))	('phospho', 'Chemical', '-', (61, 68))	('AKT', 'Gene', '11651', (69, 72))	('upregulates', 'PosReg', (49, 60))
432789	32718998	These results in UPS cell lines is similar to results seen in MPNST cell lines and suggests that the elevated mTOR/S6 activity in these tumors could contribute to accelerated growth kinetics in tumors with Pten deletion by CRISPR/Cas9 technology.	('mTOR', 'Gene', (110, 114))	('tumors', 'Disease', (136, 142))	('elevated', 'PosReg', (101, 109))	('deletion', 'Var', (211, 219))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mTOR', 'Gene', '56717', (110, 114))	('activity', 'MPA', (118, 126))	('S6', 'Chemical', 'MESH:C012008', (115, 117))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Pten', 'Gene', (206, 210))	('tumors', 'Disease', (194, 200))	('accelerated', 'PosReg', (163, 174))	('growth kinetics', 'MPA', (175, 190))
432791	32718998	As these western blots are examining tumor-derived cell lines, and not tumor lysates, it is possible the differences in pS6 and pERK levels between cell lines can be attriuted to additional mutations or epigenetic events that were gained during culture to select for divergent signaling properties.	('S6', 'Chemical', 'MESH:C012008', (121, 123))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('pERK', 'Gene', '13666', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('pERK', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('pS6', 'MPA', (120, 123))	('epigenetic', 'Var', (203, 213))	('tumor', 'Disease', (71, 76))
432803	32718998	In contrast, CP-Dox extends median survival to 24 days, significantly longer than free doxorubicin or vehicle treatment (Figure 4A).	('median', 'MPA', (28, 34))	('CP-Dox', 'Chemical', '-', (13, 19))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))	('CP-Dox', 'Var', (13, 19))
432819	32718998	However, at 24 hours post-injection, the CP-Dox formulation results in significantly higher intratumoral concentrations of doxorubicin, showing the improved accumulation and retention of the nanoparticle formulation in the MPNSTs.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('accumulation', 'MPA', (157, 169))	('higher', 'PosReg', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('doxorubicin', 'Chemical', 'MESH:D004317', (123, 134))	('improved', 'PosReg', (148, 156))	('CP-Dox', 'Var', (41, 47))	('tumor', 'Disease', (97, 102))	('CP-Dox', 'Chemical', '-', (41, 47))	('retention', 'MPA', (174, 183))
432821	32718998	This drug accumulation study supports the notion that CP-Dox improves survival in MPNSTs partially due to increased tumor bioavailability.	('CP-Dox', 'Chemical', '-', (54, 60))	('CP-Dox', 'Var', (54, 60))	('survival', 'MPA', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('improves', 'PosReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('increased', 'PosReg', (106, 115))	('tumor', 'Disease', (116, 121))
432827	32718998	Based on these findings, we hypothesized that CD8+ T cell infiltration would correlate with improved response to doxorubicin-containing therapy.	('improved', 'PosReg', (92, 100))	('CD8+', 'Var', (46, 50))	('response to doxorubicin-containing therapy', 'MPA', (101, 143))	('doxorubicin', 'Chemical', 'MESH:D004317', (113, 124))
432829	32718998	In MPNSTs, CD8+ T cell infiltration increases in tumors treated with CP-Dox compared to vehicle (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('CD8+ T cell infiltration', 'CPA', (11, 35))	('CP-Dox', 'Var', (69, 75))	('increases', 'PosReg', (36, 45))	('CP-Dox', 'Chemical', '-', (69, 75))
432831	32718998	In UPS tumors, CD8+ T cells are elevated in both CP-Dox and free doxorubicin-treated tumors, compared to vehicle alone (Figure 5D).	('elevated', 'PosReg', (32, 40))	('UPS tumors', 'Disease', (3, 13))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('CD8+', 'MPA', (15, 19))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('T cells are elevated', 'Phenotype', 'HP:0100828', (20, 40))	('CP-Dox', 'Chemical', '-', (49, 55))	('CP-Dox', 'Var', (49, 55))	('UPS tumors', 'Disease', 'MESH:D017118', (3, 13))	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
432840	32718998	To directly compare the preclinical efficacy of chimeric polypeptide nanoparticle-based chemotherapeutic formulations in genetically-identical tumors of different sarcoma subtypes, we generated MPNST and UPS models with deletions in Pten, Nf1, and Cdkn2a using both Cre/loxP and CRISPR/Cas9 approaches.	('tumors of different sarcoma', 'Disease', (143, 170))	('Cdkn2a', 'Gene', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('deletions', 'Var', (220, 229))	('Pten', 'Gene', (233, 237))	('tumors of different sarcoma', 'Disease', 'MESH:D012509', (143, 170))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('Nf1', 'Gene', (239, 242))
432841	32718998	In the MPNST model, we observed that CP-Dox significantly extends animal survival and slows tumor growth (Figure 4A-B).	('CP-Dox', 'Var', (37, 43))	('slows', 'NegReg', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('animal survival', 'CPA', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('extends', 'PosReg', (58, 65))	('CP-Dox', 'Chemical', '-', (37, 43))
432842	32718998	To our knowledge, this is the first demonstration in a primary tumor model that CP-Dox improves response in comparison to free doxorubicin.	('tumor', 'Disease', (63, 68))	('doxorubicin', 'Chemical', 'MESH:D004317', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CP-Dox', 'Chemical', '-', (80, 86))	('CP-Dox', 'Var', (80, 86))	('response', 'MPA', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('improves', 'PosReg', (87, 95))
432843	32718998	In contrast to our observations in MPNSTs, we found that CP-Dox has no survival advantage over conventional doxorubicin in the UPS tumors (Figure 4C-D).	('CP-Dox', 'Chemical', '-', (57, 63))	('CP-Dox', 'Var', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('UPS tumors', 'Disease', (127, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('UPS tumors', 'Disease', 'MESH:D017118', (127, 137))	('doxorubicin', 'Chemical', 'MESH:D004317', (108, 119))
432859	32718998	These data demonstrate that homozygous loss of Pten is required to accelerate MPNST or UPS tumor formation, as heterozygous Pten loss was not sufficient to accelerate tumor onset.	('UPS tumor', 'Disease', (87, 96))	('UPS tumor', 'Disease', 'MESH:D017118', (87, 96))	('MPNST', 'CPA', (78, 83))	('Pten', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('loss', 'Var', (39, 43))	('accelerate', 'PosReg', (67, 77))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (167, 172))
432861	32718998	In comparing our Cre/loxP and CRISPR/Cas9 models, we determined that Pten deletion can accelerate sarcoma initiation in both MPNST and UPS models.	('sarcoma initiation', 'Disease', (98, 116))	('deletion', 'Var', (74, 82))	('sarcoma initiation', 'Disease', 'MESH:D012509', (98, 116))	('accelerate', 'PosReg', (87, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('Pten', 'Gene', (69, 73))
432862	32718998	As expected for Pten deletion and PI3K pathway activation, levels of phosphorylated AKT are observed with Pten deletion in cell lines derived from all tumors.	('levels', 'MPA', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('AKT', 'Gene', '11651', (84, 87))	('phosphorylated', 'MPA', (69, 83))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('Pten', 'Gene', (106, 110))	('AKT', 'Gene', (84, 87))	('phospho', 'Chemical', '-', (69, 76))	('deletion', 'Var', (111, 119))
432863	32718998	For example, PI3K-mediated phospho-S6 induction is observed only in tumor-derived cell lines where Pten is mutated by CRISPR/Cas9 technology, not with Cre/loxP technology, and the upregulation of phospho-ERK is detected only in some cell lines derived from UPS tumors, but not MPNSTs.	('tumor', 'Disease', (68, 73))	('S6', 'Chemical', 'MESH:C012008', (35, 37))	('UPS tumors', 'Disease', (257, 267))	('tumor', 'Disease', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('Pten', 'Gene', (99, 103))	('mutated', 'Var', (107, 114))	('ERK', 'Gene', (204, 207))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('phospho', 'Chemical', '-', (196, 203))	('ERK', 'Gene', '26413', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('UPS tumors', 'Disease', 'MESH:D017118', (257, 267))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('phospho', 'Chemical', '-', (27, 34))
432864	32718998	First, the Rosa26-LSL-Cas9-containing mice are on a different genetic background that could be more sensitive to Pten deletion, resulting in altered cellular signaling.	('altered', 'Reg', (141, 148))	('Rosa26', 'Gene', (11, 17))	('Pten', 'Gene', (113, 117))	('cellular signaling', 'MPA', (149, 167))	('mice', 'Species', '10090', (38, 42))	('Rosa26', 'Gene', '14910', (11, 17))	('deletion', 'Var', (118, 126))
432865	32718998	Second, constitutive activation of the Cas9 enzyme could increase phospho-S6 levels in tumors from LSL-Cas9; NC mice, potentially influencing signaling cascades.	('influencing', 'Reg', (130, 141))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Cas9', 'Gene', (39, 43))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('phospho-S6 levels', 'MPA', (66, 83))	('increase', 'PosReg', (57, 65))	('mice', 'Species', '10090', (112, 116))	('phospho', 'Chemical', '-', (66, 73))	('activation', 'PosReg', (21, 31))	('LSL-Cas9', 'Var', (99, 107))	('S6', 'Chemical', 'MESH:C012008', (74, 76))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
432866	32718998	Third, Pten deletion may increase phospho-ERK levels in UPS tumors due to relatively low levels in Pten wildtype tumors, whereas phospho-ERK levels are already elevated in Pten wildtype MPNSTs, and therefore Pten loss may be unable to activate the MAPK/ERK pathway beyond baseline levels.	('tumors', 'Disease', (113, 119))	('MAPK', 'Gene', '26413', (248, 252))	('ERK', 'Gene', '26413', (253, 256))	('UPS tumors', 'Disease', 'MESH:D017118', (56, 66))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('MAPK', 'Gene', (248, 252))	('ERK', 'Gene', (137, 140))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('ERK', 'Gene', (42, 45))	('deletion', 'Var', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('increase', 'PosReg', (25, 33))	('ERK', 'Gene', '26413', (137, 140))	('tumors', 'Disease', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('ERK', 'Gene', '26413', (42, 45))	('Pten', 'Gene', (7, 11))	('UPS tumors', 'Disease', (56, 66))	('phospho', 'Chemical', '-', (129, 136))	('ERK', 'Gene', (253, 256))	('phospho', 'Chemical', '-', (34, 41))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
432874	32718998	The development of new approaches to model patient-relevant mutations in preclinical models of different sarcoma subtypes will accelerate bench-to-bedside studies of new treatment paradigms.	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('patient', 'Species', '9606', (43, 50))	('sarcoma', 'Disease', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('mutations', 'Var', (60, 69))
432880	32718998	Pharmacokinetic studies indicate improved biodistribution in CP-Dox-treated MPNSTs, but not in UPS tumors.	('UPS tumors', 'Disease', (95, 105))	('CP-Dox', 'Chemical', '-', (61, 67))	('CP-Dox-treated', 'Var', (61, 75))	('biodistribution', 'MPA', (42, 57))	('UPS tumors', 'Disease', 'MESH:D017118', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('improved', 'PosReg', (33, 41))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
432951	32133276	Resection of the abdominal or RM was associated with a survival benefit compared to patients treated by CTX.	('patients', 'Species', '9606', (84, 92))	('Resection', 'Var', (0, 9))	('RM', 'Disease', 'MESH:D009362', (30, 32))	('CTX', 'Gene', '1593', (104, 107))	('CTX', 'Gene', (104, 107))	('benefit', 'PosReg', (64, 71))	('survival', 'MPA', (55, 63))
432987	30718311	Women with low-grade endometrioid EC had significantly lower SPC risks in gum and other mouth (SIR=0.57, 95% CI=0.30-0.97), lung and bronchus (SIR=0.72, 95% CI=0.660.77), and lymphocytic leukemia (SIR=0.71, 95% CI=0.54-0.93), while women with high-risk EC histological subtypes experienced significantly higher SPC risk at several anatomical sites.	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (175, 195))	('EC', 'Phenotype', 'HP:0012114', (253, 255))	('EC', 'Phenotype', 'HP:0012114', (34, 36))	('Women', 'Species', '9606', (0, 5))	('women', 'Species', '9606', (232, 237))	('low-grade endometrioid EC', 'Var', (11, 36))	('lower', 'NegReg', (55, 60))	('leukemia', 'Phenotype', 'HP:0001909', (187, 195))	('lymphocytic leukemia', 'Disease', (175, 195))
433005	30718311	We categorized ICD-O-3 codes into the following groups: endometrioid and mucinous adenocarcinoma (8380-8383, 8140, 8210, 8211, 8560, 8260, 8262, 8263, 8570, 8261, 8480-8482), serous (8441, 8460, 8461), carcinosarcoma (8950, 8951, 8980, 8981), clear cell (8310), mixed epithelial (8323, 8255), and sarcoma (8800-8935).	('serous', 'Disease', (175, 181))	('8560', 'Var', (127, 131))	('8323', 'Var', (280, 284))	('clear cell', 'Disease', (243, 253))	('sarcoma', 'Disease', 'MESH:D012509', (297, 304))	('sarcoma', 'Disease', (297, 304))	('sarcoma', 'Disease', 'MESH:D012509', (209, 216))	('8441', 'Var', (183, 187))	('carcinosarcoma', 'Disease', (202, 216))	('sarcoma', 'Disease', (209, 216))	('8380-8383', 'Var', (98, 107))	('8800-8935', 'Var', (306, 315))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (73, 96))	('mixed epithelial', 'Disease', (262, 278))	('carcinosarcoma', 'Disease', 'MESH:D002296', (202, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (297, 304))	('8570', 'Var', (151, 155))	('mucinous adenocarcinoma', 'Disease', (73, 96))	('8310', 'Var', (255, 259))	('8950', 'Var', (218, 222))	('8263', 'Var', (145, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('endometrioid', 'Disease', (56, 68))
433033	30718311	Among women diagnosed with low-grade endometrioid EC, risks of vaginal (SIR=4.82, 95% CI=3.62-6.29) and kidney (SIR=1.38, 95% CI=1.19-1.60) cancers were increased while gum and other mouth (SIR=0.57, 95% CI=0.30-0.97), lung and bronchus (SIR=0.72, 95% CI=0.66-0.77), and lymphocytic leukemia (SIR=0.71, 95% CI=0.54-0.93) were lower than the general population.	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (271, 291))	('leukemia', 'Phenotype', 'HP:0001909', (283, 291))	('low-grade', 'Var', (27, 36))	('vaginal', 'Disease', (63, 70))	('increased', 'PosReg', (153, 162))	('kidney', 'Disease', (104, 110))	('women', 'Species', '9606', (6, 11))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('EC', 'Phenotype', 'HP:0012114', (50, 52))	('lower', 'NegReg', (326, 331))	('lymphocytic leukemia', 'Disease', (271, 291))
433037	30718311	Kidney SPC risks were elevated among women with low-grade endometrioid (SIR=1.38, 95% CI=1.19-1.60) mixed carcinosarcomas (SIR=2.77, 95% CI=1.43-4.84) and sarcomas (SIR=2.68, 95% CI=1.43-4.58), while bladder SPC risks were higher among women with high-grade endometrioid (SIR=1.42, 95% CI=1.01-1.95) or carcinosarcomas (SIR=2.48, 95% CI=1.36-4.16).	('Kidney SPC', 'Disease', (0, 10))	('elevated', 'PosReg', (22, 30))	('sarcomas', 'Disease', 'MESH:D012509', (310, 318))	('sarcomas', 'Phenotype', 'HP:0100242', (310, 318))	('sarcomas', 'Disease', (310, 318))	('carcinosarcomas', 'Disease', (106, 121))	('sarcomas', 'Disease', 'MESH:D012509', (155, 163))	('carcinosarcomas', 'Disease', (303, 318))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcomas', 'Disease', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (310, 317))	('low-grade', 'Var', (48, 57))	('women', 'Species', '9606', (37, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('women', 'Species', '9606', (236, 241))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcomas', 'Disease', (113, 121))	('carcinosarcomas', 'Disease', 'MESH:D002296', (106, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('carcinosarcomas', 'Disease', 'MESH:D002296', (303, 318))
433038	30718311	Women with high-grade endometrioid (SIR=1.87, 95% CI=1.02-3.13) and carcinosarcoma (SIR=3.87, 95% CI=1.42-8.43) had higher risks of AML.	('carcinosarcoma', 'Disease', 'MESH:D002296', (68, 82))	('Women', 'Species', '9606', (0, 5))	('AML', 'Disease', (132, 135))	('carcinosarcoma', 'Disease', (68, 82))	('AML', 'Phenotype', 'HP:0004808', (132, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('AML', 'Disease', 'MESH:D015470', (132, 135))	('high-grade', 'Var', (11, 21))
433040	30718311	For example, only women with low-grade endometrioid EC experienced a higher risk of SPC of the breast (SIR=1.05, 95% CI= 1.00-1.10) while women with carcinosarcoma had an elevated risk of myeloid and monocytic leukemia (SIR=3.03, 95% CI=1.22-6.24).	('SPC of the breast', 'Disease', (84, 101))	('leukemia', 'Phenotype', 'HP:0001909', (210, 218))	('EC', 'Phenotype', 'HP:0012114', (52, 54))	('women', 'Species', '9606', (18, 23))	('carcinosarcoma', 'Disease', 'MESH:D002296', (149, 163))	('low-grade', 'Var', (29, 38))	('myeloid and monocytic leukemia', 'Phenotype', 'HP:0005531', (188, 218))	('myeloid and monocytic leukemia', 'Disease', 'MESH:D007951', (188, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('women', 'Species', '9606', (138, 143))	('carcinosarcoma', 'Disease', (149, 163))
433049	30718311	For example, our observation that lung/bronchus and esophageal SPCs were significantly lower among women with low-grade endometrioid EC is likely related to the well-established link between cigarette smoking and decreased risk of EC, particularly of the endometrioid type.	('esophageal SPCs', 'Disease', (52, 67))	('EC', 'Phenotype', 'HP:0012114', (133, 135))	('lower', 'NegReg', (87, 92))	('low-grade', 'Var', (110, 119))	('women', 'Species', '9606', (99, 104))	('esophageal SPCs', 'Disease', 'MESH:D004941', (52, 67))	('EC', 'Phenotype', 'HP:0012114', (231, 233))
433050	30718311	Similarly, increased risks of colorectal SPC following low- and high-grade endometrioid and clear cell ECs could partially be related to obesity .	('colorectal SPC', 'Disease', (30, 44))	('EC', 'Phenotype', 'HP:0012114', (103, 105))	('clear cell ECs', 'Disease', (92, 106))	('low-', 'Var', (55, 59))	('obesity', 'Disease', 'MESH:D009765', (137, 144))	('obesity', 'Disease', (137, 144))	('colorectal SPC', 'Disease', 'MESH:D015179', (30, 44))	('obesity', 'Phenotype', 'HP:0001513', (137, 144))
433051	30718311	Heritable causes could also underlie links between EC and increased risk of subsequent cancers, particularly colorectal, ovarian, bladder, and small intestine cancers, as risk of these malignancies is elevated among individuals with Lynch syndrome, a familial disorder caused by mutations in DNA mismatch repair genes .	('colorectal', 'Disease', 'MESH:D015179', (109, 119))	('malignancies', 'Disease', 'MESH:D009369', (185, 197))	('malignancies', 'Disease', (185, 197))	('DNA mismatch repair genes', 'Gene', (292, 317))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', (159, 166))	('elevated', 'PosReg', (201, 209))	('mutations', 'Var', (279, 288))	('a familial disorder', 'Disease', (249, 268))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder', 'Disease', (130, 137))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('Lynch syndrome', 'Disease', (233, 247))	('cancers', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian', 'Disease', (121, 128))	('a familial disorder', 'Disease', 'MESH:D009358', (249, 268))	('colorectal', 'Disease', (109, 119))	('EC', 'Phenotype', 'HP:0012114', (51, 53))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('caused by', 'Reg', (269, 278))	('Lynch syndrome', 'Disease', 'MESH:D003123', (233, 247))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
433052	30718311	Although Lynch syndrome confers a high absolute risk of cancer development, the low frequency of highly penetrant mutations in Lynch syndrome genes likely accounts for a small proportion of SPCs .	('mutations', 'Var', (114, 123))	('Lynch syndrome', 'Disease', (9, 23))	('SPCs', 'Disease', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Lynch syndrome', 'Disease', 'MESH:D003123', (9, 23))	('Lynch syndrome', 'Disease', (127, 141))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('Lynch syndrome', 'Disease', 'MESH:D003123', (127, 141))
433063	30718311	While a recent meta-analysis did not show an increased odds of overall SPC among patients receiving cisplatin, there was a trend towards increased odds of secondary leukemias or myelodysplastic syndromes, in line with our observations of higher rates of several types of leukemias overall and for certain histological subtypes.	('leukemias', 'Disease', 'MESH:D007938', (165, 174))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (178, 203))	('leukemia', 'Phenotype', 'HP:0001909', (165, 173))	('leukemias', 'Disease', 'MESH:D007938', (271, 280))	('leukemia', 'Phenotype', 'HP:0001909', (271, 279))	('patients', 'Species', '9606', (81, 89))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (178, 203))	('leukemias', 'Disease', (165, 174))	('leukemias', 'Phenotype', 'HP:0001909', (165, 174))	('myelodysplastic syndromes', 'Disease', (178, 203))	('cisplatin', 'Var', (100, 109))	('leukemias', 'Phenotype', 'HP:0001909', (271, 280))	('leukemias', 'Disease', (271, 280))
433081	25973951	To clarify the role of HIF-1alpha in regulating tumor response to radiation therapy, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1alpha.	('tumor', 'Disease', (48, 53))	('deleted', 'Var', (182, 189))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (144, 163))	('HIF-1alpha', 'Gene', (190, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (144, 163))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mouse', 'Species', '10090', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('soft tissue sarcoma', 'Disease', (144, 163))
433082	25973951	Deletion of HIF-1alpha sensitized primary sarcomas to RT in vivo.	('sarcomas', 'Disease', 'MESH:D012509', (42, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('HIF-1alpha', 'Gene', (12, 22))	('sarcomas', 'Disease', (42, 50))	('sensitized', 'Reg', (23, 33))	('Deletion', 'Var', (0, 8))
433083	25973951	Moreover, cell lines derived from primary sarcomas lacking HIF-1alpha, or in which HIF-1alpha was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1alpha can promote radiation resistance in a cell autonomous manner.	('promote', 'PosReg', (190, 197))	('radiation resistance', 'CPA', (198, 218))	('sarcomas lacking HIF-1alpha', 'Disease', (42, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('knocked down', 'Var', (98, 110))	('clonogenic survival', 'CPA', (126, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('HIF-1alpha', 'Gene', (83, 93))	('sarcomas lacking HIF-1alpha', 'Disease', 'MESH:D001259', (42, 69))	('decreased', 'NegReg', (116, 125))
433090	25973951	A 2007 meta-analysis of all 61 published clinical trials to date revealed that 87% of the studies demonstrated that modifiers of tumor hypoxia during radiation therapy resulted in either improvement in loco-regional control, overall survival, or both.	('improvement', 'PosReg', (187, 198))	('loco-regional control', 'CPA', (202, 223))	('overall survival', 'CPA', (225, 241))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('modifiers', 'Var', (116, 125))	('tumor hypoxia', 'Disease', (129, 142))	('tumor hypoxia', 'Disease', 'MESH:D000860', (129, 142))
433100	25973951	Previous studies investigating the role of HIF-1alpha in tumor response to radiation therapy using transplanted tumor model systems suggest that HIF-1alpha may both promote radiation resistance and radiation sensitivity.	('HIF-1alpha', 'Var', (145, 155))	('HIF-1alpha in tumor', 'Disease', 'MESH:D009369', (43, 62))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('radiation sensitivity', 'CPA', (198, 219))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('promote', 'PosReg', (165, 172))	('HIF-1alpha in tumor', 'Disease', (43, 62))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (57, 62))	('radiation resistance', 'CPA', (173, 193))
433101	25973951	For example, HIF-1alpha can sensitize tumor cells to radiation by promoting ATP metabolism, proliferation, and p53 activation, but HIF-1alpha can also cause resistance to radiation therapy by promoting endothelial cell survival.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('endothelial cell survival', 'CPA', (202, 227))	('promoting', 'PosReg', (66, 75))	('activation', 'PosReg', (115, 125))	('promoting', 'PosReg', (192, 201))	('p53', 'Gene', '22060', (111, 114))	('HIF-1alpha', 'Var', (131, 141))	('ATP', 'Chemical', 'MESH:D000255', (76, 79))	('p53', 'Gene', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cause', 'Reg', (151, 156))	('ATP metabolism', 'CPA', (76, 90))	('proliferation', 'CPA', (92, 105))
433104	25973951	We show that deletion of HIF-1alpha in this sarcoma model sensitizes tumor cells to radiation therapy in a cell-autonomous manner.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('tumor', 'Disease', (69, 74))	('deletion', 'Var', (13, 21))	('sarcoma', 'Disease', (44, 51))	('sensitizes', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('HIF-1alpha', 'Gene', (25, 35))
433115	25973951	Consistent with previous findings from our group, sarcomas derived from adult skeletal muscle satellite cells with activation of oncogenic RAS and deletion of p53 fall in a spectrum of histological subtypes ranging from undifferentiated pleomorphic sarcoma (UPS, Figure 2B) to RMS (Figure 2C).	('activation', 'PosReg', (115, 125))	('undifferentiated pleomorphic sarcoma', 'Disease', (220, 256))	('p53', 'Gene', (159, 162))	('sarcomas', 'Disease', 'MESH:D012509', (50, 58))	('p53', 'Gene', '22060', (159, 162))	('oncogenic', 'Protein', (129, 138))	('deletion', 'Var', (147, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('fall', 'Phenotype', 'HP:0002527', (163, 167))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (220, 256))	('sarcomas', 'Disease', (50, 58))	('RMS', 'Disease', (277, 280))	('RMS', 'Phenotype', 'HP:0002859', (277, 280))
433123	25973951	Sarcoma cells from tumors from P7NP and P7NPH1 mice were dissociated and cultured to deplete stromal cells.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('Sarcoma', 'Disease', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('P7NP', 'Var', (31, 35))	('P7NPH1', 'Var', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mice', 'Species', '10090', (47, 51))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
433128	25973951	As HIF-1alpha was ablated at the start of tumorigenesis, this could potentially modify tumor subtype, such as tumor differentiation status.	('HIF-1alpha', 'Gene', (3, 13))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('ablated', 'Var', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('modify', 'Reg', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
433133	25973951	Both tumors from P7NP and P7NPH1 mice ranged from containing low hypoxia to high hypoxia content (Figure 3I-L).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('P7NP', 'Var', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('P7NPH1', 'Var', (26, 32))	('hypoxia to high hypoxia', 'Disease', 'MESH:D000860', (65, 88))	('hypoxia to high hypoxia', 'Disease', (65, 88))	('mice', 'Species', '10090', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
433134	25973951	Furthermore, there was no difference between the range of hypoxia content between tumors from P7NP and P7NPH1 mice (Figure 3M).	('P7NPH1', 'Var', (103, 109))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('hypoxia', 'Disease', (58, 65))	('mice', 'Species', '10090', (110, 114))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('P7NP', 'Var', (94, 98))
433135	25973951	This suggests that the tumor hypoxic content varies, and the loss of HIF-1alpha does not alter the presence of tumor hypoxia in this mouse model of primary soft tissue sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('HIF-1alpha', 'Gene', (69, 79))	('tumor hypoxic', 'Disease', 'MESH:D009369', (23, 36))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (156, 175))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor hypoxic', 'Disease', (23, 36))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (156, 175))	('tumor hypoxia', 'Disease', 'MESH:D000860', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor hypoxia', 'Disease', (111, 124))	('soft tissue sarcoma', 'Disease', (156, 175))	('mouse', 'Species', '10090', (133, 138))	('loss', 'Var', (61, 65))
433136	25973951	Similar to our previous results in which deleting HIF-1alpha did not affect tumor initiation or growth in primary soft tissue sarcomas initiated by expression of KrasG12D and p53 deletion, we did not observe a significant difference in time to tumor initiation after 4-OHT injection (Figure 4A) or tumor growth (Figure 4B) between sarcomas in P7NP and P7NPH1 mice.	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (114, 133))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (114, 134))	('tumor initiation', 'Disease', (244, 260))	('tumor', 'Disease', (76, 81))	('soft tissue sarcoma', 'Disease', (114, 133))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', (298, 303))	('tumor initiation', 'Disease', 'MESH:D009369', (76, 92))	('sarcomas', 'Disease', (126, 134))	('sarcomas', 'Disease', 'MESH:D012509', (331, 339))	('sarcomas', 'Phenotype', 'HP:0100242', (331, 339))	('tumor initiation', 'Disease', (76, 92))	('sarcomas', 'Disease', (331, 339))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('p53', 'Gene', (175, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('p53', 'Gene', '22060', (175, 178))	('G12D', 'Mutation', 'rs121913529', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('HIF-1alpha', 'Gene', (50, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (331, 338))	('deletion', 'Var', (179, 187))	('mice', 'Species', '10090', (359, 363))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('4-OHT', 'Chemical', 'MESH:C032278', (267, 272))	('tumor', 'Disease', (244, 249))	('deleting', 'Var', (41, 49))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (114, 133))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor initiation', 'Disease', 'MESH:D009369', (244, 260))
433137	25973951	To investigate the impact of deleting HIF-1alpha in tumor cells on radiation response of primary sarcomas, we generated a separate cohort of sarcomas in P7NP and P7NPH1 littermate mice.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('deleting', 'Var', (29, 37))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('sarcomas', 'Disease', 'MESH:D012509', (141, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (141, 149))	('mice', 'Species', '10090', (180, 184))	('sarcomas', 'Disease', (97, 105))	('HIF-1alpha in tumor', 'Disease', (38, 57))	('HIF-1alpha in tumor', 'Disease', 'MESH:D009369', (38, 57))
433140	25973951	P7NP sarcomas (n=20) recurred between 2-50 days after the last dose of irradiation; in contrast, P7NPH1 sarcomas (n=22) did not start to recur until 40 days after irradiation with 13.6% surviving to 180 days without any evidence of tumor recurrence (Figure 4C).	('sarcomas', 'Disease', 'MESH:D012509', (104, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('P7NP', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('sarcomas', 'Disease', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('tumor', 'Disease', (232, 237))	('sarcomas', 'Disease', (5, 13))
433141	25973951	Taken together, the data indicate that although HIF-1alpha has diverse targets that may play opposing roles in response to radiation therapy, the overall effect of deleting HIF-1alpha in vivo in this mouse model of soft tissue sarcoma is radiosensitization.	('radiosensitization', 'CPA', (238, 256))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (215, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (215, 234))	('HIF-1alpha', 'Gene', (173, 183))	('mouse', 'Species', '10090', (200, 205))	('deleting', 'Var', (164, 172))	('soft tissue sarcoma', 'Disease', (215, 234))
433142	25973951	The radiosensitization phenotype in P7NPH1 sarcomas in vivo may be dependent on tumor cell HIF-1alpha signaling within the tumor cells themselves (cell-autonomous) and/or through extracellular remodeling of tumor stroma (non-cell-autonomous).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (123, 128))	('radiosensitization', 'MPA', (4, 22))	('P7NPH1', 'Var', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor stroma', 'Disease', (207, 219))	('tumor', 'Disease', (80, 85))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('tumor stroma', 'Disease', 'MESH:D009369', (207, 219))	('tumor', 'Disease', (207, 212))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('sarcomas', 'Disease', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('dependent', 'Reg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('HIF-1alpha signaling', 'MPA', (91, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
433144	25973951	After serial passaging the sarcoma cells to deplete stromal cells, we confirmed deletion of HIF-1alpha in the sarcoma cells by PCR as in Figure 3A.	('sarcoma', 'Disease', (27, 34))	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('deletion', 'Var', (80, 88))	('sarcoma', 'Disease', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('HIF-1alpha', 'Gene', (92, 102))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))
433146	25973951	There was no difference in sarcoma cell proliferation in vitro between the cell lines from P7NP and P7NPH1 mice (Figure 4D).	('sarcoma', 'Disease', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('P7NP', 'Var', (91, 95))	('P7NPH1', 'Var', (100, 106))	('mice', 'Species', '10090', (107, 111))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))
433150	25973951	When these sarcoma cells were exposed to increasing doses of radiation under normoxia, at all doses of radiation tested, P7NP sarcoma cells were more capable of forming colonies than P7NPH1 sarcoma cells (Figure 4E).	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcoma', 'Disease', (11, 18))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcoma', 'Disease', (190, 197))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('P7NP', 'Var', (121, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('forming colonies', 'CPA', (161, 177))	('sarcoma', 'Disease', 'MESH:D012509', (11, 18))	('sarcoma', 'Disease', (126, 133))
433158	25973951	Both P7NP and P7NPH1 tumor cells had similar basal tail lengths without irradiation, and irradiation induced an increase in tail length (Figure 5A).	('tail length', 'MPA', (124, 135))	('tumor', 'Disease', (21, 26))	('P7NPH1', 'Var', (14, 20))	('increase', 'PosReg', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('P7NP', 'Var', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
433165	25973951	Similar to CellROX measurements of total intracellular ROS after irradiation, P7NP and P7NPH1 cells have similar levels of mitochondrial superoxide generation at 2, 24, and 72 hours after irradiation (Figure 5C).	('superoxide', 'Chemical', 'MESH:D013481', (137, 147))	('mitochondrial superoxide generation', 'MPA', (123, 158))	('P7NP', 'Var', (78, 82))	('ROS', 'Chemical', 'MESH:D017382', (55, 58))
433172	25973951	However, protein carbonylation was resolving for some of the cell lines by 72 hours after irradiation in both P7NP and P7NPH1 cells as indicated by a decrease in carbonyl group staining intensity in the first (P7NP tumor #1) and fourth (P7NPH1 tumor #2) panels at 72 hours.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('decrease', 'NegReg', (150, 158))	('protein carbonylation', 'MPA', (9, 30))	('carbonyl group staining intensity', 'MPA', (162, 195))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('P7NPH1', 'Var', (119, 125))
433173	25973951	Together, these results indicate that P7NP and P7NPH1 sarcoma cells accumulate similar levels of ROS and also similar levels of ROS-induced protein damage after irradiation.	('ROS', 'MPA', (97, 100))	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('protein damage', 'Disease', 'MESH:D004194', (140, 154))	('ROS', 'Chemical', 'MESH:D017382', (128, 131))	('P7NP', 'Var', (38, 42))	('sarcoma', 'Disease', (54, 61))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('protein damage', 'Disease', (140, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))
433178	25973951	Increased accumulation of LC3A/B-II after chloroquine treatment (Figure 6) indicated that both P7NP and P7NPH1 cells up-regulated autophagic flux in response to radiation and there was no discernable difference in functional autophagic flux between P7NP and P7NPH1 cells.	('response to radiation', 'MPA', (149, 170))	('P7NP', 'Var', (95, 99))	('P7NPH1', 'Var', (104, 110))	('up-regulated', 'PosReg', (117, 129))	('LC3A/B-II', 'Protein', (26, 35))	('autophagic flux', 'CPA', (130, 145))	('chloroquine', 'Chemical', 'MESH:D002738', (42, 53))	('Increased accumulation of LC3A', 'Phenotype', 'HP:0032428', (0, 30))
433182	25973951	This showed that while P7NP cells had increased lactate accumulation 24 hours after 6 Gy irradiation, this accumulation was not evident in P7NPH1 cells.	('P7NP', 'Var', (23, 27))	('lactate accumulation', 'MPA', (48, 68))	('increased', 'PosReg', (38, 47))	('lactate', 'Chemical', 'MESH:D019344', (48, 55))	('increased lactate accumulation', 'Phenotype', 'HP:0003128', (38, 68))
433184	25973951	This showed that while extracellular lactate concentration was higher for P7NP cells when compared to P7NPH1 cells at baseline and 2 hours after irradiation, both P7NP and P7NPH1 cells have increased extracellular lactate by 24 hours.	('P7NP', 'Var', (74, 78))	('P7NPH1', 'Var', (172, 178))	('extracellular lactate concentration', 'MPA', (23, 58))	('lactate', 'Chemical', 'MESH:D019344', (214, 221))	('lactate', 'Chemical', 'MESH:D019344', (37, 44))	('increased extracellular lactate', 'Phenotype', 'HP:0002151', (190, 221))	('increased', 'PosReg', (190, 199))	('higher', 'PosReg', (63, 69))	('P7NP', 'Var', (163, 167))	('extracellular lactate', 'MPA', (200, 221))
433190	25973951	These experiments showed that at baseline, OCR measurements were similar between P7NP and P7NPH1 sarcoma cells (Figure 7C).	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('P7NP', 'Var', (81, 85))	('P7NPH1', 'Var', (90, 96))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))
433192	25973951	The OCR results suggest that at 24 hours after irradiation, although the baseline OCR was similar between P7NP and P7NPH1 cells, P7NPH1 cells may have increased flux or accumulation of ETC substrates such as NADH or succinate that result in increased maximal oxygen consumption and reserve capacity after FCCP-mediated ETC and ATP synthase dissociation.	('increased', 'PosReg', (151, 160))	('increased', 'PosReg', (241, 250))	('succinate', 'Chemical', 'MESH:D019802', (216, 225))	('FCCP', 'Chemical', 'MESH:D002259', (305, 309))	('oxygen', 'Chemical', 'MESH:D010100', (259, 265))	('NADH', 'Chemical', 'MESH:D009243', (208, 212))	('accumulation', 'PosReg', (169, 181))	('maximal oxygen consumption', 'MPA', (251, 277))	('P7NPH1', 'Var', (129, 135))	('reserve capacity', 'MPA', (282, 298))	('flux', 'MPA', (161, 165))	('ATP', 'Chemical', 'MESH:D000255', (327, 330))
433211	25973951	In this study, we generated a novel primary mouse model of soft tissue sarcoma expressing oncogenic NRAS with p53 deletion that resembles human RMS and UPS.	('p53', 'Gene', (110, 113))	('mouse', 'Species', '10090', (44, 49))	('soft tissue sarcoma', 'Disease', (59, 78))	('human', 'Species', '9606', (138, 143))	('RMS', 'Phenotype', 'HP:0002859', (144, 147))	('p53', 'Gene', '22060', (110, 113))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (59, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (59, 78))	('deletion', 'Var', (114, 122))
433212	25973951	Other studies including those from our group have shown that by introducing driver mutations in PAX7-expressing adult skeletal muscle stem cells, primary soft tissue sarcomas develop in a continuum of RMS and UPS, suggesting that these entities may be more similar than previously anticipated.	('mutations', 'Var', (83, 92))	('sarcomas', 'Disease', 'MESH:D012509', (166, 174))	('develop', 'Reg', (175, 182))	('PAX7', 'Gene', (96, 100))	('RMS', 'Phenotype', 'HP:0002859', (201, 204))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (154, 173))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (154, 173))	('sarcomas', 'Disease', (166, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (166, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (154, 174))	('soft tissue sarcoma', 'Disease', (154, 173))	('PAX7', 'Gene', '18509', (96, 100))
433213	25973951	We then deleted HIF-1alpha in the tumor cells of these sarcomas at the time of sarcoma initiation.	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('tumor', 'Disease', (34, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcomas', 'Disease', (55, 63))	('sarcoma initiation', 'Disease', (79, 97))	('HIF-1alpha', 'Gene', (16, 26))	('deleted', 'Var', (8, 15))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('sarcoma initiation', 'Disease', 'MESH:D012509', (79, 97))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))
433214	25973951	Complete deletion of HIF-1alpha was confirmed by PCR for recombination of the genomic Hif-1alphaFL DNA, qRT-PCR for the exon 2-containing Hif-1alpha transcript, and by Western Blot for HIF-1alpha protein in stroma-depleted tumor cells.	('HIF-1alpha', 'Gene', (21, 31))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('deletion', 'Var', (9, 17))	('Hif-1alphaFL', 'Gene', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (223, 228))
433215	25973951	Deletion of HIF-1alpha in sarcomas in P7NP mice, did not affect the timing of sarcomagenesis or sarcoma growth kinetics.	('mice', 'Species', '10090', (43, 47))	('sarcomagenesis or sarcoma', 'Disease', 'MESH:D012509', (78, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('HIF-1alpha in sarcomas', 'Disease', 'MESH:D012509', (12, 34))	('sarcomagenesis or sarcoma', 'Disease', (78, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('HIF-1alpha in sarcomas', 'Disease', (12, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('Deletion', 'Var', (0, 8))
433218	25973951	Moreover, sarcoma cells lacking HIF-1alpha by either genomic ablation or shRNA knockdown were also sensitized to radiation in vitro by clonogenic assays.	('sensitized', 'Reg', (99, 109))	('sarcoma', 'Disease', (10, 17))	('HIF-1alpha', 'Protein', (32, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('lacking', 'NegReg', (24, 31))	('shRNA', 'Gene', (73, 78))	('knockdown', 'Var', (79, 88))	('sarcoma', 'Disease', 'MESH:D012509', (10, 17))
433221	25973951	However, when we examined these pathways in sarcoma cells with an intact or deleted HIF-1alpha, no significant differences in these pathways were observed after irradiation in 21% oxygen in vitro.	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('HIF-1alpha', 'Gene', (84, 94))	('oxygen', 'Chemical', 'MESH:D010100', (180, 186))	('deleted', 'Var', (76, 83))	('sarcoma', 'Disease', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))
433225	25973951	Furthermore, this result was recapitulated by irradiating sarcoma cells with successful Hif-1alpha knockdown by shRNA.	('knockdown', 'Var', (99, 108))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('Hif-1alpha', 'Gene', (88, 98))	('sarcoma', 'Disease', (58, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
433227	25973951	In summary, we have established a novel mouse model of soft tissue sarcoma in which deletion of HIF-1alpha increases the sensitivity of tumors to fractionated radiation therapy in vivo.	('tumors', 'Disease', (136, 142))	('HIF-1alpha', 'Gene', (96, 106))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (55, 74))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('deletion', 'Var', (84, 92))	('increases', 'PosReg', (107, 116))	('sensitivity', 'MPA', (121, 132))	('soft tissue sarcoma', 'Disease', (55, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (55, 74))	('mouse', 'Species', '10090', (40, 45))
433228	25973951	This is the first study to show that deletion of HIF-1alpha increased the sensitivity of cancer to radiation therapy in an autochthonous tumor model.	('HIF-1alpha', 'Gene', (49, 59))	('tumor', 'Disease', (137, 142))	('deletion', 'Var', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('increased the sensitivity of cancer to radiation therapy', 'Phenotype', 'HP:0011133', (60, 116))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('increased', 'PosReg', (60, 69))	('sensitivity', 'MPA', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
433353	23589762	Despite initial R0-resection in 97% of the cases (82.4% of patients treated at our institution, 18.4% of patients treated externally), local relapse within the observation period was seen in 21.7% of the patients.	('patients', 'Species', '9606', (204, 212))	('patients', 'Species', '9606', (105, 113))	('local relapse', 'CPA', (135, 148))	('patients', 'Species', '9606', (59, 67))	('R0-resection', 'Var', (16, 28))
433440	21695701	The five trans-femoral amputation patients in that prior series had a mean TESS of 63.7 +- 9.1, worse than our TFR patients, but not to a degree that bears strong clinical meaning.	('TESS', 'MPA', (75, 79))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (34, 42))	('trans-femoral amputation', 'Var', (9, 33))
433524	30393581	The subset of mature CIK co-expressing CD3 and CD56 molecules (CD3+CD56+) was present with a median of 35% (range 28 - 60%), while 85% (range 58 - 95%) of CD3+ cells were also CD8+ (Fig.	('CD8', 'Gene', '925', (176, 179))	('CD56', 'Gene', (47, 51))	('CD56', 'Gene', (67, 71))	('CIK', 'Chemical', '-', (21, 24))	('CD3', 'Var', (39, 42))	('CD56', 'Gene', '4684', (47, 51))	('CD8', 'Gene', (176, 179))	('CD56', 'Gene', '4684', (67, 71))
433557	30393581	Tumor-associated defects in the HLA-antigen presentation may occur at various levels of the intracellular HLA machinery affecting antigen processing/loading molecules, HLA-heavy chains or beta2microglobulin.	('beta2microglobulin', 'Gene', '567', (188, 206))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('HLA-antigen presentation', 'MPA', (32, 56))	('antigen processing/loading molecules', 'MPA', (130, 166))	('HLA-heavy', 'Protein', (168, 177))	('occur', 'Reg', (61, 66))	('defects', 'Var', (17, 24))	('beta2microglobulin', 'Gene', (188, 206))
433561	30393581	Based on our preclinical findings, we could imagine that CIK may contribute to the elimination of residual sCSC spared by other therapies, contributing to reduce the risk of later relapse.	('reduce', 'NegReg', (155, 161))	('CIK', 'Chemical', '-', (57, 60))	('residual sCSC', 'Disease', (98, 111))	('CIK', 'Var', (57, 60))
433584	30393581	eGFP.Wpre (LV-Oct4.eGFP) was obtained by replacing the expression cassette hPGK.eGFP into LV-PGK.eGFP with the hOct4-eGFP, cleaved from phOct4-eGFP vector, by insertion into SalI and XhoI restriction enzyme sites.	('hOct4', 'Gene', (111, 116))	('hOct4', 'Gene', '5460', (137, 142))	('LV-Oct4.eGFP', 'Gene', (11, 23))	('LV-Oct4.eGFP', 'Gene', '5460', (11, 23))	('hOct4', 'Gene', '5460', (111, 116))	('hPGK.eGFP', 'Var', (75, 84))	('hOct4', 'Gene', (137, 142))
433591	30393581	Limiting dilution assay was performed with fractions of eGFP+ (90%) and eGFP- (96%) sarcoma cells obtained by Flow Activated Cell Sorting (MoFlow, Beckman Coulter s.r.l.)	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('eGFP-', 'Var', (72, 77))	('sarcoma', 'Disease', (84, 91))
433653	29610659	BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom.	('BMH4-983956', 'Var', (19, 30))	('Cancer', 'Disease', 'MESH:D009369', (37, 43))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Cancer', 'Disease', (37, 43))
433696	29610659	Overall, the chance of having an event (relapse, death or second malignancy) was increased by 42% (HR 1.42, 95% CI 1.13-1.77, p = 0.002) in the CCLG group compared to the GPOH group.	('CCLG', 'Chemical', '-', (144, 148))	('malignancy', 'Disease', 'MESH:D009369', (65, 75))	('CCLG', 'Var', (144, 148))	('malignancy', 'Disease', (65, 75))	('death', 'Disease', 'MESH:D003643', (49, 54))	('death', 'Disease', (49, 54))	('GPOH', 'Chemical', '-', (171, 175))
433720	29610659	There was a 68% increase in the death rate among CCLG patients compared to those in GPOH, after allowing for local therapy and other factors (Table 5, p = 0.05).	('death', 'Disease', (32, 37))	('CCLG', 'Chemical', '-', (49, 53))	('patients', 'Species', '9606', (54, 62))	('CCLG', 'Var', (49, 53))	('GPOH', 'Chemical', '-', (84, 88))	('death', 'Disease', 'MESH:D003643', (32, 37))
433758	28524158	Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma Sarcomas are rare and heterogeneous cancers.	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (97, 123))	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('Sarcomas', 'Disease', (124, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('DICER1', 'Gene', '23405', (14, 20))	('sarcomas', 'Disease', (24, 32))	('embryonal rhabdomyosarcoma', 'Disease', (97, 123))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('DICER1', 'Gene', (14, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('Sarcomas', 'Disease', 'MESH:D012509', (124, 132))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mutations', 'Var', (69, 78))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (97, 123))	('Sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('DICER1', 'Gene', '23405', (62, 68))	('DICER1', 'Gene', (62, 68))
433759	28524158	We assessed the contribution of DICER1 mutations to sarcoma development.	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('sarcoma', 'Disease', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('mutations', 'Var', (39, 48))	('DICER1', 'Gene', (32, 38))	('DICER1', 'Gene', '23405', (32, 38))
433761	28524158	The RNase III domains were Sanger sequenced in six additional sarcomas to identify hotspot DICER1 variants.	('sarcomas', 'Disease', 'MESH:D012509', (62, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('RNase III', 'Gene', '29102', (4, 13))	('RNase III', 'Gene', (4, 13))	('sarcomas', 'Disease', (62, 70))	('DICER1', 'Gene', (91, 97))	('DICER1', 'Gene', '23405', (91, 97))	('variants', 'Var', (98, 106))
433764	28524158	We identified nine other DICER1 variants.	('variants', 'Var', (32, 40))	('DICER1', 'Gene', (25, 31))	('DICER1', 'Gene', '23405', (25, 31))
433765	28524158	One somatic variant (p.L1070V) identified in a pleomorphic sarcoma and one germline variant (c.2257-7A>G) may be pathogenic, but the others are considered to be benign.	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('c.2257-7A>G', 'Mutation', 'c.2257-7A>G', (93, 104))	('p.L1070V', 'Mutation', 'rs1434023676', (21, 29))	('p.L1070V', 'Var', (21, 29))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (47, 66))	('pathogenic', 'Reg', (113, 123))	('pleomorphic sarcoma', 'Disease', (47, 66))
433766	28524158	We show that deleterious DICER1 mutations underlie the genetic basis of only a small fraction of sarcomas, in particular ERMS of the urogenital tract.	('DICER1', 'Gene', (25, 31))	('DICER1', 'Gene', '23405', (25, 31))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('ERMS', 'Phenotype', 'HP:0006743', (121, 125))	('mutations', 'Var', (32, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (97, 105))	('ERMS of the urogenital tract', 'Disease', (121, 149))
433769	28524158	However, a small number of cases manifest in individuals with germline mutations in genes associated with cancer predisposition syndromes, such as TP53, NF1, RB1, APC, RECQL4, and HRAS.	('RECQL4', 'Gene', (168, 174))	('TP53', 'Gene', (147, 151))	('RB1', 'Gene', '5925', (158, 161))	('HRAS', 'Gene', '3265', (180, 184))	('NF1', 'Gene', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('NF1', 'Gene', '4763', (153, 156))	('RECQL4', 'Gene', '9401', (168, 174))	('cancer', 'Disease', (106, 112))	('HRAS', 'Gene', (180, 184))	('APC', 'Disease', 'MESH:D011125', (163, 166))	('germline mutations', 'Var', (62, 80))	('RB1', 'Gene', (158, 161))	('TP53', 'Gene', '7157', (147, 151))	('APC', 'Disease', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
433771	28524158	Along with translocations, intra-exonic somatic mutations may also contribute to sarcoma development.	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('intra-exonic somatic mutations', 'Var', (27, 57))	('contribute', 'Reg', (67, 77))
433775	28524158	further substantiated the association by reporting sarcomas in germline DICER1 mutation carriers.	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('DICER1', 'Gene', (72, 78))	('DICER1', 'Gene', '23405', (72, 78))	('sarcomas', 'Disease', (51, 59))	('mutation', 'Var', (79, 87))
433779	28524158	In contrast, an Askin/Ewing family tumour that arose in a 13-year-old germline DICER1 mutation carrier (for more details, see) was not found to harbour a characteristic RNase IIIb hotspot mutation (Foulkes, unpublished data).	('RNase III', 'Gene', '29102', (169, 178))	('DICER1', 'Gene', (79, 85))	('Ewing family tumour', 'Disease', 'MESH:C563168', (22, 41))	('DICER1', 'Gene', '23405', (79, 85))	('Ewing family tumour', 'Disease', (22, 41))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('mutation', 'Var', (86, 94))	('RNase III', 'Gene', (169, 178))
433780	28524158	There are also several reports of somatic DICER1 RNase IIIb hotspot mutations in uterine carcinosarcoma (Table 1 and Supplementary Table S1c).	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('DICER1', 'Gene', '23405', (42, 48))	('carcinosarcoma', 'Disease', (89, 103))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (81, 103))	('carcinosarcoma', 'Disease', 'MESH:D002296', (89, 103))	('mutations', 'Var', (68, 77))	('RNase III', 'Gene', '29102', (49, 58))	('DICER1', 'Gene', (42, 48))	('RNase III', 'Gene', (49, 58))
433781	28524158	More recently, DICER1 mutations have been strongly implicated in the pathogenesis of embryonal rhabdomyosarcoma (ERMS) of the uterine cervix (cERMS) the ovary, and anaplastic sarcoma of the kidney (D1ASK).	('ERMS', 'Phenotype', 'HP:0006743', (143, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (175, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (175, 196))	('uterine cervix', 'Phenotype', 'HP:0030160', (126, 140))	('sarcoma of the kidney', 'Disease', (175, 196))	('DICER1', 'Gene', (15, 21))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (85, 111))	('embryonal rhabdomyosarcoma', 'Disease', (85, 111))	('mutations', 'Var', (22, 31))	('ERMS', 'Phenotype', 'HP:0006743', (113, 117))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (95, 111))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (85, 111))	('DICER1', 'Gene', '23405', (15, 21))	('implicated', 'Reg', (51, 61))
433782	28524158	Characteristic hotspot DICER1 RNase IIIb mutations were identified in the three aforementioned lesions.	('mutations', 'Var', (41, 50))	('DICER1', 'Gene', '23405', (23, 29))	('RNase III', 'Gene', (30, 39))	('RNase III', 'Gene', '29102', (30, 39))	('DICER1', 'Gene', (23, 29))
433783	28524158	Biallelic somatic DICER1 mutations were similarly detected in a case of adult-onset cERMS.	('ERMS', 'Phenotype', 'HP:0006743', (85, 89))	('mutations', 'Var', (25, 34))	('adult-onset cERMS', 'Disease', (72, 89))	('DICER1', 'Gene', (18, 24))	('DICER1', 'Gene', '23405', (18, 24))	('detected', 'Reg', (50, 58))
433784	28524158	Despite the above evidence, the true contribution of DICER1 mutations to sarcomas is not yet known.	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('DICER1', 'Gene', (53, 59))	('sarcomas', 'Disease', (73, 81))	('DICER1', 'Gene', '23405', (53, 59))	('mutations', 'Var', (60, 69))
433785	28524158	In this study, we aimed to uncover the contribution of DICER1 mutations to a convenience sample of 61 predominantly adult-onset sarcomas of various subtypes.	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('DICER1', 'Gene', (55, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomas', 'Disease', (128, 136))	('DICER1', 'Gene', '23405', (55, 61))	('mutations', 'Var', (62, 71))
433794	28524158	We screened for deletions or duplications of DICER1 in the germline of 53 patients from whom good quality non-tumour DNA was available (cases 1-52 and 56) using an in-house multiplex ligation-dependent probe amplification (MLPA) assay, as described previously.	('deletions', 'Var', (16, 25))	('DICER1', 'Gene', (45, 51))	('DICER1', 'Gene', '23405', (45, 51))	('duplications', 'Var', (29, 41))	('patients', 'Species', '9606', (74, 82))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
433796	28524158	We identified multiple DICER1 variants in an ultimately fatal case of abdominal ERMS that arose in a 23-year-old female following a short history of abdominal pain (case 1) (Figure 1 and Supplementary Tables S2a and S3).	('DICER1', 'Gene', '23405', (23, 29))	('variants', 'Var', (30, 38))	('pain', 'Phenotype', 'HP:0012531', (159, 163))	('ERMS', 'Phenotype', 'HP:0006743', (80, 84))	('abdominal pain', 'Phenotype', 'HP:0002027', (149, 163))	('abdominal pain', 'Disease', (149, 163))	('DICER1', 'Gene', (23, 29))	('abdominal ERMS', 'Disease', (70, 84))	('abdominal pain', 'Disease', 'MESH:D015746', (149, 163))
433797	28524158	The ERMS, obtained following chemo- and radiotherapy (see Figure 1), harboured a DICER1 RNase IIIb hotspot mutation in exon 25 (c.5439G>T; p.E1813D), which co-occurred with a predicted-truncating DICER1 mutation in exon 11 (c.1785_1786insA; p.T596Nfs*3), both of which were not detected by regular sequencing techniques in the patient's germline.	('DICER1', 'Gene', '23405', (196, 202))	('c.1785_1786insA; p.T596Nfs*3', 'Var', (224, 252))	('RNase III', 'Gene', '29102', (88, 97))	('patient', 'Species', '9606', (327, 334))	('RNase III', 'Gene', (88, 97))	('c.5439G>T; p.E1813D', 'Var', (128, 147))	('p.E1813D', 'Var', (139, 147))	('ERMS', 'Phenotype', 'HP:0006743', (4, 8))	('p.T596Nfs*3', 'Var', (241, 252))	('p.E1813D', 'Mutation', 'p.E1813D', (139, 147))	('p.T596Nfs*3', 'Mutation', 'p.T596NfsX3', (241, 252))	('DICER1', 'Gene', (81, 87))	('DICER1', 'Gene', '23405', (81, 87))	('c.5439G>T', 'Mutation', 'c.5439G>T', (128, 137))	('c.1785_1786insA', 'Mutation', 'c.1785_1786insA', (224, 239))	('DICER1', 'Gene', (196, 202))
433798	28524158	The patient carried an additional germline insertion (c.2040+53_2040+54insT) in intron 12 of DICER1 (Figure 1C).	('c.2040+53_2040+54insT', 'Mutation', 'rs397807177', (54, 75))	('c.2040+53_2040+54insT', 'Var', (54, 75))	('DICER1', 'Gene', (93, 99))	('patient', 'Species', '9606', (4, 11))	('DICER1', 'Gene', '23405', (93, 99))
433799	28524158	Given the young age of sarcoma onset, we also screened the patient's germline and tumour samples for TP53 mutations and did not identify any pathogenic TP53 alterations (Supplementary Table S5).	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', '7157', (101, 105))	('patient', 'Species', '9606', (59, 66))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('TP53', 'Gene', '7157', (152, 156))	('tumour', 'Disease', (82, 88))	('sarcoma onset', 'Disease', 'MESH:D012509', (23, 36))	('TP53', 'Gene', (101, 105))	('TP53', 'Gene', (152, 156))	('mutations', 'Var', (106, 115))	('sarcoma onset', 'Disease', (23, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))
433800	28524158	Further characterisation of the DICER1 mutations revealed that the exon 11 mutation was in trans with both the intron 12 and exon 25 mutations.	('DICER1', 'Gene', (32, 38))	('DICER1', 'Gene', '23405', (32, 38))	('mutations', 'Var', (39, 48))
433801	28524158	Cloning of a cDNA fragment encompassing all three mutations revealed that the transcript bearing the exon 11, c.1785_1786insA insertion was almost always degraded by nonsense-mediated decay as only 3 of 48 sequenced clones expressed the mutation.	('c.1785_1786insA', 'Var', (110, 125))	('degraded', 'NegReg', (154, 162))	('transcript', 'MPA', (78, 88))	('c.1785_1786insA', 'Mutation', 'c.1785_1786insA', (110, 125))
433803	28524158	Because of DICER1's involvement in the above-mentioned ERMS, we sequenced a further 72 sarcomas (60 sarcomas of various subtypes and 12 Ewing sarcomas; Supplementary Tables S2a and S2b) and an additional 9 DICER1 variants were identified (Supplementary Table S3).	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('DICER1', 'Gene', (206, 212))	('sarcomas', 'Disease', 'MESH:D012509', (142, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcomas', 'Disease', (142, 150))	('sarcomas', 'Disease', (87, 95))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('involvement', 'Reg', (20, 31))	('sarcomas', 'Disease', 'MESH:D012509', (100, 108))	('DICER1', 'Gene', '23405', (11, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('sarcomas', 'Disease', (100, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (136, 150))	('DICER1', 'Gene', (11, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Ewing sarcomas', 'Disease', (136, 150))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (136, 150))	('variants', 'Var', (213, 221))	('ERMS', 'Phenotype', 'HP:0006743', (55, 59))	('DICER1', 'Gene', '23405', (206, 212))
433804	28524158	One somatic variant, c.3208C>G (p.L1070V), identified in a pleomorphic sarcoma with giant cells (case 46), is predicted to be damaging by both PolyPhen2 and SIFT with a score of 1 and 0.01, respectively.	('pleomorphic sarcoma', 'Disease', (59, 78))	('SIFT', 'Disease', 'None', (157, 161))	('c.3208C>G', 'Mutation', 'rs1434023676', (21, 30))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (59, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('SIFT', 'Disease', (157, 161))	('c.3208C>G', 'Var', (21, 30))	('p.L1070V', 'Mutation', 'rs1434023676', (32, 40))
433806	28524158	An intronic DICER1 variant, c.2257-7A>G, had previously been identified in the germline of patient 73.	('c.2257-7A>G', 'Mutation', 'c.2257-7A>G', (28, 39))	('c.2257-7A>G', 'Var', (28, 39))	('DICER1', 'Gene', (12, 18))	('DICER1', 'Gene', '23405', (12, 18))	('patient', 'Species', '9606', (91, 98))
433808	28524158	Based on mutation frequency data and in silico effect predictions, the remaining seven variants are unlikely to be involved in the pathogenesis of the sarcomas in question.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcomas', 'Disease', (151, 159))	('variants', 'Var', (87, 95))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))
433810	28524158	We therefore screened for deletions or duplications in the germline of 53 patients from whom good quality non-tumour DNA was available (cases 1-52 and 56) and no such alterations were identified (Supplementary Figure S3).	('duplications', 'Var', (39, 51))	('deletions', 'Var', (26, 35))	('patients', 'Species', '9606', (74, 82))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
433811	28524158	Copy number alterations of DICER1 have been identified in various cancers including breast cancer, ovarian cancer and melanoma.	('ovarian cancer', 'Disease', 'MESH:D010051', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('DICER1', 'Gene', '23405', (27, 33))	('Copy number alterations', 'Var', (0, 23))	('ovarian cancer', 'Disease', (99, 113))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('breast cancer', 'Disease', (84, 97))	('DICER1', 'Gene', (27, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (99, 113))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', (66, 73))	('identified', 'Reg', (44, 54))
433812	28524158	We screened for CNVs of DICER1 in 59 sarcomas using a ddPCR experiment (chosen due to low DNA input requirement) and detected copy number changes involving the DICER1 locus in 5 cases (8.5%), each of which was a unique subtype (Supplementary Table S6).	('copy number changes', 'Var', (126, 145))	('DICER1', 'Gene', '23405', (24, 30))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('CNVs', 'Var', (16, 20))	('DICER1', 'Gene', (160, 166))	('DICER1', 'Gene', '23405', (160, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('DICER1', 'Gene', (24, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcomas', 'Disease', (37, 45))
433814	28524158	Germline mutations in DICER1 predispose to several early childhood or adolescent-onset phenotypes, including pleuroplumonary blastoma, Sertoli-Leydig cell tumour and paediatric cystic nephroma.	('Germline mutations', 'Var', (0, 18))	('pleuroplumonary blastoma', 'Phenotype', 'HP:0100528', (109, 133))	('Sertoli-Leydig cell tumour', 'Phenotype', 'HP:0100619', (135, 161))	('pleuroplumonary blastoma', 'Disease', (109, 133))	('cystic nephroma', 'Disease', (177, 192))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('Leydig cell tumour', 'Phenotype', 'HP:0100618', (143, 161))	('cystic nephroma', 'Disease', 'MESH:D018201', (177, 192))	('DICER1', 'Gene', (22, 28))	('DICER1', 'Gene', '23405', (22, 28))	('pleuroplumonary blastoma', 'Disease', 'MESH:D018202', (109, 133))	('predispose to', 'Reg', (29, 42))	('tumour', 'Disease', (155, 161))
433815	28524158	Genetically, DICER1 syndrome-associated tumours are most often characterised by a predisposing germline DICER1 mutation that inactivates one allele, coupled with a highly distinctive second somatic missense mutation affecting one of the RNase IIIb metal ion-binding sites on the other allele.	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('DICER1', 'Gene', '23405', (13, 19))	('DICER1', 'Gene', (104, 110))	('inactivates', 'NegReg', (125, 136))	('metal', 'Chemical', 'MESH:D008670', (248, 253))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumours', 'Disease', (40, 47))	('DICER1', 'Gene', '23405', (104, 110))	('allele', 'MPA', (141, 147))	('RNase III', 'Gene', '29102', (237, 246))	('RNase III', 'Gene', (237, 246))	('mutation', 'Var', (111, 119))	('DICER1', 'Gene', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
433816	28524158	Although most DICER1-related lesions manifest in early childhood, it is becoming increasingly evident that the acquisition of two somatic DICER1 mutations can lead to a later-onset of neoplasia, as was observed in case 1.	('neoplasia', 'Disease', (184, 193))	('mutations', 'Var', (145, 154))	('DICER1', 'Gene', (14, 20))	('DICER1', 'Gene', '23405', (14, 20))	('neoplasia', 'Phenotype', 'HP:0002664', (184, 193))	('DICER1', 'Gene', (138, 144))	('DICER1', 'Gene', '23405', (138, 144))	('neoplasia', 'Disease', 'MESH:D009369', (184, 193))	('lead to', 'Reg', (159, 166))
433817	28524158	Most ERMS that arise in the context of DICER1 mutations involve the urogenital system and interestingly, the biallelically mutated ERMS from our study arose in the broad ligament, which is the peritoneal fold that attaches the uterus, fallopian tubes and ovaries to the pelvis.	('ERMS', 'Disease', (5, 9))	('fallopian tubes', 'Disease', (235, 250))	('mutations', 'Var', (46, 55))	('involve the urogenital system', 'Phenotype', 'HP:0000119', (56, 85))	('ovaries to the pelvis', 'Disease', (255, 276))	('DICER1', 'Gene', (39, 45))	('ovaries to the pelvis', 'Disease', 'MESH:D010386', (255, 276))	('ERMS', 'Phenotype', 'HP:0006743', (131, 135))	('fallopian tubes', 'Disease', 'MESH:D005184', (235, 250))	('ERMS', 'Phenotype', 'HP:0006743', (5, 9))	('DICER1', 'Gene', '23405', (39, 45))	('involve', 'Reg', (56, 63))
433818	28524158	Although a limited number of other sarcoma subtypes have been found to carry both truncating and/or RNase IIIb hotspot somatic DICER1 mutations (Table 1 and Supplementary Table S1c), ERMS appears to be the subtype that is most commonly DICER1 mutated.	('DICER1', 'Gene', (127, 133))	('DICER1', 'Gene', '23405', (127, 133))	('sarcoma', 'Disease', (35, 42))	('ERMS', 'Phenotype', 'HP:0006743', (183, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('ERMS', 'Disease', (183, 187))	('DICER1', 'Gene', (236, 242))	('mutations', 'Var', (134, 143))	('DICER1', 'Gene', '23405', (236, 242))	('RNase III', 'Gene', (100, 109))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('RNase III', 'Gene', '29102', (100, 109))
433820	28524158	Genetic testing should be performed particularly if ERMS are seen to arise in constellation with one or more known DICER1 syndrome phenotypes, as the identification of germline DICER1 mutations has important implications for the screening and counselling of patients and their families.	('ERMS', 'Phenotype', 'HP:0006743', (52, 56))	('mutations', 'Var', (184, 193))	('DICER1', 'Gene', (115, 121))	('DICER1', 'Gene', (177, 183))	('DICER1', 'Gene', '23405', (115, 121))	('ERMS', 'Disease', (52, 56))	('DICER1', 'Gene', '23405', (177, 183))	('patients', 'Species', '9606', (258, 266))
433821	28524158	In summary, our study demonstrates that likely-pathogenic DICER1 mutations underlie the genetic basis of only a small fraction of sarcomas, with ERMS the most likely sarcoma subtype to harbour such mutations.	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('DICER1', 'Gene', (58, 64))	('DICER1', 'Gene', '23405', (58, 64))	('sarcomas', 'Disease', (130, 138))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('sarcoma', 'Disease', (166, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('ERMS', 'Phenotype', 'HP:0006743', (145, 149))	('sarcoma', 'Disease', (130, 137))	('sarcomas', 'Disease', 'MESH:D012509', (130, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('mutations', 'Var', (65, 74))
433977	23280377	Other cytogenetic abnormalities detected in EML patients are t(15;17), t(9;11), t(1;11), t(8;17), t(8;16), del(16q), del(5q), del(20q), monosomy 7, and trisomy 4.	('monosomy 7', 'Var', (136, 146))	('t(8;16', 'Var', (98, 104))	('EML', 'Phenotype', 'HP:0001978', (44, 47))	('del(16q', 'Var', (107, 114))	('t(9;11', 'Var', (71, 77))	('t(1;11', 'Var', (80, 86))	('del(5q', 'Var', (117, 123))	('del(20q', 'Var', (126, 133))	('t(8;17', 'Var', (89, 95))	('trisomy', 'Disease', (152, 159))	('patients', 'Species', '9606', (48, 56))	('t(15;17', 'Var', (61, 68))
433979	23280377	A retrospective analysis of 92 adult patients with myeloid sarcoma identified a higher incidence in patients with the following aberrations: t(8;21), 11q23 (MLL rearrangement), monosomy 7, and trisomy 8.	('monosomy 7', 'Var', (177, 187))	('t(8;21', 'Var', (141, 147))	('MLL', 'Gene', '4297', (157, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('patients', 'Species', '9606', (37, 45))	('MLL', 'Gene', (157, 160))	('11q23', 'Var', (150, 155))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (51, 66))	('trisomy 8', 'Var', (193, 202))	('patients', 'Species', '9606', (100, 108))	('myeloid sarcoma', 'Disease', (51, 66))
433980	23280377	conducted genomic profiling of seven myeloid sarcoma cases by array comparative genomic hybridization, and no cases of t(8;21) were identified; however in their series chromosome 8 abnormalities occurred most frequently (3/7 cases).	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('myeloid sarcoma', 'Disease', (37, 52))	('chromosome 8 abnormalities', 'Var', (168, 194))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (37, 52))	('occurred', 'Reg', (195, 203))
433983	23280377	A well-documented molecular abnormality is a mutation in the nucleophosmin (NPM)-1 gene.	('nucleophosmin (NPM)-1', 'Gene', (61, 82))	('nucleophosmin (NPM)-1', 'Gene', '4869', (61, 82))	('mutation', 'Var', (45, 53))
433984	23280377	In one study, cytoplasmic NPM, correlating with the NPM1 mutation, was the most common molecular lesion in leukemia cells of AML patients with EML.	('AML', 'Disease', 'MESH:D015470', (125, 128))	('mutation', 'Var', (57, 65))	('EML', 'Phenotype', 'HP:0001978', (143, 146))	('patients', 'Species', '9606', (129, 137))	('AML', 'Disease', (125, 128))	('AML', 'Phenotype', 'HP:0004808', (125, 128))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('leukemia', 'Disease', (107, 115))	('NPM1', 'Gene', (52, 56))
433985	23280377	Accounting for approximately one-third of all AML, the NPM1 mutation is considered a founder genetic alteration, which is stable over the course of AML, as demonstrated by late relapses reported at 8 years and the occurrence of myeloid sarcoma after 20 years.	('mutation', 'Var', (60, 68))	('AML', 'Phenotype', 'HP:0004808', (148, 151))	('AML', 'Phenotype', 'HP:0004808', (46, 49))	('AML', 'Disease', (148, 151))	('AML', 'Disease', (46, 49))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (228, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('NPM1', 'Gene', (55, 59))	('AML', 'Disease', 'MESH:D015470', (148, 151))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('myeloid sarcoma', 'Disease', (228, 243))
433986	23280377	For example, the NPM1 mutation induces hematopoietic cell proliferation in the posterior blood island and the ventral aorta of the zebrafish as well as in the spleen of transgenic mice.	('mutation', 'Var', (22, 30))	('transgenic mice', 'Species', '10090', (169, 184))	('induces', 'Reg', (31, 38))	('zebrafish', 'Species', '7955', (131, 140))	('NPM1', 'Gene', (17, 21))	('hematopoietic cell proliferation in', 'CPA', (39, 74))
434034	22241790	Copy number losses define subgroups of dedifferentiated liposarcoma with poor prognosis and genomic instability Molecular events underlying progression of well-differentiated liposarcoma (WDLS) to dedifferentiated liposarcoma (DDLS) are poorly defined.	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('liposarcoma', 'Disease', (214, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('liposarcoma', 'Phenotype', 'HP:0012034', (56, 67))	('liposarcoma', 'Disease', 'MESH:D008080', (56, 67))	('WD', 'Disease', 'MESH:D006527', (188, 190))	('liposarcoma', 'Disease', (175, 186))	('liposarcoma', 'Disease', 'MESH:D008080', (214, 225))	('liposarcoma', 'Phenotype', 'HP:0012034', (214, 225))	('Copy number losses', 'Var', (0, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('liposarcoma', 'Phenotype', 'HP:0012034', (175, 186))	('liposarcoma', 'Disease', 'MESH:D008080', (175, 186))	('liposarcoma', 'Disease', (56, 67))
434035	22241790	This study sought to identify copy number alterations (CNAs) associated with dedifferentiation of WDLS, with DDLS morphology, and with patient outcomes.	('patient', 'Species', '9606', (135, 142))	('WD', 'Disease', 'MESH:D006527', (98, 100))	('associated', 'Reg', (61, 71))	('dedifferentiation', 'Disease', (77, 94))	('copy number alterations', 'Var', (30, 53))
434038	22241790	Loss of the chromosome segment 11q23-24, the most common event, was observed only in DDLS that morphologically resembled the genomically complex sarcomas undifferentiated pleomorphic sarcoma and myxofibrosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('sarcomas undifferentiated pleomorphic sarcoma and myxofibrosarcoma', 'Disease', 'MESH:D012509', (145, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('DDLS', 'Disease', (85, 89))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (199, 211))	('Loss', 'Var', (0, 4))
434040	22241790	Common copy number losses were associated with transcriptional downregulation of potential tumor suppressors and adipogenesis-related genes (e.g., EI24 and CEBPA).	('adipogenesis-related genes', 'Gene', (113, 139))	('CEBPA', 'Gene', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CEBPA', 'Gene', '1050', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('transcriptional', 'MPA', (47, 62))	('copy number losses', 'Var', (7, 25))	('EI24', 'Gene', (147, 151))	('tumor', 'Disease', (91, 96))	('downregulation', 'NegReg', (63, 77))	('EI24', 'Gene', '9538', (147, 151))
434042	22241790	CNAs in liposarcoma improve risk stratification for patients and will help identify potential tumor suppressors driving liposarcoma progression.	('risk stratification', 'MPA', (28, 47))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('liposarcoma', 'Phenotype', 'HP:0012034', (8, 19))	('liposarcoma', 'Disease', 'MESH:D008080', (8, 19))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('liposarcoma', 'Disease', (120, 131))	('tumor', 'Disease', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('liposarcoma', 'Disease', 'MESH:D008080', (120, 131))	('liposarcoma', 'Disease', (8, 19))	('CNAs', 'Var', (0, 4))	('liposarcoma', 'Phenotype', 'HP:0012034', (120, 131))	('patients', 'Species', '9606', (52, 60))
434053	22241790	Among WDLS and DDLS, over 90% of tumors have amplification of the chromosome segment 12q13-15.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('WD', 'Disease', 'MESH:D006527', (6, 8))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('amplification', 'Var', (45, 58))
434067	22241790	The gene-based and region of interest (ROI) copy number calls of -2, -1, 0, 1, or 2 (deletion, loss, copy-neutral, gain, amplification; as assessed by RAE) were computed on three samples cohorts (DDLS only, WDLS only, and all samples).	('WD', 'Disease', 'MESH:D006527', (207, 209))	('gain', 'PosReg', (115, 119))	('copy-neutral', 'Var', (101, 113))	('deletion', 'Var', (85, 93))	('loss', 'NegReg', (95, 99))
434086	22241790	Less common CNAs in WDLS included gains at 1q21-25 and 7q34 and copy number losses at 1q25-44, 8q24, 9p24, 10q26, 11p13-15, 13q14, 13q31, 18q23, and 22q11-13.	('13q14', 'Var', (124, 129))	('WD', 'Disease', 'MESH:D006527', (20, 22))	('losses', 'NegReg', (76, 82))	('1q21-25', 'Var', (43, 50))	('gains', 'PosReg', (34, 39))	('11p13-15', 'Var', (114, 122))
434087	22241790	Copy number alterations observed in specimens of WDLS regions within tumors classified histologically as DDLS (27% of WDLS specimens) were compared to those observed in samples from tumors classified histologically as WDLS.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('WD', 'Disease', 'MESH:D006527', (218, 220))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('WDLS regions within tumors', 'Disease', (49, 75))	('WDLS regions within tumors', 'Disease', 'MESH:D001929', (49, 75))	('Copy', 'Var', (0, 4))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('WD', 'Disease', 'MESH:D006527', (49, 51))	('WD', 'Disease', 'MESH:D006527', (118, 120))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
434092	22241790	Nine such CNAs were observed: losses centered at 3p14-21, 3q29, 9p22-24, 10p15, 11q23-24, 17q21, and 19q13 and gains at 17p11 and 20q11 (Tables 2, S5).	('gains', 'PosReg', (111, 116))	('10p15', 'Var', (73, 78))	('p11', 'Gene', (122, 125))	('9p22-24', 'Var', (64, 71))	('losses', 'NegReg', (30, 36))	('11q23-24', 'Var', (80, 88))	('p11', 'Gene', '6281', (122, 125))
434096	22241790	The previously observed amplification of 1p32, which includes the JUN locus, was observed in 15 DDLS (28%) but also in 5 WDLS (9%; FDR = 0.03) so did not meet our criteria for a progression-associated CNA.	('amplification', 'Var', (24, 37))	('p32', 'Gene', '3622', (42, 45))	('p32', 'Gene', (42, 45))	('WD', 'Disease', 'MESH:D006527', (121, 123))
434105	22241790	Clinical variables (margin, gender, age, and presentation status) did not associate with DSS; however, loss of 19q13 was associated with significant reduction in DSS (HR 7.36, p=0.0025, Table 4, Figure 2).	('reduction', 'NegReg', (149, 158))	('loss', 'Var', (103, 107))	('19q13', 'Gene', (111, 116))	('DSS', 'MPA', (162, 165))	('DSS', 'Chemical', '-', (162, 165))	('DSS', 'Chemical', '-', (89, 92))
434111	22241790	The transition from WDLS to DDLS is characterized by downregulation of the normal adipogenesis program, and several genes that regulate this process were identified in regions of copy number loss.	('copy number loss', 'Var', (179, 195))	('downregulation', 'NegReg', (53, 67))	('WD', 'Disease', 'MESH:D006527', (20, 22))	('DDLS', 'Disease', (28, 32))
434122	22241790	Tumors with 11q23-24 loss, compared to those without this loss, have higher percentages of their genomes altered by CNAs and higher frequencies of other progression-associated CNAs.	('loss', 'NegReg', (21, 25))	('11q23-24', 'Var', (12, 20))	('higher', 'PosReg', (69, 75))	('Tumors', 'Disease', (0, 6))	('genomes altered', 'MPA', (97, 112))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('higher', 'PosReg', (125, 131))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CNAs', 'Disease', (116, 120))
434123	22241790	The genomic complexity associated with 11q23-24 was of particular interest in the context of our examination of tumor histology.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('11q23-24', 'Var', (39, 47))
434129	22241790	Loss of 19q13, although associated with progression of WDLS, was not associated with an overall increase in genomic complexity, with the other progression-associated CNAs, or with DDLS histology.	('WD', 'Disease', 'MESH:D006527', (55, 57))	('Loss', 'Var', (0, 4))	('19q13', 'Gene', (8, 13))
434131	22241790	In this relatively homogenous group of tumors (in terms of size, site and margin status), outcome could not be clearly stratified based on clinical factors, but loss of 19q13 was associated with both LRFS and DSS.	('DSS', 'Disease', (209, 212))	('associated', 'Reg', (179, 189))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('LRFS', 'Disease', (200, 204))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('19q13', 'Gene', (169, 174))	('loss of', 'Var', (161, 168))	('tumors', 'Disease', (39, 45))	('DSS', 'Chemical', '-', (209, 212))
434138	22241790	Loss of 11q23-24, either in response to an unknown event or as an independent event, is associated with tumors that are chromosomally complex and are morphologically similar to myxofibrosarcomas or UPS.	('myxofibrosarcomas or UPS', 'Disease', 'MESH:D017118', (177, 201))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('tumors', 'Disease', (104, 110))	('myxofibrosarcomas or UPS', 'Disease', (177, 201))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('11q23-24', 'Gene', (8, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (181, 193))	('associated', 'Reg', (88, 98))	('Loss', 'Var', (0, 4))
434140	22241790	Loss of 19q13 is associated with an aggressive phenotype, perhaps as a result of reduced expression of CEBPA and is independent of morphology.	('CEBPA', 'Gene', '1050', (103, 108))	('expression', 'MPA', (89, 99))	('aggressive', 'Disease', (36, 46))	('19q13', 'Gene', (8, 13))	('Loss of', 'Var', (0, 7))	('reduced', 'NegReg', (81, 88))	('CEBPA', 'Gene', (103, 108))
434144	22241790	For example, 11q23-24 carries the gene EI24, implicated in regulation of p53 and representing a potential tumor suppressor in DDLS, and 11q23-24 loss is associated with resistance to etoposide-based chemotherapies in other diseases.	('11q23-24', 'Var', (136, 144))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('etoposide', 'Chemical', 'MESH:D005047', (183, 192))	('loss', 'NegReg', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('associated', 'Reg', (153, 163))	('EI24', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('EI24', 'Gene', '9538', (39, 43))	('tumor', 'Disease', (106, 111))
434149	22241790	Using comparative genomic hybridization, common, specific progression-associated copy number alterations (CNAs) were identified in 79% of DDLS but were rarely found in WDLS.	('WD', 'Disease', 'MESH:D006527', (168, 170))	('DDLS', 'Disease', (138, 142))	('copy number alterations', 'Var', (81, 104))
434186	31298514	Patients with MMMT were found to have a higher mean age compared with the other groups (62.40+-7.97 years vs 49.80+-5.87 years in LMS, 39.60+-13.22 years in ESS, and 51.89+-20.74 years in other sarcomas).	('sarcomas', 'Disease', (194, 202))	('LMS', 'Disease', 'MESH:D007890', (130, 133))	('Patients', 'Species', '9606', (0, 8))	('MMMT', 'Var', (14, 18))	('ESS', 'Disease', (157, 160))	('sarcomas', 'Disease', 'MESH:D012509', (194, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('LMS', 'Disease', (130, 133))	('LMS', 'Phenotype', 'HP:0100243', (130, 133))
434232	31298514	The number of patients with positive lymph nodes was low in our study, and survival times were found to be significantly shorter for those with positive lymph nodes.	('positive', 'Var', (144, 152))	('shorter', 'NegReg', (121, 128))	('survival times', 'CPA', (75, 89))	('patients', 'Species', '9606', (14, 22))
434252	31298514	We also found that the presence of residual tumor and positive Ki-67 decreased DFS; however, the decreases were not statistically significant for either comparison, presumably due to the low number of patients.	('patients', 'Species', '9606', (201, 209))	('Ki-67', 'Gene', (63, 68))	('decreased', 'NegReg', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('DFS', 'MPA', (79, 82))	('positive', 'Var', (54, 62))	('tumor', 'Disease', (44, 49))
434263	30379650	EWSR1-PATZ1 fusion positive spindle and round cell sarcoma is one such new tumor entity.	('fusion', 'Var', (12, 18))	('sarcoma', 'Disease', (51, 58))	('EWSR1', 'Gene', '2130', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('tumor', 'Disease', (75, 80))	('EWSR1', 'Gene', (0, 5))
434264	30379650	Herein, we report two EWSR1-PATZ1 fusion positive spindle and round cell sarcomas with overlapping histological features and polyphenotypic differentiation.	('EWSR1', 'Gene', '2130', (22, 27))	('fusion', 'Var', (34, 40))	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('EWSR1', 'Gene', (22, 27))	('sarcomas', 'Disease', (73, 81))	('spindle', 'Disease', (50, 57))
434268	30379650	Fluorescence in-situ hybridization revealed rearrangement at EWSR1 locus.	('EWSR1', 'Gene', (61, 66))	('EWSR1', 'Gene', '2130', (61, 66))	('rearrangement', 'Var', (44, 57))
434270	30379650	EWSR1-PATZ1 fusion positive spindle and round cell sarcomas show abundant intratumoral fibrosis and polyphenotypic differentiation, thus mimicking a range of tumors including desmoplastic small round cell tumor.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('desmoplastic small round cell tumor', 'Disease', (175, 210))	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('EWSR1', 'Gene', '2130', (0, 5))	('intratumoral fibrosis', 'Disease', (74, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcomas', 'Disease', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('intratumoral fibrosis', 'Disease', 'MESH:D005355', (74, 95))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('EWSR1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('fusion positive', 'Var', (12, 27))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (175, 210))
434274	30379650	Ewing sarcoma, the prototypic round cell sarcoma, harbors pathognomonic fusions involving EWSR1 and members of ETS family of transcription factors.	('sarcoma', 'Disease', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (0, 13))	('EWSR1', 'Gene', (90, 95))	('Ewing sarcoma', 'Disease', (0, 13))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('sarcoma', 'Disease', 'MESH:D012509', (6, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('EWSR1', 'Gene', '2130', (90, 95))	('fusions', 'Var', (72, 79))	('sarcoma', 'Disease', (6, 13))
434275	30379650	A group of round cell neoplasms, often referred to as Ewing-like sarcoma, harbor CIC and BCOR rearrangements, and are now categorized as CIC-rearranged and BCOR-rearranged sarcomas, respectively.	('sarcomas', 'Phenotype', 'HP:0100242', (172, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('neoplasms', 'Phenotype', 'HP:0002664', (22, 31))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (54, 72))	('sarcomas', 'Disease', (172, 180))	('harbor', 'Reg', (74, 80))	('CIC', 'Gene', (81, 84))	('BCOR', 'MPA', (89, 93))	('rearrangements', 'Var', (94, 108))	('Ewing-like sarcoma', 'Disease', 'MESH:D012512', (54, 72))	('neoplasms', 'Disease', 'MESH:D009369', (22, 31))	('Ewing-like sarcoma', 'Disease', (54, 72))	('neoplasms', 'Disease', (22, 31))	('neoplasm', 'Phenotype', 'HP:0002664', (22, 30))	('sarcomas', 'Disease', 'MESH:D012509', (172, 180))
434276	30379650	A few patients with Ewing-like sarcoma show EWSR1 rearrangements involving fusion partners other than ETS family of transcription factors.	('EWSR1', 'Gene', '2130', (44, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('involving', 'Reg', (65, 74))	('Ewing-like sarcoma', 'Disease', 'MESH:D012512', (20, 38))	('patients', 'Species', '9606', (6, 14))	('EWSR1', 'Gene', (44, 49))	('rearrangements', 'Var', (50, 64))	('Ewing-like sarcoma', 'Disease', (20, 38))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (20, 38))
434277	30379650	A recent comprehensive study of round cell sarcomas using high-throughput RNA sequencing identified 5 tumors with EWSR1-PATZ1 (a non-ETS gene) fusion, which on expression profiling clustered away from other EWSR1-fusion positive cases, suggesting a novel tumor entity, one genetically unrelated to other EWRS1 fusion positive round cell sarcomas.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('EWSR1', 'Gene', '2130', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('EWSR1', 'Gene', '2130', (207, 212))	('tumors', 'Disease', (102, 108))	('tumor', 'Disease', (255, 260))	('sarcomas', 'Disease', 'MESH:D012509', (337, 345))	('EWSR1', 'Gene', (114, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (337, 345))	('sarcomas', 'Disease', (337, 345))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('tumor', 'Disease', (102, 107))	('sarcomas', 'Disease', (43, 51))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (337, 344))	('fusion', 'Var', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('EWSR1', 'Gene', (207, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
434278	30379650	In this study, we report 2 EWSR1-PATZ1 fusion positive spindle and round cell sarcomas showing unique morphologic and polyphenotypic differentiation on immunohistochemistry.	('EWSR1', 'Gene', (27, 32))	('sarcomas', 'Disease', (78, 86))	('EWSR1', 'Gene', '2130', (27, 32))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('fusion', 'Var', (39, 45))
434282	30379650	A EWSR1 gene rearrangement was considered positive if more than 15% of cells showed separation of the red (5' probe) and the green (3' probe) signals by a distance at least two times greater than the size of one hybridization signal.	('rearrangement', 'Var', (13, 26))	('separation', 'MPA', (84, 94))	('EWSR1', 'Gene', '2130', (2, 7))	('EWSR1', 'Gene', (2, 7))
434304	30379650	Interphase FISH performed using a break-apart probe to the EWSR1 revealed rearrangement of this locus in both cases.	('EWSR1', 'Gene', (59, 64))	('EWSR1', 'Gene', '2130', (59, 64))	('rearrangement', 'Var', (74, 87))
434306	30379650	The solid fusion assay in both cases revealed fusion transcripts involving EWSR1 Exon9 (ENST00000414183) and PATZ1 Exon1 (ENST00000215919) with 530 supporting unique fusion reads for case 1 and 431 for case 2 (Fig.	('EWSR1', 'Gene', '2130', (75, 80))	('PATZ1', 'Gene', (109, 114))	('ENST00000414183', 'Var', (88, 103))	('EWSR1', 'Gene', (75, 80))	('ENST00000215919', 'Var', (122, 137))
434308	30379650	Ewing sarcoma, Ewing-like tumors and related tumors involving the bone and soft tissue constitute a heterogenous group of neoplasms with 4 recognized subclasses: 1) classic Ewing sarcoma family of tumors with fusion involving EWSR1 or FUS to members of the ETS family of transcription factors that include FLI1, ERG, ETV1/4, and FEV, 2) Ewing-like sarcomas associated with CIC and BCOR rearrangements, 3) sarcomas with EWSR1 fusions to non-ETS family genes, a class that includes EWSR1-PATZ1 and EWSR1-NFATc2 (other non-ETS fusion partners described in isolated reports include SP3  and SMARCA5),  and 4) unclassified round cell sarcomas, a group that lacks known fusions.	('neoplasms', 'Disease', (122, 131))	('Ewing sarcoma', 'Disease', (173, 186))	('EWSR1', 'Gene', (419, 424))	('EWSR1', 'Gene', '2130', (496, 501))	('EWSR1', 'Gene', '2130', (480, 485))	('sarcomas', 'Disease', (405, 413))	('sarcomas', 'Disease', 'MESH:D012509', (348, 356))	('sarcoma', 'Phenotype', 'HP:0100242', (629, 636))	('sarcomas', 'Phenotype', 'HP:0100242', (348, 356))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('sarcomas', 'Disease', (348, 356))	('EWSR1', 'Gene', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (405, 412))	('Ewing-like sarcoma', 'Disease', (337, 355))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (337, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (348, 355))	('neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('EWSR1', 'Gene', (480, 485))	('BCOR', 'Gene', (381, 385))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('fusions', 'Var', (425, 432))	('EWSR1', 'Gene', (496, 501))	('tumors', 'Disease', (197, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('neoplasm', 'Phenotype', 'HP:0002664', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('tumors', 'Disease', (45, 51))	('EWSR1', 'Gene', '2130', (419, 424))	('Ewing sarcoma', 'Disease', (0, 13))	('unclassified', 'Disease', (605, 617))	('rearrangements', 'Var', (386, 400))	('neoplasms', 'Disease', 'MESH:D009369', (122, 131))	('sarcomas', 'Disease', 'MESH:D012509', (629, 637))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('EWSR1', 'Gene', '2130', (226, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (629, 637))	('sarcomas', 'Disease', (629, 637))	('Ewing-like tumors', 'Disease', 'MESH:D012512', (15, 32))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('sarcomas', 'Disease', 'MESH:D012509', (405, 413))	('Ewing-like tumors', 'Disease', (15, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (173, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (405, 413))	('tumors', 'Disease', (26, 32))	('Ewing-like sarcoma', 'Disease', 'MESH:D012512', (337, 355))
434309	30379650	The precise classification of tumors showing rearrangements involving EWSR1 and non-ETS family of transcription factors (class #3 from above) remains uncertain.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('EWSR1', 'Gene', (70, 75))	('rearrangements', 'Var', (45, 59))	('EWSR1', 'Gene', '2130', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
434310	30379650	Although these tumors share EWSR1 rearrangements, it remains to be seen whether they account for a biologically homogeneous group, as the fusion partners are biologically and functionally unrelated.	('rearrangements', 'Var', (34, 48))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('EWSR1', 'Gene', '2130', (28, 33))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('EWSR1', 'Gene', (28, 33))
434311	30379650	Other morphologically distinctive tumors with EWSR1 rearrangements not considered related to the Ewing family of tumors include desmoplastic small round cell tumor (DSRCT), myoepithelioma of soft tissues, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma and clear cell sarcoma.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (205, 223))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (265, 283))	('tumors', 'Disease', (113, 119))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (239, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (128, 163))	('desmoplastic small round cell tumor', 'Disease', (128, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('myxoid chondrosarcoma', 'Disease', (239, 260))	('liposarcoma', 'Phenotype', 'HP:0012034', (212, 223))	('myoepithelioma of soft', 'Disease', 'MESH:D009208', (173, 195))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('EWSR1', 'Gene', '2130', (46, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('clear cell sarcoma', 'Disease', (265, 283))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (246, 260))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('rearrangements', 'Var', (52, 66))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (205, 223))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumors', 'Disease', (34, 40))	('EWSR1', 'Gene', (46, 51))	('DSRCT', 'Disease', (165, 170))	('myxoid liposarcoma', 'Disease', (205, 223))	('myoepithelioma of soft', 'Disease', (173, 195))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('DSRCT', 'Disease', 'MESH:D058405', (165, 170))
434312	30379650	Herein, we describe 2 spindle and round cell sarcomas with EWSR1 fusion to a non-ETS gene (PATZ1) with overlapping histological features: monotonous proliferation of round to spindled cells, pseudoalveolar architecture, infrequent mitoses, abundant intratumoral stromal bands, and polyphenotypic differentiation.	('EWSR1', 'Gene', (59, 64))	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('tumor', 'Disease', (254, 259))	('pseudoalveolar architecture', 'CPA', (191, 218))	('round to spindled cells', 'CPA', (166, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('EWSR1', 'Gene', '2130', (59, 64))	('sarcomas', 'Disease', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('mitoses', 'CPA', (231, 238))	('fusion', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('spindle and', 'Disease', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('PATZ1', 'Gene', (91, 96))
434322	30379650	The EWRS1-PATZ1 fusion has also been detected in cerebral ganglioglioma and pediatric high-grade gliomas and gangliogliomas.	('cerebral ganglioglioma', 'Disease', 'MESH:D018303', (49, 71))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('gangliogliomas', 'Disease', (109, 123))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('gliomas', 'Disease', (97, 104))	('EWRS1-PATZ1', 'Gene', (4, 15))	('gangliogliomas', 'Disease', 'MESH:D018303', (109, 123))	('cerebral ganglioglioma', 'Disease', (49, 71))	('detected', 'Reg', (37, 45))	('gliomas', 'Disease', (116, 123))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('fusion', 'Var', (16, 22))
434327	30379650	However, the tumors lacked FOXO1 rearrangements on the fusion assay and/or FISH assay.	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('lacked', 'NegReg', (20, 26))	('rearrangements', 'Var', (33, 47))	('FOXO1', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
434329	30379650	To the best of our knowledge, EWSR1 translocation has not been reported in any histological subtype of rhabdomyosarcoma or malignant peripheral nerve sheath tumor.	('EWSR1', 'Gene', '2130', (30, 35))	('rhabdomyosarcoma or malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D009442', (103, 162))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (103, 119))	('EWSR1', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('translocation', 'Var', (36, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (123, 162))
434336	30379650	Myoepithelial carcinoma also deserves strong consideration given that EWSR1 alteration has been identified in half of all reported cases.	('EWSR1', 'Gene', (70, 75))	('Myoepithelial carcinoma', 'Disease', 'MESH:D009208', (0, 23))	('EWSR1', 'Gene', '2130', (70, 75))	('Myoepithelial carcinoma', 'Disease', (0, 23))	('alteration', 'Var', (76, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
434339	30379650	Given the relatively monotonous cellular features, EWSR1 rearrangement and CD99 positivity, conventional Ewing sarcoma deserves consideration, particularly prior to the identification of the fusion partner.	('CD99', 'Gene', (75, 79))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('EWSR1', 'Gene', (51, 56))	('EWSR1', 'Gene', '2130', (51, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (105, 118))	('rearrangement', 'Var', (57, 70))	('Ewing sarcoma', 'Disease', (105, 118))
434341	30379650	RNA sequencing has demonstrated that tumors with fusions involving EWSR1 or FUS with members of the ETS transcription factor genes cluster tightly together in a homogenous group.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('EWSR1', 'Gene', '2130', (67, 72))	('fusions', 'Var', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('EWSR1', 'Gene', (67, 72))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
434342	30379650	Tumors with EWSR1 fusions to non- ETS genes (PATZ1, NFATc2, POU5F1, SMARCA5) from a separate cluster, unrelated to the former neoplasms suggesting that each of these constitute a distinct entity.	('NFATc2', 'Gene', (52, 58))	('neoplasms', 'Disease', 'MESH:D009369', (126, 135))	('neoplasms', 'Disease', (126, 135))	('fusions', 'Var', (18, 25))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('neoplasm', 'Phenotype', 'HP:0002664', (126, 134))	('PATZ1', 'Gene', (45, 50))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('EWSR1', 'Gene', (12, 17))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('EWSR1', 'Gene', '2130', (12, 17))
434347	30379650	Although the tumors illustrated here show immunohistochemical overlap with CIC-rearranged sarcomas, the identification of EWRS1 fusion would exclude both CIC- and BCOR-rearranged sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('sarcomas', 'Disease', (179, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('EWRS1', 'Gene', (122, 127))	('sarcomas', 'Disease', (90, 98))	('fusion', 'Var', (128, 134))	('exclude', 'NegReg', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('sarcomas', 'Disease', 'MESH:D012509', (179, 187))
434348	30379650	EWSR1-PATZ1 fusion results from intrachromosomal inversion at 22q12; the two genes are located around 2 Mbp apart.	('fusion', 'Var', (12, 18))	('results from', 'Reg', (19, 31))	('EWSR1', 'Gene', '2130', (0, 5))	('EWSR1', 'Gene', (0, 5))
434354	30379650	Although the precise mechanism for this phenomenon is unknown, the chimeric EWSR1-WT1 protein transcript activates neural reprogramming factor ASCL1, accounting for neural differentiation.	('protein', 'Protein', (86, 93))	('chimeric', 'Var', (67, 75))	('EWSR1', 'Gene', (76, 81))	('activates', 'PosReg', (105, 114))	('EWSR1', 'Gene', '2130', (76, 81))	('neural reprogramming factor', 'CPA', (115, 142))
434355	30379650	Activation of transcriptional factors along multiple lineages might thus be responsible for polyphenotypic differentiation in DSRCT and, by extension, the EWSR1-PATZ1 fusion positive sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('sarcoma', 'Disease', (183, 190))	('DSRCT', 'Disease', (126, 131))	('EWSR1', 'Gene', (155, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('EWSR1', 'Gene', '2130', (155, 160))	('DSRCT', 'Disease', 'MESH:D058405', (126, 131))	('fusion', 'Var', (167, 173))
434358	30379650	The unique immunohistochemical profile and data from expression profiling support EWRS1-PATZ1 spindle and round cell sarcomas as an entity distinct from Ewing sarcoma.	('EWRS1-PATZ1', 'Var', (82, 93))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (153, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('sarcomas', 'Disease', (117, 125))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (153, 166))	('Ewing sarcoma', 'Disease', (153, 166))
434361	30379650	Regardless of the uncertainties surrounding the precise classification of EWRS1-PATZ1 spindle and round cell sarcoma, pathologists should consider this entity when confronted with an unusual immunohistochemical phenotype, particularly those that express neural/melanocytic and myogenic markers, and in instances where DSRCT and myoepithelial carcinoma is being considered.	('DSRCT', 'Disease', (318, 323))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('myoepithelial carcinoma', 'Disease', (328, 351))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('DSRCT', 'Disease', 'MESH:D058405', (318, 323))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (328, 351))	('sarcoma', 'Disease', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('EWRS1-PATZ1', 'Var', (74, 85))
434476	25822802	Data was extracted from all included studies to a standardized form that included the first author's name, year of publication, number of patients, country of origin, size of tumor, recurrence or metastasis, TNM stage, cut-off value for E-cadherin positivity, and overall survival (OS) curves or 5-year overall survival for patients with positive and negative E-cadherin expression.	('TNM', 'Gene', (208, 211))	('patients', 'Species', '9606', (324, 332))	('tumor', 'Disease', (175, 180))	('negative', 'NegReg', (351, 359))	('E-cadherin', 'Gene', (360, 370))	('TNM', 'Gene', '10178', (208, 211))	('E-cadherin', 'Gene', (237, 247))	('positive', 'Var', (338, 346))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('E-cadherin', 'Gene', '999', (237, 247))	('E-cadherin', 'Gene', '999', (360, 370))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patients', 'Species', '9606', (138, 146))
434487	25822802	Soft tissue sarcomas: Assessment of the association of E-cadherin expression and 5-year overall survival in STS cases resulted in a pooled OR of 4.047 (95% CI: 2.127-7.700; Z = 4.26; P = 0.000; Fig 3), indicating that the loss of E-cadherin was significantly associated with poorer prognosis in STS.	('E-cadherin', 'Gene', (55, 65))	('E-cadherin', 'Gene', '999', (55, 65))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('Soft tissue sarcomas', 'Phenotype', 'HP:0030448', (0, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('STS', 'Phenotype', 'HP:0030448', (295, 298))	('sarcomas', 'Disease', (12, 20))	('E-cadherin', 'Gene', (230, 240))	('E-cadherin', 'Gene', '999', (230, 240))	('loss', 'Var', (222, 226))	('STS', 'Phenotype', 'HP:0030448', (108, 111))
434502	25822802	In contrast, in sarcomas, the expression of E-cadherin is associated with a similar, but reverse, process known as mesenchymal to epithelial reverting transition (MET), which may play an important role in tumors of mesenchymal origin.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('sarcomas', 'Disease', (16, 24))	('mesenchymal to epithelial reverting transition', 'Disease', (115, 161))	('associated', 'Reg', (58, 68))	('expression', 'Var', (30, 40))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))	('tumors', 'Disease', (205, 211))
434543	25184926	The immuno-histochemical technique revealed focal positivity for epithelial membrane antigen (EMA) and TLEI (Wnt pathway, synovial sarcoma) and negativity for cytokeratins (AE1/AE3), emphasizing a poorly differentiated profile of this SS (Figure 4).	('cytokeratins', 'Protein', (159, 171))	('SS', 'Phenotype', 'HP:0100242', (235, 237))	('AE3', 'Gene', '6508', (177, 180))	('synovial sarcoma', 'Disease', (122, 138))	('negativity', 'Var', (144, 154))	('epithelial membrane antigen', 'Protein', (65, 92))	('TLEI', 'CPA', (103, 107))	('AE1', 'Gene', '6521', (173, 176))	('AE3', 'Gene', (177, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('AE1', 'Gene', (173, 176))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (122, 138))	('synovial sarcoma', 'Disease', 'MESH:D013584', (122, 138))
434553	25184926	Over 90% of the SS present translocation between chromosome 18 and X, t(X; 18) (p11; q11) arising from the fusion of gene SYT with the gene SSX1 (biphasic) or SSX2 (monophasic).	('SS', 'Phenotype', 'HP:0100242', (16, 18))	('SSX2', 'Gene', (159, 163))	('SYT', 'Gene', '6760', (122, 125))	('SSX1', 'Gene', '6756', (140, 144))	('SS', 'Phenotype', 'HP:0100242', (140, 142))	('fusion', 'Var', (107, 113))	('translocation', 'MPA', (27, 40))	('SSX1', 'Gene', (140, 144))	('SYT', 'Gene', (122, 125))	('SS', 'Phenotype', 'HP:0100242', (159, 161))	('SSX2', 'Gene', '6757', (159, 163))	('p11', 'Gene', '8909', (80, 83))	('p11', 'Gene', (80, 83))
434583	22359263	MRCL accounts for 40-50% of liposarcomas and is almost always associated with a chromosomal translocation, most commonly t(12;16)(q13;p11) though a number of less common translocations have also been described.	('liposarcoma', 'Phenotype', 'HP:0012034', (28, 39))	('t(12;16)(q13;p11', 'Var', (121, 137))	('associated', 'Reg', (62, 72))	('MRCL', 'Phenotype', 'HP:0012268', (0, 4))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('liposarcomas', 'Phenotype', 'HP:0012034', (28, 40))	('MRCL', 'Disease', (0, 4))	('liposarcomas', 'Disease', 'MESH:D008080', (28, 40))	('liposarcomas', 'Disease', (28, 40))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (121, 138))
434625	22359263	Importantly, although most patients had the classic t(12;16)(q13;p11) translocation there were four patients with different cytogenetics: t(10;16;12), t(12;22), t(15;17) as well as one patient with normal cytogenetics that was repeated and confirmed (growth of normal host cells could not be excluded).	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (52, 69))	('t(15;17', 'Var', (161, 168))	('patient', 'Species', '9606', (185, 192))	('patient', 'Species', '9606', (27, 34))	('patient', 'Species', '9606', (100, 107))	('t(10;16;12', 'Var', (138, 148))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (100, 108))	('t(12;22', 'Var', (151, 158))
434648	22359263	Most cases contain t(12;16) (q13;p11) producing the FUS-CHOP fusion protein although a notable minority contain the t(12;22)(q13;12) translocation associated EWSR1-CHOP (containing EWSR1, the Ewings sarcoma (EWS) breakpoint region 1).	('FUS', 'Gene', (52, 55))	('Ewings sarcoma', 'Phenotype', 'HP:0012254', (192, 206))	('CHOP', 'Gene', '1649', (56, 60))	('EWS', 'Gene', '2130', (181, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('FUS', 'Gene', '2521', (52, 55))	('Ewings sarcoma', 'Disease', 'MESH:C563168', (192, 206))	('t(12;22)(q13;12) translocation', 'Var', (116, 146))	('EWS', 'Gene', (208, 211))	('EWS', 'Gene', (158, 161))	('CHOP', 'Gene', (56, 60))	('EWSR1', 'Gene', '2130', (158, 163))	('EWSR1', 'Gene', '2130', (181, 186))	('CHOP', 'Gene', '1649', (164, 168))	('p11', 'Gene', '8909', (33, 36))	('p11', 'Gene', (33, 36))	('EWS', 'Gene', (181, 184))	('Ewings sarcoma', 'Disease', (192, 206))	('EWS', 'Gene', '2130', (208, 211))	('CHOP', 'Gene', (164, 168))	('EWS', 'Gene', '2130', (158, 161))	('EWSR1', 'Gene', (158, 163))	('EWSR1', 'Gene', (181, 186))
434680	21808716	There are also options for reconstruction by means of allograft or autograft interposition in combination with a total hip or even pelvis prosthesis, by transposition of the hip joint or by arthrodesis and hindfoot rotationplasty.	('arthrodesis', 'Disease', 'None', (190, 201))	('arthrodesis', 'Disease', (190, 201))	('autograft interposition', 'Phenotype', 'HP:0011540', (67, 90))	('transposition', 'Var', (153, 166))
434873	30779786	Intracellular KSHV genome numbers were also increased by IFIT knockdown, consistent with inhibition of KSHV DNA replication by IFITs.	('KSHV', 'Species', '37296', (14, 18))	('KS', 'Phenotype', 'HP:0100726', (103, 105))	('KSHV', 'Species', '37296', (103, 107))	('KS', 'Phenotype', 'HP:0100726', (14, 16))	('KSHV', 'Gene', (14, 18))	('IFIT', 'Gene', (57, 61))	('increased', 'PosReg', (44, 53))	('knockdown', 'Var', (62, 71))
434874	30779786	RNA seq demonstrated that IFIT depletion also led to downregulation of IFN beta and several interferon-stimulated genes (ISGs), especially OAS proteins.	('downregulation', 'NegReg', (53, 67))	('IFN beta', 'Gene', '3456', (71, 79))	('IFN beta', 'Gene', (71, 79))	('OAS', 'Disease', (139, 142))	('depletion', 'Var', (31, 40))
434894	30779786	Both NLRP1, a protein component of the inflammasome, and IFI16 may restrict KSHV reactivation, since depletion of NLRP1 or IFI16 results in increased lytic replication.	('IFI16', 'Gene', (123, 128))	('lytic replication', 'CPA', (150, 167))	('NLRP1', 'Gene', (114, 119))	('KS', 'Phenotype', 'HP:0100726', (76, 78))	('KSHV', 'MPA', (76, 80))	('KSHV', 'Species', '37296', (76, 80))	('IFI16', 'Gene', '3428', (57, 62))	('depletion', 'Var', (101, 110))	('IFI16', 'Gene', (57, 62))	('increased', 'PosReg', (140, 149))	('IFI16', 'Gene', '3428', (123, 128))
434895	30779786	Similarly, RIG-I, a cytosolic RNA sensor, may be important in limiting KSHV reactivation from latency as KSHV lytic replication was enhanced in RIG-I-/- cells.	('RIG-I', 'Gene', (11, 16))	('KSHV', 'Species', '37296', (105, 109))	('enhanced', 'PosReg', (132, 140))	('KS', 'Phenotype', 'HP:0100726', (71, 73))	('KSHV', 'Species', '37296', (71, 75))	('lytic replication', 'CPA', (110, 127))	('RIG-I-/-', 'Var', (144, 152))	('KS', 'Phenotype', 'HP:0100726', (105, 107))
434905	30779786	In mice, Ifit1, a homolog of human IFIT1B, specifically recognizes uniquely modified viral RNAs that lack 2'O-methylation of their 5' mRNA caps (cap0-mRNAs).	("2'O-methylation", 'MPA', (106, 121))	('caps', 'Gene', '828', (139, 143))	('RNAs', 'Protein', (91, 95))	('caps', 'Gene', (139, 143))	('mice', 'Species', '10090', (3, 7))	('Ifit1', 'Gene', '15957', (9, 14))	('Ifit1', 'Gene', (9, 14))	('lack', 'NegReg', (101, 105))	('IFIT1B', 'Gene', (35, 41))	('human', 'Species', '9606', (29, 34))	('IFIT1B', 'Gene', '439996', (35, 41))	('modified', 'Var', (76, 84))
434955	30779786	IFIT depletion enhanced KSHV virion production (25-32 fold) while KSHV DNA copy number increased only 9-fold, suggesting that IFITs may restrict expression of late genes that are needed for virion formation, egress or infectivity.	('depletion', 'Var', (5, 14))	('KS', 'Phenotype', 'HP:0100726', (66, 68))	('KSHV', 'Species', '37296', (66, 70))	('KSHV', 'Species', '37296', (24, 28))	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('expression', 'MPA', (145, 155))	('KSHV virion production', 'MPA', (24, 46))	('enhanced', 'PosReg', (15, 23))	('restrict', 'NegReg', (136, 144))
434959	30779786	Consistent with its effect on virus production, IFIT KD was associated with broad enhancement of KSHV lytic gene expression.	('expression', 'MPA', (113, 123))	('KSHV lytic gene', 'Gene', (97, 112))	('KSHV', 'Species', '37296', (97, 101))	('KS', 'Phenotype', 'HP:0100726', (97, 99))	('enhancement', 'PosReg', (82, 93))	('IFIT KD', 'Var', (48, 55))
434974	30779786	IFIT depletion enhanced KSHV DNA replication and upregulated viral mRNA expression, contributing to increased virion production.	('depletion', 'Var', (5, 14))	('increased', 'PosReg', (100, 109))	('KSHV', 'Species', '37296', (24, 28))	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('viral mRNA expression', 'MPA', (61, 82))	('upregulated', 'PosReg', (49, 60))	('enhanced', 'PosReg', (15, 23))	('KSHV DNA', 'MPA', (24, 32))	('virion production', 'MPA', (110, 127))
434975	30779786	There were 99 cellular genes whose transcript abundance decreased by 50% or more upon IFIT KD when KSHV lytic replication was induced.	('cellular genes', 'Gene', (14, 28))	('transcript abundance', 'MPA', (35, 55))	('decreased', 'NegReg', (56, 65))	('IFIT KD', 'Var', (86, 93))	('KS', 'Phenotype', 'HP:0100726', (99, 101))	('KSHV', 'Species', '37296', (99, 103))
434980	30779786	IFN beta expression was downregulated significantly (p<0.0001) to 7% in IFIT KD cells compared to the control (Fig 5B).	('IFIT KD cells', 'Var', (72, 85))	('downregulated', 'NegReg', (24, 37))	('to 7', 'Species', '1214577', (63, 67))	('expression', 'MPA', (9, 19))	('IFN beta', 'Gene', '3456', (0, 8))	('IFN beta', 'Gene', (0, 8))
434981	30779786	Therefore, IFITs appear to enhance IFN beta production and downstream ISG expression during KSHV lytic replication, and depletion of IFITs results in a blunted type 1 interferon response.	('KS', 'Phenotype', 'HP:0100726', (92, 94))	('expression', 'MPA', (74, 84))	('IFN beta', 'Gene', (35, 43))	('blunted', 'NegReg', (152, 159))	('depletion', 'Var', (120, 129))	('enhance', 'PosReg', (27, 34))	('KSHV', 'Species', '37296', (92, 96))	('IFN beta', 'Gene', '3456', (35, 43))
434991	30779786	The RtcB analysis demonstrated that upon IFIT KD, RNase L cleavage decreased significantly at site 36 in tRNA-His, site 27 in non-protein-coding RNA RNY4 and site 30 in non-protein-coding RNA RNY5.	('RtcB', 'Gene', (4, 8))	('RNY5', 'Gene', (192, 196))	('RNY4', 'Gene', '6086', (149, 153))	('RNase L', 'Gene', (50, 57))	('RNY4', 'Gene', (149, 153))	('RNase L', 'Gene', '6041', (50, 57))	('RtcB', 'Gene', '51493', (4, 8))	('His', 'Chemical', 'MESH:D006639', (110, 113))	('IFIT KD', 'Var', (41, 48))	('decreased', 'NegReg', (67, 76))	('RNY5', 'Gene', '6090', (192, 196))
434993	30779786	Consistent with lower cleavage activity of RNase L, total RNA yield increased significantly upon IFITs KD compared to the control (Fig 6E).	('cleavage activity', 'MPA', (22, 39))	('RNA yield', 'MPA', (58, 67))	('RNase L', 'Gene', '6041', (43, 50))	('RNase L', 'Gene', (43, 50))	('increased', 'PosReg', (68, 77))	('lower', 'NegReg', (16, 21))	('IFITs KD', 'Var', (97, 105))
435007	30779786	Therefore, IFIT1 and IFIT3, while preferentially recognizing cap0 structures, are also capable of binding to both viral and cellular capped mRNA (cap1 or cap2).	('binding', 'Interaction', (98, 105))	('cap1', 'Gene', (146, 150))	('IFIT1', 'Gene', (11, 16))	('cap2', 'Gene', '10486', (154, 158))	('cap2', 'Gene', (154, 158))	('IFIT3', 'Gene', (21, 26))	('IFIT1', 'Gene', '3434', (11, 16))	('cap1', 'Gene', '10487', (146, 150))	('cap0', 'Var', (61, 65))	('IFIT3', 'Gene', '3437', (21, 26))	('preferentially', 'PosReg', (34, 48))
435026	30779786	We examined the potential role of IFITs as KSHV inhibitory proteins by knocking down IFITs and then inducing KSHV lytic replication.	('inducing', 'Reg', (100, 108))	('KSHV', 'Species', '37296', (109, 113))	('KS', 'Phenotype', 'HP:0100726', (43, 45))	('KSHV', 'Species', '37296', (43, 47))	('KSHV', 'MPA', (109, 113))	('KS', 'Phenotype', 'HP:0100726', (109, 111))	('knocking', 'Var', (71, 79))	('IFITs', 'Gene', (85, 90))
435029	30779786	Consistent with these findings, IFIT KD also led to increased lytic KSHV mRNA accumulation.	('increased', 'PosReg', (52, 61))	('KSHV', 'Species', '37296', (68, 72))	('lytic KSHV mRNA accumulation', 'MPA', (62, 90))	('KS', 'Phenotype', 'HP:0100726', (68, 70))	('IFIT KD', 'Var', (32, 39))
435045	30779786	By using the RtcB-ligase assay, which measures the production of cyclic 3' phosphate moieties at specific RNase L cleavage sites, we were able to determine that ISG KD does lead to a functional decrease in RNase L activity.	('ISG KD', 'Var', (161, 167))	('RtcB', 'Gene', '51493', (13, 17))	('activity', 'MPA', (214, 222))	('RNase L', 'Gene', '6041', (106, 113))	('RNase L', 'Gene', (206, 213))	('RNase L', 'Gene', (106, 113))	('RtcB', 'Gene', (13, 17))	('RNase L', 'Gene', '6041', (206, 213))	('decrease', 'NegReg', (194, 202))	("cyclic 3' phosphate", 'Chemical', '-', (65, 84))
435053	30779786	Further, IFIT depletion led to decreases in IFNbeta as well as several other antiviral effectors of the interferon pathway, suggesting that IFITs may possess broad antiviral effects by virtue of their ability to amplify the interferon response.	('antiviral effects', 'MPA', (164, 181))	('decreases', 'NegReg', (31, 40))	('depletion', 'Var', (14, 23))	('IFNbeta', 'Gene', (44, 51))	('IFNbeta', 'Gene', '3456', (44, 51))
435058	30779786	IFIT1 (L-019616-00-0005), IFIT2 (L-012582-02-0005), IFIT3 (L-017691-00-0005) and negative control On-target plus Smart Pool siRNAs (D-001810-03) were purchased from Thermo Scientific.	('L-019616-00-0005', 'Var', (7, 23))	('IFIT1', 'Gene', '3434', (0, 5))	('IFIT3', 'Gene', (52, 57))	('IFIT2', 'Gene', (26, 31))	('IFIT3', 'Gene', '3437', (52, 57))	('IFIT2', 'Gene', '3433', (26, 31))	('L-012582-02-0005', 'Var', (33, 49))	('IFIT1', 'Gene', (0, 5))	('L-017691-00-0005', 'Var', (59, 75))
435060	30779786	IFIT1 GIPZ shRNA clones (RHS4531-EG3434) were purchased from Dharmacon.	('IFIT1', 'Gene', (0, 5))	('IFIT1', 'Gene', '3434', (0, 5))	('RHS4531-EG3434', 'Var', (25, 39))
435085	30779786	Cells were harvested by centrifugation and stored at -80 C. All subsequent procedures were performed at 4 C. The cell pellet was suspended in 50 ml buffer A (20 mM HEPES pH 7.5, 300 mM NaCl, 10% glycerol, 2 mM DTT, 0.1 mM EDTA, 1% Triton X-100) with proteinase inhibitor (0.3mug/ml aprotinin, 0.5mug/ml leupeptin and 0.7mug/ml pepstatin A), 10mug/ml DNase and 10mug/ml lysozyme.	('0.3mug/ml', 'Var', (272, 281))	('HEPES', 'Chemical', 'MESH:D006531', (164, 169))	('proteinase', 'Gene', (250, 260))	('glycerol', 'Chemical', 'MESH:D005990', (195, 203))	('NaCl', 'Chemical', 'MESH:D012965', (185, 189))	('proteinase', 'Gene', '100862685', (250, 260))	('Triton X-100', 'Chemical', 'MESH:D017830', (231, 243))	('DTT', 'Chemical', 'MESH:D004229', (210, 213))	('EDTA', 'Chemical', 'MESH:D004492', (222, 226))
435096	30779786	Cells were lysed by freeze-thawing in hypotonic buffer containing 20mM HEPES, pH7.3, 2mM MgCl2, 10% glycerol, 0.2mM EGTA, 1mM DTT, 1x protease inhibitor cocktail (Sigma) and RNasin (Promega).	('HEPES', 'Chemical', 'MESH:D006531', (71, 76))	('pH7.3', 'Var', (78, 83))	('hypotonic', 'Disease', (38, 47))	('glycerol', 'Chemical', 'MESH:D005990', (100, 108))	('hypotonic', 'Disease', 'MESH:D009123', (38, 47))	('EGTA', 'Chemical', 'MESH:D004533', (116, 120))	('DTT', 'Chemical', 'MESH:D004229', (126, 129))	('MgCl2', 'Chemical', 'MESH:D015636', (89, 94))
435116	30575309	An important prognostic indicator is resectability of disease with studies documenting a median OS of 38 months in patients with completely resected disease vs 11 months in those that were unresectable.14 The use of adjuvant chemotherapy12, 13 or radiotherapy14 may improve outcomes; however, studies are limited by small sample sizes and lack of randomization.	('radiotherapy14', 'Var', (247, 261))	('patients', 'Species', '9606', (115, 123))	('outcomes', 'MPA', (274, 282))	('improve', 'PosReg', (266, 273))	('OS', 'Chemical', '-', (96, 98))
435179	29433875	Alterations in Cancer Stem Cell Marker CD44 Expression Predict Oncologic Outcome in Soft Tissue Sarcomas Cancer stem cells (CSCs) have been shown to resist chemotherapy and promote metastasis after cytotoxic therapies.	('Sarcomas', 'Disease', (96, 104))	('Sarcomas', 'Disease', 'MESH:D012509', (96, 104))	('metastasis', 'CPA', (181, 191))	('CD44', 'Gene', '960', (39, 43))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Alterations', 'Var', (0, 11))	('Sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('CD44', 'Gene', (39, 43))	('Soft Tissue Sarcomas', 'Phenotype', 'HP:0030448', (84, 104))	('promote', 'PosReg', (173, 180))	('resist chemotherapy', 'CPA', (149, 168))
435187	29433875	Analysis of 74 TCGA STS cases with complete clinical and genomic data revealed that CD44 copy number alterations (CNA) predicted worse DSS (9.89 months vs. 72.5 months, P=0.007) and a trend for worse OS (14.03 months vs. 38.6 months, P=0.12), while ALDH1 and EGFR CNA did not.	('CD44', 'Gene', '960', (84, 88))	('copy number alterations', 'Var', (89, 112))	('OS', 'Chemical', '-', (200, 202))	('CD44', 'Gene', (84, 88))	('ALDH1', 'Gene', (249, 254))	('EGFR', 'Gene', '1956', (259, 263))	('ALDH1', 'Gene', '216', (249, 254))	('DSS', 'Chemical', '-', (135, 138))	('DSS', 'Disease', (135, 138))	('EGFR', 'Gene', (259, 263))	('STS', 'Phenotype', 'HP:0030448', (20, 23))
435222	29433875	Using Z-scores to analyze changes in gene expression, the mean Z-scores (+-SEM) for CD44, ALDH1, and EGFR in the STS TCGA dataset were -.035+-.11, -.098+-.12, and .132+-.15, respectively (Table 4).	('CD44', 'Gene', '960', (84, 88))	('ALDH1', 'Gene', (90, 95))	('CD44', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('STS', 'Phenotype', 'HP:0030448', (113, 116))	('ALDH1', 'Gene', '216', (90, 95))	('-.098+-.12', 'Var', (147, 157))
435224	29433875	In contrast, univariate analysis failed to show an association of H-score for either ALDH (HR = 0.98, 95% CI 0.95-1.01, p=.286) or EGFR (HR = 1.001, 95% CI 0.98-1.02, p=.876) with worse DSS or OS (Table 5).	('ALDH', 'Gene', (85, 89))	('worse DSS', 'Disease', (180, 189))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('OS', 'Chemical', '-', (193, 195))	('DSS', 'Chemical', '-', (186, 189))	('H-score', 'Var', (66, 73))
435225	29433875	As depicted in Figure 2, cBioPortal Kaplan-Meier analyses of TCGA STS data revealed that increased CD44 copy number alterations (CNA) predicted worse DFS (9.89 months vs. 72.5 months, p =.007).	('DFS', 'Disease', (150, 153))	('CD44', 'Gene', '960', (99, 103))	('copy number alterations', 'Var', (104, 127))	('CD44', 'Gene', (99, 103))	('STS', 'Phenotype', 'HP:0030448', (66, 69))	('increased', 'PosReg', (89, 98))
435240	29433875	Overall, ALDH expression has been more closely associated with worse outcomes than other CSC markers in many human cancers, including STS.	('expression', 'Var', (14, 24))	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('ALDH', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('STS', 'Disease', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('STS', 'Phenotype', 'HP:0030448', (134, 137))	('associated', 'Reg', (47, 57))
435267	29095301	Although ASPS resembles a wide variety of neoplastic conditions, such as metastatic renal cell carcinoma, paraganglioma, granular cell tumor, and melanoma, the tumor specific chromosomal translocation der (17) t(X;17) (p11;q25), which causes the fusion of the transcription factor TEF3 located on Xp11.22 with a novel gene at 17q25, named ASPL is diagnostic for ASPS.	('der (17) t(', 'Var', (201, 212))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (84, 104))	('granular cell tumor', 'Disease', 'MESH:D016586', (121, 140))	('neoplastic conditions', 'Disease', (42, 63))	('p11', 'Gene', '6281', (298, 301))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('ASPS', 'Gene', '79058', (9, 13))	('p11', 'Gene', '6281', (219, 222))	('ASPS', 'Phenotype', 'HP:0012218', (9, 13))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (73, 104))	('ASPS', 'Gene', (362, 366))	('p11', 'Gene', (298, 301))	('paraganglioma', 'Disease', (106, 119))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('metastatic renal cell carcinoma', 'Disease', (73, 104))	('ASPL', 'Gene', '79058', (339, 343))	('p11', 'Gene', (219, 222))	('paraganglioma', 'Disease', 'MESH:D010235', (106, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumor', 'Disease', (135, 140))	('ASPS', 'Gene', '79058', (362, 366))	('tumor', 'Disease', (160, 165))	('ASPS', 'Phenotype', 'HP:0012218', (362, 366))	('paraganglioma', 'Phenotype', 'HP:0002668', (106, 119))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('granular cell tumor', 'Disease', (121, 140))	('TEF3', 'Gene', (281, 285))	('ASPS', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TEF3', 'Gene', '7004', (281, 285))	('neoplastic conditions', 'Disease', 'MESH:D009135', (42, 63))	('ASPL', 'Gene', (339, 343))
435285	29095301	The tumor-specific ASPL-TFE3 fusion gene was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and sequencing, which led to the final diagnosis of lingual ASPS, T2bN0M2, Stage IIB, according to the 7th edition of the TNM Classification of Malignant Tumors.	('tumor', 'Disease', (4, 9))	('TFE3', 'Gene', '7030', (24, 28))	('ASPS', 'Gene', '79058', (175, 179))	('ASPL', 'Gene', (19, 23))	('T2bN0M2', 'Var', (181, 188))	('Malignant Tumors', 'Disease', (259, 275))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('ASPS', 'Phenotype', 'HP:0012218', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Tumors', 'Phenotype', 'HP:0002664', (269, 275))	('led to', 'Reg', (137, 143))	('TFE3', 'Gene', (24, 28))	('ASPS', 'Gene', (175, 179))	('ASPL', 'Gene', '79058', (19, 23))	('Malignant Tumors', 'Disease', 'MESH:D018198', (259, 275))
435307	29095301	Although ASPS, clear cell sarcoma of soft tissue, and translocation-associated renal cell carcinoma are all defined as MITF-associated tumors, they are morphologically and clinically distinct, yet share certain clinical features such as a disproportionate incidence among younger individuals and a strong propensity to metastasize.	('ASPS', 'Phenotype', 'HP:0012218', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('ASPS', 'Gene', (9, 13))	('MITF', 'Gene', (119, 123))	('translocation-associated', 'Var', (54, 78))	('sarcoma', 'Disease', 'MESH:D012509', (26, 33))	('MITF', 'Gene', '4286', (119, 123))	('sarcoma', 'Disease', (26, 33))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('ASPS', 'Gene', '79058', (9, 13))	('renal cell carcinoma', 'Disease', (79, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (79, 99))
435324	29095301	In the PALETTE trial, pazopanib achieved significantly longer PFS than placebo, with a median PFS of 4.6 months (95% CI 3.7-4.8) for pazopanib compared with 1.6 months (0.9-1.8) for placebo [hazard ratio (HR) 0.31; 95% CI 0.24-0.40; P <  0001], and the drug has thus become an important treatment option for metastatic soft tissue sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (331, 338))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (319, 338))	('pazopanib', 'Var', (133, 142))	('sarcoma', 'Disease', (331, 338))	('sarcoma', 'Phenotype', 'HP:0100242', (331, 338))	('pazopanib', 'Chemical', 'MESH:C516667', (133, 142))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))
435442	33562486	MFS and UPS presenting with these mutations rely on Skp2, an oncogene that promotes cell turnover, to proliferate, and thus Li et al.	('Skp2', 'Gene', '6502', (52, 56))	('promotes', 'PosReg', (75, 83))	('Skp2', 'Gene', (52, 56))	('cell turnover', 'CPA', (84, 97))	('proliferate', 'CPA', (102, 113))	('mutations', 'Var', (34, 43))
435475	27863422	Second, the top 20 positively scored drug hits (including 18 distinct drugs) that share a gene expression profile similar to the pattern obtained by the silencing of EWS/FLI1 via RNAi approaches (siEWS/FLI1) were identified.	('FLI1', 'Gene', '2313', (202, 206))	('EWS', 'Phenotype', 'HP:0012254', (166, 169))	('silencing', 'Var', (153, 162))	('FLI1', 'Gene', (170, 174))	('FLI1', 'Gene', '2313', (170, 174))	('EWS', 'Phenotype', 'HP:0012254', (198, 201))	('FLI1', 'Gene', (202, 206))
435478	27863422	A panel of sarcoma cell lines including 3 EWS lines, each with a confirmed EWS gene rearrangements and two non-tumorigenic and one benign osteoid osteoma control cell lines (Hs 822.T., Hs 863.T., and Hs 919.T.	('sarcoma', 'Disease', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('osteoma', 'Phenotype', 'HP:0100246', (146, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('EWS', 'Phenotype', 'HP:0012254', (75, 78))	('osteoid osteoma', 'Phenotype', 'HP:0030433', (138, 153))	('tumor', 'Disease', (111, 116))	('EWS', 'Gene', (75, 78))	('rearrangements', 'Var', (84, 98))	('sarcoma', 'Disease', 'MESH:D012509', (11, 18))	('EWS', 'Phenotype', 'HP:0012254', (42, 45))	('benign osteoid osteoma', 'Disease', 'MESH:D010017', (131, 153))	('benign osteoid osteoma', 'Disease', (131, 153))
435485	27863422	Several classes of agents were found to be highly synergistic in combination with auranofin, including the next generation HSP90 inhibitors ganetespib (STA-9090; Synta Pharmaceuticals) and AUY922 (Novartis).	('auranofin', 'Chemical', 'MESH:D001310', (82, 91))	('AUY922', 'Var', (189, 195))	('HSP90', 'Gene', (123, 128))	('AUY922', 'Chemical', 'MESH:C528044', (189, 195))	('ganetespib', 'Chemical', 'MESH:C533237', (140, 150))	('HSP90', 'Gene', '3320', (123, 128))	('STA', 'Gene', '2656', (152, 155))	('STA', 'Gene', (152, 155))	('combination', 'Interaction', (65, 76))	('Synta', 'Chemical', '-', (162, 167))
435492	27863422	Treatment with siFLI1-#3, or to a greater extent, siBPEF1, significantly decreased the EWS-FLI1 protein expression in A673 cells with type I fusion at 48h after transfection, as compared with the siControl treatment (Figure 3A).	('FLI1', 'Gene', '2313', (17, 21))	('protein', 'Protein', (96, 103))	('siControl', 'Chemical', '-', (196, 205))	('decreased', 'NegReg', (73, 82))	('siBPEF1', 'Var', (50, 57))	('FLI1', 'Gene', (17, 21))	('FLI1', 'Gene', '2313', (91, 95))	('EWS', 'Phenotype', 'HP:0012254', (87, 90))	('FLI1', 'Gene', (91, 95))
435493	27863422	In addition, A673 cells became resistant to auranofin after the silencing of EWS-FLI1 gene, as evidenced by the significant increase in the IC50 values of A673 cells treated by siFLI1-#3 or siBPEF1 followed by the incubation of auranofin for 72 h (siFLI1-#3 and siBPEF1 IC50 values are above 1.0 mumol/L), as compared with the counterpart of the siControl group (siControl, IC50 = 0.27 +- 0.02 mumol/L) (Figure 3B).	('IC50', 'MPA', (140, 144))	('FLI1', 'Gene', (179, 183))	('increase', 'PosReg', (124, 132))	('siControl', 'Chemical', '-', (363, 372))	('EWS', 'Phenotype', 'HP:0012254', (77, 80))	('siBPEF1', 'Var', (262, 269))	('auranofin', 'Chemical', 'MESH:D001310', (44, 53))	('silencing', 'NegReg', (64, 73))	('siControl', 'Chemical', '-', (346, 355))	('FLI1', 'Gene', (250, 254))	('FLI1', 'Gene', (81, 85))	('FLI1', 'Gene', '2313', (250, 254))	('auranofin', 'Chemical', 'MESH:D001310', (228, 237))	('FLI1', 'Gene', '2313', (81, 85))	('FLI1', 'Gene', '2313', (179, 183))
435495	27863422	Ridaura  (auranofin) is typically delivered orally (capsules containing 3 mg auranofin) and has been repurposed in several clinical trials with limited results (i.e., clinicaltrials.gov identifier: NCT01419691, NCT02126527, and NCT02126527).	('auranofin', 'Chemical', 'MESH:D001310', (77, 86))	('NCT02126527', 'Var', (211, 222))	('NCT02126527', 'Var', (228, 239))	('auranofin', 'Chemical', 'MESH:D001310', (10, 19))
435549	27863422	In addition to the drugs that are predicted to reverse the disease gene expression, we identified the drugs that share an expression profile similar to the silence of EWS/FLI1, a key causative factor in the pathogenesis of EWS, and the drugs that may overcome clinical drug resistance.	('FLI1', 'Gene', '2313', (171, 175))	('drug resistance', 'Phenotype', 'HP:0020174', (269, 284))	('EWS', 'Disease', (223, 226))	('silence', 'Var', (156, 163))	('EWS', 'Phenotype', 'HP:0012254', (167, 170))	('FLI1', 'Gene', (171, 175))	('EWS', 'Phenotype', 'HP:0012254', (223, 226))
435555	27863422	Meanwhile, two active phase II clinical trials where non-small-cell-lung cancer patients will be treated with entinostat before chemotherapy (NCT01935947) and anti-PD1 treatment (NCT01928576) are ongoing, which indicates the feasibility of combination studies of entinostat with other targeted agents as an epigenetic-based therapy in EWS treatment.	('lung cancer', 'Disease', (68, 79))	('NCT01928576', 'Var', (179, 190))	('patients', 'Species', '9606', (80, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('EWS', 'Phenotype', 'HP:0012254', (335, 338))	('NCT01935947', 'Var', (142, 153))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))
435557	27863422	In addition, the Genomics of Drug Sensitivity in Cancer (GDSC) database shows that cancer cells with EWS-FLI1 mutations are preferentially sensitive to elesclomol as compare with the wide-type counterparts (http://www.cancerrxgene.org/translation/Drug/1031#t_scatter_1031), which is consistent with our in vitro drug screens.	('elesclomol', 'Chemical', 'MESH:C512195', (152, 162))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('preferentially', 'PosReg', (124, 138))	('mutations', 'Var', (110, 119))	('EWS', 'Phenotype', 'HP:0012254', (101, 104))	('cancer', 'Disease', (218, 224))	('sensitive to elesclomol', 'MPA', (139, 162))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('FLI1', 'Gene', (105, 109))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (29, 45))	('Cancer', 'Disease', (49, 55))	('FLI1', 'Gene', '2313', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (83, 89))
435587	27863422	Our validation screen identified three HSP90 inhibitors: geldanamycin, ganetespib, and AUY922.	('HSP90', 'Gene', '3320', (39, 44))	('geldanamycin', 'Chemical', 'MESH:C001277', (57, 69))	('ganetespib', 'Chemical', 'MESH:C533237', (71, 81))	('AUY922', 'Var', (87, 93))	('AUY922', 'Chemical', 'MESH:C528044', (87, 93))	('HSP90', 'Gene', (39, 44))
435592	27863422	AUY922 is an isoxazole-based HSP90 inhibitor that antagonizes the ATPase activity of the protein.	('AUY922', 'Var', (0, 6))	('ATPase', 'Protein', (66, 72))	('activity', 'MPA', (73, 81))	('AUY922', 'Chemical', 'MESH:C528044', (0, 6))	('ATP', 'Chemical', 'MESH:D000255', (66, 69))	('antagonizes', 'NegReg', (50, 61))	('isoxazole', 'Chemical', 'MESH:D007555', (13, 22))	('HSP90', 'Gene', (29, 34))	('HSP90', 'Gene', '3320', (29, 34))
435596	27863422	NCT01227018, a phase 2 study STA-9090 as second or third-line therapy for metastatic pancreas cancer, was terminated due to interim analysis found the study drug to be ineffective (15 patients were enrolled).	('pancreas cancer', 'Phenotype', 'HP:0002894', (85, 100))	('patients', 'Species', '9606', (184, 192))	('pancreas cancer', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('pancreas cancer', 'Disease', 'MESH:D010190', (85, 100))	('STA', 'Gene', '2656', (29, 32))	('STA', 'Gene', (29, 32))	('NCT01227018', 'Var', (0, 11))
435705	27733179	was also the first study to suggest that there is a relationship between positive margins and tumour-related mortality.	('tumour', 'Disease', (94, 100))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('positive margins', 'Var', (73, 89))
435709	27733179	Deep seated lesions, tumour size > 10 cm, high-grade and recurrence after radical surgery are all found to be high risks factors for distant metastasis.	('high-grade', 'Var', (42, 52))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('distant metastasis', 'CPA', (133, 151))	('tumour', 'Disease', (21, 27))
435712	27733179	Lack of re-excision after local failure has proven to be associated with a decreased overall survival and an increased risk of metastasis as found in the study of Zagars et al..	('local failure', 'Disease', (26, 39))	('Lack', 'Var', (0, 4))	('local failure', 'Disease', 'MESH:D012594', (26, 39))	('overall survival', 'CPA', (85, 101))	('metastasis', 'CPA', (127, 137))	('decreased', 'NegReg', (75, 84))
435729	27733179	On multivariable analysis adjusting for patient age and tumour size, IMRT retained significance as an independent predictor of reduced local recurrence.	('patient', 'Species', '9606', (40, 47))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('IMRT', 'Var', (69, 73))	('reduced', 'NegReg', (127, 134))	('tumour', 'Disease', (56, 62))	('local recurrence', 'CPA', (135, 151))
435749	27733179	It has been suggested that HDR brachytherapy may be associated with lower incidences of severe toxicity.	('HDR', 'Var', (27, 30))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('toxicity', 'Disease', (95, 103))
435786	23060122	Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions SMARCB1 gene alterations were first described in highly malignant rhabdoid tumors of the kidney, brain (atypical teratoid/rhabdoid tumor) and soft tissue.	('teratoid/rhabdoid tumor', 'Disease', (191, 214))	('malignant rhabdoid tumors', 'Disease', (134, 159))	('Epithelioid sarcoma', 'Disease', (0, 19))	('deletions', 'Var', (68, 77))	('Epithelioid sarcoma', 'Disease', 'MESH:D012509', (0, 19))	('SMARCB1', 'Gene', '6598', (60, 67))	('rhabdoid tumors of the kidney', 'Disease', 'MESH:D018335', (144, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('SMARCB1', 'Gene', '6598', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('rhabdoid tumors of the kidney', 'Disease', (144, 173))	('SMARCB1', 'Gene', (60, 67))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (134, 159))	('tumors of the kidney', 'Phenotype', 'HP:0009726', (153, 173))	('SMARCB1', 'Gene', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('teratoid/rhabdoid tumor', 'Disease', 'MESH:C000597569', (191, 214))
435788	23060122	However, investigations of SMARCB1 gene alterations in epithelioid sarcoma have produced conflicting results.	('SMARCB1', 'Gene', (27, 34))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (55, 74))	('epithelioid sarcoma', 'Disease', (55, 74))	('alterations', 'Var', (40, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('SMARCB1', 'Gene', '6598', (27, 34))
435789	23060122	The aim of this study was to evaluate SMARCB1 status using Sanger sequencing of the coding region and multiplex ligation dependent probe amplification, a rapid and sensitive method for detecting intragenic deletions and duplications, which has not been used in previous studies.	('deletions', 'Var', (206, 215))	('SMARCB1', 'Gene', '6598', (38, 45))	('duplications', 'Var', (220, 232))	('SMARCB1', 'Gene', (38, 45))
435793	23060122	These results confirm the high frequency of SMARCB1 deletions in epithelioid sarcoma and show that multiplex ligation dependent probe amplification is a reliable method for detection of deletions in these cases which can be performed on formalin-fixed, paraffin-embedded tissue.	('epithelioid sarcoma', 'Disease', (65, 84))	('SMARCB1', 'Gene', '6598', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('SMARCB1', 'Gene', (44, 51))	('paraffin', 'Chemical', 'MESH:D010232', (253, 261))	('deletions', 'Var', (52, 61))	('formalin', 'Chemical', 'MESH:D005557', (237, 245))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (65, 84))
435794	23060122	Given the high percentage of SMARCB1 alterations in epithelioid sarcoma, these findings argue against using SMARCB1 gene deletion as a tool in distinguishing them from malignant rhabdoid tumors.	('SMARCB1', 'Gene', (108, 115))	('epithelioid sarcoma', 'Disease', (52, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('malignant rhabdoid tumors', 'Disease', (168, 193))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('SMARCB1', 'Gene', '6598', (29, 36))	('SMARCB1', 'Gene', (29, 36))	('alterations', 'Var', (37, 48))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (168, 193))	('SMARCB1', 'Gene', '6598', (108, 115))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (52, 71))
435797	23060122	The diagnosis of malignant rhabdoid tumor was revolutionized by the discovery of SMARCB1 alterations in these tumors with subsequent loss of protein expression detectable by immunohistochemistry.	('protein expression', 'MPA', (141, 159))	('SMARCB1', 'Gene', '6598', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('SMARCB1', 'Gene', (81, 88))	('loss', 'NegReg', (133, 137))	('tumors', 'Disease', (110, 116))	('malignant rhabdoid tumor', 'Disease', (17, 41))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (17, 41))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('alterations', 'Var', (89, 100))
435798	23060122	Comprehensive genomic analysis using high density single nucleotide polymorphism based oligonucleotide arrays, multiplex ligation dependent probe amplification and coding sequence analysis has shown that 98% of malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor and extra renal rhabdoid tumors have bi-allelic SMARCB1 alterations with few additional karyotypic abnormalities.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (211, 235))	('teratoid/rhabdoid tumor', 'Disease', 'MESH:C000597569', (246, 269))	('teratoid/rhabdoid tumor', 'Disease', (246, 269))	('extra renal rhabdoid tumors', 'Disease', (274, 301))	('extra renal rhabdoid tumors', 'Disease', 'MESH:D018335', (274, 301))	('SMARCB1', 'Gene', '6598', (318, 325))	('malignant rhabdoid tumor', 'Disease', (211, 235))	('SMARCB1', 'Gene', (318, 325))	('oligonucleotide', 'Chemical', 'MESH:D009841', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('alterations', 'Var', (326, 337))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))
435800	23060122	Soft tissue tumors comprise the majority of cases, and include epithelioid sarcoma, schwannomas associated with germline SMARCB1 abnormalities, and a subset of cases diagnosed as epithelioid malignant peripheral nerve sheath tumors, pediatric undifferentiated sarcomas, synovial sarcomas, myoepithelial carcinomas and extraskeletal myxoid chondrosarcomas.	('epithelioid sarcoma', 'Disease', (63, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('schwannomas', 'Phenotype', 'HP:0100008', (84, 95))	('associated', 'Reg', (96, 106))	('myoepithelial carcinomas', 'Disease', (289, 313))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (191, 231))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (303, 313))	('abnormalities', 'Var', (129, 142))	('sarcomas', 'Disease', 'MESH:D012509', (346, 354))	('sarcomas', 'Disease', 'MESH:D012509', (260, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (346, 354))	('schwannomas', 'Disease', 'MESH:D009442', (84, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (260, 268))	('sarcomas', 'Disease', (346, 354))	('sarcomas', 'Disease', (260, 268))	('SMARCB1', 'Gene', (121, 128))	('SMARCB1', 'Gene', '6598', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (270, 287))	('synovial sarcomas', 'Disease', (270, 287))	('schwannomas', 'Disease', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('tumors', 'Disease', (12, 18))	('myxoid chondrosarcomas', 'Disease', (332, 354))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (63, 82))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (332, 354))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('myoepithelial carcinomas', 'Disease', 'MESH:D009208', (289, 313))	('sarcomas', 'Disease', 'MESH:D012509', (279, 287))	('sarcoma', 'Phenotype', 'HP:0100242', (346, 353))	('sarcomas', 'Phenotype', 'HP:0100242', (279, 287))	('sarcomas', 'Disease', (279, 287))	('synovial sarcomas', 'Disease', 'MESH:D013584', (270, 287))	('epithelioid malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (179, 231))	('Soft tissue tumors', 'Phenotype', 'HP:0031459', (0, 18))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (339, 354))	('tumors', 'Disease', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
435806	23060122	Regardless of the classical or proximal type designation, these tumors express epithelial and mesenchymal markers with loss of SMARCB1, reminiscent of malignant rhabdoid tumor.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SMARCB1', 'Gene', '6598', (127, 134))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (151, 175))	('SMARCB1', 'Gene', (127, 134))	('malignant rhabdoid tumor', 'Disease', (151, 175))	('loss', 'Var', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('express', 'Reg', (71, 78))
435810	23060122	While some may argue that proximal epithelioid sarcoma and malignant rhabdoid tumor represent different manifestations of the same tumor, differential CD34 expression and the rarity of epithelioid sarcoma in adolescents and young adults with germline SMARCB1 mutations support these tumors as distinct entities.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (35, 54))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('CD34', 'Gene', (151, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('tumors', 'Disease', (283, 289))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (185, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('epithelioid sarcoma', 'Disease', (35, 54))	('mutations', 'Var', (259, 268))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('epithelioid sarcoma', 'Disease', (185, 204))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('CD34', 'Gene', '947', (151, 155))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (59, 83))	('tumor', 'Disease', (283, 288))	('SMARCB1', 'Gene', (251, 258))	('SMARCB1', 'Gene', '6598', (251, 258))	('malignant rhabdoid tumor', 'Disease', (59, 83))
435811	23060122	Furthermore, malignant rhabdoid tumors most often show isolated 22q abnormalities whereas many proximal and classical epithelioid sarcomas have chromosome 22 abnormalities in addition to a more complex karyotype including abnormalities on chromosomes 6, 7, 8, 14, 18, 20 and 21.	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('isolated 22q abnormalities', 'Var', (55, 81))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (13, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (118, 138))	('malignant rhabdoid tumors', 'Disease', (13, 38))	('epithelioid sarcomas', 'Disease', (118, 138))
435812	23060122	Investigations of SMARCB1 gene alterations in epithelioid sarcoma have shown conflicting results.	('alterations', 'Var', (31, 42))	('SMARCB1', 'Gene', (18, 25))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (46, 65))	('epithelioid sarcoma', 'Disease', (46, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('SMARCB1', 'Gene', '6598', (18, 25))
435813	23060122	Previously reported data from 3 studies which cumulatively included 65 SMARCB1 negative tumors by immunohistochemistry showed that the percentage of cases with homozygous SMARCB1 deletions ranged from 5-71%.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('SMARCB1', 'Gene', '6598', (71, 78))	('SMARCB1', 'Gene', (71, 78))	('deletions', 'Var', (179, 188))	('SMARCB1', 'Gene', '6598', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('SMARCB1', 'Gene', (171, 178))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
435814	23060122	In addition to chromosome 22 deletions, there are also 3 reports of SMARCB1 inactivating mutations in epithelioid sarcoma, including 2 frameshift and 1 nonsense mutations.	('frameshift', 'Var', (135, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('inactivating', 'NegReg', (76, 88))	('SMARCB1', 'Gene', (68, 75))	('SMARCB1', 'Gene', '6598', (68, 75))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (102, 121))	('epithelioid sarcoma', 'Disease', (102, 121))
435818	23060122	The aim of this study was to better establish the percent and spectrum of SMARCB1 gene abnormalities in epithelioid sarcoma, using sequencing to identify mutations, and multiplex ligation dependent probe amplification for the detection of small deletions and duplication within the SMARCB1 gene.	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (104, 123))	('duplication', 'Var', (259, 270))	('SMARCB1', 'Gene', (282, 289))	('epithelioid sarcoma', 'Disease', (104, 123))	('SMARCB1', 'Gene', '6598', (74, 81))	('SMARCB1', 'Gene', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('SMARCB1', 'Gene', '6598', (282, 289))
435839	23060122	While approximately 98% of malignant rhabdoid tumors harbor bi-allelic SMARCB1 gene abnormalities with few additional karyotypic abnormalities, there is conflicting data for epithelioid sarcoma.	('SMARCB1', 'Gene', '6598', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('malignant rhabdoid tumors', 'Disease', (27, 52))	('SMARCB1', 'Gene', (71, 78))	('bi-allelic', 'Var', (60, 70))	('abnormalities', 'Var', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (174, 193))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (27, 52))	('epithelioid sarcoma', 'Disease', (174, 193))
435841	23060122	Of 7 (5 proximal and 2 classical) immunohistochemistry negative cases, 5 (71%) proximal epithelioid sarcomas demonstrated homozygous deletions of SMARCB1 using bacterial artificial chromosome probes for dual-color fluorescence in situ hybridization.	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (88, 108))	('deletions', 'Var', (133, 142))	('SMARCB1', 'Gene', (146, 153))	('epithelioid sarcomas', 'Disease', (88, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (100, 108))	('SMARCB1', 'Gene', '6598', (146, 153))
435842	23060122	Semi-quantitative polymerase chain reaction of SMARCB1 exon 1was performed on 4 of the cases with homozygous deletions and showed concordant results.	('SMARCB1', 'Gene', (47, 54))	('deletions', 'Var', (109, 118))	('SMARCB1', 'Gene', '6598', (47, 54))
435847	23060122	describing a case of proximal epithelioid sarcoma with a c.769C>T mutation in exon 6 resulting in the generation of an in-frame stopcodon.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('c.769C>T', 'Mutation', 'c.769C>T', (57, 65))	('c.769C>T', 'Var', (57, 65))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (30, 49))	('epithelioid sarcoma', 'Disease', (30, 49))
435849	23060122	As tabulated in the article, a total of 11 cases (58%, 4 proximal and 7 classical) were shown to harbor homozygous deletions of SMARCB1 with 9 identified through fluorescence in situ hybridization and an additional 2 by quantitative polymerase chain reaction for exon 4.	('SMARCB1', 'Gene', (128, 135))	('SMARCB1', 'Gene', '6598', (128, 135))	('deletions', 'Var', (115, 124))
435850	23060122	This was the first series to demonstrate SMARCB1 deletions in both proximal and classical epithelioid sarcoma.	('SMARCB1', 'Gene', (41, 48))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (90, 109))	('proximal', 'Disease', (67, 75))	('epithelioid sarcoma', 'Disease', (90, 109))	('deletions', 'Var', (49, 58))	('SMARCB1', 'Gene', '6598', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
435851	23060122	Taken together, the above studies demonstrate that SMARCB1 deletions are far more common than gene mutations in epithelioid sarcoma; however, the exact number of cases with primary gene abnormalities varies dramatically between published reports.	('primary gene abnormalities', 'Disease', (173, 199))	('primary gene abnormalities', 'Disease', 'MESH:D025063', (173, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('deletions', 'Var', (59, 68))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (112, 131))	('epithelioid sarcoma', 'Disease', (112, 131))	('SMARCB1', 'Gene', '6598', (51, 58))	('common', 'Reg', (82, 88))	('SMARCB1', 'Gene', (51, 58))
435856	23060122	The finding of this high rate of bilallelic loss or inactivation of SMARCB1 in a high percentage of both proximal and classical epithelioid sarcoma tumors tested is consistent with the two hit model of carcinogenesis associated with loss of function of a tumor suppressor gene, and correlates with the near universal biallelic loss or inactivation of SMARCB1 seen in malignant rhabdoid tumor.	('epithelioid sarcoma tumors', 'Disease', 'MESH:D012509', (128, 154))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (367, 391))	('malignant rhabdoid tumor', 'Disease', (367, 391))	('SMARCB1', 'Gene', (68, 75))	('loss', 'NegReg', (44, 48))	('SMARCB1', 'Gene', '6598', (68, 75))	('inactivation', 'NegReg', (335, 347))	('tumor', 'Disease', (386, 391))	('epithelioid sarcoma tumors', 'Disease', (128, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (386, 391))	('inactivation', 'Var', (52, 64))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('carcinogenesis', 'Disease', (202, 216))	('SMARCB1', 'Gene', '6598', (351, 358))	('bilallelic', 'Var', (33, 43))	('tumor', 'Disease', (255, 260))	('SMARCB1', 'Gene', (351, 358))	('loss', 'NegReg', (327, 331))	('carcinogenesis', 'Disease', 'MESH:D063646', (202, 216))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
435857	23060122	Although 2 of our cases only showed heterozygous deletions, the loss of SMARCB1 protein expression suggests the presence of an undetected abnormality of SMARCB1 in the other allele.	('SMARCB1', 'Gene', (72, 79))	('SMARCB1', 'Gene', '6598', (153, 160))	('SMARCB1', 'Gene', '6598', (72, 79))	('SMARCB1', 'Gene', (153, 160))	('loss', 'NegReg', (64, 68))	('protein', 'Protein', (80, 87))	('deletions', 'Var', (49, 58))	('expression', 'MPA', (88, 98))
435861	23060122	It is important to note that the high percentage of cases with homozygous deletions, relatively low number of cases with intragenic deletions and subset of cases where only a single gene defect could be identified raises the possibility that loss of SMARCB1 protein expression may be a secondary event in epithelioid sarcoma.	('deletions', 'Var', (74, 83))	('protein', 'Protein', (258, 265))	('SMARCB1', 'Gene', '6598', (250, 257))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (305, 324))	('sarcoma', 'Phenotype', 'HP:0100242', (317, 324))	('SMARCB1', 'Gene', (250, 257))	('epithelioid sarcoma', 'Disease', (305, 324))	('loss', 'Var', (242, 246))
435862	23060122	The driving force for chromosome 22 deletions seen in epithelioid sarcoma may actually result from selection of a nearby gene instead of SMARCB1.	('deletions', 'Var', (36, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (54, 73))	('SMARCB1', 'Gene', '6598', (137, 144))	('SMARCB1', 'Gene', (137, 144))	('epithelioid sarcoma', 'Disease', (54, 73))
435865	23060122	As a result, the finding of bi-allelic mutations or deletions in SMARCB1 should not be used as criteria to support reclassifying epithelioid sarcoma as malignant rhabdoid tumor.	('malignant rhabdoid tumor', 'Disease', (152, 176))	('bi-allelic mutations', 'Var', (28, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (129, 148))	('SMARCB1', 'Gene', '6598', (65, 72))	('deletions', 'Var', (52, 61))	('epithelioid sarcoma', 'Disease', (129, 148))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (152, 176))	('SMARCB1', 'Gene', (65, 72))
435866	23060122	Being able to reliably differentiate epithelioid sarcoma and malignant rhabdoid tumor is important due to differences in treatment, prognosis and the association of malignant rhabdoid tumor with germline mutations necessitating additional genetic testing and family counseling.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (61, 85))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (37, 56))	('germline mutations', 'Var', (195, 213))	('malignant rhabdoid tumor', 'Disease', (61, 85))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (165, 189))	('epithelioid sarcoma', 'Disease', (37, 56))	('malignant rhabdoid tumor', 'Disease', (165, 189))	('association', 'Interaction', (150, 161))
435867	23060122	Despite intensive treatment for patients with malignant rhabdoid tumor, many patients die of widespread metastatic disease, especially those with germline mutations and second primary lesions.	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (46, 70))	('patients', 'Species', '9606', (32, 40))	('germline mutations', 'Var', (146, 164))	('malignant rhabdoid tumor', 'Disease', (46, 70))	('patients', 'Species', '9606', (77, 85))	('widespread', 'Disease', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
435875	23060122	Until recently, many used SMARCB1 deletions or absence of SMARCB1 protein expression by immunohistochemistry as evidence for the diagnosis of malignant rhabdoid tumor, especially in children.	('expression', 'MPA', (74, 84))	('protein', 'Protein', (66, 73))	('absence', 'NegReg', (47, 54))	('SMARCB1', 'Gene', '6598', (26, 33))	('deletions', 'Var', (34, 43))	('SMARCB1', 'Gene', (26, 33))	('SMARCB1', 'Gene', '6598', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('children', 'Species', '9606', (182, 190))	('SMARCB1', 'Gene', (58, 65))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (142, 166))	('malignant rhabdoid tumor', 'Disease', (142, 166))
435877	23060122	Our study demonstrates that the majority of both proximal and classical epithelioid sarcoma have homozygous deletions of SMARCB1, which can be identified with multiplex ligation dependent probe amplification.	('SMARCB1', 'Gene', (121, 128))	('SMARCB1', 'Gene', '6598', (121, 128))	('epithelioid sarcoma', 'Disease', (72, 91))	('proximal', 'Disease', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('deletions', 'Var', (108, 117))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (72, 91))
435878	23060122	Given the high percentage of SMARCB1 alterations in epithelioid sarcoma, these findings argue against using SMARCB1 gene deletion to distinguish epithelioid sarcoma from malignant rhabdoid tumor.	('SMARCB1', 'Gene', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('malignant rhabdoid tumor', 'Disease', (170, 194))	('epithelioid sarcoma', 'Disease', (52, 71))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (170, 194))	('epithelioid sarcoma', 'Disease', (145, 164))	('SMARCB1', 'Gene', '6598', (29, 36))	('SMARCB1', 'Gene', (29, 36))	('alterations', 'Var', (37, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('SMARCB1', 'Gene', '6598', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (52, 71))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (145, 164))
436012	31215499	Recent reports have shown that FAM83H is also involved in the progression of human cancers in conjunction with tumor-associated molecules, such as MYC and beta-catenin.	('MYC', 'Gene', (147, 150))	('beta-catenin', 'Gene', (155, 167))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('FAM83H', 'Var', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('beta-catenin', 'Gene', '1499', (155, 167))	('MYC', 'Gene', '4609', (147, 150))	('tumor', 'Disease', (111, 116))	('involved', 'Reg', (46, 54))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
436015	31215499	The expression of nuclear FAM83H, cytoplasmic FAM83H, and beta-catenin were significantly associated with each other and significantly associated with shorter survival of osteosarcoma patients by univariate analysis.	('beta-catenin', 'Gene', (58, 70))	('survival', 'MPA', (159, 167))	('nuclear FAM83H', 'Var', (18, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('cytoplasmic FAM83H', 'Var', (34, 52))	('patients', 'Species', '9606', (184, 192))	('expression', 'Species', '29278', (4, 14))	('shorter', 'NegReg', (151, 158))	('beta-catenin', 'Gene', '1499', (58, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('associated', 'Reg', (90, 100))	('associated', 'Reg', (135, 145))	('osteosarcoma', 'Disease', (171, 183))
436016	31215499	In multivariate analysis, cytoplasmic expression of FAM83H was an independent indicator of shorter survival of osteosarcoma patients (overall survival; P <  0.001, relapse-free survival; P <  0.001).	('expression', 'Species', '29278', (38, 48))	('FAM83H', 'Var', (52, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('osteosarcoma', 'Disease', (111, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (111, 123))	('survival', 'MPA', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('shorter', 'NegReg', (91, 98))	('patients', 'Species', '9606', (124, 132))
436017	31215499	In U2OS, MG63, and KHOS/NP osteosarcoma cells, the knock-down of FAM83H decreased proliferation and invasion activity and overexpression of FAM83H increased proliferation and invasion activity.	('expression', 'Species', '29278', (126, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (27, 39))	('KHOS/NP osteosarcoma', 'Disease', (19, 39))	('increased', 'PosReg', (147, 156))	('KHOS/NP osteosarcoma', 'Disease', 'MESH:D012516', (19, 39))	('U2OS', 'CellLine', 'CVCL:0042', (3, 7))	('FAM83H', 'Var', (65, 71))	('decreased', 'NegReg', (72, 81))	('invasion activity', 'CPA', (175, 192))	('knock-down', 'Var', (51, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('proliferation', 'CPA', (82, 95))	('MG63', 'CellLine', 'CVCL:0426', (9, 13))	('invasion activity', 'CPA', (100, 117))	('proliferation', 'CPA', (157, 170))
436018	31215499	In KHOS/NP cells, knock-down of FAM83H significantly inhibited, and overexpression of FAM83H significantly increased in vivo growth of cells.	('KHOS', 'Chemical', '-', (3, 7))	('FAM83H', 'Var', (32, 38))	('inhibited', 'NegReg', (53, 62))	('FAM83H', 'Var', (86, 92))	('increased', 'PosReg', (107, 116))	('expression', 'Species', '29278', (72, 82))	('overexpression', 'PosReg', (68, 82))	('knock-down', 'Var', (18, 28))
436019	31215499	In addition, the knock-down of FAM83H decreased protein expression of beta-catenin, active beta-catenin, cyclin D1, vimentin, and snail.	('decreased', 'NegReg', (38, 47))	('snail', 'Gene', '6615', (130, 135))	('protein expression', 'MPA', (48, 66))	('FAM83H', 'Var', (31, 37))	('beta-catenin', 'Gene', (70, 82))	('expression', 'Species', '29278', (56, 66))	('beta-catenin', 'Gene', (91, 103))	('knock-down', 'Var', (17, 27))	('beta-catenin', 'Gene', '1499', (70, 82))	('cyclin D1', 'Gene', '595', (105, 114))	('vimentin', 'Gene', '7431', (116, 124))	('active', 'MPA', (84, 90))	('snail', 'Gene', (130, 135))	('cyclin D1', 'Gene', (105, 114))	('vimentin', 'Gene', (116, 124))	('beta-catenin', 'Gene', '1499', (91, 103))
436020	31215499	Overexpression of FAM83H increased protein expression of beta-catenin, active beta-catenin, cyclin D1, vimentin, and snail.	('vimentin', 'Gene', '7431', (103, 111))	('cyclin D1', 'Gene', '595', (92, 101))	('vimentin', 'Gene', (103, 111))	('increased', 'PosReg', (25, 34))	('expression', 'Species', '29278', (4, 14))	('FAM83H', 'Var', (18, 24))	('snail', 'Gene', '6615', (117, 122))	('protein expression', 'MPA', (35, 53))	('cyclin D1', 'Gene', (92, 101))	('expression', 'Species', '29278', (43, 53))	('beta-catenin', 'Gene', (78, 90))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (78, 90))	('snail', 'Gene', (117, 122))	('beta-catenin', 'Gene', '1499', (57, 69))
436021	31215499	However, the expression of beta-catenin mRNA was not significantly altered with knock-down or overexpression of FAM83H.	('expression', 'Species', '29278', (13, 23))	('beta-catenin', 'Gene', '1499', (27, 39))	('expression', 'MPA', (13, 23))	('FAM83H', 'Var', (112, 118))	('expression', 'Species', '29278', (98, 108))	('beta-catenin', 'Gene', (27, 39))
436022	31215499	In addition, FAM83H and beta-catenin shown to directly interact via immunoprecipitation and nuclear and cytoplasmic localization of beta-catenin was decreased with knock-down of FAM83H.	('FAM83H', 'Var', (178, 184))	('beta-catenin', 'Gene', (24, 36))	('knock-down', 'Var', (164, 174))	('beta-catenin', 'Gene', (132, 144))	('beta-catenin', 'Gene', '1499', (24, 36))	('beta-catenin', 'Gene', '1499', (132, 144))	('decreased', 'NegReg', (149, 158))
436023	31215499	Moreover, the ubiquitination and proteasomal degradation of beta-catenin was increased with knock-down of FAM83H.	('FAM83H', 'Var', (106, 112))	('ubiquitination', 'MPA', (14, 28))	('proteasomal degradation', 'MPA', (33, 56))	('beta-catenin', 'Gene', (60, 72))	('increased', 'PosReg', (77, 86))	('beta-catenin', 'Gene', '1499', (60, 72))	('knock-down', 'Var', (92, 102))
436024	31215499	This study suggests that FAM83H is involved in the progression of osteosarcomas via a mechanism involving the stabilization of beta-catenin and the promotion of proliferation and invasiveness of osteosarcomas.	('invasiveness of osteosarcomas', 'Disease', 'MESH:D012516', (179, 208))	('osteosarcomas', 'Disease', (195, 208))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('osteosarcomas', 'Disease', 'MESH:D012516', (66, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('beta-catenin', 'Gene', (127, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('beta-catenin', 'Gene', '1499', (127, 139))	('FAM83H', 'Var', (25, 31))	('osteosarcomas', 'Phenotype', 'HP:0002669', (195, 208))	('osteosarcomas', 'Disease', (66, 79))	('stabilization', 'MPA', (110, 123))	('promotion', 'PosReg', (148, 157))	('osteosarcomas', 'Phenotype', 'HP:0002669', (66, 79))	('proliferation', 'CPA', (161, 174))	('osteosarcoma', 'Phenotype', 'HP:0002669', (195, 207))	('involved', 'Reg', (35, 43))	('osteosarcomas', 'Disease', 'MESH:D012516', (195, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('invasiveness of osteosarcomas', 'Disease', (179, 208))
436026	31215499	Mutation of FAM83H is the main etiological factor for human autosomal dominant hypocalcified amelogenesis imperfecta.	('Mutation', 'Var', (0, 8))	('autosomal dominant hypocalcified amelogenesis imperfecta', 'Disease', 'MESH:D000567', (60, 116))	('FAM83H', 'Gene', (12, 18))	('etiological', 'Reg', (31, 42))	('amelogenesis imperfecta', 'Phenotype', 'HP:0000705', (93, 116))	('human', 'Species', '9606', (54, 59))
436028	31215499	However, there are controversial reports for the role of FAM83H in human cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('FAM83H', 'Var', (57, 63))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
436031	31215499	The roles of FAM83H in the progression of human cancers involve changes in the proliferation and invasiveness of cancer cells.	('cancers', 'Disease', (48, 55))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (97, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('invasiveness of cancer', 'Disease', (97, 119))	('human', 'Species', '9606', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('changes', 'Reg', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('FAM83H', 'Var', (13, 19))
436032	31215499	In colon cancer cells, overexpression of FAM83H is suggested to be involved in the progression of cancer cells by disorganizing keratin cytoskeleton structures.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (9, 15))	('involved', 'Reg', (67, 75))	('disorganizing', 'NegReg', (114, 127))	('overexpression', 'PosReg', (23, 37))	('FAM83H', 'Var', (41, 47))	('expression', 'Species', '29278', (27, 37))	('keratin cytoskeleton structures', 'MPA', (128, 159))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('cancer', 'Disease', (98, 104))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('colon cancer', 'Disease', (3, 15))
436033	31215499	In addition, FAM83H increases proliferation of prostatic cancer cells, hepatocellular carcinoma cells, and clear cell renal cell carcinoma cells.	('hepatocellular carcinoma cells', 'Disease', 'MESH:D006528', (71, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (107, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('prostatic cancer', 'Disease', 'MESH:D011471', (47, 63))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (107, 138))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('prostatic cancer', 'Phenotype', 'HP:0012125', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('increases', 'PosReg', (20, 29))	('proliferation', 'CPA', (30, 43))	('hepatocellular carcinoma cells', 'Disease', (71, 101))	('clear cell renal cell carcinoma', 'Disease', (107, 138))	('FAM83H', 'Var', (13, 19))	('prostatic cancer', 'Disease', (47, 63))
436035	31215499	Moreover, higher expression of FAM83H is associated with an increased recurrence rate of prostatic cancer patients and shorter survival of uterine cancer, hepatocellular carcinoma, and clear cell renal cell carcinoma patients.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('clear cell renal cell carcinoma', 'Disease', (185, 216))	('prostatic cancer', 'Disease', (89, 105))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('expression', 'MPA', (17, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('hepatocellular carcinoma', 'Disease', (155, 179))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (185, 216))	('FAM83H', 'Var', (31, 37))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (217, 225))	('shorter', 'NegReg', (119, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('expression', 'Species', '29278', (17, 27))	('uterine cancer', 'Phenotype', 'HP:0010784', (139, 153))	('prostatic cancer', 'Disease', 'MESH:D011471', (89, 105))	('prostatic cancer', 'Phenotype', 'HP:0012125', (89, 105))	('cancer', 'Disease', (99, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('higher', 'PosReg', (10, 16))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (185, 216))
436036	31215499	These findings suggest that FAM83H has a vital role in tumorigenesis and progression of human malignant tumors, and might be involved in the progression of various types of human cancers.	('FAM83H', 'Var', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('malignant tumors', 'Disease', 'MESH:D018198', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (55, 60))	('progression', 'CPA', (73, 84))	('human', 'Species', '9606', (173, 178))	('cancers', 'Disease', (179, 186))	('human', 'Species', '9606', (88, 93))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('malignant tumors', 'Disease', (94, 110))	('involved', 'Reg', (125, 133))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
436037	31215499	However, the expression of FAM83H is down-regulated in astrocytoma and oligodendroglioma of the brain, and higher expression of FAM83H is associated with favorable prognosis of glioma and head and neck cancer patients.	('head and neck cancer', 'Phenotype', 'HP:0012288', (188, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('FAM83H', 'Gene', (27, 33))	('astrocytoma', 'Disease', 'MESH:D001254', (55, 66))	('astrocytoma', 'Disease', (55, 66))	('neck cancer', 'Disease', 'MESH:D006258', (197, 208))	('neck cancer', 'Disease', (197, 208))	('expression', 'MPA', (114, 124))	('expression', 'Species', '29278', (13, 23))	('glioma', 'Disease', (177, 183))	('FAM83H', 'Var', (128, 134))	('oligodendroglioma of the brain', 'Disease', 'MESH:D009837', (71, 101))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Disease', (82, 88))	('higher', 'PosReg', (107, 113))	('oligodendroglioma of the brain', 'Disease', (71, 101))	('down-regulated', 'NegReg', (37, 51))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('expression', 'Species', '29278', (114, 124))	('patients', 'Species', '9606', (209, 217))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('expression', 'MPA', (13, 23))
436042	31215499	Therefore, new therapeutic approaches are needed to improve therapeutic efficacy in osteosarcoma patients, and we hypothesize that the FAM83H might be involved in the oncogenesis of the osteosarcoma based on the role of FAM83H in cancer progression in conjunction with MYC and the beta-catenin pathway.	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('beta-catenin', 'Gene', '1499', (281, 293))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('osteosarcoma', 'Phenotype', 'HP:0002669', (186, 198))	('MYC', 'Gene', (269, 272))	('FAM83H', 'Var', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('involved', 'Reg', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('osteosarcoma', 'Disease', (186, 198))	('beta-catenin', 'Gene', (281, 293))	('cancer', 'Disease', (230, 236))	('osteosarcoma', 'Disease', (84, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('MYC', 'Gene', '4609', (269, 272))	('osteosarcoma', 'Disease', 'MESH:D012516', (186, 198))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))	('patients', 'Species', '9606', (97, 105))
436045	31215499	Therefore, when considering p27 and cyclin D1 as down-stream signaling molecules of the beta-catenin pathway, there might be an association between FAM83H and the beta-catenin pathway.	('beta-catenin', 'Gene', (163, 175))	('cyclin D1', 'Gene', '595', (36, 45))	('p27', 'Gene', '3429', (28, 31))	('p27', 'Gene', (28, 31))	('FAM83H', 'Var', (148, 154))	('cyclin D1', 'Gene', (36, 45))	('association', 'Interaction', (128, 139))	('beta-catenin', 'Gene', (88, 100))	('beta-catenin', 'Gene', '1499', (163, 175))	('beta-catenin', 'Gene', '1499', (88, 100))
436047	31215499	Therefore, FAM83H and the beta-catenin pathway might have roles in the progression of osteosarcomas.	('beta-catenin', 'Gene', '1499', (26, 38))	('FAM83H', 'Var', (11, 17))	('osteosarcomas', 'Disease', (86, 99))	('osteosarcomas', 'Phenotype', 'HP:0002669', (86, 99))	('roles', 'Reg', (58, 63))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('osteosarcomas', 'Disease', 'MESH:D012516', (86, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('beta-catenin', 'Gene', (26, 38))
436053	31215499	The osteosarcomas were grouped according to age (< 30 y versus >= 30 y), sex (male versus female), tumor size (<= 8 cm versus > 8 cm), tumor stage (I versus II-IV), histologic grade (1 and 2 versus 3 and 4), lymph node metastasis (absence versus presence), and distant metastasis (absence versus presence).	('<=', 'Var', (111, 113))	('tumor', 'Disease', (99, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('osteosarcomas', 'Disease', (4, 17))	('osteosarcomas', 'Phenotype', 'HP:0002669', (4, 17))	('lymph node metastasis', 'CPA', (208, 229))	('osteosarcomas', 'Disease', 'MESH:D012516', (4, 17))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('distant metastasis', 'CPA', (261, 279))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
436059	31215499	The nuclear and cytoplasmic expression of FAM83H were separately evaluated, and the expression of beta-catenin was evaluated by overall cellular level.	('FAM83H', 'Var', (42, 48))	('expression', 'Species', '29278', (28, 38))	('expression', 'Species', '29278', (84, 94))	('beta-catenin', 'Gene', (98, 110))	('beta-catenin', 'Gene', '1499', (98, 110))
436063	31215499	Therefore, because we have used two TMA cores in each case, the final immunohistochemical staining score for Cy-FAM83H, Nu-FAM83H, and beta-catenin was ranged from zero to sixteen.	('Cy-FAM83H', 'Chemical', '-', (109, 118))	('beta-catenin', 'Gene', (135, 147))	('Cy-FAM83H', 'Var', (109, 118))	('Nu-FAM83H', 'Chemical', '-', (120, 129))	('beta-catenin', 'Gene', '1499', (135, 147))	('TMA', 'Chemical', '-', (36, 39))
436084	31215499	Thereafter, the eluted proteins were immunoblotted with anti-FAM83H, anti-beta-catenin, anti-ubiquitin, and anti-actin antibodies.	('anti-ubiquitin', 'Var', (88, 102))	('beta-catenin', 'Gene', (74, 86))	('anti-FAM83H', 'Var', (56, 67))	('beta-catenin', 'Gene', '1499', (74, 86))
436090	31215499	To determine positivity for the immunohistochemical staining for FAM83H and beta-catenin, receiver operating characteristic curve analysis was preformed, and the cut-off points were determined at the points with the highest positive likelihood ratio point for the estimation of the death of osteosarcoma patients.	('sarcoma', 'Phenotype', 'HP:0100242', (296, 303))	('patients', 'Species', '9606', (304, 312))	('death of osteosarcoma', 'Disease', 'MESH:D012516', (282, 303))	('FAM83H', 'Var', (65, 71))	('beta-catenin', 'Gene', (76, 88))	('death of osteosarcoma', 'Disease', (282, 303))	('beta-catenin', 'Gene', '1499', (76, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (291, 303))
436097	31215499	When we compared FAM83H protein expression in normal human osteoblast cells and human osteosarcoma cells, U2OS, MG63, and KHOS/NP osteosarcoma cells showed higher expression of FAM83H compared with normal osteoblast cells (Fig.	('U2OS', 'CellLine', 'CVCL:0042', (106, 110))	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('osteosarcoma', 'Disease', (86, 98))	('KHOS/NP osteosarcoma', 'Disease', (122, 142))	('FAM83H', 'Var', (177, 183))	('osteosarcoma', 'Disease', 'MESH:D012516', (86, 98))	('expression', 'Species', '29278', (163, 173))	('human', 'Species', '9606', (80, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('MG63', 'CellLine', 'CVCL:0426', (112, 116))	('osteosarcoma', 'Disease', (130, 142))	('higher', 'PosReg', (156, 162))	('osteosarcoma', 'Disease', 'MESH:D012516', (130, 142))	('KHOS/NP osteosarcoma', 'Disease', 'MESH:D012516', (122, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('human', 'Species', '9606', (53, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('expression', 'MPA', (163, 173))	('expression', 'Species', '29278', (32, 42))
436098	31215499	In human osteosarcoma tissue, immunohistochemical expression of FAM83H and beta-catenin were observed in both the cytoplasm and nuclei of osteosarcoma cells (Fig.	('beta-catenin', 'Gene', '1499', (75, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('human', 'Species', '9606', (3, 8))	('osteosarcoma', 'Phenotype', 'HP:0002669', (138, 150))	('osteosarcoma', 'Disease', (138, 150))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (138, 150))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('beta-catenin', 'Gene', (75, 87))	('osteosarcoma', 'Disease', (9, 21))	('expression', 'Species', '29278', (50, 60))	('FAM83H', 'Var', (64, 70))
436099	31215499	Although, previous reports have presented very rare expression of FAM83H in the nuclei of cells, cytoplasmic and nuclear expression of FAM83H have been presented in human cancers.	('human', 'Species', '9606', (165, 170))	('expression', 'Species', '29278', (121, 131))	('expression', 'Species', '29278', (52, 62))	('FAM83H', 'Var', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('FAM83H', 'Var', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
436102	31215499	The cut-off values for the positivity of cytoplasmic expression of FAM83H (Cy-FAM83H), nuclear expression of FAM83H (Nu-FAM83H), and beta-catenin expression were determined with receiver operating character curve analysis to predict the death of osteosarcoma patients.	('beta-catenin', 'Gene', '1499', (133, 145))	('Cy-FAM83H', 'Chemical', '-', (75, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('patients', 'Species', '9606', (259, 267))	('death of osteosarcoma', 'Disease', (237, 258))	('death of osteosarcoma', 'Disease', 'MESH:D012516', (237, 258))	('expression', 'Species', '29278', (53, 63))	('beta-catenin', 'Gene', (133, 145))	('FAM83H', 'Var', (67, 73))	('expression', 'Species', '29278', (146, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (246, 258))	('expression', 'Species', '29278', (95, 105))	('FAM83H', 'Var', (109, 115))	('Nu-FAM83H', 'Chemical', '-', (117, 126))
436103	31215499	The cut-off points for the expression of Cy-FAM83H, Nu-FAM83H, and beta-catenin were eight, twelve, and eleven, respectively (Fig.	('expression', 'Species', '29278', (27, 37))	('beta-catenin', 'Gene', '1499', (67, 79))	('Cy-FAM83H', 'Chemical', '-', (41, 50))	('beta-catenin', 'Gene', (67, 79))	('Cy-FAM83H', 'Var', (41, 50))	('Nu-FAM83H', 'Chemical', '-', (52, 61))	('Nu-FAM83H', 'Var', (52, 61))
436104	31215499	With these cut-off values, the positive expression of Cy-FAM83H, Nu-FAM83H, and beta-catenin were seen in 47.1% (16 of 34), 44.1% (15 of 34), and 38.2% (13 of 34) of osteosarcomas, respectively.	('Nu-FAM83H', 'Chemical', '-', (65, 74))	('Cy-FAM83H', 'Var', (54, 63))	('beta-catenin', 'Gene', (80, 92))	('osteosarcomas', 'Disease', (166, 179))	('osteosarcoma', 'Phenotype', 'HP:0002669', (166, 178))	('beta-catenin', 'Gene', '1499', (80, 92))	('osteosarcomas', 'Phenotype', 'HP:0002669', (166, 179))	('Cy-FAM83H', 'Chemical', '-', (54, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('osteosarcomas', 'Disease', 'MESH:D012516', (166, 179))	('expression', 'Species', '29278', (40, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('positive expression', 'PosReg', (31, 50))	('Nu-FAM83H', 'Var', (65, 74))
436105	31215499	Cy-FAM83H positivity was significantly associated with age of the patients (P = 0.013), larger tumor size (P = 0.039), higher tumor stage (P = 0.002), and higher histologic grade (P = 0.002).	('Cy-FAM83H', 'Chemical', '-', (0, 9))	('Cy-FAM83H positivity', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('patients', 'Species', '9606', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('associated', 'Reg', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', (126, 131))
436106	31215499	Nu-FAM83H positivity was significantly associated with larger tumor size (P = 0.016), higher tumor stage (P <  0.001), and higher histologic grade (P <  0.001).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (62, 67))	('positivity', 'Var', (10, 20))	('tumor', 'Disease', (93, 98))	('Nu-FAM83H positivity', 'Var', (0, 20))	('Nu-FAM83H', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
436107	31215499	In addition, there was significant association between Cy-FAM83H, Nu-FAM83H, and beta-catenin expression (Cy-FAM83H versus Nu-FAM83H; P <  0.001, Cy-FAM83H versus beta-catenin; P = 0.042, Nu-FAM83H versus beta-catenin; P = 0.002) (Table 2).	('Cy-FAM83H', 'Chemical', '-', (106, 115))	('beta-catenin', 'Gene', '1499', (81, 93))	('beta-catenin', 'Gene', (163, 175))	('beta-catenin', 'Gene', (205, 217))	('expression', 'Species', '29278', (94, 104))	('Cy-FAM83H', 'Chemical', '-', (146, 155))	('beta-catenin', 'Gene', '1499', (205, 217))	('Cy-FAM83H', 'Chemical', '-', (55, 64))	('Nu-FAM83H', 'Chemical', '-', (188, 197))	('beta-catenin', 'Gene', '1499', (163, 175))	('beta-catenin', 'Gene', (81, 93))	('Nu-FAM83H', 'Chemical', '-', (123, 132))	('Nu-FAM83H', 'Chemical', '-', (66, 75))	('Cy-FAM83H', 'Var', (55, 64))
436108	31215499	In univariate survival analysis, age of the patients (OS; P = 0.048, RFS; P = 0.027), tumor size (OS; P = 0.012, RFS; P = 0.012), tumor stage (OS; P = 0.023, RFS; P = 0.020), histologic grade (OS; P = 0.023, RFS; P = 0.020), distant metastasis (OS; P = 0.006, RFS; P = 0.009), Cy-FAM83H expression (OS; P = 0.001, RFS; P <  0.001), Nu-FAM83H expression (OS; P = 0.002, RFS; P = 0.001), and beta-catenin (OS; P = 0.006, RFS; P = 0.012) were significantly associated with both OS and RFS of osteosarcoma patients (Table 3).	('RFS of osteosarcoma', 'Disease', (482, 501))	('Nu-FAM83H expression', 'Var', (332, 352))	('distant metastasis', 'CPA', (225, 243))	('Nu-FAM83H', 'Chemical', '-', (332, 341))	('associated', 'Reg', (454, 464))	('beta-catenin', 'Gene', (390, 402))	('OS', 'Chemical', '-', (193, 195))	('beta-catenin', 'Gene', '1499', (390, 402))	('OS', 'Chemical', '-', (98, 100))	('tumor', 'Disease', (130, 135))	('Cy-FAM83H', 'Chemical', '-', (277, 286))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('OS', 'Chemical', '-', (143, 145))	('OS', 'Chemical', '-', (475, 477))	('RFS of osteosarcoma', 'Disease', 'MESH:D005198', (482, 501))	('OS', 'Chemical', '-', (404, 406))	('OS', 'Chemical', '-', (54, 56))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('osteosarcoma', 'Phenotype', 'HP:0002669', (489, 501))	('expression', 'Species', '29278', (342, 352))	('OS', 'Chemical', '-', (245, 247))	('expression', 'Species', '29278', (287, 297))	('patients', 'Species', '9606', (502, 510))	('Cy-FAM83H expression', 'Var', (277, 297))	('OS', 'Chemical', '-', (299, 301))	('tumor', 'Disease', (86, 91))	('OS', 'Chemical', '-', (354, 356))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (494, 501))
436109	31215499	Cy-FAM83H positivity predicted a 12.106-fold (95% confidence interval [95% CI]; 2.736-53.563) greater risk of shorter OS and a 14.253-fold (95% CI; 3.225-62.994) greater risk of shorter RFS in osteosarcoma patients.	('shorter OS', 'Disease', (110, 120))	('Cy-FAM83H', 'Chemical', '-', (0, 9))	('Cy-FAM83H positivity', 'Var', (0, 20))	('OS', 'Chemical', '-', (118, 120))	('patients', 'Species', '9606', (206, 214))	('osteosarcoma', 'Phenotype', 'HP:0002669', (193, 205))	('osteosarcoma', 'Disease', (193, 205))	('osteosarcoma', 'Disease', 'MESH:D012516', (193, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))
436110	31215499	Nu-FAM83H positivity predicted a 5.865-fold (95% CI; 1.874-18.355) greater risk of shorter OS and a 6.294-fold (95% CI; 2.038-19.431) greater risk of shorter RFS in osteosarcoma patients.	('osteosarcoma', 'Disease', (165, 177))	('shorter OS', 'Disease', (83, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (165, 177))	('osteosarcoma', 'Disease', 'MESH:D012516', (165, 177))	('patients', 'Species', '9606', (178, 186))	('Nu-FAM83H', 'Chemical', '-', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('Nu-FAM83H', 'Var', (0, 9))	('OS', 'Chemical', '-', (91, 93))	('RFS', 'MPA', (158, 161))	('shorter', 'NegReg', (150, 157))
436112	31215499	The Kaplan-Meier survival curves according to the expressions of Cy-FAM83H, Nu-FAM83H, and beta-catenin are presented in Fig.	('Cy-FAM83H', 'Chemical', '-', (65, 74))	('beta-catenin', 'Gene', (91, 103))	('Cy-FAM83H', 'Var', (65, 74))	('expression', 'Species', '29278', (50, 60))	('beta-catenin', 'Gene', '1499', (91, 103))	('Nu-FAM83H', 'Chemical', '-', (76, 85))
436113	31215499	Multivariate analysis was performed with the factors significantly associated with OS or RFS by univariate analysis: the age of patients, tumor size, tumor stage, lymph node metastasis, distant metastasis, histologic grade, Cy-FAM83H expression, Nu-FAM83H expression, and beta-catenin expression.	('beta-catenin', 'Gene', (272, 284))	('tumor', 'Disease', (138, 143))	('OS', 'Chemical', '-', (83, 85))	('Nu-FAM83H', 'Chemical', '-', (246, 255))	('expression', 'Species', '29278', (285, 295))	('beta-catenin', 'Gene', '1499', (272, 284))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Cy-FAM83H expression', 'Var', (224, 244))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('expression', 'Species', '29278', (234, 244))	('expression', 'MPA', (285, 295))	('patients', 'Species', '9606', (128, 136))	('Nu-FAM83H expression', 'Var', (246, 266))	('tumor', 'Disease', (150, 155))	('expression', 'Species', '29278', (256, 266))	('distant metastasis', 'CPA', (186, 204))	('lymph node metastasis', 'CPA', (163, 184))	('Cy-FAM83H', 'Chemical', '-', (224, 233))	('tumor', 'Disease', 'MESH:D009369', (150, 155))
436114	31215499	Multivariate analysis revealed presence of distant metastasis (OS; P = 0.005, RFS; P = 0.012) and Cy-FAM83H expression (OS; P <  0.001, RFS; P <  0.001) as independent indicators of poor prognostic of OS and RFS in osteosarcoma patients.	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('OS', 'Chemical', '-', (63, 65))	('distant metastasis', 'CPA', (43, 61))	('Cy-FAM83H', 'Chemical', '-', (98, 107))	('patients', 'Species', '9606', (228, 236))	('expression', 'Species', '29278', (108, 118))	('OS', 'Chemical', '-', (201, 203))	('osteosarcoma', 'Disease', (215, 227))	('OS', 'Chemical', '-', (120, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (215, 227))	('Cy-FAM83H expression', 'Var', (98, 118))	('osteosarcoma', 'Disease', 'MESH:D012516', (215, 227))
436115	31215499	Cy-FAM83H expression indicated a 15.463-fold (95% CI; 3.196-74.809) greater risk of death and a 15.825-fold (95% CI; 3.461-72.358) greater risk of relapse or death of osteosarcoma patients (Table 4).	('relapse', 'Disease', (147, 154))	('Cy-FAM83H', 'Chemical', '-', (0, 9))	('death of osteosarcoma', 'Disease', (158, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('Cy-FAM83H expression', 'Var', (0, 20))	('death of osteosarcoma', 'Disease', 'MESH:D012516', (158, 179))	('death', 'Disease', 'MESH:D003643', (158, 163))	('death', 'Disease', (158, 163))	('expression', 'Species', '29278', (10, 20))	('death', 'Disease', 'MESH:D003643', (84, 89))	('death', 'Disease', (84, 89))	('patients', 'Species', '9606', (180, 188))	('osteosarcoma', 'Phenotype', 'HP:0002669', (167, 179))	('greater', 'PosReg', (68, 75))
436116	31215499	As the expression of FAM83H was significantly associated with advanced clinicopathological factors such as larger tumor size, higher tumor stage, and higher histologic grade, we evaluated the effect of the FAM83H on the proliferation and invasiveness of osteosarcoma cells.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('FAM83H', 'Var', (21, 27))	('osteosarcoma', 'Phenotype', 'HP:0002669', (254, 266))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('expression', 'Species', '29278', (7, 17))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (133, 138))	('associated', 'Reg', (46, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('invasiveness of osteosarcoma', 'Disease', 'MESH:D012516', (238, 266))	('invasiveness of osteosarcoma', 'Disease', (238, 266))
436117	31215499	As expected, the knock-down of FAM83H with shRNA for FAM83H inhibited proliferation, and overexpression of FAM83H increased the proliferation of U2OS and MG63 osteosarcoma cells (Fig.	('U2OS', 'CPA', (145, 149))	('MG63', 'CellLine', 'CVCL:0426', (154, 158))	('osteosarcoma', 'Disease', (159, 171))	('FAM83H', 'Var', (107, 113))	('increased', 'PosReg', (114, 123))	('expression', 'Species', '29278', (93, 103))	('knock-down', 'Var', (17, 27))	('proliferation', 'CPA', (70, 83))	('inhibited', 'NegReg', (60, 69))	('overexpression', 'PosReg', (89, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (159, 171))	('proliferation', 'CPA', (128, 141))	('osteosarcoma', 'Phenotype', 'HP:0002669', (159, 171))	('U2OS', 'CellLine', 'CVCL:0042', (145, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
436118	31215499	In addition, the migration and invasion activities of osteosarcoma cells were significantly inhibited with knock-down of FAM83H and increased with overexpression of FAM83H in U2OS and MG63 cells (Fig.	('U2OS', 'CellLine', 'CVCL:0042', (175, 179))	('FAM83H', 'Var', (165, 171))	('inhibited', 'NegReg', (92, 101))	('expression', 'Species', '29278', (151, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('FAM83H', 'Var', (121, 127))	('increased', 'PosReg', (132, 141))	('knock-down', 'Var', (107, 117))	('MG63', 'CellLine', 'CVCL:0426', (184, 188))	('overexpression', 'PosReg', (147, 161))	('osteosarcoma', 'Disease', (54, 66))	('osteosarcoma', 'Phenotype', 'HP:0002669', (54, 66))	('osteosarcoma', 'Disease', 'MESH:D012516', (54, 66))
436119	31215499	Moreover, overexpression of FAM83H significantly increased in vivo growth of KHOS/NP cells, and knock-down of FAM83H significantly inhibited in vivo growth of KHOS/NP cells (Fig.	('FAM83H', 'Var', (28, 34))	('KHOS', 'Chemical', '-', (159, 163))	('increased', 'PosReg', (49, 58))	('expression', 'Species', '29278', (14, 24))	('KHOS', 'Chemical', '-', (77, 81))	('knock-down', 'Var', (96, 106))	('FAM83H', 'Var', (110, 116))	('inhibited', 'NegReg', (131, 140))
436120	31215499	Furthermore, overexpression of FAM83H was significantly associated with increased pulmonary metastases (Fig.	('increased pulmonary metastases', 'Disease', 'MESH:D009362', (72, 102))	('expression', 'Species', '29278', (17, 27))	('increased pulmonary metastases', 'Disease', (72, 102))	('FAM83H', 'Var', (31, 37))	('overexpression', 'PosReg', (13, 27))
436121	31215499	The five mice with FAM83H-overexpressing KHOS/NP cells showed grossly visible pulmonary metastatic nodules, but no grossly visible metastatic pulmonary nodule in neither cells transfected with control vectors nor shRNA for FAM83H.	('FAM83H-overexpressing', 'Var', (19, 40))	('mice', 'Species', '10090', (9, 13))	('KHOS', 'Chemical', '-', (41, 45))	('pulmonary metastatic nodules', 'CPA', (78, 106))
436122	31215499	Microscopically, FAM83H-overexpressing cells showed more pulmonary metastasis compared with cells transfected with control vectors or shRNA for FAM83H (mean number of metastatic nodule per mice: FAM83H-overexpression; 9.4, control vectors; 1.6, shFAM83H; 0.8) (Fig.	('expression', 'Species', '29278', (206, 216))	('mice', 'Species', '10090', (189, 193))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (57, 77))	('FAM83H-overexpressing', 'Var', (17, 38))	('FAM83H-overexpression', 'Var', (195, 216))	('pulmonary metastasis', 'Disease', (57, 77))
436124	31215499	The expression of mRNA and protein of cyclin D1, snail, and vimentin were decreased with the knock-down of FAM83H and increased with the overexpression of FAM83H in both U2OS and MG63 cells (Fig.	('snail', 'Gene', (49, 54))	('MG63', 'CellLine', 'CVCL:0426', (179, 183))	('expression', 'Species', '29278', (4, 14))	('FAM83H', 'Var', (107, 113))	('FAM83H', 'Var', (155, 161))	('expression', 'MPA', (4, 14))	('increased', 'PosReg', (118, 127))	('overexpression', 'PosReg', (137, 151))	('vimentin', 'Gene', '7431', (60, 68))	('expression', 'Species', '29278', (141, 151))	('snail', 'Gene', '6615', (49, 54))	('U2OS', 'CellLine', 'CVCL:0042', (170, 174))	('knock-down', 'Var', (93, 103))	('decreased', 'NegReg', (74, 83))	('cyclin D1', 'Gene', '595', (38, 47))	('vimentin', 'Gene', (60, 68))	('cyclin D1', 'Gene', (38, 47))
436125	31215499	The expression of p27 protein and mRNA were increased with knockdown of FAM83H and decreased with FAM83H overexpression (Fig.	('expression', 'Species', '29278', (4, 14))	('decreased', 'NegReg', (83, 92))	('FAM83H', 'Var', (72, 78))	('increased', 'PosReg', (44, 53))	('expression', 'MPA', (4, 14))	('p27', 'Gene', '3429', (18, 21))	('p27', 'Gene', (18, 21))	('knockdown', 'Var', (59, 68))	('mRNA', 'MPA', (34, 38))	('expression', 'Species', '29278', (109, 119))
436126	31215499	However, despite no significant change in expression of mRNA of beta-catenin with the knock-down or overexpression of FAM83H, the protein expression of beta-catenin and active beta-catenin were decreased with the knock-down of FAM83H and increased with the overexpression of FAM83H (Fig.	('FAM83H', 'Var', (227, 233))	('expression', 'Species', '29278', (42, 52))	('expression', 'Species', '29278', (261, 271))	('beta-catenin', 'Gene', (176, 188))	('knock-down', 'Var', (213, 223))	('FAM83H', 'Var', (275, 281))	('beta-catenin', 'Gene', (152, 164))	('expression', 'Species', '29278', (104, 114))	('increased', 'PosReg', (238, 247))	('beta-catenin', 'Gene', '1499', (176, 188))	('expression', 'Species', '29278', (138, 148))	('beta-catenin', 'Gene', '1499', (152, 164))	('beta-catenin', 'Gene', (64, 76))	('decreased', 'NegReg', (194, 203))	('beta-catenin', 'Gene', '1499', (64, 76))	('protein expression', 'MPA', (130, 148))
436127	31215499	5, FAM83H did not affect the mRNA expression of beta-catenin, but the expression of total beta-catenin and active beta-catenin were associated with FAM83H expression.	('beta-catenin', 'Gene', (114, 126))	('beta-catenin', 'Gene', (48, 60))	('active', 'MPA', (107, 113))	('expression', 'Species', '29278', (155, 165))	('FAM83H expression', 'Var', (148, 165))	('beta-catenin', 'Gene', (90, 102))	('expression', 'Species', '29278', (70, 80))	('beta-catenin', 'Gene', '1499', (114, 126))	('beta-catenin', 'Gene', '1499', (48, 60))	('expression', 'MPA', (70, 80))	('beta-catenin', 'Gene', '1499', (90, 102))	('associated', 'Reg', (132, 142))	('expression', 'Species', '29278', (34, 44))
436129	31215499	Immunoprecipitation for FAM83H or beta-catenin in MG63 cells showed complex formation of FAM83H and beta-catenin.	('FAM83H', 'Var', (89, 95))	('beta-catenin', 'Gene', (100, 112))	('beta-catenin', 'Gene', '1499', (100, 112))	('beta-catenin', 'Gene', '1499', (34, 46))	('MG63', 'CellLine', 'CVCL:0426', (50, 54))	('beta-catenin', 'Gene', (34, 46))
436130	31215499	After immunoprecipitation with FAM83H, immunoblot bands for beta-catenin was detected and vice versa (Fig.	('FAM83H', 'Var', (31, 37))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))
436131	31215499	In addition, when we performed fractionation of cell lysates of MG63 cells after knock-down of FAM83H, cytoplasmic and nuclear expression of beta-catenin was low compared with the cells transfected with control shRNA (Fig.	('knock-down', 'Var', (81, 91))	('expression', 'Species', '29278', (127, 137))	('low', 'NegReg', (158, 161))	('beta-catenin', 'Gene', (141, 153))	('beta-catenin', 'Gene', '1499', (141, 153))	('FAM83H', 'Var', (95, 101))	('MG63', 'CellLine', 'CVCL:0426', (64, 68))
436133	31215499	Because FAM83H influenced the expression and subcellular localization of beta-catenin, we investigated whether FAM83H is involved in post-translational protein stabilization of beta-catenin.	('expression', 'MPA', (30, 40))	('beta-catenin', 'Gene', (73, 85))	('influenced', 'Reg', (15, 25))	('subcellular localization', 'MPA', (45, 69))	('beta-catenin', 'Gene', '1499', (73, 85))	('beta-catenin', 'Gene', (177, 189))	('FAM83H', 'Var', (8, 14))	('expression', 'Species', '29278', (30, 40))	('beta-catenin', 'Gene', '1499', (177, 189))
436134	31215499	For this purpose, we examined the protein stability of beta-catenin in MG63 cells via treatment with cycloheximide after transfection with either control shRNA or FAM83H shRNA.	('beta-catenin', 'Gene', (55, 67))	('examined', 'Reg', (21, 29))	('FAM83H', 'Var', (163, 169))	('cycloheximide', 'Chemical', 'MESH:D003513', (101, 114))	('beta-catenin', 'Gene', '1499', (55, 67))	('MG63', 'CellLine', 'CVCL:0426', (71, 75))
436135	31215499	5d, the protein stability of beta-catenin in MG63 cells transfected with FAM83H shRNA was greatly reduced (as indicated by more rapid depletion) than in MG63 cells transfected with control shRNA.	('MG63', 'CellLine', 'CVCL:0426', (45, 49))	('FAM83H', 'Var', (73, 79))	('beta-catenin', 'Gene', (29, 41))	('depletion', 'MPA', (134, 143))	('MG63', 'CellLine', 'CVCL:0426', (153, 157))	('reduced', 'NegReg', (98, 105))	('protein stability', 'MPA', (8, 25))	('beta-catenin', 'Gene', '1499', (29, 41))
436136	31215499	Furthermore, the protein expression of beta-catenin in MG63 cells transfected with FAM83H shRNA decreased within one-hour of treatment of MG132, but the protein expression of beta-catenin in MG63 cells transfected with control shRNA did not decrease after up to two hours (Fig.	('expression', 'Species', '29278', (161, 171))	('expression', 'Species', '29278', (25, 35))	('protein expression', 'MPA', (17, 35))	('MG132', 'Chemical', 'MESH:C072553', (138, 143))	('decreased', 'NegReg', (96, 105))	('MG63', 'CellLine', 'CVCL:0426', (55, 59))	('beta-catenin', 'Gene', '1499', (175, 187))	('MG132', 'Var', (138, 143))	('FAM83H', 'Var', (83, 89))	('MG63', 'CellLine', 'CVCL:0426', (191, 195))	('beta-catenin', 'Gene', (39, 51))	('beta-catenin', 'Gene', (175, 187))	('beta-catenin', 'Gene', '1499', (39, 51))
436137	31215499	These results suggest that the decreased expression level of beta-catenin with knock-down of FAM83H depends on proteasome-mediated protein degradation.	('beta-catenin', 'Gene', '1499', (61, 73))	('expression', 'Species', '29278', (41, 51))	('knock-down', 'Var', (79, 89))	('decreased', 'NegReg', (31, 40))	('FAM83H', 'Gene', (93, 99))	('beta-catenin', 'Gene', (61, 73))	('expression level', 'MPA', (41, 57))	('proteasome-mediated protein degradation', 'MPA', (111, 150))
436141	31215499	6e, immunoprecipitated beta-catenin MG63 cells transfected with FAM83H shRNA clearly showed the poly-ubiquitination pattern of beta-catenin compared to MG63 cells transfected with control shRNA.	('poly-ubiquitination pattern', 'MPA', (96, 123))	('beta-catenin', 'Gene', (23, 35))	('MG63', 'CellLine', 'CVCL:0426', (152, 156))	('MG63', 'CellLine', 'CVCL:0426', (36, 40))	('beta-catenin', 'Gene', (127, 139))	('FAM83H', 'Var', (64, 70))	('beta-catenin', 'Gene', '1499', (23, 35))	('beta-catenin', 'Gene', '1499', (127, 139))
436142	31215499	In this study, we investigate the roles and relationship of FAM83H and beta-catenin in osteosarcomas and show that the expression of FAM83H and beta-catenin are closely associated, and their expression are involved in the progression of osteosarcomas.	('osteosarcomas', 'Phenotype', 'HP:0002669', (237, 250))	('beta-catenin', 'Gene', (144, 156))	('beta-catenin', 'Gene', '1499', (144, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('involved', 'Reg', (206, 214))	('sarcomas', 'Phenotype', 'HP:0100242', (242, 250))	('osteosarcomas', 'Disease', 'MESH:D012516', (87, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('beta-catenin', 'Gene', (71, 83))	('expression', 'MPA', (191, 201))	('beta-catenin', 'Gene', '1499', (71, 83))	('osteosarcomas', 'Disease', (87, 100))	('osteosarcoma', 'Phenotype', 'HP:0002669', (237, 249))	('osteosarcomas', 'Disease', 'MESH:D012516', (237, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('FAM83H', 'Var', (133, 139))	('osteosarcomas', 'Disease', (237, 250))	('osteosarcomas', 'Phenotype', 'HP:0002669', (87, 100))	('associated', 'Reg', (169, 179))	('expression', 'Species', '29278', (191, 201))	('expression', 'Species', '29278', (119, 129))
436143	31215499	In human osteosarcoma tissue samples, the expression of Cy-FAM83H and Nu-FAM83H were associated with advanced clinicopathologic factors such as larger tumor size, higher tumor stage, and higher histologic grade of osteosarcomas.	('osteosarcoma', 'Disease', 'MESH:D012516', (214, 226))	('human', 'Species', '9606', (3, 8))	('Cy-FAM83H', 'Chemical', '-', (56, 65))	('tumor', 'Disease', (170, 175))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('Cy-FAM83H', 'Var', (56, 65))	('Nu-FAM83H', 'Chemical', '-', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('associated', 'Reg', (85, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (214, 226))	('osteosarcomas', 'Disease', 'MESH:D012516', (214, 227))	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('expression', 'Species', '29278', (42, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('osteosarcoma', 'Disease', (9, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcomas', 'Disease', (214, 227))	('Nu-FAM83H', 'Var', (70, 79))	('tumor', 'Disease', (151, 156))	('osteosarcomas', 'Phenotype', 'HP:0002669', (214, 227))	('osteosarcoma', 'Disease', (214, 226))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
436144	31215499	Moreover, both Cy-FAM83H and Nu-FAM83H positivity were significantly associated with shorter OS and RFS of osteosarcoma patients by univariate analysis.	('RFS of osteosarcoma', 'Disease', (100, 119))	('Cy-FAM83H', 'Var', (15, 24))	('Nu-FAM83H', 'Chemical', '-', (29, 38))	('Nu-FAM83H', 'Var', (29, 38))	('OS', 'Chemical', '-', (93, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('RFS of osteosarcoma', 'Disease', 'MESH:D005198', (100, 119))	('shorter OS', 'Disease', (85, 95))	('patients', 'Species', '9606', (120, 128))	('Cy-FAM83H', 'Chemical', '-', (15, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
436145	31215499	Despite the limited number of cases of osteosarcomas, higher expression of Cy-FAM83H was an independent indicator of poor prognosis and shorter OS and RFS of osteosarcoma patients in multivariate analysis.	('expression', 'Species', '29278', (61, 71))	('Cy-FAM83H', 'Chemical', '-', (75, 84))	('osteosarcomas', 'Disease', 'MESH:D012516', (39, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (39, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (158, 170))	('higher', 'PosReg', (54, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('Cy-FAM83H', 'Var', (75, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('patients', 'Species', '9606', (171, 179))	('RFS of osteosarcoma', 'Disease', 'MESH:D005198', (151, 170))	('osteosarcomas', 'Disease', (39, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('OS', 'Chemical', '-', (144, 146))	('RFS of osteosarcoma', 'Disease', (151, 170))	('expression', 'MPA', (61, 71))	('osteosarcomas', 'Phenotype', 'HP:0002669', (39, 52))
436146	31215499	In line with these results, higher expression of FAM83H was significantly associated with higher tumor stage and shorter survival of hepatocellular carcinomas and clear cell renal cell carcinoma patients.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (163, 194))	('expression', 'MPA', (35, 45))	('survival', 'MPA', (121, 129))	('FAM83H', 'Var', (49, 55))	('tumor', 'Disease', (97, 102))	('higher', 'PosReg', (28, 34))	('patients', 'Species', '9606', (195, 203))	('shorter', 'NegReg', (113, 120))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (133, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (163, 194))	('expression', 'Species', '29278', (35, 45))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (133, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (174, 194))	('higher', 'PosReg', (90, 96))	('hepatocellular carcinomas', 'Disease', (133, 158))	('clear cell renal cell carcinoma', 'Disease', (163, 194))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
436147	31215499	In addition, the expression of FAM83H gene was consistently overexpressed in various human cancers such as lung, breast, colon, liver, ovary, pancreas, and stomach cancers, and higher expression of FAM83H gene was associated with shorter survival of uterine cancer patients.	('liver', 'Disease', (128, 133))	('stomach cancers', 'Disease', (156, 171))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('stomach cancers', 'Phenotype', 'HP:0012126', (156, 171))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('expression', 'MPA', (184, 194))	('pancreas', 'Disease', 'MESH:D010190', (142, 150))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colon', 'Disease', (121, 126))	('ovary', 'Disease', (135, 140))	('FAM83H', 'Var', (198, 204))	('patients', 'Species', '9606', (265, 273))	('FAM83H', 'Gene', (31, 37))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancer', 'Disease', (164, 170))	('cancers', 'Disease', (164, 171))	('expression', 'Species', '29278', (184, 194))	('cancer', 'Disease', (258, 264))	('human', 'Species', '9606', (85, 90))	('breast', 'Disease', (113, 119))	('higher', 'PosReg', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('expression', 'Species', '29278', (17, 27))	('shorter', 'NegReg', (230, 237))	('stomach cancers', 'Disease', 'MESH:D013274', (156, 171))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (91, 97))	('cancers', 'Disease', (91, 98))	('lung', 'Disease', (107, 111))	('uterine cancer', 'Phenotype', 'HP:0010784', (250, 264))	('pancreas', 'Disease', (142, 150))	('overexpressed', 'PosReg', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
436148	31215499	However, in contrast, gene expression of FAM83H lower in brain astrocytoma and brain oligodendroglioma, and lower expression of FAM83H in these tumors was associated with shorter disease-free survival of patients.	('tumors', 'Disease', (144, 150))	('lower', 'NegReg', (108, 113))	('expression', 'MPA', (114, 124))	('brain astrocytoma', 'Disease', 'MESH:D001254', (57, 74))	('patients', 'Species', '9606', (204, 212))	('gene expression', 'MPA', (22, 37))	('FAM83H', 'Var', (41, 47))	('shorter', 'NegReg', (171, 178))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('FAM83H', 'Var', (128, 134))	('brain oligodendroglioma', 'Disease', (79, 102))	('disease-free survival', 'CPA', (179, 200))	('expression', 'Species', '29278', (27, 37))	('lower', 'NegReg', (48, 53))	('expression', 'Species', '29278', (114, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('brain oligodendroglioma', 'Disease', 'MESH:D009837', (79, 102))	('brain astrocytoma', 'Disease', (57, 74))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
436149	31215499	Therefore, there is a possibility that the role of FAM83H in tumorigenesis might differ according to cancer types.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('FAM83H', 'Var', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
436152	31215499	However, despite a difference in the prognostic role of FAM83H according to the type of cancer and the limited number of cases of osteosarcoma used in this study, our results suggest that FAM83H expression might be used as a prognostic marker for osteosarcoma patients.	('cancer', 'Disease', (88, 94))	('FAM83H', 'Var', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (130, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (247, 259))	('osteosarcoma', 'Phenotype', 'HP:0002669', (247, 259))	('patients', 'Species', '9606', (260, 268))	('osteosarcoma', 'Disease', (247, 259))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('expression', 'Species', '29278', (195, 205))	('osteosarcoma', 'Disease', (130, 142))
436154	31215499	Supportively, in this study, in addition to the prognostic significance of Cy-FAM83H and Nu-FAM83H expression in osteosarcoma patients, overexpression of FAM83H increased proliferation of osteosarcoma cells, and knock-down of FAM83H inhibited proliferation of osteosarcoma cells both in vitro and in vivo.	('osteosarcoma', 'Disease', 'MESH:D012516', (188, 200))	('patients', 'Species', '9606', (126, 134))	('expression', 'Species', '29278', (140, 150))	('osteosarcoma', 'Disease', (260, 272))	('osteosarcoma', 'Disease', 'MESH:D012516', (260, 272))	('knock-down', 'Var', (212, 222))	('inhibited', 'NegReg', (233, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('proliferation', 'CPA', (243, 256))	('increased', 'PosReg', (161, 170))	('osteosarcoma', 'Disease', (113, 125))	('expression', 'Species', '29278', (99, 109))	('proliferation', 'CPA', (171, 184))	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('Cy-FAM83H', 'Chemical', '-', (75, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (260, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))	('Nu-FAM83H', 'Chemical', '-', (89, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('FAM83H', 'Var', (154, 160))	('osteosarcoma', 'Disease', (188, 200))
436155	31215499	Moreover, overexpression of FAM83H increased expression of beta-catenin, active beta-catenin, and cyclin D1, and decreased expression of p27.	('FAM83H', 'Var', (28, 34))	('p27', 'Gene', '3429', (137, 140))	('increased', 'PosReg', (35, 44))	('expression', 'MPA', (123, 133))	('p27', 'Gene', (137, 140))	('beta-catenin', 'Gene', '1499', (59, 71))	('expression', 'Species', '29278', (14, 24))	('expression', 'Species', '29278', (45, 55))	('active', 'MPA', (73, 79))	('beta-catenin', 'Gene', (80, 92))	('cyclin D1', 'Gene', '595', (98, 107))	('expression', 'MPA', (45, 55))	('cyclin D1', 'Gene', (98, 107))	('beta-catenin', 'Gene', '1499', (80, 92))	('decreased', 'NegReg', (113, 122))	('beta-catenin', 'Gene', (59, 71))	('expression', 'Species', '29278', (123, 133))
436156	31215499	In line with our results, knock-down of FAM83H inhibited proliferation of prostate cancer cells and clear cell renal cell carcinoma cells.	('clear cell renal cell carcinoma', 'Disease', (100, 131))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('knock-down', 'Var', (26, 36))	('inhibited', 'NegReg', (47, 56))	('prostate cancer', 'Disease', (74, 89))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (100, 131))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('proliferation', 'CPA', (57, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (100, 131))	('FAM83H', 'Var', (40, 46))
436157	31215499	In hepatocellular carcinomas, overexpression of FAM83H increased proliferation of cancer cells in vitro and in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('proliferation', 'CPA', (65, 78))	('FAM83H', 'Var', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (3, 28))	('hepatocellular carcinomas', 'Disease', (3, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('increased', 'PosReg', (55, 64))	('overexpression', 'PosReg', (30, 44))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (3, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('expression', 'Species', '29278', (34, 44))
436159	31215499	In addition to the role of FAM83H in the proliferation of cancer cells, FAM83H was involved in the invasiveness of cancer cells.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (58, 64))	('involved', 'Reg', (83, 91))	('FAM83H', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('invasiveness of cancer', 'Disease', (99, 121))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (99, 121))
436160	31215499	Overexpression of FAM83H increased the migration and invasion activity of osteosarcoma cells, which was associated with increased expression of vimentin and snail.	('osteosarcoma', 'Disease', 'MESH:D012516', (74, 86))	('invasion activity', 'CPA', (53, 70))	('expression', 'MPA', (130, 140))	('snail', 'Gene', '6615', (157, 162))	('osteosarcoma', 'Phenotype', 'HP:0002669', (74, 86))	('increased', 'PosReg', (25, 34))	('expression', 'Species', '29278', (4, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('FAM83H', 'Var', (18, 24))	('snail', 'Gene', (157, 162))	('migration', 'CPA', (39, 48))	('vimentin', 'Gene', '7431', (144, 152))	('increased', 'PosReg', (120, 129))	('expression', 'Species', '29278', (130, 140))	('vimentin', 'Gene', (144, 152))	('osteosarcoma', 'Disease', (74, 86))
436161	31215499	Moreover, overexpression of FAM83H was associated with more pulmonary metastasis of KHOS/NP cells in vivo (Fig.	('FAM83H', 'Var', (28, 34))	('KHOS', 'Chemical', '-', (84, 88))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (60, 80))	('expression', 'Species', '29278', (14, 24))	('more', 'PosReg', (55, 59))	('overexpression', 'PosReg', (10, 24))	('pulmonary metastasis', 'Disease', (60, 80))
436164	31215499	In human breast cancers, the expression of snail was associated with shorter survival of patients.	('expression', 'Var', (29, 39))	('survival', 'CPA', (77, 85))	('human', 'Species', '9606', (3, 8))	('breast cancers', 'Phenotype', 'HP:0003002', (9, 23))	('shorter', 'NegReg', (69, 76))	('snail', 'Gene', (43, 48))	('patients', 'Species', '9606', (89, 97))	('expression', 'Species', '29278', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancers', 'Disease', 'MESH:D001943', (9, 23))	('breast cancers', 'Disease', (9, 23))	('snail', 'Gene', '6615', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
436165	31215499	Therefore, when considering the roles of FAM83H in the expression of vimentin and snail, FAM83H-mediated EMT, which enhances invasiveness of osteosarcomas, might explain how FAM83H is involved in the progression of osteosarcoma.	('expression', 'Species', '29278', (55, 65))	('osteosarcoma', 'Disease', (141, 153))	('osteosarcoma', 'Disease', 'MESH:D012516', (141, 153))	('osteosarcomas', 'Phenotype', 'HP:0002669', (141, 154))	('osteosarcoma', 'Phenotype', 'HP:0002669', (215, 227))	('snail', 'Gene', '6615', (82, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('osteosarcoma', 'Phenotype', 'HP:0002669', (141, 153))	('snail', 'Gene', (82, 87))	('osteosarcoma', 'Disease', (215, 227))	('osteosarcoma', 'Disease', 'MESH:D012516', (215, 227))	('vimentin', 'Gene', '7431', (69, 77))	('invasiveness of osteosarcomas', 'Disease', (125, 154))	('vimentin', 'Gene', (69, 77))	('enhances', 'PosReg', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('FAM83H-mediated', 'Var', (89, 104))	('invasiveness of osteosarcomas', 'Disease', 'MESH:D012516', (125, 154))
436166	31215499	Consistently, knock-down of FAM83H disrupted keratin cytoskeleton organization and inhibited the migration activity of colon cancer cells.	('FAM83H', 'Gene', (28, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('colon cancer', 'Disease', (119, 131))	('inhibited', 'NegReg', (83, 92))	('knock-down', 'Var', (14, 24))	('keratin', 'Protein', (45, 52))	('disrupted', 'NegReg', (35, 44))
436173	31215499	Especially, the expressions of both FAM83H and beta-catenin were associated with shorter survival of osteosarcoma patients.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('beta-catenin', 'Gene', '1499', (47, 59))	('expressions', 'Var', (16, 27))	('osteosarcoma', 'Disease', (101, 113))	('FAM83H', 'Var', (36, 42))	('osteosarcoma', 'Phenotype', 'HP:0002669', (101, 113))	('beta-catenin', 'Gene', (47, 59))	('expression', 'Species', '29278', (16, 26))	('osteosarcoma', 'Disease', 'MESH:D012516', (101, 113))	('patients', 'Species', '9606', (114, 122))	('survival', 'MPA', (89, 97))	('shorter', 'NegReg', (81, 88))
436174	31215499	These findings suggest that both FAM83H and beta-catenin are closely associated and involved in the progression of osteosarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('associated', 'Reg', (69, 79))	('beta-catenin', 'Gene', (44, 56))	('osteosarcomas', 'Disease', (115, 128))	('FAM83H', 'Var', (33, 39))	('osteosarcomas', 'Phenotype', 'HP:0002669', (115, 128))	('osteosarcoma', 'Phenotype', 'HP:0002669', (115, 127))	('osteosarcomas', 'Disease', 'MESH:D012516', (115, 128))	('beta-catenin', 'Gene', '1499', (44, 56))	('involved', 'Reg', (84, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
436179	31215499	In MG63 osteosarcoma cells, knock-down or overexpression of FAM83H did not significantly affect the level of beta-catenin mRNA, but the protein level of beta-catenin decreased with knock-down of FAM83H and increased with overexpression of FAM83H.	('increased', 'PosReg', (206, 215))	('knock-down', 'Var', (181, 191))	('MG63', 'CellLine', 'CVCL:0426', (3, 7))	('beta-catenin', 'Gene', (153, 165))	('decreased', 'NegReg', (166, 175))	('beta-catenin', 'Gene', (109, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('osteosarcoma', 'Phenotype', 'HP:0002669', (8, 20))	('osteosarcoma', 'Disease', (8, 20))	('expression', 'Species', '29278', (46, 56))	('expression', 'Species', '29278', (225, 235))	('osteosarcoma', 'Disease', 'MESH:D012516', (8, 20))	('FAM83H', 'Var', (195, 201))	('beta-catenin', 'Gene', '1499', (153, 165))	('beta-catenin', 'Gene', '1499', (109, 121))	('protein level', 'MPA', (136, 149))
436180	31215499	In addition, FAM83H directly bound to beta-catenin and retarded proteasomal degradation of beta-catenin.	('beta-catenin', 'Gene', (38, 50))	('beta-catenin', 'Gene', '1499', (38, 50))	('beta-catenin', 'Gene', (91, 103))	('retarded', 'Disease', (55, 63))	('bound', 'Interaction', (29, 34))	('retarded', 'Disease', 'MESH:D008607', (55, 63))	('beta-catenin', 'Gene', '1499', (91, 103))	('FAM83H', 'Var', (13, 19))
436181	31215499	When we induced knock-down of FAM83H, ubiquitination of beta-catenin increased which subsequently increased its degradation.	('ubiquitination', 'MPA', (38, 52))	('increased', 'PosReg', (69, 78))	('beta-catenin', 'Gene', (56, 68))	('beta-catenin', 'Gene', '1499', (56, 68))	('increased', 'PosReg', (98, 107))	('FAM83H', 'Gene', (30, 36))	('degradation', 'MPA', (112, 123))	('knock-down', 'Var', (16, 26))
436183	31215499	Consistently, FAM83H-mediated stabilization of beta-catenin has been suggested in colorectal cancers.	('beta-catenin', 'Gene', '1499', (47, 59))	('colorectal cancers', 'Disease', 'MESH:D015179', (82, 100))	('stabilization', 'MPA', (30, 43))	('colorectal cancers', 'Disease', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('beta-catenin', 'Gene', (47, 59))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('FAM83H-mediated', 'Var', (14, 29))
436184	31215499	Overexpression of FAM83H suppressed cytoplasmic CK1alpha and thereby supported nuclear localization of beta-catenin with de-phosphorylation mediated stabilization.	('stabilization', 'MPA', (149, 162))	('de-phosphorylation', 'MPA', (121, 139))	('nuclear localization', 'MPA', (79, 99))	('expression', 'Species', '29278', (4, 14))	('beta-catenin', 'Gene', (103, 115))	('FAM83H', 'Var', (18, 24))	('CK1', 'Species', '2498238', (48, 51))	('beta-catenin', 'Gene', '1499', (103, 115))	('suppressed', 'NegReg', (25, 35))	('CK1alpha', 'Protein', (48, 56))	('cytoplasmic', 'MPA', (36, 47))	('supported', 'PosReg', (69, 78))
436185	31215499	In liver and kidney cancer, FAM83H expression was associated with the expression of cyclin D1, cyclin E1, and downstream signaling of the Wnt/beta-catenin pathway.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('kidney cancer', 'Phenotype', 'HP:0009726', (13, 26))	('FAM83H expression', 'Var', (28, 45))	('cyclin D1', 'Gene', '595', (84, 93))	('liver and kidney cancer', 'Disease', 'MESH:D006528', (3, 26))	('expression', 'Species', '29278', (35, 45))	('beta-catenin', 'Gene', (142, 154))	('cyclin D1', 'Gene', (84, 93))	('expression', 'Species', '29278', (70, 80))	('beta-catenin', 'Gene', '1499', (142, 154))	('expression', 'MPA', (70, 80))	('cyclin E1', 'Gene', (95, 104))	('associated', 'Reg', (50, 60))
436186	31215499	Therefore, these findings suggest that FAM83H is involved in the progression of osteosarcoma by mediating stabilization of beta-catenin from its proteasomal degradation.	('beta-catenin', 'Gene', '1499', (123, 135))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('stabilization', 'MPA', (106, 119))	('involved', 'Reg', (49, 57))	('osteosarcoma', 'Disease', (80, 92))	('FAM83H', 'Var', (39, 45))	('beta-catenin', 'Gene', (123, 135))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
436188	31215499	In addition, in our results, the expression of beta-catenin was significantly associated with shorter OS and RFS of osteosarcoma patients in univariate analysis.	('beta-catenin', 'Gene', '1499', (47, 59))	('OS', 'Chemical', '-', (102, 104))	('shorter OS', 'Disease', (94, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('expression', 'Var', (33, 43))	('patients', 'Species', '9606', (129, 137))	('RFS of osteosarcoma', 'Disease', 'MESH:D005198', (109, 128))	('RFS of osteosarcoma', 'Disease', (109, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('expression', 'Species', '29278', (33, 43))	('beta-catenin', 'Gene', (47, 59))
436189	31215499	Although there is one controversial report, the expression of beta-catenin has been reported to be associated with poor prognosis of cancer patients including those with soft-tissue sarcomas.	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (170, 190))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('beta-catenin', 'Gene', (62, 74))	('expression', 'Species', '29278', (48, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('sarcomas', 'Disease', (182, 190))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('beta-catenin', 'Gene', '1499', (62, 74))	('cancer', 'Disease', (133, 139))	('expression', 'Var', (48, 58))	('patients', 'Species', '9606', (140, 148))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (170, 189))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('associated', 'Reg', (99, 109))
436191	31215499	However, as we have shown in human osteosarcoma tissue samples, western blotting of subcellular fractionated protein and confocal microscopic images indicate that FAM83H expression was observed in the cytoplasmic membrane, cytoplasm, and nuclei.	('osteosarcoma', 'Phenotype', 'HP:0002669', (35, 47))	('FAM83H', 'Var', (163, 169))	('osteosarcoma', 'Disease', (35, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (35, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('human', 'Species', '9606', (29, 34))	('expression', 'Species', '29278', (170, 180))
436192	31215499	In addition, both Cy-FAM83H and Nu-FAM83H expression were significantly associated with higher stage, larger tumor size, and higher histologic grade of osteosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('expression', 'Species', '29278', (42, 52))	('Nu-FAM83H', 'Var', (32, 41))	('Cy-FAM83H', 'Chemical', '-', (18, 27))	('associated', 'Reg', (72, 82))	('osteosarcomas', 'Disease', (152, 165))	('Nu-FAM83H', 'Chemical', '-', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (152, 164))	('osteosarcomas', 'Phenotype', 'HP:0002669', (152, 165))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Cy-FAM83H', 'Var', (18, 27))	('osteosarcomas', 'Disease', 'MESH:D012516', (152, 165))	('tumor', 'Disease', (109, 114))
436193	31215499	Moreover, both Cy-FAM83H and Nu-FAM83H expression was significantly associated with shorter survival of osteosarcoma patients in univariate analysis.	('Cy-FAM83H', 'Var', (15, 24))	('Nu-FAM83H', 'Chemical', '-', (29, 38))	('osteosarcoma', 'Disease', (104, 116))	('osteosarcoma', 'Phenotype', 'HP:0002669', (104, 116))	('osteosarcoma', 'Disease', 'MESH:D012516', (104, 116))	('survival', 'MPA', (92, 100))	('shorter', 'NegReg', (84, 91))	('Cy-FAM83H', 'Chemical', '-', (15, 24))	('expression', 'Species', '29278', (39, 49))	('patients', 'Species', '9606', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('Nu-FAM83H expression', 'Var', (29, 49))
436194	31215499	Consistently, both Cy-FAM83H and Nu-FAM83H expression were associated with shorter survival of hepatocellular carcinoma and clear cell renal cell carcinoma patients.	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('clear cell renal cell carcinoma', 'Disease', (124, 155))	('Cy-FAM83H', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('Nu-FAM83H', 'Chemical', '-', (33, 42))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (124, 155))	('survival', 'MPA', (83, 91))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('expression', 'Species', '29278', (43, 53))	('shorter', 'NegReg', (75, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('Cy-FAM83H', 'Chemical', '-', (19, 28))	('hepatocellular carcinoma', 'Disease', (95, 119))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 155))	('Nu-FAM83H expression', 'Var', (33, 53))
436195	31215499	In multivariate analysis, Nu-FAM83H expression was an independent indicator of shorter survival of hepatocellular carcinoma and clear cell renal cell carcinoma patients.	('survival', 'MPA', (87, 95))	('patients', 'Species', '9606', (160, 168))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (128, 159))	('clear cell renal cell carcinoma', 'Disease', (128, 159))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('shorter', 'NegReg', (79, 86))	('Nu-FAM83H', 'Chemical', '-', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (128, 159))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('expression', 'Species', '29278', (36, 46))	('hepatocellular carcinoma', 'Disease', (99, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))	('Nu-FAM83H expression', 'Var', (26, 46))
436196	31215499	Therefore, nuclear localization of FAM83H was suggested as an important indicator of cancer progression.	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('FAM83H', 'Var', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
436197	31215499	However, in osteosarcoma, the statistical prognostic significance of Cy-FAM83H expression was potent in comparison to Nu-FAM83H expression in multivariate analysis.	('expression', 'Species', '29278', (79, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('Nu-FAM83H', 'Chemical', '-', (118, 127))	('Cy-FAM83H expression', 'Var', (69, 89))	('Cy-FAM83H', 'Chemical', '-', (69, 78))	('osteosarcoma', 'Disease', (12, 24))	('expression', 'Species', '29278', (128, 138))	('osteosarcoma', 'Phenotype', 'HP:0002669', (12, 24))	('osteosarcoma', 'Disease', 'MESH:D012516', (12, 24))
436199	31215499	However, despite this limitation, knock-down or overexpression of FAM83H influenced proliferation and/or invasiveness of various human cancers such as osteosarcoma, prostate cancer, hepatocellular carcinoma, and clear cell renal cell carcinoma patients.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (212, 243))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('FAM83H', 'Var', (66, 72))	('invasiveness', 'CPA', (105, 117))	('patients', 'Species', '9606', (244, 252))	('hepatocellular carcinoma', 'Disease', (182, 206))	('influenced', 'Reg', (73, 83))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('expression', 'Species', '29278', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('proliferation', 'CPA', (84, 97))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (212, 243))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('knock-down', 'Var', (34, 44))	('cancers', 'Disease', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('overexpression', 'PosReg', (48, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('clear cell renal cell carcinoma', 'Disease', (212, 243))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (182, 206))	('osteosarcoma', 'Disease', (151, 163))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (223, 243))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('prostate cancer', 'Disease', (165, 180))	('human', 'Species', '9606', (129, 134))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (182, 206))
436200	31215499	Therefore, it is suggested that the overall expression of FAM83H is important in the progression of FAM83H and higher expression of FAM83H might promote tumor progression.	('FAM83H', 'Disease', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('higher expression', 'PosReg', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('FAM83H', 'Var', (132, 138))	('expression', 'Species', '29278', (118, 128))	('promote', 'PosReg', (145, 152))	('expression', 'Species', '29278', (44, 54))
436201	31215499	In conclusion, we showed that FAM38H expression is important for the proliferation and invasiveness of osteosarcoma cells and suggest that stabilizing beta-catenin protein by FAM38H can be a biochemical mechanism to explain the significant association between FAM38H expression and shorter survival of osteosarcoma patients.	('expression', 'Species', '29278', (37, 47))	('FAM38H', 'Chemical', '-', (175, 181))	('expression', 'Species', '29278', (267, 277))	('beta-catenin', 'Gene', (151, 163))	('beta-catenin', 'Gene', '1499', (151, 163))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('osteosarcoma', 'Phenotype', 'HP:0002669', (302, 314))	('shorter', 'NegReg', (282, 289))	('FAM38H', 'Var', (175, 181))	('patients', 'Species', '9606', (315, 323))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (307, 314))	('FAM38H', 'Chemical', '-', (260, 266))	('FAM38H', 'Chemical', '-', (30, 36))	('invasiveness of osteosarcoma', 'Disease', (87, 115))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('osteosarcoma', 'Disease', (302, 314))	('osteosarcoma', 'Disease', 'MESH:D012516', (302, 314))	('FAM38H', 'Var', (260, 266))	('invasiveness of osteosarcoma', 'Disease', 'MESH:D012516', (87, 115))
436202	31215499	These results highlight FAM83H as a new prognostic maker as well as a new therapeutic target of osteosarcoma.	('osteosarcoma', 'Disease', (96, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (96, 108))	('osteosarcoma', 'Disease', 'MESH:D012516', (96, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('FAM83H', 'Var', (24, 30))
436350	31870357	MYOD1 mutation, RAS pathway mutation, NCOA2 or VGLL2 gene fusion) and diagnostic (e.g.	('VGLL2', 'Gene', (47, 52))	('RAS pathway', 'Pathway', (16, 27))	('NCOA2', 'Gene', '10499', (38, 43))	('mutation', 'Var', (6, 14))	('MYOD1', 'Gene', '4654', (0, 5))	('mutation', 'Var', (28, 36))	('NCOA2', 'Gene', (38, 43))	('VGLL2', 'Gene', '245806', (47, 52))	('MYOD1', 'Gene', (0, 5))
436357	31870357	We screened 82 samples, including 66 samples of RMS patient tissues (GSE16382 [N = 8] and GSE66533 [N = 58)) and 16 samples of normal striated muscle tissues (GSE39454 [N = 5], GSE17674 [N = 5] and GSE38417 [N = 6]).	('GSE38417', 'Var', (198, 206))	('GSE39454', 'Var', (159, 167))	('GSE66533', 'Var', (90, 98))	('RMS', 'Disease', (48, 51))	('GSE16382', 'Var', (69, 77))	('patient', 'Species', '9606', (52, 59))	('GSE17674', 'Var', (177, 185))
436366	31870357	Slides with lengths of 1-2 mm were deparaffinised, heat repaired with EDTA antigen repair solution (pH = 9.0) and incubated with anti-CDK1 rabbit monoclonal antibody (EPR165 [ab133327]; 1:1000 dilution; Abcam) and anti-Cyclin B1 rabbit monoclonal antibody (Y106 [ab32053]; 1:250 dilution; Abcam).	('EDTA', 'Chemical', 'MESH:D004492', (70, 74))	('Cyclin B1', 'Gene', (219, 228))	('Y106 [', 'Var', (257, 263))	('paraffin', 'Chemical', 'MESH:D010232', (37, 45))	('Cyclin B1', 'Gene', '891', (219, 228))
436399	31870357	In RMS, E-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl) acrylic acid reduces CDK1 protein level and inhibited RMS cell activity.	('RMS cell activity', 'CPA', (105, 122))	('CDK1 protein level', 'MPA', (72, 90))	('inhibited', 'NegReg', (95, 104))	('E-3-', 'Var', (8, 12))	("E-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl) acrylic acid", 'Chemical', '-', (8, 63))	('reduces', 'NegReg', (64, 71))
436401	31870357	RMS in heterozygous p53 mice exhibits higher CCNB1 expression than RMS in heterozygous Patched1 (Ptch1) mice.	('mice', 'Species', '10090', (24, 28))	('mice', 'Species', '10090', (104, 108))	('Patched1', 'Gene', (87, 95))	('expression', 'MPA', (51, 61))	('p53', 'Var', (20, 23))	('higher', 'PosReg', (38, 44))	('CCNB1', 'Gene', (45, 50))	('Ptch1', 'Gene', '19206', (97, 102))	('Ptch1', 'Gene', (97, 102))	('Patched1', 'Gene', '19206', (87, 95))
436424	31870357	reported that miR-363-3p controls the growth of lung adenocarcinoma by reducing the expression of PCNA.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('reducing', 'NegReg', (71, 79))	('PCNA', 'Gene', (98, 102))	('growth', 'MPA', (38, 44))	('PCNA', 'Gene', '5111', (98, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('expression', 'MPA', (84, 94))	('miR-363-3p', 'Var', (14, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinoma', 'Disease', (48, 67))
436428	31870357	Inactivation of the P53 pathway could induce the development of RMS.	('induce', 'PosReg', (38, 44))	('P53', 'Gene', (20, 23))	('P53', 'Gene', '7157', (20, 23))	('Inactivation', 'Var', (0, 12))	('development of RMS', 'CPA', (49, 67))
436430	31870357	As the PI3K-Akt signalling is active in RMS, targeting this pathway could inhibit the activation of hypoxia-inducible factor-1alpha, thereby inducing the formation of apoptosis-sensitive cells.	('Akt', 'Gene', '207', (12, 15))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (100, 131))	('Akt', 'Gene', (12, 15))	('activation', 'MPA', (86, 96))	('formation of apoptosis-sensitive cells', 'CPA', (154, 192))	('inhibit', 'NegReg', (74, 81))	('hypoxia-inducible factor-1alpha', 'Gene', (100, 131))	('inducing', 'Reg', (141, 149))	('targeting', 'Var', (45, 54))
436439	31443718	Evidence shows that the dysregulation of alternative splicing (AS) events is involved in tumor pathogenesis and progression.	('involved', 'Reg', (77, 85))	('dysregulation', 'Var', (24, 37))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('alternative splicing', 'MPA', (41, 61))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
436454	31443718	Many studies have demonstrated that the dysregulation of AS events is involved in tumor pathogenesis and progression.	('dysregulation', 'Var', (40, 53))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('involved', 'Reg', (70, 78))	('tumor', 'Disease', (82, 87))
436457	31443718	Aberrant splicing, which can lead to pathologic conditions, such as cancer, may be induced by the action of tumor suppressors or the mutation of oncogene splicing factors, thereby influencing cancer-related pathways.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutation', 'Var', (133, 141))	('splicing factor', 'Gene', '10569', (154, 169))	('lead to', 'Reg', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('influencing', 'Reg', (180, 191))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (192, 198))	('Aberrant splicing', 'Var', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', (68, 74))	('splicing factor', 'Gene', (154, 169))	('induced', 'Reg', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
436458	31443718	Moreover, the dysregulation of splicing behavior has been found to be associated with mutations or abnormal splicing factor expression.	('abnormal', 'Var', (99, 107))	('mutations', 'Var', (86, 95))	('splicing factor', 'Gene', (108, 123))	('dysregulation', 'Var', (14, 27))	('splicing behavior', 'MPA', (31, 48))	('associated', 'Reg', (70, 80))	('splicing factor', 'Gene', '10569', (108, 123))
436462	31443718	Moreover, it is now possible to identify unknown transcripts and splicing isoforms using RNA-seq, in addition to acquiring the computable measurement of alternatively-spliced protein variants, which can then be tested for associations with cancer.	('tested', 'Reg', (211, 217))	('cancer', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('variants', 'Var', (183, 191))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('associations', 'Interaction', (222, 234))
436479	31443718	To explore how AS events occur and their role in STS, we preliminarily examined genetic alterations in MDM2, EWSR1, CDKN2A, and HMGA2, the four key genes involved in STS, and then assessed their correlation with AS events.	('genetic alterations', 'Var', (80, 99))	('EWSR1', 'Gene', '2130', (109, 114))	('HMGA2', 'Gene', (128, 133))	('CDKN2A', 'Gene', (116, 122))	('examined', 'Reg', (71, 79))	('CDKN2A', 'Gene', '1029', (116, 122))	('MDM2', 'Gene', '4193', (103, 107))	('MDM2', 'Gene', (103, 107))	('EWSR1', 'Gene', (109, 114))	('HMGA2', 'Gene', '8091', (128, 133))
436480	31443718	First, the cBio Cancer Genomics Portal (cBioPortal), an open platform for exploring multidimensional cancer genomics data (http://www.cbioportal.org/), was utilized to assess for gene copy number alteration (CNA) and mutation.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('mutation', 'Var', (217, 225))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
436498	31443718	In the cBioPortal platform data, the most common alterations of MDM2 were amplifications, and there were a few missense mutations.	('amplifications', 'Var', (74, 88))	('alterations', 'Var', (49, 60))	('MDM2', 'Gene', '4193', (64, 68))	('MDM2', 'Gene', (64, 68))	('missense mutations', 'Var', (111, 129))
436499	31443718	For EWSR1, the alterations occurred only in a small number of cases, including amplification and deep deletion, as well as one case of missense mutation.	('deep deletion', 'Var', (97, 110))	('amplification', 'Var', (79, 92))	('EWSR1', 'Gene', (4, 9))	('EWSR1', 'Gene', '2130', (4, 9))
436500	31443718	The most frequent alterations in HMGA2 were amplifications.	('HMGA2', 'Gene', '8091', (33, 38))	('amplifications', 'Var', (44, 58))	('alterations', 'Reg', (18, 29))	('HMGA2', 'Gene', (33, 38))
436501	31443718	Events associated with CDKN2A included mostly deep deletion and a few amplifications, as well as one case of a truncation mutation (Fig.	('deep deletion', 'Var', (46, 59))	('CDKN2A', 'Gene', '1029', (23, 29))	('CDKN2A', 'Gene', (23, 29))
436508	31443718	Among the three histologic subtypes of STS, AP events were the leading factors for predicting patients' OS rates, which may indicate that AS events are likely to mostly be involved in the progression of STS and that tumor progression, in some patients, may involve the AP-type splicing of oncogenes or tumor suppressor genes.	('tumor', 'Disease', (216, 221))	('patients', 'Species', '9606', (94, 102))	('OS', 'Chemical', '-', (104, 106))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('patients', 'Species', '9606', (243, 251))	('tumor', 'Disease', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('AP-type splicing', 'Var', (269, 285))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
436535	31443718	Over the past two decades, increasing attention has been paid to the regulatory mechanisms of splicing thought to influence tumor development.	('influence', 'Reg', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('splicing', 'Var', (94, 102))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
436536	31443718	The dysregulation of AS events has been reported to contribute to the pathogenesis of several kinds of tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('dysregulation', 'Var', (4, 17))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('contribute', 'Reg', (52, 62))
436545	31443718	Alternative splicing of genes would generate a large number of aberrant mRNA and protein isoforms with diverse regulatory and functional properties in cancer.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('generate', 'Reg', (36, 44))	('aberrant', 'Var', (63, 71))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Alternative splicing', 'Var', (0, 20))
436563	31443718	Although our study did not provide sufficient evidence, we suspect that genetic alterations in STS oncogenes or tumor suppressors may affect the recognition of splicing sites by splicing factors, which, in turn, causes the activation of oncogenes or the inactivation of tumor suppressors.	('splicing factor', 'Gene', (178, 193))	('oncogenes', 'CPA', (237, 246))	('genetic alterations', 'Var', (72, 91))	('splicing factor', 'Gene', '10569', (178, 193))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('causes', 'Reg', (212, 218))	('inactivation', 'CPA', (254, 266))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('affect', 'Reg', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (112, 117))	('activation', 'PosReg', (223, 233))	('recognition of splicing sites', 'MPA', (145, 174))	('tumor', 'Disease', (270, 275))
436568	31443718	However, since splicing events are regulated by splicing factors through the involvement of exonic or intronic regulatory sequences, related reports have indicated that DNA mutations, DNA methylation, and the aberrant histone modification of splicing factors may influence their recognition of splicing sites, further leading to changes in splicing events.	('leading to changes', 'Reg', (318, 336))	('splicing factor', 'Gene', (48, 63))	('aberrant', 'Var', (209, 217))	('splicing events', 'MPA', (340, 355))	('splicing factor', 'Gene', '10569', (48, 63))	('splicing factor', 'Gene', (242, 257))	('mutations', 'Var', (173, 182))	('DNA', 'Gene', (169, 172))	('recognition of splicing sites', 'MPA', (279, 308))	('histone', 'MPA', (218, 225))	('splicing factor', 'Gene', '10569', (242, 257))	('influence', 'Reg', (263, 272))
436576	31443718	Further in-depth analyses of alternative RNA splicing could provide new insights into the mechanisms of oncogenesis and indicate novel avenues for cancer therapy.	('cancer', 'Disease', (147, 153))	('alternative RNA', 'Var', (29, 44))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))
436589	30651969	PLD is associated with less cardiotoxicity, nausea, alopecia, and myelosuppression than free doxorubicin; this reduced toxicity obviates the need for premedication.	('nausea', 'Disease', 'MESH:D009325', (44, 50))	('myelosuppression', 'Disease', (66, 82))	('cardiotoxicity', 'Disease', 'MESH:D066126', (28, 42))	('cardiotoxicity', 'Disease', (28, 42))	('toxicity obviates', 'Disease', (119, 136))	('less', 'NegReg', (23, 27))	('alopecia', 'Disease', (52, 60))	('nausea', 'Phenotype', 'HP:0002018', (44, 50))	('myelosuppression', 'Disease', 'MESH:D001855', (66, 82))	('alopecia', 'Phenotype', 'HP:0001596', (52, 60))	('toxicity obviates', 'Disease', 'MESH:D064420', (119, 136))	('doxorubicin', 'Chemical', 'MESH:D004317', (93, 104))	('PLD', 'Var', (0, 3))	('nausea', 'Disease', (44, 50))
436655	30651969	PLD is a unique formulation of doxorubicin in that the agent is contained in liposomes coated with hydrophilic methoxypoly (ethylene glycol), that diminishes uptake of the agent by the reticuloendothelial system and consequently increases the half-life of the drug in blood to approximately 50-60 h. PLD localizes to tumors due to increased vascular permeability, resulting in greater drug concentration in tumor in comparison to free doxorubicin.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('ethylene glycol', 'Chemical', 'MESH:D019855', (124, 139))	('doxorubicin', 'Chemical', 'MESH:D004317', (435, 446))	('greater', 'PosReg', (377, 384))	('increased', 'PosReg', (331, 340))	('PLD', 'Var', (300, 303))	('tumor', 'Disease', (317, 322))	('drug concentration', 'MPA', (385, 403))	('tumor', 'Disease', 'MESH:D009369', (407, 412))	('doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (407, 412))	('tumors', 'Disease', (317, 323))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('tumor', 'Disease', (407, 412))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('drug in blood', 'Phenotype', 'HP:0020170', (260, 273))	('vascular permeability', 'MPA', (341, 362))
436658	30651969	However, a higher incidence of palmar-plantar erythrodysesthesia was noted in the cohort receiving PLD.	('palmar-plantar erythrodysesthesia', 'Disease', 'MESH:C536338', (31, 64))	('palmar-plantar erythrodysesthesia', 'Disease', (31, 64))	('plantar erythrodysesthesia', 'Phenotype', 'HP:0100870', (38, 64))	('PLD', 'Var', (99, 102))
436660	30651969	In addition to its activity in STS, PLD has an improved toxicity profile as compared with free doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (95, 106))	('STS', 'Phenotype', 'HP:0030448', (31, 34))	('PLD', 'Var', (36, 39))	('activity', 'MPA', (19, 27))	('toxicity', 'Disease', 'MESH:D064420', (56, 64))	('toxicity', 'Disease', (56, 64))
436668	30651969	In addition to reduced cardiotoxicity, PLD has markedly reduced nausea, alopecia, and myelosuppression, and no anti-emetics or other pre-medications or growth factors are usually needed.	('nausea', 'Disease', (64, 70))	('nausea', 'Disease', 'MESH:D009325', (64, 70))	('reduced', 'NegReg', (56, 63))	('nausea', 'Phenotype', 'HP:0002018', (64, 70))	('alopecia', 'Disease', (72, 80))	('cardiotoxicity', 'Disease', 'MESH:D066126', (23, 37))	('alopecia', 'Phenotype', 'HP:0001596', (72, 80))	('myelosuppression', 'Disease', 'MESH:D001855', (86, 102))	('PLD', 'Var', (39, 42))	('myelosuppression', 'Disease', (86, 102))	('cardiotoxicity', 'Disease', (23, 37))
436676	30651969	Furthermore, PLD results in higher concentrations of drug in tumor than free doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (77, 88))	('concentrations of drug', 'MPA', (35, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('higher', 'PosReg', (28, 34))	('PLD', 'Var', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
436704	28271093	Next generation sequencing of the tumor revealed several genetic alterations, including ATRX (S2094), DNMT3A (R167fs*58), MED12 (G44V), and TP53 (R181P).	('R167fs*58', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('TP53', 'Gene', (140, 144))	('G44V', 'Mutation', 'rs199469672', (129, 133))	('MED12', 'Gene', (122, 127))	('DNMT3A', 'Gene', (102, 108))	('ATRX', 'Gene', '546', (88, 92))	('DNMT3A', 'Gene', '1788', (102, 108))	('S2094', 'Var', (94, 99))	('TP53', 'Gene', '7157', (140, 144))	('MED12', 'Gene', '9968', (122, 127))	('R181P', 'Mutation', 'p.R181P', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('ATRX', 'Gene', (88, 92))	('R167fs', 'Mutation', 'p.R167fsX', (110, 116))
436731	28271093	Next generation sequencing identified several genetic alterations, including ATRX (S2094), DNMT3A (R167fs*58), MED12 (G44V), and TP53 (R181P).	('MED12', 'Gene', '9968', (111, 116))	('DNMT3A', 'Gene', (91, 97))	('R167fs', 'Mutation', 'p.R167fsX', (99, 105))	('DNMT3A', 'Gene', '1788', (91, 97))	('G44V', 'Mutation', 'rs199469672', (118, 122))	('S2094', 'Var', (83, 88))	('R181P', 'Mutation', 'p.R181P', (135, 140))	('ATRX', 'Gene', '546', (77, 81))	('R167fs*58', 'Var', (99, 108))	('TP53', 'Gene', '7157', (129, 133))	('MED12', 'Gene', (111, 116))	('TP53', 'Gene', (129, 133))	('ATRX', 'Gene', (77, 81))
436733	28271093	DNMT3A mutations have not been reported in LMS or other soft tissue sarcomas.	('sarcomas', 'Disease', (68, 76))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (56, 76))	('LMS', 'Disease', (43, 46))	('DNMT3A', 'Gene', (0, 6))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('DNMT3A', 'Gene', '1788', (0, 6))	('LMS', 'Phenotype', 'HP:0100243', (43, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('mutations', 'Var', (7, 16))
436735	28271093	TP53 mutations have been reported in 25-47% of uterine leiomyosarcomas and one study reported allelic loss of TP53 locus in 75% of cases.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('TP53', 'Gene', '7157', (0, 4))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (55, 69))	('reported', 'Reg', (25, 33))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (47, 69))	('mutations', 'Var', (5, 14))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (55, 70))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (55, 70))	('leiomyosarcomas', 'Disease', (55, 70))	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (47, 70))
436876	24551846	Due to the important roles of CCN family proteins in skeletal development, abnormal expression of CCN proteins is related to the tumorigenesis of primary bone tumors such as osteosarcoma, Ewing sarcoma, and chondrosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('CCN', 'Chemical', '-', (30, 33))	('CCN', 'Gene', (98, 101))	('chondrosarcoma', 'Disease', 'MESH:D002813', (207, 221))	('chondrosarcoma', 'Disease', (207, 221))	('tumor', 'Disease', (129, 134))	('osteosarcoma', 'Phenotype', 'HP:0002669', (174, 186))	('bone tumors', 'Phenotype', 'HP:0010622', (154, 165))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (188, 201))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (188, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('related', 'Reg', (114, 121))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (207, 221))	('bone tumor', 'Phenotype', 'HP:0010622', (154, 164))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CCN', 'Chemical', '-', (98, 101))	('expression', 'MPA', (84, 94))	('primary bone tumors', 'Disease', (146, 165))	('abnormal', 'Var', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('osteosarcoma', 'Disease', (174, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('Ewing sarcoma', 'Disease', (188, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('osteosarcoma', 'Disease', 'MESH:D012516', (174, 186))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('primary bone tumors', 'Disease', 'MESH:D001859', (146, 165))	('proteins', 'Protein', (102, 110))
436889	24551846	Importantly, in vivo studies have indicated that aberrant expression of CCN proteins is involved in many diseases, including arthritis, atherosclerosis, fibrosis, diabetic nephropathy, retinopathy, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('CCN', 'Chemical', '-', (72, 75))	('retinopathy', 'Phenotype', 'HP:0000488', (185, 196))	('arthritis', 'Phenotype', 'HP:0001369', (125, 134))	('nephropathy', 'Phenotype', 'HP:0000112', (172, 183))	('aberrant expression', 'Var', (49, 68))	('involved', 'Reg', (88, 96))	('atherosclerosis', 'Disease', 'MESH:D050197', (136, 151))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('atherosclerosis', 'Disease', (136, 151))	('fibrosis', 'Disease', 'MESH:D005355', (153, 161))	('fibrosis', 'Disease', (153, 161))	('atherosclerosis', 'Phenotype', 'HP:0002621', (136, 151))	('arthritis', 'Disease', 'MESH:D001168', (125, 134))	('arthritis', 'Disease', (125, 134))	('CCN proteins', 'Protein', (72, 84))	('retinopathy', 'Disease', (185, 196))	('diabetic nephropathy', 'Disease', (163, 183))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (163, 183))	('cancer', 'Disease', (202, 208))	('retinopathy', 'Disease', 'MESH:D012164', (185, 196))
436896	24551846	CCN2 could also bind to coreceptors of the Wnt receptor LDL-receptor related protein 6 (LRP6) and LRP1 through variant modules.	('variant modules', 'Var', (111, 126))	('LRP1', 'Gene', '4035', (98, 102))	('CCN2', 'Gene', (0, 4))	('LDL-receptor related protein 6', 'Gene', '4040', (56, 86))	('bind', 'Interaction', (16, 20))	('LDL-receptor related protein 6', 'Gene', (56, 86))	('LRP6', 'Gene', '4040', (88, 92))	('LRP6', 'Gene', (88, 92))	('LRP1', 'Gene', (98, 102))
436911	24551846	CCN2 has been demonstrated to induce proliferation of chondrocytes through the MAPK/ERK signaling pathway, and knockdown of CCN2 expression inhibits cell proliferation and increases apoptosis.	('inhibits', 'NegReg', (140, 148))	('induce', 'PosReg', (30, 36))	('increases', 'PosReg', (172, 181))	('knockdown', 'Var', (111, 120))	('ERK', 'Gene', '5594', (84, 87))	('MAPK', 'Gene', (79, 83))	('ERK', 'Gene', (84, 87))	('MAPK', 'Gene', '5595;5594;5595', (79, 83))	('rat', 'Species', '10116', (44, 47))	('CCN2', 'Gene', (124, 128))	('apoptosis', 'CPA', (182, 191))	('proliferation', 'CPA', (37, 50))	('cell proliferation', 'CPA', (149, 167))	('rat', 'Species', '10116', (161, 164))	('rat', 'Species', '10116', (21, 24))
436913	24551846	Other studies have otherwise indicated that high CCN3 expression is associated with increased proliferation rates or tumor promoting potential in many cancer types.	('expression', 'MPA', (54, 64))	('rat', 'Species', '10116', (108, 111))	('high', 'Var', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('rat', 'Species', '10116', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', (117, 122))	('proliferation rates', 'CPA', (94, 113))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancer', 'Disease', (151, 157))	('increased', 'PosReg', (84, 93))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('CCN3', 'Gene', (49, 53))
436916	24551846	Knockdown of CCN1 expression induces cardiovascular defects and is associated with embryonic lethality due to placental vascular inefficiency and compromised blood vessels.	('cardiovascular defects', 'Phenotype', 'HP:0001626', (37, 59))	('induces', 'Reg', (29, 36))	('vascular inefficiency', 'Disease', (120, 141))	('Knockdown', 'Var', (0, 9))	('CCN1', 'Gene', (13, 17))	('cardiovascular defects', 'Disease', 'MESH:D002318', (37, 59))	('embryonic lethality', 'Disease', 'MESH:D020964', (83, 102))	('associated', 'Reg', (67, 77))	('embryonic lethality', 'Disease', (83, 102))	('placental vascular inefficiency', 'Phenotype', 'HP:0011416', (110, 141))	('vascular inefficiency', 'Disease', 'MESH:D000783', (120, 141))	('cardiovascular defects', 'Disease', (37, 59))
436917	24551846	In vivo results show that CCN2-null mutant mice show angiogenic deficiency in the growth plates during endochondral bone formation.	('mice', 'Species', '10090', (43, 47))	('angiogenic deficiency', 'Disease', (53, 74))	('mutant', 'Var', (36, 42))	('CCN2-null', 'Gene', (26, 35))	('angiogenic deficiency', 'Disease', 'MESH:D007153', (53, 74))
436940	24551846	CCN3 has also been shown to inhibit osteoblast differentiation by neutralizing BMP2, a well-known enhancer of osteoblastogenesis in MC3T3 osteoblast precursor cells, in in vivo studies.	('osteoblast differentiation', 'CPA', (36, 62))	('MC3T3', 'CellLine', 'CVCL:0D74', (132, 137))	('BMP2', 'Gene', (79, 83))	('CCN3', 'Gene', (0, 4))	('neutralizing', 'Var', (66, 78))	('inhibit', 'NegReg', (28, 35))
436946	24551846	In that study, point mutations in CCN6 were shown to relate to the autosomal recessive skeletal disease progressive pseudorheumatoid dysplasia, a human disease resulting in progressive degeneration of articular cartilage.	('autosomal recessive skeletal disease progressive pseudorheumatoid dysplasia', 'Disease', 'MESH:C535387', (67, 142))	('CCN6', 'Gene', '8838', (34, 38))	('skeletal disease', 'Phenotype', 'HP:0000924', (87, 103))	('human', 'Species', '9606', (146, 151))	('degeneration of articular cartilage', 'Disease', 'MESH:D002357', (185, 220))	('CCN6', 'Gene', (34, 38))	('degeneration of articular cartilage', 'Disease', (185, 220))	('relate', 'Reg', (53, 59))	('point mutations', 'Var', (15, 30))
436955	24551846	They also found that CCN1 knockdown inhibited in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice.	('inhibited', 'NegReg', (36, 45))	('migration', 'CPA', (86, 95))	('mice', 'Species', '10090', (134, 138))	('lung metastases', 'Disease', (115, 130))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('osteosarcoma', 'Disease', (55, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('CCN1', 'Gene', (21, 25))	('rat', 'Species', '10116', (89, 92))	('lung metastases', 'Disease', 'MESH:D009362', (115, 130))	('knockdown', 'Var', (26, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))
436957	24551846	In addition, another study showed that CCN3 was expressed in primary tumors of osteosarcoma patients and that a high CCN3 expression level was associated with an increased risk of developing lung metastases.	('primary tumors', 'Disease', 'MESH:D009369', (61, 75))	('tumors of osteosarcoma', 'Disease', 'MESH:D012516', (69, 91))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CCN3', 'Gene', (117, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (79, 91))	('associated with', 'Reg', (143, 158))	('high', 'Var', (112, 116))	('lung metastases', 'Disease', (191, 206))	('patients', 'Species', '9606', (92, 100))	('lung metastases', 'Disease', 'MESH:D009362', (191, 206))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors of osteosarcoma', 'Disease', (69, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('expression level', 'MPA', (122, 138))	('primary tumors', 'Disease', (61, 75))
436966	24551846	The same study also suggested that a low level of CCN3 expression was associated with better patient prognosis.	('patient', 'Species', '9606', (93, 100))	('CCN3', 'Gene', (50, 54))	('low level', 'Var', (37, 46))	('expression', 'MPA', (55, 65))
436984	24551846	In vivo mouse model results showed that 093G9 also inhibited primary tumor growth and spontaneous lymph node metastases.	('093G9', 'Var', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('metastases', 'Disease', 'MESH:D009362', (109, 119))	('tumor', 'Disease', (69, 74))	('metastases', 'Disease', (109, 119))	('mouse', 'Species', '10090', (8, 13))	('inhibited', 'NegReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
436994	24551846	They also demonstrated that CCN3 increased the bone metastatic potential of 66cl4 cells, which are breast cancer cells metastasizing to the lungs.	('CCN3', 'Var', (28, 32))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('bone metastatic potential', 'CPA', (47, 72))	('increased', 'PosReg', (33, 42))	('rat', 'Species', '10116', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
436995	24551846	In accordance with this opinion, CCN3 was shown to impair osteoblast differentiation and affect receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin ratios of osteoblasts, thereby enhancing osteoclastogenesis.	('receptor activator of NF-kappaB ligand', 'Gene', '8600', (96, 134))	('osteoblast differentiation', 'CPA', (58, 84))	('osteoclastogenesis', 'CPA', (200, 218))	('CCN3', 'Var', (33, 37))	('osteoprotegerin', 'Gene', (143, 158))	('RANKL', 'Gene', '8600', (136, 141))	('RANKL', 'Gene', (136, 141))	('osteoprotegerin', 'Gene', '4982', (143, 158))	('impair', 'NegReg', (51, 57))	('affect', 'Reg', (89, 95))	('enhancing', 'PosReg', (190, 199))	('rat', 'Species', '10116', (159, 162))	('receptor activator of NF-kappaB ligand', 'Gene', (96, 134))
437025	24551846	As they have crucial roles in osteo/chondrogenesis during development, abnormal expression of CCN proteins is implicated in tumors that grow in the bone microenvironment such as primary bone tumors and bone metastases.	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('abnormal', 'Var', (71, 79))	('tumors', 'Disease', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('expression', 'MPA', (80, 90))	('bone tumor', 'Phenotype', 'HP:0010622', (186, 196))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('proteins', 'Protein', (98, 106))	('bone tumors', 'Phenotype', 'HP:0010622', (186, 197))	('CCN', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('primary bone tumors', 'Disease', (178, 197))	('bone metastases', 'Disease', 'MESH:D009362', (202, 217))	('tumors', 'Disease', (124, 130))	('implicated', 'Reg', (110, 120))	('primary bone tumors', 'Disease', 'MESH:D001859', (178, 197))	('bone metastases', 'Disease', (202, 217))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('CCN', 'Chemical', '-', (94, 97))
437044	21056138	Inhibiting FAK or Akt inhibited FAK or Akt phosphorylation and the stimulation of adhesion by increased pressure (n=5 each, p<0.01 each).	('FAK', 'Gene', (32, 35))	('pressure', 'MPA', (104, 112))	('FAK', 'Gene', '5747', (32, 35))	('inhibited', 'NegReg', (22, 31))	('Inhibiting', 'Var', (0, 10))	('Akt', 'Gene', (18, 21))	('Akt', 'Gene', '207', (39, 42))	('FAK', 'Gene', (11, 14))	('FAK', 'Gene', '5747', (11, 14))	('Akt', 'Gene', '207', (18, 21))	('Akt', 'Gene', (39, 42))	('adhesion', 'MPA', (82, 90))	('stimulation', 'PosReg', (67, 78))
437072	21056138	20muM Y15 or 10muM Akt IV inhibitor pretreatment prevented pressure-associated increased adhesion in fibrous histiosarcoma, HT-1080, and A-673 cells (Fig.	('increased', 'PosReg', (79, 88))	('Akt', 'Gene', '207', (19, 22))	('adhesion', 'MPA', (89, 97))	('fibrous histiosarcoma', 'Disease', (101, 122))	('Y15', 'Var', (6, 9))	('HT-1080', 'CellLine', 'CVCL:0317', (124, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Akt', 'Gene', (19, 22))	('fibrous histiosarcoma', 'Disease', 'MESH:D010411', (101, 122))
437076	21056138	Akt inhibition reduced basal A-673 adhesion 85+-3% and histiosarcoma adhesion 98+-1% (n=5, p<0.001 each), and blocked pressure-stimulated adhesion.	('basal A-673', 'MPA', (23, 34))	('inhibition', 'Var', (4, 14))	('Akt', 'Gene', '207', (0, 3))	('reduced', 'NegReg', (15, 22))	('histiosarcoma', 'Disease', 'None', (55, 68))	('histiosarcoma', 'Disease', (55, 68))	('Akt', 'Gene', (0, 3))	('blocked', 'NegReg', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
437077	21056138	Y15 decreased basal HT-1080 adhesion 43+-4% (n=5, p<0.01), A-673 adhesion 80+-4% (n=5, p<0.001), and fibrous histiosarcoma adhesion 56+-3% (n=5, p<0.001), and blocked pressure-stimulated adhesion in all three.	('decreased', 'NegReg', (4, 13))	('HT-1080', 'CellLine', 'CVCL:0317', (20, 27))	('fibrous histiosarcoma', 'Disease', (101, 122))	('Y15', 'Var', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('basal HT-1080', 'MPA', (14, 27))	('fibrous histiosarcoma', 'Disease', 'MESH:D010411', (101, 122))	('A-673 adhesion', 'MPA', (59, 73))	('blocked', 'NegReg', (159, 166))
437080	21056138	Phosphorylated FAK (Y397) increased by 9+-1% (n=9, p<0.001) in HT-1080 cells while Akt (S473) phosphorylation increased 11+-3% (n=9, p<0.01).	('FAK', 'Gene', '5747', (15, 18))	('FAK', 'Gene', (15, 18))	('Akt', 'Gene', (83, 86))	('Phosphorylated', 'MPA', (0, 14))	('HT-1080', 'CellLine', 'CVCL:0317', (63, 70))	('Y397', 'Var', (20, 24))	('Akt', 'Gene', '207', (83, 86))	('Y397', 'Chemical', '-', (20, 24))
437081	21056138	Y15 decreased FAK phosphorylation by 11+-2% (n=9, p<0.01) and prevented the pressure-stimulated increase in FAK phosphorylation.	('decreased', 'NegReg', (4, 13))	('FAK', 'Gene', '5747', (14, 17))	('decreased FAK', 'Phenotype', 'HP:0032341', (4, 17))	('Y15', 'Var', (0, 3))	('prevented', 'NegReg', (62, 71))	('FAK', 'Gene', '5747', (108, 111))	('FAK', 'Gene', (14, 17))	('FAK', 'Gene', (108, 111))
437083	21056138	Pressure stimulated FAK (Y397) and AKT phosphorylation 17+-2% and 14+-2% in primary histiosarcoma cells (n=4, p<0.001 each).	('histiosarcoma', 'Disease', (84, 97))	('AKT', 'Gene', (35, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('FAK', 'Gene', (20, 23))	('FAK', 'Gene', '5747', (20, 23))	('Y397', 'Var', (25, 29))	('Y397', 'Chemical', '-', (25, 29))	('histiosarcoma', 'Disease', 'None', (84, 97))	('AKT', 'Gene', '207', (35, 38))
437084	21056138	Y15 decreased FAK and AKT phosphorylation by 33+-7% and 24+-2% (n=4, p<0.001 each), and prevented the pressure-stimulated increase in FAK and Akt phosphorylation.	('Akt', 'Gene', (142, 145))	('decreased', 'NegReg', (4, 13))	('AKT', 'Gene', '207', (22, 25))	('FAK', 'Gene', '5747', (14, 17))	('decreased FAK', 'Phenotype', 'HP:0032341', (4, 17))	('FAK', 'Gene', '5747', (134, 137))	('Y15', 'Var', (0, 3))	('FAK', 'Gene', (134, 137))	('AKT', 'Gene', (22, 25))	('Akt', 'Gene', '207', (142, 145))	('FAK', 'Gene', (14, 17))	('prevented', 'NegReg', (88, 97))
437124	23887603	The findings of this study provide a rationale for the clinical study of the fully human immunocytokine L19-TNF in combination with doxorubicin in patients with soft-tissue sarcoma.	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (161, 180))	('soft-tissue sarcoma', 'Disease', (161, 180))	('L19-TNF', 'Var', (104, 111))	('rat', 'Species', '10116', (37, 40))	('human', 'Species', '9606', (83, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('patients', 'Species', '9606', (147, 155))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (161, 180))	('doxorubicin', 'Chemical', 'MESH:D004317', (132, 143))
437153	23887603	Melphalan is not commonly used for the systemic therapy of sarcoma and there is a need to learn about the clinical potential of the combination of L19-TNF with doxorubicin (the drug of choice for first-line treatment of most soft-tissue sarcomas).	('sarcomas', 'Disease', 'MESH:D012509', (237, 245))	('L19-TNF', 'Var', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('sarcoma', 'Disease', (59, 66))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (225, 244))	('sarcomas', 'Phenotype', 'HP:0100242', (237, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcomas', 'Disease', (237, 245))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (225, 244))	('soft-tissue sarcoma', 'Disease', (225, 244))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (225, 245))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('sarcoma', 'Disease', (237, 244))	('doxorubicin', 'Chemical', 'MESH:D004317', (160, 171))
437154	23887603	Moreover, it remains unclear whether it is better to use the F8 (specific to the EDA domain of fibronectin) or L19 (specific to EDB) for tumour-targeting applications.	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('L19', 'Var', (111, 114))	('tumour', 'Disease', (137, 143))
437157	23887603	F8-TNF, when used in combination with doxorubicin, led to complete and long-lasting tumour eradications in both the models.	('tumour eradications', 'Disease', 'MESH:D009369', (84, 103))	('doxorubicin', 'Chemical', 'MESH:D004317', (38, 49))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour eradications', 'Disease', (84, 103))	('F8-TNF', 'Var', (0, 6))
437192	23887603	The cumulated uptake (area under the time activity curve) of the L19 antibody was greater in tumour than in liver and kidney (clearance-related organs that often exhibit a higher antibody uptake compared to other tissues).	('tumour', 'Disease', (93, 99))	('L19', 'Var', (65, 68))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('uptake', 'MPA', (14, 20))	('greater', 'PosReg', (82, 89))
437194	23887603	Figure 2 presents representative immunofluorescence findings of tumour sections stained with L19, F8 and KSF antibody (specific to hen egg lysozyme and used here as negative control).	('L19', 'Var', (93, 96))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumour', 'Disease', (64, 70))
437200	23887603	We studied the therapeutic activity of intravenous administrations of F8-TNF (2 mug), doxorubicin (5 mg kg-1) or the combination of the two agents at the recommended dose in immunocompetent mice bearing WEHI-164 sarcoma (Figure 4) and 180 sarcoma (Figure 5).	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('sarcoma', 'Disease', 'MESH:D012509', (239, 246))	('sarcoma', 'Disease', (239, 246))	('doxorubicin', 'Chemical', 'MESH:D004317', (86, 97))	('rat', 'Species', '10116', (59, 62))	('sarcoma', 'Disease', 'MESH:D012509', (212, 219))	('mice', 'Species', '10090', (190, 194))	('sarcoma', 'Disease', (212, 219))	('F8-TNF', 'Var', (70, 76))
437203	23887603	F8-TNF as a single agent exhibited a potent tumour growth inhibition compared to the saline control group (P<0.0001; the statistical analysis is presented in Supplementary Material 3), resulting in complete cures of 40% of the animals.	('saline', 'Chemical', 'MESH:D012965', (85, 91))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('F8-TNF', 'Var', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
437204	23887603	The combination therapy of F8-TNF with doxorubicin led to an enhanced antitumour effect and to complete tumour eradications (four out of five mice and five out of five mice in WEHI-164 and 180 sarcomas, respectively).	('enhanced', 'PosReg', (61, 69))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('sarcomas', 'Disease', 'MESH:D012509', (193, 201))	('doxorubicin', 'Chemical', 'MESH:D004317', (39, 50))	('tumour eradications', 'Disease', (104, 123))	('tumour', 'Disease', (74, 80))	('mice', 'Species', '10090', (168, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('mice', 'Species', '10090', (142, 146))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour eradications', 'Disease', 'MESH:D009369', (104, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('sarcomas', 'Disease', (193, 201))	('F8-TNF', 'Var', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('tumour', 'Disease', (104, 110))
437205	23887603	Treatments were very well tolerated, except for the combination treatment group of F8-TNF with doxorubicin against WEHI-164 tumours, where mice exhibited weight loss up to 15%.	('weight loss', 'Disease', (154, 165))	('F8-TNF', 'Var', (83, 89))	('doxorubicin', 'Chemical', 'MESH:D004317', (95, 106))	('weight loss', 'Phenotype', 'HP:0001824', (154, 165))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('rat', 'Species', '10116', (30, 33))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('weight loss', 'Disease', 'MESH:D015431', (154, 165))	('mice', 'Species', '10090', (139, 143))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
437212	23887603	In parallel experiments, the histological analysis of tumour sections after treatment revealed the formation of massive necrosis within the neoplastic mass already 4 hours after the administration of F8-TNF (Supplementary Material 5).	('F8-TNF', 'Var', (200, 206))	('neoplastic mass', 'Phenotype', 'HP:0002664', (140, 155))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('rat', 'Species', '10116', (190, 193))	('necrosis within the neoplastic', 'Disease', 'MESH:D001929', (120, 150))	('necrosis within the neoplastic', 'Disease', (120, 150))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
437221	23887603	F8-TNF eradicated sarcomas in almost all treated animals in two murine immunocompetent models of the disease, when the agent was administered in combination with doxorubicin.	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('eradicated', 'NegReg', (7, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcomas', 'Disease', (18, 26))	('murine', 'Species', '10090', (64, 70))	('F8-TNF', 'Var', (0, 6))	('doxorubicin', 'Chemical', 'MESH:D004317', (162, 173))
437225	23887603	Murine sarcomas treated with F8-TNF turned black after treatment.	('sarcomas', 'Disease', 'MESH:D012509', (7, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('F8-TNF', 'Var', (29, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (7, 15))	('sarcomas', 'Disease', (7, 15))	('Murine', 'Species', '10090', (0, 6))
437239	22693489	The EWS/ATF-1 translocation was found in 28 (53.84%) of 31 patients studied, and mutation of BRAF or NRAS was found in only 2 of 22 patients analyzed cases (3.84%).	('BRAF', 'Gene', (93, 97))	('NRAS', 'Gene', (101, 105))	('EWS/ATF-1', 'Gene', (4, 13))	('translocation', 'Var', (14, 27))	('found', 'Reg', (32, 37))	('NRAS', 'Gene', '4893', (101, 105))	('EWS/ATF-1', 'Gene', '466;2130', (4, 13))	('patients', 'Species', '9606', (59, 67))	('BRAF', 'Gene', '673', (93, 97))	('patients', 'Species', '9606', (132, 140))
437248	22693489	Unlike melanomas, most CCS tumors are characterized by a recurrent chromosomal translocation, t(12; 22), resulting in fusion of the EWS gene on 22q12 with the ATF1 gene on 12q13.	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CCS tumors', 'Disease', 'MESH:D009369', (23, 33))	('EWS', 'Gene', '2130', (132, 135))	('EWS', 'Gene', (132, 135))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('ATF1', 'Gene', (159, 163))	('melanomas', 'Disease', (7, 16))	('CCS tumors', 'Disease', (23, 33))	('ATF1', 'Gene', '466', (159, 163))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (57, 92))	('fusion', 'Var', (118, 124))	('melanomas', 'Phenotype', 'HP:0002861', (7, 16))	('melanomas', 'Disease', 'MESH:D008545', (7, 16))
398774	22693489	Several fusion transcript types have been described, with a predominance of type 1 fusing exon 8 of EWS with exon 4 of ATF1 and type 2 fusing exon 7 of EWS with exon 5 of ATF1.	('ATF1', 'Gene', '466', (119, 123))	('exon 4', 'Var', (109, 115))	('ATF1', 'Gene', '466', (171, 175))	('EWS', 'Gene', '2130', (152, 155))	('EWS', 'Gene', (152, 155))	('EWS', 'Gene', '2130', (100, 103))	('ATF1', 'Gene', (119, 123))	('ATF1', 'Gene', (171, 175))	('EWS', 'Gene', (100, 103))
437250	22693489	All the mutations were detected in the kinase domain of the BRAF gene and found in exons 11 and 15.	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('mutations', 'Var', (8, 17))
437251	22693489	The most common mutation (V599E) is the T1796A single-base substitution in exon 15, leading to an exchange of valine for glutamic acid at position 599.	('V599E', 'Mutation', 'p.V599E', (26, 31))	('T1796A', 'Mutation', 'c.1796T>A', (40, 46))	('exchange', 'Var', (98, 106))	('V599E', 'Var', (26, 31))	('T1796A', 'Var', (40, 46))	('valine for glutamic acid at position 599', 'Mutation', 'p.E599V', (110, 150))
437258	22693489	A confirmation of diagnosis is obtained by immunohistochemistry with a diffuse or focal positivity for S-100 protein and melanocyte-associated antigen HMB-45, positivity for neuron-specific enolase (NSE).	('neuron-specific enolase', 'Gene', (174, 197))	('NSE', 'Gene', '2026', (199, 202))	('positivity', 'Var', (159, 169))	('S-100 protein', 'Protein', (103, 116))	('neuron-specific enolase', 'Gene', '2026', (174, 197))	('NSE', 'Gene', (199, 202))
437293	22693489	Only one of the 22 CCS harboured a BRAF mutation (V599E); it was the well-known valine to glutamic acid change in position 599.	('V599E', 'Mutation', 'p.V599E', (50, 55))	('BRAF', 'Gene', (35, 39))	('V599E);', 'Var', (50, 57))	('valine to glutamic acid change in position 599', 'Mutation', 'p.V599E', (80, 126))	('BRAF', 'Gene', '673', (35, 39))
437296	22693489	The two tumours that presented a BRAF or NRAS mutation also presented the ATF1-EWS fusion gene and were considered atypical.	('EWS', 'Gene', '2130', (79, 82))	('EWS', 'Gene', (79, 82))	('NRAS', 'Gene', '4893', (41, 45))	('BRAF', 'Gene', '673', (33, 37))	('ATF1', 'Gene', '466', (74, 78))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('presented', 'Reg', (60, 69))	('tumours', 'Disease', (8, 15))	('BRAF', 'Gene', (33, 37))	('NRAS', 'Gene', (41, 45))	('ATF1', 'Gene', (74, 78))	('mutation', 'Var', (46, 54))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
437330	22693489	CCS is characterized by a recurrent chromosomal translocation t(12; 22), which results in fusion of the EWS gene on 22q with the ATF1 gene on 12q.	('EWS', 'Gene', '2130', (104, 107))	('EWS', 'Gene', (104, 107))	('CCS', 'Disease', (0, 3))	('fusion', 'Var', (90, 96))	('ATF1', 'Gene', (129, 133))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (26, 61))	('ATF1', 'Gene', '466', (129, 133))
437332	22693489	In the current study, 90.32% of the analyzed tumors (28 of 31 tumors) had this translocation.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('translocation', 'Var', (79, 92))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (45, 51))
437334	22693489	Indeed, CCS is a sarcoma subtype, and the characteristic EWS/ATF1 translocation, resulting in the chimeric protein EWS/ATF1, is responsible for the melanocytic differentiation.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcoma subtype', 'Disease', 'MESH:D012509', (17, 32))	('EWS/ATF1', 'Gene', (57, 65))	('translocation', 'Var', (66, 79))	('EWS/ATF1', 'Gene', (115, 123))	('EWS/ATF1', 'Gene', '466;2130', (115, 123))	('sarcoma subtype', 'Disease', (17, 32))	('EWS/ATF1', 'Gene', '466;2130', (57, 65))	('responsible', 'Reg', (128, 139))	('CCS', 'Disease', (8, 11))
437336	22693489	Because of the extensive clinical, histologic, and immunohistochemical similarities with melanoma, we decided to analyze whether CCS also has mutations in the BRAF and NRAS gene.	('mutations', 'Var', (142, 151))	('BRAF', 'Gene', (159, 163))	('NRAS', 'Gene', '4893', (168, 172))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('BRAF', 'Gene', '673', (159, 163))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('NRAS', 'Gene', (168, 172))
437338	22693489	The two tumours which were found to harbor mutations in the BRAF and NRAS gene also presented the ATF1-EWS fusion gene and were considered atypical.	('NRAS', 'Gene', '4893', (69, 73))	('ATF1', 'Gene', '466', (98, 102))	('EWS', 'Gene', '2130', (103, 106))	('EWS', 'Gene', (103, 106))	('tumours', 'Disease', (8, 15))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('mutations', 'Var', (43, 52))	('tumours', 'Disease', 'MESH:D009369', (8, 15))	('NRAS', 'Gene', (69, 73))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('ATF1', 'Gene', (98, 102))	('presented', 'Reg', (84, 93))
437339	22693489	Therefore, we support the hypothesis that CCS belongs to the soft tissue sarcoma family and that the melanin synthesis is due to the specific action of the chimeric EWF/ATF1 protein via MITF activation.	('MITF', 'Gene', (186, 190))	('chimeric', 'Var', (156, 164))	('melanin', 'Chemical', 'MESH:D008543', (101, 108))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (61, 80))	('sarcoma', 'Disease', (73, 80))	('activation', 'PosReg', (191, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('ATF1', 'Gene', (169, 173))	('melanin synthesis', 'MPA', (101, 118))	('ATF1', 'Gene', '466', (169, 173))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))	('protein', 'Protein', (174, 181))	('MITF', 'Gene', '4286', (186, 190))
437363	22693489	However, clear cell sarcoma is genetically distinct lacking melanoma-associated BRAF mutations and instead harboring recurrent and characteristic chromosomal translocations involving the EWSR1 gene.	('clear cell sarcoma', 'Disease', (9, 27))	('BRAF', 'Gene', (80, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('EWSR1', 'Gene', (187, 192))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (9, 27))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('mutations', 'Var', (85, 94))	('lacking', 'NegReg', (52, 59))	('BRAF', 'Gene', '673', (80, 84))	('EWSR1', 'Gene', '2130', (187, 192))
437447	21994717	The sequence of WDSV present in the STEC cell line revealed a total of 27 point mutations over the entire genome (12,706 bp) compared to the previous sequence.	('WDSV', 'Gene', (16, 20))	('WDSV', 'Species', '39720', (16, 20))	('STEC', 'CellLine', 'None', (36, 40))	('point mutations', 'Var', (74, 89))
437448	21994717	Only six of these mutations altered amino acid sequences: one in the amino terminus of RT, four in the surface domain (SU) of envelope, and one in the Orf B protein.	('altered', 'Reg', (28, 35))	('amino', 'MPA', (36, 41))	('Orf B', 'Gene', (151, 156))	('env', 'Gene', (126, 129))	('env', 'Gene', '100775105', (126, 129))	('Orf B', 'Gene', '1403499', (151, 156))	('mutations', 'Var', (18, 27))
437449	21994717	A significant sequence variation was identified in the transmembrane region (TM) of env: the insertion of one guanine and one cytosine residue at nt 9340 and nt 9347, respectively.	('guanine', 'Chemical', 'MESH:D006147', (110, 117))	('env', 'Gene', (84, 87))	('nt 9340', 'Var', (146, 153))	('env', 'Gene', '100775105', (84, 87))	('cytosine', 'Chemical', 'MESH:D003596', (126, 134))	('nt 9347', 'Var', (158, 165))
437450	21994717	These insertions result in a frameshift and the generation of a stop codon at nt 9451 compared with the stop at nt 9649 in the original WDSV molecular clone.	('WDSV', 'Species', '39720', (136, 140))	('frameshift', 'Var', (29, 39))	('nt 9451', 'Var', (78, 85))	('result in', 'Reg', (17, 26))
437474	21994717	The WDSV rv-cyclin is a 297 amino acid protein that, in addition to the cyclin box (a.a. 1-220), also contains an acidic transcription activation domain (a.a. 240-270) with a TAF9 binding motif (a.a. 257-266) in its extended C terminal region (Figure 4, left).	('activation', 'PosReg', (135, 145))	('a.a. 257-266', 'Var', (195, 207))	('WDSV', 'Species', '39720', (4, 8))	('binding', 'Interaction', (180, 187))	('a.a.', 'Var', (154, 158))	('TAF9', 'Gene', (175, 179))	('TAF9', 'Gene', '6880', (175, 179))
437476	21994717	Whether detected as native protein in naturally infected tumor cells (Figure 3) or over-expressed in a variety of mammalian and piscine cell lines, the WDSV rv-cyclin is primarily localized in the nucleus and is concentrated in perichromatin fibrils and interchromatin granule clusters (IGCs; also known as nuclear speckles) (Figure 4, right).	('infected tumor', 'Disease', (48, 62))	('WDSV rv-cyclin', 'Var', (152, 166))	('mammalian', 'Species', '9606', (114, 123))	('rv-cyclin', 'Var', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('WDSV', 'Species', '39720', (152, 156))	('infected tumor', 'Disease', 'MESH:D009369', (48, 62))
437482	21994717	Fusion of the GAL4 DNA binding domain to rv-cyclin or to the isolated AD resulted in activation of transcription from a GAL4 responsive luciferase reporter.	('Fusion', 'Var', (0, 6))	('GAL4', 'Gene', (120, 124))	('transcription', 'MPA', (99, 112))	('GAL4', 'Gene', (14, 18))	('GAL4', 'Gene', '3960', (120, 124))	('activation', 'PosReg', (85, 95))	('GAL4', 'Gene', '3960', (14, 18))	('binding', 'Interaction', (23, 30))
437483	21994717	Mutation V260S within the AD eliminated activation of transcription from the GAL4 luciferase reporter.	('GAL4', 'Gene', (77, 81))	('GAL4', 'Gene', '3960', (77, 81))	('V260S', 'Mutation', 'p.V260S', (9, 14))	('V260S', 'Var', (9, 14))	('transcription', 'MPA', (54, 67))	('activation', 'MPA', (40, 50))	('eliminated', 'NegReg', (29, 39))
437484	21994717	Inhibition of the WDSV promoter is also dependent upon the rv-cyclin AD and the V260S mutation relieves this inhibition.	('WDSV', 'Species', '39720', (18, 22))	('V260S mutation', 'Var', (80, 94))	('V260S', 'Mutation', 'p.V260S', (80, 85))	('relieves', 'NegReg', (95, 103))
437486	21994717	Binding of rv-cyclin to TAF9 is dependent upon amino acid V260 and binding was lost with a V260S mutation.	('TAF9', 'Gene', (24, 28))	('TAF9', 'Gene', '6880', (24, 28))	('lost', 'NegReg', (79, 83))	('V260S', 'Mutation', 'p.V260S', (91, 96))	('Binding', 'Interaction', (0, 7))	('binding', 'Interaction', (67, 74))	('V260S', 'Var', (91, 96))
437487	21994717	The conservative V260F mutation retains binding to TAF9 and function in reporter assays.	('TAF9', 'Gene', (51, 55))	('TAF9', 'Gene', '6880', (51, 55))	('V260F', 'Mutation', 'p.V260F', (17, 22))	('V260F', 'Var', (17, 22))	('function', 'MPA', (60, 68))	('binding', 'Interaction', (40, 47))
437498	21994717	Based on these observations an interaction of WDSV rv-cyclin with cdk3 was evaluated and it was found that rv-cyclin also interacts directly with cdk3 and activates cdk3 phosphorylation of pRb.	('pRb', 'Gene', '5925', (189, 192))	('cdk3', 'Gene', '1018', (165, 169))	('activates', 'PosReg', (155, 164))	('rv-cyclin', 'Var', (107, 116))	('cdk3', 'Gene', (146, 150))	('cdk3', 'Gene', (66, 70))	('cdk3', 'Gene', '1018', (146, 150))	('cdk3', 'Gene', '1018', (66, 70))	('interacts', 'Interaction', (122, 131))	('pRb', 'Gene', (189, 192))	('WDSV', 'Species', '39720', (46, 50))	('cdk3', 'Gene', (165, 169))
437502	21994717	Cyclin C was first identified in complementation assays using yeast deficient in Cln genes.	('Cln', 'Gene', '5111', (81, 84))	('Cyclin C', 'Gene', (0, 8))	('Cln', 'Gene', (81, 84))	('deficient', 'Var', (68, 77))	('yeast', 'Species', '4932', (62, 67))	('Cyclin C', 'Gene', '892', (0, 8))
437504	21994717	In transgenic mice, expression of rv-cyclin from a keratin promoter was associated with severe squamous cell hyperplasia and dysplasia at sites of injury such as tail clipping.	('tail clipping', 'Disease', (162, 175))	('associated with', 'Reg', (72, 87))	('squamous cell hyperplasia', 'Phenotype', 'HP:0002860', (95, 120))	('rv-cyclin', 'Var', (34, 43))	('transgenic mice', 'Species', '10090', (3, 18))	('squamous cell hyperplasia and dysplasia', 'Disease', 'MESH:D002294', (95, 134))
437506	21994717	No increase in tumor incidence was seen in rv-cyclin transgenic fish exposed to N-ethyl N-nitrosourea (ENU), a chemical carcinogen, over that observed in control transgenic fish treated with ENU.	('transgenic', 'Species', '10090', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('transgenic', 'Species', '10090', (53, 63))	('transgenic', 'Var', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('rv-cyclin', 'Gene', (43, 52))	('N-ethyl N-nitrosourea', 'Chemical', 'MESH:D005038', (80, 101))
437510	21994717	Additionally, the time to development of tumor, after exposure to DMBA, was increased in rv-cyclin transgenic fish.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('rv-cyclin', 'Gene', (89, 98))	('tumor', 'Disease', (41, 46))	('increased', 'PosReg', (76, 85))	('transgenic', 'Species', '10090', (99, 109))	('transgenic', 'Var', (99, 109))	('DMBA', 'Chemical', 'MESH:C082386', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
437522	21994717	However, in the presence of the PKC inhibitor, bisindolymaleimide hydrochloride, the growth of these cells was significantly diminished.	('bisindolymaleimide hydrochloride', 'Chemical', '-', (47, 79))	('PKC', 'Gene', (32, 35))	('diminished', 'NegReg', (125, 135))	('PKC', 'Gene', '5578;18750', (32, 35))	('bisindolymaleimide', 'Var', (47, 65))	('growth of', 'CPA', (85, 94))
437523	21994717	Treatment of NIH-3T3-Orf B cells with concentrations of staurosporine known to induce apoptosis did not cause death of these cells, and in a screen to identify downstream targets of activated PKC, the pro-apoptotic protein, BAD, was found to be inactivated by phosphorylation at residues 112, 136 and 155, substrates of activated PKC and AKT signaling pathways.	('phosphorylation at residues 112', 'Var', (260, 291))	('PKC', 'Gene', (330, 333))	('staurosporine', 'Chemical', 'MESH:D019311', (56, 69))	('PKC', 'Gene', '5578;18750', (192, 195))	('NIH-3T3', 'CellLine', 'CVCL:0594', (13, 20))	('AKT', 'Gene', (338, 341))	('Orf B', 'Gene', (21, 26))	('PKC', 'Gene', '5578;18750', (330, 333))	('pro-apoptotic protein, BAD', 'Gene', '572', (201, 227))	('Orf B', 'Gene', '1403499', (21, 26))	('PKC', 'Gene', (192, 195))	('inactivated', 'NegReg', (245, 256))	('AKT', 'Gene', '207', (338, 341))
437525	21994717	Overall, these studies indicate that expression of Orf B leads to the activation of PKC and AKT signaling pathways and has the capacity to transform cells in vitro.	('transform', 'Reg', (139, 148))	('expression', 'Var', (37, 47))	('AKT', 'Gene', '207', (92, 95))	('Orf B', 'Gene', (51, 56))	('PKC', 'Gene', '5578;18750', (84, 87))	('PKC', 'Gene', (84, 87))	('cells', 'CPA', (149, 154))	('AKT', 'Gene', (92, 95))	('activation', 'PosReg', (70, 80))	('Orf B', 'Gene', '1403499', (51, 56))
437546	21994717	The rv-cyclin may also interfere with innate immune mechanisms by blocking NF-kappaB and interferon transcription.	('blocking', 'NegReg', (66, 74))	('interfere', 'NegReg', (23, 32))	('NF-kappaB', 'Gene', (75, 84))	('rv-cyclin', 'Var', (4, 13))	('interferon transcription', 'MPA', (89, 113))	('NF-kappaB', 'Gene', '4790', (75, 84))
437563	25353281	Both neoplasms demonstrated diffuse immunoreactivity for MUC4, a highly specific marker for SEF, and both demonstrated evidence of rearrangement of both the EWSR1 and CREB3L1 genes which have recently shown to be fused in this entity.	('neoplasms', 'Phenotype', 'HP:0002664', (5, 14))	('EWSR1', 'Gene', '2130', (157, 162))	('immunoreactivity', 'MPA', (36, 52))	('neoplasms', 'Disease', 'MESH:D009369', (5, 14))	('neoplasms', 'Disease', (5, 14))	('MUC4', 'Gene', '4585', (57, 61))	('CREB3L1', 'Gene', '90993', (167, 174))	('neoplasm', 'Phenotype', 'HP:0002664', (5, 13))	('CREB3L1', 'Gene', (167, 174))	('rearrangement', 'Var', (131, 144))	('EWSR1', 'Gene', (157, 162))	('MUC4', 'Gene', (57, 61))
437568	25353281	The distinctive nature of these lesions was later corroborated by the demonstration of distinctive, characteristic genetic alterations in each of them; specifically, deletion of the SMARCB1 gene and SMARCB1 protein loss in RTK, the ETV6-NTRK3 gene fusion in cellular CMN, and the YWHAE-FAM22 gene fusion in a subset of CCSK.	('YWHAE', 'Gene', (280, 285))	('deletion', 'Var', (166, 174))	('ETV6', 'Gene', '2120', (232, 236))	('NTRK3', 'Gene', (237, 242))	('CCSK', 'Chemical', '-', (319, 323))	('YWHAE', 'Gene', '7531', (280, 285))	('loss', 'NegReg', (215, 219))	('CCSK', 'Phenotype', 'HP:0006770', (319, 323))	('protein', 'Protein', (207, 214))	('NTRK3', 'Gene', '4916', (237, 242))	('CMN', 'Phenotype', 'HP:0100881', (267, 270))	('SMARCB1', 'Gene', (182, 189))	('SMARCB1', 'Gene', '6598', (182, 189))	('ETV6', 'Gene', (232, 236))	('SMARCB1', 'Gene', '6598', (199, 206))	('SMARCB1', 'Gene', (199, 206))
437569	25353281	Over the past 20 years, a variety of translocation-associated soft tissue sarcomas have been documented to arise primarily within the kidney.	('sarcomas', 'Disease', (74, 82))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (62, 82))	('translocation-associated', 'Var', (37, 61))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (62, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
437579	25353281	The standard antibodies used, vendors, pretreatments, and dilutions were as follows: desmin (Dako M0760, clone D33, steam, 1:100), cytokeratin AE1/3 (Chemicon, steam, 1:4000) vimentin (Ventana, 790-2917, prediluted), EMA (Ventana, 760-4259, steam, prediluted), CD99 (Leica, Clone 12E7, steam, prediluted), Bcl2 (Leica, ORG-8714, steam, prediluted), S100 protein (Ventana, 760-2914, stream, prediluted), and CD34 (Immunotech/Coulter, catalog 0786, steam, prediluted).	('S100', 'Gene', (349, 353))	('CD99', 'Gene', '4267', (261, 265))	('desmin', 'Gene', '1674', (85, 91))	('CD34', 'Gene', (407, 411))	('CD34', 'Gene', '947', (407, 411))	('S100', 'Gene', '6271', (349, 353))	('Bcl2', 'Gene', (306, 310))	('AE1/3', 'Gene', (143, 148))	('Ventana', 'Var', (363, 370))	('CD99', 'Gene', (261, 265))	('Bcl2', 'Gene', '596', (306, 310))	('vimentin', 'Gene', '7431', (175, 183))	('AE1/3', 'Gene', '6521;6508', (143, 148))	('desmin', 'Gene', (85, 91))	('vimentin', 'Gene', (175, 183))
437606	25353281	By fluorescence in situ hybridization, both neoplasms demonstrated evidence of rearrangement of the EWSR1 gene and the CREB3L1 gene (Figure 5).	('neoplasms', 'Disease', (44, 53))	('EWSR1', 'Gene', (100, 105))	('rearrangement', 'Var', (79, 92))	('CREB3L1', 'Gene', (119, 126))	('neoplasms', 'Phenotype', 'HP:0002664', (44, 53))	('EWSR1', 'Gene', '2130', (100, 105))	('CREB3L1', 'Gene', '90993', (119, 126))	('neoplasm', 'Phenotype', 'HP:0002664', (44, 52))	('neoplasms', 'Disease', 'MESH:D009369', (44, 53))
437614	25353281	An alternative FUS-CREB3L1 resulting from a t(11;16)(p11;q11) chromosome translocation was subsequently found in a minority of LGFMS.	('FUS', 'Gene', (15, 18))	('CREB3L1', 'Gene', '90993', (19, 26))	('FUS', 'Gene', '2521', (15, 18))	('CREB3L1', 'Gene', (19, 26))	('t(11;16)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (44, 61))	('t(11;16)(p11;q11) chromosome', 'Var', (44, 72))
437623	25353281	This 16cm neoplasm harbored the EWSR1-CREB3L1 gene fusion that is more commonly seen in SEF (including our two cases of renal SEF) than in LGFMS of soft tissue.	('CREB3L1', 'Gene', '90993', (38, 45))	('EWSR1', 'Gene', '2130', (32, 37))	('neoplasm', 'Disease', 'MESH:D009369', (10, 18))	('neoplasm', 'Phenotype', 'HP:0002664', (10, 18))	('fusion', 'Var', (51, 57))	('EWSR1', 'Gene', (32, 37))	('SEF', 'Disease', (88, 91))	('CREB3L1', 'Gene', (38, 45))	('neoplasm', 'Disease', (10, 18))	('renal SEF', 'Disease', (120, 129))
437673	24575739	Paediatric sarcomas include either tumours carrying fusion oncoproteins, generated by recurrent chromosomal translocations (i.e.	('tumours', 'Disease', (35, 42))	('chromosomal translocations', 'Var', (96, 122))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcomas', 'Disease', (11, 19))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))
437701	24575739	The most relevant mechanism of drug resistance in U-2OS/DX580 and Saos-2/DX580 is the increased DX efflux mediated by ABCB1 (MDR1) membrane transporter as consequence of both amplification and over-expression of MDR1.	('U-2OS', 'CellLine', 'CVCL:0042', (50, 55))	('ABCB1', 'Gene', '5243', (118, 123))	('increased', 'PosReg', (86, 95))	('MDR1', 'Gene', (212, 216))	('U-2OS/DX580', 'Var', (50, 61))	('drug resistance', 'Phenotype', 'HP:0020174', (31, 46))	('amplification', 'Var', (175, 188))	('over-expression', 'PosReg', (193, 208))	('MDR1', 'Gene', (125, 129))	('MDR1', 'Gene', '5243', (125, 129))	('DX efflux', 'MPA', (96, 105))	('Saos-2/DX580', 'Var', (66, 78))	('MDR1', 'Gene', '5243', (212, 216))	('ABCB1', 'Gene', (118, 123))
437702	24575739	The major mechanism of CDDP resistance is the increase of both intracellular levels and enzymatic activity of glutathione-S-transferase P1-1 (GSTP1-1) and of, at a much lower extent, mu-class GST.	('CDDP', 'Var', (23, 27))	('increase', 'PosReg', (46, 54))	('enzymatic activity', 'MPA', (88, 106))	('GSTP1-1', 'Gene', '2950', (142, 149))	('glutathione', 'Chemical', 'MESH:D005978', (110, 121))	('mu-class GST', 'Protein', (183, 195))	('CDDP', 'Chemical', 'MESH:D002945', (23, 27))	('GSTP1-1', 'Gene', (142, 149))	('intracellular levels', 'MPA', (63, 83))
437704	24575739	The following locus were verified: D16S539, D18S51, D19S433, D21S11, D2S1338, D3S1358, D5S818, D8S1179, FGA, SE33, TH01, TPOX VWA.	('D2S1338', 'Var', (69, 76))	('D19S433', 'Var', (52, 59))	('D5S818', 'Var', (87, 93))	('FGA', 'Gene', '2243', (104, 107))	('D3S1358', 'Var', (78, 85))	('FGA', 'Gene', (104, 107))	('D16S539', 'Var', (35, 42))	('D8S1179', 'Var', (95, 102))	('D21S11', 'Var', (61, 67))	('D18S51', 'Var', (44, 50))
437741	24575739	The efficiency of delay appeared to be higher in maltonis- than in malten-treated samples.	('maltonis-', 'Var', (49, 58))	('maltonis', 'Chemical', 'MESH:C512308', (49, 57))	('higher', 'PosReg', (39, 45))
437747	24575739	Sensitivity varied in a range from 2.6 to 12.5 muM in patient-derived cell lines, without any remarkable difference either among the tumour histotypes nor in sarcomas carrying specific translocations or displaying complex genetic aberrations.	('patient', 'Species', '9606', (54, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('muM', 'Gene', (47, 50))	('sarcomas', 'Disease', (158, 166))	('tumour', 'Disease', (133, 139))	('translocations', 'Var', (185, 199))	('sarcomas', 'Disease', 'MESH:D012509', (158, 166))	('muM', 'Gene', '56925', (47, 50))
437755	24575739	To better define the molecular response triggered by maltonis, we evaluated the expression of genes known to regulate cell cycle progression, proliferation and apoptotic response by Q-PCR.	('maltonis', 'Chemical', 'MESH:C512308', (53, 61))	('proliferation', 'CPA', (142, 155))	('Q-PCR', 'Var', (182, 187))	('cell cycle progression', 'CPA', (118, 140))	('expression', 'MPA', (80, 90))	('apoptotic response', 'CPA', (160, 178))
437804	24575739	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/14/137/prepub This work was supported by: AIRC (IG2103_14049 to K. Scotlandi, and IG10353 to P.L.	('IG10353', 'Var', (186, 193))	('AIRC', 'Gene', '10606', (146, 150))	('IG2103_14049', 'Var', (152, 164))	('AIRC', 'Gene', (146, 150))
437823	22563327	Imperfect base pairing of the miRNA with sites in mRNAs, most commonly within the 3' UTR, results in mRNA repression, caused by mRNA destabilization and/or inhibition of translation (Huntzinger and Izaurralde,).	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('inhibition', 'NegReg', (156, 166))	('translation', 'MPA', (170, 181))	('mRNA', 'MPA', (128, 132))	('Imperfect base pairing', 'Var', (0, 22))	('mRNA repression', 'MPA', (101, 116))	('destabilization', 'NegReg', (133, 148))	('results in', 'Reg', (90, 100))
437844	22563327	The promoters with start sites at 127880/86 and 123751/60 are active during latency and the resulting pri-miRNAs contain miR-K1-K9 and miR-K11 within a ~4.8-kb intron and miR-K10/miR-K12 in their 3' terminal exon.	('miR', 'Gene', (135, 138))	('127880/86', 'Var', (34, 43))	('123751/60', 'Var', (48, 57))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (171, 174))	('miR', 'Gene', (171, 174))	('miR', 'Gene', '220972', (106, 109))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', (179, 182))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('miR', 'Gene', '220972', (135, 138))
437898	22563327	An A to G polymorphism in the miR-K5 passenger strand (position 121,315) was found in >20% of all KSHV sequences analyzed (Marshall et al.,).	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('polymorphism', 'Var', (10, 22))	('A to G polymorphism', 'Var', (3, 22))	('KSHV', 'Gene', (98, 102))	('KSHV', 'Species', '37296', (98, 102))
437899	22563327	This single nucleotide polymorphism (SNP) was reported elsewhere to alter the structure of the miR-K5 stem, which results in reduced processing of pri-miR-K5 by Drosha and lower levels of miR-K5 expression (Cai et al.,; Gottwein et al.,).	('Drosha', 'Gene', '29102', (161, 167))	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (95, 98))	('miR', 'Gene', (188, 191))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', (151, 154))	('alter', 'Reg', (68, 73))	('miR', 'Gene', '220972', (188, 191))	('lower', 'NegReg', (172, 177))	('reduced', 'NegReg', (125, 132))	('Drosha', 'Gene', (161, 167))	('levels', 'MPA', (178, 184))	('single nucleotide polymorphism', 'Var', (5, 35))	('expression', 'Species', '29278', (195, 205))	('structure', 'MPA', (78, 87))
437901	22563327	Other reported variants of pre-miR-K9 are likely to also dramatically alter either miR-K9 sequence or expression (Marshall et al.,).	('expression', 'Species', '29278', (102, 112))	('expression', 'MPA', (102, 112))	('sequence', 'MPA', (90, 98))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('alter', 'Reg', (70, 75))	('variants', 'Var', (15, 23))
437903	22563327	Two reports described the detection of miRNA offset RNAs (moRNAs or moRs) and small RNAs antisense to the KSHV miRNAs (Lin et al.,; Umbach and Cullen,).	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('antisense', 'Var', (89, 98))	('miR', 'Gene', '220972', (111, 114))	('KSHV', 'Species', '37296', (106, 110))	('miR', 'Gene', (111, 114))
437911	22563327	The expression of KSHV antisense miRNAs appears to be restricted to lytic replication and the recovery of -5p and -3p sequences suggests that they are products of the miRNA biogenesis machinery.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('miR', 'Gene', '220972', (167, 170))	('expression', 'Species', '29278', (4, 14))	('miR', 'Gene', (167, 170))	('antisense', 'Var', (23, 32))	('KSHV', 'Species', '37296', (18, 22))	('KSHV', 'Gene', (18, 22))
437932	22563327	used Ago2-immunoprecipitation coupled with microarray analysis of associated RNAs (RIP-Chip) to identify mRNAs that are enriched in RISC complexes in cells expressing KSHV miRNAs compared to control cells.	('RISC', 'Gene', (132, 136))	('miR', 'Gene', '220972', (172, 175))	('Ago2', 'Gene', '27161', (5, 9))	('miR', 'Gene', (172, 175))	('RISC', 'Gene', '59342', (132, 136))	('Ago2', 'Gene', (5, 9))	('KSHV', 'Species', '37296', (167, 171))	('KSHV', 'Var', (167, 171))
437953	22563327	The loss of reporter regulation upon mutation of the miRNA binding site is currently the only way to demonstrate the potential of a direct regulatory interaction in human cells.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('human', 'Species', '9606', (165, 170))	('mutation', 'Var', (37, 45))	('reporter regulation', 'MPA', (12, 31))	('loss', 'NegReg', (4, 8))
437967	22563327	While a role of miR-K11 in KSHV-induced cancer has not been demonstrated, such a role appears likely, because (1) the constitutive expression of its analog miR-155 in B cells or hematopoietic stem cells causes B cell- or myelo-proliferative disease (Costinean et al.,; O'Connell et al.,), (2) EBV-induced cellular miR-155 is essential for the survival and growth of EBV-transformed lymphoblastoid cells (Linnstaedt et al.,), (3) a viral miR-155 analog encoded by the oncogenic chicken alpha-herpesvirus Marek's disease virus (MDV) was found to be essential for lymphomagenesis by MDV in chickens (Zhao et al.,), and (4) the constitutive expression of miR-K11 in human hematopoietic cells that were reconstituted into a humanized mouse model phenocopied expression of miR-155 and lead to an expansion of splenic B cells (Boss et al.,).	("Marek's disease virus", 'Species', '10390', (503, 524))	('expression', 'Var', (753, 763))	('EBV', 'Species', '10376', (293, 296))	('human', 'Species', '9606', (662, 667))	('miR-155', 'Gene', '406947', (437, 444))	('expression', 'Species', '29278', (753, 763))	('MDV', 'Species', '10390', (526, 529))	('miR', 'Gene', (767, 770))	('miR', 'Gene', (156, 159))	('miR', 'Gene', '220972', (314, 317))	('expansion', 'PosReg', (790, 799))	('expression', 'Species', '29278', (131, 141))	('chicken', 'Species', '9031', (477, 484))	('cancer', 'Disease', (40, 46))	('mouse', 'Species', '10090', (729, 734))	('herpesvirus', 'Species', '39059', (491, 502))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', '220972', (437, 440))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('miR-155', 'Gene', (767, 774))	('KSHV', 'Species', '37296', (27, 31))	('miR-155', 'Gene', (156, 163))	('miR', 'Gene', '220972', (651, 654))	('miR', 'Gene', (314, 317))	('myelo-proliferative disease', 'Disease', 'MESH:D018630', (221, 248))	('chicken', 'Species', '9031', (587, 594))	('miR-155', 'Gene', '406947', (767, 774))	('miR-155', 'Gene', '406947', (156, 163))	('MDV', 'Species', '10390', (580, 583))	('expression', 'Species', '29278', (637, 647))	('miR', 'Gene', (16, 19))	('miR', 'Gene', (651, 654))	('miR', 'Gene', (437, 440))	('miR-155', 'Gene', (314, 321))	('chickens', 'Species', '9031', (587, 595))	('lymphoma', 'Phenotype', 'HP:0002665', (561, 569))	('myelo-proliferative disease', 'Disease', (221, 248))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('miR-155', 'Gene', '406947', (314, 321))	('human', 'Species', '9606', (719, 724))	('miR', 'Gene', '220972', (767, 770))	('EBV', 'Species', '10376', (366, 369))	('splenic B cells', 'CPA', (803, 818))	('miR', 'Gene', '220972', (156, 159))	('miR-155', 'Gene', (437, 444))
437971	22563327	Recently, a more complex analogy has been demonstrated between KSHV miR-K10a and the cellular miRNA miR-142-3p (Gottwein et al.,).	('miR-142', 'Gene', '406934', (100, 107))	('miR', 'Gene', '220972', (68, 71))	('KSHV', 'Species', '37296', (63, 67))	('miR', 'Gene', (68, 71))	('KSHV', 'Var', (63, 67))	('miR-142', 'Gene', (100, 107))	('miR', 'Gene', '220972', (100, 103))	('miR', 'Gene', (100, 103))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))
437975	22563327	In fact, only 15% of the PAR-CLIP sites predicted as targets of the two miR-K10a variants were not also predicted to be targets of miR-142-3p-1_5.	('miR-142', 'Gene', '406934', (131, 138))	('LIP', 'Disease', (30, 33))	('LIP', 'Disease', 'MESH:C536528', (30, 33))	('miR-142', 'Gene', (131, 138))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (72, 75))	('miR', 'Gene', (131, 134))	('variants', 'Var', (81, 89))
437991	22563327	Two independent studies reported that deletion of the intronic miRNAs, miR-K1-9 and miR-K11, from KSHV bac36 causes a two to fourfold increase in RTA transcript levels, a similarly modest increase in downstream viral lytic gene expression and an approximately twofold increase in virus yield from 293T cells, suggesting that the intronic miRNAs modulate the latent to lytic switch in favor of latency (Lei et al.,; Lu et al.,).	('miR', 'Gene', '220972', (84, 87))	('KSHV', 'Gene', (98, 102))	('increase', 'PosReg', (188, 196))	('expression', 'Species', '29278', (228, 238))	('increase', 'PosReg', (134, 142))	('miR', 'Gene', (338, 341))	('increase', 'PosReg', (268, 276))	('miR', 'Gene', (84, 87))	('modulate', 'Reg', (345, 353))	('deletion', 'Var', (38, 46))	('293T', 'CellLine', 'CVCL:0063', (297, 301))	('RTA transcript levels', 'MPA', (146, 167))	('miR', 'Gene', '220972', (71, 74))	('viral lytic gene expression', 'MPA', (211, 238))	('miR', 'Gene', '220972', (63, 66))	('latent', 'MPA', (358, 364))	('KSHV', 'Species', '37296', (98, 102))	('miR', 'Gene', (71, 74))	('miR', 'Gene', (63, 66))	('miR', 'Gene', '220972', (338, 341))
437995	22563327	In a complementary approach, Bellare and Ganem transfected antisense inhibitors against individual miRNAs into human foreskin fibroblasts (HFFs) infected with rKSHV.219, a recombinant KSHV containing an RFP reporter under control of the lytic PAN promoter (Vieira and O'Hearn,).	('rKSHV.219', 'Gene', (159, 168))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('HFF', 'CellLine', 'CVCL:3285', (139, 142))	('human', 'Species', '9606', (111, 116))	('KSHV', 'Species', '37296', (184, 188))	('KSHV', 'Species', '37296', (160, 164))	('antisense', 'Var', (59, 68))
438023	22563327	Consistent with a function of the KSHV miRNAs in the epigenetic modification of the KSHV and cellular genomes, deletion of the intronic miRNAs resulted in an overall reduction of CpG methylation of the viral and cellular genomes.	('miR', 'Gene', '220972', (39, 42))	('KSHV', 'Species', '37296', (34, 38))	('miR', 'Gene', (39, 42))	('reduction', 'NegReg', (166, 175))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('KSHV', 'Species', '37296', (84, 88))	('CpG methylation', 'MPA', (179, 194))	('deletion', 'Var', (111, 119))
438033	22563327	More recently, several other miRNAs were reported to also bind the p21 3' UTR and the 3' UTR of a second CDKI, p27, but the functional impact of these interactions in the context of KSHV infection remains to be established (Gottwein et al.,).	('bind', 'Interaction', (58, 62))	('KSHV infection', 'Disease', (182, 196))	('miR', 'Gene', '220972', (29, 32))	('p21', 'Var', (67, 70))	('miR', 'Gene', (29, 32))	('KSHV infection', 'Disease', 'MESH:C537372', (182, 196))
438061	33033246	Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('expression', 'Species', '29278', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('elimination', 'Var', (64, 75))	('cancers', 'Disease', (112, 119))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('induces', 'Reg', (76, 83))	('cell apoptosis', 'CPA', (84, 98))
438062	33033246	Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells.	('Cas9', 'Gene', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('CRISPR', 'Gene', (9, 15))	('Cas9', 'Gene', '46806597', (16, 20))	('cancer', 'Disease', (249, 255))	('patient', 'Species', '9606', (76, 83))	('disruption', 'Var', (212, 222))	('CRISPR', 'Gene', '70873', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
438063	33033246	As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models.	('transcription', 'Protein', (97, 110))	('mortality', 'Disease', 'MESH:D003643', (167, 176))	('tyrosine kinase', 'Var', (122, 137))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mortality', 'Disease', (167, 176))	('reducing', 'NegReg', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
438070	33033246	Unlike other genetic diseases such as Duchenne muscular dystrophy or cystic fibrosis, cancer development involves several genetic mutations that can deregulate multiple genes.	('genetic diseases', 'Disease', 'MESH:D030342', (13, 29))	('Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (38, 65))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cystic fibrosis', 'Disease', 'MESH:D003550', (69, 84))	('mutations', 'Var', (130, 139))	('deregulate', 'Reg', (149, 159))	('genetic diseases', 'Disease', (13, 29))	('cystic fibrosis', 'Disease', (69, 84))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (47, 65))	('Duchenne muscular dystrophy', 'Disease', (38, 65))	('cancer', 'Disease', (86, 92))
438072	33033246	This is the case for the so-called fusion oncogenes (FOs), which are chimeric genes resulting from in-frame fusions of the coding sequences of two genes involved in a chromosomal rearrangement.	('cas', 'Gene', '9564', (12, 15))	('fusion oncogenes', 'Disease', (35, 51))	('fusions', 'Var', (108, 115))	('cas', 'Gene', (12, 15))
438073	33033246	Silencing of FO transcripts has been shown to inhibit tumor cell growth in vitro and in vivo, demonstrating FO addiction in many human cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('inhibit', 'NegReg', (46, 53))	('cancers', 'Disease', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('human', 'Species', '9606', (129, 134))	('tumor', 'Disease', (54, 59))	('Silencing', 'Var', (0, 9))	('S', 'Chemical', 'MESH:D013455', (0, 1))
438076	33033246	Analysis of data from The Cancer Genome Atlas suggests that FOs drive the development of more than 16% of human cancers, including mesodermal cancers (typically leukemias, lymphomas and sarcomas).	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('human', 'Species', '9606', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lymphomas', 'Disease', 'MESH:D008223', (172, 181))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('lymphomas', 'Phenotype', 'HP:0002665', (172, 181))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', (112, 119))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('Cancer', 'Disease', (26, 32))	('leukemias', 'Disease', 'MESH:D007938', (161, 170))	('cancers', 'Disease', (142, 149))	('drive', 'Reg', (64, 69))	('sarcomas', 'Disease', 'MESH:D012509', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcomas', 'Disease', (186, 194))	('lymphomas', 'Disease', (172, 181))	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('leukemia', 'Phenotype', 'HP:0001909', (161, 169))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('leukemias', 'Disease', (161, 170))	('FOs', 'Var', (60, 63))
438081	33033246	CRISPR/Cas9 induced breaks can be repaired by one of two major double-strand break (DSB) repair pathways: the inefficient but error-free homology-directed repair (HDR) pathway, which requires a DNA template; and the highly efficient but error-prone non-homologous end joining (NHEJ) pathway, which does not require a DNA template.	('CRISPR', 'Gene', (0, 6))	('CRISPR', 'Gene', '70873', (0, 6))	('S', 'Chemical', 'MESH:D013455', (85, 86))	('breaks', 'Var', (20, 26))	('Cas9', 'Gene', '46806597', (7, 11))	('Cas9', 'Gene', (7, 11))	('S', 'Chemical', 'MESH:D013455', (3, 4))
438090	33033246	Our rationale was to devise a genome editing approach to specifically disrupt FOs in cancer cells that fulfils two strict criteria: i) it would not affect the exonic sequences or the expression of wild-type alleles involved in the rearrangement, and ii) it would be feasible irrespective of the FO isoform or the patient-specific breakpoint.	('FOs', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('editing', 'Var', (37, 44))	('expression', 'Species', '29278', (183, 193))	('cancer', 'Disease', (85, 91))	('patient', 'Species', '9606', (313, 320))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('disrupt', 'Var', (70, 77))
438091	33033246	To test this approach, we first used a cellular model of Ewing sarcoma, one of the most common cancers in children/adolescents characterized by a chromosomal translocation that fuses the transactivation domain of the RNA-binding protein EWSR1 to the DNA-binding domain of an ETS protein, most commonly FLI1.	('Ewing sarcoma', 'Disease', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('fuses', 'Var', (177, 182))	('transactivation domain', 'MPA', (187, 209))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('S', 'Chemical', 'MESH:D013455', (277, 278))	('S', 'Chemical', 'MESH:D013455', (239, 240))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('children', 'Species', '9606', (106, 114))
438092	33033246	The EWSR1-FLI1 (EF) fusion acts as a dominant transcription factor, and cells are addicted to EF expression.	('EWSR1-FLI1', 'Gene', (4, 14))	('fusion', 'Var', (20, 26))	('expression', 'Species', '29278', (97, 107))
438097	33033246	Using a single sgRNA lentiviral expression vector (pLV-U6sgRNA-EFSCas9), we tested the efficiency of genomic deletion with four combinations of sgRNAs (sgE3-sgF6, sgE3-sgF8, sgE6-sgF6, sgE6-sgF8) in the A673 Ewing sarcoma cell line.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (208, 221))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (208, 221))	('genomic deletion', 'CPA', (101, 117))	('sgE6-sgF8', 'Gene', (185, 194))	('expression', 'Species', '29278', (32, 42))	('Ewing sarcoma', 'Disease', (208, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('sgE6-sgF6', 'Gene', (174, 183))	('sgE3-sgF8', 'Gene', (163, 172))	('sgE3-sgF6', 'Var', (152, 161))	('tested', 'Reg', (76, 82))
438100	33033246	Cleavage with sgE3-sgF8 resulted in high deletion efficiency, generating the largest (27.7 kb) EF deletion and resulting in the complete loss of the EWSR1 transactivation domain and a frameshift alteration of the entire FLI1 DNA-binding region (Supplementary Fig.	('FLI1', 'Gene', (220, 224))	('transactivation domain', 'MPA', (155, 177))	('S', 'Chemical', 'MESH:D013455', (245, 246))	('sgE3-sgF8', 'Gene', (14, 23))	('deletion', 'Var', (98, 106))	('EWSR1', 'Gene', (149, 154))	('frameshift', 'Reg', (184, 194))	('loss', 'NegReg', (137, 141))	('S', 'Chemical', 'MESH:D013455', (151, 152))
438101	33033246	Notably, targeted deep-sequencing of sgE3- or sgF8-targeted A673 cells revealed 62% and 66% insertion/deletion (indels) in EWSR1 and FLI1 on-target sites, respectively (Supplementary Table 2a, b).	('EWSR1', 'Gene', (123, 128))	('insertion/deletion', 'Var', (92, 110))	('sgF8-targeted', 'Gene', (46, 59))	('S', 'Chemical', 'MESH:D013455', (125, 126))	('S', 'Chemical', 'MESH:D013455', (169, 170))	('FLI1', 'Gene', (133, 137))
438103	33033246	We first examined the capacity of LVCas9_EF to generate EF deletions in A673 and also RD-ES Ewing sarcoma cells, which harbor different EF isoforms.	('Cas9', 'Gene', (36, 40))	('S', 'Chemical', 'MESH:D013455', (90, 91))	('Cas9', 'Gene', '46806597', (36, 40))	('deletions', 'Var', (59, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('Ewing sarcoma', 'Disease', (92, 105))
438131	33033246	Consistent with the growth phenotype observations, EF-targeted cells had higher levels (5-8-fold) of apoptosis, measured both by propidium iodide staining (subG1 cells, Fig.	('apoptosis', 'CPA', (101, 110))	('propidium iodide', 'Chemical', 'MESH:D011419', (129, 145))	('EF-targeted', 'Var', (51, 62))	('higher', 'PosReg', (73, 79))
438132	33033246	2h), than control transduced cells, suggesting that CRISPR-mediated abrogation of EF is sufficient to inhibit the survival, proliferation, and clonogenicity of EF-expressing Ewing sarcoma cells in vitro.	('CRISPR', 'Gene', (52, 58))	('clonogenicity', 'CPA', (143, 156))	('Ewing sarcoma', 'Disease', (174, 187))	('proliferation', 'CPA', (124, 137))	('CRISPR', 'Gene', '70873', (52, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (174, 187))	('abrogation', 'Var', (68, 78))	('survival', 'CPA', (114, 122))	('inhibit', 'NegReg', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (174, 187))
438135	33033246	In silico analysis predicted that an inversion of the FO targeted region will produce a truncated protein similar to that induced by DNA deletion (Supplementary Fig.	('S', 'Chemical', 'MESH:D013455', (147, 148))	('inversion', 'Var', (37, 46))	('truncated protein', 'MPA', (88, 105))
438144	33033246	Immunohistochemistry for Cas9 confirmed adenoviral delivery into the tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('Cas9', 'Gene', (25, 29))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('Cas9', 'Gene', '46806597', (25, 29))	('tumors', 'Disease', (69, 75))	('adenoviral', 'Var', (40, 50))
438149	33033246	No cells harboring an EF deletion were present in the tumors suggesting that CRISPR-mediated abrogation of EF is sufficient to inhibit survival of Ewing sarcoma cells in vivo.	('abrogation', 'Var', (93, 103))	('Ewing sarcoma', 'Disease', (147, 160))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('CRISPR', 'Gene', '70873', (77, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('deletion', 'Var', (25, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (147, 160))	('CRISPR', 'Gene', (77, 83))	('inhibit', 'NegReg', (127, 134))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (147, 160))	('survival', 'CPA', (135, 143))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
438150	33033246	Furthermore, targeted deep-sequencing of PCR amplicons covering the 50 most probable predicted off-target sites associated with sgE3 and sgF8 ruled out mutations in EF-targeted xenografted tumors analyzed 6 weeks after AdV injection (Supplementary Table 3).	('AdV', 'Species', '10508', (219, 222))	('mutations', 'Var', (152, 161))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Disease', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('sgF8', 'Gene', (137, 141))	('sgE3', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('S', 'Chemical', 'MESH:D013455', (234, 235))
438154	33033246	We next examined the capacity of FO targeted deletions to reduce PDX growth by measuring tumor size.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('reduce', 'NegReg', (58, 64))	('deletions', 'Var', (45, 54))	('P', 'Chemical', 'MESH:D010758', (65, 66))	('PDX', 'Disease', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
438163	33033246	Corresponding FO deletion and treatment of A673 cells with 0.05 mug/ml doxorubicin resulted in a greater reduction of cell viability (50%) than single treatments (39% or 42% with AdCas9_EF or doxorubicin treatment alone, respectively) (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (192, 203))	('Cas9', 'Gene', (181, 185))	('reduction', 'NegReg', (105, 114))	('deletion', 'Var', (17, 25))	('cell viability', 'CPA', (118, 132))	('Cas9', 'Gene', '46806597', (181, 185))	('doxorubicin', 'Chemical', 'MESH:D004317', (71, 82))
438170	33033246	Four sgRNAs targeting BCR intron 8 and ABL intron 1 regions were designed to induce a 133.9 kb deletion of the BA FO (Supplementary Table 1), resulting in an extensive deletion of the BCR transactivation domain and a frameshift alteration of the entire ABL1 DNA-binding domain (Fig.	('deletion', 'Var', (95, 103))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('ABL', 'Gene', '25', (253, 256))	('BCR', 'Gene', (22, 25))	('BCR', 'Gene', (184, 187))	('ABL', 'Gene', '25', (39, 42))	('BA', 'Chemical', '-', (111, 113))	('ABL1', 'Gene', '25', (253, 257))	('BCR', 'Gene', '613', (22, 25))	('BCR', 'Gene', '613', (184, 187))	('ABL', 'Gene', (253, 256))	('ABL', 'Gene', (39, 42))	('ABL1', 'Gene', (253, 257))	('frameshift', 'MPA', (217, 227))	('deletion', 'MPA', (168, 176))
438174	33033246	All four sgRNA combinations efficiently abrogated the expression of BA as confirmed by RT-PCR and Sanger sequencing (Fig.	('expression', 'MPA', (54, 64))	('BA', 'Chemical', '-', (68, 70))	('abrogated', 'NegReg', (40, 49))	('S', 'Chemical', 'MESH:D013455', (98, 99))	('P', 'Chemical', 'MESH:D010758', (90, 91))	('expression', 'Species', '29278', (54, 64))	('combinations', 'Var', (15, 27))
438179	33033246	Targeted deep-sequencing of sgB8.1 or sgA1.1-targeted K562 cells revealed 85% and 82% indels in BCR and ABL1 on-target sites, respectively (Supplementary Table 2).	('BCR', 'Gene', (96, 99))	('sgA1.1-targeted', 'Gene', (38, 53))	('ABL1', 'Gene', (104, 108))	('BCR', 'Gene', '613', (96, 99))	('indels', 'Var', (86, 92))	('S', 'Chemical', 'MESH:D013455', (140, 141))	('K562', 'CellLine', 'CVCL:0004', (54, 58))	('ABL1', 'Gene', '25', (104, 108))
438180	33033246	Similarly, targeted deep-sequencing of PCR amplicons covering the most probable predicted off-target sites associated with sgB8.1 and sgA1.1 ruled out mutations in BA-targeted K562 cells after pLVCas9_BA electroporation (Supplementary Table 3).	('P', 'Chemical', 'MESH:D010758', (39, 40))	('BA', 'Chemical', '-', (164, 166))	('S', 'Chemical', 'MESH:D013455', (221, 222))	('Cas9', 'Gene', '46806597', (196, 200))	('BA', 'Chemical', '-', (201, 203))	('K562', 'CellLine', 'CVCL:0004', (176, 180))	('Cas9', 'Gene', (196, 200))	('sgB8.1', 'Gene', (123, 129))	('mutations', 'Var', (151, 160))	('S', 'Chemical', 'MESH:D013455', (0, 1))
438185	33033246	In silico analysis showed that an inversion of the FO targeted region will produce a truncated protein similar to the one induced by DNA deletion (Supplementary Fig.	('S', 'Chemical', 'MESH:D013455', (147, 148))	('produce', 'Reg', (75, 82))	('inversion', 'Var', (34, 43))	('truncated protein', 'MPA', (85, 102))
438197	33033246	A combinatorial approach using BA deletion with a standard-of-care therapeutic option in CML (imatinib, 0.105 mug/ml) resulted in a significant reduction in K562 cell viability compared with any of the treatments in monotherapy (Fig.	('CML', 'Disease', 'MESH:D015464', (89, 92))	('K562 cell viability', 'CPA', (157, 176))	('K562', 'CellLine', 'CVCL:0004', (157, 161))	('BA', 'Chemical', '-', (31, 33))	('imatinib', 'Chemical', 'MESH:D000068877', (94, 102))	('CML', 'Disease', (89, 92))	('deletion', 'Var', (34, 42))	('reduction', 'NegReg', (144, 153))
438204	33033246	Our CRISPR/Cas9-based approach induces two targeted intronic DSBs in both genes involved in a FO that, importantly, produces a cancer cell-specific genomic deletion that is dependent on the presence of the FO, and has no effect on wild-type gene expression in non-cancer cells.	('Cas9', 'Gene', '46806597', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('CRISPR', 'Gene', (4, 10))	('cancer', 'Disease', (264, 270))	('DSBs', 'Var', (61, 65))	('DSBs', 'Chemical', 'MESH:C007563', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('expression', 'Species', '29278', (246, 256))	('CRISPR', 'Gene', '70873', (4, 10))	('cancer', 'Disease', (127, 133))	('Cas9', 'Gene', (11, 15))	('deletion', 'Var', (156, 164))
438206	33033246	Exploiting an adenoviral in vivo delivery of CRISPR components, we further demonstrate that CRISPR/Cas9-mediated deletion in advance PDX cancer models results in efficient induction of cancer cell death and reduces tumor burden and mortality.	('mortality', 'Disease', 'MESH:D003643', (232, 241))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('CRISPR', 'Gene', (92, 98))	('reduces', 'NegReg', (207, 214))	('Cas9', 'Gene', '46806597', (99, 103))	('CRISPR', 'Gene', (45, 51))	('CRISPR', 'Gene', '70873', (92, 98))	('death', 'Disease', (197, 202))	('Cas9', 'Gene', (99, 103))	('mortality', 'Disease', (232, 241))	('P', 'Chemical', 'MESH:D010758', (96, 97))	('P', 'Chemical', 'MESH:D010758', (49, 50))	('CRISPR', 'Gene', '70873', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', (215, 220))	('deletion', 'Var', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('death', 'Disease', 'MESH:D003643', (197, 202))
438209	33033246	Due to the complex genomic scenario in cancer cells, including co-existence of other oncogenes, tumor suppressor genes, DNA damage response and DNA repair pathways alterations, a case-by-case FO study could shed light to the applicability of the strategy to eliminate different types of cancer cells.	('cas', 'Gene', '9564', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cas', 'Gene', (179, 182))	('tumor', 'Disease', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cas', 'Gene', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('alterations', 'Var', (164, 175))	('cas', 'Gene', '9564', (179, 182))
438211	33033246	The strategy involves directly targeting the patient-specific breakpoint to introduce a suicide gene into the genome of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('suicide gene', 'Var', (88, 100))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('patient', 'Species', '9606', (45, 52))	('introduce', 'Reg', (76, 85))
438216	33033246	As described in the present study, combinatorial approaches using gene editing with other therapeutic options (e.g., chemotherapy) further increases the efficacy of this approach, allowing better responses with lower chemotherapy doses for the elimination of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('responses', 'MPA', (196, 205))	('increases', 'PosReg', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('gene editing', 'Var', (66, 78))	('cancer', 'Disease', (259, 265))
438245	33033246	Briefly, cells were seeded at 1.1 x 107 cells/dish in 15-cm dishes the day before transfection, and were transfected by the calcium-phosphate method using 14.6 and 7.9 mug of second-generation packaging plasmids (psPAX2 and pMD.2G, Addgene #12260 and #12259, respectively) and 22.5 mug of the appropriate transfer plasmid depending on the experiment.	('P', 'Chemical', 'MESH:D010758', (215, 216))	('pMD', 'Disease', (224, 227))	('#12259', 'Var', (251, 257))	('pMD', 'Disease', 'None', (224, 227))	('calcium-phosphate', 'Chemical', 'MESH:C020243', (124, 141))
438278	33033246	Sample and reference DNA (Agilent) samples were labeled with Cy5 and Cy3 dyes (Agilent), respectively.	('Cy5', 'Var', (61, 64))	('Cy5', 'Chemical', 'MESH:C085321', (61, 64))	('Cy3 dyes', 'Var', (69, 77))	('Cy3', 'Chemical', '-', (69, 72))	('S', 'Chemical', 'MESH:D013455', (0, 1))
438280	33033246	The EWSR1 break-apart (Kreatech), EWSR1-FLI1 dual-fusion (Cytocell) and BCR-ABL1 dual-fusion FISH probe (Kreatech) FISH probes were used to detect t(11;22) and t(9;22) chromosomal translocations.	('BCR-ABL1', 'Gene', (72, 80))	('S', 'Chemical', 'MESH:D013455', (117, 118))	('BCR-ABL1', 'Gene', '613;25', (72, 80))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('t(11;22', 'Var', (147, 154))	('EWSR1-FLI1', 'Gene', (34, 44))	('S', 'Chemical', 'MESH:D013455', (95, 96))	('S', 'Chemical', 'MESH:D013455', (6, 7))
438297	33033246	PDX models were established from patient biopsies (HSJD-ES-006, HSJD-ES-013, HSJD-ES-018) at Sant Joan de Deu Hospital (Barcelona, Spain).	('S', 'Chemical', 'MESH:D013455', (52, 53))	('patient', 'Species', '9606', (33, 40))	('S', 'Chemical', 'MESH:D013455', (70, 71))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('S', 'Chemical', 'MESH:D013455', (65, 66))	('S', 'Chemical', 'MESH:D013455', (93, 94))	('S', 'Chemical', 'MESH:D013455', (131, 132))	('HSJD-ES-018', 'Var', (77, 88))	('HSJD-ES-013', 'Var', (64, 75))	('S', 'Chemical', 'MESH:D013455', (78, 79))	('S', 'Chemical', 'MESH:D013455', (57, 58))	('S', 'Chemical', 'MESH:D013455', (83, 84))	('HSJD-ES-006', 'Var', (51, 62))
438327	33033246	A patent has been filed relating to the data presented in this research study by S.R-P., R.T-R. and M.M-L. (EP18382746.8).	('P', 'Chemical', 'MESH:D010758', (109, 110))	('M.M-L.', 'Var', (100, 106))	('P', 'Chemical', 'MESH:D010758', (85, 86))	('S.R-P.', 'Var', (81, 87))	('S', 'Chemical', 'MESH:D013455', (81, 82))	('R.T-R.', 'Var', (89, 95))
438328	30338611	Novel MXD4-NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated.	('Primary ovarian sarcomas', 'Disease', (107, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('MXD4', 'Gene', '10608', (6, 10))	('NUTM1', 'Gene', '256646', (11, 16))	('tumors', 'Disease', (151, 157))	('fusion', 'Var', (17, 23))	('primary ovarian undifferentiated small round cell sarcoma', 'Disease', 'MESH:D018228', (49, 106))	('Primary ovarian sarcomas', 'Disease', 'MESH:D010051', (107, 131))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('NUTM1', 'Gene', (11, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('MXD4', 'Gene', (6, 10))	('undifferentiated small round cell sarcoma Primary', 'Phenotype', 'HP:0030447', (65, 114))
438334	30338611	Small round cell sarcoma is a heterogeneous group of tumors arising from various sites, and the prognosis of this disease is poor.7, 8 Fusion genes resulting from chromosomal rearrangements have been considered as a significant oncogenic factor in many mesenchymal malignancies,9 and tumor-specific fusion genes contribute to the classification of small round cell sarcomas into several histologic subtypes,8 that is, EWSR1-FLI1 fusion in Ewing sarcoma10 and PAX3/8 fusions in alveolar rhabdomyosarcoma.11  Recent advances in sequencing technology have enabled the comprehensive detection of fusion genes in the cancer genome and transcriptome.	('Ewing sarcoma10', 'Disease', (439, 454))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('PAX3', 'Gene', (459, 463))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('sarcoma', 'Disease', 'MESH:D012509', (365, 372))	('Ewing sarcoma10', 'Disease', 'MESH:C563168', (439, 454))	('sarcomas', 'Disease', 'MESH:D012509', (365, 373))	('sarcoma', 'Disease', (365, 372))	('fusion genes', 'Var', (592, 604))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('sarcomas', 'Phenotype', 'HP:0100242', (365, 373))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('sarcomas', 'Disease', (365, 373))	('sarcoma', 'Phenotype', 'HP:0100242', (445, 452))	('EWSR1', 'Gene', (418, 423))	('PAX3', 'Gene', '5077', (459, 463))	('cancer', 'Disease', (612, 618))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (612, 618))	('sarcoma', 'Phenotype', 'HP:0100242', (365, 372))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('sarcoma', 'Disease', 'MESH:D012509', (495, 502))	('tumors', 'Disease', (53, 59))	('mesenchymal malignancies', 'Disease', (253, 277))	('sarcoma', 'Disease', (495, 502))	('alveolar rhabdomyosarcoma', 'Disease', (477, 502))	('mesenchymal malignancies', 'Disease', 'MESH:C535700', (253, 277))	('sarcoma', 'Disease', 'MESH:D012509', (17, 24))	('FLI1', 'Gene', (424, 428))	('sarcoma', 'Disease', (17, 24))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (495, 502))	('cancer', 'Disease', 'MESH:D009369', (612, 618))	('sarcoma', 'Disease', 'MESH:D012509', (445, 452))	('EWSR1', 'Gene', '2130', (418, 423))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (477, 502))	('FLI1', 'Gene', '2313', (424, 428))	('sarcoma', 'Disease', (445, 452))	('tumor', 'Disease', (53, 58))	('Ewing sarcoma10', 'Phenotype', 'HP:0012254', (439, 454))	('tumor', 'Disease', (284, 289))
438366	30338611	Blots were then incubated with either anti-mouse or anti-rabbit horseradish peroxidase-conjugated secondary antibodies (NA931 and NA934, GE Healthcare; dilution ratio 1:10 000), and visualized by chemiluminescence.	('NA931', 'Var', (120, 125))	('rabbit', 'Species', '9986', (57, 63))	('horseradish', 'Species', '3704', (64, 75))	('NA934', 'Var', (130, 135))	('mouse', 'Species', '10090', (43, 48))
438368	30338611	A stopgain mutation in PRUNE2 (also known as BMCC1) that had an important role in regulating differentiation, survival, and aggressiveness of the tumor cells27 was detected.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('aggressiveness of the tumor', 'Disease', 'MESH:D001523', (124, 151))	('aggressiveness of the tumor', 'Disease', (124, 151))	('survival', 'CPA', (110, 118))	('BMCC1', 'Gene', '158471', (45, 50))	('mutation', 'Var', (11, 19))	('PRUNE2', 'Gene', '158471', (23, 29))	('BMCC1', 'Gene', (45, 50))	('aggressiveness', 'Phenotype', 'HP:0000718', (124, 138))	('PRUNE2', 'Gene', (23, 29))
438372	30338611	Given that the NUTM1 rearrangement was considered as an oncogenic driver event and an attractive therapeutic target in "NUT midline carcinoma (NMC),"28, 29 we focused on the MXD4-NUTM1 fusion transcript to perform subsequent analyses.	('NUTM1', 'Gene', (15, 20))	('MXD4', 'Gene', '10608', (174, 178))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (120, 141))	('NUTM1', 'Gene', '256646', (179, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('NUTM1', 'Gene', (179, 184))	('rearrangement', 'Var', (21, 34))	('NUTM1', 'Gene', '256646', (15, 20))	('NUT midline carcinoma', 'Disease', (120, 141))	('MXD4', 'Gene', (174, 178))
438380	30338611	We identified a nonsense mutation in PRUNE2 that was reported to be a potentially oncogenic30 but not therapeutically targetable mutated genes at that time.	('PRUNE2', 'Gene', (37, 43))	('PRUNE2', 'Gene', '158471', (37, 43))	('nonsense mutation', 'Var', (16, 33))
438384	30338611	42 Although MXD1-NUTM1 fusion has been reported in gastric sarcoma, MXD4 has not been previously reported as a fusion partner of NUTM1.	('NUTM1', 'Gene', (129, 134))	('MXD1', 'Gene', '4084', (12, 16))	('fusion', 'Var', (23, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('gastric sarcoma', 'Disease', (51, 66))	('gastric sarcoma', 'Disease', 'MESH:D013274', (51, 66))	('NUTM1', 'Gene', '256646', (17, 22))	('NUTM1', 'Gene', (17, 22))	('MXD4', 'Gene', (68, 72))	('MXD1', 'Gene', (12, 16))	('gastric sarcoma', 'Phenotype', 'HP:0045038', (51, 66))	('reported', 'Reg', (39, 47))	('NUTM1', 'Gene', '256646', (129, 134))	('MXD4', 'Gene', '10608', (68, 72))
438387	30338611	Further functional analysis focusing on MYC is needed to prove the significance of NUTM1 fusions whose partners were the MAD gene family such as MXD1 or MXD4 in tumorigenesis, especially sarcomagenesis.	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('MYC', 'Gene', '4609', (40, 43))	('NUTM1', 'Gene', '256646', (83, 88))	('MXD1', 'Gene', (145, 149))	('fusions', 'Var', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('MXD4', 'Gene', (153, 157))	('sarcoma', 'Disease', (187, 194))	('NUTM1', 'Gene', (83, 88))	('MXD4', 'Gene', '10608', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('MYC', 'Gene', (40, 43))	('MXD1', 'Gene', '4084', (145, 149))	('tumor', 'Disease', (161, 166))
438492	28296680	Fluorescence in situ hybridization was successful in all cases and confirmed EWSR1 rearrangement in 2 of 4 tumors demonstrating morphologic features of Ewing sarcoma/peripheral PNET and concurrent CD99 and Fli-1 expression.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (152, 165))	('CD99', 'Gene', (197, 201))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Fli-1', 'Gene', '2313', (206, 211))	('rearrangement', 'Var', (83, 96))	('tumors', 'Disease', (107, 113))	('Fli-1', 'Gene', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('CD99', 'Gene', '4267', (197, 201))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('Ewing sarcoma', 'Disease', (152, 165))	('EWSR1', 'Gene', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('EWSR1', 'Gene', '2130', (77, 82))
438503	28296680	Some gynecologic PNETs harbor EWSR1 rearrangements and thus are considered of the peripheral type or Ewing sarcoma, a neoplasm with a wide morphologic spectrum that is defined by translocations producing fusion of EWSR1 to various members of the ETS family of transcription factors.	('EWSR1', 'Gene', '2130', (30, 35))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('neoplasm', 'Disease', (118, 126))	('neoplasm', 'Disease', 'MESH:D009369', (118, 126))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('EWSR1', 'Gene', (214, 219))	('EWSR1', 'Gene', (30, 35))	('rearrangements', 'Var', (36, 50))	('fusion', 'Var', (204, 210))	('EWSR1', 'Gene', '2130', (214, 219))	('Ewing sarcoma', 'Disease', (101, 114))
438517	28296680	Endogenous peroxidase activity was blocked by H2O2 before antibody incubation.	('activity', 'MPA', (22, 30))	('H2O2', 'Chemical', 'MESH:D006861', (46, 50))	('H2O2', 'Var', (46, 50))	('Endogenous', 'MPA', (0, 10))
438581	28296680	Nuclear Fli-1 positivity was observed 85.7% of central PNETs and was diffuse in half and focal in the remainder, while it was diffusely expressed in all 4 Ewing sarcoma/peripheral PNETs.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (155, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('central PNETs', 'Disease', (47, 60))	('positivity', 'Var', (14, 24))	('Fli-1', 'Gene', '2313', (8, 13))	('Ewing sarcoma', 'Disease', (155, 168))	('Fli-1', 'Gene', (8, 13))
438586	28296680	FISH analysis was successful in all 19 tumors and detected EWSR1 rearrangement in only 2 (11.1%) cases in the vulva and uterus which both showed morphologic features consistent with Ewing sarcoma/peripheral PNET (Figure 3D).	('EWSR1', 'Gene', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('EWSR1', 'Gene', '2130', (59, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('rearrangement', 'Var', (65, 78))	('Ewing sarcoma', 'Disease', (182, 195))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('tumors', 'Disease', (39, 45))
438593	28296680	Tumors that were composed entirely of sheets of primitive small round blue cells and showed both membranous CD99 and nuclear Fli-1 expression, but absence of GFAP staining by immunohistochemistry were more likely to harbor an EWSR1 rearrangement detectable by FISH, consistent with Ewing sarcoma/peripheral PNET.	('rearrangement', 'Var', (232, 245))	('EWSR1', 'Gene', '2130', (226, 231))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (282, 295))	('CD99', 'Gene', '4267', (108, 112))	('absence', 'NegReg', (147, 154))	('Fli-1', 'Gene', (125, 130))	('GFAP', 'Gene', (158, 162))	('Fli-1', 'Gene', '2313', (125, 130))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Ewing sarcoma', 'Disease', (282, 295))	('CD99', 'Gene', (108, 112))	('EWSR1', 'Gene', (226, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('GFAP', 'Gene', '2670', (158, 162))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (282, 295))
438600	28296680	Among the 14 PNETs with known EWSR1 rearrangement status reported in the cervix, vagina, and vulva, approximately 87%, including our single vulvar tumor, are Ewing sarcoma/peripheral PNETs confirmed by FISH or RT-PCR.	('EWSR1', 'Gene', '2130', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('vulvar tumor', 'Phenotype', 'HP:0030416', (140, 152))	('Ewing sarcoma', 'Disease', (158, 171))	('vulvar tumor', 'Disease', (140, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (158, 171))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (158, 171))	('EWSR1', 'Gene', (30, 35))	('vulvar tumor', 'Disease', 'MESH:D014846', (140, 152))	('rearrangement', 'Var', (36, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
438604	28296680	In many studies without molecular genetic analysis, the diagnosis of PNET particularly of the peripheral type was rendered based on the presence of CD99 positivity in the setting of a predominately small round blue cell tumor with or without rosettes.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('rosettes', 'Phenotype', 'HP:0031925', (242, 250))	('CD99', 'Gene', '4267', (148, 152))	('tumor', 'Disease', (220, 225))	('rosette', 'Phenotype', 'HP:0031925', (242, 249))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('positivity', 'Var', (153, 163))	('CD99', 'Gene', (148, 152))	('presence', 'Var', (136, 144))
438607	28296680	Whether some reports lacking confirmation of EWSR1 rearrangement truly represent Ewing sarcoma/peripheral PNET is subject to debate.	('Ewing sarcoma', 'Disease', (81, 94))	('EWSR1', 'Gene', (45, 50))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('EWSR1', 'Gene', '2130', (45, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('rearrangement', 'Var', (51, 64))
438610	28296680	Absence of EWSR1 rearrangement in our 2 tumors initially classified as Ewing sarcoma/peripheral PNET prompted re-review of the morphologic and immunohistochemical findings.	('Ewing sarcoma', 'Disease', (71, 84))	('EWSR1', 'Gene', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('rearrangement', 'Var', (17, 30))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (71, 84))	('EWSR1', 'Gene', '2130', (11, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
438612	28296680	It is possible that these 2 tumors harbor genetic abnormalities other than rearrangement of EWSR1.	('tumors harbor genetic abnormalities', 'Disease', (28, 63))	('EWSR1', 'Gene', '2130', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors harbor genetic abnormalities', 'Disease', 'MESH:D030342', (28, 63))	('EWSR1', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('rearrangement', 'Var', (75, 88))
438613	28296680	Presence of an EWSR1 rearrangement in gynecologic PNETs may allow patients with Ewing sarcoma/peripheral PNET to be treated with therapeutic regimens used for the Ewing family of tumors in which a combination of surgery and/or radiation and multiagent systemic chemotherapy result in a 70% 5-year survival rate for localized disease.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('localized disease', 'Disease', (315, 332))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('rearrangement', 'Var', (21, 34))	('EWSR1', 'Gene', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('EWSR1', 'Gene', '2130', (15, 20))	('Ewing sarcoma', 'Disease', (80, 93))	('Presence', 'Var', (0, 8))	('patients', 'Species', '9606', (66, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
438617	28296680	Epigenetic profiling of central PNETs arising in the female genital tract, particularly in the ovary and uterus where central PNETs tend to be encountered, is a worthwhile endeavor and may enable more accurate diagnosis and therapeutic strategies for patients affected by this rare tumor type.	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('ovary', 'Disease', 'MESH:D010051', (95, 100))	('central PNETs', 'Disease', (24, 37))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('Epigenetic', 'Var', (0, 10))	('patients', 'Species', '9606', (251, 259))	('ovary', 'Disease', (95, 100))
438633	28296680	However, all published gynecologic Ewing sarcoma/peripheral PNETs and our 2 tumors that harbor EWSR1 rearrangement were CD99-positive; thus, absent CD99 staining should prompt reconsideration of the diagnosis of Ewing sarcoma/peripheral PNET in the setting of a small round blue cell tumor.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('CD99', 'Gene', (120, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (212, 225))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (212, 225))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('Ewing sarcoma', 'Disease', (35, 48))	('CD99', 'Gene', '4267', (120, 124))	('EWSR1', 'Gene', '2130', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('CD99', 'Gene', (148, 152))	('Ewing sarcoma', 'Disease', (212, 225))	('CD99', 'Gene', '4267', (148, 152))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('rearrangement', 'Var', (101, 114))	('EWSR1', 'Gene', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('tumor', 'Disease', (284, 289))
438650	28296680	Tumors that consist of small round blue cells with concurrent strong and diffuse membranous CD99 and nuclear Fli-1 staining likely harbor EWSR1 rearrangement.	('EWSR1', 'Gene', (138, 143))	('rearrangement', 'Var', (144, 157))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD99', 'Gene', (92, 96))	('EWSR1', 'Gene', '2130', (138, 143))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CD99', 'Gene', '4267', (92, 96))	('Fli-1', 'Gene', '2313', (109, 114))	('harbor', 'Reg', (131, 137))	('Fli-1', 'Gene', (109, 114))
438713	26640482	Li-Fraumeni syndrome has been postulated to be associated with mutation of p53 tumour suppressor gene and this leads in some children to the development of sarcomas and their mothers tend to have an increased risk of carcinoma of the breast with siblings having an increased risk for the development of malignancy.	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('tumour', 'Disease', (79, 85))	('malignancy', 'Disease', (303, 313))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('associated', 'Reg', (47, 57))	('sarcomas', 'Disease', 'MESH:D012509', (156, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('carcinoma of the breast', 'Disease', 'MESH:D001943', (217, 240))	('sarcomas', 'Disease', (156, 164))	('mutation', 'Var', (63, 71))	('p53', 'Gene', '7157', (75, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('children', 'Species', '9606', (125, 133))	('malignancy', 'Disease', 'MESH:D009369', (303, 313))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('leads', 'Reg', (111, 116))	('p53', 'Gene', (75, 78))	('carcinoma of the breast', 'Disease', (217, 240))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
439050	24932171	Nevertheless, some studies suggest that giving and receiving emotional support has positive effects on the emotional well-being of patients with a high competence in emotional communication, while the same social support can have a negative impact on the emotional well-being of those with a low competence in emotional communication.	('patients', 'Species', '9606', (131, 139))	('high competence', 'Var', (147, 162))	('emotional well-being', 'CPA', (107, 127))	('positive', 'PosReg', (83, 91))
439150	22791883	Potent VEGF blockade with aflibercept was demonstrated to induce concurrent tumor endothelial and perivascular cell apoptosis, associated with rapid and dramatic reductions in vessel number, branching and perfusion in an orthotopic model of established tumors from the Ewing sarcoma family.	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('reductions', 'NegReg', (162, 172))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('perfusion', 'CPA', (205, 214))	('vessel number', 'CPA', (176, 189))	('tumors', 'Disease', (253, 259))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (269, 282))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (269, 282))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (253, 258))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('aflibercept', 'Gene', (26, 37))	('VEGF', 'Gene', '7422', (7, 11))	('Ewing sarcoma', 'Disease', (269, 282))	('blockade', 'Var', (12, 20))	('VEGF', 'Gene', (7, 11))
439151	22791883	Such changes may lead to endothelial dysfunction, a loss of vascular integrity and subsequent vascular collapse or bleeding.	('endothelial dysfunction', 'Disease', 'MESH:C536439', (25, 48))	('vascular collapse', 'CPA', (94, 111))	('bleeding', 'Disease', 'MESH:D006470', (115, 123))	('loss', 'NegReg', (52, 56))	('bleeding', 'Disease', (115, 123))	('changes', 'Var', (5, 12))	('endothelial dysfunction', 'Disease', (25, 48))	('lead to', 'Reg', (17, 24))	('vascular integrity', 'CPA', (60, 78))
439172	22791883	Future considerations for trials of antiangiogenic agents in pediatrics should consider incorporating studies of VEGF single nucleotide polymorphisms, dynamic imaging endpoints and an assessment of a broader base of serum markers including the CXCL12 (SDF-1)/CXCR4 axis.	('CXCL12', 'Gene', (244, 250))	('SDF-1', 'Gene', (252, 257))	('CXCR4', 'Gene', (259, 264))	('VEGF', 'Gene', (113, 117))	('single nucleotide polymorphisms', 'Var', (118, 149))	('CXCL12', 'Gene', '6387', (244, 250))	('VEGF', 'Gene', '7422', (113, 117))	('CXCR4', 'Gene', '7852', (259, 264))	('SDF-1', 'Gene', '6387', (252, 257))
439419	31511074	They are characterised by germline mutations of genes that lead to the early onset of distinctive tumour subtypes in specific organs.	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (35, 44))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Disease', (98, 104))
439440	31511074	In the American NLST trial, annual low-dose chest CT in long-term smokers reduced lung cancer mortality by 20% compared to annual chest radiography.	('low-dose', 'Var', (35, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('reduced', 'NegReg', (74, 81))
439626	31511074	These tumours also show amplification of MDM2 and CDK4 positivity on FISH testing, whereas lipomas do not.	('lipomas', 'Disease', (91, 98))	('CDK4', 'Gene', (50, 54))	('lipomas', 'Disease', 'MESH:D008067', (91, 98))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('positivity', 'Var', (55, 65))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('MDM', 'Disease', (41, 44))	('lipomas', 'Phenotype', 'HP:0012032', (91, 98))	('amplification', 'Var', (24, 37))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('lipomas', 'Phenotype', 'HP:0001012', (91, 98))	('MDM', 'Disease', 'MESH:D007645', (41, 44))	('lipoma', 'Phenotype', 'HP:0012032', (91, 97))	('tumours', 'Disease', (6, 13))
439678	31511074	Advance DWI and PWI may further improve accuracy of MRI in discriminating various subtype of kidney cancers and has shown potential in discriminating chromophobe RCC from other subtypes.	('chromophobe RCC', 'Disease', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('kidney cancer', 'Phenotype', 'HP:0009726', (93, 106))	('PWI', 'Var', (16, 19))	('kidney cancers', 'Phenotype', 'HP:0009726', (93, 107))	('kidney cancers', 'Disease', 'MESH:D007680', (93, 107))	('chromophobe RCC', 'Disease', 'MESH:D002292', (150, 165))	('kidney cancers', 'Disease', (93, 107))	('improve', 'PosReg', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))
439744	31511074	More than 66% of the responders indicated that the benefits of AI and machine learning are much bigger or slightly bigger than the risks for cancer imaging.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('machine learning', 'Var', (70, 86))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
439993	31511074	2000;20(6):1585-603 High-quality evidence shows that MRI in biopsy-naive men can reduce the number of men who need prostate biopsy and can reduce the number of diagnoses of clinically insignificant cancers that are unlikely to cause harm.	('men', 'Species', '9606', (73, 76))	('reduce', 'NegReg', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('reduce', 'NegReg', (139, 145))	('men', 'Species', '9606', (102, 105))	('MRI', 'Var', (53, 56))
440017	31511074	The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT.	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))	('MDP', 'Chemical', 'MESH:D000119', (83, 86))	('patients', 'Species', '9606', (36, 44))	('prostate cancer', 'Disease', (60, 75))	('bone metastases', 'Disease', (17, 32))	('18F-fluoride', 'Chemical', '-', (152, 164))	('bone metastases', 'Disease', 'MESH:D009362', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('18F-fluoride PET/CT', 'Var', (174, 193))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('18F-fluoride', 'Chemical', '-', (174, 186))	('Tc', 'Chemical', 'MESH:D013667', (80, 82))
440093	31511074	131I-MIBG--a new agent in diagnosis and treatment of pheochromocytoma.	('men', 'Species', '9606', (45, 48))	('131I-MIBG--', 'Var', (0, 11))	('pheochromocytoma', 'Disease', (53, 69))	('pheochromocytoma', 'Disease', 'MESH:D010673', (53, 69))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('131I-MIBG', 'Chemical', '-', (0, 9))
440105	31511074	PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions.	('prostate cancer', 'Disease', (75, 90))	('PSMA', 'Gene', '2346', (42, 46))	('[68Ga', 'Var', (19, 24))	('gallium', 'Chemical', 'MESH:D005708', (25, 32))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Ga', 'Chemical', 'MESH:D005708', (22, 24))	('PSMA', 'Gene', (42, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (75, 90))	('tumour lesions', 'Disease', (142, 156))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))	('tumour lesions', 'Disease', 'MESH:D001932', (142, 156))	('humans', 'Species', '9606', (111, 117))
440121	31511074	For both metastatic and myeloma bone disease, deficiencies in the ability of serum biomarkers to reflect disease status particularly in later stages of the disease strengthens the need for quantitative whole body imaging.	('myeloma bone disease', 'Disease', 'MESH:D009101', (24, 44))	('deficiencies', 'Var', (46, 58))	('myeloma bone disease', 'Disease', (24, 44))	('metastatic', 'Disease', (9, 19))
440230	31511074	Probing molecular changes will aid not only cancer diagnosis, but also provide tumour grading, based on gene-expression analysis and imaging measurements of cell proliferation and changes in metabolism; staging, based on imaging of metastatic spread and elevation of protein biomarkers; and the detection of therapeutic response, using serial molecular imaging measurements or monitoring of serum markers.	('changes', 'Var', (18, 25))	('changes', 'Reg', (180, 187))	('men', 'Species', '9606', (368, 371))	('cell proliferation', 'CPA', (157, 175))	('metastatic spread', 'CPA', (232, 249))	('cancer', 'Disease', (44, 50))	('men', 'Species', '9606', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('metabolism', 'MPA', (191, 201))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('protein biomarkers', 'MPA', (267, 285))	('tumour', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
440383	31511074	Methods: Retrospective analysis of 388 prostate cancer patients enrolled in five prospective studies (NCT02940262, NCT03368547, NCT03042312, UCLA IRB#17-001336, NCT03515577).	('NCT02940262', 'Var', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('prostate cancer', 'Disease', (39, 54))	('NCT03368547', 'Var', (115, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (39, 54))	('patients', 'Species', '9606', (55, 63))	('NCT03042312', 'Var', (128, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))
440450	31511074	In this study, we aim to study the value of b800/b0 in addition to ADC values.	('AD', 'Disease', 'MESH:D000544', (67, 69))	('AD', 'Disease', (67, 69))	('b800/b0', 'Var', (44, 51))
440456	31511074	Conclusion The b800/b0 ratio in diffusion weighted imaging could help to differentiate benign from malignant gallbladder lesions, and it may be more reliable than the ADC values in the quantitative assessment of the DWI.	('AD', 'Disease', 'MESH:D000544', (167, 169))	('gallbladder lesions', 'Disease', (109, 128))	('AD', 'Disease', (167, 169))	('b800/b0', 'Var', (15, 22))	('men', 'Species', '9606', (204, 207))	('gallbladder lesions', 'Disease', 'MESH:D005705', (109, 128))
440578	31511074	More recently, F18 FDG-PET/CT, imaging which has various oncological applications, has been recommended as an important complementary tool in the detection of bone metastases and evaluation of therapy response.	('men', 'Species', '9606', (126, 129))	('men', 'Species', '9606', (97, 100))	('bone metastases', 'Disease', 'MESH:D009362', (159, 174))	('bone metastases', 'Disease', (159, 174))	('FDG', 'Chemical', 'MESH:D019788', (19, 22))	('F18', 'Var', (15, 18))
440603	31511074	While diagnostic certainty was comparable, ratings for lesion conspicuity were significantly higher for the combination of CI/IO (4(3-5)) compared to CI only (3(3-4);p<0.05).	('higher', 'PosReg', (93, 99))	('CI/IO', 'Var', (123, 128))	('IO', 'Chemical', '-', (126, 128))
440653	31511074	The study was performed in 404 patients with NPC who had undergone MR imaging with a standard protocol which included T1W, T2W- fat-suppressed (FS), contrast-enhanced-T1W (CE-T1W) and CE-T1W-FS sequences.	('NPC', 'Disease', 'MESH:D052556', (45, 48))	('T2W-', 'Var', (123, 127))	('NPC', 'Disease', (45, 48))	('T1W', 'Var', (118, 121))	('patients', 'Species', '9606', (31, 39))
440705	31511074	Distant metastases free survival was significantly better in patients with ypT0-2 (versus ypT3-4, P=0.0028) and ypN0 (versus ypN1-2, P=0.0040).	('metastases', 'Disease', (8, 18))	('ypT0-2', 'Var', (75, 81))	('metastases', 'Disease', 'MESH:D009362', (8, 18))	('patients', 'Species', '9606', (61, 69))	('ypN0', 'Var', (112, 116))	('better', 'PosReg', (51, 57))
440713	31511074	The values of ADCbm were significantly higher (p<0.01) in women, 477.3+-17.7 mum/s (95% IC), than in men, 426.3+-14.0 mum/s (95% IC).	('higher', 'PosReg', (39, 45))	('men', 'Species', '9606', (101, 104))	('477.3+-17.7', 'Var', (65, 76))	('women', 'Species', '9606', (58, 63))	('men', 'Species', '9606', (60, 63))	('AD', 'Disease', 'MESH:D000544', (14, 16))	('AD', 'Disease', (14, 16))
440729	31511074	Methods: Single-site retrospective analysis of histologically confirmed FH-deficient renal cancer, or patients with renal cancer and Germline FH mutation.	('renal cancer', 'Disease', (116, 128))	('FH-deficient renal cancer', 'Disease', (72, 97))	('renal cancer', 'Phenotype', 'HP:0009726', (85, 97))	('FH', 'Gene', '2271', (72, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (116, 128))	('FH-deficient renal cancer', 'Disease', 'MESH:D007680', (72, 97))	('Germline', 'Var', (133, 141))	('patients', 'Species', '9606', (102, 110))	('renal cancer', 'Disease', 'MESH:D007680', (85, 97))	('renal cancer', 'Disease', 'MESH:D007680', (116, 128))	('FH', 'Gene', '2271', (142, 144))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
440853	33477279	Non-invasive fluorescence imaging demonstrated that complete tumor resection with a precise margin, preservation of function, and prevention of distant metastasis, was achieved with fluorescence-guided surgery (FGS) with a GFP-reporter adenovirus.	('adenovirus', 'Species', '10508', (236, 246))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('distant metastasis', 'CPA', (144, 162))	('GFP-reporter', 'Var', (223, 235))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
440858	33477279	Multicolor fluorescent mutants and sophisticated imaging instrumentation and software enabled researchers to detect the location of cancer cells and monitor their molecular functions and dynamics in mouse models.	('mouse', 'Species', '10090', (199, 204))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutants', 'Var', (23, 30))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
440859	33477279	We developed three types of cancer-targeting oncolytic adenoviruses that are driven by the hTERT promoter: OBP-301, OBP-401, and OBP-301 with KillerRed (Figure 1).	('OBP-301', 'Var', (107, 114))	('adenovirus', 'Species', '10508', (55, 65))	('OBP-401', 'Chemical', '-', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('OBP-301', 'Chemical', '-', (107, 114))	('OBP-301', 'Var', (129, 136))	('OBP-301', 'Chemical', '-', (129, 136))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('hTERT', 'Gene', '7015', (91, 96))	('cancer', 'Disease', (28, 34))	('hTERT', 'Gene', (91, 96))	('OBP-401', 'Var', (116, 123))
440876	33477279	For example, FUCCI imaging showed that CSC-derived tumor spheres which comprise quiescent cancer cells expressing FUCCI-red, can remain quiescent for more than 14 days, and are resistant to conventional chemotherapy and radiotherapy (Figure 2A).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('FUCCI', 'Chemical', '-', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', (51, 56))	('FUCCI-red', 'Var', (114, 123))	('FUCCI', 'Chemical', '-', (114, 119))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
440897	33477279	Patients who underwent FGS with 5-ALA had longer 6-month progression-free survival rates (41%) than those who had bright light surgery (BLS) (21%).	('5-ALA', 'Chemical', 'MESH:C000614854', (32, 37))	('progression-free survival rates', 'CPA', (57, 88))	('FGS', 'Var', (23, 26))	('longer', 'PosReg', (42, 48))	('Patients', 'Species', '9606', (0, 8))
440919	33477279	We then demonstrated that OBP-401-based FGS improved surgical resection and disease-free survival using an orthotopic mouse sarcoma mouse model.	('FGS', 'Var', (40, 43))	('sarcoma', 'Disease', (124, 131))	('OBP-401-based', 'Gene', (26, 39))	('surgical resection', 'CPA', (53, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('mouse', 'Species', '10090', (118, 123))	('mouse', 'Species', '10090', (132, 137))	('improved', 'PosReg', (44, 52))	('disease-free survival', 'CPA', (76, 97))	('OBP-401', 'Chemical', '-', (26, 33))
440920	33477279	We developed the orthotopic model of STS by injecting HT1080 cells into muscle tissue since HT1080 cells have the potential to grow rapidly, invade the surrounding muscle, and metastasize to the lung(s).	('HT1080', 'CellLine', 'CVCL:0317', (92, 98))	('metastasize', 'CPA', (176, 187))	('HT1080', 'CellLine', 'CVCL:0317', (54, 60))	('STS', 'Phenotype', 'HP:0030448', (37, 40))	('HT1080 cells', 'Var', (92, 104))
440960	33477279	Patient-derived xenograft (PDX) models are currently being widely used for molecular biological studies, drug evaluation, and development of new strategies since PDXs maintain histologic, genetic, and epigenetic characteristics of their donor tumors in live mice.	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('tumors', 'Disease', (243, 249))	('epigenetic', 'Var', (201, 211))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('mice', 'Species', '10090', (258, 262))	('Patient', 'Species', '9606', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
441015	32064289	Reverse transcription-polymerase chain reaction analysis identified an Ewing sarcoma breakpoint region 1-ETS-related gene (EWSR1- ERG) fusion transcripts.	('EWSR1', 'Gene', (123, 128))	('ERG', 'Gene', (130, 133))	('EWSR1', 'Gene', '2130', (123, 128))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('fusion', 'Var', (135, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('ERG', 'Gene', '2078', (130, 133))
441035	31303577	To date, a single cancer cell line, HCT116, derived from a human colorectal cancer harboring a naturally-arising mutation in the MMR protein MLH1, has been used successfully for these studies.	('MMR', 'Gene', '50771', (129, 132))	('human', 'Species', '9606', (59, 64))	('HCT116', 'CellLine', 'CVCL:0291', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('MMR', 'Gene', (129, 132))	('colorectal cancer', 'Disease', (65, 82))	('mutation in', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('MLH1', 'Gene', '4292', (141, 145))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('MLH1', 'Gene', (141, 145))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', (18, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))
441036	31303577	Here, we sought to determine if somatic deletion of the MMR protein MSH2 using CRISPR-Cas9 could be used to expand the repertoire of dMMR cancer cell lines for use in forward genetic screens.	('cancer', 'Disease', (138, 144))	('CRISPR', 'Gene', (79, 85))	('MMR', 'Gene', '50771', (134, 137))	('MMR', 'Gene', (56, 59))	('deletion', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('MMR', 'Gene', '50771', (56, 59))	('CRISPR', 'Gene', '70873', (79, 85))	('MMR', 'Gene', (134, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('MSH2', 'Gene', (68, 72))
441041	31303577	MSI was observed in three out of five loci analyzed in both A673-M1 and A673-M8 clones compared to the parental, MMR-proficient, A673 cell line (Fig.	('MMR', 'Gene', (113, 116))	('MMR', 'Gene', '50771', (113, 116))	('A673-M1', 'Var', (60, 67))	('A673-M8', 'Var', (72, 79))
441042	31303577	We next tested whether MMR deletion would facilitate MSI in tumor cell lines derived from genetically-engineered mouse cancer models (GEMMs), which also exhibit very low mutation frequencies compared to many human malignancies.	('tested', 'Reg', (8, 14))	('MMR', 'Gene', '50771', (23, 26))	('facilitate', 'PosReg', (42, 52))	('malignancies', 'Disease', (214, 226))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MMR', 'Gene', (23, 26))	('deletion', 'Var', (27, 35))	('cancer', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('malignancies', 'Disease', 'MESH:D009369', (214, 226))	('MSI', 'MPA', (53, 56))	('tumor', 'Disease', (60, 65))	('mouse', 'Species', '10090', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (208, 213))
441052	31303577	Selections were performed against three cellular toxins: bortezomib (an inhibitor of the subunit beta5 of the proteasome, PSMB5), MLN4924 (a NEDD8-activating enzyme (NAE) inhibitor), and CD437 (a DNA polymerase alpha (POLA1) inhibitor).	('CD437', 'Chemical', 'MESH:C099555', (187, 192))	('MLN4924', 'Chemical', 'MESH:C539933', (130, 137))	('NEDD8', 'Gene', '18002', (141, 146))	('beta5', 'Gene', (97, 102))	('beta5', 'Gene', '16776', (97, 102))	('MLN4924', 'Var', (130, 137))	('NEDD8', 'Gene', (141, 146))	('bortezomib', 'Chemical', 'MESH:D000069286', (57, 67))
441055	31303577	We next performed additional selections using bortezomib, CD437, and MLN4924.	('MLN4924', 'Var', (69, 76))	('CD437', 'Chemical', 'MESH:C099555', (58, 63))	('CD437', 'Var', (58, 63))	('MLN4924', 'Chemical', 'MESH:C539933', (69, 76))	('bortezomib', 'Chemical', 'MESH:D000069286', (46, 56))
441057	31303577	Following 2 weeks of selection, compound-resistant colonies emerged and were expanded from both A673-M1 (4 clones) and Msh2-null mSCLC cells (11 clones).	('A673-M1', 'Var', (96, 103))	('Msh2-null', 'Gene', (119, 128))	('SCLC', 'Disease', (130, 134))	('SCLC', 'Disease', 'MESH:D018288', (130, 134))	('SCLC', 'Phenotype', 'HP:0030357', (130, 134))
441058	31303577	Bortezomib-resistant alleles have been reported within exon 2 of PSMB5, which encodes a binding pocket for the drug.	('PSMB5', 'Gene', (65, 70))	('Bortezomib', 'Chemical', 'MESH:D000069286', (0, 10))	('alleles', 'Var', (21, 28))
441061	31303577	We identified PSMB5 mutations in MMR-deficient A673 (4 out of 4 clones harbored mutations) and mSCLC cell lines (11 out of 11 clones harbored PSMB5 exon 2 mutations), including mutations previously reported to mediate bortezomib resistance (Fig.	('MMR', 'Gene', '50771', (33, 36))	('PSMB5', 'Gene', (142, 147))	('SCLC', 'Phenotype', 'HP:0030357', (96, 100))	('MMR', 'Gene', (33, 36))	('SCLC', 'Disease', (96, 100))	('SCLC', 'Disease', 'MESH:D018288', (96, 100))	('mutations', 'Var', (20, 29))	('bortezomib', 'Chemical', 'MESH:D000069286', (218, 228))	('PSMB5', 'Gene', (14, 19))
441062	31303577	All mutations identified in PSMB5 mapped to the bortezomib binding pocket (Fig.	('mutations', 'Var', (4, 13))	('bortezomib', 'Chemical', 'MESH:D000069286', (48, 58))	('mapped', 'Reg', (34, 40))	('PSMB5', 'Gene', (28, 33))
441064	31303577	We also tested 7 out of the 11 mSCLC clones that harbored Psmb5 mutations and confirmed in vitro resistance to bortezomib (Figure 2C, D).	('tested', 'Reg', (8, 14))	('SCLC', 'Disease', (32, 36))	('SCLC', 'Disease', 'MESH:D018288', (32, 36))	('Psmb5', 'Gene', '19173', (58, 63))	('Psmb5', 'Gene', (58, 63))	('SCLC', 'Phenotype', 'HP:0030357', (32, 36))	('bortezomib', 'Chemical', 'MESH:D000069286', (111, 121))	('mutations', 'Var', (64, 73))
441065	31303577	We confirmed that all clones harboring PSMB5 mutations exhibited bortezomib resistance (2.36 to 13.84-fold increase in EC50), whereas resistance to etoposide was not observed (Figure 2A-D; Figure S3A, B).	('etoposide', 'Chemical', 'MESH:D005047', (148, 157))	('bortezomib resistance', 'MPA', (65, 86))	('mutations', 'Var', (45, 54))	('increase', 'PosReg', (107, 115))	('exhibited', 'Reg', (55, 64))	('bortezomib', 'Chemical', 'MESH:D000069286', (65, 75))	('PSMB5', 'Gene', (39, 44))
441067	31303577	After 2 weeks of selection, compound-resistant colonies emerged and were expanded from both A673-M1 (4 clones) and Msh2-null mSCLC cells (17 clones).	('SCLC', 'Phenotype', 'HP:0030357', (126, 130))	('SCLC', 'Disease', (126, 130))	('SCLC', 'Disease', 'MESH:D018288', (126, 130))	('Msh2-null', 'Gene', (115, 124))	('A673-M1', 'Var', (92, 99))
441069	31303577	We identified POLA1 mutations in the MMR-deficient A673 (4 out of 4 clones harbored mutations) and mSCLC lines (11 out of 17 clones harbored mutations) (Figure 3B, D, E).	('MMR', 'Gene', '50771', (37, 40))	('SCLC', 'Phenotype', 'HP:0030357', (100, 104))	('POLA1', 'Gene', (14, 19))	('MMR', 'Gene', (37, 40))	('SCLC', 'Disease', (100, 104))	('SCLC', 'Disease', 'MESH:D018288', (100, 104))	('mutations', 'Var', (20, 29))
441071	31303577	We confirmed CD437-resistance in all 4 clones from A673-M1 cell line and 11 out of 17 mSCLC clones harboring putative compound-resistant alleles to CD437 (Figure 3A, B).	('CD437-resistance', 'Var', (13, 29))	('SCLC', 'Phenotype', 'HP:0030357', (87, 91))	('CD437', 'Chemical', 'MESH:C099555', (13, 18))	('CD437', 'Chemical', 'MESH:C099555', (148, 153))	('SCLC', 'Disease', (87, 91))	('SCLC', 'Disease', 'MESH:D018288', (87, 91))
441072	31303577	The six mSCLC resistant clones that did not harbor POLA1 mutations exhibited resistance to both CD437 and etoposide, which suggested a generalized mechanism of acquired resistance drove expansion of these clones during compound selection (Figure S3C, D).	('SCLC', 'Disease', (9, 13))	('SCLC', 'Disease', 'MESH:D018288', (9, 13))	('resistance', 'MPA', (77, 87))	('POLA1', 'Gene', (51, 56))	('SCLC', 'Phenotype', 'HP:0030357', (9, 13))	('mutations', 'Var', (57, 66))	('etoposide', 'Chemical', 'MESH:D005047', (106, 115))	('exhibited', 'Reg', (67, 76))	('CD437', 'Chemical', 'MESH:C099555', (96, 101))
441073	31303577	The ten mSCLC clones harboring POLA1 mutations all exhibited CD437 resistance (5.31 to 15.05-fold increase in EC50), whereas no difference in sensitivity to etoposide was observed (Figure 3C, D; Figure S3E, F).	('SCLC', 'Disease', (9, 13))	('exhibited', 'Reg', (51, 60))	('SCLC', 'Disease', 'MESH:D018288', (9, 13))	('CD437', 'Chemical', 'MESH:C099555', (61, 66))	('POLA1', 'Gene', (31, 36))	('SCLC', 'Phenotype', 'HP:0030357', (9, 13))	('mutations', 'Var', (37, 46))	('increase', 'PosReg', (98, 106))	('etoposide', 'Chemical', 'MESH:D005047', (157, 166))	('CD437 resistance', 'MPA', (61, 77))
441075	31303577	Therefore, we performed selections using MLN4924 in the MSH2-null clone, A673-M1, at three concentrations for MLN4924 (see Methods).	('MLN4924', 'Chemical', 'MESH:C539933', (110, 117))	('MLN4924', 'Var', (41, 48))	('MLN4924', 'Var', (110, 117))	('MSH2-null', 'Gene', (56, 65))	('MLN4924', 'Chemical', 'MESH:C539933', (41, 48))
441077	31303577	We validated that all MLN clones exhibited resistance to MLN4924 (21.75 to 135.03-fold increase in EC50), while no difference in etoposide resistance was observed (Figure 4A,B; Figure S3F).	('etoposide', 'Chemical', 'MESH:D005047', (129, 138))	('MLN4924', 'Chemical', 'MESH:C539933', (57, 64))	('increase', 'PosReg', (87, 95))	('MLN4924', 'Var', (57, 64))
441078	31303577	We next determined if the target of MLN4924, NAE subunit encoded by UBA3, could be identified by WES of MLN4924-resistant clones.	('MLN4924', 'Chemical', 'MESH:C539933', (104, 111))	('MLN4924', 'Chemical', 'MESH:C539933', (36, 43))	('MLN4924', 'Var', (36, 43))	('UBA3', 'Gene', (68, 72))	('UBA3', 'Gene', '22200', (68, 72))
441080	31303577	This gene encodes the NAE subunit targeted by MLN4924, and three of the mutations observed, A171T, E204K, and Y352H, were previously reported as MLN4924-resistant alleles (Figure 4D).	('E204K', 'Var', (99, 104))	('A171T', 'Var', (92, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (46, 53))	('MLN4924', 'Var', (46, 53))	('Y352H', 'Mutation', 'rs1029837632', (110, 115))	('E204K', 'Mutation', 'p.E204K', (99, 104))	('A171T', 'Mutation', 'rs765544948', (92, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (145, 152))	('Y352H', 'Var', (110, 115))
441082	31303577	However, no other clones shared more than 6 somatic mutations, suggesting that the other clones arose independently, including A673-MLN-A and A673-MLN-C that shared the A171T mutation in UBA3.	('A171T', 'Var', (169, 174))	('A673-MLN-A', 'Var', (127, 137))	('UBA3', 'Gene', (187, 191))	('UBA3', 'Gene', '22200', (187, 191))	('A171T', 'Mutation', 'rs765544948', (169, 174))	('A673-MLN-C', 'Var', (142, 152))
441088	31303577	Therefore, cancer cell lines with induced MMR deficiency and hypermutation represent a tool with wide potential application in cancer genetics and drug discovery.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('hypermutation', 'Var', (61, 74))	('MMR deficiency', 'Disease', 'MESH:C536928', (42, 56))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('MMR deficiency', 'Disease', (42, 56))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (11, 17))
441106	31303577	Secondary antibodies were incubated for 30 min at RT using IRDye 800CW donkey anti-rabbit IgG (H+L) (#926-32213, LI-COR), and IRDye 680RD donkey anti-mouse IgG (H+L) (#926-68072, LI-COR), at dilution 1:10,000.	('COR', 'Gene', '108031', (182, 185))	('COR', 'Gene', '108031', (116, 119))	('#926-68072', 'Var', (167, 177))	('#926-32213', 'Var', (101, 111))	('COR', 'Gene', (182, 185))	('COR', 'Gene', (116, 119))	('mouse', 'Species', '10090', (150, 155))
441117	31303577	After 24h, Bortezomib was dispensed using TECAN D300e setting up a minimum concentration of EC5072h and a maximum concentration of EC10072h.	('EC10072h', 'Var', (131, 139))	('EC5072h', 'Var', (92, 99))	('EC5072', 'CellLine', 'CVCL:C887', (92, 98))	('Bortezomib', 'Chemical', 'MESH:D000069286', (11, 21))
441118	31303577	10 cm plates for each MMR deficient cell lines (1 million cells per plate) were treated with bortezomib or CD437 at EC1001wk / 1.5, EC1001wk, and EC1001wk x 1.5 concentrations.	('EC1001', 'CellLine', 'CVCL:F672', (146, 152))	('EC1001', 'CellLine', 'CVCL:F672', (132, 138))	('EC1001', 'CellLine', 'CVCL:F672', (116, 122))	('MMR', 'Gene', (22, 25))	('bortezomib', 'Chemical', 'MESH:D000069286', (93, 103))	('MMR', 'Gene', '50771', (22, 25))	('EC1001wk x', 'Var', (146, 156))	('CD437', 'Chemical', 'MESH:C099555', (107, 112))	('EC1001wk', 'Var', (132, 140))	('EC1001wk /', 'Var', (116, 126))
441122	31303577	10 cm plates for each MMR deficient cell lines (3 million cells per plate) were treated with botezomib, MLN4924, and CD437 at EC1001wk / 1.5, EC1001wk / 1.25, EC1001wk, and EC1001wk x 1.25, EC1001wk x 1.5 concentrations.	('MLN4924', 'Chemical', 'MESH:C539933', (104, 111))	('EC1001', 'CellLine', 'CVCL:F672', (190, 196))	('EC1001', 'CellLine', 'CVCL:F672', (159, 165))	('EC1001', 'CellLine', 'CVCL:F672', (173, 179))	('MLN4924', 'Var', (104, 111))	('EC1001wk / 1.25', 'Var', (142, 157))	('MMR', 'Gene', (22, 25))	('EC1001', 'CellLine', 'CVCL:F672', (126, 132))	('EC1001wk', 'Var', (159, 167))	('EC1001wk / 1.5', 'Var', (126, 140))	('CD437', 'Chemical', 'MESH:C099555', (117, 122))	('MMR', 'Gene', '50771', (22, 25))	('botezomib', 'Chemical', '-', (93, 102))	('EC1001wk x', 'Var', (173, 183))	('EC1001', 'CellLine', 'CVCL:F672', (142, 148))
441123	31303577	Media with either bortezomib, MLN4924, or CD437 was replenished every 3 - 4 days over the course of 2 weeks followed by growth in media without compound for 1 week.	('MLN4924', 'Chemical', 'MESH:C539933', (30, 37))	('CD437', 'Chemical', 'MESH:C099555', (42, 47))	('bortezomib', 'Chemical', 'MESH:D000069286', (18, 28))	('MLN4924', 'Var', (30, 37))	('CD437', 'Var', (42, 47))
441128	31303577	For each murine SCLC cell lines, the somatic mutations in 319-N1 were defined by the VAF > 0.15 and VAF < 0.05 for 319-T1 and 319-T2.	('319-N1', 'Gene', (58, 64))	('murine', 'Species', '10090', (9, 15))	('319-T2', 'Var', (126, 132))	('319-T1', 'Var', (115, 121))	('SCLC', 'Disease', (16, 20))	('SCLC', 'Disease', 'MESH:D018288', (16, 20))	('SCLC', 'Phenotype', 'HP:0030357', (16, 20))
441129	31303577	For human cell lines, MuTect2 was used to identify somatic mutations in clones A673-M1 and A673-M8 comparing to the A673 parental cell line.	('A673-M8', 'Var', (91, 98))	('human', 'Species', '9606', (4, 9))	('A673-M1', 'Var', (79, 86))	('mutations', 'Var', (59, 68))
441130	31303577	Somatic mutations for each clones (A673-M1 and A673-M8) were defined by VAF > 0.15 and VAF < 0.05 for the other human cell lines.	('A673-M8', 'Var', (47, 54))	('human', 'Species', '9606', (112, 117))	('A673-M1', 'Var', (35, 42))
441133	31303577	MSH2 deletion induces hypermutation in mammalian cancer cell lines.	('deletion', 'Var', (5, 13))	('MSH2', 'Gene', (0, 4))	('hypermutation', 'MPA', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('induces', 'Reg', (14, 21))	('mammalian', 'Species', '9606', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
441138	31303577	Cancer cells harboring defective DNA mismatch repair have been used to identify targets of selective cancer toxins.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('defective', 'Var', (23, 32))
441139	31303577	However, naturally-arising DNA mismatch repair defects are infrequent in many types of cancer.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('defects', 'Var', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
441140	31303577	Here, we demonstrate that CRISPR-Cas9-mediated mutation of MSH2 is sufficient to induce hypermutation and enable forward genetic screening for drug targets in mammalian cells.	('mammalian', 'Species', '9606', (159, 168))	('hypermutation', 'MPA', (88, 101))	('CRISPR', 'Gene', '70873', (26, 32))	('MSH2', 'Gene', (59, 63))	('mutation', 'Var', (47, 55))	('CRISPR', 'Gene', (26, 32))	('induce', 'Reg', (81, 87))
441147	27873216	FTICR-MSI identified m/z 241.0118 as inositol cyclic phosphate and m/z 160.8417 as carnitine.	('m/z 160.8417', 'Var', (67, 79))	('m/z 241.0118', 'Var', (21, 33))	('inositol cyclic phosphate', 'Chemical', 'MESH:C010199', (37, 62))	('inositol cyclic phosphate', 'MPA', (37, 62))	('TIC', 'Phenotype', 'HP:0100033', (1, 4))	('carnitine', 'Chemical', 'MESH:D002331', (83, 92))
441200	27873216	The analysis revealed three metabolite ions that were significantly associated to patient survival in sarcoma patients: m/z 180.90 (P = 0.006) and m/z 240.88 (P = 0.022), both indicative of a poor overall survival in soft tissue sarcoma patients; and m/z 160.81 (P = 0.017) indicative of a poor metastasis-free survival in myxofibrosarcoma patients.	('patient', 'Species', '9606', (82, 89))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('sarcoma', 'Disease', (229, 236))	('sarcoma', 'Disease', 'MESH:D012509', (332, 339))	('patients', 'Species', '9606', (340, 348))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('sarcoma', 'Disease', (102, 109))	('patients', 'Species', '9606', (237, 245))	('sarcoma', 'Disease', (332, 339))	('patient', 'Species', '9606', (237, 244))	('m/z 160.81', 'Var', (251, 261))	('patient', 'Species', '9606', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('myxofibrosarcoma', 'Disease', 'None', (323, 339))	('m/z 180.90', 'Var', (120, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (332, 339))	('patient', 'Species', '9606', (340, 347))	('m/z 240.88', 'Var', (147, 157))	('associated', 'Reg', (68, 78))	('myxofibrosarcoma', 'Disease', (323, 339))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (217, 236))	('metastasis-free', 'CPA', (295, 310))	('patients', 'Species', '9606', (110, 118))
441275	26167500	In contrast, STAT3 in certain tumors is constitutively activated by genetic alterations.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('genetic alterations', 'Var', (68, 87))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('STAT3', 'Gene', '6774', (13, 18))	('STAT3', 'Gene', (13, 18))	('activated', 'PosReg', (55, 64))
441357	26167500	Some types of adoptive cell transfer therapies are ongoing for patients with sarcomas, including autologous DC transport therapy for soft tissue sarcomas (NCT01347034) and hematopoietic cell transplantation and natural killer cell transport therapies for Ewing's sarcomas and rhabdomyosarcomas (NCT02100891).	('sarcomas', 'Disease', 'MESH:D012509', (285, 293))	('sarcomas', 'Phenotype', 'HP:0100242', (285, 293))	('sarcomas', 'Disease', (285, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (255, 271))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (255, 270))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('soft tissue sarcomas', 'Disease', (133, 153))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (276, 293))	('sarcomas', 'Disease', (77, 85))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (133, 153))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (276, 292))	('NCT01347034', 'Var', (155, 166))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (133, 153))	("Ewing's sarcomas and rhabdomyosarcomas", 'Disease', 'MESH:C563168', (255, 293))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('sarcomas', 'Disease', 'MESH:D012509', (263, 271))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('sarcomas', 'Phenotype', 'HP:0100242', (263, 271))	('sarcomas', 'Disease', (145, 153))	('patients', 'Species', '9606', (63, 71))	('sarcomas', 'Disease', (263, 271))
441413	23652877	68% of cells had extra intact SYT signals, indicating polysomy or polyploidy of a presumed neoplastic clone.	('polyploidy', 'Disease', (66, 76))	('SYT', 'Gene', (30, 33))	('polysomy', 'Var', (54, 62))	('polyploidy', 'Disease', 'MESH:D011123', (66, 76))	('SYT', 'Gene', '6760', (30, 33))
441454	23652877	In another study, patients treated with greater than 6g/m2 of etoposide had 197 times the risk of secondary leukemia compared to those treated with less than 1.2g/m2.	('etoposide', 'Chemical', 'MESH:D005047', (62, 71))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('leukemia', 'Disease', 'MESH:D007938', (108, 116))	('leukemia', 'Disease', (108, 116))	('greater than 6g/m2', 'Var', (40, 58))	('patients', 'Species', '9606', (18, 26))	('etoposide', 'Gene', (62, 71))
441460	24735727	This tumor family also includes alveolar soft part sarcoma, perivascular epithelioid cell neoplasms, Xp11 translocation renal cell carcinoma, and melanoma.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('alveolar soft part sarcoma', 'Disease', (32, 58))	('Xp11 translocation', 'Var', (101, 119))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 140))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('epithelioid cell neoplasms', 'Disease', 'MESH:D054973', (73, 99))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (41, 58))	('neoplasms', 'Phenotype', 'HP:0002664', (90, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (90, 98))	('renal cell carcinoma', 'Disease', (120, 140))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (32, 58))	('epithelioid cell neoplasms', 'Disease', (73, 99))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (32, 58))	('tumor', 'Disease', (5, 10))
441475	24735727	The MiTF/TFE tumor family includes alveolar soft part sarcoma (ASPS), Xp11 translocation renal cell carcinoma (RCC), t(6;11) RCC, perivascular epithelioid cell tumor (PEComa), melanoma, and clear cell sarcoma of soft tissues.	('ASPS', 'Gene', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (89, 109))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('TFE tumor', 'Disease', 'MESH:D009369', (9, 18))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (190, 208))	('ASPS', 'Gene', '79058', (63, 67))	('epithelioid cell tumor', 'Disease', 'MESH:D054973', (143, 165))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (44, 61))	('PEComa', 'Disease', 'MESH:D054973', (167, 173))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (35, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('ASPS', 'Phenotype', 'HP:0012218', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (35, 61))	('PEComa', 'Disease', (167, 173))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('renal cell carcinoma', 'Disease', (89, 109))	('MiTF', 'Gene', '4286', (4, 8))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (89, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('alveolar soft part sarcoma', 'Disease', (35, 61))	('clear cell sarcoma', 'Disease', (190, 208))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('TFE tumor', 'Disease', (9, 18))	('MiTF', 'Gene', (4, 8))	('Xp11 translocation', 'Var', (70, 88))	('epithelioid cell tumor', 'Phenotype', 'HP:0032060', (143, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('epithelioid cell tumor', 'Disease', (143, 165))
441478	24735727	Thus, Argani and colleagues have proposed that melanotic Xp11 TRCs demonstrate features seen in ASPS, PEComa, Xp11 RCC, and melanoma.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('ASPS', 'Gene', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('ASPS', 'Gene', '79058', (96, 100))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('PEComa', 'Disease', (102, 108))	('ASPS', 'Phenotype', 'HP:0012218', (96, 100))	('PEComa', 'Disease', 'MESH:D054973', (102, 108))	('melanotic Xp11', 'Var', (47, 61))
441479	24735727	However, melanotic XP11 TRCs are separated from these tumors by their combination of melanin pigmentation, immunohistochemical negativity for S-100 and markers of epithelial and muscle differentiation, and most critically, rearrangement of TFE3.	('TFE3', 'Gene', '7030', (240, 244))	('S-100', 'Gene', '6271', (142, 147))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('pigmentation', 'Disease', 'MESH:D010859', (93, 105))	('rearrangement', 'Var', (223, 236))	('pigmentation', 'Disease', (93, 105))	('melanin', 'Chemical', 'MESH:D008543', (85, 92))	('S-100', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TFE3', 'Gene', (240, 244))	('melanotic XP11 TRCs', 'Disease', (9, 28))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
441499	24735727	Tumor cells were negative for all epithelial and renal tubule markers including pan-cytokeratin (CK), epithelial membrane antigen, BerEP-4, CD10, CK34betaE12, CK8/18, CK7, and carbonic anhydrase IX.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD10', 'Gene', '4311', (140, 144))	('CK34betaE12', 'Var', (146, 157))	('carbonic anhydrase IX', 'Gene', (176, 197))	('CK8', 'Gene', '3856', (159, 162))	('CK8', 'Gene', (159, 162))	('CK7', 'Gene', (167, 170))	('CK7', 'Gene', '3855', (167, 170))	('CD10', 'Gene', (140, 144))	('carbonic anhydrase IX', 'Gene', '768', (176, 197))
441509	24735727	The present case demonstrated other clinical and histologic features previously described in melanotic Xp11 TRC, including presenting symptoms of abdominal pain and female predisposition (all but one reported case to date occurring in females).	('abdominal pain', 'Disease', 'MESH:D015746', (146, 160))	('pain', 'Phenotype', 'HP:0012531', (156, 160))	('abdominal pain', 'Phenotype', 'HP:0002027', (146, 160))	('melanotic', 'Var', (93, 102))	('abdominal pain', 'Disease', (146, 160))	('Xp11', 'Gene', (103, 107))
441515	24735727	Two novel immunohistochemical results here were positivity with progesterone receptor (estrogen receptor was negative) and CD117 (C-kit), which is typically reported as negative.	('CD117', 'Gene', '3815', (123, 128))	('CD117', 'Gene', (123, 128))	('estrogen receptor', 'Gene', (87, 104))	('positivity', 'Var', (48, 58))	('estrogen receptor', 'Gene', '2099', (87, 104))	('C-kit', 'Gene', (130, 135))	('progesterone receptor', 'Gene', (64, 85))	('progesterone receptor', 'Gene', '5241', (64, 85))	('C-kit', 'Gene', '3815', (130, 135))
441518	24735727	As described above, immunohistochemical negativity with all epithelial and renal tubule markers, S-100, desmin and actin eliminates many of these other diagnostic possibilities.	('S-100', 'Gene', '6271', (97, 102))	('actin', 'Protein', (115, 120))	('negativity', 'Var', (40, 50))	('desmin', 'Gene', (104, 110))	('eliminates', 'NegReg', (121, 131))	('desmin', 'Gene', '1674', (104, 110))	('S-100', 'Gene', (97, 102))
441526	24735727	One caveat of molecular verification is that Chang and colleagues identified a PSF-TFE3 fusion in melanotic Xp11 TRC that is also reported in Xp11 RCC.	('PSF', 'Gene', (79, 82))	('melanotic', 'Gene', (98, 107))	('TFE3', 'Gene', '7030', (83, 87))	('RCC', 'Disease', (147, 150))	('PSF', 'Gene', '3490', (79, 82))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('TFE3', 'Gene', (83, 87))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('fusion', 'Var', (88, 94))
441564	32181374	In an exploratory covariate analysis, female gender, age, high dose, and larger tumor size were associated with worse ESAS scores across all time points.	('ESAS', 'Chemical', '-', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('high dose', 'Var', (58, 67))	('ESAS', 'Disease', (118, 122))	('worse', 'NegReg', (112, 117))
441606	32181374	Tumor size was associated with higher overall total score (P <= 0.001), pain (P <= 0.001), tiredness (P = 0.007), shortness of breath (P = 0.03), and overall wellbeing (P = 0.001).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('pain', 'Phenotype', 'HP:0012531', (72, 76))	('total score', 'MPA', (46, 57))	('pain', 'Disease', 'MESH:D010146', (72, 76))	('tiredness', 'Phenotype', 'HP:0012378', (91, 100))	('pain', 'Disease', (72, 76))	('Tumor size', 'Var', (0, 10))	('shortness of breath', 'Phenotype', 'HP:0002098', (114, 133))	('tiredness', 'Disease', (91, 100))	('higher', 'PosReg', (31, 37))	('shortness of breath', 'Disease', (114, 133))	('tiredness', 'Disease', 'MESH:D005221', (91, 100))	('shortness of breath', 'Disease', 'MESH:D004417', (114, 133))
441695	31007495	However, large areas of undifferentiated cells with myogenin positivity along with CD99 negativity argued against such a diagnosis.	('CD99', 'Gene', '4267', (83, 87))	('myogenin', 'Gene', (52, 60))	('CD99', 'Gene', (83, 87))	('myogenin', 'Gene', '4656', (52, 60))	('positivity', 'Var', (61, 71))
441712	30619193	Together, these data suggest a regulatory role for KSHV vIL-6 in functionally modulating B cell biology by promoting CSR, which may in part explain how KSHV infection influences humoral immunity and affect KSHV pathogenesis.	('KSHV', 'Species', '37296', (206, 210))	('KSHV', 'Species', '37296', (51, 55))	('KSHV', 'Var', (51, 55))	('KS', 'Phenotype', 'HP:0100726', (206, 208))	('CSR', 'MPA', (117, 120))	('promoting', 'PosReg', (107, 116))	('KSHV infection', 'Disease', 'MESH:C537372', (152, 166))	('vIL-6', 'Gene', (56, 61))	('influences', 'Reg', (167, 177))	('KS', 'Phenotype', 'HP:0100726', (51, 53))	('KS', 'Phenotype', 'HP:0100726', (152, 154))	('KSHV infection', 'Disease', (152, 166))	('vIL-6', 'Gene', '4961449', (56, 61))	('humoral', 'MPA', (178, 185))	('KSHV', 'Species', '37296', (152, 156))	('affect', 'Reg', (199, 205))	('KSHV', 'Disease', (206, 210))	('modulating', 'Reg', (78, 88))
441729	30619193	At the donor S-region, Smu, and downstream acceptor S-region, AID deaminates dC to deoxyuridines (dU) creating G:U mismatches.	('mismatches', 'Var', (115, 125))	('dC', 'Chemical', 'MESH:D003841', (77, 79))	('G:U mismatches', 'Var', (111, 125))	('dU', 'Chemical', 'MESH:D003857', (98, 100))	('deoxyuridines', 'Chemical', 'MESH:D003857', (83, 96))	('dC to deoxyuridines', 'MPA', (77, 96))	('donor', 'Species', '9606', (7, 12))
441733	30619193	It is evident that KSHV affects various aspects of humoral immunity.	('KS', 'Phenotype', 'HP:0100726', (19, 21))	('KSHV', 'Var', (19, 23))	('KSHV', 'Species', '37296', (19, 23))	('affects', 'Reg', (24, 31))
441738	30619193	Furthermore, we show that viral IL-6 (vIL-6), but not murine IL-6, augmented CSR.	('vIL-6', 'Gene', (38, 43))	('viral', 'Var', (26, 31))	('murine', 'Species', '10090', (54, 60))	('CSR', 'Disease', (77, 80))	('vIL-6', 'Gene', '4961449', (38, 43))	('augmented', 'PosReg', (67, 76))
441760	30619193	293TX cells were transfected at 70% confluence with pCMV delta 8.2, pCMV VSV-G, and the pSin, vFLIP, vGPCR, or vIL-6 plasmids from the Boshoff lentiviral library using Polyplus transfection reagent.	('vGPCR', 'Gene', '4961465', (101, 106))	('vIL-6', 'Gene', (111, 116))	('vGPCR', 'Gene', (101, 106))	('pCMV', 'Var', (52, 56))	('vFLIP', 'Chemical', '-', (94, 99))	('293TX', 'CellLine', 'CVCL:0045', (0, 5))	('vIL-6', 'Gene', '4961449', (111, 116))	('pSin', 'Gene', (88, 92))
441776	30619193	We initiated our studies using CH12F3-2 cells, a unique mouse lymphoma system that undergoes class-switching from IgM to IgA in the presence of alphaCD40, IL-4, and TGFbeta (CIT).	('alphaCD40', 'Var', (144, 153))	('mouse', 'Species', '10090', (56, 61))	('lymphoma', 'Disease', (62, 70))	('CH12F3-2', 'CellLine', 'CVCL:E067', (31, 39))	('lymphoma', 'Disease', 'MESH:D008223', (62, 70))	('lymphoma', 'Phenotype', 'HP:0002665', (62, 70))
441779	30619193	In this system, iSLK.219 cells are infected with a recombinant KSHV construct, rKSHV.219, which expresses GFP under the elongation factor-1 (EF-1) promoter upon latency establishment, and expresses RFP under the polyadenylated nuclear (PAN) promoter when the virus is reactivated with doxycycline.	('doxycycline', 'Chemical', 'MESH:D004318', (285, 296))	('KSHV', 'Species', '37296', (63, 67))	('GFP', 'Var', (106, 109))	('RFP', 'Gene', '2358', (198, 201))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('KS', 'Phenotype', 'HP:0100726', (80, 82))	('KSHV', 'Species', '37296', (80, 84))	('RFP', 'Gene', (198, 201))
441780	30619193	Hence, to establish infection efficiency of CH12F3-2 cells by KSHV, iSLK (KSHV-negative) or iSLK.219 (KSHV-positive) cells were reactivated for 24 h with doxycycline before the addition of CH12F3-2 cells.	('KSHV', 'Species', '37296', (74, 78))	('KS', 'Phenotype', 'HP:0100726', (102, 104))	('CH12F3-2', 'CellLine', 'CVCL:E067', (44, 52))	('infection efficiency', 'Disease', (20, 40))	('KSHV', 'Species', '37296', (62, 66))	('infection efficiency', 'Disease', 'MESH:D007239', (20, 40))	('iSLK.219', 'Var', (92, 100))	('KS', 'Phenotype', 'HP:0100726', (62, 64))	('doxycycline', 'Chemical', 'MESH:D004318', (154, 165))	('KSHV', 'Species', '37296', (102, 106))	('CH12F3-2', 'CellLine', 'CVCL:E067', (189, 197))	('KS', 'Phenotype', 'HP:0100726', (74, 76))
441802	30619193	LPS/IL-4-activated splenic B cells cultured with KSHV exhibited a ~70% increase in class-switching to IgG1 compared to B cells cultured without virus or with UV-KSHV (Figure 2B), indicating that replication-competent virus, not antigen exposure, enhanced CSR.	('KSHV', 'Species', '37296', (161, 165))	('enhanced', 'PosReg', (246, 254))	('IgG1', 'Gene', '105243590', (102, 106))	('KSHV', 'Species', '37296', (49, 53))	('KSHV', 'Var', (49, 53))	('KS', 'Phenotype', 'HP:0100726', (161, 163))	('LPS', 'Gene', (0, 3))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('class-switching', 'MPA', (83, 98))	('LPS', 'Gene', '3664', (0, 3))	('increase', 'PosReg', (71, 79))	('CSR', 'Disease', (255, 258))	('IgG1', 'Gene', (102, 106))
441810	30619193	These data indicate that KSHV enhances the efficiency of CSR to some isotypes in the presence of certain cytokines, and that viral infection mediates this effect.	('KSHV', 'Species', '37296', (25, 29))	('KSHV', 'Var', (25, 29))	('KS', 'Phenotype', 'HP:0100726', (25, 27))	('viral infection', 'Disease', 'MESH:D001102', (125, 140))	('cytokines', 'MPA', (105, 114))	('efficiency', 'MPA', (43, 53))	('enhances', 'PosReg', (30, 38))	('CSR', 'CPA', (57, 60))	('viral infection', 'Disease', (125, 140))
441812	30619193	To further determine the mechanism whereby KSHV enhanced CSR efficiency in B cells, we evaluated AID and germline transcript mRNA levels (Figures 2D,E), and cell proliferation (via CFSE staining, Figure 2F).	('rat', 'Species', '10116', (169, 172))	('cell proliferation', 'CPA', (157, 175))	('enhanced', 'PosReg', (48, 56))	('CSR efficiency', 'CPA', (57, 71))	('AID', 'MPA', (97, 100))	('KS', 'Phenotype', 'HP:0100726', (43, 45))	('KSHV', 'Species', '37296', (43, 47))	('KSHV', 'Var', (43, 47))
441834	30619193	While IL-4-stimulated B cells transduced with vIL-6 resulted in a 47% increase in class-switching to IgG1 (Figure 3C), cells treated with mIL-6 showed no difference to control cells (Figure 3D).	('increase', 'PosReg', (70, 78))	('class-switching', 'MPA', (82, 97))	('transduced', 'Var', (30, 40))	('vIL-6', 'Gene', (46, 51))	('IgG1', 'Gene', (101, 105))	('mIL-6', 'Gene', '16193', (138, 143))	('IgG1', 'Gene', '105243590', (101, 105))	('mIL-6', 'Gene', (138, 143))	('vIL-6', 'Gene', '4961449', (46, 51))
441839	30619193	Although the increase in the level of IgA-switching observed in CH12F3-2 B cells transduced with vIL-6 was lower than that of IgG1 observed with mouse splenic B cells (Figures 3C,D), vIL-6 expression showed a trend to augment switching to IgA (~10%), which was not observed with vFLIP or vGPCR (Figure 4A).	('switching', 'MPA', (226, 235))	('lower', 'NegReg', (107, 112))	('vFLIP', 'Chemical', '-', (279, 284))	('vIL-6', 'Gene', (183, 188))	('IgA-switching', 'MPA', (38, 51))	('increase', 'PosReg', (13, 21))	('expression', 'Var', (189, 199))	('increase in the level of IgA', 'Phenotype', 'HP:0003261', (13, 41))	('vIL-6', 'Gene', '4961449', (97, 102))	('CH12F3-2 B', 'CellLine', 'CVCL:E067', (64, 74))	('IgA', 'MPA', (239, 242))	('vIL-6', 'Gene', '4961449', (183, 188))	('vGPCR', 'Gene', (288, 293))	('IgG1', 'Gene', (126, 130))	('vGPCR', 'Gene', '4961465', (288, 293))	('mouse', 'Species', '10090', (145, 150))	('IgG1', 'Gene', '105243590', (126, 130))	('vIL-6', 'Gene', (97, 102))	('augment', 'PosReg', (218, 225))
441840	30619193	Accordingly, CH12F3-2 cells were transduced with empty vector or vIL-6 and stimulated or not with cytokines (CIT) for 24 h to evaluate the consequence of vIL-6 expression on AID levels.	('vIL-6', 'Gene', '4961449', (154, 159))	('vIL-6', 'Gene', (65, 70))	('CH12F3-2', 'CellLine', 'CVCL:E067', (13, 21))	('vIL-6', 'Gene', '4961449', (65, 70))	('transduced', 'Var', (33, 43))	('vIL-6', 'Gene', (154, 159))
441850	30619193	The current study shows that KSHV impacts Ig diversification by enhancing CSR.	('enhancing', 'PosReg', (64, 73))	('CSR', 'CPA', (74, 77))	('KSHV', 'Species', '37296', (29, 33))	('Ig diversification', 'CPA', (42, 60))	('KS', 'Phenotype', 'HP:0100726', (29, 31))	('KSHV', 'Var', (29, 33))
441857	30619193	Yet, we found that transduction of vFLIP or vGPCR did not enhance CSR levels (Figure 4A) in the conditions of our murine assays.	('enhance', 'PosReg', (58, 65))	('murine', 'Species', '10090', (114, 120))	('vGPCR', 'Gene', '4961465', (44, 49))	('vFLIP', 'Chemical', '-', (35, 40))	('CSR levels', 'MPA', (66, 76))	('vFLIP', 'Gene', (35, 40))	('vGPCR', 'Gene', (44, 49))	('transduction', 'Var', (19, 31))
441866	30619193	However, we found that the extent of class-switching that occurred in B cells stimulated for CSR was always greater than the percentage of cells expressing GFP or RFP (Figures 1A, 2A), implying that the increased class-switching levels were due to direct and paracrine effects.	('RFP', 'Gene', (163, 166))	('CSR', 'Var', (93, 96))	('RFP', 'Gene', '2358', (163, 166))	('class-switching', 'MPA', (37, 52))
441871	30619193	We are cognizant that lentiviral transduction of vIL-6 may produce levels of this viral cytokine that are much greater than those in KSHV-infected cells.	('levels of', 'MPA', (67, 76))	('vIL-6', 'Gene', (49, 54))	('lentiviral transduction', 'Var', (22, 45))	('KSHV-infected', 'Disease', (133, 146))	('KSHV-infected', 'Disease', 'MESH:C537372', (133, 146))	('viral cytokine', 'MPA', (82, 96))	('vIL-6', 'Gene', '4961449', (49, 54))	('greater', 'PosReg', (111, 118))	('KS', 'Phenotype', 'HP:0100726', (133, 135))
441879	30619193	We observed that murine splenocytes exposed to KSHV only augmented class-switching efficiency to IgG1 when stimulated with IL-4 (Figure 2A), an immunomodulatory cytokine secreted by Th2 and mast cells.	('IgG1', 'Gene', (97, 101))	('murine', 'Species', '10090', (17, 23))	('IgG1', 'Gene', '105243590', (97, 101))	('class-switching efficiency', 'MPA', (67, 93))	('KSHV', 'Species', '37296', (47, 51))	('augmented', 'PosReg', (57, 66))	('KSHV', 'Var', (47, 51))	('KS', 'Phenotype', 'HP:0100726', (47, 49))
441883	30619193	KSHV is also hypothesized to favor a Th2-mediated response due to inflammation generated from hyperactivation of the humoral immune system, which is paralleled with a diminished Th1-mediated antiviral response.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('rat', 'Species', '10116', (83, 86))	('inflammation', 'Disease', (66, 78))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('favor', 'PosReg', (29, 34))	('Th2-mediated response', 'MPA', (37, 58))	('inflammation', 'Disease', 'MESH:D007249', (66, 78))
441893	30619193	These data points to/suggest a role for isotype-switching in settings of co-infection, but its contribution to the development of KSHV-related lymphoproliferative diseases needs to be further investigated.	('lymphoproliferative diseases', 'Disease', 'MESH:D008232', (143, 171))	('isotype-switching', 'Var', (40, 57))	('lymphoproliferative diseases', 'Phenotype', 'HP:0005523', (143, 171))	('KS', 'Phenotype', 'HP:0100726', (130, 132))	('KSHV', 'Species', '37296', (130, 134))	('lymphoproliferative diseases', 'Disease', (143, 171))
441898	30619193	Although we did not examine the effector function of the KSHV-exposed class-switched B cells, our study similarly shows that KSHV could augment switching to IgG1 and IgA.	('IgG1', 'Gene', (157, 161))	('switching', 'MPA', (144, 153))	('IgG1', 'Gene', '105243590', (157, 161))	('KS', 'Phenotype', 'HP:0100726', (125, 127))	('KSHV', 'Species', '37296', (125, 129))	('KSHV', 'Var', (125, 129))	('KS', 'Phenotype', 'HP:0100726', (57, 59))	('KSHV', 'Species', '37296', (57, 61))	('IgA', 'Gene', (166, 169))	('augment', 'PosReg', (136, 143))
441942	23473686	Modeling the potential benefit of protons versus photons for a mixture of pediatric brain tumours suggested a lesser decline in intelligence quotient (IQ) scores during the first 5 years after treatment with IMPT compared to IMRT due to a reduction in the volume of supratentorial brain exposed to the lowest doses.	('pediatric brain tumours', 'Disease', 'MESH:D001932', (74, 97))	('reduction', 'NegReg', (239, 248))	('decline', 'NegReg', (117, 124))	('brain tumours', 'Phenotype', 'HP:0030692', (84, 97))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('intelligence quotient', 'Phenotype', 'HP:0001249', (128, 149))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('pediatric brain tumours', 'Disease', (74, 97))	('IMPT', 'Var', (208, 212))
441945	23473686	Considering a 5-year-old male with a CSF shunt, the estimated math scores fall to 88 (IMRT) vs. 97 (3DPT) vs. 98 (IMPT) and those treated with photons begin to approach the abnormal range Figure 2).	('shunt', 'Var', (41, 46))	('fall', 'Phenotype', 'HP:0002527', (74, 78))	('CSF', 'Gene', (37, 40))	('CSF shunt', 'Phenotype', 'HP:0001693', (37, 46))	('CSF', 'Gene', '1437', (37, 40))	('fall', 'NegReg', (74, 78))	('math scores', 'CPA', (62, 73))
441964	23473686	A comprehensive analysis that included 10 patients (mean age, 8 years) planned for proton therapy using craniospinal irradiation doses of 23.4 Gy and 36 Gy estimated that the secondary cancer risks were highest for patients treated using photon arc-rotation or 3DCRT plans versus IMPT plans, even when secondary neutron weighting factors were applied.	('patients', 'Species', '9606', (215, 223))	('arc-rotation', 'Disease', 'MESH:D009069', (245, 257))	('arc-rotation', 'Disease', (245, 257))	('3DCRT plans', 'Var', (261, 272))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('patients', 'Species', '9606', (42, 50))	('cancer', 'Disease', (185, 191))
442034	23473686	In conclusion, protons offer the possibility of significant reduction of normal tissue doses concurrently with tumour control results similar to those obtained with photon RT.	('normal tissue doses', 'MPA', (73, 92))	('protons', 'Var', (15, 22))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('reduction', 'NegReg', (60, 69))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))
442037	23473686	3DPT also reduced the predicted risk of secondary cancer by 30% and IMPT by 50% compared to IMRT.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('reduced', 'NegReg', (10, 17))	('3DPT', 'Var', (0, 4))	('IMPT', 'Disease', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
442069	30819134	Gene fusions are an important category of driver mutations in paediatric sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('Gene fusions', 'Var', (0, 12))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('sarcomas', 'Disease', (73, 81))
442102	30819134	Furthermore, in the context of our patients, there is a role to explore if having 2 aberrant gene fusion variants implies increased oncogenicity in these rare tumours.	('tumours', 'Disease', (159, 166))	('oncogenicity', 'CPA', (132, 144))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('variants', 'Var', (105, 113))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('patients', 'Species', '9606', (35, 43))	('tumours', 'Disease', 'MESH:D009369', (159, 166))
442109	30819134	However, most are in agreement that detection of translocations at the exon level will have implications for diagnosis, prognosis and treatment of EWS patients.	('translocations', 'Var', (49, 63))	('patients', 'Species', '9606', (151, 159))	('implications', 'Reg', (92, 104))	('EWS', 'Phenotype', 'HP:0012254', (147, 150))	('EWS', 'Gene', '2130', (147, 150))	('EWS', 'Gene', (147, 150))
442113	30819134	Under such circumstances, obscure translocations that lead EWSR1 insertion into partner genes may be more readily detectable.	('EWSR1', 'Gene', (59, 64))	('EWSR1', 'Gene', '2130', (59, 64))	('insertion', 'Var', (65, 74))	('EWS', 'Phenotype', 'HP:0012254', (59, 62))
442115	30819134	In general, paediatric cancers appear to be the consequence of chromosomal rearrangements, rather than mutation events.	('chromosomal rearrangements', 'Var', (63, 89))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
442118	30819134	Identification of specific fusion transcripts, including unusual variants of gene-related splices may help in the development of novel therapeutics to block their aberrant activity in cancer cells.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('variants', 'Var', (65, 73))
442123	30819134	The identification of gene fusions may offer insights into the biology of these exceptionally rare neoplasms; and more importantly, bear clinical relevance for future targeted therapy.	('neoplasm', 'Phenotype', 'HP:0002664', (99, 107))	('neoplasms', 'Phenotype', 'HP:0002664', (99, 108))	('insights', 'Reg', (45, 53))	('neoplasms', 'Disease', 'MESH:D009369', (99, 108))	('neoplasms', 'Disease', (99, 108))	('gene fusions', 'Var', (22, 34))
442133	29759550	This review explores the brief history of sarcoma research and what sarcomas can still teach us about the future of cancer research, especially in regard to novel immunotherapy targets, the role of epigenetics in disease progression and chemoresistance, and the benefits of more focused clinical trials.	('sarcoma', 'Disease', (42, 49))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcomas', 'Disease', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('sarcoma', 'Disease', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('epigenetics', 'Var', (198, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
442161	29759550	Despite the recent advancements of immune checkpoint inhibitors as evidenced by the 3 recently approved PD-L1 inhibitors and 2 PD-1 inhibitors in the past year (Table 1), the first attempts to harness the body's immune system to fight cancer was conducted in the 1890s.	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('PD-L1', 'Gene', '29126', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('inhibitors', 'Var', (110, 120))	('PD-L1', 'Gene', (104, 109))
442174	29759550	The impact of this and subsequent papers published by Bishop and Varmus was to show that the root of many cancers lay in the mutation of genes already found within a healthy cell.	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('mutation', 'Var', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
442176	29759550	With the idea that genetic mutations cause cancer, the most important cancer gene discovery was made while studying sarcoma.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (43, 49))	('genetic mutations', 'Var', (19, 36))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('sarcoma', 'Disease', (116, 123))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cause', 'Reg', (37, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
442180	29759550	In a research study published in 1990, the doctors examined DNA samples from five Li-Fraumeni syndrome carrying families, ultimately finding an autosomal dominant inheritance of the mutated TP53 gene, which is translated into the p53 tumor suppressor protein.	('mutated', 'Var', (182, 189))	('Li-Fraumeni syndrome', 'Disease', (82, 102))	('tumor', 'Disease', (234, 239))	('p53', 'Gene', '7157', (230, 233))	('TP53', 'Gene', '7157', (190, 194))	('TP53', 'Gene', (190, 194))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (82, 102))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('p53', 'Gene', (230, 233))
442185	29759550	chromosomal translocations or point mutations), and 2) sarcomas with unknown gene mutations.	('point mutations', 'Var', (30, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcomas', 'Disease', (55, 63))	('chromosomal translocations', 'Var', (0, 26))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))
442186	29759550	Soft-tissue sarcomas with identifiable gene mutations can be subtyped even further to the specific translocation or point mutation that provides useful diagnostic and prognostic information.	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('Soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (0, 20))	('sarcomas', 'Disease', (12, 20))	('point mutation', 'Var', (116, 130))
442194	29759550	Due to the genetic simplicity of several sarcomas driven by balanced chromosomal translocations, the noise of chromosomal instability and multiplied passenger mutations is reduced and epigenetic control in cancer can be brought into focus.	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('sarcomas', 'Disease', (41, 49))	('chromosomal instability', 'Phenotype', 'HP:0040012', (110, 133))	('balanced chromosomal translocations', 'Var', (60, 95))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('driven by', 'Reg', (50, 59))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
442197	29759550	We also predict that sarcomas can be the standard-bearer in understanding mechanisms of drug resistance that revolve around the generation of cancer stem cells through epigenetic means to reverse differentiation.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('epigenetic means', 'Var', (168, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('sarcomas', 'Disease', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('drug resistance', 'Phenotype', 'HP:0020174', (88, 103))	('sarcomas', 'Disease', 'MESH:D012509', (21, 29))	('cancer', 'Disease', (142, 148))
442199	29759550	The high mutational burden common in certain cancers can muddy the interpretation of individual events as either drivers of or passengers to oncogenesis.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutational', 'Var', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Disease', (45, 52))
442201	29759550	Many sarcomas driven by a balanced chromosomal translocation arise in pediatric patients with few somatic passenger mutations that have accumulated randomly over time.	('patients', 'Species', '9606', (80, 88))	('driven by', 'Reg', (14, 23))	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('balanced chromosomal translocation', 'Var', (26, 60))	('sarcomas', 'Disease', (5, 13))
442210	29759550	These studies have demonstrated how crucial epigenetic integrity is at enhancer regions and may point to universal epigenetic means of reversing the state of differentiation, which is often associated with malignant disease.	('epigenetic', 'Var', (44, 54))	('epigenetic', 'Var', (115, 125))	('malignant disease', 'Disease', (206, 223))	('malignant disease', 'Disease', 'MESH:D009369', (206, 223))
442232	29759550	In researching these interactions, we can understand the biology of how MDSCs are promoting metastasis outside the realm of immune system suppression, which could open other avenues of immunotherapy that could impact many other cancers outside sarcoma.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('cancers', 'Disease', (228, 235))	('sarcoma', 'Disease', (244, 251))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('metastasis', 'CPA', (92, 102))	('MDSCs', 'Var', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('promoting', 'PosReg', (82, 91))	('impact', 'Reg', (210, 216))	('sarcoma', 'Disease', 'MESH:D012509', (244, 251))	('immune system suppression', 'Phenotype', 'HP:0002721', (124, 149))
442239	29759550	Models of synovial sarcoma and alveolar soft part sarcoma are a few examples where the introduction of a single human transgene faithfully generates the sarcoma in mice and the partial responses to chemotherapy and resistance are similar to what is observed in clinical practice.	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (31, 57))	('synovial sarcoma', 'Disease', (10, 26))	('human', 'Species', '9606', (112, 117))	('alveolar soft part sarcoma', 'Disease', (31, 57))	('synovial sarcoma', 'Disease', 'MESH:D013584', (10, 26))	('mice', 'Species', '10090', (164, 168))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (10, 26))	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('introduction', 'Var', (87, 99))	('sarcoma', 'Disease', (153, 160))	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('sarcoma', 'Disease', (19, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (40, 57))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (31, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))
442241	29759550	The accrual of these resistant cells within a population of tumor cells is likely due to the epigenetic reversal of the state of differentiation.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('epigenetic', 'Var', (93, 103))
442242	29759550	Thus having genetically simple sarcomas to understand the mechanisms of resistance is beneficial not only from the perspective of identifying accompanying driver gene mutations, but the epigenetic means to switch a cell's fate from differentiated to more pluripotent.	('epigenetic', 'Var', (186, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('sarcomas', 'Disease', (31, 39))	('mutations', 'Var', (167, 176))	('switch', 'Reg', (206, 212))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
442246	29759550	This allows rare sarcomas with a shared mutation to be included with lung, breast, and other more common cancers.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('mutation', 'Var', (40, 48))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('lung', 'Disease', (69, 73))	('sarcomas', 'Disease', (17, 25))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('breast', 'Disease', (75, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
442250	29759550	Gastrointestinal stromal tumors (GIST) with KIT mutations are a prime example of a soft-tissue sarcoma that benefited from a more focused patient enrollment in the clinical trial that tested Imatinib (Gleevec).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (83, 102))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('KIT', 'Gene', (44, 47))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('sarcoma', 'Disease', (95, 102))	('patient', 'Species', '9606', (138, 145))	('Imatinib', 'Chemical', 'MESH:D000068877', (191, 199))	('Gastrointestinal stromal tumors', 'Disease', (0, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('mutations', 'Var', (48, 57))
442264	29034313	M002 resulted in a significant intratumoral increase in effector CD4+ and CD8+ T cells and activated monocytes, and a decrease in myeloid-derived suppressor cells (MDSCs) in immunocompetent mice.	('CD8', 'Gene', '925', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('increase', 'PosReg', (44, 52))	('myeloid-derived suppressor cells', 'CPA', (130, 162))	('M002', 'Var', (0, 4))	('decrease', 'NegReg', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mice', 'Species', '10090', (190, 194))	('tumor', 'Disease', (36, 41))	('CD8', 'Gene', (74, 77))
442265	29034313	Compared to parent virus R3659 (no IL-12 production), M002 resulted in higher CD8:MDSC and CD8:T regulatory cell (Treg) ratios, suggesting that M002 creates a more favorable immune tumor microenvironment.	('higher', 'PosReg', (71, 77))	('CD8', 'Gene', (91, 94))	('CD8', 'Gene', (78, 81))	('CD8', 'Gene', '925', (91, 94))	('tumor', 'Disease', (181, 186))	('CD8', 'Gene', '925', (78, 81))	('M002', 'Var', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('M002', 'Var', (54, 58))
442275	29034313	Herpes simplex virus 1 (HSV-1) has been successfully engineered for oncolytic HSV (oHSV) therapy by introducing mutations in both copies of the gamma134.5 gene in order to prevent a productive infection in normal cells while maintaining the virus's oncolytic activity against cancer cells.	('productive infection', 'MPA', (182, 202))	('oncolytic activity', 'MPA', (249, 267))	('cancer', 'Disease', (276, 282))	('gamma134.5', 'Gene', (144, 154))	('gamma134', 'Chemical', '-', (144, 152))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('introducing', 'Reg', (100, 111))	('Herpes simplex', 'Phenotype', 'HP:0012302', (0, 14))	('prevent', 'NegReg', (172, 179))	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('oHSV', 'Chemical', '-', (83, 87))	('Herpes simplex virus 1', 'Species', '10298', (0, 22))	('HSV-1', 'Species', '10298', (24, 29))
442276	29034313	In addition to killing cancer cells directly, the virus is immunogenic; as the virus lyses tumor cells and creates inflammation, newly exposed cancer antigens may be cross-presented, triggering both an innate and an adaptive anti-tumor immune response.	('tumor', 'Disease', (230, 235))	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('inflammation', 'Disease', (115, 127))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Disease', (143, 149))	('virus', 'Var', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', (91, 96))	('triggering', 'Reg', (183, 193))
442279	29034313	In mice bearing intracranial gliomas, treatment with M002 significantly improved survival compared to treatment with the parent HSV R3659, which lacks IL-12.	('survival', 'CPA', (81, 89))	('M002', 'Var', (53, 57))	('intracranial gliomas', 'Disease', (16, 36))	('mice', 'Species', '10090', (3, 7))	('improved', 'PosReg', (72, 80))	('gliomas', 'Phenotype', 'HP:0009733', (29, 36))	('intracranial gliomas', 'Disease', 'MESH:D005910', (16, 36))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))
442285	29034313	Short tandem repeat analyses performed by the University of Alabama at Birmingham (UAB) Heflin Center for Genomic Science repeatedly on the tumors revealed the absence of human DNA.	('absence', 'NegReg', (160, 167))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Short tandem repeat', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('human', 'Species', '9606', (171, 176))
442299	29034313	M002 replicated to a titer of 5.7 +- 2.3 x 105 PFU/mL in SARC-28 and 5.7 +- 2.5 x 105 PFU/mL in SARC-45, suggesting M002 readily infects and efficiently replicates in both tumor models (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('replicates', 'CPA', (153, 163))	('M002', 'Var', (116, 120))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
442304	29034313	Similarly, MST was extended in mice bearing intracranial SARC-45 tumors after treatment with M002 (46.7 +- 16.4 versus 11.2 +- 0.5 days; p = 0.002) with three long-term survivors at 120 days compared to zero survivors in the saline-treated group (Figure 4).	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mice', 'Species', '10090', (31, 35))	('M002', 'Var', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
442306	29034313	To determine whether a single dose of M002 could prolong survival in immunocompetent mice and to determine immune effects of M002, we injected mice bearing SARC-28 or SARC-45 intratumorally with either saline, M002, or R3659, the parent virus of M002 without the murine IL-12 gene.	('mice', 'Species', '10090', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('murine', 'Species', '10090', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('M002', 'Var', (38, 42))	('tumor', 'Disease', (180, 185))	('R3659', 'Var', (219, 224))	('mice', 'Species', '10090', (143, 147))	('prolong', 'PosReg', (49, 56))	('survival', 'CPA', (57, 65))
442307	29034313	Tumor growth was inhibited (Figure 5A), and MST was significantly prolonged in mice bearing SARC-28 after treatment with a single 1 x 107 PFU dose of R3659 (20.9 +- 0.8 days) or M002 (20.2 +- 0.8 days) compared to saline alone (16.4 +- 0.6 days) (Figure 5C).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MST', 'CPA', (44, 47))	('R3659', 'Var', (150, 155))	('mice', 'Species', '10090', (79, 83))	('M002', 'Var', (178, 182))	('prolonged', 'PosReg', (66, 75))	('inhibited', 'NegReg', (17, 26))	('Tumor growth', 'CPA', (0, 12))
442308	29034313	Similarly, in mice bearing SARC-45, tumor growth was inhibited (Figure 5B) and MST was significantly prolonged after treatment with a single 1 x 107 PFU dose of M002 (25.7 +- 4.9 days) or R3659 (23.3 +- 3.9 days) compared to saline alone (18.3 +- 1.9 days) (Figure 5D).	('inhibited', 'NegReg', (53, 62))	('M002', 'Var', (161, 165))	('mice', 'Species', '10090', (14, 18))	('R3659', 'Var', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('prolonged', 'PosReg', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('MST', 'CPA', (79, 82))	('tumor', 'Disease', (36, 41))
442310	29034313	To assess the immune response to treatment with M002, we harvested SARC-28 tumors from immunocompetent mice 0, 3, and 10 days after a single intratumoral injection with saline, R3659, or M002 and analyzed them by flow cytometry (Figure 6A).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('R3659', 'Var', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('SARC-28', 'Gene', (67, 74))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('M002', 'Var', (187, 191))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
442311	29034313	Compared to treatment with saline alone, tumors treated with M002 demonstrated a 9-fold and 6-fold increase in the proportion of CD4+ (CD45+CD4+CD3+) and CD8+ (CD45+CD8+CD3+) cells, respectively, on day 3, and a 5-fold and 2-fold increase in CD4+ and CD8+ cells on day 10 (Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('CD8', 'Gene', (154, 157))	('CD45', 'Gene', '19264', (160, 164))	('tumors', 'Disease', (41, 47))	('CD3', 'Gene', (169, 172))	('CD4+', 'CPA', (242, 246))	('CD45', 'Gene', (160, 164))	('CD45', 'Gene', '19264', (135, 139))	('CD8', 'Gene', '925', (251, 254))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('CD8', 'Gene', '925', (165, 168))	('CD3', 'Gene', '12501', (169, 172))	('CD8', 'Gene', '925', (154, 157))	('CD45', 'Gene', (135, 139))	('CD3', 'Gene', (144, 147))	('increase', 'PosReg', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('CD8', 'Gene', (251, 254))	('CD8', 'Gene', (165, 168))	('CD3', 'Gene', '12501', (144, 147))	('CD4+', 'Var', (129, 133))	('increase', 'PosReg', (230, 238))
442313	29034313	Of note, tumors treated with M002 demonstrated an 8-fold and 3-fold increase in activated monocytes on days 3 and 10, respectively, compared to tumors treated with saline.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('activated monocytes', 'CPA', (80, 99))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('increase', 'PosReg', (68, 76))	('tumors', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('M002', 'Var', (29, 33))
442314	29034313	While M002 resulted in a significant decrease in intratumoral myeloid-derived suppressor cells (MDSCs; CD45+CD11b+Gr1+INT) compared to saline, the proportion of T regulatory cells (Tregs; CD45+CD4+CD3+CD25+FoxP3+) was increased (Figure 6D).	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CD25', 'Gene', (201, 205))	('CD25', 'Gene', '16184', (201, 205))	('CD45', 'Gene', '19264', (103, 107))	('decrease', 'NegReg', (37, 45))	('increased', 'PosReg', (218, 227))	('CD45', 'Gene', '19264', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CD45', 'Gene', (103, 107))	('T regulatory cells', 'CPA', (161, 179))	('FoxP3', 'Gene', (206, 211))	('CD11b', 'Gene', '16409', (108, 113))	('M002', 'Var', (6, 10))	('CD45', 'Gene', (188, 192))	('CD3', 'Gene', (197, 200))	('CD11b', 'Gene', (108, 113))	('FoxP3', 'Gene', '20371', (206, 211))	('tumor', 'Disease', (54, 59))	('CD3', 'Gene', '12501', (197, 200))
442316	29034313	Furthermore, the CD8:MDSC and CD8:Treg ratios were 4.9-fold and 1.6-fold higher at day 10 in M002 compared to R3659, suggesting that M002 creates a more favorable immune tumor microenvironment.	('CD8', 'Gene', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('CD8', 'Gene', '925', (30, 33))	('M002', 'Var', (133, 137))	('CD8', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CD8', 'Gene', '925', (17, 20))	('tumor', 'Disease', (170, 175))	('M002', 'Var', (93, 97))	('higher', 'PosReg', (73, 79))
442330	29034313	Trials using oHSV with concurrent radiation (NCT02453191) or pembrolizumab, a programmed cell death protein-1 (PD-1) inhibitor (NCT03069378), are recruiting adults with advanced sarcoma.	('programmed cell death protein-1', 'Gene', '18566', (78, 109))	('PD-1', 'Gene', '18566', (111, 115))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('oHSV', 'Chemical', '-', (13, 17))	('PD-1', 'Gene', (111, 115))	('pembrolizumab', 'Chemical', 'MESH:C582435', (61, 74))	('programmed cell death protein-1', 'Gene', (78, 109))	('NCT02453191', 'Var', (45, 56))	('sarcoma', 'Disease', (178, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
442334	29034313	Our in vivo studies examining the response to a single dose of M002 in immunocompromised mice bearing SARC-28 and SARC-45 in an immunoprivileged location confirmed the significant oncolytic effect of M002 in the absence of an adaptive host immune system.	('mice', 'Species', '10090', (89, 93))	('oncolytic effect', 'CPA', (180, 196))	('M002', 'Var', (200, 204))
442339	29034313	Evaluation of the host immune response to treatment with M002 revealed a marked increase in tumor-infiltrating CD4+ and CD8+ T cells and CD4+ and CD8+ T cells with enhanced effector function, as indicated by intracellular interferon gamma (IFN-gamma) and granzyme B expression compared to saline.	('interferon gamma (IFN-gamma', 'Gene', '15978', (222, 249))	('M002', 'Var', (57, 61))	('CD8', 'Gene', (120, 123))	('increase', 'PosReg', (80, 88))	('enhanced', 'PosReg', (164, 172))	('CD8', 'Gene', '925', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('CD8', 'Gene', (146, 149))	('CD8', 'Gene', '925', (146, 149))	('effector function', 'CPA', (173, 190))
442341	29034313	In particular, compared to R3659 or saline treatment, tumors demonstrated increased activated monocytes after treatment with M002.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('activated monocytes', 'CPA', (84, 103))	('increased', 'PosReg', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('M002', 'Var', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
442342	29034313	Furthermore, the CD8:MDSC and CD8:Treg ratios were significantly higher at day 10 in M002 compared to R3659, suggesting that M002 creates a more favorable immune tumor microenvironment.	('CD8', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('CD8', 'Gene', '925', (30, 33))	('CD8', 'Gene', (17, 20))	('tumor', 'Disease', (162, 167))	('CD8', 'Gene', '925', (17, 20))	('M002', 'Var', (85, 89))	('M002', 'Var', (125, 129))	('higher', 'PosReg', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
442343	29034313	reported similar results in which M002 prolonged survival in intracranial glioma-bearing mice, and immunohistologic examination of tumor sections showed a significant influx of macrophages, CD4+ cells, and CD8+ cells in M002-treated tumors compared to R3659, as would be expected with the IL-12 expression that occurs during M002 replication and not with R3659 replication.	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('M002', 'Var', (34, 38))	('tumor', 'Disease', (131, 136))	('CD8', 'Gene', '925', (206, 209))	('prolonged', 'PosReg', (39, 48))	('influx', 'PosReg', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (233, 238))	('glioma', 'Disease', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('M002', 'Var', (325, 329))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('CD8', 'Gene', (206, 209))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('mice', 'Species', '10090', (89, 93))	('CD4+ cells', 'MPA', (190, 200))
442353	29034313	In our studies, we found a significant increase in intratumoral Tregs after treatment with oHSV.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('oHSV', 'Var', (91, 95))	('tumor', 'Disease', (56, 61))	('increase', 'PosReg', (39, 47))	('oHSV', 'Chemical', '-', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
442359	29034313	Expansion of Tregs is associated with tumor expression of immunosuppressive checkpoint molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4), PD-1/programmed death-ligand 1 (PD-L1), and indolamine 2,3-dioxygenase (IDO).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('CTLA-4', 'Gene', '12477', (139, 145))	('expression', 'MPA', (44, 54))	('PD-1/programmed death-ligand 1', 'Gene', (148, 178))	('PD-L1', 'Gene', '60533', (180, 185))	('PD-1/programmed death-ligand 1', 'Gene', '60533;18566', (148, 178))	('CTLA-4', 'Gene', (139, 145))	('cytotoxic T lymphocyte antigen-4', 'Gene', (105, 137))	('Tregs', 'Gene', (13, 18))	('cytotoxic T lymphocyte antigen-4', 'Gene', '12477', (105, 137))	('indolamine 2,3-dioxygenase', 'Gene', '15930', (192, 218))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('IDO', 'Gene', (220, 223))	('PD-L1', 'Gene', (180, 185))	('IDO', 'Gene', '15930', (220, 223))	('associated', 'Reg', (22, 32))	('Expansion', 'Var', (0, 9))
442365	29034313	R3659 is the parent virus for M002 with deletion of the native thymidine kinase locus and deleted regions of both gamma134.5 loci.	('deletion', 'Var', (40, 48))	('R3659', 'Var', (0, 5))	('gamma134', 'Chemical', '-', (114, 122))
442397	29034313	Once tumors reached a volume of approximately 200 mm3, mice were randomly divided into cohorts of 10 mice each and received one intratumoral injection of either normal saline (n = 10), R3659 (1 x 107 PFU/20 muL; n = 10), or M002 (1 x 107 PFU/20 muL; n = 10).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (55, 59))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Disease', (133, 138))	('1 x 107 PFU/20', 'Var', (192, 206))	('tumor', 'Disease', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
442410	29034313	Samples were then analyzed using the third panel of antibodies, which included surface staining for CD45-allophycocyanin, CD3-PercPcy5.5, CD4-BV510, and CD8-BV605, followed by intracellular staining for markers indicating T cell effector activity, granzyme B-Pacific Blue, and interferon gamma (IFN-gamma)-PE.cy7.	('CD8', 'Gene', (153, 156))	('CD8', 'Gene', '925', (153, 156))	('interferon gamma (IFN-gamma', 'Gene', '15978', (277, 304))	('CD3', 'Gene', (122, 125))	('CD4-BV510', 'Var', (138, 147))	('CD3', 'Gene', '12501', (122, 125))	('CD45', 'Gene', '19264', (100, 104))	('CD45', 'Gene', (100, 104))
442683	30699189	Mechanistically, vIRF1 inhibits p53 function to increase the expression of DNA methyltransferase 1 (DNMT1) and DNA methylation of the promoter of pre-miR-218-1, a precursor of miR-218-5p, and increases the expression of a long non-coding RNA OIP5 antisense RNA 1 (lnc-OIP5-AS1), which acts as a competing endogenous RNA (ceRNA) of miR-218-5p to inhibit its function and reduce its stability.	('vIRF1', 'Gene', (17, 22))	('DNMT1', 'Gene', '1786', (100, 105))	('p53', 'Gene', '7157', (32, 35))	('OIP5', 'Gene', '11339', (242, 246))	('OIP5', 'Gene', (268, 272))	('inhibits', 'NegReg', (23, 31))	('function', 'MPA', (357, 365))	('miR-218-1', 'Gene', '407000', (150, 159))	('reduce', 'NegReg', (370, 376))	('miR-218-5p', 'Var', (331, 341))	('p53', 'Gene', (32, 35))	('DNMT1', 'Gene', (100, 105))	('OIP5', 'Gene', (242, 246))	('increases', 'PosReg', (192, 201))	('expression', 'MPA', (206, 216))	('DNA methyltransferase 1', 'Gene', (75, 98))	('vIRF1', 'Gene', '4961464', (17, 22))	('expression', 'MPA', (61, 71))	('DNA methyltransferase 1', 'Gene', '1786', (75, 98))	('inhibit', 'NegReg', (345, 352))	('OIP5', 'Gene', '11339', (268, 272))	('stability', 'MPA', (381, 390))	('miR-218-1', 'Gene', (150, 159))	('increase', 'PosReg', (48, 56))
442684	30699189	Moreover, lnc-OIP5-AS1 increases DNA methylation of the pre-miR-218-1 promoter.	('DNA methylation', 'MPA', (33, 48))	('miR-218-1', 'Gene', (60, 69))	('miR-218-1', 'Gene', '407000', (60, 69))	('increases', 'PosReg', (23, 32))	('lnc-OIP5-AS1', 'Var', (10, 22))
442685	30699189	Finally, deletion of vIRF1 from the KSHV genome reduces the level of lnc-OIP5-AS1, increases the level of miR-218-5p, and inhibits KSHV-induced invasion.	('increases', 'PosReg', (83, 92))	('vIRF1', 'Gene', (21, 26))	('inhibits', 'NegReg', (122, 130))	('deletion', 'Var', (9, 17))	('KS', 'Phenotype', 'HP:0100726', (131, 133))	('KSHV', 'Species', '37296', (131, 135))	('level of lnc-OIP5-AS1', 'MPA', (60, 81))	('reduces', 'NegReg', (48, 55))	('level of miR-218-5p', 'MPA', (97, 116))	('KSHV', 'Species', '37296', (36, 40))	('KSHV-induced invasion', 'CPA', (131, 152))	('vIRF1', 'Gene', '4961464', (21, 26))	('KS', 'Phenotype', 'HP:0100726', (36, 38))
442691	30699189	We found that the crosstalk between miR-218-5p and lnc-OIP5-AS1 contributed to vIRF1-induced cell motility and proliferation via increasing HMGB2 and CMPK1 expression.	('HMGB2', 'Gene', '3148', (140, 145))	('HMGB2', 'Gene', (140, 145))	('CMPK1', 'Gene', (150, 155))	('increasing', 'PosReg', (129, 139))	('lnc-OIP5-AS1', 'Gene', (51, 63))	('proliferation', 'CPA', (111, 124))	('CMPK1', 'Gene', '51727', (150, 155))	('miR-218-5p', 'Var', (36, 46))	('cell motility', 'CPA', (93, 106))	('vIRF1', 'Gene', '4961464', (79, 84))	('expression', 'MPA', (156, 166))	('vIRF1', 'Gene', (79, 84))
442707	30699189	Based on the size, non-coding RNAs could be vaguely divided into three groups: microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs).	('miR', 'Gene', (90, 93))	('long non-coding RNAs', 'Var', (99, 119))	('miR', 'Gene', '220972', (90, 93))
442714	30699189	We found that vIRF1 promoted cell migration, invasion and proliferation by epigenetically silencing miR-218-5p and activating lncRNA-OIP5-AS1 transcription.	('vIRF1', 'Gene', (14, 19))	('proliferation', 'CPA', (58, 71))	('lncRNA-OIP5-AS1', 'Gene', (126, 141))	('transcription', 'MPA', (142, 155))	('miR-218-5p', 'Gene', (100, 110))	('promoted', 'PosReg', (20, 28))	('cell migration', 'CPA', (29, 43))	('activating', 'PosReg', (115, 125))	('invasion', 'CPA', (45, 53))	('epigenetically silencing', 'Var', (75, 99))	('vIRF1', 'Gene', '4961464', (14, 19))
442715	30699189	Further, we uncovered that the crosstalk between miR-218-5p and lnc-OIP5-AS1 contributed to vIRF1-induced cell motility and proliferation via increasing HMGB2 and CMPK1 expression.	('miR-218-5p', 'Var', (49, 59))	('cell motility', 'CPA', (106, 119))	('vIRF1', 'Gene', '4961464', (92, 97))	('proliferation', 'CPA', (124, 137))	('HMGB2', 'Gene', '3148', (153, 158))	('CMPK1', 'Gene', (163, 168))	('expression', 'MPA', (169, 179))	('vIRF1', 'Gene', (92, 97))	('HMGB2', 'Gene', (153, 158))	('lnc-OIP5-AS1', 'Gene', (64, 76))	('CMPK1', 'Gene', '51727', (163, 168))	('increasing', 'PosReg', (142, 152))
442724	30699189	As a known tumor suppressor, miR-218-5p was significantly down-regulated in vIRF1- transduced cells, and hence was selected for further validation by qRT-PCR.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('vIRF1', 'Gene', '4961464', (76, 81))	('down-regulated', 'NegReg', (58, 72))	('vIRF1', 'Gene', (76, 81))	('miR-218-5p', 'Var', (29, 39))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
442726	30699189	Then, we sought to determine whether the downregulation of miR-218-5p might contribute to vIRF1 promotion of cell motility, and proliferation.	('miR-218-5p', 'Var', (59, 69))	('vIRF1', 'Gene', '4961464', (90, 95))	('cell motility', 'CPA', (109, 122))	('promotion', 'PosReg', (96, 105))	('vIRF1', 'Gene', (90, 95))	('proliferation', 'CPA', (128, 141))	('downregulation', 'NegReg', (41, 55))
442727	30699189	As expected, overexpression of miR-218-5p in vIRF1-transduced HUVECs reversed vIRF1-enhanced cell migration and invasion (S2 Fig, Fig 1J and 1K) as well as cell proliferation (Fig 1L).	('miR-218-5p', 'Var', (31, 41))	('vIRF1', 'Gene', (45, 50))	('invasion', 'CPA', (112, 120))	('vIRF1', 'Gene', '4961464', (78, 83))	('cell migration', 'CPA', (93, 107))	('vIRF1', 'Gene', (78, 83))	('cell proliferation', 'CPA', (156, 174))	('vIRF1', 'Gene', '4961464', (45, 50))
442729	30699189	We confirmed that miR-218-5p decreased the 3'UTR reporter activities of both high mobility group box 2 (HMGB2) and cytidine/uridine monophosphate kinase 1 (CMPK1) (Fig 2A), which was further shown in a dose-dependent fashion (Fig 2B).	('miR-218-5p', 'Var', (18, 28))	("3'UTR reporter activities", 'MPA', (43, 68))	('CMPK1', 'Gene', '51727', (156, 161))	('cytidine/uridine monophosphate kinase 1', 'Gene', (115, 154))	('high mobility group box 2', 'Gene', '3148', (77, 102))	('HMGB2', 'Gene', '3148', (104, 109))	('decreased', 'NegReg', (29, 38))	('HMGB2', 'Gene', (104, 109))	('cytidine/uridine monophosphate kinase 1', 'Gene', '51727', (115, 154))	('high mobility group box 2', 'Gene', (77, 102))	('CMPK1', 'Gene', (156, 161))
442730	30699189	Indeed, overexpression of miR-218-5p suppressed the levels of HMGB2 and CMPK1 proteins in a dose-dependent manner (Fig 2C).	('overexpression', 'PosReg', (8, 22))	('HMGB2', 'Gene', '3148', (62, 67))	('HMGB2', 'Gene', (62, 67))	('CMPK1', 'Gene', (72, 77))	('miR-218-5p', 'Var', (26, 36))	('proteins', 'Protein', (78, 86))	('CMPK1', 'Gene', '51727', (72, 77))	('levels', 'MPA', (52, 58))	('suppressed', 'NegReg', (37, 47))
442732	30699189	To further confirm that miR-218-5p directly targeted HMGB2 and CMPK1, we performed mutagenesis with miR-218-5p (Fig 2E and 2F).	('miR-218-5p', 'Var', (100, 110))	('CMPK1', 'Gene', (63, 68))	('CMPK1', 'Gene', '51727', (63, 68))	('HMGB2', 'Gene', '3148', (53, 58))	('HMGB2', 'Gene', (53, 58))
442733	30699189	The mutant mimic did not have any effect on the 3'UTR reporter activities of HMGB2 and CMPK1 (Fig 2G), and the levels of HMGB2 and CMPK1 proteins (Fig 2H).	('mutant', 'Var', (4, 10))	('HMGB2', 'Gene', '3148', (77, 82))	('CMPK1', 'Gene', (87, 92))	('HMGB2', 'Gene', '3148', (121, 126))	('HMGB2', 'Gene', (121, 126))	("3'UTR reporter activities", 'MPA', (48, 73))	('CMPK1', 'Gene', (131, 136))	('CMPK1', 'Gene', '51727', (87, 92))	('CMPK1', 'Gene', '51727', (131, 136))	('HMGB2', 'Gene', (77, 82))
442738	30699189	Moreover, knock-down of HMGB2 and CMPK1 also inhibited KSHV-induced cell migration and invasion (Fig 4J-4L).	('KSHV', 'Species', '37296', (55, 59))	('HMGB2', 'Gene', '3148', (24, 29))	('HMGB2', 'Gene', (24, 29))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('CMPK1', 'Gene', (34, 39))	('knock-down', 'Var', (10, 20))	('CMPK1', 'Gene', '51727', (34, 39))	('inhibited', 'NegReg', (45, 54))
442742	30699189	These results indicated that vIRF1 might suppress miR-218-5p by reducing the expression of primary form pre-miR-218-1 and its host gene SLIT2 by epigenetically silencing their promoter.	('reducing', 'NegReg', (64, 72))	('expression', 'MPA', (77, 87))	('vIRF1', 'Gene', '4961464', (29, 34))	('SLIT2', 'Gene', '9353', (136, 141))	('promoter', 'MPA', (176, 184))	('epigenetically silencing', 'Var', (145, 169))	('vIRF1', 'Gene', (29, 34))	('suppress', 'NegReg', (41, 49))	('miR-218-1', 'Gene', (108, 117))	('miR-218-1', 'Gene', '407000', (108, 117))	('SLIT2', 'Gene', (136, 141))
442745	30699189	Moreover, treatment with a potent inhibitor of DNA methylation, 5-aza, not only blocked vIRF1 suppression of miR-218-5p (Fig 5G), but also decreased the expression of its targets HMGB2 and CMPK1 (Fig 5H).	('HMGB2', 'Gene', '3148', (179, 184))	('blocked', 'NegReg', (80, 87))	('suppression', 'NegReg', (94, 105))	('HMGB2', 'Gene', (179, 184))	('CMPK1', 'Gene', (189, 194))	('vIRF1', 'Gene', '4961464', (88, 93))	('decreased', 'NegReg', (139, 148))	('vIRF1', 'Gene', (88, 93))	('miR-218-5p', 'Var', (109, 119))	('CMPK1', 'Gene', '51727', (189, 194))	('expression', 'MPA', (153, 163))	('5-aza', 'Chemical', 'MESH:D001374', (64, 69))
442746	30699189	These results revealed that vIRF1 silencing of miR-218-5p expression was due to DNA methylation on its promoter.	('vIRF1', 'Gene', (28, 33))	('expression', 'MPA', (58, 68))	('miR-218-5p', 'Var', (47, 57))	('vIRF1', 'Gene', '4961464', (28, 33))	('silencing', 'NegReg', (34, 43))
442747	30699189	DNA methyltransferase 1 (DNMT1) mediates DNA methylation and has been reported to cause miR-218-5p silencing.	('silencing', 'MPA', (99, 108))	('DNMT1', 'Gene', '1786', (25, 30))	('cause', 'Reg', (82, 87))	('DNA methyltransferase 1', 'Gene', '1786', (0, 23))	('miR-218-5p', 'Var', (88, 98))	('mediates', 'Reg', (32, 40))	('DNMT1', 'Gene', (25, 30))	('DNA methyltransferase 1', 'Gene', (0, 23))
442750	30699189	Knock-down of DNMT1 expression with specific siRNAs (siDNMT1) reduced the hypermethylation of the promoter of pre-miR-218-1 in vIRF1 expressing cells (Fig 6C), and enhanced the expression of SLIT2, pre-miR-218-1 and miR-218-5p (Fig 6D).	('DNMT1', 'Gene', (55, 60))	('hypermethylation of the promoter', 'MPA', (74, 106))	('DNMT1', 'Gene', '1786', (55, 60))	('enhanced', 'PosReg', (164, 172))	('SLIT2', 'Gene', '9353', (191, 196))	('reduced', 'NegReg', (62, 69))	('miR-218-1', 'Gene', (114, 123))	('miR-218-1', 'Gene', '407000', (202, 211))	('miR-218-1', 'Gene', (202, 211))	('SLIT2', 'Gene', (191, 196))	('vIRF1', 'Gene', '4961464', (127, 132))	('miR-218-1', 'Gene', '407000', (114, 123))	('expression', 'MPA', (177, 187))	('DNMT1', 'Gene', (14, 19))	('DNMT1', 'Gene', '1786', (14, 19))	('miR-218-5p', 'Var', (216, 226))	('vIRF1', 'Gene', (127, 132))
442756	30699189	These results indicated that vIRF1-induced miR-218-5p inhibition via aberrant DNA methylation at the pre-miR-218-1 promoter by inhibiting p53 to cause DNMT1 upregulation.	('p53', 'Gene', (138, 141))	('vIRF1', 'Gene', '4961464', (29, 34))	('DNMT1', 'Gene', '1786', (151, 156))	('miR-218-1', 'Gene', '407000', (105, 114))	('miR-218-1', 'Gene', (105, 114))	('p53', 'Gene', '7157', (138, 141))	('aberrant', 'Var', (69, 77))	('inhibiting', 'NegReg', (127, 137))	('inhibition', 'NegReg', (54, 64))	('vIRF1', 'Gene', (29, 34))	('upregulation', 'PosReg', (157, 169))	('miR-218-5p', 'Gene', (43, 53))	('DNA', 'Protein', (78, 81))	('DNMT1', 'Gene', (151, 156))
442761	30699189	Of these, miRNA-218-5p mimics reduced the luciferase activities of lnc-OIP5-AS1 (S3) and lnc-OIP5-AS1 (S4) reporters (Fig 7D) in a dose-dependent fashion (S6 Fig).	('lnc-OIP5-AS1', 'Var', (67, 79))	('-218-5p', 'Chemical', '-', (15, 22))	('luciferase', 'Enzyme', (42, 52))	('miR', 'Gene', '220972', (10, 13))	('activities', 'MPA', (53, 63))	('miR', 'Gene', (10, 13))	('reduced', 'NegReg', (30, 37))	('lnc-OIP5-AS1', 'Var', (89, 101))
442764	30699189	To determine whether lnc-OIP5-AS1 could act as a ceRNA to abrogate the function of miR-218-5p by releasing its binding to the targeted transcripts, we knocked down lnc-OIP5-AS1 with specific Smart Silencer in HUVECs and performed an RNA immunoprecipitation (RIP) assay on Ago2 (S7 Fig).	('function', 'MPA', (71, 79))	('lnc-OIP5-AS1', 'Gene', (164, 176))	('Ago2', 'Gene', (272, 276))	('releasing', 'PosReg', (97, 106))	('binding', 'Interaction', (111, 118))	('knocked', 'Var', (151, 158))	('abrogate', 'NegReg', (58, 66))	('Ago2', 'Gene', '27161', (272, 276))
442765	30699189	We found that silencing of lnc-OIP5-AS1 in HUVECs increased the HMGB2 and CMPK1 transcripts in the Ago2 complex (Fig 7G).	('silencing', 'Var', (14, 23))	('Ago2', 'Gene', (99, 103))	('HMGB2', 'Gene', '3148', (64, 69))	('HMGB2', 'Gene', (64, 69))	('CMPK1', 'Gene', '51727', (74, 79))	('increased', 'PosReg', (50, 59))	('transcripts', 'MPA', (80, 91))	('Ago2', 'Gene', '27161', (99, 103))	('CMPK1', 'Gene', (74, 79))	('lnc-OIP5-AS1', 'Gene', (27, 39))
442766	30699189	Furthermore, overexpression of lnc-OIP5-AS1 (S3) and lnc-OIP5-AS1 (S4) fragments abolished the inhibition of HMGB2 and CMPK1 3'UTR reporter activities by miR-218-5p (Fig 7H).	('HMGB2', 'Gene', (109, 114))	('CMPK1', 'Gene', (119, 124))	('HMGB2', 'Gene', '3148', (109, 114))	('inhibition', 'NegReg', (95, 105))	('CMPK1', 'Gene', '51727', (119, 124))	('miR-218-5p', 'Var', (154, 164))	('abolished', 'NegReg', (81, 90))
442767	30699189	These results demonstrated the sequestration of miR-218-5p by lnc-OIP5-AS1, which relieved the inhibition of the HMGB2/CMPK1 transcripts by miR-218-5p.	('HMGB2', 'Gene', '3148', (113, 118))	('HMGB2', 'Gene', (113, 118))	('CMPK1', 'Gene', (119, 124))	('sequestration', 'MPA', (31, 44))	('transcripts', 'MPA', (125, 136))	('CMPK1', 'Gene', '51727', (119, 124))	('miR-218-5p', 'Var', (140, 150))	('inhibition', 'MPA', (95, 105))	('miR-218-5p', 'Var', (48, 58))
442768	30699189	Intriguingly, overexpression of miR-218-5p significantly reduced the level of vIRF1-induced lnc-OIP5-AS1 (Fig 7I).	('level of', 'MPA', (69, 77))	('vIRF1', 'Gene', '4961464', (78, 83))	('miR-218-5p', 'Var', (32, 42))	('vIRF1', 'Gene', (78, 83))	('reduced', 'NegReg', (57, 64))
442769	30699189	Conversely, inhibition of lnc-OIP5-AS1 reversed vIRF1 inhibition of the expression of both pre-miR-218-1 and miR-218-5p (Fig 7J).	('vIRF1', 'Gene', (48, 53))	('miR-218-1', 'Gene', (95, 104))	('miR-218-1', 'Gene', '407000', (95, 104))	('inhibition', 'NegReg', (54, 64))	('expression', 'MPA', (72, 82))	('miR-218-5p', 'Var', (109, 119))	('vIRF1', 'Gene', '4961464', (48, 53))
442770	30699189	We further performed knock down of Dicer to prevent maturation of miR-218-5p from pre-miR-218-1 and then examined the effect of silencing lnc-OIP5-AS1 on miR-218-5p stability (S8 Fig).	('Dicer', 'Gene', '23405', (35, 40))	('Dicer', 'Gene', (35, 40))	('lnc-OIP5-AS1', 'Gene', (138, 150))	('silencing', 'Var', (128, 137))	('miR-218-1', 'Gene', (86, 95))	('miR-218-1', 'Gene', '407000', (86, 95))	('knock down', 'Var', (21, 31))
442771	30699189	As a result, silencing of lnc-OIP5-AS1 attenuated vIRF1-induced DNMT1, HMGB2 and CMPK1 expression (Fig 7L).	('CMPK1', 'Gene', '51727', (81, 86))	('vIRF1', 'Gene', '4961464', (50, 55))	('attenuated', 'NegReg', (39, 49))	('expression', 'MPA', (87, 97))	('vIRF1', 'Gene', (50, 55))	('DNMT1', 'Gene', (64, 69))	('lnc-OIP5-AS1', 'Gene', (26, 38))	('HMGB2', 'Gene', '3148', (71, 76))	('HMGB2', 'Gene', (71, 76))	('DNMT1', 'Gene', '1786', (64, 69))	('silencing', 'Var', (13, 22))	('CMPK1', 'Gene', (81, 86))
442772	30699189	Consistent with these results, silencing of lnc-OIP5-AS1 inhibited vIRF1-induced cell migration, invasion and proliferation (Fig 7M and 7N).	('silencing', 'Var', (31, 40))	('inhibited', 'NegReg', (57, 66))	('vIRF1', 'Gene', '4961464', (67, 72))	('vIRF1', 'Gene', (67, 72))	('lnc-OIP5-AS1', 'Gene', (44, 56))	('invasion', 'CPA', (97, 105))	('cell migration', 'CPA', (81, 95))
442773	30699189	To further dissect the functions of vIRF1 in the context of KSHV genome, we constructed a KSHV mutant with ORF-K9 deleted using a two-step red recombination system as previously described.	('vIRF1', 'Gene', '4961464', (36, 41))	('KS', 'Phenotype', 'HP:0100726', (90, 92))	('KSHV', 'Species', '37296', (90, 94))	('deleted', 'Var', (114, 121))	('vIRF1', 'Gene', (36, 41))	('mutant', 'Var', (95, 101))	('KSHV', 'Species', '37296', (60, 64))	('ORF-K9', 'Gene', (107, 113))	('KS', 'Phenotype', 'HP:0100726', (60, 62))
442774	30699189	As expected, we did not detect the expression of vIRF1 in iSLK-RGB-K9 mutant cells, while the levels of vIRF4 and ORF57 had minimal changes (S9D Fig).	('not', 'NegReg', (20, 23))	('vIRF1', 'Gene', (49, 54))	('iSLK-RGB-K9', 'Gene', (58, 69))	('mutant', 'Var', (70, 76))	('vIRF4', 'Gene', (104, 109))	('vIRF4', 'Gene', '4961495', (104, 109))	('vIRF1', 'Gene', '4961464', (49, 54))
442775	30699189	Similarly, HUVECs infected by the mutant virus had no vIRF1 expression (S9E Fig) but had minimal changes in the levels of vIRF4 and ORF57 (S9F Fig).	('expression', 'MPA', (60, 70))	('vIRF4', 'Gene', '4961495', (122, 127))	('vIRF1', 'Gene', '4961464', (54, 59))	('vIRF1', 'Gene', (54, 59))	('vIRF4', 'Gene', (122, 127))	('mutant', 'Var', (34, 40))
442777	30699189	Because HUVECs transduced with lentiviral vIRF1 at a MOI of 2 showed a vIRF1 mRNA expression level similar to that of wild type KSHV-infected HUVECs (S1 Fig), we transduced vIRF1_mutant cells with 2 MOI of lentiviral vIRF1.	('vIRF1', 'Gene', (217, 222))	('lentiviral', 'Var', (31, 41))	('vIRF1', 'Gene', (42, 47))	('vIRF1', 'Gene', '4961464', (173, 178))	('vIRF1', 'Gene', '4961464', (71, 76))	('vIRF1', 'Gene', (173, 178))	('KSHV-infected HUVECs', 'Disease', (128, 148))	('KS', 'Phenotype', 'HP:0100726', (128, 130))	('vIRF1', 'Gene', '4961464', (42, 47))	('vIRF1', 'Gene', (71, 76))	('vIRF1', 'Gene', '4961464', (217, 222))	('KSHV-infected HUVECs', 'Disease', 'MESH:C537372', (128, 148))
442778	30699189	We found that loss of vIRF1 not only reduced cell migration and invasion (Fig 8A) but also decreased the level of hypermethylation in the pre-miR-218-1 promoter (Fig 8B).	('loss', 'Var', (14, 18))	('invasion', 'CPA', (64, 72))	('cell migration', 'CPA', (45, 59))	('vIRF1', 'Gene', '4961464', (22, 27))	('vIRF1', 'Gene', (22, 27))	('miR-218-1', 'Gene', '407000', (142, 151))	('level of hypermethylation', 'MPA', (105, 130))	('reduced', 'NegReg', (37, 44))	('miR-218-1', 'Gene', (142, 151))	('decreased', 'NegReg', (91, 100))
442779	30699189	Importantly, complementation with vIRF1 in vIRF1_mut-infected HUVECs was sufficient to rescue cell migration and invasion induced by KSHV (Fig 8A), and reverse the level of hypermethylation in the pre-miR-218-1 promoter induced by KSHV (Fig 8B).	('hypermethylation', 'MPA', (173, 189))	('vIRF1', 'Gene', (34, 39))	('invasion', 'CPA', (113, 121))	('KSHV', 'Gene', (133, 137))	('complementation', 'Var', (13, 28))	('rescue', 'PosReg', (87, 93))	('vIRF1', 'Gene', '4961464', (43, 48))	('cell migration', 'CPA', (94, 108))	('KSHV', 'Species', '37296', (231, 235))	('miR-218-1', 'Gene', '407000', (201, 210))	('vIRF1', 'Gene', '4961464', (34, 39))	('KS', 'Phenotype', 'HP:0100726', (231, 233))	('vIRF1', 'Gene', (43, 48))	('KSHV', 'Species', '37296', (133, 137))	('miR-218-1', 'Gene', (201, 210))	('KS', 'Phenotype', 'HP:0100726', (133, 135))
442780	30699189	We also observed a significant decrease of lnc-OIP5-AS1 expression, and an increase of miR-218-5p and pre-miR-218-1 expression in the mutant cells compared to both KSHV_wild-type infected cells and vIRF1-transduced mutant cells (Fig 8C).	('miR-218-5p', 'MPA', (87, 97))	('KSHV', 'Species', '37296', (164, 168))	('expression', 'MPA', (116, 126))	('miR-218-1', 'Gene', (106, 115))	('lnc-OIP5-AS1', 'Protein', (43, 55))	('miR-218-1', 'Gene', '407000', (106, 115))	('vIRF1', 'Gene', '4961464', (198, 203))	('decrease', 'NegReg', (31, 39))	('vIRF1', 'Gene', (198, 203))	('expression', 'MPA', (56, 66))	('increase', 'PosReg', (75, 83))	('mutant', 'Var', (134, 140))	('KS', 'Phenotype', 'HP:0100726', (164, 166))
442781	30699189	Furthermore, deletion of vIRF1 reduced the expression of DNMT1, HMGB2 and CMPK1 while complementation with vIRF1 was sufficient to rescue the expression levels of these proteins (Fig 8D).	('reduced', 'NegReg', (31, 38))	('vIRF1', 'Gene', (107, 112))	('HMGB2', 'Gene', (64, 69))	('CMPK1', 'Gene', '51727', (74, 79))	('vIRF1', 'Gene', (25, 30))	('HMGB2', 'Gene', '3148', (64, 69))	('expression levels', 'MPA', (142, 159))	('DNMT1', 'Gene', (57, 62))	('deletion', 'Var', (13, 21))	('DNMT1', 'Gene', '1786', (57, 62))	('expression', 'MPA', (43, 53))	('vIRF1', 'Gene', '4961464', (25, 30))	('CMPK1', 'Gene', (74, 79))	('vIRF1', 'Gene', '4961464', (107, 112))
442782	30699189	Meanwhile, inhibition of miR-218-5p with a specific inhibitor in both mutant cells and vIRF1-transduced mutant cells increased cell migration and invasion (Fig 8E).	('cell migration', 'CPA', (127, 141))	('miR-218-5p', 'Protein', (25, 35))	('vIRF1', 'Gene', (87, 92))	('increased', 'PosReg', (117, 126))	('mutant', 'Var', (70, 76))	('mutant', 'Var', (104, 110))	('inhibition', 'NegReg', (11, 21))	('vIRF1', 'Gene', '4961464', (87, 92))	('invasion', 'CPA', (146, 154))
442783	30699189	Similar increase in cell migration and invasion was also observed in the mutant and vIRF1-transduced mutant cells following overexpression of lnc-OIP5-AS1 (S3) and lnc-OIP5-AS1 (S4) fragments (Fig 8F).	('lnc-OIP5-AS1', 'Var', (142, 154))	('increase', 'PosReg', (8, 16))	('cell migration', 'CPA', (20, 34))	('invasion', 'CPA', (39, 47))	('vIRF1', 'Gene', '4961464', (84, 89))	('vIRF1', 'Gene', (84, 89))	('mutant', 'Var', (73, 79))	('mutant', 'Var', (101, 107))
442790	30699189	Further, deletion of vIRF1 from the KSHV genome reduced KSHV-induced cell migration, invasion and proliferation.	('vIRF1', 'Gene', (21, 26))	('deletion', 'Var', (9, 17))	('KS', 'Phenotype', 'HP:0100726', (56, 58))	('reduced', 'NegReg', (48, 55))	('KSHV', 'Species', '37296', (56, 60))	('KSHV', 'Species', '37296', (36, 40))	('vIRF1', 'Gene', '4961464', (21, 26))	('KS', 'Phenotype', 'HP:0100726', (36, 38))	('proliferation', 'CPA', (98, 111))	('KSHV-induced', 'Gene', (56, 68))
442793	30699189	MiR-218-5p, a vertebrate-specific intronic miRNA co-regulated with its host genes SLIT2/SLIT3, functions as a tumor suppressor by modulating multiple pathways.	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('SLIT2', 'Gene', '9353', (82, 87))	('MiR-218-5p', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('SLIT2', 'Gene', (82, 87))	('SLIT3', 'Gene', '6586', (88, 93))	('SLIT3', 'Gene', (88, 93))	('modulating', 'Reg', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
442801	30699189	With regard to its role in cancer, lnc-OIP5-AS1 exhibits multifaceted and complex features.	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('lnc-OIP5-AS1', 'Var', (35, 47))	('cancer', 'Disease', (27, 33))
442802	30699189	For example, lnc-OIP5-AS1 is shown to be a tumor suppressor and inhibit HeLa cells proliferation by interacting with the RBP HuR to reduce HuR's availability for binding target mRNAs, or associating with GAK mRNA to impair GAK mRNA stability.	('HeLa cells proliferation', 'CPA', (72, 96))	('GAK', 'Gene', (223, 226))	('HuR', 'Gene', '1994', (125, 128))	('inhibit', 'NegReg', (64, 71))	('HuR', 'Gene', (139, 142))	('tumor', 'Disease', (43, 48))	('GAK', 'Gene', '2580', (223, 226))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('GAK', 'Gene', (204, 207))	('lnc-OIP5-AS1', 'Var', (13, 25))	('HuR', 'Gene', '1994', (139, 142))	('binding', 'Interaction', (162, 169))	('reduce', 'NegReg', (132, 138))	('HeLa', 'CellLine', 'CVCL:0030', (72, 76))	('GAK', 'Gene', '2580', (204, 207))	('availability for', 'MPA', (145, 161))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('interacting', 'Interaction', (100, 111))	('impair', 'NegReg', (216, 222))	('HuR', 'Gene', (125, 128))
442803	30699189	On the contrary, lnc-OIP5-AS1 can exert oncogenic functions in several other cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('oncogenic functions', 'CPA', (40, 59))	('lnc-OIP5-AS1', 'Var', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
442805	30699189	Silencing of lnc-OIP5-AS1 repressed YAP-Notch signaling pathway activity leading to decrease of glioma cells' proliferation, migration in vitro and tumor formation in vivo.	('decrease', 'NegReg', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('migration', 'CPA', (125, 134))	('YAP', 'Gene', '10413', (36, 39))	('tumor', 'Disease', (148, 153))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('YAP', 'Gene', (36, 39))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('activity', 'MPA', (64, 72))	('Silencing', 'Var', (0, 9))	('lnc-OIP5-AS1', 'Gene', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('glioma', 'Disease', (96, 102))
442806	30699189	Moreover, lnc-OIP5-AS1 was highly expressed in lung adenocarcinoma tissues and cells, and the loss of lnc-OIP5-AS1 inhibited lung adenocarcinoma cell proliferation, migration and invasion.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('lung adenocarcinoma tissues', 'Disease', 'MESH:D000077192', (47, 74))	('lung adenocarcinoma', 'Disease', (125, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('lung adenocarcinoma tissues', 'Disease', (47, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('loss', 'Var', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('invasion', 'CPA', (179, 187))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('inhibited', 'NegReg', (115, 124))	('lnc-OIP5-AS1', 'Gene', (102, 114))
442811	30699189	On the other hand, miR-218-5p has been reported to interact with lnc-MALAT1, participating in choriocarcinoma growth.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('interact', 'Interaction', (51, 59))	('MALAT1', 'Gene', '378938', (69, 75))	('MALAT1', 'Gene', (69, 75))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (94, 109))	('miR-218-5p', 'Var', (19, 29))	('participating in', 'Reg', (77, 93))	('choriocarcinoma growth', 'Disease', (94, 116))	('choriocarcinoma growth', 'Disease', 'MESH:D002822', (94, 116))
442812	30699189	We showed that lnc-OIP5-AS1 functioned as a ceRNA and sequestered miR-218-5p to relieve its binding and targeting of HMGB2 and CMPK1 transcripts.	('binding', 'Interaction', (92, 99))	('lnc-OIP5-AS1', 'Var', (15, 27))	('CMPK1', 'Gene', (127, 132))	('HMGB2', 'Gene', '3148', (117, 122))	('HMGB2', 'Gene', (117, 122))	('targeting', 'MPA', (104, 113))	('CMPK1', 'Gene', '51727', (127, 132))	('relieve', 'NegReg', (80, 87))
442814	30699189	Interestingly, by an unclear mechanism, lnc-OIP5-AS1 also increased DNMT1 expression to promote DNA methylation of the pre-miR-218-1 promoter, leading to decreased level of miR-218-1.	('miR-218-1', 'Gene', (173, 182))	('expression', 'MPA', (74, 84))	('decreased', 'NegReg', (154, 163))	('miR-218-1', 'Gene', '407000', (173, 182))	('increased', 'PosReg', (58, 67))	('promote', 'PosReg', (88, 95))	('lnc-OIP5-AS1', 'Var', (40, 52))	('miR-218-1', 'Gene', (123, 132))	('miR-218-1', 'Gene', '407000', (123, 132))	('DNA methylation', 'MPA', (96, 111))	('DNMT1', 'Gene', (68, 73))	('DNMT1', 'Gene', '1786', (68, 73))
442815	30699189	In conclusion, our study revealed that vIRF1 promoted cell migration, invasion and proliferation by a p53- and lnc-OIP5-AS1-mediated down-regulation of miR-218-5p, leading to increased expression levels of its target genes HMGB2 and CMPK1 (Fig 8G).	('expression levels', 'MPA', (185, 202))	('proliferation', 'CPA', (83, 96))	('HMGB2', 'Gene', '3148', (223, 228))	('vIRF1', 'Gene', '4961464', (39, 44))	('CMPK1', 'Gene', (233, 238))	('p53', 'Gene', '7157', (102, 105))	('miR-218-5p', 'Var', (152, 162))	('HMGB2', 'Gene', (223, 228))	('down-regulation', 'NegReg', (133, 148))	('promoted', 'PosReg', (45, 53))	('CMPK1', 'Gene', '51727', (233, 238))	('vIRF1', 'Gene', (39, 44))	('p53', 'Gene', (102, 105))	('increased', 'PosReg', (175, 184))	('cell migration', 'CPA', (54, 68))	('invasion', 'CPA', (70, 78))
442819	30699189	The established iSLK-RGB-BAC16 and iSLK-RGB-K9 mutant cells were cultivated in DMEM supplemented with 10% fetal bovine serum (FBS), 1 mug/ml puromycin, 250 mug/ml G418, and 1.2 mg/ml hygromycin B. HEK293T and continuous cell lines human umbilical vein endothelial cells (catalog #CRL-1730, ATCC, Manassas, VA, USA) were maintained as previously described.	('HEK293T', 'CellLine', 'CVCL:0063', (197, 204))	('puromycin', 'Chemical', 'MESH:D011691', (141, 150))	('fetal bovine serum (FBS), 1', 'Gene', '26232', (106, 133))	('DMEM', 'Chemical', '-', (79, 83))	('iSLK-RGB-K9', 'Gene', (35, 46))	('human', 'Species', '9606', (231, 236))	('hygromycin B', 'Chemical', 'MESH:D006921', (183, 195))	('G418', 'Chemical', 'MESH:C010680', (163, 167))	('fetal bovine serum (FBS), 1', 'Gene', (106, 133))	('mutant', 'Var', (47, 53))
442822	30699189	The respective sequences of HMGB2 3'UTR, CMPK1 3'UTR and lncRNA-OIP5-AS1 fragments containing putative miR-218-5p binding sites (S1: 365-1167; S2: 3078-3539; S3: 4293-4701 and S4: 7775-8169) were amplified by PCR and inserted into the pGL3-Control plasmid (Promega, Madison, WI, USA), respectively.	('HMGB2', 'Gene', '3148', (28, 33))	('S2: 3078-3539; S3: 4293-4701', 'Var', (143, 171))	('HMGB2', 'Gene', (28, 33))	('pGL3', 'Gene', (235, 239))	('CMPK1', 'Gene', (41, 46))	('CMPK1', 'Gene', '51727', (41, 46))	('pGL3', 'Gene', '6391', (235, 239))	('S4: 7775-8169', 'Var', (176, 189))	('S1', 'Var', (129, 131))
442830	30699189	After incubating for 5 min, the lysates were precleared by centrifugation at 14,000 rpm for 10 minutes, and then were added to streptaviden magnetic beads (Thermo Fisher Scientific, Waltham, America), which were incubated with Biotin-labeled miR-218-5p, miR-218-5p mut 2, or Neg.	('Biotin', 'Chemical', 'MESH:D001710', (227, 233))	('miR-218-5p mut', 'Var', (254, 268))	('miR-218-5p', 'Var', (242, 252))
442836	30699189	RGB-BAC16 and RGB-K9 mutant DNA were transfected into iSLK cells and selected using 1 mug/ml puromycin, 250 mug/ml G418, and 1.2 mg/ml hygromycin B for 3 weeks to establish stable viral producer cell lines, iSLK-RGB-BAC16 and iSLK-RGB-K9 mutant cells.	('puromycin', 'Chemical', 'MESH:D011691', (93, 102))	('mutant', 'Var', (21, 27))	('RGB-K9', 'Gene', (14, 20))	('G418', 'Chemical', 'MESH:C010680', (115, 119))	('hygromycin B', 'Chemical', 'MESH:D006921', (135, 147))	('RGB-BAC16', 'Gene', (0, 9))
442837	30699189	To produce virus stocks for infection, iSLK-RGB-BAC16 and iSLK-RGB-K9 mutant cells were plated at 30 to 40% confluence and induced with both Doxycycline (Dox) (1 mug/ml) and sodium butyrate (NaB) (1 mM).	('Doxycycline', 'Chemical', 'MESH:D004318', (141, 152))	('iSLK-RGB-K9', 'Gene', (58, 69))	('stocks', 'Species', '3724', (17, 23))	('Dox', 'Chemical', 'MESH:D004318', (141, 144))	('mutant', 'Var', (70, 76))	('infection', 'Disease', (28, 37))	('infection', 'Disease', 'MESH:D007239', (28, 37))	('sodium butyrate', 'Chemical', 'MESH:D020148', (174, 189))	('NaB', 'Chemical', '-', (191, 194))	('Dox', 'Chemical', 'MESH:D004318', (154, 157))
442839	30699189	The pellet was resuspended, supplemented with 8 mug/mL polybrene and then incubated with 105 HUVECs in a 6-well plate for 4 h. The primers for construction and identification of K9 mutant bacmid were designed as previously described and the sequences of the primers could be found in S2 Table.	('K9 mutant', 'Var', (178, 187))	('mutant', 'Var', (181, 187))	('polybrene', 'Chemical', 'MESH:D006583', (55, 64))
442847	29036465	Herein, by using splicing sensitive arrays, we have uncovered an extensive splicing program activated upon inhibition of the PI3K/AKT/mTOR signaling pathway by BEZ235.	('splicing program', 'MPA', (75, 91))	('mTOR', 'Gene', (134, 138))	('AKT', 'Gene', '207', (130, 133))	('BEZ235', 'Var', (160, 166))	('mTOR', 'Gene', '2475', (134, 138))	('inhibition', 'NegReg', (107, 117))	('AKT', 'Gene', (130, 133))	('BEZ235', 'Chemical', 'MESH:C531198', (160, 166))
442850	29036465	Knockdown of hnRNPM expression abolished a subset of BEZ235-induced splicing changes that contained hnRNPM binding sites, enhanced BEZ235 cytotoxicity and limited the clonogenicity of ES cells.	('hnRNPM', 'Gene', '4670', (100, 106))	('cytotoxicity', 'Disease', 'MESH:D064420', (138, 150))	('enhanced', 'PosReg', (122, 130))	('ES', 'Phenotype', 'HP:0012254', (184, 186))	('splicing changes', 'MPA', (68, 84))	('limited', 'NegReg', (155, 162))	('abolished', 'NegReg', (31, 40))	('BEZ235', 'Var', (131, 137))	('clonogenicity of ES cells', 'CPA', (167, 192))	('hnRNPM', 'Gene', (13, 19))	('binding', 'Interaction', (107, 114))	('cytotoxicity', 'Disease', (138, 150))	('BEZ235', 'Chemical', 'MESH:C531198', (131, 137))	('hnRNPM', 'Gene', '4670', (13, 19))	('BEZ235', 'Chemical', 'MESH:C531198', (53, 59))	('hnRNPM', 'Gene', (100, 106))
442866	29036465	Dysregulation of several components of this pathway, such as AKT, 4E-BP1, S6K1 and eIF-4G, is associated with poor survival in rhabdomyosarcoma, a pediatric sarcoma of soft tissues displaying very similar histology and therapeutic treatment with ES.	('Dysregulation', 'Var', (0, 13))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('S6K1', 'Gene', (74, 78))	('sarcoma', 'Disease', (157, 164))	('rhabdomyosarcoma', 'Disease', (127, 143))	('ES', 'Phenotype', 'HP:0012254', (246, 248))	('AKT', 'Gene', (61, 64))	('S6K1', 'Gene', '6198', (74, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('eIF-4G', 'Gene', (83, 89))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('4E-BP1', 'Gene', '1978', (66, 72))	('sarcoma', 'Disease', (136, 143))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (127, 143))	('poor', 'NegReg', (110, 114))	('eIF-4G', 'Gene', '1981', (83, 89))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (127, 143))	('AKT', 'Gene', '207', (61, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('4E-BP1', 'Gene', (66, 72))
442872	29036465	Alternative splicing (AS) of pre-mRNAs represents an important layer of gene expression that is often altered in human cancer cells.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('Alternative splicing', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (113, 118))
442879	29036465	Moreover, up-regulation of hnRNPM correlated with poor prognosis in sarcoma patients and its knockdown in ES cells significantly reduced clonogenicity.	('knockdown', 'Var', (93, 102))	('clonogenicity', 'CPA', (137, 150))	('sarcoma', 'Disease', (68, 75))	('hnRNPM', 'Gene', '4670', (27, 33))	('patients', 'Species', '9606', (76, 84))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('reduced', 'NegReg', (129, 136))	('up-regulation', 'PosReg', (10, 23))	('ES', 'Phenotype', 'HP:0012254', (106, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('hnRNPM', 'Gene', (27, 33))
442880	29036465	These findings suggest that hnRNPM expression is a valuable prognostic factor in ES and that inhibition of its activity could represent a suitable therapeutic target to increase susceptibility of ES cells to treatment with PI3K/AKT/mTOR inhibitors.	('AKT', 'Gene', '207', (228, 231))	('AKT', 'Gene', (228, 231))	('mTOR', 'Gene', (232, 236))	('mTOR', 'Gene', '2475', (232, 236))	('ES', 'Phenotype', 'HP:0012254', (81, 83))	('hnRNPM', 'Gene', (28, 34))	('ES', 'Phenotype', 'HP:0012254', (196, 198))	('inhibition', 'Var', (93, 103))	('hnRNPM', 'Gene', '4670', (28, 34))
442897	29036465	The TC71 cell line was established from a 22-year-old man with metastatic ES that arose in the humerus; it was derived from a biopsy of recurrent tumor at the primary site and it carries the characteristic chromosomal translocation t(11;22)(q24;q12) leading EWS-FLI-1 fusion.	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (232, 249))	('man', 'Species', '9606', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('ES', 'Phenotype', 'HP:0012254', (74, 76))	('EWS-FLI-1', 'Gene', (258, 267))	('EWS-FLI-1', 'Gene', '2130', (258, 267))	('t(11;22)(q24;q12', 'Var', (232, 248))
442898	29036465	Western blot analyses of the phosphorylation status of AKT (phAKT) and of the mTORC1 target 4E-BP1 (slow mobility bands) indicated that BEZ235 was the most effective inhibitor of the pathway (Supplementary Figure S1A).	('BEZ235', 'Var', (136, 142))	('AKT', 'Gene', (62, 65))	('BEZ235', 'Chemical', 'MESH:C531198', (136, 142))	('AKT', 'Gene', (55, 58))	('mTORC1', 'Gene', (78, 84))	('4E-BP1', 'Gene', (92, 98))	('AKT', 'Gene', '207', (62, 65))	('AKT', 'Gene', '207', (55, 58))	('mTORC1', 'Gene', '382056', (78, 84))	('4E-BP1', 'Gene', '1978', (92, 98))
442899	29036465	Accordingly, BEZ235 was also the most potent inhibitor of the clonogenic activity of ES cells (Supplementary Figure S1B).	('ES', 'Phenotype', 'HP:0012254', (85, 87))	('clonogenic activity', 'CPA', (62, 81))	('BEZ235', 'Chemical', 'MESH:C531198', (13, 19))	('BEZ235', 'Var', (13, 19))
442900	29036465	Importantly, the cytostatic activity of BEZ235 was not due to induction of cell death, as measured by propidium iodide (PI) staining and flow cytometry, whereas wortmannin treatment strongly induced apoptosis (Supplementary Figure S1C).	('induced', 'Reg', (191, 198))	('BEZ235', 'Var', (40, 46))	('wortmannin', 'Chemical', 'MESH:D000077191', (161, 171))	('propidium iodide', 'Chemical', 'MESH:D011419', (102, 118))	('apoptosis', 'CPA', (199, 208))	('BEZ235', 'Chemical', 'MESH:C531198', (40, 46))
442901	29036465	A dose-response experiment indicated that BEZ235 significantly reduced TC71 cell clonogenic potential at 30 nM, and almost completely abolished it at 300 nM and 3 muM (Figure 1A).	('BEZ235', 'Var', (42, 48))	('reduced', 'NegReg', (63, 70))	('muM', 'Gene', '56925', (163, 166))	('BEZ235', 'Chemical', 'MESH:C531198', (42, 48))	('muM', 'Gene', (163, 166))	('TC71 cell clonogenic potential', 'CPA', (71, 101))	('abolished', 'NegReg', (134, 143))
442902	29036465	PI staining showed that viability was only slightly affected by the treatment with 30 and 300 nM of BEZ235, while 3 muM BEZ235 elicited strong cytotoxic effects (Figure 1B).	('BEZ235', 'Chemical', 'MESH:C531198', (120, 126))	('BEZ235', 'Gene', (100, 106))	('muM', 'Gene', (116, 119))	('BEZ235', 'Chemical', 'MESH:C531198', (100, 106))	('cytotoxic effects', 'CPA', (143, 160))	('BEZ235', 'Var', (120, 126))	('muM', 'Gene', '56925', (116, 119))
442905	29036465	To monitor the effect of BEZ235 on cell cycle progression, we performed a BrdU pulse in the last 30 min of treatment with 300 nM BEZ235, or the vehicle DMSO alone, for 16 h. BEZ235 induced a significant increase in G1-phase (41% versus 64%) cells and reduction in S-phase (43% versus 20%) cells (Figure 1D and E).	('DMSO', 'Chemical', 'MESH:D004121', (152, 156))	('BEZ235', 'Chemical', 'MESH:C531198', (129, 135))	('BEZ235', 'Chemical', 'MESH:C531198', (174, 180))	('BEZ235', 'Chemical', 'MESH:C531198', (25, 31))	('reduction', 'NegReg', (251, 260))	('increase', 'PosReg', (203, 211))	('BEZ235', 'Var', (174, 180))
442914	29036465	BEZ235 treatment exerted a significantly higher impact on cassette exon events (577 regulated exon cassette events; P = 5.74E-128) in comparison with what expected from the array design (Figure 2E, Supplementary Figure S2C).	('higher impact', 'PosReg', (41, 54))	('cassette exon events', 'MPA', (58, 78))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('BEZ235 treatment', 'Var', (0, 16))
442926	29036465	HnRNPM was the most up-regulated RBP mRNA by BEZ235 treatment (Figure 4B) and this increase resulted in concomitant up-regulation of the protein (Figure 5B).	('RBP', 'Gene', '57794', (33, 36))	('up-regulated', 'PosReg', (20, 32))	('BEZ235', 'Var', (45, 51))	('HnRNPM', 'Gene', (0, 6))	('BEZ235', 'Chemical', 'MESH:C531198', (45, 51))	('up-regulation', 'PosReg', (116, 129))	('HnRNPM', 'Gene', '4670', (0, 6))	('protein', 'Protein', (137, 144))	('RBP', 'Gene', (33, 36))
442928	29036465	U1C, U2AF65 and U170K; Figure 5C).	('U2AF65', 'Gene', (5, 11))	('U1C', 'Gene', (0, 3))	('U2AF65', 'Gene', '11338', (5, 11))	('U1C', 'Gene', '6631', (0, 3))	('U170K', 'Var', (16, 21))
442929	29036465	However, treatment with BEZ235 augmented the fraction of hnRNPM protein co-sedimenting with U1C, U170K and U2AF65 in the soluble nucleoplasm (~60%), consistent with its engagement in spliceosomal activity.	('U2AF65', 'Gene', '11338', (107, 113))	('BEZ235', 'Chemical', 'MESH:C531198', (24, 30))	('hnRNPM', 'Gene', (57, 63))	('augmented', 'PosReg', (31, 40))	('hnRNPM', 'Gene', '4670', (57, 63))	('U170K', 'Var', (97, 102))	('U1C', 'Gene', '6631', (92, 95))	('U2AF65', 'Gene', (107, 113))	('U1C', 'Gene', (92, 95))	('BEZ235', 'Var', (24, 30))
442931	29036465	Furthermore, we found that co-immunoprecipitation of hnRNPM with the spliceosomal protein U170K, a core component of the U1 snRNP, was robustly increased upon BEZ235 treatment (2.5 times; Figure 5D).	('co-immunoprecipitation', 'MPA', (27, 49))	('hnRNPM', 'Gene', (53, 59))	('BEZ235', 'Var', (159, 165))	('hnRNPM', 'Gene', '4670', (53, 59))	('U1 snRNP', 'Gene', '26871;55599', (121, 129))	('BEZ235', 'Chemical', 'MESH:C531198', (159, 165))	('increased', 'PosReg', (144, 153))	('U1 snRNP', 'Gene', (121, 129))
442932	29036465	These findings indicate that inhibition of the PI3K/AKT/mTOR pathway in ES cells promotes expression and functional recruitment of hnRNPM to the splicing machinery, thus possibly affecting the splicing response to this stress.	('mTOR', 'Gene', (56, 60))	('hnRNPM', 'Gene', (131, 137))	('mTOR', 'Gene', '2475', (56, 60))	('ES', 'Phenotype', 'HP:0012254', (72, 74))	('promotes', 'PosReg', (81, 89))	('AKT', 'Gene', (52, 55))	('affecting', 'Reg', (179, 188))	('hnRNPM', 'Gene', '4670', (131, 137))	('splicing response to this stress', 'MPA', (193, 225))	('expression', 'MPA', (90, 100))	('functional recruitment', 'MPA', (105, 127))	('inhibition', 'Var', (29, 39))	('AKT', 'Gene', '207', (52, 55))
442936	29036465	Cassette exons containing proximal hnRNPM consensus motifs (last 220 nt upstream or first 241 nt downstream; group 2 and 3 introns) were completely reverted by hnRNPM silencing (Figure 6C).	('hnRNPM', 'Gene', (35, 41))	('hnRNPM', 'Gene', '4670', (35, 41))	('hnRNPM', 'Gene', (160, 166))	('hnRNPM', 'Gene', '4670', (160, 166))	('silencing', 'Var', (167, 176))
442939	29036465	On the contrary, cassette exons flanked by distal intronic consensus motifs (first 241 nt upstream or last 220 nt downstream; group 1 and 4) were not affected by hnRNPM knockdown (Figure 6D).	('knockdown', 'Var', (169, 178))	('hnRNPM', 'Gene', '4670', (162, 168))	('hnRNPM', 'Gene', (162, 168))
442946	29036465	Importantly, binding of hnRNPM to PAX6, SPTAN1, SETD4 pre-mRNAs (groups 2 and 3) was increased upon BEZ235 treatment, while that to group 1 NFAT5 pre-mRNA was decreased (Figure 6F).	('SPTAN1', 'Gene', '6709', (40, 46))	('binding', 'Interaction', (13, 20))	('SPTAN1', 'Gene', (40, 46))	('PAX6', 'Gene', (34, 38))	('PAX6', 'Gene', '5080', (34, 38))	('BEZ235', 'Chemical', 'MESH:C531198', (100, 106))	('NFAT5', 'Gene', (140, 145))	('NFAT5', 'Gene', '10725', (140, 145))	('SETD4', 'Gene', '54093', (48, 53))	('increased', 'PosReg', (85, 94))	('hnRNPM', 'Gene', (24, 30))	('treatment', 'Var', (107, 116))	('hnRNPM', 'Gene', '4670', (24, 30))	('BEZ235 treatment', 'Var', (100, 116))	('SETD4', 'Gene', (48, 53))
442951	29036465	These experiments demonstrate that modulation of hnRNPM expression contributes to the molecular response of ES cells to inhibition of the PI3K/AKT/mTOR pathway.	('hnRNPM', 'Gene', (49, 55))	('ES', 'Phenotype', 'HP:0012254', (108, 110))	('modulation', 'Var', (35, 45))	('hnRNPM', 'Gene', '4670', (49, 55))	('molecular response', 'MPA', (86, 104))	('AKT', 'Gene', '207', (143, 146))	('inhibition', 'NegReg', (120, 130))	('mTOR', 'Gene', '2475', (147, 151))	('AKT', 'Gene', (143, 146))	('mTOR', 'Gene', (147, 151))
442954	29036465	To this end, we used ES cell lines displaying the same (type 2, LAP-35 and TC71) or different (type 1, SKNMC) EWS-FLI-1 chromosomal translocation.	('EWS-FLI-1', 'Gene', '2130', (110, 119))	('chromosomal translocation', 'Var', (120, 145))	('SKNMC', 'CellLine', 'CVCL:0530', (103, 108))	('EWS-FLI-1', 'Gene', (110, 119))	('ES', 'Phenotype', 'HP:0012254', (21, 23))
442958	29036465	In line with this hypothesis, hnRNPM depletion significantly increased the sensitivity of ES cells to BEZ235 (Figure 7D and Supplementary Figure S7).	('BEZ235', 'Chemical', 'MESH:C531198', (102, 108))	('depletion', 'Var', (37, 46))	('ES', 'Phenotype', 'HP:0012254', (90, 92))	('hnRNPM', 'Gene', (30, 36))	('increased', 'PosReg', (61, 70))	('hnRNPM', 'Gene', '4670', (30, 36))	('sensitivity', 'MPA', (75, 86))
442961	29036465	We identified 159 cases with alteration, and considered patients with hnRNPM Z-score >=0.5 as up-regulated and genes with Z-score <=0.5 as down-regulated.	('hnRNPM', 'Gene', (70, 76))	('Z-score >=0.5', 'Var', (77, 90))	('patients', 'Species', '9606', (56, 64))	('hnRNPM', 'Gene', '4670', (70, 76))	('up-regulated', 'PosReg', (94, 106))	('down-regulated', 'NegReg', (139, 153))	('alteration', 'Var', (29, 39))
442964	29036465	These results indicate that high hnRNPM expression levels represent a critical prognostic factor for ES malignancy, predicting shorter overall survival of patients.	('shorter', 'NegReg', (127, 134))	('ES malignancy', 'Disease', 'MESH:C563168', (101, 114))	('hnRNPM', 'Gene', (33, 39))	('overall survival', 'MPA', (135, 151))	('hnRNPM', 'Gene', '4670', (33, 39))	('ES', 'Phenotype', 'HP:0012254', (101, 103))	('patients', 'Species', '9606', (155, 163))	('high', 'Var', (28, 32))	('ES malignancy', 'Disease', (101, 114))	('expression levels', 'MPA', (40, 57))
442971	29036465	In particular, we found that hnRNPM is specifically up-regulated in response to the treatment and activates a splicing program contributing to drug resistance (Figure 7F), suggesting that modulation of hnRNPM activity could represent a novel therapeutic target for ES treatment.	('modulation', 'Var', (188, 198))	('hnRNPM', 'Gene', '4670', (202, 208))	('ES', 'Phenotype', 'HP:0012254', (265, 267))	('drug resistance', 'Phenotype', 'HP:0020174', (143, 158))	('up-regulated', 'PosReg', (52, 64))	('hnRNPM', 'Gene', (29, 35))	('hnRNPM', 'Gene', '4670', (29, 35))	('activates', 'PosReg', (98, 107))	('drug resistance', 'MPA', (143, 158))	('splicing program', 'MPA', (110, 126))	('hnRNPM', 'Gene', (202, 208))	('contributing', 'Reg', (127, 139))
442975	29036465	For instance, mTOR inhibition abrogated a negative feedback on IGF1R, resulting in AKT activation both in cancer cell lines and in patient tumors.	('AKT', 'Gene', '207', (83, 86))	('mTOR', 'Gene', '2475', (14, 18))	('activation', 'PosReg', (87, 97))	('inhibition', 'Var', (19, 29))	('AKT', 'Gene', (83, 86))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('IGF1R', 'Gene', '3480', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('IGF1R', 'Gene', (63, 68))	('cancer', 'Disease', (106, 112))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('patient', 'Species', '9606', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('negative feedback', 'MPA', (42, 59))	('abrogated', 'NegReg', (30, 39))	('mTOR', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
442977	29036465	Second-generation agents, like MLN0128 (Takeda) and the dual inhibitor BEZ235 (Novartis) used in the present study, display inhibitory activity on both mTORC1 and mTORC2 and avoid AKT reactivation, representing valuable alternatives for sarcoma treatment.	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('MLN0128', 'Var', (31, 38))	('mTORC1', 'Gene', (152, 158))	('mTORC2', 'Gene', '74343', (163, 169))	('inhibitory activity', 'MPA', (124, 143))	('MLN0128', 'Chemical', 'MESH:C572449', (31, 38))	('sarcoma', 'Disease', 'MESH:D012509', (237, 244))	('AKT', 'Gene', (180, 183))	('avoid', 'NegReg', (174, 179))	('BEZ235', 'Chemical', 'MESH:C531198', (71, 77))	('mTORC1', 'Gene', '382056', (152, 158))	('sarcoma', 'Disease', (237, 244))	('mTORC2', 'Gene', (163, 169))	('AKT', 'Gene', '207', (180, 183))
442980	29036465	Thus, identification of new potential targets to improve the effect of PI3K/AKT/mTOR inhibition, while preventing acquisition of resistance, could greatly help the efficacy of sarcoma therapy.	('AKT', 'Gene', '207', (76, 79))	('help', 'PosReg', (155, 159))	('mTOR', 'Gene', (80, 84))	('sarcoma', 'Disease', (176, 183))	('inhibition', 'Var', (85, 95))	('efficacy', 'CPA', (164, 172))	('acquisition of resistance', 'MPA', (114, 139))	('mTOR', 'Gene', '2475', (80, 84))	('AKT', 'Gene', (76, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('improve', 'PosReg', (49, 56))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))
442986	29036465	Here, we demonstrate that inhibition of the PI3K/AKT/mTOR pathway affects hnRNPM sub-nuclear localization, promoting its co-fractionation with spliceosomal proteins like U1C, U170K and U2AF65 and its co-immunoprecipitation with U170K (Figure 5C).	('U2AF65', 'Gene', '11338', (185, 191))	('U170K', 'Var', (175, 180))	('AKT', 'Gene', (49, 52))	('promoting', 'PosReg', (107, 116))	('U1C', 'Gene', '6631', (170, 173))	('inhibition', 'NegReg', (26, 36))	('sub-nuclear localization', 'MPA', (81, 105))	('hnRNPM', 'Gene', (74, 80))	('mTOR', 'Gene', (53, 57))	('hnRNPM', 'Gene', '4670', (74, 80))	('mTOR', 'Gene', '2475', (53, 57))	('U1C', 'Gene', (170, 173))	('U2AF65', 'Gene', (185, 191))	('AKT', 'Gene', '207', (49, 52))	('U170K', 'Var', (228, 233))	('co-fractionation', 'MPA', (121, 137))
442999	29036465	Accordingly, ES mesenchymal features become more pronounced with EWS-FLI-1 knockdown.	('pronounced', 'PosReg', (49, 59))	('knockdown', 'Var', (75, 84))	('EWS-FLI-1', 'Gene', '2130', (65, 74))	('EWS-FLI-1', 'Gene', (65, 74))	('ES mesenchymal features', 'CPA', (13, 36))	('ES', 'Phenotype', 'HP:0012254', (13, 15))
443002	29036465	Since hnRNPM knockdown abolishes most of these events (Figure 6), it is likely that it directly participates to their splicing regulation upon inhibition of the PI3K/AKT/mTOR pathway.	('hnRNPM', 'Gene', (6, 12))	('hnRNPM', 'Gene', '4670', (6, 12))	('AKT', 'Gene', '207', (166, 169))	('abolishes', 'NegReg', (23, 32))	('mTOR', 'Gene', (170, 174))	('splicing regulation', 'MPA', (118, 137))	('mTOR', 'Gene', '2475', (170, 174))	('AKT', 'Gene', (166, 169))	('knockdown', 'Var', (13, 22))	('participates', 'Reg', (96, 108))
443005	29036465	Remarkably, hnRNPK co-sediments with U1 and U2AF splicing factors but its subnuclear localization was not affected by PI3K/AKT/mTOR inhibition.	('U2AF', 'Var', (44, 48))	('AKT', 'Gene', '207', (123, 126))	('hnRNPK', 'Gene', (12, 18))	('mTOR', 'Gene', (127, 131))	('mTOR', 'Gene', '2475', (127, 131))	('AKT', 'Gene', (123, 126))	('hnRNPK', 'Gene', '3190', (12, 18))
443009	29036465	Furthermore, high hnRNPM expression was associated to decrease in the overall survival (P-value = 1.17E-03) of sarcoma patients.	('hnRNPM', 'Gene', (18, 24))	('decrease', 'NegReg', (54, 62))	('overall survival', 'MPA', (70, 86))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('hnRNPM', 'Gene', '4670', (18, 24))	('high', 'Var', (13, 17))	('expression', 'MPA', (25, 35))	('patients', 'Species', '9606', (119, 127))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))
443014	29036465	Thus, it is also possible that PI3K/AKT/mTOR inhibition partly elicits transcriptome reprogramming by modulating the activity of kinases and phosphatases involved in splicing regulation.	('modulating', 'Reg', (102, 112))	('activity', 'MPA', (117, 125))	('AKT', 'Gene', '207', (36, 39))	('elicits', 'Reg', (63, 70))	('mTOR', 'Gene', (40, 44))	('mTOR', 'Gene', '2475', (40, 44))	('AKT', 'Gene', (36, 39))	('kinases', 'Enzyme', (129, 136))	('inhibition', 'Var', (45, 55))	('transcriptome', 'MPA', (71, 84))	('phosphatases', 'Enzyme', (141, 153))
443110	33130216	The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers KRAS is mutated in ~90% of pancreatic ductal adenocarcinomas, ~35% of colorectal cancers and ~20% of non-small-cell lung cancers.	('KRAS', 'Gene', (94, 98))	('panRAF plus SRC', 'Disease', (21, 36))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('colorectal cancers', 'Disease', 'MESH:D015179', (184, 202))	('cancers', 'Disease', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('non-small-cell lung cancers', 'Disease', (215, 242))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('KRAS', 'Gene', '3845', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (141, 174))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (141, 173))	('pancreatic ductal adenocarcinomas', 'Disease', (141, 174))	('KRAS', 'Gene', (114, 118))	('non-small-cell lung cancers', 'Disease', 'MESH:D002289', (215, 242))	('lung cancers', 'Phenotype', 'HP:0100526', (230, 242))	('colorectal cancers', 'Disease', (184, 202))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('mutated', 'Var', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancers', 'Disease', (235, 242))	('KRAS', 'Gene', '3845', (94, 98))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('panRAF plus SRC', 'Disease', 'MESH:D007625', (21, 36))	('cancers', 'Disease', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('CCT3833', 'Chemical', '-', (62, 69))
443113	33130216	We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice.	('RAF', 'Protein', (30, 33))	('mice', 'Species', '10090', (147, 151))	('inhibits', 'NegReg', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('CCT3833', 'Var', (13, 20))	('CCT3833', 'Chemical', '-', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('SRC', 'Protein', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('inhibits', 'NegReg', (98, 106))	('KRAS-mutant', 'Var', (45, 56))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
443114	33130216	CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options.	('prolongs', 'PosReg', (110, 118))	('patient', 'Species', '9606', (150, 157))	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('G12VKRAS', 'Var', (165, 173))	('sarcoma', 'Disease', (187, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('CCT3833', 'Chemical', '-', (0, 7))	('progression-free survival', 'CPA', (119, 144))
443116	33130216	Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('patients', 'Species', '9606', (169, 177))	('cancers', 'Disease', (201, 208))	('sarcoma', 'Disease', (121, 128))	('CCT3833', 'Chemical', '-', (130, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('patient', 'Species', '9606', (169, 176))	('patient', 'Species', '9606', (83, 90))	('KRAS-mutant', 'Gene', (96, 107))	('KRAS-mutant', 'Var', (96, 107))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))
443118	33130216	CCT3833 inhibits both signaling pathways in vitro and in vivo, inhibits tumor growth and leads to regressions in mice.	('signaling pathways', 'Pathway', (22, 40))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('regressions', 'CPA', (98, 109))	('tumor', 'Disease', (72, 77))	('inhibits', 'NegReg', (63, 71))	('inhibits', 'NegReg', (8, 16))	('CCT3833', 'Var', (0, 7))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('CCT3833', 'Chemical', '-', (0, 7))
443119	33130216	CCT3833 significantly prolonged progression-free survival of a patient with a G12VKRAS spindle cell sarcoma.	('sarcoma', 'Disease', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('CCT3833', 'Gene', (0, 7))	('CCT3833', 'Chemical', '-', (0, 7))	('patient', 'Species', '9606', (63, 70))	('progression-free survival', 'CPA', (32, 57))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))	('prolonged', 'PosReg', (22, 31))	('G12VKRAS', 'Var', (78, 86))
443125	33130216	Critically, KRAS is mutated in ~20% NSCLC, ~90% PDAC and ~35% CRC.	('Critically', 'Disease', (0, 10))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('NSCLC', 'Disease', (36, 41))	('PDAC', 'Phenotype', 'HP:0006725', (48, 52))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('mutated', 'Var', (20, 27))
443128	33130216	Notably, direct inhibitors of KRAS are limited to the p.G12C KRAS-mutant, so an alternative is to target downstream effectors in the RAF/MEK/ERK pathway, which has led to the development of RAF, MEK and ERK drugs.	('MEK', 'Gene', (137, 140))	('MEK', 'Gene', '5609', (137, 140))	('MEK', 'Gene', (195, 198))	('MEK', 'Gene', '5609', (195, 198))	('KRAS-mutant', 'Gene', (61, 72))	('p.G12C', 'Mutation', 'rs121913530', (54, 60))	('p.G12C', 'Var', (54, 60))
443134	33130216	Critically, SRC is a validated target in KRAS-mutant CRC, PDAC and NSCLC and it is known that G12CKRAS and SRC inhibitors work synergistically to inhibit G12CKRAS NSCLC cell proliferation.	('Critically', 'Disease', (0, 10))	('inhibit', 'NegReg', (146, 153))	('NSCLC', 'Disease', (163, 168))	('G12CKRAS', 'Var', (154, 162))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('NSCLC', 'Disease', (67, 72))	('PDAC', 'Phenotype', 'HP:0006725', (58, 62))	('KRAS-mutant', 'Var', (41, 52))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('CRC', 'Phenotype', 'HP:0003003', (53, 56))
443136	33130216	We show that CCT3833 does not drive paradoxical activation of the RAF/MEK/ERK pathway in KRAS-mutant cells and that its ability to exert dual inhibition of RAF and SRC provides effective therapy in preclinical KRAS-mutant PDAC, CRC and NSCLC models.	('NSCLC', 'Disease', 'MESH:D002289', (236, 241))	('CRC', 'Disease', (228, 231))	('PDAC', 'Disease', (222, 226))	('PDAC', 'Phenotype', 'HP:0006725', (222, 226))	('CCT3833', 'Var', (13, 20))	('MEK', 'Gene', (70, 73))	('KRAS-mutant', 'Var', (89, 100))	('CRC', 'Phenotype', 'HP:0003003', (228, 231))	('MEK', 'Gene', '5609', (70, 73))	('CCT3833', 'Chemical', '-', (13, 20))	('NSCLC', 'Disease', (236, 241))	('KRAS-mutant', 'Var', (210, 221))
443137	33130216	We show that CCT3833 is superior to single-agent panRAF or SRC inhibitors and comparable with combination panRAF + SRC inhibitors in standard two-dimensional tissue culture and more significantly, in three-dimensional spheroids, which are of intermediate complexity between standard monolayer cultures in vitro and tumors in vivo.	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('tumors', 'Disease', (315, 321))	('CCT3833', 'Var', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('CCT3833', 'Chemical', '-', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))
443142	33130216	Here, we describe a patient with a spindle cell sarcoma presenting a p.G12V KRAS mutation.	('p.G12V', 'Var', (69, 75))	('KRAS', 'Gene', (76, 80))	('sarcoma', 'Disease', (48, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('patient', 'Species', '9606', (20, 27))	('p.G12V', 'Mutation', 'rs121913529', (69, 75))	('sarcoma', 'Disease', 'MESH:D012509', (48, 55))
443144	33130216	Despite being in the dose escalation phase, CCT3833 achieved a progression-free survival (PFS) of >10 months, and we provide comprehensive analysis of the mechanism of action of CCT3833 in KRAS-mutant cancers to reveal how this patient and others could benefit from this agent.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('CCT3833', 'Gene', (178, 185))	('CCT3833', 'Var', (44, 51))	('cancers', 'Disease', (201, 208))	('CCT3833', 'Chemical', '-', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('CCT3833', 'Chemical', '-', (178, 185))	('patient', 'Species', '9606', (228, 235))	('KRAS-mutant', 'Gene', (189, 200))
443150	33130216	All animal procedures were carried out in accordance with National Home Office regulations under the Animals (Scientific Procedures) Act 1986 under license PPL-70/7635 and PPL-70/7701 and within guidelines set out by the CRUK Manchester Institute and The Institute of Cancer Research Animal Welfare and Ethical Review Bodies, and described in accordance with Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.	('PPL-70/7635', 'Var', (156, 167))	('Cancer', 'Phenotype', 'HP:0002664', (268, 274))	('Cancer', 'Disease', (268, 274))	('PPL-70/7701', 'Var', (172, 183))	('Cancer', 'Disease', 'MESH:D009369', (268, 274))
443152	33130216	In selectivity screens CCT3833 is mostly inactive against other kinases, with the important exception of SFKs (Supplementary Figure S1A, available at https://doi.org/10.1016/j.annonc.2020.10.483) with SRC inhibition at 27 nM inhibition of the SFK lymphocyte-specific protein tyrosine kinase at 19 nM (Figure 1C, Supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('SFK', 'Gene', (105, 108))	('CCT3833', 'Var', (23, 30))	('SFK', 'Gene', (243, 246))	('inhibition', 'NegReg', (205, 215))	('inhibition', 'NegReg', (225, 235))	('SFK', 'Gene', '396442;6714;20779', (105, 108))	('CCT3833', 'Chemical', '-', (23, 30))	('SFK', 'Gene', '396442;6714;20779', (243, 246))
443153	33130216	Docking studies predict that CCT3833 is a type II inhibitor that binds to the inactive 'DFG-out' conformation of BRAF, and to CRAF and SRC through similar mechanisms (Figure 1D-F).	('BRAF', 'Gene', '673', (113, 117))	('CCT3833', 'Var', (29, 36))	('CRAF', 'Gene', '5894', (126, 130))	('binds', 'Interaction', (65, 70))	('CRAF', 'Gene', (126, 130))	('BRAF', 'Gene', (113, 117))	('DFG', 'Chemical', '-', (88, 91))	('CCT3833', 'Chemical', '-', (29, 36))
443155	33130216	These binding similarities indicate how CCT3833 inhibits both RAF and SRC and we confirm that CCT3833 inhibits both ERK (ppERK; downstream of CRAF) and SFK (ppSFK) phosphorylation in a dose-dependent manner in HCT-116 (CRC), A549 (NSCLC) (Figure 1G) and MIA-PaCa2 (PDAC) cells (Supplementary Figure S1B, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('CCT3833', 'Chemical', '-', (94, 101))	('CRAF', 'Gene', '5894', (142, 146))	('inhibits', 'NegReg', (102, 110))	('CRC', 'Phenotype', 'HP:0003003', (219, 222))	('CCT3833', 'Var', (94, 101))	('SFK', 'Gene', '396442;6714;20779', (159, 162))	('HCT-116', 'CellLine', 'CVCL:0291', (210, 217))	('SFK', 'Gene', '396442;6714;20779', (152, 155))	('phosphorylation', 'MPA', (164, 179))	('MIA-PaCa2', 'CellLine', 'CVCL:0428', (254, 263))	('NSCLC', 'Disease', 'MESH:D002289', (231, 236))	('SFK', 'Gene', (159, 162))	('SFK', 'Gene', (152, 155))	('ERK', 'Protein', (116, 119))	('PDAC', 'Phenotype', 'HP:0006725', (265, 269))	('CRAF', 'Gene', (142, 146))	('CCT3833', 'Chemical', '-', (40, 47))	('NSCLC', 'Disease', (231, 236))	('A549', 'CellLine', 'CVCL:0023', (225, 229))
443156	33130216	Our docking studies predict a steric clash would occur between the pyridopyrazinone moiety of CCT3833 and a T338I (the so-called gatekeeper residue) substitution in chicken SRC (Supplementary Figure S2A, available at https://doi.org/10.1016/j.annonc.2020.10.483) and accordingly, we show that CCT3833 inhibits wild-type SRC but not T341ISRC (the human equivalent of T338I) in either HEK-293 or HCT-116 cells (Supplementary Figure S2B-E, available at https://doi.org/10.1016/j.annonc.2020.10.483), supporting our predictions for binding mechanism.	('inhibits', 'NegReg', (301, 309))	('CCT3833', 'Chemical', '-', (94, 101))	('T338I', 'Mutation', 'p.T338I', (108, 113))	('pyridopyrazinone', 'Chemical', '-', (67, 83))	('CCT3833', 'Chemical', '-', (293, 300))	('HEK-293', 'CellLine', 'CVCL:0045', (383, 390))	('substitution', 'Var', (149, 161))	('T338I', 'Mutation', 'p.T338I', (366, 371))	('chicken', 'Species', '9031', (165, 172))	('T341ISRC', 'Mutation', 'c.341T>ISRC', (332, 340))	('gatekeeper', 'Species', '111938', (129, 139))	('human', 'Species', '9606', (346, 351))	('HCT-116', 'CellLine', 'CVCL:0291', (394, 401))	('CCT3833', 'Var', (293, 300))
443157	33130216	The data above show that CCT3833 is a panRAF inhibitor that also inhibits SRC.	('inhibits', 'NegReg', (65, 73))	('CCT3833', 'Var', (25, 32))	('SRC', 'MPA', (74, 77))	('CCT3833', 'Chemical', '-', (25, 32))
443158	33130216	Notably, RAF and SRC are validated targets in RAS-mutant cancers, because RAF signals downstream of oncogenic KRAS, and SFKs drive cancer cell proliferation and survival.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('survival', 'CPA', (161, 169))	('cancer', 'Disease', (57, 63))	('SFK', 'Gene', (120, 123))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('RAS-mutant', 'Var', (46, 56))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('SFK', 'Gene', '396442;6714;20779', (120, 123))	('drive', 'PosReg', (125, 130))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
443159	33130216	Accordingly, we show that CCT3833 is active against a panel of KRAS-mutant PDAC, CRC and NSCLC cell lines, whereas it is less potent against KRAS/BRAF wild-type cells (Figure 2A, Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('BRAF', 'Gene', (146, 150))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('CCT3833', 'Var', (26, 33))	('KRAS-mutant', 'Disease', (63, 74))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('CCT3833', 'Chemical', '-', (26, 33))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('BRAF', 'Gene', '673', (146, 150))	('NSCLC', 'Disease', (89, 94))
443160	33130216	Moreover, compared with other RAF inhibitors, in short-term growth assays CCT3833 inhibits HCT-116 growth more potently than the clinically evaluated panRAF inhibitors TAK-632, ARQ736 and MLN-2480 (Figure 2B, Supplementary Figure S3A, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('TAK-632', 'Chemical', 'MESH:C586564', (168, 175))	('CCT3833', 'Var', (74, 81))	('HCT-116', 'CellLine', 'CVCL:0291', (91, 98))	('HCT-116', 'Gene', (91, 98))	('CCT3833', 'Chemical', '-', (74, 81))	('inhibits', 'NegReg', (82, 90))
443161	33130216	We also show that CCT3833 is more effective than the multikinase inhibitor sorafenib or the BRAF-mutant selective inhibitors PLX4720 and dabrafenib, and that only the MEK inhibitor trametinib is more potent than CCT3833 at inhibiting HCT-116 cells (Figure 2B, Supplementary Figure S3A, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('MEK', 'Gene', (167, 170))	('MEK', 'Gene', '5609', (167, 170))	('BRAF', 'Gene', '673', (92, 96))	('CCT3833', 'Chemical', '-', (18, 25))	('PLX4720', 'Chemical', 'MESH:C528407', (125, 132))	('trametinib', 'Chemical', 'MESH:C560077', (181, 191))	('BRAF', 'Gene', (92, 96))	('inhibiting', 'NegReg', (223, 233))	('HCT-116', 'CellLine', 'CVCL:0291', (234, 241))	('CCT3833', 'Var', (18, 25))	('sorafenib', 'Chemical', 'MESH:D000077157', (75, 84))	('HCT-116 cells', 'CPA', (234, 247))	('dabrafenib', 'Chemical', 'MESH:C561627', (137, 147))	('CCT3833', 'Chemical', '-', (212, 219))
443162	33130216	We observe similar responses in SW620 (CRC; Figure 2C, Supplementary Figure S3B, available at https://doi.org/10.1016/j.annonc.2020.10.483), A549 (Figure 2D), MIA-PaCa2 (Supplementary Figure S3C and D, available at https://doi.org/10.1016/j.annonc.2020.10.483) and Calu-1 cells (NSCLC, Supplementary Figure S3E, available at https://doi.org/10.1016/j.annonc.2020.10.483), where CCT3833 inhibits growth more effectively than all other RAF inhibitors, with only trametinib being significantly more potent.	('CCT3833', 'Chemical', '-', (378, 385))	('SW620', 'CellLine', 'CVCL:0547', (32, 37))	('NSCLC', 'Disease', (279, 284))	('Calu-1', 'CellLine', 'CVCL:0608', (265, 271))	('A549', 'CellLine', 'CVCL:0023', (141, 145))	('growth', 'MPA', (395, 401))	('inhibits', 'NegReg', (386, 394))	('CCT3833', 'Var', (378, 385))	('NSCLC', 'Disease', 'MESH:D002289', (279, 284))	('trametinib', 'Chemical', 'MESH:C560077', (460, 470))	('MIA-PaCa2', 'CellLine', 'CVCL:0428', (159, 168))	('CRC', 'Phenotype', 'HP:0003003', (39, 42))
443163	33130216	Although the panRAF inhibitor TAK-632, and the BRAF inhibitors PLX4720 and dabrafenib inhibit BRAF more potently than CCT3833 in in vitro enzyme assays, CCT3833 is more potent at inhibiting KRAS-mutant cancer cell growth, so we examine downstream signaling.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('BRAF', 'Gene', (94, 98))	('inhibiting', 'NegReg', (179, 189))	('PLX4720', 'Chemical', 'MESH:C528407', (63, 70))	('KRAS-mutant', 'Gene', (190, 201))	('dabrafenib', 'Chemical', 'MESH:C561627', (75, 85))	('CCT3833', 'Chemical', '-', (153, 160))	('BRAF', 'Gene', (47, 51))	('CCT3833', 'Chemical', '-', (118, 125))	('BRAF', 'Gene', '673', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('inhibit', 'NegReg', (86, 93))	('TAK-632', 'Chemical', 'MESH:C586564', (30, 37))	('CCT3833', 'Var', (153, 160))	('BRAF', 'Gene', '673', (94, 98))
443164	33130216	In HCT-116, SW620, A549, MIA-PaCa2 and Calu-1 cells, PLX4720 induces paradoxical activation of the ERK pathway and although sorafenib and TAK-632 inhibit ppERK, they are less potent than CCT3833 in their ability to do so (Figure 2E, Supplementary Figure S3F-G, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('inhibit', 'NegReg', (146, 153))	('ppERK', 'Pathway', (154, 159))	('SW620', 'CellLine', 'CVCL:0547', (12, 17))	('PLX4720', 'Var', (53, 60))	('TAK-632', 'Chemical', 'MESH:C586564', (138, 145))	('sorafenib', 'Chemical', 'MESH:D000077157', (124, 133))	('CCT3833', 'Chemical', '-', (187, 194))	('activation', 'PosReg', (81, 91))	('PLX4720', 'Chemical', 'MESH:C528407', (53, 60))	('ERK pathway', 'Pathway', (99, 110))	('MIA-PaCa2', 'CellLine', 'CVCL:0428', (25, 34))	('Calu-1', 'CellLine', 'CVCL:0608', (39, 45))	('HCT-116', 'CellLine', 'CVCL:0291', (3, 10))	('A549', 'CellLine', 'CVCL:0023', (19, 23))	('A549', 'Var', (19, 23))
443165	33130216	Note also that PLX4720, sorafenib and TAK-632 do not inhibit ppSFK in these cells, whereas CCT3833 potently inhibits ppSFK (Figure 2E, Supplementary Figure S3F-G, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('TAK-632', 'Chemical', 'MESH:C586564', (38, 45))	('SFK', 'Gene', (119, 122))	('inhibits', 'NegReg', (108, 116))	('CCT3833', 'Chemical', '-', (91, 98))	('PLX4720', 'Chemical', 'MESH:C528407', (15, 22))	('SFK', 'Gene', (63, 66))	('SFK', 'Gene', '396442;6714;20779', (119, 122))	('SFK', 'Gene', '396442;6714;20779', (63, 66))	('sorafenib', 'Chemical', 'MESH:D000077157', (24, 33))	('CCT3833', 'Var', (91, 98))
443167	33130216	Thus, CCT3833 inhibits both CRAF and SRC in KRAS-mutant cancers and so we investigate the contribution of these two activities to the inhibition of long-term cell growth.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('inhibits', 'NegReg', (14, 22))	('CRAF', 'Gene', (28, 32))	('CRAF', 'Gene', '5894', (28, 32))	('KRAS-mutant', 'Gene', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CCT3833', 'Var', (6, 13))	('SRC', 'MPA', (37, 40))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('CCT3833', 'Chemical', '-', (6, 13))
443168	33130216	We show that CCT3833 induces significant caspase-3/7 activation, whereas PLX4720, sorafenib, trametinib and TAK-632 do not activate caspase-3/7 to the same extent (Figure 3A, Supplementary Figure S3H, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('PLX4720', 'Chemical', 'MESH:C528407', (73, 80))	('caspase-3/7', 'Gene', (132, 143))	('activation', 'PosReg', (53, 63))	('TAK-632', 'Chemical', 'MESH:C586564', (108, 115))	('CCT3833', 'Var', (13, 20))	('caspase-3/7', 'Gene', '836;840', (41, 52))	('sorafenib', 'Chemical', 'MESH:D000077157', (82, 91))	('trametinib', 'Chemical', 'MESH:C560077', (93, 103))	('CCT3833', 'Chemical', '-', (13, 20))	('caspase-3/7', 'Gene', (41, 52))	('caspase-3/7', 'Gene', '836;840', (132, 143))
443169	33130216	Accordingly, in long-term clonogenic proliferation assays, only CCT3833 fully inhibits HCT-116, SW620, A549 and MIA-PaCa2 cell growth, whereas colonies are still evident with PLX4720, sorafenib, TAK-632 and also trametinib (Figure 3B, Supplementary Figure S3I and J, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('SW620', 'Gene', (96, 101))	('HCT-116', 'CellLine', 'CVCL:0291', (87, 94))	('CCT3833', 'Var', (64, 71))	('MIA-PaCa2', 'CellLine', 'CVCL:0428', (112, 121))	('HCT-116', 'Gene', (87, 94))	('A549', 'CellLine', 'CVCL:0023', (103, 107))	('sorafenib', 'Chemical', 'MESH:D000077157', (184, 193))	('PLX4720', 'Var', (175, 182))	('trametinib', 'Chemical', 'MESH:C560077', (212, 222))	('A549', 'CPA', (103, 107))	('SW620', 'CellLine', 'CVCL:0547', (96, 101))	('CCT3833', 'Chemical', '-', (64, 71))	('inhibits', 'NegReg', (78, 86))	('PLX4720', 'Chemical', 'MESH:C528407', (175, 182))	('TAK-632', 'Chemical', 'MESH:C586564', (195, 202))
443173	33130216	Moreover, together these agents mimic the effects of CCT3833 (Figure 2E) and inhibit both ppERK and ppSFK (Figure 4A).	('CCT3833', 'Var', (53, 60))	('SFK', 'Gene', (102, 105))	('inhibit', 'NegReg', (77, 84))	('CCT3833', 'Chemical', '-', (53, 60))	('SFK', 'Gene', '396442;6714;20779', (102, 105))
443174	33130216	In long-term clonogenic growth assays, neither TAK-632 nor saracatinib alone inhibit colony formation, whereas together they do inhibit colony formation, both in HCT-116 cells and in H23 lung adenocarcinoma cells, again mimicking the effects of CCT3833 alone (Figure 4B, Supplementary Figure S5A, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('H23', 'CellLine', 'CVCL:1547', (183, 186))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (187, 206))	('inhibit', 'NegReg', (128, 135))	('inhibit', 'NegReg', (77, 84))	('HCT-116', 'CellLine', 'CVCL:0291', (162, 169))	('TAK-632', 'Var', (47, 54))	('lung adenocarcinoma', 'Disease', (187, 206))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (187, 206))	('CCT3833', 'Chemical', '-', (245, 252))	('colony formation', 'CPA', (136, 152))	('colony formation', 'CPA', (85, 101))	('saracatinib', 'Chemical', 'MESH:C515233', (59, 70))	('TAK-632', 'Chemical', 'MESH:C586564', (47, 54))
443177	33130216	Moreover, TAK-632 and bosutinib co-operate to inhibit the short-term growth of HCT-116, SW620 (Figure 4D-E), A549 and MIA-PaCa2 cells (Supplementary Figure S5B, available at https://doi.org/10.1016/j.annonc.2020.10.483), again mimicking the effect of CCT3833 alone.	('TAK-632', 'Chemical', 'MESH:C586564', (10, 17))	('MIA-PaCa2', 'CellLine', 'CVCL:0428', (118, 127))	('HCT-116', 'CellLine', 'CVCL:0291', (79, 86))	('SW620', 'CellLine', 'CVCL:0547', (88, 93))	('bosutinib', 'Var', (22, 31))	('inhibit', 'NegReg', (46, 53))	('bosutinib', 'Chemical', 'MESH:C471992', (22, 31))	('short-term growth', 'CPA', (58, 75))	('S5B', 'Gene', '5711', (156, 159))	('CCT3833', 'Chemical', '-', (251, 258))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('S5B', 'Gene', (156, 159))
443180	33130216	We show that CCT3833 has good oral bioavailability in mice, excellent pharmacokinetic properties (Figure 5A, Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2020.10.483), achieves plasma and tumor concentrations well above the GI50 for the target cancer cells and does not accumulate following daily oral doses (Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2020.10.483, Figure 2A).	('tumor', 'Disease', (213, 218))	('achieves', 'PosReg', (193, 201))	('GI50', 'Gene', (249, 253))	('GI50', 'Gene', '50723', (249, 253))	('plasma', 'MPA', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('CCT3833', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('mice', 'Species', '10090', (54, 58))	('CCT3833', 'Chemical', '-', (13, 20))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
443181	33130216	We tested CCT3833 in a mouse model of PDAC driven by oncogenic KRAS and inactivating mutation of the tumor suppressor TP53 (KPC cells).	('CCT3833', 'Chemical', '-', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('driven', 'Reg', (43, 49))	('inactivating mutation', 'Var', (72, 93))	('TP53', 'Gene', (118, 122))	('TP53', 'Gene', '22059', (118, 122))	('PDAC', 'Disease', (38, 42))	('mouse', 'Species', '10090', (23, 28))	('PDAC', 'Phenotype', 'HP:0006725', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
443182	33130216	We confirm, commensurate with our human cell observations, that, CCT3833 is more effective than the other pathway inhibitors apart from trametinib at blocking KPC cell growth in short-term proliferation assays, but only CCT3833 completely abrogates growth of these cells in long-term assays (Figure 5B and C, Supplementary Figure S6A and B, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('human', 'Species', '9606', (34, 39))	('trametinib', 'Chemical', 'MESH:C560077', (136, 146))	('abrogates', 'NegReg', (239, 248))	('CCT3833', 'Var', (220, 227))	('CCT3833', 'Var', (65, 72))	('CCT3833', 'Chemical', '-', (220, 227))	('growth', 'CPA', (249, 255))	('CCT3833', 'Chemical', '-', (65, 72))
443183	33130216	Accordingly, CCT3833 is more potent at inducing caspase-3/7 activation (Supplementary Figure S6C and D, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('caspase-3/7', 'Gene', (48, 59))	('CCT3833', 'Var', (13, 20))	('activation', 'MPA', (60, 70))	('CCT3833', 'Chemical', '-', (13, 20))	('inducing', 'Reg', (39, 47))	('caspase-3/7', 'Gene', '836;840', (48, 59))
443184	33130216	We show CCT3833 blocks ERK and SFK phosphorylation and suppresses tumor growth in KPC cells grown as allografts in mice (Figure 5D-F, Supplementary Figure S7A, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('SFK', 'Gene', '396442;6714;20779', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Disease', (66, 71))	('CCT3833', 'Chemical', '-', (8, 15))	('SFK', 'Gene', (31, 34))	('phosphorylation', 'MPA', (35, 50))	('ERK', 'Protein', (23, 26))	('CCT3833', 'Var', (8, 15))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('suppresses', 'NegReg', (55, 65))	('blocks', 'NegReg', (16, 22))
443185	33130216	Critically, CCT3833 inhibits a human KRAS-mutant PDAC patient-derived xenograft (PDX)(Figure 5G, Supplementary Figure S7B, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('Critically', 'Disease', (0, 10))	('patient', 'Species', '9606', (54, 61))	('inhibits', 'NegReg', (20, 28))	('CCT3833', 'Chemical', '-', (12, 19))	('human', 'Species', '9606', (31, 36))	('PDAC', 'Gene', (49, 53))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('PDAC', 'Phenotype', 'HP:0006725', (49, 53))	('CCT3833', 'Var', (12, 19))
443188	33130216	Finally, CCT3833 also inhibits ppERK and ppSFK in lung A549 cells and more importantly, at doses that are well tolerated in mice (Supplementary Figure S8, available at https://doi.org/10.1016/j.annonc.2020.10.483), CCT3833 inhibits ERK and SRC, and causes regression of A549 tumors xenografts in mice (Figure 5J and K), and it mediates a significant reduction in the size of foci in the A549 pseudo metastasis tail vein injection model (Supplementary Figure S7E-I, available at https://doi.org/10.1016/j.annonc.2020.10.483).	('ERK', 'MPA', (232, 235))	('inhibits', 'NegReg', (223, 231))	('mice', 'Species', '10090', (124, 128))	('A549', 'CellLine', 'CVCL:0023', (270, 274))	('CCT3833', 'Var', (9, 16))	('CCT3833', 'Var', (215, 222))	('A549', 'CellLine', 'CVCL:0023', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('SFK', 'Gene', '396442;6714;20779', (43, 46))	('inhibits', 'NegReg', (22, 30))	('ppERK', 'Gene', (31, 36))	('A549', 'CellLine', 'CVCL:0023', (387, 391))	('size', 'CPA', (367, 371))	('SFK', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('A549 pseudo metastasis tail vein injection model', 'CPA', (387, 435))	('mice', 'Species', '10090', (296, 300))	('tumors', 'Disease', (275, 281))	('reduction', 'NegReg', (350, 359))	('regression', 'CPA', (256, 266))	('CCT3833', 'Chemical', '-', (9, 16))	('CCT3833', 'Chemical', '-', (215, 222))	('tumors', 'Disease', 'MESH:D009369', (275, 281))
443201	33130216	qd continuous dosing of CCT3833, the patient achieved progression-free survival for 8 months, and did not progress until the 12th cycle of treatment.	('CCT3833', 'Chemical', '-', (24, 31))	('CCT3833', 'Var', (24, 31))	('achieved', 'PosReg', (45, 53))	('patient', 'Species', '9606', (37, 44))
443202	33130216	Together with our preclinical data, this indicates that CCT3833 has potential for the treatment of KRAS-mutant tumors.	('CCT3833', 'Chemical', '-', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('KRAS-mutant', 'Gene', (99, 110))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('CCT3833', 'Var', (56, 63))
443203	33130216	Specifically, our preclinical data demonstrate that CCT3833 is effective in KRAS-mutant CRC, NSCLC and PDAC due to its dual anti-panRAF plus anti-SRC activity.	('NSCLC', 'Disease', (93, 98))	('CCT3833', 'Chemical', '-', (52, 59))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('PDAC', 'Phenotype', 'HP:0006725', (103, 107))	('PDAC', 'Disease', (103, 107))	('CCT3833', 'Var', (52, 59))	('CRC', 'Phenotype', 'HP:0003003', (88, 91))	('KRAS-mutant', 'Gene', (76, 87))
443206	33130216	Our findings that CCT3833 inhibits the growth of KRAS-driven murine PDAC in vitro, and in vivo, are aligned to the literature, validating SRC as a therapeutic target in PDAC, where its overexpression or hyperactivation are markers of poor clinical outcome.	('inhibits', 'NegReg', (26, 34))	('PDAC', 'Phenotype', 'HP:0006725', (169, 173))	('growth', 'MPA', (39, 45))	('CCT3833', 'Chemical', '-', (18, 25))	('PDAC', 'Disease', (68, 72))	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('murine', 'Species', '10090', (61, 67))	('CCT3833', 'Var', (18, 25))
443209	33130216	This plasticity may explain the shorter duration of response to BRAF and MEK inhibitors in CRC and may also underpin why mutant KRAS opposes the antitumor effects of EGFR inhibitors in CRC.	('KRAS', 'Gene', (128, 132))	('BRAF', 'Gene', '673', (64, 68))	('mutant', 'Var', (121, 127))	('opposes', 'NegReg', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('CRC', 'Phenotype', 'HP:0003003', (185, 188))	('BRAF', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('MEK', 'Gene', (73, 76))	('MEK', 'Gene', '5609', (73, 76))	('tumor', 'Disease', (149, 154))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))
443210	33130216	Notably, MEK and EGFR inhibitors cooperate to block EGFR inhibitor-resistant CRC tumor growth, and we propose therefore that CCT3833 is effective in CRC because it targets the two key pathways downstream from mutant RAS and the hyperactivated receptor tyrosine kinases such as EGFR.	('EGFR', 'Gene', (52, 56))	('EGFR', 'Gene', '1956', (277, 281))	('receptor tyrosine kinase', 'Gene', (243, 267))	('EGFR', 'Gene', (17, 21))	('CCT3833', 'Chemical', '-', (125, 132))	('RAS', 'Protein', (216, 219))	('CRC tumor', 'Disease', (77, 86))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', '1956', (17, 21))	('MEK', 'Gene', '5609', (9, 12))	('CCT3833', 'Var', (125, 132))	('EGFR', 'Gene', (277, 281))	('CRC tumor', 'Disease', 'MESH:D015179', (77, 86))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))	('MEK', 'Gene', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('mutant', 'Var', (209, 215))	('receptor tyrosine kinase', 'Gene', '5979', (243, 267))
443214	33130216	Again, we posit that CCT3833 is effective in NSCLC because of its ability to simultaneously inhibit SRC and ERK signaling.	('NSCLC', 'Disease', (45, 50))	('CCT3833', 'Var', (21, 28))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('inhibit', 'NegReg', (92, 99))	('CCT3833', 'Chemical', '-', (21, 28))
443215	33130216	Critically, CCT3833 mediates tumor regression in G12SKRAS-mutant NSCLC xenografts, so it could be considered for treatment of KRAS-mutant NSCLC patients who fail chemotherapy and/or immunotherapy.	('Critically', 'Disease', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('NSCLC', 'Disease', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('CCT3833', 'Chemical', '-', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('patients', 'Species', '9606', (144, 152))	('tumor', 'Disease', (29, 34))	('G12SKRAS-mutant', 'Var', (49, 64))	('CCT3833', 'Gene', (12, 19))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('G12SKRAS', 'CellLine', 'CVCL:H221', (49, 57))	('NSCLC', 'Disease', (65, 70))
443216	33130216	In summary, we describe the discovery of CCT3833, a new panRAF/SRC inhibitor, and show that it is effective in KRAS-mutant cancer models, because RAF and SRC are central nodes in KRAS-mutant cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('KRAS-mutant', 'Var', (111, 122))	('cancers', 'Disease', (191, 198))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('CCT3833', 'Var', (41, 48))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('CCT3833', 'Chemical', '-', (41, 48))
443217	33130216	CCT3833 differs from the RAF dimer inhibitor LY3009120 because it also inhibits SRC and is effective in PDAC.	('LY3009120', 'Chemical', 'MESH:C000600963', (45, 54))	('CCT3833', 'Var', (0, 7))	('SRC', 'MPA', (80, 83))	('PDAC', 'Disease', (104, 108))	('CCT3833', 'Chemical', '-', (0, 7))	('PDAC', 'Phenotype', 'HP:0006725', (104, 108))	('inhibits', 'NegReg', (71, 79))
443218	33130216	We posit that CCT3833 inhibits tumor growth in RAS-mutant models through on-target inhibition of BRAF and CRAF, and additional on-target inhibition of SRC.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('CRAF', 'Gene', '5894', (106, 110))	('inhibition', 'NegReg', (83, 93))	('CCT3833', 'Chemical', '-', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('RAS-mutant', 'Var', (47, 57))	('inhibition', 'NegReg', (137, 147))	('CCT3833', 'Var', (14, 21))	('SRC', 'Gene', (151, 154))	('inhibits', 'NegReg', (22, 30))	('BRAF', 'Gene', '673', (97, 101))	('CRAF', 'Gene', (106, 110))	('BRAF', 'Gene', (97, 101))
443219	33130216	Critically, CCT3833 induces tumor cell death and elicits therapeutic efficacy at well-tolerated doses in mice, and it is evaluated in patients in a phase I clinical trial, achieving a proof-of-concept unconfirmed clinical response in a patient with aggressive KRAS-mutant spindle cell sarcoma who was not eligible for other treatments.	('Critically', 'Disease', (0, 10))	('sarcoma', 'Disease', 'MESH:D012509', (285, 292))	('sarcoma', 'Disease', (285, 292))	('elicits', 'Reg', (49, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CCT3833', 'Chemical', '-', (12, 19))	('tumor cell death', 'Disease', 'MESH:D003643', (28, 44))	('patients', 'Species', '9606', (134, 142))	('KRAS-mutant', 'Var', (260, 271))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('patient', 'Species', '9606', (236, 243))	('mice', 'Species', '10090', (105, 109))	('tumor cell death', 'Disease', (28, 44))	('patient', 'Species', '9606', (134, 141))	('CCT3833', 'Var', (12, 19))
443223	31139520	Gene fusions of Ewing sarcoma breakpoint region 1 (EWSR1) with members of the cAMP response element-binding protein family (CREB) of transcription factors (CREB1, activating transcription factor 1 (ATF1), and cAMP response element modulator (CREM)) have been described in histopathologically diverse mesenchymal neoplasms such as AFH, hyalinising clear cell carcinomas of salivary glands, primary pulmonary myxoid sarcoma, and clear cell sarcoma.	('clear cell sarcoma', 'Disease', (427, 445))	('described', 'Reg', (259, 268))	('EWSR1', 'Gene', '2130', (51, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (414, 421))	('ATF1', 'Gene', (198, 202))	('cAMP response element modulator', 'Gene', '1390', (209, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (438, 445))	('Ewing sarcoma breakpoint region 1', 'Gene', (16, 49))	('activating transcription factor 1', 'Gene', '466', (163, 196))	('AFH', 'Disease', (330, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('carcinomas', 'Phenotype', 'HP:0030731', (358, 368))	('neoplasms', 'Phenotype', 'HP:0002664', (312, 321))	('fusions', 'Var', (5, 12))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('cAMP', 'Chemical', '-', (209, 213))	('CREB', 'Gene', (124, 128))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (300, 321))	('CREB', 'Gene', (156, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('primary pulmonary myxoid sarcoma', 'Disease', (389, 421))	('CREM', 'Gene', (242, 246))	('ATF1', 'Gene', '466', (198, 202))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (16, 49))	('EWSR1', 'Gene', (51, 56))	('carcinomas of salivary glands', 'Phenotype', 'HP:0100684', (358, 387))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (427, 445))	('CREM', 'Gene', '1390', (242, 246))	('CREB1', 'Gene', (156, 161))	('activating transcription factor 1', 'Gene', (163, 196))	('CREB', 'Gene', '1385', (124, 128))	('cAMP response element modulator', 'Gene', (209, 240))	('CREB', 'Gene', '1385', (156, 160))	('primary pulmonary myxoid sarcoma', 'Disease', 'MESH:D045888', (389, 421))	('CREB1', 'Gene', '1385', (156, 161))	('cAMP', 'Chemical', '-', (78, 82))	('mesenchymal neoplasms', 'Disease', (300, 321))	('carcinomas of salivary glands', 'Disease', 'MESH:D012468', (358, 387))	('carcinomas of salivary glands', 'Disease', (358, 387))
443233	31139520	Molecular genetic studies have revealed that AFH often demonstrates Ewing sarcoma breakpoint region 1-cAMP response element binding 1 (EWSR1-CREB1) fusion as a result of t(2:22) (q33;q12) and, less commonly, Ewing sarcoma breakpoint region 1-activating transcription factor 1 (EWSR1-ATF1) or fused in sarcoma-activating transcription factor 1 (FUS-ATF1) resulting respectively from t(12:22) (q13;q12) or t(12;16) (q13;p11).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (208, 221))	('p11', 'Gene', (418, 421))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (68, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (301, 308))	('FUS-ATF1', 'Gene', (344, 352))	('CREB1', 'Gene', (141, 146))	('Ewing sarcoma breakpoint region 1', 'Gene', (208, 241))	('fused in sarcoma-activating transcription factor 1', 'Gene', (292, 342))	('ATF1', 'Gene', (348, 352))	('activating transcription factor 1', 'Gene', (242, 275))	('ATF1', 'Gene', (283, 287))	('EWSR1', 'Gene', '2130', (135, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('t(2:22) (q33;q12', 'Var', (170, 186))	('CREB1', 'Gene', '1385', (141, 146))	('EWSR1', 'Gene', '2130', (277, 282))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (208, 241))	('activating transcription factor 1', 'Gene', '466', (309, 342))	('ATF1', 'Gene', '466', (348, 352))	('ATF1', 'Gene', '466', (283, 287))	('FUS-ATF1', 'Gene', '466;2521', (344, 352))	('Ewing sarcoma breakpoint region 1', 'Gene', (68, 101))	('EWSR1', 'Gene', (135, 140))	('cAMP', 'Chemical', '-', (102, 106))	('p11', 'Gene', '6281', (418, 421))	('EWSR1', 'Gene', (277, 282))	('fused in sarcoma-activating transcription factor 1', 'Gene', '466', (292, 342))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('activating transcription factor 1', 'Gene', '466', (242, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
443235	31139520	EWSR1-ATF1 fusions have been found in clear cell sarcoma and the hyalinising clear cell carcinoma of the salivary gland, whereas EWSR1-CREB1 fusion is the only fusion reported in primary pulmonary myxoid sarcoma to date.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('CREB1', 'Gene', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('primary pulmonary myxoid sarcoma', 'Disease', (179, 211))	('CREB1', 'Gene', '1385', (135, 140))	('ATF1', 'Gene', (6, 10))	('EWSR1', 'Gene', '2130', (0, 5))	('carcinoma of the salivary gland', 'Phenotype', 'HP:0100684', (88, 119))	('EWSR1', 'Gene', (129, 134))	('primary pulmonary myxoid sarcoma', 'Disease', 'MESH:D045888', (179, 211))	('fusions', 'Var', (11, 18))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (38, 56))	('ATF1', 'Gene', '466', (6, 10))	('carcinoma of the salivary gland', 'Disease', 'MESH:D012468', (88, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('EWSR1', 'Gene', (0, 5))	('found', 'Reg', (29, 34))	('carcinoma of the salivary gland', 'Disease', (88, 119))	('clear cell sarcoma', 'Disease', (38, 56))	('EWSR1', 'Gene', '2130', (129, 134))
443254	31139520	The analysis confirmed the disruption of the EWSR1 gene at 22q12 and the disruption of the CREB1 gene at 2q33, without disruption of the ATF gene at 12q13.	('EWSR1', 'Gene', (45, 50))	('CREB1', 'Gene', '1385', (91, 96))	('EWSR1', 'Gene', '2130', (45, 50))	('disruption', 'Var', (27, 37))	('CREB1', 'Gene', (91, 96))	('ATF', 'Gene', '2668', (137, 140))	('ATF', 'Gene', (137, 140))	('disruption', 'Var', (73, 83))
443265	31139520	The majority of the EWSR1 rearrangements in the myxoid variant involve EWSR1-CREB1 with, less commonly, EWSR1-ATF1 resulting from t(12;22) (q13;q12).	('t(12;22) (q13;q12', 'Var', (130, 147))	('ATF1', 'Gene', (110, 114))	('EWSR1', 'Gene', (104, 109))	('EWSR1', 'Gene', '2130', (20, 25))	('ATF1', 'Gene', '466', (110, 114))	('CREB1', 'Gene', '1385', (77, 82))	('EWSR1', 'Gene', (71, 76))	('CREB1', 'Gene', (77, 82))	('EWSR1', 'Gene', '2130', (104, 109))	('EWSR1', 'Gene', (20, 25))	('rearrangements', 'Var', (26, 40))	('EWSR1', 'Gene', '2130', (71, 76))
443346	28168073	On FDG-PET/CT, there was no accumulation in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('FDG-PET/CT', 'Var', (3, 13))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
443348	28168073	According to the immunohistochemical examination, the spindle cells were CK AE1/3 (+), alpha-SMA (+), S100 (-), desmin (-), Bcl2 (+), and TdT (-).	('desmin', 'Gene', '1674', (112, 118))	('AE1/3', 'Gene', '6521;6508', (76, 81))	('TdT', 'Gene', (138, 141))	('Bcl2', 'Gene', (124, 128))	('TdT', 'Gene', '1791', (138, 141))	('Bcl2', 'Gene', '596', (124, 128))	('desmin', 'Gene', (112, 118))	('AE1/3', 'Gene', (76, 81))	('S100', 'Var', (102, 106))
443395	26735859	Most radiation-induced AS show MYC gene amplifications, with a subset of cases harboring KDR, PTPRB and PLCG1 mutations.	('PTPRB', 'Gene', (94, 99))	('mutations', 'Var', (110, 119))	('MYC', 'Gene', (31, 34))	('AS', 'Gene', '23047', (23, 25))	('KDR', 'Gene', '3791', (89, 92))	('PLCG1', 'Gene', (104, 109))	('AS', 'Phenotype', 'HP:0200058', (23, 25))	('PLCG1', 'Gene', '5335', (104, 109))	('MYC', 'Gene', '4609', (31, 34))	('KDR', 'Gene', (89, 92))	('PTPRB', 'Gene', '5787', (94, 99))	('amplifications', 'Var', (40, 54))
443400	26735859	Concurrent CIC mutations and CIC rearrangements were identified in both index cases, with a CIC-LEUTX fusion detected in one case.	('men', 'Species', '9606', (42, 45))	('LEUTX', 'Gene', (96, 101))	('LEUTX', 'Gene', '342900', (96, 101))	('CIC', 'Gene', '23152', (29, 32))	('mutations', 'Var', (15, 24))	('CIC', 'Gene', '23152', (92, 95))	('CIC', 'Gene', '23152', (11, 14))	('CIC', 'Gene', (29, 32))	('CIC', 'Gene', (92, 95))	('CIC', 'Gene', (11, 14))
443404	26735859	In contrast, PLCG1 and KDR mutations occurred in both primary and secondary AS, accounting for 9.5% and 7%, respectively, with a predilection for breast and bone/viscera location, regardless of MYC status.	('mutations', 'Var', (27, 36))	('AS', 'Phenotype', 'HP:0200058', (76, 78))	('MYC', 'Gene', '4609', (194, 197))	('KDR', 'Gene', '3791', (23, 26))	('PLCG1', 'Gene', '5335', (13, 18))	('occurred', 'Reg', (37, 45))	('breast', 'Disease', (146, 152))	('MYC', 'Gene', (194, 197))	('KDR', 'Gene', (23, 26))	('AS', 'Gene', '23047', (76, 78))	('PLCG1', 'Gene', (13, 18))
443414	26735859	Recurrent somatic mutations involving angiogenic signaling pathways, such as KDR, PTPRB, and PLCG1, have been identified in about 40% of AS, while only rare mutations were reported in RAS, PIK3CA, TP53, FLT4, and TIE1.	('TIE1', 'Gene', '7075', (213, 217))	('PLCG1', 'Gene', (93, 98))	('PIK3CA', 'Gene', (189, 195))	('TP53', 'Gene', (197, 201))	('KDR', 'Gene', '3791', (77, 80))	('AS', 'Gene', '23047', (137, 139))	('AS', 'Gene', '23047', (185, 187))	('identified', 'Reg', (110, 120))	('PLCG1', 'Gene', '5335', (93, 98))	('FLT4', 'Gene', '2324', (203, 207))	('FLT4', 'Gene', (203, 207))	('TP53', 'Gene', '7157', (197, 201))	('AS', 'Phenotype', 'HP:0200058', (137, 139))	('PIK3CA', 'Gene', '5290', (189, 195))	('AS', 'Phenotype', 'HP:0200058', (185, 187))	('PTPRB', 'Gene', '5787', (82, 87))	('PTPRB', 'Gene', (82, 87))	('KDR', 'Gene', (77, 80))	('angiogenic signaling pathways', 'Pathway', (38, 67))	('TIE1', 'Gene', (213, 217))	('mutations', 'Var', (18, 27))
443415	26735859	PTPRB mutations with or without co-existing PLCG1 mutations have been reported exclusively in secondary or MYC-amplified AS.	('MYC', 'Gene', '4609', (107, 110))	('PLCG1', 'Gene', '5335', (44, 49))	('MYC', 'Gene', (107, 110))	('reported', 'Reg', (70, 78))	('PTPRB', 'Gene', '5787', (0, 5))	('PTPRB', 'Gene', (0, 5))	('AS', 'Gene', '23047', (121, 123))	('PLCG1', 'Gene', (44, 49))	('AS', 'Phenotype', 'HP:0200058', (121, 123))	('secondary', 'Disease', (94, 103))	('mutations', 'Var', (6, 15))
443416	26735859	In contrast, KDR mutations have been reported in both radiation-induced AS after breast cancer and primary AS (breast and heart).	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('KDR', 'Gene', '3791', (13, 16))	('reported', 'Reg', (37, 45))	('AS', 'Gene', '23047', (72, 74))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('AS', 'Phenotype', 'HP:0200058', (72, 74))	('KDR', 'Gene', (13, 16))	('AS', 'Phenotype', 'HP:0200058', (107, 109))	('mutations', 'Var', (17, 26))	('AS', 'Gene', '23047', (107, 109))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
443421	26735859	The candidate abnormalities were then screened in a large and diverse cohort of AS spanning different clinicopathologic features and compared to other known genetic events, such as PLCG1/KDR mutations and MYC/FLT4 amplification.	('MYC', 'Gene', '4609', (205, 208))	('KDR', 'Gene', '3791', (187, 190))	('PLCG1', 'Gene', '5335', (181, 186))	('FLT4', 'Gene', '2324', (209, 213))	('FLT4', 'Gene', (209, 213))	('mutations', 'Var', (191, 200))	('KDR', 'Gene', (187, 190))	('MYC', 'Gene', (205, 208))	('AS', 'Gene', '23047', (80, 82))	('AS', 'Phenotype', 'HP:0200058', (80, 82))	('PLCG1', 'Gene', (181, 186))
443450	26735859	The FISH break-apart assay confirmed the presence of CIC rearrangements, with small and constant gaps, typical for an intra-chromosomal translocation (Fig.	('men', 'Species', '9606', (66, 69))	('rearrangements', 'Var', (57, 71))	('CIC', 'Gene', (53, 56))	('CIC', 'Gene', '23152', (53, 56))
443463	26735859	The MuTect and VarScan algorithms applied on the RNAseq data identified co-existent missense CIC mutations in both index cases, but not in the remaining 3 AS with classic vasoformative morphology.	('CIC', 'Gene', '23152', (93, 96))	('mutations', 'Var', (97, 106))	('CIC', 'Gene', (93, 96))	('AS', 'Gene', '23047', (155, 157))	('missense', 'Var', (84, 92))	('AS', 'Phenotype', 'HP:0200058', (155, 157))
443464	26735859	AS1 harbored a CIC exon 15 mutation and AS2 a CIC exon 18 mutation, both being validated by Sanger sequencing in the tumor DNA, but not present in the germline DNA extracted from normal tissue (Fig.	('CIC', 'Gene', '23152', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CIC', 'Gene', '23152', (15, 18))	('AS2', 'Gene', '11883', (40, 43))	('tumor', 'Disease', (117, 122))	('AS2', 'Gene', (40, 43))	('CIC', 'Gene', (46, 49))	('AS', 'Phenotype', 'HP:0200058', (40, 42))	('mutation', 'Var', (27, 35))	('CIC', 'Gene', (15, 18))	('AS', 'Phenotype', 'HP:0200058', (0, 2))	('AS1', 'Gene', '5729', (0, 3))	('AS1', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
443465	26735859	As additional hot spot mutations were reported in oligodendroglioma, including CIC exons 5, 19, and 20, we screened an additional 95 AS for these 5 exons by direct sequencing.	('CIC', 'Gene', (79, 82))	('AS', 'Gene', '23047', (133, 135))	('AS', 'Phenotype', 'HP:0200058', (133, 135))	('mutations', 'Var', (23, 32))	('oligodendroglioma', 'Disease', (50, 67))	('oligodendroglioma', 'Disease', 'MESH:D009837', (50, 67))	('CIC', 'Gene', '23152', (79, 82))
443467	26735859	AS6 had two synchronous CIC exon 19 mutations and AS7 harbored a homozygous exon 19 mutation (Fig.	('AS', 'Gene', '23047', (50, 52))	('synchronous CIC', 'Disease', (12, 27))	('synchronous CIC', 'Disease', 'MESH:D009378', (12, 27))	('AS', 'Phenotype', 'HP:0200058', (50, 52))	('mutations', 'Var', (36, 45))	('AS', 'Gene', '23047', (0, 2))	('AS', 'Phenotype', 'HP:0200058', (0, 2))
443469	26735859	In total we identified 9 (9%) AS harboring various CIC alterations, including gene rearrangements and/or missense mutations; their clinicopathologic features being summarized in Table 1.	('gene rearrangements', 'Var', (78, 97))	('missense mutations', 'Var', (105, 123))	('CIC', 'Gene', (51, 54))	('AS', 'Gene', '23047', (30, 32))	('AS', 'Phenotype', 'HP:0200058', (30, 32))	('men', 'Species', '9606', (92, 95))	('CIC', 'Gene', '23152', (51, 54))
443474	26735859	All except one lacked other genetic abnormalities; only one primary breast AS (AS4) showed coexisting CIC and PLCG1 mutations.	('AS', 'Phenotype', 'HP:0200058', (79, 81))	('AS', 'Gene', '23047', (75, 77))	('genetic abnormalities', 'Disease', 'MESH:D030342', (28, 49))	('AS', 'Phenotype', 'HP:0200058', (75, 77))	('PLCG1', 'Gene', (110, 115))	('CIC', 'Gene', '23152', (102, 105))	('mutations', 'Var', (116, 125))	('genetic abnormalities', 'Disease', (28, 49))	('PLCG1', 'Gene', '5335', (110, 115))	('AS', 'Gene', '23047', (79, 81))	('CIC', 'Gene', (102, 105))
443475	26735859	Aside from the index cases, there were 2 additional CIC-mutant AS displaying an epithelioid phenotype, with limited vasoformation: a deep-seated soft tissue AS from the neck in a 21 year-old man, harboring 2 distinct CIC mutations (AS6) and a cutaneous scalp AS bearing a homozygous CIC mutation (AS7) (Fig.	('AS', 'Gene', '23047', (297, 299))	('AS', 'Phenotype', 'HP:0200058', (259, 261))	('AS', 'Phenotype', 'HP:0200058', (157, 159))	('CIC', 'Gene', '23152', (217, 220))	('man', 'Species', '9606', (191, 194))	('AS', 'Gene', '23047', (232, 234))	('mutations', 'Var', (221, 230))	('AS', 'Phenotype', 'HP:0200058', (297, 299))	('CIC', 'Gene', (283, 286))	('CIC', 'Gene', (52, 55))	('AS', 'Phenotype', 'HP:0200058', (232, 234))	('AS', 'Phenotype', 'HP:0200058', (63, 65))	('AS', 'Gene', '23047', (63, 65))	('AS', 'Gene', '23047', (259, 261))	('cutaneous scalp AS', 'Disease', 'MESH:C538225', (243, 261))	('CIC', 'Gene', (217, 220))	('CIC', 'Gene', '23152', (283, 286))	('AS', 'Gene', '23047', (157, 159))	('cutaneous scalp AS', 'Disease', (243, 261))	('CIC', 'Gene', '23152', (52, 55))
443476	26735859	The remaining 4 cases with single heterozygous CIC mutations exhibited a more classic morphology, with well to moderately formed vascular channels and pleomorphic cytology (Fig.	('CIC', 'Gene', '23152', (47, 50))	('mutations', 'Var', (51, 60))	('CIC', 'Gene', (47, 50))	('exhibited', 'Reg', (61, 70))
443479	26735859	By unsupervised hierarchical clustering of RNA sequencing data of >100 cases of various sarcoma types, the 2 index AS cases with CIC-gene rearrangements showed an overlapping gene signature with a group of SBRCTs, including CIC-DUX4 positive cases (data not shown).	('men', 'Species', '9606', (147, 150))	('CIC', 'Gene', (224, 227))	('AS', 'Phenotype', 'HP:0200058', (115, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('CIC', 'Gene', '23152', (129, 132))	('rearrangements', 'Var', (138, 152))	('DUX4', 'Gene', (228, 232))	('CIC', 'Gene', (129, 132))	('sarcoma', 'Disease', (88, 95))	('CIC', 'Gene', '23152', (224, 227))	('DUX4', 'Gene', '100288687', (228, 232))	('AS', 'Gene', '23047', (115, 117))
443484	26735859	A total of 11 (9.5%) AS harbored PLCG1 mutations of the 116 informative cases (Supplemental Table S4).	('AS', 'Gene', '23047', (21, 23))	('mutations', 'Var', (39, 48))	('harbored', 'Reg', (24, 32))	('PLCG1', 'Gene', (33, 38))	('men', 'Species', '9606', (85, 88))	('AS', 'Phenotype', 'HP:0200058', (21, 23))	('PLCG1', 'Gene', '5335', (33, 38))
443487	26735859	Most PLCG1 mutations (9, 82%) occurred in exon 18 (p.R707Q, 8; p.R707L), affecting the auto-inhibitory Src homology 2 (cSH2) domain, with only 2 in exon 11 (p.S345F), within the PLCx catalytic domain.	('PLCG1', 'Gene', '5335', (5, 10))	('mutations', 'Var', (11, 20))	('p.R707Q', 'Mutation', 'p.R707Q', (51, 58))	('p.R707L', 'Mutation', 'p.R707L', (63, 70))	('PLCG1', 'Gene', (5, 10))	('affecting', 'Reg', (73, 82))	('p.S345F', 'Mutation', 'rs559611655', (157, 164))	('p.R707Q', 'Var', (51, 58))
443488	26735859	Both PLCG1 p.S345F mutations occurred in primary AS, one each in breast and spleen.	('PLCG1', 'Gene', '5335', (5, 10))	('p.S345F', 'Mutation', 'rs559611655', (11, 18))	('occurred', 'Reg', (29, 37))	('PLCG1', 'Gene', (5, 10))	('p.S345F', 'Var', (11, 18))	('AS', 'Gene', '23047', (49, 51))	('AS', 'Phenotype', 'HP:0200058', (49, 51))
443491	26735859	KDR missense mutations were found in 8 (7%) of 113 informative cases (Supplemental Table S4), seen exclusively in female patients (mean age, 56 years; range 23-77).	('KDR', 'Gene', (0, 3))	('men', 'Species', '9606', (76, 79))	('missense mutations', 'Var', (4, 22))	('KDR', 'Gene', '3791', (0, 3))	('found', 'Reg', (28, 33))	('patients', 'Species', '9606', (121, 129))
443492	26735859	Five KDR mutations occurred in primary breast AS and 2 in secondary AS after radiotherapy for breast cancer, co-exhibiting MYC amplification.	('KDR', 'Gene', '3791', (5, 8))	('AS', 'Gene', '23047', (46, 48))	('AS', 'Phenotype', 'HP:0200058', (46, 48))	('mutations', 'Var', (9, 18))	('MYC', 'Gene', '4609', (123, 126))	('occurred', 'Reg', (19, 27))	('AS', 'Gene', '23047', (68, 70))	('AS', 'Phenotype', 'HP:0200058', (68, 70))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('KDR', 'Gene', (5, 8))	('MYC', 'Gene', (123, 126))	('breast cancer', 'Disease', (94, 107))
443494	26735859	The most common hot spot mutation was KDR exon 16 (codon 771; transmembrane domain) seen in 5 cases.	('codon', 'Var', (51, 56))	('KDR', 'Gene', (38, 41))	('KDR', 'Gene', '3791', (38, 41))
443495	26735859	Additional less common spots included KDR exon 15 mutation (codon 717 and 731, extracellular domain Ig-like C2 type 7) in 2 cases and KDR exon 24 (codon 1065, kinase domain) in 1 case.	('KDR', 'Gene', (38, 41))	('KDR', 'Gene', '3791', (134, 137))	('codon 717', 'Var', (60, 69))	('KDR', 'Gene', '3791', (38, 41))	('codon', 'Var', (147, 152))	('KDR', 'Gene', (134, 137))
443497	26735859	As both KDR and PLCG1 genes are involved in the VEGFR2 (vascular endothelial growth factor receptor 2) signaling pathway, it is not surprising that activating KDR/PLCG1 mutations are present in similar AS subsets, such as primary or secondary breast AS (15/52, 29%) and bone/viscera (3/19, 16%) locations (p = 0.012).	('AS', 'Gene', '23047', (250, 252))	('mutations', 'Var', (169, 178))	('AS', 'Gene', '23047', (202, 204))	('involved', 'Reg', (32, 40))	('AS', 'Phenotype', 'HP:0200058', (250, 252))	('VEGFR2', 'Gene', (48, 54))	('PLCG1', 'Gene', (163, 168))	('AS', 'Phenotype', 'HP:0200058', (202, 204))	('PLCG1', 'Gene', (16, 21))	('PLCG1', 'Gene', '5335', (16, 21))	('vascular endothelial growth factor receptor 2', 'Gene', (56, 101))	('VEGFR2', 'Gene', '3791', (48, 54))	('KDR', 'Gene', (159, 162))	('KDR', 'Gene', (8, 11))	('activating', 'PosReg', (148, 158))	('PLCG1', 'Gene', '5335', (163, 168))	('KDR', 'Gene', '3791', (159, 162))	('vascular endothelial growth factor receptor 2', 'Gene', '3791', (56, 101))	('KDR', 'Gene', '3791', (8, 11))
443507	26735859	None of them had PLCG1/KDR mutations.	('mutations', 'Var', (27, 36))	('KDR', 'Gene', '3791', (23, 26))	('PLCG1', 'Gene', '5335', (17, 22))	('KDR', 'Gene', (23, 26))	('PLCG1', 'Gene', (17, 22))
443514	26735859	The presence of MYC amplification had only a trend towards worse DFS (p=0.083) and OS (p = 0.062), but the presence of FLT4 amplification was associated with a short OS (p = 0.037).	('MYC', 'Gene', '4609', (16, 19))	('FLT4', 'Gene', (119, 123))	('presence', 'Var', (107, 115))	('FLT4', 'Gene', '2324', (119, 123))	('MYC', 'Gene', (16, 19))	('DFS', 'MPA', (65, 68))	('short OS', 'Disease', (160, 168))	('amplification', 'Var', (124, 137))
443516	26735859	Even at the molecular level, AS emerges as a multifaceted disease, with mostly non-overlapping genetic signatures across clinical subsets; the majority of the alterations described to date, such as MYC/FLT4 amplifications and PLCG1/PTPRB mutations, affecting secondary AS.	('PTPRB', 'Gene', '5787', (232, 237))	('AS', 'Phenotype', 'HP:0200058', (29, 31))	('PTPRB', 'Gene', (232, 237))	('alterations', 'Var', (159, 170))	('PLCG1', 'Gene', '5335', (226, 231))	('FLT4', 'Gene', (202, 206))	('MYC', 'Gene', '4609', (198, 201))	('mutations', 'Var', (238, 247))	('AS', 'Phenotype', 'HP:0200058', (269, 271))	('FLT4', 'Gene', '2324', (202, 206))	('amplifications', 'Var', (207, 221))	('PLCG1', 'Gene', (226, 231))	('AS', 'Gene', '23047', (269, 271))	('MYC', 'Gene', (198, 201))	('AS', 'Gene', '23047', (29, 31))
443521	26735859	The results are remarkable with identification of similar CIC gene rearrangements co-existing with CIC mutations in both cases.	('mutations', 'Var', (103, 112))	('CIC', 'Gene', '23152', (99, 102))	('men', 'Species', '9606', (76, 79))	('CIC', 'Gene', '23152', (58, 61))	('CIC', 'Gene', (99, 102))	('CIC', 'Gene', (58, 61))
443523	26735859	In total, CIC alterations were detected in 9% of AS cases showing a predilection for young patients and lacking MYC/FLT4 amplifications.	('alterations', 'Var', (14, 25))	('CIC', 'Gene', (10, 13))	('detected', 'Reg', (31, 39))	('FLT4', 'Gene', (116, 120))	('patients', 'Species', '9606', (91, 99))	('FLT4', 'Gene', '2324', (116, 120))	('MYC', 'Gene', '4609', (112, 115))	('AS', 'Phenotype', 'HP:0200058', (49, 51))	('CIC', 'Gene', '23152', (10, 13))	('AS', 'Gene', '23047', (49, 51))	('MYC', 'Gene', (112, 115))
443528	26735859	CIC-related fusions account for two-thirds of EWSR1-negative SBRCTs, with the CIC-DUX4 fusion exhibiting high chimeric CIC protein expression and an enhanced transcriptional activity of CIC downstream targets, including the PEA3 family genes, such as ETV1, ETV4, and ETV5.	('DUX4', 'Gene', '100288687', (82, 86))	('SBRCTs', 'Disease', (61, 67))	('CIC', 'Gene', '23152', (186, 189))	('PEA3', 'Gene', (224, 228))	('ETV1', 'Gene', '2115', (251, 255))	('ETV5', 'Gene', (267, 271))	('CIC', 'Gene', (78, 81))	('PEA3', 'Gene', '2118', (224, 228))	('CIC', 'Gene', '23152', (119, 122))	('chimeric', 'MPA', (110, 118))	('CIC', 'Gene', '23152', (0, 3))	('EWSR1', 'Gene', '2130', (46, 51))	('ETV5', 'Gene', '2119', (267, 271))	('ETV4', 'Gene', (257, 261))	('CIC', 'Gene', '23152', (78, 81))	('CIC', 'Gene', (186, 189))	('enhanced', 'PosReg', (149, 157))	('DUX4', 'Gene', (82, 86))	('transcriptional activity', 'MPA', (158, 182))	('ETV1', 'Gene', (251, 255))	('EWSR1', 'Gene', (46, 51))	('expression', 'MPA', (131, 141))	('CIC', 'Gene', (119, 122))	('ETV4', 'Gene', '2118', (257, 261))	('fusion', 'Var', (87, 93))	('CIC', 'Gene', (0, 3))
443531	26735859	A high frequency (69-78%) of homozygous CIC mutations has been reported in oligodendrogliomas with 1p/19q deletion.	('1p/19q deletion', 'Var', (99, 114))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (75, 93))	('CIC', 'Gene', '23152', (40, 43))	('oligodendrogliomas', 'Disease', (75, 93))	('CIC', 'Gene', (40, 43))	('mutations', 'Var', (44, 53))
443532	26735859	The biallelic CIC inactivation caused by mutation and deletion also results in up-regulation of the CIC-targeted genes (ETV1, ETV4, ETV5, CCND1).	('CIC', 'Gene', (100, 103))	('CIC', 'Gene', (14, 17))	('ETV1', 'Gene', (120, 124))	('inactivation', 'NegReg', (18, 30))	('ETV5', 'Gene', (132, 136))	('ETV4', 'Gene', (126, 130))	('deletion', 'Var', (54, 62))	('CIC', 'Gene', '23152', (100, 103))	('CCND1', 'Gene', '595', (138, 143))	('ETV1', 'Gene', '2115', (120, 124))	('ETV4', 'Gene', '2118', (126, 130))	('mutation', 'Var', (41, 49))	('CCND1', 'Gene', (138, 143))	('CIC', 'Gene', '23152', (14, 17))	('ETV5', 'Gene', '2119', (132, 136))	('up-regulation', 'PosReg', (79, 92))
443533	26735859	Most CIC mutations reported in oligodendroglioma occur in the HMG-domain or are protein-truncating mutations.	('oligodendroglioma', 'Disease', (31, 48))	('mutations', 'Var', (9, 18))	('CIC', 'Gene', '23152', (5, 8))	('oligodendroglioma', 'Disease', 'MESH:D009837', (31, 48))	('CIC', 'Gene', (5, 8))
443534	26735859	In contrast, CIC mutations identified in AS clustered in exons 18-20 (single, double or homozygous mutations), targeting the nuclear localization and repressor activity of the CIC protein.	('nuclear localization', 'MPA', (125, 145))	('CIC', 'Gene', (176, 179))	('repressor activity', 'MPA', (150, 168))	('CIC', 'Gene', '23152', (13, 16))	('AS', 'Gene', '23047', (41, 43))	('targeting', 'Reg', (111, 120))	('AS', 'Phenotype', 'HP:0200058', (41, 43))	('CIC', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))	('CIC', 'Gene', '23152', (176, 179))
443542	26735859	The 3 PLCG1 mutations (p.R707Q) co-existed with PTPRB mutations and occurred in 9% of AS tested.	('PLCG1', 'Gene', (6, 11))	('PLCG1', 'Gene', '5335', (6, 11))	('p.R707Q', 'Var', (23, 30))	('PTPRB', 'Gene', '5787', (48, 53))	('AS', 'Gene', '23047', (86, 88))	('p.R707Q', 'Mutation', 'p.R707Q', (23, 30))	('PTPRB', 'Gene', (48, 53))	('AS', 'Phenotype', 'HP:0200058', (86, 88))
443544	26735859	A different PLCG1 missense mutation (p.S345F) was also more recently reported in cutaneous (19%) and nodal (13%) peripheral T-cell lymphoma.	('T-cell lymphoma', 'Disease', (124, 139))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (124, 139))	('cell lymphoma', 'Phenotype', 'HP:0012191', (126, 139))	('p.S345F', 'Var', (37, 44))	('reported', 'Reg', (69, 77))	('cutaneous', 'Disease', (81, 90))	('PLCG1', 'Gene', (12, 17))	('p.S345F', 'Mutation', 'rs559611655', (37, 44))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (124, 139))	('PLCG1', 'Gene', '5335', (12, 17))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
443545	26735859	Our study screened a large cohort of AS cases for both hot spots and found 11 (9.5%) PLCG1-mutated cases, confirming that p.R707Q mutation occurs in both primary (breast, heart) and secondary AS.	('p.R707Q', 'Mutation', 'p.R707Q', (122, 129))	('PLCG1', 'Gene', '5335', (85, 90))	('AS', 'Gene', '23047', (37, 39))	('AS', 'Phenotype', 'HP:0200058', (37, 39))	('AS', 'Gene', '23047', (192, 194))	('p.R707Q', 'Var', (122, 129))	('AS', 'Phenotype', 'HP:0200058', (192, 194))	('occurs', 'Reg', (139, 145))	('PLCG1', 'Gene', (85, 90))
443546	26735859	Our results also show PLCG1 p.S345F in 2 primary AS (breast, spleen), a previously unreported finding.	('PLCG1', 'Gene', '5335', (22, 27))	('p.S345F', 'Mutation', 'rs559611655', (28, 35))	('p.S345F', 'Var', (28, 35))	('PLCG1', 'Gene', (22, 27))	('AS', 'Gene', '23047', (49, 51))	('AS', 'Phenotype', 'HP:0200058', (49, 51))
443548	26735859	The p.S345F mutation alters the PLCx protein catalytic domain, thus activating the downstream calmodulin/calcineurin signaling through facilitating the interaction with lipids and its phosphodiesterase activity.	('facilitating', 'PosReg', (135, 147))	('activating', 'PosReg', (68, 78))	('lipids', 'Protein', (169, 175))	('phosphodiesterase activity', 'MPA', (184, 210))	('PLCx', 'Enzyme', (32, 36))	('calmodulin/calcineurin signaling', 'MPA', (94, 126))	('catalytic domain', 'MPA', (45, 61))	('alters', 'Reg', (21, 27))	('interaction', 'Interaction', (152, 163))	('lipids', 'Chemical', 'MESH:D008055', (169, 175))	('p.S345F', 'Var', (4, 11))	('p.S345F', 'Mutation', 'rs559611655', (4, 11))
443549	26735859	In contrast, the codon 707 mutation maps at the c-terminal Src homology 2 (cSH2) domain; mutations at this site preventing the intramolecular interaction of phosphorylated PLCgamma1 and triggering constitutive activation of DAG and IP-dependent signaling.	('intramolecular interaction', 'MPA', (127, 153))	('IP', 'Chemical', '-', (232, 234))	('PLCgamma1', 'Gene', '5335', (172, 181))	('preventing', 'NegReg', (112, 122))	('DAG', 'Chemical', 'MESH:D004075', (224, 227))	('mutations', 'Var', (89, 98))	('triggering', 'Reg', (186, 196))	('DAG', 'Pathway', (224, 227))	('PLCgamma1', 'Gene', (172, 181))	('constitutive activation', 'MPA', (197, 220))
443550	26735859	In our previous study, we reported activating KDR mutations in 10% of AS, being only identified in primary breast or secondary AS after breast cancer.	('AS', 'Phenotype', 'HP:0200058', (70, 72))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('KDR', 'Gene', '3791', (46, 49))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('mutations', 'Var', (50, 59))	('breast cancer', 'Disease', (136, 149))	('AS', 'Gene', '23047', (127, 129))	('activating', 'PosReg', (35, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('KDR', 'Gene', (46, 49))	('AS', 'Phenotype', 'HP:0200058', (127, 129))	('AS', 'Gene', '23047', (70, 72))
443551	26735859	Kunze et al reported two cases of cardiac AS harboring KDR mutation each in the extracellular immunogloulin domain (R720W) and transmembrane domain (T771K).	('R720W', 'Var', (116, 121))	('KDR', 'Gene', (55, 58))	('AS', 'Gene', '23047', (42, 44))	('T771K', 'Mutation', 'p.T771K', (149, 154))	('T771K', 'Var', (149, 154))	('KDR', 'Gene', '3791', (55, 58))	('AS', 'Phenotype', 'HP:0200058', (42, 44))	('R720W', 'Mutation', 'p.R720W', (116, 121))
443553	26735859	Our results also show that KDR and PLCG1 mutations, accounting for 17% of AS cases, are mutually exclusive and evenly distributed among primary and secondary AS, mainly affecting breast and only occasionally present in bone or viscera, with no impact on morphology or outcome.	('mutations', 'Var', (41, 50))	('KDR', 'Gene', (27, 30))	('AS', 'Gene', '23047', (74, 76))	('PLCG1', 'Gene', (35, 40))	('breast', 'Disease', (179, 185))	('AS', 'Gene', '23047', (158, 160))	('AS', 'Phenotype', 'HP:0200058', (74, 76))	('AS', 'Phenotype', 'HP:0200058', (158, 160))	('KDR', 'Gene', '3791', (27, 30))	('PLCG1', 'Gene', '5335', (35, 40))	('affecting', 'Reg', (169, 178))
443554	26735859	Both KDR and PLCG1 mutations share a common VEGFR2/PLCgamma1 signaling pathway.	('VEGFR2', 'Gene', (44, 50))	('PLCgamma1', 'Gene', (51, 60))	('KDR', 'Gene', '3791', (5, 8))	('PLCG1', 'Gene', '5335', (13, 18))	('mutations', 'Var', (19, 28))	('PLCgamma1', 'Gene', '5335', (51, 60))	('VEGFR2', 'Gene', '3791', (44, 50))	('KDR', 'Gene', (5, 8))	('PLCG1', 'Gene', (13, 18))
443556	26735859	Although activating KDR mutations are relatively rare in AS, KDR is universally overexpressed in AS through alternative yet undefined mechanisms.	('AS', 'Gene', '23047', (97, 99))	('KDR', 'Gene', (20, 23))	('AS', 'Phenotype', 'HP:0200058', (97, 99))	('AS', 'Phenotype', 'HP:0200058', (57, 59))	('KDR', 'Gene', '3791', (61, 64))	('activating', 'PosReg', (9, 19))	('KDR', 'Gene', '3791', (20, 23))	('mutations', 'Var', (24, 33))	('KDR', 'Gene', (61, 64))	('AS', 'Gene', '23047', (57, 59))
443558	26735859	An alternative mechanism of VEGFR activation in secondary AS is the presence of FLT4 (a.k.a.	('AS', 'Phenotype', 'HP:0200058', (58, 60))	('VEGFR', 'Gene', '3791', (28, 33))	('AS', 'Gene', '23047', (58, 60))	('presence', 'Var', (68, 76))	('FLT4', 'Gene', (80, 84))	('VEGFR', 'Gene', (28, 33))	('FLT4', 'Gene', '2324', (80, 84))
443559	26735859	VEGFR3) amplification, which mostly occurs in association with MYC amplification.	('MYC', 'Gene', (63, 66))	('amplification', 'Var', (8, 21))	('VEGFR3', 'Gene', (0, 6))	('MYC', 'Gene', '4609', (63, 66))	('VEGFR3', 'Gene', '2324', (0, 6))
443562	26735859	Only one case of a primary scalp AS had FLT4 amplification in the absence of MYC abnormalities by FISH.	('FLT4', 'Gene', '2324', (40, 44))	('MYC abnormalities', 'Disease', 'MESH:D000014', (77, 94))	('AS', 'Phenotype', 'HP:0200058', (33, 35))	('MYC abnormalities', 'Disease', (77, 94))	('FLT4', 'Gene', (40, 44))	('scalp', 'Disease', 'MESH:C538225', (27, 32))	('scalp', 'Disease', (27, 32))	('AS', 'Gene', '23047', (33, 35))	('amplification', 'Var', (45, 58))
443564	26735859	MYC deregulation is a well-known oncogenic event involving a wide array of human cancers, lying at the crossroads of diverse signal transduction pathways, including cell growth, metabolism, differentiation, transformation, cell cycle, and angiogenesis.	('MYC', 'Gene', (0, 3))	('deregulation', 'Var', (4, 16))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('MYC', 'Gene', '4609', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))
443572	26735859	We describe recurrent, novel, CIC gene rearrangements in a subset of young adults with primary soft tissue and visceral AS, with or without concurrent CIC mutations, associated with up-regulation of CIC-target genes, such as ETV1, ETV4, and ETV5.	('ETV5', 'Gene', (241, 245))	('AS', 'Gene', '23047', (120, 122))	('ETV4', 'Gene', '2118', (231, 235))	('men', 'Species', '9606', (48, 51))	('CIC', 'Gene', '23152', (30, 33))	('AS', 'Phenotype', 'HP:0200058', (120, 122))	('ETV1', 'Gene', '2115', (225, 229))	('rearrangements', 'Var', (39, 53))	('CIC', 'Gene', '23152', (151, 154))	('CIC', 'Gene', '23152', (199, 202))	('CIC', 'Gene', (30, 33))	('ETV1', 'Gene', (225, 229))	('CIC', 'Gene', (199, 202))	('ETV5', 'Gene', '2119', (241, 245))	('ETV4', 'Gene', (231, 235))	('CIC', 'Gene', (151, 154))	('up-regulation', 'PosReg', (182, 195))
443573	26735859	An additional subset of AS harbored only missense CIC mutations, occurring with predilection in younger patients with primary AS, and being associated with a highly aggressive clinical course.	('associated', 'Reg', (140, 150))	('CIC', 'Gene', '23152', (50, 53))	('missense', 'Var', (41, 49))	('AS', 'Gene', '23047', (126, 128))	('AS', 'Phenotype', 'HP:0200058', (126, 128))	('CIC', 'Gene', (50, 53))	('AS', 'Gene', '23047', (24, 26))	('AS', 'Phenotype', 'HP:0200058', (24, 26))	('patients', 'Species', '9606', (104, 112))
443574	26735859	The mutually exclusive KDR/PLCG1 mutations were present in both primary and secondary AS, but restricted to breast, bone and viscera, with no histologic or prognostic correlates.	('PLCG1', 'Gene', (27, 32))	('KDR', 'Gene', '3791', (23, 26))	('mutations', 'Var', (33, 42))	('present', 'Reg', (48, 55))	('PLCG1', 'Gene', '5335', (27, 32))	('AS', 'Gene', '23047', (86, 88))	('KDR', 'Gene', (23, 26))	('AS', 'Phenotype', 'HP:0200058', (86, 88))
443591	25030655	Over the last decade, unprecedented advances in the discovery of disease-specific genetic alterations and in the successful translation of mechanism-based targeted therapies have improved the outcome for patients with sarcoma and other cancer types.	('patients', 'Species', '9606', (204, 212))	('improved', 'PosReg', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('sarcoma', 'Disease', 'MESH:D012509', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('genetic alterations', 'Var', (82, 101))	('sarcoma', 'Disease', (218, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))
443601	25030655	Underlying these cancer hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions.	('genetic', 'Var', (78, 85))	('genome instability', 'Disease', (38, 56))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('inflammation', 'Disease', 'MESH:D007249', (134, 146))	('inflammation', 'Disease', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
443609	25030655	While more common cancers, such as non-small cell lung cancer (NSCLC; EGFR mutation, KRAS mutation, BRAF mutation, EML4-ALK- or ROS1 rearrangement, RET aberrant) and breast cancer (Her2/Neu, ER+/PR+) are increasingly being treated according to a biomarker-driven approach, the 'one size fits all' approach is still the standard of care for sarcoma patients.	('NSCLC', 'Disease', (63, 68))	('patients', 'Species', '9606', (348, 356))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('sarcoma', 'Disease', 'MESH:D012509', (340, 347))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('breast cancer', 'Disease', (166, 179))	('KRAS', 'Gene', (85, 89))	('Her2', 'Gene', '2064', (181, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('sarcoma', 'Disease', (340, 347))	('non-small cell lung cancer', 'Disease', (35, 61))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('cancers', 'Disease', (18, 25))	('Neu', 'Gene', (186, 189))	('Neu', 'Gene', '2064', (186, 189))	('EGFR', 'Gene', '1956', (70, 74))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('Her2', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (100, 104))	('EML4', 'Gene', (115, 119))	('ROS1', 'Gene', '6098', (128, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (340, 347))	('EML4', 'Gene', '27436', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('RET', 'Gene', '5979', (148, 151))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (35, 61))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (39, 61))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('ALK', 'Gene', '238', (120, 123))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('ALK', 'Gene', (120, 123))	('EGFR', 'Gene', (70, 74))	('ROS1', 'Gene', (128, 132))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (35, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('KRAS', 'Gene', '3845', (85, 89))	('RET', 'Gene', (148, 151))
443626	25030655	This data system should provide information to enable clinicians to predict the appropriate therapy (eg, imatinib for KIT-mutant GIST) and contraindications (eg, anti-EGFR monoclonal antibody therapy for KRAS-mutated colorectal cancer [CRC]).	('GIST', 'Phenotype', 'HP:0100723', (129, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('imatinib', 'Chemical', 'MESH:D000068877', (105, 113))	('KIT-mutant', 'Var', (118, 128))	('KRAS', 'Gene', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('colorectal cancer', 'Disease', (217, 234))	('KRAS', 'Gene', '3845', (204, 208))	('EGFR', 'Gene', '1956', (167, 171))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('EGFR', 'Gene', (167, 171))
443641	25030655	In another report, a patient with BRAF V600E-mutated GIST resistant to imatinib was treated successfully with the BRAF inhibitor dabrafenib.	('GIST', 'Phenotype', 'HP:0100723', (53, 57))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('V600E-mutated', 'Var', (39, 52))	('patient', 'Species', '9606', (21, 28))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('dabrafenib', 'Chemical', 'MESH:C561627', (129, 139))	('BRAF', 'Gene', '673', (34, 38))	('imatinib', 'Chemical', 'MESH:D000068877', (71, 79))	('BRAF', 'Gene', (34, 38))
443647	25030655	Evidence in Genetic Disease: For example, tuberous sclerosis complex (TSC) is caused by an aberrant TSC1 gene which results in up-regulation of the mTOR pathway.	('TSC1', 'Gene', (100, 104))	('up-regulation', 'PosReg', (127, 140))	('TSC', 'Gene', '7248;7249', (100, 103))	('mTOR', 'Gene', (148, 152))	('mTOR', 'Gene', '2475', (148, 152))	('TSC', 'Gene', '7248;7249', (70, 73))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (42, 60))	('TSC', 'Gene', (100, 103))	('TSC1', 'Gene', '7248', (100, 104))	('TSC', 'Gene', (70, 73))	('aberrant', 'Var', (91, 99))	('tuberous sclerosis', 'Disease', (42, 60))
443651	25030655	For instance, Ewing's sarcoma cell lines harboring the EWSR1-FLI1 gene translocation was shown to be markedly sensitive to poly(ADP-ribose) polymerase (PARP) inhibition as a single agent or in combination with temozolomide.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (14, 29))	('poly(ADP-ribose) polymerase', 'Gene', '142', (123, 150))	('PARP', 'Gene', '142', (152, 156))	('poly(ADP-ribose) polymerase', 'Gene', (123, 150))	("Ewing's sarcoma", 'Disease', (14, 29))	('EWSR1', 'Gene', (55, 60))	('gene translocation', 'Var', (66, 84))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (14, 29))	('FLI1', 'Gene', '2313', (61, 65))	('temozolomide', 'Chemical', 'MESH:D000077204', (210, 222))	('EWSR1', 'Gene', '2130', (55, 60))	('PARP', 'Gene', (152, 156))	('FLI1', 'Gene', (61, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('sensitive', 'MPA', (110, 119))
443654	25030655	In one study, genome sequencing identified loss-of-function mutation in TSC1 as a basis for everolimus sensitivity in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('loss-of-function', 'NegReg', (43, 59))	('mutation', 'Var', (60, 68))	('TSC1', 'Gene', (72, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (118, 132))	('bladder cancer', 'Disease', (118, 132))	('everolimus', 'Chemical', 'MESH:D000068338', (92, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))	('everolimus', 'MPA', (92, 102))	('TSC1', 'Gene', '7248', (72, 76))
443668	25030655	An exploratory morphoproteomic study of the resistant tumor specimen detected DR4 in the patient's tumor as the basis of sensitivity and the emergence of several prosurvival proteins (phosphorylated (p)-NF-kappaBp65 (Ser 536), p-STAT3 (Tyr 705), p-ERK 1/2 (Thr 202/Tyr 204), p-mTOR (Ser 2448), FASN, and Bcl-2) as plausible mechanisms of resistance.	('patient', 'Species', '9606', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('DR4', 'Gene', (78, 81))	('STAT3', 'Gene', (229, 234))	('Ser 2448', 'Var', (283, 291))	('Ser', 'Chemical', 'MESH:D012694', (283, 286))	('tumor', 'Disease', (99, 104))	('Tyr', 'Chemical', 'MESH:D014443', (265, 268))	('FASN', 'Gene', '2194', (294, 298))	('STAT3', 'Gene', '6774', (229, 234))	('Ser 536', 'Var', (217, 224))	('Thr', 'Chemical', 'MESH:D013912', (257, 260))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Bcl-2', 'Gene', (304, 309))	('Thr', 'Var', (257, 260))	('DR4', 'Gene', '3126', (78, 81))	('ERK 1/2', 'Gene', (248, 255))	('Ser', 'Chemical', 'MESH:D012694', (217, 220))	('mTOR', 'Gene', (277, 281))	('Bcl-2', 'Gene', '596', (304, 309))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('FASN', 'Gene', (294, 298))	('Tyr', 'Chemical', 'MESH:D014443', (236, 239))	('mTOR', 'Gene', '2475', (277, 281))	('tumor', 'Disease', (54, 59))	('ERK 1/2', 'Gene', '5595;5594', (248, 255))
443673	25030655	The sequencing uncovered a KIAA1549-BRAF mutation resulting from a tandem duplication event in the background of a homozygous deletion of PTEN as a driving genomic aberration.	('PTEN', 'Gene', (138, 142))	('PTEN', 'Gene', '5728', (138, 142))	('tandem duplication', 'Var', (67, 85))	('KIAA1549-BRAF', 'Disease', (27, 40))	('KIAA1549-BRAF', 'Disease', 'None', (27, 40))
443678	25030655	The trials are adaptively designed to expand to include tumor types with that aberration that respond and tumor types that shut down and do not respond.	('aberration', 'Var', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (106, 111))
443679	25030655	For instance, the NCT01524978 BRAF umbrella trial enrolls BRAF V600-mutant patients with tumor types other than melanoma.	('V600-mutant', 'Var', (63, 74))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', (89, 94))	('BRAF', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('BRAF', 'Gene', '673', (30, 34))	('melanoma', 'Disease', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('BRAF', 'Gene', '673', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('BRAF', 'Gene', (58, 62))
443693	25030655	GIST preclinical models have shown a synergistic effect of CTLA4 blockade combined with imatinib.	('CTLA4', 'Gene', '1493', (59, 64))	('CTLA4', 'Gene', (59, 64))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('imatinib', 'Chemical', 'MESH:D000068877', (88, 96))	('blockade', 'Var', (65, 73))	('synergistic', 'MPA', (37, 48))
443694	25030655	In fact, two clinical trials are currently exploring this strategy for GIST (NCT01643278) and solid tumors, including sarcomas (NCT01738139).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('GIST', 'Phenotype', 'HP:0100723', (71, 75))	('NCT01738139', 'Var', (128, 139))	('solid tumors', 'Disease', 'MESH:D009369', (94, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcomas', 'Disease', (118, 126))	('NCT01643278', 'Var', (77, 88))	('solid tumors', 'Disease', (94, 106))
443711	33652741	Most ES cases carry the fusion of the Ewing Sarcoma Breakpoint Region 1 (EWSR1) and FLI1 (Friend leukemia virus integration site 1) genes, leading to an EWS-FLI1 fused protein, which is associated with autophagy, a homeostatic and catabolic mechanism under normal and pathological conditions.	('Ewing Sarcoma Breakpoint Region 1', 'Gene', (38, 71))	('Friend leukemia virus integration site 1', 'Gene', (90, 130))	('autophagy', 'CPA', (202, 211))	('protein', 'Protein', (168, 175))	('EWS-FLI1', 'Gene', (153, 161))	('fusion', 'Var', (24, 30))	('Sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('Ewing Sarcoma Breakpoint Region 1', 'Gene', '2130', (38, 71))	('FLI1', 'Gene', (84, 88))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('Friend leukemia virus integration site 1', 'Gene', '2313', (90, 130))
443719	33652741	The vast majority of ES cases are characterized by the t(11;22)(q24;q12) chromosomal translocation, leading to the fusion of a 5' segment of the EWSR1 gene (Ewing Sarcoma breakpoint region 1) and a 3' portion of the FLI1 (Friend leukemia virus integration site 1).	('Sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('Ewing Sarcoma breakpoint region 1', 'Gene', (157, 190))	('EWSR1', 'Gene', (145, 150))	('Friend leukemia virus integration site 1', 'Gene', '2313', (222, 262))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('Friend leukemia virus integration site 1', 'Gene', (222, 262))	('fusion', 'Var', (115, 121))	('Ewing Sarcoma breakpoint region 1', 'Gene', '2130', (157, 190))	('leukemia', 'Phenotype', 'HP:0001909', (229, 237))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (55, 72))	('FLI1', 'Gene', (216, 220))
443750	33652741	The monoallelic deletion of Beclin-1 is detected in breast and ovarian cancer.	('detected', 'Reg', (40, 48))	('Beclin-1', 'Gene', (28, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('monoallelic deletion', 'Var', (4, 24))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (52, 77))
443752	33652741	Moreover, Beclin-1 knockout in mice increases the development of spontaneous lymphomas, lung cancers, and liver cancers.	('liver cancers', 'Disease', 'MESH:D006528', (106, 119))	('liver cancers', 'Disease', (106, 119))	('knockout', 'Var', (19, 27))	('lung cancers', 'Disease', 'MESH:D008175', (88, 100))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Beclin-1', 'Gene', (10, 18))	('lung cancers', 'Phenotype', 'HP:0100526', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mice', 'Species', '10090', (31, 35))	('lymphomas', 'Disease', (77, 86))	('lymphomas', 'Disease', 'MESH:D008223', (77, 86))	('increases', 'PosReg', (36, 45))	('lung cancers', 'Disease', (88, 100))	('lymphomas', 'Phenotype', 'HP:0002665', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('liver cancers', 'Phenotype', 'HP:0002896', (106, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
443754	33652741	The deletion of Atg7 develops spontaneous benign liver adenomas.	('benign liver adenomas', 'Disease', 'MESH:D018248', (42, 63))	('Atg7', 'Gene', (16, 20))	('liver adenomas', 'Phenotype', 'HP:0012028', (49, 63))	('benign liver adenomas', 'Disease', (42, 63))	('deletion', 'Var', (4, 12))	('Atg7', 'Gene', '10533', (16, 20))
443764	33652741	Several studies in this field show that miR125a and miR351 target and destroy UVRAG mRNA.	('miR351', 'Gene', (52, 58))	('UVRAG', 'Disease', (78, 83))	('miR125a', 'Var', (40, 47))	('target', 'Reg', (59, 65))	('miR351', 'Gene', '723910', (52, 58))	('destroy', 'NegReg', (70, 77))
443766	33652741	In Ewsr1 KO mice, the levels of miR125a and miR351 are increased, a condition that leads to the reduction of UVRAG and LC3II autophagy markers.	('LC3', 'Gene', (119, 122))	('Ewsr1', 'Gene', (3, 8))	('miR125a', 'Var', (32, 39))	('mice', 'Species', '10090', (12, 16))	('miR351', 'Gene', '723910', (44, 50))	('UVRAG', 'CPA', (109, 114))	('miR351', 'Gene', (44, 50))	('Ewsr1', 'Gene', '14030', (3, 8))	('LC3', 'Gene', '84557', (119, 122))	('reduction', 'NegReg', (96, 105))
443768	33652741	In SK-ES-1 cells (anaplastic osteosarcoma or ES cell line), Beclin-1 knockdown strongly decreased the basic cancer properties of the cell line, such as proliferation, migration, and invasion.	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('proliferation', 'CPA', (152, 165))	('SK-ES-1', 'CellLine', 'CVCL:0627', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('migration', 'CPA', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))	('decreased', 'NegReg', (88, 97))	('osteosarcoma', 'Disease', (29, 41))	('invasion', 'CPA', (182, 190))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('knockdown', 'Var', (69, 78))	('cancer', 'Disease', (108, 114))	('Beclin-1', 'Gene', (60, 68))
443770	33652741	A silencing of Beclin-1 leads to the inhibition of matrix metallopeptidase (MMP)-9 expressions.	('inhibition', 'NegReg', (37, 47))	('matrix metallopeptidase (MMP)-9', 'Gene', '4318', (51, 82))	('expressions', 'MPA', (83, 94))	('silencing', 'Var', (2, 11))	('Beclin-1', 'Gene', (15, 23))
443773	33652741	Furthermore, it has been shown that EWS-FLI1-dependent autophagy inhibited apoptotic cell death, which was confirmed through the reduction of PUMA and cytosolic cyto-chrome-c, two major pro-apoptotic regulators.	('PUMA', 'Gene', (142, 146))	('apoptotic cell death', 'CPA', (75, 95))	('EWS-FLI1-dependent', 'Var', (36, 54))	('reduction', 'NegReg', (129, 138))	('autophagy', 'CPA', (55, 64))	('PUMA', 'Gene', '27113', (142, 146))	('inhibited', 'NegReg', (65, 74))	('cyto-chrome-c', 'Gene', '54205', (161, 174))	('cyto-chrome-c', 'Gene', (161, 174))
443774	33652741	Inhibition of autophagy with 3-MA (3-Methyladenine) re-sensitizes the ES cell line to apoptotic cell death.	('autophagy', 'CPA', (14, 23))	('3-MA', 'Chemical', 'MESH:C025946', (29, 33))	('3-Methyladenine', 'Chemical', 'MESH:C025946', (35, 50))	('Inhibition', 'Var', (0, 10))
443780	33652741	In ES cell lines after the silencing of PTEN, treatment with temsirolimus (a potent mTOR inhibitor) increased autophagy as a protective mechanism under this condition, but the effect of temsirolimus was lost when PTEN was expressed.	('PTEN', 'Gene', '5728', (213, 217))	('temsirolimus', 'Disease', (186, 198))	('increased', 'PosReg', (100, 109))	('silencing', 'Var', (27, 36))	('temsirolimus', 'Disease', 'None', (186, 198))	('autophagy', 'CPA', (110, 119))	('PTEN', 'Gene', (40, 44))	('temsirolimus', 'Disease', (61, 73))	('PTEN', 'Gene', '5728', (40, 44))	('mTOR', 'Gene', '2475', (84, 88))	('temsirolimus', 'Disease', 'None', (61, 73))	('mTOR', 'Gene', (84, 88))	('PTEN', 'Gene', (213, 217))
443787	33652741	The silence of DRAM in ES cells reduced autophagy and apoptotic cell death.	('silence', 'Var', (4, 11))	('apoptotic cell death', 'CPA', (54, 74))	('DRAM', 'Gene', '55332', (15, 19))	('reduced', 'NegReg', (32, 39))	('autophagy', 'CPA', (40, 49))	('DRAM', 'Gene', (15, 19))
443816	33652741	Furthermore, mTOR inhibition enhances the efficacy of chemotherapy, and re-sensitization may be via sensitizing the chemo-resistant CSC population.	('enhances', 'PosReg', (29, 37))	('efficacy', 'CPA', (42, 50))	('inhibition', 'Var', (18, 28))	('mTOR', 'Gene', (13, 17))	('mTOR', 'Gene', '2475', (13, 17))	('CS', 'Gene', '1431', (132, 134))
443833	22698408	In some cases, this downregulation may be directly achieved by decreased expression of DICER1 and DROSHA, key processing enzymes of miRNA production or mutations in their binding partners.	('binding', 'Interaction', (171, 178))	('mutations', 'Var', (152, 161))	('decreased', 'NegReg', (63, 72))	('DICER1', 'Gene', (87, 93))	('downregulation', 'NegReg', (20, 34))	('DROSHA', 'Gene', (98, 104))	('expression', 'MPA', (73, 83))	('DROSHA', 'Gene', '14000', (98, 104))
443836	22698408	Similarly, in rare cases of heterozygous germline DICER1 mutations, the pleuropulmonary blastomas to which patients are predisposed retain an intact DICER1 allele in tumor tissue.	('pleuropulmonary blastomas', 'Disease', 'MESH:C537516', (72, 97))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('pleuropulmonary blastomas', 'Phenotype', 'HP:0100528', (72, 97))	('mutations', 'Var', (57, 66))	('pleuropulmonary blastomas', 'Disease', (72, 97))	('DICER1', 'Gene', (50, 56))	('DICER1', 'MPA', (149, 155))	('patients', 'Species', '9606', (107, 115))
443837	22698408	Somatic point mutations in DICER1 associated with nonepithelial ovarian cancers are hypomorphic, likely resulting in expression of a full-length protein but in loss of some specific miRNAs and retention of others, further suggesting a requirement for DICER1 and miRNA expression in tumors.	('DICER1', 'Gene', (27, 33))	('associated', 'Reg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('ovarian cancers', 'Phenotype', 'HP:0100615', (64, 79))	('loss', 'NegReg', (160, 164))	('expression', 'MPA', (117, 127))	('tumors', 'Disease', (282, 288))	('nonepithelial ovarian cancers', 'Disease', 'MESH:D010051', (50, 79))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('nonepithelial ovarian cancers', 'Disease', (50, 79))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('point mutations', 'Var', (8, 23))	('specific miRNAs', 'MPA', (173, 188))
443839	22698408	In a mouse model of Dicer1 deletion in the liver, tumors emerge several months after deletion following a period of hepatic repopulation by Dicer1-intact "escapers".	('Dicer1', 'Gene', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('deletion', 'Var', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('deletion', 'Var', (85, 93))	('mouse', 'Species', '10090', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
443841	22698408	Similarly, in both an Emu-myc lymphoma model and a retinoblastoma model, viable tumors could not be identified following homozygous Dicer1 deletion.	('retinoblastoma', 'Disease', 'MESH:D012175', (51, 65))	('retinoblastoma', 'Disease', (51, 65))	('deletion', 'Var', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Emu-myc lymphoma', 'Disease', (22, 38))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('lymphoma', 'Phenotype', 'HP:0002665', (30, 38))	('Dicer1', 'Gene', (132, 138))	('Emu-myc lymphoma', 'Disease', 'MESH:D008223', (22, 38))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('retinoblastoma', 'Phenotype', 'HP:0009919', (51, 65))
443843	22698408	To better understand how cancer cells respond to loss of miRNA expression, we characterized the effects of homozygous deletion of Dicer1-conditional alleles on the tumorigenicity of an established line of murine sarcoma cells and on the cellular phenotype of immortalized murine mesenchymal stem cells (MSCs).	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('Dicer1-conditional', 'Gene', (130, 148))	('murine', 'Species', '10090', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('sarcoma', 'Disease', 'MESH:D012509', (212, 219))	('murine', 'Species', '10090', (272, 278))	('cancer', 'Disease', (25, 31))	('deletion', 'Var', (118, 126))	('sarcoma', 'Disease', (212, 219))
443844	22698408	Previously, we generated Dicer1-heterozygous tumors by injection of Adeno-Cre virus into the hindlimbs of KrasLSL-G12D;Trp53f/f;Dicer1f/f mice.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Trp53f/f', 'Var', (119, 127))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('G12D', 'Mutation', 'rs121913529', (114, 118))	('Kras', 'Gene', (106, 110))	('mice', 'Species', '10090', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Kras', 'Gene', '3845', (106, 110))
443850	22698408	These results suggest that sarcoma cells survive after homozygous Dicer1 deletion but have a growth disadvantage relative to cells retaining Dicer1 expression.	('sarcoma', 'Disease', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('Dicer1', 'Gene', (66, 72))	('growth disadvantage', 'CPA', (93, 112))	('deletion', 'Var', (73, 81))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))
443853	22698408	By quantitative Northern blot, miR-22 was present at ~4,000 copies per cell in Dicer1f/- sarcoma cells (Fig.	('Dicer1f/-', 'Var', (79, 88))	('miR-22', 'Gene', (31, 37))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))
443856	22698408	In Dicer1f/- cells, the five most abundant miRNAs were miR-22 (13%), let-7f (7%), let-7a (7%), let-7c (7%), and miR-21 (6%) (Table S1).	('Dicer1f/-', 'Var', (3, 12))	('miR-21', 'Gene', '387140', (112, 118))	('let-7f', 'Var', (69, 75))	('miR-22', 'Var', (55, 61))	('let-7c', 'Var', (95, 101))	('miR-21', 'Gene', (112, 118))	('let-7a', 'Gene', (82, 88))	('let-7a', 'Gene', '387244', (82, 88))
443859	22698408	In total, our results establish let-7 as the dominant seed in Dicer1f/- sarcoma cells and confirm the loss of mature miRNAs following Dicer1 deletion.	('sarcoma', 'Disease', (72, 79))	('deletion', 'Var', (141, 149))	('mature miRNAs', 'MPA', (110, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('loss', 'NegReg', (102, 106))	('Dicer1', 'Gene', (134, 140))
443864	22698408	Our findings indicate that genetic ablation of Dicer1 is tolerated in mouse sarcoma cells in vitro.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('mouse', 'Species', '10090', (70, 75))	('genetic ablation', 'Var', (27, 43))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Dicer1', 'Gene', (47, 53))
443867	22698408	Upon subcutaneous injection of 1 x 106 cells into the flanks of immune-compromised mice, Dicer1-/- cells were indeed tumorigenic, forming tumors at 7/18 sites within 24 days, as compared to 4/8 sites by day 14 for the original Dicer1f/- strain.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Dicer1-/- cells', 'Var', (89, 104))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (117, 122))	('mice', 'Species', '10090', (83, 87))	('forming', 'PosReg', (130, 137))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
443870	22698408	Pathologic analysis of either Dicer1-/- or Dicer1f/- tumors identified both as high grade sarcomas with pleomorphic nuclei and abnormal mitoses, consistent with previous reports of KRAS-driven sarcoma models (Fig.	('sarcoma', 'Disease', (90, 97))	('sarcoma', 'Disease', 'MESH:D012509', (193, 200))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sarcoma', 'Disease', (193, 200))	('sarcomas', 'Disease', (90, 98))	('Dicer1-/-', 'Var', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Dicer1f/-', 'Var', (43, 52))	('KRAS', 'Gene', '16653', (181, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('KRAS', 'Gene', (181, 185))	('tumors', 'Disease', (53, 59))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
443872	22698408	As before, the rate was slower than the parental Dicer1f/- line, with the first tumors appearing 7 days after injection of the Dicer1f/- cells and 21 days after injection of the Dicer1-/- cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('Dicer1f/- cells', 'Var', (127, 142))
443873	22698408	Thus, the absence of DICER1 impairs but does not preclude tumor formation, even in an immunocompetent background.	('DICER1', 'Gene', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('impairs', 'NegReg', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('absence', 'Var', (10, 17))
443874	22698408	Although the sarcoma cells at the time of the injection were Dicer1-/-, it is possible that in vivo selection resulted in outgrowth of contaminating Dicer1f/- cells.	('Dicer1-/-', 'Var', (61, 70))	('Dicer1f/-', 'Var', (149, 158))	('sarcoma', 'Disease', 'MESH:D012509', (13, 20))	('outgrowth', 'CPA', (122, 131))	('sarcoma', 'Disease', (13, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))
443884	22698408	To delete Dicer1, we carried out Adeno-Cre-GFP infection and sorted the infected cells by GFP.	('infection', 'Disease', 'MESH:D007239', (47, 56))	('delete', 'Var', (3, 9))	('infection', 'Disease', (47, 56))	('Dicer1', 'Gene', (10, 16))
443885	22698408	S3B), as well as a decrease in mature miRNA levels by qPCR (Fig.	('S3B', 'Gene', '11778', (0, 3))	('decrease', 'NegReg', (19, 27))	('S3B', 'Gene', (0, 3))	('qPCR', 'Var', (54, 58))	('mature miRNA levels', 'MPA', (31, 50))
443886	22698408	However, as observed for the sarcoma cells, additional passage led to a decrease in the deletion-specific PCR band (Fig.	('deletion-specific', 'Var', (88, 105))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('sarcoma', 'Disease', (29, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('decrease', 'NegReg', (72, 80))
443892	22698408	We have carried out homozygous Dicer1 deletion in a Dicer1-conditional KRAS-activated, Trp53-null sarcoma cell line and observed resultant loss of miRNA expression by small RNA sequencing.	('Dicer1', 'Gene', (31, 37))	('loss', 'NegReg', (139, 143))	('KRAS', 'Gene', (71, 75))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('KRAS', 'Gene', '16653', (71, 75))	('miRNA expression', 'MPA', (147, 163))	('sarcoma', 'Disease', (98, 105))	('deletion', 'Var', (38, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
443895	22698408	Similar to the sarcoma model, MSCs that had undergone homozygous Dicer1 deletion were readily isolatable but exhibited a reduction in proliferation, a delay in G1, and an increase in basal apoptosis.	('increase', 'PosReg', (171, 179))	('basal apoptosis', 'CPA', (183, 198))	('Dicer1', 'Gene', (65, 71))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('delay', 'NegReg', (151, 156))	('sarcoma', 'Disease', (15, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('proliferation', 'CPA', (134, 147))	('reduction', 'NegReg', (121, 130))	('deletion', 'Var', (72, 80))
443897	22698408	Tumors derived from Dicer1-/- injections exhibit strong PCR genotyping bands for (i) recombined Dicer1 and (ii) wild-type Dicer1, derived from host wild-type tissue associated with the tumors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (185, 191))	('Dicer1', 'Gene', (96, 102))	('recombined', 'Var', (85, 95))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('Dicer1-/-', 'Var', (20, 29))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
443899	22698408	This stark difference in genotype demonstrates that the tumors that arose from Dicer1-/- injections are composed predominantly of Dicer1-/- cells.	('Dicer1-/- cells', 'Var', (130, 145))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Dicer1-/- injections', 'Var', (79, 99))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))
443907	22698408	In addition, the histologic resemblance of Dicer1-/- sarcomas to Dicer1f/- sarcomas, as well as the retention of cell type-specific cell surface markers in Dicer1-/- MSCs, suggest that cellular identity is largely retained despite loss of miRNAs.	('sarcomas', 'Disease', (75, 83))	('Dicer1f/-', 'Var', (65, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcomas', 'Disease', 'MESH:D012509', (75, 83))	('sarcomas', 'Disease', (53, 61))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
443909	22698408	Based on the outgrowth of DICER1-expressing cells in vitro relative to Dicer1-/- cells, and the proliferative delay observed in monoclonal Dicer1-/- cells, we conclude that the absence of Dicer1-null cells in previously characterized mouse models of cancer is due in part to the preferential outgrowth, in vivo, of cells expressing DICER1.	('preferential', 'PosReg', (279, 291))	('mouse', 'Species', '10090', (234, 239))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('DICER1', 'Var', (332, 338))	('Dicer1-null', 'Gene', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
443913	22698408	Notably, inactivation of TRP53 activity is a common feature in both the sarcoma and MSC models presented here and may facilitate or be required for viability in the absence of DICER1.	('activity', 'MPA', (31, 39))	('sarcoma', 'Disease', (72, 79))	('TRP53', 'Gene', (25, 30))	('TRP53', 'Gene', '22059', (25, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('facilitate', 'PosReg', (118, 128))	('inactivation', 'Var', (9, 21))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('MSC', 'Disease', (84, 87))
443915	22698408	However, TRP53 loss alone only prolongs proliferative capacity of Dicer1-/- MEFs for a few additional passages (personal communication with S.N.	('TRP53', 'Gene', '22059', (9, 14))	('TRP53', 'Gene', (9, 14))	('loss', 'NegReg', (15, 19))	('Dicer1-/- MEFs', 'Var', (66, 80))	('proliferative', 'MPA', (40, 53))	('prolongs', 'PosReg', (31, 39))	('MEFs', 'CellLine', 'CVCL:9115', (76, 80))
443916	22698408	Jones), suggesting that other events, such as activation of oncogenes or inactivation of additional tumor suppressor genes, are required.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('inactivation', 'Var', (73, 85))	('oncogenes', 'Gene', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
443917	22698408	In addition to expanding our understanding of DICER1 in tumorigenesis, the cell lines reported here may complement existing models such as the hypomorphic DICER1 HCT116 line, a human colorectal cancer line containing homozygous deletion of exon 5 in the DICER1 gene.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (183, 200))	('deletion of', 'Var', (228, 239))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (183, 200))	('HCT116', 'CellLine', 'CVCL:0291', (162, 168))	('human', 'Species', '9606', (177, 182))	('colorectal cancer', 'Disease', (183, 200))	('DICER1', 'Gene', (254, 260))
443919	22698408	Sarcoma cells were generated from hindlimb injection of Adeno-Cre into KrasLSL-G12D;Trp53f/f;Dicer1f/f mice as described previously.	('G12D', 'Mutation', 'rs121913529', (79, 83))	('Trp53f/f', 'Var', (84, 92))	('Kras', 'Gene', (71, 75))	('mice', 'Species', '10090', (103, 107))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('Kras', 'Gene', '3845', (71, 75))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
443944	22341347	At a multiplicity of infection (MOI) of 5, GLV-1h68 was cytotoxic to three cell lines, resulting in >80% cytotoxicity over 7 days.	('GLV-1h68', 'Var', (43, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (105, 117))	('cytotoxicity', 'Disease', (105, 117))	('GLV-1h68', 'Species', '502057', (43, 51))
444019	22341347	Many replication-competent oncolytic viruses have been designed with deletions of specific genes that allow for preferential viral replication and lytic activity in malignant tumor cells, but not normal cells.	('tumor', 'Disease', (175, 180))	('lytic activity', 'CPA', (147, 161))	('viral replication', 'CPA', (125, 142))	('deletions', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('preferential', 'PosReg', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
444027	22341347	GLV-1h68 also carries an insertional mutation in hemagglutinin gene and the F14.5L locus.	('hemagglutinin', 'Gene', '3707652', (49, 62))	('hemagglutinin', 'Gene', (49, 62))	('insertional mutation', 'Var', (25, 45))	('GLV-1h68', 'Species', '502057', (0, 8))
444028	22341347	Inactivation of hemagglutinin is thought to reduce the virulence of vaccinia.	('vaccinia', 'Species', '10245', (68, 76))	('reduce', 'NegReg', (44, 50))	('virulence', 'MPA', (55, 64))	('hemagglutinin', 'Gene', (16, 29))	('hemagglutinin', 'Gene', '3707652', (16, 29))	('Inactivation', 'Var', (0, 12))
444041	22341347	At MOI of 5, GLV-1h68 was highly cytotoxic to two of the cell lines (HT-1080 and U-2 OS), resulting in >= 90% cytotoxicity over a 7-day period.	('cytotoxicity', 'Disease', 'MESH:D064420', (110, 122))	('HT-1080', 'CellLine', 'CVCL:0317', (69, 76))	('GLV-1h68', 'Var', (13, 21))	('cytotoxicity', 'Disease', (110, 122))	('GLV-1h68', 'Species', '502057', (13, 21))
444047	22341347	Animals treated with GLV-1h68 exhibited near complete tumor regression over a 28-day period without any observed toxicity, while control animals demonstrated rapid tumor progression requiring sacrifice by day 28.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('tumor', 'Disease', (164, 169))	('GLV-1h68', 'Species', '502057', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('GLV-1h68', 'Var', (21, 29))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
444049	22341347	These results demonstrate that a single intratumoral injection GLV-1h68 exhibits significant therapeutic efficacy leading to near complete tumor regression without toxicity.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('toxicity', 'Disease', 'MESH:D064420', (164, 172))	('tumor', 'Disease', (45, 50))	('GLV-1h68', 'Species', '502057', (63, 71))	('GLV-1h68', 'Var', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('toxicity', 'Disease', (164, 172))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('therapeutic efficacy', 'CPA', (93, 113))
444055	22341347	In conclusion, this study demonstrates that GLV-1h68 may exhibit significant therapeutic effects against human sarcoma cell lines in vitro and in vivo.	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('GLV-1h68', 'Var', (44, 52))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('human', 'Species', '9606', (105, 110))	('GLV-1h68', 'Species', '502057', (44, 52))	('therapeutic effects', 'CPA', (77, 96))
444057	22038993	BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human bone sarcoma xenografts (OS-1, EW-5 and EW-8) which demonstrated high, modest or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R.	('bone sarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('rat', 'Species', '10116', (135, 138))	('bone sarcoma xenografts', 'Disease', (76, 99))	('nude mice', 'Species', '10090', (7, 16))	('bone sarcoma xenografts', 'Disease', 'MESH:D001847', (76, 99))	('human', 'Species', '9606', (70, 75))	('R1507', 'Var', (187, 192))	('IGF-1R-expressing', 'Gene', (52, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('OS-1', 'Gene', '2487', (101, 105))	('OS-1', 'Gene', (101, 105))
444062	22038993	Biodistribution studies showed specific accumulation of 111In-R1507 in OS-1 and EW-5 xenografts (27.5+-6.5%ID/g and 14.0+-2.8%ID/g, 3 days p.i., respectively).	('111In-R1507', 'Var', (56, 67))	('OS-1', 'Gene', '2487', (71, 75))	('OS-1', 'Gene', (71, 75))
444079	22038993	IGF-1R blocking resulted in marked anti-tumor activity in several bone sarcoma xenografts and significant anti-tumor activity was observed in a variety of sarcoma patients, including osteosarcoma and Ewing sarcoma patients, with little to no side effects.	('sarcoma', 'Disease', (206, 213))	('patients', 'Species', '9606', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('sarcoma', 'Disease', 'MESH:D012509', (188, 195))	('osteosarcoma', 'Phenotype', 'HP:0002669', (183, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('sarcoma', 'Disease', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('osteosarcoma and Ewing sarcoma', 'Disease', 'MESH:C563168', (183, 213))	('bone sarcoma xenografts', 'Disease', (66, 89))	('sarcoma', 'Disease', (155, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('bone sarcoma xenografts', 'Disease', 'MESH:D001847', (66, 89))	('blocking', 'Var', (7, 15))	('IGF-1R', 'Gene', (0, 6))	('bone sarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('patients', 'Species', '9606', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('sarcoma', 'Disease', (71, 78))	('sarcoma', 'Disease', 'MESH:D012509', (206, 213))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (200, 213))
444091	22038993	To accomplish this, we examined the in vivo distribution of 111In-R1507 with immuno-SPECT in several bone sarcoma xenografts, including two osteosarcoma (OS-1 and OS-33) and two Ewing sarcoma xenografts (EW-5 and EW-8).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('osteosarcoma', 'Phenotype', 'HP:0002669', (140, 152))	('osteosarcoma', 'Disease', (140, 152))	('osteosarcoma', 'Disease', 'MESH:D012516', (140, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('Ewing sarcoma xenografts', 'Disease', (178, 202))	('OS-1', 'Gene', '2487', (154, 158))	('OS-1', 'Gene', (154, 158))	('Ewing sarcoma xenografts', 'Disease', 'MESH:C563168', (178, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('bone sarcoma xenografts', 'Disease', (101, 124))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (178, 191))	('111In-R1507', 'Var', (60, 71))	('bone sarcoma xenografts', 'Disease', 'MESH:D001847', (101, 124))	('bone sarcoma', 'Phenotype', 'HP:0002669', (101, 113))
444108	22038993	Several EW-5 tumors were subjected to autoradiography to visualize intratumoral distribution of 111In-R1507.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('rat', 'Species', '10116', (70, 73))	('tumors', 'Disease', (13, 19))	('111In-R1507', 'Var', (96, 107))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Disease', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
444110	22038993	R1507, a fully human monoclonal antibody directed against an epitope on the extracellular domain of the human IGF-1R, was obtained from Roche Diagnostics (Mannheim, Germany) and radiolabeled with 111In.	('human', 'Species', '9606', (104, 109))	('IGF-1R', 'Gene', (110, 116))	('human', 'Species', '9606', (15, 20))	('R1507', 'Var', (0, 5))
444119	22038993	Tumor-bearing (OS-1 and EW-5) mice were intravenously injected with a mixture of 125I- and 111In-labeled R1507 (0.2 MBq each).	('mice', 'Species', '10090', (30, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('OS-1', 'Gene', '2487', (15, 19))	('OS-1', 'Gene', (15, 19))	('R1507', 'Var', (105, 110))
444122	22038993	For immuno-SPECT, OS-1 and EW-5 tumor-bearing mice received an intravenous injection of 3 mug 111In-labeled R1507 (20 MBq; n=6).	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('R1507', 'Var', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (46, 50))	('OS-1', 'Gene', (18, 22))	('OS-1', 'Gene', '2487', (18, 22))	('tumor', 'Disease', (32, 37))
444125	22038993	Mice bearing OS-33, EW-8 and OS-1/OS-33 tumors were injected with 3 mug 111In-labeled R1507 as well (20 MBq; n=4 per group), and scanned on day 3 post injection followed by dissection of relevant tissues.	('R1507', 'Var', (86, 91))	('OS-1/OS-33 tumors', 'Disease', (29, 46))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('OS-1/OS-33 tumors', 'Disease', 'MESH:C567932', (29, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
444126	22038993	An additional group of OS-33 tumor-bearing mice (n=6) was co-injected with 300 mug unlabeled R1507, scanned on day 3 and dissected.	('mice', 'Species', '10090', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('R1507', 'Var', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))
444137	22038993	The biodistribution of 111In-R1507 and 125I-R1507 in nude mice bearing s.c. OS-1 and EW-5 tumor xenografts was determined 1, 3 and 7 days post injection, and the results are summarized in Figure 2.	('nude mice', 'Species', '10090', (53, 62))	('125I-R1507', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('111In-R1507', 'Var', (23, 34))	('OS-1', 'Gene', '2487', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('OS-1', 'Gene', (76, 80))
444138	22038993	From day 1 onwards, 111In-R1507 efficiently and specifically accumulated in the OS-1 tumor (15.7+-4.0 %ID/g), and uptake levels improved even further on day 3 and 7 (27.5+-6.5 %ID/g and 25.8+-5.8 %ID/g, respectively).	('111In-R1507', 'Var', (20, 31))	('improved', 'PosReg', (128, 136))	('uptake levels', 'MPA', (114, 127))	('OS-1 tumor', 'Disease', (80, 90))	('OS-1 tumor', 'Disease', 'MESH:C567932', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
444139	22038993	In EW-5 tumors, 111In-R1507 demonstrated the same pattern concerning tumor accumulation over time, although tumor uptake levels were less than observed in OS-1 tumors.	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (8, 14))	('111In-R1507', 'Var', (16, 27))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('OS-1 tumors', 'Disease', 'MESH:C567932', (155, 166))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (8, 13))	('rat', 'Species', '10116', (35, 38))	('tumor', 'Disease', (160, 165))	('OS-1 tumors', 'Disease', (155, 166))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
444144	22038993	In contrast, tumor accumulation of 125I-R1507 remained relatively low in both xenografts.	('tumor', 'Disease', (13, 18))	('125I-R1507', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('low', 'NegReg', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
444147	22038993	In both bone sarcomas, tumor uptake of 125I-R1507 was significantly lower compared to 111In-R1507 at all time points (p<0.05).	('bone sarcomas', 'Disease', (8, 21))	('bone sarcoma', 'Phenotype', 'HP:0002669', (8, 20))	('lower', 'NegReg', (68, 73))	('125I-R1507', 'Var', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('bone sarcomas', 'Phenotype', 'HP:0002669', (8, 21))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('bone sarcomas', 'Disease', 'MESH:D001847', (8, 21))
444148	22038993	Tumor-to-blood and tumor-to-liver ratios of 125I-R1507 in OS-1 tumors were highest at day 7 (1.2+-0.6) and day 1 (3.0+-0.7), respectively.	('tumor', 'Disease', (63, 68))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('125I-R1507', 'Var', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (19, 24))	('rat', 'Species', '10116', (34, 37))	('OS-1 tumors', 'Disease', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('OS-1 tumors', 'Disease', 'MESH:C567932', (58, 69))
444149	22038993	In EW-5 tumors, tumor-to-blood and tumor-to-liver ratios of 125I-R1507 were both highest at day 7, which were 0.4+-0.1 and 1.7+-0.4, respectively.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('rat', 'Species', '10116', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumor', 'Disease', (16, 21))	('125I-R1507', 'Var', (60, 70))	('tumor', 'Disease', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
444150	22038993	Since 111In-R1507 clearly demonstrated superior tumor targeting properties compared to 125I-R1507 in both osteosarcoma and Ewing sarcoma models, we used 111In-R1507 in the immuno-SPECT studies.	('tumor', 'Disease', (48, 53))	('111In-R1507', 'Var', (6, 17))	('osteosarcoma and Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 136))	('superior', 'PosReg', (39, 47))	('rat', 'Species', '10116', (33, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
444152	22038993	Representative immuno-SPECT/CT images acquired at day 1, 3 and 7 post injection of 111In-R1507 in an OS-1 tumor are shown in Figure 3A.	('111In-R1507', 'Var', (83, 94))	('OS-1 tumor', 'Disease', (101, 111))	('OS-1 tumor', 'Disease', 'MESH:C567932', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
444161	22038993	To investigate whether the heterogeneous distribution pattern of 111In-R1507 was the result of loss of IGF-1R expression in certain areas of the tumor, tumors were subjected to IHC after dissection.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('111In-R1507', 'Var', (65, 76))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', (145, 150))	('expression', 'MPA', (110, 120))	('tumors', 'Disease', (152, 158))	('IGF-1R', 'Gene', (103, 109))	('loss', 'NegReg', (95, 99))
444163	22038993	In the EW-5 tumor, autoradiography demonstrated a heterogeneous uptake pattern of 111In-R1507.	('heterogeneous uptake pattern', 'MPA', (50, 78))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('111In-R1507', 'Var', (82, 93))	('rat', 'Species', '10116', (42, 45))
444170	22038993	Figure 3C clearly demonstrates that there is virtually no tumor-uptake of 111In-R1507 in EW-8 tumors on immuno-SPECT scans, similar to the OS-33 tumors.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('OS-33 tumors', 'Disease', (139, 151))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('OS-33 tumors', 'Disease', 'MESH:C567932', (139, 151))	('tumor', 'Disease', (145, 150))	('tumors', 'Disease', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumor', 'Disease', (94, 99))	('rat', 'Species', '10116', (25, 28))	('111In-R1507', 'Var', (74, 85))	('EW-8', 'Gene', (89, 93))
444174	22038993	Table 1 summarizes tumor uptake and distribution of 111In-R1507 in all bone sarcoma xenografts used in this study.	('111In-R1507', 'Var', (52, 63))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('bone sarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('bone sarcoma xenografts', 'Disease', (71, 94))	('tumor', 'Disease', (19, 24))	('bone sarcoma xenografts', 'Disease', 'MESH:D001847', (71, 94))
444181	22038993	The IGF-1R-positive and highly IGF-1R therapy responsive OS-1 xenograft demonstrated specific accumulation of 111In-R1507 throughout the whole tumor.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (143, 148))	('111In-R1507', 'Var', (110, 121))	('OS-1', 'Gene', '2487', (57, 61))	('OS-1', 'Gene', (57, 61))	('accumulation', 'PosReg', (94, 106))	('rat', 'Species', '10116', (79, 82))	('IGF-1R', 'Gene', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
444182	22038993	Interestingly, the EW-5 xenograft which is also IGF-1R positive, but only modestly responsive to anti-IGF-1R therapy demonstrated a very heterogeneous tumor distribution pattern of 111In-R1507.	('rat', 'Species', '10116', (124, 127))	('111In-R1507', 'Var', (181, 192))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
444183	22038993	Consequently, 111In-R1507 tumor uptake in EW-5 tumors was significantly lower than observed in OS-1 tumors.	('tumor', 'Disease', (100, 105))	('OS-1 tumors', 'Disease', 'MESH:C567932', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Disease', (47, 53))	('OS-1 tumors', 'Disease', (95, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('111In-R1507', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('lower', 'NegReg', (72, 77))	('tumors', 'Disease', (100, 106))	('EW-5', 'Var', (42, 46))	('tumor', 'Disease', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
444189	22038993	Although not always easy to target, compounds that differ structurally from R1507 may show superior tumor penetrating capacities resulting in improved receptor targeting.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('rat', 'Species', '10116', (111, 114))	('tumor', 'Disease', (100, 105))	('superior', 'PosReg', (91, 99))	('improved', 'PosReg', (142, 150))	('R1507', 'Var', (76, 81))	('receptor targeting', 'MPA', (151, 169))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
444190	22038993	Another possible explanation for improved targeting with BMS-754807 is that this compound inhibits insulin receptor (IR) signaling as well.	('IR', 'Gene', '16337', (117, 119))	('inhibits', 'NegReg', (90, 98))	('insulin receptor', 'Gene', '16337', (99, 115))	('BMS-754807', 'Var', (57, 67))	('insulin receptor', 'Gene', (99, 115))
444194	22038993	Only for R1507 therapy, 111In-R1507 immuno-SPECT is able to give more detailed information concerning the degree of tumor response.	('R1507 therapy', 'Var', (9, 22))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))
444218	22038993	More evidence concerning the importance of target accessibility was found in the distribution of 111In-R1507 throughout EW-8 tumors.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('111In-R1507', 'Var', (97, 108))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))
444220	22038993	When a bone sarcoma patient demonstrates 111In-R1507 only in a small region of the tumor, IGF-1R monotherapy may not be sufficient.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('111In-R1507', 'Var', (41, 52))	('tumor', 'Disease', (83, 88))	('bone sarcoma', 'Disease', (7, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('patient', 'Species', '9606', (20, 27))	('bone sarcoma', 'Disease', 'MESH:D001847', (7, 19))	('rat', 'Species', '10116', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('bone sarcoma', 'Phenotype', 'HP:0002669', (7, 19))
444223	22038993	In addition, inhibition of IGF-1R may significantly potentiate the antitumor activity of conventional chemotherapeutic drugs.	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('potentiate', 'PosReg', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('IGF-1R', 'Gene', (27, 33))	('tumor', 'Disease', (71, 76))
444230	22038993	Since R1507 does not cross-react with murine IGF-1R, the high tumor-to-background ratios seen in our models may be lower in patients because radiolabeled R1507 will also recognize IGF-1R expressed in normal human tissues, such as muscle, cartilage and bone.	('R1507', 'Var', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cartilage', 'Disease', (238, 247))	('cartilage', 'Disease', 'MESH:D002357', (238, 247))	('rat', 'Species', '10116', (82, 85))	('human', 'Species', '9606', (207, 212))	('murine', 'Species', '10090', (38, 44))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('IGF-1R', 'Gene', (180, 186))
444234	22038993	More importantly, we demonstrated a positive correlation between 111In-R1507 immuno-SPECT and the degree of R1507 therapy response, while IGF-1R expression of the same tumors on IHC or WB did not show such a correlation.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('R1507', 'Var', (108, 113))	('rat', 'Species', '10116', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
444240	22038993	In this study, we investigated whether 111In-R1507 immuno-SPECT, a novel non-invasive, in vivo screening method to visualize membranous IGF-1R expression and accessibility, can be used to predict treatment response to the IGF-1R inhibitor R1507 in bone sarcomas.	('bone sarcomas', 'Phenotype', 'HP:0002669', (248, 261))	('sarcomas', 'Phenotype', 'HP:0100242', (253, 261))	('bone sarcomas', 'Disease', 'MESH:D001847', (248, 261))	('bone sarcomas', 'Disease', (248, 261))	('bone sarcoma', 'Phenotype', 'HP:0002669', (248, 260))	('R1507', 'Var', (239, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))
444427	28837697	KSHV was shown to manipulate the metabolism of host cells and to induce similar metabolic changes to those found in non-viral cancers.	('non-viral cancers', 'Disease', 'MESH:D016751', (116, 133))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('metabolic', 'MPA', (80, 89))	('metabolism', 'MPA', (33, 43))	('induce', 'Reg', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('manipulate', 'Reg', (18, 28))	('non-viral cancers', 'Disease', (116, 133))
444445	28837697	KS cells, as other cancers, have a distinct metabolism and KSHV was shown to alter several metabolic pathways in its host cell.	('KSHV', 'Species', '37296', (59, 63))	('KSHV', 'Var', (59, 63))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('alter', 'Reg', (77, 82))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('KS', 'Phenotype', 'HP:0100726', (59, 61))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('metabolism', 'MPA', (44, 54))	('metabolic pathways', 'Pathway', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
444478	28837697	For example, KSHV miR-K12-10a-3p, K12-4-3p and K12-8-3p are over represented in the exosomes while KSHV miR-K12-11-3p and K12-4-5p are underrepresented (Fig 1F and S1 Table).	('KS', 'Phenotype', 'HP:0100726', (13, 15))	('KSHV', 'Species', '37296', (13, 17))	('K12-8-3p', 'Var', (47, 55))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('over', 'PosReg', (60, 64))	('miR', 'Gene', '220972', (104, 107))	('K12-4-3p', 'Var', (34, 42))	('miR', 'Gene', (104, 107))	('KS', 'Phenotype', 'HP:0100726', (99, 101))	('KSHV', 'Species', '37296', (99, 103))
444479	28837697	Moreover, specific cellular miRNAs that are over represented in KLEC compared to LEC such as miR-145-5p and 143-3p (S2 Table), were not found to be enriched in KLEC-derived exosomes (S3 Table).	('miR-145', 'Gene', (93, 100))	('miR-145', 'Gene', '406937', (93, 100))	('KLEC', 'Chemical', '-', (160, 164))	('KLEC', 'Chemical', '-', (64, 68))	('143-3p', 'Var', (108, 114))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('miR', 'Gene', (93, 96))	('miR', 'Gene', '220972', (93, 96))
444506	28837697	This suggests that transfer of the KSHV miRNAs into non-infected cells reduces mitochondrial respiration.	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('mitochondrial respiration', 'MPA', (79, 104))	('transfer', 'Var', (19, 27))	('KSHV', 'Species', '37296', (35, 39))	('KS', 'Phenotype', 'HP:0100726', (35, 37))	('KSHV', 'Gene', (35, 39))	('reduces', 'NegReg', (71, 78))
444513	28837697	KSHV has been shown to activate HIF1alpha and HIF2alpha during latency and we have observed that expression of KSHV miRNAs induces HIF1alpha stabilisation.	('activate', 'PosReg', (23, 31))	('KSHV', 'Species', '37296', (0, 4))	('stabilisation', 'MPA', (141, 154))	('HIF2alpha', 'Gene', (46, 55))	('expression', 'Var', (97, 107))	('induces', 'Reg', (123, 130))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('HIF1alpha', 'Gene', '3091', (32, 41))	('miR', 'Gene', '220972', (116, 119))	('KSHV', 'Species', '37296', (111, 115))	('miR', 'Gene', (116, 119))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('HIF1alpha', 'Gene', (131, 140))	('HIF1alpha', 'Gene', '3091', (131, 140))	('KSHV', 'Gene', (111, 115))	('HIF1alpha', 'Gene', (32, 41))
444544	28837697	To test whether this unexpected effect is due to the metabolic changes induced by these exosomes, we mimicked the exosome metabolic effect by expressing the HIF1alpha P402A/P564A stable mutant in LEC (Fig 5D).	('HIF1alpha', 'Gene', (157, 166))	('HIF1alpha', 'Gene', '3091', (157, 166))	('P402A', 'Var', (167, 172))	('P564A', 'Var', (173, 178))	('P402A', 'SUBSTITUTION', 'None', (167, 172))	('P564A', 'SUBSTITUTION', 'None', (173, 178))
444545	28837697	Over-expression of HIF1alpha had a similar effect to exosome treatment, leading to a 40% reduction in the viral copy number 48 hours' post KSHV infection (Fig 5E).	('KSHV infection', 'Disease', 'MESH:C537372', (139, 153))	('HIF1alpha', 'Gene', '3091', (19, 28))	('viral copy number', 'MPA', (106, 123))	('KSHV infection', 'Disease', (139, 153))	('KS', 'Phenotype', 'HP:0100726', (139, 141))	('reduction', 'NegReg', (89, 98))	('Over-expression', 'Var', (0, 15))	('HIF1alpha', 'Gene', (19, 28))
444548	28837697	We therefore hypothesised that inducing aerobic glycolysis in nearby non-infected cells supports the growth of KSHV-infected cells.	('KSHV-infected', 'Disease', (111, 124))	('KSHV-infected', 'Disease', 'MESH:C537372', (111, 124))	('inducing', 'Var', (31, 39))	('aerobic glycolysis', 'MPA', (40, 58))	('KS', 'Phenotype', 'HP:0100726', (111, 113))
444551	28837697	HUVEC over-expressing stable mutant HIF1alpha had a similar effect on KLEC growth (Fig 5H), supporting the notion that this increased growth is indeed due to the reverse Warburg effect.	('HIF1alpha', 'Gene', (36, 45))	('KLEC growth', 'MPA', (70, 81))	('mutant', 'Var', (29, 35))	('HIF1alpha', 'Gene', '3091', (36, 45))	('KLEC', 'Chemical', '-', (70, 74))
444557	28837697	Taken together, these results suggest a metabolic feedback where KSHV infected cells induce aerobic glycolysis in cells in their microenvironment, and those as a result secrete high energy metabolites that support the KSHV infected cells.	('KSHV', 'Species', '37296', (65, 69))	('aerobic glycolysis', 'MPA', (92, 110))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('infected', 'Var', (70, 78))	('KSHV', 'Gene', (65, 69))	('KS', 'Phenotype', 'HP:0100726', (218, 220))	('KSHV', 'Species', '37296', (218, 222))	('secrete high energy metabolites', 'MPA', (169, 200))	('iron', 'Chemical', 'MESH:D007501', (137, 141))	('induce', 'Reg', (85, 91))
444577	28837697	This is based on: (i) our previous observation that expression of the KSHV miRNAs is sufficient to induce aerobic glycolysis, (ii) our observation that the KSHV miRNAs are active in recipient cells to regulate the same metabolic target genes as in KSHV infected cells and (iii) the fact that exosomes secreted from DeltamiR-KLEC, which do not contain the viral miRNAs, do not have the same effect.	('induce', 'PosReg', (99, 105))	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', '220972', (320, 323))	('expression', 'Var', (52, 62))	('KS', 'Phenotype', 'HP:0100726', (156, 158))	('miR', 'Gene', '220972', (361, 364))	('miR', 'Gene', (75, 78))	('miR', 'Gene', '220972', (161, 164))	('KSHV', 'Species', '37296', (156, 160))	('KSHV', 'Species', '37296', (70, 74))	('metabolic target genes', 'MPA', (219, 241))	('miR', 'Gene', (320, 323))	('regulate', 'Reg', (201, 209))	('miR', 'Gene', (361, 364))	('KLEC', 'Chemical', '-', (324, 328))	('aerobic glycolysis', 'MPA', (106, 124))	('KS', 'Phenotype', 'HP:0100726', (248, 250))	('miR', 'Gene', (161, 164))	('KSHV', 'Gene', (70, 74))	('KSHV', 'Species', '37296', (248, 252))	('KS', 'Phenotype', 'HP:0100726', (70, 72))
444630	28837697	Expression of human and KSHV miRNA reads were quantified using PaTMaN rapid aligner to the miRbase release 21 database of miRNA sequences [http://mirbase.org] allowing for 1 mismatch (or counting only perfect matches if more than one miRNA was matched).	('miR', 'Gene', (91, 94))	('mismatch', 'Var', (174, 182))	('miR', 'Gene', '220972', (29, 32))	('KSHV', 'Species', '37296', (24, 28))	('miR', 'Gene', (29, 32))	('human', 'Species', '9606', (14, 19))	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', '220972', (234, 237))	('miR', 'Gene', (122, 125))	('miR', 'Gene', (234, 237))	('miR', 'Gene', '220972', (91, 94))
444742	26068307	This expression pattern is partially due to epigenetic deregulation of retinal development; epigenetic perturbations also contribute to tumor progression.	('retinal development', 'CPA', (71, 90))	('epigenetic perturbations', 'Var', (92, 116))	('epigenetic deregulation', 'Var', (44, 67))	('contribute', 'Reg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
444749	26068307	Amplification of the MYCN oncogene is one of the most frequent genetic lesions in neuroblastoma and is associated with poor outcome.	('Amplification', 'Var', (0, 13))	('associated', 'Reg', (103, 113))	('neuroblastoma', 'Disease', 'MESH:D009447', (82, 95))	('neuroblastoma', 'Disease', (82, 95))	('neuroblastoma', 'Phenotype', 'HP:0003006', (82, 95))	('MYCN oncogene', 'Gene', (21, 34))
444750	26068307	Germline mutations in the transcription factor PHOX2B, which normally coordinates proliferation and differentiation of the sympathoadrenal lineage during development, can predispose children to neuroblastoma.	('Germline mutations', 'Var', (0, 18))	('neuroblastoma', 'Disease', 'MESH:D009447', (194, 207))	('PHOX2B', 'Gene', '8929', (47, 53))	('neuroblastoma', 'Disease', (194, 207))	('neuroblastoma', 'Phenotype', 'HP:0003006', (194, 207))	('predispose', 'Reg', (171, 181))	('children', 'Species', '9606', (182, 190))	('PHOX2B', 'Gene', (47, 53))
444751	26068307	Similarly, germline mutations in the ALK gene can lead to perturbations in signal transduction pathways in the same lineage and predispose children to neuroblastoma.	('signal transduction pathways', 'Pathway', (75, 103))	('lead to', 'Reg', (50, 57))	('ALK', 'Gene', (37, 40))	('neuroblastoma', 'Phenotype', 'HP:0003006', (151, 164))	('predispose', 'Reg', (128, 138))	('children', 'Species', '9606', (139, 147))	('ALK', 'Gene', '238', (37, 40))	('germline mutations', 'Var', (11, 29))	('neuroblastoma', 'Disease', 'MESH:D009447', (151, 164))	('perturbations', 'MPA', (58, 71))	('neuroblastoma', 'Disease', (151, 164))
444754	26068307	The recent discovery of recurrent somatic mutations in the ARID1A/1B genes, which encode chromatin remodeling proteins, and in the ATRX gene, which encodes an ATP-dependent helicase, points to a role for epigenetics in neuroblastoma initiation and progression.	('ATRX', 'Gene', '546', (131, 135))	('neuroblastoma', 'Phenotype', 'HP:0003006', (219, 232))	('ARID1A/1B', 'Gene', (59, 68))	('ARID1A/1B', 'Gene', '8289;57492', (59, 68))	('neuroblastoma initiation', 'Disease', 'MESH:D009447', (219, 243))	('neuroblastoma initiation', 'Disease', (219, 243))	('ATRX', 'Gene', (131, 135))	('mutations', 'Var', (42, 51))
444757	26068307	ATRX mutations are associated with the older age group, but it is unclear whether they directly contribute to the poor outcome in this patient population.	('associated', 'Reg', (19, 29))	('patient', 'Species', '9606', (135, 142))	('ATRX', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('ATRX', 'Gene', '546', (0, 4))
444765	26068307	Recent genomic analysis showed that most pediatric conventional melanomas are very similar to adult melanomas, with oncogenic BRAF mutations, TERT promoter mutations, and UV-induced DNA damage.	('mutations', 'Var', (131, 140))	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('melanomas', 'Disease', (64, 73))	('TERT', 'Gene', '7015', (142, 146))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('melanomas', 'Disease', (100, 109))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('TERT', 'Gene', (142, 146))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))
444768	26068307	Although most cases are sporadic, the risk of osteosarcoma is increased in those with various genetic diseases, including hereditary retinoblastoma, Li Fraumeni syndrome, and germline mutations of RecQL4.	('RecQL4', 'Gene', '9401', (197, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('genetic diseases', 'Disease', 'MESH:D030342', (94, 110))	('genetic diseases', 'Disease', (94, 110))	('retinoblastoma', 'Phenotype', 'HP:0009919', (133, 147))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (122, 147))	('germline mutations', 'Var', (175, 193))	('osteosarcoma', 'Disease', (46, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('Fraumeni syndrome', 'Disease', 'MESH:D016864', (152, 169))	('Fraumeni syndrome', 'Disease', (152, 169))	('osteosarcoma', 'Disease', 'MESH:D012516', (46, 58))	('hereditary retinoblastoma', 'Disease', (122, 147))	('RecQL4', 'Gene', (197, 203))
444773	26068307	Interestingly, children who have germline mutations in the RB1 gene and develop retinoblastoma as infants are predisposed to develop osteosarcoma in adolescence.	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('germline mutations', 'Var', (33, 51))	('RB1', 'Gene', (59, 62))	('infants', 'Species', '9606', (98, 105))	('retinoblastoma', 'Disease', 'MESH:D012175', (80, 94))	('retinoblastoma', 'Disease', (80, 94))	('children', 'Species', '9606', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('develop', 'PosReg', (125, 132))	('RB1', 'Gene', '5925', (59, 62))	('retinoblastoma', 'Phenotype', 'HP:0009919', (80, 94))	('osteosarcoma', 'Disease', (133, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))
444774	26068307	Virtually all osteosarcomas have initiating mutations in the TP53 tumor suppressor gene, which is important for DNA repair, stress response, and cell cycle progression.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('osteosarcomas', 'Disease', (14, 27))	('osteosarcomas', 'Phenotype', 'HP:0002669', (14, 27))	('osteosarcoma', 'Phenotype', 'HP:0002669', (14, 26))	('osteosarcomas', 'Disease', 'MESH:D012516', (14, 27))	('mutations', 'Var', (44, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
444776	26068307	Importantly, the mechanism of TP53 gene inactivation is unique among human cancers: many osteosarcoma tumors have translocations in the first intron of the gene that separate the promoter of the TP53 gene from the coding region, generating an inactive allele.	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', (195, 199))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (89, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('translocations', 'Var', (114, 128))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('inactive', 'MPA', (243, 251))	('osteosarcoma tumors', 'Disease', (89, 108))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', '7157', (30, 34))	('TP53', 'Gene', '7157', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
444783	26068307	Most Ewing sarcoma tumors have a translocation involving the EWS gene on chromosome 22 and the FLI gene on chromosome 11 (EWS-FLI).	('FLI', 'Gene', (95, 98))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (5, 25))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (5, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('FLI', 'Gene', '2314', (126, 129))	('FLI', 'Gene', (126, 129))	('FLI', 'Gene', '2314', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('EWS', 'Gene', '2130', (61, 64))	('EWS', 'Gene', (61, 64))	('translocation', 'Var', (33, 46))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('Ewing sarcoma tumors', 'Disease', (5, 25))	('EWS', 'Gene', '2130', (122, 125))	('EWS', 'Gene', (122, 125))
444787	26068307	Indeed, in addition to TP53, the only other significant recurrent mutations in EWS are in STAG2 (17%), which encodes part of the cohesion complex important for sister chromatid cohesion during M-phase of the cell cycle, and CDKN2A (11%), which encodes the cell cycle regulation proteins p16INK4a and p14ARF.	('mutations', 'Var', (66, 75))	('EWS', 'Gene', (79, 82))	('EWS', 'Gene', '2130', (79, 82))	('p14ARF', 'Gene', '1029', (300, 306))	('CDKN2A', 'Gene', '1029', (224, 230))	('STAG2', 'Gene', (90, 95))	('STAG2', 'Gene', '10735', (90, 95))	('p16INK4a', 'Gene', (287, 295))	('p14ARF', 'Gene', (300, 306))	('p16INK4a', 'Gene', '1029', (287, 295))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('CDKN2A', 'Gene', (224, 230))
444788	26068307	Patients with tumors harboring both STAG2 and TP53 mutations have a poor clinical outcome.	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (46, 50))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('STAG2', 'Gene', (36, 41))	('TP53', 'Gene', (46, 50))	('STAG2', 'Gene', '10735', (36, 41))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
444797	26068307	In contrast, patients with ARMS have an inferior clinical outcome, and their tumors often contain a translocation between the FOXO1A gene on chromosome 13q14 and either PAX3 on chromosome 2q35 or PAX7 on chromosome 1p36.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('PAX3', 'Gene', (169, 173))	('ARMS', 'Phenotype', 'HP:0006779', (27, 31))	('PAX7', 'Gene', (196, 200))	('FOXO1A', 'Gene', (126, 132))	('patients', 'Species', '9606', (13, 21))	('translocation', 'Var', (100, 113))	('contain', 'Reg', (90, 97))	('FOXO1A', 'Gene', '2308', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('PAX7', 'Gene', '5081', (196, 200))	('PAX3', 'Gene', '5077', (169, 173))
444798	26068307	Recent results suggest that translocation-negative ARMS tumors have molecular profiles more similar to those of ERMS tumors, so the current trend is to classify rhabdomyosarcoma as being translocation-positive or translocation-negative rather than in the histopathologic terms of ARMS and ERMS.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (161, 177))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('ARMS', 'Phenotype', 'HP:0006779', (51, 55))	('ARMS tumors', 'Disease', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('ERMS tumors', 'Disease', (112, 123))	('ERMS', 'Phenotype', 'HP:0006743', (289, 293))	('ERMS', 'Phenotype', 'HP:0006743', (112, 116))	('rhabdomyosarcoma', 'Disease', (161, 177))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('ARMS', 'Phenotype', 'HP:0006779', (280, 284))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (161, 177))	('ERMS tumors', 'Disease', 'MESH:D009369', (112, 123))	('translocation-negative', 'Var', (28, 50))	('ARMS tumors', 'Disease', 'MESH:D009369', (51, 62))
444802	26068307	Translocation-positive rhabdomyosarcoma tumors have stable genomes similar to those of the Ewing sarcoma tumors described above, and they lack high rates of recurrent mutations in known cancer or developmental pathways.	('rhabdomyosarcoma tumors', 'Disease', (23, 46))	('Ewing sarcoma tumors', 'Disease', (91, 111))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (23, 39))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('Translocation-positive', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (91, 111))	('rhabdomyosarcoma tumors', 'Disease', 'MESH:D012208', (23, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
444803	26068307	In contrast, the translocation-negative tumors have features of an unstable genome, with the most recurrently mutated pathway being the RAS signal transduction pathway.	('RAS signal transduction pathway', 'Pathway', (136, 167))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('translocation-negative', 'Var', (17, 39))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
444804	26068307	Those mutations are associated with high-risk disease but their correlation with outcome in translocation-negative rhabdomyosarcoma is unknown.	('rhabdomyosarcoma', 'Disease', (115, 131))	('associated', 'Reg', (20, 30))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (115, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (115, 131))	('mutations', 'Var', (6, 15))
444809	26068307	However, patients with familial adenomatous polyposis, Beckwith-Wiedemann syndrome, and trisomy 18 and infants with very low birth weight (< 1500 grams) are at increased risk for hepatoblastoma.	('patients', 'Species', '9606', (9, 17))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (179, 193))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (23, 53))	('low birth weight', 'Phenotype', 'HP:0001518', (121, 137))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (55, 82))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (32, 53))	('increased risk for hepatoblastoma', 'Phenotype', 'HP:0001402', (160, 193))	('infants', 'Species', '9606', (103, 110))	('hepatoblastoma', 'Disease', 'MESH:D018197', (179, 193))	('familial adenomatous polyposis', 'Disease', (23, 53))	('trisomy 18', 'Var', (88, 98))	('Beckwith-Wiedemann syndrome', 'Disease', (55, 82))	('hepatoblastoma', 'Disease', (179, 193))
444810	26068307	Beta-catenin mutations and deletions are common in embryonal and mixed subtypes of sporadic hepatoblastoma.	('hepatoblastoma', 'Phenotype', 'HP:0002884', (92, 106))	('sporadic hepatoblastoma', 'Disease', (83, 106))	('mixed subtypes', 'Species', '384619', (65, 79))	('deletions', 'Var', (27, 36))	('Beta-catenin', 'Protein', (0, 12))	('mutations', 'Var', (13, 22))	('sporadic hepatoblastoma', 'Disease', 'MESH:D018197', (83, 106))	('common', 'Reg', (41, 47))
444851	26068307	All models use the same retinal progenitor cell-specific Cre-transgene (Chx10-Cre) and different combinations of null or floxed alleles of the Rb family with p53 pathway inactivation:  Ostx-Cre; Rblox/Lox;p53Lox/Lox Ostx-Cre; Rblox/Lox;p53Lox/Lox;p107-/- Ostx-Cre; Rblox/Lox;p53Lox/Lox;ATRXLox/Lox The genetically engineered mouse models of osteosarcoma are based on conditional inactivation of the Rb and p53 pathways in osteoblasts.	('conditional inactivation', 'Var', (367, 391))	('osteosarcoma', 'Disease', 'MESH:D012516', (341, 353))	('lox', 'Gene', '4015', (267, 270))	('Lox', 'Gene', (208, 211))	('Lox', 'Gene', (239, 242))	('p107', 'Gene', '5933', (247, 251))	('Lox', 'Gene', '4015', (290, 293))	('Lox', 'Gene', (294, 297))	('lox', 'Gene', (197, 200))	('lox', 'Gene', (228, 231))	('Lox', 'Gene', '4015', (243, 246))	('mouse', 'Species', '10090', (325, 330))	('Lox', 'Gene', (278, 281))	('Chx10', 'Gene', (72, 77))	('Lox', 'Gene', '4015', (201, 204))	('Lox', 'Gene', '4015', (232, 235))	('Lox', 'Gene', '4015', (282, 285))	('lox', 'Gene', '4015', (122, 125))	('Lox', 'Gene', (212, 215))	('osteosarcoma', 'Phenotype', 'HP:0002669', (341, 353))	('Lox', 'Gene', '4015', (271, 274))	('lox', 'Gene', (267, 270))	('Chx10', 'Gene', '338917', (72, 77))	('Lox', 'Gene', (290, 293))	('Lox', 'Gene', (243, 246))	('Lox', 'Gene', '4015', (208, 211))	('Lox', 'Gene', '4015', (239, 242))	('Lox', 'Gene', '4015', (294, 297))	('Lox', 'Gene', '4015', (212, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (346, 353))	('Lox', 'Gene', (201, 204))	('Lox', 'Gene', (282, 285))	('lox', 'Gene', '4015', (197, 200))	('lox', 'Gene', (122, 125))	('lox', 'Gene', '4015', (228, 231))	('Lox', 'Gene', '4015', (278, 281))	('Lox', 'Gene', (232, 235))	('osteosarcoma', 'Disease', (341, 353))	('Lox', 'Gene', (271, 274))	('p107', 'Gene', (247, 251))	('p53 pathways', 'Pathway', (406, 418))
444853	26068307	More recently, new models of neuroblastoma have been developed that include mutations in Alk and Lin28b.	('Alk', 'Gene', (89, 92))	('mutations', 'Var', (76, 85))	('neuroblastoma', 'Disease', (29, 42))	('Alk', 'Gene', '238', (89, 92))	('Lin28b', 'Gene', (97, 103))	('neuroblastoma', 'Phenotype', 'HP:0003006', (29, 42))	('Lin28b', 'Gene', '389421', (97, 103))	('neuroblastoma', 'Disease', 'MESH:D009447', (29, 42))
444854	26068307	We have also included Atrx mutations to model the indolent form of disease in Stage 4 patients older than 12 years.	('mutations', 'Var', (27, 36))	('Atrx', 'Gene', (22, 26))	('Atrx', 'Gene', '546', (22, 26))	('patients', 'Species', '9606', (86, 94))
444866	26068307	For example, RB1 inactivation contributes to retinoblastoma initiation by promoting cell-cycle progression, but the RB1 protein is also required for rod photoreceptor differentiation.	('inactivation', 'Var', (17, 29))	('RB1', 'Gene', '5925', (13, 16))	('RB1', 'Gene', '5925', (116, 119))	('RB1', 'Gene', (13, 16))	('retinoblastoma initiation', 'Disease', 'MESH:D012175', (45, 70))	('retinoblastoma', 'Phenotype', 'HP:0009919', (45, 59))	('promoting', 'PosReg', (74, 83))	('RB1', 'Gene', (116, 119))	('retinoblastoma initiation', 'Disease', (45, 70))	('cell-cycle progression', 'CPA', (84, 106))
444870	26068307	When a tumor-initiating mutation occurs in those distinct progenitor cell populations, the result may vary dramatically depending on the competence of that cell at that particular stage of development.	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('mutation', 'Var', (24, 32))	('tumor', 'Disease', (7, 12))
444871	26068307	In one cell population, an oncogenic mutation may result in a tumor with cellular features of skeletal muscle such as rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', (118, 134))	('result in', 'Reg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutation', 'Var', (37, 45))	('tumor', 'Disease', (62, 67))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (118, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (118, 134))
444872	26068307	In another cell population, the same oncogenic mutation may lead to rapid cell death or, alternatively, to a tumor with osteogenic features.	('lead to', 'Reg', (60, 67))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('rapid cell death', 'CPA', (68, 84))	('tumor', 'Disease', (109, 114))
444873	26068307	Thus, the competence of individual progenitor cells combined with the specific oncogenic mutations influence when and where pediatric solid tumors arise during development.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('pediatric solid tumors', 'Disease', (124, 146))	('influence', 'Reg', (99, 108))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (124, 146))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
444928	21815749	We assumed a linear relationship between the Gd-DTPA concentration and DeltaR1 (R1 = 1/T1), with a relaxivity r1 = 2.92 mM-1s-1 8.	('DeltaR1', 'Var', (71, 78))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (45, 52))	('DeltaR1', 'DELETION', 'None', (71, 78))	('Gd-DTPA concentration', 'MPA', (45, 66))
444929	21815749	It was further assumed that Gd-DTPA affected the relaxation rate of all tissue water molecules (so-called fast water exchange: water moves freely over vascular and cellular boundaries over the time-scale of the image acquisition).	('Gd-DTPA', 'Var', (28, 35))	('relaxation rate', 'MPA', (49, 64))	('water', 'Chemical', 'MESH:D014867', (79, 84))	('water', 'Chemical', 'MESH:D014867', (127, 132))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (28, 35))	('water', 'Chemical', 'MESH:D014867', (111, 116))	('affected', 'Reg', (36, 44))
444997	21815749	Our own measurements of tumour necrosis suggested more centrally located effects by plinabulin (data not shown), and consistent with that we found a larger benefit when radiation and plinabulin were combined.	('plinabulin', 'Chemical', 'MESH:C514351', (84, 94))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour necrosis', 'Disease', 'MESH:D009336', (24, 39))	('tumour necrosis', 'Disease', (24, 39))	('plinabulin', 'Chemical', 'MESH:C514351', (183, 193))	('plinabulin', 'Var', (84, 94))
445089	22566750	in a study of 33 cases of sporadic RMS showed that 3 of 13 children younger than 3 years of age at diagnosis (compared with none of the 20 children older than 3 years of age) had germline mutations in their p53 gene.	('germline mutations', 'Var', (179, 197))	('children', 'Species', '9606', (139, 147))	('RMS', 'Phenotype', 'HP:0002859', (35, 38))	('p53', 'Gene', '7157', (207, 210))	('p53', 'Gene', (207, 210))	('children', 'Species', '9606', (59, 67))
445117	21422656	The chromosomal translocation producing the EWS/FLI1 fusion transcript characterizes clinical Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('FLI1', 'Gene', (48, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('FLI1', 'Gene', '2313', (48, 52))	('EWS', 'Gene', '2130', (44, 47))	('characterizes', 'Reg', (71, 84))	('EWS', 'Gene', (44, 47))	('Ewing sarcoma', 'Disease', (94, 107))	('fusion', 'Var', (53, 59))
445142	21422656	The cell line CHLA-9 was established at diagnosis from a 14-year-old female with a thoracic PNET, and the CHLA-10 line was established from the same patient after 4 cycles of chemotherapy, at which time the tumor cells had become p53 mutant.	('mutant', 'Var', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('p53', 'Gene', '7157', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('CHLA-9', 'CellLine', 'CVCL:M150', (14, 20))	('patient', 'Species', '9606', (149, 156))	('tumor', 'Disease', (207, 212))	('p53', 'Gene', (230, 233))
445180	21422656	Although the antibody had little effect in cell culture, it produced a significant decrease in the growth of human tumor xenografts, indicating a potential effect on the tumor microenvironment.	('human', 'Species', '9606', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (170, 175))	('decrease', 'NegReg', (83, 91))	('antibody', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
445182	21422656	Small-molecule inhibitors of CXCR2 have been tested in inflammatory diseases; dual CXCR1/ CXCR2 inhibitors such as SCH-479833 and SCH-527123 have been evaluated preclinically in cancer.	('SCH-479833', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('CXCR1', 'Gene', (83, 88))	('SCH-527123', 'Var', (130, 140))	('CXCR2', 'Gene', (90, 95))	('CXCR2', 'Gene', '3579', (90, 95))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('CXCR2', 'Gene', '3579', (29, 34))	('CXCR1', 'Gene', '3577', (83, 88))	('CXCR2', 'Gene', (29, 34))
445314	34046352	We found that CBXs and their co-expressed genes were mainly involved in GO:0000398 (mRNA splicing, via spliceosome) for BP, GO:0005634 (nucleus) for CC, and GO:0003682 (chromatin binding) for MF.	('GO:0003682', 'Var', (157, 167))	('GO:0005634', 'Var', (124, 134))	('CBXs', 'Chemical', '-', (14, 18))	('GO:0000398', 'Var', (72, 82))	('involved', 'Reg', (60, 68))
445328	34046352	These have revealed that the overexpression of GM2, GD2, and GD3 immunogenicity gangliosides can trigger an antibody response and improve the survival rate of patients with melanoma.	('improve', 'PosReg', (130, 137))	('overexpression', 'PosReg', (29, 43))	('GD2', 'Var', (52, 55))	('antibody', 'MPA', (108, 116))	('GM2', 'Chemical', '-', (47, 50))	('GD3', 'Gene', '117189', (61, 64))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('GD3', 'Gene', (61, 64))	('survival rate', 'CPA', (142, 155))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('GM2', 'Var', (47, 50))	('trigger', 'PosReg', (97, 104))	('patients', 'Species', '9606', (159, 167))	('gangliosides', 'Chemical', 'MESH:D005732', (80, 92))
445344	34046352	In hepatocellular carcinoma, the knockdown of CBX2 restrained the proliferation of HCC cells and increased the phosphorylation of YAP.	('YAP', 'Gene', (130, 133))	('CBX2', 'Gene', (46, 50))	('hepatocellular carcinoma', 'Disease', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('increased', 'PosReg', (97, 106))	('restrained', 'NegReg', (51, 61))	('knockdown', 'Var', (33, 42))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('proliferation', 'CPA', (66, 79))	('CBX2', 'Gene', '84733', (46, 50))	('YAP', 'Gene', '10413', (130, 133))	('phosphorylation', 'MPA', (111, 126))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
445349	34046352	Similar findings have been reported for glioma; high expression levels of HP1-gamma (CBX3) are known to predict a worse prognosis.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('CBX3', 'Gene', '11335', (85, 89))	('HP1-gamma', 'Gene', '11335', (74, 83))	('HP1-gamma', 'Gene', (74, 83))	('glioma', 'Disease', (40, 46))	('CBX3', 'Gene', (85, 89))	('high', 'Var', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
445354	34046352	These authors used HP1-gamma (CBX3) siRNA to knockdown HP1-gamma (CBX3) and thus block proliferation ability, thus resulting in increased levels of apoptosis and cell cycle arrest at the G0 and G1 phase; these findings were consistent with those reported in the present study.	('HP1-gamma', 'Gene', '11335', (19, 28))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (162, 179))	('proliferation ability', 'CPA', (87, 108))	('CBX3', 'Gene', '11335', (30, 34))	('HP1-gamma', 'Gene', (55, 64))	('levels', 'MPA', (138, 144))	('increased', 'PosReg', (128, 137))	('arrest', 'Disease', 'MESH:D006323', (173, 179))	('CBX3', 'Gene', '11335', (66, 70))	('HP1-gamma', 'Gene', (19, 28))	('CBX3', 'Gene', (30, 34))	('arrest', 'Disease', (173, 179))	('apoptosis', 'CPA', (148, 157))	('HP1-gamma', 'Gene', '11335', (55, 64))	('block', 'NegReg', (81, 86))	('knockdown', 'Var', (45, 54))	('CBX3', 'Gene', (66, 70))
445357	34046352	reported that the cell growth and migration of human lung cancer cell was suppressed by the knockdown of CBX4, both in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('suppressed', 'NegReg', (74, 84))	('CBX4', 'Gene', '8535', (105, 109))	('knockdown', 'Var', (92, 101))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('CBX4', 'Gene', (105, 109))	('human', 'Species', '9606', (47, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('lung cancer', 'Disease', (53, 64))
445372	34046352	However, high expression levels of CBX7 were associated with a reduced OS and DFS in patient with prostate cancers and ovarian cancers.	('prostate cancers and ovarian cancers', 'Disease', 'MESH:D011471', (98, 134))	('patient', 'Species', '9606', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('reduced', 'NegReg', (63, 70))	('DFS', 'Disease', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ovarian cancers', 'Phenotype', 'HP:0100615', (119, 134))	('CBX7', 'Gene', '23492', (35, 39))	('prostate cancers', 'Phenotype', 'HP:0012125', (98, 114))	('high', 'Var', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('CBX7', 'Gene', (35, 39))
445410	33713582	2 ,  4 ,  5  From the molecular point of view, the WWTR1 (WW Domain Containing Transcription Regulator 1) - CAMTA1 (Calmodulin Binding Transcription Activator 1) and YAP (Yes-associated protein 1)-TFE3 (Transcription Factor Binding To IGHM Enhancer 3) rearrangements are found in approximately 90% and 10% of all cases, respectively.	('WWTR1', 'Gene', (51, 56))	('YAP', 'Gene', '10413', (166, 169))	('WWTR1', 'Gene', '25937', (51, 56))	('Yes-associated protein 1', 'Gene', '10413', (171, 195))	('WW Domain Containing Transcription Regulator 1', 'Gene', (58, 104))	('TFE3', 'Gene', (197, 201))	('YAP', 'Gene', (166, 169))	('CAMTA1', 'Gene', '23261', (108, 114))	('Calmodulin Binding Transcription Activator 1', 'Gene', (116, 160))	('Calmodulin Binding Transcription Activator 1', 'Gene', '23261', (116, 160))	('TFE3', 'Gene', '7030', (197, 201))	('WW Domain Containing Transcription Regulator 1', 'Gene', '25937', (58, 104))	('Yes-associated protein 1', 'Gene', (171, 195))	('CAMTA1', 'Gene', (108, 114))	('rearrangements', 'Var', (252, 266))
445411	33713582	6 ,  7  Recently, gene fusions involving WWTR1 with a partner different from CAMTA1 have also been reported.	('WWTR1', 'Gene', (41, 46))	('WWTR1', 'Gene', '25937', (41, 46))	('CAMTA1', 'Gene', (77, 83))	('gene fusions', 'Var', (18, 30))	('CAMTA1', 'Gene', '23261', (77, 83))
445412	33713582	8  The detection of these rearrangements is today a hallmark in diagnosis, all the more in those cases marked by aggressive morphological features, where the differential diagnosis with angiosarcoma can be challenging, or atypical presentations.	('angiosarcoma', 'Disease', 'MESH:D006394', (186, 198))	('angiosarcoma', 'Disease', (186, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('angiosarcoma', 'Phenotype', 'HP:0200058', (186, 198))	('rearrangements', 'Var', (26, 40))
445533	33194758	focused on NGS RNA-based approaches to detect sarcoma-specific rearrangements, confirming their potential usefulness in routine diagnostic setting.	('rearrangements', 'Var', (63, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('sarcoma', 'Disease', (46, 53))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))
445534	33194758	For example, gastrointestinal stromal tumors (GIST) commonly harbor KIT or PDGFRA mutations and less frequently show SDH or NF1 gene inactivation.	('NF1', 'Gene', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (13, 44))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (13, 44))	('SDH', 'Gene', '10993', (117, 120))	('harbor', 'Reg', (61, 67))	('KIT', 'Gene', '3815', (68, 71))	('mutations', 'Var', (82, 91))	('PDGFRA', 'Gene', '5156', (75, 81))	('GIST', 'Phenotype', 'HP:0100723', (46, 50))	('SDH', 'Gene', (117, 120))	('PDGFRA', 'Gene', (75, 81))	('KIT', 'Gene', (68, 71))	('gastrointestinal stromal tumors', 'Disease', (13, 44))	('NF1', 'Gene', '4763', (124, 127))
445535	33194758	They found that 20% of wild type GIST harbored pathogenic KIT mutations and became eligible for TK inhibitors, underlining the importance of NGS technologies as a diagnostic tool.	('GIST', 'Phenotype', 'HP:0100723', (33, 37))	('KIT', 'Gene', '3815', (58, 61))	('pathogenic', 'Reg', (47, 57))	('KIT', 'Gene', (58, 61))	('mutations', 'Var', (62, 71))
445540	33194758	Despite the discovery of genetic aberrations and a deeper understanding of their role in sarcoma pathophysiology, the cornerstone of treatment for the majority of these advanced and metastatic tumors, chemotherapy, has changed little over the years.	('genetic aberrations', 'Var', (25, 44))	('tumors', 'Disease', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('sarcoma', 'Disease', (89, 96))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))
445550	33194758	The authors identified NSC130813 (NERI02; F06) and triptolide as valuable agents for overcoming cisplatin resistance, and also confirmed mitogen-activated protein kinase (MAPK) and fibroblast growth factor receptor (FGFR) pathways as novel therapeutic targets in this disease setting.	('overcoming', 'PosReg', (85, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('cisplatin resistance', 'MPA', (96, 116))	('NSC130813', 'Var', (23, 32))	('triptolide', 'Chemical', 'MESH:C001899', (51, 61))
445573	33194758	Although prognosis is very poor, a methylated state of the MGMT gene promoter has been shown to predict a better response to temozolomide therapy.	('response to temozolomide therapy', 'MPA', (113, 145))	('better', 'PosReg', (106, 112))	('methylated', 'Var', (35, 45))	('temozolomide', 'Chemical', 'MESH:D000077204', (125, 137))	('MGMT', 'Gene', (59, 63))	('MGMT', 'Gene', '4255', (59, 63))
445645	32405060	Cryopreservation, however, can increase the proportion of damaged cells and may not successfully recover all the malignant and other non-malignant cells in the tumor.	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Cryopreservation', 'Var', (0, 16))	('tumor', 'Disease', (160, 165))	('increase', 'PosReg', (31, 39))
445652	32405060	For example, in neuroblastoma, testing each of the four protocols on a single resection sample (HTAPP-244) yielded a similar number of high-quality nuclei (7,896, 6,157, 7,531 and 7,415 for EZ, CST, NST and TST, respectively) (Fig.	('HTAPP', 'Chemical', '-', (96, 101))	('neuroblastoma', 'Disease', 'MESH:D009447', (16, 29))	('7,896', 'Var', (156, 161))	('neuroblastoma', 'Disease', (16, 29))	('neuroblastoma', 'Phenotype', 'HP:0003006', (16, 29))
445702	32405060	For those samples that we prospectively collected for snRNA-Seq (neuroblastoma HTAPP-244-SMP-451 and HTAPP-656-SMP-3481), freezing of tumor samples was performed as quickly as possible after sample collection using a standard biobanking technique and the dates when samples were frozen were recorded.	('neuroblastoma', 'Phenotype', 'HP:0003006', (65, 78))	('HTAPP', 'Chemical', '-', (101, 106))	('HTAPP-656-SMP-3481', 'Var', (101, 119))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('neuroblastoma', 'Disease', 'MESH:D009447', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('neuroblastoma', 'Disease', (65, 78))	('tumor', 'Disease', (134, 139))	('HTAPP', 'Chemical', '-', (79, 84))
445765	32405060	367118, clone 63D3; 1:20 dilution) and PE-cy7 anti-human CD24 (BioLegend, cat.	('CD24', 'Gene', '100133941', (57, 61))	('CD24', 'Gene', (57, 61))	('PE-cy7 anti-human', 'Var', (39, 56))	('human', 'Species', '9606', (51, 56))	('PE-cy7', 'Chemical', '-', (39, 45))
445782	32405060	Either 10,000 or 8,000 nuclei (V2 or V3 10x Genomics, respectively) of the single-nucleus suspension were loaded onto the Chromium Chips for the Chromium Single Cell 3' Library (V2, PN-120233; V3, PN-1000075) according to the manufacturer's recommendations (10x Genomics).	('Chromium', 'Chemical', 'MESH:D002857', (145, 153))	('V2', 'Var', (178, 180))	('Cell 3', 'Gene', (161, 167))	('Chromium', 'Chemical', 'MESH:D002857', (122, 130))	('Cell 3', 'Gene', '1057', (161, 167))
445812	32405060	Raw data will also be available in the controlled access repository DUOS (https://duos.broadinstitute.org/), under DUOS Dataset IDs DUOS-000111, DUOS-000112, DUOS-000113 and DUOS-000114.	('DUOS-000114', 'Var', (174, 185))	('DUOS-000112', 'Var', (145, 156))	('IDs DUOS-000111', 'Disease', (128, 143))	('DUOS-000113', 'Var', (158, 169))	('IDs DUOS-000111', 'Disease', 'MESH:C535742', (128, 143))
445820	32405060	has a patent 'Methods for Treating MICA-Related Disorders' (#20100111973) with royalties paid, a patent 'Tumor Antigens and Uses Thereof' (#7250291) issued, a patent 'Angiopoiten-2 Biomarkers Predictive of Anti-immune Checkpoint Response' (#20170248603) pending, a patent 'Compositions and Methods for Identification, Assessment, Prevention and Treatment of Melanoma using PD-L1 Isoforms' (#20160340407) pending, a patent 'Therapeutic Peptides' (#20160046716) pending, a patent 'Therapeutic Peptides' (#20140004112) pending, a patent 'Therapeutic Peptides' (#20170022275) pending, a patent 'Therapeutic Peptides' (#20170008962) pending, a patent 'Therapeutic Peptides' (patent no.	('PD-L1', 'Gene', '29126', (373, 378))	('#20160340407', 'Var', (390, 402))	('Melanoma', 'Phenotype', 'HP:0002861', (358, 366))	('MICA', 'Gene', (35, 39))	('MICA', 'Gene', '100507436', (35, 39))	('Melanoma', 'Disease', 'MESH:D008545', (358, 366))	('Melanoma', 'Disease', (358, 366))	('PD-L1', 'Gene', (373, 378))	('Tumor', 'Phenotype', 'HP:0002664', (105, 110))
445957	28784104	In contrast, Khorana et al., evaluating the benefit of outpatient thromboprophylaxis with LMWH in high-risk patients in a multicenter randomized study, recently showed that thromboprophylaxis with dalteparin in cancer patients is associated with a non-significantly reduced risk of VTE and significantly increased risk of clinically relevant bleeding.	('thromboprophylaxis', 'Var', (173, 191))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('LMWH', 'Chemical', 'MESH:D006495', (90, 94))	('patients', 'Species', '9606', (218, 226))	('bleeding', 'Disease', 'MESH:D006470', (342, 350))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('dalteparin', 'Chemical', 'MESH:D017985', (197, 207))	('reduced', 'NegReg', (266, 273))	('bleeding', 'Disease', (342, 350))	('VTE', 'Disease', 'MESH:D054556', (282, 285))	('VTE', 'Disease', (282, 285))	('outpatient', 'Species', '9606', (55, 65))	('patients', 'Species', '9606', (108, 116))	('clinical', 'Species', '191496', (322, 330))
445967	26371783	Novel PAX3-NCOA1 Fusions in Biphenotypic Sinonasal Sarcoma with Focal Rhabdomyoblastic Differentiation Sarcomas arising in the sinonasal region are uncommon and encompass a wide variety of tumor types, including the newly described biphenotypic sinonasal sarcoma (BSNS), which is characterized by a monomorphic spindle cell proliferation with dual neural and myogenic phenotypes.	('biphenotypic sinonasal sarcoma', 'Disease', (232, 262))	('Biphenotypic Sinonasal Sarcoma', 'Disease', 'MESH:C535701', (28, 58))	('tumor', 'Disease', (189, 194))	('Sarcomas', 'Disease', (103, 111))	('Sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('Sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('Sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('Biphenotypic Sinonasal Sarcoma', 'Disease', (28, 58))	('PAX3', 'Gene', '5077', (6, 10))	('PAX3', 'Gene', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('biphenotypic sinonasal sarcoma', 'Disease', 'MESH:C535701', (232, 262))	('Sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('NCOA1', 'Gene', '8648', (11, 16))	('Fusions', 'Var', (17, 24))	('NCOA1', 'Gene', (11, 16))
445968	26371783	Most BSNSs harbor a pathognomonic PAX3-MAML3 fusion driven by t(2;4)(q35;q31.1), while the alternative fusion partner gene remains unidentified in a subset of PAX3-rearranged cases.	('PAX3', 'Gene', '5077', (159, 163))	('pathognomonic', 'Reg', (20, 33))	('t(2;4)(q35;q31.1)', 'STRUCTURAL_ABNORMALITY', 'None', (62, 79))	('PAX3', 'Gene', (159, 163))	('driven', 'Reg', (52, 58))	('t(2;4)(q35;q31.1', 'Var', (62, 78))	('fusion', 'Var', (45, 51))	('PAX3', 'Gene', '5077', (34, 38))	('BSNSs', 'Disease', (5, 10))	('PAX3', 'Gene', (34, 38))	('MAML3', 'Gene', '55534', (39, 44))	('MAML3', 'Gene', (39, 44))
445969	26371783	As NCOA1 on 2p23 is a known partner in PAX3-related fusions in other tumor types (i.e.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PAX3', 'Gene', '5077', (39, 43))	('tumor', 'Disease', (69, 74))	('PAX3', 'Gene', (39, 43))	('NCOA1', 'Gene', '8648', (3, 8))	('NCOA1', 'Gene', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('fusions', 'Var', (52, 59))
445975	26371783	In conclusion, we report a novel PAX3-NCOA1 fusion in BSNS, which appears to be associated with focal rhabdomyoblastic differentiation and should be distinguished from PAX3-NCOA1-positive alveolar rhabdomyosarcoma or malignant Triton tumor.	('PAX3', 'Gene', '5077', (33, 37))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (188, 213))	('PAX3', 'Gene', '5077', (168, 172))	('fusion', 'Var', (44, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('associated with', 'Reg', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('NCOA1', 'Gene', (38, 43))	('NCOA1', 'Gene', (173, 178))	('BSNS', 'Disease', (54, 58))	('malignant Triton tumor', 'Phenotype', 'HP:0100697', (217, 239))	('alveolar rhabdomyosarcoma', 'Disease', (188, 213))	('NCOA1', 'Gene', '8648', (38, 43))	('malignant Triton tumor', 'Disease', 'MESH:D018198', (217, 239))	('PAX3', 'Gene', (33, 37))	('NCOA1', 'Gene', '8648', (173, 178))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (197, 213))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (188, 213))	('PAX3', 'Gene', (168, 172))	('malignant Triton tumor', 'Disease', (217, 239))
445999	26371783	As both cases showed PAX3 gene abnormalities by FISH, further FISH and RT-PCR assays were performed to identify potential novel partners.	('PAX3', 'Gene', '5077', (21, 25))	('abnormalities', 'Var', (31, 44))	('PAX3', 'Gene', (21, 25))
446000	26371783	In parallel, published literature was reviewed for all PAX3-fusion partners reported, revealing PAX3-NCOA1 and PAX3-NCOA2 fusions have been previously described in a small subset of alveolar rhabdomyosarcoma (ARMS).	('NCOA1', 'Gene', '8648', (101, 106))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (182, 207))	('described', 'Reg', (151, 160))	('ARMS', 'Phenotype', 'HP:0006779', (209, 213))	('NCOA1', 'Gene', (101, 106))	('RMS', 'Phenotype', 'HP:0002859', (210, 213))	('PAX3', 'Gene', '5077', (111, 115))	('PAX3', 'Gene', '5077', (96, 100))	('fusions', 'Var', (122, 129))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (182, 207))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (191, 207))	('PAX3', 'Gene', (96, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('PAX3', 'Gene', (55, 59))	('PAX3', 'Gene', '5077', (55, 59))	('alveolar rhabdomyosarcoma', 'Disease', (182, 207))	('PAX3', 'Gene', (111, 115))
446009	26371783	FISH fusion assays confirmed a novel PAX3-NCOA1 fusion in both cases (Fig.	('PAX3', 'Gene', (37, 41))	('PAX3', 'Gene', '5077', (37, 41))	('fusion', 'Var', (48, 54))	('NCOA1', 'Gene', '8648', (42, 47))	('NCOA1', 'Gene', (42, 47))
446025	26371783	Case #7 was a BSNS harboring PAX3 rearrangement without MAML3 or NCOA1 abnormalities in a 44-year-old man manifesting proptosis.	('proptosis', 'Phenotype', 'HP:0000520', (118, 127))	('PAX3', 'Gene', '5077', (29, 33))	('rearrangement', 'Var', (34, 47))	('PAX3', 'Gene', (29, 33))	('man', 'Species', '9606', (102, 105))	('man', 'Species', '9606', (106, 109))	('MAML3', 'Gene', '55534', (56, 61))	('MAML3', 'Gene', (56, 61))	('NCOA1 abnormalities', 'Disease', 'MESH:D000014', (65, 84))	('NCOA1 abnormalities', 'Disease', (65, 84))
446042	26371783	The canonical PAX3-MAML3 fusions have been identified in the majority (76%) of BSNSs, with PAX3 rearrangements being the consistent genetic alteration in nearly all (96%) BSNSs.	('BSNSs', 'Disease', (79, 84))	('rearrangements', 'Var', (96, 110))	('PAX3', 'Gene', '5077', (91, 95))	('PAX3', 'Gene', (91, 95))	('PAX3', 'Gene', '5077', (14, 18))	('PAX3', 'Gene', (14, 18))	('MAML3', 'Gene', '55534', (19, 24))	('MAML3', 'Gene', (19, 24))
446045	26371783	In the current study, we took a combined approach using FISH and RT-PCR with different primer pairs to identify the PAX3-NCOA1 fusions.	('NCOA1', 'Gene', (121, 126))	('PAX3', 'Gene', '5077', (116, 120))	('PAX3', 'Gene', (116, 120))	('fusions', 'Var', (127, 134))	('NCOA1', 'Gene', '8648', (121, 126))
446057	26371783	It remains unclear the reason for discrepancy between S100 protein/SOX10 expression, but it might be related to the multiple specificities against both S100A and S100B or the cross-reactivity of the current polyclonal S100 antibody with equivalent epitopes in similar proteins.	('S100A', 'SUBSTITUTION', 'None', (152, 157))	('S100A', 'Var', (152, 157))	('S100B', 'Gene', (162, 167))
446064	26371783	Demonstration of PAX3 gene abnormalities by FISH can serve as a useful diagnostic tool in the differential diagnosis of a sinonasal low-grade spindle cell tumor with neural and myogenic features, especially in patients without NF1.	('NF1', 'Gene', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('PAX3', 'Gene', (17, 21))	('tumor', 'Disease', (155, 160))	('PAX3', 'Gene', '5077', (17, 21))	('patients', 'Species', '9606', (210, 218))	('NF1', 'Gene', '4763', (227, 230))	('abnormalities', 'Var', (27, 40))
446069	26371783	Interestingly, a subset of infantile/congenital SC-RMS harbors NCOA2 rearrangements, being fused with either SRF or TEAD1 gene.	('harbors', 'Reg', (55, 62))	('RMS', 'Phenotype', 'HP:0002859', (51, 54))	('SRF', 'Disease', 'None', (109, 112))	('infantile/congenital SC-RMS', 'Disease', (27, 54))	('SRF', 'Disease', (109, 112))	('rearrangements', 'Var', (69, 83))	('NCOA2', 'Gene', (63, 68))
446072	26371783	A comprehensive immunohistochemical panel and FISH analysis for PAX3 gene rearrangements should be considered in difficult cases, especially in limited tissue biopsies.	('PAX3', 'Gene', '5077', (64, 68))	('PAX3', 'Gene', (64, 68))	('rearrangements', 'Var', (74, 88))
446073	26371783	Our findings suggest that PAX3-NCOA1 fusions can be seen in a small subset of both BSNS and ARMS, and might be implicated in the rhabdomyoblastic phenotype shared by these two distinct tumor types.	('tumor', 'Disease', (185, 190))	('NCOA1', 'Gene', (31, 36))	('BSNS', 'Disease', (83, 87))	('PAX3', 'Gene', '5077', (26, 30))	('PAX3', 'Gene', (26, 30))	('fusions', 'Var', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('rhabdomyoblastic', 'Disease', (129, 145))	('RMS', 'Phenotype', 'HP:0002859', (93, 96))	('ARMS', 'Phenotype', 'HP:0006779', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('NCOA1', 'Gene', '8648', (31, 36))	('implicated', 'Reg', (111, 121))
446076	24733554	We hypothesized that delivery of oncogenes into mouse skeletal muscle using a retroviral (RCAS-TVA) system would result in sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('mouse', 'Species', '10090', (48, 53))	('TVA', 'Chemical', 'MESH:C050413', (95, 98))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('RCAS', 'Chemical', '-', (90, 94))	('result in', 'Reg', (113, 122))	('sarcoma', 'Disease', (123, 130))	('oncogenes', 'Var', (33, 42))
446079	24733554	Disrupting the G1 checkpoint CDKN2 (p16/p19-/-) resulted in sarcoma in 30% of p16/p19-/-xN-tva mice with a median latency of 23 weeks (range 8-40 weeks).	('CDKN2', 'Gene', (29, 34))	('mice', 'Species', '10090', (95, 99))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('p16/p19-/-xN-tva', 'Var', (78, 94))	('p16/p19-/-', 'Var', (36, 46))	('Disrupting', 'Var', (0, 10))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('resulted in', 'Reg', (48, 59))	('CDKN2', 'Gene', '1029', (29, 34))
446081	24733554	p16/p19-/-xAKE mice also developed sarcomas (24% incidence; median 9 weeks) yet 31% of mice also developed lung sarcomas.	('p16/p19-/-xAKE', 'Var', (0, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('sarcomas', 'Disease', (112, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('mice', 'Species', '10090', (87, 91))	('sarcomas', 'Disease', (35, 43))	('lung sarcomas', 'Disease', 'MESH:D012509', (107, 120))	('sarcomas', 'Disease', 'MESH:D012509', (112, 120))	('mice', 'Species', '10090', (15, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('sarcomas', 'Disease', 'MESH:D012509', (35, 43))	('lung sarcomas', 'Disease', (107, 120))
446084	24733554	Oncogene delivery by the RCAS-TVA system can generate sarcomas in mice with a defective cell cycle checkpoint.	('RCAS', 'Chemical', '-', (25, 29))	('TVA', 'Chemical', 'MESH:C050413', (30, 33))	('Oncogene delivery', 'Var', (0, 17))	('mice', 'Species', '10090', (66, 70))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('defective cell cycle checkpoint', 'Phenotype', 'HP:0011018', (78, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('generate', 'Reg', (45, 53))	('rat', 'Species', '10116', (49, 52))	('sarcomas', 'Disease', (54, 62))
446093	24733554	Current models of sarcoma include zebrafish - an elegant genetic system that has many advantages such as rapid generation of mutants and ease of live animal imaging, but may not faithfully recapitulate sarcomagenesis in mammals.	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('zebrafish', 'Species', '7955', (34, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('sarcoma', 'Disease', (18, 25))	('rat', 'Species', '10116', (115, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('mutants', 'Var', (125, 132))	('sarcoma', 'Disease', 'MESH:D012509', (202, 209))	('sarcoma', 'Disease', (202, 209))
446103	24733554	Oncogene delivery resulted in the generation of soft tissue sarcomas; however this was dependent upon abrogation of the p16/p19 tumor suppressor locus.	('sarcomas', 'Disease', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (48, 68))	('Oncogene delivery', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (48, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('tumor', 'Disease', (128, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('rat', 'Species', '10116', (38, 41))
446113	24733554	An in vitro assay was performed in cells derived from skeletal muscle harvested from 1-2 day old p16/p19-/-xAKE, p16/p19-/-xBKE and p16/p19-/-xN-tva mice as previously described.	('p16/p19-/-xBKE', 'Var', (113, 127))	('p16/p19-/-xAKE', 'Var', (97, 111))	('mice', 'Species', '10090', (149, 153))
446115	24733554	1-2 day old p16/p19-/-xAKE, p16/p19-/-xBKE or p16/p19-/-xN-tva mouse pups were injected with GFP or EV expressing DF-1 cells in both hind limbs.	('mouse', 'Species', '10090', (63, 68))	('p16/p19-/-xBKE', 'Var', (28, 42))	('p16/p19-/-xN-tva', 'Var', (46, 62))
446145	24733554	Since the CDKN2 locus, which encodes p16 (INK4a) and p19 (ARF) genes, has been implicated in human and murine sarcoma pathogenesis, we also sought to determine if dysregulation of this tumor suppressor would play a cooperative role in sarcomagenesis in the RCAS-TVA system.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('play', 'Reg', (208, 212))	('sarcoma', 'Disease', (110, 117))	('CDKN2', 'Gene', '1029', (10, 15))	('dysregulation', 'Var', (163, 176))	('tumor', 'Disease', (185, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('sarcoma', 'Disease', (235, 242))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('implicated', 'Reg', (79, 89))	('rat', 'Species', '10116', (220, 223))	('TVA', 'Chemical', 'MESH:C050413', (262, 265))	('RCAS', 'Chemical', '-', (257, 261))	('ARF', 'Gene', '12578', (58, 61))	('INK4a', 'Gene', (42, 47))	('human', 'Species', '9606', (93, 98))	('CDKN2', 'Gene', (10, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('INK4a', 'Gene', '1029', (42, 47))	('ARF', 'Gene', (58, 61))	('murine', 'Species', '10090', (103, 109))
446151	24733554	Similarly, in p16/p19+/-xN-tva mice and p16/p19-/-xBKE mice an average of 7.3% and 3.3% of cells respectively were GFP+ (data not shown).	('GFP+', 'Var', (115, 119))	('p16/p19-/-xBKE', 'Var', (40, 54))	('mice', 'Species', '10090', (55, 59))	('mice', 'Species', '10090', (31, 35))	('p16/p19+/-xN-tva', 'Var', (14, 30))
446152	24733554	Collectively, these experiments demonstrate that retroviral infection of neonatal skeletal muscle cells in p16/p19-/-xN-tva, p16/p19-/-xAKE and p16/p19 -/-xBKE mice is successful using RCAS vectors.	('p16/p19-/-xAKE', 'Var', (125, 139))	('RCAS', 'Chemical', '-', (185, 189))	('rat', 'Species', '10116', (39, 42))	('infection of neonatal skeletal', 'Disease', (60, 90))	('mice', 'Species', '10090', (160, 164))	('infection of neonatal skeletal', 'Disease', 'OMIM:202370', (60, 90))	('p16/p19 -/-xBKE', 'Var', (144, 159))	('p16/p19-/-xN-tva', 'Var', (107, 123))
446158	24733554	Dysregulation of the CDKN2A locus, due to either mutation or methylation, which encodes p16 and p19, has been reported in several subtypes of human sarcomas; consequently we examined if abrogation of this tumor suppressor in the RCAS-TVA system would promote sarcoma formation.	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('abrogation', 'Var', (186, 196))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('sarcomas', 'Disease', 'MESH:D012509', (148, 156))	('sarcoma', 'Disease', (148, 155))	('sarcoma', 'Disease', 'MESH:D012509', (259, 266))	('promote', 'PosReg', (251, 258))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('human', 'Species', '9606', (142, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('sarcoma', 'Disease', (259, 266))	('CDKN2A', 'Gene', (21, 27))	('sarcomas', 'Disease', (148, 156))	('RCAS', 'Chemical', '-', (229, 233))	('TVA', 'Chemical', 'MESH:C050413', (234, 237))
446160	24733554	Thus, we delivered a mixture of DF-1 producing RCAS-KrasG12D, RCAS-c-Myc, and/or RCAS-Igf2 cells into the left hindlimbs of p16/p19-/-xN-tva, p16/p19-/-xAKE or p16/p19-/-xBKE strains.	('RCAS-Igf2', 'Gene', (81, 90))	('RCAS-c-Myc', 'Gene', (62, 72))	('RCAS', 'Chemical', '-', (81, 85))	('RCAS-Igf2', 'Gene', '16002', (81, 90))	('RCAS', 'Chemical', '-', (47, 51))	('RCAS-c-Myc', 'Gene', '420332', (62, 72))	('RCAS', 'Chemical', '-', (62, 66))	('Kras', 'Gene', (52, 56))	('Kras', 'Gene', '16653', (52, 56))	('p16/p19-/-xN-tva', 'Var', (124, 140))
446171	24733554	Although p16/p19-/-xAKE mice had a similar incidence (24%; 16/67 animals) and latency of tumor formation (median 9 weeks, range 6-25 weeks) to the p16/p19-/-xBKE strain, a striking increase in sarcoma formation distant to the injection site was observed.	('sarcoma', 'Disease', 'MESH:D012509', (193, 200))	('mice', 'Species', '10090', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('sarcoma', 'Disease', (193, 200))	('p16/p19-/-xAKE', 'Var', (9, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('increase', 'PosReg', (181, 189))
446188	24733554	Other immunohistochemical phenotypes observed in our models included myofibroblastic differentiation (SMA+, desmin+/-), rhabdomyosarcomatous differentiation (MyoD1+, desmin+/-, SMA+/-) and an undifferentiated round cell tumor (Figure 3F).	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (120, 136))	('MyoD1', 'Gene', (158, 163))	('rhabdomyosarcomatous', 'Disease', 'None', (120, 140))	('rhabdomyosarcomatous', 'Disease', (120, 140))	('tumor', 'Disease', (220, 225))	('SMA+', 'Var', (102, 106))	('SMA+/-', 'Var', (177, 183))	('myofibroblastic', 'Disease', (69, 84))	('MyoD1', 'Gene', '17927', (158, 163))	('desmin', 'Gene', (108, 114))	('desmin', 'Gene', '13346', (108, 114))	('desmin', 'Gene', '13346', (166, 172))	('desmin', 'Gene', (166, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
446205	24733554	AKE and BKE mice with functional CDKN2 (p16/p19+/+) did not develop sarcomas following injection with RCAS vectors carrying known oncogenes (Table 1; Figure 2).	('RCAS', 'Chemical', '-', (102, 106))	('CDKN2', 'Gene', '1029', (33, 38))	('sarcomas', 'Disease', (68, 76))	('p16/p19+/+', 'Var', (40, 50))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('mice', 'Species', '10090', (12, 16))	('develop', 'PosReg', (60, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('CDKN2', 'Gene', (33, 38))
446208	24733554	Thus, abrogation of a tumor suppressor is likely required for sarcomagenesis in this system.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('abrogation', 'Var', (6, 16))	('sarcoma', 'Disease', (62, 69))
446209	24733554	Other mouse models of sarcoma also demonstrate tumor formation is dependent on oncogene activation in conjunction with loss of a tumor suppressor pathway such as p53 or p16/p19.	('activation', 'PosReg', (88, 98))	('p53', 'Gene', (162, 165))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('rat', 'Species', '10116', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('p53', 'Gene', '22059', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('sarcoma', 'Disease', (22, 29))	('oncogene', 'Protein', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('tumor', 'Disease', (47, 52))	('p16/p19', 'Var', (169, 176))	('mouse', 'Species', '10090', (6, 11))
446214	24733554	We identified flank sarcomas in 13 of 52 experimental animals (p16/p19-/- xN-tva; n = 10 and p16/p19-/- xAKE; n = 3).	('p16/p19-/- xAKE', 'Var', (93, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('flank sarcomas', 'Disease', 'MESH:D021501', (14, 28))	('flank sarcomas', 'Disease', (14, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
446229	24733554	Distant disease developed most frequently in the p16/p19-/- xAKE strain (31% of the affected mice) compared to p16/p19-/- xBKE (7%) and p16/p19-/- xN-tva (0).	('p16/p19-/- xAKE', 'Var', (49, 64))	('Distant disease', 'Disease', (0, 15))	('mice', 'Species', '10090', (93, 97))
446230	24733554	Further work to more globally compare injection site sarcomas and distant disease using expression analysis may help identify co-operative mutations that promote tumor dissemination in sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('rat', 'Species', '10116', (132, 135))	('promote', 'PosReg', (154, 161))	('mutations', 'Var', (139, 148))	('tumor', 'Disease', (162, 167))	('sarcoma', 'Disease', (53, 60))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcoma', 'Disease', 'MESH:D012509', (185, 192))	('sarcomas', 'Disease', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('sarcoma', 'Disease', (185, 192))
446232	24733554	We hypothesized that tva expression in terminally differentiated tissue such as skeletal muscle would result in a consistent tumour type such as rhabdomyosarcoma (RMS), yet we observed morphologically undifferentiated sarcomas that had immunohistochemical evidence of myofibroblastic, rhabdomyosarcomatous or fibroblastic differentiation.	('myofibroblastic', 'Disease', (268, 283))	('RMS', 'Phenotype', 'HP:0002859', (163, 166))	('fibroblastic differentiation', 'CPA', (309, 337))	('sarcoma', 'Phenotype', 'HP:0100242', (294, 301))	('tva', 'Gene', (21, 24))	('rhabdomyosarcoma', 'Disease', (145, 161))	('rhabdomyosarcomatous', 'Disease', 'None', (285, 305))	('rhabdomyosarcoma', 'Disease', (285, 301))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (145, 161))	('sarcomas', 'Disease', 'MESH:D012509', (218, 226))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (145, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (218, 226))	('expression', 'Var', (25, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('sarcomas', 'Disease', (218, 226))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (285, 301))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (285, 301))	('result in', 'Reg', (102, 111))	('rhabdomyosarcomatous', 'Disease', (285, 305))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))
446268	22174674	The development of cancer is linked to six major hallmarks that explain how cells transgress from a normal to a neoplastic state, including (i) sustained proliferative signaling, (ii) evasion of growth suppression, (iii) activated invasion and metastasis, (iv) enabled replicative immortality, (v) induced angiogenesis and (vi) resistance to cell death.	('enabled', 'PosReg', (261, 268))	('angiogenesis', 'CPA', (306, 318))	('activated', 'PosReg', (221, 230))	('invasion', 'CPA', (231, 239))	('metastasis', 'CPA', (244, 254))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('growth suppression', 'MPA', (195, 213))	('cancer', 'Disease', (19, 25))	('evasion', 'Var', (184, 191))	('neoplastic state', 'Phenotype', 'HP:0002664', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('induced', 'PosReg', (298, 305))	('resistance to cell death', 'CPA', (328, 352))	('replicative immortality', 'CPA', (269, 292))
446282	22174674	Here, we show that KSHV miRNAs also contribute to the inhibition of apoptosis in infected cells.	('KSHV', 'Gene', (19, 23))	('apoptosis', 'CPA', (68, 77))	('inhibition', 'NegReg', (54, 64))	('KSHV', 'Species', '37296', (19, 23))	('miRNAs', 'Var', (24, 30))
446283	22174674	We show that cell lines expressing KSHV miRNAs are less sensitive to both caspase-dependent and -independent apoptosis induction by staurosporine or etoposide.	('etoposide', 'Chemical', 'MESH:D005047', (149, 158))	('KSHV', 'Species', '37296', (35, 39))	('miRNAs', 'Var', (40, 46))	('less', 'NegReg', (51, 55))	('KSHV miRNAs', 'Var', (35, 46))	('sensitive', 'MPA', (56, 65))	('staurosporine', 'Chemical', 'MESH:D019311', (132, 145))
446285	22174674	Using site-directed mutagenesis, we found that KSHV miR-K12-1, K12-3 and K12-4-3p are responsible for Casp3 regulation.	('Casp3', 'MPA', (102, 107))	('K12-4-3p', 'Var', (73, 81))	('KSHV', 'Gene', (47, 51))	('miR-K12-1', 'Var', (52, 61))	('K12-3', 'Var', (63, 68))	('KSHV', 'Species', '37296', (47, 51))
446332	22174674	The lack of miR-K12-9 activity could relate to its lower expression in the context of the K10/12 construct (Tables S1 and S2).	('expression', 'MPA', (57, 67))	('miR-K12-9', 'Var', (12, 21))	('K10/12', 'Gene', '4961446', (90, 96))	('expression', 'Species', '29278', (57, 67))	('lower', 'NegReg', (51, 56))	('activity', 'MPA', (22, 30))	('K10/12', 'Gene', (90, 96))
446333	22174674	As opposed to what would have been expected based on the DG-75-K10/12 small RNA sequencing data, miR-K12-11 appeared to be functional in the FLP-K10/12, and we confirmed that it accumulated in higher amounts in these cells compared to the DG-75-K10/12 cells (data not shown).	('K10/12', 'Gene', (145, 151))	('miR-K12-11', 'Var', (97, 107))	('K10/12', 'Gene', (245, 251))	('K10/12', 'Gene', '4961446', (63, 69))	('K10/12', 'Gene', '4961446', (145, 151))	('higher amounts', 'PosReg', (193, 207))	('FLP', 'Gene', '15445', (141, 144))	('K10/12', 'Gene', '4961446', (245, 251))	('FLP', 'Gene', (141, 144))	('K10/12', 'Gene', (63, 69))	('accumulated', 'PosReg', (178, 189))
446338	22174674	The initial analysis of Casp3 3' UTR revealed 8mer or 7mer seed-matches for miR-K12-4-3p (one M8A1 site), miR-K12-1 (two M8 sites), and miR-K12-3 (one A1 site).	('miR-K12-4-3p', 'Var', (76, 88))	('miR-K12-1', 'Var', (106, 115))	('miR-K12-3', 'Gene', (136, 145))	('miR-K12-3', 'Gene', '9149', (136, 145))
446340	22174674	We found that as suggested by the seed-matches quality, miR-K12-1, K12-3 and K12-4-3p (in decreasing order of repression observed) were able to significantly regulate the expression of the reporter fused to the 3' UTR of Casp3 (Figure 5B).	('expression', 'MPA', (171, 181))	('miR-K12-1', 'Var', (56, 65))	('K12-3', 'Var', (67, 72))	('K12-4-3p', 'Var', (77, 85))	('regulate', 'Reg', (158, 166))	('expression', 'Species', '29278', (171, 181))
446341	22174674	Expression of miR-K12-2 and K12-10, or of miRNAs with no predicted seed-matches (miR-K12-5, K12-6 and K12-9) had no effect on the Casp3 sensor.	('K12-6', 'Var', (92, 97))	('miR-K12-5', 'Var', (81, 90))	('K12-10', 'Var', (28, 34))	('K12-9', 'Var', (102, 107))	('Expression', 'Species', '29278', (0, 10))	('miR-K12-2', 'Var', (14, 23))	('Casp3 sensor', 'MPA', (130, 142))
446342	22174674	The resulting luciferase reporters were tested with miRNA expression constructs for either the 10 intronic miRNAs, or the individual miR-K12-1, K12-3 and K12-4-3p.	('miR-K12-1', 'Var', (133, 142))	('K12-3', 'Var', (144, 149))	('K12-4-3p', 'Var', (154, 162))	('expression', 'Species', '29278', (58, 68))
446351	22174674	In order to assess whether the down-regulation of Casp3 in naturally KSHV infected cells was caused by the specific presence of the three previously identified miRNAs, we used an antisense approach to inhibit specifically miR-K12-1, K12-3 and K12-4-3p.	('Casp3', 'Protein', (50, 55))	('KSHV infected', 'Disease', 'MESH:C537372', (69, 82))	('inhibit', 'NegReg', (201, 208))	('miR-K12-1', 'Var', (222, 231))	('KSHV infected', 'Disease', (69, 82))	('K12-4-3p', 'Var', (243, 251))	('K12-3', 'Var', (233, 238))	('down-regulation', 'NegReg', (31, 46))
446353	22174674	In three independent experiments, transfection of a cocktail of 2'OMe oligonucleotides against miR-K12-1, K12-3 and K12-4-3p (2'OMe-miR-K12-1/3/4) in BC-3 cells resulted in a modest but measurable increase of Casp3 protein level compared to a control 2'OMe oligonucleotide (2'OMe-miR-67) (1.4-fold on average, p = 0.0486) (Figure 7E).	('oligonucleotides', 'Chemical', 'MESH:D009841', (70, 86))	('miR-67', 'Gene', (280, 286))	('Casp3 protein level', 'MPA', (209, 228))	('increase', 'PosReg', (197, 205))	('miR-67', 'Gene', '259740', (280, 286))	('K12-4-3p', 'Var', (116, 124))	('K12-3', 'Var', (106, 111))	('miR-K12-1', 'Var', (95, 104))
446357	22174674	Taking these results altogether, we can definitely conclude that Casp3 is regulated at both mRNA and protein levels by the KSHV-encoded miR-K12-1, K12-3, and K12-4-3p.	('miR-K12-1', 'Var', (136, 145))	('KSHV', 'Species', '37296', (123, 127))	('regulated', 'Reg', (74, 83))	('Casp3', 'Gene', (65, 70))	('K12-3', 'Var', (147, 152))	('K12-4-3p', 'Var', (158, 166))
446365	22174674	These data suggests that the KSHV-encoded miR-K12-1, K12-3 and K12-4-3p contribute to protection of etoposide-induced apoptosis in KSHV infected iLECs.	('etoposide', 'Chemical', 'MESH:D005047', (100, 109))	('K12-3', 'Var', (53, 58))	('protection', 'PosReg', (86, 96))	('KSHV infected', 'Disease', 'MESH:C537372', (131, 144))	('etoposide-induced', 'MPA', (100, 117))	('KSHV', 'Species', '37296', (131, 135))	('KSHV', 'Species', '37296', (29, 33))	('K12-4-3p', 'Var', (63, 71))	('KSHV infected', 'Disease', (131, 144))
446370	22174674	For example, miR-K12-11 has been shown to target a subset of genes that are also targeted by its homologous human miRNA, miR-155, that shares an identical seed region with this miRNA.	('human', 'Species', '9606', (108, 113))	('miR-155', 'Gene', '406947', (121, 128))	('miR-K12-11', 'Var', (13, 23))	('miR-155', 'Gene', (121, 128))
446371	22174674	Among the validated targets of miR-K12-11 are two transcription factors, BACH1 and Fos.	('Fos', 'Gene', '2353', (83, 86))	('BACH1', 'Gene', (73, 78))	('Fos', 'Gene', (83, 86))	('miR-K12-11', 'Var', (31, 41))	('BACH1', 'Gene', '571', (73, 78))
446388	22174674	We also measured Casp3 activity in the HEK293 cells, and showed that the presence of KSHV miRNAs resulted in a sharp decrease of Casp3/7 activity upon staurosporine induction.	('presence', 'Var', (73, 81))	('KSHV', 'Gene', (85, 89))	('293 cells', 'CellLine', 'CVCL:0045', (42, 51))	('Casp3/7', 'Enzyme', (129, 136))	('activity', 'MPA', (137, 145))	('staurosporine', 'Chemical', 'MESH:D019311', (151, 164))	('decrease', 'NegReg', (117, 125))	('KSHV', 'Species', '37296', (85, 89))	('HEK293', 'CellLine', 'CVCL:0045', (39, 45))
446393	22174674	To discover cellular targets of KSHV miRNAs, we used a microarray-based approach to identify transcripts regulated by KSHV miRNAs in both the B lymphocyte DG-75 cell line and the endothelial EA.hy926 cell line.	('KSHV', 'Species', '37296', (118, 122))	('transcripts', 'MPA', (93, 104))	('KSHV', 'Species', '37296', (32, 36))	('miRNAs', 'Var', (123, 129))	('EA.hy926', 'CellLine', 'CVCL:3901', (191, 199))	('KSHV', 'Gene', (118, 122))
446400	22174674	We confirmed that a Casp3 3' UTR luciferase reporter construct is regulated by three KSHV miRNAs, and we identified three miRNAs, miR-K12-1, miR-K12-3 and miR-K12-4-3p, as being responsible for this regulation, as well as their binding sites within Casp3 3' UTR.	('Casp3 3', 'Gene', (20, 27))	('miR-K12-3', 'Gene', (141, 150))	('miR-K12-3', 'Gene', '9149', (141, 150))	('miR-K12-4-3p', 'Var', (155, 167))	('KSHV', 'Species', '37296', (85, 89))	('miR-K12-1', 'Var', (130, 139))
446402	22174674	We also showed that inhibition of miR-K12-1, K12-3 and K12-4-3p in KSHV-infected cells resulted in an upregulation of Casp3 expression, which in turn translated into an increase in apoptosis, as assessed by cleaved Casp3 quantification and TUNEL assay analysis.	('miR-K12-1', 'Var', (34, 43))	('K12-4-3p', 'Var', (55, 63))	('K12-3', 'Var', (45, 50))	('KSHV-infected', 'Disease', (67, 80))	('KSHV-infected', 'Disease', 'MESH:C537372', (67, 80))	('expression', 'Species', '29278', (124, 134))	('increase', 'PosReg', (169, 177))	('apoptosis', 'CPA', (181, 190))	('inhibition', 'NegReg', (20, 30))	('expression', 'MPA', (124, 134))	('upregulation', 'PosReg', (102, 114))	('Casp3', 'Protein', (118, 123))
446408	22174674	In summary, our findings demonstrate that KSHV miR-K12-1, K12-3 and K12-4-3p target the effector caspase 3.	('caspase 3', 'Gene', (97, 106))	('KSHV', 'Species', '37296', (42, 46))	('caspase 3', 'Gene', '836', (97, 106))	('target', 'Reg', (77, 83))	('K12-4-3p', 'Var', (68, 76))	('KSHV', 'Gene', (42, 46))	('miR-K12-1', 'Var', (47, 56))	('K12-3', 'Var', (58, 63))
446409	22174674	The down-regulation of Casp3 by KSHV miRNAs results in a decrease in apoptosis activity in different cell types including endothelial cells that are biologically relevant for KSHV infection in vivo.	('KSHV', 'Species', '37296', (175, 179))	('decrease', 'NegReg', (57, 65))	('miRNAs', 'Var', (37, 43))	('apoptosis activity', 'CPA', (69, 87))	('KSHV', 'Species', '37296', (32, 36))	('KSHV infection', 'Disease', 'MESH:C537372', (175, 189))	('KSHV infection', 'Disease', (175, 189))	('down-regulation', 'NegReg', (4, 19))	('Casp3', 'Protein', (23, 28))	('KSHV', 'Gene', (32, 36))
446440	22174674	Efficiency of the selection was then assayed by beta-galactosidase staining, for the loss of beta-galactosidase activity, and/or by northern blot for the detection of the miRNA.	('beta-galactosidase', 'Gene', (93, 111))	('loss of beta-galactosidase activity', 'Phenotype', 'HP:0008166', (85, 120))	('beta-galactosidase', 'Gene', '2720', (48, 66))	('loss', 'NegReg', (85, 89))	('miRNA', 'Var', (171, 176))	('beta-galactosidase', 'Gene', (48, 66))	('activity', 'MPA', (112, 120))	('beta-galactosidase', 'Gene', '2720', (93, 111))
446474	22174674	Primary antibodies used in Western blotting were anti-caspase-3 (06-735; UpState), anti-PARP-1 and anti-gamma-tubulin (GTU-88; Sigma-Aldrich).	('anti-gamma-tubulin', 'Var', (99, 117))	('anti-PARP-1', 'Var', (83, 94))	('caspase-3', 'Gene', (54, 63))	('caspase-3', 'Gene', '836', (54, 63))
446475	22174674	IRDye 800CW-conjugated anti-rabbit and anti-mouse (926-32213 and 926-32212; Li-Cor Biosciences) immunoglobulins were used as secondary antibodies.	('800CW', 'Chemical', '-', (6, 11))	('926-32213', 'Var', (51, 60))	('926-32212', 'Var', (65, 74))	('rabbit', 'Species', '9986', (28, 34))	('mouse', 'Species', '10090', (44, 49))
446477	22174674	Probes were 5' 32P-radiolabelled oligodeoxynucleotides antisense to the miRNA sequence or to part of the U6 snRNA sequence.	('miRNA sequence', 'MPA', (72, 86))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (33, 54))	('32P', 'Chemical', 'MESH:C000615311', (15, 18))	('antisense', 'Var', (55, 64))
446548	31380135	Therefore, the detection of MDM2 amplification in the osteosarcomatous part is not sufficient to distinguish between ESOS and DDL with heterologous osteosarcomatous differentiation.	('DDL', 'Disease', (126, 129))	('osteosarcomatous differentiation', 'Phenotype', 'HP:0002669', (148, 180))	('ESOS', 'Disease', (117, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('amplification', 'Var', (33, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('osteosarcomatous part', 'Disease', 'MESH:D018227', (54, 75))	('heterologous osteosarcomatous differentiation', 'Disease', 'MESH:D012734', (135, 180))	('osteosarcomatous part', 'Disease', (54, 75))	('MDM2', 'Gene', '4193', (28, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (148, 160))	('MDM2', 'Gene', (28, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (54, 66))	('heterologous osteosarcomatous differentiation', 'Disease', (135, 180))
446550	31380135	In diagnostic work-up for cases of bone-forming soft tissue sarcomas with MDM2 amplification, it should be noted that frequency of DDL is much higher compared to ESOS; therefore, the possibility of a DDL should be carefully evaluated; thus a thorough sampling of the fatty tissue surrounding the tumor becomes imperative.	('sarcomas', 'Disease', (60, 68))	('MDM2', 'Gene', '4193', (74, 78))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (48, 68))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('MDM2', 'Gene', (74, 78))	('tumor', 'Disease', (296, 301))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('DDL', 'Disease', (131, 134))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('amplification', 'Var', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
446676	27783991	However, approximately half of all patients with intermediate or high-grade STS will develop metastatic disease, with a 5-year survival of only 50%.	('STS', 'Phenotype', 'HP:0030448', (76, 79))	('intermediate', 'Var', (49, 61))	('metastatic disease', 'CPA', (93, 111))	('patients', 'Species', '9606', (35, 43))	('develop', 'PosReg', (85, 92))
446679	27783991	Three expression casettes (RUC-GFP, LacZ, gusA) were inserted into F14.5L, J2R and A56R loci of the viral genome, respectively, resulting in attenuated virulence, enhanced tumour-specific targeting, and the ability to monitor viral transgene expression.	('virulence', 'MPA', (152, 161))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('J2R', 'Var', (75, 78))	('attenuated', 'NegReg', (141, 151))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (172, 178))	('enhanced', 'PosReg', (163, 171))	('A56R', 'Mutation', 'p.A56R', (83, 87))	('A56R', 'Var', (83, 87))
446696	27783991	Whilst GLV-1h68 has been shown to have a potent anti-tumour effect, the precise mechanism of its cytotoxicity is still unclear.	('tumour', 'Disease', (53, 59))	('cytotoxicity', 'Disease', 'MESH:D064420', (97, 109))	('GLV-1h68', 'Species', '502057', (7, 15))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('GLV-1h68', 'Var', (7, 15))	('cytotoxicity', 'Disease', (97, 109))
446699	27783991	One area of recent research has been the role of GLV-1h68 in inducing apoptosis, with several studies demonstrating an increase in caspase 3 cleavage.	('caspase 3', 'Gene', (131, 140))	('caspase 3', 'Gene', '836', (131, 140))	('GLV-1h68', 'Species', '502057', (49, 57))	('rat', 'Species', '10116', (109, 112))	('inducing', 'MPA', (61, 69))	('increase', 'PosReg', (119, 127))	('apoptosis', 'CPA', (70, 79))	('GLV-1h68', 'Var', (49, 57))
446709	27783991	Evaluation by MTT cell proliferation assay showed that GLV-1h68 had a cytotoxic effect on BN175 cells and that this increased in a time- and dose-dependent fashion (Figure 1C).	('GLV-1h68', 'Var', (55, 63))	('GLV-1h68', 'Species', '502057', (55, 63))	('rat', 'Species', '10116', (30, 33))	('MTT', 'Chemical', 'MESH:C070243', (14, 17))	('cytotoxic effect', 'CPA', (70, 86))
446711	27783991	On analysis at 72 hours, the cytotoxicity of GLV-1h68 at MOI of 0.01 was significantly increased when combined with 2, 4 and 8 Gy compared to viral treatment alone and at an MOI of 0.1 the cytotoxicity was significantly increased with 4 and 8 Gy (Two-way ANOVA with Bonferroni post-test; p <0.001).	('increased', 'PosReg', (220, 229))	('increased', 'PosReg', (87, 96))	('cytotoxicity', 'Disease', (29, 41))	('GLV-1h68', 'Species', '502057', (45, 53))	('cytotoxicity', 'Disease', 'MESH:D064420', (29, 41))	('cytotoxicity', 'Disease', (189, 201))	('combined', 'Interaction', (102, 110))	('GLV-1h68', 'Var', (45, 53))	('cytotoxicity', 'Disease', 'MESH:D064420', (189, 201))
446714	27783991	The combination of GLV-1h68 and radiation resulted in significantly increased cytotoxicity in one of three cell lines (Supplementary Figure S1).	('GLV-1h68', 'Species', '502057', (19, 27))	('cytotoxicity', 'Disease', (78, 90))	('GLV-1h68', 'Var', (19, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('increased', 'PosReg', (68, 77))
446725	27783991	On western blot analysis, the addition of GLV-1h68 to EBRT, at 2 and 4 Gy, resulted in an increase in caspase 3 cleavage compared to EBRT therapy alone.	('cleavage', 'MPA', (112, 120))	('increase', 'PosReg', (90, 98))	('EBRT', 'Chemical', '-', (54, 58))	('EBRT', 'Chemical', '-', (133, 137))	('caspase 3', 'Gene', '836', (102, 111))	('GLV-1h68', 'Species', '502057', (42, 50))	('caspase 3', 'Gene', (102, 111))	('GLV-1h68', 'Var', (42, 50))
446732	27783991	Both GLV-1h68 and EBRT alone induced caspase 3/7 cleavage and this induction significantly increased with the combination of GLV-1h68 and 4 Gy compared to either agent alone (Two-way ANOVA with Bonferroni post-test; p <0.01), (Figure 3D).	('caspase 3', 'Gene', '836', (37, 46))	('GLV-1h68', 'Var', (125, 133))	('caspase 3', 'Gene', (37, 46))	('cleavage', 'MPA', (49, 57))	('EBRT', 'Chemical', '-', (18, 22))	('GLV-1h68', 'Species', '502057', (125, 133))	('increased', 'PosReg', (91, 100))	('GLV-1h68', 'Species', '502057', (5, 13))
446734	27783991	The identification of cleaved caspase 3 and 9 at 48 hours after treatment suggests that GLV-1h68 may cause cell death by intrinsic pathway-mediated apoptosis (Figure 3E).	('GLV-1h68', 'Var', (88, 96))	('cell death', 'CPA', (107, 117))	('intrinsic pathway-mediated', 'Pathway', (121, 147))	('cause', 'PosReg', (101, 106))	('caspase 3', 'Gene', (30, 39))	('caspase 3', 'Gene', '836', (30, 39))	('GLV-1h68', 'Species', '502057', (88, 96))
446750	27783991	The level of MCL-1 decreased substantially with GLV-1h68 therapy alone in the human sarcoma cell lines and showed a further decrease when combined with EBRT (Figure 4C).	('MCL-1', 'Gene', (13, 18))	('level', 'MPA', (4, 9))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Disease', (84, 91))	('GLV-1h68', 'Species', '502057', (48, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('decrease', 'NegReg', (124, 132))	('decreased', 'NegReg', (19, 28))	('EBRT', 'Chemical', '-', (152, 156))	('human', 'Species', '9606', (78, 83))	('GLV-1h68', 'Var', (48, 56))	('MCL-1', 'Gene', '4170', (13, 18))
446756	27783991	GLV-1h68 decreased the expression level of all IAP proteins but with no further reduction when combined with EBRT.	('EBRT', 'Chemical', '-', (109, 113))	('GLV-1h68', 'Species', '502057', (0, 8))	('expression level', 'MPA', (23, 39))	('decreased', 'NegReg', (9, 18))	('GLV-1h68', 'Var', (0, 8))	('IAP proteins', 'Protein', (47, 59))
446757	27783991	GLV-1h68 appeared to have the greatest effect on the N-ras mutant HT1080 cells, in which the levels of XIAP, CIAP-1, CIAP-2 and Survivin decreased with GLV-1h68 alone and were completely undetectable after combination therapy with GLV-1h68 and EBRT.	('XIAP', 'Gene', (103, 107))	('N-ras', 'Gene', (53, 58))	('GLV-1h68', 'Species', '502057', (0, 8))	('levels', 'MPA', (93, 99))	('XIAP', 'Gene', '331', (103, 107))	('mutant', 'Var', (59, 65))	('CIAP-1, CIAP-2', 'Disease', 'MESH:D003924', (109, 123))	('Survivin', 'MPA', (128, 136))	('GLV-1h68', 'Species', '502057', (152, 160))	('EBRT', 'Chemical', '-', (244, 248))	('HT1080', 'CellLine', 'CVCL:0317', (66, 72))	('GLV-1h68', 'Species', '502057', (231, 239))	('decreased', 'NegReg', (137, 146))
446765	27783991	Animals were engrafted with 1 x 107 BN175 cells prior to undergoing either ILP with GLV-1h68 alone or femoral artery and vein ligation, followed by EBRT at 48 and 72 hours post-procedure.	('ligation', 'Var', (126, 134))	('GLV-1h68', 'Species', '502057', (84, 92))	('GLV-1h68', 'Gene', (84, 92))	('EBRT', 'Chemical', '-', (148, 152))
446767	27783991	Furthermore, the combination of GLV-1h68 and EBRT was found to significantly increase time to humane endpoint compared to either agent alone (one-way ANOVA, Tukey's post-hoc test p <0.0001).	('GLV-1h68', 'Var', (32, 40))	('EBRT', 'Gene', (45, 49))	('combination', 'Interaction', (17, 28))	('EBRT', 'Chemical', '-', (45, 49))	('time to humane endpoint', 'CPA', (86, 109))	('human', 'Species', '9606', (94, 99))	('increase', 'PosReg', (77, 85))	('GLV-1h68', 'Species', '502057', (32, 40))
446780	27783991	A small but significant increase in cytotoxicity was seen with the combination of GLV-1h68 at both 2 and 4 Gy on MTT assays.	('increase', 'PosReg', (24, 32))	('MTT', 'Chemical', 'MESH:C070243', (113, 116))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('combination', 'Var', (67, 78))	('GLV-1h68', 'Species', '502057', (82, 90))	('GLV-1h68', 'Gene', (82, 90))	('cytotoxicity', 'Disease', (36, 48))
446788	27783991	Infection with GLV-1h68 was also shown to downregulate a number of anti-apoptotic proteins, such as MCL-1, BCL-XL and the IAP family.	('MCL-1', 'Gene', '4170', (100, 105))	('MCL-1', 'Gene', (100, 105))	('GLV-1h68', 'Var', (15, 23))	('anti-apoptotic proteins', 'MPA', (67, 90))	('BCL-XL', 'Gene', (107, 113))	('IAP', 'Protein', (122, 125))	('downregulate', 'NegReg', (42, 54))	('GLV-1h68', 'Species', '502057', (15, 23))	('BCL-XL', 'Gene', '598', (107, 113))
446789	27783991	Although vaccinia virus has also been shown to result in a reduction in a range of cellular transcripts, a reduction in the pro-apoptotic proteins Bak and Bax was not seen.	('vaccinia virus', 'Species', '10245', (9, 23))	('Bax', 'Gene', '581', (155, 158))	('Bak', 'Gene', (147, 150))	('reduction', 'NegReg', (59, 68))	('Bak', 'Gene', '578', (147, 150))	('Bax', 'Gene', (155, 158))	('vaccinia virus', 'Var', (9, 23))
446791	27783991	These data suggest that infection with GLV-1h68 preferentially downregulates anti-apoptotic proteins, resulting in an overall shift in protein expression within the cell tipping the balance in favour of apoptosis (Figure 6).	('anti-apoptotic proteins', 'MPA', (77, 100))	('shift', 'Reg', (126, 131))	('protein expression', 'MPA', (135, 153))	('downregulates', 'NegReg', (63, 76))	('infection', 'Var', (24, 33))	('GLV-1h68', 'Species', '502057', (39, 47))	('GLV-1h68', 'Gene', (39, 47))
446792	27783991	A further decrease in the expression of anti-apoptotic proteins was noted when GLV-1h68 was combined with EBRT compared with either modality alone.	('expression of', 'MPA', (26, 39))	('GLV-1h68', 'Species', '502057', (79, 87))	('EBRT', 'Chemical', '-', (106, 110))	('decrease', 'NegReg', (10, 18))	('combined', 'Interaction', (92, 100))	('anti-apoptotic proteins', 'Protein', (40, 63))	('GLV-1h68', 'Var', (79, 87))
446796	27783991	Furthermore, in other preclinical models, infection with vaccinia virus has been shown to be capable of inducing necrosis and necroptosis.	('necrosis', 'Disease', 'MESH:D009336', (113, 121))	('inducing', 'PosReg', (104, 112))	('necroptosis', 'CPA', (126, 137))	('vaccinia virus', 'Protein', (57, 71))	('vaccinia virus', 'Species', '10245', (57, 71))	('necrosis', 'Disease', (113, 121))	('infection', 'Var', (42, 51))
446798	27783991	Using this aggressive limb sarcoma model, the combination of delivering GLV-1h68 by ILP and EBRT significantly improved survival and proved to be far superior to single agent therapy.	('sarcoma', 'Disease', (27, 34))	('EBRT', 'Chemical', '-', (92, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('GLV-1h68', 'Var', (72, 80))	('survival', 'CPA', (120, 128))	('improved', 'PosReg', (111, 119))	('GLV-1h68', 'Species', '502057', (72, 80))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('aggressive limb', 'Phenotype', 'HP:0000718', (11, 26))
446878	27295141	Seven patients received pazopanib (400-800mg daily), while one patient each received sunitinib (37.5mg daily) and sorafenib (400mg BID).	('BID', 'Gene', '637', (131, 134))	('pazopanib', 'Chemical', 'MESH:C516667', (24, 33))	('patient', 'Species', '9606', (6, 13))	('BID', 'Gene', (131, 134))	('400-800mg', 'Var', (35, 44))	('sorafenib', 'Chemical', 'MESH:D000077157', (114, 123))	('patients', 'Species', '9606', (6, 14))	('patient', 'Species', '9606', (63, 70))	('sunitinib', 'Chemical', 'MESH:D000077210', (85, 94))
446899	27295141	In preclinical and clinical studies, targeting mTOR has proven to be a novel method to inhibit cells that have acquired resistance to angiogenesis inhibition.	('mTOR', 'Gene', '2475', (47, 51))	('targeting', 'Var', (37, 46))	('mTOR', 'Gene', (47, 51))
446907	27295141	A recent phase I trial of pazopanib/everolimus demonstrated that the presence of molecular alterations in the PI3K/AKT/mTOR pathway (PTEN loss, PIK3CA mutations, AKT mutation, NF1 mutation, or RICTOR amplification) did not predict response in patients with advanced solid tumors refractory to standard therapy (p = 0.764).	('AKT', 'Gene', '207', (162, 165))	('AKT', 'Gene', '207', (115, 118))	('NF1', 'Gene', (176, 179))	('PIK3CA', 'Gene', '5290', (144, 150))	('RICTOR', 'Gene', '253260', (193, 199))	('everolimus', 'Chemical', 'MESH:D000068338', (36, 46))	('solid tumors', 'Disease', (266, 278))	('patients', 'Species', '9606', (243, 251))	('RICTOR', 'Gene', (193, 199))	('mTOR', 'Gene', (119, 123))	('mutations', 'Var', (151, 160))	('pazopanib', 'Chemical', 'MESH:C516667', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('PIK3CA', 'Gene', (144, 150))	('solid tumors', 'Disease', 'MESH:D009369', (266, 278))	('AKT', 'Gene', (162, 165))	('AKT', 'Gene', (115, 118))	('PTEN loss', 'Disease', 'MESH:D006223', (133, 142))	('mTOR', 'Gene', '2475', (119, 123))	('mutation', 'Var', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('NF1', 'Gene', '4763', (176, 179))	('mutation', 'Var', (180, 188))	('PTEN loss', 'Disease', (133, 142))
446910	27295141	The addition of everolimus in patients with acquired resistance to VEGFRi resulted in 3/6 evaluable patients receiving clinical benefit at 4 months in our small series of patients with recurrent and metastatic sarcoma.	('sarcoma', 'Disease', (210, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('VEGFR', 'Gene', (67, 72))	('patients', 'Species', '9606', (171, 179))	('everolimus', 'Chemical', 'MESH:D000068338', (16, 26))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (100, 108))	('acquired resistance', 'Var', (44, 63))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('VEGFR', 'Gene', '3791', (67, 72))
446959	34012925	Kirsten rat sarcoma viral oncogene (KRAS) mutations, common in NSCLC, are associated with poor prognosis, likely due to poor responses to most systemic therapies and lack of targeted drugs.	('NSCLC', 'Disease', (63, 68))	('rat', 'Species', '10116', (8, 11))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('sarcoma', 'Disease', (12, 19))	('KRAS', 'Gene', (36, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('mutations', 'Var', (42, 51))
446960	34012925	The latest published clinical trial data on new small-molecule KRAS G12C inhibitors, AMG510 and MRTX849, indicate that these molecules may potentially help treat KRAS-mutant NSCLC.	('KRAS-mutant', 'Var', (162, 173))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('KRAS G12C', 'Gene', (63, 72))	('AMG510', 'Chemical', '-', (85, 91))	('help', 'PosReg', (151, 155))	('G12C', 'Mutation', 'rs121913530', (68, 72))	('NSCLC', 'Disease', (174, 179))
446961	34012925	Simultaneously, within the immuno-therapeutic process, immune efficacy has been observed in those patients who have KRAS mutations.	('KRAS', 'Gene', (116, 120))	('mutations', 'Var', (121, 130))	('patients', 'Species', '9606', (98, 106))
446965	34012925	Compared with other mutations, Kirsten rat sarcoma viral oncogene (KRAS) mutations are among the most common mutations in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('rat', 'Species', '10116', (39, 42))	('common', 'Reg', (102, 108))	('sarcoma', 'Disease', (43, 50))	('NSCLC', 'Disease', (122, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('mutations', 'Var', (73, 82))
446966	34012925	However, patients with NSCLC harbouring KRAS mutations respond poorly to chemotherapy and have a poor overall prognosis.	('patients', 'Species', '9606', (9, 17))	('poorly', 'NegReg', (63, 69))	('mutations', 'Var', (45, 54))	('KRAS', 'Gene', (40, 44))	('NSCLC', 'Disease', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))
446977	34012925	Among them, KRAS most significantly impacts human cancer ( Figure 1 ).	('human', 'Species', '9606', (44, 49))	('impacts', 'Reg', (36, 43))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('KRAS', 'Var', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
446978	34012925	The small G protein encoded by the mutated KRAS oncogene can still bind to GTP but prevents the GAP from increasing guanosine triphosphatase activity, inhibiting GTP hydrolysis to GDP and facilitating KRAS binding to GTP to maintain the active state.	('mutated', 'Var', (35, 42))	('GTP', 'Chemical', 'MESH:D006160', (162, 165))	('increasing', 'PosReg', (105, 115))	('binding', 'Interaction', (206, 213))	('bind', 'Interaction', (67, 71))	('GTP', 'Chemical', 'MESH:D006160', (217, 220))	('GTP hydrolysis', 'MPA', (162, 176))	('KRAS', 'Gene', (43, 47))	('inhibiting', 'NegReg', (151, 161))	('GDP', 'Chemical', 'MESH:D006153', (180, 183))	('prevents', 'NegReg', (83, 91))	('guanosine triphosphatase activity', 'MPA', (116, 149))	('GTP', 'Chemical', 'MESH:D006160', (75, 78))	('small G protein', 'Protein', (4, 19))
446980	34012925	KRAS mutations are some of the most common drivers of NSCLC and are almost only detected in lung adenocarcinoma and rarely found in squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('mutations', 'Var', (5, 14))	('squamous cell carcinoma', 'Disease', (132, 155))	('detected', 'Reg', (80, 88))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('lung adenocarcinoma', 'Disease', (92, 111))	('NSCLC', 'Disease', (54, 59))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))	('KRAS', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
446981	34012925	Over 80% of KRAS mutations occur in codon 12, and the most common mutations are KRAS G12C (mutation of glycine to cysteine; approximately 40%), KRAS G12V (mutation of glycine to valine; approximately 18-21%), and KRAS G12D (mutation of glycine to aspartic acid; approximately 17-18%), amongst others.	('G12C', 'Mutation', 'rs121913530', (85, 89))	('cysteine', 'Chemical', 'MESH:D003545', (114, 122))	('KRAS G12C', 'Var', (80, 89))	('G12V', 'Mutation', 'rs121913529', (149, 153))	('glycine', 'Chemical', 'MESH:D005998', (103, 110))	('G12D', 'Mutation', 'rs121913529', (218, 222))	('KRAS', 'Gene', (12, 16))	('aspartic acid', 'Chemical', 'MESH:D001224', (247, 260))	('glycine', 'Chemical', 'MESH:D005998', (236, 243))	('valine', 'Chemical', 'MESH:D014633', (178, 184))	('KRAS G12D', 'Var', (213, 222))	('mutations', 'Var', (17, 26))	('glycine', 'Chemical', 'MESH:D005998', (167, 174))
446983	34012925	Patients with KRAS-mutant NSCLC have a shorter median overall survival (OS) and a lower two-year survival rate.	('overall survival', 'MPA', (54, 70))	('Patients', 'Species', '9606', (0, 8))	('two-year', 'CPA', (88, 96))	('rat', 'Species', '10116', (106, 109))	('NSCLC', 'Disease', (26, 31))	('KRAS-mutant', 'Var', (14, 25))	('shorter', 'NegReg', (39, 46))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))	('lower', 'NegReg', (82, 87))
446984	34012925	At present, for NSCLC patients harbouring KRAS mutations, platinum-containing chemotherapy is central to a variety of treatments.	('KRAS', 'Gene', (42, 46))	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (47, 56))	('NSCLC', 'Disease', (16, 21))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('platinum', 'Chemical', 'MESH:D010984', (58, 66))
446985	34012925	A variety of studies have shown that KRAS mutations adversely affect OS and progression-free survival (PFS) and lower disease control rate (DCR) in patients with advanced NSCLC.	('affect', 'Reg', (62, 68))	('patients', 'Species', '9606', (148, 156))	('progression-free survival', 'CPA', (76, 101))	('KRAS', 'Gene', (37, 41))	('DCR', 'Chemical', '-', (140, 143))	('rat', 'Species', '10116', (134, 137))	('NSCLC', 'Disease', (171, 176))	('disease control rate', 'MPA', (118, 138))	('mutations', 'Var', (42, 51))	('lower', 'NegReg', (112, 117))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
446986	34012925	Furthermore, an earlier study showed that patients carrying KRAS mutations had high frequencies of liver (P = 0.01) and brain (P = 0.04) metastasis at baseline by radiological evaluation, suggesting that the presence of KRAS mutations may lead to more aggressive disease manifestations.	('mutations', 'Var', (225, 234))	('lead to', 'Reg', (239, 246))	('presence', 'Var', (208, 216))	('aggressive disease manifestations', 'CPA', (252, 285))	('KRAS', 'Gene', (60, 64))	('liver', 'CPA', (99, 104))	('patients', 'Species', '9606', (42, 50))	('KRAS', 'Gene', (220, 224))	('mutations', 'Var', (65, 74))
446988	34012925	However, KRAS mutations can counteract the therapeutic effects of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, which are approved for the treatment of EGFR-mutant NSCLC but have poor efficacy in KRAS-mutant NSCLC.	('EGFR', 'Gene', (179, 183))	('erlotinib', 'Chemical', 'MESH:D000069347', (128, 137))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('NSCLC', 'Disease', (235, 240))	('NSCLC', 'Disease', (191, 196))	('gefitinib', 'Chemical', 'MESH:D000077156', (114, 123))	('NSCLC', 'Disease', 'MESH:D002289', (235, 240))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('mutations', 'Var', (14, 23))	('EGFR', 'Gene', '1956', (179, 183))
446989	34012925	In summary, currently available therapeutic options have little, if any, effect on NSCLC patients carrying KRAS mutations, whose prognoses remain poor.	('KRAS', 'Gene', (107, 111))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('mutations', 'Var', (112, 121))	('patients', 'Species', '9606', (89, 97))
446995	34012925	A recent study showed that in NSCLC, KRAS mutation status positively correlated with TMB, PD-L1 expression, and T cell infiltration.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('correlated', 'Reg', (69, 79))	('rat', 'Species', '10116', (125, 128))	('PD-L1', 'Gene', '29126', (90, 95))	('TMB', 'Chemical', '-', (85, 88))	('KRAS', 'Gene', (37, 41))	('TMB', 'Disease', (85, 88))	('NSCLC', 'Disease', (30, 35))	('T cell infiltration', 'CPA', (112, 131))	('mutation status', 'Var', (42, 57))	('PD-L1', 'Gene', (90, 95))
446997	34012925	The high T cell infiltration suggests that KRAS-mutant NSCLC may respond well to immunotherapy.	('KRAS-mutant', 'Var', (43, 54))	('rat', 'Species', '10116', (22, 25))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLC', 'Disease', (55, 60))
447001	34012925	A subgroup analysis of randomised phase III study CheckMate057 indicated that during the second-line treatment for patients who carry KRAS mutations, nivolumab monotherapy had a higher OS benefit than docetaxel monotherapy (HR = 0.52; 95% CI: 0.29-0.95).	('patients', 'Species', '9606', (115, 123))	('mutations', 'Var', (139, 148))	('nivolumab', 'Chemical', 'MESH:D000077594', (150, 159))	('docetaxel', 'Chemical', 'MESH:D000077143', (201, 210))	('OS benefit', 'MPA', (185, 195))	('KRAS', 'Gene', (134, 138))
447002	34012925	Additionally, the subgroup with KRAS mutations had the highest OS benefit in nivolumab monotherapy, while the OS benefit of patients with wild-type KRAS was limited (HR = 0.98; 95% CI: 0.29-0.95).	('nivolumab', 'Chemical', 'MESH:D000077594', (77, 86))	('nivolumab monotherapy', 'MPA', (77, 98))	('mutations', 'Var', (37, 46))	('KRAS mutations', 'Var', (32, 46))	('patients', 'Species', '9606', (124, 132))
447005	34012925	The exploratory analysis of KEYNOTE-042 showed that the first-line pembrolizumab monotherapy in patients with KRAS-mutant NSCLC has higher PFS (12 months vs. 6 months; HR = 0.51; 95% CI: 0.29-0.87) and OS (28 months vs. 11 months; HR = 0.42; 95% CI: 0.22-0.81) than platinum-containing chemotherapy.	('higher', 'PosReg', (132, 138))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('rat', 'Species', '10116', (9, 12))	('platinum', 'Chemical', 'MESH:D010984', (266, 274))	('pembrolizumab', 'Chemical', 'MESH:C582435', (67, 80))	('patients', 'Species', '9606', (96, 104))	('NSCLC', 'Disease', (122, 127))	('PFS', 'MPA', (139, 142))	('KRAS-mutant', 'Var', (110, 121))
447008	34012925	Furthermore, many studies have suggested that there may be a synergistic effect between KRAS G12C inhibitors and immunotherapy drugs.	('inhibitors', 'Var', (98, 108))	('G12C', 'Mutation', 'rs121913530', (93, 97))	('G12C inhibitors', 'Var', (93, 108))	('KRAS', 'Gene', (88, 92))	('synergistic', 'Interaction', (61, 72))
447009	34012925	In preclinical studies, the use of AMG510 in immune-competent mice allowed T cells, especially CD8+ T cells, to infiltrate a large number of tumours, resulting in a pro-inflammatory tumour microenvironment that produced durable responses alone or in combination with ICI.	('tumours', 'Disease', (141, 148))	('AMG510', 'Var', (35, 41))	('CD8', 'Gene', '925', (95, 98))	('rat', 'Species', '10116', (118, 121))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('mice', 'Species', '10090', (62, 66))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('tumour', 'Disease', (182, 188))	('tumour', 'Disease', (141, 147))	('AMG510', 'Chemical', '-', (35, 41))	('CD8', 'Gene', (95, 98))
447013	34012925	A retrospective study suggested that, among the common subtypes of KRAS mutations, the KRAS G12D mutation was related to poor OS (HR: 2.43; 95% CI: 1.15-5.16; P = 0.021), while the remaining KRAS mutation subtypes had no significant correlation with OS.	('KRAS', 'Gene', (87, 91))	('poor OS', 'Disease', (121, 128))	('G12D', 'Var', (92, 96))	('G12D', 'Mutation', 'rs121913529', (92, 96))
447015	34012925	Additionally, KRAS G12C mutation is related to weakly positive expression of PD-L1 (1%-49%) which suggests that it may predict immunotherapy benefits.	('positive', 'PosReg', (54, 62))	('KRAS G12C mutation', 'Var', (14, 32))	('PD-L1', 'Gene', (77, 82))	('expression', 'MPA', (63, 73))	('PD-L1', 'Gene', '29126', (77, 82))	('G12C', 'Mutation', 'rs121913530', (19, 23))
447016	34012925	Another retrospective study of patients with advanced KRAS-mutant NSCLC treated with immunosuppressive agents showed no significant differences in OS or PFS among the main KRAS mutation subtypes (G12A, G12C, G12D, G12V, and G13C).	('G12C', 'Mutation', 'rs121913530', (202, 206))	('G12D', 'Var', (208, 212))	('NSCLC', 'Disease', (66, 71))	('G12V', 'Var', (214, 218))	('G12A', 'Var', (196, 200))	('G12D', 'Mutation', 'rs121913529', (208, 212))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('G12V', 'Mutation', 'rs121913529', (214, 218))	('G13C', 'Var', (224, 228))	('patients', 'Species', '9606', (31, 39))	('G12C', 'Var', (202, 206))	('G12A', 'Mutation', 'rs121913529', (196, 200))	('G13C', 'Mutation', 'rs121913535', (224, 228))
447017	34012925	In one Lung Cancer Mutation Consortium (LCMC) study, 27% of patients with lung adenocarcinoma had KRAS mutations, and as many as one-third of these patients had another carcinogenic driver.	('patients', 'Species', '9606', (148, 156))	('mutations', 'Var', (103, 112))	('carcinogenic', 'Disease', (169, 181))	('Lung Cancer', 'Disease', 'MESH:D008175', (7, 18))	('patients', 'Species', '9606', (60, 68))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('Lung Cancer', 'Phenotype', 'HP:0100526', (7, 18))	('Lung Cancer', 'Disease', (7, 18))	('lung adenocarcinoma', 'Disease', (74, 93))	('KRAS', 'Gene', (98, 102))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (74, 93))	('Cancer', 'Phenotype', 'HP:0002664', (12, 18))	('carcinogenic', 'Disease', 'MESH:D063646', (169, 181))
447018	34012925	discovered three clusters based on strong expression: co-mutation with serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) known as the KL subgroup, tumour protein 53 (TP53)(KP subgroup), and cyclin-dependent kinase inhibitor 2A/B (CDNK2A/B) inactivation plus thyroid transcription factor-1 low expression (KC subgroup).	('2A/B', 'SUBSTITUTION', 'None', (242, 246))	('2A/B', 'Var', (242, 246))	('TP53', 'Gene', (174, 178))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('thyroid transcription factor-1', 'Gene', '7080', (266, 296))	('LKB1', 'Gene', (123, 127))	('tumour', 'Disease', (155, 161))	('serine/threonine kinase 11', 'Gene', (71, 97))	('2A/B', 'SUBSTITUTION', 'None', (232, 236))	('2A/B', 'Var', (232, 236))	('STK11', 'Gene', (99, 104))	('co-mutation', 'Var', (54, 65))	('TP53', 'Gene', '7157', (174, 178))	('inactivation', 'Var', (248, 260))	('STK11', 'Gene', '6794', (99, 104))	('liver kinase B1', 'Gene', (106, 121))	('LKB1', 'Gene', '6794', (123, 127))	('thyroid transcription factor-1', 'Gene', (266, 296))	('liver kinase B1', 'Gene', '6794', (106, 121))	('serine/threonine kinase 11', 'Gene', '6794', (71, 97))
447020	34012925	These clusters had various biological characteristics and treatment reaction: the ORR of immunotherapy for NSCLC due to KRAS mutations alone, KRAS co-mutations with STK11/LKB1 and TP53 was approximately 28.6%, 7.4% (because the blocking of PD-1 by immunosuppressive agents was reduced), and 35.7% (showing better efficacy), respectively.	('KRAS', 'Gene', (142, 146))	('mutations', 'Var', (125, 134))	('NSCLC', 'Disease', (107, 112))	('LKB1', 'Gene', (171, 175))	('STK11', 'Gene', (165, 170))	('PD-1', 'Gene', (240, 244))	('LKB1', 'Gene', '6794', (171, 175))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('TP53', 'Gene', '7157', (180, 184))	('TP53', 'Gene', (180, 184))	('STK11', 'Gene', '6794', (165, 170))	('KRAS', 'Gene', (120, 124))
447021	34012925	Patients with co-mutations in KEAP1/NFE2L2 have a significantly shorter survival (HR = 1.96; 95%CI: 1.33-2.92; p <= 0.001).	('NFE2L2', 'Gene', (36, 42))	('survival', 'MPA', (72, 80))	('KEAP1', 'Gene', (30, 35))	('NFE2L2', 'Gene', '4780', (36, 42))	('Patients', 'Species', '9606', (0, 8))	('co-mutations', 'Var', (14, 26))	('KEAP1', 'Gene', '9817', (30, 35))	('shorter', 'NegReg', (64, 71))
447022	34012925	This may be owing to the high levels of tumour-infiltrating cytotoxic CD8+ cells, a significantly high overall mutation load, and high expression of PD-L1 in the KP subgroup tumours.	('PD-L1', 'Gene', (149, 154))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('tumour', 'Disease', (40, 46))	('PD-L1', 'Gene', '29126', (149, 154))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('tumour', 'Disease', (174, 180))	('tumours', 'Disease', (174, 181))	('rat', 'Species', '10116', (53, 56))	('expression', 'MPA', (135, 145))	('CD8', 'Gene', (70, 73))	('mutation', 'Var', (111, 119))	('CD8', 'Gene', '925', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))
447023	34012925	In the KL subgroup tumours, STK11 deletion promotes neutrophil recruitment, and the production of pro-inflammatory cytokines leads to a significant reduction in the number and function of T cells.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('reduction', 'NegReg', (148, 157))	('production of pro-inflammatory cytokines', 'MPA', (84, 124))	('promotes', 'PosReg', (43, 51))	('STK11', 'Gene', (28, 33))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('deletion', 'Var', (34, 42))	('STK11', 'Gene', '6794', (28, 33))	('neutrophil recruitment', 'CPA', (52, 74))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
447024	34012925	Besides, STK11/LKB1 inactivation reduces the expression levels of PD-L1.	('STK11', 'Gene', '6794', (9, 14))	('reduces', 'NegReg', (33, 40))	('expression levels', 'MPA', (45, 62))	('PD-L1', 'Gene', '29126', (66, 71))	('inactivation', 'Var', (20, 32))	('LKB1', 'Gene', (15, 19))	('STK11', 'Gene', (9, 14))	('PD-L1', 'Gene', (66, 71))	('LKB1', 'Gene', '6794', (15, 19))
447025	34012925	KRAS-mutant NSCLC with KEAP1 mutations were mostly immune inert tumours, with low T cell inflammation and low expression of PD-L1 ligands.	('low T cell inflammation', 'Disease', (78, 101))	('PD-L1', 'Gene', (124, 129))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('mutations', 'Var', (29, 38))	('PD-L1', 'Gene', '29126', (124, 129))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('low T cell', 'Phenotype', 'HP:0005403', (78, 88))	('NSCLC', 'Disease', (12, 17))	('KEAP1', 'Gene', '9817', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('KEAP1', 'Gene', (23, 28))	('low T cell inflammation', 'Disease', 'MESH:D007249', (78, 101))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
447034	34012925	However, because of the heterogeneity of KRAS-mutant NSCLC, especially the existence of co-mutations, individualised immunotherapy is needed.	('KRAS-mutant', 'Var', (41, 52))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('NSCLC', 'Disease', (53, 58))
447036	34012925	The most common type of KRAS mutation is KRAS G12C.	('G12C', 'Mutation', 'rs121913530', (46, 50))	('KRAS', 'Disease', (24, 28))	('KRAS G12C', 'Var', (41, 50))
447039	34012925	KRAS G12C allele inhibitors trap oncoproteins in an inactive state by inhibiting the reactivation of exchanged nucleotides, thereby blocking the proliferation of tumour cells that depend on the protein's signalling pathways.	('tumour', 'Disease', (162, 168))	('reactivation of exchanged nucleotides', 'MPA', (85, 122))	('rat', 'Species', '10116', (152, 155))	('blocking', 'NegReg', (132, 140))	('inhibiting', 'NegReg', (70, 80))	('KRAS G12C', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('G12C', 'Mutation', 'rs121913530', (5, 9))	('oncoproteins', 'Protein', (33, 45))	('tumour', 'Disease', 'MESH:D009369', (162, 168))
447041	34012925	Preclinical studies have shown that AMG510 can inhibit almost all measurable ERK phosphorylations, a key downstream effector of KRAS, thereby enabling KRAS G12C mutant tumour mice to achieve long-lasting tumour regression.	('mice', 'Species', '10090', (175, 179))	('tumour', 'Disease', (204, 210))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('AMG510', 'Var', (36, 42))	('enabling', 'PosReg', (142, 150))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('inhibit', 'NegReg', (47, 54))	('G12C', 'Mutation', 'rs121913530', (156, 160))	('ERK', 'Protein', (77, 80))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Disease', (168, 174))	('KRAS G12C mutant', 'Var', (151, 167))	('tumour', 'Disease', 'MESH:D009369', (204, 210))	('AMG510', 'Chemical', '-', (36, 42))
447042	34012925	According to the latest data published by the CodeBreak 100 study, among the 59 patients who carry the KRAS G12C mutation in patients with advanced NSCLC undergoing multi-line therapy, a total of 19 patients had definite objective remission, with an ORR of 32.2% [95% CI: 20.62-45.64]; 52 patients had clear disease controVS-6766l, with a DCR of 88.1% (95% CI: 77.07-95.09).	('KRAS', 'Gene', (103, 107))	('mutation', 'Var', (113, 121))	('patients', 'Species', '9606', (289, 297))	('patients', 'Species', '9606', (80, 88))	('G12C', 'Mutation', 'rs121913530', (108, 112))	('DCR', 'Chemical', '-', (339, 342))	('NSCLC', 'Disease', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (125, 133))
447046	34012925	In terms of safety, during treatment with AMG510, no dose-limiting side effects were observed, and no treatment-related deaths occurred.	('AMG510', 'Var', (42, 48))	('deaths', 'Disease', (120, 126))	('AMG510', 'Chemical', '-', (42, 48))	('deaths', 'Disease', 'MESH:D003643', (120, 126))
447047	34012925	These findings indicate that AMG510 is safe, causes remission and long-lasting benefits in patients with KRAS-mutant NSCLC.	('NSCLC', 'Disease', (117, 122))	('benefits', 'PosReg', (79, 87))	('patients', 'Species', '9606', (91, 99))	('AMG510', 'Var', (29, 35))	('KRAS-mutant', 'Gene', (105, 116))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('AMG510', 'Chemical', '-', (29, 35))
447048	34012925	Based on the positive results from the preliminary clinical trials, FDA has granted Sotorasib (AMG510) the title of breakthrough therapy for the treatment of locally advanced or metastatic NSCLC with KRAS G12C mutation on December 8, 2020.	('NSCLC', 'Disease', (189, 194))	('KRAS G12C', 'Var', (200, 209))	('AMG510', 'Chemical', '-', (95, 101))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('Sotorasib', 'Chemical', '-', (84, 93))	('G12C', 'Mutation', 'rs121913530', (205, 209))
447050	34012925	A preclinical study of another oral, selective, small molecule (MRTX849) targeting KRAS G12C showed a broad spectrum of activity in tumours with the KRAS G12C mutation in in vivo models, resulting in significant tumour regression in most models.	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumour', 'Disease', (132, 138))	('tumours', 'Disease', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('KRAS G12C', 'Var', (149, 158))	('KRAS G12C', 'Gene', (83, 92))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('G12C', 'Mutation', 'rs121913530', (88, 92))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', (212, 218))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('G12C', 'Mutation', 'rs121913530', (154, 158))
447055	34012925	The currently published data show that the efficacy of MRTX849 is slightly better than that of AMG510; however, the adverse effects are more significant, especially cardiac toxicity.	('MRTX849', 'Var', (55, 62))	('cardiac toxicity', 'Disease', 'MESH:D066126', (165, 181))	('cardiac toxicity', 'Disease', (165, 181))	('AMG510', 'Chemical', '-', (95, 101))
447060	34012925	Although the emergence of KRAS G12C inhibitors has brought hope to patients with KRAS G12C mutations, the duration of response (DOR) (range 1.1 to 13.6 months) is not as good as the EGFR inhibitors (range 7.3 to 22.0 months).	('rat', 'Species', '10116', (108, 111))	('EGFR', 'Gene', '1956', (182, 186))	('patients', 'Species', '9606', (67, 75))	('EGFR', 'Gene', (182, 186))	('G12C', 'Mutation', 'rs121913530', (31, 35))	('G12C', 'Mutation', 'rs121913530', (86, 90))	('mutations', 'Var', (91, 100))	('KRAS', 'Gene', (81, 85))
447062	34012925	In addition to the KRAS G12C mutation, mutations such as KRAS G12D also play an important role in the occurrence and development of tumours.	('G12C', 'Mutation', 'rs121913530', (24, 28))	('G12D', 'Mutation', 'rs121913529', (62, 66))	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumours', 'Disease', (132, 139))	('KRAS G12D', 'Var', (57, 66))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))
447064	34012925	The specificity of MRTX1133 to KRAS G12D is more than 1000 times that of wild-type KRAS, and its half-life is more than 50 hours.	('G12D', 'Mutation', 'rs121913529', (36, 40))	('specificity', 'MPA', (4, 15))	('MRTX1133', 'Gene', (19, 27))	('KRAS G12D', 'Var', (31, 40))
447067	34012925	A study screened out a specific small-molecule SOS1 inhibitor, BAY-293, which can effectively destroy the mutual effect between KRAS and SOS1, prevent the formation of the KRAS-SOS1 complex, and thereby inhibit the activity of all KRAS mutants.	('KRAS', 'Disease', (231, 235))	('destroy', 'NegReg', (94, 101))	('formation', 'Interaction', (155, 164))	('complex', 'Interaction', (182, 189))	('activity', 'MPA', (215, 223))	('prevent', 'NegReg', (143, 150))	('SOS1', 'Gene', (177, 181))	('SOS1', 'Gene', (137, 141))	('SOS1', 'Gene', (47, 51))	('mutual effect', 'MPA', (106, 119))	('BAY-293', 'CellLine', 'CVCL:M658', (63, 70))	('mutants', 'Var', (236, 243))	('SOS1', 'Gene', '6654', (177, 181))	('SOS1', 'Gene', '6654', (47, 51))	('SOS1', 'Gene', '6654', (137, 141))	('inhibit', 'NegReg', (203, 210))
447068	34012925	Another SOS1 inhibitor, BI-1701963, is in Phase I clinical trial (ClinicalTrials.gov Identifier: NCT04111458).	('SOS1', 'Gene', '6654', (8, 12))	('BI-1701963', 'Var', (24, 34))	('BI-1701963', 'Chemical', '-', (24, 34))	('SOS1', 'Gene', (8, 12))
447080	34012925	Currently, many BRAF inhibitors, for instance, dabrafenib, vemurafenib, and encorafenib, have been approved to target BRAF V600 mutations, but RAF kinase inhibitors do not perform well in KRAS-mutant cells.	('vemurafenib', 'Chemical', 'MESH:D000077484', (59, 70))	('BRAF', 'Gene', (118, 122))	('dabrafenib', 'Chemical', 'MESH:C561627', (47, 57))	('V600 mutations', 'Var', (123, 137))	('encorafenib', 'Chemical', 'MESH:C000601108', (76, 87))
447081	34012925	ATP-competitive RAF inhibitors inhibit ERK signalling in mutant BRAF cells but enhance signal transduction in wild-type BRAF cells.	('ERK signalling', 'MPA', (39, 53))	('signal transduction', 'MPA', (87, 106))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('enhance', 'PosReg', (79, 86))	('mutant', 'Var', (57, 63))	('inhibit', 'NegReg', (31, 38))
447082	34012925	The study found that type 1.5 RAF inhibitor, PLX-8394, and type II inhibitors, AZ-628 and LY3009120, had a certain inhibitory effect on KRAS-mutant cells and did not cause the contradictory MAPK pathway activation.	('inhibitory effect', 'MPA', (115, 132))	('LY3009120', 'Chemical', 'MESH:C000600963', (90, 99))	('AZ-628', 'Chemical', 'MESH:C000592454', (79, 85))	('LY3009120', 'Var', (90, 99))	('AZ-628', 'Var', (79, 85))	('PLX-8394', 'Chemical', 'MESH:C000602642', (45, 53))
447086	34012925	MEK inhibitors have shown potential efficacy in cancers with MEK or BRAF mutations, especially in BRAF V600E mutant tumour cell lines.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Disease', (48, 55))	('MEK', 'Gene', (61, 64))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('V600E mutant', 'Var', (103, 115))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('tumour', 'Disease', (116, 122))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', (68, 72))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('mutations', 'Var', (73, 82))
447087	34012925	However, data from a number of studies have shown that the MEK1/MEK2 inhibitors, smeltinib (AZD6244; ARRY-142886) and trametinib (GSKll20212) cannot improve the prognosis of patients with KRAS-mutant NSCLC.	('MEK2', 'Gene', '5605', (64, 68))	('MEK2', 'Gene', (64, 68))	('smeltinib', 'Chemical', '-', (81, 90))	('MEK1', 'Gene', '5604', (59, 63))	('ARRY-142886', 'Chemical', 'MESH:C517975', (101, 112))	('GSKll20212', 'Chemical', '-', (130, 140))	('NSCLC', 'Disease', (200, 205))	('patients', 'Species', '9606', (174, 182))	('KRAS-mutant', 'Var', (188, 199))	('AZD6244', 'Chemical', 'MESH:C517975', (92, 99))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('MEK1', 'Gene', (59, 63))	('trametinib', 'Chemical', 'MESH:C560077', (118, 128))
447088	34012925	The reason may be that MEK inhibitors can induce signal feedback of the MAPK pathway in KRAS-mutant tumours, resulting in drug resistance to MEK inhibitors.	('tumours', 'Disease', (100, 107))	('drug resistance', 'Phenotype', 'HP:0020174', (122, 137))	('MAPK pathway', 'Pathway', (72, 84))	('induce', 'Reg', (42, 48))	('signal feedback', 'MPA', (49, 64))	('KRAS-mutant', 'Gene', (88, 99))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('KRAS-mutant', 'Var', (88, 99))	('drug resistance', 'MPA', (122, 137))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('resulting in', 'Reg', (109, 121))
447098	34012925	SHP2 plays an indispensable role in KRAS mutation-driven tumours.	('mutation-driven', 'Var', (41, 56))	('SHP2', 'Gene', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('KRAS', 'Gene', (36, 40))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('SHP2', 'Gene', '5781', (0, 4))
447102	34012925	Notably, JAB-3312 can block the PD-1 pathway of T cells and the KRAS-MAPK pathway of tumour cells by inhibiting SHP2; thus, it plays a dual role in tumour immunity and tumour targeting.	('tumour', 'Disease', (148, 154))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('JAB-3312', 'Var', (9, 17))	('tumour', 'Disease', (85, 91))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('PD-1 pathway', 'Pathway', (32, 44))	('SHP2', 'Gene', (112, 116))	('block', 'NegReg', (22, 27))	('tumour', 'Disease', (168, 174))	('KRAS-MAPK pathway', 'Pathway', (64, 81))	('SHP2', 'Gene', '5781', (112, 116))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('inhibiting', 'NegReg', (101, 111))
447105	34012925	Currently, ERK inhibitors such as JSI-1187-01, ASN007, and KO-947 are in Phase I clinical trials; ClinicalTrials.gov Identifier: NCT04418167, NCT03415126, and NCT03051035, respectively.	('JSI-1187-01', 'CellLine', 'CVCL:9E39', (34, 45))	('NCT04418167', 'Var', (129, 140))	('NCT03415126', 'Var', (142, 153))	('NCT03051035', 'Var', (159, 170))
447106	34012925	PI3K-AKT-mTOR pathway inhibition: PI3K is a cell effector molecule downstream of KRAS, and PI3K inhibitors BKM120, GDC0941, and XL147 have shown promising results in Phase I clinical trials.	('BKM120', 'Var', (107, 113))	('mTOR', 'Gene', (9, 13))	('AKT', 'Gene', '207', (5, 8))	('PI3K', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (9, 13))	('GDC0941', 'Var', (115, 122))	('BKM120', 'Chemical', 'MESH:C571178', (107, 113))	('AKT', 'Gene', (5, 8))
447109	34012925	mTOR is a serine/threonine kinase downstream of PI3K in the PI3K-AKT-mTOR pathway.	('mTOR', 'Gene', '2475', (69, 73))	('mTOR', 'Gene', (69, 73))	('AKT', 'Gene', (65, 68))	('PI3K', 'Var', (48, 52))	('serine', 'Chemical', 'MESH:D012694', (10, 16))	('AKT', 'Gene', '207', (65, 68))	('mTOR', 'Gene', '2475', (0, 4))	('mTOR', 'Gene', (0, 4))
447110	34012925	The mTOR inhibitor rapamycin and its analogues (CCI-779, RAD001, and AP23573), which induce cell cycle arrest in the G1 Phase, have certain anti-tumour activity in NSCLC.	('AP23573', 'Var', (69, 76))	('tumour', 'Disease', (145, 151))	('NSCLC', 'Disease', (164, 169))	('rapamycin', 'Chemical', 'MESH:D020123', (19, 28))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('arrest', 'Disease', (103, 109))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (92, 109))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('CCI-779', 'Chemical', 'MESH:C401859', (48, 55))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('arrest', 'Disease', 'MESH:D006323', (103, 109))
447111	34012925	AZD2014 is a new mTOR inhibitor in Phase I/II clinical studies (ClinicalTrials.gov Identifier: NCT02583542).	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('AZD2014', 'Var', (0, 7))	('AZD2014', 'Chemical', 'MESH:C585537', (0, 7))
447112	34012925	Inactivation of a single MAPK or PI3K pathway has poor efficacy in KRAS-mutated tumours.	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('tumours', 'Disease', (80, 87))	('PI3K pathway', 'Pathway', (33, 45))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('MAPK', 'Pathway', (25, 29))	('Inactivation', 'Var', (0, 12))
447114	34012925	Janus kinase-signal transducer and activator of transcription 3 (STAT3) inhibition: In KRAS-mutant NSCLC, after inhibiting MEK, STAT3 is activated via fibroblast growth factor receptor and Janus kinase; combined inhibition of this receptor, MEK, and Janus kinase can promote tumour regression.	('KRAS-mutant', 'Gene', (87, 98))	('KRAS-mutant', 'Var', (87, 98))	('NSCLC', 'Disease', (99, 104))	('STAT3', 'Gene', '6774', (128, 133))	('promote', 'PosReg', (267, 274))	('STAT3', 'Gene', (128, 133))	('tumour', 'Phenotype', 'HP:0002664', (275, 281))	('STAT3', 'Gene', '6774', (65, 70))	('tumour', 'Disease', 'MESH:D009369', (275, 281))	('tumour', 'Disease', (275, 281))	('STAT3', 'Gene', (65, 70))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
447115	34012925	KRAS-mutated tumour cells can be killed by inhibiting other synergetic lethal genes responsible for their growth and survival.	('inhibiting', 'NegReg', (43, 53))	('KRAS-mutated', 'Var', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Disease', (13, 19))
447118	34012925	demonstrated that KRAS-mutant NSCLC relies on GATA2, and the deletion of GATA2 reduces the activity of KRAS-mutant NSCLC cells without affecting the wild-type cells.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Disease', (115, 120))	('reduces', 'NegReg', (79, 86))	('deletion', 'Var', (61, 69))	('GATA2', 'Gene', (46, 51))	('GATA2', 'Gene', (73, 78))	('activity', 'MPA', (91, 99))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('rat', 'Species', '10116', (7, 10))	('GATA2', 'Gene', '2624', (46, 51))	('NSCLC', 'Disease', (30, 35))	('GATA2', 'Gene', '2624', (73, 78))
447120	34012925	In addition, the nuclear outlet receptor, exportin 1, has a strong synergetic lethal effect on KRAS-mutated cancer cells in vitro and in vivo.	('synergetic lethal effect', 'MPA', (67, 91))	('exportin 1', 'Gene', '7514', (42, 52))	('exportin 1', 'Gene', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('KRAS-mutated', 'Var', (95, 107))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
447123	34012925	found that KRAS mutations enhanced tumour dependence on HSP90.	('KRAS', 'Gene', (11, 15))	('enhanced', 'PosReg', (26, 34))	('mutations', 'Var', (16, 25))	('HSP90', 'Protein', (56, 61))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour dependence', 'Disease', 'MESH:D009376', (35, 52))	('tumour dependence', 'Disease', (35, 52))
447124	34012925	They also found that tumours significantly regressed when treated with HSP90 inhibitors in a mouse model of lung adenocarcinoma driven by KRAS.	('lung adenocarcinoma', 'Disease', (108, 127))	('inhibitors', 'Var', (77, 87))	('mouse', 'Species', '10090', (93, 98))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('regressed', 'NegReg', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('tumours', 'Disease', (21, 28))	('HSP90', 'Protein', (71, 76))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))
447126	34012925	In a Phase II trial of ganetespib combined with docetaxel, the combination failed to improve PFS or OS in patients with KRAS-mutant NSCLC.	('docetaxel', 'Chemical', 'MESH:D000077143', (48, 57))	('PFS', 'Disease', (93, 96))	('ganetespib', 'Chemical', 'MESH:C533237', (23, 33))	('NSCLC', 'Disease', (132, 137))	('patients', 'Species', '9606', (106, 114))	('KRAS-mutant', 'Var', (120, 131))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))
447127	34012925	AUY922 is a highly effective ATP-competitive HSP90 inhibitor.	('AUY922', 'Chemical', 'MESH:C528044', (0, 6))	('ATP', 'Chemical', 'MESH:D000255', (29, 32))	('AUY922', 'Var', (0, 6))	('ATP-competitive', 'Protein', (29, 44))
447134	34012925	In a Phase II study of onartuzumab combined with erlotinib, no response was observed in KRAS-mutant NSCLC.	('erlotinib', 'Chemical', 'MESH:D000069347', (49, 58))	('NSCLC', 'Disease', (100, 105))	('onartuzumab', 'Chemical', 'MESH:C584058', (23, 34))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('KRAS-mutant', 'Var', (88, 99))
447138	34012925	The ERK-RAS Homolog Family Member A (RHOA) -FAK pathway is necessary to maintain KRAS-mutant lung adenocarcinoma.	('FAK', 'Gene', '5747', (44, 47))	('lung adenocarcinoma', 'Disease', (93, 112))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (93, 112))	('FAK', 'Gene', (44, 47))	('RHOA', 'Gene', '387', (37, 41))	('KRAS-mutant', 'Var', (81, 92))	('RHOA', 'Gene', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
447139	34012925	Inhibition of FAK can selectively induce KRAS-mutant cell death and lead to KRAS-mutant lung cancer regression.	('lung cancer', 'Disease', (88, 99))	('induce', 'PosReg', (34, 40))	('lead to', 'Reg', (68, 75))	('KRAS-mutant', 'Disease', (41, 52))	('FAK', 'Gene', '5747', (14, 17))	('death', 'Disease', 'MESH:D003643', (58, 63))	('death', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('Inhibition', 'Var', (0, 10))	('FAK', 'Gene', (14, 17))	('KRAS-mutant', 'Gene', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
447150	34012925	The immunotherapy of KRAS-mutant NSCLC has shown promising efficacy.	('KRAS-mutant', 'Var', (21, 32))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('NSCLC', 'Disease', (33, 38))
447156	34012925	We believe that drug combinations can help patients with KRAS-mutant NSCLC bring more effective treatment.	('NSCLC', 'Disease', (69, 74))	('patients', 'Species', '9606', (43, 51))	('KRAS-mutant', 'Var', (57, 68))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))
447171	33717062	PD-1 blockade with nivolumab has a synergistic effect with sunitinib, supporting the use of TKI and anti-PD-1 approach in sarcomas, and perhaps in other cancers.	('sunitinib', 'Chemical', 'MESH:D000077210', (59, 68))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('blockade', 'Var', (5, 13))	('cancers', 'Disease', (153, 160))	('PD-1', 'Gene', (0, 4))	('sarcomas', 'Disease', (122, 130))	('synergistic', 'MPA', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('sarcomas', 'Disease', 'MESH:D012509', (122, 130))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('nivolumab', 'Chemical', 'MESH:D000077594', (19, 28))
447185	33717062	To assess the effect of this combination, we generated DCs pulsed with sarcoma cells and describe T cell and DC functional changes after treatment with (1) sunitinib, (2) nivolumab and (3) sunitinib with nivolumab, including T-cell subpopulation composition, T-cell proliferation and IFN-gamma production.	('sunitinib', 'Var', (189, 198))	('sunitinib', 'Chemical', 'MESH:D000077210', (189, 198))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('nivolumab', 'Chemical', 'MESH:D000077594', (171, 180))	('sunitinib', 'Chemical', 'MESH:D000077210', (156, 165))	('sarcoma', 'Disease', (71, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('T-cell proliferation', 'CPA', (259, 279))	('nivolumab', 'Chemical', 'MESH:D000077594', (204, 213))
447257	33717062	These data demonstrate that sarcoma cells loaded in DCs have a tolerogenic effect on T cells thus leading to strong Treg induction, while sunitinib contrasts this sarcoma tolerogenic feature, restoring the values to those observed with unstimulated T cells.	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('restoring', 'PosReg', (192, 201))	('sarcoma', 'Disease', (28, 35))	('sarcoma', 'Disease', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('sunitinib', 'Chemical', 'MESH:D000077210', (138, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('Treg', 'Chemical', '-', (116, 120))	('DCs', 'Var', (52, 55))	('Treg', 'CPA', (116, 120))	('induction', 'PosReg', (121, 130))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))
447410	28710396	Moreover, dedicated RNA-seq algorithms allow obtaining genomic information such as point mutations, insertions/deletions, translocations and genomic integrations from foreign organisms: well-known oncogenic and tumor progression mechanisms.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('insertions/deletions', 'Var', (100, 120))	('point mutations', 'Var', (83, 98))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('translocations', 'Var', (122, 136))
447445	28710396	Two other cancer signatures performed similar to CINSARC: BREAST REYAL08 72GENES and ROSTY CERVICAL CANCER PROLIFERATION CLUSTER.	('REYAL08 72GENES', 'Var', (65, 80))	('CANCER', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('ROSTY CERVICAL CANCER PROLIFERATION CLUSTER', 'CPA', (85, 128))	('BREAST', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
447465	28710396	However, due to the decrease in statistical power, CINSARC mostly produces non-significant prognoses in three datasets (PMID: 17410195, 21720365 and 17023574, cancer types are: B-cell acute lymphoblastic leukemia, multiple myeloma and ovarian tumors, respectively).	('cancer', 'Disease', (159, 165))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (184, 212))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (190, 212))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('decrease', 'NegReg', (20, 28))	('multiple myeloma and ovarian tumors', 'Disease', 'MESH:D009101', (214, 249))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (184, 212))	('multiple myeloma', 'Phenotype', 'HP:0006775', (214, 230))	('ovarian tumors', 'Phenotype', 'HP:0100615', (235, 249))	('21720365', 'Var', (136, 144))	('acute lymphoblastic leukemia', 'Disease', (184, 212))	('17023574', 'Var', (149, 157))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('leukemia', 'Phenotype', 'HP:0001909', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
447541	27083867	Most cases of intussusception in adults are due to a pathologic lead point within the bowel and are malignant in over 50 % of cases, thereby necessitating surgery and resection of the affected bowel segment.	('due to', 'Reg', (44, 50))	('intussusception', 'Phenotype', 'HP:0002576', (14, 29))	('bowel', 'Disease', 'MESH:D015212', (86, 91))	('bowel segment', 'Disease', 'MESH:C537538', (193, 206))	('intussusception', 'Disease', (14, 29))	('bowel segment', 'Disease', (193, 206))	('bowel', 'Disease', (86, 91))	('bowel', 'Disease', 'MESH:D015212', (193, 198))	('pathologic', 'Var', (53, 63))	('bowel', 'Disease', (193, 198))
447577	25176165	Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified all cases of synovial sarcoma (ICD-O-3 codes 9040, 9041, 9042, and 9043) diagnosed from 1990 to 2009.	('9041', 'Var', (136, 140))	('synovial sarcoma', 'Disease', (98, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (98, 114))	('synovial sarcoma', 'Disease', 'MESH:D013584', (98, 114))
447635	25176165	observed that although chemotherapy was routinely used in the management of localized synovial sarcoma, the occurrence of relapse was higher in adult and pediatric patients receiving chemotherapy than among those patients not receiving chemotherapy.	('localized synovial sarcoma', 'Disease', 'MESH:D013584', (76, 102))	('higher', 'PosReg', (134, 140))	('localized synovial sarcoma', 'Disease', (76, 102))	('chemotherapy', 'Var', (183, 195))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (164, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (86, 102))
447761	24491244	For appendiceal tumors, patients with low grade mucinous carcinoma peritonei (which is also described as disseminated peritoneal adenomucinosis or pseudomyxoma peritonei (PMP)) experience better clinical outcomes than those with higher grade non-mucinous appendiceal malignancies.	('appendiceal malignancies', 'Disease', 'MESH:D001063', (255, 279))	('low grade', 'Var', (38, 47))	('better', 'PosReg', (188, 194))	('adenomucinosis or pseudomyxoma peritonei', 'Disease', (129, 169))	('adenomucinosis or pseudomyxoma peritonei', 'Disease', 'MESH:D011553', (129, 169))	('appendiceal tumors', 'Disease', 'MESH:D001063', (4, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('patients', 'Species', '9606', (24, 32))	('appendiceal tumors', 'Disease', (4, 22))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (48, 66))	('appendiceal malignancies', 'Disease', (255, 279))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (48, 66))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mucinous carcinoma', 'Disease', (48, 66))
447774	24491244	This finding confirms data from our institution, and others, that demonstrate a significant survival advantage for patients undergoing R0/R1 resection compared to those with R2 resections.	('patients', 'Species', '9606', (115, 123))	('R0/R1 resection', 'Var', (135, 150))	('survival', 'CPA', (92, 100))
447846	32923122	Among them are cell cycle regulators, including the cyclin-dependent kinase inhibitors p21 and p16, the oncogene SRC-3 and the tumor suppressor p53.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('p21', 'Gene', (87, 90))	('p21', 'Gene', '12575', (87, 90))	('p16', 'Var', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cyclin-dependent kinase', 'Enzyme', (52, 75))
447849	32923122	Furthermore, a specific interactor of PSME3 has been recently identified, namely PIP30, which positively modulates the interaction of PSME3 to the 20S proteasome complex and alters the selectivity of the PSME3/20S proteasome complex toward different peptides.	('interaction', 'Interaction', (119, 130))	('modulates', 'Reg', (105, 114))	('PIP30', 'Var', (81, 86))	('PIP30', 'Chemical', '-', (81, 86))	('alters', 'Reg', (174, 180))	('selectivity', 'MPA', (185, 196))	('PSME3', 'Gene', (134, 139))	('peptides', 'Chemical', 'MESH:D010455', (250, 258))
447887	32923122	First, we analyzed PSME3 mRNA levels by real-time qRT-PCR in three human melanoma cell lines (A375, WM3526 and WM3682), one human lung cancer cell line (A549) and two colon cancer cell lines (HT29 and T84), and we observed that PSME3 was notably upregulated in each cell line compared to the control normal lung fibroblast cell line MRC5 (Figure 1(a)).	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('melanoma', 'Disease', (73, 81))	('PSME3', 'Gene', (228, 233))	('A549', 'CellLine', 'CVCL:0023', (153, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (167, 179))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('HT29', 'CellLine', 'CVCL:0320', (192, 196))	('WM3526', 'Var', (100, 106))	('lung cancer', 'Disease', (130, 141))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('MRC5', 'CellLine', 'CVCL:0440', (333, 337))	('colon cancer', 'Disease', 'MESH:D015179', (167, 179))	('WM3682', 'Chemical', '-', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('A375', 'Var', (94, 98))	('upregulated', 'PosReg', (246, 257))	('A375', 'CellLine', 'CVCL:0132', (94, 98))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('human', 'Species', '9606', (124, 129))	('WM3682', 'Var', (111, 117))	('colon cancer', 'Disease', (167, 179))	('human', 'Species', '9606', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
447897	32923122	Crucially, this result was not merely due to differences in the cellular level of the beta-globin construct, which in fact were higher in tumor cell lines overexpressing PSME3 (Fig.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('cellular level', 'MPA', (64, 78))	('PSME3', 'Var', (170, 175))	('higher', 'PosReg', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
447902	32923122	All together, these results indicate: i) a negative role of PSME3 in the MHC-I antigen presentation pathway since antigen presentation was reduced in all cancer lines overexpressing the PSME3 regulator while the beta-globin protein and the MHC-I molecules were more abundant in the same cell lines and ii) that the inverse correlation between PSME3 expression and antigen presentation is not restricted to a specific epitope or MHC-I molecule.	('expression', 'Species', '29278', (349, 359))	('cancer', 'Disease', (154, 160))	('overexpressing', 'Var', (167, 181))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('antigen presentation', 'MPA', (114, 134))	('reduced', 'NegReg', (139, 146))	('PSME3', 'Var', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('MHC-I antigen presentation pathway', 'Pathway', (73, 107))	('negative', 'NegReg', (43, 51))
447923	32923122	Interestingly, while non-inhibited cells displayed a decrease in antigen presentation with PSME3 overexpression, a partial increase in MHC-I antigen presentation was observed when cells were treated with epoxomicin (Figure 2(e)).	('epoxomicin', 'Chemical', 'MESH:C078846', (204, 214))	('decrease', 'NegReg', (53, 61))	('PSME3', 'Protein', (91, 96))	('antigen presentation', 'MPA', (65, 85))	('increase', 'PosReg', (123, 131))	('expression', 'Species', '29278', (101, 111))	('overexpression', 'Var', (97, 111))	('MHC-I antigen presentation', 'MPA', (135, 161))
447929	32923122	Considering our finding showing that endogenous overexpression of the PSME3 regulator negatively affects MHC-I antigen presentation in cancer cells, we speculated whether PSME3 knockdown might restore PTP-dependent antigen presentation.	('MHC-I antigen presentation', 'MPA', (105, 131))	('cancer', 'Disease', (135, 141))	('negatively', 'NegReg', (86, 96))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('expression', 'Species', '29278', (52, 62))	('knockdown', 'Var', (177, 186))	('PSME3', 'Gene', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PTP', 'Gene', '5967', (201, 204))	('overexpression', 'PosReg', (48, 62))	('affects', 'Reg', (97, 104))	('restore', 'PosReg', (193, 200))	('PTP', 'Gene', (201, 204))
447931	32923122	As expected, PSME3 knockdown (Figure 3(a)) enhanced p21 protein levels in all cancer cell lines compared to scrambled siRNA (Figure 3(b)).	('enhanced', 'PosReg', (43, 51))	('knockdown', 'Var', (19, 28))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('p21', 'Gene', (52, 55))	('p21', 'Gene', '12575', (52, 55))	('PSME3', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
447932	32923122	More importantly in terms of PTP-dependent antigen presentation, we observed a close correlation between PSME3 knockdown and the increase of the SL8 epitope at the cell surface (Figure 3(c)).	('knockdown', 'Var', (111, 120))	('SL8', 'Gene', (145, 148))	('PTP', 'Gene', (29, 32))	('PSME3', 'Gene', (105, 110))	('increase', 'PosReg', (129, 137))	('PTP', 'Gene', '5967', (29, 32))
447936	32923122	Of great interest, we observed that miRNA-7 inhibited PSME3 expression (Fig.	('miRNA-7', 'Var', (36, 43))	('inhibited', 'NegReg', (44, 53))	('expression', 'Species', '29278', (60, 70))	('PSME3', 'Protein', (54, 59))
447957	32923122	A PSME3 gene sequence mutation that leads to the replacement of Asn 151 by Tyr (N151Y) has been reported to impair the ability of the regulator to activate the trypsin-like activity of the 20S proteasome.	('Asn', 'Gene', (64, 67))	('N151Y', 'Mutation', 'p.N151Y', (80, 85))	('activate', 'PosReg', (147, 155))	('mutation', 'Var', (22, 30))	('ability', 'MPA', (119, 126))	('trypsin-like activity', 'MPA', (160, 181))	('Asn 151 by Tyr', 'Mutation', 'p.N151Y', (64, 78))	('PSME3', 'Gene', (2, 7))	('20S proteasome', 'Enzyme', (189, 203))	('replacement', 'Var', (49, 60))	('impair', 'NegReg', (108, 114))
447958	32923122	A375cXI cells were transfected with increasing amounts of Flag-PSME3 WT or mutated Flag-PSME3-N151Y.	('N151Y', 'Mutation', 'p.N151Y', (94, 99))	('mutated Flag-PSME3-N151Y', 'Var', (75, 99))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('Flag-PSME3-N151Y', 'Var', (83, 99))
447959	32923122	First, we showed by western-blotting that the mutated regulator was no longer able to degrade the p21 protein likely as a direct consequence of its inability to activate the trypsin-like activity of the 20S proteasome.	('p21', 'Gene', '12575', (98, 101))	('inability', 'NegReg', (148, 157))	('activate', 'MPA', (161, 169))	('mutated', 'Var', (46, 53))	('degrade', 'NegReg', (86, 93))	('trypsin-like activity', 'MPA', (174, 195))	('p21', 'Gene', (98, 101))
447961	32923122	More importantly, PSME3-N151Y inhibited SL8 antigen production and presentation at the cell surface from Glob-intron-SL8 less efficiently than PSME3-WT (Figure 4(b)).	('Glob', 'Gene', '8706', (105, 109))	('inhibited', 'NegReg', (30, 39))	('SL8 antigen production', 'MPA', (40, 62))	('presentation at the cell surface', 'MPA', (67, 99))	('N151Y', 'Mutation', 'p.N151Y', (24, 29))	('PSME3-N151Y', 'Var', (18, 29))	('Glob', 'Gene', (105, 109))
447963	32923122	Two explanations are therefore consistent with this result: i) exogenous mutated PSME3-N151Y may no longer be localized in the nucleus; or ii) exogenous mutated PSME3-N151Y may have lost its capacity to bind to the 20S proteasome and, therefore, contrary to PSME3-WT it is no longer able to inhibit proteasome activity.	('20S proteasome', 'Protein', (215, 229))	('PSME3-N151Y', 'Var', (161, 172))	('lost', 'NegReg', (182, 186))	('inhibit', 'NegReg', (291, 298))	('activity', 'MPA', (310, 318))	('N151Y', 'Mutation', 'p.N151Y', (167, 172))	('N151Y', 'Mutation', 'p.N151Y', (87, 92))	('proteasome', 'MPA', (299, 309))	('bind', 'Interaction', (203, 207))	('PSME3-N151Y', 'Gene', (81, 92))
447964	32923122	To discriminate between these two alternative hypotheses, we first examined the distribution of the mutated PSME3-N151Y as well as its capacity to bind to the 20S proteasome in cellulo.	('N151Y', 'Mutation', 'p.N151Y', (114, 119))	('bind', 'Interaction', (147, 151))	('mutated', 'Var', (100, 107))	('PSME3-N151Y', 'Gene', (108, 119))
447965	32923122	Since we did not observe any differences in the localization that could explain the differences in the production of MHC class I epitopes between the cell lines expressing the mutated or the WT regulators, we determined whether mutated Flag-PSME3-N151Y retained the capacity to bind to the nuclear 20S proteasome in cellulo.	('bind', 'Interaction', (278, 282))	('mutated', 'Var', (228, 235))	('nuclear', 'Protein', (290, 297))	('N151Y', 'Mutation', 'p.N151Y', (247, 252))	('Flag-PSME3-N151Y', 'Gene', (236, 252))
447966	32923122	We confirmed further the interaction between PSME3 WT and mutated PSME3-N151Y with the 20S core proteasome by coimmunoprecipitation using an antibody directed against the PSME3 regulator (Figure 4(e)).	('interaction', 'Interaction', (25, 36))	('N151Y', 'Mutation', 'p.N151Y', (72, 77))	('mutated', 'Var', (58, 65))	('PSME3-N151Y', 'Gene', (66, 77))
447967	32923122	Localization and capacity to bind to the 20S core were equivalent between exogenous PSME3 WT and mutated PSME3-N151Y, again demonstrating that the PSME3-20S proteasome complex is involved in the processing/degradation of PTP-derived antigenic peptides.	('N151Y', 'Mutation', 'p.N151Y', (111, 116))	('PTP', 'Gene', (221, 224))	('PTP', 'Gene', '5967', (221, 224))	('mutated PSME3-N151Y', 'Var', (97, 116))	('PSME3-N151Y', 'Var', (105, 116))	('peptides', 'Chemical', 'MESH:D010455', (243, 251))
447969	32923122	Moreover, Cas9-A375 PSME3-knockout cell line (A375cXI) cells transfected with PSME3-DeltaNLS slightly prevented nuclear 20S proteasome degradation of the p21 protein in a PSME3-dependent manner compared to cells transfected with PSME3 WT (Figure 4(f)).	('PSME3-DeltaNLS', 'Var', (78, 92))	('nuclear 20S proteasome degradation', 'MPA', (112, 146))	('p21', 'Gene', '12575', (154, 157))	('prevented', 'NegReg', (102, 111))	('A375', 'CellLine', 'CVCL:0132', (15, 19))	('A375', 'CellLine', 'CVCL:0132', (46, 50))	('p21', 'Gene', (154, 157))
447970	32923122	This result suggests that the low levels of PSME3-DeltaNLS in the nucleus retained the capacity to partially activate the nuclear 20S proteasome and, furthermore, demonstrate that the degradation of the p21 protein is a nuclear and not a cytoplasmic event (Figure 4(F)).	('p21', 'Gene', (203, 206))	('p21', 'Gene', '12575', (203, 206))	('degradation', 'MPA', (184, 195))	('nuclear 20S proteasome', 'Enzyme', (122, 144))	('activate', 'PosReg', (109, 117))	('PSME3-DeltaNLS', 'Var', (44, 58))
447971	32923122	In parallel, when we examined the effect of the partial relocalization of PSME3-DeltaNLS in the cytoplasm on the antigenic presentation pathway, we observed an increase in PTP-dependent antigen presentation compared to the loss of antigen presentation in cells expressing exogenous nuclear PSME3 WT (Figure 4(g)).	('PTP', 'Gene', '5967', (172, 175))	('increase', 'PosReg', (160, 168))	('PSME3-DeltaNLS', 'Var', (74, 88))	('PTP', 'Gene', (172, 175))
447973	32923122	The above results raised at least two alternative hypothesis regarding the role of PSME3 in the PTP-dependent proteasomal degradation pathway: i) PSME3 may inhibit 20S proteasomal peptidase activities responsible for producing antigenic peptides with the correct characteristics (i.e.	('inhibit', 'NegReg', (156, 163))	('PTP', 'Gene', '5967', (96, 99))	('peptides', 'Chemical', 'MESH:D010455', (237, 245))	('activities', 'MPA', (190, 200))	('PSME3', 'Var', (146, 151))	('PTP', 'Gene', (96, 99))	('20S proteasomal peptidase', 'Enzyme', (164, 189))
447974	32923122	length and anchor residues) to serve in MHC-I pathway, with a consequent decrease in production of PTP-dependent epitopes; or ii) PSME3 may stimulate specific 20S proteasomal activities that cause further degradation of the correct size MHC-I antigenic epitopes.	('PSME3', 'Var', (130, 135))	('degradation', 'MPA', (205, 216))	('PTP', 'Gene', (99, 102))	('stimulate', 'PosReg', (140, 149))	('correct size', 'MPA', (224, 236))	('activities', 'MPA', (175, 185))	('decrease', 'NegReg', (73, 81))	('20S proteasomal', 'Enzyme', (159, 174))	('MHC-I', 'Gene', (237, 242))	('PTP', 'Gene', '5967', (99, 102))
447988	32923122	In fact, although binding of PSME3 did not result in significantly increased rates of substrate hydrolysis (Figure 5(b,c)), it may modify proteasome cleavage specificities to generate different patterns of peptide products as already extensively demonstrated for REGalpha/beta Such a change in enzymatic properties may potentially affect the formation of specific antigenic peptides such as SIINFEKL.	('binding', 'Var', (18, 25))	('SIINFEKL', 'Disease', (391, 399))	('REGalpha/beta', 'Gene', '5720', (263, 276))	('peptides', 'Chemical', 'MESH:D010455', (374, 382))	('proteasome cleavage specificities', 'MPA', (138, 171))	('PSME3', 'Gene', (29, 34))	('formation of', 'MPA', (342, 354))	('substrate hydrolysis', 'MPA', (86, 106))	('affect', 'Reg', (331, 337))	('patterns of peptide products', 'MPA', (194, 222))	('REGalpha/beta', 'Gene', (263, 276))	('modify', 'Reg', (131, 137))
448001	32923122	To further depict the role of PSME3 in tumorigenicity and cancer immune response, we genetically deleted PSME3 in the MCA205 sarcoma cancer cell line using the CRISPR/Cas9 technology (Figure 6(b), upper panel and Fig.	('sarcoma cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('sarcoma cancer', 'Disease', 'MESH:D009369', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('deleted', 'Var', (97, 104))	('cancer', 'Disease', (133, 139))	('PSME3', 'Gene', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('tumor', 'Disease', (39, 44))	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
448003	32923122	We observed that Cas9-PSME3 MCA205 clones induce a stronger activation of B3Z hybridoma compared to the parental murine cell line (Figure 6(b), lower panel).	('MCA205', 'Gene', (28, 34))	('activation', 'PosReg', (60, 70))	('Cas9-PSME3', 'Var', (17, 27))	('B3Z hybridoma', 'CPA', (74, 87))	('murine', 'Species', '10090', (113, 119))	('B3Z', 'Chemical', '-', (74, 77))
448006	32923122	Rather, a decrease both in the steady-state level and in the recovery of MHC- I molecules is observed in the Cas9-PSME3 MCA205 clone while those cells elicit a better cancer immune response.	('MHC- I', 'Gene', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('recovery', 'MPA', (61, 69))	('cancer', 'Disease', (167, 173))	('decrease', 'NegReg', (10, 18))	('Cas9-PSME3 MCA205', 'Var', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
448007	32923122	This result convincingly supports the idea that the effect of PSME3 on antigen presentation takes place earlier than the loading of the antigenic peptides and the exporting steps of the MHC class I peptide complex.	('peptides', 'Chemical', 'MESH:D010455', (146, 154))	('antigen presentation', 'MPA', (71, 91))	('PSME3', 'Var', (62, 67))
448012	32923122	This result indicates that the loss of PSME3 induces a decrease in the tumorigenicity of sarcoma cells.	('loss', 'Var', (31, 35))	('PSME3', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('decrease', 'NegReg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('tumor', 'Disease', (71, 76))
448014	32923122	We observed that the relative tumor growth in Nude mice vs C57BL/6 mice was higher for the Cas9-PSME3 MCA205 clones than MCA205 WT (Figure 6(d) and Fig.	('Cas9-PSME3', 'Var', (91, 101))	('mice', 'Species', '10090', (51, 55))	('MCA205', 'Gene', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Nude mice', 'Species', '10090', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('higher', 'PosReg', (76, 82))	('tumor', 'Disease', (30, 35))	('mice', 'Species', '10090', (67, 71))
448015	32923122	This difference suggests that the enhanced eradication of Cas9-PSME3 MCA205 clones compared to MCA205 WT in immunocompetent mice is partly mediated by the adaptive immune system.	('enhanced', 'PosReg', (34, 42))	('eradication', 'CPA', (43, 54))	('mice', 'Species', '10090', (124, 128))	('Cas9-PSME3', 'Var', (58, 68))	('MCA205', 'Gene', (69, 75))
448020	32923122	The only observed phenotypes reported so far for PSME3-/- mice are a small reduction in the number of specific CD8+ T lymphocytes and growth retardation.	('growth retardation', 'Disease', 'MESH:D006130', (134, 152))	('growth retardation', 'Disease', (134, 152))	('mice', 'Species', '10090', (58, 62))	('reduction', 'NegReg', (75, 84))	('growth retardation', 'Phenotype', 'HP:0001510', (134, 152))	('PSME3-/-', 'Var', (49, 57))
448025	32923122	The knock-down of PSME3 in different cancer cell lines using either siRNA, miRNA-7 overexpression, cisplatin treatment or the CRISPR/Cas9 technology rescued the ability of the tumor cells to activate CD8+ T cells in-vitro and enhanced the antitumor response in vivo by inducing the presence of tumor associated antigen from different sequences.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('expression', 'Species', '29278', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', (243, 248))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('PSME3', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('cancer', 'Disease', (37, 43))	('knock-down', 'Var', (4, 14))	('inducing', 'Reg', (269, 277))	('activate', 'PosReg', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('enhanced', 'PosReg', (226, 234))	('CD8+ T cells', 'CPA', (200, 212))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))
448029	32923122	In fact, we demonstrated that knocking out of PSME3 could reduce the growth of MCA205 sarcoma tumors in immunocompetent mice.	('PSME3', 'Gene', (46, 51))	('mice', 'Species', '10090', (120, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('growth', 'CPA', (69, 75))	('sarcoma tumors', 'Disease', 'MESH:D012509', (86, 100))	('reduce', 'NegReg', (58, 64))	('knocking out', 'Var', (30, 42))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('MCA205', 'Gene', (79, 85))	('sarcoma tumors', 'Disease', (86, 100))
448031	32923122	This experiment indicates that the knockout of PSME3 could induce the presentation of new PTP-MIPs that are recognized by CD8+T cells and thus delay tumor growth.	('delay tumor', 'Disease', (143, 154))	('PSME3', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('PTP', 'Gene', '5967', (90, 93))	('presentation', 'MPA', (70, 82))	('induce', 'PosReg', (59, 65))	('knockout', 'Var', (35, 43))	('PTP', 'Gene', (90, 93))	('delay tumor', 'Disease', 'MESH:D009369', (143, 154))
448032	32923122	Interestingly, a recent study reported that PSME3 can affect MHC class I presentation by decreasing the expression levels of immunoproteasomes through a molecular mechanism involving modulation of the JAK-STAT pathway obtained via enhancement of proteasomal degradation of phosphorylated STAT-3 in bone marrow-derived and splenic DC, MEF and HeLa cells.	('modulation', 'Reg', (183, 193))	('PSME3', 'Var', (44, 49))	('JAK-STAT pathway', 'Pathway', (201, 217))	('expression', 'Species', '29278', (104, 114))	('decreasing', 'NegReg', (89, 99))	('MEF', 'CellLine', 'CVCL:9115', (334, 337))	('enhancement', 'PosReg', (231, 242))	('HeLa', 'CellLine', 'CVCL:0030', (342, 346))	('proteasomal degradation', 'MPA', (246, 269))	('affect', 'Reg', (54, 60))	('expression levels of immunoproteasomes', 'MPA', (104, 142))	('MHC class', 'Gene', (61, 70))
448046	32923122	Indeed, we were able to restore a proper immune response against TA-PTPs by manipulating the localization of PSME3 with the DeltaNLS construct.	('manipulating', 'Reg', (76, 88))	('PTP', 'Gene', '5967', (68, 71))	('restore', 'PosReg', (24, 31))	('localization', 'MPA', (93, 105))	('PSME3', 'Protein', (109, 114))	('PTP', 'Gene', (68, 71))	('DeltaNLS', 'Var', (124, 132))	('immune', 'MPA', (41, 47))
448050	32923122	Two different explanations might be proposed to explain the ability of PSME3 to decrease PTP-dependent antigen presentation: PSME3 might (i) inhibit PTP processing via the proteasome complex or (ii) enhance the destruction by 20S proteasome of MHC-I epitopes embedded in PTPs.	('PTP', 'Gene', '5967', (271, 274))	('20S proteasome', 'Enzyme', (226, 240))	('PTP', 'Gene', (89, 92))	('enhance', 'PosReg', (199, 206))	('PTP', 'Gene', '5967', (89, 92))	('PTP', 'Gene', '5967', (149, 152))	('PTP', 'Gene', (271, 274))	('destruction', 'MPA', (211, 222))	('decrease PTP', 'Phenotype', 'HP:0032198', (80, 92))	('MHC-I', 'Gene', (244, 249))	('PSME3', 'Var', (125, 130))	('PTP', 'Gene', (149, 152))	('inhibit', 'NegReg', (141, 148))	('decrease', 'NegReg', (80, 88))
448060	32923122	Moreover, mutated and DeltaNLS-PSME3 constructs played a less active role in PTP degradation, indicating that the main function of PSME3 was to modulate the activity of the nuclear proteasomal complex, with strong inhibitory consequences not only on MHC-I endogenous antigen presentation but also on MHC-I exogenous pathway.	('PSME3', 'Var', (131, 136))	('PTP', 'Gene', (77, 80))	('MHC-I exogenous pathway', 'Pathway', (300, 323))	('nuclear proteasomal complex', 'Enzyme', (173, 200))	('MHC-I endogenous antigen presentation', 'MPA', (250, 287))	('modulate', 'Reg', (144, 152))	('activity', 'MPA', (157, 165))	('PTP', 'Gene', '5967', (77, 80))
448072	29776413	Unexpectedly, plerixafor led to an increase in cell viability and proliferation in standard cell growth conditions, and to chemotactic migration towards plerixafor.	('increase', 'PosReg', (35, 43))	('plerixafor', 'Var', (14, 24))	('plerixafor', 'Chemical', 'MESH:C088327', (153, 163))	('proliferation', 'CPA', (66, 79))	('cell viability', 'CPA', (47, 61))	('chemotactic migration', 'CPA', (123, 144))	('plerixafor', 'Chemical', 'MESH:C088327', (14, 24))
448116	29776413	9271), phospho-ERK1/2 (Thr202/Tyr204) (Cat-No.	('Thr202', 'Chemical', '-', (23, 29))	('Tyr204', 'Chemical', '-', (30, 36))	('Thr202/Tyr204', 'Var', (23, 36))	('ERK1/2', 'Gene', '5595;5594', (15, 21))	('ERK1/2', 'Gene', (15, 21))
448120	29776413	2101), and phospho-PDGFRB (Tyr751) (Cat-No.	('Tyr751', 'Var', (27, 33))	('PDGFRB', 'Gene', (19, 25))	('PDGFRB', 'Gene', '5159', (19, 25))	('Tyr751', 'Chemical', '-', (27, 33))
448126	29776413	Small interfering RNA (siRNA) directed at CXCR4 (FlexiTube SI02664242) and a non-silencing negative control (AllStars negative control; SI03650318) were functionally verified by the manufacturer (Qiagen; Hilden, Germany) and in prior publications.	('CXCR4', 'Gene', '7852', (42, 47))	('SI03650318', 'Var', (136, 146))	('CXCR4', 'Gene', (42, 47))
448145	29776413	Splicing isoforms and post-translational modifications such as glycosylation and ubiquitination can affect CXCR4 surface expression and function.	('CXCR4', 'Gene', (107, 112))	('function', 'MPA', (136, 144))	('affect', 'Reg', (100, 106))	('glycosylation', 'Var', (63, 76))	('ubiquitination', 'Var', (81, 95))	('CXCR4', 'Gene', '7852', (107, 112))
448146	29776413	Because such CXCR4 splicing variants have been reported in Ewing sarcoma, we first examined CXCR4 protein expression in Western blots of whole cell lysates.	('CXCR4', 'Gene', '7852', (92, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('CXCR4', 'Gene', (92, 97))	('variants', 'Var', (28, 36))	('Ewing sarcoma', 'Disease', (59, 72))	('CXCR4', 'Gene', '7852', (13, 18))	('CXCR4', 'Gene', (13, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))	('reported', 'Reg', (47, 55))
448161	29776413	However, despite this demonstration of target binding, a significant decrease in CXCR4 surface expression due to siRNA silencing did not abrogate proliferative plerixafor effects in CXCR4-high cells (Fig.	('CXCR4', 'Gene', (182, 187))	('CXCR4', 'Gene', '7852', (81, 86))	('siRNA', 'Gene', (113, 118))	('plerixafor', 'Chemical', 'MESH:C088327', (160, 170))	('abrogate', 'NegReg', (137, 145))	('CXCR4', 'Gene', (81, 86))	('decrease', 'NegReg', (69, 77))	('CXCR4', 'Gene', '7852', (182, 187))	('silencing', 'Var', (119, 128))
448228	29776413	Supporting this hypothesis, not only plerixafor resulted in activation of PDGFRB but also inhibition of the CXCR4 signaling pathway on the level of Galphai (pertussis toxin) and in TC-32 cells SRC (dasatinib).	('SRC', 'Gene', '6714', (193, 196))	('inhibition', 'NegReg', (90, 100))	('CXCR4', 'Gene', (108, 113))	('SRC', 'Gene', (193, 196))	('PDGFRB', 'Gene', '5159', (74, 80))	('TC-32', 'CellLine', 'CVCL:7151', (181, 186))	('plerixafor', 'Chemical', 'MESH:C088327', (37, 47))	('plerixafor', 'Var', (37, 47))	('activation', 'PosReg', (60, 70))	('PDGFRB', 'Gene', (74, 80))	('CXCR4', 'Gene', '7852', (108, 113))	('dasatinib', 'Chemical', 'MESH:D000069439', (198, 207))
448234	29776413	The RTK ERBB2 was shown to promote CXCR4 expression and thereby metastasis, while in turn CXCL12 ligand transactivated ERBB2.	('ERBB2', 'Gene', '2064', (8, 13))	('CXCR4', 'Gene', (35, 40))	('CXCL12', 'Gene', (90, 96))	('ERBB2', 'Gene', (8, 13))	('ERBB2', 'Gene', (119, 124))	('ERBB2', 'Gene', '2064', (119, 124))	('promote', 'PosReg', (27, 34))	('transactivated', 'PosReg', (104, 118))	('CXCL12', 'Gene', '6387', (90, 96))	('CXCR4', 'Gene', '7852', (35, 40))	('metastasis', 'CPA', (64, 74))	('RTK', 'Var', (4, 7))
448237	29776413	Of interest to future studies in sarcomas, silencing of CXCR4 axis contributions sufficed to compromise initial establishment of prostate cancers in bone microenvironment, whereas established bone tumors were sensitive only to RTK inhibitors.	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('bone tumors', 'Disease', (192, 203))	('bone tumors', 'Disease', 'MESH:D001859', (192, 203))	('prostate cancers', 'Phenotype', 'HP:0012125', (129, 145))	('prostate cancers', 'Disease', (129, 145))	('bone tumors', 'Phenotype', 'HP:0010622', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('silencing', 'Var', (43, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcomas', 'Disease', 'MESH:D012509', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('CXCR4', 'Gene', '7852', (56, 61))	('prostate cancers', 'Disease', 'MESH:D011471', (129, 145))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('sarcomas', 'Disease', (33, 41))	('compromise', 'NegReg', (93, 103))	('CXCR4', 'Gene', (56, 61))
448243	29776413	The unexpected observation that plerixafor treatment resulted in an increase in relative cell number and migration of Ewing sarcoma cell lines in vitro raises a number of questions: Is this effect specific to cancer type and model, experimental conditions in vitro, and the CXCR4-inhibiting agent used?	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('CXCR4', 'Gene', '7852', (274, 279))	('plerixafor', 'Chemical', 'MESH:C088327', (32, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('Ewing sarcoma cell lines', 'Disease', (118, 142))	('plerixafor', 'Var', (32, 42))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('Ewing sarcoma cell lines', 'Disease', 'MESH:C563168', (118, 142))	('cancer', 'Disease', (209, 215))	('CXCR4', 'Gene', (274, 279))	('increase', 'PosReg', (68, 76))	('migration', 'CPA', (105, 114))	('relative cell number', 'CPA', (80, 100))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
448317	26398363	In our case the diagnosis was advanced urethral sarcoma (T4N0M0), with positive surgical margin in a clinically severe patient with cardiomyopathy that led to an unfavorable outcome.	('urethral sarcoma', 'Disease', 'MESH:D014526', (39, 55))	('patient', 'Species', '9606', (119, 126))	('T4N0M0', 'Var', (57, 63))	('cardiomyopathy', 'Disease', 'MESH:D009202', (132, 146))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (132, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('urethral sarcoma', 'Disease', (39, 55))	('cardiomyopathy', 'Disease', (132, 146))
448423	24550583	As shown in the Figure 2a and b, KLH enhanced the production of IFN-gamma and TNF-alpha (17- and 23-times higher than control, respectively), which is strongly comparable to that of IL-2 (5 U/mL).	('production', 'MPA', (50, 60))	('IL-2', 'Gene', '16183', (182, 186))	('TNF-alpha', 'Gene', '21926', (78, 87))	('IFN-gamma', 'Gene', '15978', (64, 73))	('IL-2', 'Gene', (182, 186))	('KLH', 'Var', (33, 36))	('higher', 'PosReg', (106, 112))	('TNF-alpha', 'Gene', (78, 87))	('enhanced', 'PosReg', (37, 45))	('IFN-gamma', 'Gene', (64, 73))
448462	24550583	We think that KLH exhibited its antiproliferative activity against Meth A sarcoma cells [Figure 4] by inducing the apoptosis mechanism of Meth A cells.	('KLH', 'Var', (14, 17))	('apoptosis mechanism', 'CPA', (115, 134))	('antiproliferative activity', 'MPA', (32, 58))	('inducing', 'PosReg', (102, 110))	('Meth A sarcoma', 'Disease', (67, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('Meth A sarcoma', 'Disease', 'MESH:D012509', (67, 81))
448490	31466240	While mice deficient in MMP2 exhibit relatively mild skeletal defects which result in reduced bone mineralization and joint erosion, mutations in human MMP2 and MMP14 cause the severe connective tissue syndromes known as MONA (Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia) and Winchester Syndrome, respectively.	('cause', 'Reg', (167, 172))	('skeletal defects', 'Disease', (53, 69))	('mice', 'Species', '10090', (6, 10))	('connective tissue syndromes', 'Disease', (184, 211))	('Winchester Syndrome', 'Disease', (297, 316))	('Osteolysis', 'Phenotype', 'HP:0002797', (240, 250))	('subcutaneous Nodulosis', 'Phenotype', 'HP:0001482', (252, 274))	('skeletal defects', 'Phenotype', 'HP:0000924', (53, 69))	('MONA', 'Gene', '4313', (221, 225))	('Multicentric Osteolysis', 'Disease', (227, 250))	('MMP2', 'Gene', (152, 156))	('mutations', 'Var', (133, 142))	('Athropathia', 'Disease', 'None', (280, 291))	('joint erosion', 'CPA', (118, 131))	('reduced', 'NegReg', (86, 93))	('skeletal defects', 'Disease', 'MESH:C538496', (53, 69))	('subcutaneous Nodulosis', 'Disease', 'MESH:D012218', (252, 274))	('Winchester Syndrome', 'Disease', 'MESH:C536709', (297, 316))	('MMP14', 'Gene', (161, 166))	('MONA', 'Gene', (221, 225))	('Multicentric Osteolysis', 'Disease', 'MESH:D031845', (227, 250))	('Athropathia', 'Disease', (280, 291))	('subcutaneous Nodulosis', 'Disease', (252, 274))	('reduced bone mineralization', 'Phenotype', 'HP:0004349', (86, 113))	('human', 'Species', '9606', (146, 151))	('bone mineralization', 'CPA', (94, 113))
448492	31466240	In genetically-modified mouse models, MMP14 overexpression induces mammary gland adenocarcinoma formation and pancreatic cancer development.	('mouse', 'Species', '10090', (24, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (110, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('adenocarcinoma', 'Disease', (81, 95))	('induces', 'PosReg', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (81, 95))	('pancreatic cancer', 'Disease', (110, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (110, 127))	('MMP14', 'Gene', (38, 43))	('overexpression', 'Var', (44, 58))
448499	31466240	Moreover, MMP14 not only induces the proteolysis of collagen I but is also involved in the degradation of various other ECM components such as collagens II-IV, gelatins, fibronectin, tenascin, laminins, fibrin, vitronectin, nidogen, and aggrecan.	('involved', 'Reg', (75, 83))	('nidogen', 'Chemical', 'MESH:C114729', (224, 231))	('MMP14', 'Var', (10, 15))	('tenascin', 'Gene', (183, 191))	('induces', 'Reg', (25, 32))	('proteolysis', 'MPA', (37, 48))	('degradation', 'MPA', (91, 102))	('tenascin', 'Gene', '3371', (183, 191))	('fibronectin', 'Gene', (170, 181))	('collagen', 'Protein', (52, 60))	('vitronectin', 'Gene', '7448', (211, 222))	('vitronectin', 'Gene', (211, 222))	('fibronectin', 'Gene', '2335', (170, 181))
448505	31466240	Moreover, MMP14 is required for lamellipodia formation and motility of myeloid progenitors, a process dependent on the MMP14 cytoplasmic domain, which activates the Rho GTPase Rac1 through its association with the adaptor protein p130Cas.	('Rac1', 'Gene', (176, 180))	('p130Cas', 'Gene', '9564', (230, 237))	('MMP14', 'Var', (119, 124))	('association', 'Interaction', (193, 204))	('p130Cas', 'Gene', (230, 237))	('Rac1', 'Gene', '5879', (176, 180))	('activates', 'PosReg', (151, 160))
448515	31466240	Experimentally, MMP14 overexpression in the synovial sarcoma cell line SW982 has been shown to induce spindle shape morphology and an EMT-like phenotype, in conjunction with enhanced cell invasiveness.	('synovial sarcoma', 'Disease', (44, 60))	('MMP14', 'Gene', (16, 21))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (44, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('synovial sarcoma', 'Disease', 'MESH:D013584', (44, 60))	('EMT-like phenotype', 'CPA', (134, 152))	('spindle shape morphology', 'CPA', (102, 126))	('overexpression', 'Var', (22, 36))	('induce', 'PosReg', (95, 101))
448516	31466240	Together, these reports establish the tight association between MMP14 and the mesenchymal phenotype, suggesting that MMP14 may also contribute to determining the phenotypical characteristics of sarcomas.	('contribute', 'Reg', (132, 142))	('MMP14', 'Var', (117, 122))	('sarcomas', 'Disease', 'MESH:D012509', (194, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('sarcomas', 'Disease', (194, 202))
448517	31466240	Copy number alterations in sarcomas are generally rare.	('sarcomas', 'Phenotype', 'HP:0100242', (27, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcomas', 'Disease', (27, 35))	('Copy number alterations', 'Var', (0, 23))	('sarcomas', 'Disease', 'MESH:D012509', (27, 35))
448531	31466240	Moreover, high MMP14 expression is mainly observed in spindle cell monophasic fibrous synovial sarcomas.	('MMP14', 'Gene', (15, 20))	('fibrous synovial sarcomas', 'Disease', 'MESH:D013584', (78, 103))	('fibrous synovial sarcomas', 'Disease', (78, 103))	('expression', 'MPA', (21, 31))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (86, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('high', 'Var', (10, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (86, 102))	('observed', 'Reg', (42, 50))
448573	31466240	The ability of E2F to control the promoters of MMP genes couples Rb deregulation to the acquisition of metastatic properties by cancer cells.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('MMP genes', 'Gene', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('deregulation', 'Var', (68, 80))	('cancer', 'Disease', (128, 134))
448579	31466240	Another level of MMP14 regulation occurs through the DNA methylation of the MMP14 promoter which, like 70% of the human genes annotated so far, contains CpG islands.	('MMP14', 'Gene', (76, 81))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('DNA methylation', 'Var', (53, 68))	('MMP14', 'Gene', (17, 22))	('human', 'Species', '9606', (114, 119))
448581	31466240	Both during differentiation and cancer, the affinity of this TF to its consensus DNA binding sequence can be modulated by DNA methylation.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('affinity', 'Interaction', (44, 52))	('modulated', 'Reg', (109, 118))	('methylation', 'Var', (126, 137))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
448582	31466240	It is becoming increasingly clear that, along with altered global gene expression, also the genomic distribution of methylated DNA sequences (called methylome) is distorted in malignant cells compared to that of their healthy counterparts.	('genomic', 'MPA', (92, 99))	('distorted', 'Reg', (163, 172))	('N', 'Chemical', 'MESH:D009584', (128, 129))	('methylated', 'Var', (116, 126))
448585	31466240	The cancer suppressor protein kinase D1 (PKD1), a repressor of different MMPs, including MMP14, is highly expressed in normal breast tissue, but epigenetically silenced by DNA methylation in invasive breast cancer, where MMP14 and other MMPs are induced.	('N', 'Chemical', 'MESH:D009584', (173, 174))	('invasive breast cancer', 'Disease', 'MESH:D001943', (191, 213))	('MMPs', 'Gene', '4312;337179;4313;17390;4314;4317;4318;4320;4322;4323;17387;4324;4325;4326;64386;10893;64386;10893;64386;10893', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('PKD1', 'Gene', (41, 45))	('cancer', 'Disease', (207, 213))	('protein kinase D1', 'Gene', '5587', (22, 39))	('PKD1', 'Gene', '5310', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('MMPs', 'Gene', (237, 241))	('MMPs', 'Gene', '4312;337179;4313;17390;4314;4317;4318;4320;4322;4323;17387;4324;4325;4326;64386;10893;64386;10893;64386;10893', (237, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('protein kinase D1', 'Gene', (22, 39))	('MMPs', 'Gene', (73, 77))	('invasive breast cancer', 'Disease', (191, 213))	('cancer', 'Disease', (4, 10))	('epigenetically silenced', 'Var', (145, 168))	('DNA methylation', 'Var', (172, 187))
448589	31466240	However, MMP14-targeting microRNAs, such as miR-193a-3p and miR-133a inhibit osteosarcoma proliferation, invasion, and metastasis.	('invasion', 'CPA', (105, 113))	('osteosarcoma proliferation', 'Disease', (77, 103))	('miR-133a', 'Var', (60, 68))	('miR-193a-3p', 'Var', (44, 55))	('osteosarcoma proliferation', 'Disease', 'MESH:D012516', (77, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('metastasis', 'CPA', (119, 129))	('inhibit', 'NegReg', (69, 76))
448632	31466240	In migrating mesenchymal cells, MMP14-containing storage endosomes become polarized in front of the nucleus in the direction of cell migration and their positioning depends on the function of the linker of nucleoskeleton and cytoskeleton (LINC) complex in connecting the nucleus and the centrosome.	('cell migration', 'CPA', (128, 142))	('MMP14-containing', 'Var', (32, 48))	('N', 'Chemical', 'MESH:D009584', (241, 242))	('depends', 'Reg', (165, 172))
448633	31466240	Nuclear deformation depends on its stiffness and, interestingly, loss of MMP14 causes alterations of the nuclear envelope and nuclear softening, further indicating a relationship between MMP14 and the nucleus.	('alterations', 'Reg', (86, 97))	('MMP14', 'Gene', (73, 78))	('loss', 'Var', (65, 69))	('nuclear softening', 'CPA', (126, 143))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('nuclear envelope', 'CPA', (105, 121))
448639	31466240	Knock-down of MMP14 in triple negative breast cancer cells, which have a mesenchymal phenotype, reduces blood vessel invasion but not lymphatic vessel invasion.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('reduces', 'NegReg', (96, 103))	('Knock-down', 'Var', (0, 10))	('blood vessel invasion', 'CPA', (104, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('MMP14', 'Gene', (14, 19))	('breast cancer', 'Disease', (39, 52))
448752	27019694	For an accurate approach, a large-scale immunohistochemistry panel, containing mandatorily the CD45, MPO, CD15, CD79a, CD3, CD34, CD117, CD99, TdT and Ki-67 proved to be useful.	('CD34', 'Gene', '947', (124, 128))	('TdT', 'Gene', (143, 146))	('CD45', 'Gene', '5788', (95, 99))	('CD99', 'Gene', (137, 141))	('CD79a', 'Gene', '973', (112, 117))	('TdT', 'Gene', '1791', (143, 146))	('MPO', 'Gene', '4353', (101, 104))	('CD79a', 'Gene', (112, 117))	('CD15', 'Gene', '2526', (106, 110))	('CD15', 'Gene', (106, 110))	('MPO', 'Gene', (101, 104))	('CD45', 'Gene', (95, 99))	('CD3', 'Var', (119, 122))	('CD99', 'Gene', '4267', (137, 141))	('CD117', 'Gene', '3815', (130, 135))	('man', 'Species', '9606', (79, 82))	('CD34', 'Gene', (124, 128))	('CD117', 'Gene', (130, 135))
448755	27019694	Two major issues of the correct diagnostic orientation are the recognition of a possible non-lymphoid CD45 positivity and ruling-out of the aberrant CD99 antigen from the pivotal markers in this tumour type.	('CD45', 'Gene', '5788', (102, 106))	('aberrant', 'Var', (140, 148))	('positivity', 'Reg', (107, 117))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('CD99', 'Gene', '4267', (149, 153))	('tumour', 'Disease', (195, 201))	('CD45', 'Gene', (102, 106))	('CD99', 'Gene', (149, 153))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
448756	27019694	On the other hand, MPO positivity is a prominent feature for a tumour of myeloid origin that overrides the unusual and aberrant antigen expression (CD79a, CD99).	('MPO', 'Gene', '4353', (19, 22))	('tumour of myeloid', 'Disease', 'MESH:D009369', (63, 80))	('CD99', 'Gene', '4267', (155, 159))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('CD99', 'Gene', (155, 159))	('CD79a', 'Gene', '973', (148, 153))	('MPO', 'Gene', (19, 22))	('tumour of myeloid', 'Disease', (63, 80))	('positivity', 'Var', (23, 33))	('CD79a', 'Gene', (148, 153))
448772	27019694	AML with t(8;21) is more frequently cause myeloid sarcoma, therefore applying FISH probes to test the genotype of the tumor is also recommended to get more information about these rare tumors.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (42, 57))	('cause', 'Reg', (36, 41))	('tumors', 'Disease', (185, 191))	('myeloid sarcoma', 'Disease', (42, 57))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('t(8;21', 'Var', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', (118, 123))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('AML', 'Disease', (0, 3))
448781	24651452	Functionally, CXCR4-positive cells migrated and invaded towards an SDF-1a gradient and these aggressive properties were impeded by both the CXCR4 small molecule inhibitor AMD3100, and by knockdown of CXCR4.	('CXCR4', 'Gene', '7852', (140, 145))	('CXCR4', 'Gene', (200, 205))	('impeded', 'NegReg', (120, 127))	('knockdown', 'Var', (187, 196))	('invaded', 'CPA', (48, 55))	('CXCR4', 'Gene', '7852', (14, 19))	('CXCR4', 'Gene', (140, 145))	('CXCR4', 'Gene', '7852', (200, 205))	('CXCR4', 'Gene', (14, 19))
448782	24651452	In addition, CXCR4-dependent migration and invasion were inhibited by small molecule inhibitors of Cdc42 and Rac1, mechanistically implicating these Rho-GTPases as downstream mediators of the CXCR4-dependent phenotype.	('Rac1', 'Gene', '5879', (109, 113))	('invasion', 'CPA', (43, 51))	('Rac1', 'Gene', (109, 113))	('inhibited', 'NegReg', (57, 66))	('CXCR4', 'Gene', '7852', (192, 197))	('inhibitors', 'Var', (85, 95))	('Cdc42', 'Gene', '998', (99, 104))	('CXCR4', 'Gene', '7852', (13, 18))	('CXCR4', 'Gene', (13, 18))	('CXCR4', 'Gene', (192, 197))	('Cdc42', 'Gene', (99, 104))
448792	24651452	Significantly, high CXCR4 expression has also been associated with metastatic disease and poor outcome in many other human cancers of both epithelial and non-epithelial origin, including breast cancer, pancreatic cancer, leukemia, rhabdomyosarcoma and osteosarcoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('metastatic disease', 'Disease', (67, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('leukemia', 'Phenotype', 'HP:0001909', (221, 229))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (202, 219))	('high', 'Var', (15, 19))	('CXCR4', 'Gene', '7852', (20, 25))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('leukemia', 'Disease', 'MESH:D007938', (221, 229))	('CXCR4', 'Gene', (20, 25))	('leukemia', 'Disease', (221, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('human', 'Species', '9606', (117, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (202, 219))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (231, 247))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Disease', (187, 200))	('osteosarcoma', 'Phenotype', 'HP:0002669', (252, 264))	('pancreatic cancer', 'Disease', (202, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (123, 130))	('rhabdomyosarcoma and osteosarcoma', 'Disease', 'MESH:D012516', (231, 264))
448797	24651452	Importantly, inhibition of the CXCR4/SDF-1alpha axis inhibits the aggressive cellular phenotype, thus revealing the potential contribution of CXCR4 signaling to Ewing sarcoma metastasis.	('CXCR4', 'Gene', '7852', (142, 147))	('CXCR4', 'Gene', (142, 147))	('aggressive cellular phenotype', 'CPA', (66, 95))	('Ewing sarcoma metastasis', 'Disease', 'MESH:C563168', (161, 185))	('inhibition', 'Var', (13, 23))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (161, 174))	('Ewing sarcoma metastasis', 'Disease', (161, 185))	('CXCR4', 'Gene', '7852', (31, 36))	('inhibits', 'NegReg', (53, 61))	('CXCR4', 'Gene', (31, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
448878	24651452	Consistent with pharmacologic inhibitor studies, knockdown of CXCR4 significantly impaired the migration of both CHLA-25 and TC-32 cells toward SDF-1alpha (Figure 4E & F).	('knockdown', 'Var', (49, 58))	('impaired', 'NegReg', (82, 90))	('CXCR4', 'Gene', '7852', (62, 67))	('TC-32', 'CellLine', 'CVCL:7151', (125, 130))	('CXCR4', 'Gene', (62, 67))	('migration', 'CPA', (95, 104))	('CHLA-25', 'Chemical', '-', (113, 120))
448881	24651452	Both CHLA-25 and TC-32 cells invaded through the Matrigel  layer toward SDF-1alpha, and invasion was abrogated by both AMD3100 (Figure 5A & B) and by CXCR4 knockdown (Figure 5C & D).	('abrogated', 'NegReg', (101, 110))	('invasion', 'CPA', (88, 96))	('CXCR4', 'Gene', '7852', (150, 155))	('TC-32', 'CellLine', 'CVCL:7151', (17, 22))	('CXCR4', 'Gene', (150, 155))	('CHLA-25', 'Chemical', '-', (5, 12))	('AMD3100', 'Var', (119, 126))
448882	24651452	Thus, CXCR4-positive Ewing sarcoma cells are stimulated to migrate and invade towards SDF-1alpha but modulation of the CXCR4/SDF-1alpha axis by pharmacologic or genetic means can profoundly inhibit this response.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('CXCR4', 'Gene', '7852', (119, 124))	('CXCR4', 'Gene', '7852', (6, 11))	('Ewing sarcoma', 'Disease', (21, 34))	('modulation', 'Var', (101, 111))	('CXCR4', 'Gene', (119, 124))	('CXCR4', 'Gene', (6, 11))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('invade', 'CPA', (71, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))	('migrate', 'CPA', (59, 66))
448890	24651452	Exposure of Ewing sarcoma cells to either NSC 23766 or ML 141, small molecule inhibitors of Rac1 and Cdc42, respectively, resulted in significant inhibition of both migration (Figure 6B & C, D) and invasion (Figure 6E).	('Rac1', 'Gene', '5879', (92, 96))	('Ewing sarcoma', 'Disease', (12, 25))	('Rac1', 'Gene', (92, 96))	('inhibition', 'NegReg', (146, 156))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (12, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('Cdc42', 'Gene', (101, 106))	('inhibitors', 'Var', (78, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (12, 25))	('ML', 'Disease', 'MESH:C537366', (55, 57))	('and', 'CPA', (194, 197))	('migration', 'CPA', (165, 174))	('Cdc42', 'Gene', '998', (101, 106))
448891	24651452	In particular, inhibition of Rac1 nearly completely abrogated the chemotactic invasion of CXCR4-positive Ewing sarcoma cells.	('abrogated', 'NegReg', (52, 61))	('Rac1', 'Gene', (29, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('CXCR4', 'Gene', (90, 95))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('Ewing sarcoma', 'Disease', (105, 118))	('chemotactic invasion of', 'CPA', (66, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('CXCR4', 'Gene', '7852', (90, 95))	('Rac1', 'Gene', '5879', (29, 33))	('inhibition', 'Var', (15, 25))
448894	24651452	Exposure to SDF-1alpha potentiated Rac1 activity in both cell populations but activation of Rac1 was reproducibly most pronounced in SDF-1alpha-stimulated CXCR4-high cells.	('Rac1', 'Gene', '5879', (92, 96))	('CXCR4', 'Gene', (155, 160))	('Rac1', 'Gene', (92, 96))	('CXCR4', 'Gene', '7852', (155, 160))	('Rac1', 'Gene', '5879', (35, 39))	('SDF-1alpha-stimulated', 'Var', (133, 154))	('Rac1', 'Gene', (35, 39))
448907	24651452	In particular, interrogation of gene expression databases identified an association between high levels of the CXCR4 transcript and metastatic disease.	('metastatic disease', 'Disease', (132, 150))	('CXCR4', 'Gene', (111, 116))	('high', 'Var', (92, 96))	('CXCR4', 'Gene', '7852', (111, 116))
448923	24651452	Moreover, we have also found that inhibiting Rac1 blocks SDF-1alpha -independent invasion of serum starved Ewing cells that do not express high levels of CXCR4 (data not shown).	('inhibiting', 'Var', (34, 44))	('CXCR4', 'Gene', '7852', (154, 159))	('SDF-1alpha', 'Gene', (57, 67))	('Rac1', 'Gene', '5879', (45, 49))	('CXCR4', 'Gene', (154, 159))	('Rac1', 'Gene', (45, 49))	('blocks', 'NegReg', (50, 56))
449172	32344731	Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation.	('sarcoma', 'Disease', (93, 100))	('alterations', 'Var', (50, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
449173	32344731	As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors.	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('appear', 'Reg', (31, 37))	('disruptions', 'Var', (3, 14))	('sarcoma', 'Disease', (71, 78))	('CDK pathways', 'Pathway', (18, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
449178	32344731	Two broad groups of sarcomas exist:those with simple karyotypes, often characterized by a specific, disease-driving alterations and those with complex karyotypes, where there are multiple genomic losses, gains, and amplifications.	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcomas', 'Disease', (20, 28))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('amplifications', 'Var', (215, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
449187	32344731	For example, CDK11 variants have multiple functions in mediating transcription, mitosis, hormone receptor signaling, autophagy, and apoptosis.	('apoptosis', 'CPA', (132, 141))	('hormone receptor', 'Gene', (89, 105))	('hormone receptor', 'Gene', '3164', (89, 105))	('autophagy', 'CPA', (117, 126))	('mitosis', 'CPA', (80, 87))	('CDK11', 'Gene', (13, 18))	('CDK11', 'Gene', '23097', (13, 18))	('mediating transcription', 'MPA', (55, 78))	('variants', 'Var', (19, 27))
449189	32344731	As CDKs control crucial processes required for cell survival and propagation, their hyperactivation (typically through mutation, gene amplification, or altered expression of their regulators) is commonly observed in cancer.	('mutation', 'Var', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('CDKs', 'Gene', (3, 7))	('altered', 'Reg', (152, 159))	('hyperactivation', 'PosReg', (84, 99))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('gene amplification', 'Var', (129, 147))
449192	32344731	As our knowledge of sarcoma biology has increased, there is a growing appreciation for CDK pathway dysregulation in promoting disease progression.	('sarcoma', 'Disease', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('dysregulation', 'Var', (99, 112))	('CDK pathway', 'Pathway', (87, 98))	('promoting', 'PosReg', (116, 125))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('disease progression', 'CPA', (126, 145))
449196	32344731	These complexes are inactive until phosphorylated at a conserved threonine residue in the T-loop region of the CDK (T172 in CDK4, T177 in CDK6) by a CDK-activating kinase (CAK), widely considered to be cyclin H-CDK7 but possibly including other kinases.	('threonine', 'Chemical', 'MESH:D013912', (65, 74))	('CAK', 'Gene', '1022', (172, 175))	('CDK7', 'Gene', (211, 215))	('CDK-activating kinase', 'Gene', (149, 170))	('CAK', 'Gene', (172, 175))	('cyclin H', 'Gene', '902', (202, 210))	('T177', 'Var', (130, 134))	('CDK-activating kinase', 'Gene', '1022', (149, 170))	('CDK7', 'Gene', '1022', (211, 215))	('CDK6', 'Gene', (138, 142))	('CDK6', 'Gene', '1021', (138, 142))	('cyclin H', 'Gene', (202, 210))
449213	32344731	Although they share DNA sequences, the proteins are translated in overlapping reading frames; consequently, p16INK4a and ARF (p14 in humans, p19 in mice) bear no amino acid sequence identity and have unrelated functions.	('p14', 'Gene', (126, 129))	('ARF', 'Disease', (121, 124))	('p19', 'Gene', (141, 144))	('p16INK4a', 'Var', (108, 116))	('p14', 'Gene', '1029', (126, 129))	('p19', 'Gene', '1029', (141, 144))	('mice', 'Species', '10090', (148, 152))	('humans', 'Species', '9606', (133, 139))	('ARF', 'Disease', 'MESH:D058186', (121, 124))
449214	32344731	While p16INK4a is a specific inhibitor of D-CDK4/6 kinases that promotes G1 phase arrest by RB1 activation, ARF has multiple targets through which it elicits cell cycle arrest, apoptosis, autophagy, and/or other tumor suppressive biological changes.	('CDK4/6', 'Gene', '1019;1021', (44, 50))	('arrest', 'Disease', 'MESH:D006323', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('elicits', 'Reg', (150, 157))	('arrest', 'Disease', 'MESH:D006323', (82, 88))	('p16INK4a', 'Var', (6, 14))	('RB1', 'Gene', (92, 95))	('autophagy', 'CPA', (188, 197))	('activation', 'PosReg', (96, 106))	('ARF', 'Disease', (108, 111))	('CDK4/6', 'Gene', (44, 50))	('arrest', 'Disease', (169, 175))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (158, 175))	('tumor', 'Disease', (212, 217))	('apoptosis', 'CPA', (177, 186))	('promotes', 'PosReg', (64, 72))	('arrest', 'Disease', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('ARF', 'Disease', 'MESH:D058186', (108, 111))
449222	32344731	Despite this knowledge, tumor analyses of 9p21 often fail to adequately discriminate between alterations in INK4a versus ARF at the CDKN2A locus and frequently underestimate potential contributions of INK4b.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('underestimate', 'NegReg', (160, 173))	('ARF', 'Disease', (121, 124))	('tumor', 'Disease', (24, 29))	('alterations', 'Var', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('p21', 'Gene', '1026', (43, 46))	('INK4a', 'Gene', (108, 113))	('p21', 'Gene', (43, 46))	('ARF', 'Disease', 'MESH:D058186', (121, 124))
449223	32344731	This is especially true for less studied, rare tumors like sarcomas where many subtypes display 9p21 deletions but the relative importance of each gene to tumor pathogenesis remains poorly understood.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('sarcomas', 'Disease', 'MESH:D012509', (59, 67))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('p21', 'Gene', '1026', (97, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcomas', 'Disease', (59, 67))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('p21', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('deletions', 'Var', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))
449225	32344731	The development of mouse models with selective, tissue specific inactivation of each gene at the INK4b/ARF/INK4a locus will reveal their independent roles in development of MPNST and other sarcomas.	('inactivation', 'Var', (64, 76))	('ARF', 'Disease', (103, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (189, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('sarcomas', 'Disease', (189, 197))	('mouse', 'Species', '10090', (19, 24))	('ARF', 'Disease', 'MESH:D058186', (103, 106))	('MPNST', 'Disease', (173, 178))	('sarcomas', 'Disease', 'MESH:D012509', (189, 197))
449226	32344731	The following sections summarize notable CDK and CDK pathway alterations associated with the more common adult and childhood subtypes of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('adult', 'Disease', (105, 110))	('CDK pathway', 'Pathway', (49, 60))	('associated', 'Reg', (73, 83))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('alterations', 'Var', (61, 72))	('sarcoma', 'Disease', (137, 144))
449231	32344731	Strikingly, the only gene whose alterations were associated with worse overall survival across all types of localized soft tissue sarcomas was CDKN2A.	('sarcomas', 'Disease', (130, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (118, 138))	('alterations', 'Var', (32, 43))	('CDKN2A', 'Gene', (143, 149))	('sarcomas', 'Disease', 'MESH:D012509', (130, 138))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (118, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
449235	32344731	Loss of regions within chr 13q is the most frequent genomic alteration (up to 78% of tumors), which leads to deletion of the RB1 gene located on chr13q14.2.	('deletion', 'Var', (109, 117))	('RB1', 'Gene', (125, 128))	('Loss', 'NegReg', (0, 4))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
449236	32344731	Genetic mutation, deletion, or silencing of chr9p21, the region containing CDKN2A, result in loss of p16INK4a and unrestricted activation of cyclin D-CDK4/6 kinases.	('CDK4/6', 'Gene', '1019;1021', (150, 156))	('p21', 'Gene', '1026', (48, 51))	('p16INK4a', 'Protein', (101, 109))	('loss', 'NegReg', (93, 97))	('CDKN2A', 'Gene', (75, 81))	('p21', 'Gene', (48, 51))	('CDK4/6', 'Gene', (150, 156))	('mutation', 'Var', (8, 16))	('activation', 'PosReg', (127, 137))	('deletion', 'Var', (18, 26))	('silencing', 'NegReg', (31, 40))
449237	32344731	As noted above, the MDM2 (mouse double minute-2) oncoprotein ubiquitinates the p53 tumor suppressor and promotes its proteasomal degradation.	('mouse double minute-2', 'Gene', (26, 47))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('proteasomal degradation', 'MPA', (117, 140))	('tumor', 'Disease', (83, 88))	('MDM2', 'Var', (20, 24))	('mouse double minute-2', 'Gene', '17246', (26, 47))	('promotes', 'PosReg', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('ubiquitinates', 'MPA', (61, 74))
449243	32344731	Notably, all but one of the tumors that were analyzed for mutations expressed wildtype NRAS, BRAF, and PIK3CA.	('mutations', 'Var', (58, 67))	('BRAF', 'Gene', (93, 97))	('NRAS', 'Gene', '4893', (87, 91))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('BRAF', 'Gene', '673', (93, 97))	('PIK3CA', 'Gene', (103, 109))	('PIK3CA', 'Gene', '5290', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('NRAS', 'Gene', (87, 91))
449247	32344731	demonstrated that conditional KrasG12D/+;Cdkn2aflox/flox mice efficiently develop UPS.	('mice', 'Species', '10090', (57, 61))	('KrasG12D/+', 'Var', (30, 40))	('develop UPS', 'CPA', (74, 85))
449248	32344731	Other studies showed that intramuscular targeting of the Neurofibromatosis Type 1 (Nf1) gene, which encodes a negative regulator of Ras, combined with deletion of Cdkn2a leads to UPS formation.	('UPS formation', 'CPA', (179, 192))	('Cdkn2a', 'Gene', (163, 169))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (57, 74))	('Neurofibromatosis Type 1', 'Gene', (57, 81))	('Nf1', 'Gene', (83, 86))	('deletion', 'Var', (151, 159))	('leads to', 'Reg', (170, 178))	('Neurofibromatosis Type 1', 'Gene', '4763', (57, 81))
449257	32344731	Additional mutations that have been observed in MFS include those causing inactivation of the NF1 gene, which causes heightened Ras signaling and upregulation of CCND1 transcription.	('NF1', 'Gene', '4763', (94, 97))	('mutations', 'Var', (11, 20))	('CCND1', 'Gene', (162, 167))	('upregulation', 'PosReg', (146, 158))	('heightened', 'PosReg', (117, 127))	('CCND1', 'Gene', '595', (162, 167))	('transcription', 'MPA', (168, 181))	('Ras signaling', 'MPA', (128, 141))	('NF1', 'Gene', (94, 97))	('inactivation', 'Var', (74, 86))
449258	32344731	Increased cyclin D1 has been shown to drive tumorigenesis in NF1 mutant/Ras-activated cancers.	('cyclin D1', 'Protein', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('drive', 'PosReg', (38, 43))	('NF1', 'Gene', (61, 64))	('Increased', 'PosReg', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('NF1', 'Gene', '4763', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutant/Ras-activated', 'Var', (65, 85))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('tumor', 'Disease', (44, 49))
449265	32344731	Additional genomic alterations cause tumor progression into DDLPS, which in turn leads to increased risk for metastasis and death.	('genomic alterations', 'Var', (11, 30))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('LPS', 'Disease', 'MESH:C536528', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('metastasis', 'CPA', (109, 119))	('cause', 'Reg', (31, 36))	('death', 'Disease', 'MESH:D003643', (124, 129))	('LPS', 'Disease', (62, 65))	('death', 'Disease', (124, 129))
449268	32344731	Normally, CHOP is induced during stress conditions and causes growth arrest; however, the fusion of TLS prevents its normal function.	('growth arrest', 'Phenotype', 'HP:0001510', (62, 75))	('normal function', 'MPA', (117, 132))	('CHOP', 'Disease', (10, 14))	('stress', 'Disease', (33, 39))	('fusion', 'Var', (90, 96))	('TLS', 'Protein', (100, 103))	('growth arrest', 'Disease', (62, 75))	('growth arrest', 'Disease', 'MESH:D006323', (62, 75))	('stress', 'Disease', 'MESH:D000079225', (33, 39))	('prevents', 'NegReg', (104, 112))
449269	32344731	TLS-CHOP causes abnormal expression of G1 phase regulators, such as cyclin D1, cyclin E, CDK4, and CDK2, and its constitutive expression in mice is sufficient to drive M/RCLPS formation with 100% penetrance.	('LPS', 'Disease', 'MESH:C536528', (172, 175))	('mice', 'Species', '10090', (140, 144))	('LPS', 'Disease', (172, 175))	('expression', 'MPA', (25, 35))	('TLS-CHOP', 'Var', (0, 8))	('CDK4', 'Gene', (89, 93))	('drive', 'PosReg', (162, 167))	('cyclin D1', 'Gene', (68, 77))	('cyclin E', 'Gene', (79, 87))	('CDK2', 'Gene', (99, 103))
449274	32344731	One of the most frequent disruptions in LMS is hyperactivation of the PI3K-Akt-mTOR pathway, whether through deletion of PTEN or amplification/upregulation of IGF1R, AKT, RICTOR, and MTOR.	('mTOR', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (79, 83))	('amplification/upregulation', 'PosReg', (129, 155))	('PTEN', 'Gene', (121, 125))	('AKT', 'Gene', '207', (166, 169))	('deletion', 'Var', (109, 117))	('IGF1R', 'Gene', '3480', (159, 164))	('Akt', 'Gene', '207', (75, 78))	('PTEN', 'Gene', '5728', (121, 125))	('MTOR', 'Gene', '2475', (183, 187))	('Akt', 'Gene', (75, 78))	('RICTOR', 'Gene', (171, 177))	('AKT', 'Gene', (166, 169))	('RICTOR', 'Gene', '253260', (171, 177))	('amplification/upregulation', 'Var', (129, 155))	('hyperactivation', 'PosReg', (47, 62))	('IGF1R', 'Gene', (159, 164))	('MTOR', 'Gene', (183, 187))
449277	32344731	Deletions and promoter methylation of the CDKN2A gene as well as amplification of MYC have been observed in patient LMS specimens.	('promoter', 'MPA', (14, 22))	('MYC', 'Gene', '4609', (82, 85))	('amplification', 'MPA', (65, 78))	('CDKN2A', 'Gene', (42, 48))	('patient', 'Species', '9606', (108, 115))	('Deletions', 'Var', (0, 9))	('MYC', 'Gene', (82, 85))
449281	32344731	NF1 is an autosomal dominant condition that occurs through germline loss-of-function mutation of the neurofibromin 1 gene (NF1), which as noted above ultimately results in hyperactivation of Ras.	('loss-of-function', 'NegReg', (68, 84))	('neurofibromin 1', 'Gene', '4763', (101, 116))	('mutation', 'Var', (85, 93))	('NF1', 'Gene', '4763', (123, 126))	('NF1', 'Gene', (123, 126))	('hyperactivation', 'MPA', (172, 187))	('NF1', 'Gene', (0, 3))	('neurofibromin 1', 'Gene', (101, 116))	('Ras', 'Protein', (191, 194))	('NF1', 'Gene', '4763', (0, 3))
449285	32344731	Both sporadic and NF1-associated MPNSTs have complex karyotypes characterized by NF1-inactivating mutations along with frequent genetic disruptions of CDKN2A and polycomb repressor complex-2 (PRC2) components, SUZ12 or EED.	('NF1', 'Gene', (81, 84))	('SUZ12', 'Gene', '23512', (210, 215))	('SUZ12', 'Gene', (210, 215))	('NF1', 'Gene', '4763', (81, 84))	('mutations', 'Var', (98, 107))	('EED', 'Gene', '8726', (219, 222))	('EED', 'Gene', (219, 222))	('CDKN2A', 'Gene', (151, 157))	('NF1', 'Gene', (18, 21))	('NF1', 'Gene', '4763', (18, 21))	('MPNSTs', 'Phenotype', 'HP:0100697', (33, 39))
449286	32344731	Inactivation of PRC2, which causes loss of histone H3 lysine 27 (H3K27) tri-methylation and global changes in gene expression, is a marker of poor survival in MPNST.	('histone H3', 'Protein', (43, 53))	('changes', 'Reg', (99, 106))	('loss', 'NegReg', (35, 39))	('lysine', 'Chemical', 'MESH:D008239', (54, 60))	('PRC2', 'Gene', (16, 20))	('gene expression', 'MPA', (110, 125))	('Inactivation', 'Var', (0, 12))	('H3K27', 'Protein', (65, 70))	('tri-methylation', 'MPA', (72, 87))
449288	32344731	Since most MPNSTs lack CDKN2A because of early genomic deletion of the locus in pre-malignant lesions, the de-repression of CCND1 and CCNE1 upon PRC2 loss would be expected to drive MPNST progression by abolishing RB1 activity.	('RB1', 'Enzyme', (214, 217))	('CCND1', 'Gene', (124, 129))	('CCNE1', 'Gene', '898', (134, 139))	('CCNE1', 'Gene', (134, 139))	('abolishing', 'NegReg', (203, 213))	('CDKN2A', 'Gene', (23, 29))	('lack', 'NegReg', (18, 22))	('CCND1', 'Gene', '595', (124, 129))	('de-repression', 'NegReg', (107, 120))	('PRC2', 'Gene', (145, 149))	('MPNST', 'Disease', (182, 187))	('activity', 'MPA', (218, 226))	('MPNSTs', 'Phenotype', 'HP:0100697', (11, 17))	('loss', 'NegReg', (150, 154))	('drive', 'PosReg', (176, 181))	('deletion', 'Var', (55, 63))
449289	32344731	Additional CDK pathway alterations commonly seen in MPNSTs include inactivating mutations of TP53, loss or mis-localization of the CDK inhibitor, p27KIP1, and amplification or increased expression of cyclin E1.	('amplification', 'Var', (159, 172))	('cyclin E1', 'Gene', (200, 209))	('increased', 'PosReg', (176, 185))	('p27KIP1', 'Gene', '1027', (146, 153))	('CDK pathway', 'Pathway', (11, 22))	('TP53', 'Gene', (93, 97))	('cyclin E1', 'Gene', '898', (200, 209))	('inactivating mutations', 'Var', (67, 89))	('MPNSTs', 'Phenotype', 'HP:0100697', (52, 58))	('mis-localization', 'MPA', (107, 123))	('loss', 'NegReg', (99, 103))	('expression', 'MPA', (186, 196))	('p27KIP1', 'Gene', (146, 153))	('alterations', 'Reg', (23, 34))
449292	32344731	In MPNSTs, RABL6A was found to promote MPNST pathogenesis, in part, through its downregulation of p27KIP1, activation of CDKs, and inhibition of RB1.	('p27KIP1', 'Gene', (98, 105))	('RB1', 'Protein', (145, 148))	('MPNSTs', 'Phenotype', 'HP:0100697', (3, 9))	('promote', 'PosReg', (31, 38))	('MPNST pathogenesis', 'Disease', (39, 57))	('activation', 'PosReg', (107, 117))	('p27KIP1', 'Gene', '1027', (98, 105))	('RABL6A', 'Var', (11, 17))	('downregulation', 'NegReg', (80, 94))	('CDKs', 'Protein', (121, 125))	('inhibition', 'NegReg', (131, 141))
449294	32344731	The first MPNST GEMM combined Nf1 and Trp53 linked germline mutations, while subsequent work showed that combined loss of Nf1 with either Cdkn2a or Pten is also sufficient to generate MPNSTs.	('Trp53', 'Gene', (38, 43))	('Nf1', 'Gene', (122, 125))	('loss', 'Var', (114, 118))	('Trp53', 'Gene', '22059', (38, 43))	('MPNSTs', 'Phenotype', 'HP:0100697', (184, 190))	('Nf1', 'Gene', (30, 33))
449296	32344731	Spatial and temporal control of MPNST development has been achieved by injecting adenoviral Cre recombinase into the sciatic nerve of Nf1flox/flox; Cdkn2aflox/flox mice.	('Nf1flox/flox; Cdkn2aflox/flox', 'Var', (134, 163))	('mice', 'Species', '10090', (164, 168))	('Cdkn2aflox/flox', 'Var', (148, 163))
449317	32344731	The most common mutations in conventional chondrosarcoma are found in isocitrate dehydrogenase genes (IDH), which produce enzymes that catalyze the conversion of isocitrate to alpha-ketoglutarate.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('isocitrate', 'Chemical', 'MESH:C034219', (70, 80))	('common', 'Reg', (9, 15))	('mutations', 'Var', (16, 25))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (42, 56))	('isocitrate', 'Chemical', 'MESH:C034219', (162, 172))	('IDH', 'Gene', (102, 105))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (176, 195))	('chondrosarcoma', 'Disease', (42, 56))	('chondrosarcoma', 'Disease', 'MESH:D002813', (42, 56))
449320	32344731	ERMS typically has a good prognosis, and the most recurrent genetic alteration is loss of heterozygosity at chr 11p15 locus.	('ERMS', 'Disease', (0, 4))	('p15', 'Gene', '1030', (114, 117))	('loss of heterozygosity', 'Var', (82, 104))	('p15', 'Gene', (114, 117))
449323	32344731	In fusion-positive ARMS, the mutational burden is low with the most common alterations being gene amplifications of chr 2p24 (containing MYC) and chr 12q13-q14 (containing CDK4).	('MYC', 'Gene', '4609', (137, 140))	('MYC', 'Gene', (137, 140))	('chr 12q13-q14', 'Var', (146, 159))	('chr 2p24', 'Gene', (116, 124))
449326	32344731	Tumors with amplifications in the CDK4 region are associated with worse overall survival.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('overall survival', 'MPA', (72, 88))	('worse', 'NegReg', (66, 71))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CDK4', 'Gene', (34, 38))	('amplifications', 'Var', (12, 26))
449328	32344731	The most common mutations occur in the Ras oncogenic pathway; either in one of the Ras genes (NRAS, HRAS, KRAS) or its effectors, BRAF and PIK3CA.	('NRAS', 'Gene', (94, 98))	('PIK3CA', 'Gene', '5290', (139, 145))	('HRAS', 'Gene', '3265', (100, 104))	('BRAF', 'Gene', '673', (130, 134))	('HRAS', 'Gene', (100, 104))	('mutations', 'Var', (16, 25))	('NRAS', 'Gene', '4893', (94, 98))	('BRAF', 'Gene', (130, 134))	('Ras genes', 'Gene', (83, 92))	('PIK3CA', 'Gene', (139, 145))	('Ras oncogenic pathway', 'Pathway', (39, 60))	('occur', 'Reg', (26, 31))
449329	32344731	Additionally, focal losses in TP53, NF1, and CDK2NA are frequently observed within tumors as well as copy number gains in chr 12q14-15 (containing MDM2 and CDK4).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('NF1', 'Gene', (36, 39))	('TP53', 'Gene', (30, 34))	('NF1', 'Gene', '4763', (36, 39))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('copy number gains', 'Var', (101, 118))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('losses', 'NegReg', (20, 26))	('CDK2NA', 'Gene', (45, 51))
449335	32344731	Deletion, loss of heterozygosity, and mutations arise frequently in CDK-related tumor suppressor genes (TP53, RB1, CDKN2A, PTEN) as well as amplifications of oncogenes (CDK4, MDM2, MYC, TWIST1, CCND3, CCNE1).	('CDKN2A', 'Gene', (115, 121))	('CCNE1', 'Gene', '898', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CCND3', 'Gene', (194, 199))	('PTEN', 'Gene', (123, 127))	('MYC', 'Gene', '4609', (181, 184))	('PTEN', 'Gene', '5728', (123, 127))	('mutations', 'Var', (38, 47))	('CCND3', 'Gene', '896', (194, 199))	('Deletion', 'Var', (0, 8))	('loss of heterozygosity', 'Var', (10, 32))	('TP53', 'Gene', (104, 108))	('CDK4', 'Gene', (169, 173))	('TWIST1', 'Gene', (186, 192))	('MDM2', 'Gene', (175, 179))	('tumor', 'Disease', (80, 85))	('MYC', 'Gene', (181, 184))	('CCNE1', 'Gene', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('TWIST1', 'Gene', '7291', (186, 192))
449338	32344731	Indeed, genetically engineered mouse and pig models with inactivating mutations in RB1 and/or TP53 provide useful in vivo models of the disease.	('RB1', 'Gene', (83, 86))	('pig', 'Species', '9823', (41, 44))	('mouse', 'Species', '10090', (31, 36))	('TP53', 'Gene', (94, 98))	('inactivating mutations', 'Var', (57, 79))
449339	32344731	For example, dual inactivation of RB1 and TP53 in osteoblast precursors in mice caused early onset OS development while homozygous mutation of TP53 in Yucatan mini-pigs yielded cranial OS tumors with altered expression of mutant p53 target genes, including upregulation of cyclin B1.	('cranial OS tumors', 'Disease', (177, 194))	('mice', 'Species', '10090', (75, 79))	('cranial OS tumors', 'Disease', 'MESH:C567932', (177, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('caused', 'Reg', (80, 86))	('upregulation', 'PosReg', (257, 269))	('dual inactivation', 'Var', (13, 30))	('TP53', 'Gene', (42, 46))	('altered', 'Reg', (200, 207))	('expression', 'MPA', (208, 218))	('pigs', 'Species', '9823', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cyclin B1', 'Gene', (273, 282))	('RB1', 'Gene', (34, 37))	('cyclin B1', 'Gene', '397662', (273, 282))	('early onset OS development', 'CPA', (87, 113))	('mutation', 'Var', (131, 139))
449350	32344731	Expressing EWS-FLI1 in primitive mesenchymal tissues in combination with Trp53 deletion results in poorly differentiated soft tissue sarcomas; however, a true EwS mouse model is yet to be developed.	('sarcomas', 'Disease', (133, 141))	('results in', 'Reg', (88, 98))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (121, 141))	('Trp53', 'Gene', (73, 78))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('EWS', 'Gene', '14030', (11, 14))	('poorly', 'Disease', (99, 105))	('mouse', 'Species', '10090', (163, 168))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (121, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('deletion', 'Var', (79, 87))	('Trp53', 'Gene', '22059', (73, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('EWS', 'Gene', (11, 14))
449361	32344731	In agreement with those results, knockdown or pharmacological inhibition of CDK9 in SS cells caused cell death, growth arrest, and reduced motility.	('death', 'Disease', 'MESH:D003643', (105, 110))	('death', 'Disease', (105, 110))	('growth arrest', 'Disease', 'MESH:D006323', (112, 125))	('growth arrest', 'Disease', (112, 125))	('knockdown', 'Var', (33, 42))	('CDK9', 'Gene', '1025', (76, 80))	('reduced', 'NegReg', (131, 138))	('motility', 'CPA', (139, 147))	('growth arrest', 'Phenotype', 'HP:0001510', (112, 125))	('CDK9', 'Gene', (76, 80))
449373	32344731	In LPS cells, knockdown of CDK11 correlated with a decrease in anti-apoptotic factors.	('LPS', 'Disease', 'MESH:C536528', (3, 6))	('anti-apoptotic factors', 'MPA', (63, 85))	('CDK11', 'Gene', '23097', (27, 32))	('decrease', 'NegReg', (51, 59))	('knockdown', 'Var', (14, 23))	('CDK11', 'Gene', (27, 32))	('LPS', 'Disease', (3, 6))
449383	32344731	Most cancers display two to eight mutations that provide a selective growth advantage; these are classified as "driver" mutations.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('growth advantage', 'CPA', (69, 85))	('mutations', 'Var', (34, 43))
449385	32344731	Driver genes, which can be defined as those bearing specific alterations (e.g., point mutation, amplification, translocation, deletion or epigenetic modifications) that critically promote tumorigenesis in a significant percentage of tumors, have been categorized into major signaling pathways required for cell fate, survival, and genome maintenance.	('tumor', 'Disease', (188, 193))	('amplification', 'Var', (96, 109))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Disease', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('translocation', 'Var', (111, 124))	('point mutation', 'Var', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('epigenetic modifications', 'Var', (138, 162))	('deletion', 'Var', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('promote', 'PosReg', (180, 187))	('pig', 'Species', '9823', (139, 142))
449386	32344731	Each driver mutation alone is thought to provide a small growth advantage to the cell, but when that increased rate of growth accumulates over years and is compounded by the effects of other driver mutations, large neoplasms can result.	('small growth', 'Phenotype', 'HP:0001510', (51, 63))	('neoplasms', 'Phenotype', 'HP:0002664', (215, 224))	('neoplasms', 'Disease', 'MESH:D009369', (215, 224))	('mutation', 'Var', (12, 20))	('neoplasms', 'Disease', (215, 224))
449389	32344731	Activating KRAS mutations occur in over 90% of PDAC lesions of all grades whereas inactivation of CDKN2A, p53, and SMAD4 is seen with increasing frequency in type 2 and 3 pancreatic intraepithelial neoplasms.	('KRAS', 'Gene', (11, 15))	('Activating', 'PosReg', (0, 10))	('neoplasms', 'Phenotype', 'HP:0002664', (198, 207))	('PDAC', 'Disease', (47, 51))	('PDAC', 'Phenotype', 'HP:0006725', (47, 51))	('intraepithelial neoplasms', 'Phenotype', 'HP:0032187', (182, 207))	('mutations', 'Var', (16, 25))	('pancreatic intraepithelial neoplasms', 'Disease', (171, 207))	('SMAD4', 'Gene', '4089', (115, 120))	('pancreatic intraepithelial neoplasms', 'Disease', 'MESH:D010190', (171, 207))	('SMAD4', 'Gene', (115, 120))
449390	32344731	Those findings, supported by biological evidence from genetically engineered mouse models, suggest KRAS alterations drive PDAC initiation while subsequent mutations in CDKN2A and other tumor suppressors are rate-limiting for tumor progression.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('alterations', 'Var', (104, 115))	('mutations', 'Var', (155, 164))	('drive', 'Reg', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('PDAC', 'Disease', (122, 126))	('PDAC', 'Phenotype', 'HP:0006725', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CDKN2A', 'Gene', (168, 174))	('KRAS', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('mouse', 'Species', '10090', (77, 82))
449392	32344731	Ras has traditionally proven challenging to target pharmacologically, although a unique inhibitor of the KRasG12C mutant (prevalent in lung cancer, rare in PDAC) is currently in clinical trials (NCT03681483, NCT04185883).	('KRas', 'Gene', (105, 109))	('KRas', 'Gene', '16653', (105, 109))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('mutant', 'Var', (114, 120))	('PDAC', 'Phenotype', 'HP:0006725', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
449393	32344731	Recently, there has been rising interest in targeting MEK and CDK4/6 for PDAC treatment as mutant KRas promotes MEK activation and CDKN2A loss causes CDK4/6 activation.	('CDK4/6', 'Gene', '1019;1021', (150, 156))	('MEK', 'Gene', '5609', (54, 57))	('loss', 'NegReg', (138, 142))	('MEK', 'Gene', (112, 115))	('MEK', 'Gene', '5609', (112, 115))	('CDK4/6', 'Gene', '1019;1021', (62, 68))	('CDK4/6', 'Gene', (150, 156))	('PDAC', 'Phenotype', 'HP:0006725', (73, 77))	('KRas', 'Gene', (98, 102))	('activation', 'PosReg', (116, 126))	('KRas', 'Gene', '16653', (98, 102))	('CDK4/6', 'Gene', (62, 68))	('activation', 'PosReg', (157, 167))	('promotes', 'PosReg', (103, 111))	('mutant', 'Var', (91, 97))	('CDKN2A', 'Gene', (131, 137))	('MEK', 'Gene', (54, 57))
449396	32344731	In some cases, CDK alterations drive sarcoma initiation while in others they are important for malignant progression.	('sarcoma initiation', 'Disease', (37, 55))	('CDK', 'Protein', (15, 18))	('sarcoma initiation', 'Disease', 'MESH:D012509', (37, 55))	('alterations', 'Var', (19, 30))	('drive', 'PosReg', (31, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
449397	32344731	For example, the vast majority of WD/DDLPS lesions harbor amplification of CDK4 as part of the chr 12q-13-15 amplicon, which occurs early in their genesis and provides a clear selective growth advantage.	('LPS', 'Disease', 'MESH:C536528', (39, 42))	('WD', 'Disease', 'MESH:D006527', (34, 36))	('CDK4', 'Gene', (75, 79))	('LPS', 'Disease', (39, 42))	('amplification', 'Var', (58, 71))
449401	32344731	It is less clear for some sarcomas if CDK pathway dysregulation is a driving event essential to their development.	('CDK pathway', 'Pathway', (38, 49))	('sarcomas', 'Disease', (26, 34))	('dysregulation', 'Var', (50, 63))	('sarcomas', 'Disease', 'MESH:D012509', (26, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))
449404	32344731	A key reason for defining driver mutations in tumors is to identify the most relevant, actionable targets to improve available therapies for patients, which for sarcoma are severely lacking.	('sarcoma', 'Disease', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (33, 42))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('tumors', 'Disease', (46, 52))	('patients', 'Species', '9606', (141, 149))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
449407	32344731	Second, is there compelling pre-clinical data demonstrating a clear tumor suppressive benefit of CDK inactivation in that subtype of sarcoma?	('tumor', 'Disease', (68, 73))	('sarcoma', 'Disease', (133, 140))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('inactivation', 'Var', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CDK', 'Protein', (97, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
449408	32344731	The next section addresses the latter issue and reveals growing evidence that CDK-targeted therapy may have clinical efficacy against multiple subtypes of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('CDK-targeted therapy', 'Var', (78, 98))	('sarcoma', 'Disease', (155, 162))
449409	32344731	As we will discuss, the success of CDK4/6 inhibitors in patients with dedifferentiated liposarcoma has validated CDK4 gene amplification as a driver mutation in this subtype and is leading the way for similar trials in additional soft tissue sarcoma subtypes.	('patients', 'Species', '9606', (56, 64))	('sarcoma', 'Disease', 'MESH:D012509', (242, 249))	('liposarcoma', 'Disease', 'MESH:D008080', (87, 98))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('liposarcoma', 'Phenotype', 'HP:0012034', (87, 98))	('CDK4', 'Gene', (113, 117))	('sarcoma', 'Disease', (242, 249))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (230, 249))	('CDK4/6', 'Gene', '1019;1021', (35, 41))	('sarcoma', 'Disease', (91, 98))	('gene amplification', 'Var', (118, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('liposarcoma', 'Disease', (87, 98))	('CDK4/6', 'Gene', (35, 41))
449424	32344731	The efficacy of CDK4/6 inhibitors relies on the presence of wild-type RB1 in the cancer cells as inhibition of CDK4/6 blocks proliferation through the accumulation of hypo-phosphorylated RB1.	('inhibition', 'Var', (97, 107))	('CDK4/6', 'Gene', (16, 22))	('hypo-phosphorylated', 'MPA', (167, 186))	('accumulation', 'PosReg', (151, 163))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('proliferation', 'CPA', (125, 138))	('cancer', 'Disease', (81, 87))	('CDK4/6', 'Gene', '1019;1021', (111, 117))	('RB1', 'Protein', (187, 190))	('CDK4/6', 'Gene', '1019;1021', (16, 22))	('CDK4/6', 'Gene', (111, 117))	('blocks', 'NegReg', (118, 124))
449435	32344731	In pancreatic ductal adenocarcinoma, the same MEK-CDK4 inhibitor combination triggered SASP-dependent tumor vascularization that facilitated chemotherapy uptake as well as increased CD8+ T cell infiltration into tumors that potentiated PD-1 checkpoint blockade.	('pancreatic ductal adenocarcinoma', 'Disease', (3, 35))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('chemotherapy uptake', 'CPA', (141, 160))	('MEK', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('increased', 'PosReg', (172, 181))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (3, 35))	('facilitated', 'PosReg', (129, 140))	('CD8+ T', 'MPA', (182, 188))	('tumors', 'Disease', (212, 218))	('combination', 'Var', (65, 76))	('SASP-dependent', 'MPA', (87, 101))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (212, 217))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 35))	('MEK', 'Gene', '5609', (46, 49))
449436	32344731	In sarcomas, the prevalence of CDK dysregulation has galvanized efforts investigating CDK-targeted therapy to combat disease progression.	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('sarcomas', 'Disease', (3, 11))	('dysregulation', 'Var', (35, 48))
449439	32344731	Among the rationale combination therapies evaluated, THZ531, a CDK12 inhibitor, was found to synergize with PARP inhibitors to prevent DNA damage repair and induce tumor cell death in EwS, significantly diminishing the tumor growth in mouse xenograft and PDX models of the disease.	('tumor', 'Disease', (164, 169))	('prevent', 'NegReg', (127, 134))	('tumor', 'Disease', (219, 224))	('CDK12', 'Gene', '69131', (63, 68))	('PARP', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('diminishing', 'NegReg', (203, 214))	('THZ531', 'Chemical', 'MESH:C000618758', (53, 59))	('THZ531', 'Var', (53, 59))	('mouse', 'Species', '10090', (235, 240))	('DNA damage repair', 'MPA', (135, 152))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor cell death', 'Disease', 'MESH:D003643', (164, 180))	('induce', 'Reg', (157, 163))	('CDK12', 'Gene', (63, 68))	('PARP', 'Gene', '11545', (108, 112))	('tumor cell death', 'Disease', (164, 180))
449444	32344731	Disrupting those checkpoints with WEE1 inhibitors in cells that have incompletely replicated DNA or damaged DNA causes premature mitosis, leading to severe chromosomal abnormalities and aneuploidy that provoke mitotic catastrophe and death.	('premature mitosis', 'Disease', (119, 136))	('aneuploidy', 'Disease', (186, 196))	('death', 'Disease', 'MESH:D003643', (234, 239))	('death', 'Disease', (234, 239))	('premature mitosis', 'Disease', 'MESH:C536271', (119, 136))	('Disrupting', 'Var', (0, 10))	('aneuploidy', 'Disease', 'MESH:D000782', (186, 196))	('mitotic catastrophe', 'CPA', (210, 229))	('chromosomal abnormalities', 'Disease', (156, 181))	('WEE1', 'Gene', '7465', (34, 38))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (156, 181))	('provoke', 'Reg', (202, 209))	('WEE1', 'Gene', (34, 38))
449446	32344731	One group showed that the WEE1 inhibitor, MK-1775, exacerbated the cytotoxic effects of a DNA replication stress drug, gemcitabine, in MPNST, UPS, and OS cell lines.	('stress', 'Disease', (106, 112))	('gemcitabine', 'Chemical', 'MESH:C056507', (119, 130))	('stress', 'Disease', 'MESH:D000079225', (106, 112))	('exacerbated', 'PosReg', (51, 62))	('cytotoxic effects', 'CPA', (67, 84))	('WEE1', 'Gene', (26, 30))	('WEE1', 'Gene', '7465', (26, 30))	('MK-1775', 'Var', (42, 49))	('MK-1775', 'Chemical', 'MESH:C549567', (42, 49))
449447	32344731	More recently, studies in EwS cells showed that inhibition of the ATR-CHK1 checkpoint pathway activates CDK2, which enhances DNA replication stress by targeting a subunit of the ribonucleotide reductase enzyme for proteasomal degradation.	('stress', 'Disease', 'MESH:D000079225', (141, 147))	('stress', 'Disease', (141, 147))	('CDK2', 'Gene', (104, 108))	('enhances', 'PosReg', (116, 124))	('inhibition', 'Var', (48, 58))	('targeting', 'Reg', (151, 160))	('CHK1', 'Gene', (70, 74))	('ATR', 'Gene', (66, 69))	('ATR', 'Gene', '545', (66, 69))	('CHK1', 'Gene', '1111', (70, 74))
449454	32344731	Currently, there is a multi-center phase 2 trial of palbociclib monotherapy in Spain for patients who have advanced sarcomas with elevated expression of CDK4 (NCT03242382).	('sarcomas', 'Disease', (116, 124))	('CDK4', 'Protein', (153, 157))	('NCT03242382', 'Var', (159, 170))	('palbociclib', 'Chemical', 'MESH:C500026', (52, 63))	('sarcomas', 'Disease', 'MESH:D012509', (116, 124))	('elevated', 'PosReg', (130, 138))	('patients', 'Species', '9606', (89, 97))	('expression', 'MPA', (139, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
449458	32344731	For instance, recent pre-clinical studies in pancreatic adenocarcinoma suggest that CDK4/6 inhibitors should be administered after (not before) cytotoxic chemotherapeutics since activation of RB1 represses the DNA repair machinery and enhances DNA damage-induced tumor cell death.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (45, 70))	('represses', 'NegReg', (196, 205))	('enhances', 'PosReg', (235, 243))	('activation', 'Var', (178, 188))	('CDK4/6', 'Gene', (84, 90))	('pancreatic adenocarcinoma', 'Disease', (45, 70))	('tumor cell death', 'Disease', (263, 279))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('DNA', 'Pathway', (210, 213))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (45, 70))	('CDK4/6', 'Gene', '1019;1021', (84, 90))	('RB1', 'Gene', (192, 195))	('tumor cell death', 'Disease', 'MESH:D003643', (263, 279))
449461	32344731	One of the more frequent changes is inactivation of the CDKN2A locus, resulting in loss of ARF-p53 and p16INK4a-RB1 tumor suppressive signaling and consequent hyperactivation of cell cycle CDKs.	('ARF', 'Disease', 'MESH:D058186', (91, 94))	('hyperactivation', 'PosReg', (159, 174))	('ARF', 'Disease', (91, 94))	('p16INK4a-RB1', 'Var', (103, 115))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('changes', 'Var', (25, 32))	('cell cycle CDKs', 'CPA', (178, 193))	('CDKN2A', 'Gene', (56, 62))	('inactivation', 'Var', (36, 48))	('tumor', 'Disease', (116, 121))	('loss', 'NegReg', (83, 87))
449475	31297226	With dexrazoxane, males (n = 33) demonstrated less deterioration in circumferential strain by 3.4% (95% CI 0.01 to 6.8), and females (n = 29) demonstrated less reduction in SF by 5.7% (95% CI 2.1 to 9.3), and had mitigation of increases in cavity size and wall stress.	('dexrazoxane', 'Var', (5, 16))	('reduction', 'NegReg', (160, 169))	('increases', 'PosReg', (227, 236))	('circumferential strain', 'MPA', (68, 90))	('dexrazoxane', 'Chemical', 'MESH:D064730', (5, 16))	('cavity size', 'CPA', (240, 251))	('to 9', 'Species', '1214577', (196, 200))	('wall stress', 'CPA', (256, 267))
449480	31297226	Anthracycline chemotherapy can cause dose-dependent cardiotoxicity and children with sarcoma are treated with some of the highest doses of these agents.	('Anthracycline', 'Var', (0, 13))	('Anthracycline', 'Chemical', 'MESH:D018943', (0, 13))	('cardiotoxicity', 'Disease', 'MESH:D066126', (52, 66))	('cardiotoxicity', 'Disease', (52, 66))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('children', 'Species', '9606', (71, 79))	('sarcoma', 'Disease', (85, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
449485	31297226	Anthracyclines are commonly used in the treatment of childhood cancers, but they confer a substantial risk of dose-dependent cardiotoxicity and associated cardiovascular morbidity and mortality.	('cardiotoxicity', 'Disease', 'MESH:D066126', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('cardiotoxicity', 'Disease', (125, 139))	('childhood cancers', 'Disease', 'MESH:C536928', (53, 70))	('childhood cancers', 'Disease', (53, 70))	('cardiovascular morbidity', 'Phenotype', 'HP:0001626', (155, 179))	('Anthracyclines', 'Var', (0, 14))
449535	31297226	Subjects treated with dexrazoxane had slightly lower SF (30.1% vs 33.0%, p=0.025), higher LVIDS (p=0.002), worse circumferential strain (p=0.045), higher meridional ESS (p=0.031) and borderline increased circumferential ESS (p=0.064) in comparison with those not treated with dexrazoxane.	('lower', 'NegReg', (47, 52))	('circumferential strain', 'MPA', (113, 135))	('dexrazoxane', 'Chemical', 'MESH:D064730', (22, 33))	('dexrazoxane', 'Chemical', 'MESH:D064730', (276, 287))	('circumferential', 'MPA', (204, 219))	('LVIDS', 'MPA', (90, 95))	('ESS', 'Chemical', '-', (220, 223))	('worse', 'NegReg', (107, 112))	('ESS', 'Chemical', '-', (165, 168))	('higher', 'PosReg', (147, 153))	('meridional ESS', 'MPA', (154, 168))	('higher', 'PosReg', (83, 89))	('dexrazoxane', 'Var', (22, 33))
449545	31297226	In males, dexrazoxane was associated with an attenuation of the deterioration of circumferential strain by 3.4% early after therapy, without significant effects 1-2 years post-therapy.	('deterioration', 'MPA', (64, 77))	('attenuation', 'NegReg', (45, 56))	('dexrazoxane', 'Chemical', 'MESH:D064730', (10, 21))	('dexrazoxane', 'Var', (10, 21))
449546	31297226	In females, dexrazoxane was associated with an attenuation of the decline in SF (5.7% difference); the increases in LVIDD, LVIDS and wall stress; and the decreases in relative wall thickness early after therapy, and sustained attenuation of the increases in LVIDD and LVIDS 1-2 years post-therapy.	('decline', 'NegReg', (66, 73))	('dexrazoxane', 'Chemical', 'MESH:D064730', (12, 23))	('increases', 'PosReg', (103, 112))	('attenuation', 'NegReg', (47, 58))	('relative wall thickness', 'MPA', (167, 190))	('LVIDD', 'MPA', (116, 121))	('wall stress', 'MPA', (133, 144))	('dexrazoxane', 'Var', (12, 23))	('decreases', 'NegReg', (154, 163))
449560	31297226	Second, we found that changes in cardiac structure and function occurred early after high-dose anthracyclines and persisted to 1-2 years postdoxorubicin.	('anthracyclines', 'Var', (95, 109))	('changes', 'Reg', (22, 29))	('anthracyclines', 'Chemical', 'MESH:D018943', (95, 109))	('postdoxorubicin', 'Chemical', '-', (137, 152))	('cardiac', 'MPA', (33, 40))	('function', 'MPA', (55, 63))
449565	31297226	The mechanisms by which dexrazoxane may provide greater cardioprotection to females have not been established and it is possible that dexrazoxane may mitigate cardiotoxicity similarly in both sexes, but females derive more benefit due to greater underlying susceptibility.	('dexrazoxane', 'Var', (134, 145))	('dexrazoxane', 'Chemical', 'MESH:D064730', (134, 145))	('cardiotoxicity', 'Disease', 'MESH:D066126', (159, 173))	('dexrazoxane', 'Chemical', 'MESH:D064730', (24, 35))	('cardiotoxicity', 'Disease', (159, 173))
449614	27684804	Conversely, identification of the SS18-SSX1 or SS18-SSX2 fusion gene resulting from the chromosomal translocation t (X;18)(p11;q11), first published in 1994, reportedly has a sensitivity of 94% and a specificity of 100% by RT-PCR.	('SSX2', 'Gene', (52, 56))	('SS18', 'Gene', '6760', (34, 38))	('SSX1', 'Gene', (39, 43))	('SSX2', 'Gene', '6757', (52, 56))	('SS18', 'Gene', (47, 51))	('t (X;18)(p11;q11', 'Var', (114, 130))	('SS18', 'Gene', '6760', (47, 51))	('SS18', 'Gene', (34, 38))	('SSX1', 'Gene', '6756', (39, 43))
449662	33564073	Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1.	('eIF4E', 'Gene', (62, 67))	('phosphorylation', 'MPA', (68, 83))	('E2F1', 'Gene', (152, 156))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('represses', 'NegReg', (88, 97))	('FOXM1', 'Gene', (158, 163))	('sarcoma', 'Disease', (112, 119))	('blocks', 'NegReg', (55, 61))	('eIF4E', 'Gene', '1977', (62, 67))	('ETC-168', 'Chemical', '-', (28, 35))	('silencing', 'Var', (17, 26))	('expression', 'MPA', (98, 108))
449663	33564073	Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells.	('antiproliferative activity', 'CPA', (80, 106))	('S63845', 'Chemical', 'MESH:C000614727', (52, 58))	('STS', 'Phenotype', 'HP:0030448', (115, 118))	('S63845', 'Var', (52, 58))	('ETC-168', 'Chemical', '-', (25, 32))	('combination', 'Interaction', (10, 21))
449673	33564073	Mice with either single or double knockout of MNK1 and MNK2 were viable and born without abnormalities.	('double knockout', 'Var', (27, 42))	('MNK1', 'Gene', (46, 50))	('MNK2', 'Gene', (55, 59))	('Mice', 'Species', '10090', (0, 4))
449674	33564073	Consistent with these findings, small-molecule inhibitors targeting MNK1/2 (e.g., CGP57380, BAY1143269, eFT508, and SEL201) demonstrated promising anticancer efficacy and desirable safety.	('BAY1143269', 'Chemical', 'MESH:C000622122', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('BAY1143269', 'Var', (92, 102))	('MNK1/2', 'Gene', (68, 74))	('CGP57380', 'Chemical', 'MESH:C466997', (82, 90))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('CGP57380', 'Gene', (82, 90))
449675	33564073	Among these compounds, CGP57380 is widely used as a tool compound of MNK inhibitor.	('CGP57380', 'Chemical', 'MESH:C466997', (23, 31))	('MNK', 'Gene', (69, 72))	('MNK', 'Gene', '538', (69, 72))	('CGP57380', 'Var', (23, 31))
449676	33564073	BAY1143269 inhibited MNK1 activity and its downstream factors including genes involved in cell cycle, survival, immune response, and epithelial-mesenchymal transition.	('BAY1143269', 'Var', (0, 10))	('epithelial-mesenchymal', 'CPA', (133, 155))	('MNK1', 'Protein', (21, 25))	('immune response', 'CPA', (112, 127))	('cell cycle', 'CPA', (90, 100))	('BAY1143269', 'Chemical', 'MESH:C000622122', (0, 10))	('inhibited', 'NegReg', (11, 20))	('activity', 'MPA', (26, 34))
449677	33564073	MNK1/2 inhibitor eFT508 is currently under clinical trials in hematological malignancies; it also inhibited the translation of PD-L1 in a murine liver cancer model which was driven by MYC and KRAS.	('malignancies', 'Disease', (76, 88))	('inhibited', 'NegReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('translation', 'MPA', (112, 123))	('eFT508', 'Var', (17, 23))	('liver cancer', 'Disease', 'MESH:D006528', (145, 157))	('liver cancer', 'Phenotype', 'HP:0002896', (145, 157))	('MYC', 'Gene', '17869', (184, 187))	('PD-L1', 'Gene', '60533', (127, 132))	('KRAS', 'Gene', (192, 196))	('MYC', 'Gene', (184, 187))	('PD-L1', 'Gene', (127, 132))	('KRAS', 'Gene', '16653', (192, 196))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))	('liver cancer', 'Disease', (145, 157))	('hematological malignancies', 'Phenotype', 'HP:0004377', (62, 88))	('murine', 'Species', '10090', (138, 144))
449689	33564073	In addition, phospho-MNK1 (at Thr197/202, Thr255, and Thr385 sites) and phospho-MNK2 (at Thr249 site) were markedly increased across cancer cells, relative to ASC52telo and HUtSMC cells (Fig.	('Thr385', 'Var', (54, 60))	('Thr197', 'Chemical', '-', (30, 36))	('phospho-MNK1', 'MPA', (13, 25))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('Thr385', 'Chemical', '-', (54, 60))	('Thr255', 'Chemical', '-', (42, 48))	('cancer', 'Disease', (133, 139))	('Thr249', 'Chemical', '-', (89, 95))	('increased', 'PosReg', (116, 125))	('phospho-MNK2', 'MPA', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
449693	33564073	STS cells stably expressing shRNAs against either MNK1 or MNK2 developed significantly smaller xenografts in NOD scid gamma (NSG) mice (Fig.	('mice', 'Species', '10090', (130, 134))	('MNK2', 'Gene', (58, 62))	('STS', 'Phenotype', 'HP:0030448', (0, 3))	('xenografts in', 'CPA', (95, 108))	('smaller', 'NegReg', (87, 94))	('MNK1', 'Var', (50, 54))
449695	33564073	At the dose of 1 muM, ETC-168 achieved desirable inhibition of the kinase activity of MNK1 (58%) and MNK2 (97%), suggesting that ETC-168 acts as a MNK2-biased, dual-MNK inhibitor in cells.	('kinase activity', 'MPA', (67, 82))	('MNK', 'Gene', (86, 89))	('ETC-168', 'Chemical', '-', (22, 29))	('MNK', 'Gene', (165, 168))	('ETC-168', 'Chemical', '-', (129, 136))	('MNK', 'Gene', '538', (101, 104))	('MNK', 'Gene', '538', (147, 150))	('MNK', 'Gene', (101, 104))	('ETC-168', 'Var', (129, 136))	('MNK', 'Gene', '538', (86, 89))	('MNK', 'Gene', '538', (165, 168))	('inhibition', 'NegReg', (49, 59))	('MNK', 'Gene', (147, 150))
449697	33564073	In general, ETC-168 showed a greater potency than the rest of the agents (Fig.	('ETC-168', 'Var', (12, 19))	('ETC-168', 'Chemical', '-', (12, 19))	('potency', 'MPA', (37, 44))
449699	33564073	For instance, in LPS141 and MESSA, ETC-168 induced dose-dependent growth suppression and inhibited 50% of cell viability at a dose of 5 muM, while other inhibitors were less active (Fig.	('ETC-168', 'Var', (35, 42))	('MESSA', 'Chemical', '-', (28, 33))	('inhibited', 'NegReg', (89, 98))	('growth suppression', 'CPA', (66, 84))	('LPS141', 'Chemical', '-', (17, 23))	('ETC-168', 'Chemical', '-', (35, 42))	('LPS', 'Phenotype', 'HP:0012034', (17, 20))
449700	33564073	ETC-168 treatment elicited a consistent increase of cells in G0/G1 phase among LPS141, LP6, and MESSA cells in a dose-dependent manner (Fig.	('LPS141', 'Var', (79, 85))	('cells in G0/G1 phase', 'CPA', (52, 72))	('LP6', 'Chemical', '-', (87, 90))	('MESSA', 'Chemical', '-', (96, 101))	('increase', 'PosReg', (40, 48))	('ETC-168', 'Chemical', '-', (0, 7))	('LPS141', 'Chemical', '-', (79, 85))	('LPS', 'Phenotype', 'HP:0012034', (79, 82))
449704	33564073	Based on IC50 values, LP6 and LPS141 represented ETC-168 sensitive LPS cells, while MESSA, SK-UT-1, and SK-UT-1B served as representative ETC-168 sensitive uterine LMS cells (Fig.	('LMS', 'Phenotype', 'HP:0100243', (164, 167))	('LPS', 'Phenotype', 'HP:0012034', (67, 70))	('LPS', 'Disease', (67, 70))	('SK-UT-1B', 'Chemical', '-', (104, 112))	('LP6', 'Var', (22, 25))	('SK-UT-1', 'Chemical', '-', (104, 111))	('LPS141', 'Chemical', '-', (30, 36))	('LPS', 'Disease', (30, 33))	('LPS', 'Disease', 'MESH:C536528', (67, 70))	('LP6', 'Chemical', '-', (22, 25))	('SK-UT-1', 'Chemical', '-', (91, 98))	('MESSA', 'Chemical', '-', (84, 89))	('ETC-168', 'Chemical', '-', (49, 56))	('LPS', 'Phenotype', 'HP:0012034', (30, 33))	('ETC-168', 'Chemical', '-', (138, 145))	('LPS', 'Disease', 'MESH:C536528', (30, 33))
449708	33564073	Interestingly, inhibition of MNK1/2 by ETC-168 elevated the expression of MNK1/2 at both transcript and protein levels, suggestive of a potential feedback mechanism via which STS cells turn on a compensatory gene expression program upon kinase inhibition (Supplementary Fig.	('ETC-168', 'Gene', (39, 46))	('expression', 'MPA', (60, 70))	('compensatory gene expression program', 'MPA', (195, 231))	('MNK1/2', 'Gene', (74, 80))	('ETC-168', 'Chemical', '-', (39, 46))	('elevated', 'PosReg', (47, 55))	('STS', 'Phenotype', 'HP:0030448', (175, 178))	('inhibition', 'Var', (15, 25))
449710	33564073	However, neither protein nor mRNA level of MCL1 responded to MNK1/2 knockdown in LPS141 cells (Fig.	('MNK1/2', 'Gene', (61, 67))	('LPS141', 'Chemical', '-', (81, 87))	('LPS', 'Phenotype', 'HP:0012034', (81, 84))	('mRNA level', 'MPA', (29, 39))	('knockdown', 'Var', (68, 77))
449711	33564073	Mirroring the phenotypes of genetic silencing, ETC-168 abolished p-4E in both LPS141 and MESSA within 1 h, whereas it reduced MCL1 protein only in MESSA cells independent of transcription (Fig.	('MESSA', 'Chemical', '-', (89, 94))	('MCL1 protein', 'MPA', (126, 138))	('p-4E', 'MPA', (65, 69))	('MESSA', 'Chemical', '-', (147, 152))	('ETC-168', 'Chemical', '-', (47, 54))	('reduced', 'NegReg', (118, 125))	('LPS141', 'Chemical', '-', (78, 84))	('abolished', 'NegReg', (55, 64))	('LPS', 'Phenotype', 'HP:0012034', (78, 81))	('ETC-168', 'Var', (47, 54))
449716	33564073	As a subtype-specific translational target of MNK1/2, MCL1 protein declined upon treatment with ETC-168, eFT508, and 4EGI-1 in MESSA cells but not in LPS141 cells (Fig.	('ETC-168', 'Var', (96, 103))	('eFT508', 'Var', (105, 111))	('MCL1', 'Gene', (54, 58))	('MESSA', 'Chemical', '-', (127, 132))	('declined', 'NegReg', (67, 75))	('LPS141', 'Chemical', '-', (150, 156))	('LPS', 'Phenotype', 'HP:0012034', (150, 153))	('ETC-168', 'Chemical', '-', (96, 103))	('4EGI-1', 'Var', (117, 123))
449717	33564073	Notably, albeit p-4E has been shown as a key factor to enhance oncogenic translation function by MNK1/2, cellular responsiveness of p-4E to MNK kinase inhibitors decoupled from the growth-inhibitory effect of these compounds in STS.	('MNK', 'Gene', (140, 143))	('MNK', 'Gene', '538', (97, 100))	('STS', 'Phenotype', 'HP:0030448', (228, 231))	('MNK', 'Gene', (97, 100))	('enhance', 'PosReg', (55, 62))	('oncogenic translation function', 'MPA', (63, 93))	('MNK', 'Gene', '538', (140, 143))	('p-4E', 'Var', (16, 20))
449718	33564073	At the dose of 30 muM, ETC-168 effectively suppressed both p-4E and cell viability, whereas CGP57380 and eFT508 showed minor impact on cell viability in spite of p-4E inhibition (Figs.	('cell viability', 'CPA', (68, 82))	('ETC-168', 'Chemical', '-', (23, 30))	('inhibition', 'NegReg', (167, 177))	('p-4E', 'MPA', (162, 166))	('CGP57380', 'Chemical', 'MESH:C466997', (92, 100))	('p-4E', 'Enzyme', (59, 63))	('CGP57380', 'Var', (92, 100))	('suppressed', 'NegReg', (43, 53))
449723	33564073	In contrast, p-4E was consistently inhibited by ETC-168 across all tested LPS and ULMS cells (Supplementary Fig.	('ETC-168', 'Var', (48, 55))	('LMS', 'Phenotype', 'HP:0100243', (83, 86))	('LPS', 'Phenotype', 'HP:0012034', (74, 77))	('LPS', 'Disease', (74, 77))	('inhibited', 'NegReg', (35, 44))	('ETC-168', 'Chemical', '-', (48, 55))	('LPS', 'Disease', 'MESH:C536528', (74, 77))
449732	33564073	In contrast, protein levels of E2F1, FOXM1, and WEE1 were downregulated consistently by ETC-168 in drug-sensitive STS cells after 24-h drug incubation (Fig.	('E2F1', 'Gene', (31, 35))	('STS', 'Phenotype', 'HP:0030448', (114, 117))	('ETC-168', 'Chemical', '-', (88, 95))	('FOXM1', 'Gene', (37, 42))	('downregulated', 'NegReg', (58, 71))	('protein levels', 'MPA', (13, 27))	('ETC-168', 'Var', (88, 95))	('WEE1', 'Gene', (48, 52))
449733	33564073	Silencing of MNK1 and MNK2 also cooperatively decreased the abundance of E2F1, FOXM1, and WEE1 proteins in LPS141 cells (Fig.	('MNK2', 'Gene', (22, 26))	('LPS', 'Phenotype', 'HP:0012034', (107, 110))	('MNK1', 'Gene', (13, 17))	('decreased', 'NegReg', (46, 55))	('abundance', 'MPA', (60, 69))	('FOXM1', 'Gene', (79, 84))	('Silencing', 'Var', (0, 9))	('E2F1', 'Protein', (73, 77))	('LPS141', 'Chemical', '-', (107, 113))
449737	33564073	1), depletion of FOXM1, E2F1, and WEE1 attenuated the cell viability and anchorage-independent growth of both LPS141 and MESSA cells (Fig.	('LPS', 'Phenotype', 'HP:0012034', (110, 113))	('E2F1', 'Var', (24, 28))	('attenuated', 'NegReg', (39, 49))	('MESSA', 'Chemical', '-', (121, 126))	('WEE1', 'Gene', (34, 38))	('depletion', 'MPA', (4, 13))	('anchorage-independent growth', 'CPA', (73, 101))	('cell viability', 'CPA', (54, 68))	('LPS141', 'Chemical', '-', (110, 116))	('FOXM1', 'Gene', (17, 22))
449738	33564073	Importantly, silencing of FOXM1 and WEE1 also impaired subcutaneous tumor formation by STS cells (Fig.	('tumor', 'Disease', (68, 73))	('STS', 'Phenotype', 'HP:0030448', (87, 90))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (55, 73))	('impaired', 'NegReg', (46, 54))	('WEE1', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('FOXM1', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('silencing', 'Var', (13, 22))
449739	33564073	Uterine LMS cells were in general more sensitive to ETC-168 than LPS cells (Fig.	('sensitive', 'MPA', (39, 48))	('LPS', 'Phenotype', 'HP:0012034', (65, 68))	('ETC-168', 'Var', (52, 59))	('LMS', 'Phenotype', 'HP:0100243', (8, 11))	('LPS', 'Disease', 'MESH:C536528', (65, 68))	('ETC-168', 'Chemical', '-', (52, 59))	('LPS', 'Disease', (65, 68))
449742	33564073	Remarkably, pharmacological inhibition of MCL1 by S63845, a small molecule with high binding affinity to the BH3-binding groove of MCL1, potently inhibited the viability of MESSA, LPS141, and LP6 cells with IC50 values of 0.96, 0.25, and 0.26 muM, respectively (Supplementary Fig.	('binding', 'Interaction', (85, 92))	('LP6', 'Chemical', '-', (192, 195))	('LPS', 'Phenotype', 'HP:0012034', (180, 183))	('BH3', 'Chemical', 'MESH:C006008', (109, 112))	('LPS141', 'Chemical', '-', (180, 186))	('S63845', 'Chemical', 'MESH:C000614727', (50, 56))	('viability', 'CPA', (160, 169))	('inhibited', 'NegReg', (146, 155))	('MESSA', 'Chemical', '-', (173, 178))	('S63845', 'Var', (50, 56))	('MCL1', 'Gene', (131, 135))
449744	33564073	In de-differentiated LPS cells, S63845 and ETC-168 exhibited a strong, synergistic growth-inhibitory effect in vitro, as evidenced by a Sum Bliss Score above 240 in both LPS141 and LP6 cells (Fig.	('LPS', 'Disease', 'MESH:C536528', (21, 24))	('LPS', 'Disease', 'MESH:C536528', (170, 173))	('LPS141', 'Chemical', '-', (170, 176))	('LP6', 'Chemical', '-', (181, 184))	('S63845', 'Chemical', 'MESH:C000614727', (32, 38))	('ETC-168', 'Chemical', '-', (43, 50))	('LPS', 'Phenotype', 'HP:0012034', (170, 173))	('LPS', 'Disease', (170, 173))	('S63845', 'Var', (32, 38))	('LPS', 'Phenotype', 'HP:0012034', (21, 24))	('LPS', 'Disease', (21, 24))	('synergistic growth-inhibitory effect', 'MPA', (71, 107))
449746	33564073	Co-treatment of S63845 and ETC-168 induced pronounced cleavage of Poly (ADP-Ribose) Polymerase 1 (PARP1) and Caspase 3 in LPS141, LP6, and MESSA cells, indicative of an enhanced apoptotic cell death (Fig.	('Poly (ADP-Ribose) Polymerase 1', 'Gene', '142', (66, 96))	('death', 'Disease', 'MESH:D003643', (193, 198))	('death', 'Disease', (193, 198))	('Poly (ADP-Ribose) Polymerase 1', 'Gene', (66, 96))	('LPS141', 'Chemical', '-', (122, 128))	('ETC-168', 'Gene', (27, 34))	('S63845', 'Chemical', 'MESH:C000614727', (16, 22))	('PARP1', 'Gene', '142', (98, 103))	('Caspase', 'Protein', (109, 116))	('MESSA', 'Chemical', '-', (139, 144))	('PARP1', 'Gene', (98, 103))	('S63845', 'Var', (16, 22))	('LPS', 'Phenotype', 'HP:0012034', (122, 125))	('ETC-168', 'Chemical', '-', (27, 34))	('cleavage', 'MPA', (54, 62))	('LP6', 'Chemical', '-', (130, 133))
449748	33564073	Hence, inhibition of MCL1 augments the efficacy of ETC-168 in MNK1/2 inhibitor-responsive STS cells in vitro.	('efficacy', 'MPA', (39, 47))	('MCL1', 'Gene', (21, 25))	('inhibition', 'Var', (7, 17))	('augments', 'PosReg', (26, 34))	('STS', 'Phenotype', 'HP:0030448', (90, 93))	('ETC-168', 'Chemical', '-', (51, 58))
449752	33564073	Echoing our observations made from in vitro treatment, ETC-168 treatment strongly inhibited p-4E in tumor grafts, while S63845 treatment stabilized MCL1 (Fig.	('S63845', 'Var', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('p-4E', 'Enzyme', (92, 96))	('inhibited', 'NegReg', (82, 91))	('tumor', 'Disease', (100, 105))	('ETC-168', 'Gene', (55, 62))	('S63845', 'Chemical', 'MESH:C000614727', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('ETC-168', 'Chemical', '-', (55, 62))
449753	33564073	Single agent treatment with S63845 triggered a modest induction of cleaved-PARP, while combination of ETC-168 and S63845 exerted a robust synergy in activating the expression of both cleaved-PARP and cleaved-Caspase 3.	('PARP', 'Gene', '142', (191, 195))	('S63845', 'Var', (28, 34))	('PARP', 'Gene', (75, 79))	('expression', 'MPA', (164, 174))	('S63845', 'Chemical', 'MESH:C000614727', (114, 120))	('activating', 'MPA', (149, 159))	('S63845', 'Chemical', 'MESH:C000614727', (28, 34))	('ETC-168', 'Chemical', '-', (102, 109))	('S63845', 'Var', (114, 120))	('PARP', 'Gene', '142', (75, 79))	('PARP', 'Gene', (191, 195))	('ETC-168', 'Var', (102, 109))
449754	33564073	These data indicate a promising bioavailability and in vivo activity of ETC-168/S63845 combo in tumor-bearing mice, providing valuable insights for follow-up studies of developing optimal delivery strategy, as well as improving dosing and schedule of drug treatment.	('bioavailability', 'MPA', (32, 47))	('S63845', 'Chemical', 'MESH:C000614727', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('mice', 'Species', '10090', (110, 114))	('activity', 'MPA', (60, 68))	('ETC-168', 'Chemical', '-', (72, 79))	('ETC-168/S63845', 'Var', (72, 86))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
449761	33564073	Since loss of MNK1/2 can be tolerated by normal cells, MNK1/2 are desirable cancer targets for pharmacologic inhibition.	('loss', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('MNK1/2', 'Gene', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
449763	33564073	Several small-molecule inhibitors against MNK1/2 kinase activity have been developed including CGP57380, eFT508, BAY1143269, and SEL201.	('CGP57380', 'Chemical', 'MESH:C466997', (95, 103))	('BAY1143269', 'Chemical', 'MESH:C000622122', (113, 123))	('CGP57380', 'Var', (95, 103))	('MNK1/2', 'Enzyme', (42, 48))	('BAY1143269', 'Var', (113, 123))
449765	33564073	Our comparative evaluation of ETC-168, CGP57380, and eFT508 revealed a superior antiproliferative efficacy of ETC-168 against STS cells.	('antiproliferative efficacy', 'CPA', (80, 106))	('ETC-168', 'Var', (110, 117))	('ETC-168', 'Chemical', '-', (30, 37))	('CGP57380', 'Chemical', 'MESH:C466997', (39, 47))	('superior', 'PosReg', (71, 79))	('STS', 'Phenotype', 'HP:0030448', (126, 129))	('ETC-168', 'Chemical', '-', (110, 117))
449769	33564073	Inhibition of MNK1/2-eIF4E showed a limited impact on protein synthesis of MCL1 in LPS cells.	('LPS', 'Disease', (83, 86))	('LPS', 'Phenotype', 'HP:0012034', (83, 86))	('protein synthesis', 'MPA', (54, 71))	('eIF4E', 'Gene', '1977', (21, 26))	('LPS', 'Disease', 'MESH:C536528', (83, 86))	('Inhibition', 'Var', (0, 10))	('eIF4E', 'Gene', (21, 26))
449771	33564073	The differential kinetics and strength of cleaved-PARP and cleaved-Caspase 3 between LP6 and LPS141 in response to ETC-168/S63845 combo (Fig.	('ETC-168', 'Chemical', '-', (115, 122))	('LPS141', 'Chemical', '-', (93, 99))	('LPS', 'Phenotype', 'HP:0012034', (93, 96))	('cleaved-Caspase 3', 'Enzyme', (59, 76))	('PARP', 'Gene', '142', (50, 54))	('S63845', 'Chemical', 'MESH:C000614727', (123, 129))	('ETC-168/S63845 combo', 'Var', (115, 135))	('PARP', 'Gene', (50, 54))	('LP6', 'Chemical', '-', (85, 88))
449784	33564073	Sarcoma cells with high expression of both MNK1 and MNK2 (e.g., LPS141, LP6, MLS402, MESSA, SK-UT-1, SK-UT-1B, and T778) were more responsive to MNK inhibitors (Fig.	('MNK', 'Gene', '538', (52, 55))	('LP6', 'Var', (72, 75))	('MESSA', 'Chemical', '-', (85, 90))	('Sarcoma', 'Disease', (0, 7))	('LP6', 'Chemical', '-', (72, 75))	('MNK', 'Gene', '538', (43, 46))	('SK-UT-1B', 'Chemical', '-', (101, 109))	('SK-UT-1', 'Chemical', '-', (101, 108))	('LPS', 'Phenotype', 'HP:0012034', (64, 67))	('SK-UT-1', 'Chemical', '-', (92, 99))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('MLS402', 'Var', (77, 83))	('LPS141', 'Chemical', '-', (64, 70))	('MNK', 'Gene', (145, 148))	('MNK', 'Gene', (52, 55))	('more', 'PosReg', (126, 130))	('MNK', 'Gene', (43, 46))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('MNK', 'Gene', '538', (145, 148))
449804	33564073	LMS cell lines (Shef-LMS01-w1, Shef-LMS01-ws), alveolar RMS cell line RH5 and all LPS cell lines were maintained in Roswell Park Memorial Institute medium 1640 (RPMI-1640, Biowest).	('LMS', 'Phenotype', 'HP:0100243', (0, 3))	('LPS', 'Disease', 'MESH:C536528', (82, 85))	('Shef-LMS01-ws', 'Var', (31, 44))	('LMS01', 'CellLine', 'CVCL:0628', (36, 41))	('RMS', 'Phenotype', 'HP:0002859', (56, 59))	('LPS', 'Disease', (82, 85))	('LMS', 'Phenotype', 'HP:0100243', (36, 39))	('LPS', 'Phenotype', 'HP:0012034', (82, 85))	('LMS01', 'CellLine', 'CVCL:0628', (21, 26))	('LMS', 'Phenotype', 'HP:0100243', (21, 24))
449809	33564073	ETC-168 was kindly provided by Experimental Drug Development Centre (EDDC), A*STAR, Singapore; CGP57380, eFT508, 4EGI-1, Cycloheximide, and S63845 were purchased from Abcam, MedChemExpress, Tocris Bioscience, Sigma-Aldrich, and Chemietek, respectively.	('S63845', 'Var', (140, 146))	('Cycloheximide', 'Chemical', 'MESH:D003513', (121, 134))	('CGP57380', 'Chemical', 'MESH:C466997', (95, 103))	('ETC-168', 'Chemical', '-', (0, 7))	('CGP57380', 'Var', (95, 103))	('S63845', 'Chemical', 'MESH:C000614727', (140, 146))
449857	33588810	Among fourteen patients with the lesion at the tubular long bones, typical osteolytic destruction appeared with the lesion in two patients having mesh-like or moth-eaten destruction within the medullary cavity, and the other 12 patients had lytic destruction with varying sizes and ill-defined margins (Figs.	('osteolytic destruction', 'Phenotype', 'HP:0002797', (75, 97))	('patients', 'Species', '9606', (15, 23))	('lytic destruction', 'CPA', (241, 258))	('patients', 'Species', '9606', (228, 236))	('osteolytic destruction', 'CPA', (75, 97))	('patients', 'Species', '9606', (130, 138))	('lesion at the tubular long bones', 'Phenotype', 'HP:0011314', (33, 65))	('lesion', 'Var', (116, 122))
78409	31885956	JAK2 V617F mutation was negative.	('V617F', 'SUBSTITUTION', 'None', (5, 10))	('JAK2', 'Gene', '3717', (0, 4))	('JAK2', 'Gene', (0, 4))	('V617F', 'Var', (5, 10))
449956	31485411	T315I-mutated myeloid sarcoma Myeloid Sarcoma (MS) is diagnosed by an extramedullary proliferation of immature granulocytic cells.	('Sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (14, 29))	('T315I', 'Mutation', 'rs121913459', (0, 5))	('Myeloid Sarcoma', 'Disease', (30, 45))	('Myeloid Sarcoma', 'Disease', 'MESH:D023981', (30, 45))	('myeloid sarcoma', 'Disease', (14, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('T315I-mutated', 'Var', (0, 13))
449958	31485411	CML is characterized by BCR-ABL1 gene rearrangement and therapies with tyrosine kinase inhibitors (TKI) are very effective.	('BCR-ABL1', 'Gene', (24, 32))	('rearrangement', 'Var', (38, 51))	('CML', 'Disease', 'MESH:D015464', (0, 3))	('BCR-ABL1', 'Gene', '613;25', (24, 32))	('CML', 'Phenotype', 'HP:0005506', (0, 3))	('CML', 'Disease', (0, 3))
449959	31485411	However, TKI resistance may occur secondary to the development of ABL1 mutations.	('mutations', 'Var', (71, 80))	('ABL1', 'Gene', (66, 70))	('TKI resistance', 'Disease', (9, 23))	('ABL1', 'Gene', '25', (66, 70))
449961	31485411	We report the first case of a patient with T315I mutated myeloid sarcoma that occurred after complete cytogenetic response with dasatinib of a chronic phase CML.	('T315I', 'Mutation', 'rs121913459', (43, 48))	('patient', 'Species', '9606', (30, 37))	('CML', 'Disease', 'MESH:D015464', (157, 160))	('CML', 'Phenotype', 'HP:0005506', (157, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('CML', 'Disease', (157, 160))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (57, 72))	('T315I mutated', 'Var', (43, 56))	('dasatinib', 'Chemical', 'MESH:D000069439', (128, 137))	('myeloid sarcoma', 'Disease', (57, 72))
449968	31485411	Threonine-to-isoleucine exchange at amino acid position 315 (T315I) can lead to resistance to most TKIs, and is only sensitive to ponatinib.	('resistance', 'MPA', (80, 90))	('T315I', 'Var', (61, 66))	('T315I', 'Mutation', 'rs121913459', (61, 66))	('ponatinib', 'Chemical', 'MESH:C545373', (130, 139))	('Threonine-to-isoleucine exchange at amino acid position 315', 'Mutation', 'rs121913459', (0, 59))	('lead to', 'Reg', (72, 79))	('Threonine-to-isoleucine', 'Var', (0, 23))	('TKIs', 'MPA', (99, 103))
449972	31485411	Here, we report a case of T315I-mutated MS that occurred after pre-existing chronic phase CML had a complete cytogenetic response in BM with Dasatinib treatment.	('Dasatinib', 'Chemical', 'MESH:D000069439', (141, 150))	('T315I', 'Mutation', 'rs121913459', (26, 31))	('CML', 'Disease', 'MESH:D015464', (90, 93))	('T315I-mutated', 'Var', (26, 39))	('CML', 'Phenotype', 'HP:0005506', (90, 93))	('CML', 'Disease', (90, 93))
449974	31485411	Bone marrow (BM) biopsy report showed chronic phase CML with Philadelphia chromosome positive cells containing 46,XY,t(8:17)(p21;q25),t(9;22)(q34;q11.2) by karyotype in 20/20 cells.	('CML', 'Disease', (52, 55))	('t(8:17)(p21;q25', 'Var', (117, 132))	('46,XY,t(8:17)(p21;q25),t(9;22)(q34;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (111, 152))	('CML', 'Disease', 'MESH:D015464', (52, 55))	('t(9;22)(q34;q11.2', 'Var', (134, 151))	('CML', 'Phenotype', 'HP:0005506', (52, 55))
449977	31485411	Fluorescence in situ hybridization (FISH) was performed and positive for BCR/ABL1 gene rearrangement in 55% interphased cells identified.	('BCR', 'Gene', (73, 76))	('BCR', 'Gene', '613', (73, 76))	('rearrangement', 'Var', (87, 100))	('ABL1', 'Gene', '25', (77, 81))	('ABL1', 'Gene', (77, 81))
449978	31485411	BCR/ABL1 major (p210) fusion transcript was 296% International Scale (IS) by reverse transcriptase-polymerase chain reaction (RT-PCR) quantification analysis, while p190 transcripts were not detected.	('BCR/ABL1 major', 'Gene', '613', (0, 14))	('p210', 'Var', (16, 20))	('BCR/ABL1 major', 'Gene', (0, 14))	('p190', 'Gene', (165, 169))	('p190', 'Gene', '8506', (165, 169))
449986	31485411	Next generation sequencing (NGS) using a commercial panel (Foundation One Heme) on the bone biopsy revealed an unexpected T315I mutation in a p190 BCR-ABL1 fusion transcript with mutation allele frequency of 31.5% as well as ETV6-BCR fusion.	('T315I', 'Var', (122, 127))	('p190', 'Gene', (142, 146))	('BCR', 'Gene', '613', (230, 233))	('BCR-ABL1', 'Gene', '613;25', (147, 155))	('T315I', 'Mutation', 'rs121913459', (122, 127))	('ETV6', 'Gene', '2120', (225, 229))	('ETV6', 'Gene', (225, 229))	('BCR-ABL1', 'Gene', (147, 155))	('BCR', 'Gene', (230, 233))	('BCR', 'Gene', (147, 150))	('BCR', 'Gene', '613', (147, 150))	('p190', 'Gene', '8506', (142, 146))
449995	31485411	T315I mutation is a single base substitution act>att resulting in a threonine-to-isoleucine exchange at amino acid position 315 on BCR-ABL1 kinase domain.	('T315I', 'Var', (0, 5))	('threonine-to-isoleucine exchange at amino acid position 315', 'Mutation', 'rs121913459', (68, 127))	('BCR-ABL1', 'Gene', (131, 139))	('T315I', 'Mutation', 'rs121913459', (0, 5))	('threonine-to-isoleucine', 'MPA', (68, 91))	('BCR-ABL1', 'Gene', '613;25', (131, 139))
449996	31485411	This threonine controls the access of the inhibitors to the active site, acting as a gate keeper, so its substitution to isoleucine leads to the lack of activity by the tyrosine kinase inhibitors.	('substitution', 'Var', (105, 117))	('isoleucine', 'Chemical', 'MESH:D007532', (121, 131))	('tyrosine', 'Enzyme', (169, 177))	('threonine', 'Chemical', 'MESH:D013912', (5, 14))	('lack', 'NegReg', (145, 149))	('activity', 'MPA', (153, 161))
449997	31485411	T315I mutation has been well reported in CML and B-cell acute lymphoblastic leukemia.	('CML', 'Disease', 'MESH:D015464', (41, 44))	('lymphoblastic leukemia', 'Disease', (62, 84))	('CML', 'Phenotype', 'HP:0005506', (41, 44))	('T315I', 'Mutation', 'rs121913459', (0, 5))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (56, 84))	('T315I mutation', 'Var', (0, 14))	('CML', 'Disease', (41, 44))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (62, 84))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (62, 84))
450001	31485411	Despite this finding, the patient was later diagnosed with an isolated T315I mutated myeloid sarcoma of his femur.	('patient', 'Species', '9606', (26, 33))	('T315I', 'Mutation', 'rs121913459', (71, 76))	('myeloid sarcoma', 'Disease', (85, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('isolated T315I mutated', 'Var', (62, 84))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (85, 100))
450006	31485411	In our case, MS cells with p190 transcript Ph chromosome by NGS likely emerge after TKI therapy, and subsequently or simultaneously acquired T315I mutation, leading to resistance.	('p190', 'Gene', (27, 31))	('T315I mutation', 'Var', (141, 155))	('T315I', 'Mutation', 'rs121913459', (141, 146))	('p190', 'Gene', '8506', (27, 31))
450009	31485411	ETV6 alterations result in loss of the N-terminal pointed oligomerization domain and/or the ETS DNA-binding domain, which were predicted to be inactivating.	('N-terminal pointed oligomerization domain', 'MPA', (39, 80))	('ETS DNA-binding domain', 'MPA', (92, 114))	('ETV6', 'Gene', '2120', (0, 4))	('alterations', 'Var', (5, 16))	('loss', 'NegReg', (27, 31))	('ETV6', 'Gene', (0, 4))
450013	31485411	To our best knowledge, this is the first case report that describes the T315I mutated MS as a clonal and unique form of progression in a patient with CP-CML with otherwise adequate disease control by Dasatinib.	('Dasatinib', 'Chemical', 'MESH:D000069439', (200, 209))	('patient', 'Species', '9606', (137, 144))	('CP-CML', 'Disease', (150, 156))	('T315I', 'Var', (72, 77))	('CP-CML', 'Disease', 'MESH:D015464', (150, 156))	('T315I', 'Mutation', 'rs121913459', (72, 77))	('CML', 'Phenotype', 'HP:0005506', (153, 156))
450052	30322385	KRAS mutation in secondary malignant histiocytosis arising from low grade follicular lymphoma Transformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur.	('classic Hodgkin lymphoma', 'Disease', 'MESH:D006689', (234, 258))	('secondary malignant histiocytosis', 'Disease', (17, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (250, 258))	('histiocytosis', 'Phenotype', 'HP:0100727', (37, 50))	('classic Hodgkin lymphoma', 'Disease', (234, 258))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (171, 186))	('lymphoma', 'Disease', (123, 131))	('lymphoma', 'Disease', (178, 186))	('lymphoma', 'Disease', 'MESH:D008223', (178, 186))	('lymphoma', 'Disease', (85, 93))	('lymphoma', 'Disease', 'MESH:D008223', (123, 131))	('lymphoma', 'Disease', 'MESH:D008223', (85, 93))	('lymphoma', 'Disease', (250, 258))	('KRAS', 'Gene', '3845', (0, 4))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (171, 186))	('lymphoma', 'Disease', 'MESH:D008223', (250, 258))	('follicular lymphoma', 'Disease', 'MESH:D008224', (112, 131))	('KRAS', 'Gene', (0, 4))	('B-cell lymphoma', 'Disease', (171, 186))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (242, 258))	('follicular lymphoma', 'Disease', 'MESH:D008224', (74, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (178, 186))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('lymphoma', 'Phenotype', 'HP:0002665', (85, 93))	('follicular lymphoma', 'Disease', (112, 131))	('mutation', 'Var', (5, 13))	('follicular lymphoma', 'Disease', (74, 93))
450055	30322385	FISH analysis confirmed the presence of IgH/BCL2 rearrangement in both the low grade follicular lymphoma (FL) and transformed Langerhans cells sarcoma (LCS) samples, demonstrating a clonal relationship.	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('follicular lymphoma', 'Disease', 'MESH:D008224', (85, 104))	('Langerhans cells sarcoma', 'Disease', 'MESH:D054752', (126, 150))	('Langerhans cells sarcoma', 'Disease', (126, 150))	('rearrangement', 'Var', (49, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('follicular lymphoma', 'Disease', (85, 104))	('IgH/BCL2', 'Gene', (40, 48))
450056	30322385	Comparative whole exome sequencing was then performed, which identified a KRAS p.G13D mutation in the LCS that was not present in the FL.	('p.G13D', 'Mutation', 'rs112445441', (79, 85))	('LCS', 'Gene', (102, 105))	('KRAS p.G13D', 'Var', (74, 85))
450100	30322385	The shared CREBBP mutation (NM_001079846:exon29:c.4920_4922del:p.1640_1641del) has a VAF lower than other shared variants (0.31 in FL and 0.23 in LCS), and may represent a shared somatically acquired driver mutation.	('lower', 'NegReg', (89, 94))	('exon29:c.4920_4922del', 'Var', (41, 62))	('CREBBP', 'Gene', '1387', (11, 17))	('VAF', 'MPA', (85, 88))	('exon29:c.4920_4922del', 'DELETION', 'None', (41, 62))	('p.1640_1641del', 'Mutation', 'p.1640_1641del', (63, 77))	('CREBBP', 'Gene', (11, 17))	('p.1640_1641del', 'Var', (63, 77))
450102	30322385	Included among these variants were KMT2D p.R5097* and BCL2 p.S203 N, which have been previously identified in FL.	('p.S203 N', 'Mutation', 'rs377753316', (59, 67))	('p.R5097*', 'Var', (41, 49))	('p.R5097*', 'Mutation', 'p.R5097*', (41, 49))	('KMT2D', 'Gene', '8085', (35, 40))	('p.S203 N', 'Var', (59, 67))	('BCL2', 'Gene', (54, 58))	('KMT2D', 'Gene', (35, 40))
450107	30322385	However, there were no significant abnormalities identified in the Langerhans cell sarcoma sample with the exception of KRAS p. G13D and a CNV gain on chromosome 22q11.23, which was also observed in the follicular lymphoma sample (Table 3).	('Langerhans cell sarcoma', 'Disease', (67, 90))	('G13D', 'Var', (128, 132))	('CNV gain', 'Disease', 'MESH:D015430', (139, 147))	('lymphoma', 'Phenotype', 'HP:0002665', (214, 222))	('follicular lymphoma', 'Disease', 'MESH:D008224', (203, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('follicular lymphoma', 'Disease', (203, 222))	('Langerhans cell sarcoma', 'Disease', 'MESH:D054752', (67, 90))	('CNV gain', 'Disease', (139, 147))	('G13D', 'SUBSTITUTION', 'None', (128, 132))
450109	30322385	Our patient's pathologic studies include a wide range of morphologic variation in the neoplastic clone, ranging from low grade FL to DLBCL to later on, LCS.	('patient', 'Species', '9606', (4, 11))	('LCS', 'Disease', (152, 155))	('DLBCL', 'Disease', (133, 138))	('low grade', 'Var', (117, 126))
450112	30322385	The reason for the absence of clonal IgH rearrangement in the LCS sample is not entirely clear, but could be due to additional genetic alterations affecting the specific binding of the PCR primers or decreased assay sensitivity in formalin fixed tissue.	('formalin', 'Chemical', 'MESH:D005557', (231, 239))	('assay', 'MPA', (210, 215))	('specific binding', 'Interaction', (161, 177))	('affecting', 'Reg', (147, 156))	('alterations', 'Var', (135, 146))	('decreased', 'NegReg', (200, 209))	('genetic alterations', 'Var', (127, 146))
450115	30322385	The shared CREBBP mutation (NM_001079846:exon29:c.4920_4922del:p.1640_1641del) is an interesting finding.	('exon29:c.4920_4922del', 'Var', (41, 62))	('CREBBP', 'Gene', '1387', (11, 17))	('exon29:c.4920_4922del', 'DELETION', 'None', (41, 62))	('p.1640_1641del', 'Mutation', 'p.1640_1641del', (63, 77))	('CREBBP', 'Gene', (11, 17))	('p.1640_1641del', 'Var', (63, 77))
450116	30322385	CREBBP mutations, particularly mutations of the acetyltransferase domain, has been implicated as an early driver event in follicular lymphoma.	('mutations', 'Var', (31, 40))	('follicular lymphoma', 'Disease', 'MESH:D008224', (122, 141))	('CREBBP', 'Gene', (0, 6))	('follicular lymphoma', 'Disease', (122, 141))	('CREBBP', 'Gene', '1387', (0, 6))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('acetyltransferase', 'Enzyme', (48, 65))
450117	30322385	Although the specific CREBBP mutation that we have detected in this case has not been previously reported in COSMIC database, it does occur within this functional acetyltransferase domain (p.1342-p.1649).	('p.1342-p.1649', 'Var', (189, 202))	('CREBBP', 'Gene', '1387', (22, 28))	('CREBBP', 'Gene', (22, 28))
450119	30322385	The additional SNP microarray results also suggest that the LCS likely originated from an earlier follicular lymphoma with t(14;18).	('follicular lymphoma', 'Disease', 'MESH:D008224', (98, 117))	('LCS', 'Disease', (60, 63))	('follicular lymphoma', 'Disease', (98, 117))	('lymphoma', 'Phenotype', 'HP:0002665', (109, 117))	('originated from', 'Reg', (71, 86))	('t(14;18', 'Var', (123, 130))
450124	30322385	RAS mutations have been implicated in a number of hematologic malignancies, with NRAS mutations being more prevalent than KRAS mutations, particularly in myeloid neoplasms.	('mutations', 'Var', (86, 95))	('prevalent', 'Reg', (107, 116))	('RAS', 'Gene', (0, 3))	('hematologic malignancies', 'Disease', 'MESH:D019337', (50, 74))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (154, 171))	('NRAS', 'Gene', (81, 85))	('hematologic malignancies', 'Disease', (50, 74))	('neoplasm', 'Phenotype', 'HP:0002664', (162, 170))	('neoplasms', 'Phenotype', 'HP:0002664', (162, 171))	('implicated', 'Reg', (24, 34))	('mutations', 'Var', (4, 13))	('myeloid neoplasms', 'Disease', (154, 171))	('NRAS', 'Gene', '4893', (81, 85))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (154, 171))
450125	30322385	RAS-MAPK alterations have also been frequently described in hairy cell leukemia and multiple myeloma, but are more rarely seen in other lymphoproliferative disorders, such as diffuse large B-cell lymphoma.	('hairy cell leukemia', 'Disease', (60, 79))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (189, 204))	('lymphoproliferative disorders', 'Disease', 'MESH:D008232', (136, 165))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (60, 79))	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (136, 165))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (189, 204))	('B-cell lymphoma', 'Disease', (189, 204))	('alterations', 'Var', (9, 20))	('lymphoma', 'Phenotype', 'HP:0002665', (196, 204))	('multiple myeloma', 'Disease', 'MESH:D009101', (84, 100))	('described', 'Reg', (47, 56))	('multiple myeloma', 'Phenotype', 'HP:0006775', (84, 100))	('multiple myeloma', 'Disease', (84, 100))	('lymphoproliferative disorders', 'Disease', (136, 165))	('RAS-MAPK', 'Gene', (0, 8))
450126	30322385	In studies analyzing mutational profiles of follicular lymphoma, a pathogenic role for RAS mutation in the development of follicular lymphoma has not been described, although it has been reported as a rare event in cases of histologic transformation.	('follicular lymphoma', 'Disease', (44, 63))	('mutation', 'Var', (91, 99))	('follicular lymphoma', 'Disease', 'MESH:D008224', (122, 141))	('follicular lymphoma', 'Disease', (122, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (55, 63))	('follicular lymphoma', 'Disease', 'MESH:D008224', (44, 63))
450127	30322385	In a study of 55 primary DLBCL samples, KRAS p.G13D mutation was identified in 2 cases, thus is it possible that RAS mutations could drive the pathogenesis of a relatively rare subset of primary and secondary DLBCL.	('drive', 'Reg', (133, 138))	('mutations', 'Var', (117, 126))	('p.G13D', 'Mutation', 'rs112445441', (45, 51))
450132	30322385	A recent abstract presentation retrospectively reviewed cases of histiocytic sarcomas and discovered RAS/MAPK mutations in 44% (n = 8) of cases.	('mutations', 'Var', (110, 119))	('sarcomas', 'Disease', (77, 85))	('histiocytic sarcoma', 'Disease', (65, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('RAS/MAPK', 'Gene', (101, 109))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (65, 84))
450134	30322385	Some of the cases of histiocytic sarcoma also possessed mutations that are common in B-cell lymphoma (such as MYD88, SOCS1, KMT2D, ARID1A) and furthermore, a subset of patients with histiocytic sarcoma had concurrent or prior history of B-cell lymphoma, including follicular lymphoma, which raised the possibility of transdifferentiation.	('SOCS1', 'Gene', (117, 122))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (237, 252))	('ARID1A', 'Gene', '8289', (131, 137))	('follicular lymphoma', 'Disease', (264, 283))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (85, 100))	('mutations', 'Var', (56, 65))	('B-cell lymphoma', 'Disease', (237, 252))	('KMT2D', 'Gene', '8085', (124, 129))	('histiocytic sarcoma', 'Disease', (182, 201))	('MYD88', 'Gene', '4615', (110, 115))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (85, 100))	('B-cell lymphoma', 'Disease', (85, 100))	('SOCS1', 'Gene', '8651', (117, 122))	('histiocytic sarcoma', 'Disease', (21, 40))	('MYD88', 'Gene', (110, 115))	('lymphoma', 'Phenotype', 'HP:0002665', (244, 252))	('lymphoma', 'Phenotype', 'HP:0002665', (275, 283))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (182, 201))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (237, 252))	('KMT2D', 'Gene', (124, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('follicular lymphoma', 'Disease', 'MESH:D008224', (264, 283))	('patients', 'Species', '9606', (168, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('ARID1A', 'Gene', (131, 137))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (21, 40))
450135	30322385	This suggests that RAS/MAPK mutations are actually quite common in histiocytic neoplasms, even some that may be secondary to B-cell lymphoma, and that given their prevalence, may actively participate in driving this disease process.	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('neoplasms', 'Disease', (79, 88))	('neoplasm', 'Phenotype', 'HP:0002664', (79, 87))	('B-cell lymphoma', 'Disease', (125, 140))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (125, 140))	('neoplasms', 'Disease', 'MESH:D009369', (79, 88))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (125, 140))	('participate', 'Reg', (188, 199))	('common', 'Reg', (57, 63))	('neoplasms', 'Phenotype', 'HP:0002664', (79, 88))	('RAS/MAPK', 'Gene', (19, 27))	('mutations', 'Var', (28, 37))
450137	30322385	Recent mouse models have demonstrated that expression of KRAS p.G12D mutation in lung myeloid cells induce the development of pulmonary Langerhans cell histiocytosis (LCH).	('p.G12D', 'Mutation', 'rs121913529', (62, 68))	('pulmonary Langerhans', 'Disease', 'MESH:C538636', (126, 146))	('mouse', 'Species', '10090', (7, 12))	('KRAS p.G12D', 'Var', (57, 68))	('histiocytosis', 'Phenotype', 'HP:0100727', (152, 165))	('pulmonary Langerhans', 'Disease', (126, 146))	('induce', 'PosReg', (100, 106))
450138	30322385	NRAS p.Q61K mutations have also been reported at higher frequency in cases of pulmonary LCH, but have not thus far been seen in non-pulmonary cases.	('p.Q61K', 'Var', (5, 11))	('p.Q61K', 'Mutation', 'rs121913254', (5, 11))	('NRAS', 'Gene', (0, 4))	('pulmonary LCH', 'Disease', (78, 91))	('NRAS', 'Gene', '4893', (0, 4))
450139	30322385	A study of 61 cases of non-pulmonary LCH reported BRAF V600E mutations in half of cases, also detected several other point mutations including TP53 p.R175H, KRAS p.G13D and MET p.E168D.	('p.R175H', 'Var', (148, 155))	('TP53', 'Gene', (143, 147))	('p.G13D', 'Mutation', 'rs112445441', (162, 168))	('non-pulmonary', 'Disease', (23, 36))	('BRAF', 'Gene', (50, 54))	('p.E168D', 'Mutation', 'p.E168D', (177, 184))	('p.R175H', 'Mutation', 'rs28934578', (148, 155))	('V600E', 'Mutation', 'rs113488022', (55, 60))	('TP53', 'Gene', '7157', (143, 147))	('KRAS p.G13D', 'Var', (157, 168))	('BRAF', 'Gene', '673', (50, 54))	('MET p.E168D', 'Var', (173, 184))
450142	30322385	Activating mutations in BRAF other than V600E have also been detected in LCH.	('LCH', 'Disease', (73, 76))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('V600E', 'Var', (40, 45))
450143	30322385	Furthermore, cases without BRAF V600E mutation have demonstrated a high prevalence of somatic MAP2K1 mutation, which are mutually exclusive with BRAF mutations.	('BRAF', 'Gene', (145, 149))	('MAP2K1', 'Gene', (94, 100))	('V600E', 'Mutation', 'rs113488022', (32, 37))	('BRAF', 'Gene', '673', (27, 31))	('V600E', 'Var', (32, 37))	('BRAF', 'Gene', (27, 31))	('mutation', 'Var', (101, 109))	('MAP2K1', 'Gene', '5604', (94, 100))	('BRAF', 'Gene', '673', (145, 149))
450146	30322385	Interestingly, a recent report of histiocytic sarcoma transdifferentiation from B-lymphoblastic leukemia demonstrated NRAS p.G12D mutation, further suggesting RAS pathway alterations may be important in the transdifferentiation process.	('histiocytic sarcoma', 'Disease', (34, 53))	('B-lymphoblastic leukemia', 'Disease', 'MESH:D015456', (80, 104))	('B-lymphoblastic leukemia', 'Disease', (80, 104))	('p.G12D', 'Mutation', 'rs121913529', (123, 129))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('NRAS', 'Gene', (118, 122))	('p.G12D', 'Var', (123, 129))	('NRAS', 'Gene', '4893', (118, 122))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (82, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (34, 53))
450149	30322385	Detection of KRAS mutation is now recommended in colorectal carcinoma, since its presence indicates resistance to targeted therapy against upstream signaling proteins (i.e.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (49, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('mutation', 'Var', (18, 26))	('KRAS', 'Gene', (13, 17))	('colorectal carcinoma', 'Disease', (49, 69))
450151	30322385	Recent studies have shown specific efficacy of cetuximab in colorectal cancer patients with KRAS p.G13D mutations (the same mutation detected in our patient) and not other KRAS mutations.	('patient', 'Species', '9606', (78, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('patients', 'Species', '9606', (78, 86))	('KRAS', 'Gene', (92, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('patient', 'Species', '9606', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cetuximab', 'Chemical', 'MESH:D000068818', (47, 56))	('p.G13D mutations', 'Var', (97, 113))	('p.G13D', 'Mutation', 'rs112445441', (97, 103))	('colorectal cancer', 'Disease', (60, 77))
450153	30322385	It is important to recognize that while the results of whole exome sequencing in this case suggest complex genetic reprogramming may occur during the transdifferentiation process, this method may fail to identify all possible genetic abnormalities, including splice variants or chromosomal gains/losses.	('genetic abnormalities', 'Disease', (226, 247))	('genetic abnormalities', 'Disease', 'MESH:D030342', (226, 247))	('splice variants', 'Var', (259, 274))	('chromosomal gains/losses', 'Var', (278, 302))
450154	30322385	However, the detection of an activating KRAS mutation, which is not typically associated with B-cell lymphoma, combined with the growing body of evidence that this signaling pathway is essential to the development of Langerhans cell neoplasms, suggests that acquisition of this mutation could potentially drive or influence transdifferentiation.	('lymphoma', 'Phenotype', 'HP:0002665', (101, 109))	('influence', 'Reg', (314, 323))	('Langerhans cell neoplasms', 'Disease', 'MESH:D054752', (217, 242))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (94, 109))	('neoplasm', 'Phenotype', 'HP:0002664', (233, 241))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (94, 109))	('KRAS', 'Gene', (40, 44))	('B-cell lymphoma', 'Disease', (94, 109))	('mutation', 'Var', (45, 53))	('transdifferentiation', 'CPA', (324, 344))	('neoplasms', 'Phenotype', 'HP:0002664', (233, 242))	('activating', 'PosReg', (29, 39))	('Langerhans cell neoplasms', 'Disease', (217, 242))	('drive', 'Reg', (305, 310))
450156	30322385	Our findings demonstrate characterize genetic events that may occur during transdifferentiation and further emphasizes the role of alterations of RAS-RAF-MEK-ERK signaling in the pathogenesis of Langerhans cell neoplasms.	('Langerhans cell neoplasms', 'Disease', 'MESH:D054752', (195, 220))	('neoplasms', 'Phenotype', 'HP:0002664', (211, 220))	('alterations', 'Var', (131, 142))	('ERK', 'Gene', '5594', (158, 161))	('RAF', 'Gene', '22882', (150, 153))	('neoplasm', 'Phenotype', 'HP:0002664', (211, 219))	('RAF', 'Gene', (150, 153))	('ERK', 'Gene', (158, 161))	('Langerhans cell neoplasms', 'Disease', (195, 220))	('MEK', 'Gene', (154, 157))	('MEK', 'Gene', '5609', (154, 157))
450167	30322385	separation of the 5' and 3' MYC and BCL2 probes due to a translocation or abnormal FISH signal patterns due to fusions) was above the relevant cut-off values at 95% confidence.	('fusions', 'Var', (111, 118))	('MYC', 'Gene', (28, 31))	('MYC', 'Gene', '4609', (28, 31))	('BCL2', 'Gene', (36, 40))	('translocation', 'CPA', (57, 70))
450170	30322385	Analysis of BRAF V600E mutation was performed using COBAS 4800 BRAF Mutation assay according to the manufacturer's protocol (Roche Molecular Diagnostics).	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (63, 67))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('BRAF', 'Gene', (63, 67))
450171	30322385	The results were reported as follows: i) V600E mutation detected, ii) V600E mutation not detected, or iii) invalid (ie, no result was obtained on the COBAS test).	('V600E', 'Mutation', 'rs113488022', (70, 75))	('V600E mutation detected', 'Var', (41, 64))	('V600E', 'Var', (70, 75))	('V600E', 'Mutation', 'rs113488022', (41, 46))
450172	30322385	The COBAS BRAF Mutation assay can detect the BRAF V600E mutation at greater than 5% mutation level.	('V600E', 'Mutation', 'rs113488022', (50, 55))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('V600E', 'Var', (50, 55))
450178	30322385	This assay identifies the following mutations in codon 12: G12S, G12D, G12V, G12C, G12A, G12R; in codon 13: G13D; and in codon 61: Q61H (61CAA > CAT), Q61L, Q61R, Q61H (61CAA > CAC).	('G12V', 'Var', (71, 75))	('G12A', 'Var', (83, 87))	('G12S', 'Mutation', 'rs121913530', (59, 63))	('G12D', 'Var', (65, 69))	('Q61H', 'Mutation', 'rs17851045', (131, 135))	('Q61R', 'Mutation', 'rs121913240', (157, 161))	('Q61H', 'Mutation', 'rs17851045', (163, 167))	('G12D', 'Mutation', 'rs121913529', (65, 69))	('G12R', 'Mutation', 'rs121913530', (89, 93))	('61CAA > CAC', 'Mutation', 'rs17851045', (169, 180))	('G12C', 'Mutation', 'rs121913530', (77, 81))	('G12A', 'Mutation', 'rs121913529', (83, 87))	('G12S', 'Var', (59, 63))	('G13D', 'Mutation', 'rs112445441', (108, 112))	('Q61R', 'Var', (157, 161))	('Q61L', 'Var', (151, 155))	('G13D', 'Var', (108, 112))	('G12V', 'Mutation', 'rs121913529', (71, 75))	('G12C', 'Var', (77, 81))	('Q61L', 'Mutation', 'rs121913240', (151, 155))	('61CAA > CAT', 'Mutation', 'c.61CAA>CAT', (137, 148))
450189	29403218	Myeloid sarcoma is a relatively common in certain particular type of acute myeloid leukemia (AML) with distinct cytogenetic abnormalities like AML with maturation and t(8;21) (q22;q22), acute myelomonocytic leukemia with eosinophilia and Inv (16)(p13q22) or t(16;16) (p13;q22) and AML associated with 11q23 abnormalities.	('acute myelomonocytic leukemia', 'Phenotype', 'HP:0004820', (186, 215))	('eosinophilia', 'Disease', 'MESH:D004802', (221, 233))	('AML', 'Disease', 'MESH:D015470', (281, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('AML', 'Disease', (281, 284))	('AML', 'Phenotype', 'HP:0004808', (281, 284))	('eosinophilia', 'Phenotype', 'HP:0001880', (221, 233))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('acute myelomonocytic leukemia', 'Disease', 'MESH:D015479', (186, 215))	('acute myeloid leukemia', 'Disease', (69, 91))	('AML', 'Disease', (143, 146))	('AML', 'Phenotype', 'HP:0004808', (143, 146))	('t(16;16) (p13;q22', 'Var', (258, 275))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('t(8;21) (q22;q22', 'Var', (167, 183))	('Inv', 'Gene', '27130', (238, 241))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (69, 91))	('AML', 'Phenotype', 'HP:0004808', (93, 96))	('Inv', 'Gene', (238, 241))	('AML', 'Disease', (93, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (75, 91))	('Myeloid sarcoma', 'Disease', 'MESH:D023981', (0, 15))	('common', 'Reg', (32, 38))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (69, 91))	('Myeloid sarcoma', 'Disease', (0, 15))	('eosinophilia', 'Disease', (221, 233))	('leukemia', 'Phenotype', 'HP:0001909', (207, 215))	('acute myelomonocytic leukemia', 'Disease', (186, 215))
450282	26131394	Cytogenetic fluorescence in situ hybridization analysis performed on the paraffin-embedded sections from the paraspinal mass was positive for deletion of the CHIC2 gene, indicating fusion of FIP1L1/PDGFRA.	('CHIC2', 'Gene', '26511', (158, 163))	('paraffin', 'Chemical', 'MESH:D010232', (73, 81))	('PDGFRA', 'Gene', '5156', (198, 204))	('PDGFRA', 'Gene', (198, 204))	('CHIC2', 'Gene', (158, 163))	('deletion', 'Var', (142, 150))	('FIP1L1', 'Gene', '81608', (191, 197))	('FIP1L1', 'Gene', (191, 197))
450283	26131394	Fluorescence in situ hybridization analysis on the bone marrow aspirate was positive for deletion of the CHIC2 gene in 28.5% of 200 interphase nuclei and was negative for BCR/ABL1, PDGFRB rearrangement, FGFR1 rearrangement, RUNX1T1/RUNX1, and MLL.	('RUNX1T1', 'Gene', '862', (224, 231))	('PDGFRB', 'Gene', (181, 187))	('MLL', 'Gene', (243, 246))	('PDGFRB', 'Gene', '5159', (181, 187))	('RUNX1', 'Gene', '861', (224, 229))	('RUNX1', 'Gene', (232, 237))	('CHIC2', 'Gene', (105, 110))	('BCR/ABL1', 'Gene', '613;25', (171, 179))	('BCR/ABL1', 'Gene', (171, 179))	('deletion', 'Var', (89, 97))	('FGFR1', 'Gene', (203, 208))	('RUNX1T1', 'Gene', (224, 231))	('positive', 'Reg', (76, 84))	('RUNX1', 'Gene', '861', (232, 237))	('FGFR1', 'Gene', '2260', (203, 208))	('RUNX1', 'Gene', (224, 229))	('MLL', 'Gene', '4297', (243, 246))
450512	32085583	Therefore, modification of the viral capsid protein to bind to a tumor-specific antigen is a useful method for inducing the tumor tropism of virus infection.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (124, 129))	('inducing', 'Reg', (111, 119))	('modification', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor tropism of virus infection', 'Disease', 'MESH:D014412', (124, 156))	('tumor tropism of virus infection', 'Disease', (124, 156))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
450516	32085583	Therefore, replacement of the wild-type E1 promoter with the promoters of cancer-related genes is a useful method for enhancing the tumor tropism of virus replication.	('replacement', 'Var', (11, 22))	('tumor tropism', 'Disease', (132, 145))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('enhancing', 'PosReg', (118, 127))	('tumor tropism', 'Disease', 'MESH:D009369', (132, 145))
450517	32085583	There are many kinds of tumor-specific promoters, including those for the genes encoding human telomerase reverse transcriptase (hTERT), midkine, cyclooxygenase-2, and survivin; insertion of each of these promoters can selectively enhance the replication of adenovirus in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('adenovirus', 'Protein', (258, 268))	('midkine', 'Gene', '4192', (137, 144))	('human', 'Species', '9606', (89, 94))	('tumor', 'Disease', (272, 277))	('telomerase reverse transcriptase', 'Gene', (95, 127))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('midkine', 'Gene', (137, 144))	('cyclooxygenase-2', 'Gene', '5743', (146, 162))	('tumor', 'Disease', (24, 29))	('hTERT', 'Gene', '7015', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('telomerase reverse transcriptase', 'Gene', '7015', (95, 127))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('cyclooxygenase-2', 'Gene', (146, 162))	('replication', 'MPA', (243, 254))	('insertion', 'Var', (178, 187))	('adenovirus', 'Species', '28285', (258, 268))	('hTERT', 'Gene', (129, 134))	('enhance', 'PosReg', (231, 238))
450534	32085583	In normal cells without telomerase activity, cell division induces cell cycle arrest and senescence-related cell death via shortening of the chromosomal telomere end (Figure 2).	('arrest', 'Disease', (78, 84))	('shortening', 'NegReg', (123, 133))	('cell division', 'Var', (45, 58))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('senescence-related cell death', 'CPA', (89, 118))
450561	32085583	showed that the oncolytic adenovirus Delta-24-RGD induces the activation of c-Jun N-terminal kinase (JNK) and phosphorylation of Bcl-2, leading to the suppression of Bcl-2/Beclin 1 autophagy suppressor complexes and autophagy induction.	('autophagy induction', 'CPA', (216, 235))	('suppression', 'NegReg', (151, 162))	('Delta-24-RGD', 'Var', (37, 49))	('Bcl-2', 'Protein', (129, 134))	('adenovirus', 'Species', '28285', (26, 36))	('phosphorylation', 'CPA', (110, 125))	('Bcl-2/Beclin 1', 'Protein', (166, 180))	('activation', 'PosReg', (62, 72))
450566	32085583	Regarding the molecular mechanism underlying OBP-301's enhancement of chemosensitivity, adenoviral E1A protein upregulates the expression of E2F1 and microRNA-29, leading to suppression of the anti-apoptotic myeloid cell leukemia 1 protein.	('E2F1', 'Gene', (141, 145))	('upregulates', 'PosReg', (111, 122))	('anti-apoptotic', 'CPA', (193, 207))	('expression', 'MPA', (127, 137))	('OBP', 'Gene', (45, 48))	('microRNA-29', 'Gene', '407021', (150, 161))	('microRNA-29', 'Gene', (150, 161))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (208, 229))	('myeloid cell leukemia', 'Disease', (208, 229))	('leukemia', 'Phenotype', 'HP:0001909', (221, 229))	('suppression', 'NegReg', (174, 185))	('OBP', 'Gene', '29991', (45, 48))	('adenoviral E1A', 'Var', (88, 102))	('myeloid cell leukemia', 'Disease', 'MESH:D007951', (208, 229))
450578	32085583	Gastric cancer patients with GFP-positive peritoneal tumor cells show poor prognoses.	('GFP-positive', 'Var', (29, 41))	('patients', 'Species', '9606', (15, 23))	('cancer', 'Disease', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
450581	32085583	Thus, the OBP-401-based imaging system is a novel diagnostic option for the assessment of CAR expression and genetic alterations in bone and soft-tissue sarcoma cells.	('OBP', 'Gene', (10, 13))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (141, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('CAR', 'Gene', '1525', (90, 93))	('genetic alterations', 'Var', (109, 128))	('CAR', 'Gene', (90, 93))	('sarcoma cells', 'Disease', (153, 166))	('sarcoma cells', 'Disease', 'MESH:D012509', (153, 166))	('OBP', 'Gene', '29991', (10, 13))
450590	32085583	In particular, the OBP-401-based FGS significantly reduced local recurrence and lung metastasis in orthotopic xenograft tumor models with human osteosarcoma and fibrosarcoma cells compared to bright-light surgery.	('reduced', 'NegReg', (51, 58))	('local recurrence', 'CPA', (59, 75))	('fibrosarcoma', 'Disease', 'MESH:D005354', (161, 173))	('OBP', 'Gene', (19, 22))	('fibrosarcoma', 'Disease', (161, 173))	('FGS', 'Var', (33, 36))	('osteosarcoma', 'Phenotype', 'HP:0002669', (144, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('sarcoma cells', 'Disease', 'MESH:D012509', (166, 179))	('lung metastasis in orthotopic xenograft tumor', 'Disease', (80, 125))	('OBP', 'Gene', '29991', (19, 22))	('lung metastasis in orthotopic xenograft tumor', 'Disease', 'MESH:D009362', (80, 125))	('osteosarcoma', 'Disease', (144, 156))	('human', 'Species', '9606', (138, 143))	('osteosarcoma', 'Disease', 'MESH:D012516', (144, 156))	('sarcoma cells', 'Disease', (166, 179))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
450599	32085583	Patients with Li-Fraumeni syndrome, who carry a germline mutation in the p53 gene, are predisposed to bone and soft-tissue sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcomas', 'Disease', (123, 131))	('p53', 'Gene', (73, 76))	('Li-Fraumeni syndrome', 'Disease', (14, 34))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (111, 131))	('Patients', 'Species', '9606', (0, 8))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('sarcomas', 'Disease', 'MESH:D012509', (123, 131))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (111, 130))	('germline mutation', 'Var', (48, 65))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (14, 34))
450600	32085583	Additionally, genetically engineered mice with mutated p53 genes have been shown to predominantly develop bone and soft-tissue sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (115, 135))	('p53', 'Gene', (55, 58))	('sarcomas', 'Disease', (127, 135))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (115, 134))	('mutated', 'Var', (47, 54))	('sarcomas', 'Disease', 'MESH:D012509', (127, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('develop', 'PosReg', (98, 105))	('mice', 'Species', '10090', (37, 41))
450602	32085583	Therefore, the restoration of the p53 gene is expected to be an attractive therapeutic strategy for inducing strong tumor suppression.	('p53', 'Gene', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('restoration', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
450627	32085583	p53-armed OBP-702 is a next-generation oncolytic virus that is expected to overcome the refractoriness of tumors to OBP-301 and to suppress tumor-related bone destruction in osteosarcoma.	('OBP', 'Gene', (116, 119))	('suppress', 'NegReg', (131, 139))	('refractoriness of tumors to OBP-301', 'Disease', (88, 123))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('p53-armed', 'Var', (0, 9))	('tumor', 'Disease', (106, 111))	('osteosarcoma', 'Phenotype', 'HP:0002669', (174, 186))	('OBP', 'Gene', (10, 13))	('refractoriness of tumors to OBP-301', 'Disease', 'MESH:D000069279', (88, 123))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('OBP', 'Gene', '29991', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('bone destruction', 'Phenotype', 'HP:0002797', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('OBP', 'Gene', '29991', (10, 13))	('osteosarcoma', 'Disease', (174, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('osteosarcoma', 'Disease', 'MESH:D012516', (174, 186))	('tumor', 'Disease', (140, 145))
450639	30745580	The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('sarcoma', 'Disease', (4, 11))	('sarcomas', 'Disease', (171, 179))	('cancer', 'Disease', (84, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('sarcoma', 'Disease', 'MESH:D012509', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('sarcoma', 'Disease', (171, 178))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('translocations', 'Var', (185, 199))
450650	30745580	Genetically, sarcomas divide into two groups: those with complex genomes comprising of approximately 60% of all cases and those with characteristic genetic alterations, such as chromosomal translocations, that are often drivers of sarcomagenesis.	('sarcomas', 'Disease', (13, 21))	('sarcomagenesis', 'Disease', (231, 245))	('chromosomal translocations', 'Var', (177, 203))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	('sarcomagenesis', 'Disease', 'None', (231, 245))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (231, 238))
450653	30745580	It has shown that cancer cells gradually acquire genetic aberrations such as mutations, changes in gene copy numbers, and gene fusions, but only a few hundred of these alterations are essential for tumourigenesis or for cancer cell survival.	('tumour', 'Disease', (198, 204))	('gene copy numbers', 'MPA', (99, 116))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('changes', 'Reg', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('cancer', 'Disease', (18, 24))	('tumour', 'Disease', 'MESH:D009369', (198, 204))
450654	30745580	Sarcomas with high rate of mutations include subtypes such as leiomyosarcoma, osteosarcoma, undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.	('mutations', 'Var', (27, 36))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('osteosarcoma', 'Disease', 'MESH:D012516', (78, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('leiomyosarcoma', 'Disease', (62, 76))	('liposarcoma', 'Disease', 'MESH:D008080', (150, 161))	('undifferentiated pleomorphic sarcoma', 'Disease', (92, 128))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('osteosarcoma', 'Phenotype', 'HP:0002669', (78, 90))	('liposarcoma', 'Disease', (150, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (62, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('Sarcomas', 'Disease', (0, 8))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (62, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('liposarcoma', 'Phenotype', 'HP:0012034', (150, 161))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (92, 128))	('osteosarcoma', 'Disease', (78, 90))
450655	30745580	Sarcomas with chromosomal translocations express specific fusion genes that are drivers of sarcomagenesis but seldom acquire secondary genetic aberrations.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcomagenesis', 'Disease', (91, 105))	('fusion genes', 'Var', (58, 70))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('sarcomagenesis', 'Disease', 'None', (91, 105))	('Sarcomas', 'Disease', (0, 8))	('chromosomal translocations', 'Var', (14, 40))
450657	30745580	The most common genetic aberrations found in this study were amplifications of the MDM2, CDK4, HMG2 genes, and deletions in the RB1, TP53, PTEN,CDKN2A and NF1 genes.	('HMG2', 'Gene', '3148', (95, 99))	('NF1', 'Gene', '4763', (155, 158))	('RB1', 'Gene', (128, 131))	('TP53', 'Gene', (133, 137))	('PTEN', 'Gene', (139, 143))	('CDKN2A', 'Gene', (144, 150))	('HMG2', 'Gene', (95, 99))	('MDM2', 'Gene', '4193', (83, 87))	('PTEN', 'Gene', '5728', (139, 143))	('RB1', 'Gene', '5925', (128, 131))	('CDK4', 'Gene', (89, 93))	('CDKN2A', 'Gene', '1029', (144, 150))	('deletions', 'Var', (111, 120))	('TP53', 'Gene', '7157', (133, 137))	('NF1', 'Gene', (155, 158))	('CDK4', 'Gene', '1019', (89, 93))	('amplifications', 'Var', (61, 75))	('MDM2', 'Gene', (83, 87))
450689	30745580	To investigate if the outgrowing PDC still resemble the sarcoma tissues from which they were originated, we determined the expression of fusion proteins in sarcomas with translocations by proximity ligation assay (PLA) or RT-PCR.	('sarcoma', 'Disease', 'MESH:D012509', (156, 163))	('translocations', 'Var', (170, 184))	('sarcoma', 'Disease', (56, 63))	('sarcomas', 'Disease', 'MESH:D012509', (156, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcoma', 'Disease', (156, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('sarcomas', 'Disease', (156, 164))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))
450696	30745580	In the present study we show the functional and genotypic analysis of six cases of patients affected with sarcomas with translocations consisting of one aRMS, two alveolar soft part sarcomas (ASPS), one synovial sarcoma (SS) and two Ewing sarcoma (ES).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('ASPS', 'Gene', '79058', (192, 196))	('synovial sarcoma', 'Disease', 'MESH:D013584', (203, 219))	('ASPS', 'Phenotype', 'HP:0012218', (192, 196))	('translocations', 'Var', (120, 134))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (163, 189))	('alveolar soft part sarcomas', 'Phenotype', 'HP:0012218', (163, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (203, 219))	('alveolar soft part sarcomas', 'Disease', 'MESH:D018234', (163, 190))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (172, 189))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('ES', 'Phenotype', 'HP:0012254', (248, 250))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('Ewing sarcoma', 'Disease', (233, 246))	('sarcomas', 'Disease', (182, 190))	('patients', 'Species', '9606', (83, 91))	('SS', 'Phenotype', 'HP:0012570', (221, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('aRMS', 'Phenotype', 'HP:0006779', (153, 157))	('ASPS', 'Gene', (192, 196))	('sarcomas', 'Disease', 'MESH:D012509', (106, 114))	('soft part sarcomas', 'Phenotype', 'HP:0030448', (172, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))	('alveolar soft part sarcomas', 'Disease', (163, 190))	('sarcomas', 'Disease', (106, 114))	('synovial sarcoma', 'Disease', (203, 219))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (233, 246))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (233, 246))
450700	30745580	We detected the expression of the PAX3-FOXO1A fusion transcript in the PDC (K-RMS1) by RT-PCR confirming the presence of aRMS cells (Fig.	('FOXO1A', 'Gene', (39, 45))	('aRMS', 'Phenotype', 'HP:0006779', (121, 125))	('FOXO1A', 'Gene', '2308', (39, 45))	('PAX3', 'Gene', '5077', (34, 38))	('PAX3', 'Gene', (34, 38))	('fusion', 'Var', (46, 52))
450724	30745580	1) Consistent with the activation of mTOR/PI3K pathway in the ASPS3 biopsy and derived PDC, several mTOR/PI3K inhibitors were active in functional screens such as PF04691502, Dactolisib and Gedatolisib with sDSS values above 10 in relation to healthy bone marrow cell controls.	('PF04691502', 'Var', (163, 173))	('ASPS', 'Gene', (62, 66))	('Gedatolisib', 'Chemical', 'MESH:C549060', (190, 201))	('SS', 'Phenotype', 'HP:0012570', (209, 211))	('sDSS', 'Chemical', '-', (207, 211))	('ASPS', 'Gene', '79058', (62, 66))	('mTOR/PI3K pathway', 'Pathway', (37, 54))	('Dactolisib', 'Chemical', 'MESH:C531198', (175, 185))	('ASPS', 'Phenotype', 'HP:0012218', (62, 66))
450735	30745580	Few inhibitors were selectively active in K-SS3 such as the PI3K inhibitor Copanlisib/Aliqopa , the ALK/FAK1 inhibitor CEP-37440, the MEK inhibitor AZD-8330 and the AKT inhibitor Triciribine (Fig.	('MEK', 'Gene', (134, 137))	('AKT', 'Gene', (165, 168))	('Aliqopa', 'Chemical', '-', (86, 93))	('Triciribine', 'Chemical', 'MESH:C023764', (179, 190))	('CEP-37440', 'Chemical', 'MESH:C000611391', (119, 128))	('FAK1', 'Gene', '5747', (104, 108))	('K-SS3', 'Disease', (42, 47))	('SS', 'Phenotype', 'HP:0012570', (44, 46))	('CEP-37440', 'Var', (119, 128))	('MEK', 'Gene', '5609', (134, 137))	('Copanlisib', 'Chemical', 'MESH:C000589253', (75, 85))	('ALK', 'Gene', (100, 103))	('FAK1', 'Gene', (104, 108))	('AKT', 'Gene', '207', (165, 168))	('AZD-8330', 'Chemical', 'MESH:C581956', (148, 156))	('ALK', 'Gene', '238', (100, 103))
450744	30745580	The EWSR1-FLI1 fusion was detected in the biopsy (data not shown) and in 95% of the cells in the PDC confirming the presence of Ewing sarcoma cells (Fig.	('fusion', 'Var', (15, 21))	('FLI1', 'Gene', '2313', (10, 14))	('EWSR1', 'Gene', '2130', (4, 9))	('FLI1', 'Gene', (10, 14))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('Ewing sarcoma', 'Disease', (128, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('EWSR1', 'Gene', (4, 9))
450761	30745580	Dasatinib was active in all PDCs derived from sarcomas with translocations and other sarcoma subtypes (Figs.	('sarcomas', 'Disease', (46, 54))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (85, 101))	('translocations', 'Var', (60, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('sarcoma subtypes', 'Disease', (85, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
450764	30745580	Genomic sequencing of cancer cell lines has shown that mutations accumulate during serial passages.	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('mutations', 'Var', (55, 64))
450801	27649156	This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer.	('dysfunctional', 'Disease', (126, 139))	('dysfunctional', 'Disease', 'MESH:D006331', (126, 139))	('stem cell', 'CPA', (277, 286))	('activation', 'PosReg', (170, 180))	('dysfunctional', 'Disease', 'MESH:D006331', (55, 68))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (356, 375))	('leads to', 'Reg', (117, 125))	('activation', 'PosReg', (229, 239))	('chromosomal breakage', 'Var', (207, 227))	('activation', 'PosReg', (74, 84))	('dysfunctional', 'Disease', (55, 68))	('chromosomal breakage', 'Phenotype', 'HP:0040012', (207, 227))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('transduction pathways', 'Pathway', (184, 205))	('genes', 'Gene', (331, 336))	('hallmarks of cancer', 'Disease', (356, 375))	('activation', 'PosReg', (317, 327))
450811	27649156	Paramount to this discussion is the crucial relevance of the seemingly inherent genetic instability of cancer and its relationship to cancer initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer initiation', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer initiation', 'Disease', (134, 151))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('genetic instability', 'Var', (80, 99))
450818	27649156	Additionally, which of these alterations represents the vital oncogenes that not only initiate the cancer process, but are mandatory for the cancer cell's survival?	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('alterations', 'Var', (29, 40))	('cancer', 'Disease', (99, 105))	('rat', 'Species', '10116', (33, 36))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', (141, 147))
450827	27649156	During progression, the process becomes increasingly irreversible with the onset of genetic instability, a higher growth rate, changes in biochemical and metabolic processes and morphological changes.	('changes', 'Reg', (127, 134))	('growth rate', 'CPA', (114, 125))	('higher', 'PosReg', (107, 113))	('genetic', 'Var', (84, 91))	('biochemical and', 'MPA', (138, 153))	('rat', 'Species', '10116', (121, 124))
450831	27649156	In essence, this theory states that cancer results from a single somatic cell that has accumulated multiple DNA mutations and that cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle.	('cancer', 'Disease', (131, 137))	('mutations', 'Var', (183, 192))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('rat', 'Species', '10116', (166, 169))	('caused by', 'Reg', (173, 182))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('rat', 'Species', '10116', (222, 225))	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
450832	27649156	DNA damage may result from intrinsic insults, such as base pair mismatching during DNA replication, collapse of replication forks or even as a result of reactive oxygen species produced during abnormal cellular metabolism.	('result', 'Reg', (15, 21))	('abnormal cellular metabolism', 'Phenotype', 'HP:0011017', (193, 221))	('replication forks', 'CPA', (112, 129))	('base pair mismatching', 'Var', (54, 75))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (153, 176))
450835	27649156	It is proposed here that poorly-corrected double-strand DNA breaks are mandatory for the initiation of the abnormal genomic process that results in the production of vital oncogenes, which then orchestrate neoplastic transformation.	('rat', 'Species', '10116', (201, 204))	('double-strand DNA breaks', 'Var', (42, 66))	('production', 'MPA', (152, 162))	('results in', 'Reg', (137, 147))
450863	27649156	Evidence of the direct involvement of the RAG gene in gene translocations resulting in gene fusions comes from studies in mice.	('mice', 'Species', '10090', (122, 126))	('gene translocations', 'Var', (54, 73))	('RAG', 'Gene', (42, 45))	('gene fusions', 'MPA', (87, 99))
450865	27649156	We can envision the rampant effects of uncontrolled recombination activating genes in the cancer cell.	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('uncontrolled', 'Var', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
450869	27649156	Miki demonstrated the disruption of the APC gene caused by somatic insertion of a transposon in a colon cancer.	('APC', 'Disease', 'MESH:D011125', (40, 43))	('rat', 'Species', '10116', (12, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('APC', 'Disease', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('disruption', 'NegReg', (22, 32))	('colon cancer', 'Disease', (98, 110))	('transposon', 'Var', (82, 92))
450870	27649156	Work by Iskow also revealed novel transposon insertions at high frequency in human lung cancer genomes.The implication is that disruption of the normal cellular mechanisms that suppress transposon activity may facilitated the mutation process that drives the progression of the cancer.	('cancer', 'Disease', (88, 94))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('transposon', 'Protein', (186, 196))	('mutation process', 'CPA', (226, 242))	('lung cancer', 'Disease', (83, 94))	('disruption', 'Var', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('facilitated', 'PosReg', (210, 221))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (278, 284))	('human', 'Species', '9606', (77, 82))
450875	27649156	The resulting hyper-mutation state should increase the efficiency of additional mutations beneficial to cancer cell survival.	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('hyper-mutation', 'Var', (14, 28))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('increase', 'PosReg', (42, 50))
450881	27649156	The sequencing and analysis only focused on point mutations and small insertions or deletions in 3281 tumors across 12 tumor types.	('tumor', 'Disease', (119, 124))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('insertions', 'Var', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deletions', 'Var', (84, 93))
450884	27649156	The most common mutation class among the known cancer genes was a chromosomal translocation that created a chimeric gene or apposed a gene to the regulatory element of another gene.	('created', 'Reg', (97, 104))	('mutation', 'Var', (16, 24))	('chimeric gene', 'MPA', (107, 120))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
450886	27649156	The Philadelphia chromosome commonly present in chronic myelogenous leukemia results from the interchange between the end of the long arm of chromosome 9 and the long arm of chromosome 22.	('leukemia', 'Phenotype', 'HP:0001909', (68, 76))	('myelogenous leukemia', 'Disease', (56, 76))	('results from', 'Reg', (77, 89))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (48, 76))	('interchange', 'Var', (94, 105))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (56, 76))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (56, 76))
450887	27649156	It is now clear that gene fusions play an important role in the initial steps of carcinogenesis.	('gene fusions', 'Var', (21, 33))	('carcinogenesis', 'Disease', (81, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))
450888	27649156	The available data show that gene fusions occur in all malignancies.	('malignancies', 'Disease', (55, 67))	('occur', 'Reg', (42, 47))	('malignancies', 'Disease', 'MESH:D009369', (55, 67))	('gene fusions', 'Var', (29, 41))
450889	27649156	Furthermore, gene fusions have been shown to be present in the stem cell compartment of early progenitors in acute leukemias, as well as in progenitor cells that give rise to liposarcoma.	('leukemias', 'Phenotype', 'HP:0001909', (115, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('gene fusions', 'Var', (13, 25))	('liposarcoma', 'Disease', (175, 186))	('acute leukemias', 'Disease', 'MESH:D015470', (109, 124))	('acute leukemias', 'Phenotype', 'HP:0002488', (109, 124))	('acute leukemia', 'Phenotype', 'HP:0002488', (109, 123))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('liposarcoma', 'Phenotype', 'HP:0012034', (175, 186))	('liposarcoma', 'Disease', 'MESH:D008080', (175, 186))	('acute leukemias', 'Disease', (109, 124))
450893	27649156	Driver mutations participate in the consequences of the cancer process.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('participate', 'Reg', (17, 28))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (7, 16))
450904	27649156	In acute myeloid leukemia, more than 50% of adult patients have cancer cells that contain non-random chromosomal abnormalities, including most significantly gene translocations.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('patients', 'Species', '9606', (50, 58))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('gene translocations', 'Var', (157, 176))	('acute myeloid leukemia', 'Disease', (3, 25))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('chromosomal abnormalities', 'Disease', (101, 126))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (101, 126))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
450906	27649156	However, transcription activator fusions were the first recognized somatic mutations in this disease and have been shown to initiate this disease in mice.	('mice', 'Species', '10090', (149, 153))	('fusions', 'Var', (33, 40))	('mutations', 'Var', (75, 84))
450907	27649156	Furthermore, there are prognostic implications of many of the genetic changes found in acute leukemia.	('genetic changes', 'Var', (62, 77))	('acute leukemia', 'Disease', (87, 101))	('acute leukemia', 'Phenotype', 'HP:0002488', (87, 101))	('acute leukemia', 'Disease', 'MESH:D015470', (87, 101))	('leukemia', 'Phenotype', 'HP:0001909', (93, 101))
450908	27649156	A striking example is the impact of mutations involving the runt-related transcription activator gene AML1 (also known as RUNX1 and CBFA2).	('CBFA2', 'Gene', '861', (132, 137))	('CBFA2', 'Gene', (132, 137))	('mutations', 'Var', (36, 45))	('AML1', 'Gene', (102, 106))	('RUNX1', 'Gene', (122, 127))	('AML1', 'Gene', '861', (102, 106))	('RUNX1', 'Gene', '861', (122, 127))
450910	27649156	AML1 mutations are associated with resistance to standard induction therapy with inferior survival for younger and older patients.	('AML1', 'Gene', '861', (0, 4))	('inferior', 'NegReg', (81, 89))	('mutations', 'Var', (5, 14))	('AML1', 'Gene', (0, 4))	('patients', 'Species', '9606', (121, 129))
450911	27649156	Mendler also found that the gene expression profile associated with such AML1 mutations is very similar to that present in normal hematopoietic stem cells and progenitors.	('AML1', 'Gene', (73, 77))	('AML1', 'Gene', '861', (73, 77))	('mutations', 'Var', (78, 87))
450912	27649156	Other similar types of translocations involving the MLL transcription activator also have a characteristic distinct gene expression profile consistent with that seen in a hematopoietic progenitor or stem cell.	('MLL', 'Gene', '4297', (52, 55))	('MLL', 'Gene', (52, 55))	('translocations', 'Var', (23, 37))
450913	27649156	Chromosomal translocations in acute leukemia often rearrange the regulatory and coding regions of a variety of transcription factor genes.	('Chromosomal translocations', 'Var', (0, 26))	('acute leukemia', 'Phenotype', 'HP:0002488', (30, 44))	('leukemia', 'Phenotype', 'HP:0001909', (36, 44))	('coding regions', 'MPA', (80, 94))	('rearrange', 'Reg', (51, 60))	('acute leukemia', 'Disease', 'MESH:D015470', (30, 44))	('acute leukemia', 'Disease', (30, 44))	('regulatory', 'MPA', (65, 75))
450924	27649156	The assumption is that these mutations lead to a transformation of that normal cell to one that is more primitive with a new proliferative capacity and is capable of expanding clonally while inherently self-sustaining.	('mutations', 'Var', (29, 38))	('lead to', 'Reg', (39, 46))	('rat', 'Species', '10116', (132, 135))
450927	27649156	The only remaining controversy is whether or not the cancer initiation cell arises from crucial mutations in a tissue stem cell, its progenitor cell or both.	('cancer initiation', 'Disease', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer initiation', 'Disease', 'MESH:D009369', (53, 70))	('mutations', 'Var', (96, 105))
450931	27649156	Furthermore, most significantly upon silencing the SS18-SSX fused transcription activator gene with sequence-specific siRNAs, these cells exhibited morphological transition from spherical growth in suspension to adherent growth in a monolayer, additional expression of later mesenchymal lineage genes and broader differentiation potentials into osteocytes, chondrocytes and adipocytes.	('adipocytes', 'CPA', (374, 384))	('SSX', 'Gene', (56, 59))	('adherent growth', 'CPA', (212, 227))	('chondrocytes', 'CPA', (357, 369))	('exhibited', 'Reg', (138, 147))	('differentiation potentials', 'CPA', (313, 339))	('SS18', 'Gene', '6760', (51, 55))	('SSX', 'Gene', '727837', (56, 59))	('expression', 'MPA', (255, 265))	('silencing', 'Var', (37, 46))	('spherical growth', 'CPA', (178, 194))	('morphological transition', 'CPA', (148, 172))	('SS18', 'Gene', (51, 55))
450940	27649156	Like others, he utilized a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice allowing the identification of a highly tumorigenic subpopulation of pancreatic cancer cells that expressed the cell surface markers CD44, CD24 and epithelial-specific antigen (ESA).	('pancreatic cancer', 'Disease', (199, 216))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (66, 92))	('pancreatic adenocarcinomas', 'Disease', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mice', 'Species', '10090', (125, 129))	('tumor', 'Disease', (170, 175))	('epithelial-specific antigen (ESA', 'Gene', (278, 310))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (66, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('CD24', 'Var', (269, 273))	('human', 'Species', '9606', (60, 65))	('epithelial-specific antigen (ESA)', 'Gene', '14252', (278, 311))	('CD44', 'Var', (263, 267))
450956	27649156	In transfection studies, the PAX3-FKHR fusion activates the transcription of reporter genes containing PAX DNA-binding sites and is 10- to 100-fold more potent as a transcriptional activator than the PAX3 wildtype.	('PAX3', 'Gene', '5077', (200, 204))	('FKHR', 'Gene', '2308', (34, 38))	('PAX3', 'Gene', (200, 204))	('PAX3', 'Gene', '5077', (29, 33))	('PAX3', 'Gene', (29, 33))	('activates', 'PosReg', (46, 55))	('FKHR', 'Gene', (34, 38))	('transcription', 'MPA', (60, 73))	('fusion', 'Var', (39, 45))	('transcriptional', 'MPA', (165, 180))
450961	27649156	Likewise, Riggi transformed primary mesenchymal progenitor cells into tumors resembling human myxoid liposarcoma by the insertion of the FUS-CHOP gene.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('insertion', 'Var', (120, 129))	('liposarcoma', 'Phenotype', 'HP:0012034', (101, 112))	('FUS', 'Gene', '233908', (137, 140))	('myxoid liposarcoma', 'Disease', (94, 112))	('FUS', 'Gene', (137, 140))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('CHOP', 'Gene', '13198', (141, 145))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (94, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('human', 'Species', '9606', (88, 93))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (94, 112))	('CHOP', 'Gene', (141, 145))
450967	27649156	Recurrent fusions of the gene TMPRSS2 and the ETV1 transcription activator gene have been identified in prostate cancers by Tomlins.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('prostate cancers', 'Disease', 'MESH:D011471', (104, 120))	('identified', 'Reg', (90, 100))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('TMPRSS2', 'Gene', '7113', (30, 37))	('ETV1', 'Gene', (46, 50))	('prostate cancers', 'Phenotype', 'HP:0012125', (104, 120))	('prostate cancers', 'Disease', (104, 120))	('ETV1', 'Gene', '2115', (46, 50))	('fusions', 'Var', (10, 17))	('TMPRSS2', 'Gene', (30, 37))
450976	27649156	The PAX3-FKHR fusion gene results from a translocation between chromosomes 2 and 13 in rhabdomyosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('translocation', 'Var', (41, 54))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (87, 104))	('results from', 'Reg', (26, 38))	('rhabdomyosarcomas', 'Disease', (87, 104))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('FKHR', 'Gene', (9, 13))	('PAX3', 'Gene', '5077', (4, 8))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (87, 104))	('PAX3', 'Gene', (4, 8))	('FKHR', 'Gene', '2308', (9, 13))
450978	27649156	Fredericks demonstrated that the fused protein of this vital oncogene is highly expressed in the nucleus, displays altered binding of a reference PAX DNA target and can excessively activate transcription relative to the wildtype PAX3.	('rat', 'Species', '10116', (18, 21))	('binding', 'Interaction', (123, 130))	('PAX3', 'Gene', '5077', (229, 233))	('PAX3', 'Gene', (229, 233))	('fused', 'Var', (33, 38))	('activate', 'PosReg', (181, 189))	('altered', 'Reg', (115, 122))	('transcription', 'MPA', (190, 203))	('protein', 'Protein', (39, 46))
450984	27649156	Although the SSX family of genes normally functions as suppressors, when SSX1 is fused to SYT1 in the SYT1-SSX1 gene in synovial sarcoma, the fused gene is capable of increasing the expression of both cyclin A and D1.	('SYT1', 'Gene', '6857', (102, 106))	('fused', 'Var', (142, 147))	('SSX', 'Gene', '727837', (107, 110))	('SSX', 'Gene', (13, 16))	('cyclin A', 'Gene', '890', (201, 209))	('SYT1', 'Gene', (90, 94))	('SSX', 'Gene', '727837', (73, 76))	('synovial sarcoma', 'Disease', (120, 136))	('cyclin A', 'Gene', (201, 209))	('SSX1', 'Gene', '6756', (107, 111))	('synovial sarcoma', 'Disease', 'MESH:D013584', (120, 136))	('SSX1', 'Gene', (107, 111))	('SSX', 'Gene', (107, 110))	('expression', 'MPA', (182, 192))	('SSX1', 'Gene', '6756', (73, 77))	('SYT1', 'Gene', '6857', (90, 94))	('SYT1', 'Gene', (102, 106))	('SSX', 'Gene', '727837', (13, 16))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (120, 136))	('SSX1', 'Gene', (73, 77))	('SSX', 'Gene', (73, 76))	('increasing', 'PosReg', (167, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
450988	27649156	Functional studies confirmed that the ectopic expression of the oncogenic AML1-ETO fusion protein constitutively activated pathways leading to increased stem cell renewal (Jagged1/Notch pathway) and provoked accumulation of DNA damage.	('DNA damage', 'MPA', (224, 234))	('increased', 'PosReg', (143, 152))	('stem cell renewal', 'CPA', (153, 170))	('AML1', 'Gene', (74, 78))	('Notch', 'Gene', '4851', (180, 185))	('Notch', 'Gene', (180, 185))	('Jagged1', 'Gene', '182', (172, 179))	('ectopic expression', 'Var', (38, 56))	('Jagged1', 'Gene', (172, 179))	('AML1', 'Gene', '861', (74, 78))	('accumulation', 'PosReg', (208, 220))
450991	27649156	Mutations are the underpinnings of the cancer process.	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))
450994	27649156	A self-evident major premise supporting the veracity of any molecular genetic model for carcinogenesis assumes that certain mutations in cancer are vital to its initiation and early progression.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('carcinogenesis', 'Disease', (88, 102))	('mutations', 'Var', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))
450995	27649156	In addition, such instigating mutations must characteristically have the capacity to remain in the genome of certain cell progeny, resulting in the recapitulation of the cancer initiation process and early progression within that subpopulation of new cells.	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer initiation process', 'Disease', 'MESH:D009369', (170, 195))	('mutations', 'Var', (30, 39))	('cancer initiation process', 'Disease', (170, 195))
450996	27649156	Here, it is proposed that the sentinel event resulting in the initiation of the cancer process is the externally- or internally-mediated development of double-strand DNA breaks within tissue stem cells and/or progenitor cells that allow the occurrence of gene rearrangements.	('initiation of the cancer', 'Disease', 'MESH:D009369', (62, 86))	('initiation of the cancer', 'Disease', (62, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('double-strand DNA', 'Var', (152, 169))
451010	27649156	Furthermore, he distinguished oncogene mutations that occur early in the multistage process of tumor development because of their potential critical role in determining subsequent aspects of the abnormal circuitry in the evolving cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('determining', 'Reg', (157, 168))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('oncogene', 'Gene', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
451021	27649156	It was first demonstrated in the case of Imatinib that the subsequent development of additional mutations in the region of the targeted drug binding site completely subverts the efficacy of the targeted drug.	('binding', 'Interaction', (141, 148))	('efficacy', 'MPA', (178, 186))	('Imatinib', 'Chemical', 'MESH:D000068877', (41, 49))	('rat', 'Species', '10116', (20, 23))	('subverts', 'NegReg', (165, 173))	('mutations', 'Var', (96, 105))
451032	27649156	Since they are required for the fine regulation of transcription, the implication of this is that any dysfunction of microRNAs could significantly contribute to the cancer process.	('dysfunction', 'Var', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('contribute', 'Reg', (147, 157))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
451034	27649156	There is the logical possibility that mutations affecting microRNA function are also a probable component of the progressive mutational events that result from the cell mutator phenotypic transformation orchestrated by the activity of vital oncogenes (Figure 1).	('mutations', 'Var', (38, 47))	('microRNA', 'Gene', (58, 66))	('rat', 'Species', '10116', (210, 213))
451042	27649156	Those results provided proof of principle that inhibiting the interaction of mutant cancer-specific transcription activators with the normal cellular binding partners required for their oncogenic activity provides a novel strategy for the development of unique effective tumor-specific anticancer drugs.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('interaction', 'Interaction', (62, 73))	('inhibiting', 'NegReg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('tumor', 'Disease', (271, 276))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rat', 'Species', '10116', (224, 227))	('mutant', 'Var', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (271, 276))
451062	27649156	These extracellular vesicles contained double-stranded full-length H-ras.	('H-ras', 'Gene', (67, 72))	('double-stranded', 'Var', (39, 54))	('H-ras', 'Gene', '3265', (67, 72))
451064	27649156	The detection of mutations in cell-free DNA from patients with cancer has been well established.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('patients', 'Species', '9606', (49, 57))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (63, 69))
451092	23326307	Finally, knocking down Sp3 using small inhibitory RNA duplex (siRNA) reduced AFAP1L1 expression significantly, which was partially restored by expressing siRNA-resistant Sp3.	('expression', 'MPA', (85, 95))	('reduced', 'NegReg', (69, 76))	('knocking', 'Var', (9, 17))	('AFAP1L1', 'Gene', '134265', (77, 84))	('expression', 'Species', '29278', (85, 95))	('AFAP1L1', 'Gene', (77, 84))
451114	23326307	Plasmids harboring mutations in the Sp-binding site (SBS) or Ets-binding site (EBS) were created by PCR-based mutagenesis using PGV-(-224) as a template.	('EBS', 'Chemical', '-', (79, 82))	('SBS', 'Disease', 'MESH:C536611', (53, 56))	('Sp', 'Chemical', '-', (36, 38))	('mutations', 'Var', (19, 28))	('SBS', 'Disease', (53, 56))
451115	23326307	Briefly, PCR was performed with pairs of primers containing mutations in SBS1 (-86 -GGGCGGGGCGG- -76 to GTTCGGTTCGG), SBS2 (-102 -GGGCGG- -97 to GTTCGG), EBS1 (-60 -ATCCT- -56 to ATAAT) and EBS2 (-121 -TTCCG- -117 to TTAAG).	('GGGCGG- -97 to GTTCGG', 'Mutation', 'c.--97GGGCGG>GTTCGG', (130, 151))	('-102 -GGGCGG- -97 to', 'Var', (124, 144))	('-86', 'Var', (79, 82))	('EBS1', 'Gene', (154, 158))	('TTCCG- -117 to TTAAG', 'Mutation', 'c.--117TTCCG>TTAAG', (202, 222))	('SBS', 'Disease', (73, 76))	('SBS', 'Disease', (118, 121))	('ATCCT- -56 to ATAAT', 'Mutation', 'c.--56ATCCT>ATAAT', (165, 184))	('GGGCGGGGCGG- -76 to GTTCGGTTCGG', 'Mutation', 'c.--76GGGCGGGGCGG>GTTCGGTTCGG', (84, 115))	('EBS', 'Chemical', '-', (190, 193))	('EBS', 'Chemical', '-', (154, 157))	('EBS2', 'Gene', (190, 194))	('SBS', 'Disease', 'MESH:C536611', (73, 76))	('mutations', 'Var', (60, 69))	('SBS', 'Disease', 'MESH:C536611', (118, 121))
451131	23326307	Membranes were probed with anti-AFAP1L1 (1:2000), anti-Sp1 (1C6, 1:1000), anti-Sp3 (1:1000), anti-beta-tubulin (1:1000), anti-acetyl H3K9 (1:2500) and anti-Flag (1:2000) antibodies.	('anti-Sp1', 'Var', (50, 58))	('Sp', 'Chemical', '-', (79, 81))	('anti-acetyl', 'Var', (121, 132))	('AFAP1L1', 'Gene', '134265', (32, 39))	('anti-Sp3', 'Var', (74, 82))	('Sp', 'Chemical', '-', (55, 57))	('AFAP1L1', 'Gene', (32, 39))
451132	23326307	To knock down the Sp1 and Sp3 genes, two different siRNAs were used (siSp1#1 and siSp1#2 for Sp1; siSp3#1 and siSp3#2 for Sp3).	('Sp', 'Chemical', '-', (18, 20))	('Sp', 'Chemical', '-', (71, 73))	('Sp', 'Chemical', '-', (93, 95))	('Sp1', 'Gene', (18, 21))	('Sp', 'Chemical', '-', (112, 114))	('Sp', 'Chemical', '-', (26, 28))	('siSp1', 'Var', (81, 86))	('Sp', 'Chemical', '-', (122, 124))	('knock', 'Var', (3, 8))	('Sp', 'Chemical', '-', (83, 85))	('Sp', 'Chemical', '-', (100, 102))	('Sp3 genes', 'Gene', (26, 35))
451144	23326307	The proximal (-60 to -56) and distal (-102 to -97) Ets-binding motifs were designated Ets-binding site 1 (EBS1) and 2 (EBS2), respectively.	('-102 to -97', 'Var', (38, 49))	('-60 to -56', 'Var', (14, 24))	('EBS', 'Chemical', '-', (119, 122))	('EBS', 'Chemical', '-', (106, 109))
451145	23326307	The proximal Sp1-binding site (-86 to -76) contained two overlapping consensus sequences (-86 to -81 and -81 to -76) and was conserved completely in all three species, and was designated SBS1.	('SBS', 'Disease', 'MESH:C536611', (187, 190))	('-86 to -81', 'Var', (90, 100))	('SBS', 'Disease', (187, 190))	('Sp', 'Chemical', '-', (13, 15))
451148	23326307	To investigate the role of Ets and Sp transcription factors in the promoter activity, four types of luciferase reporters with mutations in the conserved sequence of each binding site were constructed using PGV-(-224) as a template and designated PGV-mtEBS1, PGV-mtEBS2, PGV-mtSBS1, and PGV-mtSBS2.	('EBS', 'Chemical', '-', (264, 267))	('SBS', 'Disease', (292, 295))	('EBS', 'Chemical', '-', (252, 255))	('SBS', 'Disease', 'MESH:C536611', (292, 295))	('SBS', 'Disease', (276, 279))	('mutations', 'Var', (126, 135))	('SBS', 'Disease', 'MESH:C536611', (276, 279))	('Sp', 'Chemical', '-', (35, 37))
451149	23326307	When EBS1 was mutated, the promoter activity was reduced by 50% compared to PGV-(-224), although PGV-(-71) which retained EBS1 also showed reduced activity (Fig.	('mutated', 'Var', (14, 21))	('EBS1', 'Gene', (122, 126))	('reduced', 'NegReg', (49, 56))	('EBS', 'Chemical', '-', (5, 8))	('promoter activity', 'MPA', (27, 44))	('EBS', 'Chemical', '-', (122, 125))	('activity', 'MPA', (147, 155))
451150	23326307	However, the effect was most remarkable when SBS1 was mutated, which resulted in a 75% reduction in promoter activity (Fig.	('SBS', 'Disease', (45, 48))	('mutated', 'Var', (54, 61))	('SBS', 'Disease', 'MESH:C536611', (45, 48))	('promoter activity', 'MPA', (100, 117))	('reduction', 'NegReg', (87, 96))
451152	23326307	Mutations in EBS2 or SBS2 had less significant effects on the promoter activity (Fig.	('SBS', 'Disease', (21, 24))	('SBS', 'Disease', 'MESH:C536611', (21, 24))	('Mutations', 'Var', (0, 9))	('EBS', 'Chemical', '-', (13, 16))	('promoter activity', 'MPA', (62, 79))	('EBS2', 'Gene', (13, 17))
451213	23326307	Notably, one study shows that promoters containing multiple adjacent Sp-binding sites form significantly more stable Sp3-DNA complexes than those with single Sp-binding sites, and as a consequence, Sp3 efficiently displaces Sp1 from preformed Sp1-DNA complexes from such sites.	('Sp', 'Chemical', '-', (198, 200))	('Sp3', 'Var', (198, 201))	('Sp', 'Chemical', '-', (158, 160))	('Sp', 'Chemical', '-', (243, 245))	('Sp1', 'Protein', (224, 227))	('displaces', 'NegReg', (214, 223))	('Sp', 'Chemical', '-', (117, 119))	('Sp', 'Chemical', '-', (224, 226))	('Sp', 'Chemical', '-', (69, 71))	('Sp3-DNA', 'Protein', (117, 124))
451217	23326307	S2), si-1 may have a negative effect on the transcription of AFAP1L1.	('AFAP1L1', 'Gene', '134265', (61, 68))	('transcription', 'MPA', (44, 57))	('AFAP1L1', 'Gene', (61, 68))	('negative', 'NegReg', (21, 29))	('si-1', 'Var', (5, 9))
451222	23326307	Sp3 enhances the growth of pancreatic cancer cells by suppressing p27 expression through interaction with GC-rich promoter elements.	('interaction', 'Interaction', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('suppressing', 'NegReg', (54, 65))	('p27', 'Protein', (66, 69))	('pancreatic cancer', 'Disease', (27, 44))	('growth', 'MPA', (17, 23))	('expression', 'Species', '29278', (70, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (27, 44))	('Sp3', 'Var', (0, 3))	('expression', 'MPA', (70, 80))	('enhances', 'PosReg', (4, 12))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))
451223	23326307	In breast cancer, Sp3 accelerates tumor cell growth by acting as a repressor of TGF signaling.	('accelerates', 'PosReg', (22, 33))	('tumor', 'Disease', (34, 39))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('Sp3', 'Var', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
451224	23326307	A recent report demonstrated the expression of Sp3 to be an independent prognostic factor for the poor survival of head and neck cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('neck cancer', 'Disease', 'MESH:D006258', (124, 135))	('neck cancer', 'Disease', (124, 135))	('expression', 'Var', (33, 43))	('expression', 'Species', '29278', (33, 43))	('patients', 'Species', '9606', (136, 144))	('head and neck cancer', 'Phenotype', 'HP:0012288', (115, 135))	('Sp3', 'Gene', (47, 50))
451227	23326307	Considering that Sp3 is expressed at higher levels in soft tissue sarcomas and transactivates the AFAP1L1 gene, targeting Sp3 could be a powerful approach to treating advanced soft tissue sarcomas.	('AFAP1L1', 'Gene', (98, 105))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Disease', (188, 196))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (176, 196))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('targeting', 'Var', (112, 121))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (54, 74))	('sarcomas', 'Disease', (66, 74))	('sarcomas', 'Disease', 'MESH:D012509', (188, 196))	('sarcomas', 'Phenotype', 'HP:0100242', (188, 196))	('AFAP1L1', 'Gene', '134265', (98, 105))
451276	32379517	Thirteen patients with MPNST (39%) had an NF-1 mutation (20 patients with available data).	('patients', 'Species', '9606', (9, 17))	('MPNST', 'Phenotype', 'HP:0100697', (23, 28))	('MPNST', 'Disease', (23, 28))	('NF-1', 'Gene', '4763', (42, 46))	('patients', 'Species', '9606', (60, 68))	('mutation', 'Var', (47, 55))	('NF-1', 'Gene', (42, 46))
451305	32379517	More than a third of AYAs with MPNST had an NF-1 mutation, which is associated with worse prognosis compared with sporadic MPNST.	('NF-1', 'Gene', (44, 48))	('mutation', 'Var', (49, 57))	('NF-1', 'Gene', '4763', (44, 48))	('MPNST', 'Phenotype', 'HP:0100697', (123, 128))	('MPNST', 'Phenotype', 'HP:0100697', (31, 36))
451306	32379517	Patients with MPNST respond relatively poorly to chemotherapy and those arising in the setting of NF-1 mutations may have inferior response rates.	('NF-1', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('MPNST', 'Disease', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('MPNST', 'Phenotype', 'HP:0100697', (14, 19))	('NF-1', 'Gene', '4763', (98, 102))
451307	32379517	Loss of the NF-1 protein leads to activation of the RAS signaling pathway; however, therapeutic attempts to target RAS signaling and downstream pathways have had disappointing results.	('protein', 'Protein', (17, 24))	('activation', 'PosReg', (34, 44))	('RAS signaling pathway', 'Pathway', (52, 73))	('NF-1', 'Gene', '4763', (12, 16))	('Loss', 'Var', (0, 4))	('NF-1', 'Gene', (12, 16))
451314	32379517	Others have reported a better prognosis for AYAs with metastatic synovial sarcoma compared with that for adults.32, Despite similar histological features, characteristic t(X;18) translocation, and fusion transcripts, adults with synovial sarcoma have worse outcomes compared to children with synovial sarcoma.	('synovial sarcoma', 'Disease', (229, 245))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (65, 81))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (292, 308))	('synovial sarcoma', 'Disease', 'MESH:D013584', (292, 308))	('synovial sarcoma', 'Disease', 'MESH:D013584', (65, 81))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (229, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('synovial sarcoma', 'Disease', 'MESH:D013584', (229, 245))	('synovial sarcoma', 'Disease', (65, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (301, 308))	('synovial sarcoma', 'Disease', (292, 308))	('fusion transcripts', 'Var', (197, 215))	('children', 'Species', '9606', (278, 286))
451316	32379517	The majority of AYAs with liposarcoma had a "myxoid" variant, characterized by a t(12:16)(q13;p11) translocation, resulting in the formation of a FUS-CHOP fusion oncoprotein (rarer aberrations include t(12;22)(q13;a12) resulting in DDIT3-EWSR1 fusion protein).	('liposarcoma', 'Disease', (26, 37))	('EWSR1', 'Gene', (238, 243))	('DDIT3', 'Gene', (232, 237))	('liposarcoma', 'Disease', 'MESH:D008080', (26, 37))	('liposarcoma', 'Phenotype', 'HP:0012034', (26, 37))	('EWSR1', 'Gene', '2130', (238, 243))	('t(12;22)(q13;a12', 'Var', (201, 217))	('DDIT3', 'Gene', '1649', (232, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('t(12:16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (81, 98))
451342	32379517	Younger age at diagnosis of STS is associated with a higher chance of inherited susceptibility; however, family history was not available for two-thirds of patients.	('patients', 'Species', '9606', (156, 164))	('age', 'Gene', '5973', (8, 11))	('inherited', 'Var', (70, 79))	('age', 'Gene', (8, 11))	('STS', 'Phenotype', 'HP:0030448', (28, 31))
451375	31464900	3): MPO(+), LCA(+), BCL-2(+), C-myc(+), ER(-), PR(-), cerbB2(-), CK5/6(-), ECad(-), CK(-), P120(-), CD20(-), PAX5(-), CD3(-), CD5(-), BCL-6(-), CD10(-), MUM-1(-), Ki-67 60%.	('CD5', 'Gene', (126, 129))	('CD20', 'Gene', '54474', (100, 104))	('MPO', 'Gene', '4353', (4, 7))	('P120(-)', 'Chemical', 'MESH:C058526', (91, 98))	('MPO', 'Gene', (4, 7))	('C-myc', 'Gene', '4609', (30, 35))	('CD5', 'Gene', '921', (126, 129))	('P120', 'Var', (91, 95))	('LCA(+)', 'Chemical', 'MESH:D017493', (12, 18))	('CD10', 'Gene', '4311', (144, 148))	('PAX5', 'Gene', (109, 113))	('ECad', 'Gene', (75, 79))	('MUM-1', 'Gene', (153, 158))	('CD10', 'Gene', (144, 148))	('BCL-2', 'Gene', '596', (20, 25))	('PAX5', 'Gene', '5079', (109, 113))	('BCL-2', 'Gene', (20, 25))	('C-myc', 'Gene', (30, 35))	('CD20', 'Gene', (100, 104))	('BCL-6', 'Gene', (134, 139))	('ECad', 'Gene', '999', (75, 79))	('BCL-6', 'Gene', '604', (134, 139))	('MUM-1', 'Gene', '84939', (153, 158))
451405	31464900	Several genetic anomalies have been associated with GS, such as t(8; 21) and in(16), which result in AML1/ETO (RUNX1/RUNX1T1) and CBF/MYH11 gene fusions respectively.	('AML1', 'Gene', (101, 105))	('RUNX1', 'Gene', (111, 116))	('ETO', 'Gene', '862', (106, 109))	('RUNX1T1', 'Gene', '862', (117, 124))	('RUNX1', 'Gene', '861', (117, 122))	('MYH11', 'Gene', (134, 139))	('RUNX1', 'Gene', '861', (111, 116))	('anomalies', 'Disease', 'MESH:D000014', (16, 25))	('AML1', 'Gene', '861', (101, 105))	('GS', 'Disease', 'MESH:D023981', (52, 54))	('MYH11', 'Gene', '4629', (134, 139))	('ETO', 'Gene', (106, 109))	('RUNX1T1', 'Gene', (117, 124))	('anomalies', 'Disease', (16, 25))	('fusions', 'Var', (145, 152))	('RUNX1', 'Gene', (117, 122))
451428	28319067	Specifically, we demonstrate that MCAM depletion, like KDM3A depletion, inhibits cell migration in vitro and experimental metastasis in vivo, and that MCAM partially rescues impaired migration due to KDM3A knock-down.	('depletion', 'Var', (39, 48))	('KDM3A', 'Gene', '55818', (200, 205))	('knock-down', 'Var', (206, 216))	('KDM3A', 'Gene', (55, 60))	('inhibits', 'NegReg', (72, 80))	('KDM3A', 'Gene', (200, 205))	('KDM3A', 'Gene', '55818', (55, 60))
451441	28319067	EWS/Ets fusions are key drivers of Ewing Sarcoma pathogenesis, as fusion silencing results in growth arrest and apoptosis .	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('Sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('apoptosis', 'CPA', (112, 121))	('EWS', 'Gene', (0, 3))	('growth arrest', 'Phenotype', 'HP:0001510', (94, 107))	('fusion', 'Var', (66, 72))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('Ewing Sarcoma', 'Disease', (35, 48))	('growth arrest', 'Disease', 'MESH:D006323', (94, 107))	('EWS', 'Gene', '2130', (0, 3))	('growth arrest', 'Disease', (94, 107))
451445	28319067	Epigenetic dysregulation has recently emerged as a very important mechanism of tumor initiation and progression , with an especially important role in pediatric cancers .	('Epigenetic dysregulation', 'Var', (0, 24))	('tumor initiation', 'Disease', 'MESH:D009369', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pediatric cancers', 'Disease', 'MESH:D009369', (151, 168))	('tumor initiation', 'Disease', (79, 95))	('pediatric cancers', 'Disease', (151, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
451452	28319067	This analysis revealed 131 transcripts downregulated 1.5-fold or greater upon KDM3A knock-down with both shRNAs, compared to the Scrambled control (Supplemental Table 1).	('transcripts', 'MPA', (27, 38))	('KDM3A', 'Gene', '55818', (78, 83))	('knock-down', 'Var', (84, 94))	('downregulated', 'NegReg', (39, 52))	('KDM3A', 'Gene', (78, 83))
451453	28319067	Interestingly, functional annotation analysis showed genes downregulated upon KDM3A knock-down to cluster into multiple biological process groups potentially relevant to cancer, including cell adhesion, cell motility/migration, vascular development and receptor signaling (Figure 1A and Supplemental Table 2).	('cell adhesion', 'CPA', (188, 201))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('vascular development', 'CPA', (228, 248))	('cancer', 'Disease', (170, 176))	('cell motility/migration', 'CPA', (203, 226))	('downregulated', 'NegReg', (59, 72))	('KDM3A', 'Gene', '55818', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('knock-down', 'Var', (84, 94))	('KDM3A', 'Gene', (78, 83))
451454	28319067	Expression profiling also revealed 60 upregulated transcripts (1.5-fold or greater) upon KDM3A knock-down (Supplemental Table 1), which showed significant clustering with one functional annotation group, developmental processes (Supplemental Table 2).	('knock-down', 'Var', (95, 105))	('KDM3A', 'Gene', (89, 94))	('developmental processes', 'CPA', (204, 227))	('upregulated', 'PosReg', (38, 49))	('transcripts', 'MPA', (50, 61))	('KDM3A', 'Gene', '55818', (89, 94))
451455	28319067	The finding that KDM3A, a known activator of gene expression through removal of repressive H3K9 histone methyl 1 and 2 marks, positively regulates genes involved in cell adhesion suggested a possible basis for its colony growth-promoting role, shown in our previous studies .	('regulates', 'Reg', (137, 146))	('KDM3A', 'Gene', (17, 22))	('removal', 'Var', (69, 76))	('colony growth-promoting', 'CPA', (214, 237))	('genes involved', 'MPA', (147, 161))	('H3K9 histone', 'Protein', (91, 103))	('KDM3A', 'Gene', '55818', (17, 22))	('cell adhesion', 'CPA', (165, 178))
451457	28319067	Indeed, examination of the most significantly downregulated genes upon KDM3A knock-down (FDR (false discovery rate) < 0.1; Figure 1B), revealed, out of 13 total genes, 7 genes previously implicated in the promotion of metastasis in other cancers (CD44, MCAM, CTGF, CD9, RGNEF, SERPINE1 and KLF5).	('CD44', 'Gene', '960', (247, 251))	('CTGF', 'Gene', (259, 263))	('CD44', 'Gene', (247, 251))	('KLF5', 'Gene', (290, 294))	('KDM3A', 'Gene', (71, 76))	('SERPINE1', 'Gene', '5054', (277, 285))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('knock-down', 'Var', (77, 87))	('MCAM', 'Disease', (253, 257))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('CD9', 'Gene', (265, 268))	('downregulated', 'NegReg', (46, 59))	('metastasis in other cancers', 'Disease', (218, 245))	('RGNEF', 'Gene', (270, 275))	('KDM3A', 'Gene', '55818', (71, 76))	('promotion', 'PosReg', (205, 214))	('SERPINE1', 'Gene', (277, 285))	('metastasis in other cancers', 'Disease', 'MESH:D009362', (218, 245))	('CTGF', 'Gene', '1490', (259, 263))	('CD9', 'Gene', '928', (265, 268))	('RGNEF', 'Gene', '64283', (270, 275))	('KLF5', 'Gene', '688', (290, 294))
451458	28319067	Further, examination of changes in expression of specific genes contributing to the biological process groups in Figure 1A, revealed two-fold or greater downregulation, upon KDM3A knock-down, of 12 genes previously linked to metastasis in other cancers  (Figure 1C; of note, TNC has recently been shown to be metastasis-promotional in Ewing Sarcoma).	('TNC', 'Gene', '3371', (275, 278))	('KDM3A', 'Gene', (174, 179))	('TNC', 'Gene', (275, 278))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (335, 348))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('Sarcoma', 'Phenotype', 'HP:0100242', (341, 348))	('knock-down', 'Var', (180, 190))	('Ewing Sarcoma', 'Disease', (335, 348))	('metastasis in other cancers', 'Disease', 'MESH:D009362', (225, 252))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (335, 348))	('KDM3A', 'Gene', '55818', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('metastasis in other cancers', 'Disease', (225, 252))	('downregulation', 'NegReg', (153, 167))
451463	28319067	In both cell lines, cells with KDM3A knock-down (Figure 2, A and C) showed approximately a 50 percent decrease in migration compared to those harboring the Scrambled control (Figure 2, B and D).	('KDM3A', 'Gene', '55818', (31, 36))	('decrease', 'NegReg', (102, 110))	('migration', 'CPA', (114, 123))	('KDM3A', 'Gene', (31, 36))	('knock-down', 'Var', (37, 47))
451464	28319067	As was the case with the Boyden chamber assay, A673 cells with KDM3A knock-down showed impaired migration into the wound compared to the Scrambled controls, again by an average of approximately 50 percent (Supplemental Figure 1).	('impaired', 'NegReg', (87, 95))	('KDM3A', 'Gene', (63, 68))	('migration into the wound', 'CPA', (96, 120))	('knock-down', 'Var', (69, 79))	('KDM3A', 'Gene', '55818', (63, 68))
451476	28319067	In order to verify our expression profiling results and determine whether KDM3A is a more general regulator of MCAM expression in Ewing Sarcoma, we examined the effects of KDM3A knock-down on MCAM levels in multiple Ewing Sarcoma cell lines, including A673 and TC32 cells.	('KDM3A', 'Gene', '55818', (172, 177))	('multiple Ewing Sarcoma', 'Disease', (207, 229))	('TC32', 'CellLine', 'CVCL:7151', (261, 265))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (130, 143))	('knock-down', 'Var', (178, 188))	('Ewing Sarcoma', 'Disease', (130, 143))	('KDM3A', 'Gene', (172, 177))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (216, 229))	('KDM3A', 'Gene', '55818', (74, 79))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (130, 143))	('KDM3A', 'Gene', (74, 79))	('multiple Ewing Sarcoma', 'Disease', 'MESH:C563168', (207, 229))	('Sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('Sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (216, 229))
451477	28319067	These studies revealed consistent downregulation of MCAM levels upon KDM3A knock-down (Figure 4), indicating that KDM3A is an important regulator of MCAM expression in Ewing Sarcoma.	('knock-down', 'Var', (75, 85))	('KDM3A', 'Gene', '55818', (69, 74))	('KDM3A', 'Gene', '55818', (114, 119))	('KDM3A', 'Gene', (69, 74))	('downregulation', 'NegReg', (34, 48))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (168, 181))	('KDM3A', 'Gene', (114, 119))	('MCAM levels', 'MPA', (52, 63))	('Ewing Sarcoma', 'Disease', (168, 181))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (168, 181))	('Sarcoma', 'Phenotype', 'HP:0100242', (174, 181))
451478	28319067	To further evaluate MCAM as a candidate downstream effector of KDM3A pro-metastatic action, we examined whether MCAM knock-down could phenocopy the effects of KDM3A depletion.	('KDM3A', 'Gene', '55818', (159, 164))	('KDM3A', 'Gene', (63, 68))	('MCAM', 'Gene', (112, 116))	('knock-down', 'Var', (117, 127))	('KDM3A', 'Gene', (159, 164))	('KDM3A', 'Gene', '55818', (63, 68))
451480	28319067	In a Boyden chamber assay, upon MCAM knock-down using two different targeting shRNAs (Figure 5A and C), MCAM depletion resulted in diminished migration compared to cells with the Scrambled control, by approximately 50 percent in A673 cells and 30 percent in TC32 cells (Figure 5B and D).	('TC32', 'CellLine', 'CVCL:7151', (258, 262))	('migration', 'CPA', (142, 151))	('depletion', 'NegReg', (109, 118))	('diminished', 'NegReg', (131, 141))	('MCAM', 'Gene', (104, 108))	('knock-down', 'Var', (37, 47))
451482	28319067	Mice injected with MCAM knock-down cells developed an approximately 3-fold lower metastatic tumor burden compared to those injected with the Scrambled control cells (Figure 6).	('lower', 'NegReg', (75, 80))	('MCAM', 'Gene', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('knock-down', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (92, 97))
451486	28319067	Further, using ChIP for the H3K9me2 mark negatively regulated by KDM3A, we found that levels of this mark in the same region increased upon KDM3A knock-down (Figure 7A).	('KDM3A', 'Gene', (140, 145))	('levels', 'MPA', (86, 92))	('increased', 'PosReg', (125, 134))	('KDM3A', 'Gene', (65, 70))	('knock-down', 'Var', (146, 156))	('KDM3A', 'Gene', '55818', (140, 145))	('KDM3A', 'Gene', '55818', (65, 70))
451487	28319067	As an additional control, ChIP for KDM3A at a distal region (10 Kbp upstream of the MCAM transcription start site), revealed neither evidence of specific KDM3A localization, nor changes in levels of the H3K9me2 mark upon KDM3A knock-down (Figure 7B).	('KDM3A', 'Gene', (154, 159))	('KDM3A', 'Gene', '55818', (221, 226))	('levels', 'MPA', (189, 195))	('knock-down', 'Var', (227, 237))	('Kbp', 'Gene', (64, 67))	('KDM3A', 'Gene', (35, 40))	('KDM3A', 'Gene', (221, 226))	('KDM3A', 'Gene', '55818', (154, 159))	('KDM3A', 'Gene', '55818', (35, 40))	('Kbp', 'Gene', '26128', (64, 67))
451488	28319067	Together, these data support a mechanism whereby KDM3A, at least in part, regulates MCAM expression directly, through interaction with the MCAM promoter region and H3K9 demethylation.	('demethylation', 'Var', (169, 182))	('expression', 'MPA', (89, 99))	('regulates', 'Reg', (74, 83))	('MCAM', 'Gene', (84, 88))	('H3K9', 'Protein', (164, 168))	('KDM3A', 'Gene', (49, 54))	('interaction', 'Interaction', (118, 129))	('KDM3A', 'Gene', '55818', (49, 54))
451492	28319067	This analysis revealed potent downregulation of MCAM upon Ets1 knock-down (Figure 7C), demonstrating that Ets1 contributes to control of MCAM expression.	('Ets1', 'Gene', (106, 110))	('Ets1', 'Gene', '2113', (106, 110))	('downregulation', 'NegReg', (30, 44))	('Ets1', 'Gene', (58, 62))	('Ets1', 'Gene', '2113', (58, 62))	('knock-down', 'Var', (63, 73))	('MCAM', 'Gene', (48, 52))
451493	28319067	Similarly, we found that Ets1 depletion in TC32 cells also resulted in diminished MCAM levels (Supplemental Figure 4B).	('Ets1', 'Gene', '2113', (25, 29))	('diminished', 'NegReg', (71, 81))	('MCAM levels', 'MPA', (82, 93))	('depletion', 'Var', (30, 39))	('Ets1', 'Gene', (25, 29))	('TC32', 'CellLine', 'CVCL:7151', (43, 47))
451496	28319067	Using ChIP-qPCR approaches analogous to those above, we found that KDM3A specifically interacts with the genomic region flanking the Ets1 transcription start site, and that KDM3A depletion results in augmented H3K9me2 levels in the same region (Figure 7E), consistent with direct regulation of Ets1 expression through H3K9 demethylation by KDM3A.	('Ets1', 'Gene', (294, 298))	('Ets1', 'Gene', (133, 137))	('KDM3A', 'Gene', (340, 345))	('KDM3A', 'Gene', '55818', (173, 178))	('H3K9me2 levels', 'MPA', (210, 224))	('depletion', 'Var', (179, 188))	('KDM3A', 'Gene', '55818', (67, 72))	('augmented', 'PosReg', (200, 209))	('KDM3A', 'Gene', '55818', (340, 345))	('KDM3A', 'Gene', (173, 178))	('Ets1', 'Gene', '2113', (294, 298))	('Ets1', 'Gene', '2113', (133, 137))	('interacts', 'Interaction', (86, 95))	('KDM3A', 'Gene', (67, 72))
451497	28319067	Further, using ChIP-qPCR for Ets1, we found that Ets1 specifically interacted with an MCAM upstream regulatory region containing multiple candidate Ets binding sites, and that this interaction was abolished upon Ets1 knock-down (Figure 7F), thus supporting a direct mechanism for this regulatory relationship as well.	('MCAM upstream regulatory region', 'MPA', (86, 117))	('Ets1', 'Gene', '2113', (212, 216))	('Ets1', 'Gene', (212, 216))	('Ets1', 'Gene', (49, 53))	('knock-down', 'Var', (217, 227))	('interacted', 'Interaction', (67, 77))	('Ets1', 'Gene', '2113', (49, 53))	('Ets1', 'Gene', '2113', (29, 33))	('Ets1', 'Gene', (29, 33))
451499	28319067	Lastly, in support of the clinical relevance of our findings and an important role for MCAM in Ewing Sarcoma biology, interrogation of the same Ewing Sarcoma patient cohorts  revealed a significant association between high MCAM expression in tumors and poor survival (Figure 8).	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (95, 108))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (144, 157))	('high', 'Var', (218, 222))	('patient', 'Species', '9606', (158, 165))	('Ewing Sarcoma', 'Disease', (95, 108))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('Sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('Ewing Sarcoma', 'Disease', (144, 157))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (144, 157))	('Sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))	('expression', 'MPA', (228, 238))	('poor survival', 'CPA', (253, 266))	('MCAM', 'Protein', (223, 227))
451507	28319067	Epigenetic modifiers have been increasingly implicated in cancer, including the malignant biology of Ewing Sarcoma .	('Ewing Sarcoma', 'Disease', (101, 114))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('implicated', 'Reg', (44, 54))	('Sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('Epigenetic modifiers', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('cancer', 'Disease', (58, 64))
451510	28319067	KDM3A was shown to demethylate the promoter of the long non-coding RNA MALAT1, which resulted in an increase in MALAT1 levels, and in the metastasis-associated phenotypes of cell migration and invasion .	('cell migration', 'CPA', (174, 188))	('metastasis-associated phenotypes', 'CPA', (138, 170))	('KDM3A', 'Gene', (0, 5))	('MALAT1', 'Gene', '378938', (71, 77))	('MALAT1', 'Gene', '378938', (112, 118))	('demethylate', 'Var', (19, 30))	('KDM3A', 'Gene', '55818', (0, 5))	('MALAT1', 'Gene', (112, 118))	('MALAT1', 'Gene', (71, 77))	('increase', 'PosReg', (100, 108))	('invasion', 'CPA', (193, 201))
451514	28319067	These same processes are known to contribute to neoplasia and tumor progression, and MCAM expression has been shown to correlate with poor prognosis, metastasis and disease progression in a number of different cancer types, including melanoma, prostate, ovarian, gastric, non-small cell lung, gallbladder, and breast cancers .	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('metastasis', 'CPA', (150, 160))	('non-small cell lung', 'Disease', (272, 291))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('neoplasia and tumor', 'Disease', 'MESH:D009369', (48, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (317, 324))	('prostate', 'Disease', (244, 252))	('expression', 'Var', (90, 100))	('cancer', 'Disease', (317, 323))	('gastric', 'Disease', (263, 270))	('neoplasia', 'Phenotype', 'HP:0002664', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('breast cancers', 'Disease', 'MESH:D001943', (310, 324))	('breast cancers', 'Disease', (310, 324))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('melanoma', 'Disease', (234, 242))	('ovarian', 'Disease', (254, 261))	('breast cancers', 'Phenotype', 'HP:0003002', (310, 324))	('gallbladder', 'Disease', (293, 304))	('MCAM', 'Gene', (85, 89))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
451528	28319067	Notably, EWS/Ets fusions have been found to repress, rather than activate, many genes and biological processes known to be involved in the promotion of metastatic phenotypes, such as cell adhesion and migration.	('migration', 'CPA', (201, 210))	('EWS', 'Gene', '2130', (9, 12))	('EWS', 'Gene', (9, 12))	('activate', 'PosReg', (65, 73))	('cell adhesion', 'CPA', (183, 196))	('fusions', 'Var', (17, 24))	('repress', 'NegReg', (44, 51))	('genes', 'Gene', (80, 85))
451548	28319067	The primary antibodies used were: KDM3A (1:1000, ProMab, #30134), MCAM (1:1000, Proteintech, #17564-1-AP), Ets1 (1:1000, Cell Signaling, #14069), and alpha-Tubulin (1:20,000, Sigma, #T5168).	('alpha-Tubulin', 'Gene', '10376', (150, 163))	('KDM3A', 'Gene', (34, 39))	('1:1000', 'Var', (72, 78))	('Ets1', 'Gene', (107, 111))	('Ets1', 'Gene', '2113', (107, 111))	('KDM3A', 'Gene', '55818', (34, 39))	('alpha-Tubulin', 'Gene', (150, 163))
451558	28319067	ChIP analysis of control (Scrambled shRNA), KDM3A knock-down and Ets1 knock-down Ewing Sarcoma A673 cells was performed as described in Supplemental Methods.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('Sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing Sarcoma', 'Disease', (81, 94))	('Ets1', 'Gene', '2113', (65, 69))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('knock-down', 'Var', (70, 80))	('Ets1', 'Gene', (65, 69))	('KDM3A', 'Gene', '55818', (44, 49))	('KDM3A', 'Gene', (44, 49))
451562	26024286	We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody-drug conjugates (ADCs) exhibited subnanomolar IC50 values against AML cell lines in vitro.	('monomethyl auristatin F', 'Chemical', 'MESH:C513576', (102, 125))	('IC50', 'MPA', (219, 223))	('AML', 'Disease', 'MESH:D015470', (239, 242))	('tumor', 'Disease', (21, 26))	('AML', 'Phenotype', 'HP:0004808', (239, 242))	('anti-SAIL', 'Var', (154, 163))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('AML', 'Disease', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
451563	26024286	In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('AML', 'Disease', 'MESH:D015470', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('anti-SAIL', 'Var', (60, 69))	('AML', 'Phenotype', 'HP:0004808', (34, 37))	('AML', 'Disease', (34, 37))
451567	26024286	The regulatory approvals of brentuximab vedotin and ado-trastuzumab emtansine have demonstrated that ADCs can provide significant clinical advantages compared with unconjugated antibodies.	('ado-trastuzumab emtansine', 'Chemical', 'MESH:C550911', (52, 77))	('ADCs', 'Var', (101, 105))	('advantages', 'PosReg', (139, 149))
451585	26024286	Antibodies were purchased as follows, Miltenyi Biotec (Bergisch Gladbach, Germany): CD33 (catalog number 130-091-732), CD34 (130-095-393), CD38 (130-099-151); Biolegend (San Diego, CA, USA): CD5 (300622), CD19 (302208), CD56 (318332); eBioscience (San Diego, CA, USA): CD3 (48-0037-42), CD14 (25-0149), Lineage cocktail (22-7778-72).	('CD38', 'Gene', '952', (139, 143))	('CD19', 'Gene', (205, 209))	('CD14', 'Gene', '929', (287, 291))	('CD14', 'Gene', (287, 291))	('CD56', 'Gene', '4684', (220, 224))	('CD5', 'Gene', (220, 223))	('CD19', 'Gene', '930', (205, 209))	('CD5', 'Gene', '921', (220, 223))	('CD34', 'Gene', (119, 123))	('CD33', 'Gene', '945', (84, 88))	('CD56', 'Gene', (220, 224))	('CD5', 'Gene', (191, 194))	('CD34', 'Gene', '947', (119, 123))	('CD38', 'Gene', (139, 143))	('302208', 'Var', (211, 217))	('CD33', 'Gene', (84, 88))	('CD5', 'Gene', '921', (191, 194))	('Biotec', 'Chemical', '-', (47, 53))
451628	26024286	Across a panel of cancer cell lines, copy number generally did not correlate with ADC activity in vitro, a phenomenon observed for ADCs against other targets.	('activity', 'MPA', (86, 94))	('copy number', 'Var', (37, 48))	('ADC', 'Enzyme', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
451634	26024286	Taken together, these data demonstrated that anti-SAIL ADCs were antigen-specific and exhibited potent cytotoxic activity toward AML cell lines in vitro.	('anti-SAIL', 'Var', (45, 54))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('AML', 'Disease', (129, 132))	('AML', 'Phenotype', 'HP:0004808', (129, 132))	('ADCs', 'Protein', (55, 59))	('cytotoxic activity', 'CPA', (103, 121))
451636	26024286	In the OCI-AML3 and THP1 AML models, significant tumor growth inhibition was observed for the anti-SAIL ADCs compared with the nontargeting isotype control ADC at a dose level of 3 mg/kg (Figure 6a and b).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('THP1', 'Gene', (20, 24))	('THP1', 'Gene', '2736', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('anti-SAIL', 'Var', (94, 103))	('tumor', 'Disease', (49, 54))	('AML', 'Disease', 'MESH:D015470', (25, 28))	('AML', 'Disease', 'MESH:D015470', (11, 14))	('AML', 'Phenotype', 'HP:0004808', (25, 28))	('AML', 'Phenotype', 'HP:0004808', (11, 14))	('AML', 'Disease', (25, 28))	('AML', 'Disease', (11, 14))
451658	26024286	In two AML cell line xenograft models, anti-SAIL ADCs were found to exhibit strong antitumor activity compared with a nonspecific isotype control ADC or with naked anti-SAIL mAbs (Figure 6).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('anti-SAIL', 'Var', (39, 48))	('AML', 'Disease', 'MESH:D015470', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('AML', 'Disease', (7, 10))	('AML', 'Phenotype', 'HP:0004808', (7, 10))
451661	26024286	Moreover, we have demonstrated that ADCs against SAIL have high in vitro potency and demonstrate high antitumor activity in vivo in multiple xenograft models.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('ADCs', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
451753	24422949	Despite these results, no data are available examining the use of 18FDG PET/CT in CBS, and the possible role of functional imaging in determining the management of these patients has been poorly investigated.	('patients', 'Species', '9606', (170, 178))	('CBS', 'Disease', 'MESH:D006712', (82, 85))	('CBS', 'Disease', (82, 85))	('18FDG', 'Chemical', 'MESH:D019788', (66, 71))	('CT', 'Chemical', 'MESH:D002251', (76, 78))	('18FDG', 'Var', (66, 71))
451765	28947952	Identification of SRF-E2F1 fusion transcript in EWSR-negative myoepithelioma of the soft tissue Myoepithelial neoplasms (MN) are rare and not well-circumstanced entities displaying a heterogeneous spectrum of genetic abnormalities, including EWSR1, FUS and PLAG1 rearrangements.	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('FUS', 'Gene', (249, 252))	('MN', 'Phenotype', 'HP:0031492', (121, 123))	('myoepithelioma', 'Disease', 'MESH:D009208', (62, 76))	('Myoepithelial neoplasms', 'Disease', (96, 119))	('fusion', 'Var', (27, 33))	('FUS', 'Gene', '2521', (249, 252))	('EWSR1', 'Gene', (242, 247))	('PLAG1', 'Gene', (257, 262))	('E2F1', 'Gene', (22, 26))	('Myoepithelial neoplasms', 'Phenotype', 'HP:0031492', (96, 119))	('genetic abnormalities', 'Disease', 'MESH:D030342', (209, 230))	('MN', 'CellLine', 'CVCL:U508', (121, 123))	('SRF', 'Gene', '6722', (18, 21))	('neoplasm', 'Phenotype', 'HP:0002664', (110, 118))	('genetic abnormalities', 'Disease', (209, 230))	('E2F1', 'Gene', '1869', (22, 26))	('PLAG1', 'Gene', '5324', (257, 262))	('Myoepithelial neoplasms', 'Disease', 'MESH:D009208', (96, 119))	('EWSR1', 'Gene', '2130', (242, 247))	('SRF', 'Gene', (18, 21))	('myoepithelioma', 'Disease', (62, 76))
451768	28947952	A novel SRF-E2F1 fusion was detected in two cases: one was negative for other fusions while the other showed also the presence of FUS-KLF17.	('detected', 'Reg', (28, 36))	('KLF17', 'Gene', (134, 139))	('fusion', 'Var', (17, 23))	('E2F1', 'Gene', '1869', (12, 16))	('SRF', 'Gene', '6722', (8, 11))	('E2F1', 'Gene', (12, 16))	('FUS', 'Gene', (130, 133))	('FUS', 'Gene', '2521', (130, 133))	('SRF', 'Gene', (8, 11))	('KLF17', 'Gene', '128209', (134, 139))
451771	28947952	Moreover, ectopical expression of SRF-E2F1 demonstrated that the chimeric transcript is functionally active and could affect tumor growth.	('SRF', 'Gene', '6722', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('affect', 'Reg', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('ectopical', 'Var', (10, 19))	('SRF', 'Gene', (34, 37))	('E2F1', 'Gene', '1869', (38, 42))	('E2F1', 'Gene', (38, 42))
451778	28947952	According to the literature, nearly half of myoepithelial neoplasm carries EWSR1 translocations to an ever increasing variety of partners.	('myoepithelial neoplasm', 'Disease', 'MESH:D009208', (44, 66))	('EWSR1', 'Gene', '2130', (75, 80))	('myoepithelial neoplasm', 'Phenotype', 'HP:0031492', (44, 66))	('neoplasm', 'Phenotype', 'HP:0002664', (58, 66))	('myoepithelial neoplasm', 'Disease', (44, 66))	('translocations', 'Var', (81, 95))	('EWSR1', 'Gene', (75, 80))
451781	28947952	In addition to EWSR1, also PLAG1 translocations have been described in MN cases with ductal differentiation.	('ductal', 'Disease', (85, 91))	('described', 'Reg', (58, 67))	('PLAG1', 'Gene', (27, 32))	('translocations', 'Var', (33, 47))	('EWSR1', 'Gene', (15, 20))	('MN', 'CellLine', 'CVCL:U508', (71, 73))	('PLAG1', 'Gene', '5324', (27, 32))	('MN', 'Phenotype', 'HP:0031492', (71, 73))	('EWSR1', 'Gene', '2130', (15, 20))
451789	28947952	Instead, the FUS positive case (L108) was predicted to carry a fusion between SRF and E2F1, besides the primary chimeric transcript involving FUS and KLF17 genes.	('FUS', 'Gene', (142, 145))	('E2F1', 'Gene', '1869', (86, 90))	('E2F1', 'Gene', (86, 90))	('FUS', 'Gene', '2521', (142, 145))	('SRF', 'Gene', (78, 81))	('KLF17', 'Gene', (150, 155))	('FUS', 'Gene', (13, 16))	('fusion', 'Var', (63, 69))	('FUS', 'Gene', '2521', (13, 16))	('SRF', 'Gene', '6722', (78, 81))	('KLF17', 'Gene', '128209', (150, 155))
451795	28947952	In both L107 and L108, SRF and E2F1 exons involved in the fusion gene were highly expressed when compared to the ones not participating in the chimera (Figure 2).	('E2F1', 'Gene', (31, 35))	('L107', 'Var', (8, 12))	('SRF', 'Gene', (23, 26))	('L108', 'Var', (17, 21))	('SRF', 'Gene', '6722', (23, 26))	('E2F1', 'Gene', '1869', (31, 35))
451801	28947952	In both L107 and L108, corresponding to one spindle cell and one mixed type myoepithelioma respectively (Figure 3C), the rearrangement of SRF gene was observed in about 20% of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('L107', 'Var', (8, 12))	('SRF', 'Gene', '6722', (138, 141))	('tumor', 'Disease', (176, 181))	('type myoepithelioma', 'Disease', 'MESH:D009208', (71, 90))	('type myoepithelioma', 'Disease', (71, 90))	('L108', 'Var', (17, 21))	('SRF', 'Gene', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
451804	28947952	Interestingly, the two SRF-E2F1 positive patients were younger than the other three cases with a mean age at diagnosis of 29.5 vs 45.3 years (P < 0.05), even if the cohort analyzed was too small to draw any definitive conclusion.	('SRF', 'Gene', (23, 26))	('patients', 'Species', '9606', (41, 49))	('E2F1', 'Gene', '1869', (27, 31))	('SRF', 'Gene', '6722', (23, 26))	('positive', 'Var', (32, 40))	('E2F1', 'Gene', (27, 31))
451814	28947952	It is well known that gene fusions are a relevant class of "driver mutations" in cancer, particularly in hematologic malignancies and in a subset of sarcomas.	('hematologic malignancies', 'Disease', 'MESH:D019337', (105, 129))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('sarcomas', 'Disease', 'MESH:D012509', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('hematologic malignancies', 'Disease', (105, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('sarcomas', 'Disease', (149, 157))	('gene fusions', 'Var', (22, 34))
451817	28947952	Here, we report a novel fusion event, consisting in a SRF-E2F1 fusion in two cases of soft tissue ME, one mixed type tumor and one spindle cell myoepithelioma, respectively.	('type tumor', 'Disease', 'MESH:D009369', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('SRF', 'Gene', (54, 57))	('myoepithelioma', 'Disease', 'MESH:D009208', (144, 158))	('fusion', 'Var', (63, 69))	('SRF', 'Gene', '6722', (54, 57))	('type tumor', 'Disease', (112, 122))	('myoepithelioma', 'Disease', (144, 158))	('E2F1', 'Gene', '1869', (58, 62))	('E2F1', 'Gene', (58, 62))
451824	28947952	Recently, fusion genes involving SRF were detected in some types of mesenchymal tumors, including SRF-NCOA2 in one case of infantile spindle cell rhabdomyosarcoma and SRF-RELA in 7 cases of myofribroma and myopericytoma.	('NCOA2', 'Gene', '10499', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SRF', 'Gene', (33, 36))	('SRF', 'Gene', (167, 170))	('myofribroma and myopericytoma', 'Disease', 'MESH:D000077777', (190, 219))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (146, 162))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (68, 86))	('RELA', 'Gene', (171, 175))	('RELA', 'Gene', '5970', (171, 175))	('NCOA2', 'Gene', (102, 107))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (146, 162))	('detected', 'Reg', (42, 50))	('fusion genes', 'Var', (10, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('mesenchymal tumors', 'Disease', (68, 86))	('SRF', 'Gene', '6722', (98, 101))	('SRF', 'Gene', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('SRF', 'Gene', '6722', (33, 36))	('rhabdomyosarcoma', 'Disease', (146, 162))	('SRF', 'Gene', '6722', (167, 170))
451827	28947952	Yet, deregulation of E2F1 expression can either promote or inhibit tumorigenesis depending on the nature of the cellular context.	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('E2F1', 'Gene', '1869', (21, 25))	('deregulation', 'Var', (5, 17))	('inhibit', 'NegReg', (59, 66))	('promote', 'PosReg', (48, 55))	('E2F1', 'Gene', (21, 25))
451834	28947952	Together, these data suggest that SRF-E2F1 fusion could be a secondary event acquired during tumor clonal genetic evolution.	('SRF', 'Gene', '6722', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('SRF', 'Gene', (34, 37))	('fusion', 'Var', (43, 49))	('E2F1', 'Gene', '1869', (38, 42))	('E2F1', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
451837	28947952	The biological relevance of the two genes involved and the fact that this event was found to occur in two different patients, suggest that SRF-E2F1 fusion could be relevant in the tumor natural history, being a late event in the tumor biology time course.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('SRF', 'Gene', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', (229, 234))	('E2F1', 'Gene', '1869', (143, 147))	('E2F1', 'Gene', (143, 147))	('fusion', 'Var', (148, 154))	('SRF', 'Gene', '6722', (139, 142))
451854	28947952	Moreover, copy number analysis (detection of large amplifications or deletions) was performed making a consensus between two softwares (Control FREEC and ADTEX) with paired tumour/matched normal samples.	('deletions', 'Var', (69, 78))	('tumour', 'Disease', (173, 179))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
451931	23383402	Ewing sarcoma is characterized by IGF pathway activating translocations of the EWSR1 gene.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', (79, 84))	('EWSR1', 'Gene', '2130', (79, 84))	('Ewing sarcoma', 'Disease', (0, 13))	('translocations', 'Var', (57, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('activating', 'PosReg', (46, 56))
451937	23383402	IGF-1R blockade can also be combined with other agents, specifically vincristine, doxorubicin, or imatinib for synergy.	('doxorubicin', 'Chemical', 'MESH:D004317', (82, 93))	('vincristine', 'Chemical', 'MESH:D014750', (69, 80))	('blockade', 'Var', (7, 15))	('imatinib', 'Chemical', 'MESH:D000068877', (98, 106))	('IGF-1R', 'Gene', (0, 6))
451940	23383402	Alveolar rhabdomyosarcoma is associated with a fusion protein resulting from translocations in the PAX3 or PAX7 genes and FOXO1.	('FOXO1', 'Gene', (122, 127))	('PAX7', 'Gene', '5081', (107, 111))	('FOXO1', 'Gene', '2308', (122, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('PAX3', 'Gene', '5077', (99, 103))	('PAX3', 'Gene', (99, 103))	('translocations', 'Var', (77, 91))	('Alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (0, 25))	('Alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (0, 25))	('Alveolar rhabdomyosarcoma', 'Disease', (0, 25))	('PAX7', 'Gene', (107, 111))	('associated', 'Reg', (29, 39))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (9, 25))
451945	23383402	Nearly 20 years after that first observation, a mouse xenograft model using six different osteosarcoma cell lines demonstrated objective responses to R1507, a monoclonal anti-IGF1R antibody, in vivo.	('mouse', 'Species', '10090', (48, 53))	('osteosarcoma', 'Disease', (90, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('R1507', 'Var', (150, 155))
451949	23383402	The IGF-1R inhibitor AEW541 had promising effects on proliferation.	('proliferation', 'CPA', (53, 66))	('AEW541', 'Var', (21, 27))	('AEW541', 'Chemical', '-', (21, 27))
451950	23383402	The role of IGF-1R signaling in the pathogenesis of Wilms tumor was proposed at least as early as 1989, when an anti-IGF-1R antibody slowed tumor growth in an in vivo model.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Wilms tumor', 'Disease', (52, 63))	('Wilms tumor', 'Phenotype', 'HP:0002667', (52, 63))	('slowed', 'NegReg', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('anti-IGF-1R', 'Var', (112, 123))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Wilms tumor', 'Disease', 'MESH:D009396', (52, 63))	('tumor', 'Disease', (140, 145))
451952	23383402	Increased gene copy number of IGF-1R has been associated with recurrence, and in general with worse outcomes in Wilms tumor.	('recurrence', 'Disease', (62, 72))	('Wilms tumor', 'Phenotype', 'HP:0002667', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Increased gene copy number', 'Var', (0, 26))	('Wilms tumor', 'Disease', (112, 123))	('Wilms tumor', 'Disease', 'MESH:D009396', (112, 123))	('IGF-1R', 'Gene', (30, 36))	('associated', 'Reg', (46, 56))
451955	23383402	Most recently, a mouse xenograft model in which cells from a Wilms tumor cell line were grown orthotopically within mouse kidney was used to show that AEW541, an IGF-1R inhibitor, reduced tumor growth.	('tumor', 'Disease', (188, 193))	('mouse', 'Species', '10090', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('AEW541', 'Var', (151, 157))	('Wilms tumor', 'Disease', (61, 72))	('Wilms tumor', 'Disease', 'MESH:D009396', (61, 72))	('reduced', 'NegReg', (180, 187))	('Wilms tumor', 'Phenotype', 'HP:0002667', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('AEW541', 'Chemical', '-', (151, 157))	('mouse', 'Species', '10090', (116, 121))
451961	23383402	Cell lines highly expressing IGF-1R were much more likely to develop osteolytic lesions when injected into mouse tibia compared to the same cells without IGF-1R.	('osteolytic lesions', 'Disease', 'MESH:D030981', (69, 87))	('IGF-1R', 'Var', (29, 35))	('mouse', 'Species', '10090', (107, 112))	('osteolytic lesions', 'Phenotype', 'HP:0002797', (69, 87))	('osteolytic lesions', 'Disease', (69, 87))	('develop', 'PosReg', (61, 68))
451967	23383402	Genetically, pediatric gliomas are more commonly associated with PDGFR-alpha aberrations compared to adult gliomas, which are more commonly associated with aberrations in EGFR signaling.	('EGFR', 'Gene', (171, 175))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('associated', 'Reg', (49, 59))	('gliomas', 'Disease', (23, 30))	('PDGFR-alpha', 'Gene', '5156', (65, 76))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('aberrations', 'Var', (77, 88))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('EGFR', 'Gene', '1956', (171, 175))	('PDGFR-alpha', 'Gene', (65, 76))
451968	23383402	Gene amplification of IGF-1R has been shown in high grade pediatric gliomas.	('IGF-1R', 'Gene', (22, 28))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('Gene amplification', 'Var', (0, 18))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('shown', 'Reg', (38, 43))
451972	23383402	There were hints of antiproliferative activity of R1507 in some medulloblastoma cell lines.	('medulloblastoma', 'Phenotype', 'HP:0002885', (64, 79))	('antiproliferative', 'MPA', (20, 37))	('medulloblastoma', 'Disease', (64, 79))	('R1507', 'Var', (50, 55))	('medulloblastoma', 'Disease', 'MESH:D008527', (64, 79))
451974	23383402	In adults, approximately 85% of GIST is at least partially driven by mutations in KIT or PDGFRA, a finding that led to the current imatinib- and sunitinib-based regimens used to treat most adult GIST.	('mutations', 'Var', (69, 78))	('driven', 'Reg', (59, 65))	('PDGFRA', 'Gene', '5156', (89, 95))	('imatinib', 'Chemical', 'MESH:D000068877', (131, 139))	('sunitinib', 'Chemical', 'MESH:D000077210', (145, 154))	('GIST', 'Phenotype', 'HP:0100723', (195, 199))	('GIST', 'Disease', (32, 36))	('GIST', 'Phenotype', 'HP:0100723', (32, 36))	('KIT', 'Gene', (82, 85))	('PDGFRA', 'Gene', (89, 95))
451975	23383402	On the other hand, pediatric GIST usually does not have the KIT and PDGFRA mutations that normally characterize adult GIST.	('PDGFRA', 'Gene', (68, 74))	('KIT', 'Gene', (60, 63))	('mutations', 'Var', (75, 84))	('GIST', 'Phenotype', 'HP:0100723', (118, 122))	('GIST', 'Phenotype', 'HP:0100723', (29, 33))	('PDGFRA', 'Gene', '5156', (68, 74))
451989	23383402	In vivo studies combining IGF-1R inhibitors with rapamycin resulted in more sustained antitumor effect compared to either agent alone in a mouse xenograft model.	('rapamycin', 'Chemical', 'MESH:D020123', (49, 58))	('IGF-1R', 'Gene', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mouse', 'Species', '10090', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('inhibitors', 'Var', (33, 43))
451993	23383402	In vitro studies with ARMS cells demonstrated that co-treatment with NVP-AEW541, an IGF1R inhibitor, combined with lapatinib, a HER2 antagonist, reduced the phosphorylation of IGF-1R and consequently decreased IGF mediated signaling in cells resistant to IGF-1R modulators alone.	('AEW541', 'Chemical', '-', (73, 79))	('IGF mediated signaling', 'MPA', (210, 232))	('HER2', 'Gene', (128, 132))	('reduced', 'NegReg', (145, 152))	('IGF-1R', 'Protein', (176, 182))	('HER2', 'Gene', '2064', (128, 132))	('lapatinib', 'Chemical', 'MESH:D000077341', (115, 124))	('phosphorylation', 'MPA', (157, 172))	('decreased', 'NegReg', (200, 209))	('NVP-AEW541', 'Var', (69, 79))	('decreased IGF', 'Phenotype', 'HP:0002850', (200, 213))	('ARMS', 'Phenotype', 'HP:0006779', (22, 26))
452010	23383402	In spite of the low response rates in most trials of IGF-1R inhibitors, the dramatic images seen in the patients who did respond encourage further research in this important signaling pathway.	('IGF-1R', 'Gene', (53, 59))	('inhibitors', 'Var', (60, 70))	('patients', 'Species', '9606', (104, 112))
452037	20181247	RNA-Expression of survivin and two other stem cell-associated genes (Hiwi, hTERT) was correlated with a 15.5-fold increased risk of tumor-related death for soft tissue sarcoma patients.	('patients', 'Species', '9606', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('RNA-Expression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (156, 175))	('survivin', 'Gene', (18, 26))	('Hiwi', 'Gene', '9271', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('sarcoma', 'Disease', (168, 175))	('Hiwi', 'Gene', (69, 73))	('hTERT', 'Gene', '7015', (75, 80))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('tumor', 'Disease', (132, 137))	('hTERT', 'Gene', (75, 80))
452145	34007275	Aware of the heterogeneity of the literature, and based on the experience that a vast majority of MRI scans have an inconspicuous finding, while posing a significant psychological burden on the patient and a financial strain on the health system, we asked whether the currently recommended frequency of MRI scans is necessary.	('patient', 'Species', '9606', (194, 201))	('MRI', 'Gene', (98, 101))	('scans', 'Var', (102, 107))
452148	34007275	However, not only sarcoma recurrence but also biopsies and therapeutic resections can lead to local irritation and pain, some of which assume a chronic course.	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('biopsies', 'Var', (46, 54))	('sarcoma', 'Disease', (18, 25))	('pain', 'Phenotype', 'HP:0012531', (115, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('pain', 'Disease', 'MESH:D010146', (115, 119))	('pain', 'Disease', (115, 119))	('irritation', 'Disease', (100, 110))	('lead to', 'Reg', (86, 93))	('irritation', 'Disease', 'MESH:D001523', (100, 110))
452162	31913509	Cumulative anthracycline exposure (per 100mg/m2) was associated with poorer verbal reasoning (beta=-0.14 Z-scores, p=.04), reading (beta=-0.09 Z-scores, p=.04) and patient-reported vitality (relative risk= 1.32, 95% confidence interval 1.09-1.59).	('verbal reasoning', 'CPA', (76, 92))	('anthracycline', 'Chemical', 'MESH:D018943', (11, 24))	('patient', 'Species', '9606', (164, 171))	('anthracycline', 'Var', (11, 24))	('poorer', 'NegReg', (69, 75))	('patient-reported vitality', 'CPA', (164, 189))	('reading', 'CPA', (123, 130))
452182	31913509	Higher exposure to anthracyclines was associated with worse performance in verbal reasoning (beta =-0.14, p=0.04), reading (beta =-0.09, p=0.04), and initiation (beta =-0.14, p=0.02; Table 3) [Note: beta represents the non-standardized estimate, unit = z-score/ (100mg/m2); e.g., with average anthracycline dose of 274.11 mg/m2, verbal reasoning score was 0.38 standard deviations lower].	('anthracyclines', 'Chemical', 'MESH:D018943', (19, 33))	('verbal reasoning score', 'CPA', (329, 351))	('reading', 'CPA', (115, 122))	('anthracycline', 'Chemical', 'MESH:D018943', (293, 306))	('lower', 'NegReg', (381, 386))	('anthracycline', 'Chemical', 'MESH:D018943', (19, 32))	('verbal reasoning', 'CPA', (75, 91))	('274.11 mg/m2', 'Var', (315, 327))
452183	31913509	Higher doses of anthracyclines were also associated with poorer patient-reported HRQOL (Supplemental Table S2), including role limitation due to physical health (risk ratio (RR)=1.25, 95% confidence interval (CI)=1.06-1.47), vitality (RR=1.32, 95%CI=1.09-1.59), and mental health (RR=1.26, 95%CI=1.06-1.51).	('HRQOL', 'MPA', (81, 86))	('role limitation', 'Disease', (122, 137))	('physical health', 'Disease', (145, 160))	('mental health', 'Disease', (266, 279))	('anthracyclines', 'Chemical', 'MESH:D018943', (16, 30))	('patient', 'Species', '9606', (64, 71))	('vitality', 'Disease', (225, 233))	('poorer', 'NegReg', (57, 63))	('anthracyclines', 'Var', (16, 30))
452190	31913509	Treatment with anthracyclines was associated with worse neurocognitive and HRQOL outcomes.	('anthracyclines', 'Var', (15, 29))	('HRQOL', 'Disease', (75, 80))	('anthracyclines', 'Chemical', 'MESH:D018943', (15, 29))
452192	31913509	Anthracyclines are associated with cardiotoxicity, which in turn could lead to neurocognitive impairment.	('lead to', 'Reg', (71, 78))	('cardiotoxicity', 'Disease', 'MESH:D066126', (35, 49))	('neurocognitive impairment', 'Phenotype', 'HP:0100543', (79, 104))	('cardiotoxicity', 'Disease', (35, 49))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('neurocognitive impairment', 'Disease', (79, 104))	('neurocognitive impairment', 'Disease', 'MESH:D019965', (79, 104))	('Anthracyclines', 'Var', (0, 14))
452194	31913509	Anthracyclines have been associated with neurocognitive impairment in adult survivors of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('associated', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('neurocognitive impairment', 'Phenotype', 'HP:0100543', (41, 66))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('Anthracyclines', 'Chemical', 'MESH:D018943', (0, 14))	('neurocognitive impairment', 'Disease', (41, 66))	('neurocognitive impairment', 'Disease', 'MESH:D019965', (41, 66))	('Anthracyclines', 'Var', (0, 14))
452197	31913509	In those studies anthracyclines have been associated with temporary neurocognitive impairments, during and immediately after treatment, but results from our study suggest a more long-term effect.	('neurocognitive impairment', 'Phenotype', 'HP:0100543', (68, 93))	('neurocognitive impairments', 'Disease', 'MESH:D019965', (68, 94))	('anthracyclines', 'Var', (17, 31))	('anthracyclines', 'Chemical', 'MESH:D018943', (17, 31))	('neurocognitive impairments', 'Disease', (68, 94))	('neurocognitive impairments', 'Phenotype', 'HP:0100543', (68, 94))
452290	29390485	Second-generation sequencing was used to detect the mutations of 16 tumor-related driver genes in peripheral blood and biopsies.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
452327	29390485	Recent studies have found that thalidomide inhibits tumor angiogenesis by inhibiting the secretion of fibroblast growth factor.	('thalidomide', 'Var', (31, 42))	('inhibiting', 'NegReg', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('thalidomide', 'Chemical', 'MESH:D013792', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('inhibits', 'NegReg', (43, 51))	('secretion of fibroblast growth factor', 'MPA', (89, 126))
452329	29390485	In addition, thalidomide reduces the synthesis of integrin subunits, inhibits cyclooxygenase-2, and reduces microvessel density within the tumor.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('reduces', 'NegReg', (100, 107))	('reduces', 'NegReg', (25, 32))	('thalidomide', 'Chemical', 'MESH:D013792', (13, 24))	('inhibits', 'NegReg', (69, 77))	('cyclooxygenase-2', 'Gene', '5743', (78, 94))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cyclooxygenase-2', 'Gene', (78, 94))	('synthesis', 'MPA', (37, 46))	('integrin subunits', 'Protein', (50, 67))	('thalidomide', 'Var', (13, 24))
452330	29390485	Additionally, thalidomide can activate CRBN-E3 ligase activity, leading to the ubiquitination and degradation of transcription factor IKZF1 and IKZF3, and eventually the disorder of B cells.	('CRBN', 'Gene', '51185', (39, 43))	('IKZF3', 'Gene', (144, 149))	('activate', 'PosReg', (30, 38))	('CRBN', 'Gene', (39, 43))	('IKZF1', 'Gene', '10320', (134, 139))	('thalidomide', 'Var', (14, 25))	('IKZF3', 'Gene', '22806', (144, 149))	('ubiquitination', 'MPA', (79, 93))	('IKZF1', 'Gene', (134, 139))	('thalidomide', 'Chemical', 'MESH:D013792', (14, 25))	('activity', 'MPA', (54, 62))	('degradation', 'MPA', (98, 109))
452331	29390485	Thalidomide can also enhance the immune system to kill tumor cells by activating T cell and reducing T cell inhibitory factor.	('reducing', 'NegReg', (92, 100))	('T cell inhibitory factor', 'MPA', (101, 125))	('immune system', 'CPA', (33, 46))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('enhance', 'PosReg', (21, 28))	('T cell', 'CPA', (81, 87))	('Thalidomide', 'Chemical', 'MESH:D013792', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('activating', 'PosReg', (70, 80))	('tumor', 'Disease', (55, 60))	('Thalidomide', 'Var', (0, 11))
452333	29390485	Furthermore, thalidomide improves the quality of the terminal stage of cancer.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('thalidomide', 'Chemical', 'MESH:D013792', (13, 24))	('improves', 'PosReg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('thalidomide', 'Var', (13, 24))
452352	26137468	There have been vast advancements on identifying diagnostic markers for sarcomas including chromosomal translocations, but very little progress has been made to identify targeted therapies against them.	('sarcomas', 'Disease', 'MESH:D012509', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('chromosomal translocations', 'Var', (91, 117))	('sarcomas', 'Disease', (72, 80))
452364	26137468	Potential reasons for this include rarity of tumor incidence, genetic complexity, and late stage at diagnosis leading to poor prognosis.	('genetic complexity', 'Var', (62, 80))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))
452376	26137468	Studies, including ours, have shown that miRNAs deregulation occurs in osteosarcoma (Maire et al.,; Thayanithy et al.,).	('miR', 'Gene', '220972', (41, 44))	('deregulation', 'Var', (48, 60))	('miR', 'Gene', (41, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('osteosarcoma', 'Disease', (71, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))
452392	26137468	Similar results were obtained with knock down of miR-21 that is usually overexpressed in osteosarcoma, which targets RECK and affects the activation of MMPs (Kang et al.,; Ziyan et al.,).	('osteosarcoma', 'Disease', (89, 101))	('RECK', 'Gene', '8434', (117, 121))	('MMPs', 'Gene', '4313;4318', (152, 156))	('knock down', 'Var', (35, 45))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('miR-21', 'Gene', (49, 55))	('activation', 'MPA', (138, 148))	('affects', 'Reg', (126, 133))	('RECK', 'Gene', (117, 121))	('MMPs', 'Gene', (152, 156))	('miR-21', 'Gene', '406991', (49, 55))
452407	26137468	The most common genetic alteration is transcript fusion of transcription regulators EWS and Ets leading to a novel transcriptional factor that drives oncogenesis.	('transcriptional factor', 'MPA', (115, 137))	('Ets', 'Gene', (92, 95))	('EWS', 'Gene', '2130', (84, 87))	('EWS', 'Gene', (84, 87))	('transcript fusion', 'Var', (38, 55))
452433	26137468	Most of them have C-KIT or PDGFRA mutations.	('PDGFRA', 'Gene', '5156', (27, 33))	('PDGFRA', 'Gene', (27, 33))	('C-KIT', 'Gene', '3815', (18, 23))	('C-KIT', 'Gene', (18, 23))	('mutations', 'Var', (34, 43))
452460	26137468	miR-29 levels are significantly low in RMS and re-expression leads to cell cycle arrest and differentiation in RMS cell lines (Weiss et al.,).	('leads to', 'Reg', (61, 69))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('cell cycle arrest', 'CPA', (70, 87))	('re-expression', 'Var', (47, 60))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('RMS', 'Phenotype', 'HP:0002859', (111, 114))	('differentiation', 'CPA', (92, 107))	('RMS', 'Phenotype', 'HP:0002859', (39, 42))
452464	26137468	Ectopic expression of miR-29 leads to G1 arrest and cell death.	('miR', 'Gene', '220972', (22, 25))	('Ectopic expression', 'Var', (0, 18))	('cell death', 'CPA', (52, 62))	('G1 arrest', 'CPA', (38, 47))	('leads to', 'Reg', (29, 37))	('miR', 'Gene', (22, 25))
452472	26137468	Our group identified p53 inactivation in most of the MPNST patients via a genome-wide transcriptome analysis (Subramanian et al.,).	('p53', 'Gene', '7157', (21, 24))	('patients', 'Species', '9606', (59, 67))	('p53', 'Gene', (21, 24))	('inactivation', 'Var', (25, 37))
452480	26137468	Interestingly, miR-21 was found to be over expressed in schwannomas, which are benign tumors consisting of NF2 mutations.	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('schwannomas', 'Phenotype', 'HP:0100008', (56, 67))	('benign tumors', 'Disease', (79, 92))	('miR-21', 'Gene', '406991', (15, 21))	('schwannomas', 'Disease', (56, 67))	('NF2', 'Gene', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('over expressed', 'PosReg', (38, 52))	('benign tumors', 'Disease', 'MESH:D009369', (79, 92))	('NF2', 'Gene', '4771', (107, 110))	('schwannomas', 'Disease', 'MESH:D009442', (56, 67))	('miR-21', 'Gene', (15, 21))
452502	26137468	They functionally validated that lower levels of let-7 leads to overexpression of HMGA2 in LMS.	('lower', 'Var', (33, 38))	('HMGA2', 'Gene', (82, 87))	('overexpression', 'PosReg', (64, 78))	('LMS', 'Phenotype', 'HP:0100243', (91, 94))	('HMGA2', 'Gene', '8091', (82, 87))
452540	26137468	The cholesterol group enhances the cellular uptake of the antagomirs due to their binding affinity to the cell surface membrane receptors.	('enhances', 'PosReg', (22, 30))	('cellular uptake', 'CPA', (35, 50))	('cholesterol', 'Var', (4, 15))	('cholesterol', 'Chemical', 'MESH:D002784', (4, 15))	('binding affinity', 'Interaction', (82, 98))
452578	26137468	Re-introduction or replacement of such tumor suppressor miRNAs can be applied as targeted therapy or adjuvant therapy to the existing chemotherapy.	('miR', 'Gene', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('miR', 'Gene', '220972', (56, 59))	('tumor', 'Disease', (39, 44))	('replacement', 'Var', (19, 30))
452582	26137468	In fact, miR-34 replacement therapy has shown promise against cancer cell survival, stemness, metastasis, and chemoresistance in various cancer cell types and animal models and is under Phase I clinical trial undertaken by MiRNA Therapeutics (Bader,).	('chemoresistance', 'CPA', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('stemness', 'Disease', 'MESH:D020295', (84, 92))	('stemness', 'Disease', (84, 92))	('metastasis', 'CPA', (94, 104))	('miR-34', 'Gene', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('miR-34', 'Gene', '407040', (9, 15))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('replacement therapy', 'Var', (16, 35))
452808	30256258	Expanding the Spectrum of Genetic Alterations in Pseudomyogenic Hemangioendothelioma with Recurrent Novel ACTB-FOSB Gene Fusions Pseudomyogenic hemangioendothelioma (PHE) is an uncommon, rarely metastasizing vascular neoplasm affecting with predilection young adults.	('FOSB', 'Gene', (111, 115))	('vascular neoplasm', 'Phenotype', 'HP:0100742', (208, 225))	('FOSB', 'Gene', '2354', (111, 115))	('Hemangioendothelioma', 'Disease', (64, 84))	('hemangioendothelioma', 'Disease', 'MESH:D006390', (144, 164))	('hemangioendothelioma', 'Disease', (144, 164))	('Fusions', 'Var', (121, 128))	('neoplasm', 'Phenotype', 'HP:0002664', (217, 225))	('Hemangioendothelioma', 'Disease', 'MESH:D006390', (64, 84))	('ACTB', 'Gene', (106, 110))	('ACTB', 'Gene', '60', (106, 110))	('metastasizing vascular neoplasm', 'Disease', (194, 225))	('metastasizing vascular neoplasm', 'Disease', 'MESH:D009362', (194, 225))
452812	30256258	The clinicopathologic features and behavior of PHE associated with the ACTB-FOSB gene fusion were similar to those harboring the SERPINE1-FOSB; except that tumors with the ACTB variant were more often associated with solitary presentation.	('ACTB-FOSB', 'Gene', (71, 80))	('variant', 'Var', (177, 184))	('solitary presentation', 'Disease', (217, 238))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('associated', 'Reg', (201, 211))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('ACTB', 'Gene', (172, 176))	('tumors', 'Disease', (156, 162))
452831	30256258	Briefly, MSK-IMPACT is a comprehensive molecular profiling assay that involves hybridization capture and deep sequencing of all exons and selected introns of up to 468 oncogenes and tumor-suppressor genes, allowing the detection of point mutations, small and large insertions or deletions, and rearrangements.	('rearrangements', 'Var', (294, 308))	('tumor', 'Disease', (182, 187))	('insertions', 'Var', (265, 275))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('deletions', 'Var', (279, 288))	('point mutations', 'Var', (232, 247))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
452847	30256258	These cases were further analyzed for other known gene partners of FOSB and FOS fusions described in various vascular neoplasms, including ZFP36, WWTR1 and ACTB.	('FOS', 'Gene', '2353', (67, 70))	('neoplasms', 'Phenotype', 'HP:0002664', (118, 127))	('vascular neoplasm', 'Phenotype', 'HP:0100742', (109, 126))	('fusions', 'Var', (80, 87))	('WWTR1', 'Gene', '25937', (146, 151))	('neoplasm', 'Phenotype', 'HP:0002664', (118, 126))	('vascular neoplasms', 'Disease', 'MESH:D019043', (109, 127))	('FOS', 'Gene', (67, 70))	('ZFP36', 'Gene', (139, 144))	('FOS', 'Gene', (76, 79))	('vascular neoplasms', 'Phenotype', 'HP:0100742', (109, 127))	('ZFP36', 'Gene', '7538', (139, 144))	('FOS', 'Gene', '2353', (76, 79))	('vascular neoplasms', 'Disease', (109, 127))	('WWTR1', 'Gene', (146, 151))
452860	30256258	This molecular subset of epithelioid hemangiomas with FOSB-gene rearrangements is often associated with worrisome histologic features, including increased cellularity, nuclear pleomorphism and focal necrosis.	('epithelioid hemangiomas', 'Disease', 'MESH:D006391', (25, 48))	('necrosis', 'Disease', (199, 207))	('hemangioma', 'Phenotype', 'HP:0001028', (37, 47))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (25, 47))	('cellularity', 'CPA', (155, 166))	('increased', 'PosReg', (145, 154))	('necrosis', 'Disease', 'MESH:D009336', (199, 207))	('epithelioid hemangiomas', 'Phenotype', 'HP:0032060', (25, 48))	('FOSB-gene', 'Gene', (54, 63))	('epithelioid hemangiomas', 'Disease', (25, 48))	('hemangiomas', 'Phenotype', 'HP:0001028', (37, 48))	('nuclear', 'Disease', (168, 175))	('associated', 'Reg', (88, 98))	('rearrangements', 'Var', (64, 78))
452861	30256258	An additional genetic group of epithelioid hemangiomas, preferentially occurring in skeletal anatomic sites, is characterized by recurrent gene fusions involving the FOS gene with a variety of gene partners, including LMNA and VIM.	('VIM', 'Gene', (227, 230))	('hemangioma', 'Phenotype', 'HP:0001028', (43, 53))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (31, 53))	('FOS', 'Gene', (166, 169))	('LMNA', 'Gene', '4000', (218, 222))	('epithelioid hemangiomas', 'Phenotype', 'HP:0032060', (31, 54))	('VIM', 'Gene', '7431', (227, 230))	('gene fusions', 'Var', (139, 151))	('epithelioid hemangiomas', 'Disease', (31, 54))	('hemangiomas', 'Phenotype', 'HP:0001028', (43, 54))	('epithelioid hemangiomas', 'Disease', 'MESH:D006391', (31, 54))	('FOS', 'Gene', '2353', (166, 169))	('LMNA', 'Gene', (218, 222))
452865	30256258	The mechanism through which an identical ACTB-FOSB fusion triggers the pathogenesis of two distinct vascular neoplasms, characterized by either benign or intermediate grande of malignancy, with or without vasoformative properties, remains to be determined.	('vascular neoplasms', 'Disease', 'MESH:D019043', (100, 118))	('vascular neoplasms', 'Phenotype', 'HP:0100742', (100, 118))	('neoplasm', 'Phenotype', 'HP:0002664', (109, 117))	('vascular neoplasms', 'Disease', (100, 118))	('ACTB-FOSB', 'Protein', (41, 50))	('neoplasms', 'Phenotype', 'HP:0002664', (109, 118))	('fusion', 'Var', (51, 57))	('malignancy', 'Disease', 'MESH:D009369', (177, 187))	('triggers', 'Reg', (58, 66))	('malignancy', 'Disease', (177, 187))	('vascular neoplasm', 'Phenotype', 'HP:0100742', (100, 117))
452871	30256258	The breakpoints of FOSB gene seen in the ACTB-FOSB variant were similar to those previously reported in SERPINE1-FOSB and ZFP36-FOSB gene fusions, involving exon 2 of FOSB gene.	('ZFP36', 'Gene', '7538', (122, 127))	('FOSB', 'Gene', (167, 171))	('ACTB-FOSB', 'Gene', (41, 50))	('variant', 'Var', (51, 58))	('FOSB gene', 'Gene', (19, 28))	('ZFP36', 'Gene', (122, 127))
452876	30256258	More recently, this peculiar group of tumors has been expanded to include a cohort of malignant epithelioid neoplasms defined by GLI1-associated fusions with various partners including ACTB, MALAT1 and PTCH1 genes.	('PTCH1', 'Gene', '5727', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('neoplasm', 'Phenotype', 'HP:0002664', (108, 116))	('GLI1', 'Gene', '2735', (129, 133))	('MALAT1', 'Gene', '378938', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('PTCH1', 'Gene', (202, 207))	('malignant epithelioid neoplasms', 'Disease', (86, 117))	('MALAT1', 'Gene', (191, 197))	('GLI1', 'Gene', (129, 133))	('ACTB', 'Gene', (185, 189))	('fusions', 'Var', (145, 152))	('neoplasms', 'Phenotype', 'HP:0002664', (108, 117))	('malignant epithelioid neoplasms', 'Disease', 'MESH:D054973', (86, 117))
452883	30256258	Immunohistochemically, apart from cytokeratin positivity, all tumors showed positivity for vascular markers CD31 and FLI1 confirming the vascular origin.	('CD31', 'Gene', '5175', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('FLI1', 'Gene', '2313', (117, 121))	('tumors', 'Disease', (62, 68))	('positivity', 'Var', (76, 86))	('FLI1', 'Gene', (117, 121))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('CD31', 'Gene', (108, 112))
452925	28945358	Mutation of CTD lysines in heptad position 7 to consensus serines reduced overall TAF15 fibril binding, suggesting that electrostatic interactions contribute to complex formation.	('reduced', 'NegReg', (66, 73))	('TAF15', 'Gene', (82, 87))	('lysines', 'Chemical', 'MESH:D008239', (16, 23))	('CTD', 'Gene', '1283', (12, 15))	('Mutation', 'Var', (0, 8))	('serines', 'Chemical', 'MESH:D012694', (58, 65))	('TAF15', 'Gene', '8148', (82, 87))	('CTD', 'Gene', (12, 15))
452926	28945358	Conversely, mutations of position 7 asparagine residues and truncation of the acidic tail had little effect.	('asparagine', 'Protein', (36, 46))	('mutations', 'Var', (12, 21))	('asparagine', 'Chemical', 'MESH:D001216', (36, 46))
452937	28945358	Indeed, the affinity of engineered FUS LC and TAF15 LC variants for wild-type hydrogels directly correlates with transcriptional activation.	('TAF15', 'Gene', '8148', (46, 51))	('variants', 'Var', (55, 63))	('affinity', 'Interaction', (12, 20))	('TAF15', 'Gene', (46, 51))	('transcriptional activation', 'MPA', (113, 139))	('FUS', 'Gene', (35, 38))	('FUS', 'Gene', '2521', (35, 38))
452942	28945358	RNA pol II CTD heptad sequence degeneracies, a common feature of complex organisms, were shown to modulate proline isomerization and dephosphorylation, indicating diverse local heptad conformations can subtly tune interactions with regulatory factors.	('RNA pol II CTD', 'Gene', (0, 14))	('modulate', 'Reg', (98, 106))	('RNA pol II CTD', 'Gene', '32100', (0, 14))	('degeneracies', 'Var', (31, 43))	('tune', 'Reg', (209, 213))	('proline', 'Chemical', 'MESH:D011392', (107, 114))	('proline isomerization', 'MPA', (107, 128))	('dephosphorylation', 'MPA', (133, 150))	('interactions', 'Interaction', (214, 226))
452953	28945358	Variants generated are as follows: CTD N2A WT (N1775A, N1783A), CTD K5S WT (K1838S, K1859S, K1866S, K1873S, and K1887S), CTD Delta1961-1970, CTD27-37 (residues 1773-1852), CTD38-52 (residues 1853-1970), CTD43-52 (residues 1888-1970), CTD27-52 T1779A, DeltaP1785, P1802A, S1798A, S1822A, A1835T, Y1846A, S1857A, S1868A, S1878A, P1886A, Y1895A, P1911A, T1919A, Y1923A, T1926A, T1933A, T1943A, T1945A.	('T1926A', 'Mutation', 'c.1926T>A', (367, 373))	('T1945A', 'Var', (391, 397))	('S1798A', 'Var', (271, 277))	('P1802A', 'Mutation', 'p.P1802A', (263, 269))	('CTD', 'Gene', '1283', (172, 175))	('N1775A', 'Mutation', 'p.N1775A', (47, 53))	('K1859S', 'Mutation', 'p.K1859S', (84, 90))	('P1911A', 'Var', (343, 349))	('Y1895A', 'Mutation', 'p.Y1895A', (335, 341))	('P1802A', 'Var', (263, 269))	('T1926A', 'Var', (367, 373))	('S1868A', 'Mutation', 'p.S1868A', (311, 317))	('CTD', 'Gene', (121, 124))	('Y1846A', 'Mutation', 'p.Y1846A', (295, 301))	('DeltaP1785', 'DELETION', 'None', (251, 261))	('N2A', 'Chemical', '-', (39, 42))	('CTD', 'Gene', '1283', (234, 237))	('CTD', 'Gene', '1283', (35, 38))	('CTD', 'Gene', '1283', (203, 206))	('Y1923A', 'Mutation', 'p.Y1923A', (359, 365))	('A1835T', 'Var', (287, 293))	('CTD', 'Gene', (64, 67))	('K1866S', 'Mutation', 'p.K1866S', (92, 98))	('S1878A', 'Var', (319, 325))	('T1933A', 'Mutation', 'c.1933T>A', (375, 381))	('CTD', 'Gene', (141, 144))	('S1822A', 'Var', (279, 285))	('Y1923A', 'Var', (359, 365))	('T1943A', 'Mutation', 'c.1943T>A', (383, 389))	('K5S', 'Mutation', 'p.K5S', (68, 71))	('CTD', 'Gene', '1283', (121, 124))	('S1878A', 'Mutation', 'p.S1878A', (319, 325))	('N1783A', 'Mutation', 'p.N1783A', (55, 61))	('S1857A', 'Var', (303, 309))	('Y1895A', 'Var', (335, 341))	('CTD', 'Gene', (172, 175))	('K1873S', 'Mutation', 'p.K1873S', (100, 106))	('P1886A', 'Mutation', 'p.P1886A', (327, 333))	('CTD27-52', 'Gene', (234, 242))	('S1798A', 'Mutation', 'p.S1798A', (271, 277))	('Delta1961', 'Mutation', 'c.del1961', (125, 134))	('Y1846A', 'Var', (295, 301))	('T1919A', 'Var', (351, 357))	('DeltaP1785', 'Var', (251, 261))	('CTD', 'Gene', '1283', (64, 67))	('S1857A', 'Mutation', 'p.S1857A', (303, 309))	('A1835T', 'Mutation', 'c.1835A>T', (287, 293))	('T1779A', 'Mutation', 'c.1779T>A', (243, 249))	('T1933A', 'Var', (375, 381))	('S1868A', 'Var', (311, 317))	('CTD', 'Gene', '1283', (141, 144))	('T1945A', 'Mutation', 'c.1945T>A', (391, 397))	('P1886A', 'Var', (327, 333))	('CTD', 'Gene', (203, 206))	('CTD', 'Gene', (234, 237))	('CTD', 'Gene', (35, 38))	('K1838S', 'Mutation', 'p.K1838S', (76, 82))	('CTD27-52', 'Gene', '1283', (234, 242))	('T1779A', 'Var', (243, 249))	('K1887S', 'Mutation', 'p.K1887S', (112, 118))	('S1822A', 'Mutation', 'p.S1822A', (279, 285))	('P1911A', 'Mutation', 'p.P1911A', (343, 349))	('T1919A', 'Mutation', 'c.1919T>A', (351, 357))	('T1943A', 'Var', (383, 389))
452954	28945358	Single-cysteine variants (S1966C) were also engineered in CTD27-52 WT, N2A, and K5S.	('cysteine', 'Chemical', 'MESH:D003545', (7, 15))	('S1966C', 'Var', (26, 32))	('N2A', 'Chemical', '-', (71, 74))	('S1966C', 'Mutation', 'p.S1966C', (26, 32))	('CTD27-52', 'Gene', (58, 66))	('CTD27-52', 'Gene', '1283', (58, 66))	('K5S', 'Mutation', 'p.K5S', (80, 83))
452956	28945358	Missense mutations produce local perturbations in chemical structure that were observed as chemical shift perturbations in the HSQC spectrum of CTD27-52 (Figure S1).	('chemical shift perturbations', 'MPA', (91, 119))	('chemical structure', 'MPA', (50, 68))	('CTD27-52', 'Gene', (144, 152))	('HSQC spectrum', 'MPA', (127, 140))	('CTD27-52', 'Gene', '1283', (144, 152))	('Missense mutations', 'Var', (0, 18))
452991	28945358	Dynamic and kinetic parameters describing RNA pol II CTD27-52 WT and K5S interaction with sonicated TAF15 LC fibrils were derived from experimental DeltaR2 and DEST data and fit with DESTfit in Matlab as previously described.	('CTD27-52', 'Gene', (53, 61))	('TAF15', 'Gene', '8148', (100, 105))	('DeltaR2', 'Var', (148, 155))	('CTD27-52', 'Gene', '1283', (53, 61))	('RNA pol II CTD', 'Gene', (42, 56))	('interaction', 'Interaction', (73, 84))	('K5S', 'Mutation', 'p.K5S', (69, 72))	('TAF15', 'Gene', (100, 105))	('RNA pol II CTD', 'Gene', '32100', (42, 56))	('DeltaR2', 'DELETION', 'None', (148, 155))
452993	28945358	We performed parallel tempering metadynamics in well-tempered ensembles (PTMetaD-WTE) simulations of 44-residue fragment of RNA pol II CTD (residues 1927-1970) in explicit water with ff99SBws and TIP4P/2005 using GROMACS-4.6.7  and Plumed 2.2 .	('RNA pol II CTD', 'Gene', (124, 138))	('ff99SBws', 'Var', (183, 191))	('water', 'Chemical', 'MESH:D014867', (172, 177))	('RNA pol II CTD', 'Gene', '32100', (124, 138))
452999	28945358	Fluorescently labeled CTD variants were prepared using two approaches: 1) For experiments comparing N2A, K5S, and WT in different NaCl concentrations, a single cysteine was introduced (S1966C) in N2A, K5S, and WT CTD27-52 plasmids in preparation for Alexa Fluor-488 maleimide labeling.	('CTD', 'Gene', (213, 216))	('S1966C', 'Mutation', 'p.S1966C', (185, 191))	('N2A', 'Chemical', '-', (196, 199))	('NaCl', 'Chemical', 'MESH:D012965', (130, 134))	('K5S', 'Mutation', 'p.K5S', (105, 108))	('N2A', 'Chemical', '-', (100, 103))	('CTD27-52', 'Gene', (213, 221))	('cysteine', 'Chemical', 'MESH:D003545', (160, 168))	('CTD', 'Gene', '1283', (22, 25))	('CTD27-52', 'Gene', '1283', (213, 221))	('K5S', 'Mutation', 'p.K5S', (201, 204))	('CTD', 'Gene', (22, 25))	('CTD', 'Gene', '1283', (213, 216))	('S1966C', 'Var', (185, 191))	('Alexa Fluor-488 maleimide', 'Chemical', '-', (250, 275))
453000	28945358	CTD 27-52 S1966C variants were purified from LB media as described above and buffer exchanged into pH 7.4 20 mM NaPi 300 mM NaCl, 1 mM DTT to eliminate any disulfides before snap freezing and storage at -80  C. Protein samples were desalted using 2 mL 7000 MWCO spin desalting columns (Zeba, ThermoFisher) into pH 7.5 20 mM Tris, 200 mM NaCl to remove DTT immediately before maleimide conjugation.	('S1966C', 'Mutation', 'p.S1966C', (10, 16))	('DTT', 'Chemical', 'MESH:D004229', (352, 355))	('variants', 'Var', (17, 25))	('salt', 'Chemical', 'MESH:D012492', (234, 238))	('disulfides', 'Chemical', 'MESH:D004220', (156, 166))	('LB media', 'Chemical', '-', (45, 53))	('DTT', 'Chemical', 'MESH:D004229', (135, 138))	('CTD', 'Gene', (0, 3))	('salt', 'Chemical', 'MESH:D012492', (269, 273))	('maleimide', 'Chemical', 'MESH:C043592', (375, 384))	('NaCl', 'Chemical', 'MESH:D012965', (337, 341))	('Tris', 'Chemical', '-', (324, 328))	('S1966C variants', 'Var', (10, 25))	('NaCl', 'Chemical', 'MESH:D012965', (124, 128))	('CTD', 'Gene', '1283', (0, 3))	('NaPi', 'Chemical', '-', (112, 116))
453002	28945358	2) For experiments comparing WT and CTD Delta1961-1970, 15N-labeled protein was purified as describe above.	('CTD', 'Gene', '1283', (36, 39))	('CTD', 'Gene', (36, 39))	('Delta1961-1970', 'Var', (40, 54))	('Delta1961', 'Mutation', 'c.del1961', (40, 49))	('15N', 'Chemical', '-', (56, 59))
453005	28945358	300 muL of 1 muM CTD 27-52 WT-Alexa 488, N2A-Alexa 488, K5S-Alexa 488, DyLight 488 labeled CTD27-52 WT, or DyLight 488 labeled CTD Delta1961-1970 was then added to each well of a 24-well glass bottom MatTek plate which contained three 2 muL hydrogels of mCherry-TAF15 LC per well.	('TAF15', 'Gene', '8148', (262, 267))	('CTD', 'Gene', (17, 20))	('CTD', 'Gene', '1283', (91, 94))	('K5S', 'Mutation', 'p.K5S', (56, 59))	('Alexa 488', 'Chemical', '-', (30, 39))	('Alexa 488', 'Chemical', '-', (45, 54))	('CTD', 'Gene', (127, 130))	('Alexa 488', 'Chemical', '-', (60, 69))	('CTD', 'Gene', '1283', (17, 20))	('CTD27-52', 'Gene', (91, 99))	('CTD', 'Gene', '1283', (127, 130))	('CTD', 'Gene', (91, 94))	('muM', 'Gene', '56925', (13, 16))	('CTD27-52', 'Gene', '1283', (91, 99))	('N2A', 'Chemical', '-', (41, 44))	('Delta1961-1970', 'Var', (131, 145))	('muM', 'Gene', (13, 16))	('Delta1961', 'Mutation', 'c.del1961', (131, 140))	('TAF15', 'Gene', (262, 267))
453012	28945358	Ultimately, we used standard 1HN-detected triple resonance experiments (see Methods) in combination with HSQCs of a series of CTD variants to assign all non-overlapped backbone resonances of CTD27-52 (Figure S1, see methods for catalog of CTD variants).	('variants', 'Var', (130, 138))	('CTD27-52', 'Gene', '1283', (191, 199))	('CTD', 'Gene', (126, 129))	('non-overlapped', 'MPA', (153, 167))	('overlapped backbone', 'Phenotype', 'HP:0003302', (157, 176))	('1HN', 'Chemical', '-', (29, 32))	('CTD', 'Gene', '1283', (191, 194))	('CTD', 'Gene', '1283', (239, 242))	('CTD', 'Gene', (191, 194))	('CTD', 'Gene', (239, 242))	('CTD', 'Gene', '1283', (126, 129))	('CTD27-52', 'Gene', (191, 199))
453016	28945358	Using Calpha, Cbeta, 15N, 1HN, and CO shifts as inputs to the delta2D algorithm for predicting secondary structure population, CTD27-52 is predicted to be predominantly random coil (62%) with minor populations of dihedral angles consistent with polyproline II helix (25%) and extended beta-sheet (13%) (Figure 1C).	('Calpha', 'Chemical', '-', (6, 12))	('polyproline', 'Chemical', 'MESH:C011083', (245, 256))	('1HN', 'Chemical', '-', (26, 29))	('polyproline', 'Var', (245, 256))	('CTD27-52', 'Gene', (127, 135))	('CTD27-52', 'Gene', '1283', (127, 135))	('random coil', 'MPA', (169, 180))	('15N', 'Chemical', '-', (21, 24))	('Cbeta', 'Chemical', '-', (14, 19))
453035	28945358	However, in the presence of sonicated fibrils we reliably observe decreased peak intensity and increased transverse relaxation, DeltaR2, of CTD27-52 which can be explained by transient binding of CTD27-52 to the high molecular weight fibrillar segments.	('DeltaR2', 'Var', (128, 135))	('increased', 'PosReg', (95, 104))	('binding', 'Interaction', (185, 192))	('CTD27-52', 'Gene', (196, 204))	('decreased', 'NegReg', (66, 75))	('CTD27-52', 'Gene', (140, 148))	('CTD27-52', 'Gene', '1283', (196, 204))	('CTD27-52', 'Gene', '1283', (140, 148))	('transverse relaxation', 'MPA', (105, 126))	('peak intensity', 'MPA', (76, 90))	('DeltaR2', 'DELETION', 'None', (128, 135))
453036	28945358	DeltaR2 values are maximal for heptads 27-33 of RNA pol II CTD27-52 (Figures 3B-C, S4B), suggesting that the N-terminal half of CTD27-52 more frequently or tightly binds fibrils, possibly because the acidic C-terminal tail of CTD27-52 remains unbound.	('binds', 'Interaction', (164, 169))	('CTD27-52', 'Gene', (226, 234))	('CTD27-52', 'Gene', (59, 67))	('RNA pol II CTD', 'Gene', (48, 62))	('DeltaR2', 'DELETION', 'None', (0, 7))	('CTD27-52', 'Gene', '1283', (226, 234))	('fibrils', 'Protein', (170, 177))	('CTD27-52', 'Gene', (128, 136))	('DeltaR2', 'Var', (0, 7))	('CTD27-52', 'Gene', '1283', (59, 67))	('CTD27-52', 'Gene', '1283', (128, 136))	('RNA pol II CTD', 'Gene', '32100', (48, 62))
453037	28945358	Notably, sonicated TAF15 fibrils produce markedly higher DeltaR2 values than sonicated hnRNPA2 fibrils: adding 2 mg/mL of TAF15 fibrils to CTD27-52 produces maximum DeltaR2 values of 14 s-1, whereas 9 mg/ml hnRNPA2 fibrils is necessary to produce similar relaxation enhancements (Figure 3C).	('CTD27-52', 'Gene', (139, 147))	('hnRNPA2', 'Gene', '3181', (207, 214))	('CTD27-52', 'Gene', '1283', (139, 147))	('hnRNPA2', 'Gene', (87, 94))	('TAF15', 'Gene', (122, 127))	('mum', 'Gene', '56925', (161, 164))	('DeltaR2', 'DELETION', 'None', (57, 64))	('TAF15', 'Gene', '8148', (19, 24))	('hnRNPA2', 'Gene', (207, 214))	('DeltaR2', 'Var', (57, 64))	('DeltaR2', 'DELETION', 'None', (165, 172))	('mum', 'Gene', (161, 164))	('TAF15', 'Gene', '8148', (122, 127))	('DeltaR2', 'Var', (165, 172))	('hnRNPA2', 'Gene', '3181', (87, 94))	('TAF15', 'Gene', (19, 24))
453038	28945358	However, similar DeltaR2 vs. CTD residue number profiles suggest similar CTD27-52 binding modes to both TAF15 and hnRNPA2 fibrils.	('CTD', 'Gene', (29, 32))	('hnRNPA2', 'Gene', '3181', (114, 121))	('CTD', 'Gene', '1283', (73, 76))	('TAF15', 'Gene', '8148', (104, 109))	('hnRNPA2', 'Gene', (114, 121))	('DeltaR2', 'DELETION', 'None', (17, 24))	('CTD', 'Gene', (73, 76))	('CTD', 'Gene', '1283', (29, 32))	('DeltaR2', 'Var', (17, 24))	('CTD27-52', 'Gene', (73, 81))	('CTD27-52', 'Gene', '1283', (73, 81))	('TAF15', 'Gene', (104, 109))	('binding', 'Interaction', (82, 89))
453040	28945358	The observation of DeltaR2 values that are nearly field-independent (Figure S3C-D, S4C-E) support a model where DeltaR2 arises from binding of CTD to the surface of large (> 1 MDa) hnRNPA2 or TAF15 fibrils, rather than from direct observation of a bound state.	('hnRNPA2', 'Gene', (181, 188))	('CTD', 'Gene', (143, 146))	('DeltaR2', 'DELETION', 'None', (19, 26))	('TAF15', 'Gene', (192, 197))	('DeltaR2', 'DELETION', 'None', (112, 119))	('DeltaR2', 'Var', (19, 26))	('DeltaR2', 'Var', (112, 119))	('hnRNPA2', 'Gene', '3181', (181, 188))	('binding', 'Interaction', (132, 139))	('CTD', 'Gene', '1283', (143, 146))	('arises from', 'Reg', (120, 131))	('TAF15', 'Gene', '8148', (192, 197))
453041	28945358	The maximum value of DeltaR2 then provides a lower bound for the first order kinetic on-rate for binding which must be reversible as the CTD in the sample is stable and not consumed by irreversible binding within 1 s. Addition of supernatant extracted from centrifuged sonicated fibrils results in no observable DeltaR2, demonstrating that residual soluble species within sonicated hydrogels are not responsible for observed DeltaR2 (Figures 3C, 3D).	('mum', 'Gene', (8, 11))	('CTD', 'Gene', (137, 140))	('DeltaR2', 'DELETION', 'None', (312, 319))	('DeltaR2', 'DELETION', 'None', (21, 28))	('DeltaR2', 'Var', (312, 319))	('DeltaR2', 'Var', (21, 28))	('DeltaR2', 'DELETION', 'None', (425, 432))	('CTD', 'Gene', '1283', (137, 140))	('mum', 'Gene', '56925', (8, 11))	('DeltaR2', 'Var', (425, 432))
453042	28945358	Separately, addition of 2 mg/mL monomeric mCherry-TAF15 LC also does not increase R2 (Figure 3D), further demonstrating that DeltaR2 arises from transient fibril binding.	('DeltaR2', 'Var', (125, 132))	('TAF15', 'Gene', (50, 55))	('binding', 'Interaction', (162, 169))	('TAF15', 'Gene', '8148', (50, 55))	('DeltaR2', 'DELETION', 'None', (125, 132))
453043	28945358	We next sought to test the two following questions: 1) Given that the highest DeltaR2 values occur near N1775 and N1782, are asparagine CTD residues critical for TAF15 recruitment?	('TAF15', 'Gene', '8148', (162, 167))	('asparagine', 'Chemical', 'MESH:D001216', (125, 135))	('N1775', 'Var', (104, 109))	('CTD', 'Gene', (136, 139))	('DeltaR2', 'DELETION', 'None', (78, 85))	('DeltaR2', 'Var', (78, 85))	('N1782', 'Var', (114, 119))	('TAF15', 'Gene', (162, 167))	('CTD', 'Gene', '1283', (136, 139))
453045	28945358	Therefore, we made two CTD27-52 variants substituting either two N-terminal asparagines (N1775, N1782) with alanines (N2A) or five central lysines (K1838, K1859, K1866, K1873, and K1887) with consensus serines (K5S).	('asparagines', 'Chemical', 'MESH:D001216', (76, 87))	('CTD27-52', 'Gene', (23, 31))	('N1782', 'Var', (96, 101))	('CTD27-52', 'Gene', '1283', (23, 31))	('alanines', 'Chemical', 'MESH:D000409', (108, 116))	('K1838', 'Var', (148, 153))	('N1775', 'Var', (89, 94))	('N2A', 'Chemical', '-', (118, 121))	('serines', 'Chemical', 'MESH:D012694', (202, 209))	('K1866', 'Var', (162, 167))	('lysines', 'Chemical', 'MESH:D008239', (139, 146))	('K1887', 'Var', (180, 185))	('K5S', 'Mutation', 'p.K5S', (211, 214))	('K1873', 'Var', (169, 174))	('K1859', 'Var', (155, 160))
453046	28945358	Note that chemical shift perturbations in the HSQC spectra of CTD27-52 variants N2A (Figure S5A) and K5S (Figure S5B) as compared to that of WT are localized within heptads containing mutations, suggesting no global structural differences are caused by these CTD variants.	('CTD27-52', 'Gene', '1283', (62, 70))	('K5S', 'Var', (101, 104))	('variants N2A', 'Var', (71, 83))	('HSQC spectra', 'MPA', (46, 58))	('CTD', 'Gene', (62, 65))	('S5B', 'Gene', (113, 116))	('N2A', 'Var', (80, 83))	('S5B', 'Gene', '5711', (113, 116))	('CTD27-52', 'Gene', (62, 70))	('CTD', 'Gene', '1283', (259, 262))	('N2A', 'Chemical', '-', (80, 83))	('CTD', 'Gene', '1283', (62, 65))	('K5S', 'Mutation', 'p.K5S', (101, 104))	('chemical shift', 'MPA', (10, 24))	('CTD', 'Gene', (259, 262))
453047	28945358	To account for variability observed in hydrogel preparations, multiple trials mixing each CTD27-52 variant and sonicated TAF15 fibril sample were performed (Figure S4B); variant-dependent trends in DeltaR2 are consistent across all trials and magnetic field strengths (Figure S4F).	('TAF15', 'Gene', '8148', (121, 126))	('DeltaR2', 'DELETION', 'None', (198, 205))	('variant', 'Var', (99, 106))	('DeltaR2', 'Var', (198, 205))	('TAF15', 'Gene', (121, 126))	('CTD27-52', 'Gene', (90, 98))	('CTD27-52', 'Gene', '1283', (90, 98))
453048	28945358	CTD27-52 N2A displays DeltaR2 values indistinguishable from that of CTD27-52 wild-type (Figure 3D), suggesting N1775 and N1782 sidechains do not directly mediate binding.	('CTD27-52', 'Gene', (68, 76))	('DeltaR2', 'DELETION', 'None', (22, 29))	('N1775', 'Var', (111, 116))	('DeltaR2', 'Var', (22, 29))	('CTD27-52', 'Gene', '1283', (68, 76))	('N1782', 'Var', (121, 126))	('CTD27-52', 'Gene', (0, 8))	('CTD27-52', 'Gene', '1283', (0, 8))	('binding', 'Interaction', (162, 169))	('N2A', 'Chemical', '-', (9, 12))
453049	28945358	However, CTD27-52 K5S shows DeltaR2 values ~30% less than wild type (Figure 3D), suggesting lysine contacts do contribute to binding.	('lysine', 'Chemical', 'MESH:D008239', (92, 98))	('DeltaR2', 'Var', (28, 35))	('DeltaR2', 'DELETION', 'None', (28, 35))	('K5S', 'Mutation', 'p.K5S', (18, 21))	('binding', 'Interaction', (125, 132))	('lysine', 'Var', (92, 98))	('contribute', 'Reg', (111, 121))	('less', 'NegReg', (48, 52))	('CTD27-52', 'Gene', (9, 17))	('CTD27-52', 'Gene', '1283', (9, 17))
453050	28945358	This decrease in DeltaR2 values cannot be directly attributed to a decrease in the population of fibril-bound CTD K5S as compared to that of WT, because differences in transverse relaxation enhancements are dependent on not only bound populations but also binding/unbinding rates as well as possibly on chemical shift differences in the bound state.	('enhancements', 'PosReg', (190, 202))	('CTD', 'Gene', '1283', (110, 113))	('transverse relaxation', 'MPA', (168, 189))	('DeltaR2', 'DELETION', 'None', (17, 24))	('binding/unbinding', 'Interaction', (256, 273))	('K5S', 'Mutation', 'p.K5S', (114, 117))	('CTD', 'Gene', (110, 113))	('DeltaR2', 'Var', (17, 24))
453054	28945358	Briefly, selective saturation of slowly relaxing 15N longitudinal magnetization in the bound state is transferred to the monomeric, NMR-visible state by exchange (i.e.	('exchange', 'Var', (153, 161))	('15N', 'Chemical', '-', (49, 52))	('slowly relaxing 15N longitudinal magnetization', 'MPA', (33, 79))
453059	28945358	A simple two-state model with a single fibril-bound state does not allow simultaneous fitting of DeltaR2 and DEST data, as demonstrated by the poor fit of experimental DeltaR2 (Figure 4A, gray).	('DeltaR2', 'Var', (97, 104))	('DeltaR2', 'DELETION', 'None', (97, 104))	('DeltaR2', 'DELETION', 'None', (168, 175))	('DeltaR2', 'Var', (168, 175))
453060	28945358	As previously described for Abeta peptides binding Abeta protofibrils, to account for the surely diverse conformational ensemble of CTD bound to TAF15 fibrils, a simple phenomenological extension to a two-state model, accounting for the fact that a single residue may be in direct contact with the TAF15 fibril in some bound-conformation while tethered to the surface via the binding of other residues in other bound states, results in excellent fits of DeltaR2 and DEST data (Figure 4A, 4B).	('DEST data', 'MPA', (466, 475))	('TAF15', 'Gene', '8148', (145, 150))	('TAF15', 'Gene', (298, 303))	('CTD', 'Gene', '1283', (132, 135))	('fits', 'Disease', (446, 450))	('CTD', 'Gene', (132, 135))	('DeltaR2', 'DELETION', 'None', (454, 461))	('TAF15', 'Gene', (145, 150))	('DeltaR2', 'Var', (454, 461))	('TAF15', 'Gene', '8148', (298, 303))	('fits', 'Disease', 'MESH:D012640', (446, 450))
453061	28945358	Intermediate saturation transfer values are observed in the central region (K1887, K1936), consistent with the patterns in DeltaR2.	('saturation transfer', 'MPA', (13, 32))	('DeltaR2', 'DELETION', 'None', (123, 130))	('DeltaR2', 'Var', (123, 130))	('K1936', 'Var', (83, 88))	('K1887', 'Var', (76, 81))
453067	28945358	The average 15N transverse relaxation rate of each residue when directly contacting, R2direct-contact, or tethered, R2tethered(i), to the surface provides insight into the local motions experienced by the chain in each state.	('R2direct-contact', 'Var', (85, 101))	('15N', 'Chemical', '-', (12, 15))	('15N transverse relaxation', 'MPA', (12, 37))	('R2tethered', 'Var', (116, 126))
453068	28945358	Because mutation of 5 central lysines to serines modestly reduced recruitment of CTD27-52 as observed by DeltaR2 experiments, we next investigated interactions between CTD27-52 K5S and TAF15 fibrils via DEST NMR.	('interactions', 'Interaction', (147, 159))	('CTD27-52', 'Gene', (81, 89))	('DeltaR2', 'DELETION', 'None', (105, 112))	('CTD27-52', 'Gene', '1283', (81, 89))	('DeltaR2', 'Var', (105, 112))	('K5S', 'Mutation', 'p.K5S', (177, 180))	('TAF15', 'Gene', (185, 190))	('CTD27-52', 'Gene', (168, 176))	('lysines', 'Chemical', 'MESH:D008239', (30, 37))	('CTD27-52', 'Gene', '1283', (168, 176))	('mutation', 'Var', (8, 16))	('TAF15', 'Gene', '8148', (185, 190))	('recruitment', 'MPA', (66, 77))	('reduced', 'NegReg', (58, 65))	('investigated', 'Reg', (134, 146))	('serines', 'Chemical', 'MESH:D012694', (41, 48))
453069	28945358	Residues near lysine-to-serine substitutions in CTD27-52 K5S show modestly decreased saturation transfer in the presence of TAF15 fibrils compared to the same residues in CTD27-52 WT (Figure S6), suggesting that substitution of five lysines with consensus serines may impede assembly by removing lysine-localized interactions between heptads and TAF15 fibrils.	('K5S', 'Mutation', 'p.K5S', (57, 60))	('serines', 'Chemical', 'MESH:D012694', (256, 263))	('CTD27-52', 'Gene', (48, 56))	('substitution', 'Var', (212, 224))	('removing', 'NegReg', (287, 295))	('heptads', 'Protein', (334, 341))	('lysine', 'Chemical', 'MESH:D008239', (14, 20))	('substitutions', 'Var', (31, 44))	('TAF15', 'Gene', (346, 351))	('assembly', 'MPA', (275, 283))	('lysine-localized interactions', 'MPA', (296, 325))	('lysine', 'Chemical', 'MESH:D008239', (233, 239))	('TAF15', 'Gene', '8148', (346, 351))	('CTD27-52', 'Gene', '1283', (48, 56))	('TAF15', 'Gene', (124, 129))	('lysines', 'Chemical', 'MESH:D008239', (233, 240))	('serine', 'Chemical', 'MESH:D012694', (256, 262))	('lysine', 'Chemical', 'MESH:D008239', (296, 302))	('serine', 'Chemical', 'MESH:D012694', (24, 30))	('TAF15', 'Gene', '8148', (124, 129))	('CTD27-52', 'Gene', (171, 179))	('saturation transfer', 'MPA', (85, 104))	('impede', 'NegReg', (268, 274))	('CTD27-52', 'Gene', '1283', (171, 179))	('decreased', 'NegReg', (75, 84))
453073	28945358	Because DeltaR2 values are comparable to 2 mg/ml TAF15, lack of DEST in the presence of hnRNPA2 fibrils may be due to decreased population or altered residence time in the fibril-bound state.	('DeltaR2', 'Var', (8, 15))	('TAF15', 'Gene', '8148', (49, 54))	('hnRNPA2', 'Gene', '3181', (88, 95))	('decreased', 'NegReg', (118, 127))	('DEST', 'MPA', (64, 68))	('TAF15', 'Gene', (49, 54))	('hnRNPA2', 'Gene', (88, 95))	('DeltaR2', 'DELETION', 'None', (8, 15))
453074	28945358	Given that NMR samples of CTD27-52 variants and sonicated mCherry-TAF15 LC hydrogel fibrils were relatively unstable and inherently variable due to differences in sonicated hydrogel preps (Figure S4B), we sought to verify the contribution of lysine residues and other electrostatic interactions to CTD-TAF15 assembly using fluorescence localization and recovery after photobleaching (FRAP) experiments.	('CTD', 'Gene', (26, 29))	('TAF15', 'Gene', '8148', (66, 71))	('CTD', 'Gene', (298, 301))	('TAF15', 'Gene', '8148', (302, 307))	('variants', 'Var', (35, 43))	('CTD27-52', 'Gene', (26, 34))	('lysine', 'Chemical', 'MESH:D008239', (242, 248))	('CTD27-52', 'Gene', '1283', (26, 34))	('TAF15', 'Gene', (66, 71))	('CTD', 'Gene', '1283', (26, 29))	('TAF15', 'Gene', (302, 307))	('CTD', 'Gene', '1283', (298, 301))
453075	28945358	Using a hydrogel localization assay adapted from McKnight and colleagues, we quantified CTD27-52 variants' recruitment to, and penetrance within, 2 mul intact mCherry-TAF15 LC hydrogels.	('recruitment', 'MPA', (107, 118))	('TAF15', 'Gene', (167, 172))	('CTD27-52', 'Gene', '1283', (88, 96))	('variants', 'Var', (97, 105))	('TAF15', 'Gene', '8148', (167, 172))	('CTD27-52', 'Gene', (88, 96))
453076	28945358	A serine-to-cysteine substitution (S1966C) was introduced in all three variants (WT, K5S, and N2A) in order to label each variant with a single Alexa Fluor dye via maleimide-thiol conjugation, and a solution of 1 muM Alexa Fluor tagged CTD was added to preformed mCherry-TAF15 LC hydrogels.	('S1966C', 'Mutation', 'p.S1966C', (35, 41))	('Alexa Fluor', 'Chemical', '-', (144, 155))	('Alexa Fluor', 'Chemical', '-', (217, 228))	('TAF15', 'Gene', '8148', (271, 276))	('muM', 'Gene', (213, 216))	('maleimide', 'Chemical', 'MESH:C043592', (164, 173))	('cysteine', 'Chemical', 'MESH:D003545', (12, 20))	('N2A', 'Chemical', '-', (94, 97))	('CTD', 'Gene', '1283', (236, 239))	('TAF15', 'Gene', (271, 276))	('K5S', 'Mutation', 'p.K5S', (85, 88))	('muM', 'Gene', '56925', (213, 216))	('CTD', 'Gene', (236, 239))	('S1966C', 'Var', (35, 41))	('serine', 'Chemical', 'MESH:D012694', (2, 8))
453082	28945358	Conversely, K5S exhibits increased penetrance of CTD fluorescence to the center of the hydrogel and reduced fluorescence intensity around the exterior.	('CTD', 'Gene', '1283', (49, 52))	('K5S', 'Var', (12, 15))	('increased', 'PosReg', (25, 34))	('reduced', 'NegReg', (100, 107))	('fluorescence intensity around the', 'MPA', (108, 141))	('CTD', 'Gene', (49, 52))	('penetrance', 'MPA', (35, 45))	('K5S', 'Mutation', 'p.K5S', (12, 15))
453083	28945358	Although this experiment is not at equilibrium, the distinct kinetic pattern of K5S localization presumably arises because it is less easily trapped by high avidity binding of TAF15 hydrogel fibrils than WT and N2A (Figure 6A, S7).	('TAF15', 'Gene', '8148', (176, 181))	('K5S', 'Var', (80, 83))	('binding', 'Interaction', (165, 172))	('TAF15', 'Gene', (176, 181))	('N2A', 'Chemical', '-', (211, 214))	('K5S', 'Mutation', 'p.K5S', (80, 83))	('hydrogel', 'Protein', (182, 190))
453085	28945358	Increasing the concentration of salt ions screens out electrostatic interactions between CTD variants and TAF15, therefore Alexa-Fluor labeled CTD fluorescence within each TAF15 hydrogel may decrease.	('TAF15', 'Gene', '8148', (172, 177))	('CTD', 'Gene', (89, 92))	('TAF15', 'Gene', (106, 111))	('CTD', 'Gene', (143, 146))	('variants', 'Var', (93, 101))	('Alexa-Fluor', 'Chemical', '-', (123, 134))	('TAF15', 'Gene', (172, 177))	('salt', 'Chemical', 'MESH:D012492', (32, 36))	('CTD', 'Gene', '1283', (89, 92))	('TAF15', 'Gene', '8148', (106, 111))	('CTD', 'Gene', '1283', (143, 146))	('screens out', 'Reg', (42, 53))	('electrostatic interactions', 'MPA', (54, 80))	('decrease', 'NegReg', (191, 199))
453087	28945358	By contrast, N2A exhibits a half life and diffusion coefficient similar to WT (Figure 6C).	('diffusion', 'MPA', (42, 51))	('N2A', 'Var', (13, 16))	('N2A', 'Chemical', '-', (13, 16))
453089	28945358	Given these observed differences in fluorescence localization and FRAP due to changes in salt concentration, we next attempted to use NMR to measure DeltaR2 of CTD27-52 WT in the presence of sonicated TAF15 fibrils and buffers with varying salt concentrations.	('TAF15', 'Gene', (201, 206))	('CTD27-52', 'Gene', '1283', (160, 168))	('salt', 'Chemical', 'MESH:D012492', (89, 93))	('salt', 'Chemical', 'MESH:D012492', (240, 244))	('TAF15', 'Gene', '8148', (201, 206))	('fluorescence localization', 'MPA', (36, 61))	('DeltaR2', 'DELETION', 'None', (149, 156))	('CTD27-52', 'Gene', (160, 168))	('DeltaR2', 'Var', (149, 156))
453090	28945358	Unfortunately, our standard sample concentrations of 250 muM CTD27-52 mixed with sonicated TAF15 fibrils rapidly precipitate in 100 mM NaCl buffer, precluding measurement of DeltaR2.	('TAF15', 'Gene', (91, 96))	('muM', 'Gene', (57, 60))	('CTD27-52', 'Gene', (61, 69))	('CTD27-52', 'Gene', '1283', (61, 69))	('DeltaR2', 'DELETION', 'None', (174, 181))	('DeltaR2', 'Var', (174, 181))	('TAF15', 'Gene', '8148', (91, 96))	('muM', 'Gene', '56925', (57, 60))	('NaCl', 'Chemical', 'MESH:D012965', (135, 139))
453093	28945358	This salt concentration threshold may be near 200 mM NaCl, because increasing the salt concentration above 200 mM in our NMR sample preps does not significantly affect the interaction between CTD27-52 WT and TAF15 fibrils: DeltaR2 values of CTD27-52 WT + 2 mg/mL TAF15 fibrils in 400 mM NaCl were within error of DeltaR2 values in 200 mM NaCl (Figure S8A).	('NaCl', 'Chemical', 'MESH:D012965', (53, 57))	('NaCl', 'Chemical', 'MESH:D012965', (287, 291))	('NaCl', 'Chemical', 'MESH:D012965', (338, 342))	('CTD27-52', 'Gene', (192, 200))	('CTD27-52', 'Gene', '1283', (192, 200))	('salt', 'Chemical', 'MESH:D012492', (82, 86))	('CTD27-52', 'Gene', '1283', (241, 249))	('TAF15', 'Gene', '8148', (263, 268))	('TAF15', 'Gene', '8148', (208, 213))	('CTD27-52', 'Gene', (241, 249))	('salt', 'Chemical', 'MESH:D012492', (5, 9))	('DeltaR2', 'DELETION', 'None', (223, 230))	('DeltaR2', 'DELETION', 'None', (313, 320))	('TAF15', 'Gene', (263, 268))	('DeltaR2', 'Var', (223, 230))	('TAF15', 'Gene', (208, 213))	('DeltaR2', 'Var', (313, 320))
453095	28945358	Because removing five of the CTD's nine positively charged residues (8 lysines and R1810) both reduces apparent binding to sonicated TAF15 fibrils (DeltaR2 decrease by ~30%) and increases diffusion within TAF15 hydrogels by roughly 50%, we suggest that the increased prevalence of positively charged degeneracies in the human CTD may serve to modulate interactions with assemblies such as TAF15.	('DeltaR2', 'Var', (148, 155))	('TAF15', 'Gene', (133, 138))	('TAF15', 'Gene', '8148', (389, 394))	('diffusion', 'MPA', (188, 197))	('human', 'Species', '9606', (320, 325))	('TAF15', 'Gene', '8148', (133, 138))	('CTD', 'Gene', '1283', (29, 32))	('interactions', 'Interaction', (352, 364))	('increases', 'PosReg', (178, 187))	('TAF15', 'Gene', (205, 210))	('CTD', 'Gene', (326, 329))	('TAF15', 'Gene', '8148', (205, 210))	('modulate', 'Reg', (343, 351))	('reduces', 'NegReg', (95, 102))	('DeltaR2', 'DELETION', 'None', (148, 155))	('R1810', 'Var', (83, 88))	('CTD', 'Gene', '1283', (326, 329))	('CTD', 'Gene', (29, 32))	('binding', 'Interaction', (112, 119))	('lysines', 'Chemical', 'MESH:D008239', (71, 78))	('TAF15', 'Gene', (389, 394))
453097	28945358	Unfortunately, NMR samples of 250 muM CTD27-52 Delta1961-1970, a CTD variant lacking the last ten residues, rapidly aggregate upon the addition of sonicated TAF15 fibrils at concentrations as low as 0.2 mg/mL.	('CTD', 'Gene', '1283', (38, 41))	('muM', 'Gene', '56925', (34, 37))	('CTD', 'Gene', '1283', (65, 68))	('TAF15', 'Gene', (157, 162))	('muM', 'Gene', (34, 37))	('CTD', 'Gene', (65, 68))	('aggregate', 'Reg', (116, 125))	('CTD', 'Gene', (38, 41))	('CTD27-52', 'Gene', (38, 46))	('Delta1961-1970', 'Var', (47, 61))	('CTD27-52', 'Gene', '1283', (38, 46))	('TAF15', 'Gene', '8148', (157, 162))	('Delta1961', 'Mutation', 'c.del1961', (47, 56))
453098	28945358	Interestingly, CTD27-52 Delta1961-1970 is stable in NMR sample buffer at concentrations up to 1 mM, indicating that the combination of CTD Delta1961-1970 and sonicated TAF15 fibrils induces aggregation.	('CTD27-52', 'Gene', '1283', (15, 23))	('aggregation', 'MPA', (190, 201))	('induces', 'Reg', (182, 189))	('Delta1961', 'Mutation', 'c.del1961', (24, 33))	('CTD', 'Gene', '1283', (135, 138))	('Delta1961-1970', 'Var', (139, 153))	('TAF15', 'Gene', (168, 173))	('CTD', 'Gene', '1283', (15, 18))	('Delta1961', 'Mutation', 'c.del1961', (139, 148))	('CTD', 'Gene', (15, 18))	('CTD', 'Gene', (135, 138))	('CTD27-52', 'Gene', (15, 23))	('TAF15', 'Gene', '8148', (168, 173))
453100	28945358	Based on these observations, it is possible that removing the acidic C-terminal tail increases association between CTD monomers and TAF15 sonicated fibrils.	('association', 'Interaction', (95, 106))	('removing', 'Var', (49, 57))	('increases', 'PosReg', (85, 94))	('CTD', 'Gene', '1283', (115, 118))	('TAF15', 'Gene', '8148', (132, 137))	('CTD', 'Gene', (115, 118))	('TAF15', 'Gene', (132, 137))
453101	28945358	However, when dilute CTD Delta1961-1970 is incubated with intact TAF15 hydrogels, CTD Delta1961-1970 fluorescence localization and recovery after photobleaching are almost identical to that of WT (the half life and diffusion rate of CTD Delta1961-1970 were 56.6 +- 7.1 seconds and 0.096 +- 0.012 mum2/s, respectively, compared to 58.0 +- 0.3 seconds and 0.094 +- 0.001 mum2/s for WT) (Figure S8D-E).	('CTD', 'Gene', (82, 85))	('Delta1961-1970', 'Var', (237, 251))	('mum', 'Gene', '56925', (369, 372))	('Delta1961', 'Mutation', 'c.del1961', (237, 246))	('Delta1961-1970', 'Var', (86, 100))	('CTD', 'Gene', (21, 24))	('CTD', 'Gene', (233, 236))	('Delta1961', 'Mutation', 'c.del1961', (25, 34))	('mum', 'Gene', (369, 372))	('CTD', 'Gene', '1283', (21, 24))	('TAF15', 'Gene', (65, 70))	('Delta1961', 'Mutation', 'c.del1961', (86, 95))	('mum', 'Gene', '56925', (296, 299))	('CTD', 'Gene', '1283', (82, 85))	('CTD', 'Gene', '1283', (233, 236))	('mum', 'Gene', (296, 299))	('TAF15', 'Gene', '8148', (65, 70))
453102	28945358	For these experiments, CTD WT and Delta1961-1970 were selectively labeled at the N-terminus with Alexa Fluor NHS ester dyes.	('CTD', 'Gene', (23, 26))	('Alexa Fluor NHS ester', 'Chemical', '-', (97, 118))	('Delta1961', 'Mutation', 'c.del1961', (34, 43))	('CTD', 'Gene', '1283', (23, 26))	('Delta1961-1970', 'Var', (34, 48))
453107	28945358	Our molecular simulations suggest that heptad 52, which contains the rare P1956L degeneracy, forms a transient alpha-helix, although we were unable to corroborate this experimentally.	('corroborate', 'Chemical', '-', (151, 162))	('P1956L', 'Var', (74, 80))	('transient alpha-helix', 'MPA', (101, 122))	('P1956L', 'Mutation', 'p.P1956L', (74, 80))
453108	28945358	While a transient helix near P1956L may play a role in the CTD's interactions with binding partners, it is clear based on both our NMR and simulations that the CTD is predominantly disordered.	('play', 'Reg', (40, 44))	('CTD', 'Gene', '1283', (59, 62))	('P1956L', 'Mutation', 'p.P1956L', (29, 35))	('CTD', 'Gene', (59, 62))	('P1956L', 'Var', (29, 35))	('interactions', 'Interaction', (65, 77))	('disordered', 'Disease', 'MESH:D030342', (181, 191))	('CTD', 'Gene', '1283', (160, 163))	('CTD', 'Gene', (160, 163))	('disordered', 'Disease', (181, 191))
453113	28945358	NMR and hydrogel binding assays using several CTD variants and at different salt concentrations suggest that degenerate lysines at position 7 in the human RNA pol II CTD mediate interaction with TAF15 fibril assemblies and that the acidic tail does not participate in the interactions.	('RNA pol II CTD', 'Gene', '32100', (155, 169))	('interaction', 'Interaction', (178, 189))	('TAF15', 'Gene', (195, 200))	('CTD', 'Gene', '1283', (166, 169))	('degenerate', 'Var', (109, 119))	('salt', 'Chemical', 'MESH:D012492', (76, 80))	('CTD', 'Gene', '1283', (46, 49))	('human', 'Species', '9606', (149, 154))	('RNA pol II CTD', 'Gene', (155, 169))	('CTD', 'Gene', (166, 169))	('lysines', 'Chemical', 'MESH:D008239', (120, 127))	('mediate', 'Reg', (170, 177))	('fibril assemblies', 'Protein', (201, 218))	('CTD', 'Gene', (46, 49))	('TAF15', 'Gene', '8148', (195, 200))
453114	28945358	Interestingly, although removal of residues 1961-1970, comprising the acidic C-terminal tail of the CTD (ISPDDSDEEN), does not alter binding of CTD to intact TAF15 hydrogels based on FRAP experiments, NMR samples of CTD Delta1961-1970 and sonicated TAF15 LC fibrils rapidly precipitate.	('CTD', 'Gene', '1283', (216, 219))	('CTD', 'Gene', '1283', (144, 147))	('CTD', 'Gene', '1283', (100, 103))	('TAF15', 'Gene', '8148', (158, 163))	('Delta1961', 'Mutation', 'c.del1961', (220, 229))	('CTD', 'Gene', (216, 219))	('Delta1961-1970', 'Var', (220, 234))	('CTD', 'Gene', (100, 103))	('TAF15', 'Gene', (158, 163))	('TAF15', 'Gene', '8148', (249, 254))	('CTD', 'Gene', (144, 147))	('TAF15', 'Gene', (249, 254))
453116	28945358	These results suggest FET fusion proteins bind RNA pol II CTD via multivalent interactions: numerous tyrosines, serines, and threonines within consensus YSPTSPS heptads may form polar contacts with FET SYGQ repeats, and R1810 and lysine degeneracies may form electrostatic interactions with FET aspartic and glutamic acids.	('threonines', 'Chemical', 'MESH:D013912', (125, 135))	('RNA pol II CTD', 'Gene', (47, 61))	('form', 'Reg', (254, 258))	('R1810', 'Var', (220, 225))	('polar contacts', 'MPA', (178, 192))	('serines', 'Chemical', 'MESH:D012694', (112, 119))	('RNA pol II CTD', 'Gene', '32100', (47, 61))	('tyrosines', 'Chemical', 'MESH:D014443', (101, 110))	('electrostatic', 'MPA', (259, 272))	('glutamic', 'Protein', (308, 316))	('form', 'Reg', (173, 177))	('glutamic acids', 'Chemical', 'MESH:D005971', (308, 322))	('lysine', 'Chemical', 'MESH:D008239', (230, 236))
453146	27014915	Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFalpha-induced cell death, whereas inhibition of RIP1 blocks TNFalpha-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways.	('caspase', 'Gene', '841;842', (14, 21))	('caspase', 'Gene', (171, 178))	('caspases', 'Gene', (14, 22))	('RIP3', 'Gene', '11035', (33, 37))	('RIP1', 'Gene', '8737', (106, 110))	('caspase', 'Gene', '841;842', (171, 178))	('caspases', 'Gene', '841;842', (14, 22))	('RIP3', 'Gene', (33, 37))	('caspases', 'Gene', (171, 179))	('RIP1', 'Gene', '8737', (184, 188))	('TNFalpha', 'Gene', (55, 63))	('TNFalpha', 'Gene', (118, 126))	('cell death', 'CPA', (72, 82))	('caspases', 'Gene', '841;842', (171, 179))	('RIP1', 'Gene', '8737', (24, 28))	('RIP1', 'Gene', (106, 110))	('caspase', 'Gene', (135, 142))	('inhibition', 'Var', (92, 102))	('RIP1', 'Gene', (184, 188))	('blocks', 'NegReg', (38, 44))	('TNFalpha', 'Gene', '7124', (55, 63))	('caspase', 'Gene', '841;842', (135, 142))	('TNFalpha', 'Gene', '7124', (118, 126))	('RIP1', 'Gene', (24, 28))	('caspase', 'Gene', (14, 21))
453162	27014915	Therefore, blocking NF-kappaB activation might impair T cell activation and function in cancer patients, and its side effects on T cells in the tumor microenvironment should be considered with great care.	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('activation', 'PosReg', (30, 40))	('impair T cell activation', 'Phenotype', 'HP:0005419', (47, 71))	('T cell activation', 'CPA', (54, 71))	('function', 'CPA', (76, 84))	('blocking', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('NF-kappaB', 'Protein', (20, 29))	('impair', 'NegReg', (47, 53))
453171	27014915	The human colon carcinoma cell lines SW620 and LS411N are relatively resistant to radiation in a one day assay (Figure 2A).	('SW620', 'CellLine', 'CVCL:0547', (37, 42))	('human', 'Species', '9606', (4, 9))	('colon carcinoma', 'Disease', 'MESH:D015179', (10, 25))	('colon carcinoma', 'Disease', (10, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('LS411N', 'Var', (47, 53))
453178	27014915	Patients with high cIAP1 protein levels had a significantly lower survival time as compared to patients with medium to low or undetectable cIAP1 protein levels in the tumor cells.	('patients', 'Species', '9606', (95, 103))	('protein', 'Protein', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('high', 'Var', (14, 18))	('cIAP1', 'Gene', (19, 24))	('cIAP1', 'Gene', (139, 144))	('survival time', 'CPA', (66, 79))	('Patients', 'Species', '9606', (0, 8))	('cIAP1', 'Gene', '329', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cIAP1', 'Gene', '329', (19, 24))	('tumor', 'Disease', (167, 172))	('lower', 'NegReg', (60, 65))
453179	27014915	Furthermore, patients with high cIAP1 protein levels in the tumor cells also exhibited a significantly higher recurrence rate as compared to patients with medium to low and undetectable cIAP1 protein levels in the tumor cells (Figure 3B).	('higher', 'PosReg', (103, 109))	('protein', 'Protein', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('high', 'Var', (27, 31))	('cIAP1', 'Gene', (186, 191))	('cIAP1', 'Gene', '329', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (214, 219))	('cIAP1', 'Gene', (32, 37))	('cIAP1', 'Gene', '329', (32, 37))	('tumor', 'Disease', (60, 65))	('recurrence rate', 'CPA', (110, 125))	('patients', 'Species', '9606', (141, 149))
453222	27014915	On day 6, the radiation only, BV6 only, and radiation+BV6 had significantly lower mean tumor volumes than the control group, and the radiation+BV6 group had a significantly lower mean tumor volume than BV6 only (p < 0.01).	('BV6', 'Chemical', '-', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('BV6', 'Chemical', '-', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('radiation+BV6', 'Var', (44, 57))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (87, 92))	('BV6', 'Chemical', '-', (143, 146))	('BV6', 'Chemical', '-', (202, 205))	('lower', 'NegReg', (76, 81))	('tumor', 'Disease', (184, 189))	('lower', 'NegReg', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
453237	27014915	Within day 4, the combined radiation and BV6 group had significantly lower tumor volume than the BV6 only group (p < 0.01).	('BV6', 'Var', (41, 44))	('lower', 'NegReg', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('BV6', 'Chemical', '-', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('BV6', 'Chemical', '-', (97, 100))	('tumor', 'Disease', (75, 80))
453238	27014915	Within day 6, the combined radiation and BV6 group had significantly lower tumor volume than the BV6 only and control groups, and the radiation only group had significantly lower tumor volume than the BV6 only group.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('BV6', 'Var', (41, 44))	('lower', 'NegReg', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('BV6', 'Chemical', '-', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lower', 'NegReg', (173, 178))	('BV6', 'Chemical', '-', (97, 100))	('BV6', 'Chemical', '-', (201, 204))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', (179, 184))
453239	27014915	Within day 8, the combined radiation and BV6 group had significantly lower tumor volume than the BV6 only and control groups (p < 0.01).	('BV6', 'Var', (41, 44))	('lower', 'NegReg', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('BV6', 'Chemical', '-', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('BV6', 'Chemical', '-', (97, 100))	('tumor', 'Disease', (75, 80))
453251	27014915	Radiation is known to activate NF-kappaB, and NF-kappaB has been shown to confer tumor cell radioresistance.	('NF-kappaB', 'Protein', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('NF-kappaB', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('activate', 'PosReg', (22, 30))	('tumor', 'Disease', (81, 86))
453255	27014915	In agreement with early reports that BV6 induce cIAP1 and cIAP2 degradation to increase NIK stability to activate the alternate NF-kappaB, we observed that BV6 induces the alternate NF-kappaB activation.	('increase', 'PosReg', (79, 87))	('NIK', 'Gene', '9020', (88, 91))	('NIK', 'Gene', (88, 91))	('BV6', 'Chemical', '-', (37, 40))	('cIAP1', 'Gene', (48, 53))	('cIAP1', 'Gene', '329', (48, 53))	('cIAP2', 'Gene', (58, 63))	('cIAP2', 'Gene', '330', (58, 63))	('alternate NF-kappaB', 'MPA', (172, 191))	('activation', 'PosReg', (192, 202))	('BV6', 'Var', (156, 159))	('activate', 'PosReg', (105, 113))	('BV6', 'Chemical', '-', (156, 159))
453259	27014915	Strikingly, we demonstrated that BV6 enhances TNFalpha function in the induction of tumor cell apoptosis and necroptosis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('BV6', 'Chemical', '-', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('enhances', 'PosReg', (37, 45))	('TNFalpha', 'Gene', (46, 54))	('tumor', 'Disease', (84, 89))	('function', 'MPA', (55, 63))	('necroptosis', 'CPA', (109, 120))	('TNFalpha', 'Gene', '7124', (46, 54))	('BV6', 'Var', (33, 36))
453260	27014915	However, the BV6 and TNFalpha-induced apoptosis and necroptosis pathways do not compensate for each other since blocking either caspases alone or RIP1/RIP3 alone still inhibits cell death.	('blocking', 'Var', (112, 120))	('RIP1', 'Gene', (146, 150))	('cell death', 'CPA', (177, 187))	('TNFalpha', 'Gene', (21, 29))	('RIP3', 'Gene', '11035', (151, 155))	('inhibits', 'NegReg', (168, 176))	('caspases', 'Gene', '841;842', (128, 136))	('BV6', 'Chemical', '-', (13, 16))	('RIP1', 'Gene', '8737', (146, 150))	('TNFalpha', 'Gene', '7124', (21, 29))	('caspases', 'Gene', (128, 136))	('RIP3', 'Gene', (151, 155))
453263	27014915	In this study, we observed that inhibition of RIP1 but not RIP3 diminishes caspase 8 activation, whereas inhibition of RIP1 or RIP3 both blocks radiation/TNFalpha-induced cell death.	('TNFalpha', 'Gene', (154, 162))	('RIP3', 'Gene', '11035', (127, 131))	('activation', 'MPA', (85, 95))	('inhibition', 'Var', (32, 42))	('blocks', 'NegReg', (137, 143))	('inhibition', 'Var', (105, 115))	('RIP1', 'Gene', (46, 50))	('RIP3', 'Gene', '11035', (59, 63))	('TNFalpha', 'Gene', '7124', (154, 162))	('RIP1', 'Gene', '8737', (46, 50))	('RIP1', 'Gene', (119, 123))	('RIP3', 'Gene', (127, 131))	('caspase 8', 'Gene', '841', (75, 84))	('RIP3', 'Gene', (59, 63))	('RIP1', 'Gene', '8737', (119, 123))	('caspase 8', 'Gene', (75, 84))	('diminishes', 'NegReg', (64, 74))
453346	26257296	The COG cohort included all eligible patients enrolled on the following COG clinical trials for newly diagnosed metastatic or localized EWS: INT-0091 (enrolled December 1988 to November 1992); INT-0154 (enrolled May 1995 - September 1998); CCG-7951 (enrolled February 1996 to November 1998); AEWS0031 (enrolled May 2001 - August 2005); and AEWS02P1 (enrolled March 2004 - April 2008).	('COG', 'Chemical', '-', (4, 7))	('EWS', 'Gene', (293, 296))	('EWS', 'Gene', (341, 344))	('EWS', 'Gene', '2130', (293, 296))	('EWS', 'Gene', '2130', (341, 344))	('patients', 'Species', '9606', (37, 45))	('INT-0154', 'Var', (193, 201))	('COG', 'Chemical', '-', (72, 75))	('EWS', 'Gene', '2130', (136, 139))	('EWS', 'Gene', (136, 139))
453350	26257296	Patients enrolled in INT-0091, INT-0154, and CCG-7951 were <= 30 years at the time of diagnosis and those enrolled in AEWS02P1 and AEWS0031 were <= 50 years at the time of diagnosis.	('INT-0154', 'Var', (31, 39))	('EWS', 'Gene', '2130', (132, 135))	('EWS', 'Gene', (132, 135))	('Patients', 'Species', '9606', (0, 8))	('EWS', 'Gene', '2130', (119, 122))	('EWS', 'Gene', (119, 122))	('CCG-7951', 'Var', (45, 53))	('INT-0091', 'Var', (21, 29))
453505	24816908	IGF1R is present on most tumor cells, and inhibition of this receptor slowed tumor growth and increased the antitumor activity of chemotherapy, radiation, and biologic agents in xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('increased', 'PosReg', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('inhibition', 'Var', (42, 52))	('IGF1R', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('slowed', 'NegReg', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (112, 117))	('IGF1R', 'Gene', '3480', (0, 5))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
453523	24816908	These data provide a direct link involving IGF-1 in TRAIL-induced cell death resistance and suggest that inhibition of IGF1R action with ganitumab could enhance the pro-apoptotic effect of conatumumab in some tumor types.	('tumor', 'Disease', (209, 214))	('inhibition', 'Var', (105, 115))	('TRAIL', 'Gene', '8743', (52, 57))	('IGF-1', 'Gene', '3479', (43, 48))	('IGF1R', 'Gene', (119, 124))	('IGF-1', 'Gene', (43, 48))	('enhance', 'PosReg', (153, 160))	('pro-apoptotic effect', 'MPA', (165, 185))	('conatumumab', 'Chemical', 'MESH:C554537', (189, 200))	('TRAIL', 'Gene', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('ganitumab', 'Chemical', 'MESH:C545764', (137, 146))	('IGF1R', 'Gene', '3480', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
453525	24816908	Pro-apoptotic receptor agonists have been shown to induce apoptosis in vitro and in vivo in a broad spectrum of tumor cell lines, including lung, colorectal, pancreatic, and ovarian cancers, as well as sarcoma.	('ovarian cancer', 'Phenotype', 'HP:0100615', (174, 188))	('colorectal', 'Disease', (146, 156))	('ovarian cancers', 'Disease', (174, 189))	('agonists', 'Var', (23, 31))	('induce', 'PosReg', (51, 57))	('ovarian cancers', 'Disease', 'MESH:D010051', (174, 189))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('sarcoma', 'Disease', 'MESH:D012509', (202, 209))	('tumor', 'Disease', (112, 117))	('colorectal', 'Disease', 'MESH:D015179', (146, 156))	('sarcoma', 'Disease', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('ovarian cancers', 'Phenotype', 'HP:0100615', (174, 189))	('pancreatic', 'Disease', 'MESH:D010195', (158, 168))	('apoptosis', 'CPA', (58, 67))	('coma', 'Phenotype', 'HP:0001259', (205, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('lung', 'Disease', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('pancreatic', 'Disease', (158, 168))	('Pro-apoptotic', 'Protein', (0, 13))
453545	24816908	The 3 mg/kg Q3W conatumumab dose was predicted to have a Cmin of 10 microg/mL, approximately 4-fold higher than the EC50 value in the xenograft model, and the highest dose of 15 mg/kg Q3W was selected to ensure trough concentrations above the EC90 in most patients.	('EC90', 'CellLine', 'CVCL:1B47', (243, 247))	('conatumumab', 'Gene', (16, 27))	('Q3W', 'Var', (12, 15))	('patients', 'Species', '9606', (256, 264))	('trough', 'MPA', (211, 217))	('higher', 'PosReg', (100, 106))	('Cmin', 'MPA', (57, 61))	('conatumumab', 'Chemical', 'MESH:C554537', (16, 27))
453582	24816908	Adverse events previously associated with IGF1R inhibitors, including ganitumab, were hyperglycemia (5 %; 3 %>=grade 3), thrombocytopenia (1 %; 1 % grade 3); and neutropenia (3 %; 1 % grade 3).	('hyperglycemia', 'Disease', (86, 99))	('neutropenia', 'Disease', (162, 173))	('thrombocytopenia', 'Disease', 'MESH:D013921', (121, 137))	('ganitumab', 'Chemical', 'MESH:C545764', (70, 79))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (121, 137))	('hyperglycemia', 'Phenotype', 'HP:0003074', (86, 99))	('neutropenia', 'Disease', 'MESH:D009503', (162, 173))	('inhibitors', 'Var', (48, 58))	('IGF1R', 'Gene', (42, 47))	('thrombocytopenia', 'Disease', (121, 137))	('neutropenia', 'Phenotype', 'HP:0001875', (162, 173))	('hyperglycemia', 'Disease', 'MESH:D006943', (86, 99))	('IGF1R', 'Gene', '3480', (42, 47))
453603	24816908	Given the support for interaction between the TRAIL and IGF-1 pathways and the evidence that inhibition of IGF-1 sensitizes cells for death ligand-induced apoptosis, we postulated that the combination of ganitumab and conatumumab might increase antitumor response in the clinical setting.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('conatumumab', 'Chemical', 'MESH:C554537', (218, 229))	('ganitumab', 'Chemical', 'MESH:C545764', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('TRAIL', 'Gene', '8743', (46, 51))	('tumor', 'Disease', (249, 254))	('increase', 'PosReg', (236, 244))	('IGF-1', 'Gene', '3479', (107, 112))	('TRAIL', 'Gene', (46, 51))	('IGF-1', 'Gene', (107, 112))	('IGF-1', 'Gene', '3479', (56, 61))	('inhibition', 'Var', (93, 103))	('IGF-1', 'Gene', (56, 61))
453613	24816908	The Colo 205 model has mutations in APC, BRAF, SMAD4, and TP53; therefore, evaluation of the mutation status of the patients in this trial could provide additional information but has not been undertaken at this time.	('Colo', 'Species', '307630', (4, 8))	('TP53', 'Gene', (58, 62))	('patients', 'Species', '9606', (116, 124))	('SMAD4', 'Gene', (47, 52))	('mutations', 'Var', (23, 32))	('BRAF', 'Gene', (41, 45))	('APC', 'Disease', 'MESH:D011125', (36, 39))	('APC', 'Disease', (36, 39))
453615	24816908	Determination and appropriate application of biomarkers is complex andmay emerge only after a new drug has been in use in patients for some time, as exemplified by the case of epidermal growth factor receptor inhibitor resistance in tumors harboring KRAS mutations.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('epidermal growth factor receptor', 'Gene', '1956', (176, 208))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('patients', 'Species', '9606', (122, 130))	('KRAS', 'Gene', (250, 254))	('epidermal growth factor receptor', 'Gene', (176, 208))	('KRAS', 'Gene', '3845', (250, 254))	('mutations', 'Var', (255, 264))
453654	23772300	For hybridization, DNA from 50,000 sorted nuclei and genomic DNA of pooled commercial 46, XX reference (Promega, Wisconsin) was digested with DNaseI and labeled with Cy-5 dUTP and Cy-3 dUTP, respectively, using a BioPrime labeling kit (Invitrogen).	('dUTP', 'Chemical', 'MESH:C027078', (171, 175))	('dUTP', 'Chemical', 'MESH:C027078', (185, 189))	('Cy-5 dUTP', 'Var', (166, 175))	('Cy-5', 'Chemical', 'MESH:C085321', (166, 170))	('Cy-3 dUTP', 'Var', (180, 189))	('Cy-3 dUTP', 'Chemical', 'MESH:C088941', (180, 189))
453658	23772300	A series of regions targeted by focal copy number aberrations were identified in the 2.5N populations [Amplified: 4q12 (LNX1), 4p14 (UBE2K), 5p15.33 (hTERT)] [Deleted: 9p21.3 (CDKN2A), Xq23 (TRPC5*), 1p36.13 (PAX7)].	('UBE2K', 'Gene', (133, 138))	('numb', 'Gene', (43, 47))	('p21', 'Gene', '1026', (169, 172))	('TRPC5', 'Gene', '7224', (191, 196))	('TERT', 'Gene', (151, 155))	('p21', 'Gene', (169, 172))	('UBE2K', 'Gene', '3093', (133, 138))	('TRPC5', 'Gene', (191, 196))	('TERT', 'Gene', '7015', (151, 155))	('numb', 'Gene', '8650', (43, 47))	('CDKN2A', 'Gene', (176, 182))	('LNX1', 'Gene', '84708', (120, 124))	('1p36.13', 'Var', (200, 207))	('LNX1', 'Gene', (120, 124))	('CDKN2A', 'Gene', '1029', (176, 182))
453659	23772300	In addition, we detected an interstitial 1q32.2-q42.13 deletion with a breakpoints located at the TAF5L locus (q42.13) and HHAT* (q32.2).	('HHAT', 'Gene', (123, 127))	('TAF5L', 'Gene', (98, 103))	('TAF5L', 'Gene', '27097', (98, 103))	('HHAT', 'Gene', '55733', (123, 127))	('q42.13', 'Var', (111, 117))
453662	23772300	The presence of these shared and unique focal deletions seen in UPS1 and UPS2 suggests that the 2.5N populations represent two distinct clonal populations that arose during the clinical history of this tumor.	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('deletions', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', (202, 207))
453664	23772300	Previous reports have shown that genetic amplifications and deletions have a direct effect on protein expression, which can result in cancerous phenotypes when cancer-promoting regions are affected by these copy number changes.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('deletions', 'Var', (60, 69))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (134, 140))	('effect', 'Reg', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('protein expression', 'MPA', (94, 112))	('cancerous', 'Disease', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('numb', 'Gene', '8650', (212, 216))	('cancerous', 'Disease', 'MESH:D009369', (134, 143))	('numb', 'Gene', (212, 216))	('result in', 'Reg', (124, 133))
453666	23772300	Evidence of this claim is fortified by the loss of three loci (interstitial 1q32.2-q42.13 and 15q14-q21.3, and the homozygous deletion of TRPC5) in UPS1 that were not detected in UPS2.	('TRPC5', 'Gene', '7224', (138, 143))	('deletion', 'Var', (126, 134))	('loss', 'NegReg', (43, 47))	('TRPC5', 'Gene', (138, 143))
453670	23772300	Studies pertaining to LNX1 show that alterations of this gene are often found in glial tumors, but not much work has been done to show alterations/expression in other tissue types.	('found', 'Reg', (72, 77))	('glial tumors', 'Disease', 'MESH:D005910', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('glial tumors', 'Disease', (81, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('LNX1', 'Gene', '84708', (22, 26))	('alterations', 'Var', (37, 48))	('LNX1', 'Gene', (22, 26))
453672	23772300	Amplification of LNX1 may lead to an increase of NUMB degradation and higher susceptibility to unstable regulation of progenitor cells in other tissues such as mesenchyme that lead to soft tissue sarcomas like UPS.	('susceptibility to unstable regulation', 'MPA', (77, 114))	('Amplification', 'Var', (0, 13))	('NUMB', 'Gene', (49, 53))	('sarcomas', 'Disease', (196, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('NUMB', 'Gene', '8650', (49, 53))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (184, 204))	('increase', 'PosReg', (37, 45))	('sarcomas', 'Disease', 'MESH:D012509', (196, 204))	('LNX1', 'Gene', '84708', (17, 21))	('LNX1', 'Gene', (17, 21))	('lead to', 'Reg', (176, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (196, 204))
453683	23772300	Furthermore, PAX7 (PAX3 can as well) can form chimeric genes with FKHR and is strongly associated with another sarcoma called alveolar rhabdomyosarcoma.	('sarcoma', 'Disease', (144, 151))	('PAX3', 'Gene', '5077', (19, 23))	('FKHR', 'Gene', (66, 70))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('PAX3', 'Gene', (19, 23))	('chimeric', 'Interaction', (46, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (126, 151))	('FKHR', 'Gene', '2308', (66, 70))	('sarcoma', 'Disease', (111, 118))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (126, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('associated with', 'Reg', (87, 102))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (135, 151))	('alveolar rhabdomyosarcoma', 'Disease', (126, 151))	('PAX7', 'Var', (13, 17))
453684	23772300	It should also be noted that PAX7-mutant mice develop abnormalities involving the maxilla and nose, but no additional studies have been done to relate these findings to human UPS in the maxillary sinus.	('PAX7-mutant', 'Var', (29, 40))	('mice', 'Species', '10090', (41, 45))	('abnormalities involving the maxilla', 'Disease', 'MESH:D002485', (54, 89))	('abnormalities involving the maxilla', 'Disease', (54, 89))	('human', 'Species', '9606', (169, 174))	('abnormalities involving the maxilla', 'Phenotype', 'HP:0000326', (54, 89))
453685	23772300	Cyclin-dependent kinase inhibitor 2A (CDKN2A, p16) is a well-known tumor-suppressor that is often mutated or deleted in many cancer types.	('deleted', 'Var', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (0, 36))	('p16', 'Gene', '1029', (46, 49))	('man', 'Species', '9606', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CDKN2A', 'Gene', (38, 44))	('tumor', 'Disease', (67, 72))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('p16', 'Gene', (46, 49))	('Cyclin-dependent kinase inhibitor 2A', 'Gene', (0, 36))	('CDKN2A', 'Gene', '1029', (38, 44))
453686	23772300	Deletion of CDKN2A has also been identified in other cases of UPS, a broad range of sarcomas, as well as, in many other cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('CDKN2A', 'Gene', (12, 18))	('man', 'Species', '9606', (109, 112))	('UPS', 'Disease', (62, 65))	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('CDKN2A', 'Gene', '1029', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('identified', 'Reg', (33, 43))	('cancers', 'Disease', (120, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcomas', 'Disease', (84, 92))	('Deletion', 'Var', (0, 8))
453687	23772300	A deletion of CDKN2A leads to a loss of cell cycle regulation and can result in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CDKN2A', 'Gene', '1029', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('loss', 'NegReg', (32, 36))	('deletion', 'Var', (2, 10))	('tumor', 'Disease', (80, 85))	('cell cycle', 'CPA', (40, 50))	('result in', 'Reg', (70, 79))	('CDKN2A', 'Gene', (14, 20))
453691	23772300	Amplification of TERT is thought to occur through the homozygous deletion of CDKN2A (p16) seen in both UPS1 and UPS, which is an upstream suppressor of TERT and provides an explanation for a proposed pathway leading to cellular immortalization and progression to sarcomagenesis for this instance of UPS.	('p16', 'Gene', (85, 88))	('TERT', 'Gene', '7015', (152, 156))	('CDKN2A', 'Gene', (77, 83))	('TERT', 'Gene', (17, 21))	('cellular immortalization', 'CPA', (219, 243))	('TERT', 'Gene', '7015', (17, 21))	('sarcoma', 'Disease', 'MESH:D012509', (263, 270))	('CDKN2A', 'Gene', '1029', (77, 83))	('sarcoma', 'Disease', (263, 270))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('p16', 'Gene', '1029', (85, 88))	('TERT', 'Gene', (152, 156))	('deletion', 'Var', (65, 73))	('UPS1', 'Disease', (103, 107))
453693	23772300	Due to the homozygous deletion of CDKN2A, the CDKN1A/CDKN2A complex, as well as, an alternative p53/p73/CDKN2A transcriptional inhibition complex of TERT cannot form and effectively suppress TERT expression.	('CDKN2A', 'Gene', '1029', (104, 110))	('CDKN1A', 'Gene', (46, 52))	('p73', 'Gene', (100, 103))	('p53', 'Gene', (96, 99))	('CDKN2A', 'Gene', (53, 59))	('TERT', 'Gene', '7015', (149, 153))	('TERT', 'Gene', '7015', (191, 195))	('CDKN1A', 'Gene', '1026', (46, 52))	('TERT', 'Gene', (191, 195))	('p53', 'Gene', '7157', (96, 99))	('deletion', 'Var', (22, 30))	('CDKN2A', 'Gene', '1029', (53, 59))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('TERT', 'Gene', (149, 153))	('CDKN2A', 'Gene', (104, 110))	('suppress', 'NegReg', (182, 190))	('p73', 'Gene', '7161', (100, 103))
453696	23772300	This study provides the first instance of identifying genomic alterations that potentially play an active role in a sarcoma that is both rare and relatively unexplored in basic research.	('sarcoma', 'Disease', (116, 123))	('genomic alterations', 'Var', (54, 73))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
453722	23509421	The high tensile strength and fatigue resistance of metal would make it suitable for load-bearing applications, but the large mismatch in Young's modulus between metal and bone can lead to peri-implant bone resorption, a phenomenon known as stress shielding.	('peri-implant bone resorption', 'CPA', (189, 217))	('mismatch', 'Var', (126, 134))	('metal', 'Chemical', 'MESH:D008670', (52, 57))	('metal', 'Chemical', 'MESH:D008670', (162, 167))	('lead to', 'Reg', (181, 188))	('bone resorption', 'Phenotype', 'HP:0002797', (202, 217))	('fatigue', 'Phenotype', 'HP:0012378', (30, 37))	('peri-implant bone resorption', 'Phenotype', 'HP:0000700', (189, 217))
453824	31488130	Cell cycle regulatory gene such as P16 showed alteration and tumor suppressor gene P53 mutation were also found in FDCS.	('alteration', 'Reg', (46, 56))	('P16', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('P53', 'Gene', (83, 86))	('P16', 'Gene', '1029', (35, 38))	('FDCS', 'Disease', (115, 119))	('mutation', 'Var', (87, 95))	('P53', 'Gene', '7157', (83, 86))	('tumor', 'Disease', (61, 66))
453829	31488130	found that the involvement of BRAF mutations in the development of bladder UC was infrequent.	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('bladder UC', 'Disease', (67, 77))	('mutations', 'Var', (35, 44))
453839	30704460	Complex chromosomal aberrations such as amplifications and deletions of DNA sequences are frequently observed in pediatric sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('pediatric sarcomas', 'Disease', (113, 131))	('observed', 'Reg', (101, 109))	('DNA sequences', 'Gene', (72, 85))	('deletions', 'Var', (59, 68))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (113, 131))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (8, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('amplifications', 'Var', (40, 54))
453840	30704460	Evaluation of copy number variations (CNVs) associated with pediatric sarcoma patients at the time of diagnosis or following therapy offers an opportunity to assess dysregulated molecular targets and signaling pathways that may drive sarcoma development, progression, or relapse.	('sarcoma', 'Disease', (234, 241))	('sarcoma', 'Disease', (70, 77))	('drive', 'PosReg', (228, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('patients', 'Species', '9606', (78, 86))	('pediatric sarcoma', 'Disease', (60, 77))	('sarcoma', 'Disease', 'MESH:D012509', (234, 241))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (60, 77))	('copy number variations', 'Var', (14, 36))
453855	30704460	Genetic variation is one of many characteristics of pediatric sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Genetic variation', 'Var', (0, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('pediatric sarcomas', 'Disease', (52, 70))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (52, 70))
453859	30704460	Many of these chromosomal changes may be responsible for pediatric sarcoma progression and relapse, but the underlying cause of the large number of copy number amplifications and deletions remains unclear.	('changes', 'Var', (26, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('responsible', 'Reg', (41, 52))	('pediatric sarcoma', 'Disease', (57, 74))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (57, 74))
453860	30704460	Genetic alterations that serve as prognostic biomarkers for aggressive pediatric sarcomas will be investigated to also determine if they can be used as predictive biomarkers of therapeutic response.	('Genetic alterations', 'Var', (0, 19))	('aggressive pediatric sarcomas', 'Disease', (60, 89))	('aggressive pediatric sarcomas', 'Disease', 'MESH:D063766', (60, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
453862	30704460	Comprehensive molecular profiling of OS shows copy number amplification and overexpression of genes in chr8 and chr17p11.2-p12 that strongly correlate with OS progression and relapse.	('p12', 'Gene', '56655', (123, 126))	('copy number amplification', 'Var', (46, 71))	('correlate with', 'Reg', (141, 155))	('relapse', 'CPA', (175, 182))	('chr8', 'Gene', (103, 107))	('overexpression', 'PosReg', (76, 90))	('p12', 'Gene', (123, 126))
453863	30704460	Amplification of MET, CCNE1, and PDGFRalpha genes provides promising prognostic biomarkers for tailoring personalized therapies for OS patients.	('Amplification', 'Var', (0, 13))	('patients', 'Species', '9606', (135, 143))	('CCNE1', 'Gene', (22, 27))	('MET', 'Gene', (17, 20))	('PDGFRalpha', 'Gene', '5156', (33, 43))	('PDGFRalpha', 'Gene', (33, 43))	('CCNE1', 'Gene', '898', (22, 27))
453866	30704460	The frequent gains and amplifications associated with short-term survival include 12q13.3-q14.1 and 8p11.1-11.2 which harbor CDK4, MYCN, GLI, MDM2, FGFR1, and FGFR4 genes.	('CDK4', 'Gene', (125, 129))	('FGFR4', 'Gene', (159, 164))	('CDK4', 'Gene', '1019', (125, 129))	('FGFR4', 'Gene', '2264', (159, 164))	('MDM2', 'Gene', '4193', (142, 146))	('GLI', 'Gene', (137, 140))	('FGFR1', 'Gene', (148, 153))	('MYCN', 'Gene', (131, 135))	('MYCN', 'Gene', '4613', (131, 135))	('GLI', 'Gene', '2735', (137, 140))	('amplifications', 'Var', (23, 37))	('gains', 'PosReg', (13, 18))	('MDM2', 'Gene', (142, 146))	('FGFR1', 'Gene', '2260', (148, 153))
453871	30704460	As mentioned above, chromosomal aberrations such as DNA copy number amplifications and deletions are frequently observed in pediatric sarcomas and can be retrospectively integrated with drug response data to ultimately allow for predictions of response to chemotherapies.	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('allow', 'Reg', (219, 224))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (20, 43))	('DNA', 'Gene', (52, 55))	('deletions', 'Var', (87, 96))	('pediatric sarcomas', 'Disease', (124, 142))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (124, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))
453874	30704460	Comprehensive literature reviews were also conducted to collect CNV amplifications and deletions of many genes from the PubMed repository which may serve as a tool for predicting clinical outcomes in all three types of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('sarcomas', 'Disease', (219, 227))	('deletions', 'Var', (87, 96))	('sarcomas', 'Disease', 'MESH:D012509', (219, 227))	('clinical', 'Species', '191496', (179, 187))
453875	30704460	Genomic variations can contribute to differences in cancer cell drug responses.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('contribute', 'Reg', (23, 33))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('Genomic variations', 'Var', (0, 18))
453890	30704460	Hierarchy clustering analyses for delineating the pattern of genomic CNVs were conducted to stratify sarcoma patients based on their relapse and metastasis status where CNV distributions greater than the 85% range represented amplification (OS = 2.710, ESFTs = 0.147, RMS = 0.7) and less than the 15% range signified deletion (OS = 1.414, ESFTs = - 0.1467, RMS = - 1.213) (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('patients', 'Species', '9606', (109, 117))	('ESFTs = - 0.1467', 'Var', (339, 355))	('sarcoma', 'Disease', (101, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('deletion', 'Disease', (317, 325))	('amplification', 'Var', (226, 239))
453892	30704460	Combination of copy number amplification and deletion were observed in chromosomes 1, 10 and 12 which are comprised of genes amplified or deleted in OS pathogenesis such as RAD21, MYC, PTEN, IGF1R, and TP53 (Fig.	('PTEN', 'Gene', '5728', (185, 189))	('TP53', 'Gene', (202, 206))	('MYC', 'Gene', '4609', (180, 183))	('IGF1R', 'Gene', (191, 196))	('copy number', 'Var', (15, 26))	('RAD21', 'Gene', (173, 178))	('RAD21', 'Gene', '5885', (173, 178))	('IGF1R', 'Gene', '3480', (191, 196))	('MYC', 'Gene', (180, 183))	('deletion', 'Var', (45, 53))	('PTEN', 'Gene', (185, 189))	('TP53', 'Gene', '7157', (202, 206))
453896	30704460	Moreover, MYC, which is located in 8q24.21, showed the highest amplification frequency of 0.78 in OS, 0.69 in ESFTs, and was not amplified in RMS with a frequency of 0.32.	('ESFTs', 'Disease', (110, 115))	('0.69', 'Var', (102, 106))	('MYC', 'Gene', '4609', (10, 13))	('MYC', 'Gene', (10, 13))
453898	30704460	Transcription factor genes on chromosome 1 such as NOTCH2 (deletion), PRKAB2 (amplification) and SELL (amplification) also shared similar copy number alterations in all three types of sarcomas (Figs.	('NOTCH2', 'Gene', (51, 57))	('SELL', 'Gene', (97, 101))	('sarcomas', 'Disease', 'MESH:D012509', (184, 192))	('PRKAB2', 'Gene', (70, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (184, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('sarcomas', 'Disease', (184, 192))	('SELL', 'Gene', '6402', (97, 101))	('NOTCH2', 'Gene', '4853', (51, 57))	('deletion', 'Var', (59, 67))	('PRKAB2', 'Gene', '5565', (70, 76))
453901	30704460	As described above, 63 genes that serve as potential prognostic biomarkers were extracted from bone and soft tissue sarcoma cell lines described in the CCLE where CNVs were categorized based on their high frequencies of amplifications and deletions (Table 2).	('CCLE', 'Chemical', '-', (152, 156))	('amplifications', 'MPA', (220, 234))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('sarcoma', 'Disease', (116, 123))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (104, 123))	('deletions', 'Var', (239, 248))
453912	30704460	For example, IGF1R copy number amplification correlated with sensitivity to clofarabine (Fig.	('clofarabine', 'Chemical', 'MESH:D000077866', (76, 87))	('IGF1R', 'Gene', (13, 18))	('copy number amplification', 'Var', (19, 44))	('sensitivity to clofarabine', 'MPA', (61, 87))	('IGF1R', 'Gene', '3480', (13, 18))	('correlated', 'Reg', (45, 55))
453914	30704460	Since lower concentrations of drug were needed to inhibit growth of the sarcoma cell lines with IGFR1 copy number amplications [see right panel that compares AUC of clofarabine in cell lines with IGF1R gene deletion (clofarabine nonsensitive) or amplification (clofarabine sensitive)].	('clofarabine', 'Chemical', 'MESH:D000077866', (217, 228))	('sarcoma', 'Disease', (72, 79))	('IGFR1', 'Gene', (96, 101))	('clofarabine', 'Chemical', 'MESH:D000077866', (165, 176))	('clofarabine', 'Chemical', 'MESH:D000077866', (261, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('IGFR1', 'Gene', '100132417', (96, 101))	('amplification', 'Var', (246, 259))	('amplications', 'Var', (114, 126))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('IGF1R', 'Gene', (196, 201))	('IGF1R', 'Gene', '3480', (196, 201))
453919	30704460	While certain pediatric sarcomas like RMS and ESFTs are more genetically defined by having chromosomal translocations, other pediatric sarcomas such as OS are considered to be more genetically complex in nature.	('RMS', 'Disease', (38, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('ESFTs', 'Disease', (46, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('chromosomal translocations', 'Var', (91, 117))	('pediatric sarcomas', 'Disease', (125, 143))	('pediatric sarcomas', 'Disease', (14, 32))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (125, 143))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (14, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))
453920	30704460	Similarly, alveolar rhabdomyosarcoma is characterized by a chromosomal translocation t(2;13) (q35;q14) or t(1;13)(p36;q14) fusing the PAX3 or PAX7 with FOXO1.	('PAX7', 'Gene', '5081', (142, 146))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (11, 36))	('t(1;13)(p36;q14', 'Var', (106, 121))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (20, 36))	('PAX3', 'Gene', '5077', (134, 138))	('PAX7', 'Gene', (142, 146))	('PAX3', 'Gene', (134, 138))	('FOXO1', 'Gene', '2308', (152, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (11, 36))	('FOXO1', 'Gene', (152, 157))	('t(2;13) (q35;q14', 'Var', (85, 101))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (106, 122))	('alveolar rhabdomyosarcoma', 'Disease', (11, 36))
453921	30704460	On the contrary, in sporadic osteosarcoma there are various genetic alterations such as aberrations on chromosomes 15q and 8p where inconsistent rearrangements and copy number alteration have been observed.	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('osteosarcoma', 'Disease', (29, 41))	('aberrations', 'Var', (88, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))
453924	30704460	Therefore, along with identifying downstream targets of these molecularly-characterized and complex pediatric sarcomas, it is equally imperative to assess and identify other acquired genetic changes such as CNVs involving genetic amplifications and/or deletions that may provide novel therapeutic options to improve clinical outcomes.	('deletions', 'Var', (252, 261))	('clinical', 'Species', '191496', (316, 324))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('pediatric sarcomas', 'Disease', (100, 118))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (100, 118))
453927	30704460	This comprehensive study investigated band and gene alterations of somatic copy number amplification and deletion in 27 bone and soft tissue sarcoma using aCGH arrays (Affymetrix).	('deletion', 'Var', (105, 113))	('sarcoma', 'Disease', (141, 148))	('CGH', 'Gene', (156, 159))	('CGH', 'Gene', '3342', (156, 159))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (129, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))
453934	30704460	Genetic alterations that result in changes to MYC, such as MYC amplification, can dysregulate its normal function and alter the balance between being a tumor suppressor versus being tumorigenic.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('dysregulate', 'Reg', (82, 93))	('MYC', 'Gene', (59, 62))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('MYC', 'Gene', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('MYC', 'Gene', '4609', (59, 62))	('normal function', 'MPA', (98, 113))	('MYC', 'Gene', '4609', (46, 49))	('changes', 'Var', (35, 42))	('balance', 'MPA', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('alter', 'Reg', (118, 123))
453935	30704460	The long arm (1q) of chromosome 1 also signifies amplification with gene SELL showing higher significance in OS.	('SELL', 'Gene', (73, 77))	('SELL', 'Gene', '6402', (73, 77))	('amplification', 'Var', (49, 62))
453936	30704460	However, CNVs associated with recurrence in these pediatric sarcomas correlate with poor prognosis by specific chromosomal translocations or variations in OS, RMS, and ESFTs that can serve as prognostic biomarkers for these diseases.	('pediatric sarcomas', 'Disease', 'MESH:D063766', (50, 68))	('chromosomal translocations', 'Var', (111, 137))	('variations', 'Var', (141, 151))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('ESFTs', 'Gene', (168, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('RMS', 'Gene', (159, 162))	('pediatric sarcomas', 'Disease', (50, 68))
453938	30704460	We identified CNVs in 63 genes among the three pediatric sarcomas (OS, RMS, and ESFTs) that correlated with the recurrence of the diseases, suggesting CNVs in the 63 genes may provide prognostic biomarkers for these sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (216, 224))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (47, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('sarcomas', 'Disease', (216, 224))	('correlated', 'Reg', (92, 102))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('RMS', 'Disease', (71, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('CNVs', 'Var', (151, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcomas', 'Disease', 'MESH:D012509', (216, 224))	('pediatric sarcomas', 'Disease', (47, 65))	('sarcomas', 'Disease', (57, 65))
453939	30704460	The 63 genes have high frequency of amplifications as well as deletions in these sarcomas.	('sarcomas', 'Disease', (81, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('deletions', 'Var', (62, 71))	('amplifications', 'MPA', (36, 50))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
453942	30704460	ESFTs exhibit frequently mutated STAG2 on chromosome Xq25 with a high deletion frequency of 0.75 in our study.	('mutated', 'Var', (25, 32))	('STAG2', 'Gene', (33, 38))	('STAG2', 'Gene', '10735', (33, 38))
453947	30704460	Figure 6a, b show that CNVs in IGFR1 result in IGFR1 serving as a sensitive biomarker of therapeutic response to Clofarabine.	('IGFR1', 'Gene', (31, 36))	('CNVs', 'Var', (23, 27))	('IGFR1', 'Gene', '100132417', (31, 36))	('IGFR1', 'Gene', (47, 52))	('IGFR1', 'Gene', '100132417', (47, 52))	('Clofarabine', 'Chemical', 'MESH:D000077866', (113, 124))
453951	30704460	In our study, we evaluated CNVs as well as their frequencies of amplification (copy number gain) and deletion (copy number loss) in a large cohort of OS, ESFTs, and RMS patient samples and sarcoma cell lines.	('deletion', 'Var', (101, 109))	('sarcoma', 'Disease', (189, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('patient', 'Species', '9606', (169, 176))	('ESFTs', 'Disease', (154, 159))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))
453955	30704460	All genomic variants in DGV were detected by different experiment methods, including Bacterial Artificial Chromosome (BAC) and oligonucleotide-based chromosomal Comparative Genomic Hybridization (Oligo-cCGH), aCGH, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), sequencing, single nucleotide polymorphism (SNP) array and Digital array.	('oligonucleotide', 'Chemical', 'MESH:D009841', (127, 142))	('DGV', 'Gene', (24, 27))	('single nucleotide polymorphism', 'Var', (303, 333))	('variants', 'Var', (12, 20))	('DGV', 'Chemical', '-', (24, 27))	('CGH', 'Gene', (203, 206))	('CGH', 'Gene', '3342', (203, 206))	('CGH', 'Gene', (210, 213))	('CGH', 'Gene', '3342', (210, 213))
453963	30704460	All segments of copy number variations for 27 sarcoma cell lines were collected from CCLE, which were tested by Affymetrix Genome-Wide Human SNP Array 6.0.	('CCLE', 'Chemical', '-', (85, 89))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('copy number variations', 'Var', (16, 38))	('Human', 'Species', '9606', (135, 140))	('sarcoma', 'Disease', (46, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
453976	30704460	Copy number alterations were derived from aCGH chips and measured using log2 ratios of the fluorescence intensities from two channels (Cy3 and Cy5), one for the target sample and the other for the reference sample.	('Cy5', 'Var', (143, 146))	('Cy3', 'Var', (135, 138))	('CGH', 'Gene', '3342', (43, 46))	('CGH', 'Gene', (43, 46))
453992	28491276	DSRCT is associated with a unique translocation t(11:22) (p13, q12) resulting in a fusion of the EWSR1 and the Wilm's tumor WT1 genes.	('DSRCT', 'Disease', (0, 5))	('EWSR1', 'Gene', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (111, 123))	('WT1', 'Gene', '7490', (124, 127))	('WT1', 'Gene', (124, 127))	('EWSR1', 'Gene', '2130', (97, 102))	('fusion', 'Var', (83, 89))	("Wilm's tumor", 'Disease', (111, 123))	("Wilm's tumor", 'Disease', 'MESH:D009396', (111, 123))
454001	28491276	Indeed, expression of EWS-WT1 induces PDGFA, a potent mitogen for fibroblast and endothelial cells.	('EWS-WT1', 'Gene', '7490', (22, 29))	('PDGFA', 'Gene', (38, 43))	('PDGFA', 'Gene', '5154', (38, 43))	('EWS-WT1', 'Gene', (22, 29))	('induces', 'Reg', (30, 37))	('expression', 'Var', (8, 18))
454002	28491276	Particularly, PDGFA blockade may be interesting in DSRCT because of a profuse stromal reaction and neoangiogenesis surrounding tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('stromal reaction', 'CPA', (78, 94))	('neoangiogenesis', 'CPA', (99, 114))	('blockade', 'Var', (20, 28))	('PDGFA', 'Gene', (14, 19))	('DSRCT', 'Disease', (51, 56))	('PDGFA', 'Gene', '5154', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
454067	28491276	Thus, IGFR1 inhibitors and multi-targeted kinase inhibitors may be another treatment strategy, probably in combination with chemotherapy.	('IGFR1', 'Gene', '100132417', (6, 11))	('IGFR1', 'Gene', (6, 11))	('inhibitors', 'Var', (12, 22))
454076	28061772	The ctDNA level, estimated from the somatic allele frequencies of these six mutations, was high in plasma taken at the time of surgery, at levels similar to the primary tumour.	('mutations', 'Var', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('ctDNA level', 'MPA', (4, 15))	('primary tumour', 'Disease', (161, 175))	('primary tumour', 'Disease', 'MESH:D009369', (161, 175))
454081	28061772	The ctDNA represented the genomic profile of the tumour, supporting clinical use of liquid biopsies to identify tumour-specific mutations as well as recurrent disease.	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('mutations', 'Var', (128, 137))	('tumour', 'Disease', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('tumour', 'Disease', (49, 55))
454082	28061772	Cancers arise through a sequential alteration of the genome, resulting in a heterogeneous tumour that continuously evolves as the disease progress.	('resulting in', 'Reg', (61, 73))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('rat', 'Species', '10116', (39, 42))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('alteration', 'Var', (35, 45))	('tumour', 'Disease', (90, 96))	('tumour', 'Disease', 'MESH:D009369', (90, 96))
454097	28061772	However, a recent study described exome sequencing of a primary soft tissue sarcoma tumour and a single plasma sample collected at time of metastasis, and showed that new mutations had appeared in ctDNA after progression on chemotherapy and targeted treatment.	('soft tissue sarcoma tumour', 'Disease', 'MESH:D012509', (64, 90))	('appeared', 'Reg', (185, 193))	('ctDNA', 'Gene', (197, 202))	('soft tissue sarcoma tumour', 'Disease', (64, 90))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (64, 83))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('mutations', 'Var', (171, 180))
454114	28061772	Among these, seven point mutations were identified in the genes COL2A1 (intronic), NF1 (p.K354R), PTGS2 (intronic), LRP2 (p.Q4132E), KRAS (p.G12V), PRRC2C (p.R1257G) and GATA6 (p.A29A), as well as a frameshift deletion in PRG4 (p.R791fs) (Table 1 and Additional file 2).	('LRP2', 'Gene', (116, 120))	('PRRC2C', 'Gene', (148, 154))	('frameshift deletion', 'Var', (199, 218))	('p.G12V', 'Mutation', 'rs121913529', (139, 145))	('p.R791fs', 'Mutation', 'p.R791fsX', (228, 236))	('PRRC2C', 'Gene', '23215', (148, 154))	('COL2A1', 'Gene', (64, 70))	('p.Q4132E', 'Var', (122, 130))	('PRG4', 'Gene', '10216', (222, 226))	('PTGS2', 'Gene', '5743', (98, 103))	('NF1', 'Gene', '4763', (83, 86))	('GATA6', 'Gene', '2627', (170, 175))	('p.R1257G', 'Var', (156, 164))	('p.Q4132E', 'Mutation', 'p.Q4132E', (122, 130))	('p.R791fs', 'Var', (228, 236))	('LRP2', 'Gene', '4036', (116, 120))	('PRG4', 'Gene', (222, 226))	('NF1', 'Gene', (83, 86))	('p.K354R', 'Mutation', 'rs1135402801', (88, 95))	('p.G12V', 'Var', (139, 145))	('p.K354R', 'Var', (88, 95))	('p.A29A', 'Var', (177, 183))	('COL2A1', 'Gene', '1280', (64, 70))	('PTGS2', 'Gene', (98, 103))	('p.R1257G', 'Mutation', 'p.R1257G', (156, 164))	('p.A29A', 'SUBSTITUTION', 'None', (177, 183))	('GATA6', 'Gene', (170, 175))
454115	28061772	Targeted resequencing using a smaller ThunderBolts Cancer panel (Raindance Technologies, Billerica, Massachusetts, US) confirmed the identified KRAS mutation in the primary tumour at an allele frequency of 66%, similar to the 60% frequency found using the 900 gene panel (Additional file 2).	('primary tumour', 'Disease', 'MESH:D009369', (165, 179))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('primary tumour', 'Disease', (165, 179))	('KRAS', 'Gene', (144, 148))	('mutation', 'Var', (149, 157))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))
454117	28061772	Targeted resequencing of the plasma samples, using the NCGC 900 cancer gene panel, confirmed the presence of six of the eight above mutations in all three plasma samples with allele frequencies ranging from 2.1-75% (Fig.	('mutations', 'Var', (132, 141))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
454120	28061772	One new mutation in the splice site of RAD52, a C > T mutation with an allele frequency of 5.5%, was detected in the cfDNA collected before surgery.	('C > T', 'Var', (48, 53))	('RAD52', 'Gene', (39, 44))	('RAD52', 'Gene', '5893', (39, 44))
454122	28061772	Targeted resequencing using the ThunderBolts Cancer panel confirmed the presence of KRAS (p.G12V)) in all plasma samples (Additional file 2).	('p.G12V', 'Mutation', 'rs121913529', (90, 96))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('presence', 'Reg', (72, 80))	('KRAS (p.G12V', 'Var', (84, 96))
454123	28061772	The ctDNA level was estimated from the somatic allele frequency of the recurrent mutations in the genes COL2A1, NF1, PTGS2, LRP2, KRAS and PRRC2C.	('LRP2', 'Gene', '4036', (124, 128))	('COL2A1', 'Gene', '1280', (104, 110))	('PTGS2', 'Gene', (117, 122))	('PRRC2C', 'Gene', (139, 145))	('PTGS2', 'Gene', '5743', (117, 122))	('NF1', 'Gene', (112, 115))	('KRAS', 'Gene', (130, 134))	('COL2A1', 'Gene', (104, 110))	('NF1', 'Gene', '4763', (112, 115))	('LRP2', 'Gene', (124, 128))	('mutations', 'Var', (81, 90))	('PRRC2C', 'Gene', '23215', (139, 145))
454128	28061772	Targeted resequencing of the primary tumour and the normal sample identified eight somatic mutations of which six were also present in the plasma samples.	('primary tumour', 'Disease', 'MESH:D009369', (29, 43))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (91, 100))	('primary tumour', 'Disease', (29, 43))
454129	28061772	Among the mutations, KRAS (p.G12V) and NF1 (p.K354R) were predicted by dbNSFP to have a deleterious effect on the protein function.	('p.K354R', 'Var', (44, 51))	('effect', 'Reg', (100, 106))	('NF1', 'Gene', (39, 42))	('p.G12V', 'Mutation', 'rs121913529', (27, 33))	('NF1', 'Gene', '4763', (39, 42))	('KRAS (p.G12V', 'Var', (21, 33))	('protein function', 'MPA', (114, 130))	('p.K354R', 'Mutation', 'rs1135402801', (44, 51))
454130	28061772	It has been reported that simultaneous inactivation of TP53 and activation of KRAS induced quick formation of spindle-cell sarcoma in soft tissues in double transgenic mice.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('TP53', 'Gene', (55, 59))	('transgenic mice', 'Species', '10090', (157, 172))	('KRAS', 'Gene', (78, 82))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('activation', 'PosReg', (64, 74))	('inactivation', 'Var', (39, 51))	('sarcoma', 'Disease', (123, 130))
454134	28061772	Germline and somatic loss of NF1 in neurofibromatosis patients cause malignant peripheral nerve sheath tumours and GISTs.	('loss', 'Var', (21, 25))	('neurofibromatosis', 'Disease', (36, 53))	('patients', 'Species', '9606', (54, 62))	('cause', 'Reg', (63, 68))	('NF1', 'Gene', (29, 32))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('GIST', 'Disease', 'MESH:D046152', (115, 119))	('NF1', 'Gene', '4763', (29, 32))	('malignant peripheral nerve sheath tumours', 'Disease', 'MESH:D018319', (69, 110))	('GIST', 'Disease', (115, 119))	('malignant peripheral nerve sheath tumours', 'Disease', (69, 110))	('neurofibromatosis', 'Disease', 'MESH:C537392', (36, 53))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (36, 53))	('malignant peripheral nerve', 'Phenotype', 'HP:0100697', (69, 95))
454135	28061772	In addition, somatic NF1 mutations, including deletions, have been reported in a wide variety of paediatric and adult soft-tissue sarcomas with complex karyotypes.	('paediatric', 'Disease', (97, 107))	('mutations', 'Var', (25, 34))	('sarcomas', 'Disease', (130, 138))	('NF1', 'Gene', (21, 24))	('reported', 'Reg', (67, 75))	('NF1', 'Gene', '4763', (21, 24))	('sarcomas', 'Disease', 'MESH:D012509', (130, 138))	('deletions', 'Var', (46, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
454137	28061772	The synonymous mutation in GATA6 and the frameshift deletion in PRG4 could not be detected in the plasma samples.	('PRG4', 'Gene', '10216', (64, 68))	('GATA6', 'Gene', (27, 32))	('PRG4', 'Gene', (64, 68))	('GATA6', 'Gene', '2627', (27, 32))	('frameshift deletion', 'Var', (41, 60))
454140	28061772	A mutation in RAD52, a gene involved in DNA recombination, was detected in the plasma collected before surgery, but was not observed in the primary tumour nor in the plasma sample collected after surgery or at recurrence.	('RAD52', 'Gene', (14, 19))	('mutation', 'Var', (2, 10))	('RAD52', 'Gene', '5893', (14, 19))	('primary tumour', 'Disease', (140, 154))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('primary tumour', 'Disease', 'MESH:D009369', (140, 154))
454142	28061772	Discrepancy of mutation pattern between DNA from primary tumours and plasma have also previously been reported, showing that liquid biopsies may better capture all mutations present in the primary tumour and/or liver metastasis and can thus be used to overcome the challenges posed by intra-tumour genetic heterogeneity.	('intra-tumour', 'Disease', 'MESH:D009369', (285, 297))	('primary tumour', 'Disease', 'MESH:D009369', (49, 63))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('intra-tumour', 'Disease', (285, 297))	('tumour', 'Phenotype', 'HP:0002664', (291, 297))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumours', 'Disease', (57, 64))	('primary tumour', 'Disease', (189, 203))	('primary tumour', 'Disease', (49, 63))	('mutations', 'Var', (164, 173))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('primary tumour', 'Disease', 'MESH:D009369', (189, 203))
454152	28061772	The findings show that the level of tumour-specific mutations in liquid biopsies is correlated to disease course in sarcomas, including clinical manifestation of metastatic disease.	('sarcomas', 'Disease', (116, 124))	('mutations', 'Var', (52, 61))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', (36, 42))	('correlated', 'Reg', (84, 94))	('sarcomas', 'Disease', 'MESH:D012509', (116, 124))	('metastatic disease', 'Disease', (162, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
454160	26864131	More patients receiving pazopanib experienced best response of stable disease versus placebo.	('pazopanib', 'Chemical', 'MESH:C516667', (24, 33))	('stable disease', 'MPA', (63, 77))	('patients', 'Species', '9606', (5, 13))	('pazopanib', 'Var', (24, 33))
454167	26864131	In the PALETTE study, median progression-free survival (PFS; primary endpoint) was significantly longer for pazopanib compared with placebo {median 20.0 [95% confidence interval (CI): 17.9-21.3] weeks vs. 7.0 [95% CI: 4.4-8.1] weeks; hazard ratio [HR] = 0.35 [95% CI: 0.26-0.48]; P < 0.001} as determined by an independent radiologist.	('longer', 'PosReg', (97, 103))	('pazopanib', 'Chemical', 'MESH:C516667', (108, 117))	('progression-free survival', 'CPA', (29, 54))	('pazopanib', 'Var', (108, 117))
454194	26864131	A greater proportion of patients in the pazopanib arm experienced a best response of stable disease as compared with patients in the placebo arm (58 vs. 31% by independent radiology, 65 vs. 38% by investigator assessment).	('pazopanib', 'Chemical', 'MESH:C516667', (40, 49))	('stable disease', 'MPA', (85, 99))	('pazopanib', 'Var', (40, 49))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (117, 125))
454195	26864131	Incidence of any on-therapy AE was higher in the pazopanib arm than in the placebo arm (100 vs. 75%).	('higher', 'PosReg', (35, 41))	('pazopanib', 'Var', (49, 58))	('pazopanib', 'Chemical', 'MESH:C516667', (49, 58))
454198	26864131	Over a third of patients (35%) in the pazopanib arm experienced an SAE compared with 19% in the placebo arm.	('SAE', 'Disease', (67, 70))	('pazopanib', 'Chemical', 'MESH:C516667', (38, 47))	('patients', 'Species', '9606', (16, 24))	('pazopanib', 'Var', (38, 47))
454203	26864131	Other commonly reported (>10% in either treatment arm) Grade 3 AEs were fatigue (observed in pazopanib arm only) and tumor pain (10% pazopanib arm vs. 6% placebo arm).	('fatigue', 'Disease', 'MESH:D005221', (72, 79))	('fatigue', 'Disease', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('pazopanib', 'Var', (133, 142))	('tumor pain', 'Disease', 'MESH:D010146', (117, 127))	('fatigue', 'Phenotype', 'HP:0012378', (72, 79))	('pain', 'Phenotype', 'HP:0012531', (123, 127))	('AEs', 'Chemical', '-', (63, 66))	('pazopanib', 'Chemical', 'MESH:C516667', (93, 102))	('pazopanib', 'Chemical', 'MESH:C516667', (133, 142))	('tumor pain', 'Disease', (117, 127))
454210	26864131	Alanine transaminase was elevated in 16 (52%) patients in the pazopanib arm and 2 (13%) patients in the placebo arm.	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (88, 96))	('pazopanib', 'Chemical', 'MESH:C516667', (62, 71))	('elevated', 'PosReg', (25, 33))	('Alanine transaminase', 'MPA', (0, 20))	('pazopanib', 'Var', (62, 71))
454214	26864131	In our investigation of the efficacy and safety of pazopanib in the Japanese cohort of the PALETTE study, pazopanib demonstrated significantly longer PFS compared with placebo.	('PFS', 'CPA', (150, 153))	('pazopanib', 'Chemical', 'MESH:C516667', (51, 60))	('longer', 'PosReg', (143, 149))	('pazopanib', 'Var', (106, 115))	('pazopanib', 'Chemical', 'MESH:C516667', (106, 115))
454220	26864131	Decreased weight and decreased appetite were more frequent in the pazopanib arm of the Japanese population (65 and 58%, respectively) compared with the pazopanib arm of the global population (48 and 40%, respectively).	('decreased appetite', 'Phenotype', 'HP:0004396', (21, 39))	('decreased', 'NegReg', (21, 30))	('Decreased', 'NegReg', (0, 9))	('pazopanib', 'Chemical', 'MESH:C516667', (152, 161))	('pazopanib', 'Chemical', 'MESH:C516667', (66, 75))	('pazopanib', 'Var', (66, 75))	('weight', 'Disease', (10, 16))	('Decreased weight', 'Phenotype', 'HP:0004325', (0, 16))	('appetite', 'CPA', (31, 39))
454227	26864131	In the PALETTE global population, pneumothorax occurred in eight (3%) patients in the pazopanib arm and one (1%) patient in the placebo arm.	('patient', 'Species', '9606', (113, 120))	('patients', 'Species', '9606', (70, 78))	('patient', 'Species', '9606', (70, 77))	('pazopanib', 'Chemical', 'MESH:C516667', (86, 95))	('pneumothorax', 'Disease', (34, 46))	('pneumothorax', 'Phenotype', 'HP:0002107', (34, 46))	('pazopanib', 'Var', (86, 95))
454332	19807660	Epigenetic chromatin modifying agents have been shown to induce cancer cell differentiation and are currently being used clinically to treat cancer.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('induce', 'PosReg', (57, 63))	('cancer', 'Disease', (141, 147))	('Epigenetic chromatin', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
454338	19807660	Histone acetylation promotes the open state of chromatin structure (termed euchromatin) in which genes are actively transcribed.	('Histone', 'Gene', (0, 7))	('acetylation', 'Var', (8, 19))	('Histone', 'Gene', '43229', (0, 7))	('promotes', 'PosReg', (20, 28))	('open', 'MPA', (33, 37))
454343	19807660	Acetylation of the lysine residues is thought to remove their positive charges, reducing the affinity of the histone for the DNA.	('affinity', 'Interaction', (93, 101))	('positive charges', 'MPA', (62, 78))	('Acetylation', 'Var', (0, 11))	('histone', 'Gene', '43229', (109, 116))	('lysine', 'Chemical', 'MESH:D008239', (19, 25))	('reducing', 'NegReg', (80, 88))	('remove', 'NegReg', (49, 55))	('histone', 'Gene', (109, 116))
454348	19807660	Histones have been observed in mono-, di- or tri-methylated states.	('di-', 'Var', (38, 41))	('Histone', 'Gene', '43229', (0, 7))	('tri-methylated', 'Var', (45, 59))	('Histone', 'Gene', (0, 7))
454353	19807660	Regulated by the DNA methyltransferase protein family (DNMTs), DNA methylation of CpG clusters (termed CpG islands) is highly associated with transcriptional repression.	('associated', 'Reg', (126, 136))	('DNA methyltransferase', 'Gene', (17, 38))	('CpG clusters', 'Gene', (82, 94))	('DNA methyltransferase', 'Gene', '1786', (17, 38))	('transcriptional repression', 'MPA', (142, 168))	('methylation', 'Var', (67, 78))
454356	19807660	It has been suggested that the combination of various histone modifications represent a "histone code" recognized by non-histone proteins to form complexes that regulate gene expression.	('histone', 'Gene', (54, 61))	('modifications', 'Var', (62, 75))	('histone', 'Gene', '43229', (121, 128))	('histone', 'Gene', (89, 96))	('histone', 'Gene', '43229', (54, 61))	('histone', 'Gene', '43229', (89, 96))	('regulate', 'Reg', (161, 169))	('histone', 'Gene', (121, 128))	('gene expression', 'MPA', (170, 185))
454367	19807660	Though systematic knock out studies of histones in mice have not been conducted, one can expect with reasonable certainty that histone ablation would result in severe embryonic lethality, especially based on limited evidence from Drosophila, in which knock out of a variant of H2A leads to embryonic lethality.	('embryonic lethality', 'Disease', (290, 309))	('embryonic lethality', 'Disease', 'MESH:D020964', (167, 186))	('histone', 'Gene', (39, 46))	('mice', 'Species', '10090', (51, 55))	('histone', 'Gene', (127, 134))	('H2A', 'Gene', (277, 280))	('ablation', 'NegReg', (135, 143))	('variant', 'Var', (266, 273))	('embryonic lethality', 'Disease', (167, 186))	('histone', 'Gene', '43229', (39, 46))	('knock out', 'Var', (251, 260))	('Drosophila', 'Species', '7227', (230, 240))	('histone', 'Gene', '43229', (127, 134))	('embryonic lethality', 'Disease', 'MESH:D020964', (290, 309))
454372	19807660	Additionally, disruption of any of the Dnmt gene locus during embryonic development results in global DNA hypomethylation and lethality.	('Dnmt', 'Gene', (39, 43))	('global DNA hypomethylation', 'MPA', (95, 121))	('Dnmt', 'Gene', '1786', (39, 43))	('lethality', 'CPA', (126, 135))	('disruption', 'Var', (14, 24))
454373	19807660	Deletion of various HDACs in mouse models result in embryonic lethality, and conditional knockout animals show severe phenotypes and are neonatally lethal.	('HDAC', 'Gene', (20, 24))	('HDAC', 'Gene', '9734', (20, 24))	('embryonic lethality', 'Disease', 'MESH:D020964', (52, 71))	('embryonic lethality', 'Disease', (52, 71))	('mouse', 'Species', '10090', (29, 34))	('result in', 'Reg', (42, 51))	('Deletion', 'Var', (0, 8))
454375	19807660	Histone modifications and DNA methylation, guided by linker histone 1 (H1) have also been shown to be critical for B cell development.	('Histone', 'Gene', (0, 7))	('DNA methylation', 'MPA', (26, 41))	('Histone', 'Gene', '43229', (0, 7))	('modifications', 'Var', (8, 21))	('H1', 'Gene', '3009', (71, 73))	('histone 1', 'Gene', (60, 69))	('B cell development', 'CPA', (115, 133))	('histone 1', 'Gene', '3009', (60, 69))
454377	19807660	Epigenetic changes have been implicated in a variety of diseases, from monogenic diseases like Rett Syndrome: where a mutation in the Methyl CpG Binding Protein 2 results in a loss of transcriptional repression causing impaired neurodevelopment in female infants: to cancer.	('impaired neurodevelopment', 'Disease', (219, 244))	('cancer', 'Disease', (267, 273))	('loss', 'NegReg', (176, 180))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('Methyl CpG Binding Protein 2', 'Gene', (134, 162))	('implicated', 'Reg', (29, 39))	('Methyl CpG Binding Protein 2', 'Gene', '4204', (134, 162))	('infants', 'Species', '9606', (255, 262))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('mutation', 'Var', (118, 126))	('causing', 'Reg', (211, 218))	('Rett Syndrome', 'Disease', (95, 108))	('transcriptional repression', 'MPA', (184, 210))
454381	19807660	Global alterations found in many cancers include hypomethylation of DNA and hypoacetylation of histones.	('hypoacetylation', 'MPA', (76, 91))	('histone', 'Gene', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('hypomethylation', 'Var', (49, 64))	('histone', 'Gene', '43229', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('DNA', 'Protein', (68, 71))
454382	19807660	In addition to gene-specific hypermethylation of DNA, these alterations lead to oncogene activation (R-ras, cyclin D2) and tumor suppressor silencing (RB1, p16).	('cyclin D2', 'Gene', (108, 117))	('R-ras', 'Protein', (101, 106))	('tumor', 'Disease', (123, 128))	('RB1', 'Gene', '5925', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('oncogene', 'Gene', (80, 88))	('p16', 'Gene', '1029', (156, 159))	('hypermethylation', 'Var', (29, 45))	('activation', 'PosReg', (89, 99))	('p16', 'Gene', (156, 159))	('cyclin D2', 'Gene', '894', (108, 117))	('RB1', 'Gene', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
454384	19807660	It is possible that in cancer, reversible epigenetic gene repression is replaced by aberrant permanent silencing.	('epigenetic gene repression', 'Var', (42, 68))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
454387	19807660	These proteins form chromosomal multi-protein complexes, which facilitate heterochromatin compaction via histone methyltransferase activity, in order to epigenetically control gene expression.	('histone methyltransferase', 'Gene', '56979', (105, 130))	('facilitate', 'PosReg', (63, 73))	('activity', 'MPA', (131, 139))	('histone methyltransferase', 'Gene', (105, 130))	('heterochromatin compaction', 'CPA', (74, 100))	('control', 'Reg', (168, 175))	('epigenetically', 'Var', (153, 167))	('gene expression', 'MPA', (176, 191))
454390	19807660	In the current model, human PRC2 has methyltransferase activity and methylates H3K27, a classical mark of transcriptional repression.	('activity', 'MPA', (55, 63))	('PRC2', 'Gene', (28, 32))	('methyltransferase', 'Enzyme', (37, 54))	('methylates', 'Var', (68, 78))	('human', 'Species', '9606', (22, 27))	('H3K27', 'Protein', (79, 84))
454398	19807660	In cancer cells, PRC2-mediated methylation of H3 causes de novo methylation of normally unmethylated CpG islands, suggesting that PcG proteins are responsible for marking cells in a tumor-specific manner.	('PcG', 'Gene', (130, 133))	('tumor', 'Disease', (182, 187))	('PcG', 'Gene', '40358', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('de novo methylation', 'MPA', (56, 75))	('methylation', 'Var', (31, 42))	('cancer', 'Disease', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
454399	19807660	Interestingly, MSCs that have lost their differentiation capacity with long-term in vitro culture also show targeting of PcG proteins Ezh2 and Bmi1 to promoter sites, suggesting PcG-mediated epigenetic reprogramming represses transcription to maintain cells in an immature, undifferentiated state.	('represses', 'NegReg', (216, 225))	('Bmi1', 'Gene', (143, 147))	('PcG', 'Gene', (178, 181))	('Ezh2', 'Gene', '2146', (134, 138))	('PcG', 'Gene', '40358', (178, 181))	('Ezh2', 'Gene', (134, 138))	('epigenetic', 'Var', (191, 201))	('PcG', 'Gene', (121, 124))	('Bmi1', 'Gene', '648', (143, 147))	('PcG', 'Gene', '40358', (121, 124))	('transcription', 'MPA', (226, 239))
454402	19807660	Specific epigenetic alterations correlate with sarcoma tumors, though more studies are needed to thoroughly understand the role of combinations of chromatin markers on tumor progression (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('epigenetic alterations', 'Var', (9, 31))	('tumor', 'Disease', (168, 173))	('correlate', 'Reg', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('sarcoma tumors', 'Disease', (47, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('sarcoma tumors', 'Disease', 'MESH:D012509', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
454404	19807660	In vitro work has shown that osteosarcoma cell lines display aberrant DNA hyper- and hypo-methylation.	('hypo-methylation', 'Var', (85, 101))	('DNA hyper-', 'MPA', (70, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('osteosarcoma', 'Disease', (29, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))
454405	19807660	We have previously shown that epigenetic changes are important for sarcoma differentiation.	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('epigenetic changes', 'Var', (30, 48))	('sarcoma', 'Disease', (67, 74))
454406	19807660	Sequential chromatin immunoprecipitation (ChIP) experiments reveal that MSCs differentiated along the osteogenic lineage contain me-H3K4, the classical active chromatin mark, at the promoter regions of both c-myc and cyclin D1 (downstream Wnt/beta-catenin signaling targets) bound to beta-catenin.	('bound', 'Interaction', (275, 280))	('cyclin D1', 'Gene', '595', (217, 226))	('beta-catenin', 'Gene', (284, 296))	('me-H3K4', 'Var', (129, 136))	('c-myc', 'Gene', '4609', (207, 212))	('beta-catenin', 'Gene', (243, 255))	('c-myc', 'Gene', (207, 212))	('beta-catenin', 'Gene', '1499', (284, 296))	('beta-catenin', 'Gene', '1499', (243, 255))	('cyclin D1', 'Gene', (217, 226))
454423	19807660	Ewing's sarcoma is a sarcoma of the bone and soft tissue characterized by a specific fusion of the EWS gene with a member of the ETS gene family, most commonly FLI1.	('fusion', 'Var', (85, 91))	("Ewing's sarcoma", 'Disease', (0, 15))	('sarcoma of the bone', 'Disease', (21, 40))	('sarcoma of the bone', 'Disease', 'MESH:D001847', (21, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('FLI1', 'Gene', (160, 164))	('sarcoma of the bone', 'Phenotype', 'HP:0010622', (21, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('FLI1', 'Gene', '2313', (160, 164))	('EWS', 'Gene', '2130', (99, 102))	('EWS', 'Gene', (99, 102))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))
454425	19807660	Moreover, only Ewing's sarcoma cells with silenced fusions are able to differentiate along adipogenic and osteogenic lineages.	('osteogenic lineages', 'CPA', (106, 125))	('silenced', 'Var', (42, 50))	('differentiate', 'Reg', (71, 84))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (15, 30))	("Ewing's sarcoma", 'Disease', (15, 30))	('adipogenic', 'MPA', (91, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (15, 30))
454431	19807660	Aberrant MSC differentiation has also been implicated in osteosarcoma formation.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('osteosarcoma', 'Disease', 'MESH:D012516', (57, 69))	('Aberrant', 'Var', (0, 8))	('implicated', 'Reg', (43, 53))	('osteosarcoma', 'Phenotype', 'HP:0002669', (57, 69))	('osteosarcoma', 'Disease', (57, 69))
454432	19807660	Jain, et al showed that brief inactivation of the myc oncogene in a conditional transgenic mouse model of osteosarcoma resulted in regression of the tumor and differentiation of the tumor cells into mature osteocytes.	('myc oncogene', 'Gene', (50, 62))	('osteosarcoma', 'Disease', (106, 118))	('inactivation', 'Var', (30, 42))	('tumor', 'Disease', (182, 187))	('differentiation', 'CPA', (159, 174))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('osteosarcoma', 'Disease', 'MESH:D012516', (106, 118))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('mouse', 'Species', '10090', (91, 96))	('regression', 'NegReg', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
454433	19807660	Moreover, re-activation of myc induced apoptosis, rather than restoring tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('apoptosis', 'CPA', (39, 48))	('tumor', 'Disease', (72, 77))	('re-activation', 'Var', (10, 23))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('myc', 'Protein', (27, 30))
454434	19807660	This suggests that an epigenetic change during myc inactivation renders terminally differentiated osteocytes less permissive for tumorigenesis than MSCs.	('epigenetic change', 'Var', (22, 39))	('less', 'NegReg', (109, 113))	('inactivation', 'Var', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('terminally differentiated osteocytes', 'CPA', (72, 108))	('myc', 'Protein', (47, 50))	('tumor', 'Disease', (129, 134))
454442	19807660	Inappropriate MSC differentiation, as controlled by both genetic assaults and epigenetic modifications, may result in tumor formation.	('result in', 'Reg', (108, 117))	('epigenetic modifications', 'Var', (78, 102))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('MSC differentiation', 'CPA', (14, 33))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))
454443	19807660	If sarcomas are indeed transformed MSCs at various stages of differentiation arrest, it may be possible to promote differentiation of the tumor along its proper cellular lineage via chromatin modification.	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('tumor', 'Disease', (138, 143))	('sarcomas', 'Disease', (3, 11))	('arrest', 'Disease', 'MESH:D006323', (77, 83))	('differentiation', 'CPA', (115, 130))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('chromatin', 'Var', (182, 191))	('promote', 'PosReg', (107, 114))	('arrest', 'Disease', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
454458	19807660	In the presence of physiological levels of RA, a conformational change results in RAR's release from the HDAC complex and subsequent association with transcriptional activators, including HATs leading to increased transcription.	('association', 'Interaction', (133, 144))	('RAR', 'Gene', '5914', (82, 85))	('release', 'MPA', (88, 95))	('results in', 'Reg', (71, 81))	('increased', 'PosReg', (204, 213))	('HDAC', 'Gene', (105, 109))	('conformational change', 'Var', (49, 70))	('HDAC', 'Gene', '9734', (105, 109))	('transcription', 'MPA', (214, 227))	('RA', 'Chemical', 'MESH:D014212', (43, 45))	('RAR', 'Gene', (82, 85))	('RA', 'Chemical', 'MESH:D014212', (82, 84))
454490	19807660	Synovial sarcoma is characterized by a translocation of the SYT gene with a member of the SSX gene family.	('SSX', 'Gene', '727837', (90, 93))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('SYT', 'Gene', (60, 63))	('sarcoma', 'Disease', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SYT', 'Gene', '6760', (60, 63))	('translocation', 'Var', (39, 52))	('SSX', 'Gene', (90, 93))
454503	19807660	Malignant rhabdoid tumor cell lines treated with 5-azacytidine differentiate into smooth muscle-like cells.	('smooth muscle-like cells', 'CPA', (82, 106))	('Malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (0, 24))	('Malignant rhabdoid tumor', 'Disease', (0, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('5-azacytidine', 'Chemical', 'MESH:D001374', (49, 62))	('5-azacytidine', 'Var', (49, 62))
454508	19807660	The use of epigenetic modifying agents as differentiation inducers will be critical to advancing alternative cancer therapies which are less invasive and which are more selective for tumor cells.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('epigenetic modifying', 'Var', (11, 31))
454509	19807660	Histone acetyltransferases (HATs), Histone Deacetylases (HDACs), Histone Methyltransferases (HMTs) and Histone Demethylases (HDMs) modify chromatin to epigenetically promote or repress transcription.	('Histone', 'Gene', (0, 7))	('Histone', 'Gene', (65, 72))	('transcription', 'MPA', (185, 198))	('HMT', 'Gene', (93, 96))	('Histone', 'Gene', (35, 42))	('Histone', 'Gene', (103, 110))	('Histone', 'Gene', '43229', (0, 7))	('HMT', 'Gene', '56979', (93, 96))	('Histone', 'Gene', '43229', (65, 72))	('Histone', 'Gene', '43229', (35, 42))	('epigenetically', 'Var', (151, 165))	('Histone', 'Gene', '43229', (103, 110))	('HDAC', 'Gene', (57, 61))	('repress', 'NegReg', (177, 184))	('HDAC', 'Gene', '9734', (57, 61))	('promote', 'PosReg', (166, 173))	('modify', 'Reg', (131, 137))
454515	19807660	It is, of course, possible that either DNA methylation or histone modifications act as the initiating epigenetic event, depending on the context of the signal.	('histone', 'Gene', (58, 65))	('histone', 'Gene', '43229', (58, 65))	('DNA methylation', 'Var', (39, 54))	('modifications', 'Var', (66, 79))
454516	19807660	However, during spontaneous gene silencing, such as that found in cancer, histone deacetylation may turn off a tumor suppressor gene and DNA methylation may maintain the inactivation of the gene.	('histone', 'Gene', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('turn off', 'NegReg', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('gene', 'Var', (28, 32))	('inactivation', 'MPA', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', (111, 116))	('histone', 'Gene', '43229', (74, 81))	('DNA', 'Var', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))	('deacetylation', 'Var', (82, 95))
454523	19807660	Disruption of one epigenetic alteration will inevitably affect others: hypermethylation of CpG islands in promoter regions of genes can lead to the deacetylation of surrounding histones and this hypoacetylation can trigger DNA methylation to targeted areas.	('trigger', 'Reg', (215, 222))	('deacetylation', 'MPA', (148, 161))	('lead to', 'Reg', (136, 143))	('histone', 'Gene', '43229', (177, 184))	('DNA methylation', 'MPA', (223, 238))	('hypermethylation', 'Var', (71, 87))	('histone', 'Gene', (177, 184))
454524	19807660	DNA methylation has also been linked with histone methylation.	('linked', 'Reg', (30, 36))	('histone', 'Gene', '43229', (42, 49))	('methylation', 'Var', (4, 15))	('histone', 'Gene', (42, 49))
454526	19807660	Evidence from Neurospora suggests that histone methylation patterns guide DNA methylation: mutations in a HMT abolish DNA methylation-mediated gene-silencing.	('histone', 'Gene', (39, 46))	('abolish', 'NegReg', (110, 117))	('Neurospora', 'Species', '5141', (14, 24))	('histone', 'Gene', '43229', (39, 46))	('DNA methylation-mediated gene-silencing', 'MPA', (118, 157))	('mutations', 'Var', (91, 100))	('HMT', 'Gene', (106, 109))	('HMT', 'Gene', '56979', (106, 109))
454528	19807660	In a mouse model, deletion of Lsh, which encodes a SNF2 helicase important in chromatin remodeling, results in genome-wide loss of CpG methylation and interestingly, Lsh interacts with de novo DNMTs but not the maintenance DNMT, suggesting its role in establishing specific DNA methylation via chromatin remodeling.	('Lsh', 'Gene', (30, 33))	('CpG methylation', 'MPA', (131, 146))	('Lsh', 'Gene', '15201', (166, 169))	('loss', 'NegReg', (123, 127))	('Lsh', 'Gene', '15201', (30, 33))	('mouse', 'Species', '10090', (5, 10))	('Lsh', 'Gene', (166, 169))	('deletion', 'Var', (18, 26))
454530	19807660	Consequently, actively transcribed chromatin containing acetylated histones is deacetylated and is methylated in a repressive manner.	('acetylated', 'Var', (56, 66))	('histone', 'Gene', (67, 74))	('histone', 'Gene', '43229', (67, 74))
454531	19807660	Methylation of H3K9 then serves as docking site for HP1, which further facilitates chromatin compaction and transcriptional silencing.	('HP1', 'Gene', '23468', (52, 55))	('H3K9', 'Protein', (15, 19))	('HP1', 'Gene', (52, 55))	('transcriptional silencing', 'CPA', (108, 133))	('Methylation', 'Var', (0, 11))	('chromatin compaction', 'CPA', (83, 103))	('facilitates', 'PosReg', (71, 82))
454532	19807660	Additionally, DNMTs have been shown to bind both HP1 and HMTs on repressed histones, resulting in increased de novo DNA methylation.	('DNMTs', 'Var', (14, 19))	('de novo DNA methylation', 'MPA', (108, 131))	('histone', 'Gene', '43229', (75, 82))	('bind', 'Interaction', (39, 43))	('HMT', 'Gene', (57, 60))	('increased', 'PosReg', (98, 107))	('HMT', 'Gene', '56979', (57, 60))	('HP1', 'Gene', (49, 52))	('histone', 'Gene', (75, 82))	('HP1', 'Gene', '23468', (49, 52))
454539	19807660	During epigenetic treatment, such as with HDACI or DNA demethylating agents, the chromatin state can be manipulated to repress or activate transcription in a directed, sequential manner.	('HDAC', 'Gene', (42, 46))	('activate', 'PosReg', (130, 138))	('HDAC', 'Gene', '9734', (42, 46))	('epigenetic treatment', 'Var', (7, 27))	('transcription', 'MPA', (139, 152))	('repress', 'NegReg', (119, 126))
454542	19807660	In this way, maintained acetylation of histones and demethylation of DNA act in concert to synergistically re-activate silenced genes.	('re-activate', 'PosReg', (107, 118))	('histone', 'Gene', (39, 46))	('silenced genes', 'Gene', (119, 133))	('DNA', 'Gene', (69, 72))	('histone', 'Gene', '43229', (39, 46))	('acetylation', 'MPA', (24, 35))	('demethylation', 'Var', (52, 65))
454544	19807660	In this way, the combinatorial use of various epigenetic modifying agents may be a rational method of re-establishing the proper differentiation of tumor cells (Fig.	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('epigenetic modifying agents', 'Var', (46, 73))
454550	19807660	Many epigenetic changes occur in cancers, such as global DNA hypomethylation, targeted DNA hypermethylation, and deregulation of some PcG proteins.	('global', 'MPA', (50, 56))	('epigenetic changes', 'Var', (5, 23))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('PcG', 'Gene', (134, 137))	('cancers', 'Disease', (33, 40))	('PcG', 'Gene', '40358', (134, 137))	('deregulation', 'MPA', (113, 125))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('targeted DNA', 'Var', (78, 90))
454554	19807660	Epigenetic aberrancies are commonly found in a variety of cancers and one therapeutic avenue to be explored may be differentiation therapy.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Epigenetic aberrancies', 'Var', (0, 22))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('found', 'Reg', (36, 41))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
454567	33562681	We first demonstrated that TP4 can induce necrotic cell death in human synovial sarcoma AsKa-SS and SW982 cells lines.	('human', 'Species', '9606', (65, 70))	('necrotic cell death', 'Disease', (42, 61))	('synovial sarcoma AsKa-SS', 'Disease', 'MESH:D013584', (71, 95))	('necrotic cell death', 'Disease', 'MESH:D003643', (42, 61))	('induce', 'Reg', (35, 41))	('TP4', 'Var', (27, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (71, 87))	('synovial sarcoma AsKa-SS', 'Disease', (71, 95))	('SW982', 'CellLine', 'CVCL:1734', (100, 105))	('TP4', 'Chemical', '-', (27, 30))
454568	33562681	In addition, we saw that TP4 initiates reactive oxygen species (ROS) production and downregulates antioxidant proteins, such as uncoupling protein-2, superoxide dismutase (SOD)-1, and SOD-2.	('superoxide dismutase (SOD)-1', 'Gene', '6647', (150, 178))	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('downregulates', 'NegReg', (84, 97))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (39, 62))	('TP4', 'Var', (25, 28))	('uncoupling protein-2', 'Gene', (128, 148))	('uncoupling protein-2', 'Gene', '7351', (128, 148))	('antioxidant proteins', 'MPA', (98, 118))	('initiates', 'PosReg', (29, 38))	('superoxide dismutase (SOD)-1', 'Gene', (150, 178))	('reactive oxygen species', 'MPA', (39, 62))	('TP4', 'Chemical', '-', (25, 28))	('SOD-2', 'Gene', '6648', (184, 189))	('SOD-2', 'Gene', (184, 189))
454569	33562681	Moreover, TP4-induced mitochondrial hyperpolarization is followed by elevation of mitochondrial ROS.	('hyperpolarization', 'PosReg', (36, 53))	('TP4', 'Chemical', '-', (10, 13))	('mitochondrial ROS', 'MPA', (82, 99))	('TP4-induced', 'Var', (10, 21))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('mitochondrial', 'MPA', (22, 35))	('elevation', 'PosReg', (69, 78))
454570	33562681	Calcium overload is also triggered by TP4, and cell death can be attenuated by a necrosis inhibitor, ROS scavenger or calcium chelator.	('TP4', 'Chemical', '-', (38, 41))	('calcium', 'Chemical', 'MESH:D002118', (118, 125))	('necrosis', 'Disease', 'MESH:D009336', (81, 89))	('TP4', 'Var', (38, 41))	('Calcium', 'Disease', (0, 7))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('necrosis', 'Disease', (81, 89))
454571	33562681	In our experiments, TP4 displayed strong anticancer activity in human synovial sarcoma cells by disrupting oxidative status, promoting mitochondrial hyperpolarization and causing calcium overload.	('human', 'Species', '9606', (64, 69))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TP4', 'Var', (20, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('TP4', 'Chemical', '-', (20, 23))	('promoting', 'PosReg', (125, 134))	('mitochondrial hyperpolarization', 'MPA', (135, 166))	('synovial sarcoma', 'Disease', 'MESH:D013584', (70, 86))	('calcium overload', 'MPA', (179, 195))	('disrupting', 'NegReg', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('calcium', 'Chemical', 'MESH:D002118', (179, 186))	('synovial sarcoma', 'Disease', (70, 86))	('cancer', 'Disease', (45, 51))	('oxidative status', 'MPA', (107, 123))	('causing', 'Reg', (171, 178))
454584	33562681	Many new approaches for the treatment of metastatic synovial sarcoma are currently under investigation, including targeted agents, epigenetic modulators, compounds that interfere with DNA damage response, and immunotherapy.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (52, 68))	('age', 'Gene', (123, 126))	('age', 'Gene', '5973', (191, 194))	('synovial sarcoma', 'Disease', 'MESH:D013584', (52, 68))	('epigenetic modulators', 'Var', (131, 152))	('age', 'Gene', '5973', (123, 126))	('synovial sarcoma', 'Disease', (52, 68))	('age', 'Gene', (191, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
454591	33562681	However, TP4 also induces mitochondrial dysfunction in glioblastoma cells.	('TP4', 'Chemical', '-', (9, 12))	('glioblastoma', 'Disease', (55, 67))	('induces', 'Reg', (18, 25))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (26, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (26, 51))	('TP4', 'Var', (9, 12))	('mitochondrial dysfunction', 'Disease', (26, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))
454593	33562681	To examine the antisynovial sarcoma activity of TP4, human synovial sarcoma cells, SW982 and Aska-SS, were exposed to TP4 at doses ranging from 0 to 100 mug/mL.	('synovial sarcoma', 'Disease', (19, 35))	('TP4', 'Chemical', '-', (48, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('TP4', 'Chemical', '-', (118, 121))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (19, 35))	('synovial sarcoma', 'Disease', 'MESH:D013584', (19, 35))	('synovial sarcoma', 'Disease', (59, 75))	('human', 'Species', '9606', (53, 58))	('TP4', 'Var', (118, 121))	('SW982', 'CellLine', 'CVCL:1734', (83, 88))	('synovial sarcoma', 'Disease', 'MESH:D013584', (59, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (59, 75))	('Aska-SS', 'CellLine', 'CVCL:6C43', (93, 100))
454595	33562681	A dose-dependent cytotoxic effect was observed after exposure to TP4 in both SW982 and Aska-SS cells.	('TP4', 'Chemical', '-', (65, 68))	('cytotoxic effect', 'CPA', (17, 33))	('SW982', 'CellLine', 'CVCL:1734', (77, 82))	('TP4', 'Var', (65, 68))	('Aska-SS', 'CellLine', 'CVCL:6C43', (87, 94))
454599	33562681	Results showed that cytotoxic effects were observed after 1 h and 3 h after exposure to TP4 in SW982 cells and Aska-SS cells, respectively.	('Aska-SS', 'CellLine', 'CVCL:6C43', (111, 118))	('SW982', 'CellLine', 'CVCL:1734', (95, 100))	('TP4', 'Chemical', '-', (88, 91))	('TP4', 'Var', (88, 91))	('cytotoxic effects', 'CPA', (20, 37))
454602	33562681	Cell shrinkage was observed after exposure to TP4 or stausporine; however, only exposure to TP4 increased the percentage of cells with incorporated PI (Figure 2A).	('TP4', 'Var', (92, 95))	('age', 'Gene', '5973', (117, 120))	('stausporine', 'Chemical', '-', (53, 64))	('TP4', 'Chemical', '-', (46, 49))	('age', 'Gene', (11, 14))	('age', 'Gene', (117, 120))	('age', 'Gene', '5973', (11, 14))	('TP4', 'Chemical', '-', (92, 95))
454603	33562681	Release of cyclophilin A into culture supernatant can serve as a marker for necrotic cell death, and we found that TP4 increased cyclophilin A in the supernatant, but not the apoptotic marker, caspase-3, in the lysate (Figure 2B).	('caspase-3', 'Gene', (193, 202))	('necrotic cell death', 'Disease', 'MESH:D003643', (76, 95))	('TP4', 'Chemical', '-', (115, 118))	('necrotic cell death', 'Disease', (76, 95))	('TP4', 'Var', (115, 118))	('caspase-3', 'Gene', '836', (193, 202))	('cyclophilin A', 'MPA', (129, 142))	('increased', 'PosReg', (119, 128))
454612	33562681	We found that TP4 dramatically reduced the levels of UCP-2, SOD-1, and SOD-2.	('SOD-1', 'Gene', (60, 65))	('reduced', 'NegReg', (31, 38))	('SOD-2', 'Gene', '6648', (71, 76))	('TP4', 'Chemical', '-', (14, 17))	('SOD-2', 'Gene', (71, 76))	('UCP-2', 'Gene', (53, 58))	('TP4', 'Var', (14, 17))	('levels', 'MPA', (43, 49))	('SOD-1', 'Gene', '6647', (60, 65))	('UCP-2', 'Gene', '7351', (53, 58))
454614	33562681	Therefore, we next checked whether TP4 impairs mitochondrial function.	('TP4', 'Var', (35, 38))	('impairs', 'NegReg', (39, 46))	('TP4', 'Chemical', '-', (35, 38))	('mitochondrial function', 'MPA', (47, 69))
454617	33562681	In SW982 cells, TMRE intensity was significantly induced after 30 min of TP4 exposure (Figure 4A,B).	('induced', 'PosReg', (49, 56))	('TP4', 'Chemical', '-', (73, 76))	('TMRE', 'Chemical', '-', (16, 20))	('SW982', 'CellLine', 'CVCL:1734', (3, 8))	('TP4', 'Var', (73, 76))	('TMRE intensity', 'MPA', (16, 30))
454619	33562681	These results indicated that TP4 induces mitochondrial hyperpolarization.	('mitochondrial hyperpolarization', 'MPA', (41, 72))	('TP4', 'Var', (29, 32))	('TP4', 'Chemical', '-', (29, 32))
454620	33562681	Thus, we further assessed whether mitochondrial ROS were increased by TP4.	('TP4', 'Chemical', '-', (70, 73))	('mitochondrial ROS', 'MPA', (34, 51))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('TP4', 'Var', (70, 73))	('increased', 'PosReg', (57, 66))
454622	33562681	We found that TP4 increased MitoSOX Red intensity in SW982 cells at 60, 180 and 300 min after treatment (Figure 4E,F).	('MitoSOX Red intensity', 'MPA', (28, 49))	('increased', 'PosReg', (18, 27))	('MitoSOX Red', 'Chemical', 'MESH:C000597839', (28, 39))	('TP4', 'Chemical', '-', (14, 17))	('SW982', 'CellLine', 'CVCL:1734', (53, 58))	('TP4', 'Var', (14, 17))
454623	33562681	In addition, MitoSOX Red intensity was elevated by TP4 in AsKa-SS cells at 180 and 300 min after TP4 treatment (Figure 4G,H).	('TP4', 'Chemical', '-', (51, 54))	('TP4', 'Chemical', '-', (97, 100))	('elevated', 'PosReg', (39, 47))	('TP4', 'Var', (51, 54))	('MitoSOX Red', 'Chemical', 'MESH:C000597839', (13, 24))	('MitoSOX Red intensity', 'MPA', (13, 34))
454624	33562681	Together, the data showed that TP4 induced mitochondrial hyperpolarization, which was coincident with excessive mitochondrial ROS production.	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('mitochondrial hyperpolarization', 'MPA', (43, 74))	('TP4', 'Var', (31, 34))	('mitochondrial ROS production', 'MPA', (112, 140))	('excessive mitochondrial ROS production', 'Phenotype', 'HP:0025464', (102, 140))	('excessive', 'PosReg', (102, 111))	('TP4', 'Chemical', '-', (31, 34))
454627	33562681	We found that TP4 elevates intracellular calcium levels in both SW982 (Figure 5A,B) and AsKa-SS (Figure 5C,D) cells.	('TP4', 'Chemical', '-', (14, 17))	('elevates', 'PosReg', (18, 26))	('TP4', 'Var', (14, 17))	('SW982', 'CellLine', 'CVCL:1734', (64, 69))	('intracellular calcium levels', 'MPA', (27, 55))	('calcium', 'Chemical', 'MESH:D002118', (41, 48))	('elevates intracellular calcium', 'Phenotype', 'HP:0003575', (18, 48))
454628	33562681	However, TP4-induced elevation of intracellular calcium was more rapid and transient in SW982 cells than it was in AsKa-SS cells.	('calcium', 'Chemical', 'MESH:D002118', (48, 55))	('elevation of intracellular calcium', 'Phenotype', 'HP:0003575', (21, 55))	('intracellular calcium', 'MPA', (34, 55))	('SW982', 'CellLine', 'CVCL:1734', (88, 93))	('TP4', 'Chemical', '-', (9, 12))	('TP4-induced', 'Var', (9, 20))	('elevation', 'PosReg', (21, 30))
454629	33562681	The calcium chelator, BAPTA, abolished TP4-induced ROS generation in SW982 cells (Figure 5E,F) but not in AsKa-SS cells (Figure 5G,H).	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('TP4', 'Chemical', '-', (39, 42))	('BAPTA', 'Chemical', 'MESH:C025603', (22, 27))	('abolished', 'NegReg', (29, 38))	('ROS generation', 'MPA', (51, 65))	('SW982', 'CellLine', 'CVCL:1734', (69, 74))	('calcium', 'Chemical', 'MESH:D002118', (4, 11))	('TP4-induced', 'Var', (39, 50))
454636	33562681	In a previous study on triple-negative breast cancer cells, TP4 was shown to induce FOSB activation via elevation of intracellular calcium.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('FOSB', 'Protein', (84, 88))	('calcium', 'Chemical', 'MESH:D002118', (131, 138))	('elevation of intracellular calcium', 'Phenotype', 'HP:0003575', (104, 138))	('intracellular calcium', 'MPA', (117, 138))	('activation', 'PosReg', (89, 99))	('TP4', 'Chemical', '-', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('elevation', 'PosReg', (104, 113))	('TP4', 'Var', (60, 63))	('breast cancer', 'Disease', (39, 52))
454637	33562681	Here, we found that TP4 also disrupts calcium homeostasis in synovial sarcoma cells (Figure 5A-D); however, the activation status of FOSB in TP4-treated synovial sarcoma cells remains unclear.	('TP4', 'Chemical', '-', (141, 144))	('TP4', 'Var', (20, 23))	('calcium homeostasis', 'MPA', (38, 57))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (153, 169))	('calcium', 'Chemical', 'MESH:D002118', (38, 45))	('synovial sarcoma', 'Disease', (61, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('synovial sarcoma', 'Disease', 'MESH:D013584', (153, 169))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (61, 77))	('synovial sarcoma', 'Disease', 'MESH:D013584', (61, 77))	('disrupts', 'NegReg', (29, 37))	('synovial sarcoma', 'Disease', (153, 169))	('TP4', 'Chemical', '-', (20, 23))
454642	33562681	Elevated ROS was observed at 60 min after TP4 exposure (Figure 3E,F), while TP4-induced elevation of intracellular calcium was observed later, at 180 min (Figure 5C,D).	('TP4', 'Chemical', '-', (42, 45))	('ROS', 'MPA', (9, 12))	('calcium', 'Chemical', 'MESH:D002118', (115, 122))	('TP4', 'Chemical', '-', (76, 79))	('TP4', 'Var', (42, 45))	('elevation of intracellular calcium', 'Phenotype', 'HP:0003575', (88, 122))	('intracellular calcium', 'MPA', (101, 122))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))
454643	33562681	Excessive ROS is known to damage intracellular biological molecules such as nucleic acids, proteins, and lipids, which leads to cell death through various mechanisms.	('leads to', 'Reg', (119, 127))	('ROS', 'Var', (10, 13))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('age', 'Gene', '5973', (29, 32))	('proteins', 'Protein', (91, 99))	('lipids', 'Chemical', 'MESH:D008055', (105, 111))	('cell death', 'CPA', (128, 138))	('age', 'Gene', (29, 32))
454644	33562681	Therefore, modulation of intracellular ROS levels may be a valuable strategy for cancer treatments.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('modulation', 'Var', (11, 21))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
454650	33562681	We found that TP4 induces mitochondrial hyperpolarization and subsequent elevation of mitochondrial ROS (Figure 4).	('TP4', 'Chemical', '-', (14, 17))	('mitochondrial hyperpolarization', 'MPA', (26, 57))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('TP4', 'Var', (14, 17))	('mitochondrial ROS', 'MPA', (86, 103))	('elevation', 'PosReg', (73, 82))
454653	33562681	Therefore, TP4 may be able to enhance the efficacy of current synovial sarcoma therapeutics, due to its downregulation of antioxidant proteins.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (62, 78))	('TP4', 'Var', (11, 14))	('synovial sarcoma', 'Disease', 'MESH:D013584', (62, 78))	('synovial sarcoma', 'Disease', (62, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('enhance', 'PosReg', (30, 37))	('downregulation', 'NegReg', (104, 118))	('TP4', 'Chemical', '-', (11, 14))
454654	33562681	In addition to its antioxidant activity, UCP-2 regulates ATP production and the proton gradient within mitochondria, and UCP-2 knockout cells exhibit elevated mitochondrial membrane potential.	('UCP-2', 'Gene', (41, 46))	('mitochondrial membrane potential', 'MPA', (159, 191))	('regulates', 'Reg', (47, 56))	('ATP', 'Chemical', 'MESH:D000255', (57, 60))	('knockout', 'Var', (127, 135))	('elevated', 'PosReg', (150, 158))	('UCP-2', 'Gene', '7351', (121, 126))	('UCP-2', 'Gene', '7351', (41, 46))	('antioxidant activity', 'MPA', (19, 39))	('UCP-2', 'Gene', (121, 126))
454655	33562681	Correspondingly, we found that TP4-induced mitochondrial hyperpolarization (Figure 4A,B) is accompanied by reduced UCP-2 level (Figure 3I) and increased mitochondrial ROS generation (Figure 4E,F).	('increased', 'PosReg', (143, 152))	('increased mitochondrial ROS generation', 'Phenotype', 'HP:0025464', (143, 181))	('ROS', 'Chemical', 'MESH:D017382', (167, 170))	('UCP-2', 'Gene', (115, 120))	('TP4-induced', 'Var', (31, 42))	('TP4', 'Chemical', '-', (31, 34))	('mitochondrial ROS generation', 'MPA', (153, 181))	('reduced', 'NegReg', (107, 114))	('mitochondrial', 'MPA', (43, 56))	('UCP-2', 'Gene', '7351', (115, 120))	('hyperpolarization', 'PosReg', (57, 74))
454657	33562681	In the present study, we demonstrated that TP4 induces mitochondrial hyperpolarization in synovial sarcoma cells.	('induces', 'Reg', (47, 54))	('synovial sarcoma', 'Disease', 'MESH:D013584', (90, 106))	('synovial sarcoma', 'Disease', (90, 106))	('TP4', 'Chemical', '-', (43, 46))	('mitochondrial hyperpolarization', 'MPA', (55, 86))	('TP4', 'Var', (43, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (90, 106))
454660	33562681	While current chemotherapeutic agents mainly induce apoptotic cell death, TP4 induces necrotic cell death (Figure 2).	('induces', 'Reg', (78, 85))	('necrotic cell death', 'Disease', 'MESH:D003643', (86, 105))	('necrotic cell death', 'Disease', (86, 105))	('age', 'Gene', (31, 34))	('TP4', 'Chemical', '-', (74, 77))	('apoptotic cell death', 'CPA', (52, 72))	('TP4', 'Var', (74, 77))	('age', 'Gene', '5973', (31, 34))
454665	33562681	Furthermore, we found that in this context, TP4 induces calcium overload, mitochondrial dysfunction, ROS production, and impaired antioxidant defense, followed by necrotic cell death.	('impaired', 'NegReg', (121, 129))	('antioxidant defense', 'MPA', (130, 149))	('calcium', 'Chemical', 'MESH:D002118', (56, 63))	('necrotic cell death', 'Disease', 'MESH:D003643', (163, 182))	('TP4', 'Chemical', '-', (44, 47))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (74, 99))	('induces', 'Reg', (48, 55))	('necrotic cell death', 'Disease', (163, 182))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (74, 99))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('mitochondrial dysfunction', 'Disease', (74, 99))	('ROS production', 'MPA', (101, 115))	('calcium overload', 'MPA', (56, 72))	('TP4', 'Var', (44, 47))
454666	33562681	Further studies are required to determine whether TP4 can also cause synovial sarcoma cell death in vivo.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (69, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('cause', 'Reg', (63, 68))	('synovial sarcoma cell death', 'Disease', (69, 96))	('TP4', 'Chemical', '-', (50, 53))	('synovial sarcoma cell death', 'Disease', 'MESH:D013584', (69, 96))	('TP4', 'Var', (50, 53))
454688	33562681	TP4 causes necrosis in synovial sarcoma cells via induction of calcium overload, mitochondrial hyperpolarization, and oxidative stress.	('mitochondrial hyperpolarization', 'CPA', (81, 112))	('TP4', 'Var', (0, 3))	('necrosis', 'Disease', (11, 19))	('synovial sarcoma', 'Disease', (23, 39))	('calcium', 'Chemical', 'MESH:D002118', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('calcium overload', 'MPA', (63, 79))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (23, 39))	('oxidative', 'MPA', (118, 127))	('necrosis', 'Disease', 'MESH:D009336', (11, 19))	('oxidative stress', 'Phenotype', 'HP:0025464', (118, 134))	('synovial sarcoma', 'Disease', 'MESH:D013584', (23, 39))	('TP4', 'Chemical', '-', (0, 3))
454709	32957532	However, it is important to note that latency can be established independently of RTA activity, as a KSHV RTA deletion mutant can establish latency with robust LANA expression.	('latency', 'MPA', (140, 147))	('KSHV', 'Species', '37296', (101, 105))	('KSHV RTA', 'Gene', (101, 109))	('KS', 'Phenotype', 'HP:0100726', (101, 103))	('deletion mutant', 'Var', (110, 125))
454710	32957532	After 24 to 72 h, the epigenetic profile of the KSHV genome shifts from activating marks towards repressive H3K27 trimethylation and H2AK119 ubiquitylation marks.	('epigenetic', 'MPA', (22, 32))	('H3K27', 'Protein', (108, 113))	('KS', 'Phenotype', 'HP:0100726', (48, 50))	('H2AK119', 'Var', (133, 140))	('KSHV', 'Species', '37296', (48, 52))	('H2AK119', 'Chemical', '-', (133, 140))	('KSHV', 'Gene', (48, 52))	('activating marks', 'MPA', (72, 88))	('trimethylation', 'MPA', (114, 128))
454729	32957532	SUMOylation has been shown to alter protein localization, activity, or stability through alteration of protein-protein interaction surfaces.	('SUMOylation', 'Var', (0, 11))	('activity', 'MPA', (58, 66))	('alter', 'Reg', (30, 35))	('protein-protein', 'Protein', (103, 118))	('protein', 'Protein', (36, 43))	('alteration', 'Reg', (89, 99))	('stability', 'MPA', (71, 80))	('rat', 'Species', '10116', (93, 96))
454737	32957532	Protein arginine methyltransferase 1 (PRMT1) augments LANA histone binding, and a methylation mimetic mutant of LANA induces tighter control of lytic gene expression.	('mutant', 'Var', (102, 108))	('PRMT1', 'Gene', '3276', (38, 43))	('LANA histone', 'Protein', (54, 66))	('control', 'MPA', (133, 140))	('LANA', 'Gene', (112, 116))	('tighter', 'PosReg', (125, 132))	('PRMT1', 'Gene', (38, 43))	('induces', 'Reg', (117, 124))	('Protein arginine methyltransferase 1', 'Gene', '3276', (0, 36))	('Protein arginine methyltransferase 1', 'Gene', (0, 36))	('lytic gene', 'Gene', (144, 154))	('augments', 'PosReg', (45, 53))	('binding', 'Interaction', (67, 74))
454743	32957532	Pharmacological disruption of BRD2 and BRD4 leads to the loss of a DNA loop tethering the latent and lytic control regions of the KSHV genome, triggering reactivation.	('BRD2', 'Gene', '6046', (30, 34))	('BRD2', 'Gene', (30, 34))	('disruption', 'Var', (16, 26))	('BRD4', 'Gene', (39, 43))	('DNA loop tethering', 'Protein', (67, 85))	('loss', 'NegReg', (57, 61))	('KS', 'Phenotype', 'HP:0100726', (130, 132))	('KSHV', 'Species', '37296', (130, 134))	('reactivation', 'MPA', (154, 166))	('BRD4', 'Gene', '23476', (39, 43))
454756	32957532	K15- and vFLIP-stimulated NF-kappaB activation was shown to be dependent on MALT1, and inhibition of MALT1 protease activity stimulated KSHV reactivation in PEL cell lines.	('MALT1 protease', 'Gene', '10892', (101, 115))	('NF-kappaB', 'Gene', '4790', (26, 35))	('NF-kappaB', 'Gene', (26, 35))	('MALT1', 'Gene', '10892', (76, 81))	('stimulated', 'Reg', (125, 135))	('MALT1', 'Gene', '10892', (101, 106))	('activation', 'PosReg', (36, 46))	('MALT1 protease', 'Gene', (101, 115))	('K15', 'Gene', '3866', (0, 3))	('MALT1', 'Gene', (76, 81))	('KSHV reactivation', 'MPA', (136, 153))	('MALT1', 'Gene', (101, 106))	('PEL', 'Phenotype', 'HP:0030069', (157, 160))	('K15', 'Gene', (0, 3))	('KS', 'Phenotype', 'HP:0100726', (136, 138))	('KSHV', 'Species', '37296', (136, 140))	('inhibition', 'Var', (87, 97))
454762	32957532	If this constitutive activation is interrupted by knockdown of STAT3, levels of transcriptional repressor KAP1 decrease, and lytic reactivation ensues.	('lytic reactivation', 'CPA', (125, 143))	('knockdown', 'Var', (50, 59))	('KAP1', 'Gene', (106, 110))	('STAT3', 'Gene', '6774', (63, 68))	('decrease', 'NegReg', (111, 119))	('KAP1', 'Gene', '10155', (106, 110))	('STAT3', 'Gene', (63, 68))
454775	32957532	Loss of IFIT1, IFIT2, and IFIT3 leads to broad increases in lytic gene expression and subsequent virion production, implicating them in control of KSHV latency.	('KSHV', 'Species', '37296', (147, 151))	('expression', 'MPA', (71, 81))	('KS', 'Phenotype', 'HP:0100726', (147, 149))	('IFIT2', 'Gene', (15, 20))	('IFIT3', 'Gene', '3437', (26, 31))	('IFIT1', 'Gene', (8, 13))	('IFIT2', 'Gene', '3433', (15, 20))	('virion', 'CPA', (97, 103))	('lytic gene', 'Gene', (60, 70))	('increases', 'PosReg', (47, 56))	('Loss', 'Var', (0, 4))	('IFIT1', 'Gene', '3434', (8, 13))	('IFIT3', 'Gene', (26, 31))
454781	32957532	A role for IFNgamma in control of KSHV latency is reasonable, as a close KSHV relative, murine gammaherpesvirus 68 (MHV68), reactivates from latency more readily in mice deficient in IFNgamma or its receptor.	('KS', 'Phenotype', 'HP:0100726', (34, 36))	('KSHV', 'Species', '37296', (34, 38))	('murine gammaherpesvirus 68', 'Species', '33708', (88, 114))	('mice', 'Species', '10090', (165, 169))	('reactivates', 'MPA', (124, 135))	('KSHV', 'Species', '37296', (73, 77))	('MHV68', 'Species', '1440122', (116, 121))	('KS', 'Phenotype', 'HP:0100726', (73, 75))	('IFNgamma', 'Protein', (183, 191))	('deficient', 'Var', (170, 179))
454804	32957532	The deletion of the KSHV miRNA locus leads to a more open chromatin landscape with decreased H3K9 methylation, increased H3 acetylation, and a loss of DNA methylation.	('KS', 'Phenotype', 'HP:0100726', (20, 22))	('KSHV', 'Species', '37296', (20, 24))	('increased', 'PosReg', (111, 120))	('decreased', 'NegReg', (83, 92))	('miR', 'Gene', (25, 28))	('DNA methylation', 'MPA', (151, 166))	('more', 'PosReg', (48, 52))	('loss', 'NegReg', (143, 147))	('deletion', 'Var', (4, 12))	('H3K9', 'Protein', (93, 97))	('miR', 'Gene', '29116', (25, 28))	('H3 acetylation', 'MPA', (121, 135))	('methylation', 'MPA', (98, 109))
454822	32957532	This domain is typically targeted by the cellular E3 ubiquitin ligase mouse double minute 2 homolog (MDM2), but competition by NCOA2 ensures the accumulation of RTA and activation of the lytic cycle.	('lytic cycle', 'CPA', (187, 198))	('MDM2', 'Gene', '17246', (101, 105))	('competition', 'Var', (112, 123))	('accumulation', 'PosReg', (145, 157))	('NCOA2', 'Gene', (127, 132))	('RTA', 'MPA', (161, 164))	('MDM2', 'Gene', (101, 105))
454837	32957532	Posttranslational modifications of LANA also play a major role in hypoxia-mediated KSHV reactivation.	('KSHV', 'Species', '37296', (83, 87))	('KS', 'Phenotype', 'HP:0100726', (83, 85))	('Posttranslational modifications', 'Var', (0, 31))	('hypoxia', 'Disease', (66, 73))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('LANA', 'Protein', (35, 39))
454845	32957532	Inhibition of the extracellular signal-regulated kinase (ERK) pathway, the Jun N-terminal kinase (JNK) pathway, or the p38 pathway leads to defects in KSHV reactivation.	('KSHV', 'Species', '37296', (151, 155))	('KS', 'Phenotype', 'HP:0100726', (151, 153))	('Jun N-terminal kinase', 'Gene', '5599', (75, 96))	('KSHV', 'Gene', (151, 155))	('Jun N-terminal kinase', 'Gene', (75, 96))	('JNK', 'Gene', (98, 101))	('Inhibition', 'Var', (0, 10))	('JNK', 'Gene', '5599', (98, 101))	('defects', 'NegReg', (140, 147))	('p38 pathway', 'Pathway', (119, 130))
454892	32957532	By targeting the cellular immune system, KSHV creates a less hostile microenvironment for lytic reactivation.	('targeting', 'Reg', (3, 12))	('KSHV', 'Species', '37296', (41, 45))	('KS', 'Phenotype', 'HP:0100726', (41, 43))	('KSHV', 'Var', (41, 45))
454896	32957532	TLR 7 and 8, which sense single-stranded RNA, have been shown to trigger reactivation of KSHV when stimulated by co-infection with vesicular stomatitis virus.	('KS', 'Phenotype', 'HP:0100726', (89, 91))	('KSHV', 'Species', '37296', (89, 93))	('co-infection', 'Disease', (113, 125))	('single-stranded', 'Var', (25, 40))	('KSHV', 'Gene', (89, 93))	('TLR 7', 'Gene', '51284', (0, 5))	('co-infection', 'Disease', 'MESH:D060085', (113, 125))	('stomatitis', 'Phenotype', 'HP:0010280', (141, 151))	('vesicular stomatitis virus', 'Species', '11276', (131, 157))	('TLR 7', 'Gene', (0, 5))	('reactivation', 'MPA', (73, 85))
454902	32957532	B-cell specific expression of LANA leads to lymphoma, follicular hyperplasia, and increased germinal center formation in transgenic mice.	('lymphoma', 'Disease', 'MESH:D008223', (44, 52))	('increased germinal center formation', 'Phenotype', 'HP:0002849', (82, 117))	('hyperplasia', 'Disease', (65, 76))	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	('expression', 'Var', (16, 26))	('follicular hyperplasia', 'Phenotype', 'HP:0002729', (54, 76))	('hyperplasia', 'Disease', 'MESH:D006965', (65, 76))	('leads to', 'Reg', (35, 43))	('LANA', 'Gene', (30, 34))	('increased', 'PosReg', (82, 91))	('germinal center formation', 'CPA', (92, 117))	('transgenic mice', 'Species', '10090', (121, 136))	('lymphoma', 'Disease', (44, 52))
454903	32957532	Similarly, vFLIP transgenic mice tend to develop lymphomas and other B-cell-driven tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('lymphomas', 'Disease', (49, 58))	('develop', 'PosReg', (41, 48))	('tumors', 'Disease', (83, 89))	('lymphomas', 'Disease', 'MESH:D008223', (49, 58))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('vFLIP', 'Gene', (11, 16))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('lymphomas', 'Phenotype', 'HP:0002665', (49, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))	('transgenic mice', 'Species', '10090', (17, 32))	('transgenic', 'Var', (17, 27))
454908	32957532	The introduction of the KSHV genome into certain cell types has been demonstrated to be sufficient for oncogenesis.	('rat', 'Species', '10116', (76, 79))	('KSHV', 'Species', '37296', (24, 28))	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('introduction', 'Var', (4, 16))	('oncogenesis', 'CPA', (103, 114))	('KSHV genome', 'Gene', (24, 35))
454915	32957532	A different model of KSHV oncogenesis involving bone-marrow-derived mesenchymal stem cells demonstrated a dependence on inflammatory "KS-like" culture conditions to promote epigenetic de-repression and subsequent transformation.	('KS', 'Phenotype', 'HP:0100726', (21, 23))	('epigenetic de-repression', 'Var', (173, 197))	('rat', 'Species', '10116', (98, 101))	('KSHV', 'Species', '37296', (21, 25))	('promote', 'PosReg', (165, 172))	('KS', 'Phenotype', 'HP:0100726', (134, 136))	('transformation', 'CPA', (213, 227))
454925	32957532	This disruption inhibited the proliferation of KSHV-infected cells in vitro and induced regression of PEL xenograft tumors in mice.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('inhibited', 'NegReg', (16, 25))	('KSHV-infected', 'Disease', 'MESH:D007239', (47, 60))	('mice', 'Species', '10090', (126, 130))	('rat', 'Species', '10116', (37, 40))	('disruption', 'Var', (5, 15))	('KSHV-infected', 'Disease', (47, 60))	('KS', 'Phenotype', 'HP:0100726', (47, 49))	('regression', 'CPA', (88, 98))	('PEL', 'Phenotype', 'HP:0030069', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('PEL', 'Disease', (102, 105))	('proliferation', 'CPA', (30, 43))
454926	32957532	Inhibition of the MALT1 protease, a crucial facilitator of vFLIP- and K15-mediated NF-kappaB activation, triggered lytic activation and reduced growth and survival of PEL cells both in vitro and in a xenograft model.	('MALT1 protease', 'Gene', (18, 32))	('NF-kappaB', 'Gene', '4790', (83, 92))	('reduced', 'NegReg', (136, 143))	('Inhibition', 'Var', (0, 10))	('NF-kappaB', 'Gene', (83, 92))	('PEL', 'Phenotype', 'HP:0030069', (167, 170))	('lytic activation', 'CPA', (115, 131))	('MALT1 protease', 'Gene', '10892', (18, 32))	('K15', 'Gene', '3866', (70, 73))	('K15', 'Gene', (70, 73))
454927	32957532	Combination therapy composed of the protein kinase C activator PEP005 and the bromodomain and extra terminal (BET) protein inhibitor JQ1 robustly induced KSHV lytic reactivation, inhibiting PEL growth in in vitro and in vivo models.	('BET', 'Gene', '92737', (110, 113))	('KS', 'Phenotype', 'HP:0100726', (154, 156))	('BET', 'Gene', (110, 113))	('inhibiting', 'NegReg', (179, 189))	('PEL growth', 'CPA', (190, 200))	('PEP005', 'Var', (63, 69))	('KSHV', 'Gene', (154, 158))	('PEL', 'Phenotype', 'HP:0030069', (190, 193))	('KSHV', 'Species', '37296', (154, 158))	('induced', 'Reg', (146, 153))
454981	31788090	ES is an aggressive tumour with high occurrence of metastasis in children and young teenagers, and is caused by chromosomal fusion in EWSR1 genes.	('EWSR1', 'Gene', '2130', (134, 139))	('ES', 'Disease', 'MESH:D012512', (0, 2))	('children', 'Species', '9606', (65, 73))	('aggressive tumour', 'Disease', 'MESH:D001523', (9, 26))	('caused by', 'Reg', (102, 111))	('aggressive tumour', 'Disease', (9, 26))	('EWSR1', 'Gene', (134, 139))	('chromosomal fusion', 'Var', (112, 130))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
455011	31788090	According to the presence of the EWSR1 gene rearrangement in only one of the three carcinomas (Ewing's sarcoma and hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands) studied by Moller et al, it may be concluded that the patient described in the present study was negative for EWSR1 gene rearrangement, suggesting that other mechanisms may be involved in the pathogenesis of this tumour type.	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('carcinomas', 'Disease', 'MESH:D002277', (83, 93))	('EWSR1', 'Gene', '2130', (33, 38))	('hidradenoma of the skin', 'Disease', (115, 138))	('patient', 'Species', '9606', (246, 253))	('rearrangement', 'Var', (44, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('EWSR1', 'Gene', '2130', (302, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('hidradenoma of the skin', 'Disease', 'MESH:D018250', (115, 138))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (95, 110))	('tumour', 'Phenotype', 'HP:0002664', (405, 411))	('tumour', 'Disease', 'MESH:D009369', (405, 411))	('mucoepidermoid carcinoma of the salivary glands', 'Disease', 'MESH:D018277', (143, 190))	('carcinomas', 'Disease', (83, 93))	('EWSR1', 'Gene', (33, 38))	('tumour', 'Disease', (405, 411))	('mucoepidermoid carcinoma of the salivary glands', 'Disease', (143, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('EWSR1', 'Gene', (302, 307))	("Ewing's sarcoma", 'Disease', (95, 110))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (95, 110))
455066	31027106	The mean tumor size was <=5 cm, 5 to 10 cm, and >10 cm in 3, 8, and 2 studies.	('tumor', 'Disease', (9, 14))	('<=5', 'Var', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))
455104	31027106	In another research by Blakely et al, expression of PDL-1 was associated with tumor necrosis, as well as tumor behavior and clinical outcomes of various tumor types, which may reveal a potential correlation between tumor necrosis and other immunohistochemical markers.	('tumor necrosis', 'Disease', (215, 229))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('PDL-1', 'Gene', '29126', (52, 57))	('tumor necrosis', 'Disease', 'MESH:D009336', (78, 92))	('tumor necrosis', 'Disease', (78, 92))	('tumor behavior', 'Disease', 'MESH:D001523', (105, 119))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('associated with', 'Reg', (62, 77))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('PDL-1', 'Gene', (52, 57))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('expression', 'Var', (38, 48))	('tumor necrosis', 'Disease', 'MESH:D009336', (215, 229))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor behavior', 'Disease', (105, 119))
455176	25435942	Furthermore, a recent study identified an association between CD99 overexpression and EWS/FLI1 fusion: EWS/FLI1 may downregulate microRNAs (miR), such as miR-30-5p, which may interact with the 3'-untranslated region of CD99 and post-transcriptionally downregulate its expression.	('CD99', 'Gene', '4267', (62, 66))	('EWS', 'Gene', '2130', (103, 106))	('EWS', 'Gene', (103, 106))	('FLI1', 'Gene', (107, 111))	('downregulate', 'NegReg', (251, 263))	('expression', 'MPA', (268, 278))	('FLI1', 'Gene', '2313', (107, 111))	('downregulate', 'NegReg', (116, 128))	('CD99', 'Gene', (219, 223))	('FLI1', 'Gene', (90, 94))	('CD99', 'Gene', '4267', (219, 223))	('FLI1', 'Gene', '2313', (90, 94))	('CD99', 'Gene', (62, 66))	('miR-30-5p', 'Var', (154, 163))	('EWS', 'Gene', '2130', (86, 89))	('EWS', 'Gene', (86, 89))
455177	25435942	Additionally, alternative chromosomal translocations with analogous fusion of EWS to other partners have been reported; for example, the rare t(16;21)(p11;q22) translocation and fusion of the ETS-related gene ETS domain to fused in sarcoma has previously been reported in renal pPNET.	('ETS domain', 'Gene', (209, 219))	('sarcoma', 'Disease', 'MESH:D012509', (232, 239))	('sarcoma', 'Disease', (232, 239))	('fusion', 'Var', (178, 184))	('t(16;21)(p11;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (142, 159))	('renal pPNET', 'Phenotype', 'HP:0030409', (272, 283))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('EWS', 'Gene', '2130', (78, 81))	('EWS', 'Gene', (78, 81))	('renal pPNET', 'Disease', (272, 283))
455192	24281118	This indicates that miRNA deregulation contributes to the initiation and progression of cancer.	('contributes', 'Reg', (39, 50))	('deregulation', 'Var', (26, 38))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('nt', 'Chemical', 'MESH:D009711', (41, 43))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
455194	24281118	This review discusses deregulated miRNAs in solid tumors, and focuses on their emerging prognostic potential.	('deregulated', 'Var', (22, 33))	('solid tumors', 'Disease', 'MESH:D009369', (44, 56))	('nt', 'Chemical', 'MESH:D009711', (103, 105))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('solid tumors', 'Disease', (44, 56))
455207	24281118	Current published research suggests that aberrantly expressed miRNAs are involved in many molecular processes of cancer biology.	('nt', 'Chemical', 'MESH:D009711', (5, 7))	('nt', 'Chemical', 'MESH:D009711', (47, 49))	('miR', 'Gene', '220972', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('miR', 'Gene', (62, 65))	('cancer', 'Disease', (113, 119))	('aberrantly expressed', 'Var', (41, 61))	('involved', 'Reg', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
455232	24281118	Additional mechanisms of miRNA deregulation include altered expression of miRNAs as a consequence of excessive or deficient processing, aberrant transcription of the precursors by the epigenetic silencing of miRNA promoters or as a result of the activity of oncogenic transcription factors, and rarely, point mutations in mature miRNAs or in target sequences that can interfere with normal target recruitment.	('processing', 'MPA', (124, 134))	('expression', 'MPA', (60, 70))	('result', 'Reg', (232, 238))	('miR', 'Gene', '220972', (329, 332))	('nt', 'Chemical', 'MESH:D009711', (306, 308))	('nt', 'Chemical', 'MESH:D009711', (369, 371))	('miR', 'Gene', (329, 332))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', '220972', (25, 28))	('nt', 'Chemical', 'MESH:D009711', (121, 123))	('activity', 'MPA', (246, 254))	('deficient', 'NegReg', (114, 123))	('miR', 'Gene', '220972', (208, 211))	('miR', 'Gene', (74, 77))	('miR', 'Gene', (25, 28))	('nt', 'Chemical', 'MESH:D009711', (406, 408))	('point mutations', 'Var', (303, 318))	('miR', 'Gene', (208, 211))	('altered', 'Reg', (52, 59))	('transcription', 'MPA', (145, 158))	('nt', 'Chemical', 'MESH:D009711', (142, 144))	('epigenetic silencing', 'Var', (184, 204))
455243	24281118	After DNA damage in several types of cancer, silencing of miR-34a through aberrant CpG methylation of its promoter has been found to dominate over miR-34a's transactivation by p53.	('miR-34a', 'Gene', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('p53', 'Gene', (176, 179))	('cancer', 'Disease', (37, 43))	('silencing', 'MPA', (45, 54))	('p53', 'Gene', '7157', (176, 179))	('miR-34a', 'Gene', '407040', (58, 65))	('nt', 'Chemical', 'MESH:D009711', (80, 82))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('miR-34a', 'Gene', '407040', (147, 154))	('miR-34a', 'Gene', (147, 154))	('aberrant', 'Var', (74, 82))
455246	24281118	Characteristically, the first evidence came with the work of Ma et al., who proved that the expression of miR-10b could initiate metastatic machinery in breast cancer by indirectly activating a well-characterized pro-metastatic gene, RHOC.	('activating', 'Reg', (181, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('miR-10b', 'Gene', '406903', (106, 113))	('expression', 'Var', (92, 102))	('metastatic machinery', 'CPA', (129, 149))	('RHOC', 'Gene', '389', (234, 238))	('initiate', 'PosReg', (120, 128))	('RHOC', 'Gene', (234, 238))	('miR-10b', 'Gene', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))
455249	24281118	Sequence-specific anti-miRNA oligonucleotides (antagomirs) have emerged as a novel class in cancer drug development.	('mir', 'Gene', '220972', (53, 56))	('nt', 'Chemical', 'MESH:D009711', (19, 21))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('nt', 'Chemical', 'MESH:D009711', (48, 50))	('anti-miRNA', 'Var', (18, 28))	('miRNA oligonucleotides', 'Chemical', '-', (23, 45))	('mir', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('nt', 'Chemical', 'MESH:D009711', (113, 115))
455260	24281118	In the same study, the introduction of exogenous let-7 in the A549 lung adenocarcinoma cell line resulted in growth inhibition.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('growth', 'MPA', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('exogenous', 'Var', (39, 48))	('nt', 'Chemical', 'MESH:D009711', (24, 26))	('A549 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 86))	('A549 lung adenocarcinoma', 'Disease', (62, 86))	('let-7', 'Gene', (49, 54))
455266	24281118	identified a set of five miRNAs (low let-7a and miR-221, and high miR-137, miR-372, and miR-182) that predicted treatment outcome in NSCLC patients.	('miR', 'Gene', '220972', (75, 78))	('miR-182', 'Gene', (88, 95))	('miR-182', 'Gene', '406958', (88, 95))	('miR', 'Gene', '220972', (66, 69))	('NSCLC', 'Disease', (133, 138))	('miR', 'Gene', (75, 78))	('miR-221', 'Gene', (48, 55))	('nt', 'Chemical', 'MESH:D009711', (3, 5))	('miR', 'Gene', (66, 69))	('miR', 'Gene', '220972', (25, 28))	('miR-221', 'Gene', '407006', (48, 55))	('low let-7a', 'Var', (33, 43))	('miR-372', 'Gene', (75, 82))	('miR', 'Gene', '220972', (88, 91))	('miR-137', 'Gene', (66, 73))	('nt', 'Chemical', 'MESH:D009711', (144, 146))	('miR-137', 'Gene', '406928', (66, 73))	('patients', 'Species', '9606', (139, 147))	('miR', 'Gene', (25, 28))	('miR', 'Gene', '220972', (48, 51))	('predicted', 'Reg', (102, 111))	('miR', 'Gene', (88, 91))	('nt', 'Chemical', 'MESH:D009711', (119, 121))	('miR-372', 'Gene', '442917', (75, 82))	('miR', 'Gene', (48, 51))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))
455282	24281118	In epithelial ovarian cancer, aberrant miRNA expression can differentiate normal versus cancer tissues.	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('aberrant', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('epithelial ovarian cancer', 'Disease', (3, 28))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (3, 28))	('nt', 'Chemical', 'MESH:D009711', (36, 38))	('nt', 'Chemical', 'MESH:D009711', (67, 69))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (3, 28))
455293	24281118	Another study on the miRNA profiling of prostate cancer detected the differential expression of 51 individual miRNAs between benign lesions and carcinoma tumors, the majority of which (72%, among which let-7, miR-16, -23, -92, 103, -125, -143, -145, -195, -199, -221, -222, and -497) were downregulated in carcinoma samples.	('miR', 'Gene', '220972', (209, 212))	('miR', 'Gene', (21, 24))	('nt', 'Chemical', 'MESH:D009711', (76, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('downregulated', 'NegReg', (289, 302))	('let-7', 'Var', (202, 207))	('carcinoma', 'Disease', 'MESH:D002277', (306, 315))	('carcinoma', 'Disease', (144, 153))	('expression', 'MPA', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('miR', 'Gene', (209, 212))	('prostate cancer', 'Disease', 'MESH:D011471', (40, 55))	('miR-16', 'Gene', (209, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('carcinoma tumors', 'Disease', 'MESH:D009369', (144, 160))	('prostate cancer', 'Disease', (40, 55))	('carcinoma', 'Disease', 'MESH:D002277', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', (110, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (306, 315))	('miR-16', 'Gene', '51573', (209, 215))	('miR', 'Gene', '220972', (21, 24))	('carcinoma', 'Disease', (306, 315))	('carcinoma tumors', 'Disease', (144, 160))
455309	24281118	This indicates a potential application of missing miR-101 in the therapy of liver cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('miR-1', 'Gene', '79187', (50, 55))	('nt', 'Chemical', 'MESH:D009711', (21, 23))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('liver cancer', 'Disease', 'MESH:D006528', (76, 88))	('missing', 'Var', (42, 49))	('miR-1', 'Gene', (50, 55))	('liver cancer', 'Disease', (76, 88))
455316	24281118	Moreover, in a miRNA microarray expression profiling study, high miR-21 expression in these tumors was identified as a potent predictor of poor survival and poor therapeutic outcome.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('high', 'Var', (60, 64))	('nt', 'Chemical', 'MESH:D009711', (106, 108))	('nt', 'Chemical', 'MESH:D009711', (123, 125))	('miR-21', 'Gene', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('expression', 'MPA', (72, 82))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('miR-21', 'Gene', '406991', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
455323	24281118	Low let-7g and high miR-214 were found to be associated with an unfavorable survival outcome that is independent of clinical covariates, including the depth of invasion, lymph-node metastasis, and stage.	('high', 'Var', (15, 19))	('miR-214', 'Gene', '406996', (20, 27))	('let-7g', 'Gene', (4, 10))	('nt', 'Chemical', 'MESH:D009711', (110, 112))	('miR-214', 'Gene', (20, 27))	('let-7g', 'Gene', '406890', (4, 10))	('Low', 'Var', (0, 3))
455329	24281118	Additionally, a high expression of miR-196a-2 was a predictor of poor survival.	('miR-196a-2', 'Gene', '406973', (35, 45))	('high', 'Var', (16, 20))	('poor survival', 'CPA', (65, 78))	('miR-196a-2', 'Gene', (35, 45))
455330	24281118	Others have also identified that aberrant expression of miR-196a and miR-217 can discriminate PDAC from the samples of healthy pancreas, and from the pancreas of patients with chronic pancreatitis.	('patients', 'Species', '9606', (162, 170))	('nt', 'Chemical', 'MESH:D009711', (167, 169))	('miR-1', 'Gene', (56, 61))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (176, 196))	('miR-217', 'Gene', '406999', (69, 76))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (176, 196))	('pancreatitis', 'Phenotype', 'HP:0001733', (184, 196))	('miR-217', 'Gene', (69, 76))	('nt', 'Chemical', 'MESH:D009711', (20, 22))	('chronic pancreatitis', 'Disease', (176, 196))	('discriminate', 'Reg', (81, 93))	('miR-1', 'Gene', '79187', (56, 61))	('nt', 'Chemical', 'MESH:D009711', (39, 41))	('PDAC', 'Disease', (94, 98))	('PDAC', 'Phenotype', 'HP:0006725', (94, 98))	('aberrant expression', 'Var', (33, 52))
455358	24281118	MiR-34 was investigated in 117 primary osteosarcoma (OS) samples and was found to be decreased in tumor samples by means of deletions and epigenetic inactivation.	('osteosarcoma', 'Phenotype', 'HP:0002669', (39, 51))	('decreased', 'NegReg', (85, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('OS', 'Phenotype', 'HP:0002669', (53, 55))	('MiR-34', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('deletions', 'Var', (124, 133))	('epigenetic inactivation', 'Var', (138, 161))	('tumor', 'Disease', (98, 103))	('osteosarcoma', 'Disease', (39, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (39, 51))	('MiR-34', 'Gene', '407040', (0, 6))
455366	24281118	Furthermore, a 15-bp variable nucleotide tandem repeat located immediately 5' to the pre-mir-137 sequence has been shown to alter the processing and function of miR-137 in melanoma cell lines.	('miR-137', 'Gene', (161, 168))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('miR-137', 'Gene', '406928', (161, 168))	('processing', 'MPA', (134, 144))	('mir-137', 'Gene', (89, 96))	('function', 'MPA', (149, 157))	('variable nucleotide tandem repeat', 'Var', (21, 54))	('alter', 'Reg', (124, 129))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))	('mir-137', 'Gene', '406928', (89, 96))
455378	24281118	In addition, the loss of let-7a, which is a regulator of integrin beta-3 expression, was shown to be involved in the development and progression of malignant melanoma.	('nt', 'Chemical', 'MESH:D009711', (126, 128))	('let-7a', 'Gene', (25, 31))	('nt', 'Chemical', 'MESH:D009711', (58, 60))	('malignant melanoma', 'Disease', (148, 166))	('malignant melanoma', 'Phenotype', 'HP:0002861', (148, 166))	('nt', 'Chemical', 'MESH:D009711', (155, 157))	('involved', 'Reg', (101, 109))	('malignant melanoma', 'Disease', 'MESH:D008545', (148, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('loss', 'Var', (17, 21))
455400	24281118	analyzed tumor samples of 102 patients and identified that low miR-200a and miR-9 could predict patient survival.	('patient', 'Species', '9606', (30, 37))	('patient survival', 'CPA', (96, 112))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('miR-200a', 'Gene', (63, 71))	('nt', 'Chemical', 'MESH:D009711', (35, 37))	('patient', 'Species', '9606', (96, 103))	('miR-200a', 'Gene', '406983', (63, 71))	('predict', 'Reg', (88, 95))	('tumor', 'Disease', (9, 14))	('miR', 'Gene', (63, 66))	('low', 'Var', (59, 62))	('patients', 'Species', '9606', (30, 38))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (76, 79))	('nt', 'Chemical', 'MESH:D009711', (101, 103))	('miR', 'Gene', '220972', (76, 79))	('nt', 'Chemical', 'MESH:D009711', (46, 48))
455404	24281118	Among cancers of the digestive system, deregulated miRNAs of prognostic value have been identified in HCC and gastric cancer.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('HCC', 'Disease', (102, 105))	('deregulated', 'Var', (39, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('cancers', 'Disease', (6, 13))	('nt', 'Chemical', 'MESH:D009711', (91, 93))
455419	24281118	A survival analysis of the pooled cohorts demonstrated that high miR-21 expression was associated with a poor prognosis in stage II or stage III patients, indicating its potential prognostic value.	('patients', 'Species', '9606', (145, 153))	('nt', 'Chemical', 'MESH:D009711', (150, 152))	('nt', 'Chemical', 'MESH:D009711', (174, 176))	('high', 'Var', (60, 64))	('miR-21', 'Gene', (65, 71))	('expression', 'MPA', (72, 82))	('miR-21', 'Gene', '406991', (65, 71))
455420	24281118	Overexpressed miR-21 was also correlated with poor survival in early stage NSCLC and in breast cancer.	('miR-21', 'Gene', '406991', (14, 20))	('Overexpressed', 'Var', (0, 13))	('poor', 'NegReg', (46, 50))	('miR-21', 'Gene', (14, 20))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
455422	24281118	They found an association of high miR-21 expression with a poor prognosis of breast cancer patients.	('high', 'Var', (29, 33))	('miR-21', 'Gene', (34, 40))	('breast cancer', 'Disease', (77, 90))	('patients', 'Species', '9606', (91, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('miR-21', 'Gene', '406991', (34, 40))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
455425	24281118	Moreover, in another relatively small study, high miR-155 expression in primary tumors correlated with poor survival in early stage lung adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('expression', 'MPA', (58, 68))	('stage lung adenocarcinoma', 'Disease', (126, 151))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('stage lung adenocarcinoma', 'Disease', 'MESH:D000077192', (126, 151))	('high', 'Var', (45, 49))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('miR-155', 'Gene', '406947', (50, 57))	('poor', 'NegReg', (103, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (132, 151))	('miR-155', 'Gene', (50, 57))
455426	24281118	In gastric cancer, high expression of miR-214 was identified as a prognosticator of unfavorable outcomes in Japanese patients, independently of clinical covariates, including the clinical stage.	('nt', 'Chemical', 'MESH:D009711', (136, 138))	('nt', 'Chemical', 'MESH:D009711', (122, 124))	('high', 'Var', (19, 23))	('nt', 'Chemical', 'MESH:D009711', (53, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('miR-214', 'Gene', '406996', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancer', 'Disease', (3, 17))	('patients', 'Species', '9606', (117, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('miR-214', 'Gene', (38, 45))
455437	24281118	The notion that single nucleotide polymorphisms (SNPs) in protein-coding genes can affect the functions of encoded proteins and influence the individual susceptibility to cancers is well established.	('influence', 'Reg', (128, 137))	('affect', 'Reg', (83, 89))	('protein-coding genes', 'Gene', (58, 78))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('single nucleotide polymorphisms', 'Var', (16, 47))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('functions of encoded proteins', 'MPA', (94, 123))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
455438	24281118	Currently, SNPs in miRNA genes, and also in their network genes (miRNA-binding sites, and miRNA processing machinery) is being investigated for cancer risk associations.	('miR', 'Gene', '220972', (19, 22))	('nt', 'Chemical', 'MESH:D009711', (5, 7))	('miR', 'Gene', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('miR', 'Gene', '220972', (65, 68))	('cancer', 'Disease', (144, 150))	('miR', 'Gene', (65, 68))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('SNPs', 'Var', (11, 15))
455440	24281118	found that mir-196a2 rs11614913:T4C and mir-499 rs3746444:A4G variant genotypes were associated with significantly increased risks of breast cancer.	('nt', 'Chemical', 'MESH:D009711', (67, 69))	('mir-196a2', 'Gene', (11, 20))	('rs11614913:T4C', 'Var', (21, 35))	('breast cancer', 'Disease', (134, 147))	('rs3746444:A4G', 'Var', (48, 61))	('A4G', 'Mutation', 'c.4A>G', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('rs3746444', 'Mutation', 'rs3746444', (48, 57))	('T4C', 'Var', (32, 35))	('rs11614913', 'Mutation', 'rs11614913', (21, 31))	('nt', 'Chemical', 'MESH:D009711', (110, 112))	('T4C', 'Mutation', 'c.4T>C', (32, 35))	('mir-196a2', 'Gene', '406973', (11, 20))	('mir-499', 'Gene', '574501', (40, 47))	('mir-499', 'Gene', (40, 47))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
455441	24281118	identified a G to C polymorphism (rs2910164) within the sequence of the mir-146a precursor and demonstrated that a variant C allele led to increased levels of mature miR-146 in patients with breast and ovarian cancer and predisposed these patients to an earlier age of onset of familial breast and ovarian cancer.	('variant', 'Var', (115, 122))	('miR-1', 'Gene', (166, 171))	('mir-146a', 'Gene', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mir-146a', 'Gene', '406938', (72, 80))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (287, 312))	('nt', 'Chemical', 'MESH:D009711', (244, 246))	('rs2910164', 'Mutation', 'rs2910164', (34, 43))	('familial breast and ovarian cancer', 'Disease', 'MESH:D061325', (278, 312))	('nt', 'Chemical', 'MESH:D009711', (3, 5))	('levels', 'MPA', (149, 155))	('increased', 'PosReg', (139, 148))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (191, 216))	('predisposed', 'Reg', (221, 232))	('miR-1', 'Gene', '79187', (166, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (298, 312))	('nt', 'Chemical', 'MESH:D009711', (120, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (202, 216))	('nt', 'Chemical', 'MESH:D009711', (182, 184))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (239, 247))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('rs2910164', 'Var', (34, 43))
455442	24281118	It was also found that individuals with a common polymorphism in pre-mir-146a had decreased miR-146a expression and presented an increased risk of acquiring papillary thyroid carcinoma.	('mir-146a', 'Gene', (69, 77))	('miR-146a', 'Gene', (92, 100))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (157, 184))	('common polymorphism', 'Var', (42, 61))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (157, 184))	('mir-146a', 'Gene', '406938', (69, 77))	('nt', 'Chemical', 'MESH:D009711', (121, 123))	('papillary thyroid carcinoma', 'Disease', (157, 184))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (167, 184))	('miR-146a', 'Gene', '406938', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('expression', 'MPA', (101, 111))	('decreased', 'NegReg', (82, 91))
455636	23380347	We found individuals treated with amputation were at the greatest risk for functional impairments and activity limitations; amputations of the lower limb were associated with unemployment, unmarried status and low levels of physical activity; and amputations above the knee were associated with annual incomes <$20,000 per year.	('lower limb', 'Phenotype', 'HP:0006385', (143, 153))	('amputations', 'Disease', (124, 135))	('amputations', 'Var', (247, 258))	('activity limitations', 'CPA', (102, 122))	('associated', 'Reg', (159, 169))	('functional impairments', 'Disease', (75, 97))	('amputation', 'Var', (34, 44))	('functional impairments', 'Disease', 'MESH:D003072', (75, 97))
455647	23380347	It will be both interesting and important to evaluate the expansion cohort to determine if the therapeutic advances have improved outcome and decreased late sequelae or whether they have improved initial outcome but worsen the functional outcomes for a group of survivors with a high risk of complications.	('advances', 'Var', (107, 115))	('decreased late sequelae', 'Disease', (142, 165))	('improved', 'PosReg', (121, 129))	('functional outcomes', 'MPA', (227, 246))	('improved', 'PosReg', (187, 195))	('outcome', 'MPA', (130, 137))	('worsen', 'NegReg', (216, 222))	('decreased late sequelae', 'Disease', 'MESH:D020518', (142, 165))
455734	29971677	In contrast, in the LVSI-sarcoma group, ifosfamide (HR 0.48, 95% CI 0.20-1.11, p = 0.09) and anthracycline (HR 0.35, 95% CI 0.11-1.12, p = 0.08) were suggestive for improved PFS, although this did not reach statistical significance.	('improved', 'PosReg', (165, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('LVSI-sarcoma', 'Disease', (20, 32))	('anthracycline', 'Chemical', 'MESH:D018943', (93, 106))	('LVSI-sarcoma', 'Disease', 'MESH:D012509', (20, 32))	('anthracycline', 'Var', (93, 106))	('PFS', 'Disease', (174, 177))	('ifosfamide', 'Chemical', 'MESH:D007069', (40, 50))
455745	29971677	While intriguing to speculate that low-grade carcinoma is associated with increased LVSI-sarcoma, this association is most likely skewed by the impact of sarcoma dominance.	('carcinoma', 'Disease', 'MESH:D009369', (45, 54))	('low-grade', 'Var', (35, 44))	('carcinoma', 'Disease', (45, 54))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('LVSI-sarcoma', 'Disease', (84, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('LVSI-sarcoma', 'Disease', 'MESH:D012509', (84, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
455823	26315812	Endogenous peroxidase activity and non-specific binding were blocked with 3 % H2O2 and non-immune sera, respectively.	('H2O2', 'Chemical', 'MESH:D006861', (78, 82))	('H2O2', 'Var', (78, 82))	('blocked', 'NegReg', (61, 68))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('activity', 'MPA', (22, 30))	('non-specific binding', 'Interaction', (35, 55))
455855	26315812	The nuclear pleomorphism is generally notable in leiomyosarcoma which was not seen in this case.	('nuclear pleomorphism', 'Var', (4, 24))	('notable', 'Reg', (38, 45))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (49, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('leiomyosarcoma', 'Disease', (49, 63))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (49, 63))
455923	25940699	Systemic versus oligometastatic diasporas may be dependent on the types of mutations present in the cancer cells (quality of the diaspora migrants), the quality of the original tumor site (factors in the homeland that cause the population to migrate), and the quality of the new hostland (factors that allow immigrants to establish and flourish) (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('original tumor', 'Disease', (168, 182))	('original tumor', 'Disease', 'MESH:D009369', (168, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutations', 'Var', (75, 84))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
455927	25940699	Initiation genes afford a selective advantage to primary tumor cells to enter circulation.	('genes', 'Var', (11, 16))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))
455938	25940699	Several investigations have demonstrated the marked genetic and epigenetic heterogeneity present in metastatic cancer sites within the same patient.	('epigenetic', 'Var', (64, 74))	('patient', 'Species', '9606', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('metastatic', 'Disease', (100, 110))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
455942	25940699	found that variant metastatic cells pre-exist in a heterogeneous primary tumor as opposed to originating through adaption during metastasis from an otherwise homogenous primary tumor.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('variant', 'Var', (11, 18))
455962	25940699	Examples of pro-metastatic microRNAs include microRNA-10b (upregulated in primary breast tumors that had metastasized), microRNA-21 (correlated with advanced stage, incidence of metastases, and poor outcomes in breast and pancreatic tumors), and microRNA-373/520c (increased expression in breast metastases).	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('breast tumors', 'Phenotype', 'HP:0100013', (82, 95))	('metastases', 'Disease', 'MESH:D009362', (296, 306))	('breast metastases', 'Disease', (289, 306))	('metastases', 'Disease', (178, 188))	('microRNA-373/520c', 'Var', (246, 263))	('metastases', 'Disease', (296, 306))	('microRNA-21', 'Gene', (120, 131))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (222, 239))	('microRNA-21', 'Gene', '406991', (120, 131))	('upregulated', 'PosReg', (59, 70))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('increased', 'PosReg', (265, 274))	('breast metastases', 'Disease', 'MESH:D009362', (289, 306))	('microRNA-10b', 'Gene', '406903', (45, 57))	('microRNA-10b', 'Gene', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('breast tumors', 'Disease', 'MESH:D001943', (82, 95))	('breast and pancreatic tumors', 'Disease', 'MESH:D010190', (211, 239))	('breast tumors', 'Disease', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
455964	25940699	found microRNA-200c was associated with polymetastatic progression in a oligometastatic cell line, derived from patients treated with high-dose radiotherapy, tested in a xenograft model.	('associated with', 'Reg', (24, 39))	('polymetastatic progression', 'CPA', (40, 66))	('patients', 'Species', '9606', (112, 120))	('microRNA-200c', 'Var', (6, 19))
455967	25940699	MicroRNA-127-5p, microRNA-544a, and microRNA-655-3p were shown to limit, but not fully inhibit, metastasis in a model of breast cancer lung colonization.	('metastasis', 'CPA', (96, 106))	('MicroRNA-127-5p', 'Var', (0, 15))	('limit', 'NegReg', (66, 71))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('microRNA-544a', 'Var', (17, 30))	('microRNA-655-3p', 'Var', (36, 51))
456070	25940699	Cadeddu et al conducted a retrospective study (n = 38) and found that in men with prostate cancer and positive lymph nodes, treated with LND +/- RP, that the 5- and 10-yr prostate cancer specific survival was better in men who had undergone LND + RP.	('prostate cancer', 'Disease', 'MESH:D011471', (171, 186))	('men', 'Species', '9606', (219, 222))	('better', 'PosReg', (209, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (171, 186))	('men', 'Species', '9606', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('prostate cancer', 'Disease', (82, 97))	('prostate cancer', 'Disease', (171, 186))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('LND + RP', 'Var', (241, 249))	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))
456104	20543858	Recent Advances in the Molecular Pathogenesis of Ewing's Sarcoma Tumor development is a complex process resulting from interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context.	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (49, 64))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('Tumor', 'Phenotype', 'HP:0002664', (65, 70))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (49, 64))	('mutations', 'Var', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	("Ewing's Sarcoma", 'Disease', (49, 64))
456118	20543858	Approximately 85% of Ewing's sarcoma tumor specimens harbor the t(11;22)(q24;q12) chromosomal abnormality.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (21, 36))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (64, 81))	("Ewing's sarcoma tumor", 'Disease', (21, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	("Ewing's sarcoma tumor", 'Disease', 'MESH:C563168', (21, 42))	('t(11;22)(q24;q12', 'Var', (64, 80))
456137	20543858	These data suggest that the molecular pathways used in NIH3T3 mouse fibroblasts may be different from those used in bona fide Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (126, 141))	('NIH3T3', 'Var', (55, 61))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (126, 141))	('NIH3T3', 'CellLine', 'CVCL:0594', (55, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('mouse fibroblasts', 'CellLine', 'CVCL:0594', (62, 79))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (126, 141))
456165	20543858	In this latter study, however, EWS/FLI accelerated the tumor development typically seen with p53 deletion, and changed the predominant tumor type from osteosarcoma to an "undifferentiated" sarcoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))	('sarcoma', 'Disease', 'MESH:D012509', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('sarcoma', 'Disease', (189, 196))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('accelerated', 'PosReg', (39, 50))	('sarcoma', 'Disease', (156, 163))	('p53', 'Gene', '7157', (93, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('tumor', 'Disease', (135, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('FLI', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('osteosarcoma', 'Disease', (151, 163))	('p53', 'Gene', (93, 96))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('FLI', 'Gene', '2314', (35, 38))	('tumor', 'Disease', (55, 60))	('deletion', 'Var', (97, 105))
456167	20543858	Interestingly, it has been recently suggested that genomic differences in microsatellite content near critical EWS/FLI target genes may prohibit the development of a mouse model (see below).	('FLI', 'Gene', (115, 118))	('microsatellite content', 'MPA', (74, 96))	('genomic differences', 'Var', (51, 70))	('mouse', 'Species', '10090', (166, 171))	('development of a mouse model', 'CPA', (149, 177))	('FLI', 'Gene', '2314', (115, 118))	('prohibit', 'NegReg', (136, 144))
456178	20543858	The identification of microsatellites as cancer-relevant EWS/FLI binding sites suggests that such elements have important roles in the development of Ewing's sarcoma.	('FLI', 'Gene', '2314', (61, 64))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('FLI', 'Gene', (61, 64))	('roles', 'Reg', (122, 127))	('microsatellites', 'Var', (22, 37))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (150, 165))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	("Ewing's sarcoma", 'Disease', (150, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
456180	20543858	EWS/FLI binding to GGAA microsatellites was associated solely with gene activation.	('FLI', 'Gene', '2314', (4, 7))	('FLI', 'Gene', (4, 7))	('microsatellites', 'Var', (24, 39))	('gene', 'MPA', (67, 71))
456183	20543858	For example, EWS/FLI has been shown to be phosphorylated in Ewing's sarcoma cell lines, and phosphorylation modulates DNA binding and transcriptional activity in a heterologous system, suggesting that this modification may be relevant to the oncogenic function of EWS/FLI.	('transcriptional activity', 'CPA', (134, 158))	("Ewing's sarcoma", 'Disease', (60, 75))	('FLI', 'Gene', '2314', (17, 20))	('DNA', 'Protein', (118, 121))	('FLI', 'Gene', (17, 20))	('modulates', 'Reg', (108, 117))	('phosphorylation', 'Var', (92, 107))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (60, 75))	('FLI', 'Gene', '2314', (268, 271))	('FLI', 'Gene', (268, 271))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (60, 75))
456221	20543858	However, the fact that EWS/FLI has not been sufficient to transform any human cell type in vitro implies that there are parallel pathways and/or cooperating mutations working in conjunction with EWS/FLI.	('FLI', 'Gene', '2314', (27, 30))	('FLI', 'Gene', '2314', (199, 202))	('human', 'Species', '9606', (72, 77))	('FLI', 'Gene', (27, 30))	('mutations', 'Var', (157, 166))	('FLI', 'Gene', (199, 202))
456233	20543858	Knock-down of CD99 in Ewing's sarcoma cell lines resulted in decreased growth in tissue culture, diminished colony formation in soft agar assays, reduced cell motility, and smaller tumors with less metastasis in xenograft models.	('diminished', 'NegReg', (97, 107))	('cell motility', 'CPA', (154, 167))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('Knock-down', 'Var', (0, 10))	('reduced', 'NegReg', (146, 153))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (22, 37))	('colony formation in soft agar assays', 'CPA', (108, 144))	('CD99', 'Gene', (14, 18))	('smaller', 'NegReg', (173, 180))	("Ewing's sarcoma", 'Disease', (22, 37))	('decreased growth', 'Phenotype', 'HP:0001510', (61, 77))	('decreased', 'NegReg', (61, 70))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (22, 37))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('growth in tissue culture', 'CPA', (71, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
456234	20543858	Alterations in the RB and p53 pathways are likely cooperating mutations in Ewing's sarcoma.	('Alterations', 'Var', (0, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (75, 90))	('p53', 'Gene', (26, 29))	("Ewing's sarcoma", 'Disease', (75, 90))	('p53', 'Gene', '7157', (26, 29))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (75, 90))
456235	20543858	For example, expression of the cell cycle progression protein cyclin D1 (which phosphorylates and inactivates RB) is generally upregulated, while the cell cycle inhibitory proteins RB and p16INK4A are often mutated or deleted in Ewing's sarcoma.	('deleted', 'Var', (218, 225))	('cyclin D1', 'Gene', (62, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('expression', 'MPA', (13, 23))	('p16INK4A', 'Gene', (188, 196))	('upregulated', 'PosReg', (127, 138))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (229, 244))	('cell', 'CPA', (31, 35))	("Ewing's sarcoma", 'Disease', (229, 244))	('p16INK4A', 'Gene', '1029', (188, 196))	('cyclin D1', 'Gene', '595', (62, 71))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (229, 244))
456236	20543858	Mutations in this pathway also have prognostic value, with patients harboring p53 or p16INK4a/ARF deletions having a worse prognosis than those without.	('ARF', 'Disease', (94, 97))	('p16INK4a', 'Gene', (85, 93))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (78, 81))	('patients', 'Species', '9606', (59, 67))	('p16INK4a', 'Gene', '1029', (85, 93))	('ARF', 'Disease', 'MESH:D058186', (94, 97))	('p53', 'Gene', '7157', (78, 81))	('deletions', 'Var', (98, 107))
456237	20543858	The biologic basis for these observations may be related to oncogenic stress mediated by the EWS/FLI fusion, as expression of EWS/FLI in primary fibroblasts leads to growth arrest or cell death.	('leads to', 'Reg', (157, 165))	('FLI', 'Gene', '2314', (130, 133))	('expression', 'Var', (112, 122))	('death', 'Disease', 'MESH:D003643', (188, 193))	('oncogenic stress', 'Disease', 'MESH:D004194', (60, 76))	('death', 'Disease', (188, 193))	('growth arrest', 'Phenotype', 'HP:0001510', (166, 179))	('FLI', 'Gene', (130, 133))	('FLI', 'Gene', '2314', (97, 100))	('oncogenic stress', 'Disease', (60, 76))	('growth arrest', 'Disease', 'MESH:D006323', (166, 179))	('FLI', 'Gene', (97, 100))	('growth arrest', 'Disease', (166, 179))
456238	20543858	Inhibition of the p53 and/or RB pathways in these models bypasses these effects, suggesting that there may be selective pressure in vivo for cooperating mutations in these pathways.	('mutations', 'Var', (153, 162))	('p53', 'Gene', (18, 21))	('RB pathways', 'Pathway', (29, 40))	('p53', 'Gene', '7157', (18, 21))
456241	20543858	Deletion of 9p21.3, containing the CDKN2A gene that encodes p16INK4a/ARF, was deleted in 14-67% of Ewing's tumors and cell lines.	('ARF', 'Disease', (69, 72))	('p16INK4a', 'Gene', (60, 68))	('CDKN2A', 'Gene', '1029', (35, 41))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (99, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	("Ewing's tumors", 'Disease', (99, 113))	('p16INK4a', 'Gene', '1029', (60, 68))	("Ewing's tumors", 'Disease', 'MESH:C563168', (99, 113))	('ARF', 'Disease', 'MESH:D058186', (69, 72))	('CDKN2A', 'Gene', (35, 41))	('deleted', 'Var', (78, 85))	('Deletion', 'Var', (0, 8))
456244	20543858	Deletion of 6p has also been associated with worse outcome in diagnostic Ewing's sarcoma samples.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (73, 88))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (73, 88))	("Ewing's sarcoma", 'Disease', (73, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('Deletion', 'Var', (0, 8))
456253	20543858	Finally new technology will allow for the identification of mutations that cooperate with EWS/FLI and its targets to bypass the many mechanisms in place to prevent uncontrolled proliferation and other cancerous phenotypes.	('cancerous', 'Disease', (201, 210))	('uncontrolled', 'MPA', (164, 176))	('cancerous', 'Disease', 'MESH:D009369', (201, 210))	('FLI', 'Gene', '2314', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('FLI', 'Gene', (94, 97))	('mutations', 'Var', (60, 69))
456258	20216376	This patient had documented ALPS type Ia with a germline missense mutation in exon 9 of the TNFRSF6 gene (973 A>T, D244V) encoding Fas (CD95/Apo-1).	('TNFRSF6', 'Gene', (92, 99))	('patient', 'Species', '9606', (5, 12))	('Fas', 'Chemical', 'MESH:C038178', (131, 134))	('D244V', 'Var', (115, 120))	('ALPS type Ia', 'Disease', 'MESH:D056735', (28, 40))	('CD95', 'Gene', (136, 140))	('973 A>T', 'Var', (106, 113))	('CD95', 'Gene', '355', (136, 140))	('Apo-1', 'Gene', (141, 146))	('TNFRSF6', 'Gene', '355', (92, 99))	('973 A>T', 'Mutation', 'rs28929498', (106, 113))	('D244V', 'Mutation', 'rs28929498', (115, 120))	('ALPS type Ia', 'Disease', (28, 40))	('Apo-1', 'Gene', '355', (141, 146))
456266	20216376	Given the central role of defective Fas signaling in ALPS, histiocytes may be yet another lineage at risk for neoplastic transformation secondary to a block in apoptosis.	('ALPS', 'Disease', 'MESH:D056735', (53, 57))	('defective', 'Var', (26, 35))	('Fas', 'Chemical', 'MESH:C038178', (36, 39))	('Fas', 'Protein', (36, 39))	('block', 'NegReg', (151, 156))	('apoptosis', 'Protein', (160, 169))	('ALPS', 'Disease', (53, 57))
456267	20216376	Autoimmune lymphoproliferative syndrome (ALPS) represents a paradigm for defective lymphocyte apoptosis leading to a plethora of clinical manifestations including autoimmune phenomena, lymphadenopathy and splenomegaly, with an increased risk of lymphoid malignancies of B-cell lineage.	('splenomegaly', 'Disease', (205, 217))	('ALPS', 'Disease', (41, 45))	('lymphadenopathy', 'Disease', 'MESH:D008206', (185, 200))	('leading to', 'Reg', (104, 114))	('Autoimmune lymphoproliferative syndrome', 'Disease', (0, 39))	('lymphadenopathy', 'Disease', (185, 200))	('splenomegaly', 'Disease', 'MESH:D013163', (205, 217))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (185, 200))	('splenomegaly', 'Phenotype', 'HP:0001744', (205, 217))	('Autoimmune lymphoproliferative syndrome', 'Disease', 'MESH:D056735', (0, 39))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (245, 266))	('lymphoid malignancies', 'Disease', (245, 266))	('defective lymphocyte', 'Phenotype', 'HP:0001888', (73, 93))	('ALPS', 'Disease', 'MESH:D056735', (41, 45))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (245, 266))	('defective', 'Var', (73, 82))	('defective lymphocyte apoptosis', 'Phenotype', 'HP:0002731', (73, 103))	('autoimmune phenomena', 'Phenotype', 'HP:0002960', (163, 183))	('plethora', 'Phenotype', 'HP:0001050', (117, 125))	('lymphoproliferative syndrome', 'Phenotype', 'HP:0005523', (11, 39))
456278	20216376	Flow cytometry analysis performed in 1998 showed 2.1% (absolute 95/uL) alpha/beta+, CD4-/CD8- T cells (DNTs) (normal <1%) in keeping with the history of ALPS.	('alpha/beta+', 'Var', (71, 82))	('CD4', 'Gene', (84, 87))	('ALPS', 'Disease', (153, 157))	('ALPS', 'Disease', 'MESH:D056735', (153, 157))	('DNTs', 'Chemical', 'MESH:C023514', (103, 107))	('CD4', 'Gene', '920', (84, 87))
456323	20216376	In follicular lymphoma, the prototype of this model, juxtaposition of BCL2 besides the IGH enhancer region, leads to overexpression of BCL-2 and consequent lymphoma.	('IGH', 'Gene', (87, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (14, 22))	('BCL2', 'Gene', '596', (70, 74))	('follicular lymphoma', 'Disease', 'MESH:D008224', (3, 22))	('follicular lymphoma', 'Disease', (3, 22))	('lymphoma', 'Disease', (14, 22))	('BCL-2', 'Gene', '596', (135, 140))	('BCL2', 'Gene', (70, 74))	('overexpression', 'PosReg', (117, 131))	('lymphoma', 'Disease', (156, 164))	('lymphoma', 'Disease', 'MESH:D008223', (14, 22))	('BCL-2', 'Gene', (135, 140))	('juxtaposition', 'Var', (53, 66))	('lymphoma', 'Disease', 'MESH:D008223', (156, 164))	('IGH', 'Gene', '3492', (87, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))
456324	20216376	In MALT lymphomas, translocation of API2 (gene coding for inhibitor of apoptosis protein-2) on chromosome 11, adjacent to the MALT1 on chromosome 18 leads to activation of the canonical NF-kappaB pathway by targeting NEMO for ubiquitination, in addition to repression of the mitochondrial apoptosis pathway by repression of Smac.	('API2', 'Gene', (36, 40))	('MALT1', 'Gene', '10892', (126, 131))	('lymphoma', 'Phenotype', 'HP:0002665', (8, 16))	('API2', 'Gene', '330', (36, 40))	('Smac', 'Gene', (324, 328))	('NEMO', 'Gene', (217, 221))	('inhibitor of apoptosis protein-2', 'Gene', (58, 90))	('repression', 'NegReg', (257, 267))	('Smac', 'Gene', '56616', (324, 328))	('translocation', 'Var', (19, 32))	('MALT lymphomas', 'Disease', (3, 17))	('activation', 'PosReg', (158, 168))	('MALT1', 'Gene', (126, 131))	('repression', 'NegReg', (310, 320))	('targeting', 'Reg', (207, 216))	('inhibitor of apoptosis protein-2', 'Gene', '329', (58, 90))	('mitochondrial apoptosis pathway', 'Pathway', (275, 306))	('NEMO', 'Gene', '8517', (217, 221))	('MALT lymphomas', 'Disease', 'MESH:D018442', (3, 17))	('canonical NF-kappaB pathway', 'Pathway', (176, 203))	('lymphomas', 'Phenotype', 'HP:0002665', (8, 17))
456329	20216376	The additional germline defects in Fas-induced apoptosis seen in ALPS further contribute to the accumulation of histiocytes, and may lead to their malignant transformation.	('ALPS', 'Disease', (65, 69))	('accumulation', 'PosReg', (96, 108))	('lead to', 'Reg', (133, 140))	('Fas-induced', 'Protein', (35, 46))	('ALPS', 'Disease', 'MESH:D056735', (65, 69))	('histiocytes', 'CPA', (112, 123))	('accumulation of histiocytes', 'Phenotype', 'HP:0003651', (96, 123))	('malignant transformation', 'CPA', (147, 171))	('Fas', 'Chemical', 'MESH:C038178', (35, 38))	('defects', 'Var', (24, 31))
456423	30976505	Surgical options for the treatment of malignancies include total or subtotal claviculectomy with or without reconstruction (fibular autograft or allograft) as supported by the literature.	('malignancies', 'Disease', 'MESH:D009369', (38, 50))	('subtotal', 'Var', (68, 76))	('malignancies', 'Disease', (38, 50))
456434	27315524	More than 80 % of HGOSs exhibited a specific combination of single base substitutions, loss of heterozygosity (LOH), or large-scale genome instability signatures characteristic of breast cancer 1/2, and early onset (BRCA1/2)-deficient tumours.	('genome instability', 'CPA', (132, 150))	('exhibited', 'Reg', (24, 33))	('loss', 'Var', (87, 91))	('tumours', 'Phenotype', 'HP:0002664', (235, 242))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('BRCA1/2)-deficient tumours', 'Disease', 'OMIM:612555', (216, 242))	('breast cancer', 'Disease', (180, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))
456435	27315524	The findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.	('osteosarcoma', 'Disease', (89, 101))	('chromosomal instability', 'Var', (58, 81))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('result in', 'Reg', (116, 125))	('chromosomal instability', 'Phenotype', 'HP:0040012', (58, 81))	('drive', 'Reg', (52, 57))	('BRCA-like', 'Disease', (145, 154))
456438	27315524	They did, however, find a recurrent fusion gene involving PMP22 (which encodes peripheral myelin protein 22) and ELOVL5 (which encodes ELOVL fatty acid elongase 5).	('ELOVL fatty acid elongase 5', 'Gene', '60481', (135, 162))	('peripheral myelin protein 22', 'Gene', '5376', (79, 107))	('ELOVL5', 'Gene', (113, 119))	('ELOVL5', 'Gene', '60481', (113, 119))	('PMP22', 'Gene', '5376', (58, 63))	('ELOVL fatty acid elongase 5', 'Gene', (135, 162))	('PMP22', 'Gene', (58, 63))	('fusion', 'Var', (36, 42))	('peripheral myelin protein 22', 'Gene', (79, 107))
456439	27315524	Furthermore, all cell lines had completely abrogated the p53 response, largely caused by copy number-neutral fusions and aberrations of TP53.	('rat', 'Species', '10116', (125, 128))	('aberrations', 'Var', (121, 132))	('caused', 'Reg', (79, 85))	('abrogated', 'NegReg', (43, 52))	('p53', 'Gene', (57, 60))	('copy number-neutral fusions', 'Var', (89, 116))	('TP53', 'Gene', (136, 140))	('p53', 'Gene', '7157', (57, 60))
456442	27315524	Modulation of Aven-ATM-CHEK1 may also provide a novel strategy towards improving HGOS therapy.	('Modulation', 'Var', (0, 10))	('Aven', 'Gene', '57099', (14, 18))	('Aven', 'Gene', (14, 18))	('rat', 'Species', '10116', (56, 59))	('ATM-CHEK1', 'Gene', '472;1111', (19, 28))	('HGOS therapy', 'Disease', (81, 93))	('ATM-CHEK1', 'Gene', (19, 28))
456466	27315524	There is an association between mutational load and tumour neo-antigens, apparently important to the effectiveness of a new generation of immunotherapies (e.g., immune checkpoint inhibitors).	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('mutational load', 'Var', (32, 47))	('tumour', 'Disease', (52, 58))	('rat', 'Species', '10116', (128, 131))
456469	27315524	Interruption of the PD-L1/PD-1 pathway therefore represents an attractive therapeutic strategy to reinvigorate tumour-specific T cell immunity.	('PD-1', 'Gene', (26, 30))	('PD-1', 'Gene', '5133', (26, 30))	('Interruption', 'Var', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('rat', 'Species', '10116', (88, 91))	('PD-L1', 'Gene', (20, 25))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('rat', 'Species', '10116', (106, 109))	('tumour', 'Disease', (111, 117))	('PD-L1', 'Gene', '29126', (20, 25))
456472	27315524	These levels of expression, together with the poorer outcome of sarcoma patients with PD-L1 positivity, justify further exploration of the role of PD-L1 antibody in the treatment of sarcomas.	('PD-L1', 'Gene', '29126', (147, 152))	('rat', 'Species', '10116', (125, 128))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('PD-L1', 'Gene', '29126', (86, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('sarcomas', 'Disease', (182, 190))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Disease', 'MESH:D012509', (182, 189))	('sarcoma', 'Disease', (64, 71))	('PD-L1', 'Gene', (147, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('PD-L1', 'Gene', (86, 91))	('positivity', 'Var', (92, 102))	('sarcoma', 'Disease', (182, 189))	('patients', 'Species', '9606', (72, 80))
456486	27315524	A novel mouse model for peripheral CS has emphasized that, in addition to biallelic inactivation of exostosin glycosyltransferase (EXT1 or -2) in chondrocytes, additional alterations affecting either the TP53 or cyclin-dependent kinase inhibitor 2A (CDKN2A) cause malignant transformation towards secondary peripheral chondrosarcoma.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (318, 332))	('EXT1', 'Gene', (131, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (325, 332))	('CDKN2A', 'Gene', '12578', (250, 256))	('malignant transformation', 'CPA', (264, 288))	('CS', 'Phenotype', 'HP:0006765', (35, 37))	('CDKN2A', 'Gene', (250, 256))	('cause', 'Reg', (258, 263))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '12578', (212, 248))	('chondrosarcoma', 'Disease', (318, 332))	('chondrosarcoma', 'Disease', 'MESH:D002813', (318, 332))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (212, 248))	('rat', 'Species', '10116', (175, 178))	('mouse', 'Species', '10090', (8, 13))	('TP53', 'Gene', (204, 208))	('alterations', 'Var', (171, 182))	('EXT1', 'Gene', '14042', (131, 135))
456487	27315524	It was shown that mutations in isocitrate dehydrogenase (IDH1 or -2) are an early event for central tumours: the oncometabolite D-2-hydroxyglutarate induced by the mutation inhibits osteogenic differentiation and promotes chondrogenic differentiation, causing enchondromas of bone.	('enchondromas', 'Phenotype', 'HP:0030038', (260, 272))	('central tumours', 'Disease', 'MESH:D009369', (92, 107))	('chondrogenic differentiation', 'CPA', (222, 250))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (128, 148))	('enchondromas', 'Disease', 'MESH:D002812', (260, 272))	('rat', 'Species', '10116', (37, 40))	('promotes', 'PosReg', (213, 221))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('IDH1', 'Gene', (57, 61))	('osteogenic differentiation', 'CPA', (182, 208))	('mutation', 'Var', (164, 172))	('causing', 'Reg', (252, 259))	('central tumours', 'Disease', (92, 107))	('IDH1', 'Gene', '3417', (57, 61))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('enchondromas', 'Disease', (260, 272))	('inhibits', 'NegReg', (173, 181))	('rat', 'Species', '10116', (144, 147))
456489	27315524	Other additional genetic alterations are instead involved, affecting amongst others the TP53 and retinoblastoma (Rb) pathways, as well as collagen, type II, alpha 1 (COL2A1), neuroblastoma RAS viral oncogene homolog (NRAS), and other signalling pathways (e.g., hedgehog, mTOR, Bcl-2, survivin).	('COL2A1', 'Gene', '1280', (166, 172))	('hedgehog', 'Gene', (261, 269))	('genetic alterations', 'Var', (17, 36))	('Bcl-2', 'Gene', '596', (277, 282))	('mTOR', 'Gene', (271, 275))	('NRAS', 'Gene', (217, 221))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (175, 198))	('neuroblastoma', 'Phenotype', 'HP:0003006', (175, 188))	('affecting', 'Reg', (59, 68))	('type II', 'Pathway', (148, 155))	('survivin', 'Gene', (284, 292))	('retinoblastoma', 'Gene', (97, 111))	('mTOR', 'Gene', '2475', (271, 275))	('COL2A1', 'Gene', (166, 172))	('alterations', 'Var', (25, 36))	('Rb', 'Phenotype', 'HP:0009919', (113, 115))	('rat', 'Species', '10116', (29, 32))	('neuroblastoma RAS viral', 'Disease', (175, 198))	('NRAS', 'Gene', '4893', (217, 221))	('collagen', 'Gene', (138, 146))	('retinoblastoma', 'Gene', '5925', (97, 111))	('Bcl-2', 'Gene', (277, 282))	('retinoblastoma', 'Phenotype', 'HP:0009919', (97, 111))
456491	27315524	The diagnosis is supported by identification of a translocation involving the transcription factor HEY1 and the nuclear receptor coactivator 2 (NCOA2).	('NCOA2', 'Gene', '10499', (144, 149))	('NCOA2', 'Gene', (144, 149))	('HEY1', 'Gene', (99, 103))	('translocation', 'Var', (50, 63))	('nuclear receptor coactivator 2', 'Gene', '10499', (112, 142))	('nuclear receptor coactivator 2', 'Gene', (112, 142))	('HEY1', 'Gene', '23462', (99, 103))
456503	27315524	David Herrero-Martin, Barcelona, provided data on non-coding RNAs in EwS.	('EwS', 'Phenotype', 'HP:0012254', (69, 72))	('EwS', 'Gene', (69, 72))	('EwS', 'Gene', '2130', (69, 72))	('non-coding', 'Var', (50, 60))
456513	27315524	proposed to consider EwS as tumours carrying only fusions involving FET family proteins (EWSR1 or FUS) with ETS transcription factor genes (ERG and PEA3 types).	('EwS', 'Phenotype', 'HP:0012254', (21, 24))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('PEA3', 'Gene', '2118', (148, 152))	('ERG', 'Gene', (140, 143))	('EwS', 'Gene', '2130', (21, 24))	('EwS', 'Gene', (21, 24))	('EWSR1', 'Gene', '2130', (89, 94))	('fusions', 'Var', (50, 57))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('PEA3', 'Gene', (148, 152))	('FUS', 'Gene', (98, 101))	('FUS', 'Gene', '2521', (98, 101))	('EWSR1', 'Gene', (89, 94))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))	('ERG', 'Gene', '2078', (140, 143))
456516	27315524	Gunther Richter, Munich, reported that next-generation sequencing (NGS) data confirm EWS/ETS translocations as the crucial driver event of EwS tumourigenesis.	('translocations', 'Var', (93, 107))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('EwS', 'Phenotype', 'HP:0012254', (139, 142))	('EwS tumour', 'Disease', 'MESH:C563168', (139, 149))	('EWS', 'Gene', (85, 88))	('EWS', 'Gene', '2130', (85, 88))	('EwS tumour', 'Disease', (139, 149))	('rat', 'Species', '10116', (48, 51))
456519	27315524	Moreover, JQ1 inhibits proliferation, induces apoptosis and reduces EwS tumour growth.	('apoptosis', 'CPA', (46, 55))	('tumour growth', 'Disease', 'MESH:D006130', (72, 85))	('inhibits', 'NegReg', (14, 22))	('EwS tumour', 'Disease', (68, 78))	('EwS tumour', 'Disease', 'MESH:C563168', (68, 78))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour growth', 'Disease', (72, 85))	('induces', 'Reg', (38, 45))	('rat', 'Species', '10116', (30, 33))	('JQ1', 'Var', (10, 13))	('EwS', 'Phenotype', 'HP:0012254', (68, 71))	('proliferation', 'CPA', (23, 36))	('reduces', 'NegReg', (60, 67))
456520	27315524	When combined with phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor BEZ235, inhibition of BRD3/4 may offer new opportunities for combination therapy in EwS.	('inhibition', 'Var', (91, 101))	('BRD3', 'Gene', '8019', (105, 109))	('EwS', 'Gene', (167, 170))	('PI3', 'Gene', (67, 70))	('BRD3', 'Gene', (105, 109))	('phosphatidylinositol-4', 'Chemical', '-', (19, 41))	('BEZ235', 'Chemical', 'MESH:C531198', (83, 89))	('EwS', 'Phenotype', 'HP:0012254', (167, 170))	('EwS', 'Gene', '2130', (167, 170))	('PI3', 'Gene', '5266', (67, 70))
456527	27315524	Co-targeting these RTKs was synergistic or at least additive in 6/6 EwS cell lines in vitro, with the most pronounced effects in IGF-1R-targeted combinations, indicating that IGF-1R deserves further investigation, particularly in combinations.	('RTK', 'Gene', '5979', (19, 22))	('EwS', 'Gene', (68, 71))	('IGF-1R', 'Gene', '3480', (175, 181))	('IGF-1R', 'Gene', (129, 135))	('IGF-1R', 'Gene', '3480', (129, 135))	('RTK', 'Gene', (19, 22))	('IGF-1R', 'Gene', (175, 181))	('combinations', 'Var', (145, 157))	('EwS', 'Gene', '2130', (68, 71))	('EwS', 'Phenotype', 'HP:0012254', (68, 71))
456540	27315524	Analysis of ctDNA copy numbers is suited for integration in preclinical studies and Phase I/II trials as an additional response marker.	('rat', 'Species', '10116', (50, 53))	('copy numbers', 'Var', (18, 30))	('ctDNA', 'Gene', (12, 17))
456647	22833265	Aberrant expression of miRNAs has been reported in many types of cancers and can function as tumor suppressor genes or oncogenes.	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('expression', 'MPA', (9, 19))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('reported', 'Reg', (39, 47))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
456657	22833265	Two doxorubicin resistant neuroblastoma cancer cell lines had amplification of the chromosome 7q21 region and overexpression of FZD1 and MDR1 (multidrug resistant gene) was found in these doxorubicin resistant neuroblastoma cell lines.	('neuroblastoma', 'Disease', (210, 223))	('FZD1', 'Gene', (128, 132))	('neuroblastoma cancer', 'Disease', (26, 46))	('MDR1', 'Gene', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('neuroblastoma', 'Phenotype', 'HP:0003006', (210, 223))	('neuroblastoma cancer', 'Disease', 'MESH:D009447', (26, 46))	('neuroblastoma', 'Disease', 'MESH:D009447', (26, 39))	('doxorubicin', 'Chemical', 'MESH:D004317', (188, 199))	('MDR1', 'Gene', '5243', (137, 141))	('doxorubicin', 'Chemical', 'MESH:D004317', (4, 15))	('neuroblastoma', 'Disease', (26, 39))	('neuroblastoma', 'Phenotype', 'HP:0003006', (26, 39))	('amplification', 'Var', (62, 75))	('neuroblastoma', 'Disease', 'MESH:D009447', (210, 223))	('FZD1', 'Gene', '8321', (128, 132))	('overexpression', 'PosReg', (110, 124))
456658	22833265	In this study, FZD1 silencing dramatically reduced MDR1 expression.	('FZD1', 'Gene', '8321', (15, 19))	('FZD1', 'Gene', (15, 19))	('MDR1', 'Gene', (51, 55))	('expression', 'MPA', (56, 66))	('MDR1', 'Gene', '5243', (51, 55))	('reduced', 'NegReg', (43, 50))	('silencing', 'Var', (20, 29))
456685	22833265	Cell invasion/migration and lung metastasis were inhibited in miR-31 transfected MDA-MB-231 cells compared to controls.	('miR-31', 'Gene', (62, 68))	('transfected', 'Var', (69, 80))	('Cell invasion/migration', 'CPA', (0, 23))	('miR-31', 'Gene', '407035', (62, 68))	('rat', 'Species', '10116', (17, 20))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (81, 91))	('lung metastasis', 'CPA', (28, 43))	('inhibited', 'NegReg', (49, 58))
456694	22833265	High methylation at the FZD4 loci was associated with progression-free survival in epithelial ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('associated with', 'Reg', (38, 53))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (83, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('FZD4', 'Gene', '8322', (24, 28))	('High methylation', 'Var', (0, 16))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (83, 108))	('FZD4', 'Gene', (24, 28))	('epithelial ovarian cancer', 'Disease', (83, 108))
456695	22833265	Though no studies have reported about FZD4 expression in cancer and normal tissues, methylation at the FZD4 locus may be a good cancer marker.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('FZD4', 'Gene', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('methylation', 'Var', (84, 95))	('cancer', 'Disease', (57, 63))	('FZD4', 'Gene', '8322', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('FZD4', 'Gene', (38, 42))	('FZD4', 'Gene', '8322', (103, 107))	('cancer', 'Disease', (128, 134))
456698	22833265	Over-expression of miR-493 decreased T24 and J82 cell migration and motility and FZD4 protein levels and luciferase activity in miR-493 transfected T24 cells was decreased compared to controls, indicating that FZD4 is a target gene of miR-493.	('miR-493', 'Gene', (235, 242))	('miR-493', 'Gene', '574450', (128, 135))	('luciferase', 'Enzyme', (105, 115))	('decreased', 'NegReg', (27, 36))	('miR-493', 'Gene', (19, 26))	('decreased', 'NegReg', (162, 171))	('J82', 'CellLine', 'CVCL:0359', (45, 48))	('FZD4', 'Gene', '8322', (81, 85))	('FZD4', 'Gene', '8322', (210, 214))	('miR-493', 'Gene', '574450', (235, 242))	('rat', 'Species', '10116', (57, 60))	('miR-493', 'Gene', '574450', (19, 26))	('transfected', 'Var', (136, 147))	('FZD4', 'Gene', (81, 85))	('activity', 'MPA', (116, 124))	('FZD4', 'Gene', (210, 214))	('motility', 'CPA', (68, 76))	('miR-493', 'Gene', (128, 135))
456699	22833265	Also knockdown of FZD4 decreased cell migration and motility in T24 and J82 cells.	('knockdown', 'Var', (5, 14))	('J82', 'CellLine', 'CVCL:0359', (72, 75))	('rat', 'Species', '10116', (41, 44))	('FZD4', 'Gene', '8322', (18, 22))	('decreased', 'NegReg', (23, 32))	('FZD4', 'Gene', (18, 22))
456708	22833265	Also in another report, high FZD6 expression was significantly correlated with poor survival in human neuroblastoma.	('expression', 'MPA', (34, 44))	('human', 'Species', '9606', (96, 101))	('neuroblastoma', 'Disease', 'MESH:D009447', (102, 115))	('FZD6', 'Gene', (29, 33))	('neuroblastoma', 'Disease', (102, 115))	('high', 'Var', (24, 28))	('neuroblastoma', 'Phenotype', 'HP:0003006', (102, 115))	('poor', 'NegReg', (79, 83))
456719	22833265	Additionally high FZD7 expression correlated with a significantly shorter survival time in colon and gastric cancer.	('shorter', 'NegReg', (66, 73))	('high', 'Var', (13, 17))	('colon and gastric cancer', 'Disease', 'MESH:D013274', (91, 115))	('expression', 'MPA', (23, 33))	('FZD7', 'Gene', (18, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('survival time', 'CPA', (74, 87))
456723	22833265	Knockdown of FZD7 decreased cell growth in colon cancer cell lines with APC or CTNNB1 gene mutations, caused an increase in SNAI2 mRNA, a decrease in E-cadherin mRNA and inhibited MET (mesenchymal-epithelial transition) in non-adherent colorectal cancer cell carcinoid cell lines LIM1863-Mph..	('cell growth', 'CPA', (28, 39))	('decreased', 'NegReg', (18, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (43, 55))	('mRNA', 'MPA', (130, 134))	('APC', 'Phenotype', 'HP:0005227', (72, 75))	('APC', 'Disease', 'MESH:D011125', (72, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (236, 253))	('inhibited', 'NegReg', (170, 179))	('APC', 'Disease', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colon cancer', 'Disease', 'MESH:D015179', (43, 55))	('CTNNB1', 'Gene', (79, 85))	('decrease', 'NegReg', (138, 146))	('MET', 'MPA', (180, 183))	('CTNNB1', 'Gene', '1499', (79, 85))	('SNAI2', 'Gene', (124, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (236, 253))	('colon cancer', 'Disease', (43, 55))	('colorectal cancer', 'Disease', (236, 253))	('E-cadherin', 'Gene', (150, 160))	('E-cadherin', 'Gene', '999', (150, 160))	('increase', 'PosReg', (112, 120))	('mutations', 'Var', (91, 100))	('carcinoid', 'Phenotype', 'HP:0100570', (259, 268))	('SNAI2', 'Gene', '6591', (124, 129))
456728	22833265	Patient groups with high FZD7 and high Wnt11 were significantly associated with shorter disease free survival compared to low FZD7 and low Wnt11 groups.	('high FZD7', 'Var', (20, 29))	('Wnt11', 'Gene', (139, 144))	('disease free survival', 'CPA', (88, 109))	('Wnt11', 'Gene', (39, 44))	('shorter', 'NegReg', (80, 87))	('Wnt11', 'Gene', '7481', (139, 144))	('Wnt11', 'Gene', '7481', (39, 44))	('Patient', 'Species', '9606', (0, 7))
456729	22833265	For example, compounds such as FJ9 and small interfering peptides (RHPDs) suppressed cell growth and activity of the Wnt/beta-catenin signaling pathway by inhibiting interaction between FZD7 and Dishevelled (DVL) in cancer cell lines.	('DVL', 'Gene', (208, 211))	('Wnt/beta-catenin signaling pathway', 'Pathway', (117, 151))	('suppressed', 'NegReg', (74, 84))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('activity', 'MPA', (101, 109))	('cell growth', 'CPA', (85, 96))	('interaction', 'Interaction', (166, 177))	('Dishevelled', 'Gene', '8215', (195, 206))	('inhibiting', 'NegReg', (155, 165))	('Dishevelled', 'Gene', (195, 206))	('FJ9', 'Var', (31, 34))	('FZD7', 'Gene', (186, 190))	('cancer', 'Disease', (216, 222))	('DVL', 'Gene', '8215', (208, 211))
456733	22833265	Primary tumor growth and lung metastasis were inhibited in miR-23b transfected colon cancer cells (HCT-) compared to controls.	('colon cancer', 'Disease', (79, 91))	('Primary tumor', 'Disease', (0, 13))	('miR-23b', 'Gene', '407011', (59, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('transfected', 'Var', (67, 78))	('lung metastasis', 'CPA', (25, 40))	('miR-23b', 'Gene', (59, 66))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('Primary tumor', 'Disease', 'MESH:D009369', (0, 13))	('inhibited', 'NegReg', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
456735	22833265	Also knockdown of FZD7 decreased cell invasion in HCT-116 cells.	('knockdown', 'Var', (5, 14))	('HCT-116', 'CellLine', 'CVCL:0291', (50, 57))	('FZD7', 'Gene', (18, 22))	('cell invasion in HCT-116 cells', 'CPA', (33, 63))	('decreased', 'NegReg', (23, 32))
456740	22833265	Deletion of a part of chromosome band 7q11.23 was reported in Williams syndrome and human FZD9, previously reported as FZD3, in the deletion region was cloned by Wang et al.. FZD9 was reported to be expressed in normal brain, testis, eye, skeletal muscle and kidney and FZD9 expression was up-regulated in glioblastoma and astrocytoma.	('Williams syndrome', 'Disease', (62, 79))	('Williams syndrome', 'Disease', 'MESH:D018980', (62, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (306, 318))	('FZD9', 'Gene', (90, 94))	('astrocytoma', 'Disease', 'MESH:D001254', (323, 334))	('up-regulated', 'PosReg', (290, 302))	('FZD9', 'Gene', (270, 274))	('astrocytoma', 'Disease', (323, 334))	('glioblastoma', 'Disease', (306, 318))	('FZD9', 'Gene', (175, 179))	('Deletion', 'Var', (0, 8))	('FZD3', 'Gene', '7976', (119, 123))	('glioblastoma', 'Phenotype', 'HP:0012174', (306, 318))	('FZD3', 'Gene', (119, 123))	('human', 'Species', '9606', (84, 89))	('FZD9', 'Gene', '8326', (90, 94))	('FZD9', 'Gene', '8326', (270, 274))	('FZD9', 'Gene', '8326', (175, 179))	('expression', 'MPA', (275, 285))	('astrocytoma', 'Phenotype', 'HP:0009592', (323, 334))
456742	22833265	The FZD9 promoter is methylated in glioblastoma multiforme, myelodysplastic syndromes and acute myeloid leukemia and hypermethylation was associated with poor survival in these diseases.	('FZD9', 'Gene', (4, 8))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (35, 58))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (90, 112))	('myelodysplastic syndromes', 'Disease', (60, 85))	('hypermethylation', 'Var', (117, 133))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (60, 85))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (60, 85))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (90, 112))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (96, 112))	('FZD9', 'Gene', '8326', (4, 8))	('glioblastoma multiforme', 'Disease', (35, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('acute myeloid leukemia', 'Disease', (90, 112))
456752	22833265	Based on the recent literature, some groups have documented the effectiveness of anti-FZD10 antibody therapy to synovial sarcomas (SS) since FZD10 increases cell growth in synovial sarcoma.	('synovial sarcomas', 'Phenotype', 'HP:0012570', (112, 129))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (172, 188))	('increases', 'PosReg', (147, 156))	('synovial sarcoma', 'Disease', 'MESH:D013584', (172, 188))	('FZD10', 'Var', (141, 146))	('synovial sarcomas', 'Disease', (112, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('synovial sarcomas', 'Disease', 'MESH:D013584', (112, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('SS', 'Phenotype', 'HP:0100242', (131, 133))	('cell growth', 'CPA', (157, 168))	('synovial sarcoma', 'Disease', (172, 188))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (112, 128))	('synovial sarcoma', 'Disease', 'MESH:D013584', (112, 128))	('rat', 'Species', '10116', (24, 27))
456762	22833265	ROR2 knockdown blocks the Wnt/JNK pathway and inhibits cell metastasis in several cancer cells (osteosarcoma, melanoma, kidney and prostate cancer) (Figure1B and 1D).	('blocks', 'NegReg', (15, 21))	('osteosarcoma', 'Phenotype', 'HP:0002669', (96, 108))	('knockdown', 'Var', (5, 14))	('cancer', 'Disease', (82, 88))	('inhibits', 'NegReg', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('Wnt/JNK pathway', 'Pathway', (26, 41))	('melanoma', 'Disease', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('osteosarcoma', 'Disease', (96, 108))	('cell metastasis in', 'CPA', (55, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (96, 108))	('cancer', 'Disease', (140, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('kidney and prostate cancer', 'Disease', 'MESH:D011471', (120, 146))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('ROR2', 'Gene', (0, 4))	('ROR2', 'Gene', '4920', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))
456767	22833265	In the Wnt/beta-catenin signaling pathways in cancer cells, the function of APC gene, a crucial tumor suppressor, is decreased or lost because of gene mutation.	('lost', 'NegReg', (130, 134))	('crucial tumor', 'Disease', (88, 101))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Disease', (46, 52))	('decreased', 'NegReg', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('APC', 'Phenotype', 'HP:0005227', (76, 79))	('APC', 'Disease', 'MESH:D011125', (76, 79))	('gene mutation', 'Var', (146, 159))	('APC', 'Disease', (76, 79))	('function', 'MPA', (64, 72))	('crucial tumor', 'Disease', 'MESH:D009369', (88, 101))
456768	22833265	Down regulation of the Wnt antagonists and mutation of APC/beta-catenin genes is often paralleled with up-regulation of FZDs (Table 1), but their direct relationships are not currently understood.	('up-regulation', 'PosReg', (103, 116))	('mutation', 'Var', (43, 51))	('APC', 'Phenotype', 'HP:0005227', (55, 58))	('Down', 'NegReg', (0, 4))	('APC', 'Disease', 'MESH:D011125', (55, 58))	('APC', 'Disease', (55, 58))
456774	22833265	These specific chromosome deletions may cause over-expression of these FZDs thorough loss of a particular miRNA (Figure 2).	('cause', 'Reg', (40, 45))	('deletions', 'Var', (26, 35))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (106, 109))	('over-expression', 'MPA', (46, 61))	('loss', 'NegReg', (85, 89))
456779	22833265	As a therapeutic approach, some groups have used anti-human FZD10 antibody for cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('FZD10', 'Gene', (60, 65))	('anti-human', 'Var', (49, 59))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('human', 'Species', '9606', (54, 59))
456826	22074680	Our patient had received a full course of radiation therapy in her pelvic area and, hypothetically, the bladder sarcoma developed from radiation-induced genetic alterations.	('bladder sarcoma', 'Disease', (104, 119))	('genetic alterations', 'Var', (153, 172))	('patient', 'Species', '9606', (4, 11))	('developed from', 'Reg', (120, 134))	('bladder sarcoma', 'Disease', 'MESH:D001745', (104, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
456871	32499311	In amenorrheic women <40 years not on hormonal treatments, serum estadriol <17 pg/mL and FSH >30 IU/L were considered indicative of POI.	('women', 'Species', '9606', (15, 20))	('>30', 'Var', (93, 96))	('POI', 'Disease', (132, 135))	('estadriol', 'Chemical', '-', (65, 74))	('serum estadriol', 'MPA', (59, 74))	('FSH', 'MPA', (89, 92))
456872	32499311	Leydig cell failure was diagnosed in male survivors on sex-hormone replacement therapy or serum total testosterone <250 ng/dL and LH >9.85 IU/L if untreated.	('Leydig cell failure', 'Disease', 'MESH:D007984', (0, 19))	('Leydig cell failure', 'Disease', (0, 19))	('LH >9.85', 'Var', (130, 138))	('testosterone', 'Chemical', 'MESH:D013739', (102, 114))
456935	32499311	Exposure to cisplatin has also been associated with reduced fertility and hypogonadism in males.	('cisplatin', 'Var', (12, 21))	('reduced', 'NegReg', (52, 59))	('hypogonadism', 'Phenotype', 'HP:0000135', (74, 86))	('fertility', 'CPA', (60, 69))	('reduced fertility', 'Phenotype', 'HP:0000144', (52, 69))	('hypogonadism', 'Disease', (74, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (12, 21))	('hypogonadism', 'Disease', 'MESH:D007006', (74, 86))	('hypogonadism in males', 'Phenotype', 'HP:0000026', (74, 95))
456943	32499311	Inefficient movement is a deterrent to regular participation in physical activity and problematic in a population already at risk for cardiovascular conditions.	('cardiovascular condition', 'Phenotype', 'HP:0001626', (134, 158))	('cardiovascular conditions', 'Disease', 'MESH:D002318', (134, 159))	('cardiovascular conditions', 'Disease', (134, 159))	('Inefficient', 'Var', (0, 11))
457001	31277591	The nomogram showed that metastasis, which had the largest absolute values, was the strongest contributor to the risk of prognosis, followed by age > 30 years old, large tumor (> 100 mm), nonsurgical treatment, local and unknown EOD, being black, intermediate tumor size (> 50 and <= 100 mm), and being male.	('tumor', 'Disease', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor', 'Disease', (170, 175))	('> 100 mm', 'Var', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('metastasis', 'Disease', (25, 35))
457005	31277591	Similarly, the IDI values for 3, 5, and 10 years of follow-up examinations were 0.026, 0.028, and 0.029 in the training cohort and 0.021, 0.023, and 0.025 in the validation cohort, respectively.	('0.021', 'Var', (131, 136))	('0.029', 'Var', (98, 103))	('IDI', 'Chemical', '-', (15, 18))
457085	30687558	Genetic testing to confirm the expression of the chimeric gene ASPL-TFE3 caused by chromosomal translocation der(17)t(X;17)(p11:q25) is a useful indicator for a definitive diagnosis of ASPS.	('der(17)t(X;17)(p11:q25', 'Var', (109, 131))	('TFE3', 'Gene', (68, 72))	('der(17)t(X;17)(p11:q25)', 'STRUCTURAL_ABNORMALITY', 'None', (109, 132))	('ASPL', 'Gene', '79058', (63, 67))	('ASPS', 'Disease', (185, 189))	('ASPL', 'Gene', (63, 67))	('ASPS', 'Phenotype', 'HP:0012218', (185, 189))	('caused by', 'Reg', (73, 82))	('TFE3', 'Gene', '7030', (68, 72))	('ASPS', 'Disease', 'MESH:D018234', (185, 189))
457110	21541215	Immunostains of the atypical lymphoid cells were strongly KSHV+ (Figure 2), MUM1/IRF4+, CD79a rare+, CD20-.	('KSHV+', 'Var', (58, 63))	('KSHV', 'Species', '37296', (58, 62))	('CD79a rare+', 'Var', (88, 99))	('CD20', 'Gene', '54474', (101, 105))	('CD20', 'Gene', (101, 105))
457168	20454648	(Figures 1 and 2) Lymphoid markers, epithelial markers, and neuroendocrine markers were all negative (CD20, CD3, CD23, CD5, CD10, CD68, CD45 RO, Kappa, Lambda, cytokeratin, EMA, synaptophysin, and chromogranin).	('EMA', 'Gene', '4582', (173, 176))	('CD3', 'Var', (108, 111))	('negative', 'NegReg', (92, 100))	('CD20', 'Gene', (102, 106))	('CD10', 'Gene', (124, 128))	('CD20', 'Gene', '54474', (102, 106))	('CD5', 'Gene', '921', (119, 122))	('CD45', 'Gene', '5788', (136, 140))	('CD10', 'Gene', '4311', (124, 128))	('CD23', 'Gene', '2208', (113, 117))	('EMA', 'Gene', (173, 176))	('CD68', 'Gene', (130, 134))	('synaptophysin', 'Gene', (178, 191))	('CD45', 'Gene', (136, 140))	('CD23', 'Gene', (113, 117))	('CD68', 'Gene', '968', (130, 134))	('synaptophysin', 'Gene', '6855', (178, 191))	('CD5', 'Gene', (119, 122))
457179	31113844	In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus.	('ADI-PEG20', 'Chemical', '-', (117, 126))	('pyrimidine', 'Chemical', 'MESH:C030986', (36, 46))	('DTX', 'Chemical', 'MESH:D000077143', (91, 94))	('c-Myc', 'Gene', '4609', (167, 172))	('ADI-PEG20', 'Var', (117, 126))	('translocation', 'MPA', (139, 152))	('c-Myc', 'Gene', (167, 172))
457181	31113844	In vivo studies demonstrate that the combination of ADI-PEG20:GEM: DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma.	('GEM', 'Chemical', 'MESH:C056507', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('sarcoma', 'Disease', (227, 234))	('ADI-PEG20', 'Chemical', '-', (200, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('DTX', 'Chemical', 'MESH:D000077143', (67, 70))	('tumor', 'Disease', (87, 92))	('GEM', 'Chemical', 'MESH:C056507', (211, 214))	('ADI-PEG20', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('sarcoma', 'Disease', 'MESH:D012509', (227, 234))	('ADI-PEG20', 'Var', (200, 209))	('DTX', 'Chemical', 'MESH:D000077143', (220, 223))	('ADI-PEG20', 'Chemical', '-', (52, 61))
457182	31113844	The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression.	('tumors', 'Disease', (15, 21))	('stabilization', 'MPA', (60, 73))	('c-MYC', 'Gene', '4609', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('GEM', 'Chemical', 'MESH:C056507', (110, 113))	('hENT1', 'Gene', '2030', (143, 148))	('increase', 'PosReg', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('ADI-PEG20', 'Chemical', '-', (27, 36))	('expression', 'MPA', (149, 159))	('ADI-PEG20', 'Var', (27, 36))	('hENT1', 'Gene', (143, 148))	('c-MYC', 'Gene', (77, 82))	('DTX', 'Chemical', 'MESH:D000077143', (41, 44))	('potentiating', 'PosReg', (83, 95))
457194	31113844	ADI-PEG20 converts extracellular arginine into citrulline, starving ASS1-deficient tumors of extracellular arginine, and resulting in tumor growth inhibition.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('citrulline', 'MPA', (47, 57))	('arginine', 'Chemical', 'MESH:D001120', (33, 41))	('citrulline', 'Chemical', 'MESH:D002956', (47, 57))	('tumor', 'Disease', (83, 88))	('ADI-PEG20', 'Var', (0, 9))	('deficient tumors', 'Disease', (73, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('ASS1', 'Gene', '445', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('ASS1', 'Gene', (68, 72))	('ADI-PEG20', 'Chemical', '-', (0, 9))	('deficient tumors', 'Disease', 'MESH:D009369', (73, 89))	('arginine', 'Chemical', 'MESH:D001120', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (134, 139))	('extracellular arginine', 'MPA', (93, 115))
457195	31113844	Although initially tumors respond to ADI-PEG20, ASS1-deficient tumors eventually become resistant to this treatment by reexpressing ASS1.	('deficient tumors', 'Disease', 'MESH:D009369', (53, 69))	('tumors', 'Disease', (19, 25))	('ASS1', 'Gene', '445', (132, 136))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('ASS1', 'Gene', '445', (48, 52))	('ASS1', 'Gene', (132, 136))	('deficient tumors', 'Disease', (53, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ADI-PEG20', 'Chemical', '-', (37, 46))	('ASS1', 'Gene', (48, 52))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('ADI-PEG20', 'Var', (37, 46))
457206	31113844	Preclinical modeling in pancreatic and bladder cancers has shown that ADI-PEG20 increases the effectiveness of GEM, in vitro and in vivo, by blocking the increase in expression of RRM2, a known resistance marker of GEM.	('ADI-PEG20', 'Chemical', '-', (70, 79))	('bladder cancers', 'Phenotype', 'HP:0009725', (39, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('pancreatic and bladder cancers', 'Disease', 'MESH:D001749', (24, 54))	('GEM', 'Chemical', 'MESH:C056507', (111, 114))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('RRM2', 'Gene', '6241', (180, 184))	('blocking', 'NegReg', (141, 149))	('increases', 'PosReg', (80, 89))	('RRM2', 'Gene', (180, 184))	('GEM', 'Chemical', 'MESH:C056507', (215, 218))	('ADI-PEG20', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('expression', 'MPA', (166, 176))	('effectiveness', 'MPA', (94, 107))
457207	31113844	The effects of ADI-PEG20 in combination with DTX have only been studied in prostate cancer, demonstrating reduced tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('prostate cancer', 'Disease', (75, 90))	('DTX', 'Chemical', 'MESH:D000077143', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ADI-PEG20', 'Chemical', '-', (15, 24))	('tumor', 'Disease', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (75, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))	('reduced', 'NegReg', (106, 113))	('ADI-PEG20', 'Var', (15, 24))
457208	31113844	Given the efficacy of ADI-PEG20 in combination with these two agents separately, these data suggest that a direct analysis of the triple combination of ADI-PEG20, DTX, and GEM could offer a new therapeutic option in sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('ADI-PEG20', 'Chemical', '-', (152, 161))	('DTX', 'Chemical', 'MESH:D000077143', (163, 166))	('sarcoma', 'Disease', 'MESH:D012509', (216, 223))	('ADI-PEG20', 'Var', (152, 161))	('ADI-PEG20', 'Chemical', '-', (22, 31))	('GEM', 'Chemical', 'MESH:C056507', (172, 175))	('sarcoma', 'Disease', (216, 223))
457209	31113844	In this study, the mechanism and efficacy of ADI-PEG20, DTX, and GEM in sarcoma, pancreatic cancer, and melanoma cells were examined in vitro and in vivo in order to develop a novel therapeutic strategy for treating cancers deficient in ASS1.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('DTX', 'Chemical', 'MESH:D000077143', (56, 59))	('ADI-PEG20', 'Var', (45, 54))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('ASS1', 'Gene', (237, 241))	('ASS1', 'Gene', '445', (237, 241))	('cancers deficient', 'Disease', (216, 233))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('cancers deficient', 'Disease', 'MESH:D009369', (216, 233))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('GEM', 'Chemical', 'MESH:C056507', (65, 68))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('sarcoma', 'Disease', (72, 79))	('ADI-PEG20', 'Chemical', '-', (45, 54))	('pancreatic cancer', 'Disease', (81, 98))
457211	31113844	The expression of ASS1 results in the stabilization of c-Myc.	('ASS1', 'Gene', (18, 22))	('ASS1', 'Gene', '445', (18, 22))	('c-Myc', 'Gene', '4609', (55, 60))	('c-Myc', 'Gene', (55, 60))	('stabilization', 'MPA', (38, 51))	('expression', 'Var', (4, 14))
457214	31113844	This suggests that treatment of tumors with ADI-PEG20 and DTX potentiates the anticancer activities of GEM by increasing GEM uptake.	('DTX', 'Chemical', 'MESH:D000077143', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('GEM', 'Chemical', 'MESH:C056507', (121, 124))	('ADI-PEG20', 'Var', (44, 53))	('GEM', 'Chemical', 'MESH:C056507', (103, 106))	('cancer', 'Disease', (82, 88))	('GEM uptake', 'CPA', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ADI-PEG20', 'Chemical', '-', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('potentiates', 'PosReg', (62, 73))	('tumors', 'Disease', (32, 38))	('increasing', 'PosReg', (110, 120))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
457228	31113844	Cells were treated with 1 mumol/L of ADI-PEG20 (Polaris), increasing doses of DTX (S1148, Selleckchem), and increasing doses of GEM (S1714, Selleckchem), either alone or in combination, in phenol red-free MEM (11966-025, Thermo Fisher).	('phenol red', 'Chemical', 'MESH:D010637', (189, 199))	('GEM', 'Chemical', 'MESH:C056507', (128, 131))	('ADI-PEG20', 'Chemical', '-', (37, 46))	('Polaris', 'Gene', '21821', (48, 55))	('Polaris', 'Gene', (48, 55))	('DTX', 'Chemical', 'MESH:D000077143', (78, 81))	('ADI-PEG20', 'Var', (37, 46))
457241	31113844	Mice were treated with ADI-PEG20 (Polaris) intramuscularly at 320 international units per meter cubed (IU/m3) twice weekly, GEM (Lilly) by intraperitoneal injections at 125 milligram/kilogram (mg/kg) twice weekly, and DTX (Sandoz) at 10 mg/kg weekly, or combinations of the drugs based on treatment group.	('GEM', 'Chemical', 'MESH:C056507', (124, 127))	('Polaris', 'Gene', '21821', (34, 41))	('ADI-PEG20', 'Chemical', '-', (23, 32))	('Polaris', 'Gene', (34, 41))	('Mice', 'Species', '10090', (0, 4))	('DTX', 'Chemical', 'MESH:D000077143', (218, 221))	('ADI-PEG20', 'Var', (23, 32))
457247	31113844	dCK expression increased significantly in acute and long-term treatment of ADI-PEG20 (WT(ADI) and LTAT; Fig.	('ADI-PEG20', 'Var', (75, 84))	('LTAT', 'Chemical', '-', (98, 102))	('expression', 'MPA', (4, 14))	('dCK', 'Gene', (0, 3))	('increased', 'PosReg', (15, 24))	('ADI-PEG20', 'Chemical', '-', (75, 84))	('dCK', 'Gene', '39429', (0, 3))
457251	31113844	From acute to long-term treatment of ADI-PEG20, dCK localization was increased in the cytoplasmic fraction (Fig.	('dCK', 'Gene', '39429', (48, 51))	('increased', 'PosReg', (69, 78))	('ADI-PEG20', 'Chemical', '-', (37, 46))	('dCK', 'Gene', (48, 51))	('ADI-PEG20', 'Var', (37, 46))
457254	31113844	These results indicate that upon ADI-PEG20 treatment, SK-LMS-1 cells increase dCK and decrease RRM2, rendering the cells sensitive to GEM treatment, but lack the upregulation of the hENT1 transporter that would allow GEM into the cell, suggesting intrinsic transporter-associated resistance.	('RRM2', 'Gene', (95, 99))	('increase', 'PosReg', (69, 77))	('GEM', 'Chemical', 'MESH:C056507', (217, 220))	('upregulation', 'PosReg', (162, 174))	('dCK', 'Gene', (78, 81))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (54, 62))	('hENT1', 'Gene', '2030', (182, 187))	('ADI-PEG20', 'Chemical', '-', (33, 42))	('dCK', 'Gene', '39429', (78, 81))	('lack', 'NegReg', (153, 157))	('hENT1', 'Gene', (182, 187))	('decrease', 'NegReg', (86, 94))	('ADI-PEG20', 'Var', (33, 42))	('RRM2', 'Gene', '6241', (95, 99))	('GEM', 'Chemical', 'MESH:C056507', (134, 137))
457266	31113844	This shows that synergy of ADI-PEG20 combined with GEM and DTX increases with ADI-PEG20 treatment from acute to long term, and suggests strong synergy associated with longer term ADI-PEG20 treatment in SK-LMS-1 cells.	('synergy', 'MPA', (16, 23))	('ADI-PEG20', 'Var', (78, 87))	('DTX', 'Chemical', 'MESH:D000077143', (59, 62))	('GEM', 'Chemical', 'MESH:C056507', (51, 54))	('ADI-PEG20', 'Chemical', '-', (78, 87))	('synergy', 'Interaction', (143, 150))	('ADI-PEG20', 'Chemical', '-', (179, 188))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (202, 210))	('ADI-PEG20', 'Chemical', '-', (27, 36))
457267	31113844	To determine the mechanism by which GEM-induced cell death occurs in the presence of ADI-PEG20 and DTX, we hypothesized that the effect of this combination relied on c-Myc stabilization, as c-Myc has been shown to be stabilized in cell lines that are treated with ADI-PEG20.	('c-Myc', 'Gene', '4609', (166, 171))	('ADI-PEG20', 'Var', (85, 94))	('c-Myc', 'Gene', '4609', (190, 195))	('as c', 'Gene', (187, 191))	('c-Myc', 'Gene', (166, 171))	('GEM', 'Chemical', 'MESH:C056507', (36, 39))	('c-Myc', 'Gene', (190, 195))	('DTX', 'Chemical', 'MESH:D000077143', (99, 102))	('ADI-PEG20', 'Chemical', '-', (85, 94))	('as c', 'Gene', '29108', (187, 191))	('ADI-PEG20', 'Chemical', '-', (264, 273))
457268	31113844	c-Myc expression did increase significantly in acute or long-term ADI-PEG20-treated cells when compared with WT SK-LMS-1 (Fig.	('expression', 'MPA', (6, 16))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (112, 120))	('increase', 'PosReg', (21, 29))	('c-Myc', 'Gene', '4609', (0, 5))	('ADI-PEG20-treated', 'Var', (66, 83))	('ADI-PEG20', 'Chemical', '-', (66, 75))	('c-Myc', 'Gene', (0, 5))
457270	31113844	ADI-PEG20 long-term treatment stabilized c-Myc within the nucleus (Fig.	('c-Myc', 'Gene', '4609', (41, 46))	('stabilized', 'MPA', (30, 40))	('ADI-PEG20', 'Var', (0, 9))	('c-Myc', 'Gene', (41, 46))	('ADI-PEG20', 'Chemical', '-', (0, 9))
457285	31113844	Taken together, these data show that c-Myc expression and localization is coordinated by ADI-PEG20 and DTX treatment.	('localization', 'MPA', (58, 70))	('ADI-PEG20', 'Var', (89, 98))	('DTX', 'Chemical', 'MESH:D000077143', (103, 106))	('c-Myc', 'Gene', '4609', (37, 42))	('ADI-PEG20', 'Chemical', '-', (89, 98))	('c-Myc', 'Gene', (37, 42))	('expression', 'MPA', (43, 53))
457290	31113844	Uptake of the probe increased with combo treatment in both WT and LTAT cell lines, and was blunted when cells were pretreated with a c-Myc inhibitor, shown quantitatively and with representative pictures (Fig.	('increased', 'PosReg', (20, 29))	('Uptake', 'MPA', (0, 6))	('combo', 'Var', (35, 40))	('blunted', 'NegReg', (91, 98))	('c-Myc', 'Gene', '4609', (133, 138))	('LTAT', 'Chemical', '-', (66, 70))	('c-Myc', 'Gene', (133, 138))
457298	31113844	To determine if the sensitivity to GEM and DTX could be correlated to ASS1 negativity as a biomarker, and therefore have efficacy across a wider range of cancer systems, we explored if the combination of ADI-PEG20/GEM/DTX would be effective in a broad range of cancer subtypes where GEM and DTX were used.	('GEM', 'Chemical', 'MESH:C056507', (35, 38))	('ASS1', 'Gene', (70, 74))	('ASS1', 'Gene', '445', (70, 74))	('ADI-PEG20', 'Chemical', '-', (204, 213))	('ADI-PEG20/GEM/DTX', 'Var', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('DTX', 'Chemical', 'MESH:D000077143', (43, 46))	('GEM', 'Chemical', 'MESH:C056507', (283, 286))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('DTX', 'Chemical', 'MESH:D000077143', (218, 221))	('DTX', 'Chemical', 'MESH:D000077143', (291, 294))	('GEM', 'Chemical', 'MESH:C056507', (214, 217))
457303	31113844	To evaluate if increased expression of ASS1 in these cell lines would improve GEM uptake via increased hENT1 surface expression, WT and LTAT cell lines were treated with ADI-PEG20, GEM, and DTX (combo).	('LTAT', 'Chemical', '-', (136, 140))	('GEM uptake', 'CPA', (78, 88))	('ADI-PEG20', 'Chemical', '-', (170, 179))	('increased', 'PosReg', (93, 102))	('hENT1', 'Gene', '2030', (103, 108))	('ASS1', 'Gene', (39, 43))	('improve', 'PosReg', (70, 77))	('DTX', 'Chemical', 'MESH:D000077143', (190, 193))	('ASS1', 'Gene', '445', (39, 43))	('ADI-PEG20', 'Var', (170, 179))	('GEM', 'Chemical', 'MESH:C056507', (78, 81))	('hENT1', 'Gene', (103, 108))	('GEM', 'Chemical', 'MESH:C056507', (181, 184))
457304	31113844	All cell lines were then incubated with the cytidine-5-carboxyfluorescein probe, and all demonstrated increased uptake as a result of the combo treatment (Fig.	('combo', 'Var', (138, 143))	('cytidine-5-carboxyfluorescein', 'Chemical', '-', (44, 73))	('uptake', 'MPA', (112, 118))	('increased', 'PosReg', (102, 111))
457306	31113844	hENT1 surface expression was shown to increase across cell lines from WT to LTAT treated with combo compared with NT.	('hENT1', 'Gene', '2030', (0, 5))	('increase', 'PosReg', (38, 46))	('combo', 'Var', (94, 99))	('hENT1', 'Gene', (0, 5))	('LTAT', 'Chemical', '-', (76, 80))	('surface expression', 'MPA', (6, 24))
457308	31113844	Next, cell death analysis with the combination treatment demonstrated a robust increase in cell death across all cancer types, with both acute and long-term treatment of ADI-PEG20 compared with NT (Fig.	('increase', 'PosReg', (79, 87))	('cell death', 'CPA', (91, 101))	('ADI-PEG20', 'Chemical', '-', (170, 179))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('ADI-PEG20', 'Var', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
457310	31113844	These results indicate that the treatment of ADI-PEG20, GEM, and DTX within multiple cancer types increases hENT1 surface expression, which renders the cells susceptible to this combination treatment.	('ADI-PEG20', 'Chemical', '-', (45, 54))	('DTX', 'Chemical', 'MESH:D000077143', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('GEM', 'Chemical', 'MESH:C056507', (56, 59))	('cancer', 'Disease', (85, 91))	('ADI-PEG20', 'Var', (45, 54))	('hENT1', 'Gene', '2030', (108, 113))	('increases', 'PosReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hENT1', 'Gene', (108, 113))
457314	31113844	In examining the effects of arginine depletion therapy on the individual treatment components, ADI-PEG20 alone had a significant but short-term (21-day) growth inhibitory effect compared with control (Fig.	('growth inhibitory effect', 'CPA', (153, 177))	('arginine', 'Chemical', 'MESH:D001120', (28, 36))	('ADI-PEG20', 'Chemical', '-', (95, 104))	('ADI-PEG20 alone', 'Var', (95, 110))
457316	31113844	Similar to ADI-PEG20 alone, there is a short-term but significant effect on tumor growth for the combination of ADI-PEG20 and DTX; DTX alone had little effect on tumor growth (Fig.	('ADI-PEG20', 'Chemical', '-', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ADI-PEG20', 'Var', (112, 121))	('DTX', 'Chemical', 'MESH:D000077143', (131, 134))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ADI-PEG20', 'Chemical', '-', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('DTX', 'Chemical', 'MESH:D000077143', (126, 129))
457320	31113844	Finally, the effect of ADI-PEG20 combined with GEM and DTX demonstrated an improvement over GEM and DTX alone (Fig.	('DTX', 'Chemical', 'MESH:D000077143', (55, 58))	('DTX', 'Chemical', 'MESH:D000077143', (100, 103))	('improvement', 'PosReg', (75, 86))	('ADI-PEG20', 'Chemical', '-', (23, 32))	('GEM', 'Chemical', 'MESH:C056507', (47, 50))	('GEM', 'Chemical', 'MESH:C056507', (92, 95))	('ADI-PEG20', 'Var', (23, 32))
457322	31113844	ASS1 deficiency is a recurrent feature across many types of cancers and is associated with decreased overall survival and an earlier appearance of metastases.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('deficiency', 'Var', (5, 15))	('metastases', 'Disease', 'MESH:D009362', (147, 157))	('decreased', 'NegReg', (91, 100))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('overall survival', 'CPA', (101, 117))	('ASS1', 'Gene', '445', (0, 4))	('metastases', 'Disease', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('ASS1', 'Gene', (0, 4))
457327	31113844	Previous work has identified changes in the GEM pathway that occur as a result of arginine starvation induced by ADI-PEG20.	('arginine starvation', 'MPA', (82, 101))	('changes', 'Reg', (29, 36))	('ADI-PEG20', 'Var', (113, 122))	('arginine', 'Chemical', 'MESH:D001120', (82, 90))	('GEM pathway', 'Pathway', (44, 55))	('ADI-PEG20', 'Chemical', '-', (113, 122))	('GEM', 'Chemical', 'MESH:C056507', (44, 47))
457331	31113844	Furthermore, these data show that even when ASS1 reexpresses in long-term treatment with ADI-PEG20 (LTAT), the combination treatment remains significantly effective.	('ADI-PEG20', 'Var', (89, 98))	('LTAT', 'Chemical', '-', (100, 104))	('ASS1', 'Gene', (44, 48))	('ASS1', 'Gene', '445', (44, 48))	('ADI-PEG20', 'Chemical', '-', (89, 98))
457332	31113844	Prior work from our laboratory demonstrated that ADI-PEG20 was able to induce a conditional synthetic lethality in ASS1-deficient cells placed in a prolonged state of arginine starvation.	('ADI-PEG20', 'Chemical', '-', (49, 58))	('ASS1', 'Gene', (115, 119))	('ASS1', 'Gene', '445', (115, 119))	('arginine', 'Chemical', 'MESH:D001120', (167, 175))	('induce', 'PosReg', (71, 77))	('ADI-PEG20', 'Var', (49, 58))
457336	31113844	There are now two clinical trials using mitotic inhibitors that should allow for increased uptake of GEM based on our findings, which include NCT03449901, a phase II trial of ADI-PEG 20 in combination with GEM and DTX for the treatment of STS, and NCT02101580, a phase IB trial with ADI-PEG20 plus nab-paclitaxel and GEM in subjects with pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('NCT03449901', 'Var', (142, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (338, 355))	('paclitaxel', 'Chemical', 'MESH:D017239', (302, 312))	('GEM', 'Chemical', 'MESH:C056507', (317, 320))	('STS', 'Phenotype', 'HP:0030448', (239, 242))	('pancreatic cancer', 'Disease', (338, 355))	('GEM', 'Chemical', 'MESH:C056507', (101, 104))	('nab', 'Chemical', '-', (298, 301))	('NCT02101580', 'Var', (248, 259))	('pancreatic cancer', 'Disease', 'MESH:D010190', (338, 355))	('ADI-PEG20', 'Chemical', '-', (283, 292))	('DTX', 'Chemical', 'MESH:D000077143', (214, 217))	('STS', 'Disease', (239, 242))	('GEM', 'Chemical', 'MESH:C056507', (206, 209))	('ADI-PEG 20', 'Chemical', '-', (175, 185))
457338	31113844	As ASS1 deficiency is primarily found in cancer cells of patients, rather than normal tissue, our laboratory continues to explore biomarker-driven metabolic therapies that allow for an effective multiagent treatment in this ASS1-deficient population.	('ASS1', 'Gene', '445', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('patients', 'Species', '9606', (57, 65))	('cancer', 'Disease', (41, 47))	('deficiency', 'Var', (8, 18))	('ASS1', 'Gene', (224, 228))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('ASS1', 'Gene', '445', (224, 228))	('ASS1', 'Gene', (3, 7))
457341	31113844	This work provides the preclinical justification for the ongoing clinical trial utilizing ADI-PEG20, gemcitabine, and docetaxel in sarcoma.	('ADI-PEG20', 'Chemical', '-', (90, 99))	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('sarcoma', 'Disease', (131, 138))	('gemcitabine', 'Chemical', 'MESH:C056507', (101, 112))	('docetaxel', 'Chemical', 'MESH:D000077143', (118, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('ADI-PEG20', 'Var', (90, 99))
457445	27821818	It has been suggested that some constituents in herbal medicine, such as aristolochic acid and heavy metal, are associated with an increased risk of urinary tract cancers.	('urinary tract cancers', 'Disease', 'MESH:D014571', (149, 170))	('urinary tract cancers', 'Disease', (149, 170))	('aristolochic acid', 'Var', (73, 90))	('herbal medicine', 'Species', '1407750', (48, 63))	('metal', 'Chemical', 'MESH:D008670', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('aristolochic acid', 'Chemical', 'MESH:C000228', (73, 90))	('heavy metal', 'Var', (95, 106))	('increased risk of urinary tract', 'Phenotype', 'HP:0000010', (131, 162))	('associated', 'Reg', (112, 122))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (149, 169))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
457483	24130893	Truncated SSX Protein Suppresses Synovial Sarcoma Cell Proliferation by Inhibiting the Localization of SS18-SSX Fusion Protein Synovial sarcoma is a relatively rare high-grade soft tissue sarcoma that often develops in the limbs of young people and induces the lung and the lymph node metastasis resulting in poor prognosis.	('Suppresses', 'NegReg', (22, 32))	('Sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('sarcoma', 'Disease', 'MESH:D012509', (188, 195))	('sarcoma', 'Disease', (188, 195))	('SSX', 'Gene', (108, 111))	('people', 'Species', '9606', (238, 244))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (127, 143))	('Inhibiting', 'NegReg', (72, 82))	('SSX', 'Gene', '6757', (10, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('SS18', 'Gene', (103, 107))	('lung and', 'CPA', (261, 269))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('Sarcoma Cell', 'Disease', 'MESH:D012509', (42, 54))	('sarcoma', 'Disease', (136, 143))	('SSX', 'Gene', (10, 13))	('Sarcoma Cell', 'Disease', (42, 54))	('Truncated', 'Var', (0, 9))	('Localization', 'MPA', (87, 99))	('SS18', 'Gene', '6760', (103, 107))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (176, 195))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (33, 49))	('induces', 'PosReg', (249, 256))	('lymph node metastasis', 'CPA', (274, 295))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('SSX', 'Gene', '6757', (108, 111))
457491	24130893	Furthermore, cell proliferation and colony formation of synovial sarcoma SYO-1 and YaFuSS cells were suppressed by exogenous tSSX expression.	('synovial sarcoma SYO-1', 'Disease', 'MESH:D013584', (56, 78))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (56, 72))	('exogenous', 'Var', (115, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('cell proliferation', 'CPA', (13, 31))	('colony formation', 'CPA', (36, 52))	('SSX', 'Gene', '6757', (126, 129))	('SSX', 'Gene', (126, 129))	('synovial sarcoma SYO-1', 'Disease', (56, 78))	('YaFuSS cells', 'CPA', (83, 95))	('suppressed', 'NegReg', (101, 111))
457497	24130893	However, specific chromosomal translocation of t(X; 18) (p11.2;q11.2) has been identified in patients with synovial sarcoma.	('identified', 'Reg', (79, 89))	('p11', 'Gene', (57, 60))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (107, 123))	('synovial sarcoma', 'Disease', 'MESH:D013584', (107, 123))	('chromosomal translocation', 'Var', (18, 43))	('p11', 'Gene', '6281', (57, 60))	('synovial sarcoma', 'Disease', (107, 123))	('patients', 'Species', '9606', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
457498	24130893	The fusion of the SS18 gene on chromosome 18 to the SSX gene on chromosome X results in the expression of fusion protein SS18-SSX composed of the NH3-terminal half of the amino acids from SS18 and COOH-terminal amino acids of the SSX.	('SSX', 'Gene', '6757', (52, 55))	('results in', 'Reg', (77, 87))	('fusion', 'Var', (4, 10))	('SSX', 'Gene', (230, 233))	('SSX', 'Gene', '6757', (126, 129))	('SSX', 'Gene', '6757', (230, 233))	('SSX', 'Gene', (126, 129))	('SS18', 'Gene', (18, 22))	('expression', 'MPA', (92, 102))	('SSX', 'Gene', (52, 55))
457516	24130893	Synovial sarcoma cell line SYO-1 bearing the SS18-SSX2 translocation was established previously.	('SYO-1', 'Gene', (27, 32))	('SYO-1', 'Gene', '55027', (27, 32))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('SSX2', 'Gene', (50, 54))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('translocation', 'Var', (55, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SSX2', 'Gene', '6757', (50, 54))
457518	24130893	Localization of full-length SS18 and SSX proteins tagged to GFP was observed under fluorescence microscope, after the constructs pEGFP-SS18, pEGFP-SSX1, and pEGFP-SSX2 were transfected into SYO-1 cells.	('SSX1', 'Gene', '6756', (147, 151))	('SSX', 'Gene', '6757', (37, 40))	('SSX2', 'Gene', (163, 167))	('SSX', 'Gene', (37, 40))	('pEGFP-SS18', 'Var', (129, 139))	('SYO-1', 'Gene', '55027', (190, 195))	('SSX', 'Gene', '6757', (147, 150))	('SSX1', 'Gene', (147, 151))	('SSX', 'Gene', (147, 150))	('SYO-1', 'Gene', (190, 195))	('SSX', 'Gene', '6757', (163, 166))	('SSX2', 'Gene', '6757', (163, 167))	('SSX', 'Gene', (163, 166))
457527	24130893	Localization of tSS18 (truncated SS18 composing of 1-379 amino acids), tSSX1, and tSSX2 (truncated SSX composing of 111-188 amino acids) was observed after transfection of pEGFP-tSS18, pEGFP-tSSX1 and pEGFP-tSSX2 into SYO-1 cells.	('SSX', 'Gene', (72, 75))	('SSX', 'Gene', '6757', (99, 102))	('pEGFP-tSS18', 'Var', (172, 183))	('SSX', 'Gene', '6757', (83, 86))	('SSX', 'Gene', (99, 102))	('SSX', 'Gene', '6757', (192, 195))	('SYO-1', 'Gene', (218, 223))	('SYO-1', 'Gene', '55027', (218, 223))	('SSX2', 'Gene', (83, 87))	('SSX', 'Gene', (83, 86))	('SSX1', 'Gene', '6756', (192, 196))	('SSX', 'Gene', '6757', (208, 211))	('SSX1', 'Gene', (192, 196))	('SSX', 'Gene', (192, 195))	('SSX2', 'Gene', '6757', (83, 87))	('tSS18', 'Gene', (16, 21))	('SSX', 'Gene', '6757', (72, 75))	('SSX', 'Gene', (208, 211))	('Localization', 'MPA', (0, 12))	('SSX2', 'Gene', (208, 212))	('SSX1', 'Gene', '6756', (72, 76))	('SSX2', 'Gene', '6757', (208, 212))	('SSX1', 'Gene', (72, 76))
457530	24130893	We confirmed that the proteins from these plasmid constructs were successfully expressed in HEK293 cells by western blotting with anti-SS18 and anti-SSX antibodies (Figure S3).	('anti-SS18', 'Var', (130, 139))	('HEK293 cells', 'CellLine', 'CVCL:0045', (92, 104))	('SSX', 'Gene', '6757', (149, 152))	('SSX', 'Gene', (149, 152))
457545	24130893	As described above, the localization of SS18-SSX2 was affected by the co-expression of tSSX2 in SYO-1 cells.	('affected', 'Reg', (54, 62))	('SSX2', 'Gene', '6757', (88, 92))	('localization', 'MPA', (24, 36))	('SYO-1', 'Gene', (96, 101))	('SSX2', 'Gene', '6757', (45, 49))	('SSX2', 'Gene', (88, 92))	('co-expression', 'Var', (70, 83))	('SSX2', 'Gene', (45, 49))	('SYO-1', 'Gene', '55027', (96, 101))
457547	24130893	SYO-1 cells were transfected with GFP-fused tSSX2 or GFP vector alone as control, split 48 h after transfection, and the cells expressing the fluorescence proteins were observed and counted on day 4, 6, and 8 after transfection.	('GFP-fused', 'Var', (34, 43))	('SSX2', 'Gene', '6757', (45, 49))	('SYO-1', 'Gene', '55027', (0, 5))	('SSX2', 'Gene', (45, 49))	('SYO-1', 'Gene', (0, 5))
457551	24130893	SYO-1 cells were transfected with GFP-tagged tSSX2 or GFP vector alone, split 48 h after transfection, and selected with G418 for three weeks.	('GFP-tagged', 'Var', (34, 44))	('SSX2', 'Gene', (46, 50))	('G418', 'Chemical', 'MESH:C010680', (121, 125))	('SYO-1', 'Gene', '55027', (0, 5))	('SSX2', 'Gene', '6757', (46, 50))	('SYO-1', 'Gene', (0, 5))
457554	24130893	Reduced number of colonies was observed in YaFuSS cell line transfected with GFP-tagged tSSX1 (Figure 6B).	('SSX1', 'Gene', (89, 93))	('SSX1', 'Gene', '6756', (89, 93))	('Reduced', 'NegReg', (0, 7))	('GFP-tagged', 'Var', (77, 87))
457573	24130893	Our results showing disappearance of SS18-SSX speckles by exogenous tSSX transfection agrees with their results, and the phenomenon we found might show the disruption of SS18-SSX-driven altered BAF complex antagonized by tSSX.	('transfection', 'Var', (73, 85))	('SSX', 'Gene', '6757', (222, 225))	('SSX', 'Gene', (222, 225))	('BAF', 'Gene', '8815', (194, 197))	('SSX', 'Gene', (69, 72))	('SSX', 'Gene', '6757', (175, 178))	('SSX', 'Gene', (175, 178))	('SSX', 'Gene', '6757', (69, 72))	('SSX', 'Gene', '6757', (42, 45))	('altered', 'Protein', (186, 193))	('BAF', 'Gene', (194, 197))	('SSX', 'Gene', (42, 45))
457601	24130893	Images were acquired with SenSys0401E (Roper Scientific Germany, Ottobrunn, Germany), DMRA2 (Leica Microsystems, Wetzlar, Germany) and Leica Cytogenetic Workstation (CW4000; Leica Microsystems Imaging Ltd, Cambridge, UK).	('Leica Microsystems', 'Disease', 'None', (93, 111))	('Leica Microsystems', 'Disease', (93, 111))	('SenSys0401E', 'Var', (26, 37))	('Leica Microsystems', 'Disease', 'None', (174, 192))	('Leica Microsystems', 'Disease', (174, 192))
457627	28745570	The tumor exhibited a high proliferation index with Ki-67 (methylation-inhibited binding protein 1 [MIB-1]) positivity in the nuclei of 30% of the tumor cells.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('positivity', 'Var', (108, 118))	('MIB-1', 'Gene', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('methylation-inhibited binding protein 1', 'Gene', (59, 98))	('MIB-1', 'Gene', '57534', (100, 105))	('methylation-inhibited binding protein 1', 'Gene', '57534', (59, 98))
457630	28745570	The spindle tumor cells were CD34+ (Figure 1, B).	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CD34+', 'Var', (29, 34))
457633	28745570	The tumor was also positive for amplification of MDM2 (12q15) by fluorescence in situ hybridization (FISH), not shown here.	('tumor', 'Disease', (4, 9))	('amplification', 'Var', (32, 45))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('positive', 'Reg', (19, 27))
457688	28745570	Occasional aberrant expression of keratin is reported in melanomas and certain sarcomas, such as Ewing sarcoma and leiomyosarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (97, 110))	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (97, 110))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (115, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcomas', 'Disease', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('aberrant', 'Var', (11, 19))	('keratin', 'Protein', (34, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('Ewing sarcoma', 'Disease', (97, 110))	('leiomyosarcoma', 'Disease', (115, 129))	('melanomas', 'Disease', (57, 66))	('expression', 'MPA', (20, 30))	('reported', 'Reg', (45, 53))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (115, 129))
457693	28745570	Overexpression of nuclear STAT6 results from NAB2-STAT6 fusion identified in SFTs.	('NAB2', 'Gene', '4665', (45, 49))	('fusion', 'Var', (56, 62))	('STAT6', 'Gene', (50, 55))	('STAT6', 'Gene', (26, 31))	('STAT6', 'Gene', '6778', (26, 31))	('NAB2', 'Gene', (45, 49))	('STAT6', 'Gene', '6778', (50, 55))
457706	28745570	In addition, perivascular hypercellularity, tumor herniation into vascular lumens, necrosis, and expression of p75NTR is more frequently associated with MPNST than cellular schwannoma in a large study.	('p75NTR', 'Gene', (111, 117))	('MPNST', 'Disease', (153, 158))	('schwannoma', 'Phenotype', 'HP:0100008', (173, 183))	('necrosis', 'Disease', (83, 91))	('expression', 'Var', (97, 107))	('associated with', 'Reg', (137, 152))	('p75NTR', 'Gene', '4804', (111, 117))	('perivascular', 'CPA', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('men', 'Species', '9606', (77, 80))	('necrosis', 'Disease', 'MESH:D009336', (83, 91))	('schwannoma', 'Disease', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('schwannoma', 'Disease', 'MESH:D009442', (173, 183))	('MPNST', 'Phenotype', 'HP:0100697', (153, 158))	('tumor', 'Disease', (44, 49))	('hernia', 'Phenotype', 'HP:0100790', (50, 56))
457709	28745570	Although cytokeratins generally show positivity in synovial sarcoma, the monophasic spindle cell variant of synovial sarcoma is less frequently positive (50%-80%) than its biphasic counterpart.	('synovial sarcoma', 'Disease', 'MESH:D013584', (51, 67))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (108, 124))	('synovial sarcoma', 'Disease', 'MESH:D013584', (108, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('cytokeratins', 'Protein', (9, 21))	('synovial sarcoma', 'Disease', (51, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('synovial sarcoma', 'Disease', (108, 124))	('positivity', 'Var', (37, 47))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (51, 67))
457763	28745570	Moreover, the t(7;16)(q33;p11) translocation resulting in a FUS-CREB3L2 fusion gene characteristic of low-grade fibromyxoid sarcoma has been detected in some SEF cases.	('fibromyxoid sarcoma', 'Disease', (112, 131))	('t(7;16)(q33;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (14, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('FUS', 'Gene', (60, 63))	('CREB3L2', 'Gene', '64764', (64, 71))	('FUS', 'Gene', '2521', (60, 63))	('t(7;16)(q33;p11', 'Var', (14, 29))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (112, 131))	('CREB3L2', 'Gene', (64, 71))
457780	28745570	Loss of SDH subunit B (SDHB) expression by IHC effectively identifies SDH-deficient GISTs, some of which have loss-of-function germline mutations in one of the SDH subunits (A, B, C, or D).	('SDH', 'Gene', (160, 163))	('SDH', 'Gene', (23, 26))	('SDH subunit B', 'Gene', '6390', (8, 21))	('SDHB', 'Gene', '6390', (23, 27))	('SDH-deficient GISTs', 'Disease', 'MESH:D007153', (70, 89))	('SDH', 'Gene', '6390', (8, 11))	('SDH', 'Gene', '6390', (70, 73))	('SDH', 'Gene', '6390', (160, 163))	('loss-of-function', 'NegReg', (110, 126))	('Loss', 'NegReg', (0, 4))	('SDHB', 'Gene', (23, 27))	('SDH', 'Gene', '6390', (23, 26))	('mutations', 'Var', (136, 145))	('SDH', 'Gene', (8, 11))	('SDH-deficient GISTs', 'Disease', (70, 89))	('SDH', 'Gene', (70, 73))	('SDH subunit B', 'Gene', (8, 21))	('GISTs', 'Phenotype', 'HP:0100723', (84, 89))
457788	28745570	SOX-10 reportedly shows positivity in two-thirds of epithelioid MPNSTs.	('SOX-10', 'Gene', (0, 6))	('positivity', 'Var', (24, 34))	('MPNST', 'Phenotype', 'HP:0100697', (64, 69))	('SOX-10', 'Gene', '6663', (0, 6))	('epithelioid MPNSTs', 'Disease', (52, 70))
457799	28745570	SOX10, a panschwannian and melanocytic marker, may also show positivity in myoepithelial cell tumors (Figure 8, A through C).	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('myoepithelial cell tumors', 'Disease', (75, 100))	('SOX10', 'Gene', '6663', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('SOX10', 'Gene', (0, 5))	('myoepithelial cell tumors', 'Disease', 'MESH:D009208', (75, 100))	('positivity', 'Var', (61, 71))
457827	28745570	Nodular fasciitis has been historically regarded as a reactive process, given its self-limiting nature, but is now thought to be neoplastic owing to the identification of recurrent translocation t(17;22)(p13;q13) that results in MYH9-USP6 fusion.	('USP6', 'Gene', (234, 238))	('MYH9', 'Gene', (229, 233))	('USP6', 'Gene', '9098', (234, 238))	('t(17;22)(p13;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (195, 212))	('Nodular fasciitis', 'Disease', (0, 17))	('results in', 'Reg', (218, 228))	('MYH9', 'Gene', '4627', (229, 233))	('fasciitis', 'Phenotype', 'HP:0100537', (8, 17))	('t(17;22)(p13;q13', 'Var', (195, 211))	('translocation t(17;22)(p13;q13', 'Var', (181, 211))	('Nodular fasciitis', 'Disease', 'MESH:D005208', (0, 17))
457838	28745570	The t(9;22)(q22;q12) translocation resulting in EWSR1-NR4A3 fusion has been found as the sole anomaly, while a number of other rare fusion partners for NR4A3 have been recently identified, including t(9;17)(q22;q11) and t(9;15)(q22;q21).	('t(9;17)(q22;q11', 'Var', (199, 214))	('NR4A3', 'Gene', (54, 59))	('NR4A3', 'Gene', '8013', (54, 59))	('t(9;17)(q22;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (199, 215))	('t(9;15)(q22;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (220, 236))	('fusion', 'Interaction', (60, 66))	('NR4A3', 'Gene', (152, 157))	('t(9;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 20))	('NR4A3', 'Gene', '8013', (152, 157))	('sole anomaly', 'Disease', (89, 101))	('t(9;15)(q22;q21', 'Var', (220, 235))	('sole anomaly', 'Disease', 'MESH:C535620', (89, 101))
457849	28745570	Most MIFSs carry t(1;10)(p22;q24), which results in TGFBR3-MGEA5 fusion.	('TGFBR3', 'Gene', (52, 58))	('t(1;10)(p22;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (17, 33))	('TGFBR3', 'Gene', '7049', (52, 58))	('MGEA5', 'Gene', '10724', (59, 64))	('results in', 'Reg', (41, 51))	('t(1;10)(p22;q24', 'Var', (17, 32))	('MGEA5', 'Gene', (59, 64))
457866	28745570	It also shows positivity in acute myeloid leukemia and a subset of prostate carcinomas.	('prostate carcinomas', 'Disease', 'MESH:D011471', (67, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (34, 50))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (28, 50))	('positivity', 'Var', (14, 24))	('acute myeloid leukemia', 'Disease', (28, 50))	('prostate carcinomas', 'Disease', (67, 86))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (28, 50))
457871	28745570	PRKCB expression has also been shown to be a sensitive and specific marker for EWSR1 rearrangements and a potential therapeutic target, thus warranting further investigation.	('PRKCB', 'Gene', (0, 5))	('EWSR1', 'Gene', (79, 84))	('men', 'Species', '9606', (94, 97))	('rearrangements', 'Var', (85, 99))
457873	28745570	FISH analysis using break-apart probe is highly sensitive (>90%) in detecting EWSR1 rearrangements but does not identify its translocation partner, whereas RT-PCR analysis is a specific test in identifying the EWSR1-FLI1 fusion gene but has a suboptimal sensitivity (54%) in formalin-fixed paraffin-embedded tissue.	('FLI1', 'Gene', '2313', (216, 220))	('men', 'Species', '9606', (93, 96))	('EWSR1', 'Gene', (78, 83))	('rearrangements', 'Var', (84, 98))	('formalin', 'Chemical', 'MESH:D005557', (275, 283))	('paraffin', 'Chemical', 'MESH:D010232', (290, 298))	('FLI1', 'Gene', (216, 220))
457884	28745570	A t(2;13)(q35;q14) or t(1;13)(p36;q14) translocation resulting in PAX3-FOXO1 or PAX7-FOXO1 fusion genes occurs in most cases.	('PAX3', 'Gene', '5077', (66, 70))	('FOXO1', 'Gene', (71, 76))	('FOXO1', 'Gene', '2308', (71, 76))	('FOXO1', 'Gene', '2308', (85, 90))	('PAX7', 'Gene', '5081', (80, 84))	('FOXO1', 'Gene', (85, 90))	('PAX7', 'Gene', (80, 84))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (2, 18))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (22, 38))	('fusion genes', 'Var', (91, 103))	('t(1', 'Var', (22, 25))	('t(2;13)(q35;q14', 'Var', (2, 17))	('PAX3', 'Gene', (66, 70))
457899	28745570	In 2006, two cases of "Ewing-like sarcoma" were found to harbor a recurrent t(4;19)(q35;q13) translocation, which resulted in fusion between CIC, a human homolog of Drosophila capicua, which encodes a high-mobility group box transcription factor, and DUX4, a double homeodomain gene.	('resulted in', 'Reg', (114, 125))	('DUX4', 'Gene', (251, 255))	('fusion', 'Var', (126, 132))	('CIC', 'Gene', (141, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('capicua', 'Gene', (176, 183))	('DUX4', 'Gene', '100288687', (251, 255))	('human', 'Species', '9606', (148, 153))	('Ewing-like sarcoma', 'Disease', (23, 41))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (76, 92))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (23, 41))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (23, 41))	('Drosophila', 'Species', '7227', (165, 175))	('capicua', 'Gene', '53560', (176, 183))
457900	28745570	To date, CIC-DUX4 fusion is the most frequent genetic alteration in EWSR1/FUS-negative undifferentiated small round cell tumors, while a number of other fusion partners for CIC have been recently identified.	('DUX4', 'Gene', (13, 17))	('DUX4', 'Gene', '100288687', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('FUS', 'Gene', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('FUS', 'Gene', '2521', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('fusion', 'Var', (18, 24))
457901	28745570	CIC-rearranged sarcomas primarily occur in soft tissue but may rarely affect bone.	('sarcomas primarily occur in soft tissue', 'Phenotype', 'HP:0100242', (15, 54))	('CIC-rearranged', 'Var', (0, 14))	('occur', 'Reg', (34, 39))	('sarcomas', 'Disease', 'MESH:D012509', (15, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('sarcomas', 'Disease', (15, 23))
457914	33370249	Alterations of m6A regulators were common, and ALKBH5 showed the highest frequency of copy number gain, while ZC3H13 had the highest frequency of loss.	('ZC3H13', 'Gene', (110, 116))	('Alterations', 'Var', (0, 11))	('m6A', 'Gene', (15, 18))	('copy', 'MPA', (86, 90))	('ALKBH5', 'Gene', '54890', (47, 53))	('m6A', 'Gene', '56339', (15, 18))	('ALKBH5', 'Gene', (47, 53))	('ZC3H13', 'Gene', '23091', (110, 116))	('gain', 'PosReg', (98, 102))
457915	33370249	CNVs and mutations were closely correlated with histology (P<0.001) and tumor size (P=0.040), and CNVs were correlated with mRNA expression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('correlated', 'Reg', (108, 118))	('tumor', 'Disease', (72, 77))	('mutations', 'Var', (9, 18))	('correlated', 'Reg', (32, 42))	('mRNA expression', 'MPA', (124, 139))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
457916	33370249	Furthermore, patients with gains of METTL16, RMB15, RMB15B, YTHDC, and YTHDF3 displayed poorer overall survival (OS), and patients with gains of RBM15 and YTHDC2 and loss of IGF2BP1 had poorer disease-free survival (DFS).	('disease-free survival', 'CPA', (193, 214))	('patients', 'Species', '9606', (13, 21))	('loss', 'Var', (166, 170))	('poorer', 'NegReg', (186, 192))	('RMB15B', 'Gene', (52, 58))	('overall survival', 'MPA', (95, 111))	('YTHDC2', 'Gene', (155, 161))	('IGF2BP1', 'Gene', '10642', (174, 181))	('YTHDF3', 'Gene', '253943', (71, 77))	('poorer', 'NegReg', (88, 94))	('RBM15', 'Gene', '64783', (145, 150))	('RMB15', 'Gene', (45, 50))	('patients', 'Species', '9606', (122, 130))	('METTL16', 'Gene', (36, 43))	('YTHDF3', 'Gene', (71, 77))	('IGF2BP1', 'Gene', (174, 181))	('YTHDC2', 'Gene', '64848', (155, 161))	('gains', 'PosReg', (136, 141))	('METTL16', 'Gene', '79066', (36, 43))	('RBM15', 'Gene', (145, 150))
457917	33370249	Further analysis indicated that CNVs and mutations of KIAA1429, YTHDF3, and IGF2BP1 were independent risk factors predicting OS and DFS.	('mutations', 'Var', (41, 50))	('IGF2BP1', 'Gene', (76, 83))	('KIAA1429', 'Gene', (54, 62))	('predicting', 'Reg', (114, 124))	('KIAA1429', 'Gene', '25962', (54, 62))	('IGF2BP1', 'Gene', '10642', (76, 83))	('YTHDF3', 'Gene', '253943', (64, 70))	('risk', 'Reg', (101, 105))	('YTHDF3', 'Gene', (64, 70))	('DFS', 'Disease', (132, 135))
457928	33370249	Methylation of N6-adenosine (m6A) is the most common type of RNA modification and is involved in a variety of cancer behaviors.	('cancer', 'Disease', (110, 116))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('involved in', 'Reg', (85, 96))	('m6A', 'Gene', (29, 32))	('m6A', 'Gene', '56339', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('adenosine', 'Chemical', 'MESH:D000241', (18, 27))
457933	33370249	In this study, we evaluated the copy number variations (CNVs) and mutations of these m6A regulators and aimed to provide a useful molecular tool to predict the outcome of sarcomas and deepen our understanding of the molecular mechanisms of the development of sarcomas.	('mutations', 'Var', (66, 75))	('copy number', 'Var', (32, 43))	('sarcomas', 'Disease', (171, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcomas', 'Disease', 'MESH:D012509', (259, 267))	('sarcomas', 'Phenotype', 'HP:0100242', (259, 267))	('m6A', 'Gene', (85, 88))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('m6A', 'Gene', '56339', (85, 88))	('sarcomas', 'Disease', (259, 267))
457940	33370249	The 206 patients were divided into 2 groups according to the presence of CNVs and mutations in the m6A regulators.	('mutations', 'Var', (82, 91))	('m6A', 'Gene', (99, 102))	('m6A', 'Gene', '56339', (99, 102))	('patients', 'Species', '9606', (8, 16))
457942	33370249	Mutations of m6A regulators were detected in only 11 of the 206 samples of patients with genomic data (Table 1).	('Mutations', 'Var', (0, 9))	('m6A', 'Gene', (13, 16))	('m6A', 'Gene', '56339', (13, 16))	('patients', 'Species', '9606', (75, 83))
457943	33370249	However, CNVs of the 18 m6A regulators were commonly found in all 206 samples of patients with CNV data (Figure 1A), with the number of events of loss (941/3708) and gain (1023/3708) being similar (Figure 1B) (Table 2).	('m6A', 'Gene', (24, 27))	('loss', 'NegReg', (146, 150))	('m6A', 'Gene', '56339', (24, 27))	('patients', 'Species', '9606', (81, 89))	('gain', 'PosReg', (166, 170))	('1023/3708', 'Var', (172, 181))
457946	33370249	To determine the role of m6A regulators in soft-tissue sarcoma, we analyzed the correlation of CNVs and mutations of m6A regulators with patient clinicopathological characteristics including age, sex, histologic diagnosis, presence of metastasis, tumor size, and FNCLCC grade.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('m6A', 'Gene', (117, 120))	('mutations', 'Var', (104, 113))	('patient', 'Species', '9606', (137, 144))	('m6A', 'Gene', '56339', (25, 28))	('sarcoma', 'Disease', (55, 62))	('tumor', 'Disease', (247, 252))	('m6A', 'Gene', '56339', (117, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('m6A', 'Gene', (25, 28))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (43, 62))
457948	33370249	The relationship between alterations in m6A regulators and corresponding mRNA expression levels was then analyzed.	('alterations', 'Var', (25, 36))	('m6A', 'Gene', '56339', (40, 43))	('m6A', 'Gene', (40, 43))	('mRNA expression levels', 'MPA', (73, 95))
457950	33370249	We also validated the findings in bladder cancer and found that copy number gains were correlated with higher mRNA expression in bladder cancer (Supplementary Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('bladder cancer', 'Disease', (129, 143))	('higher', 'PosReg', (103, 109))	('bladder cancer', 'Disease', (34, 48))	('mRNA expression', 'MPA', (110, 125))	('copy number gains', 'Var', (64, 81))
457954	33370249	Multivariate Cox regression analyses indicated that CNVs and mutations of writer KIAA1429 and readers YTHDF3 and IGF2BP1 were independent risk factors predicting OS and DFS (Table 4).	('YTHDF3', 'Gene', (102, 108))	('predicting', 'Reg', (151, 161))	('CNVs', 'Var', (52, 56))	('IGF2BP1', 'Gene', (113, 120))	('KIAA1429', 'Gene', (81, 89))	('mutations', 'Var', (61, 70))	('YTHDF3', 'Gene', '253943', (102, 108))	('KIAA1429', 'Gene', '25962', (81, 89))	('IGF2BP1', 'Gene', '10642', (113, 120))	('DFS', 'Disease', (169, 172))
457957	33370249	To validate the above conclusion, we then tested it in patients who were affected by 2 types of CNVs, copy number gain of writers and copy number loss of erasers.	('loss', 'NegReg', (146, 150))	('copy number', 'Var', (134, 145))	('copy number', 'Var', (102, 113))	('gain', 'PosReg', (114, 118))	('tested', 'Reg', (42, 48))	('patients', 'Species', '9606', (55, 63))
457959	33370249	As shown in Figure 6A, patients with a copy number gain of writers in combination with a loss of erasers had worse OS than those with only a copy number gain of writers (Figure 6A, 6B, Table 4).	('patients', 'Species', '9606', (23, 31))	('copy number', 'Var', (39, 50))	('gain', 'PosReg', (51, 55))
457971	33370249	In fact, genetic alteration is considered one of many features of sarcomas, and it has been demonstrated that CNVs and other alterations could result in dysregulated gene expression, subsequently leading to the development of sarcoma.	('sarcoma', 'Disease', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('dysregulated gene expression', 'MPA', (153, 181))	('CNVs', 'Var', (110, 114))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('alterations', 'Var', (125, 136))	('sarcoma', 'Disease', 'MESH:D012509', (226, 233))	('sarcomas', 'Disease', (66, 74))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('leading to', 'Reg', (196, 206))	('result in', 'Reg', (143, 152))	('sarcoma', 'Disease', (226, 233))	('genetic alteration', 'Var', (9, 27))
457976	33370249	According to previous studies, the most important clinical risk factors for recurrence are high-grade, larger tumor size, and aggressive histology, as found in undifferentiated pleomorphic sarcoma, leiomyosarcoma, and dedifferentiated liposarcoma.	('leiomyosarcoma', 'Disease', (198, 212))	('liposarcoma', 'Disease', (235, 246))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (198, 212))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('liposarcoma', 'Phenotype', 'HP:0012034', (235, 246))	('liposarcoma', 'Disease', 'MESH:D008080', (235, 246))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (198, 212))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (160, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('undifferentiated pleomorphic sarcoma', 'Disease', (160, 196))	('high-grade', 'Var', (91, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
457977	33370249	Further, the present analysis revealed the alterations of RBM15 (writer), YTHDC2 (reader), and IGF2BP1 (reader) were associated with an adverse prognosis.	('YTHDC2', 'Gene', '64848', (74, 80))	('IGF2BP1', 'Gene', (95, 102))	('YTHDC2', 'Gene', (74, 80))	('associated', 'Reg', (117, 127))	('RBM15', 'Gene', '64783', (58, 63))	('IGF2BP1', 'Gene', '10642', (95, 102))	('alterations', 'Var', (43, 54))	('RBM15', 'Gene', (58, 63))
457981	33370249	The prognosis of patients with dedifferentiated liposarcoma and soft-tissue leiomyosarcoma from TCGA was evaluated and prognostic markers were identified, showing that hypermethylation and certain chromosomal amplifications were associated with poor outcomes of dedifferentiated liposarcoma, while miRNA-181b was related to the shorter survival time of soft-tissue leiomyosarcoma.	('leiomyosarcoma', 'Disease', (365, 379))	('liposarcoma', 'Phenotype', 'HP:0012034', (48, 59))	('liposarcoma', 'Disease', 'MESH:D008080', (279, 290))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (76, 90))	('miRNA-181b', 'Var', (298, 308))	('liposarcoma', 'Disease', 'MESH:D008080', (48, 59))	('hypermethylation', 'Var', (168, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (372, 379))	('liposarcoma', 'Disease', (279, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (283, 290))	('leiomyosarcoma', 'Disease', (76, 90))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (365, 379))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (365, 379))	('patients', 'Species', '9606', (17, 25))	('liposarcoma', 'Disease', (48, 59))	('liposarcoma', 'Phenotype', 'HP:0012034', (279, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (76, 90))
457988	33370249	Consistently, the expression levels of mRNA writers, in contrast to those of readers and erasers, were indicated as risk factors of patients' survival.	('risk', 'Reg', (116, 120))	('patients', 'Species', '9606', (132, 140))	('mRNA writers', 'Var', (39, 51))	('expression levels', 'MPA', (18, 35))
457992	33370249	Among the dysregulated pathways and hallmarks, JAK2 (genes downregulated in HEL cells [erythroleukemia] after the knockdown of JAK2) and CSR were the most commonly upregulated oncogenic signatures.	('JAK2', 'Gene', '3717', (127, 131))	('JAK2', 'Gene', '3717', (47, 51))	('upregulated', 'PosReg', (164, 175))	('knockdown', 'Var', (114, 123))	('erythroleukemia', 'Disease', (87, 102))	('JAK2', 'Gene', (47, 51))	('downregulated', 'NegReg', (59, 72))	('erythroleukemia', 'Disease', 'MESH:D004915', (87, 102))	('JAK2', 'Gene', (127, 131))	('HEL', 'CellLine', 'CVCL:0001', (76, 79))
458001	33370249	In future studies, genomic methods could be used to specifically modify the m6A regulators and determine the effect of m6A regulator alterations on cancer cells in vitro.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('m6A', 'Gene', (76, 79))	('m6A', 'Gene', '56339', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('m6A', 'Gene', (119, 122))	('alterations', 'Var', (133, 144))	('modify', 'Reg', (65, 71))	('m6A', 'Gene', '56339', (119, 122))
458063	33489057	SS is characterized by the presence of a pathognomonic translocation between chromosomes X and 18, t(X;18) (p11.2;q11.2), which results in several SS18:SSX fusion proteins expression.	('SSX', 'Gene', '6757', (152, 155))	('results in', 'Reg', (128, 138))	('SS18', 'Gene', '6760', (147, 151))	('SSX', 'Gene', (152, 155))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('expression', 'MPA', (172, 182))	('SS', 'Phenotype', 'HP:0012570', (147, 149))	('t(X', 'Var', (99, 102))	('SS18', 'Gene', (147, 151))	('SS', 'Phenotype', 'HP:0012570', (152, 154))
458176	26841871	The hallmarks of cancer were recently revisited, and included Deregulating cellular energetics and avoiding immune destruction as an emerging characteristic, and tumor-promoting inflammation, genome instability and mutations as enabling characteristics.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Deregulating', 'Var', (62, 74))	('tumor', 'Disease', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (215, 224))	('genome instability', 'CPA', (192, 210))	('inflammation', 'Disease', 'MESH:D007249', (178, 190))	('cancer', 'Disease', (17, 23))	('inflammation', 'Disease', (178, 190))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
458177	26841871	Multiple genomic mutations are considered responsible for the malignant transformation of normal cells, which includes: capacity of tissue invasion and metastasis, insensitivity to antigrowth signals, sustained angiogenesis, ability to evade apoptosis, self-sufficient growth signals, limitless replication potential evasion of immune surveillance, DNA damage and several causative conditions of cellular stress such as DNA replication, mitosis and oxidative proteotoxic and metabolic processes.	('mitosis', 'Disease', 'None', (437, 444))	('mutations', 'Var', (17, 26))	('mitosis', 'Disease', (437, 444))	('DNA replication', 'Disease', (420, 435))
458180	26841871	There are two conflicting views on carcinogenesis; "genocentric view" proposes that favorable gene mutations and epigenetic alterations are early events in cancer, leading to altered cell phenotypes and clonal expansion.	('favorable gene', 'Gene', (84, 98))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cell phenotypes', 'CPA', (183, 198))	('carcinogenesis', 'Disease', 'MESH:D063646', (35, 49))	('mutations', 'Var', (99, 108))	('epigenetic alterations', 'Var', (113, 135))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('carcinogenesis', 'Disease', (35, 49))	('altered', 'Reg', (175, 182))
458202	26841871	For the M-Tert gene (accession number NM_009354.1) the primers were: sense 5'-GGATTGCCACTGGCTCCG-3'; antisense 5'-TGCCTGACCTCCTCTTGTGAC-3'.	('Tert', 'Gene', (10, 14))	("antisense 5'-TGCCTGACCTCCTCTTGTGAC-3", 'Var', (101, 137))	('Tert', 'Gene', '21752', (10, 14))
458224	26841871	RNA levels of TG180 were almost twice higher than NIH-3 T3 cell line and almost eight times higher than whole blood cells.	('RNA levels', 'MPA', (0, 10))	('higher', 'PosReg', (38, 44))	('TG180', 'Var', (14, 19))	('NIH-3 T3', 'CellLine', 'CVCL:0594', (50, 58))
458245	26841871	Increased rate of chromosome instability in tumors generates karyotypical diversity, a striking feature for the maintenance of the tumor.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('chromosome', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('chromosome instability', 'Phenotype', 'HP:0040012', (18, 40))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('karyotypical diversity', 'MPA', (61, 83))	('tumor', 'Disease', (44, 49))
458250	26841871	Genomic instability contributes to the development of CICs by directly transforming somatic stem cells, reprogramming differentiated cancer cellsfaced to different conditions found in the cellular microenvironment, and a number of other mechanisms.	('transforming', 'Reg', (71, 83))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('CICs', 'Disease', (54, 58))	('Genomic instability', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
458251	26841871	Many evidences support the idea of tetraploidy as a link to aneuploidy.	('tetraploidy', 'Var', (35, 46))	('aneuploidy', 'Disease', (60, 70))	('aneuploidy', 'Disease', 'MESH:D000782', (60, 70))
458253	26841871	Furthermore, in the present work it was detected diplochromosomes thus, it is reasonable to suggest that the standard karyotype of TG180 could be a result of an initial tetraploidy via endoreduplication, an event that drives tumor cells to acquire higher chromosome numbers.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tetraploidy', 'Var', (169, 180))	('tumor', 'Disease', (225, 230))	('TG180', 'Gene', (131, 136))	('result', 'Reg', (148, 154))
458261	26841871	So, it is possible that the Robertsonian translocation observed in TG180 may have caused fusion of some genes, producing chimeric proteins that may have activated cell proliferation, inactivated tumor suppressor genes or affected DNA repair.	('fusion', 'Var', (89, 95))	('tumor', 'Disease', (195, 200))	('activated', 'PosReg', (153, 162))	('Robertsonian translocation', 'Disease', (28, 54))	('chimeric', 'Var', (121, 129))	('DNA', 'MPA', (230, 233))	('inactivated', 'NegReg', (183, 194))	('cell proliferation', 'CPA', (163, 181))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('affected', 'Reg', (221, 229))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('caused', 'Reg', (82, 88))	('TG180', 'Gene', (67, 72))
458262	26841871	Even telomerase expression may have changed as a result ofstructural chromosomal abnormalities, once that was identified by SNP-array a fusion between IRX2-TERT genes caused by an interstitial deletion in the short arm of chromosome 5 (5p15.33).	('fusion', 'Var', (136, 142))	('TERT', 'Gene', '21752', (156, 160))	('IRX2', 'Gene', (151, 155))	('chromosomal abnormalities', 'Disease', (69, 94))	('short arm', 'Phenotype', 'HP:0009824', (209, 218))	('changed', 'Reg', (36, 43))	('caused by', 'Reg', (167, 176))	('IRX2', 'Gene', '16372', (151, 155))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (69, 94))	('TERT', 'Gene', (156, 160))
458280	26841871	Some cytogenetic studies and comparative genomic hybridization in epithelial tumors of mice with telomere dysfunction revealed a high rate of genomic aberrations among them; some non-reciprocal translocations, regional amplifications and deletions.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('deletions', 'Var', (238, 247))	('epithelial tumors', 'Disease', 'MESH:D002277', (66, 83))	('mice', 'Species', '10090', (87, 91))	('non-reciprocal translocations', 'Var', (179, 208))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('telomere dysfunction', 'Disease', 'MESH:C536801', (97, 117))	('epithelial tumors', 'Disease', (66, 83))	('regional amplifications', 'Var', (210, 233))	('telomere dysfunction', 'Disease', (97, 117))
458285	26841871	We believe that genetic instability generates a crisis process in which most cells, even the ones with an ideal chromosome balance, undergo apoptosis due to telomere erosion, and just rare cells will adapt and keep telomere integrity, by telomerase over-expression, enabling proliferation and promoting tumor progression, as proposed elsewhere.	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('telomerase', 'Var', (238, 248))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('telomere erosion', 'MPA', (157, 173))	('proliferation', 'CPA', (275, 288))	('tumor', 'Disease', (303, 308))	('enabling', 'PosReg', (266, 274))	('telomere integrity', 'MPA', (215, 233))	('promoting', 'PosReg', (293, 302))	('over-expression', 'PosReg', (249, 264))	('undergo', 'Reg', (132, 139))
458293	25810689	Of 64 spindle cell/pleomorphic neoplasms (in which DDL was a differential diagnosis), 21.9% showed MDM2 amplification.	('neoplasm', 'Phenotype', 'HP:0002664', (31, 39))	('neoplasms', 'Disease', (31, 40))	('pleomorphic neoplasms', 'Disease', (19, 40))	('MDM2', 'Gene', (99, 103))	('neoplasms', 'Disease', 'MESH:D009369', (31, 40))	('pleomorphic neoplasms', 'Disease', 'MESH:D008228', (19, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (31, 40))	('amplification', 'Var', (104, 117))
458299	25810689	Inflammatory DDL may resemble IgG4-associated sclerosing lesions or inflammatory myofibroblastic tumor, histologically low grade pattern DDL can mimic fibromatosis or low grade fibromyxoid sarcoma, and some patterns of WDL/DDL resemble pleomorphic or myxoid liposarcomatous subtypes.	('fibromyxoid sarcoma', 'Disease', (177, 196))	('myofibroblastic tumor', 'Disease', (81, 102))	('myxoid liposarcomatous subtypes', 'Disease', 'MESH:D045888', (251, 282))	('myxoid liposarcomatous', 'Phenotype', 'HP:0012268', (251, 273))	('low grade', 'Var', (119, 128))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (81, 102))	('fibromatosis', 'Disease', (151, 163))	('myofibroblastic tumor', 'Disease', 'MESH:D009369', (81, 102))	('liposarcoma', 'Phenotype', 'HP:0012034', (258, 269))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (262, 269))	('IgG4-associated sclerosing lesions', 'Disease', (30, 64))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (177, 196))	('fibromatosis', 'Disease', 'MESH:D005350', (151, 163))	('Inflammatory DDL', 'Disease', (0, 16))	('myxoid liposarcomatous subtypes', 'Disease', (251, 282))
458304	25810689	MDM2 amplification is also associated with other sarcomas such as parosteal osteosarcoma and intimal sarcoma, so while it is not entirely specific for WDL and DDL, its assessment by FISH has been developed as an adjunctive tool for their diagnosis.	('parosteal osteosarcoma', 'Disease', (66, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('amplification', 'Var', (5, 18))	('associated', 'Reg', (27, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('parosteal osteosarcoma', 'Disease', 'MESH:D012516', (66, 88))	('intimal sarcoma', 'Disease', (93, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('MDM2', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
458315	25810689	One patient had 2 separate lipomatous neoplasms tested (1 positive for MDM2 amplification, the other negative).	('lipomatous neoplasms', 'Phenotype', 'HP:0012031', (27, 47))	('lipoma', 'Phenotype', 'HP:0012032', (27, 33))	('neoplasm', 'Phenotype', 'HP:0002664', (38, 46))	('positive', 'Reg', (58, 66))	('lipomatous neoplasms', 'Disease', (27, 47))	('lipomatous neoplasms', 'Disease', 'MESH:D008080', (27, 47))	('MDM2', 'Gene', (71, 75))	('neoplasms', 'Phenotype', 'HP:0002664', (38, 47))	('amplification', 'Var', (76, 89))
458326	25810689	For example, of 201 spindle cell tumors studied by Kashima et al., 7 had MDM2 amplification (3 spindle cell sarcomas NOS, 2 osteosarcomas, and 2 myxofibrosarcomas), of which all were retroperitoneal or intra-abdominal, with some on subsequent review showing WDL components, and these were all reclassified as DDL.	('myxofibrosarcomas', 'Disease', 'None', (145, 162))	('osteosarcomas', 'Phenotype', 'HP:0002669', (124, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('MDM2', 'Gene', (73, 77))	('spindle cell', 'Disease', (95, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcomas', 'Disease', 'MESH:D012516', (124, 137))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('WDL', 'Disease', (258, 261))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (154, 162))	('DDL', 'Disease', (309, 312))	('amplification', 'Var', (78, 91))	('myxofibrosarcomas', 'Disease', (145, 162))	('osteosarcomas', 'Disease', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
458450	30006631	Genomic studies suggest that a subset of OS, including OS tumour cell lines (TCLs), exhibit genomic loss of heterozygosity (LOH) patterns reminiscent of BRCA1 or BRCA2 mutant tumours.	('OS tumour', 'Disease', 'MESH:C567932', (55, 64))	('BRCA2', 'Gene', (162, 167))	('mutant', 'Var', (168, 174))	('loss of heterozygosity', 'NegReg', (100, 122))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA1', 'Gene', '672', (153, 158))	('BRCA2', 'Gene', '675', (162, 167))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('tumours', 'Disease', 'MESH:D009369', (175, 182))	('BRCA1', 'Gene', (153, 158))	('OS tumour', 'Disease', (55, 64))	('tumours', 'Disease', (175, 182))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
458451	30006631	This raises the possibility that PARP inhibitors (PARPi), used to treat BRCA1/2 mutant cancers, could be used to target OS.	('cancers', 'Disease', (87, 94))	('BRCA1/2', 'Gene', (72, 79))	('mutant', 'Var', (80, 86))	('BRCA1/2', 'Gene', '672;675', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('PARP', 'Gene', '1302', (50, 54))	('PARP', 'Gene', '1302', (33, 37))	('PARP', 'Gene', (33, 37))	('PARP', 'Gene', (50, 54))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
458461	30006631	BRCAness describes tumours that possess histopathological and molecular characteristics similar to those found in patients with germ-line BRCA1 or BRCA2 gene defects, including a distinctive DNA repair defect arising from loss of Homologous Recombination (HR) and drug sensitivity effects associated with this HR defect, including exquisite PARP inhibitor sensitivity.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('HR defect', 'Disease', (310, 319))	('BRCA1', 'Gene', '672', (138, 143))	('DNA repair', 'MPA', (191, 201))	('BRCA2', 'Gene', '675', (147, 152))	('HR defect', 'Disease', 'MESH:D005128', (310, 319))	('BRCA1', 'Gene', (138, 143))	('PARP', 'Gene', '1302', (341, 345))	('defects', 'Var', (158, 165))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('BRCAness describes tumours', 'Disease', 'MESH:D009369', (0, 26))	('PARP', 'Gene', (341, 345))	('patients', 'Species', '9606', (114, 122))	('BRCA2', 'Gene', (147, 152))	('loss', 'Var', (222, 226))	('drug sensitivity', 'Phenotype', 'HP:0020174', (264, 280))	('BRCAness describes tumours', 'Disease', (0, 26))
458463	30006631	identified large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours and recurrent mutations in tumour suppressor genes associated with homologous recombination and related DNA repair processes, including FANCA BRCA2 and ATM.	('mutations', 'Var', (111, 120))	('BRCA1/2-deficient tumours', 'Disease', (71, 96))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('ATM', 'Gene', (249, 252))	('BRCA2', 'Gene', (239, 244))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('BRCA2', 'Gene', '675', (239, 244))	('BRCA1/2-deficient tumours', 'Disease', 'OMIM:612555', (71, 96))	('ATM', 'Gene', '472', (249, 252))	('genome instability', 'MPA', (23, 41))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('tumour', 'Disease', (124, 130))
458466	30006631	However, whether the scale of PARP inhibitor sensitivity seen in OS models resembles that in BRCA gene mutant tumour cell lines was unclear.	('PARP', 'Gene', '1302', (30, 34))	('PARP', 'Gene', (30, 34))	('BRCA', 'Gene', '672', (93, 97))	('mutant', 'Var', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('BRCA', 'Gene', (93, 97))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
458470	30006631	As part of this resource, we describe the sensitivity of OS tumour cell lines to three chemically distinct PARP inhibitors, comparing their sensitivity to BRCA1 mutant tumour cell lines and to a tumour cell line model with a CRISPR-Cas9 mutagenesis-engineered PARP inhibitor resistance-causing revertant mutation in BRCA1.	('PARP', 'Gene', '1302', (260, 264))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('BRCA1', 'Gene', '672', (155, 160))	('OS tumour', 'Disease', 'MESH:C567932', (57, 66))	('tumour', 'Disease', (195, 201))	('PARP', 'Gene', '1302', (107, 111))	('BRCA1', 'Gene', (155, 160))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('mutation', 'Var', (304, 312))	('mutant', 'Var', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Disease', (60, 66))	('PARP', 'Gene', (260, 264))	('PARP', 'Gene', (107, 111))	('OS tumour', 'Disease', (57, 66))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Disease', (168, 174))	('BRCA1', 'Gene', '672', (316, 321))	('BRCA1', 'Gene', (316, 321))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
458473	30006631	Given the interest in PARP inhibitor sensitivity in OS, we also included in the tumour cell line panel a PARP inhibitor sensitive breast tumour cell line, SUM149, with loss of function BRCA1 mutation (BRCA1 p.P724fs*12) as well as a PARP inhibitor resistant SUM149-subclone, SUM149.B1*.S, that has partially restored BRCA1 function because of a CRISPR-Cas9 mutagenesis-engineered BRCA1 intragenic reversion mutation.	('breast tumour', 'Disease', 'MESH:D001943', (130, 143))	('PARP', 'Gene', '1302', (105, 109))	('breast tumour', 'Disease', (130, 143))	('breast tumour', 'Phenotype', 'HP:0100013', (130, 143))	('BRCA1', 'Gene', '672', (185, 190))	('PARP', 'Gene', (22, 26))	('BRCA1', 'Gene', (185, 190))	('PARP', 'Gene', '1302', (233, 237))	('BRCA1', 'Gene', '672', (201, 206))	('BRCA1', 'Gene', (201, 206))	('mutation', 'Var', (407, 415))	('PARP', 'Gene', (105, 109))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('BRCA1', 'Gene', '672', (317, 322))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('PARP', 'Gene', (233, 237))	('tumour', 'Disease', (137, 143))	('BRCA1', 'Gene', (317, 322))	('function', 'MPA', (323, 331))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('p.P724fs*12', 'Mutation', 'p.P724fsX12', (207, 218))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('BRCA1', 'Gene', '672', (380, 385))	('tumour', 'Disease', (80, 86))	('BRCA1', 'Gene', (380, 385))	('PARP', 'Gene', '1302', (22, 26))
458474	30006631	This BRCA1 reversion mutation restores the native open reading frame of the BRCA1 gene, recapitulates RAD51 nuclear localisation (a key molecular event in BRCA1-mediated DNA repair) and causes profound PARP inhibitor resistance.	('PARP', 'Gene', '1302', (202, 206))	('native open reading frame', 'MPA', (43, 68))	('PARP', 'Gene', (202, 206))	('recapitulates', 'NegReg', (88, 101))	('BRCA1', 'Gene', '672', (155, 160))	('mutation', 'Var', (21, 29))	('BRCA1', 'Gene', '672', (76, 81))	('restores', 'PosReg', (30, 38))	('BRCA1', 'Gene', '672', (5, 10))	('BRCA1', 'Gene', (155, 160))	('causes', 'Reg', (186, 192))	('BRCA1', 'Gene', (76, 81))	('RAD51', 'Gene', (102, 107))	('BRCA1', 'Gene', (5, 10))	('RAD51', 'Gene', '5888', (102, 107))
458475	30006631	For chemosensitivity screening, we used an in-house curated small molecule library of 79 small-molecule inhibitors that are either in clinical use for the treatment of cancer or in late-stage clinical development (Supplementary Table 2).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('small-molecule', 'Var', (89, 103))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
458480	30006631	Amplification of the Fibroblast Growth Factor Receptor 1 (FGFR1) gene in OS tumour cell lines has previously been shown to predict enhanced sensitivity to FGFR inhibition by the pan-FGFR inhibitor NVP-BGJ398.	('Amplification', 'Var', (0, 13))	('OS tumour', 'Disease', (73, 82))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('Fibroblast Growth Factor Receptor 1', 'Gene', '2260', (21, 56))	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', '2260', (58, 63))	('sensitivity to FGFR inhibition', 'MPA', (140, 170))	('OS tumour', 'Disease', 'MESH:C567932', (73, 82))	('enhanced', 'PosReg', (131, 139))	('Fibroblast Growth Factor Receptor 1', 'Gene', (21, 56))
458481	30006631	To assess the ability of our screen data to identify this known chemosensitivity effect, we interrogated the screen data from OS tumour cell lines for two different FGFR inhibitors, AZ4547 and PD173074.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('AZ4547', 'Chemical', '-', (182, 188))	('OS tumour', 'Disease', (126, 135))	('FGFR', 'Gene', (165, 169))	('OS tumour', 'Disease', 'MESH:C567932', (126, 135))	('AZ4547', 'Var', (182, 188))	('PD173074', 'Var', (193, 201))	('PD173074', 'Chemical', 'MESH:C115711', (193, 201))
458482	30006631	We noted that, in general, OS TCLs exhibited greater sensitivity to AZD4547 (Fig.	('AZD4547', 'Chemical', 'MESH:C572463', (68, 75))	('sensitivity', 'MPA', (53, 64))	('AZD4547', 'Var', (68, 75))
458483	30006631	1F, p = 0.01, Mann-Whitney uncorrected test), as previously noted and found that AZ4547 vs. PD173074 sensitivities in OS TCLs were highly correlated (Fig.	('AZ4547', 'Var', (81, 87))	('PD173074', 'Var', (92, 100))	('AZ4547', 'Chemical', '-', (81, 87))	('PD173074', 'Chemical', 'MESH:C115711', (92, 100))
458484	30006631	We also found that OS tumour cell lines with FGFR1 amplification (G292, NOS1 and CAL72) or FGFR1 gain (HU09 and NY) were significantly more sensitive to both AZ547 and PD173074 than those OS tumour cell lines without FGFR1 copy number alterations (Fig.	('OS tumour', 'Disease', (188, 197))	('PD173074', 'Var', (168, 176))	('NOS1', 'Gene', '4842', (72, 76))	('FGFR1', 'Gene', '2260', (45, 50))	('OS tumour', 'Disease', (19, 28))	('FGFR1', 'Gene', '2260', (91, 96))	('NOS1', 'Gene', (72, 76))	('gain', 'PosReg', (97, 101))	('FGFR1', 'Gene', '2260', (217, 222))	('more', 'PosReg', (135, 139))	('amplification', 'Var', (51, 64))	('sensitive', 'MPA', (140, 149))	('OS tumour', 'Disease', 'MESH:C567932', (188, 197))	('FGFR1', 'Gene', (45, 50))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('FGFR1', 'Gene', (91, 96))	('OS tumour', 'Disease', 'MESH:C567932', (19, 28))	('FGFR1', 'Gene', (217, 222))	('PD173074', 'Chemical', 'MESH:C115711', (168, 176))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
458487	30006631	Recent analysis of exome DNA resequencing data from treatment naive OS has suggested that a significant fraction of OS might exhibit a pattern of chromosomal aberrations, specifically chromosomal loss of heterozygosity (LOH) effects, that are somewhat reminiscent of mutational patterns seen in tumours from cancer patients with germ-line BRCA1 or BRCA2 gene mutations.	('loss of', 'NegReg', (196, 203))	('tumour', 'Phenotype', 'HP:0002664', (295, 301))	('BRCA2', 'Gene', (348, 353))	('mutations', 'Var', (359, 368))	('BRCA1', 'Gene', (339, 344))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('tumours', 'Phenotype', 'HP:0002664', (295, 302))	('cancer', 'Disease', (308, 314))	('tumours', 'Disease', 'MESH:D009369', (295, 302))	('patients', 'Species', '9606', (315, 323))	('tumours', 'Disease', (295, 302))	('BRCA2', 'Gene', '675', (348, 353))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (146, 169))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('BRCA1', 'Gene', '672', (339, 344))
458488	30006631	These characteristics of BRCAness might have therapeutic implications, as the DNA repair defects thought to lead to this particular type of LOH effect, can often cause sensitivity to PARPi.	('BRCAness', 'Disease', 'None', (25, 33))	('PARP', 'Gene', '1302', (183, 187))	('PARP', 'Gene', (183, 187))	('defects', 'Var', (89, 96))	('cause', 'Reg', (162, 167))	('BRCAness', 'Disease', (25, 33))
458493	30006631	As positive and negative controls respectively, we included in the screen BRCA1 mutant, PARPi sensitive SUM149 cells and a PARPi resistant SUM149 subclone with a BRCA1 reversion mutation, described elsewhere.	('PARP', 'Gene', '1302', (123, 127))	('PARP', 'Gene', (123, 127))	('mutant', 'Var', (80, 86))	('BRCA1', 'Gene', '672', (162, 167))	('BRCA1', 'Gene', '672', (74, 79))	('BRCA1', 'Gene', (162, 167))	('PARP', 'Gene', '1302', (88, 92))	('BRCA1', 'Gene', (74, 79))	('PARP', 'Gene', (88, 92))
458496	30006631	We also noted additional BRCA1 mutant tumour cell lines (MDAMB436, HCC1395) and a BRCA1 promoter hypermethylated tumour cell line HCC38 to display PARPi sensitivity, as did a number of synovial sarcoma tumour cell lines (SYO1, CME, HS-SYII, ASKA), as described earlier (Fig.	('PARP', 'Gene', '1302', (147, 151))	('BRCA1', 'Gene', '672', (82, 87))	('MDAMB436', 'CellLine', 'CVCL:0623', (57, 65))	('HCC38', 'CellLine', 'CVCL:1267', (130, 135))	('BRCA1', 'Gene', (82, 87))	('PARP', 'Gene', (147, 151))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('synovial sarcoma tumour', 'Disease', (185, 208))	('tumour', 'Disease', (202, 208))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (185, 201))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('mutant', 'Var', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('BRCA1', 'Gene', '672', (25, 30))	('HCC1395', 'CellLine', 'CVCL:1249', (67, 74))	('BRCA1', 'Gene', (25, 30))	('tumour', 'Disease', (113, 119))	('synovial sarcoma tumour', 'Disease', 'MESH:D013584', (185, 208))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('tumour', 'Disease', (38, 44))
458498	30006631	Out of 18 OS tumour cell lines assessed, only LM7 demonstrated profound sensitivity to PARPi of a scale similar to that seen in BRCA1 mutant SUM149 cells (Fig.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('PARP', 'Gene', '1302', (87, 91))	('OS tumour', 'Disease', (10, 19))	('PARP', 'Gene', (87, 91))	('OS tumour', 'Disease', 'MESH:C567932', (10, 19))	('BRCA1', 'Gene', '672', (128, 133))	('LM7', 'CellLine', 'CVCL:0515', (46, 49))	('BRCA1', 'Gene', (128, 133))	('mutant', 'Var', (134, 140))
458505	30006631	Although exome sequencing of LM7 cells did not identify BRCA1 nor BRCA2 gene alterations, LM7 cells exhibited comparable olaparib sensitivity to BRCA2 defective (BRCA2 c.6774delT truncating mutant) CAPAN1 pancreatic ductal carcinoma cells (ANOVA p = 0.3757) but significantly greater sensitivity to olaparib than BRCA1 mutant SUM149 cells (ANOVA p = 0.0119), the BRCA1 revertant SUM149 subclone, and a previously validated PARPi resistant BRCA2 revertant CAPAN1 subclone, CAPAN1.B2*.S (ANOVA p < 0.0001, Fig.	('BRCA2', 'Gene', (66, 71))	('BRCA2', 'Gene', (145, 150))	('BRCA1', 'Gene', '672', (313, 318))	('CAPAN1', 'CellLine', 'CVCL:0237', (472, 478))	('BRCA1', 'Gene', (313, 318))	('BRCA2', 'Gene', '675', (162, 167))	('olaparib', 'Chemical', 'MESH:C531550', (121, 129))	('pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (205, 232))	('BRCA2', 'Gene', '675', (439, 444))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('PARP', 'Gene', '1302', (423, 427))	('BRCA2', 'Gene', '675', (66, 71))	('BRCA2', 'Gene', '675', (145, 150))	('CAPAN1', 'CellLine', 'CVCL:0237', (455, 461))	('LM7', 'CellLine', 'CVCL:0515', (29, 32))	('CAPAN1', 'CellLine', 'CVCL:0237', (198, 204))	('BRCA1', 'Gene', '672', (56, 61))	('olaparib', 'Chemical', 'MESH:C531550', (299, 307))	('c.6774delT', 'Mutation', 'c.6774delT', (168, 178))	('PARP', 'Gene', (423, 427))	('LM7', 'CellLine', 'CVCL:0515', (90, 93))	('BRCA1', 'Gene', (56, 61))	('defective', 'NegReg', (151, 160))	('BRCA1', 'Gene', '672', (363, 368))	('BRCA1', 'Gene', (363, 368))	('BRCA2', 'Gene', (162, 167))	('pancreatic ductal carcinoma', 'Disease', (205, 232))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (216, 232))	('BRCA2', 'Gene', (439, 444))	('c.6774delT', 'Var', (168, 178))
458506	30006631	LM7 cells also exhibited similar sensitivity to Talazoparib, demonstrating significantly greater sensitivity to this PARPi than CAPAN1.B2*.S and SUM149.B1*.S (ANOVA p < 0.001, Fig.	('CAPAN1', 'CellLine', 'CVCL:0237', (128, 134))	('Talazoparib', 'Chemical', 'MESH:C586365', (48, 59))	('PARP', 'Gene', '1302', (117, 121))	('LM7', 'CellLine', 'CVCL:0515', (0, 3))	('PARP', 'Gene', (117, 121))	('SUM149.B1*.S', 'Var', (145, 157))
458509	30006631	We investigated whether LM7 cells exhibited a RAD51 nuclear localisation defect, finding that in response to DNA damage, LM7 cells exhibited significantly decreased nuclear RAD51 foci formation, compared to SAOS2 cells (p = 0.0005, Student's t test, Fig.	('nuclear', 'CPA', (165, 172))	('RAD51', 'Gene', (46, 51))	('decreased', 'NegReg', (155, 164))	('RAD51', 'Gene', (173, 178))	('LM7', 'CellLine', 'CVCL:0515', (24, 27))	('RAD51', 'Gene', '5888', (46, 51))	('RAD51', 'Gene', '5888', (173, 178))	('LM7', 'CellLine', 'CVCL:0515', (121, 124))	('LM7', 'Var', (121, 124))
458517	30006631	By comparing the PARP inhibitor sensitivity of OS tumour cell lines to the scale of sensitivity in breast tumour cell lines with BRCA1 defects and also isogenic tumour cell models with a well-established and clinically relevant mechanism of PARP inhibitor resistance, we have been able to make a comparative analysis that suggests that whilst most OS tumour cell lines do not exhibit the exquisite level of PARP inhibitor sensitivity seen in BRCA1 mutant breast tumour cell lines, the LM7 model does display evidence of BRCAness and a PARP inhibitor sensitivity phenotype.	('breast tumour', 'Disease', 'MESH:D001943', (99, 112))	('breast tumour', 'Disease', (455, 468))	('breast tumour', 'Phenotype', 'HP:0100013', (455, 468))	('BRCA1', 'Gene', '672', (129, 134))	('breast tumour', 'Disease', (99, 112))	('PARP', 'Gene', '1302', (17, 21))	('BRCA1', 'Gene', (129, 134))	('PARP', 'Gene', '1302', (535, 539))	('breast tumour', 'Phenotype', 'HP:0100013', (99, 112))	('OS tumour', 'Disease', 'MESH:C567932', (47, 56))	('PARP', 'Gene', '1302', (241, 245))	('BRCAness', 'Disease', (520, 528))	('tumour', 'Phenotype', 'HP:0002664', (351, 357))	('BRCAness', 'Disease', 'None', (520, 528))	('BRCA1 defects and also isogenic tumour', 'Disease', 'MESH:D010051', (129, 167))	('tumour', 'Phenotype', 'HP:0002664', (462, 468))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('PARP', 'Gene', '1302', (407, 411))	('OS tumour', 'Disease', 'MESH:C567932', (348, 357))	('PARP', 'Gene', (535, 539))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('PARP', 'Gene', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('PARP', 'Gene', (241, 245))	('OS tumour', 'Disease', (47, 56))	('PARP', 'Gene', (407, 411))	('LM7', 'CellLine', 'CVCL:0515', (485, 488))	('BRCA1', 'Gene', '672', (442, 447))	('mutant', 'Var', (448, 454))	('OS tumour', 'Disease', (348, 357))	('BRCA1', 'Gene', (442, 447))	('breast tumour', 'Disease', 'MESH:D001943', (455, 468))
458519	30006631	Nevertheless, we did find that the five-day drug exposure used was sufficient to document differences in PARP inhibitor sensitivity between BRCA1 mutant and BRCA1 revertant clones; the synthetic lethal effects of PARP inhibitors in in vitro cell culture often require drug exposure over several cell cycles (Farmer et al., 2005), but the five-day exposure appears sufficient here.	('PARP', 'Gene', (105, 109))	('BRCA1', 'Gene', (140, 145))	('BRCA1', 'Gene', (157, 162))	('PARP', 'Gene', '1302', (213, 217))	('PARP', 'Gene', (213, 217))	('mutant', 'Var', (146, 152))	('PARP', 'Gene', '1302', (105, 109))	('BRCA1', 'Gene', '672', (140, 145))	('BRCA1', 'Gene', '672', (157, 162))
458539	28454547	PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options.	('inhibitors', 'Var', (84, 94))	('tumor', 'Disease', (143, 148))	('synergistic', 'MPA', (28, 39))	('Enhancing', 'PosReg', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('PARP1', 'Gene', '142', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('sarcoma', 'Disease', (98, 105))	('PARP1', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('PARP1', 'Gene', (0, 5))	('tumor', 'Disease', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('PARP1', 'Gene', '142', (0, 5))
458541	28454547	We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('targeting', 'Var', (27, 36))	('trabectedin', 'Chemical', 'MESH:D000077606', (54, 65))	('tumor', 'Disease', (88, 93))	('PARP1', 'Gene', (21, 26))
458543	28454547	Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents.	('cell cycle arrest at G2/M checkpoint', 'CPA', (101, 137))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (101, 118))	('Trabectedin', 'Chemical', 'MESH:D000077606', (0, 11))	('DNA', 'CPA', (89, 92))	('combination', 'Interaction', (43, 54))	('potentiated', 'PosReg', (77, 88))	('PARP1', 'Gene', (22, 27))	('apoptosis', 'CPA', (142, 151))	('inhibitors', 'Var', (66, 76))	('PARP1', 'Gene', (60, 65))
458548	28454547	Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.	('silencing', 'NegReg', (104, 113))	('olaparib', 'Chemical', 'MESH:C531550', (20, 28))	('overexpression', 'Var', (65, 79))	('trabectedin', 'Chemical', 'MESH:D000077606', (8, 19))	('reduced', 'NegReg', (84, 91))	('increased', 'PosReg', (43, 52))	('trabectedin/olaparib', 'Protein', (8, 28))	('PARP1', 'Gene', (59, 64))
458551	28454547	Unfortunately, despite several preclinical data confirming an increased antitumor activity by combining PARP1 inhibitors with either chemotherapy or radiotherapy, dose escalation in phase 1 combination studies has been greatly hampered by the observed hematologic toxicities.	('increased', 'PosReg', (62, 71))	('hematologic toxicities', 'Disease', (252, 274))	('PARP1', 'Gene', (104, 109))	('tumor', 'Disease', (76, 81))	('hematologic toxicities', 'Disease', 'MESH:D006402', (252, 274))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('inhibitors', 'Var', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
458552	28454547	As a consequence, PARP1 inhibitors are today registered as monotherapy in cancers bearing DNA-repair deficiencies and the strong rational to combine selected cytotoxics (especially alkylators) with PARP1 inhibitors has to face the risk of myelotoxicity.	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('myelotoxicity', 'Disease', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cytotoxics', 'Disease', (158, 168))	('cancers', 'Disease', (74, 81))	('myelotoxicity', 'Disease', 'MESH:D001855', (239, 252))	('deficiencies', 'Var', (101, 113))	('cytotoxics', 'Disease', 'MESH:D064420', (158, 168))	('PARP1', 'Gene', (18, 23))
458559	28454547	The observed results were subsequently validated in other tumor types and by combining PARP1 inhibitors with other cytotoxics characterized by different mechanisms of action.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('PARP1', 'Gene', (87, 92))	('cytotoxics', 'Disease', 'MESH:D064420', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cytotoxics', 'Disease', (115, 125))	('inhibitors', 'Var', (93, 103))
458574	28454547	Briefly, 750 ng of samples and control DNA in a total volume of 10.1 muL were digested with restriction enzymes and labeled with Cy3 and Cy5.	('Cy5', 'Var', (137, 140))	('Cy5', 'Chemical', 'MESH:C085321', (137, 140))	('Cy3', 'Chemical', '-', (129, 132))	('Cy3', 'Var', (129, 132))
458603	28454547	Subsequently, we showed that after 24-h treatment with the combination of trabectedin (0.125 nM) and olaparib (1.25 muM) there was a variable but significant increase in P-H2AX positive cells if compared to single agents and untreated controls (Fig.	('muM', 'Gene', (116, 119))	('P-H2', 'Gene', '1912', (170, 174))	('P-H2', 'Gene', (170, 174))	('0.125', 'Var', (87, 92))	('olaparib', 'Chemical', 'MESH:C531550', (101, 109))	('trabectedin', 'Chemical', 'MESH:D000077606', (74, 85))	('increase', 'PosReg', (158, 166))	('muM', 'Gene', '56925', (116, 119))
458609	28454547	To further explain differences in PARylation activity, we performed mutational analysis of PARP1 gene and we found the Val762Ala single nucleotide polymorphism in SJSA-1 and SW684 cells (Additional file 2: Figure S2).	('Val762Ala', 'Var', (119, 128))	('SA', 'Chemical', 'MESH:C012546', (165, 167))	('Val762Ala', 'SUBSTITUTION', 'None', (119, 128))	('PARP1', 'Gene', (91, 96))	('single nucleotide polymorphism', 'Var', (129, 159))	('SW684', 'CellLine', 'CVCL:1726', (174, 179))
458613	28454547	This effect was consistently stronger in high-PARP1-expressing cells (TC-106, DMR, 402.91) and led to a significant inhibition of tumor cell colony growth (p < 0.001; Fig.	('TC-106', 'Chemical', '-', (70, 76))	('high-PARP1-expressing', 'Var', (41, 62))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('inhibition', 'NegReg', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('DMR', 'Chemical', '-', (78, 81))	('tumor', 'Disease', (130, 135))	('stronger', 'PosReg', (29, 37))
458616	28454547	In high-PARP1-expressing cells the trabectedin IC50s were significantly reduced if compared to low-PARP1-expressing cells both in combination with olaparib and veliparib (p = 0.01 and p = 0.02, respectively; Additional file 2: Figure S3).	('reduced', 'NegReg', (72, 79))	('trabectedin', 'Chemical', 'MESH:D000077606', (35, 46))	('high-PARP1-expressing', 'Var', (3, 24))	('50s', 'Species', '1214577', (49, 52))	('olaparib', 'Chemical', 'MESH:C531550', (147, 155))	('veliparib', 'Chemical', 'MESH:C521013', (160, 169))
458620	28454547	Of note is that the doxorubicin-resistant leiomyosarcoma cell line MES-SA-DX5 also displayed cross-resistance to trabectedin, but addition of PARP1 inhibitors restored sensitivity to a clinically achievable trabectedin concentration (Additional file 1: Table S1 and Additional file 2: Figure S2e).	('inhibitors', 'Var', (148, 158))	('sensitivity', 'MPA', (168, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('trabectedin', 'Chemical', 'MESH:D000077606', (207, 218))	('PARP1', 'Gene', (142, 147))	('restored', 'PosReg', (159, 167))	('doxorubicin', 'Chemical', 'MESH:D004317', (20, 31))	('MES', 'Chemical', 'MESH:C004550', (67, 70))	('leiomyosarcoma', 'Disease', (42, 56))	('trabectedin', 'Chemical', 'MESH:D000077606', (113, 124))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (42, 56))	('SA', 'Chemical', 'MESH:C012546', (71, 73))	('addition', 'Var', (130, 138))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (42, 56))
458640	28454547	In DMR s.c. models, cell proliferation was significantly reduced (PCNA, Fig.	('reduced', 'NegReg', (57, 64))	('DMR', 'Chemical', '-', (3, 6))	('DMR', 'Var', (3, 6))	('cell proliferation', 'CPA', (20, 38))
458653	28454547	We investigated PARylation in both low- vs. high-PARP1-expressing cells and PARP1-silenced vs. wild-type counterparts (Additional file 2: Figure S7A) after the treatment with different chemotherapeutic agents: cisplatin, dacarbazine, actinomycin-D, etoposide, doxorubicin, and gemcitabine characterized by different mechanism of action: crosslinking, methylation, transcription inhibition, topoisomerase II inhibition, DNA intercalation, and nucleotide mimicking, respectively.	('topoisomerase II', 'Enzyme', (390, 406))	('dacarbazine', 'Chemical', 'MESH:D003606', (221, 232))	('doxorubicin', 'Chemical', 'MESH:D004317', (260, 271))	('transcription', 'MPA', (364, 377))	('etoposide', 'Chemical', 'MESH:D005047', (249, 258))	('cisplatin', 'Chemical', 'MESH:D002945', (210, 219))	('inhibition', 'NegReg', (407, 417))	('actinomycin-D', 'Chemical', 'MESH:D003609', (234, 247))	('methylation', 'Var', (351, 362))	('gemcitabine', 'Chemical', 'MESH:C056507', (277, 288))
458656	28454547	After PARP1 silencing in MSTO-H211 cells, PARylation was invariably decreased if compared to parental cells after each treatment.	('decreased', 'NegReg', (68, 77))	('PARylation', 'MPA', (42, 52))	('silencing', 'Var', (12, 21))	('MSTO-H211', 'CellLine', 'CVCL:1430', (25, 34))	('PARP1', 'Gene', (6, 11))
458657	28454547	We identified and demonstrated that PARP1 basal expression is crucial in the mechanism behind the synergy between PARP1 inhibitors and trabectedin independent of BRCA1/2 status, in several robust models across different histotypes.	('inhibitors', 'Var', (120, 130))	('BRCA1/2', 'Gene', (162, 169))	('PARP1', 'Gene', (114, 119))	('trabectedin', 'Chemical', 'MESH:D000077606', (135, 146))	('BRCA1/2', 'Gene', '672;675', (162, 169))	('PARP1', 'Gene', (36, 41))
458658	28454547	The chemo-sensitization observed in high-PARP1-expressing cells suggests that PARP1 inhibitors may extend and improve the clinical application of DNA-repair targeting when combined with other cytotoxics also.	('inhibitors', 'Var', (84, 94))	('cytotoxics', 'Disease', (192, 202))	('improve', 'PosReg', (110, 117))	('PARP1', 'Gene', (78, 83))	('cytotoxics', 'Disease', 'MESH:D064420', (192, 202))
458660	28454547	This observation fueled the idea to target key points in DNA-repair machinery to increase cytotoxicity and brought about the development of several compounds, among which PARP1 inhibitors eventually demonstrated clinical efficacy.	('PARP1', 'Gene', (171, 176))	('cytotoxicity', 'Disease', 'MESH:D064420', (90, 102))	('cytotoxicity', 'Disease', (90, 102))	('inhibitors', 'Var', (177, 187))
458664	28454547	Our hypothesis stemmed from the observation that trabectedin not only induced a peculiar DNA damage but also caused impairment in the DNA-repair machinery that might become lethal in presence of PARP1 inhibitors.	('trabectedin', 'Chemical', 'MESH:D000077606', (49, 60))	('DNA-repair', 'MPA', (134, 144))	('DNA damage', 'MPA', (89, 99))	('trabectedin', 'Var', (49, 60))	('induced', 'Reg', (70, 77))	('impairment', 'NegReg', (116, 126))
458667	28454547	For example, single nucleotide polymorphism in the PARP1 gene (Val762Ala) is known to result in a less efficient PARP1 variant, which may partly explain differences in the degree of PARylation.	('less efficient', 'NegReg', (98, 112))	('Val762Ala', 'Var', (63, 72))	('PARP1', 'Gene', (51, 56))	('single nucleotide polymorphism', 'Var', (13, 43))	('Val762Ala', 'SUBSTITUTION', 'None', (63, 72))	('variant', 'MPA', (119, 126))	('PARP1', 'Gene', (113, 118))
458688	28454547	Our data demonstrated that trabectedin is an ideal partner of PARP1 inhibitors because it potently activates PARP1.	('PARP1', 'Gene', (62, 67))	('trabectedin', 'Chemical', 'MESH:D000077606', (27, 38))	('inhibitors', 'Var', (68, 78))	('activates', 'PosReg', (99, 108))	('PARP1', 'Gene', (109, 114))
458692	28454547	Finally, olaparib and trabectedin combination is particularly attractive in tumors harboring high PARP1 expression and a specific DNA-damage response/repair and cell cycle control gene signatures that might become predictive biomarkers of response.	('trabectedin', 'Chemical', 'MESH:D000077606', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('expression', 'MPA', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('olaparib', 'Chemical', 'MESH:C531550', (9, 17))	('PARP1', 'Gene', (98, 103))	('high', 'Var', (93, 97))
458699	26436134	Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies.	('weakness', 'Disease', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('rat', 'Species', '10116', (152, 155))	('weakness', 'Disease', 'MESH:D018908', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mutant', 'Var', (50, 56))	('tumor', 'Disease', (88, 93))
458703	26436134	The pathogenesis of tumor cells has evolved to mutate or outright delete most of these mechanisms to select for the most replicative, invasive, and progressive cancer cell, creating a significant vulnerability to virus infection.	('delete', 'NegReg', (66, 72))	('virus infection', 'Disease', 'MESH:D015658', (213, 228))	('mutate', 'Var', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('virus infection', 'Disease', (213, 228))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
458713	26436134	Neuroblastoma cells are moderately susceptible to G207 (see Table 1 for summary of viruses and Figure 1 for structural schematics for preclinical and therapeutic HSVs discussed in the text) in vitro but demonstrated tumor growth reduction and even cures in immunocompetent murine models.	('tumor growth reduction', 'Disease', (216, 238))	('cures', 'CPA', (248, 253))	('murine', 'Species', '10090', (273, 279))	('tumor growth reduction', 'Disease', 'MESH:D006130', (216, 238))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (0, 13))	('Neuroblastoma', 'Disease', 'MESH:D009447', (0, 13))	('G207', 'Var', (50, 54))	('Neuroblastoma', 'Disease', (0, 13))	('rat', 'Species', '10116', (210, 213))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('rat', 'Species', '10116', (28, 31))
458714	26436134	Additionally, intratumoral injections of G207 into subcutaneous N18 tumors demonstrated regression of a remote intracranial neuroblastoma.	('tumor', 'Disease', (68, 73))	('G207', 'Var', (41, 45))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('neuroblastoma', 'Phenotype', 'HP:0003006', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('rat', 'Species', '10116', (82, 85))	('intracranial neuroblastoma', 'Disease', (111, 137))	('tumor', 'Disease', (19, 24))	('rat', 'Species', '10116', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('intracranial neuroblastoma', 'Disease', 'MESH:D009447', (111, 137))
458720	26436134	Neuroblastoma cells demonstrated equivalent viral replication with these two oHSVs, but rQT3 enhanced cytotoxicity by 65% and reduced matrix metalloproteinase activity.	('cytotoxicity', 'Disease', (102, 114))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (0, 13))	('Neuroblastoma', 'Disease', 'MESH:D009447', (0, 13))	('matrix metalloproteinase activity', 'MPA', (134, 167))	('rQT3', 'Var', (88, 92))	('rat', 'Species', '10116', (27, 30))	('enhanced', 'PosReg', (93, 101))	('cytotoxicity', 'Disease', 'MESH:D064420', (102, 114))	('Neuroblastoma', 'Disease', (0, 13))	('oHSVs', 'Chemical', '-', (77, 82))	('reduced', 'NegReg', (126, 133))
458721	26436134	In xenograft neuroblastoma models subcutaneously implanted in mice, rQT3 and rQLuc inhibited tumor growth by 85 and 82% respectively, with rQT3 demonstrating a greater inhibition of tumor growth at later time points.	('xenograft neuroblastoma', 'Disease', (3, 26))	('neuroblastoma', 'Phenotype', 'HP:0003006', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (182, 187))	('mice', 'Species', '10090', (62, 66))	('tumor', 'Disease', (93, 98))	('inhibited', 'NegReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('xenograft neuroblastoma', 'Disease', 'MESH:D009447', (3, 26))	('rat', 'Species', '10116', (151, 154))	('rQT3', 'Var', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
458722	26436134	However, rQT3 was significantly more effective against neuroblastoma in vitro than in vivo.	('rQT3', 'Var', (9, 13))	('neuroblastoma', 'Gene', (55, 68))	('neuroblastoma', 'Gene', '230972', (55, 68))	('neuroblastoma', 'Phenotype', 'HP:0003006', (55, 68))
458725	26436134	In mouse models, ex vivo rQNestin34.5 infection of neuroblastoma cells prevented tumor formation for more than 60 days compared to the control oHSV, which significantly delayed tumor formation from 25 to 35 days.	('infection of neuroblastoma', 'Disease', 'MESH:D009447', (38, 64))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('neuroblastoma', 'Phenotype', 'HP:0003006', (51, 64))	('oHSV', 'Chemical', '-', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('rQNestin34.5', 'Var', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (177, 182))	('prevented', 'NegReg', (71, 80))	('tumor', 'Disease', (81, 86))	('infection of neuroblastoma', 'Disease', (38, 64))
458731	26436134	These tumors arise from the Schwann cells that insulate peripheral nerves and are frequently associated with genetic alterations in the tumor suppressor protein known as neurofibromin-1.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor suppressor', 'Gene', (136, 152))	('associated', 'Reg', (93, 103))	('genetic alterations', 'Var', (109, 128))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor suppressor', 'Gene', '7248', (136, 152))	('neurofibromin-1', 'Gene', (170, 185))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('rat', 'Species', '10116', (121, 124))
458739	26436134	Importantly, normal human Schwann cells, which have low basal Ras activity and intact PKR defense pathways, failed to support replication of either oHSV mutant.	('human', 'Species', '9606', (20, 25))	('oHSV', 'Chemical', '-', (148, 152))	('PKR', 'Gene', '5610', (86, 89))	('basal Ras', 'Protein', (56, 65))	('mutant', 'Var', (153, 159))	('PKR', 'Gene', (86, 89))	('oHSV', 'Gene', (148, 152))
458740	26436134	A follow-up study investigated the use of G207 and hrR3 in xenograft models of MPNST as single agents and in combination with erlotinib, an inhibitor of the epidermal growth factor receptor.	('hrR3', 'Gene', (51, 55))	('erlotinib', 'Chemical', 'MESH:D000069347', (126, 135))	('G207', 'Var', (42, 46))
458747	26436134	Similar observations were reported by Prabhakar et al., who evaluated the G47Delta oHSV in xenografts from two immortalized schwannoma cell lines: the patient-derived HEI193 cell line and the spontaneous mouse schwannoma NFS2-1.	('schwannoma', 'Phenotype', 'HP:0100008', (124, 134))	('G47Delta', 'Var', (74, 82))	('schwannoma', 'Disease', (210, 220))	('patient', 'Species', '9606', (151, 158))	('HEI193', 'CellLine', 'CVCL:7670', (167, 173))	('schwannoma', 'Disease', (124, 134))	('schwannoma', 'Disease', 'MESH:D009442', (210, 220))	('mouse', 'Species', '10090', (204, 209))	('schwannoma', 'Disease', 'MESH:D009442', (124, 134))	('schwannoma', 'Phenotype', 'HP:0100008', (210, 220))	('G47Delta oHSV', 'Chemical', '-', (74, 87))
458748	26436134	Both schwannoma lines were highly susceptible to G47Delta, as evidenced by rapid tumor regression following direct injection.	('G47Delta', 'Chemical', '-', (49, 57))	('schwannoma lines', 'Disease', (5, 21))	('schwannoma', 'Phenotype', 'HP:0100008', (5, 15))	('schwannoma lines', 'Disease', 'MESH:D009442', (5, 21))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('G47Delta', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
458751	26436134	used G47Delta and armed G47Delta derivatives expressing platelet factor 4 (PF4) and IL-12 to treat an orthotopic model of MPNST in immunocompetent mice.	('G47Delta', 'Chemical', '-', (24, 32))	('mice', 'Species', '10090', (147, 151))	('G47Delta', 'Var', (5, 13))	('G47Delta', 'Chemical', '-', (5, 13))	('IL-12', 'Gene', (84, 89))
458752	26436134	A single intratumoral dose of G47Delta in sciatic nerve tumors significantly inhibited tumor growth and prolonged survival, and was further enhanced by the expression of PF4 and IL-12 in the armed G47Delta variants.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inhibited', 'NegReg', (77, 86))	('PF4', 'Gene', (170, 173))	('nerve tumors', 'Phenotype', 'HP:0030430', (50, 62))	('prolonged', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('G47Delta', 'Var', (197, 205))	('sciatic nerve tumors', 'Disease', 'MESH:D020426', (42, 62))	('rat', 'Species', '10116', (12, 15))	('G47Delta', 'Chemical', '-', (197, 205))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (87, 92))	('G47Delta', 'Var', (30, 38))	('survival', 'CPA', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (14, 19))	('enhanced', 'PosReg', (140, 148))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('G47Delta', 'Chemical', '-', (30, 38))	('sciatic nerve tumors', 'Disease', (42, 62))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
458757	26436134	The treatments successes seen with dose-escalation and intensification of standard therapies are unfortunately accompanied by a heightened risk of bone growth deformities, endocrinopathies, and secondary cancers.	('growth deformities', 'Phenotype', 'HP:0001507', (152, 170))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('endocrinopathies', 'Disease', (172, 188))	('endocrinopathies', 'Disease', 'MESH:C567425', (172, 188))	('bone growth deformities', 'Disease', (147, 170))	('dose-escalation', 'Var', (35, 50))	('bone growth deformities', 'Disease', 'MESH:D001847', (147, 170))
458762	26436134	In vivo studies revealed significant tumor growth inhibition when G207 was given intravenously, whereas intratumoral G207 treatment further resulted in complete tumor disappearance in 25% of animals.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('G207', 'Var', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (109, 114))	('rat', 'Species', '10116', (107, 110))
458763	26436134	The in vivo combination of the chemotherapeutic agent vincristine with intravenous G207 resulted in the complete regression of A-RMS in five of eight animals, while causing significant growth inhibition of E-RMS.	('vincristine', 'Chemical', 'MESH:D014750', (54, 65))	('A-RMS', 'Disease', (127, 132))	('G207', 'Var', (83, 87))	('regression', 'NegReg', (113, 123))	('growth', 'MPA', (185, 191))	('combination', 'Interaction', (12, 23))
458773	26436134	The molecular basis of the disease is characterized by a chromosomal translocation at locus (11; 22)(q24; q12), rearranging the EWS gene with FLI1, a member of the ETS family of transcription factors.	('EWS', 'Gene', '2130', (128, 131))	('EWS', 'Gene', (128, 131))	('FLI1', 'Gene', (142, 146))	('FLI1', 'Gene', '2313', (142, 146))	('rearranging', 'Var', (112, 123))
458774	26436134	The resulting EWS-FLI1 fusion gene encodes a potent transformation protein that triggers disease development.	('triggers', 'Reg', (80, 88))	('EWS', 'Gene', (14, 17))	('fusion', 'Var', (23, 29))	('FLI1', 'Gene', '2313', (18, 22))	('EWS', 'Gene', '2130', (14, 17))	('FLI1', 'Gene', (18, 22))	('disease', 'CPA', (89, 96))
458778	26436134	Although EWS cell lines were not as sensitive as RMS or osteosarcoma (OS) cell lines to HSV-mediated oncolysis in vitro, modulation of the tumor microenvironment further enhanced oHSV therapy in vivo.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('modulation', 'Var', (121, 131))	('EWS', 'Gene', '2130', (9, 12))	('EWS', 'Gene', (9, 12))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('oHSV therapy', 'MPA', (179, 191))	('tumor', 'Disease', (139, 144))	('osteosarcoma', 'Disease', (56, 68))	('enhanced', 'PosReg', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('oHSV', 'Chemical', '-', (179, 183))	('osteosarcoma', 'Disease', 'MESH:D012516', (56, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
458781	26436134	In addition, combining rRp450 treatment with blockade of vascular endothelial growth factor (VEGF), an important cytokine for tumor growth and angiogenesis, produced superior therapeutic outcomes compared to each agent as a monotherapy.	('rRp450', 'Gene', (23, 29))	('vascular endothelial growth factor', 'Gene', '7422', (57, 91))	('blockade', 'NegReg', (45, 53))	('VEGF', 'Gene', (93, 97))	('therapeutic outcomes', 'CPA', (175, 195))	('treatment', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('VEGF', 'Gene', '7422', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('vascular endothelial growth factor', 'Gene', (57, 91))	('tumor', 'Disease', (126, 131))
458785	26436134	Alternations of p53 and RB1 tumor suppressor genes are a frequent occurrence in osteosarcoma.	('tumor suppressor', 'Gene', '7248', (28, 44))	('RB1', 'Gene', (24, 27))	('Alternations', 'Var', (0, 12))	('RB1', 'Gene', '5925', (24, 27))	('p53', 'Gene', (16, 19))	('occurrence', 'Reg', (66, 76))	('p53', 'Gene', '7157', (16, 19))	('osteosarcoma', 'Disease', (80, 92))	('tumor suppressor', 'Gene', (28, 44))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
458789	26436134	Osteosarcoma cells were susceptible to NV1020 or G207 treatment in vitro and responded to rRp450 therapy in a human osteosarcoma xenograft mouse model.	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('sarcoma xenograft', 'Disease', 'MESH:D012509', (121, 138))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('NV1020', 'Var', (39, 45))	('G207', 'Var', (49, 53))	('sarcoma xenograft', 'Disease', (121, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('mouse', 'Species', '10090', (139, 144))	('human', 'Species', '9606', (110, 115))	('Osteosarcoma', 'Disease', (0, 12))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('rRp450', 'Enzyme', (90, 96))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('osteosarcoma', 'Disease', (116, 128))
458800	26436134	In vivo experiments demonstrated a significant decrease in tumor growth and increase in animal survival in those animals treated with M002 versus controls.	('tumor', 'Disease', (59, 64))	('increase', 'PosReg', (76, 84))	('M002', 'Var', (134, 138))	('decrease', 'NegReg', (47, 55))	('rat', 'Species', '10116', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('animal survival', 'CPA', (88, 103))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
458809	26436134	In animals bearing MKRT or renal Ewing sarcoma, survival was significantly increased with M002 treatment compared to vehicle.	('M002', 'Gene', (90, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (33, 46))	('survival', 'CPA', (48, 56))	('renal Ewing sarcoma', 'Disease', (27, 46))	('increased', 'PosReg', (75, 84))	('renal Ewing sarcoma', 'Disease', 'MESH:C563168', (27, 46))	('MKRT', 'Var', (19, 23))
458813	26436134	While an initial study found that human medulloblastoma, the most common malignant pediatric brain tumor, was negative for CD111, a few prior studies indicated that oHSV can infect and kill medulloblastoma cells.	('medulloblastoma', 'Phenotype', 'HP:0002885', (40, 55))	('human', 'Species', '9606', (34, 39))	('kill', 'CPA', (185, 189))	('medulloblastoma', 'Disease', 'MESH:D008527', (40, 55))	('brain tumor', 'Phenotype', 'HP:0030692', (93, 104))	('oHSV', 'Var', (165, 169))	('medulloblastoma', 'Disease', (40, 55))	('medulloblastoma', 'Disease', (190, 205))	('oHSV', 'Chemical', '-', (165, 169))	('medulloblastoma', 'Disease', 'MESH:D008527', (190, 205))	('brain tumor', 'Disease', 'MESH:D001932', (93, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('brain tumor', 'Disease', (93, 104))	('medulloblastoma', 'Phenotype', 'HP:0002885', (190, 205))
458814	26436134	demonstrated the medulloblastoma cell line D283 was sensitive to HSV1716 in vitro, and survival was increased in tumor bearing mice with evidence of viral replication within tumors for several weeks.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (113, 118))	('mice', 'Species', '10090', (127, 131))	('increased', 'PosReg', (100, 109))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('medulloblastoma', 'Disease', 'MESH:D008527', (17, 32))	('medulloblastoma', 'Phenotype', 'HP:0002885', (17, 32))	('survival', 'CPA', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('rat', 'Species', '10116', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('medulloblastoma', 'Disease', (17, 32))	('HSV1716', 'Var', (65, 72))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
458816	26436134	showed that four medulloblastoma xenografts, including three molecular subgroup 3 tumors, which portend the worst prognosis with survival rates <50%, expressed CD111 (>80% of cells)) and were highly sensitive to oHSV G207 or M002 both in vitro when cells were grown as neurospheres in stem cell-defined medium and in vivo in mice bearing intracranial tumors.	('rat', 'Species', '10116', (138, 141))	('mice', 'Species', '10090', (325, 329))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('medulloblastoma', 'Disease', 'MESH:D008527', (17, 32))	('intracranial tumors', 'Disease', (338, 357))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('medulloblastoma', 'Phenotype', 'HP:0002885', (17, 32))	('CD111', 'Var', (160, 165))	('tumors', 'Disease', (351, 357))	('tumors', 'Disease', 'MESH:D009369', (351, 357))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('oHSV', 'Chemical', '-', (212, 216))	('medulloblastoma', 'Disease', (17, 32))	('intracranial tumors', 'Disease', 'MESH:D001932', (338, 357))
458820	26436134	found that pediatric glioblastoma multiforme brain tumor stem cells, marked by the surface marker CD133, were sensitive to several gamma134.5-deleted viruses including G207 and M002, and the cells had no inherent resistance when compared to the CD133-negative cells.	('M002', 'Var', (177, 181))	('gamma134.5-deleted', 'Var', (131, 149))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('pediatric glioblastoma multiforme brain tumor', 'Disease', (11, 56))	('G207', 'Var', (168, 172))	('CD133', 'Gene', (245, 250))	('CD133', 'Gene', (98, 103))	('CD133', 'Gene', '8842', (245, 250))	('sensitive', 'Reg', (110, 119))	('CD133', 'Gene', '8842', (98, 103))	('gamma134', 'Chemical', '-', (131, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('pediatric glioblastoma multiforme brain tumor', 'Disease', 'MESH:D005909', (11, 56))	('brain tumor', 'Phenotype', 'HP:0030692', (45, 56))
458824	26436134	The first was designed to test safety of a single intratumoral or intravenous injection into patients with relapsed or refractory solid tumors excluding brain and spinal cord tumors (ClinicalTrials.gov Identifier: NCT00931931), and the second was designed to test intratumoral or peritumoral injection into the residual tumor or resected cavity of relapsed high-grade gliomas (NCT02031965).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('spinal cord tumors', 'Phenotype', 'HP:0010302', (163, 181))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('patients', 'Species', '9606', (93, 101))	('gliomas', 'Disease', (368, 375))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NCT02031965', 'Var', (377, 388))	('tumor', 'Disease', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor', 'Disease', (136, 141))	('gliomas', 'Disease', 'MESH:D005910', (368, 375))	('tumor', 'Disease', (175, 180))	('solid tumors', 'Disease', (130, 142))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('spinal cord tumors', 'Disease', 'MESH:D013120', (163, 181))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('rat', 'Species', '10116', (267, 270))	('rat', 'Species', '10116', (53, 56))	('spinal cord tumors', 'Disease', (163, 181))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('gliomas', 'Phenotype', 'HP:0009733', (368, 375))	('tumor', 'Disease', (269, 274))	('tumor', 'Disease', (55, 60))	('solid tumors', 'Disease', 'MESH:D009369', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (284, 289))
458827	26436134	A trial of G207 alone or combined with a single low-dose of radiation, which has been shown to enhance virus replication preclinically, in children 3-18 years old with recurrent or progressive supratentorial tumors has received FDA IND approval and is forthcoming (NCT02457845).	('virus replication', 'MPA', (103, 120))	('supratentorial tumors', 'Phenotype', 'HP:0030693', (193, 214))	('G207', 'Var', (11, 15))	('children', 'Species', '9606', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('supratentorial tumors', 'Disease', (193, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('supratentorial tumors', 'Disease', 'MESH:D015173', (193, 214))	('enhance', 'PosReg', (95, 102))
458968	29672864	These data demonstrate that the SSP is highly active in Ewing sarcoma and that its oncogenic activation is maintained, at least in part, by menin-dependent epigenetic mechanisms involving trithorax complexes.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('epigenetic', 'Var', (156, 166))	('menin', 'Gene', '4221', (140, 145))	('Ewing sarcoma', 'Disease', (56, 69))	('active', 'MPA', (46, 52))	('menin', 'Gene', (140, 145))
458973	29672864	EWS-FLI1 promotes oncogenesis through global alteration of chromatin structure, leading to widespread epigenetic reprogramming and disruption of normal stem cell development and differentiation.	('FLI1', 'Gene', '2313', (4, 8))	('FLI1', 'Gene', (4, 8))	('oncogenesis', 'Disease', (18, 29))	('alteration', 'Reg', (45, 55))	('disruption', 'NegReg', (131, 141))	('chromatin structure', 'MPA', (59, 78))	('EWS', 'Gene', '2130', (0, 3))	('epigenetic', 'Var', (102, 112))	('promotes', 'PosReg', (9, 17))	('EWS', 'Gene', (0, 3))
458983	29672864	Activation of the SSP in cancer has been linked to genomic amplification of the PHGDH locus, as well as to transcriptional and epigenetic mechanisms.	('linked', 'Reg', (41, 47))	('genomic amplification', 'Var', (51, 72))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('SSP', 'Gene', (18, 21))	('Activation', 'PosReg', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('PHGDH locus', 'Gene', (80, 91))
458992	29672864	Differential expression (DE) was calculated using DESeq v1.24 for (i) individual cell line MI503 vs. MI-NC treatments and (ii) combined cell line MI503 vs. MI-NC treatment.	('MI', 'Chemical', 'MESH:C011506', (91, 93))	('MI-NC', 'Disease', 'OMIM:617025', (156, 161))	('MI', 'Chemical', 'MESH:C011506', (156, 158))	('MI503', 'Var', (146, 151))	('MI-NC', 'Disease', (101, 106))	('MI503', 'Var', (91, 96))	('MI-NC', 'Disease', 'OMIM:617025', (101, 106))	('MI', 'Chemical', 'MESH:C011506', (146, 148))	('MI-NC', 'Disease', (156, 161))	('MI', 'Chemical', 'MESH:C011506', (101, 103))
458996	29672864	Lentivirus production and lentiviral gene transfer for knockdown of menin (MEN1), MLL1 (KMT2A), and PHGDH were conducted as previously described.	('menin', 'Gene', (68, 73))	('knockdown', 'Var', (55, 64))	('MLL1', 'Gene', '4297', (82, 86))	('KMT2A', 'Gene', (88, 93))	('KMT2A', 'Gene', '4297', (88, 93))	('menin', 'Gene', '4221', (68, 73))	('MLL1', 'Gene', (82, 86))	('PHGDH', 'Gene', (100, 105))	('MEN1', 'Gene', '4221', (75, 79))	('MEN1', 'Gene', (75, 79))
458997	29672864	For PHGDH knockdown, cells were transduced with lentivirus for 48 hours, followed by selection in medium containing 1.5 microg/ml puromycin for 48 hours.	('knockdown', 'Var', (10, 19))	('puromycin', 'Chemical', 'MESH:D011691', (130, 139))	('PHGDH', 'Gene', (4, 9))
459025	29672864	PHGDH knockdown led to cell death, and surviving PHGDH-low cells showed a marked inhibition of proliferation, despite abundant serine and glycine in the media (Figure 3C and supplementary material, Figure S5A).	('PHGDH-low', 'Gene', (49, 58))	('glycine', 'Chemical', 'MESH:D005998', (138, 145))	('serine', 'Chemical', 'MESH:D012694', (127, 133))	('PHGDH', 'Gene', (0, 5))	('abundant', 'PosReg', (118, 126))	('inhibition', 'NegReg', (81, 91))	('knockdown', 'Var', (6, 15))	('proliferation', 'CPA', (95, 108))
459026	29672864	Moreover, PHGDH knockdown was deleterious to cells irrespective of their ability to proliferate in serine- and glycine-free conditions.	('PHGDH', 'Gene', (10, 15))	('glycine', 'Chemical', 'MESH:D005998', (111, 118))	('serine', 'Chemical', 'MESH:D012694', (99, 105))	('knockdown', 'Var', (16, 25))
459028	29672864	Similar to PHGDH knockdown, pharmacological inhibition of PHGDH led to diminished viability and proliferation, even in serine- and glycine-replete conditions (supplementary material, Figure S5B-C).	('diminished', 'NegReg', (71, 81))	('serine', 'Chemical', 'MESH:D012694', (119, 125))	('proliferation', 'CPA', (96, 109))	('PHGDH', 'Gene', (58, 63))	('glycine', 'Chemical', 'MESH:D005998', (131, 138))	('pharmacological inhibition', 'Var', (28, 54))	('viability', 'CPA', (82, 91))
459029	29672864	To evaluate the role of PHGDH in tumorigenicity, we plated equal numbers of viable control and PHGDH knockdown cells in soft agar and measured anchorage-independent growth.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('PHGDH', 'Gene', (95, 100))	('anchorage-independent growth', 'CPA', (143, 171))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('knockdown', 'Var', (101, 110))
459031	29672864	Although tumors formed in all mice, there was a trend toward delayed engraftment and a reproducible slowing of growth in tumors established with PHGDH knockdown cells (Figure 3D).	('mice', 'Species', '10090', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('slowing', 'NegReg', (100, 107))	('tumors', 'Disease', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('slowing of growth', 'Phenotype', 'HP:0001510', (100, 117))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('growth', 'MPA', (111, 117))	('PHGDH', 'Gene', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('knockdown', 'Var', (151, 160))
459032	29672864	Thus, high expression of PHGDH supports a more proliferative, tumorigenic phenotype.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('high', 'Var', (6, 10))	('more', 'PosReg', (42, 46))	('PHGDH', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
459033	29672864	We next assessed whether the observed effects of PHGDH knockdown on cell proliferation might be due to inhibition of 1-carbon metabolism, downstream of serine biosynthesis.	('knockdown', 'Var', (55, 64))	('1-carbon metabolism', 'MPA', (117, 136))	('cell proliferation', 'CPA', (68, 86))	('PHGDH', 'Gene', (49, 54))	('serine', 'Chemical', 'MESH:D012694', (152, 158))	('1-carbon', 'Chemical', '-', (117, 125))	('inhibition', 'NegReg', (103, 113))
459034	29672864	To this end, we used lentiviral shRNA to knock down expression of SHMT2, which is the primary mediator of glycine production and the 1-carbon units used to make purines de novo in proliferating cells (supplementary material, Figure S6A).	('SHMT2', 'Gene', (66, 71))	('1-carbon', 'Chemical', '-', (133, 141))	('SHMT2', 'Gene', '6472', (66, 71))	('purines', 'Chemical', 'MESH:D011687', (161, 168))	('knock', 'Var', (41, 46))	('glycine', 'Chemical', 'MESH:D005998', (106, 113))
459038	29672864	We first confirmed that 72-hour treatment with MI-503 significantly down-regulated expression of PHGDH, PSAT1 and PSPH (Figure 4A).	('PSAT1', 'Gene', (104, 109))	('PSPH', 'Gene', '5723', (114, 118))	('down-regulated', 'NegReg', (68, 82))	('MI-503', 'Var', (47, 53))	('MI-503', 'Chemical', '-', (47, 53))	('PSAT1', 'Gene', '29968', (104, 109))	('expression', 'MPA', (83, 93))	('PSPH', 'Gene', (114, 118))	('PHGDH', 'Gene', (97, 102))
459039	29672864	Given that MI-503 leads to loss of both menin and MLL1 protein expression in Ewing sarcoma, we next investigated the specific role of each of these proteins in SSP gene regulation.	('Ewing sarcoma', 'Disease', (77, 90))	('MLL1', 'Gene', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('menin', 'Gene', '4221', (40, 45))	('expression', 'MPA', (63, 73))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('MLL1', 'Gene', '4297', (50, 54))	('MI-503', 'Chemical', '-', (11, 17))	('menin', 'Gene', (40, 45))	('MI-503', 'Var', (11, 17))	('loss', 'NegReg', (27, 31))
459040	29672864	Knock-down of menin consistently led to down-regulation of the SSP enzymes in all cell lines tested (Figure 5A-B).	('menin', 'Gene', (14, 19))	('Knock-down', 'Var', (0, 10))	('down-regulation', 'NegReg', (40, 55))	('menin', 'Gene', '4221', (14, 19))	('SSP enzymes', 'Enzyme', (63, 74))
459041	29672864	In contrast, the impact of shRNA-mediated knockdown of MLL1 on SSP gene expression was inconsistent (Figure 5C).	('MLL1', 'Gene', '4297', (55, 59))	('knockdown', 'Var', (42, 51))	('SSP gene', 'Gene', (63, 71))	('MLL1', 'Gene', (55, 59))
459044	29672864	H3K4me3 enrichment at the PHGDH promoter was reproducibly diminished after MI-503 treatment (Figure 5D).	('PHGDH', 'Gene', (26, 31))	('MI-503', 'Var', (75, 81))	('diminished', 'NegReg', (58, 68))	('MI-503', 'Chemical', '-', (75, 81))	('H3K4me3', 'Protein', (0, 7))
459045	29672864	Together these data demonstrate that menin maintains high-level expression of SSP genes in Ewing sarcoma cells and that this is mediated, at least in part, by its function in epigenetic activation of the PHGDH locus.	('PHGDH locus', 'Gene', (204, 215))	('Ewing sarcoma', 'Disease', (91, 104))	('menin', 'Gene', '4221', (37, 42))	('epigenetic activation', 'Var', (175, 196))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('SSP genes', 'Gene', (78, 87))	('menin', 'Gene', (37, 42))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('high-level expression', 'MPA', (53, 74))
459054	29672864	Importantly, the effects of MI-503 on the SSP were not secondary to reduced glucose uptake.	('glucose uptake', 'CPA', (76, 90))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('MI-503', 'Var', (28, 34))	('MI-503', 'Chemical', '-', (28, 34))	('reduced', 'NegReg', (68, 75))
459059	29672864	Taken together, these data demonstrate that menin inhibition impairs de novo generation of serine/glycine and downstream metabolites in Ewing sarcoma cells.	('de novo generation of serine/glycine', 'MPA', (69, 105))	('Ewing sarcoma', 'Disease', (136, 149))	('impairs', 'NegReg', (61, 68))	('inhibition', 'Var', (50, 60))	('menin', 'Gene', '4221', (44, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('menin', 'Gene', (44, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (136, 149))	('serine', 'Chemical', 'MESH:D012694', (91, 97))	('glycine', 'Chemical', 'MESH:D005998', (98, 105))
459062	29672864	Accumulating evidence from multiple cancers has identified deregulation of the SSP as a critical mechanism by which tumors sustain their proliferation, survival, and metastatic fitness.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('multiple cancers', 'Disease', 'MESH:D009369', (27, 43))	('deregulation', 'Var', (59, 71))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('SSP', 'Protein', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('metastatic fitness', 'CPA', (166, 184))	('multiple cancers', 'Disease', (27, 43))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('survival', 'CPA', (152, 160))
459063	29672864	High expression of SSP genes is associated with refractory disease, chemoresistance, and poor prognosis in a number of human cancers and a recent paper also linked high SSP gene expression to poor outcomes in Ewing sarcoma.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('expression', 'MPA', (5, 15))	('cancers', 'Disease', (125, 132))	('SSP genes', 'Gene', (19, 28))	('refractory disease', 'Disease', (48, 66))	('expression', 'MPA', (178, 188))	('Ewing sarcoma', 'Disease', (209, 222))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('high', 'Var', (164, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (209, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('associated', 'Reg', (32, 42))	('chemoresistance', 'Disease', (68, 83))	('SSP gene', 'Gene', (169, 177))	('human', 'Species', '9606', (119, 124))
459065	29672864	Oncogenic activation of the SSP is often a consequence of genomic amplification of the PHGDH locus and, in tumors that do not harbor this genomic lesion, transcriptional as well as epigenetic mechanisms have been identified.	('PHGDH locus', 'Gene', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('genomic amplification', 'Var', (58, 79))	('tumors', 'Disease', (107, 113))	('SSP', 'Gene', (28, 31))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('activation', 'PosReg', (10, 20))
459069	29672864	Interestingly, loss of SSP gene expression was also observed in MI-503-treated MLL-rearranged leukemia cells, demonstrating that menin-MLL-dependent activation of the SSP extends beyond Ewing sarcoma.	('SSP', 'Gene', (23, 26))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (186, 199))	('menin', 'Gene', '4221', (129, 134))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (186, 199))	('MLL', 'Gene', '4297', (79, 82))	('MI-503', 'Chemical', '-', (64, 70))	('leukemia', 'Disease', (94, 102))	('MLL', 'Gene', (79, 82))	('menin', 'Gene', (129, 134))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('Ewing sarcoma', 'Disease', (186, 199))	('MLL', 'Gene', (135, 138))	('leukemia', 'Disease', 'MESH:D007938', (94, 102))	('MLL', 'Gene', '4297', (135, 138))	('MI-503-treated', 'Var', (64, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
459070	29672864	In addition, genetic knockdown of menin in Ewing sarcoma reproducibly resulted in loss of SSP gene expression, while loss of MLL1 did not.	('expression', 'MPA', (99, 109))	('Ewing sarcoma', 'Disease', (43, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('MLL1', 'Gene', (125, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('SSP gene', 'Gene', (90, 98))	('MLL1', 'Gene', '4297', (125, 129))	('menin', 'Gene', '4221', (34, 39))	('loss', 'NegReg', (82, 86))	('knockdown', 'Var', (21, 30))	('menin', 'Gene', (34, 39))
459088	29672864	Inhibition of PHGDH was recently shown to impair the incorporation of one-carbon units from endogenous and exogenous serine into nucleotides.	('impair', 'NegReg', (42, 48))	('serine', 'Chemical', 'MESH:D012694', (117, 123))	('PHGDH', 'Gene', (14, 19))	('one', 'Chemical', '-', (70, 73))	('Inhibition', 'Var', (0, 10))	('carbon', 'Chemical', 'MESH:D002244', (74, 80))
459095	29672864	Here, we show that targeting the menin-MLL complex in Ewing sarcoma leads to loss of oncogenic serine biosynthesis, highlighting a novel role for menin in cancer.	('serine', 'Chemical', 'MESH:D012694', (95, 101))	('MLL', 'Gene', (39, 42))	('targeting', 'Var', (19, 28))	('MLL', 'Gene', '4297', (39, 42))	('menin', 'Gene', '4221', (33, 38))	('menin', 'Gene', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (54, 67))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (54, 67))	('menin', 'Gene', (33, 38))	('oncogenic serine biosynthesis', 'MPA', (85, 114))	('loss', 'NegReg', (77, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('menin', 'Gene', '4221', (146, 151))	('Ewing sarcoma', 'Disease', (54, 67))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
459097	29108227	Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma The most pressing unmet clinical need for patients with Ewing sarcoma (ES) is the prevention and treatment of metastasis.	('porcupine', 'Gene', (14, 23))	('mouse', 'Species', '10090', (63, 68))	('Ewing sarcoma', 'Disease', (158, 171))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('porcupine', 'Gene', '64840', (14, 23))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('ES', 'Phenotype', 'HP:0012254', (173, 175))	('patients', 'Species', '9606', (144, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (158, 171))	('Inhibition', 'Var', (0, 10))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (158, 171))	('metastasis free survival', 'CPA', (33, 57))	('prolongs', 'PosReg', (24, 32))	('Ewing sarcoma', 'Disease', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
459100	29108227	In vitro, WNT974 does not affect ES proliferation or sarcosphere formation, but suppresses multiple transcriptional regulators of metastasis and inhibits cell migration.	('ES', 'Phenotype', 'HP:0012254', (33, 35))	('inhibits', 'NegReg', (145, 153))	('WNT974', 'Chemical', 'MESH:C586458', (10, 16))	('WNT974', 'Var', (10, 16))	('suppresses', 'NegReg', (80, 90))	('cell migration', 'CPA', (154, 168))
459116	29108227	Our results suggest that WNT974 may represent an important treatment advance by specifically targeting ES metastasis.	('ES metastasis', 'CPA', (103, 116))	('ES', 'Phenotype', 'HP:0012254', (103, 105))	('WNT974', 'Var', (25, 31))	('WNT974', 'Chemical', 'MESH:C586458', (25, 31))
459117	29108227	WNT974 has been shown to inhibit the expression of Wnt pathway target genes in breast cancer cell lines, but we initially validated the ability of WNT974 to inhibit Wnt signaling in ES cells as well.	('WNT974', 'Chemical', 'MESH:C586458', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('Wnt signaling', 'Pathway', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('inhibit', 'NegReg', (157, 164))	('WNT974', 'Gene', (147, 153))	('WNT974', 'Var', (0, 6))	('inhibit', 'NegReg', (25, 32))	('WNT974', 'Chemical', 'MESH:C586458', (147, 153))	('expression', 'MPA', (37, 47))	('Wnt', 'Gene', (51, 54))	('ES', 'Phenotype', 'HP:0012254', (182, 184))
459120	29108227	As anticipated, expression of both genes was inhibited by WNT974 (Figure 1A, 1B) consistent with the ability of this drug to inhibit Wnt signaling.	('inhibit', 'NegReg', (125, 132))	('Wnt signaling', 'Pathway', (133, 146))	('WNT974', 'Var', (58, 64))	('WNT974', 'Chemical', 'MESH:C586458', (58, 64))	('inhibited', 'NegReg', (45, 54))	('expression', 'MPA', (16, 26))
459123	29108227	TC71, SK-ES-1, and A4573 cells were transfected with a plasmid containing a luciferase cDNA under the transcriptional control of a promoter with tandem repeats of the TCF/LEF response element (TOP) or mutant versions of the element (FOP).	('TC71', 'CellLine', 'CVCL:2213', (0, 4))	('tandem repeats', 'Var', (145, 159))	('TCF/LEF', 'Gene', '3172', (167, 174))	('mutant', 'Var', (201, 207))	('TCF/LEF', 'Gene', (167, 174))	('ES', 'Phenotype', 'HP:0012254', (9, 11))	('SK-ES-1', 'CellLine', 'CVCL:0627', (6, 13))
459125	29108227	As controls, we included the osteosarcoma cell line U2OS, which has previously been demonstrated to have strong, endogenous beta-catenin-dependent signaling, and SK-ES-1 cells stably transduced to express mutant (S33Y), constitutively active beta-catenin.	('ES', 'Phenotype', 'HP:0012254', (165, 167))	('SK-ES-1', 'CellLine', 'CVCL:0627', (162, 169))	('beta-catenin', 'Gene', (124, 136))	('S33Y', 'Mutation', 'rs121913400', (213, 217))	('beta-catenin', 'Gene', (242, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('beta-catenin', 'Gene', '1499', (124, 136))	('U2OS', 'CellLine', 'CVCL:0042', (52, 56))	('beta-catenin', 'Gene', '1499', (242, 254))	('S33Y', 'Var', (213, 217))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('osteosarcoma', 'Disease', (29, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))
459126	29108227	The SK-ES-1-S33Y cells and U2OS cells had very high ratios of TOP to FOP luciferase signals, and WNT974 decreased this activity in U2OS cells by 4-fold (15.2+-4.2 to 3.8+-1.9; Figure 1C).	('ratios', 'MPA', (52, 58))	('WNT974', 'Chemical', 'MESH:C586458', (97, 103))	('U2OS', 'CellLine', 'CVCL:0042', (27, 31))	('S33Y', 'Var', (12, 16))	('TOP to FOP', 'MPA', (62, 72))	('decreased', 'NegReg', (104, 113))	('U2OS', 'CellLine', 'CVCL:0042', (131, 135))	('S33Y', 'SUBSTITUTION', 'None', (12, 16))	('ES', 'Phenotype', 'HP:0012254', (7, 9))
459128	29108227	Taken together, these data suggest that, although WNT974 inhibits Wnt signaling in ES cell lines, the "canonical," beta-catenin-dependent pathway plays at most a minor role in these cell lines.	('WNT974', 'Chemical', 'MESH:C586458', (50, 56))	('ES', 'Phenotype', 'HP:0012254', (83, 85))	('WNT974', 'Var', (50, 56))	('beta-catenin', 'Gene', (115, 127))	('beta-catenin', 'Gene', '1499', (115, 127))	('Wnt signaling', 'Pathway', (66, 79))	('inhibits', 'NegReg', (57, 65))
459134	29108227	Interestingly, we found that WNT974 significantly decreased migration of TC71 and A4573 cells in a Boyden chamber assay (Figure 2D) and, reflecting a direct effect on the actin cytoskeleton, decreased process formation in TC71 and SK-ES-1 cells (Figures 2E, 2F) as determined by phalloidin staining.	('WNT974', 'Chemical', 'MESH:C586458', (29, 35))	('ES', 'Phenotype', 'HP:0012254', (234, 236))	('TC71', 'CellLine', 'CVCL:2213', (73, 77))	('SK-ES-1', 'CellLine', 'CVCL:0627', (231, 238))	('decreased', 'NegReg', (50, 59))	('migration', 'CPA', (60, 69))	('decreased', 'NegReg', (191, 200))	('TC71', 'CellLine', 'CVCL:2213', (222, 226))	('process formation', 'CPA', (201, 218))	('phalloidin', 'Chemical', 'MESH:D010590', (279, 289))	('WNT974', 'Var', (29, 35))
459144	29108227	Consistent with our in vitro results, WNT974 significantly suppressed expression ofAxin2 and LEF1 (confirming inhibition of Wnt signaling) and ZEB2 and SNAIL1 (key regulators of metastasis), with a modest effect on TWIST1 (Figures 3B and 3C).	('LEF1', 'Gene', (93, 97))	('ZEB2', 'Gene', '9839', (143, 147))	('SNAIL1', 'Gene', (152, 158))	('Axin2', 'Gene', '8313', (83, 88))	('SNAIL1', 'Gene', '6615', (152, 158))	('ZEB2', 'Gene', (143, 147))	('suppressed', 'NegReg', (59, 69))	('expression', 'MPA', (70, 80))	('WNT974', 'Var', (38, 44))	('WNT974', 'Chemical', 'MESH:C586458', (38, 44))	('LEF1', 'Gene', '51176', (93, 97))	('TWIST1', 'Gene', '7291', (215, 221))	('TWIST1', 'Gene', (215, 221))	('Axin2', 'Gene', (83, 88))
459152	29108227	Despite the lack of an effect on primary tumor growth, mice treated with WNT974 had a substantial prolongation of survival after amputation of the primary tumor (Figures 4D-4F).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (41, 46))	('prolongation', 'PosReg', (98, 110))	('tumor', 'Disease', (155, 160))	('mice', 'Species', '10090', (55, 59))	('survival', 'CPA', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('WNT974', 'Var', (73, 79))	('WNT974', 'Chemical', 'MESH:C586458', (73, 79))
459154	29108227	Thus, WNT974 prolongs disease-specific survival of mice bearing ES xenografts due to an effect not on primary tumor growth, but on the development of metastatic disease.	('mice', 'Species', '10090', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('prolongs', 'PosReg', (13, 21))	('WNT974', 'Var', (6, 12))	('WNT974', 'Chemical', 'MESH:C586458', (6, 12))	('ES', 'Phenotype', 'HP:0012254', (64, 66))	('disease-specific survival', 'CPA', (22, 47))
459159	29108227	In contrast to our orthotopic implantation/amputation model, WNT974 had no effect on establishment of metastases nor on survival of mice injected with cells via the tail vein (Figure 5).	('WNT974', 'Var', (61, 67))	('WNT974', 'Chemical', 'MESH:C586458', (61, 67))	('metastases', 'Disease', (102, 112))	('mice', 'Species', '10090', (132, 136))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
459160	29108227	Thus, WNT974 is affecting an early, rather than a late, step in the metastatic cascade.	('WNT974', 'Chemical', 'MESH:C586458', (6, 12))	('affecting', 'Reg', (16, 25))	('WNT974', 'Var', (6, 12))
459161	29108227	Finally, although WNT974 prolongs the survival of mice implanted with ES fragments in the pretibial space, many of the treated mice did eventually succumb to distant metastatic disease, most commonly in the lung.	('WNT974', 'Var', (18, 24))	('mice', 'Species', '10090', (127, 131))	('distant metastatic disease', 'CPA', (158, 184))	('ES', 'Phenotype', 'HP:0012254', (70, 72))	('succumb', 'Reg', (147, 154))	('survival', 'CPA', (38, 46))	('mice', 'Species', '10090', (50, 54))	('prolongs', 'PosReg', (25, 33))	('WNT974', 'Chemical', 'MESH:C586458', (18, 24))
459164	29108227	In this experiment, WNT974 significantly delayed the time to development of first lung metastasis (Figure 6).	('WNT974', 'Var', (20, 26))	('WNT974', 'Chemical', 'MESH:C586458', (20, 26))	('delayed', 'NegReg', (41, 48))
459165	29108227	Taken together, these data suggest that WNT974 inhibits an early step in the metastatic cascade, which results in a delay in the development of metastases, which translates into prolonged survival.	('prolonged', 'PosReg', (178, 187))	('delay', 'NegReg', (116, 121))	('metastases', 'Disease', 'MESH:D009362', (144, 154))	('WNT974', 'Var', (40, 46))	('WNT974', 'Chemical', 'MESH:C586458', (40, 46))	('metastatic', 'CPA', (77, 87))	('metastases', 'Disease', (144, 154))	('inhibits', 'NegReg', (47, 55))
459168	29108227	Although WNT974 did not inhibit tumor cell proliferation in vitro, nor localized tumor growth in vivo, inhibition of the expression of metastasis-associated genes and a significant effect on cell migration was seen in vitro, along with a significant delay in distant metastasis formation in vivo, which resulted in prolonged survival.	('delay', 'NegReg', (250, 255))	('metastasis-associated genes', 'Gene', (135, 162))	('prolonged', 'PosReg', (315, 324))	('WNT974', 'Var', (9, 15))	('expression', 'MPA', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('distant metastasis formation', 'CPA', (259, 287))	('cell migration', 'CPA', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('WNT974', 'Chemical', 'MESH:C586458', (9, 15))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (81, 86))	('inhibition', 'NegReg', (103, 113))
459175	29108227	While Wnt signaling is a very complex pathway, components of the pathway are key regulators of EMT and metastasis in several tumor types, and our study demonstrates that inhibition of Wnt signaling with WNT974 suppresses expression of genes associated with metastasis, many of which are considered drivers of EMT in carcinoma cells, providing a mechanistic explanation for our observation that WNT974 inhibits migration in vitro and metastasis in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('metastasis', 'CPA', (257, 267))	('inhibition', 'Var', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('WNT974', 'Gene', (203, 209))	('migration', 'CPA', (410, 419))	('tumor', 'Disease', (125, 130))	('carcinoma', 'Disease', (316, 325))	('WNT974', 'Chemical', 'MESH:C586458', (203, 209))	('carcinoma', 'Disease', 'MESH:D002277', (316, 325))	('WNT974', 'Chemical', 'MESH:C586458', (394, 400))	('expression', 'MPA', (221, 231))	('suppresses', 'NegReg', (210, 220))	('inhibits', 'NegReg', (401, 409))
459180	29108227	WNT974 inhibits both beta-catenin-dependent and beta-catenin-independent signaling pathways and so demonstrates the importance of Wnt signaling in Ewing sarcoma metastasis regardless of the involvement of beta-catenin.	('beta-catenin', 'Gene', (48, 60))	('beta-catenin', 'Gene', '1499', (21, 33))	('inhibits', 'NegReg', (7, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('beta-catenin', 'Gene', (205, 217))	('beta-catenin', 'Gene', '1499', (48, 60))	('Ewing sarcoma metastasis regardless', 'Disease', (147, 182))	('beta-catenin', 'Gene', '1499', (205, 217))	('Ewing sarcoma metastasis regardless', 'Disease', 'MESH:C563168', (147, 182))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (147, 160))	('WNT974', 'Var', (0, 6))	('WNT974', 'Chemical', 'MESH:C586458', (0, 6))	('beta-catenin', 'Gene', (21, 33))
459209	29108227	beta-catenin overactivation was achieved by transducing a vector with a S33Y mutant beta-catenin cloned into the FUGW backbone as previously described.	('S33Y', 'Var', (72, 76))	('overactivation', 'PosReg', (13, 27))	('beta-catenin', 'Gene', '1499', (0, 12))	('S33Y', 'Mutation', 'rs121913400', (72, 76))	('beta-catenin', 'Gene', (84, 96))	('beta-catenin', 'Gene', '1499', (84, 96))	('beta-catenin', 'Gene', (0, 12))
459210	29108227	Cells were seeded in a 24 well plate in triplicates, and were transfected using Lipofectamine 2000 (Invitrogen, Life Technology) with either M50 Super 8x TOPFlash (Addgene plasmid #12456) or M51 Super 8x FOPFlash (Addgene plasmid #12457) reporter construct (kindly provided by Dr. Randal Moon) and pRLSV40 (Promega).	('M51 Super', 'Var', (191, 200))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (80, 98))	('M50 Super', 'Var', (141, 150))
459225	22833626	The overall risk of cancer in patients with metal-on-metal hip implants was also no higher than in patients who had received non-metal-on-metal hip implants (relative risk 0.92, 0.81 to 1.05).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('metal-on-metal', 'Chemical', '-', (44, 58))	('metal-on-metal', 'Chemical', '-', (129, 143))	('metal-on-metal hip implants', 'Var', (44, 71))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (30, 38))	('cancer', 'Disease', (20, 26))
459236	22833626	Studies have shown short term increased serum concentrations of chromium and cobalt in patients with metal-on-metal hips.	('metal-on-metal', 'Var', (101, 115))	('metal-on-metal', 'Chemical', '-', (101, 115))	('chromium', 'Chemical', 'MESH:D002857', (64, 72))	('serum concentrations of chromium', 'MPA', (40, 72))	('cobalt', 'Chemical', 'MESH:D003035', (77, 83))	('increased', 'PosReg', (30, 39))	('patients', 'Species', '9606', (87, 95))	('cobalt', 'MPA', (77, 83))
459267	22833626	The overall risk of cancer in the metal-on-metal cohort was also no higher than in the non-metal-on-metal cohort (relative risk 0.92, 0.81 to 1.05).	('metal-on-metal', 'Chemical', '-', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('metal-on-metal', 'Chemical', '-', (34, 48))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('metal-on-metal', 'Var', (34, 48))
459272	22833626	The risk of soft tissue sarcoma in the metal-on-metal cohort was higher than in the non-metal-on-metal cohort, but not significantly so (relative risk 2.69, 0.89 to 6.71).	('metal-on-metal', 'Chemical', '-', (88, 102))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (12, 31))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (12, 31))	('metal-on-metal', 'Var', (39, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('soft tissue sarcoma', 'Disease', (12, 31))	('metal-on-metal', 'Chemical', '-', (39, 53))
459276	22833626	The standardised incidence ratio of skin melanoma in the metal-on-metal cohort was 1.37 (0.82 to 2.13), but it was still lower than in the non-metal-on-metal cohort (1.55, 1.21 to 1.95) (table 2).	('metal-on-metal', 'Chemical', '-', (57, 71))	('metal-on-metal', 'Var', (57, 71))	('metal-on-metal', 'Chemical', '-', (143, 157))	('lower', 'NegReg', (121, 126))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('skin melanoma', 'Disease', 'MESH:D008545', (36, 49))	('skin melanoma', 'Disease', (36, 49))
459279	22833626	This population based study shows that the overall short term risk of cancer is not increased in people with metal-on-metal hip implants.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('metal-on-metal', 'Chemical', '-', (109, 123))	('people', 'Species', '9606', (97, 103))	('metal-on-metal', 'Var', (109, 123))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
459282	22833626	The risk of soft tissue sarcoma of the metal-on-metal cohort was also increased, but not significantly so, compared with the risk in the non-metal-on-metal cohort.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (12, 31))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (12, 31))	('metal-on-metal', 'Var', (39, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('soft tissue sarcoma', 'Disease', (12, 31))	('metal-on-metal', 'Chemical', '-', (141, 155))	('metal-on-metal', 'Chemical', '-', (39, 53))
459293	22833626	Serum concentrations of chromium and cobalt are higher after metal-on-metal total hip arthroplasty than after metal-on-polyethylene total hip arthroplasty.	('metal-on-metal', 'Chemical', '-', (61, 75))	('hip arthroplasty', 'Disease', 'MESH:D006618', (82, 98))	('metal-on-metal', 'Var', (61, 75))	('cobalt', 'Chemical', 'MESH:D003035', (37, 43))	('hip arthroplasty', 'Disease', (138, 154))	('higher', 'PosReg', (48, 54))	('hip arthroplasty', 'Disease', 'MESH:D006618', (138, 154))	('Serum concentrations of chromium', 'MPA', (0, 32))	('metal-on-polyethylene', 'Chemical', '-', (110, 131))	('chromium', 'Chemical', 'MESH:D002857', (24, 32))	('hip arthroplasty', 'Disease', (82, 98))
459315	22833626	The risk of soft tissue sarcoma in the metal-on-metal cohort was increased but not significantly so.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (12, 31))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (12, 31))	('metal-on-metal', 'Var', (39, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('soft tissue sarcoma', 'Disease', (12, 31))	('metal-on-metal', 'Chemical', '-', (39, 53))
459414	32256184	Median progression-free survival was lower among patients who received olaratumab compared with those who received placebo (P = 0.04).	('olaratumab', 'Var', (71, 81))	('progression-free survival', 'CPA', (7, 32))	('olaratumab', 'Chemical', 'MESH:C000589393', (71, 81))	('patients', 'Species', '9606', (49, 57))	('lower', 'NegReg', (37, 42))
459586	28526051	Based on the clinical judgment, we hypothesized that patients undergoing amputation surgery may have lower function scores than those receiving limb-salvage surgeries.	('amputation surgery', 'Var', (73, 91))	('function scores', 'MPA', (107, 122))	('lower', 'NegReg', (101, 106))	('patients', 'Species', '9606', (53, 61))
459607	28526051	In this study, we confirmed that patients receiving amputation had lower MSTS score than patients undergoing limb-salvage surgery.	('amputation', 'Var', (52, 62))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (89, 97))	('lower', 'NegReg', (67, 72))	('MSTS score', 'MPA', (73, 83))
459616	26509162	Phylogenetic analysis showed that the majority of HHV8 ORF26 amplimers clustered with subtypes R (n = 11) and B2 (n = 6).	('HHV8', 'Species', '37296', (50, 54))	('amplimers', 'Var', (61, 70))	('HHV8 ORF26', 'Gene', (50, 60))
459617	26509162	This variant distribution is in agreement with that of HHV8 variants previously identified in Ugandan KS cases.	('KS', 'Phenotype', 'HP:0100726', (102, 104))	('HHV8 variant', 'Species', '37296', (55, 67))	('Ugandan KS', 'Disease', (94, 104))	('variants', 'Var', (60, 68))	('HHV8', 'Gene', (55, 59))
459650	26509162	Reference sequences for each HHV8 ORF26 subtype were DQ984689.1 (BCBLR, A/C), DQ984768.1 (HKS15, R), DQ984785.1 (431K, B1), DQ984789.1 (021K, B2), and DQ984759.1 (HKS21, J).	('HHV8', 'Species', '37296', (29, 33))	('DQ984689.1', 'Var', (53, 63))	('DQ984768.1', 'Var', (78, 88))	('DQ984785.1', 'Var', (101, 111))	('KS', 'Phenotype', 'HP:0100726', (91, 93))	('DQ984759.1', 'Var', (151, 161))	('DQ984789.1', 'Var', (124, 134))	('KS', 'Phenotype', 'HP:0100726', (164, 166))
459663	26509162	No multiple infections with different HHV8 variants were identified by nucleotide sequencing analysis.	('variants', 'Var', (43, 51))	('HHV8 variant', 'Species', '37296', (38, 50))	('HHV8', 'Gene', (38, 42))	('multiple infections', 'Phenotype', 'HP:0002719', (3, 22))
459670	26509162	Furthermore, the similar frequency rate of HHV8 positivity in invasive tumors compared to CIN2 and CIN3 lesions suggests that the virus might be involved in early phases of tumor development but is unlikely involved in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', (219, 224))	('invasive tumors', 'Disease', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('CIN', 'Disease', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('CIN', 'Disease', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('HHV8', 'Species', '37296', (43, 47))	('HHV8', 'Gene', (43, 47))	('tumor', 'Disease', (71, 76))	('CIN3', 'Phenotype', 'HP:0500052', (99, 103))	('positivity', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('CIN', 'Disease', 'MESH:D007674', (99, 102))	('tumor', 'Disease', (173, 178))	('CIN', 'Disease', 'MESH:D007674', (90, 93))	('invasive tumors', 'Disease', 'MESH:D009369', (62, 77))
459696	20737575	Mutation of the miR-145 MRE sequence in the Fli-1 3'-UTR abolished the activity of miR-145.	('miR-145', 'Gene', (16, 23))	('Mutation', 'Var', (0, 8))	('miR-145', 'Gene', '406937', (16, 23))	('activity', 'MPA', (71, 79))	('Fli-1', 'Gene', '2313', (44, 49))	('abolished', 'NegReg', (57, 66))	('miR-145', 'Gene', (83, 90))	('Fli-1', 'Gene', (44, 49))	('miR-145', 'Gene', '406937', (83, 90))
459714	20737575	Aberrant expression of Fli-1 has been recognized as a seminal event in the initiation of certain types of malignant transformation.	('Aberrant expression', 'Var', (0, 19))	('Fli-1', 'Gene', (23, 28))	('Fli-1', 'Gene', '2313', (23, 28))
459724	20737575	Fli-1 is overexpressed in virally induced leukemias and in Ewing's sarcoma as a result of a characteristic t(11;22)(q24:q12) reciprocal chromosomal translocation.	('Fli-1', 'Gene', '2313', (0, 5))	('t(11;22)(q24:q12', 'Var', (107, 123))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (59, 74))	('leukemias', 'Disease', 'MESH:D007938', (42, 51))	("Ewing's sarcoma", 'Disease', (59, 74))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (59, 74))	('overexpressed', 'PosReg', (9, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('result', 'Reg', (80, 86))	('leukemias', 'Phenotype', 'HP:0001909', (42, 51))	('leukemias', 'Disease', (42, 51))	('t(11;22)(q24:q12)', 'STRUCTURAL_ABNORMALITY', 'None', (107, 124))	('Fli-1', 'Gene', (0, 5))
459740	20737575	To further demonstrate the importance of the Fli-1 MRE, a substitution mutation was generated to test its activity.	('Fli-1', 'Gene', '2313', (45, 50))	('Fli-1', 'Gene', (45, 50))	('test', 'Reg', (97, 101))	('substitution', 'Var', (58, 70))	('activity', 'MPA', (106, 114))
459744	20737575	Correspondingly, we demonstrated that the mutation in the MRE abolished the miR-145-mdieated inhibition of the reporter gene (Fig.2D).	('miR-145', 'Gene', (76, 83))	('abolished', 'NegReg', (62, 71))	('miR-145', 'Gene', '406937', (76, 83))	('inhibition', 'MPA', (93, 103))	('mutation', 'Var', (42, 50))	('MRE', 'Gene', (58, 61))
459767	20737575	As shown in Figure 5A, tranfection with miR-145 inhibited cell proliferation as compared with control cells.	('miR-145', 'Gene', (40, 47))	('cell proliferation', 'CPA', (58, 76))	('miR-145', 'Gene', '406937', (40, 47))	('inhibited', 'NegReg', (48, 57))	('tranfection', 'Var', (23, 34))
459778	20737575	Aberrant expression of miR-145 tumor suppressor has been implicated in a variety of cellular pathways involved in carcinogenesis.	('carcinogenesis', 'Disease', (114, 128))	('Aberrant expression', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('implicated', 'Reg', (57, 67))	('tumor', 'Disease', (31, 36))	('miR-145', 'Gene', (23, 30))	('miR-145', 'Gene', '406937', (23, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
459784	20737575	The etiology of a number of virally induced leukemias as well as human Ewing's sarcoma has been associated with Fli-1 overexpression.	('leukemias', 'Disease', 'MESH:D007938', (44, 53))	('human', 'Species', '9606', (65, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('associated', 'Reg', (96, 106))	("Ewing's sarcoma", 'Disease', (71, 86))	('overexpression', 'Var', (118, 132))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (71, 86))	('leukemias', 'Disease', (44, 53))	('Fli-1', 'Gene', '2313', (112, 117))	('leukemias', 'Phenotype', 'HP:0001909', (44, 53))	('leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('Fli-1', 'Gene', (112, 117))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (71, 86))
459785	20737575	The rate-limiting oncogenic mutation in Ewing's sarcoma has been identified as a chromosomal translocation, t(11;22)(q24;q12), that leads to the expression of a chimeric transcription factor, EWS-Fli1.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (40, 55))	('chimeric', 'MPA', (161, 169))	('Fli1', 'Gene', (196, 200))	('t(11;22)(q24;q12', 'Var', (108, 124))	("Ewing's sarcoma", 'Disease', (40, 55))	('expression', 'MPA', (145, 155))	('leads to', 'Reg', (132, 140))	('Fli1', 'Gene', '2313', (196, 200))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (40, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('EWS', 'Gene', '2130', (192, 195))	('EWS', 'Gene', (192, 195))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (108, 125))
459786	20737575	Ectopic expression of Fli-1 has also been shown to be associated with decreased expression of Rb, decreased expression of GATA-1 and increased expression of Bcl-2, possibly leading to a block in apoptosis and differentiation.	('GATA-1', 'Gene', '2623', (122, 128))	('Fli-1', 'Gene', (22, 27))	('expression', 'MPA', (143, 153))	('apoptosis', 'CPA', (195, 204))	('decreased', 'NegReg', (70, 79))	('Ectopic expression', 'Var', (0, 18))	('Fli-1', 'Gene', '2313', (22, 27))	('Bcl-2', 'Gene', '596', (157, 162))	('GATA-1', 'Gene', (122, 128))	('Bcl-2', 'Gene', (157, 162))	('expression', 'MPA', (108, 118))	('expression', 'MPA', (80, 90))	('increased', 'PosReg', (133, 142))	('decreased', 'NegReg', (98, 107))	('differentiation', 'CPA', (209, 224))
459787	20737575	Aberrant expression of the Fli-1 has been recognized as a seminal event in the initiation of certain types of malignant transformation.	('Fli-1', 'Gene', (27, 32))	('Aberrant expression', 'Var', (0, 19))	('Fli-1', 'Gene', '2313', (27, 32))
459788	20737575	Indeed, the etiology of a number of virally induced leukemias, including Friend virus-induced erythroleukemia, has been associated with Fli-1 overexpression.	('leukemias', 'Disease', (52, 61))	('Fli-1', 'Gene', '2313', (136, 141))	('associated', 'Reg', (120, 130))	('erythroleukemia', 'Disease', (94, 109))	('leukemias', 'Disease', 'MESH:D007938', (52, 61))	('overexpression', 'Var', (142, 156))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('erythroleukemia', 'Disease', 'MESH:D004915', (94, 109))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('Fli-1', 'Gene', (136, 141))	('leukemias', 'Phenotype', 'HP:0001909', (52, 61))
459790	20737575	Fli-1 is expressed at high levels in F-MuLV-induced erythroleukemias, malignant melanoma, small cell carcinomas of the lung and adenocarcinomas.	('small cell carcinomas of the lung', 'Disease', (90, 123))	('malignant melanoma', 'Disease', (70, 88))	('erythroleukemias', 'Disease', 'MESH:D004915', (52, 68))	('Fli-1', 'Gene', (0, 5))	('erythroleukemias', 'Disease', (52, 68))	('small cell carcinomas of the lung', 'Phenotype', 'HP:0030357', (90, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('leukemias', 'Phenotype', 'HP:0001909', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('F-MuLV', 'Species', '11795', (37, 43))	('malignant melanoma', 'Phenotype', 'HP:0002861', (70, 88))	('adenocarcinomas', 'Disease', 'MESH:D000230', (128, 143))	('adenocarcinomas', 'Disease', (128, 143))	('malignant melanoma', 'Disease', 'MESH:D008545', (70, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('Fli-1', 'Gene', '2313', (0, 5))	('F-MuLV-induced', 'Var', (37, 51))	('small cell carcinomas of the lung', 'Disease', 'MESH:D055752', (90, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (101, 123))
459829	20737575	To detect relative levels of Fli-1 mRNA, Real-Time PCR was performed using the SYBR method at the following conditions: 95 C 30 s, 1 cycle; 95  C 5 s, 60  C 20s, 72  C 15 s, 40 cycles.	('Fli-1', 'Gene', (29, 34))	('95 C 30 s', 'Var', (120, 129))	('Fli-1', 'Gene', '2313', (29, 34))
459834	20737575	To construct the Luc-Fli-1-3'UTR-Full vector, full length 3'UTR of Fli-1 was amplified from the cDNA of LS174T cells using Fli-1 PCR primers: sense 5' CTA GAG AAG CCC ATC CTG CAC ACT 3' and antisense 5' CTA GAC GTT GTT TTT CCC AGA GCT 3', and then cloned into the pGL3 control vector at Xba1 site.	('Fli-1', 'Gene', '2313', (123, 128))	('Fli-1', 'Gene', '2313', (21, 26))	('pGL3', 'Gene', (264, 268))	('Fli-1', 'Gene', (123, 128))	('Fli-1', 'Gene', (21, 26))	('antisense 5', 'Var', (190, 201))	('pGL3', 'Gene', '6391', (264, 268))	('LS174T', 'CellLine', 'CVCL:1384', (104, 110))	('Fli-1', 'Gene', (67, 72))	('Fli-1', 'Gene', '2313', (67, 72))
459835	20737575	To create the mutated Fli-1-3'UTR vector, eight nucleotides (GUG AAG UUU UCA CCC ggt gat cg) were changed for the reporter construct.	('Fli-1', 'Gene', '2313', (22, 27))	('mutated', 'Var', (14, 21))	('Fli-1', 'Gene', (22, 27))
459894	31839739	observed that patients who underwent limb-sparing surgery or hip disarticulation had significantly reduced functional and QOL outcomes associated with urinary tract changes.	('QOL outcomes', 'MPA', (122, 134))	('urinary tract changes', 'Phenotype', 'HP:0000079', (151, 172))	('functional', 'MPA', (107, 117))	('reduced', 'NegReg', (99, 106))	('hip disarticulation', 'Var', (61, 80))	('patients', 'Species', '9606', (14, 22))
459909	31660331	Candidate Predisposition Variants in Kaposi Sarcoma as Detected by Whole-Genome Sequencing Familial clustering of classic Kaposi sarcoma (CKS) is rare with, approximately 100 families reported to date.	('Kaposi Sarcoma', 'Phenotype', 'HP:0100726', (37, 51))	('Variants', 'Var', (25, 33))	('CKS', 'Disease', 'MESH:D012514', (138, 141))	('Kaposi sarcoma', 'Disease', (122, 136))	('Kaposi Sarcoma', 'Disease', (37, 51))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (122, 136))	('Kaposi Sarcoma', 'Disease', 'MESH:D012514', (37, 51))	('CKS', 'Disease', (138, 141))	('Sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('KS', 'Phenotype', 'HP:0100726', (139, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (122, 136))
459913	31660331	Susceptibility candidates, including a homozygous deletion in RP11-259O2.1 and homozygous single-nucleotide variants in SCUBE2 and in CDHR5, were identified.	('RP11', 'Gene', (62, 66))	('CDHR5', 'Gene', '53841', (134, 139))	('RP11', 'Gene', '26121', (62, 66))	('CDHR5', 'Gene', (134, 139))	('single-nucleotide variants', 'Var', (90, 116))	('SCUBE2', 'Gene', (120, 126))	('SCUBE2', 'Gene', '57758', (120, 126))
459932	31660331	The 1 remaining candidate variant was a homozygous deletion of 9005 base pairs between the bases 1 939 257 and 1 948 262 in chromosome 5 (GRCh37) within the intron of long intergenic noncoding RNA gene RP11-259O2.1 (Supplementary Figure 2).	('Supplementary Figure 2', 'Disease', 'MESH:D017034', (216, 238))	('1 948 262', 'Var', (111, 120))	('GRCh37', 'Gene', (138, 144))	('RP11', 'Gene', (202, 206))	('deletion', 'Var', (51, 59))	('Supplementary Figure 2', 'Disease', (216, 238))	('RP11', 'Gene', '26121', (202, 206))
459933	31660331	The 2 protein-coding variants that remained were c.1489G > A (p.Pro497Ser) in SCUBE2 (Signal Peptide, CUB Domain and EGF-like Domain Containing 2) and c.2269C > T (p. Gly757Ser) in CDHR5 (Cadherin Related Family Member 5) (Supplementary Figure 3).	('c.2269C > T', 'Mutation', 'c.2269C>T', (151, 162))	('Gly757Ser', 'Var', (167, 176))	('c.1489G > A', 'Var', (49, 60))	('CUB', 'Chemical', 'MESH:C432044', (102, 105))	('Gly757Ser', 'SUBSTITUTION', 'None', (167, 176))	('c.1489G > A', 'Mutation', 'c.1489G>A', (49, 60))	('c.2269C > T', 'Var', (151, 162))	('CUB', 'Chemical', 'MESH:C432044', (79, 82))	('Cadherin Related Family Member 5', 'Gene', (188, 220))	('CDHR5', 'Gene', '53841', (181, 186))	('Cadherin Related Family Member 5', 'Gene', '53841', (188, 220))	('SCUBE2', 'Gene', (78, 84))	('CDHR5', 'Gene', (181, 186))	('p.Pro497Ser', 'Mutation', 'p.P497S', (62, 73))	('SCUBE2', 'Gene', '57758', (78, 84))
459934	31660331	Both were predicted to be either benign or tolerated by Polyphen-2 and SIFT, respectively, although the SCUBE2 variant was predicted to be damaging by DANN scoring.	('variant', 'Var', (111, 118))	('SCUBE2', 'Gene', (104, 110))	('SCUBE2', 'Gene', '57758', (104, 110))
459935	31660331	The candidate variants were validated with PCR and Sanger sequencing, and they segregated with CKS in the respective families (Table 1).	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('variants', 'Var', (14, 22))	('CKS', 'Disease', 'MESH:D012514', (95, 98))	('segregated', 'Reg', (79, 89))	('CKS', 'Disease', (95, 98))
459939	31660331	Mutations in genes WAS, IFNGR1, STIM1, and TNFRSF4 (OX40) have been found to cause childhood-onset CKS (reviewed in).	('WAS', 'Disease', (19, 22))	('WAS', 'Disease', 'None', (19, 22))	('TNFRSF4', 'Gene', (43, 50))	('cause', 'Reg', (77, 82))	('STIM1', 'Gene', (32, 37))	('IFNGR1', 'Gene', '3459', (24, 30))	('KS', 'Phenotype', 'HP:0100726', (100, 102))	('OX40', 'Gene', '7293', (52, 56))	('OX40', 'Gene', (52, 56))	('TNFRSF4', 'Gene', '7293', (43, 50))	('Mutations', 'Var', (0, 9))	('IFNGR1', 'Gene', (24, 30))	('STIM1', 'Gene', '6786', (32, 37))	('CKS', 'Disease', 'MESH:D012514', (99, 102))	('CKS', 'Disease', (99, 102))
459942	31660331	In the KapoIran family, the most promising susceptibility variant was a homozygous deletion of 9005 base pairs in the intron of long intergenic noncoding RNA (lincRNA) gene RP11-259O2.1.	('RP11', 'Gene', (173, 177))	('deletion of 9005 base pairs', 'Var', (83, 110))	('RP11', 'Gene', '26121', (173, 177))
459946	31660331	Perhaps the most promising is c.1489G > A (p.Pro497Ser) in SCUBE2.	('SCUBE2', 'Gene', (59, 65))	('SCUBE2', 'Gene', '57758', (59, 65))	('p.Pro497Ser', 'Mutation', 'p.P497S', (43, 54))	('c.1489G > A', 'Mutation', 'c.1489G>A', (30, 41))	('c.1489G > A', 'Var', (30, 41))
459958	31660331	We found 3 plausible susceptibility variants that all segregated with CKS in the families.	('CKS', 'Disease', 'MESH:D012514', (70, 73))	('segregated', 'Reg', (54, 64))	('CKS', 'Disease', (70, 73))	('KS', 'Phenotype', 'HP:0100726', (71, 73))	('variants', 'Var', (36, 44))
459959	31660331	Of these, variants in SCUBE2 and RP11-259O2.1 were the most promising due to known functions and expression in the target tissues, respectively.	('variants', 'Var', (10, 18))	('RP11', 'Gene', (33, 37))	('SCUBE2', 'Gene', (22, 28))	('RP11', 'Gene', '26121', (33, 37))	('SCUBE2', 'Gene', '57758', (22, 28))
459966	26909593	We found that the addition of STAT3 inhibitor S3I-201 to gefitinib achieved synergistic anti-proliferative and pro-apoptotic effects in all three STS cell lines examined.	('anti-proliferative', 'CPA', (88, 106))	('pro-apoptotic effects', 'CPA', (111, 132))	('S3I-201', 'Var', (46, 53))	('gefitinib', 'Chemical', 'MESH:D000077156', (57, 66))	('S3I-201', 'Chemical', 'MESH:C520337', (46, 53))
459967	26909593	This was confirmed in a fibrosarcoma xenografted mouse model, where the tumours from the combination group (418mm3) were significantly smaller than those from untreated (1032mm3) or single drug (912 and 798mm3) groups.	('fibrosarcoma', 'Disease', 'MESH:D005354', (24, 36))	('418mm3', 'Var', (108, 114))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('mouse', 'Species', '10090', (49, 54))	('fibrosarcoma', 'Disease', (24, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (24, 36))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))	('smaller', 'NegReg', (135, 142))
459980	26909593	Our unpublished data indicated that phosphorylated EGFR (pEGFR) was an independent prognostic factor of survival in STS patients.	('EGFR', 'Gene', '1956', (58, 62))	('phosphorylated', 'Var', (36, 50))	('EGFR', 'Gene', (51, 55))	('EGFR', 'Gene', (58, 62))	('patients', 'Species', '9606', (120, 128))	('EGFR', 'Gene', '1956', (51, 55))
459981	26909593	These findings indicated that suppressing EGFR may greatly benefit sarcoma patients.	('EGFR', 'Gene', '1956', (42, 46))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('EGFR', 'Gene', (42, 46))	('patients', 'Species', '9606', (75, 83))	('sarcoma', 'Disease', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('suppressing', 'Var', (30, 41))
459989	26909593	STAT3 inhibitors have been shown to have anti-proliferative and pro-apoptotic effects in vitro and in vivo in several cancers and have entered clinical trials (NCI Glioblastoma Clinical Trial No.	('Glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('NCI Glioblastoma', 'Disease', 'MESH:D005909', (160, 176))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('anti-proliferative', 'CPA', (41, 59))	('inhibitors', 'Var', (6, 16))	('STAT3', 'Gene', (0, 5))	('NCI Glioblastoma', 'Disease', (160, 176))	('pro-apoptotic effects', 'CPA', (64, 85))
459992	26909593	STAT3 forms a complex with the oncoprotein EGFR type III variant (EGFRvIII) in the nucleus and thereby mediates EGFRvIII-induced glial transformation.	('EGFR', 'Gene', (112, 116))	('glial transformation', 'CPA', (129, 149))	('mediates', 'Reg', (103, 111))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('variant', 'Var', (57, 64))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', '1956', (43, 47))	('complex', 'Interaction', (14, 21))	('EGFR', 'Gene', (43, 47))
460001	26909593	Both 778 and SW872 showed very strong positive staining against total EGFR, AKT, ERK and STAT3 as well as moderate positive staining for phosphorylated proteins, except for relative weakness for 778 against pSTAT3, which is consistent with our Western blot data.	('phosphorylated proteins', 'MPA', (137, 160))	('weakness', 'Disease', (182, 190))	('SW872', 'Var', (13, 18))	('AKT', 'Gene', '207', (76, 79))	('EGFR', 'Gene', '1956', (70, 74))	('ERK', 'Gene', '5594', (81, 84))	('weakness', 'Disease', 'MESH:D018908', (182, 190))	('ERK', 'Gene', (81, 84))	('AKT', 'Gene', (76, 79))	('EGFR', 'Gene', (70, 74))	('SW872', 'CellLine', 'CVCL:1730', (13, 18))
460002	26909593	Seven STS cell lines were initially screened for mutations in the TK domain (exons 18-24) of the EGFR gene to rule out potential interference by the target's alteration.	('mutations in', 'Var', (49, 61))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (97, 101))
460003	26909593	Single nucleotide polymorphisms in exon 20 (rs10251977, Gln787Gln G > A) and exon 23 (rs1140475, Thr903Thr C > T) occurred at an allele frequency of 0.73 and 0.09, respectively.	('rs10251977', 'Var', (44, 54))	('Gln787Gln G > A', 'Mutation', 'rs10251977', (56, 71))	('Thr903Thr C > T', 'Mutation', 'rs1140475', (97, 112))	('Thr903Thr C > T', 'Var', (97, 112))	('rs10251977', 'Mutation', 'rs10251977', (44, 54))	('rs1140475', 'Mutation', 'rs1140475', (86, 95))	('Gln787Gln G > A', 'Var', (56, 71))	('rs1140475', 'Var', (86, 95))
346054	26909593	On mutation analysis of KRAS and BRAF genes, all STS cell lines were found to be KRAS wild-type at codons 12, 13 and 61.	('KRAS', 'Gene', '3845', (81, 85))	('BRAF', 'Gene', '673', (33, 37))	('KRAS', 'Gene', '3845', (24, 28))	('BRAF', 'Gene', (33, 37))	('mutation', 'Var', (3, 11))	('KRAS', 'Gene', (81, 85))	('KRAS', 'Gene', (24, 28))
460004	26909593	SW872, SW982 and GCT (3/7 STS cell lines) demonstrated the BRAF V600E mutation (dbSNP:rs113488022, p.Val600Glu) (Table 1).	('SW872', 'CellLine', 'CVCL:1730', (0, 5))	('rs113488022', 'Mutation', 'rs113488022', (86, 97))	('p.Val600Glu', 'Var', (99, 110))	('BRAF', 'Gene', (59, 63))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('BRAF', 'Gene', '673', (59, 63))	('SW982', 'CellLine', 'CVCL:1734', (7, 12))	('p.Val600Glu', 'Mutation', 'rs113488022', (99, 110))
460009	26909593	In addition there was no significant correlation between sensitivity (IC50) of STS cell lines to gefitinib and EGF-stimulated pEGFR expression or tEGFR (Table 1, p > 0.05) and IC50 values of gefitinib were not statistically correlated with BRAF mutational status, indicating the BRAF mutation may not activate in the resistance to gefitinib in this panel of STS cell lines.	('BRAF', 'Gene', (240, 244))	('EGFR', 'Gene', (147, 151))	('mutation', 'Var', (284, 292))	('EGF', 'Gene', (147, 150))	('EGF', 'Gene', '1950', (111, 114))	('gefitinib', 'Chemical', 'MESH:D000077156', (97, 106))	('gefitinib', 'Chemical', 'MESH:D000077156', (331, 340))	('EGF', 'Gene', (127, 130))	('BRAF', 'Gene', '673', (279, 283))	('BRAF', 'Gene', '673', (240, 244))	('EGF', 'Gene', '1950', (127, 130))	('EGF', 'Gene', '1950', (147, 150))	('gefitinib', 'Chemical', 'MESH:D000077156', (191, 200))	('BRAF', 'Gene', (279, 283))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', '1956', (147, 151))	('EGFR', 'Gene', (127, 131))	('EGF', 'Gene', (111, 114))
460012	26909593	The pAKT was significantly inhibited by gefitinib treatment in the presence of EGF in 778 and 449B (% expression at gefitinib/vehicle: 778: 13%, p < 0.001; 449B: 55%, p = 0.001; HT1080: 81%, p = 0.09).	('EGF', 'Gene', '1950', (79, 82))	('449B', 'Var', (94, 98))	('AKT', 'Gene', '207', (5, 8))	('gefitinib', 'Chemical', 'MESH:D000077156', (116, 125))	('EGF', 'Gene', (79, 82))	('inhibited', 'NegReg', (27, 36))	('gefitinib', 'Chemical', 'MESH:D000077156', (40, 49))	('HT1080', 'Gene', (178, 184))	('AKT', 'Gene', (5, 8))	('HT1080', 'Gene', '8872', (178, 184))
460013	26909593	The EGF-induced pERK was blocked (gefitinib/vehicle: 16-93%) by gefitinib, with two cell lines (778: p = 0.0007 and 449B: p = 0.0028) having statistical significance.	('pERK', 'Gene', (16, 20))	('gefitinib', 'Chemical', 'MESH:D000077156', (34, 43))	('gefitinib', 'Chemical', 'MESH:D000077156', (64, 73))	('EGF', 'Gene', (4, 7))	('gefitinib', 'Var', (64, 73))	('EGF', 'Gene', '1950', (4, 7))	('pERK', 'Gene', '9451', (16, 20))
460015	26909593	Gefitinib down-regulated both pSTAT1 and pSTAT3 in all 3 cell lines, with statistical significance in 778 and 449B (gefitinib/vehicle: pSTAT1: 32% and 17%, respectively; pSTAT3: 69% and 36%, all p<=0.05) but a non-significant trend for HT1080 (95% and 99%, p > 0.05).	('HT1080', 'Gene', (236, 242))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('STAT1', 'Gene', (31, 36))	('STAT1', 'Gene', '6772', (31, 36))	('HT1080', 'Gene', '8872', (236, 242))	('down-regulated', 'NegReg', (10, 24))	('gefitinib', 'Chemical', 'MESH:D000077156', (116, 125))	('pSTAT3', 'Gene', (41, 47))	('449B', 'Var', (110, 114))	('STAT1', 'Gene', (136, 141))	('STAT1', 'Gene', '6772', (136, 141))
460016	26909593	The ratio of pSTAT3/pSTAT1 was significantly increased in 778 (2.5 folds, p = 0.006) and 449B (2.0 folds, p = 0.025), and slightly increased in HT1080 (1.05 folds, p = 0.60), suggesting that gefitinib failed to decrease the ratio of oncogene pSTAT3 versus tumour suppressor pSTAT1.	('STAT1', 'Gene', (21, 26))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('tumour', 'Disease', (256, 262))	('increased', 'PosReg', (45, 54))	('STAT1', 'Gene', (275, 280))	('STAT1', 'Gene', '6772', (21, 26))	('HT1080', 'Gene', (144, 150))	('STAT1', 'Gene', '6772', (275, 280))	('449B', 'Var', (89, 93))	('HT1080', 'Gene', '8872', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('gefitinib', 'Chemical', 'MESH:D000077156', (191, 200))
460019	26909593	Our additional preliminary study reported that STAT3 inhibitor S3I-201 inhibited pSTAT3 in the majority of STS cell lines, with the IC50s on the three wild-type STS cell lines 778, 449B and HT1080 being 148.5, 95.5 and 14.5muM, respectively (sensitivity threshold for S3I-201: IC50<=100muM).	('muM', 'Gene', '56925', (223, 226))	('HT1080', 'Gene', (190, 196))	('inhibited', 'NegReg', (71, 80))	('S3I-201', 'Var', (63, 70))	('pSTAT3', 'Gene', (81, 87))	('muM', 'Gene', '56925', (286, 289))	('HT1080', 'Gene', '8872', (190, 196))	('muM', 'Gene', (223, 226))	('S3I-201', 'Chemical', 'MESH:C520337', (63, 70))	('muM', 'Gene', (286, 289))	('S3I-201', 'Chemical', 'MESH:C520337', (268, 275))	('50s', 'Species', '1214577', (134, 137))
460023	26909593	The implication of this is that S3I-201 could overcome the resistance of gefitinib monotherapy and bring the needed concentration of gefitinib in the combination therapy to achieve IC50 effect lower than the sensitivity threshold (10muM) in all these three examined cell lines.	('muM', 'Gene', (233, 236))	('gefitinib', 'Chemical', 'MESH:D000077156', (73, 82))	('S3I-201', 'Var', (32, 39))	('S3I-201', 'Chemical', 'MESH:C520337', (32, 39))	('gefitinib', 'Chemical', 'MESH:D000077156', (133, 142))	('resistance', 'MPA', (59, 69))	('muM', 'Gene', '56925', (233, 236))	('lower', 'NegReg', (193, 198))	('IC50 effect', 'MPA', (181, 192))
460025	26909593	As shown in Supplementary Table 1, the combination treatment produced synergism at each ratio and sequence, while it appears the combination therapy using gefitinib and S3I-201 at their equipotent or relative lower doses of gefitinib produced stronger synergism in 778 cell line, and the combination therapy worked best in parallel.	('gefitinib', 'Chemical', 'MESH:D000077156', (224, 233))	('synergism', 'MPA', (252, 261))	('S3I-201', 'Var', (169, 176))	('gefitinib', 'Chemical', 'MESH:D000077156', (155, 164))	('S3I-201', 'Chemical', 'MESH:C520337', (169, 176))	('synergism', 'MPA', (70, 79))
460027	26909593	As shown in Figure 3D and Supplementary Figure S3, synergistic anti-colony formation was consistently achieved, showing that gefitinib and S3I-201 in combination was significantly more effective than single treatments in inhibiting sarcoma cell colony-formation (all p < 0.05).	('sarcoma', 'Disease', 'MESH:D012509', (232, 239))	('sarcoma', 'Disease', (232, 239))	('colon', 'Disease', (68, 73))	('colon', 'Disease', 'MESH:D015179', (245, 250))	('gefitinib', 'Chemical', 'MESH:D000077156', (125, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('S3I-201', 'Var', (139, 146))	('colon', 'Disease', 'MESH:D015179', (68, 73))	('S3I-201', 'Chemical', 'MESH:C520337', (139, 146))	('colon', 'Disease', (245, 250))	('gefitinib', 'Var', (125, 134))	('inhibiting', 'NegReg', (221, 231))
460032	26909593	Importantly, the addition of S3I-201 to gefitinib dramatically perturbed the ratios of pSTAT3/pSTAT1 in all of them compared to vehicle control (combination/vehicle: HT1080: 52%, p = 0.0006; 449B: 47%, p = 0.24 and 778: 19%, p < 0.001) or gefitinib alone (combination/gefitinib: HT1080: 49%, p = 0.027; 449B: 24%, p = 0.15 and 778: 7.7%, p = 0.0036) (Figure 4C).	('HT1080', 'Gene', (279, 285))	('STAT1', 'Gene', '6772', (95, 100))	('HT1080', 'Gene', '8872', (279, 285))	('HT1080', 'Gene', (166, 172))	('gefitinib', 'Chemical', 'MESH:D000077156', (268, 277))	('HT1080', 'Gene', '8872', (166, 172))	('gefitinib', 'Chemical', 'MESH:D000077156', (239, 248))	('S3I-201', 'Var', (29, 36))	('perturbed', 'Reg', (63, 72))	('gefitinib', 'Chemical', 'MESH:D000077156', (40, 49))	('STAT1', 'Gene', (95, 100))	('ratios', 'MPA', (77, 83))	('S3I-201', 'Chemical', 'MESH:C520337', (29, 36))
460040	26909593	After 24 hours intramuscular inoculation of HT1080, mice were randomly divided and treated by vehicle DMSO, 2.5mg/kg S3I-201 or 5mg/kg S3I-201, which was given intraperitoneally.	('S3I-201', 'Var', (117, 124))	('mice', 'Species', '10090', (52, 56))	('DMSO', 'Chemical', 'MESH:D004121', (102, 106))	('HT1080', 'Gene', (44, 50))	('S3I-201', 'Chemical', 'MESH:C520337', (117, 124))	('HT1080', 'Gene', '8872', (44, 50))	('S3I-201', 'Chemical', 'MESH:C520337', (135, 142))
460045	26909593	We next examined whether using S3I-201 could also improve the effectiveness of gefitinib using our mouse model in two independent combination therapy experiments.	('mouse', 'Species', '10090', (99, 104))	('gefitinib', 'Chemical', 'MESH:D000077156', (79, 88))	('S3I-201', 'Var', (31, 38))	('S3I-201', 'Chemical', 'MESH:C520337', (31, 38))	('effectiveness', 'MPA', (62, 75))	('improve', 'PosReg', (50, 57))
460046	26909593	Twenty-four hours post-inoculation of HT1080, all mice were randomly divided into 4 groups and treated with vehicle control (1% Tween 80), 1mg/kg S3I-201 (intraperitoneally), 10mg/kg gefitinib (gavage) or combination with 1mg/kg S3I-201 and 10mg/kg gefitinib once daily.	('HT1080', 'Gene', '8872', (38, 44))	('S3I-201', 'Var', (146, 153))	('gefitinib', 'Chemical', 'MESH:D000077156', (249, 258))	('gefitinib', 'Chemical', 'MESH:D000077156', (183, 192))	('HT1080', 'Gene', (38, 44))	('S3I-201', 'Chemical', 'MESH:C520337', (146, 153))	('mice', 'Species', '10090', (50, 54))	('S3I-201', 'Chemical', 'MESH:C520337', (229, 236))	('Tween 80', 'Chemical', 'MESH:D011136', (128, 136))
460049	26909593	On day 18 post-treatment in the first experiment, the tumours from combination therapy group (418mm3) were significantly smaller than those from untreated (1032mm3) and single drug treated (912 and 798mm3) groups (non-parametric and parametric methods: combination/vehicle p < 0.001; combination/gefitinib monotherapy p < 0.001; combination/S3I-201 p < 0.05) (Figure 5C).	('418mm3', 'Var', (94, 100))	('gefitinib', 'Chemical', 'MESH:D000077156', (296, 305))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('smaller', 'NegReg', (121, 128))	('S3I-201', 'Chemical', 'MESH:C520337', (341, 348))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
460069	26909593	The sensitivity to EGFR TKIs has been positively associated with activating mutations in EGFR gene such as deletion mutations occurring around codon 746-750 in exon 19 and the substitution of leucine with arginine at codon 858 in exon 21 (L858).	('deletion mutations', 'Var', (107, 125))	('leucine with arginine at codon 858', 'Mutation', 'rs121434568', (192, 226))	('EGFR', 'Gene', (89, 93))	('sensitivity', 'MPA', (4, 15))	('activating', 'PosReg', (65, 75))	('substitution of leucine', 'Var', (176, 199))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))	('EGFR', 'Gene', '1956', (89, 93))
460070	26909593	In NSCLC, about 70-80% patients with activating mutant EGFR gene were sensitive to EGFR TKI, compared with only 10-20% response rate in wild-type EGFR gene.	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', '1956', (55, 59))	('NSCLC', 'Disease', (3, 8))	('mutant', 'Var', (48, 54))	('EGFR', 'Gene', '1956', (146, 150))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', (83, 87))	('EGFR', 'Gene', (146, 150))	('activating', 'PosReg', (37, 47))	('sensitive', 'MPA', (70, 79))
460072	26909593	In our mutation analysis, the lack of EGFR TK activating mutation in our panel of STS cell lines indicated that these cells may not be sensitive to EGFR-targeted therapy.	('EGFR', 'Gene', '1956', (38, 42))	('mutation', 'Var', (57, 65))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('activating', 'PosReg', (46, 56))
460073	26909593	In a cohort of 958 patients, only 2 of 38 samples from the sarcoma subset were positive for EGFR mutation.	('sarcoma', 'Disease', (59, 66))	('mutation', 'Var', (97, 105))	('patients', 'Species', '9606', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('EGFR', 'Gene', '1956', (92, 96))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('EGFR', 'Gene', (92, 96))
460074	26909593	In a synovial sarcoma study, only 2 of 13 tissue samples were positive for EGFR TK mutation, with no EGFR amplification on FISH analysis and a further study on EGFR gene amplification from patients with endometrial stromal sarcoma also showed 10/10 negative results.	('synovial sarcoma', 'Disease', (5, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('endometrial stromal sarcoma', 'Disease', (203, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', '1956', (160, 164))	('EGFR', 'Gene', (101, 105))	('positive', 'Reg', (62, 70))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (203, 230))	('mutation', 'Var', (83, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (5, 21))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (5, 21))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', '1956', (75, 79))	('patients', 'Species', '9606', (189, 197))	('EGFR', 'Gene', (75, 79))
460075	26909593	It has been reported recently that KRAS and BRAF mutations were negatively correlated with the response to targeting EGFR treatment in lung and colorectal cancers.	('colorectal cancers', 'Disease', 'MESH:D015179', (144, 162))	('BRAF', 'Gene', '673', (44, 48))	('KRAS', 'Gene', (35, 39))	('mutations', 'Var', (49, 58))	('EGFR', 'Gene', '1956', (117, 121))	('BRAF', 'Gene', (44, 48))	('EGFR', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancers', 'Disease', (144, 162))	('KRAS', 'Gene', '3845', (35, 39))	('lung', 'Disease', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('negatively', 'NegReg', (64, 74))
460076	26909593	The KRAS mutation was not detected in our panel and was consistent with previous studies which showed only 2 of 54 samples from patients with STS had KRAS mutations.	('KRAS', 'Gene', '3845', (4, 8))	('mutations', 'Var', (155, 164))	('KRAS', 'Gene', (4, 8))	('patients', 'Species', '9606', (128, 136))	('KRAS', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (150, 154))
460078	26909593	Unexpectedly, we discovered that 3 STS cell lines SW872, SW982 and GCT contained a BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (88, 93))	('SW982', 'CellLine', 'CVCL:1734', (57, 62))	('V600E', 'Var', (88, 93))	('BRAF', 'Gene', '673', (83, 87))	('SW872', 'CellLine', 'CVCL:1730', (50, 55))	('BRAF', 'Gene', (83, 87))
460080	26909593	Other mutations (such as non-T790M EGFR mutations D761Y, L747S and T854A, amplification of c-Met, loss of PTEN, PIK3CA mutations and BIM BH3 deletion) have been reported to result in the resistance to EGFR TKIs in some cancers.	('T790M', 'Mutation', 'rs121434569', (29, 34))	('PIK3CA', 'Gene', '5290', (112, 118))	('BIM BH3', 'Gene', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('EGFR', 'Gene', (201, 205))	('L747S', 'Mutation', 'rs397517097', (57, 62))	('resistance', 'MPA', (187, 197))	('D761Y', 'Mutation', 'rs121913418', (50, 55))	('EGFR', 'Gene', (35, 39))	('loss', 'NegReg', (98, 102))	('PTEN', 'Gene', (106, 110))	('c-Met', 'Gene', (91, 96))	('result', 'Reg', (173, 179))	('PIK3CA', 'Gene', (112, 118))	('D761Y', 'Var', (50, 55))	('T854A', 'Mutation', 'c.854T>A', (67, 72))	('deletion', 'Var', (141, 149))	('EGFR', 'Gene', '1956', (201, 205))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('L747S', 'Var', (57, 62))	('cancers', 'Disease', (219, 226))	('PTEN', 'Gene', '5728', (106, 110))	('T854A', 'Var', (67, 72))	('non-T790M', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('EGFR', 'Gene', '1956', (35, 39))	('c-Met', 'Gene', '4233', (91, 96))
460081	26909593	However, the roles of these mutations in sarcoma still remain unknown.	('sarcoma', 'Disease', (41, 48))	('mutations', 'Var', (28, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))
460089	26909593	STAT protein activation, dimerization and nuclear translocation are induced after phosphorylation of JAK by growth factors, cytokine receptors or non-receptor tyrosine kinases signalling.	('nuclear translocation', 'MPA', (42, 63))	('JAK', 'Gene', (101, 104))	('phosphorylation', 'Var', (82, 97))	('dimerization', 'MPA', (25, 37))	('STAT protein activation', 'MPA', (0, 23))	('tyrosine', 'Chemical', 'MESH:D014443', (159, 167))
460098	26909593	The imbalance in STAT3/STAT1 favoured oncogenesis, and appeared to direct tumourigenesis in the EGFR pathway.	('direct', 'PosReg', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('EGFR', 'Gene', (96, 100))	('favoured', 'PosReg', (29, 37))	('oncogenesis', 'CPA', (38, 49))	('tumour', 'Disease', (74, 80))	('imbalance', 'Var', (4, 13))	('STAT1', 'Gene', (23, 28))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('STAT1', 'Gene', '6772', (23, 28))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))	('EGFR', 'Gene', '1956', (96, 100))
460106	26909593	The STAT3 inhibitor S31-201 selectively blocked STAT3 activity via inhibition of STAT3 dimerization and SH2 domain-mediated interference of DNA binding and transcriptional activity, while S3I-201 has minimal effect on STAT1.	('interference', 'NegReg', (124, 136))	('S31-201', 'Chemical', '-', (20, 27))	('S3I-201', 'Chemical', 'MESH:C520337', (188, 195))	('inhibition', 'NegReg', (67, 77))	('blocked', 'NegReg', (40, 47))	('STAT3 activity', 'MPA', (48, 62))	('STAT3 dimerization', 'Protein', (81, 99))	('STAT1', 'Gene', (218, 223))	('transcriptional activity', 'MPA', (156, 180))	('DNA binding', 'Interaction', (140, 151))	('S31-201', 'Var', (20, 27))	('STAT1', 'Gene', '6772', (218, 223))	('SH2 domain-mediated', 'Var', (104, 123))
460107	26909593	Western blot data showed that the combination of gefitinib and S3I-201 or gefitinib plus anti-STAT3 siRNA induced significant further down-regulation of STAT3 phosphorylation and led to substantial decrease in the ratio of pSTAT3/pSTAT1.	('decrease', 'NegReg', (198, 206))	('gefitinib', 'Chemical', 'MESH:D000077156', (74, 83))	('S3I-201', 'Var', (63, 70))	('gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))	('down-regulation', 'NegReg', (134, 149))	('STAT1', 'Gene', (231, 236))	('S3I-201', 'Chemical', 'MESH:C520337', (63, 70))	('STAT1', 'Gene', '6772', (231, 236))	('STAT3 phosphorylation', 'MPA', (153, 174))	('ratio', 'MPA', (214, 219))	('gefitinib', 'Var', (49, 58))
460111	26909593	Several studies in other solid cancers (lung and ovarian cancers) have also indicated that STAT3 activation was associated with EGFR resistance and blocking both EGFR and JAK/STAT signalling pathways at different levels (JAK inhibitors AZD1480 or P6, or siRNA against JAK or STAT3) have shown synergistic therapeutic effects compared with EGFR inhibition alone.	('AZD1480', 'Var', (236, 243))	('EGFR', 'Gene', (339, 343))	('EGFR', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('solid cancers', 'Disease', (25, 38))	('lung and ovarian cancers', 'Disease', 'MESH:D010051', (40, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('EGFR', 'Gene', (128, 132))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('ovarian cancers', 'Phenotype', 'HP:0100615', (49, 64))	('JAK/STAT signalling pathways', 'Pathway', (171, 199))	('EGFR', 'Gene', '1956', (339, 343))	('activation', 'PosReg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('EGFR', 'Gene', '1956', (162, 166))	('STAT3', 'Gene', (91, 96))	('AZD1480', 'Chemical', 'MESH:C545606', (236, 243))	('EGFR', 'Gene', '1956', (128, 132))	('blocking', 'NegReg', (148, 156))	('solid cancers', 'Disease', 'MESH:D009369', (25, 38))
460113	26909593	Although we and others reported that siRNA-mediated knockdown of STAT3 enhanced gefitinib sensitivity, other STAT3 inhibitors including targeting SH2, DNA binding or N-terminal domains need to be further investigated.	('enhanced', 'PosReg', (71, 79))	('gefitinib sensitivity', 'MPA', (80, 101))	('gefitinib', 'Chemical', 'MESH:D000077156', (80, 89))	('knockdown', 'Var', (52, 61))	('STAT3', 'Gene', (65, 70))
460118	26909593	The addition of STAT3 inhibitor S3I-201 to gefitinib achieved synergistic anti-proliferation and pro-apoptotic effects in all three wild-type STS cell lines and this is confirmed in a fibrosarcoma xenografted mouse model, where the tumours from the combination group were significantly smaller than those from untreated or single drug groups.	('tumours', 'Disease', 'MESH:D009369', (232, 239))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (184, 196))	('fibrosarcoma', 'Disease', 'MESH:D005354', (184, 196))	('tumours', 'Disease', (232, 239))	('S3I-201', 'Chemical', 'MESH:C520337', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('S3I-201', 'Var', (32, 39))	('anti-proliferation', 'CPA', (74, 92))	('pro-apoptotic effects', 'CPA', (97, 118))	('gefitinib', 'Chemical', 'MESH:D000077156', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('fibrosarcoma', 'Disease', (184, 196))	('mouse', 'Species', '10090', (209, 214))	('tumours', 'Phenotype', 'HP:0002664', (232, 239))
460126	26909593	DNA was extracted from all sarcoma cell lines using the Qiagen kit (Qiagen, Hilden, Germany) for KRAS and BRAF mutations using bidirectional Sanger sequencing, as described in the Supplementary Materials and Methods - EGFR mutation analysis, K-ras and b-raf mutation analysis.	('sarcoma', 'Disease', (27, 34))	('mutations', 'Var', (111, 120))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('KRAS', 'Gene', (97, 101))	('b-raf', 'Gene', '673', (252, 257))	('KRAS', 'Gene', '3845', (97, 101))	('BRAF', 'Gene', '673', (106, 110))	('K-ras', 'Gene', (242, 247))	('EGFR', 'Gene', '1956', (218, 222))	('BRAF', 'Gene', (106, 110))	('K-ras', 'Gene', '3845', (242, 247))	('EGFR', 'Gene', (218, 222))	('b-raf', 'Gene', (252, 257))
460137	26909593	After our two small preliminary studies for monotherapy with S3I-201 or gefitinib, we performed two independent combination therapy experiments with two different end-points: 1) all mice in the same group were sacrificed when at least one tumor volume in its group reached about 1000mm3 and 2) individual mouse was sacrificed once its tumor reached about 1000mm3.	('S3I-201', 'Chemical', 'MESH:C520337', (61, 68))	('gefitinib', 'Chemical', 'MESH:D000077156', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('mice', 'Species', '10090', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('tumor', 'Disease', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('mouse', 'Species', '10090', (305, 310))	('S3I-201', 'Var', (61, 68))	('tumor', 'Disease', (335, 340))
460144	25664332	Chromosomal translocations are fundamental to the development of Ewing Sarcoma, linked to the changes in gene expression affecting transcription factors.	('Sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (65, 78))	('Chromosomal', 'Var', (0, 11))	('Ewing Sarcoma', 'Disease', (65, 78))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (65, 78))
460160	25664332	These chromosomal translocations include t(11;22) of the EWS gene on chromosome 22 juxtaposed with Fli-1 on chromosome 11 (Delattre, 1992) and t(21;22), EWS gene on chromosome 22 juxtaposed with the erg gene on chromosome 21 (Kaneko, 1997, Zucman, 1993).	('erg', 'Gene', '2078', (199, 202))	('erg', 'Gene', (199, 202))	('EWS', 'Gene', '2130', (153, 156))	('EWS', 'Gene', (153, 156))	('EWS', 'Gene', '2130', (57, 60))	('t(21;22', 'Var', (143, 150))	('EWS', 'Gene', (57, 60))	('t(11;22', 'Var', (41, 48))	('Fli-1', 'Gene', (99, 104))	('Fli-1', 'Gene', '2313', (99, 104))
460172	25664332	HAT activity is shown to be modulated by amplification, over-expression, mutation or translocation in various cancers (, Timmermann, 2001).	('cancers', 'Disease', (110, 117))	('over-expression', 'Var', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('amplification', 'Var', (41, 54))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('mutation', 'Var', (73, 81))	('activity', 'MPA', (4, 12))	('translocation', 'Var', (85, 98))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('modulated', 'Reg', (28, 37))
460173	25664332	HDACs have been found to be associated with aberrant transcription factors and are known to mediate the function of the oncogenic translocation products in lymphoma (Dhordain, 1998).	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('associated', 'Reg', (28, 38))	('transcription', 'Protein', (53, 66))	('lymphoma', 'Disease', (156, 164))	('aberrant', 'Var', (44, 52))	('lymphoma', 'Disease', 'MESH:D008223', (156, 164))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))
460182	25664332	HDAC inhibitors have been shown to induce differentiation, cause growth arrest and apoptosis in many cancer cells including human breast cancer cells, ovarian cancer cells, prostate cancer cells, colon cancer cells, lung cancer cells, leukemia, lymphoma and AML (Carrillo, 2009, Fortson, 2011).	('AML', 'Disease', (258, 261))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('lymphoma', 'Disease', 'MESH:D008223', (245, 253))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('growth arrest', 'Phenotype', 'HP:0001510', (65, 78))	('induce', 'Reg', (35, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('cancer', 'Disease', (137, 143))	('growth arrest', 'Disease', 'MESH:D006323', (65, 78))	('colon cancer', 'Disease', (196, 208))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('differentiation', 'CPA', (42, 57))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('HDAC', 'Gene', '9734', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (182, 188))	('apoptosis', 'CPA', (83, 92))	('growth arrest', 'Disease', (65, 78))	('leukemia', 'Phenotype', 'HP:0001909', (235, 243))	('HDAC', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('lymphoma', 'Phenotype', 'HP:0002665', (245, 253))	('cancer', 'Disease', (221, 227))	('prostate cancer', 'Disease', 'MESH:D011471', (173, 188))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cause', 'Reg', (59, 64))	('ovarian cancer', 'Disease', 'MESH:D010051', (151, 165))	('colon cancer', 'Phenotype', 'HP:0003003', (196, 208))	('prostate cancer', 'Phenotype', 'HP:0012125', (173, 188))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('leukemia', 'Disease', (235, 243))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('leukemia', 'Disease', 'MESH:D007938', (235, 243))	('prostate cancer', 'Disease', (173, 188))	('breast cancer', 'Disease', (130, 143))	('cancer', 'Disease', (101, 107))	('lung cancer', 'Disease', (216, 227))	('inhibitors', 'Var', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('colon cancer', 'Disease', 'MESH:D015179', (196, 208))	('human', 'Species', '9606', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (202, 208))	('AML', 'Disease', 'MESH:D015470', (258, 261))	('lymphoma', 'Disease', (245, 253))	('ovarian cancer', 'Disease', (151, 165))
460198	25664332	Here, we propose that the aberrant fusion protein EWS-ERG/EWS-Fli-1 may regulate RXRalpha transcriptional activity by forming complex with the transcriptional repressors, HDACs.	('HDAC', 'Gene', '9734', (171, 175))	('aberrant', 'Var', (26, 34))	('Fli-1', 'Gene', (62, 67))	('Fli-1', 'Gene', '2313', (62, 67))	('HDAC', 'Gene', (171, 175))	('RXRalpha transcriptional activity', 'MPA', (81, 114))	('regulate', 'Reg', (72, 80))	('complex', 'Interaction', (126, 133))	('EWS', 'Gene', (50, 53))	('ERG', 'Gene', '2078', (54, 57))	('EWS', 'Gene', '2130', (50, 53))	('EWS', 'Gene', (58, 61))	('ERG', 'Gene', (54, 57))	('EWS', 'Gene', '2130', (58, 61))
460211	25664332	Cells were treated with 9-cis-Retinoic acid or vehicle control for 24 hours or medium was replaced with fresh medium containing VPA (0.1 mM, 1 mM and 3 mM) or TSA (0.02 muM, 0.2 muM and 2 muM) or vehicle control for 24 hours.	('9-cis-Retinoic acid', 'Chemical', 'MESH:D000077556', (24, 43))	('muM', 'Gene', (188, 191))	('0.02', 'Var', (164, 168))	('muM', 'Gene', (178, 181))	('muM', 'Gene', '56925', (169, 172))	('TSA', 'Chemical', 'MESH:C012589', (159, 162))	('muM', 'Gene', (169, 172))	('VPA', 'Chemical', 'MESH:D014635', (128, 131))	('muM', 'Gene', '56925', (188, 191))	('muM', 'Gene', '56925', (178, 181))
460267	25664332	5838 cells were treated with variable amounts of Trichostatin-A (0.02 muM , 0.2 muM and 2 muM )/Valproic acid (0.1 mM, 1 mM and 3 mM) and vehicle control for 24 hours.	('Valproic acid', 'Chemical', 'MESH:D014635', (96, 109))	('muM', 'Gene', '56925', (90, 93))	('Trichostatin-A', 'Chemical', 'MESH:C012589', (49, 63))	('muM', 'Gene', '56925', (70, 73))	('muM', 'Gene', '56925', (80, 83))	('muM', 'Gene', (90, 93))	('0.02', 'Var', (65, 69))	('muM', 'Gene', (70, 73))	('muM', 'Gene', (80, 83))
460301	25664332	Deregulation of HDAC activities have been reported in several cancers.	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('HDAC', 'Gene', (16, 20))	('HDAC', 'Gene', '9734', (16, 20))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
460308	25664332	In this study, we found that VPA and TSA reversed the inhibitory properties of RXRalpha transcriptional activity caused by aberrant EWS-ERG/EWS-Fli-1 oncoproteins and also induced cell death in Ewing Sarcoma cells.	('ERG', 'Gene', '2078', (136, 139))	('Sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('death in Ewing Sarcoma', 'Disease', 'MESH:C563168', (185, 207))	('TSA', 'Chemical', 'MESH:C012589', (37, 40))	('VPA', 'Chemical', 'MESH:D014635', (29, 32))	('death in Ewing Sarcoma', 'Disease', (185, 207))	('Fli-1', 'Gene', (144, 149))	('RXRalpha transcriptional', 'Gene', (79, 103))	('EWS', 'Gene', '2130', (132, 135))	('inhibitory properties', 'MPA', (54, 75))	('EWS', 'Gene', '2130', (140, 143))	('induced', 'Reg', (172, 179))	('Fli-1', 'Gene', '2313', (144, 149))	('aberrant', 'Var', (123, 131))	('oncoproteins', 'Protein', (150, 162))	('ERG', 'Gene', (136, 139))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (194, 207))	('EWS', 'Gene', (132, 135))	('EWS', 'Gene', (140, 143))
460310	25664332	We also have shown that dominant negative form of CBP induced apoptosis and it is known that aberrant fusion protein EWS-ERG and EWS-Fli-1 function as anti-apoptotic factors in Ewing Sarcoma cells (Ramakrishnan, 2004).	('Ewing Sarcoma', 'Disease', (177, 190))	('EWS', 'Gene', '2130', (117, 120))	('induced', 'Reg', (54, 61))	('EWS', 'Gene', (117, 120))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (177, 190))	('Sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('ERG', 'Gene', '2078', (121, 124))	('ERG', 'Gene', (121, 124))	('aberrant', 'Var', (93, 101))	('apoptosis', 'CPA', (62, 71))	('EWS', 'Gene', '2130', (129, 132))	('EWS', 'Gene', (129, 132))	('CBP', 'Gene', '1387', (50, 53))	('CBP', 'Gene', (50, 53))	('Fli-1', 'Gene', (133, 138))	('Fli-1', 'Gene', '2313', (133, 138))	('negative', 'NegReg', (33, 41))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (177, 190))
460325	25664332	In contrast to other drugs that are undergoing clinical evaluation, VPA is a well tolerated drug and a well established anti-epileptic drug clinically and pharmacologically.	('VPA', 'Chemical', 'MESH:D014635', (68, 71))	('epileptic', 'Disease', 'MESH:D004827', (125, 134))	('VPA', 'Var', (68, 71))	('epileptic', 'Disease', (125, 134))	('erg', 'Gene', (39, 42))	('erg', 'Gene', '2078', (39, 42))
460341	31193489	For treatment, one and/or two intravenous injections of a complex of small non-coding RNAs (sncRNAs) a-miR-155, piR-30074, and miR-125b with a 2-diethylaminoethyl-dextran methyl methacrylate copolymer (DDMC) delivery system were used.	('a-miR-155', 'Var', (101, 110))	('DDMC', 'Chemical', '-', (202, 206))	('miR-125b', 'Var', (127, 135))	('2-diethylaminoethyl-dextran methyl methacrylate copolymer', 'Chemical', '-', (143, 200))	('125b', 'Chemical', '-', (131, 135))
460345	31193489	As a result, the mice fully recovered from virus-induced sarcoma after two treatments with a complex including the DDMC vector and a-miR-155, piR-30074, and miR-125b.	('mice', 'Species', '10090', (17, 21))	('miR-125b', 'Var', (157, 165))	('125b', 'Chemical', '-', (161, 165))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('DDMC', 'Chemical', '-', (115, 119))	('sarcoma', 'Disease', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
460347	31193489	Treatment of virus-induced sarcoma of mice with a-miR-155, piR-30074, and miR-125b as active component of anti-cancer complex and DDMC vector as delivery system due to epigenetic-regulated transformation of cancer cells into cells with non-cancerous physiology and morphology and full recovery of disease.	('sarcoma', 'Disease', (27, 34))	('miR-125b', 'Var', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('125b', 'Chemical', '-', (78, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('epigenetic-regulated', 'Var', (168, 188))	('mice', 'Species', '10090', (38, 42))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (240, 246))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('DDMC', 'Chemical', '-', (130, 134))
460348	31193489	Complex of a-miR-155, piR-30074, and miR-125b with DDMC vector induced full recovery from virus-induced sarcoma in mice.	('piR-30074', 'Var', (22, 31))	('sarcoma', 'Disease', (104, 111))	('mice', 'Species', '10090', (115, 119))	('DDMC', 'Chemical', '-', (51, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('125b', 'Chemical', '-', (41, 45))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('a-miR-155', 'Var', (11, 20))	('miR-125b', 'Var', (37, 45))
460349	31193489	Complex of DDMC/a-miR-155, piR-30074, and miR-125b transformed sarcoma cells into other types non-cancerous cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('sarcoma', 'Disease', (63, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('DDMC', 'Chemical', '-', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('miR-125b', 'Var', (42, 50))	('cancer', 'Disease', (98, 104))	('DDMC/a-miR-155', 'Var', (11, 25))	('125b', 'Chemical', '-', (46, 50))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('transformed', 'Reg', (51, 62))
460351	31193489	Complex of the DDMC vector with a-miR-155, piR-30074, and miR-125b induced apoptosis in transformed cells.	('induced', 'Reg', (67, 74))	('a-miR-155', 'Var', (32, 41))	('apoptosis', 'CPA', (75, 84))	('miR-125b', 'Var', (58, 66))	('125b', 'Chemical', '-', (62, 66))	('DDMC', 'Chemical', '-', (15, 19))	('piR-30074', 'Var', (43, 52))
460360	31193489	In this study, we investigated the action of small non-coding RNAs a-miR-155, piR-30074, and miR-125b in a murine model of RSV-induced cancer.	('cancer', 'Disease', (135, 141))	('investigated', 'Reg', (18, 30))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('RSV', 'Species', '11886', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('miR-125b', 'Var', (93, 101))	('125b', 'Chemical', '-', (97, 101))	('murine', 'Species', '10090', (107, 113))
460366	31193489	The most effective in our experiments was using of the complex of DDMC delivery system with a-miR-155, piR-30074, and miR-125b for treatment of colorectal, lung, cervix, and glioblastoma cancer cell lines.	('a-miR-155', 'Var', (92, 101))	('glioblastoma cancer', 'Disease', (174, 193))	('125b', 'Chemical', '-', (122, 126))	('DDMC', 'Chemical', '-', (66, 70))	('piR-30074', 'Var', (103, 112))	('cervix', 'Disease', (162, 168))	('lung', 'Disease', (156, 160))	('colorectal', 'Disease', 'MESH:D015179', (144, 154))	('glioblastoma cancer', 'Disease', 'MESH:D005909', (174, 193))	('miR-125b', 'Var', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('colorectal', 'Disease', (144, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (174, 186))
460367	31193489	We performed a series of in vivo experiments in a very rare mouse model of virus-induced human cancer with the highest transformation efficiency in mouse cells.. We used the most effective in preliminary in vitro experiments sncRNAs a-miR-155, piR-30074, and miR-125b in complex with DDMC vector.	('human', 'Species', '9606', (89, 94))	('sncRNAs', 'Var', (225, 232))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('mouse', 'Species', '10090', (148, 153))	('cancer', 'Disease', (95, 101))	('DDMC', 'Chemical', '-', (284, 288))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mouse', 'Species', '10090', (60, 65))	('miR-125b', 'Var', (259, 267))	('125b', 'Chemical', '-', (263, 267))
460414	31193489	In the series of experiments, we observed a two-fold increase in the lifespan of mice with Rous sarcoma after one injection of the complex of the polymer delivery system with a-miR-155, piR-30074, and miR-125b (the 1st group).	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('mice', 'Species', '10090', (81, 85))	('Rous sarcoma', 'Disease', (91, 103))	('polymer', 'Chemical', 'MESH:D011108', (146, 153))	('increase', 'PosReg', (53, 61))	('a-miR-155', 'Var', (175, 184))	('piR-30074', 'Var', (186, 195))	('miR-125b', 'Var', (201, 209))	('125b', 'Chemical', '-', (205, 209))	('Rous sarcoma', 'Disease', 'MESH:D001357', (91, 103))
460419	31193489	Using the complex of DDMC with a-miR-155, piR-30074, and miR-125b for two intravenous treatments of mice with sarcoma due to full recovery of mice.	('miR-125b', 'Var', (57, 65))	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('DDMC', 'Chemical', '-', (21, 25))	('sarcoma', 'Disease', (110, 117))	('mice', 'Species', '10090', (100, 104))	('125b', 'Chemical', '-', (61, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('piR-30074', 'Var', (42, 51))	('mice', 'Species', '10090', (142, 146))
460431	31193489	Then, we added the complex of a-miR-155, piR-30074 and miR-125b with the DDMC delivery system at the same concentration per milliliter of culture medium to the tumor cells.	('DDMC', 'Chemical', '-', (73, 77))	('125b', 'Chemical', '-', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('piR-30074', 'Var', (41, 50))	('miR-125b', 'Var', (55, 63))	('a-miR-155', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))
460435	31193489	Thus, in this series of in vitro experiments, we obtained morphologically tumor cells, tumor stem cells, and apoptotic tumor cells, nuclear translocation of Annexin A4, and expression of Oct4 and CD117 + in tumor cells of dead mice with one treatment with the complex of DDMC/a-miR-155, piR-30074, and miR-125b.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('nuclear translocation', 'MPA', (132, 153))	('DDMC/a-miR-155', 'Var', (271, 285))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('Oct4', 'Gene', '100846986', (187, 191))	('tumor', 'Disease', (74, 79))	('miR-125b', 'Var', (302, 310))	('piR-30074', 'Var', (287, 296))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CD117', 'Gene', '16590', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mice', 'Species', '10090', (227, 231))	('Annexin A4', 'Gene', (157, 167))	('Annexin A4', 'Gene', '11746', (157, 167))	('DDMC', 'Chemical', '-', (271, 275))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (207, 212))	('125b', 'Chemical', '-', (306, 310))	('tumor', 'Disease', (119, 124))	('CD117', 'Gene', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('Oct4', 'Gene', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (119, 124))
460436	31193489	Adding of the complex DDMC/a-miR-155, piR-30074, and miR-125b in cell culture of dead mice from the 1st group due to appearance of majority of morphologically same types of cells, which had had morphological characteristics of non-cancerous cells and expressed CD4+ protein.	('CD4', 'Gene', (261, 264))	('miR-125b', 'Var', (53, 61))	('piR-30074', 'Var', (38, 47))	('125b', 'Chemical', '-', (57, 61))	('expressed', 'Reg', (251, 260))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('CD4', 'Gene', '12504', (261, 264))	('mice', 'Species', '10090', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('DDMC', 'Chemical', '-', (22, 26))
460442	31193489	RVP3 causes the rejection of RSV-induced tumors, but the TSTA characteristic of RSV-induced tumors is present.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('RVP3', 'Var', (0, 4))	('RSV', 'Species', '11886', (80, 83))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('RSV', 'Species', '11886', (29, 32))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('TSTA', 'Gene', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('TSTA', 'Gene', '15519', (57, 61))	('tumors', 'Disease', (92, 98))
460454	31193489	We observed significant down-regulation of src genes and src-dependent pathway genes (v-myc and stat3) after the treatment of animals with the complex of DDMC/a-miR-155, piR-30074 and miR-125b.	('DDMC', 'Chemical', '-', (154, 158))	('myc', 'Gene', '17869', (88, 91))	('125b', 'Chemical', '-', (188, 192))	('stat3', 'Gene', (96, 101))	('DDMC/a-miR-155', 'Var', (154, 168))	('src', 'Gene', '20779', (43, 46))	('src', 'Gene', '20779', (57, 60))	('src', 'Gene', (57, 60))	('src', 'Gene', (43, 46))	('myc', 'Gene', (88, 91))	('piR-30074', 'Var', (170, 179))	('stat3', 'Gene', '20848', (96, 101))	('down-regulation', 'NegReg', (24, 39))	('miR-125b', 'Var', (184, 192))
460461	31193489	In this study, we investigated a combination of a-miR-155, piR-30074 and miR-125b in complex with a DDMC polymer delivery system as a new class of anti-cancer treatment.	('polymer', 'Chemical', 'MESH:D011108', (105, 112))	('cancer', 'Disease', (152, 158))	('DDMC', 'Chemical', '-', (100, 104))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('125b', 'Chemical', '-', (77, 81))	('miR-125b', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
460477	31193489	As known, miR-125b is the double-faced miRNA, which is down-regulate expression of oncogenes in solid tumors, and promote development of hematological malignancies.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('hematological malignancies', 'Disease', (137, 163))	('solid tumors', 'Disease', (96, 108))	('miR-125b', 'Var', (10, 18))	('development', 'CPA', (122, 133))	('expression', 'MPA', (69, 79))	('125b', 'Chemical', '-', (14, 18))	('hematological malignancies', 'Disease', 'MESH:D019337', (137, 163))	('hematological malignancies', 'Phenotype', 'HP:0004377', (137, 163))	('down-regulate', 'NegReg', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('solid tumors', 'Disease', 'MESH:D009369', (96, 108))	('promote', 'PosReg', (114, 121))
460488	31193489	In our previous studies, we observed transformation of colorectal adenocarcinoma, Hela cells combined with right atrium cancer, and acute myeloid leukemia cells into other non-cancerous cells after treatment with a-miR-155 alone or in combination with factors of differentiation.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('acute myeloid leukemia', 'Disease', (132, 154))	('colorectal adenocarcinoma', 'Disease', (55, 80))	('transformation', 'Reg', (37, 51))	('cancer', 'Disease', (120, 126))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (132, 154))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('Hela', 'CellLine', 'CVCL:0030', (82, 86))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (55, 80))	('a-miR-155', 'Var', (213, 222))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (138, 154))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (132, 154))
460490	31193489	TEs can induce genetic instability, which result in gene deregulation, chromosome rearrangement, and deleterious mutation caused to a number of cancers, such as leukemia, breast, ovarian, and colon cancers.	('leukemia', 'Disease', (161, 169))	('leukemia', 'Disease', 'MESH:D007938', (161, 169))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('gene deregulation', 'MPA', (52, 69))	('breast', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('ovarian', 'Disease', (179, 186))	('mutation', 'Var', (113, 121))	('colon cancers', 'Phenotype', 'HP:0003003', (192, 205))	('induce', 'Reg', (8, 14))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancers', 'Disease', (144, 151))	('genetic instability', 'MPA', (15, 34))	('colon cancers', 'Disease', 'MESH:D015179', (192, 205))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('chromosome rearrangement', 'CPA', (71, 95))	('TEs', 'Chemical', 'MESH:C004551', (0, 3))	('colon cancers', 'Disease', (192, 205))	('TEs', 'Var', (0, 3))	('leukemia', 'Phenotype', 'HP:0001909', (161, 169))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('caused', 'Reg', (122, 128))
460503	31193489	Functionally, piR-8041 inhibited expression of ERK1/2/MAPK signaling and reduced cell proliferation.	('cell proliferation', 'CPA', (81, 99))	('piR-8041', 'Chemical', '-', (14, 22))	('MAPK', 'Gene', '26413;26417', (54, 58))	('inhibited', 'NegReg', (23, 32))	('reduced', 'NegReg', (73, 80))	('ERK1/2', 'Gene', '26417;26413', (47, 53))	('expression', 'MPA', (33, 43))	('piR-8041', 'Var', (14, 22))	('ERK1/2', 'Gene', (47, 53))	('MAPK', 'Gene', (54, 58))
460507	31193489	Two intravenous injections of the complex of a-miR-155, miR-125b, and piR-30074 with the DDMC delivery system induced a full recovery from virus-induced cancer in mice.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('125b', 'Chemical', '-', (60, 64))	('DDMC', 'Chemical', '-', (89, 93))	('cancer', 'Disease', (153, 159))	('piR-30074', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mice', 'Species', '10090', (163, 167))	('miR-125b', 'Var', (56, 64))	('a-miR-155', 'Var', (45, 54))
460508	31193489	One intravenous injection of DDMC/a-miR-155, piR-30074 and miR-125b resulted in increase of lifespan of mice with sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('increase', 'PosReg', (80, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('mice', 'Species', '10090', (104, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('lifespan', 'CPA', (92, 100))	('piR-30074', 'Var', (45, 54))	('sarcomas', 'Disease', (114, 122))	('miR-125b', 'Var', (59, 67))	('DDMC', 'Chemical', '-', (29, 33))	('125b', 'Chemical', '-', (63, 67))	('DDMC/a-miR-155', 'Var', (29, 43))
460509	31193489	Treatment of animals with DDMC/a-miR-155, piR-30074 and miR-125b due to activation of apoptosis and the inhibition of Src-associated pathways.	('activation', 'PosReg', (72, 82))	('inhibition', 'NegReg', (104, 114))	('125b', 'Chemical', '-', (60, 64))	('DDMC/a-miR-155', 'Var', (26, 40))	('piR-30074', 'Var', (42, 51))	('Src', 'Gene', '20779', (118, 121))	('Src', 'Gene', (118, 121))	('miR-125b', 'Var', (56, 64))	('DDMC', 'Chemical', '-', (26, 30))	('apoptosis', 'CPA', (86, 95))
460556	28716069	Sensitivity to immunotherapy is thought to be secondary to higher DNA mutation rates, for example those found in melanoma and non-small cell lung cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (126, 152))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (126, 152))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-small cell lung cancer', 'Disease', (126, 152))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('mutation', 'Var', (70, 78))
460559	28716069	Until recently, most of the genetic alterations were identified mostly in secondary but not in primary angiosarcomas.	('genetic alterations', 'Var', (28, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('angiosarcoma', 'Phenotype', 'HP:0200058', (103, 115))	('angiosarcomas', 'Disease', (103, 116))	('angiosarcomas', 'Disease', 'MESH:D006394', (103, 116))	('angiosarcomas', 'Phenotype', 'HP:0200058', (103, 116))
460758	20628498	Moreover, some data suggest that functional TP53 can promote the lytic cycle of some viruses.	('lytic cycle', 'CPA', (65, 76))	('TP53', 'Gene', '7157', (44, 48))	('functional', 'Var', (33, 43))	('TP53', 'Gene', (44, 48))	('promote', 'PosReg', (53, 60))
460918	29210522	presented a dual drug delivery system using tri-axial structured nanofibers, in which the core region consisted of one drug and poly(vinylpyrrolidone) (PVP), the intermediate region consisted of PCL, and the sheath region consisted of the second drug and hygroscopic layer.	('PVP', 'Chemical', 'MESH:D011205', (152, 155))	('in', 'Chemical', 'MESH:D007204', (162, 164))	('PCL', 'Gene', (195, 198))	('in', 'Chemical', 'MESH:D007204', (77, 79))	('poly(vinylpyrrolidone)', 'Chemical', 'MESH:D011205', (128, 150))	('in', 'Chemical', 'MESH:D007204', (134, 136))	('poly', 'Var', (128, 132))	('in', 'Chemical', 'MESH:D007204', (40, 42))	('PCL', 'Gene', '2324', (195, 198))
461061	29210522	Silencing of gene expression by small-interfering RNA (siRNA) represents a potential strategy for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('small-interfering', 'Var', (32, 49))	('in', 'Chemical', 'MESH:D007204', (46, 48))	('Silencing', 'NegReg', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('in', 'Chemical', 'MESH:D007204', (38, 40))	('in', 'Chemical', 'MESH:D007204', (6, 8))	('rat', 'Species', '10116', (87, 90))
461078	29210522	Most importantly, the in vivo study with intracranial xenograft tumor model in BALB/c nude mice indicated that the gene/drug dual delivery microfibers showed better tumor inhibition effect as compared to single drug delivery microfibers and commercial drug treatment.	('in', 'Chemical', 'MESH:D007204', (76, 78))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('nude mice', 'Species', '10090', (86, 95))	('tumor', 'Disease', (64, 69))	('in', 'Chemical', 'MESH:D007204', (205, 207))	('intracranial xenograft tumor', 'Disease', 'MESH:D001932', (41, 69))	('gene/drug dual delivery', 'Var', (115, 138))	('in', 'Chemical', 'MESH:D007204', (22, 24))	('intracranial xenograft tumor', 'Disease', (41, 69))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('in', 'Chemical', 'MESH:D007204', (171, 173))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('in', 'Chemical', 'MESH:D007204', (96, 98))	('in', 'Chemical', 'MESH:D007204', (41, 43))	('tumor', 'Disease', (165, 170))
461113	29210522	The DOX-loaded NaYF4:Yb3+, Er3+@SiO2 nanocomposite fibers were obtained by electrospinning of precursor solution containing alpha-NaYF4:Yb3+, Er3+ nanocrystals, and annealing at 550  C, followed by dispersion in DOX aqueous solution.	('in', 'Chemical', 'MESH:D007204', (118, 120))	('in', 'Chemical', 'MESH:D007204', (87, 89))	('in', 'Chemical', 'MESH:D007204', (67, 69))	('DOX', 'Chemical', 'MESH:D004317', (212, 215))	('DOX', 'Chemical', 'MESH:D004317', (4, 7))	('in', 'Chemical', 'MESH:D007204', (84, 86))	('in', 'Chemical', 'MESH:D007204', (120, 122))	('Er3+', 'Chemical', '-', (27, 31))	('Er3+', 'Var', (142, 146))	('in', 'Chemical', 'MESH:D007204', (209, 211))	('in', 'Chemical', 'MESH:D007204', (171, 173))	('Er3+', 'Chemical', '-', (142, 146))	('nanocrystals', 'Disease', 'None', (147, 159))	('nanocrystals', 'Disease', (147, 159))	('SiO2', 'Chemical', 'MESH:D012822', (32, 36))
461114	29210522	The as-prepared DOX-NaYF4:Yb3+, Er3+@SiO2 composite nanofibers exhibited sustained release of DOX in a pH-sensitive manner.	('sustained release of DOX', 'MPA', (73, 97))	('SiO2', 'Chemical', 'MESH:D012822', (37, 41))	('Er3+@SiO2', 'Var', (32, 41))	('DOX', 'Chemical', 'MESH:D004317', (94, 97))	('in', 'Chemical', 'MESH:D007204', (78, 80))	('in', 'Chemical', 'MESH:D007204', (98, 100))	('DOX', 'Chemical', 'MESH:D004317', (16, 19))	('Er3+', 'Chemical', '-', (32, 36))
461154	29210522	In addition, the results suggested that BCSCs cultured on nanofibers may inhibit their differentiation and increase their resistance to docetaxel and doxorubicin.	('nanofibers', 'Var', (58, 68))	('in', 'Chemical', 'MESH:D007204', (73, 75))	('increase', 'PosReg', (107, 115))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('differentiation', 'CPA', (87, 102))	('in', 'Chemical', 'MESH:D007204', (107, 109))	('docetaxel', 'Chemical', 'MESH:D000077143', (136, 145))	('in', 'Chemical', 'MESH:D007204', (159, 161))	('inhibit', 'NegReg', (73, 80))
461202	29210522	The peptide enhanced adhesion, spreading and infiltration of the metastatic prostate cancer cells on the scaffolds.	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('in', 'Chemical', 'MESH:D007204', (37, 39))	('peptide', 'Var', (4, 11))	('rat', 'Species', '10116', (51, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('enhanced', 'PosReg', (12, 20))	('spreading', 'CPA', (31, 40))	('in', 'Chemical', 'MESH:D007204', (45, 47))	('prostate cancer', 'Disease', (76, 91))	('infiltration', 'CPA', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('adhesion', 'CPA', (21, 29))
461304	27905051	Hormonal therapy with megestrol acetate, gonadotropin-releasing hormone (GnRH) analogues, and aromatase inhibitors can delay progression for long periods of time in low-grade oestrogen receptor-positive ESS, and it is preferred over chemotherapy as front-line palliative treatment (IV, C).	('gonadotropin-releasing hormone', 'Gene', (41, 71))	('gonadotropin-releasing hormone', 'Gene', '2796', (41, 71))	('low-grade', 'Var', (165, 174))	('megestrol acetate', 'Chemical', 'MESH:D019290', (22, 39))
461330	27905051	Frequently, tumors of the PEComa family share dysregulated activation of the mechanistic target of rapamycin (mTOR) signaling through mutations in the TSC1 or TSC2 genes.	('mTOR', 'Gene', (110, 114))	('mechanistic target of rapamycin', 'Gene', (77, 108))	('mTOR', 'Gene', '2475', (110, 114))	('mechanistic target of rapamycin', 'Gene', '2475', (77, 108))	('tumors of the PEComa', 'Disease', (12, 32))	('TSC1', 'Gene', '7248', (151, 155))	('TSC2', 'Gene', '7249', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors of the PEComa', 'Disease', 'MESH:D054973', (12, 32))	('TSC2', 'Gene', (159, 163))	('mutations', 'Var', (134, 143))	('TSC1', 'Gene', (151, 155))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('activation', 'PosReg', (59, 69))
461332	27905051	The Inflammatory myofibroblastic tumor (IMT) is associated with rearrangements of the ALK (anaplastic lymphoma kinase) locus on chromosome 2p23.13.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (91, 110))	('ALK', 'Gene', '238', (86, 89))	('anaplastic lymphoma kinase', 'Gene', (91, 117))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('associated', 'Reg', (48, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (17, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ALK', 'Gene', (86, 89))	('tumor', 'Disease', (33, 38))	('anaplastic lymphoma kinase', 'Gene', '238', (91, 117))	('rearrangements', 'Var', (64, 78))
461371	24678438	Over 90% of ES/PNETs have a chromosomal translocation involving the Ewing's sarcoma breakpoint region 1 (ESWR1).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (68, 83))	('chromosomal translocation', 'Var', (28, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('ES/PNETs', 'Disease', (12, 20))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (68, 83))	('ESWR1', 'Gene', (105, 110))	("Ewing's sarcoma", 'Disease', (68, 83))
461374	24678438	The tumor in Case 2 was positive for the presence of the Ewing sarcoma gene-FLI1 gene (EWS-FLI1) fusion transcript associated with ES/PNET.	('tumor', 'Disease', (4, 9))	('Ewing sarcoma', 'Disease', (57, 70))	('EWS-FLI1', 'Gene', '2130;2313', (87, 95))	('ES/PNET', 'Disease', (131, 138))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('FLI1', 'Gene', '2313', (76, 80))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('FLI1', 'Gene', (76, 80))	('associated', 'Reg', (115, 125))	('fusion transcript', 'Var', (97, 114))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('EWS-FLI1', 'Gene', (87, 95))	('FLI1', 'Gene', '2313', (91, 95))	('FLI1', 'Gene', (91, 95))
461380	24678438	Because positivity for CD99 and/or FLI-1 is suggestive of but not specific for ES/PNET, it is necessary to include them in a comprehensive panel of immunohistochemical markers that will help rule out muscle, lymphoid, epithelial, germ cell, neuroglial, and Merkel cell tumors.	('neuroglial', 'Disease', (241, 251))	('CD99', 'Gene', (23, 27))	('germ cell', 'CPA', (230, 239))	('FLI-1', 'Gene', '2313', (35, 40))	('Merkel cell tumors', 'Disease', 'MESH:D015266', (257, 275))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('FLI-1', 'Gene', (35, 40))	('Merkel cell tumors', 'Disease', (257, 275))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('positivity', 'Var', (8, 18))	('muscle', 'Disease', (200, 206))	('lymphoid', 'Disease', (208, 216))	('epithelial', 'Disease', (218, 228))
461381	24678438	ES/PNETs are characterized by specific chromosomal translocations, resulting in a fusion of the EWSR1 gene (22q12) with one of the members of the E26 transformation-specific family of transcription factors.	('EWSR1', 'Gene', (96, 101))	('EWSR1', 'Gene', '2130', (96, 101))	('ES/PNETs', 'Disease', (0, 8))	('fusion', 'Var', (82, 88))
461382	24678438	FISH break-apart assay confirmed the presence of a translocation involving EWSR1 in Case 1, but RT-PCR analysis did not detect which specific translocation was present.	('EWSR1', 'Gene', (75, 80))	('EWSR1', 'Gene', '2130', (75, 80))	('translocation', 'Var', (51, 64))
461407	23217126	MDM2 amplification at chromosome 12q13-q15, which is present in all tumor samples, is a key driver of dedifferentiated liposarcoma .	('tumor', 'Disease', (68, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Disease', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('liposarcoma', 'Disease', 'MESH:D008080', (119, 130))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('liposarcoma', 'Phenotype', 'HP:0012034', (119, 130))
461408	23217126	Pleomorphic liposarcoma tumor samples harbor gains and deletions in multiple chromosomal regions with the most common being deletion (60%) at chromosome 13q14.2-q14.3 (RB1) in addition to complex genomic rearrangements .	('RB1', 'Gene', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('liposarcoma tumor', 'Disease', (12, 29))	('RB1', 'Gene', '5925', (168, 171))	('gains', 'PosReg', (45, 50))	('liposarcoma', 'Phenotype', 'HP:0012034', (12, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('liposarcoma tumor', 'Disease', 'MESH:D008080', (12, 29))	('deletion', 'Var', (124, 132))	('deletions', 'Var', (55, 64))
461409	23217126	Mutations are common in different types of liposarcoma including TP53 mutations in 17% of pleomorphic liposarcomas; NF1 mutations in 10.5% of myxofibrosarcoma, 8% of pleomorphic liposarcomas; and PIK3CA mutations in 18% of MRC .	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('TP53', 'Gene', '7157', (65, 69))	('PIK3CA', 'Gene', (196, 202))	('liposarcomas', 'Phenotype', 'HP:0012034', (102, 114))	('liposarcoma', 'Disease', (178, 189))	('myxofibrosarcoma', 'Disease', 'None', (142, 158))	('mutations', 'Var', (120, 129))	('liposarcoma', 'Phenotype', 'HP:0012034', (102, 113))	('pleomorphic liposarcomas', 'Disease', (90, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (166, 190))	('liposarcoma', 'Disease', (43, 54))	('liposarcomas', 'Phenotype', 'HP:0012034', (178, 190))	('NF1', 'Gene', '4763', (116, 119))	('liposarcoma', 'Disease', 'MESH:D008080', (102, 113))	('liposarcoma', 'Phenotype', 'HP:0012034', (178, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', (65, 69))	('MRC', 'Disease', (223, 226))	('myxofibrosarcoma', 'Disease', (142, 158))	('PIK3CA', 'Gene', '5290', (196, 202))	('NF1', 'Gene', (116, 119))	('liposarcoma', 'Phenotype', 'HP:0012034', (43, 54))	('mutations', 'Var', (203, 212))	('pleomorphic liposarcomas', 'Disease', (166, 190))	('liposarcoma', 'Disease', 'MESH:D008080', (178, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (90, 114))	('liposarcoma', 'Disease', (102, 113))	('liposarcoma', 'Disease', 'MESH:D008080', (43, 54))	('MRC', 'CellLine', 'CVCL:0440', (223, 226))
461410	23217126	Single nucleotide polymorphism (SNP) microarrays allow the detection of copy number alterations and acquired uniparental disomy (aUPD also known as copy number neutral loss of heterozygosity), which occurs when both copies of a chromosome originate from the same parent, in the most cases without a change in copy number.	('uniparental disomy', 'Disease', (109, 127))	('uniparental disomy', 'Disease', 'MESH:D024182', (109, 127))	('alterations', 'Var', (84, 95))	('copy', 'Var', (72, 76))
461412	23217126	We retrieved raw data (Affymetrix GeneChip Human DNA-oligonucleotide SNP array CEL files) from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) for a total of 319 soft tissue sarcoma (STS) tumor samples from 5 GEO series with the following accession numbers: GSE8046 (20 samples),  GSE15696 (10 samples), GSE20709 (25 samples),  GSE21124 (207 tumor samples),  and GSE24715 (57 samples) (Additional file 1: Table S1) .	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (191, 210))	('GSE8046', 'Var', (287, 294))	('tumor', 'Disease', (371, 376))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (191, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('GSE15696', 'Var', (310, 318))	('GSE20709', 'Var', (333, 341))	('soft tissue sarcoma', 'Disease', (191, 210))	('GSE24715', 'Var', (392, 400))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('GSE21124', 'Var', (357, 365))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('Human', 'Species', '9606', (43, 48))
461426	23217126	Mutations of KIT (75%) and PDGFRA (28%),  and deletions at chromosome 14q (68-70%), 1p (53-56%), and 22q (40%) are common in GIST .	('PDGFRA', 'Gene', '5156', (27, 33))	('PDGFRA', 'Gene', (27, 33))	('deletions at', 'Var', (46, 58))	('Mutations', 'Var', (0, 9))	('KIT', 'Gene', (13, 16))
461428	23217126	GISTs with deletion at chromosome 14q were associated with better disease free survival (DFS) (P < 0.005), whereas tumors with deletion at chromosome 1p (P < 0.00007) and 22q (P < 0.004) were associated with poorer DFS .	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('disease free survival', 'CPA', (66, 87))	('tumors', 'Disease', (115, 121))	('better', 'PosReg', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('deletion', 'Var', (11, 19))
461429	23217126	Taken together, our data indicates that not just gain-of-function mutations like KIT and PDGFRA but also loss-of-function mutations and reduction to homozygosity through aUPD at chromosomes 1p, 14q and 22q may contribute to pathophysiology of GIST.	('mutations', 'Var', (66, 75))	('PDGFRA', 'Gene', '5156', (89, 95))	('KIT', 'Gene', (81, 84))	('mutations', 'Var', (122, 131))	('gain-of-function', 'PosReg', (49, 65))	('GIST', 'Disease', (243, 247))	('loss-of-function', 'NegReg', (105, 121))	('PDGFRA', 'Gene', (89, 95))
461431	23217126	Copy number analysis studies have shown that deletion at chromosome 17p is common in leiomyosarcoma tumor samples,  indicating that the 17p region may harbor tumor suppressor genes that may be homozygously mutated or methylated following aUPD.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (100, 105))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (85, 99))	('leiomyosarcoma tumor', 'Disease', 'MESH:D007890', (85, 105))	('leiomyosarcoma tumor', 'Disease', (85, 105))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('deletion', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
461433	23217126	Previously deletion  and aUPD  in the RB1 region at chromosome 13q14.2 were reported in pleomorphic liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (100, 111))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (88, 111))	('RB1', 'Gene', (38, 41))	('aUPD', 'Var', (25, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('RB1', 'Gene', '5925', (38, 41))	('pleomorphic liposarcoma', 'Disease', (88, 111))	('deletion', 'Var', (11, 19))
461438	23217126	Thus aUPD in these regions could result in decreased or increased expression of candidate cancer genes depending on which parental allele is duplicated.	('increased', 'PosReg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'MPA', (66, 76))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('aUPD', 'Var', (5, 9))
461439	23217126	aUPD regions with homozygous deletion that could potentially harbor tumor suppressor genes are summarized in Additional file 6: Table S3.	('tumor', 'Disease', (68, 73))	('deletion', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
461443	23217126	The frequency and distribution of aUPD is significantly higher in fusion-negative STS than translocation driven STS suggesting an alternative mechanism underlying tumor development.	('aUPD', 'Disease', (34, 38))	('distribution', 'MPA', (18, 30))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('fusion-negative', 'Var', (66, 81))	('higher', 'PosReg', (56, 62))
461449	21837674	Alterations of the mTOR signaling pathway are common in malignancies, including several types of sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('Alterations', 'Var', (0, 11))	('sarcoma', 'Disease', (97, 104))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('common', 'Reg', (46, 52))	('mTOR signaling pathway', 'Pathway', (19, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('malignancies', 'Disease', (56, 68))
461459	21837674	Aberrant activity in several molecular pathways has been linked to the pathogenesis of various sarcoma subtypes.	('sarcoma subtypes', 'Disease', 'MESH:D012509', (95, 111))	('Aberrant activity', 'Var', (0, 17))	('sarcoma subtypes', 'Disease', (95, 111))	('linked', 'Reg', (57, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('molecular pathways', 'Pathway', (29, 47))
461460	21837674	Mahalingam et al recently published an in-depth review of the molecular alterations in sarcomas, which include the up-regulation or mutational activation of receptor tyrosine kinases (KIT, insulin-like growth factor 1 receptor [IGF-1R], epidermal growth factor receptor [EGFR], and platelet-derived growth factor receptor) and members of the phosphatidylinositol 3-kinase (PI3K)/threonine protein kinase Akt (Akt)/mammalian target of rapamycin (mTOR) pathway; loss or deletions of tumor suppressor genes (eg, retinoblastoma, p53, and phosphatase and tensin homolog [PTEN]); increased vascular endothelial growth factor (VEGF) pathway expression and angiogenesis; mutations, amplification, or overexpression of oncogenes (eg, the v-myc myelocytomatosis viral oncogene homolog [c-Myc], Ras, and the v-src sarcoma viral oncogene homolog [Src]); and dysregulation of apoptosis through B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) overexpression.	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (803, 810))	('Myc', 'Gene', (778, 781))	('epidermal growth factor receptor', 'Gene', (237, 269))	('retinoblastoma', 'Disease', (509, 523))	('sarcoma', 'Disease', (87, 94))	('insulin-like growth factor 1 receptor', 'Gene', (189, 226))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('tumor', 'Disease', (481, 486))	('Akt', 'Gene', (404, 407))	('sarcomas', 'Disease', (87, 95))	('increased vascular endothelial growth', 'Phenotype', 'HP:0031052', (574, 611))	('epidermal growth factor receptor', 'Gene', '1956', (237, 269))	('p53', 'Gene', '7157', (525, 528))	('Akt', 'Gene', '207', (404, 407))	('dysregulation', 'CPA', (846, 859))	('tumor', 'Disease', 'MESH:D009369', (481, 486))	('apoptosis', 'CPA', (863, 872))	('EGFR', 'Gene', (271, 275))	('vascular endothelial growth factor', 'Gene', '7422', (584, 618))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('threonine', 'Chemical', 'MESH:D013912', (379, 388))	('VEGF', 'Gene', '7422', (620, 624))	('PTEN', 'Gene', (566, 570))	('p53', 'Gene', (525, 528))	('Akt', 'Gene', (409, 412))	('vascular endothelial growth factor', 'Gene', (584, 618))	('IGF-1R', 'Gene', '3480', (228, 234))	('B-cell chronic lymphocytic leukemia/lymphoma 2', 'Gene', '596', (881, 927))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (189, 226))	('retinoblastoma', 'Disease', 'MESH:D012175', (509, 523))	('VEGF', 'Gene', (620, 624))	('IGF-1R', 'Gene', (228, 234))	('Myc', 'Gene', '4609', (778, 781))	('v-myc myelocytomatosis viral oncogene homolog', 'Gene', (729, 774))	('tumor', 'Phenotype', 'HP:0002664', (481, 486))	('deletions', 'Var', (468, 477))	('overexpression', 'PosReg', (692, 706))	('increased', 'PosReg', (574, 583))	('Bcl-2', 'Gene', (929, 934))	('Akt', 'Gene', '207', (409, 412))	('sarcoma', 'Disease', 'MESH:D012509', (803, 810))	('cell chronic lymphocytic leukemia', 'Phenotype', 'HP:0005539', (883, 916))	('angiogenesis', 'CPA', (649, 661))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (888, 916))	('PTEN', 'Gene', '5728', (566, 570))	('mutations', 'Var', (663, 672))	('sarcoma', 'Disease', (803, 810))	('EGFR', 'Gene', '1956', (271, 275))	('mammalian target of rapamycin', 'Gene', '2475', (414, 443))	('leukemia', 'Phenotype', 'HP:0001909', (908, 916))	('B-cell chronic lymphocytic leukemia/lymphoma 2', 'Gene', (881, 927))	('Bcl-2', 'Gene', '596', (929, 934))	('phosphatase', 'Pathway', (534, 545))	('v-myc myelocytomatosis viral oncogene homolog', 'Gene', '4609', (729, 774))	('retinoblastoma', 'Phenotype', 'HP:0009919', (509, 523))	('lymphoma', 'Phenotype', 'HP:0002665', (917, 925))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))	('mammalian target of rapamycin', 'Gene', (414, 443))
461477	21837674	Because of the complex network of downstream effects linked to the activation of mTOR, dysregulation of the pathway is linked to several malignancies.	('malignancies', 'Disease', 'MESH:D009369', (137, 149))	('activation', 'PosReg', (67, 77))	('malignancies', 'Disease', (137, 149))	('dysregulation', 'Var', (87, 100))	('mTOR', 'Gene', (81, 85))	('linked', 'Reg', (119, 125))
461478	21837674	Abnormal mTOR activity, including the dysregulation of members of its pathway (such as growth factor receptors and tumor suppressors), has been documented in several tumor types, including colorectal, lung, and breast cancers.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (166, 171))	('breast cancers', 'Disease', (211, 225))	('lung', 'Disease', (201, 205))	('dysregulation', 'Var', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('colorectal', 'Disease', 'MESH:D015179', (189, 199))	('breast cancers', 'Phenotype', 'HP:0003002', (211, 225))	('documented', 'Reg', (144, 154))	('breast cancers', 'Disease', 'MESH:D001943', (211, 225))	('colorectal', 'Disease', (189, 199))	('mTOR activity', 'MPA', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
461479	21837674	Overexpression of growth factor receptors or mutation of their associated receptor tyrosine kinases leads to increased signaling through the PI3K/Akt/mTOR pathway.	('signaling', 'MPA', (119, 128))	('growth', 'Protein', (18, 24))	('Akt', 'Gene', (146, 149))	('Akt', 'Gene', '207', (146, 149))	('mutation', 'Var', (45, 53))	('increased', 'PosReg', (109, 118))
461482	21837674	Deletions of the tumor suppressors TSC1/TSC2 and NF1 are associated with both benign sarcoma-like tumors, such as angiomyolipomas, lymphangioleiomyomatosis, rhabdomyomas, neurofibromas, hamartomas, and schwannomas, and malignant sarcomas, such as malignant peripheral nerve sheath tumors.	('hamartomas', 'Disease', (186, 196))	('lymphangioleiomyomatosis', 'Disease', 'MESH:D018192', (131, 155))	('lymphangioleiomyomatosis', 'Disease', (131, 155))	('rhabdomyomas', 'Phenotype', 'HP:0009730', (157, 169))	('schwannomas', 'Phenotype', 'HP:0100008', (202, 213))	('sarcomas', 'Phenotype', 'HP:0100242', (229, 237))	('rhabdomyomas', 'Disease', (157, 169))	('tumor', 'Disease', (98, 103))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (247, 287))	('tumor', 'Disease', (281, 286))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (247, 287))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('malignant peripheral nerve sheath tumors', 'Disease', (247, 287))	('hamartomas', 'Disease', 'MESH:D006222', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('neurofibromas', 'Disease', 'MESH:D009455', (171, 184))	('neurofibromas', 'Phenotype', 'HP:0001067', (171, 184))	('hamartomas', 'Phenotype', 'HP:0010566', (186, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (131, 155))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('malignant sarcomas', 'Disease', 'MESH:D009369', (219, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('TSC1', 'Gene', (35, 39))	('rhabdomyomas', 'Disease', 'MESH:D012207', (157, 169))	('tumor', 'Disease', (17, 22))	('schwannomas', 'Disease', 'MESH:D009442', (202, 213))	('sarcoma-like tumors', 'Disease', 'MESH:D012509', (85, 104))	('TSC2', 'Gene', '7249', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('angiomyolipomas', 'Disease', 'MESH:D018207', (114, 129))	('sarcoma-like tumors', 'Disease', (85, 104))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('schwannomas', 'Disease', (202, 213))	('TSC1', 'Gene', '7248', (35, 39))	('angiomyolipoma', 'Phenotype', 'HP:0006772', (114, 128))	('angiomyolipomas', 'Disease', (114, 129))	('NF1', 'Gene', '4763', (49, 52))	('malignant sarcomas', 'Disease', (219, 237))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('neurofibromas', 'Disease', (171, 184))	('TSC2', 'Gene', (40, 44))	('NF1', 'Gene', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('Deletions', 'Var', (0, 9))	('associated', 'Reg', (57, 67))
461483	21837674	Because of the key role of mTOR in regulating these pathways, the inhibition of mTOR has become a desirable therapeutic option in the treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mTOR', 'Gene', (80, 84))	('inhibition', 'Var', (66, 76))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
461490	21837674	Temsirolimus, a prodrug of sirolimus, is a selective binding inhibitor of mTOR that acts on a variety of tumor cells, in particular those with a PTEN deletion.	('Temsirolimus', 'Chemical', 'MESH:C401859', (0, 12))	('PTEN', 'Gene', (145, 149))	('sirolimus', 'Chemical', 'MESH:D020123', (27, 36))	('PTEN', 'Gene', '5728', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('deletion', 'Var', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('sirolimus', 'Chemical', 'MESH:D020123', (3, 12))
461503	21837674	In another study that used a rhabdomyosarcoma Rh30 mouse xenograft model, a high correlation coefficient was reported between decreases in phosphorylation of threonine residue 70 (Thr) of 4E-BP1 and tumor growth inhibition with temsirolimus.	('tumor', 'Disease', (199, 204))	('Thr', 'Chemical', '-', (180, 183))	('rhabdomyosarcoma', 'Disease', (29, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (29, 45))	('mouse', 'Species', '10090', (51, 56))	('4E-BP1', 'Var', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (29, 45))	('temsirolimus', 'Chemical', 'MESH:C401859', (228, 240))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('threonine', 'Chemical', 'MESH:D013912', (158, 167))	('decreases', 'NegReg', (126, 135))
461504	21837674	These results suggest that decreases in Thr phosphorylation of 4E-BP1 may be a useful surrogate marker for determining inhibition of mTOR activity in tumors.	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('decreases', 'NegReg', (27, 36))	('Thr', 'Chemical', '-', (40, 43))	('Thr phosphorylation', 'MPA', (40, 59))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('4E-BP1', 'Var', (63, 69))
461582	21837674	Top-line data recently presented from the SUCCEED trial demonstrate that treatment with oral ridaforolimus resulted in a 28% reduction (P = .0001) in the risk of progression compared with placebo (hazard ratio, 0.72) and a statistically significant 21% (3.1 week) improvement in median PFS (ridaforolimus vs placebo, 17.7 weeks vs 14.6 weeks).	('reduction', 'NegReg', (125, 134))	('ridaforolimus', 'Chemical', 'MESH:C515074', (291, 304))	('improvement', 'PosReg', (264, 275))	('ridaforolimus', 'Var', (93, 106))	('PFS', 'MPA', (286, 289))	('ridaforolimus', 'Chemical', 'MESH:C515074', (93, 106))
461584	21837674	The incidence of stomatitis (52%) and other AEs was higher with ridaforolimus than with placebo; these findings were consistent with safety data reported for other mTOR inhibitors.	('stomatitis', 'Disease', 'MESH:D013280', (17, 27))	('ridaforolimus', 'Chemical', 'MESH:C515074', (64, 77))	('stomatitis', 'Disease', (17, 27))	('AEs', 'Chemical', '-', (44, 47))	('stomatitis', 'Phenotype', 'HP:0010280', (17, 27))	('ridaforolimus', 'Var', (64, 77))
461599	21837674	Dysregulation of mTOR-associated signaling pathways has been observed in several malignancies, including sarcomas.	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('Dysregulation', 'Var', (0, 13))	('malignancies', 'Disease', (81, 93))	('observed', 'Reg', (61, 69))	('sarcomas', 'Disease', 'MESH:D012509', (105, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('sarcomas', 'Disease', (105, 113))	('mTOR-associated signaling pathways', 'Pathway', (17, 51))
461743	32673360	After that, samples from GSE124158 including malignant sarcoma patients and healthy subjects were randomly allocated to training group and test group at a ratio of 3:1.	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('malignant sarcoma', 'Disease', (45, 62))	('malignant sarcoma', 'Disease', 'MESH:D012509', (45, 62))	('GSE124158', 'Var', (25, 34))	('patients', 'Species', '9606', (63, 71))
461750	32673360	In addition, external test data sets E-MTAB-3273, E-MTAB-3888 and E-MTAB-5126, containing 10 synovial serum samples, 6 liposarcoma serum samples, 5 leiomyosarcoma serum samples, and 14 healthy controls were downloaded from the Array Express.	('leiomyosarcoma', 'Disease', (148, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (148, 162))	('E-MTAB-5126', 'Var', (66, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (148, 162))	('liposarcoma', 'Disease', (119, 130))	('liposarcoma', 'Disease', 'MESH:D008080', (119, 130))	('liposarcoma', 'Phenotype', 'HP:0012034', (119, 130))
461797	32673360	3 Jun 2020  PONE-D-19-34131R1 A novel serum miRNA-pair classifier for diagnosis of sarcoma PLOS ONE Dear Dr. Zhu, Thank you for submitting your manuscript to PLOS ONE.	('sarcoma', 'Disease', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('PONE-D-19-34131R1', 'Var', (12, 29))	('PONE-D-19-34131', 'Chemical', '-', (12, 27))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))
461804	31052299	Inhibiting antioxidants expression, while at the same time elevating intracellular reactive oxygen species (ROS) levels, have been proposed as a valid strategy to overcome ES cancer progression.	('Inhibiting', 'Var', (0, 10))	('ROS', 'Chemical', 'MESH:D017382', (108, 111))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('elevating intracellular reactive oxygen species', 'Phenotype', 'HP:0025464', (59, 106))	('elevating', 'PosReg', (59, 68))	('antioxidants expression', 'MPA', (11, 34))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (83, 106))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('ES', 'Phenotype', 'HP:0012254', (172, 174))
461808	31052299	Recently, beta3-adrenergic receptor (beta3-AR) antagonism has been proposed as a possible strategy in cancer therapy for its ability to induce apoptosis by increasing intracellular levels of ROS.	('beta3-adrenergic receptor', 'Gene', (10, 35))	('induce', 'PosReg', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('antagonism', 'Var', (47, 57))	('ROS', 'MPA', (191, 194))	('beta3-adrenergic receptor', 'Gene', '155', (10, 35))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('apoptosis', 'CPA', (143, 152))	('beta3-AR', 'Gene', '155', (37, 45))	('ROS', 'Chemical', 'MESH:D017382', (191, 194))	('intracellular levels', 'MPA', (167, 187))	('beta3-AR', 'Gene', (37, 45))	('increasing', 'PosReg', (156, 166))
461810	31052299	Since ES cells are susceptible to an increased oxidative stress to reduce cell viability, here we demonstrate that administration of beta3-ARs antagonist, SR59230A, improves the apigenin effect on cell death, identifying beta3-AR as a potential discriminating factor that could address the use of apigenin in ES.	('apigenin', 'Chemical', 'MESH:D047310', (297, 305))	('ES', 'Phenotype', 'HP:0012254', (6, 8))	('apigenin', 'Chemical', 'MESH:D047310', (178, 186))	('SR59230A', 'Chemical', 'MESH:C097869', (155, 163))	('ES', 'Phenotype', 'HP:0012254', (309, 311))	('oxidative stress', 'Phenotype', 'HP:0025464', (47, 63))	('apigenin effect', 'MPA', (178, 193))	('improves', 'PosReg', (165, 173))	('beta3-AR', 'Gene', '155', (221, 229))	('SR59230A', 'Var', (155, 163))	('beta3-AR', 'Gene', (221, 229))	('beta3-AR', 'Gene', '155', (133, 141))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (37, 63))	('beta3-AR', 'Gene', (133, 141))
461817	31052299	It was observed that depletion of intracellular GSH decreases cell viability and enhances the efficacy of ROS-generating anticancer agents such as fenretinide.	('GSH', 'Chemical', 'MESH:D005978', (48, 51))	('efficacy', 'MPA', (94, 102))	('ROS-generating', 'MPA', (106, 120))	('decreases', 'NegReg', (52, 61))	('cell viability', 'CPA', (62, 76))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('enhances', 'PosReg', (81, 89))	('depletion', 'Var', (21, 30))	('fenretinide', 'Chemical', 'MESH:D017313', (147, 158))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('GSH', 'Protein', (48, 51))
461825	31052299	Overexpression of beta3-ARs has been associated with cancer growth, recruitment of circulating stromal cell precursors to the tumour sites, and enhancement of stem cell traits.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('stem cell traits', 'CPA', (159, 175))	('cancer', 'Disease', (53, 59))	('recruitment', 'CPA', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('beta3-AR', 'Gene', (18, 26))	('beta3-AR', 'Gene', '155', (18, 26))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Overexpression', 'Var', (0, 14))	('enhancement', 'PosReg', (144, 155))
461836	31052299	The analysis of various ROS species levels measured at different times showed that the amount of most of ROS species decreased at the highest dose of apigenin (50 muM) after 24 h of treatment when it inhibits the expression of the most antioxidant proteins examined.	('expression', 'MPA', (213, 223))	('apigenin', 'Chemical', 'MESH:D047310', (150, 158))	('muM', 'Gene', '56925', (163, 166))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('amount', 'MPA', (87, 93))	('decreased', 'NegReg', (117, 126))	('inhibits', 'NegReg', (200, 208))	('muM', 'Gene', (163, 166))	('ROS', 'Chemical', 'MESH:D017382', (105, 108))	('50', 'Var', (160, 162))
461844	31052299	We showed an increase of mitochondrial ROS levels and an inhibition of GSH amount after 24h of treatment with SR59230A (Figure 3D).	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('SR59230A', 'Chemical', 'MESH:C097869', (110, 118))	('mitochondrial ROS levels', 'MPA', (25, 49))	('GSH amount', 'MPA', (71, 81))	('inhibition', 'NegReg', (57, 67))	('increase of mitochondrial ROS levels', 'Phenotype', 'HP:0025464', (13, 49))	('GSH', 'Chemical', 'MESH:D005978', (71, 74))	('increase', 'PosReg', (13, 21))	('SR59230A', 'Var', (110, 118))
461845	31052299	Interestingly, SR59230A inhibited the UCP2 expression in accord with previous data reported in melanoma cells (Figure 3E).	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('UCP2', 'Gene', '7351', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('SR59230A', 'Chemical', 'MESH:C097869', (15, 23))	('inhibited', 'NegReg', (24, 33))	('expression', 'MPA', (43, 53))	('UCP2', 'Gene', (38, 42))	('SR59230A', 'Var', (15, 23))
461846	31052299	These results indicate that the treatment with SR59230A could improve the effects of apigenin action by increasing ROS mitochondrial levels.	('effects', 'MPA', (74, 81))	('apigenin', 'Chemical', 'MESH:D047310', (85, 93))	('SR59230A', 'Var', (47, 55))	('improve', 'PosReg', (62, 69))	('ROS mitochondrial levels', 'MPA', (115, 139))	('ROS', 'Chemical', 'MESH:D017382', (115, 118))	('SR59230A', 'Chemical', 'MESH:C097869', (47, 55))	('increasing', 'PosReg', (104, 114))
461847	31052299	Therefore, we tested the impact of the administration of apigenin and/or SR59230A (10 muM) on the survival of A673 cells (Figure 3F).	('muM', 'Gene', '56925', (86, 89))	('SR59230A', 'Chemical', 'MESH:C097869', (73, 81))	('muM', 'Gene', (86, 89))	('SR59230A', 'Var', (73, 81))	('tested', 'Reg', (14, 20))	('apigenin', 'Chemical', 'MESH:D047310', (57, 65))
461850	31052299	Moreover, we observed that the expression of antioxidant levels was decreased after 24 h of treatment with BRL37344, and the same reduction was observed with apigenin treatment (Figure 4D).	('decreased', 'NegReg', (68, 77))	('apigenin', 'Chemical', 'MESH:D047310', (158, 166))	('antioxidant levels', 'MPA', (45, 63))	('expression', 'MPA', (31, 41))	('BRL37344', 'Var', (107, 115))	('BRL37344', 'Chemical', 'MESH:C057368', (107, 115))
461856	31052299	Insights into the binding mode of apigenin with the two modelled targets revealed a key role played by the residues involved in the binding of beta-ARs agonists/antagonists with the receptor, i.e., D117, F309, and N332.	('D117', 'Var', (198, 202))	('F309', 'Var', (204, 208))	('apigenin', 'Chemical', 'MESH:D047310', (34, 42))	('binding', 'Interaction', (18, 25))	('N332', 'Var', (214, 218))	('binding', 'Interaction', (132, 139))
461857	31052299	In particular, the 7-OH moiety of apigenin established two H-bond interactions with the side chains of D117 and N331, acting as a donor and acceptor, respectively.	('apigenin', 'Chemical', 'MESH:D047310', (34, 42))	('donor', 'Species', '9606', (130, 135))	('H-bond interactions', 'Interaction', (59, 78))	('D117', 'Var', (103, 107))	('N331', 'Var', (112, 116))
461858	31052299	Moreover, the chromone core (i.e., the moiety formed by A+B in Figure 4A) of the ligand is sandwiched by F309 and V118, forming pi-pi and pi-alkyl interactions.	('chromone', 'Chemical', 'MESH:D002867', (14, 22))	('pi-alkyl', 'Var', (138, 146))	('forming', 'Reg', (120, 127))	('pi-pi', 'Var', (128, 133))
461859	31052299	Other common interactions are a T-shaped pi-pi stacking engaged by the phenyl ring of apigenin (C in Figure 5A) and the side chain of F198 as well as a H-bond formed by the hydroxyl group in position 4' and the guanidinium group of the R315 side chain.	('H-bond', 'Var', (152, 158))	('interactions', 'Interaction', (13, 25))	('apigenin', 'Chemical', 'MESH:D047310', (86, 94))	('guanidinium', 'Chemical', 'MESH:D019791', (211, 222))
461861	31052299	As further proof, an analysis of the second messenger cyclic AMP (cAMP) levels was performed showing increased cAMP levels in the presence of BRL37344 and in the same way with apigenin 50 muM after 30 min of exposition, confirming that apigenin could act as beta3-AR agonist (Figure 5B).	('apigenin', 'Chemical', 'MESH:D047310', (236, 244))	('beta3-AR', 'Gene', '155', (258, 266))	('muM', 'Gene', (188, 191))	('increased', 'PosReg', (101, 110))	('beta3-AR', 'Gene', (258, 266))	('cyclic AMP', 'Chemical', 'MESH:D000242', (54, 64))	('cAMP levels', 'MPA', (111, 122))	('apigenin', 'Chemical', 'MESH:D047310', (176, 184))	('BRL37344', 'Var', (142, 150))	('BRL37344', 'Chemical', 'MESH:C057368', (142, 150))	('muM', 'Gene', '56925', (188, 191))	('cAMP', 'Chemical', 'MESH:D000242', (66, 70))	('cAMP', 'Chemical', 'MESH:D000242', (111, 115))
461870	31052299	Transition ions, as Cu2+ and Fe2+ present in biological systems, can affect the pro-oxidant activity of flavonoids, leading to inhibition of mitochondrial breathing.	('affect', 'Reg', (69, 75))	('pro-oxidant activity', 'MPA', (80, 100))	('Fe2+', 'Chemical', 'MESH:C038178', (29, 33))	('Cu2+', 'Chemical', '-', (20, 24))	('Fe2+', 'Var', (29, 33))	('flavonoids', 'Chemical', 'MESH:D005419', (104, 114))	('inhibition', 'NegReg', (127, 137))	('mitochondrial breathing', 'MPA', (141, 164))
461888	31052299	This study revealed the importance of beta3-ARs in the maintenance of GSH homeostasis in glioma cells by Gi/0-protein but not by Gs-protein in U-251 cells.	('beta3-AR', 'Gene', '155', (38, 46))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('GSH', 'Chemical', 'MESH:D005978', (70, 73))	('beta3-AR', 'Gene', (38, 46))	('U-251', 'CellLine', 'CVCL:0021', (143, 148))	('glioma', 'Disease', (89, 95))	('Gi/0-protein', 'Var', (105, 117))	('GSH homeostasis', 'MPA', (70, 85))
461933	31052299	The crystal structures of turkey beta1-AR (2Y03) and human beta2-AR (3PDS) were downloaded from the Protein Data Bank and used as a template in the homology modelling procedure.	('beta2-AR', 'Gene', '154', (59, 67))	('turkey', 'Species', '9103', (26, 32))	('human', 'Species', '9606', (53, 58))	('2Y03', 'Var', (43, 47))	('beta2-AR', 'Gene', (59, 67))
461936	31052299	Statistical analysis was performed using Graph Pad Prism software (GraphPad, San Diego, CA, USA) by one-way analysis of variance (ANOVA) and two-way analysis for all experiments except for the analysis of GSH levels after SR59230A treatment, followed by Bonferroni post hoc analysis.	('SR59230A', 'Chemical', 'MESH:C097869', (222, 230))	('GSH', 'Chemical', 'MESH:D005978', (205, 208))	('GSH levels', 'MPA', (205, 215))	('SR59230A', 'Var', (222, 230))
461990	32899322	Mast Cells, microRNAs and Others: The Role of Translational Research on Colorectal Cancer in the Forthcoming Era of Precision Medicine Colorectal cancer (CRC) is a heterogeneous disease, molecularly and anatomically, that develops in a multi-step process requiring the accumulation of several genetic or epigenetic mutations that lead to the gradual transformation of normal mucosa into cancer.	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (72, 89))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('Colorectal cancer', 'Disease', (135, 152))	('Mast', 'Gene', (0, 4))	('Colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (72, 89))	('epigenetic mutations', 'Var', (304, 324))	('cancer', 'Disease', (387, 393))	('cancer', 'Disease', 'MESH:D009369', (387, 393))	('Colorectal Cancer', 'Disease', (72, 89))	('Mast', 'Gene', '11092', (0, 4))	('genetic', 'Var', (293, 300))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('CRC', 'Phenotype', 'HP:0003003', (154, 157))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))
461993	32899322	Colorectal cancer (CRC) is a heterogeneous disease, molecularly and anatomically, that develops in a multi-step process requiring the accumulation of several genetic or epigenetic mutations that lead to the gradual transformation of normal mucosa into cancer.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('epigenetic mutations', 'Var', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', (252, 258))	('lead to', 'Reg', (195, 202))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Colorectal cancer', 'Disease', (0, 17))	('cancer', 'Disease', (11, 17))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))
461996	32899322	There are currently three main routes of CRC carcinogenesis: chromosomal instability, DNA replication errors and epigenetic regulation, which includes aberrant hypermethylation and gene silencing.	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('CRC carcinogenesis', 'Disease', 'MESH:D015179', (41, 59))	('epigenetic', 'MPA', (113, 123))	('gene silencing', 'Var', (181, 195))	('aberrant hypermethylation', 'Var', (151, 176))	('chromosomal instability', 'Phenotype', 'HP:0040012', (61, 84))	('CRC carcinogenesis', 'Disease', (41, 59))
462001	32899322	However, after thirty years, the attention shifted to molecular biomarkers, i.e., the Kirsten rat sarcoma (KRAS) mutation.	('rat', 'Species', '10116', (94, 97))	('mutation', 'Var', (113, 121))	('attention shifted', 'Phenotype', 'HP:0000736', (33, 50))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('sarcoma', 'Disease', (98, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
462038	32899322	published the first systemic and comprehensive array-based analysis to evaluate 389 miRNA expression levels in CRC and normal colonic tissues, identifying 37 aberrantly expressed miRNAs in CRC and demonstrating the overexpression of miRNA-20a, miRNA-21, miRNA-106a, miRNA-181b, and miRNA-203 in tumor tissues.	('miRNA-21', 'Gene', (244, 252))	('miRNA-181b', 'Var', (266, 276))	('colonic', 'Disease', 'MESH:D003110', (126, 133))	('overexpression', 'PosReg', (215, 229))	('CRC', 'Phenotype', 'HP:0003003', (189, 192))	('colonic', 'Disease', (126, 133))	('rat', 'Species', '10116', (204, 207))	('miRNA-20a', 'Gene', '406982', (233, 242))	('miRNA-106a', 'Var', (254, 264))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('miRNA-20a', 'Gene', (233, 242))	('miRNA-203', 'Gene', '406986', (282, 291))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('miRNA-203', 'Gene', (282, 291))	('miRNA-21', 'Gene', '406991', (244, 252))	('tumor', 'Disease', (295, 300))
462049	32899322	The plasma levels of three miRNAs, miR-24, miR-320a and miR423-5p, can be monitored to predict the post-operative risk of metastasis in CRC patients.	('miR423', 'Gene', (56, 62))	('miR423', 'Gene', '494335', (56, 62))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('miR-320a', 'Gene', '407037', (43, 51))	('miR-320a', 'Gene', (43, 51))	('patients', 'Species', '9606', (140, 148))	('CRC', 'Disease', (136, 139))	('metastasis', 'CPA', (122, 132))	('miR-24', 'Var', (35, 41))	('rat', 'Species', '10116', (107, 110))
462055	32899322	Regarding miRNAs in tumor tissue, miRNA-143 and miRNA-145 were the first to be associated with CRC tumorigenesis.	('tumor', 'Disease', (99, 104))	('associated', 'Reg', (79, 89))	('miRNA-143', 'Var', (34, 43))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))	('miRNA-145', 'Gene', '406937', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('miRNA-145', 'Gene', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (20, 25))
462060	32899322	In fact, some miRNAs, such as miRNA-320 and miRNA-498, were significantly correlated with recurrence-free survival in colon cancer.	('correlated with', 'Reg', (74, 89))	('colon cancer', 'Disease', (118, 130))	('miRNA-320', 'Var', (30, 39))	('colon cancer', 'Disease', 'MESH:D015179', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('recurrence-free survival', 'CPA', (90, 114))	('colon cancer', 'Phenotype', 'HP:0003003', (118, 130))	('miRNA-498', 'Var', (44, 53))
462063	32899322	Patients with CRC and high levels of let-7 may benefit from anti-EGFR therapy (cetuximab) due to its downregulatory effect on KRAS.	('benefit', 'PosReg', (47, 54))	('let-7', 'Gene', (37, 42))	('downregulatory', 'NegReg', (101, 115))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('high', 'Var', (22, 26))	('CRC', 'Phenotype', 'HP:0003003', (14, 17))	('KRAS', 'Disease', (126, 130))	('Patients', 'Species', '9606', (0, 8))	('cetuximab', 'Chemical', 'MESH:D000068818', (79, 88))
462067	32899322	Rat sarcoma (RAS) proteins are a group of nucleotide guanosine triphosphate (GTPases) involved in several crucial cell processes, and their mutations play a pivotal role in human carcinogenesis.	('sarcoma', 'Disease', (4, 11))	('Rat', 'Species', '10116', (0, 3))	('carcinogenesis', 'Disease', 'MESH:D063646', (179, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('nucleotide guanosine triphosphate', 'Chemical', '-', (42, 75))	('carcinogenesis', 'Disease', (179, 193))	('human', 'Species', '9606', (173, 178))	('mutations', 'Var', (140, 149))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('GTP', 'Chemical', 'MESH:D006160', (77, 80))
462068	32899322	Among them, the KRAS mutation is mainly involved in preventing the hydrolysis of the GTP complex, leading to cell proliferation via several signaling pathways.	('cell proliferation', 'CPA', (109, 127))	('GTP', 'Chemical', 'MESH:D006160', (85, 88))	('preventing', 'NegReg', (52, 62))	('leading to', 'Reg', (98, 108))	('GTP', 'Protein', (85, 88))	('mutation', 'Var', (21, 29))	('KRAS', 'Gene', (16, 20))	('hydrolysis', 'MPA', (67, 77))	('rat', 'Species', '10116', (121, 124))
462070	32899322	The results of studies performed on patients with advanced or recurrent CRC have revealed that out of 35% of patients with KRAS mutations, 25% had mutations at codon 12, and 10% had mutations at codon 13.	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (109, 117))	('mutations', 'Var', (128, 137))	('had', 'Gene', '23498', (178, 181))	('CRC', 'Phenotype', 'HP:0003003', (72, 75))	('mutations at', 'Var', (147, 159))	('had', 'Gene', '23498', (143, 146))	('KRAS', 'Gene', (123, 127))	('had', 'Gene', (178, 181))	('had', 'Gene', (143, 146))
462073	32899322	Although there is no clear evidence of the relationship between KRAS mutations and CRC stage and location, patients with codon 12 mutations were found to be more commonly affected by advanced stage proximal tumors with mucinous histology.	('mucin', 'Gene', '100508689', (219, 224))	('affected', 'Reg', (171, 179))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('mucin', 'Gene', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('mutations', 'Var', (130, 139))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('patients', 'Species', '9606', (107, 115))	('codon 12', 'Gene', (121, 129))
462074	32899322	Furthermore, some authors showed that codon 13 mutation was related to a 40% increase in short-term mortality from colon cancer and was associated with advanced Dukes stage.	('associated', 'Reg', (136, 146))	('colon cancer', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('codon 13 mutation', 'Var', (38, 55))	('increase', 'PosReg', (77, 85))	('mortality', 'Disease', 'MESH:D003643', (100, 109))	('colon cancer', 'Phenotype', 'HP:0003003', (115, 127))	('colon cancer', 'Disease', 'MESH:D015179', (115, 127))	('mortality', 'Disease', (100, 109))
462078	32899322	Furthermore, KRAS mutations seem to be associated with worse survival among patients undergoing repeat hepatectomy.	('KRAS', 'Gene', (13, 17))	('patients', 'Species', '9606', (76, 84))	('associated', 'Reg', (39, 49))	('mutations', 'Var', (18, 27))
462080	32899322	The rationale beyond the accurate study of the specific type of KRAS mutation can be explained by the fact that the constitutively activated RAS/RAF/MAPK pathway (in case of mutation in codons 12 and 13) makes the targeting of epidermal growth factor receptor (EGFR) therapeutically useless.	('EGFR', 'Gene', '1956', (261, 265))	('mutation', 'Var', (174, 182))	('RAF', 'Gene', '22882', (145, 148))	('RAF', 'Gene', (145, 148))	('rat', 'Species', '10116', (29, 32))	('KRAS', 'Gene', (64, 68))	('epidermal growth factor receptor', 'Gene', (227, 259))	('mutation', 'Var', (69, 77))	('EGFR', 'Gene', (261, 265))	('rat', 'Species', '10116', (4, 7))	('epidermal growth factor receptor', 'Gene', '1956', (227, 259))
462081	32899322	Therefore, mutated KRAS represents a negative predictive biomarker for the response to anti-EGFR therapy in patients affected by metastatic CRC.	('patients', 'Species', '9606', (108, 116))	('CRC', 'Phenotype', 'HP:0003003', (140, 143))	('KRAS', 'Gene', (19, 23))	('EGFR', 'Gene', '1956', (92, 96))	('metastatic CRC', 'Disease', (129, 143))	('EGFR', 'Gene', (92, 96))	('mutated', 'Var', (11, 18))
462084	32899322	The emerging field of liquid biopsies to detect mutational status could have meaningful clinical implications to individualize an optimal targeted therapy, especially for patients with KRAS-mutated metastatic CRC.	('metastatic CRC', 'Disease', (198, 212))	('KRAS-mutated', 'Var', (185, 197))	('CRC', 'Phenotype', 'HP:0003003', (209, 212))	('patients', 'Species', '9606', (171, 179))
462090	32899322	Although BRAF can be mutated in several sites, the V600E mutation occurs in approximately 80% of cases and is characterized by a nucleotide (1799T > A) change resulting in an amino acid change leading to constitutive kinase activity.	('leading to', 'Reg', (193, 203))	('V600E', 'Var', (51, 56))	('amino', 'MPA', (175, 180))	('constitutive kinase activity', 'MPA', (204, 232))	('1799T > A', 'Mutation', 'rs113488022', (141, 150))	('V600E', 'Mutation', 'rs113488022', (51, 56))
462091	32899322	The percentage of BRAF gene mutations has been reported in 15% of all human cancer types and in approximately 10% of CRC.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('BRAF gene', 'Gene', (18, 27))	('cancer', 'Disease', (76, 82))	('mutations', 'Var', (28, 37))	('CRC', 'Disease', (117, 120))
462092	32899322	V600E BRAF mutation has been shown to be an acquired genetic event, occurring more frequently in older women (>60 years old) with right-sided primary tumors, CRC stage II/III and metastatic disease.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('CRC', 'Phenotype', 'HP:0003003', (158, 161))	('CRC stage II/III', 'Disease', (158, 174))	('metastatic disease', 'Disease', (179, 197))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('BRAF', 'Gene', (6, 10))	('women', 'Species', '9606', (103, 108))	('V600E', 'Var', (0, 5))
462093	32899322	Conversely, patients with non-V600E mutations are usually younger, with left-sided primary tumors in a less advanced stage.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('patients', 'Species', '9606', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('non-V600E', 'Var', (26, 35))
462099	32899322	A study on CRC patients with BRAF mutations limited by a small sample size suggests a potential negative predictive role of BRAF mutations in patients treated with anti-EGFR drugs.	('patients', 'Species', '9606', (15, 23))	('CRC', 'Phenotype', 'HP:0003003', (11, 14))	('BRAF', 'Gene', (29, 33))	('mutations', 'Var', (129, 138))	('negative', 'NegReg', (96, 104))	('EGFR', 'Gene', '1956', (169, 173))	('EGFR', 'Gene', (169, 173))	('CRC', 'Disease', (11, 14))	('patients', 'Species', '9606', (142, 150))	('BRAF', 'Gene', (124, 128))	('mutations', 'Var', (34, 43))
462100	32899322	Nevertheless, anti-EGFR drugs associated with FOLFOXIRI (FOLinic acid, Fluorouracil, Oxaliplatin, IRInotecan) seem to result in a higher objective response rate (ORR) than FOLFOXIRI alone in patients with the V600E mutation.	('Fluorouracil', 'Chemical', 'MESH:D005472', (71, 83))	('rat', 'Species', '10116', (156, 159))	('objective response', 'MPA', (137, 155))	('patients', 'Species', '9606', (191, 199))	('higher', 'PosReg', (130, 136))	('FOLinic acid', 'Chemical', 'MESH:D002955', (57, 69))	('EGFR', 'Gene', '1956', (19, 23))	('FOLFOXIRI', 'Chemical', '-', (172, 181))	('V600E', 'Mutation', 'rs113488022', (209, 214))	('IRInotecan', 'Chemical', 'MESH:D000077146', (98, 108))	('EGFR', 'Gene', (19, 23))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (85, 96))	('FOLFOXIRI', 'Chemical', '-', (46, 55))	('V600E', 'Var', (209, 214))
462101	32899322	BRAF inhibitors have revolutionized the treatment of V600E BRAF metastatic melanoma, but the rationale underlying the use of such inhibitors cannot explain a response in CRC patients because the molecular landscape is more complex and heterogeneous.	('V600E', 'Mutation', 'rs113488022', (53, 58))	('patients', 'Species', '9606', (174, 182))	('V600E', 'Var', (53, 58))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('rat', 'Species', '10116', (93, 96))
462102	32899322	Recently, in the BEACON trial, an open-label, phase III trial, it has been demonstrated that a combination of encorafenib, cetuximab and binimetinib (triplet-therapy group) resulted in a higher response rate and higher overall survival in patients with metastatic CRC with the V600E BRAF mutations if compared with the standard therapy, i.e., cetuximab and irinotecan or cetuximab and FOLFIRI.	('BEACON', 'Gene', (17, 23))	('response', 'MPA', (194, 202))	('cetuximab', 'Chemical', 'MESH:D000068818', (371, 380))	('V600E', 'Var', (277, 282))	('BEACON', 'Gene', '59286', (17, 23))	('higher', 'PosReg', (212, 218))	('FOLFIRI', 'Chemical', '-', (385, 392))	('higher', 'PosReg', (187, 193))	('overall survival', 'CPA', (219, 235))	('BRAF', 'Gene', (283, 287))	('CRC', 'Phenotype', 'HP:0003003', (264, 267))	('metastatic CRC', 'Disease', (253, 267))	('irinotecan', 'Chemical', 'MESH:D000077146', (357, 367))	('encorafenib', 'Chemical', 'MESH:C000601108', (110, 121))	('rat', 'Species', '10116', (203, 206))	('cetuximab', 'Chemical', 'MESH:D000068818', (123, 132))	('V600E', 'Mutation', 'rs113488022', (277, 282))	('patients', 'Species', '9606', (239, 247))	('rat', 'Species', '10116', (82, 85))	('binimetinib', 'Chemical', 'MESH:C581313', (137, 148))	('cetuximab', 'Chemical', 'MESH:D000068818', (343, 352))
462103	32899322	In the era of precision medicine, the predictive value of BRAF mutation in CRCs is still controversial and needs more efforts to further stratify the BRAF mutant population (considering non-V600E BRAF mutations) and to include other potential targets, improving the efficacy of multiple personalized therapies and establishing a new standard of care.	('V600E', 'Mutation', 'rs113488022', (190, 195))	('rat', 'Species', '10116', (139, 142))	('improving', 'PosReg', (252, 261))	('mutation', 'Var', (63, 71))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('CRCs', 'Disease', (75, 79))
462129	31897843	Liquid biopsies also enable monitoring of tumor clonal evolution and detection of therapy-relevant novel mutations arising during treatment.	('mutations', 'Var', (105, 114))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
462139	31897843	It is currently unclear what the gold standard is for early cancer detection programs in children with cancer predisposition syndromes stemming from gene mutations in the germline, such as Li-Fraumeni (TP53), Von Hippel Lindau (VHL), familial adenomatous polyposis (APC), DICER1 syndrome or subtypes of primary immunodeficiencies.	('primary immunodeficiencies', 'Disease', 'MESH:D007153', (303, 329))	('cancer', 'Disease', (103, 109))	('VHL', 'Disease', 'MESH:D006623', (228, 231))	('TP53', 'Gene', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Li-Fraumeni', 'Disease', (189, 200))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('familial adenomatous polyposis (APC), DICER1 syndrome', 'Disease', 'MESH:D011125', (234, 287))	('children', 'Species', '9606', (89, 97))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (189, 200))	('primary immunodeficiencies', 'Disease', (303, 329))	('VHL', 'Disease', (228, 231))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('TP53', 'Gene', '7157', (202, 206))	('Von Hippel Lindau', 'Gene', '7428', (209, 226))	('immunodeficiencies', 'Phenotype', 'HP:0002721', (311, 329))	('cancer', 'Disease', (60, 66))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (243, 264))	('Von Hippel Lindau', 'Gene', (209, 226))	('mutations', 'Var', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
462146	31897843	Further evidence of the feasibility of ctDNA detection across different pediatric cancers and different biological sources will come from the ongoing NGSkids (NCT02546453) and MICCHADO (NCT03496402) trials.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('pediatric cancer', 'Disease', 'MESH:D009369', (72, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('NCT02546453', 'Var', (159, 170))	('NCT03496402', 'Chemical', 'MESH:C079985', (186, 197))	('pediatric cancer', 'Disease', (72, 88))	('GS', 'Disease', 'MESH:D011125', (151, 153))
462147	31897843	Recent evidence demonstrates that copy number alterations, a mandatory analysis for risk stratification, can be determined from cell-free DNA in blood plasma from neuroblastoma patients.	('neuroblastoma', 'Disease', 'MESH:D009447', (163, 176))	('copy number alterations', 'Var', (34, 57))	('neuroblastoma', 'Disease', (163, 176))	('patients', 'Species', '9606', (177, 185))	('neuroblastoma', 'Phenotype', 'HP:0003006', (163, 176))
462149	31897843	showed that the two activating ALK mutations commonly occurring in neuroblastomas can be detected in plasma by droplet digital PCR with high sensitivity and specificity (90-100%), producing results concordant to those achieved with deep sequencing.	('ALK', 'Gene', '238', (31, 34))	('neuroblastomas', 'Phenotype', 'HP:0003006', (67, 81))	('activating', 'PosReg', (20, 30))	('neuroblastomas', 'Disease', 'MESH:D009447', (67, 81))	('ALK', 'Gene', (31, 34))	('neuroblastomas', 'Disease', (67, 81))	('neuroblastoma', 'Phenotype', 'HP:0003006', (67, 80))	('mutations', 'Var', (35, 44))
462150	31897843	Quantitative PCR-based detection of MYCN amplifications in peripheral blood from neuroblastoma patients was proven feasible in 2002, before the concept of cancer liquid biopsies was established.	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('neuroblastoma', 'Disease', 'MESH:D009447', (81, 94))	('amplifications', 'Var', (41, 55))	('neuroblastoma', 'Disease', (81, 94))	('MYCN', 'Gene', (36, 40))	('neuroblastoma', 'Phenotype', 'HP:0003006', (81, 94))	('MYCN', 'Gene', '4613', (36, 40))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
462152	31897843	The diagnostic hallmark for Ewing sarcoma is a rearrangement involving the EWSR1 gene, most commonly EWSR1-FLI1 and EWSR1-ERG rearrangements, while other rare translocation partners have been reported.	('rearrangements', 'Var', (126, 140))	('EWSR1', 'Gene', '2130', (75, 80))	('ERG', 'Gene', '2078', (122, 125))	('rearrangement', 'Var', (47, 60))	('ERG', 'Gene', (122, 125))	('EWSR1', 'Gene', '2130', (116, 121))	('EWSR1', 'Gene', (101, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('FLI1', 'Gene', (107, 111))	('Ewing sarcoma', 'Disease', (28, 41))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (28, 41))	('FLI1', 'Gene', '2313', (107, 111))	('EWSR1', 'Gene', (116, 121))	('EWSR1', 'Gene', '2130', (101, 106))	('EWSR1', 'Gene', (75, 80))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))
462160	31897843	Tumor-specific copy number and/or single-nucleotide alterations were detected in plasma from all but one patient.	('patient', 'Species', '9606', (105, 112))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('detected', 'Reg', (69, 77))	('copy number', 'Var', (15, 26))	('single-nucleotide alterations', 'Var', (34, 63))
462162	31897843	A small proof-of-concept study developed and applied a PCR assay detecting internal tandem duplications in BCOR, a hallmark of clear cell sarcoma of the kidney, to plasma samples.	('hallmark of clear cell sarcoma of the kidney', 'Disease', 'MESH:D018227', (115, 159))	('BCOR', 'Gene', (107, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('BCOR', 'Gene', '54880', (107, 111))	('hallmark of clear cell sarcoma of the kidney', 'Disease', (115, 159))	('internal tandem duplications', 'Var', (75, 103))
462165	31897843	Classification of brain tumors by methylation analysis appears to outperform histopathological diagnostics at least for several tumor types.	('brain tumor', 'Phenotype', 'HP:0030692', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor type', 'Disease', (128, 138))	('methylation', 'Var', (34, 45))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor type', 'Disease', 'MESH:D009369', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('brain tumors', 'Phenotype', 'HP:0030692', (18, 30))	('brain tumors', 'Disease', 'MESH:D001932', (18, 30))	('brain tumors', 'Disease', (18, 30))
462178	31897843	Tumor-specific copy number alterations and RB1 mutations detected in the vitreous fluid using shallow whole-genome sequencing strongly correlated with the need for eye enucleation.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (47, 56))	('vitreous fluid', 'Phenotype', 'HP:0100832', (73, 87))	('RB1', 'Gene', (43, 46))	('copy number alterations', 'Var', (15, 38))	('correlated with', 'Reg', (135, 150))	('RB1', 'Gene', '5925', (43, 46))
462206	31897843	Recurrent genetic alterations or hotspot mutations that are tumor-specific are ideal targets for ctDNA diagnostics or MRD detection.	('mutations', 'Var', (41, 50))	('genetic alterations', 'Var', (10, 29))	('ctDNA', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
462207	31897843	This includes ALKF1174 and ALKR1275 mutations and MYCN amplifications in primary neuroblastomas, the BRAFV600E mutation in Langerhans cell histiocytosis, and EWSR1 translocations in Ewing sarcoma, to name a few.	('ALK', 'Gene', '238', (14, 17))	('neuroblastomas', 'Disease', 'MESH:D009447', (81, 95))	('ALK', 'Gene', (14, 17))	('neuroblastoma', 'Phenotype', 'HP:0003006', (81, 94))	('ALK', 'Gene', '238', (27, 30))	('BRAFV600E', 'Mutation', 'rs113488022', (101, 110))	('histiocytosis', 'Phenotype', 'HP:0100727', (139, 152))	('ALK', 'Gene', (27, 30))	('MYCN', 'Gene', (50, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('Langerhans cell histiocytosis', 'Disease', 'MESH:D006646', (123, 152))	('Langerhans cell histiocytosis', 'Disease', (123, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('EWSR1', 'Gene', '2130', (158, 163))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (182, 195))	('neuroblastomas', 'Phenotype', 'HP:0003006', (81, 95))	('BRAFV600E', 'Var', (101, 110))	('Ewing sarcoma', 'Disease', (182, 195))	('MYCN', 'Gene', '4613', (50, 54))	('neuroblastomas', 'Disease', (81, 95))	('EWSR1', 'Gene', (158, 163))
462213	31897843	The first randomized controlled trials in pediatric oncology that will collect liquid biopsies to explore its potential are currently being initiated (NCT02546453, NCT03496402, NCT03336931).	('NCT03336931', 'Chemical', 'MESH:C079985', (177, 188))	('NCT02546453', 'Var', (151, 162))	('NCT03496402', 'Var', (164, 175))	('oncology', 'Phenotype', 'HP:0002664', (52, 60))	('NCT03336931', 'Var', (177, 188))	('NCT03496402', 'Chemical', 'MESH:C079985', (164, 175))
462218	31897843	A well-validated and highly sensitive test to detect lymphoma-associated genetic alterations might reduce the number of lymph node biopsies necessary to diagnose lymphadenitis as opposed to lymphoma.	('lymphoma', 'Disease', (53, 61))	('lymphoma', 'Disease', 'MESH:D008223', (53, 61))	('lymphadenitis', 'Phenotype', 'HP:0002840', (162, 175))	('genetic alterations', 'Var', (73, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('lymphadenitis', 'Disease', 'MESH:D008199', (162, 175))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('reduce', 'NegReg', (99, 105))	('lymphadenitis', 'Disease', (162, 175))	('lymphoma', 'Disease', (190, 198))	('lymphoma', 'Disease', 'MESH:D008223', (190, 198))
462223	31372595	Comparative RNA-Sequencing Analysis Benefits a Pediatric Patient With Relapsed Cancer Clinical detection of sequence and structural variants in known cancer genes points to viable treatment options for a minority of children with cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('Relapsed Cancer', 'Disease', 'None', (70, 85))	('cancer', 'Disease', (150, 156))	('variants', 'Var', (132, 140))	('Patient', 'Species', '9606', (57, 64))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Relapsed Cancer', 'Disease', (70, 85))	('children', 'Species', '9606', (216, 224))
462236	31372595	Because EWSR1 breakapart fluorescence in situ hybridization confirmed an EWSR rearrangement but concomitant WT1 breakapart fluorescence in situ hybridization was negative, the molecular criterion for DSRCT was not met, and a final diagnosis of poorly differentiated sarcoma, not otherwise specified, was rendered.	('sarcoma', 'Disease', 'MESH:D012509', (266, 273))	('EWSR1', 'Gene', (8, 13))	('sarcoma', 'Disease', (266, 273))	('WT1', 'Gene', '7490', (108, 111))	('WT1', 'Gene', (108, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('EWSR1', 'Gene', '2130', (8, 13))	('EWSR rearrangement', 'Var', (73, 91))	('rearrangement', 'Var', (78, 91))
462243	31372595	The POG team identified three somatic variants of unclear therapeutic significance: PDGFRA p.V299F, PRKCB p.D341N and SVIL p.L1374R.	('SVIL', 'Gene', '6840', (118, 122))	('PRKCB', 'Gene', (100, 105))	('p.D341N', 'Var', (106, 113))	('p.L1374R', 'Mutation', 'rs199726033', (123, 131))	('PRKCB', 'Gene', '5579', (100, 105))	('p.D341N', 'Mutation', 'p.D341N', (106, 113))	('PDGFRA', 'Gene', (84, 90))	('p.V299F', 'Mutation', 'p.V299F', (91, 98))	('p.L1374R', 'Var', (123, 131))	('SVIL', 'Gene', (118, 122))	('p.V299F', 'Var', (91, 98))
462244	31372595	No germline single-nucleotide variants with established cancer relevance were detected.	('cancer', 'Disease', (56, 62))	('single-nucleotide variants', 'Var', (12, 38))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
462321	31372595	Standard, internally derived thresholds were followed to determine definitive presence of a translocation that involved the EWSR1 and WT1 loci.	('WT1', 'Gene', '7490', (134, 137))	('EWSR1', 'Gene', (124, 129))	('WT1', 'Gene', (134, 137))	('EWSR1', 'Gene', '2130', (124, 129))	('translocation', 'Var', (92, 105))
462380	32648496	CCSK is the second most common primary renal malignancy of childhood, characterized by BCOR exon 15 internal tandem duplications in most cases and YWHAE-NUTM2 fusion in few others.	('CCSK', 'Disease', (0, 4))	('CCSK', 'Chemical', '-', (0, 4))	('renal malignancy', 'Phenotype', 'HP:0009726', (39, 55))	('YWHAE', 'Gene', (147, 152))	('BCOR', 'Gene', '54880', (87, 91))	('primary renal malignancy', 'Disease', 'MESH:D007680', (31, 55))	('CCSK', 'Phenotype', 'HP:0006770', (0, 4))	('primary renal malignancy', 'Disease', (31, 55))	('YWHAE', 'Gene', '7531', (147, 152))	('internal tandem duplications', 'Var', (100, 128))	('BCOR', 'Gene', (87, 91))
462488	33673232	Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression.	('obesity', 'Disease', 'MESH:D009765', (160, 167))	('expression levels', 'MPA', (28, 45))	('implicated', 'Reg', (97, 107))	('diabetes', 'Disease', 'MESH:D003920', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('obesity', 'Disease', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('obesity', 'Phenotype', 'HP:0001513', (160, 167))	('alterations', 'Var', (13, 24))	('cancer', 'Disease', (172, 178))	('activation', 'PosReg', (49, 59))	('diabetes', 'Disease', (150, 158))
462490	33673232	A deeper understanding of the biological relevance of this network of IGF1R modulators might provide novel therapeutic opportunities to block this system in neoplasia.	('neoplasia', 'Disease', (157, 166))	('neoplasia', 'Disease', 'MESH:D009369', (157, 166))	('modulators', 'Var', (76, 86))	('IGF1R', 'Gene', (70, 75))	('neoplasia', 'Phenotype', 'HP:0002664', (157, 166))
462494	33673232	Alterations in IGF expression or function result in pathological conditions including diabetes, growth retardation, osteoporosis, neurodegenerative diseases, obesity and cancer.	('cancer', 'Disease', (170, 176))	('Alterations', 'Var', (0, 11))	('diabetes', 'Disease', 'MESH:D003920', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('neurodegenerative diseases', 'Disease', (130, 156))	('obesity', 'Phenotype', 'HP:0001513', (158, 165))	('function', 'MPA', (33, 41))	('osteoporosis', 'Disease', (116, 128))	('growth retardation', 'Phenotype', 'HP:0001510', (96, 114))	('expression', 'MPA', (19, 29))	('osteoporosis', 'Phenotype', 'HP:0000939', (116, 128))	('result in', 'Reg', (42, 51))	('osteoporosis', 'Disease', 'MESH:D010024', (116, 128))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('diabetes', 'Disease', (86, 94))	('obesity', 'Disease', (158, 165))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (130, 156))	('growth retardation', 'Disease', 'MESH:D006130', (96, 114))	('growth retardation', 'Disease', (96, 114))	('IGF', 'Gene', (15, 18))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (130, 156))	('obesity', 'Disease', 'MESH:D009765', (158, 165))
462516	33673232	In 1993, Sell and colleagues demonstrated that the simian virus 40 large tumor antigen (SV40 TAg) was unable to transform fibroblasts derived from mouse embryos homozygous for a null mutation of the igf1r gene (R- cells).	('igf1r', 'Gene', (199, 204))	('mouse', 'Species', '10090', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('igf1r', 'Gene', '16001', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('null mutation', 'Var', (178, 191))	('simian virus 40', 'Species', '1891767', (51, 66))
462519	33673232	These mutations include focal amplification of IGF1R and IGF1, and frameshift indels in the recessive cancer genes IGF2R and IGFBP5.	('recessive cancer', 'Disease', 'MESH:D009369', (92, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('recessive cancer', 'Disease', (92, 108))	('IGF1', 'Gene', (57, 61))	('IGF1R', 'Gene', (47, 52))	('IGF2R', 'Gene', (115, 120))	('frameshift indels', 'Var', (67, 84))	('IGFBP5', 'Gene', (125, 131))	('IGFBP5', 'Gene', '3488', (125, 131))	('IGF2R', 'Gene', '3482', (115, 120))
462520	33673232	Amplification of the IGF1R was also identified in a percentage of breast tumors, co-occurring with the CKS1BP7 pseudogene amplification, gastrointestinal stromal tumors, melanoma, and pancreatic adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (137, 168))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (137, 168))	('pancreatic adenocarcinoma', 'Disease', (184, 209))	('breast tumors', 'Phenotype', 'HP:0100013', (66, 79))	('CKS1BP7', 'Gene', '137529', (103, 110))	('CKS1BP7', 'Gene', (103, 110))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('amplification', 'Var', (122, 135))	('gastrointestinal stromal tumors', 'Disease', (137, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (184, 209))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (184, 209))	('Amplification', 'Var', (0, 13))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('pseudogene amplification', 'Var', (111, 135))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('IGF1R', 'Gene', (21, 26))	('identified', 'Reg', (36, 46))	('breast tumors', 'Disease', (66, 79))	('breast tumors', 'Disease', 'MESH:D001943', (66, 79))
462521	33673232	For instance, IGF1R activation occurs as a consequence of mutations of tumor suppressor genes including breast cancer gene-1 (BRCA1), the Wilm's tumor protein-1 (WT1), the von Hippel-Lindau gene (VHL) and p53 (TP53).	('mutations', 'Var', (58, 67))	('breast cancer gene-1', 'Gene', (104, 124))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('VHL', 'Gene', (196, 199))	('WT1', 'Gene', (162, 165))	('TP53', 'Gene', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('von Hippel-Lindau gene', 'Gene', (172, 194))	('von Hippel-Lindau gene', 'Gene', '7428', (172, 194))	('tumor', 'Disease', (145, 150))	('p53', 'Gene', '7157', (205, 208))	('WT1', 'Gene', '7490', (162, 165))	("Wilm's tumor protein-1", 'Gene', (138, 160))	('VHL', 'Gene', '7428', (196, 199))	("Wilm's tumor protein-1", 'Gene', '7490', (138, 160))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('p53', 'Gene', (205, 208))	('IGF1R', 'Gene', (14, 19))	('tumor', 'Disease', (71, 76))	('BRCA1', 'Gene', '672', (126, 131))	('TP53', 'Gene', '7157', (210, 214))	('BRCA1', 'Gene', (126, 131))	('breast cancer gene-1', 'Gene', '672', (104, 124))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('activation', 'PosReg', (20, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
462529	33673232	In glioma, a specific mutation in phosphatase and tensin homologue (PTEN) gene, a tumor suppressor and lipid phosphatase, determines the truncation of its C-terminal region with consequent gain of neo-morphic and phosphatase-independent activity, which stimulates IGF1 synthesis.	('IGF1 synthesis', 'MPA', (264, 278))	('mutation', 'Var', (22, 30))	('gain', 'PosReg', (189, 193))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('stimulates', 'PosReg', (253, 263))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('truncation', 'MPA', (137, 147))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('neo-morphic', 'CPA', (197, 208))	('PTEN', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PTEN', 'Gene', '5728', (68, 72))	('glioma', 'Disease', (3, 9))	('C-terminal region', 'MPA', (155, 172))	('tumor', 'Disease', (82, 87))	('phosphatase and tensin homologue', 'Gene', '5728', (34, 66))
462538	33673232	Additional cancer genes modulated by a dysregulated IGF1R-STAT3 axis are ALDH1 and Nanog, which enhance the epithelial-to-mesenchymal transition (EMT)-associated cancer stem cells (CSC)-like properties in non-small cell lung cancer and colorectal cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (225, 231))	('ALDH1', 'Gene', '216', (73, 78))	('cancer', 'Disease', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('colorectal cancer', 'Phenotype', 'HP:0003003', (236, 253))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('lung cancer', 'Disease', (220, 231))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('Nanog', 'Gene', '79923', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('Nanog', 'Gene', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('ALDH1', 'Gene', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('colorectal cancer', 'Disease', 'MESH:D015179', (236, 253))	('STAT3', 'Gene', (58, 63))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('colorectal cancer', 'Disease', (236, 253))	('enhance', 'PosReg', (96, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('dysregulated', 'Var', (39, 51))	('STAT3', 'Gene', '6774', (58, 63))	('cancer', 'Disease', (11, 17))
462545	33673232	Aberrant activation of IGF system in cancer has been associated with resistance to cytotoxic therapy, including chemotherapy and radiotherapy, and targeted therapy.	('activation', 'PosReg', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (37, 43))	('IGF', 'Protein', (23, 26))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
462549	33673232	Significantly, simultaneous IGFBP2 depletion and pharmacological inhibition of Akt and MAPK pathways sensitized esophageal adenocarcinoma cells to cisplatin therapy.	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('adenocarcinoma', 'Disease', (123, 137))	('Akt', 'Pathway', (79, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('MAPK pathways', 'Pathway', (87, 100))	('adenocarcinoma', 'Disease', 'MESH:D000230', (123, 137))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (112, 137))	('IGFBP2', 'Gene', '3485', (28, 34))	('sensitized', 'Reg', (101, 111))	('depletion', 'Var', (35, 44))	('IGFBP2', 'Gene', (28, 34))
462556	33673232	It is well established that ionizing radiation activates tyrosine kinase receptors involved in DNA damage response, including the IGF1R, as in fact targeting the IGF1R enhances radiosensitivity of different cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tyrosine', 'Chemical', 'MESH:D014443', (57, 65))	('targeting', 'Var', (148, 157))	('enhances', 'PosReg', (168, 176))	('IGF1R', 'Gene', (162, 167))	('tyrosine kinase receptors', 'Enzyme', (57, 82))
462566	33673232	Alterations in IGFBP2 expression are associated with resistance to both anti-IGF1R agents and dasatinib in rhabdomyosarcoma and non-small cell lung cancer cells, respectively.	('rhabdomyosarcoma', 'Disease', (107, 123))	('resistance', 'MPA', (53, 63))	('lung cancer', 'Disease', (143, 154))	('Alterations', 'Var', (0, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('IGFBP2', 'Gene', '3485', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (107, 123))	('IGFBP2', 'Gene', (15, 21))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('associated', 'Reg', (37, 47))	('dasatinib', 'Chemical', 'MESH:D000069439', (94, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (107, 123))
462567	33673232	Particularly, loss of IGFBP2 is associated with resistance to anti-IGF1R treatment due to hyperactivation of IGF signaling in rhabdomyosarcoma, while overexpression of IGFBP2 drives dasatinib resistance through activation of FAK in non-small cell lung cancer cells.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (126, 142))	('lung cancer', 'Disease', 'MESH:D008175', (247, 258))	('IGFBP2', 'Gene', (168, 174))	('loss', 'Var', (14, 18))	('hyperactivation', 'PosReg', (90, 105))	('FAK', 'Gene', (225, 228))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('IGFBP2', 'Gene', '3485', (22, 28))	('dasatinib', 'Chemical', 'MESH:D000069439', (182, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('FAK', 'Gene', '5747', (225, 228))	('IGF signaling', 'MPA', (109, 122))	('IGFBP2', 'Gene', (22, 28))	('rhabdomyosarcoma', 'Disease', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (232, 258))	('lung cancer', 'Disease', (247, 258))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (236, 258))	('dasatinib resistance', 'MPA', (182, 202))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (126, 142))	('IGFBP2', 'Gene', '3485', (168, 174))
462575	33673232	In particular, IGF2 overexpression determined enhanced transforming capability of MCF7 cells compared to control cells as well as increased glucose consumption, increased lactate production, increased mRNA expression of glucose and lactate transporters and glycolytic enzymes.	('transforming capability', 'CPA', (55, 78))	('overexpression', 'Var', (20, 34))	('IGF2', 'Gene', '3481', (15, 19))	('lactate', 'Chemical', 'MESH:D019344', (232, 239))	('glucose', 'Chemical', 'MESH:D005947', (220, 227))	('glucose', 'Chemical', 'MESH:D005947', (140, 147))	('increased lactate production', 'Phenotype', 'HP:0003128', (161, 189))	('increased', 'PosReg', (191, 200))	('IGF2', 'Gene', (15, 19))	('lactate', 'Chemical', 'MESH:D019344', (171, 178))	('increased glucose', 'Phenotype', 'HP:0003074', (130, 147))	('enhanced', 'PosReg', (46, 54))	('lactate production', 'MPA', (171, 189))	('increased', 'PosReg', (130, 139))	('increased', 'PosReg', (161, 170))	('MCF7', 'CellLine', 'CVCL:0031', (82, 86))	('glycolytic enzymes', 'Enzyme', (257, 275))	('glucose consumption', 'MPA', (140, 159))
462589	33673232	Interestingly, circRASSF2 regulates laryngeal squamous-cell carcinoma cells malignancy by sponging miR-302b-3p and enhancing the expression of IGF1R.	('circRASSF2', 'Gene', (15, 25))	('regulates', 'Reg', (26, 35))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('expression', 'MPA', (129, 139))	('squamous-cell carcinoma cells malignancy', 'Disease', 'MESH:D002294', (46, 86))	('miR-302b-3p', 'Gene', (99, 110))	('sponging', 'Var', (90, 98))	('IGF1R', 'Gene', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('enhancing', 'PosReg', (115, 124))	('squamous-cell carcinoma cells malignancy', 'Disease', (46, 86))
462592	33673232	Among other major components of the IGF axis, IGF1 is upregulated by the action of circRUNX1 on miR-145-5p or circ_0014130 on miR-142-5p, in colorectal or nonsmall cell lung cancer, respectively, with substantial effects on cell proliferation, cell cycle progression, cell migration and inhibition of apoptosis.	('cell cycle progression', 'CPA', (244, 266))	('apoptosis', 'CPA', (301, 310))	('upregulated', 'PosReg', (54, 65))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (155, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('effects', 'Reg', (213, 220))	('cell proliferation', 'CPA', (224, 242))	('circRUNX1', 'Gene', (83, 92))	('colorectal or nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (141, 180))	('IGF1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('miR-142-5p', 'Var', (126, 136))	('colorectal or nonsmall cell lung cancer', 'Disease', (141, 180))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (158, 180))	('miR-145', 'Gene', '406937', (96, 103))	('cell migration', 'CPA', (268, 282))	('miR-142-5p', 'Chemical', '-', (126, 136))	('miR-145', 'Gene', (96, 103))	('circ_0014130', 'Var', (110, 122))
462594	33673232	In hepatoblastoma cells, circHMGCS1 exerts its oncogenic role by sponging the tumor suppressing action of miR-503-5p, thus upregulating IGF2 and the PI3K-Akt signaling pathway.	('miR-503-5p', 'Var', (106, 116))	('hepatoblastoma', 'Disease', (3, 17))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (3, 17))	('upregulating', 'PosReg', (123, 135))	('circHMGCS1', 'Gene', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('IGF2', 'Gene', '3481', (136, 140))	('miR-503-5p', 'Chemical', '-', (106, 116))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PI3K-Akt signaling pathway', 'Pathway', (149, 175))	('tumor', 'Disease', (78, 83))	('IGF2', 'Gene', (136, 140))	('hepatoblastoma', 'Disease', 'MESH:D018197', (3, 17))
462598	33673232	Accordingly, dysregulation of RBPs is frequently associated with pathological conditions including cancer.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('dysregulation', 'Var', (13, 26))	('associated', 'Reg', (49, 59))	('cancer', 'Disease', (99, 105))	('RBP', 'Gene', '5950', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('RBP', 'Gene', (30, 33))
462604	33673232	As shown in hepatocellular carcinoma and Ewing sarcoma cells, knockdown of IGF2BPs is associated with downregulation of IGF1R mRNA and protein and consequent inhibition of in vitro cell viability, proliferation, clonogenicity and migration.	('clonogenicity', 'CPA', (212, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('IGF1R', 'Gene', (120, 125))	('Ewing sarcoma', 'Disease', (41, 54))	('downregulation', 'NegReg', (102, 116))	('IGF2', 'Gene', '3481', (75, 79))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (12, 36))	('hepatocellular carcinoma', 'Disease', (12, 36))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (12, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (41, 54))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (41, 54))	('migration', 'CPA', (230, 239))	('inhibition', 'NegReg', (158, 168))	('proliferation', 'CPA', (197, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('IGF2', 'Gene', (75, 79))	('in vitro cell viability', 'CPA', (172, 195))	('knockdown', 'Var', (62, 71))
462620	33673232	In chronic myeloid leukemia cells IGF2BP3 depletion determined a reduction of IGF2 production and increased susceptibility to ionizing radiation as measured by apoptosis, effect that was partially reversed by treatment with recombinant IGF2.	('susceptibility to ionizing radiation', 'MPA', (108, 144))	('IGF2', 'Gene', (236, 240))	('IGF2', 'Gene', '3481', (78, 82))	('IGF2BP3', 'Gene', '10643', (34, 41))	('IGF2BP3', 'Gene', (34, 41))	('increased', 'PosReg', (98, 107))	('depletion', 'Var', (42, 51))	('IGF2', 'Gene', (34, 38))	('reduction', 'NegReg', (65, 74))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (3, 27))	('myeloid leukemia', 'Disease', (11, 27))	('IGF2', 'Gene', '3481', (236, 240))	('leukemia', 'Phenotype', 'HP:0001909', (19, 27))	('apoptosis', 'CPA', (160, 169))	('myeloid leukemia', 'Disease', 'MESH:D007951', (11, 27))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (11, 27))	('IGF2', 'Gene', '3481', (34, 38))	('IGF2', 'Gene', (78, 82))	('susceptibility to ionizing radiation', 'Phenotype', 'HP:0011133', (108, 144))
462629	33673232	A-to-I editing of IGFBP7 generates different isoforms, which are differentially susceptible to proteolytic cleavage, an event that profoundly impacts the biological activity of this protein.	('IGFBP7', 'Gene', (18, 24))	('editing', 'Var', (7, 14))	('IGFBP7', 'Gene', '3490', (18, 24))	('biological activity', 'MPA', (154, 173))	('impacts', 'Reg', (142, 149))
462643	33673232	Accordingly, DDR1 depletion inhibits IGF1R- or IR-A-elicited proliferation, migration and colony formation after cognate ligand stimulation.	('IR', 'Gene', '3643', (47, 49))	('inhibits', 'NegReg', (28, 36))	('migration', 'CPA', (76, 85))	('DDR1', 'Gene', '780', (13, 17))	('depletion', 'Var', (18, 27))	('DDR1', 'Gene', (13, 17))	('IGF1R-', 'Gene', (37, 43))	('colony formation', 'CPA', (90, 106))
462646	33673232	DDR1 crosstalk with the IGF axis can also modulate cell differentiation.	('cell differentiation', 'CPA', (51, 71))	('crosstalk', 'Var', (5, 14))	('DDR1', 'Gene', '780', (0, 4))	('DDR1', 'Gene', (0, 4))	('modulate', 'Reg', (42, 50))
462648	33673232	On the contrary, IGF1R depletion impairs collagen-dependent phosphorylation of DDR1, further pointing out the reciprocity of this functional crosstalk.	('DDR1', 'Gene', (79, 83))	('impairs', 'NegReg', (33, 40))	('depletion', 'Var', (23, 32))	('IGF1R', 'Gene', (17, 22))	('DDR1', 'Gene', '780', (79, 83))	('collagen-dependent phosphorylation', 'MPA', (41, 75))
462664	33673232	At functional levels, E-cadherin depletion determines increased cell cycle progression and enhanced sensitivity to IGF1R/IR-targeted therapy.	('depletion', 'Var', (33, 42))	('E-cadherin', 'Gene', (22, 32))	('E-cadherin', 'Gene', '999', (22, 32))	('sensitivity', 'MPA', (100, 111))	('increased', 'PosReg', (54, 63))	('IR', 'Gene', '3643', (121, 123))	('cell cycle progression', 'CPA', (64, 86))	('enhanced', 'PosReg', (91, 99))	('enhanced sensitivity to IGF1R', 'Phenotype', 'HP:0030269', (91, 120))
462665	33673232	Mechanistically, E-cadherin and IGF1R colocalize to adherens junctions, and this interaction is significantly decreased after IGF1 stimulation indicating that the E-cadherin/IGF1R interaction is disrupted for proper IGF1R function.	('IGF1R', 'Gene', (32, 37))	('E-cadherin', 'Gene', '999', (163, 173))	('stimulation', 'Var', (131, 142))	('IGF1', 'Gene', (126, 130))	('decreased', 'NegReg', (110, 119))	('colocalize', 'Interaction', (38, 48))	('E-cadherin', 'Gene', (17, 27))	('E-cadherin', 'Gene', '999', (17, 27))	('E-cadherin', 'Gene', (163, 173))
462676	32950930	One objective response was observed for an angiosarcoma treated with pazopanib for FLT4 amplification; 4 patients had a stable disease, including a long-lasting 33 months stabilization.	('patients', 'Species', '9606', (105, 113))	('amplification', 'Var', (88, 101))	('pazopanib', 'Chemical', 'MESH:C516667', (69, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('angiosarcoma', 'Disease', 'MESH:D006394', (43, 55))	('FLT4', 'Gene', (83, 87))	('angiosarcoma', 'Disease', (43, 55))	('FLT4', 'Gene', '2324', (83, 87))	('angiosarcoma', 'Phenotype', 'HP:0200058', (43, 55))
462688	32950930	Sarcomas can be classified according to their genomic characteristics, driven by a single genomic abnormality (translocation, amplification, mutation or tumor suppressor gene loss) or harboring a complex genomic profile characterized by several gains, amplifications and losses of numerous chromosomes or chromosome regions, and numerous genetic translocations.	('amplifications', 'Var', (252, 266))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('gains', 'PosReg', (245, 250))	('translocation', 'Var', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('amplification', 'Var', (126, 139))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('loss', 'NegReg', (175, 179))	('mutation', 'Var', (141, 149))	('losses', 'NegReg', (271, 277))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
462695	32950930	Tyrosine-kinase inhibitors targeting KIT or PDGFRA gain-of-function mutations in GIST are the best example of such reliable biomarkers.	('GIST', 'Gene', (81, 85))	('KIT', 'Gene', '3815', (37, 40))	('gain-of-function', 'PosReg', (51, 67))	('KIT', 'Gene', (37, 40))	('mutations', 'Var', (68, 77))	('PDGFRA', 'Gene', '5156', (44, 50))	('PDGFRA', 'Gene', (44, 50))
462703	32950930	The present study used data from ProfiLER to describe the frequency and distribution of actionable alterations in locally advanced or metastatic sarcomas, to explore their use for guiding molecular targeted-agents recommendations, and to describe responses to molecular-based recommended therapy.	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('locally advanced', 'Disease', (114, 130))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('alterations', 'Var', (99, 110))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('sarcomas', 'Disease', (145, 153))
462719	32950930	Decisions were based on an algorithm (Supplementary Table S2) defined using COSMIC database (Catalogue Of Somatic Mutation In Cancer) and the FATHMM (Functional Analysis Through Hidden Markov Models) score when variants of unknown functional and/or clinical significance were identified.	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Cancer', 'Disease', (126, 132))	('Cancer', 'Disease', 'MESH:D009369', (126, 132))	('variants', 'Var', (211, 219))
462756	32950930	The sarcoma cohort showed that 67% of patients had an identified molecular alteration, 30% of patients had molecular based recommended therapy and 8% initiated the proposed treatment, these proportions are similar to those reported in 2579 patients with various histological tumor types in the Profiler-01 study.	('sarcoma', 'Disease', (4, 11))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('molecular alteration', 'Var', (65, 85))	('patients', 'Species', '9606', (240, 248))	('patients', 'Species', '9606', (38, 46))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (275, 280))
462758	32950930	Our series suggests that copy-number alterations may be more common than mutations in sarcomas, with the limitation of a sequencing panel covering mostly carcinoma-associated oncogenes and tumor suppressors and covering an overall limited number of DNA base pairs.	('carcinoma', 'Disease', (154, 163))	('tumor', 'Disease', (189, 194))	('sarcomas', 'Disease', 'MESH:D012509', (86, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('copy-number alterations', 'Var', (25, 48))	('carcinoma', 'Disease', 'MESH:D009369', (154, 163))	('common', 'Reg', (61, 67))	('sarcomas', 'Disease', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
462759	32950930	Those findings are however consistent with those of TCGA database, whereas NGS showed that mutations were the most frequent genomic alteration, and TP53 was the most frequent genomic alteration in a large cohort of sarcomas.	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('sarcomas', 'Disease', 'MESH:D012509', (215, 223))	('mutations', 'Var', (91, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('sarcomas', 'Disease', (215, 223))
462761	32950930	It also highlights the complexity of MTB decision-making, facing with multiple molecular alterations in a single tumor, variants of unknown functional and/or clinical significance or unknown predictive impacts of some hotspot variants (depending on tumor types).	('tumor', 'Disease', (113, 118))	('variants', 'Var', (226, 234))	('variants', 'Var', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
462770	32950930	One patient with angiosarcoma harboring FLT4 amplification presented a good quality partial response to pazopanib.	('FLT4', 'Gene', '2324', (40, 44))	('angiosarcoma', 'Phenotype', 'HP:0200058', (17, 29))	('angiosarcoma', 'Disease', 'MESH:D006394', (17, 29))	('patient', 'Species', '9606', (4, 11))	('pazopanib', 'Chemical', 'MESH:C516667', (104, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('angiosarcoma', 'Disease', (17, 29))	('FLT4', 'Gene', (40, 44))	('amplification', 'Var', (45, 58))
462781	32950930	An increasing number of gene fusions are being discovered in sarcomas, and are mainly used for diagnostic purposes.	('sarcomas', 'Disease', (61, 69))	('gene fusions', 'Var', (24, 36))	('discovered', 'Reg', (47, 57))	('sarcomas', 'Disease', 'MESH:D012509', (61, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
462787	29700887	CIC-NUTM1 fusion: A case which expands the spectrum of NUT-rearranged epithelioid malignancies NUT carcinoma (NC) shows very aggressive clinical behavior, occurs predominantly in the thorax and head and neck region of children and adults, and is defined by the presence of NUT (aka NUTM1) rearrangement, mostly BRD4-NUTM1 fusion resulting from t(15;19)(q13; p13.1).	('NUTM1', 'Gene', '256646', (4, 9))	('NUTM1', 'Gene', (4, 9))	('NUTM1', 'Gene', '256646', (282, 287))	('NUT', 'Gene', '256646', (4, 7))	('NUT', 'Gene', (4, 7))	('NUTM1', 'Gene', (282, 287))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (125, 153))	('children', 'Species', '9606', (218, 226))	('NUT', 'Gene', '256646', (282, 285))	('NUT', 'Gene', (282, 285))	('NUT', 'Gene', '256646', (273, 276))	('NUT', 'Gene', (273, 276))	('p13', 'Gene', (358, 361))	('BRD4', 'Gene', (311, 315))	('CIC', 'Gene', '23152', (0, 3))	('NUT', 'Gene', '256646', (95, 98))	('resulting from', 'Reg', (329, 343))	('NUT', 'Gene', (95, 98))	('NUT', 'Gene', (316, 319))	('p13', 'Gene', '440926', (358, 361))	('NUT', 'Gene', (55, 58))	('NUT', 'Gene', '256646', (316, 319))	('NUT', 'Gene', '256646', (55, 58))	('BRD4', 'Gene', '23476', (311, 315))	('NUTM1', 'Gene', '256646', (316, 321))	('epithelioid malignancies', 'Disease', 'MESH:D012509', (70, 94))	('epithelioid malignancies', 'Disease', (70, 94))	('NUTM1', 'Gene', (316, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('fusion', 'Var', (322, 328))	('CIC', 'Gene', (0, 3))
462788	29700887	So-called "NUT variants" harbor alternate fusions between NUTM1 and BRD3, NSD3, ZNF532, or unknown partners.	('fusions', 'Interaction', (42, 49))	('BRD3', 'Gene', (68, 72))	('NUT', 'Gene', '256646', (58, 61))	('NSD3', 'Gene', (74, 78))	('BRD3', 'Gene', '8019', (68, 72))	('NUT', 'Gene', '256646', (11, 14))	('ZNF532', 'Gene', '55205', (80, 86))	('NUT', 'Gene', (58, 61))	('ZNF532', 'Gene', (80, 86))	('NUT', 'Gene', (11, 14))	('NUTM1', 'Gene', (58, 63))	('NSD3', 'Gene', '54904', (74, 78))	('variants', 'Var', (15, 23))	('NUTM1', 'Gene', '256646', (58, 63))
462789	29700887	Rare cases of pediatric tumors with CIC-NUTM1 fusion were recently reported in somatic soft tissue, brain, and kidney.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CIC', 'Gene', '23152', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('NUTM1', 'Gene', (40, 45))	('fusion', 'Var', (46, 52))	('CIC', 'Gene', (36, 39))	('pediatric tumors', 'Disease', 'MESH:D063766', (14, 30))	('pediatric tumors', 'Disease', (14, 30))	('NUTM1', 'Gene', '256646', (40, 45))
462790	29700887	However, such cases have not been identified in adult patients and the presence of a fusion between CIC, characteristic of CIC-rearranged sarcoma, and NUTM1-a defining feature of NC-poses a diagnostic challenge.	('fusion', 'Var', (85, 91))	('CIC', 'Gene', (100, 103))	('CIC-rearranged sarcoma', 'Disease', (123, 145))	('CIC', 'Gene', '23152', (100, 103))	('patients', 'Species', '9606', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('NUTM1', 'Gene', '256646', (151, 156))	('CIC', 'Gene', '23152', (123, 126))	('NUTM1', 'Gene', (151, 156))	('CIC-rearranged sarcoma', 'Disease', 'MESH:D012509', (123, 145))	('CIC', 'Gene', (123, 126))
462794	29700887	Fluorescence in situ hybridization and targeted next-generation sequencing identified a CIC-NUTM1 fusion resulting from t(15;19)(q14;q13.2).	('CIC', 'Gene', '23152', (88, 91))	('t(15;19)(q14;q13.2', 'Var', (120, 138))	('t(15;19)(q14;q13.2)', 'STRUCTURAL_ABNORMALITY', 'None', (120, 139))	('CIC', 'Gene', (88, 91))	('NUTM1', 'Gene', '256646', (92, 97))	('NUTM1', 'Gene', (92, 97))
462799	29700887	NC is defined by NUTM1 rearrangements and roughly 75% of cases harbor BRD4-NUTM1 fusion resulting from t (15;19)(q14;p13.1).	('NUTM1', 'Gene', (75, 80))	('fusion', 'Var', (81, 87))	('NUTM1', 'Gene', '256646', (17, 22))	('p13', 'Gene', (117, 120))	('BRD4', 'Gene', '23476', (70, 74))	('NUTM1', 'Gene', (17, 22))	('resulting from', 'Reg', (88, 102))	('p13', 'Gene', '440926', (117, 120))	('BRD4', 'Gene', (70, 74))	('NUTM1', 'Gene', '256646', (75, 80))
462800	29700887	The remaining cases harbor either BRD3-NUTM1 fusion resulting from t(15;19)(q14;p34.2), NSD3-NUTM1 fusion resulting from t(8;15)(p12;q15), ZNF532-NUT, or NUTM1 fusion with an unknown partner gene.	('NUT', 'Gene', '256646', (154, 157))	('t(8;15)(p12;q15', 'Var', (121, 136))	('NUT', 'Gene', (154, 157))	('NUT', 'Gene', '256646', (146, 149))	('NUTM1', 'Gene', '256646', (154, 159))	('NUT', 'Gene', (146, 149))	('NUTM1', 'Gene', (154, 159))	('NSD3', 'Gene', (88, 92))	('t(15;19)(q14;p34.2)', 'STRUCTURAL_ABNORMALITY', 'None', (67, 86))	('ZNF532', 'Gene', (139, 145))	('BRD3', 'Gene', (34, 38))	('t(8;15)(p12;q15)', 'STRUCTURAL_ABNORMALITY', 'None', (121, 137))	('NUTM1', 'Gene', '256646', (39, 44))	('NSD3', 'Gene', '54904', (88, 92))	('NUTM1', 'Gene', (39, 44))	('NUT', 'Gene', '256646', (39, 42))	('NUT', 'Gene', (39, 42))	('ZNF532', 'Gene', '55205', (139, 145))	('NUTM1', 'Gene', '256646', (93, 98))	('NUTM1', 'Gene', (93, 98))	('BRD3', 'Gene', '8019', (34, 38))	('NUT', 'Gene', (93, 96))	('NUT', 'Gene', '256646', (93, 96))
462802	29700887	The identification of characteristic CIC rearrangements in a subset of round cell tumors lacking EWSR1 rearrangement in recent years led to the recognition of CIC-rearranged sarcomas as a distinct entity, separate from Ewing sarcoma.	('CIC-rearranged sarcoma', 'Disease', 'MESH:D012509', (159, 181))	('sarcomas', 'Disease', (174, 182))	('Ewing sarcoma', 'Disease', (219, 232))	('rearrangements', 'Var', (41, 55))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (219, 232))	('EWSR1', 'Gene', '2130', (97, 102))	('CIC', 'Gene', '23152', (159, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('round cell tumors', 'Disease', (71, 88))	('CIC', 'Gene', (37, 40))	('EWSR1', 'Gene', (97, 102))	('CIC-rearranged sarcoma', 'Disease', (159, 181))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (219, 232))	('CIC', 'Gene', (159, 162))	('round cell tumors', 'Disease', 'MESH:D058405', (71, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('CIC', 'Gene', '23152', (37, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))
462803	29700887	Most cases harbor CIC-DUX4 fusion resulting from either t(4;19) or t(10;19).	('DUX4', 'Gene', '100288687', (22, 26))	('CIC', 'Gene', (18, 21))	('t(4;19', 'Var', (56, 62))	('t(10;19', 'Var', (67, 74))	('CIC', 'Gene', '23152', (18, 21))	('DUX4', 'Gene', (22, 26))
462805	29700887	Recently, cases of pediatric round cell tumors harboring CIC-NUTM1 fusions were identified in somatic soft tissue (N = 3, 2/3 in the head), brain (N = 2), or kidney (N = 1).	('NUTM1', 'Gene', (61, 66))	('fusions', 'Var', (67, 74))	('CIC', 'Gene', '23152', (57, 60))	('round cell tumors', 'Disease', 'MESH:D058405', (29, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('CIC', 'Gene', (57, 60))	('NUTM1', 'Gene', '256646', (61, 66))	('round cell tumors', 'Disease', (29, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
462806	29700887	In addition, rare cases of round cell tumors located in somatic soft tissue, visceral locations, and brain were shown to harbor NUTM1 rearrangement with fusion partners other than CIC, including BRD4 (N = 3), BRD3, BCORL1, and MXD1 (one case each) fusions:several of which had a myoepithelial-like appearance, and it is possible that these cases further expand the spectrum of NC.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('BRD4', 'Gene', '23476', (195, 199))	('CIC', 'Gene', '23152', (180, 183))	('rearrangement', 'Var', (134, 147))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('BCORL1', 'Gene', (215, 221))	('MXD1', 'Gene', (227, 231))	('round cell tumors', 'Disease', (27, 44))	('CIC', 'Gene', (180, 183))	('BRD4', 'Gene', (195, 199))	('BRD3', 'Gene', (209, 213))	('BCORL1', 'Gene', '63035', (215, 221))	('round cell tumors', 'Disease', 'MESH:D058405', (27, 44))	('BRD3', 'Gene', '8019', (209, 213))	('NUTM1', 'Gene', '256646', (128, 133))	('MXD1', 'Gene', '4084', (227, 231))	('NUTM1', 'Gene', (128, 133))
462807	29700887	We report herein a case of malignant epithelioid neoplasm with CIC-NUTM1 fusion arising in somatic soft tissue of the head in an adult patient and highlight the morphologic, cytogenetic, molecular, and immunohistochemical features of what we favor to be an NC with a novel fusion gene.	('CIC', 'Gene', (63, 66))	('patient', 'Species', '9606', (135, 142))	('NUTM1', 'Gene', (67, 72))	('malignant epithelioid neoplasm', 'Disease', 'MESH:D054973', (27, 57))	('neoplasm', 'Phenotype', 'HP:0002664', (49, 57))	('malignant epithelioid neoplasm', 'Disease', (27, 57))	('CIC', 'Gene', '23152', (63, 66))	('fusion', 'Var', (73, 79))	('NUTM1', 'Gene', '256646', (67, 72))
462828	29700887	Additional FISH analysis confirmed the rearrangements of both CIC and NUTM1 (Figure 3B,C).	('NUTM1', 'Gene', '256646', (70, 75))	('rearrangements', 'Var', (39, 53))	('CIC', 'Gene', '23152', (62, 65))	('NUTM1', 'Gene', (70, 75))	('CIC', 'Gene', (62, 65))
462831	29700887	Immunohistochemical staining for NUT has been shown to be highly specific for NC and is positive in the vast majority of cases, resulting from NUTM1 fusions with either BRD4, BRD3, NSD3, ZNF532, or unknown partners.	('NSD3', 'Gene', '54904', (181, 185))	('NUT', 'Gene', '256646', (33, 36))	('fusions', 'Var', (149, 156))	('NUTM1', 'Gene', '256646', (143, 148))	('NUT', 'Gene', (33, 36))	('NUTM1', 'Gene', (143, 148))	('NUT', 'Gene', '256646', (143, 146))	('ZNF532', 'Gene', (187, 193))	('BRD3', 'Gene', (175, 179))	('NUT', 'Gene', (143, 146))	('NSD3', 'Gene', (181, 185))	('resulting from', 'Reg', (128, 142))	('BRD4', 'Gene', '23476', (169, 173))	('ZNF532', 'Gene', '55205', (187, 193))	('BRD3', 'Gene', '8019', (175, 179))	('BRD4', 'Gene', (169, 173))
462843	29700887	In line with our case, a previously reported neoplasm with CIC-NUTM1 fusion arising in the kidney showed only limited expression of WT1 (30% of cells) and negativity for ETV4, distinct from CIC-rearranged sarcoma.	('neoplasm', 'Disease', (45, 53))	('CIC-rearranged sarcoma', 'Disease', 'MESH:D012509', (190, 212))	('CIC', 'Gene', (59, 62))	('neoplasm', 'Phenotype', 'HP:0002664', (45, 53))	('CIC', 'Gene', '23152', (190, 193))	('NUTM1', 'Gene', '256646', (63, 68))	('neoplasm', 'Disease', 'MESH:D009369', (45, 53))	('CIC-rearranged sarcoma', 'Disease', (190, 212))	('NUTM1', 'Gene', (63, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('CIC', 'Gene', (190, 193))	('ETV4', 'Gene', (170, 174))	('CIC', 'Gene', '23152', (59, 62))	('fusion', 'Var', (69, 75))	('WT1', 'Gene', '7490', (132, 135))	('WT1', 'Gene', (132, 135))	('ETV4', 'Gene', '2118', (170, 174))
462848	29700887	On the other hand, there are some CIC-NUTM1-positive and likely other variant NUTM1-fusion tumors that are indisputably distinct from NC and better classified as sarcomas, including those of the central nervous system.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('NUTM1', 'Gene', (78, 83))	('sarcomas', 'Disease', 'MESH:D012509', (162, 170))	('NUTM1', 'Gene', '256646', (38, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('NUTM1-fusion tumors', 'Disease', 'MESH:D007714', (78, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('NUTM1', 'Gene', (38, 43))	('CIC', 'Gene', '23152', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('NUTM1', 'Gene', '256646', (78, 83))	('variant', 'Var', (70, 77))	('sarcomas', 'Disease', (162, 170))	('NUTM1-fusion tumors', 'Disease', (78, 97))	('CIC', 'Gene', (34, 37))
462849	29700887	Moreover, gene expression profiling performed in a large series of round cell sarcomas demonstrated that tumors with CIC-NUTM1 fusion (N = 3) clustered tightly with CIC-DUX4 and CIC-FOXO4-positive sarcomas and separate from NCs harboring BRD3/4-NUTM1 fusion, indicating a likely biologic relationship between these CIC-rearranged neoplasms.	('tumors', 'Disease', (105, 111))	('CIC-FOXO4-positive sarcomas', 'Disease', 'MESH:D012509', (178, 205))	('BRD3', 'Gene', (238, 242))	('neoplasm', 'Phenotype', 'HP:0002664', (330, 338))	('sarcomas', 'Disease', 'MESH:D012509', (197, 205))	('sarcomas', 'Phenotype', 'HP:0100242', (197, 205))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('CIC', 'Gene', (315, 318))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('neoplasms', 'Phenotype', 'HP:0002664', (330, 339))	('sarcomas', 'Disease', (197, 205))	('DUX4', 'Gene', '100288687', (169, 173))	('CIC', 'Gene', (165, 168))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('sarcomas', 'Disease', (78, 86))	('BRD3', 'Gene', '8019', (238, 242))	('CIC', 'Gene', (117, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('NUTM1', 'Gene', '256646', (121, 126))	('NUTM1', 'Gene', (121, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('CIC', 'Gene', (178, 181))	('CIC-FOXO4-positive sarcomas', 'Disease', (178, 205))	('CIC', 'Gene', '23152', (315, 318))	('neoplasms', 'Disease', 'MESH:D009369', (330, 339))	('CIC', 'Gene', '23152', (165, 168))	('NUTM1', 'Gene', '256646', (245, 250))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('CIC', 'Gene', '23152', (117, 120))	('NUTM1', 'Gene', (245, 250))	('fusion', 'Var', (127, 133))	('neoplasms', 'Disease', (330, 339))	('CIC', 'Gene', '23152', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('DUX4', 'Gene', (169, 173))
462864	31645760	However, since it has proven difficult to identify tumor-specific mutations that function as neoantigens for CD4+ T cells using existing MHC-II antigen prediction algorithms, considerable uncertainty remains as to whether strict tumor specificity in the CD4+ T cell compartment is required during spontaneous or ICT-induced anti-tumor responses especially for tumors that do not express MHC-II.	('mutations', 'Var', (66, 75))	('tumors', 'Disease', 'MESH:D009369', (360, 366))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('MHC-II', 'Gene', '111364', (387, 393))	('tumor', 'Disease', (329, 334))	('tumor', 'Disease', (360, 365))	('MHC-II', 'Gene', (137, 143))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumors', 'Phenotype', 'HP:0002664', (360, 366))	('tumor', 'Disease', (229, 234))	('MHC-II', 'Gene', '111364', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('tumors', 'Disease', (360, 366))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MHC-II', 'Gene', (387, 393))	('ICT', 'Chemical', '-', (312, 315))
462866	31645760	Although we have identified point mutations in laminin-alpha subunit 4 (G1254VLAMA4; mLAMA4) and asparagine-linked glycosylation 8 glucosyltransferase (A506TALG8; mALG8) as major MHC-I neoantigens in T3, the identities of T3-specific MHC-II antigens remain unknown.	('MHC-II', 'Gene', '111364', (234, 240))	('T3', 'Chemical', 'MESH:D014284', (222, 224))	('LAMA4', 'Gene', (86, 91))	('MHC-II', 'Gene', (234, 240))	('mLAMA4', 'Gene', (85, 91))	('LAMA4', 'Gene', '16775', (86, 91))	('LAMA4', 'Gene', (78, 83))	('point mutations', 'Var', (28, 43))	('mALG8', 'Gene', (163, 168))	('T3', 'Chemical', 'MESH:D014284', (200, 202))	('mALG8', 'Gene', '381903', (163, 168))	('mLAMA4', 'Gene', '16775', (85, 91))	('LAMA4', 'Gene', '16775', (78, 83))
462867	31645760	Using newly developed predictive algorithms, we identify an N710Y somatic point mutation in integrin-beta1 (mITGB1) as a major MHC-II neoantigen of T3 sarcoma cells.	('MHC-II', 'Gene', '111364', (127, 133))	('mITGB1', 'Gene', (108, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('N710Y', 'Mutation', 'p.N710Y', (60, 65))	('integrin-beta1', 'Gene', (92, 106))	('mITGB1', 'Gene', '16412', (108, 114))	('MHC-II', 'Gene', (127, 133))	('integrin-beta1', 'Gene', '16412', (92, 106))	('T3', 'Chemical', 'MESH:D014284', (148, 150))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('N710Y', 'Var', (60, 65))	('sarcoma', 'Disease', (151, 158))
462874	31645760	One candidate, an N710Y mutant of integrin beta1 (mITGB1), met all our criteria (Fig.	('N710Y', 'Var', (18, 23))	('mITGB1', 'Gene', (50, 56))	('N710Y', 'Mutation', 'p.N710Y', (18, 23))	('mITGB1', 'Gene', '16412', (50, 56))	('integrin beta1', 'Gene', (34, 48))	('integrin beta1', 'Gene', '16412', (34, 48))
462877	31645760	To confirm this result, T3-derived CD4+ TIL were stained with MHC-II tetramers carrying either the 707-721 mITGB1 peptide or irrelevant peptide (CLIP).	('mITGB1', 'Gene', '16412', (107, 113))	('MHC-II', 'Gene', (62, 68))	('T3', 'Chemical', 'MESH:D014284', (24, 26))	('mITGB1', 'Gene', (107, 113))	('707-721', 'Var', (99, 106))	('MHC-II', 'Gene', '111364', (62, 68))
462879	31645760	Cytokine profiling of mITGB1-specific CD4+ TIL from T3 tumors revealed that they produced IFNgamma, TNFalpha, and IL-2 but not IL-4, IL-10, IL-17 or IL-22, indicating a Th1-like phenotype (Extended Data Fig.	('IL-22', 'Gene', '50929', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('TNFalpha', 'Gene', '21926', (100, 108))	('IL-10', 'Gene', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mITGB1', 'Gene', (22, 28))	('IL-17', 'Gene', '16171', (140, 145))	('IL-2', 'Gene', '16183', (114, 118))	('tumors', 'Disease', (55, 61))	('mITGB1', 'Gene', '16412', (22, 28))	('IL-2', 'Gene', (114, 118))	('IL-17', 'Gene', (140, 145))	('IL-22', 'Gene', (149, 154))	('IFNgamma', 'Gene', '15978', (90, 98))	('IL-4', 'Gene', (127, 131))	('TNFalpha', 'Gene', (100, 108))	('CD4+', 'Var', (38, 42))	('T3', 'Chemical', 'MESH:D014284', (52, 54))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('IL-10', 'Gene', '16153', (133, 138))	('IFNgamma', 'Gene', (90, 98))	('IL-2', 'Gene', '16183', (149, 153))	('IL-4', 'Gene', '16189', (127, 131))	('IL-2', 'Gene', (149, 153))
462881	31645760	To assess whether T3-specific CD4+ T cells selectively recognized the mutant, we compared mutant to WT Itgb1 peptides in ELISPOT analyses using freshly isolated T3 CD4+ TIL.	('mutant', 'Var', (90, 96))	('Itgb1', 'Gene', '16412', (103, 108))	('T3', 'Chemical', 'MESH:D014284', (161, 163))	('T3', 'Chemical', 'MESH:D014284', (18, 20))	('Itgb1', 'Gene', (103, 108))
462884	31645760	Mapping experiments revealed that the MHC-II binding core of mITGB1 consists of 9 amino acids (710YNEAIVHVV718) where the mutant Y710 residue functions as an I-Ab anchor (Extended Data Fig.	('I-Ab', 'Chemical', '-', (158, 162))	('Y710', 'Var', (129, 133))	('MHC-II', 'Gene', (38, 44))	('mITGB1', 'Gene', (61, 67))	('mITGB1', 'Gene', '16412', (61, 67))	('MHC-II', 'Gene', '111364', (38, 44))
462886	31645760	Elution of peptides bound to I-Ab on T3.CIITA and analysis by mass spectrometry identified two mITGB1 peptides encompassing the Y710 mutation (a 17mer and a 14mer; Fig.	('mITGB1', 'Gene', (95, 101))	('Y710', 'Var', (128, 132))	('mITGB1', 'Gene', '16412', (95, 101))	('I-Ab', 'Chemical', '-', (29, 33))	('T3', 'Chemical', 'MESH:D014284', (37, 39))
462890	31645760	To assess whether CD4+ T cells are required during ICT-induced rejection, we expressed MHC-I and/or MHC-II neoantigens from T3 sarcoma cells in an oncogene-driven sarcoma cell line generated from a KrasLSL-G12D/+ x p53fl/fl mouse injected intramuscularly with lentiviral cre-recombinase (KP9025).	('sarcoma', 'Disease', 'MESH:D012509', (163, 170))	('MHC-II', 'Gene', '111364', (100, 106))	('ICT', 'Chemical', '-', (51, 54))	('sarcoma', 'Disease', (163, 170))	('G12D', 'Mutation', 'p.G12D', (206, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('p53', 'Gene', (215, 218))	('mouse', 'Species', '10090', (224, 229))	('sarcoma', 'Disease', (127, 134))	('T3', 'Chemical', 'MESH:D014284', (124, 126))	('MHC-II', 'Gene', (100, 106))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('KP9025', 'Var', (288, 294))	('MHC-I', 'Gene', (87, 92))	('p53', 'Gene', '22060', (215, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
462892	31645760	As this challenge-resection-rechallenge approach promotes immune control or rejection of even poorly immunogenic tumor cells used in the initial priming step, these results supported the conclusion that KP9025 sarcoma cells were not immunogenic.	('sarcoma', 'Disease', (210, 217))	('immune control', 'CPA', (58, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('promotes', 'PosReg', (49, 57))	('rejection', 'CPA', (76, 85))	('immunogenic tumor', 'Disease', 'MESH:D009369', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('KP9025', 'Var', (203, 209))	('immunogenic tumor', 'Disease', (101, 118))
462898	31645760	Therefore, we generated KP9025 cells that lacked MHC-II neoantigens but co-expressed two strong MHC-I neoantigens: the MHC-I epitope of ovalbumin (SIINFEKL) and the R913L mutant of spectrin-beta2 (mSB2), which we previously showed contributed to the spontaneous rejection of the MCA-induced d42m1 sarcoma line in WT mice.	('MHC-II', 'Gene', '111364', (49, 55))	('sarcoma', 'Disease', 'MESH:D012509', (297, 304))	('spectrin-beta2', 'Gene', (181, 195))	('R913L', 'Mutation', 'p.R913L', (165, 170))	('sarcoma', 'Disease', (297, 304))	('sarcoma', 'Phenotype', 'HP:0100242', (297, 304))	('MHC-II', 'Gene', (49, 55))	('R913L', 'Var', (165, 170))	('mice', 'Species', '10090', (316, 320))	('MCA', 'Chemical', 'MESH:D008748', (279, 282))	('spectrin-beta2', 'Gene', '20742', (181, 195))
462902	31645760	We then asked whether mITGB1-specific CD4+ TIL displayed a Th1 phenotype similar to that seen with T3 tumors.	('T3', 'Chemical', 'MESH:D014284', (99, 101))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('CD4+ TIL', 'Var', (38, 46))	('mITGB1', 'Gene', (22, 28))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('mITGB1', 'Gene', '16412', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
462922	31645760	Vaccination of naive recipients with irradiated parental KP9025, KP.mLAMA4, or KP.mITGB1 cells was not sufficient to protect mice from subsequent challenge with T3 sarcoma cells.	('mice', 'Species', '10090', (125, 129))	('T3', 'Chemical', 'MESH:D014284', (161, 163))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('mITGB1', 'Gene', (82, 88))	('KP9025', 'Var', (57, 63))	('mLAMA4', 'Gene', (68, 74))	('mITGB1', 'Gene', '16412', (82, 88))	('sarcoma', 'Disease', (164, 171))	('mLAMA4', 'Gene', '16775', (68, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
462949	31645760	Using a novel hidden Markov model-based tool (hmMHC), we predict and then validate that an N710Y point mutation in the integrin ITGB1 forms a major MHC-II restricted neoepitope of the T3 MCA sarcoma.	('T3', 'Chemical', 'MESH:D014284', (184, 186))	('MCA', 'Chemical', 'MESH:D008748', (187, 190))	('sarcoma', 'Disease', 'MESH:D012509', (191, 198))	('MHC-II', 'Gene', '111364', (148, 154))	('sarcoma', 'Disease', (191, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('ITGB1', 'Gene', (128, 133))	('ITGB1', 'Gene', '16412', (128, 133))	('N710Y point', 'Var', (91, 102))	('MHC-II', 'Gene', (148, 154))	('N710Y', 'Mutation', 'p.N710Y', (91, 96))
462950	31645760	It is reasonable that mITGB1 represents a major MHC-II neoantigen of T3 tumor cells because ITGB1 is the second most highly expressed mutation in T3 and the point mutation in mITGB1 generates a novel anchor residue that promotes high affinity binding to I-Ab.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('I-Ab', 'Chemical', '-', (254, 258))	('promotes', 'PosReg', (220, 228))	('ITGB1', 'Gene', (176, 181))	('ITGB1', 'Gene', '16412', (92, 97))	('binding', 'Interaction', (243, 250))	('mITGB1', 'Gene', (22, 28))	('MHC-II', 'Gene', (48, 54))	('mITGB1', 'Gene', '16412', (22, 28))	('ITGB1', 'Gene', (23, 28))	('point mutation', 'Var', (157, 171))	('tumor', 'Disease', (72, 77))	('ITGB1', 'Gene', '16412', (176, 181))	('T3', 'Chemical', 'MESH:D014284', (69, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('MHC-II', 'Gene', '111364', (48, 54))	('ITGB1', 'Gene', (92, 97))	('high', 'MPA', (229, 233))	('mITGB1', 'Gene', (175, 181))	('I-Ab', 'Protein', (254, 258))	('mITGB1', 'Gene', '16412', (175, 181))	('ITGB1', 'Gene', '16412', (23, 28))	('T3', 'Chemical', 'MESH:D014284', (146, 148))
462952	31645760	Localization of mITGB1 on the cell membrane would likely also facilitate efficient access by APCs, although we did not directly address this question in the current study.	('facilitate', 'PosReg', (62, 72))	('mITGB1', 'Gene', (16, 22))	('access', 'MPA', (83, 89))	('APCs', 'Gene', (93, 97))	('mITGB1', 'Gene', '16412', (16, 22))	('APCs', 'Gene', '20219', (93, 97))	('Localization', 'Var', (0, 12))
462980	31645760	The identification of point mutations in T3 and KP sarcomas and the prediction of MHC class I epitopes in KP and F244 sarcomas was performed as previously described.	('sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('point mutations', 'Var', (22, 37))	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcomas', 'Disease', (51, 59))	('T3', 'Chemical', 'MESH:D014284', (41, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcomas', 'Disease', (118, 126))
462990	31645760	The T3-specific mutant amino acid was placed in the center of the peptide and was flanked on both sides with 13 amino acids of wild type peptide sequence.	('T3-specific', 'Gene', (4, 15))	('mutant', 'Var', (16, 22))	('T3', 'Chemical', 'MESH:D014284', (4, 6))
462992	31645760	10,000 TIL-derived T cells or 50,000 TDLN-derived T cells were stimulated with 500,000 splenocytes isolated from naive mice pulsed with 2mug ml-1 29-mer peptide (class II) or 1muM 15-mer peptide (class I).	('29-mer', 'Var', (146, 152))	('mice', 'Species', '10090', (119, 123))	('mul', 'Gene', '68729', (66, 69))	('mul', 'Gene', (66, 69))
463076	31623602	However, this information was used to guide therapy in only one case, a case in which a BRAF V600E mutation was found and the patient was then treated with a BRAF inhibitor with the clinical suspicion of melanoma, albeit, all melanoma markers were negative on repeated testing (discussed below, case 2).	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('V600E', 'Var', (93, 98))	('BRAF', 'Gene', (88, 92))	('melanoma', 'Disease', (204, 212))	('V600E', 'Mutation', 'p.V600E', (93, 98))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('patient', 'Species', '9606', (126, 133))	('BRAF', 'Gene', '673', (88, 92))	('BRAF', 'Gene', '673', (158, 162))	('BRAF', 'Gene', (158, 162))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))
463079	31623602	On univariate analysis, poor PS (median OS for ECOG PS >=2: 4 months vs. PS 0-1: 22 months), number of metastatic sites (median OS for > 1 site: 7 months vs. 1 site: 22 months), elevated lactate dehydrogenase (median OS for elevated LDH 5 months vs. normal 21 months), and high NLR (high NLR 4 months vs. normal 13 months) significantly impacted OS (Fig.	('lactate', 'Chemical', 'MESH:D019344', (187, 194))	('elevated lactate dehydrogenase', 'Phenotype', 'HP:0025435', (178, 208))	('poor', 'Var', (24, 28))	('elevated', 'PosReg', (178, 186))	('impacted', 'Reg', (337, 345))	('lactate dehydrogenase', 'MPA', (187, 208))
463104	31623602	NGS identified a BRAF V600E and TP53 mutation in addition to a KDR germline polymorphism.	('TP53', 'Gene', '7157', (32, 36))	('BRAF', 'Gene', '673', (17, 21))	('BRAF', 'Gene', (17, 21))	('TP53', 'Gene', (32, 36))	('V600E', 'Var', (22, 27))	('V600E', 'Mutation', 'p.V600E', (22, 27))
463160	29849960	VEGFR-2 has TK activity approximately one order of magnitude greater than that of VEGFR-1, and the knockout of the VEGFR-2/flk-1 gene in mice has shown that it is the major positive signal transducer in angiogenesis.	('knockout', 'Var', (99, 107))	('TK activity', 'MPA', (12, 23))	('flk-1', 'Gene', '16542', (123, 128))	('flk-1', 'Gene', (123, 128))	('mice', 'Species', '10090', (137, 141))
463163	29849960	Therefore, the inhibition of VEGFR-2 activity by specific targeted inhibitors of VEGFR-2 is a promising strategy for inhibiting tumor angiogenesis.	('inhibitors', 'Var', (67, 77))	('inhibition', 'NegReg', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('VEGFR-2', 'Gene', (81, 88))	('rat', 'Species', '10116', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inhibiting', 'NegReg', (117, 127))	('activity', 'MPA', (37, 45))	('tumor', 'Disease', (128, 133))
463168	29849960	Especially in advanced gastric cancer, apatinib has been shown to significantly prolong the survival time of patients after standard chemotherapy has failed, and can effectively improve treatment compliance.	('survival time', 'CPA', (92, 105))	('treatment compliance', 'CPA', (186, 206))	('gastric cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('patients', 'Species', '9606', (109, 117))	('improve', 'PosReg', (178, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (23, 37))	('apatinib', 'Var', (39, 47))	('prolong', 'PosReg', (80, 87))	('apatinib', 'Chemical', 'MESH:C553458', (39, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (23, 37))
463336	24753854	Nevertheless a basal expression of WT1 in monocytes and in vitro cultured unloaded DC was observed, the electroporation of in vitro cultured DC with WT1-mRNA resulted in a higher expression of WT1 by the DC.	('electroporation', 'Var', (104, 119))	('expression', 'MPA', (179, 189))	('WT1', 'Gene', '7490', (35, 38))	('higher', 'PosReg', (172, 178))	('WT1', 'Gene', '7490', (149, 152))	('WT1', 'Gene', (149, 152))	('WT1', 'Gene', (35, 38))	('WT1', 'Gene', '7490', (193, 196))	('WT1', 'Gene', (193, 196))
463404	24753854	In conclusion, WT1 is overexpressed in the majority of uterine sarcomas and the presence of WT1 worsens their prognosis, suggesting a role for WT1 in the tumourigenesis of uterine sarcoma.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('WT1', 'Gene', (92, 95))	('sarcoma', 'Disease', (63, 70))	('sarcomas', 'Disease', (63, 71))	('WT1', 'Gene', '7490', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('sarcoma', 'Disease', 'MESH:D012509', (180, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcoma', 'Disease', (180, 187))	('presence', 'Var', (80, 88))	('tumour', 'Disease', (154, 160))	('prognosis', 'MPA', (110, 119))	('WT1', 'Gene', (143, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('worsens', 'NegReg', (96, 103))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (55, 70))	('WT1', 'Gene', (15, 18))	('WT1', 'Gene', '7490', (143, 146))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (172, 187))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('WT1', 'Gene', '7490', (15, 18))	('sarcomas', 'Disease', 'MESH:D012509', (63, 71))
463413	24753854	Pooled data (mean results) revealed WT1 positivity in 7/36 samples (19%) in the tumour cells, while 22/35 samples (63%) were positive if only WT1 positivity in the blood vessels was taken into account.	('tumour', 'Disease', (80, 86))	('WT1', 'Gene', '7490', (142, 145))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('WT1', 'Gene', (142, 145))	('WT1', 'Gene', '7490', (36, 39))	('WT1', 'Gene', (36, 39))	('positivity', 'Var', (40, 50))
463459	24753854	Immunohistochemical staining, which was performed as described before (Coosemans et al., 2007), showed WT1 positivity in 10% of the tumour cells and the intratumoural endothelial cells showed widely distributed WT1 positivity (Coosemans et al., 2008).	('WT1', 'Gene', (211, 214))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('positivity', 'Var', (107, 117))	('WT1', 'Gene', '7490', (103, 106))	('tumour', 'Disease', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('WT1', 'Gene', (103, 106))	('WT1', 'Gene', '7490', (211, 214))	('tumour', 'Disease', 'MESH:D009369', (132, 138))
463506	24753854	Electroporation of DCs with WT1-RNA resulted in an increase of WT1 in the DCs compared to the unloaded state.	('increase', 'PosReg', (51, 59))	('WT1', 'Gene', '7490', (63, 66))	('WT1', 'Gene', '7490', (28, 31))	('WT1', 'Gene', (28, 31))	('Electroporation', 'Var', (0, 15))	('WT1', 'Gene', (63, 66))
463527	24597959	In univariate analysis, the mitotic index (<=5) and tumor size (<=5 cm) were associated with a significantly decreased risk of local relapse.	('decreased', 'NegReg', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('<=5', 'Var', (43, 46))	('tumor', 'Disease', (52, 57))	('mitotic index', 'CPA', (28, 41))	('local relapse', 'CPA', (127, 140))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
463551	24597959	We retrospectively analyzed all prognostic factors, including patient characteristics (sex, age, ECOG performance status), tumor characteristics (tumor site in rectum, tumor size, KIT, CD34, MI/50 HPF, NIH categories, Miettinen categories, necrosis, histological subtype, and mutational status), surgical management (type of procedure, radical vs conservative surgery, margins [R0 vs R1 vs R2 or R0 vs R1-R2 or R0-R1 vs R2], tumor rupture, surgery-related complications), and medical treatment (imatinib treatment group vs non-imatinib treatment group).	('tumor', 'Disease', (425, 430))	('necrosis', 'Disease', (240, 248))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (425, 430))	('CD34', 'Gene', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor rupture', 'Disease', 'MESH:D012421', (425, 438))	('tumor', 'Disease', (123, 128))	('patient', 'Species', '9606', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (425, 430))	('imatinib', 'Chemical', 'MESH:D000068877', (495, 503))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (168, 173))	('CD34', 'Gene', '947', (185, 189))	('imatinib', 'Chemical', 'MESH:D000068877', (527, 535))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('R0 vs R1-R2', 'Var', (396, 407))	('tumor rupture', 'Disease', (425, 438))	('necrosis', 'Disease', 'MESH:D009336', (240, 248))	('R0-R1 vs R2]', 'Var', (411, 423))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
463599	24597959	The presentation and symptoms of these 41 rectal GISTs were not different from those commonly found for other rectal tumors despite the fact that the clinical presentation was sometimes misleading, with rectal GISTs causing genitourinary and gynecological symptoms because of compression or invasion of adjacent pelvic organs.	('causing', 'Reg', (216, 223))	('genitourinary and gynecological symptoms', 'Phenotype', 'HP:0000119', (224, 264))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('GISTs', 'Phenotype', 'HP:0100723', (210, 215))	('GISTs', 'Phenotype', 'HP:0100723', (49, 54))	('rectal tumors', 'Disease', 'MESH:D012004', (110, 123))	('rectal tumors', 'Phenotype', 'HP:0100743', (110, 123))	('rectal tumors', 'Disease', (110, 123))	('rectal GISTs', 'Var', (203, 215))
463601	24597959	The mutational status was only determined in a subset of 12 patients, in whom KIT exon 11 mutations were demonstrated in 10, KIT exon 9 mutation in 1, and no mutation in 1.	('mutations', 'Var', (90, 99))	('mutation', 'Var', (136, 144))	('patients', 'Species', '9606', (60, 68))	('KIT exon 9', 'Gene', (125, 135))	('KIT exon 11', 'Gene', (78, 89))
463617	24597959	Nevertheless, resections with clear margins (R0 resections) were more common with abdominoperineal procedures than with conservative surgery (8/11 and 14/30, respectively), but tumor recurrence occurred similarly in both groups of patients: in 6 of 11 patients (54%) after abdominoperineal surgery and in 11 of 30 patients (46.6%) after conservative surgery.	('patients', 'Species', '9606', (314, 322))	('patients', 'Species', '9606', (231, 239))	('abdominoperineal procedures', 'Var', (82, 109))	('patients', 'Species', '9606', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))
463634	24597959	Based on these data, we suggest that a therapeutic strategy combining surgery with preoperative imatinib therapy should be systematically considered for patients with rectal GISTs, specifically for patients with larger tumors, marginally resectable tumors, or tumors close to the anal sphincters because imatinib may potentially increase the proportion of patients able to undergo conservative surgery rather than the more morbid abdominoperineal resection.	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (356, 364))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('GISTs', 'Phenotype', 'HP:0100723', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumors', 'Disease', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('imatinib', 'Chemical', 'MESH:D000068877', (304, 312))	('increase', 'PosReg', (329, 337))	('imatinib', 'Chemical', 'MESH:D000068877', (96, 104))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('patients', 'Species', '9606', (153, 161))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('imatinib', 'Var', (304, 312))	('tumors', 'Disease', (249, 255))
463641	21505452	Tetraspanin CD151 is a novel prognostic marker in poor outcome endometrial cancer Type II cancers account for 10% of endometrial cancers but 50% of recurrence.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('endometrial cancer', 'Disease', (63, 81))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('endometrial cancer', 'Phenotype', 'HP:0012114', (117, 135))	('endometrial cancers', 'Disease', 'MESH:D016889', (117, 136))	('CD151', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('endometrial cancers', 'Disease', (117, 136))	('Type II cancers', 'Disease', 'MESH:D009369', (82, 97))	('endometrial cancer', 'Disease', 'MESH:D016889', (117, 135))	('endometrial cancer', 'Phenotype', 'HP:0012114', (63, 81))	('endometrial cancer', 'Disease', 'MESH:D016889', (63, 81))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('Tetraspanin', 'Var', (0, 11))	('Type II cancers', 'Disease', (82, 97))	('CD151', 'Gene', '977', (12, 17))
463643	21505452	High CD151 expression confers poor prognosis in breast, pancreatic and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast', 'Disease', (48, 54))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('CD151', 'Gene', (5, 10))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('pancreatic and colorectal cancer', 'Disease', 'MESH:D010190', (56, 88))	('CD151', 'Gene', '977', (5, 10))
463658	21505452	Type I carcinomas show more microsatellite instability, and mutations in the PTEN, K-RAS, PIK3CA and beta-catenin genes.	('microsatellite instability', 'MPA', (28, 54))	('K-RAS', 'Gene', '3845', (83, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (7, 17))	('beta-catenin', 'Gene', (101, 113))	('K-RAS', 'Gene', (83, 88))	('PTEN', 'Gene', (77, 81))	('PIK3CA', 'Gene', (90, 96))	('PTEN', 'Gene', '5728', (77, 81))	('beta-catenin', 'Gene', '1499', (101, 113))	('mutations', 'Var', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('Type I carcinomas', 'Disease', 'MESH:D017827', (0, 17))	('PIK3CA', 'Gene', '5290', (90, 96))	('Type I carcinomas', 'Disease', (0, 17))
463659	21505452	Alterations of p53, STK15, p16, E-cadherin and HER-2 are more frequently found in type II cancers.	('found', 'Reg', (73, 78))	('E-cadherin', 'Gene', (32, 42))	('type II cancers', 'Disease', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('STK15', 'Gene', (20, 25))	('Alterations', 'Var', (0, 11))	('STK15', 'Gene', '6790', (20, 25))	('E-cadherin', 'Gene', '999', (32, 42))	('HER-2', 'Gene', '2064', (47, 52))	('p16', 'Gene', (27, 30))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('HER-2', 'Gene', (47, 52))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('type II cancers', 'Disease', 'MESH:D009369', (82, 97))	('p16', 'Gene', '1029', (27, 30))
463730	21505452	Contrary to our expectation, we found that high CD151 expression is positively correlated with improved survival.	('expression', 'MPA', (54, 64))	('CD151', 'Gene', (48, 53))	('high', 'Var', (43, 47))	('CD151', 'Gene', '977', (48, 53))	('survival', 'CPA', (104, 112))	('improved', 'PosReg', (95, 103))
463748	21505452	Thus, tetraspanin CD151 may be involved in various aspects of the metastatic cascade.	('tetraspanin', 'Var', (6, 17))	('involved', 'Reg', (31, 39))	('CD151', 'Gene', (18, 23))	('CD151', 'Gene', '977', (18, 23))
463757	21505452	This study suggests that, in patients with CD151 positive tumours, survival is significantly better than those with CD151 negative tumours.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('CD151', 'Gene', '977', (43, 48))	('patients', 'Species', '9606', (29, 37))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('CD151', 'Gene', '977', (116, 121))	('tumours', 'Disease', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('survival', 'MPA', (67, 75))	('positive', 'Var', (49, 57))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumours', 'Disease', (58, 65))	('CD151', 'Gene', (43, 48))	('CD151', 'Gene', (116, 121))	('better', 'PosReg', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))
463803	31695517	One of these studies assessed the effectiveness of various radiotherapy doses for extramedullary leukemic manifestation (chloroma), and low-dose radiotherapy (<=26 Gy) was found to have good local control compared to high-dose regimes.	('extramedullary leukemic manifestation', 'Disease', (82, 119))	('extramedullary leukemic manifestation', 'Phenotype', 'HP:0001978', (82, 119))	('chloroma', 'Disease', 'MESH:D023981', (121, 129))	('chloroma', 'Disease', (121, 129))	('<=26 Gy', 'Var', (159, 166))	('low-dose', 'Var', (136, 144))
463830	24675385	We examined cancer incidence in relation to frequency of consumption of organic food for all cancers combined (except non-melanoma skin cancer) and for 16 of the most common cancer sites or types of cancer: oral cavity and pharynx (C00-C14), oesophagus (C15), stomach (C16), colorectum (C18-C20), pancreas (C25), lung (C34), malignant melanoma (C43), breast (C50), endometrium (C54), ovary (C56), kidney (renal cell carcinoma) (C64), bladder (C67), brain (C71, C75.1-C75.3, C72, D32, D33, D35.2-D35.4, D42, D43, and D44.3-D44.5), non-Hodgkin lymphoma (C82-C85), multiple myeloma (C90), and leukaemia (C91-C95).	('carcinoma', 'Phenotype', 'HP:0030731', (416, 425))	('ovary', 'Disease', (384, 389))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (534, 550))	('malignant melanoma', 'Disease', (325, 343))	('lymphoma', 'Phenotype', 'HP:0002665', (542, 550))	('ovary', 'Disease', 'MESH:D010051', (384, 389))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (199, 205))	('non-melanoma skin cancer', 'Disease', (118, 142))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('multiple myeloma', 'Disease', 'MESH:D009101', (562, 578))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('leukaemia', 'Disease', (590, 599))	('D32', 'Var', (479, 482))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (405, 425))	('D43', 'Var', (507, 510))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('D33', 'Var', (484, 487))	('non-Hodgkin lymphoma', 'Disease', (530, 550))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (530, 550))	('cancer', 'Disease', (174, 180))	('malignant melanoma', 'Phenotype', 'HP:0002861', (325, 343))	('skin cancer', 'Phenotype', 'HP:0008069', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('multiple myeloma', 'Disease', (562, 578))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (530, 550))	('pancreas', 'Disease', (297, 305))	('malignant melanoma', 'Disease', 'MESH:D008545', (325, 343))	('C72', 'Var', (474, 477))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('leukaemia', 'Disease', 'MESH:D007938', (590, 599))	('renal cell carcinoma', 'Disease', (405, 425))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (405, 425))	('D35.2-D35.4', 'Var', (489, 500))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('D42', 'Var', (502, 505))	('cancer', 'Disease', (12, 18))	('pancreas', 'Disease', 'MESH:D010190', (297, 305))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (118, 142))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('D44.3-D44.5', 'Var', (516, 527))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('C75.1-C75.3', 'Var', (461, 472))	('multiple myeloma', 'Phenotype', 'HP:0006775', (562, 578))
463864	24675385	Figure 3 shows the relative risk of non-Hodgkin lymphoma in women who reported usually or always consuming organic food compared with never consuming organic food within various sub-groups of women, for example, upper socioeconomic status and lower socioeconomic status, and smokers and non-smokers.	('upper socioeconomic status', 'Var', (212, 238))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (40, 56))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (36, 56))	('women', 'Species', '9606', (60, 65))	('non-Hodgkin lymphoma', 'Disease', (36, 56))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (36, 56))	('women', 'Species', '9606', (192, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (48, 56))
463923	24351866	In addition, the only equipment needed for RT-LAMP is a cost-effective laboratory water bath or a heat block that supplies a constant temperature of 63  C. A one-step RT-LAMP assay was standardized for the rapid detection of EBV latent/lytic transcript (EBNA1, EBNA2, LMP1, LMP2A or BZLF1) and performed using five designed primers (GenBank accession numbers M12553.1, K03333.1, AF023171.1, GU979730.1 and EU340368.1) that recognized a total of six distinct regions in the target sequence (Table 1).	('EBNA2', 'Gene', '17494192', (261, 266))	('water', 'Chemical', 'MESH:D014867', (82, 87))	('LMP2A', 'Gene', '17494231', (274, 279))	('GU979730.1', 'CellLine', 'CVCL:E680', (391, 401))	('LMP2A', 'Gene', (274, 279))	('EU340368.1', 'Var', (406, 416))	('EBV', 'Species', '10376', (225, 228))	('EBNA1', 'Gene', (254, 259))	('BZLF1', 'Gene', (283, 288))	('BZLF1', 'Gene', '3783744', (283, 288))	('EBNA1', 'Gene', '17494214', (254, 259))	('EBNA2', 'Gene', (261, 266))
463943	24351866	The detection limit of RT-LAMP for latent and lytic transcripts by visual fluorescence exhibited a lower sensitivity for the positive samples (103, 102, 103, 104 and 104 PBMC out of 1 x 106 BJAB cells) compared to the Raji cell line dilutions (103, 102, 103, 103 and 103 Raji cells out of 1 x 106 BJAB cells).	('Raji', 'CellLine', 'CVCL:0511', (218, 222))	('103', 'Var', (143, 146))	('BJAB', 'CellLine', 'CVCL:5711', (297, 301))	('lower', 'NegReg', (99, 104))	('Raji', 'CellLine', 'CVCL:0511', (271, 275))	('BJAB', 'CellLine', 'CVCL:5711', (190, 194))	('sensitivity', 'MPA', (105, 116))
463970	24351866	The third is a virus-producing phase, encoding approximately 100 viral proteins, including BZLF1, and initiating virus production.	('BZLF1', 'Gene', (91, 96))	('BZLF1', 'Gene', '3783744', (91, 96))	('encoding', 'Var', (38, 46))
464004	24351866	The primers or probes sequence used in conventional RT-PCR and RT-qPCR reactions for EBNA2, LMP1, LMP2A, BZLF1 and GAPDH were designed (GenBank accession numbers: K03333.1, AF023171.1, GU979791.1, EU340368.1 and BC023632.2), the primers or probes sequence for EBNA1 were designed based on AY825078.1 used in conventional RT-PCR and M13941.1 used in RT-qPCR, which are listed in Table S3.	('BZLF1', 'Gene', (105, 110))	('LMP2A', 'Gene', (98, 103))	('GU979791.1', 'CellLine', 'CVCL:E680', (185, 195))	('BZLF1', 'Gene', '3783744', (105, 110))	('AY825078.1', 'Var', (289, 299))	('EBNA1', 'Gene', (260, 265))	('LMP2A', 'Gene', '17494231', (98, 103))	('GAPDH', 'Gene', '2597', (115, 120))	('GAPDH', 'Gene', (115, 120))	('EBNA2', 'Gene', (85, 90))	('EBNA1', 'Gene', '17494214', (260, 265))	('EBNA2', 'Gene', '17494192', (85, 90))
464021	23774169	ERG is also expressed in a subset of prostate carcinomas and Ewing sarcomas due to ERG-involving translocations, so that this marker is also of high interest for the study of these malignancies.	('prostate carcinomas', 'Disease', (37, 56))	('malignancies', 'Disease', 'MESH:D009369', (181, 193))	('translocations', 'Var', (97, 111))	('Ewing sarcomas', 'Disease', (61, 75))	('prostate carcinomas', 'Disease', 'MESH:D011472', (37, 56))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (61, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('ERG-involving', 'Gene', (83, 96))	('malignancies', 'Disease', (181, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (61, 75))
464035	23774169	ERG-involving translocations also occur in a small subset of Ewing sarcoma, and this largely correlates with ERG-expression in this sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('translocations', 'Var', (14, 28))	('Ewing sarcoma', 'Disease', (61, 74))	('occur', 'Reg', (34, 39))	('sarcoma', 'Disease', (132, 139))	('ERG-involving', 'Gene', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('sarcoma', 'Disease', (67, 74))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
464062	23774169	In-situ hybridization studies with an ERG break-apart probe showed no evidence for ERG gene rearrangement in any of the 16 epithelioid sarcomas examined (Fig.	('ERG gene', 'Gene', (83, 91))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (123, 143))	('epithelioid sarcomas', 'Disease', (123, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('rearrangement', 'Var', (92, 105))
464076	23774169	Lack of ERG gene rearrangements in epithelioid sarcoma does not support the possibility that ERG expression in this setting is a due to an ERG-involving translocation, as is the case in a 40-50% of prostatic carcinomas  and 10% of Ewing sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('prostatic carcinomas', 'Disease', (198, 218))	('epithelioid sarcoma', 'Disease', (35, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (237, 245))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (231, 244))	('Ewing sarcomas', 'Disease', (231, 245))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (231, 245))	('Lack of ERG', 'Phenotype', 'HP:0000550', (0, 11))	('ERG', 'Gene', (8, 11))	('translocation', 'Var', (153, 166))	('prostatic carcinomas', 'Disease', 'MESH:D011472', (198, 218))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (231, 245))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (35, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
464084	23774169	INI1/SMARCB1 gene product is a chromatin remodeling protein known to be lost in virtually all epithelioid sarcomas through inactivating mutations and genomic losses involving its locus at 22q11.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('INI1/SMARCB1', 'Gene', (0, 12))	('losses', 'NegReg', (158, 164))	('lost', 'NegReg', (72, 76))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (94, 114))	('epithelioid sarcomas', 'Disease', (94, 114))	('inactivating mutations', 'Var', (123, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))
464089	23774169	Loss of INI1/SMARCB1 is also well known in malignant rhabdoid tumor (renal and extrarenal), and atypical teratoid rhabdoid tumor in the central nervous system, and genomic losses involving SMARCB1 locus have also been reported in schwannomatosis.	('teratoid rhabdoid tumor', 'Disease', 'MESH:C000597569', (105, 128))	('schwannomatosis', 'Disease', (230, 245))	('SMARCB1', 'Gene', (189, 196))	('schwannomatosis', 'Disease', 'MESH:C536641', (230, 245))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('malignant rhabdoid tumor', 'Disease', (43, 67))	('genomic losses', 'Var', (164, 178))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (43, 67))	('INI1/SMARCB1', 'Gene', (8, 20))	('teratoid rhabdoid tumor', 'Disease', (105, 128))	('reported', 'Reg', (218, 226))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
464108	33036192	In the past few years, mutational analysis and next-generation sequencing (NGS) approaches have shown that somatic mutations in BRAF or neuroblastoma RAS viral oncogene homolog (NRAS) genes promote deregulated survival and migration when combined with genetic alterations and/or epigenetic events that support senescence bypass.	('promote', 'PosReg', (190, 197))	('NRAS', 'Gene', '4893', (178, 182))	('mutations', 'Var', (115, 124))	('deregulated', 'MPA', (198, 209))	('neuroblastoma', 'Disease', 'MESH:D009447', (136, 149))	('neuroblastoma', 'Disease', (136, 149))	('NRAS', 'Gene', (178, 182))	('BRAF', 'Gene', (128, 132))	('neuroblastoma', 'Phenotype', 'HP:0003006', (136, 149))
464119	33036192	The serine/threonine protein kinase BRAF, physiologically involved in the control of cellular growth, is mutated in about 50% of all melanomas.	('melanomas', 'Disease', (133, 142))	('serine', 'Chemical', 'MESH:D012694', (4, 10))	('serine/threonine', 'Enzyme', (4, 20))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('mutated', 'Var', (105, 112))
464120	33036192	Although 20 individual BRAF mutations have been described, approximately 90% of BRAF-mutant melanomas present a mutation leading to the substitution of the valine 600 residue by glutamic acid (V600E).	('melanomas', 'Disease', (92, 101))	('BRAF-mutant', 'Var', (80, 91))	('valine 600 residue by glutamic acid', 'Mutation', 'rs113488022', (156, 191))	('V600E', 'Mutation', 'rs113488022', (193, 198))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('BRAF-mutant', 'Gene', (80, 91))	('substitution', 'Var', (136, 148))	('melanomas', 'Disease', 'MESH:D008545', (92, 101))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('V600E', 'Var', (193, 198))
464121	33036192	BRAF mutation per se is not sufficient to promote melanoma formation, but several studies have highlighted a crucial role of the mutant protein in disease progression.	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('BRAF', 'Gene', (0, 4))	('protein', 'Protein', (136, 143))	('mutation', 'Var', (5, 13))	('mutant', 'Var', (129, 135))
464123	33036192	Several BRAF inhibitors have been developed and approved for the treatment of melanoma and other BRAF-mutant tumors.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('BRAF-mutant', 'Var', (97, 108))	('BRAF', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('BRAF-mutant', 'Gene', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
464125	33036192	They shut down signaling through extracellular signal-regulated kinase (ERK) and, consequently, inhibit cellular growth in BRAF-mutant melanoma cells and induce tumor regression in xenograft models.	('melanoma cells', 'Disease', 'MESH:D008545', (135, 149))	('melanoma cells', 'Disease', (135, 149))	('BRAF-mutant', 'Gene', (123, 134))	('induce', 'PosReg', (154, 160))	('ERK', 'Gene', (72, 75))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('ERK', 'Gene', '5594', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('extracellular signal-regulated kinase', 'Gene', '5594', (33, 70))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cellular growth', 'CPA', (104, 119))	('BRAF-mutant', 'Var', (123, 134))	('signaling', 'MPA', (15, 24))	('inhibit', 'NegReg', (96, 103))	('extracellular signal-regulated kinase', 'Gene', (33, 70))	('tumor', 'Disease', (161, 166))	('shut down', 'NegReg', (5, 14))
464135	33036192	As described above, they are used as either monotherapy or, more often, in combination with dabrafenib, vemurafenib, and encorafenib, respectively, in patients affected by BRAF-mutant advanced melanoma.	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('dabrafenib', 'Chemical', 'MESH:C561627', (92, 102))	('vemurafenib', 'Chemical', 'MESH:D000077484', (104, 115))	('patients', 'Species', '9606', (151, 159))	('encorafenib', 'Chemical', 'MESH:C000601108', (121, 132))	('BRAF-mutant', 'Var', (172, 183))
464136	33036192	MEK inhibitors also determine modest benefits in terms of PFS for melanoma patients whose tumors carry missense mutations in NRAS (occurring in about 20% of melanoma cases).	('NRAS', 'Gene', (125, 129))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('NRAS', 'Gene', '4893', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('patients', 'Species', '9606', (75, 83))	('tumors', 'Disease', (90, 96))	('missense mutations', 'Var', (103, 121))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))
464138	33036192	When KIT is mutated, in exons 11 and 13, the regular growth and differentiation of melanocytes becomes uncontrolled; moreover, these mutations are generally mutually exclusive with the more frequent ones, such as those in BRAF and NRAS.	('NRAS', 'Gene', (231, 235))	('KIT', 'Gene', (5, 8))	('mutated', 'Var', (12, 19))	('NRAS', 'Gene', '4893', (231, 235))
464141	33036192	Current immunotherapy approaches to human malignant melanoma include: monoclonal antibodies against immune checkpoint (ICIs), T-cell therapy, and cancer vaccines.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('malignant melanoma', 'Phenotype', 'HP:0002861', (42, 60))	('malignant melanoma', 'Disease', 'MESH:D008545', (42, 60))	('ICIs', 'Gene', '57509', (119, 123))	('malignant melanoma', 'Disease', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('human', 'Species', '9606', (36, 41))	('ICIs', 'Gene', (119, 123))	('monoclonal', 'Var', (70, 80))
464154	33036192	Nivolumab (BMS-936558, MDX-1106) and pembrolizumab (MK-3475) represent the two most important monoclonal antibodies against PD-1.	('BMS-936558', 'Var', (11, 21))	('MK-3475', 'Chemical', 'MESH:C582435', (52, 59))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('pembrolizumab', 'Chemical', 'MESH:C582435', (37, 50))	('PD-1', 'Gene', (124, 128))
464163	33036192	Several PDL-1 inhibitors are now involved in clinical trials for melanoma.	('PDL-1', 'Gene', (8, 13))	('PDL-1', 'Gene', '29126', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('inhibitors', 'Var', (14, 24))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
464200	33036192	Simultaneous downregulation of both RAF and MET reverted resistance in vitro, and it has been proposed as a possible therapeutic approach for the treatment of BRAF-mutant melanomas.	('BRAF-mutant', 'Var', (159, 170))	('melanomas', 'Disease', (171, 180))	('downregulation', 'NegReg', (13, 27))	('BRAF-mutant', 'Gene', (159, 170))	('melanomas', 'Disease', 'MESH:D008545', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('RAF', 'Protein', (36, 39))	('MET', 'Gene', (44, 47))	('MET', 'Gene', '79811', (44, 47))
464201	33036192	Most importantly, the authors confirmed increased HGF expression in stromal cells of BRAF-mutant melanoma patients undergoing BRAF-targeted treatment in vivo, which resulted in poor prognosis and decreased response to treatments.	('expression', 'MPA', (54, 64))	('BRAF-mutant', 'Gene', (85, 96))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('HGF', 'Gene', '3082', (50, 53))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('increased HGF expression', 'Phenotype', 'HP:0030269', (40, 64))	('decreased', 'NegReg', (196, 205))	('BRAF-mutant', 'Var', (85, 96))	('increased', 'PosReg', (40, 49))	('response to treatments', 'MPA', (206, 228))	('patients', 'Species', '9606', (106, 114))	('HGF', 'Gene', (50, 53))
464205	33036192	Furthermore, vemurafenib treatment increases the production of transforming growth factor beta (TGF-beta) by melanoma cells; TGF-beta, in turn, causes CAFs' activation and increased fibronectin production, involved in BRAF inhibitors' resistance (Figure 3D).	('fibronectin', 'Gene', (182, 193))	('CAFs', 'Gene', (151, 155))	('vemurafenib', 'Chemical', 'MESH:D000077484', (13, 24))	('increased', 'PosReg', (172, 181))	('causes', 'Reg', (144, 150))	('TGF-beta', 'Var', (125, 133))	('melanoma cells', 'Disease', 'MESH:D008545', (109, 123))	('fibronectin', 'Gene', '2335', (182, 193))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma cells', 'Disease', (109, 123))	('activation', 'PosReg', (157, 167))	('production', 'MPA', (49, 59))	('transforming growth factor beta', 'Gene', (63, 94))	('increased fibronectin', 'Phenotype', 'HP:0032463', (172, 193))	('transforming growth factor beta', 'Gene', '7124', (63, 94))
464208	33036192	Uncontrolled production of reactive oxygen species (ROS) by TME fibroblasts is also associated with resistance to BRAF-targeted agents in melanoma (Figure 3E).	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('Uncontrolled', 'Var', (0, 12))	('associated', 'Reg', (84, 94))	('resistance', 'MPA', (100, 110))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (27, 50))
464225	33036192	Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), for example, is an important tumor suppressor gene often mutated/deleted in several cancer types, including melanoma; indeed, PTEN loss is present and concomitant with BRAF mutations in about 44% of melanomas and is associated with reduced OS.	('reduced', 'NegReg', (296, 303))	('PTEN', 'Gene', '5728', (190, 194))	('BRAF', 'Gene', (232, 236))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('melanoma', 'Disease', (263, 271))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('melanomas', 'Disease', 'MESH:D008545', (263, 272))	('mutations', 'Var', (237, 246))	('melanomas', 'Disease', (263, 272))	('PTEN loss', 'Disease', 'MESH:D006223', (190, 199))	('melanoma', 'Disease', 'MESH:D008545', (263, 271))	('PTEN', 'Gene', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))	('cancer', 'Disease', (148, 154))	('melanomas', 'Phenotype', 'HP:0002861', (263, 272))	('PTEN', 'Gene', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', (93, 98))	('PTEN loss', 'Disease', (190, 199))	('PTEN', 'Gene', '5728', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
464234	33036192	Tim3 inhibition partially reverted the dysfunctional condition of T cells and increased their antitumor abilities.	('inhibition', 'Var', (5, 15))	('Tim3', 'Gene', '84868', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Tim3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('increased', 'PosReg', (78, 87))	('tumor', 'Disease', (98, 103))	('dysfunctional condition', 'MPA', (39, 62))
464237	33036192	Inhibition of this receptor together with PD-1 may counteract dysregulated T cells' activity in a manner similar to Tim3 inhibition.	('Inhibition', 'Var', (0, 10))	('Tim3', 'Gene', (116, 120))	('Tim3', 'Gene', '84868', (116, 120))
464246	33036192	High levels of IGF-1 and FGFR-3 have been found in biopsies of melanoma patients treated with BRAF inhibitors in monotherapy or in combination with MEK inhibitors and IGF-1, and its receptor (IGF-1R) are associated with resistance to MAPK inhibitors.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('FGFR-3', 'Gene', (25, 31))	('BRAF', 'Gene', (94, 98))	('IGF-1', 'Gene', '3479', (15, 20))	('High levels of IGF-1', 'Phenotype', 'HP:0030269', (0, 20))	('IGF-1', 'Gene', (15, 20))	('FGFR-3', 'Gene', '2261', (25, 31))	('inhibitors', 'Var', (99, 109))	('IGF-1', 'Gene', '3479', (167, 172))	('IGF-1', 'Gene', (167, 172))	('IGF-1R', 'Gene', (192, 198))	('IGF-1', 'Gene', '3479', (192, 197))	('IGF-1', 'Gene', (192, 197))	('associated', 'Reg', (204, 214))	('IGF-1R', 'Gene', '3480', (192, 198))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('patients', 'Species', '9606', (72, 80))
464261	33036192	In BRAF-mutant melanomas, uncontrolled MAPK activation leads to an increased production of different ILs and VEGF that influence the activity of the immune system toward a protumor condition.	('tumor', 'Disease', (175, 180))	('BRAF-mutant', 'Gene', (3, 14))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('MAPK', 'Gene', (39, 43))	('melanomas', 'Disease', 'MESH:D008545', (15, 24))	('influence', 'Reg', (119, 128))	('increased', 'PosReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('activity', 'MPA', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('melanomas', 'Disease', (15, 24))	('BRAF-mutant', 'Var', (3, 14))
464263	33036192	Moreover, pharmacological blockades or genetic manipulation of key components of MAPK pathway drastically decrease tumor production of immunosuppressive cytokines, allowing for the development of an immune microenvironment favorable to tumor suppression.	('MAPK', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('genetic manipulation', 'Var', (39, 59))	('tumor', 'Disease', (115, 120))	('decrease', 'NegReg', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('pharmacological', 'Var', (10, 25))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('blockades', 'Var', (26, 35))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
464271	33036192	Although with somewhat conflicting results, anti-CTLA-4 therapy would seem to bring more favorable effects on Tregs inhibition.	('Tregs', 'Chemical', '-', (110, 115))	('Tregs inhibition', 'CPA', (110, 126))	('anti-CTLA-4', 'Var', (44, 55))
464273	33036192	In mice models of melanoma, CTLA-4 blockade increases the intratumor effector T cells/Tregs ratio, through fragment crystallizable (Fc)-gamma receptor (FcgammaR)-dependent mechanism.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('tumor', 'Disease', (63, 68))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('blockade', 'Var', (35, 43))	('Tregs', 'Chemical', '-', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))	('increases', 'PosReg', (44, 53))	('CTLA-4', 'Gene', (28, 34))
464292	33036192	In particular, melanoma cells, releasing miRNA-125b-5p in the microenvironment, inhibit the lysosomal acid lipase A (LIPA) and promote M2-macrophages' phenotype and their survival.	('miRNA-125b', 'Chemical', '-', (41, 51))	('survival', 'CPA', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma cells', 'Disease', 'MESH:D008545', (15, 29))	('inhibit', 'NegReg', (80, 87))	('miRNA-125b-5p', 'Var', (41, 54))	('melanoma cells', 'Disease', (15, 29))	('promote', 'PosReg', (127, 134))	("M2-macrophages' phenotype", 'CPA', (135, 160))	('LIPA', 'Gene', (117, 121))	('lysosomal acid lipase A', 'MPA', (92, 115))	('LIPA', 'Gene', '3988', (117, 121))
464300	33036192	TAMs' transformation process, mediated by STAT6 inactivation and NFkB phosphorylation, results in an increase of IL-12 production by TAMs and a reduction in inhibitory cytokine levels, such as IL-10 and C-C motif chemokine 22 (CCL22).	('increase of IL-12 production', 'Phenotype', 'HP:0030783', (101, 129))	('TAMs', 'Chemical', '-', (0, 4))	('CCL22', 'Gene', (227, 232))	('STAT6', 'Gene', '6778', (42, 47))	('inhibitory cytokine levels', 'MPA', (157, 183))	('C-C motif chemokine', 'MPA', (203, 222))	('IL-10', 'Gene', (193, 198))	('IL-12 production', 'MPA', (113, 129))	('increase', 'PosReg', (101, 109))	('inactivation', 'Var', (48, 60))	('CCL22', 'Gene', '6367', (227, 232))	('NFkB', 'Gene', (65, 69))	('reduction', 'NegReg', (144, 153))	('TAMs', 'Chemical', '-', (133, 137))	('STAT6', 'Gene', (42, 47))	('IL-10', 'Gene', '3586', (193, 198))
464301	33036192	TAMs induce immunotherapy resistance also by inhibiting the recruitment of CD8+ T lymphocytes in the tumor site.	('induce', 'PosReg', (5, 11))	('TAMs', 'Chemical', '-', (0, 4))	('CD8', 'Gene', '925', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('TAMs', 'Var', (0, 4))	('inhibiting', 'NegReg', (45, 55))	('recruitment', 'MPA', (60, 71))	('immunotherapy resistance', 'CPA', (12, 36))	('CD8', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
464308	33036192	Moreover, Lopez Gonzalez and collaborators demonstrated that, if inhibition of glycogen synthase kinase 3 beta (GSK3beta) obstructs DC differentiation, a constitutively active GSK3beta overcomes the IL-10 inhibition, leading to DC maturation.	('GSK3beta', 'Gene', (176, 184))	('IL-10', 'Gene', '3586', (199, 204))	('glycogen synthase kinase 3 beta', 'Gene', '2932', (79, 110))	('GSK3beta', 'Gene', '2931', (176, 184))	('GSK3beta', 'Gene', (112, 120))	('IL-10', 'Gene', (199, 204))	('DC maturation', 'CPA', (228, 241))	('obstructs', 'NegReg', (122, 131))	('glycogen synthase kinase 3 beta', 'Gene', (79, 110))	('inhibition', 'Var', (65, 75))	('GSK3beta', 'Gene', '2931', (112, 120))	('leading to', 'Reg', (217, 227))	('DC differentiation', 'CPA', (132, 150))
464319	33036192	BRAF-mutant and PTEN-loss melanomas show, after an initial response to treatments, the development of resistance to BRAF inhibitors mediated by reactivation of MAPK and PI3K pathways.	('PTEN-loss melanomas', 'Disease', 'MESH:D006223', (16, 35))	('BRAF-mutant', 'Gene', (0, 11))	('PTEN-loss melanomas', 'Disease', (16, 35))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('BRAF', 'Gene', (116, 120))	('resistance', 'MPA', (102, 112))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('reactivation', 'PosReg', (144, 156))	('BRAF-mutant', 'Var', (0, 11))
464320	33036192	In this molecular background, drug resistance seems to be mediated also by the protective effect of fibronectin, upregulated by BRAF inhibition.	('fibronectin', 'Gene', (100, 111))	('upregulated', 'PosReg', (113, 124))	('inhibition', 'Var', (133, 143))	('fibronectin', 'Gene', '2335', (100, 111))	('drug resistance', 'Disease', (30, 45))	('drug resistance', 'Phenotype', 'HP:0020174', (30, 45))
464321	33036192	Phosphoproteomic analysis conducted on BRAF-mutant melanoma cell lines showed, after treatment with vemurafenib or after BRAF gene silencing, an increased expression of fibronectin, only in PTEN-loss contexts.	('BRAF', 'Gene', (121, 125))	('PTEN-loss', 'Disease', (190, 199))	('fibronectin', 'Gene', (169, 180))	('gene silencing', 'Var', (126, 140))	('vemurafenib', 'Chemical', 'MESH:D000077484', (100, 111))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (155, 165))	('PTEN-loss', 'Disease', 'MESH:D006223', (190, 199))	('increased expression of fibronectin', 'Phenotype', 'HP:0032463', (145, 180))	('BRAF-mutant', 'Var', (39, 50))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('fibronectin', 'Gene', '2335', (169, 180))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
464325	33036192	Therefore, BRAF inhibition promotes a remodeling of melanoma microenvironment, by which the tumor cells escape to pharmacological blockade.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('BRAF', 'Gene', (11, 15))	('inhibition', 'Var', (16, 26))
464328	33036192	An interesting work of intravital imaging of BRAF-mutant melanoma cells showed that, in co-culture systems, the treatment with BRAF inhibitors determines reactivation of MAPK pathway in areas with high stromal density; this condition is influenced by matrix remodeling associated to integrin beta1/FAK/Src signaling.	('inhibitors', 'Var', (132, 142))	('melanoma cells', 'Disease', 'MESH:D008545', (57, 71))	('integrin beta1', 'Gene', (283, 297))	('FAK', 'Gene', (298, 301))	('FAK', 'Gene', '5747', (298, 301))	('MAPK pathway', 'Pathway', (170, 182))	('integrin beta1', 'Gene', '3688', (283, 297))	('BRAF', 'Gene', (127, 131))	('Src', 'Gene', '6714', (302, 305))	('melanoma cells', 'Disease', (57, 71))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('Src', 'Gene', (302, 305))	('reactivation', 'MPA', (154, 166))	('BRAF-mutant', 'Var', (45, 56))
464468	31277040	Further molecular studies include checking for BRAF mutations.	('mutations', 'Var', (52, 61))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))
464484	31277040	found that the primary tumor size indicated the 5-year survival rate: tumors <5 cm had a survival rate of 82%; 5-10 cm, 68%; and >10 cm, 51%.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('5-10 cm', 'Var', (111, 118))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
464486	31277040	Survival rates for both grades were affected by size: tumors of high grade and smaller than 5 cm in diameter had a survival rate of 79%; 5-10 cm, 63%; and more than 10 cm, 41%.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('5-10 cm', 'Var', (137, 144))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
464705	27428199	Larger than 17 cm of maximum tumor diameter (75.0% vs. 95.7% at 3 years, P = 0.06), >1000 cm3 of tumor volume (76.9% vs. 95.5% at 3 years, P = 0.08), and LR (75.6% vs. 100.0% at 3 years, P = 0.05) showed a tendency for poor OS in univariate analysis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('OS', 'Chemical', '-', (224, 226))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (29, 34))	('>1000 cm3', 'Var', (84, 93))
464733	22389451	A RASSF1A polymorphism restricts p53/p73 activation and associates with poor survival and accelerated age of onset of soft tissue sarcoma RASSF1A (Ras association domain containing family 1A), a tumor suppressor gene that is frequently inactivated in human cancers, is phosphorylated by Ataxia Telangiectasia Mutated (ATM) on Ser131 upon DNA damage, leading to activation of a p73-dependent apoptotic response.	('tumor', 'Disease', (195, 200))	('Ataxia', 'Phenotype', 'HP:0001251', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('p53', 'Gene', '7157', (33, 36))	('p73', 'Gene', '7161', (37, 40))	('RASSF1A', 'Gene', '11186', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('p73', 'Gene', (37, 40))	('p73', 'Gene', '7161', (377, 380))	('RASSF1A', 'Gene', '11186', (2, 9))	('restricts', 'NegReg', (23, 32))	('p73', 'Gene', (377, 380))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('ATM', 'Gene', (318, 321))	('RASSF1A', 'Gene', (138, 145))	('p53', 'Gene', (33, 36))	('sarcoma', 'Disease', (130, 137))	('RASSF1A', 'Gene', (2, 9))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (118, 137))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('polymorphism', 'Var', (10, 22))	('Telangiectasia', 'Phenotype', 'HP:0001009', (294, 308))	('Ataxia Telangiectasia Mutated', 'Gene', (287, 316))	('Ser131', 'Chemical', '-', (326, 332))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('human', 'Species', '9606', (251, 256))	('Ataxia Telangiectasia Mutated', 'Gene', '472', (287, 316))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('ATM', 'Gene', '472', (318, 321))	('cancers', 'Disease', (257, 264))	('activation', 'PosReg', (361, 371))
464741	22389451	Although loss of heterozygosity (LOH) has been observed, RASSF1A is more frequently epigenetically inactivated by hypermethylation of CpG islands within the promoter and the first exon, limiting expression in a wide variety of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('expression', 'MPA', (195, 205))	('RASSF1A', 'Gene', '11186', (57, 64))	('hypermethylation', 'Var', (114, 130))	('limiting', 'NegReg', (186, 194))	('human', 'Species', '9606', (227, 232))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('inactivated', 'NegReg', (99, 110))	('RASSF1A', 'Gene', (57, 64))
464753	22389451	A rare mutation of the ATM phosphorylation site, Ser131Phe, ablates the ability of RASSF1A to respond to DNA damage and inhibit cell growth.	('cell growth', 'CPA', (128, 139))	('ATM', 'Gene', (23, 26))	('ablates', 'NegReg', (60, 67))	('respond to DNA damage', 'MPA', (94, 115))	('RASSF1A', 'Gene', (83, 90))	('Ser131Phe', 'Var', (49, 58))	('inhibit', 'NegReg', (120, 127))	('Ser131Phe', 'SUBSTITUTION', 'None', (49, 58))	('ability', 'MPA', (72, 79))	('ATM', 'Gene', '472', (23, 26))	('RASSF1A', 'Gene', '11186', (83, 90))
464754	22389451	As with the majority of alterations observed in the RASSF1A sequence, Ser131Phe does not appear to be an inherited polymorphism that can be identified at significant frequencies in the population.	('Ser131Phe', 'SUBSTITUTION', 'None', (70, 79))	('RASSF1A', 'Gene', '11186', (52, 59))	('Ser131Phe', 'Var', (70, 79))	('RASSF1A', 'Gene', (52, 59))
464755	22389451	RASSF1 c.397G>T (rs2073498) is a high frequency single nucleotide polymorphism (SNP) with a minor allele frequency (MAF) of up to 17% in European populations (International HAPMAP 1,000 Genomes Project; Figure S1).	('c.397G>T', 'Mutation', 'rs2073498', (7, 15))	('RASSF1', 'Gene', '11186', (0, 6))	('rs2073498', 'Mutation', 'rs2073498', (17, 26))	('c.397G>T', 'Var', (7, 15))	('RASSF1', 'Gene', (0, 6))
464757	22389451	The minor(Ser) allele of RASSF1A p.Ala133Ser has been associated with an increased risk of breast cancer and early onset breast cancer in BRCA1/2 mutation carriers as well as increased lung cancer risk in Japanese and Chinese populations.	('BRCA1/2', 'Gene', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('BRCA1/2', 'Gene', '672;675', (138, 145))	('RASSF1A', 'Gene', '11186', (25, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Ser', 'Chemical', 'MESH:D012694', (41, 44))	('Ser', 'Chemical', 'MESH:D012694', (10, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('RASSF1A', 'Gene', (25, 32))	('p.Ala133Ser', 'Mutation', 'rs2073498', (33, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', (91, 104))	('p.Ala133Ser', 'Var', (33, 44))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('lung cancer', 'Disease', (185, 196))	('breast cancer', 'Disease', (121, 134))
464759	22389451	In humans, we go on to demonstrate that the minor allele of RASSF1 c.397G>T associates with altered soft-tissue sarcoma incidence and survival, a tumor type that is clearly suppressed and regulated by the p53 pathway.	('RASSF1', 'Gene', '11186', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (100, 119))	('p53', 'Gene', (205, 208))	('survival', 'CPA', (134, 142))	('c.397G>T', 'Var', (67, 75))	('tumor', 'Disease', (146, 151))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('p53', 'Gene', '7157', (205, 208))	('humans', 'Species', '9606', (3, 9))	('RASSF1', 'Gene', (60, 66))	('sarcoma', 'Disease', (112, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('c.397G>T', 'Mutation', 'rs2073498', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
464767	22389451	U2OS Tet-On cells (purchased from Clontech, California) that inducibly expressed RASSF1A p.133Ala and RASSF1A p.133Ser upon doxycycline induction were established following puromycin selection as described in the manufacturers protocol.	('RASSF1A', 'Gene', (102, 109))	('p.133Ser', 'Var', (110, 118))	('doxycycline', 'Chemical', 'MESH:D004318', (124, 135))	('RASSF1A', 'Gene', '11186', (81, 88))	('Ala', 'Chemical', 'MESH:D000409', (94, 97))	('U2OS', 'CellLine', 'CVCL:0042', (0, 4))	('California', 'Disease', 'MESH:D004670', (44, 54))	('p.133Ala', 'Var', (89, 97))	('RASSF1A', 'Gene', '11186', (102, 109))	('puromycin', 'Chemical', 'MESH:D011691', (173, 182))	('Ser', 'Chemical', 'MESH:D012694', (115, 118))	('California', 'Disease', (44, 54))	('Tet', 'Chemical', 'MESH:C010349', (5, 8))	('RASSF1A', 'Gene', (81, 88))
464782	22389451	Replacement of alanine at position 133 by serine is predicted to destabilise one alpha-helical turn (Figure S2A, Lower).	('destabilise', 'NegReg', (65, 76))	('alanine at position 133 by serine', 'Mutation', 'rs2073498', (15, 48))	('alanine', 'Var', (15, 22))	('Replacement', 'Var', (0, 11))
464803	22389451	It has previously been shown that MST2 phosphorylates LATS1 on two critical residues, Ser909 and Thr1079, resulting in LATS1 kinase activation.	('Thr1079', 'Var', (97, 104))	('activation', 'PosReg', (132, 142))	('LATS1', 'Gene', (54, 59))	('MST2', 'Gene', (34, 38))	('Thr1079', 'Chemical', '-', (97, 104))	('MST2', 'Gene', '6788', (34, 38))	('Ser909', 'Chemical', '-', (86, 92))	('LATS1', 'Gene', (119, 124))	('LATS1', 'Gene', '9113', (54, 59))	('LATS1', 'Gene', '9113', (119, 124))	('Ser909', 'Var', (86, 92))
464804	22389451	Western blot analysis of the immunoprecipitates with an antibody that specifically recognizes LATS1 on phospho-Ser909 (to monitor kinase activation) demonstrated that LATS1 appeared to be activated by MST2 only in the immunoprecipitated complexes from cells expressing the p.133 Ala isoform (Figure 1G), consistent with the data in Figure 1F.	('LATS1', 'Gene', '9113', (94, 99))	('Ala', 'Chemical', 'MESH:D000409', (279, 282))	('LATS1', 'Gene', (167, 172))	('MST2', 'Gene', (201, 205))	('LATS1', 'Gene', '9113', (167, 172))	('activated', 'PosReg', (188, 197))	('p.133', 'Var', (273, 278))	('Ser909', 'Chemical', '-', (111, 117))	('MST2', 'Gene', '6788', (201, 205))	('LATS1', 'Gene', (94, 99))
464812	22389451	To extend these observations to overall tumourigenicity, colony-forming assays were carried out with H1299 cells expressing RASSF1A-p.133Ala, RASSF1A-p.133Ser or RASSF1A mutated in the ATM phosphorylation site, RASSF1A-p.131Phe.	('ATM', 'Gene', '472', (185, 188))	('RASSF1A', 'Gene', '11186', (211, 218))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('H1299', 'CellLine', 'CVCL:0060', (101, 106))	('tumour', 'Disease', (40, 46))	('RASSF1A', 'Gene', (124, 131))	('RASSF1A', 'Gene', (142, 149))	('RASSF1A', 'Gene', (162, 169))	('RASSF1A-p.133Ser', 'Gene', (142, 158))	('mutated', 'Var', (170, 177))	('ATM', 'Gene', (185, 188))	('RASSF1A', 'Gene', (211, 218))	('RASSF1A', 'Gene', '11186', (124, 131))	('Ala', 'Chemical', 'MESH:D000409', (137, 140))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('RASSF1A-p.133Ser', 'Gene', '11186', (142, 158))	('RASSF1A', 'Gene', '11186', (142, 149))	('RASSF1A', 'Gene', '11186', (162, 169))
464817	22389451	Indeed, depletion of RASSF1A in HeLa cells attenuates the stabilization of p53 and expression of its target genes in response to cisplatin (Figure S5).	('depletion', 'Var', (8, 17))	('RASSF1A', 'Gene', (21, 28))	('HeLa', 'CellLine', 'CVCL:0030', (32, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('RASSF1A', 'Gene', '11186', (21, 28))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('attenuates', 'NegReg', (43, 53))	('stabilization', 'MPA', (58, 71))	('expression', 'MPA', (83, 93))	('response to cisplatin', 'MPA', (117, 138))
464818	22389451	As DNA damage activation of MST2 and LATS1 is dependent on ATM phosphorylation of RASSF1A, we speculated that RASSF1A p.Ala133Ser may also affect the activation of p53.	('LATS1', 'Gene', (37, 42))	('RASSF1A', 'Gene', (82, 89))	('ATM', 'Gene', '472', (59, 62))	('p53', 'Gene', '7157', (164, 167))	('affect', 'Reg', (139, 145))	('MST2', 'Gene', (28, 32))	('RASSF1A', 'Gene', '11186', (82, 89))	('LATS1', 'Gene', '9113', (37, 42))	('p53', 'Gene', (164, 167))	('RASSF1A', 'Gene', (110, 117))	('p.Ala133Ser', 'Mutation', 'rs2073498', (118, 129))	('MST2', 'Gene', '6788', (28, 32))	('ATM', 'Gene', (59, 62))	('RASSF1A', 'Gene', '11186', (110, 117))	('p.Ala133Ser', 'Var', (118, 129))	('activation', 'MPA', (150, 160))
464820	22389451	In cells treated with cycloheximide to inhibit protein synthesis, expression of RASSF1A-p.133Ala prolongs the stability of p53 to a greater extent than RASSF1A-p.133Ser (Figure 3A).	('RASSF1A-p.133Ser', 'Gene', '11186', (152, 168))	('prolongs', 'PosReg', (97, 105))	('RASSF1A', 'Gene', '11186', (80, 87))	('Ala', 'Chemical', 'MESH:D000409', (93, 96))	('stability', 'MPA', (110, 119))	('RASSF1A', 'Gene', (152, 159))	('RASSF1A', 'Gene', (80, 87))	('RASSF1A-p.133Ser', 'Gene', (152, 168))	('p53', 'Gene', (123, 126))	('cycloheximide', 'Chemical', 'MESH:D003513', (22, 35))	('expression', 'Var', (66, 76))	('p53', 'Gene', '7157', (123, 126))	('RASSF1A', 'Gene', '11186', (152, 159))
464822	22389451	Upon treatment with Adriamycin, a DNA damaging agent, expression of RASSF1A-p.133Ala enhances the accumulation of p53 and p21 (Figure 3B).	('p21', 'Gene', (122, 125))	('accumulation', 'MPA', (98, 110))	('Adriamycin', 'Chemical', 'MESH:D004317', (20, 30))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('RASSF1A', 'Gene', '11186', (68, 75))	('expression', 'Var', (54, 64))	('p21', 'Gene', '644914', (122, 125))	('Ala', 'Chemical', 'MESH:D000409', (81, 84))	('enhances', 'PosReg', (85, 93))	('RASSF1A', 'Gene', (68, 75))
464824	22389451	Complementary to these results, we find that adriamycin treatment leads to induction of PUMA protein expression which is enhanced in the presence of RASSF1A p.133Ala but not the p.133Ser isoform (Figure 3C).	('adriamycin', 'Chemical', 'MESH:D004317', (45, 55))	('Ala', 'Chemical', 'MESH:D000409', (162, 165))	('p.133Ala', 'Var', (157, 165))	('RASSF1A', 'Gene', (149, 156))	('PUMA', 'Gene', (88, 92))	('enhanced', 'PosReg', (121, 129))	('Ser', 'Chemical', 'MESH:D012694', (183, 186))	('PUMA', 'Gene', '27113', (88, 92))	('RASSF1A', 'Gene', '11186', (149, 156))
464829	22389451	Our results thus far indicate that the exchange of an alanine residue for serine at codon 133 not only impairs the ability of RASSF1A to transmit a DNA damage signal via ATM but also compromises its intrinsic ability to activate the MST/LATS/p73 and p53 tumour suppressor pathways.	('RASSF1A', 'Gene', (126, 133))	('ATM', 'Gene', (170, 173))	('exchange', 'Var', (39, 47))	('alanine residue for serine at codon 133', 'Mutation', 'rs2073498', (54, 93))	('p73', 'Gene', '7161', (242, 245))	('activate', 'PosReg', (220, 228))	('MST', 'Gene', '4294', (233, 236))	('transmit a DNA damage signal', 'MPA', (137, 165))	('p73', 'Gene', (242, 245))	('intrinsic', 'MPA', (199, 208))	('ability', 'MPA', (115, 122))	('alanine', 'Protein', (54, 61))	('compromises', 'NegReg', (183, 194))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('MST', 'Gene', (233, 236))	('tumour', 'Disease', (254, 260))	('p53', 'Gene', '7157', (250, 253))	('ATM', 'Gene', '472', (170, 173))	('RASSF1A', 'Gene', '11186', (126, 133))	('p53', 'Gene', (250, 253))	('impairs', 'NegReg', (103, 110))
464830	22389451	Inherited mutational inactivation of one copy of the p53 gene in humans results in a dramatic increase in cancer risk (Li-Fraumeni syndrome), in which 90% of individuals with a mutation will develop at least one cancer by the age of 60, with soft tissue sarcomas (STS) being one of the most common.	('sarcomas', 'Phenotype', 'HP:0100242', (254, 262))	('develop', 'PosReg', (191, 198))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (254, 261))	('increase', 'PosReg', (94, 102))	('mutational inactivation', 'Var', (10, 33))	('mutation', 'Var', (177, 185))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('soft tissue sarcomas', 'Disease', (242, 262))	('cancer', 'Disease', (212, 218))	('p53', 'Gene', '7157', (53, 56))	('STS', 'Phenotype', 'HP:0030448', (264, 267))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (242, 262))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (242, 261))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (242, 262))	('p53', 'Gene', (53, 56))	('humans', 'Species', '9606', (65, 71))	('Li-Fraumeni syndrome', 'Disease', (119, 139))
464831	22389451	Higher frequency, less penetrant, inherited SNPs that affect p53 signaling have also been clearly shown to affect STS incidence and survival.	('affect', 'Reg', (107, 113))	('p53', 'Gene', (61, 64))	('STS incidence', 'CPA', (114, 127))	('SNPs', 'Var', (44, 48))	('p53', 'Gene', '7157', (61, 64))	('survival', 'CPA', (132, 140))	('STS', 'Phenotype', 'HP:0030448', (114, 117))
464832	22389451	Our data thus far suggest that individuals carrying the minor T-allele of RASSF1 c.397G>T will have an attenuated p53/p73 signalling.	('c.397G>T', 'Mutation', 'rs2073498', (81, 89))	('attenuated', 'NegReg', (103, 113))	('RASSF1', 'Gene', '11186', (74, 80))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('p73', 'Gene', '7161', (118, 121))	('p73', 'Gene', (118, 121))	('c.397G>T', 'Var', (81, 89))	('RASSF1', 'Gene', (74, 80))
464833	22389451	We therefore wanted to address the impact of RASSF1 c.397G>T on survival of STS patients after DNA damaging therapies.	('STS', 'Phenotype', 'HP:0030448', (76, 79))	('c.397G>T', 'Var', (52, 60))	('patients', 'Species', '9606', (80, 88))	('RASSF1', 'Gene', '11186', (45, 51))	('c.397G>T', 'Mutation', 'rs2073498', (52, 60))	('RASSF1', 'Gene', (45, 51))
464835	22389451	As mentioned earlier, RASSF1 c.397G>T describes a transition in the coding DNA sequence and the patient cohort was genotyped accordingly, with the G and T-alleles designated as the major and minor alleles, respectively, whereby the T-allele encodes the RASSF1A-p.133Ser isoform.	('RASSF1', 'Gene', '11186', (22, 28))	('RASSF1A-p.133Ser', 'Gene', (253, 269))	('c.397G', 'Var', (29, 35))	('RASSF1', 'Gene', '11186', (253, 259))	('RASSF1A-p.133Ser', 'Gene', '11186', (253, 269))	('patient', 'Species', '9606', (96, 103))	('RASSF1', 'Gene', (22, 28))	('RASSF1', 'Gene', (253, 259))	('c.397G>T', 'Mutation', 'rs2073498', (29, 37))
464838	22389451	However, when segregated by gender, male patients homozygous (T/T) or heterozygous (G/T) for the minor T-allele displayed significantly shorter mean survival times compared to the G/G genotype (11.0, 50.5 & 100.9 months respectively, Kaplan Meier, log rank test p=0.016, Table 1 and Figure 4A) indicating an increasing trend towards poorer survival with RASSF1A-p.133Ser.	('RASSF1A-p.133Ser', 'Gene', (354, 370))	('patients', 'Species', '9606', (41, 49))	('with', 'Var', (349, 353))	('shorter', 'NegReg', (136, 143))	('RASSF1A-p.133Ser', 'Gene', '11186', (354, 370))
464840	22389451	A relative risk (RR) for tumor-related death of 4.88 was observed for male patients carrying at least one T-allele (Cox Regression, p=0.034, Table 1 and Figure 4B) suggesting a significant association between RASSF1 c.397G>T and survival outcome.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Cox', 'Gene', '1351', (116, 119))	('Cox', 'Gene', (116, 119))	('c.397G>T', 'Mutation', 'rs2073498', (216, 224))	('RASSF1', 'Gene', '11186', (209, 215))	('tumor', 'Disease', (25, 30))	('patients', 'Species', '9606', (75, 83))	('c.397G>T', 'Var', (216, 224))	('RASSF1', 'Gene', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
464845	22389451	Taken together, these observations support the hypothesis that individuals carrying the minor T-allele of RASSF1 c.397G>T have attenuated RASSF1A signalling and therefore poorer survival after sarcoma diagnosis and subsequent treatment.	('poorer', 'NegReg', (171, 177))	('c.397G>T', 'Mutation', 'rs2073498', (113, 121))	('attenuated', 'NegReg', (127, 137))	('sarcoma', 'Disease', 'MESH:D012509', (193, 200))	('RASSF1', 'Gene', (138, 144))	('survival', 'CPA', (178, 186))	('RASSF1A', 'Gene', (138, 145))	('RASSF1', 'Gene', '11186', (106, 112))	('c.397G>T', 'Var', (113, 121))	('sarcoma', 'Disease', (193, 200))	('RASSF1', 'Gene', '11186', (138, 144))	('RASSF1A', 'Gene', '11186', (138, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('RASSF1', 'Gene', (106, 112))
464846	22389451	These observations are also concurrent with our previous study, wherein we demonstrated that sarcoma patients whose tumours had attenuated RASSF1 signalling through epigenetic inactivation by hypermethylation of the promoter also associated with poorer prognosis.	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (101, 109))	('RASSF1', 'Gene', (139, 145))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('associated', 'Reg', (230, 240))	('sarcoma', 'Disease', (93, 100))	('epigenetic inactivation', 'Var', (165, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('attenuated', 'NegReg', (128, 138))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumours', 'Disease', (116, 123))	('RASSF1', 'Gene', '11186', (139, 145))	('hypermethylation', 'Var', (192, 208))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
464847	22389451	Interestingly, the significant association of the T-allele of RASSF1 c.397G>T with poor survival was only found in the male patients.	('c.397G>T', 'Mutation', 'rs2073498', (69, 77))	('RASSF1', 'Gene', '11186', (62, 68))	('c.397G>T', 'Var', (69, 77))	('patients', 'Species', '9606', (124, 132))	('RASSF1', 'Gene', (62, 68))
464848	22389451	To further explore the apparent sex-specific differences in responses to RASSF1 c.397G>T in overall survival of the patients in this cohort and to expand these analyses to include the well-documented epigenetic modification of RASSF1A in cancer cells, the methylation status of its promoter was included in the analyses.	('RASSF1', 'Gene', (227, 233))	('cancer', 'Disease', (238, 244))	('c.397G>T', 'Var', (80, 88))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('RASSF1', 'Gene', (73, 79))	('patients', 'Species', '9606', (116, 124))	('RASSF1A', 'Gene', (227, 234))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('RASSF1', 'Gene', '11186', (227, 233))	('epigenetic modification', 'Var', (200, 223))	('RASSF1A', 'Gene', '11186', (227, 234))	('c.397G>T', 'Mutation', 'rs2073498', (80, 88))	('RASSF1', 'Gene', '11186', (73, 79))
464850	22389451	Seventeen of the tumours were shown to contain hypermethylation of the promoter.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Disease', (17, 24))	('hypermethylation', 'Var', (47, 63))
464852	22389451	Similarly to the associations with the genotypes of RASSF1 c.397G>T, when segregated by sex, the 6 male patients whose sarcomas contained a hypermethylated promoter displayed significantly shorter mean survival times compared to those 33 males whose sarcomas did not (22.5 & 65.8 months respectively, Kaplan Meier, log rank test p=0.002, Table 1 and Figure 4C).	('sarcomas', 'Disease', (250, 258))	('sarcomas', 'Disease', (119, 127))	('c.397G>T', 'Mutation', 'rs2073498', (59, 67))	('shorter', 'NegReg', (189, 196))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('RASSF1', 'Gene', '11186', (52, 58))	('sarcomas', 'Disease', 'MESH:D012509', (250, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (250, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('c.397G>T', 'Var', (59, 67))	('RASSF1', 'Gene', (52, 58))	('patients', 'Species', '9606', (104, 112))
464853	22389451	A relative risk (RR) for tumor-related death of 9.69 was observed for male patients whose sarcomas contained a hypermethylated promoter (Cox Regression, p=0.002, Table 1 and Figure 4D).	('hypermethylated', 'Var', (111, 126))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Cox', 'Gene', '1351', (137, 140))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('tumor', 'Disease', (25, 30))	('Cox', 'Gene', (137, 140))	('patients', 'Species', '9606', (75, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('sarcomas', 'Disease', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
464854	22389451	By contrast, there was no significant difference in tumor-specific survival in the 11 female patients whose sarcomas contained a hypermethylated promoter compared to the 37 females who did not (82.3 vs 47.1 months, Kaplan Meier, p=0.368; Cox Regression, RR=0.75, p=0.644, Table 1 and Figures 4C and 4D).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('tumor', 'Disease', (52, 57))	('hypermethylated', 'Var', (129, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcomas', 'Disease', (108, 116))	('Cox', 'Gene', '1351', (238, 241))	('Cox', 'Gene', (238, 241))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('patients', 'Species', '9606', (93, 101))
464856	22389451	Specifically, the 4 male patients whose sarcomas contained a hypermethylated promoter displayed shorter mean survival times compared to those 28 males whose sarcomas did not (27.2 & 61.9 months respectively, Kaplan Meier, log rank test p=0.07, Figure 4D).	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('shorter', 'NegReg', (96, 103))	('sarcomas', 'Disease', (157, 165))	('hypermethylated promoter', 'Var', (61, 85))	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('patients', 'Species', '9606', (25, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcomas', 'Disease', 'MESH:D012509', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('sarcomas', 'Disease', (40, 48))
464857	22389451	The results reported above support a model whereby RASSF1 c.397G>T affects the p53/p73 cellular responses, leading to decreased survival rates.	('p53', 'Gene', (79, 82))	('p73', 'Gene', '7161', (83, 86))	('affects', 'Reg', (67, 74))	('p53', 'Gene', '7157', (79, 82))	('RASSF1', 'Gene', (51, 57))	('p73', 'Gene', (83, 86))	('survival rates', 'CPA', (128, 142))	('c.397G>T', 'Mutation', 'rs2073498', (58, 66))	('decreased', 'NegReg', (118, 127))	('RASSF1', 'Gene', '11186', (51, 57))	('c.397G>T', 'Var', (58, 66))
464858	22389451	However, as p53 and p73 signalling is also crucial in tumour suppression, we decided to explore the effect of RASSF1 c.397G>T on the age-dependent incidence of STS in these patients.	('p73', 'Gene', (20, 23))	('RASSF1', 'Gene', (110, 116))	('tumour suppression', 'Disease', (54, 72))	('patients', 'Species', '9606', (173, 181))	('tumour suppression', 'Disease', 'OMIM:146850', (54, 72))	('STS', 'Phenotype', 'HP:0030448', (160, 163))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('c.397G>T', 'Mutation', 'rs2073498', (117, 125))	('RASSF1', 'Gene', '11186', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('c.397G>T', 'Var', (117, 125))	('p73', 'Gene', '7161', (20, 23))
464865	22389451	Interestingly, a previous report had shown that inactivation of the ATM phosphorylation site in RASSF1A (Ser131Phe or Ala133Ser) led to lower steady state phosphorylation at Ser203.	('Ser131Phe', 'SUBSTITUTION', 'None', (105, 114))	('lower', 'NegReg', (136, 141))	('Ala133Ser', 'Var', (118, 127))	('RASSF1A', 'Gene', (96, 103))	('ATM', 'Gene', (68, 71))	('inactivation', 'Var', (48, 60))	('phosphorylation', 'MPA', (155, 170))	('RASSF1A', 'Gene', '11186', (96, 103))	('Ala133Ser', 'SUBSTITUTION', 'None', (118, 127))	('ATM', 'Gene', '472', (68, 71))	('Ser203', 'Chemical', '-', (174, 180))	('Ser131Phe', 'Var', (105, 114))
464866	22389451	It has been reported that RASSF1A function is dependent on phosphorylation of RASSF1A-Ser203 and that elimination of this phosphorylation site abrogates its ability to regulate cytokinesis, microtubule stability and cell cycle progression.	('cell cycle progression', 'CPA', (216, 238))	('elimination', 'Var', (102, 113))	('regulate cytokinesis', 'MPA', (168, 188))	('RASSF1A', 'Gene', '11186', (26, 33))	('ability', 'MPA', (157, 164))	('RASSF1A', 'Gene', '11186', (78, 85))	('Ser203', 'Chemical', '-', (86, 92))	('phosphorylation', 'MPA', (59, 74))	('microtubule stability', 'MPA', (190, 211))	('abrogates', 'NegReg', (143, 152))	('RASSF1A', 'Gene', (26, 33))	('RASSF1A', 'Gene', (78, 85))
464867	22389451	This raises the possibility that phosphorylation at Ser131 may be a prerequisite for complete phosphorylation at Ser203 and concomitantly effective RASSF1A tumor suppression.	('Ser203', 'Var', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('RASSF1A', 'Gene', (148, 155))	('tumor', 'Disease', (156, 161))	('Ser131', 'Chemical', '-', (52, 58))	('Ser203', 'Chemical', '-', (113, 119))	('RASSF1A', 'Gene', '11186', (148, 155))
464875	22389451	Taken together, these observations support the idea that RASSF1 c.397G>T results in the loss or impairment of a major tumor suppressor pathway in cells.	('loss or impairment', 'Disease', 'MESH:D003072', (88, 106))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('c.397G>T', 'Var', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('RASSF1', 'Gene', (57, 63))	('tumor', 'Disease', (118, 123))	('loss or impairment', 'Disease', (88, 106))	('c.397G>T', 'Mutation', 'rs2073498', (64, 72))	('RASSF1', 'Gene', '11186', (57, 63))
464876	22389451	In survival studies of soft tissue sarcoma patients, the minor allele associated with poorer survival with a significant relative risk of tumor-related death (50.5 vs 100.9 months, p=0.016; RR=4.82, p=0.034, Table 1) in males.	('survival', 'MPA', (93, 101))	('sarcoma', 'Disease', (35, 42))	('tumor', 'Disease', (138, 143))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (23, 42))	('patients', 'Species', '9606', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('minor', 'Var', (57, 62))	('poorer', 'NegReg', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
464878	22389451	Though the sample size of patients carrying the minor allele is low, our results suggest that RASSF1 c.397G>T deserves further validation in larger cohorts to determine its usefulness as a prognostic indicator for survival in STS patients.	('c.397G>T', 'Var', (101, 109))	('RASSF1', 'Gene', (94, 100))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (230, 238))	('STS', 'Phenotype', 'HP:0030448', (226, 229))	('c.397G>T', 'Mutation', 'rs2073498', (101, 109))	('RASSF1', 'Gene', '11186', (94, 100))
464880	22389451	However, these findings are in agreement with a previous report suggesting an association between RASSF1 c.397G>T and early onset breast cancer in BRCA1/2 mutation carriers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('BRCA1/2', 'Gene', '672;675', (147, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('RASSF1', 'Gene', '11186', (98, 104))	('c.397G>T', 'Var', (105, 113))	('c.397G>T', 'Mutation', 'rs2073498', (105, 113))	('RASSF1', 'Gene', (98, 104))	('BRCA1/2', 'Gene', (147, 154))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
464882	22389451	An intrinsic failure to respond to endogenous DNA damage stemming from cellular respiration, environmental radiation or defective DNA repair (such as BRCA1/2 inactivation) leads to increased genomic instability and susceptibility to cancer.	('genomic instability', 'MPA', (191, 210))	('defective', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('BRCA1/2', 'Gene', (150, 157))	('intrinsic failure', 'Disease', 'MESH:D020919', (3, 20))	('cancer', 'Disease', (233, 239))	('intrinsic failure', 'Disease', (3, 20))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('increased', 'PosReg', (181, 190))	('BRCA1/2', 'Gene', '672;675', (150, 157))
464883	22389451	In the case of RASSF1 c.397G>T, a defective response to endogenous DNA damage and impaired p53/p73 tumor suppressive activity would precipitate tumorigenesis at an earlier age which would be exacerbated by higher levels of genomic instability in BRCA1/2 mutation carriers.	('c.397G>T', 'Var', (22, 30))	('defective', 'NegReg', (34, 43))	('tumor', 'Disease', (99, 104))	('RASSF1', 'Gene', '11186', (15, 21))	('BRCA1/2', 'Gene', (246, 253))	('RASSF1', 'Gene', (15, 21))	('impaired', 'NegReg', (82, 90))	('precipitate', 'Reg', (132, 143))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (144, 149))	('response to endogenous DNA damage', 'MPA', (44, 77))	('p53', 'Gene', '7157', (91, 94))	('p73', 'Gene', '7161', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('p73', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('BRCA1/2', 'Gene', '672;675', (246, 253))	('c.397G>T', 'Mutation', 'rs2073498', (22, 30))	('p53', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
464884	22389451	Interestingly, we and others had previously shown that inactivation of RASSF1A signaling by methylation associates with poorer survival in a number of tumor types including soft tissue sarcomas.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (173, 193))	('RASSF1A', 'Gene', '11186', (71, 78))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (173, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('methylation', 'Var', (92, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (173, 193))	('tumor', 'Disease', (151, 156))	('inactivation', 'Var', (55, 67))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('soft tissue sarcomas', 'Disease', (173, 193))	('survival', 'MPA', (127, 135))	('RASSF1A', 'Gene', (71, 78))	('poorer', 'NegReg', (120, 126))
464885	22389451	In this report, we go on to provide evidence in a cohort of soft tissue sarcoma patients that this association is sex-specific, whereby hypermethylation of the RASSF1A promoter in tumors only associates with poorer survival in males.	('sarcoma', 'Disease', (72, 79))	('RASSF1A', 'Gene', '11186', (160, 167))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (60, 79))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('poorer', 'NegReg', (208, 214))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('RASSF1A', 'Gene', (160, 167))	('hypermethylation', 'Var', (136, 152))
464887	22389451	We also only observed the association of RASSF1 c.397G>T with the onset of STS also in the male patients (Figure 5).	('STS', 'Phenotype', 'HP:0030448', (75, 78))	('c.397G>T', 'Mutation', 'rs2073498', (48, 56))	('RASSF1', 'Gene', '11186', (41, 47))	('STS', 'Disease', (75, 78))	('association', 'Interaction', (26, 37))	('patients', 'Species', '9606', (96, 104))	('c.397G>T', 'Var', (48, 56))	('RASSF1', 'Gene', (41, 47))
464888	22389451	A male sex bias had also previously been reported for the association of RASSF1 c.397G>T with lung adenocarcinoma risk in a Japanese population.	('c.397G>T', 'Var', (80, 88))	('association', 'Interaction', (58, 69))	('RASSF1', 'Gene', (73, 79))	('lung adenocarcinoma', 'Disease', (94, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('c.397G>T', 'Mutation', 'rs2073498', (80, 88))	('RASSF1', 'Gene', '11186', (73, 79))
464889	22389451	Taken together, it is tempting to speculate that in some tissues and cancers, males could be more sensitive to reduction of RASSF1 signaling either by epigenetic silencing or the inherited predisposition of RASSF1A-p.133Ser.	('reduction', 'NegReg', (111, 120))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('epigenetic silencing', 'Var', (151, 171))	('RASSF1', 'Gene', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('RASSF1', 'Gene', (207, 213))	('RASSF1', 'Gene', '11186', (124, 130))	('signaling', 'MPA', (131, 140))	('RASSF1A-p.133Ser', 'Gene', (207, 223))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('RASSF1A-p.133Ser', 'Gene', '11186', (207, 223))	('RASSF1', 'Gene', '11186', (207, 213))	('cancers', 'Disease', (69, 76))
464894	22389451	The failure to activate RASSF1A p.133Ser in response to DNA damage may combine with AR mediated inhibition of MST to ablate residual pathway activity in male patients, explaining the sex specific clinical manifestation of RASSF1A activity either through epigenetic silencing or the inherited predisposition of RASSF1A-p.133Ser.	('RASSF1A', 'Gene', '11186', (310, 317))	('RASSF1A', 'Gene', (222, 229))	('activity', 'MPA', (141, 149))	('epigenetic silencing', 'Var', (254, 274))	('AR', 'Gene', '367', (84, 86))	('residual pathway', 'Pathway', (124, 140))	('RASSF1A', 'Gene', (24, 31))	('RASSF1A-p.133Ser', 'Gene', (310, 326))	('RASSF1A', 'Gene', '11186', (222, 229))	('Ser', 'Chemical', 'MESH:D012694', (323, 326))	('patients', 'Species', '9606', (158, 166))	('RASSF1A', 'Gene', '11186', (24, 31))	('Ser', 'Chemical', 'MESH:D012694', (37, 40))	('MST', 'Gene', '4294', (110, 113))	('RASSF1A', 'Gene', (310, 317))	('MST', 'Gene', (110, 113))	('ablate', 'NegReg', (117, 123))	('RASSF1A-p.133Ser', 'Gene', '11186', (310, 326))
464895	22389451	It would be of interest to further evaluate the potential of RASSF1 c.397G>T as a biomarker for identifying male sub-groups that may benefit from cancer surveillance at an earlier age or alternative therapeutic interventions.	('RASSF1', 'Gene', '11186', (61, 67))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('c.397G>T', 'Var', (68, 76))	('RASSF1', 'Gene', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('c.397G>T', 'Mutation', 'rs2073498', (68, 76))
464896	22389451	In conclusion, we have shown that RASSF1 c.397G>T has a profound effect on the ability of RASSF1A to respond to a DNA damage signal and to mediate its tumor suppressive effects.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('c.397G>T', 'Mutation', 'rs2073498', (41, 49))	('RASSF1', 'Gene', '11186', (34, 40))	('effect', 'Reg', (65, 71))	('RASSF1A', 'Gene', (90, 97))	('tumor', 'Disease', (151, 156))	('respond to a DNA damage signal', 'MPA', (101, 131))	('c.397G>T', 'Var', (41, 49))	('RASSF1', 'Gene', '11186', (90, 96))	('RASSF1', 'Gene', (34, 40))	('RASSF1A', 'Gene', '11186', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('RASSF1', 'Gene', (90, 96))
464897	22389451	We demonstrate for the first time an association of RASSF1 c.397G>T with poor survival outcome and earlier onset of disease in male STS patients.	('association', 'Interaction', (37, 48))	('STS', 'Phenotype', 'HP:0030448', (132, 135))	('c.397G>T', 'Mutation', 'rs2073498', (59, 67))	('RASSF1', 'Gene', '11186', (52, 58))	('patients', 'Species', '9606', (136, 144))	('c.397G>T', 'Var', (59, 67))	('RASSF1', 'Gene', (52, 58))
464898	22389451	Further validation of these associations in additional STS cohorts as well as additional tumor sites will assist in determining the extent of RASSF1 c.397G>T usefulness as a prognostic indicator for overall survival as well as therapeutic response, and as a biomarker for early screening for male patients more at risk for STS.	('c.397G>T', 'Var', (149, 157))	('RASSF1', 'Gene', (142, 148))	('STS', 'Disease', (323, 326))	('patients', 'Species', '9606', (297, 305))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('STS', 'Phenotype', 'HP:0030448', (55, 58))	('c.397G>T', 'Mutation', 'rs2073498', (149, 157))	('RASSF1', 'Gene', '11186', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('STS', 'Phenotype', 'HP:0030448', (323, 326))
464901	25321332	recently reported a Ewing-like sarcoma within the right posterior neck of a 63 year old man that was found to have a novel CIC-FOXO4 gene fusion caused by translocation t(X;19)(q13;q13.3).	('translocation t(X;19)(q13;q13.3', 'Var', (155, 186))	('man', 'Species', '9606', (88, 91))	('FOXO4', 'Gene', '4303', (127, 132))	('caused by', 'Reg', (145, 154))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (20, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('CIC', 'Gene', '23152', (123, 126))	('FOXO4', 'Gene', (127, 132))	('CIC', 'Gene', (123, 126))	('t(X;19)(q13;q13.3)', 'STRUCTURAL_ABNORMALITY', 'None', (169, 187))	('Ewing-like sarcoma', 'Disease', (20, 38))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (20, 38))
464905	25321332	In our recent genomic analysis of 62 tumors pathologically diagnosed as Ewing sarcoma, we identified seven tumors (11%) which lacked EWSR1 gene fusions and identified one tumor which harbored the same novel CIC-FOXO4 fusion.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 85))	('FOXO4', 'Gene', (211, 216))	('CIC', 'Gene', '23152', (207, 210))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('EWSR1', 'Gene', '2130', (133, 138))	('lacked', 'NegReg', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('Ewing sarcoma', 'Disease', (72, 85))	('FOXO4', 'Gene', '4303', (211, 216))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('CIC', 'Gene', (207, 210))	('EWSR1', 'Gene', (133, 138))	('tumor', 'Disease', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('fusions', 'Var', (144, 151))	('tumor', 'Disease', (171, 176))
464906	25321332	In both cases, a t(X;19)(q13;q13.3) translocation resulted in an in-frame fusion of the N-terminal exons of the CIC gene (breakpoint within exon 19 of the tumor reported by Sugita et al.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('resulted in', 'Reg', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('t(X;19)(q13;q13.3)', 'STRUCTURAL_ABNORMALITY', 'None', (17, 35))	('CIC', 'Gene', '23152', (112, 115))	('tumor', 'Disease', (155, 160))	('CIC', 'Gene', (112, 115))	('translocation', 'Var', (36, 49))
464924	25321332	Further identification and clinical follow-up of Ewing-like sarcomas lacking EWSR1 rearrangement with alternative fusions including CIC-FOXO4, CIC-DUX4, and BCOR-CCNB3 will allow refined prognostic subclassification of this emerging group of tumors.	('rearrangement', 'Var', (83, 96))	('lacking', 'NegReg', (69, 76))	('CCNB3', 'Gene', '85417', (162, 167))	('EWSR1', 'Gene', (77, 82))	('CIC', 'Gene', (132, 135))	('CIC', 'Gene', '23152', (143, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('BCOR', 'Gene', '54880', (157, 161))	('Ewing-like sarcomas', 'Disease', (49, 68))	('DUX4', 'Gene', (147, 151))	('CCNB3', 'Gene', (162, 167))	('FOXO4', 'Gene', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('BCOR', 'Gene', (157, 161))	('tumors', 'Disease', (242, 248))	('EWSR1', 'Gene', '2130', (77, 82))	('CIC', 'Gene', '23152', (132, 135))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (49, 67))	('DUX4', 'Gene', '100288687', (147, 151))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (49, 68))	('CIC', 'Gene', (143, 146))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('FOXO4', 'Gene', '4303', (136, 141))
464958	32164350	In turn, active LATS1/2 phosphorylates YAP and TAZ on the serine S127 and S381, resulting in their inactivation.	('S381', 'Var', (74, 78))	('serine', 'Chemical', 'MESH:D012694', (58, 64))	('LATS1/2', 'Gene', '9113;26524', (16, 23))	('inactivation', 'MPA', (99, 111))	('serine S127', 'MPA', (58, 69))	('LATS1/2', 'Gene', (16, 23))
464959	32164350	When the Hippo pathway is weakly active, YAP translocates to the nucleus and leads to increased target genes expression such as CTGF (connective tissue growth factor) or CYR61 (cysteine-rich angiogenic inducer 61).	('CYR61', 'Gene', (170, 175))	('cysteine-rich angiogenic inducer 61', 'Gene', (177, 212))	('Hippo', 'Gene', '37247', (9, 14))	('expression', 'MPA', (109, 119))	('increased', 'PosReg', (86, 95))	('CTGF', 'Gene', '1490', (128, 132))	('CTGF', 'Gene', (128, 132))	('CYR61', 'Gene', '3491', (170, 175))	('YAP', 'Var', (41, 44))	('connective tissue growth factor', 'Gene', '1490', (134, 165))	('Hippo', 'Gene', (9, 14))	('connective tissue growth factor', 'Gene', (134, 165))	('cysteine-rich angiogenic inducer 61', 'Gene', '3491', (177, 212))
464960	32164350	Given the crucial role of the Hippo pathway in the regulation of organ size and development, it is not surprising that dysfunctions involving this signaling pathway lead to the development of cancers.	('dysfunctions', 'Var', (119, 131))	('Hippo', 'Gene', (30, 35))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('Hippo', 'Gene', '37247', (30, 35))	('lead to', 'Reg', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
464966	32164350	Gastro-intestinal and gynecological cancers are more often associated with mutations in LATS1/2 and NF2 inhibitory kinases.	('NF2', 'Gene', (100, 103))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('LATS1/2', 'Gene', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('associated', 'Reg', (59, 69))	('NF2', 'Gene', '4771', (100, 103))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('LATS1/2', 'Gene', '9113;26524', (88, 95))
464970	32164350	In 2017, Saladi and Coll demonstrated that amplification of ACTL6A (actin-like protein 6A) and p63 increases the expression of YAP.	('Coll', 'Gene', (20, 24))	('YAP', 'Gene', (127, 130))	('expression', 'MPA', (113, 123))	('ACTL6A', 'Gene', '86', (60, 66))	('actin-like protein 6A', 'Gene', '86', (68, 89))	('p63', 'Gene', '8626', (95, 98))	('rat', 'Species', '10116', (32, 35))	('increases', 'PosReg', (99, 108))	('amplification', 'Var', (43, 56))	('ACTL6A', 'Gene', (60, 66))	('Coll', 'Gene', '33727', (20, 24))	('p63', 'Gene', (95, 98))	('actin-like protein 6A', 'Gene', (68, 89))
464974	32164350	YAP nuclear localization is strongly associated with NF2 tumor suppressor mutations in nervous system cancers.	('nuclear localization', 'MPA', (4, 24))	('NF2', 'Gene', '4771', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('nervous system cancers', 'Disease', 'MESH:D009369', (87, 109))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('nervous system cancers', 'Disease', (87, 109))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NF2', 'Gene', (53, 56))	('associated', 'Reg', (37, 47))	('nervous system cancers', 'Phenotype', 'HP:0004375', (87, 109))	('tumor', 'Disease', (57, 62))	('YAP', 'MPA', (0, 3))
464975	32164350	In addition, genetic alterations and methylations on LATS1/2 tumor suppressors have been observed in various cancers.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('methylations', 'Var', (37, 49))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('LATS1/2', 'Gene', '9113;26524', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('observed', 'Reg', (89, 97))	('rat', 'Species', '10116', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('genetic alterations', 'Var', (13, 32))	('tumor', 'Disease', (61, 66))	('LATS1/2', 'Gene', (53, 60))
465004	32164350	However, when cells are stretched, YAP is nuclear and leads to endothelial cell proliferation.	('endothelial cell proliferation', 'CPA', (63, 93))	('YAP', 'Var', (35, 38))	('rat', 'Species', '10116', (87, 90))	('leads to', 'Reg', (54, 62))
465028	32164350	Deregulation of the Hippo pathway has been repeatedly associated with the regulation of these two major mechanisms in the formation of metastases, particularly in breast cancer, glioma, and colon cancer.	('glioma', 'Disease', (178, 184))	('colon cancer', 'Phenotype', 'HP:0003003', (190, 202))	('colon cancer', 'Disease', 'MESH:D015179', (190, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Hippo', 'Gene', (20, 25))	('metastases', 'Disease', (135, 145))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('Deregulation', 'Var', (0, 12))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('metastases', 'Disease', 'MESH:D009362', (135, 145))	('colon cancer', 'Disease', (190, 202))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('Hippo', 'Gene', '37247', (20, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('breast cancer', 'Disease', (163, 176))	('associated', 'Reg', (54, 64))
465032	32164350	The loss of LATS kinase activity induces intravasation of mammary tumor cells via YAP; the same results were found in uveal melanoma with a mutation on YAP activating GNAQ (G protein subunit alpha Q).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('activity', 'MPA', (24, 32))	('tumor', 'Disease', (66, 71))	('G protein subunit alpha Q', 'Gene', (173, 198))	('G protein subunit alpha Q', 'Gene', '2776', (173, 198))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('uveal melanoma', 'Disease', (118, 132))	('LATS', 'Gene', (12, 16))	('mutation', 'Var', (140, 148))	('GNAQ', 'Gene', (167, 171))	('YAP', 'Gene', (152, 155))	('LATS', 'Gene', '43651', (12, 16))	('uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('GNAQ', 'Gene', '2776', (167, 171))	('activating', 'PosReg', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('loss', 'NegReg', (4, 8))
465037	32164350	In this context, Sharif and Coll have demonstrated in mice and zebrafish that inhibition of YAP signaling decreases extravasation and colonization of secondary sites by mammary tumor cells.	('extravasation', 'MPA', (116, 129))	('Coll', 'Gene', (28, 32))	('mice', 'Species', '10090', (54, 58))	('zebrafish', 'Species', '7955', (63, 72))	('colonization of secondary sites', 'CPA', (134, 165))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('inhibition', 'Var', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Coll', 'Gene', '33727', (28, 32))	('tumor', 'Disease', (177, 182))	('decreases', 'NegReg', (106, 115))	('rat', 'Species', '10116', (45, 48))	('YAP', 'Protein', (92, 95))
465038	32164350	All these studies suggest the role of YAP/TAZ in several steps during the metastatic process by inducing EMT, intravasation, and tumor cell survival.	('intravasation', 'MPA', (110, 123))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('EMT', 'CPA', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('inducing', 'PosReg', (96, 104))	('YAP/TAZ', 'Var', (38, 45))
465049	32164350	The translocation t(11;22)(q24;q12) between the FLI1 and EWS genes is the most common and occurs in 85% of cases, giving rise to the transcription factor EWS-FLI1.	('FLI1', 'Gene', '2313', (158, 162))	('FLI1', 'Gene', (48, 52))	('FLI1', 'Gene', '2313', (48, 52))	('giving rise to', 'Reg', (114, 128))	('EWS', 'Gene', '2130', (154, 157))	('EWS', 'Gene', (154, 157))	('EWS', 'Gene', (57, 60))	('EWS', 'Gene', '2130', (57, 60))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (18, 35))	('translocation t(11;22)(q24;q12', 'Var', (4, 34))	('FLI1', 'Gene', (158, 162))
465070	32164350	The dysregulation of the Hippo signaling pathway seems to be associated with Sox-2 signaling in OS.	('Hippo', 'Gene', '37247', (25, 30))	('Sox-2', 'Gene', '6657', (77, 82))	('dysregulation', 'Var', (4, 17))	('Hippo', 'Gene', (25, 30))	('OS', 'Phenotype', 'HP:0002669', (96, 98))	('associated', 'Reg', (61, 71))	('Sox-2', 'Gene', (77, 82))
465097	32164350	It is also able to increase cell death by increasing the expression of cleaved PARP-1 (poly [ADP-ribose] polymerase 1) or cleaved caspase-3, which are essential factors in the apoptotic death process.	('PARP-1', 'Gene', (79, 85))	('expression', 'MPA', (57, 67))	('PARP-1', 'Gene', '142', (79, 85))	('cell death', 'CPA', (28, 38))	('poly [ADP-ribose] polymerase 1', 'Gene', '142', (87, 117))	('caspase-3', 'Gene', (130, 139))	('cleaved', 'Var', (71, 78))	('increase', 'PosReg', (19, 27))	('increasing', 'PosReg', (42, 52))	('cleaved', 'Var', (122, 129))	('poly [ADP-ribose] polymerase 1', 'Gene', (87, 117))	('caspase-3', 'Gene', '836', (130, 139))
465110	32164350	JQ1 is a competitive inhibitor of BRD4 and decreases the amount of YAP-dependent transcribed genes.	('BRD4', 'Gene', '23476', (34, 38))	('BRD4', 'Gene', (34, 38))	('JQ1', 'Var', (0, 3))	('decreases', 'NegReg', (43, 52))	('amount of YAP-dependent transcribed genes', 'MPA', (57, 98))
465111	32164350	In this context, Lamoureux and Coll, demonstrated that JQ1 significantly delays tumor growth in MNNG/HOS osteosarcoma xenograft and POS-1 sarcoma syngeneic models and prolongs cancer-specific survival.	('sarcoma syngeneic', 'Disease', 'MESH:D012509', (138, 155))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('HOS osteosarcoma', 'Disease', (101, 117))	('OS', 'Phenotype', 'HP:0002669', (102, 104))	('sarcoma syngeneic', 'Disease', (138, 155))	('OS', 'Phenotype', 'HP:0002669', (133, 135))	('JQ1', 'Var', (55, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('prolongs', 'PosReg', (167, 175))	('delays', 'NegReg', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('HOS osteosarcoma', 'Disease', 'MESH:C535326', (101, 117))	('tumor', 'Disease', (80, 85))	('rat', 'Species', '10116', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Coll', 'Gene', (31, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('Coll', 'Gene', '33727', (31, 35))	('cancer', 'Disease', (176, 182))
465126	30200635	Changes in microRNA (miRNA) expression may lead to cancer development and/or contribute to its progression; however, their role in uterine sarcomas is poorly understood.	('progression', 'CPA', (95, 106))	('contribute', 'Reg', (77, 87))	('sarcomas', 'Disease', 'MESH:D012509', (139, 147))	('lead to', 'Reg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Changes', 'Var', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('cancer', 'Disease', (51, 57))	('sarcomas', 'Disease', (139, 147))
465130	30200635	In leiomyosarcoma (LMS), there was an association of lower cancer-specific survival (CSS) with the downregulation of miR-125a-5p and miR-10a-5p, and the upregulation of miR-196a-5p and miR-34c-5p.	('miR-1', 'Gene', '83856', (117, 122))	('upregulation', 'PosReg', (153, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('miR-1', 'Gene', (133, 138))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (3, 17))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (3, 17))	('miR-1', 'Gene', (117, 122))	('miR-10a', 'Gene', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('downregulation', 'NegReg', (99, 113))	('CSS', 'Chemical', '-', (85, 88))	('miR-1', 'Gene', '83856', (169, 174))	('leiomyosarcoma', 'Disease', (3, 17))	('miR-34c-5p', 'Var', (185, 195))	('miR-1', 'Gene', (169, 174))	('miR-1', 'Gene', '83856', (133, 138))	('miR-10a', 'Gene', '406902', (133, 140))	('cancer', 'Disease', (59, 65))	('lower', 'NegReg', (53, 58))
465132	30200635	In endometrial stromal sarcomas (ESS), the upregulation of miR-373-3p, miR-372-3p, and let-7b-5p, and the down-expression of let-7f-5p, miR-23-3p, and let-7b-5p were associated with lower CSS.	('down-expression', 'NegReg', (106, 121))	('CSS', 'Chemical', '-', (188, 191))	('miR-23-3p', 'Var', (136, 145))	('CSS', 'Disease', (188, 191))	('lower', 'NegReg', (182, 187))	('let-7b', 'Gene', '406884', (151, 157))	('let-7b', 'Gene', (151, 157))	('miR-372-3p', 'Var', (71, 81))	('upregulation', 'PosReg', (43, 55))	('let-7b', 'Gene', '406884', (87, 93))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (3, 31))	('endometrial stromal sarcomas', 'Disease', (3, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('let-7f-5p', 'Var', (125, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('miR-373-3p', 'Var', (59, 69))	('let-7b', 'Gene', (87, 93))
465133	30200635	Only miR-138-5p upregulation was associated with higher survival rates.	('upregulation', 'PosReg', (16, 28))	('miR-138-5p', 'Chemical', '-', (5, 15))	('miR-138-5p', 'Var', (5, 15))	('higher', 'PosReg', (49, 55))	('survival rates', 'CPA', (56, 70))
465134	30200635	miR-335-5p, miR-301a-3p, and miR-210-3p were more highly expressed in patients with tumor metastasis and relapse.	('tumor metastasis', 'Disease', 'MESH:D009362', (84, 100))	('tumor metastasis', 'Disease', (84, 100))	('miR-21', 'Gene', '406991', (29, 35))	('patients', 'Species', '9606', (70, 78))	('relapse', 'CPA', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('miR-335', 'Gene', '442904', (0, 7))	('miR-21', 'Gene', (29, 35))	('miR-335', 'Gene', (0, 7))	('miR-301a-3p', 'Var', (12, 23))
465135	30200635	miR-138-5p, miR-146b-5p, and miR-218-5p expression were associated with higher disease-free survival (DFS) in treated patients.	('miR-218-5p', 'Chemical', '-', (29, 39))	('miR-218-5p', 'Var', (29, 39))	('disease-free survival', 'CPA', (79, 100))	('miR-146b', 'Gene', (12, 20))	('miR-146b', 'Gene', '574447', (12, 20))	('higher', 'PosReg', (72, 78))	('miR-138-5p', 'Chemical', '-', (0, 10))	('patients', 'Species', '9606', (118, 126))	('miR-138-5p', 'Var', (0, 10))
465157	30200635	Shifts in the molecules' expression of miR-301a-3p, miR-29a-3p, miR-29b-3p, and miR-193b-3p and in the tumor suppressor family let-7, miR-7-5p, miR-96-5p, miR-23b-3p, and miR-335-5p were associated to recurrence, metastasis, stages, and high histological degree (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('miR-1', 'Gene', (80, 85))	('metastasis', 'CPA', (213, 223))	('miR-7-5p', 'Gene', '407045', (134, 142))	('miR-335', 'Gene', (171, 178))	('miR-23b', 'Gene', '407011', (155, 162))	('stages', 'CPA', (225, 231))	('miR-96-5p', 'Var', (144, 153))	('miR-29b-3p', 'Var', (64, 74))	('recurrence', 'CPA', (201, 211))	('miR-301a-3p', 'Var', (39, 50))	('tumor', 'Disease', (103, 108))	('miR-23b', 'Gene', (155, 162))	('miR-7-5p', 'Gene', (134, 142))	('associated', 'Reg', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('miR-29a-3p', 'Var', (52, 62))	('miR-335', 'Gene', '442904', (171, 178))	('miR-1', 'Gene', '83856', (80, 85))
465159	30200635	Significant associations of the downregulation of miR-125a-5p and miR-10a-5 with a lower CSS were observed in LMS, whereas miR-196a-5p and miR-34c-5p upregulation were associated to low CSS (Figure 2).	('miR-1', 'Gene', (66, 71))	('downregulation', 'NegReg', (32, 46))	('miR-1', 'Gene', '83856', (123, 128))	('LMS', 'Disease', (110, 113))	('miR-1', 'Gene', '83856', (66, 71))	('CSS', 'Chemical', '-', (186, 189))	('CSS', 'MPA', (89, 92))	('lower', 'NegReg', (83, 88))	('miR-10a', 'Gene', (66, 73))	('CSS', 'Chemical', '-', (89, 92))	('miR-1', 'Gene', (50, 55))	('upregulation', 'PosReg', (150, 162))	('miR-10a', 'Gene', '406902', (66, 73))	('miR-1', 'Gene', '83856', (50, 55))	('miR-1', 'Gene', (123, 128))	('miR-34c-5p', 'Var', (139, 149))
465162	30200635	The overall survival of ESS patients showed association with six miRNAs' (let-7b-5p, miR-138-5p, miR-373-3p, miR-372-3p, let-7f-5p, and miR-23b-5p) differential gene expression.	('let-7b', 'Gene', '406884', (74, 80))	('let-7b', 'Gene', (74, 80))	('miR-23b', 'Gene', (136, 143))	('miR-373-3p', 'Var', (97, 107))	('miR-138-5p', 'Chemical', '-', (85, 95))	('association', 'Interaction', (44, 55))	('miR-138-5p', 'Var', (85, 95))	('miR-372-3p', 'Var', (109, 119))	('miR-23b', 'Gene', '407011', (136, 143))	('patients', 'Species', '9606', (28, 36))	('let-7f-5p', 'Var', (121, 130))
465164	30200635	In these samples, miR-373-3p and miR-372-3p up-regulation showed correlation with a lower CSS, as well as let-7f-5p and miR-23b-3p downregulation.	('miR-373-3p', 'Var', (18, 28))	('CSS', 'Chemical', '-', (90, 93))	('CSS', 'CPA', (90, 93))	('miR-372-3p', 'Gene', (33, 43))	('let-7f-5p', 'Var', (106, 115))	('miR-23b', 'Gene', (120, 127))	('up-regulation', 'PosReg', (44, 57))	('lower', 'NegReg', (84, 89))	('downregulation', 'NegReg', (131, 145))	('miR-23b', 'Gene', '407011', (120, 127))
465165	30200635	Only miR-138-5p upregulation was associated with higher survival.	('miR-138-5p', 'Var', (5, 15))	('upregulation', 'PosReg', (16, 28))	('higher', 'PosReg', (49, 55))	('miR-138-5p', 'Chemical', '-', (5, 15))
465167	30200635	Three miRNAs (miR-335-5p, miR-301a-3p and miR-210-3p) presented differences of expression when we compared two groups of patients: those who had adjuvant treatment and developed metastasis or tumor recurrence (n = 41) with patients who also had adjuvant treatment but did not develop metastasis or relapse (n = 13) (Figure 5).	('miR-335', 'Gene', (14, 21))	('tumor', 'Disease', (192, 197))	('miR-301a-3p', 'Var', (26, 37))	('differences', 'Reg', (64, 75))	('miR-21', 'Gene', (42, 48))	('expression', 'MPA', (79, 89))	('miR-335', 'Gene', '442904', (14, 21))	('miR-21', 'Gene', '406991', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('metastasis', 'CPA', (178, 188))	('patients', 'Species', '9606', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('patients', 'Species', '9606', (121, 129))
465173	30200635	In the association analysis of the miRNA expression and metastasis and/or relapse in LMS and CS patients, there was a significant differential expression of miR-335-5p (p = 0.015) and miR-301a-3p (p = 0.025) only in LMS.	('metastasis', 'CPA', (56, 66))	('miR-301a-3p', 'Var', (184, 195))	('miR-335', 'Gene', '442904', (157, 164))	('relapse', 'CPA', (74, 81))	('patients', 'Species', '9606', (96, 104))	('miR-335', 'Gene', (157, 164))
465175	30200635	We performed a correlation analysis with all tumor groups that showed a positive association between three miRNAs (miR-138-5p, miR-146-5p and miR-218-5p) with DFS (Table 4); of these, the miR-138-5p displayed a strong correlation with DFS (p < 0.001) (Figure 7).	('miR-1', 'Gene', (127, 132))	('miR-138-5p', 'Chemical', '-', (115, 125))	('miR-1', 'Gene', '83856', (188, 193))	('DFS', 'Disease', (235, 238))	('miR-1', 'Gene', '83856', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('miR-1', 'Gene', (115, 120))	('miR-218-5p', 'Var', (142, 152))	('miR-1', 'Gene', '83856', (115, 120))	('miR-138-5p', 'Chemical', '-', (188, 198))	('miR-1', 'Gene', (188, 193))	('miR-218-5p', 'Chemical', '-', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
465177	30200635	In order to assess the miRNAs' network of genetic interactions and their potential targets, the miR-146b-5p, miR-218-5p and miR-138-5p were selected based on their association with DFS in US and carcinomas patients who had undergone adjuvant treatment (Figure 9, Figure 10 and Figure 11).	('miR-138-5p', 'Chemical', '-', (124, 134))	('miR-146b', 'Gene', (96, 104))	('carcinomas', 'Disease', (195, 205))	('association', 'Interaction', (164, 175))	('miR-138-5p', 'Var', (124, 134))	('miR-146b', 'Gene', '574447', (96, 104))	('miR-218-5p', 'Chemical', '-', (109, 119))	('DFS', 'Disease', (181, 184))	('patients', 'Species', '9606', (206, 214))	('miR-218-5p', 'Var', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinomas', 'Disease', 'MESH:D002277', (195, 205))
465181	30200635	miR-218-5p was directly associated to the CDKN1A gene, and indirectly to the SMO gene.	('miR-218-5p', 'Var', (0, 10))	('associated', 'Reg', (24, 34))	('SMO', 'Gene', '6608', (77, 80))	('miR-218-5p', 'Chemical', '-', (0, 10))	('CDKN1A', 'Gene', (42, 48))	('SMO', 'Gene', (77, 80))	('CDKN1A', 'Gene', '1026', (42, 48))
465182	30200635	Lastly, miR-138-5p was related to the IGF1R gene.	('miR-138-5p', 'Chemical', '-', (8, 18))	('related', 'Reg', (23, 30))	('miR-138-5p', 'Var', (8, 18))	('IGF1R', 'Gene', (38, 43))	('IGF1R', 'Gene', '3480', (38, 43))
465196	30200635	miR-196a-5p, miR-34c-5p, miR-125a-5p, and miR-10a-5p expressions were associated with CSS in LMS women.	('CSS', 'Chemical', '-', (86, 89))	('miR-10a', 'Gene', '406902', (42, 49))	('miR-1', 'Gene', (25, 30))	('women', 'Species', '9606', (97, 102))	('miR-1', 'Gene', '83856', (42, 47))	('miR-1', 'Gene', '83856', (0, 5))	('miR-1', 'Gene', '83856', (25, 30))	('miR-34c-5p', 'Var', (13, 23))	('miR-1', 'Gene', (0, 5))	('associated', 'Reg', (70, 80))	('CSS', 'Disease', (86, 89))	('miR-10a', 'Gene', (42, 49))	('miR-1', 'Gene', (42, 47))
465198	30200635	Differential expressions of let-7b-5p, miR-138-5p, miR-373-3p, miR-372-3p, let-7f-5p, and miR-23b-3p were associated with CSS in HG-ESS.	('miR-372-3p', 'Var', (63, 73))	('associated', 'Reg', (106, 116))	('miR-138-5p', 'Chemical', '-', (39, 49))	('miR-138-5p', 'Var', (39, 49))	('let-7b', 'Gene', '406884', (28, 34))	('let-7f-5p', 'Var', (75, 84))	('miR-23b', 'Gene', '407011', (90, 97))	('let-7b', 'Gene', (28, 34))	('CSS', 'Disease', (122, 125))	('HG-ESS', 'Disease', (129, 135))	('miR-23b', 'Gene', (90, 97))	('CSS', 'Chemical', '-', (122, 125))	('miR-373-3p', 'Var', (51, 61))
465211	30200635	Changes in miR-25 expression have already been associated with lymph node metastasis in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (88, 100))	('associated with', 'Reg', (47, 62))	('miR-25', 'Gene', '407014', (11, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('expression', 'MPA', (18, 28))	('miR-25', 'Gene', (11, 17))	('Changes', 'Var', (0, 7))	('osteosarcoma', 'Phenotype', 'HP:0002669', (88, 100))	('lymph node metastasis', 'CPA', (63, 84))	('osteosarcoma', 'Disease', (88, 100))
465217	30200635	We found that miR-29b-3p and miR-29a-3p regulate SGK1; miR-335-5p, miR-125b-5p and miR-193b-3p regulate SHMT1; miR-130a-3p regulates GJA1; and miR-18a-5p and let-7i-5p regulate THBS1.	('miR-1', 'Gene', '83856', (143, 148))	('SHMT1', 'Gene', '6470', (104, 109))	('miR-1', 'Gene', (111, 116))	('THBS1', 'Gene', (177, 182))	('miR-1', 'Gene', (143, 148))	('GJA1', 'Gene', '2697', (133, 137))	('THBS1', 'Gene', '7057', (177, 182))	('GJA1', 'Gene', (133, 137))	('miR-1', 'Gene', '83856', (83, 88))	('regulates', 'Reg', (123, 132))	('let-7i', 'Gene', (158, 164))	('miR-335', 'Gene', '442904', (55, 62))	('miR-1', 'Gene', '83856', (67, 72))	('SGK1', 'Gene', '6446', (49, 53))	('miR-1', 'Gene', (83, 88))	('miR-29a-3p', 'Var', (29, 39))	('miR-1', 'Gene', (67, 72))	('SGK1', 'Gene', (49, 53))	('regulate', 'Reg', (95, 103))	('miR-335', 'Gene', (55, 62))	('regulate', 'Reg', (40, 48))	('SHMT1', 'Gene', (104, 109))	('miR-29b-3p', 'Var', (14, 24))	('miR-1', 'Gene', '83856', (111, 116))	('let-7i', 'Gene', '406891', (158, 164))
465218	30200635	This analysis indicates that the deregulation of these molecules can be associated with more aggressive tumor phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('associated', 'Reg', (72, 82))	('aggressive tumor', 'Disease', 'MESH:D001523', (93, 109))	('deregulation', 'Var', (33, 45))	('aggressive tumor', 'Disease', (93, 109))
465221	30200635	Our data revealed that the expression profile of three miRNAs miR-146b-5p (p = 0.032) miR-218-5p (p = 0.048) and miR-138-5p (p < 0.001) correlated to DFS in patients that had undergone adjuvant treatment.	('miR-218-5p', 'Var', (86, 96))	('DFS', 'Disease', (150, 153))	('miR-146b', 'Gene', (62, 70))	('miR-146b', 'Gene', '574447', (62, 70))	('expression', 'MPA', (27, 37))	('patients', 'Species', '9606', (157, 165))	('miR-138-5p', 'Chemical', '-', (113, 123))	('miR-218-5p', 'Chemical', '-', (86, 96))	('miR-138-5p', 'Var', (113, 123))	('correlated', 'Reg', (136, 146))
465230	30200635	Although its function is uncertain, the miR-138-5p is an important IGF1R regulator.	('IGF1R', 'Gene', (67, 72))	('miR-138-5p', 'Chemical', '-', (40, 50))	('IGF1R', 'Gene', '3480', (67, 72))	('miR-138-5p', 'Var', (40, 50))
465233	30200635	There is a clue that when correlated with DFS, the expression of miR-146b-5p, miR-218-5p and miR-138-5p may have a role in adjuvant therapy response in US patients.	('miR-138-5p', 'Chemical', '-', (93, 103))	('adjuvant therapy response', 'CPA', (123, 148))	('miR-138-5p', 'Var', (93, 103))	('miR-146b', 'Gene', (65, 73))	('miR-218-5p', 'Chemical', '-', (78, 88))	('role', 'Reg', (115, 119))	('miR-146b', 'Gene', '574447', (65, 73))	('patients', 'Species', '9606', (155, 163))	('miR-218-5p', 'Var', (78, 88))
465246	30200635	We found miR-146b-5p, miR-218-5p and miR-138-5p with higher expression in patients who underwent treatment.	('expression', 'MPA', (60, 70))	('miR-218-5p', 'Chemical', '-', (22, 32))	('higher', 'PosReg', (53, 59))	('miR-138-5p', 'Chemical', '-', (37, 47))	('patients', 'Species', '9606', (74, 82))	('miR-146b', 'Gene', (9, 17))	('miR-218-5p', 'Var', (22, 32))	('miR-138-5p', 'Var', (37, 47))	('miR-146b', 'Gene', '574447', (9, 17))
465247	30200635	Concerning metastasis and recurrence, miR-210-3p was associated with ESS metastasis; miR-127-5p was related to CS relapse; and two members of the miR-29 family (29a-3p and 29b-3p) were associated with aggressive phenotypes in LMS.	('miR-127-5p', 'Gene', '100302123', (85, 95))	('miR-21', 'Gene', (38, 44))	('associated', 'Reg', (185, 195))	('LMS', 'Disease', (226, 229))	('miR-127-5p', 'Gene', (85, 95))	('associated', 'Reg', (53, 63))	('related', 'Reg', (100, 107))	('miR-21', 'Gene', '406991', (38, 44))	('ESS', 'Disease', (69, 72))	('29a-3p', 'Var', (161, 167))
465248	30200635	Besides this, the upregulation of miR-196a-5p, miR-34c-5p, miR-373-3p, miR-372-3p and downregulation of let-7b-5p were strongly associated with a lower CSS.	('upregulation', 'PosReg', (18, 30))	('miR-1', 'Gene', '83856', (34, 39))	('miR-34c-5p', 'Var', (47, 57))	('CSS', 'Chemical', '-', (152, 155))	('let-7b', 'Gene', '406884', (104, 110))	('lower', 'NegReg', (146, 151))	('miR-372-3p', 'Var', (71, 81))	('downregulation', 'NegReg', (86, 100))	('let-7b', 'Gene', (104, 110))	('miR-1', 'Gene', (34, 39))	('miR-373-3p', 'Var', (59, 69))	('CSS', 'Disease', (152, 155))
465258	28549153	Fusions often function as oncoproteins or cancer drivers.	('Fusions', 'Var', (0, 7))	('function', 'Reg', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
465261	28549153	More recently, gene fusions in solid tumors and in prostate cancer in particular have been shown to drive carcinogenic processes such as invasiveness (e.g.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('carcinogenic', 'Disease', 'MESH:D063646', (106, 118))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('carcinogenic', 'Disease', (106, 118))	('solid tumors', 'Disease', (31, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('gene fusions', 'Var', (15, 27))	('invasiveness', 'CPA', (137, 149))	('drive', 'PosReg', (100, 105))	('prostate cancer', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('solid tumors', 'Disease', 'MESH:D009369', (31, 43))
465263	28549153	Thus, gene fusions are being recognized as important diagnostic and prognostic biomarkers in malignant hematological disorders and childhood sarcomas.	('gene fusions', 'Var', (6, 18))	('malignant hematological disorders', 'Disease', 'MESH:D019337', (93, 126))	('malignant hematological disorders', 'Disease', (93, 126))	('sarcomas', 'Disease', 'MESH:D012509', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('sarcomas', 'Disease', (141, 149))	('hematological disorders', 'Phenotype', 'HP:0001871', (103, 126))
465266	28549153	used a fusion network approach to reveal that certain parental proteins of fusions occupy central positions in PPI networks losing their functional activities following fusion events in cancer as well as that fusions escape regulation by losing post-translational modification sites.	('losing', 'NegReg', (238, 244))	('regulation', 'MPA', (224, 234))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('fusions', 'Var', (209, 216))	('functional activities', 'MPA', (137, 158))	('post-translational modification sites', 'MPA', (245, 282))	('escape', 'NegReg', (217, 223))	('losing', 'NegReg', (124, 130))	('PPI', 'Gene', (111, 114))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
465267	28549153	To demonstrate the systematic identification of PPI of fusions, uncovering their influence on networks and thus on cancer phenotypes, we present here chimeric protein-protein interaction (ChiPPI) method.	('cancer', 'Disease', (115, 121))	('influence', 'Reg', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('fusions', 'Var', (55, 62))
465274	28549153	In addition, we downloaded the COSMIC datasets of all point mutations in human genes in cancers.	('point mutations', 'Var', (54, 69))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('human', 'Species', '9606', (73, 78))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
465286	28549153	Inclusion of new interactors into the BCR/ABL network is likely to promote the disease phenotype, since CRKL and RASA1 regulate tumorigenic signaling in chronic myeloid leukemia, JAK2 mutation and fusion is tumorigenic in myeloproliferative disorders and in acute myeloid leukemia (AML) and CD2AP and INPPL1 are suspected oncogenes involved in segmental glomerulosclerosis type 3 and Metabolic Syndrome, all of which potentially represent drug targets in disease therapy (Figure 3).	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (153, 177))	('AML', 'Disease', (282, 285))	('AML', 'Phenotype', 'HP:0004808', (282, 285))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CRKL', 'Gene', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (222, 250))	('RASA1', 'Gene', (113, 118))	('segmental glomerulosclerosis', 'Phenotype', 'HP:0000097', (344, 372))	('myeloproliferative disorders', 'Disease', (222, 250))	('INPPL1', 'Gene', '3636', (301, 307))	('BCR/ABL', 'Gene', '25;613', (38, 45))	('CD2AP', 'Gene', '23607', (291, 296))	('acute myeloid leukemia', 'Disease', (258, 280))	('Metabolic Syndrome', 'Disease', 'MESH:D008659', (384, 402))	('mutation', 'Var', (184, 192))	('CD2AP', 'Gene', (291, 296))	('myeloid leukemia', 'Disease', (161, 177))	('AML', 'Disease', 'MESH:D015470', (282, 285))	('JAK2', 'Gene', '3717', (179, 183))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (354, 372))	('glomerulosclerosis', 'Disease', (354, 372))	('tumor', 'Disease', (128, 133))	('INPPL1', 'Gene', (301, 307))	('tumor', 'Disease', (207, 212))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (258, 280))	('glomerulosclerosis', 'Disease', 'MESH:D005921', (354, 372))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('leukemia', 'Phenotype', 'HP:0001909', (272, 280))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('myeloid leukemia', 'Disease', 'MESH:D007951', (161, 177))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (258, 280))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (222, 250))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (161, 177))	('Metabolic Syndrome', 'Disease', (384, 402))	('RASA1', 'Gene', '5921', (113, 118))	('CRKL', 'Gene', '1399', (104, 108))	('JAK2', 'Gene', (179, 183))	('BCR/ABL', 'Gene', (38, 45))	('leukemia', 'Phenotype', 'HP:0001909', (169, 177))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (264, 280))	('myeloid leukemia', 'Disease', 'MESH:D007951', (264, 280))	('fusion', 'Var', (197, 203))
465287	28549153	For example, we can observe the new domains in the fusions as follows: ESTid=L22179.1 (the KMT2A/AFF1 fusion in ChiTaRS-3.1) has seven new domains (Actin, Vfa1, Ery_res_leader2, Filament_head, YL1, DUF3446 and HPS3_Mid), which were not in the parental proteins KMT2A and AFF1.	('AFF1', 'Gene', (97, 101))	('KMT2A', 'Gene', '4297', (261, 266))	('AFF1', 'Gene', '4299', (271, 275))	('KMT2A', 'Gene', (91, 96))	('KMT2A', 'Gene', '4297', (91, 96))	('AFF1', 'Gene', '4299', (97, 101))	('YL1', 'Gene', '6944', (193, 196))	('YL1', 'Gene', (193, 196))	('AFF1', 'Gene', (271, 275))	('DUF3446', 'Var', (198, 205))	('KMT2A', 'Gene', (261, 266))
465299	28549153	The upper right network (Figure 6) includes the lymphoma-associated ALK fusions, the carcinoma-associated transcription factor for IGHM, the enhancer 3 (TFE3) fusions and the sarcoma-associated EWSR1 fusions.	('TFE3', 'Gene', (153, 157))	('sarcoma', 'Disease', (175, 182))	('fusions', 'Var', (159, 166))	('carcinoma', 'Disease', (85, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('ALK', 'Gene', (68, 71))	('IGHM', 'Gene', (131, 135))	('lymphoma', 'Disease', (48, 56))	('TFE3', 'Gene', '7030', (153, 157))	('EWSR1', 'Gene', (194, 199))	('IGHM', 'Gene', '3507', (131, 135))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('ALK', 'Gene', '238', (68, 71))	('sarcoma', 'Disease', 'MESH:D012509', (175, 182))	('lymphoma', 'Disease', 'MESH:D008223', (48, 56))	('EWSR1', 'Gene', '2130', (194, 199))	('lymphoma', 'Phenotype', 'HP:0002665', (48, 56))
465300	28549153	The lower right network (Figure 6) contains mainly hematological MLL fusions connected to HMGA2 fusions that are typically found in solid tumors.	('HMGA2', 'Gene', (90, 95))	('solid tumors', 'Disease', 'MESH:D009369', (132, 144))	('MLL', 'Gene', '4297', (65, 68))	('MLL', 'Gene', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('solid tumors', 'Disease', (132, 144))	('fusions', 'Var', (96, 103))	('HMGA2', 'Gene', '8091', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
465301	28549153	Taken together, these results indicate that parental proteins in fusions are indeed central nodes in the PPI networks and they produce together one highly connected large cancer PPI network that unify different cancer-associated nodes within different cancer phenotype.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (211, 217))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('fusions', 'Var', (65, 72))
465302	28549153	BCR and ABL), then the effect of a fusion event could be 2-fold: loss of interactions through deletion of protein domains in the fusion and enhanced activity of the fusion.	('loss', 'NegReg', (65, 69))	('ABL', 'Gene', '25', (8, 11))	('deletion', 'Var', (94, 102))	('enhanced', 'PosReg', (140, 148))	('ABL', 'Gene', (8, 11))	('interactions', 'Interaction', (73, 85))	('activity', 'MPA', (149, 157))	('protein domains', 'Protein', (106, 121))	('BCR', 'Gene', (0, 3))	('BCR', 'Gene', '613', (0, 3))
465308	28549153	To directly compare the association of fusion events or other types of mutation to loss of tumor suppressors from PPI networks, we took 572 cancer genes from the COSMIC database that are causally linked to cancer mutations and asked what changes occur to tumor suppressors in their corresponding PPI networks upon gene mutation (Supplementary Table S1 and 2 and Supplementary Data).	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Disease', (140, 146))	('mutation', 'Var', (319, 327))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutations', 'Var', (213, 222))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', (91, 96))	('S1 and 2', 'Gene', '5707;5708', (349, 357))
465310	28549153	Further, the rate of loss of tumor suppressors from mutant gene PPI networks was found to be similar to that of fusion gene PPI networks (25% compared to 20%, respectively).	('mutant gene', 'Var', (52, 63))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))
465312	28549153	Having shown that fusions dramatically skew PPI networks, we next asked if these network aberrations are associated with particular signaling pathways in different cancer types.	('PPI networks', 'MPA', (44, 56))	('fusions', 'Var', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('associated', 'Reg', (105, 115))	('skew', 'Reg', (39, 43))
465314	28549153	This resulted in 238 characterized fusions for leukemia, 51 for sarcoma and 69 for solid tumors (in our training set).	('leukemia', 'Disease', 'MESH:D007938', (47, 55))	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('leukemia', 'Disease', (47, 55))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('solid tumors', 'Disease', (83, 95))	('sarcoma', 'Disease', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('fusions', 'Var', (35, 42))	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))
465317	28549153	Thus, in leukemia KEGG analysis revealed Notch, TGF-beta, ErbB, MAPK, Jak- STAT, Wnt, T-cell receptor and B-cell receptor pathway activation (Figure 7).	('T-cell', 'Pathway', (86, 92))	('Notch', 'Var', (41, 46))	('ErbB', 'Gene', '1956', (58, 62))	('TGF-beta', 'Gene', (48, 56))	('activation', 'PosReg', (130, 140))	('leukemia', 'Phenotype', 'HP:0001909', (9, 17))	('leukemia', 'Disease', 'MESH:D007938', (9, 17))	('B-cell receptor pathway', 'Pathway', (106, 129))	('TGF-beta', 'Gene', '7040', (48, 56))	('leukemia', 'Disease', (9, 17))	('MAPK', 'Gene', (64, 68))	('ErbB', 'Gene', (58, 62))
465319	28549153	Taken together, these results indicate that pathway enrichment specific for fusions follows a similar pattern to total pathway activity in the studied cancer types.	('fusions', 'Var', (76, 83))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))
465321	28549153	We have compared the PPI networks of fusion proteins with the protein PPI networks of both parental proteins, and have mapped additional (non-fusion) cancer mutations to parental proteins or to other proteins that coincide in the fusion protein PPI network.	('mutations', 'Var', (157, 166))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
465325	28549153	Thus, ChiPPI provides a predictive model for demonstrating how fusions may act as drivers of cancer by reducing or losing interactions with tumor suppressors in PPI networks.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('interactions', 'Interaction', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('reducing', 'NegReg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('losing', 'NegReg', (115, 121))	('fusions', 'Var', (63, 70))	('tumor', 'Disease', (140, 145))
465331	28549153	Wnt, Notch and TGF beta, there is also a set of pathways specifically affected by fusions, in leukemia, i.e.	('TGF beta', 'Gene', (15, 23))	('fusions', 'Var', (82, 89))	('TGF beta', 'Gene', '7040', (15, 23))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('leukemia', 'Disease', (94, 102))	('affected', 'Reg', (70, 78))	('leukemia', 'Disease', 'MESH:D007938', (94, 102))
465335	28549153	Our findings fit well with previous observations on pathways enrichment in cancer based on the analysis of mutation load or altered gene expression leading us to speculate that both fusion events and other types of alterations, including mutation and gene expression alterations, are similarly selected for in cancer and they might be mediated by network aberrations affecting similar pathways.	('cancer', 'Disease', (310, 316))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutation', 'Var', (107, 115))	('cancer', 'Disease', 'MESH:D009369', (310, 316))
465338	28549153	To conclude, the ChiPPI results suggest a new role for fusions proteins as hubs in cancer interaction networks, confirming previous studies.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (83, 89))	('fusions', 'Var', (55, 62))
465361	28442918	Once the T-cell becomes activated, other costimulatory molecules are expressed, such as 4.1BB, OX40, and CD40L.	('OX40', 'Gene', (95, 99))	('OX40', 'Gene', '22163', (95, 99))	('4.1BB', 'Var', (88, 93))	('CD40L', 'Gene', (105, 110))	('CD40L', 'Gene', '21947', (105, 110))
465373	28442918	Of note, mice deficient in PD-1 develop autoimmune diseases from unchecked immune activation, and blocking this pathway in PD-1-proficient mice with chronic viral infections restores antiviral immunity and reverses T-cell exhaustion.	('T-cell exhaustion', 'Phenotype', 'HP:0005435', (215, 232))	('autoimmune diseases', 'Disease', (40, 59))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (40, 59))	('chronic viral infections', 'Disease', (149, 173))	('blocking', 'Var', (98, 106))	('T-cell', 'MPA', (215, 221))	('PD-1', 'Gene', (27, 31))	('autoimmune disease', 'Phenotype', 'HP:0002960', (40, 58))	('restores', 'PosReg', (174, 182))	('antiviral immunity', 'MPA', (183, 201))	('chronic viral infections', 'Disease', 'MESH:D001102', (149, 173))	('mice', 'Species', '10090', (139, 143))	('mice', 'Species', '10090', (9, 13))	('autoimmune diseases', 'Disease', 'MESH:D001327', (40, 59))
465387	28442918	Intuitively, tumors that have escaped immune surveillance and express PD-L1 on the cell surface should benefit from either anti-PD-1 or anti-PD-L1 therapy.	('PD-L1', 'Gene', (141, 146))	('PD-L1', 'Gene', '29126', (70, 75))	('PD-L1', 'Gene', '29126', (141, 146))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('anti-PD-1', 'Var', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('benefit', 'PosReg', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PD-L1', 'Gene', (70, 75))
465399	28442918	Alternatively, mutations also may be dramatically increased in tumors demonstrating mismatch repair (MMR) deficiency, and this can result in microsatellite instability (MSI) and sensitivity to PD-1 inhibition.	('result in', 'Reg', (131, 140))	('microsatellite instability', 'MPA', (141, 167))	('increased', 'PosReg', (50, 59))	('deficiency', 'Var', (106, 116))	('mutations', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('MSI', 'Disease', 'None', (169, 172))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MSI', 'Disease', (169, 172))
465401	28442918	Whole-exome sequencing demonstrated a mean of 1,782 mutations per tumor in the MMR-deficient cohort, compared to 73 in the proficient group.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (52, 61))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('MMR-deficient', 'Gene', (79, 92))
465405	28442918	Wu et al found that for 43 melanoma patients treated with PD-1 blockade, those with high circulating levels of Ang2 (defined as >3,175 pg/mL) or rising levels during treatment had reduced overall survival, suggesting that Ang2 may mediate resistance to checkpoint inhibitors, and could be used to select and follow patients.	('Ang2', 'Gene', (111, 115))	('patients', 'Species', '9606', (36, 44))	('Ang2', 'Gene', '285', (111, 115))	('PD-1', 'Gene', (58, 62))	('reduced', 'NegReg', (180, 187))	('Ang2', 'Gene', (222, 226))	('overall survival', 'CPA', (188, 204))	('blockade', 'Var', (63, 71))	('patients', 'Species', '9606', (315, 323))	('melanoma', 'Disease', (27, 35))	('Ang2', 'Gene', '285', (222, 226))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
465409	28442918	Mutations in tumor can account for downregulation of MHC and decreased immunogenicity, or altered dendritic cell migration.	('tumor', 'Disease', (13, 18))	('immunogenicity', 'MPA', (71, 85))	('altered', 'Reg', (90, 97))	('MHC', 'Protein', (53, 56))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('downregulation', 'NegReg', (35, 49))	('decreased', 'NegReg', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('dendritic cell migration', 'CPA', (98, 122))
465452	28442918	As opposed to the myelosuppression usually seen with conventional chemotherapy, the toxicity of anti-PD-1 antibodies has often been immune-related such as pneumonitis, colitis, hepatitis, hypophysitis, and thyroiditis.	('hypophysitis', 'Disease', (188, 200))	('myelosuppression', 'Disease', (18, 34))	('colitis', 'Disease', (168, 175))	('pneumonitis', 'Disease', 'MESH:D011014', (155, 166))	('thyroiditis', 'Disease', (206, 217))	('hepatitis', 'Phenotype', 'HP:0012115', (177, 186))	('colitis', 'Disease', 'MESH:D003092', (168, 175))	('pneumonitis', 'Disease', (155, 166))	('hepatitis', 'Disease', 'MESH:D056486', (177, 186))	('antibodies', 'Var', (106, 116))	('myelosuppression', 'Disease', 'MESH:D001855', (18, 34))	('hepatitis', 'Disease', (177, 186))	('thyroiditis', 'Disease', 'MESH:D013959', (206, 217))	('hypophysitis', 'Disease', 'MESH:D000072659', (188, 200))	('toxicity', 'Disease', 'MESH:D064420', (84, 92))	('anti-PD-1', 'Gene', (96, 105))	('colitis', 'Phenotype', 'HP:0002583', (168, 175))	('thyroiditis', 'Phenotype', 'HP:0100646', (206, 217))	('toxicity', 'Disease', (84, 92))
465456	28442918	Such patients being treated with anti-PD-1 antibodies should be monitored carefully, and be considered for drainage or other medical management that could include steroids.	('steroids', 'Chemical', 'MESH:D013256', (163, 171))	('antibodies', 'Var', (43, 53))	('patients', 'Species', '9606', (5, 13))	('anti-PD-1 antibodies', 'Var', (33, 53))
465463	28442918	Some conventional chemotherapy drugs such as cyclophosphamide, platinum analogs, and taxanes can elicit immunogenicity by recruiting immune cells to the microenvironment, stimulating natural killer-dependent antitumor immunity and T-cell responses, and disrupting immune suppressor mechanisms by depleting regulatory T-cells and myeloid-derived suppressor cells.	('immunogenicity', 'MPA', (104, 118))	('depleting', 'NegReg', (296, 305))	('disrupting', 'NegReg', (253, 263))	('cyclophosphamide', 'Var', (45, 61))	('recruiting', 'PosReg', (122, 132))	('stimulating', 'PosReg', (171, 182))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('taxanes', 'Chemical', 'MESH:D043823', (85, 92))	('platinum', 'Chemical', 'MESH:D010984', (63, 71))	('immune suppressor mechanisms', 'CPA', (264, 292))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('T-cell responses', 'CPA', (231, 247))	('regulatory T-cells', 'CPA', (306, 324))	('elicit', 'Reg', (97, 103))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (45, 61))	('tumor', 'Disease', (212, 217))
465476	27909727	A total of eight different human STS cell lines were used in the study: Fibrosarcoma (HT1080), liposarcoma (SW872, T778 and MLS-402), synovial sarcoma (SW982, SYO1 and 1273) and pleomorphic sarcoma (U2197).	('SYO1', 'Gene', (159, 163))	('SW872', 'CellLine', 'CVCL:1730', (108, 113))	('human', 'Species', '9606', (27, 32))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (178, 197))	('liposarcoma', 'Disease', 'MESH:D008080', (95, 106))	('HT1080', 'CellLine', 'CVCL:0317', (86, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('pleomorphic sarcoma', 'Disease', (178, 197))	('liposarcoma', 'Disease', (95, 106))	('U2197', 'CellLine', 'CVCL:0043', (199, 204))	('synovial sarcoma', 'Disease', (134, 150))	('SYO1', 'Gene', '55027', (159, 163))	('Fibrosarcoma', 'Phenotype', 'HP:0100244', (72, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('synovial sarcoma', 'Disease', 'MESH:D013584', (134, 150))	('SW982', 'Var', (152, 157))	('STS', 'Phenotype', 'HP:0030448', (33, 36))	('Fibrosarcoma', 'Disease', (72, 84))	('liposarcoma', 'Phenotype', 'HP:0012034', (95, 106))	('Fibrosarcoma', 'Disease', 'MESH:D005354', (72, 84))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (134, 150))	('SW982', 'CellLine', 'CVCL:1734', (152, 157))
465479	27909727	By contrast, EGCG decreased proliferation and viability of all cell lines except for the 1273 synovial sarcoma cell line.	('proliferation', 'CPA', (28, 41))	('EGCG', 'Chemical', 'MESH:C045651', (13, 17))	('decreased', 'NegReg', (18, 27))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (94, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('EGCG', 'Var', (13, 17))	('synovial sarcoma', 'Disease', 'MESH:D013584', (94, 110))	('viability', 'CPA', (46, 55))	('synovial sarcoma', 'Disease', (94, 110))
465510	27909727	Eight different human STS cell lines were used in the present study: HT1080 (fibrosarcoma), SW872 (liposarcoma), T778 (liposarcoma), MLS-402 (liposarcoma), SW982 (synovial sarcoma), SYO1 (synovial sarcoma), 1273 (synovial sarcoma) and U2197 (pleomorphic sarcoma/malignant fibrous histiocytoma).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (213, 229))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (242, 261))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (163, 179))	('liposarcoma', 'Disease', (99, 110))	('STS', 'Phenotype', 'HP:0030448', (22, 25))	('fibrosarcoma', 'Disease', (77, 89))	('liposarcoma', 'Phenotype', 'HP:0012034', (142, 153))	('liposarcoma', 'Disease', 'MESH:D008080', (119, 130))	('SYO1', 'Gene', (182, 186))	('liposarcoma', 'Disease', 'MESH:D008080', (142, 153))	('histiocytoma', 'Phenotype', 'HP:0012315', (280, 292))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('pleomorphic sarcoma', 'Disease', (242, 261))	('liposarcoma', 'Phenotype', 'HP:0012034', (99, 110))	('human', 'Species', '9606', (16, 21))	('HT1080', 'CellLine', 'CVCL:0317', (69, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('synovial sarcoma', 'Disease', (188, 204))	('liposarcoma', 'Disease', (119, 130))	('SW982', 'Var', (156, 161))	('liposarcoma', 'Disease', 'MESH:D008080', (99, 110))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (77, 89))	('synovial sarcoma', 'Disease', (163, 179))	('synovial sarcoma', 'Disease', (213, 229))	('SW872', 'Var', (92, 97))	('liposarcoma', 'Disease', (142, 153))	('U2197', 'Var', (235, 240))	('synovial sarcoma', 'Disease', 'MESH:D013584', (188, 204))	('synovial sarcoma', 'Disease', 'MESH:D013584', (213, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('synovial sarcoma', 'Disease', 'MESH:D013584', (163, 179))	('SW982', 'CellLine', 'CVCL:1734', (156, 161))	('SYO1', 'Gene', '55027', (182, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('fibrosarcoma', 'Disease', 'MESH:D005354', (77, 89))	('SW872', 'CellLine', 'CVCL:1730', (92, 97))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (188, 204))	('T778', 'Var', (113, 117))	('liposarcoma', 'Phenotype', 'HP:0012034', (119, 130))	('U2197', 'CellLine', 'CVCL:0043', (235, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
465511	27909727	HT1080, SW872 and SW982 were purchased from CLS Cell Lines Service GmbH (Eppelheim, Germany) and were cultured in Dulbecco's modified Eagle's medium (DMEM; PAN-Biotech GmbH, Aidenbach, Germany) supplemented with 10% foetal bovine serum (FBS; Thermo Fisher Scientific, Inc., Waltham, MA, USA), 1% penicillin (100 U/ml) and 1% streptomycin (100 microg/ml; PAN-Biotech GmbH).	('DMEM', 'Chemical', '-', (150, 154))	('SW982', 'CellLine', 'CVCL:1734', (18, 23))	('bovine', 'Species', '9913', (223, 229))	('FBS', 'Disease', 'MESH:D005198', (237, 240))	('streptomycin', 'Chemical', 'MESH:D013307', (325, 337))	('SW872', 'CellLine', 'CVCL:1730', (8, 13))	('penicillin', 'Chemical', 'MESH:D010406', (296, 306))	('SW872', 'Var', (8, 13))	('HT1080', 'CellLine', 'CVCL:0317', (0, 6))	('SW982', 'Var', (18, 23))	('FBS', 'Disease', (237, 240))
465565	27909727	Notably, similar chemosensitizing and chemopreventive activities have been described for silibinin; in vivo studies revealed that silibinin synergistically enhances the apoptosis-inducing activity of doxorubicin and ameliorates doxorubicin-induced cardiotoxicity.	('silibinin', 'Var', (130, 139))	('silibinin', 'Chemical', 'MESH:D000077385', (130, 139))	('enhances', 'PosReg', (156, 164))	('silibinin', 'Chemical', 'MESH:D000077385', (89, 98))	('apoptosis-inducing activity', 'CPA', (169, 196))	('cardiotoxicity', 'Disease', 'MESH:D066126', (248, 262))	('ameliorates', 'PosReg', (216, 227))	('doxorubicin', 'Chemical', 'MESH:D004317', (228, 239))	('cardiotoxicity', 'Disease', (248, 262))	('doxorubicin', 'Chemical', 'MESH:D004317', (200, 211))
465611	33655917	Compared with follicular dendritic cells and Langerhans cells of the same family, tumor cells are negative for CD21, CD23, CD35, D2-40, CD207, CD1a, and CK.	('CD1a', 'Gene', '909', (143, 147))	('CD35', 'Gene', (123, 127))	('CD21', 'Gene', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('CD23', 'Gene', (117, 121))	('CD1a', 'Gene', (143, 147))	('CD21', 'Gene', '1380', (111, 115))	('D2-40', 'Var', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CD207', 'Gene', '50489', (136, 141))	('CD35', 'Gene', '1378', (123, 127))	('tumor', 'Disease', (82, 87))	('CD23', 'Gene', '2208', (117, 121))	('CD207', 'Gene', (136, 141))
465669	27100936	Histologic ICD-0-3 codes were used to include: synovial sarcoma, NOS (9040/3); synovial sarcoma, spindle cell (9041/3); synovial sarcoma, epithelioid cell (9042/3); and synovial sarcoma, biphasic (9043/3).	('OS', 'Chemical', '-', (66, 68))	('synovial sarcoma', 'Disease', 'MESH:D013584', (169, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (169, 185))	('synovial sarcoma', 'Disease', (120, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('synovial sarcoma', 'Disease', (79, 95))	('synovial sarcoma', 'Disease', 'MESH:D013584', (120, 136))	('ICD', 'Disease', (11, 14))	('9041/3', 'Var', (111, 117))	('synovial sarcoma', 'Disease', 'MESH:D013584', (79, 95))	('synovial sarcoma', 'Disease', (47, 63))	('ICD', 'Disease', 'OMIM:252500', (11, 14))	('synovial sarcoma', 'Disease', 'MESH:D013584', (47, 63))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (120, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (79, 95))	('synovial sarcoma', 'Disease', (169, 185))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (47, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
465729	27100936	Radiation therapy was associated with increased DSS on univariate Kaplan-Meier analysis, while surgical resection was not associated with statistically significantly improved survival outcomes.	('Radiation therapy', 'Var', (0, 17))	('DSS', 'MPA', (48, 51))	('DSS', 'Chemical', '-', (48, 51))
465745	27807479	Regulatory genes for the mTOR pathway are lost or mutated in many cancers, leading to enhanced activation of mTOR and increased cell resistance to apoptosis.	('cell resistance to apoptosis', 'CPA', (128, 156))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('enhanced activation', 'PosReg', (86, 105))	('mTOR', 'Gene', '2475', (109, 113))	('increased', 'PosReg', (118, 127))	('mutated', 'Var', (50, 57))	('mTOR', 'Gene', (109, 113))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('mTOR', 'Gene', '2475', (25, 29))	('mTOR', 'Gene', (25, 29))
465746	27807479	Disruption of mTOR activation interrupts this antiapoptotic effect and mTOR-dependent angiogenesis, both of which are essential for the development and propagation of malignant cells.	('mTOR', 'Gene', '2475', (14, 18))	('interrupts', 'NegReg', (30, 40))	('mTOR', 'Gene', '2475', (71, 75))	('mTOR', 'Gene', (71, 75))	('antiapoptotic effect', 'MPA', (46, 66))	('angiogenesis', 'CPA', (86, 98))	('mTOR', 'Gene', (14, 18))	('Disruption', 'Var', (0, 10))
465748	27807479	Preclinical studies have shown mTOR inhibitors to have a potent inhibitory effect in various cancers including B-cell lymphocyte growth, prostate tumors, and renal carcinomas and that they exert antimyeloma activity in multiple myeloma.	('renal carcinomas', 'Phenotype', 'HP:0005584', (158, 174))	('myeloma', 'Disease', (228, 235))	('mTOR', 'Gene', '2475', (31, 35))	('prostate tumors', 'Disease', (137, 152))	('prostate tumors', 'Disease', 'MESH:D011471', (137, 152))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('multiple myeloma', 'Phenotype', 'HP:0006775', (219, 235))	('inhibitory effect', 'MPA', (64, 81))	('B-cell lymphocyte growth', 'CPA', (111, 135))	('multiple myeloma', 'Disease', 'MESH:D009101', (219, 235))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('myeloma', 'Disease', 'MESH:D009101', (199, 206))	('renal carcinomas', 'Disease', 'MESH:C538614', (158, 174))	('myeloma', 'Disease', 'MESH:D009101', (228, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('cancers', 'Disease', (93, 100))	('mTOR', 'Gene', (31, 35))	('inhibitors', 'Var', (36, 46))	('multiple myeloma', 'Disease', (219, 235))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('myeloma', 'Disease', (199, 206))	('renal carcinomas', 'Disease', (158, 174))
465946	22454562	IHC assessments in human cancer biopsies have found elevated levels of HIF-1alpha and/or HIF-2alpha protein in the majority of primary human cancers and their metastases.	('metastases', 'Disease', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('protein', 'Protein', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('HIF-2alpha', 'Var', (89, 99))	('metastases', 'Disease', 'MESH:D009362', (159, 169))	('HIF-1alpha', 'Protein', (71, 81))	('human', 'Species', '9606', (135, 140))	('levels', 'MPA', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancer', 'Disease', (25, 31))	('human', 'Species', '9606', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('elevated', 'PosReg', (52, 60))
465983	22454562	HIF-1alpha (45%) was more frequently expressed than HIF-2alpha (30%), but clinicopathological variables representing tumor aggressiveness correlated more often with HIF-2alpha, than HIF-1alpha.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor aggressiveness', 'Disease', (117, 137))	('HIF-2alpha', 'Var', (165, 175))	('aggressiveness', 'Phenotype', 'HP:0000718', (123, 137))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (117, 137))
465991	32570879	Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs).	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', (158, 163))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('identify', 'Reg', (213, 221))	('copy number alterations', 'Var', (248, 271))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('Tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutations', 'Var', (234, 243))
465993	32570879	Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (105, 111))	('cancers', 'Disease', (105, 112))	('genes-pathways', 'Pathway', (282, 296))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('impacts', 'Reg', (201, 208))	('cancer', 'Disease', (365, 371))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancer', 'Disease', (71, 77))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('variants', 'Var', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))
465994	32570879	We identified 3343 germline single nucleotide variants (SNVs) and small indel variants:1670 in oncogenes and 1673 in tumor suppressor genes:generating an average of 124 germline variants/case.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('variants:1670', 'Var', (78, 91))	('tumor', 'Disease', (117, 122))	('single nucleotide variants', 'Var', (28, 54))	('oncogenes', 'Gene', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
465998	32570879	Genomic analysis of tumors has dramatically reshaped cancer treatment through the identification of genetic variants that provide diagnostic and prognostic information and that aid in therapeutic selection.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('aid', 'Gene', '57379', (177, 180))	('variants', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('aid', 'Gene', (177, 180))	('reshaped', 'Reg', (44, 52))
466005	32570879	A recent precision medicine study focused on molecular characterization of rare cancers identified actionable variants over 92% of the time, with 52% receiving a matched therapy.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('variants', 'Var', (110, 118))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
466018	32570879	Variants were then further categorized as either a passenger mutation or a functional driver mutation using the Cancer Genome Interpreter tool .	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Variants', 'Var', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', (112, 118))
466019	32570879	From germline variants found to be in cancer predisposition genes, six (all heterozygous) were identified to be pathogenic or likely pathogenic by the more stringent ACMG guidelines: BRCA2-Q2859Kfs (gray zone lymphoma), SDHA-R75* (spindle cell breast cancer), SDHC-A3Rfs (gastrointestinal stromal tumor), RUNX1-M151L (glioblastoma), FANCC-c.456+4A>T splice site/exon skipping (anaplastic astrocytoma), and MUTYH-G396D (alveolar soft part sarcoma) (Table 2).	('R75*', 'Var', (225, 229))	('FANCC', 'Gene', '2176', (333, 338))	('cell breast cancer', 'Disease', 'MESH:D001943', (239, 257))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (272, 302))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('lymphoma', 'Phenotype', 'HP:0002665', (209, 217))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (438, 445))	('MUTYH', 'Gene', '4595', (406, 411))	('R75*', 'SUBSTITUTION', 'None', (225, 229))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (272, 302))	('SDHC', 'Gene', (260, 264))	('BRCA2', 'Gene', (183, 188))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (377, 399))	('c.456+4A>T', 'Mutation', 'rs104886456', (339, 349))	('FANCC', 'Gene', (333, 338))	('RUNX1', 'Gene', (305, 310))	('RUNX1', 'Gene', '861', (305, 310))	('cancer', 'Disease', (38, 44))	('gastrointestinal stromal tumor', 'Disease', (272, 302))	('M151L', 'Mutation', 'p.M151L', (311, 316))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (388, 399))	('lymphoma', 'Disease', (209, 217))	('SDHA', 'Gene', (220, 224))	('glioblastoma', 'Disease', 'MESH:D005909', (318, 330))	('lymphoma', 'Disease', 'MESH:D008223', (209, 217))	('BRCA2', 'Gene', '675', (183, 188))	('G396D', 'Mutation', 'rs36053993', (412, 417))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('cancer', 'Disease', (251, 257))	('cell breast cancer', 'Disease', (239, 257))	('SDHA', 'Gene', '6389', (220, 224))	('glioblastoma', 'Disease', (318, 330))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('variants', 'Var', (14, 22))	('sarcoma', 'Disease', 'MESH:D012509', (438, 445))	('SDHC', 'Gene', '6391', (260, 264))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (419, 445))	('glioblastoma', 'Phenotype', 'HP:0012174', (318, 330))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (428, 445))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('sarcoma', 'Disease', (438, 445))	('MUTYH', 'Gene', (406, 411))	('anaplastic astrocytoma', 'Disease', (377, 399))
466023	32570879	Interestingly the SPEN-Q3621* nonsense variant that was identified in this tumor likely truncates the protein product (a hormone inducible transcriptional repressor), resulting in loss of a portion of a domain that is necessary for interactions with other nuclear co-repressors.	('interactions', 'Interaction', (232, 244))	('domain', 'MPA', (203, 209))	('Q3621*', 'SUBSTITUTION', 'None', (23, 29))	('loss', 'NegReg', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('SPEN', 'Gene', '23013', (18, 22))	('truncates', 'NegReg', (88, 97))	('protein product', 'MPA', (102, 117))	('Q3621*', 'Var', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SPEN', 'Gene', (18, 22))	('tumor', 'Disease', (75, 80))
466024	32570879	While SPEN mutations are reported in 8% (8/97) of MCC samples in COSMIC, this variant is not functionally characterized and its effect on protein function is unknown.	('SPEN', 'Gene', (6, 10))	('amp', 'Chemical', 'MESH:D000249', (55, 58))	('SPEN', 'Gene', '23013', (6, 10))	('mutations', 'Var', (11, 20))
466025	32570879	Actionable variants found in the patient cohort were classified in the four categories: FDA-approved for rare cancer type, FDA-approved for different cancer type, clinical trial for rare cancer type, clinical trial for different cancer type.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (110, 116))	('patient', 'Species', '9606', (33, 40))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', (187, 193))	('variants', 'Var', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
466027	32570879	In fact, only one patient had a variant with an FDA approved therapy, and three had a variant with a clinical trial for their tumor type (Figure 2).	('variant', 'Var', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('patient', 'Species', '9606', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
466030	32570879	When comparing our WES tumor/germline with tumor only analysis, there was general concordance in the classification of known pathogenic variants and VUS.	('variants', 'Var', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (43, 48))
466031	32570879	However, while most of the pathogenic/likely pathogenic variants where found to be somatic using both assays, the vast majority (~80%) of the clinically reported VUS turn out to be inherited when using the tumor/germline analysis (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('VUS', 'Disease', (162, 165))	('tumor', 'Disease', (206, 211))	('variants', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
466033	32570879	Additionally, our tumor/germline approach identified a single pathogenic variant that turned out to be germline in origin.	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('variant', 'Var', (73, 80))	('tumor', 'Disease', (18, 23))
466034	32570879	This frameshift variant (A3fs) in the C subunit of the succinate dehydrogenase (SDH) gene was found in a patient with gastrointestinal stromal tumor (GIST).	('found', 'Reg', (94, 99))	('patient', 'Species', '9606', (105, 112))	('gastrointestinal stromal tumor', 'Disease', (118, 148))	('A3fs', 'Var', (25, 29))	('succinate dehydrogenase', 'Gene', '6390', (55, 78))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (118, 148))	('SDH', 'Gene', '6390', (80, 83))	('A3fs', 'FRAMESHIFT', 'None', (25, 29))	('succinate dehydrogenase', 'Gene', (55, 78))	('SDH', 'Gene', (80, 83))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (118, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
466038	32570879	The percentage of cases harboring an inherited pathogenic variant appears to differ between rare vs. common (i.e., lung, breast, colon, rectal, and prostate) cancers (Table 3).	('breast', 'Disease', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('lung', 'Disease', (115, 119))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('variant', 'Var', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colon', 'Disease', (129, 134))	('rectal', 'Disease', (136, 142))
466040	32570879	In contrast, common cancers taken from 3451 combined cases in TCGA, showed 7.9% of variants as germline pathogenic or likely pathogenic.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('variants', 'Var', (83, 91))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
466041	32570879	This increased rate of inherited pathogenic variants in rare cancer was found to be statistically significant using the Fisher exact test (p = 0.01800).	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('variants', 'Var', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
466043	32570879	There is a consistent yet slight increase in the overall percentage of germline variants detected in rare tumors in our cohort when compared to the other rare tumor cohorts (Table 4).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('increase', 'PosReg', (33, 41))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('germline variants', 'Var', (71, 88))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (106, 111))
466044	32570879	Copy number analysis (CNA) performed using Sequenza on all WES cases and analyzed using the GISTIC2 pipeline, produced a heatmap of the overall amplification and deletion scores across all chromosomes to compare cases (Figure 4A).	('deletion', 'Var', (162, 170))	('amplification', 'MPA', (144, 157))	('amp', 'Chemical', 'MESH:D000249', (144, 147))
466046	32570879	As shown the total number of amplified oncogenes and deletions of tumor suppressor genes in our cohort was widely variable from case to case (Table S4).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('deletions', 'Var', (53, 62))	('amp', 'Chemical', 'MESH:D000249', (29, 32))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
466047	32570879	Nine of the 27 cases contained at least one amplification of an oncogenic gene or loss of a TSG.	('oncogenic gene', 'Gene', (64, 78))	('amp', 'Chemical', 'MESH:D000249', (44, 47))	('amplification', 'Var', (44, 57))	('TSG', 'Gene', (92, 95))	('loss', 'NegReg', (82, 86))
466048	32570879	Of the cases containing amplification of oncogenic genes (~50% cases), the average was eight oncogenes/case (min 3, max 56).	('amplification', 'Var', (24, 37))	('min 3', 'Gene', '966', (109, 114))	('min 3', 'Gene', (109, 114))	('amp', 'Chemical', 'MESH:D000249', (24, 27))	('oncogenic genes', 'Gene', (41, 56))
466056	32570879	We used the TCGA containing 3149 common and 2120 rare cancers showed amplifications are more prevalent than deletions: rare (2.25-fold) and common cancers (3-fold) (Figure S1A).	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('amplifications', 'Var', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancers', 'Disease', (147, 154))	('amp', 'Chemical', 'MESH:D000249', (69, 72))
466057	32570879	Common cancers have an overall greater number of amplifications (2.8-fold) and deletions (2.2-fold) than rare cancers.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancers', 'Disease', (110, 117))	('amplifications', 'MPA', (49, 63))	('deletions', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('amp', 'Chemical', 'MESH:D000249', (49, 52))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
466058	32570879	When this analysis is limited only to per sample amplifications of oncogenes and deletions of tumor suppressor genes, the same trend is seen (Figure S1B,C).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('deletions', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('amp', 'Chemical', 'MESH:D000249', (43, 46))	('tumor', 'Disease', (94, 99))	('amp', 'Chemical', 'MESH:D000249', (49, 52))
466059	32570879	Whether these differences could be attributed to a specific cancer type, we graphed the total number of amplifications and deletions per sample for all protein coding genes across all of the rare and common cancer types individually (Figure S2A).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('deletions', 'Var', (123, 132))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('amp', 'Chemical', 'MESH:D000249', (104, 107))	('amp', 'Chemical', 'MESH:D000249', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
466060	32570879	To determine the alteration frequencies of pathways known to be involved in cancer, we mapped all variants to genes in 11 canonical signaling pathways.	('canonical signaling pathways', 'Pathway', (122, 150))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('variants', 'Var', (98, 106))
466064	32570879	Interestingly, all 27 cases had germline variants detected in the RTK-RAS pathway key to cell survival (CS) (101 total variants), Hippo (138) and Notch pathways (238), and 24 of 27 cases showed a variant in the WNT pathway (75 total) which, excluding the RTK-RAS pathway, are all largely comprised of TSGs.	('variants', 'Var', (41, 49))	('Hippo', 'Pathway', (130, 135))	('Notch', 'Gene', (146, 151))	('detected', 'Reg', (50, 58))	('WNT pathway', 'Pathway', (211, 222))	('variant', 'Var', (196, 203))	('RTK-RAS pathway', 'Pathway', (66, 81))	('variants', 'Var', (119, 127))	('Notch', 'Gene', '4853', (146, 151))
466065	32570879	When looking at somatic variants, 20 cases had at least one variant in the Notch pathway (36 total), while eight cases had a variant in the WNT pathway (11 total), both CF determinants.	('WNT pathway', 'Pathway', (140, 151))	('variant', 'Var', (60, 67))	('Notch', 'Gene', (75, 80))	('Notch', 'Gene', '4853', (75, 80))
466067	32570879	The number total of cases showing a predicted germline driver mutation was limited to 23, with (n = 5) cases each showing variants in WNT, Notch (n = 4) cases and each in RTK-RAS and TP53 (n = 3) in Hippo.	('variants', 'Var', (122, 130))	('WNT', 'Gene', (134, 137))	('TP53', 'Gene', '7157', (183, 187))	('Notch', 'Gene', '4853', (139, 144))	('TP53', 'Gene', (183, 187))	('RTK-RAS', 'Gene', (171, 178))	('Notch', 'Gene', (139, 144))
466068	32570879	Of the somatic variants, the predicted drivers clustered around the Notch and p53 pathways with four and five respectively, with one case showing a double hit in TP53.	('Notch', 'Gene', (68, 73))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('p53', 'Gene', (78, 81))	('Notch', 'Gene', '4853', (68, 73))	('variants', 'Var', (15, 23))	('p53', 'Gene', '7157', (78, 81))
466070	32570879	The most severe of these likely to have a functional effect was found in the anaplastic astrocytoma case, which saw both a driver mutation (rs149840192, p.A289V) and an amplification of at least five extra copies of the EGFR.	('rs149840192', 'Var', (140, 151))	('amp', 'Chemical', 'MESH:D000249', (169, 172))	('p.A289V', 'Mutation', 'rs149840192', (153, 160))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (77, 99))	('EGFR', 'Gene', (220, 224))	('p.A289V', 'Var', (153, 160))	('anaplastic astrocytoma', 'Disease', (77, 99))	('rs149840192', 'Mutation', 'rs149840192', (140, 151))	('EGFR', 'Gene', '1956', (220, 224))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))	('amplification', 'MPA', (169, 182))
466071	32570879	This was of particular interest as both amplifications and mutations in EGFR have been shown to be drivers in many cancer types and may confer efficacy of treatment with tyrosine kinase inhibitors.	('cancer', 'Disease', (115, 121))	('amp', 'Chemical', 'MESH:D000249', (40, 43))	('EGFR', 'Gene', '1956', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('EGFR', 'Gene', (72, 76))	('mutations', 'Var', (59, 68))	('drivers', 'Reg', (99, 106))	('efficacy', 'PosReg', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('confer', 'Reg', (136, 142))	('amplifications', 'Var', (40, 54))
466072	32570879	With respect to TSG double hits we identified only one case, metastatic chondrosarcoma, that contained both a driver mutation and a CNA.	('chondrosarcoma', 'Disease', 'MESH:D002813', (72, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('chondrosarcoma', 'Disease', (72, 86))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (72, 86))	('mutation', 'Var', (117, 125))
466075	32570879	Tumor-only NGS fails to provide a complete picture since germline sequencing is absent which can generate false positive biomarkers, that may lead to targeting of a variant unrelated to cancer development and/or not be present on the panel.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('variant', 'Var', (165, 172))	('lead to', 'Reg', (142, 149))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
466080	32570879	For example, in a patient with glioblastoma, tumor-normal match pair WES identified a germline variant RUNX1-M151L deemed likely pathogenic (ACMG guidelines) but not reported with tumor-only NGS (Caris Life Sciences) as it was not included in their panel.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('RUNX1', 'Gene', '861', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('variant', 'Var', (95, 102))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (180, 185))	('glioblastoma', 'Disease', (31, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('patient', 'Species', '9606', (18, 25))	('pathogenic', 'Reg', (129, 139))	('amp', 'Chemical', 'MESH:D000249', (6, 9))	('M151L', 'Mutation', 'p.M151L', (109, 114))	('RUNX1', 'Gene', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
466082	32570879	Over-expression of RUNX1 in U87 GBM cells inhibited tumor growth by extensive down-regulation of target genes and deregulation of key developmental pathways.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('U87', 'Gene', '641648', (28, 31))	('RUNX1', 'Gene', (19, 24))	('tumor', 'Disease', (52, 57))	('RUNX1', 'Gene', '861', (19, 24))	('inhibited', 'NegReg', (42, 51))	('down-regulation', 'NegReg', (78, 93))	('deregulation', 'Reg', (114, 126))	('key developmental pathways', 'Pathway', (130, 156))	('Over-expression', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('U87', 'Gene', (28, 31))
466086	32570879	We identified IDH1 and PIK3CA gene variants which occurred at the same site.	('PIK3CA', 'Gene', (23, 29))	('variants', 'Var', (35, 43))	('PIK3CA', 'Gene', '5290', (23, 29))	('IDH1', 'Gene', (14, 18))	('IDH1', 'Gene', '3417', (14, 18))
466087	32570879	The IDH1 variant occurred at amino acid 132 in the IDH1 gene in two sarcoma cases; chondrosarcoma R132C and pleiomorphic sarcoma R132G substitution respectively.	('IDH1', 'Gene', '3417', (51, 55))	('IDH1', 'Gene', '3417', (4, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('occurred', 'Reg', (17, 25))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('sarcoma', 'Disease', (68, 75))	('R132G', 'Mutation', 'rs121913499', (129, 134))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))	('R132G substitution', 'Var', (129, 147))	('chondrosarcoma', 'Disease', (83, 97))	('sarcoma', 'Disease', (90, 97))	('chondrosarcoma', 'Disease', 'MESH:D002813', (83, 97))	('IDH1', 'Gene', (4, 8))	('IDH1', 'Gene', (51, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('R132C', 'Mutation', 'rs121913499', (98, 103))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))	('pleiomorphic sarcoma', 'Disease', 'MESH:D012509', (108, 128))	('pleiomorphic sarcoma', 'Disease', (108, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('sarcoma', 'Disease', (121, 128))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (83, 97))
466088	32570879	The pleomorphic sarcoma with a concurrent IDH1 R132G mutation and a SUFU splice site mutation may indicate that the Hedgehog (Hh) pathway is operant in these cells independent of SHH ligand expression since SUFU is a negative regulator of Hh signaling.	('R132G', 'Mutation', 'rs121913499', (47, 52))	('SHH', 'Gene', (179, 182))	('IDH1', 'Gene', '3417', (42, 46))	('pleomorphic sarcoma', 'Disease', (4, 23))	('R132G', 'Var', (47, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('SHH', 'Gene', '6469', (179, 182))	('SUFU', 'Gene', (207, 211))	('IDH1', 'Gene', (42, 46))	('SUFU', 'Gene', '51684', (207, 211))	('SUFU', 'Gene', (68, 72))	('pleomorphic sarcoma', 'Disease', 'MESH:D012509', (4, 23))	('SUFU', 'Gene', '51684', (68, 72))
466089	32570879	Further, a frameshift mutation in SUFU was found in our metastatic mucoepidermoid sarcoma patient indicative of active Hh signaling amenable for therapeutic intervention.	('frameshift mutation', 'Var', (11, 30))	('SUFU', 'Gene', (34, 38))	('SUFU', 'Gene', '51684', (34, 38))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('patient', 'Species', '9606', (90, 97))	('sarcoma', 'Disease', (82, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
466090	32570879	The mutant IDH1 makes it a highly promising candidate for the IDH1 small molecule inhibitor ivosidenib approved for AML.	('mutant', 'Var', (4, 10))	('IDH1', 'Gene', '3417', (11, 15))	('IDH1', 'Gene', '3417', (62, 66))	('AML', 'Disease', 'MESH:D015470', (116, 119))	('ivosidenib', 'Chemical', 'MESH:C000627630', (92, 102))	('IDH1', 'Gene', (62, 66))	('AML', 'Disease', (116, 119))	('IDH1', 'Gene', (11, 15))
466091	32570879	The PIK3CA variant occurred at amino acid E542K in two rare salivary gland tumors, myoepithelioma and mucoepidermoid tumor.	('mucoepidermoid tumor', 'Disease', 'MESH:D018298', (102, 122))	('myoepithelioma', 'Disease', (83, 97))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('E542K', 'Mutation', 'rs121913273', (42, 47))	('PIK3CA', 'Gene', (4, 10))	('occurred', 'Reg', (19, 27))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (60, 81))	('myoepithelioma', 'Disease', 'MESH:D009208', (83, 97))	('amino acid E542K', 'Var', (31, 47))	('PIK3CA', 'Gene', '5290', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mucoepidermoid tumor', 'Disease', (102, 122))	('tumors', 'Disease', (75, 81))
466092	32570879	A concurrent HRAS mutation identified in salivary mucoepidermoid tumor patient will most likely not respond to a PI3KCA inhibitor, however, the myoepithelioma patient could benefit from off-label therapy.	('HRAS', 'Gene', (13, 17))	('myoepithelioma', 'Disease', 'MESH:D009208', (144, 158))	('mucoepidermoid tumor', 'Disease', (50, 70))	('mutation', 'Var', (18, 26))	('mucoepidermoid tumor', 'Disease', 'MESH:D018298', (50, 70))	('patient', 'Species', '9606', (159, 166))	('HRAS', 'Gene', '3265', (13, 17))	('myoepithelioma', 'Disease', (144, 158))	('patient', 'Species', '9606', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
466094	32570879	TP53 is the most common gene to carry pathogenic variants in common cancers with an average of 44.4%.	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (0, 4))	('variants', 'Var', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('pathogenic', 'Reg', (38, 48))
466097	32570879	Both ARID1A and CDKN2A mutations are context dependent tumor suppressor genes that may be targetable in a synthetic lethal pair such as with a EGLN (prolyl hydroxylase) inhibitor (targeting HIF1alpha) or MTAP deletions with a PRMT5 (arginine N-methyltransferase 5) inhibitor dependent tumors respectively.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ARID1A', 'Gene', (5, 11))	('PRMT5', 'Gene', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('ARID1A', 'Gene', '8289', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('deletions', 'Var', (209, 218))	('tumors', 'Disease', (285, 291))	('mutations', 'Var', (23, 32))	('HIF1alpha', 'Gene', '3091', (190, 199))	('CDKN2A', 'Gene', (16, 22))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('PRMT5', 'Gene', '10419', (226, 231))	('HIF1alpha', 'Gene', (190, 199))	('MTAP', 'Gene', (204, 208))	('CDKN2A', 'Gene', '1029', (16, 22))	('tumor', 'Disease', (285, 290))	('tumor', 'Disease', (55, 60))	('MTAP', 'Gene', '4507', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
466100	32570879	FOXL2 mutations was found in Granulosa cell ovarian cancer case, ~5% of ovarian cancer, which functions as a DNA binding forkhead transcription factor required for granulosa cell differentiation.	('Granulosa cell ovarian cancer', 'Disease', 'MESH:D006106', (29, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (44, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))	('FOXL2', 'Gene', '668', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('Granulosa cell ovarian cancer', 'Disease', (29, 58))	('found', 'Reg', (20, 25))	('FOXL2', 'Gene', (0, 5))	('ovarian cancer', 'Disease', (72, 86))	('mutations', 'Var', (6, 15))
466101	32570879	The Cys134Trp mutation in FOXL2 is associated increased cell cycling and downregulation of genes associated with apoptosis.	('cell cycling', 'CPA', (56, 68))	('FOXL2', 'Gene', '668', (26, 31))	('Cys134Trp', 'Chemical', '-', (4, 13))	('increased', 'PosReg', (46, 55))	('Cys134Trp', 'Var', (4, 13))	('FOXL2', 'Gene', (26, 31))	('downregulation', 'NegReg', (73, 87))
466102	32570879	The tumor suppressor-oncogene pair TNFAIP3 and CHD1L both have a frameshift deletion respectively is found in our gray zone lymphoma patient.	('CHD1L', 'Gene', (47, 52))	('tumor', 'Disease', (4, 9))	('frameshift deletion', 'Var', (65, 84))	('TNFAIP3', 'Gene', '7128', (35, 42))	('CHD1L', 'Gene', '9557', (47, 52))	('TNFAIP3', 'Gene', (35, 42))	('patient', 'Species', '9606', (133, 140))	('lymphoma', 'Disease', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('lymphoma', 'Disease', 'MESH:D008223', (124, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))
466107	32570879	Oncogenic KIT mutations (e.g., non-frameshift deletions) are well established in GIST.	('non-frameshift deletions', 'Var', (31, 55))	('KIT', 'Gene', '3815', (10, 13))	('KIT', 'Gene', (10, 13))
466108	32570879	We are the first to document a concurrent loss of CTCF and a KIT activating mutation in GIST, however, in SDH-deficient GIST, CTCF may be epigenetically silenced.	('CTCF', 'Gene', (126, 130))	('CTCF', 'Gene', '10664', (50, 54))	('mutation', 'Var', (76, 84))	('KIT', 'Gene', '3815', (61, 64))	('GIST', 'Gene', (88, 92))	('CTCF', 'Gene', '10664', (126, 130))	('CTCF', 'Gene', (50, 54))	('SDH-deficient GIST', 'Disease', 'MESH:D046152', (106, 124))	('KIT', 'Gene', (61, 64))	('SDH-deficient GIST', 'Disease', (106, 124))	('loss', 'NegReg', (42, 46))
466109	32570879	Copy number alterations (CNAs) play a role in cancer type (e.g., breast, colorectal), tumor progression, overall prognosis, and response to therapy.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('tumor', 'Disease', (86, 91))	('breast', 'Disease', (65, 71))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
466111	32570879	Deletion frequencies were generally lower in the rare tumor cohort with the exception of sarcomas, which showed a number of per-sample deletions (133/case) that was higher than any other rare tumor types and higher than all common cancers save prostate (180/case) (Figure S1B,C).	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('sarcomas', 'Disease', (89, 97))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('amp', 'Chemical', 'MESH:D000249', (129, 132))	('cancers', 'Disease', (231, 238))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('prostate', 'Disease', (244, 252))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Disease', (54, 59))	('deletions', 'Var', (135, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
466114	32570879	Further, sarcomas showed an increased frequency of deletions of tumor suppressor genes (Figure S2C).	('tumor', 'Disease', (64, 69))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('deletions', 'Var', (51, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('sarcomas', 'Disease', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
466119	32570879	This limitation did not allow us to assess many important questions concerning the overall stability of some genomic regions compared to others in rare cancer, any impacts of epigenetic regulation, etc.	('cancer', 'Disease', (152, 158))	('epigenetic regulation', 'Var', (175, 196))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
466133	32570879	For MuTect2 results, variants were filtered based on the MuTect2-assigned filter flag, quality score, and read depth (FILTER = PASS, QUAL > 20 and DP > 20).	('DP > 20', 'Var', (147, 154))	('MuTect2-assigned', 'Gene', (57, 73))	('DP', 'Chemical', 'MESH:D004176', (147, 149))
466137	32570879	Using vcftools, the remaining variants were restricted to either known oncosignaling genes for pathway analysis or known oncogenes and tumor suppressor genes for the double hit analysis.	('variants', 'Var', (30, 38))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
466138	32570879	Mutations in these gene sets were assessed for driver status using the Cancer Genome Interpreter (CGI).	('Cancer', 'Disease', (71, 77))	('Mutations', 'Var', (0, 9))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
466139	32570879	Heat maps showing the frequency of amplifications/deletions in 2.5 Mbp windows along the chromosomes were generated using the R package chromoMap v0.2.	('Mbp', 'Gene', (67, 70))	('amp', 'Chemical', 'MESH:D000249', (35, 38))	('Mbp', 'Gene', '4155', (67, 70))	('amplifications/deletions', 'Var', (35, 59))
466148	32570879	The following are available online at , Figure S1: CNA gene counts from TCGA rare and common cancer cohorts; Figure S2: CNA gene counts from TCGA rare and common cancer cohorts, broken down by cancer type; Table S1: 1670 were found in oncogenes and 1673 were in tumor suppressor genes, generating an average of 124 germline variants per case; Table S2: The number of somatic SNVs and small indels detected in all cases totaled 523, with 306 in oncogenes and 217 in tumor suppressor genes; Table S3: Classification of oncogenic genes (OG) and tumor suppressor genes (TSG) was defined by the Oncogene; Table S4: Total number of amplified oncogenes and deletions of tumor suppressor genes in the cohort rare cancer cases; Table S5: Drivers genes with additional copy number variation:Double Hits; Table S6: GO Enrichment analysis.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (663, 668))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (465, 470))	('broken down', 'Phenotype', 'HP:0001061', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('broken', 'Disease', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (663, 668))	('broken', 'Disease', 'MESH:D050723', (178, 184))	('tumor', 'Disease', (542, 547))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (542, 547))	('tumor', 'Phenotype', 'HP:0002664', (465, 470))	('cancer', 'Disease', (705, 711))	('tumor', 'Phenotype', 'HP:0002664', (663, 668))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Disease', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (705, 711))	('tumor', 'Phenotype', 'HP:0002664', (542, 547))	('deletions', 'Var', (650, 659))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('amp', 'Chemical', 'MESH:D000249', (626, 629))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (465, 470))	('cancer', 'Disease', 'MESH:D009369', (705, 711))
466231	31829526	Data on BRAF/MEK inhibitors are limited by the fact that fewer vulvar melanomas carry a BRAF mutation, but in those with a BRAF V600 mutation this provides a good option 52, 67.	('MEK', 'Gene', '5609', (13, 16))	('BRAF', 'Gene', '673', (8, 12))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('BRAF', 'Gene', (8, 12))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('BRAF', 'Gene', (123, 127))	('V600 mutation', 'Var', (128, 141))	('BRAF', 'Gene', '673', (123, 127))	('vulvar melanomas', 'Phenotype', 'HP:0030418', (63, 79))	('vulvar melanomas', 'Disease', 'MESH:D008545', (63, 79))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (63, 78))	('vulvar melanomas', 'Disease', (63, 79))	('mutation', 'Var', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('MEK', 'Gene', (13, 16))
466232	31829526	Due to the relatively high number of KIT mutations in vulvovaginal melanoma, tyrosine kinase inhibitors may be a treatment option in the future.	('mutations', 'Var', (41, 50))	('KIT', 'Gene', '3815', (37, 40))	('vulvovaginal melanoma', 'Disease', 'MESH:D014848', (54, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('tyrosine', 'Chemical', 'None', (77, 85))	('vulvovaginal melanoma', 'Phenotype', 'HP:0030418', (54, 75))	('KIT', 'Gene', (37, 40))	('vulvovaginal melanoma', 'Disease', (54, 75))
466327	31903155	In a subset of patients (6/27, 22%), a high number of mutations of unknown significance suggestive of a high tumor mutational burden (TMB) were detected.	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
466328	31903155	Conclusions: NGS from cerebrospinal fluid is feasible in routine clinical practice and yields therapeutically relevant alterations in a large subset of patients.	('NGS', 'Var', (13, 16))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('alterations', 'Reg', (119, 130))	('yields', 'Reg', (87, 93))	('patients', 'Species', '9606', (152, 160))
466333	31903155	Precision medicine and the use of targeted therapies, which are tailored to match individual tumor-driving mutations, have led to relevant changes of standard clinical care in patients with systemic cancer and have significantly improved outcomes for patients with different types of cancer such as melanoma and lung carcinoma.	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('patients', 'Species', '9606', (251, 259))	('cancer', 'Disease', (199, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('improved', 'PosReg', (229, 237))	('melanoma', 'Phenotype', 'HP:0002861', (299, 307))	('melanoma and lung carcinoma', 'Disease', 'MESH:D008545', (299, 326))	('systemic cancer', 'Disease', (190, 205))	('cancer', 'Disease', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('patients', 'Species', '9606', (176, 184))	('changes', 'Reg', (139, 146))	('mutations', 'Var', (107, 116))	('tumor', 'Disease', (93, 98))	('systemic cancer', 'Disease', 'MESH:D009369', (190, 205))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
466343	31903155	"Liquid biopsy" or the mutational analysis of ctTNA in accessible body fluids by targeted next generation sequencing (NGS) is commonly applied in patients with systemic cancer and the resulting comprehensive genomic information can give patients access to targeted therapies.	('ctTNA', 'Gene', (46, 51))	('systemic cancer', 'Disease', (160, 175))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('mutational', 'Var', (23, 33))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('systemic cancer', 'Disease', 'MESH:D009369', (160, 175))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('patients', 'Species', '9606', (237, 245))
466353	31903155	Therefore, an amplicon-based NGS assay was applied that targets not only point mutations and deletions but also therapeutically relevant amplifications and gene fusions to facilitate access to targeted therapies within the framework of an interdisciplinary molecular tumor board.	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('deletions', 'Var', (93, 102))	('point mutations', 'Var', (73, 88))	('interdisciplinary molecular tumor board', 'Disease', 'MESH:D009369', (239, 278))	('interdisciplinary molecular tumor board', 'Disease', (239, 278))	('N', 'Chemical', 'MESH:D009584', (29, 30))
466360	31903155	Briefly, the OncomineTM Focus Assay (OFA) is a multi-biomarker NGS system that enables the detection of variants in 52 key solid tumor genes (see Supplementary Table 1).	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('variants', 'Var', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('tumor', 'Disease', (129, 134))
466362	31903155	The OFA allows concurrent analysis of DNA and RNA to simultaneously detect single nucleotide variants (SNVs) and insertions/deletions (indels) in mutation hotspots as well as copy number variations (CNVs) and gene fusions.	('N', 'Chemical', 'MESH:D009584', (47, 48))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('N', 'Chemical', 'MESH:D009584', (200, 201))	('copy number variations', 'Var', (175, 197))	('single nucleotide variants', 'Var', (75, 101))	('N', 'Chemical', 'MESH:D009584', (104, 105))	('insertions/deletions', 'Var', (113, 133))
466367	31903155	Data analysis was performed with the dedicated software provided by the manufacturer, the Integrated Genomics Viewer (IGV, Broad Institute), and a proprietary database calling tool for the identification of single nucleotide polymorphisms (SNPs) and the tumor genetic evaluation of the identified alterations (Supplementary Fig.	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('single nucleotide polymorphisms', 'Var', (207, 238))	('N', 'Chemical', 'MESH:D009584', (241, 242))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
466373	31903155	The Archer Sarcoma kit is a targeted sequencing assay to simultaneously detect and identify fusions of 26 genes associated with soft tissue cancers (Supplementary Table 1).	('soft tissue cancers', 'Disease', (128, 147))	('fusions', 'Var', (92, 99))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('soft tissue cancers', 'Disease', 'MESH:D009369', (128, 147))	('Sarcoma', 'Disease', (11, 18))	('Sarcoma', 'Disease', 'MESH:D012509', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('associated', 'Reg', (112, 122))	('Sarcoma', 'Phenotype', 'HP:0100242', (11, 18))
466376	31903155	CSF of three lung cancer patients (#1, #4 and #27) whose cancer progressed under tyrosine kinase inhibitor (TKI) treatment were analyzed for TKI resistance mutations in the EGFR gene (T790M mutation).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('cancer', 'Disease', (57, 63))	('tyrosine', 'Chemical', 'None', (81, 89))	('EGFR', 'Gene', '1956', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('T790M mutation', 'Var', (184, 198))	('EGFR', 'Gene', (173, 177))	('T790M', 'Mutation', 'rs121434569', (184, 189))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
466392	31903155	cfDNA was used for the analysis of point mutations, insertions/deletions, and copy number variations.	('point mutations', 'Var', (35, 50))	('insertions/deletions', 'Var', (52, 72))	('N', 'Chemical', 'MESH:D009584', (3, 4))
466397	31903155	Among patients with somatic alterations, we observed a median number of 3 (range 1-47) mutations in the Oncomine panel.	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (87, 96))	('Oncomine panel', 'Gene', (104, 118))	('alterations', 'Var', (28, 39))
466402	31903155	In 4/27 patients (#22, #24, #25, #27) no targeted therapy was recommended although an actionable mutation was discovered: In one patient, several mutations were identified in overlapping pathways, potentially indicating resistance to respective targeted approaches (#22).	('mutations', 'Var', (146, 155))	('patients', 'Species', '9606', (8, 16))	('patient', 'Species', '9606', (8, 15))	('indicating', 'Reg', (209, 219))	('identified', 'Reg', (161, 171))	('patient', 'Species', '9606', (129, 136))
466406	31903155	NGS from CSF revealed the previously detected primary EGFR-mutation; however, neither the targetable T790M resistance mutation nor another relevant actionable mutation was detected.	('T790M', 'Var', (101, 106))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))	('T790M', 'Mutation', 'rs121434569', (101, 106))
466414	31903155	Lumbar puncture and MRI of brain and spine revealed LM and targeted NGS sequencing from the CSF identified an activating EGFR mutation (Exon 21) (see also #1, Table 4), which was later confirmed in the primary tumor biopsy by PCR as well.	('EGFR', 'Gene', '1956', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('mutation', 'Var', (126, 134))	('EGFR', 'Gene', (121, 125))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('activating', 'PosReg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
466419	31903155	Similarly, in a 58-year-old female patient (#4, Table 4) with newly diagnosed NSCLC (adenocarcinoma, UICC stage IV, cT2b, cN0, cM1c) with pulmonary, bone, brain, and leptomeningeal metastasis, systemic chemotherapy was switched to in-label afatinib in addition to intrathecal methotrexate injections after activating EGFR mutations (Exon 18, p.G719C; exon 20, p.S768I) were diagnosed by liquid CSF biopsy.	('adenocarcinoma', 'Disease', (85, 99))	('p.S768I', 'Mutation', 'rs121913465', (360, 367))	('p.G719C', 'Mutation', 'rs28929495', (342, 349))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('EGFR', 'Gene', '1956', (317, 321))	('p.S768I', 'Var', (360, 367))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('activating', 'PosReg', (306, 316))	('Exon 18', 'Var', (333, 340))	('EGFR', 'Gene', (317, 321))	('afatinib', 'Chemical', 'MESH:C522924', (240, 248))	('methotrexate', 'Chemical', 'MESH:D008727', (276, 288))	('patient', 'Species', '9606', (35, 42))	('NSCLC', 'Disease', (78, 83))	('p.G719C', 'Var', (342, 349))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
466420	31903155	Further analysis revealed that the activating EGFR mutations were confirmed in the bone metastasis.	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', '1956', (46, 50))	('activating', 'PosReg', (35, 45))	('bone metastasis', 'CPA', (83, 98))	('EGFR', 'Gene', (46, 50))
466421	31903155	However, the primary tumor did not contain EGFR exon 18 and 20 mutations but an activating EGFR exon 19 mutation (p.P753Q) which was observed in neither the CSF liquid biopsy nor in the bone metastasis.	('EGFR', 'Gene', (91, 95))	('tumor', 'Disease', (21, 26))	('EGFR', 'Gene', '1956', (43, 47))	('p.P753Q', 'Var', (114, 121))	('activating', 'PosReg', (80, 90))	('p.P753Q', 'Mutation', 'p.P753Q', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('EGFR', 'Gene', '1956', (91, 95))	('EGFR', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
466425	31903155	NGS from CSF revealed an EZR/ROS1 fusion as well as an MTOR mutation.	('mutation', 'Var', (60, 68))	('ROS1', 'Gene', '6098', (29, 33))	('MTOR', 'Gene', '2475', (55, 59))	('fusion', 'Var', (34, 40))	('EZR', 'Gene', '7430', (25, 28))	('MTOR', 'Gene', (55, 59))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('ROS1', 'Gene', (29, 33))	('EZR', 'Gene', (25, 28))
466430	31903155	Dysregulation of FGFR signaling can lead to downstream activation of mitogen activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K)/AKT pathways and it has been shown, that patients with FGFR amplifications profit from PIK3CA/AKT directed therapy with everolimus.	('patients', 'Species', '9606', (187, 195))	('FGFR', 'Gene', (17, 21))	('AKT', 'Gene', '207', (146, 149))	('PIK3CA', 'Gene', (233, 239))	('phosphoinositide-3-kinase', 'Gene', (113, 138))	('Dysregulation', 'Var', (0, 13))	('amplifications', 'Var', (206, 220))	('AKT', 'Gene', (240, 243))	('MAPK', 'Gene', '5594', (103, 107))	('everolimus', 'Chemical', 'MESH:C107135', (266, 276))	('MAPK', 'Gene', (103, 107))	('AKT', 'Gene', (146, 149))	('phosphoinositide-3-kinase', 'Gene', '5290', (113, 138))	('PIK3CA', 'Gene', '5290', (233, 239))	('FGFR', 'Gene', (201, 205))	('profit', 'PosReg', (221, 227))	('AKT', 'Gene', '207', (240, 243))	('activation', 'PosReg', (55, 65))
466431	31903155	Furthermore, FGFR amplification may confer resistance to CDK4/6 inhibitors.	('FGFR', 'Gene', (13, 17))	('CDK4/6', 'Gene', (57, 63))	('confer', 'Reg', (36, 42))	('resistance to', 'MPA', (43, 56))	('amplification', 'Var', (18, 31))	('CDK4/6', 'Gene', '1019;1021', (57, 63))
466437	31903155	NGS from CSF detected a targetable BRAF mutation (p.V600E) as well as an activating ERBB2-mutation (#3, Table 4).	('ERBB2', 'Gene', (84, 89))	('BRAF', 'Gene', (35, 39))	('p.V600E', 'Mutation', 'rs113488022', (50, 57))	('p.V600E', 'Var', (50, 57))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('activating', 'PosReg', (73, 83))	('ERBB2', 'Gene', '2064', (84, 89))	('BRAF', 'Gene', '673', (35, 39))
466439	31903155	In view of the additional ERBB2 mutation, which affects the RAS/RAF/MEK/ERK pathway, the tumor board recommended an off-label therapy with combined BRAF- and MEK-inhibition together with the intrathecal application of methotrexate.	('MEK', 'Gene', (158, 161))	('ERBB2', 'Gene', (26, 31))	('RAF', 'Gene', '22882', (64, 67))	('RAF', 'Gene', '22882', (149, 152))	('MEK', 'Gene', '5609', (68, 71))	('ERBB2', 'Gene', '2064', (26, 31))	('RAF', 'Gene', (64, 67))	('BRAF', 'Gene', '673', (148, 152))	('mutation', 'Var', (32, 40))	('ERK', 'Gene', '5594', (72, 75))	('tumor', 'Disease', (89, 94))	('MEK', 'Gene', (68, 71))	('BRAF', 'Gene', (148, 152))	('RAF', 'Gene', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('methotrexate', 'Chemical', 'MESH:D008727', (218, 230))	('MEK', 'Gene', '5609', (158, 161))	('ERK', 'Gene', (72, 75))	('affects', 'Reg', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
466448	31903155	CSF cytology was negative for atypical cells, but a PIK3CA mutation was found in the NGS analysis.	('found', 'Reg', (72, 77))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('PIK3CA', 'Gene', (52, 58))	('mutation', 'Var', (59, 67))	('PIK3CA', 'Gene', '5290', (52, 58))
466455	31903155	This increased number of mutations in comparison to other cases suggests a high tumor mutational burden (TMB high) which has been associated in recent studies with response to immune checkpoint inhibition in various cancers.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
466475	31903155	In one breast cancer patient with radiologically and clinically suspected LM, cfDNA showed a targetable PIK3CA mutation.	('one breast', 'Phenotype', 'HP:0012813', (3, 13))	('patient', 'Species', '9606', (21, 28))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('breast cancer', 'Disease', (7, 20))	('PIK3CA', 'Gene', (104, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('mutation', 'Var', (111, 119))	('PIK3CA', 'Gene', '5290', (104, 110))
466480	31903155	These high numbers of mutations point to an increased tumor mutational burden (TMB).	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (22, 31))	('increased', 'PosReg', (44, 53))	('tumor', 'Disease', (54, 59))
466484	31903155	A high TMB (defined according to various cut-offs ranging from >=10 to >=20 mutations per Mb) might increase the number of distinct neoepitopes presented on the surface of tumor cells and hence lead to greater tumor immunogenicity.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('greater', 'PosReg', (202, 209))	('lead to', 'Reg', (194, 201))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('increase', 'PosReg', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
466489	31903155	Cancer cells continuously acquire new mutations due to genomic instability and/or selective pressure from the tissue microenvironment and clinical treatment.	('acquire', 'Reg', (26, 33))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (38, 47))
466490	31903155	Recent data indicate that CNS manifestations of systemic cancer often carry genetic alterations that can differ from those observed in primary tumors and systemic metastasis.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('genetic alterations', 'Var', (76, 95))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('primary tumors', 'Disease', (135, 149))	('systemic cancer', 'Disease', 'MESH:D009369', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('primary tumors', 'Disease', 'MESH:D001932', (135, 149))	('systemic cancer', 'Disease', (48, 63))
466491	31903155	In this respect, CNS metastases seem to harbor more clinically actionable mutations than the primary tumor and might thus better respond to targeted therapies.	('metastases', 'Disease', 'MESH:D009362', (21, 31))	('metastases', 'Disease', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', (101, 106))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('CNS', 'Disease', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
466501	31903155	In conclusion, our study highlights that the collection and genomic profiling of CSF using a commercially available, amplicon-based NGS approach is technically feasible and identifies targetable genetic alterations in a substantial subset of patients.	('CSF', 'Disease', (81, 84))	('N', 'Chemical', 'MESH:D009584', (132, 133))	('patients', 'Species', '9606', (242, 250))	('genetic alterations', 'Var', (195, 214))
466520	29581706	Some sarcoma subtypes are associated with known genetic factors, such as the translocation involving chromosomes X and 18 specific to synovial sarcoma, or the common t(11;22)(q24;q12) translocation present in the majority of Ewing's sarcoma cases.	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('synovial sarcoma', 'Disease', (134, 150))	('sarcoma subtype', 'Disease', (5, 20))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (225, 240))	("Ewing's sarcoma", 'Disease', (225, 240))	('t(11;22)(q24;q12', 'Var', (166, 182))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (166, 183))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (134, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (225, 240))	('sarcoma subtype', 'Disease', 'MESH:D012509', (5, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('associated', 'Reg', (26, 36))	('translocation', 'Var', (77, 90))	('synovial sarcoma', 'Disease', 'MESH:D013584', (134, 150))
466521	29581706	Sarcomas may be associated with diseases such as p53 mutations, basal cell nevus syndrome, Werner's syndrome, tuberous sclerosis, neurofibromatosis, Gardner's syndrome, and Li-Fraumeni syndrome.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('p53', 'Gene', '7157', (49, 52))	('neurofibromatosis', 'Disease', (130, 147))	('tuberous sclerosis', 'Disease', (110, 128))	('Li-Fraumeni syndrome', 'Disease', (173, 193))	('associated', 'Reg', (16, 26))	('basal cell nevus syndrome', 'Disease', (64, 89))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (173, 193))	('p53', 'Gene', (49, 52))	("Werner's syndrome", 'Disease', 'MESH:D014898', (91, 108))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('mutations', 'Var', (53, 62))	("Werner's syndrome", 'Disease', (91, 108))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (130, 147))	('basal cell nevus syndrome', 'Disease', 'MESH:D001478', (64, 89))	("Gardner's syndrome", 'Disease', 'MESH:D005736', (149, 167))	('Sarcomas', 'Disease', (0, 8))	("Gardner's syndrome", 'Disease', (149, 167))	('nevus', 'Phenotype', 'HP:0003764', (75, 80))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (110, 128))	('neurofibromatosis', 'Disease', 'MESH:C537392', (130, 147))	('basal cell nevus', 'Phenotype', 'HP:0002671', (64, 80))
466580	29581706	noted significantly lower 60-month survival for patients with distant metastasis but not for patients with regional lymph node metastasis, similar to the findings in the present study.	('lower', 'NegReg', (20, 25))	('60-month survival', 'MPA', (26, 43))	('distant metastasis', 'Var', (62, 80))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (93, 101))
466611	28377484	A partial response occurred in 2 (8%) of the evaluable patients (95% CI 1.0-26.0%), one with PIK3CA E542K mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (170, 177))	('PIK3CA', 'Gene', '5290', (93, 99))	('sarcoma', 'Disease', (132, 139))	('E542K', 'Mutation', 'rs121913273', (100, 105))	('sarcoma', 'Disease', (170, 177))	('patients', 'Species', '9606', (55, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (113, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('embryonal rhabdomyosarcoma', 'Disease', (113, 139))	('E542K mutant', 'Var', (100, 112))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (113, 139))	('PIK3CA', 'Gene', (93, 99))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (123, 139))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
466649	28377484	We analyzed next generation sequencing data from the Cancer Genome Atlas (TCGA) and six other sarcoma studies, and figures were generated to show copy number alterations and mutations in selected genes in these sarcoma projects.	('Cancer Genome Atlas', 'Disease', (53, 72))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (53, 72))	('sarcoma', 'Disease', (94, 101))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcoma', 'Disease', (211, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('mutations', 'Var', (174, 183))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))
466672	28377484	Next-generation sequencing analysis of the patient revealed PIK3CA E542K aberration.	('PIK3CA', 'Gene', (60, 66))	('patient', 'Species', '9606', (43, 50))	('PIK3CA', 'Gene', '5290', (60, 66))	('E542K', 'Var', (67, 72))	('E542K', 'Mutation', 'rs121913273', (67, 72))
466681	28377484	Mutations and copy number alterations from seven sarcoma studies are depicted in Figure 4.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('copy number alterations', 'Var', (14, 37))	('sarcoma', 'Disease', (49, 56))
466687	28377484	In-depth analysis of one of the exceptional responders revealed a PIK3CA E542K aberration in a patient with sinonasal rhabdomyosarcoma.	('E542K', 'Var', (73, 78))	('patient', 'Species', '9606', (95, 102))	('PIK3CA', 'Gene', (66, 72))	('E542K', 'Mutation', 'rs121913273', (73, 78))	('sinonasal rhabdomyosarcoma', 'Disease', 'MESH:D012208', (108, 134))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (118, 134))	('PIK3CA', 'Gene', '5290', (66, 72))	('sinonasal rhabdomyosarcoma', 'Disease', (108, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
466693	28377484	Interestingly, it has also been shown that pazopanib suppresses the PI3K pathway in rhabdomyosarcomas.	('suppresses', 'NegReg', (53, 63))	('pazopanib', 'Var', (43, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('PI3K pathway', 'Pathway', (68, 80))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (84, 101))	('rhabdomyosarcomas', 'Disease', (84, 101))	('pazopanib', 'Chemical', 'MESH:C516667', (43, 52))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (84, 100))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (84, 101))
466717	28377484	Several trials with pazopanib combinations are ongoing, including pazopanib + vorinostat (HDAC inhibitor; NCT01339871), pazopanib + everolimus (mTOR inhibitor; NCT01430572), pazopanib + lapatinib or trastuzumab (Her2 inhibitors; NCT01454804), pazopanib + gemcitabine (NCT01532687), pazopanib + pemetrexed or crizotinib (NCT01548144), and pazopanib + topotecan (NCT02357810).	('NCT01532687', 'Var', (268, 279))	('pazopanib', 'Chemical', 'MESH:C516667', (243, 252))	('pazopanib', 'Chemical', 'MESH:C516667', (20, 29))	('pazopanib', 'Chemical', 'MESH:C516667', (174, 183))	('pazopanib', 'Chemical', 'MESH:C516667', (282, 291))	('pazopanib', 'Chemical', 'MESH:C516667', (66, 75))	('pazopanib', 'Chemical', 'MESH:C516667', (338, 347))	('NCT01548144', 'Var', (320, 331))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))	('pazopanib', 'Chemical', 'MESH:C516667', (120, 129))
466765	27856382	Site-specific codes were first used to identify all primary tumors that originated in the osseous spine: C41.2 (vertebral column) and C41.4 (pelvic bones, sacrum, coccyx, and associated joints).	('coccyx', 'Disease', (163, 169))	('C41.2', 'Var', (105, 110))	('C41.4', 'Var', (134, 139))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
466815	27856382	It should be noted that among tumor histologies of OGS, we found that OGS in the context of Paget's disease portended a relatively dismal prognosis in the spine (OS of 0.7 years) when compared with the rest of the patient cohort of OGS.	('OGS', 'Var', (70, 73))	('patient', 'Species', '9606', (214, 221))	('OS', 'Chemical', '-', (162, 164))	("Paget's disease", 'Disease', 'MESH:C537701', (92, 107))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('OGS', 'Chemical', '-', (51, 54))	("Paget's disease", 'Disease', (92, 107))	('OGS', 'Chemical', '-', (70, 73))	('OGS', 'Chemical', '-', (232, 235))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
466867	23541691	Previous studies have detected KSHV seropositivity in the range of 24%-45% in several MSM cohorts, likely reflecting different KSHV infectivity in different populations and possibly the performance of the immunoassays used.	('seropositivity', 'Var', (36, 50))	('KSHV', 'Species', '37296', (31, 35))	('KSHV', 'Gene', (31, 35))	('detected', 'Reg', (22, 30))	('KSHV', 'Species', '37296', (127, 131))
466875	23541691	LIPS testing of K8.1, ORF73 fragment (LANA-Delta2 fragment) and ORF65, along with a new latent KSHV antigen v-cyclin, showed 99% sensitivity and 100% specificity for the diagnosis of patients with KS and showed similar diagnostic performance to performing ELISAs with K8.1 and ORF73.	('ORF65', 'Gene', (64, 69))	('ORF73', 'Gene', '4961527', (22, 27))	('ORF73', 'Gene', '4961527', (277, 282))	('men', 'Species', '9606', (32, 35))	('v-cyclin', 'Gene', (108, 116))	('ORF73', 'Gene', (277, 282))	('LANA', 'Gene', (38, 42))	('men', 'Species', '9606', (54, 57))	('ORF73', 'Gene', (22, 27))	('LANA', 'Gene', '4961527', (38, 42))	('v-cyclin', 'Gene', '4961471', (108, 116))	('K8.1', 'Var', (16, 20))	('KSHV', 'Species', '37296', (95, 99))	('patients', 'Species', '9606', (183, 191))
466899	23541691	Testing with the LIPS Aggregate Ag containing K8.1, ORF73 fragment, ORF65 and v-cyclin antigens with 307 serum samples from these men showed highly reproducible antibody values ranging from 0 to 705,414 LU (Fig.	('men', 'Species', '9606', (62, 65))	('ORF65', 'Gene', (68, 73))	('v-cyclin', 'Gene', (78, 86))	('ORF73', 'Gene', (52, 57))	('v-cyclin', 'Gene', '4961471', (78, 86))	('K8.1', 'Var', (46, 50))	('ORF73', 'Gene', '4961527', (52, 57))	('men', 'Species', '9606', (130, 133))
466924	23541691	Thus additional ORF73-Delta3 and ORF38 testing resulted in an additional 6% of the MSM samples as seropositive.	('resulted in', 'Reg', (47, 58))	('ORF38', 'Gene', '4961435', (33, 38))	('testing', 'Var', (39, 46))	('ORF73-Delta3', 'Gene', (16, 28))	('ORF73-Delta3', 'Gene', '4961527', (16, 28))	('MSM', 'Disease', (83, 86))	('ORF38', 'Gene', (33, 38))
466946	23541691	Despite the prominent hypergammaglobulinemia associated with HIV infection, the KSHV+/HIV+ MSM samples had only a slightly higher anti-KSHV antibody level than the KSHV+/HIV- MSM samples, which was not statistically significant.	('KSHV', 'Species', '37296', (164, 168))	('hypergammaglobulinemia', 'Disease', (22, 44))	('KSHV+/HIV+', 'Var', (80, 90))	('HIV infection', 'Disease', 'MESH:D015658', (61, 74))	('higher', 'PosReg', (123, 129))	('KSHV', 'Species', '37296', (80, 84))	('hypergammaglobulinemia', 'Phenotype', 'HP:0010702', (22, 44))	('KSHV', 'Species', '37296', (135, 139))	('hypergammaglobulinemia', 'Disease', 'MESH:D006942', (22, 44))	('anti-KSHV antibody level', 'MPA', (130, 154))	('HIV infection', 'Disease', (61, 74))
467103	22460902	In some cases, mutated cancer genes are potent biomarkers of response to targeted agents.	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('mutated', 'Var', (15, 22))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
467105	22460902	In aggregate, we found mutated cancer genes were associated with cellular response to most currently available cancer drugs.	('cellular response to', 'MPA', (65, 85))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutated', 'Var', (23, 30))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (31, 37))
467106	22460902	Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harboring the EWS-FLI1 gene translocation to PARP inhibitors.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (76, 91))	('EWS-FLI1', 'Gene', (112, 120))	("Ewing's sarcoma", 'Disease', (76, 91))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (76, 91))	('gene translocation', 'Var', (121, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('EWS-FLI1', 'Gene', '2130;2313', (112, 120))
467108	22460902	There is compelling evidence that the likelihood of a patient's cancer responding to treatment can be strongly influenced by alterations in the cancer genome.	('patient', 'Species', '9606', (54, 61))	('influenced by', 'Reg', (111, 124))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('alterations', 'Var', (125, 136))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
467110	22460902	While targeting of specific genetic changes in defined patient subsets has been successful, a poorly explained range of responses to appropriately selected therapies is often still observed in patients.	('patients', 'Species', '9606', (193, 201))	('genetic changes', 'Var', (28, 43))	('changes', 'Var', (36, 43))	('patient', 'Species', '9606', (55, 62))	('patient', 'Species', '9606', (193, 200))
467114	22460902	Cancer cell lines have subsequently been used to identify rare drug-sensitizing genotypes, including mutant EGFR, BRAF and EML4-ALK, that are highly predictive of clinical responses.	('EML4', 'Gene', (123, 127))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('ALK', 'Gene', '238', (128, 131))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('EML4', 'Gene', '27436', (123, 127))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutant', 'Var', (101, 107))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('ALK', 'Gene', (128, 131))
467128	22460902	Single gene mutations are increasingly being adopted as clinical biomarkers for the optimal application of cancer therapeutics.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Single gene mutations', 'Var', (0, 21))
467131	22460902	Similarly, sensitivity to most drugs tested was associated with a mutation in at least one cancer gene (118/130, 91%).	('sensitivity', 'MPA', (11, 22))	('associated', 'Reg', (48, 58))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutation', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
467132	22460902	Thus, diverse cancer gene mutations are implicated as markers of sensitivity or resistance to a broad range of anti-cancer drugs, indicating that genomic biomarkers could inform the therapeutic selectivity of many cancer drugs.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
467133	22460902	The mutated cancer genes most clearly associated with drug sensitivity are oncogenes that are direct targets of the relevant drug.	('mutated', 'Var', (4, 11))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('associated', 'Reg', (38, 48))	('drug sensitivity', 'Phenotype', 'HP:0020174', (54, 70))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
467137	22460902	Similarly, BRAF mutation was associated with sensitivity to BRAF and MEK1/2 inhibitors (e.g.	('mutation', 'Var', (16, 24))	('sensitivity', 'MPA', (45, 56))	('BRAF', 'Gene', (60, 64))	('MEK1/2', 'Gene', '5604;5605', (69, 75))	('BRAF', 'Gene', '673', (60, 64))	('MEK1/2', 'Gene', (69, 75))	('associated', 'Reg', (29, 39))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
467138	22460902	2a, b and c), including a structural analogue of Vemurafenib, which in clinical trials has extended the survival of BRAF mutation-positive melanoma patients.	('patients', 'Species', '9606', (148, 156))	('survival', 'MPA', (104, 112))	('BRAF', 'Gene', '673', (116, 120))	('extended', 'PosReg', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('BRAF', 'Gene', (116, 120))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (49, 60))	('mutation-positive', 'Var', (121, 138))
467139	22460902	Additionally, ERBB2 (HER2) amplification was associated with sensitivity to EGFR-family inhibitors including Lapatinib (P < 1 x 10-7, Fig.	('Lapatinib', 'MPA', (109, 118))	('EGFR', 'Gene', '1956', (76, 80))	('ERBB2', 'Gene', '2064', (14, 19))	('associated', 'Reg', (45, 55))	('ERBB2', 'Gene', (14, 19))	('EGFR', 'Gene', (76, 80))	('sensitivity to', 'MPA', (61, 75))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', (21, 25))	('amplification', 'Var', (27, 40))	('Lapatinib', 'Chemical', 'MESH:D000077341', (109, 118))
467141	22460902	We were also able to detect known associations between EGFR, FLT3, and PIK3CA mutations and drugs that target the products of these genes (Supplementary Data 5).	('EGFR', 'Gene', '1956', (55, 59))	('associations', 'Interaction', (34, 46))	('PIK3CA', 'Gene', '5290', (71, 77))	('EGFR', 'Gene', (55, 59))	('mutations', 'Var', (78, 87))	('FLT3', 'Gene', '2322', (61, 65))	('FLT3', 'Gene', (61, 65))	('PIK3CA', 'Gene', (71, 77))
467143	22460902	We also found associations between the presence of inactivating mutations in tumor suppressor genes and several drugs, which in some instances provide insight into the interplay between tumour suppressors and the cellular machinery in mediating drug sensitivity.	('tumour', 'Disease', (186, 192))	('associations', 'Interaction', (14, 26))	('drug sensitivity', 'Phenotype', 'HP:0020174', (245, 261))	('inactivating mutations', 'Var', (51, 73))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('presence', 'Var', (39, 47))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('tumor', 'Disease', (77, 82))
467144	22460902	For example, mutation of TP53, an important regulator of apoptosis and cell cycle arrest in response to cellular stress, confers resistance to Nutlin-3a (P < 1 x 10-36), an inhibitor of the MDM2 E3-ligase which negatively regulates p53 protein levels (Fig.	('MDM2', 'Gene', '4193', (190, 194))	('MDM2', 'Gene', (190, 194))	('TP53', 'Gene', (25, 29))	('mutation', 'Var', (13, 21))	('p53', 'Gene', (232, 235))	('resistance', 'MPA', (129, 139))	('p53', 'Gene', '7157', (232, 235))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (71, 88))	('TP53', 'Gene', '7157', (25, 29))
467145	22460902	Similarly, mutational inactivation of RB1, a key repressor of cell cycle progression in normal cells, confers resistance to PD-0332991 (P < 1 x 10-10), an inhibitor of the upstream cyclin-dependent kinases (CDKs) 4 and 6, which drive cell cycle progression by inhibiting pRb through phosphorylation (Fig.	('PD-0332991', 'Chemical', 'MESH:C500026', (124, 134))	('resistance', 'MPA', (110, 120))	('RB1', 'Gene', (38, 41))	('inhibiting', 'NegReg', (260, 270))	('RB1', 'Gene', '5925', (38, 41))	('PD-0332991', 'Var', (124, 134))	('cell', 'CPA', (234, 238))	('CDKs', 'Gene', '1019;1021', (207, 211))	('mutational inactivation', 'Var', (11, 34))	('pRb', 'Gene', (271, 274))	('phosphorylation', 'MPA', (283, 298))	('CDKs', 'Gene', (207, 211))	('pRb', 'Gene', '5925', (271, 274))
467146	22460902	Conversely, mutational inactivation of CDKN2A, encoding the CDK inhibitory protein p16, was associated with sensitivity to PD-0332991 (P < 1 x 10-11; Supplementary Data 5), presumably because CDKN2A mutated cells have an enhanced requirement for signaling through the CDK4/6 - pRb signaling pathway.	('CDK4/6', 'Gene', (268, 274))	('CDKN2A', 'Gene', (39, 45))	('mutational inactivation', 'Var', (12, 35))	('p16', 'Gene', '1029', (83, 86))	('pRb', 'Gene', '5925', (277, 280))	('CDKN2A', 'Gene', '1029', (192, 198))	('PD-0332991', 'Chemical', 'MESH:C500026', (123, 133))	('CDKN2A', 'Gene', '1029', (39, 45))	('CDKN2A', 'Gene', (192, 198))	('sensitivity', 'MPA', (108, 119))	('enhanced', 'PosReg', (221, 229))	('pRb', 'Gene', (277, 280))	('p16', 'Gene', (83, 86))	('CDK4/6', 'Gene', '1019;1021', (268, 274))	('associated', 'Reg', (92, 102))
467147	22460902	The association of BRAF and NRAS mutation with sensitivity to obatoclax mesylate, a pro-apoptotic drug that targets BCL2 family anti-apoptotic proteins (BCL2, BCL-XL and MCL1), likely results from the enrichment of these mutations in melanoma, since drug sensitivity among melanoma cell lines was not correlated with presence or absence of these mutations (Supplementary Fig.	('BCL-XL', 'Gene', (159, 165))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('MCL1', 'Gene', (170, 174))	('BCL2', 'Gene', (116, 120))	('BCL2', 'Gene', '596', (153, 157))	('melanoma', 'Disease', 'MESH:D008545', (273, 281))	('MCL1', 'Gene', '4170', (170, 174))	('BCL-XL', 'Gene', '598', (159, 165))	('NRAS', 'Gene', '4893', (28, 32))	('mutation', 'Var', (33, 41))	('drug sensitivity', 'Phenotype', 'HP:0020174', (250, 266))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('BCL2', 'Gene', (153, 157))	('melanoma', 'Disease', (234, 242))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('melanoma', 'Disease', (273, 281))	('BCL2', 'Gene', '596', (116, 120))	('NRAS', 'Gene', (28, 32))
467148	22460902	The tissue-specific effect of obatoclax may be related to inhibition of the melanoma survival mediator MCL1, since sensitivity of melanoma lines to ABT-263, another BCL-2 inhibitor which does not target MCL1, was not correlated with BRAF or NRAS mutation.	('BCL-2', 'Gene', '596', (165, 170))	('melanoma', 'Disease', (76, 84))	('ABT', 'Chemical', 'MESH:C002502', (148, 151))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('NRAS', 'Gene', '4893', (241, 245))	('mutation', 'Var', (246, 254))	('BCL-2', 'Gene', (165, 170))	('MCL1', 'Gene', '4170', (103, 107))	('MCL1', 'Gene', '4170', (203, 207))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('BRAF', 'Gene', (233, 237))	('MCL1', 'Gene', (203, 207))	('melanoma', 'Disease', (130, 138))	('MCL1', 'Gene', (103, 107))	('BRAF', 'Gene', '673', (233, 237))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('NRAS', 'Gene', (241, 245))
467151	22460902	Intriguingly, we did not find general associations between targeted or cytotoxic drug sensitivity patterns and mutations in TP53.	('mutations', 'Var', (111, 120))	('TP53', 'Gene', '7157', (124, 128))	('TP53', 'Gene', (124, 128))	('drug sensitivity', 'Phenotype', 'HP:0020174', (81, 97))
467152	22460902	It may be that functional inactivation of p53, through mutations or abrogation of signaling pathways that regulate its activity, is an almost universal feature of cancer cell lines and thus differential drug sensitivity between mutant and non-mutant cell lines is not observed.	('p53', 'Gene', (42, 45))	('mutations', 'Var', (55, 64))	('p53', 'Gene', '7157', (42, 45))	('drug sensitivity', 'Phenotype', 'HP:0020174', (203, 219))	('signaling pathways', 'Pathway', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('abrogation', 'NegReg', (68, 78))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('inactivation', 'NegReg', (26, 38))
467153	22460902	Mutation of NOTCH1 was associated with sensitivity to ABT-263 (P <1 x 10-9; Fig.	('sensitivity', 'MPA', (39, 50))	('NOTCH1', 'Gene', '4851', (12, 18))	('NOTCH1', 'Gene', (12, 18))	('ABT', 'Chemical', 'MESH:C002502', (54, 57))	('Mutation', 'Var', (0, 8))	('associated', 'Reg', (23, 33))
467154	22460902	2h, Supplementary Fig 10), perhaps due to decreased expression of BCL2 family members in NOTCH1 mutant cell lines (Supplementary Fig.	('BCL2', 'Gene', '596', (66, 70))	('mutant', 'Var', (96, 102))	('decreased', 'NegReg', (42, 51))	('expression', 'MPA', (52, 62))	('BCL2', 'Gene', (66, 70))	('NOTCH1', 'Gene', (89, 95))	('NOTCH1', 'Gene', '4851', (89, 95))
467155	22460902	Amplification of CCND1 (CyclinD1) or loss of SMAD4 were associated with sensitivity to multiple EGFR-family inhibitors including lapatinib and BIBW2992; and for SMAD4 this correlated with elevated EGFR gene expression (Fig.	('Amplification', 'Var', (0, 13))	('SMAD4', 'Gene', '4089', (161, 166))	('EGFR', 'Gene', (96, 100))	('SMAD4', 'Gene', '4089', (45, 50))	('SMAD4', 'Gene', (161, 166))	('sensitivity', 'MPA', (72, 83))	('elevated', 'PosReg', (188, 196))	('SMAD4', 'Gene', (45, 50))	('loss', 'NegReg', (37, 41))	('lapatinib', 'Chemical', 'MESH:D000077341', (129, 138))	('EGFR', 'Gene', '1956', (197, 201))	('expression', 'MPA', (207, 217))	('CCND1', 'Gene', (17, 22))	('EGFR', 'Gene', (197, 201))	('EGFR', 'Gene', '1956', (96, 100))
467156	22460902	Inactivation of STK11 (LKB1; P < 0.01), thought to relieve repression of mTOR, was associated with sensitivity to the HSP90 inhibitor 17-AAG.	('HSP90', 'Gene', '3320', (118, 123))	('mTOR', 'Gene', '2475', (73, 77))	('STK11', 'Gene', (16, 21))	('repression', 'MPA', (59, 69))	('LKB1', 'Gene', '6794', (23, 27))	('mTOR', 'Gene', (73, 77))	('sensitivity to the', 'MPA', (99, 117))	('STK11', 'Gene', '6794', (16, 21))	('AAG', 'Gene', (137, 140))	('associated', 'Reg', (83, 93))	('AAG', 'Gene', '4350', (137, 140))	('HSP90', 'Gene', (118, 123))	('Inactivation', 'Var', (0, 12))	('LKB1', 'Gene', (23, 27))
467158	22460902	2j), and TET2 loss with sensitivity to the WEE1/CHK1 inhibitor 681640 (P < 1 x 10-4; Fig.	('681640', 'Var', (63, 69))	('TET2', 'Gene', '54790', (9, 13))	('WEE1', 'Gene', '7465', (43, 47))	('CHK1', 'Gene', (48, 52))	('TET2', 'Gene', (9, 13))	('WEE1', 'Gene', (43, 47))	('CHK1', 'Gene', '1111', (48, 52))	('loss', 'NegReg', (14, 18))
467161	22460902	For example, while sensitivity to the EGFR/ERBB2 inhibitor lapatinib correlated with ERBB2 expression and mutation, the strongest correlate for this drug was actually expression of the matrix metalloproteinase MMP28 (e = -29.28, f=1) (Fig.	('lapatinib', 'Chemical', 'MESH:D000077341', (59, 68))	('EGFR', 'Gene', '1956', (38, 42))	('ERBB2', 'Gene', '2064', (43, 48))	('ERBB2', 'Gene', (43, 48))	('EGFR', 'Gene', (38, 42))	('ERBB2', 'Gene', (85, 90))	('mutation', 'Var', (106, 114))	('MMP28', 'Gene', (210, 215))	('MMP28', 'Gene', '79148', (210, 215))	('ERBB2', 'Gene', '2064', (85, 90))
467162	22460902	Notably, for most drugs, including those with clear linkage to cancer gene mutations, EN modeling identified multi-feature signatures of drug sensitivity.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('drug sensitivity', 'Phenotype', 'HP:0020174', (137, 153))	('mutations', 'Var', (75, 84))	('drug sensitivity', 'MPA', (137, 153))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
467165	22460902	Interestingly, expression of 8 genes identified as markers of sensitivity to the MEK inhibitor AZD6244 significantly overlapped with a 18-gene signature of sensitivity to this drug (hypergeometric test of the overlap significance: P = 3 x 10-9).	('AZD6244', 'Var', (95, 102))	('expression', 'MPA', (15, 25))	('AZD6244', 'Chemical', 'MESH:C517975', (95, 102))	('MEK', 'Gene', (81, 84))	('MEK', 'Gene', '5609', (81, 84))
467172	22460902	We identified a highly significant association between the EWS-FLI1 rearrangement that is characteristic of Ewing's sarcoma tumours and sensitivity to olaparib (AZD2281), an inhibitor of the poly-ADP ribose polymerase (PARP)(P = 1.03 x 10-26, Fig.	("Ewing's sarcoma tumours", 'Disease', (108, 131))	('rearrangement', 'Var', (68, 81))	('olaparib', 'Chemical', 'MESH:C531550', (151, 159))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('poly-ADP ribose polymerase', 'Gene', (191, 217))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (108, 123))	('EWS-FLI1', 'Gene', (59, 67))	('sensitivity', 'MPA', (136, 147))	('poly-ADP ribose polymerase', 'Gene', '142', (191, 217))	("Ewing's sarcoma tumours", 'Disease', 'MESH:C563168', (108, 131))	('EWS-FLI1', 'Gene', '2130;2313', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('AZD2281', 'Chemical', 'MESH:C531550', (161, 168))
467175	22460902	PARP inhibitors have activity in BRCA1/2 mutant cancers due to the defects in homologous recombination present in these tumors and their consequent reliance on alternative DNA damage repair pathways that are targeted by these inhibitors.	('cancers', 'Disease', (48, 55))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mutant', 'Var', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('defects', 'NegReg', (67, 74))	('BRCA1/2', 'Gene', (33, 40))	('BRCA1/2', 'Gene', '672;675', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('activity', 'MPA', (21, 29))	('homologous recombination', 'MPA', (78, 102))
467178	22460902	Unlike in Ewing's Sarcoma, we did not observe an association between BRCA1/2 mutations and sensitivity to PARP inhibitors in the 3-day screening format, which is likely due to a requirement for several rounds of division in these cells to accumulate toxic levels of DNA damage.	('BRCA1/2', 'Gene', (69, 76))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (10, 25))	('Sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('BRCA1/2', 'Gene', '672;675', (69, 76))	('mutations', 'Var', (77, 86))	("Ewing's Sarcoma", 'Disease', (10, 25))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (10, 25))
467181	22460902	Moreover, expression of EWS-FLI1 in NIH3T3 cells conferred increased sensitivity to olaparib (Supplementary Fig.	('sensitivity to olaparib', 'MPA', (69, 92))	('increased', 'PosReg', (59, 68))	('NIH3T3', 'CellLine', 'CVCL:0594', (36, 42))	('EWS-FLI1', 'Gene', (24, 32))	('olaparib', 'Chemical', 'MESH:C531550', (84, 92))	('expression', 'Var', (10, 20))	('EWS-FLI1', 'Gene', '2130;2313', (24, 32))
467184	22460902	Mutations in BRCA1 or BRCA2 are not present in these Ewing's sarcoma lines (Supplementary Data 1), and we have observed no evidence to indicate that the DNA damage response is defective in Ewing's sarcoma cells (data not shown).	('BRCA2', 'Gene', '675', (22, 27))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (189, 204))	('BRCA1', 'Gene', (13, 18))	("Ewing's sarcoma", 'Disease', (189, 204))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (53, 68))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (189, 204))	('BRCA2', 'Gene', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('Mutations', 'Var', (0, 9))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (53, 68))	("Ewing's sarcoma", 'Disease', (53, 68))	('defective', 'NegReg', (176, 185))	('DNA damage response', 'MPA', (153, 172))	('BRCA1', 'Gene', '672', (13, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
467190	22460902	The validity of this approach is supported by its effective identification of drug-genotype associations that have already been established clinically, and it sets the stage for clinical testing of novel therapeutic biomarkers, such as the association between the EWS-FLI1 translocation in Ewing's sarcoma cells and sensitivity to PARP inhibitors.	('EWS-FLI1', 'Gene', '2130;2313', (264, 272))	('association', 'Interaction', (240, 251))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (290, 305))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (290, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (298, 305))	('translocation', 'Var', (273, 286))	('EWS-FLI1', 'Gene', (264, 272))	("Ewing's sarcoma", 'Disease', (290, 305))
467196	22460902	BCR-ABL positive CML, BRAF mutant melanoma and EGFR mutant positive lung cancer and drugs that target the protein products of these genes are now well-established associations.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('lung cancer', 'Disease', (68, 79))	('CML', 'Disease', 'MESH:D015464', (17, 20))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('mutant', 'Var', (52, 58))	('mutant', 'Var', (27, 33))	('BRAF', 'Gene', '673', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('BCR-ABL', 'Gene', (0, 7))	('BRAF', 'Gene', (22, 26))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('CML', 'Disease', (17, 20))	('BCR-ABL', 'Gene', '25', (0, 7))	('EGFR', 'Gene', '1956', (47, 51))	('melanoma', 'Disease', (34, 42))	('EGFR', 'Gene', (47, 51))
467203	22460902	A MANOVA was used to examine how drug IC50 and slope values associate with tissue type, the mutation status of 64 cancer genes (including gene amplifications and homozygous deletions), rearrangements and MSI.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('rearrangements', 'Var', (185, 199))	('mutation', 'Var', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('MSI', 'Disease', 'None', (204, 207))	('associate', 'Reg', (60, 69))	('MSI', 'Disease', (204, 207))	('cancer', 'Disease', (114, 120))
467225	22460902	Samples were screened using the markers BAT25, BAT26, D5S346, D2S123 and D17S250 and were characterised as MSI if two or more markers showed instability.	('D5S346', 'Var', (54, 60))	('MSI', 'Disease', 'None', (107, 110))	('BAT25', 'Var', (40, 45))	('D2S123', 'Var', (62, 68))	('MSI', 'Disease', (107, 110))	('D17S250', 'Var', (73, 80))	('BAT26', 'Var', (47, 52))
467230	22460902	A gene was defined as mutated if it fulfilled any of these criteria: a coding sequence variant in the cancer gene, a total copy number =0 (homozygous deletion) or >=8 (amplification).	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('variant', 'Var', (87, 94))
467303	30364101	FISH studies for ETV6 rearrangement by an ETV6 break-apart probe on chromosome 12 at 12p13.2 and for SS18 by a synovial sarcoma break-apart probe on chromosome 18q11.2 were negative.	('SS18', 'Gene', (101, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('ETV6', 'Gene', (42, 46))	('men', 'Species', '9606', (31, 34))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (111, 127))	('synovial sarcoma', 'Disease', 'MESH:D013584', (111, 127))	('ETV6', 'Gene', '2120', (17, 21))	('ETV6', 'Gene', '2120', (42, 46))	('SS18', 'Gene', '6760', (101, 105))	('ETV6', 'Gene', (17, 21))	('rearrangement', 'Var', (22, 35))	('synovial sarcoma', 'Disease', (111, 127))
467314	30364101	While, in the majority of MEST tumors, positivity for ER/PR has been reported, in close to 40% of tumors these markers were negative and the tumor described in this report was also negative.	('MEST tumors', 'Disease', (26, 37))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('negative', 'NegReg', (124, 132))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', (31, 36))	('MEST tumors', 'Disease', 'MESH:D009369', (26, 37))	('tumor', 'Disease', (141, 146))	('ER/PR', 'Gene', (54, 59))	('positivity', 'Var', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
467355	25923013	SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors Metastasis is responsible for over 90% of cancer-associated mortality.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('metastatic', 'CPA', (28, 38))	('epithelial', 'Disease', (53, 63))	('SIRT7', 'Gene', (0, 5))	('SIRT7', 'Gene', '209011', (0, 5))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (68, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('inactivation', 'Var', (6, 18))	('mesenchymal tumors', 'Disease', (68, 86))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('reverses', 'NegReg', (19, 27))
467359	25923013	In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease, and poor patient prognosis, and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype.	('high', 'PosReg', (35, 39))	('aggressive cancer', 'Disease', 'MESH:D009369', (73, 90))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (14, 32))	('aggressive cancer', 'Disease', (73, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('SIRT7 levels', 'MPA', (40, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('epithelial prostate carcinomas', 'Disease', 'MESH:D011472', (3, 33))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('metastatic disease', 'Disease', (103, 121))	('patient', 'Species', '9606', (132, 139))	('depletion', 'Var', (155, 164))	('associated', 'Reg', (57, 67))	('epithelial prostate carcinomas', 'Disease', (3, 33))
467361	25923013	Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth.	('tumor', 'Disease', (119, 124))	('cancer', 'Disease', (53, 59))	('SIRT7', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('suppresses', 'NegReg', (42, 52))	('inactivation', 'Var', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
467366	25923013	Through H3K18 deacetylation at specific promoters, SIRT7 controls a tumor suppressive gene expression program that stabilizes the transformed state of cancer cells.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('SIRT7', 'Gene', (51, 56))	('H3K18', 'Protein', (8, 13))	('deacetylation', 'Var', (14, 27))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('expression', 'Species', '29278', (91, 101))	('controls', 'Reg', (57, 65))
467367	25923013	Indeed, inactivation of SIRT7 is sufficient to reverse essential properties of cancer cells, including anchorage-independent growth, loss of contact inhibition, growth in low serum conditions, and tumor growth in mouse xenograft assays.	('mouse', 'Species', '10090', (213, 218))	('SIRT7', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('growth', 'MPA', (161, 167))	('loss', 'NegReg', (133, 137))	('inactivation', 'Var', (8, 20))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('contact inhibition', 'MPA', (141, 159))	('anchorage-independent growth', 'CPA', (103, 131))	('cancer', 'Disease', (79, 85))	('tumor', 'Disease', (197, 202))
467371	25923013	Similarly, high SIRT7 expression correlated with advanced tumor stage and decreased overall and disease-free patient survival in colon carcinoma cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('overall', 'CPA', (84, 91))	('patient', 'Species', '9606', (109, 116))	('colon carcinoma', 'Disease', 'MESH:D015179', (129, 144))	('expression', 'Species', '29278', (22, 32))	('disease-free patient survival', 'CPA', (96, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('decreased', 'NegReg', (74, 83))	('high', 'Var', (11, 15))	('carcinoma cells', 'Disease', 'MESH:C538614', (135, 150))	('SIRT7', 'Gene', (16, 21))	('carcinoma cells', 'Disease', (135, 150))	('expression', 'MPA', (22, 32))	('colon carcinoma', 'Disease', (129, 144))
467382	25923013	Inactivation of SIRT7 reverses the loss of E-cadherin expression and other associated EMT changes in carcinoma cells, and surprisingly, also attenuates the invasiveness and metastasis of mesenchymal sarcoma cells.	('expression', 'MPA', (54, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('expression', 'Species', '29278', (54, 64))	('E-cadherin', 'Gene', (43, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('metastasis of mesenchymal sarcoma', 'Disease', 'MESH:D009362', (173, 206))	('E-cadherin', 'Gene', '999', (43, 53))	('attenuates', 'NegReg', (141, 151))	('carcinoma cells', 'Disease', 'MESH:C538614', (101, 116))	('metastasis of mesenchymal sarcoma', 'Disease', (173, 206))	('carcinoma cells', 'Disease', (101, 116))	('Inactivation', 'Var', (0, 12))	('SIRT7', 'Gene', (16, 21))
467388	25923013	This analysis revealed many human cancer types that harbor amplifications of SIRT7, and a smaller number with mutations at the SIRT7 locus (Fig.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('SIRT7', 'Gene', (127, 132))	('human', 'Species', '9606', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('amplifications', 'Var', (59, 73))	('cancer', 'Disease', (34, 40))	('SIRT7', 'Gene', (77, 82))
467389	25923013	SIRT7 amplifications were by far the predominant genetic change observed in several epithelial cancers (e.g., bladder, liver, prostate and breast carcinomas), as well as in sarcomas.	('bladder', 'Disease', (110, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('SIRT7', 'Gene', (0, 5))	('breast carcinomas', 'Phenotype', 'HP:0003002', (139, 156))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('epithelial cancers', 'Disease', (84, 102))	('amplifications', 'Var', (6, 20))	('liver', 'Disease', (119, 124))	('sarcomas', 'Disease', 'MESH:D012509', (173, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('prostate', 'Disease', (126, 134))	('sarcomas', 'Phenotype', 'HP:0100242', (173, 181))	('breast carcinomas', 'Disease', 'MESH:D001943', (139, 156))	('breast carcinomas', 'Disease', (139, 156))	('epithelial cancers', 'Disease', 'MESH:D000077216', (84, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('sarcomas', 'Disease', (173, 181))
467390	25923013	Notably, one study conducted on 61 prostate cancer patients showed amplification of the SIRT7 locus occurring exclusively in tumors that were metastatic and associated with poor survival (Fig.	('associated', 'Reg', (157, 167))	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('amplification', 'Var', (67, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('patients', 'Species', '9606', (51, 59))	('SIRT7', 'Gene', (88, 93))	('prostate cancer', 'Disease', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
467398	25923013	We next asked whether SIRT7 depletion affects cancer cell invasiveness using two complementary assays.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('depletion', 'Var', (28, 37))	('affects', 'Reg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('SIRT7', 'Gene', (22, 27))
467401	25923013	Consistent with this impaired migration and invasiveness, staining for F-actin (Phalloidin staining) revealed a collapsed actin cytoskeleton upon SIRT7 depletion in PC3 cells (Fig.	('actin cytoskeleton', 'MPA', (122, 140))	('PC3', 'Gene', '3853', (165, 168))	('SIRT7', 'Gene', (146, 151))	('invasiveness', 'CPA', (44, 56))	('PC3', 'Gene', (165, 168))	('migration', 'CPA', (30, 39))	('Phalloidin', 'Chemical', 'MESH:D010590', (80, 90))	('depletion', 'Var', (152, 161))	('collapsed', 'PosReg', (112, 121))
467402	25923013	Notably, SIRT7 inactivation in the HT1080 sarcoma cell line led to similar reductions in cell migration during wound healing and in Transwell invasion (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('reductions', 'NegReg', (75, 85))	('cell migration during wound healing', 'CPA', (89, 124))	('HT1080 sarcoma', 'Disease', 'MESH:D012509', (35, 49))	('SIRT7', 'Gene', (9, 14))	('Transwell invasion', 'CPA', (132, 150))	('HT1080 sarcoma', 'Disease', (35, 49))	('inactivation', 'Var', (15, 27))
467403	25923013	These observations demonstrate that inhibiting SIRT7 can reverse metastatic properties of both epithelial and mesenchymal cancer cell types.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('metastatic properties of', 'CPA', (65, 89))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('inhibiting', 'Var', (36, 46))	('SIRT7', 'Gene', (47, 52))	('reverse', 'NegReg', (57, 64))
467404	25923013	Moreover, over-expression of a SIRT7 variant bearing a point mutation in the catalytic site (H187Y) also reduced HT1080 cell invasiveness, consistent with a dominant negative effect (Fig.	('H187Y', 'Var', (93, 98))	('over-expression', 'PosReg', (10, 25))	('SIRT7', 'Gene', (31, 36))	('HT1080 cell invasiveness', 'CPA', (113, 137))	('expression', 'Species', '29278', (15, 25))	('HT1080', 'CellLine', 'CVCL:0317', (113, 119))	('variant', 'Var', (37, 44))	('reduced', 'NegReg', (105, 112))	('H187Y', 'SUBSTITUTION', 'None', (93, 98))
467406	25923013	To gain additional mechanistic insight into the role of SIRT7 in the invasion-metastasis cascade, we first focused on the effects of SIRT7 inactivation in epithelial carcinoma cells.	('carcinoma cells', 'Disease', 'MESH:C538614', (166, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (155, 175))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (155, 175))	('carcinoma cells', 'Disease', (166, 181))	('epithelial carcinoma', 'Disease', (155, 175))	('inactivation', 'Var', (139, 151))	('SIRT7', 'Gene', (133, 138))
467413	25923013	Indeed, western analysis revealed that in SIRT7 deficient PC3 cells, E-cadherin protein levels were up-regulated, and Vimentin protein levels were reduced, consistent with a reversal of the EMT phenotype (Fig.	('up-regulated', 'PosReg', (100, 112))	('SIRT7', 'Gene', (42, 47))	('Vimentin protein levels', 'MPA', (118, 141))	('E-cadherin', 'Gene', '999', (69, 79))	('PC3', 'Gene', (58, 61))	('deficient', 'Var', (48, 57))	('E-cadherin', 'Gene', (69, 79))	('reduced', 'NegReg', (147, 154))	('PC3', 'Gene', '3853', (58, 61))
467422	25923013	We found that SIRT7-inactivation in both PC3 and HT1080 cells led to reduced expression of the matrix metalloproteinase gene MMP16 (Fig.	('HT1080', 'CellLine', 'CVCL:0317', (49, 55))	('expression', 'MPA', (77, 87))	('PC3', 'Gene', '3853', (41, 44))	('reduced', 'NegReg', (69, 76))	('PC3', 'Gene', (41, 44))	('MMP16', 'Gene', (125, 130))	('SIRT7-inactivation', 'Var', (14, 32))	('expression', 'Species', '29278', (77, 87))
467437	25923013	These findings provide evidence that SIRT7 inactivation in cancer cells specifically prevents metastasis in vivo, independent of changes in intrinsic tumor cell proliferative capacity.	('metastasis', 'CPA', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('prevents', 'NegReg', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SIRT7', 'Gene', (37, 42))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', (150, 155))	('inactivation', 'Var', (43, 55))
467439	25923013	Through deacetylation of histone H3 on lysine K18 at chromatin, SIRT7 controls a tumor suppressive gene expression program that maintains the neoplastic state of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('SIRT7', 'Gene', (64, 69))	('neoplastic', 'MPA', (142, 152))	('cancer', 'Disease', (162, 168))	('lysine', 'Chemical', 'MESH:D008239', (39, 45))	('expression', 'Species', '29278', (104, 114))	('controls', 'Reg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('deacetylation', 'Var', (8, 21))	('tumor', 'Disease', (81, 86))	('neoplastic state', 'Phenotype', 'HP:0002664', (142, 158))
467441	25923013	Consistent with these functions, inactivation of SIRT7 in cancer cells leads to loss of oncogenic properties and reduces the ability of these cells to form tumors in mice.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('loss', 'NegReg', (80, 84))	('SIRT7', 'Gene', (49, 54))	('reduces', 'NegReg', (113, 120))	('oncogenic properties', 'CPA', (88, 108))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('mice', 'Species', '10090', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (58, 64))	('inactivation', 'Var', (33, 45))	('tumors', 'Disease', (156, 162))
467442	25923013	In this study, we show that in addition to its effects on primary tumors, inactivation of SIRT7 also has specific metastasis suppressing effects, reducing the migration and invasion of cancer cells in vitro and preventing metastasis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('primary tumors', 'Disease', (58, 72))	('metastasis', 'CPA', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('primary tumors', 'Disease', 'MESH:D009369', (58, 72))	('migration', 'CPA', (159, 168))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('metastasis', 'CPA', (222, 232))	('SIRT7', 'Gene', (90, 95))	('preventing', 'NegReg', (211, 221))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('reducing', 'NegReg', (146, 154))	('cancer', 'Disease', (185, 191))	('inactivation', 'Var', (74, 86))
467444	25923013	Our findings fit well with recent evidence that SIRT7 depletion reduces metastasis by colorectal cancer cells in mouse xenograft metastasis models.	('depletion', 'Var', (54, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('metastasis', 'CPA', (72, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SIRT7', 'Protein', (48, 53))	('mouse', 'Species', '10090', (113, 118))	('reduces', 'NegReg', (64, 71))
467450	25923013	Second, we detect a significant enrichment for SIRT7 amplifications in a majority of tumor types that we analyzed, including carcinomas of many tissue origins, and non-epithelial soft tissue sarcomas.	('tumor', 'Disease', (85, 90))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (179, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('carcinomas', 'Disease', 'MESH:D002277', (125, 135))	('sarcomas', 'Disease', 'MESH:D012509', (191, 199))	('carcinomas', 'Disease', (125, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (191, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (179, 198))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('sarcomas', 'Disease', (191, 199))	('SIRT7', 'Gene', (47, 52))	('amplifications', 'Var', (53, 67))
467451	25923013	Moreover, we show that in a set of prostate carcinoma samples, the SIRT7 amplifications are selectively detected in metastatic tumors with poor clinical outcome, and not observed in primary tumors with better patient survival.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('detected', 'Reg', (104, 112))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (35, 53))	('patient', 'Species', '9606', (209, 216))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('primary tumors', 'Disease', (182, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('prostate carcinoma', 'Disease', (35, 53))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('prostate carcinoma', 'Disease', 'MESH:D011472', (35, 53))	('primary tumors', 'Disease', 'MESH:D009369', (182, 196))	('amplifications', 'Var', (73, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('SIRT7', 'Gene', (67, 72))
467459	25923013	Our observations that high SIRT7 expression is associated with aggressive metastatic phenotypes of human tumors, and that SIRT7 depletion significantly impairs both primary tumor growth and metastatic spread in mouse tumor models, suggest that pharmacologic targeting of SIRT7 might be a promising therapeutic strategy, and could be used in the context of combinatorial therapy with other HDAC inhibitors.	('tumors', 'Disease', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('SIRT7', 'Gene', (271, 276))	('expression', 'MPA', (33, 43))	('associated', 'Reg', (47, 57))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (217, 222))	('metastatic spread', 'CPA', (190, 207))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('depletion', 'NegReg', (128, 137))	('tumor', 'Disease', (105, 110))	('high', 'Var', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('expression', 'Species', '29278', (33, 43))	('mouse', 'Species', '10090', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('impairs', 'NegReg', (152, 159))	('SIRT7', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('SIRT7', 'Gene', (27, 32))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('human', 'Species', '9606', (99, 104))
467476	25923013	E-cadherin antibody (610181) was purchased from BD Biosciences, SIRT1 (07-131) and beta-tubulin (05-661) antibodies were purchased from Millipore.	('E-cadherin', 'Gene', '999', (0, 10))	('E-cadherin', 'Gene', (0, 10))	('610181', 'Var', (21, 27))
467502	21618422	As a result, a total 1459 eligible patients on CCG 2861, CCG 2891, CCG 2941 and CCG 2961 were used for these analyses.	('CCG', 'Chemical', '-', (80, 83))	('CCG', 'Chemical', '-', (67, 70))	('CCG 2961', 'Var', (80, 88))	('CCG', 'Chemical', '-', (57, 60))	('CCG', 'Chemical', '-', (47, 50))	('patients', 'Species', '9606', (35, 43))	('CCG 2861', 'Var', (47, 55))
467514	21618422	Central nervous system involvement with leukemia was diagnosed if the patient had CNS3 status and these patients received additional twice weekly intrathecal cytarabine for a total of 6 doses, and if this failed to clear the leukemia cells they then received twice weekly triple intrathecal therapy for a total of 6 doses.	('leukemia', 'Phenotype', 'HP:0001909', (225, 233))	('leukemia cells', 'Disease', (225, 239))	('cytarabine', 'Chemical', 'MESH:D003561', (158, 168))	('patient', 'Species', '9606', (70, 77))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))	('patients', 'Species', '9606', (104, 112))	('patient', 'Species', '9606', (104, 111))	('leukemia cells', 'Disease', 'MESH:D015458', (225, 239))	('CNS3 status', 'Var', (82, 93))	('leukemia', 'Disease', (225, 233))	('leukemia', 'Disease', 'MESH:D007938', (225, 233))	('Central nervous system involvement', 'Disease', (0, 34))	('leukemia', 'Disease', (40, 48))	('leukemia', 'Disease', 'MESH:D007938', (40, 48))
467538	21618422	Children lost to follow-up were censored at their date of last known contact or at a cutoff 6 months prior to September 2001, January 2004, April 2005, and October 2006 for CCG 2861, CCG 2891, CCG 2941 and CCG 2961, respectively.	('CCG', 'Chemical', '-', (173, 176))	('Children', 'Species', '9606', (0, 8))	('CCG', 'Chemical', '-', (193, 196))	('CCG 2961', 'Var', (206, 214))	('CCG 2861', 'Var', (173, 181))	('CCG', 'Chemical', '-', (206, 209))	('CCG', 'Chemical', '-', (183, 186))	('CCG 2941', 'Var', (193, 201))
467546	21618422	Finally, significantly more patients with both orbital MS and CNS MS had t(8;21) cytogenetics compared to non-CNS MS and CNS3 patients, and significantly more patients with CNS MS had +21 cytogenetics compared to other EML patients.	('EML', 'Disease', (219, 222))	('patients', 'Species', '9606', (223, 231))	('more', 'PosReg', (23, 27))	('EML', 'Disease', 'None', (219, 222))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (159, 167))	('+21', 'Var', (184, 187))	('patients', 'Species', '9606', (28, 36))
467556	21618422	The risk of CNS relapse was higher in the CNS3 patients compared to the orbital MS and CNS MS patients, although not significantly.	('CNS3', 'Var', (42, 46))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (94, 102))	('CNS', 'Disease', (12, 15))
467570	21618422	They found that this occurred in 56(23%) of their 240 cases and the patients with extramedullary infiltration had a higher white cell count, higher proportion of M4/M5, and a higher incidence of inv16 and 11q23 abnormalities.	('white cell count', 'CPA', (123, 139))	('higher', 'PosReg', (116, 122))	('higher white cell count', 'Phenotype', 'HP:0001974', (116, 139))	('M4/M5', 'Var', (162, 167))	('patients', 'Species', '9606', (68, 76))	('higher', 'PosReg', (141, 147))	('inv16', 'Var', (195, 200))
467571	21618422	A small study also found a high incidence of abnormalities of chromosomes 8 and 21 in patients with granulocytic sarcomas.	('chromosomes', 'Gene', (62, 73))	('abnormalities', 'Var', (45, 58))	('granulocytic sarcomas', 'Disease', (100, 121))	('granulocytic sarcomas', 'Disease', 'MESH:D023981', (100, 121))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('patients', 'Species', '9606', (86, 94))
467730	27329820	Despite large-scale efforts to identify genetic alterations that predict sensitivity to specific small molecules, the type and number of established cancer cell lines do not yet represent the full spectrum of human cancers.	('human', 'Species', '9606', (209, 214))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (215, 221))	('alterations', 'Var', (48, 59))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('sensitivity', 'MPA', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
467747	27329820	As expected, this paediatric sarcoma harboured relatively few somatic nucleotide substitutions, although we note the existence of additional point mutations in the cell line as compared with the metastatic tissue from primary relapse (Supplementary Table 1).	('sarcoma', 'Disease', (29, 36))	('point mutations', 'Var', (141, 156))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))
467756	27329820	Specifically, we compiled a list of potentially druggable targets by combining the lists of targets of (i) biologically active compounds identified from large-scale cell line profiling experiments with established cancer cell lines, (ii) small molecules in development from 25 pharmaceutical companies and (iii) small molecules that are the subject of Children's Oncology Group clinical trials or in the process of being approved by the European Medical Agency as of May 2014.	('cancer', 'Disease', (214, 220))	('Oncology', 'Phenotype', 'HP:0002664', (363, 371))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('small', 'Var', (238, 243))	('Children', 'Species', '9606', (352, 360))	('small', 'Var', (312, 317))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
467778	27329820	Of 407 evaluable compounds, 31 (8%) compounds significantly decreased cell viability (Supplementary Table 11) including pan-CDK inhibitors (dinaciclib, alvocidib, SNS-032), topoisomerase inhibitors (SN-38, topotecan, doxorubicin), inhibitors of nicotinamide phosphoribosyltransferase (NMPRTase) (daporinad, CAY10618 and GMX-1778) and leptomycin B, an inhibitor of nuclear export.	('GMX-1778', 'Chemical', 'MESH:C401312', (320, 328))	('decreased', 'NegReg', (60, 69))	('topotecan', 'Chemical', 'MESH:D019772', (206, 215))	('leptomycin', 'Gene', (334, 344))	('cell viability', 'CPA', (70, 84))	('doxorubicin', 'Chemical', 'MESH:D004317', (217, 228))	('CAY10618', 'Var', (307, 315))	('dinaciclib', 'Chemical', 'MESH:C553669', (140, 150))	('compounds', 'Var', (17, 26))	('CAY10618', 'Chemical', '-', (307, 315))	('alvocidib', 'Chemical', 'MESH:C077990', (152, 161))	('leptomycin B', 'Chemical', 'MESH:C038753', (334, 346))	('nicotinamide', 'Chemical', 'MESH:D009536', (245, 257))	('daporinad', 'Chemical', 'MESH:C480543', (296, 305))	('SN-38', 'Chemical', 'MESH:D000077146', (199, 204))	('SNS-032', 'Chemical', 'MESH:C484864', (163, 170))
467779	27329820	Integrating the small-molecule screen with the genomic screens, we found that depleting CDK4 and XPO1 or targeting them with small molecules led to reduced cell viability (Fig.	('reduced', 'NegReg', (148, 155))	('CDK4', 'Gene', '1019', (88, 92))	('CDK4', 'Gene', (88, 92))	('XPO1', 'Gene', '7514', (97, 101))	('cell viability', 'CPA', (156, 170))	('XPO1', 'Gene', (97, 101))	('depleting', 'Var', (78, 87))
467788	27329820	We observed that treatment of CLF-PED-015-T with flavopiridol, a pan-CDK inhibitor or palbociclib or LEE011, CDK4/6 specific inhibitors, led to decreased phospho-RbSer807/811 and G0/G1 arrest but did not activate cleaved caspase-3 in vitro (Supplementary Fig.	('CLF-PED-015-T', 'Disease', (30, 43))	('CDK4/6', 'Gene', '1019;1021', (109, 115))	('decreased', 'NegReg', (144, 153))	('LEE011', 'Chemical', 'MESH:C000589651', (101, 107))	('caspase-3', 'Gene', (221, 230))	('flavopiridol', 'Chemical', 'MESH:C077990', (49, 61))	('palbociclib', 'Chemical', 'MESH:C500026', (86, 97))	('CDK4/6', 'Gene', (109, 115))	('caspase-3', 'Gene', '836', (221, 230))	('phospho-RbSer807/811', 'MPA', (154, 174))	('LEE011', 'Var', (101, 107))	('CLF-PED-015-T', 'Disease', 'OMIM:604595', (30, 43))	('G0/G1 arrest', 'CPA', (179, 191))
467789	27329820	We subsequently validated the consequences of XPO1 depletion or inhibition on viability in these cell lines.	('depletion', 'Var', (51, 60))	('inhibition', 'NegReg', (64, 74))	('XPO1', 'Gene', '7514', (46, 50))	('XPO1', 'Gene', (46, 50))
467793	27329820	We observed that deletion of TP53 provided CLF-PED-015-T a growth advantage in the pooled CRISPR-Cas9 screen (Fig.	('CLF-PED-015-T', 'Disease', 'OMIM:604595', (43, 56))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('deletion', 'Var', (17, 25))	('growth', 'MPA', (59, 65))	('CLF-PED-015-T', 'Disease', (43, 56))
467797	27329820	On the basis of this, we assessed whether XPO1 depletion affected p53 levels and function.	('affected', 'Reg', (57, 65))	('function', 'MPA', (81, 89))	('p53', 'Gene', '7157', (66, 69))	('depletion', 'Var', (47, 56))	('XPO1', 'Gene', '7514', (42, 46))	('XPO1', 'Gene', (42, 46))	('p53', 'Gene', (66, 69))
467804	27329820	These observations suggest that p53 is not the sole mediator of the response to inhibiting XPO1 in this setting, and that inhibiting or suppressing XPO1 decreased the proliferation of CLF-PED-015-T. To confirm whether these findings extended to tumours growing in vivo, we tested the CDK4 and XPO1 dependencies using a micro-dosing device.	('CLF-PED-015-T', 'Disease', 'OMIM:604595', (184, 197))	('CDK4', 'Gene', '1019', (284, 288))	('p53', 'Gene', '7157', (32, 35))	('decreased', 'NegReg', (153, 162))	('XPO1', 'Gene', (293, 297))	('XPO1', 'Gene', '7514', (91, 95))	('p53', 'Gene', (32, 35))	('XPO1', 'Gene', (148, 152))	('suppressing', 'NegReg', (136, 147))	('tested', 'Reg', (273, 279))	('tumours', 'Disease', (245, 252))	('XPO1', 'Gene', '7514', (293, 297))	('inhibiting', 'Var', (122, 132))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('XPO1', 'Gene', (91, 95))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('CDK4', 'Gene', (284, 288))	('XPO1', 'Gene', '7514', (148, 152))	('CLF-PED-015-T', 'Disease', (184, 197))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('proliferation', 'CPA', (167, 180))
467813	27329820	These observations suggest that inhibiting CDK4 or XPO1 inhibits tumour growth in vivo.	('tumour growth', 'Disease', (65, 78))	('CDK4', 'Gene', (43, 47))	('inhibits', 'NegReg', (56, 64))	('XPO1', 'Gene', '7514', (51, 55))	('tumour growth', 'Disease', 'MESH:D006130', (65, 78))	('XPO1', 'Gene', (51, 55))	('CDK4', 'Gene', '1019', (43, 47))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('inhibiting', 'Var', (32, 42))
467903	27134710	Apart from racial and ethnic disparities noted for cancers in AYC patients, other attributing factors to this dismal prognosis include lower socioeconomic status, poor parental education, poor health insurance status, untimely diagnosis, non-enrollment in cooperative group clinical trials, inadequate knowledge about the cancer diagnosis, poor quality of treatment and supportive care, differences in disease biology, genetic polymorphisms in the metabolism of chemotherapeutic drugs, and variations in adherence to therapy.	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('cancers', 'Disease', (51, 58))	('cancer', 'Disease', (322, 328))	('variations', 'Reg', (490, 500))	('differences', 'Reg', (387, 398))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('genetic polymorphisms', 'Var', (419, 440))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('patients', 'Species', '9606', (66, 74))
467954	20576167	Identification of target genes for wild type and truncated HMGA2 in mesenchymal stem-like cells The HMGA2 gene, coding for an architectural transcription factor involved in mesenchymal embryogenesis, is frequently deranged by translocation and/or amplification in mesenchymal tumours, generally leading to over-expression of shortened transcripts and a truncated protein.	('mesenchymal tumours', 'Disease', (264, 283))	('translocation', 'Var', (226, 239))	('deranged', 'Reg', (214, 222))	('truncated', 'MPA', (353, 362))	('HMGA2', 'Gene', '8091', (59, 64))	('over-expression', 'MPA', (306, 321))	('shortened transcripts', 'MPA', (325, 346))	('mesenchymal tumours', 'Disease', 'MESH:D008637', (264, 283))	('HMGA2', 'Gene', (59, 64))	('HMGA2', 'Gene', '8091', (100, 105))	('leading', 'Reg', (295, 302))	('amplification', 'Var', (247, 260))	('tumours', 'Phenotype', 'HP:0002664', (276, 283))	('protein', 'Protein', (363, 370))	('HMGA2', 'Gene', (100, 105))
467955	20576167	To identify pathways that are affected by sarcoma-associated variants of HMGA2, we have over-expressed wild type and truncated HMGA2 protein in an immortalized mesenchymal stem-like cell (MSC) line, and investigated the localisation of these proteins and their effects on differentiation and gene expression patterns.	('protein', 'Protein', (133, 140))	('HMGA2', 'Gene', (73, 78))	('sarcoma', 'Disease', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('MSC', 'Gene', '9242', (188, 191))	('MSC', 'Gene', (188, 191))	('HMGA2', 'Gene', (127, 132))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('variants', 'Var', (61, 69))
467963	20576167	Aberrations in the chromosomal region 12q14-15 that affect HMGA2 are frequent in a variety of tumours.	('tumours', 'Disease', (94, 101))	('HMGA2', 'Gene', (59, 64))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('Aberrations', 'Var', (0, 11))	('affect', 'Reg', (52, 58))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
467964	20576167	In benign tumours of mesenchymal origin, HMGA2 is often rearranged by translocation, and the resulting chimeric transcripts are formed by fusion of the DNA-binding domains, coded by exons 1-3, to ectopic sequences.	('fusion', 'Interaction', (138, 144))	('chimeric', 'Var', (103, 111))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('benign tumours', 'Disease', (3, 17))	('HMGA2', 'Gene', (41, 46))	('benign tumours', 'Disease', 'MESH:D009369', (3, 17))
467966	20576167	We have cloned and sequenced a number of these cancer-associated ectopic sequences from 12q as well as other chromosomes.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (47, 53))	('ectopic sequences', 'Var', (65, 82))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
467968	20576167	Because HMGA2 most frequently is rearranged in well-differentiated liposarcomas, border-line tumours resembling adipose tissue, most sarcoma cell lines, representing highly malignant cancers with a different tissue type, would not be appropriate to detect a phenotype when the gene is over-expressed.	('malignant cancers', 'Disease', (173, 190))	('rearranged', 'Var', (33, 43))	('HMGA2', 'Gene', (8, 13))	('malignant cancers', 'Disease', 'MESH:D009369', (173, 190))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('border-line tumours', 'Disease', 'MESH:D001882', (81, 100))	('sarcoma', 'Disease', (133, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('liposarcomas', 'Disease', 'MESH:D008080', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('liposarcomas', 'Phenotype', 'HP:0012034', (67, 79))	('border-line tumours', 'Disease', (81, 100))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('liposarcomas', 'Disease', (67, 79))	('sarcoma', 'Disease', (71, 78))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))
467990	20576167	Cells expressing eGFP-HMGA2WT or eGFP-HMGA2TRUNC accumulate the eGFP-tagged proteins in the nuclei, especially in DAPI-dense and nucleolar regions (Fig.	('accumulate', 'PosReg', (49, 59))	('eGFP-HMGA2WT', 'Var', (17, 29))	('eGFP-tagged proteins', 'Protein', (64, 84))	('proteins', 'Protein', (76, 84))	('eGFP-HMGA2TRUNC', 'Var', (33, 48))	('DAPI', 'Chemical', 'MESH:C007293', (114, 118))
467996	20576167	Although we detected no change of the known HMGA2 target Imp2 (IGF2BP2) in this system, the about 2-fold down regulation by both protein variants of both PPARalpha and PPARgamma, central regulators of adipogenesis, could contribute to the differentiation block.	('PPARgamma', 'Gene', '5468', (168, 177))	('PPARalpha', 'Gene', '5465', (154, 163))	('down regulation', 'NegReg', (105, 120))	('PPARgamma', 'Gene', (168, 177))	('PPARalpha', 'Gene', (154, 163))	('IGF2BP2', 'Gene', '10644', (63, 70))	('Imp2', 'Gene', (57, 61))	('Imp2', 'Gene', '10644', (57, 61))	('variants', 'Var', (137, 145))	('IGF2BP2', 'Gene', (63, 70))
468000	20576167	Other cytokines that were initially expressed in the parental cells and down-regulated upon HMGA2 expression were IL1B, IL1RN, IL6, IL11, IL15 and LIF1, all containing validated or predicted NF-kappaB sites and only IL11 and IL15 lack intrinsic binding sites for HMGA proteins.	('IL11', 'Gene', (216, 220))	('down-regulated', 'NegReg', (72, 86))	('IL11', 'Gene', '3589', (216, 220))	('IL6', 'Gene', '3569', (127, 130))	('expression', 'Var', (98, 108))	('NF-kappaB', 'Gene', (191, 200))	('IL15', 'Gene', '3600', (138, 142))	('HMGA2', 'Gene', (92, 97))	('IL15', 'Gene', '3600', (225, 229))	('NF-kappaB', 'Gene', '4790', (191, 200))	('IL6', 'Gene', (127, 130))	('IL1RN', 'Gene', (120, 125))	('IL11', 'Gene', (132, 136))	('IL11', 'Gene', '3589', (132, 136))	('IL1RN', 'Gene', '3557', (120, 125))	('IL15', 'Gene', (138, 142))	('IL1B', 'Gene', (114, 118))	('IL15', 'Gene', (225, 229))	('IL1B', 'Gene', '3553', (114, 118))	('binding', 'Interaction', (245, 252))
468009	20576167	There were several genes up-regulated by HMGA2WT and down- regulated in cells expressing the truncated form, such as FGF13, EHF, HCLS1, MEST, G0S2 and PTPRN2.	('PTPRN2', 'Gene', (151, 157))	('down- regulated', 'NegReg', (53, 68))	('HCLS1', 'Gene', (129, 134))	('up-regulated', 'PosReg', (25, 37))	('HCLS1', 'Gene', '3059', (129, 134))	('MEST', 'Gene', (136, 140))	('FGF13', 'Gene', (117, 122))	('MEST', 'Gene', '4232', (136, 140))	('FGF13', 'Gene', '2258', (117, 122))	('PTPRN2', 'Gene', '5799', (151, 157))	('EHF', 'Gene', '26298', (124, 127))	('HMGA2WT', 'Var', (41, 48))	('G0S2', 'Gene', '50486', (142, 146))	('G0S2', 'Gene', (142, 146))	('EHF', 'Gene', (124, 127))
468014	20576167	Based on the microarray data, the SSX gene family appeared to be co-induced in cells expressing HMGA2TRUNC, but real-time PCR was only able to verify the induction of SSX1 transcripts.	('SSX1', 'Gene', (167, 171))	('SSX', 'Gene', (167, 170))	('SSX', 'Gene', '6757', (167, 170))	('SSX', 'Gene', '6757', (34, 37))	('SSX', 'Gene', (34, 37))	('HMGA2TRUNC', 'Var', (96, 106))	('SSX1', 'Gene', '6756', (167, 171))
468019	20576167	Transgenic mice overexpressing truncated HMGA2 gene, on the other hand, develop well differentiated lipomas and abundant adipose tissue.	('truncated', 'Var', (31, 40))	('abundant adipose tissue', 'Phenotype', 'HP:0009126', (112, 135))	('lipomas', 'Phenotype', 'HP:0012032', (100, 107))	('lipomas', 'Disease', 'MESH:D008067', (100, 107))	('Transgenic mice', 'Species', '10090', (0, 15))	('lipomas', 'Disease', (100, 107))	('HMGA2', 'Gene', (41, 46))
468026	20576167	The modulation of chromatin by HMGA2 could also be responsible for the coordinated induction of the chromosome 19 KRAB-ZNF genes.	('HMGA2', 'Gene', (31, 36))	('modulation', 'Var', (4, 14))	('induction', 'PosReg', (83, 92))	('ZNF', 'Gene', (119, 122))	('ZNF', 'Gene', '284390', (119, 122))
468035	20576167	An AT-rich region 1 kb upstream from transcription start of SSX1 contains a likely binding site for HMGA2 (-1076 TATTAATAT), although it remains to be proven that it binds specifically to HMGA2TRUNC.	('SSX1', 'Gene', (60, 64))	('binding', 'Interaction', (83, 90))	('SSX1', 'Gene', '6756', (60, 64))	('-1076 TATTAATAT', 'Var', (107, 122))	('HMGA2', 'Gene', (100, 105))
468039	20576167	The induction of CXCL12 gene expression by HMGA2TRUNC is probably the cause of down-regulation of HLA-DRA and other major histocompatibility complex class II (MHC-II) proteins on the cell surface, due to this cytokine's ability to repress the class II transactivator.	('HLA-DRA', 'Gene', (98, 105))	('HMGA2TRUNC', 'Var', (43, 53))	('CXCL12', 'Gene', '6387', (17, 23))	('class II transactivator', 'Gene', '4261', (243, 266))	('class II transactivator', 'Gene', (243, 266))	('down-regulation', 'NegReg', (79, 94))	('CXCL12', 'Gene', (17, 23))	('HLA-DRA', 'Gene', '3122', (98, 105))
468042	20576167	Their lost ability to present tumor antigens on their cell surfaces may contribute to their escape from immunosurveillance and therefore this might also provide a selective advantage to sarcoma cells expressing truncated HMGA2.	('HMGA2', 'Gene', (221, 226))	('advantage', 'PosReg', (173, 182))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('lost', 'NegReg', (6, 10))	('sarcoma', 'Disease', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('ability', 'MPA', (11, 18))	('truncated', 'Var', (211, 220))	('tumor', 'Disease', (30, 35))	('escape', 'CPA', (92, 98))
468043	20576167	Since HMGA2 truncation and amplification is observed initially in the development of well-differentiated liposarcomas, borderline tumours of adipocytic differentiation, and always in combination with amplification of the p53-blocking MDM2, we do not expect a very "malignant" phenotype when HMGA2 is overexpressed on its own.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('liposarcomas', 'Disease', 'MESH:D008080', (105, 117))	('liposarcomas', 'Disease', (105, 117))	('truncation', 'Var', (12, 22))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumours', 'Disease', (130, 137))	('p53', 'Gene', (221, 224))	('p53', 'Gene', '7157', (221, 224))	('MDM2', 'Gene', '4193', (234, 238))	('HMGA2', 'Gene', (6, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('MDM2', 'Gene', (234, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('liposarcomas', 'Phenotype', 'HP:0012034', (105, 117))
468045	20576167	When truncated HMGA2 is overexpressed in transgenic mice, they develop adipose hypertrophy, which indicates that adipocytic differentiation is not completely blocked.	('adipose hypertrophy', 'Phenotype', 'HP:0030759', (71, 90))	('HMGA2', 'Gene', (15, 20))	('hypertrophy', 'Disease', (79, 90))	('develop', 'PosReg', (63, 70))	('hypertrophy', 'Disease', 'MESH:D006984', (79, 90))	('truncated', 'Var', (5, 14))	('transgenic mice', 'Species', '10090', (41, 56))
468048	20576167	To investigate these questions, we will determine the activity of truncated HMGA2 in sarcoma cells by siRNA-based knock-down in cells with the natural malignant genetic background.	('HMGA2', 'Gene', (76, 81))	('truncated', 'Var', (66, 75))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('activity', 'MPA', (54, 62))	('sarcoma', 'Disease', (85, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
468049	20576167	Our results show that over-expression of truncated HMGA2 induces a more mesenchymal (stem-like) phenotype, characterized by resistance toward differentiation, over-expression of SSX1, lost expression of certain epithelial markers and strengthened expression of mesenchymal markers.	('HMGA2', 'Gene', (51, 56))	('resistance toward differentiation', 'CPA', (124, 157))	('more', 'PosReg', (67, 71))	('mesenchymal markers', 'CPA', (261, 280))	('over-expression', 'PosReg', (159, 174))	('strengthened', 'PosReg', (234, 246))	('expression', 'MPA', (247, 257))	('SSX1', 'Gene', '6756', (178, 182))	('truncated', 'Var', (41, 50))	('expression', 'MPA', (189, 199))	('over-expression', 'PosReg', (22, 37))	('epithelial', 'CPA', (211, 221))	('lost', 'NegReg', (184, 188))	('SSX1', 'Gene', (178, 182))	('induces', 'PosReg', (57, 64))
468050	20576167	We suggest that amplification and truncation of HMGA2 in sarcoma provide the tumors with a more stem-like phenotype.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('amplification', 'Var', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('truncation', 'Var', (34, 44))	('sarcoma', 'Disease', (57, 64))	('HMGA2', 'Gene', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
468094	33503816	Then, HHV-8 infection was determined by nested PCR to obtain a 737-nt long fragment of the K1 gene (ORF-K1) using K1AG75s/K1AG1200 and VR1s/VR2as1 primer sets.	('men', 'Species', '9606', (79, 82))	('K1AG75s/K1AG1200', 'Var', (114, 130))	('ORF-K1', 'Gene', (100, 106))	('VR2', 'Gene', (140, 143))	('VR1', 'Gene', (135, 138))	('VR2', 'Gene', '56663', (140, 143))	('HHV-8 infection', 'Disease', (6, 21))	('HHV-8 infection', 'Disease', 'MESH:C537372', (6, 21))	('VR1', 'Gene', '56664', (135, 138))
468112	33503816	Thus, HHV-8 seroprevalence was 37.2% among HTLV-1 negative individuals (333/895) and 31.5% among HTLV-1 positive individuals (39/124) (p-value = 0.22).	('HHV-8', 'Gene', (6, 11))	('seroprevalence', 'Var', (12, 26))	('HHV-8', 'Species', '37296', (6, 11))	('HTLV-1', 'Species', '11908', (97, 103))	('HTLV-1', 'Species', '11908', (43, 49))	('negative', 'NegReg', (50, 58))	('HTLV-1', 'Gene', (43, 49))
468131	33503816	These 122 HHV-8 strains included many of the sequences characterized for the complete or near complete K1 gene in individuals from African countries, plus most of the classical prototype strains such as BC-1 (AF178807) and BCBL-1 (JN800483) for the A genotype and Ug52 (AF130290) and Ug81 (AF130291) for the B one.	('AF178807', 'Var', (209, 217))	('JN800483', 'Var', (231, 239))	('HHV-8', 'Species', '37296', (10, 15))	('HHV-8', 'Gene', (10, 15))
468135	33503816	Finally, the Gab135NY strain clustered in the genotype F clade, which was previously found in Kenya (KE-234-FJ884616), Uganda (HKS22-AY953882) and in France among men having sex with men (MSM) (K1-43/Berr-AF178810; P072_MCD-MK876734; P075_MCD-MK876735; P076_PEL-MK876736; P030_KS-MK876732).	('KS', 'Phenotype', 'HP:0100726', (277, 279))	('men', 'Species', '9606', (163, 166))	('men', 'Species', '9606', (183, 186))	('Gab135NY', 'Chemical', '-', (13, 21))	('P076_PEL-MK876736', 'Var', (253, 270))	('KS', 'Phenotype', 'HP:0100726', (128, 130))	('P075_MCD-MK876735; P076_PEL-MK876736', 'Var', (234, 270))	('having sex', 'Phenotype', 'HP:0030214', (167, 177))
468166	33503816	Interestingly, a recent report described the presence of such variants in 4.5% of Caucasian MSM living in Paris, France, but not in other HHV-8 infected epidemiological groups of the same area.	('HHV-8 infected', 'Disease', 'MESH:C537372', (138, 152))	('variants', 'Var', (62, 70))	('HHV-8 infected', 'Disease', (138, 152))
468189	31276706	TP53 in bone and soft tissue sarcomas Genomic and functional study of existing and emerging sarcoma targets, such as fusion proteins, chromosomal aberrations, reduced tumor suppressor activity, and oncogenic drivers, is broadening our understanding of sarcomagenesis.	('sarcoma', 'Disease', 'MESH:D012509', (252, 259))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (17, 36))	('sarcoma', 'Disease', (252, 259))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (17, 37))	('sarcomagenesis', 'Disease', 'None', (252, 266))	('TP53', 'Gene', '7157', (0, 4))	('reduced', 'NegReg', (159, 166))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('sarcoma', 'Disease', (29, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Disease', (92, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('sarcomas', 'Disease', (29, 37))	('tumor', 'Disease', (167, 172))	('chromosomal aberrations', 'Var', (134, 157))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (134, 157))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('TP53', 'Gene', (0, 4))	('sarcomagenesis', 'Disease', (252, 266))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
468191	31276706	Although mutations in TP53 were thought to be relatively low in sarcomas, modern techniques including whole-genome sequencing have recently illuminated unappreciated alterations in TP53 in osteosarcoma.	('TP53', 'Gene', (181, 185))	('mutations', 'Var', (9, 18))	('osteosarcoma', 'Phenotype', 'HP:0002669', (189, 201))	('osteosarcoma', 'Disease', (189, 201))	('osteosarcoma', 'Disease', 'MESH:D012516', (189, 201))	('sarcomas', 'Disease', 'MESH:D012509', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcomas', 'Disease', (64, 72))	('TP53', 'Gene', (22, 26))
468192	31276706	In addition, oncogenic gain-of-function activities of missense mutant p53 (mutp53) have been reported in sarcomas.	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('gain-of-function', 'PosReg', (23, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('sarcomas', 'Disease', 'MESH:D012509', (105, 113))	('p53', 'Gene', (78, 81))	('activities', 'MPA', (40, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcomas', 'Disease', (105, 113))	('p53', 'Gene', '7157', (78, 81))	('missense mutant', 'Var', (54, 69))
468193	31276706	Moreover, new targeting strategies for TP53 have been discovered: restoration of wild-type p53 (wtp53) activity through inhibition of TP53 negative regulators, reactivation of the wtp53 activity from mutp53, depletion of mutp53, and targeting of vulnerabilities in cells with TP53 deletions or mutations.	('p53', 'Gene', (224, 227))	('p53', 'Gene', '7157', (224, 227))	('activity', 'MPA', (103, 111))	('p53', 'Gene', '7157', (182, 185))	('depletion', 'MPA', (208, 217))	('deletions', 'Var', (281, 290))	('reactivation', 'MPA', (160, 172))	('TP53', 'Gene', (276, 280))	('p53', 'Gene', (91, 94))	('inhibition', 'NegReg', (120, 130))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (91, 94))	('mutations', 'Var', (294, 303))	('p53', 'Gene', '7157', (203, 206))	('p53', 'Gene', '7157', (98, 101))	('p53', 'Gene', (182, 185))	('p53', 'Gene', (203, 206))
468195	31276706	We have outlined nine bone and soft tissue sarcomas for which TP53 plays a crucial tumor suppressive role.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (31, 51))	('tumor', 'Disease', (83, 88))	('sarcomas', 'Disease', (43, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (31, 50))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('TP53', 'Var', (62, 66))
468205	31276706	Several unappreciated mutations and chromosomal abnormalities are found in osteosarcoma, including genes associated with IGF signaling, alterations in the PI3K/mTOR pathway, and somatic structural variations in TP53.	('osteosarcoma', 'Disease', (75, 87))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('mTOR', 'Gene', '2475', (160, 164))	('mTOR', 'Gene', (160, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('alterations', 'Reg', (136, 147))	('structural variations', 'Var', (186, 207))	('IGF', 'MPA', (121, 124))	('TP53', 'Gene', (211, 215))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (36, 61))	('chromosomal abnormalities', 'Disease', (36, 61))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))
468206	31276706	Genome sequencing of Ewing sarcoma reveals mutations related to DNA repair machineries.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('Ewing sarcoma', 'Disease', (21, 34))	('mutations', 'Var', (43, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))
468207	31276706	show that complex chromosome rearrangements at the early stage of Ewing sarcoma development may contribute to EWS-ETS gene fusions and other DNA rearrangements.	('EWS', 'Gene', '2130', (110, 113))	('EWS', 'Gene', (110, 113))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (66, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('Ewing sarcoma', 'Disease', (66, 79))	('contribute', 'Reg', (96, 106))	('fusions', 'Var', (123, 130))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (66, 79))
468209	31276706	These findings have further confirmed the significance of mutations and genetic abnormalities in the TP53 gene on bone and soft tissue sarcoma progression.	('mutations', 'Var', (58, 67))	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (123, 142))	('genetic abnormalities', 'Disease', 'MESH:D030342', (72, 93))	('sarcoma', 'Disease', (135, 142))	('TP53', 'Gene', (101, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('genetic abnormalities', 'Disease', (72, 93))
468210	31276706	Mutations in TP53 are detected in about half of all tumors, remaining the most frequently mutated gene in human cancers.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('human', 'Species', '9606', (106, 111))	('TP53', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
468211	31276706	Previously, mutations in TP53 were thought to occur at a relatively low frequency in sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('TP53', 'Gene', (25, 29))	('sarcomas', 'Disease', (85, 93))	('mutations', 'Var', (12, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcomas', 'Disease', 'MESH:D012509', (85, 93))
468212	31276706	This is mainly because mutations in TP53 were identified by sequencing only exonic regions in the DNA binding domain or by performing immunohistochemistry (IHC) to detect positive staining in p53-mutated tumors due to the long half-life of the mutant protein.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('TP53', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mutant', 'Var', (244, 250))	('p53', 'Gene', '7157', (192, 195))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('p53', 'Gene', (192, 195))
468214	31276706	Since the variety of alterations to TP53 and TP53 upstream regulators are detected in sarcomas, we will also discuss several distinct TP53 targeting strategies in this review article (Table 1).	('TP53', 'Gene', (45, 49))	('sarcomas', 'Disease', 'MESH:D012509', (86, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('detected', 'Reg', (74, 82))	('sarcomas', 'Disease', (86, 94))	('TP53', 'Gene', (36, 40))	('alterations', 'Var', (21, 32))
468216	31276706	Typically, tumor suppressors have loss-of-function (LOF) mutations or deletions in cancers; however, the majority of TP53 mutations are missense mutations in the DNA binding domain, such that mutant TP53 (mutp53) not only loses the tumor suppressive function but also gains oncogenic functions (GOF: gain of function) independent of wild-type TP53 (wtp53).	('p53', 'Gene', '7157', (351, 354))	('TP53', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('oncogenic functions', 'CPA', (274, 293))	('p53', 'Gene', '7157', (208, 211))	('gains', 'PosReg', (268, 273))	('mutant', 'Var', (192, 198))	('p53', 'Gene', (351, 354))	('tumor', 'Disease', (11, 16))	('p53', 'Gene', (208, 211))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('TP53', 'Gene', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('mutations', 'Var', (122, 131))	('loses', 'NegReg', (222, 227))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
468217	31276706	However, overall, the majority of TP53 mutants lose tumor suppressive function, at least partially, and some mutants show distinct oncogenic activities to promote malignant progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('oncogenic activities', 'CPA', (131, 151))	('malignant progression', 'CPA', (163, 184))	('TP53', 'Gene', (34, 38))	('tumor', 'Disease', (52, 57))	('lose', 'NegReg', (47, 51))	('promote', 'PosReg', (155, 162))	('mutants', 'Var', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
468218	31276706	These mutants' oncogenic properties are seen throughout a variety of cancers including bone and soft tissue sarcomas.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('mutants', 'Var', (6, 13))	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (96, 116))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcomas', 'Disease', (108, 116))	('bone', 'Disease', (87, 91))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (96, 115))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
468220	31276706	The link between germline mutations of TP53 and LFS was confirmed by molecular testing in 1990.	('TP53', 'Gene', (39, 43))	('germline mutations', 'Var', (17, 35))	('LFS', 'Disease', 'MESH:D016864', (48, 51))	('LFS', 'Disease', (48, 51))
468221	31276706	Over 70% of patients with LFS inherently harbor a mutation in the TP53 gene in their germlines and frequently develop various types of cancer at early ages, including osteosarcoma, rhabdomyosarcoma (RMS), brain tumors, breast cancer, leukemias, and adrenocortical carcinoma.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (181, 197))	('LFS', 'Disease', 'MESH:D016864', (26, 29))	('develop', 'Reg', (110, 117))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (249, 273))	('mutation', 'Var', (50, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (167, 179))	('patients', 'Species', '9606', (12, 20))	('cancer', 'Disease', (135, 141))	('leukemias', 'Disease', 'MESH:D007938', (234, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('osteosarcoma, rhabdomyosarcoma', 'Disease', 'MESH:D012516', (167, 197))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (249, 273))	('leukemias', 'Phenotype', 'HP:0001909', (234, 243))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('brain tumors', 'Disease', 'MESH:D001932', (205, 217))	('brain tumors', 'Phenotype', 'HP:0030692', (205, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('TP53', 'Gene', (66, 70))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('adrenocortical carcinoma', 'Disease', (249, 273))	('breast cancer', 'Disease', (219, 232))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('leukemias', 'Disease', (234, 243))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('brain tumors', 'Disease', (205, 217))	('RMS', 'Phenotype', 'HP:0002859', (199, 202))	('cancer', 'Disease', (226, 232))	('LFS', 'Disease', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
468224	31276706	report that young-onset osteosarcoma has a higher frequency of LFS-associated TP53 mutations.	('mutations', 'Var', (83, 92))	('osteosarcoma', 'Phenotype', 'HP:0002669', (24, 36))	('LFS', 'Disease', (63, 66))	('osteosarcoma', 'Disease', (24, 36))	('osteosarcoma', 'Disease', 'MESH:D012516', (24, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('TP53', 'Gene', (78, 82))	('LFS', 'Disease', 'MESH:D016864', (63, 66))
468225	31276706	Moreover, they show that the presence of a rare TP53 variant leading to an exonic splice site change, rs1800372 (p.R213R), is associated with metastasis at diagnosis of osteosarcoma.	('rs1800372 (p.R213R', 'Var', (102, 120))	('associated with', 'Reg', (126, 141))	('metastasis', 'Disease', (142, 152))	('rs1800372', 'Mutation', 'rs1800372', (102, 111))	('TP53', 'Gene', (48, 52))	('p.R213R', 'Mutation', 'rs1800372', (113, 120))	('osteosarcoma', 'Phenotype', 'HP:0002669', (169, 181))	('osteosarcoma', 'Disease', (169, 181))	('osteosarcoma', 'Disease', 'MESH:D012516', (169, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))
468232	31276706	Osteosarcomas frequently show complex karyotypes and genomic instability including gene amplifications (MYC, CCNE, Rad21, VEGFQ, AURKB, CDK4), deletions (TP53, RB1, PTEN), somatic nucleotide variants (SNVs) or short indels (TP53, ATRX, RBs, PRKDC), and structural variants (SVs: TP53, LRP1B, RB1, FHIT).	('PRKDC', 'Gene', (241, 246))	('LRP1B', 'Gene', (285, 290))	('PTEN', 'Gene', '5728', (165, 169))	('VEGF', 'Gene', '7422', (122, 126))	('Rad21', 'Gene', '5885', (115, 120))	('MYC', 'Gene', (104, 107))	('Osteosarcomas', 'Phenotype', 'HP:0002669', (0, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('VEGF', 'Gene', (122, 126))	('AURKB', 'Gene', '9212', (129, 134))	('FHIT', 'Gene', (297, 301))	('LRP1B', 'Gene', '53353', (285, 290))	('CDK4', 'Gene', (136, 140))	('CCNE', 'Gene', (109, 113))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('MYC', 'Gene', '4609', (104, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('CCNE', 'Gene', '898', (109, 113))	('Osteosarcomas', 'Disease', (0, 13))	('ATRX', 'Gene', (230, 234))	('FHIT', 'Gene', '2272', (297, 301))	('deletions', 'Var', (143, 152))	('ATRX', 'Gene', '546', (230, 234))	('CDK4', 'Gene', '1019', (136, 140))	('Rad21', 'Gene', (115, 120))	('Osteosarcomas', 'Disease', 'MESH:D012516', (0, 13))	('PRKDC', 'Gene', '5591', (241, 246))	('PTEN', 'Gene', (165, 169))	('AURKB', 'Gene', (129, 134))
468234	31276706	Mutation of TP53 is well-correlated with genomic and chromosomal instability in human high-grade osteosarcoma.	('Mutation', 'Var', (0, 8))	('well-correlated', 'Reg', (20, 35))	('osteosarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('human', 'Species', '9606', (80, 85))	('osteosarcoma', 'Disease', (97, 109))	('osteosarcoma', 'Disease', 'MESH:D012516', (97, 109))	('TP53', 'Gene', (12, 16))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
468235	31276706	One early immunohistochemistry (IHC) study shows that 27 out of 46 (58.7%) osteosarcoma specimens exhibit TP53 overexpression, a common indicator of TP53 missense mutations, while other studies show fewer TP53 mutations in osteosarcoma.	('osteosarcoma', 'Disease', (75, 87))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('missense mutations', 'Var', (154, 172))	('osteosarcoma', 'Disease', (223, 235))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (223, 235))	('osteosarcoma', 'Disease', 'MESH:D012516', (223, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('overexpression', 'PosReg', (111, 125))	('TP53', 'Gene', (106, 110))
468236	31276706	first reported intron 1 rearrangements in the TP53 gene in 3 out of 6 human osteosarcoma samples in 1987.	('rearrangements', 'Var', (24, 38))	('human', 'Species', '9606', (70, 75))	('TP53', 'Gene', (46, 50))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('osteosarcoma', 'Disease', (76, 88))	('osteosarcoma', 'Disease', 'MESH:D012516', (76, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
468237	31276706	Indeed, a recent whole-genome sequencing of 34 osteosarcoma samples has discovered similar mutations in the TP53 gene.	('osteosarcoma', 'Disease', (47, 59))	('osteosarcoma', 'Disease', 'MESH:D012516', (47, 59))	('TP53', 'Gene', (108, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('mutations', 'Var', (91, 100))	('osteosarcoma', 'Phenotype', 'HP:0002669', (47, 59))
468238	31276706	This finding is supported by the report by Ribi et al., where 16% of sporadic osteosarcomas show intron 1 rearrangements, while no other tumors have such TP53 rearrangements.	('rearrangements', 'Var', (106, 120))	('osteosarcomas', 'Disease', 'MESH:D012516', (78, 91))	('tumors', 'Disease', (137, 143))	('intron', 'Gene', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('osteosarcomas', 'Disease', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('osteosarcomas', 'Phenotype', 'HP:0002669', (78, 91))	('osteosarcoma', 'Phenotype', 'HP:0002669', (78, 90))
468240	31276706	demonstrates that TP53 alterations including structural variation (SV) and somatic nucleotide variants (SNVs) are detected in 74% of human osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('detected', 'Reg', (114, 122))	('structural', 'MPA', (45, 55))	('TP53', 'Gene', (18, 22))	('alterations', 'Var', (23, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('human', 'Species', '9606', (133, 138))	('osteosarcoma', 'Disease', (139, 151))	('osteosarcoma', 'Disease', 'MESH:D012516', (139, 151))
468241	31276706	Biologically, loss of TP53 activity is shown to promote osteogenic differentiation of bone marrow stromal cells, as well as osteosarcoma development from MSCs.	('loss', 'Var', (14, 18))	('TP53', 'Protein', (22, 26))	('osteosarcoma', 'Disease', (124, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('osteogenic differentiation', 'CPA', (56, 82))	('promote', 'PosReg', (48, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('activity', 'MPA', (27, 35))
468242	31276706	Genetic deletion or mutations of TP53 in mice with the C57BL/6 background often results in osteosarcoma development.	('results in', 'Reg', (80, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('mice', 'Species', '10090', (41, 45))	('TP53', 'Gene', (33, 37))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('osteosarcoma', 'Disease', (91, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (91, 103))	('mutations', 'Var', (20, 29))
468243	31276706	Also, mice expressing gain-of-function (GOF) TP53R172H (R172H is equivalent to human R175H) spontaneously develop metastatic tumors, including osteosarcoma at a high frequency (~30% in the C57BL/6 background).	('gain-of-function', 'PosReg', (22, 38))	('R172H', 'Mutation', 'p.R172H', (49, 54))	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('human', 'Species', '9606', (79, 84))	('TP53R172H', 'Var', (45, 54))	('osteosarcoma', 'Disease', (143, 155))	('osteosarcoma', 'Disease', 'MESH:D012516', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mice', 'Species', '10090', (6, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('R175H', 'Mutation', 'rs28934578', (85, 90))	('R172H', 'Mutation', 'p.R172H', (56, 61))
468245	31276706	Moreover, combined deletion of TP53 and RB1 in mouse osteoblasts results in development of metastatic osteosarcoma at a high frequency.	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('osteosarcoma', 'Disease', 'MESH:D012516', (102, 114))	('TP53', 'Gene', (31, 35))	('deletion', 'Var', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('RB1', 'Gene', (40, 43))	('results in development', 'Reg', (65, 87))	('mouse', 'Species', '10090', (47, 52))	('osteosarcoma', 'Disease', (102, 114))
468246	31276706	Thus, deletions and mutations in TP53 significantly contribute to osteosarcoma progression in mouse models, supporting findings in humans.	('humans', 'Species', '9606', (131, 137))	('deletions', 'Var', (6, 15))	('osteosarcoma', 'Disease', (66, 78))	('mouse', 'Species', '10090', (94, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('osteosarcoma', 'Disease', 'MESH:D012516', (66, 78))	('TP53', 'Gene', (33, 37))	('contribute', 'Reg', (52, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('mutations', 'Var', (20, 29))
468247	31276706	Previous studies have shown that mutations in TP53 are associated with chemoresistance or poor event-free survival in human osteosarcoma.	('poor', 'NegReg', (90, 94))	('osteosarcoma', 'Disease', (124, 136))	('associated', 'Reg', (55, 65))	('chemoresistance', 'CPA', (71, 86))	('mutations', 'Var', (33, 42))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('TP53', 'Gene', (46, 50))	('human', 'Species', '9606', (118, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
468249	31276706	supports this, showing that deletion of TP53 is found in an osteosarcoma cell line with acquired resistance to cisplatin.	('osteosarcoma', 'Disease', 'MESH:D012516', (60, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('TP53', 'Gene', (40, 44))	('osteosarcoma', 'Disease', (60, 72))	('deletion', 'Var', (28, 36))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))
468250	31276706	However, multiple meta-analyses suggest that while TP53 mutations could serve as an effective prognostic marker only for 2- or 3-year overall survival of patients with osteosarcoma, TP53 status does not appear to be correlated with development of metastases and chemotherapy response in patients with osteosarcoma.	('mutations', 'Var', (56, 65))	('osteosarcoma', 'Disease', 'MESH:D012516', (301, 313))	('metastases', 'Disease', 'MESH:D009362', (247, 257))	('TP53', 'Gene', (51, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (168, 180))	('osteosarcoma', 'Disease', (168, 180))	('osteosarcoma', 'Disease', 'MESH:D012516', (168, 180))	('patients', 'Species', '9606', (287, 295))	('patients', 'Species', '9606', (154, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (306, 313))	('metastases', 'Disease', (247, 257))	('correlated', 'Reg', (216, 226))	('osteosarcoma', 'Disease', (301, 313))	('osteosarcoma', 'Phenotype', 'HP:0002669', (301, 313))
468251	31276706	Considering frequent observations of the TP53 intron 1 rearrangement, it may be important to re-evaluate the clinical significance of TP53 alterations in malignancy, response to chemotherapy, and metastasis of human osteosarcoma and other types of cancer.	('cancer', 'Disease', (248, 254))	('osteosarcoma', 'Phenotype', 'HP:0002669', (216, 228))	('TP53', 'Gene', (134, 138))	('osteosarcoma', 'Disease', (216, 228))	('osteosarcoma', 'Disease', 'MESH:D012516', (216, 228))	('alterations', 'Var', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('human', 'Species', '9606', (210, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('malignancy', 'Disease', (154, 164))
468252	31276706	Alterations to regulators of TP53 can also contribute to development of osteosarcoma.	('contribute', 'Reg', (43, 53))	('Alterations', 'Var', (0, 11))	('osteosarcoma', 'Disease', (72, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (72, 84))	('TP53', 'Gene', (29, 33))	('osteosarcoma', 'Disease', 'MESH:D012516', (72, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
468256	31276706	However, mutations in TP53, but not copy number of MDM2, are correlated with overall genomic instability in high-grade human osteosarcoma.	('genomic instability', 'MPA', (85, 104))	('mutations', 'Var', (9, 18))	('correlated', 'Reg', (61, 71))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('osteosarcoma', 'Disease', (125, 137))	('osteosarcoma', 'Disease', 'MESH:D012516', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('TP53', 'Gene', (22, 26))	('human', 'Species', '9606', (119, 124))
468257	31276706	Although a multivariate analysis shows that the MDM2 polymorphism T309G which increases MDM2 expression levels via an extra SP1 binding site in the MDM2 promoter is associated with an increased risk of developing high-grade osteosarcomas in female patients, there is no conclusive literature showing correlation of MDM2 overexpression with survival and prognosis of human osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (224, 236))	('osteosarcomas', 'Disease', 'MESH:D012516', (224, 237))	('T309G', 'Var', (66, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (229, 237))	('human', 'Species', '9606', (366, 371))	('osteosarcomas', 'Disease', (224, 237))	('expression levels', 'MPA', (93, 110))	('MDM2', 'MPA', (88, 92))	('osteosarcoma', 'Phenotype', 'HP:0002669', (372, 384))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('T309G', 'Mutation', 'rs2279744', (66, 71))	('osteosarcomas', 'Phenotype', 'HP:0002669', (224, 237))	('osteosarcoma', 'Disease', (224, 236))	('osteosarcoma', 'Disease', 'MESH:D012516', (224, 236))	('MDM2', 'Gene', (48, 52))	('increases', 'PosReg', (78, 87))	('patients', 'Species', '9606', (248, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (377, 384))	('associated with', 'Reg', (165, 180))	('osteosarcoma', 'Disease', (372, 384))	('osteosarcoma', 'Disease', 'MESH:D012516', (372, 384))
468259	31276706	In addition, multiple studies have highlighted the expression of MDM4 splice variants in different tumor types.	('tumor', 'Disease', (99, 104))	('MDM4', 'Gene', (65, 69))	('splice variants', 'Var', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
468260	31276706	Overexpression of MDM4-S has been linked to poor prognosis in osteosarcoma, soft tissue sarcoma, and other cancers.	('cancers', 'Disease', (107, 114))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (62, 74))	('sarcoma', 'Disease', (67, 74))	('osteosarcoma', 'Disease', (62, 74))	('osteosarcoma', 'Disease', 'MESH:D012516', (62, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('Overexpression', 'Var', (0, 14))	('MDM4-S', 'Gene', (18, 24))	('sarcoma', 'Disease', (88, 95))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (76, 95))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
468261	31276706	Thus, MDM4-S overexpression can serve as an effective biomarker for TP53 pathway attenuation in cancers.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('attenuation', 'NegReg', (81, 92))	('MDM4-S', 'Var', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('overexpression', 'PosReg', (13, 27))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('TP53 pathway', 'Pathway', (68, 80))	('cancers', 'Disease', (96, 103))
468268	31276706	Although MYC gene amplification and TP53 mutations are detected in Pagetic osteosarcomas and loss of TP53 activity is reported to reduce Sqstm1/p62 levels, the direct role of TP53 in Pagetic osteosarcoma development remains unclear.	('loss', 'NegReg', (93, 97))	('p62', 'Gene', (144, 147))	('p62', 'Gene', '8878', (144, 147))	('Pagetic osteosarcoma', 'Disease', 'MESH:C538098', (183, 203))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('TP53', 'Gene', (101, 105))	('osteosarcoma', 'Phenotype', 'HP:0002669', (191, 203))	('TP53', 'Gene', (36, 40))	('Pagetic osteosarcoma', 'Disease', (183, 203))	('mutations', 'Var', (41, 50))	('Sqstm1', 'Gene', (137, 143))	('Pagetic osteosarcomas', 'Disease', 'MESH:C538098', (67, 88))	('MYC', 'Gene', (9, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('osteosarcomas', 'Phenotype', 'HP:0002669', (75, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('reduce', 'NegReg', (130, 136))	('Pagetic osteosarcoma', 'Disease', 'MESH:C538098', (67, 87))	('Pagetic osteosarcomas', 'Disease', (67, 88))	('detected', 'Reg', (55, 63))	('MYC', 'Gene', '4609', (9, 12))	('Sqstm1', 'Gene', '8878', (137, 143))	('activity', 'MPA', (106, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))
468273	31276706	Several other compounds that inhibit MDM2-TP53 binding have been identified, including RG7112, SAR405838, APG-115, AMG 232, and MK-8242.	('RG7112', 'Chemical', 'MESH:C579783', (87, 93))	('SAR405838', 'Var', (95, 104))	('SAR405838', 'Chemical', 'MESH:C000593797', (95, 104))	('inhibit', 'NegReg', (29, 36))	('APG', 'Chemical', '-', (106, 109))	('MK-8242', 'Chemical', '-', (128, 135))	('MDM2-TP53', 'Protein', (37, 46))	('binding', 'Interaction', (47, 54))
468277	31276706	Of these, APR-246, a PRIMA-1 analog, shows synergy in inhibiting tumor cell growth with camptothecin, a quinoline alkaloid, in the Saos2 osteosarcoma cell line exogenously expressing TP53 R273H (Saos2-TP53R273H).	('osteosarcoma', 'Phenotype', 'HP:0002669', (137, 149))	('osteosarcoma', 'Disease', (137, 149))	('osteosarcoma', 'Disease', 'MESH:D012516', (137, 149))	('PRIMA-1', 'Gene', '145270', (21, 28))	('tumor', 'Disease', (65, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('TP53 R273H', 'Var', (183, 193))	('R273H', 'Mutation', 'rs28934576', (205, 210))	('quinoline', 'Chemical', 'MESH:C037219', (104, 113))	('PRIMA-1', 'Gene', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('R273H', 'Mutation', 'rs28934576', (188, 193))	('camptothecin', 'Chemical', 'MESH:D002166', (88, 100))	('APR-246', 'Chemical', 'MESH:C533410', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('inhibiting', 'NegReg', (54, 64))
468279	31276706	Additionally, stictic acid, which was identified though computational methods for a transiently open binding pocket in the TP53 core domain, is shown to upregulate p21 and PUMA in Saos2 cells expressing TP53 R175H and G245S.	('PUMA', 'Gene', (172, 176))	('upregulate', 'PosReg', (153, 163))	('G245S', 'Mutation', 'rs28934575', (218, 223))	('PUMA', 'Gene', '27113', (172, 176))	('stictic acid', 'Chemical', 'MESH:C522101', (14, 26))	('R175H', 'Mutation', 'rs28934578', (208, 213))	('TP53 R175H', 'Var', (203, 213))	('R175H', 'Var', (208, 213))	('G245S', 'Var', (218, 223))	('p21', 'Gene', '1026', (164, 167))	('p21', 'Gene', (164, 167))
468283	31276706	Another way to target TP53 mutations is to treat cells with a compound that inhibits proteins or pathways unique and essential for survival and proliferation (vulnerabilities) in TP53-null or mutated cells with minimal impact on wtp53-expressing cells (Table 1).	('mutations', 'Var', (27, 36))	('proteins', 'Protein', (85, 93))	('p53', 'Gene', (231, 234))	('inhibits', 'NegReg', (76, 84))	('p53', 'Gene', '7157', (231, 234))	('mutated', 'Var', (192, 199))	('TP53', 'Gene', (22, 26))
468284	31276706	Such a compound may inhibit function of proteins that show a synthetically lethal interaction with TP53 mutations, including CHK1, ATM/CHK2, Plk1, Wee1, and MK2.	('CHK2', 'Gene', (135, 139))	('interaction', 'Interaction', (82, 93))	('TP53', 'Gene', (99, 103))	('CHK1', 'Gene', '1111', (125, 129))	('mutations', 'Var', (104, 113))	('ATM', 'Gene', (131, 134))	('Plk1', 'Gene', (141, 145))	('CHK2', 'Gene', '11200', (135, 139))	('Wee1', 'Gene', '7465', (147, 151))	('MK2', 'Gene', '9261', (157, 160))	('function', 'MPA', (28, 36))	('ATM', 'Gene', '472', (131, 134))	('CHK1', 'Gene', (125, 129))	('proteins', 'Protein', (40, 48))	('Plk1', 'Gene', '5347', (141, 145))	('inhibit', 'NegReg', (20, 27))	('MK2', 'Gene', (157, 160))	('Wee1', 'Gene', (147, 151))
468285	31276706	Since ~80% of osteosarcoma cases have TP53 alterations, targeting vulnerable pathways and proteins in cells lacking wtp53 activity would be a reasonable treatment strategy.	('TP53', 'Gene', (38, 42))	('p53', 'Gene', (118, 121))	('osteosarcoma', 'Disease', (14, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (14, 26))	('p53', 'Gene', '7157', (118, 121))	('osteosarcoma', 'Disease', 'MESH:D012516', (14, 26))	('alterations', 'Var', (43, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))
468286	31276706	identify HDAC (histone deacetylase) inhibitors through a 54 FDA-approved agent screen as agents having anti-growth activity and synergistic effects with proteasome inhibitors in five TP53-inactive pediatric osteosarcoma cell lines, although the underlying mechanism remains unclear.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('histone deacetylase', 'Gene', (15, 34))	('inhibitors', 'Var', (36, 46))	('HDAC', 'Gene', (9, 13))	('HDAC', 'Gene', '9734', (9, 13))	('anti-growth', 'MPA', (103, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (207, 219))	('osteosarcoma', 'Disease', (207, 219))	('osteosarcoma', 'Disease', 'MESH:D012516', (207, 219))	('histone deacetylase', 'Gene', '9734', (15, 34))
468297	31276706	The loop-like genomic rearrangements and fusions are also detected in other sarcomas including chondromyxoid fibroma and synovial sarcoma.	('sarcomas', 'Disease', (76, 84))	('detected', 'Reg', (58, 66))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (121, 137))	('chondromyxoid fibroma', 'Disease', (95, 116))	('sarcomas', 'Disease', 'MESH:D012509', (76, 84))	('synovial sarcoma', 'Disease', 'MESH:D013584', (121, 137))	('chondromyxoid fibroma', 'Disease', 'MESH:D005350', (95, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (76, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('fibroma', 'Phenotype', 'HP:0010614', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('fusions', 'Var', (41, 48))	('synovial sarcoma', 'Disease', (121, 137))
468301	31276706	also show that Ewing sarcoma has frequent mutations in the cohesin complex subunit STAG2 (21.5%), homozygous deletion of CDKN2A (13.8%) and mutations of TP53 (6.2%), as well as an increased prevalence of the BRCA2 K3326X polymorphism (7.3%).	('STAG2', 'Gene', (83, 88))	('STAG2', 'Gene', '10735', (83, 88))	('CDKN2A', 'Gene', '1029', (121, 127))	('BRCA2', 'Gene', '675', (208, 213))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (15, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (15, 28))	('K3326X', 'Mutation', 'rs11571833', (214, 220))	('BRCA2', 'Gene', (208, 213))	('mutations', 'Var', (140, 149))	('TP53', 'Gene', (153, 157))	('K3326X', 'Var', (214, 220))	('CDKN2A', 'Gene', (121, 127))	('Ewing sarcoma', 'Disease', (15, 28))	('mutations', 'Var', (42, 51))
468302	31276706	Other genome sequencing studies also identify mutations in cancer-related genes including KDR, STK11, MLH1, KRAS, and PTPN11, as well as in DNA double-strand break repair, in Ewing sarcoma tissues.	('KRAS', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MLH1', 'Gene', (102, 106))	('STK11', 'Gene', '6794', (95, 100))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (175, 188))	('PTPN11', 'Gene', (118, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (175, 188))	('mutations', 'Var', (46, 55))	('KDR', 'Gene', (90, 93))	('MLH1', 'Gene', '4292', (102, 106))	('PTPN11', 'Gene', '5781', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('Ewing sarcoma', 'Disease', (175, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('DNA double-strand break repair', 'MPA', (140, 170))	('KDR', 'Gene', '3791', (90, 93))	('STK11', 'Gene', (95, 100))	('KRAS', 'Gene', '3845', (108, 112))	('cancer', 'Disease', (59, 65))
468303	31276706	With regard to TP53 mutations, multiple articles have found that genetic alterations in the TP53 gene are detected only in ~10% of Ewing sarcomas.	('Ewing sarcomas', 'Disease', 'MESH:C563168', (131, 145))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (131, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (131, 145))	('TP53', 'Gene', (92, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('Ewing sarcomas', 'Disease', (131, 145))	('genetic alterations', 'Var', (65, 84))
468304	31276706	The two most frequently detected TP53 mutations in Ewing sarcoma are the C176F and R273X.	('C176F', 'Mutation', 'rs786202962', (73, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('C176F', 'Var', (73, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('R273X', 'Mutation', 'p.R273X', (83, 88))	('Ewing sarcoma', 'Disease', (51, 64))	('TP53', 'Gene', (33, 37))	('R273X', 'Var', (83, 88))
468307	31276706	To support this finding, silencing of EWS-FLI1 reactivates NOTCH signaling and subsequently activates TP53 to induce cell cycle arrest in Ewing sarcoma cells.	('silencing', 'Var', (25, 34))	('reactivates', 'Reg', (47, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (138, 151))	('EWS', 'Gene', (38, 41))	('TP53', 'Protein', (102, 106))	('arrest', 'Disease', 'MESH:D006323', (128, 134))	('EWS', 'Gene', '2130', (38, 41))	('FLI1', 'Gene', (42, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('FLI1', 'Gene', '2313', (42, 46))	('activates', 'PosReg', (92, 101))	('Ewing sarcoma', 'Disease', (138, 151))	('arrest', 'Disease', (128, 134))	('induce', 'PosReg', (110, 116))	('NOTCH signaling', 'MPA', (59, 74))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (117, 134))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (138, 151))
468312	31276706	Several clinical studies also support the important role of TP53 in inhibiting Ewing sarcoma progression.	('inhibiting', 'NegReg', (68, 78))	('TP53', 'Var', (60, 64))	('Ewing sarcoma', 'Disease', (79, 92))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (79, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
468313	31276706	shows that positive TP53 staining in Ewing's sarcoma is a poor prognostic factor.	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('TP53', 'Protein', (20, 24))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (37, 52))	('positive', 'Var', (11, 19))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (37, 52))	("Ewing's sarcoma", 'Disease', (37, 52))
468314	31276706	fails to observe an association between TP53 mutations and event-free survival of patients.	('mutations', 'Var', (45, 54))	('patients', 'Species', '9606', (82, 90))	('TP53', 'Gene', (40, 44))
468315	31276706	Whole-genome sequencing, rather than IHC and exome sequencing, would be necessary to clarify the significance of TP53 mutations in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (131, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (131, 144))	('mutations', 'Var', (118, 127))	('Ewing sarcoma', 'Disease', (131, 144))	('TP53', 'Gene', (113, 117))
468317	31276706	report that only three out of 30 Ewing sarcoma specimens have MDM2 gene amplification, all of which have metastasis at diagnosis, while only one out of 15 specimens without MDM2 amplification has metastasis, suggesting correlation between MDM2 amplification and metastasis.	('amplification', 'Var', (72, 85))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (33, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (33, 46))	('MDM2 gene', 'Gene', (62, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('Ewing sarcoma', 'Disease', (33, 46))
468319	31276706	Given the infrequent rate of mutations of TP53 in Ewing sarcoma, restoring TP53 activity by inhibiting upstream inhibitors of TP53 is a rational therapeutic strategy.	('restoring', 'PosReg', (65, 74))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (50, 63))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (50, 63))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (29, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('upstream inhibitors of TP53', 'MPA', (103, 130))	('activity', 'MPA', (80, 88))	('TP53', 'MPA', (75, 79))	('Ewing sarcoma', 'Disease', (50, 63))	('inhibiting', 'NegReg', (92, 102))
468322	31276706	Additionally, P5091, a USP7 inhibitor, and GSK2830371, a Wip1/PPM1D inhibitor, decrease viability of Ewing sarcoma cells, in a TP53-dependent manner.	('PPM1D', 'Gene', '8493', (62, 67))	('GSK2830371', 'Var', (43, 53))	('Wip1', 'Gene', '8493', (57, 61))	('Wip1', 'Gene', (57, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('P5091', 'Chemical', 'MESH:C576408', (14, 19))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('USP7', 'Gene', (23, 27))	('decrease', 'NegReg', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('USP7', 'Gene', '7874', (23, 27))	('PPM1D', 'Gene', (62, 67))	('Ewing sarcoma', 'Disease', (101, 114))	('P5091', 'Var', (14, 19))	('viability', 'CPA', (88, 97))	('GSK2830371', 'Chemical', 'MESH:C587624', (43, 53))
468326	31276706	The effects of YK-4-279 are additive with Nutlin-3a, in vitro and in a xenograft zebrafish model of human Ewing sarcoma cell lines.	('zebrafish', 'Species', '7955', (81, 90))	('Ewing sarcoma', 'Disease', (106, 119))	('human', 'Species', '9606', (100, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('YK-4-279', 'Var', (15, 23))
468332	31276706	Intriguingly, curcumin may radiosensitize TP53-mutated Ewing sarcoma cells by upregulating p21 and Bax and downregulating BCL-XL and MCL1, although the mechanism behind reactivation of wtp53 from mutp53 remains unclear.	('MCL1', 'Gene', '4170', (133, 137))	('p21', 'Gene', '1026', (91, 94))	('BCL-XL', 'Gene', '598', (122, 128))	('p53', 'Gene', '7157', (199, 202))	('downregulating', 'NegReg', (107, 121))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (55, 68))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (55, 68))	('p53', 'Gene', (199, 202))	('p53', 'Gene', '7157', (187, 190))	('TP53-mutated', 'Var', (42, 54))	('p21', 'Gene', (91, 94))	('BCL-XL', 'Gene', (122, 128))	('upregulating', 'PosReg', (78, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('p53', 'Gene', (187, 190))	('MCL1', 'Gene', (133, 137))	('Bax', 'Gene', (99, 102))	('curcumin', 'Chemical', 'MESH:D003474', (14, 22))	('Ewing sarcoma', 'Disease', (55, 68))	('Bax', 'Gene', '581', (99, 102))
468333	31276706	Another small molecule TP53 reactivator, RITA/NSC652287, is shown to induce apoptosis and effectively reduce tumor growth of Ewing sarcoma cell lines; however, this effect of RITA is independent of the TP53 status.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('reduce', 'NegReg', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('RITA/NSC652287', 'Var', (41, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('induce', 'PosReg', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Ewing sarcoma', 'Disease', (125, 138))	('apoptosis', 'CPA', (76, 85))	('tumor', 'Disease', (109, 114))
468342	31276706	On the other hand, de-differentiated chondrosarcoma, a high grade, non-chondroid sarcoma associated with low-grade cartilaginous lesions, have structural aberrations in chromosomes 1 and 9, as well as numerical aberrations (trisomy and tetrasomy) in chromosomes 7 and 19, without having distinct chromosomal translocations.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (37, 51))	('tetrasomy', 'Var', (236, 245))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('chondrosarcoma', 'Disease', (37, 51))	('sarcoma', 'Disease', (44, 51))	('chondrosarcoma', 'Disease', 'MESH:D002813', (37, 51))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
468344	31276706	reveals that 37% of chondrosarcoma cases have COL2A1gamma gene deletion and rearrangements, while mutations in IDH1/2 are found in 59% of cases, similar to the previous findings by Amary et al.	('chondrosarcoma', 'Disease', 'MESH:D002813', (20, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('IDH1/2', 'Gene', '3417;3418', (111, 117))	('rearrangements', 'Var', (76, 90))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (20, 34))	('deletion', 'Var', (63, 71))	('IDH1/2', 'Gene', (111, 117))	('COL2A1gamma', 'Gene', (46, 57))	('chondrosarcoma', 'Disease', (20, 34))
468345	31276706	Mutations in TP53 and RB1 are the most common changes involved in the later stage of chondrosarcoma.	('TP53', 'Gene', (13, 17))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (85, 99))	('RB1', 'Gene', (22, 25))	('common', 'Reg', (39, 45))	('Mutations', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('chondrosarcoma', 'Disease', (85, 99))	('chondrosarcoma', 'Disease', 'MESH:D002813', (85, 99))	('involved', 'Reg', (54, 62))
468346	31276706	Also, deletion and silencing of p16, an upstream regulator of RB1, are implicated in de-differentiated chondrosarcoma.	('chondrosarcoma', 'Disease', (103, 117))	('chondrosarcoma', 'Disease', 'MESH:D002813', (103, 117))	('implicated', 'Reg', (71, 81))	('p16', 'Gene', '1029', (32, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('silencing', 'Var', (19, 28))	('deletion', 'Var', (6, 14))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (103, 117))	('p16', 'Gene', (32, 35))
468347	31276706	In conventional and de-differentiated chondrosarcoma, alterations in the TP53 gene are observed in 20-50% of cases, while alterations in the RB pathway are detected in 30-96% of cases, depending on the methods of detection (exome sequencing or IHC).	('chondrosarcoma', 'Disease', (38, 52))	('conventional', 'Disease', (3, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (38, 52))	('TP53', 'Gene', (73, 77))	('RB pathway', 'Pathway', (141, 151))	('alterations', 'Var', (54, 65))	('chondrosarcoma', 'Disease', 'MESH:D002813', (38, 52))	('observed', 'Reg', (87, 95))
468348	31276706	A higher incidence of TP53 mutation is found in atypical chondrosarcomas, de-differentiated types, and mesenchymal types, while overexpression (indicating missense mutations) or alteration in TP53 is correlated with high histologic grade, presence of metastasis or local recurrence, and reduced overall survival.	('overexpression', 'PosReg', (128, 142))	('overall survival', 'CPA', (295, 311))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (57, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (57, 72))	('alteration', 'Var', (178, 188))	('local recurrence', 'CPA', (265, 281))	('mutation', 'Var', (27, 35))	('reduced', 'NegReg', (287, 294))	('chondrosarcomas', 'Disease', 'MESH:D002813', (57, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('metastasis', 'CPA', (251, 261))	('TP53', 'Gene', (192, 196))	('TP53', 'Gene', (22, 26))	('chondrosarcomas', 'Disease', (57, 72))
468351	31276706	Furthermore, a mouse model overexpressing Gli2, a protein that plays a role in regulating growth plate chondrocyte differentiation, in combination with TP53 heterozygosity develops chondrosarcoma.	('develops', 'PosReg', (172, 180))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (181, 195))	('Gli2', 'Gene', (42, 46))	('Gli2', 'Gene', '14633', (42, 46))	('mouse', 'Species', '10090', (15, 20))	('chondrosarcoma', 'Disease', 'MESH:D002813', (181, 195))	('overexpressing', 'Var', (27, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('chondrosarcoma', 'Disease', (181, 195))
468352	31276706	This is due to additive effects of overexpression of Gli2 and TP53 deficiency on inhibition of apoptosis mediated through IGFBP3 downregulation in chondrocytes.	('IGFBP3', 'Gene', '3486', (122, 128))	('Gli2', 'Gene', (53, 57))	('downregulation', 'NegReg', (129, 143))	('Gli2', 'Gene', '14633', (53, 57))	('apoptosis', 'CPA', (95, 104))	('TP53', 'Gene', (62, 66))	('deficiency', 'Var', (67, 77))	('overexpression', 'PosReg', (35, 49))	('IGFBP3', 'Gene', (122, 128))
468356	31276706	To support their finding, dasatinib, a dual BCR/ABL and Src family tyrosine kinase inhibitor, is shown to be effective in a phase 2 clinical study for multiple sarcomas, including chondrosarcoma, and significantly sensitizes chondrosarcoma cell lines harboring TP53 mutations to doxorubicin,.	('dasatinib', 'Chemical', 'MESH:D000069439', (26, 35))	('TP53', 'Gene', (261, 265))	('Src', 'Gene', (56, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('doxorubicin', 'Chemical', 'MESH:D004317', (279, 290))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (225, 239))	('ABL', 'Gene', (48, 51))	('chondrosarcoma', 'Disease', 'MESH:D002813', (180, 194))	('sensitizes', 'Reg', (214, 224))	('chondrosarcoma', 'Disease', (180, 194))	('Src', 'Gene', '6714', (56, 59))	('multiple sarcomas', 'Disease', (151, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (180, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('chondrosarcoma', 'Disease', 'MESH:D002813', (225, 239))	('mutations', 'Var', (266, 275))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('chondrosarcoma', 'Disease', (225, 239))	('multiple sarcomas', 'Disease', 'MESH:D012509', (151, 168))	('ABL', 'Gene', '25', (48, 51))
468367	31276706	PRMS also do not normally have the PAX-FKHR fusion and can have a highly complex karyotype, sometimes with abnormalities in every chromosome.	('RMS', 'Phenotype', 'HP:0002859', (1, 4))	('FKHR', 'Gene', (39, 43))	('abnormalities', 'Var', (107, 120))	('FKHR', 'Gene', '2308', (39, 43))
468370	31276706	While A1 and A2 show expression of PAX-FKHR and cell cycle regulators, the E1 and E2 subtypes contain mutations in the FGFR4/RAS/AKT pathways, as well as PTEN mutations.	('FKHR', 'Gene', '2308', (39, 43))	('E1 and E2', 'Gene', '6080', (75, 84))	('mutations', 'Var', (159, 168))	('AKT', 'Gene', '207', (129, 132))	('FKHR', 'Gene', (39, 43))	('mutations', 'Var', (102, 111))	('AKT', 'Gene', (129, 132))	('FGFR4', 'Gene', '2264', (119, 124))	('PTEN', 'Gene', (154, 158))	('FGFR4', 'Gene', (119, 124))	('PTEN', 'Gene', '5728', (154, 158))
468372	31276706	Because ARMS rarely shows inactivation or mutations of TP53, other mechanisms may be responsible for reduced wtp53 activity.	('TP53', 'Gene', (55, 59))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('RMS', 'Phenotype', 'HP:0002859', (9, 12))	('mutations', 'Var', (42, 51))
468376	31276706	Also, metastases of ERMS have high levels of TP53 expression, and the presence of TP53 mutations significantly reduces survival of patients of the E1/E2 subtypes.	('patients', 'Species', '9606', (131, 139))	('survival', 'CPA', (119, 127))	('TP53 expression', 'MPA', (45, 60))	('TP53', 'Gene', (82, 86))	('presence', 'Var', (70, 78))	('RMS', 'Phenotype', 'HP:0002859', (21, 24))	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('reduces', 'NegReg', (111, 118))	('metastases', 'Disease', (6, 16))	('mutations', 'Var', (87, 96))
468377	31276706	Intriguingly, in a kRASG12D-induced zebrafish ERMS model, deletion of TP53 enhances invasion and metastasis, while expression of a dominant-negative mutp53 in mouse MSCs expressing PAX-FKHR fusion protein is sufficient to induce ARMS tumors in mice.	('RMS', 'Phenotype', 'HP:0002859', (47, 50))	('FKHR', 'Gene', '2308', (185, 189))	('RMS', 'Phenotype', 'HP:0002859', (230, 233))	('mice', 'Species', '10090', (244, 248))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('p53', 'Gene', (152, 155))	('mouse', 'Species', '10090', (159, 164))	('p53', 'Gene', '7157', (152, 155))	('ARMS tumors', 'Disease', 'MESH:D009369', (229, 240))	('enhances', 'PosReg', (75, 83))	('TP53', 'Gene', (70, 74))	('ARMS tumors', 'Disease', (229, 240))	('deletion', 'Var', (58, 66))	('zebrafish', 'Species', '7955', (36, 45))	('FKHR', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
468378	31276706	Additionally, DNp73, the N-terminal deleted dominant-negative form of a TP53 family member, is frequently overexpressed in RMS (>80%) and is also shown to inhibit myogenic differentiation and contribute to transformation of mouse myoblast cells and RMS progression in vivo.	('mouse myoblast cells', 'CPA', (224, 244))	('transformation', 'CPA', (206, 220))	('DNp73', 'Var', (14, 19))	('RMS', 'Phenotype', 'HP:0002859', (123, 126))	('mouse', 'Species', '10090', (224, 229))	('RMS', 'Phenotype', 'HP:0002859', (249, 252))	('myogenic differentiation', 'CPA', (163, 187))	('contribute to', 'Reg', (192, 205))	('inhibit', 'NegReg', (155, 162))	('RMS progression', 'CPA', (249, 264))	('overexpressed', 'PosReg', (106, 119))
468379	31276706	CP-31398, a small molecule drug which enhances wtp53 activity and restores wtp53 function from mutp53, is shown to induce ROS-dependent cell cycle arrest and apoptosis in wtp53-carrying A204 and mutp53-expressing ERMS cell lines to reduce their tumor growth in xenograft mouse models.	('RMS', 'Phenotype', 'HP:0002859', (214, 217))	('p53', 'Gene', '7157', (49, 52))	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('mouse', 'Species', '10090', (271, 276))	('apoptosis', 'CPA', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('p53', 'Gene', (98, 101))	('ROS-dependent', 'MPA', (122, 135))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (173, 176))	('p53', 'Gene', '7157', (77, 80))	('p53', 'Gene', '7157', (198, 201))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (136, 153))	('arrest', 'Disease', (147, 153))	('p53', 'Gene', (173, 176))	('CP-31398', 'Chemical', 'MESH:C402665', (0, 8))	('p53', 'Gene', (77, 80))	('p53', 'Gene', (198, 201))	('tumor', 'Disease', (245, 250))	('enhances', 'PosReg', (38, 46))	('reduce', 'NegReg', (232, 238))	('CP-31398', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('induce', 'PosReg', (115, 121))	('p53', 'Gene', '7157', (98, 101))	('arrest', 'Disease', 'MESH:D006323', (147, 153))
468380	31276706	Given that ARMS and PRMS rarely have TP53 mutations, compounds that restore wtp53 activity would also be efficient.	('RMS', 'Phenotype', 'HP:0002859', (21, 24))	('p53', 'Gene', (78, 81))	('RMS', 'Phenotype', 'HP:0002859', (12, 15))	('TP53', 'Gene', (37, 41))	('p53', 'Gene', '7157', (78, 81))	('mutations', 'Var', (42, 51))
468381	31276706	On the other hand, for ERMS which often carries TP53 mutations, reactivating wtp53 activity from mutp53 may be an effective way to treat patients.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('ERMS', 'Disease', (23, 27))	('TP53', 'Gene', (48, 52))	('RMS', 'Phenotype', 'HP:0002859', (24, 27))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (53, 62))	('p53', 'Gene', '7157', (100, 103))	('p53', 'Gene', (100, 103))
468390	31276706	Rather, the general molecular alterations in LMS affect activities of the tumor suppressors TP53, PTEN, and/or RB1 with deletion of PTEN and RB1 and mutations of TP53.	('LMS', 'Phenotype', 'HP:0100243', (45, 48))	('affect', 'Reg', (49, 55))	('PTEN', 'Gene', (132, 136))	('RB1', 'Gene', (141, 144))	('mutations', 'Var', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('activities', 'MPA', (56, 66))	('PTEN', 'Gene', '5728', (132, 136))	('TP53', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('RB1', 'Gene', (111, 114))	('deletion', 'Var', (120, 128))	('tumor', 'Disease', (74, 79))	('PTEN', 'Gene', (98, 102))	('TP53', 'Gene', (92, 96))	('PTEN', 'Gene', '5728', (98, 102))	('LMS', 'Disease', (45, 48))
468392	31276706	Interestingly, loss of TP53, but not RB1, is sufficient to transform MSCs and induce LMS formation in mice.	('induce', 'Reg', (78, 84))	('mice', 'Species', '10090', (102, 106))	('transform', 'Reg', (59, 68))	('loss', 'Var', (15, 19))	('LMS', 'Phenotype', 'HP:0100243', (85, 88))	('TP53', 'Gene', (23, 27))	('MSCs', 'MPA', (69, 73))	('LMS formation', 'CPA', (85, 98))
468393	31276706	Besides these tumor suppressors, LMS often has mutations in ATRX (Alpha thalassemia/mental retardation syndrome X-linked) with a mutation rate of ~30% in ULMS.	('tumor', 'Disease', (14, 19))	('LMS', 'Phenotype', 'HP:0100243', (155, 158))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (72, 120))	('mental retardation', 'Phenotype', 'HP:0001249', (84, 102))	('ATRX', 'Gene', '546', (60, 64))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (72, 120))	('mutations', 'Var', (47, 56))	('LMS', 'Disease', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('LMS', 'Phenotype', 'HP:0100243', (33, 36))	('ULMS', 'Disease', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('ATRX', 'Gene', (60, 64))
468395	31276706	ULMS also harbors mutations in MED12 (mediator complex subunit 12), a coactivator involved in the interaction of transcription factors with RNA polymerase II, at a ~20% frequency, but this does not occur in non-uterine LMS.	('LMS', 'Phenotype', 'HP:0100243', (219, 222))	('MED12', 'Gene', '9968', (31, 36))	('LMS', 'Phenotype', 'HP:0100243', (1, 4))	('mediator complex subunit 12', 'Gene', '9968', (38, 65))	('MED12', 'Gene', (31, 36))	('mediator complex subunit 12', 'Gene', (38, 65))	('mutations', 'Var', (18, 27))
468396	31276706	MED12 mutation is also common in the benign tumor leiomyoma, suggesting that ULMS harboring MED12 mutations may represent the small population of tumors known to originate from leiomyoma.	('MED12', 'Gene', (92, 97))	('leiomyoma', 'Disease', 'MESH:D007889', (50, 59))	('common', 'Reg', (23, 29))	('MED12', 'Gene', '9968', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('benign tumor leiomyoma', 'Disease', 'MESH:D007889', (37, 59))	('leiomyoma', 'Disease', 'MESH:D007889', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('leiomyoma', 'Disease', (50, 59))	('MED12', 'Gene', (0, 5))	('MED12', 'Gene', '9968', (92, 97))	('benign tumor leiomyoma', 'Disease', (37, 59))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('mutation', 'Var', (6, 14))	('leiomyoma', 'Disease', (177, 186))	('mutations', 'Var', (98, 107))	('tumors', 'Disease', (146, 152))	('LMS', 'Phenotype', 'HP:0100243', (78, 81))
468398	31276706	Indeed, a mutp53 reactivator, PRIMA-1, is shown to reduce viability of IB134 ULMS and IB138 soft tissue LMS cell lines harboring TP53 mutations, while it is less effective in the wtp53-expressing IB139 LMS cell line.	('p53', 'Gene', (181, 184))	('p53', 'Gene', '7157', (181, 184))	('LMS', 'Phenotype', 'HP:0100243', (202, 205))	('LMS', 'Phenotype', 'HP:0100243', (104, 107))	('PRIMA-1', 'Gene', (30, 37))	('LMS', 'Phenotype', 'HP:0100243', (78, 81))	('reduce', 'NegReg', (51, 57))	('mutations', 'Var', (134, 143))	('p53', 'Gene', (13, 16))	('PRIMA-1', 'Gene', '145270', (30, 37))	('TP53', 'Gene', (129, 133))	('viability', 'MPA', (58, 67))	('p53', 'Gene', '7157', (13, 16))
468409	31276706	The t(X:18)(p11.2;q11.2) chromosomal translocation creates an in-frame fusion of SS18 to SSX1, SSX2, or SSX4, leading to generation of a SS18-SSX protein.	('SSX2', 'Gene', (95, 99))	('SS18', 'Gene', (137, 141))	('SSX2', 'Gene', '6757', (95, 99))	('SSX', 'Gene', '6757', (89, 92))	('SS18', 'Gene', (81, 85))	('SSX', 'Gene', '6757', (104, 107))	('SS18', 'Gene', '6760', (137, 141))	('SSX', 'Gene', '6757', (95, 98))	('SSX', 'Gene', (89, 92))	('SSX4', 'Gene', (104, 108))	('fusion', 'Var', (71, 77))	('SSX', 'Gene', '6757', (142, 145))	('SSX', 'Gene', (104, 107))	('SS18', 'Gene', '6760', (81, 85))	('SSX', 'Gene', (95, 98))	('SSX1', 'Gene', '6756', (89, 93))	('t(X:18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 24))	('SSX4', 'Gene', '6759', (104, 108))	('SSX1', 'Gene', (89, 93))	('SSX', 'Gene', (142, 145))
468413	31276706	Synovial sarcomas do not frequently display mutations in the TP53 gene.	('Synovial sarcomas', 'Disease', 'MESH:D013584', (0, 17))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('Synovial sarcomas', 'Disease', (0, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('mutations', 'Var', (44, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Synovial sarcomas', 'Phenotype', 'HP:0012570', (0, 17))	('TP53', 'Gene', (61, 65))
468414	31276706	Despite its low rate of mutations (~6%), TP53 alteration may be an effective prognostic indicator because tumors with missense mutations in the TP53 gene show significantly reduced 5-year survival when compared to non-mutated tumors.	('TP53', 'Gene', (144, 148))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('reduced', 'NegReg', (173, 180))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('5-year survival', 'CPA', (181, 196))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('missense mutations', 'Var', (118, 136))
468417	31276706	Thus, TP53 activity appears to be lowered in synovial sarcoma through MDM2/MDM4.	('activity', 'MPA', (11, 19))	('TP53', 'Protein', (6, 10))	('lowered', 'NegReg', (34, 41))	('synovial sarcoma', 'Disease', (45, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('MDM2/MDM4', 'Var', (70, 79))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (45, 61))	('synovial sarcoma', 'Disease', 'MESH:D013584', (45, 61))
468422	31276706	Indeed, Nutlin-3a and MI-219, two small molecule inhibitors of MDM2, are shown to inhibit the growth of synovial sarcoma cells in vitro.	('synovial sarcoma', 'Disease', 'MESH:D013584', (104, 120))	('inhibit', 'NegReg', (82, 89))	('synovial sarcoma', 'Disease', (104, 120))	('MI-219', 'Chemical', 'MESH:C574930', (22, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('MI-219', 'Var', (22, 28))	('MDM2', 'Gene', (63, 67))	('growth', 'MPA', (94, 100))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (104, 120))
468441	31276706	These supernumerary chromosomes frequently amplify the CDK4, HMGA2, and MDM2 genes from chromosome 12q.	('CDK4', 'Gene', '1019', (55, 59))	('HMGA2', 'Gene', '8091', (61, 66))	('HMGA2', 'Gene', (61, 66))	('amplify', 'Var', (43, 50))	('MDM2', 'Gene', (72, 76))	('CDK4', 'Gene', (55, 59))
468442	31276706	Also, well-differentiated and de-differentiated LPSs carry neochromosomes due to amplifications and rearrangements of chromosome 12q encoding oncogenes (MDM2, CDK4, YEATS2) and adipocytic differentiation factors (HMGA2, CPM).	('CDK4', 'Gene', (159, 163))	('neochromosomes', 'Gene', (59, 73))	('amplifications', 'Var', (81, 95))	('LPS', 'Phenotype', 'HP:0012034', (48, 51))	('CPM', 'Gene', (220, 223))	('YEATS2', 'Gene', (165, 171))	('CDK4', 'Gene', '1019', (159, 163))	('rearrangements', 'Var', (100, 114))	('HMGA2', 'Gene', '8091', (213, 218))	('CPM', 'Gene', '1368', (220, 223))	('HMGA2', 'Gene', (213, 218))	('LPSs', 'Disease', 'None', (48, 52))	('LPSs', 'Disease', (48, 52))	('YEATS2', 'Gene', '55689', (165, 171))
468445	31276706	identify mutations in TP53 and NF1, as well as PIK3CA mutations in myxoid/round-cell LPSs.	('PIK3CA', 'Gene', (47, 53))	('PIK3CA', 'Gene', '5290', (47, 53))	('mutations', 'Var', (9, 18))	('mutations', 'Var', (54, 63))	('LPSs', 'Disease', 'None', (85, 89))	('LPSs', 'Disease', (85, 89))	('LPS', 'Phenotype', 'HP:0012034', (85, 88))	('NF1', 'Gene', (31, 34))	('NF1', 'Gene', '4763', (31, 34))	('TP53', 'Gene', (22, 26))
468447	31276706	They also report FGFR1 amplification at chromosome 8p11.23, classical CDK4, HMGA2, and MDM2 amplification at the chromosome 12q13-15 region, and deletion of TP53BP1 at chromosome 15q15 in de-differentiated LPS.	('HMGA2', 'Gene', (76, 81))	('CDK4', 'Gene', '1019', (70, 74))	('CDK4', 'Gene', (70, 74))	('p11', 'Gene', '6281', (52, 55))	('LPS', 'Disease', 'MESH:C536528', (206, 209))	('FGFR1', 'Gene', (17, 22))	('TP53BP1', 'Gene', (157, 164))	('FGFR1', 'Gene', '2260', (17, 22))	('TP53BP1', 'Gene', '7158', (157, 164))	('p11', 'Gene', (52, 55))	('HMGA2', 'Gene', '8091', (76, 81))	('LPS', 'Phenotype', 'HP:0012034', (206, 209))	('LPS', 'Disease', (206, 209))	('deletion', 'Var', (145, 153))
468449	31276706	Mutations in TP53 are not usually high in LPS (10-20%), except for pleomorphic LPS in which ~60% of cases show TP53 mutations.	('TP53', 'Gene', (13, 17))	('LPS', 'Phenotype', 'HP:0012034', (42, 45))	('LPS', 'Disease', (42, 45))	('LPS', 'Phenotype', 'HP:0012034', (79, 82))	('LPS', 'Disease', 'MESH:C536528', (79, 82))	('LPS', 'Disease', 'MESH:C536528', (42, 45))	('pleomorphic LPS', 'Disease', 'MESH:C536528', (67, 82))	('TP53', 'Gene', (111, 115))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (116, 125))	('pleomorphic LPS', 'Disease', (67, 82))	('LPS', 'Disease', (79, 82))
468451	31276706	However, mutations in TP53 are associated with proliferation, tumor aggressiveness, reduced patient survival, and advanced disease in LPS.	('advanced disease', 'CPA', (114, 130))	('patient', 'Species', '9606', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('LPS', 'Disease', 'MESH:C536528', (134, 137))	('mutations', 'Var', (9, 18))	('LPS', 'Phenotype', 'HP:0012034', (134, 137))	('tumor aggressiveness', 'Disease', (62, 82))	('associated', 'Reg', (31, 41))	('reduced', 'NegReg', (84, 91))	('aggressiveness', 'Phenotype', 'HP:0000718', (68, 82))	('LPS', 'Disease', (134, 137))	('proliferation', 'CPA', (47, 60))	('patient survival', 'CPA', (92, 108))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (62, 82))	('TP53', 'Gene', (22, 26))
468455	31276706	Although the FUS-CHOP transgenic mice are not tumor-prone, mice show development of sarcoma resembling myxoid/round cell LPS upon deletion of the TP53 allele(s).	('CHOP', 'Gene', '1649', (17, 21))	('mice', 'Species', '10090', (59, 63))	('LPS', 'Phenotype', 'HP:0012034', (121, 124))	('LPS', 'Disease', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('transgenic mice', 'Species', '10090', (22, 37))	('tumor', 'Disease', (46, 51))	('TP53', 'Gene', (146, 150))	('CHOP', 'Gene', (17, 21))	('sarcoma', 'Disease', (84, 91))	('deletion', 'Var', (130, 138))	('LPS', 'Disease', 'MESH:C536528', (121, 124))	('FUS', 'Gene', (13, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('mice', 'Species', '10090', (33, 37))	('FUS', 'Gene', '2521', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
468456	31276706	Clinically, TP53 mutations are detected in 15-30% of cases of human myxoid/round cell LPS and are correlated with unfavorable outcomes.	('detected', 'Reg', (31, 39))	('LPS', 'Phenotype', 'HP:0012034', (86, 89))	('LPS', 'Disease', (86, 89))	('human', 'Species', '9606', (62, 67))	('LPS', 'Disease', 'MESH:C536528', (86, 89))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
468459	31276706	However, due to high frequency of MDM2 amplification and low frequency of TP53 mutations in LPS, especially in well-differentiated and de-differentiated LPS, use of MDM2 antagonists to restore TP53 activity (e.g., Nutlin-3a, RG7112, SAR405838) can be a major therapeutic strategy.	('LPS', 'Disease', 'MESH:C536528', (92, 95))	('LPS', 'Disease', 'MESH:C536528', (153, 156))	('LPS', 'Phenotype', 'HP:0012034', (153, 156))	('SAR405838', 'Chemical', 'MESH:C000593797', (233, 242))	('LPS', 'Disease', (153, 156))	('RG7112', 'Chemical', 'MESH:C579783', (225, 231))	('SAR405838', 'Var', (233, 242))	('activity', 'MPA', (198, 206))	('LPS', 'Phenotype', 'HP:0012034', (92, 95))	('LPS', 'Disease', (92, 95))	('RG7112', 'Var', (225, 231))	('TP53', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
468462	31276706	Although RG7112 stabilizes disease progression in many cases, it has significant adverse effects including neutropenia and thrombocytopenia, in as many as 40% of patients.	('patients', 'Species', '9606', (162, 170))	('stabilizes', 'PosReg', (16, 26))	('RG7112', 'Chemical', 'MESH:C579783', (9, 15))	('thrombocytopenia', 'Disease', (123, 139))	('neutropenia', 'Disease', (107, 118))	('RG7112', 'Var', (9, 15))	('thrombocytopenia', 'Disease', 'MESH:D013921', (123, 139))	('neutropenia', 'Disease', 'MESH:D009503', (107, 118))	('neutropenia', 'Phenotype', 'HP:0001875', (107, 118))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (123, 139))	('disease progression', 'CPA', (27, 46))
468463	31276706	SAR405838 is also shown to inhibit de-differentiated LPS progression in in vitro and in vivo mouse models; it induces stabilization of TP53, upregulation of TP53 targets, and induction of apoptosis in de-differentiated LPS, which has enabled this drug to enter early-phase clinical trials for multiple malignancies.	('stabilization', 'MPA', (118, 131))	('induction', 'Reg', (175, 184))	('LPS', 'Disease', (219, 222))	('LPS', 'Disease', 'MESH:C536528', (53, 56))	('malignancies', 'Disease', (302, 314))	('mouse', 'Species', '10090', (93, 98))	('SAR405838', 'Var', (0, 9))	('upregulation', 'PosReg', (141, 153))	('LPS', 'Disease', 'MESH:C536528', (219, 222))	('SAR405838', 'Chemical', 'MESH:C000593797', (0, 9))	('apoptosis', 'CPA', (188, 197))	('LPS', 'Disease', (53, 56))	('malignancies', 'Disease', 'MESH:D009369', (302, 314))	('LPS', 'Phenotype', 'HP:0012034', (53, 56))	('inhibit', 'NegReg', (27, 34))	('TP53', 'Protein', (135, 139))	('LPS', 'Phenotype', 'HP:0012034', (219, 222))
468464	31276706	As stated above, TP53 mutation status is correlated with recurrence, metastasis, and advanced stage of LPS.	('LPS', 'Disease', (103, 106))	('metastasis', 'CPA', (69, 79))	('recurrence', 'CPA', (57, 67))	('LPS', 'Phenotype', 'HP:0012034', (103, 106))	('mutation status', 'Var', (22, 37))	('LPS', 'Disease', 'MESH:C536528', (103, 106))	('correlated', 'Reg', (41, 51))	('TP53', 'Gene', (17, 21))
468472	31276706	identify recurrent mutations of angiogenesis-related genes, PTPRB (receptor-type tyrosine-protein phosphatase beta) and PLCG1 (phospholipase C, gamma1) in angiosarcomas.	('angiosarcomas', 'Phenotype', 'HP:0200058', (155, 168))	('PLCG1', 'Gene', '5335', (120, 125))	('PTPRB', 'Gene', '5787', (60, 65))	('receptor-type tyrosine-protein phosphatase beta', 'Gene', '5787', (67, 114))	('angiosarcoma', 'Phenotype', 'HP:0200058', (155, 167))	('PTPRB', 'Gene', (60, 65))	('mutations', 'Var', (19, 28))	('receptor-type tyrosine-protein phosphatase beta', 'Gene', (67, 114))	('angiosarcomas', 'Disease', (155, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (160, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('PLCG1', 'Gene', (120, 125))	('angiosarcomas', 'Disease', 'MESH:D006394', (155, 168))	('phospholipase C, gamma1', 'Gene', '5335', (127, 150))
468473	31276706	The PTPRB gene has predominantly truncating mutations in 26% of tumors, with an activating R707Q missense mutation in 9% of cases.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('PTPRB', 'Gene', '5787', (4, 9))	('R707Q missense', 'Var', (91, 105))	('R707Q', 'Mutation', 'p.R707Q', (91, 96))	('PTPRB', 'Gene', (4, 9))	('activating', 'PosReg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('truncating mutations', 'MPA', (33, 53))
468474	31276706	report that more than 50% of angiosarcomas carry some genetic alterations impacting the MAPK pathway.	('angiosarcomas', 'Disease', 'MESH:D006394', (29, 42))	('impacting', 'Reg', (74, 83))	('angiosarcomas', 'Phenotype', 'HP:0200058', (29, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('genetic alterations', 'Var', (54, 73))	('angiosarcoma', 'Phenotype', 'HP:0200058', (29, 41))	('MAPK pathway', 'Pathway', (88, 100))	('angiosarcomas', 'Disease', (29, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (34, 42))
468475	31276706	These include mutations in KRAS, HRAS, NRAS, BRAF, MAPK1, and NF1, as well as amplifications in MAPK1/CRKL, CRAF, or BRAF.	('KRAS', 'Gene', '3845', (27, 31))	('MAPK1', 'Gene', '5594', (51, 56))	('CRAF', 'Gene', (108, 112))	('NF1', 'Gene', (62, 65))	('NRAS', 'Gene', '4893', (39, 43))	('KRAS', 'Gene', (27, 31))	('MAPK1', 'Gene', '5594', (96, 101))	('CRKL', 'Gene', '1399', (102, 106))	('CRAF', 'Gene', '5894', (108, 112))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('MAPK1', 'Gene', (51, 56))	('BRAF', 'Gene', '673', (117, 121))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', (117, 121))	('amplifications', 'Var', (78, 92))	('CRKL', 'Gene', (102, 106))	('HRAS', 'Gene', '3265', (33, 37))	('MAPK1', 'Gene', (96, 101))	('NRAS', 'Gene', (39, 43))	('HRAS', 'Gene', (33, 37))	('NF1', 'Gene', '4763', (62, 65))
468476	31276706	Moreover, the most frequently detected genetic aberrations are mutations in TP53 (35%) and losses of CDKN2A (26%).	('mutations', 'Var', (63, 72))	('CDKN2A', 'Gene', (101, 107))	('losses', 'NegReg', (91, 97))	('CDKN2A', 'Gene', '1029', (101, 107))	('TP53', 'Gene', (76, 80))
468478	31276706	Additionally, FLT4 amplifications and mutations or rearrangements of PTPRB, PLCG1, CIC, FLT4, and KDR genes are detected in angiosarcomas.	('FLT4', 'Gene', '2324', (88, 92))	('FLT4', 'Gene', (88, 92))	('FLT4', 'Gene', (14, 18))	('PLCG1', 'Gene', (76, 81))	('PTPRB', 'Gene', '5787', (69, 74))	('FLT4', 'Gene', '2324', (14, 18))	('angiosarcomas', 'Disease', 'MESH:D006394', (124, 137))	('mutations', 'Var', (38, 47))	('PTPRB', 'Gene', (69, 74))	('KDR', 'Gene', (98, 101))	('CIC', 'Gene', (83, 86))	('detected', 'Reg', (112, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('angiosarcomas', 'Phenotype', 'HP:0200058', (124, 137))	('angiosarcoma', 'Phenotype', 'HP:0200058', (124, 136))	('angiosarcomas', 'Disease', (124, 137))	('rearrangements', 'Var', (51, 65))	('KDR', 'Gene', '3791', (98, 101))	('PLCG1', 'Gene', '5335', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('CIC', 'Gene', '23152', (83, 86))
468480	31276706	The involvement of TP53 in angiosarcomas is also shown by Naka et al, where frequency of TP53 mutations is dependent on the site of tumors with an overall occurrence of ~50%.	('TP53', 'Gene', (89, 93))	('angiosarcoma', 'Phenotype', 'HP:0200058', (27, 39))	('mutations', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('angiosarcomas', 'Disease', (27, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('angiosarcomas', 'Disease', 'MESH:D006394', (27, 40))	('tumors', 'Disease', (132, 138))	('angiosarcomas', 'Phenotype', 'HP:0200058', (27, 40))	('involvement', 'Reg', (4, 15))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
468486	31276706	Moreover, cre-mediated restoration of wtp53 expression in angiosarcoma developed in MDM2Tg TP53Neo/Neo mice results in inhibition of tumor growth in a syngeneic transplant model, suggesting that TP53 restoration is a potential therapeutic strategy for angiosarcomas.	('angiosarcomas', 'Disease', (252, 265))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('inhibition', 'NegReg', (119, 129))	('TP53Neo/Neo', 'Gene', (91, 102))	('angiosarcoma', 'Disease', (252, 264))	('p53', 'Gene', '7157', (40, 43))	('angiosarcoma', 'Disease', 'MESH:D006394', (58, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('angiosarcoma', 'Phenotype', 'HP:0200058', (58, 70))	('MDM2Tg', 'Var', (84, 90))	('p53', 'Gene', (40, 43))	('angiosarcoma', 'Disease', (58, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (257, 265))	('angiosarcomas', 'Disease', 'MESH:D006394', (252, 265))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('mice', 'Species', '10090', (103, 107))	('angiosarcomas', 'Phenotype', 'HP:0200058', (252, 265))	('angiosarcoma', 'Disease', 'MESH:D006394', (252, 264))	('angiosarcoma', 'Phenotype', 'HP:0200058', (252, 264))
468487	31276706	Considering the high frequency of TP53 mutations in angiosarcoma, TP53-targeted therapies may be an option for anti-angiosarcoma treatment.	('angiosarcoma', 'Disease', (52, 64))	('TP53', 'Gene', (34, 38))	('angiosarcoma', 'Phenotype', 'HP:0200058', (52, 64))	('mutations', 'Var', (39, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('angiosarcoma', 'Disease', 'MESH:D006394', (116, 128))	('angiosarcoma', 'Phenotype', 'HP:0200058', (116, 128))	('angiosarcoma', 'Disease', (116, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('angiosarcoma', 'Disease', 'MESH:D006394', (52, 64))
468495	31276706	Regarding the involvement of TP53 in UPS, a study using a large series of 143 soft tissue sarcomas identifies genomic deletion of the TP53 locus in 18.4% of tumors and TP53 mutations in 32%.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('TP53', 'Gene', (134, 138))	('TP53', 'Gene', (168, 172))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (78, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('mutations', 'Var', (173, 182))	('sarcomas', 'Disease', (90, 98))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (78, 98))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
468496	31276706	Furthermore, most tumors which do not have TP53 alterations show deletion or silencing of the p14ARF gene, a negative regulator of MDM2.	('p14ARF', 'Gene', '1029', (94, 100))	('silencing', 'NegReg', (77, 86))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('p14ARF', 'Gene', (94, 100))	('deletion', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
468499	31276706	In this review we have summarized the role of TP53 in bone and soft tissue sarcomas with emphasis on TP53 and mutations/deletions in TP53 as therapeutic targets.	('sarcomas', 'Disease', (75, 83))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (63, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (63, 82))	('sarcomas', 'Disease', 'MESH:D012509', (75, 83))	('mutations/deletions', 'Var', (110, 129))	('TP53', 'Gene', (133, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))	('bone', 'Disease', (54, 58))
468500	31276706	Alterations to TP53 or other genes in the TP53 pathway often occur in sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('Alterations', 'Var', (0, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))	('TP53', 'Gene', (15, 19))	('occur', 'Reg', (61, 66))
468501	31276706	Notably, over 70% of osteosarcoma has structural variants or mutations in the TP53 gene, Ewing sarcoma is rarely mutated for TP53 due to EWS-FLI1's inhibitory effect on TP53, non-uterine LMS has a high rate (~50%) of TP53 mutation, and well- and de-differentiated LPSs are defined by amplification of MDM2.	('LPS', 'Phenotype', 'HP:0012034', (264, 267))	('osteosarcoma', 'Disease', (21, 33))	('osteosarcoma', 'Disease', 'MESH:D012516', (21, 33))	('LMS', 'Phenotype', 'HP:0100243', (187, 190))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('EWS', 'Gene', (137, 140))	('FLI1', 'Gene', (141, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (21, 33))	('TP53', 'Gene', (217, 221))	('Ewing sarcoma', 'Disease', (89, 102))	('mutations', 'Var', (61, 70))	('FLI1', 'Gene', '2313', (141, 145))	('LPSs', 'Disease', (264, 268))	('EWS', 'Gene', '2130', (137, 140))	('LPSs', 'Disease', 'None', (264, 268))	('mutation', 'Var', (222, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('TP53', 'Gene', (78, 82))
468502	31276706	While current TP53-targeted therapies have some drawbacks in a clinical setting, including bone marrow suppression and other side effects, improved TP53-targeted therapies to restore wtp53 activity, reactivate wtp53 activity from mutp53, deplete mutp53, and target vulnerabilities in TP53-mutated/deleted cells may prove effective in therapy-resistant bone and soft tissue sarcomas in the near future.	('p53', 'Gene', '7157', (185, 188))	('sarcomas', 'Disease', (373, 381))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (361, 381))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (91, 114))	('restore', 'PosReg', (175, 182))	('p53', 'Gene', (249, 252))	('reactivate', 'Var', (199, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (373, 380))	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (212, 215))	('p53', 'Gene', (233, 236))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (361, 380))	('p53', 'Gene', (212, 215))	('bone marrow suppression', 'Disease', 'MESH:D001855', (91, 114))	('p53', 'Gene', '7157', (233, 236))	('p53', 'Gene', '7157', (249, 252))	('sarcomas', 'Disease', 'MESH:D012509', (373, 381))	('bone marrow suppression', 'Disease', (91, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (373, 381))
468564	27643881	The expression of PARP1, gammaH2AX, and BRCA2 were significantly associated with shorter disease-specific survival (DSS) and event-free survival (EFS) by univariate analysis.	('PARP1', 'Gene', '142', (18, 23))	('shorter', 'NegReg', (81, 88))	('DSS', 'Chemical', '-', (116, 119))	('disease-specific survival', 'CPA', (89, 114))	('BRCA2', 'Gene', (40, 45))	('gammaH2AX', 'Chemical', '-', (25, 34))	('BRCA2', 'Gene', '675', (40, 45))	('gammaH2AX', 'Var', (25, 34))	('PARP1', 'Gene', (18, 23))
468566	27643881	Multivariate analysis revealed the expression of PARP1 and gammaH2AX to be independent indicators of poor prognosis of DSS and EFS.	('PARP1', 'Gene', '142', (49, 54))	('PARP1', 'Gene', (49, 54))	('EFS', 'Disease', (127, 130))	('gammaH2AX', 'Chemical', '-', (59, 68))	('gammaH2AX', 'Var', (59, 68))	('DSS', 'Chemical', '-', (119, 122))	('DSS', 'Disease', (119, 122))
468568	27643881	In addition, the combined expressional patterns of PARP1, gammaH2AX, BRCA1, and BRCA2 (CSddrm) were independent prognostic predictors of DSS (P < 0.001) and EFS (P = 0.016).	('DSS', 'Chemical', '-', (137, 140))	('EFS', 'Disease', (157, 160))	('PARP1', 'Gene', '142', (51, 56))	('BRCA2', 'Gene', (80, 85))	('BRCA1', 'Gene', '672', (69, 74))	('DSS', 'Disease', (137, 140))	('PARP1', 'Gene', (51, 56))	('BRCA1', 'Gene', (69, 74))	('BRCA2', 'Gene', '675', (80, 85))	('gammaH2AX', 'Chemical', '-', (58, 67))	('gammaH2AX', 'Var', (58, 67))
468573	27643881	Therefore, the expression of DNA damage response (DDR) molecules are believed to limit the development of cancer.	('expression', 'Var', (15, 25))	('limit', 'NegReg', (81, 86))	('development of', 'CPA', (91, 105))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
468574	27643881	Mutations or defects in BRCA1/2 are closely related with early development of breast and ovarian carcinomas.	('early development of breast', 'Phenotype', 'HP:0010314', (57, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (89, 107))	('BRCA1/2', 'Gene', '672;675', (24, 31))	('related', 'Reg', (44, 51))	('breast and ovarian carcinomas', 'Disease', 'MESH:D001943', (78, 107))	('Mutations', 'Var', (0, 9))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (89, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('defects', 'Var', (13, 20))	('BRCA1/2', 'Gene', (24, 31))
468580	27643881	The expression of PARP1 and gammaH2AX were significantly associated with shorter survival of various human malignant tumors.	('PARP1', 'Gene', '142', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('human', 'Species', '9606', (101, 106))	('shorter', 'NegReg', (73, 80))	('gammaH2AX', 'Chemical', '-', (28, 37))	('gammaH2AX', 'Var', (28, 37))	('malignant tumors', 'Disease', (107, 123))	('malignant tumors', 'Disease', 'MESH:D018198', (107, 123))	('PARP1', 'Gene', (18, 23))
468581	27643881	It has been suggested that the expression of BRCA1/2 might also be related with chemoresistance and shorter survival of patients with breast carcinoma and ovarian carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('chemoresistance', 'CPA', (80, 95))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (155, 172))	('related', 'Reg', (67, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('BRCA1/2', 'Gene', '672;675', (45, 52))	('shorter', 'NegReg', (100, 107))	('patients', 'Species', '9606', (120, 128))	('breast carcinoma', 'Phenotype', 'HP:0003002', (134, 150))	('breast carcinoma and ovarian carcinoma', 'Disease', 'MESH:D001943', (134, 172))	('expression', 'Var', (31, 41))	('BRCA1/2', 'Gene', (45, 52))
468582	27643881	Moreover, our previous study demonstrated that the combined expression pattern of PARP1, gammaH2AX, BRCA1, and BRCA2 is very helpful in the prediction of the prognosis of breast carcinoma.	('BRCA2', 'Gene', (111, 116))	('breast carcinoma', 'Disease', (171, 187))	('BRCA1', 'Gene', '672', (100, 105))	('breast carcinoma', 'Disease', 'MESH:D001943', (171, 187))	('BRCA2', 'Gene', '675', (111, 116))	('gammaH2AX', 'Chemical', '-', (89, 98))	('BRCA1', 'Gene', (100, 105))	('gammaH2AX', 'Var', (89, 98))	('PARP1', 'Gene', (82, 87))	('PARP1', 'Gene', '142', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('breast carcinoma', 'Phenotype', 'HP:0003002', (171, 187))
468585	27643881	Especially, when there are defects in DSB repair by mutation of BRCA1/2, inhibition of PARP1 results in un-repairable DNA DSBs and apoptosis of cancer cells.	('PARP1', 'Gene', (87, 92))	('un-repairable DNA DSBs', 'MPA', (104, 126))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('BRCA1/2', 'Gene', (64, 71))	('mutation', 'Var', (52, 60))	('apoptosis', 'CPA', (131, 140))	('defects', 'NegReg', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BRCA1/2', 'Gene', '672;675', (64, 71))	('PARP1', 'Gene', '142', (87, 92))
468586	27643881	Although there are controversies, chemotherapeutic effectiveness of PARP1 inhibitors have been assessed in BRCA-deficient breast carcinomas and ovarian carcinomas with a BRCA1/2 mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (144, 162))	('mutation', 'Var', (178, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('breast carcinomas', 'Phenotype', 'HP:0003002', (122, 139))	('BRCA1/2', 'Gene', (170, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('BRCA-deficient breast carcinomas and ovarian carcinomas', 'Disease', 'MESH:D001943', (107, 162))	('breast carcinoma', 'Phenotype', 'HP:0003002', (122, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (144, 161))	('BRCA1/2', 'Gene', '672;675', (170, 177))	('PARP1', 'Gene', '142', (68, 73))	('deficient breast', 'Phenotype', 'HP:0003187', (112, 128))	('PARP1', 'Gene', (68, 73))
468629	27643881	In overall STSs, the expression of PARP1, gammaH2AX, and BRCA2 all correlated with aggressive tumor features, including advanced tumor stage and distant metastasis, while PARP1 and gammaH2AX correlated with poor histologic prognosticators, including higher histologic grade and increased mitotic count, as well as with expression of other DDR molecules (Table 2).	('distant metastasis', 'CPA', (145, 163))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('aggressive tumor', 'Disease', 'MESH:D001523', (83, 99))	('BRCA2', 'Gene', (57, 62))	('gammaH2AX', 'Var', (181, 190))	('tumor', 'Disease', (129, 134))	('PARP1', 'Gene', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('PARP1', 'Gene', '142', (171, 176))	('aggressive tumor', 'Disease', (83, 99))	('gammaH2AX', 'Chemical', '-', (181, 190))	('BRCA2', 'Gene', '675', (57, 62))	('STS', 'Phenotype', 'HP:0030448', (11, 14))	('higher', 'PosReg', (250, 256))	('STSs', 'Phenotype', 'HP:0030448', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mitotic count', 'CPA', (288, 301))	('correlated with', 'Reg', (67, 82))	('gammaH2AX', 'Var', (42, 51))	('PARP1', 'Gene', '142', (35, 40))	('increased', 'PosReg', (278, 287))	('tumor', 'Disease', (94, 99))	('PARP1', 'Gene', (171, 176))	('gammaH2AX', 'Chemical', '-', (42, 51))
468632	27643881	The patients having gammaH2AX-positive tumors had a 4.928-fold greater risk of death and gammaH2AX expression was significantly associated with shorter EFS.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('shorter', 'NegReg', (144, 151))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('death', 'Disease', 'MESH:D003643', (79, 84))	('gammaH2AX', 'Var', (89, 98))	('death', 'Disease', (79, 84))	('gammaH2AX', 'Chemical', '-', (89, 98))	('EFS', 'Disease', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (4, 12))	('gammaH2AX', 'Chemical', '-', (20, 29))	('tumors', 'Disease', (39, 45))	('gammaH2AX-positive', 'Var', (20, 38))
468636	27643881	The expression of PARP1, gammaH2AX, and BRCA2 were associated with shorter survival in both the subgroup of STS patients who received adjuvant chemotherapy and those that did not (Fig 4).	('PARP1', 'Gene', '142', (18, 23))	('STS', 'Phenotype', 'HP:0030448', (108, 111))	('patients', 'Species', '9606', (112, 120))	('BRCA2', 'Gene', (40, 45))	('survival', 'MPA', (75, 83))	('shorter', 'NegReg', (67, 74))	('gammaH2AX', 'Chemical', '-', (25, 34))	('BRCA2', 'Gene', '675', (40, 45))	('gammaH2AX', 'Var', (25, 34))	('PARP1', 'Gene', (18, 23))
468637	27643881	In addition, the expression of PARP1, gammaH2AX, and BRCA2 were associated with shorter survival in both the subgroup of patients who received adjuvant radiotherapy and those that did not (Fig 5).	('PARP1', 'Gene', '142', (31, 36))	('BRCA2', 'Gene', (53, 58))	('PARP1', 'Gene', (31, 36))	('survival', 'MPA', (88, 96))	('gammaH2AX', 'Chemical', '-', (38, 47))	('BRCA2', 'Gene', '675', (53, 58))	('shorter', 'NegReg', (80, 87))	('gammaH2AX', 'Var', (38, 47))	('expression', 'Var', (17, 27))	('patients', 'Species', '9606', (121, 129))
468638	27643881	In the subpopulation of low grade STSs, only the expression of PARP1 was significantly associated with shorter DSS (Fig 6A).	('PARP1', 'Gene', (63, 68))	('STSs', 'Phenotype', 'HP:0030448', (34, 38))	('shorter DSS', 'Disease', (103, 114))	('associated', 'Reg', (87, 97))	('DSS', 'Chemical', '-', (111, 114))	('STS', 'Phenotype', 'HP:0030448', (34, 37))	('PARP1', 'Gene', '142', (63, 68))	('expression', 'Var', (49, 59))
468639	27643881	However, in the subpopulation of high grade STSs, the expression of PARP1, gammaH2AX, BRCA1, and BRCA2 were significantly associated with shorter DSS, and the expression of gammaH2AX, BRCA1, and BRCA2 were significantly associated with shorter EFS (Fig 6B).	('BRCA2', 'Gene', '675', (195, 200))	('BRCA2', 'Gene', (97, 102))	('STSs', 'Phenotype', 'HP:0030448', (44, 48))	('PARP1', 'Gene', (68, 73))	('STS', 'Phenotype', 'HP:0030448', (44, 47))	('gammaH2AX', 'Var', (173, 182))	('shorter', 'NegReg', (138, 145))	('BRCA1', 'Gene', '672', (184, 189))	('BRCA2', 'Gene', '675', (97, 102))	('BRCA1', 'Gene', (184, 189))	('gammaH2AX', 'Gene', (75, 84))	('gammaH2AX', 'Chemical', '-', (173, 182))	('BRCA2', 'Gene', (195, 200))	('DSS', 'Chemical', '-', (146, 149))	('EFS', 'MPA', (244, 247))	('PARP1', 'Gene', '142', (68, 73))	('associated', 'Reg', (122, 132))	('BRCA1', 'Gene', '672', (86, 91))	('gammaH2AX', 'Chemical', '-', (75, 84))	('BRCA1', 'Gene', (86, 91))	('DSS', 'Disease', (146, 149))
468640	27643881	In addition, when further analysis was performed according to the histologic subtypes of STSs (Table 4), PARP1 expression was significantly associated with shorter survival of leiomyosarcoma, myxofibrosarcoma, and adult fibrosarcoma.	('adult fibrosarcoma', 'Disease', (214, 232))	('expression', 'Var', (111, 121))	('survival', 'MPA', (164, 172))	('STSs', 'Phenotype', 'HP:0030448', (89, 93))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (196, 208))	('leiomyosarcoma, myxofibrosarcoma', 'Disease', 'MESH:D007890', (176, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('STS', 'Phenotype', 'HP:0030448', (89, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('PARP1', 'Gene', (105, 110))	('adult fibrosarcoma', 'Disease', 'MESH:D005354', (214, 232))	('PARP1', 'Gene', '142', (105, 110))	('shorter', 'NegReg', (156, 163))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (176, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (220, 232))
468641	27643881	gammaH2AX-positivity was significantly associated with shorter EFS in synovial sarcoma and myxofibrosarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (70, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('gammaH2AX', 'Chemical', '-', (0, 9))	('synovial sarcoma and myxofibrosarcoma', 'Disease', 'MESH:D013584', (70, 107))	('shorter', 'NegReg', (55, 62))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (95, 107))	('EFS', 'MPA', (63, 66))	('gammaH2AX-positivity', 'Var', (0, 20))
468644	27643881	Because the expression of PARP1, gammaH2AX, BRCA1, and BRCA2 were closely associated each other (Table 2) and their expression predicted shorter survival of STS patients (Table 3); we evaluated the prognostic significance of the combined expression patterns of PARP1, gammaH2AX, BRCA1, and BRCA2.	('gammaH2AX', 'Chemical', '-', (33, 42))	('STS', 'Phenotype', 'HP:0030448', (157, 160))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA2', 'Gene', '675', (290, 295))	('gammaH2AX', 'Var', (268, 277))	('BRCA1', 'Gene', (44, 49))	('PARP1', 'Gene', '142', (261, 266))	('PARP1', 'Gene', (26, 31))	('gammaH2AX', 'Chemical', '-', (268, 277))	('BRCA2', 'Gene', (55, 60))	('shorter', 'NegReg', (137, 144))	('BRCA1', 'Gene', '672', (279, 284))	('BRCA1', 'Gene', (279, 284))	('patients', 'Species', '9606', (161, 169))	('PARP1', 'Gene', (261, 266))	('gammaH2AX', 'Var', (33, 42))	('BRCA2', 'Gene', '675', (55, 60))	('BRCA2', 'Gene', (290, 295))	('PARP1', 'Gene', '142', (26, 31))	('survival', 'CPA', (145, 153))
468645	27643881	When we divided STSs according to the positivity for these four markers, PARP1 expression was associated with shorter DSS in the gammaH2AX-, gammaH2AX+, BRCA1-, BRCA1+, BRCA2-, and BRCA2+ subgroups.	('BRCA2', 'Gene', (169, 174))	('PARP1', 'Gene', '142', (73, 78))	('DSS', 'Chemical', '-', (118, 121))	('BRCA1', 'Gene', '672', (161, 166))	('BRCA1', 'Gene', (161, 166))	('BRCA1', 'Gene', '672', (153, 158))	('BRCA2', 'Gene', '675', (169, 174))	('DSS', 'MPA', (118, 121))	('BRCA1', 'Gene', (153, 158))	('BRCA2', 'Gene', (181, 186))	('gammaH2AX-', 'Var', (129, 139))	('gammaH2AX', 'Chemical', '-', (141, 150))	('PARP1', 'Gene', (73, 78))	('BRCA2', 'Gene', '675', (181, 186))	('STS', 'Phenotype', 'HP:0030448', (16, 19))	('gammaH2AX', 'Chemical', '-', (129, 138))	('shorter', 'NegReg', (110, 117))	('gammaH2AX+', 'Var', (141, 151))	('STSs', 'Phenotype', 'HP:0030448', (16, 20))
468646	27643881	gammaH2AX-positivity predicted shorter DSS and EFS in the BRCA1-, BRCA1+, BRCA2-, and BRCA2+ subgroups.	('BRCA2', 'Gene', (86, 91))	('BRCA1', 'Gene', '672', (66, 71))	('BRCA1', 'Gene', (58, 63))	('DSS', 'Chemical', '-', (39, 42))	('shorter', 'NegReg', (31, 38))	('BRCA2', 'Gene', (74, 79))	('BRCA2', 'Gene', '675', (86, 91))	('EFS', 'MPA', (47, 50))	('BRCA1', 'Gene', (66, 71))	('BRCA2', 'Gene', '675', (74, 79))	('gammaH2AX', 'Chemical', '-', (0, 9))	('gammaH2AX-positivity', 'Var', (0, 20))	('BRCA1', 'Gene', '672', (58, 63))	('DSS', 'MPA', (39, 42))
468647	27643881	BRCA2 expression was associated with shorter DSS in the PARP1-, PARP1+, gammaH2AX-, gammaH2AX+, BRCA2-, and BRCA2+ subgroups (Table 5).	('BRCA2', 'Gene', (108, 113))	('BRCA2', 'Gene', '675', (0, 5))	('PARP1', 'Gene', '142', (64, 69))	('PARP1', 'Gene', '142', (56, 61))	('gammaH2AX-', 'Var', (72, 82))	('BRCA2', 'Gene', '675', (96, 101))	('PARP1', 'Gene', (56, 61))	('shorter', 'NegReg', (37, 44))	('BRCA2', 'Gene', '675', (108, 113))	('DSS', 'MPA', (45, 48))	('DSS', 'Chemical', '-', (45, 48))	('gammaH2AX', 'Chemical', '-', (84, 93))	('BRCA2', 'Gene', (0, 5))	('gammaH2AX+', 'Var', (84, 94))	('gammaH2AX', 'Chemical', '-', (72, 81))	('expression', 'Var', (6, 16))	('PARP1', 'Gene', (64, 69))	('BRCA2', 'Gene', (96, 101))
468654	27643881	Among the 112 cases of STSs, age of patients, tumor stage, PARP1 expression, gammaH2AX-positivity, and CSddrm were independent prognostic predictor for both DSS and EFS (Table 6).	('DSS', 'Chemical', '-', (157, 160))	('DSS', 'Disease', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patients', 'Species', '9606', (36, 44))	('EFS', 'Disease', (165, 168))	('gammaH2AX', 'Chemical', '-', (77, 86))	('tumor', 'Disease', (46, 51))	('STS', 'Phenotype', 'HP:0030448', (23, 26))	('STSs', 'Phenotype', 'HP:0030448', (23, 27))	('PARP1', 'Gene', '142', (59, 64))	('gammaH2AX-positivity', 'Var', (77, 97))	('PARP1', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
468662	27643881	Especially, the expression of PARP1 and gammaH2AX were independent indicators of poor prognosis of both DSS and EFS of STS patients.	('EFS', 'Disease', (112, 115))	('gammaH2AX', 'Chemical', '-', (40, 49))	('gammaH2AX', 'Var', (40, 49))	('patients', 'Species', '9606', (123, 131))	('DSS', 'Chemical', '-', (104, 107))	('DSS', 'Disease', (104, 107))	('STS', 'Phenotype', 'HP:0030448', (119, 122))	('PARP1', 'Gene', '142', (30, 35))	('PARP1', 'Gene', (30, 35))
468663	27643881	In agreement with our results, it has been reported that the expression of PARP1 is associated with the progression of various human malignant tumors, such as gastric cancer, breast cancer, ovarian cancer, glioblastoma, and chordoma.	('associated with', 'Reg', (84, 99))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('malignant tumors', 'Disease', (133, 149))	('breast cancer', 'Disease', (175, 188))	('expression', 'Var', (61, 71))	('PARP1', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (159, 173))	('chordoma', 'Phenotype', 'HP:0010762', (224, 232))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ovarian cancer', 'Disease', 'MESH:D010051', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('human', 'Species', '9606', (127, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (159, 173))	('PARP1', 'Gene', '142', (75, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (206, 218))	('chordoma', 'Gene', (224, 232))	('ovarian cancer', 'Disease', (190, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('glioblastoma', 'Disease', (206, 218))	('chordoma', 'Gene', '121775', (224, 232))	('malignant tumors', 'Disease', 'MESH:D018198', (133, 149))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('glioblastoma', 'Phenotype', 'HP:0012174', (206, 218))	('gastric cancer', 'Disease', (159, 173))
468665	27643881	In addition, our results demonstrated that the expression of PARP1 and gammaH2AX are significantly associated with shorter survival in the subpopulation of STS patients who received adjuvant chemotherapy and radiotherapy.	('patients', 'Species', '9606', (160, 168))	('STS', 'Phenotype', 'HP:0030448', (156, 159))	('gammaH2AX', 'Chemical', '-', (71, 80))	('gammaH2AX', 'Var', (71, 80))	('expression', 'Var', (47, 57))	('PARP1', 'Gene', '142', (61, 66))	('shorter', 'NegReg', (115, 122))	('PARP1', 'Gene', (61, 66))	('survival', 'MPA', (123, 131))
468668	27643881	However, even in the patients who did not received adjuvant chemotherapy or radiotherapy, the expression of PARP1 and gammaH2AX are significantly associated with shorter survival of STS patients (Figs 4 and 5).	('gammaH2AX', 'Chemical', '-', (118, 127))	('gammaH2AX', 'Var', (118, 127))	('survival', 'MPA', (170, 178))	('PARP1', 'Gene', '142', (108, 113))	('PARP1', 'Gene', (108, 113))	('shorter', 'NegReg', (162, 169))	('patients', 'Species', '9606', (21, 29))	('STS', 'Phenotype', 'HP:0030448', (182, 185))	('patients', 'Species', '9606', (186, 194))	('expression', 'Var', (94, 104))
468670	27643881	In agreement with these findings, various PARP1 inhibitors have been shown to have anticancer effects in human cancers, including STS.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancer', 'Disease', (87, 93))	('human', 'Species', '9606', (105, 110))	('PARP1', 'Gene', (42, 47))	('PARP1', 'Gene', '142', (42, 47))	('cancers', 'Disease', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('STS', 'Phenotype', 'HP:0030448', (130, 133))	('inhibitors', 'Var', (48, 58))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('STS', 'Disease', (130, 133))
468675	27643881	Therefore, the expression of gammaH2AX has been used as a sensitive marker of DNA DSBs.	('gammaH2AX', 'Chemical', '-', (29, 38))	('DNA DSBs', 'Disease', (78, 86))	('gammaH2AX', 'Var', (29, 38))
468676	27643881	However, paradoxically, the phosphorylation of H2AX during cancer therapy could confer a survival benefit to cancer cells.	('phosphorylation', 'Var', (28, 43))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('H2AX', 'Gene', '3014', (47, 51))	('H2AX', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('survival benefit', 'CPA', (89, 105))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
468682	27643881	A defects in BRCA1/2 is one of the important causes of cancer development, especially of breast and ovarian carcinomas.	('BRCA1/2', 'Gene', '672;675', (13, 20))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (100, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('causes', 'Reg', (45, 51))	('defects', 'Var', (2, 9))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (100, 118))	('breast and ovarian carcinomas', 'Disease', 'MESH:D001943', (89, 118))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('BRCA1/2', 'Gene', (13, 20))	('cancer', 'Disease', (55, 61))
468683	27643881	The risk of breast cancer by the age of 70 years has been reported as 57%-65% when there was BRCA1 mutation and 45%-49% when there was BRCA2 mutation.	('breast cancer', 'Disease', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('BRCA2', 'Gene', (135, 140))	('BRCA1', 'Gene', '672', (93, 98))	('mutation', 'Var', (99, 107))	('BRCA2', 'Gene', '675', (135, 140))	('BRCA1', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))
468684	27643881	The risk of ovarian carcinoma at 70 years old was reported as 39% and 11% with BRCA1 and BRCA2 mutation, respectively.	('BRCA2', 'Gene', '675', (89, 94))	('BRCA1', 'Gene', '672', (79, 84))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (12, 29))	('BRCA1', 'Gene', (79, 84))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (12, 29))	('ovarian carcinoma', 'Disease', (12, 29))	('BRCA2', 'Gene', (89, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('mutation', 'Var', (95, 103))
468687	27643881	A search of the cBioPortal public database indicated that genetic alteration (mutation, deletion, or amplification) of BRCA1 was seen in 0.5%-1% (1/207-2/240 cases) of STS and genetic alteration of BRCA2 was seen in 3%-6% (6/207-14/240 cases) of STS.	('amplification', 'Var', (101, 114))	('STS', 'Phenotype', 'HP:0030448', (246, 249))	('BRCA1', 'Gene', (119, 124))	('BRCA2', 'Gene', (198, 203))	('deletion', 'Var', (88, 96))	('genetic alteration', 'Var', (58, 76))	('BRCA2', 'Gene', '675', (198, 203))	('STS', 'Phenotype', 'HP:0030448', (168, 171))	('BRCA1', 'Gene', '672', (119, 124))
468695	27643881	These results are paradoxical to the tumor suppressive role of BRCA1/2 but consistent with the prognostic significance of the expression of PARP1 and gammaH2AX in STS.	('STS', 'Phenotype', 'HP:0030448', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('gammaH2AX', 'Chemical', '-', (150, 159))	('gammaH2AX', 'Var', (150, 159))	('BRCA1/2', 'Gene', '672;675', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('PARP1', 'Gene', '142', (140, 145))	('PARP1', 'Gene', (140, 145))	('BRCA1/2', 'Gene', (63, 70))
468696	27643881	In line with the findings of this study, the expression of BRCA1/2 predicted shorter survival of breast carcinoma and ovarian carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('breast carcinoma', 'Phenotype', 'HP:0003002', (97, 113))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (118, 135))	('breast carcinoma and ovarian carcinoma', 'Disease', 'MESH:D001943', (97, 135))	('BRCA1/2', 'Gene', '672;675', (59, 66))	('survival', 'MPA', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('shorter', 'NegReg', (77, 84))	('expression', 'Var', (45, 55))	('BRCA1/2', 'Gene', (59, 66))
468699	27643881	In addition, it has been reported that the expression of BRCA1 is associated with platinum-resistance in ovarian carcinomas and chemoresistance in breast carcinomas.	('associated with', 'Reg', (66, 81))	('breast carcinomas', 'Phenotype', 'HP:0003002', (147, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('platinum', 'Chemical', 'MESH:D010984', (82, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('breast carcinoma', 'Phenotype', 'HP:0003002', (147, 163))	('expression', 'Var', (43, 53))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (105, 122))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (105, 123))	('BRCA1', 'Gene', '672', (57, 62))	('ovarian carcinomas', 'Disease', (105, 123))	('BRCA1', 'Gene', (57, 62))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (105, 123))	('platinum-resistance', 'CPA', (82, 101))	('breast carcinomas', 'Disease', 'MESH:D001943', (147, 164))	('chemoresistance', 'CPA', (128, 143))	('breast carcinomas', 'Disease', (147, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
468702	27643881	The present study also shows that individual expression of PARP1, gammaH2AX, and BRCA2 are independent prognostic indicators of STSs.	('STSs', 'Disease', (128, 132))	('STSs', 'Phenotype', 'HP:0030448', (128, 132))	('BRCA2', 'Gene', (81, 86))	('PARP1', 'Gene', '142', (59, 64))	('gammaH2AX', 'Chemical', '-', (66, 75))	('BRCA2', 'Gene', '675', (81, 86))	('gammaH2AX', 'Var', (66, 75))	('PARP1', 'Gene', (59, 64))	('STS', 'Phenotype', 'HP:0030448', (128, 131))
468708	27643881	These results suggest that the expression status of the DDR molecules PARP1, gammaH2AX, BRCA1, and BRCA2 are important for the prognosis of cancer patients and support the notion that these molecules might be therapeutic targets of STS.	('BRCA1', 'Gene', (88, 93))	('PARP1', 'Gene', '142', (70, 75))	('STS', 'Phenotype', 'HP:0030448', (232, 235))	('PARP1', 'Gene', (70, 75))	('gammaH2AX', 'Chemical', '-', (77, 86))	('cancer', 'Disease', (140, 146))	('gammaH2AX', 'Var', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('expression', 'MPA', (31, 41))	('BRCA2', 'Gene', (99, 104))	('patients', 'Species', '9606', (147, 155))	('important', 'Reg', (109, 118))	('BRCA1', 'Gene', '672', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('BRCA2', 'Gene', '675', (99, 104))
468709	27643881	However, although we presented that the expression of PARP1, gammaH2AX, BRCA1, and BRCA2 are closely related with poor prognosis of STSs, this study is limited in that our cases are heterogeneous and a limited number of cases are included in each histologic subtype of STS.	('STS', 'Phenotype', 'HP:0030448', (132, 135))	('BRCA2', 'Gene', '675', (83, 88))	('BRCA1', 'Gene', '672', (72, 77))	('STSs', 'Disease', (132, 136))	('STSs', 'Phenotype', 'HP:0030448', (132, 136))	('gammaH2AX', 'Chemical', '-', (61, 70))	('BRCA1', 'Gene', (72, 77))	('gammaH2AX', 'Var', (61, 70))	('PARP1', 'Gene', '142', (54, 59))	('PARP1', 'Gene', (54, 59))	('BRCA2', 'Gene', (83, 88))	('STS', 'Phenotype', 'HP:0030448', (269, 272))	('related', 'Reg', (101, 108))
468729	25223704	For example, miR-214, miR-21, miR-31, miR-181a, and miR-155 have been reported to play pivotal roles in T cell function.	('miR-181a', 'Gene', (38, 46))	('miR-181a', 'Gene', '387176', (38, 46))	('miR-155', 'Gene', '387173', (52, 59))	('play', 'Reg', (82, 86))	('miR-31', 'Var', (30, 36))	('miR-214', 'Var', (13, 20))	('miR-155', 'Gene', (52, 59))	('miR-21', 'Var', (22, 28))	('T cell function', 'CPA', (104, 119))
468733	25223704	Because fast-growing tumor cells have been shown to highly express certain oncogenic miRNAs, such as miR-214 and miR-21, and can generate and release high levels of miRNA-containing MVs, it is possible that tumor cells can actively manipulate the antitumor activities of immune cells by delivering tumor-specific miRNAs to target immune cells via an MV-based pathway.	('manipulate', 'Reg', (232, 242))	('tumor', 'Disease', (251, 256))	('miR-21', 'Var', (113, 119))	('tumor', 'Disease', (298, 303))	('MV-based', 'Pathway', (350, 358))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('miR-214', 'Var', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
468740	25223704	Further analysis revealed that the plasma levels of miR-214 in the tumor-bearing patients were markedly enriched in MVs (Figure 1C), by which miRNAs can be delivered into recipient cells.	('miR-214', 'Var', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
468751	25223704	To confirm that the expansion of CD4+CD25highFoxp3+ Tregs was mainly due to exogenous miR-214 in MVs, miR-214-deficient LLC-derived MVs were prepared by knocking down miR-214 using antisense oligonucleotides (ASOs).	('CD25', 'Gene', (37, 41))	('CD25', 'Gene', '16184', (37, 41))	('knocking down', 'Var', (153, 166))	('miR-214', 'Gene', (167, 174))	('ASOs', 'Chemical', 'MESH:D016376', (209, 213))	('Tregs', 'Chemical', '-', (52, 57))	('oligonucleotides', 'Chemical', 'MESH:D009841', (191, 207))
468756	25223704	Likewise, the transfection of anti-miR-214 did not substantially alter mRNA or miRNA levels in the LLC MVs, with the exception of miR-214 (Supplementary information, Figure S3B and S3C).	('miRNA levels', 'MPA', (79, 91))	('miR-214', 'Var', (130, 137))	('anti-miR-214', 'Var', (30, 42))	('mRNA', 'MPA', (71, 75))	('S3B', 'Gene', '11778', (173, 176))	('S3B', 'Gene', (173, 176))
468758	25223704	Taken together, these results indicate that LLC-secreted miR-214 in MVs was delivered into the recipient CD4+ T cells sufficiently and promoted Treg expansion.	('miR-214', 'Var', (57, 64))	('Treg', 'Chemical', '-', (144, 148))	('promoted', 'PosReg', (135, 143))	('Treg expansion', 'CPA', (144, 158))
468765	25223704	As expected, the inhibition of PTEN expression potently promoted Treg expansion (Figure 3L).	('PTEN expression', 'Protein', (31, 46))	('inhibition', 'Var', (17, 27))	('Treg', 'Chemical', '-', (65, 69))	('promoted', 'PosReg', (56, 64))	('Treg expansion', 'CPA', (65, 79))
468775	25223704	The Tregs induced by tumor-secreted miR-214 strongly promoted tumor growth in the nude mice (Figure 4E and 4F), suggesting that miR-214-induced Tregs can effectively suppress the immune responses of tumor-attacking cytotoxic cells, such as natural killer (NK) cells and macrophages.	('tumor', 'Disease', (199, 204))	('miR-214-induced', 'Var', (128, 143))	('promoted', 'PosReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (21, 26))	('immune responses', 'CPA', (179, 195))	('suppress', 'NegReg', (166, 174))	('tumor', 'Disease', (62, 67))	('miR-214', 'Gene', (36, 43))	('Tregs', 'Chemical', '-', (4, 9))	('Tregs', 'Chemical', '-', (144, 149))	('nude mice', 'Species', '10090', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
468776	25223704	Two approaches were performed to directly monitor the transport of miR-214 into peripheral CD4+ T cells via tumor-derived MVs.	('miR-214', 'Var', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))
468779	25223704	The peripheral CD4+ T cells isolated from these mice contained a significant amount of miR-214mut (Figure 5B and 5C), and miR-214mut levels were markedly increased in the plasma and peaked 30 min post injection (Figure 5D).	('miR-214mut', 'MPA', (87, 97))	('miR-214mut', 'Var', (122, 132))	('increased', 'PosReg', (154, 163))	('mice', 'Species', '10090', (48, 52))
468780	25223704	The miR-214mut-transfected tumor cells were also directly injected into the mice.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('miR-214mut-transfected', 'Var', (4, 26))
468785	25223704	Consistent with findings in cancer patients and tumor-implanted mice (Figure 1), miR-214 levels in the plasma (Supplementary information, Figure S8B) and peripheral CD4+ T cells (Supplementary information, Figure S8C) of LLC MV-injected mice were significantly higher compared with those in saline-injected mice.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('LLC MV-injected', 'Var', (221, 236))	('miR-214', 'Gene', (81, 88))	('mice', 'Species', '10090', (237, 241))	('mice', 'Species', '10090', (307, 311))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('higher', 'PosReg', (261, 267))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Disease', (28, 34))	('saline', 'Chemical', 'MESH:D012965', (291, 297))	('mice', 'Species', '10090', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
468786	25223704	However, the levels of pre-miR-214 (Supplementary information, Figure S8D), as well as miR-199a, pre-miR-199a-2, and Dnm3os (Supplementary information, Figure S8E-S8G), in the peripheral CD4+ T cells did not change.	('Dnm3os', 'Gene', (117, 123))	('miR-199a-2', 'Gene', (101, 111))	('miR-199a-2', 'Gene', '723821', (101, 111))	('Dnm3os', 'Gene', '474332', (117, 123))	('miR-199a', 'Var', (87, 95))
468792	25223704	Likewise, the level of miR-214 was significantly higher in plasma from lung cancer patients than that from normal subjects (Supplementary information, Figure S9F).	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('level', 'MPA', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miR-214', 'Var', (23, 30))	('patients', 'Species', '9606', (83, 91))	('higher', 'PosReg', (49, 55))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
468794	25223704	As depicted in Supplementary information, Figure S10A, C57BL/6J mice were pre-treated with or without LLC MVs and implanted with mouse sarcoma S-180 cells.	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('S10A', 'Var', (49, 53))	('mouse', 'Species', '10090', (129, 134))	('sarcoma', 'Disease', (135, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('S10A', 'SUBSTITUTION', 'None', (49, 53))	('mice', 'Species', '10090', (64, 68))
468795	25223704	When the mice were implanted with 106 S-180 cells, the plasma miR-214 levels were more than 20-fold higher in the LLC MV-pretreated mice compared with their control counterparts (Supplementary information, Figure S10B).	('S10B', 'SUBSTITUTION', 'None', (213, 217))	('mice', 'Species', '10090', (132, 136))	('higher', 'PosReg', (100, 106))	('mice', 'Species', '10090', (9, 13))	('S10B', 'Var', (213, 217))	('plasma miR-214 levels', 'MPA', (55, 76))
468796	25223704	Consistent with previous findings, the expansion of the Tregs compromised the immune response to the tumors, and the growth of the implanted tumors was significantly more rapid in the LLC MV-pretreated mice (Supplementary information, Figure S10C, left panel; Figure S10D, upper panel).	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('growth', 'CPA', (117, 123))	('expansion', 'Var', (39, 48))	('mice', 'Species', '10090', (202, 206))	('compromised', 'NegReg', (62, 73))	('S10C', 'Mutation', 'p.S10C', (242, 246))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('S10D', 'Mutation', 'p.S10D', (267, 271))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('Tregs', 'Chemical', '-', (56, 61))	('more rapid', 'PosReg', (166, 176))	('tumors', 'Disease', (101, 107))
468800	25223704	Both the 293T cells and 293T MVs contained low levels of miR-214 (Supplementary information, Figure S11A and S11B).	('S11A', 'Var', (100, 104))	('293T', 'CellLine', 'CVCL:0063', (24, 28))	('miR-214', 'Gene', (57, 64))	('293T', 'CellLine', 'CVCL:0063', (9, 13))	('S11A', 'SUBSTITUTION', 'None', (100, 104))	('S11B', 'Var', (109, 113))	('S11B', 'SUBSTITUTION', 'None', (109, 113))
468801	25223704	The overexpression of miR-214 in 293T cells (Supplementary information, Figure S11C) resulted in the production of MVs containing high levels of miR-214 (Supplementary information, Figure S11D).	('miR-214', 'Var', (145, 152))	('S11D', 'Var', (188, 192))	('S11D', 'SUBSTITUTION', 'None', (188, 192))	('miR-214', 'Gene', (22, 29))	('S11C', 'SUBSTITUTION', 'None', (79, 83))	('293T', 'CellLine', 'CVCL:0063', (33, 37))	('overexpression', 'PosReg', (4, 18))	('S11C', 'Var', (79, 83))
468804	25223704	The LLC MV-induced downregulation of PTEN expression in mouse peripheral CD4+ T cells was reversed after the depletion of miR-214 from the LLC MVs (Figure 6B).	('expression', 'MPA', (42, 52))	('mouse', 'Species', '10090', (56, 61))	('PTEN', 'Gene', (37, 41))	('depletion', 'MPA', (109, 118))	('miR-214', 'Var', (122, 129))	('downregulation', 'NegReg', (19, 33))
468805	25223704	In addition, although the control 293T MVs did not affect CD4+ T cell PTEN expression, the "modified" 293T MVs, which contained high levels of miR-214, resulted in the downregulation of PTEN expression in CD4+ T cells (Figure 6B).	('293T', 'CellLine', 'CVCL:0063', (34, 38))	('PTEN', 'Protein', (186, 190))	('downregulation', 'NegReg', (168, 182))	('miR-214', 'Var', (143, 150))	('293T', 'CellLine', 'CVCL:0063', (102, 106))	('expression', 'MPA', (191, 201))
468807	25223704	This induction of Tregs by LLC MVs, however, was largely inhibited by the removal of miR-214 from the LLC MVs (Figure 6C and 6D).	('inhibited', 'NegReg', (57, 66))	('Tregs', 'CPA', (18, 23))	('miR-214', 'Gene', (85, 92))	('Tregs', 'Chemical', '-', (18, 23))	('removal', 'Var', (74, 81))
468808	25223704	Consistent with this result, the growth of the implanted sarcoma in the LLC MV-treated mice was significantly faster than that in the saline- or normal 293T MV-treated control mice (Figure 6E and 6F).	('saline', 'Chemical', 'MESH:D012965', (134, 140))	('mice', 'Species', '10090', (87, 91))	('MV-treated', 'Var', (76, 86))	('faster', 'PosReg', (110, 116))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('293T', 'CellLine', 'CVCL:0063', (152, 156))	('mice', 'Species', '10090', (176, 180))	('growth', 'CPA', (33, 39))	('sarcoma', 'Disease', (57, 64))	('LLC MV-treated', 'Var', (72, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
468811	25223704	To determine whether the observed pro-tumor effects of the tumor-derived MVs were truly Treg-dependent, inducible Treg-deficient mice (diphtheria toxin-treated Foxp3DTR mice) were treated with tumor-derived MVs (Supplementary information, Figure S12A).	('Treg', 'Chemical', '-', (114, 118))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Treg', 'Chemical', '-', (88, 92))	('tumor', 'Disease', (59, 64))	('S12A', 'Var', (246, 250))	('S12A', 'SUBSTITUTION', 'None', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('mice', 'Species', '10090', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('mice', 'Species', '10090', (129, 133))	('tumor', 'Disease', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
468812	25223704	Our results indicated that the levels of miR-214 in peripheral CD4+ T cells of Foxp3DTR mice and wild-type Foxp3+ littermates were significantly increased after LLC MV injection, whereas the levels of miR-214 were unchanged in mice injected with LLC MV/miR-214def (Supplementary information, Figure S12B).	('levels', 'MPA', (31, 37))	('S12B', 'Var', (299, 303))	('Foxp3DTR', 'Var', (79, 87))	('increased', 'PosReg', (145, 154))	('mice', 'Species', '10090', (227, 231))	('S12B', 'SUBSTITUTION', 'None', (299, 303))	('mice', 'Species', '10090', (88, 92))
468813	25223704	Wild-type Foxp3+ mice treated with LLC MVs had a higher percentage of Tregs in peripheral CD4+ T cells compared to wild-type Foxp3+ mice treated with LLC MV/miR-214def (Supplementary information, Figure S12C).	('MVs', 'Var', (39, 42))	('mice', 'Species', '10090', (17, 21))	('mice', 'Species', '10090', (132, 136))	('S12C', 'Mutation', 'p.S12C', (203, 207))	('Tregs', 'Chemical', '-', (70, 75))	('higher', 'PosReg', (49, 55))	('Tregs in', 'CPA', (70, 78))
468815	25223704	The growth rate of the implanted sarcoma in the LLC MV-treated Foxp3+ mice was significantly faster than that in the LLC MV/miR-214def-treated Foxp3+ mice (Supplementary information, Figure S12D and S12E).	('mice', 'Species', '10090', (150, 154))	('Foxp3+', 'Var', (63, 69))	('S12D', 'Mutation', 'p.S12D', (190, 194))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('growth rate', 'CPA', (4, 15))	('S12E', 'Mutation', 'p.S12E', (199, 203))	('mice', 'Species', '10090', (70, 74))	('faster', 'PosReg', (93, 99))	('sarcoma', 'Disease', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))
468817	25223704	Importantly, Treg elimination in the adult Foxp3DTR mice resulted in a more rapid development of terminal autoimmune disease compared with the Foxp3+ mice.	('Foxp3DTR', 'Var', (43, 51))	('mice', 'Species', '10090', (150, 154))	('autoimmune disease', 'Disease', (106, 124))	('Treg elimination', 'CPA', (13, 29))	('Treg', 'Chemical', '-', (13, 17))	('mice', 'Species', '10090', (52, 56))	('autoimmune disease', 'Disease', 'MESH:D001327', (106, 124))	('autoimmune disease', 'Phenotype', 'HP:0002960', (106, 124))
468822	25223704	We generated 293T MVs containing anti-miR-214 ASOs by transfecting 293T cells with anti-miR-214 ASOs.	('anti-miR-214', 'Var', (33, 45))	('ASOs', 'Chemical', 'MESH:D016376', (46, 50))	('293T', 'CellLine', 'CVCL:0063', (67, 71))	('anti-miR-214', 'Var', (83, 95))	('293T', 'CellLine', 'CVCL:0063', (13, 17))	('ASOs', 'Chemical', 'MESH:D016376', (96, 100))
468823	25223704	Transfection of anti-miR-214 ASOs into the 293T cells did not substantially affect the protein, mRNA, or miRNA levels in the 293T MVs (Supplementary information, Figure S13A-S13C).	('S13C', 'Mutation', 'p.S13C', (174, 178))	('affect', 'Reg', (76, 82))	('ASOs', 'Chemical', 'MESH:D016376', (29, 33))	('293T', 'CellLine', 'CVCL:0063', (125, 129))	('S13A', 'SUBSTITUTION', 'None', (169, 173))	('S13A', 'Var', (169, 173))	('293T', 'CellLine', 'CVCL:0063', (43, 47))	('miRNA levels', 'MPA', (105, 117))	('protein', 'MPA', (87, 94))	('mRNA', 'MPA', (96, 100))	('anti-miR-214', 'Var', (16, 28))
468825	25223704	As expected, treatment with the anti-miR-214 ASOs significantly decreased sarcoma-induced miR-214 levels in CD4+ T cells (Supplementary information, Figure S13D).	('S13D', 'Mutation', 'p.S13D', (156, 160))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('sarcoma', 'Disease', (74, 81))	('ASOs', 'Chemical', 'MESH:D016376', (45, 49))	('anti-miR-214', 'Var', (32, 44))	('decreased', 'NegReg', (64, 73))
468826	25223704	Consequently, treatment with the anti-miR-214 ASOs successfully rescued the S-180 sarcoma-induced reduction of PTEN levels (Supplementary information, Figure S14B) and thus suppressed the expansion of CD4+CD25highFoxp3+ Tregs (Supplementary information, Figure S14C and S14D).	('S14B', 'SUBSTITUTION', 'None', (158, 162))	('PTEN levels', 'MPA', (111, 122))	('S14B', 'Var', (158, 162))	('ASOs', 'Chemical', 'MESH:D016376', (46, 50))	('S14C', 'Mutation', 'p.S14C', (261, 265))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('S14D', 'Mutation', 'p.S14D', (270, 274))	('reduction', 'NegReg', (98, 107))	('CD25', 'Gene', '16184', (205, 209))	('Tregs', 'Chemical', '-', (220, 225))	('sarcoma', 'Disease', (82, 89))	('CD25', 'Gene', (205, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('suppressed', 'NegReg', (173, 183))
468827	25223704	Importantly, compared with the control mice treated with saline or 293T MVs containing a control oligonucleotide (anti-ncRNA), the mice treated with anti-miR-214 ASO-containing 293T MVs exhibited a significantly decreased growth rate and tumor size (Supplementary information, Figure S14E-S14G).	('anti-miR-214', 'Var', (149, 161))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('decreased growth', 'Phenotype', 'HP:0001510', (212, 228))	('saline', 'Chemical', 'MESH:D012965', (57, 63))	('ASO', 'Chemical', 'MESH:D016376', (162, 165))	('S14G', 'Mutation', 'p.S14G', (289, 293))	('oligonucleotide', 'Chemical', 'MESH:D009841', (97, 112))	('293T', 'CellLine', 'CVCL:0063', (67, 71))	('mice', 'Species', '10090', (131, 135))	('S14E', 'Mutation', 'p.S14E', (284, 288))	('decreased', 'NegReg', (212, 221))	('decreased growth rate', 'Phenotype', 'HP:0001510', (212, 233))	('tumor', 'Disease', (238, 243))	('293T', 'CellLine', 'CVCL:0063', (177, 181))	('growth rate', 'CPA', (222, 233))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('ncRNA', 'Gene', (119, 124))	('ncRNA', 'Gene', '54719', (119, 124))	('mice', 'Species', '10090', (39, 43))
468832	25223704	We next used the p53-/-,K-rasG12D mouse model to test the effects of MV delivery of anti-miR-214 ASOs.	('anti-miR-214', 'Var', (84, 96))	('ASOs', 'Chemical', 'MESH:D016376', (97, 101))	('mouse', 'Species', '10090', (34, 39))	('p53', 'Gene', '22060', (17, 20))	('p53', 'Gene', (17, 20))
468834	25223704	Compared with the p53-/-,K-rasG12D mice treated with 293T MVs containing anti-ncRNA, the p53-/-,K-rasG12D mice treated with the anti-miR-214 ASO-containing 293T MVs displayed decreased growth of spontaneous lung tumors (Figure 7C-7F).	('293T', 'CellLine', 'CVCL:0063', (156, 160))	('p53', 'Gene', (89, 92))	('lung tumors', 'Disease', 'MESH:D008175', (207, 218))	('293T', 'CellLine', 'CVCL:0063', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('decreased', 'NegReg', (175, 184))	('p53', 'Gene', '22060', (89, 92))	('p53', 'Gene', (18, 21))	('lung tumors', 'Phenotype', 'HP:0100526', (207, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('growth', 'CPA', (185, 191))	('p53', 'Gene', '22060', (18, 21))	('anti-miR-214', 'Var', (128, 140))	('lung tumors', 'Disease', (207, 218))	('mice', 'Species', '10090', (106, 110))	('mice', 'Species', '10090', (35, 39))	('ASO', 'Chemical', 'MESH:D016376', (141, 144))	('ncRNA', 'Gene', (78, 83))	('ncRNA', 'Gene', '54719', (78, 83))	('decreased growth', 'Phenotype', 'HP:0001510', (175, 191))
468835	25223704	Anti-miR-214 ASOs also successfully suppressed the expansion of CD4+CD25highFoxp3+ Tregs in the blood and spleen of p53-/-,K-rasG12D mice (Figure 7G and 7H).	('suppressed', 'NegReg', (36, 46))	('mice', 'Species', '10090', (133, 137))	('expansion', 'CPA', (51, 60))	('CD25', 'Gene', (68, 72))	('CD25', 'Gene', '16184', (68, 72))	('p53', 'Gene', '22060', (116, 119))	('Tregs', 'Chemical', '-', (83, 88))	('ASOs', 'Chemical', 'MESH:D016376', (13, 17))	('Anti-miR-214', 'Var', (0, 12))	('p53', 'Gene', (116, 119))
468836	25223704	These results indicate that MV delivery of anti-miR-214 ASOs is an efficient method to abolish tumor-induced Treg expansion and inhibit the growth of tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('inhibit', 'NegReg', (128, 135))	('ASOs', 'Chemical', 'MESH:D016376', (56, 60))	('Treg', 'Chemical', '-', (109, 113))	('anti-miR-214', 'Var', (43, 55))	('abolish', 'NegReg', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (95, 100))
468849	25223704	(c) Similarly, the administration of tumor MVs containing a mutant miR-214 significantly increased the amount of mutant miR-214 in the peripheral CD4+ T cells of mice (Figure 5B-5E).	('mutant', 'Var', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('miR-214', 'Gene', (67, 74))	('mutant', 'Var', (60, 66))	('mice', 'Species', '10090', (162, 166))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('miR-214', 'Gene', (120, 127))	('increased', 'PosReg', (89, 98))
468853	25223704	In agreement with previous studies, our in vitro assay indicated that the expansion of Tregs could be induced by molecules that were present in the tumor-derived MVs, which likely included miR-214.	('miR-214', 'Var', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('Tregs', 'CPA', (87, 92))	('Tregs', 'Chemical', '-', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
468868	25223704	Because peripheral T cells and tumor-secreted miR-214 are both in circulation, peripheral T cells may have more ample access to miR-214 compared to other cells in different organs/tissues.	('miR-214', 'Var', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
468869	25223704	By directly tracking exogenous miR-214 both in vitro and in vivo, our data clearly show that tumor cell-secreted miR-214 can sufficiently enter into CD4+ T cells (Figure 5) and modulate PTEN expression and target cell function (Figures 3 and 6).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PTEN', 'Protein', (186, 190))	('modulate', 'Reg', (177, 185))	('tumor', 'Disease', (93, 98))	('miR-214', 'Var', (113, 120))	('expression', 'MPA', (191, 201))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
468877	25223704	By employing cell-derived MVs to deliver anti-miR-214 ASOs into peripheral CD4+ T cells, we successfully reversed the downregulation of PTEN in CD4+ T cells and blocked the expansion of the CD4+CD25highFoxp3+Treg population (Figure 7 and Supplementary information, Figure S14).	('CD25', 'Gene', (194, 198))	('downregulation', 'NegReg', (118, 132))	('CD25', 'Gene', '16184', (194, 198))	('Treg', 'Chemical', '-', (208, 212))	('ASOs', 'Chemical', 'MESH:D016376', (54, 58))	('anti-miR-214', 'Var', (41, 53))	('blocked', 'NegReg', (161, 168))	('PTEN', 'Gene', (136, 140))
468878	25223704	As expected, the MV-delivered anti-miR-214 ASOs effectively decreased the growth of the implanted and spontaneous tumors (Figure 7 and Supplementary information, Figure S14).	('decreased', 'NegReg', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('anti-miR-214', 'Var', (30, 42))	('ASOs', 'Chemical', 'MESH:D016376', (43, 47))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
468882	25223704	After the MVs enter the recipient CD4+ T cells, miR-214 decreases PTEN protein expression and facilitates Treg expansion, which, in turn, results in host immune suppression and tumor growth.	('miR-214', 'Var', (48, 55))	('host immune suppression', 'CPA', (149, 172))	('expression', 'MPA', (79, 89))	('decreases', 'NegReg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('Treg', 'Chemical', '-', (106, 110))	('facilitates', 'PosReg', (94, 105))	('Treg expansion', 'CPA', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('PTEN protein', 'Protein', (66, 78))	('results in', 'Reg', (138, 148))
468884	25223704	As an extension of this idea, we demonstrated that the inhibition of Treg-mediated immune suppression induced by tumor-secreted miR-214 via MV delivery of functional anti-miR-214 ASOs into CD4+ T cells represents a novel and effective therapeutic approach for cancer treatment.	('miR-214', 'Gene', (128, 135))	('tumor', 'Disease', (113, 118))	('Treg-mediated immune suppression', 'CPA', (69, 101))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Treg', 'Chemical', '-', (69, 73))	('ASOs', 'Chemical', 'MESH:D016376', (179, 183))	('inhibition', 'NegReg', (55, 65))	('anti-miR-214', 'Var', (166, 178))
468890	25223704	The Foxp3DTR mice (where DTR is diphtheria toxin receptor) were generously provided by Prof Alexander Rudensky (Memorial Sloan-Kettering Cancer Center, New York) and maintained under specific pathogen-free conditions at Nanjing University.	('mice', 'Species', '10090', (13, 17))	('Memorial Sloan-Kettering Cancer', 'Disease', 'MESH:D008569', (112, 143))	('Foxp3DTR', 'Var', (4, 12))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Memorial Sloan-Kettering Cancer', 'Disease', (112, 143))
468899	23921231	In a SYT-SSX2 transgenic model, we show that a constitutive Wnt/beta-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of beta-catenin blocks SS tumor formation.	('transgenic', 'Species', '10090', (14, 24))	('SSX2', 'Gene', '6757', (9, 13))	('SSX2', 'Gene', (9, 13))	('activated', 'PosReg', (98, 107))	('SSX2', 'Gene', (115, 119))	('constitutive Wnt/beta-catenin signal', 'MPA', (47, 83))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('loss', 'Var', (173, 177))	('SS tumor', 'Disease', 'MESH:D009369', (201, 209))	('beta-catenin', 'Protein', (181, 193))	('genetic loss', 'Var', (165, 177))	('SS tumor', 'Disease', (201, 209))	('SSX2', 'Gene', '6757', (115, 119))	('inhibition', 'NegReg', (125, 135))
468913	23921231	beta-catenin and SYT-SSX2 coexisted in active nuclear complexes, and a functional link between the two proteins was established when SYT-SSX2 depletion in primary human SS cells led to a marked attenuation of beta-catenin nuclear accumulation.	('SSX2', 'Gene', '6757', (137, 141))	('SS', 'Gene', '23956', (169, 171))	('SSX2', 'Gene', '6757', (21, 25))	('attenuation', 'NegReg', (194, 205))	('human', 'Species', '9606', (163, 168))	('SSX2', 'Gene', (137, 141))	('SSX2', 'Gene', (21, 25))	('depletion', 'Var', (142, 151))	('SS', 'Gene', '23956', (137, 139))	('SS', 'Gene', '23956', (21, 23))	('beta-catenin nuclear accumulation', 'MPA', (209, 242))
468915	23921231	Whether activated by genetic lesions or epigenetic mechanisms, an aberrant Wnt/beta-catenin signal is often considered a marker for poor disease prognosis, and is implicated in tumor progression and invasiveness.	('implicated', 'Reg', (163, 173))	('genetic lesions', 'Disease', 'MESH:D020022', (21, 36))	('Wnt/beta-catenin signal', 'MPA', (75, 98))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('genetic lesions', 'Disease', (21, 36))	('aberrant', 'Var', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))
468916	23921231	Deregulation of Wnt/beta-catenin signaling in SS was described in several studies (>300 tumors examined) where beta-catenin accumulation was detected in the majority of tumors and was predictive of poor survival.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('Deregulation', 'Var', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('SS', 'Gene', '23956', (46, 48))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Wnt/beta-catenin signaling', 'MPA', (16, 42))	('beta-catenin accumulation', 'MPA', (111, 136))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumors', 'Disease', (169, 175))
468939	23921231	The appearance of tumors in the remaining 3 SG3 mutants prompted us to perform an immunohistochemical analysis of the sarcoma tissues to determine the status of beta-catenin.	('sarcoma', 'Disease', (118, 125))	('mutants', 'Var', (48, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('SG3', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
468941	23921231	Most importantly, all the sarcomas of the SG1 and SG2 mice displayed a strong nuclear and/or cytoplasmic beta-catenin signal, suggesting deregulation of Wnt/beta-catenin signaling in the tumors (Figure 1C right images, compare with IgG control; Figure 2A).	('SG2', 'Var', (50, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('sarcomas', 'Disease', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('SG1', 'Var', (42, 45))	('IgG', 'Gene', '16059', (232, 235))	('Wnt/beta-catenin signaling', 'MPA', (153, 179))	('sarcomas', 'Disease', 'MESH:D012509', (26, 34))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('IgG', 'Gene', (232, 235))	('mice', 'Species', '10090', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('nuclear and/or', 'MPA', (78, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('deregulation', 'PosReg', (137, 149))
468948	23921231	Thus, in a conditional SYT-SSX2 transgenic model where expression of the fusion is sufficient for malignant transformation of muscle precursors, depletion mutations of the beta-catenin locus negatively affects development of detectable SS tumors.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('beta-catenin', 'Gene', (172, 184))	('expression', 'Species', '29278', (55, 65))	('SSX2', 'Gene', '6757', (27, 31))	('transgenic', 'Species', '10090', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('depletion mutations', 'Var', (145, 164))	('affects', 'Reg', (202, 209))	('SSX2', 'Gene', (27, 31))	('negatively', 'NegReg', (191, 201))	('SS tumors', 'Disease', (236, 245))	('development of detectable', 'CPA', (210, 235))	('SS tumors', 'Disease', 'MESH:D009369', (236, 245))
468955	23921231	Taken together, these results show that deregulation of beta-catenin is a persistent feature of SYT-SSX2-induced SS tumors and is necessary for their development.	('beta-catenin', 'Protein', (56, 68))	('SSX2', 'Gene', '6757', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('deregulation', 'Var', (40, 52))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('SS tumors', 'Disease', 'MESH:D009369', (113, 122))	('SSX2', 'Gene', (100, 104))	('SS tumors', 'Disease', (113, 122))
468957	23921231	For in vitro analysis we chose the C2C12 myoblasts, as they are equivalent to the Myf5 myoblasts where the SG1 tumors developed.	('Myf5', 'Gene', '17877', (82, 86))	('C2C12', 'Var', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Myf5', 'Gene', (82, 86))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))
468959	23921231	To locate the origin of beta-catenin activating signal, we sequentially infected C2C12 myoblasts with SYT-SSX2- and DKK1-(potent inhibitor of the Wnt receptor; 28)- expressing retroviruses, at 80%-90% rates.	('SSX2', 'Gene', (106, 110))	('SSX2', 'Gene', '6757', (106, 110))	('DKK1-', 'Var', (116, 121))
468964	23921231	In the mSS cells, ectopic DKK1 inhibited an intrinsic beta-catenin/TCF activity in a dose-dependent fashion (Figure 4A), thereby revealing a constitutive Wnt signal.	('TCF', 'Chemical', '-', (67, 70))	('DKK1', 'Gene', (26, 30))	('mSS', 'Gene', '23956', (7, 10))	('inhibited', 'NegReg', (31, 40))	('intrinsic beta-catenin/TCF activity', 'MPA', (44, 79))	('mSS', 'Gene', (7, 10))	('ectopic', 'Var', (18, 25))
468975	23921231	Pyrvinium activates the CK1alpha kinase, and through its nuclear effects, it bypasses surface signaling.	('CK1alpha kinase', 'Enzyme', (24, 39))	('Pyrvinium', 'Var', (0, 9))	('CK1', 'Species', '2498238', (24, 27))	('nuclear effects', 'MPA', (57, 72))	('activates', 'PosReg', (10, 19))	('Pyrvinium', 'Chemical', 'MESH:C024631', (0, 9))	('surface signaling', 'MPA', (86, 103))
468977	23921231	A two-day treatment with incremental doses of pyrvinium induced gradual beta-catenin nuclear exit and its accumulation at intercellular junctions (Figure S4A; white arrows).	('beta-catenin', 'Protein', (72, 84))	('nuclear exit', 'CPA', (85, 97))	('accumulation', 'MPA', (106, 118))	('pyrvinium', 'Var', (46, 55))	('pyrvinium', 'Chemical', 'MESH:C024631', (46, 55))
468978	23921231	In addition, pyrvinium significantly reduced beta-catenin reporter activity in SYT-SSX2-transduced cells (Figure S4B).	('pyrvinium', 'Chemical', 'MESH:C024631', (13, 22))	('SSX2', 'Gene', '6757', (83, 87))	('reduced', 'NegReg', (37, 44))	('pyrvinium', 'Var', (13, 22))	('beta-catenin reporter activity', 'MPA', (45, 75))	('SSX2', 'Gene', (83, 87))
468980	23921231	At concentrations similar to those used with C2C12 cells, pyrvinium abrogated mSS cell growth (Figure S4C) and significantly reduced their constitutive beta-catenin activity (Figure S4D).	('pyrvinium', 'Var', (58, 67))	('constitutive beta-catenin activity', 'MPA', (139, 173))	('pyrvinium', 'Chemical', 'MESH:C024631', (58, 67))	('reduced', 'NegReg', (125, 132))	('mSS', 'Gene', (78, 81))	('abrogated', 'NegReg', (68, 77))	('mSS', 'Gene', '23956', (78, 81))
468987	23921231	Mutational analysis by direct sequencing of both regions in CTNNB1 and APC revealed that the two genes are clear of Wnt activating mutations in SYO-1 and HS-SY-II cells (Supplementary Methods).	('mutations', 'Var', (131, 140))	('SYO-1', 'Gene', (144, 149))	('CTNNB1', 'Gene', (60, 66))	('CTNNB1', 'Gene', '1499', (60, 66))	('SYO-1', 'Gene', '55027', (144, 149))	('HS-SY-II', 'CellLine', 'CVCL:8719', (154, 162))
468991	23921231	Similar to pyrvinium, SSTC-104 induced striking morphological changes, as the cells displayed enhanced spreading and a noticeable increase in the number of intercellular junctions, enriched for beta-catenin, mediated by long cytoplasmic extensions (Figures 5C and S6B; white arrows).	('enhanced', 'PosReg', (94, 102))	('pyrvinium', 'Chemical', 'MESH:C024631', (11, 20))	('spreading', 'CPA', (103, 112))	('increase', 'PosReg', (130, 138))	('SSTC-104', 'Var', (22, 30))	('SSTC-104', 'Chemical', '-', (22, 30))
469014	23921231	To elucidate the mechanism of Wnt/beta-catenin pathway deregulation by SYT-SSX2, we conducted deletion analysis of SYT-SSX2 to identify the distinct regions involved in beta-catenin nuclear localization and activation.	('deletion', 'Var', (94, 102))	('SSX2', 'Gene', '6757', (119, 123))	('SSX2', 'Gene', '6757', (75, 79))	('Wnt/beta-catenin pathway', 'Pathway', (30, 54))	('SSX2', 'Gene', (119, 123))	('SSX2', 'Gene', (75, 79))
469018	23921231	In the current analyses, we found that a deletion mutation in SSXRD (SXdl9), that abrogates beta-catenin nuclear localization and activation (Figures 7 and S9A), reduces levels of the Wnt/beta-catenin targets cyclin D1 and Myc (Figure S9C), and reverses the myogenesis block induced by SYT-SSX2 in C2C12 cells (Figure S9B).	('SSX2', 'Gene', '6757', (290, 294))	('deletion mutation', 'Var', (41, 58))	('myogenesis', 'MPA', (258, 268))	('cyclin D1', 'Gene', '12443', (209, 218))	('SSX', 'Gene', (290, 293))	('abrogates', 'NegReg', (82, 91))	('SSX', 'Gene', '6757', (290, 293))	('SSX2', 'Gene', (290, 294))	('Myc', 'Gene', (223, 226))	('reduces', 'NegReg', (162, 169))	('beta-catenin nuclear localization', 'MPA', (92, 125))	('SSX', 'Gene', '6757', (62, 65))	('reverses', 'NegReg', (245, 253))	('levels of', 'MPA', (170, 179))	('SSX', 'Gene', (62, 65))	('cyclin D1', 'Gene', (209, 218))	('Myc', 'Gene', '17869', (223, 226))	('activation', 'MPA', (130, 140))
469021	23921231	Whereas removal of the entire N-terminal segment (residues 1-40) led to a significant decrease in beta-catenin nuclear accumulation and signaling (Figure 7A and 7B; SXdl40), removal of the first 20 amino acids or residues 15-44 of SYT-SSX2 abolished beta-catenin reporter activity without impairing its nuclear accumulation (Figure 7A and 7B; SXdl20 and SXdlSNH).	('signaling', 'MPA', (136, 145))	('abolished', 'NegReg', (240, 249))	('beta-catenin reporter activity', 'MPA', (250, 280))	('SSX2', 'Gene', (235, 239))	('beta-catenin nuclear accumulation', 'MPA', (98, 131))	('decrease', 'NegReg', (86, 94))	('SSX2', 'Gene', '6757', (235, 239))	('removal', 'Var', (174, 181))
469022	23921231	Thus, our SYT-SSX2 deletion mutation data dissociate beta-catenin nuclear localization from its transcriptional activation.	('SSX2', 'Gene', (14, 18))	('beta-catenin', 'Protein', (53, 65))	('SSX2', 'Gene', '6757', (14, 18))	('deletion mutation', 'Var', (19, 36))
469030	23921231	Consistent with deregulated beta-catenin as a major feature of SS in humans, we find that primary human SS tumors (4/4) display elevated levels of nuclear beta-catenin (Figure S10A/B).	('SS', 'Gene', '23956', (63, 65))	('nuclear beta-catenin', 'MPA', (147, 167))	('S10A', 'SUBSTITUTION', 'None', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('elevated', 'PosReg', (128, 136))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('S10A', 'Var', (176, 180))	('human', 'Species', '9606', (69, 74))	('SS tumors', 'Disease', 'MESH:D009369', (104, 113))	('SS tumors', 'Disease', (104, 113))	('levels', 'MPA', (137, 143))	('human', 'Species', '9606', (98, 103))	('humans', 'Species', '9606', (69, 75))	('SS', 'Gene', '23956', (104, 106))
469046	23921231	In the transgenic model where SYT-SSX2 expression in muscle precursors leads to SS tumor formation at three months of age with 100% penetrance, we show that such tumors fail to develop in a beta-catenin deficient background.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('a beta', 'Gene', '14961', (188, 194))	('expression', 'Var', (39, 49))	('expression', 'Species', '29278', (39, 49))	('SSX2', 'Gene', '6757', (34, 38))	('SS tumor', 'Disease', (80, 88))	('SS tumor', 'Disease', 'MESH:D009369', (80, 88))	('tumors', 'Disease', (162, 168))	('a beta', 'Gene', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('SSX2', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('transgenic', 'Species', '10090', (7, 17))	('leads to', 'Reg', (71, 79))
469047	23921231	Whereas heterozygosity for beta-catenin (SG2) led to a significant reduction in the number of detectable tumors, visible tumors were absent in three months old beta-catenin-null SYT-SSX2 transgenic mice (SG3).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('transgenic mice', 'Species', '10090', (187, 202))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('reduction', 'NegReg', (67, 76))	('SSX2', 'Gene', '6757', (182, 186))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('SSX2', 'Gene', (182, 186))	('heterozygosity', 'Var', (8, 22))	('absent', 'NegReg', (133, 139))
469054	23921231	Consistent with this, recent studies demonstrated an anti-invasive function for CK1alpha (via inhibition of Wnt signaling) in malignant melanoma, and established CK1alpha as a potent negative regulator of the Wnt pathway in the intestine.	('malignant melanoma', 'Disease', 'MESH:D008545', (126, 144))	('Wnt pathway', 'Pathway', (209, 220))	('malignant melanoma', 'Disease', (126, 144))	('CK1alpha', 'Var', (162, 170))	('CK1', 'Species', '2498238', (162, 165))	('CK1alpha', 'Var', (80, 88))	('anti-invasive', 'CPA', (53, 66))	('CK1', 'Species', '2498238', (80, 83))	('Wnt signaling', 'Pathway', (108, 121))	('malignant melanoma', 'Phenotype', 'HP:0002861', (126, 144))
469055	23921231	CTNNB1 activating mutations in human SS have been previously reported.	('CTNNB1', 'Gene', '1499', (0, 6))	('activating', 'PosReg', (7, 17))	('SS', 'Gene', '23956', (37, 39))	('CTNNB1', 'Gene', (0, 6))	('human', 'Species', '9606', (31, 36))	('mutations', 'Var', (18, 27))
469057	23921231	Thus, we predict that SSTC-104 would be effective in SS tumors arising from activating Wnt signaling due to genetic and epigenetic mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('activating', 'MPA', (76, 86))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('epigenetic', 'Var', (120, 130))	('SS tumors', 'Disease', 'MESH:D009369', (53, 62))	('SS tumors', 'Disease', (53, 62))	('SSTC-104', 'Chemical', '-', (22, 30))
469058	23921231	The effects we observe with DKK1 indicate that the SYT-SSX2 oncogene generates receptor-mediated upstream signals to activate the Wnt/beta-catenin cascade, and our microarray analyses revealed the upregulation of an autocrine Wnt/beta-catenin loop by SYT-SSX2 expression.	('autocrine Wnt/beta-catenin loop', 'MPA', (216, 247))	('upregulation', 'PosReg', (197, 209))	('Wnt/beta-catenin cascade', 'Pathway', (130, 154))	('SSX2', 'Gene', '6757', (255, 259))	('expression', 'Var', (260, 270))	('activate', 'PosReg', (117, 125))	('SSX2', 'Gene', '6757', (55, 59))	('SSX2', 'Gene', (255, 259))	('expression', 'Species', '29278', (260, 270))	('SSX2', 'Gene', (55, 59))
469060	23921231	One important phenotypic consequence shared by pyrvinium, SSTC-104, LRP6 knockdown, DKK1 treatment (Data not shown), and SYT-SSX2 depletion in human SS cells, was a noticeable increase in cytoskeletal spread and formation of intercellular junctions enriched for beta-catenin, indicating a common effect on relocating beta-catenin to the cell surface.	('pyrvinium', 'Chemical', 'MESH:C024631', (47, 56))	('DKK1', 'Var', (84, 88))	('SSX2', 'Gene', (125, 129))	('increase', 'PosReg', (176, 184))	('human', 'Species', '9606', (143, 148))	('SS', 'Gene', '23956', (149, 151))	('depletion', 'Var', (130, 139))	('SSTC-104', 'Chemical', '-', (58, 66))	('SS', 'Gene', '23956', (125, 127))	('cytoskeletal spread', 'CPA', (188, 207))	('pyrvinium', 'Var', (47, 56))	('SSX2', 'Gene', '6757', (125, 129))	('LRP6', 'Gene', (68, 72))	('SS', 'Gene', '23956', (58, 60))	('knockdown', 'Var', (73, 82))
469063	23921231	In advanced human cancer, deregulation of Wnt/beta-catenin signaling contributes to tumor progression.	('deregulation', 'Var', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Wnt/beta-catenin signaling', 'Pathway', (42, 68))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', (84, 89))	('contributes', 'Reg', (69, 80))	('human', 'Species', '9606', (12, 17))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
469065	23921231	malignant melanomas; 46), and in certain cases, it occurs through epigenetic deregulation of its components (e.g.	('malignant melanoma', 'Phenotype', 'HP:0002861', (0, 18))	('malignant melanoma', 'Disease', 'MESH:D008545', (0, 18))	('malignant melanoma', 'Disease', (0, 18))	('melanomas', 'Disease', (10, 19))	('epigenetic deregulation', 'Var', (66, 89))	('occurs through', 'Reg', (51, 65))	('malignant melanomas', 'Phenotype', 'HP:0002861', (0, 19))	('melanomas', 'Disease', 'MESH:D008545', (10, 19))
469071	23921231	Upon SYT-SSX2 expression, and in SS tumors, it appears that the Wnt circuitry of lineage determinants is aberrantly mobilized (Figure S11, Table S3).	('expression', 'Var', (14, 24))	('SSX2', 'Gene', (9, 13))	('expression', 'Species', '29278', (14, 24))	('SS tumors', 'Disease', 'MESH:D009369', (33, 42))	('SS tumors', 'Disease', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('SSX2', 'Gene', '6757', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
469072	23921231	Deregulation of embryonic determinants in adult somatic cells could result in cellular catastrophe, as their normal function could transition the cell to a cancerous state (e.g.	('cancerous', 'Disease', (156, 165))	('Deregulation', 'Var', (0, 12))	('result in', 'Reg', (68, 77))	('cellular catastrophe', 'CPA', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancerous', 'Disease', 'MESH:D009369', (156, 165))	('transition', 'Reg', (131, 141))
469077	23921231	The prevalence of beta-catenin deregulation in human SS tumors combined with our findings indicate that targeting Wnt in SS would benefit a substantial proportion of SS patients.	('beta-catenin', 'Protein', (18, 30))	('SS', 'Gene', '23956', (121, 123))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('patients', 'Species', '9606', (169, 177))	('deregulation', 'Var', (31, 43))	('SS', 'Gene', '23956', (53, 55))	('SS', 'Gene', '23956', (166, 168))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('SS tumors', 'Disease', 'MESH:D009369', (53, 62))	('human', 'Species', '9606', (47, 52))	('SS tumors', 'Disease', (53, 62))
469084	23921231	Genotyping of all single, double and triple mutant mice was performed by PCR with primers recommended by the authors and by the Jackson Lab.	('triple mutant', 'Var', (37, 50))	('double', 'Var', (26, 32))	('mice', 'Species', '10090', (51, 55))
469089	23921231	Construction of POZ-SYT-SSX2-HA-FLAG deletion mutants designated SXdl1-dl9 was described previously.	('SSX2', 'Gene', '6757', (24, 28))	('SSX2', 'Gene', (24, 28))	('deletion mutants', 'Var', (37, 53))
469090	23921231	Construction of the N-terminal SYT-SSX2 deletion mutants, and LZRS-DKK1 is described in Supplementary Methods.	('deletion mutants', 'Var', (40, 56))	('SSX2', 'Gene', (35, 39))	('SSX2', 'Gene', '6757', (35, 39))
469092	23921231	DKK1 expression and beta-catenin localization were quantified 48 hours after infection with LZRS- DKK1.	('LZRS- DKK1', 'Var', (92, 102))	('expression', 'MPA', (5, 15))	('expression', 'Species', '29278', (5, 15))	('DKK1', 'Gene', (0, 4))
469095	23921231	The DNA mix also contained 0.5mug of LEF and 0.5 mug of beta-catenin expression vectors, 0.5 mug of TOP-FLASH or FOP-FLASH (background control) reporter vector, and titrated amounts of SYT-SSX2, SXdl mutants, DKK1 or empty control vectors, depending on the experiment, except in the assays where mSS intrinsic Wnt/beta-catenin activity is measured.	('mSS', 'Gene', '23956', (296, 299))	('mutants', 'Var', (200, 207))	('SXdl', 'Var', (195, 199))	('SSX2', 'Gene', '6757', (189, 193))	('FOP-', 'Phenotype', 'HP:0500062', (113, 117))	('mSS', 'Gene', (296, 299))	('expression vectors', 'Species', '29278', (69, 87))	('SSX2', 'Gene', (189, 193))
469111	23785647	We draw attention to the recently established link between defects in the STAG2 gene and Ewing's sarcoma, glioblastoma and melanoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (89, 104))	('defects', 'Var', (59, 66))	('glioblastoma', 'Disease', (106, 118))	('STAG2', 'Gene', (74, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('STAG2', 'Gene', '10735', (74, 79))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('melanoma', 'Disease', (123, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (89, 104))	("Ewing's sarcoma", 'Disease', (89, 104))
469142	23785647	Researchers at Georgetown School of Medicine, Washington, USA, have found defective copies of STAG2 gene in 21% of Ewing's sarcoma, 19% of melanoma and 19% of glioblastoma.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('STAG2', 'Gene', (94, 99))	('defective copies', 'Var', (74, 90))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (115, 130))	('melanoma', 'Disease', (139, 147))	('STAG2', 'Gene', '10735', (94, 99))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('glioblastoma', 'Disease', (159, 171))	("Ewing's sarcoma", 'Disease', (115, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (159, 171))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (115, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (159, 171))
469149	21448591	Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer To gain a greater understanding of the potential of the Aurora kinase A inhibitor MLN8237 in the treatment of pediatric malignancies.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Aurora kinase A', 'Gene', (63, 78))	('Aurora kinase A', 'Gene', (200, 215))	('Aurora kinase A', 'Gene', '20878', (200, 215))	('pediatric malignancies', 'Disease', 'MESH:D063766', (254, 276))	('MLN8237', 'Chemical', 'MESH:C550258', (89, 96))	('pediatric malignancies', 'Disease', (254, 276))	('Aurora kinase A', 'Gene', '20878', (63, 78))	('MLN8237', 'Chemical', 'MESH:C550258', (226, 233))	('MLN8237', 'Var', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))
469150	21448591	The activity of MLN8237 was evaluated against 28 neuroblastoma and Ewing sarcoma cell lines, and its in vivo efficacy was studied over a range of doses against 12 pediatric tumor xenograft models.	('neuroblastoma', 'Disease', (49, 62))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('MLN8237', 'Var', (16, 23))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('neuroblastoma', 'Phenotype', 'HP:0003006', (49, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('neuroblastoma', 'Disease', 'MESH:D009447', (49, 62))	('MLN8237', 'Chemical', 'MESH:C550258', (16, 23))	('Ewing sarcoma', 'Disease', (67, 80))
469151	21448591	In vitro neuroblastoma cell lines were generally more sensitive to MLN8237 than Ewing sarcoma lines.	('Ewing sarcoma lines', 'Disease', 'MESH:C563168', (80, 99))	('neuroblastoma', 'Disease', (9, 22))	('MLN8237', 'Var', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('sensitive', 'Reg', (54, 63))	('Ewing sarcoma lines', 'Disease', (80, 99))	('MLN8237', 'Chemical', 'MESH:C550258', (67, 74))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
469152	21448591	MLN8237 demonstrated significant activity in vivo against solid tumor models at the maximum tolerated dose (MTD); however, only 2 of 6 neuroblastoma models had objective responses at 0.25MTD.	('neuroblastoma', 'Disease', 'MESH:D009447', (135, 148))	('mum', 'Gene', '56925', (88, 91))	('neuroblastoma', 'Disease', (135, 148))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('mum', 'Gene', (88, 91))	('solid tumor', 'Disease', (58, 69))	('neuroblastoma', 'Phenotype', 'HP:0003006', (135, 148))	('MLN8237', 'Var', (0, 7))	('solid tumor', 'Disease', 'MESH:D009369', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
469153	21448591	In contrast, MLN8237 induced objective responses at its MTD and at 0.5MTD in three ALL models and in two out of three at 0.25MTD.	('MLN8237', 'Var', (13, 20))	('ALL', 'Phenotype', 'HP:0006721', (83, 86))	('objective responses', 'MPA', (29, 48))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))
469155	21448591	Mitotic indices increased 6-12 h after MLN8237 administration.	('Mitotic indices', 'CPA', (0, 15))	('increased', 'PosReg', (16, 25))	('MLN8237', 'Var', (39, 46))	('MLN8237', 'Chemical', 'MESH:C550258', (39, 46))
469156	21448591	AURKA copy number variation was frequent in xenografts, and expression was highly correlated with copy number.	('AURKA', 'Gene', (0, 5))	('expression', 'MPA', (60, 70))	('AURKA', 'Gene', '20878', (0, 5))	('copy number variation', 'Var', (6, 27))
469157	21448591	Objective responses were more frequent in tumors with decreased AURKA copy number (5/8) compared to those with increased gene copy number (2/14).	('AURKA', 'Gene', (64, 69))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('Objective responses', 'CPA', (0, 19))	('decreased', 'NegReg', (54, 63))	('copy number', 'Var', (70, 81))	('AURKA', 'Gene', '20878', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
469159	21448591	These data support clinical development of MLN8237 in childhood cancer.	('MLN8237', 'Chemical', 'MESH:C550258', (43, 50))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('MLN8237', 'Var', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
469161	21448591	Thus, interfering with mitosis has proven to be a successful cancer treatment strategy.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('interfering', 'Var', (6, 17))	('cancer', 'Disease', (61, 67))	('mitosis', 'Disease', (23, 30))	('mitosis', 'Disease', 'None', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
469173	21448591	Most of these inhibitors show a broad range of activity, with AZD-1152 being an example of a selective Aurora kinase B inhibitor and MLN8054 (or its derived compound, MLN8237, used in the present study) an example of a selective Aurora kinase A inhibitor.	('MLN8054', 'Chemical', 'MESH:C518940', (133, 140))	('AZD-1152', 'Chemical', 'MESH:C520647', (62, 70))	('Aurora kinase B', 'Gene', '20877', (103, 118))	('MLN8237', 'Chemical', 'MESH:C550258', (167, 174))	('AZD-1152', 'Var', (62, 70))	('Aurora kinase B', 'Gene', (103, 118))	('MLN8054', 'Var', (133, 140))	('activity', 'MPA', (47, 55))
469175	21448591	Although p53 is frequently non-functional in cancer cells, inhibition of Aurora kinase A by MLN8054 can lead to p73-dependent apoptosis in p53-deficient cells.	('inhibition', 'NegReg', (59, 69))	('p53', 'Gene', '22060', (139, 142))	('MLN8054', 'Chemical', 'MESH:C518940', (92, 99))	('p73', 'Gene', '22062', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Aurora kinase A', 'Enzyme', (73, 88))	('p53', 'Gene', (9, 12))	('MLN8054', 'Var', (92, 99))	('p53', 'Gene', (139, 142))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('lead to', 'Reg', (104, 111))	('cancer', 'Disease', (45, 51))	('p53', 'Gene', '22060', (9, 12))	('p73', 'Gene', (112, 115))
469178	21448591	The PPTP has reported the single-agent evaluation of activity of the Aurora kinase A inhibitor MLN8237 against its panels of in vitro cell lines and in vivo xenograft models.	('PPTP', 'Chemical', '-', (4, 8))	('activity', 'MPA', (53, 61))	('MLN8237', 'Chemical', 'MESH:C550258', (95, 102))	('MLN8237', 'Var', (95, 102))
469181	21448591	Despite these encouraging results, issues of how responsiveness relates to drug exposure in mice and humans, the dose range over which MLN8237 exerts significant antitumor activity, and the correlation of sensitivity to Aurora kinase A expression remain unanswered.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('MLN8237', 'Chemical', 'MESH:C550258', (135, 142))	('MLN8237', 'Var', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('humans', 'Species', '9606', (101, 107))	('tumor', 'Disease', (166, 171))	('mice', 'Species', '10090', (92, 96))
469182	21448591	Here, we report the in vitro activity of MLN8237 against an extended panel of neuroblastoma and Ewing sarcoma cell lines, and we report in vivo dose-response efficacy studies focusing on neuroblastoma and pediatric ALL xenografts, as well as assessment of pharmacokinetic, pharmacodynamic, and molecular parameters associated with these responses.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('neuroblastoma', 'Disease', 'MESH:D009447', (78, 91))	('neuroblastoma', 'Disease', 'MESH:D009447', (187, 200))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('neuroblastoma', 'Disease', (78, 91))	('neuroblastoma', 'Disease', (187, 200))	('MLN8237', 'Chemical', 'MESH:C550258', (41, 48))	('neuroblastoma', 'Phenotype', 'HP:0003006', (78, 91))	('neuroblastoma', 'Phenotype', 'HP:0003006', (187, 200))	('Ewing sarcoma', 'Disease', (96, 109))	('MLN8237', 'Var', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('ALL', 'Phenotype', 'HP:0006721', (215, 218))
469184	21448591	Cells were incubated in the presence of MLN8237 for 96 h at concentrations from 1 nM to 10 muM and analyzed as previously described.	('MLN8237', 'Var', (40, 47))	('MLN8237', 'Chemical', 'MESH:C550258', (40, 47))	('muM', 'Gene', (91, 94))	('muM', 'Gene', '56925', (91, 94))
469206	21448591	Millennium Pharmaceuticals, Inc., through the Cancer Therapy Evaluation Program (NCI), provided MLN8237 to the Pediatric Preclinical Testing Program.	('Cancer', 'Disease', (46, 52))	('Cancer', 'Disease', 'MESH:D009369', (46, 52))	('MLN8237', 'Chemical', 'MESH:C550258', (96, 103))	('MLN8237', 'Var', (96, 103))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
469207	21448591	MLN8237 was dissolved in DMSO and diluted in culture media for in vitro tests or was suspended in 10% 2-hydroxypropyl-beta-cyclodextrin and 1% sodium bicarbonate in water and administered to mice via oral gavage twice daily for 5 days repeated each week for a total of 6 weeks for the solid tumor xenografts, and for 3 weeks for the leukemia xenografts at doses of 20.8 mg/kg (the MTD), 10.4, 5.2, and 2.6 mg/kg.	('leukemia', 'Phenotype', 'HP:0001909', (333, 341))	('leukemia', 'Disease', 'MESH:D007938', (333, 341))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('leukemia', 'Disease', (333, 341))	('MLN8237', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('mice', 'Species', '10090', (191, 195))	('solid tumor', 'Disease', (285, 296))	('solid tumor', 'Disease', 'MESH:D009369', (285, 296))
469211	21448591	Accumulation of mitotic cells was used as a pharmacodynamic measure of Aurora kinase A inhibition in NB-1771 tumor-bearing animals dosed with 20.8 mg/kg MLN8237.	('inhibition', 'NegReg', (87, 97))	('NB-1771 tumor', 'Disease', (101, 114))	('NB-1771 tumor', 'Disease', 'MESH:D009369', (101, 114))	('Aurora kinase A', 'Enzyme', (71, 86))	('MLN8237', 'Chemical', 'MESH:C550258', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MLN8237', 'Var', (153, 160))
469212	21448591	Tumors were collected from animals at 0, 2, 6, 8, 12, and 24 h following MLN8237 dosing from 3 mice per time point and were formalin-fixed and paraffin-embedded.	('formalin', 'Chemical', 'MESH:D005557', (124, 132))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (95, 99))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('MLN8237', 'Chemical', 'MESH:C550258', (73, 80))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MLN8237', 'Var', (73, 80))	('paraffin', 'Chemical', 'MESH:D010232', (143, 151))
469221	21448591	Then, the segmentation algorithm implemented in the DNAcopy package from Bioconductor was applied to the above log2 ratio data to identify copy number alterations for each tumor sample.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('copy number alterations', 'Var', (139, 162))
469222	21448591	In order to evaluate the activity of MLN8237 against cell lines in vitro, an expanded panel of Ewing sarcoma (n = 11) and neuroblastoma (n = 17) cell lines was tested by DIMSCAN.	('MLN8237', 'Chemical', 'MESH:C550258', (37, 44))	('Ewing sarcoma', 'Disease', (95, 108))	('MLN8237', 'Var', (37, 44))	('neuroblastoma', 'Disease', 'MESH:D009447', (122, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (95, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('neuroblastoma', 'Disease', (122, 135))	('neuroblastoma', 'Phenotype', 'HP:0003006', (122, 135))
469224	21448591	The sensitivity of the Ewing sarcoma cell lines was generally less than the median for both measurements (ratio < 1), whereas neuroblastoma cell lines were generally more sensitive to MLN8237 (ratio > 1).	('Ewing sarcoma', 'Disease', (23, 36))	('neuroblastoma', 'Phenotype', 'HP:0003006', (126, 139))	('MLN8237', 'Var', (184, 191))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (23, 36))	('sensitivity', 'MPA', (4, 15))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (23, 36))	('neuroblastoma', 'Disease', 'MESH:D009447', (126, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('neuroblastoma', 'Disease', (126, 139))	('less', 'NegReg', (62, 66))	('MLN8237', 'Chemical', 'MESH:C550258', (184, 191))
469225	21448591	Only one Ewing sarcoma cell line, CHLA-56, was completely resistant (IC50 > 10 muM) to MLN8237 exposure in vitro.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (9, 22))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (9, 22))	('muM', 'Gene', '56925', (79, 82))	('MLN8237 exposure', 'Var', (87, 103))	('MLN8237', 'Chemical', 'MESH:C550258', (87, 94))	('CHLA-56', 'CellLine', 'CVCL:M150', (34, 41))	('muM', 'Gene', (79, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('Ewing sarcoma', 'Disease', (9, 22))
469227	21448591	The cytotoxicity of MLN8237 (as assessed by minimum T/C values (Ymin) approaching 0) was variable, with a median Ymin value of 10.9%, and a range from 0.5 to 48% (Table 1).	('cytotoxicity', 'Disease', (4, 16))	('MLN8237', 'Chemical', 'MESH:C550258', (20, 27))	('MLN8237', 'Var', (20, 27))	('mum', 'Gene', '56925', (48, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))	('mum', 'Gene', (48, 51))
469229	21448591	We previously reported MLN8237 as highly effective against the PPTP's neuroblastoma and ALL xenograft models.	('neuroblastoma', 'Disease', (70, 83))	('ALL', 'Phenotype', 'HP:0006721', (88, 91))	('MLN8237', 'Var', (23, 30))	('neuroblastoma', 'Phenotype', 'HP:0003006', (70, 83))	('neuroblastoma', 'Disease', 'MESH:D009447', (70, 83))	('PPTP', 'Chemical', '-', (63, 67))	('MLN8237', 'Chemical', 'MESH:C550258', (23, 30))
469230	21448591	With the aim of confirming these results, the efficacy of MLN8237 as a single agent at its MTD (20.8 mg/kg administered twice daily) was evaluated in 9 solid tumor (6 of them neuroblastoma) and 3 ALL xenograft models (Table 2).	('solid tumor', 'Disease', (152, 163))	('solid tumor', 'Disease', 'MESH:D009369', (152, 163))	('MLN8237', 'Chemical', 'MESH:C550258', (58, 65))	('ALL', 'Phenotype', 'HP:0006721', (196, 199))	('neuroblastoma', 'Disease', 'MESH:D009447', (175, 188))	('MLN8237', 'Var', (58, 65))	('neuroblastoma', 'Disease', (175, 188))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('neuroblastoma', 'Phenotype', 'HP:0003006', (175, 188))
469235	21448591	MLN8237 induced significant differences in EFS distributions compared to controls in all solid tumor models except SK-N-AS, and in all three ALL models.	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('solid tumor', 'Disease', (89, 100))	('EFS', 'MPA', (43, 46))	('solid tumor', 'Disease', 'MESH:D009369', (89, 100))	('MLN8237', 'Var', (0, 7))	('ALL', 'Phenotype', 'HP:0006721', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SK-N-AS', 'Chemical', '-', (115, 122))	('differences', 'Reg', (28, 39))
469238	21448591	To investigate the efficacy of MLN8237 over a range of doses, we evaluated the efficacy of the drug in vivo at the MTD and 0.5, 0.25, and 0.125 of the MTD dose in six solid tumors and 3 ALL models that demonstrated stable disease or regression at the highest dose level.	('ALL', 'Phenotype', 'HP:0006721', (186, 189))	('solid tumors', 'Disease', (167, 179))	('stable disease', 'Disease', (215, 229))	('stable disease', 'Disease', 'MESH:D060050', (215, 229))	('solid tumors', 'Disease', 'MESH:D009369', (167, 179))	('MLN8237', 'Chemical', 'MESH:C550258', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('MLN8237', 'Var', (31, 38))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
469240	21448591	At the 0.5MTD dose (10.4 mg/kg), only two of six solid tumor models demonstrated objective responses (NB-1771, NB-1643), indicating a steep dose-response relationship for MLN8237 (Table 2).	('MLN8237', 'Chemical', 'MESH:C550258', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MLN8237', 'Var', (171, 178))	('solid tumor', 'Disease', (49, 60))	('solid tumor', 'Disease', 'MESH:D009369', (49, 60))
469241	21448591	Dose-response relationships for KT-10, for which antitumor activity was observed only at the highest dose, and for NB-1643, for which MLN8237 exhibited broad-range activity, are shown in Fig.	('MLN8237', 'Chemical', 'MESH:C550258', (134, 141))	('MLN8237', 'Var', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
469242	21448591	By contrast, for the ALL panel, MLN8237 induced CR in each of three ALL models at 0.5MTD, and even at 0.25MTD, two out of three xenografts were classified as objective responses (one CR, one PR; Fig.	('MLN8237', 'Var', (32, 39))	('ALL', 'Phenotype', 'HP:0006721', (21, 24))	('ALL', 'Phenotype', 'HP:0006721', (68, 71))	('induced', 'PosReg', (40, 47))	('MLN8237', 'Chemical', 'MESH:C550258', (32, 39))
469243	21448591	1, panels c and d), suggesting that the leukemia xenografts are more sensitive to MLN8237 than the solid tumor models.	('MLN8237', 'Chemical', 'MESH:C550258', (82, 89))	('MLN8237', 'Var', (82, 89))	('solid tumor', 'Disease', (99, 110))	('solid tumor', 'Disease', 'MESH:D009369', (99, 110))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('leukemia', 'Disease', (40, 48))	('leukemia', 'Disease', 'MESH:D007938', (40, 48))
469244	21448591	Pharmacokinetic parameters for MLN8237 in mice were assessed to evaluate whether the drug levels associated with the high level of anticancer activity observed for the xenograft models are attainable in the clinical setting.	('cancer', 'Disease', (135, 141))	('mice', 'Species', '10090', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('MLN8237', 'Chemical', 'MESH:C550258', (31, 38))	('MLN8237', 'Var', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
469246	21448591	At the 20.8 mg/kg dose, MLN8237 was rapidly absorbed with a Tmax of 0.5 h and a corresponding Cmax of 42.5 muM.	('muM', 'Gene', '56925', (107, 110))	('muM', 'Gene', (107, 110))	('MLN8237', 'Chemical', 'MESH:C550258', (24, 31))	('MLN8237', 'Var', (24, 31))
469249	21448591	Pharmacodynamic markers of MLN8237 on target effects were investigated in mice bearing the NB-1771 tumor xenograft by assaying for a transient accumulation of mitotic cells that occurs subsequent to Aurora kinase A inhibition.	('mice', 'Species', '10090', (74, 78))	('accumulation', 'PosReg', (143, 155))	('Aurora kinase A', 'Enzyme', (199, 214))	('inhibition', 'NegReg', (215, 225))	('MLN8237', 'Chemical', 'MESH:C550258', (27, 34))	('mitotic cells', 'MPA', (159, 172))	('MLN8237', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('NB-1771 tumor', 'Disease', (91, 104))	('NB-1771 tumor', 'Disease', 'MESH:D009369', (91, 104))
469252	21448591	The mitotic indices as evaluated through these two markers increased (approximately twofold) within 6 h following MLN8237 dosing, peaked at 12 h (three to fivefold increase), and returned to baseline levels 24 h after dosing (Fig.	('mitotic indices', 'CPA', (4, 19))	('MLN8237', 'Chemical', 'MESH:C550258', (114, 121))	('increased', 'PosReg', (59, 68))	('increase', 'PosReg', (164, 172))	('MLN8237', 'Var', (114, 121))
469253	21448591	Aurora kinases are overexpressed in Ewing sarcoma as a consequence of the EWS-FLI1 gene fusion while the gene expression of Aurora kinase A in neuroblastoma is not augmented.	('Aurora kinase', 'Gene', (0, 13))	('EWS', 'Gene', '14030', (74, 77))	('Aurora kinase', 'Gene', (124, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('FLI1', 'Gene', '14247', (78, 82))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('EWS', 'Gene', (74, 77))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (36, 49))	('neuroblastoma', 'Disease', (143, 156))	('FLI1', 'Gene', (78, 82))	('Aurora kinase', 'Gene', '41446', (0, 13))	('overexpressed', 'PosReg', (19, 32))	('fusion', 'Var', (88, 94))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('Ewing sarcoma', 'Disease', (36, 49))	('Aurora kinase', 'Gene', '41446', (124, 137))
469257	21448591	In many instances, copy number alteration at the Aurora kinase A locus (AURKA) was attributed to large genomic regions, even entire chromosomal arms, undergoing amplification or deletion on chromosome 20 (Supplemental Fig.	('deletion', 'Var', (178, 186))	('AURKA', 'Gene', (72, 77))	('copy number alteration', 'Var', (19, 41))	('AURKA', 'Gene', '20878', (72, 77))
469259	21448591	The correlation of gene expression variation with AURKA copy number status was very strong (Pearson R = 0.573) for the PPTP models.	('AURKA', 'Gene', (50, 55))	('PPTP', 'Chemical', '-', (119, 123))	('AURKA', 'Gene', '20878', (50, 55))	('variation', 'Var', (35, 44))
469260	21448591	Copy number loss was noted in 8 models, and their response to therapy ranged from PD1 (insensitive, EW-5, BT-28) to CR or MCR (sensitive, ALL-17, NB-1771, NB-1643, OS-1).	('PD1', 'Gene', '18566', (82, 85))	('ALL', 'Phenotype', 'HP:0006721', (138, 141))	('loss', 'NegReg', (12, 16))	('Copy number', 'Var', (0, 11))	('PD1', 'Gene', (82, 85))
469261	21448591	Conversely, copy gain was observed in approximately one half of the rhabdomyosarcoma lines, suggesting that at least some of the relatively high expression across the entire rhabdomyosarcoma group may have arisen due to copy gain at the Aurora kinase A locus.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (174, 190))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (68, 84))	('rhabdomyosarcoma lines', 'Disease', 'MESH:D012208', (68, 90))	('rhabdomyosarcoma lines', 'Disease', (68, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (174, 190))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (68, 84))	('rhabdomyosarcoma', 'Disease', (174, 190))	('rhabdomyosarcoma', 'Disease', (68, 84))	('expression', 'MPA', (145, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('copy gain', 'Var', (220, 229))
469263	21448591	Of the 14 tumors exhibiting copy number gain, there were only 2 that had objective responses to MLN8237 at the MTD.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('MLN8237', 'Chemical', 'MESH:C550258', (96, 103))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('MLN8237', 'Var', (96, 103))	('copy number gain', 'Var', (28, 44))
469265	21448591	MLN8237, which has 200-fold specificity for Aurora kinase A inhibition versus Aurora kinase B, showed high-level activity at its MTD in its initial PPTP evaluation; therefore, it was critical to validate and extend these previous results.	('PPTP', 'Chemical', '-', (148, 152))	('Aurora kinase B', 'Gene', (78, 93))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('inhibition', 'NegReg', (60, 70))	('MLN8237', 'Var', (0, 7))	('Aurora kinase B', 'Gene', '20877', (78, 93))	('Aurora kinase A', 'Enzyme', (44, 59))
469266	21448591	This was done by evaluating MLN8237 against an extensive number of Ewing sarcoma and neuroblastoma cancer lines in vitro, and by assessing its activity in vivo against neuroblastoma and ALL xenografts across a range of doses with pharmacokinetic and pharmacodynamic correlation.	('ALL', 'Phenotype', 'HP:0006721', (186, 189))	('neuroblastoma', 'Phenotype', 'HP:0003006', (168, 181))	('neuroblastoma cancer', 'Disease', (85, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('neuroblastoma', 'Disease', 'MESH:D009447', (85, 98))	('neuroblastoma', 'Disease', (168, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('MLN8237', 'Chemical', 'MESH:C550258', (28, 35))	('neuroblastoma cancer', 'Disease', 'MESH:D009447', (85, 105))	('neuroblastoma', 'Disease', 'MESH:D009447', (168, 181))	('neuroblastoma', 'Disease', (85, 98))	('MLN8237', 'Var', (28, 35))	('activity', 'MPA', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('neuroblastoma', 'Phenotype', 'HP:0003006', (85, 98))	('Ewing sarcoma', 'Disease', (67, 80))
469271	21448591	The most intriguing set of results was that MLN8237 performed more impressively than other investigational drugs, and even established drugs, against the neuroblastoma panel as a single agent at its MTD.	('MLN8237', 'Chemical', 'MESH:C550258', (44, 51))	('MLN8237', 'Var', (44, 51))	('neuroblastoma', 'Disease', 'MESH:D009447', (154, 167))	('neuroblastoma', 'Disease', (154, 167))	('neuroblastoma', 'Phenotype', 'HP:0003006', (154, 167))
469272	21448591	The Aurora kinases play critical roles in cell division, and alteration of their expression and function has been associated with oncogenesis.	('alteration', 'Var', (61, 71))	('function', 'MPA', (96, 104))	('oncogenesis', 'Disease', (130, 141))	('associated', 'Reg', (114, 124))	('Aurora kinase', 'Gene', '41446', (4, 17))	('Aurora kinase', 'Gene', (4, 17))	('expression', 'MPA', (81, 91))
469275	21448591	Thus, Ewing sarcomas, with genetic alterations that enhance Aurora kinase A expression, should have higher sensitivity than the lower expressing neuroblastoma or ALL panels.	('ALL', 'Phenotype', 'HP:0006721', (162, 165))	('neuroblastoma', 'Disease', (145, 158))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (6, 20))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (6, 20))	('Aurora kinase A', 'Protein', (60, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('neuroblastoma', 'Phenotype', 'HP:0003006', (145, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('sensitivity', 'MPA', (107, 118))	('enhance', 'PosReg', (52, 59))	('expression', 'MPA', (76, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (6, 19))	('Ewing sarcomas', 'Disease', (6, 20))	('genetic alterations', 'Var', (27, 46))	('neuroblastoma', 'Disease', 'MESH:D009447', (145, 158))
469276	21448591	The results presented in this study confirm our previous results of high-level activity for MLN8237 against neuroblastoma and ALL xenografts, which express markedly lower Aurora kinase A levels compared to other PPTP xenografts, thereby calling into question the premise that overexpression of Aurora kinase A is associated with more effective cell kill upon kinase inhibition.	('neuroblastoma', 'Disease', 'MESH:D009447', (108, 121))	('MLN8237', 'Chemical', 'MESH:C550258', (92, 99))	('lower', 'NegReg', (165, 170))	('neuroblastoma', 'Disease', (108, 121))	('MLN8237', 'Var', (92, 99))	('ALL', 'Phenotype', 'HP:0006721', (126, 129))	('neuroblastoma', 'Phenotype', 'HP:0003006', (108, 121))	('Aurora kinase A levels', 'MPA', (171, 193))	('PPTP', 'Chemical', '-', (212, 216))	('cell', 'CPA', (344, 348))
469279	21448591	Increased copy number was present in half of the rhabdomyosarcomas and in 14 of the solid tumors.	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (49, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('rhabdomyosarcomas', 'Disease', (49, 66))	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (49, 65))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (49, 66))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('copy number', 'Var', (10, 21))	('solid tumors', 'Disease', (84, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
469280	21448591	Loss of copy number was detected in 7 solid tumors and ALL-17.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('solid tumors', 'Disease', (38, 50))	('Loss', 'NegReg', (0, 4))	('ALL', 'Phenotype', 'HP:0006721', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('solid tumors', 'Disease', 'MESH:D009369', (38, 50))	('copy number', 'Var', (8, 19))
469281	21448591	Although there is no absolute relationship between copy number variation and tumor sensitivity, of the 14 solid tumors with increased copy number, there were only two that showed sensitivity to MLN8237 (1 PR, 1 SD).	('MLN8237', 'Chemical', 'MESH:C550258', (194, 201))	('solid tumors', 'Disease', (106, 118))	('MLN8237', 'Var', (194, 201))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
469282	21448591	The in vitro activity of MLN8237 against the Ewing sarcoma and neuroblastoma extended panels (n = 11 and n = 17, respectively) is consistent with the PPTP's Stage 1 results for MLN8237, which showed median relative and absolute IC50 values against all of the cell lines in the PPTP in vitro panel of 49 and 61 nM, respectively.	('MLN8237', 'Var', (177, 184))	('neuroblastoma', 'Phenotype', 'HP:0003006', (63, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('PPTP', 'Chemical', '-', (277, 281))	('MLN8237', 'Chemical', 'MESH:C550258', (25, 32))	('MLN8237', 'Var', (25, 32))	('Ewing sarcoma', 'Disease', (45, 58))	('neuroblastoma', 'Disease', 'MESH:D009447', (63, 76))	('PPTP', 'Chemical', '-', (150, 154))	('MLN8237', 'Chemical', 'MESH:C550258', (177, 184))	('neuroblastoma', 'Disease', (63, 76))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (45, 58))
469284	21448591	Further, one Ewing sarcoma cell line (CHLA-56) was resistant to MLN8237 (IC50 > 10 muM).	('MLN8237', 'Chemical', 'MESH:C550258', (64, 71))	('Ewing sarcoma', 'Disease', (13, 26))	('muM', 'Gene', '56925', (83, 86))	('MLN8237', 'Var', (64, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('CHLA-56', 'CellLine', 'CVCL:M150', (38, 45))	('muM', 'Gene', (83, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))
469285	21448591	Recently, a functional Aurora kinase A mutation (T217D) that renders the kinase impervious to MLN8054 and MLN8237 inhibition has been reported and points to a mechanism of resistance independent from levels of expression.	('MLN8237', 'Chemical', 'MESH:C550258', (106, 113))	('MLN8054', 'Chemical', 'MESH:C518940', (94, 101))	('MLN8237', 'Var', (106, 113))	('T217D', 'Mutation', 'p.T217D', (49, 54))	('T217D', 'Var', (49, 54))
469287	21448591	We have confirmed the high level of activity of MLN8237 against xenograft models of neuroblastoma and ALL, when administered as a single agent at its MTD.	('neuroblastoma', 'Disease', 'MESH:D009447', (84, 97))	('ALL', 'Phenotype', 'HP:0006721', (102, 105))	('neuroblastoma', 'Disease', (84, 97))	('activity', 'MPA', (36, 44))	('neuroblastoma', 'Phenotype', 'HP:0003006', (84, 97))	('MLN8237', 'Chemical', 'MESH:C550258', (48, 55))	('MLN8237', 'Var', (48, 55))
469289	21448591	However, the efficacy of MLN8237 (as indicated by the Median Group Response) was reduced or lost for most of the solid tumor models with dose reduction (Fig.	('solid tumor', 'Disease', (113, 124))	('MLN8237', 'Chemical', 'MESH:C550258', (25, 32))	('solid tumor', 'Disease', 'MESH:D009369', (113, 124))	('MLN8237', 'Var', (25, 32))	('reduced', 'NegReg', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('lost', 'NegReg', (92, 96))
469293	21448591	In mice receiving MLN8237 at 10 mg/kg, the Cmax and AUC0-24 h were 16 and 39muM h, respectively, with the 12 h level being 1.2 muM.	('muM', 'Gene', (127, 130))	('mice', 'Species', '10090', (3, 7))	('muM', 'Gene', '56925', (76, 79))	('MLN8237', 'Chemical', 'MESH:C550258', (18, 25))	('muM', 'Gene', (76, 79))	('MLN8237', 'Var', (18, 25))	('muM', 'Gene', '56925', (127, 130))
469296	21448591	This is consistent with previous observations using the Aurora kinase A inhibitor MLN8054 in a colon tumor xenograft and is likely due to the time it takes for a sufficient number of cells to transit the cell cycle and accumulate in mitosis subsequent to Aurora kinase A inhibition as well as to the time during which MLN8237 drug levels are above a threshold level required for Aurora kinase A inhibition.	('MLN8237', 'Chemical', 'MESH:C550258', (318, 325))	('colon tumor', 'Disease', 'MESH:D015179', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('MLN8054', 'Chemical', 'MESH:C518940', (82, 89))	('MLN8054', 'Var', (82, 89))	('colon tumor', 'Phenotype', 'HP:0100273', (95, 106))	('mitosis', 'Disease', (233, 240))	('mitosis', 'Disease', 'None', (233, 240))	('accumulate', 'PosReg', (219, 229))	('colon tumor', 'Disease', (95, 106))
469297	21448591	The comparable mitotic indices estimated using MPM2 and pHistH3 as mitotic markers are consistent with specific inhibition of Aurora kinase A by MLN8237 in vivo, as histone H3 is phosphorylated by Aurora kinase B.	('Aurora kinase A', 'Enzyme', (126, 141))	('MPM2', 'Gene', (47, 51))	('inhibition', 'NegReg', (112, 122))	('Aurora kinase B', 'Gene', '20877', (197, 212))	('MLN8237', 'Chemical', 'MESH:C550258', (145, 152))	('MPM2', 'Gene', '14235', (47, 51))	('MLN8237', 'Var', (145, 152))	('Aurora kinase B', 'Gene', (197, 212))
469298	21448591	A likely critical step in the development of MLN8237 for use in the treatment of pediatric cancers is the development of effective drug combinations.	('pediatric cancers', 'Disease', 'MESH:D009369', (81, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('pediatric cancers', 'Disease', (81, 98))	('MLN8237', 'Chemical', 'MESH:C550258', (45, 52))	('MLN8237', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
469299	21448591	The limited activity observed at reduced doses of MLN8237 as a single agent against most solid tumor xenografts may be overcome if synergistic interactions with other drugs can be identified.	('MLN8237', 'Var', (50, 57))	('solid tumor', 'Disease', (89, 100))	('solid tumor', 'Disease', 'MESH:D009369', (89, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
469300	21448591	Combinations of MLN8237 with established drugs against in vivo models of pediatric solid tumors and ALL are under evaluation by the PPTP.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('PPTP', 'Chemical', '-', (132, 136))	('MLN8237', 'Var', (16, 23))	('pediatric solid tumors', 'Disease', (73, 95))	('ALL', 'Phenotype', 'HP:0006721', (100, 103))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (73, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (16, 23))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
469301	21448591	The cumulative evidence of anti-tumor activity observed in preclinical testing together with the results presented here provides strong rationale for expeditious evaluation of MLN8237 in the childhood cancer setting.	('MLN8237', 'Var', (176, 183))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('MLN8237', 'Chemical', 'MESH:C550258', (176, 183))	('tumor', 'Disease', (32, 37))
469306	32238403	The genomic landscape of ERMS demonstrates a range of putative driver mutations, and thus the recognition of the pathological mechanisms driving tumor maintenance should be critical for identifying effective targeted treatments at the level of the individual patients.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('ERMS', 'Phenotype', 'HP:0006743', (25, 29))	('patients', 'Species', '9606', (259, 267))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ERMS', 'Disease', (25, 29))	('tumor', 'Disease', (145, 150))	('RMS', 'Phenotype', 'HP:0002859', (26, 29))
469310	32238403	ARMS is defined by either the t(2;13) or t(1;13) chromosomal translocation, resulting in a fusion gene of PAX3:FOXO1 or PAX7:FOXO1 and a limited number of secondary genomic alterations.	('PAX7', 'Gene', (120, 124))	('PAX3', 'Gene', (106, 110))	('FOXO1', 'Gene', (125, 130))	('fusion gene', 'Var', (91, 102))	('PAX3', 'Gene', '5077', (106, 110))	('FOXO1', 'Gene', '2308', (125, 130))	('FOXO1', 'Gene', '2308', (111, 116))	('RMS', 'Phenotype', 'HP:0002859', (1, 4))	('PAX7', 'Gene', '5081', (120, 124))	('FOXO1', 'Gene', (111, 116))
469311	32238403	Further, diagnostic criteria from the International Classification of Rhabdomyosarcoma (ICR) classifies FOXO1 fusion-negative RMS with only focal alveolar histology to be FOXO1 fusion-negative ARMS.	('RMS', 'Disease', (126, 129))	('FOXO1', 'Gene', '2308', (171, 176))	('RMS', 'Phenotype', 'HP:0002859', (126, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('FOXO1', 'Gene', (171, 176))	('Rhabdomyosarcoma', 'Disease', (70, 86))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (70, 86))	('FOXO1', 'Gene', (104, 109))	('RMS', 'Phenotype', 'HP:0002859', (194, 197))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (70, 86))	('fusion-negative', 'Var', (110, 125))	('FOXO1', 'Gene', '2308', (104, 109))
469312	32238403	In contrast, ERMS has several implied causative mutations with p53 loss, RAS pathway activation, and MYOD1 mutation being among the frequent molecular features of this disease.	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('ERMS', 'Disease', (13, 17))	('MYOD1', 'Gene', (101, 106))	('RMS', 'Phenotype', 'HP:0002859', (14, 17))	('activation', 'PosReg', (85, 95))	('loss', 'NegReg', (67, 71))	('ERMS', 'Phenotype', 'HP:0006743', (13, 17))	('mutation', 'Var', (107, 115))	('RAS pathway', 'Pathway', (73, 84))	('MYOD1', 'Gene', '4654', (101, 106))
469313	32238403	The MYOD1 mutation and VGLL2 gene fusions define an aggressive and rare subtype with distinct morphological features apart from ERMS called sclerosing and spindle cell rhabdomyosarcoma.	('RMS', 'Phenotype', 'HP:0002859', (129, 132))	('ERMS called sclerosing', 'Disease', (128, 150))	('ERMS', 'Phenotype', 'HP:0006743', (128, 132))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (168, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('MYOD1', 'Gene', '4654', (4, 9))	('VGLL2', 'Gene', '245806', (23, 28))	('rhabdomyosarcoma', 'Disease', (168, 184))	('fusions', 'Var', (34, 41))	('MYOD1', 'Gene', (4, 9))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (168, 184))	('VGLL2', 'Gene', (23, 28))
469315	32238403	One report suggests that the RAS pathway alone may be mutationally activated in ~45% of ERMS tumors, but this observation is yet to be borne out with clinical responses to MEK inhibitors.	('RMS', 'Phenotype', 'HP:0002859', (89, 92))	('RAS pathway', 'Pathway', (29, 40))	('ERMS tumors', 'Disease', (88, 99))	('activated', 'PosReg', (67, 76))	('MEK', 'Gene', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MEK', 'Gene', '5609', (172, 175))	('mutationally', 'Var', (54, 66))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('ERMS tumors', 'Disease', 'MESH:D009369', (88, 99))	('ERMS', 'Phenotype', 'HP:0006743', (88, 92))
469342	32238403	Of note, a somatic variant of unknown significance was identified in the TP53 gene (c. 91G > A p.V31I).	('91G > A', 'SUBSTITUTION', 'None', (87, 94))	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('p.V31I', 'Mutation', 'rs201753350', (95, 101))	('91G > A', 'Var', (87, 94))
469345	32238403	The variant found in the patient, TP53 p.V31I, has been reported with varying degrees of interpretation, such as benign, uncertain significance, and pathogenic, in ClinVar with respect to LFS.	('LFS', 'Disease', (188, 191))	('TP53', 'Gene', (34, 38))	('p.V31I', 'Var', (39, 45))	('p.V31I', 'Mutation', 'rs201753350', (39, 45))	('patient', 'Species', '9606', (25, 32))	('LFS', 'Disease', 'MESH:D016864', (188, 191))	('TP53', 'Gene', '7157', (34, 38))
469346	32238403	Additionally, somatic mutations in the BUB1B (c.1649G > A p.R550Q) and CSF1R (c.2737dupC p.Q913Pfs*29) genes were identified using the OncoPanel assay.	('p.R550Q', 'Mutation', 'rs28989187', (58, 65))	('c.1649G > A', 'Var', (46, 57))	('CSF1R', 'Gene', (71, 76))	('p.Q913Pfs*29', 'Mutation', 'p.Q913PfsX29', (89, 101))	('BUB1B', 'Gene', '701', (39, 44))	('c.2737dupC', 'Mutation', 'c.2737dupC', (78, 88))	('c.1649G > A', 'Mutation', 'rs28989187', (46, 57))	('BUB1B', 'Gene', (39, 44))	('CSF1R', 'Gene', '1436', (71, 76))	('c.2737dupC p.Q913Pfs', 'Var', (78, 98))
469347	32238403	The OncoPanel detects mutations in exonic DNA sequences of 300 cancer genes and 113 introns across 35 genes for rearrangement detection (Supplemental Information; Methods).	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (63, 69))
469348	32238403	Loss of BUB1B, a critical component of the mitotic checkpoint, has been reported to be associated with chromosomal instability in ERMS.	('chromosomal instability', 'MPA', (103, 126))	('ERMS', 'Disease', (130, 134))	('associated', 'Reg', (87, 97))	('BUB1B', 'Gene', '701', (8, 13))	('chromosomal instability', 'Phenotype', 'HP:0040012', (103, 126))	('BUB1B', 'Gene', (8, 13))	('RMS', 'Phenotype', 'HP:0002859', (131, 134))	('ERMS', 'Phenotype', 'HP:0006743', (130, 134))	('Loss', 'Var', (0, 4))
469350	32238403	Moreover, missense mutations in BUB1B have been found in five families with MVA.	('BUB1B', 'Gene', (32, 37))	('BUB1B', 'Gene', '701', (32, 37))	('found', 'Reg', (48, 53))	('missense mutations', 'Var', (10, 28))
469353	32238403	Because of the history of at least one congenital anomaly (esophageal atresia), ERMS diagnosis, and discovery of the somatic mutation in the BUB1B gene, the patient was simultaneously screened for MVA and evaluated for germline mutations in BUB1B.	('BUB1B', 'Gene', '701', (241, 246))	('patient', 'Species', '9606', (157, 164))	('BUB1B', 'Gene', '701', (141, 146))	('congenital anomaly', 'Disease', 'MESH:D000013', (39, 57))	('BUB1B', 'Gene', (241, 246))	('BUB1B', 'Gene', (141, 146))	('ERMS', 'Phenotype', 'HP:0006743', (80, 84))	('esophageal atresia', 'Disease', (59, 77))	('esophageal atresia', 'Disease', 'MESH:D004933', (59, 77))	('congenital anomaly', 'Disease', (39, 57))	('RMS', 'Phenotype', 'HP:0002859', (81, 84))	('mutation', 'Var', (125, 133))	('esophageal atresia', 'Phenotype', 'HP:0002032', (59, 77))
469354	32238403	Furthermore, two tests were subsequently explored: the first sequenced the patient's peripheral blood for deletion/duplication analysis of the BUB1B gene, and the second test examined germline chromosomal mosaicism.	('patient', 'Species', '9606', (75, 82))	('BUB1B', 'Gene', '701', (143, 148))	('BUB1B', 'Gene', (143, 148))	('deletion/duplication analysis', 'Var', (106, 135))
469357	32238403	Whole-exome sequencing from fixed-formalin, paraffin-embedded (FFPE) tumor tissue and buccal swab was performed for the detection of somatic mutations, insertion/deletion (indel) events, and/or copy-number alterations, as well as potential germline mutations (Table 1; Methods).	('insertion/deletion', 'Var', (152, 170))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('formalin', 'Chemical', 'MESH:D005557', (34, 42))	('paraffin', 'Chemical', 'MESH:D010232', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('copy-number alterations', 'Var', (194, 217))
469359	32238403	After filtering further for mutations that also showed increased copy number (log2 tumor/normal read ratio > 0.4) and TPM > 100, we identified 137 mutations of interest (Fig.	('mutations', 'Var', (147, 156))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))
469360	32238403	3; Supplemental Table S1), including mutations in FGFR1.	('mutations', 'Var', (37, 46))	('FGFR1', 'Gene', '2260', (50, 55))	('FGFR1', 'Gene', (50, 55))
469368	32238403	Additionally, a high-impact frameshift mutation was found in NIPBL (c.3360_3376delTGACAGAAGAAGCTCTG p.Asp1121fs).	('NIPBL', 'Gene', (61, 66))	('c.3360_3376delTGACAGAAGAAGCTCTG', 'Mutation', 'c.3360_3376delTGACAGAAGAAGCTCTG', (68, 99))	('p.Asp1121fs', 'Mutation', 'p.D1121fsX', (100, 111))	('c.3360_3376delTGACAGAAGAAGCTCTG', 'Var', (68, 99))	('p.Asp1121fs', 'Var', (100, 111))	('NIPBL', 'Gene', '25836', (61, 66))
469373	32238403	Large clusters were formed by samples harboring mutations in TP53, FGFR4, NRAS, HRAS, and the PAX7:FOXO1 fusion.	('FOXO1', 'Gene', '2308', (99, 104))	('HRAS', 'Gene', '3265', (80, 84))	('PAX7', 'Gene', '5081', (94, 98))	('FOXO1', 'Gene', (99, 104))	('NRAS', 'Gene', (74, 78))	('FGFR4', 'Gene', '2264', (67, 72))	('FGFR4', 'Gene', (67, 72))	('NRAS', 'Gene', '4893', (74, 78))	('HRAS', 'Gene', (80, 84))	('PAX7', 'Gene', (94, 98))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', '7157', (61, 65))	('mutations', 'Var', (48, 57))
469375	32238403	SMS-CTR, RD, and Hs729T were found to be the closest in the cluster with the patient.	('CTR', 'Gene', '799', (4, 7))	('CTR', 'Gene', (4, 7))	('patient', 'Species', '9606', (77, 84))	('Hs729T', 'Var', (17, 23))
469376	32238403	Both the patient and the cell lines were found to have mutations in TP53, BUB1B, APC, ATRX, HRAS, ATR, CPS1, AURKA, LAG3, MUC16, AURKB, SYNE1, PKHD1, FOS, DCC, CHD9, ALK, and CENPF.	('SYNE1', 'Gene', (136, 141))	('AURKA', 'Gene', (109, 114))	('DCC', 'Gene', '1630', (155, 158))	('MUC16', 'Gene', '94025', (122, 127))	('HRAS', 'Gene', '3265', (92, 96))	('LAG3', 'Gene', '3902', (116, 120))	('ATRX', 'Gene', (86, 90))	('ATR', 'Gene', (86, 89))	('SYNE1', 'Gene', '23345', (136, 141))	('patient', 'Species', '9606', (9, 16))	('TP53', 'Gene', (68, 72))	('FOS', 'Gene', (150, 153))	('HRAS', 'Gene', (92, 96))	('DCC', 'Gene', (155, 158))	('ATRX', 'Gene', '546', (86, 90))	('FOS', 'Gene', '2353', (150, 153))	('ATR', 'Gene', '545', (98, 101))	('LAG3', 'Gene', (116, 120))	('MUC16', 'Gene', (122, 127))	('AURKB', 'Gene', '9212', (129, 134))	('mutations', 'Var', (55, 64))	('BUB1B', 'Gene', '701', (74, 79))	('CHD9', 'Gene', '80205', (160, 164))	('ATR', 'Gene', '545', (86, 89))	('TP53', 'Gene', '7157', (68, 72))	('CHD9', 'Gene', (160, 164))	('BUB1B', 'Gene', (74, 79))	('APC', 'Disease', 'MESH:D011125', (81, 84))	('CENPF', 'Gene', (175, 180))	('PKHD1', 'Gene', (143, 148))	('APC', 'Disease', (81, 84))	('PKHD1', 'Gene', '5314', (143, 148))	('ALK', 'Gene', '238', (166, 169))	('ATR', 'Gene', (98, 101))	('CENPF', 'Gene', '1063', (175, 180))	('CPS1', 'Gene', (103, 107))	('AURKA', 'Gene', '6790', (109, 114))	('CPS1', 'Gene', '1373', (103, 107))	('ALK', 'Gene', (166, 169))	('AURKB', 'Gene', (129, 134))
469387	32238403	Samples counted as within the patient's endotype were SMS-CTR, Hs729T, RD, RMS13, CW9019, COG-R-486h, and RMS559.	('CW9019', 'Var', (82, 88))	('RMS559', 'Var', (106, 112))	('CTR', 'Gene', (58, 61))	('patient', 'Species', '9606', (30, 37))	('RMS', 'Phenotype', 'HP:0002859', (106, 109))	('RMS', 'Phenotype', 'HP:0002859', (75, 78))	('RMS13', 'Var', (75, 80))	('COG-R-486h', 'Chemical', '-', (90, 100))	('CW9019', 'CellLine', 'CVCL:N820', (82, 88))	('Hs729T', 'Var', (63, 69))	('COG-R-486h', 'Var', (90, 100))	('CTR', 'Gene', '799', (58, 61))
469388	32238403	Further, the case sample shares mutations in PIK3C2G, PIK3IP1, and PIK3R3 with SMS-CTR, RD, and Hs729.	('PIK3R3', 'Gene', (67, 73))	('PIK3IP1', 'Gene', '113791', (54, 61))	('PIK3IP1', 'Gene', (54, 61))	('CTR', 'Gene', '799', (83, 86))	('PIK3C2G', 'Gene', (45, 52))	('CTR', 'Gene', (83, 86))	('mutations', 'Var', (32, 41))	('PIK3C2G', 'Gene', '5288', (45, 52))	('PIK3R3', 'Gene', '8503', (67, 73))
469389	32238403	Some samples outside the patient's endotype were found to have PI3KCA and PI3KC2A mutations, and conversely, not all samples within the patient's endotype were found to have all of the same PI3K mutations.	('PI3KCA', 'Var', (63, 69))	('patient', 'Species', '9606', (136, 143))	('PI3KC2A', 'Gene', '5286', (74, 81))	('patient', 'Species', '9606', (25, 32))	('mutations', 'Var', (82, 91))	('PI3KC2A', 'Gene', (74, 81))
469390	32238403	However, the majority of samples with whole-exome sequencing data outside of the patient's endotype did not harbor a mutation within the PI3K genes of interest, whereas all of the samples within the patient's endotype did harbor at least one PI3K mutation.	('mutation', 'Var', (117, 125))	('PI3K', 'Gene', (137, 141))	('patient', 'Species', '9606', (81, 88))	('patient', 'Species', '9606', (199, 206))
469392	32238403	Despite several advances in understanding the dominant molecular pathways of ERMS, our data show that only 40% of ERMS tumors have known driving mutations, leaving the remaining 60% of ERMS with a completely unknown biology.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('ERMS tumors', 'Disease', 'MESH:D009369', (114, 125))	('RMS', 'Phenotype', 'HP:0002859', (78, 81))	('ERMS', 'Phenotype', 'HP:0006743', (77, 81))	('ERMS', 'Phenotype', 'HP:0006743', (185, 189))	('mutations', 'Var', (145, 154))	('RMS', 'Phenotype', 'HP:0002859', (186, 189))	('ERMS', 'Phenotype', 'HP:0006743', (114, 118))	('RMS', 'Phenotype', 'HP:0002859', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ERMS tumors', 'Disease', (114, 125))
469394	32238403	Gene variants identified by next-generation deep sequencing, but not by ancillary tests, included BUB1B (an ERMS-associated germline variant) and a somatic variant of DICER1.	('ERMS', 'Phenotype', 'HP:0006743', (108, 112))	('BUB1B', 'Gene', '701', (98, 103))	('variants', 'Var', (5, 13))	('DICER1', 'Gene', (167, 173))	('DICER1', 'Gene', '23405', (167, 173))	('RMS', 'Phenotype', 'HP:0002859', (109, 112))	('BUB1B', 'Gene', (98, 103))
469398	32238403	Overexpression of BUB1B is also related to poor prognosis and progression of other types of cancer, such as breast, gastric, colorectal, and prostate.	('prostate', 'Disease', (141, 149))	('BUB1B', 'Gene', '701', (18, 23))	('colorectal', 'Disease', (125, 135))	('BUB1B', 'Gene', (18, 23))	('cancer', 'Disease', (92, 98))	('gastric', 'Disease', (116, 123))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('breast', 'Disease', (108, 114))	('Overexpression', 'Var', (0, 14))	('colorectal', 'Disease', 'MESH:D015179', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
469401	32238403	Further, germline mutations in DICER1 can cause DICER1 syndrome, a rare pediatric tumor predisposition syndrome.	('DICER1', 'Gene', (31, 37))	('DICER1', 'Gene', (48, 54))	('DICER1', 'Gene', '23405', (31, 37))	('DICER1', 'Gene', '23405', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cause', 'Reg', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('germline mutations', 'Var', (9, 27))
469402	32238403	In DICER1-associated tumors, one allele is inactivated by a germline mutation in DICER1 and the other allele has a somatic missense mutation that affects one of the RNase IIIb metal ion-binding sites.	('affects', 'Reg', (146, 153))	('DICER1', 'Gene', '23405', (3, 9))	('germline mutation', 'Var', (60, 77))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('metal', 'Chemical', 'MESH:D008670', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('DICER1', 'Gene', (81, 87))	('DICER1', 'Gene', '23405', (81, 87))	('DICER1', 'Gene', (3, 9))	('inactivated', 'NegReg', (43, 54))	('RNase', 'Protein', (165, 170))
469404	32238403	In this case, however, no germline mutations were found in DICER1, and the expression of DICER1 (198.53 TPM) was not decreased compared to the normal cohort of skeletal muscles from the GTEx project (median TPM, 14.03).	('DICER1', 'Gene', (89, 95))	('DICER1', 'Gene', (59, 65))	('198.53 TPM', 'Var', (97, 107))	('DICER1', 'Gene', '23405', (59, 65))	('expression', 'MPA', (75, 85))	('DICER1', 'Gene', '23405', (89, 95))
469405	32238403	Additionally, none of the somatic mutations found harbored the characteristic RNase IIIb hotspot variant consistent in previous sarcomas.	('variant', 'Var', (97, 104))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomas', 'Disease', (128, 136))	('RNase IIIb', 'Gene', (78, 88))
469406	32238403	The patient's frameshift variant in this case has not been reported in the International Pleuropulmonary Blastoma Registry, the majority of which are frameshift or nonsense mutations (A Hill, pers.	('nonsense mutations', 'Var', (164, 182))	('Pleuropulmonary Blastoma', 'Phenotype', 'HP:0100528', (89, 113))	('patient', 'Species', '9606', (4, 11))	('Pleuropulmonary Blastoma', 'Disease', (89, 113))	('frameshift', 'Var', (150, 160))	('Pleuropulmonary Blastoma', 'Disease', 'MESH:C537516', (89, 113))
469410	32238403	A large-scale study focusing on the mutational landscape of rhabdomyosarcoma found mutations in PIK3CA and PIK3CD, as well as coexisting mutations in PIK3CA and a RAS family gene.	('PIK3CA', 'Gene', (150, 156))	('mutations', 'Var', (83, 92))	('rhabdomyosarcoma', 'Disease', (60, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('PIK3CA', 'Gene', '5290', (150, 156))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (60, 76))	('PIK3CD', 'Gene', '5293', (107, 113))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('PIK3CD', 'Gene', (107, 113))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (60, 76))
469411	32238403	On a smaller scale, a co-occurrence of two missense mutations in PIK3CA (35 G > A, G12D) and KRAS (1636C > A, Q546K) were observed in an undifferentiated pleomorphic sarcoma case.	('undifferentiated pleomorphic sarcoma', 'Disease', (137, 173))	('Q546K', 'Mutation', 'rs121913286', (110, 115))	('1636C > A', 'Mutation', 'rs121913286', (99, 108))	('KRAS', 'Gene', (93, 97))	('Q546K', 'Var', (110, 115))	('KRAS', 'Gene', '3845', (93, 97))	('35 G > A', 'Var', (73, 81))	('PIK3CA', 'Gene', (65, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('35 G > A', 'Mutation', 'rs121913529', (73, 81))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (137, 173))	('G12D', 'Var', (83, 87))	('PIK3CA', 'Gene', '5290', (65, 71))	('G12D', 'Mutation', 'rs121913529', (83, 87))
469412	32238403	Functionally, PIK3CA mutations have mainly been reported to cluster on helical (exon 9) and kinase (exon 20) domain.	('PIK3CA', 'Gene', '5290', (14, 20))	('PIK3CA', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
469413	32238403	In accordance with several previous genomic studies, a mutation in PIK3CA was found leading to a premature termination codon (a stop gained) at codon 140.	('PIK3CA', 'Gene', '5290', (67, 73))	('leading to', 'Reg', (84, 94))	('mutation', 'Var', (55, 63))	('premature termination codon', 'MPA', (97, 124))	('PIK3CA', 'Gene', (67, 73))
469414	32238403	Several other effectors of the PI3K pathway were found to be mutated, such as PIK3AP1, PIK3C2G, PIK3CB, PIK3CD, PIK3R1, PIK3R3, and PIK3R5, suggesting a role in the PI3K pathway in the oncogenesis of ERMS in this patient.	('PIK3R5', 'Gene', (132, 138))	('PIK3R3', 'Gene', (120, 126))	('PIK3C2G', 'Gene', (87, 94))	('PIK3C2G', 'Gene', '5288', (87, 94))	('patient', 'Species', '9606', (213, 220))	('RMS', 'Phenotype', 'HP:0002859', (201, 204))	('mutated', 'Var', (61, 68))	('PIK3R1', 'Gene', (112, 118))	('PIK3AP1', 'Gene', '118788', (78, 85))	('PIK3R5', 'Gene', '23533', (132, 138))	('ERMS', 'Phenotype', 'HP:0006743', (200, 204))	('PIK3CD', 'Gene', '5293', (104, 110))	('ERMS', 'Disease', (200, 204))	('PIK3AP1', 'Gene', (78, 85))	('PIK3R3', 'Gene', '8503', (120, 126))	('role', 'Reg', (153, 157))	('PIK3CB', 'Gene', (96, 102))	('PIK3CB', 'Gene', '5291', (96, 102))	('PIK3R1', 'Gene', '5295', (112, 118))	('PIK3CD', 'Gene', (104, 110))	('PI3K pathway', 'Pathway', (31, 43))
469416	32238403	As a basis for surrogate functional studies, hierarchical agglomerative clustering identified SMS-CTR, RD, and Hs729T to be the most genetically similar cell line to the patient's samples.	('CTR', 'Gene', (98, 101))	('Hs729T', 'Var', (111, 117))	('patient', 'Species', '9606', (170, 177))	('CTR', 'Gene', '799', (98, 101))
363347	32238403	RMS559, CW9019, CCA, RD, Hs729T, COG-R-486h, and SMS-CTR were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin.	('streptomycin', 'Chemical', 'MESH:D013307', (176, 188))	('RMS', 'Phenotype', 'HP:0002859', (0, 3))	('COG-R-486h', 'Chemical', '-', (33, 43))	('CW9019', 'Var', (8, 14))	('DMEM', 'Chemical', '-', (105, 109))	('CTR', 'Gene', '799', (53, 56))	('penicillin', 'Chemical', 'MESH:D010406', (165, 175))	('Hs729T', 'Var', (25, 31))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (71, 103))	('CTR', 'Gene', (53, 56))	('CW9019', 'CellLine', 'CVCL:N820', (8, 14))
469421	32238403	A commercial sequencing-based assay for germline TP53 mutations was performed by Ambry Genetics from peripheral mononuclear cell DNA.	('TP53', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('TP53', 'Gene', '7157', (49, 53))
469424	32238403	Somatic and germline mutations (point mutations, insertions/deletions [indels], and functional and structural variants), as well as copy-number variation, were analyzed using tumor and matched normal exome sequencing data.	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (175, 180))	('insertions/deletions', 'Var', (49, 69))	('tumor', 'Disease', 'MESH:D009369', (175, 180))
469462	31645210	In this study, greater than 90% of NOD.B10Sn-H2b/J male mice (n = 115) exhibited dilation and fibrosis of the seminal vesicle and >50% contained variable numbers of inflammatory infiltrates.	('NOD.B10Sn-H2b/J', 'Var', (35, 50))	('rat', 'Species', '10116', (184, 187))	('fibrosis of the seminal vesicle', 'Disease', 'MESH:D005355', (94, 125))	('mice', 'Species', '10090', (56, 60))	('exhibited', 'Reg', (71, 80))	('dilation', 'CPA', (81, 89))	('fibrosis of the seminal vesicle', 'Disease', (94, 125))
469520	31645210	The rete testis was expanded by eosinophilic fibrillar material (fibrosis) amid increased numbers of tubule profiles.	('fibrosis', 'Disease', (65, 73))	('increased', 'PosReg', (80, 89))	('fibrosis', 'Disease', 'MESH:D005355', (65, 73))	('eosinophilic fibrillar', 'Var', (32, 54))
469597	31645210	This is caused by mutations in the NF1 and NF2 genes (chromosome 22).	('NF1', 'Gene', '24592', (35, 38))	('caused by', 'Reg', (8, 17))	('NF2', 'Gene', (43, 46))	('NF1', 'Gene', (35, 38))	('NF2', 'Gene', '25744', (43, 46))	('mutations', 'Var', (18, 27))
469620	31645210	ENU exposure can lead to schwannoma due to a mutation of neu/erdB-2 at nucleotide 2012.	('neu/erdB-2', 'Gene', (57, 67))	('schwannoma', 'Disease', (25, 35))	('lead to', 'Reg', (17, 24))	('schwannoma', 'Disease', 'MESH:D009442', (25, 35))	('ENU', 'Chemical', 'MESH:D005038', (0, 3))	('mutation', 'Var', (45, 53))	('schwannoma', 'Phenotype', 'HP:0100008', (25, 35))
469632	31645210	Due to the association of schwannoma with neurofibromatosis, a recurrent condition caused by a genetic mutation, definitive diagnosis can be important, not only for human patients, but also for toxicologic pathologists to accurately inform stakeholders of a given study.	('neurofibroma', 'Phenotype', 'HP:0001067', (42, 54))	('schwannoma', 'Disease', 'MESH:D009442', (26, 36))	('human', 'Species', '9606', (165, 170))	('schwannoma', 'Disease', (26, 36))	('association', 'Interaction', (11, 22))	('schwannoma', 'Phenotype', 'HP:0100008', (26, 36))	('patients', 'Species', '9606', (171, 179))	('neurofibromatosis', 'Disease', (42, 59))	('rat', 'Species', '10116', (226, 229))	('mutation', 'Var', (103, 111))	('neurofibromatosis', 'Disease', 'MESH:C537392', (42, 59))	('caused by', 'Reg', (83, 92))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (42, 59))
469713	31645210	Phthalates, the agent in Case 1, have been shown to decrease testosterone production by Leydig cells.	('testosterone', 'Chemical', 'MESH:D013739', (61, 73))	('Phthalates', 'Var', (0, 10))	('Phthalates', 'Chemical', 'MESH:C032279', (0, 10))	('decrease testosterone', 'Phenotype', 'HP:0040171', (52, 73))	('decrease', 'NegReg', (52, 60))	('testosterone production', 'MPA', (61, 84))
469809	31645210	Mast cells arise from hematopoietic stem cells which are CD34+, CD117+ and CD13+.	('CD34', 'Gene', '305081', (57, 61))	('CD34', 'Gene', (57, 61))	('CD13+', 'Var', (75, 80))	('CD117+', 'Var', (64, 70))
469870	31645210	; spinal cord and nerve infections in zebrafish (Danio rerio) attributed to Pseudoloma neurophiiia; and zebrafish skeletal muscle infections due to Pleistophora hyphessobryconis, the etiologic agent of "Neon Tetra Disease."	('zebrafish skeletal muscle infections', 'Disease', 'MESH:D007239', (104, 140))	('Pseudoloma neurophiiia', 'Disease', (76, 98))	('zebrafish', 'Species', '7955', (38, 47))	('Pleistophora hyphessobryconis', 'Species', '689837', (148, 177))	('Neon Tetra', 'Species', '42492', (203, 213))	('Danio rerio', 'Species', '7955', (49, 60))	('spinal cord and nerve infections', 'Disease', 'MESH:D013118', (2, 34))	('Pseudoloma neurophiiia', 'Disease', 'None', (76, 98))	('zebrafish', 'Species', '7955', (104, 113))	('Pleistophora', 'Var', (148, 160))	('zebrafish skeletal muscle infections', 'Disease', (104, 140))
469908	29552265	The mass demonstrated internal heterogeneity including foci of T1-hyperintense signal suggestive of internal hemorrhage (vs fat), markedly T2-hyperintense soft tissue elements with avid enhancement on contrast-enhanced fat-suppressed T1-weighted imaging, and mild T2-hyperintense peritumoral edema (Fig.	('T1-hyperintense signal', 'MPA', (63, 85))	('edema', 'Phenotype', 'HP:0000969', (292, 297))	('peritumoral edema', 'Disease', 'MESH:D004487', (280, 297))	('internal hemorrhage', 'Disease', 'MESH:D006470', (100, 119))	('T2-hyperintense', 'Var', (139, 154))	('enhancement', 'PosReg', (186, 197))	('internal hemorrhage', 'Disease', (100, 119))	('peritumoral edema', 'Disease', (280, 297))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('internal hemorrhage', 'Phenotype', 'HP:0011029', (100, 119))
469944	29552265	These are typically deep-seated and infiltrative tumors with nuclear pleomorphism, brisk mitotic activity, and internal necrosis.	('nuclear pleomorphism', 'Var', (61, 81))	('necrosis', 'Disease', (120, 128))	('internal necrosis', 'Phenotype', 'HP:0010885', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('necrosis', 'Disease', 'MESH:D009336', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))
469959	29552265	Furthermore, in a small case series, molecular analysis using targeted next-generation sequencing was used to analyze conventional myopericytoma and myopericytomatosis cases, which reportedly identified recurrent PDGFRbeta mutations in 4 of 5 cases of myopericytomatosis and 3 of 5 myopericytomas.	('mutations', 'Var', (223, 232))	('myopericytoma', 'Disease', 'MESH:D000077777', (282, 295))	('myopericytomatosis', 'Disease', (252, 270))	('myopericytoma', 'Disease', 'MESH:D000077777', (131, 144))	('myopericytomatosis', 'Disease', 'None', (149, 167))	('myopericytoma', 'Disease', (282, 295))	('myopericytoma', 'Disease', 'MESH:D000077777', (149, 162))	('PDGFRbeta', 'Gene', '5159', (213, 222))	('myopericytoma', 'Disease', (131, 144))	('myopericytomatosis', 'Disease', 'None', (252, 270))	('myopericytoma', 'Disease', 'MESH:D000077777', (252, 265))	('myopericytoma', 'Disease', (149, 162))	('myopericytoma and myopericytomatosis', 'Disease', 'MESH:D000077777', (131, 167))	('PDGFRbeta', 'Gene', (213, 222))	('myopericytomatosis', 'Disease', (149, 167))	('myopericytoma', 'Disease', (252, 265))
469960	29552265	As mutations in PDGFRbeta have been described in familial infantile myofibromatosis, these findings support the belief that myopericytoma and myopericytomatosis reside within the same biologic spectrum as infantile myofibromatosis and other perivascular tumors.	('infantile myofibromatosis', 'Disease', 'MESH:C562978', (58, 83))	('tumors', 'Disease', (254, 260))	('familial infantile myofibromatosis', 'Disease', 'MESH:C562978', (49, 83))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('familial infantile myofibromatosis', 'Disease', (49, 83))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('PDGFRbeta', 'Gene', '5159', (16, 25))	('myofibromatosis', 'Phenotype', 'HP:0020135', (215, 230))	('infantile myofibromatosis', 'Disease', 'MESH:C562978', (205, 230))	('myopericytoma and myopericytomatosis', 'Disease', 'MESH:D000077777', (124, 160))	('PDGFRbeta', 'Gene', (16, 25))	('infantile myofibromatosis', 'Disease', (205, 230))	('myofibromatosis', 'Phenotype', 'HP:0020135', (68, 83))	('described', 'Reg', (36, 45))	('mutations', 'Var', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('perivascular tumors', 'Phenotype', 'HP:0012520', (241, 260))
469980	27191494	These reports reveal that deregulated miRNAs are involved in the occurrence and development of KS.	('deregulated', 'Var', (26, 37))	('men', 'Species', '9606', (87, 90))	('involved', 'Reg', (49, 57))	('KS', 'Phenotype', 'HP:0100726', (95, 97))	('miRNAs', 'MPA', (38, 44))
469982	27191494	Knockout of miR-126-3p can cause a loss in blood vessel integrity and result in hemorrhage during embryonic development in zebrafish, showing that miR-126-3p controls blood vessel integrity and angiogenesis.	('zebrafish', 'Species', '7955', (123, 132))	('loss in blood vessel', 'Disease', 'MESH:D009383', (35, 55))	('loss in blood vessel', 'Disease', (35, 55))	('miR-126-3p', 'Gene', '100302148', (147, 157))	('miR-126-3p', 'Gene', (147, 157))	('men', 'Species', '9606', (115, 118))	('hemorrhage', 'Disease', (80, 90))	('blood vessel', 'CPA', (167, 179))	('Knockout', 'Var', (0, 8))	('hemorrhage', 'Disease', 'MESH:D006470', (80, 90))	('miR-126-3p', 'Gene', '100302148', (12, 22))	('miR-126-3p', 'Gene', (12, 22))	('result in', 'Reg', (70, 79))
470000	27191494	The cell invasion assay demonstrated that more cells traversed the transwell membrane among miR-126-3p inhibitor transfected cells, and fewer cells among the miR-126-3p mimic transfected cells.	('miR-126-3p', 'Gene', (92, 102))	('miR-126-3p', 'Gene', '100302148', (158, 168))	('miR-126-3p', 'Gene', (158, 168))	('miR-126-3p', 'Gene', '100302148', (92, 102))	('more', 'PosReg', (42, 46))	('fewer', 'NegReg', (136, 141))	('transfected', 'Var', (113, 124))	('cells traversed the transwell membrane', 'CPA', (47, 85))
470015	27191494	miRNAs can act as oncogenes and tumor suppressors associated with deregulated gene expression in cancer caused by gene amplification, deletion, mutation, and epigenetic silencing.	('epigenetic silencing', 'Var', (158, 178))	('cancer', 'Disease', (97, 103))	('deregulated gene expression', 'MPA', (66, 93))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('gene amplification', 'Var', (114, 132))	('mutation', 'Var', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('deletion', 'Var', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
470028	27191494	PI3K is a complex composed of regulatory subunits (p85alpha, p85beta, and p85gamma) and catalytic subunits (p110), and acts as a pivotal growth factor signal.	('PI3K', 'Var', (0, 4))	('p85beta', 'Gene', '5296', (61, 68))	('p85alpha', 'Gene', (51, 59))	('p85beta', 'Gene', (61, 68))	('p85alpha', 'Gene', '5295', (51, 59))
470030	27191494	The deletion of PIK3R2 increases insulin-induced Akt activation, leading to increased anti-apoptosis.	('insulin', 'Gene', (33, 40))	('anti-apoptosis', 'CPA', (86, 100))	('increased', 'PosReg', (76, 85))	('insulin', 'Gene', '3630', (33, 40))	('PIK3R2', 'Gene', (16, 22))	('deletion', 'Var', (4, 12))	('Akt', 'Gene', '207', (49, 52))	('PIK3R2', 'Gene', '5296', (16, 22))	('increases', 'PosReg', (23, 32))	('Akt', 'Gene', (49, 52))
470042	27191494	The primers used for the detection of miR-126-3p, U6, PIK3R2 and beta-actin were the Hs_miR-126 miScript Primer Assay (MS00003430, Qiagen), the Hs_RNU6 miScript Primer Assay (MS00033740, Qiagen), the Hs_PIK3R2 Primer Assay (QT01006005, Qiagen) and the Hs_beta-actin Primer Assay (QT00095431, Qiagen), respectively.	('beta-actin', 'Gene', (65, 75))	('PIK3R2', 'Gene', (203, 209))	('PIK3R2', 'Gene', '5296', (203, 209))	('miR-126', 'Gene', (88, 95))	('miR-126', 'Gene', '406913', (38, 45))	('beta-actin', 'Gene', '728378', (65, 75))	('miR-126-3p', 'Gene', (38, 48))	('QT01006005', 'Var', (224, 234))	('miR-126-3p', 'Gene', '100302148', (38, 48))	('miR-126', 'Gene', (38, 45))	('PIK3R2', 'Gene', (54, 60))	('beta-actin', 'Gene', '728378', (255, 265))	('MS00003430', 'Var', (119, 129))	('beta-actin', 'Gene', (255, 265))	('miR-126', 'Gene', '406913', (88, 95))	('PIK3R2', 'Gene', '5296', (54, 60))	('MS00033740', 'Var', (175, 185))
470055	27191494	To generate the luciferase reporter plasmid, the wild-type or mutant PIK3R2 3'-UTR were amplified from genomic DNA and cloned into pmirGlO vectors (Promega, Wisconsin, USA) using the following primers: PIK3R2 wild-type 3'UTR forward primer, 5'-CCACGAGCTGGGAGGCAGGTTTTGTACGGTACGTTGTTATTG ATATG ATATAAAACATCAAC-3', reverse primer, 5'-TCG AGTTGATGTTTTATATCATAT CAATAACAACGTAC CGTACAAAACCTGCCTCCCAGCTCGTGGAGCT-3'.	('PIK3R2', 'Gene', (202, 208))	('mutant', 'Var', (62, 68))	('PIK3R2', 'Gene', '5296', (202, 208))	('PIK3R2', 'Gene', '5296', (69, 75))	('PIK3R2', 'Gene', (69, 75))
470056	27191494	PIK3R2 mutant-type 3'UTR forward primer, 5'-CCAC GAGCTGGGAGGCAGGTTTT GTTGCCATGCTTGTT ATTGATATGATATAAAACATCAAC -3', reverse primer, 5'- TCGAGTTGATGTTTTATATCATATCAATAACAA GCATGGCAACAAAACCTGCCTCCCAGCTCGTGGA GCT -3'.	('mutant-type', 'Var', (7, 18))	('PIK3R2', 'Gene', '5296', (0, 6))	('PIK3R2', 'Gene', (0, 6))
470058	27191494	The cells were co-transfected with 0.8 mug wild-type or mutant PIK3R2 pmirGlO luciferase reporter and 40 nM miR-126-3p mimic or miR-126-3p inhibitor using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA).	('Lipofectamine', 'Chemical', 'MESH:C086724', (155, 168))	('mutant', 'Var', (56, 62))	('PIK3R2', 'Gene', '5296', (63, 69))	('PIK3R2', 'Gene', (63, 69))	('miR-126-3p', 'Gene', '100302148', (108, 118))	('miR-126-3p', 'Gene', '100302148', (128, 138))	('miR-126-3p', 'Gene', (108, 118))	('miR-126-3p', 'Gene', (128, 138))
470165	22587892	Molecular HLA typing of the cell lines, performed at Leiden University Medical Center (LUMC), was converted to serological equivalents (no serological equivalents exist for HLA-Cw*16 and -Cw*12): SK-ES-1 (A2/A11/B7/B44/Cw5/Cw7), SK-N-MC (A1/A25/B8/Cw7), CADO-ES (A11/A24/B15/B40/Cw4/Cw7), STA-ET-2.1 (A11/A24/B18/B40/Cw2/Cw5), TC71 (A2/A68/B15/B44/Cw3/Cw5), IOR/BER (A2/A11/B18/B51/Cw7/Cw15).	('A11/A24/B15/B40/Cw4/Cw7', 'Var', (263, 286))	('CADO-ES', 'Chemical', '-', (254, 261))	('SK-ES-1', 'CellLine', 'CVCL:0627', (196, 203))	('SK-N-MC', 'CellLine', 'CVCL:0530', (229, 236))	('A11/A24/B18/B40/Cw2/Cw5', 'Var', (301, 324))
470166	22587892	The EBV B-LCL 107 cell line was generated from a healthy blood bank donor expressing HLA alleles which are ligands to all inhibitory killer cell immunoglobulin receptors.	('donor', 'Species', '9606', (68, 73))	('HLA', 'Gene', (85, 88))	('alleles', 'Var', (89, 96))
470195	22587892	In addition, and consistent with the observed comparable ligand expression, blocking of NKG2D and DNAM1 on resting natural killer cells in 51Cr release assays reduced natural killer cell-mediated cytolysis of both chemotherapy-sensitive and -resistant cell lines to a similar degree (data not shown).	('51Cr release', 'MPA', (139, 151))	('DNAM1', 'Gene', '10666', (98, 103))	('reduced', 'NegReg', (159, 166))	('natural killer cell-mediated cytolysis', 'CPA', (167, 205))	('NKG2D', 'Gene', '22914', (88, 93))	('blocking', 'Var', (76, 84))	('NKG2D', 'Gene', (88, 93))	('DNAM1', 'Gene', (98, 103))
470216	22587892	Pre-treatment of the chemotherapy-resistant CADO-ES cell line with HDI NaB, MS-275 and SAHA sensitized, in a dose-dependent manner, for natural killer cell cytotoxicity (as shown for NaB in Figure 4F; paired t-test (medium versus 1/20 of IC50 value), p < 0.05 at effector-to-target ratio's >= 5:1).	('HDI NaB', 'Gene', (67, 74))	('cytotoxicity', 'Disease', (156, 168))	('CADO-ES', 'Chemical', '-', (44, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (156, 168))	('MS-275', 'Var', (76, 82))	('NaB', 'Chemical', '-', (183, 186))	('SAHA', 'Chemical', 'MESH:D000077337', (87, 91))	('NaB', 'Chemical', '-', (71, 74))	('MS-275', 'Chemical', 'MESH:C118739', (76, 82))
470226	22587892	Based on available data about caspase-8 expression and p53 mutation status in our panel of cell lines, however, the observed cross-resistance to resting natural killer cells cannot be explained by aberrant expression or the mutation status of these proteins alone.	('p53', 'Gene', '7157', (55, 58))	('p53', 'Gene', (55, 58))	('caspase-8', 'Gene', '841', (30, 39))	('mutation', 'Var', (59, 67))	('caspase-8', 'Gene', (30, 39))
470236	22587892	Moreover, and in addition to the observed comparable constitutive expression of activating NKG2D and DNAM1-ligands, blocking of NKG2D and DNAM1 on resting natural killer cells reduced natural killer cell-mediated cytolysis of both chemotherapy-sensitive and -resistant cells to a similar degree.	('DNAM1', 'Gene', '10666', (101, 106))	('blocking', 'Var', (116, 124))	('reduced', 'NegReg', (176, 183))	('natural killer cell-mediated cytolysis', 'CPA', (184, 222))	('DNAM1', 'Gene', (138, 143))	('NKG2D', 'Gene', '22914', (128, 133))	('DNAM1', 'Gene', (101, 106))	('DNAM1', 'Gene', '10666', (138, 143))	('NKG2D', 'Gene', '22914', (91, 96))	('NKG2D', 'Gene', (128, 133))	('NKG2D', 'Gene', (91, 96))
470245	22587892	In addition to recognition by natural killer cells, expression of NKG2D ligands might improve anti-tumour immune responses by specific T-lymphocyte subsets.	('NKG2D', 'Gene', '22914', (66, 71))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('NKG2D', 'Gene', (66, 71))	('tumour', 'Disease', (99, 105))	('improve', 'PosReg', (86, 93))	('expression', 'Var', (52, 62))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
470259	22587892	Natural killer cell cytotoxicity depended on NKG2D-NKG2D ligand interactions, since blocking of NKG2D abrogated cytolysis.	('blocking', 'Var', (84, 92))	('cytolysis', 'MPA', (112, 121))	('NKG2D', 'Gene', '22914', (45, 50))	('NKG2D', 'Gene', '22914', (51, 56))	('NKG2D', 'Gene', '22914', (96, 101))	('cytotoxicity', 'Disease', (20, 32))	('NKG2D', 'Gene', (45, 50))	('NKG2D', 'Gene', (51, 56))	('NKG2D', 'Gene', (96, 101))	('abrogated', 'NegReg', (102, 111))	('cytotoxicity', 'Disease', 'MESH:D064420', (20, 32))	('interactions', 'Interaction', (64, 76))
470384	31395100	Case reports in the literature have shown remarkable response of visceral and cutaneous angiosarcoma involvement in patients treated with an anti-PD-1 antibody.	('cutaneous angiosarcoma involvement', 'Disease', (78, 112))	('patients', 'Species', '9606', (116, 124))	('cutaneous angiosarcoma involvement', 'Disease', 'MESH:D006394', (78, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('anti-PD-1', 'Var', (141, 150))	('angiosarcoma', 'Phenotype', 'HP:0200058', (88, 100))
470426	31395100	Comparison of tumor and normal DNA identified 287 tumor mutations, with only 6 missense mutations.	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', (50, 55))
470427	31395100	Missense mutations occurred in the genes NBPF10, NBPF15, ZNF678, VPS8, PCLO and ABCB1.	('NBPF15', 'Gene', '284565', (49, 55))	('VPS8', 'Gene', '23355', (65, 69))	('ZNF678', 'Gene', (57, 63))	('VPS8', 'Gene', (65, 69))	('NBPF10', 'Gene', '100132406', (41, 47))	('occurred', 'Reg', (19, 27))	('NBPF15', 'Gene', (49, 55))	('PCLO', 'Gene', '27445', (71, 75))	('PCLO', 'Gene', (71, 75))	('ZNF678', 'Gene', '339500', (57, 63))	('ABCB1', 'Gene', (80, 85))	('NBPF10', 'Gene', (41, 47))	('ABCB1', 'Gene', '5243', (80, 85))	('Missense mutations', 'Var', (0, 18))
470429	31395100	Mutations in the PLCO gene have been found in poorly differentiated hepatocellular carcinoma as well as in hematological malignancies, however its role in the pathogenesis of either is not known.	('hematological malignancies', 'Phenotype', 'HP:0004377', (107, 133))	('found', 'Reg', (37, 42))	('hematological malignancies', 'Disease', (107, 133))	('Mutations', 'Var', (0, 9))	('hematological malignancies', 'Disease', 'MESH:D019337', (107, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (68, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (68, 92))	('PLCO', 'Gene', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('hepatocellular carcinoma', 'Disease', (68, 92))
470431	31395100	Interestingly, the ABCB1 gene has been implicated in the export of taxanes and other cytotoxic agents, and gene polymorphisms have been shown to have both predictive value in ovarian cancer.	('ABCB1', 'Gene', (19, 24))	('ovarian cancer', 'Phenotype', 'HP:0100615', (175, 189))	('export of taxanes', 'MPA', (57, 74))	('polymorphisms', 'Var', (112, 125))	('implicated', 'Reg', (39, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (175, 189))	('taxanes', 'Chemical', 'MESH:D043823', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('ovarian cancer', 'Disease', (175, 189))	('ABCB1', 'Gene', '5243', (19, 24))
470442	31395100	Numerous studies combining CTLA-4 inhibition with immunotherapy, tyrosine kinase inhibitors, or chemotherapy are ongoing for sarcoma patients (ie Trabectedin, Ipilimumab and Nivolumab (NCT03138161), Ipilimumab and Imatinib (NCT01738139).	('Imatinib', 'Chemical', 'MESH:D000068877', (214, 222))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('CTLA-4', 'Gene', (27, 33))	('patients', 'Species', '9606', (133, 141))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (199, 209))	('Nivolumab', 'Chemical', 'MESH:D000077594', (174, 183))	('sarcoma', 'Disease', (125, 132))	('Trabectedin', 'Chemical', 'MESH:D000077606', (146, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('inhibition', 'NegReg', (34, 44))	('NCT03138161', 'Var', (185, 196))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (159, 169))
470446	31395100	In a pooled radiation-associated and sporadic angiosarcoma analysis, a subset of patients shared a mutational signature of UV light (preponderance of C   T substitutions) similar to UV-associated skin carcinoma of the scalp.	('angiosarcoma', 'Disease', 'MESH:D006394', (46, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('angiosarcoma', 'Disease', (46, 58))	('skin carcinoma of the scalp', 'Disease', (196, 223))	('substitutions', 'Var', (156, 169))	('patients', 'Species', '9606', (81, 89))	('angiosarcoma', 'Phenotype', 'HP:0200058', (46, 58))	('UV light', 'Gene', (123, 131))	('skin carcinoma of the scalp', 'Disease', 'MESH:C538225', (196, 223))
470448	31395100	UV mutation signature and overall mutation burden in melanoma patients confer clinical benefit to CTLA-4 inhibition, but not to adoptive cellular therapies.	('benefit', 'PosReg', (87, 94))	('inhibition', 'NegReg', (105, 115))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('mutation', 'Var', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('mutation', 'Var', (3, 11))	('CTLA-4', 'Gene', (98, 104))	('patients', 'Species', '9606', (62, 70))
470450	31395100	These tumors may exhibit thousands of mutations, and respond exceedingly well to checkpoint inhibitors, leading to multiple FDA indications for cancers with microsatellite instability.	('leading to', 'Reg', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('exhibit', 'Reg', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('microsatellite instability', 'Var', (157, 183))
470451	31395100	Outside of MSI, mutational burden has also correlated with response to checkpoint inhibitors in various solid cancers.	('MSI', 'Disease', 'None', (11, 14))	('solid cancers', 'Disease', 'MESH:D009369', (104, 117))	('mutational burden', 'Var', (16, 33))	('correlated', 'Reg', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MSI', 'Disease', (11, 14))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('solid cancers', 'Disease', (104, 117))	('response', 'MPA', (59, 67))
470454	31395100	While insufficient alone, the tumor mutational load can certainly increase the probability of neoantigen signature and response to checkpoint inhibition.	('increase', 'PosReg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutational load', 'Var', (36, 51))	('neoantigen signature', 'MPA', (94, 114))	('tumor', 'Disease', (30, 35))
470458	31395100	A pan-cancer analysis showed that increased numbers of indel frameshift mutations in renal cell carcinoma and melanoma are associated with higher cytotoxic T cell infiltration, higher neoantigen formation, and better immunotherapy responses.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('higher', 'PosReg', (177, 183))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (85, 105))	('melanoma', 'Disease', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('immunotherapy responses', 'CPA', (217, 240))	('indel frameshift mutations', 'Var', (55, 81))	('renal cell carcinoma', 'Disease', (85, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cytotoxic T cell infiltration', 'CPA', (146, 175))	('neoantigen formation', 'MPA', (184, 204))	('cancer', 'Disease', (6, 12))	('higher', 'PosReg', (139, 145))
470459	31395100	Another pan-cancer analysis from TCGA (The Cancer Genome Atlas) database showed 1.5 predicted peptides per fusion across different cancer types, with frameshift fusions generating more immunogenic epitopes than in-frame fusions.	('Cancer', 'Disease', (43, 49))	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('frameshift fusions', 'Var', (150, 168))	('Cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('immunogenic epitopes', 'MPA', (185, 205))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('more', 'PosReg', (180, 184))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
470460	31395100	These findings are particularly important, because some patients with driver fusions may be excluded from checkpoint inhibitor trials due to their low tumor mutation burden.	('patients', 'Species', '9606', (56, 64))	('driver fusions', 'Var', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('low tumor', 'Disease', (147, 156))	('low tumor', 'Disease', 'MESH:D009800', (147, 156))
470463	31395100	We can only postulate that the prior chemotherapy and radiation might have generated more neoantigens potentially driven by fusions, promoting expansion of these memory T cells, eliciting cytotoxic reactions with checkpoint inhibition and perhaps that AGEN1884 may have augmented this antigen-specific immune response.	('AGEN1884', 'Chemical', '-', (252, 260))	('promoting expansion', 'PosReg', (133, 152))	('checkpoint inhibition', 'MPA', (213, 234))	('cytotoxic', 'CPA', (188, 197))	('AGEN1884', 'Var', (252, 260))	('augmented', 'PosReg', (270, 279))	('eliciting', 'Reg', (178, 187))
470485	31395100	Personalis Cancer DNA Pipeline was used to identify tumor somatic variants, short insertions and deletions.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Cancer', 'Disease', (11, 17))	('short insertions', 'Var', (76, 92))	('Cancer', 'Disease', 'MESH:D009369', (11, 17))	('deletions', 'Var', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
470495	28775288	Peptide transfection induced cytotoxicity relative to untreated and TAT-NLS peptide treated Ewing's sarcoma cells.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (92, 107))	('cytotoxicity', 'Disease', (29, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('cytotoxicity', 'Disease', 'MESH:D064420', (29, 41))	('transfection', 'Var', (8, 20))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (92, 107))	("Ewing's sarcoma", 'Disease', (92, 107))	('Peptide transfection', 'Var', (0, 20))
470496	28775288	The peptide inhibited clonogenicity, cell cycle, bromo-deoxy uridine (BrdU) uptake and invasion capacity of treated cells.	('inhibited', 'NegReg', (12, 21))	('peptide', 'Var', (4, 11))	('invasion capacity', 'CPA', (87, 104))	('bromo-deoxy uridine', 'Chemical', 'MESH:D001973', (49, 68))	('BrdU', 'Chemical', 'MESH:D001973', (70, 74))	('cell cycle', 'CPA', (37, 47))	('bromo-deoxy', 'MPA', (49, 60))	('clonogenicity', 'CPA', (22, 35))
470504	28775288	A defining feature of the malignant cells is the presence of a translocation, between the central exons of the EWSR1 gene (Ewing Sarcoma breakpoint region 1; chromosome 22) to the central exons of an ets family gene; frequently FLI1 (Friend Leukaemia Integration 1; chromosome11) or ERG (v-ets erythroblastosis virus E26 oncogene homolog; chromosome 21) t(11;22) and t(21;22), respectively.	('t(11;22', 'Var', (354, 361))	('translocation', 'Var', (63, 76))	('Friend Leukaemia Integration 1', 'Gene', (234, 264))	('v-ets erythroblastosis virus E26 oncogene homolog', 'Gene', (288, 337))	('t(21', 'Var', (367, 371))	('Ewing Sarcoma breakpoint region 1', 'Gene', (123, 156))	('EWSR1', 'Gene', (111, 116))	('v-ets erythroblastosis virus E26 oncogene homolog', 'Gene', '2078', (288, 337))	('FLI1', 'Gene', (228, 232))	('Ewing Sarcoma breakpoint region 1', 'Gene', '2130', (123, 156))	('ERG', 'Gene', '2078', (283, 286))	('EWSR1', 'Gene', '2130', (111, 116))	('FLI1', 'Gene', '2313', (228, 232))	('Friend Leukaemia Integration 1', 'Gene', '2313', (234, 264))	('Sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('ERG', 'Gene', (283, 286))
470522	28775288	relative to blank (0.37 a.u in A673 and 0.21 a.u in EWS502) was observed indicating the nuclear penetration of the peptide (Fig.	('EWS', 'Gene', '2130', (52, 55))	('nuclear penetration', 'CPA', (88, 107))	('A673', 'Var', (31, 35))	('EWS', 'Gene', (52, 55))
470528	28775288	Next, toxicity in non-tumorigenic and EWS-FLI1 translocation negative HEK293 and AG1522 cells was ascertained.	('translocation', 'Var', (47, 60))	('toxicity', 'Disease', 'MESH:D064420', (6, 14))	('toxicity', 'Disease', (6, 14))	('HEK293', 'CellLine', 'CVCL:0045', (70, 76))	('EWS-FLI1', 'Gene', (38, 46))	('EWS-FLI1', 'Gene', '2130;2313', (38, 46))
470555	28775288	The results from peptide interaction studies indicate that the peptide is capable of interacting with EWS-FLI1 protein and this interaction can occur in the presence of the GGAA microsatellite repeat sequences.	('EWS-FLI1', 'Gene', (102, 110))	('interacting', 'Interaction', (85, 96))	('protein', 'Protein', (111, 118))	('EWS-FLI1', 'Gene', '2130;2313', (102, 110))	('microsatellite', 'Var', (178, 192))
470570	28775288	Compared with the traditional cancer treatments such as chemotherapy or radioactive treatment, peptides with high specificity against cancer cells may present a way of killing cancer cells while protecting normal cells.	('peptides', 'Var', (95, 103))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('peptides', 'Chemical', 'MESH:D010455', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
470571	28775288	Targeting EWS-FLI1 is potentially efficacious since there is evidence for a direct role in tumorigenesis through an altered transcriptional program executed by the chimeric protein in tumour cells; in addition the translocation occurs in the background of low mutation rate further affirming its role in the aetiology of Ewing's sarcoma.	('transcriptional', 'MPA', (124, 139))	('tumorigenesis', 'CPA', (91, 104))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (321, 336))	('EWS-FLI1', 'Gene', (10, 18))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	("Ewing's sarcoma", 'Disease', (321, 336))	('translocation', 'Var', (214, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (329, 336))	('tumour', 'Disease', (184, 190))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (321, 336))	('EWS-FLI1', 'Gene', '2130;2313', (10, 18))
470572	28775288	In order to better understand the role of the junction region (a.a. 251-280) sequences, which we had previously shown to inhibit the tumorigenic properties of Ewing's sarcoma cells, the amino acids corresponding to this region were introduced into Ewing's sarcoma cells and its effects were analysed.	('inhibit', 'NegReg', (121, 128))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (248, 263))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (159, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	("Ewing's sarcoma", 'Disease', (159, 174))	("Ewing's sarcoma", 'Disease', (248, 263))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (159, 174))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (248, 263))	('tumorigenic properties', 'CPA', (133, 155))	('sequences', 'Var', (77, 86))	('introduced', 'Reg', (232, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
470575	28775288	However, functional effects of different amino acids in the fusion region of EWS-FLI1 were not determined hence it was not optimal to design effective mutant form of the target peptide which could possess a contraindicating activity.	('EWS-FLI1', 'Gene', '2130;2313', (77, 85))	('mutant', 'Var', (151, 157))	('EWS-FLI1', 'Gene', (77, 85))
470596	28775288	As a consequence we find scope for design optimization/modifications to the peptide which can help disrupt the EWS-FLI1-DNA interactions or protein-protein interactions that can potentially compromise the transcriptional activity of the chimeric protein.	('optimization/modifications', 'Var', (42, 68))	('EWS-FLI1', 'Gene', (111, 119))	('EWS-FLI1', 'Gene', '2130;2313', (111, 119))	('transcriptional activity', 'MPA', (205, 229))	('disrupt', 'NegReg', (99, 106))	('protein-protein interactions', 'Protein', (140, 168))	('compromise', 'NegReg', (190, 200))
470650	26555296	USP18 -/- FVB/N mice spontaneously develop tumors predominantly on the back of the neck with most tumors evident between 6-12 months (80 % penetrance).	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('develop', 'PosReg', (35, 42))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('USP18 -/- FVB/N', 'Var', (0, 15))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('mice', 'Species', '10090', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
470659	26555296	USP18 null mice develop leiomyosarcoma recapitulating key features of clinical leiomyosarcomas and patients with reduced-USP18 tumor levels have an unfavorable outcome.	('leiomyosarcomas', 'Disease', 'MESH:D007890', (79, 94))	('leiomyosarcomas', 'Disease', (79, 94))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('USP18', 'Gene', (0, 5))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (79, 94))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (24, 38))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (79, 93))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (79, 93))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (24, 38))	('reduced-USP18', 'Var', (113, 126))	('patients', 'Species', '9606', (99, 107))	('mice', 'Species', '10090', (11, 15))	('tumor', 'Disease', (127, 132))	('leiomyosarcoma', 'Disease', (24, 38))	('leiomyosarcoma', 'Disease', (79, 93))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
470670	26555296	If there were a way to identify subsets of sarcomas with specific genetic alterations, this would improve the classification or treatment outcomes for these malignancies.	('improve', 'PosReg', (98, 105))	('malignancies', 'Disease', 'MESH:D009369', (157, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('malignancies', 'Disease', (157, 169))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('genetic alterations', 'Var', (66, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcomas', 'Disease', (43, 51))
470671	26555296	For instance, polysomy of chromosome 8 in humans (syntenic to polysomy 15 in mice) is reported in complex sarcomas including leiomyosarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('mice', 'Species', '10090', (77, 81))	('polysomy', 'Var', (14, 22))	('sarcomas', 'Disease', 'MESH:D012509', (132, 140))	('sarcomas', 'Disease', (106, 114))	('sarcomas', 'Disease', 'MESH:D012509', (106, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('reported', 'Reg', (86, 94))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (125, 140))	('sarcomas', 'Disease', (132, 140))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (125, 140))	('humans', 'Species', '9606', (42, 48))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (125, 139))	('leiomyosarcomas', 'Disease', (125, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))
470680	26555296	Subsequent generation of USP18 knockout mice on a pure C57Bl/6 background found homozygous deletion of USP18 was embryonic lethal.	('mice', 'Species', '10090', (40, 44))	('deletion', 'Var', (91, 99))	('USP18', 'Gene', (103, 108))
470682	26555296	C57Bl/6-129-USP18 knockout mice were also hypersensitive to type I IFN as seen when they were treated with the IFN-inducer, poly-IC; this was fatal for USP18 knockout, but not for the wild-type mice.	('USP18', 'Gene', (152, 157))	('mice', 'Species', '10090', (27, 31))	('mice', 'Species', '10090', (194, 198))	('knockout', 'Var', (158, 166))	('hypersensitive', 'Disease', (42, 56))	('C57Bl/6-129-USP18', 'Var', (0, 17))	('hypersensitive', 'Disease', 'MESH:D004342', (42, 56))
470686	26555296	These murine sarcomas recapitulate critical characteristics of human leiomyosarcoma including aneuploidy, overexpression of MYC and deregulation of P53.	('sarcomas', 'Disease', (13, 21))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (69, 83))	('human', 'Species', '9606', (63, 68))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (69, 83))	('aneuploidy', 'Disease', (94, 104))	('P53', 'Protein', (148, 151))	('deregulation', 'Var', (132, 144))	('overexpression', 'PosReg', (106, 120))	('MYC', 'Protein', (124, 127))	('aneuploidy', 'Disease', 'MESH:D000782', (94, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcomas', 'Disease', 'MESH:D012509', (13, 21))	('murine', 'Species', '10090', (6, 12))	('sarcomas', 'Phenotype', 'HP:0100242', (13, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('leiomyosarcoma', 'Disease', (69, 83))
470688	26555296	While loss of USP18 did not significantly impact overall survival or disease-free survival, it did significantly decrease the time to metastasis indicating a key role for USP18 levels in leiomyosarcoma clinical biology.	('leiomyosarcoma', 'Disease', (187, 201))	('decrease', 'NegReg', (113, 121))	('loss', 'Var', (6, 10))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (187, 201))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (187, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('time to metastasis', 'CPA', (126, 144))	('USP18', 'Gene', (14, 19))
470711	26555296	MYC siRNA #1 (#s70224), MYC siRNA #2 (#s70226) and negative control (#4390843) were individually transfected into cells using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions and with triplicate replicate transfections.	('#s70226', 'Var', (38, 45))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (126, 144))	('#s70224', 'Var', (14, 21))
470770	26555296	While loss of USP18 preceded sarcoma formation, these sarcoma cell lines did not depend on loss of USP18 expression for survival, growth or tumorigenicity.	('loss', 'Var', (6, 10))	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('USP18', 'Gene', (99, 104))	('sarcoma', 'Disease', (29, 36))	('sarcoma', 'Disease', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('USP18', 'Gene', (14, 19))	('tumor', 'Disease', (140, 145))
470783	26555296	KHC1 and KHC2 cells were each growth inhibited by the JAK2-STAT3 pathway inhibitor JSI-124 (Additional file 1: Figure.	('JSI-124', 'Var', (83, 90))	('JAK2', 'Gene', (54, 58))	('JAK2', 'Gene', '16452', (54, 58))	('STAT3', 'Gene', '20848', (59, 64))	('JSI-124', 'Chemical', 'MESH:C038106', (83, 90))	('STAT3', 'Gene', (59, 64))
470802	26555296	Inactivation of PTEN in smooth muscle cells produced small mice with smooth muscle hyperplasia affecting blood vessels and the urinary and intestinal tracts, but not in the uterus.	('muscle hyperplasia', 'Disease', 'MESH:D006965', (76, 94))	('mice', 'Species', '10090', (59, 63))	('muscle hyperplasia', 'Disease', (76, 94))	('PTEN', 'Gene', '19211', (16, 20))	('muscle hyperplasia', 'Phenotype', 'HP:0003712', (76, 94))	('PTEN', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
470805	26555296	In an experiment to specifically inactivate BRCA1, P53 and Rb in murine ovarian epithelial cells, tumors arose instead from adjacent smooth muscle and were diagnosed as leiomyosarcomas.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (169, 183))	('BRCA1', 'Gene', (44, 49))	('tumors', 'Disease', (98, 104))	('leiomyosarcomas', 'Disease', (169, 184))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('BRCA1', 'Gene', '12189', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('P53', 'Gene', (51, 54))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (169, 184))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (169, 184))	('inactivate', 'Var', (33, 43))	('murine', 'Species', '10090', (65, 71))
470811	26555296	Defects in IFN signaling can augment tumorigenesis in the 3-MCA-sarcoma model; evidence from USP18 null mice identified an amplified IFN response as compared to wild-type mice, which is thought to provide a less permissive environment for tumors.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('amplified', 'PosReg', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('mice', 'Species', '10090', (171, 175))	('MCA-sarcoma', 'Disease', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('Defects', 'Var', (0, 7))	('mice', 'Species', '10090', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (239, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('USP18', 'Gene', (93, 98))	('IFN response', 'MPA', (133, 145))	('MCA-sarcoma', 'Disease', 'MESH:D020244', (60, 71))
470821	26555296	Loss of PTEN sensitized leiomyosarcoma cells to rapamycin treatment, however tumors with different driver mutations will likely have different drug sensitivities.	('sensitized', 'Reg', (13, 23))	('tumors', 'Disease', (77, 83))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (24, 38))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('PTEN', 'Gene', '19211', (8, 12))	('PTEN', 'Gene', (8, 12))	('leiomyosarcoma', 'Disease', (24, 38))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (24, 38))	('rapamycin', 'Chemical', 'MESH:D020123', (48, 57))	('Loss', 'Var', (0, 4))
470824	26555296	Activating the IFN pathway either directly with IFN or with an IFN-inducing agent might target leiomyosarcomas.	('leiomyosarcomas', 'Disease', 'MESH:D007890', (95, 110))	('IFN pathway', 'Pathway', (15, 26))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (95, 109))	('leiomyosarcomas', 'Disease', (95, 110))	('Activating', 'Var', (0, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (95, 110))
470833	26555296	This possibility is consistent with the leiomyosarcoma formation seen when PI3K/mTOR signaling is inappropriately activated in smooth muscle cells by deletion of the negative regulator, PTEN.	('PTEN', 'Gene', '19211', (186, 190))	('activated', 'PosReg', (114, 123))	('leiomyosarcoma', 'Disease', (40, 54))	('mTOR', 'Gene', (80, 84))	('PTEN', 'Gene', (186, 190))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (40, 54))	('mTOR', 'Gene', '56717', (80, 84))	('deletion', 'Var', (150, 158))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (40, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
470844	25254972	We found that complement activation increased STAT3 tyrosine phosphorylation (Y705) of KSHV-infected cells, which was required for the enhanced cell survival.	('STAT3', 'Gene', '6774', (46, 51))	('KSHV', 'Species', '37296', (87, 91))	('STAT3', 'Gene', (46, 51))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('Y705', 'Var', (78, 82))	('KS', 'Phenotype', 'HP:0100726', (87, 89))	('increased', 'PosReg', (36, 45))
470845	25254972	Furthermore, overexpression of either CD55 or CD59 in latently KSHV-infected cells was sufficient to inhibit complement activation, prevent STAT3 Y705 phosphorylation and abolish the enhanced survival of cells cultured in growth factor-depleted condition.	('KSHV', 'Species', '37296', (63, 67))	('inhibit', 'NegReg', (101, 108))	('CD55', 'Var', (38, 42))	('survival', 'CPA', (192, 200))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('complement activation', 'MPA', (109, 130))	('enhanced', 'PosReg', (183, 191))	('overexpression', 'PosReg', (13, 27))	('STAT3', 'Gene', '6774', (140, 145))	('CD59', 'Var', (46, 50))	('prevent', 'NegReg', (132, 139))	('STAT3', 'Gene', (140, 145))	('abolish', 'NegReg', (171, 178))
470864	25254972	KSHV maintains latency by evolving effective mechanisms for episome persistence, silencing expression of viral lytic genes, and promotion of survival and proliferation of infected cells.	('KSHV', 'Species', '37296', (0, 4))	('expression', 'MPA', (91, 101))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('survival', 'CPA', (141, 149))	('KSHV', 'Gene', (0, 4))	('promotion', 'PosReg', (128, 137))	('episome persistence', 'MPA', (60, 79))	('silencing', 'Var', (81, 90))	('rat', 'Species', '10116', (161, 164))	('viral lytic genes', 'Gene', (105, 122))	('proliferation', 'CPA', (154, 167))
470866	25254972	The STAT3 pathway, which can be activated by both KSHV-encoded IL-6 (vIL-6) and cellular IL-6, is essential for the survival of PEL cells.	('IL-6', 'Gene', (70, 74))	('IL-6', 'Gene', '3569', (63, 67))	('PEL', 'Phenotype', 'HP:0030069', (128, 131))	('IL-6', 'Gene', '3569', (70, 74))	('vIL-6', 'Gene', (69, 74))	('KS', 'Phenotype', 'HP:0100726', (50, 52))	('vIL-6', 'Gene', '4961449', (69, 74))	('IL-6', 'Gene', (89, 93))	('STAT3', 'Gene', '6774', (4, 9))	('KSHV', 'Species', '37296', (50, 54))	('IL-6', 'Gene', (63, 67))	('KSHV-encoded', 'Var', (50, 62))	('STAT3', 'Gene', (4, 9))	('IL-6', 'Gene', '3569', (89, 93))
470874	25254972	Soluble proteins include factor H and its related proteins and variants, and factor I while membrane-associated proteins include CD35, CD46, CD55, and CD59.	('CD35', 'Gene', (129, 133))	('variants', 'Var', (63, 71))	('CD46', 'Gene', '4179', (135, 139))	('CD46', 'Gene', (135, 139))	('CD35', 'Gene', '1378', (129, 133))	('factor H', 'Gene', '3075', (25, 33))	('factor H', 'Gene', (25, 33))
470875	25254972	In particular, factor H together with factor I bind to and cleave C3b in the alternative complement pathway, effectively preventing its further activation.	('preventing', 'NegReg', (121, 131))	('activation', 'MPA', (144, 154))	('bind to', 'Interaction', (47, 54))	('factor H', 'Gene', '3075', (15, 23))	('factor H', 'Gene', (15, 23))	('cleave', 'Var', (59, 65))	('C3b', 'Gene', (66, 69))	('C3b', 'Gene', '718', (66, 69))	('alternative complement pathway', 'Pathway', (77, 107))
470880	25254972	In this study, we have unexpectedly discovered that KSHV activates the complement system during latency.	('activates', 'PosReg', (57, 66))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('KSHV', 'Species', '37296', (52, 56))	('KSHV', 'Var', (52, 56))
470911	25254972	Together, these results suggest that KSHV might induce activation of the complement system during latency.	('activation', 'PosReg', (55, 65))	('KS', 'Phenotype', 'HP:0100726', (37, 39))	('KSHV', 'Species', '37296', (37, 41))	('KSHV', 'Var', (37, 41))
470988	25254972	When we exchanged the medium for endothelial cell basal media without growth factors containing 10% heat-inactivated or normal human serum, Y705 phosphorylation decreased rapidly within 30 min in both TIME and TIME-KSHV cells (Figure 7B).	('human', 'Species', '9606', (127, 132))	('decreased', 'NegReg', (161, 170))	('KS', 'Phenotype', 'HP:0100726', (215, 217))	('TIME-KSHV', 'CellLine', 'CVCL:0047', (210, 219))	('Y705', 'Var', (140, 144))
470993	25254972	Under the same condition, we continued to detect S727 phosphorylation in TIME-KSHV cells grown in heat-inactivated or normal human serum (Figure 7B).	('KS', 'Phenotype', 'HP:0100726', (78, 80))	('S727', 'Var', (49, 53))	('human', 'Species', '9606', (125, 130))	('TIME-KSHV', 'CellLine', 'CVCL:0047', (73, 82))	('phosphorylation', 'MPA', (54, 69))
470994	25254972	These results are consistent with the observation of kaposin B activation of S727 but not Y705 phosphorylation in primary human endothelial cells latently infected by KSHV.	('human', 'Species', '9606', (122, 127))	('Y705', 'Var', (90, 94))	('S727', 'Var', (77, 81))	('KS', 'Phenotype', 'HP:0100726', (167, 169))	('KSHV', 'Species', '37296', (167, 171))	('activation', 'PosReg', (63, 73))
471004	25254972	CD55 primarily inhibits C3 activation and amplification of the activated complement system while CD59 inhibits C5b-9 formation.	('CD55', 'Var', (0, 4))	('amplification', 'MPA', (42, 55))	('C5b', 'Gene', '727', (111, 114))	('CD59', 'Var', (97, 101))	('inhibits', 'NegReg', (15, 23))	('inhibits', 'NegReg', (102, 110))	('C5b', 'Gene', (111, 114))
471005	25254972	As expected, overexpression of either CD55 or CD59 protein was sufficient to significantly decrease C5b-9 deposition on TIME-KSHV cells exposed to normal human serum (Figure 8D and S14).	('human', 'Species', '9606', (154, 159))	('CD59 protein', 'Var', (46, 58))	('CD55', 'Var', (38, 42))	('KS', 'Phenotype', 'HP:0100726', (125, 127))	('TIME-KSHV', 'CellLine', 'CVCL:0047', (120, 129))	('C5b', 'Gene', (100, 103))	('C5b', 'Gene', '727', (100, 103))	('decrease', 'NegReg', (91, 99))
471006	25254972	Overexpression of CD55 also significantly decreased C3b deposition on TIME-KSHV cells; however, overexpression of CD59, as expected, had minimal effect on C3b deposition on these cells (Figure 8E).	('TIME-KSHV', 'CellLine', 'CVCL:0047', (70, 79))	('decreased C3b', 'Phenotype', 'HP:0005421', (42, 55))	('decreased', 'NegReg', (42, 51))	('C3b deposition', 'Phenotype', 'HP:0012576', (52, 66))	('CD55', 'Var', (18, 22))	('C3b deposition', 'Phenotype', 'HP:0012576', (155, 169))	('C3b', 'Gene', (155, 158))	('KS', 'Phenotype', 'HP:0100726', (75, 77))	('C3b', 'Gene', '718', (155, 158))	('C3b', 'Gene', (52, 55))	('C3b', 'Gene', '718', (52, 55))
471007	25254972	Importantly, overexpression of either CD55 or CD59 protein was sufficient to reduce STAT3 Y705 phosphorylation in TIME-KSHV cells cultured for 24 h in growth factor-depleted medium containing normal human serum (Figure 8F).	('reduce', 'NegReg', (77, 83))	('human', 'Species', '9606', (199, 204))	('STAT3', 'Gene', '6774', (84, 89))	('TIME-KSHV', 'CellLine', 'CVCL:0047', (114, 123))	('CD55', 'Var', (38, 42))	('protein', 'Protein', (51, 58))	('STAT3', 'Gene', (84, 89))	('overexpression', 'PosReg', (13, 27))	('CD59', 'Var', (46, 50))	('KS', 'Phenotype', 'HP:0100726', (119, 121))
471017	25254972	Thus, latency is the default program by which KSHV evades the host immunity.	('KSHV', 'Species', '37296', (46, 50))	('KSHV', 'Var', (46, 50))	('evades', 'NegReg', (51, 57))	('KS', 'Phenotype', 'HP:0100726', (46, 48))
471018	25254972	In this study, we have unexpectedly found that KSHV activates the complement system during latency.	('KS', 'Phenotype', 'HP:0100726', (47, 49))	('KSHV', 'Species', '37296', (47, 51))	('KSHV', 'Var', (47, 51))	('activates', 'PosReg', (52, 61))
471044	25254972	Importantly, we have shown that overexpression of either CD55 or CD59 in latently KSHV-infected cells is sufficient to abolish complement activation.	('CD55', 'Var', (57, 61))	('overexpression', 'PosReg', (32, 46))	('CD59', 'Var', (65, 69))	('KSHV', 'Species', '37296', (82, 86))	('abolish', 'NegReg', (119, 126))	('KS', 'Phenotype', 'HP:0100726', (82, 84))	('complement activation', 'MPA', (127, 148))
471045	25254972	These results are consistent with the facts that CD55 binds to C3b while CD59 binds to C5b-8 complex.	('C5b', 'Gene', '727', (87, 90))	('C3b', 'Gene', '718', (63, 66))	('CD55', 'Var', (49, 53))	('C3b', 'Gene', (63, 66))	('binds', 'Interaction', (78, 83))	('binds', 'Interaction', (54, 59))	('C5b', 'Gene', (87, 90))
471046	25254972	We have therefore concluded that KSHV activates the complement system by downregulating complement regulatory proteins during latent infection.	('infection', 'Disease', 'MESH:D007239', (133, 142))	('downregulating', 'NegReg', (73, 87))	('KS', 'Phenotype', 'HP:0100726', (33, 35))	('KSHV', 'Species', '37296', (33, 37))	('KSHV', 'Var', (33, 37))	('activates', 'PosReg', (38, 47))	('infection', 'Disease', (133, 142))	('complement regulatory proteins', 'Protein', (88, 118))
471074	25254972	In summary, we have identified a distinct mechanism by which KSHV subverts the alternative complement pathway by downregulating complement regulatory proteins, which results in the activation of the STAT3 pathway and enhanced cell survival.	('KSHV', 'Var', (61, 65))	('subverts', 'NegReg', (66, 74))	('alternative complement pathway', 'Pathway', (79, 109))	('enhanced', 'PosReg', (217, 225))	('complement regulatory proteins', 'Protein', (128, 158))	('activation', 'PosReg', (181, 191))	('STAT3', 'Gene', '6774', (199, 204))	('downregulating', 'NegReg', (113, 127))	('KS', 'Phenotype', 'HP:0100726', (61, 63))	('KSHV', 'Species', '37296', (61, 65))	('cell survival', 'CPA', (226, 239))	('STAT3', 'Gene', (199, 204))
471075	25254972	The deregulation of the complement system might promote KSHV latency and contribute to persistent infection and development of KS tumors.	('deregulation', 'Var', (4, 16))	('contribute', 'Reg', (73, 83))	('KSHV', 'Disease', (56, 60))	('infection', 'Disease', 'MESH:D007239', (98, 107))	('KS', 'Phenotype', 'HP:0100726', (127, 129))	('KS', 'Phenotype', 'HP:0100726', (56, 58))	('KS tumors', 'Disease', 'MESH:D009369', (127, 136))	('KSHV', 'Species', '37296', (56, 60))	('persistent infection', 'Phenotype', 'HP:0031035', (87, 107))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('KS tumors', 'Disease', (127, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('promote', 'PosReg', (48, 55))	('infection', 'Disease', (98, 107))
471088	25254972	Stattic (STAT3 inhibitor), JAK inhibitor I, LY294002 (PI3K inhibitor), SB203580 (p38 inhibitor), U0126 (MEK inhibitor), U-73122 (Phospholipase C inhibitor), and Src inhibitor I were purchased from Calbiochem (San Diego, CA).	('p38', 'Gene', '1432', (81, 84))	('SB203580', 'Chemical', 'MESH:C093642', (71, 79))	('Src', 'Gene', (161, 164))	('STAT3', 'Gene', (9, 14))	('SB203580', 'Var', (71, 79))	('LY294002', 'Chemical', 'MESH:C085911', (44, 52))	('U-73122', 'Var', (120, 127))	('p38', 'Gene', (81, 84))	('Src', 'Gene', '6714', (161, 164))	('U0126', 'Chemical', 'MESH:C113580', (97, 102))	('MEK', 'Gene', (104, 107))	('LY294002', 'Var', (44, 52))	('MEK', 'Gene', '5609', (104, 107))	('U-73122', 'Chemical', 'MESH:C060229', (120, 127))	('STAT3', 'Gene', '6774', (9, 14))
471106	25254972	Based on the certificate of analysis of the serum from the manufacturer, appropriate amounts of the purified complement factor was added to the complement factor-depleted human serum to achieve the functional activity ratio of CH50/ml that is equivalent to normal human serum.	('functional activity', 'MPA', (198, 217))	('human', 'Species', '9606', (264, 269))	('rat', 'Species', '10116', (218, 221))	('CH50/ml', 'Var', (227, 234))	('human', 'Species', '9606', (171, 176))
471129	21942527	Molecular Pathogenesis of Ewing Sarcoma: New Therapeutic and Transcriptional Targets Approximately one-third of sarcomas contain specific translocations.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('sarcomas', 'Disease', (112, 120))	('Ewing Sarcoma', 'Disease', (26, 39))	('translocations', 'Var', (138, 152))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('Sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('sarcomas', 'Disease', 'MESH:D012509', (112, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
471139	21942527	Rare cases of Ewing sarcoma show fusions of EWS to other ETS-family genes [such as ETV1, E1AF (ETV4), and FEV], or similar fusions of the EWS-related gene FUS (FUS-ERG or FUS-FEV) .	('E1AF', 'Gene', (89, 93))	('ETV1', 'Gene', (83, 87))	('FUS', 'Gene', '2521', (171, 174))	('ERG', 'Gene', '2078', (164, 167))	('E1AF', 'Gene', '2118', (89, 93))	('ETV4', 'Gene', (95, 99))	('FUS', 'Gene', (160, 163))	('ETV1', 'Gene', '2115', (83, 87))	('fusions', 'Var', (123, 130))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (14, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (14, 27))	('ETV4', 'Gene', '2118', (95, 99))	('FUS', 'Gene', '2521', (160, 163))	('FUS', 'Gene', (155, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('FUS-FEV', 'Gene', (171, 178))	('Ewing sarcoma', 'Disease', (14, 27))	('fusions', 'Var', (33, 40))	('FUS', 'Gene', (171, 174))	('EWS', 'Gene', (44, 47))	('FUS-FEV', 'Gene', '2521', (171, 178))	('FUS', 'Gene', '2521', (155, 158))	('ERG', 'Gene', (164, 167))
471140	21942527	On the basis of the general rule for sarcomas with chimeric transcription factors that all translocation variants associated with a specific sarcoma involve genes from the same transcription factor family, sarcomas with these rare EWS-ETS fusions are generally subsumed into the broad Ewing sarcoma--like category.	('sarcomas', 'Disease', 'MESH:D012509', (206, 214))	('sarcoma', 'Disease', (206, 213))	('sarcomas', 'Phenotype', 'HP:0100242', (206, 214))	('sarcoma', 'Disease', (141, 148))	('sarcomas', 'Disease', (206, 214))	('variants', 'Var', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcoma', 'Disease', 'MESH:D012509', (37, 44))	('sarcoma', 'Disease', 'MESH:D012509', (291, 298))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('sarcoma', 'Disease', (37, 44))	('sarcoma', 'Disease', (291, 298))	('translocation', 'Gene', (91, 104))	('sarcomas', 'Disease', (37, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (285, 298))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (285, 298))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('involve', 'Reg', (149, 156))	('associated', 'Reg', (114, 124))	('Ewing sarcoma', 'Disease', (285, 298))	('sarcoma', 'Disease', 'MESH:D012509', (206, 213))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))
471152	21942527	One explanation for these discrepancies is that EWS-FLI1 may trigger a generic ETS-mediated transformation process in NIH3T3 cells rather than a Ewing sarcoma-specific process.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (145, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (145, 158))	('ETS-mediated transformation process', 'CPA', (79, 114))	('trigger', 'Reg', (61, 68))	('EWS-FLI1', 'Var', (48, 56))	('NIH3T3', 'CellLine', 'CVCL:0594', (118, 124))	('Ewing sarcoma', 'Disease', (145, 158))
471159	21942527	As an example, expression of EWS-FLI1 in hTERT-immortalized human fibroblasts results in a growth arrest that is p53 dependent .	('hTERT', 'Gene', '7015', (41, 46))	('expression', 'Var', (15, 25))	('EWS-FLI1', 'Gene', (29, 37))	('growth arrest', 'Disease', 'MESH:D006323', (91, 104))	('growth arrest', 'Disease', (91, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (91, 104))	('hTERT', 'Gene', (41, 46))	('p53', 'Gene', '7157', (113, 116))	('p53', 'Gene', (113, 116))	('human', 'Species', '9606', (60, 65))
471160	21942527	Mutation in p53, or other components of the p53 pathway, may then allow for stable expression of EWS-FLI1 and for the growth and survival of those cells.	('survival', 'CPA', (129, 137))	('Mutation', 'Var', (0, 8))	('p53', 'Gene', (12, 15))	('growth', 'CPA', (118, 124))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (44, 47))	('allow', 'Reg', (66, 71))	('p53', 'Gene', '7157', (44, 47))	('expression', 'MPA', (83, 93))	('EWS-FLI1', 'Gene', (97, 105))
471161	21942527	Although mutations in p53 itself are present in only 10% to 15% of Ewing sarcoma cases, other alterations in the p53 pathway (including loss of p14ARF/p16CDKN2A, or amplification of HDM2) may be present in additional cases .	('p53', 'Gene', (113, 116))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('p14ARF', 'Gene', (144, 150))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('p53', 'Gene', (22, 25))	('HDM2', 'Gene', (182, 186))	('HDM2', 'Gene', '4193', (182, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('amplification', 'Var', (165, 178))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', '7157', (113, 116))	('loss', 'NegReg', (136, 140))	('p14ARF', 'Gene', '1029', (144, 150))	('Ewing sarcoma', 'Disease', (67, 80))
471169	21942527	Even with the caveats noted above about the use of murine cells, these studies are consistent with the emerging concept that EWS-FLI1 may inhibit normal differentiation and may induce the so-called Ewing sarcoma phenotype.	('normal differentiation', 'CPA', (146, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (198, 211))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (198, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('EWS-FLI1', 'Var', (125, 133))	('induce', 'Reg', (177, 183))	('Ewing sarcoma', 'Disease', (198, 211))	('inhibit', 'NegReg', (138, 145))	('murine', 'Species', '10090', (51, 57))
471175	21942527	In another series of studies, introduction of EWS-FLI1 into murine MSCs induced oncogenic transformation, whereas introduction of the fusion into human MSCs did not .	('murine', 'Species', '10090', (60, 66))	('human', 'Species', '9606', (146, 151))	('introduction', 'Var', (30, 42))	('induced', 'Reg', (72, 79))	('oncogenic transformation', 'CPA', (80, 104))	('EWS-FLI1', 'Gene', (46, 54))
471178	21942527	The definitive identification of the cell of origin would ultimately allow for a bottom-up approach to modeling Ewing sarcoma, in which EWS-FLI1 and additional alterations could be introduced into those precursor cells and the contributions of each alteration to tumorigenesis could be studied in detail.	('modeling Ewing sarcoma', 'Disease', (103, 125))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('EWS-FLI1', 'Gene', (136, 144))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (112, 125))	('alterations', 'Var', (160, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('tumor', 'Disease', (263, 268))	('modeling Ewing sarcoma', 'Disease', 'MESH:C563168', (103, 125))
471184	21942527	In this approach, investigators begin with patient-derived Ewing sarcoma cells, knock down EWS-FLI1 expression with RNAi, and study the changes that occur following this manipulation (and others).	('knock', 'Var', (80, 85))	('patient', 'Species', '9606', (43, 50))	('EWS-FLI1', 'Gene', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('Ewing sarcoma', 'Disease', (59, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (59, 72))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (59, 72))
471191	21942527	Although this pathway is often considered to be a parallel or complementary pathway to the EWS-FLI1 oncoprotein, EWS-FLI1 itself may regulate the activity of the pathway in Ewing sarcoma.	('EWS-FLI1', 'Var', (113, 121))	('Ewing sarcoma', 'Disease', (173, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('activity', 'MPA', (146, 154))	('regulate', 'Reg', (133, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (173, 186))
471194	21942527	Consistent with this working model, the cell death observed in one model of Ewing sarcoma following EWS-FLI1 knockdown partially depended on IGFBP3 .	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('IGFBP3', 'Gene', (141, 147))	('cell death', 'CPA', (40, 50))	('knockdown', 'Var', (109, 118))	('Ewing sarcoma', 'Disease', (76, 89))	('EWS-FLI1', 'Gene', (100, 108))	('IGFBP3', 'Gene', '3486', (141, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (76, 89))
471254	21942527	This interaction has particular relevance to oncogenesis in Ewing sarcoma because inhibition of this interaction (via a peptide-based inhibitor or a small-molecule inhibitor) induces apoptosis and inhibits xenograft tumor growth of Ewing sarcoma cell lines .	('tumor', 'Disease', (216, 221))	('Ewing sarcoma', 'Disease', (232, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (232, 245))	('inhibition', 'Var', (82, 92))	('induces', 'Reg', (175, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (232, 245))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (60, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('inhibits', 'NegReg', (197, 205))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('apoptosis', 'CPA', (183, 192))	('Ewing sarcoma', 'Disease', (60, 73))
471286	33308312	Unfortunately, unplanned excision in non-referral centers remains a common problem for STS and exposes patients to a higher risk of residual disease and local recurrence (LR).Patients who underwent unplanned excisions have been found to have an overall risk of local recurrence of 34% instead of a 6% risk of those who underwent planned oncological excisions, with a 5-year estimated local recurrence-free survival of 63.7% versus 89.7%.	('STS', 'Phenotype', 'HP:0030448', (87, 90))	('local recurrence', 'CPA', (261, 277))	('Patients', 'Species', '9606', (175, 183))	('unplanned excisions', 'Var', (198, 217))	('patients', 'Species', '9606', (103, 111))
471323	31439678	We identified a high number of genetic alterations within the RAS/RAF/MAPK pathway in 21 of 21 cases, with alterations in NF1 (6 of 21), MAP2K1 (5 of 21), PTPN11 (4 of 21), BRAF (4 of 21), KRAS (4 of 21), NRAS (1 of 21), and LZTR1 (1 of 21), including single cases with homozygous deletion of NF1, high-level amplification of PTPN11, and a novel TTYH3-BRAF fusion.	('KRAS', 'Gene', (189, 193))	('RAF', 'Gene', (66, 69))	('NF1', 'Gene', '4763', (293, 296))	('PTPN11', 'Gene', (326, 332))	('BRAF', 'Gene', '673', (352, 356))	('LZTR1', 'Gene', '8216', (225, 230))	('NRAS', 'Gene', '4893', (205, 209))	('BRAF', 'Gene', (352, 356))	('NF1', 'Gene', (293, 296))	('PTPN11', 'Gene', '5781', (326, 332))	('alterations', 'Var', (107, 118))	('RAS', 'Chemical', 'MESH:D011883', (62, 65))	('RAS', 'Chemical', 'MESH:D011883', (206, 209))	('PTPN11', 'Gene', (155, 161))	('MAP2K1', 'Gene', (137, 143))	('RAF', 'Gene', (174, 177))	('RAS', 'Chemical', 'MESH:D011883', (190, 193))	('RAF', 'Gene', '673;5894', (353, 356))	('TTYH3', 'Gene', (346, 351))	('RAF', 'Gene', '673;5894', (66, 69))	('BRAF', 'Gene', '673', (173, 177))	('NRAS', 'Gene', (205, 209))	('PTPN11', 'Gene', '5781', (155, 161))	('TTYH3', 'Gene', '80727', (346, 351))	('BRAF', 'Gene', (173, 177))	('amplification', 'Var', (309, 322))	('NF1', 'Gene', '4763', (122, 125))	('KRAS', 'Gene', '3845', (189, 193))	('MAP2K1', 'Gene', '5604', (137, 143))	('LZTR1', 'Gene', (225, 230))	('deletion', 'Var', (281, 289))	('NF1', 'Gene', (122, 125))	('RAF', 'Gene', '673;5894', (174, 177))	('RAF', 'Gene', (353, 356))
471324	31439678	Concurrent NF1 and PTPN11 mutations were present in 3 of 21 cases, and 5 of 7 cases with alterations in NF1 and/or PTPN11 had disease involving the gastrointestinal tract.	('present', 'Reg', (41, 48))	('PTPN11', 'Gene', '5781', (19, 25))	('disease involving the gastrointestinal tract', 'Phenotype', 'HP:0011024', (126, 170))	('PTPN11', 'Gene', '5781', (115, 121))	('mutations', 'Var', (26, 35))	('NF1', 'Gene', (11, 14))	('PTPN11', 'Gene', (115, 121))	('NF1', 'Gene', (104, 107))	('alterations', 'Var', (89, 100))	('NF1', 'Gene', '4763', (11, 14))	('NF1', 'Gene', '4763', (104, 107))	('PTPN11', 'Gene', (19, 25))
471325	31439678	Following unsupervised clustering of gene expression data, cases with NF1 and/or PTPN11 abnormalities formed a distinct tumor subgroup.	('PTPN11', 'Gene', (81, 87))	('NF1', 'Gene', '4763', (70, 73))	('clusterin', 'Gene', '1191', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('abnormalities', 'Var', (88, 101))	('clusterin', 'Gene', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('PTPN11', 'Gene', '5781', (81, 87))	('NF1', 'Gene', (70, 73))	('tumor', 'Disease', (120, 125))
471326	31439678	A subset of NF1/PTPN11 wild-type cases had frequent mutations in B-cell lymphoma associated genes and/or clonal IG gene rearrangements.	('mutations', 'Var', (52, 61))	('B-cell lymphoma', 'Disease', (65, 80))	('NF1', 'Gene', (12, 15))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (65, 80))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (65, 80))	('NF1', 'Gene', '4763', (12, 15))	('IG gene', 'Gene', (112, 119))	('PTPN11', 'Gene', '5781', (16, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))	('PTPN11', 'Gene', (16, 22))
471327	31439678	Our findings expand the current understanding of the molecular pathogenesis of this rare tumor and suggest the existence of a distinct subtype of primary histiocytic sarcoma characterized by NF1/PTPN11 alterations with predilection for the gastrointestinal tract.	('histiocytic sarcoma', 'Disease', (154, 173))	('PTPN11', 'Gene', (195, 201))	('NF1', 'Gene', (191, 194))	('NF1', 'Gene', '4763', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (154, 173))	('alterations', 'Var', (202, 213))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('PTPN11', 'Gene', '5781', (195, 201))
471338	31439678	BRAF p.V600E mutations have been reported in approximately 12% of 108 published cases with molecular or immunohistochemical data, and additional alterations in members of the RAS/MAPK and PI3K/AKT pathways, including other BRAF variants, KRAS, HRAS, NRAS, MAP2K1, PIK3CA, PTPN11 and PTEN are also described (see Online Supplementary Tables S1 and S2 for a complete list of references).	('AKT', 'Gene', '207', (193, 196))	('HRAS', 'Gene', (244, 248))	('NRAS', 'Gene', (250, 254))	('PTEN', 'Gene', (283, 287))	('BRAF', 'Gene', '673', (223, 227))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (223, 227))	('BRAF', 'Gene', (0, 4))	('PIK3CA', 'Gene', '5290', (264, 270))	('RAS', 'Chemical', 'MESH:D011883', (239, 242))	('p.V600E', 'Mutation', 'rs113488022', (5, 12))	('RAS', 'Chemical', 'MESH:D011883', (175, 178))	('p.V600E', 'Var', (5, 12))	('PTEN', 'Gene', '5728', (283, 287))	('RAS', 'Chemical', 'MESH:D011883', (245, 248))	('alterations', 'Reg', (145, 156))	('RAS', 'Chemical', 'MESH:D011883', (251, 254))	('PTPN11', 'Gene', (272, 278))	('AKT', 'Gene', (193, 196))	('PIK3CA', 'Gene', (264, 270))	('KRAS', 'Gene', '3845', (238, 242))	('NRAS', 'Gene', '4893', (250, 254))	('PTPN11', 'Gene', '5781', (272, 278))	('MAP2K1', 'Gene', '5604', (256, 262))	('KRAS', 'Gene', (238, 242))	('MAP2K1', 'Gene', (256, 262))	('HRAS', 'Gene', '3265', (244, 248))
471343	31439678	Alignment and variant calling were performed following the Center for Cancer Research Collaborative Bioinformatics Resource (CCBR) pipeline (https://github.com/CCBR/Pipeliner) as described in the Online Supplementary Methods.	('Cancer', 'Disease', (70, 76))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('variant', 'Var', (14, 21))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))
471346	31439678	Multiple and occasionally concurrent mutations involving genes of the RAS/MAPK pathway (Figure 2, Online Supplementary Table S4 and Online Supplementary Figure S2) were identified in 19 of the 21 cases.	('RAS/MAPK pathway', 'Pathway', (70, 86))	('mutations', 'Var', (37, 46))	('identified', 'Reg', (169, 179))	('RAS', 'Chemical', 'MESH:D011883', (70, 73))
471347	31439678	The most frequently mutated RAS/MAPK pathway genes were NF1 and MAP2K1 (5 cases each).	('RAS/MAPK pathway', 'Pathway', (28, 44))	('NF1', 'Gene', '4763', (56, 59))	('MAP2K1', 'Gene', '5604', (64, 70))	('RAS', 'Chemical', 'MESH:D011883', (28, 31))	('MAP2K1', 'Gene', (64, 70))	('NF1', 'Gene', (56, 59))	('mutated', 'Var', (20, 27))
471348	31439678	Interestingly, 4 of 5 cases with NF1 mutations involved the GI tract, although one biopsy sequenced was a supraclavicular lymph node.	('GI tract', 'Disease', (60, 68))	('NF1', 'Gene', (33, 36))	('involved', 'Reg', (47, 55))	('NF1', 'Gene', '4763', (33, 36))	('mutations', 'Var', (37, 46))
471349	31439678	Three of the cases had a single NF1 mutation (p.Q1822* [His01]; p.V1182D [His02]; p.Q1086* [His16]), whereas the other two had two mutations each (p.R304* and p.Q1775* [His12]; p.L298* and p.K660fs [His17]).	('p.Q1822* [', 'Var', (46, 56))	('His12', 'Chemical', '-', (169, 174))	('His17', 'Chemical', '-', (199, 204))	('p.Q1775* [His12', 'Var', (159, 174))	('NF1', 'Gene', (32, 35))	('p.L298*', 'Var', (177, 184))	('p.Q1822*', 'Mutation', 'p.Q1822*', (46, 54))	('p.Q1086*', 'Mutation', 'p.Q1086*', (82, 90))	('NF1', 'Gene', '4763', (32, 35))	('His02', 'Chemical', '-', (74, 79))	('p.K660fs [', 'Var', (189, 199))	('p.L298*', 'Mutation', 'p.L298*', (177, 184))	('p.K660fs', 'Mutation', 'p.K660fsX', (189, 197))	('p.V1182D', 'Mutation', 'p.V1182D', (64, 72))	('p.V1182D [His02]; p.Q1086* [His16', 'Var', (64, 97))	('p.R304*', 'Var', (147, 154))	('p.Q1775*', 'Mutation', 'p.Q1775*', (159, 167))	('p.R304*', 'Mutation', 'p.R304*', (147, 154))
471351	31439678	In addition to NF1 mutations, 3 of the 5 cases showed concurrent mutations in PTPN11 (p.F71V [His01]; p.E76G [His02]; p.A72V [His12]).	('p.A72V', 'Mutation', 'rs121918454', (118, 124))	('NF1', 'Gene', (15, 18))	('PTPN11', 'Gene', (78, 84))	('His12', 'Chemical', '-', (126, 131))	('NF1', 'Gene', '4763', (15, 18))	('His02', 'Chemical', '-', (110, 115))	('p.F71V', 'Mutation', 'rs397507512', (86, 92))	('PTPN11', 'Gene', '5781', (78, 84))	('p.F71V [His01]; p.E76G [His02]; p.A72V [His12]', 'Var', (86, 132))	('p.E76G', 'Mutation', 'rs121918465', (102, 108))
471352	31439678	PTPN11 mutations were present within the autoinhibitory N-SH2 domain at amino acid residues known to be associated with a gain-of-function consequence and described in Noonan syndrome and juvenile myelomonocytic leukemia (JMML).	('leukemia', 'Phenotype', 'HP:0001909', (212, 220))	('juvenile myelomonocytic leukemia', 'Disease', 'MESH:D054429', (188, 220))	('PTPN11', 'Gene', '5781', (0, 6))	('JMML', 'Disease', (222, 226))	('Noonan syndrome', 'Disease', (168, 183))	('PTPN11', 'Gene', (0, 6))	('Noonan syndrome', 'Disease', 'MESH:D009634', (168, 183))	('JMML', 'Phenotype', 'HP:0012209', (222, 226))	('juvenile myelomonocytic leukemia', 'Disease', (188, 220))	('JMML', 'Disease', 'MESH:D054429', (222, 226))	('juvenile myelomonocytic leukemia', 'Phenotype', 'HP:0012209', (188, 220))	('mutations', 'Var', (7, 16))
471353	31439678	One case without a PTPN11 mutation [His17] had an additional mutation in GNAI2 at p.R179H, a codon previously shown to be targeted by activating mutations and 1 of the 5 NF1 mutated cases also had a mutation in JAK2 at p.V617F [His12].	('His12', 'Chemical', '-', (228, 233))	('GNAI2', 'Gene', '2771', (73, 78))	('NF1', 'Gene', (170, 173))	('JAK2', 'Gene', (211, 215))	('p.R179H', 'Var', (82, 89))	('NF1', 'Gene', '4763', (170, 173))	('GNAI2', 'Gene', (73, 78))	('PTPN11', 'Gene', '5781', (19, 25))	('p.V617F', 'Mutation', 'rs77375493', (219, 226))	('His17', 'Chemical', '-', (36, 41))	('p.V617F [His12', 'Var', (219, 233))	('JAK2', 'Gene', '3717', (211, 215))	('p.R179H', 'Mutation', 'rs137853227', (82, 89))	('PTPN11', 'Gene', (19, 25))
471354	31439678	A fourth PTPN11 mutated case at p.E76K [His18] did not have another RAS pathway mutation; however, it had high level amplification of the mutated PTPN11 allele (see below).	('p.E76K [', 'Var', (32, 40))	('His18', 'Chemical', '-', (40, 45))	('RAS', 'Chemical', 'MESH:D011883', (68, 71))	('PTPN11', 'Gene', '5781', (9, 15))	('amplification', 'MPA', (117, 130))	('PTPN11', 'Gene', (9, 15))	('PTPN11', 'Gene', '5781', (146, 152))	('p.E76K', 'Mutation', 'rs121918464', (32, 38))	('PTPN11', 'Gene', (146, 152))
471355	31439678	Additional mutations involving the RAS/MAPK pathway were detected in another 13 cases, none of which had NF1 or PTPN11 mutations.	('PTPN11', 'Gene', (112, 118))	('mutations', 'Var', (11, 20))	('NF1', 'Gene', (105, 108))	('NF1', 'Gene', '4763', (105, 108))	('PTPN11', 'Gene', '5781', (112, 118))	('RAS', 'Chemical', 'MESH:D011883', (35, 38))	('detected', 'Reg', (57, 65))	('mutations', 'Var', (119, 128))	('RAS/MAPK pathway', 'Pathway', (35, 51))
471356	31439678	MAP2K1 mutations were present in five cases and involved known hotspot regions in exons 2 and 3, the negative regulatory region (p.F53L [His10, His14]; p.K57E [His05]) and the catalytic core domain (p.I103N [His14]; p.C121S [His08, His11]).	('MAP2K1', 'Gene', (0, 6))	('p.K57E', 'Mutation', 'rs397516790', (152, 158))	('p.F53L [His10', 'Var', (129, 142))	('His10', 'Chemical', '-', (137, 142))	('p.I103N', 'Mutation', 'rs730880502', (199, 206))	('p.F53L', 'Mutation', 'rs1057519728', (129, 135))	('p.I103N [His14]; p.C121S [His08', 'Var', (199, 230))	('involved', 'Reg', (48, 56))	('His14', 'Chemical', '-', (208, 213))	('p.C121S', 'Mutation', 'rs1057519731', (216, 223))	('MAP2K1', 'Gene', '5604', (0, 6))	('p.K57E [His05]', 'Var', (152, 166))	('His14', 'Chemical', '-', (144, 149))	('mutations', 'Var', (7, 16))
471357	31439678	As well as the mutation at p.C121S, case [His11] had two additional MAP2K1 mutations at p.Y125C and p.R181K.	('p.R181K', 'Mutation', 'p.R181K', (100, 107))	('MAP2K1', 'Gene', '5604', (68, 74))	('p.Y125C', 'Mutation', 'p.Y125C', (88, 95))	('p.R181K', 'Var', (100, 107))	('p.C121S', 'Mutation', 'rs1057519731', (27, 34))	('MAP2K1', 'Gene', (68, 74))
471358	31439678	The functional consequences of these mutations are not known; however, the p.Y125C substitution also involved the catalytic core domain in the same allele as the pathogenic p.C121S mutation.	('p.Y125C', 'Mutation', 'p.Y125C', (75, 82))	('catalytic core domain', 'MPA', (114, 135))	('involved', 'Reg', (101, 109))	('p.Y125C', 'Var', (75, 82))	('p.C121S', 'Mutation', 'rs1057519731', (173, 180))	('p.C121S', 'Var', (173, 180))
471359	31439678	One case with a MAP2K1 mutation had a co-occurring non-canonical BRAF mutation (p.G469V [His10]) and two additional cases had BRAF p.V600E [His04 and His15] mutations.	('His10', 'Chemical', '-', (89, 94))	('His04', 'Chemical', '-', (140, 145))	('MAP2K1', 'Gene', '5604', (16, 22))	('mutation', 'Var', (23, 31))	('p.G469V', 'Mutation', 'rs121913355', (80, 87))	('BRAF', 'Gene', (126, 130))	('MAP2K1', 'Gene', (16, 22))	('BRAF', 'Gene', '673', (65, 69))	('BRAF', 'Gene', '673', (126, 130))	('BRAF', 'Gene', (65, 69))	('p.G469V [His10]', 'Var', (80, 95))	('p.V600E', 'Mutation', 'rs113488022', (131, 138))
471360	31439678	Pathogenic KRAS mutations were detected in four cases (p.G12D [His21]; p.G12C [His09]; p.Q61H [His07] and p.A146V [His20]), one of which, [His21] also had a mutation in RAF1 (p.D486G).	('p.D486G', 'Var', (175, 182))	('p.G12D [His21]; p.G12C [His09]; p.Q61H [His07]', 'Var', (55, 101))	('His21', 'Chemical', '-', (63, 68))	('p.Q61H', 'Mutation', 'rs17851045', (87, 93))	('His07', 'Chemical', '-', (95, 100))	('p.G12D', 'Mutation', 'rs121913529', (55, 61))	('KRAS', 'Gene', '3845', (11, 15))	('His20', 'Chemical', '-', (115, 120))	('p.A146V', 'Mutation', 'rs1057519725', (106, 113))	('RAF1', 'Gene', '5894', (169, 173))	('His09', 'Chemical', '-', (79, 84))	('KRAS', 'Gene', (11, 15))	('[His21]', 'Var', (138, 145))	('p.A146V [His20]', 'Var', (106, 121))	('p.D486G', 'Mutation', 'rs397516815', (175, 182))	('RAF1', 'Gene', (169, 173))	('detected', 'Reg', (31, 39))	('p.G12C', 'Mutation', 'rs121913530', (71, 77))	('Pathogenic', 'Reg', (0, 10))	('His21', 'Chemical', '-', (139, 144))
471361	31439678	A single case had an NRAS mutation at p.Q61R [His19].	('NRAS', 'Gene', '4893', (21, 25))	('NRAS', 'Gene', (21, 25))	('p.Q61R', 'Mutation', 'rs11554290', (38, 44))	('p.Q61R [', 'Var', (38, 46))
471362	31439678	Finally, a mutation in LZTR1 (p.R118H) was identified in case [His13].	('LZTR1', 'Gene', '8216', (23, 28))	('p.R118H', 'Var', (30, 37))	('LZTR1', 'Gene', (23, 28))	('p.R118H', 'Mutation', 'rs769001939', (30, 37))
471364	31439678	Mutations in LZTR1 have recently been shown to dysregulate RAS ubiquitination leading to increased RAS activity.	('dysregulate', 'Reg', (47, 58))	('RAS', 'Chemical', 'MESH:D011883', (99, 102))	('RAS', 'Protein', (59, 62))	('RAS', 'Chemical', 'MESH:D011883', (59, 62))	('Mutations', 'Var', (0, 9))	('RAS activity', 'MPA', (99, 111))	('increased', 'PosReg', (89, 98))	('LZTR1', 'Gene', '8216', (13, 18))	('LZTR1', 'Gene', (13, 18))
471365	31439678	The p.R118H mutation affects a conserved residue in the Kelch domain and is reported once in the COSMIC database.	('p.R118H', 'Var', (4, 11))	('conserved residue in the Kelch domain', 'MPA', (31, 68))	('affects', 'Reg', (21, 28))	('p.R118H', 'Mutation', 'rs769001939', (4, 11))
471366	31439678	Mutations in LZTR1 are not typically associated with histiocytic tumors.	('histiocytic tumors', 'Disease', 'MESH:D015620', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (37, 47))	('LZTR1', 'Gene', '8216', (13, 18))	('LZTR1', 'Gene', (13, 18))	('histiocytic tumors', 'Disease', (53, 71))
471368	31439678	Mutations involving the PI3K pathway were identified in four cases, including two with KRAS mutations and two with NF1 alterations, with mutations identified in PTEN (p.Q171* [His16]; p.D24H and c.79+1G>C [His20] and p.L140* [His21]), PIK3CD (p.E1021K [His20]) and MTOR (p.I2501F [His03]).	('PI3K pathway', 'Pathway', (24, 36))	('c.79+1G>C', 'Mutation', 'c.79+1G>C', (195, 204))	('His20', 'Chemical', '-', (253, 258))	('p.D24H', 'Var', (184, 190))	('p.D24H', 'Mutation', 'rs786201995', (184, 190))	('His20', 'Chemical', '-', (206, 211))	('p.E1021K', 'Mutation', 'rs397518423', (243, 251))	('MTOR', 'Gene', (265, 269))	('PIK3CD', 'Gene', '5293', (235, 241))	('p.Q171*', 'Mutation', 'p.Q171*', (167, 174))	('MTOR', 'Gene', '2475', (265, 269))	('p.Q171* [His16]; p.D24H', 'Var', (167, 190))	('PTEN', 'Gene', (161, 165))	('PIK3CD', 'Gene', (235, 241))	('KRAS', 'Gene', '3845', (87, 91))	('NF1', 'Gene', '4763', (115, 118))	('p.L140*', 'Mutation', 'p.L140*', (217, 224))	('p.L140* [His21]', 'Var', (217, 232))	('c.79+1G>C [His20]', 'Var', (195, 212))	('p.I2501F [His03]', 'Var', (271, 287))	('His21', 'Chemical', '-', (226, 231))	('PTEN', 'Gene', '5728', (161, 165))	('p.E1021K [His20]', 'Var', (243, 259))	('KRAS', 'Gene', (87, 91))	('NF1', 'Gene', (115, 118))	('p.I2501F', 'Mutation', 'p.I2501F', (271, 279))
471369	31439678	Additional mutations in genes previously reported to be mutated in B-cell lymphomas were detected in SGK1 (p.R285K, p.I238T, p.H237Y, p.K213R and p.P147S [His07]; p.E162G and p.K136R [His14]; p.Q125H [His20]; c.437+1G>A and c.362-1G>A [His21]), NOTCH2 (p.I2304fs [His20]), DTX1 (p.W37* [His04]), TNFRSF14 (p.T169fs [His21]), CARD11 (p.R179Q [His21]), NFKBIE (p.L410fs [His20]), GNA13 (p.F4V [His08]), POT1 (p.R273W [His14]) and BCL2 (p.E136D [His10]).	('p.P147S', 'Mutation', 'rs935610270', (146, 153))	('SGK1', 'Gene', '6446', (101, 105))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (67, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('p.W37*', 'Mutation', 'p.W37*', (279, 285))	('p.T169fs [His21]', 'Var', (306, 322))	('DTX1', 'Gene', '1840', (273, 277))	('p.K213R', 'Mutation', 'p.K213R', (134, 141))	('His21', 'Chemical', '-', (342, 347))	('p.I2304fs', 'Mutation', 'rs771237928', (253, 262))	('NOTCH2', 'Gene', (245, 251))	('p.R273W [His14', 'Var', (407, 421))	('SGK1', 'Gene', (101, 105))	('p.Q125H', 'Mutation', 'rs1170253783', (192, 199))	('p.F4V [His08]', 'Var', (385, 398))	('p.W37', 'Var', (279, 284))	('p.R285K', 'Mutation', 'p.R285K', (107, 114))	('CARD11', 'Gene', (325, 331))	('p.I238T', 'Mutation', 'rs949959358', (116, 123))	('POT1', 'Gene', '25913', (401, 405))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (67, 82))	('DTX1', 'Gene', (273, 277))	('lymphomas', 'Phenotype', 'HP:0002665', (74, 83))	('His20', 'Chemical', '-', (369, 374))	('p.R273W', 'Mutation', 'p.R273W', (407, 414))	('p.L410fs', 'Mutation', 'p.L410fsX', (359, 367))	('His14', 'Chemical', '-', (416, 421))	('His04', 'Chemical', '-', (287, 292))	('p.R179Q', 'Mutation', 'p.R179Q', (333, 340))	('His21', 'Chemical', '-', (316, 321))	('His10', 'Chemical', '-', (443, 448))	('CARD11', 'Gene', '84433', (325, 331))	('His20', 'Chemical', '-', (264, 269))	('His14', 'Chemical', '-', (184, 189))	('GNA13', 'Gene', '10672', (378, 383))	('POT1', 'Gene', (401, 405))	('BCL2', 'Gene', '596', (428, 432))	('NFKBIE', 'Gene', '4794', (351, 357))	('p.L410fs [His20]', 'Var', (359, 375))	('p.K136R', 'Mutation', 'p.K136R', (175, 182))	('His21', 'Chemical', '-', (236, 241))	('NFKBIE', 'Gene', (351, 357))	('His07', 'Chemical', '-', (155, 160))	('c.437+1G>A', 'Mutation', 'c.437+1G>A', (209, 219))	('p.R179Q [His21]', 'Var', (333, 348))	('His20', 'Chemical', '-', (201, 206))	('NOTCH2', 'Gene', '4853', (245, 251))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (67, 83))	('B-cell lymphomas', 'Disease', (67, 83))	('c.362-1G>A', 'Mutation', 'rs186450029', (224, 234))	('p.T169fs', 'Mutation', 'p.T169fsX', (306, 314))	('p.H237Y', 'Mutation', 'p.H237Y', (125, 132))	('TNFRSF14', 'Gene', '8764', (296, 304))	('p.E136D', 'Mutation', 'p.E136D', (434, 441))	('TNFRSF14', 'Gene', (296, 304))	('p.E162G', 'Mutation', 'p.E162G', (163, 170))	('p.F4V', 'Mutation', 'p.F4V', (385, 390))	('BCL2', 'Gene', (428, 432))	('GNA13', 'Gene', (378, 383))
471370	31439678	In addition to mutations in the signaling pathways described above, mutations in epigenetic modifiers and/or transcription factors were detected in eight cases, including five with SETD2 mutations (c.7432-2A>C [His01]; p.V1820E [His02]; p.P132fs [His03]; c.4715+1G>T [His17] and c.7432-1G>A [His18]), two with ARID1A mutations (p.L2011fs [His10] and p.G2087R [His20]) and single cases with CREBBP (p.Y1433C [His10]), KMT2D (p.E2225fs and p.K1752fs [His20]), DDX3X (p.V206M [His20]), POU2AF1 (c.16+2T>G [His20]), IKZF3 (p.L162R [His10]), STAT6 (p.D419G [His10]) and MEF2B (p.R64H [His19]) mutations.	('His10', 'Chemical', '-', (408, 413))	('His10', 'Chemical', '-', (528, 533))	('c.16+2T>G [His20]', 'Var', (492, 509))	('p.K1752fs', 'Mutation', 'p.K1752fsX', (438, 447))	('p.V1820E', 'Mutation', 'p.V1820E', (219, 227))	('His20', 'Chemical', '-', (474, 479))	('c.16+2T>G', 'Mutation', 'c.16+2T>G', (492, 501))	('p.E2225fs', 'Var', (424, 433))	('His02', 'Chemical', '-', (229, 234))	('p.R64H [His19', 'Var', (572, 585))	('c.4715+1G>T', 'Mutation', 'c.4715+1G>T', (255, 266))	('KMT2D', 'Gene', '8085', (417, 422))	('DDX3X', 'Gene', (458, 463))	('p.L162R', 'Mutation', 'rs775825971', (519, 526))	('POU2AF1', 'Gene', '5450', (483, 490))	('p.E2225fs', 'Mutation', 'p.E2225fsX', (424, 433))	('IKZF3', 'Gene', '22806', (512, 517))	('MEF2B', 'Gene', '100271849', (565, 570))	('p.R64H', 'Mutation', 'rs371035718', (572, 578))	('ARID1A', 'Gene', (310, 316))	('p.D419G [His10]', 'Var', (544, 559))	('p.D419G', 'Mutation', 'p.D419G', (544, 551))	('p.L2011fs [His10]', 'Var', (328, 345))	('His20', 'Chemical', '-', (449, 454))	('CREBBP', 'Gene', (390, 396))	('His20', 'Chemical', '-', (503, 508))	('His10', 'Chemical', '-', (553, 558))	('STAT6', 'Gene', (537, 542))	('His20', 'Chemical', '-', (360, 365))	('His18', 'Chemical', '-', (292, 297))	('p.P132fs', 'Mutation', 'p.P132fsX', (237, 245))	('ARID1A', 'Gene', '8289', (310, 316))	('SETD2', 'Gene', (181, 186))	('p.L2011fs', 'Mutation', 'p.L2011fsX', (328, 337))	('DDX3X', 'Gene', '1654', (458, 463))	('MEF2B', 'Gene', (565, 570))	('p.L162R [His10]', 'Var', (519, 534))	('His10', 'Chemical', '-', (339, 344))	('His17', 'Chemical', '-', (268, 273))	('IKZF3', 'Gene', (512, 517))	('c.7432-1G>A', 'Mutation', 'rs777018406', (279, 290))	('KMT2D', 'Gene', (417, 422))	('SETD2', 'Gene', '29072', (181, 186))	('p.G2087R', 'Mutation', 'p.G2087R', (350, 358))	('STAT6', 'Gene', '6778', (537, 542))	('p.K1752fs [His20', 'Var', (438, 454))	('POU2AF1', 'Gene', (483, 490))	('p.Y1433C [', 'Var', (398, 408))	('p.V206M', 'Mutation', 'p.V206M', (465, 472))	('CREBBP', 'Gene', '1387', (390, 396))	('p.Y1433C', 'Mutation', 'p.Y1433C', (398, 406))	('c.7432-2A>C', 'Mutation', 'c.7432-2A>C', (198, 209))
471371	31439678	SETD2 mutations were exclusive to the NF1/PTPN11 mutated group, including one case found to have homozygous deletion of NF1 and one case with PTPN11 gene amplification (both described below), while the ARID1A, CREBBP, KMT2D, DDX3X, IKZF3, STAT6 and MEF2B mutations were present in the NF1/PTPN11 wild-type group.	('ARID1A', 'Gene', (202, 208))	('NF1', 'Gene', (120, 123))	('MEF2B', 'Gene', '100271849', (249, 254))	('CREBBP', 'Gene', (210, 216))	('NF1', 'Gene', (285, 288))	('IKZF3', 'Gene', (232, 237))	('PTPN11', 'Gene', (142, 148))	('STAT6', 'Gene', '6778', (239, 244))	('NF1', 'Gene', '4763', (38, 41))	('ARID1A', 'Gene', '8289', (202, 208))	('KMT2D', 'Gene', '8085', (218, 223))	('PTPN11', 'Gene', '5781', (142, 148))	('SETD2', 'Gene', (0, 5))	('NF1', 'Gene', (38, 41))	('mutations', 'Var', (6, 15))	('deletion', 'Var', (108, 116))	('MEF2B', 'Gene', (249, 254))	('DDX3X', 'Gene', (225, 230))	('CREBBP', 'Gene', '1387', (210, 216))	('SETD2', 'Gene', '29072', (0, 5))	('PTPN11', 'Gene', (42, 48))	('PTPN11', 'Gene', (289, 295))	('IKZF3', 'Gene', '22806', (232, 237))	('PTPN11', 'Gene', '5781', (42, 48))	('KMT2D', 'Gene', (218, 223))	('PTPN11', 'Gene', '5781', (289, 295))	('STAT6', 'Gene', (239, 244))	('DDX3X', 'Gene', '1654', (225, 230))	('NF1', 'Gene', '4763', (120, 123))	('NF1', 'Gene', '4763', (285, 288))
471372	31439678	Known pathogenic mutations in TP53 were identified in 2 of 21 cases (p.G245S [His07]; p.R175H [His16]).	('His07', 'Chemical', '-', (78, 83))	('p.G245S', 'Mutation', 'rs28934575', (69, 76))	('TP53', 'Gene', (30, 34))	('p.G245S [His07]; p.R175H [His16', 'Var', (69, 100))	('p.R175H', 'Mutation', 'rs28934578', (86, 93))	('TP53', 'Gene', '7157', (30, 34))
471373	31439678	A homozygous deletion in the NF1 gene was identified in an additional case [His03] from a lymph node and confirmed using a fluorescence in situ hybridization (FISH) probe targeting the deleted area.	('deletion', 'Var', (13, 21))	('NF1', 'Gene', '4763', (29, 32))	('NF1', 'Gene', (29, 32))
471375	31439678	The three cases with a single NF1 mutation [His01, His02 and His16] showed loss-of-heterozygosity (LOH) or copy number loss involving chromosome 17 including the NF1 gene.	('NF1', 'Gene', (162, 165))	('copy number loss', 'Var', (107, 123))	('NF1', 'Gene', (30, 33))	('NF1', 'Gene', '4763', (162, 165))	('NF1', 'Gene', '4763', (30, 33))	('His02', 'Chemical', '-', (51, 56))	('loss-of-heterozygosity', 'NegReg', (75, 97))
471377	31439678	This case harbored a known variant in the N-SH2 domain (p.E76K) of the amplified PTPN11 allele.	('PTPN11', 'Gene', (81, 87))	('p.E76K', 'Mutation', 'rs121918464', (56, 62))	('p.E76K', 'Var', (56, 62))	('PTPN11', 'Gene', '5781', (81, 87))
471382	31439678	Cases with NF1/PTPN11 alterations had associated losses or LOH of chromosome 10 or 10q and chromosome 17 or 17p in 3 of 5 cases assessed by OncoScan [His01, His02, His12] and confirmed by FISH in two cases (Online Supplementary Figure S3A-C).	('PTPN11', 'Gene', (15, 21))	('His02', 'Chemical', '-', (157, 162))	('His12', 'Chemical', '-', (164, 169))	('LOH', 'NegReg', (59, 62))	('alterations', 'Var', (22, 33))	('PTPN11', 'Gene', '5781', (15, 21))	('NF1', 'Gene', (11, 14))	('NF1', 'Gene', '4763', (11, 14))	('losses', 'NegReg', (49, 55))
471383	31439678	Focal CDKN2A losses were present by OncoScan or confirmed by FISH in six cases that were NF1/PTPN11 wild-type [His05, His06, His10, His15, His19, His20] and included five cases with homozygous deletion [His05, His06, His10, His19, His20].	('His10', 'Chemical', '-', (217, 222))	('His06', 'Var', (210, 215))	('His20', 'Chemical', '-', (146, 151))	('PTPN11', 'Gene', '5781', (93, 99))	('NF1', 'Gene', (89, 92))	('CDKN2A', 'Gene', (6, 12))	('His10', 'Chemical', '-', (125, 130))	('NF1', 'Gene', '4763', (89, 92))	('His10', 'Var', (217, 222))	('His19', 'Var', (224, 229))	('His20]', 'Var', (146, 152))	('losses', 'NegReg', (13, 19))	('His20', 'Chemical', '-', (231, 236))	('His20]', 'Var', (231, 237))	('His10', 'Var', (125, 130))	('PTPN11', 'Gene', (93, 99))	('CDKN2A', 'Gene', '1029', (6, 12))
471384	31439678	Both TP53 mutated cases had LOH involving the gene, with one NF1 mutated case [His16, not assessed by OncoScan] showing a near-haploid genome with loss of chromosome 17 and the second case [His07] showing LOH at chromosome 17p.	('mutated', 'Var', (10, 17))	('LOH', 'Var', (28, 31))	('NF1', 'Gene', (61, 64))	('NF1', 'Gene', '4763', (61, 64))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('loss', 'NegReg', (147, 151))	('His07', 'Chemical', '-', (190, 195))
471392	31439678	Re-clustering segregated the remaining samples into three groups: normal controls (4 samples), cases with NF1 or PTPN11 abnormalities (5 samples), and a third heterogeneous group comprising NF1/PTPN11 wild-type cases (9 samples) (Figure 5).	('clusterin', 'Gene', (3, 12))	('PTPN11', 'Gene', (113, 119))	('NF1', 'Gene', (190, 193))	('PTPN11', 'Gene', '5781', (113, 119))	('NF1', 'Gene', '4763', (190, 193))	('NF1', 'Gene', (106, 109))	('PTPN11', 'Gene', '5781', (194, 200))	('NF1', 'Gene', '4763', (106, 109))	('PTPN11', 'Gene', (194, 200))	('clusterin', 'Gene', '1191', (3, 12))	('abnormalities', 'Var', (120, 133))
471401	31439678	Five cases had clonal rearrangement of the IGH and/or the IGK locus [His04, His10, His14, His20, His21], while two cases (including one with IG rearrangement) showed rearrangements of the TRG locus [His13, His20].	('[His13', 'Var', (198, 204))	('His21', 'Chemical', '-', (97, 102))	('His20', 'Var', (90, 95))	('[His04', 'Var', (68, 74))	('TRG', 'Gene', (188, 191))	('IGK', 'Gene', (58, 61))	('His10', 'Chemical', '-', (76, 81))	('His14', 'Var', (83, 88))	('IGH', 'Gene', (43, 46))	('IGH', 'Gene', '3492', (43, 46))	('His20', 'Chemical', '-', (206, 211))	('IGK', 'Gene', '50802', (58, 61))	('His20', 'Chemical', '-', (90, 95))	('His04', 'Chemical', '-', (69, 74))	('TRG', 'Gene', '6965', (188, 191))	('His14', 'Chemical', '-', (83, 88))
471403	31439678	All five clonally rearranged cases for IG were NF1/PTPN11 wild-type and all had additional mutations in transcriptional regulators and/or signaling pathway genes previously reported altered in B-cell lymphoma (see above).	('altered', 'Reg', (182, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (200, 208))	('signaling pathway genes', 'Gene', (138, 161))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (193, 208))	('PTPN11', 'Gene', '5781', (51, 57))	('NF1', 'Gene', (47, 50))	('B-cell lymphoma', 'Disease', (193, 208))	('mutations', 'Var', (91, 100))	('NF1', 'Gene', '4763', (47, 50))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (193, 208))	('PTPN11', 'Gene', (51, 57))
471404	31439678	Three additional cases in the NF1/PTPN11 wild-type group had at least one B-cell associated gene mutation [His07, His08 and His19].	('PTPN11', 'Gene', '5781', (34, 40))	('[His07', 'Var', (106, 112))	('NF1', 'Gene', (30, 33))	('PTPN11', 'Gene', (34, 40))	('NF1', 'Gene', '4763', (30, 33))	('His08', 'Var', (114, 119))	('His07', 'Chemical', '-', (107, 112))	('His19]', 'Var', (124, 130))
471406	31439678	In total, 8 of the 14 cases in the NF1/PTPN11 wild-type subgroup had clonal IG gene rearrangements or mutations in genes reported to be mutated in B-cell lymphomas (Figure 2).	('PTPN11', 'Gene', (39, 45))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (147, 162))	('IG gene', 'Gene', (76, 83))	('lymphomas', 'Phenotype', 'HP:0002665', (154, 163))	('lymphoma', 'Phenotype', 'HP:0002665', (154, 162))	('PTPN11', 'Gene', '5781', (39, 45))	('mutations', 'Var', (102, 111))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (147, 163))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (147, 163))	('B-cell lymphomas', 'Disease', (147, 163))	('NF1', 'Gene', (35, 38))	('NF1', 'Gene', '4763', (35, 38))
471408	31439678	Moreover, it identifies two molecular subgroups based on the presence or absence of NF1/PTPN11 alterations and prevalence of SETD2 mutations, and independently through unsupervised clustering of RNA-Seq data.	('PTPN11', 'Gene', (88, 94))	('mutations', 'Var', (131, 140))	('absence', 'NegReg', (73, 80))	('NF1', 'Gene', (84, 87))	('PTPN11', 'Gene', '5781', (88, 94))	('NF1', 'Gene', '4763', (84, 87))	('alterations', 'Var', (95, 106))	('SETD2', 'Gene', '29072', (125, 130))	('clusterin', 'Gene', (181, 190))	('clusterin', 'Gene', '1191', (181, 190))	('SETD2', 'Gene', (125, 130))
471413	31439678	The majority of the NF1/PTPN11 mutant cases had more than one MAPK pathway activating mutation.	('mutant', 'Var', (31, 37))	('PTPN11', 'Gene', '5781', (24, 30))	('MAPK pathway', 'Pathway', (62, 74))	('PTPN11', 'Gene', (24, 30))	('NF1', 'Gene', (20, 23))	('NF1', 'Gene', '4763', (20, 23))
471414	31439678	Three of the seven cases had co-occurring NF1 and PTPN11 mutations, while a fourth case had a co-occurring mutation in GNAI2 involving a codon previously shown to activate the MAPK pathway.	('PTPN11', 'Gene', (50, 56))	('GNAI2', 'Gene', (119, 124))	('MAPK pathway', 'Pathway', (176, 188))	('GNAI2', 'Gene', '2771', (119, 124))	('mutations', 'Var', (57, 66))	('activate', 'PosReg', (163, 171))	('PTPN11', 'Gene', '5781', (50, 56))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', (42, 45))
471415	31439678	Additionally, while the remaining PTPN11 mutated case did not have a co-occurring RAS mutation, it did have high-level amplification of the mutated PTPN11 allele.	('PTPN11', 'Gene', '5781', (34, 40))	('mutated', 'Var', (41, 48))	('RAS', 'Chemical', 'MESH:D011883', (82, 85))	('PTPN11', 'Gene', (34, 40))	('amplification', 'MPA', (119, 132))	('PTPN11', 'Gene', '5781', (148, 154))	('PTPN11', 'Gene', (148, 154))
471416	31439678	In NF1 mutant melanoma, the frequent presence of a second gene mutation often involving PTPN11 (or another RASopathy gene) has led to the suggestion that NF1 inactivation is insufficient to cause full activation of the downstream MAPK pathway and tumorigenesis.	('melanoma', 'Disease', (14, 22))	('activation', 'PosReg', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('RASopathy', 'Disease', (107, 116))	('inactivation', 'Var', (158, 170))	('mutant', 'Var', (7, 13))	('tumor', 'Disease', (247, 252))	('NF1', 'Gene', (154, 157))	('RASopathy', 'Disease', 'None', (107, 116))	('PTPN11', 'Gene', '5781', (88, 94))	('NF1', 'Gene', (3, 6))	('NF1', 'Gene', '4763', (154, 157))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('NF1', 'Gene', '4763', (3, 6))	('downstream MAPK pathway', 'Pathway', (219, 242))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('PTPN11', 'Gene', (88, 94))
471417	31439678	This hypothesis has been given further credence by recent data showing that NF1 loss-of-function mutant cell lines are dependent on SHP2 (encoded by PTPN11) mediated signaling for oncogenic RAS/MAPK pathway activation, raising the possibility that activating mutations of PTPN11 may synergize with NF1 loss-of-function mutations to further potentiate the oncogenic activity of the pathway.	('activating', 'PosReg', (248, 258))	('PTPN11', 'Gene', (149, 155))	('mutations', 'Var', (319, 328))	('mutant', 'Var', (97, 103))	('PTPN11', 'Gene', '5781', (149, 155))	('NF1', 'Gene', '4763', (298, 301))	('RAS', 'Chemical', 'MESH:D011883', (190, 193))	('NF1', 'Gene', '4763', (76, 79))	('oncogenic activity', 'CPA', (355, 373))	('mutations', 'Var', (259, 268))	('SHP2', 'Gene', '5781', (132, 136))	('PTPN11', 'Gene', (272, 278))	('NF1', 'Gene', (298, 301))	('loss-of-function', 'NegReg', (302, 318))	('loss-of-function', 'NegReg', (80, 96))	('NF1', 'Gene', (76, 79))	('PTPN11', 'Gene', '5781', (272, 278))	('SHP2', 'Gene', (132, 136))	('potentiate', 'PosReg', (340, 350))
471418	31439678	In contrast to the NF1/PTPN11 positive subgroup, the NF1/PTPN11 wild-type cluster was comprised primarily of cases with prototypic RAS/MAPK pathway activating mutations involving KRAS, NRAS, BRAF and MAP2K1.	('KRAS', 'Gene', '3845', (179, 183))	('BRAF', 'Gene', (191, 195))	('KRAS', 'Gene', (179, 183))	('NRAS', 'Gene', (185, 189))	('mutations', 'Var', (159, 168))	('PTPN11', 'Gene', (23, 29))	('NF1', 'Gene', '4763', (53, 56))	('PTPN11', 'Gene', '5781', (23, 29))	('NF1', 'Gene', (53, 56))	('NF1', 'Gene', '4763', (19, 22))	('RAS', 'Chemical', 'MESH:D011883', (180, 183))	('MAP2K1', 'Gene', '5604', (200, 206))	('PTPN11', 'Gene', (57, 63))	('BRAF', 'Gene', '673', (191, 195))	('NRAS', 'Gene', '4893', (185, 189))	('RAS/MAPK pathway', 'Pathway', (131, 147))	('NF1', 'Gene', (19, 22))	('MAP2K1', 'Gene', (200, 206))	('PTPN11', 'Gene', '5781', (57, 63))	('RAS', 'Chemical', 'MESH:D011883', (186, 189))	('RAS', 'Chemical', 'MESH:D011883', (131, 134))
471419	31439678	Interestingly, eight of the 14 cases in this subgroup contained IG gene rearrangements and/or additional mutations in genes commonly associated with B-cell lymphoproliferative disorders.	('B-cell lymphoproliferative disorders', 'Disease', 'MESH:D015448', (149, 185))	('B-cell lymphoproliferative disorders', 'Disease', (149, 185))	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (156, 185))	('mutations', 'Var', (105, 114))	('contained', 'Reg', (54, 63))
471420	31439678	These included one or more mutations in epigenetic regulators, transcription factors or signaling pathway genes, including CREBBP, KMT2D, DDX3X, ARID1A, MEF2B, SGK1, TNFRSF14, DTX1, GNA13, STAT6 and CARD11.	('mutations', 'Var', (27, 36))	('TNFRSF14', 'Gene', '8764', (166, 174))	('CREBBP', 'Gene', (123, 129))	('CARD11', 'Gene', (199, 205))	('ARID1A', 'Gene', (145, 151))	('TNFRSF14', 'Gene', (166, 174))	('STAT6', 'Gene', (189, 194))	('KMT2D', 'Gene', '8085', (131, 136))	('DTX1', 'Gene', '1840', (176, 180))	('MEF2B', 'Gene', '100271849', (153, 158))	('ARID1A', 'Gene', '8289', (145, 151))	('GNA13', 'Gene', '10672', (182, 187))	('CARD11', 'Gene', '84433', (199, 205))	('CREBBP', 'Gene', '1387', (123, 129))	('DDX3X', 'Gene', (138, 143))	('SGK1', 'Gene', '6446', (160, 164))	('STAT6', 'Gene', '6778', (189, 194))	('DTX1', 'Gene', (176, 180))	('transcription factors', 'Gene', (63, 84))	('MEF2B', 'Gene', (153, 158))	('SGK1', 'Gene', (160, 164))	('KMT2D', 'Gene', (131, 136))	('GNA13', 'Gene', (182, 187))	('epigenetic regulators', 'Gene', (40, 61))	('DDX3X', 'Gene', '1654', (138, 143))	('signaling pathway genes', 'Gene', (88, 111))
471421	31439678	Clonal IG rearrangements were identified in five cases and a BCL2 gene rearrangement was identified in one case, while neither were definitively detected in the NF1/PTPN11 subgroup.	('BCL2', 'Gene', (61, 65))	('PTPN11', 'Gene', '5781', (165, 171))	('rearrangements', 'Var', (10, 24))	('PTPN11', 'Gene', (165, 171))	('NF1', 'Gene', (161, 164))	('BCL2', 'Gene', '596', (61, 65))	('NF1', 'Gene', '4763', (161, 164))
471424	31439678	In their series, they showed enrichment for a mutational signature resembling aberrant somatic hypermutation in cases that had a history of B-cell lymphoma or that had mutations in genes that are frequently mutated in B-cell lymphoma.	('B-cell lymphoma', 'Disease', 'MESH:D016393', (140, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (225, 233))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (218, 233))	('B-cell lymphoma', 'Disease', (140, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (147, 155))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (140, 155))	('B-cell lymphoma', 'Disease', (218, 233))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (218, 233))	('aberrant somatic hypermutation', 'Disease', (78, 108))	('mutations', 'Var', (168, 177))
471425	31439678	Interestingly, they also found recurrent CDKN2A alterations that were more frequent in cases with a history of B-cell lymphoma or the aberrant somatic hypermutation signature.	('alterations', 'Var', (48, 59))	('B-cell lymphoma', 'Disease', (111, 126))	('frequent', 'Reg', (75, 83))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (111, 126))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (111, 126))	('CDKN2A', 'Gene', (41, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('CDKN2A', 'Gene', '1029', (41, 47))
471427	31439678	Concurrent mutations in RAS/MAPK pathway genes were less common in the NF1/PTPN11 wild-type group, occurring in 4 of 14 cases with alterations.	('PTPN11', 'Gene', (75, 81))	('mutations', 'Var', (11, 20))	('NF1', 'Gene', (71, 74))	('NF1', 'Gene', '4763', (71, 74))	('occurring', 'Reg', (99, 108))	('RAS', 'Chemical', 'MESH:D011883', (24, 27))	('PTPN11', 'Gene', '5781', (75, 81))	('RAS/MAPK pathway', 'Pathway', (24, 40))
471428	31439678	Two cases had concurrent mutations in MAP2K1 [His11 and His14].	('MAP2K1', 'Gene', (38, 44))	('His14', 'Chemical', '-', (56, 61))	('[His11', 'Var', (45, 51))	('MAP2K1', 'Gene', '5604', (38, 44))	('His14]', 'Var', (56, 62))
471429	31439678	The other two had co-occurring BRAF (p.G469V) and MAP2K1 (p.F53L) mutations [His10] or KRAS (p.G12D) and RAF1 (p.D486G) mutations [His21].	('p.D486G', 'Mutation', 'rs397516815', (111, 118))	('KRAS', 'Gene', (87, 91))	('MAP2K1', 'Gene', '5604', (50, 56))	('RAF1', 'Gene', (105, 109))	('p.G12D', 'Var', (93, 99))	('RAF1', 'Gene', '5894', (105, 109))	('His21', 'Chemical', '-', (131, 136))	('KRAS', 'Gene', '3845', (87, 91))	('p.G469V', 'Var', (37, 44))	('MAP2K1', 'Gene', (50, 56))	('p.F53L', 'Mutation', 'rs1057519728', (58, 64))	('p.G12D', 'Mutation', 'rs121913529', (93, 99))	('p.G469V', 'Mutation', 'rs121913355', (37, 44))	('BRAF', 'Gene', '673', (31, 35))	('p.F53L) mutations [His10]', 'Var', (58, 83))	('p.D486G', 'Var', (111, 118))	('His10', 'Chemical', '-', (77, 82))	('BRAF', 'Gene', (31, 35))
471430	31439678	These data are consistent with the limited published data in HS in which reported occurrences of multiple RAS/MAPK pathway mutations tend to manifest as co-occurring MAP2K1 mutations or involve atypical BRAF mutations, with co-occurring BRAF (p.G464V) and KRAS (p.Q61H), BRAF (p.D594N) and KRAS (p.A146T), BRAF (p.G469R) and NF1 (p.W2229*) and BRAF (p.F595L) and HRAS (p.Q61R) mutations described.	('BRAF', 'Gene', '673', (344, 348))	('NF1', 'Gene', (325, 328))	('BRAF', 'Gene', (344, 348))	('RAS', 'Chemical', 'MESH:D011883', (106, 109))	('mutations', 'Var', (208, 217))	('KRAS', 'Gene', (290, 294))	('p.F595L', 'Var', (350, 357))	('p.Q61H', 'Mutation', 'rs17851045', (262, 268))	('KRAS', 'Gene', '3845', (290, 294))	('MAP2K1', 'Gene', '5604', (166, 172))	('p.A146T', 'Var', (296, 303))	('MAP2K1', 'Gene', (166, 172))	('p.F595L', 'Mutation', 'rs121913341', (350, 357))	('p.G469R', 'Var', (312, 319))	('p.W2229*', 'Mutation', 'p.W2229*', (330, 338))	('BRAF', 'Gene', '673', (237, 241))	('KRAS', 'Gene', '3845', (256, 260))	('BRAF', 'Gene', (237, 241))	('RAS/MAPK', 'Gene', (106, 114))	('p.G464V', 'Var', (243, 250))	('RAS', 'Chemical', 'MESH:D011883', (364, 367))	('mutations', 'Var', (173, 182))	('BRAF', 'Gene', '673', (203, 207))	('p.G464V', 'Mutation', 'rs121913348', (243, 250))	('KRAS', 'Gene', (256, 260))	('BRAF', 'Gene', (203, 207))	('p.D594N', 'Var', (277, 284))	('p.D594N', 'Mutation', 'rs397516896', (277, 284))	('BRAF', 'Gene', '673', (306, 310))	('BRAF', 'Gene', (306, 310))	('RAS', 'Chemical', 'MESH:D011883', (291, 294))	('RAS', 'Chemical', 'MESH:D011883', (257, 260))	('p.W2229*', 'Var', (330, 338))	('NF1', 'Gene', '4763', (325, 328))	('p.A146T', 'Mutation', 'rs121913527', (296, 303))	('p.Q61R', 'Mutation', 'rs11554290', (369, 375))	('BRAF', 'Gene', (271, 275))	('BRAF', 'Gene', '673', (271, 275))	('HRAS', 'Gene', '3265', (363, 367))	('p.G469R', 'Mutation', 'rs121913357', (312, 319))	('mutations', 'Var', (123, 132))	('HRAS', 'Gene', (363, 367))
471431	31439678	Interestingly, in the latter case the unusual BRAF mutation was shown to have weak oncogenic activity requiring the co-operation of the HRAS mutation for full activity.	('oncogenic activity', 'CPA', (83, 101))	('HRAS', 'Gene', (136, 140))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('HRAS', 'Gene', '3265', (136, 140))	('mutation', 'Var', (51, 59))
471433	31439678	To exclude as many germline SNPs as possible we filtered all variants using stringent criteria for their representation in control populations (gnomAD) and took CADD scores, as well as presence in the Catalogue of Somatic Mutations in Cancer (COSMIC) into consideration.	('Cancer', 'Phenotype', 'HP:0002664', (235, 241))	('variants', 'Var', (61, 69))	('Cancer', 'Disease', 'MESH:D009369', (235, 241))	('Cancer', 'Disease', (235, 241))
471436	31439678	We show frequent mutations and alterations in genes of the RAS/MAPK pathway, suggesting that patients could potentially benefit from genomic evaluation and targeted therapy, and we report a distinct molecular subtype of pHS that correlates with the NF1/PTPN11 status of the tumor and frequently involves the GI tract.	('patients', 'Species', '9606', (93, 101))	('PTPN11', 'Gene', (253, 259))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('NF1', 'Gene', (249, 252))	('RAS', 'Chemical', 'MESH:D011883', (59, 62))	('pHS', 'Disease', (220, 223))	('NF1', 'Gene', '4763', (249, 252))	('involves', 'Reg', (295, 303))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('mutations', 'Var', (17, 26))	('PTPN11', 'Gene', '5781', (253, 259))
471437	31439678	Finally, we also identify a subset of NF1/PTPN11 wild-type cases with mutations in B-cell lymphoma associated genes and/or clonal IG gene rearrangements.	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('mutations', 'Var', (70, 79))	('PTPN11', 'Gene', '5781', (42, 48))	('B-cell lymphoma', 'Disease', (83, 98))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (83, 98))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (83, 98))	('PTPN11', 'Gene', (42, 48))	('NF1', 'Gene', (38, 41))	('NF1', 'Gene', '4763', (38, 41))
471453	32047685	Next-generation sequencing revealed a EWSR1-FLI1 fusion, along with a CHEK2 mutation and microsatellite stability.	('CHEK2', 'Gene', '11200', (70, 75))	('CHEK2', 'Gene', (70, 75))	('revealed', 'Reg', (27, 35))	('fusion', 'Var', (49, 55))	('FLI1', 'Gene', '2313', (44, 48))	('FLI1', 'Gene', (44, 48))	('mutation', 'Var', (76, 84))
471540	28465156	The prevalence of KSHV infection based on miRNAs qPCR is significantly higher than the prevalence determined by seropositivity, and this is more obvious for immuno-depressed patients.	('higher', 'PosReg', (71, 77))	('KSHV infection', 'Disease', 'MESH:C537372', (18, 32))	('immuno-depressed', 'Disease', 'MESH:D000275', (157, 173))	('immuno-depressed', 'Disease', (157, 173))	('KSHV infection', 'Disease', (18, 32))	('miRNAs qPCR', 'Var', (42, 53))	('KS', 'Phenotype', 'HP:0100726', (18, 20))
471576	28465156	Work in Dr. Calin's laboratory is supported in part by the grant /NCI 1 R01 CA182905-01, the  in Melanoma grant from NCI (P50 CA093459), AIM at Melanoma Foundation and the Miriam and Jim Mulva research funds, the  (2P50CA127001), a Developmental Research award from Leukemia SPORE, a CLL Moonshot Flagship project, a 2015 Knowledge GAP MDACC grant, an Owens Foundation grant, and the Estate of C. G. Johnson, Jr., Dr. Fuentes-Mattei was supported in part by Award Number P50 CA140388 from the  and by the NIH Clinical Research Loan Repayment Program.	('Melanoma', 'Disease', 'MESH:D008545', (144, 152))	('Melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('Leukemia', 'Phenotype', 'HP:0001909', (266, 274))	('Melanoma', 'Disease', (144, 152))	('Melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('P50 CA140388', 'Var', (471, 483))	('Melanoma', 'Disease', 'MESH:D008545', (97, 105))	('CLL', 'Phenotype', 'HP:0005550', (284, 287))	('Melanoma', 'Disease', (97, 105))
471652	30665434	In brief, this closed cohort consisted of subjects ART eligible according to the WHO guidelines (ART initiation with CD4 < 200 cells/uL), residing within 20 Km of Kampala, and willing to comply with the study procedures.	('< 200 cells/uL', 'Var', (121, 135))	('ART', 'Chemical', '-', (51, 54))	('ART', 'Chemical', '-', (97, 100))	('CD4', 'Gene', (117, 120))	('CD4', 'Gene', '920', (117, 120))
471744	23652821	In this non-trial setting, port-associated complications were more frequent (14%) with trabectedin compared to other continuous infusion protocols administered at our outpatient therapy center.	('outpatient', 'Species', '9606', (167, 177))	('port-associated', 'Disease', (27, 42))	('trabectedin', 'Var', (87, 98))	('trabectedin', 'Chemical', 'MESH:D000077606', (87, 98))
471856	32746832	Delays in diagnosis are associated with larger tumours, increased risk of metastases, and increased risk of amputation rather than limb salvage surgery.	('amputation', 'CPA', (108, 118))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('metastases', 'Disease', (74, 84))	('tumours', 'Disease', (47, 54))	('metastases', 'Disease', 'MESH:D009362', (74, 84))	('Delays', 'Var', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
472183	30949328	Subsequently, molecular study using fluorescence in situ hybridization (FISH) had shown rearrangement of EWSR1 gene in 100% of the analyzes nuclei that confirm the diagnosis of Ewing's sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (177, 192))	("Ewing's sarcoma", 'Disease', (177, 192))	('EWSR1', 'Gene', (105, 110))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (177, 192))	('rearrangement', 'Var', (88, 101))	('EWSR1', 'Gene', '2130', (105, 110))
472204	30949328	A definitive diagnosis of Ewing's sarcoma can be achieved through molecular analysis that detect EWSR1/FLI-1 fusion.	('FLI-1', 'Gene', (103, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('EWSR1', 'Gene', (97, 102))	('FLI-1', 'Gene', '2313', (103, 108))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (26, 41))	('EWSR1', 'Gene', '2130', (97, 102))	("Ewing's sarcoma", 'Disease', (26, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (26, 41))	('fusion', 'Var', (109, 115))
472214	27270875	Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation Myxoid liposarcoma has the pathognomonic fusion oncogene FUS-DDIT3 encoding a chimeric transcription factor.	('human', 'Species', '9606', (44, 49))	('DDIT3', 'Gene', (101, 106))	('FUS', 'Gene', '2521', (178, 181))	('Myxoid liposarcoma', 'Disease', (121, 139))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (50, 68))	('FUS', 'Gene', (97, 100))	('translocation', 'Var', (107, 120))	('myxoid liposarcoma', 'Disease', (50, 68))	('Myxoid liposarcoma', 'Disease', 'MESH:D018208', (121, 139))	('FUS', 'Gene', '2521', (97, 100))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (50, 68))	('liposarcoma', 'Phenotype', 'HP:0012034', (57, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('DDIT3', 'Gene', '1649', (182, 187))	('liposarcoma', 'Phenotype', 'HP:0012034', (128, 139))	('Myxoid liposarcoma', 'Phenotype', 'HP:0012268', (121, 139))	('DDIT3', 'Gene', '1649', (101, 106))	('FUS', 'Gene', (178, 181))	('DDIT3', 'Gene', (182, 187))
472215	27270875	Metastatic risk is higher with an increased round cell component and has been linked to aberrations involving the IGFR/PI3K/AKT pathway.	('Metastatic', 'CPA', (0, 10))	('round cell component', 'CPA', (44, 64))	('PI3', 'Gene', '5266', (119, 122))	('higher', 'PosReg', (19, 25))	('AKT', 'Gene', (124, 127))	('IGFR', 'Gene', (114, 118))	('PI3', 'Gene', (119, 122))	('linked', 'Reg', (78, 84))	('aberrations', 'Var', (88, 99))	('increased', 'PosReg', (34, 43))	('AKT', 'Gene', '207', (124, 127))	('IGFR', 'Gene', '3480', (114, 118))
472220	27270875	DL-221 cells grew an adhering monolayer and COBRA-FISH showed an aneuploid karyotype with t(12;16)(q13;p11) and several other rearrangements; RT-PCR demonstrated a FUS-DDIT3 fusion transcript type 1.	('DDIT3', 'Gene', '1649', (168, 173))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (90, 107))	('FUS', 'Gene', (164, 167))	('FUS', 'Gene', '2521', (164, 167))	('DDIT3', 'Gene', (168, 173))	('t(12;16)(q13;p11', 'Var', (90, 106))
472221	27270875	Both the cell line and the original tumor harbored a TP53 compound heterozygous mutation in exon 4 and 7 and were wild type for PIK3CA.	('compound heterozygous mutation', 'Var', (58, 88))	('PIK3CA', 'Gene', '5290', (128, 134))	('original tumor', 'Disease', (27, 41))	('TP53', 'Gene', '7157', (53, 57))	('PIK3CA', 'Gene', (128, 134))	('original tumor', 'Disease', 'MESH:D009369', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('TP53', 'Gene', (53, 57))
472222	27270875	Moreover, among the 1254 variants called by whole exome sequencing, there was 77% concordance between the cell line and parent tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('variants', 'Var', (25, 33))	('parent tumor', 'Disease', 'MESH:D063129', (120, 132))	('parent tumor', 'Disease', (120, 132))
472223	27270875	The recently described hotspot mutation in the TERT promoter region in myxoid liposarcomas was also found at C228T in DL-221.	('TERT', 'Gene', (47, 51))	('C228T', 'Mutation', 'rs876658729', (109, 114))	('liposarcomas', 'Phenotype', 'HP:0012034', (78, 90))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (71, 89))	('TERT', 'Gene', '7015', (47, 51))	('myxoid liposarcomas', 'Disease', (71, 90))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (71, 90))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (71, 90))	('liposarcoma', 'Phenotype', 'HP:0012034', (78, 89))	('C228T', 'Var', (109, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
472238	27270875	;; Less than 5% of the cases harbour a t(12;22)(q13;q12) leading to an EWSR1-DDIT3 fusion, of which four different transcripts are described.	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (39, 56))	('leading to', 'Reg', (57, 67))	('t(12;22)(q13;q12', 'Var', (39, 55))	('DDIT3', 'Gene', (77, 82))	('EWSR1', 'Gene', (71, 76))	('DDIT3', 'Gene', '1649', (77, 82))	('EWSR1', 'Gene', '2130', (71, 76))
472243	27270875	;; Activating mutations in PIK3CA are found in 14-18% of MLS and loss of expression of PTEN is found in 12% of the tumors and is mutually exclusive from PIK3CA mutations.	('PIK3CA', 'Gene', '5290', (153, 159))	('PIK3CA', 'Gene', (153, 159))	('PTEN', 'Gene', (87, 91))	('MLS', 'Disease', 'MESH:C537466', (57, 60))	('MLS', 'Disease', (57, 60))	('PTEN', 'Gene', '5728', (87, 91))	('MLS', 'Phenotype', 'HP:0012268', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('PIK3CA', 'Gene', (27, 33))	('Activating', 'PosReg', (3, 13))	('tumors', 'Disease', (115, 121))	('expression', 'MPA', (73, 83))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('PIK3CA', 'Gene', '5290', (27, 33))	('mutations', 'Var', (14, 23))
472245	27270875	The PIK3CA mutation rate, IGFR expression and loss of PTEN were higher in tumors with a round cell component suggesting that this pathway might be involved in round cell transformation and tumor progression.	('IGFR', 'Gene', '3480', (26, 30))	('PTEN', 'Gene', '5728', (54, 58))	('tumor', 'Disease', (74, 79))	('IGFR', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('PIK3CA', 'Gene', (4, 10))	('mutation', 'Var', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expression', 'MPA', (31, 41))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (189, 194))	('involved', 'Reg', (147, 155))	('loss', 'NegReg', (46, 50))	('PTEN', 'Gene', (54, 58))	('higher', 'Reg', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('PIK3CA', 'Gene', '5290', (4, 10))	('tumors', 'Disease', (74, 80))
472246	27270875	TP53 mutations and reduced protein expression of p16INK4/p14ARF have been identified in a subset of tumors, most frequently in round cell components.	('round cell components', 'Disease', (127, 148))	('p14ARF', 'Gene', (57, 63))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('p16INK4', 'Gene', '1029', (49, 56))	('protein expression', 'MPA', (27, 45))	('p16INK4', 'Gene', (49, 56))	('p14ARF', 'Gene', '1029', (57, 63))	('tumors', 'Disease', (100, 106))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('reduced', 'NegReg', (19, 26))	('identified', 'Reg', (74, 84))
472247	27270875	Hotspot mutations in the TERT (telomerase reverse transcriptase) promoter region were recently reported in MLS (23% to 74%).	('TERT', 'Gene', (25, 29))	('mutations', 'Var', (8, 17))	('MLS', 'Disease', 'MESH:C537466', (107, 110))	('MLS', 'Disease', (107, 110))	('TERT', 'Gene', '7015', (25, 29))	('MLS', 'Phenotype', 'HP:0012268', (107, 110))
472248	27270875	; These mutations led to increased protein expression of TERT and have been implicated in telomerase dysregulation and the resultant proliferative capability of tumor cells.	('proliferative capability', 'CPA', (133, 157))	('TERT', 'Gene', (57, 61))	('increased', 'PosReg', (25, 34))	('TERT', 'Gene', '7015', (57, 61))	('mutations', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('protein expression', 'MPA', (35, 53))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('telomerase', 'Protein', (90, 100))	('implicated', 'Reg', (76, 86))	('tumor', 'Disease', (161, 166))
472260	27270875	Two color FUS split apart FISH was performed on interphase cells using a probe mix containing bacterial artificial chromosome (BAC) clone RP11-196G11 direct labeled with FITC (FITC-dUTP) (Roche diagnostics GmbH, Mannheim, Germany) and clone RP11-120K18 direct labeled with Cy3 (Roche).	('FITC', 'Chemical', 'MESH:D016650', (170, 174))	('FITC', 'Chemical', 'MESH:D016650', (176, 180))	('FITC-dUTP', 'Chemical', '-', (176, 185))	('Cy3', 'Chemical', '-', (273, 276))	('RP11-196G11', 'Var', (138, 149))	('FUS', 'Gene', (10, 13))	('FUS', 'Gene', '2521', (10, 13))
472266	27270875	The following Cell Signaling Technology (Danvers, MA) antibodies were also used for western blot: anti-AKT (#2920), anti-phospho-AKT (Ser473) (#9271), anti-AXL (#4566) and PTEN (#9559).	('AKT', 'Gene', '207', (103, 106))	('PTEN', 'Gene', '5728', (172, 176))	('AKT', 'Gene', '207', (129, 132))	('AKT', 'Gene', (103, 106))	('AXL', 'Gene', (156, 159))	('AXL', 'Gene', '558', (156, 159))	('#4566', 'Var', (161, 166))	('Ser473) (#9271', 'Var', (134, 148))	('#2920', 'Var', (108, 113))	('#9271', 'Var', (143, 148))	('Ser473', 'Chemical', '-', (134, 140))	('AKT', 'Gene', (129, 132))	('#9559', 'Var', (178, 183))	('PTEN', 'Gene', (172, 176))
472295	27270875	The composite karyotype of the DL-221 cell line at passage p31 and p68 was 71~75<3n+->,der(X)t(X;15)(q;q)x2,-Y,der(2)t(X;2)(q;p)t(2;3)(q;p)x2,-4,+5,der(7)t(7;X)(q;q),+i(7)(q10),+7,+8,+8,-9,+11,t(12;16)(q13;p11),-13,+14,-15,der(17)t(10;17)(p;p),+18,+19,+20,+21,idic(22)[10]/ 71~75<3n+->,der(X)t(X;15)(q;q)x2,-Y,der(2)t(X;2)(q;p)t(2;3)(q;p)x2,der(4)t(2;4)(q;p),-4,+5,der(7)t(5;7)(p;q),der(7)t(7;X)(q;q),+8,+8,-9,+10,+11,t(12;16)(q13;p11)x2,-13,+14,-15,+18,+19,+20,+21,+22[6] (Figure 1C).	('p31', 'Gene', '529', (59, 62))	('der(17)t(10;17)(p;p)', 'STRUCTURAL_ABNORMALITY', 'None', (223, 243))	('der', 'Var', (286, 289))	('der(2)t(X;2)(q;p)t(2;3)(q;p)', 'STRUCTURAL_ABNORMALITY', 'None', (111, 139))	('der(2)t(X;2)(q;p)t(2;3)(q;p)', 'STRUCTURAL_ABNORMALITY', 'None', (310, 338))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (193, 210))	('p68', 'Gene', (67, 70))	('der(7)t(7;X)(q;q)', 'STRUCTURAL_ABNORMALITY', 'None', (148, 165))	('der(4)t(2;4)(q;p)', 'STRUCTURAL_ABNORMALITY', 'None', (341, 358))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (418, 435))	('der(X)t(X;15)(q;q)', 'STRUCTURAL_ABNORMALITY', 'None', (87, 105))	('der(X)t(X;15)(q;q)', 'STRUCTURAL_ABNORMALITY', 'None', (286, 304))	('der(7)t(7;X)(q;q)', 'STRUCTURAL_ABNORMALITY', 'None', (383, 400))	('p68', 'Gene', '10714', (67, 70))	('p31', 'Gene', (59, 62))	('der(7)t(5;7)(p;q)', 'STRUCTURAL_ABNORMALITY', 'None', (365, 382))
472303	27270875	The estimated molecular weight of the protein detected with anti-DDIT3 is around 75 kDa in 402-91 and DL-221 and around 100 kDa in 1765-92, corresponding to the estimated weight of the chimeric fusion proteins of 75 kDa and 100 kDa for type 1 and 8 fusion proteins, respectively.	('DDIT3', 'Gene', (65, 70))	('DL-221', 'Var', (102, 108))	('DDIT3', 'Gene', '1649', (65, 70))
472308	27270875	Target panel sequencing revealed two different TP53 mutations in the cell line, c.374C>G, p.T125R in exon 4 and c.715A>G, p.N239D in exon 7.	('c.374C>G', 'Mutation', 'rs786201057', (80, 88))	('p.T125R', 'Var', (90, 97))	('p.N239D', 'Var', (122, 129))	('c.374C>G', 'Var', (80, 88))	('c.715A>G', 'Mutation', 'rs876660807', (112, 120))	('p.T125R', 'Mutation', 'rs786201057', (90, 97))	('p.N239D', 'Mutation', 'rs876660807', (122, 129))	('c.715A>G', 'Var', (112, 120))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
472309	27270875	The original tumor also harbored these pathogenic variations.	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('original tumor', 'Disease', 'MESH:D009369', (4, 18))	('variations', 'Var', (50, 60))	('original tumor', 'Disease', (4, 18))
472312	27270875	Mutational analysis of the TERT promoter region revealed a C228T mutation in DL-221 (Figure S2).	('C228T', 'Var', (59, 64))	('TERT', 'Gene', (27, 31))	('C228T', 'Mutation', 'rs876658729', (59, 64))	('TERT', 'Gene', '7015', (27, 31))	('DL-221', 'Gene', (77, 83))
472314	27270875	None of the cell lines harbored the second reported hotspot mutation in MLS, C250T.	('C250T', 'Mutation', 'rs770137671', (77, 82))	('MLS', 'Disease', 'MESH:C537466', (72, 75))	('MLS', 'Disease', (72, 75))	('MLS', 'Phenotype', 'HP:0012268', (72, 75))	('C250T', 'Var', (77, 82))
472335	27270875	Analysis of these alleles using DAVID showed significant p-values from both Panther (p = 5.2 x 10-5) and KEGG (p = 4.8 x 10-4) for the Wnt signaling pathway, which includes Polyphen2-predicted "probably damaging" variants in APC (p.R99W), APC2 (p.G323R), and TP53 (p.N239D, p.T125R) (Table S3).	('p.G323R', 'Mutation', 'rs143870588', (245, 252))	('APC2', 'Gene', (239, 243))	('APC2', 'Gene', '10297', (239, 243))	('APC', 'Disease', 'MESH:D011125', (239, 242))	('APC', 'Disease', (225, 228))	('APC', 'Disease', (239, 242))	('p.T125R', 'Mutation', 'rs786201057', (274, 281))	('p.N239D', 'Var', (265, 272))	('TP53', 'Gene', '7157', (259, 263))	('p.T125R', 'Var', (274, 281))	('p.R99W', 'Var', (230, 236))	('TP53', 'Gene', (259, 263))	('p.R99W', 'Mutation', 'p.R99W', (230, 236))	('p.N239D', 'Mutation', 'rs876660807', (265, 272))	('Wnt signaling pathway', 'Pathway', (135, 156))	('p.G323R', 'Var', (245, 252))	('APC', 'Disease', 'MESH:D011125', (225, 228))
472337	27270875	Driver mutations such as the two TP53 missense mutations p.T125R and p.N239D that were characterized in the primary tumor were confirmed in both samples and retained consistent allele frequencies (metastatic p.T125R 0.43 allele freq, depth = 54, cell line 0.46 allele freq, depth = 54; p.N239D metastatic 0.4 allele freq, depth = 37, cell line 0.32 allele freq, depth = 50).	('p.T125R', 'Mutation', 'rs786201057', (208, 215))	('p.T125R', 'Mutation', 'rs786201057', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('p.N239D', 'Var', (69, 76))	('TP53', 'Gene', '7157', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p.N239D', 'Var', (286, 293))	('p.T125R', 'Var', (208, 215))	('TP53', 'Gene', (33, 37))	('p.T125R', 'Var', (57, 64))	('tumor', 'Disease', (116, 121))	('p.N239D', 'Mutation', 'rs876660807', (286, 293))	('p.N239D', 'Mutation', 'rs876660807', (69, 76))
472341	27270875	Of these 28 alleles, five are predicted "Probably damaging" by Polyphen2 (FAT4 p.P1313S; DSPP p.D1152N; SP140L p.C181R; IFIH1 p.L125M; and IPPK p.R130W).	('p.L125M', 'Var', (126, 133))	('p.D1152N; SP140L p.C181R', 'Var', (94, 118))	('p.P1313S', 'Var', (79, 87))	('damaging', 'Reg', (50, 58))	('p.D1152N', 'Mutation', 'p.D1152N', (94, 102))	('IFIH1', 'Gene', '64135', (120, 125))	('IFIH1', 'Gene', (120, 125))	('p.C181R', 'Mutation', 'rs764456337', (111, 118))	('IPPK', 'Gene', '64768', (139, 143))	('p.R130W', 'Mutation', 'rs75957544', (144, 151))	('p.C181R', 'Var', (111, 118))	('p.P1313S', 'Mutation', 'p.P1313S', (79, 87))	('IPPK', 'Gene', (139, 143))	('p.R130W', 'Var', (144, 151))	('p.L125M', 'Mutation', 'rs139219083', (126, 133))
472346	27270875	SV40 suppresses the transcriptional activity of the tumor suppressor p53 and hence affects the p53 pathway in the cells.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('transcriptional activity', 'MPA', (20, 44))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('tumor', 'Disease', (52, 57))	('suppresses', 'NegReg', (5, 15))	('SV40', 'Var', (0, 4))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('affects', 'Reg', (83, 90))
472352	27270875	The FUS-DDIT3 translocation and the TP53 mutations were present in both samples.	('mutations', 'Var', (41, 50))	('DDIT3', 'Gene', (8, 13))	('TP53', 'Gene', '7157', (36, 40))	('DDIT3', 'Gene', '1649', (8, 13))	('TP53', 'Gene', (36, 40))	('FUS', 'Gene', (4, 7))	('FUS', 'Gene', '2521', (4, 7))
472360	27270875	Alterations of the p53 pathway have been described in several studies on MLS and the percentage of cases with an alteration varies from <5% to 83%.	('Alterations', 'Var', (0, 11))	('MLS', 'Disease', 'MESH:C537466', (73, 76))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('MLS', 'Disease', (73, 76))	('MLS', 'Phenotype', 'HP:0012268', (73, 76))
472361	27270875	;;;; Whole exome sequencing of the DL-221 cell line revealed two TP53 missense mutations, T125R in exon 4 and N239D in exon 7; both mutations lead to the substitution of an amino acid of a different class and are expected to be deleterious.	('N239D', 'Mutation', 'rs876660807', (110, 115))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('N239D in', 'Var', (110, 118))	('T125R', 'Var', (90, 95))	('substitution', 'Var', (154, 166))	('lead to', 'Reg', (142, 149))	('T125R', 'Mutation', 'rs786201057', (90, 95))
472362	27270875	TP53 alterations are most frequently encountered in the hotspot exons 5 to 8; these two mutations have both been reported before in carcinomas (cosmic database).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('carcinomas', 'Disease', (132, 142))	('alterations', 'Var', (5, 16))	('carcinomas', 'Disease', 'MESH:D002277', (132, 142))
472363	27270875	PIK3CA mutations have been identified in 14-18% of the MLS cases and are associated with round cell progression and shorter disease-specific survival.	('shorter', 'NegReg', (116, 123))	('identified', 'Reg', (27, 37))	('round cell', 'Disease', (89, 99))	('MLS', 'Disease', 'MESH:C537466', (55, 58))	('MLS', 'Disease', (55, 58))	('PIK3CA', 'Gene', (0, 6))	('associated', 'Reg', (73, 83))	('PIK3CA', 'Gene', '5290', (0, 6))	('MLS', 'Phenotype', 'HP:0012268', (55, 58))	('mutations', 'Var', (7, 16))
472373	27270875	Point mutations in the telomerase reverse transcriptase (TERT) promotor region have been identified in 23% (3/13) to 74% (29/39) of MLS.	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (57, 61))	('MLS', 'Disease', 'MESH:C537466', (132, 135))	('Point mutations', 'Var', (0, 15))	('MLS', 'Disease', (132, 135))	('identified', 'Reg', (89, 99))	('MLS', 'Phenotype', 'HP:0012268', (132, 135))
472375	27270875	The mutation creates a new transcription factor-binding site leading to an upregulation of TERT and finally lengthening of the telomeres.	('upregulation', 'PosReg', (75, 87))	('TERT', 'Gene', (91, 95))	('mutation', 'Var', (4, 12))	('TERT', 'Gene', '7015', (91, 95))
472379	27270875	HDAC inhibitors have shown inhibitory and cytotoxic effects on several soft tissue sarcoma tumor cell models grown in vitro and in vivo, including the 402-91 cell line.	('HDAC', 'Gene', (0, 4))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (71, 90))	('HDAC', 'Gene', '9734', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('inhibitors', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('sarcoma tumor', 'Disease', 'MESH:D012509', (83, 96))	('sarcoma tumor', 'Disease', (83, 96))	('cytotoxic effects', 'CPA', (42, 59))
472381	27270875	Epigenetic alterations might be involved in the transcriptional regulation of MLS.	('Epigenetic alterations', 'Var', (0, 22))	('MLS', 'Disease', 'MESH:C537466', (78, 81))	('MLS', 'Disease', (78, 81))	('MLS', 'Phenotype', 'HP:0012268', (78, 81))	('involved', 'Reg', (32, 40))
472399	23198186	Angiosarcoma of small bowel may be associated with previous radiation treatment, chemotherapy, and chemical toxin exposure, specifically polyvinyl chloride.	('Angiosarcoma of small bowel', 'Disease', 'MESH:D006394', (0, 27))	('polyvinyl', 'Var', (137, 146))	('polyvinyl chloride', 'Chemical', 'MESH:D011143', (137, 155))	('associated', 'Reg', (35, 45))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('Angiosarcoma of small bowel', 'Disease', (0, 27))
472591	22613930	Expression of epithelial markers is also seen in some primary bone tumours, notably adamantinoma and chordoma; the former also express podoplanin, and the latter S100 and brachyury.	('podoplanin', 'Gene', (135, 145))	('brachyury', 'Gene', '6899', (171, 180))	('S100', 'Var', (162, 166))	('bone tumour', 'Phenotype', 'HP:0010622', (62, 73))	('primary bone tumours', 'Disease', 'MESH:D001859', (54, 74))	('primary bone tumours', 'Disease', (54, 74))	('brachyury', 'Gene', (171, 180))	('chordoma', 'Phenotype', 'HP:0010762', (101, 109))	('podoplanin', 'Gene', '10630', (135, 145))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('adamantinoma and chordoma', 'Disease', 'MESH:D050398', (84, 109))
472595	22613930	Monoclonal kappa or lambda light chain expression can be identified in myeloma or plasmacytoma.	('myeloma or plasmacytoma', 'Disease', 'MESH:D010954', (71, 94))	('Monoclonal', 'Var', (0, 10))	('plasmacytoma', 'Phenotype', 'HP:0011857', (82, 94))	('lambda light chain expression', 'Protein', (20, 49))	('identified', 'Reg', (57, 67))	('myeloma or plasmacytoma', 'Disease', (71, 94))
472601	22613930	Mutations in the p53 gene result in the accumulation of p53 protein in the nucleus.	('p53', 'Gene', (56, 59))	('p53', 'Gene', '7157', (56, 59))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (17, 20))	('accumulation', 'PosReg', (40, 52))	('p53', 'Gene', '7157', (17, 20))
472607	22613930	Cytogenetic analysis of bone tumours is especially useful in the detection of the 11;22 translocation which is commonly found in Ewing's sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('bone tumours', 'Disease', 'MESH:D001859', (24, 36))	('bone tumours', 'Disease', (24, 36))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (129, 144))	('bone tumour', 'Phenotype', 'HP:0010622', (24, 35))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))	('translocation', 'Var', (88, 101))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (129, 144))	("Ewing's sarcoma", 'Disease', (129, 144))
472609	22613930	Molecular genetic analysis is used to characterise changes in gene and gene expression in tumour cells, particularly translocations and mutations in oncogenes and tumour suppressor genes.	('oncogenes', 'Gene', (149, 158))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('changes', 'Reg', (51, 58))	('translocations', 'Var', (117, 131))	('mutations', 'Var', (136, 145))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Disease', (90, 96))	('tumour', 'Disease', (163, 169))
472613	22613930	The most common of these translocations is t [11; 22] (q24; q12), which is present in nearly 85% of cases of Ewing's sarcoma; this results in a tumourigenic fusion protein composed of the 5'- end of the EWS gene and 3'- end of the ETS family gene FLI1: This EWS-FLI1 fusion product has been reported in other malignant round cell tumours including neuroblastoma and mesenchymal chondrosarcoma.	('EWS', 'Gene', (258, 261))	('results in', 'Reg', (131, 141))	('t [', 'Var', (43, 46))	('FLI1', 'Gene', (262, 266))	('tumour', 'Phenotype', 'HP:0002664', (330, 336))	('tumour', 'Disease', 'MESH:D009369', (330, 336))	("Ewing's sarcoma", 'Disease', (109, 124))	('translocations', 'Var', (25, 39))	('tumour', 'Disease', (330, 336))	('FLI1', 'Gene', '2313', (262, 266))	('malignant round cell tumours', 'Disease', (309, 337))	('EWS', 'Gene', '2130', (203, 206))	('EWS', 'Gene', '2130', (258, 261))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('mesenchymal chondrosarcoma', 'Disease', (366, 392))	('malignant round cell tumours', 'Disease', 'MESH:D018208', (309, 337))	('neuroblastoma', 'Disease', (348, 361))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('tumour', 'Disease', (144, 150))	('neuroblastoma', 'Phenotype', 'HP:0003006', (348, 361))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (109, 124))	('FLI1', 'Gene', (247, 251))	('neuroblastoma', 'Disease', 'MESH:D009447', (348, 361))	('sarcoma', 'Phenotype', 'HP:0100242', (385, 392))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (378, 392))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (109, 124))	('tumours', 'Phenotype', 'HP:0002664', (330, 337))	('mesenchymal chondrosarcoma', 'Disease', 'MESH:D018211', (366, 392))	('FLI1', 'Gene', '2313', (247, 251))	('EWS', 'Gene', (203, 206))
472616	22613930	Molecular studies are also useful in identifying loss or mutation in certain tumour suppressor genes, such as p53 and the retinoblastoma gene, both of which are associated with the pathogenesis of osteosarcoma.	('mutation', 'Var', (57, 65))	('p53', 'Gene', (110, 113))	('loss', 'NegReg', (49, 53))	('retinoblastoma', 'Phenotype', 'HP:0009919', (122, 136))	('associated', 'Reg', (161, 171))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('p53', 'Gene', '7157', (110, 113))	('tumour', 'Disease', (77, 83))	('retinoblastoma', 'Gene', '5925', (122, 136))	('osteosarcoma', 'Disease', (197, 209))	('osteosarcoma', 'Phenotype', 'HP:0002669', (197, 209))	('osteosarcoma', 'Disease', 'MESH:D012516', (197, 209))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('retinoblastoma', 'Gene', (122, 136))
472621	22613930	DNA aneuploidy has been documented in benign bone tumours and does not equate with malignancy.	('benign bone tumours', 'Disease', (38, 57))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('benign bone tumours', 'Disease', 'MESH:D001859', (38, 57))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('bone tumour', 'Phenotype', 'HP:0010622', (45, 56))	('malignancy', 'Disease', (83, 93))	('aneuploidy', 'Var', (4, 14))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
472622	22613930	However, aneuploidy is more prevalent in high grade malignant tumours and is an independent risk factor for predicting metastasis.	('aneuploidy', 'Var', (9, 19))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('metastasis', 'CPA', (119, 129))	('prevalent', 'Reg', (28, 37))	('malignant tumours', 'Disease', 'MESH:D009369', (52, 69))	('malignant tumours', 'Disease', (52, 69))
472659	21527020	Post-transplantation KS develops in 23% to 28% of HHV8 seropositive patients and in only 0.7% of seronegative patients.	('HHV8', 'Gene', (50, 54))	('patients', 'Species', '9606', (68, 76))	('seropositive', 'Var', (55, 67))	('patients', 'Species', '9606', (110, 118))	('HHV8', 'Species', '37296', (50, 54))
472677	21527020	Renal recipient patients who were seropositive for HHV-8 before transplantation, have a risk to develop KS of 23% to 28% that is significantly higher compared to risk of 0.7% in patients who are seronegative before receiving a kidney transplant.	('HHV-8', 'Gene', (51, 56))	('HHV-8', 'Species', '37296', (51, 56))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (178, 186))	('seropositive', 'Var', (34, 46))
472686	21527020	Overall, there was a statistically significant higher risk of HHV-8 seropositivity in haemodialysis (OR = 10.24, 95% CI: 3.5 - 32.1) and HIV (OR = 42.27, 95%CI: 12.7 - 150) patients compared to blood donors, although several variables between the three enrolled groups cannot be excluded.	('HHV-8', 'Species', '37296', (62, 67))	('patients', 'Species', '9606', (173, 181))	('haemodialysis', 'Disease', (86, 99))	('higher', 'PosReg', (47, 53))	('seropositivity', 'Var', (68, 82))	('HHV-8', 'Gene', (62, 67))
472704	21527020	Approximately 50% of the adult population of Brazilian Amerindians was reported to have antibodies to HHV-8, compared with only 11% of HIV-negative injection drug users in Argentina.	('HHV-8', 'Species', '37296', (102, 107))	('antibodies', 'Var', (88, 98))	('HHV-8', 'Gene', (102, 107))
472718	21483840	The local intratumoral administration of [D]-K3H3L9 in the athymic and syngeneic mice models significantly inhibited tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mice', 'Species', '10090', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('[D]-K3H3L9', 'Chemical', '-', (41, 51))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('[D]-K3H3L9', 'Var', (41, 51))	('inhibited', 'NegReg', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
472723	21483840	Overall survival is approximately 50% at 5 years and up to 60% of high grade STS develop distant metastases; these data support the use of an aggressive approach for the treatment STS.	('develop', 'Reg', (81, 88))	('high grade', 'Var', (66, 76))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('metastases', 'Disease', (97, 107))
472731	21483840	D-amino acid peptides could show potent oncolytic activity and high selectivity in prostate carcinoma and preserved their activity also in xenograft models in vivo .	('peptides', 'Chemical', 'MESH:D010455', (13, 21))	('D-amino acid peptide', 'Chemical', '-', (0, 20))	('prostate carcinoma', 'Disease', (83, 101))	('prostate carcinoma', 'Disease', 'MESH:D011472', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('D-amino acid peptides', 'Var', (0, 21))	('oncolytic', 'CPA', (40, 49))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (83, 101))	('activity', 'MPA', (122, 130))
472735	21483840	D-amino acids instead can bind better to negatively charged membranes of tumors than to zwitterionic membranes of normal mammalian cells.	('mammalian', 'Species', '9606', (121, 130))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('bind', 'Interaction', (26, 30))	('D-amino acids', 'Var', (0, 13))	('tumors', 'Disease', (73, 79))	('D-amino acids', 'Chemical', '-', (0, 13))
472740	21483840	In previous studies the [D]-K3H3L9 peptide has already shown an oncolytic activity against prostate carcinoma in cell culture and also in an in vivo xenograft model.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('[D]-K3H3L9', 'Chemical', '-', (24, 34))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (91, 109))	('[D]-K3H3L9', 'Var', (24, 34))	('oncolytic activity', 'MPA', (64, 82))	('prostate carcinoma', 'Disease', (91, 109))	('prostate carcinoma', 'Disease', 'MESH:D011472', (91, 109))
472808	21483840	At higher dosage [D]-K3H3L9 displayed an antiproliferative effect towards both sarcoma cell lines.	('sarcoma', 'Disease', (79, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('[D]-K3H3L9', 'Chemical', '-', (17, 27))	('antiproliferative effect', 'CPA', (41, 65))	('[D]-K3H3L9', 'Var', (17, 27))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
472810	21483840	As well as for the determination of cell vitality and proliferation the assay revealed a dose dependence regarding the genotoxic effect of [D]-K3H3L9.	('[D]-K3H3L9', 'Var', (139, 149))	('genotoxic', 'CPA', (119, 128))	('[D]-K3H3L9', 'Chemical', '-', (139, 149))
472813	21483840	Note that the BFS-1 cells show a destroyed structure after treatment with 50 microM of [D]-K3H3L9 whereas SW982 cells have almost intact cell compartments and membranes.	('structure', 'MPA', (43, 52))	('destroyed', 'NegReg', (33, 42))	('[D]-K3H3L9', 'Var', (87, 97))	('BFS', 'Chemical', 'MESH:C006703', (14, 17))	('SW982', 'CellLine', 'CVCL:1734', (106, 111))	('[D]-K3H3L9', 'Chemical', '-', (87, 97))
472852	21483840	In both cases (SW982 and BFS-1) a significant inhibition of vessel formation are seen after [D]-K3H3L9 therapy.	('SW982', 'CellLine', 'CVCL:1734', (15, 20))	('inhibition', 'NegReg', (46, 56))	('[D]-K3H3L9', 'Var', (92, 102))	('BFS', 'Chemical', 'MESH:C006703', (25, 28))	('vessel formation', 'CPA', (60, 76))	('[D]-K3H3L9', 'Chemical', '-', (92, 102))
472856	21483840	The most important result is that [D]-K3H3L9 markedly reduced tumor volume in both athymic and immunocompetent xenografts, and the tumor completely disappeared in two of the mice.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('[D]-K3H3L9', 'Chemical', '-', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (62, 67))	('[D]-K3H3L9', 'Var', (34, 44))	('tumor', 'Disease', (131, 136))	('reduced', 'NegReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
472860	21483840	In addition, [D]-K3H3L9 is selective towards and much more active on the sarcoma cells than the primary human fibroblasts.	('more', 'PosReg', (54, 58))	('active', 'MPA', (59, 65))	('[D]-K3H3L9', 'Chemical', '-', (13, 23))	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('human', 'Species', '9606', (104, 109))	('[D]-K3H3L9', 'Var', (13, 23))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
472867	21483840	A comparison of cell viability between primary human fibroblasts, which normally occur in physiological conditions, at pH 7.3, and malignant cells in acidic milieu (pH 6.3) demonstrates a strong selectivity of [D]-K3H3L9 against cancer cells.	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('[D]-K3H3L9', 'Chemical', '-', (210, 220))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('[D]-K3H3L9', 'Var', (210, 220))	('human', 'Species', '9606', (47, 52))
472885	21483840	In addition to the potent inhibition of tumor growth the immunohistochemical laminin-staining of the tumors treated with [D]-K3H3L9 revealed a significant decrease in vasculature compared with untreated mice (Fig.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('vasculature', 'MPA', (167, 178))	('mice', 'Species', '10090', (203, 207))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (101, 106))	('[D]-K3H3L9', 'Chemical', '-', (121, 131))	('inhibition', 'NegReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('decrease', 'NegReg', (155, 163))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('[D]-K3H3L9', 'Var', (121, 131))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumors', 'Disease', (101, 107))
472893	21483840	In summary, this study shows that [D]-K3H3L9 can be administered intratumorally, and it dramatically reduces the tumor growth of various sarcoma xenografts.	('tumor', 'Disease', (113, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('[D]-K3H3L9', 'Chemical', '-', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('[D]-K3H3L9', 'Var', (34, 44))	('reduces', 'NegReg', (101, 108))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('sarcoma', 'Disease', (137, 144))
472897	21483840	In addition, the immunogenicity of short fragments containing D-amino acids has been shown to be reduced markedly compared with their all-L- or all-D-amino acid derivates.	('D-amino acids', 'Chemical', '-', (62, 75))	('reduced', 'NegReg', (97, 104))	('immunogenicity', 'MPA', (17, 31))	('D-amino acid', 'Chemical', '-', (62, 74))	('D-amino acids', 'Var', (62, 75))	('D-amino acid', 'Chemical', '-', (148, 160))
473036	23638012	CCSK is the most frequently hypermethylated, but least frequently hypomethylated, at CpG sites among these sarcomas, and exhibited 490 hypermethylated and 46 hypomethylated CpG sites in compared with NK.	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('hypermethylated', 'Var', (135, 150))	('CCSK', 'Chemical', '-', (0, 4))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('CCSK', 'Gene', (0, 4))	('CCSK', 'Phenotype', 'HP:0006770', (0, 4))	('NK', 'Phenotype', 'HP:0009726', (200, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('sarcomas', 'Disease', (107, 115))
473039	23638012	Moreover, combined bisulfite restriction analysis could be applied for the detection of hypermethylation of a THBS1 CpG site.	('bisulfite', 'Chemical', 'MESH:C042345', (19, 28))	('hypermethylation', 'Var', (88, 104))	('THBS1', 'Gene', (110, 115))
473045	23638012	CMN is a kind of fibroblastic sarcoma of infancy and characterized by a specific chromosomal translocation, t(12;15)(p13;q25), which results in the fusion of ETV6 and NTRK3 genes.	('CMN', 'Disease', (0, 3))	('CMN', 'Phenotype', 'HP:0100881', (0, 3))	('ETV6', 'Gene', (158, 162))	('sarcoma of infancy', 'Disease', (30, 48))	('ETV6', 'Gene', '2120', (158, 162))	('t(12;15)(p13;q25', 'Var', (108, 124))	('NTRK3', 'Gene', '4916', (167, 172))	('t(12;15)(p13;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (108, 125))	('sarcoma of infancy', 'Disease', 'MESH:D012509', (30, 48))	('fusion', 'Var', (148, 154))	('NTRK3', 'Gene', (167, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
473047	23638012	RTK is a highly aggressive tumor occurring in young children, has a dismal outcome, and is characterized by pathological rhabdoid features and molecular biallelic inactivation of the SMARCB1 (hSNF5/INI1) gene.	('SMARCB1', 'Gene', '6598', (183, 190))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('INI1', 'Gene', (198, 202))	('children', 'Species', '9606', (52, 60))	('biallelic', 'Var', (153, 162))	('SMARCB1', 'Gene', (183, 190))	('tumor', 'Disease', (27, 32))	('INI1', 'Gene', '6598', (198, 202))	('hSNF5', 'Gene', '6598', (192, 197))	('RTK', 'Disease', (0, 3))	('hSNF5', 'Gene', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
473050	23638012	In RTK and CMN, molecular markers, i.e., loss of SMARCB1 expression and ETV6-NTRK3 fusion, respectively, are useful for an ancillary diagnosis, whereas the diagnosis of nephroblastoma and CCSK is exclusively based on histologic features.	('ETV6-NTRK3 fusion', 'Gene', (72, 89))	('expression', 'MPA', (57, 67))	('loss', 'Var', (41, 45))	('CMN', 'Phenotype', 'HP:0100881', (11, 14))	('nephroblastoma', 'Disease', 'MESH:D009396', (169, 183))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (72, 89))	('nephroblastoma', 'Disease', (169, 183))	('CCSK', 'Phenotype', 'HP:0006770', (188, 192))	('SMARCB1', 'Gene', '6598', (49, 56))	('CCSK', 'Disease', (188, 192))	('CCSK', 'Chemical', '-', (188, 192))	('nephroblastoma', 'Phenotype', 'HP:0002667', (169, 183))	('SMARCB1', 'Gene', (49, 56))
473053	23638012	Alterations of DNA methylation have been well documented as an important peculiarity of cancer cells, and two patterns of DNA-methylation changes have been observed in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('DNA', 'Protein', (15, 18))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
473054	23638012	The other is hypermethylation of CpG islands located in promoter regions of tumor suppressor genes that has conventionally been associated with transcriptional silencing in cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('hypermethylation', 'Var', (13, 29))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
473055	23638012	These aberrant DNA methylations are thought to be closely related to the development of cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('aberrant', 'Var', (6, 14))	('related', 'Reg', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
473056	23638012	In Wilms' tumor, hypermethylation of HACE1, RASSF1A and SIM1 and hypomethylation of GRIPR were reported, whereas the DNA methylation analysis in pediatric renal sarcomas including RTK, CCSK has not been reported yet.	('HACE1', 'Gene', (37, 42))	('RASSF1A', 'Gene', '11186', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('GRIPR', 'Gene', (84, 89))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (3, 15))	('RASSF1A', 'Gene', (44, 51))	('SIM1', 'Gene', (56, 60))	('pediatric renal sarcomas', 'Disease', (145, 169))	('CCSK', 'Disease', (185, 189))	('CCSK', 'Chemical', '-', (185, 189))	('reported', 'Reg', (95, 103))	('RTK', 'Disease', (180, 183))	('pediatric renal sarcomas', 'Disease', 'MESH:D007674', (145, 169))	('hypomethylation', 'Var', (65, 80))	("Wilms' tumor", 'Disease', (3, 15))	("Wilms' tumor", 'Disease', 'MESH:D009396', (3, 15))	('renal sarcomas', 'Phenotype', 'HP:0008663', (155, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('CCSK', 'Phenotype', 'HP:0006770', (185, 189))	('HACE1', 'Gene', '57531', (37, 42))	('hypermethylation', 'Var', (17, 33))
473075	23638012	The numbers of selected hyper- and hypomethylated CpG probes in each tumor are listed in Table 2.	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('hypomethylated', 'Var', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
473079	23638012	To further select marker genes for methylation-based tumor-type classification, we defined tumor-specific differentially methylated genes as those with average beta-value differences of >0.3 (hypermethylated) or <-0.3 (hypomethylated) compared to each of other tumor groups and NK.	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NK', 'Phenotype', 'HP:0009726', (278, 280))	('<-0.3', 'Var', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('tumor', 'Disease', (91, 96))
473083	23638012	MGMT and PTEN were selected because of hypermethylation in 3 tumors, while VHL was selected because of hypomethylation in CCSK and RTK.	('VHL', 'Disease', (75, 78))	('MGMT', 'Gene', (0, 4))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('CCSK', 'Chemical', '-', (122, 126))	('PTEN', 'Gene', (9, 13))	('CCSK', 'Phenotype', 'HP:0006770', (122, 126))	('PTEN', 'Gene', '5728', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('hypermethylation', 'Var', (39, 55))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('VHL', 'Disease', 'MESH:D006623', (75, 78))	('MGMT', 'Gene', '4255', (0, 4))
473086	23638012	As shown in Figure 2A, CREG1, ALDOC, THBS1, and PKN1 were hypermethylated in CCSK, whereas RTK, ESFT, and NK were hypomethylated at specific CpG loci, as analyzed by the Infinium assay.	('CCSK', 'Phenotype', 'HP:0006770', (77, 81))	('NK', 'Phenotype', 'HP:0009726', (106, 108))	('ALDOC', 'Gene', '230', (30, 35))	('CREG1', 'Gene', (23, 28))	('hypermethylated', 'Var', (58, 73))	('PKN1', 'Gene', '5585', (48, 52))	('CREG1', 'Gene', '8804', (23, 28))	('PKN1', 'Gene', (48, 52))	('CCSK', 'Disease', (77, 81))	('CCSK', 'Chemical', '-', (77, 81))	('ALDOC', 'Gene', (30, 35))
473087	23638012	PTEN was hypomethylated in NK, while variably methylated in sarcoma cases.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('NK', 'Phenotype', 'HP:0009726', (27, 29))	('hypomethylated', 'Var', (9, 23))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
473088	23638012	ADRA1D was also hypermethylated in CCSK but hypomethylated in ESFT in comparison with NK, whereas variably methylated in RTK.	('ADRA1D', 'Gene', (0, 6))	('NK', 'Phenotype', 'HP:0009726', (86, 88))	('hypomethylated', 'Var', (44, 58))	('ADRA1D', 'Gene', '146', (0, 6))	('CCSK', 'Chemical', '-', (35, 39))	('CCSK', 'Phenotype', 'HP:0006770', (35, 39))
473094	23638012	To confirm the specificity of THBS1 hypermethylation in CCSK among pediatric renal tumors, we additionally analyzed Wilms' tumor and CMN.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	("Wilms' tumor", 'Disease', (116, 128))	('CCSK', 'Disease', (56, 60))	('THBS1', 'Gene', (30, 35))	("Wilms' tumor", 'Disease', 'MESH:D009396', (116, 128))	('hypermethylation', 'Var', (36, 52))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (116, 128))	('pediatric renal tumors', 'Disease', 'MESH:D007674', (67, 89))	('CCSK', 'Chemical', '-', (56, 60))	('CCSK', 'Phenotype', 'HP:0006770', (56, 60))	('CMN', 'Phenotype', 'HP:0100881', (133, 136))	('renal tumor', 'Phenotype', 'HP:0009726', (77, 88))	('renal tumors', 'Phenotype', 'HP:0009726', (77, 89))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('pediatric renal tumors', 'Disease', (67, 89))
473097	23638012	As shown in Figure 4 and Table 4, the digestion of bisulfite PCR products with HpyCH4IV clearly indicated that a CpG site of THBS1 in all CCSK cases was hypermethylated.	('hypermethylated', 'Var', (153, 168))	('CCSK', 'Disease', (138, 142))	('CCSK', 'Chemical', '-', (138, 142))	('CCSK', 'Phenotype', 'HP:0006770', (138, 142))	('bisulfite', 'Chemical', 'MESH:C042345', (51, 60))
473098	23638012	However, none of other tumor groups exhibited hypermethylation of the CpG site of THBS1.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('hypermethylation', 'Var', (46, 62))	('tumor', 'Disease', (23, 28))	('THBS1', 'Gene', (82, 87))
473099	23638012	The results strongly indicate that hypermethylation of THBS1 is a specific characteristic of CCSK among pediatric renal tumors, and could be utilized as diagnostic maker of this tumor.	('hypermethylation', 'Var', (35, 51))	('tumor', 'Disease', (178, 183))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('pediatric renal tumors', 'Disease', 'MESH:D007674', (104, 126))	('renal tumors', 'Phenotype', 'HP:0009726', (114, 126))	('CCSK', 'Disease', (93, 97))	('renal tumor', 'Phenotype', 'HP:0009726', (114, 125))	('CCSK', 'Chemical', '-', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('THBS1', 'Gene', (55, 60))	('CCSK', 'Phenotype', 'HP:0006770', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('pediatric renal tumors', 'Disease', (104, 126))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (120, 125))
473106	23638012	For example, biallelic inactivation of SMARCB1 as evidenced by negative immunohistochemical staining has high sensitivity and specificity for the diagnosis of RTK, and ETV6-NTRK3 fusion is a marker for CMN of the cellular type.	('SMARCB1', 'Gene', '6598', (39, 46))	('SMARCB1', 'Gene', (39, 46))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (168, 185))	('RTK', 'Disease', (159, 162))	('ETV6-NTRK3 fusion', 'Gene', (168, 185))	('CMN', 'Phenotype', 'HP:0100881', (202, 205))	('biallelic inactivation', 'Var', (13, 35))
473108	23638012	Since THBS1 hypermethylation is highly specific for CCSK, as we presented in this study, this finding should be useful for a molecular marker of this tumor.	('THBS1', 'Gene', (6, 11))	('CCSK', 'Disease', (52, 56))	('hypermethylation', 'Var', (12, 28))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('CCSK', 'Chemical', '-', (52, 56))	('CCSK', 'Phenotype', 'HP:0006770', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
473110	23638012	DNA methylation has been proposed as a diagnostic marker for certain cancers.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
473112	23638012	In contrast, our findings showed that hypermethylation of a single locus of THBS1 is sufficient for the differentiation of CCSK from other pediatric tumors and it could serve as a robust diagnostic marker for this tumor.	('hypermethylation', 'Var', (38, 54))	('CCSK', 'Chemical', '-', (123, 127))	('CCSK', 'Phenotype', 'HP:0006770', (123, 127))	('pediatric tumors', 'Disease', 'MESH:D063766', (139, 155))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('pediatric tumors', 'Disease', (139, 155))	('THBS1', 'Gene', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (214, 219))	('CCSK', 'Disease', (123, 127))
473113	23638012	Hypermethylation of the THBS1 CpG site has been observed in some tumors.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Hypermethylation', 'Var', (0, 16))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('observed', 'Reg', (48, 56))
473115	23638012	also reported that the hypermethylation of THBS1 is associated with a poor prognosis in penile squamous cell carcinoma.	('penile squamous cell carcinoma', 'Disease', 'MESH:D004414', (88, 118))	('associated', 'Reg', (52, 62))	('penile squamous cell carcinoma', 'Disease', (88, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('hypermethylation', 'Var', (23, 39))	('THBS1', 'Gene', (43, 48))
473117	23638012	By employing a knockout mouse model, several studies have shown that the absence of THBS1 leads to increased vascularization and THBS1 protein inhibits tumor progression in several ways, including direct effects on cellular growth and apoptosis in the stromal compartment.	('apoptosis', 'CPA', (235, 244))	('cellular growth', 'CPA', (215, 230))	('inhibits', 'NegReg', (143, 151))	('mouse', 'Species', '10090', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('THBS1', 'Var', (129, 134))	('THBS1', 'Gene', (84, 89))	('vascularization', 'CPA', (109, 124))	('increased', 'PosReg', (99, 108))	('protein', 'Protein', (135, 142))	('absence', 'Var', (73, 80))
473118	23638012	Since CCSK is known to be rich in a fine vascular network, it is reasonable to presume that hypermethylation of the THBS1 CpG site is involved in the pathogenesis of CCSK.	('CCSK', 'Chemical', '-', (6, 10))	('involved', 'Reg', (134, 142))	('CCSK', 'Phenotype', 'HP:0006770', (6, 10))	('CCSK', 'Disease', (166, 170))	('hypermethylation', 'Var', (92, 108))	('CCSK', 'Chemical', '-', (166, 170))	('CCSK', 'Phenotype', 'HP:0006770', (166, 170))	('THBS1', 'Gene', (116, 121))
473119	23638012	This is possibly due to hypermethylated CpG sites of THBS1 in CCSK that we identified as not being responsible for THBS1 expression, and other CpG sites are related to the regulation of THBS1 expression.	('THBS1', 'Gene', (53, 58))	('hypermethylated', 'Var', (24, 39))	('CCSK', 'Phenotype', 'HP:0006770', (62, 66))	('CCSK', 'Chemical', '-', (62, 66))
473120	23638012	In fact, other CpG probes (cg19570574: chr15: 37660116-37660117/hg18, cg04051458: chr15: 37660352-37660353/hg18) in the upstream region of the THBS1 transcription start site were hypomethylated in CCSK based on our assay.	('CCSK', 'Phenotype', 'HP:0006770', (197, 201))	('cg04051458: chr15', 'Var', (70, 87))	('cg19570574:', 'Var', (27, 38))	('CCSK', 'Disease', (197, 201))	('hypomethylated', 'Var', (179, 193))	('CCSK', 'Chemical', '-', (197, 201))
473134	32019274	SS18-SSX1 and miR-214 cointroduction accelerated sarcoma onset, indicating that miR-214 is a cooperative oncomiR in synovial sarcomagenesis.	('miR', 'Gene', (80, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('miR', 'Gene', (109, 112))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '735281', (80, 83))	('SSX1', 'Gene', '6756', (5, 9))	('sarcoma', 'Disease', 'MESH:D012509', (125, 132))	('miR', 'Gene', '735281', (109, 112))	('SSX1', 'Gene', (5, 9))	('sarcoma', 'Disease', (125, 132))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (116, 139))	('miR', 'Gene', '735281', (14, 17))	('accelerated', 'PosReg', (37, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcomagenesis', 'Disease', (116, 139))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('sarcoma', 'Disease', (49, 56))	('synovial sarcomagenesis', 'Disease', 'MESH:D013581', (116, 139))	('cointroduction', 'Var', (22, 36))
473142	32019274	In addition, SWI/SNF disruption by SS18-SSX fusion proteins induces activation of WNT/beta-catenin signaling.	('SWI/SNF', 'Gene', (13, 20))	('SSX', 'Gene', '6757', (40, 43))	('beta-catenin', 'Gene', (86, 98))	('SSX', 'Gene', (40, 43))	('activation', 'PosReg', (68, 78))	('disruption', 'Var', (21, 31))	('beta-catenin', 'Gene', '12387', (86, 98))
473144	32019274	Although PTEN, CTNNB1, and APC mutations have been reported in synovial sarcoma, the frequency of secondary mutations in this disease is not very high.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (63, 79))	('synovial sarcoma', 'Disease', 'MESH:D013584', (63, 79))	('mutations', 'Var', (31, 40))	('CTNNB1', 'Gene', (15, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('reported', 'Reg', (51, 59))	('PTEN', 'Gene', '19211', (9, 13))	('PTEN', 'Gene', (9, 13))	('APC', 'Disease', 'MESH:D011125', (27, 30))	('APC', 'Disease', (27, 30))	('synovial sarcoma', 'Disease', (63, 79))	('CTNNB1', 'Gene', '12387', (15, 21))
473152	32019274	We showed that expression of microRNA miR-214 accelerates the onset of synovial sarcoma.	('microRNA miR-214', 'Var', (29, 45))	('accelerates', 'PosReg', (46, 57))	('synovial sarcoma', 'Disease', (71, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (71, 87))	('synovial sarcoma', 'Disease', 'MESH:D013584', (71, 87))
473167	32019274	Together, these results show that introduction of SS18-SSX1 into eMCs can induce sarcomas which recapitulated the phenotypes of human synovial sarcoma, such as typical biphasic morphologies and expression of synovial sarcoma-specific biomarkers.	('induce', 'PosReg', (74, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('synovial sarcoma', 'Disease', (208, 224))	('sarcomas', 'Disease', (81, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('synovial sarcoma', 'Disease', (134, 150))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (208, 224))	('SSX1', 'Gene', '6756', (55, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('human', 'Species', '9606', (128, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))	('synovial sarcoma', 'Disease', 'MESH:D013584', (208, 224))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (134, 150))	('SSX1', 'Gene', (55, 59))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('introduction', 'Var', (34, 46))	('synovial sarcoma', 'Disease', 'MESH:D013584', (134, 150))
473169	32019274	Gene set enrichment analysis (GSEA) using gene sets for eMCs showed enrichment of the SNF5 gene set containing genes upregulated in mouse embryonic fibroblasts with Snf5 knockout in the SS18-SSX1-expressing cohort (Figure 2A and Table S1), and the changes were detected 48 h after SS18-SSX1 introduction.	('knockout', 'Var', (170, 178))	('Snf5', 'Gene', (165, 169))	('SNF5', 'Gene', (86, 90))	('Snf5', 'Gene', '20587', (165, 169))	('upregulated', 'PosReg', (117, 128))	('mouse', 'Species', '10090', (132, 137))	('SSX1', 'Gene', '6756', (191, 195))	('SSX1', 'Gene', '6756', (286, 290))	('SNF5', 'Gene', '20587', (86, 90))	('GSEA', 'Chemical', '-', (30, 34))	('SSX1', 'Gene', (191, 195))	('SSX1', 'Gene', (286, 290))
473173	32019274	Upregulation of ATF2 and TLE1 is important in the development of human synovial sarcoma and recruitment of TLE1 to the ATF2 binding locus downregulates expression of the tumor suppressor EGR1.	('human', 'Species', '9606', (65, 70))	('TLE1', 'Gene', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('synovial sarcoma', 'Disease', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (71, 87))	('synovial sarcoma', 'Disease', 'MESH:D013584', (71, 87))	('downregulates', 'NegReg', (138, 151))	('expression', 'MPA', (152, 162))	('recruitment', 'Var', (92, 103))
473180	32019274	Southern blotting showed that tumors showed integrations of multiple retroviral copies (Figure S1A).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('integrations', 'Var', (44, 56))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
473190	32019274	To examine the cooperativity between SS18-SSX1 and miR-199a2 or miR-214, SS18-SSX1, either microRNA sequences were coexpressed in eMCs and subjected to sarcoma induction experiments (Figure 4A).	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('SSX1', 'Gene', (78, 82))	('sarcoma', 'Disease', (152, 159))	('SSX1', 'Gene', '6756', (42, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('miR-214', 'Var', (64, 71))	('SSX1', 'Gene', (42, 46))	('SSX1', 'Gene', '6756', (78, 82))
473191	32019274	Coexpression of miR-214 but not miR-199a2 significantly accelerated SS18-SSX1-induced synovial sarcoma development with 14.4 and 29.2 weeks of mean latency, respectively (Figure 4B).	('synovial sarcoma', 'Disease', 'MESH:D013584', (86, 102))	('miR-214', 'Var', (16, 23))	('SSX1', 'Gene', '6756', (73, 77))	('synovial sarcoma', 'Disease', (86, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('SSX1', 'Gene', (73, 77))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (86, 102))	('accelerated', 'PosReg', (56, 67))
473195	32019274	In situ hybridization showed miR-214 expression in both the nucleus and cytoplasm of SS18-SSX1- and miR-214-coexpressing tumor cells (Figure 4F), suggesting that miR-214 mainly functions in tumor cells.	('SSX1', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('miR-214', 'Gene', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (190, 195))	('SSX1', 'Gene', '6756', (90, 94))	('miR-214-coexpressing', 'Var', (100, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
473196	32019274	Subsequently, we found that expression of miR-214 was correlated with a worse prognosis in human synovial sarcoma cases (Figure 4G).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (97, 113))	('synovial sarcoma', 'Disease', 'MESH:D013584', (97, 113))	('expression', 'MPA', (28, 38))	('miR-214', 'Var', (42, 49))	('synovial sarcoma', 'Disease', (97, 113))	('human', 'Species', '9606', (91, 96))
473201	32019274	Nevertheless, exogenous introduction of miR-214 or Dnm3os into synovial sarcomas and silencing of miR-214 by anti-miR-214 did not induce growth promotion, migration, or invasion (Figure S4B-D), suggesting that miR-214 might not function in a cell intrinsic manner.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (63, 79))	('migration', 'CPA', (155, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('invasion', 'CPA', (169, 177))	('growth promotion', 'CPA', (137, 153))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (63, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (72, 80))	('miR-214', 'Gene', (98, 105))	('synovial sarcomas', 'Disease', 'MESH:D013584', (63, 80))	('synovial sarcomas', 'Disease', (63, 80))	('Dnm3os', 'Var', (51, 57))	('silencing', 'Var', (85, 94))
473205	32019274	The mouse Cxcl15/Il8, a counterpart of human CXCL8/IL8, was upregulated in both human synovial sarcoma and mouse synovial sarcoma with miR-214 expression.	('synovial sarcoma', 'Disease', (113, 129))	('synovial sarcoma', 'Disease', 'MESH:D013584', (113, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('upregulated', 'PosReg', (60, 71))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (113, 129))	('synovial sarcoma', 'Disease', (86, 102))	('Cxcl15', 'Gene', (10, 16))	('human', 'Species', '9606', (80, 85))	('human', 'Species', '9606', (39, 44))	('mouse', 'Species', '10090', (4, 9))	('synovial sarcoma', 'Disease', 'MESH:D013584', (86, 102))	('mouse', 'Species', '10090', (107, 112))	('Il8', 'Gene', (17, 20))	('CXCL8', 'Gene', '3576', (45, 50))	('CXCL8', 'Gene', (45, 50))	('miR-214 expression', 'Var', (135, 153))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (86, 102))	('Il8', 'Gene', '20309', (17, 20))	('Cxcl15', 'Gene', '20309', (10, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
473218	32019274	Although upregulation of miR-214 in our mouse model was achieved by insertions of retroviral sequences that act as an enhancer, the mechanism of miR-214 and DNM30S upregulation in human synovial sarcoma remains unclear.	('miR-214', 'Gene', (145, 152))	('upregulation', 'PosReg', (9, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('insertions', 'Var', (68, 78))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (186, 202))	('enhancer', 'PosReg', (118, 126))	('human', 'Species', '9606', (180, 185))	('DNM30S', 'Gene', (157, 163))	('synovial sarcoma', 'Disease', 'MESH:D013584', (186, 202))	('synovial sarcoma', 'Disease', (186, 202))	('mouse', 'Species', '10090', (40, 45))	('miR-214', 'Gene', (25, 32))	('upregulation', 'PosReg', (164, 176))
473224	32019274	have recently identified gene fusions between CTDSP1/2 and DNM3OS in a subset of dedifferentiated liposarcomas.	('gene fusions', 'Var', (25, 37))	('liposarcomas', 'Phenotype', 'HP:0012034', (98, 110))	('liposarcomas', 'Disease', 'MESH:D008080', (98, 110))	('CTDSP1/2', 'Gene', (46, 54))	('liposarcomas', 'Disease', (98, 110))	('liposarcoma', 'Phenotype', 'HP:0012034', (98, 109))	('DNM3OS', 'Gene', '474332', (59, 65))	('CTDSP1/2', 'Gene', '227292;52468', (46, 54))	('DNM3OS', 'Gene', (59, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
473225	32019274	The fusions induce upregulation of both DNM3OS and miR-214, as seen in the murine synovial sarcoma with retroviral integration at the Dnm3os locus.	('DNM3OS', 'Gene', '474332', (40, 46))	('synovial sarcoma', 'Disease', (82, 98))	('murine', 'Species', '10090', (75, 81))	('DNM3OS', 'Gene', (40, 46))	('upregulation', 'PosReg', (19, 31))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (82, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('synovial sarcoma', 'Disease', 'MESH:D013584', (82, 98))	('miR-214', 'Gene', (51, 58))	('fusions', 'Var', (4, 11))
473228	32019274	Tumor suppressor Pten has been reported to be a target of miR-214 in human cancer, and its expression was indeed reduced by miR-214.	('expression', 'MPA', (91, 101))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('human', 'Species', '9606', (69, 74))	('reduced', 'NegReg', (113, 120))	('Tumor', 'Protein', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('miR-214', 'Var', (58, 65))	('miR-214', 'Var', (124, 131))
473229	32019274	In our study, downregulation of Pten did not show a remarkable growth promoting effect (Figure S5A,B), although a previous study showed that Pten knockout in the SS18-SSX1- and SS18-SSX2-induced synovial sarcoma mouse models promoted invasion and metastasis.	('Pten', 'Gene', (141, 145))	('promoted', 'PosReg', (225, 233))	('SSX1', 'Gene', '6756', (167, 171))	('synovial sarcoma', 'Disease', (195, 211))	('SSX1', 'Gene', (167, 171))	('SSX2', 'Gene', '6757', (182, 186))	('synovial sarcoma', 'Disease', 'MESH:D013584', (195, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('SSX2', 'Gene', (182, 186))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (195, 211))	('knockout', 'Var', (146, 154))	('mouse', 'Species', '10090', (212, 217))
473236	32019274	Functional modulation of tumor-associated neutrophils by IL-8 has also been described as a poor prognostic factor for malignancies.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('modulation', 'Var', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('IL-8', 'Gene', (57, 61))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('malignancies', 'Disease', (118, 130))
473237	32019274	As the tumor promoting effect of Dnm3os via cancer-associated fibroblasts was also demonstrated in esophageal cancer, dynamic modulation of the tumor microenvironment might also be achieved by the Dnm3os/miR-214 axis.	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', (110, 116))	('Dnm3os', 'Var', (33, 39))	('tumor', 'Disease', (7, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('esophageal cancer', 'Disease', (99, 116))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
473239	32019274	Nevertheless, significant acceleration of sarcoma development was achieved by miR-214 expression, indicating that T-cell function is dispensable for miR-214-induced modulation of the tumor microenvironment.	('sarcoma', 'Disease', (42, 49))	('miR-214 expression', 'Var', (78, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('expression', 'Var', (86, 96))	('acceleration', 'PosReg', (26, 38))
473240	32019274	Modulations of the adenosine A2A receptor and the TGF-beta signaling by miR-214 have been proposed to have potential roles in cytokine secretion and in the inflammatory response.	('miR-214', 'Var', (72, 79))	('cytokine secretion', 'MPA', (126, 144))	('adenosine A2A receptor', 'Gene', (19, 41))	('inflammatory response', 'CPA', (156, 177))	('TGF-beta', 'MPA', (50, 58))	('adenosine A2A receptor', 'Gene', '11540', (19, 41))	('Modulations', 'Var', (0, 11))	('roles', 'Reg', (117, 122))
473241	32019274	A previous study showed that long non-coding RNA NEAT1 transactivates IL-8 by relocating SFPQ to the nuclear paraspeckle.	('transactivates', 'Var', (55, 69))	('SFPQ', 'Gene', (89, 93))	('SFPQ', 'Gene', '71514', (89, 93))	('relocating', 'PosReg', (78, 88))	('NEAT1', 'Gene', '66961', (49, 54))	('NEAT1', 'Gene', (49, 54))	('IL-8', 'Gene', (70, 74))
473253	32019274	The following primary antibodies were used: Anti-FLAG M2 (Sigma, Burlington, MA, USA), anti-AE1/AE3 (DAKO, Santa Clara, CA, USA), anti-BCL2 (Santa Cruz Biotechnology, Dallas, TX, USA), anti-TLE1 (Santa Cruz Biotechnology), and anti-CD163 (Bioss Antibodies, Woburn, MA, USA).	('AE1/AE3', 'Gene', '20533;20536', (92, 99))	('CD163', 'Gene', (232, 237))	('AE1/AE3', 'Gene', (92, 99))	('anti-BCL2', 'Var', (130, 139))	('CD163', 'Gene', '93671', (232, 237))	('anti-TLE1', 'Var', (185, 194))
473254	32019274	The following primary antibodies were used: Anti-FLAG (M2, Sigma), anti-alpha-tubulin (Sigma), anti-Pten (Cell Signaling Technology, Danvers, MA, USA), anti-Timp2 (Cell Signaling Technology), anti-Ezh1 (Santa Cruz), and anti-Gapdh (Hytest, Turku, Finland).	('Timp2', 'Gene', (157, 162))	('Timp2', 'Gene', '21858', (157, 162))	('anti-Pten', 'Var', (95, 104))	('Ezh1', 'Gene', '14055', (197, 201))	('Gapdh', 'Gene', '14433', (225, 230))	('Gapdh', 'Gene', (225, 230))	('Ezh1', 'Gene', (197, 201))	('anti-alpha-tubulin', 'Var', (67, 85))
473257	32019274	Gene expression data of human sarcoma samples were obtained from the GEO database (GSE20196, GES87437, GSE12102, GSE32569, and GSE66533).	('human', 'Species', '9606', (24, 29))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('GES87437', 'Var', (93, 101))	('GSE12102', 'Var', (103, 111))	('GES87437', 'Chemical', '-', (93, 101))	('sarcoma', 'Disease', (30, 37))	('GSE20196', 'Var', (83, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('GSE66533', 'Var', (127, 135))
473259	32019274	Probes and primers for pri-miR-214, miR-214_3p, miR-214_5p, pri-miR-199a-2, miR-199a-2_3p, miR-199a-2_5p, sno202, and u6 were purchased from Thermo Fisher Scientific.	('miR-199a-2', 'Gene', (76, 86))	('miR-199a-2', 'Gene', '723821', (64, 74))	('miR-214_5p', 'Var', (48, 58))	('miR-199a-2', 'Gene', (91, 101))	('miR-214_3p', 'Var', (36, 46))	('miR-199a-2', 'Gene', '723821', (76, 86))	('miR-199a-2', 'Gene', (64, 74))	('miR-199a-2', 'Gene', '723821', (91, 101))
473283	31754538	They are associated with a non-random, reciprocal translocation between chromosomes 11 and 22, t(11;22) (q24;q12), with the resultant formation of EWS E26 transformation specific-fusion gene.	('t(11;22) (q24;q12', 'Var', (95, 112))	('EWS', 'Gene', (147, 150))	('EWS', 'Gene', '2130', (147, 150))
473313	31754538	Areas of haemorrhage or necrosis may be evident as regions of high signal intensity on T1WI and T2WI compared to the skeletal muscle.	('T2WI', 'Var', (96, 100))	('haemorrhage or necrosis', 'Disease', 'MESH:D006470', (9, 32))	('T1WI', 'MPA', (87, 91))	('high', 'PosReg', (62, 66))	('haemorrhage or necrosis', 'Disease', (9, 32))
473320	31754538	Definitive diagnosis is made with Fluorescence in-situ hybridisation (FISH) to detect the rearrangement of the 22q12 (EWSR1 gene).	('EWS', 'Gene', (118, 121))	('rearrangement', 'Var', (90, 103))	('EWS', 'Gene', '2130', (118, 121))
473350	30314519	Identification of a novel MTAP-RAF1 fusion in a soft tissue sarcoma RAF family activating fusions have been described as a potentially targetable molecular finding in a subset of soft tissue sarcomas.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (179, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (48, 67))	('RAF1', 'Gene', (31, 35))	('fusion', 'Var', (36, 42))	('RAF', 'Gene', '22882', (31, 34))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('MTAP', 'Gene', (26, 30))	('sarcoma', 'Disease', (60, 67))	('MTAP', 'Gene', '4507', (26, 30))	('RAF', 'Gene', (31, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('RAF', 'Gene', '22882', (68, 71))	('soft tissue sarcomas', 'Disease', (179, 199))	('sarcoma', 'Disease', 'MESH:D012509', (191, 198))	('sarcoma', 'Disease', (191, 198))	('sarcomas', 'Phenotype', 'HP:0100242', (191, 199))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (179, 199))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (179, 198))	('RAF', 'Gene', (68, 71))	('RAF1', 'Gene', '5894', (31, 35))
473351	30314519	To further expand upon the landscape of this genetic feature, we describe a novel MTAP-RAF1 activating fusion identified in a S100 positive soft tissue sarcoma.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (140, 159))	('S100', 'Gene', (126, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('fusion', 'Var', (103, 109))	('MTAP', 'Gene', (82, 86))	('S100', 'Gene', '6271', (126, 130))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (140, 159))	('RAF1', 'Gene', (87, 91))	('RAF1', 'Gene', '5894', (87, 91))	('MTAP', 'Gene', '4507', (82, 86))	('soft tissue sarcoma', 'Disease', (140, 159))	('activating', 'PosReg', (92, 102))
473354	30314519	Comprehensive molecular profiling was performed to help establish the diagnosis and revealed a novel MTAP-RAF1 fusion that includes the tyrosine kinase domain of RAF1.	('MTAP', 'Gene', (101, 105))	('MTAP', 'Gene', '4507', (101, 105))	('RAF1', 'Gene', (106, 110))	('fusion', 'Var', (111, 117))	('RAF1', 'Gene', '5894', (106, 110))	('RAF1', 'Gene', '5894', (162, 166))	('RAF1', 'Gene', (162, 166))	('tyrosine kinase domain', 'MPA', (136, 158))
473356	30314519	Identification of novel fusions involving the MAPK/ERK pathway in sarcomas may provide new avenues for precision medicine strategies involving targeted kinase inhibitors.	('ERK', 'Gene', (51, 54))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('ERK', 'Gene', '5594', (51, 54))	('MAPK', 'Gene', '5594', (46, 50))	('sarcomas', 'Disease', (66, 74))	('MAPK', 'Gene', (46, 50))	('fusions', 'Var', (24, 31))
473358	30314519	To further expand upon the landscape of activating RAF family fusions identified in sarcomas, we report a case of soft tissue sarcoma harboring a novel MTAP-RAF1 fusion.	('RAF', 'Gene', (157, 160))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (114, 133))	('RAF', 'Gene', '22882', (51, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('MTAP', 'Gene', (152, 156))	('RAF', 'Gene', (51, 54))	('soft tissue sarcoma', 'Disease', (114, 133))	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('MTAP', 'Gene', '4507', (152, 156))	('RAF1', 'Gene', (157, 161))	('RAF1', 'Gene', '5894', (157, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('RAF', 'Gene', '22882', (157, 160))	('fusion', 'Var', (162, 168))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (114, 133))	('sarcomas', 'Disease', (84, 92))
473372	30314519	S100 positivity is also common in ossifying fibromyxoid tumors, though is typically negative in the malignant cases.	('positivity', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('fibromyxoid tumors', 'Disease', 'MESH:D009369', (44, 62))	('fibromyxoid tumors', 'Disease', (44, 62))	('S100', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('S100', 'Gene', '6271', (0, 4))	('common', 'Reg', (24, 30))
473382	30314519	Next-generation sequencing (NGS) also reported a low tumor mutation burden of two mutations per megabase and lack of an ultraviolet (UV)-signature as measured by C   T mutations at dipyrimidine sites.	('low tumor', 'Disease', 'MESH:D009800', (49, 58))	('dipyrimidine', 'Chemical', '-', (181, 193))	('low tumor', 'Disease', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (168, 177))
473385	30314519	To our knowledge, we report the first observation of an oncogenic MTAP-RAF1 fusion.	('RAF1', 'Gene', '5894', (71, 75))	('MTAP', 'Gene', '4507', (66, 70))	('RAF1', 'Gene', (71, 75))	('fusion', 'Var', (76, 82))	('MTAP', 'Gene', (66, 70))
473389	30314519	Recurrent activating BRAF fusions have been reported in several soft tissue sarcoma subtypes.	('sarcoma subtypes', 'Disease', 'MESH:D012509', (76, 92))	('sarcoma subtypes', 'Disease', (76, 92))	('fusions', 'Var', (26, 33))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (64, 83))	('BRAF', 'Gene', '673', (21, 25))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (64, 83))	('activating', 'Var', (10, 20))	('BRAF', 'Gene', (21, 25))	('reported', 'Reg', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('soft tissue sarcoma', 'Disease', (64, 83))
473390	30314519	Additionally, BRAF activating mutations have been identified in clear cell sarcomas with observed response to vemurafenib.	('sarcomas', 'Disease', (75, 83))	('activating', 'PosReg', (19, 29))	('vemurafenib', 'Chemical', 'MESH:D000077484', (110, 121))	('BRAF', 'Gene', '673', (14, 18))	('clear cell sarcoma', 'Disease', (64, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('mutations', 'Var', (30, 39))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (64, 82))	('BRAF', 'Gene', (14, 18))	('sarcomas', 'Disease', 'MESH:D012509', (75, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
473392	30314519	Though systemic therapy was not indicated in the described case, identification of novel fusions involving the MAPK/ERK pathway in soft tissue sarcomas may provide new avenues for precision medicine strategies involving targeted kinase inhibitors.	('sarcomas', 'Phenotype', 'HP:0100242', (143, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('fusions', 'Var', (89, 96))	('MAPK', 'Gene', '5594', (111, 115))	('soft tissue sarcomas', 'Disease', (131, 151))	('ERK', 'Gene', '5594', (116, 119))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (131, 151))	('MAPK', 'Gene', (111, 115))	('ERK', 'Gene', (116, 119))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (131, 150))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (131, 151))
473405	29038346	Finally, we found that combinations with cisplatin or PARP inhibitors enhanced the anti-tumour cell effect of ATRi, suggesting that either single agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment.	('ATR', 'Gene', (152, 155))	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('SS', 'Phenotype', 'HP:0012570', (249, 251))	('ATR', 'Gene', '545', (190, 193))	('ATR', 'Gene', (190, 193))	('tumour', 'Disease', (88, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('PARP', 'Gene', '142', (54, 58))	('enhanced', 'PosReg', (70, 78))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('ATR', 'Gene', '545', (110, 113))	('ATR', 'Gene', (110, 113))	('combinations', 'Var', (23, 35))	('PARP', 'Gene', (54, 58))	('ATR', 'Gene', '545', (152, 155))
473419	29038346	The potential of such an approach is best exemplified by the use of small molecule PARP inhibitors in BRCA1/2 mutant cancers.	('PARP', 'Gene', '142', (83, 87))	('BRCA1/2', 'Gene', '672;675', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutant', 'Var', (110, 116))	('PARP', 'Gene', (83, 87))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('BRCA1/2', 'Gene', (102, 109))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
473428	29038346	In the case of the VX970 resistance screen (Figure 4), 24h after transfection, VX970 (final concentration 0.75 muM) or vehicle (DMSO) was added to cells.	('VX970', 'Gene', (19, 24))	('VX970', 'CellLine', 'CVCL:3864', (79, 84))	('VX970', 'Var', (79, 84))	('VX970', 'CellLine', 'CVCL:3864', (19, 24))	('DMSO', 'Chemical', 'MESH:D004121', (128, 132))
473430	29038346	In brief, SYO-1 and HS-SY-II cells were exposed to 0.04 muM VX970 plus a drug library of 79 small molecules (Supplementary Table 2), in a 384-well-plate format.	('VX970', 'Var', (60, 65))	('SYO-1', 'Gene', (10, 15))	('HS-SY-II', 'CellLine', 'CVCL:8719', (20, 28))	('VX970', 'CellLine', 'CVCL:3864', (60, 65))	('SYO-1', 'Gene', '55027', (10, 15))
473433	29038346	SS18-SSX1, SS18-SSX2 and the SS18-SSX1 Delta71-78 mutant cDNAs were cloned into the pLX301 lentiviral transfer vector.	('SSX2', 'Gene', (16, 20))	('SS18', 'Gene', '6760', (29, 33))	('SSX1', 'Gene', '6756', (5, 9))	('SS18', 'Gene', (11, 15))	('SS', 'Phenotype', 'HP:0012570', (16, 18))	('Delta71-78', 'Var', (39, 49))	('SSX2', 'Gene', '6757', (16, 20))	('SSX1', 'Gene', (5, 9))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SS18', 'Gene', (0, 4))	('SS', 'Phenotype', 'HP:0012570', (29, 31))	('SSX1', 'Gene', '6756', (34, 38))	('SS18', 'Gene', '6760', (11, 15))	('SSX1', 'Gene', (34, 38))	('Delta71', 'Mutation', 'c.del71', (39, 46))	('SS', 'Phenotype', 'HP:0012570', (5, 7))	('SS18', 'Gene', (29, 33))	('SS18', 'Gene', '6760', (0, 4))	('SS', 'Phenotype', 'HP:0012570', (11, 13))
473450	29038346	In vivo efficacy studies were performed using SA13412 patient-derived SS xenografts at Crown Biosciences or using HS-SY-II tumour cells grown subcutaneously in the flank of female NOD SCID mice or Balb/C nude mice at the ICR, London, respectively.	('patient', 'Species', '9606', (54, 61))	('mice', 'Species', '10090', (209, 213))	('HS-SY-II tumour', 'Disease', (114, 129))	('nude mice', 'Species', '10090', (204, 213))	('mice', 'Species', '10090', (189, 193))	('SS', 'Phenotype', 'HP:0012570', (70, 72))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('SA13412', 'Var', (46, 53))	('SCID', 'Disease', 'MESH:D053632', (184, 188))	('HS-SY-II tumour', 'Disease', 'MESH:C567159', (114, 129))	('SA13412', 'Chemical', '-', (46, 53))	('SCID', 'Disease', (184, 188))
473471	29038346	The identification of ATR as a candidate genetic dependency was particularly interesting for a number of reasons: (i) compared to other cancer histologies, we found the five SS tumour cell lines to be amongst the most sensitive tumour cell lines to ATR siRNA and to respond in a relatively consistent fashion (Figure 2A), suggesting a relatively penetrant effect; (ii) relatively little is understood about the sensitivity of SS tumours to small molecule DDR inhibitors, such as ATR inhibitors; and (iii) ATR inhibitors such as VX970 and AZD6738 have recently entered clinical trials for cancer treatment (e.g.	('VX970', 'CellLine', 'CVCL:3864', (528, 533))	('tumour', 'Disease', (228, 234))	('cancer', 'Disease', (136, 142))	('SS tumours', 'Disease', 'MESH:D009369', (426, 436))	('SS tumour', 'Disease', 'MESH:D009369', (426, 435))	('AZD6738', 'Var', (538, 545))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (588, 594))	('ATR', 'Gene', '545', (479, 482))	('ATR', 'Gene', (22, 25))	('ATR', 'Gene', '545', (249, 252))	('SS', 'Phenotype', 'HP:0012570', (174, 176))	('cancer', 'Phenotype', 'HP:0002664', (588, 594))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('ATR', 'Gene', (505, 508))	('SS tumour', 'Disease', (174, 183))	('SS tumours', 'Disease', (426, 436))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumour', 'Disease', (177, 183))	('tumour', 'Phenotype', 'HP:0002664', (429, 435))	('tumour', 'Disease', 'MESH:D009369', (429, 435))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('SS', 'Phenotype', 'HP:0012570', (426, 428))	('tumours', 'Phenotype', 'HP:0002664', (429, 436))	('tumour', 'Disease', (429, 435))	('cancer', 'Disease', 'MESH:D009369', (588, 594))	('ATR', 'Gene', '545', (22, 25))	('ATR', 'Gene', (249, 252))	('VX970', 'Var', (528, 533))	('ATR', 'Gene', (479, 482))	('SS tumour', 'Disease', 'MESH:D009369', (174, 183))	('ATR', 'Gene', '545', (505, 508))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('tumour', 'Disease', 'MESH:D009369', (228, 234))
473473	29038346	Compared to previously-validated ATRi resistant HCT116 colorectal cancer cells, all five SS cell lines were profoundly sensitive to VX970 (ANOVA p<0.0001), each exhibiting SF50 (concentration required to cause 50% reduction in cell survival) values of   0.1 microM (Figure 2B).	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('ATR', 'Gene', '545', (33, 36))	('ATR', 'Gene', (33, 36))	('SS', 'Phenotype', 'HP:0012570', (89, 91))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('HCT116', 'CellLine', 'CVCL:0291', (48, 54))	('sensitive', 'MPA', (119, 128))	('colorectal cancer', 'Disease', (55, 72))	('VX970', 'CellLine', 'CVCL:3864', (132, 137))	('VX970', 'Var', (132, 137))
473475	29038346	Defects in the tumour suppressor gene ARID1A cause ATRi sensitivity, both in vitro and in vivo.	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('ARID1A', 'Gene', '8289', (38, 44))	('ARID1A', 'Gene', (38, 44))	('tumour', 'Disease', (15, 21))	('Defects', 'Var', (0, 7))	('cause', 'Reg', (45, 50))	('ATR', 'Gene', '545', (51, 54))	('ATR', 'Gene', (51, 54))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
473477	29038346	Furthermore, when comparing the VX970 sensitivity of SS tumour cell lines to those with other molecular defects associated with ATRi sensitivity, namely ATM gene defects, ARID1A mutations and Ewing's sarcoma (EWS) associated EWS-FLI fusions, the SS tumour cell lines showed a similar extent of VX970-sensitivity to EWS tumour cells and ARID1A-defective tumour cells (Figure 1D, Supplementary Figure 1E).	('SS tumour', 'Disease', 'MESH:D009369', (53, 62))	('EWS', 'Gene', (225, 228))	('EWS', 'Phenotype', 'HP:0012254', (209, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('EWS', 'Gene', '2130', (315, 318))	('FLI', 'Gene', (229, 232))	('SS', 'Phenotype', 'HP:0012570', (246, 248))	('tumour', 'Phenotype', 'HP:0002664', (353, 359))	('ATM', 'Gene', (153, 156))	('tumour', 'Disease', 'MESH:D009369', (353, 359))	('EWS', 'Phenotype', 'HP:0012254', (225, 228))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (192, 207))	('ARID1A', 'Gene', (336, 342))	('SS tumour', 'Disease', (246, 255))	('tumour', 'Disease', (353, 359))	('EWS', 'Gene', '2130', (209, 212))	('ATR', 'Gene', '545', (128, 131))	('FLI', 'Gene', '2314', (229, 232))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (192, 207))	('VX970', 'CellLine', 'CVCL:3864', (32, 37))	('SS', 'Phenotype', 'HP:0012570', (53, 55))	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('tumour', 'Phenotype', 'HP:0002664', (319, 325))	('tumour', 'Disease', 'MESH:D009369', (249, 255))	('VX970', 'CellLine', 'CVCL:3864', (294, 299))	('tumour', 'Disease', 'MESH:D009369', (319, 325))	('EWS', 'Gene', '2130', (225, 228))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('ARID1A', 'Gene', '8289', (336, 342))	('SS tumour', 'Disease', (53, 62))	('tumour', 'Disease', (249, 255))	('tumour', 'Disease', (319, 325))	('EWS', 'Gene', (315, 318))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))	('ARID1A', 'Gene', (171, 177))	("Ewing's sarcoma", 'Disease', (192, 207))	('SS tumour', 'Disease', 'MESH:D009369', (246, 255))	('ATM', 'Gene', '472', (153, 156))	('EWS', 'Phenotype', 'HP:0012254', (315, 318))	('EWS', 'Gene', (209, 212))	('mutations', 'Var', (178, 187))	('ATR', 'Gene', (128, 131))	('ARID1A', 'Gene', '8289', (171, 177))
473478	29038346	This consistent in vitro sensitivity of SS tumour cell lines to ATRi was also observed with other ATR inhibitors, including the clinical ATRi AZD6738 (AstraZeneca) and the toolbox inhibitors AZ20 (AstraZeneca) and VE821 (Vertex Pharmaceuticals) (Supplementary Figure 1F-H), suggesting that these effects were not specific to VX970 and represented a drug class effect.	('AZ20', 'Chemical', '-', (191, 195))	('SS', 'Phenotype', 'HP:0012570', (40, 42))	('VX970', 'CellLine', 'CVCL:3864', (325, 330))	('ATR', 'Gene', '545', (64, 67))	('ATR', 'Gene', (64, 67))	('ATR', 'Gene', (98, 101))	('SS tumour', 'Disease', 'MESH:D009369', (40, 49))	('ATR', 'Gene', '545', (137, 140))	('AZD6738', 'Var', (142, 149))	('Supplementary Figure 1F-H', 'Disease', (246, 271))	('ATR', 'Gene', '545', (98, 101))	('Supplementary Figure 1F-H', 'Disease', 'MESH:D017034', (246, 271))	('ATR', 'Gene', (137, 140))	('SS tumour', 'Disease', (40, 49))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))
473480	29038346	Treatment of mice bearing established patient-derived SS xenografts (PDX SA13412; SS18-SSX1 translocation-positive) with VX970 caused a significant inhibition of tumour growth (ANOVA p<0.0001, Figure 2E) and extended the survival of tumour-bearing mice (log-rank test p=0.0451, Figure 2F).	('mice', 'Species', '10090', (13, 17))	('extended', 'PosReg', (208, 216))	('SS', 'Phenotype', 'HP:0012570', (82, 84))	('SS18', 'Gene', (82, 86))	('VX970', 'CellLine', 'CVCL:3864', (121, 126))	('survival', 'CPA', (221, 229))	('tumour growth', 'Disease', 'MESH:D006130', (162, 175))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('tumour', 'Disease', 'MESH:D009369', (233, 239))	('tumour', 'Disease', (233, 239))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('SS', 'Phenotype', 'HP:0012570', (87, 89))	('SA13412', 'Chemical', '-', (73, 80))	('tumour', 'Disease', 'MESH:D009369', (162, 168))	('SS18', 'Gene', '6760', (82, 86))	('tumour', 'Disease', (162, 168))	('SS', 'Phenotype', 'HP:0012570', (54, 56))	('inhibition', 'NegReg', (148, 158))	('patient', 'Species', '9606', (38, 45))	('tumour growth', 'Disease', (162, 175))	('mice', 'Species', '10090', (248, 252))	('SSX1', 'Gene', '6756', (87, 91))	('VX970', 'Var', (121, 126))	('SSX1', 'Gene', (87, 91))
473486	29038346	In comparison to the expression of full-length SS18-SSX1 or SS18-SSX2 fusion proteins, expression of an SS18-SSX1 variant with the final eight residues of SSX1 deleted (Delta71-78) did not cause a reduction in SMARCB1 levels, nor an increase in AXIN2 mRNA (Figure 2G-H).	('variant', 'Var', (114, 121))	('SSX1', 'Gene', (109, 113))	('reduction', 'NegReg', (197, 206))	('Delta71', 'Mutation', 'c.del71', (169, 176))	('SS', 'Phenotype', 'HP:0012570', (104, 106))	('SS', 'Phenotype', 'HP:0012570', (65, 67))	('SMARCB1', 'Gene', '6598', (210, 217))	('AXIN2', 'Gene', (245, 250))	('SS18', 'Gene', '6760', (60, 64))	('SS18', 'Gene', (104, 108))	('SMARCB1', 'Gene', (210, 217))	('SSX1', 'Gene', '6756', (155, 159))	('SSX1', 'Gene', '6756', (52, 56))	('SSX1', 'Gene', (155, 159))	('SSX1', 'Gene', (52, 56))	('SS', 'Phenotype', 'HP:0012570', (47, 49))	('SS18', 'Gene', '6760', (104, 108))	('SS18', 'Gene', (47, 51))	('SS', 'Phenotype', 'HP:0012570', (52, 54))	('AXIN2', 'Gene', '8313', (245, 250))	('SSX2', 'Gene', (65, 69))	('increase', 'PosReg', (233, 241))	('SS', 'Phenotype', 'HP:0012570', (60, 62))	('SSX2', 'Gene', '6757', (65, 69))	('SS18', 'Gene', (60, 64))	('SSX1', 'Gene', '6756', (109, 113))	('SS18', 'Gene', '6760', (47, 51))
473497	29038346	To assess the replication fork stress phenotype in more detail, we used DNA fibre analysis and found that VX970 exposure caused a significant reduction in replication fork speed in SYO-1 SS tumour cells (p<0.0001, paired t-test, Figure 3F, Supplementary Figure 4A-B).	('reduction', 'NegReg', (142, 151))	('SS', 'Phenotype', 'HP:0012570', (187, 189))	('VX970', 'CellLine', 'CVCL:3864', (106, 111))	('VX970', 'Var', (106, 111))	('SYO-1 SS tumour', 'Disease', 'MESH:D009369', (181, 196))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('SYO-1 SS tumour', 'Disease', (181, 196))	('replication fork speed', 'MPA', (155, 177))
473501	29038346	We found that the exposure of SYO-1 cells to VX970 enhanced the R-loop IHC signal (p<0.001, Student's t-test, Figure 3H).	('enhanced', 'PosReg', (51, 59))	('VX970', 'CellLine', 'CVCL:3864', (45, 50))	('VX970', 'Var', (45, 50))	('SYO-1', 'Gene', '55027', (30, 35))	('SYO-1', 'Gene', (30, 35))	('R-loop IHC signal', 'MPA', (64, 81))
473506	29038346	To gain more insight into the processes involved in ATRi sensitivity, we took a relatively unbiased approach using an siRNA "resistance" screen to identify genes that could reverse the ATRi sensitivity phenotype in a SS tumour cell line.	('genes', 'Var', (156, 161))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('SS', 'Phenotype', 'HP:0012570', (217, 219))	('ATR', 'Gene', '545', (185, 188))	('ATR', 'Gene', (185, 188))	('SS tumour', 'Disease', 'MESH:D009369', (217, 226))	('ATR', 'Gene', '545', (52, 55))	('ATR', 'Gene', (52, 55))	('SS tumour', 'Disease', (217, 226))
473511	29038346	We found that the CCNE1 siRNA SMARTpool used in the siRNA screen also reduced the extent of VX970-induced apoptosis in SYO-1 cells (Figure 4F).	('reduced', 'NegReg', (70, 77))	('CCNE1', 'Gene', '898', (18, 23))	('CCNE1', 'Gene', (18, 23))	('VX970-induced', 'Var', (92, 105))	('SYO-1', 'Gene', (119, 124))	('VX970', 'CellLine', 'CVCL:3864', (92, 97))	('SYO-1', 'Gene', '55027', (119, 124))
473514	29038346	However, Cyclin E protein expression itself was not regulated by ectopic expression of SS18-SSX1, SS18-SSX2 or SS18-SSX1 Delta71-78 fusions (Supplementary Figure 4E).	('SS', 'Phenotype', 'HP:0012570', (98, 100))	('SSX2', 'Gene', '6757', (103, 107))	('SS18', 'Gene', (98, 102))	('SS', 'Phenotype', 'HP:0012570', (103, 105))	('SSX1', 'Gene', '6756', (92, 96))	('SSX1', 'Gene', '6756', (116, 120))	('SSX1', 'Gene', (92, 96))	('Delta71', 'Mutation', 'c.del71', (121, 128))	('SSX1', 'Gene', (116, 120))	('SS', 'Phenotype', 'HP:0012570', (87, 89))	('SS18', 'Gene', (87, 91))	('SS', 'Phenotype', 'HP:0012570', (111, 113))	('SS18', 'Gene', '6760', (98, 102))	('SS18', 'Gene', (111, 115))	('Cyclin E protein', 'Protein', (9, 25))	('SS', 'Phenotype', 'HP:0012570', (92, 94))	('SS18', 'Gene', '6760', (87, 91))	('SS18', 'Gene', '6760', (111, 115))	('Delta71-78', 'Var', (121, 131))	('SSX2', 'Gene', (103, 107))
473521	29038346	In validation experiments in a third SS tumour cell line, Yamato-SS, we found that the addition of either olaparib or talazoparib enhanced the effects of VX970 (Figure 5C-D).	('SS', 'Phenotype', 'HP:0012570', (37, 39))	('enhanced', 'PosReg', (130, 138))	('VX970', 'CellLine', 'CVCL:3864', (154, 159))	('VX970', 'Var', (154, 159))	('effects', 'MPA', (143, 150))	('olaparib', 'Chemical', 'MESH:C531550', (106, 114))	('SS tumour', 'Disease', 'MESH:D009369', (37, 46))	('talazoparib', 'Chemical', 'MESH:C586365', (118, 129))	('SS tumour', 'Disease', (37, 46))	('Yamato-SS', 'Chemical', '-', (58, 67))	('SS', 'Phenotype', 'HP:0012570', (65, 67))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))
473524	29038346	For example, in non-SS tumour cells, the combination of VX970 with platinum salts has been reported as synergistic; we found that the combination of VX970 and cisplatin generated a synergistic effect on cell inhibition in both SYO-1 and HS-SY-II cells, generating synergy volumes of 465 muM2 and 334 muM2, respectively (Figure 5E-H).	('cisplatin', 'Var', (159, 168))	('SYO-1', 'Gene', '55027', (227, 232))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('SYO-1', 'Gene', (227, 232))	('HS-SY-II', 'CellLine', 'CVCL:8719', (237, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('SS', 'Phenotype', 'HP:0012570', (20, 22))	('muM2', 'Gene', '9589', (300, 304))	('VX970', 'CellLine', 'CVCL:3864', (56, 61))	('VX970', 'CellLine', 'CVCL:3864', (149, 154))	('platinum', 'Chemical', 'MESH:D010984', (67, 75))	('SS tumour', 'Disease', 'MESH:D009369', (20, 29))	('muM2', 'Gene', (300, 304))	('SS tumour', 'Disease', (20, 29))	('cell inhibition', 'CPA', (203, 218))	('muM2', 'Gene', '9589', (287, 291))	('VX970', 'Var', (149, 154))	('muM2', 'Gene', (287, 291))
473527	29038346	We observed largely non-synergistic effects in each of these cases, although in HS-SY-II cells, the combination of VX970 plus the active derivate of cyclophosphamide (4-HC) caused a mild synergistic effect (Supplementary Figure 5).	('4-HC', 'Chemical', 'MESH:C011272', (167, 171))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (149, 165))	('synergistic effect', 'MPA', (187, 205))	('HS-SY-II', 'CellLine', 'CVCL:8719', (80, 88))	('VX970', 'Var', (115, 120))	('VX970', 'CellLine', 'CVCL:3864', (115, 120))
473535	29038346	At the mechanistic level, our data suggest that the expression of SS18-SSX fusion genes generates a relatively moderate form of replication fork stress that is enhanced by ATR inhibition (for example, Figure 3F-G).	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('SSX', 'Gene', (71, 74))	('SSX', 'Gene', '6757', (71, 74))	('enhanced', 'PosReg', (160, 168))	('ATR', 'Gene', '545', (172, 175))	('SS18', 'Gene', '6760', (66, 70))	('SS', 'Phenotype', 'HP:0012570', (66, 68))	('ATR', 'Gene', (172, 175))	('replication fork stress', 'MPA', (128, 151))	('expression', 'Var', (52, 62))	('SS18', 'Gene', (66, 70))
473541	29636527	ViscumTT treatment induced G1 arrest in TP53 wild-type and null-mutant cells, but S arrest in TP53 mutant cells.	('S arrest', 'Disease', (82, 90))	('S arrest', 'Disease', 'MESH:D006323', (82, 90))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('G1 arrest', 'CPA', (27, 36))	('mutant', 'Var', (99, 105))
473545	29636527	Enhanced CDKN1A and GADD45A expression further played a role in viscumTT-induced apoptosis with involvement of stress-induced MAPK8 and inactivation of MAPK1/3.	('inactivation', 'Var', (136, 148))	('MAPK1', 'Gene', '5594', (152, 157))	('expression', 'MPA', (28, 38))	('GADD45A', 'Gene', '1647', (20, 27))	('MAPK1', 'Gene', (152, 157))	('CDKN1A', 'Gene', '1026', (9, 15))	('MAPK8', 'Gene', '5599', (126, 131))	('viscumTT-induced', 'Disease', (64, 80))	('CDKN1A', 'Gene', (9, 15))	('GADD45A', 'Gene', (20, 27))	('MAPK8', 'Gene', (126, 131))	('Enhanced', 'PosReg', (0, 8))
473546	29636527	Furthermore, viscumTT inhibited the pro-survival pathway STAT3 by dephosphorylation of the two sites, Tyr705 and Ser727, by down-regulation of total STAT3 and its direct downstream targets BIRC5 and C-MYC.	('STAT3', 'Gene', '6774', (149, 154))	('Ser727', 'Var', (113, 119))	('down-regulation', 'NegReg', (124, 139))	('inhibited', 'NegReg', (22, 31))	('Tyr705', 'Chemical', '-', (102, 108))	('Ser727', 'Chemical', '-', (113, 119))	('C-MYC', 'Gene', (199, 204))	('STAT3', 'Gene', (149, 154))	('dephosphorylation', 'MPA', (66, 83))	('BIRC5', 'Gene', (189, 194))	('STAT3', 'Gene', '6774', (57, 62))	('STAT3', 'Gene', (57, 62))	('BIRC5', 'Gene', '332', (189, 194))	('C-MYC', 'Gene', '4609', (199, 204))	('pro-survival pathway', 'Pathway', (36, 56))	('Tyr705', 'Var', (102, 108))
473560	29636527	Around 10-20% of osteosarcomas have rearranged TP53 and dysregulated cell cycles.	('osteosarcomas', 'Disease', (17, 30))	('rearranged', 'Var', (36, 46))	('osteosarcomas', 'Phenotype', 'HP:0002669', (17, 30))	('osteosarcomas', 'Disease', 'MESH:D012516', (17, 30))	('TP53', 'Gene', '7157', (47, 51))	('dysregulated', 'Reg', (56, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('cell cycles', 'CPA', (69, 80))	('TP53', 'Gene', (47, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))
473564	29636527	Today, influencing cell cycle regulatory proteins may offer a promising approach in cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('influencing', 'Var', (7, 18))	('cell', 'Protein', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
473571	29636527	1A) and null-mutant (Saos-2) cells in G1 phase, whereas TP53 mutant cells (143B) remained in S phase (Fig.	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('mutant', 'Var', (61, 67))
473572	29636527	Likewise, viscumTT affected the cell cycle in TP53 wild-type and null-mutant cells in G1 phase, whereas TP53 mutant cells showed higher cell counts in S phase.	('affected', 'Reg', (19, 27))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('S phase', 'CPA', (151, 158))	('TP53', 'Gene', '7157', (46, 50))	('higher', 'PosReg', (129, 135))	('TP53', 'Gene', (46, 50))	('cell cycle', 'CPA', (32, 42))	('cell counts', 'CPA', (136, 147))	('mutant', 'Var', (109, 115))	('G1 phase', 'CPA', (86, 94))
473578	29636527	One of these five up-regulated genes was GADD45A which showed a 30-fold increase in TP53 wild-type and mutant cells after viscum and viscumTT treatment, but less in null mutant cells.	('increase', 'PosReg', (72, 80))	('GADD45A', 'Gene', '1647', (41, 48))	('mutant', 'Var', (103, 109))	('TP53', 'Gene', '7157', (84, 88))	('GADD45A', 'Gene', (41, 48))	('TP53', 'Gene', (84, 88))
473579	29636527	CDKN1A a second up-regulated gene was triggered predominantly by TT and viscumTT treatment and to a distinctly greater extent in TP53 mutant and null-mutant cells.	('up-regulated', 'PosReg', (16, 28))	('TP53', 'Gene', '7157', (129, 133))	('CDKN1A', 'Gene', (0, 6))	('CDKN1A', 'Gene', '1026', (0, 6))	('TP53', 'Gene', (129, 133))	('mutant', 'Var', (134, 140))
473580	29636527	SKP2 as only down-regulated gene in all three cell lines showed approximately 70-fold decrease in TP53 wild-type (U2OS) and around 20-fold decrease in mutant cells (143B) after viscum and viscumTT incubation.	('mutant', 'Var', (151, 157))	('SKP2', 'Gene', '6502', (0, 4))	('U2OS', 'CellLine', 'CVCL:0042', (114, 118))	('TP53', 'Gene', '7157', (98, 102))	('decrease', 'NegReg', (86, 94))	('decrease', 'NegReg', (139, 147))	('SKP2', 'Gene', (0, 4))	('TP53', 'Gene', (98, 102))
473583	29636527	Viscum and viscumTT increased CDKN1A to a greater extent in TP53 wild-type (up to 8-fold and 13-fold increase, respectively) and mutant cells (up to 7-fold and 15-fold increase, respectively), whereas TT (up to 8-fold increase) had the same effect in both cell lines.	('increase', 'PosReg', (168, 176))	('increased', 'PosReg', (20, 29))	('CDKN1A', 'Gene', (30, 36))	('increase', 'PosReg', (101, 109))	('CDKN1A', 'Gene', '1026', (30, 36))	('to 7', 'Species', '1214577', (146, 150))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('mutant', 'Var', (129, 135))
473585	29636527	However, GADD45A was more strongly up-regulated in TP53 wild-type (up to 56-fold after viscum and 44-fold after viscumTT) and mutant cells (up to 36-fold after viscum and 24-fold after viscumTT) than in null-mutant cells (Fig.	('GADD45A', 'Gene', (9, 16))	('TP53', 'Gene', (51, 55))	('GADD45A', 'Gene', '1647', (9, 16))	('TP53', 'Gene', '7157', (51, 55))	('mutant', 'Var', (126, 132))	('up-regulated', 'PosReg', (35, 47))
473587	29636527	On the other hand, SKP2 was drastically down-regulated (up to 140-fold decrease) in TP53 wild type (U2OS) and mutant (143B) cells after viscum and viscumTT treatment (Fig.	('U2OS', 'CellLine', 'CVCL:0042', (100, 104))	('decrease', 'NegReg', (71, 79))	('SKP2', 'Gene', (19, 23))	('mutant', 'Var', (110, 116))	('TP53', 'Gene', '7157', (84, 88))	('TP53', 'Gene', (84, 88))	('SKP2', 'Gene', '6502', (19, 23))	('down-regulated', 'NegReg', (40, 54))
473588	29636527	In TP53 null-mutant (Saos-2) cells, the effect was weaker (approximately 3-fold decrease, Fig.	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('decrease', 'NegReg', (80, 88))	('null-mutant', 'Var', (8, 19))
473591	29636527	Viscum and viscumTT led to down-regulation of CDKN1A in TP53 wild-type (U2OS) and mutant (143B) cells after 6/9 h of incubation, whereas null-mutant cells showed similar protein expression to control cells (Fig.	('CDKN1A', 'Gene', (46, 52))	('CDKN1A', 'Gene', '1026', (46, 52))	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('U2OS', 'CellLine', 'CVCL:0042', (72, 76))	('down-regulation', 'NegReg', (27, 42))	('mutant', 'Var', (82, 88))
473601	29636527	The TT-mediated G1 arrest was not prevented by knock down of GADD45A but attenuated by siCDKN1A and combined siRNAs (Fig.	('GADD45A', 'Gene', '1647', (61, 68))	('G1 arrest', 'CPA', (16, 25))	('GADD45A', 'Gene', (61, 68))	('attenuated', 'NegReg', (73, 83))	('CDKN1A', 'Gene', (89, 95))	('CDKN1A', 'Gene', '1026', (89, 95))	('knock down', 'Var', (47, 57))
473602	29636527	In TP53 mutant (143B) cells viscum led to a non-significant increase of cells in S phase but this effect was reduced by siGADD45A, left unchanged by siCDKN1A and enhanced by combined siRNAs.	('GADD45A', 'Gene', '1647', (122, 129))	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('increase', 'PosReg', (60, 68))	('mutant', 'Var', (8, 14))	('GADD45A', 'Gene', (122, 129))	('CDKN1A', 'Gene', (151, 157))	('reduced', 'NegReg', (109, 116))	('CDKN1A', 'Gene', '1026', (151, 157))	('cells in S phase', 'CPA', (72, 88))
473603	29636527	Furthermore, the TT-mediated G1 arrest increased after GADD45A knock down and decreased after siCDKN1A and the combination.	('knock down', 'Var', (63, 73))	('GADD45A', 'Gene', '1647', (55, 62))	('increased', 'PosReg', (39, 48))	('CDKN1A', 'Gene', (96, 102))	('TT-mediated G1 arrest', 'CPA', (17, 38))	('decreased', 'NegReg', (78, 87))	('CDKN1A', 'Gene', '1026', (96, 102))	('GADD45A', 'Gene', (55, 62))
473607	29636527	Furthermore, in TP53 wild-type cells knock down of CDKN1A and both genes led to stronger induction of apoptosis after TT and viscumTT treatment.	('CDKN1A', 'Gene', '1026', (51, 57))	('apoptosis', 'CPA', (102, 111))	('knock down', 'Var', (37, 47))	('CDKN1A', 'Gene', (51, 57))	('TP53', 'Gene', '7157', (16, 20))	('stronger', 'PosReg', (80, 88))	('TP53', 'Gene', (16, 20))
473608	29636527	In 143B cells each siRNA variant was effective in viscum, TT and viscumTT treatment, but CDKN1A knock down led to the greatest inhibition of apoptosis by viscumTT.	('knock down', 'Var', (96, 106))	('CDKN1A', 'Gene', (89, 95))	('CDKN1A', 'Gene', '1026', (89, 95))	('inhibition', 'NegReg', (127, 137))	('apoptosis', 'CPA', (141, 150))
473617	29636527	U2OS cells were sensitive to viscum (Figure S3A,B) and apoptosis was prevented up to 35% by SP600125 (Fig.	('SP600125', 'Var', (92, 100))	('SP600125', 'Chemical', 'MESH:C432165', (92, 100))	('U2OS', 'CellLine', 'CVCL:0042', (0, 4))	('apoptosis', 'CPA', (55, 64))
473618	29636527	Interestingly, viscumTT-induced apoptosis in both cell lines and the TT-effect in 143B cells was significantly enhanced when preincubated with SP600125.	('SP600125', 'Var', (143, 151))	('enhanced', 'PosReg', (111, 119))	('SP600125', 'Chemical', 'MESH:C432165', (143, 151))	('apoptosis', 'CPA', (32, 41))
473623	29636527	Viscum, TT and viscumTT led to dephosphorylation of Tyr705 and Ser727 with further total STAT3 degradation (Fig.	('Tyr705', 'Chemical', '-', (52, 58))	('dephosphorylation', 'MPA', (31, 48))	('Ser727', 'Var', (63, 69))	('Ser727', 'Chemical', '-', (63, 69))	('STAT3', 'Gene', '6774', (89, 94))	('STAT3', 'Gene', (89, 94))	('Tyr705', 'Protein', (52, 58))
473624	29636527	Additionally, direct downstream targets of Tyr705 phosphorylated STAT3, such as BIRC5 and MYC-proto-oncogene (MYC) were effected.	('BIRC5', 'Gene', '332', (80, 85))	('BIRC5', 'Gene', (80, 85))	('MYC', 'Gene', (90, 93))	('MYC', 'Gene', (110, 113))	('MYC-proto-oncogene', 'Gene', (90, 108))	('Tyr705 phosphorylated', 'Var', (43, 64))	('STAT3', 'Gene', '6774', (65, 70))	('Tyr705', 'Chemical', '-', (43, 49))	('MYC', 'Gene', '4609', (90, 93))	('MYC', 'Gene', '4609', (110, 113))	('STAT3', 'Gene', (65, 70))	('MYC-proto-oncogene', 'Gene', '4609', (90, 108))
473644	29636527	This study indicates viscumTT-induced cell cycle alterations and induction of apoptosis occur in wild-type, mutant as well as null-mutant TP53 osteosarcoma cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('osteosarcoma', 'Disease', (143, 155))	('apoptosis', 'CPA', (78, 87))	('null-mutant', 'Var', (126, 137))	('osteosarcoma', 'Disease', 'MESH:D012516', (143, 155))	('TP53', 'Gene', '7157', (138, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('mutant', 'Var', (108, 114))	('TP53', 'Gene', (138, 142))	('cell cycle alterations', 'Phenotype', 'HP:0011018', (38, 60))	('cell cycle alterations', 'CPA', (38, 60))
473654	29636527	Interestingly, the MAPK8 inhibitor SP600125 was not able to suppress apoptosis in TT and viscumTT-treated 143B and U2OS cells in this study or in Ewing's sarcoma.	('SP600125', 'Var', (35, 43))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (146, 161))	('MAPK8', 'Gene', '5599', (19, 24))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (146, 161))	('suppress', 'NegReg', (60, 68))	("Ewing's sarcoma", 'Disease', (146, 161))	('MAPK8', 'Gene', (19, 24))	('apoptosis', 'CPA', (69, 78))	('U2OS', 'CellLine', 'CVCL:0042', (115, 119))	('SP600125', 'Chemical', 'MESH:C432165', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))
473659	29636527	The STAT3 pathway is mainly associated with survival and proliferation and often constitutively activated by phosphorylation at Tyr705 in cancer, also in osteosarcoma.	('phosphorylation at Tyr705', 'Var', (109, 134))	('cancer', 'Disease', (138, 144))	('osteosarcoma', 'Disease', (154, 166))	('osteosarcoma', 'Phenotype', 'HP:0002669', (154, 166))	('associated', 'Reg', (28, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (154, 166))	('Tyr705', 'Chemical', '-', (128, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('STAT3', 'Gene', '6774', (4, 9))	('activated', 'PosReg', (96, 105))	('STAT3', 'Gene', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
473660	29636527	Meanwhile, other phosphorylation sites are known, Ser727 being commonly activated by MAPK1/3 but also negatively regulated by MAPK8.	('MAPK1', 'Gene', (85, 90))	('MAPK8', 'Gene', '5599', (126, 131))	('Ser727', 'Var', (50, 56))	('activated', 'PosReg', (72, 81))	('MAPK1', 'Gene', '5594', (85, 90))	('negatively', 'NegReg', (102, 112))	('MAPK8', 'Gene', (126, 131))	('Ser727', 'Chemical', '-', (50, 56))
473699	29636527	GADD45A (#9662), CDKN1A (#2947), STAT3 (#4904), STAT3 Ser727 (#94994), STAT3 Tyr705 (#9145), pMAPK1/3 (ERK1/2, #4370), MYC (#9402) and BIRC5 (#2803) were purchased from Cell Signaling Technology (Danvers, MA, USA).	('STAT3', 'Gene', (48, 53))	('#94994', 'Var', (62, 68))	('STAT3', 'Gene', '6774', (33, 38))	('GADD45A', 'Gene', '1647', (0, 7))	('#2947', 'Var', (25, 30))	('#9402', 'Var', (124, 129))	('STAT3', 'Gene', (71, 76))	('Tyr705', 'Chemical', '-', (77, 83))	('STAT3', 'Gene', '6774', (48, 53))	('ERK1/2', 'Gene', (103, 109))	('ERK1/2', 'Gene', '5595;5594', (103, 109))	('CDKN1A', 'Gene', (17, 23))	('STAT3', 'Gene', '6774', (71, 76))	('CDKN1A', 'Gene', '1026', (17, 23))	('MYC', 'Gene', (119, 122))	('MAPK1', 'Gene', '5594', (94, 99))	('BIRC5', 'Gene', '332', (135, 140))	('Ser727', 'Chemical', '-', (54, 60))	('BIRC5', 'Gene', (135, 140))	('#4904', 'Var', (40, 45))	('#9145', 'Var', (85, 90))	('MYC', 'Gene', '4609', (119, 122))	('GADD45A', 'Gene', (0, 7))	('STAT3', 'Gene', (33, 38))	('#9662', 'Var', (9, 14))	('MAPK1', 'Gene', (94, 99))
473701	29636527	ss-actin (ACTB) directly conjugated to HRP (#A3854, Sigma-Aldrich) and CCND1 (ab134175, Abcam, Cambridge, GB) were also used.	('#A3854', 'Var', (44, 50))	('CCND1', 'Gene', (71, 76))	('ACTB', 'Gene', '60', (10, 14))	('ACTB', 'Gene', (10, 14))	('CCND1', 'Gene', '595', (71, 76))
473733	25805798	Concurrent targeting of angiogenic cytokines and antagonism of the PD-1 negative regulatory pathway might intensify immune-mediated tumor destruction.	('PD-1', 'Gene', (67, 71))	('PD-1', 'Gene', '5133', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('intensify', 'PosReg', (106, 115))	('tumor', 'Disease', (132, 137))	('antagonism', 'Var', (49, 59))
473744	25805798	Because TFE3 and MITF bind to the same DNA motif, their dysregulation triggers alterations in oncogenic pathways that are shared between ASPS and CCS.	('oncogenic pathways', 'Pathway', (94, 112))	('TFE3', 'Gene', (8, 12))	('triggers alterations', 'Reg', (70, 90))	('MITF', 'Gene', '4286', (17, 21))	('MITF', 'Gene', (17, 21))	('ASPS', 'Phenotype', 'HP:0012218', (137, 141))	('ASPS', 'Gene', (137, 141))	('dysregulation', 'Var', (56, 69))	('TFE3', 'Gene', '7030', (8, 12))	('ASPS', 'Gene', '79058', (137, 141))
473765	25805798	The trial was also open to rare patients with translocation-associated renal cell carcinoma that involves activating mutations in TFE3 and patients with melanoma less than 18 years of age, but no patients with these diseases were enrolled.	('mutations', 'Var', (117, 126))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (139, 147))	('renal cell carcinoma', 'Disease', (71, 91))	('TFE3', 'Gene', (130, 134))	('melanoma', 'Disease', (153, 161))	('activating', 'PosReg', (106, 116))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('patients', 'Species', '9606', (196, 204))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (71, 91))	('TFE3', 'Gene', '7030', (130, 134))
473774	25805798	Individual vaccine aliquots were cryopreserved based upon overall tumor cell yield as follows: >= 6x105 to < 6x106 total, 1x105 aliquots (dose level 1); >= 6x106 to <= 3x107 total, 1x106 aliquots (dose level 2); 3x107 to 1x108 total, 4x106 aliquots (dose level 3); >= 1x108 total, 1x107 aliquots (dose level 4).	('>= 6x106 to <= 3x107', 'Var', (153, 173))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('>= 6x105 to < 6x106', 'Var', (95, 114))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
473873	25805798	In preclinical models, blockade of this GM-CSF driven suppressive pathway using a dominant negative MFG-E8 mutant intensifies tumor destruction through inhibition of Treg activity, and efforts to translate this combinatorial vaccine strategy to testing in patients are underway.	('GM-CSF', 'Gene', (40, 46))	('mutant', 'Var', (107, 113))	('intensifies', 'NegReg', (114, 125))	('inhibition', 'NegReg', (152, 162))	('GM-CSF', 'Gene', '1437', (40, 46))	('MFG-E8', 'Gene', '4240', (100, 106))	('patients', 'Species', '9606', (256, 264))	('MFG-E8', 'Gene', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('suppressive pathway', 'Pathway', (54, 73))	('Treg activity', 'CPA', (166, 179))	('blockade', 'NegReg', (23, 31))	('tumor', 'Disease', (126, 131))
473895	25805798	Vaccination enhanced immune responses as assessed through biopsies of immunization sites, delayed-type hypersensitivity reactions, and metastases.	('hypersensitivity', 'Disease', (103, 119))	('Vaccination', 'Var', (0, 11))	('metastases', 'Disease', (135, 145))	('immune responses', 'CPA', (21, 37))	('hypersensitivity', 'Disease', 'MESH:D004342', (103, 119))	('delayed-type hypersensitivity', 'Phenotype', 'HP:0002972', (90, 119))	('metastases', 'Disease', 'MESH:D009362', (135, 145))	('enhanced', 'PosReg', (12, 20))
473902	23804705	In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CI-1040', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PD0325901', 'Var', (20, 29))	('CI-1040', 'Chemical', 'MESH:C120227', (9, 16))	('tumor', 'Disease', (108, 113))	('PD0325901', 'Chemical', 'MESH:C506614', (20, 29))	('decreased', 'NegReg', (30, 39))
473906	23804705	This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human AS, and it highlights the utility of spontaneous canine cancers as a model of human disease.	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('human AS', 'Disease', (121, 129))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('canine', 'Species', '9615', (176, 182))	('cancers', 'Disease', (183, 190))	('MEK', 'Gene', (20, 23))	('MEK', 'Gene', '5609', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('inhibitors', 'Var', (24, 34))	('human', 'Species', '9606', (121, 126))	('AS', 'Phenotype', 'HP:0200058', (127, 129))	('human', 'Species', '9606', (205, 210))	('canine', 'Species', '9615', (107, 113))	('canine HSA', 'Disease', (107, 117))
473910	23804705	For example, K-Ras2 mutations have been detected in 9 of 24 sporadic hepatic angiosarcomas and also in hepatic AS after occupational exposure to vinyl chloride.	('AS', 'Phenotype', 'HP:0200058', (111, 113))	('K-Ras2', 'Gene', (13, 19))	('sporadic hepatic angiosarcomas', 'Disease', 'MESH:D006394', (60, 90))	('sporadic hepatic angiosarcomas', 'Disease', (60, 90))	('vinyl chloride', 'Chemical', 'MESH:D014752', (145, 159))	('detected', 'Reg', (40, 48))	('angiosarcomas', 'Phenotype', 'HP:0200058', (77, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('mutations', 'Var', (20, 29))	('angiosarcoma', 'Phenotype', 'HP:0200058', (77, 89))
473925	23804705	Our study indicated that MEK inhibitors may form part of an effective strategy for treatment of canine HSA or human AS, and it highlighted the utility of spontaneous canine cancers as a model for human disease.	('human AS', 'Disease', (110, 118))	('inhibitors', 'Var', (29, 39))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Disease', (173, 180))	('MEK', 'Gene', (25, 28))	('AS', 'Phenotype', 'HP:0200058', (116, 118))	('human', 'Species', '9606', (196, 201))	('MEK', 'Gene', '5609', (25, 28))	('canine', 'Species', '9615', (166, 172))	('human', 'Species', '9606', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('canine', 'Species', '9615', (96, 102))	('canine HSA', 'Disease', (96, 106))
473948	23804705	Membranes were blocked with 10% non-fat milk and then incubated with antibodies against phospho-ERK (Thr202/Tyr204) (E10; Cell Signaling, Danvers, MA), ERK (Cell Signaling), alpha-tubulin (Sigma-Aldrich), and phospho-S6 (S235/236) (2F9; Cell Signaling).	('phospho-S6 (S235/236', 'Var', (209, 229))	('ERK', 'Gene', (152, 155))	('alpha-tubulin', 'Protein', (174, 187))	('Tyr204', 'Chemical', '-', (108, 114))	('Thr202', 'Chemical', '-', (101, 107))
473977	23804705	HSA tumors were found to express phospho-ERK1/2, with the majority of the signal present in cells lining irregular blood vessels and areas near the outer portion of the tumor (Figure 1A-O).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (169, 174))	('phospho-ERK1/2', 'Var', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
474015	23804705	At the completion of the experiment, the tumor burden of mice treated with CI-1040 was significantly smaller than that of untreated mice or of mice treated with vehicle alone (Figure 4B).	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('CI-1040', 'Var', (75, 82))	('CI-1040', 'Chemical', 'MESH:C120227', (75, 82))	('mice', 'Species', '10090', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('smaller', 'NegReg', (101, 108))	('mice', 'Species', '10090', (143, 147))
474021	23804705	If this resistant tumorgraft is included in the statistical analysis, the tumor volumes of the CI-1040 treated mice are no longer significantly different than tumor volumes of the non-treated group but remain statistically smaller than tumors from vehicle-treated mice.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('smaller', 'NegReg', (223, 230))	('tumor', 'Disease', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumors', 'Disease', (236, 242))	('CI-1040', 'Var', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mice', 'Species', '10090', (264, 268))	('tumor', 'Disease', (159, 164))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('mice', 'Species', '10090', (111, 115))	('CI-1040', 'Chemical', 'MESH:C120227', (95, 102))	('tumor', 'Disease', (236, 241))
474025	23804705	As in CI-1040 treated tumors, PD0325901 significantly decreased tumor growth compared to non-treated and vehicle-treated tumors (Figure 4E, F).	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('PD0325901', 'Chemical', 'MESH:C506614', (30, 39))	('CI-1040', 'Chemical', 'MESH:C120227', (6, 13))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('decreased', 'NegReg', (54, 63))	('tumors', 'Disease', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('PD0325901', 'Var', (30, 39))	('tumors', 'Disease', (121, 127))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
474030	23804705	At the completion of the experiment, the tumor burden of four remaining mice treated with sorafenib was significantly smaller than that of untreated mice or of mice treated with vehicle alone (Figure 5A, B).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('sorafenib', 'Chemical', 'MESH:D000077157', (90, 99))	('tumor', 'Disease', (41, 46))	('sorafenib', 'Var', (90, 99))	('mice', 'Species', '10090', (149, 153))	('mice', 'Species', '10090', (160, 164))	('smaller', 'NegReg', (118, 125))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
474064	23804705	In total, 9 of 12 tumors tested were positive for phosphorylated ERK1/2.	('phosphorylated', 'Var', (50, 64))	('ERK1/2', 'Protein', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('positive', 'Reg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
474073	23804705	Each of these genes stimulates cellular proliferation and oncogenic transformation by activation of the mitogen-activated protein kinase (MAPK) signaling pathway.	('oncogenic transformation', 'CPA', (58, 82))	('stimulates', 'PosReg', (20, 30))	('MAPK', 'Gene', (138, 142))	('genes', 'Var', (14, 19))	('activation', 'PosReg', (86, 96))	('cellular proliferation', 'CPA', (31, 53))	('MAPK', 'Gene', '5595;5594;477575;26413;5595;26417', (138, 142))
474074	23804705	Mice engineered to express knock-in mutations (D1226N or Y1228C) in the activation loop of Met develop a high incidence of angiosarcoma with moderately pleiomorphic endothelial cells, cavernous blood vessels, and palisading epithelioid-like cells.	('angiosarcoma', 'Phenotype', 'HP:0200058', (123, 135))	('Y1228C', 'Mutation', 'p.Y1228C', (57, 63))	('D1226N', 'Mutation', 'rs757575555', (47, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Y1228C', 'Var', (57, 63))	('angiosarcoma', 'Disease', 'MESH:D006394', (123, 135))	('Met', 'Gene', (91, 94))	('cavernous blood vessels', 'Phenotype', 'HP:0001048', (184, 207))	('angiosarcoma', 'Disease', (123, 135))	('Mice', 'Species', '10090', (0, 4))	('D1226N', 'Var', (47, 53))
474085	23804705	Using immunohistochemistry on FFPE HSA samples, we observed isolated cells or clusters of tumor cells expressing phosphorylated ERK1/2 in 60% of samples examined.	('phosphorylated', 'Var', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ERK1/2', 'Gene', (128, 134))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
474088	23804705	We have sequenced for reported mutations in several candidate genes including VEGFR and B-Raf, but to date we have not identified any activating mutations.	('B-Raf', 'Gene', (88, 93))	('mutations', 'Var', (31, 40))	('VEGF', 'Gene', '403802', (78, 82))	('B-Raf', 'Gene', '475526', (88, 93))	('VEGF', 'Gene', (78, 82))
474095	23804705	reported knockdown of ERK2 but not ERK1 decreased cell motility in a 3D microenvironment.	('ERK1', 'Gene', (35, 39))	('knockdown', 'Var', (9, 18))	('ERK2', 'Gene', (22, 26))	('cell motility in a 3D microenvironment', 'CPA', (50, 88))	('ERK1', 'Gene', '26417', (35, 39))
474096	23804705	reported knock down of ERK2 but not ERK1 in NIH 3T3 cells reduces Ras-mediated colony formation.	('reduces', 'NegReg', (58, 65))	('ERK2', 'Gene', (23, 27))	('ERK1', 'Gene', (36, 40))	('knock down', 'Var', (9, 19))	('NIH 3T3', 'CellLine', 'CVCL:0594', (44, 51))	('Ras-mediated colony formation', 'CPA', (66, 95))	('ERK1', 'Gene', '26417', (36, 40))
474112	23804705	We observed that whereas both cutaneous HSA xenografts and cardiac HSA tumorgrafts were sensitive to MEK1/2 inhibition by CI-1040, cardiac tumorgrafts were more sensitive to sorafenib (Figure 4, 6).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CI-1040', 'Chemical', 'MESH:C120227', (122, 129))	('inhibition', 'NegReg', (108, 118))	('MEK1/2', 'Gene', '611939', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cardiac tumorgrafts', 'Disease', 'MESH:D006331', (131, 150))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cardiac tumorgrafts', 'Disease', (131, 150))	('MEK1/2', 'Gene', (101, 107))	('CI-1040', 'Var', (122, 129))	('tumor', 'Disease', (71, 76))	('sorafenib', 'Chemical', 'MESH:D000077157', (174, 183))
474113	23804705	Also, cardiac HSA tumorgrafts were sensitive to a second MEK inhibitor PD0325901 (Figure 4E, F).	('PD0325901', 'Var', (71, 80))	('MEK', 'Gene', '5609', (57, 60))	('tumor', 'Disease', (18, 23))	('PD0325901', 'Chemical', 'MESH:C506614', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('MEK', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
474114	23804705	These results demonstrate that MEK signaling is necessary for growth of HSA in vivo and provide a strong rationale for clinical evaluation of MEK inhibitors, either alone or in combination, for the treatment of HSA.	('HSA', 'Disease', (211, 214))	('inhibitors', 'Var', (146, 156))	('MEK', 'Gene', (31, 34))	('MEK', 'Gene', '5609', (31, 34))	('MEK', 'Gene', (142, 145))	('MEK', 'Gene', '5609', (142, 145))
474124	23804705	Our study indicates MEK inhibitors may form part of an effective therapeutic strategy for treatment of canine HSA or human AS and highlights the utility of spontaneous canine cancers as a model for human disease.	('canine', 'Species', '9615', (103, 109))	('human AS', 'Disease', (117, 125))	('human', 'Species', '9606', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('MEK', 'Gene', (20, 23))	('MEK', 'Gene', '5609', (20, 23))	('inhibitors', 'Var', (24, 34))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('human', 'Species', '9606', (198, 203))	('AS', 'Phenotype', 'HP:0200058', (123, 125))	('cancers', 'Disease', (175, 182))	('canine HSA', 'Disease', (103, 113))	('canine', 'Species', '9615', (168, 174))
474131	33200058	Pazopanib has been linked to the incidence of spontaneous pneumothorax in previous case studies.	('pneumothorax', 'Phenotype', 'HP:0002107', (58, 70))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('pneumothorax', 'Disease', 'MESH:D011030', (58, 70))	('spontaneous pneumothorax', 'Phenotype', 'HP:0002108', (46, 70))	('pneumothorax', 'Disease', (58, 70))	('linked', 'Reg', (19, 25))	('Pazopanib', 'Var', (0, 9))
474180	33200058	Pazopanib was thought to have caused the necrosis, and therefore, the medication was stopped.	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('necrosis', 'Disease', 'MESH:D009336', (41, 49))	('Pazopanib', 'Var', (0, 9))	('necrosis', 'Disease', (41, 49))
474214	30123424	Recently, the small molecule YK-4-279 was shown to interfere directly with the EWS-FLI1 activity by blocking its interaction with RNA helicase A.	('blocking', 'NegReg', (100, 108))	('RNA helicase A', 'Gene', '1660', (130, 144))	('activity', 'MPA', (88, 96))	('EWS-FLI1', 'Gene', (79, 87))	('RNA helicase A', 'Gene', (130, 144))	('interfere', 'NegReg', (51, 60))	('EWS-FLI1', 'Gene', '2130;2313', (79, 87))	('YK-4-279', 'Var', (29, 37))	('interaction', 'Interaction', (113, 124))
474239	30123424	A minimum of 1-fold change in gene expression upon EWS-FLI1 modulation (72 h dox treatment) and a p-value cutoff after False Discovery Rate (FDR) adjustment for multiple testing of 0.01 was accepted for further analysis.	('change', 'Reg', (20, 26))	('dox', 'Chemical', 'MESH:D004318', (77, 80))	('EWS-FLI1', 'Gene', (51, 59))	('modulation', 'Var', (60, 70))	('EWS-FLI1', 'Gene', '2130;2313', (51, 59))
474244	30123424	In particular, multiple members of the ribosomal protein family, BIRC3, NLRP1, GSN and NGFR were affected by EWS-FLI1 modulation and chemical inhibition (Figure 2B).	('GSN', 'Gene', '2934', (79, 82))	('BIRC3', 'Gene', '330', (65, 70))	('EWS-FLI1', 'Gene', (109, 117))	('NLRP1', 'Gene', (72, 77))	('GSN', 'Gene', (79, 82))	('NGFR', 'Gene', '4804', (87, 91))	('NGFR', 'Gene', (87, 91))	('EWS-FLI1', 'Gene', '2130;2313', (109, 117))	('modulation', 'Var', (118, 128))	('affected', 'Reg', (97, 105))	('BIRC3', 'Gene', (65, 70))	('NLRP1', 'Gene', '22861', (72, 77))
474248	30123424	For validation of the test system, we confirmed differential sensitivity of EwS cells to the EWS-FLI1 targeting compound YK-2-479 under EWS-FLI1-high versus -low conditions (Supplementary Figure 1B).	('EWS-FLI1', 'Gene', '2130;2313', (93, 101))	('Supplementary Figure 1B', 'Disease', (174, 197))	('EwS', 'Gene', '2130', (76, 79))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (174, 197))	('EWS-FLI1', 'Gene', (136, 144))	('YK-2-479', 'Var', (121, 129))	('EwS', 'Gene', (76, 79))	('EWS-FLI1', 'Gene', '2130;2313', (136, 144))	('EWS-FLI1', 'Gene', (93, 101))
474268	30123424	Next, we tested inhibitors of BCL2, BCL-X(L), and MCL-1 (ABT-199, A-1155463, S63845, respectively).	('BCL-X(L)', 'Gene', '598', (36, 44))	('BCL2', 'Gene', (30, 34))	('BCL2', 'Gene', '596', (30, 34))	('BCL-X(L', 'Gene', (36, 43))	('ABT', 'Chemical', 'MESH:C002502', (57, 60))	('S63845', 'Var', (77, 83))
474272	30123424	Using immunoblot we confirmed a decrease in MCL-1 protein expression upon dox-induced knockdown of EWS-FLI1 in A673/TR/shEF cells (Figure 4A and 4C).	('MCL-1 protein expression', 'MPA', (44, 68))	('knockdown', 'Var', (86, 95))	('dox', 'Chemical', 'MESH:D004318', (74, 77))	('EWS-FLI1', 'Gene', (99, 107))	('EWS-FLI1', 'Gene', '2130;2313', (99, 107))	('decrease', 'NegReg', (32, 40))
474276	30123424	Strikingly, knockdown of MCL-1 (Figure 4B) led to a similar drug effect on EwS cell viability as the knockdown of EWS-FLI1 in the A673/TR/shEF system.	('EWS-FLI1', 'Gene', '2130;2313', (114, 122))	('MCL-1', 'Gene', (25, 30))	('knockdown', 'Var', (12, 21))	('EwS', 'Gene', '2130', (75, 78))	('EwS', 'Gene', (75, 78))	('EWS-FLI1', 'Gene', (114, 122))	('knockdown', 'Var', (101, 110))
474278	30123424	EWS-FLI1 knockdown strongly reduced MCL-1 protein expression (60% reduction) (Figure 4A and 4C), while levels of anti-apoptotic proteins BCL-2 and BCL-X(L) were decreased and increased by 50%, respectively (Figure 4C).	('MCL-1 protein expression', 'MPA', (36, 60))	('reduced', 'NegReg', (28, 35))	('knockdown', 'Var', (9, 18))	('reduced MCL', 'Phenotype', 'HP:0025066', (28, 39))	('EWS-FLI1', 'Gene', (0, 8))	('levels of', 'MPA', (103, 112))	('BCL-X(L', 'Gene', (147, 154))	('BCL-X(L)', 'Gene', '598', (147, 155))	('increased', 'PosReg', (175, 184))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('reduction', 'NegReg', (66, 75))
474282	30123424	Intriguingly, we found IER3 to be strongly induced upon conditional EWS-FLI1 knockdown in A673/TR/shEF (Figure 4E) and, with the only exception of SK-N-MC, in four of five additional cell lines upon transient knockdown of EWS-FLI1.	('IER3', 'Gene', '8870', (23, 27))	('EWS-FLI1', 'Gene', (222, 230))	('EWS-FLI1', 'Gene', (68, 76))	('knockdown', 'Var', (77, 86))	('EWS-FLI1', 'Gene', '2130;2313', (68, 76))	('SK-N-MC', 'Chemical', '-', (147, 154))	('EWS-FLI1', 'Gene', '2130;2313', (222, 230))	('IER3', 'Gene', (23, 27))	('induced', 'PosReg', (43, 50))
474283	30123424	Ectopic expression of IER3 on its own slightly increased navitoclax sensitivity of A673/TR/shEF cells, though the level of this increase did not achieve significance (Supplementary Figure 3).	('IER3', 'Gene', '8870', (22, 26))	('Ectopic expression', 'Var', (0, 18))	('increased', 'PosReg', (47, 56))	('navitoclax', 'Chemical', 'MESH:C528561', (57, 67))	('navitoclax sensitivity', 'MPA', (57, 79))	('IER3', 'Gene', (22, 26))
474284	30123424	Thus, it is conceivable that a combination of MCL-1 expression modulation and IER3 dependent subcellular re-localization in response to EWS-FLI1 depletion is contributing to the observed gain in navitoclax sensitivity, suggesting a major role for MCL-1 in apoptosis regulation and navitoclax resistance of EwS.	('navitoclax sensitivity', 'MPA', (195, 217))	('modulation', 'Var', (63, 73))	('IER3', 'Gene', '8870', (78, 82))	('EwS', 'Gene', '2130', (306, 309))	('gain', 'PosReg', (187, 191))	('MCL-1', 'Gene', (46, 51))	('EWS-FLI1', 'Gene', (136, 144))	('EwS', 'Gene', (306, 309))	('navitoclax', 'Chemical', 'MESH:C528561', (281, 291))	('EWS-FLI1', 'Gene', '2130;2313', (136, 144))	('IER3', 'Gene', (78, 82))	('navitoclax', 'Chemical', 'MESH:C528561', (195, 205))
474296	30123424	topotecan and irinotecan), we identified novel targeted small molecules which are either used in the treatment of other cancer types, such are obatoclax and belinostat, or already in early clinical development for pediatric indications and therefore hold promise for future use in the treatment of Ewing sarcoma.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('topotecan', 'Chemical', 'MESH:D019772', (0, 9))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (298, 311))	('small', 'Var', (56, 61))	('Ewing sarcoma', 'Disease', (298, 311))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (298, 311))	('irinotecan', 'Chemical', 'MESH:D000077146', (14, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('belinostat', 'Chemical', 'MESH:C487081', (157, 167))
474311	30123424	Our results show that EWS-FLI1 expression potentiates the inhibitory effect of agents like cytarabine, bortezomib and gambogic acid.	('potentiates', 'PosReg', (42, 53))	('cytarabine', 'Chemical', 'MESH:D003561', (91, 101))	('EWS-FLI1', 'Gene', (22, 30))	('gambogic acid', 'Chemical', 'MESH:C052659', (118, 131))	('bortezomib', 'Chemical', 'MESH:D000069286', (103, 113))	('inhibitory effect of', 'MPA', (58, 78))	('EWS-FLI1', 'Gene', '2130;2313', (22, 30))	('expression', 'Var', (31, 41))
474316	30123424	Additionally, we observed that knockdown of EWS-FLI1 greatly reduces the expression of MCL-1, identifying this BCL-2 family member as a directly EWS-FLI1 activated target.	('EWS-FLI1', 'Gene', (145, 153))	('MCL-1', 'Gene', (87, 92))	('EWS-FLI1', 'Gene', (44, 52))	('EWS-FLI1', 'Gene', '2130;2313', (145, 153))	('EWS-FLI1', 'Gene', '2130;2313', (44, 52))	('expression', 'MPA', (73, 83))	('reduces', 'NegReg', (61, 68))	('knockdown', 'Var', (31, 40))
474317	30123424	We found that EWS-FLI1 modulation results in upregulation of IER3, which was previously reported to be responsible for MCL-1 translocation to nuclear speckles.	('IER3', 'Gene', (61, 65))	('EWS-FLI1', 'Gene', '2130;2313', (14, 22))	('IER3', 'Gene', '8870', (61, 65))	('upregulation', 'PosReg', (45, 57))	('EWS-FLI1', 'Gene', (14, 22))	('modulation', 'Var', (23, 33))
474318	30123424	The appearance of MCL-1 in nuclear speckles was also observed in our EwS model cell line upon knockdown of EWS-FLI1.	('knockdown', 'Var', (94, 103))	('EWS-FLI1', 'Gene', '2130;2313', (107, 115))	('EwS', 'Gene', '2130', (69, 72))	('EwS', 'Gene', (69, 72))	('EWS-FLI1', 'Gene', (107, 115))
474319	30123424	In 293T cells, IER3 ectopic expression induced apoptosis in an MCL-1 and BIM1 dependent but NOXA and PUMA independent manner.	('293T', 'CellLine', 'CVCL:0063', (3, 7))	('IER3', 'Gene', '8870', (15, 19))	('apoptosis', 'CPA', (47, 56))	('NOXA', 'Gene', (92, 96))	('ectopic expression', 'Var', (20, 38))	('IER3', 'Gene', (15, 19))	('NOXA', 'Gene', '5366', (92, 96))
474323	30123424	It should be noted that, with regard to navitoclax sensitivity, SK-N-MC EwS cells behaved differently from all other EwS cell lines tested.	('EwS', 'Gene', '2130', (117, 120))	('EwS', 'Gene', '2130', (72, 75))	('EwS', 'Gene', (72, 75))	('EwS', 'Gene', (117, 120))	('SK-N-MC', 'Var', (64, 71))	('navitoclax', 'Chemical', 'MESH:C528561', (40, 50))	('SK-N-MC EwS', 'CellLine', 'CVCL:0530', (64, 75))
474324	30123424	Modulating EWS-FLI1 expression in a dox-inducible EWS-FLI1 shRNA expressing clone of that cell line, shSK-E17T, failed to induce navitoclax sensitivity (Supplementary Figure 6A).	('Modulating', 'Var', (0, 10))	('EWS-FLI1', 'Gene', '2130;2313', (11, 19))	('EWS-FLI1', 'Gene', (50, 58))	('dox', 'Chemical', 'MESH:D004318', (36, 39))	('EWS-FLI1', 'Gene', '2130;2313', (50, 58))	('E17T', 'Mutation', 'p.E17T', (106, 110))	('navitoclax', 'Chemical', 'MESH:C528561', (129, 139))	('EWS-FLI1', 'Gene', (11, 19))
474325	30123424	Consistent with this finding, EWS-FLI1 knockdown did not reduce MCL-1 nor increase IER3 expression levels (Supplementary Figure 6A and 6B).	('reduce', 'NegReg', (57, 63))	('reduce MCL', 'Phenotype', 'HP:0025066', (57, 67))	('knockdown', 'Var', (39, 48))	('increase', 'PosReg', (74, 82))	('EWS-FLI1', 'Gene', (30, 38))	('IER3', 'Gene', (83, 87))	('IER3', 'Gene', '8870', (83, 87))	('MCL-1', 'MPA', (64, 69))	('EWS-FLI1', 'Gene', '2130;2313', (30, 38))
474339	30123424	For the dose-response curves shown in Supplementary Figure 5, cells were treated for 48 h with dox (1 microg/ml) to induce EWS-FLI1 knockdown and then were treated with Navitoclax (3.5 microM) for 72 h in the presence or absence of dox.	('Navitoclax', 'Chemical', 'MESH:C528561', (169, 179))	('knockdown', 'Var', (132, 141))	('dox', 'Chemical', 'MESH:D004318', (232, 235))	('EWS-FLI1', 'Gene', (123, 131))	('dox', 'Chemical', 'MESH:D004318', (95, 98))	('EWS-FLI1', 'Gene', '2130;2313', (123, 131))
474342	30123424	BAX and NOXA knockout cell lines were obtained from Haplogen GmbH, where a gene-trap retrovirus was used to inactivate single human genes in KBM7 as described previously.	('human', 'Species', '9606', (126, 131))	('BAX', 'Gene', (0, 3))	('BAX', 'Gene', '581', (0, 3))	('NOXA', 'Gene', (8, 12))	('inactivate', 'Var', (108, 118))	('NOXA', 'Gene', '5366', (8, 12))	('KBM7', 'Gene', (141, 145))	('KBM7', 'CellLine', 'CVCL:A426', (141, 145))
474358	30123424	Serial dilutions in a range between 20 microM and 0.05 microM were applied for 72 h. In the case where the knockdown of EWS-FLI1 was induced, the induction with dox started 24 h prior to the drug treatment and the cells were kept in dox during the drug treatment.	('knockdown', 'Var', (107, 116))	('EWS-FLI1', 'Gene', (120, 128))	('EWS-FLI1', 'Gene', '2130;2313', (120, 128))	('dox', 'Chemical', 'MESH:D004318', (233, 236))	('dox', 'Chemical', 'MESH:D004318', (161, 164))
474369	30123424	Antibodies used were against MCL-1 (#4572, Cell Signaling, New England Biolabs, Frankfurt am Main, Germany), BCL-X(L) (ab178844, Abcam, Cambridge, MA, USA), BCL-2 (ab18210, Abcam), BCL-2 (ab18210, Abcam, Cambridge, MA, USA) IEX-1/IER3 (sc-8454, Santa Cruz, Santa Cruz, CA, USA), FLI1 (MBS177100, My Biosource, San Diego, CA, USA), alpha-TUBULIN (CP06, Calbiochem, Merck, Vienna, Austria), GAPDH (AM4300, Ambion, Thermo Fisher Scientific).	('IEX-1', 'Gene', (224, 229))	('alpha-TUBULIN', 'Gene', (331, 344))	('BCL-X(L)', 'Gene', '598', (109, 117))	('IER3', 'Gene', (230, 234))	('IEX-1', 'Gene', '8870', (224, 229))	('GAPDH', 'Gene', '2597', (389, 394))	('alpha-TUBULIN', 'Gene', '10376', (331, 344))	('GAPDH', 'Gene', (389, 394))	('IER3', 'Gene', '8870', (230, 234))	('BCL-X(L', 'Gene', (109, 116))	('MBS177100', 'Var', (285, 294))
474464	29218302	The equivalent pathognomonic COL1A1-PDGFB gene fusion found in human dermatofibrosarcoma protuberans was found in a dermatofibrosarcoma protuberans-like canine tumor, with the equivalent fusion found being COL3A1-PDGFB in the dog.	('COL1A1', 'Gene', '1277', (29, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (116, 147))	('human', 'Species', '9606', (63, 68))	('COL1A1', 'Gene', (29, 35))	('canine', 'Species', '9615', (153, 159))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (69, 100))	('dog', 'Species', '9615', (226, 229))	('COL3A1', 'Gene', (206, 212))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (123, 135))	('tumor', 'Disease', (160, 165))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (76, 88))	('fusion', 'Var', (47, 53))	('dermatofibrosarcoma protuberans', 'Disease', (116, 147))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('pathognomonic', 'Reg', (15, 28))	('COL3A1', 'Gene', '478835', (206, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('dermatofibrosarcoma protuberans', 'Disease', (69, 100))
474579	32275708	The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma.	('neuroblastoma', 'Disease', (124, 137))	('immune marker expression', 'MPA', (86, 110))	('neuroblastoma', 'Phenotype', 'HP:0003006', (124, 137))	('ATRX', 'Gene', (58, 62))	('deletions', 'Var', (63, 72))	('elevated', 'PosReg', (77, 85))	('ATRX', 'Gene', '546', (58, 62))	('neuroblastoma', 'Disease', 'MESH:D009447', (124, 137))
474599	32275708	Pediatric cancers tend to have fewer mutations than adult cancers, and while there has been limited testing of immunotherapies in pediatric cancer patients, the currently available data suggest lower response rates than adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('fewer', 'NegReg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('adult cancers', 'Disease', (52, 65))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('lower', 'NegReg', (194, 199))	('cancers', 'Disease', (10, 17))	('cancer', 'Disease', (10, 16))	('response', 'MPA', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('patients', 'Species', '9606', (147, 155))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Disease', (140, 146))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('adult cancers', 'Disease', 'MESH:D009369', (220, 233))	('cancer', 'Disease', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('adult cancers', 'Disease', (220, 233))	('cancer', 'Disease', (226, 232))	('cancers', 'Disease', (226, 233))	('cancers', 'Disease', (58, 65))	('adult cancers', 'Disease', 'MESH:D009369', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
474705	32275708	ATRX gene deletions were enriched in cluster 1 (Fisher's Exact Test: p < 0.05).	('deletions', 'Var', (10, 19))	('ATRX', 'Gene', '546', (0, 4))	('ATRX', 'Gene', (0, 4))
474718	32275708	Four out of six samples had a deletion in the ATRX gene.	('deletion', 'Var', (30, 38))	('ATRX', 'Gene', '546', (46, 50))	('ATRX', 'Gene', (46, 50))
474721	32275708	We showed earlier that tumors with ATRX deletions tend to have higher adaptive immune expression, and we found a similar pattern in an independent set of MYCN-NA neuroblastoma samples.	('MYCN', 'Gene', (154, 158))	('tumors', 'Disease', (23, 29))	('neuroblastoma', 'Disease', (162, 175))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('deletions', 'Var', (40, 49))	('ATRX', 'Gene', '546', (35, 39))	('MYCN', 'Gene', '4613', (154, 158))	('neuroblastoma', 'Phenotype', 'HP:0003006', (162, 175))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('adaptive immune expression', 'MPA', (70, 96))	('ATRX', 'Gene', (35, 39))	('higher', 'PosReg', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('neuroblastoma', 'Disease', 'MESH:D009447', (162, 175))
474763	32275708	In both cases, the presence of immune-associated expression correlated with better patient outcomes compared to tumors with proliferative signaling pathways associated with translation initiation and cell cycle regulation.	('expression', 'MPA', (49, 59))	('presence', 'Var', (19, 27))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('better', 'PosReg', (76, 82))	('patient', 'Species', '9606', (83, 90))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
474773	32275708	Our analysis found significant variation in immune marker expression, including markers of response to checkpoint blockade therapy, and identified ATRX deletions as a potential biomarker of immune infiltrated tumors in MYCN-NA neuroblastoma.	('neuroblastoma', 'Disease', (227, 240))	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('MYCN', 'Gene', (219, 223))	('ATRX', 'Gene', (147, 151))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('neuroblastoma', 'Phenotype', 'HP:0003006', (227, 240))	('variation', 'Reg', (31, 40))	('MYCN', 'Gene', '4613', (219, 223))	('immune marker expression', 'MPA', (44, 68))	('ATRX', 'Gene', '546', (147, 151))	('deletions', 'Var', (152, 161))	('neuroblastoma', 'Disease', 'MESH:D009447', (227, 240))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
474789	32275708	Amplification of the host immune response may further limit tumor growth and lead to immune-mediated tumor cell death.	('lead to', 'Reg', (77, 84))	('Amplification', 'Var', (0, 13))	('tumor cell death', 'Disease', (101, 117))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor cell death', 'Disease', 'MESH:D003643', (101, 117))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('limit', 'NegReg', (54, 59))
474825	32275708	Did the authors assess all cluster combinations and identify only wound healing and translational regulation as important in osteosarcoma...what about cell cycle,etc.. General comments: - Line 22: Though many accept that pediatric tumours have fewer mutations relative to adult cancers, this is not true for all pediatric cancers.	('cancers', 'Disease', 'MESH:D009369', (278, 285))	('osteosarcoma', 'Disease', (125, 137))	('osteosarcoma', 'Disease', 'MESH:D012516', (125, 137))	('adult cancers', 'Disease', 'MESH:D009369', (272, 285))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancers', 'Disease', 'MESH:D009369', (322, 329))	('tumours', 'Disease', (231, 238))	('adult cancers', 'Disease', (272, 285))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('cancers', 'Disease', (278, 285))	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('tumours', 'Disease', 'MESH:D009369', (231, 238))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('cancers', 'Phenotype', 'HP:0002664', (322, 329))	('cancers', 'Disease', (322, 329))	('mutations', 'Var', (250, 259))	('fewer', 'NegReg', (244, 249))
474859	31807166	Abnormal expression and mutations of genes are involved in the development and progression of ES.	('genes', 'Gene', (37, 42))	('ES', 'Phenotype', 'HP:0012254', (94, 96))	('involved', 'Reg', (47, 55))	('ES', 'Disease', 'MESH:D012512', (94, 96))	('mutations', 'Var', (24, 33))
474863	31807166	Stromal antigen 2 mutation occurs in 20% of ES cases and is associated with distant metastasis, although whether it may be considered a prognostic marker for ES remains controversial.	('distant metastasis', 'CPA', (76, 94))	('Stromal antigen 2', 'Gene', (0, 17))	('Stromal antigen 2', 'Gene', '10735', (0, 17))	('mutation', 'Var', (18, 26))	('ES', 'Phenotype', 'HP:0012254', (158, 160))	('ES', 'Phenotype', 'HP:0012254', (44, 46))	('ES', 'Disease', 'MESH:D012512', (158, 160))	('ES', 'Disease', 'MESH:D012512', (44, 46))	('associated', 'Reg', (60, 70))
474864	31807166	Other molecular genetic alterations associated with ES include abnormal expression of platelet-derived growth factor receptor beta and mammalian target of rapamycin, as well as CDKN2A and TP53 mutations.	('CDKN2A', 'Gene', (177, 183))	('ES', 'Disease', 'MESH:D012512', (52, 54))	('CDKN2A', 'Gene', '1029', (177, 183))	('platelet-derived growth factor receptor beta', 'Gene', '5159', (86, 130))	('mutations', 'Var', (193, 202))	('ES', 'Phenotype', 'HP:0012254', (52, 54))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))	('platelet-derived growth factor receptor beta', 'Gene', (86, 130))	('mammalian target of rapamycin', 'Gene', '2475', (135, 164))	('mammalian target of rapamycin', 'Gene', (135, 164))
474877	31807166	Following standardization of the chip results, 1,133, 1,290 and 768 DEGs between ES and healthy tissues were extracted from the GSE17674, GSE17679 and GSE45544 mRNA expression profile data sets, respectively.	('GSE17674', 'Var', (128, 136))	('ES', 'Phenotype', 'HP:0012254', (81, 83))	('GSE45544', 'Var', (151, 159))	('ES', 'Disease', 'MESH:D012512', (81, 83))
474907	31807166	Microinjections of tropomyosin into epithelial cells can induce rapid cell migration; TNNT1 may contribute to the interaction between actin and tropomyosin, thus regulating cell migration and invasion.	('TNNT1', 'Gene', (86, 91))	('TNNT1', 'Gene', '7138', (86, 91))	('rapid cell migration', 'CPA', (64, 84))	('Microinjections', 'Var', (0, 15))	('interaction', 'Interaction', (114, 125))	('invasion', 'CPA', (192, 200))	('cell migration', 'CPA', (173, 187))	('regulating', 'Reg', (162, 172))	('contribute', 'Reg', (96, 106))	('induce', 'Reg', (57, 63))
474917	31807166	The results of the analysis in the present study demonstrated that high expression of TNNT1 was significantly associated with poor OS in patients with ES, consistent with the above findings.	('ES', 'Phenotype', 'HP:0012254', (151, 153))	('ES', 'Disease', 'MESH:D012512', (151, 153))	('TNNT1', 'Gene', (86, 91))	('poor OS', 'Disease', (126, 133))	('TNNT1', 'Gene', '7138', (86, 91))	('patients', 'Species', '9606', (137, 145))	('associated', 'Reg', (110, 120))	('high expression', 'Var', (67, 82))
474923	31807166	Whole exome sequence data have been previously used to estimate the gene mutation rate of TTN, which identified TTN mutations in colorectal cancer, suggesting that TTN mutations may serve a specific role in the occurrence or progression of colorectal cancer.	('colorectal cancer', 'Disease', (129, 146))	('TTN', 'Gene', (164, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (240, 257))	('TTN', 'Gene', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('TTN', 'Gene', '7273', (112, 115))	('colorectal cancer', 'Disease', (240, 257))	('TTN', 'Gene', '7273', (164, 167))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('TTN', 'Gene', (90, 93))	('mutations', 'Var', (116, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('TTN', 'Gene', '7273', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (240, 257))	('mutations', 'Var', (168, 177))
474926	31807166	The Cancer Genome Atlas-based aggregation analysis revealed that the missense mutation of TTN was associated with good prognosis in lung squamous cell carcinoma.	('missense mutation', 'Var', (69, 86))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('TTN', 'Gene', (90, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 160))	('lung squamous cell carcinoma', 'Disease', (132, 160))	('TTN', 'Gene', '7273', (90, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
474927	31807166	However, no studies are currently available on TTN in ES, but the LASSO COX regression and OS analysis results of the present study demonstrated that high expression of TTN was associated with poor prognosis of patients with ES and may serve an important role in the development of ES.	('ES', 'Phenotype', 'HP:0012254', (282, 284))	('TTN', 'Gene', (47, 50))	('patients', 'Species', '9606', (211, 219))	('ES', 'Disease', 'MESH:D012512', (282, 284))	('high expression', 'Var', (150, 165))	('TTN', 'Gene', '7273', (47, 50))	('ES', 'Phenotype', 'HP:0012254', (54, 56))	('LASSO', 'Chemical', 'MESH:C000188', (66, 71))	('ES', 'Phenotype', 'HP:0012254', (225, 227))	('TTN', 'Gene', (169, 172))	('ES', 'Disease', 'MESH:D012512', (225, 227))	('ES', 'Disease', 'MESH:D012512', (54, 56))	('TTN', 'Gene', '7273', (169, 172))
474934	31807166	The results of the present study demonstrated that a high expression of MYL3 was associated with poor prognosis in patients with ES, and this result may help explain the molecular mechanism of ES.	('patients', 'Species', '9606', (115, 123))	('MYL3', 'Gene', '4634', (72, 76))	('high', 'Var', (53, 57))	('ES', 'Phenotype', 'HP:0012254', (193, 195))	('ES', 'Disease', 'MESH:D012512', (193, 195))	('ES', 'Phenotype', 'HP:0012254', (129, 131))	('MYL3', 'Gene', (72, 76))	('ES', 'Disease', 'MESH:D012512', (129, 131))
474936	31807166	High expression of TMOD1 is a key biomarker for poor prognosis in patients with oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (80, 108))	('High', 'Var', (0, 4))	('TMOD1', 'Gene', '7111', (19, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 108))	('TMOD1', 'Gene', (19, 24))	('patients', 'Species', '9606', (66, 74))
474941	31807166	High expression of TNNT1 is a prognostic biomarker for a variety of cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('High', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('TNNT1', 'Gene', (19, 24))	('TNNT1', 'Gene', '7138', (19, 24))
474962	30942427	In addition, the proliferation ability was blocked by the knockdown of CBX3 through the application of CBX3 siRNA, and CBX3 knockdown also led to increased apoptosis and cell cycle arrest at G0 and G1 phases in osteosarcoma cells.	('knockdown', 'Var', (124, 133))	('CBX3', 'Gene', '11335', (71, 75))	('CBX3', 'Gene', '11335', (119, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('proliferation ability', 'CPA', (17, 38))	('increased', 'PosReg', (146, 155))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (170, 187))	('blocked', 'NegReg', (43, 50))	('CBX3', 'Gene', '11335', (103, 107))	('CBX3', 'Gene', (71, 75))	('CBX3', 'Gene', (119, 123))	('osteosarcoma', 'Disease', (211, 223))	('osteosarcoma', 'Phenotype', 'HP:0002669', (211, 223))	('CBX3', 'Gene', (103, 107))	('osteosarcoma', 'Disease', 'MESH:D012516', (211, 223))	('apoptosis', 'CPA', (156, 165))
474964	30942427	Meanwhile, high CBX3 is a predictor of the poor prognosis of osteosarcoma patients.	('CBX3', 'Gene', '11335', (16, 20))	('osteosarcoma', 'Disease', (61, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('patients', 'Species', '9606', (74, 82))	('CBX3', 'Gene', (16, 20))	('high', 'Var', (11, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))
474973	30942427	Chromobox protein homolog 3 (CBX3) belongs to the heterochomatin protein 1 (HP1) family, which is involved in transcriptional activation or repression, cell differentiation and growth and epigenetic modifications.	('involved', 'Reg', (98, 106))	('HP1', 'Gene', (76, 79))	('CBX3', 'Gene', (29, 33))	('repression', 'NegReg', (140, 150))	('epigenetic', 'Var', (188, 198))	('Chromobox protein homolog 3', 'Gene', (0, 27))	('Chromobox protein homolog 3', 'Gene', '11335', (0, 27))	('HP1', 'Gene', '23468', (76, 79))	('CBX3', 'Gene', '11335', (29, 33))
475027	30942427	It was shown from the results that there was an association between high CBX3 expression and shorter OS (P<0.0001; Fig.	('expression', 'MPA', (78, 88))	('shorter OS', 'Disease', (93, 103))	('high', 'Var', (68, 72))	('CBX3', 'Gene', '11335', (73, 77))	('OS', 'Chemical', '-', (101, 103))	('CBX3', 'Gene', (73, 77))
475036	30942427	4C, the proliferation rate of the MG63 cells was markedly inhibited by the knockdown of CBX3 expression in comparison with the NC siRNA group.	('MG63', 'CellLine', 'CVCL:0426', (34, 38))	('CBX3', 'Gene', (88, 92))	('knockdown', 'Var', (75, 84))	('inhibited', 'NegReg', (58, 67))	('CBX3', 'Gene', '11335', (88, 92))
475038	30942427	Thus, CBX3 knockdown prevented the growth of osteosarcoma MG63.	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('MG63', 'CellLine', 'CVCL:0426', (58, 62))	('prevented', 'NegReg', (21, 30))	('osteosarcoma', 'Disease', (45, 57))	('CBX3', 'Gene', '11335', (6, 10))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('growth', 'MPA', (35, 41))	('knockdown', 'Var', (11, 20))	('CBX3', 'Gene', (6, 10))
475041	30942427	5A, the number of cells in the G0 and G1 phases had an increase of 14.60% (t=5.163, P=0.0067) in the CBX3 siRNA group while there was a decrease by 9.30% (t=8.664, P=0.001) in the S phase and a decrease by 5.30% (t=4.743, P=0.009) in the G2/M phase following the knockout of CBX3.	('increase', 'PosReg', (55, 63))	('CBX3', 'Gene', (101, 105))	('CBX3', 'Gene', '11335', (275, 279))	('knockout', 'Var', (263, 271))	('decrease', 'NegReg', (136, 144))	('G2/M phase', 'CPA', (238, 248))	('G1 phases', 'CPA', (38, 47))	('CBX3', 'Gene', '11335', (101, 105))	('S phase', 'CPA', (180, 187))	('CBX3', 'Gene', (275, 279))	('decrease', 'NegReg', (194, 202))
475044	30942427	The results demonstrated that knockdown of CBX3 expression can suppress the proliferation of MG63 cells via the increase in the proportion of cells in the G0 and G1 phases of the cell cycle and a decrease in the percentage of cells during the G2/M and S phases.	('decrease', 'NegReg', (196, 204))	('MG63', 'CellLine', 'CVCL:0426', (93, 97))	('proliferation', 'CPA', (76, 89))	('CBX3', 'Gene', (43, 47))	('increase', 'PosReg', (112, 120))	('knockdown', 'Var', (30, 39))	('suppress', 'NegReg', (63, 71))	('CBX3', 'Gene', '11335', (43, 47))
475045	30942427	In addition, knockdown of CBX3 expression induced apoptosis.	('CBX3', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('CBX3', 'Gene', '11335', (26, 30))	('apoptosis', 'CPA', (50, 59))
475046	30942427	The conserved chromatin binding proteins comprising the heterochomatin protein 1 (HP1) family, are directly associated with the methylated H3K9 (the methyl groups of histone H3 at lysine 9) promoter region, and therefore, take part in the heterochromatin silencing of gene expression.	('H3K9', 'Protein', (139, 143))	('lysine', 'Chemical', 'MESH:D008239', (180, 186))	('associated', 'Interaction', (108, 118))	('HP1', 'Gene', '23468', (82, 85))	('methylated', 'Var', (128, 138))	('HP1', 'Gene', (82, 85))	('heterochromatin', 'MPA', (239, 254))	('take part', 'Reg', (222, 231))
475047	30942427	The aberrant expression of HP1 can result in different human diseases, such as organism defects and cancer progression.	('organism defects', 'Disease', (79, 95))	('result in', 'Reg', (35, 44))	('human diseases', 'Disease', (55, 69))	('human', 'Species', '9606', (55, 60))	('organism defects', 'Disease', 'MESH:D019965', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('aberrant expression', 'Var', (4, 23))	('HP1', 'Gene', '23468', (27, 30))	('HP1', 'Gene', (27, 30))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
475055	30942427	Slezak et al found a positive correlation between Ki-67 expression and the CBX3 expression level, which could predict an unfavorable prognosis of prostate cancer patients.	('prostate cancer', 'Disease', (146, 161))	('patients', 'Species', '9606', (162, 170))	('CBX3', 'Gene', '11335', (75, 79))	('predict', 'Reg', (110, 117))	('expression level', 'MPA', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('prostate cancer', 'Disease', 'MESH:D011471', (146, 161))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('CBX3', 'Gene', (75, 79))	('Ki-67', 'Var', (50, 55))
475063	30942427	It was shown that the proliferation of MG63 cells was significantly prohibited by the knockdown of CBX3 expression via the increase in the percentage of cells during the G0 and G1 phases and a decrease in the proportion of the cells in the G2/M and S phases.	('G1 phases', 'CPA', (177, 186))	('expression', 'Protein', (104, 114))	('knockdown', 'Var', (86, 95))	('CBX3', 'Gene', '11335', (99, 103))	('prohibited', 'NegReg', (68, 78))	('CBX3', 'Gene', (99, 103))	('increase', 'PosReg', (123, 131))	('decrease', 'NegReg', (193, 201))	('MG63', 'CellLine', 'CVCL:0426', (39, 43))
475066	30942427	The dismal prognosis of patients suffering from osteosarcoma can be predicted by high CBX3 expression.	('CBX3', 'Gene', (86, 90))	('expression', 'MPA', (91, 101))	('high', 'Var', (81, 85))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('osteosarcoma', 'Disease', (48, 60))	('osteosarcoma', 'Disease', 'MESH:D012516', (48, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('CBX3', 'Gene', '11335', (86, 90))	('patients', 'Species', '9606', (24, 32))
475071	30942427	CBX3 chromobox protein homolog 3 HP1 heterochromatin protein 1 DMEM Dulbecco's modified Eagle's medium NBT normal brain tissue siRNA small interfering RNA qPCR quantitative polymerase chain reaction GAPDH glyceraldehyde-3-phosphate dehydrogenase CCK-8 Cell-Counting Kit-8 PBS phosphate-buffered saline OS overall survival DFS disease-free survival H3K9 methyl groups of histone H3 at lysine 9 HP1gamma heterochromatin protein 1gamma	('NBT', 'Chemical', 'MESH:D009580', (103, 106))	('HP1', 'Gene', (33, 36))	('phosphate-buffered saline', 'Chemical', '-', (276, 301))	('GAPDH', 'Gene', '2597', (199, 204))	('OS', 'Chemical', '-', (302, 304))	('CBX3', 'Gene', '11335', (0, 4))	('lysine', 'Chemical', 'MESH:D008239', (384, 390))	('CBX3', 'Gene', (0, 4))	('GAPDH', 'Gene', (199, 204))	('H3K9 methyl groups', 'Var', (348, 366))	('DMEM', 'Chemical', '-', (63, 67))	('HP1', 'Gene', (393, 396))	('HP1', 'Gene', '23468', (33, 36))	('HP1gamma', 'Gene', '11335', (393, 401))	('PBS', 'Chemical', '-', (272, 275))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (68, 102))	('HP1gamma', 'Gene', (393, 401))	('heterochromatin protein 1gamma', 'Gene', (402, 432))	('chromobox protein homolog 3', 'Gene', (5, 32))	('chromobox protein homolog 3', 'Gene', '11335', (5, 32))	('heterochromatin protein 1gamma', 'Gene', '11335', (402, 432))	('HP1', 'Gene', '23468', (393, 396))
475194	25973288	Also, mutation in succinate dehydrogenase gene (SDH) may lead to familial paraganglioma.	('familial paraganglioma', 'Disease', 'MESH:D010235', (65, 87))	('SDH', 'Gene', '6390', (48, 51))	('mutation', 'Var', (6, 14))	('lead to', 'Reg', (57, 64))	('SDH', 'Gene', (48, 51))	('familial paraganglioma', 'Disease', (65, 87))	('paraganglioma', 'Phenotype', 'HP:0002668', (74, 87))
475195	25973288	Three subunits of SDH gene mutation have been described in the literature and 33% of patients with SDH subunit B mutation have a positive family history.	('mutation', 'Var', (113, 121))	('SDH', 'Gene', (99, 102))	('SDH', 'Gene', '6390', (18, 21))	('patients', 'Species', '9606', (85, 93))	('SDH', 'Gene', (18, 21))	('SDH', 'Gene', '6390', (99, 102))
475225	25973288	Encasement of abdominal aorta and/or IVC without luminal compression is highly suggestive of retroperitoneal lymphoma.	('retroperitoneal lymphoma', 'Disease', 'MESH:D012186', (93, 117))	('lymphoma', 'Phenotype', 'HP:0002665', (109, 117))	('retroperitoneal lymphoma', 'Disease', (93, 117))	('Encasement', 'Var', (0, 10))	('men', 'Species', '9606', (6, 9))
475248	22473867	Subsequently, the patient sustained multiple recurrences of Ewing sarcoma beginning on Day +100, treated with chemotherapy, radiation, surgery, investigational monoclonal antibody against the insulin-like growth factor receptor-1 (CP751871, figitumumab), and an investigational tumor lysate dendritic cell vaccine.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('tumor', 'Disease', (278, 283))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (60, 73))	('CP751871', 'Var', (231, 239))	('patient', 'Species', '9606', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('Ewing sarcoma', 'Disease', (60, 73))
475262	22473867	Granulocytes were left shifted with decreased side light scatter consistent with hypogranularity, abnormal dim CD11b, and aberrant CD14 expression.	('left shifted', 'Phenotype', 'HP:0032239', (18, 30))	('expression', 'MPA', (136, 146))	('aberrant', 'Var', (122, 130))	('CD11b', 'Gene', '3684', (111, 116))	('CD11b', 'Gene', (111, 116))	('abnormal dim', 'Var', (98, 110))	('CD14', 'Gene', (131, 135))	('CD14', 'Gene', '929', (131, 135))	('side light scatter', 'MPA', (46, 64))	('decreased', 'NegReg', (36, 45))
475274	22473867	Complex and hypodiploid karyotypes are seen more frequently in t-MDS/AML in comparison to de novo disease, as are specific aberrations such as 5q-, monosomy 7, and 11q23/MLL abnormalities.	('monosomy 7', 'Var', (148, 158))	('AML', 'Disease', 'MESH:D015470', (69, 72))	('AML', 'Phenotype', 'HP:0004808', (69, 72))	('AML', 'Disease', (69, 72))	('MLL abnormalities', 'Disease', (170, 187))	('5q-', 'Var', (143, 146))	('hypodiploid', 'Disease', 'None', (12, 23))	('MLL abnormalities', 'Disease', 'MESH:D000014', (170, 187))	('MDS', 'Phenotype', 'HP:0002863', (65, 68))	('hypodiploid', 'Disease', (12, 23))	('MDS', 'Disease', (65, 68))	('MDS', 'Disease', 'MESH:D009190', (65, 68))
475276	22473867	In a recent study by Tiu et al., the addition of single nucleotide polymorphism arrays led to detection of chromosomal defects in 74% in patients with MDS (versus 44% with conventional cytogenetics alone).	('detection', 'Reg', (94, 103))	('single nucleotide polymorphism arrays', 'Var', (49, 86))	('patients', 'Species', '9606', (137, 145))	('MDS', 'Phenotype', 'HP:0002863', (151, 154))	('chromosomal defects', 'Var', (107, 126))	('MDS', 'Disease', (151, 154))	('MDS', 'Disease', 'MESH:D009190', (151, 154))
475286	22473867	The various methods and indications for use include XY-FISH (in case of sex-mismatched HSCT) and different molecular methods including PCR for variable number tandem repeats (VNTRs: repeats of 10-100 base pairs) or short tandem repeats (STRs) (repeats of 2-6 base pairs), real-time PCR for donor/recipient specific polymorphisms, or restriction fragment length polymorphisms (RFLP).	('restriction fragment length polymorphisms', 'Var', (333, 374))	('donor', 'Species', '9606', (290, 295))	('short tandem repeats', 'Var', (215, 235))
475299	22473867	Consistent with this, 36 of 74 (49%) of previously reported cases of DCL had cytogenetic abnormalities typical of therapy-related disease, including abnormalities involving 11q23, 21q22, and chromosomes 5, 7, 8 and 21, and three of these cases were known to have had a history of post-transplant radiation or pre-transplant exposure to chemotherapy in the donor.	('11q23', 'Gene', (173, 178))	('DCL', 'Disease', (69, 72))	('DCL', 'Chemical', '-', (69, 72))	('abnormalities', 'Var', (149, 162))	('donor', 'Species', '9606', (356, 361))	('21q22', 'Protein', (180, 185))
475320	22473867	Lenalidomide is active in the subgroup of patients with MDS with deletion of 5q, although the utility of this agent in t-MDS is unclear especially in the absence of deletion 5q..	('MDS', 'Phenotype', 'HP:0002863', (56, 59))	('MDS', 'Disease', (121, 124))	('MDS', 'Disease', 'MESH:D009190', (121, 124))	('MDS', 'Phenotype', 'HP:0002863', (121, 124))	('Lenalidomide', 'Chemical', 'MESH:D000077269', (0, 12))	('MDS', 'Disease', (56, 59))	('MDS', 'Disease', 'MESH:D009190', (56, 59))	('patients', 'Species', '9606', (42, 50))	('deletion', 'Var', (65, 73))
475334	22473867	Although unlikely to be curative, DLI in the setting of donor cell MDS has been reported to be associated with improvements in hematologic parameters.	('DLI', 'Var', (34, 37))	('improvements', 'PosReg', (111, 123))	('MDS', 'Disease', (67, 70))	('MDS', 'Disease', 'MESH:D009190', (67, 70))	('MDS', 'Phenotype', 'HP:0002863', (67, 70))	('hematologic parameters', 'MPA', (127, 149))	('donor', 'Species', '9606', (56, 61))
475368	30148241	Interphase fluorescent in situ hybridization showed a signal pattern consistent with FLI1-EWSR1 rearrangement.	('FLI1', 'Gene', '2313', (85, 89))	('EWSR1', 'Gene', (90, 95))	('rearrangement', 'Var', (96, 109))	('EWSR1', 'Gene', '2130', (90, 95))	('FLI1', 'Gene', (85, 89))
475369	30148241	EWSR1 rearrangement was confirmed by a second (break-apart) probe set.	('EWSR1', 'Gene', (0, 5))	('rearrangement', 'Var', (6, 19))	('EWSR1', 'Gene', '2130', (0, 5))
475379	30148241	Before the results of the fluorescent in situ hybridization, which ultimately detected the FLI1-EWSR1 rearrangement, a PET scan was performed to assist in diagnosis and to plan treatment.	('rearrangement', 'Var', (102, 115))	('EWSR1', 'Gene', (96, 101))	('EWSR1', 'Gene', '2130', (96, 101))	('detected', 'Reg', (78, 86))	('FLI1', 'Gene', '2313', (91, 95))	('FLI1', 'Gene', (91, 95))
475408	29487221	Our data are the first prospective study to suggest that ablation therapy in selected patients who are stable on chemotherapy can provide a significant progression-free interval off therapy and warrants further study in a randomized trial.	('progression-free', 'MPA', (152, 168))	('ablation', 'Var', (57, 65))	('patients', 'Species', '9606', (86, 94))
475412	29487221	Based on prior studies, this degree of response certainly supports the hypothesis that ablation after stability on chemotherapy can serve as a well-tolerated maintenance therapy and provide a significant PFS along with a chemotherapy-free interval for patients with metastatic soft tissue sarcoma [7], [8].	('patients', 'Species', '9606', (252, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (289, 296))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (277, 296))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (277, 296))	('soft tissue sarcoma', 'Disease', (277, 296))	('ablation', 'Var', (87, 95))
475458	29487221	Based on prior studies, this magnitude of response certainly supports the hypothesis that ablation after stability on chemotherapy can serve as a well-tolerated maintenance therapy and provide a significant PFS along with a chemotherapy-free holiday for patients with metastatic soft tissue sarcoma [14], [15].	('soft tissue sarcoma', 'Disease', (279, 298))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (279, 298))	('patients', 'Species', '9606', (254, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (279, 298))	('ablation', 'Var', (90, 98))
475533	25544668	Inhibition of vascular endothelial growth factor A and hypoxia inducible factor 1alpha maximize the effects of radiation in sarcoma mouse models through destruction of tumor vasculature Human sarcomas with a poor response to radiation therapy (RT) and vascular endothelial growth factor A (VEGF-A) inhibition have upregulation of hypoxia inducible factor 1alpha (HIF-1alpha) and HIF-1alpha target genes.	('VEGF-A', 'Gene', (290, 296))	('hypoxia inducible factor 1alpha', 'Gene', '15251', (330, 361))	('inhibition', 'Var', (298, 308))	('hypoxia inducible factor 1alpha', 'Gene', (55, 86))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('HIF-1alpha', 'Gene', (363, 373))	('sarcoma', 'Disease', (124, 131))	('poor response to radiation', 'Phenotype', 'HP:0011133', (208, 234))	('hypoxia inducible factor 1alpha', 'Gene', (330, 361))	('tumor', 'Disease', (168, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('vascular endothelial growth factor A', 'Gene', '22339', (252, 288))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('Human', 'Species', '9606', (186, 191))	('mouse', 'Species', '10090', (132, 137))	('vascular endothelial growth factor A', 'Gene', (252, 288))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('sarcomas', 'Disease', 'MESH:D012509', (192, 200))	('sarcoma', 'Disease', (192, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('hypoxia inducible factor 1alpha', 'Gene', '15251', (55, 86))	('sarcomas', 'Disease', (192, 200))	('vascular endothelial growth factor A', 'Gene', '22339', (14, 50))	('upregulation', 'PosReg', (314, 326))	('vascular endothelial growth factor A', 'Gene', (14, 50))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
475545	25544668	Inhibition of VEGF-A or its receptors can effectively suppress tumor angiogenesis in mouse models of STS.	('tumor', 'Disease', (63, 68))	('mouse', 'Species', '10090', (85, 90))	('STS', 'Phenotype', 'HP:0030448', (101, 104))	('suppress', 'NegReg', (54, 62))	('VEGF-A', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
475550	25544668	Analysis of pre-treatment tumor biopsies by gene expression microarrays using Gene Set Enrichment Analysis (GSEA) found the Gene Ontology (GO) category "Response to hypoxia" was upregulated in poor responders, and hierarchical clustering based on 140 hypoxia-responsive genes reliably separated poor responders from good responders.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('hypoxia', 'Disease', (251, 258))	('upregulated', 'PosReg', (178, 189))	('hypoxia', 'Disease', 'MESH:D000860', (251, 258))	('hypoxia', 'Disease', 'MESH:D000860', (165, 172))	('hypoxia', 'Disease', (165, 172))	('poor', 'Var', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
475557	25544668	Hind limb tumors were generated in LSL-KrasG12D/+/Trp53fl/fl mice with conditional mutations in oncogenic K-ras and the p53 tumor suppressor gene as previously described.	('limb tumors', 'Disease', (5, 16))	('p53', 'Gene', (52, 55))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('mice', 'Species', '10090', (61, 65))	('tumor', 'Disease', (10, 15))	('K-ras', 'Gene', '16653', (106, 111))	('K-ras', 'Gene', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('p53', 'Gene', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('p53', 'Gene', '22059', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutations', 'Var', (83, 92))	('Trp53', 'Gene', '22059', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('limb tumors', 'Disease', 'MESH:D017880', (5, 16))	('Trp53', 'Gene', (50, 55))	('p53', 'Gene', '22059', (120, 123))
475564	25544668	Antibodies used were anti-TUNEL (ApopTag Peroxidase kit, Millipore), anti-HIF-1alpha (Ab-4, Novus), and anti-CA9 (NB100-417, Novus).	('CA9', 'Gene', '230099', (109, 112))	('anti-HIF-1alpha', 'Var', (69, 84))	('CA9', 'Gene', (109, 112))
475571	25544668	Upon treatment of HT1080 xenografts for 12 days, DC101, metronomic doxorubicin, or RT as single agents inhibited tumor growth between 29-64% compared to control tumors, and combining any two modalities inhibited tumor growth by 54-73% (Fig.	('tumor', 'Disease', (113, 118))	('DC101', 'Var', (49, 54))	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('inhibited', 'NegReg', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('inhibited', 'NegReg', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('HT1080', 'CellLine', 'CVCL:0317', (18, 24))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (212, 217))
475589	25544668	We have previously demonstrated effective knockdown of HIF-1alpha in HT1080 cells using HIF-1alpha shRNA, and HIF-1alpha silencing in HT1080 cells results in decreased proliferation in vitro under both normoxic and hypoxic conditions.	('proliferation', 'CPA', (168, 181))	('silencing', 'Var', (121, 130))	('decreased', 'NegReg', (158, 167))	('hypoxic conditions', 'Disease', 'MESH:D009135', (215, 233))	('HIF-1alpha', 'Gene', (110, 120))	('HT1080', 'CellLine', 'CVCL:0317', (134, 140))	('hypoxic conditions', 'Disease', (215, 233))	('HT1080', 'CellLine', 'CVCL:0317', (69, 75))
475591	25544668	The most effective bimodality therapy was the combination of HIF-1alpha shRNA and DC101, which inhibited tumor growth by 82%.	('inhibited', 'NegReg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('DC101', 'Gene', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HIF-1alpha shRNA', 'Var', (61, 77))	('tumor', 'Disease', (105, 110))
475608	25544668	To examine the effects of HIF-1alpha blockade and RT in STS cell lines, we knocked down HIF-1alpha in HT1080 cells using shRNA (Fig.	('knocked', 'Var', (75, 82))	('HIF-1alpha blockade', 'Disease', 'MESH:D055191', (26, 45))	('HT1080', 'CellLine', 'CVCL:0317', (102, 108))	('HIF-1alpha', 'Gene', (88, 98))	('HIF-1alpha blockade', 'Disease', (26, 45))	('STS', 'Phenotype', 'HP:0030448', (56, 59))
475610	25544668	We found that combining HIF-1alpha knockdown and RT had at most an additive effect in blocking proliferation in both normoxia and hypoxia (Fig.	('knockdown', 'Var', (35, 44))	('blocking', 'NegReg', (86, 94))	('HIF-1alpha', 'Protein', (24, 34))	('normoxia and hypoxia', 'Disease', 'MESH:D000860', (117, 137))	('proliferation', 'CPA', (95, 108))
475618	25544668	In this trial, the addition of VEGF-A inhibition to RT significantly increased the proportion of tumors with a good response to RT to nearly 50%.	('increased', 'PosReg', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('VEGF-A', 'Gene', (31, 37))	('inhibition', 'Var', (38, 48))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
475624	25544668	They demonstrated that HIF-1alpha inhibition can either increase or decrease cancer cell sensitivity to RT via pleiotropic effects on cancer cell apoptosis, metabolism, and proliferation, but HIF-1alpha inhibition increases EC sensitivity to RT by inhibiting EC survival.	('inhibition', 'Var', (34, 44))	('decrease', 'NegReg', (68, 76))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('inhibition', 'Var', (203, 213))	('cancer', 'Disease', (134, 140))	('increases', 'PosReg', (214, 223))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('inhibiting', 'NegReg', (248, 258))	('EC survival', 'CPA', (259, 270))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('metabolism', 'MPA', (157, 167))	('HIF-1alpha', 'Gene', (192, 202))
475627	25544668	For example, HIF-1alpha can indirectly inhibit BRCA1 activity, and studies of hereditary breast cancer samples in patients with BRCA1 mutations showed increased HIF-1alpha positive tumor cells compared to sporadic breast cancer samples.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('increased', 'PosReg', (151, 160))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (78, 102))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('breast cancer', 'Disease', (214, 227))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('inhibit', 'NegReg', (39, 46))	('mutations', 'Var', (134, 143))	('patients', 'Species', '9606', (114, 122))	('BRCA1', 'Protein', (47, 52))	('hereditary breast cancer', 'Disease', (78, 102))	('activity', 'MPA', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('BRCA1', 'Gene', (128, 133))	('HIF-1alpha', 'Gene', (161, 171))	('tumor', 'Disease', (181, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
475636	25544668	This study describes a three-pronged approach to block the growth of STS by targeting tumor vasculature: RT to induce EC apoptosis, VEGF-A inhibition to block the major survival factor for EC, and either HIF-1alpha inhibition to block or eradicate the hypoxic tumor response.	('tumor', 'Disease', (260, 265))	('inhibition', 'Var', (139, 149))	('eradicate', 'NegReg', (238, 247))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('hypoxic tumor', 'Disease', (252, 265))	('VEGF-A', 'Gene', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('hypoxic tumor', 'Disease', 'MESH:D009369', (252, 265))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('STS', 'Phenotype', 'HP:0030448', (69, 72))
475864	28295221	There was no significant difference in Q-TWiSTs with either of the approaches because PFS was similar in the 2 arms, but pazopanib was associated with a higher rate of AEs.	('pazopanib', 'Chemical', 'MESH:C516667', (121, 130))	('AEs', 'Chemical', '-', (168, 171))	('TWiST', 'Gene', (41, 46))	('AEs', 'Disease', (168, 171))	('pazopanib', 'Var', (121, 130))	('TWiST', 'Gene', '7291', (41, 46))
475896	31516753	LAG-3 was expressed in murine tumor-infiltrating lymphocytes, and its blockade decreased tumor growth and enhanced secretion of interferon-gamma by CD8 + and CD4+ T cells.	('CD8', 'Gene', '925', (148, 151))	('secretion of interferon-gamma', 'MPA', (115, 144))	('enhanced', 'PosReg', (106, 114))	('decreased', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('murine', 'Species', '10090', (23, 29))	('LAG-3', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CD8', 'Gene', (148, 151))	('blockade', 'Var', (70, 78))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (89, 94))
475928	31516753	In brief, tumors were dissociated by sufficient mincing in complete RPMI 1640 medium followed by collagenase Type IV (Sigma-Aldrich) and DNase I (Sigma-Aldrich) digestion for 1 hour at 37 C and filtering through 70-mum nylon cell strainers in phosphate buffer saline.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('saline', 'Chemical', 'MESH:D012965', (260, 266))	('RPMI', 'Chemical', '-', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('phosphate', 'Chemical', 'MESH:D010710', (243, 252))	('digestion', 'Var', (161, 170))
475954	31516753	Importantly, the high expression of LAG-3 was significantly associated with a high pathological grade (low grade vs. high grade, P < 0.001), a more advanced tumor stage (I+II vs. III+IV, P = 0.016) (Table 1).	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('LAG-3', 'Gene', (36, 41))	('high', 'Var', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('associated', 'Reg', (60, 70))
475969	31516753	In this model, treatment with anti-LAG-3 antibody significantly decreased the tumor burden (P < 0.001) ( Figure 5D).	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('anti-LAG-3', 'Var', (30, 40))	('decreased', 'NegReg', (64, 73))
475970	31516753	Tumor-infiltrating CD8+ T cells and CD4+ T cells from mice treated with anti-LAG-3 antibodies showed a significant increase in IFNgamma compared with control mice (Figure 5E).	('CD8', 'Gene', (19, 22))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD8', 'Gene', '925', (19, 22))	('anti-LAG-3 antibodies', 'Var', (72, 93))	('mice', 'Species', '10090', (158, 162))	('IFNgamma', 'Protein', (127, 135))	('increase', 'PosReg', (115, 123))	('mice', 'Species', '10090', (54, 58))
475980	31516753	These findings suggest that the presence of LAG-3 in TILs facilitates tumor cell proliferation and induces tumor recurrence or metastasis.	('induces', 'Reg', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('facilitates', 'PosReg', (58, 69))	('tumor', 'Disease', (70, 75))	('presence', 'Var', (32, 40))	('LAG-3', 'Gene', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
475981	31516753	reported that CD4+ cells represent a positive prognostic factor in STS based on univariate analyses, but they did not find a statistically significant correlation (P = 0.15) between CD8+ T cells and prognosis, which differs from our results.	('CD4+ cells', 'Var', (14, 24))	('CD8', 'Gene', (182, 185))	('STS', 'Phenotype', 'HP:0030448', (67, 70))	('CD8', 'Gene', '925', (182, 185))
475989	31516753	The present data show that the anti-LAG-3 antibody inhibited the growth of MCA205 fibrosarcoma in syngeneic C57BL/6 mice, supporting the clinical development of this novel immunotherapy in sarcoma.	('mice', 'Species', '10090', (116, 120))	('sarcoma', 'Disease', (189, 196))	('anti-LAG-3', 'Var', (31, 41))	('sarcoma', 'Disease', (87, 94))	('growth', 'CPA', (65, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('MCA205 fibrosarcoma', 'Disease', (75, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (82, 94))	('inhibited', 'NegReg', (51, 60))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))	('MCA205 fibrosarcoma', 'Disease', 'MESH:D005354', (75, 94))
475991	31516753	In MCA205 tumor-bearing mice, antibody blockade of LAG-3 efficiently decreased tumor growth and enhanced CD8+ T-cell effector function.	('CD8', 'Gene', (105, 108))	('LAG-3', 'Gene', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('CD8', 'Gene', '925', (105, 108))	('tumor', 'Disease', (79, 84))	('mice', 'Species', '10090', (24, 28))	('tumor', 'Disease', (10, 15))	('enhanced', 'PosReg', (96, 104))	('decreased', 'NegReg', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('antibody blockade', 'Var', (30, 47))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
475996	31516753	Our results suggest that LAG-3 is overexpressed on TILs, and anti-LAG-3 restrains tumor progression.	('restrains', 'NegReg', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('anti-LAG-3', 'Var', (61, 71))
476044	28538874	In a retrospective comparative analysis conducted at the Evandro Chagas National Institute of Infectious Diseases in Rio de Janeiro and at the Comprehensive Care Center for HIV/AIDS patients in Nashville, it was shown that immunosuppression was associated with an increased risk of developing neoplasias defining AIDS.	('AIDS', 'Disease', (177, 181))	('AIDS', 'Disease', 'MESH:D000163', (177, 181))	('HIV', 'Species', '12721', (173, 176))	('immunosuppression', 'Var', (223, 240))	('neoplasia', 'Phenotype', 'HP:0002664', (293, 302))	('AIDS', 'Disease', (313, 317))	('patients', 'Species', '9606', (182, 190))	('neoplasias', 'Disease', 'MESH:D009369', (293, 303))	('AIDS', 'Disease', 'MESH:D000163', (313, 317))	('neoplasias', 'Disease', (293, 303))
476074	23443465	MSCs are tolerant of ectopic EWS/FLI expression, which is accompanied by a molecular signature most similar to Ewing sarcoma.	('FLI', 'Gene', '2314', (33, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('FLI', 'Gene', (33, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('ectopic', 'Var', (21, 28))	('Ewing sarcoma', 'Disease', (111, 124))
476087	23443465	Unfortunately, despite the inferred hierarchical simplicity of EWS/FLI-mediated gene dysregulation in Ewing sarcoma, in vitro and animal models have been unable to fully recapitulate the process of oncogenic transformation under conditions of induced EWS/FLI expression in normal cells and tissues.	('Ewing sarcoma', 'Disease', (102, 115))	('dysregulation', 'Var', (85, 98))	('FLI', 'Gene', '2314', (255, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('FLI', 'Gene', (255, 258))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('FLI', 'Gene', '2314', (67, 70))	('FLI', 'Gene', (67, 70))
476090	23443465	For example, ectopic expression of EWS/FLI in a variety of non-malignant human and animal cell lines is either toxic (Lessnick et al.,), induces a gene signature discordant with that observed in patient-derived cell lines (Braunreiter et al.,) or is simply incapable of mediating the entire phenotypic spectrum of oncogenic transformation (Lessnick et al.,; Riggi et al.,).	('FLI', 'Gene', '2314', (39, 42))	('gene signature', 'MPA', (147, 161))	('FLI', 'Gene', (39, 42))	('induces', 'Reg', (137, 144))	('patient', 'Species', '9606', (195, 202))	('human', 'Species', '9606', (73, 78))	('ectopic expression', 'Var', (13, 31))
476106	23443465	In a similar series of experiments using a murine myoblast cell line (C2C12), which is capable of osteogenic, myogenic, and adipogenic differentiation, Eliazer and colleagues demonstrated a comparable tolerance of ectopic EWS/FLI expression and impaired terminal differentiation into muscle and bone.	('ectopic', 'Var', (214, 221))	('C2C12', 'CellLine', 'CVCL:0188', (70, 75))	('FLI', 'Gene', '2314', (226, 229))	('murine', 'Species', '10090', (43, 49))	('impaired', 'NegReg', (245, 253))	('FLI', 'Gene', (226, 229))
476142	23443465	Ectopic EWS/FLI expression also resulted in cell surface immunophenotypes and gene expression profiles consistent with Ewing sarcoma, although no in vitro or in vivo measures of transformation were assessed.	('FLI', 'Gene', (12, 15))	('resulted in', 'Reg', (32, 43))	('expression', 'Var', (16, 26))	('cell surface', 'MPA', (44, 56))	('Ewing sarcoma', 'Disease', (119, 132))	('gene expression profiles', 'MPA', (78, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (119, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('Ectopic', 'Var', (0, 7))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (119, 132))	('FLI', 'Gene', '2314', (12, 15))
476163	23443465	Various pre- and post-centrifugation techniques have been described to enrich the mononuclear cell layer with likely MSC populations including hypotonic red blood cell lysis buffers, negative selection antibody beads (removing hematopoietic stem cells) and cell sorting using a FACS or MACS-type systems.	('MACS', 'Gene', (286, 290))	('hypotonic red blood', 'Disease', (143, 162))	('MACS', 'Gene', '54453', (286, 290))	('negative selection', 'Var', (183, 201))	('hypotonic red blood', 'Disease', 'MESH:D006402', (143, 162))
476180	23443465	To circumvent these issues, immortalizing cells with retroviral hTERT, SV40 T-antigen and E7 transgenes can substantially prolong the proliferative life span of hMSCs without loss of tri-lineage potential (Terai et al.,; Wolbank et al.,; Li et al.,).	('E7 transgenes', 'Var', (90, 103))	('hTERT', 'Gene', (64, 69))	('hTERT', 'Gene', '7015', (64, 69))	('proliferative life span', 'CPA', (134, 157))	('SV40', 'Gene', (71, 75))	('hMSCs', 'CPA', (161, 166))	('prolong', 'NegReg', (122, 129))
476203	21437217	The majority of ARMS are characterized by specific translocations between the DNA binding encoding domain of either the PAX3 or PAX7 genes and the transactivation encoding domain of FOXO1.	('translocations', 'Var', (51, 65))	('RMS', 'Phenotype', 'HP:0002859', (17, 20))	('PAX7', 'Gene', '5081', (128, 132))	('PAX3', 'Gene', (120, 124))	('ARMS', 'Disease', (16, 20))	('PAX7', 'Gene', (128, 132))
476205	21437217	Other genetic events are associated with these tumors including those considered to cooperate with the fusion gene product in ARMS such as MYCN amplification and overexpression, and mutation of TP53.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('RMS', 'Phenotype', 'HP:0002859', (127, 130))	('TP53', 'Gene', '7157', (194, 198))	('mutation', 'Var', (182, 190))	('MYCN', 'Gene', (139, 143))	('TP53', 'Gene', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('MYCN', 'Gene', '4613', (139, 143))
476207	21437217	In both ARMS and ERMS loss of heterozygosity or imprinting is thought to lead to overexpression of the gene encoding the insulin-like growth factor 2 (IGF2).	('loss of heterozygosity', 'Var', (22, 44))	('RMS', 'Phenotype', 'HP:0002859', (18, 21))	('overexpression', 'PosReg', (81, 95))	('insulin-like growth factor 2', 'Gene', '3481', (121, 149))	('insulin-like growth factor 2', 'Gene', (121, 149))	('RMS', 'Phenotype', 'HP:0002859', (9, 12))	('IGF2', 'Gene', (151, 155))
476218	21437217	In addition, loss of p53 has been shown to be associated with increased expression of IGF2 in RMS, even though the mechanisms supporting this are not fully elucidated.	('increased', 'PosReg', (62, 71))	('IGF2', 'Gene', (86, 90))	('p53', 'Gene', '7157', (21, 24))	('RMS', 'Disease', (94, 97))	('increased expression of IGF2', 'Phenotype', 'HP:0030269', (62, 90))	('RMS', 'Phenotype', 'HP:0002859', (94, 97))	('expression', 'MPA', (72, 82))	('loss', 'Var', (13, 17))	('p53', 'Gene', (21, 24))
476222	21437217	Only cells expressing both IGF2 and PAX3-FOXO1 developed invasive, poorly differentiated tumors with low rate of apoptosis.	('IGF2', 'Gene', (27, 31))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('invasive', 'CPA', (57, 65))	('developed', 'PosReg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('PAX3-FOXO1', 'Var', (36, 46))
476251	21437217	In vivo experiments using the RMS cell line RH30 have shown that IGFBP-6 overexpression resulted in a marked delay in tumor growth in nude mice.	('delay', 'NegReg', (109, 114))	('RH30', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('RH30', 'Gene', '6007', (44, 48))	('IGFBP-6', 'Gene', '3489', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('overexpression', 'Var', (73, 87))	('nude mice', 'Species', '10090', (134, 143))	('tumor', 'Disease', (118, 123))	('IGFBP-6', 'Gene', (65, 72))	('RMS', 'Phenotype', 'HP:0002859', (30, 33))
476259	21437217	Recently, it has been shown, both in vitro and in vivo, that IGF1R survival signaling in RMS is primarily maintained through the AKT pathway, and that effective disruption of the IGF1R survival signaling results in decreased AKT activation.	('RMS', 'Phenotype', 'HP:0002859', (89, 92))	('AKT', 'Gene', '207', (225, 228))	('AKT', 'Gene', '207', (129, 132))	('activation', 'PosReg', (229, 239))	('IGF1R', 'Gene', (179, 184))	('AKT', 'Gene', (225, 228))	('disruption', 'Var', (161, 171))	('decreased', 'NegReg', (215, 224))	('AKT', 'Gene', (129, 132))
476263	21437217	It has been described that patients with an increased phosphorylation of AKT, that result from a disruption in the feedback mechanism between mTOR and IRS, have a poorer survival.	('disruption', 'Var', (97, 107))	('IRS', 'Gene', '3376', (151, 154))	('mTOR', 'Gene', (142, 146))	('mTOR', 'Gene', '2475', (142, 146))	('AKT', 'Gene', (73, 76))	('IRS', 'Gene', (151, 154))	('feedback mechanism', 'MPA', (115, 133))	('patients', 'Species', '9606', (27, 35))	('poorer', 'NegReg', (163, 169))	('increased', 'PosReg', (44, 53))	('AKT', 'Gene', '207', (73, 76))	('phosphorylation', 'MPA', (54, 69))
476267	21437217	A small number of clinical responses in patients with sarcomas have been reported across the different phase I clinical trials using IGF1R antibodies and have raised hope for the success of this therapeutic modality.	('IGF1R', 'Gene', (133, 138))	('patients', 'Species', '9606', (40, 48))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('antibodies', 'Var', (139, 149))	('sarcomas', 'Disease', (54, 62))
476271	21437217	More recently, in a preliminary report of the SARC011, a phase II trial in multiple sarcoma types, described 3 objective radiological responses in patients with RMS treated with the anti-IGF1R antibody R1507.	('RMS', 'Phenotype', 'HP:0002859', (161, 164))	('R1507', 'Var', (202, 207))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Disease', (84, 91))	('patients', 'Species', '9606', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('RMS', 'Disease', (161, 164))
476273	21437217	Despite the difficulties of drawing conclusions from small numbers of RMS patients treated with anti-IGF1R antibodies, it is plausible to suggest that such single agent therapy in RMS might be insufficient to cause a clinically significant and persistent disruption in the IGF-mediated survival signalling, as seen in other neoplasias where IGF2 plays a relevant role.	('anti-IGF1R antibodies', 'Var', (96, 117))	('disruption', 'Reg', (255, 265))	('anti-IGF1R', 'Gene', (96, 106))	('patients', 'Species', '9606', (74, 82))	('IGF-mediated survival signalling', 'Pathway', (273, 305))	('neoplasias', 'Disease', 'MESH:D009369', (324, 334))	('RMS', 'Disease', (180, 183))	('neoplasias', 'Phenotype', 'HP:0002664', (324, 334))	('RMS', 'Phenotype', 'HP:0002859', (70, 73))	('antibodies', 'Var', (107, 117))	('insufficient', 'Disease', 'MESH:D000309', (193, 205))	('RMS', 'Phenotype', 'HP:0002859', (180, 183))	('neoplasias', 'Disease', (324, 334))	('insufficient', 'Disease', (193, 205))
476302	21437217	However, in RMS patients, despite some responses observed with R1507, targeting IGF1R alone does not seem the optimal strategy due to the complexity of this pathway and the key role of IGF2 in this pathology.	('IGF1R', 'Gene', (80, 85))	('R1507', 'Var', (63, 68))	('patients', 'Species', '9606', (16, 24))	('RMS', 'Disease', (12, 15))	('RMS', 'Phenotype', 'HP:0002859', (12, 15))
476311	33639499	SEF of the gluteal region can induce sciatalgia.	('sciatalgia', 'Disease', (37, 47))	('sciatalgia', 'Disease', 'None', (37, 47))	('SEF', 'Var', (0, 3))	('induce', 'Reg', (30, 36))
476351	33639499	SEF of the gluteal region can induced clinically a sciatic nerve pain.	('pain', 'Phenotype', 'HP:0012531', (65, 69))	('induced', 'Reg', (30, 37))	('sciatic nerve pain', 'Phenotype', 'HP:0011868', (51, 69))	('SEF', 'Var', (0, 3))	('sciatic nerve pain', 'Disease', 'MESH:D009437', (51, 69))	('sciatic nerve pain', 'Disease', (51, 69))
476415	30050977	To begin operative planning, we will first need to visualize the involvement of the skeletal structures of the pelvis with the large soft tissue sarcoma by thresholding between 250HU and 1520HU and limiting the bounding box at the L3-L4 intervertebral disk proximally.	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (133, 152))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (133, 152))	('soft tissue sarcoma', 'Disease', (133, 152))	('limiting', 'NegReg', (198, 206))	('bounding box', 'MPA', (211, 223))	('thresholding', 'Var', (156, 168))
476447	29581640	Metastases can be as common as 40% with high-grade tumours and occur most commonly in the lung, but may also affect liver, brain and bone.	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('affect', 'Reg', (109, 115))	('Metastases', 'Disease', (0, 10))	('high-grade', 'Var', (40, 50))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))	('tumours', 'Disease', (51, 58))
476501	27986986	Other inclusion criteria were body weight >=15 kg for patients 6 to <18 years of age and >=12.5 kg for patients 2 to <6 years of age, white blood cell count >2.5 x 109/L, absolute neutrophil count (ANC) >=1.5 x 109/L, platelet count >=100 x 109/L (at screening and prior to chemotherapy), and Eastern Cooperative Oncology Group performance status <=2 for patients >=12 years of age.	('patients', 'Species', '9606', (355, 363))	('>=100 x 109/L', 'Var', (233, 246))	('patients', 'Species', '9606', (54, 62))	('>=1.5', 'Var', (203, 208))	('white blood cell count', 'CPA', (134, 156))	('Oncology', 'Phenotype', 'HP:0002664', (313, 321))	('patients', 'Species', '9606', (103, 111))	('>2.5', 'Var', (157, 161))
476532	27986986	Subcutaneous injection of lipegfilgrastim 100 microg/kg approximately 24 h after the last dose of chemotherapy in week 1 of the chemotherapy regimen resulted in mean (+-SD) C max values of 292 +- 178 ng/mL in the youngest age group, 303 +- 144 ng/mL in the mid-age group, and 341 +- 381 ng/mL in the oldest age group (Table 2).	('SD', 'Disease', 'MESH:D029461', (169, 171))	('lipegfilgrastim', 'Var', (26, 41))	('C max', 'MPA', (173, 178))
476580	27986986	Among the three chemotherapy regimens used in this study, VIDE was the most myelosuppressive, with the lowest ANC nadir; however, lipegfilgrastim has been shown to stimulate the highest recovery of neutrophils in patients who received VIDE, along with the highest CD34+ level in the recovery period (Table 3), compared with the other chemotherapy regimens in this study.	('recovery', 'MPA', (186, 194))	('CD34', 'Gene', '947', (264, 268))	('nadir', 'Chemical', '-', (114, 119))	('VIDE', 'Chemical', '-', (58, 62))	('stimulate', 'PosReg', (164, 173))	('lipegfilgrastim', 'Var', (130, 145))	('patients', 'Species', '9606', (213, 221))	('VIDE', 'Chemical', '-', (235, 239))	('CD34', 'Gene', (264, 268))
476590	27986986	In a randomized phase 2 study of pediatric patients with sarcoma, 68% of those receiving pegfilgrastim and 83% of patients treated with filgrastim experienced febrile neutropenia.	('patients', 'Species', '9606', (43, 51))	('neutropenia', 'Phenotype', 'HP:0001875', (167, 178))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('febrile neutropenia', 'Disease', (159, 178))	('febrile neutropenia', 'Disease', 'MESH:D009503', (159, 178))	('sarcoma', 'Disease', (57, 64))	('patients', 'Species', '9606', (114, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('pegfilgrastim', 'Var', (89, 102))
476607	26979396	EC-8105 was found to be the most potent analog and was able to suppress EWS-FLI1 activity at concentrations nontoxic to other cell types.	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', (72, 75))	('FLI1', 'Gene', '2313', (76, 80))	('FLI1', 'Gene', (76, 80))	('EC-8105', 'Var', (0, 7))	('activity', 'MPA', (81, 89))	('rat', 'Species', '10116', (100, 103))	('suppress', 'NegReg', (63, 71))	('EC-8105', 'Chemical', '-', (0, 7))
476608	26979396	EC-8042 was substantially less toxic than mithramycin in multiple species but maintained suppression of EWS-FLI1 at similar concentrations.	('EWS', 'Gene', '2130', (104, 107))	('EWS', 'Gene', (104, 107))	('rat', 'Species', '10116', (131, 134))	('FLI1', 'Gene', '2313', (108, 112))	('FLI1', 'Gene', (108, 112))	('EC-8042', 'Var', (0, 7))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('mithramycin', 'Chemical', 'MESH:D008926', (42, 53))	('suppression', 'NegReg', (89, 100))
476630	26979396	In this report, we show that EC-8105 was a more potent EWS-FLI1 inhibitor than mithramycin and yet maintained a comparable toxicity profile.	('FLI1', 'Gene', (59, 63))	('EWS', 'Gene', '2130', (55, 58))	('EWS', 'Gene', (55, 58))	('FLI1', 'Gene', '2313', (59, 63))	('toxicity', 'Disease', (123, 131))	('EC-8105', 'Var', (29, 36))	('mithramycin', 'Chemical', 'MESH:D008926', (79, 90))	('EC-8105', 'Chemical', '-', (29, 36))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))
476664	26979396	However, EC-8105 (grey arrow) improved the suppression of EWS-FLI1 by almost 10-fold, with an IC50 of 2 nmol/L (95% CI, 2-3) as opposed to 17 nmol/L (95% CI, 15-18) for MMA (Fig.	('suppression', 'MPA', (43, 54))	('MMA', 'Chemical', '-', (169, 172))	('FLI1', 'Gene', (62, 66))	('EC-8105', 'Var', (9, 16))	('FLI1', 'Gene', '2313', (62, 66))	('EC-8105', 'Chemical', '-', (9, 16))	('EWS', 'Gene', (58, 61))	('EWS', 'Gene', '2130', (58, 61))	('improved', 'PosReg', (30, 38))
476669	26979396	In addition, at concentrations that should be achievable in patients (see below), there was marked suppression of EWS-FLI1 activity as measured by NR0B1 mRNA expression, with EC-8105 at 15 nmol/L showing a fold change of 0.19 (95% CI, 0.17-0.20) and at 5 nmol/L showing statistically significant suppression at a fold change of 0.68 (95% CI, 0.58-0.78; P = 0.0002)(Supplementary Fig.	('suppression', 'NegReg', (296, 307))	('EWS', 'Gene', '2130', (114, 117))	('EWS', 'Gene', (114, 117))	('NR0B1', 'Gene', (147, 152))	('EC-8105', 'Chemical', '-', (175, 182))	('patients', 'Species', '9606', (60, 68))	('rat', 'Species', '10116', (23, 26))	('NR0B1', 'Gene', '190', (147, 152))	('FLI1', 'Gene', (118, 122))	('FLI1', 'Gene', '2313', (118, 122))	('suppression', 'NegReg', (99, 110))	('activity', 'MPA', (123, 131))	('EC-8105', 'Var', (175, 182))	('mRNA expression', 'MPA', (153, 168))
476670	26979396	Finally, the suppression of EWS-FLI1 observed in these studies translates into a marked suppression in cell viability and an IC50 of 3.29 nmol/L (95% CI, 3.1-3.5) for EC-8105, which is again substantially lower than the IC50 of MMA of 15.5 nmol/L (95% CI, 14.7-17.1)(Fig.	('EC-8105', 'Chemical', '-', (167, 174))	('cell viability', 'CPA', (103, 117))	('EWS', 'Gene', '2130', (28, 31))	('MMA', 'Chemical', '-', (228, 231))	('FLI1', 'Gene', (32, 36))	('FLI1', 'Gene', '2313', (32, 36))	('EC-8105', 'Var', (167, 174))	('suppression', 'NegReg', (88, 99))	('suppression', 'NegReg', (13, 24))	('EWS', 'Gene', (28, 31))
476675	26979396	Next, we verified that siRNA silencing of EWS-FLI1 did in fact lead to the suppression of the EWS-FLI1 induced targets and induction of the suppressed targets (Supplementary Fig.	('EWS', 'Gene', '2130', (94, 97))	('EWS', 'Gene', (94, 97))	('silencing', 'Var', (29, 38))	('FLI1', 'Gene', '2313', (98, 102))	('FLI1', 'Gene', (46, 50))	('suppression', 'NegReg', (75, 86))	('FLI1', 'Gene', '2313', (46, 50))	('FLI1', 'Gene', (98, 102))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
476682	26979396	It is notable that EC-8105 achieved similar suppression of EWS-FLI1 targets at 5 to 15 nmol/L as was seen at 50 to 100 nmol/L of mithramycin (Fig.	('EWS', 'Gene', (59, 62))	('FLI1', 'Gene', (63, 67))	('mithramycin', 'Chemical', 'MESH:D008926', (129, 140))	('FLI1', 'Gene', '2313', (63, 67))	('EC-8105', 'Var', (19, 26))	('EC-8105', 'Chemical', '-', (19, 26))	('suppression', 'NegReg', (44, 55))	('EWS', 'Gene', '2130', (59, 62))
476695	26979396	We confirmed that 50 nmol/L EC-8042 suppressed NR0B1 expression to the identical degree as mithramycin, with a fold change of 0.62 (95% CI, 0.50-0.72, P <0.0001) vs. 0.62 (95% CI, 0.50-0.72, P <0.0001)(Fig.	('NR0B1', 'Gene', '190', (47, 52))	('suppressed', 'NegReg', (36, 46))	('mithramycin', 'Chemical', 'MESH:D008926', (91, 102))	('EC-8042', 'Chemical', 'MESH:C576677', (28, 35))	('EC-8042', 'Var', (28, 35))	('expression', 'MPA', (53, 63))	('NR0B1', 'Gene', (47, 52))
476702	26979396	Importantly, since EWS-FLI1 is not found in these cell lines, there was no consistent alteration in expression of this panel of genes like with EC-8042, EC-8105 or mithramycin.	('EC-8105', 'Var', (153, 160))	('mithramycin', 'Chemical', 'MESH:D008926', (164, 175))	('EC-8105', 'Chemical', '-', (153, 160))	('EC-8042', 'Chemical', 'MESH:C576677', (144, 151))	('expression', 'MPA', (100, 110))	('EWS', 'Gene', (19, 22))	('EWS', 'Gene', '2130', (19, 22))	('EC-8042', 'Var', (144, 151))	('FLI1', 'Gene', (23, 27))	('FLI1', 'Gene', '2313', (23, 27))	('rat', 'Species', '10116', (90, 93))
476703	26979396	To confirm suppression of EWS-FLI1 targets at the protein level, we treated TC32 and TC71 cells with either mithramycin or EC-8042 for 18 h. In TC32 cells, 50 nmol/L of mithramycin or EC-8042 suppressed the EWS-FLI1 targets EZH2, NR0B1, and ID2 (Fig.	('NR0B1', 'Gene', '190', (230, 235))	('EZH2', 'Gene', '2146', (224, 228))	('suppressed', 'NegReg', (192, 202))	('ID2', 'Gene', '3398', (241, 244))	('EC-8042', 'Chemical', 'MESH:C576677', (123, 130))	('EZH2', 'Gene', (224, 228))	('EWS', 'Gene', (26, 29))	('ID2', 'Gene', (241, 244))	('TC71', 'CellLine', 'CVCL:2213', (85, 89))	('EWS', 'Gene', (207, 210))	('FLI1', 'Gene', (211, 215))	('mithramycin', 'Chemical', 'MESH:D008926', (108, 119))	('NR0B1', 'Gene', (230, 235))	('EC-8042', 'Chemical', 'MESH:C576677', (184, 191))	('FLI1', 'Gene', (30, 34))	('TC32', 'Var', (144, 148))	('EWS', 'Gene', '2130', (26, 29))	('FLI1', 'Gene', '2313', (211, 215))	('mithramycin', 'Chemical', 'MESH:D008926', (169, 180))	('FLI1', 'Gene', '2313', (30, 34))	('EWS', 'Gene', '2130', (207, 210))
476705	26979396	Importantly, in contrast to mithramycin, the suppression of EWS-FLI1 by EC-8042 happened in the absence of DNA damage, as measured by the phosphorylation of gammaH2AX (Fig.	('suppression', 'NegReg', (45, 56))	('gammaH2AX', 'Protein', (157, 166))	('EWS', 'Gene', '2130', (60, 63))	('EWS', 'Gene', (60, 63))	('EC-8042', 'Chemical', 'MESH:C576677', (72, 79))	('phosphorylation', 'MPA', (138, 153))	('EC-8042', 'Var', (72, 79))	('FLI1', 'Gene', '2313', (64, 68))	('mithramycin', 'Chemical', 'MESH:D008926', (28, 39))	('FLI1', 'Gene', (64, 68))
476706	26979396	Furthermore, the concentration that causes EWS-FLI1 target suppression more closely approximates the cell viability IC50 of 37.8 nmol/L (95% CI, 35.6-40.0), for EC-8042 than the 15.5 nmol/L (95% CI, 14.7-17.1) value for mithramycin (Fig.	('suppression', 'NegReg', (59, 70))	('EC-8042', 'Var', (161, 168))	('EC-8042', 'Chemical', 'MESH:C576677', (161, 168))	('mithramycin', 'Chemical', 'MESH:D008926', (220, 231))	('cell viability', 'CPA', (101, 115))	('EWS', 'Gene', '2130', (43, 46))	('EWS', 'Gene', (43, 46))	('FLI1', 'Gene', (47, 51))	('rat', 'Species', '10116', (24, 27))	('FLI1', 'Gene', '2313', (47, 51))
476708	26979396	To model this cleaner cytotoxicity of EC-8042 and EC-8105, we evaluated the effect of drug treatment using time-lapse microscopy.	('cytotoxicity', 'Disease', (22, 34))	('EC-8042', 'Var', (38, 45))	('EC-8105', 'Chemical', '-', (50, 57))	('EC-8042', 'Chemical', 'MESH:C576677', (38, 45))	('cytotoxicity', 'Disease', 'MESH:D064420', (22, 34))
476725	26979396	Finally, all cell lines that were p53 mutated were statistically more sensitive to mithramycin and EC-8105 but not EC-8042 consistent with the known DNA-damaging properties of these agents (Supplementary Fig.	('mutated', 'Var', (38, 45))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('more', 'PosReg', (65, 69))	('EC-8105', 'Chemical', '-', (99, 106))	('mithramycin', 'Chemical', 'MESH:D008926', (83, 94))	('EC-8042', 'Chemical', 'MESH:C576677', (115, 122))	('sensitive', 'MPA', (70, 79))
476734	26979396	EC-8042 also showed excellent activity in the resistant TC71 model, but the activity was independent of route of administration.	('TC71', 'CellLine', 'CVCL:2213', (56, 60))	('EC-8042', 'Var', (0, 7))	('EC-8042', 'Chemical', 'MESH:C576677', (0, 7))	('resistant TC71 model', 'CPA', (46, 66))	('activity', 'MPA', (30, 38))	('rat', 'Species', '10116', (121, 124))
476741	26979396	Even at this low dose of EC-8042, every tumor in every mouse showed some level of regression following variable periods of tumor growth, remaining suppressed until therapy was discontinued (Fig.	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mouse', 'Species', '10090', (55, 60))	('EC-8042', 'Chemical', 'MESH:C576677', (25, 32))	('EC-8042', 'Var', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
476767	26979396	Since we know EC-8042 is less toxic, this approach as a surrogate for toxicity is disfavored.	('toxicity', 'Disease', 'MESH:D064420', (70, 78))	('EC-8042', 'Chemical', 'MESH:C576677', (14, 21))	('toxicity', 'Disease', (70, 78))	('EC-8042', 'Var', (14, 21))
476772	26979396	Both analogs achieve suppression of EWS-FLI1 with limited (EC-8105) or no (EC-8042) associated DNA damage, while mithramycin suppressed EWS-FLI1 at relatively high concentrations that produced marked DNA damage.	('EWS', 'Gene', (136, 139))	('EC-8042', 'Var', (75, 82))	('FLI1', 'Gene', (140, 144))	('EWS', 'Gene', '2130', (136, 139))	('EC-8105', 'Chemical', '-', (59, 66))	('mithramycin', 'Chemical', 'MESH:D008926', (113, 124))	('EWS', 'Gene', '2130', (36, 39))	('EWS', 'Gene', (36, 39))	('EC-8042', 'Chemical', 'MESH:C576677', (75, 82))	('FLI1', 'Gene', (40, 44))	('rat', 'Species', '10116', (171, 174))	('FLI1', 'Gene', '2313', (40, 44))	('suppression', 'NegReg', (21, 32))	('EC-8105', 'Var', (59, 66))	('FLI1', 'Gene', '2313', (140, 144))
476773	26979396	The fact that tumors markedly regressed under EC-8105 treatment and have a substantially lower IC50 with this agent relative to EC-8042 suggests that some DNA damage assists the mechanism of EWS-FLI1 suppression.	('FLI1', 'Gene', (195, 199))	('lower', 'NegReg', (89, 94))	('EC-8105', 'Var', (46, 53))	('EC-8042', 'Chemical', 'MESH:C576677', (128, 135))	('tumors', 'Disease', (14, 20))	('EWS', 'Gene', (191, 194))	('EWS', 'Gene', '2130', (191, 194))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('EC-8105', 'Chemical', '-', (46, 53))	('IC50', 'MPA', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('FLI1', 'Gene', '2313', (195, 199))
476775	26979396	This is reflected in our in vivo results, where the less-sensitive TC71 xenograft was p53 mutant while TC32 was p53 wild type and much more sensitive in our previously published study.	('p53', 'Gene', '7157', (86, 89))	('mutant', 'Var', (90, 96))	('p53', 'Gene', (112, 115))	('TC71', 'CellLine', 'CVCL:2213', (67, 71))	('p53', 'Gene', '7157', (112, 115))	('p53', 'Gene', (86, 89))
476846	25398666	In our previous study, we developed a murine neurofibroma model by conditional deletion of one allele of the Pten tumor suppressor gene and activation of the K-rasG12D oncogene in the Schwann progenitor cells (driven by the mGFAP-Cre line).	('neurofibroma', 'Disease', (45, 57))	('Pten', 'Gene', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('neurofibroma', 'Disease', 'MESH:D009455', (45, 57))	('neurofibroma', 'Phenotype', 'HP:0001067', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('activation', 'PosReg', (140, 150))	('tumor', 'Disease', (114, 119))	('murine', 'Species', '10090', (38, 44))	('deletion', 'Var', (79, 87))	('K-rasG12D', 'Gene', (158, 167))
476902	32295077	Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (70, 106))	('tumors', 'Disease', (127, 133))	('undifferentiated pleomorphic sarcoma', 'Disease', (70, 106))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('depletion', 'Var', (24, 33))	('ability', 'MPA', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (156, 161))	('initiate', 'Reg', (147, 155))	('reduced', 'NegReg', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
476904	32295077	Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('SORE6+', 'Var', (122, 128))	('more', 'PosReg', (154, 158))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
476905	32295077	In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival.	('patient', 'Species', '9606', (60, 67))	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('lower', 'NegReg', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('sarcoma', 'Disease', (52, 59))	('differentiation', 'CPA', (100, 115))	('patients', 'Species', '9606', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('tumor', 'Disease', (87, 92))	('invasive potential', 'CPA', (117, 135))	('SOX2', 'Gene', (33, 37))	('expression', 'Var', (38, 48))	('patient survival', 'CPA', (146, 162))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patient', 'Species', '9606', (146, 153))
476938	32295077	Nevertheless, cells overexpressing SOX2 were more tumorigenic and grew tumors in immunodeficient mice significantly faster than controls cells (Figure 3F,G).	('immunodeficient', 'Disease', 'MESH:D007153', (81, 96))	('immunodeficient', 'Disease', (81, 96))	('more', 'PosReg', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('SOX2', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('faster', 'PosReg', (116, 122))	('mice', 'Species', '10090', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('overexpressing', 'Var', (20, 34))	('tumors', 'Disease', (71, 77))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
476944	32295077	As expected, SORE6+ T-5H-O cells showed a significantly higher expression of SOX2 than the SORE6- subpopulation (Figure S4D,E).	('expression', 'MPA', (63, 73))	('SOX2', 'Protein', (77, 81))	('higher', 'PosReg', (56, 62))	('T-5H-O', 'Chemical', '-', (20, 26))	('SORE6+ T-5H-O', 'Var', (13, 26))
476949	32295077	At the end-point, tumor weights confirmed that SORE6+ cells generated significantly larger tumors than those obtained from SORE6- cells (Figure 4F).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (18, 23))	('larger', 'PosReg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (91, 96))	('SORE6+ cells', 'Var', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
476951	32295077	We found that SORE6+ cells produced tumors in all cases after the inoculation of 5000 or 1000 cells and in 2 out of 5 tumors (2/5) after the inoculation of 100 cells.	('SORE6+', 'Var', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('produced', 'PosReg', (27, 35))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
476953	32295077	Therefore, the tumor-initiation frequency (TIF) calculated using ELDA software was 7-fold higher in SORE6+ cells (1 tumor-initiating cell out of 185) compared to SORE6- cells (1 out of 1273) (Figure 4H).	('SORE6+ cells', 'Var', (100, 112))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('higher', 'PosReg', (90, 96))	('tumor', 'Disease', (116, 121))
476959	32295077	In these experiments, EC-8042 was the most efficient drug to reduce the SORE6+ subpopulation, being able to induce a 75% decrease of SORE6+ cells with a concentration in the order of its IC60.	('EC-8042', 'Var', (22, 29))	('EC-8042', 'Chemical', 'MESH:C576677', (22, 29))	('decrease', 'NegReg', (121, 129))	('SORE6+ cells', 'MPA', (133, 145))
476960	32295077	In addition, time course analysis after the treatment with concentrations in the order of the IC60 values also confirmed the higher potential of EC-8042 to eradicate SORE6+ cells in comparison with doxorubicin, trabectedin and paclitaxel (Figure 6A-C).	('eradicate', 'NegReg', (156, 165))	('paclitaxel', 'Chemical', 'MESH:D017239', (227, 237))	('doxorubicin', 'Chemical', 'MESH:D004317', (198, 209))	('SORE6+', 'MPA', (166, 172))	('EC-8042', 'Chemical', 'MESH:C576677', (145, 152))	('trabectedin', 'Chemical', 'MESH:D000077606', (211, 222))	('EC-8042', 'Var', (145, 152))
476964	32295077	In addition, we found that EC-8042-treatment sharply reduced the percentage of SORE6+ cells even before the apoptotic effect become evident (Figure 6D,E).	('reduced', 'NegReg', (53, 60))	('EC-8042-treatment', 'Var', (27, 44))	('EC-8042', 'Chemical', 'MESH:C576677', (27, 34))
476965	32295077	On one hand, trabectedin eliminated SORE6+ cells through the induction of apoptosis and, on the other hand, EC-8042 would be able to switch-off SORE6-related transcriptional activity, thus possibly affecting their CSC-associated properties, prior to the induction of apoptosis.	('SORE6-related', 'Gene', (144, 157))	('switch-off', 'NegReg', (133, 143))	('eliminated', 'NegReg', (25, 35))	('CSC-associated', 'MPA', (214, 228))	('EC-8042', 'Chemical', 'MESH:C576677', (108, 115))	('trabectedin', 'Chemical', 'MESH:D000077606', (13, 24))	('EC-8042', 'Var', (108, 115))	('affecting', 'Reg', (198, 207))
476989	32295077	In addition, a plasmid containing the human OCT4 promoter driving the expression of GFP was used to show that OCT4-expressing osteosarcoma cells were much more tumorigenic than OCT4 negative cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('osteosarcoma', 'Disease', (126, 138))	('human', 'Species', '9606', (38, 43))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('OCT4-expressing', 'Var', (110, 125))	('more', 'PosReg', (155, 159))	('tumor', 'Disease', (160, 165))
476990	32295077	In line with these works, we found that SORE6+ UPS cells displayed greater potential than SORE6- cells to form tumorspheres in vitro and to develop tumors in vivo, thus confirming their CSC phenotype.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('SORE6+ UPS', 'Var', (40, 50))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
477001	32295077	After EC8042 treatment, SORE6+ cells disappeared before apoptosis become evident, thus suggesting that EC-8042 was able to repress the expression of SOX2, as we previously observed in a related myxoid liposarcoma model.	('repress', 'NegReg', (123, 130))	('EC8042', 'Chemical', 'MESH:C576677', (6, 12))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (194, 212))	('liposarcoma', 'Phenotype', 'HP:0012034', (201, 212))	('myxoid liposarcoma', 'Disease', (194, 212))	('SOX2', 'Gene', (149, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (194, 212))	('EC-8042', 'Chemical', 'MESH:C576677', (103, 110))	('EC-8042', 'Var', (103, 110))
477002	32295077	According to this, it was reported that mithramycin was able to reduce in vivo proliferation of glioblastoma cells through the downregulation of SOX2 expression and its target genes.	('mithramycin', 'Chemical', 'MESH:D008926', (40, 51))	('expression', 'MPA', (150, 160))	('reduce', 'NegReg', (64, 70))	('SOX2', 'Gene', (145, 149))	('glioblastoma', 'Disease', (96, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (96, 108))	('downregulation', 'NegReg', (127, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('mithramycin', 'Var', (40, 51))
477004	32295077	Given that EC-8042 is 10-fold less toxic than mithramycin, it could represent a suitable therapeutic option to eliminate CSCs in sarcomas.	('mithramycin', 'Chemical', 'MESH:D008926', (46, 57))	('CSCs', 'Disease', (121, 125))	('EC-8042', 'Chemical', 'MESH:C576677', (11, 18))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('EC-8042', 'Var', (11, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcomas', 'Disease', (129, 137))
477128	30559960	The best chance of cure was linked to excision of the tumour with clear margins.	('excision', 'Var', (38, 46))	('tumour', 'Disease', (54, 60))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
477155	28748534	We identified Arhgap1, which is a negative regulator of CDC42, as a novel, direct target of miR-130b.	('CDC42', 'Gene', '998', (56, 61))	('Arhgap1', 'Gene', '392', (14, 21))	('CDC42', 'Gene', (56, 61))	('Arhgap1', 'Gene', (14, 21))	('miR-130b', 'Var', (92, 100))
477158	28748534	Finally, small molecule inhibition of PAK1 blocked miR-130b activation of JNK and downstream AP-1 target genes, including primary miR-130b transcripts, and mir-130b oncogenic properties, thus identifying PAK1 as a novel therapeutic target for ES.	('miR-130b', 'Gene', (51, 59))	('PAK1', 'Gene', (204, 208))	('mir-130b', 'Gene', '406920', (156, 164))	('mir-130b', 'Gene', (156, 164))	('JNK', 'Gene', (74, 77))	('PAK1', 'Gene', '5058', (38, 42))	('ES', 'Phenotype', 'HP:0012254', (243, 245))	('blocked', 'NegReg', (43, 50))	('AP-1', 'Gene', '2353', (93, 97))	('activation', 'PosReg', (60, 70))	('inhibition', 'Var', (24, 34))	('JNK', 'Gene', '5599', (74, 77))	('PAK1', 'Gene', (38, 42))	('AP-1', 'Gene', (93, 97))	('PAK1', 'Gene', '5058', (204, 208))
477176	28748534	PAKs are serine/threonine kinases that function as downstream effectors for several oncogenic signaling networks and alterations in PAKs have been attributed to carcinogenesis and metastasis in several tumors .	('alterations', 'Var', (117, 128))	('metastasis', 'CPA', (180, 190))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('attributed', 'Reg', (147, 157))	('carcinogenesis', 'Disease', 'MESH:D063646', (161, 175))	('carcinogenesis', 'Disease', (161, 175))	('PAKs', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
477198	28748534	For miR-130b targeted 3'-UTR assays, TC71 cells in a 6-well plate were co-transfected with 250 ng of the indicated hRL(Renilla luciferase)-ARHGAP1 wild-type or mutant reporter plasmids and 30 nM of either miR-130b or scrambled control mimics.	('ARHGAP1', 'Gene', '392', (139, 146))	('mutant', 'Var', (160, 166))	('ARHGAP1', 'Gene', (139, 146))	('TC71', 'CellLine', 'CVCL:2213', (37, 41))
477223	28748534	1 x 106 TC71 cells stably overexpressing miR-130b or scrambled control were injected into the tail vein of 10 (5 per group) Rag2-/- mice.	('Rag2', 'Gene', (124, 128))	('TC71', 'CellLine', 'CVCL:2213', (8, 12))	('mice', 'Species', '10090', (132, 136))	('miR-130b', 'Var', (41, 49))	('Rag2', 'Gene', '5897', (124, 128))
477239	28748534	Furthermore, analysis of The Cancer Genome Atlas (TCGA) sarcoma cohort suggests there is clinical significance of high miR-130b in not only pediatric, but also adult sarcomas.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (29, 48))	('high', 'Var', (114, 118))	('sarcoma cohort', 'Disease', 'MESH:D012509', (56, 70))	('sarcomas', 'Disease', 'MESH:D012509', (166, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (166, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('sarcomas', 'Disease', (166, 174))	('sarcoma cohort', 'Disease', (56, 70))	('miR-130b', 'Gene', (119, 127))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Cancer Genome Atlas', 'Disease', (29, 48))
477241	28748534	We then examined the expression of miR-130b in ES cell lines relative to MSCs and decided to overexpress miR-130b in TC71 cells and inhibit miR1-30b in MHH cells for functional studies (Figure 1B).	('inhibit', 'NegReg', (132, 139))	('TC71', 'CellLine', 'CVCL:2213', (117, 121))	('miR1', 'Gene', (140, 144))	('miR1', 'Gene', '79187', (140, 144))	('miR-130b', 'Var', (105, 113))	('overexpress', 'PosReg', (93, 104))	('ES', 'Phenotype', 'HP:0012254', (47, 49))
477246	28748534	Conversely, loss-of-function studies demonstrated that inhibition of miR-130b levels in the MHH-ES1 cell line decreases tumor cell proliferation and invasive potential (Figure 1D, 1F).	('decreases tumor', 'Disease', (110, 125))	('ES', 'Phenotype', 'HP:0012254', (96, 98))	('miR-130b', 'Gene', (69, 77))	('decreases tumor', 'Disease', 'MESH:D009369', (110, 125))	('invasive potential', 'CPA', (149, 167))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('inhibition', 'Var', (55, 65))
477247	28748534	Taken together these results suggest miR-130b can contribute to the more aggressive, disseminated properties of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (112, 125))	('contribute', 'Reg', (50, 60))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (112, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (112, 125))	('miR-130b', 'Var', (37, 45))
477250	28748534	TC71/130b injected mice showed significantly increased number of metastatic lung nodules compared to the control mice at the time of sacrifice (Figure 2A, 2B).	('TC71', 'CellLine', 'CVCL:2213', (0, 4))	('increased', 'PosReg', (45, 54))	('TC71/130b', 'Var', (0, 9))	('metastatic lung nodules', 'CPA', (65, 88))	('mice', 'Species', '10090', (113, 117))	('mice', 'Species', '10090', (19, 23))
477262	28748534	We observed miR-130b activated CDC42, as measured by colorimetric ELISA, whereas total CDC42 protein levels remained unchanged (Figure 3A).	('CDC42', 'Gene', '998', (87, 92))	('CDC42', 'Gene', '998', (31, 36))	('miR-130b', 'Var', (12, 20))	('CDC42', 'Gene', (31, 36))	('CDC42', 'Gene', (87, 92))	('activated', 'PosReg', (21, 30))
477265	28748534	Previous studies investigating ARHGAP1 demonstrate that loss of ARHGAP1 leads to constitutive activation of CDC42 and subsequent downstream effector signaling.	('loss', 'Var', (56, 60))	('ARHGAP1', 'Gene', (64, 71))	('ARHGAP1', 'Gene', '392', (64, 71))	('CDC42', 'Gene', '998', (108, 113))	('ARHGAP1', 'Gene', (31, 38))	('CDC42', 'Gene', (108, 113))	('ARHGAP1', 'Gene', '392', (31, 38))	('activation', 'PosReg', (94, 104))
477267	28748534	TC71 cells overexpressing miR-130b demonstrated downregulation of ARHGAP1 mRNA and protein by qPCR and western blot (Figure 3C).	('TC71', 'CellLine', 'CVCL:2213', (0, 4))	('ARHGAP1', 'Gene', (66, 73))	('downregulation', 'NegReg', (48, 62))	('ARHGAP1', 'Gene', '392', (66, 73))	('miR-130b', 'Var', (26, 34))
477268	28748534	Conversely, knockdown of miR-130b in MHH cells resulted in modest mRNA, but significant protein level increases for ARHGAP1 (Figure 3D).	('knockdown', 'Var', (12, 21))	('increases', 'PosReg', (102, 111))	('ARHGAP1', 'Gene', (116, 123))	('ARHGAP1', 'Gene', '392', (116, 123))	('protein level', 'MPA', (88, 101))	('mRNA', 'MPA', (66, 70))	('miR-130b', 'Gene', (25, 33))
477273	28748534	In response to miR-130b overexpression, PAK1 has enhanced phosphorylation by immunoblotting analyses (Figure 4A).	('phosphorylation', 'MPA', (58, 73))	('enhanced', 'PosReg', (49, 57))	('miR-130b', 'Var', (15, 23))	('overexpression', 'PosReg', (24, 38))	('PAK1', 'Gene', '5058', (40, 44))	('PAK1', 'Gene', (40, 44))
477274	28748534	Conversely, knockdown of miR-130b resulted in decreased phospho-PAK1 levels (Figure 4B).	('PAK1', 'Gene', '5058', (64, 68))	('PAK1', 'Gene', (64, 68))	('knockdown', 'Var', (12, 21))	('decreased', 'NegReg', (46, 55))	('miR-130b', 'Gene', (25, 33))
477279	28748534	Expression levels of several cytoskeletal reorganization genes, n-WASP, SPEC1, and SPEC 2 remained relatively unchanged when miR-130b is overexpressed suggesting miR-130b may be stimulating downstream PAK1 effectors (Figure 4C).	('n-WASP', 'Gene', '8976', (64, 70))	('SPEC1', 'Gene', (72, 77))	('Expression', 'MPA', (0, 10))	('SPEC 2', 'Gene', (83, 89))	('stimulating', 'PosReg', (178, 189))	('miR-130b', 'Var', (162, 170))	('SPEC1', 'Gene', '56882', (72, 77))	('PAK1', 'Gene', (201, 205))	('SPEC 2', 'Gene', '56990', (83, 89))	('PAK1', 'Gene', '5058', (201, 205))	('n-WASP', 'Gene', (64, 70))
477283	28748534	Taken together, these data suggest that miR-130b regulation of CDC42 and PAK1 results in downstream activation of the JNK pathway.	('JNK', 'Gene', (118, 121))	('CDC42', 'Gene', '998', (63, 68))	('CDC42', 'Gene', (63, 68))	('JNK', 'Gene', '5599', (118, 121))	('PAK1', 'Gene', '5058', (73, 77))	('miR-130b', 'Var', (40, 48))	('PAK1', 'Gene', (73, 77))	('activation', 'PosReg', (100, 110))
477284	28748534	In order to determine if the effects of miR-130b could be pharmacologically mitigated, we used an inhibitor of PAK1, IPA3.	('PAK1', 'Gene', '5058', (111, 115))	('IPA3', 'Chemical', '-', (117, 121))	('PAK1', 'Gene', (111, 115))	('miR-130b', 'Var', (40, 48))
477286	28748534	Using IPA3, the increased proliferation due to miR-130b in TC71 cells was attenuated (Figure 4E).	('IPA3', 'Chemical', '-', (6, 10))	('TC71', 'CellLine', 'CVCL:2213', (59, 63))	('increased', 'PosReg', (16, 25))	('miR-130b', 'Var', (47, 55))	('attenuated', 'NegReg', (74, 84))	('proliferation', 'CPA', (26, 39))
477287	28748534	Furthermore, IPA3 also reduced the c-JUN and JNK levels induced by miR-130b (Figure 4F).	('JNK', 'Gene', '5599', (45, 48))	('c-JUN', 'Gene', '3725', (35, 40))	('miR-130b', 'Var', (67, 75))	('reduced', 'NegReg', (23, 30))	('JNK', 'Gene', (45, 48))	('IPA3', 'Chemical', '-', (13, 17))	('c-JUN', 'Gene', (35, 40))
477290	28748534	Collectively, these data confirm a targetable CDC42/PAK1/JNK regulatory network promoted by miR-130b.	('promoted', 'PosReg', (80, 88))	('JNK', 'Gene', (57, 60))	('CDC42', 'Gene', '998', (46, 51))	('PAK1', 'Gene', '5058', (52, 56))	('miR-130b', 'Var', (92, 100))	('CDC42', 'Gene', (46, 51))	('JNK', 'Gene', '5599', (57, 60))	('PAK1', 'Gene', (52, 56))
477291	28748534	The microarray data and RPPA provide evidence that miR-130b induces the activation of JNK/SAPK and subsequent phosphorylation of its downstream target, c-JUN.	('activation', 'PosReg', (72, 82))	('JNK', 'Gene', '5599', (86, 89))	('miR-130b', 'Var', (51, 59))	('phosphorylation', 'MPA', (110, 125))	('c-JUN', 'Gene', '3725', (152, 157))	('JNK', 'Gene', (86, 89))	('c-JUN', 'Gene', (152, 157))
477293	28748534	To further confirm AP-1 is activated, we fractionated protein lysates from cells overexpressing miR-130b.	('AP-1', 'Gene', (19, 23))	('AP-1', 'Gene', '2353', (19, 23))	('miR-130b', 'Var', (96, 104))
477294	28748534	Western blot analysis demonstrates that phosphorylated c-JUN and total c-JUN are increased in response to miR-130b overexpression but phospho-c-JUN is enriched in the nuclear fraction further confirming AP-1 is being activated (Figure 5A), while treatment with IPA3 and FRAX597 rescued the increased expression of c-JUN and AP-1 target genes (Figure 5B, Supplemental Figure 4E, 4F).	('c-JUN', 'Gene', '3725', (71, 76))	('miR-130b', 'Var', (106, 114))	('AP-1', 'Gene', '2353', (203, 207))	('FRAX597', 'Chemical', 'MESH:C584676', (270, 277))	('c-JUN', 'Gene', (71, 76))	('c-JUN', 'Gene', (314, 319))	('AP-1', 'Gene', '2353', (324, 328))	('expression', 'MPA', (300, 310))	('c-JUN', 'Gene', '3725', (142, 147))	('c-JUN', 'Gene', '3725', (55, 60))	('IPA3', 'Chemical', '-', (261, 265))	('c-JUN', 'Gene', (55, 60))	('AP-1', 'Gene', (203, 207))	('c-JUN', 'Gene', '3725', (314, 319))	('c-JUN', 'Gene', (142, 147))	('AP-1', 'Gene', (324, 328))
477296	28748534	Finally, knockdown of miR-130b also decreased the expression of c-JUN and AP-1 targets by qPCR and western blot analysis, suggesting miR-130b is specifically mediating this oncogenic transcriptional program (Figure 5C, 5D).	('c-JUN', 'Gene', '3725', (64, 69))	('knockdown', 'Var', (9, 18))	('AP-1', 'Gene', (74, 78))	('c-JUN', 'Gene', (64, 69))	('AP-1', 'Gene', '2353', (74, 78))	('miR-130b', 'Gene', (22, 30))	('miR-130b', 'Var', (133, 141))	('expression', 'MPA', (50, 60))	('decreased', 'NegReg', (36, 45))
477305	28748534	The induction of the pri-miR-130b transcript by TPA and the induction of JNK, c-JUN, and AP-1 target genes by overexpression of miR-130b suggest that a positive feedback loop is functioning to drive an oncogenic, metastatic gene regulatory network in Ewing sarcoma.	('JNK', 'Gene', (73, 76))	('c-JUN', 'Gene', '3725', (78, 83))	('c-JUN', 'Gene', (78, 83))	('miR-130b', 'Var', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('JNK', 'Gene', '5599', (73, 76))	('Ewing sarcoma', 'Disease', (251, 264))	('TPA', 'Chemical', 'MESH:D013755', (48, 51))	('AP-1', 'Gene', (89, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (251, 264))	('pri-miR-130b', 'Gene', (21, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (251, 264))	('AP-1', 'Gene', '2353', (89, 93))
477313	28748534	Here we demonstrate a previously unknown gene regulatory network regulated by miR-130b in Ewing sarcoma that contributes metastatic phenotypes both in vitro and in vivo.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('metastatic', 'MPA', (121, 131))	('Ewing sarcoma', 'Disease', (90, 103))	('miR-130b', 'Var', (78, 86))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 103))
477314	28748534	We have further elucidated a mechanism in which miR-130b promotes sustained CDC42 activation through downregulation of ARHGAP1, a negative regulator of CDC42 and novel direct target of miR-130b.	('downregulation', 'NegReg', (101, 115))	('miR-130b', 'Var', (48, 56))	('ARHGAP1', 'Gene', (119, 126))	('ARHGAP1', 'Gene', '392', (119, 126))	('CDC42', 'Gene', '998', (76, 81))	('activation', 'PosReg', (82, 92))	('CDC42', 'Gene', '998', (152, 157))	('CDC42', 'Gene', (152, 157))	('CDC42', 'Gene', (76, 81))	('promotes', 'PosReg', (57, 65))
477315	28748534	Prolonged activation of CDC42 by miR-130b leads to downstream AP-1 activation and target gene expression that promotes sarcoma invasion, migration, and proliferation.	('CDC42', 'Gene', '998', (24, 29))	('activation', 'PosReg', (67, 77))	('AP-1', 'Gene', '2353', (62, 66))	('proliferation', 'CPA', (152, 165))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('CDC42', 'Gene', (24, 29))	('promotes', 'PosReg', (110, 118))	('migration', 'CPA', (137, 146))	('sarcoma', 'Disease', (119, 126))	('expression', 'MPA', (94, 104))	('AP-1', 'Gene', (62, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('miR-130b', 'Var', (33, 41))	('activation', 'PosReg', (10, 20))
477316	28748534	A positive feedback network was demonstrated by the ability of AP-1 to bind to the miR-130b promoter and induce transcription of the primary miR-130b.	('induce', 'PosReg', (105, 111))	('AP-1', 'Gene', '2353', (63, 67))	('miR-130b', 'Gene', (83, 91))	('bind', 'Interaction', (71, 75))	('AP-1', 'Gene', (63, 67))	('miR-130b', 'Var', (141, 149))	('transcription', 'MPA', (112, 125))
477317	28748534	Finally, we could abrogate the effects induced by miR-130b and AP-1 using a PAK1 inhibitor, IPA3.	('AP-1', 'Gene', '2353', (63, 67))	('AP-1', 'Gene', (63, 67))	('miR-130b', 'Var', (50, 58))	('PAK1', 'Gene', '5058', (76, 80))	('IPA3', 'Chemical', '-', (92, 96))	('PAK1', 'Gene', (76, 80))
477320	28748534	Interestingly, the contribution of PAK1 in Ewing sarcoma development and metastasis has been severely understudied, and inhibition of this signaling node, in combination with approved standard treatment protocols, may offer new therapeutic options for patients with metastatic disease.	('PAK1', 'Gene', (35, 39))	('Ewing sarcoma', 'Disease', (43, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('inhibition', 'Var', (120, 130))	('patients', 'Species', '9606', (252, 260))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('PAK1', 'Gene', '5058', (35, 39))
477323	28748534	We did observe an increase in phospho-c-JUN levels with IPA3 which is most likely due to stress caused by treatment with IPA3.	('increase', 'PosReg', (18, 26))	('c-JUN', 'Gene', '3725', (38, 43))	('IPA3', 'Chemical', '-', (121, 125))	('c-JUN', 'Gene', (38, 43))	('IPA3', 'Chemical', '-', (56, 60))	('IPA3', 'Var', (56, 60))
477333	28748534	While miR-130b has been independently shown to contribute to metastatic properties in other malignancies, we cannot exclude the contribution of the fusion transcript to aid in metastatic potential dictated by miR-130b.	('miR-130b', 'Gene', (6, 14))	('miR-130b', 'Var', (209, 217))	('aid', 'Gene', '57379', (169, 172))	('contribute', 'Reg', (47, 57))	('malignancies', 'Disease', (92, 104))	('metastatic potential', 'CPA', (176, 196))	('aid', 'Gene', (169, 172))	('malignancies', 'Disease', 'MESH:D009369', (92, 104))	('metastatic properties', 'CPA', (61, 82))
477361	27601837	The ES/PNET family of tumors is characterized by the presence of nonrandom translocations leading to the fusion of EWS gene on 22q12 with one of the several members of the ETS family of transcription factors.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('fusion', 'Var', (105, 111))	('EWS', 'Gene', '2130', (115, 118))	('EWS', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))	('ES/PNET', 'Disease', (4, 11))
477379	27601837	Ki67 expression constitutes a valuable indicator of poor prognosis in localized Ewing's sarcoma family of tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (80, 95))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Ki67', 'Var', (0, 4))	("Ewing's sarcoma", 'Disease', (80, 95))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
477444	25649949	NM_005894), mouse (NM_009690) and rat (NM_001025685), using CLC Sequence Viewer 6 (QIAGEN) and L-ALIGN (http://embnet.vital-it.ch/software/ LALIGN_form.html).	('NM_001025685', 'Var', (39, 51))	('mouse', 'Species', '10090', (12, 17))	('NM_009690', 'Var', (19, 28))	('rat', 'Species', '10116', (34, 37))
477446	25649949	It was almost consistent with predicted CDS of canine AIM (99.8%, 1,021 of 1,023 bp), however, there were two single amino-acid replacements (F7L and R138C).	('R138C', 'Var', (150, 155))	('F7L', 'Mutation', 'p.F7L', (142, 145))	('F7L', 'Var', (142, 145))	('R138C', 'Mutation', 'p.R138C', (150, 155))	('CDS of canine AIM', 'Phenotype', 'HP:0012738', (40, 57))	('canine', 'Species', '9615', (47, 53))
477469	25649949	In this study, expression ratios of AIM and CD36 mRNA in several histiocytic sarcoma cell lines were observed.	('CD36', 'Var', (44, 48))	('histiocytic sarcoma', 'Disease', (65, 84))	('rat', 'Species', '10116', (26, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('CD36', 'Species', '42374', (44, 48))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (65, 84))
477606	24736584	In our patient group with mostly high-grade and therefore high-risk STS, the rate of local relapse of 18% is consistent with other data sets in extremity STS, as is the rate of metastatic spread of 32%.	('high-risk', 'Var', (58, 67))	('patient', 'Species', '9606', (7, 14))	('metastatic spread', 'CPA', (177, 194))	('STS', 'Phenotype', 'HP:0030448', (154, 157))	('STS', 'Phenotype', 'HP:0030448', (68, 71))	('local relapse', 'CPA', (85, 98))	('high-grade', 'Var', (33, 43))	('STS', 'Disease', (68, 71))
477644	33361335	Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression.	('Fusion', 'Var', (0, 6))	('SSX', 'Gene', '727837', (18, 21))	('polycomb', 'Gene', '12416', (238, 246))	('drives', 'PosReg', (99, 105))	('BAF-mediated', 'Protein', (205, 217))	('polycomb', 'Gene', (238, 246))	('disrupt', 'NegReg', (177, 184))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('balance', 'MPA', (189, 196))	('SS18', 'Gene', (10, 14))	('SSX', 'Gene', (18, 21))
477647	33361335	Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity.	('polycomb', 'Gene', '12416', (29, 37))	('H3K27me3', 'Protein', (61, 69))	('H2AK119ub', 'Var', (80, 89))	('eviction', 'NegReg', (70, 78))	('H2AK119ub', 'Chemical', '-', (80, 89))	('polycomb', 'Gene', (29, 37))	('SyS', 'Phenotype', 'HP:0012570', (172, 175))
477651	33361335	Its defining genetic feature is the chromosomal translocation t(X:18; p11:q11), which generates fusions between the nearly entire coding sequence of the SS18 gene and a portion of an SSX gene family member (SSX1 and SSX2 being the two most commonly implicated).	('SSX1', 'Gene', (207, 211))	('SSX', 'Gene', (207, 210))	('SS18', 'Gene', (153, 157))	('SSX', 'Gene', '727837', (183, 186))	('SSX', 'Gene', '727837', (207, 210))	('SSX1', 'Gene', '6756', (207, 211))	('fusions', 'Var', (96, 103))	('SSX', 'Gene', (216, 219))	('SSX', 'Gene', '727837', (216, 219))	('SSX', 'Gene', (183, 186))
477663	33361335	Accordingly, recent studies suggest that small-molecule-mediated degradation of the BAF component BRD9 can reverse oncogenic gene regulation in SyS.	('oncogenic gene regulation', 'MPA', (115, 140))	('reverse', 'NegReg', (107, 114))	('small-molecule-mediated degradation', 'Var', (41, 76))	('degradation', 'Var', (65, 76))	('SyS', 'Phenotype', 'HP:0012570', (144, 147))	('BRD9', 'Gene', (98, 102))	('BRD9', 'Gene', '105246', (98, 102))	('SyS', 'Disease', (144, 147))
477670	33361335	Together, these events initiate a SyS-specific oncogenic program that is completely reversible upon SS18-SSX silencing, suggesting that a pharmacological approach aimed at epigenetic regulatory events may offer realistic therapeutic opportunities in established tumors.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('SSX', 'Gene', (105, 108))	('tumors', 'Disease', (262, 268))	('initiate', 'Reg', (23, 31))	('SSX', 'Gene', '727837', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('SyS', 'Phenotype', 'HP:0012570', (34, 37))	('silencing', 'Var', (109, 118))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('oncogenic', 'CPA', (47, 56))	('SyS-specific', 'MPA', (34, 46))
477676	33361335	Expression of SS18-SSX in all four organoids was confirmed by qRT-PCR (Fig 1B) and by chromatin analyses using the H3K36me3 histone mark in the SSX1 3' terminal region as an indicator of transcription (Fig 1C).	('SSX1', 'Gene', '6756', (144, 148))	('SSX', 'Gene', (19, 22))	('SSX1', 'Gene', (144, 148))	('SSX', 'Gene', '727837', (19, 22))	('H3K36me3', 'Var', (115, 123))	('SSX', 'Gene', (144, 147))	('SSX', 'Gene', '727837', (144, 147))
477685	33361335	Once again, we observed the genes preferentially expressed in SyS to be associated with broader BAF domains, whereas no such difference was detected among the transcripts more highly expressed in unrelated sarcomas (Figs 3E and S3F).	('sarcomas', 'Disease', 'MESH:D012509', (206, 214))	('sarcomas', 'Phenotype', 'HP:0100242', (206, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('sarcomas', 'Disease', (206, 214))	('associated', 'Reg', (72, 82))	('SyS', 'Var', (62, 65))	('SyS', 'Phenotype', 'HP:0012570', (62, 65))	('preferentially', 'PosReg', (34, 48))
477700	33361335	We found that SS18-SSX is preferentially recruited to two distinct chromatin states: those bearing the polycomb mark H3K27me3 (H3K27me3 only: 1,338 sites, 27.4%; bivalent domains: 835 sites, 17.1%), and primed enhancers, marked by a high H3K4me1 to H3K27ac ratio (1,405 sites, 28.8%) (Fig 4E).	('SSX', 'Gene', (19, 22))	('H3K4me1', 'MPA', (238, 245))	('SSX', 'Gene', '727837', (19, 22))	('polycomb', 'Gene', (103, 111))	('polycomb', 'Gene', '12416', (103, 111))	('H3K27me3', 'Var', (117, 125))
477701	33361335	It must be noted, however, that the sites marked by H3K27me3 to which SS18-SSX is recruited represent 6.54% of all the sites bearing H3K27me3.	('SSX', 'Gene', '727837', (75, 78))	('H3K27me3', 'Var', (133, 141))	('SSX', 'Gene', (75, 78))	('H3K27me3', 'Var', (52, 60))
477703	33361335	The relatively high proportion of SS18-SSX-binding sites pre-marked with H3K27me3 prompted us to investigate whether H3K27me3 itself might favor the recruitment of the fusion protein.	('recruitment', 'MPA', (149, 160))	('favor', 'PosReg', (139, 144))	('SSX', 'Gene', (39, 42))	('SSX', 'Gene', '727837', (39, 42))	('H3K27me3', 'Var', (117, 125))	('H3K27me3', 'Var', (73, 81))
477704	33361335	To this end, we treated C3H10T1/2 cells with the selective EZH2 inhibitor EPZ6438 for 8 d prior to SS18-SSX expression.	('SSX', 'Gene', '727837', (104, 107))	('EZH2', 'Gene', '14056', (59, 63))	('EPZ6438', 'Var', (74, 81))	('EZH2', 'Gene', (59, 63))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (24, 33))	('EPZ6438', 'Chemical', 'MESH:C000593333', (74, 81))	('SSX', 'Gene', (104, 107))
477715	33361335	Remarkably, SS18-SSX depletion also restored the original BAF complex width observed in naive C3H10T1/2 cells (Fig S5C), further highlighting the tight functional relationship between altered BAF domain deposition and SS18-SSX expression.	('SSX', 'Gene', '727837', (223, 226))	('BAF complex', 'CPA', (58, 69))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (94, 103))	('depletion', 'Var', (21, 30))	('SSX', 'Gene', (17, 20))	('restored', 'PosReg', (36, 44))	('SSX', 'Gene', '727837', (17, 20))	('SSX', 'Gene', (223, 226))
477721	33361335	Finally, consistent with the observed chromatin state reversibility upon SS18-SSX depletion (Fig 4H and I), CRE expression in C3H10T1/2SS18-SSX1 cells resulted in a significant reversion of their transcriptional profile to that preceding SS18-SSX introduction (Fig 5F), the lack of complete reversion being most likely due to incomplete depletion of SS18-SSX.	('SSX', 'Gene', (355, 358))	('SSX1', 'Gene', '6756', (140, 144))	('expression', 'Var', (112, 122))	('SSX', 'Gene', (243, 246))	('SSX', 'Gene', '727837', (355, 358))	('SSX', 'Gene', (78, 81))	('reversion', 'NegReg', (177, 186))	('SSX', 'Gene', '727837', (78, 81))	('SSX1', 'Gene', (140, 144))	('SSX', 'Gene', (140, 143))	('CRE', 'Gene', (108, 111))	('SSX', 'Gene', '727837', (243, 246))	('SSX', 'Gene', '727837', (140, 143))	('transcriptional profile', 'MPA', (196, 219))
477732	33361335	We initially focused on the 1338 PRC2-marked genomic regions that undergo H3K27me3 removal upon SS18-SSX expression and compared the signal levels of RING1B, H2AK119ub, and H3K27me3 between control and SS18-SSX-expressing cells.	('H2AK119ub', 'Chemical', '-', (158, 167))	('SSX', 'Gene', (101, 104))	('SSX', 'Gene', (207, 210))	('RING1B', 'Gene', '19821', (150, 156))	('H3K27me3', 'Var', (173, 181))	('SSX', 'Gene', '727837', (101, 104))	('SSX', 'Gene', '727837', (207, 210))	('RING1B', 'Gene', (150, 156))	('H2AK119ub', 'Var', (158, 167))	('H3K27me3', 'Protein', (74, 82))
477733	33361335	Remarkably, binding of the fusion protein increased the signal of both RING1B and the H2AK119ub mark at these genomic regions, concomitant to nearly complete removal of H3K27me3 (Fig 6A and B).	('increased', 'PosReg', (42, 51))	('H2AK119ub mark', 'Var', (86, 100))	('RING1B', 'Gene', (71, 77))	('H2AK119ub', 'Chemical', '-', (86, 95))	('binding', 'Interaction', (12, 19))	('removal', 'NegReg', (158, 165))	('signal', 'MPA', (56, 62))	('RING1B', 'Gene', '19821', (71, 77))	('H3K27me3', 'Protein', (169, 177))
477735	33361335	However, neither RING1B nor H2AK119ub global protein levels were increased in SS18-SSX-expressing cells (Fig S7A).	('SSX', 'Gene', (83, 86))	('increased', 'PosReg', (65, 74))	('H2AK119ub', 'Chemical', '-', (28, 37))	('RING1B', 'Gene', '19821', (17, 23))	('SSX', 'Gene', '727837', (83, 86))	('RING1B', 'Gene', (17, 23))	('H2AK119ub', 'Var', (28, 37))
477737	33361335	We also identified strong RING1B and H2AK119ub ChIP-seq signals at the broad Q4 SMARCA2/4 domains in SyS organoids at similar or even higher levels than H3K27me3 marked polycomb sites (Fig 6C and D).	('RING1B', 'Gene', '19821', (26, 32))	('polycomb', 'Gene', '12416', (169, 177))	('SyS', 'Phenotype', 'HP:0012570', (101, 104))	('ChIP-seq', 'MPA', (47, 55))	('H2AK119ub', 'Var', (37, 46))	('RING1B', 'Gene', (26, 32))	('H2AK119ub', 'Chemical', '-', (37, 46))	('polycomb', 'Gene', (169, 177))
477740	33361335	Whereas RING1B is a core member of all PRC1 complex variants, RYBP is primarily associated with ncPRC1 complexes.	('RYBP', 'Gene', (62, 66))	('RING1B', 'Gene', (8, 14))	('variants', 'Var', (52, 60))	('PRC1', 'Gene', '233406', (39, 43))	('associated', 'Reg', (80, 90))	('RING1B', 'Gene', '19821', (8, 14))	('PRC1', 'Gene', (39, 43))	('RYBP', 'Gene', '56353', (62, 66))	('PRC1', 'Gene', '233406', (98, 102))	('PRC1', 'Gene', (98, 102))
477741	33361335	We therefore reasoned that by recruiting de novo PRC1 variants at its binding sites, SS18-SSX might increase detectable interactions between RING1B and RYBP.	('RING1B', 'Gene', (141, 147))	('PRC1', 'Gene', '233406', (49, 53))	('RYBP', 'Gene', '56353', (152, 156))	('SSX', 'Gene', '727837', (90, 93))	('interactions', 'Interaction', (120, 132))	('PRC1', 'Gene', (49, 53))	('RYBP', 'Gene', (152, 156))	('RING1B', 'Gene', '19821', (141, 147))	('increase', 'PosReg', (100, 108))	('variants', 'Var', (54, 62))	('SSX', 'Gene', (90, 93))
477745	33361335	Taken together, these results demonstrate that SS18-SSX induces functional uncoupling of the canonical PRC2-PRC1 complexes at its direct binding sites, by recruiting a ncPRC1 variant that sustains transcriptional activation (Fig 6K).	('PRC1', 'Gene', '233406', (108, 112))	('SSX', 'Gene', '727837', (52, 55))	('PRC1', 'Gene', (108, 112))	('PRC1', 'Gene', '233406', (170, 174))	('sustains transcriptional activation', 'MPA', (188, 223))	('PRC1', 'Gene', (170, 174))	('uncoupling', 'MPA', (75, 85))	('recruiting', 'PosReg', (155, 165))	('variant', 'Var', (175, 182))	('SSX', 'Gene', (52, 55))
477746	33361335	Because reconfiguration of chromatin remodeling complexes may provide new opportunities to uncover epigenetic vulnerabilities, we interrogated the DepMap database of cancer dependencies for SyS-selective vulnerability to inactivation of any of the six PRC1 variants.	('cancer dependencies', 'Disease', (166, 185))	('variants', 'Var', (257, 265))	('SyS', 'Phenotype', 'HP:0012570', (190, 193))	('cancer dependencies', 'Disease', 'MESH:D009369', (166, 185))	('PRC1', 'Gene', '233406', (252, 256))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('PRC1', 'Gene', (252, 256))
477752	33361335	As previously observed in leukemia, USP7 depletion in SyS resulted in the partial disassembly of the ncPRC1 complex, as illustrated by the marked decrease in interactions between RING1B and RYBP in the SyS cell line HSSYII (Fig 7F).	('leukemia', 'Phenotype', 'HP:0001909', (26, 34))	('USP7', 'Gene', (36, 40))	('PRC1', 'Gene', '233406', (103, 107))	('leukemia', 'Disease', 'MESH:D007938', (26, 34))	('RING1B', 'Gene', (179, 185))	('SyS', 'Phenotype', 'HP:0012570', (54, 57))	('leukemia', 'Disease', (26, 34))	('interactions', 'Interaction', (158, 170))	('PRC1', 'Gene', (103, 107))	('RING1B', 'Gene', '19821', (179, 185))	('RYBP', 'Gene', (190, 194))	('SyS', 'Phenotype', 'HP:0012570', (202, 205))	('depletion', 'Var', (41, 50))	('decrease', 'NegReg', (146, 154))	('RYBP', 'Gene', '56353', (190, 194))
477753	33361335	Importantly, loss of USP7 did not affect the expression levels of SS18-SSX in either cell line (data not shown).	('SSX', 'Gene', (71, 74))	('SSX', 'Gene', '727837', (71, 74))	('expression', 'MPA', (45, 55))	('USP7', 'Gene', (21, 25))	('loss', 'Var', (13, 17))
477754	33361335	Consistent with its selective detrimental effect observed in DepMap, USP7 depletion produced a significant decrease in proliferation of the SyS HSSYII and SYO1 cell lines, but not of the Ewing sarcoma A673 and RDES lines, despite comparable baseline protein expression levels (Fig 7G).	('depletion', 'Var', (74, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (187, 200))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (187, 200))	('SyS', 'Phenotype', 'HP:0012570', (140, 143))	('decrease', 'NegReg', (107, 115))	('USP7', 'Gene', (69, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('Ewing sarcoma', 'Disease', (187, 200))	('proliferation', 'CPA', (119, 132))
477755	33361335	Accordingly, synovial sarcoma cells (as represented by two cell lines and one organoid model) displayed markedly higher sensitivity to incremental doses of the USP7 inhibitor FT827 than Ewing sarcoma cells (Fig S8E).	('USP7', 'Gene', (160, 164))	('sensitivity', 'MPA', (120, 131))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (186, 199))	('FT827', 'Chemical', '-', (175, 180))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (186, 199))	('synovial sarcoma', 'Disease', (13, 29))	('FT827', 'Var', (175, 180))	('higher', 'PosReg', (113, 119))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (13, 29))	('Ewing sarcoma', 'Disease', (186, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('synovial sarcoma', 'Disease', 'MESH:D013584', (13, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
477756	33361335	Taken together, these results identify an epigenetic dependency of SyS cells to USP7 depletion that is directly linked to the molecular function of SS18-SSX.	('USP7', 'Gene', (80, 84))	('SyS', 'Phenotype', 'HP:0012570', (67, 70))	('SSX', 'Gene', (153, 156))	('depletion', 'NegReg', (85, 94))	('SSX', 'Gene', '727837', (153, 156))	('epigenetic', 'Var', (42, 52))
477760	33361335	Our results show that SS18-SSX establishes a distinctive SyS chromatin landscape by retargeting BAF complexes to new genomic locations, from which the repressive histone modification H3K27me3 deposited by PRC2 is removed and to which a ncPRC1 complex is recruited.	('PRC1', 'Gene', '233406', (238, 242))	('SyS', 'Phenotype', 'HP:0012570', (57, 60))	('PRC2', 'Gene', (205, 209))	('SSX', 'Gene', (27, 30))	('PRC1', 'Gene', (238, 242))	('SSX', 'Gene', '727837', (27, 30))	('H3K27me3', 'Var', (183, 191))
477768	33361335	For example, loss of ncPRC1 in epithelial cells of the skin results in decreased expression of genes involved in cell adhesion and cytoskeletal organization.	('PRC1', 'Gene', '233406', (23, 27))	('PRC1', 'Gene', (23, 27))	('loss', 'Var', (13, 17))	('expression of genes', 'MPA', (81, 100))	('decreased', 'NegReg', (71, 80))
477800	33361335	Global decrease in H3K27m3 was obtained by treating C3H10T1/2 cells for 8 d with 10 muM EPZ6438 (Selleckchem).	('EPZ6438', 'Var', (88, 95))	('C3H10T1/2', 'CellLine', 'CVCL:0190', (52, 61))	('EPZ6438', 'Chemical', 'MESH:C000593333', (88, 95))	('decrease', 'NegReg', (7, 15))	('H3K27m3', 'Protein', (19, 26))
477802	33361335	5-7 d after infection and puromycin selection, HSSYII, SYO1, A673, and RDES populations showing a substantial USP7 knockdown were established.	('infection', 'Disease', (12, 21))	('puromycin', 'Chemical', 'MESH:D011691', (26, 35))	('infection', 'Disease', 'MESH:D007239', (12, 21))	('knockdown', 'Var', (115, 124))
477804	33361335	After cross-link reversal, RNase A, and proteinase K treatment, immunoprecipitated DNA was extracted with AMP Pure beads (Beckman Coulter).	('cross-link', 'Var', (6, 16))	('RNase A', 'Gene', (27, 34))	('RNase A', 'Gene', '19752', (27, 34))	('AMP', 'Chemical', 'MESH:D000249', (106, 109))
477805	33361335	Antibodies used for these studies were SMARCA2/4 (39805; Active Motif), H3K4me1 (ab8895; Abcam), H3K4me3 (07-473; Millipore), H3K9ac (ab4441; Abcam), H3K27ac (39133; Active Motif), H3K27me3 (07-449; Millipore), H3K36me3 (ab9050; Abcam), V5 (ab15828; Abcam), RING1B (5694; Cell Signaling), H2AK119ub (8240; Cell Signaling), RYBP (59451204; Sigma-Aldrich), and USP7 (A300-033A; Bethyl Laboratories).	('RING1B', 'Gene', (258, 264))	('RING1B', 'Gene', '19821', (258, 264))	('RYBP', 'Gene', (323, 327))	('H2AK119ub', 'Var', (289, 298))	('H3K27me3', 'Var', (181, 189))	('H2AK119ub', 'Chemical', '-', (289, 298))	('H3K36me3', 'Var', (211, 219))	('RYBP', 'Gene', '56353', (323, 327))
477924	32417737	But co-expression of vimentin and keratin is thought to be characteristic of ES.	('co-expression', 'Var', (4, 17))	('vimentin', 'Gene', (21, 29))	('vimentin', 'Gene', '7431', (21, 29))	('keratin', 'Protein', (34, 41))
477947	32326412	As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis.	('YAP/TAZ', 'Gene', (125, 132))	('tumor', 'Disease', (178, 183))	('invasion', 'CPA', (57, 65))	('rat', 'Species', '10116', (49, 52))	('proliferation', 'CPA', (31, 44))	('migration', 'CPA', (46, 55))	('self-renewal', 'CPA', (17, 29))	('YAP/TAZ', 'Gene', '10413;6901', (125, 132))	('expression', 'MPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('perturbed', 'Var', (101, 110))	('rat', 'Species', '10116', (38, 41))	('metastasis', 'CPA', (196, 206))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
477956	32326412	However, although tumorigenesis is driven by a patient-specific diversity of de-novo mutations, the metastatic process converges on common cellular plasticity mechanisms of normal development hijacked by the cancer cell and driven by interaction with the cancer cell s microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('patient', 'Species', '9606', (47, 54))	('cancer', 'Disease', (208, 214))	('tumor', 'Disease', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('mutations', 'Var', (85, 94))	('driven by', 'Reg', (35, 44))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
477959	32326412	TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis, while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors upon inactivation of the oncogenic driver.	('cancer', 'Disease', (145, 151))	('drive', 'PosReg', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('inactivation', 'Var', (237, 249))	('cancer', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('resistance to chemotherapy', 'MPA', (177, 203))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Disease', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('elevated', 'PosReg', (15, 23))	('TAZ', 'Gene', '6901', (0, 3))	('TAZ', 'Gene', (0, 3))	('tumors', 'Disease', (225, 231))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('promote', 'PosReg', (169, 176))
477975	32326412	YAP and TAZ subcellular localization, stability and activity are regulated by protein phosphorylation, negatively on serines 127 and 397 (YAP) and 89 and 311 (TAZ) and positively on tyrosine 357 (YAP) and 316 (TAZ).	('tyrosine', 'Chemical', 'MESH:D014443', (182, 190))	('negatively', 'NegReg', (103, 113))	('tyrosine 357', 'Var', (182, 194))	('activity', 'MPA', (52, 60))	('serines 127', 'Var', (117, 128))	('TAZ', 'Gene', '6901', (210, 213))	('TAZ', 'Gene', '6901', (159, 162))	('TAZ', 'Gene', (210, 213))	('TAZ', 'Gene', '6901', (8, 11))	('TAZ', 'Gene', (159, 162))	('TAZ', 'Gene', (8, 11))	('serines', 'Chemical', 'MESH:D012694', (117, 124))
477978	32326412	The TAZ promoter region contains binding sites for E26 (ETS), forkhead box (FOXO) and serum response factor (SRF) transcription factors and has been previously reported bound by ETS transcription factor variants ETV1, 4, and 5 in prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (230, 245))	('prostate cancer', 'Phenotype', 'HP:0012125', (230, 245))	('variants', 'Var', (203, 211))	('E26', 'Protein', (51, 54))	('ETV1, 4, and 5', 'Gene', '2115;2118;2119', (212, 226))	('SRF', 'Gene', (109, 112))	('serum response factor', 'Gene', '6722', (86, 107))	('serum response factor', 'Gene', (86, 107))	('TAZ', 'Gene', '6901', (4, 7))	('TAZ', 'Gene', (4, 7))	('prostate cancer', 'Disease', (230, 245))	('bound', 'Interaction', (169, 174))	('binding', 'Interaction', (33, 40))	('SRF', 'Gene', '6722', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
477979	32326412	It is therefore possible, though not yet investigated, that aberrantly expressed ETS transcription factors in bone sarcomas (i.e., Ewing sarcoma) may affect TAZ transcription.	('bone sarcomas', 'Disease', (110, 123))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (131, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (131, 144))	('TAZ', 'Gene', (157, 160))	('TAZ', 'Gene', '6901', (157, 160))	('aberrantly expressed', 'Var', (60, 80))	('bone sarcomas', 'Phenotype', 'HP:0002669', (110, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('affect', 'Reg', (150, 156))	('Ewing sarcoma', 'Disease', (131, 144))	('bone sarcoma', 'Phenotype', 'HP:0002669', (110, 122))	('bone sarcomas', 'Disease', 'MESH:D012509', (110, 123))	('ETS transcription factors', 'Gene', (81, 106))
477983	32326412	In cancer, both YAP and TAZ RNA are frequently increased, but the mechanisms behind this upregulation remain largely elusive and may involve both transcriptional and post-transcriptional mechanisms through suppression of the YAP/TAZ regulatory microRNAs, including miR-15a, miR-141-3p, mir-194, miR-195, miR-375, miR-381, miR-584, miR-125, miR-185, miR-9-3p and miR-129-5p, to name a few.	('TAZ', 'Gene', (229, 232))	('miR-584', 'Gene', '693169', (322, 329))	('miR-185', 'Gene', (340, 347))	('miR-129-5p', 'Gene', (362, 372))	('mir-194', 'Var', (286, 293))	('miR-584', 'Gene', (322, 329))	('-3p', 'Chemical', '-', (354, 357))	('suppression', 'NegReg', (206, 217))	('miR-15a', 'Gene', (265, 272))	('miR-129-5p', 'Gene', '100302178', (362, 372))	('miR-381', 'Gene', '494330', (313, 320))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('YAP/TAZ', 'Gene', '10413;6901', (225, 232))	('miR-185', 'Gene', '406961', (340, 347))	('miR-125', 'Var', (331, 338))	('-3p', 'Chemical', '-', (281, 284))	('miR-195', 'Gene', '406971', (295, 302))	('YAP', 'MPA', (16, 19))	('YAP/TAZ', 'Gene', (225, 232))	('miR-9-3p', 'Gene', '407051', (349, 357))	('miR-15a', 'Gene', '406948', (265, 272))	('miR-9-3p', 'Gene', (349, 357))	('miR-195', 'Gene', (295, 302))	('miR-375', 'Gene', '494324', (304, 311))	('miR-141-3p', 'Var', (274, 284))	('TAZ', 'Gene', (24, 27))	('cancer', 'Disease', (3, 9))	('increased', 'PosReg', (47, 56))	('TAZ', 'Gene', '6901', (24, 27))	('miR-375', 'Gene', (304, 311))	('miR-381', 'Gene', (313, 320))	('TAZ', 'Gene', '6901', (229, 232))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
478004	32326412	On the other hand, tyrosine 357-phosphorylated YAP binds and activates a complex between beta-catenin and the transcription factor TBX5 in the nucleus of beta-catenin driven cancers to activate a number of anti-apoptotic genes, including WWTR1.	('TBX5', 'Gene', '6910', (131, 135))	('tyrosine 357-phosphorylated', 'Var', (19, 46))	('TBX5', 'Gene', (131, 135))	('activate', 'PosReg', (185, 193))	('binds', 'Interaction', (51, 56))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('WWTR1', 'Gene', (238, 243))	('activates', 'PosReg', (61, 70))	('WWTR1', 'Gene', '25937', (238, 243))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))	('beta-catenin', 'Protein', (89, 101))	('complex', 'Interaction', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('YAP', 'Gene', (47, 50))	('anti-apoptotic genes', 'Gene', (206, 226))
478006	32326412	For example, miR-135b-5p was demonstrated to promote osteogenic differentiation of mesenchymal stem cells (MSC) through targeting of LATS1 and MOB1, thus supporting YAP/TAZ nuclear translocation.	('YAP/TAZ', 'Gene', '10413;6901', (165, 172))	('LATS1', 'Gene', (133, 138))	('MOB1', 'Gene', '3627', (143, 147))	('rat', 'Species', '10116', (36, 39))	('MOB1', 'Gene', (143, 147))	('LATS1', 'Gene', '9113', (133, 138))	('miR-135b-5p', 'Var', (13, 24))	('supporting', 'PosReg', (154, 164))	('promote', 'PosReg', (45, 52))	('YAP/TAZ', 'Gene', (165, 172))	('targeting', 'NegReg', (120, 129))
478008	32326412	MicroRNAs miR-214-3p and miR-23a-5p shed from osteoclasts in exosomes downregulate osteoblast function by targeting upstream YAP regulatory fibroblast growth factor receptor and the YAP/RUNX2 transcriptional complex, respectively.	('YAP regulatory fibroblast growth factor receptor', 'Protein', (125, 173))	('osteoblast function', 'CPA', (83, 102))	('targeting', 'Reg', (106, 115))	('miR-214-3p', 'Var', (10, 20))	('-3p', 'Chemical', '-', (17, 20))	('downregulate', 'NegReg', (70, 82))	('miR-23a-5p', 'Var', (25, 35))
478052	32326412	On the other hand, during early development of the pre-implantation embryo, Yap and Taz appear to substitute for each other, and Yap/Taz double-knockout leads to death prior to the morula stage.	('Yap', 'Gene', (129, 132))	('double-knockout', 'Var', (137, 152))	('Taz', 'Gene', '6901', (84, 87))	('Taz', 'Gene', '6901', (133, 136))	('Taz', 'Gene', (84, 87))	('Yap', 'Gene', '22601', (76, 79))	('Yap', 'Gene', (76, 79))	('Taz', 'Gene', (133, 136))	('death', 'Disease', (162, 167))	('death', 'Disease', 'MESH:D003643', (162, 167))	('leads to', 'Reg', (153, 161))	('pre-implantation embryo', 'Phenotype', 'HP:0032479', (51, 74))	('Yap', 'Gene', '22601', (129, 132))
478070	32326412	In response to TGFbeta signaling, phosphorylated complexes of SMAD2/3-4 directly interact with TAZ, which is required for their nuclear retention and transcriptional activity, while high YAP was reported to suppress BMP-induced phosphorylation and activity of SMAD1, 5 and 8.	('TAZ', 'Gene', (95, 98))	('TGFbeta', 'Gene', (15, 22))	('activity', 'MPA', (248, 256))	('suppress', 'NegReg', (207, 215))	('TGFbeta', 'Gene', '7039', (15, 22))	('SMAD', 'Gene', (260, 264))	('TAZ', 'Gene', '6901', (95, 98))	('BMP', 'Gene', '649', (216, 219))	('SMAD', 'Gene', (62, 66))	('SMAD', 'Gene', '4089;4086;4089;17128;4090;4093', (260, 264))	('SMAD1, 5 and 8', 'Gene', '4086;4090;4093', (260, 274))	('SMAD', 'Gene', '4089;4086;4089;17128;4090;4093', (62, 66))	('high YAP', 'Var', (182, 190))	('interact', 'Interaction', (81, 89))	('BMP', 'Gene', (216, 219))
478079	32326412	In fact, Snai1/Snai2 co-deletion in the mouse resulted in a loss of expression of several YAP/TAZ-TEAD target genes, including Ctgf, ankyrin repeat domain 1 (Ankrd1), AXL receptor tyrosine kinase (Axl), Dickkopf 1 (Dkk1) and Cyr61.	('expression', 'MPA', (68, 78))	('loss', 'NegReg', (60, 64))	('Snai2', 'Gene', (15, 20))	('mouse', 'Species', '10090', (40, 45))	('Dickkopf 1', 'Gene', '13380', (203, 213))	('Snai2', 'Gene', '20583', (15, 20))	('Axl', 'Gene', (197, 200))	('AXL receptor tyrosine kinase', 'Gene', '26362', (167, 195))	('YAP/TAZ', 'Gene', '10413;6901', (90, 97))	('AXL receptor tyrosine kinase', 'Gene', (167, 195))	('YAP/TAZ', 'Gene', (90, 97))	('Snai1', 'Gene', '20613', (9, 14))	('Cyr61', 'Gene', (225, 230))	('Ankrd1', 'Gene', '107765', (158, 164))	('Cyr61', 'Gene', '16007', (225, 230))	('Snai1', 'Gene', (9, 14))	('Ctgf', 'Gene', '14219', (127, 131))	('Dkk1', 'Gene', '13380', (215, 219))	('Dickkopf 1', 'Gene', (203, 213))	('co-deletion', 'Var', (21, 32))	('Dkk1', 'Gene', (215, 219))	('Ctgf', 'Gene', (127, 131))	('Axl', 'Gene', '26362', (197, 200))	('ankyrin repeat domain 1', 'Gene', '107765', (133, 156))	('Ankrd1', 'Gene', (158, 164))	('ankyrin repeat domain 1', 'Gene', (133, 156))
478097	32326412	Moreover, incorporation of alpha-smooth muscle actin in contractile stress fibers of MSC favor osteogenic differentiation in a YAP-dependent fashion.	('incorporation', 'Var', (10, 23))	('osteogenic differentiation', 'CPA', (95, 121))	('rat', 'Species', '10116', (17, 20))	('alpha-smooth muscle actin', 'Protein', (27, 52))	('favor', 'PosReg', (89, 94))
478098	32326412	In fact, YAP depletion was shown to downregulate the expression of osteogenic genes and of focal adhesion components paxillin, beta-1 integrin and zyxin in human MSC in vitro.	('paxillin', 'Gene', '5829', (117, 125))	('downregulate', 'NegReg', (36, 48))	('paxillin', 'Gene', (117, 125))	('depletion', 'Var', (13, 22))	('zyxin', 'Gene', (147, 152))	('beta-1 integrin', 'Gene', '3688', (127, 142))	('expression', 'MPA', (53, 63))	('human', 'Species', '9606', (156, 161))	('zyxin', 'Gene', '7791', (147, 152))	('beta-1 integrin', 'Gene', (127, 142))	('osteogenic genes', 'Gene', (67, 83))
478102	32326412	As a consequence, Snai1/Snai2 double-knockout in mice did not affect the osteoprogenitor lineage commitment of MSC but impaired their ability to complete the terminal steps of their osteoblastogenic program paralleled by the protein destabilization of Yap/Taz.	('Snai2', 'Gene', (24, 29))	('Snai1', 'Gene', (18, 23))	('mice', 'Species', '10090', (49, 53))	('impaired', 'NegReg', (119, 127))	('Taz', 'Gene', (256, 259))	('Snai2', 'Gene', '20583', (24, 29))	('Taz', 'Gene', '6901', (256, 259))	('Yap', 'Gene', (252, 255))	('double-knockout', 'Var', (30, 45))	('Yap', 'Gene', '22601', (252, 255))	('Snai1', 'Gene', '20613', (18, 23))	('osteoblastogenic program', 'CPA', (182, 206))
478109	32326412	These include miR-23a-5p, which targets the RUNX2/YAP transcriptional complex, and miR-214-3p, which targets, among others, the YAP/TAZ regulatory FGF receptor and osteoblastic transcription factor ATF4.	('osteoblastic', 'Disease', 'None', (164, 176))	('ATF4', 'Gene', (198, 202))	('YAP/TAZ', 'Gene', (128, 135))	('miR-23a-5p', 'Var', (14, 24))	('osteoblastic', 'Disease', (164, 176))	('miR-214-3p', 'Var', (83, 93))	('YAP/TAZ', 'Gene', '10413;6901', (128, 135))	('ATF4', 'Gene', '468', (198, 202))	('-3p', 'Chemical', '-', (90, 93))
478110	32326412	Dysregulation of the RANKL/RANK pathway is involved in bone destructive diseases such as osteoporosis, rheumatoid arthritis and cancer bone metastasis.	('osteoporosis', 'Disease', 'MESH:D010024', (89, 101))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (103, 123))	('osteoporosis', 'Disease', (89, 101))	('cancer bone metastasis', 'Disease', (128, 150))	('Dysregulation', 'Var', (0, 13))	('rheumatoid arthritis', 'Disease', (103, 123))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (103, 123))	('RANKL', 'Gene', '8600', (21, 26))	('RANKL', 'Gene', (21, 26))	('arthritis', 'Phenotype', 'HP:0001369', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('osteoporosis', 'Phenotype', 'HP:0000939', (89, 101))	('bone destructive diseases', 'Disease', (55, 80))	('cancer bone metastasis', 'Disease', 'MESH:D001859', (128, 150))	('involved', 'Reg', (43, 51))
478129	32326412	It is therefore likely that the dysregulation of YAP/TAZ may contribute to the pathogenesis of chondrosarcoma.	('YAP/TAZ', 'Gene', '10413;6901', (49, 56))	('dysregulation', 'Var', (32, 45))	('contribute', 'Reg', (61, 71))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (95, 109))	('chondrosarcoma', 'Disease', (95, 109))	('chondrosarcoma', 'Disease', 'MESH:D002813', (95, 109))	('YAP/TAZ', 'Gene', (49, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
478133	32326412	In addition, inhibition of the YAP/TAZ-activating kinases SRC and RAC was reported to interfere with the migratory and invasive properties of chondrosarcoma cells, while BMP-7-induced SRC activation promoted chondrosarcoma cell migration.	('SRC', 'Gene', '6714', (184, 187))	('rat', 'Species', '10116', (231, 234))	('promoted', 'PosReg', (199, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('interfere', 'NegReg', (86, 95))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (208, 222))	('SRC', 'Gene', (184, 187))	('chondrosarcoma', 'Disease', 'MESH:D002813', (142, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('chondrosarcoma', 'Disease', (142, 156))	('rat', 'Species', '10116', (108, 111))	('BMP-7', 'Gene', '655', (170, 175))	('SRC', 'Gene', '6714', (58, 61))	('RAC', 'Gene', (66, 69))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (142, 156))	('BMP-7', 'Gene', (170, 175))	('YAP/TAZ', 'Gene', '10413;6901', (31, 38))	('RAC', 'Gene', '207', (66, 69))	('inhibition', 'Var', (13, 23))	('chondrosarcoma', 'Disease', (208, 222))	('chondrosarcoma', 'Disease', 'MESH:D002813', (208, 222))	('SRC', 'Gene', (58, 61))	('YAP/TAZ', 'Gene', (31, 38))
478134	32326412	Although YAP/TAZ were not investigated in these studies, it may be speculated that the observed molecular alterations affected chondrosarcoma adherence and invasion phenotypes through abrogated YAP/TAZ signaling.	('rat', 'Species', '10116', (110, 113))	('YAP/TAZ', 'Gene', (9, 16))	('abrogated', 'NegReg', (184, 193))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (127, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('YAP/TAZ', 'Gene', '10413;6901', (9, 16))	('YAP/TAZ', 'Gene', (194, 201))	('affected', 'Reg', (118, 126))	('chondrosarcoma adherence', 'Disease', 'MESH:D002813', (127, 151))	('YAP/TAZ', 'Gene', '10413;6901', (194, 201))	('alterations', 'Var', (106, 117))	('invasion', 'CPA', (156, 164))	('chondrosarcoma adherence', 'Disease', (127, 151))
478137	32326412	Potentially, this downregulation was mediated by epigenetic restoration of the expression of the inhibitory YAP/TAZ-binding scaffold protein angiomotin (AMOT).	('epigenetic restoration', 'Var', (49, 71))	('YAP/TAZ', 'Gene', '10413;6901', (108, 115))	('expression', 'MPA', (79, 89))	('AMOT', 'Gene', (153, 157))	('AMOT', 'Gene', '154796', (153, 157))	('angiomotin', 'Gene', '154796', (141, 151))	('angiomotin', 'Gene', (141, 151))	('downregulation', 'NegReg', (18, 32))	('YAP/TAZ', 'Gene', (108, 115))	('rat', 'Species', '10116', (65, 68))
478143	32326412	Metastatic events were either not or only slightly more frequent in patients with nuclear YAP (53%) than in those lacking nuclear YAP immunoreactivity (36%).	('patients', 'Species', '9606', (68, 76))	('nuclear YAP', 'Var', (82, 93))	('Metastatic events', 'CPA', (0, 17))
478144	32326412	However, knockdown of YAP in osteosarcoma cell lines suppressed in vitro tumor cell proliferation, clonogenicity and invasion, as well as tumor formation in mice.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('knockdown', 'Var', (9, 18))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Disease', (138, 143))	('invasion', 'CPA', (117, 125))	('rat', 'Species', '10116', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (73, 78))	('YAP', 'Gene', (22, 25))	('osteosarcoma', 'Disease', (29, 41))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('suppressed', 'NegReg', (53, 63))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))
478146	32326412	Consistent with its important role in osteosarcoma pathogenesis, the modeling of osteosarcoma in p53 heterozygous mice by activating hedgehog signaling in mature osteoblasts revealed the activation of Yap, and Yap knockdown significantly reduced the tumorigenic potential of osteosarcoma cells in this model.	('osteosarcoma', 'Disease', (275, 287))	('activation', 'PosReg', (187, 197))	('osteosarcoma', 'Disease', (38, 50))	('osteosarcoma', 'Disease', 'MESH:D012516', (38, 50))	('osteosarcoma', 'Disease', 'MESH:D012516', (275, 287))	('tumor', 'Disease', (250, 255))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))	('p53', 'Gene', (97, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('reduced', 'NegReg', (238, 245))	('Yap', 'Gene', '22601', (210, 213))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('p53', 'Gene', '22060', (97, 100))	('Yap', 'Gene', '22601', (201, 204))	('osteosarcoma', 'Phenotype', 'HP:0002669', (38, 50))	('osteosarcoma', 'Phenotype', 'HP:0002669', (275, 287))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('mice', 'Species', '10090', (114, 118))	('osteosarcoma', 'Disease', (81, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('Yap', 'Gene', (210, 213))	('knockdown', 'Var', (214, 223))	('Yap', 'Gene', (201, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (280, 287))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
478147	32326412	Of note, several hedgehog-signaling components, including smoothened (SMO), GLI family zinc finger proteins 1 and 2 (GLI1 and GLI2) and patched 1 (PTCH1), were found overexpressed in human osteosarcoma, and knockdown of GLI2 recapitulated the YAP knockdown effect in suppressing the proliferation, invasion and EMT of osteosarcoma cell lines.	('GLI1', 'Gene', '2735', (117, 121))	('invasion', 'CPA', (298, 306))	('SMO', 'Gene', '6608', (70, 73))	('smoothened', 'Gene', '6608', (58, 68))	('osteosarcoma', 'Disease', (189, 201))	('osteosarcoma', 'Disease', 'MESH:D012516', (189, 201))	('osteosarcoma', 'Phenotype', 'HP:0002669', (318, 330))	('suppressing', 'NegReg', (267, 278))	('SMO', 'Gene', (70, 73))	('human', 'Species', '9606', (183, 188))	('GLI2', 'Gene', (220, 224))	('PTCH1', 'Gene', '5727', (147, 152))	('GLI2', 'Gene', (126, 130))	('GLI2', 'Gene', '2736', (220, 224))	('GLI2', 'Gene', '2736', (126, 130))	('GLI1', 'Gene', (117, 121))	('rat', 'Species', '10116', (290, 293))	('osteosarcoma', 'Phenotype', 'HP:0002669', (189, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (323, 330))	('overexpressed', 'PosReg', (166, 179))	('osteosarcoma', 'Disease', (318, 330))	('osteosarcoma', 'Disease', 'MESH:D012516', (318, 330))	('patched 1', 'Gene', (136, 145))	('GLI family zinc finger proteins 1 and 2', 'Gene', '2736', (76, 115))	('smoothened', 'Gene', (58, 68))	('knockdown', 'Var', (207, 216))	('PTCH1', 'Gene', (147, 152))	('patched 1', 'Gene', '5727', (136, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))
478148	32326412	Similarly, inactivation of the Lats1/2-activating adaptor proteins Mob1a/1b or the heterozygous loss of Nf2 in a p53+/- background resulted in osteosarcoma development with frequent metastases in about 24% and 63% of knockout mice, respectively.	('resulted in', 'Reg', (131, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (143, 155))	('metastases', 'Disease', 'MESH:D009362', (182, 192))	('osteosarcoma', 'Disease', (143, 155))	('osteosarcoma', 'Disease', 'MESH:D012516', (143, 155))	('metastases', 'Disease', (182, 192))	('mice', 'Species', '10090', (226, 230))	('p53', 'Gene', '22060', (113, 116))	('Lats1', 'Gene', (31, 36))	('Nf2', 'Gene', '18016', (104, 107))	('inactivation', 'Var', (11, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Nf2', 'Gene', (104, 107))	('Lats1', 'Gene', '16798', (31, 36))	('p53', 'Gene', (113, 116))
478151	32326412	While all these data are consistent with an important role of activated nuclear YAP in osteosarcoma, there is little data on the potential role of TAZ in human patients.	('human', 'Species', '9606', (154, 159))	('patients', 'Species', '9606', (160, 168))	('activated nuclear', 'Var', (62, 79))	('TAZ', 'Gene', '6901', (147, 150))	('TAZ', 'Gene', (147, 150))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('osteosarcoma', 'Disease', (87, 99))	('osteosarcoma', 'Disease', 'MESH:D012516', (87, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
478157	32326412	Hsa-miR-135b overexpression was demonstrated to increase osteosarcoma xenograft growth.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('osteosarcoma', 'Disease', 'MESH:D012516', (57, 69))	('overexpression', 'Var', (13, 27))	('Hsa-miR-135b', 'Gene', '442891', (0, 12))	('Hsa-miR-135b', 'Gene', (0, 12))	('rat', 'Species', '10116', (39, 42))	('osteosarcoma', 'Phenotype', 'HP:0002669', (57, 69))	('osteosarcoma', 'Disease', (57, 69))	('increase', 'PosReg', (48, 56))
478164	32326412	The oncogenic driver of the disease is an Ewing sarcoma breakpoint region 1/E26 (EWSR1-ETS) gene fusion leading to the expression of a potent, aberrantly cell reprograming transcription factor, most frequently EWS-FLI1 (Ewing sarcoma RNA binding protein-Friend leukemia virus integration site 1).	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('EWSR1', 'Gene', '2130', (81, 86))	('leukemia', 'Disease', (261, 269))	('Ewing sarcoma', 'Disease', (220, 233))	('Ewing sarcoma', 'Disease', (42, 55))	('leukemia', 'Disease', 'MESH:D007938', (261, 269))	('leukemia', 'Phenotype', 'HP:0001909', (261, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('EWS-FLI1', 'Gene', (210, 218))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (220, 233))	('fusion', 'Var', (97, 103))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (220, 233))	('rat', 'Species', '10116', (281, 284))	('EWSR1', 'Gene', (81, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (42, 55))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (42, 55))
478169	32326412	While there is ample experimental evidence for high EWS-FLI1 levels activating cell cycle- and suppressing differentiation-associated genes, thus driving self-renewal and proliferation of Ewing sarcoma cells, recent studies indicated that low EWS-FLI1 levels may promote Ewing sarcoma migration, invasion and metastasis.	('Ewing sarcoma migration', 'Disease', 'MESH:C563168', (271, 294))	('promote', 'PosReg', (263, 270))	('EWS-FLI1', 'Gene', (243, 251))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (188, 201))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (188, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('driving', 'PosReg', (146, 153))	('invasion', 'CPA', (296, 304))	('self-renewal', 'CPA', (154, 166))	('low', 'Var', (239, 242))	('Ewing sarcoma migration', 'Disease', (271, 294))	('rat', 'Species', '10116', (178, 181))	('Ewing sarcoma', 'Disease', (188, 201))	('activating', 'PosReg', (68, 78))	('rat', 'Species', '10116', (288, 291))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (271, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('metastasis', 'CPA', (309, 319))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (271, 284))
478178	32326412	Interestingly, while in osteosarcoma, TNC binding to alpha9beta1 integrin promoted metastasis by repressing YAP nuclear translocation and target gene activation, TNC binding to alpha5beta1 integrin in Ewing sarcoma promoted metastasis by activating YAP, potentially through activating tyrosine phosphorylation by SRC kinase.	('tyrosine', 'Chemical', 'MESH:D014443', (285, 293))	('metastasis', 'CPA', (224, 234))	('beta1 integrin', 'Gene', (59, 73))	('Ewing sarcoma', 'Disease', (201, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('activating', 'PosReg', (238, 248))	('beta1 integrin', 'Gene', '3688', (59, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (24, 36))	('TNC', 'Gene', (38, 41))	('beta1 integrin', 'Gene', (183, 197))	('YAP', 'MPA', (249, 252))	('beta1 integrin', 'Gene', '3688', (183, 197))	('TNC', 'Gene', '3371', (38, 41))	('activation', 'PosReg', (150, 160))	('repressing', 'NegReg', (97, 107))	('TNC', 'Gene', (162, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('SRC', 'Gene', '6714', (313, 316))	('YAP nuclear translocation', 'MPA', (108, 133))	('activating', 'PosReg', (274, 284))	('promoted', 'PosReg', (74, 82))	('binding', 'Var', (166, 173))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (201, 214))	('metastasis', 'CPA', (83, 93))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (201, 214))	('tyrosine phosphorylation', 'MPA', (285, 309))	('osteosarcoma', 'Disease', (24, 36))	('osteosarcoma', 'Disease', 'MESH:D012516', (24, 36))	('TNC', 'Gene', '3371', (162, 165))	('SRC', 'Gene', (313, 316))	('promoted', 'PosReg', (215, 223))
478182	32326412	Interestingly, we and others have seen a selective increase in TAZ but not YAP transcription upon the knockdown of EWS-FLI1 in Ewing sarcoma cells (Bierbaumer et al., in revision).	('increase', 'PosReg', (51, 59))	('EWS-FLI1', 'Gene', (115, 123))	('TAZ', 'Gene', '6901', (63, 66))	('knockdown', 'Var', (102, 111))	('Ewing sarcoma', 'Disease', (127, 140))	('TAZ', 'Gene', (63, 66))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (127, 140))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (127, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('YAP transcription', 'MPA', (75, 92))
478185	32326412	Downstream of Rho-F-actin signaling the transcriptional co-activator MRTFB is enriched on YAP/TEAD-bound target genes upon the knockdown of EWS-FLI1, which get activated and drive the phenotypic switch from a proliferative to a highly migratory phenotype.	('MRTFB', 'Gene', '57496', (69, 74))	('activated', 'PosReg', (160, 169))	('MRTFB', 'Gene', (69, 74))	('drive', 'Reg', (174, 179))	('EWS-FLI1', 'Gene', (140, 148))	('rat', 'Species', '10116', (238, 241))	('proliferative', 'CPA', (209, 222))	('rat', 'Species', '10116', (216, 219))	('knockdown', 'Var', (127, 136))	('highly migratory phenotype', 'CPA', (228, 254))
478198	32326412	These data suggest that, while fluctuations in EWS-FLI1 may be involved in the initiation of the metastatic process by inducing EMT/MET-like processes involving YAP/TAZ, persistent YAP/TAZ activity is selected during Ewing sarcoma metastasis.	('YAP/TAZ', 'Gene', '10413;6901', (181, 188))	('EMT/MET-like processes', 'MPA', (128, 150))	('fluctuations', 'Var', (31, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('involved', 'Reg', (63, 71))	('Ewing sarcoma metastasis', 'Disease', 'MESH:C563168', (217, 241))	('EWS-FLI1', 'Gene', (47, 55))	('YAP/TAZ', 'Gene', (161, 168))	('YAP/TAZ', 'Gene', (181, 188))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (217, 230))	('inducing', 'Reg', (119, 127))	('Ewing sarcoma metastasis', 'Disease', (217, 241))	('YAP/TAZ', 'Gene', '10413;6901', (161, 168))
478206	32326412	It is typically composed of multinucleated osteoclast-like giant cells, mononuclear macrophage-like osteoclast precursor cells and mononuclear osteoblast-derived spindle-shaped stromal cells characterized by histone H3.3 (H3F3A) mutations, which are considered the neoplastic tumor component.	('H3F3A', 'Gene', (222, 227))	('neoplastic tumor', 'Disease', 'MESH:D009369', (265, 281))	('histone H3.3', 'Gene', '3021', (208, 220))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('mutations', 'Var', (229, 238))	('histone H3.3', 'Gene', (208, 220))	('H3F3A', 'Gene', '3020', (222, 227))	('neoplastic tumor', 'Disease', (265, 281))
478207	32326412	Thus, it cannot be excluded that the ensuing general epigenetic deregulation may also affect YAP/TAZ pathway components.	('YAP/TAZ', 'Gene', (93, 100))	('YAP/TAZ', 'Gene', '10413;6901', (93, 100))	('epigenetic deregulation', 'Var', (53, 76))	('affect', 'Reg', (86, 92))
478209	32326412	Here, YAP or TAZ are activated by gene rearrangements with either the transcription factor TFE3 (YAP-TFE3) or the calmodulin-binding transcription activator CAMTA1 (TAZ-CAMTA1) and retaining the YAP/TAZ TEAD-binding and WW domains.	('TAZ', 'Gene', '6901', (13, 16))	('TAZ', 'Gene', '6901', (165, 168))	('TFE3', 'Gene', (91, 95))	('TAZ', 'Gene', (13, 16))	('TAZ', 'Gene', (165, 168))	('TFE3', 'Gene', '7030', (91, 95))	('YAP/TAZ', 'Gene', '10413;6901', (195, 202))	('YAP', 'Gene', (6, 9))	('CAMTA1', 'Gene', '23261', (169, 175))	('CAMTA1', 'Gene', (157, 163))	('YAP-TFE3', 'Gene', '7030', (97, 105))	('YAP/TAZ', 'Gene', (195, 202))	('calmodulin', 'Gene', '801', (114, 124))	('gene rearrangements', 'Var', (34, 53))	('calmodulin', 'Gene', (114, 124))	('TFE3', 'Gene', (101, 105))	('YAP-TFE3', 'Gene', (97, 105))	('CAMTA1', 'Gene', (169, 175))	('TFE3', 'Gene', '7030', (101, 105))	('TAZ', 'Gene', '6901', (199, 202))	('TEAD-binding', 'MPA', (203, 215))	('TAZ', 'Gene', (199, 202))	('CAMTA1', 'Gene', '23261', (157, 163))
478240	32326412	It has also been shown to reactivate YAP-suppressed SOX9 in rat chondrosarcoma cells, leading to chondrocytic re-differentiation.	('chondrocytic re-differentiation', 'CPA', (97, 128))	('YAP-suppressed', 'Var', (37, 51))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (64, 78))	('SOX9', 'Gene', (52, 56))	('rat', 'Species', '10116', (60, 63))	('reactivate YAP-suppressed', 'Var', (26, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('chondrosarcoma', 'Disease', 'MESH:D002813', (64, 78))	('leading to', 'Reg', (86, 96))	('chondrosarcoma', 'Disease', (64, 78))
478246	32326412	Using this approach, we identified an association of high AMOT expression with improved outcomes in both Ewing sarcoma and osteosarcoma (unpublished).	('osteosarcoma', 'Phenotype', 'HP:0002669', (123, 135))	('high', 'Var', (53, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('improved', 'PosReg', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Ewing sarcoma and osteosarcoma', 'Disease', 'MESH:C563168', (105, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('AMOT', 'Gene', '154796', (58, 62))	('AMOT', 'Gene', (58, 62))
478247	32326412	Tankyrase, a PARP family member, is known to bind and degrade this negative YAP/TAZ regulatory protein, and tankyrase inhibition was demonstrated to stabilize AMOT and reduce YAP/TAZ nuclear translocation and TEAD target gene expression, potentially offering a therapeutic option in these bone cancers (Figure 4).	('bone cancers', 'Disease', 'MESH:D001859', (289, 301))	('PARP', 'Gene', (13, 17))	('expression', 'MPA', (226, 236))	('PARP', 'Gene', '8658', (13, 17))	('degrade', 'NegReg', (54, 61))	('AMOT', 'Gene', (159, 163))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('YAP/TAZ', 'Gene', '10413;6901', (76, 83))	('bone cancers', 'Disease', (289, 301))	('tankyrase', 'Gene', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('YAP/TAZ', 'Gene', (76, 83))	('Tankyrase', 'Gene', '8658', (0, 9))	('tankyrase', 'Gene', '8658', (108, 117))	('rat', 'Species', '10116', (140, 143))	('Tankyrase', 'Gene', (0, 9))	('inhibition', 'Var', (118, 128))	('YAP/TAZ', 'Gene', '10413;6901', (175, 182))	('reduce', 'NegReg', (168, 174))	('YAP/TAZ', 'Gene', (175, 182))	('AMOT', 'Gene', '154796', (159, 163))
478251	32326412	Therefore, the inhibition of YAP and TAZ here may prevent the emergence of drug resistance or restore drug sensitivity.	('prevent', 'NegReg', (50, 57))	('TAZ', 'Gene', (37, 40))	('TAZ', 'Gene', '6901', (37, 40))	('drug resistance', 'MPA', (75, 90))	('drug resistance', 'Phenotype', 'HP:0020174', (75, 90))	('emergence', 'MPA', (62, 71))	('restore', 'PosReg', (94, 101))	('drug sensitivity', 'Phenotype', 'HP:0020174', (102, 118))	('drug sensitivity', 'MPA', (102, 118))	('inhibition', 'Var', (15, 25))
478257	32326412	YAP/TAZ nuclear activation may be assigned to epigenetic silencing or the loss of YAP/TAZ negative regulatory proteins (RASSF family members, NF2, AMOT and MOB1) or to the activation of receptor tyrosine kinases (SRC, FGFR, FAK, etc.)	('RASSF', 'Gene', (120, 125))	('SRC', 'Gene', '6714', (213, 216))	('epigenetic silencing', 'Var', (46, 66))	('MOB1', 'Gene', (156, 160))	('NF2', 'Gene', '4771', (142, 145))	('RASSF', 'Gene', '42734', (120, 125))	('NF2', 'Gene', (142, 145))	('loss', 'NegReg', (74, 78))	('AMOT', 'Gene', '154796', (147, 151))	('SRC', 'Gene', (213, 216))	('YAP/TAZ', 'Gene', '10413;6901', (82, 89))	('FAK', 'Gene', (224, 227))	('tyrosine', 'Chemical', 'MESH:D014443', (195, 203))	('activation', 'PosReg', (16, 26))	('YAP/TAZ', 'Gene', (82, 89))	('AMOT', 'Gene', (147, 151))	('FAK', 'Gene', '5747', (224, 227))	('MOB1', 'Gene', '3627', (156, 160))	('YAP/TAZ', 'Gene', '10413;6901', (0, 7))	('YAP/TAZ', 'Gene', (0, 7))	('activation', 'PosReg', (172, 182))
478285	32317857	Certain progress has been made in directly targeting many transcription factors, in particular, chimeric kinases and mutant proteins involved in cancer development ( and Tables 1 and 2).	('cancer', 'Disease', (145, 151))	('proteins', 'Protein', (124, 132))	('mutant', 'Var', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('chimeric', 'Var', (96, 104))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
478287	32317857	This translocation fuses the ETS variant gene 6 (ETV6) in chromosome 12 with the neurotrophin 3 receptor gene (NTRK3) kinase domain, resulting in activation of multiple signaling cascades including the RAS and PI3K-AKT pathways.	('ETV6', 'Gene', (49, 53))	('activation', 'PosReg', (146, 156))	('NTRK3', 'Gene', '4916', (111, 116))	('ETS variant gene 6', 'Gene', '2120', (29, 47))	('fuses', 'Var', (19, 24))	('AKT', 'Gene', '207', (215, 218))	('NTRK3', 'Gene', (111, 116))	('ETV6', 'Gene', '2120', (49, 53))	('AKT', 'Gene', (215, 218))	('ETS variant gene 6', 'Gene', (29, 47))
478293	32317857	Genetic inhibition of fusion gene by antisense oligonucleotides or siRNA could be another option.	('oligonucleotides', 'Chemical', 'MESH:D009841', (47, 63))	('antisense oligonucleotides', 'Var', (37, 63))	('inhibition', 'NegReg', (8, 18))
478294	32317857	Thus, it was reported that antisense oligonucleotides and siRNA inhibited expression of EWS-FLI1, chimeric gene specific for Ewing's sarcoma, in cell cultures and in the xenograft model in vivo, as well as decrease of SS18-SSX1 gene expression in synovial sarcoma.	('antisense oligonucleotides', 'Var', (27, 53))	("Ewing's sarcoma", 'Disease', (125, 140))	('synovial sarcoma', 'Disease', (247, 263))	('expression', 'MPA', (233, 243))	('oligonucleotides', 'Chemical', 'MESH:D009841', (37, 53))	('SS18', 'Gene', (218, 222))	('synovial sarcoma', 'Disease', 'MESH:D013584', (247, 263))	('expression', 'MPA', (74, 84))	('EWS', 'Gene', (88, 91))	('FLI1', 'Gene', (92, 96))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (247, 263))	('SS18', 'Gene', '6760', (218, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (125, 140))	('FLI1', 'Gene', '2313', (92, 96))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (125, 140))	('inhibited', 'NegReg', (64, 73))	('decrease', 'NegReg', (206, 214))	('SSX1', 'Gene', '6756', (223, 227))	('EWS', 'Gene', '2130', (88, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('SSX1', 'Gene', (223, 227))
478298	32317857	Moreover, epigenetic regulators influence PAX3-FOXO1 interaction with transcriptional partners as well.	('FOXO1', 'Gene', '2308', (47, 52))	('influence', 'Reg', (32, 41))	('FOXO1', 'Gene', (47, 52))	('interaction', 'Interaction', (53, 64))	('epigenetic regulators', 'Var', (10, 31))	('PAX3', 'Gene', '5077', (42, 46))	('PAX3', 'Gene', (42, 46))
478305	32317857	Furthermore, the drug repurposing approach is even more applicable for STS with oncogenic mutations: gastrointestinal stromal tumors (GIST) with activating mutations in c-KIT, PDGFA and BRAF, myxoid round cell liposarcoma with activating mutation in PI3K/Akt signaling component PI3CA ( and Table 2).	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('gastrointestinal stromal tumors', 'Disease', (101, 132))	('GIST', 'Phenotype', 'HP:0100723', (134, 138))	('liposarcoma', 'Disease', (210, 221))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('PDGFA', 'Gene', (176, 181))	('liposarcoma', 'Phenotype', 'HP:0012034', (210, 221))	('mutations', 'Var', (156, 165))	('myxoid round cell liposarcoma', 'Phenotype', 'HP:0012268', (192, 221))	('c-KIT', 'Gene', (169, 174))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (101, 132))	('Akt', 'Gene', (255, 258))	('BRAF', 'Gene', '673', (186, 190))	('c-KIT', 'Gene', '3815', (169, 174))	('liposarcoma', 'Disease', 'MESH:D008080', (210, 221))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (101, 132))	('BRAF', 'Gene', (186, 190))	('STS', 'Phenotype', 'HP:0030448', (71, 74))	('Akt', 'Gene', '207', (255, 258))	('PDGFA', 'Gene', '5154', (176, 181))
478318	32317857	Based on these findings, the studies of anticancer activity of IGF1R inhibitors, monoclonal antibodies R1507, MK-0646, cixutumumab, ganitumab, and figitumumab were started for several STS subtypes; some of them reached clinical trials.	('figitumumab', 'Chemical', 'MESH:C525021', (147, 158))	('STS', 'Phenotype', 'HP:0030448', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cixutumumab', 'Chemical', 'MESH:C557414', (119, 130))	('IGF1R', 'Gene', (63, 68))	('ganitumab', 'Chemical', 'MESH:C545764', (132, 141))	('inhibitors', 'Var', (69, 79))	('MK-0646', 'Chemical', 'MESH:C569480', (110, 117))	('IGF1R', 'Gene', '3480', (63, 68))
478320	32317857	Thus, monoclonal endoglin-targeting antibodies, TRC105, OMTX503 and OMTX703, have demonstrated the decrease in tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts as well as in angiosarcoma in clinical trials of Phase I/II.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('endoglin', 'Gene', '2022', (17, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('patient', 'Species', '9606', (174, 181))	('angiosarcoma', 'Disease', 'MESH:D006394', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('OMTX703', 'Var', (68, 75))	('angiosarcoma', 'Disease', (215, 227))	('tumor', 'Disease', (111, 116))	('decrease', 'NegReg', (99, 107))	('endoglin', 'Gene', (17, 25))	('Ewing sarcoma', 'Disease', (127, 140))	('angiosarcoma', 'Phenotype', 'HP:0200058', (215, 227))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (127, 140))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (127, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
478323	32317857	Efficacy of antitumor action of AURK inhibitors MLN8237 and tozasertib was demonstrated in vitro on Ewing's sarcoma cell lines and in vivo in xenograft models.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (100, 115))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	("Ewing's sarcoma", 'Disease', (100, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (100, 115))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tozasertib', 'Gene', (60, 70))	('AURK', 'Protein', (32, 36))	('tumor', 'Disease', (16, 21))	('tozasertib', 'Chemical', 'MESH:C484810', (60, 70))	('MLN8237', 'Chemical', 'MESH:C550258', (48, 55))	('MLN8237', 'Var', (48, 55))
478326	32317857	Direct inhibitors of ezrin, small molecules NSC305787 and NSC668394, demonstrated statistically significant reduction in tumor growth in vitro using the model of osteosarcoma.	('NSC305787', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('ezrin', 'Gene', '7430', (21, 26))	('osteosarcoma', 'Disease', (162, 174))	('ezrin', 'Gene', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('osteosarcoma', 'Phenotype', 'HP:0002669', (162, 174))	('osteosarcoma', 'Disease', 'MESH:D012516', (162, 174))	('NSC668394', 'Var', (58, 67))	('reduction', 'NegReg', (108, 117))
478328	32317857	Inactivating mutation in SMARCB1/INI1 is an oncogene driver in rhabdoid tumors, and the loss of functional SMARCB1/INI1 leads to increase in ezrin expression.	('INI1', 'Gene', '6598', (115, 119))	('INI1', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SMARCB1', 'Gene', (107, 114))	('loss of functional', 'Var', (88, 106))	('SMARCB1', 'Gene', '6598', (107, 114))	('INI1', 'Gene', '6598', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Inactivating mutation', 'Var', (0, 21))	('increase', 'PosReg', (129, 137))	('rhabdoid tumors', 'Disease', (63, 78))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (63, 78))	('SMARCB1', 'Gene', '6598', (25, 32))	('ezrin', 'Gene', (141, 146))	('ezrin', 'Gene', '7430', (141, 146))	('SMARCB1', 'Gene', (25, 32))	('INI1', 'Gene', (115, 119))
478362	32210275	Here, we describe the structure-guided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome.	('inhibits', 'NegReg', (81, 89))	('human', 'Species', '9606', (142, 147))	('XL177A', 'Var', (54, 60))	('USP7', 'Gene', (90, 94))
478363	32210275	Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of ~500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells.	('TP53', 'Gene', (366, 370))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('mutations', 'Var', (251, 260))	('suppresses', 'NegReg', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('XL177A', 'Gene', (163, 169))	('TP53', 'Gene', (264, 268))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (343, 349))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('knockout', 'Var', (371, 379))	('growth suppression', 'CPA', (404, 422))
478371	32210275	Although many cancers are driven by mutant TP53, roughly half of all adult malignancies and 95% of pediatric cancers harbor intact WT TP53 and may benefit from therapeutic approaches that stabilize p53.	('cancers', 'Disease', (14, 21))	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('driven by', 'Reg', (26, 35))	('pediatric cancers', 'Disease', (99, 116))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('malignancies', 'Disease', (75, 87))	('cancers', 'Disease', (109, 116))	('pediatric cancers', 'Disease', 'MESH:D009369', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutant', 'Var', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('TP53', 'Gene', (43, 47))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
478375	32210275	These findings have spurred interest in the development of specific USP7 inhibitors, as there now appear to be several cancer indications that may benefit from USP7 modulation.	('USP7', 'Gene', (160, 164))	('modulation', 'Var', (165, 175))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
478378	32210275	To that end, we undertook the development of novel irreversible XL188 analogs that could be comprehensively profiled for USP7 selectivity and then used as chemical tools to elucidate cellular responses to selective USP7 inhibition.	('analogs', 'Var', (70, 77))	('XL188', 'Chemical', '-', (64, 69))	('XL188', 'Gene', (64, 69))
478380	32210275	Evaluation of XL177A and its enantiomer, XL177B, as a negative control, across a broad panel of 484 cancer cell lines and in a series of targeted confirmatory studies, found that TP53 mutational status predicted response to selective USP7 inhibition across multiple cancer lineages.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('predicted', 'Reg', (202, 211))	('mutational', 'Var', (184, 194))	('cancer', 'Disease', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('USP7', 'Gene', (234, 238))	('inhibition', 'NegReg', (239, 249))	('response', 'MPA', (212, 220))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('TP53', 'Gene', (179, 183))
478384	32210275	Chemical synthesis and biochemical characterization of >50 XL188 analogs (Liu et al., in preparation) culminated in development of XL177A as a highly potent and selective irreversible inhibitor of USP7 (Fig.	('USP7', 'Gene', (197, 201))	('XL188', 'Gene', (59, 64))	('XL188', 'Chemical', '-', (59, 64))	('XL177A', 'Var', (131, 137))
478385	32210275	In an enzymatic assay using full-length USP7 and fluorogenic substrate ubiquitin-7-amino-4-methylcoumarin (Ub-AMC), XL177A inhibited USP7 with an IC50 of 0.34 nM (Fig.	('USP7', 'Gene', (133, 137))	('inhibited', 'NegReg', (123, 132))	('XL177A', 'Var', (116, 122))	('Ub-AMC', 'Chemical', '-', (107, 113))	('ubiquitin-7-amino-4-methylcoumarin', 'Chemical', '-', (71, 105))
478391	32210275	We also employed live cell treatment and competitive ABPP to demonstrate that XL177A inhibits USP7 in cyto, with an IC50 of 39 nM after 6 hr treatment (Fig.	('ABPP', 'Gene', (53, 57))	('inhibits', 'NegReg', (85, 93))	('ABPP', 'Gene', '351', (53, 57))	('USP7 in cyto', 'MPA', (94, 106))	('XL177A', 'Var', (78, 84))
478393	32210275	As expected, treatment of MCF7 cells, which express WT TP53, with XL177A induced rapid degradation of HDM2 within 2 hours, followed by increases in p53 and downstream p21 protein levels (Fig.	('HDM2', 'Gene', (102, 106))	('TP53', 'Var', (55, 59))	('HDM2', 'Gene', '4193', (102, 106))	('increases', 'PosReg', (135, 144))	('p53', 'MPA', (148, 151))	('p21', 'Gene', '1026', (167, 170))	('degradation', 'NegReg', (87, 98))	('p21', 'Gene', (167, 170))
478395	32210275	Indeed, 1 muM XL177A induced complete G1 arrest in MCF7 cells after 24 hours (Figs.	('muM', 'Gene', '56925', (10, 13))	('arrest', 'Disease', (41, 47))	('XL177A', 'Var', (14, 20))	('muM', 'Gene', (10, 13))	('arrest', 'Disease', 'MESH:D006323', (41, 47))
478399	32210275	We thus investigated binding mode using structure-activity-relationship (SAR) studies, USP7 mutant enzyme studies, hydrogen-deuterium exchange mass spectrometry (HDX), and molecular dynamics (MD) simulations.	('investigated', 'Reg', (8, 20))	('mutant', 'Var', (92, 98))	('USP7', 'Gene', (87, 91))	('hydrogen', 'Chemical', 'MESH:D006859', (115, 123))	('deuterium', 'Chemical', 'MESH:D003903', (124, 133))
478400	32210275	The 4-hydroxy-piperidine group of XL188 forms hydrogen-bonding interactions with the sidechain carboxylic group of USP7 Q297 and the peptide backbone of V296 and is required for USP7 inhibition: XL024 (IC50 = 8 muM), which has a hydrogen atom instead of this hydroxyl group, is ~1,000-fold less potent than XL112 (a racemic mixture of XL177A and XL177B, IC50 = 0.0059 muM) and is ~10-fold less potent than XL058 (IC50 = 0.904 muM), which lacks the Cys223-reactive chloro atom (Fig.	('hydrogen', 'Chemical', 'MESH:D006859', (229, 237))	('muM', 'Gene', '56925', (368, 371))	('muM', 'Gene', (426, 429))	('Cys223-reactive chloro atom', 'MPA', (448, 475))	('less', 'NegReg', (290, 294))	('Cys', 'Chemical', 'MESH:D003545', (448, 451))	('XL188', 'Chemical', '-', (34, 39))	('XL024', 'Var', (195, 200))	('muM', 'Gene', (368, 371))	('muM', 'Gene', '56925', (211, 214))	('muM', 'Gene', (211, 214))	('hydrogen', 'Chemical', 'MESH:D006859', (46, 54))	('potent', 'MPA', (295, 301))	('muM', 'Gene', '56925', (426, 429))
478401	32210275	In addition, two XL188-resistant USP7 mutants, F291N and Q351S, are inhibited by XL177A with 100-fold loss in potency compared to wild-type enzyme (Figs.	('USP7', 'Gene', (33, 37))	('F291N', 'Mutation', 'p.F291N', (47, 52))	('Q351S', 'Var', (57, 62))	('F291N', 'Var', (47, 52))	('inhibited', 'NegReg', (68, 77))	('XL188', 'Chemical', '-', (17, 22))	('Q351S', 'Mutation', 'p.Q351S', (57, 62))	('loss', 'NegReg', (102, 106))	('potency', 'MPA', (110, 117))
478402	32210275	Both XL188 and XL177A strongly protected the BL1 and alpha-4/5 loops surrounding the S4-S5 pocket from exchange (Fig.	('XL188', 'Var', (5, 10))	('BL1', 'Protein', (45, 48))	('XL177A', 'Var', (15, 21))	('XL188', 'Chemical', '-', (5, 10))
478405	32210275	These helices likely became destabilized upon XL177A binding, leading to exposure of the backbone hydrogens.	('backbone hydrogens', 'MPA', (89, 107))	('hydrogens', 'Chemical', 'MESH:D006859', (98, 107))	('XL177A', 'Var', (46, 52))	('binding', 'Interaction', (53, 60))	('exposure', 'MPA', (73, 81))
478406	32210275	MD simulations of XL177A binding with covalent labeling of C223 and H-bonding to Q297 taken as priors showed a decrease in water contacts of the alpha4/5 and S4-S5 residues as well as an increase in water contacts for the region from alpha2 to alpha4 when compared to the unbound USP7 construct, consistent with HDX experimental data.	('increase', 'PosReg', (187, 195))	('binding', 'Interaction', (25, 32))	('XL177A', 'Gene', (18, 24))	('water', 'Chemical', 'MESH:D014867', (199, 204))	('water contacts', 'MPA', (199, 213))	('C223', 'Var', (59, 63))	('water', 'Chemical', 'MESH:D014867', (123, 128))	('water contacts', 'MPA', (123, 137))	('decrease', 'NegReg', (111, 119))
478408	32210275	Taken together, these data suggest that XL177A possesses similar binding sites and a similar binding mode to that of XL188 but induces additional conformation changes in protein dynamics compared to XL188.	('induces', 'Reg', (127, 134))	('conformation changes', 'MPA', (146, 166))	('protein dynamics', 'MPA', (170, 186))	('XL188', 'Chemical', '-', (199, 204))	('XL188', 'Chemical', '-', (117, 122))	('XL177A', 'Var', (40, 46))
478412	32210275	We found that XL177A significantly blocked USP7 labeling by DUB ABPs in a dose-dependent manner while remaining selective against 59 other DUBs (Fig.	('USP7 labeling', 'MPA', (43, 56))	('blocked', 'NegReg', (35, 42))	('XL177A', 'Var', (14, 20))	('ABP', 'Chemical', '-', (64, 67))
478413	32210275	First, we synthesized XL177A-DTB, an XL177A analog with a desthiobiotin (DTB) affinity tag, and demonstrated that it retained USP7 inhibitory activity (Table S1).	('desthiobiotin', 'Chemical', 'MESH:C004749', (58, 71))	('USP7 inhibitory activity', 'MPA', (126, 150))	('XL177A-DTB', 'Var', (22, 32))	('DTB', 'Chemical', 'MESH:C004749', (73, 76))	('DTB', 'Chemical', 'MESH:C004749', (29, 32))
478416	32210275	Of the 566 proteins covalently modified by XL177A-DTB, only USP7 exhibited>3-fold inhibition of labeling when treated with XL177A at 1 or 10 muM (Fig.	('proteins', 'Protein', (11, 19))	('muM', 'Gene', '56925', (141, 144))	('muM', 'Gene', (141, 144))	('XL177A-DTB', 'Var', (43, 53))	('labeling', 'MPA', (96, 104))	('DTB', 'Chemical', 'MESH:C004749', (50, 53))
478422	32210275	Interestingly, hierarchical clustering revealed that XL177A and Nutlin-3A transcriptional profiles were correlated at both low (0.1 muM XL177A and 1 muM Nutlin-3A) and high (1 muM XL177A and 10 muM Nutlin-3A) doses, while XL177B clustered with the vehicle (DMSO)-treated control cells (Fig.	('Nutlin-3', 'Chemical', 'MESH:C482205', (198, 206))	('0.1', 'Var', (128, 131))	('transcriptional profiles', 'MPA', (74, 98))	('Nutlin-3', 'Chemical', 'MESH:C482205', (153, 161))	('muM', 'Gene', '56925', (149, 152))	('Nutlin-3', 'Chemical', 'MESH:C482205', (64, 72))	('muM', 'Gene', '56925', (176, 179))	('muM', 'Gene', '56925', (132, 135))	('XL177A', 'Gene', (53, 59))	('DMSO', 'Chemical', 'MESH:D004121', (257, 261))	('muM', 'Gene', (149, 152))	('muM', 'Gene', '56925', (194, 197))	('muM', 'Gene', (176, 179))	('muM', 'Gene', (132, 135))	('muM', 'Gene', (194, 197))	('Nutlin-3A', 'Gene', (64, 73))
478423	32210275	While XL177A did upregulate a set of genes not affected by Nutlin-3A, the overall transcriptional profile of these compounds led us to systematically evaluate whether they were enriched for similar gene sets.	('XL177A', 'Var', (6, 12))	('Nutlin-3', 'Chemical', 'MESH:C482205', (59, 67))	('upregulate', 'PosReg', (17, 27))
478428	32210275	USP7 inhibition by XL177A thus elicits a transcriptional signature that strongly phenocopies that of direct MDM2 inhibition by Nutlin-3A, suggesting that p53 upregulation may be the most relevant consequence of USP7 inhibition in TP53-WT MCF7 cells.	('elicits', 'Reg', (31, 38))	('Nutlin-3', 'Chemical', 'MESH:C482205', (127, 135))	('USP7', 'Gene', (0, 4))	('inhibition', 'NegReg', (5, 15))	('p53', 'Gene', (154, 157))	('MDM2', 'Gene', '4193', (108, 112))	('XL177A', 'Var', (19, 25))	('MDM2', 'Gene', (108, 112))	('upregulation', 'PosReg', (158, 170))
478429	32210275	We considered that XL177A may produce different effects in TP53-WT versus TP53-mutant cells and thus sought to profile XL177A in a panel of cancer cell lines with diverse genomic backgrounds.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TP53-mutant', 'Var', (74, 85))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
478430	32210275	We screened XL177A, XL177B, and Nutlin-3A in 8-point dose response against a panel of 484 cancer cell lines using barcoded cancer cell lines/PRISM technology.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('XL177A', 'Var', (12, 18))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('XL177B', 'Var', (20, 26))	('Nutlin-3', 'Chemical', 'MESH:C482205', (32, 40))
478432	32210275	Interestingly, XL177A sensitivity was highly correlated with MDM2 and UBE2D3 (an E2 conjugating enzyme for p53) KO and highly anti-correlated with TP53 KO, implying that p53 is a key predictor of response to USP7 inhibition across the entire panel of cells.	('UBE2D3', 'Gene', '7323', (70, 76))	('MDM2', 'Gene', '4193', (61, 65))	('MDM2', 'Gene', (61, 65))	('UBE2D3', 'Gene', (70, 76))	('XL177A', 'Var', (15, 21))	('anti-correlated', 'NegReg', (126, 141))	('correlated', 'Reg', (45, 55))
478434	32210275	To validate our results from the unbiased screen, we tested effects of XL177A, XL177B and Nutlin-3A using individual cell lines.	('XL177A', 'Var', (71, 77))	('tested', 'Reg', (53, 59))	('XL177B', 'Var', (79, 85))	('Nutlin-3', 'Chemical', 'MESH:C482205', (90, 98))
478441	32210275	These results suggest that, while the globally selective USP7 inhibitor XL177A acts through a p53-dependent mechanism, P5091 and GNE-6640 may have as yet unknown targets that lead to p53-independent effects.	('GNE', 'Gene', '10020', (129, 132))	('P5091', 'Var', (119, 124))	('GNE', 'Gene', (129, 132))	('XL177A', 'Var', (72, 78))
478442	32210275	Given the highly p53-dependent nature of response to XL177A, we sought to identify whether genetic modulation of USP7 also produces p53-dependent effects in cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('USP7', 'Gene', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('genetic modulation', 'Var', (91, 109))	('cancer', 'Disease', (157, 163))
478445	32210275	Overall, available genetic data confirm that response to USP7 modulation is correlated with TP53 status across multiple cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('modulation', 'Var', (62, 72))	('USP7', 'Gene', (57, 61))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('correlated', 'Reg', (76, 86))
478447	32210275	Both sgMDM2 and sgUSP7 led to sustained reductions in the parental cells of both A549 and RKO (Figs.	('MDM2', 'Gene', (7, 11))	('sgUSP7', 'Var', (16, 22))	('MDM2', 'Gene', '4193', (7, 11))	('reductions', 'NegReg', (40, 50))
478448	32210275	6G and S13), indicating that TP53-KO improves the fitness of these cells in response to USP7 or MDM2 modulation.	('improves', 'PosReg', (37, 45))	('MDM2', 'Gene', '4193', (96, 100))	('MDM2', 'Gene', (96, 100))	('TP53-KO', 'Var', (29, 36))	('fitness of these cells', 'CPA', (50, 72))
478449	32210275	Thus, the cell killing effect of USP7 KO is, as with MDM2 KO and XL177A treatment, at least partially mediated by p53 in TP53-WT cells.	('MDM2', 'Gene', (53, 57))	('MDM2', 'Gene', '4193', (53, 57))	('USP7 KO', 'Var', (33, 40))	('cell killing effect', 'CPA', (10, 29))
478452	32210275	Moreover, comparison of the sensitivity profile of XL177A across over 400 cancer cell lines with sensitivity profiles generated in those same cell lines with KD / KO of over 18,000 genes identified USP7 KO as exhibiting the most similar profile.	('KD', 'Disease', 'MESH:C537017', (158, 160))	('USP7 KO', 'Var', (198, 205))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
478454	32210275	We note that XL177A is not an in vivo probe, and we thus have a limited understanding of its selectivity, potency, and potential toxicity in more complex animal models.	('toxicity', 'Disease', (129, 137))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))	('XL177A', 'Var', (13, 19))
478456	32210275	Overwhelmingly, our studies revealed mutational status of the tumor suppressor p53 to be the key cellular feature predicting sensitivity to USP7 by XL177A.	('p53', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('mutational', 'Var', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
478457	32210275	In addition, TP53 KO rendered TP53-WT cells resistant to XL177A, and transcriptome-wide response to XL177A phenocopied effects of Nutlin-3A, a validated inhibitor of MDM2-mediated p53 ubiquitination and therefore a compound expected to stabilize p53 and inhibit its proteasomal degradation.	('XL177A', 'Var', (100, 106))	('TP53 KO', 'Var', (13, 20))	('Nutlin-3', 'Chemical', 'MESH:C482205', (130, 138))	('p53', 'Gene', (246, 249))	('ubiquitination', 'MPA', (184, 198))	('proteasomal degradation', 'MPA', (266, 289))	('inhibit', 'NegReg', (254, 261))	('MDM2', 'Gene', '4193', (166, 170))	('MDM2', 'Gene', (166, 170))
478460	32210275	Despite the high TP53 mutation rate in cancer, several cancer types have a low rate of TP53 mutation, especially hematopoietic and pediatric malignancies.	('mutation', 'Var', (22, 30))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pediatric malignancies', 'Disease', 'MESH:D063766', (131, 153))	('hematopoietic', 'Disease', (113, 126))	('pediatric malignancies', 'Disease', (131, 153))	('TP53', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('TP53', 'Gene', (17, 21))
478466	32210275	We propose that USP7 inhibitors are p53 activators that should be explored clinically as single agents or in combination studies in hematopoietic and pediatric malignancies with a low rate of TP53 mutation.	('USP7', 'Gene', (16, 20))	('mutation', 'Var', (197, 205))	('pediatric malignancies', 'Disease', 'MESH:D063766', (150, 172))	('TP53', 'Gene', (192, 196))	('pediatric malignancies', 'Disease', (150, 172))
478467	32210275	While USP7 inhibition may stabilize p53 by inducing MDM2 degradation, we note that the p53-dependent effects of USP7 inhibition may not be solely driven by MDM2.	('MDM2', 'Gene', (156, 160))	('USP7', 'Gene', (112, 116))	('inhibition', 'Var', (11, 21))	('inducing', 'Reg', (43, 51))	('MDM2', 'Gene', '4193', (52, 56))	('MDM2', 'Gene', (52, 56))	('MDM2', 'Gene', '4193', (156, 160))
478468	32210275	Previous studies have shown that USP7 inhibition or knockdown also leads to decreased DNA damage tolerance via degradation of RAD18 (replication-associated repair), CSB (nucleotide excision repair), and ALKBH2/3 (alkylation repair), and USP7 has been shown to regulate both p14/Arf (which mediates p53 stability) and Tip60 (which mediates p53 transcriptional activity).	('CSB', 'Gene', (165, 168))	('USP7', 'Gene', (33, 37))	('CSB', 'Gene', '1443', (165, 168))	('p14/Arf', 'Gene', '1029', (274, 281))	('ALKBH2/3', 'Gene', '121642;221120', (203, 211))	('Tip60', 'Gene', '10524', (317, 322))	('regulate', 'Reg', (260, 268))	('DNA', 'CPA', (86, 89))	('decreased', 'NegReg', (76, 85))	('RAD18', 'Gene', (126, 131))	('p14/Arf', 'Gene', (274, 281))	('inhibition', 'Var', (38, 48))	('RAD18', 'Gene', '56852', (126, 131))	('USP7', 'Gene', (237, 241))	('knockdown', 'Var', (52, 61))	('Tip60', 'Gene', (317, 322))	('ALKBH2/3', 'Gene', (203, 211))
478470	32210275	p53 (9282s), p21 (2947s), GAPDH (2118s), and USP7 (4833s) antibodies were obtained from Cell Signaling Technology.	('9282s', 'Var', (5, 10))	('p21', 'Gene', '1026', (13, 16))	('4833s', 'Var', (51, 56))	('GAPDH', 'Gene', '2597', (26, 31))	('GAPDH', 'Gene', (26, 31))	('p21', 'Gene', (13, 16))	('2118s', 'Var', (33, 38))
478473	32210275	BAX (Hs00180269_m1), CDKN1A (Hs00355782_m1), DDB2 (Hs03044953_m1), GADD45A (Hs00169255_m1), GAPDH (402869), MDM2 (Hs00540450_s1), and TP53 (Hs01034249_m1) Taqman probes were obtained from Thermo-Fisher.	('GADD45A', 'Gene', '1647', (67, 74))	('Hs00355782_m1', 'Var', (29, 42))	('Hs03044953_m1', 'Var', (51, 64))	('Hs00169255_m1', 'Var', (76, 89))	('DDB2', 'Gene', '1643', (45, 49))	('GADD45A', 'Gene', (67, 74))	('Hs00180269_m1', 'Var', (5, 18))	('BAX', 'Gene', (0, 3))	('BAX', 'Gene', '581', (0, 3))	('Hs00540450_s1', 'Var', (114, 127))	('DDB2', 'Gene', (45, 49))	('Hs01034249_m1', 'Var', (140, 153))	('CDKN1A', 'Gene', '1026', (21, 27))	('CDKN1A', 'Gene', (21, 27))	('GAPDH', 'Gene', '2597', (92, 97))	('MDM2', 'Gene', '4193', (108, 112))	('GAPDH', 'Gene', (92, 97))	('MDM2', 'Gene', (108, 112))
478475	32210275	HEK 293AD, G401, G402, and MESSA were purchased from ATCC.	('HEK 293AD', 'CellLine', 'CVCL:9804;0.11626790172461349', (0, 9))	('G401', 'Var', (11, 15))	('G402', 'Var', (17, 21))
478481	32210275	Fractions were pooled, concentrated and frozen at -80  C. The construct encoding the catalytic domain of USP7 C223A was generated by site-directed mutagenesis, and the protein was purified as described for the WT enzyme.	('USP7', 'Gene', (105, 109))	('C223A', 'Mutation', 'c.223C>A', (110, 115))	('C223A', 'Var', (110, 115))
478494	32210275	Search parameters specified fixed carbamidomethylation of cysteine, and variable oxidation (methionine) and XL177A modification (cysteine).	('methionine', 'Chemical', 'MESH:D008715', (92, 102))	('cysteine', 'Chemical', 'MESH:D003545', (58, 66))	('XL177A modification', 'Var', (108, 127))	('carbamidomethylation', 'MPA', (34, 54))	('cysteine', 'Chemical', 'MESH:D003545', (129, 137))
478510	32210275	Briefly, USP7 (50 microM in 20 mM Hepes (pH 7.5), 200 mM NaCl, 1 mM TCEP, 5% glycerol H2O) was pre-incubated at room temperature (21  C) with the indicated compound in a 10:1 compound:USP7 ratio (XL041 for 60 min, XL177A for 30 min), then diluted with 15-fold D2O buffer (pD 7.5) at room temperature.	('NaCl', 'Chemical', 'MESH:D012965', (57, 61))	('XL041', 'Var', (196, 201))	('glycerol', 'Chemical', 'MESH:D005990', (77, 85))	('Hepes', 'Chemical', 'MESH:D006531', (34, 39))	('H2O', 'Chemical', 'MESH:D014867', (86, 89))	('XL177A', 'Var', (214, 220))	('D2O', 'Chemical', 'MESH:D017666', (260, 263))	('TCEP', 'Chemical', 'MESH:C080938', (68, 72))
478541	32210275	MCF7 cells were seeded in a 384 well plate at 2500 cells per well, allowed to adhere for 24 hours, then treated with two doses in triplicate of XL177A, XL177B, Nutlin-3, or DMSO.	('XL177B', 'Var', (152, 158))	('DMSO', 'Chemical', 'MESH:D004121', (173, 177))	('Nutlin-3', 'Chemical', 'MESH:C482205', (160, 168))	('XL177A', 'Var', (144, 150))
478689	31069017	In November 2014, as the risk of morcellating an occult uterine sarcoma could worsen survival outcomes due to potential intra-abdominal disease dissemination, the U.S. Food and Drug Administration (FDA) released a safety communication with a warning regarding the use of the electromechanical morcellator devices for women undergoing myomectomy/hysterectomy.	('women', 'Species', '9606', (317, 322))	('intra-abdominal disease dissemination', 'Disease', (120, 157))	('worsen', 'NegReg', (78, 84))	('intra-abdominal disease dissemination', 'Disease', 'MESH:D009103', (120, 157))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('sarcoma', 'Disease', (64, 71))	('survival', 'MPA', (85, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('morcellating', 'Var', (33, 45))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (56, 71))
478773	31069017	For diagnostic purposes, tumours showing three or all of the four following features should be considered as sarcomas: >=5 cm in greatest dimension, infiltrative margins, >=5 mitotic figures per 10 high power field, and moderate to severe cytologic atypia.	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('>=5', 'Var', (171, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('tumours', 'Disease', (25, 32))	('sarcomas', 'Disease', (109, 117))
478800	24894790	It is also described as being linked with paralysis of the affected limb, congenital myopathy, amputation stumps, the use of poorly fitting suction-type prosthesis, 20210A mutation in the prothrombin gene, activated protein c resistance, and syndromes such as the Prader-Labhart-Willi and Klippel-Trenaunay syndrome.	('congenital myopathy', 'Disease', (74, 93))	('paralysis', 'Disease', 'MESH:D010243', (42, 51))	('protein c', 'Gene', '5624', (216, 225))	('myopathy', 'Phenotype', 'HP:0003198', (85, 93))	('congenital myopathy', 'Disease', 'MESH:D009224', (74, 93))	('activated protein c resistance', 'Phenotype', 'HP:0012175', (206, 236))	('Prader-Labhart-Willi', 'Disease', (264, 284))	('activated', 'MPA', (206, 215))	('20210A mutation', 'Var', (165, 180))	('amputation stumps', 'Disease', (95, 112))	('protein c', 'Gene', (216, 225))	('Klippel-Trenaunay syndrome', 'Disease', 'MESH:D007715', (289, 315))	('paralysis', 'Disease', (42, 51))	('linked', 'Reg', (30, 36))	('paralysis', 'Phenotype', 'HP:0003470', (42, 51))	('prothrombin', 'Gene', (188, 199))	('Klippel-Trenaunay syndrome', 'Disease', (289, 315))	('prothrombin', 'Gene', '2147', (188, 199))
478828	24894790	Laboratory testing must investigate for alterations of antithrombin III, protein C, protein S, and for the presence of mutations in the prothrombin G20210A and methylene tetrahydrofolate reductase C677T genes.	('protein C', 'Gene', '5624', (73, 82))	('C677T', 'Gene', (197, 202))	('C677T', 'Mutation', 'rs1188383936', (197, 202))	('G20210A', 'Gene', (148, 155))	('protein S', 'Protein', (84, 93))	('antithrombin III', 'Phenotype', 'HP:0001976', (55, 71))	('alterations', 'Reg', (40, 51))	('antithrombin III', 'Gene', (55, 71))	('G20210A', 'Mutation', 'rs1799963', (148, 155))	('protein C', 'Gene', (73, 82))	('prothrombin', 'Gene', (136, 147))	('mutations', 'Var', (119, 128))	('prothrombin', 'Gene', '2147', (136, 147))	('antithrombin III', 'Gene', '462', (55, 71))
478833	24894790	Their exact mode of action is still unknown, but erythromycin appears to have anti-inflammatory effects, and has shown to inhibit the chemotaxis of leukocytes, monocytes, and eosinophils.	('anti-inflammatory effects', 'CPA', (78, 103))	('erythromycin', 'Chemical', 'MESH:D004917', (49, 61))	('chemotaxis of leukocytes', 'CPA', (134, 158))	('erythromycin', 'Var', (49, 61))	('inhibit', 'NegReg', (122, 129))
478873	29067537	In addition, pazopanib inhibits the VEGF and PDGF pathway, which may lead to vascular endothelial damage.	('VEGF', 'Gene', (36, 40))	('pazopanib', 'Chemical', 'MESH:C516667', (13, 22))	('vascular', 'Disease', (77, 85))	('lead to', 'Reg', (69, 76))	('VEGF', 'Gene', '7422', (36, 40))	('pazopanib', 'Var', (13, 22))	('inhibits', 'NegReg', (23, 31))
478966	28115942	These properties were validated in human osteosarcoma cell lines, suggesting that CD117+Stro-1+ cells possess CSC properties.	('CSC properties', 'CPA', (110, 124))	('osteosarcoma', 'Disease', (41, 53))	('osteosarcoma', 'Phenotype', 'HP:0002669', (41, 53))	('human', 'Species', '9606', (35, 40))	('CD117+Stro-1+', 'Var', (82, 95))	('osteosarcoma', 'Disease', 'MESH:D012516', (41, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
478979	28115942	CD47 is a transmembrane protein that acts as a self-signal on normal cells by inhibiting macrophage phagocytosis, and high expression of CD47 is a poor prognostic factor.	('CD47', 'Gene', '961', (0, 4))	('macrophage phagocytosis', 'CPA', (89, 112))	('CD47', 'Gene', (137, 141))	('CD47', 'Gene', (0, 4))	('inhibiting', 'NegReg', (78, 88))	('high expression', 'Var', (118, 133))	('CD47', 'Gene', '961', (137, 141))
478981	28115942	Interestingly, CD47 blockage increased the macrophage phagocytosis of tumor cells, indicating that this could be an effective immunotherapeutic approach.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('CD47', 'Gene', '961', (15, 19))	('increased', 'PosReg', (29, 38))	('CD47', 'Gene', (15, 19))	('blockage', 'Var', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
478991	28115942	Aberrant expression of Oct3/4 and Nanog has also been suggested to fulfill an oncogenic role in tumorigenesis and the development of CSCs.	('Nanog', 'Gene', (34, 39))	('Aberrant expression', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('CSCs', 'Disease', (133, 137))	('Oct3/4', 'Gene', '5460', (23, 29))	('Nanog', 'Gene', '79923', (34, 39))	('Oct3/4', 'Gene', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
478994	28115942	OS521Oct4-pGFP+ cells were capable of self-renewal in several passages, forming heterogeneous tumors for Oct-4/GFP expression.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('forming', 'Reg', (72, 79))	('OS521Oct4-pGFP+', 'Var', (0, 15))	('OS521', 'CellLine', 'CVCL:8530', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('Oct-4/GFP', 'Gene', (105, 114))
479001	28115942	Aberrant Wnt signaling has been reported in various tumors and shown to be associated with CSC activity.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Aberrant', 'Var', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('reported', 'Reg', (32, 40))	('associated', 'Reg', (75, 85))	('Wnt signaling', 'Pathway', (9, 22))	('CSC activity', 'Disease', (91, 103))
479005	28115942	reported that ALDH activity in highly metastatic K7M2 cells is reduced by Notch inhibition and is also associated with increased resistance to oxidative stress, migration, invasion, and VEGF expression, suggesting that ALDH activity may be regulated by Notch signaling.	('inhibition', 'NegReg', (80, 90))	('oxidative stress', 'Phenotype', 'HP:0025464', (143, 159))	('reduced', 'NegReg', (63, 70))	('resistance to oxidative stress', 'MPA', (129, 159))	('VEGF', 'Gene', (186, 190))	('ALDH', 'Gene', '11670', (14, 18))	('ALDH', 'Gene', '11670', (219, 223))	('Notch', 'Var', (74, 79))	('activity', 'MPA', (19, 27))	('K7M2', 'CellLine', 'CVCL:V455', (49, 53))	('ALDH', 'Gene', (219, 223))	('invasion', 'CPA', (172, 180))	('ALDH', 'Gene', (14, 18))	('migration', 'CPA', (161, 170))	('expression', 'MPA', (191, 201))	('VEGF', 'Gene', '22339', (186, 190))	('increased', 'PosReg', (119, 128))
479007	28115942	reported that TGF-beta1 signaling and a hypoxic environment induced CSC phenotypes in a non-CSC population and that the blockage of TGF-beta1 signaling inhibited the dedifferentiation and clonogenicity of osteosarcoma cells and reduced CSC self-renewal capacity, suggesting that CSCs may be yielded from differentiated cells.	('clonogenicity', 'CPA', (188, 201))	('TGF-beta1', 'Gene', '7040', (14, 23))	('induced', 'Reg', (60, 67))	('TGF-beta1', 'Gene', (14, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('reduced', 'NegReg', (228, 235))	('osteosarcoma', 'Disease', (205, 217))	('TGF-beta1', 'Gene', '7040', (132, 141))	('osteosarcoma', 'Disease', 'MESH:D012516', (205, 217))	('TGF-beta1', 'Gene', (132, 141))	('CSC self-renewal capacity', 'CPA', (236, 261))	('osteosarcoma', 'Phenotype', 'HP:0002669', (205, 217))	('CSC', 'MPA', (68, 71))	('inhibited', 'NegReg', (152, 161))	('blockage', 'Var', (120, 128))	('dedifferentiation', 'CPA', (166, 183))
479014	28115942	Deregulation of the expression of miRNAs has been shown to contribute to cancer development through various mechanisms, including deletions, amplifications, or mutations involving miRNA loci, epigenetic silencing, and the dysregulation of transcription factors that target specific miRNAs.	('cancer', 'Disease', (73, 79))	('deletions', 'Var', (130, 139))	('epigenetic silencing', 'Var', (192, 212))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('expression', 'MPA', (20, 30))	('mutations', 'Var', (160, 169))	('miR', 'Gene', (180, 183))	('Deregulation', 'Var', (0, 12))	('miR', 'Gene', '29116', (282, 285))	('miR', 'Gene', '29116', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('miR', 'Gene', (34, 37))	('amplifications', 'Var', (141, 155))	('miR', 'Gene', '29116', (34, 37))	('miR', 'Gene', (282, 285))	('contribute', 'Reg', (59, 69))
479029	28115942	The proportion of CD133+ cells decreased and inhibition of sphere formation, proliferation, and migration was decreased by the overexpression of HIF2PUT, while the knockdown of HIF2PUT showed the opposite function via alteration of HIF-2alpha mRNA expression.	('inhibition', 'NegReg', (45, 55))	('migration', 'CPA', (96, 105))	('CD133', 'Gene', (18, 23))	('CD133', 'Gene', '8842', (18, 23))	('alteration', 'Reg', (218, 228))	('decreased', 'NegReg', (31, 40))	('HIF-2alpha', 'Gene', (232, 242))	('decreased', 'NegReg', (110, 119))	('overexpression', 'PosReg', (127, 141))	('HIF2PUT', 'Var', (145, 152))	('HIF-2alpha', 'Gene', '2034', (232, 242))	('sphere formation', 'CPA', (59, 75))	('proliferation', 'CPA', (77, 90))
479041	28115942	investigated the efficacy of LY2940002, a PIK3 inhibitor that prevents the phosphorylation of protein kinase B, and revealed that this compound increased the number of cells in the G0/G1 phase and induced apoptosis via the activation of caspase-3, caspase-9, and PARP in osteosarcoma stem cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (271, 283))	('LY2940002', 'Chemical', '-', (29, 38))	('prevents', 'NegReg', (62, 70))	('apoptosis', 'CPA', (205, 214))	('caspase-3', 'Gene', '836', (237, 246))	('protein', 'Protein', (94, 101))	('caspase-9', 'Gene', '842', (248, 257))	('LY2940002', 'Var', (29, 38))	('induced', 'PosReg', (197, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('caspase-3', 'Gene', (237, 246))	('PARP', 'Gene', '1302', (263, 267))	('activation', 'PosReg', (223, 233))	('PIK3', 'Gene', (42, 46))	('osteosarcoma', 'Disease', (271, 283))	('osteosarcoma', 'Disease', 'MESH:D012516', (271, 283))	('PIK3', 'Gene', '5294', (42, 46))	('phosphorylation', 'MPA', (75, 90))	('PARP', 'Gene', (263, 267))	('increased', 'PosReg', (144, 153))	('caspase-9', 'Gene', (248, 257))
479042	28115942	Preclinical experiments with in vivo models have not been completed, although a phase I study of SF1126, a novel inhibitor of PI3 kinase and mTOR that includes an active moiety consisting of LY294002, for patients with relapsed or refractory neuroblastoma is reportedly ongoing.	('mTOR', 'Gene', '2475', (141, 145))	('patients', 'Species', '9606', (205, 213))	('mTOR', 'Gene', (141, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (242, 255))	('SF1126', 'Gene', (97, 103))	('neuroblastoma', 'Disease', (242, 255))	('LY294002', 'Var', (191, 199))	('neuroblastoma', 'Phenotype', 'HP:0003006', (242, 255))	('clinical', 'Species', '191496', (3, 11))	('LY294002', 'Chemical', 'MESH:C085911', (191, 199))
479049	28115942	Histone deacetylase (HDAC) inhibitors have been reported to suppress CSC phenotypes in solid malignancies.	('CSC phenotypes', 'Disease', (69, 83))	('HDAC', 'Gene', '9734', (21, 25))	('suppress', 'NegReg', (60, 68))	('inhibitors', 'Var', (27, 37))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('Histone deacetylase', 'Gene', '9734', (0, 19))	('Histone deacetylase', 'Gene', (0, 19))	('malignancies', 'Disease', (93, 105))	('HDAC', 'Gene', (21, 25))
479050	28115942	tested HDAC inhibitors on sarcospheres of osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma and reported that MC1742 and MC2625 inhibited sphere growth by inducing apoptosis with increased acetyl-H3 and acetyl-tubulin levels.	('MC1742', 'Var', (110, 116))	('inducing', 'NegReg', (155, 163))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('rhabdomyosarcoma', 'Disease', (75, 91))	('increased', 'PosReg', (179, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (75, 91))	('apoptosis', 'CPA', (164, 173))	('sphere growth', 'CPA', (138, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (75, 91))	('MC2625', 'Var', (121, 127))	('HDAC', 'Gene', '9734', (7, 11))	('osteosarcoma', 'Disease', (42, 54))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))	('Ewing sarcoma', 'Disease', (56, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('inhibited', 'NegReg', (128, 137))	('HDAC', 'Gene', (7, 11))	('MC2625', 'CellLine', 'CVCL:W203', (121, 127))
479054	28115942	Synthetic molecular mimics of tumor suppressor miRNAs or the inhibition of oncogenic miRNAs by chemically modified antisense oligonucleotides (ASOs) have been widely tested in preclinical trials.	('miR', 'Gene', (85, 88))	('oligonucleotides', 'Chemical', 'MESH:D009841', (125, 141))	('miR', 'Gene', (47, 50))	('miR', 'Gene', '29116', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('ASOs', 'Chemical', 'MESH:D016376', (143, 147))	('miR', 'Gene', '29116', (47, 50))	('tumor', 'Disease', (30, 35))	('antisense', 'Var', (115, 124))	('clinical', 'Species', '191496', (179, 187))
479055	28115942	Chemical modifications, including 2'-O-methyl, 2'-O-methoxyethyl, 2'-fluoro, and locked nucleic acid (LNA), have improved the stability, biodistribution, and delivery of ASOs.	('stability', 'MPA', (126, 135))	("2'-O-methyl", 'Var', (34, 45))	("2'-O-methyl", 'Chemical', '-', (34, 45))	('ASOs', 'Chemical', 'MESH:D016376', (170, 174))	('biodistribution', 'MPA', (137, 152))	("2'-fluoro", 'Var', (66, 75))	('delivery', 'MPA', (158, 166))	('improved', 'PosReg', (113, 121))	("2'-O-methoxyethyl", 'Var', (47, 64))	('fluoro', 'Chemical', '-', (69, 75))	("2'-O-methoxyethyl", 'Chemical', '-', (47, 64))
479058	28115942	Inversely, the silencing of miR-133a with LNA reduced cell invasion and the systemic administration of LNA along with cisplatin suppressed lung metastasis.	('lung metastasis', 'CPA', (139, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('silencing', 'Var', (15, 24))	('reduced', 'NegReg', (46, 53))	('suppressed', 'NegReg', (128, 138))	('miR', 'Gene', (28, 31))	('cell invasion', 'CPA', (54, 67))	('miR', 'Gene', '29116', (28, 31))
479070	28115942	Ap-SAL-NP exhibited specific cytotoxicity toward SaOS2 CD133+ cells and intravenous injections via the tail vein of tumor-bearing mice exhibited significant antitumor activity compared with salinomycin and a control compound.	('mice', 'Species', '10090', (130, 134))	('cytotoxicity', 'Disease', (29, 41))	('CD133', 'Gene', (55, 60))	('Ap-SAL-NP', 'Chemical', '-', (0, 9))	('CD133', 'Gene', '8842', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cytotoxicity', 'Disease', 'MESH:D064420', (29, 41))	('tail vein of tumor', 'Phenotype', 'HP:0030713', (103, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('salinomycin', 'Chemical', 'MESH:C010327', (190, 201))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (161, 166))	('Ap-SAL-NP', 'Var', (0, 9))
479084	28115942	To date, most reports have focused on the common CSC markers such as CD133 or ALDH, which would be reasonable if the sarcoma stem cell subpopulations emerge after the accumulation of further epigenetic or genetic alterations in a subset of tumor cells.	('CD133', 'Gene', (69, 74))	('tumor', 'Disease', (240, 245))	('CD133', 'Gene', '8842', (69, 74))	('sarcoma', 'Disease', (117, 124))	('ALDH', 'Gene', (78, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('epigenetic', 'Var', (191, 201))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('ALDH', 'Gene', '11670', (78, 82))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
479123	25621030	2B), positivity for cluster of differentiation (CD)99 (Fig.	('positivity', 'Var', (5, 15))	('CD', 'Disease', 'MESH:D006223', (48, 50))	('cluster', 'Gene', (20, 27))
479197	23252384	Previous studies have evaluated vaccines targeting the breakpoints in the BCR-ABL translocation in patients with chronic myelogenous leukemia and EWS-FLI1 in patients with Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('FLI1', 'Gene', '2313', (150, 154))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (172, 185))	('EWS', 'Gene', '2130', (146, 149))	('EWS', 'Gene', (146, 149))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (113, 141))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (121, 141))	('BCR-ABL', 'Gene', (74, 81))	('BCR-ABL', 'Gene', '25', (74, 81))	('patients', 'Species', '9606', (99, 107))	('Ewing sarcoma', 'Disease', (172, 185))	('patients', 'Species', '9606', (158, 166))	('chronic myelogenous leukemia', 'Disease', (113, 141))	('breakpoints', 'Var', (55, 66))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (113, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (172, 185))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('FLI1', 'Gene', (150, 154))
479205	23252384	Approximately 90% of synovial sarcoma cases are characterized by a specific translocation t(x;18)(p11.2;q11.2).	('synovial sarcoma', 'Disease', 'MESH:D013584', (21, 37))	('t(x;18)(p11.2;q11.2', 'Var', (90, 109))	('t(x;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (90, 110))	('synovial sarcoma', 'Disease', (21, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (21, 37))
479209	23252384	They identified an epitope, SS393 (GYDQIMPKK) with HLA-A24 binding affinity and found that peptide-specific T cells with cytolytic activity against SYT-SSX-expressing tumor cells could be cultured from synovial sarcoma patients.	('SSX', 'Gene', '6757', (152, 155))	('SYT', 'Gene', (148, 151))	('SSX', 'Gene', (152, 155))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (202, 218))	('synovial sarcoma', 'Disease', (202, 218))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('HLA-A', 'Gene', '3105', (51, 56))	('synovial sarcoma', 'Disease', 'MESH:D013584', (202, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('SYT', 'Gene', '6760', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('patients', 'Species', '9606', (219, 227))	('SS393', 'Var', (28, 33))	('HLA-A', 'Gene', (51, 56))	('tumor', 'Disease', (167, 172))	('cytolytic', 'MPA', (121, 130))
479210	23252384	They further identified that this epitope could be modified at an anchor residue (agretope-modified, K9I substitution - GYDQIMPKI) to increase HLA-A24 binding and generation of CTL responses in vitro with cross-reactivity to the native epitope.	('K9I substitution -', 'Var', (101, 119))	('binding', 'Interaction', (151, 158))	('HLA-A', 'Gene', '3105', (143, 148))	('CTL responses', 'MPA', (177, 190))	('HLA-A', 'Gene', (143, 148))	('increase', 'PosReg', (134, 142))
479211	23252384	They previously conducted a clinical trial evaluating the safety and immunological efficacy of the SS393 peptide in HLA-A24+ patients with recurrent synovial sarcoma.	('synovial sarcoma', 'Disease', (149, 165))	('HLA-A', 'Gene', '3105', (116, 121))	('HLA-A', 'Gene', (116, 121))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (149, 165))	('synovial sarcoma', 'Disease', 'MESH:D013584', (149, 165))	('SS393', 'Var', (99, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('patients', 'Species', '9606', (125, 133))
479212	23252384	In the current study, they evaluate this peptide as well as the K9I variant, alone or with IFN-alpha, in a trial of HLA-A24+ patients with metastatic synovial sarcoma.	('synovial sarcoma', 'Disease', (150, 166))	('HLA-A', 'Gene', '3105', (116, 121))	('K9I', 'Var', (64, 67))	('HLA-A', 'Gene', (116, 121))	('IFN-alpha', 'Gene', '3439', (91, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('IFN-alpha', 'Gene', (91, 100))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (150, 166))	('synovial sarcoma', 'Disease', 'MESH:D013584', (150, 166))	('patients', 'Species', '9606', (125, 133))
479214	23252384	Patients were treated in one of four groups with either SS393 or modified K9I at a dose of 0.1 or 1 mg, administered alone or with incomplete Freund's adjuvant (IFA) and 3 x 106U IFN-alpha given on days 1 and 3.	('SS393', 'Var', (56, 61))	('IFN-alpha', 'Gene', '3439', (179, 188))	('Patients', 'Species', '9606', (0, 8))	('IFN-alpha', 'Gene', (179, 188))	('modified K9I', 'Var', (65, 77))
479220	23252384	The authors conclude that: the vaccines could be safely administered; more patients receiving peptide with adjuvants had stable disease compared with those receiving peptide alone, indicating 'the adjuvant activity of IFA and IFN-alpha enhance the anti-tumor effects of the peptide vaccine'; more patients receiving the modified peptide experienced 'greater than twofold increase in the frequency of CTLs' as measured by tetramer staining; increases in CTL frequency had no relation to clinical responses; and response observed in patients receiving peptide plus adjuvant 'is encouraging and warrants further investigation, ideally in an adjuvant setting'.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('patients', 'Species', '9606', (297, 305))	('patients', 'Species', '9606', (531, 539))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('IFN-alpha', 'Gene', '3439', (226, 235))	('CTLs', 'MPA', (400, 404))	('IFN-alpha', 'Gene', (226, 235))	('tumor', 'Disease', (253, 258))	('increase', 'PosReg', (371, 379))	('modified', 'Var', (320, 328))
479314	22783134	reported that treatment with methanol extract of Paecilomyces sinclairii resulted in inhibited growth of Sarcoma 180 tumor cells and prolongation of the life span of mice by 32.3%, compared with the control.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Paecilomyces', 'Var', (49, 61))	('methanol', 'Chemical', 'MESH:D000432', (29, 37))	('inhibited', 'NegReg', (85, 94))	('prolongation', 'PosReg', (133, 145))	('Sarcoma 180 tumor', 'Disease', 'MESH:D012510', (105, 122))	('mice', 'Species', '10090', (166, 170))	('Sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('Sarcoma 180 tumor', 'Disease', (105, 122))	('growth', 'CPA', (95, 101))
479367	22009261	Plasmids expressing M2-Flag-tagged EWS-FLI-1, EWS, or FLI-1 were provided by Dr. Liu Yang (the University of Washington School of Medicine, Seattle, WA).	('EWS', 'Gene', '2130', (35, 38))	('EWS', 'Gene', (35, 38))	('FLI-1', 'Gene', '2313', (39, 44))	('EWS', 'Gene', '2130', (46, 49))	('EWS', 'Gene', (46, 49))	('FLI-1', 'Gene', (39, 44))	('M2-Flag-tagged', 'Var', (20, 34))	('FLI-1', 'Gene', '2313', (54, 59))	('FLI-1', 'Gene', (54, 59))	('EWS-FLI-1', 'Gene', '2130', (35, 44))	('EWS-FLI-1', 'Gene', (35, 44))
479426	22009261	4C, D) following the subcutaneous injection of TC-CAPER-alpha-pLV cells were significantly inhibited compared with the TC-pLV control cells.	('TC-CAPER-alpha-pLV', 'Var', (47, 65))	('TC-pLV', 'Chemical', '-', (119, 125))	('alpha-pLV', 'Chemical', '-', (56, 65))	('inhibited', 'NegReg', (91, 100))
479438	22009261	By contrast, transfection of EWS-FLI-1 into mesenchymal stem cells (MSC) using cDNA transfection led to decreased CAPER-alpha expression (Fig.	('EWS-FLI-1', 'Gene', (29, 38))	('CAPER-alpha', 'Gene', (114, 125))	('expression', 'MPA', (126, 136))	('transfection', 'Var', (13, 25))	('EWS-FLI-1', 'Gene', '2130', (29, 38))	('decreased', 'NegReg', (104, 113))	('CAPER-alpha', 'Gene', '9584', (114, 125))
479446	22009261	Furthermore, transfection of EWS-FLI-1 into MSC led to increased VEGF165 expression as assessed by RT-PCR (Fig.	('EWS-FLI-1', 'Gene', (29, 38))	('transfection', 'Var', (13, 25))	('EWS-FLI-1', 'Gene', '2130', (29, 38))	('increased', 'PosReg', (55, 64))	('VEGF', 'Gene', '7422', (65, 69))	('expression', 'MPA', (73, 83))	('VEGF', 'Gene', (65, 69))
479463	22009261	Elevated VEGF has been shown in several different tumors, including Ewing's sarcoma, and is associated with increased tumor vessel density and poor patient outcomes.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (68, 83))	('Elevated', 'Var', (0, 8))	('VEGF', 'Gene', (9, 13))	('increased', 'PosReg', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('VEGF', 'Gene', '7422', (9, 13))	('patient', 'Species', '9606', (148, 155))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (68, 83))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (50, 55))	("Ewing's sarcoma", 'Disease', (68, 83))
479487	22009261	The most common translocation is between the EWS and FLI genes resulting in production of the EWS-FLI-1 fusion protein, which functions as an aberrant transcription factor.	('EWS', 'Gene', (45, 48))	('EWS', 'Gene', '2130', (45, 48))	('EWS-FLI-1', 'Gene', '2130', (94, 103))	('EWS', 'Gene', (94, 97))	('FLI', 'Gene', (53, 56))	('EWS', 'Gene', '2130', (94, 97))	('production', 'MPA', (76, 86))	('translocation', 'Var', (16, 29))	('EWS-FLI-1', 'Gene', (94, 103))
479492	22009261	Here we have demonstrated that inhibiting EWS-FLI-1 in TC-71 or A4573 cells led to increased CAPER-alpha.	('increased', 'PosReg', (83, 92))	('CAPER-alpha', 'Gene', (93, 104))	('inhibiting', 'Var', (31, 41))	('EWS-FLI-1', 'Gene', (42, 51))	('CAPER-alpha', 'Gene', '9584', (93, 104))	('A4573', 'CellLine', 'CVCL:6245', (64, 69))	('TC-71', 'CellLine', 'CVCL:2213', (55, 60))	('EWS-FLI-1', 'Gene', '2130', (42, 51))
479493	22009261	By contrast, transfecting EWS-FLI-1 into MSC cells resulted in decreased expression of CAPER-alpha.	('transfecting', 'Var', (13, 25))	('CAPER-alpha', 'Gene', (87, 98))	('EWS-FLI-1', 'Gene', (26, 35))	('decreased', 'NegReg', (63, 72))	('EWS-FLI-1', 'Gene', '2130', (26, 35))	('expression', 'MPA', (73, 83))	('CAPER-alpha', 'Gene', '9584', (87, 98))
479643	32458597	Patients harboring mutations of the BRCA1 and BRCA2 genes as well as patients affected by Lynch syndrome are ideal candidate to risk reduction surgery.	('Lynch syndrome', 'Disease', (90, 104))	('BRCA1', 'Gene', (36, 41))	('BRCA2', 'Gene', (46, 51))	('Lynch syndrome', 'Disease', 'MESH:D003123', (90, 104))	('mutations', 'Var', (19, 28))	('BRCA2', 'Gene', '675', (46, 51))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (69, 77))	('BRCA1', 'Gene', '672', (36, 41))
479647	32458597	Patients harboring BRCA1 and BRCA2 mutations have to be counseled about their risk.	('BRCA2', 'Gene', (29, 34))	('Patients', 'Species', '9606', (0, 8))	('BRCA1', 'Gene', '672', (19, 24))	('BRCA2', 'Gene', '675', (29, 34))	('BRCA1', 'Gene', (19, 24))	('mutations', 'Var', (35, 44))
479699	32458597	Possible, COVID-19 outbreak would push decision makers in improving quality of the health care system and prevent the paucity of medical resources, worldwide.	('COVID-19', 'Disease', 'MESH:C000657245', (10, 18))	('outbreak', 'Var', (19, 27))	('COVID-19', 'Disease', (10, 18))	('improving', 'PosReg', (58, 67))
479715	31251393	In particular, patients treated with radiotherapy, anthracyclines, platinum agents, or alkylating agents are vulnerable to subsequent neoplasms.	('patients', 'Species', '9606', (15, 23))	('neoplasms', 'Phenotype', 'HP:0002664', (134, 143))	('anthracyclines', 'Var', (51, 65))	('platinum', 'Chemical', 'MESH:D010984', (67, 75))	('anthracyclines', 'Chemical', 'MESH:D018943', (51, 65))	('neoplasms', 'Disease', 'MESH:D009369', (134, 143))	('neoplasms', 'Disease', (134, 143))
479779	31251393	For example, RB1 and TP53 inactivation is common in radiation-related sarcomas, and somatic mutations in these genes have been linked or variability in treatment efficacy.	('TP53', 'Gene', (21, 25))	('inactivation', 'Var', (26, 38))	('RB1', 'Gene', '5925', (13, 16))	('sarcomas', 'Disease', 'MESH:D012509', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('sarcomas', 'Disease', (70, 78))	('RB1', 'Gene', (13, 16))	('TP53', 'Gene', '7157', (21, 25))
479805	31093468	SMARCA1 deletions existed in 1/56 dedifferentiated liposarcomas and 1/48 undifferentiated sarcomas.	('SMARCA1', 'Gene', (0, 7))	('liposarcoma', 'Phenotype', 'HP:0012034', (51, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (73, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('SMARCA1', 'Gene', '6594', (0, 7))	('undifferentiated sarcomas', 'Disease', (73, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('existed', 'Reg', (18, 25))	('liposarcomas', 'Disease', 'MESH:D008080', (51, 63))	('liposarcomas', 'Phenotype', 'HP:0012034', (51, 63))	('deletions', 'Var', (8, 17))	('liposarcomas', 'Disease', (51, 63))
479807	31093468	SMARCA1 IHC was studied in the sarcoma subtypes with potential SMARCA1 alterations in our institutional cases.	('SMARCA1', 'Gene', (0, 7))	('sarcoma', 'Disease', (31, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('SMARCA1', 'Gene', '6594', (0, 7))	('rat', 'Species', '10116', (75, 78))	('SMARCA1', 'Gene', (63, 70))	('alterations', 'Var', (71, 82))	('SMARCA1', 'Gene', '6594', (63, 70))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))
479828	31093468	SMARCA1 deletions were present in only one case of dedifferentiated liposarcoma among 56 cases of liposarcomas (1.7%) and in only one of 48 (2%) undifferentiated sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('liposarcoma', 'Disease', (68, 79))	('undifferentiated sarcomas', 'Disease', (145, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('liposarcoma', 'Disease', (98, 109))	('liposarcomas', 'Disease', 'MESH:D008080', (98, 110))	('liposarcoma', 'Phenotype', 'HP:0012034', (68, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('SMARCA1', 'Gene', (0, 7))	('liposarcomas', 'Phenotype', 'HP:0012034', (98, 110))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (145, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('liposarcoma', 'Disease', 'MESH:D008080', (68, 79))	('liposarcoma', 'Phenotype', 'HP:0012034', (98, 109))	('deletions', 'Var', (8, 17))	('SMARCA1', 'Gene', '6594', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('liposarcomas', 'Disease', (98, 110))	('liposarcoma', 'Disease', 'MESH:D008080', (98, 109))
479838	31093468	In the 3 cases of undifferentiated sarcoma with loss of SMARCA1, the adjacent normal tissue also did not express SMARCA1.	('SMARCA1', 'Gene', '6594', (113, 120))	('loss', 'Var', (48, 52))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (18, 42))	('undifferentiated sarcoma', 'Disease', (18, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('SMARCA1', 'Gene', (56, 63))	('SMARCA1', 'Gene', (113, 120))	('SMARCA1', 'Gene', '6594', (56, 63))
479840	31093468	The chromatin remodeling complexes can in turn be altered by epigenetic events like methylation, mutations or genomic alterations.	('mutations', 'Var', (97, 106))	('methylation', 'Var', (84, 95))	('genomic alterations', 'Var', (110, 129))	('chromatin', 'Enzyme', (4, 13))	('altered', 'Reg', (50, 57))	('rat', 'Species', '10116', (122, 125))
479845	31093468	In ovarian cancer, 46% of ovarian clear-cell carcinomas and 30% endometrioid ovarian carcinomas carried ARID1A mutations.	('mutations', 'Var', (111, 120))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (77, 95))	('ovarian clear-cell carcinomas', 'Disease', (26, 55))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('endometrioid ovarian carcinomas', 'Disease', (64, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian clear-cell carcinomas', 'Disease', 'MESH:D008649', (26, 55))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ARID1A', 'Gene', '8289', (104, 110))	('ARID1A', 'Gene', (104, 110))	('ovarian cancer', 'Disease', (3, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('endometrioid ovarian carcinomas', 'Disease', 'MESH:D016889', (64, 95))
479852	31093468	Mutations or alterations of the chromatin remodeling complexes also co-occur with other oncogenic alterations, e.g.	('co-occur', 'Reg', (68, 76))	('Mutations', 'Var', (0, 9))	('rat', 'Species', '10116', (102, 105))	('rat', 'Species', '10116', (17, 20))	('alterations', 'Reg', (13, 24))
479856	31093468	A recent study on gastric carcinomas found SMARCA1 silenced by aberrant methylation in gastric cancer cells.	('silenced', 'NegReg', (51, 59))	('gastric carcinomas', 'Disease', 'MESH:D013274', (18, 36))	('gastric carcinomas', 'Disease', (18, 36))	('SMARCA1', 'Gene', '6594', (43, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('methylation', 'Var', (72, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('aberrant methylation', 'Var', (63, 83))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('SMARCA1', 'Gene', (43, 50))
479860	31093468	In addition, SMARCA1 genomic alterations may have different effect on protein expression.	('genomic alterations', 'Var', (21, 40))	('SMARCA1', 'Gene', '6594', (13, 20))	('protein expression', 'MPA', (70, 88))	('rat', 'Species', '10116', (33, 36))	('SMARCA1', 'Gene', (13, 20))
479866	31093468	The molecular mechanisms of SMARCA1 inactivation merit further investigation in order to understand and utilize its role in diagnostic, prognostic and therapeutic purposes.	('SMARCA1', 'Gene', '6594', (28, 35))	('inactivation', 'Var', (36, 48))	('SMARCA1', 'Gene', (28, 35))
479905	25360585	Using whole transcriptome paired end RNA sequencing (RNA-seq) we unexpectedly identified BCOR-CCNB3 fusion transcripts in an undifferentiated spindle cell sarcoma.	('BCOR', 'Gene', '54880', (89, 93))	('CCNB3', 'Gene', (94, 99))	('sarcoma', 'Disease', (155, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('CCNB3', 'Gene', '85417', (94, 99))	('fusion transcripts', 'Var', (100, 118))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('BCOR', 'Gene', (89, 93))
479907	25360585	Five additional undifferentiated sarcomas with BCOR-CCNB3 fusions were identified in a series of 42 pediatric and adult unclassified sarcomas.	('sarcomas', 'Disease', (133, 141))	('BCOR', 'Gene', (47, 51))	('CCNB3', 'Gene', '85417', (52, 57))	('BCOR', 'Gene', '54880', (47, 51))	('fusions', 'Var', (58, 65))	('sarcomas', 'Disease', 'MESH:D012509', (33, 41))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (16, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('undifferentiated sarcomas', 'Disease', (16, 41))	('sarcomas', 'Disease', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('CCNB3', 'Gene', (52, 57))
479918	25360585	One such recurrent cytogenetic alteration seen in a subset of 'Ewing sarcoma-like' round cell undifferentiated sarcomas lacking the pathognomonic EWSR1-ETS fusions is the t(4;19)(q35;q13) or t(10;19)(q26.3;q13) translocations, both leading to fusion of CIC (capicua homolog) with the DUX4 (double homeobox 4) gene.	("'Ewing sarcoma", 'Phenotype', 'HP:0012254', (62, 76))	('t(10;19)(q26.3;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (191, 210))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('fusion', 'Interaction', (243, 249))	('double homeobox 4', 'Gene', '100288687', (290, 307))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (94, 119))	('CIC', 'Gene', (253, 256))	("'Ewing sarcoma", 'Disease', (62, 76))	('DUX4', 'Gene', (284, 288))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	("'Ewing sarcoma", 'Disease', 'MESH:C563168', (62, 76))	('double homeobox 4', 'Gene', (290, 307))	('EWSR1', 'Gene', (146, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('DUX4', 'Gene', '100288687', (284, 288))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (171, 187))	('CIC', 'Gene', '23152', (253, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('t(4', 'Var', (171, 174))	('undifferentiated sarcomas', 'Disease', (94, 119))	('EWSR1', 'Gene', '2130', (146, 151))
479919	25360585	Round cell sarcomas with the CIC DUX4 fusion may represent a clinically aggressive subset of undifferentiated sarcomas, and although these tumors share transcriptional subprograms with Ewing sarcoma, distinct immunophenotypic features suggest a discrete pathological entity.	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (93, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('sarcomas', 'Disease', (110, 118))	('DUX4', 'Gene', '100288687', (33, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('Ewing sarcoma', 'Disease', (185, 198))	('CIC', 'Gene', (29, 32))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('undifferentiated sarcomas', 'Disease', (93, 118))	('tumors', 'Disease', (139, 145))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('CIC', 'Gene', '23152', (29, 32))	('fusion', 'Var', (38, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcomas', 'Disease', (11, 19))	('DUX4', 'Gene', (33, 37))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (185, 198))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (185, 198))
479926	25360585	Tumors harboring the BCOR-CCNB3 fusion appear to share some clinical and morphological overlap with the Ewing family of tumors, including the frequent occurrence in long bones of adolescents and young adults, but also appear to have differences, including a strong male predilection and a potentially less aggressive clinical course.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('CCNB3', 'Gene', '85417', (26, 31))	('Tumors', 'Disease', (0, 6))	('fusion', 'Var', (32, 38))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CCNB3', 'Gene', (26, 31))	('BCOR', 'Gene', (21, 25))	('BCOR', 'Gene', '54880', (21, 25))
479929	25360585	We also report on the development of a targeted RT-PCR assay to detect the BCOR-CCNB3 fusion in clinical formalin-fixed paraffin embedded tumor specimens.	('CCNB3', 'Gene', (80, 85))	('tumor', 'Disease', (138, 143))	('formalin', 'Chemical', 'MESH:D005557', (105, 113))	('fusion', 'Var', (86, 92))	('BCOR', 'Gene', (75, 79))	('CCNB3', 'Gene', '85417', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('BCOR', 'Gene', '54880', (75, 79))	('paraffin', 'Chemical', 'MESH:D010232', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
479931	25360585	Tumors that lacked characteristic sarcoma-associated chromosomal translocations or fusion genes by cytogenetics, FISH and/or RT-PCR (translocation-negative cases) were selected for inclusion in this study.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sarcoma', 'Disease', (34, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('fusion', 'Var', (83, 89))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))
479937	25360585	Seven negative controls were also analyzed including six tumors with characteristic molecular genetic aberrations that would not be expected to harbor a BCOR-CCNB3 fusion: three cases of Ewing sarcoma with pathognomonic EWSR1 rearrangements, aberrations, one sarcoma with CIC gene rearrangement, an alveolar soft part sarcoma with ASPSCR1-TFE3 fusion, a mucoepidermoid carcinoma with MECT1-MAML2 fusion and a normal tonsil.	('TFE3', 'Gene', '7030', (339, 343))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (354, 378))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (299, 325))	('BCOR', 'Gene', '54880', (153, 157))	('CIC', 'Gene', '23152', (272, 275))	('MECT1', 'Gene', '23373', (384, 389))	('Ewing sarcoma', 'Disease', (187, 200))	('CCNB3', 'Gene', (158, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (318, 325))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('MAML2', 'Gene', '84441', (390, 395))	('EWSR1', 'Gene', (220, 225))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (299, 325))	('BCOR', 'Gene', (153, 157))	('ASPSCR1', 'Gene', '79058', (331, 338))	('sarcoma', 'Disease', 'MESH:D012509', (259, 266))	('sarcoma', 'Disease', (259, 266))	('rearrangements', 'Var', (226, 240))	('sarcoma', 'Disease', 'MESH:D012509', (193, 200))	('alveolar soft part sarcoma', 'Disease', (299, 325))	('MECT1', 'Gene', (384, 389))	('aberrations', 'Var', (242, 253))	('sarcoma', 'Disease', (193, 200))	('ASPSCR1', 'Gene', (331, 338))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('CIC', 'Gene', (272, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (187, 200))	('CCNB3', 'Gene', '85417', (158, 163))	('sarcoma', 'Disease', 'MESH:D012509', (318, 325))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (187, 200))	('EWSR1', 'Gene', '2130', (220, 225))	('mucoepidermoid carcinoma', 'Disease', (354, 378))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (308, 325))	('TFE3', 'Gene', (339, 343))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('sarcoma', 'Disease', (318, 325))	('tumors', 'Disease', (57, 63))	('MAML2', 'Gene', (390, 395))
479962	25360585	As in case T107 described above, the chimeric transcript joined the last codon of BCOR to exon 5 of CCNB3 in all cases.	('CCNB3', 'Gene', (100, 105))	('chimeric', 'Var', (37, 45))	('CCNB3', 'Gene', '85417', (100, 105))	('BCOR', 'Gene', (82, 86))	('BCOR', 'Gene', '54880', (82, 86))
479967	25360585	In total, BCOR-CCNB3 fusion transcripts were identified in 6 of 42 undifferentiated unclassified sarcomas (14.3%) examined by RNA-seq and RT-PCR.	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('BCOR', 'Gene', '54880', (10, 14))	('identified', 'Reg', (45, 55))	('CCNB3', 'Gene', (15, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('fusion', 'Var', (21, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (97, 105))	('BCOR', 'Gene', (10, 14))	('CCNB3', 'Gene', '85417', (15, 20))
479970	25360585	The original diagnosis for two tumors was spindle cell sarcoma and spindle cell neoplasm (T107 and T290, respectively); both tumors contained areas with a prominent spindle cell pattern and in the case of T107, were arranged in a vague fascicular architecture.	('spindle cell neoplasm', 'Disease', 'MESH:D002277', (67, 88))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('spindle cell pattern', 'CPA', (165, 185))	('sarcoma', 'Disease', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('tumors', 'Disease', (125, 131))	('T107', 'Var', (205, 209))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('neoplasm', 'Phenotype', 'HP:0002664', (80, 88))	('spindle cell neoplasm', 'Disease', (67, 88))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))
479975	25360585	In two cases (T150 and T290), additional pre-treatment resection specimens were available following the diagnostic biopsy, highlighting the variable cellular morphology of these tumors.	('T290', 'Var', (23, 27))	('tumors', 'Disease', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
479977	25360585	Post-treatment samples were available for evaluation in four cases, including 3 relapsed tumor specimens (T149, T150, and T236).	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('T236', 'Var', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
479995	25360585	In recent years, the emergence of next-generation genomic sequencing technologies, and in particular RNA-seq, has led to the discovery of previously unrecognized cryptic intra-chromosomal rearrangements (inversions, deletions, segmental duplications) producing novel oncogenic fusion genes in sarcomas, including the recent identification of the BCOR-CCNB3 gene fusion in 'Ewing-like' sarcomas in 2012.	('sarcomas', 'Phenotype', 'HP:0100242', (385, 393))	('CCNB3', 'Gene', (351, 356))	('sarcomas', 'Disease', 'MESH:D012509', (293, 301))	('sarcoma', 'Phenotype', 'HP:0100242', (385, 392))	('sarcomas', 'Disease', (385, 393))	('sarcomas', 'Phenotype', 'HP:0100242', (293, 301))	('sarcoma', 'Phenotype', 'HP:0100242', (293, 300))	('BCOR', 'Gene', (346, 350))	('sarcomas', 'Disease', (293, 301))	("'Ewing-like' sarcomas", 'Disease', (372, 393))	('CCNB3', 'Gene', '85417', (351, 356))	("'Ewing-like' sarcomas", 'Phenotype', 'HP:0012254', (372, 393))	('fusion', 'Var', (362, 368))	("'Ewing-like' sarcomas", 'Disease', 'MESH:C563168', (372, 393))	('sarcomas', 'Disease', 'MESH:D012509', (385, 393))	('BCOR', 'Gene', '54880', (346, 350))
479996	25360585	Since this original description by Pierron et al., a second series of 10 sarcomas with the BCOR-CCNB3 fusion in translocation-negative sarcomas has recently been reported.	('BCOR', 'Gene', '54880', (91, 95))	('CCNB3', 'Gene', (96, 101))	('fusion', 'Var', (102, 108))	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('sarcomas', 'Disease', 'MESH:D012509', (135, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('sarcomas', 'Disease', (73, 81))	('BCOR', 'Gene', (91, 95))	('CCNB3', 'Gene', '85417', (96, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('sarcomas', 'Disease', (135, 143))
479997	25360585	In the present study, we initially used RNA-seq to identify a BCOR-CCNB3 fusion gene in an unclassified spindle cell sarcoma.	('fusion gene', 'Var', (73, 84))	('sarcoma', 'Disease', (117, 124))	('BCOR', 'Gene', '54880', (62, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('CCNB3', 'Gene', (67, 72))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('BCOR', 'Gene', (62, 66))	('CCNB3', 'Gene', '85417', (67, 72))
479998	25360585	This prompted us to screen for additional cases of the BCOR-CCNB3 fusion in translocation-negative undifferentiated unclassified sarcomas arising in either bone or soft tissue to further characterize the pathology and clinical course of sarcomas harboring this newly discovered fusion gene.	('sarcomas', 'Disease', 'MESH:D012509', (237, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('BCOR', 'Gene', (55, 59))	('CCNB3', 'Gene', '85417', (60, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (237, 245))	('BCOR', 'Gene', '54880', (55, 59))	('fusion', 'Var', (66, 72))	('sarcomas', 'Disease', (237, 245))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('CCNB3', 'Gene', (60, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcomas', 'Disease', (129, 137))
480002	25360585	The morphologic features of these 5 cases varied from predominantly spindle cell morphology (T107, T290) to cases with ovoid and angulated cells interspersed with areas of spindle cell morphology, a pattern unusual for either classic Ewing sarcoma or the emerging entity of CIC-DUX4-positive sarcomas, both of which are characterized by more uniform small round cell morphology.	('T290', 'Var', (99, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (292, 300))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('CIC', 'Gene', '23152', (274, 277))	('DUX4', 'Gene', (278, 282))	('classic Ewing sarcoma', 'Disease', (226, 247))	('classic Ewing sarcoma', 'Disease', 'MESH:C563168', (226, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('T107', 'Var', (93, 97))	('sarcomas', 'Disease', (292, 300))	('DUX4', 'Gene', '100288687', (278, 282))	('CIC', 'Gene', (274, 277))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (234, 247))	('sarcomas', 'Disease', 'MESH:D012509', (292, 300))	('spindle cell morphology', 'CPA', (68, 91))
480014	25360585	Significantly, however, anRT-PCR assay for detecting the BCOR-CCNB3 fusion in formalin-fixed paraffin-embedded as well as in frozen tumor tissue was able to reproducibly and robustly detect the fusion transcript in all cases (including the formalin-fixed paraffin-embedded block from T149), including recurrent and metastatic tumor samples, even in those with ambiguous or negative CCNB3 immunostaining.	('paraffin', 'Chemical', 'MESH:D010232', (93, 101))	('tumor', 'Disease', (132, 137))	('formalin', 'Chemical', 'MESH:D005557', (240, 248))	('BCOR', 'Gene', '54880', (57, 61))	('CCNB3', 'Gene', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('fusion', 'Var', (68, 74))	('BCOR', 'Gene', (57, 61))	('CCNB3', 'Gene', '85417', (382, 387))	('tumor', 'Disease', (326, 331))	('paraffin', 'Chemical', 'MESH:D010232', (255, 263))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('formalin', 'Chemical', 'MESH:D005557', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('CCNB3', 'Gene', (382, 387))	('detect', 'Reg', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('CCNB3', 'Gene', '85417', (62, 67))	('metastatic', 'CPA', (315, 325))
480021	25360585	A high predominance of X chromosome inversions arising in the male germline and resulting in hemophilia A has been hypothesized to be related to the inability of the single X chromosome in males to use the homologous X chromosome as a template for recombination-mediated repair during meiosis.	('hemophilia A', 'Disease', (93, 105))	('resulting in', 'Reg', (80, 92))	('X chromosome inversions', 'Var', (23, 46))	('hemophilia A', 'Disease', 'MESH:D006467', (93, 105))
480029	25360585	The pathogenic role of BCOR-CCNB3 fusions in sarcomas remains to be determined.	('sarcomas', 'Disease', 'MESH:D012509', (45, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcomas', 'Disease', (45, 53))	('CCNB3', 'Gene', '85417', (28, 33))	('BCOR', 'Gene', (23, 27))	('CCNB3', 'Gene', (28, 33))	('BCOR', 'Gene', '54880', (23, 27))	('fusions', 'Var', (34, 41))
480030	25360585	Whereas CCNB3 is thought to be a meiotic cyclin restricted to spermatocytes, the BCOR gene, originally discovered to encode a nuclear corepressor of BCL6, regulates mesenchymal stem cell function through epigenetic modification of histone methylation.	('histone', 'Protein', (231, 238))	('epigenetic modification', 'Var', (204, 227))	('BCL6', 'Gene', (149, 153))	('CCNB3', 'Gene', (8, 13))	('cyclin', 'Gene', '5111', (41, 47))	('cyclin', 'Gene', (41, 47))	('regulates', 'Reg', (155, 164))	('mesenchymal stem cell function', 'CPA', (165, 195))	('BCOR', 'Gene', '54880', (81, 85))	('BCOR', 'Gene', (81, 85))	('CCNB3', 'Gene', '85417', (8, 13))	('BCL6', 'Gene', '604', (149, 153))
480061	25207808	Recent studies indicate that a low Hb level is an unfavorable prognostic factor in diverse cancer types, including non-small cell lung cancer (NSCLC), ovarian carcinoma and pancreatic cancer.	('cancer', 'Disease', (184, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('non-small cell lung cancer', 'Disease', (115, 141))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Hb level', 'MPA', (35, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (173, 190))	('cancer', 'Disease', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('NSCLC', 'Disease', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (115, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (151, 168))	('pancreatic cancer', 'Disease', (173, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('low Hb level', 'Phenotype', 'HP:0020062', (31, 43))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('ovarian carcinoma', 'Disease', (151, 168))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (119, 141))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (151, 168))	('low', 'Var', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (115, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (173, 190))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
480076	25207808	For anemia, the pre-published and most commonly used cut-off value of Hb level <13 g/dl in males and Hb level <12 g/dl in females was applied.	('<13 g/dl', 'Var', (79, 87))	('anemia', 'Disease', 'MESH:D000740', (4, 10))	('anemia', 'Disease', (4, 10))	('anemia', 'Phenotype', 'HP:0001903', (4, 10))
480096	25207808	Univariate analysis identified a high tumor grade (G1+G2 versus G3, p = 0.002) and a low Hb level (<13 g/dl in males and <12 g/dl in females versus >=13 g/dl in males and >=12 g/dl in females, p<0.001) as poor prognostic factors for CSS in our study cohort (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('low Hb level', 'Phenotype', 'HP:0020062', (85, 97))	('low', 'NegReg', (85, 88))	('high tumor', 'Disease', (33, 43))	('Hb level', 'MPA', (89, 97))	('G1+G2', 'Var', (51, 56))	('CSS', 'Disease', (233, 236))	('high tumor', 'Disease', 'MESH:D009369', (33, 43))	('CSS', 'Chemical', '-', (233, 236))
480105	25207808	Another study, that included 206 patients with ovarian carcinoma, showed a decreased OS in patients with low Hb levels.	('low Hb levels', 'Phenotype', 'HP:0020062', (105, 118))	('patients', 'Species', '9606', (91, 99))	('low', 'Var', (105, 108))	('patients', 'Species', '9606', (33, 41))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (47, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('Hb levels', 'MPA', (109, 118))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (47, 64))	('ovarian carcinoma', 'Disease', (47, 64))	('low Hb level', 'Phenotype', 'HP:0020062', (105, 117))	('OS', 'Chemical', '-', (85, 87))	('decreased', 'NegReg', (75, 84))
480113	25207808	They also analyzed the relationship between anaemia, survival, and event separately for patients with malignant fibrous histiocytomas (MFHs) and liposarcomas and found that a low Hb level was a significant adverse prognostic factor for EFS in MFHs and liposarcomas.	('malignant fibrous histiocytomas', 'Disease', (102, 133))	('liposarcomas', 'Disease', (145, 157))	('anaemia', 'Phenotype', 'HP:0001903', (44, 51))	('Hb level', 'MPA', (179, 187))	('liposarcomas', 'Disease', 'MESH:D008080', (252, 264))	('liposarcoma', 'Phenotype', 'HP:0012034', (252, 263))	('low Hb level', 'Phenotype', 'HP:0020062', (175, 187))	('liposarcomas', 'Phenotype', 'HP:0012034', (252, 264))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('MFHs', 'Disease', (243, 247))	('liposarcomas', 'Disease', 'MESH:D008080', (145, 157))	('malignant fibrous histiocytomas', 'Disease', 'MESH:D051677', (102, 133))	('liposarcoma', 'Phenotype', 'HP:0012034', (145, 156))	('liposarcomas', 'Disease', (252, 264))	('low', 'Var', (175, 178))	('liposarcomas', 'Phenotype', 'HP:0012034', (145, 157))	('EFS', 'Disease', (236, 239))	('anaemia', 'Disease', 'MESH:D000740', (44, 51))	('anaemia', 'Disease', (44, 51))	('patients', 'Species', '9606', (88, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('sarcomas', 'Phenotype', 'HP:0100242', (256, 264))
480142	24388362	Exposure to PU-H71 resulted in depletion of critical proteins including AKT, pERK, RAF-1, c-MYC, c-KIT, IGF1R, hTERT and EWS-FLI1 in Ewing cell lines.	('pERK', 'Gene', (77, 81))	('depletion', 'MPA', (31, 40))	('hTERT', 'Gene', '7015', (111, 116))	('c-KIT', 'Protein', (97, 102))	('hTERT', 'Gene', (111, 116))	('PU-H71', 'Chemical', 'MESH:C526550', (12, 18))	('PU-H71', 'Var', (12, 18))	('pERK', 'Gene', '13666', (77, 81))	('RAF-1, c-MYC', 'Gene', '110157', (83, 95))	('AKT', 'Pathway', (72, 75))	('IGF1R', 'Gene', (104, 109))
480143	24388362	Our results indicated that Ewing sarcoma tumor growth and the metastatic burden were significantly reduced in the mice injected with PU-H71 compared to the control mice.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mice', 'Species', '10090', (164, 168))	('Ewing sarcoma tumor', 'Disease', (27, 46))	('Ewing sarcoma tumor', 'Disease', 'MESH:C563168', (27, 46))	('mice', 'Species', '10090', (114, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('reduced', 'NegReg', (99, 106))	('PU-H71', 'Chemical', 'MESH:C526550', (133, 139))	('metastatic burden', 'CPA', (62, 79))	('PU-H71', 'Var', (133, 139))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (27, 40))
480147	24388362	This provides a strong rationale for clinical evaluation of PU-H71 alone and in combination with bortezomib in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('Ewing sarcoma', 'Disease', (111, 124))	('PU-H71', 'Chemical', 'MESH:C526550', (60, 66))	('bortezomib', 'Chemical', 'MESH:D000069286', (97, 107))	('PU-H71', 'Var', (60, 66))
480153	24388362	Monoclonal antibodies to IGF1R have shown promise in a small group of patients with Ewing sarcoma.	('Ewing sarcoma', 'Disease', (84, 97))	('patients', 'Species', '9606', (70, 78))	('Monoclonal', 'Var', (0, 10))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('IGF1R', 'Gene', (25, 30))
480156	24388362	Malignant cells are exposed to external stressors such as hypoxia, nutrient deprivation and chemotherapeutic agents and internal stresses such as the accumulation of mutated and incorrectly folded proteins, making them dependent on HSPs for survival.	('proteins', 'Protein', (197, 205))	('hypoxia', 'Disease', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('mutated', 'Var', (166, 173))
480157	24388362	HSP90 also protects less stable proteins produced by DNA mutations such as mutated p53 and fusion proteins like BCR-ABL.	('p53', 'Gene', (83, 86))	('BCR-ABL', 'Gene', (112, 119))	('BCR-ABL', 'Gene', '25', (112, 119))	('mutated', 'Var', (75, 82))	('p53', 'Gene', '22060', (83, 86))
480161	24388362	PU-H71 was shown to be effective in triple-negative breast cancer models and Bcl6 dependent B-cell lymphomas.	('lymphomas', 'Phenotype', 'HP:0002665', (99, 108))	('PU-H71', 'Chemical', 'MESH:C526550', (0, 6))	('lymphomas', 'Disease', 'MESH:D008223', (99, 108))	('PU-H71', 'Var', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (92, 108))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (99, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('cell lymphoma', 'Phenotype', 'HP:0012191', (94, 107))	('Bcl6', 'Gene', (77, 81))	('lymphomas', 'Disease', (99, 108))	('Bcl6', 'Gene', '12053', (77, 81))
480194	24388362	Cell lysates from A673 and SK-PN-DW were prepared in the Moore lab at MSKCC and shipped to the RPPA core facility at MD Anderson Cancer Center, Houston, TX, where RPPA was performed as described in their earlier work.	('SK-PN-DW', 'Chemical', '-', (27, 35))	('Cancer', 'Disease', (129, 135))	('A673', 'Var', (18, 22))	('Cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Cancer', 'Disease', 'MESH:D009369', (129, 135))
480205	24388362	We established a mouse model in NSG mice to study tumor initiation in aminimal residual disease setting by doing limiting dilution of A673 cells transduced with GFP Luciferase.	('mouse', 'Species', '10090', (17, 22))	('GFP', 'Var', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mice', 'Species', '10090', (36, 40))	('aminimal residual disease', 'Disease', (70, 95))	('tumor', 'Disease', (50, 55))
480212	24388362	Mice were randomized to 3 groups, control group (n = 3, treated with vehicle from day 1), early treatment group (n = 3, treated with PU-H71 from day 1) and late treatment group (n = 3, treated with PU-H71 from day 7 when they showed tumor on imaging).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (233, 238))	('PU-H71', 'Chemical', 'MESH:C526550', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('Mice', 'Species', '10090', (0, 4))	('PU-H71', 'Chemical', 'MESH:C526550', (133, 139))	('PU-H71', 'Var', (133, 139))
480234	24388362	PU-H71 also demonstrated significant growth inhibition in early cultures derived from patient samples (Figure 1A).	('patient', 'Species', '9606', (86, 93))	('PU-H71', 'Chemical', 'MESH:C526550', (0, 6))	('PU-H71', 'Var', (0, 6))	('growth inhibition', 'CPA', (37, 54))
480245	24388362	We looked at the expression of proteins involved in key signaling pathways in Ewing sarcoma and noted that with increasing concentration of PU-H71, there was a decrease in expression of AKT, MYC, pERK, RAF-1, IGF1R, PDGFRA and c-KIT (Figure 3B).	('PDGFRA', 'Gene', '18595', (216, 222))	('PU-H71', 'Var', (140, 146))	('AKT', 'Pathway', (186, 189))	('decrease', 'NegReg', (160, 168))	('pERK', 'Gene', (196, 200))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('PDGFRA', 'Gene', (216, 222))	('c-KIT', 'Gene', (227, 232))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('IGF1R', 'Gene', (209, 214))	('expression', 'MPA', (172, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('RAF-1', 'Gene', (202, 207))	('pERK', 'Gene', '13666', (196, 200))	('PU-H71', 'Chemical', 'MESH:C526550', (140, 146))	('MYC', 'Protein', (191, 194))	('Ewing sarcoma', 'Disease', (78, 91))
480250	24388362	RPPA analysis showed that pSRC, pPDK1, GSK3, B-RAF, C-RAF, c-KIT, AKT and pAKT are decreased after treatment with 1 microM PU-H71 in both A673 and SK-PN-DW cell lines (Supplementary Figure 1).	('PU-H71', 'Var', (123, 129))	('SK-PN-DW', 'Chemical', '-', (147, 155))	('GSK3', 'Gene', '56637', (39, 43))	('C-RAF', 'Gene', '5894', (52, 57))	('c-KIT', 'CPA', (59, 64))	('decreased', 'NegReg', (83, 92))	('pAKT', 'CPA', (74, 78))	('AKT', 'CPA', (66, 69))	('GSK3', 'Gene', (39, 43))	('B-RAF', 'Gene', '673', (45, 50))	('SRC', 'Gene', '6714', (27, 30))	('SRC', 'Gene', (27, 30))	('PDK1', 'Gene', '228026', (33, 37))	('C-RAF', 'Gene', (52, 57))	('B-RAF', 'Gene', (45, 50))	('PU-H71', 'Chemical', 'MESH:C526550', (123, 129))	('PDK1', 'Gene', (33, 37))
480269	24388362	We also noted a greater expression of PARP p85 and cleaved caspase 7 in A673, CHP100, TC71 and SK-PN-DW when both drugs were used in combination compared to either drugs alone or vehicle (Figure 6C).	('p85', 'Gene', (43, 46))	('TC71', 'CellLine', 'CVCL:2213', (86, 90))	('expression', 'MPA', (24, 34))	('A673', 'Var', (72, 76))	('p85', 'Gene', '21981', (43, 46))	('caspase', 'Protein', (59, 66))	('greater', 'PosReg', (16, 23))	('SK-PN-DW', 'Chemical', '-', (95, 103))	('cleaved', 'MPA', (51, 58))
480272	24388362	PU-H71 treated cells had a small increase in the ubiquitinated proteins.	('PU-H71', 'Chemical', 'MESH:C526550', (0, 6))	('ubiquitinated proteins', 'MPA', (49, 71))	('PU-H71', 'Var', (0, 6))
480273	24388362	However, the combination of PU-H71 and bortezomib led to marked accumulation of ubiquitinated proteins (Figure 6).	('bortezomib', 'Gene', (39, 49))	('ubiquitinated proteins', 'MPA', (80, 102))	('PU-H71', 'Var', (28, 34))	('bortezomib', 'Chemical', 'MESH:D000069286', (39, 49))	('combination', 'Interaction', (13, 24))	('PU-H71', 'Chemical', 'MESH:C526550', (28, 34))	('accumulation', 'PosReg', (64, 76))
480274	24388362	We performed proteasome activity assay in A673 cells using either PU-H71 (250 nM), BTZ (5 nM) or in combination.	('PU-H71', 'Chemical', 'MESH:C526550', (66, 72))	('PU-H71 (250 nM', 'Var', (66, 80))	('BTZ', 'Chemical', '-', (83, 86))	('proteasome', 'MPA', (13, 23))
480276	24388362	When cells were treated with PU-H71 for 24 h, we noted an increase in the proteasome activity.	('proteasome activity', 'MPA', (74, 93))	('increase', 'PosReg', (58, 66))	('PU-H71', 'Chemical', 'MESH:C526550', (29, 35))	('PU-H71', 'Var', (29, 35))
480285	24388362	PU-H71 was noted to have IC50s around 2-8 fold lower than 17-AAG in triple negative breast cancer cell lines.	('50s', 'Species', '1214577', (27, 30))	('lower', 'NegReg', (47, 52))	('PU-H71', 'Chemical', 'MESH:C526550', (0, 6))	('17-AAG', 'Chemical', 'MESH:C112765', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('PU-H71', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('IC50s', 'MPA', (25, 30))	('breast cancer', 'Disease', (84, 97))
480290	24388362	PU-H71 inhibited proliferation of Ewing sarcoma cells lines and patient tumor samples and induced apoptosis via activation of caspase 3/7.	('proliferation', 'CPA', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PU-H71', 'Chemical', 'MESH:C526550', (0, 6))	('patient', 'Species', '9606', (64, 71))	('apoptosis', 'CPA', (98, 107))	('PU-H71', 'Var', (0, 6))	('caspase 3/7', 'Pathway', (126, 137))	('activation', 'PosReg', (112, 122))	('tumor', 'Disease', (72, 77))	('Ewing sarcoma cells lines', 'Disease', (34, 59))	('inhibited', 'NegReg', (7, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (34, 47))	('Ewing sarcoma cells lines', 'Disease', 'MESH:C563168', (34, 59))	('induced', 'Reg', (90, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
480298	24388362	In our work, we have seen a decrease in the expression of pERK, RAF-1 and AKT in Ewing cell lines exposed to PU-H71 (Figure 3B).	('expression', 'MPA', (44, 54))	('pERK', 'Gene', '13666', (58, 62))	('AKT', 'Pathway', (74, 77))	('RAF-1', 'Gene', (64, 69))	('pERK', 'Gene', (58, 62))	('decrease', 'NegReg', (28, 36))	('PU-H71', 'Chemical', 'MESH:C526550', (109, 115))	('PU-H71', 'Var', (109, 115))
480299	24388362	The IGF1R mediated pathway was shown to play a prominent role in Ewing sarcoma cell lines and blockade of the IGF1R pathway led to growth inhibition, decreased colony formation in soft agar and decreased migratory ability in vitro.	('growth inhibition', 'CPA', (131, 148))	('Ewing sarcoma cell lines', 'Disease', (65, 89))	('Ewing sarcoma cell lines', 'Disease', 'MESH:C563168', (65, 89))	('migratory ability in vitro', 'CPA', (204, 230))	('colony formation in soft agar', 'CPA', (160, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('decreased', 'NegReg', (194, 203))	('blockade', 'Var', (94, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))	('decreased', 'NegReg', (150, 159))	('IGF1R', 'Gene', (110, 115))
480303	24388362	In our study we have shown that Ewing cell lines treated with PU-H71 had decreased expression of IGF1R, suggesting a potential additive or synergistic effect when combined with IGF1R inhibitors.	('decreased', 'NegReg', (73, 82))	('PU-H71', 'Var', (62, 68))	('expression', 'MPA', (83, 93))	('IGF1R', 'Gene', (97, 102))	('PU-H71', 'Chemical', 'MESH:C526550', (62, 68))
480305	24388362	In our immunoblot analysis, both c-MYC and EWS-FLI1 were decreased when A673 and SK-PN-DW were treated with PU-H71 (Figure 3B).	('c-MYC', 'MPA', (33, 38))	('PU-H71', 'Chemical', 'MESH:C526550', (108, 114))	('A673', 'Var', (72, 76))	('EWS-FLI1', 'Gene', (43, 51))	('decreased', 'NegReg', (57, 66))	('SK-PN-DW', 'Chemical', '-', (81, 89))
480306	24388362	We have seen a decrease in metastatic burden in our mouse model when tumor-bearing mice were treated with PU-H71.	('metastatic burden', 'CPA', (27, 44))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('decrease', 'NegReg', (15, 23))	('PU-H71', 'Var', (106, 112))	('tumor', 'Disease', (69, 74))	('mouse', 'Species', '10090', (52, 57))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PU-H71', 'Chemical', 'MESH:C526550', (106, 112))
480309	24388362	Interestingly, we have seen a decrease in c-KIT expression in A673 and SK-PN-DW cell lines treated with PU-H71.	('c-KIT', 'Protein', (42, 47))	('PU-H71', 'Chemical', 'MESH:C526550', (104, 110))	('decrease', 'NegReg', (30, 38))	('PU-H71', 'Var', (104, 110))	('SK-PN-DW', 'Chemical', '-', (71, 79))
480310	24388362	RPPA analysis showed that phosphosinositide dependent kinase 1 (PDK1) and glycogen synthase kinase 3 (GSK3) are decreased after treatment with PU-H71 in A673 and SK-PN-DW, and both these proteins are downstream in the insulin receptor signaling pathway.	('GSK3', 'Gene', '56637', (102, 106))	('PDK1', 'Gene', (64, 68))	('PU-H71', 'Var', (143, 149))	('glycogen synthase kinase 3', 'Gene', '56637', (74, 100))	('phosphosinositide dependent kinase 1', 'MPA', (26, 62))	('insulin receptor', 'Gene', '16337', (218, 234))	('A673', 'Var', (153, 157))	('SK-PN-DW', 'Chemical', '-', (162, 170))	('GSK3', 'Gene', (102, 106))	('glycogen synthase kinase 3', 'Gene', (74, 100))	('insulin receptor', 'Gene', (218, 234))	('decreased', 'NegReg', (112, 121))	('PU-H71', 'Chemical', 'MESH:C526550', (143, 149))	('PDK1', 'Gene', '228026', (64, 68))
480311	24388362	Immunohistochemistry revealed that CD31, a marker for angiogenesis, was decreased in mice treated with PU-H71 compared to the vehicle treated mice suggesting an additional mechanism for tumor inhibition.	('mice', 'Species', '10090', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('CD31', 'Gene', (35, 39))	('PU-H71', 'Chemical', 'MESH:C526550', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('decreased', 'NegReg', (72, 81))	('PU-H71', 'Var', (103, 109))	('tumor', 'Disease', (186, 191))	('mice', 'Species', '10090', (142, 146))	('CD31', 'Gene', '18613', (35, 39))
480315	24388362	Immunoblot analysis of ubiquitinated proteins in A673 and SK-PN-DW cells treated with PBS, PU-H71, bortezomib and combination of PU-H71 and bortezomib (Figure 6D) reveals a potential mechanism underlying the synergism.	('PU-H71', 'Var', (129, 135))	('PBS', 'Disease', (86, 89))	('bortezomib', 'Chemical', 'MESH:D000069286', (140, 150))	('bortezomib', 'Chemical', 'MESH:D000069286', (99, 109))	('SK-PN-DW', 'Chemical', '-', (58, 66))	('ubiquitinated proteins', 'MPA', (23, 45))	('PU-H71', 'Chemical', 'MESH:C526550', (91, 97))	('PU-H71', 'Chemical', 'MESH:C526550', (129, 135))	('PBS', 'Disease', 'MESH:D011535', (86, 89))	('PU-H71', 'Var', (91, 97))
480318	24388362	The combination of PU-H71 and bortezomib further increases the amount of ubiquitinated proteins leading to proteotoxic stress to the tumor cell.	('bortezomib', 'Chemical', 'MESH:D000069286', (30, 40))	('PU-H71', 'Var', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('increases', 'PosReg', (49, 58))	('PU-H71', 'Chemical', 'MESH:C526550', (19, 25))	('tumor', 'Disease', (133, 138))	('proteotoxic stress', 'MPA', (107, 125))	('amount of ubiquitinated proteins', 'MPA', (63, 95))
480320	24388362	Similar to 17-AAG in multiple myeloma model, we noted a significant reduction in proteasome activity when PU-H71 was combined with bortezomib compared to bortezomib alone at 24 h drug exposure in A673 cells (Figure 6E).	('bortezomib', 'Chemical', 'MESH:D000069286', (154, 164))	('17-AAG', 'Chemical', 'MESH:C112765', (11, 17))	('PU-H71', 'Var', (106, 112))	('combined', 'Interaction', (117, 125))	('myeloma', 'Disease', (30, 37))	('myeloma', 'Disease', 'MESH:D009101', (30, 37))	('bortezomib', 'Chemical', 'MESH:D000069286', (131, 141))	('reduction', 'NegReg', (68, 77))	('proteasome activity', 'MPA', (81, 100))	('PU-H71', 'Chemical', 'MESH:C526550', (106, 112))	('multiple myeloma', 'Phenotype', 'HP:0006775', (21, 37))
480330	23401795	Microsatellite Instability in Sarcoma: Fact or Fiction?	('Microsatellite Instability', 'Var', (0, 26))	('Sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('Sarcoma', 'Disease', (30, 37))	('Sarcoma', 'Disease', 'MESH:D012509', (30, 37))
480335	23401795	Emerging evidence in Ewing sarcoma has demonstrated an intriguing mechanistic role of microsatellite DNA in the activation of key EWS/FLI-target genes.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('EWS', 'Gene', (130, 133))	('activation', 'PosReg', (112, 122))	('FLI', 'Gene', '2314', (134, 137))	('FLI', 'Gene', (134, 137))	('Ewing sarcoma', 'Disease', (21, 34))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('EWS', 'Gene', '2130', (130, 133))	('microsatellite DNA', 'Var', (86, 104))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))
480336	23401795	These findings provide an alternative perspective to the biological implications of microsatellite instability in sarcoma and warrant further investigation using sophisticated detection techniques, sensitive microsatellite loci, and appropriately powered study designs.	('sarcoma', 'Disease', (114, 121))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('microsatellite instability', 'Var', (84, 110))
480340	23401795	The repetitive nature of microsatellite DNA renders it more susceptible to mutagenesis during DNA replication and furthermore, the lack of evolutionary pressure on these noncoding regions has licensed an impressive rate of microsatellite polymorphisms in the human population overtime.	('microsatellite', 'Var', (25, 39))	('microsatellite', 'Var', (223, 237))	('susceptible', 'Reg', (60, 71))	('human', 'Species', '9606', (259, 264))	('more', 'PosReg', (55, 59))
480343	23401795	For example, MSI involving a trinucleotide repeat will increase or decrease in size by a multiple three base pairs and so forth.	('increase', 'PosReg', (55, 63))	('decrease', 'NegReg', (67, 75))	('trinucleotide repeat', 'Var', (29, 49))	('trinucleotide', 'Chemical', '-', (29, 42))	('size', 'MPA', (79, 83))
480344	23401795	Microsatellite instability was discovered and characterized nearly 20 years ago in patient-derived colorectal tumors.	('colorectal tumors', 'Disease', (99, 116))	('Microsatellite', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('patient', 'Species', '9606', (83, 90))	('colorectal tumors', 'Disease', 'MESH:D015179', (99, 116))
480348	23401795	Affected patients harbor germline mutations in the MMR genes, most commonly MSH2 and MLH1, predisposing to the development of colorectal, ovarian, and endometrial tumors at a young age.	('patients', 'Species', '9606', (9, 17))	('MMR', 'Gene', (51, 54))	('ovarian', 'Disease', (138, 145))	('MLH1', 'Gene', '4292', (85, 89))	('endometrial tumors', 'Disease', 'MESH:D016889', (151, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('MLH1', 'Gene', (85, 89))	('colorectal', 'Disease', (126, 136))	('predisposing to', 'Reg', (91, 106))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('germline mutations', 'Var', (25, 43))	('MSH2', 'Gene', (76, 80))	('MSH2', 'Gene', '4436', (76, 80))	('endometrial tumors', 'Disease', (151, 169))
480349	23401795	When germline mutations are present in the MMR genes, the cumulative risk of developing colorectal cancer is 60-70% and 40-80% for endometrial cancer in females.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('colorectal cancer', 'Disease', (88, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('endometrial cancer', 'Disease', (131, 149))	('germline mutations', 'Var', (5, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('MMR', 'Gene', (43, 46))	('endometrial cancer', 'Phenotype', 'HP:0012114', (131, 149))	('endometrial cancer', 'Disease', 'MESH:D016889', (131, 149))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
480351	23401795	MSI is less common in sporadic colorectal cancers, observed in only 10-15% of tumors and is attributed to either germline mutations or epigenetic silencing of the MMR genes.	('tumors', 'Disease', (78, 84))	('MMR', 'Gene', (163, 166))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('colorectal cancers', 'Disease', 'MESH:D015179', (31, 49))	('germline mutations', 'Var', (113, 131))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MSI', 'Disease', (0, 3))	('epigenetic silencing', 'Var', (135, 155))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('colorectal cancers', 'Disease', (31, 49))
480355	23401795	MSI-positive tumors are then further subclassified into MSI-low (MSI-L) and MSI-high (MSI-H) phenotypes; MSI-H tumors demonstrate MSI at 2 or more microsatellite loci, and most importantly, this subset of MSI-positive tumors posses the favorable biological attributes ascribed to MSI-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('MSI-positive tumors', 'Disease', 'MESH:D009369', (0, 19))	('MSI-H', 'Disease', 'MESH:D000848', (105, 110))	('MSI-H tumors', 'Disease', 'MESH:D009369', (105, 117))	('MSI-H', 'Disease', (86, 91))	('MSI-positive tumors', 'Disease', 'MESH:D009369', (205, 224))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('MSI-positive tumors', 'Disease', (280, 299))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('MSI-H tumors', 'Disease', (105, 117))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('MSI-H', 'Disease', 'MESH:D000848', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('MSI-positive tumors', 'Disease', 'MESH:D009369', (280, 299))	('MSI-positive tumors', 'Disease', (0, 19))	('MSI-positive tumors', 'Disease', (205, 224))	('MSI-H', 'Disease', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('MSI', 'Var', (130, 133))
480358	23401795	MSI is now revered as a distinctive phenotype in cancer cells harboring mutations or epigenetic silencing of the DNA mismatch repair genes and consequently, a valuable predictor of cancer susceptibility and a clinically relevant marker of tumor biology.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('MSI', 'Disease', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Disease', (239, 244))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (49, 55))	('epigenetic silencing', 'Var', (85, 105))
480362	23401795	Secondly, although microsatellite DNA is primary in noncoding regions of the genome, clusters of microsatellite DNA are found in coding and flanking regions of genes identified in sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('microsatellite DNA', 'Var', (97, 115))	('sarcoma', 'Disease', (180, 187))	('sarcoma', 'Disease', 'MESH:D012509', (180, 187))
480365	23401795	EWS/FLI-mediated silencing of TGFbetaIIR gene expression has been implicated in the process of oncogenic transformation in Ewing sarcoma cells.	('TGFbetaIIR', 'Gene', (30, 40))	('FLI', 'Gene', '2314', (4, 7))	('Ewing sarcoma', 'Disease', (123, 136))	('EWS', 'Gene', '2130', (0, 3))	('FLI', 'Gene', (4, 7))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (123, 136))	('silencing', 'Var', (17, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('implicated', 'Reg', (66, 76))	('EWS', 'Gene', (0, 3))
480367	23401795	BAX is downstream target of p53-mediated apoptosis and dysregulated p53 signalling plays a pivotal role in the oncogenic transformation of various sarcoma types.	('p53', 'Gene', (28, 31))	('dysregulated', 'Var', (55, 67))	('p53', 'Gene', '7157', (28, 31))	('BAX', 'Gene', (0, 3))	('BAX', 'Gene', '581', (0, 3))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('sarcoma', 'Disease', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
480368	23401795	Interestingly, members of the MMR genes, MSH6 and MSH3, also harbor coding microsatellites, which are commonly mutated in MSI-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('MSI-positive tumors', 'Disease', 'MESH:D009369', (122, 141))	('MSH3', 'Gene', '4437', (50, 54))	('harbor', 'Reg', (61, 67))	('MSH6', 'Gene', '2956', (41, 45))	('MSI-positive tumors', 'Disease', (122, 141))	('MMR', 'Gene', (30, 33))	('microsatellites', 'Var', (75, 90))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('MSH6', 'Gene', (41, 45))	('MSH3', 'Gene', (50, 54))
480370	23401795	Finally, recent investigations in Ewing sarcoma have demonstrated a mechanistic role of microsatellite DNA in EWS/FLI-mediated gene activation, which hypothetically renders these key target genes extremely biologically sensitive to repeat expansion or contraction.	('EWS', 'Gene', '2130', (110, 113))	('EWS', 'Gene', (110, 113))	('activation', 'PosReg', (132, 142))	('Ewing sarcoma', 'Disease', (34, 47))	('microsatellite DNA', 'Var', (88, 106))	('FLI', 'Gene', '2314', (114, 117))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (34, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('FLI', 'Gene', (114, 117))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (34, 47))
480376	23401795	Many studies assessing these sarcoma-specific microsatellite loci were often simultaneously assessing MSI and loss of heterozygosity (LOH) as a collective phenotype of allelic imbalance.	('imbalance', 'Phenotype', 'HP:0002172', (176, 185))	('loss of', 'Var', (110, 117))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('sarcoma', 'Disease', (29, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('MSI', 'MPA', (102, 105))
480377	23401795	Not surprisingly, these studies do not provide conclusive evidence for or against the presence of microsatellite instability in sarcoma.	('sarcoma', 'Disease', (128, 135))	('sarcoma', 'Disease', 'MESH:D012509', (128, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('microsatellite instability', 'Var', (98, 124))
480378	23401795	Two independent studies came to similar conclusions that the absence of MSI in clear cell sarcoma can be used as a useful adjunct (in addition to detection of the t(12 : 22) translocation) when differentiating clear cell sarcoma from malignant melanoma of soft parts.	('MSI', 'Gene', (72, 75))	('malignant melanoma', 'Phenotype', 'HP:0002861', (234, 252))	('sarcoma', 'Disease', (90, 97))	('sarcoma', 'Disease', 'MESH:D012509', (221, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('absence', 'Var', (61, 68))	('malignant melanoma of soft parts', 'Disease', (234, 266))	('sarcoma', 'Disease', (221, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('malignant melanoma of soft parts', 'Disease', 'MESH:D008545', (234, 266))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
480386	23401795	Based on the plethora of literature detailing this topic in colorectal cancer, the ideal microsatellite panel should consist of the following: microsatellite harboring mono- and di-nucleotide repeats, a panel of >=5 informative loci, microsatellite loci sensitive to mismatch repair deficiency and avoidance of microsatellite loci in regions highly susceptible to copy number deletion (loss of heterozygosity).	('plethora', 'Phenotype', 'HP:0001050', (13, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('mono- and di-nucleotide', 'Chemical', '-', (168, 191))	('copy number deletion', 'Var', (364, 384))	('deficiency', 'Disease', (283, 293))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('deficiency', 'Disease', 'MESH:D007153', (283, 293))	('colorectal cancer', 'Disease', (60, 77))
480387	23401795	Microsatellite analysis is routinely employed in sarcoma research, assessing tumors for global genomic instability, LOH, copy number alterations and has been extremely useful in mapping novel candidate tumor suppressor genes.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('LOH', 'Var', (116, 119))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('copy number alterations', 'Var', (121, 144))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('tumor', 'Disease', (77, 82))	('sarcoma', 'Disease', (49, 56))
480395	23401795	From the available studies in sarcoma, there is no compelling evidence to suggest a predictive value of microsatellite instability in sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('microsatellite instability', 'Var', (104, 130))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcoma', 'Disease', (30, 37))	('sarcoma', 'Disease', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
480400	23401795	Recent evidence in the Ewing sarcoma literature has demonstrated a novel, mechanistic necessity of microsatellite DNA during EWS/FLI-mediated oncogenesis.	('Ewing sarcoma', 'Disease', (23, 36))	('FLI', 'Gene', (129, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (23, 36))	('EWS', 'Gene', '2130', (125, 128))	('EWS', 'Gene', (125, 128))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (23, 36))	('microsatellite DNA', 'Var', (99, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('FLI', 'Gene', '2314', (129, 132))
480410	23401795	These data represent new evidence supporting a mechanistic role of microsatellite DNA in the EWS/FLI-mediated activation of key determinant genes driving Ewing sarcoma oncogenesis.	('microsatellite DNA', 'Var', (67, 85))	('activation', 'PosReg', (110, 120))	('Ewing sarcoma oncogenesis', 'Disease', 'MESH:C563168', (154, 179))	('EWS', 'Gene', '2130', (93, 96))	('EWS', 'Gene', (93, 96))	('FLI', 'Gene', '2314', (97, 100))	('Ewing sarcoma oncogenesis', 'Disease', (154, 179))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (154, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('FLI', 'Gene', (97, 100))
480412	23401795	If an increasing number of GGAA repeat motifs enhances EWS/FLI binding and gene activation, microsatellite instability within these response elements has potential for significant biological ramifications in Ewing sarcoma cells.	('enhances', 'PosReg', (46, 54))	('gene', 'CPA', (75, 79))	('EWS', 'Gene', (55, 58))	('EWS', 'Gene', '2130', (55, 58))	('GGAA', 'Protein', (27, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (208, 221))	('FLI', 'Gene', '2314', (59, 62))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (208, 221))	('binding', 'Interaction', (63, 70))	('motifs', 'Var', (39, 45))	('FLI', 'Gene', (59, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('Ewing sarcoma', 'Disease', (208, 221))
480419	23401795	Certainly, instability within these GGAA response elements has potential to significantly affect gene expression of key EWS/FLI targets.	('affect', 'Reg', (90, 96))	('FLI', 'Gene', '2314', (124, 127))	('instability', 'Var', (11, 22))	('EWS', 'Gene', '2130', (120, 123))	('EWS', 'Gene', (120, 123))	('FLI', 'Gene', (124, 127))	('gene expression', 'MPA', (97, 112))
480428	22053830	Aneuploid tumors contained large numbers of genetic alterations with the sum gain of at least 2 chromosomes (A-, B- or C-group) detected by HR-CGH.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Aneuploid tumors', 'Disease', 'MESH:D000782', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('genetic alterations', 'Var', (44, 63))	('Aneuploid tumors', 'Disease', (0, 16))	('C-group', 'Species', '28080', (119, 126))
480435	22053830	It has been shown that the type of fusion transcript most probably correlates with the clinical outcome and HER-2 oncogene amplification is associated with a lower risk of developing metastasis.	('amplification', 'Var', (123, 136))	('HER-2', 'Gene', (108, 113))	('HER-2', 'Gene', '2064', (108, 113))	('lower', 'NegReg', (158, 163))
480461	22053830	Briefly, sex-matched normal and tumor DNAs were labeled with SpectrumRed-dUTP and SpectrumGreen-dUTP, respectively by nick translation using a commercial kit (Vysis, Downers Grove, IL, USA).	('SpectrumRed-dUTP', 'Var', (61, 77))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('SpectrumGreen-dUTP', 'Var', (82, 100))	('SpectrumGreen-dUTP', 'Chemical', '-', (82, 100))	('dUTP', 'Chemical', 'MESH:C027078', (96, 100))	('tumor', 'Disease', (32, 37))	('dUTP', 'Chemical', 'MESH:C027078', (73, 77))
480464	22053830	Regarding the cases having been followed-up we had 10 aneuploid, 9 complex-diploid and 27 simple-diploid synovial sarcomas.	('synovial sarcomas', 'Disease', 'MESH:D013584', (105, 122))	('synovial sarcomas', 'Disease', (105, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('aneuploid', 'Var', (54, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (105, 121))	('complex-diploid', 'Var', (67, 82))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (105, 122))
480469	22053830	Aneuploid tumors contained a large number of genetic alterations with the sum gain of at least 2 chromosomes (A-, B- or C-group).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Aneuploid tumors', 'Disease', 'MESH:D000782', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Aneuploid tumors', 'Disease', (0, 16))	('C-group', 'Species', '28080', (120, 127))	('genetic alterations', 'Var', (45, 64))
480470	22053830	The "complex-diploid" samples showed numerous aberrations (equal or more than 3) such as gains of chromosome 3q, 4 and 9, and losses of chromosome 1p12-22, 3p, 4q28-q35, 5q15-35, 6q12-q23, 16q, 19, 20 and 22 (Figure 3).	('numerous aberrations', 'Disease', 'MESH:D002869', (37, 57))	('gains', 'PosReg', (89, 94))	('4q28-q35', 'Var', (160, 168))	('numerous aberrations', 'Disease', (37, 57))	('5q15-35', 'Gene', (170, 177))	('losses', 'NegReg', (126, 132))
480474	22053830	Its possible cause could be that the specific translocation is essential for the initiation of tumorgenesis, but in tumor progression (recurrence and metastasis) further genetic alterations also play a crucial role.	('initiation of tumorgenesis', 'Disease', (81, 107))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('translocation', 'Var', (46, 59))	('initiation of tumorgenesis', 'Disease', 'MESH:D007319', (81, 107))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (95, 100))
480476	22053830	Nevertheless, whether and how the biological behavior of the tumor is affected by cytogenetic changes remains uncertain.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('changes', 'Var', (94, 101))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
480485	22053830	The explanation of this phenomenon is not evident: the complex diploid tumors cannot be regarded as aneuploid, even if the complex karyotype shows evident aneuploidy (although at a more sensitive level).	('diploid tumors', 'Disease', 'MESH:C548012', (63, 77))	('diploid tumors', 'Disease', (63, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('aneuploidy', 'Var', (155, 165))
480504	30954717	Over 90% fail to express the SMARCB1/INI1 tumor-suppressor gene product, reflecting deletion or inactivation of this gene located at 22q11.23.	('tumor', 'Disease', (42, 47))	('INI1', 'Gene', (37, 41))	('inactivation', 'NegReg', (96, 108))	('deletion', 'Var', (84, 92))	('INI1', 'Gene', '6598', (37, 41))	('SMARCB1', 'Gene', '6598', (29, 36))	('SMARCB1', 'Gene', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
480683	29119046	Recent multicenter studies showing BRAFV600E positivity in almost 20% of FDC sarcoma cases as well as studies demonstrating epidermal growth factor receptor (EGFR) expression by FDC sarcomas suggest new potential targets for treatment in this otherwise elusive entity.	('FDC sarcoma', 'Disease', 'MESH:C536231', (73, 84))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('EGFR', 'Gene', (158, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('BRAFV600E', 'Mutation', 'rs113488022', (35, 44))	('positivity', 'Var', (45, 55))	('sarcomas', 'Disease', (182, 190))	('FDC sarcoma', 'Phenotype', 'HP:0031350', (73, 84))	('epidermal growth factor receptor', 'Gene', (124, 156))	('EGFR', 'Gene', '1956', (158, 162))	('FDC sarcoma', 'Disease', (178, 189))	('BRAFV600E', 'Gene', (35, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('FDC sarcoma', 'Disease', 'MESH:C536231', (178, 189))	('FDC sarcoma', 'Disease', (73, 84))	('epidermal growth factor receptor', 'Gene', '1956', (124, 156))	('FDC sarcoma', 'Phenotype', 'HP:0031350', (178, 189))
480687	27413115	Recurrent mutations arise in genes encoding several BAF/PBAF subunits, including ARID1A, ARID2, PBRM1, SMARCA4, and SMARCB1.	('SMARCB1', 'Gene', (116, 123))	('ARID', 'Disease', (81, 85))	('SMARCB1', 'Gene', '20587', (116, 123))	('BRM', 'Gene', '6595', (97, 100))	('ARID', 'Disease', (89, 93))	('ARID1A', 'Gene', '93760', (81, 87))	('ARID', 'Disease', 'None', (81, 85))	('SMARCA4', 'Gene', (103, 110))	('SMARCA4', 'Gene', '6597', (103, 110))	('BRM', 'Gene', (97, 100))	('ARID', 'Disease', 'None', (89, 93))	('mutations', 'Var', (10, 19))	('ARID1A', 'Gene', (81, 87))
480697	27413115	As we discuss below, the mechanisms revealed by fundamental studies inform our understanding of how epigenetic dysfunction contributes to cancer.	('cancer', 'Disease', (138, 144))	('epigenetic dysfunction', 'Var', (100, 122))	('contributes', 'Reg', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
480698	27413115	ATP-dependent chromatin remodelers were independently discovered in yeast, by screening for mutations that disrupt the ability of yeast to switch mating type or activate sucrose fermentation pathways, both in response to extrinsic cues.	('activate', 'PosReg', (161, 169))	('sucrose fermentation pathways', 'Pathway', (170, 199))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('yeast', 'Species', '4932', (130, 135))	('mutations', 'Var', (92, 101))	('yeast', 'Species', '4932', (68, 73))	('sucrose', 'Chemical', 'MESH:D013395', (170, 177))
480700	27413115	The observation that histone mutants were able to reverse the phenotypic defects associated with SWI/SNF mutation indicated that regulation of chromatin structure was the central function of the SWI/SNF complex.	('mutation', 'Var', (105, 113))	('SWI', 'Gene', (195, 198))	('SWI', 'Gene', '31120', (195, 198))	('SWI', 'Gene', '31120', (97, 100))	('SNF', 'Gene', (101, 104))	('SWI', 'Gene', (97, 100))	('SNF', 'Gene', '31442', (199, 202))	('SNF', 'Gene', (199, 202))	('SNF', 'Gene', '31442', (101, 104))
480706	27413115	Cells with SWI/SNF subunit mutations have disrupted chromatin structures, and fail to express many genes, leading to diverse phenotypic defects.	('mutations', 'Var', (27, 36))	('chromatin structures', 'MPA', (52, 72))	('SWI', 'Gene', '31120', (11, 14))	('SWI', 'Gene', (11, 14))	('SNF', 'Gene', (15, 18))	('disrupted', 'NegReg', (42, 51))	('leading to', 'Reg', (106, 116))	('SNF', 'Gene', '31442', (15, 18))
480713	27413115	SWI/SNF mutations also cause increased sensitivity to DNA-damaging agents, including hydroxyurea, cisplatin, methyl methanesulfonate, and UV-light.	('SWI', 'Gene', (0, 3))	('cisplatin', 'MPA', (98, 107))	('SWI', 'Gene', '31120', (0, 3))	('hydroxyurea', 'Chemical', 'MESH:D006918', (85, 96))	('mutations', 'Var', (8, 17))	('increased', 'PosReg', (29, 38))	('hydroxyurea', 'MPA', (85, 96))	('SNF', 'Gene', '31442', (4, 7))	('sensitivity to DNA-damaging agents', 'MPA', (39, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('methyl methanesulfonate', 'Chemical', 'MESH:D008741', (109, 132))	('methyl methanesulfonate', 'MPA', (109, 132))	('SNF', 'Gene', (4, 7))
480716	27413115	Because transcription, DNA repair, and chromatin modification domains are each influenced by the availability of accessible DNA, disruption of the nucleosome mobilization activity of SWI/SNF has distinct and pleiotropic effects.	('SNF', 'Gene', (187, 190))	('disruption', 'Var', (129, 139))	('SWI', 'Gene', (183, 186))	('influenced', 'Reg', (79, 89))	('SWI', 'Gene', '31120', (183, 186))	('nucleosome mobilization activity', 'MPA', (147, 179))	('SNF', 'Gene', '31442', (187, 190))
480724	27413115	Rsc2 is required for insulator boundary function at the HMR locus, and its mutation leads to a loss of the nucleosome-depleted region encompassed by the insulator.	('mutation', 'Var', (75, 83))	('nucleosome-depleted region encompassed by the', 'MPA', (107, 152))	('Rsc2', 'Gene', '851071', (0, 4))	('loss', 'NegReg', (95, 99))	('Rsc2', 'Gene', (0, 4))
480748	27413115	Some of the complexes' subunits are tissue-specific; for example, BAF53B (ACTL6B), BAF45B (DPF1), and SS18L1 (CREST, a Ca2+-responsive regulator), are found only in BAF complexes of mature, post-mitotic neurons.	('BAF45B', 'Var', (83, 89))	('SS18L1', 'Gene', (102, 108))	('SS18L1', 'Gene', '26039', (102, 108))	('BAF53B', 'Gene', (66, 72))	('Ca2+', 'Chemical', 'MESH:D000069285', (119, 123))
480749	27413115	BAF subunit composition is subject to tight regulation, as miRNA-based repression of BAF53A occurs immediately after the last mitotic division of neurons, and failure to express neural-specific subunits like BAF53B leads to defects in synaptogenesis and dendritic outgrowth.	('dendritic outgrowth', 'CPA', (254, 273))	('synaptogenesis', 'MPA', (235, 249))	('repression', 'NegReg', (71, 81))	('BAF53A', 'Gene', (85, 91))	('BAF53A', 'Gene', '86', (85, 91))	('failure', 'Var', (159, 166))	('defects', 'NegReg', (224, 231))
480751	27413115	Screening for BRG mutations revealed widespread defects in a number of different cancer cell lines, and ectopic expression of BRG in these lines often results in altered morphology.	('defects', 'NegReg', (48, 55))	('BRG', 'Gene', (14, 17))	('results in altered', 'Reg', (151, 169))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('morphology', 'CPA', (170, 180))	('cancer', 'Disease', (81, 87))	('ectopic', 'Var', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BRG', 'Gene', (126, 129))	('mutations', 'Var', (18, 27))
480757	27413115	PBAF complexes also contain BRD7 in place of BRD9, BAF45A (PHF10) instead of BAF45B/C/D (DPF1/3/2), and lack SS18 (see Figure 1).	('lack', 'NegReg', (104, 108))	('SS18', 'Gene', (109, 113))	('SS18', 'Gene', '6760', (109, 113))	('BAF45A', 'Var', (51, 57))	('BRD9', 'Gene', '65980', (45, 49))	('BRD7', 'Var', (28, 32))	('BRD9', 'Gene', (45, 49))
480763	27413115	On account of their distinct biological activities, disruption of each of these remodelers is under different selection pressure in cancer, resulting in a wide range of mutation frequencies (Figure 2b).	('resulting in', 'Reg', (140, 152))	('cancer', 'Disease', (132, 138))	('mutation frequencies', 'MPA', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('disruption', 'Var', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
480767	27413115	Some of these subunits are among the most frequently mutated genes in cancer, and highly subunit-specific mutation patterns contribute to different cancer types (Figure 2c, 3).	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('contribute', 'Reg', (124, 134))
480769	27413115	As defined by the overall number of truncating and high-functional-impact mutations, BRG is the most frequently mutated Snf2-like chromatin remodeling ATPase in cancer (Figure 2c).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ATPase', 'Gene', '27429461', (151, 157))	('Snf2', 'Gene', (120, 124))	('ATPase', 'Gene', (151, 157))	('mutations', 'Var', (74, 83))	('Snf2', 'Gene', '854465', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('BRG', 'Gene', (85, 88))
480770	27413115	Unlike many other tumor suppressors, hypermethylation and silencing of BRG is reported to be relatively uncommon.	('tumor', 'Disease', (18, 23))	('silencing', 'MPA', (58, 67))	('BRG', 'Gene', (71, 74))	('hypermethylation', 'Var', (37, 53))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
480771	27413115	However, heterozygous and biallelic inactivation of BRG occurs in tumors of the breast, lung, stomach, bladder, colon, and in several other tumor types and cell lines.	('bladder', 'Disease', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('occurs', 'Reg', (56, 62))	('lung', 'Disease', (88, 92))	('tumors of the breast', 'Phenotype', 'HP:0100013', (66, 86))	('biallelic inactivation', 'Var', (26, 48))	('tumor', 'Disease', (66, 71))	('colon', 'Disease', 'MESH:D015179', (112, 117))	('BRG', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('colon', 'Disease', (112, 117))	('tumors of the breast', 'Disease', 'MESH:D001943', (66, 86))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('bladder', 'Disease', 'MESH:D001745', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('stomach', 'Disease', (94, 101))	('tumors of the breast', 'Disease', (66, 86))	('tumor', 'Disease', (140, 145))
480772	27413115	Disruption of BRG is especially common in small cell ovarian cancer (90-100%), cancers of the skin (up to 27%), diffuse large B-cell lymphoma (10%), and non-small cell lung cancers (~11%), where it has been reported as the fifth most frequently mutated gene.	('BRG', 'Gene', (14, 17))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (157, 180))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (153, 180))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('Disruption', 'Var', (0, 10))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (126, 141))	('cancers of the skin', 'Phenotype', 'HP:0008069', (79, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('small cell ovarian cancer', 'Phenotype', 'HP:0030357', (42, 67))	('small cell ovarian cancer', 'Disease', (42, 67))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('B-cell lymphoma', 'Disease', (126, 141))	('non-small cell lung cancers', 'Disease', (153, 180))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('small cell ovarian cancer', 'Disease', 'MESH:D055752', (42, 67))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (153, 180))	('lung cancers', 'Phenotype', 'HP:0100526', (168, 180))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancers of the skin', 'Disease', 'MESH:D012878', (79, 98))	('cancers of the skin', 'Disease', (79, 98))	('common', 'Reg', (32, 38))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (126, 141))
480773	27413115	In some specific malignancies, such as certain thoracic sarcomas, biallelic inactivation of BRG occurs at elevated frequencies.	('malignancies', 'Disease', 'MESH:D009369', (17, 29))	('biallelic inactivation', 'Var', (66, 88))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('malignancies', 'Disease', (17, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcomas', 'Disease', (56, 64))	('BRG', 'Gene', (92, 95))
480774	27413115	Although it was initially thought that in most cancers BRG mutations were generally homozygous, it has since been determined that in many cancer types, a large number of mutations of BRG are heterozygous, with many mutations clustering at conserved motifs of the ATPase domain.	('mutations clustering', 'Reg', (215, 235))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', (47, 53))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('BRG', 'Gene', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', (47, 54))	('ATPase', 'Gene', '27429461', (263, 269))	('ATPase', 'Gene', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
480779	27413115	For example, K785R and T910M, respectively observed in melanoma, medulloblastoma and several cancer cell lines, have severely reduced ATPase activity, leading to anaphase bridges and failure of topoisomerase IIa to bind DNA, discussed in greater detail below.	('medulloblastoma', 'Disease', (65, 80))	('failure', 'NegReg', (183, 190))	('ATPase', 'Gene', '27429461', (134, 140))	('T910M', 'Mutation', 'p.T910M', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('bind', 'Interaction', (215, 219))	('ATPase', 'Gene', (134, 140))	('anaphase bridges', 'CPA', (162, 178))	('activity', 'MPA', (141, 149))	('reduced', 'NegReg', (126, 133))	('cancer', 'Disease', (93, 99))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('topoisomerase', 'Protein', (194, 207))	('medulloblastoma', 'Disease', 'MESH:D008527', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('K785R', 'Var', (13, 18))	('T910M', 'Var', (23, 28))	('medulloblastoma', 'Phenotype', 'HP:0002885', (65, 80))	('K785R', 'Mutation', 'rs562397332', (13, 18))
480781	27413115	In other ATP-dependent remodelers, dominant-negative mutations result in phenotypes distinct from subunit deletion, suggesting that the particular mechanisms of inactivation may lead to different downstream effects.	('ATP', 'Chemical', 'MESH:D000255', (9, 12))	('lead', 'Reg', (178, 182))	('mutations', 'Var', (53, 62))
480783	27413115	In the C-terminal ATPase subdomain of BRG, R1192 is recurrently mutated in cancer of the stomach, liver, lung, melanoma, esophagus, and breast, as well as in gliomas (Figures 3, 4).	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('esophagus', 'Disease', (121, 130))	('liver', 'Disease', (98, 103))	('cancer', 'Disease', (75, 81))	('ATPase', 'Gene', '27429461', (18, 24))	('ATPase', 'Gene', (18, 24))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('lung', 'Disease', (105, 109))	('R1192', 'Var', (43, 48))	('gliomas', 'Disease', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast', 'Disease', (136, 142))	('cancer of the stomach', 'Phenotype', 'HP:0006753', (75, 96))
480784	27413115	Moreover, the homologous position is also mutated in BTAF1, CHD1, and ATRX in several different malignancies, suggesting this well-conserved position may be an Achilles' heel of Snf2-like remodelers.	('CHD1', 'Gene', (60, 64))	('BTAF1', 'Gene', (53, 58))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('mutated', 'Var', (42, 49))	('malignancies', 'Disease', (96, 108))	('Snf2', 'Gene', (178, 182))	('Snf2', 'Gene', '854465', (178, 182))	('CHD1', 'Gene', '856911', (60, 64))
480785	27413115	Other nearby mutations at conserved residues in Motif V of the C-terminal subdomain severely compromise ATPase activity in the yeast SWI/SNF complex.	('SNF', 'Gene', '31442', (137, 140))	('activity', 'MPA', (111, 119))	('ATPase', 'Gene', '27429461', (104, 110))	('SWI', 'Gene', '31120', (133, 136))	('ATPase', 'Gene', (104, 110))	('yeast', 'Species', '4932', (127, 132))	('SNF', 'Gene', (137, 140))	('mutations', 'Var', (13, 22))	('SWI', 'Gene', (133, 136))	('compromise', 'NegReg', (93, 103))
480786	27413115	Although it is clear that commonly observed point mutations disrupt or completely abolish ATPase activity, a complete accounting of the downstream effects of these mutations in malignancy has not yet been performed.	('point mutations', 'Var', (44, 59))	('activity', 'MPA', (97, 105))	('ATPase', 'Gene', '27429461', (90, 96))	('ATPase', 'Gene', (90, 96))	('malignancy', 'Disease', 'MESH:D009369', (177, 187))	('disrupt', 'NegReg', (60, 67))	('abolish', 'NegReg', (82, 89))	('malignancy', 'Disease', (177, 187))
480787	27413115	BRM, the paralog of BRG that is not a subunit of the PBAF complex, also shows similar clustering of mutations at the N- and C-terminal helicase-like subdomains, but is much less frequently mutated in cancers (Figures 3, 4).	('mutations', 'Var', (100, 109))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('BRM', 'Gene', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('BRM', 'Gene', '6595', (0, 3))
480788	27413115	Interestingly, several in-frame deletions in the QLQ domain of BRM have been observed in primary tumors and several cancer cell lines.	('deletions', 'Var', (32, 41))	('primary tumors', 'Disease', 'MESH:D009369', (89, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Disease', (116, 122))	('BRM', 'Gene', (63, 66))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('observed', 'Reg', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRM', 'Gene', '6595', (63, 66))	('primary tumors', 'Disease', (89, 103))
480793	27413115	Among the earliest reports of the complex's tumor suppressor role was the discovery that ~50% of ovarian clear cell carcinomas and endometriosis-associated ovarian carcinomas contain inactivating ARID1A mutations.	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('ARID1A', 'Gene', (196, 202))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (156, 174))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('endometriosis-associated ovarian carcinomas', 'Disease', (131, 174))	('ovarian clear cell carcinomas', 'Disease', (97, 126))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (97, 126))	('ARID1A', 'Gene', '93760', (196, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('endometriosis', 'Phenotype', 'HP:0030127', (131, 144))	('mutations', 'Var', (203, 212))	('tumor', 'Disease', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('endometriosis-associated ovarian carcinomas', 'Disease', 'MESH:D004715', (131, 174))	('inactivating', 'Var', (183, 195))
480794	27413115	Mutations of ARID1A have since been observed at high frequency in a number of studies, including uterine endometrial carcinoma (34%), colorectal cancers (10%), as well as cancers of the bladder (29%), stomach (34%), cholangiocarcinomas (27%), neuroblastomas (11%), and pancreas (~5%).	('colorectal cancers', 'Disease', (134, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('pancreas', 'Disease', (269, 277))	('endometrial carcinoma', 'Disease', (105, 126))	('stomach', 'Disease', (201, 208))	('Mutations', 'Var', (0, 9))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (105, 126))	('cancers of the bladder', 'Disease', 'MESH:D001749', (171, 193))	('observed', 'Reg', (36, 44))	('colorectal cancers', 'Disease', 'MESH:D015179', (134, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (105, 126))	('neuroblastomas', 'Disease', (243, 257))	('cancers of the bladder', 'Phenotype', 'HP:0009725', (171, 193))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancers of the bladder', 'Disease', (171, 193))	('ARID1A', 'Gene', (13, 19))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (216, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('ARID1A', 'Gene', '93760', (13, 19))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('neuroblastomas', 'Disease', 'MESH:D009447', (243, 257))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cholangiocarcinomas', 'Disease', (216, 235))
480795	27413115	These recurrent loss-of-function mutations make ARID1A the premier tumor-suppressor subunit of the BAF complex, however very little is known about the mechanisms of how this subunit contributes to malignancy.	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ARID1A', 'Gene', (48, 54))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ARID1A', 'Gene', '93760', (48, 54))	('malignancy', 'Disease', 'MESH:D009369', (197, 207))	('loss-of-function', 'NegReg', (16, 32))	('malignancy', 'Disease', (197, 207))
480796	27413115	Mutations of ARID1A are most frequently truncating mutations (frameshifts and nonsense mutations (Figure 2c, 4), which may be degraded by nonsense-mediated decay.	('ARID1A', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('ARID1A', 'Gene', '93760', (13, 19))
480798	27413115	The hotspots of truncating mutations that occur are explained in part by frequent ARID1A mutations arising in tumors with mutated DNA polymerase epsilon (POLE).	('ARID1A', 'Gene', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('ARID1A', 'Gene', '93760', (82, 88))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (89, 98))	('mutated', 'Var', (122, 129))
480801	27413115	However, hypermethylation of the ARID1A promoter has been observed in many breast cancers, hence epigenetic silencing mechanisms are also common.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ARID1A', 'Gene', '93760', (33, 39))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('hypermethylation', 'Var', (9, 25))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('breast cancers', 'Phenotype', 'HP:0003002', (75, 89))	('observed', 'Reg', (58, 66))	('ARID1A', 'Gene', (33, 39))
480802	27413115	In ovarian cancer, mutation of ARID1A frequently co-occurs with activating mutations of phosphatidylinositol 3-kinase (PI3K).	('co-occurs', 'Reg', (49, 58))	('mutation', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ARID1A', 'Gene', (31, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Disease', (3, 17))	('ARID1A', 'Gene', '93760', (31, 37))
480804	27413115	Binding of PIP2 by Brg regulates association of the complex with actin; therefore, activating mutations of PI3K may deplete PIP2, leading to altered BAF localization or function.	('PIP2', 'Gene', (11, 15))	('PIP2', 'Gene', '854545', (11, 15))	('altered', 'Reg', (141, 148))	('mutations', 'Var', (94, 103))	('BAF', 'CPA', (149, 152))	('localization', 'MPA', (153, 165))	('PIP2', 'Gene', '854545', (124, 128))	('PI3K', 'Gene', (107, 111))	('deplete', 'NegReg', (116, 123))	('function', 'MPA', (169, 177))	('PIP2', 'Gene', (124, 128))
480807	27413115	However, ARID1B mutations are not as frequent as those of ARID1A (Figure 2c).	('ARID1A', 'Gene', (58, 64))	('mutations', 'Var', (16, 25))	('ARID1B', 'Gene', (9, 15))	('ARID1A', 'Gene', '93760', (58, 64))	('ARID1B', 'Gene', '57492', (9, 15))
480811	27413115	In renal clear cell carcinoma (ccRCC), mutation or loss of PBRM1 occurs in ~41% of cases, making it the second-most frequently mutated gene in ccRCC.	('mutation', 'Var', (39, 47))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (3, 29))	('renal clear cell carcinoma', 'Disease', (3, 29))	('BRM', 'Gene', '6595', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('loss', 'NegReg', (51, 55))	('BRM', 'Gene', (60, 63))
480812	27413115	Like ARID1A in other cancers, the majority of mutations of PBRM1 in ccRCC are truncating mutations (Figures 2c, 4), which may not result in protein expression due to nonsense-mediated decay.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('ARID1A', 'Gene', (5, 11))	('mutations', 'Var', (46, 55))	('ARID1A', 'Gene', '93760', (5, 11))	('BRM', 'Gene', '6595', (60, 63))	('ccRCC', 'Disease', (68, 73))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('truncating', 'MPA', (78, 88))	('cancers', 'Disease', (21, 28))	('BRM', 'Gene', (60, 63))
480813	27413115	However, many ccRCC cases have biallelic inactivation of PBRM1, through loss of one allele via focal/chromosomal deletion at chromosome arm 3p, and an inactivating mutation on the remaining allele.	('loss', 'NegReg', (72, 76))	('BRM', 'Gene', (58, 61))	('focal/chromosomal deletion', 'Var', (95, 121))	('ccRCC', 'Disease', (14, 19))	('inactivating', 'Reg', (151, 163))	('BRM', 'Gene', '6595', (58, 61))
480814	27413115	Furthermore, hypermethylation of the PBRM1 promoter is generally absent in ccRCC, indicating that inactivation occurs primarily through mutation or deletion.	('deletion', 'Var', (148, 156))	('ccRCC', 'Disease', (75, 80))	('absent', 'NegReg', (65, 71))	('mutation', 'Var', (136, 144))	('hypermethylation', 'MPA', (13, 29))	('BRM', 'Gene', (38, 41))	('BRM', 'Gene', '6595', (38, 41))
480815	27413115	Some tumors do contain missense mutations, and although their functional impacts remain uncertain, their presence suggests a degree of non-redundancy between these domains.	('missense mutations', 'Var', (23, 41))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
480817	27413115	In ccRCC, PBRM1 inactivation frequently coincides with mutation of the VHL (von Hippel-Lindau) tumor suppressor.	('coincides', 'Reg', (40, 49))	('BRM', 'Gene', (11, 14))	('inactivation', 'Var', (16, 28))	('VHL (von Hippel-Lindau) tumor', 'Disease', 'MESH:D006623', (71, 100))	('ccRCC', 'Disease', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutation', 'Var', (55, 63))	('BRM', 'Gene', '6595', (11, 14))
480818	27413115	However, the striking frequency of inactivating point mutations of PBRM1 alongside VHL and BAP1 mutations suggests that joint inactivation of these genes may potentiate the oncogenic nature of these defects.	('inactivation', 'Var', (126, 138))	('BAP1', 'Gene', (91, 95))	('BRM', 'Gene', (68, 71))	('potentiate', 'PosReg', (158, 168))	('BAP1', 'Gene', '852074', (91, 95))	('inactivating point mutations', 'Var', (35, 63))	('oncogenic nature', 'CPA', (173, 189))	('VHL', 'Disease', (83, 86))	('VHL', 'Disease', 'MESH:D006623', (83, 86))	('BRM', 'Gene', '6595', (68, 71))	('mutations', 'Var', (96, 105))
480822	27413115	ARID2 has been reported to contribute to repression, and is frequently mutated in melanoma, non-small cell lung cancer as well as in ~18% of hepatitis-associated hepatocellular carcinomas.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (92, 118))	('hepatitis-associated hepatocellular carcinomas', 'Disease', (141, 187))	('hepatitis-associated hepatocellular carcinomas', 'Disease', 'MESH:D056486', (141, 187))	('hepatitis', 'Phenotype', 'HP:0012115', (141, 150))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (162, 187))	('ARID', 'Disease', (0, 4))	('mutated', 'Var', (71, 78))	('non-small cell lung cancer', 'Disease', (92, 118))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('ARID', 'Disease', 'None', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))
480825	27413115	MRTs are rare but highly lethal childhood cancers that are caused by biallelic inactivation of SMARCB1 (BAF47, SNF5, or INI1), which occurs in nearly all cases.	('cancers', 'Disease', (42, 49))	('SMARCB1', 'Gene', '20587', (95, 102))	('SNF5', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('SNF5', 'Gene', '852592', (111, 115))	('SMARCB1', 'Gene', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('MRTs', 'Disease', (0, 4))	('caused by', 'Reg', (59, 68))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('biallelic', 'Var', (69, 78))
480827	27413115	As a result of failure to oppose Polycomb, the repressive mark H3K27me3 accumulates at the tumor suppressor p16/INK4A (CDKN2A) locus.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Polycomb', 'Gene', (33, 41))	('Polycomb', 'Gene', '40358', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('H3K27me3', 'Var', (63, 71))	('tumor', 'Disease', (91, 96))	('accumulates', 'PosReg', (72, 83))
480829	27413115	MRTs have remarkably stable diploid genomes except for deletions and mutations at chromosome 22q, where SMARCB1 is located.	('mutations', 'Var', (69, 78))	('SMARCB1', 'Gene', (104, 111))	('deletions', 'Var', (55, 64))	('SMARCB1', 'Gene', '20587', (104, 111))
480831	27413115	Finally, ectopic expression of SMARCB1 reverses Polycomb silencing at the tumor suppressor p16/INK4A locus, leading to cellular senescence, indicating that these tumors are driven exclusively by epigenetic regulation (except for the original genetic inactivation of SMARCB1).	('Polycomb', 'Gene', '40358', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cellular senescence', 'CPA', (119, 138))	('Polycomb', 'Gene', (48, 56))	('tumor', 'Disease', (162, 167))	('SMARCB1', 'Gene', (266, 273))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('SMARCB1', 'Gene', '20587', (31, 38))	('tumor', 'Disease', (74, 79))	('epigenetic regulation', 'Var', (195, 216))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('SMARCB1', 'Gene', (31, 38))	('SMARCB1', 'Gene', '20587', (266, 273))	('leading to', 'Reg', (108, 118))
480833	27413115	Biallelic inactivation of SMARCB1 has also been reported in 7-10% of Ewing sarcomas.	('Ewing sarcomas', 'Disease', (69, 83))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (69, 83))	('reported', 'Reg', (48, 56))	('Biallelic inactivation', 'Var', (0, 22))	('SMARCB1', 'Gene', (26, 33))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (69, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('SMARCB1', 'Gene', '20587', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
480834	27413115	In mouse models, conditional deletion of SMARCB1 leads to T cell lymphomas with short latency and 100% penetrance, suggesting that SMARCB1 inactivation can cause fast transformation alone without other genetic changes, as observed in MRTs.	('SMARCB1', 'Gene', (41, 48))	('mouse', 'Species', '10090', (3, 8))	('SMARCB1', 'Gene', (131, 138))	('SMARCB1', 'Gene', '20587', (41, 48))	('leads to', 'Reg', (49, 57))	('T cell lymphomas', 'Disease', 'MESH:D016399', (58, 74))	('T cell lymphomas', 'Disease', (58, 74))	('lymphomas', 'Phenotype', 'HP:0002665', (65, 74))	('SMARCB1', 'Gene', '20587', (131, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (65, 73))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (58, 74))	('inactivation', 'Var', (139, 151))
480835	27413115	Interestingly, rhabdoid tumors are not seen in mice with SMARCB1 inactivation, attesting to the tissue-specific and species-specific function of the complexes.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SMARCB1', 'Gene', '20587', (57, 64))	('rhabdoid tumors', 'Disease', (15, 30))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (15, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('inactivation', 'Var', (65, 77))	('SMARCB1', 'Gene', (57, 64))	('mice', 'Species', '10090', (47, 51))
480836	27413115	Importantly, the pathogenesis of most human malignancies with BAF/PBAF mutations may be different from that of MRTs.	('human', 'Species', '9606', (38, 43))	('malignancies', 'Disease', (44, 56))	('BAF/PBAF', 'Gene', (62, 70))	('mutations', 'Var', (71, 80))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))
480837	27413115	With the exception of some noteworthy examples described below, the majority of cancers bearing BAF/PBAF subunit mutations are found in older age groups, where tumors have long latencies, are highly mutated, and are genomically unstable.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('BAF/PBAF subunit', 'Gene', (96, 112))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
480839	27413115	The hallmark of synovial sarcoma is a highly characteristic translocation of chromosomes 18 and X, which fuses the dedicated BAF subunit SS18 to the SSX fusion partner on the X chromosome.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (16, 32))	('synovial sarcoma', 'Disease', 'MESH:D013584', (16, 32))	('SS18', 'Gene', (137, 141))	('translocation', 'Var', (60, 73))	('synovial sarcoma', 'Disease', (16, 32))	('SS18', 'Gene', '6760', (137, 141))
480841	27413115	BAF complexes containing the SS18-SSX fusion are retargeted to oncogenic loci such as SOX2 and PAX6, where removal of the repressive histone mark H3K27me3 results in transformation.	('results in', 'Reg', (155, 165))	('SS18', 'Gene', (29, 33))	('transformation', 'CPA', (166, 180))	('removal', 'Var', (107, 114))	('H3K27me3', 'Protein', (146, 154))	('SS18', 'Gene', '6760', (29, 33))
480842	27413115	Forced overexpression of wild-type SS18, or shRNA-mediated knockdown of the SS18-SSX fusion, is sufficient to reverse oncogenic BAF subunit composition.	('SS18', 'Gene', (76, 80))	('SS18', 'Gene', (35, 39))	('SS18', 'Gene', '6760', (76, 80))	('SS18', 'Gene', '6760', (35, 39))	('knockdown', 'Var', (59, 68))
480845	27413115	They are both childhood malignancies driven by a defining alteration of a single BAF subunit, and senescence can be achieved by repair of the affected subunit.	('alteration', 'Var', (58, 68))	('malignancies', 'Disease', 'MESH:D009369', (24, 36))	('BAF', 'Protein', (81, 84))	('malignancies', 'Disease', (24, 36))
480851	27413115	Recent work has also shown that BAF53A is a target of miR-206, a microRNA missing in rhabdomyosarcomas (RMS).	('rhabdomyosarcomas', 'Disease', (85, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('BAF53A', 'Gene', '86', (32, 38))	('BAF53A', 'Gene', (32, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (85, 102))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (85, 102))	('miR-206', 'Var', (54, 61))
480854	27413115	Ablation of the HSA domain from Sth1, the ATPase of RSC in yeast, causes the specific loss of ARPs from the complex, and a reduction in the activity of the ATPase.	('RSC', 'Gene', '5656974', (52, 55))	('loss', 'NegReg', (86, 90))	('ATPase', 'Gene', '27429461', (42, 48))	('ATPase', 'Gene', (42, 48))	('Ablation', 'Var', (0, 8))	('ATPase', 'Gene', (156, 162))	('yeast', 'Species', '4932', (59, 64))	('ATPase', 'Gene', '27429461', (156, 162))	('Sth1', 'Gene', '854680', (32, 36))	('reduction', 'NegReg', (123, 132))	('ARPs', 'Protein', (94, 98))	('activity', 'MPA', (140, 148))	('Sth1', 'Gene', (32, 36))	('RSC', 'Gene', (52, 55))
480867	27413115	PBRM1 plays a critical role in sister chromatid cohesion, where misregulation leads to genome instability, anaphase bridges, and aneuploidy.	('leads to', 'Reg', (78, 86))	('aneuploidy', 'Disease', 'MESH:D000782', (129, 139))	('BRM', 'Gene', '6595', (1, 4))	('anaphase bridges', 'CPA', (107, 123))	('aneuploidy', 'Disease', (129, 139))	('genome instability', 'CPA', (87, 105))	('misregulation', 'Var', (64, 77))	('BRM', 'Gene', (1, 4))
480871	27413115	Topoisomerases require nucleosome-free DNA, and mutants of BRG that impair ATPase activity induce loss of topoisomerase IIa (TOP2A) binding to DNA, leading to topological defects, anaphase bridges and partial arrest at the relatively uncharacterized decatenation checkpoint.	('ATPase', 'Gene', (75, 81))	('partial arrest', 'CPA', (201, 215))	('topological', 'MPA', (159, 170))	('BRG', 'Gene', (59, 62))	('decatenation checkpoint', 'MPA', (250, 273))	('anaphase bridges', 'CPA', (180, 196))	('mutants', 'Var', (48, 55))	('TOP2A', 'Gene', (125, 130))	('loss', 'NegReg', (98, 102))	('binding', 'Interaction', (132, 139))	('ATPase', 'Gene', '27429461', (75, 81))
480872	27413115	Lung cancer cell lines with BRG mutations show increased sensitivity to topoisomerase II inhibitors when EZH2 is also inhibited, suggesting interplay between BAF, TOP2A, and PRC2 in the maintenance of chromatin topology.	('PRC2', 'Gene', (174, 178))	('inhibited', 'NegReg', (118, 127))	('PRC2', 'Gene', '852873', (174, 178))	('BRG', 'Gene', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('increased', 'PosReg', (47, 56))	('interplay', 'Interaction', (140, 149))	('mutations', 'Var', (32, 41))	('sensitivity', 'MPA', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
480875	27413115	In several tumor types, inactivation of one BAF/PBAF subunit induces dependency on the continued expression of that subunit's paralog.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('induces', 'Reg', (61, 68))	('dependency on the continued expression', 'MPA', (69, 107))	('tumor', 'Disease', (11, 16))	('inactivation', 'Var', (24, 36))	('BAF/PBAF', 'Gene', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
480876	27413115	For example, tumors with BRG mutations frequently depend on the expression of BRM, while tumors with ARID1A mutations often depend on ARID1B.	('ARID1A', 'Gene', (101, 107))	('tumors', 'Disease', (89, 95))	('BRM', 'Gene', (78, 81))	('expression', 'MPA', (64, 74))	('ARID1B', 'Gene', '57492', (134, 140))	('tumors', 'Disease', (13, 19))	('ARID1A', 'Gene', '93760', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (29, 38))	('BRM', 'Gene', '6595', (78, 81))	('ARID1B', 'Gene', (134, 140))	('depend', 'Reg', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('BRG', 'Gene', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
480881	27413115	While abundant evidence indicates that BAF and PBAF defects contribute to malignancy by altering the epigenetic landscape to regulate transcription, many lines of evidence indicate that these defects have pleiotropic effects, because complexes participate in a number of other important chromatin regulatory processes.	('malignancy', 'Disease', (74, 84))	('defects', 'Var', (52, 59))	('contribute', 'Reg', (60, 70))	('PBAF', 'Gene', (47, 51))	('epigenetic landscape to regulate transcription', 'MPA', (101, 147))	('malignancy', 'Disease', 'MESH:D009369', (74, 84))	('altering', 'Reg', (88, 96))	('BAF', 'Gene', (39, 42))	('participate', 'Reg', (244, 255))
480883	27413115	As a result, the fundamental role of any given BAF and PBAF alteration in cancer is likely to be unique to each cancer type, and may reflect the idiosyncratic processes that drive each malignancy (whether oncogene addiction, autocrine signaling, mutagen exposure, chromosomal instability, etc.).	('BAF', 'Gene', (47, 50))	('reflect', 'Reg', (133, 140))	('malignancy', 'Disease', 'MESH:D009369', (185, 195))	('alteration', 'Var', (60, 70))	('malignancy', 'Disease', (185, 195))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('chromosomal instability', 'Phenotype', 'HP:0040012', (264, 287))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PBAF', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
480995	26064077	To identify patients who underwent resection of an extremity soft tissue sarcoma, the NCDB Participant User File for 1998 through 2011 was utilized first queried for all patients treated at a NCDB participating institution for tumors in the arms or legs with International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) topography codes C47.1, C47.2, C49.1, and C49.2.	('C47.2', 'Var', (360, 365))	('C47.1', 'Var', (353, 358))	('C47.1', 'CellLine', 'CVCL:L675', (353, 358))	('Oncology', 'Phenotype', 'HP:0002664', (304, 312))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (61, 80))	('C49.1', 'CellLine', 'CVCL:6519', (367, 372))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('C47.2', 'CellLine', 'CVCL:L675', (360, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('C49.2', 'Var', (378, 383))	('Participant', 'Species', '9606', (91, 102))	('C49.1', 'Var', (367, 372))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
481047	23467306	reported that clear cell sarcoma, but not malignant melanoma, was associated with the translocation t(12;22)(q13;q12) resulting in a chimeric EWS/ATF1 gene.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('malignant melanoma', 'Phenotype', 'HP:0002861', (42, 60))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (14, 32))	('chimeric', 'MPA', (133, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('EWS/ATF1', 'Gene', '466;2130', (142, 150))	('associated', 'Reg', (66, 76))	('malignant melanoma', 'Disease', 'MESH:D008545', (42, 60))	('malignant melanoma', 'Disease', (42, 60))	('EWS/ATF1', 'Gene', (142, 150))	('t(12;22)(q13;q12', 'Var', (100, 116))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (100, 117))	('translocation t(12;22)(q13;q12', 'Var', (86, 116))	('clear cell sarcoma', 'Disease', (14, 32))
481099	21188115	ET743 has shown potent antitumor activity in pre-clinical studies both in vitro and in vivo in several solid tumors, including ovarian and breast cancer, melanoma, and sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (127, 152))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumors', 'Disease', (109, 115))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('sarcoma', 'Disease', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('ET743', 'Var', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('ET743', 'Chemical', 'MESH:D000077606', (0, 5))	('tumor', 'Disease', (109, 114))
481110	21188115	Based on these observations, Herrero et al suggested the following sequence: trabectedin binds covalently to the DNA minor groove, the resulting adduct is recognized by the nucleotide-excision repair machinery, and then the recruited Rad13 (XPG) protein binds to DNA and interacts with the minor groove-bound drug by means of an arginine residue located in the COOH terminus.	('arginine', 'Var', (329, 337))	('binds', 'Interaction', (254, 259))	('XPG', 'Gene', (241, 244))	('arginine', 'Chemical', 'MESH:D001120', (329, 337))	('trabectedin', 'Chemical', 'MESH:D000077606', (77, 88))	('COOH', 'Chemical', 'MESH:D002255', (361, 365))	('interacts', 'Interaction', (271, 280))	('XPG', 'Gene', '2073', (241, 244))
481158	21188115	Two dose levels were planned for gemcitabine (800 and 1000 mg/m2) and five were planned for trabectedin (300, 400, 475, 535, and 580 mug/m2).	('trabectedin', 'Chemical', 'MESH:D000077606', (92, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (33, 44))	('800', 'Var', (46, 49))	('300', 'Var', (105, 108))
481210	21188115	Grade 3 and Grade 4 adverse events included neutropenia (63% versus 22%), elevated alanine transaminase (31% versus 1%), and hand-foot syndrome (4% versus 20%) for PLD + T versus PLD alone, respectively.	('neutropenia', 'Phenotype', 'HP:0001875', (44, 55))	('neutropenia', 'Disease', 'MESH:D009503', (44, 55))	('elevated', 'PosReg', (74, 82))	('elevated alanine transaminase', 'Phenotype', 'HP:0031964', (74, 103))	('elevated alanine', 'Phenotype', 'HP:0003348', (74, 90))	('PLD + T', 'Var', (164, 171))	('neutropenia', 'Disease', (44, 55))	('hand-foot syndrome', 'Disease', (125, 143))	('alanine transaminase', 'MPA', (83, 103))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (125, 143))
481211	21188115	On the basis of these results, the authors concluded the superior efficacy the PLD + T combination, which also demonstrates competitive efficacy compared with previously described platinum-based combinations in patients with platinum-sensitive relapsed ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (253, 267))	('patients', 'Species', '9606', (211, 219))	('platinum', 'Chemical', 'MESH:D010984', (180, 188))	('platinum', 'Chemical', 'MESH:D010984', (225, 233))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('ovarian cancer', 'Disease', (253, 267))	('ovarian cancer', 'Phenotype', 'HP:0100615', (253, 267))	('PLD', 'Var', (79, 82))
481226	21188115	A trend (P = 0.0765) for longer overall survival (but not progression-free survival) was found for patients with high ERCC1 expression levels.	('high', 'Var', (113, 117))	('overall survival', 'MPA', (32, 48))	('patients', 'Species', '9606', (99, 107))	('longer', 'PosReg', (25, 31))	('expression', 'MPA', (124, 134))	('ERCC1', 'Gene', '2067', (118, 123))	('ERCC1', 'Gene', (118, 123))
481246	21188115	A single-agent Phase I trial showed interesting activity in tumors from BRCA 1 or BRCA 2 mutation carriers, with a favorable toxicity profile.	('BRCA 2', 'Gene', '675', (82, 88))	('BRCA 2', 'Gene', (82, 88))	('activity', 'MPA', (48, 56))	('BRCA 1', 'Gene', (72, 78))	('BRCA 1', 'Gene', '672', (72, 78))	('mutation', 'Var', (89, 97))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('toxicity', 'Disease', 'MESH:D064420', (125, 133))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('toxicity', 'Disease', (125, 133))	('tumors', 'Disease', (60, 66))
481248	21188115	However, an analysis of the expansion cohort of the Phase I study of olaparib in BRCA mutation carriers showed a correlation between response and duration of the platinum-free interval, suggesting that PARPs may not be as active in patients with platinum-resistant disease.	('BRCA', 'Gene', (81, 85))	('PARP', 'Gene', (202, 206))	('platinum', 'Chemical', 'MESH:D010984', (162, 170))	('patients', 'Species', '9606', (232, 240))	('olaparib', 'Chemical', 'MESH:C531550', (69, 77))	('platinum', 'Chemical', 'MESH:D010984', (246, 254))	('PARP', 'Gene', '142', (202, 206))	('mutation', 'Var', (86, 94))	('BRCA', 'Gene', '672', (81, 85))
481274	20339529	Cytogenetics revealed the characteristic t(15;17) (q22;q21-q22) and the RT-PCR assay showed the typical PML/RARalpha fusion gene thereby confirming the diagnosis of APL.	('APL', 'Disease', (165, 168))	('APL', 'Disease', 'MESH:D015473', (165, 168))	('t(15;17) (q22;q21-q22', 'Var', (41, 62))	('CR', 'Chemical', 'MESH:D002857', (76, 78))	('RARalpha', 'Gene', (108, 116))	('PML/RAR', 'Gene', '84106;5371;5914', (104, 111))	('APL', 'Phenotype', 'HP:0004836', (165, 168))	('PML/RAR', 'Gene', (104, 111))	('RARalpha', 'Gene', '5914', (108, 116))
481307	20339529	In particular, the five EMD localizations in the LAP0389 study were in the CNS (1 patient), the skin (3 patients), and the middle ear (1 patient).	('EMD', 'Disease', (24, 27))	('EMD', 'Disease', 'None', (24, 27))	('patient', 'Species', '9606', (137, 144))	('patient', 'Species', '9606', (82, 89))	('patients', 'Species', '9606', (104, 112))	('patient', 'Species', '9606', (104, 111))	('LAP0389', 'Var', (49, 56))
481400	26629783	Expression of beta-catenin and IGF-1R was associated with reduced sarcoma-specific survival and high IGF-1R expression was associated with reduced time to distant recurrence.	('sarcoma', 'Disease', (66, 73))	('high IGF-', 'Phenotype', 'HP:0030269', (96, 105))	('beta-catenin', 'Gene', (14, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('IGF-1R', 'Gene', '3480', (101, 107))	('beta-catenin', 'Gene', '1499', (14, 26))	('IGF-1R', 'Gene', (101, 107))	('high', 'Var', (96, 100))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('expression', 'MPA', (108, 118))	('reduced', 'NegReg', (139, 146))	('IGF-1R', 'Gene', '3480', (31, 37))	('reduced', 'NegReg', (58, 65))	('IGF-1R', 'Gene', (31, 37))	('time to distant recurrence', 'CPA', (147, 173))
481407	26629783	Currently, the utility of preoperative radiation in patients with retroperitoneal sarcomas is being examined in the STRASS study, which includes patients with LMS (NCT01344018) as well as a variety of other histologies and seeks to address the question of the benefit of radiation in these unique tumors in a randomized, prospective fashion.	('patients', 'Species', '9606', (145, 153))	('NCT01344018', 'Var', (164, 175))	('LMS', 'Disease', (159, 162))	('retroperitoneal sarcomas', 'Disease', 'MESH:D012186', (66, 90))	('tumors', 'Disease', 'MESH:D009369', (297, 303))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('LMS', 'Phenotype', 'HP:0100243', (159, 162))	('retroperitoneal sarcomas', 'Phenotype', 'HP:0006729', (66, 90))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumors', 'Disease', (297, 303))	('retroperitoneal sarcomas', 'Disease', (66, 90))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('patients', 'Species', '9606', (52, 60))
481422	26629783	We found that high level of IGF-1R expression in vascular LMS was associated with worse DSS survival and time to distant recurrence (Table 2).	('time', 'CPA', (105, 109))	('expression', 'MPA', (35, 45))	('high', 'Var', (14, 18))	('DSS', 'Chemical', '-', (88, 91))	('IGF-1R', 'Gene', '3480', (28, 34))	('worse', 'NegReg', (82, 87))	('DSS survival', 'CPA', (88, 100))	('IGF-1R', 'Gene', (28, 34))	('LMS', 'Phenotype', 'HP:0100243', (58, 61))
481427	26629783	Overexpression of beta-catenin in uterine LMS has been shown to be associated to local failure .	('beta-catenin', 'Gene', (18, 30))	('LMS', 'Phenotype', 'HP:0100243', (42, 45))	('local failure', 'Disease', (81, 94))	('beta-catenin', 'Gene', '1499', (18, 30))	('Overexpression', 'Var', (0, 14))	('local failure', 'Disease', 'MESH:D012594', (81, 94))
481433	23660392	MyD88 is involved in oncogene-induced cell intrinsic inflammation and in cancer-associated extrinsic inflammation, and as such MyD88 contributes to skin, liver, pancreatic, and colon carcinogenesis, as well as sarcomagenesis.	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (177, 197))	('MyD88', 'Var', (127, 132))	('cancer', 'Disease', (73, 79))	('intrinsic inflammation', 'Disease', 'MESH:D007249', (43, 65))	('inflammation', 'Disease', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('pancreatic', 'Disease', 'MESH:D010195', (161, 171))	('inflammation', 'Disease', (53, 65))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('colon carcinogenesis', 'Disease', (177, 197))	('skin', 'Disease', (148, 152))	('sarcoma', 'Disease', (210, 217))	('liver', 'Disease', (154, 159))	('pancreatic', 'Disease', (161, 171))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('contributes', 'Reg', (133, 144))	('intrinsic inflammation', 'Disease', (43, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))
481447	23660392	Chronic inflammation promotes cancer development through multiple mechanisms including genetic and epigenetic modifications arising from genomic instability and DNA damage, mediated in part by the local generation of reactive oxygen species (ROS).	('epigenetic modifications', 'Var', (99, 123))	('Chronic inflammation', 'Disease', (0, 20))	('rat', 'Species', '10116', (207, 210))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('promotes', 'PosReg', (21, 29))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (217, 240))	('ROS', 'Chemical', 'MESH:D017382', (242, 245))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
481458	23660392	MyD88 mutation at amino acid 265 is frequent in B cell malignancies and leads to constitutive activation of NF-kappaB signaling, confirming the importance of this axis in cancer pathogenesis.	('NF-kappaB signaling', 'MPA', (108, 127))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('mutation at', 'Var', (6, 17))	('malignancies', 'Disease', 'MESH:D009369', (55, 67))	('cancer', 'Disease', (171, 177))	('activation', 'PosReg', (94, 104))	('malignancies', 'Disease', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('MyD88', 'Gene', (0, 5))
481460	23660392	TLR single nucleotide polymorphisms are associated with risk for stomach, prostate, and cervical cancers.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('stomach', 'Disease', (65, 72))	('single nucleotide polymorphisms', 'Var', (4, 35))	('cervical cancers', 'Disease', (88, 104))	('cervical cancers', 'Disease', 'MESH:D002583', (88, 104))	('prostate', 'Disease', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('TLR', 'Gene', (0, 3))	('associated', 'Reg', (40, 50))
481461	23660392	IL-1 polymorphisms are associated with lung and breast cancer, as well as gastric cancer in which IL-1 may play a role in the response to H. pylori infection.	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('breast cancer', 'Disease', (48, 61))	('lung', 'Disease', 'MESH:D008171', (39, 43))	('IL-1', 'Gene', '111343', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('H. pylori infection', 'Phenotype', 'HP:0005202', (138, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('associated', 'Reg', (23, 33))	('lung', 'Disease', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('H. pylori', 'Species', '210', (138, 147))	('infection', 'Disease', (148, 157))	('infection', 'Disease', 'MESH:D007239', (148, 157))	('IL-1', 'Gene', (98, 102))	('polymorphisms', 'Var', (5, 18))	('gastric cancer', 'Disease', (74, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('IL-1', 'Gene', '111343', (98, 102))	('IL-1', 'Gene', (0, 4))
481462	23660392	IL-1beta polymorphism is also associated with severity of anorexia/cachexia comorbidity and decreased survival in lung cancer patients.	('cachexia', 'Phenotype', 'HP:0004326', (67, 75))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('survival', 'CPA', (102, 110))	('anorexia', 'Phenotype', 'HP:0002039', (58, 66))	('polymorphism', 'Var', (9, 21))	('anorexia/cachexia comorbidity', 'Disease', 'MESH:D002100', (58, 87))	('IL-1beta', 'Gene', (0, 8))	('lung cancer', 'Disease', (114, 125))	('anorexia/cachexia comorbidity', 'Disease', (58, 87))	('patients', 'Species', '9606', (126, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('decreased', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
481465	23660392	Also, the requirement for inflammasome activation for processing of pro-IL-1beta and pro-IL-18 explains the partially overlapping results on intestinal dysbiosis, colitis, and colon carcinogenesis observed in mice deficient in genes encoding inflammasome components with those obtained in Myd88-/- mice unable to signal through the IL-1 receptor family.	('IL-1', 'Gene', (72, 76))	('Myd88', 'Gene', (289, 294))	('IL-18', 'Gene', '16173', (89, 94))	('colitis', 'Phenotype', 'HP:0002583', (163, 170))	('IL-1', 'Gene', (332, 336))	('IL-1', 'Gene', '111343', (89, 93))	('mice', 'Species', '10090', (298, 302))	('intestinal dysbiosis', 'Disease', 'MESH:D064806', (141, 161))	('IL-1', 'Gene', '111343', (72, 76))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (176, 196))	('Myd88', 'Gene', '17874', (289, 294))	('IL-1', 'Gene', '111343', (332, 336))	('mice', 'Species', '10090', (209, 213))	('colitis', 'Disease', (163, 170))	('intestinal dysbiosis', 'Disease', (141, 161))	('colon carcinogenesis', 'Disease', (176, 196))	('colitis', 'Disease', 'MESH:D003092', (163, 170))	('IL-18', 'Gene', (89, 94))	('IL-1', 'Gene', (89, 93))	('deficient', 'Var', (214, 223))
481496	23660392	MyD88 inactivation in many human tumor cell lines suppresses proliferation, which is consistent with its role in cell survival and proliferation.	('rat', 'Species', '10116', (138, 141))	('inactivation', 'Var', (6, 18))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('suppresses', 'NegReg', (50, 60))	('human', 'Species', '9606', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('rat', 'Species', '10116', (68, 71))	('tumor', 'Disease', (33, 38))	('proliferation', 'CPA', (61, 74))	('MyD88', 'Gene', (0, 5))
481498	23660392	Thus, MyD88, in an autonomous way or downstream of constitutive activation of TLRs or IL-1Rs, may cooperate with TRAF6 signaling to enable unrestricted proliferation of tumor cells.	('rat', 'Species', '10116', (103, 106))	('enable', 'PosReg', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('IL-1', 'Gene', (86, 90))	('IL-1', 'Gene', '111343', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('MyD88', 'Var', (6, 11))	('TLRs', 'Gene', (78, 82))	('tumor', 'Disease', (169, 174))	('rat', 'Species', '10116', (159, 162))	('unrestricted proliferation', 'CPA', (139, 165))
481504	23660392	Overall, the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes is dependent on an autocrine loop of IL-1alpha release, IL-1R activation, and MyD88 signaling, which leads to IkBalpha phosphorylation and NF-kappaB activation (Figure 2).	('IL-1', 'Gene', '111343', (147, 151))	('IL-1', 'Gene', '111343', (128, 132))	('oncogenic', 'Var', (60, 69))	('IL-1', 'Gene', (128, 132))	('phosphorylation', 'MPA', (210, 225))	('rat', 'Species', '10116', (79, 82))	('NF-kappaB', 'Protein', (230, 239))	('activation', 'PosReg', (240, 250))	('IkBalpha', 'Protein', (201, 209))	('IL-1', 'Gene', (147, 151))
481505	23660392	In contrast to RAS-transformed mouse embryonic fibroblasts and human melanoma cells that contain a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, in which MyD88 cooperates with RAS to induce ERK activation, RAS-transformed keratinocytes from Myd88-/-or Il1r-/- mice fail to activate NF-kappaB but not ERK.	('rat', 'Species', '10116', (183, 186))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (99, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('human', 'Species', '9606', (63, 68))	('mouse', 'Species', '10090', (31, 36))	('BRAF', 'Gene', '109880', (147, 151))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (99, 145))	('melanoma', 'Disease', (69, 77))	('mutation', 'Var', (153, 161))	('rat', 'Species', '10116', (242, 245))	('ERK', 'Gene', (208, 211))	('Myd88', 'Gene', (259, 264))	('BRAF', 'Gene', (147, 151))	('ERK', 'Gene', (318, 321))	('mice', 'Species', '10090', (278, 282))	('ERK', 'Gene', '26413', (208, 211))	('ERK', 'Gene', '26413', (318, 321))	('Myd88', 'Gene', '17874', (259, 264))
481514	23660392	Thus, RAS shares with other pro-oncogenes such as rearranged during transfection (RET), BRAF, and v-myc myelocytomatosis viral oncogene homolog (MYC) not only the ability, when activated by mutation or overexpression, to deregulate cell cycling leading to cell transformation and uncontrolled tumor growth but also through the release of soluble mediators to affect the stromal cells and the interaction between the tumor and microenvironment.	('myelocytomatosis viral', 'Disease', (104, 126))	('myc', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('MYC', 'Gene', (145, 148))	('BRAF', 'Gene', (88, 92))	('cell cycling', 'CPA', (232, 244))	('cell transformation', 'CPA', (256, 275))	('RET', 'Gene', (82, 85))	('tumor', 'Disease', (416, 421))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('myelocytomatosis viral', 'Disease', 'MESH:D001102', (104, 126))	('tumor', 'Disease', 'MESH:D009369', (416, 421))	('deregulate', 'Reg', (221, 231))	('affect', 'Reg', (359, 365))	('MYC', 'Gene', '17869', (145, 148))	('interaction', 'Interaction', (392, 403))	('BRAF', 'Gene', '109880', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (416, 421))	('mutation', 'Var', (190, 198))	('myc', 'Gene', '17869', (100, 103))	('RET', 'Gene', '19713', (82, 85))	('tumor', 'Disease', (293, 298))
481517	23660392	A number of studies establish a cell intrinsic protumorigenic function for CXCR2.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('CXCR2', 'Var', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
481525	23660392	However, when these growth arrest mechanisms fail, oncogene-induced DNA damage and the associated intrinsic inflammatory pathways activated by a SASP-like response may promote carcinogenesis.	('intrinsic inflammatory pathways', 'Pathway', (98, 129))	('arrest', 'Disease', (27, 33))	('promote', 'PosReg', (168, 175))	('oncogene-induced', 'Var', (51, 67))	('carcinogenesis', 'Disease', 'MESH:D063646', (176, 190))	('growth arrest', 'Phenotype', 'HP:0001510', (20, 33))	('carcinogenesis', 'Disease', (176, 190))	('arrest', 'Disease', 'MESH:D006323', (27, 33))
481546	23660392	However, MyD88 inhibition in vivo exacerbates pancreatic inflammation and malignant progression by enhancing the capacity of dendritic cells to promote carcinogenesis by inducing a protumorigenic Th2-type response providing another example of the opposite effects of MyD88 on tumor initiation and progression by targeting inflammation-induced carcinogenesis or modulating antitumor immunity.	('inflammation', 'Disease', 'MESH:D007249', (322, 334))	('malignant progression', 'CPA', (74, 95))	('tumor', 'Disease', (376, 381))	('inducing', 'PosReg', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('exacerbates', 'PosReg', (34, 45))	('pancreatic inflammation', 'Phenotype', 'HP:0001733', (46, 69))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('pancreatic inflammation', 'Disease', (46, 69))	('promote', 'PosReg', (144, 151))	('tumor', 'Disease', (184, 189))	('inflammation', 'Disease', (322, 334))	('inhibition', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('MyD88', 'Gene', (9, 14))	('carcinogenesis', 'Disease', (343, 357))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('tumor', 'Disease', (276, 281))	('Th2', 'Gene', (196, 199))	('enhancing', 'PosReg', (99, 108))	('carcinogenesis', 'Disease', (152, 166))	('Th2', 'Gene', '15111', (196, 199))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('carcinogenesis', 'Disease', 'MESH:D063646', (343, 357))	('pancreatic inflammation', 'Disease', 'MESH:D007249', (46, 69))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('modulating', 'Reg', (361, 371))	('inflammation', 'Disease', (57, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))
481549	23660392	In ApcMin/+ mice that carry a heterozygous truncation mutation at codon 850 of the tumor suppressor adenomatous polyposis coli (Apc) gene and generate spontaneous intestinal tumors from loss of heterozygosity, MyD88 contributes to adenoma growth and progression.	('intestinal tumors', 'Disease', 'MESH:D007414', (163, 180))	('tumor', 'Disease', (83, 88))	('Apc', 'Gene', (3, 6))	('Apc', 'Gene', '11789', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('Apc', 'Phenotype', 'HP:0005227', (3, 6))	('contributes', 'Reg', (216, 227))	('loss of heterozygosity', 'Var', (186, 208))	('adenoma growth', 'Disease', (231, 245))	('mice', 'Species', '10090', (12, 16))	('Apc', 'Gene', (128, 131))	('intestinal tumors', 'Disease', (163, 180))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Apc', 'Gene', '11789', (128, 131))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (100, 126))	('MyD88', 'Gene', (210, 215))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (100, 126))	('adenomatous polyposis coli', 'Disease', (100, 126))	('adenoma growth', 'Disease', 'MESH:D000236', (231, 245))	('Apc', 'Phenotype', 'HP:0005227', (128, 131))	('progression', 'CPA', (250, 261))	('tumor', 'Disease', (174, 179))	('rat', 'Species', '10116', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
481552	23660392	Although Myd88-/- mice are viable and apparently normal in the absence of infection, early studies highlighted an important role for MyD88 in maintaining intestinal homeostasis, in that gamma-irradiation or administration of DSS resulted in severe ulceration and inflammation, accompanied by bleeding and lethality.	('gamma-irradiation', 'Var', (186, 203))	('rat', 'Species', '10116', (252, 255))	('resulted in', 'Reg', (229, 240))	('ulceration', 'CPA', (248, 258))	('inflammation', 'Disease', 'MESH:D007249', (263, 275))	('rat', 'Species', '10116', (215, 218))	('mice', 'Species', '10090', (18, 22))	('Myd88', 'Gene', (9, 14))	('inflammation', 'Disease', (263, 275))	('Myd88', 'Gene', '17874', (9, 14))	('lethality', 'CPA', (305, 314))	('infection', 'Disease', 'MESH:D007239', (74, 83))	('MyD88', 'Gene', (133, 138))	('bleeding', 'Disease', 'MESH:D006470', (292, 300))	('bleeding', 'Disease', (292, 300))	('infection', 'Disease', (74, 83))	('intestinal homeostasis', 'MPA', (154, 176))	('DSS', 'Chemical', 'MESH:D016264', (225, 228))
481556	23660392	Mice with enterocyte-specific depletion of IKKbeta, a key regulator of NF-kappaB, developed a lower number of colonic polyps than wild type mice when treated with AOM followed by tumor promotion with DSS.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mice', 'Species', '10090', (140, 144))	('AOM', 'Chemical', 'MESH:D001397', (163, 166))	('colonic polyps', 'Disease', 'MESH:D003111', (110, 124))	('depletion', 'Var', (30, 39))	('colonic polyps', 'Disease', (110, 124))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('lower', 'NegReg', (94, 99))	('Mice', 'Species', '10090', (0, 4))	('DSS', 'Chemical', 'MESH:D016264', (200, 203))	('IKKbeta', 'Gene', (43, 50))	('IKKbeta', 'Gene', '16150', (43, 50))	('tumor', 'Disease', (179, 184))
481557	23660392	Also, when IKKbeta was specifically deleted in myeloid cells, the size of the polyps was decreased, suggesting that NF-kappaB-dependent myeloid-derived factors such as cytokines promote tumor growth.	('polyps', 'Disease', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('IKKbeta', 'Gene', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('promote', 'PosReg', (178, 185))	('tumor', 'Disease', (186, 191))	('polyps', 'Disease', 'MESH:D011127', (78, 84))	('IKKbeta', 'Gene', '16150', (11, 18))	('deleted', 'Var', (36, 43))	('decreased', 'NegReg', (89, 98))
481559	23660392	Myd88-/- mice are more susceptible to AOM/DSS-induced colitis and form more polyps that are larger and have histological characteristics of more aggressive adenomas and carcinomas with frequent mutation in the beta-catenin gene.	('AOM/DSS-induced', 'Disease', (38, 53))	('colitis', 'Phenotype', 'HP:0002583', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('carcinomas', 'Disease', 'MESH:D002277', (169, 179))	('Myd88', 'Gene', (0, 5))	('mutation', 'Var', (194, 202))	('polyps', 'Disease', (76, 82))	('aggressive adenomas', 'Disease', (145, 164))	('colitis', 'Disease', (54, 61))	('AOM', 'Chemical', 'MESH:D001397', (38, 41))	('Myd88', 'Gene', '17874', (0, 5))	('beta-catenin', 'Gene', '12387', (210, 222))	('carcinomas', 'Disease', (169, 179))	('colitis', 'Disease', 'MESH:D003092', (54, 61))	('mice', 'Species', '10090', (9, 13))	('polyps', 'Disease', 'MESH:D011127', (76, 82))	('beta-catenin', 'Gene', (210, 222))	('susceptible', 'Reg', (23, 34))	('more', 'PosReg', (140, 144))	('DSS', 'Chemical', 'MESH:D016264', (42, 45))	('aggressive adenomas', 'Disease', 'MESH:D000236', (145, 164))
481560	23660392	Although mice deficient for single TLRs in some cases show increased susceptibility to colitis, they never showed an increased incidence of AOM/DSS-induced polyps as observed in the Myd88-/- mice with the possible exception of TLR2 deficiency.	('Myd88', 'Gene', (182, 187))	('colitis', 'Disease', 'MESH:D003092', (87, 94))	('TLR2 deficiency', 'Disease', (227, 242))	('colitis', 'Disease', (87, 94))	('polyps', 'Disease', 'MESH:D011127', (156, 162))	('DSS', 'Chemical', 'MESH:D016264', (144, 147))	('AOM', 'Chemical', 'MESH:D001397', (140, 143))	('Myd88', 'Gene', '17874', (182, 187))	('deficient', 'Var', (14, 23))	('mice', 'Species', '10090', (191, 195))	('TLR2 deficiency', 'Disease', 'MESH:D007153', (227, 242))	('mice', 'Species', '10090', (9, 13))	('susceptibility', 'Reg', (69, 83))	('colitis', 'Phenotype', 'HP:0002583', (87, 94))	('polyps', 'Disease', (156, 162))	('AOM/DSS-induced', 'Disease', (140, 155))
481563	23660392	In mice deficient for the NLRP6 inflammasome, which are susceptible to spontaneous and DSS-induced colitis, IL-18 levels were decreased and the bacterial phyla Bacteroidetes (Prevotellaceae) and TM7 were expanded in the fecal microbiota.	('decreased', 'NegReg', (126, 135))	('IL-18', 'Gene', '16173', (108, 113))	('colitis', 'Phenotype', 'HP:0002583', (99, 106))	('IL-18', 'Gene', (108, 113))	('mice', 'Species', '10090', (3, 7))	('DSS', 'Chemical', 'MESH:D016264', (87, 90))	('expanded', 'PosReg', (204, 212))	('colitis', 'Disease', 'MESH:D003092', (99, 106))	('NLRP6', 'Gene', '101613', (26, 31))	('colitis', 'Disease', (99, 106))	('NLRP6', 'Gene', (26, 31))	('deficient', 'Var', (8, 17))
481572	23660392	In these two models of carcinogenesis, mucosal damage-induced inflammation has a limited role on tumor initiation but the proliferative effect of IL-22 facilitates the initiation of tumor dependent on loss of heterozygosity in the Apc locus or on AOM-induced mutation of beta-catenin or other loci.	('mucosal damage-induced inflammation', 'Disease', (39, 74))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('IL-22', 'Gene', '50929', (146, 151))	('loss', 'NegReg', (201, 205))	('tumor', 'Disease', (97, 102))	('initiation', 'MPA', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Apc', 'Gene', (231, 234))	('Apc', 'Gene', '11789', (231, 234))	('AOM', 'Chemical', 'MESH:D001397', (247, 250))	('facilitates', 'PosReg', (152, 163))	('IL-22', 'Gene', (146, 151))	('Apc', 'Phenotype', 'HP:0005227', (231, 234))	('mutation', 'Var', (259, 267))	('carcinogenesis', 'Disease', (23, 37))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('rat', 'Species', '10116', (129, 132))	('beta-catenin', 'Gene', '12387', (271, 283))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('carcinogenesis', 'Disease', 'MESH:D063646', (23, 37))	('mucosal damage-induced inflammation', 'Disease', 'MESH:D007249', (39, 74))	('beta-catenin', 'Gene', (271, 283))
481584	23660392	C57BL/6 mice are resistant to tumor formation induced by endogenous retroviruses but several immunodeficient C57BL/6 strains, including Myd88-/- and Tlr3-/-Tlr7-/-Tlr9-/- mice, spontaneously develop lymphomas caused by integration of infectious ecotropic murine leukemia viruses.	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('Tlr3', 'Gene', (149, 153))	('Tlr9', 'Gene', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('develop', 'PosReg', (191, 198))	('Myd88', 'Gene', (136, 141))	('lymphomas', 'Disease', (199, 208))	('mice', 'Species', '10090', (171, 175))	('Tlr7', 'Gene', '170743', (156, 160))	('murine leukemia viruses', 'Species', '11786', (255, 278))	('lymphoma', 'Phenotype', 'HP:0002665', (199, 207))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Tlr7', 'Gene', (156, 160))	('integration', 'Var', (219, 230))	('tumor', 'Disease', (30, 35))	('Myd88', 'Gene', '17874', (136, 141))	('lymphomas', 'Disease', 'MESH:D008223', (199, 208))	('Tlr9', 'Gene', '81897', (163, 167))	('lymphomas', 'Phenotype', 'HP:0002665', (199, 208))	('Tlr3', 'Gene', '142980', (149, 153))	('C57BL/6', 'Var', (109, 116))	('rat', 'Species', '10116', (224, 227))	('mice', 'Species', '10090', (8, 12))
481585	23660392	These viruses are generated by rearrangement of the defective endogenous retroviruses Emv2 on C57BL/6 mouse chromosome 8 with several endogenous retroviral sequences on other chromosomes.	('Emv2', 'Gene', (86, 90))	('Emv2', 'Gene', '111372', (86, 90))	('rat', 'Species', '10116', (22, 25))	('rearrangement', 'Var', (31, 44))	('mouse', 'Species', '10090', (102, 107))
481612	29466964	The immunochemistry showed CD34(+++), CD31(+++), FVIII(+), Ki-67(50%+), CD3(-), CD20(-), CD68(-), CD163(-), GPC3(-), HCC(-), CD5(-), CK19(-), PD-1(-), PD-L1(-), C-MET(-), ROS-1(-), VEGF(+), EGFR(-), HER2(-), ALK D5F3(-), VEGFR2(60%+), VEGFR3(-).	('CD68', 'Gene', '968', (89, 93))	('VEGF', 'Gene', (235, 239))	('C-MET', 'Gene', '4233', (161, 166))	('CK19', 'Gene', (133, 137))	('FVIII', 'Gene', (49, 54))	('CD68', 'Gene', (89, 93))	('HER2', 'Gene', '2064', (199, 203))	('CK19', 'Gene', '3880', (133, 137))	('CD31', 'Gene', '5175', (38, 42))	('CD34', 'Gene', '947', (27, 31))	('PD-L1', 'Gene', (151, 156))	('C-MET', 'Gene', (161, 166))	('VEGFR3', 'Gene', (235, 241))	('PD-L1', 'Gene', '29126', (151, 156))	('VEGF', 'Gene', '7422', (221, 225))	('CD31', 'Gene', (38, 42))	('HER2', 'Gene', (199, 203))	('CD20', 'Gene', (80, 84))	('VEGFR2', 'Gene', (221, 227))	('GPC3', 'Gene', (108, 112))	('CD163', 'Var', (98, 103))	('GPC3', 'Gene', '2719', (108, 112))	('VEGF', 'Gene', (221, 225))	('CD3', 'Var', (72, 75))	('VEGF', 'Gene', '7422', (181, 185))	('FVIII', 'Gene', '2157', (49, 54))	('VEGFR2', 'Gene', '3791', (221, 227))	('VEGFR3', 'Gene', '2324', (235, 241))	('CD34', 'Gene', (27, 31))	('VEGF', 'Gene', (181, 185))	('CD20', 'Gene', '54474', (80, 84))	('VEGF', 'Gene', '7422', (235, 239))
481689	27683180	Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments.	('TP53', 'Gene', (21, 25))	('pediatric cancer', 'Disease', 'MESH:D009369', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('pediatric cancer', 'Disease', (73, 89))	('malignant neoplasms', 'Disease', 'MESH:D009369', (107, 126))	('malignant neoplasms', 'Disease', (107, 126))	('SMNs', 'Chemical', '-', (128, 132))	('alterations', 'Var', (26, 37))	('malignant neoplasms', 'Disease', 'MESH:D009369', (48, 67))	('malignant neoplasms', 'Disease', (48, 67))	('neoplasms', 'Phenotype', 'HP:0002664', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('TP53', 'Gene', '7157', (21, 25))	('cancer', 'Disease', (188, 194))	('pediatric cancer', 'Disease', 'MESH:D009369', (178, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('pediatric cancer', 'Disease', (178, 194))	('cancer', 'Disease', (83, 89))	('Second', 'Disease', (100, 106))	('neoplasms', 'Phenotype', 'HP:0002664', (117, 126))
481690	27683180	To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants we analyzed germline and SMN samples from pediatric cancer survivors.	('sarcomas', 'Disease', 'MESH:D012509', (62, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('SMN', 'Gene', (97, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('SMN', 'Gene', (148, 151))	('SMN', 'Gene', '6606', (97, 100))	('SMN', 'Gene', '6606', (148, 151))	('pediatric cancer', 'Disease', (165, 181))	('variants', 'Var', (114, 122))	('sarcomas', 'Disease', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pediatric cancer', 'Disease', 'MESH:D009369', (165, 181))
481692	27683180	To assess the frequency of germline TP53 variants in SMNs, Sanger sequencing was performed to analyze germline TP53 in thirty-seven pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without history of a familial cancer predisposition syndrome but known to have developed SMNs.	('variants', 'Var', (41, 49))	('familial cancer', 'Disease', 'MESH:D009369', (228, 243))	('pediatric cancer', 'Disease', 'MESH:D009369', (132, 148))	('TP53', 'Gene', '7157', (111, 115))	('TP53', 'Gene', (36, 40))	('Cancer', 'Disease', (178, 184))	('SMNs', 'Chemical', '-', (296, 300))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TP53', 'Gene', '7157', (36, 40))	('Cancer', 'Disease', 'MESH:D009369', (178, 184))	('TP53', 'Gene', (111, 115))	('Cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pediatric cancer', 'Disease', (132, 148))	('SMNs', 'Chemical', '-', (53, 57))	('familial cancer', 'Disease', (228, 243))
481693	27683180	WES revealed TP53 mutations involving p53's DNA binding domain in both index cases, one of which was also present in the germline.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('binding', 'Interaction', (48, 55))	('mutations', 'Var', (18, 27))
481694	27683180	The germline and somatic TP53 mutant variants were enriched in the transcriptomes for both sarcomas.	('TP53', 'Gene', (25, 29))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('mutant variants', 'Var', (30, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('variants', 'Var', (37, 45))	('sarcomas', 'Disease', (91, 99))	('TP53', 'Gene', '7157', (25, 29))
481695	27683180	Analysis of TP53 coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in six patients and a synonymous single nucleotide polymorphism A639G in four others, resulting in ten out of 37 evaluable patients (27%) harboring a germline TP53 variant.	('harboring', 'Reg', (288, 297))	('TP53', 'Gene', '7157', (309, 313))	('G215C', 'Var', (95, 100))	('A639G', 'Mutation', 'rs1800372', (214, 219))	('G215C', 'Mutation', 'rs1042522', (95, 100))	('patients', 'Species', '9606', (273, 281))	('TP53', 'Gene', (309, 313))	('patients', 'Species', '9606', (157, 165))	('TP53', 'Gene', '7157', (12, 16))	('A639G', 'Var', (214, 219))	('R72P', 'Var', (121, 125))	('R72P', 'Mutation', 'rs1042522', (121, 125))	('TP53', 'Gene', (12, 16))
481697	27683180	These data support the concept that identifying germline TP53 variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive post-treatment monitoring.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('SMN', 'Gene', (152, 155))	('variants', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('SMN', 'Gene', '6606', (152, 155))	('patients', 'Species', '9606', (126, 134))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
481706	27683180	Both SMNs exhibited a similar pattern of base substitutions, and contained mutations in the tumor suppressor gene TP53, which was somatic in one patient and present in the germline of the other.	('exhibited', 'Reg', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('TP53', 'Gene', (114, 118))	('TP53', 'Gene', '7157', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('patient', 'Species', '9606', (145, 152))	('contained', 'Reg', (65, 74))	('SMNs', 'Chemical', '-', (5, 9))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', (92, 97))
481707	27683180	Loss of normal TP53 transcripts and a corresponding enrichment of the variant TP53 transcripts occurred in both SMNs, highlighting the functional importance of these mutant p53 proteins.	('Loss', 'NegReg', (0, 4))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('TP53', 'Gene', '7157', (78, 82))	('variant', 'Var', (70, 77))	('TP53', 'Gene', (78, 82))	('SMNs', 'Chemical', '-', (112, 116))
481709	27683180	These findings implicate exonic TP53 variants as a risk factor for SMN formation and suggest a strategy for identifying pediatric cancer survivors at high risk for developing SMNs.	('SMN', 'Gene', '6606', (175, 178))	('SMN', 'Gene', (67, 70))	('risk factor', 'Reg', (51, 62))	('pediatric cancer', 'Disease', (120, 136))	('TP53', 'Gene', '7157', (32, 36))	('variants', 'Var', (37, 45))	('TP53', 'Gene', (32, 36))	('SMN', 'Gene', '6606', (67, 70))	('exonic', 'Var', (25, 31))	('pediatric cancer', 'Disease', 'MESH:D009369', (120, 136))	('SMN', 'Gene', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('SMNs', 'Chemical', '-', (175, 179))
481727	27683180	Using the exome sequencing data we identified regions of copy number variation (CNV) in tumor DNAs relative to the matched normal using Control-FREEC with default parameters.	('copy number variation', 'Var', (57, 78))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
481731	27683180	Fisher's Exact Test was used to determine whether the number of A639G substitutions in the SMN sample (4 mutations in 37 tissue samples for which chemical reactions succeeded out of 41 samples total) was higher than the frequencies observed in the 1000 Genomes Project (5 mutations in 1000 genomes sequenced).	('A639G', 'Var', (64, 69))	('SMN', 'Gene', (91, 94))	('A639G', 'Mutation', 'rs1800372', (64, 69))	('SMN', 'Gene', '6606', (91, 94))
481740	27683180	WES of germline and tumor DNA from Patient 1 identified a somatic TP53 mutation (rs28934574, c.844C>T, p.Arg282Trp) (Fig.	('Patient', 'Species', '9606', (35, 42))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('p.Arg282Trp', 'Var', (103, 114))	('c.844C>T', 'Mutation', 'rs28934574', (93, 101))	('rs28934574', 'Var', (81, 91))	('rs28934574', 'Mutation', 'rs28934574', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('c.844C>T', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('p.Arg282Trp', 'Mutation', 'rs28934574', (103, 114))	('tumor', 'Disease', (20, 25))
481744	27683180	By contrast, Patient 2 harbored a heterozygous germline mutation in the TP53 gene that has been previously associated with Li-Fraumeni Syndrome (rs11540652, c.743G>A, p.Arg248Gln) (Fig.	('c.743G>A', 'Var', (157, 165))	('Li-Fraumeni Syndrome', 'Disease', (123, 143))	('TP53', 'Gene', '7157', (72, 76))	('associated', 'Reg', (107, 117))	('rs11540652', 'Var', (145, 155))	('TP53', 'Gene', (72, 76))	('c.743G>A', 'Mutation', 'rs11540652', (157, 165))	('p.Arg248Gln', 'Mutation', 'rs11540652', (167, 178))	('Patient', 'Species', '9606', (13, 20))	('rs11540652', 'Mutation', 'rs11540652', (145, 155))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (123, 143))	('p.Arg248Gln', 'Var', (167, 178))
481745	27683180	Both exomes sequenced from Patient 2's SMN (referred to as samples 'a' and 'b') showed enrichment of the germline TP53 mutation, as evidenced qualitatively by Sanger sequencing chromatograms and quantitatively by read count (Fig.	('mutation', 'Var', (119, 127))	('SMN', 'Gene', '6606', (39, 42))	('TP53', 'Gene', '7157', (114, 118))	('SMN', 'Gene', (39, 42))	('TP53', 'Gene', (114, 118))	('Patient', 'Species', '9606', (27, 34))
481749	27683180	A total of 202 somatic single nucleotide variants (SNVs) were identified Patient 1's sarcoma SMN (including 41 non-synonymous and 8 small indels - Supplementary File 1 and Supplementary Fig.	("'s sarcoma SMN", 'Disease', (82, 96))	('Patient', 'Species', '9606', (73, 80))	('single nucleotide', 'Var', (23, 40))	("'s sarcoma SMN", 'Disease', 'MESH:D012509', (82, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
481752	27683180	Sixteen dinucleotide substitutions were identified across all tumor exomes, of which 10 were unique (Supplementary File 3).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('dinucleotide substitutions', 'Var', (8, 34))	('tumor', 'Disease', (62, 67))	('dinucleotide', 'Chemical', 'MESH:D015226', (8, 20))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
481754	27683180	In addition to the high confidence TP53 driver mutations described above, Patient 2 also had a putative driver mutation (Category 2) in NCOA2, a gene encoding a transcriptional coactivator for nuclear receptors known to be altered in sarcomas.	('NCOA2', 'Gene', '10499', (136, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('sarcomas', 'Disease', (234, 242))	('TP53', 'Gene', '7157', (35, 39))	('NCOA2', 'Gene', (136, 141))	('TP53', 'Gene', (35, 39))	('Patient', 'Species', '9606', (74, 81))	('mutation', 'Var', (111, 119))	('sarcomas', 'Disease', 'MESH:D012509', (234, 242))	('sarcomas', 'Phenotype', 'HP:0100242', (234, 242))
481756	27683180	Both SMN exomes were characterized by copy number variations (Fig.	('SMN', 'Gene', '6606', (5, 8))	('copy number variations', 'Var', (38, 60))	('SMN', 'Gene', (5, 8))
481759	27683180	Numerous copy number losses occurred on chromosomes 4, 5, 6, 7, 13, 16, and 17 in both sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('copy number losses', 'Var', (9, 27))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcomas', 'Disease', (87, 95))
481766	27683180	We analyzed copy number changes involving genes described in the COSMIC cancer gene census (October 2015), which likely contribute to tumorigenesis.	('copy number changes', 'Var', (12, 31))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('contribute', 'Reg', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', (134, 139))	('cancer', 'Disease', (72, 78))
481767	27683180	Patient 1 had 216 genes affected by copy number change that were listed as associated with cancer in the COSMIC database.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('copy number change', 'Var', (36, 54))	('associated', 'Reg', (75, 85))	('Patient', 'Species', '9606', (0, 7))
481768	27683180	For Patient 2, there were 275 genes in the COSMIC database affected by copy number change, due in a large part to gains in chromosomes 1 (n = 39), 9 (n = 27), 17 (n = 27) and 19 (n = 28) (Supplementary Files 1 and 2).	('Patient', 'Species', '9606', (4, 11))	('gains', 'PosReg', (114, 119))	('copy number change', 'Var', (71, 89))
481769	27683180	Transcriptome sequencing revealed differential TP53 expression in both SMNs, with mutant TP53 highly overexpressed relative to normal skeletal muscle (Fig.	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('overexpressed', 'PosReg', (101, 114))	('TP53', 'Gene', '7157', (47, 51))	('SMNs', 'Chemical', '-', (71, 75))	('TP53', 'Gene', (47, 51))	('mutant', 'Var', (82, 88))
481770	27683180	Expression of mutant TP53 predominated in Patient 1's SMN, with 96% of reads (105 out of 109 total reads) supporting the TP53 mutation.	('TP53', 'Gene', (21, 25))	('mutant', 'Var', (14, 20))	('TP53', 'Gene', '7157', (121, 125))	('mutation', 'Var', (126, 134))	('TP53', 'Gene', (121, 125))	('SMN', 'Gene', (54, 57))	('SMN', 'Gene', '6606', (54, 57))	('Patient', 'Species', '9606', (42, 49))	('TP53', 'Gene', '7157', (21, 25))
481771	27683180	Similarly, in Patient 2's SMN expression of the mutant germline TP53 dominated, supported by 95% of the reads covering this position (407 out of 430 total reads).	('mutant', 'Var', (48, 54))	('SMN', 'Gene', (26, 29))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('SMN', 'Gene', '6606', (26, 29))	('Patient', 'Species', '9606', (14, 21))
481772	27683180	We observed a significant preponderance of two transcript isoforms producing truncated p53 proteins with a shorter N-terminus region compared to the canonical tumor suppressor p53alpha, which is the most abundant isoform in normal tissues (Fig.	('N-terminus region', 'MPA', (115, 132))	('p53', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('proteins', 'Protein', (91, 99))	('tumor', 'Disease', (159, 164))	('truncated', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
481773	27683180	Patient 2's SMN demonstrated increased expression of transcript isoform Delta40p53alpha (9.541 and 2.284 FPKM for Patients 2 and 1 respectively), whereas the Delta133p53alpha isoform was more abundant in Patient 1 (7.256 FPKM) compared to Patient 2 (2.943 FPKM) (Fig.	('Delta133p53alpha', 'Var', (158, 174))	('Patient', 'Species', '9606', (114, 121))	('Delta40p53alpha', 'Var', (72, 87))	('SMN', 'Gene', (12, 15))	('Patient', 'Species', '9606', (204, 211))	('increased', 'PosReg', (29, 38))	('SMN', 'Gene', '6606', (12, 15))	('Patient', 'Species', '9606', (239, 246))	('expression', 'MPA', (39, 49))	('Patient', 'Species', '9606', (0, 7))	('Patients', 'Species', '9606', (114, 122))
481774	27683180	This variant stimulates angiogenesis and tumor progression in a p53alpha-dependent and independent manner when overexpressed (NM_001126115; Fig.	('angiogenesis', 'CPA', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('stimulates', 'PosReg', (13, 23))	('variant', 'Var', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
481776	27683180	To determine whether germline TP53 variants are present at higher frequencies in pediatric cancer survivors developing SMNs compared to the general population, we investigated a validation cohort of 37 pediatric cancer survivors registered in the Childhood Cancer Survivor Study (CCSS) known to have developed solid SMNs.	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (30, 34))	('SMNs', 'Chemical', '-', (119, 123))	('variants', 'Var', (35, 43))	('pediatric cancer', 'Disease', (202, 218))	('pediatric cancer', 'Disease', (81, 97))	('SMNs', 'Chemical', '-', (316, 320))	('Cancer', 'Phenotype', 'HP:0002664', (257, 263))	('Cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (257, 263))	('pediatric cancer', 'Disease', 'MESH:D009369', (202, 218))	('pediatric cancer', 'Disease', 'MESH:D009369', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
481783	27683180	Four out of 37 individuals (11%) harbored a germline variant A639G located in exon 6 (R213R in the protein) (Fig.	('A639G', 'Var', (61, 66))	('R213R', 'Mutation', 'rs1800372', (86, 91))	('R213R', 'Var', (86, 91))	('A639G', 'Mutation', 'rs1800372', (61, 66))
481785	27683180	A second germline variant identified in this cohort was G215C in exon 4 (R72P in the protein, rs1042522) (Supplementary Fig.	('rs1042522', 'Mutation', 'rs1042522', (94, 103))	('G215C', 'Mutation', 'rs1042522', (56, 61))	('G215C', 'Var', (56, 61))	('R72P', 'Mutation', 'rs1042522', (73, 77))	('rs1042522', 'Var', (94, 103))
481786	27683180	5, Table 1), which was present in 6 patients and mutually exclusive with the germline A639G variant, resulting in ten out of 37 evaluable patients (27%) harboring a germline TP53 variant.	('A639G', 'Var', (86, 91))	('patients', 'Species', '9606', (36, 44))	('TP53', 'Gene', (174, 178))	('A639G', 'Mutation', 'rs1800372', (86, 91))	('patients', 'Species', '9606', (138, 146))	('TP53', 'Gene', '7157', (174, 178))
481789	27683180	Table 1 shows the proportion of the various primary cancer groups who had a TP53 variant.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TP53', 'Gene', '7157', (76, 80))	('variant', 'Var', (81, 88))	('TP53', 'Gene', (76, 80))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
481792	27683180	Proportions of HD with p53 variants did not differ from other types (p-value approximately 0.9).	('HD', 'Disease', 'MESH:D006816', (15, 17))	('variants', 'Var', (27, 35))	('p53', 'Gene', (23, 26))
481794	27683180	Given the low frequencies of patients receiving radiation only or chemotherapy only, this data does not permit testing for significant interactions between TP53 variants and specific therapies.	('patients', 'Species', '9606', (29, 37))	('TP53', 'Gene', (156, 160))	('variants', 'Var', (161, 169))	('TP53', 'Gene', '7157', (156, 160))
481799	27683180	Thus, evaluating potential germline susceptibilities is particularly important in pediatric cancer patients, in whom a germline tumor suppressor gene mutation may underlie the primary cancer formation and potentially contribute to the risk of SMN.	('cancer', 'Disease', (184, 190))	('risk', 'Reg', (235, 239))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('underlie', 'Reg', (163, 171))	('pediatric cancer', 'Disease', (82, 98))	('mutation', 'Var', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('SMN', 'Gene', (243, 246))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('patients', 'Species', '9606', (99, 107))	('contribute to', 'Reg', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('SMN', 'Gene', '6606', (243, 246))	('pediatric cancer', 'Disease', 'MESH:D009369', (82, 98))
481802	27683180	Using next-generation sequencing approaches this study identifies TP53 mutations in the exomes and transcriptomes of SMNs, which can arise as somatic alterations (as in the case of Patient 1) or germline mutations (as exemplified by Patient 2).	('SMNs', 'Disease', (117, 121))	('arise', 'Reg', (133, 138))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('SMNs', 'Chemical', '-', (117, 121))	('mutations', 'Var', (71, 80))	('Patient', 'Species', '9606', (233, 240))	('Patient', 'Species', '9606', (181, 188))
481803	27683180	Coordinated WES and RNA-Seq also indicate how mutant TP53 can be represented in SMN transcriptomes.	('SMN', 'Gene', (80, 83))	('mutant', 'Var', (46, 52))	('SMN', 'Gene', '6606', (80, 83))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))
481804	27683180	We found that in the presence of either somatic or germline TP53 mutations, wildtype TP53 is lost and mutant TP53 duplicated and overexpressed in the SMN.	('mutant', 'Var', (102, 108))	('TP53', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (109, 113))	('lost', 'NegReg', (93, 97))	('SMN', 'Gene', (150, 153))	('TP53', 'Gene', '7157', (85, 89))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (109, 113))	('SMN', 'Gene', '6606', (150, 153))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
481805	27683180	Copy number alterations were common in both SMNs, however in both cases, copy number neutral loss of heterozygosity occurred with TP53, suggesting a shared genetic mechanism distinguishable from the remainder of the exome.	('loss of heterozygosity', 'NegReg', (93, 115))	('SMNs', 'Chemical', '-', (44, 48))	('copy number neutral', 'Var', (73, 92))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))
481807	27683180	Prior analysis of an adult cancer patient with multiple primary tumors and a therapy-related acute myeloid leukemia identified a germline TP53 mutation, supporting the idea that cryptic variants in cancer susceptibility genes can define susceptibility to primary and secondary cancers.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('patient', 'Species', '9606', (34, 41))	('acute myeloid leukemia', 'Disease', (93, 115))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', (277, 283))	('TP53', 'Gene', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (93, 115))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (99, 115))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('mutation', 'Var', (143, 151))	('cancers', 'Disease', (277, 284))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (93, 115))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('TP53', 'Gene', '7157', (138, 142))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('susceptibility', 'Reg', (237, 251))	('cancer', 'Disease', (27, 33))
481808	27683180	In our study, Patient 2 had Li-Fraumeni Syndrome but no first-degree relatives with malignancy, raising the possibility that TP53 variants are more common in pediatric survivors who develop SMNs as compared to the general population.	('variants', 'Var', (130, 138))	('develop', 'PosReg', (182, 189))	('TP53', 'Gene', '7157', (125, 129))	('common', 'Reg', (148, 154))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (28, 48))	('SMNs', 'Disease', (190, 194))	('malignancy', 'Disease', 'MESH:D009369', (84, 94))	('SMNs', 'Chemical', '-', (190, 194))	('TP53', 'Gene', (125, 129))	('Li-Fraumeni Syndrome', 'Disease', (28, 48))	('malignancy', 'Disease', (84, 94))	('Patient', 'Species', '9606', (14, 21))
481809	27683180	Individuals with Li-Fraumeni syndrome, who have a known germline TP53 mutation, are at high risk for developing a diverse array of malignancies, including sarcomas, which can present in early childhood.	('malignancies', 'Disease', (131, 143))	('sarcomas', 'Disease', 'MESH:D012509', (155, 163))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcomas', 'Disease', (155, 163))	('malignancies', 'Disease', 'MESH:D009369', (131, 143))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (17, 37))	('mutation', 'Var', (70, 78))	('Li-Fraumeni syndrome', 'Disease', (17, 37))
481812	27683180	Using next-generation sequencing of both SMN exomes and transcriptomes, this work presents molecular evidence establishing that the germline TP53 variant is exclusively represented in the transcriptome in specific mRNA isoforms.	('variant', 'Var', (146, 153))	('SMN', 'Gene', '6606', (41, 44))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('SMN', 'Gene', (41, 44))
481813	27683180	This analysis identified the recurrent SNP rs1800372 in a validation cohort of pediatric cancer survivors who subsequently developed SMNs.	('rs1800372', 'Var', (43, 52))	('pediatric cancer', 'Disease', 'MESH:D009369', (79, 95))	('rs1800372', 'Mutation', 'rs1800372', (43, 52))	('pediatric cancer', 'Disease', (79, 95))	('SMNs', 'Chemical', '-', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
481814	27683180	Although rs1800372 is a synonymous variant, synonymous variants are not necessarily silent or neutral in cancer evolution, as TP53 synonymous mutations can inactivate function.	('inactivate', 'NegReg', (156, 166))	('rs1800372', 'Mutation', 'rs1800372', (9, 18))	('function', 'MPA', (167, 175))	('rs1800372', 'Var', (9, 18))	('TP53', 'Gene', (126, 130))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TP53', 'Gene', '7157', (126, 130))
481815	27683180	Indeed, rs1800372 is associated with poor outcome in primary breast cancer, and synonymous variants in the mouse Trp53 gene have been shown to influence binding of the Trp53 transcript to MDM2 and subsequent p53 function.	('Trp53', 'Gene', (168, 173))	('rs1800372', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('function', 'MPA', (212, 220))	('rs1800372', 'Mutation', 'rs1800372', (8, 17))	('mouse', 'Species', '10090', (107, 112))	('primary breast cancer', 'Disease', (53, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('MDM2', 'Gene', (188, 192))	('Trp53', 'Gene', '22059', (113, 118))	('MDM2', 'Gene', '17246', (188, 192))	('Trp53', 'Gene', '22059', (168, 173))	('influence', 'Reg', (143, 152))	('binding', 'Interaction', (153, 160))	('variants', 'Var', (91, 99))	('primary breast cancer', 'Disease', 'MESH:D001943', (53, 74))	('Trp53', 'Gene', (113, 118))
481816	27683180	Similarly, the R72P p53 variant (rs1042522), which is not classified as a deleterious mutation, has also been implicated in cancer susceptibility in humans.	('p53', 'Gene', (20, 23))	('R72P', 'Var', (15, 19))	('cancer', 'Disease', (124, 130))	('implicated', 'Reg', (110, 120))	('humans', 'Species', '9606', (149, 155))	('rs1042522', 'Mutation', 'rs1042522', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs1042522', 'Var', (33, 42))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('R72P', 'Mutation', 'rs1042522', (15, 19))
481817	27683180	To our knowledge, this analysis is the first multi-omics analysis of SMNs and determination of germline TP53 variants in survivors of pediatric malignancies.	('pediatric malignancies', 'Disease', (134, 156))	('TP53', 'Gene', '7157', (104, 108))	('SMNs', 'Chemical', '-', (69, 73))	('TP53', 'Gene', (104, 108))	('variants', 'Var', (109, 117))	('pediatric malignancies', 'Disease', 'MESH:D063766', (134, 156))
481830	27683180	In addition, for specific types of second malignancies, germline mutations in TP53, RB1 and NF1 are listed as risk factors.	('malignancies', 'Disease', 'MESH:D009369', (42, 54))	('RB1', 'Gene', (84, 87))	('NF1', 'Gene', (92, 95))	('malignancies', 'Disease', (42, 54))	('TP53', 'Gene', '7157', (78, 82))	('NF1', 'Gene', '4763', (92, 95))	('TP53', 'Gene', (78, 82))	('RB1', 'Gene', '5925', (84, 87))	('germline mutations', 'Var', (56, 74))
481836	27683180	Analysis of a larger cohort of pediatric cancer survivors developing SMNs may identify additional genetic variants that significantly correlate with second cancer development.	('correlate with', 'Reg', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('variants', 'Var', (106, 114))	('SMNs', 'Chemical', '-', (69, 73))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('pediatric cancer', 'Disease', (31, 47))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('pediatric cancer', 'Disease', 'MESH:D009369', (31, 47))
481839	27683180	Appropriately applying such approaches requires accurately identifying which individuals are at greatest risk for SMN development, and our findings strongly suggest that analyzing the TP53 gene for variants, both synonymous and non-synonymous, may be a viable strategy for identifying individuals at greatest risk of SMN formation.	('SMN', 'Gene', (317, 320))	('SMN', 'Gene', (114, 117))	('SMN', 'Gene', '6606', (317, 320))	('SMN', 'Gene', '6606', (114, 117))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('variants', 'Var', (198, 206))
481848	27683180	We identify somatic and germline TP53 mutations in sarcoma SMNs, and in a cohort of pediatric cancer survivors known to develop SMNs a TP53 polymorphism is significantly more frequent than the estimated frequency in the general population.	('SMNs', 'Chemical', '-', (59, 63))	('pediatric cancer', 'Disease', (84, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('TP53', 'Gene', '7157', (135, 139))	('SMNs', 'Chemical', '-', (128, 132))	('TP53', 'Gene', '7157', (33, 37))	('pediatric cancer', 'Disease', 'MESH:D009369', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TP53', 'Gene', (135, 139))	('sarcoma SMNs', 'Disease', (51, 63))	('TP53', 'Gene', (33, 37))	('sarcoma SMNs', 'Disease', 'MESH:D012509', (51, 63))	('mutations', 'Var', (38, 47))
481859	27680598	Growth was slowest with Vin50-G, 28+-10.3 DTEP compared to all other treatment groups (p<0.05).	('Vin50-G', 'Var', (24, 31))	('Vin50-G', 'Chemical', '-', (24, 31))	('slowest', 'NegReg', (11, 18))	('Growth', 'CPA', (0, 6))	('DTEP', 'Chemical', '-', (42, 46))
481926	27680598	Tumors implanted with Dox400-F took 6 +- 1 day for tumor volume to reach >1,000 mm3, which was no different than Control-F (p = 0.13).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('Dox400-F', 'Chemical', '-', (22, 30))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Dox400-F', 'Var', (22, 30))
481927	27680598	Tumors implanted with Vin50-F took 12.4 +- 3.5 days to reach >1,000 mm3, significantly slower than Control-F treated tumors (p = 0.01).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Vin50-F', 'Chemical', '-', (22, 29))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('Vin50-F', 'Var', (22, 29))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
481930	27680598	Given that Vin50-F had successfully slowed tumor grow, we next aimed to improve the delivery procedure and eliminate the open procedure associated with foam implantation.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('Vin50-F', 'Chemical', '-', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('Vin50-F', 'Var', (11, 18))	('slowed', 'NegReg', (36, 42))
481933	27680598	Tumors treated with Vin50-G took 28 +- 10.3 days to reach 1,000 mm3.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Vin50-G', 'Chemical', '-', (20, 27))	('Vin50-G', 'Var', (20, 27))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
481936	27680598	We found that treatment with Vin50-G produced significantly longer survival compared to all other groups (p<0.001).	('longer', 'PosReg', (60, 66))	('survival', 'CPA', (67, 75))	('Vin50-G', 'Chemical', '-', (29, 36))	('Vin50-G', 'Var', (29, 36))
482018	26425710	Following surgical staging, the patient completed systemic treatment with carboplatin (AUC 5) and paclitaxel (175 mg/m2) dosed every 21 days, followed by whole pelvic radiotherapy (5040 cGy) and vaginal brachytherapy (2283 cGy).	('2283 cGy', 'Var', (218, 226))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('patient', 'Species', '9606', (32, 39))	('5040 cGy', 'Var', (181, 189))	('carboplatin', 'Chemical', 'MESH:D016190', (74, 85))
482067	23158439	An inflammatory microenvironment and/or the age-dependent accumulation of genetic mutations and epigenetic alterations have a well-recognized importance in the pathogenesis of adult tumors.	('rat', 'Species', '10116', (111, 114))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('genetic mutations', 'Var', (74, 91))	('adult tumors', 'Disease', 'MESH:C538052', (176, 188))	('adult tumors', 'Disease', (176, 188))	('epigenetic alterations', 'Var', (96, 118))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
482069	23158439	This view is also supported by the observation that the most aggressive pediatric tumors frequently harbor chromosomal translocations involving genes that regulate embryogenesis and tissue determination.	('chromosomal translocations', 'Var', (107, 133))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('pediatric tumors', 'Disease', (72, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('harbor', 'Reg', (100, 106))	('pediatric tumors', 'Disease', 'MESH:D063766', (72, 88))
482072	23158439	Mutations of molecular components of Notch signaling have been involved in different genetic disorders.	('Notch', 'Gene', '31293', (37, 42))	('involved', 'Reg', (63, 71))	('Mutations', 'Var', (0, 9))	('genetic disorders', 'Disease', (85, 102))	('Notch', 'Gene', (37, 42))	('genetic disorders', 'Disease', 'MESH:D030342', (85, 102))
482076	23158439	Over the past few years, growing evidence also points to a role of abnormalities of Notch signaling in pediatric solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('Notch', 'Gene', '31293', (84, 89))	('solid tumors', 'Disease', 'MESH:D009369', (113, 125))	('abnormalities', 'Var', (67, 80))	('Notch', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('solid tumors', 'Disease', (113, 125))
482091	23158439	Indeed, recently we and other groups have shown pre-clinical evidence that Notch signaling modulation has anti-tumor effects in the most common pediatric STS such as ES and RMS.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Notch', 'Gene', '31293', (75, 80))	('STS', 'Phenotype', 'HP:0030448', (154, 157))	('RMS', 'Disease', (173, 176))	('tumor', 'Disease', (111, 116))	('ES', 'Phenotype', 'HP:0012254', (166, 168))	('modulation', 'Var', (91, 101))	('RMS', 'Phenotype', 'HP:0002859', (173, 176))	('Notch', 'Gene', (75, 80))
482114	23158439	For instance, LFNG-mediated modifications in most cells reduce the affinity for Jagged family ligands but not Delta family ligands.	('modifications', 'Var', (28, 41))	('LFNG', 'Gene', '3955', (14, 18))	('Jagged family', 'Protein', (80, 93))	('affinity', 'Interaction', (67, 75))	('reduce', 'NegReg', (56, 62))	('LFNG', 'Gene', (14, 18))
482118	23158439	Contrary to what is observed in T-ALL that often is triggered by a Notch1 receptor mutation, in solid cancers, few genetic alterations have been found so far in Notch signaling components.	('solid cancers', 'Disease', 'MESH:D009369', (96, 109))	('Notch', 'Gene', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Notch', 'Gene', '31293', (67, 72))	('mutation', 'Var', (83, 91))	('Notch', 'Gene', '31293', (161, 166))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('rat', 'Species', '10116', (127, 130))	('Notch1', 'Gene', (67, 73))	('solid cancers', 'Disease', (96, 109))	('Notch1', 'Gene', '4851', (67, 73))	('Notch', 'Gene', (67, 72))
482132	23158439	Finally, knockdown of SS18-SSX in SS cell lines induced loss of differentiation abilities into mesenchymal-derived tissue, strongly supporting the hypothesis of a MSC origin for this tumor.	('knockdown', 'Var', (9, 18))	('loss', 'NegReg', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('SS', 'Phenotype', 'HP:0012570', (22, 24))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('SS', 'Phenotype', 'HP:0012570', (34, 36))	('SS', 'Phenotype', 'HP:0012570', (27, 29))	('SSX', 'Gene', (27, 30))	('SSX', 'Gene', '6757', (27, 30))	('tumor', 'Disease', (183, 188))
482146	23158439	Conversely, disruption of the SS18-SSX/TLE1/ATF2 complex by silencing of SS18-SSX led to cell cycle arrest and cell death.	('disruption', 'Var', (12, 22))	('cell cycle arrest', 'CPA', (89, 106))	('SS', 'Phenotype', 'HP:0012570', (30, 32))	('TLE1', 'Gene', '7088', (39, 43))	('SS', 'Phenotype', 'HP:0012570', (78, 80))	('SSX', 'Gene', '6757', (78, 81))	('SSX', 'Gene', (78, 81))	('SS', 'Phenotype', 'HP:0012570', (35, 37))	('ATF2', 'Gene', (44, 48))	('silencing', 'NegReg', (60, 69))	('TLE1', 'Gene', (39, 43))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (89, 106))	('cell death', 'CPA', (111, 121))	('SSX', 'Gene', (35, 38))	('SSX', 'Gene', '6757', (35, 38))	('SS', 'Phenotype', 'HP:0012570', (73, 75))	('ATF2', 'Gene', '1386', (44, 48))
482149	23158439	The knockdown of TLE1 increased the transcription of EGR1 and decreased the levels of histone H3 trimethylation on Lysine 27 (H3K27me3), which is a mark of EZH2 activity.	('TLE1', 'Gene', '7088', (17, 21))	('decreased', 'NegReg', (62, 71))	('EGR1', 'Gene', (53, 57))	('EZH2', 'Gene', '2146', (156, 160))	('increased', 'PosReg', (22, 31))	('EGR1', 'Gene', '1958', (53, 57))	('TLE1', 'Gene', (17, 21))	('EZH2', 'Gene', (156, 160))	('levels of histone H3 trimethylation on Lysine 27', 'MPA', (76, 124))	('knockdown', 'Var', (4, 13))	('transcription', 'MPA', (36, 49))	('Lysine', 'Chemical', 'MESH:D008239', (115, 121))
482150	23158439	Taken together, these findings suggest that TLE1, a known effector of Notch signaling, plays a fundamental role in the SS18-SSX epigenetic regulation of gene expression in SS.	('epigenetic regulation', 'Var', (128, 149))	('TLE1', 'Gene', '7088', (44, 48))	('SS', 'Phenotype', 'HP:0012570', (119, 121))	('Notch', 'Gene', (70, 75))	('SS', 'Phenotype', 'HP:0012570', (172, 174))	('TLE1', 'Gene', (44, 48))	('SS', 'Phenotype', 'HP:0012570', (124, 126))	('Notch', 'Gene', '31293', (70, 75))	('SSX', 'Gene', '6757', (124, 127))	('SSX', 'Gene', (124, 127))
482164	23158439	HES1 expression in ES cell lines was inhibited via expression of a dominant-negative Notch1 or the use of a GSI, while it was increased after expression of active Notch1 ICD.	('Notch1', 'Gene', '4851', (85, 91))	('HES1', 'Gene', '3280', (0, 4))	('expression', 'MPA', (5, 15))	('inhibited', 'NegReg', (37, 46))	('GSI', 'Chemical', '-', (108, 111))	('Notch1', 'Gene', (163, 169))	('ICD', 'Disease', 'OMIM:252500', (170, 173))	('HES1', 'Gene', (0, 4))	('ICD', 'Disease', (170, 173))	('ES', 'Phenotype', 'HP:0012254', (19, 21))	('Notch1', 'Gene', '4851', (163, 169))	('ES', 'Phenotype', 'HP:0012254', (1, 3))	('Notch1', 'Gene', (85, 91))	('dominant-negative', 'Var', (67, 84))
482166	23158439	Inhibition of Notch signaling did not result in reduced tumor growth in vivo but rather in neuroectodermal differentiation of tumor xenografts.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('rat', 'Species', '10116', (81, 84))	('tumor', 'Disease', (56, 61))	('Notch', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Notch', 'Gene', '31293', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (126, 131))
482169	23158439	Indeed, upon EWS-FLI1 silencing, wild-type p53 ES cells showed p53 activation and triggering of the molecular cascade involving the cyclin-dependent kinase (CDK) inhibitor p21Cip1 leading to cell growth arrest followed by apoptosis.	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('activation', 'PosReg', (67, 77))	('triggering', 'Reg', (82, 92))	('apoptosis', 'CPA', (222, 231))	('p21Cip1', 'Gene', '1026', (172, 179))	('EWS-FLI1', 'Gene', (13, 21))	('growth arrest', 'Disease', (196, 209))	('EWS-FLI1', 'Gene', '2130;2313', (13, 21))	('silencing', 'Var', (22, 31))	('growth arrest', 'Disease', 'MESH:D006323', (196, 209))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('ES', 'Phenotype', 'HP:0012254', (47, 49))	('growth arrest', 'Phenotype', 'HP:0001510', (196, 209))	('p21Cip1', 'Gene', (172, 179))
482173	23158439	Subsequent studies demonstrated that HEY1 transcription is due to activation of the Notch3 receptor, the most highly expressed Notch receptor in both ES primary tumors and cell lines, by JAG1 (Jagged1).	('Jagged1', 'Gene', (193, 200))	('Notch', 'Gene', '31293', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('Notch', 'Gene', (127, 132))	('ES primary tumors', 'Disease', (150, 167))	('transcription', 'Var', (42, 55))	('rat', 'Species', '10116', (26, 29))	('JAG1', 'Gene', '182', (187, 191))	('ES', 'Phenotype', 'HP:0012254', (150, 152))	('JAG1', 'Gene', (187, 191))	('Notch', 'Gene', '31293', (127, 132))	('HEY1', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Notch', 'Gene', (84, 89))	('ES primary tumors', 'Disease', 'MESH:C563168', (150, 167))	('Jagged1', 'Gene', '182', (193, 200))	('activation', 'PosReg', (66, 76))
482174	23158439	Jagged1 over-expression was observed after EWS-FLI1 knockdown.	('Jagged1', 'Gene', '182', (0, 7))	('EWS-FLI1', 'Gene', (43, 51))	('over-expression', 'PosReg', (8, 23))	('EWS-FLI1', 'Gene', '2130;2313', (43, 51))	('Jagged1', 'Gene', (0, 7))	('knockdown', 'Var', (52, 61))
482175	23158439	Notch3 signaling was inhibited through either JAG1 silencing, GSI or over-expression of Notch negative regulator NUMB.	('Notch', 'Gene', (0, 5))	('Notch', 'Gene', '31293', (88, 93))	('over-expression', 'PosReg', (69, 84))	('NUMB', 'Gene', (113, 117))	('JAG1', 'Gene', '182', (46, 50))	('Notch', 'Gene', '31293', (0, 5))	('GSI', 'Chemical', '-', (62, 65))	('GSI', 'Var', (62, 65))	('JAG1', 'Gene', (46, 50))	('inhibited', 'NegReg', (21, 30))	('NUMB', 'Gene', '8650', (113, 117))	('Notch', 'Gene', (88, 93))	('silencing', 'NegReg', (51, 60))
482188	23158439	Moreover, while Notch1 ICD and Notch3 ICD over-expression was sufficient to prevent the proliferation of ES cells, blockade of HES1 did not have any effect.	('ICD', 'Disease', (38, 41))	('HES1', 'Gene', '3280', (127, 131))	('rat', 'Species', '10116', (95, 98))	('ICD', 'Disease', 'OMIM:252500', (23, 26))	('HES1', 'Gene', (127, 131))	('ES', 'Phenotype', 'HP:0012254', (128, 130))	('ES', 'Phenotype', 'HP:0012254', (105, 107))	('ICD', 'Disease', (23, 26))	('Notch1', 'Gene', (16, 22))	('Notch3', 'Var', (31, 37))	('proliferation', 'CPA', (88, 101))	('ICD', 'Disease', 'OMIM:252500', (38, 41))	('Notch1', 'Gene', '4851', (16, 22))	('prevent', 'NegReg', (76, 83))
482189	23158439	A recently discovered link between ES pathogenesis and epigenetic pathways could have implications for Notch signaling inactivation in this tumor.	('ES', 'Phenotype', 'HP:0012254', (35, 37))	('tumor', 'Disease', (140, 145))	('implications', 'Reg', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Notch', 'Gene', (103, 108))	('epigenetic pathways', 'Pathway', (55, 74))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Notch', 'Gene', '31293', (103, 108))	('inactivation', 'Var', (119, 131))
482192	23158439	In addition to having a primary role in epithelial-mesenchymal transition (EMT), LSD1 stimulates cell proliferation and survival by binding histone deacetylase complexes and specifically demethylating both Lysine 4 and Lysine 9 on histone H3 (H3K4 and H3K9).	('H3K9', 'Protein', (252, 256))	('histone deacetylase complexes', 'Protein', (140, 169))	('survival', 'CPA', (120, 128))	('Lysine', 'Var', (206, 212))	('rat', 'Species', '10116', (109, 112))	('Lysine', 'Var', (219, 225))	('Lysine', 'Chemical', 'MESH:D008239', (219, 225))	('stimulates', 'PosReg', (86, 96))	('Lysine', 'Chemical', 'MESH:D008239', (206, 212))	('binding', 'Interaction', (132, 139))	('cell proliferation', 'CPA', (97, 115))	('epithelial-mesenchymal transition', 'CPA', (40, 73))	('LSD1', 'Gene', (81, 85))	('demethylating', 'Var', (187, 200))
482206	23158439	demonstrated that the Notch target gene HES1 was over-expressed in RMS primary tumors and cell lines compared to normal muscle, and its inhibition through a dominant-negative HES1 form promoted skeletal muscle-like differentiation of RMS cells (Table 1).	('ES', 'Phenotype', 'HP:0012254', (176, 178))	('HES1', 'Gene', (40, 44))	('HES1', 'Gene', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('rat', 'Species', '10116', (7, 10))	('RMS', 'Phenotype', 'HP:0002859', (67, 70))	('ES', 'Phenotype', 'HP:0012254', (41, 43))	('RMS', 'Phenotype', 'HP:0002859', (234, 237))	('HES1', 'Gene', '3280', (40, 44))	('tumors', 'Disease', (79, 85))	('HES1', 'Gene', '3280', (175, 179))	('dominant-negative', 'Var', (157, 174))	('Notch', 'Gene', '31293', (22, 27))	('over-expressed', 'PosReg', (49, 63))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('skeletal muscle-like differentiation', 'CPA', (194, 230))	('inhibition', 'NegReg', (136, 146))	('promoted', 'PosReg', (185, 193))	('Notch', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
482207	23158439	Inhibition of Notch signaling with GSIs phenocopied this pro-myogenic effect and lowered HES1 expression, suggesting that HES1 de-regulation in RMS is Notch-dependent.	('HES1', 'Gene', '3280', (89, 93))	('lowered', 'NegReg', (81, 88))	('ES', 'Phenotype', 'HP:0012254', (90, 92))	('Notch', 'Gene', (14, 19))	('Notch', 'Gene', (151, 156))	('HES1', 'Gene', (122, 126))	('HES1', 'Gene', (89, 93))	('pro-myogenic effect', 'MPA', (57, 76))	('Notch', 'Gene', '31293', (14, 19))	('RMS', 'Phenotype', 'HP:0002859', (144, 147))	('Inhibition', 'Var', (0, 10))	('expression', 'MPA', (94, 104))	('de-regulation', 'NegReg', (127, 140))	('HES1', 'Gene', '3280', (122, 126))	('Notch', 'Gene', '31293', (151, 156))	('GSI', 'Chemical', '-', (35, 38))	('ES', 'Phenotype', 'HP:0012254', (123, 125))
482217	23158439	However, no overt phenotypic signs of muscle-like differentiation and myotube fusion were detected after HEY1 knockdown, suggesting a role for the Notch1-HEY1 axis in the regulation of proliferative rather than differentiative pathways in embryonal RMS cells.	('knockdown', 'Var', (110, 119))	('Notch1', 'Gene', (147, 153))	('Notch1', 'Gene', '4851', (147, 153))	('rat', 'Species', '10116', (192, 195))	('HEY1', 'Gene', (105, 109))	('rat', 'Species', '10116', (199, 202))	('RMS', 'Phenotype', 'HP:0002859', (249, 252))
482219	23158439	Notch1 knockdown in RMS cell lines reduces or abolishes tumorigenicity in xenografts.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('reduces', 'NegReg', (35, 42))	('Notch1', 'Gene', (0, 6))	('Notch1', 'Gene', '4851', (0, 6))	('RMS', 'Phenotype', 'HP:0002859', (20, 23))	('tumor', 'Disease', (56, 61))	('knockdown', 'Var', (7, 16))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('abolishes', 'NegReg', (46, 55))
482222	23158439	In a set of three embryonal and two alveolar cell lines over-expressing transcripts of Notch1, Notch3 and HES1 compared to normal human skeletal myoblasts, the cleaved forms of these receptors, Notch1 ICD and Notch3 ICD were detected in the nucleus.	('ICD', 'Disease', (216, 219))	('ES', 'Phenotype', 'HP:0012254', (107, 109))	('over-expressing', 'PosReg', (56, 71))	('Notch3', 'Gene', (95, 101))	('ICD', 'Disease', 'OMIM:252500', (201, 204))	('HES1', 'Gene', (106, 110))	('ICD', 'Disease', (201, 204))	('Notch3', 'Var', (209, 215))	('Notch1', 'Gene', (87, 93))	('Notch1', 'Gene', (194, 200))	('Notch1', 'Gene', '4851', (194, 200))	('ICD', 'Disease', 'OMIM:252500', (216, 219))	('Notch1', 'Gene', '4851', (87, 93))	('HES1', 'Gene', '3280', (106, 110))	('human', 'Species', '9606', (130, 135))
482228	23158439	In agreement with these observations, Notch3 knockdown noticeably led to a decrease in HES1 expression associated with the activation of myogenic pathways necessary for terminal differentiation such as p38 and AKT.	('HES1', 'Gene', '3280', (87, 91))	('AKT', 'Gene', (210, 213))	('decrease', 'NegReg', (75, 83))	('p38', 'Gene', '5594', (202, 205))	('Notch3', 'Gene', (38, 44))	('knockdown', 'Var', (45, 54))	('activation', 'PosReg', (123, 133))	('HES1', 'Gene', (87, 91))	('AKT', 'Gene', '207', (210, 213))	('p38', 'Gene', (202, 205))	('ES', 'Phenotype', 'HP:0012254', (88, 90))	('expression', 'MPA', (92, 102))	('myogenic pathways', 'Pathway', (137, 154))
482229	23158439	Moreover, JAG1 depletion strongly reduced both Notch3 ICD and HES1 levels, suggesting that Notch3 activation results, at least in part, from binding to Jagged-family ligands rather than from activating mutations.	('depletion', 'Var', (15, 24))	('Notch3', 'Gene', (91, 97))	('HES1', 'Gene', '3280', (62, 66))	('reduced', 'NegReg', (34, 41))	('JAG1', 'Gene', '182', (10, 14))	('ES', 'Phenotype', 'HP:0012254', (63, 65))	('activation', 'PosReg', (98, 108))	('binding', 'Interaction', (141, 148))	('JAG1', 'Gene', (10, 14))	('ICD', 'Disease', 'OMIM:252500', (54, 57))	('ICD', 'Disease', (54, 57))	('rat', 'Species', '10116', (174, 177))	('HES1', 'Gene', (62, 66))
482230	23158439	High throughput sequencing analysis on 75 ES and 89 RMS samples did not demonstrate any Notch1 mutations.	('ES', 'Phenotype', 'HP:0012254', (42, 44))	('Notch1', 'Gene', (88, 94))	('RMS', 'Phenotype', 'HP:0002859', (52, 55))	('mutations', 'Var', (95, 104))	('rat', 'Species', '10116', (79, 82))	('Notch1', 'Gene', '4851', (88, 94))
482231	23158439	Notch1 silencing had a lesser effect on the differentiation of the embryonal cell line, slightly increasing the expression of myogenin, and no effect in the alveolar cell line.	('myogenin', 'Gene', '4656', (126, 134))	('Notch1', 'Gene', (0, 6))	('Notch1', 'Gene', '4851', (0, 6))	('silencing', 'Var', (7, 16))	('myogenin', 'Gene', (126, 134))	('increasing', 'PosReg', (97, 107))	('expression', 'MPA', (112, 122))
482233	23158439	Strikingly, Notch2 knockdown reduced myogenin expression and promoted HES1 expression, indicating that Notch2 could play an opposite role in RMS cells compared to Notch3, as already suggested for skeletal muscle tissue commitment.	('HES1', 'Gene', (70, 74))	('HES1', 'Gene', '3280', (70, 74))	('knockdown', 'Var', (19, 28))	('promoted', 'PosReg', (61, 69))	('Notch2', 'Gene', '4853', (12, 18))	('RMS', 'Phenotype', 'HP:0002859', (141, 144))	('ES', 'Phenotype', 'HP:0012254', (71, 73))	('reduced', 'NegReg', (29, 36))	('Notch2', 'Gene', '4853', (103, 109))	('Notch2', 'Gene', (103, 109))	('myogenin', 'Gene', (37, 45))	('Notch2', 'Gene', (12, 18))	('expression', 'MPA', (75, 85))	('myogenin', 'Gene', '4656', (37, 45))
482234	23158439	The triggering of differentiation upon Notch3 knockdown was associated with cell cycle arrest, p21Cip1 induction and a decrease in the levels of kinases regulating cell proliferation such as ERK-1 and -2.	('p21Cip1', 'Gene', '1026', (95, 102))	('ERK-1 and -2', 'Gene', '5595;5594', (191, 203))	('decrease', 'NegReg', (119, 127))	('rat', 'Species', '10116', (176, 179))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('knockdown', 'Var', (46, 55))	('cell cycle arrest', 'CPA', (76, 93))	('induction', 'MPA', (103, 112))	('levels of kinases', 'MPA', (135, 152))	('p21Cip1', 'Gene', (95, 102))	('Notch3', 'Gene', (39, 45))
482235	23158439	All these effects were mimicked in wild-type cells or reinforced in Notch3-depleted cells by HES1 silencing, whereas HES1 over-expression partly reversed the effects of Notch3 knockdown.	('ES', 'Phenotype', 'HP:0012254', (94, 96))	('HES1', 'Gene', '3280', (117, 121))	('HES1', 'Gene', '3280', (93, 97))	('ES', 'Phenotype', 'HP:0012254', (118, 120))	('silencing', 'Var', (98, 107))	('HES1', 'Gene', (117, 121))	('HES1', 'Gene', (93, 97))
482237	23158439	Finally, Notch3 depletion, even only in a fraction of cells, inhibited the growth of alveolar RMS tumors xenografted in immune-compromised mice.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('inhibited', 'NegReg', (61, 70))	('depletion', 'Var', (16, 25))	('RMS', 'Phenotype', 'HP:0002859', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('alveolar RMS tumors', 'Disease', (85, 104))	('alveolar RMS tumors', 'Disease', 'MESH:D002282', (85, 104))	('mice', 'Species', '10090', (139, 143))	('Notch3', 'Gene', (9, 15))	('growth', 'CPA', (75, 81))
482259	23158439	In a phase I study in children with recurrent central nervous system (CNS) malignancies, MK-0752 was well tolerated at the dose and schedule recommended for phase II study progression.	('rat', 'Species', '10116', (110, 113))	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('MK-0752', 'Chemical', 'MESH:C554093', (89, 96))	('malignancies', 'Disease', (75, 87))	('MK-0752', 'Var', (89, 96))	('children', 'Species', '9606', (22, 30))
482261	23158439	Importantly, only in the two responders did MK-0752 decrease the levels of Notch1 ICD in post-treatment peripheral blood mononuclear cells.	('MK-0752', 'Var', (44, 51))	('MK-0752', 'Chemical', 'MESH:C554093', (44, 51))	('ICD', 'Disease', 'OMIM:252500', (82, 85))	('decrease', 'NegReg', (52, 60))	('ICD', 'Disease', (82, 85))	('Notch1', 'Gene', (75, 81))	('Notch1', 'Gene', '4851', (75, 81))
482265	23158439	In a phase I clinical trial conducted in adult patients with solid tumors, MK-0752 demonstrated good tolerability and evidence of Notch pathway inhibition using a once-per-week dosing schedule.	('Notch', 'Gene', (130, 135))	('MK-0752', 'Chemical', 'MESH:C554093', (75, 82))	('solid tumors', 'Disease', (61, 73))	('MK-0752', 'Var', (75, 82))	('patients', 'Species', '9606', (47, 55))	('Notch', 'Gene', '31293', (130, 135))	('solid tumors', 'Disease', 'MESH:D009369', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('inhibition', 'NegReg', (144, 154))	('rat', 'Species', '10116', (90, 93))
482269	23158439	In this study, which was based on extensive preclinical data documenting cross-talk of Notch with ER, MK0752 GSI was administered after two weeks of endocrine therapy with tamoxifen or letrozole, concomitantly with continued endocrine therapy.	('MK0752 GSI', 'Var', (102, 112))	('GSI', 'Chemical', '-', (109, 112))	('Notch', 'Gene', (87, 92))	('tamoxifen', 'Chemical', 'MESH:D013629', (172, 181))	('Notch', 'Gene', '31293', (87, 92))	('letrozole', 'Chemical', 'MESH:D000077289', (185, 194))
482270	23158439	Under these conditions, no diarrhea was observed and Ki67 reduction compared to endocrine therapy alone was seen in 17 of 20 patients.	('diarrhea', 'Phenotype', 'HP:0002014', (27, 35))	('diarrhea', 'Disease', 'MESH:D003967', (27, 35))	('diarrhea', 'Disease', (27, 35))	('Ki67', 'Var', (53, 57))	('reduction', 'NegReg', (58, 67))	('patients', 'Species', '9606', (125, 133))
482273	23158439	A chemically different GSI, RO4929097, has shown antitumor activity in animal models with a concomitant differentiated histologic profile, typical of Notch inhibition.	('Notch', 'Gene', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('GSI', 'Chemical', '-', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Notch', 'Gene', '31293', (150, 155))	('tumor', 'Disease', (53, 58))	('RO4929097', 'Var', (28, 37))
482274	23158439	have reported that in a phase I study RO4929097 was well tolerated in adult patients with refractory metastatic or advanced solid tumors and some evidence of antitumor activity was observed.	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('rat', 'Species', '10116', (61, 64))	('solid tumors', 'Disease', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('RO4929097', 'Var', (38, 47))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
482275	23158439	in a phase II study showed that patients with refractory metastatic colorectal cancer treated with RO4929097 did not have radiographic responses, suggesting that RO4929097 at the study dose and schedule has minimal single agent activity in this malignancy.	('colorectal cancer', 'Disease', (68, 85))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('malignancy', 'Disease', 'MESH:D009369', (245, 255))	('RO4929097', 'Var', (99, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('malignancy', 'Disease', (245, 255))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('RO4929097', 'Var', (162, 171))
482282	23158439	However, when tumor recurrence was studied, MRK003 in combination with Herceptin completely abolished tumor regression, while LY411575 nearly abolished it.	('tumor', 'Disease', (14, 19))	('LY411575', 'Var', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('MRK003', 'Var', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('abolished', 'NegReg', (92, 101))	('Herceptin', 'Chemical', 'MESH:D000068878', (71, 80))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('LY411575', 'Chemical', 'MESH:C484278', (126, 134))
482286	23158439	Consistent with this view, in a recently closed US National Cancer Institute sponsored phase I/II study at the Memorial Sloan-Kettering Cancer Center, (New York, NY, USA) (NCT01154452), RO4929097 has been administered in combination with a hedgehog inhibitor, GDC-0449, for the treatment of adult patients with advanced and/or metastatic sarcomas, including SS.	('sarcomas', 'Disease', 'MESH:D012509', (338, 346))	('RO4929097', 'Var', (186, 195))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (338, 346))	('Cancer', 'Disease', (136, 142))	('GDC-0449', 'Chemical', 'MESH:C538724', (260, 268))	('patients', 'Species', '9606', (297, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (338, 345))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('Cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Cancer', 'Disease', 'MESH:D009369', (136, 142))	('advanced', 'Disease', (311, 319))	('metastatic', 'CPA', (327, 337))	('sarcomas', 'Disease', (338, 346))	('SS', 'Phenotype', 'HP:0012570', (358, 360))
482287	23158439	The objectives of this study were to determine the maximum-tolerated dose of RO4929097 combined with GDC-0449 (Phase Ib) and to assess the progression-free survival of patients treated with RO4929097 alone or with the hedgehog antagonist (Phase II).	('RO4929097', 'Var', (77, 86))	('patients', 'Species', '9606', (168, 176))	('rat', 'Species', '10116', (63, 66))	('GDC-0449', 'Chemical', 'MESH:C538724', (101, 109))	('RO4929097', 'Var', (190, 199))
482312	22594313	Most activated genes had SYT-SSX2 sites enriched with H3K27me3 within their body or near their transcription start site (TSS) whereas a majority of downregulated genes were characterized by SYT-SSX2/H3K27me3-rich regions at long-range, or by modifications associated with transcription activation within the gene body or near the TSS.	('SSX2', 'Gene', (29, 33))	('SSX2', 'Gene', (194, 198))	('H3K27me3', 'Var', (54, 62))	('H3', 'Chemical', 'MESH:C012616', (54, 56))	('H3', 'Chemical', 'MESH:C012616', (199, 201))	('SSX2', 'Gene', '6757', (29, 33))	('SSX2', 'Gene', '6757', (194, 198))
482313	22594313	Hierarchical and functional clustering identified H3K27me3 as the dominant epigenetic marker associated with SYT-SSX2 binding and gene expression.	('SSX2', 'Gene', '6757', (113, 117))	('H3', 'Chemical', 'MESH:C012616', (50, 52))	('SSX2', 'Gene', (113, 117))	('H3K27me3', 'Var', (50, 58))
482328	22594313	Most often, the fusion occurs with the C-terminal half of either SSX1 or SSX2 and the association with silencing Polycomb components is preserved, creating a transcriptional imbalance: the naturally antagonistic Polycomb and SWI/SNF complexes which function in concert during development to coordinate multipotency and differentiation are brought to the same genomic sites by the mutant protein.	('SSX2', 'Gene', (73, 77))	('protein', 'Protein', (387, 394))	('creating', 'Reg', (147, 155))	('SSX1', 'Gene', '6756', (65, 69))	('Polycomb', 'Gene', '40358', (113, 121))	('Polycomb', 'Gene', (113, 121))	('Polycomb', 'Gene', '40358', (212, 220))	('SSX2', 'Gene', '6757', (73, 77))	('Polycomb', 'Gene', (212, 220))	('SSX1', 'Gene', (65, 69))	('mutant', 'Var', (380, 386))	('imbalance', 'Phenotype', 'HP:0002172', (174, 183))
482330	22594313	Both aberrant silencing and activation of target genes via Polycomb activity manipulation occur due to SYT-SSX.	('Polycomb', 'Gene', '40358', (59, 67))	('manipulation', 'Var', (77, 89))	('activation', 'PosReg', (28, 38))	('silencing', 'NegReg', (14, 23))	('SSX', 'Gene', '6757', (107, 110))	('Polycomb', 'Gene', (59, 67))	('SSX', 'Gene', (107, 110))
482332	22594313	SYT-SSX2 expression also leads to aberrant transcriptional derepression of several Polycomb targets by enhancing degradation of the Polycomb Repressive Complex 1 (PRC1) core component, Bmi1.	('Polycomb', 'Gene', (83, 91))	('expression', 'Var', (9, 19))	('Polycomb', 'Gene', (132, 140))	('Bmi1', 'Gene', '648', (185, 189))	('Polycomb', 'Gene', '40358', (132, 140))	('Bmi1', 'Gene', (185, 189))	('enhancing', 'PosReg', (103, 112))	('SSX2', 'Gene', '6757', (4, 8))	('transcriptional derepression', 'MPA', (43, 71))	('degradation', 'MPA', (113, 124))	('SSX2', 'Gene', (4, 8))	('Polycomb', 'Gene', '40358', (83, 91))
482355	22594313	H3K27me3 represents the modification characteristic of Polycomb-silenced genes, and its prominent association with SYT-SSX2 supports a role for the oncogene in the re- activation of Polycomb-silenced genes.	('association', 'Interaction', (98, 109))	('Polycomb', 'Gene', (55, 63))	('SSX2', 'Gene', '6757', (119, 123))	('SSX2', 'Gene', (119, 123))	('H3K27me3', 'Var', (0, 8))	('H3', 'Chemical', 'MESH:C012616', (0, 2))	('Polycomb', 'Gene', '40358', (182, 190))	('Polycomb', 'Gene', (182, 190))	('Polycomb', 'Gene', '40358', (55, 63))
482359	22594313	These results provide a fundamental basis for future research that will unravel the effect of SYT-SSX2 on the silenced differentiation programs stabilized by Polycomb and how their disruption leads to cellular transformation.	('leads to', 'Reg', (192, 200))	('SSX2', 'Gene', '6757', (98, 102))	('cellular transformation', 'CPA', (201, 224))	('disruption', 'Var', (181, 191))	('SSX2', 'Gene', (98, 102))	('Polycomb', 'Gene', (158, 166))	('Polycomb', 'Gene', '40358', (158, 166))
482374	22594313	This accounts for 1.3% and 0.99% of the total number of regions marked by H3K4me1 and H3K18Ac, respectively (Table3), indicating that SYT-SSX2 is associated with only a small subset of locations labeled by either of these modifications.	('H3', 'Chemical', 'MESH:C012616', (86, 88))	('SSX2', 'Gene', (138, 142))	('H3', 'Chemical', 'MESH:C012616', (74, 76))	('H3K18Ac', 'Var', (86, 93))	('SSX2', 'Gene', '6757', (138, 142))	('H3K4me1', 'Var', (74, 81))
482376	22594313	The prominence of SYT-SSX2 occupying regions enriched in H3K27me3 led to the question of their location relative to known genes.	('H3', 'Chemical', 'MESH:C012616', (57, 59))	('SSX2', 'Gene', (22, 26))	('H3K27me3', 'Var', (57, 65))	('SSX2', 'Gene', '6757', (22, 26))
482377	22594313	It has been shown that Polycomb complexes can mediate both short- and long-range control of gene expression, thus we determined the location of the overlapping regions between SYT-SSX2 and H3K27me3 relative to known genes.	('H3', 'Chemical', 'MESH:C012616', (189, 191))	('SSX2', 'Gene', (180, 184))	('Polycomb', 'Gene', '40358', (23, 31))	('Polycomb', 'Gene', (23, 31))	('H3K27me3', 'Var', (189, 197))	('SSX2', 'Gene', '6757', (180, 184))
482397	22594313	Seventy-two percent (72%) of the upregulated genes and 43.6% of the downregulated genes bound by SYT-SSX2 have associated peaks that overlap with H3K27me3 (Figure3, bottom panel) corroborating previous reports that the fusion protein is targeted to Polycomb-regulated genes.	('upregulated', 'PosReg', (33, 44))	('H3', 'Chemical', 'MESH:C012616', (146, 148))	('SSX2', 'Gene', (101, 105))	('peaks', 'MPA', (122, 127))	('Polycomb', 'Gene', '40358', (249, 257))	('Polycomb', 'Gene', (249, 257))	('SSX2', 'Gene', '6757', (101, 105))	('H3K27me3', 'Var', (146, 154))
482401	22594313	Since this modification labels enhancer elements, the association of SYT-SSX2 with these sites as well as Polycomb target sites suggests that SYT-SSX2 may effect transcription by modulating both enhancer and Polycomb function.	('SSX2', 'Gene', (73, 77))	('SSX2', 'Gene', (146, 150))	('modulating', 'Reg', (179, 189))	('effect', 'Reg', (155, 161))	('enhancer', 'MPA', (195, 203))	('Polycomb', 'Gene', '40358', (208, 216))	('Polycomb', 'Gene', (208, 216))	('transcription', 'MPA', (162, 175))	('SSX2', 'Gene', '6757', (73, 77))	('modification', 'Var', (11, 23))	('Polycomb', 'Gene', (106, 114))	('SSX2', 'Gene', '6757', (146, 150))	('Polycomb', 'Gene', '40358', (106, 114))
482412	22594313	Of the negatively regulated genes, the highest levels of overlap were also seen in the gene body and occurred with H3K4me1 and H3K27me3 (Table6).	('H3', 'Chemical', 'MESH:C012616', (127, 129))	('H3K27me3', 'Var', (127, 135))	('H3', 'Chemical', 'MESH:C012616', (115, 117))	('H3K4me1', 'Var', (115, 122))
482417	22594313	Regions enriched in H3K4me2, H3K4me3, H3K9Ac, H3K18Ac, H4K12Ac, and PolII occupancy overlap with SYT-SSX2 binding sites in over 10% of the downregulated genes, and markers associated with transcriptional elongation (H3K36me3 and H2BUb) overlap with SYT-SSX2 sites in more than 5% of the downregulated genes (compared with less than 3% of the upregulated genes).	('H3', 'Chemical', 'MESH:C012616', (29, 31))	('downregulated', 'NegReg', (287, 300))	('SSX2', 'Gene', '6757', (253, 257))	('SSX2', 'Gene', (101, 105))	('H3', 'Chemical', 'MESH:C012616', (46, 48))	('SSX2', 'Gene', (253, 257))	('H3', 'Chemical', 'MESH:C012616', (38, 40))	('SSX2', 'Gene', '6757', (101, 105))	('H3', 'Chemical', 'MESH:C012616', (20, 22))	('H3', 'Chemical', 'MESH:C012616', (216, 218))	('downregulated', 'NegReg', (139, 152))	('H3K18Ac', 'Var', (46, 53))	('H4K12Ac', 'Var', (55, 62))
482418	22594313	In summary, SYT-SSX2 associates with epigenetic markers, particularly H3K27me3 and H3K4me1.	('SSX2', 'Gene', '6757', (16, 20))	('H3K4me1', 'Var', (83, 90))	('SSX2', 'Gene', (16, 20))	('H3', 'Chemical', 'MESH:C012616', (70, 72))	('H3K27me3', 'Var', (70, 78))	('associates', 'Reg', (21, 31))	('epigenetic', 'MPA', (37, 47))	('H3', 'Chemical', 'MESH:C012616', (83, 85))
482419	22594313	Most of the upregulated genes in this analysis are marked by H3K27me3, and SYT-SSX2 appears to bind close to the TSS.	('H3', 'Chemical', 'MESH:C012616', (61, 63))	('H3K27me3', 'Var', (61, 69))	('SSX2', 'Gene', '6757', (79, 83))	('SSX2', 'Gene', (79, 83))	('upregulated', 'PosReg', (12, 23))
482420	22594313	In contrast, SYT-SSX2 occupies H3K4me1- or H3K27me3-enriched regions in a similar percentage of downregulated genes and also associates with more markers of transcriptional activation and elongation.	('SSX2', 'Gene', '6757', (17, 21))	('elongation', 'CPA', (188, 198))	('activation', 'PosReg', (173, 183))	('H3', 'Chemical', 'MESH:C012616', (43, 45))	('H3K27me3-enriched', 'Var', (43, 60))	('SSX2', 'Gene', (17, 21))	('H3K4me1-', 'Var', (31, 39))	('transcriptional', 'MPA', (157, 172))	('H3', 'Chemical', 'MESH:C012616', (31, 33))	('more', 'PosReg', (141, 145))
482423	22594313	Analysis of the upregulated genes corroborated earlier results and identified H3K27me3 as the predominant modification associated with SYT-SSX2 binding and gene expression (Figure4, top panel).	('upregulated', 'PosReg', (16, 27))	('SSX2', 'Gene', (139, 143))	('binding', 'Interaction', (144, 151))	('H3', 'Chemical', 'MESH:C012616', (78, 80))	('H3K27me3', 'Var', (78, 86))	('SSX2', 'Gene', '6757', (139, 143))
482425	22594313	It has been reported previously that genes densely covered by H3K27me3 were involved in the differentiation and development of alternate lineage pathways, thus we wanted to determine the function of the genes within this sub-cluster.	('H3', 'Chemical', 'MESH:C012616', (62, 64))	('development', 'CPA', (112, 123))	('alternate lineage pathways', 'CPA', (127, 153))	('involved', 'Reg', (76, 84))	('differentiation', 'CPA', (92, 107))	('H3K27me3', 'Var', (62, 70))
482426	22594313	To summarize, SYT-SSX2 occupies regions within and upstream of upregulated genes that are enriched in H3K27me3.	('SSX2', 'Gene', (18, 22))	('H3K27me3', 'Var', (102, 110))	('upregulated', 'PosReg', (63, 74))	('SSX2', 'Gene', '6757', (18, 22))	('H3', 'Chemical', 'MESH:C012616', (102, 104))
482434	22594313	These genes were typified by certain epigenetic attributes: upregulated genes were characterized by the predominant association of SYT-SSX2 with regions enriched with the Polycomb marker H3K27me3, whereas downregulated genes could be subdivided into at least 2 categories distinguished by occupation of the fusion protein in regions displaying either H3K27me3 enrichment at short- and long-ranges or the presence of modifications associated with transcriptional activation within the gene body or near the TSS.	('modifications', 'Var', (416, 429))	('upregulated', 'PosReg', (60, 71))	('SSX2', 'Gene', (135, 139))	('H3', 'Chemical', 'MESH:C012616', (187, 189))	('Polycomb', 'Gene', '40358', (171, 179))	('Polycomb', 'Gene', (171, 179))	('H3', 'Chemical', 'MESH:C012616', (351, 353))	('SSX2', 'Gene', '6757', (135, 139))
482443	22594313	Most genes with increased expression and marked by H3K27me3 had SYT-SSX2 binding sites within their body or near their TSS, while greater numbers of genes with decreased expression marked by H3K27me3 are occupied at a distance.	('expression', 'MPA', (26, 36))	('SSX2', 'Gene', '6757', (68, 72))	('H3', 'Chemical', 'MESH:C012616', (191, 193))	('H3K27me3', 'Var', (191, 199))	('binding', 'Interaction', (73, 80))	('SSX2', 'Gene', (68, 72))	('increased', 'PosReg', (16, 25))	('H3K27me3', 'Var', (51, 59))	('H3', 'Chemical', 'MESH:C012616', (51, 53))
482449	22594313	Moreover, previous work has indicated that these are both consequences of aberrant Polycomb function since SYT-SSX2 has been shown both to antagonize and to initiate Polycomb silencing.	('Polycomb', 'Gene', (83, 91))	('SSX2', 'Gene', (111, 115))	('Polycomb', 'Gene', (166, 174))	('Polycomb', 'Gene', '40358', (166, 174))	('SSX2', 'Gene', '6757', (111, 115))	('Polycomb', 'Gene', '40358', (83, 91))	('aberrant', 'Var', (74, 82))
482452	22594313	In a recent report on the epigenetic landscape during myogenic differentiation of the C2C12 myoblasts, gene subsets pertaining to permanently silenced programs including neurogenesis appeared to be held in check by an abundance of modified histone H3K27me3, reflecting stable silencing by Polycomb.	('Polycomb', 'Gene', (289, 297))	('H3', 'Chemical', 'MESH:C012616', (248, 250))	('modified', 'Var', (231, 239))	('histone H3K27me3', 'Protein', (240, 256))	('Polycomb', 'Gene', '40358', (289, 297))
482458	22594313	Inhibition of its activity leads to neurogenesis in C2C12 cells so misexpression of its target genes by SYT-SSX2 may result in the ectopic neural program seen in these cells.	('activity', 'MPA', (18, 26))	('SSX2', 'Gene', (108, 112))	('ectopic neural program', 'CPA', (131, 153))	('leads to', 'Reg', (27, 35))	('neurogenesis', 'CPA', (36, 48))	('SSX2', 'Gene', '6757', (108, 112))	('Inhibition', 'Var', (0, 10))	('misexpression', 'Var', (67, 80))	('result in', 'Reg', (117, 126))
482460	22594313	In ES cells, enhancers that control the expression of inactive genes involved in differentiation of multiple lineages are labeled by H3K27me3 and H3K4me1.	('H3K4me1', 'Var', (146, 153))	('H3', 'Chemical', 'MESH:C012616', (133, 135))	('H3', 'Chemical', 'MESH:C012616', (146, 148))	('H3K27me3', 'Var', (133, 141))
482466	22594313	The preeminent association of SYT-SSX2 with H3K27me3 indicates that the fusion protein does not simply target to regions of open chromatin by default, but it occupies a subset of Polycomb loci.	('H3K27me3', 'Var', (44, 52))	('association', 'Interaction', (15, 26))	('SSX2', 'Gene', '6757', (34, 38))	('H3', 'Chemical', 'MESH:C012616', (44, 46))	('SSX2', 'Gene', (34, 38))	('Polycomb', 'Gene', '40358', (179, 187))	('Polycomb', 'Gene', (179, 187))
482478	22594313	All microarray and ChIPSeq data are available at the Gene Expression Omnibus (available at http://www.ncbi.nlm.nih.gov/geo/) accessions GSE26562 (C2C12 microarray), GSE26563 (hMSC microarray, GSE26564 (SYT-SSX2 ChIPSeq), and GSE26565 (accession for all datasets).	('GSE26562', 'Var', (136, 144))	('SSX2', 'Gene', '6757', (206, 210))	('GSE26563', 'Var', (165, 173))	('SSX2', 'Gene', (206, 210))
482534	22319516	Distinct from other herpesviruses, the KSHV gpK8.1 gene encodes two alternatively spliced messages yielding glycoprotein gpK8.1A and gpK8.1B.	('gpK8.1B', 'Var', (133, 140))	('D', 'Chemical', 'MESH:D003903', (0, 1))	('KSHV gpK8.1', 'Gene', (39, 50))	('KS', 'Phenotype', 'HP:0100726', (39, 41))	('KSHV', 'Species', '37296', (39, 43))	('herpesvirus', 'Species', '39059', (20, 31))
482541	22319516	Studies have demonstrated that anti-gH and anti-gL antibodies inhibit KSHV entry without affecting binding to the target cells (Naranatt et al.,).	('gL', 'Chemical', 'MESH:C015905', (48, 50))	('KSHV entry', 'MPA', (70, 80))	('anti-gH', 'Protein', (31, 38))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('anti-gL', 'Protein', (43, 50))	('KSHV', 'Species', '37296', (70, 74))	('inhibit', 'NegReg', (62, 69))	('antibodies', 'Var', (51, 61))
482560	22319516	The extracellular domain of KSHV gB possesses 108HIFKVRRYRK117, which is a BXXBXBBXBB type HBD, and is conserved throughout the gamma2 herpesviruses.	('herpesvirus', 'Species', '39059', (135, 146))	('KSHV gB', 'Gene', (28, 35))	('KSHV', 'Species', '37296', (28, 32))	('108HIFKVRRYRK117', 'Var', (46, 62))	('KS', 'Phenotype', 'HP:0100726', (28, 30))	('HBD', 'Disease', (91, 94))	('HBD', 'Disease', 'MESH:C564145', (91, 94))
482561	22319516	KSHV gpK8.1A also possesses two possible atypical heparin-binding motifs, 150SRTTRIRV157 (XBXXBXBX) and 182TRGRDAHY189 (XBXBXXBX) whereas KSHV gH lacks the typical HBD.	('HBD', 'Disease', (164, 167))	('KSHV', 'Species', '37296', (0, 4))	('heparin', 'Chemical', 'MESH:D006493', (50, 57))	('D', 'Chemical', 'MESH:D003903', (111, 112))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('182TRGRDAHY189', 'Var', (104, 118))	('150SRTTRIRV157', 'Var', (74, 88))	('HBD', 'Disease', 'MESH:C564145', (164, 167))	('D', 'Chemical', 'MESH:D003903', (166, 167))	('KSHV', 'Species', '37296', (138, 142))	('heparin-binding', 'Protein', (50, 65))	('KS', 'Phenotype', 'HP:0100726', (138, 140))
482580	22319516	In HMVEC-d and HFF cells, KSHV interacts with integrin alpha3beta1 as demonstrated by a 30-50% reduction in infection by pre-treating cells with function blocking anti-alpha3 and beta1 antibodies and by mixing virus with soluble alpha3beta1 integrin before infection, as well as the immunoprecipitation of virus-alpha3 and beta1 complexes by anti-KSHV-gB antibodies (Akula et al.,).	('blocking', 'NegReg', (154, 162))	('complexes', 'Interaction', (329, 338))	('HFF', 'CellLine', 'CVCL:3285', (15, 18))	('anti-alpha3', 'Var', (163, 174))	('KSHV', 'Species', '37296', (347, 351))	('KS', 'Phenotype', 'HP:0100726', (347, 349))	('beta1 integrin', 'Gene', '3688', (235, 249))	('integrin alpha3', 'Gene', (46, 61))	('infection', 'MPA', (108, 117))	('reduction', 'NegReg', (95, 104))	('KSHV', 'Species', '37296', (26, 30))	('integrin alpha3', 'Gene', '3675', (46, 61))	('beta1 integrin', 'Gene', (235, 249))	('KS', 'Phenotype', 'HP:0100726', (26, 28))
482585	22319516	A study also revealed the roles of integrins (alpha3beta1, alphaVbeta3, and alphaVbeta5) in the entry of KSHV in THP-1 and primary monocyte cells (Kerur et al.,).	('KSHV', 'Gene', (105, 109))	('alphaVbeta5', 'Var', (76, 87))	('KS', 'Phenotype', 'HP:0100726', (105, 107))	('alpha3beta1', 'Protein', (46, 57))	('KSHV', 'Species', '37296', (105, 109))	('entry', 'MPA', (96, 101))	('THP-1', 'Gene', '2736', (113, 118))	('THP-1', 'Gene', (113, 118))
482589	22319516	Both centrifugation and polybrene are known to enhance virus infection without the need for the virus to interact with specific receptors.	('polybrene', 'Var', (24, 33))	('enhance', 'PosReg', (47, 54))	('virus infection', 'Disease', 'MESH:D015658', (55, 70))	('virus infection', 'Disease', (55, 70))	('polybrene', 'Chemical', 'MESH:D006583', (24, 33))
482596	22319516	Though HT1080 cell infection was inhibited by anti-alphaVbeta3 antibodies, the ability of anti-alpha3beta1 and alphaVbeta5 antibodies to block infection was not examined (Garrigues et al.,).	('block infection', 'Disease', (137, 152))	('block infection', 'Disease', 'MESH:D006327', (137, 152))	('HT1080', 'CellLine', 'CVCL:0317', (7, 13))	('HT1080', 'Gene', (7, 13))	('inhibited', 'NegReg', (33, 42))	('anti-alphaVbeta3', 'Var', (46, 62))
482612	22319516	Ectopic expression of xCT rendered the non-susceptible adherent target cells to become susceptible to KSHV infection (Kaleeba and Berger,).	('KS', 'Phenotype', 'HP:0100726', (102, 104))	('Ectopic expression', 'Var', (0, 18))	('KSHV infection', 'Disease', 'MESH:C537372', (102, 116))	('xCT', 'Gene', (22, 25))	('KSHV infection', 'Disease', (102, 116))	('xCT', 'Gene', '23657', (22, 25))
482648	22319516	Additionally, virus or gB pre-incubated with soluble alpha3beta1 integrin or a soluble form of gB in which the RGD sequence had been mutated inhibited the activation of FAK (Akula et al.,; Wang et al.,; Sharma-Walia et al.,).	('beta1 integrin', 'Gene', '3688', (59, 73))	('Sharma-Walia', 'Disease', 'MESH:C537595', (203, 215))	('FAK', 'Protein', (169, 172))	('beta1 integrin', 'Gene', (59, 73))	('Sharma-Walia', 'Disease', (203, 215))	('activation', 'MPA', (155, 165))	('mutated', 'Var', (133, 140))	('inhibited', 'NegReg', (141, 150))	('D', 'Chemical', 'MESH:D003903', (113, 114))
482649	22319516	KSHV infection studies with FAK negative (Du3) and FAK positive (Du17) mouse fibroblasts and CHO cells transfected with human alpha3 integrin demonstrated a significant role of FAK in KSHV infection (Naranatt et al.,; Krishnan et al.,).	('D', 'Chemical', 'MESH:D003903', (42, 43))	('human', 'Species', '9606', (120, 125))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('KSHV infection', 'Disease', (184, 198))	('D', 'Chemical', 'MESH:D003903', (65, 66))	('KS', 'Phenotype', 'HP:0100726', (184, 186))	('CHO', 'CellLine', 'CVCL:0213', (93, 96))	('KSHV infection', 'Disease', 'MESH:C537372', (0, 14))	('FAK', 'Var', (177, 180))	('KSHV infection', 'Disease', (0, 14))	('mouse', 'Species', '10090', (71, 76))	('KSHV infection', 'Disease', 'MESH:C537372', (184, 198))
482655	22319516	Moreover, inhibition of Pyk2 by an autophosphorylation mutant of Pyk2 also significantly reduced viral entry in DU3 cells (Krishnan et al.,).	('autophosphorylation', 'Var', (35, 54))	('inhibition', 'NegReg', (10, 20))	('Pyk2', 'Gene', '2185', (24, 28))	('Pyk2', 'Gene', (24, 28))	('Pyk2', 'Gene', '2185', (65, 69))	('Pyk2', 'Gene', (65, 69))	('DU3', 'CellLine', 'CVCL:5528', (112, 115))	('reduced', 'NegReg', (89, 96))	('viral', 'CPA', (97, 102))
482657	22319516	The autophosphorylation site of FAK (Tyr397) creates a binding site for the SH2 domain of Src kinases and the p85 subunit of PI3-K. KSHV infection induced a strong phosphorylation of Src within minutes of infection, and the phosphorylated Src colocalized with FAK (Veettil et al.,).	('p85', 'Gene', '5296', (110, 113))	('KSHV infection', 'Disease', 'MESH:C537372', (132, 146))	('phosphorylation', 'MPA', (164, 179))	('Tyr397', 'Chemical', '-', (37, 43))	('p85', 'Gene', (110, 113))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('KSHV infection', 'Disease', (132, 146))	('binding', 'Interaction', (55, 62))	('Src', 'Protein', (183, 186))	('Tyr397', 'Var', (37, 43))
482670	22319516	Treatment of cells with PI3-K inhibitors wortmannin and LY294002 reduced PI3-K activation and viral entry in a concentration dependent manner suggesting the role of PI3-K activation in the entry of KSHV in target cells.	('viral entry', 'CPA', (94, 105))	('reduced', 'NegReg', (65, 72))	('LY294002', 'Var', (56, 64))	('PI3-K', 'Enzyme', (73, 78))	('wortmannin', 'Chemical', 'MESH:D000077191', (41, 51))	('KSHV', 'Species', '37296', (198, 202))	('KS', 'Phenotype', 'HP:0100726', (198, 200))	('LY294002', 'Chemical', 'MESH:C085911', (56, 64))
482671	22319516	Induction of PI3-K eventually leads to the induction of Rho-GTPases and their effectors (Sharma-Walia et al.,; Veettil et al.,) which in turn regulates the remodeling of actin, endosome formation, and the movement of endocytic vesicles.	('movement of endocytic vesicles', 'MPA', (205, 235))	('Rho-GTPases', 'Gene', '387', (56, 67))	('Sharma-Walia', 'Disease', (89, 101))	('regulates', 'Reg', (142, 151))	('remodeling of actin', 'MPA', (156, 175))	('Rho-GTPases', 'Gene', (56, 67))	('endosome formation', 'MPA', (177, 195))	('PI3-K', 'Var', (13, 18))	('Sharma-Walia', 'Disease', 'MESH:C537595', (89, 101))
482674	22319516	Immediately following infection, KSHV induces PI3-K Rho-GTPase-dependent cytoskeletal rearrangements and the formation of structures such as filopodia (Cdc42), lamellipodia (Rac), and stress fibers (RhoA) in the target cells (Naranatt et al.,; Veettil et al.,; Greene and Gao,; Raghu et al.,).	('cytoskeletal rearrangements', 'CPA', (73, 100))	('filopodia', 'CPA', (141, 150))	('PI3-K', 'Var', (46, 51))	('Cdc42', 'Gene', (152, 157))	('lamellipodia', 'Disease', (160, 172))	('KS', 'Phenotype', 'HP:0100726', (33, 35))	('Rac', 'Gene', '207', (174, 177))	('KSHV', 'Var', (33, 37))	('KSHV', 'Species', '37296', (33, 37))	('lamellipodia', 'Disease', 'None', (160, 172))	('RhoA', 'Gene', (199, 203))	('Cdc42', 'Gene', '998', (152, 157))	('Rac', 'Gene', (174, 177))	('RhoA', 'Gene', '387', (199, 203))
482678	22319516	Treatment of target cells with a potent RhoA inhibitor, Clostridium difficile toxin B (CdTxB), or transfecting dominant-negative constructs of RhoA resulted in significant inhibition of KSHV entry by modulation of Src activity (Veettil et al.,).	('Clostridium difficile', 'Species', '1496', (56, 77))	('RhoA', 'Gene', (40, 44))	('KSHV', 'Species', '37296', (186, 190))	('KSHV entry', 'MPA', (186, 196))	('Src activity', 'MPA', (214, 226))	('RhoA', 'Gene', (143, 147))	('RhoA', 'Gene', '387', (40, 44))	('inhibition', 'NegReg', (172, 182))	('KS', 'Phenotype', 'HP:0100726', (186, 188))	('RhoA', 'Gene', '387', (143, 147))	('modulation', 'Reg', (200, 210))	('transfecting', 'Var', (98, 110))
482697	22319516	Although internalization of viral DNA was increased, the association of internalized viral capsids with microtubules was reduced upon LR disruption, microtubules disorganized, and nuclei associated viral DNA decreased (Raghu et al.,).	('increased', 'PosReg', (42, 51))	('D', 'Chemical', 'MESH:D003903', (34, 35))	('reduced', 'NegReg', (121, 128))	('microtubules', 'MPA', (149, 161))	('disruption', 'Var', (137, 147))	('D', 'Chemical', 'MESH:D003903', (204, 205))	('association', 'Interaction', (57, 68))	('decreased', 'NegReg', (208, 217))	('internalization', 'MPA', (9, 24))	('disorganized', 'NegReg', (162, 174))
482702	22319516	reported that LR disruption affects signal pathways induced by KSHV such that phospho-Src levels had increased without affecting FAK or ERK1/2.	('signal pathways', 'Pathway', (36, 51))	('KSHV', 'Species', '37296', (63, 67))	('increased', 'PosReg', (101, 110))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('phospho-Src levels', 'MPA', (78, 96))	('disruption', 'Var', (17, 27))
482704	22319516	LR disruption also affects PI3-K and RhoA with subsequent reduction in KSHV-induced RhoA mediated acetylation and aggregation of MTs (Raghu et al.,).	('PI3-K', 'CPA', (27, 32))	('affects', 'Reg', (19, 26))	('aggregation', 'CPA', (114, 125))	('KSHV-induced', 'Gene', (71, 83))	('RhoA', 'Gene', (84, 88))	('RhoA', 'Gene', (37, 41))	('RhoA', 'Gene', '387', (84, 88))	('disruption', 'Var', (3, 13))	('KS', 'Phenotype', 'HP:0100726', (71, 73))	('KSHV', 'Species', '37296', (71, 75))	('RhoA', 'Gene', '387', (37, 41))	('reduction', 'NegReg', (58, 67))
482730	22319516	The detection of KSHV by ORF65 (KSHV capsid protein) in perinuclear regions of HUVECs does not necessarily correlate with a productive endocytosis pathway and hence needs further clarification (Table 2).	('KS', 'Phenotype', 'HP:0100726', (17, 19))	('HUVEC', 'CellLine', 'CVCL:2959', (79, 84))	('productive endocytosis pathway', 'MPA', (124, 154))	('ORF65', 'Gene', (25, 30))	('KSHV', 'Species', '37296', (32, 36))	('ORF65', 'Gene', '4961451', (25, 30))	('KS', 'Phenotype', 'HP:0100726', (32, 34))	('KSHV', 'Species', '37296', (17, 21))	('KSHV', 'Var', (17, 21))
482742	22319516	Similarly, nuclear delivery of viral DNA was increased in cells expressing a constitutively active RhoA mutant and decreased in cells expressing a dominant-negative mutant of RhoA (Naranatt et al.,).	('increased', 'PosReg', (45, 54))	('RhoA', 'Gene', '387', (99, 103))	('mutant', 'Var', (104, 110))	('decreased', 'NegReg', (115, 124))	('RhoA', 'Gene', (99, 103))	('RhoA', 'Gene', (175, 179))	('D', 'Chemical', 'MESH:D003903', (37, 38))	('nuclear delivery of viral DNA', 'MPA', (11, 40))	('RhoA', 'Gene', '387', (175, 179))
482743	22319516	Taken together, these studies indicate that KSHV induces Rho-GTPases, modulates stabilization of microtubules and promotes the rapid trafficking of viral capsids toward the nucleus (Table 3).	('induces', 'PosReg', (49, 56))	('modulates', 'Reg', (70, 79))	('KSHV', 'Species', '37296', (44, 48))	('Rho-GTPases', 'Gene', '387', (57, 68))	('promotes', 'PosReg', (114, 122))	('Rho-GTPases', 'Gene', (57, 68))	('stabilization of microtubules', 'MPA', (80, 109))	('KSHV', 'Var', (44, 48))	('rapid trafficking of', 'MPA', (127, 147))	('KS', 'Phenotype', 'HP:0100726', (44, 46))
482749	22319516	As early as 5 min p.i., KSHV activates MEK (MAPK/ERK kinase) and extracellular-signal-regulated kinase (ERK; Naranatt et al.,).	('ERK', 'Gene', (104, 107))	('KSHV', 'Species', '37296', (24, 28))	('KSHV', 'Var', (24, 28))	('activates', 'PosReg', (29, 38))	('KS', 'Phenotype', 'HP:0100726', (24, 26))	('ERK', 'Gene', '5594', (49, 52))	('ERK', 'Gene', '5594', (104, 107))	('MEK', 'Gene', '5609', (39, 42))	('MAPK', 'Gene', (44, 48))	('MEK', 'Gene', (39, 42))	('ERK', 'Gene', (49, 52))	('MAPK', 'Gene', '5595;5594;5595', (44, 48))	('extracellular-signal-regulated kinase', 'MPA', (65, 102))
482751	22319516	PI3-K and protein kinase C-zeta (PKC-zeta) are recruited as upstream mediators of the KSHV ERK pathway and inhibitors specific for PI3-K, PKC-zeta, MEK, and ERK significantly reduce virus infectivity without affecting virus binding to the target cells (Table 3).	('PKC-zeta', 'Gene', '5590', (138, 146))	('ERK', 'Gene', '5594', (91, 94))	('PI3-K', 'Var', (131, 136))	('reduce', 'NegReg', (175, 181))	('KSHV', 'Species', '37296', (86, 90))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('PKC-zeta', 'Gene', (138, 146))	('ERK', 'Gene', (91, 94))	('PKC-zeta', 'Gene', (33, 41))	('ERK', 'Gene', '5594', (157, 160))	('PKC-zeta', 'Gene', '5590', (33, 41))	('ERK', 'Gene', (157, 160))	('MEK', 'Gene', (148, 151))	('MEK', 'Gene', '5609', (148, 151))	('virus infectivity', 'MPA', (182, 199))
482835	21237494	Fluorescence in situ hybridization of the ovarian mass demonstrated loss of C-MYB at 6q23 locus in 41% of the cells, and deletion of chromosome 7 and 7q in 37% and 66% of cells, respectively.	('C-MYB', 'Gene', '4602', (76, 81))	('C-MYB', 'Gene', (76, 81))	('deletion', 'Var', (121, 129))	('loss', 'NegReg', (68, 72))
482845	21237494	In addition to the detailed flow cytometric, immunohistochemical, and molecular analysis, we also provided evidence that both the sarcoma and leukemia forms shared deletion of C-MYB oncogene at chromosome 6q23 locus.	('C-MYB', 'Gene', (176, 181))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('leukemia', 'Phenotype', 'HP:0001909', (142, 150))	('leukemia', 'Disease', 'MESH:D007938', (142, 150))	('C-MYB', 'Gene', '4602', (176, 181))	('leukemia', 'Disease', (142, 150))	('sarcoma', 'Disease', (130, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('deletion', 'Var', (164, 172))
482860	21237494	Single cell suspension from bone marrow aspirate was made and stained with the following antigens: CD1a, CD2, CD3 (both surface and cytoplasm), CD4, CD5, CD7, CD8, CD10, CD11b, CD13, CD14, CD15, CD16, CD19 CD22(cytoplasm), CD33, CD34, CD36, CD38, CD41, CD45, CD56, CD61, CD64, CD71, CD79a(cytoplasm), CD117, CD123, HLA-DR, myeloperoxidase (cytoplasmic), and TdT (cytoplasmic).	('CD4', 'Gene', '920', (253, 256))	('CD1a', 'Gene', '909', (99, 103))	('CD4', 'Gene', (144, 147))	('CD34', 'Gene', '947', (229, 233))	('TdT', 'Gene', (358, 361))	('CD38', 'Var', (241, 245))	('CD5', 'Gene', '921', (149, 152))	('CD117', 'Gene', '3815', (301, 306))	('myeloperoxidase', 'Enzyme', (323, 338))	('CD4', 'Gene', (253, 256))	('CD5', 'Gene', (259, 262))	('CD10', 'Gene', (164, 168))	('CD56', 'Gene', (259, 263))	('CD7', 'Gene', '924', (277, 280))	('CD33', 'Gene', '945', (223, 227))	('CD33', 'Gene', (223, 227))	('CD19', 'Gene', '930', (201, 205))	('CD8', 'Gene', (159, 162))	('CD1a', 'Gene', (99, 103))	('CD56', 'Gene', '4684', (259, 263))	('CD36', 'Species', '42374', (235, 239))	('CD117', 'Gene', (301, 306))	('CD7', 'Gene', '924', (283, 286))	('CD36', 'Var', (235, 239))	('CD7', 'Gene', '924', (154, 157))	('CD7', 'Gene', (277, 280))	('CD61', 'Gene', (265, 269))	('CD5', 'Gene', '921', (259, 262))	('CD34', 'Gene', (229, 233))	('CD4', 'Gene', '920', (247, 250))	('CD61', 'Gene', '3690', (265, 269))	('CD45', 'Gene', (253, 257))	('CD14', 'Var', (183, 187))	('CD16', 'Var', (195, 199))	('CD7', 'Gene', (154, 157))	('CD7', 'Gene', (283, 286))	('CD45', 'Gene', '5788', (253, 257))	('CD4', 'Gene', (247, 250))	('CD123', 'Var', (308, 313))	('CD15', 'Var', (189, 193))	('CD5', 'Gene', (149, 152))	('CD11b', 'Gene', '3684', (170, 175))	('CD4', 'Gene', '920', (144, 147))	('CD11b', 'Gene', (170, 175))	('CD64', 'Var', (271, 275))	('CD8', 'Gene', '925', (159, 162))	('CD13', 'Var', (177, 181))	('CD19', 'Gene', (201, 205))	('CD10', 'Gene', '4311', (164, 168))
482877	21237494	2E), CD15 and CD33 (Fig.	('CD15', 'Var', (5, 9))	('CD33', 'Gene', (14, 18))	('CD33', 'Gene', '945', (14, 18))
482888	21237494	4A, all showed deletion of the long arm of chromosome 6 at band q23-q25 and gain of extra chromosome 7, therefore, the karyotype was as follows: 47,XX,del(6)(q23q25),+7[21].	('deletion', 'Var', (15, 23))	('del(6)(q23q25', 'Var', (151, 164))	('47,XX,del(6)(q23q25),+7', 'STRUCTURAL_ABNORMALITY', 'None', (145, 168))	('gain', 'PosReg', (76, 80))
482910	21237494	At the cytogenetic and molecular cytogenetic levels, the pure erythroid leukemia of bone marrow and the erythroblastic sarcoma of the ovary harbored similar aberrancy but exhibited difference, namely, both showed deletion of C-MYB at 6q23, but the pure erythroid leukemia of the bone marrow had trisomy 7 and the tumor cells of the ovary had monosomy 7 and deletion of the long arm of chromosome 7.	('leukemia of the bone marrow', 'Disease', (263, 290))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('leukemia of the bone marrow', 'Disease', 'MESH:D001855', (263, 290))	('C-MYB', 'Gene', (225, 230))	('monosomy 7', 'Var', (342, 352))	('tumor', 'Disease', (313, 318))	('erythroid leukemia', 'Disease', (62, 80))	('erythroid leukemia', 'Disease', 'MESH:C538442', (62, 80))	('leukemia', 'Phenotype', 'HP:0001909', (263, 271))	('leukemia', 'Phenotype', 'HP:0001909', (72, 80))	('deletion', 'Var', (357, 365))	('leukemia of bone marrow and the erythroblastic sarcoma of the ovary', 'Disease', 'MESH:D001855', (72, 139))	('C-MYB', 'Gene', '4602', (225, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('erythroid leukemia', 'Disease', (253, 271))	('erythroid leukemia', 'Disease', 'MESH:C538442', (253, 271))	('trisomy', 'Var', (295, 302))
482915	21237494	Loss of C-MYB was not reported in acute erythroid leukemia including pure erythroid leukemia before this report; however, C-MYB abnormalities including translocation, duplication and rearrangement were reported in T-acute lymphoblastic leukemia and non-Hodgkin lymphoma.	('erythroid leukemia', 'Disease', (74, 92))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (222, 244))	('C-MYB abnormalities', 'Disease', (122, 141))	('T-acute lymphoblastic leukemia', 'Disease', (214, 244))	('C-MYB', 'Gene', '4602', (8, 13))	('acute erythroid leukemia', 'Disease', (34, 58))	('C-MYB', 'Gene', (8, 13))	('acute erythroid leukemia', 'Disease', 'MESH:D015470', (34, 58))	('duplication', 'Var', (167, 178))	('T-acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (214, 244))	('lymphoma', 'Phenotype', 'HP:0002665', (261, 269))	('leukemia', 'Phenotype', 'HP:0001909', (84, 92))	('leukemia', 'Phenotype', 'HP:0001909', (236, 244))	('erythroid leukemia', 'Disease', 'MESH:C538442', (74, 92))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (253, 269))	('translocation', 'Var', (152, 165))	('non-Hodgkin lymphoma', 'Disease', (249, 269))	('C-MYB abnormalities', 'Disease', 'MESH:C537418', (122, 141))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('rearrangement', 'Var', (183, 196))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (249, 269))	('erythroid leukemia', 'Disease', 'MESH:C538442', (40, 58))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (216, 244))	('C-MYB', 'Gene', '4602', (122, 127))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (249, 269))	('C-MYB', 'Gene', (122, 127))
482916	21237494	Furthermore, the effects of deletion of other genes, especially tumor suppressor genes in the 6q23q25 region, if any, could not be assessed and was beyond the scope of this study.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('deletion', 'Var', (28, 36))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
482978	28173774	Median PFS also declined in patients receiving surgery compared to those receiving no surgery (8-15 m vs 5 m).	('patients', 'Species', '9606', (28, 36))	('surgery', 'Var', (47, 54))	('declined', 'NegReg', (16, 24))	('PFS', 'MPA', (7, 10))
483087	25992772	Genetic analyses of human RMS describe subtype-specific mutations that are used to define the biology and outcomes of the two main pediatric RMS subtypes, ERMS and ARMS.	('human', 'Species', '9606', (20, 25))	('mutations', 'Var', (56, 65))	('RMS', 'Phenotype', 'HP:0002859', (165, 168))	('RMS', 'Phenotype', 'HP:0002859', (141, 144))	('RMS', 'Phenotype', 'HP:0002859', (156, 159))	('ERMS', 'Disease', (155, 159))	('ARMS', 'Disease', (164, 168))	('RMS', 'Phenotype', 'HP:0002859', (26, 29))
483088	25992772	ARMS typically contain fusion gene products of PAX3 or PAX7 and FOXO1 genes resulting from reciprocal balanced chromosomal translocations (t(2;13)(q35;q14) or t(1;13)(p36;q14)).	('t(2;13)(q35;q14', 'Var', (139, 154))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (159, 175))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (139, 155))	('PAX3', 'Gene', (47, 51))	('resulting from', 'Reg', (76, 90))	('FOXO1', 'Gene', (64, 69))	('PAX3', 'Gene', '18505', (47, 51))	('PAX7', 'Gene', (55, 59))	('FOXO1', 'Gene', '56458', (64, 69))	('t(1;13)(p36;q14', 'Var', (159, 174))	('RMS', 'Phenotype', 'HP:0002859', (1, 4))	('PAX7', 'Gene', '18509', (55, 59))
483098	25992772	To determine whether cellular transformation of myoblasts can result in RMS, we created novel mosaic mouse models, which involved orthotopic injection and engraftment of p53-/- myoblasts into syngeneic hosts.	('RMS', 'Phenotype', 'HP:0002859', (72, 75))	('p53-/-', 'Var', (170, 176))	('result', 'Reg', (62, 68))	('mouse', 'Species', '10090', (101, 106))
483112	25992772	Mice injected with Kras-H had a median tumor latency of 3.4 weeks (range 3-6 weeks) with 83% penetrance (10/12) whereas mice injected with Kras-L had a median tumor latency of 4.6 weeks (range 4-6 weeks) with 85% penetrance (11/13, Table 1).	('pen', 'Gene', (93, 96))	('Kras-H', 'Var', (19, 25))	('mice', 'Species', '10090', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('pen', 'Gene', '30052', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (159, 164))	('pen', 'Gene', (213, 216))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (39, 44))	('pen', 'Gene', '30052', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
483116	25992772	Immunoblots demonstrated that tumors from mice injected with Kras-H myoblasts had higher Kras levels than in tumors resulting from injection of Kras-L cells (Figure 2E).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('Kras-H', 'Var', (61, 67))	('tumors', 'Disease', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mice', 'Species', '10090', (42, 46))	('higher', 'PosReg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Kras levels', 'MPA', (89, 100))
483154	25992772	In this study, we describe a novel murine model of sarcoma using mosaicism.	('sarcoma', 'Disease', (51, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('mosaicism', 'Var', (65, 74))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('murine', 'Species', '10090', (35, 41))
483156	25992772	To effectively model human disease, mutations described in patient tumors (i.e.	('human', 'Species', '9606', (21, 26))	('patient', 'Species', '9606', (59, 66))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
483164	25992772	Kras activation and p53 deficiency have been described in human sarcomas and genetically engineered animal models have also been generated using this combination.	('p53', 'Gene', (20, 23))	('human', 'Species', '9606', (58, 63))	('deficiency', 'Var', (24, 34))	('activation', 'PosReg', (5, 15))	('Kras', 'Gene', (0, 4))	('sarcomas', 'Disease', 'MESH:D012509', (64, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcomas', 'Disease', (64, 72))
483168	25992772	Mosaic mouse tumors were mostly undifferentiated despite the presence of patchy/focal MyoD1 protein expression and thus could not be irrefutably classified as RMS.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('mouse', 'Species', '10090', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('expression', 'Species', '29278', (100, 110))	('MyoD1', 'Gene', (86, 91))	('expression', 'MPA', (100, 110))	('RMS', 'Phenotype', 'HP:0002859', (159, 162))	('MyoD1', 'Gene', '17927', (86, 91))	('patchy/focal', 'Var', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
483169	25992772	Interestingly, histopathological differences were noted between tumors arising following injection of either Kras-H or Kras-L myoblasts.	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Kras-L', 'Var', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
483174	25992772	In this study, transgene expression was driven by a heterologous promoter and resulted in KrasG12D overexpression, which is a limitation of lentiviral transduction.	('expression', 'Species', '29278', (25, 35))	('expression', 'Species', '29278', (103, 113))	('resulted in', 'Reg', (78, 89))	('KrasG12D', 'Gene', '16653', (90, 98))	('overexpression', 'PosReg', (99, 113))	('KrasG12D', 'Gene', (90, 98))	('transgene', 'Var', (15, 24))
483178	25992772	Both p53 inactivation and Ras overexpression have been previously implicated in myoblast differentiation.	('myoblast differentiation', 'CPA', (80, 104))	('overexpression', 'PosReg', (30, 44))	('p53', 'Gene', (5, 8))	('inactivation', 'Var', (9, 21))	('Ras', 'Protein', (26, 29))	('implicated', 'Reg', (66, 76))	('expression', 'Species', '29278', (34, 44))
483180	25992772	This concept was initially demonstrated when human skeletal muscle progenitors were transformed using SV40 T/t antigen, human telomerase reverse transcriptase (TERT) and HrasV12G which resulted in RMS formation in murine xenografts.	('SV40 T/t', 'Var', (102, 110))	('telomerase reverse transcriptase', 'Gene', (126, 158))	('human', 'Species', '9606', (120, 125))	('TERT', 'Gene', '7015', (160, 164))	('HrasV12G', 'Var', (170, 178))	('murine', 'Species', '10090', (214, 220))	('telomerase reverse transcriptase', 'Gene', '7015', (126, 158))	('RMS formation', 'CPA', (197, 210))	('human', 'Species', '9606', (45, 50))	('resulted in', 'Reg', (185, 196))	('TERT', 'Gene', (160, 164))	('RMS', 'Phenotype', 'HP:0002859', (197, 200))
483181	25992772	When homozygous deletion of p53 was lineage-restricted in different muscle cell populations, although ERMS predominately arose from the maturing Myf6+ myoblast lineage, other skeletal muscle progenitors could give rise to different tumors on the RMS spectrum following loss of p53.	('p53', 'Gene', (28, 31))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('give rise to', 'Reg', (209, 221))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('loss', 'NegReg', (269, 273))	('deletion', 'Var', (16, 24))	('RMS', 'Phenotype', 'HP:0002859', (103, 106))	('Myf6', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('p53', 'Gene', (277, 280))	('Myf6', 'Gene', '17878', (145, 149))	('RMS', 'Phenotype', 'HP:0002859', (246, 249))	('tumors', 'Disease', (232, 238))
483182	25992772	In contrast, in a recent report RMS arose following transformation of Pax7+ myogenic progenitors with the same mutations while transformation of Myod+ progenitors resulted in UPS, illustrating how cellular lineage can affect sarcomagenesis.	('mutations', 'Var', (111, 120))	('Pax7', 'Gene', (70, 74))	('Myod', 'Gene', (145, 149))	('sarcomagenesis', 'Disease', (225, 239))	('affect', 'Reg', (218, 224))	('RMS', 'Disease', (32, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('Myod', 'Gene', '17927', (145, 149))	('sarcomagenesis', 'Disease', 'None', (225, 239))	('RMS', 'Phenotype', 'HP:0002859', (32, 35))	('Pax7', 'Gene', '18509', (70, 74))
483191	25992772	As additional mosaic mouse models are generated using different oncogenic mutations, it will be essential to investigate how the transcriptome is altered and correlate this profile with what is observed in tumor phenotype.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mouse', 'Species', '10090', (21, 26))	('tumor', 'Disease', (206, 211))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
483213	25992772	The median of the transformed gene expression from myoblast cell lines stably expressing empty vector (Control-H, Control-L) was subtracted from the median of transformed gene expression from four tumors (MK33, MK36, MK40 and MK43) or from cell lines stably expressing KrasG12D (Kras-H, Kras-L).	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('MK36', 'Var', (211, 215))	('MK43', 'Var', (226, 230))	('expression', 'Species', '29278', (35, 45))	('KrasG12D', 'Gene', '16653', (269, 277))	('MK33', 'Var', (205, 209))	('expression', 'Species', '29278', (176, 186))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('MK40', 'Var', (217, 221))	('tumors', 'Disease', (197, 203))	('KrasG12D', 'Gene', (269, 277))
483225	22318521	Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2-/- mice which phenotypically resemble nascent primary tumour cells.	('mutations', 'Var', (69, 78))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('methylcholanthrene', 'Chemical', 'MESH:D008748', (101, 119))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('tumour', 'Disease', (225, 231))	('mice', 'Species', '10090', (174, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Rag2', 'Gene', '19374', (166, 170))	('sarcomas', 'Disease', (128, 136))	('Rag2', 'Gene', (166, 170))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))
483226	22318521	Employing class I prediction algorithms, we identify mutant spectrin-beta2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection.	('expression', 'Species', '29278', (182, 192))	('spectrin-beta2', 'Gene', (60, 74))	('sarcoma', 'Disease', (121, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('spectrin-beta2', 'Gene', '20742', (60, 74))	('mutant', 'Var', (53, 59))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))
483227	22318521	We also demonstrate that cancer immunoediting of d42m1 occurs via a T cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-beta2 and other potential strong antigens.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('lacking', 'NegReg', (168, 175))	('spectrin-beta2', 'Gene', '20742', (200, 214))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('spectrin-beta2', 'Gene', (200, 214))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('promotes', 'PosReg', (114, 122))	('outgrowth', 'CPA', (123, 132))	('cancer', 'Disease', (25, 31))	('d42m1', 'Var', (49, 54))	('tumour', 'Disease', (149, 155))
483228	22318521	These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T cell-dependent immunoselection process represents one mechanism of cancer immunoediting.	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('immunogenicity', 'MPA', (42, 56))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('tumour', 'Disease', (172, 178))	('antigenic', 'MPA', (119, 128))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (292, 298))	('expression', 'Species', '29278', (98, 108))	('tumour', 'Disease', (72, 78))	('proteins', 'Protein', (136, 144))	('mutant', 'Var', (129, 135))
483232	22318521	Although d42m1 and H31m1 display mutations in known cancer genes, the functional effects of these novel mutations remain undefined.	('d42m1', 'Var', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('H31m1', 'Var', (19, 24))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
483233	22318521	Nevertheless, both tumours have cancer-causing mutations in Kras (codon 12) and Trp53 that are frequently observed in human and mouse cancers (Supplementary Table 3).	('tumours', 'Disease', (19, 26))	('Trp53', 'Gene', (80, 85))	('mouse', 'Species', '10090', (128, 133))	('Trp53', 'Gene', '7157', (80, 85))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Disease', (32, 38))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('cancer', 'Disease', (134, 140))	('mutations', 'Var', (47, 56))	('cancers', 'Disease', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('Kras', 'Gene', '3845', (60, 64))	('human', 'Species', '9606', (118, 123))	('Kras', 'Gene', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
483236	22318521	First, 46-47% of mutations in d42m1 and H31m1 are C/A or G/T transversions which represent chemical-carcinogen signatures similar to those of lung cancers from smokers (44-46%) but not seen in human cancers induced by other mechanisms (8-16%) (Fig.	('lung cancers', 'Phenotype', 'HP:0100526', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('H31m1', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', (199, 206))	('lung cancers', 'Disease', (142, 154))	('d42m1', 'Var', (30, 35))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('lung cancers', 'Disease', 'MESH:D008175', (142, 154))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancers', 'Disease', (147, 154))	('C/A', 'Disease', (50, 53))	('mutations', 'Var', (17, 26))	('human', 'Species', '9606', (193, 198))	('G/T', 'CPA', (57, 60))
483237	22318521	Second, the mutation rates of d42m1 and H31m1 are about 10-fold higher than those of lung cancers from smokers, but within 3-fold of hypermutator smoker lung cancers with mutations in DNA repair pathway genes (Fig.	('lung cancers', 'Disease', 'MESH:D008175', (153, 165))	('lung cancers', 'Phenotype', 'HP:0100526', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('H31m1', 'Var', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('DNA repair pathway genes', 'Gene', (184, 208))	('lung cancers', 'Disease', 'MESH:D008175', (85, 97))	('lung cancers', 'Phenotype', 'HP:0100526', (85, 97))	('d42m1', 'Var', (30, 35))	('lung cancers', 'Disease', (153, 165))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('mutations', 'Var', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancers', 'Disease', (85, 97))
483240	22318521	Cell lines made from three escape tumours (d42m1-es1, d42m1-es2 and d42m1-es3) formed progressively growing sarcomas when transplanted into naive WT recipients (Fig.	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('d42m1-es1', 'Var', (43, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcomas', 'Disease', (108, 116))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('d42m1-es2', 'Var', (54, 63))	('d42m1-es3', 'Var', (68, 77))	('tumours', 'Disease', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
483242	22318521	Additional analyses revealed that whereas 8 of 10 clones of d42m1 were rejected in WT mice, two clones (d42m1-T3 and d42m1-T10) grew with kinetics similar to d42m1 escape tumours (Fig.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('T10', 'Gene', (123, 126))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('T10', 'Gene', '27883', (123, 126))	('tumours', 'Disease', 'MESH:D009369', (171, 178))	('mice', 'Species', '10090', (86, 90))	('d42m1', 'Var', (158, 163))	('tumours', 'Disease', (171, 178))
483244	22318521	cDNA CapSeq of parental d42m1 cells, clones and escape tumours revealed that all expressed similar numbers of mutations (Supplementary Fig.	('tumours', 'Disease', (55, 62))	('mutations', 'Var', (110, 119))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
483247	22318521	Tumour-specific mutant proteins presented on mouse or human MHC class I molecules are known to represent one class of tumour-specific antigens for CD8+ T cells.	('tumour', 'Disease', (118, 124))	('CD8', 'Gene', (147, 150))	('mouse', 'Species', '10090', (45, 50))	('CD8', 'Gene', '925', (147, 150))	('proteins', 'Protein', (23, 31))	('mutant', 'Var', (16, 22))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('human', 'Species', '9606', (54, 59))
483248	22318521	Therefore, we used in silico analysis to assess the theoretical capacities of missense mutations from d42m1-related tumour cells to bind MHC class I proteins.	('MHC', 'Protein', (137, 140))	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('missense mutations', 'Var', (78, 96))	('bind', 'Interaction', (132, 136))	('d42m1-related', 'Gene', (102, 115))	('tumour', 'Disease', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
483254	22318521	3c), we postulated that an R913L mutation in spectrin-beta2 produced the most likely target for C3 CTLs because its expression was restricted to d42m1 regressor clones and it formed an epitope that showed high affinity binding potential to H-2Db in contrast to the WT sequence predicted to bind with low affinity (Fig.	('binding', 'Interaction', (219, 226))	('spectrin-beta2', 'Gene', '20742', (45, 59))	('R913L', 'Mutation', 'p.R913L', (27, 32))	('spectrin-beta2', 'Gene', (45, 59))	('H-2Db', 'Protein', (240, 245))	('R913L', 'Var', (27, 32))	('expression', 'Species', '29278', (116, 126))
483255	22318521	To verify the importance of mutant spectrin-beta2 on d42m1 antigenicity, we independently identified the tumour antigen recognized by the C3 CTL clone using a T cell-based expression cloning approach.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('C3 CTL', 'Gene', (138, 144))	('mutant', 'Var', (28, 34))	('spectrin-beta2', 'Gene', '20742', (35, 49))	('expression', 'Species', '29278', (172, 182))	('tumour', 'Disease', (105, 111))	('spectrin-beta2', 'Gene', (35, 49))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
483256	22318521	After three screening rounds, a single positive cDNA was identified encoding a sequence identical to the R913L spectrin-beta2 mutant (Fig.	('spectrin-beta2', 'Gene', (111, 125))	('spectrin-beta2', 'Gene', '20742', (111, 125))	('R913L', 'Mutation', 'p.R913L', (105, 110))	('R913L', 'Var', (105, 110))
483258	22318521	Mutation-specific qRT-PCR revealed the presence of mutant spectrin-beta2 mRNA in parental d42m1 tumour cells and regressor d42m1 clones, but not in progressor d42m1 clones or escape tumours (Fig.	('spectrin-beta2', 'Gene', (58, 72))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('mutant', 'Var', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumours', 'Phenotype', 'HP:0002664', (182, 189))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (182, 189))	('tumour', 'Disease', (182, 188))	('tumours', 'Disease', (182, 189))	('spectrin-beta2', 'Gene', '20742', (58, 72))	('tumour', 'Disease', (96, 102))
483260	22318521	Additionally, C3 CTLs discriminated between mutant and WT spectrin-beta2 peptide sequences when presented on an unrelated H-2Db expressing cell line (Fig.	('mutant', 'Var', (44, 50))	('spectrin-beta2', 'Gene', '20742', (58, 72))	('discriminated', 'Reg', (22, 35))	('spectrin-beta2', 'Gene', (58, 72))
483261	22318521	Using labeled H-2Db tetramers generated with mutant peptide, mutant spectrin-beta2 specific CD8+ T cells accumulated over time in parental d42m1 tumours developing in vivo and draining lymph nodes (DLNs) prior to tumour rejection (Fig.	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('tumour', 'Disease', (145, 151))	('CD8', 'Gene', (92, 95))	('spectrin-beta2', 'Gene', (68, 82))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('CD8', 'Gene', '925', (92, 95))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('tumour', 'Disease', (213, 219))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('mutant', 'Var', (61, 67))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('tumours', 'Disease', 'MESH:D009369', (145, 152))	('spectrin-beta2', 'Gene', '20742', (68, 82))	('tumours', 'Disease', (145, 152))
483263	22318521	These data demonstrate that mutant spectrin-beta2 expressed selectively in a high proportion of unedited d42m1 tumour cells evokes a T cell response in naive WT mice that promotes the elimination of antigen expressing tumour cells.	('mice', 'Species', '10090', (161, 165))	('mutant', 'Var', (28, 34))	('spectrin-beta2', 'Gene', '20742', (35, 49))	('promotes', 'PosReg', (171, 179))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('tumour', 'Disease', (218, 224))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('spectrin-beta2', 'Gene', (35, 49))	('T cell response', 'MPA', (133, 148))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', 'MESH:D009369', (218, 224))	('tumour', 'Disease', (111, 117))	('evokes', 'Reg', (124, 130))
483264	22318521	To test whether expression of mutant spectrin-beta2 was sufficient to drive rejection of d42m1 tumour cells, we enforced expression of either mutant or WT spectrin-beta2 in d42m1-es3 cells that lack this mutation (Supplementary Fig.	('spectrin-beta2', 'Gene', '20742', (155, 169))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('expression', 'Species', '29278', (121, 131))	('mutant', 'Var', (142, 148))	('tumour', 'Disease', (95, 101))	('spectrin-beta2', 'Gene', (155, 169))	('spectrin-beta2', 'Gene', '20742', (37, 51))	('expression', 'Species', '29278', (16, 26))	('spectrin-beta2', 'Gene', (37, 51))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
483266	22318521	Whereas d42m1-es3 tumour cell clones transduced with either control retrovirus or retrovirus encoding WT spectrin-beta2 (WT.1 and WT.3) grew progressively with growth kinetics similar to unmanipulated d42m1-es3 cells, d42m1-es3 clones expressing mutant spectrin-beta2 (mu.6 and mu.14) were rejected in WT mice, but not in Rag2-/- mice (Fig.	('mice', 'Species', '10090', (305, 309))	('Rag2', 'Gene', '19374', (322, 326))	('WT.1', 'Gene', '22431', (121, 125))	('mice', 'Species', '10090', (330, 334))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('WT.1', 'Gene', (121, 125))	('mutant', 'Var', (246, 252))	('spectrin-beta2', 'Gene', '20742', (253, 267))	('spectrin-beta2', 'Gene', '20742', (105, 119))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('spectrin-beta2', 'Gene', (253, 267))	('Rag2', 'Gene', (322, 326))	('tumour', 'Disease', (18, 24))	('spectrin-beta2', 'Gene', (105, 119))
483267	22318521	CD8+ T cells specific for mutant spectrin-beta2 did not infiltrate d42m1-es3 tumours expressing WT spectrin-beta2 (WT.3), but were present in rejecting d42m1-es3 tumours expressing mutant spectrin-beta2 (mu.14) (Fig.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (162, 169))	('tumours', 'Disease', (162, 169))	('spectrin-beta2', 'Gene', (188, 202))	('spectrin-beta2', 'Gene', (99, 113))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('spectrin-beta2', 'Gene', '20742', (33, 47))	('tumours', 'Disease', (77, 84))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('spectrin-beta2', 'Gene', '20742', (99, 113))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('mutant', 'Var', (26, 32))	('spectrin-beta2', 'Gene', (33, 47))	('spectrin-beta2', 'Gene', '20742', (188, 202))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
483268	22318521	Thus, mutant spectrin-beta2 is indeed a major rejection antigen of d42m1 sarcoma cells and d42m1 escape from immune control is the consequence of outgrowth of d42m1 clones that lack expression of dominant rejection antigens.	('expression', 'Species', '29278', (182, 192))	('mutant', 'Var', (6, 12))	('d42m1', 'Var', (91, 96))	('sarcoma', 'Disease', (73, 80))	('spectrin-beta2', 'Gene', (13, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('spectrin-beta2', 'Gene', '20742', (13, 27))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
483271	22318521	Specifically, we examined the in vivo growth behavior of a tumour cell mixture containing a vast majority of highly immunogenic, mutant spectrin-beta2+ d42m1-T2 cells and a minority of mutant spectrin-beta2- d42m1-T3 progressor cells.	('spectrin-beta2', 'Gene', (136, 150))	('spectrin-beta2', 'Gene', '20742', (192, 206))	('spectrin-beta2', 'Gene', (192, 206))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('highly', 'PosReg', (109, 115))	('spectrin-beta2', 'Gene', '20742', (136, 150))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))	('mutant', 'Var', (129, 135))
483272	22318521	To distinguish between the two cell types, we labeled d42m1-T2 with RFP (modified to eliminate class I epitopes) and d42m1-T3 with GFP and documented that the labeling did not alter their in vivo growth characteristics.	('RFP', 'Gene', (68, 71))	('d42m1-T3', 'Var', (117, 125))	('d42m1-T2', 'Var', (54, 62))	('RFP', 'Gene', '19720', (68, 71))
483273	22318521	We found that we could recapitulate the tumour growth phenotype of parental d42ml at a ratio of 95% d42m1-T2 cells to 5% d42m1-T3 cells (Fig.	('tumour growth', 'Disease', 'MESH:D006130', (40, 53))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('d42m1-T2', 'Var', (100, 108))	('tumour growth', 'Disease', (40, 53))
483276	22318521	Tumours harvested from Rag2-/- mice were comprised of 84% d42m1-T2 cells and 14% d42m1-T3 cells (Fig.	('Rag2', 'Gene', (23, 27))	('d42m1-T2', 'Var', (58, 66))	('mice', 'Species', '10090', (31, 35))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Rag2', 'Gene', '19374', (23, 27))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
483277	22318521	4h) and expressed mutant spectrin-beta2 (Fig.	('mutant', 'Var', (18, 24))	('spectrin-beta2', 'Gene', '20742', (25, 39))	('spectrin-beta2', 'Gene', (25, 39))
483278	22318521	In contrast, tumours that grew out in WT mice consisted of 98% d42m1-T3 tumour cells and lacked mutant spectrin-beta2 (Fig.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('mutant', 'Var', (96, 102))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('mice', 'Species', '10090', (41, 45))	('lacked', 'NegReg', (89, 95))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('spectrin-beta2', 'Gene', (103, 117))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumour', 'Disease', (13, 19))	('tumours', 'Disease', (13, 20))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('d42m1-T3', 'Var', (63, 71))	('tumour', 'Disease', (72, 78))	('spectrin-beta2', 'Gene', '20742', (103, 117))
483279	22318521	Thus, d42m1 escape tumours develop as a consequence of T cell-dependent immunoselection favoring the outgrowth of tumour cells that lack major rejection antigens.	('tumour', 'Disease', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('outgrowth', 'CPA', (101, 110))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumour', 'Disease', (19, 25))	('tumours', 'Disease', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('d42m1', 'Var', (6, 11))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
483283	22318521	Developing carcinogen-induced tumours (e.g., mouse MCA sarcomas or human smoker lung cancers) may be the preferred targets of cancer immunoediting because they express the greatest number of mutations that might function as neoantigens.	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('MCA sarcomas', 'Disease', 'MESH:D020244', (51, 63))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('MCA sarcomas', 'Disease', (51, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('mutations', 'Var', (191, 200))	('cancer', 'Disease', (126, 132))	('lung cancers', 'Disease', 'MESH:D008175', (80, 92))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('mouse', 'Species', '10090', (45, 50))	('tumours', 'Disease', (30, 37))	('cancer', 'Disease', (85, 91))	('lung cancers', 'Disease', (80, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('lung cancers', 'Phenotype', 'HP:0100526', (80, 92))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('human', 'Species', '9606', (67, 72))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
483284	22318521	However, since ~1% of the mutations in d42m1 are selectively expressed in regressor tumour clones, it is possible that spontaneous tumours arising by other means that harbour as few as 100-200 mutations could still be susceptible to immunological sculpting as they develop.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumour', 'Disease', (131, 137))	('tumour', 'Disease', (84, 90))	('tumours', 'Disease', (131, 138))	('mutations', 'Var', (26, 35))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('d42m1', 'Gene', (39, 44))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
483285	22318521	The immunodominance of mutant spectrin-beta2 in driving tumour rejection in many ways resembles that of certain viral antigens and is likely due to the presence in d42m1 of 4 copies of chromosome 11 that carries the spectrin-beta2 gene thereby producing a highly abundant neoepitope that binds to H-2Db 750-fold stronger than that of the WT sequence.	('spectrin-beta2', 'Gene', (30, 44))	('spectrin-beta2', 'Gene', '20742', (216, 230))	('stronger', 'PosReg', (312, 320))	('mutant', 'Var', (23, 29))	('spectrin-beta2', 'Gene', (216, 230))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('spectrin-beta2', 'Gene', '20742', (30, 44))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))	('binds', 'Interaction', (288, 293))	('H-2Db', 'Protein', (297, 302))
483286	22318521	Immunoepitope analysis of parental H31m1 reveals that it expresses multiple potential strong neoantigens (19 potential strong binders to H-2Db and 58 to H-2Kb) (Supplementary Fig.	('H-2Db', 'Protein', (137, 142))	('H-2Kb', 'Gene', (153, 158))	('H31m1', 'Var', (35, 40))	('H-2Kb', 'Gene', '14972', (153, 158))	('binders', 'Interaction', (126, 133))
483288	22318521	This result suggests that H31m1 displays an even more complex antigenicity than d42m1 and probably explains why H31m1 never produces escape tumours in WT mice (Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('mice', 'Species', '10090', (154, 158))	('H31m1', 'Var', (112, 117))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('tumours', 'Disease', (140, 147))
483308	22318521	We also required that the variant allele be present in at least 10% of tumour reads and no more than 5% of normal reads.	('variant', 'Var', (26, 33))	('tumour', 'Disease', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
483309	22318521	Mutation rates were estimated for each tumour sample using the number of putative "tier 1" SNVs (missense, nonsense/nonstop, splice site, silent, or noncoding RNA).	('nonsense/nonstop', 'Var', (107, 123))	('silent', 'Var', (138, 144))	('tumour', 'Disease', (39, 45))	('missense', 'Var', (97, 105))	('splice site', 'Var', (125, 136))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))
483311	22318521	The number of coverage-adjusted mutations in each sample was divided by the total size of tier 1 space in the mouse genome (43.884 Mbp) to determine the number of coding mutations per megabase (R).	('Mbp', 'Gene', (131, 134))	('mutations', 'Var', (32, 41))	('Mbp', 'Gene', '17196', (131, 134))	('mouse', 'Species', '10090', (110, 115))
483314	22318521	All 22 SNVs were PCR amplified individually in 11 samples (SK1.1, d42m1, H31m1, T2, T3, T5, T9, T10, es1, es2, and es3) using MID-tailed primers to enable sample identification.	('T10', 'Gene', '27883', (96, 99))	('H31m1', 'Var', (73, 78))	('T10', 'Gene', (96, 99))
483318	22318521	All missense mutations for each d42m1-related tumour or H31m1 were analyzed for the potential to form MHC class I neoepitopes that bind to either H-2Db or H-2Kb molecules.	('H-2Kb', 'Gene', (155, 160))	('bind', 'Interaction', (131, 135))	('tumour', 'Disease', (46, 52))	('missense mutations', 'Var', (4, 22))	('H-2Kb', 'Gene', '14972', (155, 160))	('H-2Db', 'Protein', (146, 151))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
483319	22318521	Predicted strong affinity epitopes expressed in d42m1 regressor tumours are listed in Supplementary Table 5.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('d42m1', 'Var', (48, 53))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
483320	22318521	Sequencing data from normal Rag2-/- fibroblasts, d42m1 parental cells, d42m1 regressor clones, d42m1 progressor clones, d42m1 escape tumours, and H31m1 tumour cells were compared using PHYLogeny Inference Package (PHYLIP) to generate a phylogenetic tree displaying the relatedness of each sample.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', (152, 158))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('Rag2', 'Gene', '19374', (28, 32))	('d42m1', 'Var', (120, 125))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('tumour', 'Disease', (133, 139))	('Rag2', 'Gene', (28, 32))	('tumours', 'Disease', (133, 140))	('d42m1', 'Var', (95, 100))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))
483328	22318521	Full length cDNA encoding wild type spectrin-beta2 and mutant spectrin-beta2 were cloned from parental d42m1 tumour cells by RT-PCR using primer pairs 5'-TGAGACAGTCAAGATGACGACCACGGTAGCCACA-3' and 5'-CGGGACAACAGGGAAGTTCACTTCTTCTTGCCGA-3'.	('spectrin-beta2', 'Gene', '20742', (62, 76))	('spectrin-beta2', 'Gene', (36, 50))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('mutant', 'Var', (55, 61))	('tumour', 'Disease', (109, 115))	('spectrin-beta2', 'Gene', (62, 76))	('spectrin-beta2', 'Gene', '20742', (36, 50))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
483329	22318521	Wild type and mutant spectrin-beta2 cDNA were subcloned from the TOPO-XL vector (Invitrogen) into the RV-GFP vector.	('spectrin-beta2', 'Gene', '20742', (21, 35))	('mutant', 'Var', (14, 20))	('spectrin-beta2', 'Gene', (21, 35))
483332	22318521	To remove candidate T cell epitopes in RFP, the nucleotide A was replaced by G at position 334 in the cDNA, resulting in amino acid substitution N112D.	('RFP', 'Gene', '19720', (39, 42))	('N112D', 'Var', (145, 150))	('A was replaced by G at position 334', 'Mutation', 'c.334A>G', (59, 94))	('N112D', 'Mutation', 'p.N112D', (145, 150))	('RFP', 'Gene', (39, 42))
483342	22318521	One million tumour cells were labeled with 25 muCi of Na251CrO4 (PerkinElmer, Boston, MA) for 90 minutes at 37oC, washed and 10,000 cells seeded per well in 96-well round-bottom plates.	('Na251CrO4', 'Var', (54, 63))	('tumour', 'Disease', (12, 18))	('Na251CrO4', 'Chemical', '-', (54, 63))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
483349	22318521	H-2Db tetramers conjugated to phycoerythrin (PE) were prepared with mutant spectrin-beta2 peptides and produced by the NIH Tetramer Core Facility (Emory University, Atlanta, GA).	('spectrin-beta2', 'Gene', (75, 89))	('peptides', 'Protein', (90, 98))	('spectrin-beta2', 'Gene', '20742', (75, 89))	('mutant', 'Var', (68, 74))
483351	22318521	Real-time PCR specific for wild type spectrin-beta2, mutant spectrin-beta2 and GAPDH using the SYBR Green Mastermix kit (Applied Biosystems) were performed on ABI 7000.	('spectrin-beta2', 'Gene', (60, 74))	('GAPDH', 'Gene', (79, 84))	('spectrin-beta2', 'Gene', '20742', (37, 51))	('spectrin-beta2', 'Gene', '20742', (60, 74))	('mutant', 'Var', (53, 59))	('SYBR Green', 'Chemical', '-', (95, 105))	('GAPDH', 'Gene', '14433', (79, 84))	('spectrin-beta2', 'Gene', (37, 51))
483352	22318521	The primer sequences for used for mutant spectrin-beta2 are 5'-GGTGAACCAGATTGCACT-3' and 5'-TGTCCACCAGTTCTCTGAACT-3'.	('spectrin-beta2', 'Gene', '20742', (41, 55))	('spectrin-beta2', 'Gene', (41, 55))	('mutant', 'Var', (34, 40))
483353	22318521	The point mutation in the spectrin-beta2 gene creates a PstI restriction site (CGGCAG to CTGCAG, underlined italic letters indicate the site of mutation).	('spectrin-beta2', 'Gene', '20742', (26, 40))	('point mutation', 'Var', (4, 18))	('spectrin-beta2', 'Gene', (26, 40))	('PstI restriction site', 'MPA', (56, 77))
483355	22318521	The PCR products were digested for 2 hrs at 37 C with PstI restriction enzyme, which cleaved mutant spectrin-beta2, but not wild-type spectrin-beta2, and generates a 200 bp fragment from cDNA.	('spectrin-beta2', 'Gene', (134, 148))	('spectrin-beta2', 'Gene', '20742', (100, 114))	('mutant', 'Var', (93, 99))	('spectrin-beta2', 'Gene', '20742', (134, 148))	('spectrin-beta2', 'Gene', (100, 114))
483361	22318521	Sorted CD45+ cells (host leukocytes) and CD45- cells (primary d42m1 tumour cells) were collected and genomic DNA as well as RNA was isolated to synthesize cDNA for 3730 sequencing to validate that the mutation calls detected by Illumina were somatic and tumour-specific.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (254, 260))	('tumour', 'Disease', (68, 74))	('CD45', 'Gene', '19264', (41, 45))	('mutation', 'Var', (201, 209))	('CD45', 'Gene', (7, 11))	('CD45', 'Gene', '19264', (7, 11))	('CD45', 'Gene', (41, 45))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
483384	28197348	The first consisted of highly cellular areas, composed of small-to-medium-sized cells, often with a clear cytoplasm; these were predominantly T-cells: CD3+++; CD2+++; CD4+++; CD8++; CD5+++; CD7+/(-); PD1++ (Figure 1(b)), in a polymorphous cellular background, including eosinophils and isolated large CD20+ cells.	('CD20', 'Gene', (301, 305))	('CD8++; CD5+++; CD7+/(-); PD1++', 'Var', (175, 205))	('CD8', 'Species', '1151253', (175, 178))	('CD5', 'Species', '1151252', (182, 185))	('CD3', 'Species', '1151252', (151, 154))	('CD2', 'Species', '1151252', (159, 162))	('CD4', 'Species', '1151252', (167, 170))	('CD2', 'Species', '1151252', (301, 304))	('CD20', 'Gene', '54474', (301, 305))
483385	28197348	In addition, the tumor cell phenotype included CD10+++; CD68+; LCA+; CD30 (-); Ki67+ 75%.	('CD30 (-); Ki67+ 75', 'Var', (69, 87))	('CD68+', 'Var', (56, 61))	('CD10+++; CD68+', 'Var', (47, 61))	('tumor', 'Disease', (17, 22))	('CD68', 'Species', '1151273', (56, 60))	('CD3', 'Species', '1151252', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
483387	28197348	The T-cell lymphoma component which showed CD4+++; CD10+++; PD1++; Bcl-6++, suggestive of the follicular T-helper cell phenotype, was most consistent with AITL.	('cell lymphoma', 'Phenotype', 'HP:0012191', (6, 19))	('CD4', 'Species', '1151252', (43, 46))	('CD4+++; CD10+++; PD1++; Bcl-6++', 'Var', (43, 74))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (4, 19))	('T-cell lymphoma', 'Disease', (4, 19))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (4, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))
483388	28197348	These cells were CD21+++ (Figure 1(d)); CD23+++; fascin ++; HLA-DR++.	('CD2', 'Species', '1151252', (17, 20))	('CD23+++', 'Var', (40, 47))	('CD21+++', 'Var', (17, 24))	('CD2', 'Species', '1151252', (40, 43))	('CD21', 'Species', '1151258', (17, 21))
483416	28197348	On the other hand, AITL, among the many symptoms it induces, may rarely present with polyarthropathy suggesting rheumatoid arthritis.	('arthritis', 'Phenotype', 'HP:0001369', (123, 132))	('polyarthropathy', 'Disease', 'None', (85, 100))	('rheumatoid arthritis', 'Disease', (112, 132))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (112, 132))	('polyarthropathy', 'Disease', (85, 100))	('AITL', 'Var', (19, 23))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (112, 132))
483427	32922961	Stable expression of miR-3148 in telomerized hMSC (hMSC-miR-3148) led to significant increase in in vitro adipocytic differentiation and suppression of osteoblastic differentiation.	('hMSC', 'Chemical', '-', (51, 55))	('hMSC-miR-3148', 'Chemical', '-', (51, 64))	('S', 'Chemical', 'MESH:D013455', (53, 54))	('suppression of osteoblastic differentiation', 'Disease', (137, 180))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('miR-3148', 'Var', (21, 29))	('hMSC', 'Chemical', '-', (45, 49))	('suppression of osteoblastic differentiation', 'Disease', 'MESH:D012734', (137, 180))	('increase', 'PosReg', (85, 93))	('S', 'Chemical', 'MESH:D013455', (0, 1))
483429	32922961	Global proteomic analysis using 2D-DIGE followed by mass spectrometry (MS) revealed significant changes in protein expression in hMSC-miR-3148 and enrichment in protein networks associated with carcinogenesis.	('S', 'Chemical', 'MESH:D013455', (72, 73))	('carcinogenesis', 'Disease', (194, 208))	('protein', 'Protein', (161, 168))	('S', 'Chemical', 'MESH:D013455', (131, 132))	('hMSC-miR-3148', 'Var', (129, 142))	('protein expression', 'MPA', (107, 125))	('changes', 'Reg', (96, 103))	('hMSC-miR-3148', 'Chemical', '-', (129, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (194, 208))
483430	32922961	Functional studies revealed that hMSC-miR-3148 exhibited enhanced in vitro cell proliferation, colony formation, migration, invasion, sphere formation, doxorubicin resistance, and increased active number of cells in S and G2/M cell cycle phases and formed sarcoma-like tumors with adipocyte infiltration when implanted into immunocompromised mice.	('doxorubicin', 'Chemical', 'MESH:D004317', (152, 163))	('S', 'Chemical', 'MESH:D013455', (216, 217))	('mice', 'Species', '10090', (342, 346))	('sarcoma-like tumors', 'Disease', 'MESH:D012509', (256, 275))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('increased', 'PosReg', (180, 189))	('hMSC-miR-3148', 'Var', (33, 46))	('colony formation', 'CPA', (95, 111))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('sarcoma-like tumors', 'Disease', (256, 275))	('sphere formation', 'CPA', (134, 150))	('migration', 'CPA', (113, 122))	('invasion', 'CPA', (124, 132))	('enhanced', 'PosReg', (57, 65))	('doxorubicin resistance', 'MPA', (152, 174))	('hMSC-miR-3148', 'Chemical', '-', (33, 46))
483431	32922961	SMAD2 was identified as bone fide gene target for miR-3148 using qRT-PCR, Western blotting, and UTR-based reporter assay.	('SMAD2', 'Gene', (0, 5))	('P', 'Chemical', 'MESH:D010758', (69, 70))	('miR-3148', 'Var', (50, 58))
483433	32922961	Bioinformatics analysis revealed that elevated miR-3148 expression correlates with poor prognosis in several human cancer types, including sarcoma.	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('expression', 'MPA', (56, 66))	('miR-3148', 'Var', (47, 55))	('sarcoma', 'Disease', (139, 146))	('elevated', 'PosReg', (38, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
483437	32922961	Deregulated miRNA expression is associated with large number of human cancers, including breast, colon, gastric, lung, and sarcomas.	('human', 'Species', '9606', (64, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('sarcomas', 'Disease', (123, 131))	('Deregulated', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('gastric', 'Disease', (104, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (123, 131))	('cancers', 'Disease', (70, 77))	('colon', 'Disease', (97, 102))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('associated', 'Reg', (32, 42))	('sarcomas', 'Disease', 'MESH:D012509', (123, 131))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('lung', 'Disease', (113, 117))	('breast', 'Disease', (89, 95))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
483442	32922961	Functional and molecular investigations revealed miR-3148 to promote adipogenesis and to suppress osteogenesis through direct targeting of SMAD2/TGFbeta pathway.	('TGFbeta', 'Gene', '7039', (145, 152))	('adipogenesis', 'MPA', (69, 81))	('promote', 'PosReg', (61, 68))	('osteogenesis', 'MPA', (98, 110))	('TGFbeta', 'Gene', (145, 152))	('suppress', 'NegReg', (89, 97))	('miR-3148', 'Var', (49, 57))
483443	32922961	In addition, hMSC-miR-3148 exhibited enhanced in vitro cell proliferation, colony formation, cell migration, cell invasion and sphere formation, increased active S and G2/M cell cycle phases, and formed sarcoma-like tumors when implanted into immunocompromised mice, suggesting a role for miR-3148 as regulator of stem cell differentiation and transformation.	('sarcoma-like tumors', 'Disease', (203, 222))	('hMSC-miR-3148', 'Chemical', '-', (13, 26))	('S', 'Chemical', 'MESH:D013455', (162, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('increased', 'PosReg', (145, 154))	('S', 'Chemical', 'MESH:D013455', (15, 16))	('sphere formation', 'CPA', (127, 143))	('mice', 'Species', '10090', (261, 265))	('colony formation', 'CPA', (75, 91))	('cell migration', 'CPA', (93, 107))	('hMSC-miR-3148', 'Var', (13, 26))	('formed', 'Reg', (196, 202))	('sarcoma-like tumors', 'Disease', 'MESH:D012509', (203, 222))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('enhanced', 'PosReg', (37, 45))
483447	32922961	An enhanced adipocytic differentiation was observed in hMSC-miR-3148 as evidenced by oil red staining (Fig.	('hMSC-miR-3148', 'Var', (55, 68))	('enhanced', 'PosReg', (3, 11))	('hMSC-miR-3148', 'Chemical', '-', (55, 68))	('oil red', 'Chemical', '-', (85, 92))	('adipocytic differentiation', 'CPA', (12, 38))
483449	32922961	On the other hand, hMSC-miR-3148 exhibited diminished ALP activity (Fig.	('ALP', 'Gene', (54, 57))	('hMSC-miR-3148', 'Var', (19, 32))	('ALP', 'Gene', '250', (54, 57))	('hMSC-miR-3148', 'Chemical', '-', (19, 32))	('diminished', 'NegReg', (43, 53))	('diminished ALP', 'Phenotype', 'HP:0003282', (43, 57))
483461	32922961	Sixty protein spots exhibited statistically significant change in abundance in hMSC-miR-3148 compared to hMSC-control cells (ANOVA-test p < 0.05; fold change > 1.5).	('abundance', 'MPA', (66, 75))	('S', 'Chemical', 'MESH:D013455', (107, 108))	('hMSC-', 'Chemical', '-', (105, 110))	('hMSC-miR-3148', 'Chemical', '-', (79, 92))	('change', 'Reg', (56, 62))	('hMSC-', 'Chemical', '-', (79, 84))	('S', 'Chemical', 'MESH:D013455', (81, 82))	('hMSC-miR-3148', 'Var', (79, 92))	('S', 'Chemical', 'MESH:D013455', (0, 1))
483463	32922961	Among the 40 spots, 21 spots were upregulated and 19 spots were downregulated in hMSC-miR-3148 compared to control cells (Fig.	('hMSC-miR-3148', 'Chemical', '-', (81, 94))	('upregulated', 'PosReg', (34, 45))	('hMSC-miR-3148', 'Var', (81, 94))	('downregulated', 'NegReg', (64, 77))
483469	32922961	3a revealed increased colony formation in hMSC-miR-3148 compared to control cells, which were observed in hMSC-miR-3148 as early as day 5, compared to control cells.	('hMSC-miR-3148', 'Chemical', '-', (106, 119))	('hMSC-miR-3148', 'Chemical', '-', (42, 55))	('colony formation', 'CPA', (22, 38))	('hMSC-miR-3148', 'Var', (106, 119))	('increased', 'PosReg', (12, 21))	('hMSC-miR-3148', 'Var', (42, 55))
483473	32922961	Notably, the spheroids formed by hMSC-miR-3148 were more compact whereas control cells-derived spheroids had irregular forms (Fig.	('hMSC-miR-3148', 'Chemical', '-', (33, 46))	('hMSC-miR-3148', 'Var', (33, 46))	('compact', 'CPA', (57, 64))	('more', 'PosReg', (52, 56))
483474	32922961	Cell cycle analysis revealed significant decrease in G0/G1 and significant increase in S and G2-M phases of the cell cycle in hMSC-miR-3148 compared to controls (Fig.	('G0/G1', 'CPA', (53, 58))	('hMSC-miR-3148', 'Chemical', '-', (126, 139))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('decrease', 'NegReg', (41, 49))	('S', 'Chemical', 'MESH:D013455', (128, 129))	('hMSC-miR-3148', 'Var', (126, 139))	('increase', 'PosReg', (75, 83))
483476	32922961	hMSC-miR-3148 exhibited increased resistance to doxorubicin concentration ranging from 7.8 to 125 nM (Fig.	('hMSC-miR-3148', 'Chemical', '-', (0, 13))	('resistance to doxorubicin concentration', 'MPA', (34, 73))	('hMSC-miR-3148', 'Var', (0, 13))	('doxorubicin', 'Chemical', 'MESH:D004317', (48, 59))	('increased', 'PosReg', (24, 33))
483479	32922961	Therefore, to examine the ability of hMSC-miR-3148 to form tumors in vivo, we implanted hMSC-miR-3148 and control cells loaded into Matrigel  matrix, subcutaneously into immune deficient nude mice.	('immune deficient', 'Phenotype', 'HP:0002721', (170, 186))	('hMSC-miR-3148', 'Var', (88, 101))	('nude mice', 'Species', '10090', (187, 196))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('hMSC-miR-3148', 'Chemical', '-', (88, 101))	('hMSC-miR-3148', 'Chemical', '-', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
483480	32922961	Concordant with the in vitro data, hMSC-miR-3148 cells formed tumors, which were not detected in control cells (Fig.	('hMSC-miR-3148', 'Var', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('hMSC-miR-3148', 'Chemical', '-', (35, 48))
483496	32922961	Dysregulated miRNA expression has been implicated in human diseases, including diabetes, cardiovascular, kidney diseases and cancer.	('diabetes', 'Disease', (79, 87))	('miR', 'Gene', '220972', (13, 16))	('implicated', 'Reg', (39, 49))	('miR', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cardiovascular, kidney diseases', 'Disease', 'MESH:D002318', (89, 120))	('diabetes', 'Disease', 'MESH:D003920', (79, 87))	('kidney diseases', 'Phenotype', 'HP:0000112', (105, 120))	('Dysregulated', 'Var', (0, 12))	('human', 'Species', '9606', (53, 58))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
483502	32922961	We observed that overexpression of miR-3148 in hMSC led to enhanced cell proliferation, induced a transformed cellular phenotype as well as formation of sarcoma-like tumors when implanting the cells in vivo.	('formation', 'CPA', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('transformed cellular phenotype', 'CPA', (98, 128))	('cell proliferation', 'CPA', (68, 86))	('sarcoma-like tumors', 'Disease', (153, 172))	('sarcoma-like tumors', 'Disease', 'MESH:D012509', (153, 172))	('enhanced', 'PosReg', (59, 67))	('hMSC', 'Chemical', '-', (47, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('overexpression', 'PosReg', (17, 31))	('induced', 'PosReg', (88, 95))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('miR-3148', 'Var', (35, 43))
483503	32922961	We have also observed that miR-3148 targets TGFbeta signaling pathway.	('miR-3148', 'Var', (27, 35))	('TGFbeta', 'Gene', '7039', (44, 51))	('TGFbeta', 'Gene', (44, 51))
483508	32922961	Interestingly, disruption of TGFbeta signaling in the prostate of SV40 large T antigen transgenic animals, did not affect the size of neoplastic tumors, but instead it promoted tumor metastasis.	('TGFbeta', 'Gene', (29, 36))	('S', 'Chemical', 'MESH:D013455', (66, 67))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('neoplastic tumors', 'Disease', 'MESH:D009369', (134, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('TGFbeta', 'Gene', '7039', (29, 36))	('tumor', 'Disease', (145, 150))	('promoted', 'PosReg', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('neoplastic tumors', 'Disease', (134, 151))	('tumor', 'Disease', (177, 182))	('disruption', 'Var', (15, 25))	('SV40', 'Gene', (66, 70))
483509	32922961	Also, disruption of SMAD2 accelerates malignant progression of intestinal tumors in apc knockout mice, although the total number of intestinal tumors in those animals was not affected.	('intestinal tumors', 'Disease', 'MESH:D007414', (132, 149))	('apc', 'Gene', (84, 87))	('SMAD2', 'Gene', (20, 25))	('accelerates', 'PosReg', (26, 37))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mice', 'Species', '10090', (97, 101))	('intestinal tumors', 'Disease', (63, 80))	('apc', 'Gene', '11789', (84, 87))	('disruption', 'Var', (6, 16))	('intestinal tumors', 'Disease', 'MESH:D007414', (63, 80))	('intestinal tumors', 'Disease', (132, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
483510	32922961	Taken together, the current studies suggest that disruption of TGFbeta accelerates tumorigenesis, while the loss of TGFbeta signaling is not sufficient to trigger malignant transformation.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TGFbeta', 'Gene', '7039', (63, 70))	('tumor', 'Disease', (83, 88))	('TGFbeta', 'Gene', (116, 123))	('TGFbeta', 'Gene', '7039', (116, 123))	('TGFbeta', 'Gene', (63, 70))	('disruption', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('accelerates', 'PosReg', (71, 82))
483511	32922961	Our data are in agreement with the aforementioned reports where we observed miR-3148 to promote malignant transformation of the telomerized-hMSC cells, while forced expression of miR-3148 on its own has no significant effects on the growth of primary skin derived stromal cells (Supplementary Fig.	('miR-3148', 'Var', (76, 84))	('S', 'Chemical', 'MESH:D013455', (142, 143))	('S', 'Chemical', 'MESH:D013455', (279, 280))	('promote', 'PosReg', (88, 95))	('hMSC', 'Chemical', '-', (140, 144))	('miR-3148', 'Var', (179, 187))
483512	32922961	Telomerized-hMSC model employed in current study has normal karyotype, but exhibited deletion of the Ink4a/ARF locus and therefore is more prone to malignant transformation, which provides a plausible explanation for the observed data of differential effects of miR-3148 on telomerized-hMSC compared to primary stromal cells.	('Ink4a/ARF', 'Gene', '1029', (101, 110))	('hMSC', 'Chemical', '-', (286, 290))	('prone', 'Reg', (139, 144))	('malignant transformation', 'CPA', (148, 172))	('Ink4a/ARF', 'Gene', (101, 110))	('hMSC', 'Chemical', '-', (12, 16))	('deletion', 'Var', (85, 93))
483513	32922961	It also suggests that inactivation of TGFbeta via miR-3148/SMAD2 axis is a "secondary hit" accelerating malignant transformation.	('inactivation', 'Var', (22, 34))	('malignant transformation', 'CPA', (104, 128))	('TGFbeta', 'Gene', '7039', (38, 45))	('TGFbeta', 'Gene', (38, 45))	('accelerating', 'PosReg', (91, 103))
483514	32922961	In Ewing's sarcoma (ES), elevated expression of miR-20b was shown to directly target TGFbeta receptor II (TGFBR2) leading to elevated MYC expression, hence inhibition of miR-20b reduced ES cell grow, cell cycle progression, and in vivo tumor formation, thus corroborating the important role of loss of TGFbeta signaling in promoting ES tumor formation.	('elevated', 'PosReg', (125, 133))	('inhibition', 'Var', (156, 166))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (3, 18))	('TGFbeta', 'Gene', '7039', (302, 309))	('miR-20b', 'Gene', '574032', (170, 177))	('miR-20b', 'Gene', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('MYC', 'Gene', '4609', (134, 137))	('TGFBR2', 'Gene', '7048', (106, 112))	('expression', 'MPA', (138, 148))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (3, 18))	('tumor', 'Disease', (336, 341))	('S', 'Chemical', 'MESH:D013455', (21, 22))	('TGFbeta', 'Gene', (85, 92))	('S', 'Chemical', 'MESH:D013455', (187, 188))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('elevated', 'PosReg', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('ES', 'Phenotype', 'HP:0012254', (333, 335))	('TGFbeta', 'Gene', '7039', (85, 92))	('miR-20b', 'Gene', '574032', (48, 55))	('reduced', 'NegReg', (178, 185))	('TGFBR2', 'Gene', (106, 112))	("Ewing's sarcoma", 'Disease', (3, 18))	('ES cell grow', 'CPA', (186, 198))	('miR-20b', 'Gene', (170, 177))	('cell cycle progression', 'CPA', (200, 222))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('ES', 'Phenotype', 'HP:0012254', (20, 22))	('MYC', 'Gene', (134, 137))	('ES', 'Phenotype', 'HP:0012254', (186, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('S', 'Chemical', 'MESH:D013455', (334, 335))	('TGFbeta', 'Gene', (302, 309))	('tumor', 'Disease', (236, 241))
483515	32922961	In addition to the SMAD2/TGFB pathway, miR-3148-hMSC cells exhibited upregulation and downregulation of several onco- and tumor suppressor genes, respectively.	('upregulation', 'PosReg', (69, 81))	('miR-3148-hMSC', 'Var', (39, 52))	('TGFB', 'Gene', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('downregulation', 'NegReg', (86, 100))	('TGFB', 'Gene', '7040', (25, 29))	('tumor', 'Disease', (122, 127))	('hMSC', 'Chemical', '-', (48, 52))
483516	32922961	The role of other genes in regulating hMSC differentiation and tumorigenesis in the context of miR-3148 remains to be elucidated.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('miR-3148', 'Var', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('hMSC', 'Chemical', '-', (38, 42))	('hMSC differentiation', 'CPA', (38, 58))
483518	32922961	In order to provide potential mechanism by which miR-3148 confers doxorubicin resistance, gene expression data from GSE3362 was retrieved and the upregulated and downregulated genes in doxorubicin-resistant sarcoma were identified and were crossed with the list of differentially expressed genes in miR-3148-hMSC cells.	('GSE3362', 'Chemical', '-', (116, 123))	('sarcoma', 'Disease', 'MESH:D012509', (207, 214))	('hMSC', 'Chemical', '-', (308, 312))	('doxorubicin resistance', 'MPA', (66, 88))	('sarcoma', 'Disease', (207, 214))	('downregulated', 'NegReg', (162, 175))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('doxorubicin', 'Chemical', 'MESH:D004317', (185, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('upregulated', 'PosReg', (146, 157))	('miR-3148', 'Var', (49, 57))
483522	32922961	The role of other genes in mediating doxorubicin residence in miR-3148-hMSC warrants further investigation.	('miR-3148-hMSC', 'Var', (62, 75))	('hMSC', 'Chemical', '-', (71, 75))	('doxorubicin', 'Chemical', 'MESH:D004317', (37, 48))	('doxorubicin residence', 'MPA', (37, 58))
483524	32922961	For instance, methylation of HIC ZBTB Transcriptional Repressor 1 (HIC1) and Ras Association Domain Family Member 1 (RassF1A) tumor suppressor genes was sufficient to transform bone marrow MSCs into malignant cells endowed with tumor-initiating capabilities.	('HIC1', 'Gene', '3090', (67, 71))	('transform', 'Reg', (167, 176))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('HIC ZBTB Transcriptional Repressor 1', 'Gene', '3090', (29, 65))	('S', 'Chemical', 'MESH:D013455', (190, 191))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('HIC1', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('methylation', 'Var', (14, 25))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('HIC ZBTB Transcriptional Repressor 1', 'Gene', (29, 65))	('RassF1A', 'Gene', (117, 124))	('tumor', 'Disease', (126, 131))
483528	32922961	Our current study corroborates these findings since miR-3148 overexpressing hMSC-TERT cells exhibited enhanced adipogenesis and suppressed osteogenesis, suggesting the loss of osteogenic differentiation is a common feature during malignant transformation of hMSC.	('hMSC', 'Chemical', '-', (258, 262))	('enhanced', 'PosReg', (102, 110))	('hMSC', 'Chemical', '-', (76, 80))	('osteogenesis', 'MPA', (139, 151))	('miR-3148', 'Var', (52, 60))	('hMSC-TERT', 'CellLine', 'CVCL:Z015', (76, 85))	('adipogenesis', 'MPA', (111, 123))	('loss of osteogenic differentiation', 'Disease', 'MESH:D012516', (168, 202))	('suppressed', 'NegReg', (128, 138))	('loss of osteogenic differentiation', 'Disease', (168, 202))
483529	32922961	Interestingly, we found positive correlation between elevated expression of miR-3148 and poor prognosis in several human cancer types, including sarcomas thus highlighting miR-3148 as a possible prognostic biomarker in various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('elevated', 'PosReg', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('poor prognosis', 'CPA', (89, 103))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('expression', 'MPA', (62, 72))	('miR-3148', 'Gene', (76, 84))	('miR-3148', 'Var', (172, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('human', 'Species', '9606', (227, 232))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('cancer', 'Disease', (233, 239))	('human', 'Species', '9606', (115, 120))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('sarcomas', 'Disease', (145, 153))	('cancers', 'Disease', (233, 240))	('cancer', 'Disease', (121, 127))
483530	32922961	In support of this hypothesis, recent data reported higher expression of miR-3148 in 3D-spheroids formed using the HCT116 human CRC model.	('human', 'Species', '9606', (122, 127))	('miR-3148', 'Var', (73, 81))	('expression', 'MPA', (59, 69))	('higher', 'PosReg', (52, 58))	('HCT116', 'CellLine', 'CVCL:0291', (115, 121))
483531	32922961	miR-3148-overexpressing HCT116 cells exhibited enhanced tumor formation in vivo, were resistant to hypoxic conditions and exhibited higher sensitivity to MAPKK and ERK inhibitors.	('higher', 'PosReg', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('enhanced', 'PosReg', (47, 55))	('HCT116', 'CellLine', 'CVCL:0291', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('miR-3148-overexpressing', 'Var', (0, 23))	('ERK', 'Gene', '5594', (164, 167))	('P', 'Chemical', 'MESH:D010758', (156, 157))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (99, 117))	('ERK', 'Gene', (164, 167))	('sensitivity', 'MPA', (139, 150))	('hypoxic conditions', 'Disease', (99, 117))
483532	32922961	In addition to its possible role in carcinogenesis, a role for miR-3148 in the context of other pathological conditions has been reported.	('carcinogenesis', 'Disease', (36, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (36, 50))	('miR-3148', 'Var', (63, 71))
483533	32922961	miR-3148 levels were inversely correlated with Toll-like receptor 7 (TLR7) transcript levels in peripheral blood monocytes obtained from systemic lupus erythematosus (SLE) patients.	('Toll-like receptor 7', 'Gene', '51284', (47, 67))	('systemic lupus erythematosus', 'Disease', (137, 165))	('Toll-like receptor 7', 'Gene', (47, 67))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (137, 165))	('transcript levels', 'MPA', (75, 92))	('TLR7', 'Gene', (69, 73))	('SLE', 'Disease', (167, 170))	('patients', 'Species', '9606', (172, 180))	('miR-3148', 'Var', (0, 8))	('TLR7', 'Gene', '51284', (69, 73))	('SLE', 'Disease', 'MESH:D008180', (167, 170))	('SLE', 'Phenotype', 'HP:0002725', (167, 170))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (137, 165))
483534	32922961	Interestingly, the G allele of rs3853839 in the 3' UTR of TLR7 has diminished binding capability to miR-3148, which was associated with elevated TLR7 transcript expression and increased risk for SLE, thus implicating miR-3148-TLR7 circuit in SLE pathogenesis.	('binding', 'Interaction', (78, 85))	('diminished', 'NegReg', (67, 77))	('SLE', 'Phenotype', 'HP:0002725', (195, 198))	('TLR7', 'Gene', (58, 62))	('TLR7', 'Gene', (145, 149))	('TLR7', 'Gene', '51284', (58, 62))	('transcript expression', 'MPA', (150, 171))	('TLR7', 'Gene', '51284', (145, 149))	('miR-3148', 'Gene', (100, 108))	('rs3853839', 'Var', (31, 40))	('elevated', 'PosReg', (136, 144))	('TLR7', 'Gene', (226, 230))	('SLE', 'Disease', 'MESH:D008180', (242, 245))	('SLE', 'Disease', (242, 245))	('rs3853839', 'Mutation', 'rs3853839', (31, 40))	('TLR7', 'Gene', '51284', (226, 230))	('SLE', 'Phenotype', 'HP:0002725', (242, 245))	('SLE', 'Disease', 'MESH:D008180', (195, 198))	('SLE', 'Disease', (195, 198))
483535	32922961	Elevated levels of miR-3148 were also associated with congestive heart failure (CHF) in a cohort of 44 CHF patients and 15 healthy subjects.	('congestive heart failure', 'Disease', 'MESH:D006333', (54, 78))	('CHF', 'Phenotype', 'HP:0001635', (103, 106))	('congestive heart failure', 'Phenotype', 'HP:0001635', (54, 78))	('associated with', 'Reg', (38, 53))	('CHF', 'Phenotype', 'HP:0001635', (80, 83))	('congestive heart failure', 'Disease', (54, 78))	('miR-3148', 'Var', (19, 27))	('CHF', 'Disease', 'None', (103, 106))	('CHF', 'Disease', (103, 106))	('CHF', 'Disease', 'None', (80, 83))	('CHF', 'Disease', (80, 83))	('patients', 'Species', '9606', (107, 115))
483562	32922961	Each sample was covalently labeled with a fluorophore, either Cy3 or Cy5.	('Cy3', 'Chemical', '-', (62, 65))	('Cy5', 'Var', (69, 72))	('Cy3', 'Var', (62, 65))	('Cy5', 'Chemical', 'MESH:C085321', (69, 72))
483580	32922961	The software calculated the NV of each spot on each gel from Cy3 (or Cy5) to Cy2 spot volume ratio.	('Cy3', 'Var', (61, 64))	('Cy2', 'Chemical', '-', (77, 80))	('Cy3', 'Chemical', '-', (61, 64))	('Cy5', 'Var', (69, 72))	('Cy5', 'Chemical', 'MESH:C085321', (69, 72))
483676	30024558	A biopsy procedure can also spread tumor cells to surrounding tissue and, therefore, increase the risk of local recurrence.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('local recurrence', 'CPA', (106, 122))	('biopsy', 'Var', (2, 8))	('tumor', 'Disease', (35, 40))	('increase', 'PosReg', (85, 93))
483693	30024558	Because we observed medium heterogeneity between the studies (I2 = 68.4%), we used a random-effects model for the comparison and found that the diagnostic accuracy of CNB was significantly lower than that of SB (pooled odds ratio: 0.39, 95% CI: 0.20-0.76) (Fig.	('lower', 'NegReg', (189, 194))	('CNB', 'Var', (167, 170))	('SB', 'Chemical', '-', (208, 210))
483724	29670334	Approximately 50% of patients with high-grade STS develop metastatic diseases, and the median overall survival (OS) for advanced or metastatic STS has ranged from 12 months (historical) to 18-19 months (contemporary).	('STS', 'Phenotype', 'HP:0030448', (46, 49))	('high-grade', 'Var', (35, 45))	('patients', 'Species', '9606', (21, 29))	('STS', 'Phenotype', 'HP:0030448', (143, 146))	('develop', 'PosReg', (50, 57))	('metastatic diseases', 'CPA', (58, 77))
483785	29670334	In an international, multicenter, open-label, Phase IIb trial randomizing (2:1) patients with locally advanced, unresectable, and/or metastatic STS to receive first-line IV aldoxorubicin 350 mg/m2 or doxorubicin 75 mg/m2 every 21 days (up to six cycles), the primary endpoint of PFS was significantly improved with aldoxorubicin compared to doxorubicin with a 6-month PFS rate of 46 vs 23% (P=0.02, Table 2).	('patients', 'Species', '9606', (80, 88))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (173, 186))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (315, 328))	('doxorubicin', 'Chemical', 'MESH:D004317', (175, 186))	('aldoxorubicin', 'Var', (315, 328))	('STS', 'Phenotype', 'HP:0030448', (144, 147))	('improved', 'PosReg', (301, 309))	('doxorubicin', 'Chemical', 'MESH:D004317', (200, 211))	('doxorubicin', 'Chemical', 'MESH:D004317', (317, 328))	('doxorubicin', 'Chemical', 'MESH:D004317', (341, 352))
483787	29670334	ORRs were also higher with aldoxorubicin compared to doxorubicin (25 vs 0%).	('doxorubicin', 'Chemical', 'MESH:D004317', (53, 64))	('aldoxorubicin', 'Var', (27, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (29, 40))	('higher', 'PosReg', (15, 21))	('ORRs', 'MPA', (0, 4))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (27, 40))
483788	29670334	Grades 3-4 neutropenia was more frequent with aldoxorubicin than with doxorubicin (29 vs 12%), but not grades 3-4 febrile neutropenia (14 vs 18%).	('neutropenia', 'Disease', (11, 22))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (46, 59))	('neutropenia', 'Disease', 'MESH:D009503', (122, 133))	('aldoxorubicin', 'Var', (46, 59))	('neutropenia', 'Phenotype', 'HP:0001875', (122, 133))	('neutropenia', 'Disease', 'MESH:D009503', (11, 22))	('doxorubicin', 'Chemical', 'MESH:D004317', (48, 59))	('neutropenia', 'Phenotype', 'HP:0001875', (11, 22))	('febrile neutropenia', 'Disease', (114, 133))	('febrile neutropenia', 'Disease', 'MESH:D009503', (114, 133))	('doxorubicin', 'Chemical', 'MESH:D004317', (70, 81))	('neutropenia', 'Disease', (122, 133))
483791	29670334	Overall, the total number of patients who experienced a LVEF decrease of >=10% was nine (12%) with aldoxorubicin and 11 (29%) with doxorubicin.	('patients', 'Species', '9606', (29, 37))	('doxorubicin', 'Chemical', 'MESH:D004317', (131, 142))	('decrease', 'NegReg', (61, 69))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (99, 112))	('aldoxorubicin', 'Var', (99, 112))	('LVEF', 'MPA', (56, 60))	('doxorubicin', 'Chemical', 'MESH:D004317', (101, 112))
483804	29670334	There was a trend toward significantly improved ORR in the L-sarcomas cohort treated with aldoxorubicin (10.0 vs 4.0%, P=0.0790) compared to IC.	('aldoxorubicin', 'Var', (90, 103))	('L-sarcomas', 'Disease', (59, 69))	('L-sarcomas', 'Disease', 'MESH:D012509', (59, 69))	('ORR', 'MPA', (48, 51))	('improved', 'PosReg', (39, 47))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (90, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
483808	29670334	There were more grade >=3 AEs (74.2 vs 64.3%), grade >=3 treatment-related AEs (64.3 vs 46.9%), serious AEs (42.7 vs 32.9%), and treatment-related AEs resulting in death (1.4 vs 0%) in the aldoxorubicin arm.	('AEs', 'Chemical', '-', (75, 78))	('AEs', 'Chemical', '-', (26, 29))	('grade >=3', 'Var', (47, 56))	('resulting in', 'Reg', (151, 163))	('AEs', 'Chemical', '-', (147, 150))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (189, 202))	('AEs', 'Chemical', '-', (104, 107))	('serious', 'Disease', (96, 103))
483810	29670334	Cardiac toxicity, defined by >20% decrease in LVEF, was lower in patients receiving aldoxorubicin compared to those in the IC arm receiving doxorubicin (3.8 vs 8.5%).	('Cardiac toxicity', 'Disease', (0, 16))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (84, 97))	('doxorubicin', 'Chemical', 'MESH:D004317', (140, 151))	('decrease', 'NegReg', (34, 42))	('aldoxorubicin', 'Var', (84, 97))	('lower', 'NegReg', (56, 61))	('doxorubicin', 'Chemical', 'MESH:D004317', (86, 97))	('Cardiac toxicity', 'Disease', 'MESH:D066126', (0, 16))	('patients', 'Species', '9606', (65, 73))	('LVEF', 'MPA', (46, 50))
483813	29670334	In summary, aldoxorubicin was associated with a superior PFS compared with standard of care (SOC) regimens in North America and L-sarcomas suggesting that it may be the superior anthracycline compared to doxorubicin in advanced STS.	('STS', 'Phenotype', 'HP:0030448', (228, 231))	('PFS', 'MPA', (57, 60))	('L-sarcomas', 'Disease', (128, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (12, 25))	('L-sarcomas', 'Disease', 'MESH:D012509', (128, 138))	('aldoxorubicin', 'Var', (12, 25))	('doxorubicin', 'Chemical', 'MESH:D004317', (14, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('anthracycline', 'Chemical', 'MESH:D018943', (178, 191))	('doxorubicin', 'Chemical', 'MESH:D004317', (204, 215))
483819	29670334	In the largest study to date that demonstrated superior PFS with aldoxorubicin over doxorubicin in the first-line treatment of advanced STS, aldoxorubicin produced a median PFS of 5.6 months (95% CI 3.0-8.1), OS of 15.8 months (95% CI 13.0-not reached), and ORR of 25%.	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('aldoxorubicin', 'Var', (141, 154))	('doxorubicin', 'Chemical', 'MESH:D004317', (143, 154))	('STS', 'Phenotype', 'HP:0030448', (136, 139))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (65, 78))	('PFS', 'MPA', (173, 176))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (141, 154))
483832	29670334	Heterogeneity in sarcoma subtypes across cohorts may, in part, explain the geographical differences observed in PFS seen with aldoxorubicin compared to doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (152, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcoma', 'Disease', (17, 24))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (126, 139))	('sarcoma', 'Disease', 'MESH:D012509', (17, 24))	('aldoxorubicin', 'Var', (126, 139))	('doxorubicin', 'Chemical', 'MESH:D004317', (128, 139))
483850	29670334	Interestingly, reduced alopecia was noted with aldoxorubicin and even no evidence of alopecia in a patient receiving up to 20 cycles.	('patient', 'Species', '9606', (99, 106))	('alopecia', 'CPA', (23, 31))	('alopecia', 'Phenotype', 'HP:0001596', (85, 93))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (47, 60))	('reduced', 'NegReg', (15, 22))	('aldoxorubicin', 'Var', (47, 60))	('alopecia', 'Phenotype', 'HP:0001596', (23, 31))
483852	29670334	PEGylated liposomal doxorubicin is more firmly established in the treatment of ovarian cancer, multiple myeloma, and AIDS-related Kaposi sarcoma and also has a relatively favorable toxicity profile compared to conventional doxorubicin.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('AIDS', 'Disease', 'MESH:D000163', (117, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('toxicity', 'Disease', 'MESH:D064420', (181, 189))	('Kaposi sarcoma', 'Disease', (130, 144))	('toxicity', 'Disease', (181, 189))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('doxorubicin', 'Chemical', 'MESH:D004317', (20, 31))	('multiple myeloma', 'Disease', 'MESH:D009101', (95, 111))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('PEGylated liposomal', 'Var', (0, 19))	('doxorubicin', 'Chemical', 'MESH:D004317', (223, 234))	('multiple myeloma', 'Phenotype', 'HP:0006775', (95, 111))	('ovarian cancer', 'Disease', (79, 93))	('AIDS', 'Disease', (117, 121))	('multiple myeloma', 'Disease', (95, 111))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (130, 144))
483860	29670334	Notably, there are several trials exploring combination therapy including aldoxorubicin that are ongoing or for which final results are eagerly awaited (NCT01673438, NCT02235701, NCT02235688, NCT02200757).	('NCT01673438', 'Var', (153, 164))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (74, 87))	('NCT02235701', 'Var', (166, 177))	('NCT02235688', 'Var', (179, 190))
483861	29670334	Future trials are warranted exploring aldoxorubicin's antitumor activity in other tumor types besides STS - several clinical trials are ongoing or for which final results are pending (NCT01580397, NCT02200757, and NCT02014844).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('STS', 'Phenotype', 'HP:0030448', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('NCT02014844', 'Var', (214, 225))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (38, 51))	('NCT01580397', 'Var', (184, 195))	('tumor', 'Disease', (82, 87))	('NCT02200757', 'Var', (197, 208))
483876	29465554	Fluorescence in situ hybridization (FISH) analysis performed on this pus confirmed the presence of malignant features in the involved granulocytes proving their origin from the differentiation of leukemic APL cells, as all the analyzed nuclei showed 2 promyelocytic leukemia (PML)-retinoic acid receptor-a (RARA) fusions signals.	('retinoic acid receptor-a', 'Gene', (281, 305))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (252, 274))	('PML', 'Gene', (276, 279))	('promyelocytic leukemia', 'Gene', '5371', (252, 274))	('retinoic acid receptor-a', 'Gene', '5914', (281, 305))	('APL', 'Phenotype', 'HP:0004836', (205, 208))	('RARA', 'Gene', '5914', (307, 311))	('leukemic', 'Disease', (196, 204))	('RARA', 'Gene', (307, 311))	('promyelocytic leukemia', 'Gene', (252, 274))	('PML', 'Gene', '5371', (276, 279))	('leukemia', 'Phenotype', 'HP:0001909', (266, 274))	('PML', 'Phenotype', 'HP:0004836', (276, 279))	('fusions', 'Var', (313, 320))	('leukemic', 'Disease', 'MESH:D007938', (196, 204))
483881	29465554	APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which generates a fusion transcript joining the PML (promyelocytic leukemia) and RARA (retinoic acid receptor-alpha) genes.	('RARA', 'Gene', '5914', (172, 176))	('retinoic acid receptor-alpha', 'Gene', '5914', (178, 206))	('generates', 'Reg', (97, 106))	('PML', 'Phenotype', 'HP:0004836', (139, 142))	('trans', 'Chemical', 'MESH:C057348', (116, 121))	('retinoic acid receptor-alpha', 'Gene', (178, 206))	('PML', 'Gene', (139, 142))	('promyelocytic leukemia', 'Gene', (144, 166))	('RARA', 'Gene', (172, 176))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (144, 166))	('promyelocytic leukemia', 'Gene', '5371', (144, 166))	('APL', 'Phenotype', 'HP:0004836', (0, 3))	('trans', 'Chemical', 'MESH:C057348', (46, 51))	('PML', 'Gene', '5371', (139, 142))	('fusion', 'Var', (109, 115))
483882	29465554	The chimeric protein causes a blockade of differentiation and increases self-renewal of leukemic progenitor cells.	('differentiation', 'CPA', (42, 57))	('leukemic', 'Disease', (88, 96))	('increases', 'PosReg', (62, 71))	('leukemic', 'Disease', 'MESH:D007938', (88, 96))	('chimeric', 'Var', (4, 12))
483889	29465554	Initial peripheral blood count showed hyperleukocytosis (20 G/L) including 90% of leukemic blasts cells containing Auer rods, anemia, neutropenia, and thrombocytopenia, associated with initial signs of coagulopathy.	('neutropenia', 'Disease', 'MESH:D009503', (134, 145))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (151, 167))	('coagulopathy', 'Disease', (202, 214))	('neutropenia', 'Phenotype', 'HP:0001875', (134, 145))	('leukemic', 'Disease', (82, 90))	('hyperleukocytosis', 'Disease', (38, 55))	('thrombocytopenia', 'Disease', (151, 167))	('coagulopathy', 'Disease', 'MESH:D001778', (202, 214))	('20 G/L', 'SUBSTITUTION', 'None', (57, 63))	('anemia', 'Disease', (126, 132))	('anemia', 'Disease', 'MESH:D000740', (126, 132))	('coagulopathy', 'Phenotype', 'HP:0003256', (202, 214))	('neutropenia', 'Disease', (134, 145))	('20 G/L', 'Var', (57, 63))	('leukemic', 'Disease', 'MESH:D007938', (82, 90))	('thrombocytopenia', 'Disease', 'MESH:D013921', (151, 167))	('hyperleukocytosis', 'Disease', 'None', (38, 55))	('anemia', 'Phenotype', 'HP:0001903', (126, 132))
483941	28210452	In approximately 5% of all cases, the EWS gene is implicated in other types of translocations, namely t(11,22)(q12;q12) and t(7;22)(p22;q12), which give rise to the fusion genes EWS-ERG and EWS-ETV1, respectively.	('t(7;22)(p22;q12', 'Var', (124, 139))	('ERG', 'Gene', (182, 185))	('EWS', 'Gene', (38, 41))	('ETV1', 'Gene', '2115', (194, 198))	('EWS', 'Gene', '2130', (38, 41))	('t(7;22)(p22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (124, 140))	('implicated', 'Reg', (50, 60))	('EWS', 'Gene', (190, 193))	('EWS', 'Gene', '2130', (190, 193))	('EWS', 'Gene', '2130', (178, 181))	('EWS', 'Gene', (178, 181))	('ETV1', 'Gene', (194, 198))	('ERG', 'Gene', '2078', (182, 185))
483942	28210452	One-fourth of the tumors present p16 and p53 alterations, which is associated to more aggressive behavior of the disease and a poorer response to chemotherapy.	('alterations', 'Var', (45, 56))	('p53', 'Gene', '7157', (41, 44))	('p16', 'Gene', (33, 36))	('tumors', 'Disease', (18, 24))	('aggressive behavior of the disease', 'Disease', 'MESH:D001523', (86, 120))	('p16', 'Gene', '1029', (33, 36))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('aggressive behavior of the disease', 'Disease', (86, 120))	('aggressive behavior', 'Phenotype', 'HP:0000718', (86, 105))	('p53', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
484006	28210452	Immunohistochemical techniques detect cluster of differentiation 99 (CD99) positivity in up to 98% of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CD99', 'Gene', (69, 73))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('positivity', 'Var', (75, 85))
484034	27579298	G207 is a genetically engineered HSV-1 strain F that lacks the gamma134.5 gene and contains an inactivation insertion of lacZ within the UL39 gene that stops lytic activity in nondividing cells (summary of viruses discussed in the text that have been or are being advanced to clinical trial is given in Table 1).	('HSV-1', 'Species', '10298', (33, 38))	('inactivation insertion', 'Var', (95, 117))	('lacZ', 'Gene', (121, 125))	('UL39', 'Gene', (137, 141))	('UL39', 'Gene', '2703361', (137, 141))	('stops', 'NegReg', (152, 157))	('lacks', 'NegReg', (53, 58))	('lytic', 'MPA', (158, 163))
484037	27579298	ICP 34.5 counteracts this pathway by dephosphorylating eIF-2alpha, which prevents protein synthesis shutoff.	('eIF-2alpha', 'Gene', '83939', (55, 65))	('eIF-2alpha', 'Gene', (55, 65))	('protein synthesis shutoff', 'MPA', (82, 107))	('dephosphorylating', 'Var', (37, 54))
484038	27579298	Bharatan et al studied the sensitivity of multiple sarcoma cell lines to both G207 and NV1020.	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('G207', 'Var', (78, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcoma', 'Disease', (51, 58))
484042	27579298	The oncolytic potency of NV1066 was much higher than adenovirus in neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (67, 80))	('adenovirus', 'Species', '28285', (53, 63))	('neuroblastoma', 'Disease', (67, 80))	('NV1066', 'Var', (25, 31))	('neuroblastoma', 'Phenotype', 'HP:0003006', (67, 80))	('higher', 'PosReg', (41, 47))	('oncolytic potency', 'MPA', (4, 21))
484043	27579298	Wang et al recently demonstrated that the viral construct HSV1716 was able to infect and had an antitumor response in pediatric neuroblastoma cell lines and that this response could not be predicted by the presence or absence of oncolytic engineered HSV (oHSV) entry receptors.	('pediatric neuroblastoma cell lines', 'Disease', (118, 152))	('oncolytic engineered HSV', 'Disease', 'MESH:C536395', (229, 253))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('pediatric neuroblastoma cell lines', 'Disease', 'MESH:D009447', (118, 152))	('oncolytic engineered HSV', 'Disease', (229, 253))	('tumor', 'Disease', (100, 105))	('neuroblastoma', 'Phenotype', 'HP:0003006', (128, 141))	('HSV1716', 'Var', (58, 65))	('oHSV', 'Chemical', '-', (255, 259))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
484049	27579298	Friedman et al examined the effects of M002 and G207 on medulloblastoma (MB), including group 3 tumors that are highly resistant to conventional therapies and MB cancer stem cells with the surface proteins CD15 and CD133.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('M002', 'Var', (39, 43))	('medulloblastoma', 'Disease', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Disease', (162, 168))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('G207', 'Var', (48, 52))	('MB', 'Phenotype', 'HP:0002885', (73, 75))	('MB', 'Phenotype', 'HP:0002885', (159, 161))	('CD15', 'Gene', '2526', (206, 210))	('CD133', 'Gene', (215, 220))	('CD15', 'Gene', (206, 210))	('CD133', 'Gene', '8842', (215, 220))	('medulloblastoma', 'Disease', 'MESH:D008527', (56, 71))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('medulloblastoma', 'Phenotype', 'HP:0002885', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
484050	27579298	All four human pediatric MB xenografts tested were highly sensitive to G207 and M002.	('M002', 'Var', (80, 84))	('G207', 'Var', (71, 75))	('MB', 'Phenotype', 'HP:0002885', (25, 27))	('human', 'Species', '9606', (9, 14))
484054	27579298	Gillory et al demonstrated that M002 inhibited neuroblastoma growth in vitro and in vivo.	('M002', 'Var', (32, 36))	('inhibited', 'NegReg', (37, 46))	('neuroblastoma', 'Disease', 'MESH:D009447', (47, 60))	('neuroblastoma', 'Disease', (47, 60))	('neuroblastoma', 'Phenotype', 'HP:0003006', (47, 60))
484055	27579298	Using two neuroblastoma cell lines, one with and another without MCYN amplification, they showed that M002 could successfully infect, replicate, and kill tumor cells.	('neuroblastoma', 'Phenotype', 'HP:0003006', (10, 23))	('infect', 'CPA', (126, 132))	('M002', 'Var', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('neuroblastoma', 'Disease', 'MESH:D009447', (10, 23))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('replicate', 'CPA', (134, 143))	('neuroblastoma', 'Disease', (10, 23))	('tumor', 'Disease', (154, 159))
484059	27579298	Furthermore, M002 was able to infect and diminish survival of both alveolar (SJCRH30) and embryonal (RD) RMS cell lines including the CD133+ cancer stem cells, and other investigators have shown encouraging results in vivo.	('CD133', 'Gene', (134, 139))	('infect', 'NegReg', (30, 36))	('M002', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('diminish', 'NegReg', (41, 49))	('RMS', 'Phenotype', 'HP:0002859', (105, 108))	('CD133', 'Gene', '8842', (134, 139))	('survival', 'CPA', (50, 58))	('cancer', 'Disease', (141, 147))
484067	27579298	In this study, patients will receive a 6-hour infusion of G207 through one to four catheters placed into the enhancing regions of the tumor.	('patients', 'Species', '9606', (15, 23))	('G207', 'Var', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
484127	27579298	Deletion of both copies of the thymidine kinase (TK) gene results in decreased pathogenicity for normal cells and preferential replication in tumor cells because thymidine triphosphate, which is required by a TK-deleted virus for DNA synthesis, is provided by replicating tumor cells but not normal cells.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('TK', 'Gene', '3707550', (49, 51))	('thymidine kinase', 'Gene', '3707550', (31, 47))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', (142, 147))	('preferential', 'PosReg', (114, 126))	('pathogenicity', 'MPA', (79, 92))	('replication', 'MPA', (127, 138))	('decreased', 'NegReg', (69, 78))	('thymidine triphosphate', 'Chemical', 'MESH:C024157', (162, 184))	('TK', 'Gene', '3707550', (209, 211))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('thymidine kinase', 'Gene', (31, 47))	('Deletion', 'Var', (0, 8))
484128	27579298	Similarly, deletion of vaccinia growth factor or hemagglutinin genes reduces VV virulence in normal cells and has been used in combination with TK deletions for additional protection of normal cells.	('reduces', 'NegReg', (69, 76))	('VV virulence', 'MPA', (77, 89))	('VV', 'Species', '10245', (77, 79))	('TK', 'Gene', '3707550', (144, 146))	('deletion', 'Var', (11, 19))	('vaccinia', 'Species', '10245', (23, 31))	('vaccinia', 'Gene', (23, 31))
484129	27579298	Another mechanism to protect normal cells is through deletions in the B18R gene, the product of which neutralizes secreted type-I interferons.	('B18R', 'Var', (70, 74))	('deletions', 'Var', (53, 62))	('B18R', 'SUBSTITUTION', 'None', (70, 74))
484131	27579298	Recombinant virus JX-795, which contains double deletions of B18R and TK and expresses beta-interferon, demonstrated tumor-specific replication and efficacy following systemic delivery in preclinical cancer models.	('TK', 'Gene', '3707550', (70, 72))	('double deletions', 'Var', (41, 57))	('B18R', 'SUBSTITUTION', 'None', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('B18R', 'Var', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancer', 'Disease', (200, 206))
484136	27579298	VV GLV-1h68, a mutant virus with deletions in TK and hemagglutinin genes, was engineered to encode the anti-VEGF protein GLAF-1.	('VEGF', 'Gene', (108, 112))	('VV', 'Species', '10245', (0, 2))	('GLV-1h68', 'Species', '502057', (3, 11))	('VEGF', 'Gene', '7422', (108, 112))	('TK', 'Gene', '3707550', (46, 48))	('deletions', 'Var', (33, 42))
484138	27579298	Similarly, vvDD, a Western Reserve VV with deletions in TK and VV growth factor, inhibited enhanced antitumor efficacy with an antiangiogenic effect in renal cell cancer models when armed with soluble VEGF receptor 1 protein.	('TK', 'Gene', '3707550', (56, 58))	('deletions', 'Var', (43, 52))	('antiangiogenic effect', 'CPA', (127, 148))	('VEGF', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('renal cell cancer', 'Disease', 'MESH:C538614', (152, 169))	('VV', 'Species', '10245', (35, 37))	('VV', 'Species', '10245', (63, 65))	('renal cell cancer', 'Disease', (152, 169))	('tumor', 'Disease', (104, 109))	('inhibited', 'NegReg', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('VEGF', 'Gene', '7422', (201, 205))	('renal cell cancer', 'Phenotype', 'HP:0005584', (152, 169))	('enhanced', 'PosReg', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
177337	25914746	Detection of EWS/FLI-1 fusion in non-Ewing soft tissue tumors Objectives: EWS/FLI-1 fusion mainly appears in Ewing's sarcoma or the primitive neuroectodermal tumors and represents a genomic marker for these tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (142, 164))	('non-Ewing soft tissue tumors', 'Disease', (33, 61))	('appears', 'Reg', (98, 105))	('neuroectodermal tumors', 'Disease', (142, 164))	('EWS', 'Gene', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('FLI-1', 'Gene', '2313', (78, 83))	('EWS', 'Gene', '2130', (13, 16))	('tumors', 'Disease', (207, 213))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (43, 61))	('Ewing soft tissue tumors', 'Phenotype', 'HP:0012254', (37, 61))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('tumors', 'Disease', (158, 164))	('FLI-1', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('sarcoma', 'Disease', (117, 124))	('tumors', 'Disease', (55, 61))	('FLI-1', 'Gene', (78, 83))	('non-Ewing soft tissue tumors', 'Disease', 'MESH:C563168', (33, 61))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('EWS', 'Gene', '2130', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('EWS', 'Gene', (13, 16))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (109, 124))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (132, 164))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (142, 164))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('fusion', 'Var', (84, 90))	('FLI-1', 'Gene', '2313', (17, 22))
177338	25914746	The paper investigates the presence of EWS/FLI-1 fusion in clinically diagnosed sarcoma belonging to different non-Ewing connective tissue tumors in order to search for a possible new biomarker valuable for investigators.	('connective tissue tumors', 'Phenotype', 'HP:0100242', (121, 145))	('Ewing connective tissue tumors', 'Phenotype', 'HP:0012254', (115, 145))	('sarcoma belonging', 'Disease', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	('FLI-1', 'Gene', (43, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('tumors', 'Disease', (139, 145))	('fusion', 'Var', (49, 55))	('FLI-1', 'Gene', '2313', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('sarcoma belonging', 'Disease', 'MESH:D012509', (80, 97))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
177342	25914746	The translocation results in the fusion of the N-terminal region of the EWS (Ewing's sarcoma) gene with the DNA binding domain of the proto-oncogene FLI-1 (Friend leukemia integration site 1) .	('Friend leukemia integration site 1', 'Gene', '2313', (156, 190))	('FLI-1', 'Gene', '2313', (149, 154))	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', (72, 75))	('FLI-1', 'Gene', (149, 154))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('Friend leukemia integration site 1', 'Gene', (156, 190))	('leukemia', 'Phenotype', 'HP:0001909', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcoma', 'Disease', (85, 92))	('fusion', 'Var', (33, 39))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (77, 92))	('results in', 'Reg', (18, 28))
484166	25914746	This fusion protein has the potential to promote tumorigenesis by activating the transcription of an aberrant FLI-1 factor .	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('FLI-1', 'Gene', '2313', (110, 115))	('FLI-1', 'Gene', (110, 115))	('tumor', 'Disease', (49, 54))	('activating', 'PosReg', (66, 76))	('promote', 'PosReg', (41, 48))	('aberrant', 'Var', (101, 109))	('transcription', 'MPA', (81, 94))
484168	25914746	In this study, we tried to detect EWS/FLI-1 fusion in non-Ewing soft tissue tumors, in order to search for a possible new biomarker valuable for investigators.	('EWS', 'Gene', (34, 37))	('FLI-1', 'Gene', (38, 43))	('fusion', 'Var', (44, 50))	('non-Ewing soft tissue tumors', 'Disease', (54, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('non-Ewing soft tissue tumors', 'Disease', 'MESH:C563168', (54, 82))	('Ewing soft tissue tumors', 'Phenotype', 'HP:0012254', (58, 82))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (64, 82))	('FLI-1', 'Gene', '2313', (38, 43))	('EWS', 'Gene', '2130', (34, 37))
484172	25914746	Detection of EWS/FLI-1 fusion EWS/FLI-1 fusion was screened by quantitative real-time PCR (qPCR) with Rotor Gene 6000 thermocycler (Corbett Life Science, Qiagen Sciences, Maryland, USA) using the TaqMan RNA-to-Ct 1 Step Kit (Applied Biosystems - Life Technologies, Carlsbad, CA, USA), with Hs03024497_ft primer specific for fusion.	('FLI-1', 'Gene', (17, 22))	('Ct 1', 'Gene', '1489', (210, 214))	('EWS', 'Gene', '2130', (30, 33))	('EWS', 'Gene', (30, 33))	('Hs03024497_ft', 'Var', (290, 303))	('EWS', 'Gene', '2130', (13, 16))	('EWS', 'Gene', (13, 16))	('Ct 1', 'Gene', (210, 214))	('FLI-1', 'Gene', '2313', (34, 39))	('FLI-1', 'Gene', (34, 39))	('FLI-1', 'Gene', '2313', (17, 22))
484174	25914746	Data analysis was performed with Rotor-Gene 6000 software (Corbett Life Science), determining the relative expression of EWS1/FLI-1 fusion in the test sample (with possibly fusion) compared to the similar expression in normal tissue (DeltaDeltaCt method).	('EWS', 'Gene', '2130', (121, 124))	('EWS', 'Gene', (121, 124))	('FLI-1', 'Gene', '2313', (126, 131))	('FLI-1', 'Gene', (126, 131))	('fusion', 'Var', (132, 138))
484190	25914746	It is possible that the number of tumor cells was not sufficient to generate a massive presence of mutant RNA sequences.	('tumor', 'Disease', (34, 39))	('RNA sequences', 'Protein', (106, 119))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mutant', 'Var', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
484191	25914746	Furthermore, if the tumors were not ES, the degree of fusion could be reduced, these tumors being characterized by a significant presence of other types of translocations not investigated in this study: t(9,22), t(11,22), t(12,22), t(12,16), t(X,18) .	('t(12,22', 'Var', (222, 229))	('tumors', 'Disease', (20, 26))	('reduced', 'NegReg', (70, 77))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('fusion', 'MPA', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('t(11,22', 'Var', (212, 219))	('ES', 'Phenotype', 'HP:0012254', (36, 38))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
484204	33879215	NAB2-STAT6 gene fusion has recently emerged as a sensitive and specific molecular marker and its IHC surrogate marker signal transducer and activator of transcription 6 (STAT6) has also shown significant sensitivity and specificity.	('fusion', 'Var', (16, 22))	('STAT6', 'Gene', (170, 175))	('STAT6', 'Gene', (5, 10))	('NAB2', 'Gene', '4665', (0, 4))	('STAT6', 'Gene', '6778', (170, 175))	('STAT6', 'Gene', '6778', (5, 10))	('signal transducer and activator of transcription 6', 'Gene', '6778', (118, 168))	('NAB2', 'Gene', (0, 4))
484212	33879215	The molecular hallmark of these tumors is the recurrent fusion of NAB2 and STAT6 genes located at chromosomal region 12q13.	('NAB2', 'Gene', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('fusion', 'Var', (56, 62))	('NAB2', 'Gene', '4665', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('STAT6', 'Gene', (75, 80))	('tumors', 'Disease', (32, 38))	('STAT6', 'Gene', '6778', (75, 80))
484254	33879215	is based on assessment of patient's age, mitoses/mm2, tumor size and percentage of tumor necrosis.	('patient', 'Species', '9606', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mitoses/mm2', 'Var', (41, 52))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor necrosis', 'Disease', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor necrosis', 'Disease', 'MESH:D009336', (83, 97))
484269	33879215	Gene expression profiling studies have also identified overexpression of GRIA2 gene and aberrant expression of GRIA2 protein in SFT.	('overexpression', 'PosReg', (55, 69))	('SFT', 'Disease', (128, 131))	('GRIA2', 'Gene', (111, 116))	('GRIA2', 'Gene', (73, 78))	('protein', 'Protein', (117, 124))	('GRIA2', 'Gene', '2891', (111, 116))	('GRIA2', 'Gene', '2891', (73, 78))	('aberrant', 'Var', (88, 96))	('expression', 'MPA', (97, 107))
484282	33879215	Occasional cases may also show positivity for STAT6.	('positivity', 'Var', (31, 41))	('STAT6', 'Gene', (46, 51))	('STAT6', 'Gene', '6778', (46, 51))
484337	33879215	Meningiomas usually express positivity for EMA and progesterone receptor (PR).	('progesterone receptor', 'Gene', (51, 72))	('progesterone receptor', 'Gene', '5241', (51, 72))	('EMA', 'Gene', '4582', (43, 46))	('positivity', 'Var', (28, 38))	('Meningiomas', 'Phenotype', 'HP:0002858', (0, 11))	('PR', 'Gene', '5241', (74, 76))	('EMA', 'Gene', (43, 46))	('Meningiomas', 'Disease', 'MESH:D008577', (0, 11))	('Meningiomas', 'Disease', (0, 11))
484356	33879215	Some of these tumors may express positivity for CD34 and some of the prostatic SFTs may also express PR.	('prostatic SFTs', 'Disease', 'MESH:D011472', (69, 83))	('PR', 'Gene', '5241', (101, 103))	('tumors', 'Disease', (14, 20))	('CD34', 'Gene', '947', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('prostatic SFTs', 'Disease', (69, 83))	('positivity', 'Var', (33, 43))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('express', 'Reg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('CD34', 'Gene', (48, 52))
484376	33879215	observed that the majority of tumors with NAB2ex6-STAT6ex16/17 gene fusion variants were located in extra-thoracic regions while half of the tumors with NAB2ex4-STAT6ex2 gene fusion variant involved pleuropulmonary region.	('tumors', 'Disease', (30, 36))	('NAB2ex6', 'Gene', (42, 49))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('NAB2ex4', 'Gene', '4665', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('STAT6', 'Gene', (161, 166))	('STAT6', 'Gene', (50, 55))	('NAB2ex4', 'Gene', (153, 160))	('NAB2ex6', 'Gene', '4665', (42, 49))	('variants', 'Var', (75, 83))	('STAT6', 'Gene', '6778', (161, 166))	('STAT6', 'Gene', '6778', (50, 55))
484377	33879215	did not find any direct association of gene fusion variants with malignancy.	('malignancy', 'Disease', (65, 75))	('variants', 'Var', (51, 59))	('malignancy', 'Disease', 'MESH:D009369', (65, 75))
484378	33879215	However, they observed that the association between gene fusion variants and tumor location could indirectly affect the biological behavior of SFT.	('biological behavior', 'CPA', (120, 139))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('affect', 'Reg', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('variants', 'Var', (64, 72))	('SFT', 'Disease', (143, 146))
484379	33879215	TERT promoter mutations were found to be associated with malignant SFTs in two studies.	('malignant SFTs', 'Disease', 'MESH:D009369', (57, 71))	('malignant SFTs', 'Disease', (57, 71))	('associated', 'Reg', (41, 51))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))
484387	33879215	In a recent study, TP53 mutations were identified in 41% malignant SFTs.	('malignant SFTs', 'Disease', 'MESH:D009369', (57, 71))	('malignant SFTs', 'Disease', (57, 71))	('identified', 'Reg', (39, 49))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
484388	33879215	Dedifferentiated SFTs also characteristically show TP53 mutations.	('mutations', 'Var', (56, 65))	('Dedifferentiated SFTs', 'Disease', (0, 21))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (51, 55))
484410	32398945	Due to its aberrant expression, Src has been proposed to be important in signal transduction in human sarcomas, including osteosarcoma.	('osteosarcoma', 'Disease', (122, 134))	('osteosarcoma', 'Phenotype', 'HP:0002669', (122, 134))	('expression', 'MPA', (20, 30))	('human', 'Species', '9606', (96, 101))	('aberrant', 'Var', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('Src', 'Gene', (32, 35))
484413	32398945	In mouse models of osteosarcoma, depletion of Src phosphorylation in SaOS-2 cells leads to decreased tumor growth.	('depletion', 'Var', (33, 42))	('mouse', 'Species', '10090', (3, 8))	('SaOS-2', 'CellLine', 'CVCL:0548', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('decreased tumor', 'Disease', (91, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('Src', 'Protein', (46, 49))	('osteosarcoma', 'Disease', (19, 31))	('decreased tumor', 'Disease', 'MESH:D002303', (91, 106))
484438	32440625	It has also been suggested that PTH may stimulate abnormal osteoblastic activity, and an association between elevated PTH and risk for osteosarcoma formation has been demonstrated in several in vitro and rat studies.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('stimulate', 'PosReg', (40, 49))	('rat', 'Species', '10116', (204, 207))	('elevated PTH', 'Phenotype', 'HP:0003165', (109, 121))	('osteosarcoma', 'Disease', (135, 147))	('abnormal osteoblastic activity', 'Disease', (50, 80))	('rat', 'Species', '10116', (174, 177))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('abnormal osteoblastic activity', 'Disease', 'OMIM:612348', (50, 80))	('osteosarcoma', 'Disease', 'MESH:D012516', (135, 147))	('PTH', 'Gene', (118, 121))	('PTH', 'Var', (32, 35))
484480	30265712	KSHV causes a range of cancers including Kaposi's sarcoma, pleural effusion lymphoma and multicentric Castleman's disease.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('lymphoma', 'Phenotype', 'HP:0002665', (76, 84))	('causes', 'Reg', (5, 11))	('pleural effusion', 'Phenotype', 'HP:0002202', (59, 75))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('pleural effusion lymphoma', 'Phenotype', 'HP:0011953', (59, 84))	('cancers', 'Disease', (23, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('pleural effusion lymphoma', 'Disease', (59, 84))	('pleural effusion lymphoma', 'Disease', 'MESH:D010996', (59, 84))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (41, 57))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (41, 57))	("multicentric Castleman's disease", 'Disease', (89, 121))	("multicentric Castleman's disease", 'Disease', 'MESH:C537372', (89, 121))	("Kaposi's sarcoma", 'Disease', (41, 57))
484503	30265712	PEL cells usually express CD45, CD30, CD38, and CD138, but lack the common B cell makers CD19 and CD20.	('CD20', 'Gene', (98, 102))	('CD38', 'Gene', (38, 42))	('CD138', 'Gene', (48, 53))	('CD30', 'Gene', (32, 36))	('CD45', 'Var', (26, 30))	('CD30', 'Gene', '943', (32, 36))	('CD19', 'Gene', (89, 93))	('CD38', 'Gene', '952', (38, 42))	('CD19', 'Gene', '930', (89, 93))	('CD138', 'Gene', '6382', (48, 53))	('CD20', 'Gene', '54474', (98, 102))
484530	30265712	It had been previously shown that 5x106 infected B cells cause visible tumors via subcutaneous injection in 2 out of 3 SCID mice.	('SCID', 'Disease', 'MESH:D053632', (119, 123))	('5x106 infected', 'Var', (34, 48))	('SCID', 'Disease', (119, 123))	('mice', 'Species', '10090', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
484545	30265712	The first staining panel included CD45 (PE-Cy7), CD19 (APC-eFluor780), CD20 (APC), CD138 (PE-Cy5.5) and CD22 (PE).	('CD138', 'Gene', '6382', (83, 88))	('CD20', 'Gene', (71, 75))	('APC', 'Disease', (77, 80))	('PE-Cy5', 'Chemical', '-', (90, 96))	('CD138', 'Gene', (83, 88))	('CD19', 'Gene', '930', (49, 53))	('APC', 'Disease', 'MESH:D011125', (55, 58))	('CD22', 'Gene', (104, 108))	('CD45', 'Var', (34, 38))	('CD19', 'Gene', (49, 53))	('CD22', 'Gene', '933', (104, 108))	('APC', 'Disease', (55, 58))	('CD20', 'Gene', '54474', (71, 75))	('APC', 'Disease', 'MESH:D011125', (77, 80))	('PE-Cy7', 'Chemical', '-', (40, 46))
484546	30265712	The second staining panel included CD45 (FITC), CD19 (PerCP), CD38 (PE-Cy7) and CD30 (APC).	('PE-Cy7', 'Chemical', '-', (68, 74))	('CD30', 'Gene', '943', (80, 84))	('CD38', 'Gene', (62, 66))	('CD30', 'Gene', (80, 84))	('PerCP', 'Chemical', '-', (54, 59))	('APC', 'Disease', 'MESH:D011125', (86, 89))	('APC', 'Disease', (86, 89))	('CD38', 'Gene', '952', (62, 66))	('CD19', 'Gene', (48, 52))	('FITC', 'Chemical', 'MESH:D016650', (41, 45))	('CD45', 'Var', (35, 39))	('CD19', 'Gene', '930', (48, 52))
484553	30265712	BJAB cells harboring either wild-type (WT) KSHV or the DeltavIL-6- mutant (DeltavIL-6- mutant) were injected intraperitoneally into Rag2-/-gammac-/- mice, and after five weeks tumors were visible.	('KSHV', 'Species', '37296', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('DeltavIL-6', 'Chemical', '-', (75, 85))	('BJAB', 'CellLine', 'CVCL:5711', (0, 4))	('Rag2', 'Gene', '19374', (132, 136))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('mice', 'Species', '10090', (149, 153))	('Rag2', 'Gene', (132, 136))	('DeltavIL-6-', 'Gene', (55, 66))	('mutant', 'Var', (67, 73))	('DeltavIL-6', 'Chemical', '-', (55, 65))
484559	30265712	Following preliminary analysis of tumors, single cell suspensions were made and tumor cells were analyzed by flow cytometry to determine if the presence of vIL-6 influenced gene expression of common B cell markers on tumor cells (CD45, CD19, CD20, CD22, CD30, and CD138).	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('CD138', 'Gene', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CD19', 'Gene', '930', (236, 240))	('CD22', 'Gene', (248, 252))	('presence', 'Var', (144, 152))	('gene expression', 'MPA', (173, 188))	('CD20', 'Gene', (242, 246))	('tumor', 'Disease', (217, 222))	('vIL-6', 'Gene', '4961449', (156, 161))	('tumor', 'Disease', (34, 39))	('CD22', 'Gene', '933', (248, 252))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('CD20', 'Gene', '54474', (242, 246))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('CD30', 'Gene', (254, 258))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('CD45', 'Var', (230, 234))	('tumor', 'Disease', (80, 85))	('vIL-6', 'Gene', (156, 161))	('CD138', 'Gene', '6382', (264, 269))	('CD30', 'Gene', '943', (254, 258))	('influenced', 'Reg', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (34, 40))	('CD19', 'Gene', (236, 240))
484562	30265712	Fig 2A shows the frequency of detection of the various B cell markers in tumor cells infected with either WT KSHV or DeltavIL-6 from representative animals, and a summary of the mean results in shown in Fig 2B.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('KSHV', 'Species', '37296', (109, 113))	('DeltavIL-6', 'Chemical', '-', (117, 127))	('DeltavIL-6', 'Var', (117, 127))
484580	30265712	In WT-infected cells, significant downregulation of the following markers occurred during tumor development (Fig 4A): CD45+ (92.5% to 80.1% in culture vs in tumors, respectively; p<0.0001), CD45+GFP+ (74.31% to 21.98%; p<0.0001), CD20+ (91.81% to 64.4%; p = 0.0009), CD22+ (44.61% to 8.05%; p<0.0001), and CD138+ (17.33% to 6.86%; p = 0.0001).	('tumor', 'Disease', (157, 162))	('CD22', 'Gene', (267, 271))	('CD22', 'Gene', '933', (267, 271))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('CD138', 'Gene', '6382', (306, 311))	('CD45+GFP+', 'Var', (190, 199))	('CD20', 'Gene', '54474', (230, 234))	('CD20', 'Gene', (230, 234))	('tumors', 'Disease', (157, 163))	('downregulation', 'NegReg', (34, 48))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CD138', 'Gene', (306, 311))	('CD45+', 'Var', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
484583	30265712	For example, CD45+, GFP+, CD20+, and CD22+ cells decreased in both total numbers (Fig 4B) and also in expression levels (Fig 4C).	('CD45+', 'Var', (13, 18))	('CD20', 'Gene', '54474', (26, 30))	('CD20', 'Gene', (26, 30))	('CD22', 'Gene', (37, 41))	('CD22', 'Gene', '933', (37, 41))	('decreased', 'NegReg', (49, 58))	('expression levels', 'MPA', (102, 119))
484590	30265712	The following markers were downregulated during tumor development: CD45+ (92.03% to 71.38% in culture vs in tumors, respectively; p<0.0001), CD45+GFP+ (82.04% to 25.12%; p<0.0001), CD19+ (99.3% to 98.9%; p = 0.012), CD20+ (91.0% to 63.1%; p<0.0001), CD22+ (48.24% to 9.21%; p<0.0001), and CD138+ (25.52% to 12.0%; p = 0.011).	('CD22', 'Gene', (250, 254))	('tumor', 'Disease', (108, 113))	('downregulated', 'NegReg', (27, 40))	('CD138', 'Gene', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CD22', 'Gene', '933', (250, 254))	('CD20', 'Gene', (216, 220))	('to 9', 'Species', '1214577', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('to 9', 'Species', '1214577', (264, 268))	('CD20', 'Gene', '54474', (216, 220))	('CD45+GFP+', 'Var', (141, 150))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CD19', 'Gene', (181, 185))	('tumors', 'Disease', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CD138', 'Gene', '6382', (289, 294))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('CD45+', 'Var', (67, 72))	('CD19', 'Gene', '930', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
484592	30265712	The CD45-GFP+ (8.0% to 14.06%; p = 0.024) and CD30+ (2.25% to 37.53%; p = 0.003) populations significantly increased.	('CD30', 'Gene', (46, 50))	('CD45-GFP+', 'Var', (4, 13))	('CD30', 'Gene', '943', (46, 50))	('increased', 'PosReg', (107, 116))
484594	30265712	Interestingly, the CD45-GFP+ population was significantly increased in terms of the percentage of cells during tumor formation (p = 0.024), while the MFI actually dropped during tumor formation (p = 0.0033).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', (178, 183))	('increased', 'PosReg', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('MFI', 'MPA', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('dropped', 'NegReg', (163, 170))	('CD45-GFP+', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
484602	30265712	In order to better understand the role played by vIL-6 in tumor formation, a mutant strain with the vIL-6 gene deleted was used and compared to WT KSHV.	('KSHV', 'Species', '37296', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('vIL-6', 'Gene', (49, 54))	('vIL-6', 'Gene', (100, 105))	('deleted', 'Var', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('vIL-6', 'Gene', '4961449', (49, 54))	('vIL-6', 'Gene', '4961449', (100, 105))
484606	30265712	BJAB cells mostly expressed CD45, CD19, and CD20 in culture, while only ~50% expressed CD22 and ~20% expressed CD138, regardless of the presence of the vIL-6 gene.	('CD138', 'Gene', '6382', (111, 116))	('BJAB', 'CellLine', 'CVCL:5711', (0, 4))	('vIL-6', 'Gene', (152, 157))	('CD22', 'Gene', (87, 91))	('CD19', 'Gene', (34, 38))	('CD138', 'Gene', (111, 116))	('CD22', 'Gene', '933', (87, 91))	('vIL-6', 'Gene', '4961449', (152, 157))	('CD19', 'Gene', '930', (34, 38))	('CD45', 'Var', (28, 32))	('CD20', 'Gene', '54474', (44, 48))	('CD20', 'Gene', (44, 48))
484616	30265712	However, a significant difference in the total number of tumors was found with fewer tumors present with the DeltavIL-6 virus.	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('DeltavIL-6', 'Chemical', '-', (109, 119))	('DeltavIL-6', 'Var', (109, 119))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', (85, 91))	('fewer', 'NegReg', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
484625	30265712	Analysis of the MFI of CD30 expression also revealed that the expression levels in just the positive cells were also higher in the DeltavIL-6 population.	('expression levels', 'MPA', (62, 79))	('CD30', 'Gene', '943', (23, 27))	('CD30', 'Gene', (23, 27))	('higher', 'PosReg', (117, 123))	('DeltavIL-6', 'Var', (131, 141))	('DeltavIL-6', 'Chemical', '-', (131, 141))
484638	30265712	5 different markers were found to significantly decrease during the process of tumor development, and these changes were consistent for WT and DeltavIL-6 cells: CD45, CD45+GFP+, CD20, CD22, and CD138.	('CD138', 'Gene', '6382', (194, 199))	('tumor', 'Disease', (79, 84))	('CD20', 'Gene', '54474', (178, 182))	('CD20', 'Gene', (178, 182))	('CD138', 'Gene', (194, 199))	('CD45', 'Var', (161, 165))	('DeltavIL-6', 'Chemical', '-', (143, 153))	('CD45+GFP+', 'Var', (167, 176))	('decrease', 'NegReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('CD22', 'Gene', '933', (184, 188))	('CD22', 'Gene', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
484640	30265712	However, CD30 expression was found to be significantly increased in both WT and DeltavIL-6 cells, although DeltavIL-6 cells showed a greater increase.	('DeltavIL-6', 'Var', (80, 90))	('CD30', 'Gene', '943', (9, 13))	('increased', 'PosReg', (55, 64))	('CD30', 'Gene', (9, 13))	('expression', 'MPA', (14, 24))	('DeltavIL-6', 'Chemical', '-', (107, 117))	('DeltavIL-6', 'Chemical', '-', (80, 90))
484642	30265712	However, 2 differences in gene expression were only noted in a single cell type when comparing WT to DeltavIL-6: CD19 expression was unchanged in WT cells but was downregulated in DeltavIL-6 cells, and the CD45-GFP+ population was unchanged in WT cells but was increased in DeltavIL-6 cells.	('DeltavIL-6', 'Chemical', '-', (274, 284))	('DeltavIL-6', 'Chemical', '-', (101, 111))	('CD19', 'Gene', (113, 117))	('CD19', 'Gene', '930', (113, 117))	('downregulated', 'NegReg', (163, 176))	('DeltavIL-6', 'Chemical', '-', (180, 190))	('expression', 'MPA', (118, 128))	('DeltavIL-6', 'Var', (180, 190))
484650	30265712	It is also possible that epigenetic modifications of the GFP gene took place during the process of tumor formation, resulting in a silencing of the GFP gene.	('GFP', 'Gene', (57, 60))	('tumor', 'Disease', (99, 104))	('GFP gene', 'Gene', (148, 156))	('epigenetic modifications', 'Var', (25, 49))	('silencing', 'MPA', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
484671	30014744	Increasing evidence shows that the ectopic expression of the TWEAK/Fn14 axis is associated with poor prognosis and promotes cell survival and invasion in prostate cancer, neuroblastoma, and non-small-cell lung cancer (NSCLC).	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('prostate cancer', 'Disease', (154, 169))	('non-small-cell lung cancer', 'Disease', (190, 216))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (190, 216))	('promotes', 'PosReg', (115, 123))	('Fn14', 'Gene', (67, 71))	('TWEAK', 'Gene', '8742', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (218, 223))	('ectopic expression', 'Var', (35, 53))	('NSCLC', 'Disease', (218, 223))	('neuroblastoma', 'Disease', (171, 184))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (194, 216))	('TWEAK', 'Gene', (61, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('invasion', 'CPA', (142, 150))	('neuroblastoma', 'Phenotype', 'HP:0003006', (171, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (218, 223))	('cell survival', 'CPA', (124, 137))	('neuroblastoma', 'Disease', 'MESH:D009447', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (190, 216))	('Fn14', 'Gene', '51330', (67, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (154, 169))	('prostate cancer', 'Phenotype', 'HP:0012125', (154, 169))
484678	30014744	China); the primary antibodies of TWEAK (rabbit polyclonal antibody, ab37170), Fn14 (also called TWEAKR, mouse monoclonal antibody, ab21127), p-PI3K p85 (rabbit polyclonal antibody, ab182651), anti-PI3K (mouse monoclonal antibody, BYK-0128R), AKT (rabbit polyclonal antibody, ab126811), p-AKT (rabbit polyclonal antibody, ab18206), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH; rabbit polyclonal antibody, ab70699) were from Abcam (Cambridge, MA, USA).	('AKT', 'Gene', '207', (289, 292))	('GAPDH', 'Gene', (378, 383))	('TWEAK', 'Gene', (34, 39))	('TWEAK', 'Gene', (97, 102))	('rabbit', 'Species', '9986', (154, 160))	('p-PI3K', 'Var', (142, 148))	('rabbit', 'Species', '9986', (385, 391))	('Fn14', 'Gene', '51330', (79, 83))	('mouse', 'Species', '10090', (204, 209))	('AKT', 'Gene', (243, 246))	('rabbit', 'Species', '9986', (41, 47))	('rabbit', 'Species', '9986', (248, 254))	('TWEAKR', 'Gene', '51330', (97, 103))	('p85', 'Gene', '5295', (149, 152))	('AKT', 'Gene', (289, 292))	('rabbit', 'Species', '9986', (294, 300))	('TWEAKR', 'Gene', (97, 103))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (336, 376))	('GAPDH', 'Gene', '2597', (378, 383))	('TWEAK', 'Gene', '8742', (34, 39))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (336, 376))	('AKT', 'Gene', '207', (243, 246))	('Fn14', 'Gene', (79, 83))	('p85', 'Gene', (149, 152))	('TWEAK', 'Gene', '8742', (97, 102))	('mouse', 'Species', '10090', (105, 110))
484684	30014744	The proteins were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred onto polyvinylidene difluoride (PVDF) membranes (Bio-Rad Laboratories, Hercules, CA, USA), which were probed with anti-TWEAK (1:1000), anti-Fn14 (1:1000), anti-p-PI3K p85 (1:1000), anti-PI3K (1:1000), anti-AKT (1:1000), anti-p-AKT (1:1000), and anti-GAPDH (1:1000), followed by horseradish peroxidase (HRP)-conjugated secondary antibody.	('GAPDH', 'Gene', (366, 371))	('p85', 'Gene', (283, 286))	('Rad', 'Gene', '6236', (169, 172))	('TWEAK', 'Gene', '8742', (235, 240))	('Rad', 'Gene', (169, 172))	('AKT', 'Gene', '207', (322, 325))	('1:1000', 'Var', (348, 354))	('AKT', 'Gene', '207', (343, 346))	('Fn14', 'Gene', '51330', (256, 260))	('TWEAK', 'Gene', (235, 240))	('p85', 'Gene', '5295', (283, 286))	('AKT', 'Gene', (322, 325))	('GAPDH', 'Gene', '2597', (366, 371))	('horseradish', 'Species', '3704', (394, 405))	('Fn14', 'Gene', (256, 260))	('AKT', 'Gene', (343, 346))	('1:1000', 'Var', (308, 314))
484692	30014744	After 24-h incubation, pmirGLO report vector carrying wild-type (WT) 3'-UTR or mutated 3'-UTR of miR-149 targets was co-transfected with miR-149 (10 muL, MOI = 50) or NC into the OS cells.	('miR-149', 'Gene', '406941', (97, 104))	('mutated', 'Var', (79, 86))	('miR-149', 'Gene', (137, 144))	('miR-149', 'Gene', '406941', (137, 144))	('OS', 'Phenotype', 'HP:0002669', (179, 181))	('miR-149', 'Gene', (97, 104))
484707	30014744	Cell growth assays showed that the knockdown of miR-149 accelerated cell proliferation and colony formation capability in MG-63 and HOS cell lines, respectively, indicated by MTT (Figure 3(b) and (c)) and colony formation assays (Figure 3(d) and (e)).	('knockdown', 'Var', (35, 44))	('MG-63', 'CellLine', 'CVCL:0426', (122, 127))	('cell proliferation', 'CPA', (68, 86))	('OS', 'Phenotype', 'HP:0002669', (133, 135))	('miR-149', 'Gene', (48, 55))	('colony formation assays', 'CPA', (205, 228))	('colony formation capability', 'CPA', (91, 118))	('MTT', 'Chemical', '-', (175, 178))	('HOS', 'CellLine', 'CVCL:0312', (132, 135))	('miR-149', 'Gene', '406941', (48, 55))	('accelerated', 'PosReg', (56, 67))
484715	30014744	Then, the knockdown of TNFRSF12A significantly repressed cell proliferation (Figure 5(g) and (h)) and the colony formation abilities in OS cells (Figure 5(i) and (j)).	('TNFRSF12A', 'Gene', '51330', (23, 32))	('OS', 'Phenotype', 'HP:0002669', (136, 138))	('repressed', 'NegReg', (47, 56))	('colony formation abilities in OS cells', 'CPA', (106, 144))	('TNFRSF12A', 'Gene', (23, 32))	('knockdown', 'Var', (10, 19))	('cell proliferation', 'CPA', (57, 75))
484719	30014744	Also, miR-149 gene rs2292832 polymorphism results in the risk and susceptibility of patients with cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs2292832', 'Mutation', 'rs2292832', (19, 28))	('patients', 'Species', '9606', (84, 92))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('rs2292832 polymorphism', 'Var', (19, 41))	('miR-149', 'Gene', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('miR-149', 'Gene', '406941', (6, 13))	('polymorphism', 'Var', (29, 41))	('cancers', 'Disease', (98, 105))
484720	30014744	However, some studies illustrate the reduced risk and susceptibility of miR-149 gene rs2292832 polymorphism for overall survival and recurrence in patients with digestive cancers.	('miR-149', 'Gene', (72, 79))	('rs2292832', 'Mutation', 'rs2292832', (85, 94))	('recurrence', 'CPA', (133, 143))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('patients', 'Species', '9606', (147, 155))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('rs2292832 polymorphism', 'Var', (85, 107))	('cancers', 'Disease', (171, 178))	('polymorphism', 'Var', (95, 107))	('miR-149', 'Gene', '406941', (72, 79))	('reduced', 'NegReg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
484726	30014744	To further clarify the functions of miR-149 in OS cells, we found that miR-149 suppressed cell proliferation and colony formation, but the knockdown of miR-149 reversed these effects, indicating the tumor suppressor role of miR-149 in OS cells.	('tumor', 'Disease', (199, 204))	('miR-149', 'Gene', (36, 43))	('miR-149', 'Gene', '406941', (152, 159))	('miR-149', 'Gene', '406941', (36, 43))	('colony formation', 'CPA', (113, 129))	('OS', 'Phenotype', 'HP:0002669', (235, 237))	('knockdown', 'Var', (139, 148))	('suppressed', 'NegReg', (79, 89))	('cell proliferation', 'CPA', (90, 108))	('miR-149', 'Gene', (224, 231))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('OS', 'Phenotype', 'HP:0002669', (47, 49))	('miR-149', 'Gene', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('miR-149', 'Gene', '406941', (224, 231))	('miR-149', 'Gene', (71, 78))	('miR-149', 'Gene', '406941', (71, 78))
484732	30014744	Intriguingly, we first confirmed that TNFRSF12A was a target of miR-149 and had a negative correlation with miR-149 expression in OS tissues; knockdown of TNFRSF12A inhibited cell growth and attenuated miR-149-mediated inhibition of cell proliferation in OS cells.	('TNFRSF12A', 'Gene', (155, 164))	('miR-149', 'Gene', (64, 71))	('miR-149', 'Gene', '406941', (108, 115))	('miR-149', 'Gene', '406941', (64, 71))	('miR-149', 'Gene', (202, 209))	('OS', 'Phenotype', 'HP:0002669', (130, 132))	('TNFRSF12A', 'Gene', '51330', (38, 47))	('inhibited', 'NegReg', (165, 174))	('miR-149', 'Gene', (108, 115))	('miR-149', 'Gene', '406941', (202, 209))	('attenuated', 'NegReg', (191, 201))	('OS', 'Phenotype', 'HP:0002669', (255, 257))	('cell growth', 'CPA', (175, 186))	('TNFRSF12A', 'Gene', '51330', (155, 164))	('TNFRSF12A', 'Gene', (38, 47))	('knockdown', 'Var', (142, 151))
484812	25301268	Anti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not.	('sarcoma CSCs', 'Disease', (45, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('sarcoma CSCs', 'Disease', 'MESH:D012509', (45, 57))	('Anti-proliferative', 'Var', (0, 18))
484829	25301268	Given the increasing clinical use of targeted therapies such as TKIs in clinical oncology including STS as well as the evidence suggesting that specific tyrosine kinases may promote the CSC phenotype, we sought to determine the effects of TKIs on whole tumor bulk and CSC populations in diverse models of STS.	('tyrosine kinase', 'Gene', (153, 168))	('TKIs', 'Var', (64, 68))	('oncology', 'Phenotype', 'HP:0002664', (81, 89))	('promote', 'PosReg', (174, 181))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('STS', 'Phenotype', 'HP:0030448', (305, 308))	('tyrosine kinase', 'Gene', '7294', (153, 168))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('CSC', 'Disease', (186, 189))	('tumor', 'Disease', (253, 258))	('STS', 'Phenotype', 'HP:0030448', (100, 103))
484830	25301268	We hypothesized that there would be differential effects of TKIs on CSC populations depending on their mechanism of action and that enrichment for sarcoma CSCs would be more prevalent with anti-proliferative TKIs rather than anti-angiogenic TKIs.	('sarcoma CSCs', 'Disease', 'MESH:D012509', (147, 159))	('anti-proliferative', 'Var', (189, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('sarcoma CSCs', 'Disease', (147, 159))
484855	25301268	Primary STS and benign tumor resections (SA-0689, CCS0015-012, CCS0015-010, SA-0624, and SA-0751) were obtained immediately after surgical excision through the UC Davis Comprehensive Cancer Center Biorepository.	('SA', 'Chemical', 'MESH:C012546', (89, 91))	('benign tumor', 'Disease', 'MESH:D009369', (16, 28))	('SA', 'Chemical', 'MESH:C012546', (41, 43))	('SA-0624', 'Var', (76, 83))	('SA', 'Chemical', 'MESH:C012546', (76, 78))	('SA-0689', 'Var', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CCS0015-010', 'Var', (63, 74))	('Cancer', 'Phenotype', 'HP:0002664', (183, 189))	('STS', 'Phenotype', 'HP:0030448', (8, 11))	('benign tumor', 'Disease', (16, 28))
484868	25301268	After sorting cells by FACS into ALDHbright and ALDHdim sub-populations, we observed ALDHbright cells were able to sustain long term survival in vitro (data not shown) and to form tumor xenografts in NSG mice (Additional file 2: Figure S2).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('ALDHbright', 'Var', (85, 95))	('tumor', 'Disease', (180, 185))	('FACS', 'Gene', '14081', (23, 27))	('FACS', 'Gene', (23, 27))	('mice', 'Species', '10090', (204, 208))
484888	25301268	Conversely, at 32 muM sorafenib, the percentage of ALDHbright cells declined to 0.5 +- 0.9% and 0 +- 0% after 2 and 3 days of sorafenib exposure, respectively (P < 0.001).	('ALDHbright cells', 'CPA', (51, 67))	('muM', 'Gene', '56925', (18, 21))	('declined', 'NegReg', (68, 76))	('muM', 'Gene', (18, 21))	('sorafenib', 'Var', (22, 31))	('sorafenib', 'Chemical', 'MESH:D000077157', (22, 31))	('sorafenib', 'Chemical', 'MESH:D000077157', (126, 135))
484919	25301268	Simultaneously, there was a corresponding enrichment in CCS0015-012 ALDHbright cells following exposure to both sorafenib and regorafenib.	('sorafenib', 'Chemical', 'MESH:D000077157', (112, 121))	('regorafenib', 'Chemical', 'MESH:C559147', (126, 137))	('CCS0015-012', 'Var', (56, 67))	('ALDHbright cells', 'CPA', (68, 84))
484937	25301268	In addition, the presence of CSCs, in general, and ALDH expression, in particular, has been shown to predict worse prognosis in numerous human cancers, such as breast, prostate, and kidney.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('numerous human cancers', 'Disease', (128, 150))	('kidney', 'Disease', (182, 188))	('numerous human cancers', 'Disease', 'MESH:D009369', (128, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('ALDH', 'Gene', (51, 55))	('breast', 'Disease', (160, 166))	('presence', 'Var', (17, 25))	('prostate', 'Disease', (168, 176))	('CSCs', 'Gene', (29, 33))
484941	25301268	Our study reinforces the concept that anti-proliferative therapies enrich for the CSC population in solid malignancies and that anti-proliferative TKIs may exert distinct anti-tumor strategies than anti-angiogenic ones.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('malignancies', 'Disease', (106, 118))	('anti-proliferative', 'Var', (128, 146))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
484957	21584898	A Novel WWTR1-CAMTA1 Gene Fusion is a Consistent Abnormality in Epithelioid Hemangioendothelioma of Different Anatomic Sites The classification of epithelioid vascular tumors remains challenging, as there is considerable morphologic overlap between tumor subtypes, across the spectrum from benign to malignant categories.	('CAMTA1', 'Gene', '23261', (14, 20))	('tumor', 'Disease', (249, 254))	('Abnormality in Epithelioid Hemangioendothelioma', 'Disease', (49, 96))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('Fusion', 'Var', (26, 32))	('WWTR1', 'Gene', '97064', (8, 13))	('vascular tumors', 'Phenotype', 'HP:0100742', (159, 174))	('CAMTA1', 'Gene', (14, 20))	('epithelioid vascular tumors', 'Phenotype', 'HP:0032060', (147, 174))	('tumor', 'Disease', (168, 173))	('WWTR1', 'Gene', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('Abnormality in Epithelioid Hemangioendothelioma', 'Disease', 'MESH:D018323', (49, 96))	('Epithelioid Hemangioendothelioma', 'Phenotype', 'HP:0032060', (64, 96))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('epithelioid vascular tumors', 'Disease', (147, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('epithelioid vascular tumors', 'Disease', 'MESH:D012509', (147, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
484960	21584898	A fluorescence in situ hybridization (FISH) positional cloning strategy, spanning the cytogenetically defined regions on chromosomes 1p36.3 and 3q25, confirmed rearrangements in two candidate genes from these loci in all EHE cases tested.	('men', 'Species', '9606', (169, 172))	('EH', 'Phenotype', 'HP:0032060', (221, 223))	('EHE', 'Disease', (221, 224))	('EHE', 'Phenotype', 'HP:0032060', (221, 224))	('rearrangements', 'Var', (160, 174))
484964	21584898	Our results demonstrate the presence of a WWTR1-CAMTA1 fusion in all EHE tested from bone, soft tissue and visceral location (liver, lung) in keeping with a unique and specific pathological entity.	('CAMTA1', 'Gene', '23261', (48, 54))	('EH', 'Phenotype', 'HP:0032060', (69, 71))	('CAMTA1', 'Gene', (48, 54))	('EHE', 'Phenotype', 'HP:0032060', (69, 72))	('fusion', 'Var', (55, 61))
484965	21584898	Thus, FISH or RT-PCR analysis for the presence of WWTR1-CAMTA1 fusion may serve as a useful molecular diagnostic tool in challenging diagnoses.	('fusion', 'Var', (63, 69))	('CAMTA1', 'Gene', (56, 62))	('CAMTA1', 'Gene', '23261', (56, 62))
484976	21584898	found an identical chromosomal translocation, t(1;3)(p36.3;q25) in two cases of EHE, suggesting that this may represent a recurrent abnormality in this subgroup of tumors.	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('t(1;3)(p36.3;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (46, 63))	('EH', 'Phenotype', 'HP:0032060', (80, 82))	('t(1;3)(p36.3;q25', 'Var', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('EHE', 'Phenotype', 'HP:0032060', (80, 83))
485000	21584898	Combined results confirmed the translocation t(1;3)(1p36.23;3q25.1) in all EHE cases, but in none of the EH, E-AS or epithelioid sarcoma-like EHE cases (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('E-AS', 'Phenotype', 'HP:0032060', (109, 113))	('EHE', 'Disease', (75, 78))	('EH', 'Phenotype', 'HP:0032060', (142, 144))	('E-AS or epithelioid sarcoma', 'Disease', 'MESH:D012509', (109, 136))	('EH', 'Phenotype', 'HP:0032060', (75, 77))	('EH', 'Phenotype', 'HP:0032060', (105, 107))	('EHE', 'Phenotype', 'HP:0032060', (142, 145))	('translocation t(1;3)(1p36.23', 'Var', (31, 59))	('E-AS or epithelioid sarcoma', 'Disease', (109, 136))	('EHE', 'Phenotype', 'HP:0032060', (75, 78))
485002	21584898	This suggested the breakpoint was in the region of chr.1:7626000-7768000 (hg19), between CAMTA1 exon 6 and exon 12 (ENST00000303635).	('CAMTA1', 'Gene', '23261', (89, 95))	('ENST00000303635', 'Var', (116, 131))	('CAMTA1', 'Gene', (89, 95))
485004	21584898	Two different WWTR1-CAMTA1 variant transcripts were amplified from three EHE cases.	('EH', 'Phenotype', 'HP:0032060', (73, 75))	('EHE', 'Disease', (73, 76))	('CAMTA1', 'Gene', (20, 26))	('CAMTA1', 'Gene', '23261', (20, 26))	('EHE', 'Phenotype', 'HP:0032060', (73, 76))	('variant', 'Var', (27, 34))
485014	21584898	FISH targeting to narrow-down the breakpoints from the previously mapped chromosomal regions identified rearrangements in CAMTA1 on 1p36.23 and WWTR1 on 3q25.1 in all 17 EHE tumors tested, but in none of the EH, E-AS or epithelioid sarcoma-like EHE tumors.	('EHE tumors', 'Disease', 'MESH:D009369', (245, 255))	('rearrangements', 'Var', (104, 118))	('CAMTA1', 'Gene', '23261', (122, 128))	('men', 'Species', '9606', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('EHE', 'Phenotype', 'HP:0032060', (170, 173))	('EH', 'Phenotype', 'HP:0032060', (208, 210))	('E-AS or epithelioid sarcoma-like EHE tumors', 'Disease', 'MESH:D012509', (212, 255))	('EH', 'Phenotype', 'HP:0032060', (170, 172))	('WWTR1', 'Gene', (144, 149))	('CAMTA1', 'Gene', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('EHE tumors', 'Disease', (170, 180))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('EHE', 'Phenotype', 'HP:0032060', (245, 248))	('E-AS or epithelioid sarcoma-like EHE tumors', 'Disease', (212, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('E-AS', 'Phenotype', 'HP:0032060', (212, 216))	('EH', 'Phenotype', 'HP:0032060', (245, 247))	('EHE tumors', 'Disease', 'MESH:D009369', (170, 180))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
485031	21584898	The potential role of CAMTA1 in tumor development is also supported by Barbashina et al., who showed that a deleted region on 1p36 involved CAMTA1 in a subset of gliomas.	('CAMTA1', 'Gene', (22, 28))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('gliomas', 'Disease', (162, 169))	('men', 'Species', '9606', (45, 48))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('CAMTA1', 'Gene', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('deleted', 'Var', (108, 115))	('CAMTA1', 'Gene', '23261', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('CAMTA1', 'Gene', '23261', (140, 146))	('involved', 'Reg', (131, 139))
485034	21584898	Within the Hippo pathway, WWTR1 is negatively regulated by LATS tumor suppressor kinase; phosphorylation by LATS inactivates WWTR1 by inducing 14-3-3 binding and translocation from the nucleus to the cytoplasm.	('LATS', 'Gene', '43651', (108, 112))	('WWTR1', 'Gene', (125, 130))	('tumor', 'Disease', (64, 69))	('LATS', 'Gene', (108, 112))	('LATS', 'Gene', (59, 63))	('inactivates', 'NegReg', (113, 124))	('translocation from the nucleus', 'MPA', (162, 192))	('phosphorylation', 'Var', (89, 104))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('inducing', 'PosReg', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('LATS', 'Gene', '43651', (59, 63))	('14-3-3', 'Protein', (143, 149))	('binding', 'Interaction', (150, 157))
485035	21584898	The Hippo pathway is conserved from fly to human and its deregulation in mammals often leads to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('leads to', 'Reg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('deregulation', 'Var', (57, 69))	('human', 'Species', '9606', (43, 48))
485038	21584898	Ectopic WWTR1 expression also induced cell proliferation, overcame contact inhibition, and led to tumorigenesis in nude mice.	('cell proliferation', 'CPA', (38, 56))	('contact inhibition', 'CPA', (67, 85))	('WWTR1', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('overcame', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('led to', 'Reg', (91, 97))	('Ectopic', 'Var', (0, 7))	('tumor', 'Disease', (98, 103))	('induced', 'PosReg', (30, 37))	('nude mice', 'Species', '10090', (115, 124))
485047	21584898	Particularly important is the lack of CAMTA1 and WWTR1 rearrangements in EH, an under-recognized benign tumor, that is often mis-diagnosed as EHE, resulting in overtreatment.	('WWTR1', 'Gene', (49, 54))	('benign tumor', 'Disease', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('EH', 'Phenotype', 'HP:0032060', (73, 75))	('benign tumor', 'Disease', 'MESH:D009369', (97, 109))	('men', 'Species', '9606', (169, 172))	('EH', 'Phenotype', 'HP:0032060', (142, 144))	('EHE', 'Disease', (142, 145))	('rearrangements', 'Var', (55, 69))	('CAMTA1', 'Gene', (38, 44))	('men', 'Species', '9606', (64, 67))	('EHE', 'Phenotype', 'HP:0032060', (142, 145))	('CAMTA1', 'Gene', '23261', (38, 44))	('overtreatment', 'PosReg', (160, 173))
485048	33946955	Transient Response of Olaparib on Pulmonary Artery Sarcoma Harboring Multiple Homologous Recombinant Repair Gene Alterations Primary pulmonary artery sarcoma (PPAS) is a rare malignancy arising from mesenchymal pulmonary artery cells and mimics pulmonary embolism.	('Alterations', 'Var', (113, 124))	('malignancy', 'Disease', (175, 185))	('Sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('Olaparib', 'Chemical', 'MESH:C531550', (22, 30))	('PPAS', 'Chemical', '-', (159, 163))	('Primary pulmonary artery sarcoma', 'Disease', 'MESH:D012509', (125, 157))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (245, 263))	('pulmonary embolism', 'Disease', 'MESH:D011655', (245, 263))	('malignancy', 'Disease', 'MESH:D009369', (175, 185))	('Pulmonary Artery Sarcoma', 'Disease', 'MESH:D012509', (34, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('Primary pulmonary artery sarcoma', 'Disease', (125, 157))	('pulmonary embolism', 'Disease', (245, 263))	('Pulmonary Artery Sarcoma', 'Disease', (34, 58))
485050	33946955	Here, we report a case of disseminated PPAS achieving clinical tumor response to olaparib based on comprehensive genetic profiling (CGP) showing genetic alterations involving DNA repair pathway.	('tumor', 'Disease', (63, 68))	('olaparib', 'Chemical', 'MESH:C531550', (81, 89))	('genetic alterations', 'Var', (145, 164))	('PPAS', 'Chemical', '-', (39, 43))	('DNA repair pathway', 'Pathway', (175, 193))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PPAS', 'Disease', (39, 43))
485057	33946955	Herein, we present our experience of treating a patient with PPAS harboring MDM2 amplification; CDKN2A homozygous deletion; and RAD50, PTCH1, PTEN, CHEK1, MRE11, BRCA2, RB1, and BLM hemizygous deletion, treated with next-generation sequencing (NGS)-guided olaparib (Lynparza ) and achieving a transient partial response.	('PTEN', 'Gene', '5728', (142, 146))	('BLM', 'Gene', '641', (178, 181))	('BRCA2', 'Gene', '675', (162, 167))	('PPAS', 'Chemical', '-', (61, 65))	('PTCH1', 'Gene', (135, 140))	('MDM2', 'Gene', (76, 80))	('olaparib', 'Chemical', 'MESH:C531550', (256, 264))	('MRE11', 'Gene', (155, 160))	('CHEK1', 'Gene', '1111', (148, 153))	('patient', 'Species', '9606', (48, 55))	('RAD50', 'Gene', (128, 133))	('CDKN2A', 'Gene', (96, 102))	('MRE11', 'Gene', '4361', (155, 160))	('RB1', 'Gene', (169, 172))	('amplification', 'Var', (81, 94))	('CHEK1', 'Gene', (148, 153))	('RAD50', 'Gene', '10111', (128, 133))	('PTEN', 'Gene', (142, 146))	('CDKN2A', 'Gene', '1029', (96, 102))	('BRCA2', 'Gene', (162, 167))	('PTCH1', 'Gene', '5727', (135, 140))	('RB1', 'Gene', '5925', (169, 172))	('BLM', 'Gene', (178, 181))
485064	33946955	The FFPE lung tumor was subject to next-generation sequencing (NGS) using the ACTOnco  + test (ACT Genomics, Taipei, Taiwan) to detect mutations in the coding region of 440 cancer-related genes and fusion of 31 genes.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('lung tumor', 'Disease', 'MESH:D008175', (9, 19))	('cancer', 'Disease', (173, 179))	('mutations', 'Var', (135, 144))	('lung tumor', 'Phenotype', 'HP:0100526', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('lung tumor', 'Disease', (9, 19))
485068	33946955	Although these DDR genes are all hemizygously deleted, multiple genetic lesions, alterations, and their haploinsufficient nature may lead to homologous recombination deficiency (HRD), as shown by LOH 55.5% of the genomic region interrogated.	('haploinsufficient', 'Disease', (104, 121))	('HRD', 'Disease', 'None', (178, 181))	('lead to', 'Reg', (133, 140))	('genetic lesions', 'Disease', (64, 79))	('homologous', 'MPA', (141, 151))	('HRD', 'Disease', (178, 181))	('alterations', 'Var', (81, 92))	('haploinsufficient', 'Disease', 'MESH:D058495', (104, 121))	('genetic lesions', 'Disease', 'MESH:D020022', (64, 79))	('DDR genes', 'Gene', (15, 24))
485083	33946955	In contrast, 11% of PPAS harbored clinically relevant genomic alterations that affected PDGFRA, RICTOR, CDK4, and KIT.	('RICTOR', 'Gene', '253260', (96, 102))	('PPAS', 'Disease', (20, 24))	('PPAS', 'Chemical', '-', (20, 24))	('KIT', 'Gene', (114, 117))	('PDGFRA', 'Gene', '5156', (88, 94))	('affected', 'Reg', (79, 87))	('PDGFRA', 'Gene', (88, 94))	('CDK4', 'Gene', (104, 108))	('alterations', 'Var', (62, 73))	('RICTOR', 'Gene', (96, 102))	('KIT', 'Gene', '3815', (114, 117))
485084	33946955	A total of 10 (48%) of PPAS harboring additional clinically relevant genomic alterations in EGFR, TSC2, ALK, and BRAF was considered actionable.	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', (113, 117))	('ALK', 'Gene', '238', (104, 107))	('PPAS', 'Chemical', '-', (23, 27))	('alterations', 'Var', (77, 88))	('ALK', 'Gene', (104, 107))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('TSC2', 'Gene', '7249', (98, 102))	('TSC2', 'Gene', (98, 102))
485086	33946955	The genomic amplification of the MDM2 gene in this tumor, as confirmed by IHC, might be one of the primary drivers.	('MDM2', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('genomic amplification', 'Var', (4, 25))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
485087	33946955	MDM2 amplification was observed in 18.6% of sarcoma cases based on the TCGA database (PanCancer Atlas).	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('amplification', 'Var', (5, 18))	('sarcoma', 'Disease', (44, 51))	('MDM2', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))
485088	33946955	Notably, MDM2 amplification is most common in well-differentiated liposarcoma/atypical lipomatous tumors, dedifferentiated liposarcoma, intimal sarcoma, and low-grade osteosarcoma.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Disease', (70, 77))	('liposarcoma', 'Disease', (123, 134))	('liposarcoma', 'Disease', (66, 77))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('osteosarcoma', 'Phenotype', 'HP:0002669', (167, 179))	('lipomatous tumors', 'Disease', (87, 104))	('sarcoma', 'Disease', (172, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('lipomatous tumors', 'Phenotype', 'HP:0012031', (87, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('common', 'Reg', (36, 42))	('liposarcoma', 'Phenotype', 'HP:0012034', (123, 134))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))	('MDM2', 'Gene', (9, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('liposarcoma', 'Disease', 'MESH:D008080', (123, 134))	('liposarcoma', 'Disease', 'MESH:D008080', (66, 77))	('osteosarcoma', 'Disease', (167, 179))	('osteosarcoma', 'Disease', 'MESH:D012516', (167, 179))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('lipomatous tumors', 'Disease', 'MESH:D008080', (87, 104))	('sarcoma', 'Disease', (127, 134))	('amplification', 'Var', (14, 27))
485092	33946955	In addition, the homozygous deletion of CDKN2A and hemizygous of RB1 were observed, and CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) may be an off-label option.	('RB1', 'Gene', (65, 68))	('CDK4/6', 'Gene', (88, 94))	('CDKN2A', 'Gene', (40, 46))	('RB1', 'Gene', '5925', (65, 68))	('CDKN2A', 'Gene', '1029', (40, 46))	('CDK4/6', 'Gene', '1019;1021', (88, 94))	('deletion', 'Var', (28, 36))
485094	33946955	Alternatively, the observed hemizygous deletions of several DDR genes (RAD50, BRCA2, BLM, CHEK1, MRE11, PTEN, ATM, and H2AX) might highlight a possible therapeutic route.	('MRE11', 'Gene', '4361', (97, 102))	('deletions', 'Var', (39, 48))	('DDR genes', 'Gene', (60, 69))	('BLM', 'Gene', '641', (85, 88))	('ATM', 'Gene', '472', (110, 113))	('MRE11', 'Gene', (97, 102))	('CHEK1', 'Gene', '1111', (90, 95))	('BRCA2', 'Gene', (78, 83))	('H2AX', 'Gene', '3014', (119, 123))	('BRCA2', 'Gene', '675', (78, 83))	('H2AX', 'Gene', (119, 123))	('BLM', 'Gene', (85, 88))	('CHEK1', 'Gene', (90, 95))	('ATM', 'Gene', (110, 113))	('PTEN', 'Gene', (104, 108))	('RAD50', 'Gene', (71, 76))	('RAD50', 'Gene', '10111', (71, 76))	('PTEN', 'Gene', '5728', (104, 108))
485099	33946955	Clinical trials have demonstrated the effective induction of synthetic lethality in tumors harboring BRCA1/2 pathogenic mutations and the loss or disruption of crucial HRR genes.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRCA1/2', 'Gene', (101, 108))	('synthetic lethality', 'CPA', (61, 80))	('HRR genes', 'Gene', (168, 177))	('BRCA1/2', 'Gene', '672;675', (101, 108))	('mutations', 'Var', (120, 129))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
485100	33946955	The copy number loss of BRCAness genes such as MRE11, CHEK1, RAD51, PTEN deficiency; knockdown of RAD50; and BLM have all conferred sensitivity to PARP inhibitors across different tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('MRE11', 'Gene', '4361', (47, 52))	('knockdown', 'Var', (85, 94))	('PARP', 'Gene', '142', (147, 151))	('RAD50', 'Gene', '10111', (98, 103))	('PTEN deficiency', 'Disease', 'MESH:D006223', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('PARP', 'Gene', (147, 151))	('conferred', 'Reg', (122, 131))	('CHEK1', 'Gene', '1111', (54, 59))	('BLM', 'Gene', (109, 112))	('RAD51', 'Gene', (61, 66))	('RAD51', 'Gene', '5888', (61, 66))	('PTEN deficiency', 'Disease', (68, 83))	('BRCAness', 'Disease', (24, 32))	('BLM', 'Gene', '641', (109, 112))	('CHEK1', 'Gene', (54, 59))	('BRCAness', 'Disease', 'None', (24, 32))	('tumor', 'Disease', (180, 185))	('sensitivity', 'MPA', (132, 143))	('loss', 'NegReg', (16, 20))	('copy number', 'Var', (4, 15))	('MRE11', 'Gene', (47, 52))	('RAD50', 'Gene', (98, 103))
485101	33946955	Furthermore, PARP inhibitors significantly improved survival outcomes in several studies, both as monotherapy (e.g., TOPARP-B and QUADRA) and combination therapy (e.g., PAOLA-1/ENGOT-ov25).	('PARP', 'Gene', (13, 17))	('PARP', 'Gene', (119, 123))	('PARP', 'Gene', '142', (13, 17))	('PARP', 'Gene', '142', (119, 123))	('improved', 'PosReg', (43, 51))	('inhibitors', 'Var', (18, 28))	('survival outcomes', 'CPA', (52, 69))
485103	33946955	Olaparib, an FDA-approved PARP inhibitor, has accumulated evidence establishing a relatively profound and sustained antitumor response across different tumor types, such as ovarian cancer, breast cancer, and pancreatic cancer, associated with germline BRCA1/2 mutations.	('ovarian cancer', 'Disease', (173, 187))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('ovarian cancer', 'Phenotype', 'HP:0100615', (173, 187))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (208, 225))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('tumor', 'Disease', (152, 157))	('breast cancer', 'Disease', (189, 202))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('BRCA1/2', 'Gene', (252, 259))	('associated', 'Reg', (227, 237))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('PARP', 'Gene', '142', (26, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (208, 225))	('mutations', 'Var', (260, 269))	('ovarian cancer', 'Disease', 'MESH:D010051', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('PARP', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('pancreatic cancer', 'Disease', (208, 225))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('BRCA1/2', 'Gene', '672;675', (252, 259))
485227	30626161	Presumptively, the ability to find metastases down to 1 mm or less in size is predicated on the production of osteoid by the lesions, forming a grain of sand able to be palpated between the surgeon's fingers at open exploration.	('lesions', 'Var', (125, 132))	('metastases', 'Disease', 'MESH:D009362', (35, 45))	('metastases', 'Disease', (35, 45))
485253	29721373	CAR+.CIK produced higher amounts of IL6 and IFN-gamma compared to control CIK.	('CAR+.CIK', 'Var', (0, 8))	('IL6', 'Gene', (36, 39))	('IFN-gamma', 'Gene', '3458', (44, 53))	('IL6', 'Gene', '3569', (36, 39))	('higher', 'PosReg', (18, 24))	('IFN-gamma', 'Gene', (44, 53))
485254	29721373	CAR+.CIK were highly active in mice bearing subcutaneous STS xenografts, with significant delay of tumor growth (p<0.0001) without toxicities.	('delay of tumor growth', 'Disease', 'MESH:D006130', (90, 111))	('CAR+.CIK', 'Var', (0, 8))	('toxicities', 'Disease', (131, 141))	('STS', 'Phenotype', 'HP:0030448', (57, 60))	('mice', 'Species', '10090', (31, 35))	('toxicities', 'Disease', 'MESH:D064420', (131, 141))	('delay of tumor growth', 'Disease', (90, 111))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
485297	29721373	The median ex vivo expansion of CAR+.CIK was 37 fold (range 11-645), such value is comparable to that observed with unmodified CIK (NTD.CIK) used as paired control (38 fold; range, 9-631, p = ns) (Supplemental table 1), ruling out any possible detrimental effect caused by lentiviral transduction or CD44v6 expression in CIK cells.	('CD44v6', 'Gene', '960', (300, 306))	('CD44v6', 'Gene', (300, 306))	('NTD.CIK', 'Gene', '80199', (132, 139))	('CAR+.CIK', 'Var', (32, 40))	('NTD.CIK', 'Gene', (132, 139))
485314	29721373	The rate of viable tumor cells continued to progressively decrease up to 72 hours after stopping the experiment and removal of CAR+.CIK (n = 2, supplemental Fig.	('CAR+.CIK', 'Var', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('decrease', 'NegReg', (58, 66))	('tumor', 'Disease', (19, 24))
485319	29721373	CAR+.CIK were moderately active against monocytes at (E/T 5:1), their killing activity sensibly decreased at lower E:T ratios (n = 3) (Fig.	('decreased', 'NegReg', (96, 105))	('E/T 5', 'SUBSTITUTION', 'None', (54, 59))	('killing activity', 'MPA', (70, 86))	('E/T 5', 'Var', (54, 59))
485343	29721373	We observed that blocking CD44v6 in tumor targets did not abrogate the killing activity of CAR-CIK, but it was instead reduced to values comparable with unmodified CIK.	('blocking', 'Var', (17, 25))	('killing activity', 'MPA', (71, 87))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('CD44v6', 'Gene', '960', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CD44v6', 'Gene', (26, 32))	('abrogate', 'NegReg', (58, 66))	('reduced', 'NegReg', (119, 126))	('tumor', 'Disease', (36, 41))
485389	29721373	In selected assays (n = 2) at the end of experiment, the recovery of sarcoma cells was evaluated analyzing their growth rate 72 hours after the removal of CAR+.CIK.	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('CAR+.CIK', 'Var', (155, 163))	('sarcoma', 'Disease', (69, 76))
485390	29721373	AntiCD44v6 CAR+.CIK and unmodified NTD.CIK were incubated with STS targets (E/T 1:1) for 72 h in CIK-culture medium described above.	('CD44v6', 'Gene', '960', (4, 10))	('E/T 1', 'SUBSTITUTION', 'None', (76, 81))	('CD44v6', 'Gene', (4, 10))	('E/T 1', 'Var', (76, 81))	('NTD.CIK', 'Gene', '80199', (35, 42))	('NTD.CIK', 'Gene', (35, 42))	('STS', 'Phenotype', 'HP:0030448', (63, 66))
485484	28449661	However, our analysis results showed that BCS was associated with better OS in primary breast AS and was at least non-inferior to mastectomy in secondary breast AS.	('BCS', 'Var', (42, 45))	('OS', 'Chemical', '-', (73, 75))	('better', 'PosReg', (66, 72))	('primary breast AS', 'Disease', (79, 96))	('AS', 'Phenotype', 'HP:0200058', (161, 163))	('AS', 'Phenotype', 'HP:0200058', (94, 96))
485510	26587836	Notably, inhibition of Hsp70 isoforms precluded KSHV RTC formation and RNA polymerase II (RNAPII) relocalisation to the viral genome leading to the abolishment of global KSHV transcription and subsequent viral protein synthesis and DNA replication.	('global KSHV transcription', 'MPA', (163, 188))	('Hsp70', 'Gene', '3308', (23, 28))	('KSHV', 'Species', '37296', (48, 52))	('precluded', 'NegReg', (38, 47))	('KSHV', 'Species', '37296', (170, 174))	('P', 'Chemical', 'MESH:D010758', (93, 94))	('Hsp70', 'Gene', (23, 28))	('viral protein synthesis', 'MPA', (204, 227))	('DNA replication', 'CPA', (232, 247))	('inhibition', 'Var', (9, 19))	('abolishment', 'NegReg', (148, 159))
485518	26587836	Notably, these results highlight the therapeutic potential of HSP70 inhibitors for the treatment of KSHV-related diseases, such as Kaposi's sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('HSP70', 'Gene', (62, 67))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (131, 147))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (131, 147))	('KSHV', 'Species', '37296', (100, 104))	("Kaposi's sarcoma", 'Disease', (131, 147))	('KSHV-related', 'Disease', (100, 112))	('inhibitors', 'Var', (68, 78))	('HSP70', 'Gene', '3308', (62, 67))
485536	26587836	Furthermore, lytic replication enhances genomic instability and also sustains the population of latently-infected cells that would otherwise be reduced due to the poor persistence of KSHV episomes during cell division.	('lytic replication', 'Var', (13, 30))	('KSHV', 'Species', '37296', (183, 187))	('genomic instability', 'MPA', (40, 59))	('enhances', 'PosReg', (31, 39))	('KSHV', 'Gene', (183, 187))	('sustains', 'PosReg', (69, 77))
485550	26587836	As such, HSP70 inhibitors may provide a novel therapeutic approach for the treatment of KSHV-associated malignancies, in particular it would be interesting to determine the efficacy of combining the potential of inhibiting lytic replication using HSP70 inhibitors with the previous reported effect of HSP90 inhibitors to eradicate latent KSHV reservoirs.	('HSP70', 'Gene', (247, 252))	('HSP90', 'Gene', (301, 306))	('HSP90', 'Gene', '3320', (301, 306))	('lytic', 'CPA', (223, 228))	('malignancies', 'Disease', 'MESH:D009369', (104, 116))	('HSP70', 'Gene', (9, 14))	('KSHV', 'Species', '37296', (338, 342))	('inhibitors', 'Var', (253, 263))	('inhibiting', 'NegReg', (212, 222))	('HSP70', 'Gene', '3308', (247, 252))	('malignancies', 'Disease', (104, 116))	('KSHV', 'Species', '37296', (88, 92))	('HSP70', 'Gene', '3308', (9, 14))
485583	26587836	Occasionally, cells displayed RTCs completely filled by iHsp70 (S1Aiii and S1Aiv Fig, asterisks).	('Hsp70', 'Gene', '3308', (57, 62))	('S1Aiv', 'Var', (75, 80))	('S', 'Chemical', 'MESH:D013455', (75, 76))	('Hsp70', 'Gene', (57, 62))	('S', 'Chemical', 'MESH:D013455', (64, 65))
485598	26587836	As such, VER-155008 functions as an ATP mimetic that specifically inhibits the ATPase activity of members of the HSP70 family.	('ATPase', 'Gene', '1769', (79, 85))	('inhibits', 'NegReg', (66, 74))	('activity', 'MPA', (86, 94))	('HSP70', 'Gene', '3308', (113, 118))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('ATPase', 'Gene', (79, 85))	('VER-155008', 'Var', (9, 19))	('VER-155008', 'Chemical', 'MESH:C550733', (9, 19))	('HSP70', 'Gene', (113, 118))	('ATP', 'Chemical', 'MESH:D000255', (36, 39))
485610	26587836	Importantly, in the presence of VER-155008, iHsp70 levels were not upregulated.	('Hsp70', 'Gene', (45, 50))	('VER-155008', 'Chemical', 'MESH:C550733', (32, 42))	('VER-155008', 'Var', (32, 42))	('Hsp70', 'Gene', '3308', (45, 50))
485615	26587836	The half-life of RTA and ORF57 proteins from inhibitor-treated cells were not altered compared with DMSO-treated cells (Fig 3D).	('RTA', 'Protein', (17, 20))	('ORF57', 'Gene', '4961525', (25, 30))	('inhibitor-treated', 'Var', (45, 62))	('ORF57', 'Gene', (25, 30))	('DMSO', 'Chemical', 'MESH:D004121', (100, 104))
485621	26587836	It is known that the apoptotic potential of VER-155008 is cell line-dependent and that VER-155008 can cause cell cycle arrest in human colon, breast and lung tumour cell lines.	('lung tumour', 'Phenotype', 'HP:0100526', (153, 164))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('cause', 'Reg', (102, 107))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (108, 125))	('apoptotic potential', 'CPA', (21, 40))	('cell cycle arrest', 'CPA', (108, 125))	('VER-155008', 'Chemical', 'MESH:C550733', (44, 54))	('VER-155008', 'Var', (87, 97))	('human', 'Species', '9606', (129, 134))	('breast and lung tumour', 'Disease', 'MESH:D008175', (142, 164))	('VER-155008', 'Chemical', 'MESH:C550733', (87, 97))
485632	26587836	Indeed, samples treated with up to 3 muM VER-155008 were all within 0.4 CT from the 12.7 CT of DMSO-treated samples.	('VER-155008', 'Var', (41, 51))	('DMSO', 'Chemical', 'MESH:D004121', (95, 99))	('muM', 'Gene', '56925', (37, 40))	('VER-155008', 'Chemical', 'MESH:C550733', (41, 51))	('muM', 'Gene', (37, 40))
485634	26587836	This is consistent with the cytotoxicity profile of VER-155008 in TREx BCBL1-RTA cells (Fig 3A and 3B) and the clear decrease in RTA-myc protein (which expression is not from the KSHV genome) at inhibitor concentrations higher than 3 muM (Fig 3C).	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('VER-155008', 'Var', (52, 62))	('muM', 'Gene', (234, 237))	('RTA-myc protein', 'Protein', (129, 144))	('cytotoxicity', 'Disease', (28, 40))	('decrease', 'NegReg', (117, 125))	('VER-155008', 'Chemical', 'MESH:C550733', (52, 62))	('KSHV', 'Species', '37296', (179, 183))	('muM', 'Gene', '56925', (234, 237))
485646	26587836	However, Western blotting did reveal a complete reduction of ORF57 protein in cells treated with > 40 muM VER-155008 (Fig 4C).	('VER-155008', 'Var', (106, 116))	('ORF57', 'Gene', (61, 66))	('ORF57', 'Gene', '4961525', (61, 66))	('muM', 'Gene', (102, 105))	('VER-155008', 'Chemical', 'MESH:C550733', (106, 116))	('reduction', 'NegReg', (48, 57))	('muM', 'Gene', '56925', (102, 105))
485664	26587836	In cells expressing EGFP protein, endogenous Hsc70 remained cytoplasmic (Fig 7Bi), while in EGFP-RTA-expressing cells Hsc70 strongly co-localised with RTA in the nuclei, suggesting RTA expression alone is sufficient to redistribute Hsc70 into the nucleus (Fig 7Bii).	('P', 'Chemical', 'MESH:D010758', (95, 96))	('P', 'Chemical', 'MESH:D010758', (23, 24))	('EGFP protein', 'Var', (20, 32))	('Hsc70', 'Gene', '3312', (232, 237))	('Hsc70', 'Gene', '3312', (118, 123))	('Hsc70', 'Gene', (45, 50))	('Hsc70', 'Gene', (232, 237))	('Hsc70', 'Gene', (118, 123))	('Hsc70', 'Gene', '3312', (45, 50))
485676	26587836	However, ORF57 promoter activity was not significantly decreased in the presence of VER-155008 (Fig 7D).	('ORF57', 'Gene', '4961525', (9, 14))	('VER-155008', 'Var', (84, 94))	('ORF57', 'Gene', (9, 14))	('VER-155008', 'Chemical', 'MESH:C550733', (84, 94))
485701	26587836	A significant increase in cytoplasmic Hsc70 peaks was seen in inhibitor-treated cells compared with DMSO control cells (Fig 8C).	('Hsc70', 'Gene', (38, 43))	('Hsc70', 'Gene', '3312', (38, 43))	('DMSO', 'Chemical', 'MESH:D004121', (100, 104))	('inhibitor-treated', 'Var', (62, 79))	('increase', 'PosReg', (14, 22))
485706	26587836	This demonstrates that chaperone recruitment to the nucleus is essential for the assembly of KSHV RTCs and treatment with VER-155008 was sufficient to impair nuclear chaperone recruitment and KSHV RTC formation.	('nuclear chaperone recruitment', 'MPA', (158, 187))	('KSHV', 'Species', '37296', (93, 97))	('impair', 'NegReg', (151, 157))	('VER-155008', 'Chemical', 'MESH:C550733', (122, 132))	('KSHV', 'Species', '37296', (192, 196))	('KSHV RTC formation', 'CPA', (192, 210))	('VER-155008', 'Var', (122, 132))
485711	26587836	This suggests that in the presence of Hsp70 isoform inhibition, RNAPII failed to assemble into developed RTCs and instead aberrantly formed what resembled pre-replicative sites.	('failed', 'NegReg', (71, 77))	('aberrantly', 'Reg', (122, 132))	('inhibition', 'Var', (52, 62))	('Hsp70', 'Gene', '3308', (38, 43))	('P', 'Chemical', 'MESH:D010758', (67, 68))	('Hsp70', 'Gene', (38, 43))
485714	26587836	In DMSO-reactivated cells, cell cycle arrest was evident as shown by fewer Edu-labelled cells (S9Bi Fig) consistent with previous reports that lytic KSHV in primary effusion lymphoma cell lines causes G1 cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (27, 44))	('G1', 'CellLine', 'CVCL:1929', (201, 203))	('cell cycle arrest', 'CPA', (27, 44))	('lytic KSHV', 'Var', (143, 153))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (204, 221))	('Edu', 'Chemical', '-', (75, 78))	('effusion lymphoma', 'Disease', 'MESH:D054685', (165, 182))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (157, 182))	('lymphoma', 'Phenotype', 'HP:0002665', (174, 182))	('effusion lymphoma', 'Disease', (165, 182))	('KSHV', 'Species', '37296', (149, 153))	('G1 cell cycle arrest', 'CPA', (201, 221))	('S', 'Chemical', 'MESH:D013455', (5, 6))	('DMSO', 'Chemical', 'MESH:D004121', (3, 7))	('S', 'Chemical', 'MESH:D013455', (150, 151))	('S', 'Chemical', 'MESH:D013455', (95, 96))	('causes', 'Reg', (194, 200))
485717	26587836	To confirm that inhibition of Hsp70 isoform function was able to abolish RNAPII recruitment to viral genomes, we also utilised chromatin immunoprecipitation (ChIP) assays in TREx BCBL1-RTA cells that were either reactivated for 24 h in the presence of DMSO or 2 muM VER-155008 (Fig 9C).	('recruitment to viral genomes', 'MPA', (80, 108))	('abolish', 'NegReg', (65, 72))	('RNAPII', 'Gene', (73, 79))	('P', 'Chemical', 'MESH:D010758', (161, 162))	('Hsp70', 'Gene', '3308', (30, 35))	('muM', 'Gene', '56925', (262, 265))	('VER-155008', 'Chemical', 'MESH:C550733', (266, 276))	('DMSO', 'Chemical', 'MESH:D004121', (252, 256))	('muM', 'Gene', (262, 265))	('P', 'Chemical', 'MESH:D010758', (76, 77))	('Hsp70', 'Gene', (30, 35))	('inhibition', 'Var', (16, 26))
485719	26587836	However, KSHV reactivation in DMSO-treated cells led to a drastic reduction of RNAPII at the promoter of GAPDH and a significant increase of RNAPII at the viral promoters in agreement with the previous immunofluorescence results, showing RNAPII recruitment to RTCs (Fig 9Bi).	('KSHV', 'Gene', (9, 13))	('P', 'Chemical', 'MESH:D010758', (82, 83))	('P', 'Chemical', 'MESH:D010758', (144, 145))	('P', 'Chemical', 'MESH:D010758', (107, 108))	('KSHV', 'Species', '37296', (9, 13))	('P', 'Chemical', 'MESH:D010758', (241, 242))	('DMSO', 'Chemical', 'MESH:D004121', (30, 34))	('increase', 'PosReg', (129, 137))	('GAPDH', 'Gene', '2597', (105, 110))	('RNAPII', 'MPA', (79, 85))	('RNAPII', 'MPA', (141, 147))	('reduction', 'NegReg', (66, 75))	('GAPDH', 'Gene', (105, 110))	('reactivation', 'Var', (14, 26))
485723	26587836	Hsc70 depletion was evaluated by Western blotting and by qRT-PCR, the latter showing ~ 85% Hsc70 mRNA knockdown (Fig 10A).	('Hsc70', 'Gene', (0, 5))	('Hsc70', 'Gene', '3312', (91, 96))	('knockdown', 'Var', (102, 111))	('Hsc70', 'Gene', '3312', (0, 5))	('depletion', 'MPA', (6, 15))	('Hsc70', 'Gene', (91, 96))	('P', 'Chemical', 'MESH:D010758', (61, 62))
485725	26587836	Despite a successful knockdown at the mRNA level, significant amounts of Hsc70 protein remained in Hsc70-depleted cells (Fig 10B).	('Hsc70', 'Gene', (99, 104))	('Hsc70', 'Gene', '3312', (99, 104))	('Hsc70', 'Gene', (73, 78))	('knockdown', 'Var', (21, 30))	('Hsc70', 'Gene', '3312', (73, 78))
485727	26587836	ORF57, ORF74 and gL mRNA levels were decreased by ~ 40% following Hsc70 knockdown.	('ORF57', 'Gene', '4961525', (0, 5))	('ORF57', 'Gene', (0, 5))	('Hsc70', 'Gene', (66, 71))	('Hsc70', 'Gene', '3312', (66, 71))	('decreased', 'NegReg', (37, 46))	('knockdown', 'Var', (72, 81))
485729	26587836	Viral DNA replication was also assessed following Hsc70 knockdown.	('Hsc70', 'Gene', '3312', (50, 55))	('knockdown', 'Var', (56, 65))	('Hsc70', 'Gene', (50, 55))
485732	26587836	This highlights the remarkable stability of Hsc70 protein in this cell line and it suggests that Hsc70 depletion was enough to cause a reduction in viral transcripts but not enough to cause a reduction in the amount of viral proteins, thus KSHV lytic replication remained unaffected.	('KSHV', 'Species', '37296', (240, 244))	('reduction', 'NegReg', (135, 144))	('Hsc70', 'Gene', '3312', (44, 49))	('Hsc70', 'Gene', (97, 102))	('Hsc70', 'Gene', (44, 49))	('depletion', 'Var', (103, 112))	('Hsc70', 'Gene', '3312', (97, 102))	('viral transcripts', 'MPA', (148, 165))
485770	26587836	These results may have exciting implications in combination with the recently demonstrated efficacy of ATP-competitive HSP90 inhibitors in blocking KSHV latent cycle in vitro and in a xenograft KSHV tumour model.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('HSP90', 'Gene', (119, 124))	('xenograft KSHV tumour', 'Disease', 'MESH:C537372', (184, 205))	('KSHV', 'Species', '37296', (148, 152))	('HSP90', 'Gene', '3320', (119, 124))	('xenograft KSHV tumour', 'Disease', (184, 205))	('blocking', 'NegReg', (139, 147))	('KSHV', 'Species', '37296', (194, 198))	('KSHV', 'Gene', (148, 152))	('ATP', 'Chemical', 'MESH:D000255', (103, 106))	('inhibitors', 'Var', (125, 135))
485772	26587836	Excitingly, in our cell culture models VER-155008 abrogated lytic replication without severely affecting cell viability or triggering apoptosis.	('VER-155008', 'Var', (39, 49))	('VER-155008', 'Chemical', 'MESH:C550733', (39, 49))	('lytic replication', 'CPA', (60, 77))	('abrogated', 'NegReg', (50, 59))
485789	26587836	It is interesting to note that expression of a dominant-negative Hsc70 (K71M) that cannot hydrolyze ATP during HSV-1 infection resulted in prevention of serine-2 RNAPII degradation and RTCs formation.	('P', 'Chemical', 'MESH:D010758', (165, 166))	('P', 'Chemical', 'MESH:D010758', (102, 103))	('HSV-1 infection', 'Disease', (111, 126))	('Hsc70', 'Gene', (65, 70))	('K71M', 'Var', (72, 76))	('prevention', 'NegReg', (139, 149))	('ATP', 'Chemical', 'MESH:D000255', (100, 103))	('Hsc70', 'Gene', '3312', (65, 70))	('K71M', 'Mutation', 'p.K71M', (72, 76))	('HSV-1 infection', 'Disease', 'MESH:C536395', (111, 126))	('RTCs', 'MPA', (185, 189))	('serine-2 RNAPII degradation', 'MPA', (153, 180))	('serine', 'Chemical', 'MESH:D012694', (153, 159))
485790	26587836	However, inhibition of Hsp70 isoforms by VER-155008 did not prevent the slight degradation of phospho-serine-2 RNAPII protein (Fig 3C).	('serine', 'Chemical', 'MESH:D012694', (102, 108))	('Hsp70', 'Gene', '3308', (23, 28))	('VER-155008', 'Var', (41, 51))	('Hsp70', 'Gene', (23, 28))	('P', 'Chemical', 'MESH:D010758', (114, 115))	('VER-155008', 'Chemical', 'MESH:C550733', (41, 51))
485794	26587836	Importantly, in both viruses, HSV-1 and KSHV, inhibition of Hsc70 ATPase function leads to a clear impediment in RTCs formation and presents a novel antiviral target for multiple herpesviruses.	('multiple herpesviruses', 'Phenotype', 'HP:0005353', (170, 192))	('Hsc70', 'Gene', (60, 65))	('ATPase', 'Gene', '1769', (66, 72))	('inhibition', 'Var', (46, 56))	('ATPase', 'Gene', (66, 72))	('Hsc70', 'Gene', '3312', (60, 65))	('KSHV', 'Species', '37296', (40, 44))	('HSV-1', 'Species', '10298', (30, 35))	('impediment', 'NegReg', (99, 109))	('herpesvirus', 'Species', '39059', (179, 190))	('RTCs formation', 'CPA', (113, 127))
485799	26587836	To support the conserved role of Hsp70 isoforms in herpesvirus infection, a recent study showed that cellular depletion of Hsc70 protein significantly reduced HSV-1 viral output in cell culture without adversely affecting cell viability.	('Hsp70', 'Gene', '3308', (33, 38))	('herpesvirus infection', 'Disease', 'MESH:D006566', (51, 72))	('HSV-1 viral output', 'Disease', 'MESH:C536395', (159, 177))	('reduced', 'NegReg', (151, 158))	('Hsc70', 'Gene', (123, 128))	('HSV-1 viral output', 'Disease', (159, 177))	('Hsp70', 'Gene', (33, 38))	('Hsc70', 'Gene', '3312', (123, 128))	('herpesvirus infection', 'Disease', (51, 72))	('herpesvirus infection', 'Phenotype', 'HP:0005353', (51, 72))	('depletion', 'Var', (110, 119))	('protein', 'Protein', (129, 136))
485800	26587836	Depleting Hsc70 from the HSV-1 virion also significantly reduced viral production by more than 50%.	('viral production', 'MPA', (65, 81))	('Depleting', 'Var', (0, 9))	('Hsc70', 'Gene', (10, 15))	('Hsc70', 'Gene', '3312', (10, 15))	('reduced', 'NegReg', (57, 64))	('HSV-1', 'Species', '10298', (25, 30))
485905	26587836	The siRNA ID for Hsc70 and iHsp70 were s6985 and s6968 respectively.	('Hsp70', 'Gene', (28, 33))	('s6968', 'Var', (49, 54))	('Hsc70', 'Gene', (17, 22))	('s6985', 'Var', (39, 44))	('Hsp70', 'Gene', '3308', (28, 33))	('Hsc70', 'Gene', '3312', (17, 22))
485925	33539420	circARFGEF1 functioned as a competing endogenous RNAs (ceRNAs) by binding to and inducing degradation of miR-125a-3p.	('ARFGEF1', 'Gene', (4, 11))	('degradation', 'MPA', (90, 101))	('ARFGEF1', 'Gene', '10565', (4, 11))	('miR-125a-3p', 'Chemical', '-', (105, 116))	('binding', 'Interaction', (66, 73))	('miR-125a-3p', 'Var', (105, 116))	('inducing', 'Reg', (81, 89))
485926	33539420	Mass spectrometry analysis demonstrated that glutaredoxin 3 (GLRX3) was a direct target of miR-125a-3p.	('miR-125a-3p', 'Chemical', '-', (91, 102))	('GLRX3', 'Gene', '10539', (61, 66))	('glutaredoxin 3', 'Gene', '10539', (45, 59))	('glutaredoxin 3', 'Gene', (45, 59))	('miR-125a-3p', 'Var', (91, 102))	('GLRX3', 'Gene', (61, 66))
485939	33539420	Besides KS, KSHV also causes two B-cell lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD), and KSHV-associated inflammatory cytokine syndrome (KICS).	('KSHV', 'Species', '37296', (151, 155))	('inflammatory cytokine syndrome', 'Disease', (167, 197))	('lymphoproliferative disorders', 'Disease', (40, 69))	('KSHV', 'Var', (12, 16))	('lymphoproliferative disorders', 'Disease', 'MESH:D008232', (40, 69))	('KSHV-associated', 'Disease', (151, 166))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (71, 96))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	("multicentric Castleman's disease", 'Disease', 'MESH:C537372', (107, 139))	('inflammatory cytokine syndrome', 'Disease', 'MESH:D000080424', (167, 197))	('primary effusion lymphoma', 'Disease', (71, 96))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (71, 96))	('causes', 'Reg', (22, 28))	('cytokine syndrome', 'Phenotype', 'HP:0031407', (180, 197))	('B-cell', 'Disease', (33, 39))	("multicentric Castleman's disease", 'Disease', (107, 139))	('KSHV', 'Species', '37296', (12, 16))	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (40, 69))	('MCD', 'Disease', 'MESH:D012514', (141, 144))	('MCD', 'Disease', (141, 144))
485958	33539420	We identified vIRF1-regulated circRNAs through RNA sequencing in endothelial cells infected by KSHV and a vIRF1 mutant virus.	('infected', 'Disease', 'MESH:D007239', (83, 91))	('infected', 'Disease', (83, 91))	('mutant', 'Var', (112, 118))	('KSHV', 'Species', '37296', (95, 99))	('vIRF1', 'Gene', (106, 111))
485962	33539420	Mass spectrometry analysis and luciferase reporter assay demonstrated that GLRX3 was a direct target of miR-125a-3p.	('GLRX3', 'Gene', '10539', (75, 80))	('GLRX3', 'Gene', (75, 80))	('miR-125a-3p', 'Chemical', '-', (104, 115))	('miR-125a-3p', 'Var', (104, 115))
485966	33539420	Cluster analysis showed that cells infected by KSHV_WT had a circRNA expression pattern distinct from those infected by the vIRF1_mut virus (Fig 1A).	('circRNA expression pattern', 'MPA', (61, 87))	('infected', 'Disease', 'MESH:D007239', (35, 43))	('infected', 'Disease', 'MESH:D007239', (108, 116))	('infected', 'Disease', (35, 43))	('infected', 'Disease', (108, 116))	('KSHV', 'Species', '37296', (47, 51))	('KSHV_WT', 'Var', (47, 54))
485979	33539420	The results showed that pre-mRNA of ARFGEF1 was increased in both vIRF1-transduced and KSHV-infected cells, whereas KSHV or vIRF1 has no effect on linear ARFGEF1 (Figs 2D and 2E and S2).	('increased', 'PosReg', (48, 57))	('ARFGEF1', 'Gene', (36, 43))	('KSHV', 'Species', '37296', (87, 91))	('KSHV-infected', 'Disease', 'MESH:D007239', (87, 100))	('ARFGEF1', 'Gene', (154, 161))	('vIRF1-transduced', 'Var', (66, 82))	('ARFGEF1', 'Gene', '10565', (36, 43))	('KSHV', 'Species', '37296', (116, 120))	('KSHV-infected', 'Disease', (87, 100))	('ARFGEF1', 'Gene', '10565', (154, 161))
485991	33539420	We found that either overexpression or silencing of circARFGEF1 didn't affect the mRNA level of its parental gene ARFGEF1 (S4 and S5 Figs).	('ARFGEF1', 'Gene', (114, 121))	('ARFGEF1', 'Gene', (56, 63))	('ARFGEF1', 'Gene', '10565', (114, 121))	('ARFGEF1', 'Gene', '10565', (56, 63))	('silencing', 'Var', (39, 48))	('mRNA level', 'MPA', (82, 92))
485992	33539420	Loss of circARFGEF1 significantly inhibited vIRF1-induced endothelial cell migration and invasion (Figs 3A-3C and S6).	('ARFGEF1', 'Gene', (12, 19))	('endothelial cell migration', 'CPA', (58, 84))	('inhibited', 'NegReg', (34, 43))	('invasion', 'CPA', (89, 97))	('ARFGEF1', 'Gene', '10565', (12, 19))	('Loss', 'Var', (0, 4))	('vIRF1-induced', 'Gene', (44, 57))
485993	33539420	Similarly, knockdown of circARFGEF1 impeded vIRF1-induced cell proliferation in a plate colony formation assay (Fig 3D and 3E), while the inhibitory effect on the plate colony formation by silencing of circARFGEF1 was reversed by overexpression of circARFGEF1 in EA.hy926 cells (S7 Fig).	('silencing', 'Var', (189, 198))	('impeded', 'NegReg', (36, 43))	('ARFGEF1', 'Gene', '10565', (206, 213))	('ARFGEF1', 'Gene', '10565', (28, 35))	('ARFGEF1', 'Gene', (252, 259))	('ARFGEF1', 'Gene', (206, 213))	('ARFGEF1', 'Gene', '10565', (252, 259))	('knockdown', 'Var', (11, 20))	('vIRF1-induced', 'Gene', (44, 57))	('ARFGEF1', 'Gene', (28, 35))	('EA.hy926', 'CellLine', 'CVCL:3901', (263, 271))
486002	33539420	It was showed that only miR-125a-3p reduced circARFGEF1 luciferase activity (Fig 4B).	('ARFGEF1', 'Gene', (48, 55))	('ARFGEF1', 'Gene', '10565', (48, 55))	('activity', 'MPA', (67, 75))	('reduced', 'NegReg', (36, 43))	('miR-125a-3p', 'Chemical', '-', (24, 35))	('miR-125a-3p', 'Var', (24, 35))
486003	33539420	RT-qPCR indicated that miR-125a-3p was decreased in both vIRF1-transduced and KSHV-infected EA.hy926 cells (Fig 4C and 4D).	('KSHV-infected', 'Disease', (78, 91))	('miR-125a-3p', 'Chemical', '-', (23, 34))	('miR-125a-3p', 'Var', (23, 34))	('decreased', 'NegReg', (39, 48))	('KSHV-infected', 'Disease', 'MESH:D007239', (78, 91))	('EA.hy926', 'CellLine', 'CVCL:3901', (92, 100))
486005	33539420	miR-125a-3p inhibited circARFGEF1 luciferase activity in a dose-dependent manner in a luciferase reporter assay (Fig 4E and 4F).	('inhibited', 'NegReg', (12, 21))	('miR-125a-3p', 'Var', (0, 11))	('activity', 'MPA', (45, 53))	('ARFGEF1', 'Gene', (26, 33))	('luciferase reporter', 'Enzyme', (86, 105))	('miR-125a-3p', 'Chemical', '-', (0, 11))	('ARFGEF1', 'Gene', '10565', (26, 33))
486006	33539420	To examine the binding site located in circARFGEF1 sequence, we generated the mutated miR-125a-3p according to the sequences of putative binding site (Fig 4G).	('ARFGEF1', 'Gene', '10565', (43, 50))	('ARFGEF1', 'Gene', (43, 50))	('mutated', 'Var', (78, 85))	('miR-125a-3p', 'Gene', (86, 97))	('miR-125a-3p', 'Chemical', '-', (86, 97))
486008	33539420	To determine whether the interaction between circARFGEF1 and miR-125a-3p existed in cells, we generated biotin-labeled wild type (WT) of miR-125a-3p and mutated miR-125a-3p.	('ARFGEF1', 'Gene', '10565', (49, 56))	('mutated', 'Var', (153, 160))	('miR-125a-3p', 'Chemical', '-', (61, 72))	('miR-125a-3p', 'Gene', (137, 148))	('biotin', 'Chemical', 'MESH:D001710', (104, 110))	('miR-125a-3p', 'Chemical', '-', (137, 148))	('miR-125a-3p', 'Chemical', '-', (161, 172))	('miR-125a-3p', 'Gene', (161, 172))	('ARFGEF1', 'Gene', (49, 56))
486009	33539420	Biotin-coupled RNA pull-down assay showed that circARFGEF1 was enriched in miR-125a-3p WT group but not in mutated group (Fig 4I).	('ARFGEF1', 'Gene', '10565', (51, 58))	('miR-125a-3p', 'Chemical', '-', (75, 86))	('miR-125a-3p', 'Var', (75, 86))	('Biotin', 'Chemical', 'MESH:D001710', (0, 6))	('ARFGEF1', 'Gene', (51, 58))
486012	33539420	More importantly, miR-125a-3p was degraded in circARFGEF1-expressing cells in response to actinomycin D (Fig 4L).	('degraded', 'NegReg', (34, 42))	('miR-125a-3p', 'Var', (18, 29))	('actinomycin D', 'Chemical', 'MESH:D003609', (90, 103))	('ARFGEF1', 'Gene', (50, 57))	('response to actinomycin D', 'MPA', (78, 103))	('ARFGEF1', 'Gene', '10565', (50, 57))	('miR-125a-3p', 'Chemical', '-', (18, 29))
486013	33539420	Collectively, these data suggest that circARFGEF1 served as a sponge of miR-125a-3p, inducing its degradation.	('miR-125a-3p', 'Var', (72, 83))	('ARFGEF1', 'Gene', '10565', (42, 49))	('degradation', 'MPA', (98, 109))	('inducing', 'PosReg', (85, 93))	('ARFGEF1', 'Gene', (42, 49))	('miR-125a-3p', 'Chemical', '-', (72, 83))
486015	33539420	We found that overexpression of miR-125a-3p in vIRF1-transduced cells had an inhibitory effect on vIRF1-induced cell migration and invasion (Fig 5A-5C).	('invasion', 'CPA', (131, 139))	('inhibitory effect', 'NegReg', (77, 94))	('miR-125a-3p', 'Chemical', '-', (32, 43))	('cell migration', 'CPA', (112, 126))	('miR-125a-3p', 'Var', (32, 43))	('vIRF1-induced', 'Gene', (98, 111))	('overexpression', 'PosReg', (14, 28))
486016	33539420	Consistently, overexpression of miR-125a-3p impeded vIRF1-induced cell proliferation in a plate colony formation assay (Fig 5D and 5E).	('impeded', 'NegReg', (44, 51))	('vIRF1-induced', 'Gene', (52, 65))	('miR-125a-3p', 'Chemical', '-', (32, 43))	('miR-125a-3p', 'Var', (32, 43))	('overexpression', 'PosReg', (14, 28))
486017	33539420	More importantly, induction of miR-125a-3p impaired vIRF1-enhanced angiogenesis in vivo based on a matrigel plug assay in mice (Fig 5F and 5G).	('miR-125a-3p', 'Var', (31, 42))	('mice', 'Species', '10090', (122, 126))	('angiogenesis', 'CPA', (67, 79))	('impaired', 'NegReg', (43, 51))	('vIRF1-enhanced', 'Gene', (52, 66))	('miR-125a-3p', 'Chemical', '-', (31, 42))	('vIRF1-enhanced', 'PosReg', (52, 66))
486022	33539420	A luciferase reporter assay confirmed that only miR-125a-3p significantly decreased the luciferase activity of the 3' UTR reporter of glutaredoxin 3 (GLRX3) (Fig 6B).	('miR-125a-3p', 'Chemical', '-', (48, 59))	('luciferase', 'Enzyme', (88, 98))	('miR-125a-3p', 'Var', (48, 59))	('GLRX3', 'Gene', '10539', (150, 155))	('decreased', 'NegReg', (74, 83))	('GLRX3', 'Gene', (150, 155))	('glutaredoxin 3', 'Gene', (134, 148))	('activity', 'MPA', (99, 107))	('glutaredoxin 3', 'Gene', '10539', (134, 148))
486023	33539420	Western blotting confirmed that miR-125a-3p inhibited GLRX3 protein expression (Fig 6C).	('GLRX3', 'Gene', '10539', (54, 59))	('expression', 'MPA', (68, 78))	('miR-125a-3p', 'Chemical', '-', (32, 43))	('inhibited', 'NegReg', (44, 53))	('miR-125a-3p', 'Var', (32, 43))	('GLRX3', 'Gene', (54, 59))
486024	33539420	miR-125a-3p suppressed the luciferase reporter activity of GLRX3 3'UTR in a dose-dependent manner (Fig 6D and 6E).	('miR-125a-3p', 'Var', (0, 11))	('GLRX3', 'Gene', (59, 64))	('GLRX3', 'Gene', '10539', (59, 64))	('luciferase', 'Enzyme', (27, 37))	('miR-125a-3p', 'Chemical', '-', (0, 11))	('suppressed', 'NegReg', (12, 22))
486027	33539420	Mutation in seed sequence of miR-125a-3p dramatically eliminated the inhibitory effect of miR-125a-3p on GLRX3 expression (Fig 6I and 6J).	('eliminated', 'NegReg', (54, 64))	('miR-125a-3p', 'Chemical', '-', (29, 40))	('GLRX3', 'Gene', '10539', (105, 110))	('Mutation', 'Var', (0, 8))	('expression', 'MPA', (111, 121))	('GLRX3', 'Gene', (105, 110))	('inhibitory effect', 'MPA', (69, 86))	('miR-125a-3p', 'Chemical', '-', (90, 101))
486030	33539420	These results demonstrated that circARFGEF1 served as a miR-125a-3p sponge to reverse the inhibitory effect of miR-125a-3p on GLRX3.	('miR-125a-3p', 'Chemical', '-', (111, 122))	('miR-125a-3p', 'Var', (111, 122))	('miR-125a-3p', 'Chemical', '-', (56, 67))	('ARFGEF1', 'Gene', (36, 43))	('GLRX3', 'Gene', '10539', (126, 131))	('ARFGEF1', 'Gene', '10565', (36, 43))	('GLRX3', 'Gene', (126, 131))
486032	33539420	RT-qPCR and Western blotting showed that both mRNA and protein levels of GLRX3 were elevated in vIRF1-transduced EA.hy926 cells (Fig 7A and 7B).	('elevated', 'PosReg', (84, 92))	('vIRF1-transduced', 'Gene', (96, 112))	('vIRF1-transduced', 'Var', (96, 112))	('GLRX3', 'Gene', (73, 78))	('EA.hy926', 'CellLine', 'CVCL:3901', (113, 121))	('GLRX3', 'Gene', '10539', (73, 78))
486036	33539420	To determine whether upregulated GLRX3 is required for vIRF1 promoted cell motility and angiogenesis, we performed knockdown of GLRX3 with lentivirus-mediated shRNAs in vIRF1-transduced cells (Figs 7G and S9).	('GLRX3', 'Gene', '10539', (33, 38))	('angiogenesis', 'CPA', (88, 100))	('GLRX3', 'Gene', (128, 133))	('cell motility', 'CPA', (70, 83))	('GLRX3', 'Gene', (33, 38))	('GLRX3', 'Gene', '10539', (128, 133))	('knockdown', 'Var', (115, 124))
486037	33539420	We found that knockdown of GLRX3 decreased vIRF1-induced oncogenic phenotypes (Figs 7H-7K and S10).	('GLRX3', 'Gene', (27, 32))	('vIRF1-induced', 'Gene', (43, 56))	('GLRX3', 'Gene', '10539', (27, 32))	('oncogenic', 'CPA', (57, 66))	('knockdown', 'Var', (14, 23))	('decreased', 'NegReg', (33, 42))
486038	33539420	These data collectively suggest that miR-125a-3p directly targets GLRX3 to negatively regulate vIRF1-induced cell invasion, proliferation and angiogenesis.	('GLRX3', 'Gene', (66, 71))	('proliferation', 'CPA', (124, 137))	('regulate', 'Reg', (86, 94))	('miR-125a-3p', 'Chemical', '-', (37, 48))	('GLRX3', 'Gene', '10539', (66, 71))	('miR-125a-3p', 'Var', (37, 48))	('vIRF1-induced', 'Gene', (95, 108))	('negatively', 'NegReg', (75, 85))	('angiogenesis', 'CPA', (142, 154))
486040	33539420	We have previously shown that deletion of vIRF1 from KSHV genome not only decreased KSHV-induced cell migration and invasion, but also lowered KSHV-induced angiogenesis and cellular transformation.	('vIRF1', 'Gene', (42, 47))	('cellular transformation', 'CPA', (173, 196))	('deletion', 'Var', (30, 38))	('KSHV', 'Species', '37296', (53, 57))	('KSHV', 'Species', '37296', (84, 88))	('decreased', 'NegReg', (74, 83))	('KSHV-induced angiogenesis', 'CPA', (143, 168))	('KSHV', 'Species', '37296', (143, 147))	('lowered', 'NegReg', (135, 142))
486041	33539420	Here, we found that deletion of vIRF1 abolished the ability of KSHV-induced cell proliferation in a plate colony formation assay; however, complementation with a vIRF1 construct in the vIRF1_mut virus infected cells recovered this phenomenon (Fig 8A).	('abolished', 'NegReg', (38, 47))	('KSHV', 'Species', '37296', (63, 67))	('virus infected', 'Disease', 'MESH:D001102', (195, 209))	('vIRF1', 'Gene', (32, 37))	('deletion', 'Var', (20, 28))	('cell proliferation in a plate colony formation assay', 'CPA', (76, 128))	('virus infected', 'Disease', (195, 209))
486042	33539420	Further, deletion of vIRF1 attenuated mRNA levels of circARFGEF1 and GLRX3, while complementation with the vIRF1 construct rescued their transcript levels (Fig 8B).	('ARFGEF1', 'Gene', '10565', (57, 64))	('attenuated', 'NegReg', (27, 37))	('vIRF1', 'Gene', (21, 26))	('GLRX3', 'Gene', (69, 74))	('deletion', 'Var', (9, 17))	('ARFGEF1', 'Gene', (57, 64))	('transcript levels', 'MPA', (137, 154))	('GLRX3', 'Gene', '10539', (69, 74))
486043	33539420	Correspondingly, the mRNA level of miR-125a-3p had an inverse change compared to those of circARFGEF1 and GLRX3 mRNA (Fig 8B).	('ARFGEF1', 'Gene', (94, 101))	('miR-125a-3p', 'Var', (35, 46))	('mRNA level', 'MPA', (21, 31))	('ARFGEF1', 'Gene', '10565', (94, 101))	('GLRX3', 'Gene', '10539', (106, 111))	('GLRX3', 'Gene', (106, 111))	('miR-125a-3p', 'Chemical', '-', (35, 46))
486044	33539420	Consistent with these observations, deletion of vIRF1 decreased GLRX3 protein level, which were completely reversed following vIRF1 complementation (Fig 8C).	('vIRF1', 'Gene', (48, 53))	('deletion', 'Var', (36, 44))	('GLRX3', 'Gene', '10539', (64, 69))	('decreased', 'NegReg', (54, 63))	('GLRX3', 'Gene', (64, 69))	('decreased GLRX3 protein level', 'Phenotype', 'HP:0031037', (54, 83))
486045	33539420	Additionally, silencing of circARFGEF1 in KSHV-infected cells not only reduced the ability of KSHV-induced cell proliferation in a plate colony formation assay (Figs 8D and S11A), but also resulted in increased miR-125a-3p and decreased GRLX3 (Fig 8E and 8F).	('silencing', 'Var', (14, 23))	('S11A', 'SUBSTITUTION', 'None', (173, 177))	('ARFGEF1', 'Gene', '10565', (31, 38))	('increased', 'PosReg', (201, 210))	('KSHV', 'Species', '37296', (42, 46))	('decreased', 'NegReg', (227, 236))	('GRLX3', 'MPA', (237, 242))	('KSHV-infected', 'Disease', 'MESH:D007239', (42, 55))	('miR-125a-3p', 'Chemical', '-', (211, 222))	('KSHV', 'Species', '37296', (94, 98))	('reduced', 'NegReg', (71, 78))	('miR-125a-3p', 'MPA', (211, 222))	('KSHV-infected', 'Disease', (42, 55))	('S11A', 'Var', (173, 177))	('ARFGEF1', 'Gene', (31, 38))
486046	33539420	Furthermore, knockdown of GLRX3 in KSHV-infected cells decreased their efficiency of plate colony formation (Figs 8G and S11B).	('GLRX3', 'Gene', '10539', (26, 31))	('decreased', 'NegReg', (55, 64))	('S11B', 'SUBSTITUTION', 'None', (121, 125))	('S11B', 'Var', (121, 125))	('KSHV-infected', 'Disease', 'MESH:D007239', (35, 48))	('GLRX3', 'Gene', (26, 31))	('knockdown', 'Var', (13, 22))	('KSHV-infected', 'Disease', (35, 48))
486047	33539420	Meanwhile, silencing of circARFGEF1 in vIRF1-transduced cells exhibited the similar results (Fig 8H and 8I).	('silencing', 'Var', (11, 20))	('ARFGEF1', 'Gene', '10565', (28, 35))	('ARFGEF1', 'Gene', (28, 35))
486076	33539420	miR-125a-3p exhibits a tumor suppressive function in most tumors, such as gliomas, hepatocellular carcinoma, renal cell carcinoma and ovarian carcinoma.	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (83, 107))	('tumor', 'Disease', (58, 63))	('gliomas', 'Disease', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('miR-125a-3p', 'Var', (0, 11))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (83, 107))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('renal cell carcinoma and ovarian carcinoma', 'Disease', 'MESH:C538614', (109, 151))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('hepatocellular carcinoma', 'Disease', (83, 107))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (134, 151))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('miR-125a-3p', 'Chemical', '-', (0, 11))
486077	33539420	Similar to miR-125a-3p, miR-125a-5p was decreased in gliomas, breast cancer, lung adenocarcinoma and ovarian cancer.	('lung adenocarcinoma and ovarian cancer', 'Disease', 'MESH:D000077192', (77, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('gliomas, breast cancer', 'Disease', 'MESH:D001943', (53, 75))	('miR-125a-5p', 'Var', (24, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('miR-125a-3p', 'Chemical', '-', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('decreased', 'NegReg', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
486078	33539420	In contrast, miR-125a-3p was significantly up-regulated in early lung adenocarcinomas.	('up-regulated', 'PosReg', (43, 55))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (65, 85))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (65, 85))	('miR-125a-3p', 'Chemical', '-', (13, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('miR-125a-3p', 'Var', (13, 24))	('lung adenocarcinomas', 'Disease', (65, 85))
486079	33539420	miR-125a-3p inhibited renal cell angiogenesis by targeting VEGF.	('inhibited', 'NegReg', (12, 21))	('miR-125a-3p', 'Var', (0, 11))	('renal cell angiogenesis', 'CPA', (22, 45))	('VEGF', 'Gene', '7422', (59, 63))	('miR-125a-3p', 'Chemical', '-', (0, 11))	('targeting', 'Reg', (49, 58))	('VEGF', 'Gene', (59, 63))
486080	33539420	In gliomas, circ-MAPK4 inhibited cell apoptosis and promoted cell proliferation via activating p38/MAPK signaling by sponging miR-125a-3p in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('cell apoptosis', 'CPA', (33, 47))	('p38/MAPK', 'Gene', (95, 103))	('inhibited', 'NegReg', (23, 32))	('promoted', 'PosReg', (52, 60))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))	('p38/MAPK', 'Gene', '1432', (95, 103))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('circ-MAPK4', 'Var', (12, 22))	('activating', 'PosReg', (84, 94))	('gliomas', 'Disease', (3, 10))	('miR-125a-3p', 'Chemical', '-', (126, 137))	('gliomas', 'Disease', (141, 148))	('miR-125a-3p', 'Var', (126, 137))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('cell proliferation', 'CPA', (61, 79))
486082	33539420	Similar to most tumors, in this study, our results also indicated a tumor suppressive function of miR-125a-3p.	('tumor', 'Disease', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('miR-125a-3p', 'Chemical', '-', (98, 109))	('tumor', 'Disease', (16, 21))	('miR-125a-3p', 'Var', (98, 109))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (16, 22))
486083	33539420	miR-125a-3p was decreased in both KSHV-infected cells and vIRF1-transduced cells, and overexpression of miR-125a-3p reversed vIRF1-induced oncogenic phenotypes.	('miR-125a-3p', 'Var', (104, 115))	('KSHV-infected', 'Disease', 'MESH:D007239', (34, 47))	('KSHV-infected', 'Disease', (34, 47))	('miR-125a-3p', 'Chemical', '-', (0, 11))	('miR-125a-3p', 'Chemical', '-', (104, 115))
486092	33539420	In this study, we have identified GLRX3 as a direct target of miR-125a-3p.	('GLRX3', 'Gene', (34, 39))	('GLRX3', 'Gene', '10539', (34, 39))	('miR-125a-3p', 'Var', (62, 73))	('miR-125a-3p', 'Chemical', '-', (62, 73))
486101	33539420	iSLK-RGB-BAC16 and iSLK-RGB-K9 mutant cells were grown in DMEM supplemented with 10% fetal bovine serum (FBS), 1 mug/ml puromycin, 250 mug/ml G418, and 1.2 mg/ml hygromycin B.	('iSLK-RGB-K9', 'Gene', (19, 30))	('mutant', 'Var', (31, 37))	('DMEM', 'Chemical', '-', (58, 62))
486120	33539420	By incubating 1x107 iSLK-RGB-BAC16 and iSLK-RGB-K9 mutant cells with Doxycycline (Dox) (1 mug/ml) and sodium butyrate (NaB) (1 mM) for 4-5 day, the supernatant was collected by ultracentrifugation (25, 000 g at 4 C for 3 h) using SW32 Ti rotor (Beckman Coulter Inc, USA).	('iSLK-RGB-K9', 'Gene', (39, 50))	('Doxycycline', 'Chemical', 'MESH:D004318', (69, 80))	('SW32', 'CellLine', 'CVCL:E445', (230, 234))	('Dox', 'Chemical', 'MESH:D004318', (69, 72))	('mutant', 'Var', (51, 57))	('sodium butyrate', 'Chemical', 'MESH:D020148', (102, 117))	('Dox', 'Chemical', 'MESH:D004318', (82, 85))	('NaB', 'Chemical', '-', (119, 122))
486128	33539420	RT-qPCR was employed to detect the target mRNAs or miR-125a-3p.	('miR-125a-3p', 'Chemical', '-', (51, 62))	('miR-125a-3p', 'Var', (51, 62))	('mRNAs', 'Var', (42, 47))
486157	32155762	DNA Methylation Profiling for Diagnosing Undifferentiated Sarcoma with Capicua Transcriptional Receptor (CIC) Alterations Undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors in the pediatric population.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('Undifferentiated Sarcoma', 'Disease', (41, 65))	('sarcomas', 'Disease', (151, 159))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('CIC', 'Gene', '23152', (105, 108))	('tumors', 'Disease', (202, 208))	('CIC', 'Gene', (105, 108))	('Alterations', 'Var', (110, 121))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (139, 159))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('Sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
486159	32155762	A subgroup of recently identified soft tissue sarcomas with undifferentiated round cell morphology was characterized by Capicua transcriptional receptor (CIC) rearrangements.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (34, 54))	('Capicua transcriptional receptor', 'Gene', (120, 152))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('CIC', 'Gene', '23152', (154, 157))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('CIC', 'Gene', (154, 157))	('rearrangements', 'Var', (159, 173))	('Capicua transcriptional receptor', 'Gene', '23152', (120, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('sarcomas', 'Disease', (46, 54))
486171	32155762	An advance in the diagnosis of Ewing's sarcoma was the discovery of recurrent, highly-specific balanced translocations leading to a chimeric gene fusion involving the RNA-binding TET (translocated in liposarcoma/Ewing sarcoma breakpoint region 1/TATA box binding protein-associated factor) gene family members, mainly EWSR1, and members of the E26 transformation-specific (ETS) gene family.	('chimeric', 'Var', (132, 140))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	("Ewing's sarcoma", 'Disease', (31, 46))	('TET', 'Chemical', 'MESH:C010349', (179, 182))	('sarcoma', 'Disease', (39, 46))	('EWSR1', 'Gene', '2130', (318, 323))	('sarcoma', 'Disease', 'MESH:D012509', (204, 211))	('translocations', 'Var', (104, 118))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (212, 225))	('sarcoma', 'Disease', (204, 211))	('leading to', 'Reg', (119, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('liposarcoma', 'Phenotype', 'HP:0012034', (200, 211))	('sarcoma', 'Disease', 'MESH:D012509', (218, 225))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (31, 46))	('Ewing sarcoma breakpoint region 1', 'Gene', (212, 245))	('EWSR1', 'Gene', (318, 323))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('sarcoma', 'Disease', (218, 225))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (31, 46))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (212, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))
486173	32155762	Far rarer are other gene fusions involving different TET (FUS) and ETS family members (ETV1/4, FEV, and E1A-F) and rearrangements of EWSR1 with non-ETS family genes (including NFATc2, PATZ1, SMARCA5, and SP3), which occur in fewer than 1% of ES.	('ES', 'Disease', 'MESH:C563168', (242, 244))	('E1A-F', 'Gene', '2118', (104, 109))	('NFATc2', 'Gene', '4773', (176, 182))	('FUS', 'Gene', '2521', (58, 61))	('SP3', 'Gene', '6670', (204, 207))	('PATZ1', 'Gene', '23598', (184, 189))	('PATZ1', 'Gene', (184, 189))	('SMARCA5', 'Gene', (191, 198))	('EWSR1', 'Gene', '2130', (133, 138))	('E1A-F', 'Gene', (104, 109))	('ETV1', 'Gene', (87, 91))	('rearrangements', 'Var', (115, 129))	('NFATc2', 'Gene', (176, 182))	('EWSR1', 'Gene', (133, 138))	('FUS', 'Gene', (58, 61))	('ETV1', 'Gene', '2115', (87, 91))	('SMARCA5', 'Gene', '8467', (191, 198))	('SP3', 'Gene', (204, 207))	('TET', 'Chemical', 'MESH:C010349', (53, 56))
486177	32155762	These are Ewing-like sarcomas most commonly harboring CIC and BCL6 Corepressor (BCOR) rearrangements.	('Ewing-like sarcomas', 'Disease', (10, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('harboring', 'Reg', (44, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('CIC', 'Gene', '23152', (54, 57))	('BCOR', 'Gene', (80, 84))	('BCL6 Corepressor', 'Gene', '54880', (62, 78))	('rearrangements', 'Var', (86, 100))	('BCOR', 'Gene', '54880', (80, 84))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (10, 29))	('CIC', 'Gene', (54, 57))	('BCL6 Corepressor', 'Gene', (62, 78))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (10, 29))
486214	32155762	CIC rearranged tumors are characterized by fusions involving CIC, a human homolog of Drosophila Capicua located on chromosome 19q13.2 and encoding a transcriptional repressor, functioning downstream of tyrosine kinase receptor signaling.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('human', 'Species', '9606', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('Drosophila', 'Species', '7227', (85, 95))	('fusions', 'Var', (43, 50))	('CIC', 'Gene', '23152', (61, 64))	('Capicua', 'Gene', (96, 103))	('Capicua', 'Gene', '53560', (96, 103))	('CIC', 'Gene', '23152', (0, 3))	('CIC', 'Gene', (61, 64))	('CIC', 'Gene', (0, 3))	('tumors', 'Disease', (15, 21))
486216	32155762	identified the molecular feature characterizing these tumors:the CIC-DUX4 (double-homeobox 4) chimeric protein resulting from this translocation in a report of two adult patients.	('patients', 'Species', '9606', (170, 178))	('CIC', 'Gene', (65, 68))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('DUX4', 'Gene', (69, 73))	('DUX4', 'Gene', '100288687', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('double-homeobox 4', 'Gene', '100288687', (75, 92))	('translocation', 'Var', (131, 144))	('CIC', 'Gene', '23152', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('double-homeobox 4', 'Gene', (75, 92))	('tumors', 'Disease', (54, 60))
486217	32155762	The CIC-DUX4 fusion most often results from either t(4;19(q35;q13) or, less frequently, from t(10;19)(q26;q13), the latter involving the DUX4 paralog DUX4L.	('DUX4', 'Gene', (150, 154))	('t(4;19(q35;q13', 'Var', (51, 65))	('DUX4', 'Gene', '100288687', (137, 141))	('DUX4L', 'Gene', '100288687', (150, 155))	('DUX4L', 'Gene', (150, 155))	('DUX4', 'Gene', '100288687', (150, 154))	('results from', 'Reg', (31, 43))	('DUX4', 'Gene', (8, 12))	('CIC', 'Gene', '23152', (4, 7))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (93, 110))	('DUX4', 'Gene', '100288687', (8, 12))	('DUX4', 'Gene', (137, 141))	('CIC', 'Gene', (4, 7))
486219	32155762	They encode for double-homeobox transcription factor typically expressed in germ cells as well as in the human testis, but epigenetically silenced by methylation in differentiated cells.	('encode', 'Reg', (5, 11))	('human', 'Species', '9606', (105, 110))	('double-homeobox transcription factor', 'Protein', (16, 52))	('epigenetically', 'Var', (123, 137))
486220	32155762	No significant clinical-pathologic differences have been reported between tumors harboring the t(4;19) versus the t(10;19).	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('t(4;19', 'Var', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
486222	32155762	Such genetic rearrangement increases the transcriptional activity of CIC.	('CIC', 'Gene', (69, 72))	('transcriptional activity', 'MPA', (41, 65))	('genetic rearrangement', 'Var', (5, 26))	('increases', 'PosReg', (27, 36))	('CIC', 'Gene', '23152', (69, 72))
486229	32155762	Conversely, transcriptomes of CIC-DUX4 fusion and other CIC rearranged sarcomas compared with ES family of tumors (ESFTs) with EWSR1-ETS fusions show little overlap in differentially expressed genes, supporting the distinction of these tumors from ESFTs.	('EWSR1', 'Gene', (127, 132))	('CIC', 'Gene', (56, 59))	('DUX4', 'Gene', '100288687', (34, 38))	('differentially expressed genes', 'MPA', (168, 198))	('CIC', 'Gene', (30, 33))	('sarcomas', 'Disease', 'MESH:D012509', (71, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('sarcomas', 'Disease', (71, 79))	('ES', 'Disease', 'MESH:C563168', (115, 117))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('ES', 'Disease', 'MESH:C563168', (248, 250))	('CIC', 'Gene', '23152', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CIC', 'Gene', '23152', (30, 33))	('tumors', 'Disease', (107, 113))	('EWSR1', 'Gene', '2130', (127, 132))	('fusions', 'Var', (137, 144))	('ES', 'Disease', 'MESH:C563168', (94, 96))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('DUX4', 'Gene', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
486231	32155762	The authors generated a mouse model expressing the human CIC-DUX4 fusion gene (mCDS) and compared the gene expression profile of the mCDS mutant mice with that of mice with classic ES (mES).	('mouse', 'Species', '10090', (24, 29))	('DUX4', 'Gene', (61, 65))	('DUX4', 'Gene', '100288687', (61, 65))	('mutant', 'Var', (138, 144))	('CIC', 'Gene', '23152', (57, 60))	('mES', 'Chemical', '-', (185, 188))	('human', 'Species', '9606', (51, 56))	('mice', 'Species', '10090', (163, 167))	('ES', 'Disease', 'MESH:C563168', (181, 183))	('mice', 'Species', '10090', (145, 149))	('CIC', 'Gene', (57, 60))	('ES', 'Disease', 'MESH:C563168', (186, 188))
486243	32155762	MRI studies of CIC rearranged sarcomas usually show tumor originating from the deep soft tissues of the trunk, pelvis, or proximal extremities with heterogeneous but intense post-contrast enhancement, as in the present case.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CIC', 'Gene', '23152', (15, 18))	('tumor', 'Disease', (52, 57))	('rearranged', 'Var', (19, 29))	('sarcomas', 'Disease', (30, 38))	('CIC', 'Gene', (15, 18))	('sarcomas', 'Disease', 'MESH:D012509', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
486254	32155762	Of note, nuclear WT1 positivity is also found in desmoplastic small round cell tumor and Wilms tumor, which should be considered in morphologic differential diagnosis.	('positivity', 'Var', (21, 31))	('WT1', 'Gene', '7490', (17, 20))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (49, 84))	('WT1', 'Gene', (17, 20))	('Wilms tumor', 'Phenotype', 'HP:0002667', (89, 100))	('Wilms tumor', 'Disease', (89, 100))	('found', 'Reg', (40, 45))	('Wilms tumor', 'Disease', 'MESH:D009396', (89, 100))	('desmoplastic small round cell tumor', 'Disease', (49, 84))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
486268	32155762	SBRCTs with CIC-DUX4 fusion have been shown to upregulate ETS transcription factors (ETV1 on chromosome 7p, ETV4 on chromosome 17q, ETV5 on chromosome 3q).	('CIC', 'Gene', '23152', (12, 15))	('DUX4', 'Gene', '100288687', (16, 20))	('ETV5', 'Gene', (132, 136))	('upregulate', 'PosReg', (47, 57))	('ETV1', 'Gene', (85, 89))	('ETV1', 'Gene', '2115', (85, 89))	('CIC', 'Gene', (12, 15))	('fusion', 'Var', (21, 27))	('ETV4', 'Gene', (108, 112))	('ETV4', 'Gene', '2118', (108, 112))	('DUX4', 'Gene', (16, 20))	('ETV5', 'Gene', '2119', (132, 136))
486274	32155762	It takes advantage of the concept that the epigenetic signature in cancer is a combination of both somatically acquired DNA methylation changes and features that reflect the tumor cell origin in a lineage-dependent manner.	('tumor', 'Disease', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('epigenetic', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
486277	32155762	In cancer, alteration in DNA methylation patterns can both transcriptionally inactivate tumor suppressors and increase oncogenes expression, sustaining tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('increase', 'PosReg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('sustaining', 'PosReg', (141, 151))	('inactivate', 'NegReg', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', (152, 157))	('cancer', 'Disease', (3, 9))	('alteration', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('oncogenes expression', 'MPA', (119, 139))	('tumor', 'Disease', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
486287	32155762	For cases assigned to the SBRCTs with CIC alterations, methylation class was verified by additional FISH and total RNA sequencing.	('CIC', 'Gene', (38, 41))	('CIC', 'Gene', '23152', (38, 41))	('alterations', 'Var', (42, 53))
486338	30128716	This patient had biopsy-proven metastatic synovial sarcoma with a known SS18/SSX1 fusion gene on molecular testing of the primary lesion.	('patient', 'Species', '9606', (5, 12))	('SS18', 'Gene', (72, 76))	('synovial sarcoma', 'Disease', 'MESH:D013584', (42, 58))	('SSX1', 'Gene', '6756', (77, 81))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (42, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('SSX1', 'Gene', (77, 81))	('fusion gene', 'Var', (82, 93))	('SS18', 'Gene', '6760', (72, 76))	('synovial sarcoma', 'Disease', (42, 58))
486365	28928879	Multivariate and univariate Cox proportional hazard model was used to assess for correlation of SUV1, SUV2, and the change in SUVmax with overall survival (OS) and progression-free survival (PFS).	('overall survival', 'CPA', (138, 154))	('SUVmax', 'Gene', (126, 132))	('OS', 'Chemical', '-', (156, 158))	('progression-free', 'CPA', (164, 180))	('change', 'Var', (116, 122))
486367	28928879	SUV1 higher than 11.6 had significantly worse OS (HR = 5.71, 95% CI: 1.85 - 17.61, P = 0.003) and PFS (HR = 3.16, 95% CI: 1.13 - 8.79, P = 0.03, P < 0.05 is significant).	('SUV1', 'Gene', (0, 4))	('higher', 'Var', (5, 11))	('PFS', 'CPA', (98, 101))	('OS', 'Chemical', '-', (46, 48))	('worse', 'NegReg', (40, 45))
486395	28928879	Univariate Cox proportional hazard model was used to assess effects of SUV1, SUV2, and the change of SUVmax on overall survival (OS) and progression-free survival (PFS).	('OS', 'Chemical', '-', (129, 131))	('progression-free survival', 'CPA', (137, 162))	('change', 'Var', (91, 97))	('SUVmax', 'Gene', (101, 107))
486415	28928879	A high SUV1 was associated with worse OS (1 unit increase HR = 1.05, 95% CI: 1.0-1.1, P = 0.01) and a high SUV2 was associated with worse OS (1 unit increase HR =1.2, 95% CI: 1.0-1.4, P = 0.01).	('high', 'Var', (102, 106))	('high', 'Var', (2, 6))	('OS', 'Chemical', '-', (138, 140))	('worse OS', 'Disease', (32, 40))	('worse OS', 'Disease', (132, 140))	('OS', 'Chemical', '-', (38, 40))
486418	28928879	Patients with SUV1 higher than 11.6 had significantly worse OS (HR = 5.71, 95% CI: 1.85 - 17.61, P = 0.003) and PFS (HR = 3.16, 95% CI: 1.13 - 8.79, P = 0.03) compared to those with lower SUV1 (Figure 3).	('higher', 'Var', (19, 25))	('PFS', 'CPA', (112, 115))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (60, 62))	('worse', 'NegReg', (54, 59))
486420	28928879	When the same factors were analyzed with SUV1, we found that patients who had SUV1 higher than 11.6 were significantly older than those with lower SUV1 (P = 0.008).	('higher than 11.6', 'Var', (83, 99))	('SUV1', 'Gene', (78, 82))	('patients', 'Species', '9606', (61, 69))
486421	28928879	Multivariate analysis showed that high SUV1 was significantly associated with worse OS after adjusting for age effect (P=0.02).	('worse OS', 'Disease', (78, 86))	('high', 'Var', (34, 38))	('SUV1', 'Gene', (39, 43))	('OS', 'Chemical', '-', (84, 86))
486423	28928879	High SUV1 was associated with worse OS (P = 0.01), and high SUV2 was also associated with worse OS (P = 0.01).	('High SUV1', 'Var', (0, 9))	('OS', 'Chemical', '-', (36, 38))	('high', 'Var', (55, 59))	('OS', 'Chemical', '-', (96, 98))
486488	27277260	In simple (unadjusted) analyses, older age, malignant consensus US diagnosis and greater lesion volume were all associated with significantly higher odds of confirmed malignancy.	('malignancy', 'Disease', (167, 177))	('malignant', 'Var', (44, 53))	('malignancy', 'Disease', 'MESH:D009369', (167, 177))
486493	27277260	Five of these were found to be grade 1 liposarcomas with normal histology but with cytogenetic analysis confirming MDM2 amplification.	('liposarcomas', 'Disease', 'MESH:D008080', (39, 51))	('liposarcomas', 'Phenotype', 'HP:0012034', (39, 51))	('liposarcomas', 'Disease', (39, 51))	('amplification', 'Var', (120, 133))	('MDM2', 'Gene', '4193', (115, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('MDM2', 'Gene', (115, 119))
486709	28669098	Chest radiation [relative risk (RR): 1.88 (95% confidence interval [CI]: 1.21-2.92, p < 0.005,)] and rib resection [RR: 2.64 (CI: 1.79-3.89), p < 0.0001] were associated with an increased incidence of scoliosis; thoracotomy without rib resection was not.	('scoliosis', 'Phenotype', 'HP:0002650', (201, 210))	('scoliosis', 'Disease', 'MESH:D012600', (201, 210))	('scoliosis', 'Disease', (201, 210))	('rib resection', 'Var', (101, 114))
486764	28669098	In adjusted models, when compared to no thoracic procedure or thoracoscopy alone, rib resection [RR: 2.64 (95% CI: 1.79-3.89)] was associated with an increased risk of developing scoliosis.	('scoliosis', 'Disease', 'MESH:D012600', (179, 188))	('scoliosis', 'Disease', (179, 188))	('rib resection', 'Var', (82, 95))	('scoliosis', 'Phenotype', 'HP:0002650', (179, 188))
486790	28669098	In our study, while rib resections were associated with an increased risk of developing scoliosis, thoracotomy alone (without the resection of a rib) was not associated with the long-term development of scoliosis.	('scoliosis', 'Disease', 'MESH:D012600', (203, 212))	('scoliosis', 'Disease', (203, 212))	('scoliosis', 'Phenotype', 'HP:0002650', (88, 97))	('resections', 'Var', (24, 34))	('scoliosis', 'Phenotype', 'HP:0002650', (203, 212))	('scoliosis', 'Disease', 'MESH:D012600', (88, 97))	('scoliosis', 'Disease', (88, 97))
486832	28030800	In 85% of cases the t(11;22)(q24;q12) translocation combines EWSR1 (Ewing Sarcoma breakpoint region 1) on chromosome 22 with FLI1 (Friend leukaemia virus integration site 1) on chromosome 11.	('EWSR1', 'Gene', '2130', (61, 66))	('Ewing Sarcoma breakpoint region 1', 'Gene', (68, 101))	('FLI1', 'Gene', '2313', (125, 129))	('t(11;22)(q24;q12', 'Var', (20, 36))	('FLI1', 'Gene', (125, 129))	('Friend leukaemia virus integration site 1', 'Gene', (131, 172))	('Ewing Sarcoma breakpoint region 1', 'Gene', '2130', (68, 101))	('Friend leukaemia virus integration site 1', 'Gene', '2313', (131, 172))	('Sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('EWSR1', 'Gene', (61, 66))
486836	28030800	As a consequence of imperfect base pairing of the miRNA to its seed region, a single miRNA can regulate many different target mRNAs resulting in a complex network of miRNAs and their targets.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('regulate', 'Reg', (95, 103))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('imperfect', 'Var', (20, 29))	('miR', 'Gene', '220972', (166, 169))	('base pairing', 'MPA', (30, 42))	('miR', 'Gene', (166, 169))
486840	28030800	In addition, the activity of an expressed miRNA on a putative target mRNA depends on their relative abundances in comparison to other co-expressed putative target mRNAs in a tissue specific manner, and several expressed pseudogenes and non-coding RNAs may act as competing endogenous RNA (ceRNA) for miRNA function.	('pseudogenes', 'Var', (220, 231))	('miR', 'Gene', '220972', (300, 303))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('activity', 'MPA', (17, 25))	('miR', 'Gene', (300, 303))
486854	28030800	In addition, conditional knockdown of EWS-FLI1 in the EwS cell line A673/TR/shEF revealed co-regulation of the entire set of miRNAs of the hsa-miR-17-92 cluster.	('miR-17-92', 'Gene', (143, 152))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', (143, 146))	('hsa-miR-17', 'Gene', (139, 149))	('EwS', 'Gene', '2130', (54, 57))	('co-regulation', 'MPA', (90, 103))	('miR', 'Gene', '220972', (125, 128))	('miR-17-92', 'Gene', '407975', (143, 152))	('miR', 'Gene', (125, 128))	('EWS-FLI1', 'Gene', (38, 46))	('EwS', 'Gene', (54, 57))	('knockdown', 'Var', (25, 34))	('hsa-miR-17', 'Gene', '406952', (139, 149))
486858	28030800	The whole cluster is among the small number of miRNAs down-regulated upon knockdown of EWS-FLI1 in multiple EwS cell lines.	('EwS', 'Gene', '2130', (108, 111))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('knockdown', 'Var', (74, 83))	('EwS', 'Gene', (108, 111))	('EWS-FLI1', 'Gene', (87, 95))	('down-regulated', 'NegReg', (54, 68))
486862	28030800	Previously, we assessed miRNA expression on a qPCR platform in five EwS cell lines following sh-RNA mediated knockdown of EWS-FLI1.	('EwS', 'Gene', (68, 71))	('EWS-FLI1', 'Gene', (122, 130))	('knockdown', 'Var', (109, 118))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('EwS', 'Gene', '2130', (68, 71))
486863	28030800	This data revealed that members of the hsa-miR-17-92 cluster were among the most highly down-regulated miRNAs after the EWS-FLI1 knockdown.	('miR', 'Gene', '220972', (43, 46))	('hsa-miR-17', 'Gene', '406952', (39, 49))	('miR', 'Gene', (43, 46))	('knockdown', 'Var', (129, 138))	('hsa-miR-17', 'Gene', (39, 49))	('miR-17-92', 'Gene', '407975', (43, 52))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('miR-17-92', 'Gene', (43, 52))	('down-regulated', 'NegReg', (88, 102))
486865	28030800	This finding was corroborated in A673/TR/shEF EwS cells by miR-seq after doxycycline inducible knockdown of EWS-FLI1 (Figure 1, Supplementary Table S1).	('doxycycline', 'Chemical', 'MESH:D004318', (73, 84))	('miR', 'Gene', '220972', (59, 62))	('EwS', 'Gene', '2130', (46, 49))	('knockdown', 'Var', (95, 104))	('miR', 'Gene', (59, 62))	('EwS', 'Gene', (46, 49))	('EWS-FLI1', 'Gene', (108, 116))
486870	28030800	This result indicated that the silencing of EWS-FLI1 did not have a large influence on the spectrum of AGO2 binding sites on mRNAs as identified by PAR-CLIP.	('AGO2', 'Gene', '27161', (103, 107))	('silencing', 'Var', (31, 40))	('CLIP', 'Gene', (152, 156))	('EWS-FLI1', 'Gene', (44, 52))	('CLIP', 'Gene', '7461', (152, 156))	('AGO2', 'Gene', (103, 107))
486883	28030800	The intersection of PAR-CLIP and s-alpha-hsa-miR-17-92 overexpression data yielded a list of 87 genes that were up-regulated upon s-alpha-hsa--miR-17-92 treatment and also had a PAR-CLIP hit with a seed sequence matching hsa-miR-17-92 (AAGTGCAT: 8mer for hsa-miR-18a-5p, hsa-miR-18b-5p, AAAGTGC: 7mer for miR-17-5p, hsa-miR-20a-5p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-miR-20b-5p) (Supplementary Table S4, Sheet2).	('miR', 'Gene', '220972', (259, 262))	('CLIP', 'Gene', '7461', (182, 186))	('miR-17-92', 'Gene', (143, 152))	('hsa-miR-18b', 'Gene', (271, 282))	('miR', 'Gene', '220972', (353, 356))	('miR', 'Gene', '220972', (370, 373))	('hsa-miR-17', 'Gene', (221, 231))	('miR', 'Gene', (45, 48))	('miR', 'Gene', '220972', (320, 323))	('miR', 'Gene', (275, 278))	('hsa-miR-18a', 'Gene', '406953', (255, 266))	('miR-17-5p', 'Gene', '406952', (305, 314))	('miR', 'Gene', (305, 308))	('miR-17-5p', 'Gene', (305, 314))	('hsa-miR-17', 'Gene', '406952', (221, 231))	('miR', 'Gene', (259, 262))	('miR', 'Gene', '220972', (225, 228))	('miR', 'Gene', (353, 356))	('miR-17-92', 'Gene', (45, 54))	('hsa-miR-20a', 'Gene', (316, 327))	('hsa-miR-18b', 'Gene', '574033', (271, 282))	('miR', 'Gene', '220972', (336, 339))	('hsa-miR-18a', 'Gene', (255, 266))	('miR', 'Gene', (370, 373))	('miR-106a', 'Gene', (336, 344))	('hsa-miR-20a', 'Gene', '406982', (316, 327))	('miR-17-92', 'Gene', (225, 234))	('miR', 'Gene', (320, 323))	('s-alpha-hsa', 'Var', (130, 141))	('CLIP', 'Gene', (24, 28))	('miR-17-92', 'Gene', '407975', (143, 152))	('miR', 'Gene', (225, 228))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', (336, 339))	('CLIP', 'Gene', (182, 186))	('hsa-miR-17', 'Gene', (41, 51))	('CLIP', 'Gene', '7461', (24, 28))	('miR-17-92', 'Gene', '407975', (45, 54))	('miR-17-92', 'Gene', '407975', (225, 234))	('miR', 'Gene', (143, 146))	('miR-106a', 'Gene', '406899', (336, 344))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', '220972', (275, 278))	('up-regulated', 'PosReg', (112, 124))	('hsa-miR-17', 'Gene', '406952', (41, 51))	('miR', 'Gene', '220972', (305, 308))
486896	28030800	To further validate the specific effect of hsa-miR-17-92 on the 3'UTRs of these known and novel targets, we mutated the miRNA seed sequences in CTGF and FOSL2 (Figure 4A).	('hsa-miR-17', 'Gene', '406952', (43, 53))	('mutated', 'Var', (108, 115))	('CTGF', 'Gene', (144, 148))	('FOSL2', 'Gene', (153, 158))	('FOSL2', 'Gene', '2355', (153, 158))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (47, 50))	('miR', 'Gene', (120, 123))	('miR-17-92', 'Gene', '407975', (47, 56))	('hsa-miR-17', 'Gene', (43, 53))	('miR-17-92', 'Gene', (47, 56))	('CTGF', 'Gene', '1490', (144, 148))
486897	28030800	Mutation of the hsa-miR-18ab/19ab seed sequences (identified by PAR-CLIP) in the CTGF 3'UTR caused on average a 40 fold induction of luciferase activity.	('hsa-miR-18a', 'Gene', '406953', (16, 27))	('induction', 'PosReg', (120, 129))	('Mutation', 'Var', (0, 8))	('luciferase', 'Enzyme', (133, 143))	('CLIP', 'Gene', (68, 72))	('CLIP', 'Gene', '7461', (68, 72))	('CTGF', 'Gene', '1490', (81, 85))	('hsa-miR-18a', 'Gene', (16, 27))	('activity', 'MPA', (144, 152))	('CTGF', 'Gene', (81, 85))
486901	28030800	Similar results were obtained with wildtype and miRNA seed sequence mutated 40mer oligonucleotides cloned in pmirGLO (Figure 4B).	('miR', 'Gene', (48, 51))	('mutated', 'Var', (68, 75))	('miR', 'Gene', '220972', (48, 51))
486903	28030800	Mutations at both sites raised reporter activity, yet only the increase obtained by destruction of the hsa-miR-19ab seed sequence achieved significance.	('reporter activity', 'MPA', (31, 48))	('hsa-miR-19a', 'Gene', '406979', (103, 114))	('hsa-miR-19a', 'Gene', (103, 114))	('Mutations', 'Var', (0, 9))	('raised', 'PosReg', (24, 30))
486904	28030800	In the 3'UTR of GBP3 neither mutation of the hsa-miR-148 seed (predicted by TargetScan), nor the hsa-miR-17/20a seed sequence displaying AGO2 interaction in PAR-CLIP affected luciferase activity.	('mutation', 'Var', (29, 37))	('hsa-miR-17', 'Gene', '406952', (97, 107))	('affected', 'Reg', (166, 174))	('AGO2', 'Gene', (137, 141))	('CLIP', 'Gene', '7461', (161, 165))	('activity', 'MPA', (186, 194))	('luciferase', 'Enzyme', (175, 185))	('hsa-miR-148', 'Gene', (45, 56))	('GBP3', 'Gene', '2635', (16, 20))	('hsa-miR-17', 'Gene', (97, 107))	('AGO2', 'Gene', '27161', (137, 141))	('hsa-miR-148', 'Gene', '406940', (45, 56))	('CLIP', 'Gene', (161, 165))	('GBP3', 'Gene', (16, 20))
486905	28030800	Unlike the minor increase in signal intensity of the 3'UTR fragment of BAMBI with s-alpha- hsa-miR-17-92, destruction of the hsa-miR-19ab recognition site identified by PAR-CLIP caused a significant 15fold increase in luciferase activity.	('BAMBI', 'Gene', '25805', (71, 76))	('destruction', 'Var', (106, 117))	('luciferase', 'Enzyme', (218, 228))	('hsa-miR-17', 'Gene', '406952', (91, 101))	('hsa-miR-19a', 'Gene', '406979', (125, 136))	('activity', 'MPA', (229, 237))	('CLIP', 'Gene', (173, 177))	('BAMBI', 'Gene', (71, 76))	('hsa-miR-19a', 'Gene', (125, 136))	('hsa-miR-17', 'Gene', (91, 101))	('CLIP', 'Gene', '7461', (173, 177))	('miR-17-92', 'Gene', '407975', (95, 104))	('miR-17-92', 'Gene', (95, 104))	('increase', 'PosReg', (206, 214))
486906	28030800	Again mutation of a hsa-miR-17/20a seed sequence predicted by TargetScan but not detected by PAR-CLIP did not alter luciferase signal intensity.	('CLIP', 'Gene', '7461', (97, 101))	('CLIP', 'Gene', (97, 101))	('signal intensity', 'MPA', (127, 143))	('mutation', 'Var', (6, 14))	('hsa-miR-17', 'Gene', '406952', (20, 30))	('luciferase', 'Enzyme', (116, 126))	('hsa-miR-17', 'Gene', (20, 30))
486907	28030800	In line with these results mutation of a hsa-miR-17/20a PAR-CLIP seed sequence in the 3'UTR of RUNX3 increased luciferase activity by approximately 7 fold, whereas mutation of a hsa-miR-17/20a and a hsa-miR-19ab exclusively TargetScan defined seed sequence did not significantly increase luciferase activity.	('hsa-miR-17', 'Gene', (178, 188))	('luciferase', 'Enzyme', (111, 121))	('hsa-miR-19a', 'Gene', '406979', (199, 210))	('increased', 'PosReg', (101, 110))	('hsa-miR-19a', 'Gene', (199, 210))	('mutation', 'Var', (27, 35))	('hsa-miR-17', 'Gene', '406952', (178, 188))	('activity', 'MPA', (122, 130))	('CLIP', 'Gene', (60, 64))	('CLIP', 'Gene', '7461', (60, 64))	('hsa-miR-17', 'Gene', '406952', (41, 51))	('RUNX3', 'Gene', (95, 100))	('hsa-miR-17', 'Gene', (41, 51))	('RUNX3', 'Gene', '864', (95, 100))
486923	28030800	Despite a significant overlap between target spectra obtained from three independent PAR-CLIP experiments, there was considerable quantitative variation in read counts unrelated to presence and absence of EWS-FLI1, which we and others had previously demonstrated to shape the EwS miRNome.	('miR', 'Gene', (280, 283))	('EWS-FLI1', 'Gene', (205, 213))	('CLIP', 'Gene', '7461', (89, 93))	('absence', 'Var', (194, 201))	('EwS', 'Gene', '2130', (276, 279))	('EwS', 'Gene', (276, 279))	('CLIP', 'Gene', (89, 93))	('miR', 'Gene', '220972', (280, 283))
486929	28030800	By mutation analysis of miRNA seed sequences in reporter gene assays performed for a series of newly identified hsa-miR-17-92 targets, we functionally validated their regulation via miRNA interaction sites characterized by PAR-CLIP.	('miR-17-92', 'Gene', (116, 125))	('CLIP', 'Gene', '7461', (227, 231))	('hsa-miR-17', 'Gene', '406952', (112, 122))	('miR', 'Gene', '220972', (182, 185))	('miR', 'Gene', (182, 185))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', (116, 119))	('mutation', 'Var', (3, 11))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('hsa-miR-17', 'Gene', (112, 122))	('miR-17-92', 'Gene', '407975', (116, 125))	('CLIP', 'Gene', (227, 231))
486939	28030800	Here, activation of hsa-miR-17-92 caused an increase in TGF-beta receptor 2 (TGFBR2), SMAD2 and SMAD4 expression levels, and mutations of the corresponding seed sequences indicate that hsa-miR-17 and hsa-miR-20a directly target TGFBR2, whereas hsa-miR-18a was found to modulate SMAD2 and SMAD4.	('miR-17-92', 'Gene', '407975', (24, 33))	('hsa-miR-17', 'Gene', (20, 30))	('expression levels', 'MPA', (102, 119))	('SMAD4', 'Gene', '4089', (288, 293))	('SMAD4', 'Gene', '4089', (96, 101))	('SMAD2', 'Gene', '4087', (278, 283))	('hsa-miR-17', 'Gene', '406952', (20, 30))	('increase', 'PosReg', (44, 52))	('hsa-miR-17', 'Gene', (185, 195))	('mutations', 'Var', (125, 134))	('TGFBR2', 'Gene', '7048', (228, 234))	('TGFBR2', 'Gene', '7048', (77, 83))	('SMAD2', 'Gene', (278, 283))	('SMAD2', 'Gene', '4087', (86, 91))	('hsa-miR-17', 'Gene', '406952', (185, 195))	('TGF-beta receptor 2', 'Gene', '7048', (56, 75))	('hsa-miR-18a', 'Gene', '406953', (244, 255))	('miR-17-92', 'Gene', (24, 33))	('TGF-beta receptor 2', 'Gene', (56, 75))	('SMAD2', 'Gene', (86, 91))	('hsa-miR-20a', 'Gene', (200, 211))	('SMAD4', 'Gene', (288, 293))	('TGFBR2', 'Gene', (228, 234))	('hsa-miR-18a', 'Gene', (244, 255))	('hsa-miR-20a', 'Gene', '406982', (200, 211))	('TGFBR2', 'Gene', (77, 83))	('activation', 'PosReg', (6, 16))	('SMAD4', 'Gene', (96, 101))
486949	28030800	By contrast, we observed cell autonomous constitutive SMAD1 phosphorylation resulting in activation of ID1 and ID3 transcriptional repressors.	('ID1', 'Gene', (103, 106))	('SMAD1', 'Gene', (54, 59))	('ID3', 'Gene', (111, 114))	('phosphorylation', 'Var', (60, 75))	('activation', 'PosReg', (89, 99))	('SMAD1', 'Gene', '4086', (54, 59))	('ID3', 'Gene', '3399', (111, 114))	('ID1', 'Gene', '3397', (103, 106))
486961	28030800	Taken together, our data suggest a model in which EWS-FLI1 directly represses TGFB signaling via transcriptional down-regulation of TGFBR2 and of down-stream targets via post-transcriptional regulation by miRNA cluster 17-92, whereas the same miRNAs inhibit BAMBI, potentially re-routing signaling from the TGFB to the BMP pathway.	('miR', 'Gene', (205, 208))	('miR', 'Gene', '220972', (243, 246))	('TGFBR2', 'Gene', (132, 138))	('miR', 'Gene', (243, 246))	('BMP', 'Gene', '649', (319, 322))	('BAMBI', 'Gene', (258, 263))	('represses', 'NegReg', (68, 77))	('TGFB', 'Gene', (78, 82))	('inhibit', 'NegReg', (250, 257))	('BAMBI', 'Gene', '25805', (258, 263))	('TGFB', 'Gene', (132, 136))	('TGFB', 'Gene', '7040', (78, 82))	('TGFB', 'Gene', (307, 311))	('BMP', 'Gene', (319, 322))	('EWS-FLI1', 'Var', (50, 58))	('TGFBR2', 'Gene', '7048', (132, 138))	('miR', 'Gene', '220972', (205, 208))	('TGFB', 'Gene', '7040', (132, 136))	('TGFB', 'Gene', '7040', (307, 311))	('down-regulation', 'NegReg', (113, 128))
486969	28030800	MiR seed sequences in the FOSL2 and CTGF 3'UTR were mutated using QuikChange  II Site-Directed Mutagenesis Kit (Stratagene, La Jolla, USA, 200523) according to manufacturer's instructions.	('MiR', 'Gene', (0, 3))	('MiR', 'Gene', '220972', (0, 3))	('mutated', 'Var', (52, 59))	('CTGF', 'Gene', '1490', (36, 40))	('FOSL2', 'Gene', '2355', (26, 31))	('FOSL2', 'Gene', (26, 31))	('CTGF', 'Gene', (36, 40))
486970	28030800	Oligonucleotides containing either wildtype or mutated miRNA seed sequences for FOSL2, SERPINE1, BAMBI, GBP3 and RUNX3 were directly cloned into the pmirGLO vector (Promega).	('RUNX3', 'Gene', (113, 118))	('Oligonucleotides', 'Chemical', 'MESH:D009841', (0, 16))	('GBP3', 'Gene', '2635', (104, 108))	('FOSL2', 'Gene', (80, 85))	('BAMBI', 'Gene', (97, 102))	('SERPINE1', 'Gene', '5054', (87, 95))	('SERPINE1', 'Gene', (87, 95))	('GBP3', 'Gene', (104, 108))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('mutated', 'Var', (47, 54))	('BAMBI', 'Gene', '25805', (97, 102))	('RUNX3', 'Gene', '864', (113, 118))	('FOSL2', 'Gene', '2355', (80, 85))
486979	28030800	Then AGO2 IP took place followed by RNA 3 ends dephosphorylation and linker ligation, RNA 5 ends labelling (32P-gamma-ATP), and SDS-PAGE in a 4-12% NuPAGE Bis-Tris gel (Invitrogen).	('32P', 'Chemical', 'MESH:C000615311', (108, 111))	('AGO2', 'Gene', '27161', (5, 9))	('SDS-PAGE', 'Var', (128, 136))	('Bis-Tris', 'Chemical', 'MESH:C026272', (155, 163))	('gamma-ATP', 'Chemical', '-', (112, 121))	('SDS', 'Chemical', 'MESH:D012967', (128, 131))	('AGO2', 'Gene', (5, 9))
486985	28030800	These quality filtered sequences were aligned with bowtie to human genome version hg19, (bowtie -t -v 2 -m 1 :best :strata :seed 1234 hg19) and the aligned sequences were used as input for the program PARalyzer using the following parameters in the PARalyzer .ini files: BANDWIDTH=3, CONVERSION=T>C, MINIMUM_READ_COUNT_PER_GROUP=5, MINIMUM_READ_COUNT_PER_CLUSTER=5, MINIMUM_READ_COUNT_FOR_KDE=5, MINIMUM_CLUSTER_SIZE=10, MINIMUM_CONVERSION_LOCATIONS_FOR_CLUSTER=1, MINIMUM_CONVERSION_COUNT_FOR_CLUSTER=1, MINIMUM_READ_COUNT_FOR_CLUSTER_INCLUSION=5, MINIMUM_READ_LENGTH=13, #MINIMUM_READ_LENGTH=1, MAXIMUM_NUMBER_OF_NON_CONVERSION_MISMATCHES=0, EXTEND_BY_READ,MAXIMUM_SEED_MATCH_LENGTH=8.	('MAXIMUM_NUMBER_OF_NON_CONVERSION_MISMATCHES=0', 'Var', (597, 642))	('SIZE', 'Disease', 'None', (412, 416))	('human', 'Species', '9606', (61, 66))	('SIZE', 'Disease', (412, 416))
486991	28030800	The following antibodies were used: anti-GAPDH (4300, Ambion, Thermo Fisher Scientifc, Waltham, MA, USA), anti-pSMAD1 (9516 P, Cell Signalling, Danvers, MA, USA), anti-pSMAD2 (3101 S, Cell Signalling) and anti-pSMAD3 antibody (9520 P, Cell Signalling).	('SMAD1', 'Gene', (112, 117))	('GAPDH', 'Gene', '2597', (41, 46))	('9520 P', 'Var', (227, 233))	('4300', 'Var', (48, 52))	('GAPDH', 'Gene', (41, 46))	('SMAD2', 'Gene', '4087', (169, 174))	('SMAD3', 'Gene', '4088', (211, 216))	('SMAD2', 'Gene', (169, 174))	('SMAD1', 'Gene', '4086', (112, 117))	('SMAD3', 'Gene', (211, 216))
487053	26901565	Blockade of CTLA-4 or PD-1 results in pronounced antitumor activity, and monoclonal antibody therapies against these targets improve overall survival in patients with various neoplasias.	('PD-1', 'Gene', (22, 26))	('neoplasias', 'Disease', 'MESH:D009369', (175, 185))	('neoplasias', 'Phenotype', 'HP:0002664', (175, 185))	('neoplasias', 'Disease', (175, 185))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Blockade', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CTLA-4', 'Gene', (12, 18))	('overall survival', 'CPA', (133, 149))	('tumor', 'Disease', (53, 58))	('improve', 'PosReg', (125, 132))
487066	26901565	A CTLA-4 blockade may induce restoration of antitumor immunity against histiocytic sarcoma.	('tumor', 'Disease', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (71, 90))	('CTLA-4', 'Gene', (2, 8))	('histiocytic sarcoma', 'Disease', (71, 90))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('rat', 'Species', '10116', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('blockade', 'Var', (9, 17))
487069	26901565	Recently, a challenging strategy of using antibodies to block the CTLA-4 molecule has emerged, and several studies have demonstrated the effects of CTLA-4 blockade on the induction of tumor immunity and the rejection of tumors not only in animal models but also in human patients.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (220, 225))	('CTLA-4', 'Gene', (148, 154))	('rat', 'Species', '10116', (26, 29))	('tumors', 'Disease', (220, 226))	('human', 'Species', '9606', (265, 270))	('tumor', 'Disease', (184, 189))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('rejection', 'CPA', (207, 216))	('rat', 'Species', '10116', (127, 130))	('blockade', 'Var', (155, 163))	('patients', 'Species', '9606', (271, 279))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
487072	26901565	PD-1 plays an important role in tumor immunity, and blockade of PD-1 could restore antitumor immunity to accelerate tumor eradication in various tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('blockade', 'Var', (52, 60))	('rat', 'Species', '10116', (111, 114))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('restore', 'PosReg', (75, 82))	('PD-1', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumors', 'Disease', (145, 151))	('tumor', 'Disease', (116, 121))	('accelerate', 'PosReg', (105, 115))
487097	32493417	In this set, one case was found to harbor a CREBBP-GOLGA6L2 fusion and one case a CREBBP-SRRM2 fusion.	('fusion', 'Var', (60, 66))	('SRRM2', 'Gene', (89, 94))	('SRRM2', 'Gene', '23524', (89, 94))	('GOLGA6L2', 'Gene', '283685', (51, 59))	('CREBBP', 'Gene', (44, 50))	('GOLGA6L2', 'Gene', (51, 59))	('CREBBP', 'Gene', (82, 88))	('CREBBP', 'Gene', '1387', (44, 50))	('CREBBP', 'Gene', '1387', (82, 88))
487101	32493417	Fusion transcripts are increasingly recognized as important oncogenic drivers in tumors of the central nervous system (CNS).	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (81, 117))	('Fusion transcripts', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (81, 117))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumors of the central nervous system', 'Disease', (81, 117))
487102	32493417	These include KIAA1549-BRAF, typically resulting from tandem duplication and characteristic of pilocytic astrocytoma, C11orf95-RELA in supratentorial ependymoma, and FGFR-TACC (e.g.	('supratentorial ependymoma', 'Disease', (135, 160))	('BRAF', 'Gene', '673', (23, 27))	('pilocytic astrocytoma', 'Disease', (95, 116))	('RELA', 'Gene', (127, 131))	('RELA', 'Gene', '5970', (127, 131))	('KIAA1549', 'Gene', (14, 22))	('C11orf95', 'Gene', (118, 126))	('BRAF', 'Gene', (23, 27))	('KIAA1549', 'Gene', '57670', (14, 22))	('ependymoma', 'Phenotype', 'HP:0002888', (150, 160))	('tandem duplication', 'Var', (54, 72))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (95, 116))	('supratentorial ependymoma', 'Disease', 'MESH:D004806', (135, 160))	('resulting from', 'Reg', (39, 53))	('C11orf95', 'Gene', '65998', (118, 126))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
487104	32493417	Recurrent fusion transcripts have additionally been identified in pediatric infiltrating gliomas, including those involving the MYB and MYBL1 loci.	('identified', 'Reg', (52, 62))	('MYB', 'Gene', (128, 131))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('MYBL1', 'Gene', (136, 141))	('fusion', 'Var', (10, 16))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('MYBL1', 'Gene', '4603', (136, 141))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('MYB', 'Gene', '4602', (136, 139))	('MYB', 'Gene', '4602', (128, 131))	('MYB', 'Gene', (136, 139))
487107	32493417	These tumors, termed "high grade neuroepithelial tumor with BCOR alteration" (HGNET-BCOR), are characterized in most cases by an internal tandem duplication involving exon 15 of the gene.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('BCOR', 'Gene', (84, 88))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (33, 54))	('BCOR', 'Gene', (60, 64))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (33, 54))	('BCOR', 'Gene', '54880', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BCOR', 'Gene', '54880', (60, 64))	('neuroepithelial tumor', 'Disease', (33, 54))	('internal tandem duplication', 'Var', (129, 156))
487108	32493417	Fusion transcripts involving the BCOR gene have also been described in a diversity of tumors extrinsic to the CNS including clear cell sarcoma of the kidney, ossifying fibromyxoid tumors, acute promyelocytic leukemia, endometrial stromal sarcoma (ESS), adult non-uterine sarcoma, and a subset of small blue round cell sarcomas .	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (124, 156))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('sarcoma', 'Disease', (135, 142))	('BCOR', 'Gene', '54880', (33, 37))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (188, 216))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (135, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (318, 325))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('sarcomas', 'Disease', (318, 326))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('BCOR', 'Gene', (33, 37))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', (180, 186))	('sarcoma of the kidney', 'Disease', 'MESH:D012509', (135, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('ossifying fibromyxoid tumors', 'Disease', 'MESH:D018214', (158, 186))	('ossifying fibromyxoid tumors', 'Disease', (158, 186))	('described', 'Reg', (58, 67))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (218, 245))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (263, 278))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('sarcoma', 'Disease', 'MESH:D012509', (271, 278))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (188, 216))	('sarcoma', 'Disease', 'MESH:D012509', (238, 245))	('sarcoma of the kidney', 'Disease', (135, 156))	('sarcoma', 'Disease', (271, 278))	('sarcoma', 'Disease', 'MESH:D012509', (318, 325))	('sarcoma', 'Disease', (238, 245))	('sarcomas', 'Disease', 'MESH:D012509', (318, 326))	('acute promyelocytic leukemia', 'Disease', (188, 216))	('Fusion transcripts', 'Var', (0, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (318, 326))	('sarcoma', 'Disease', (318, 325))	('leukemia', 'Phenotype', 'HP:0001909', (208, 216))	('endometrial stromal sarcoma', 'Disease', (218, 245))
487137	32493417	A targeted next generation sequencing panel (Oncomine v3) revealed truncating mutations in NF1 and ARID1A.	('truncating mutations', 'Var', (67, 87))	('ARID1A', 'Gene', (99, 105))	('NF1', 'Gene', (91, 94))	('NF1', 'Gene', '4763', (91, 94))	('ARID1A', 'Gene', '8289', (99, 105))
487140	32493417	In addition, targeted PCR followed by Sanger sequencing and immunohistochemistry was conducted to rule out mutations of H3F3A at codons 27 and 34.	('H3F3A', 'Gene', (120, 125))	('mutations', 'Var', (107, 116))	('H3F3A', 'Gene', '3020', (120, 125))
487141	32493417	If current recommendations for the adult setting were to be applied, the presence of TERT promoter mutation in combination with an absence of IDH1/IDH2 mutation would be compatible with a diagnosis of diffuse astrocytic glioma, with molecular features of glioblastoma, WHO grade IV.	('TERT', 'Gene', (85, 89))	('presence', 'Var', (73, 81))	('IDH1', 'Gene', '3417', (142, 146))	('glioblastoma', 'Disease', (255, 267))	('TERT', 'Gene', '7015', (85, 89))	('IDH1', 'Gene', (142, 146))	('mutation', 'Var', (99, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (255, 267))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('IDH2', 'Gene', (147, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (255, 267))	('astrocytic glioma', 'Disease', 'MESH:D001254', (209, 226))	('IDH2', 'Gene', '3418', (147, 151))	('astrocytic glioma', 'Disease', (209, 226))
487158	32493417	Furthermore, we compared the BCOR-CREBBP fusion product in the present case to that of previously reported chimeric transcripts involving BCOR rearrangements with CREBBP or EP300 in ESS and pediatric gliomas.	('BCOR', 'Gene', (138, 142))	('rearrangements', 'Var', (143, 157))	('CREBBP', 'Gene', '1387', (163, 169))	('gliomas', 'Disease', (200, 207))	('gliomas', 'Phenotype', 'HP:0009733', (200, 207))	('BCOR', 'Gene', (29, 33))	('CREBBP', 'Gene', (34, 40))	('BCOR', 'Gene', '54880', (138, 142))	('gliomas', 'Disease', 'MESH:D005910', (200, 207))	('BCOR', 'Gene', '54880', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('ESS', 'Disease', (182, 185))	('CREBBP', 'Gene', '1387', (34, 40))	('EP300', 'Gene', (173, 178))	('EP300', 'Gene', '2033', (173, 178))	('CREBBP', 'Gene', (163, 169))
487159	32493417	The previously reported events include BCOR-CREBBP and CREBBP-BCOR fusions in ESS, and EP300-BCOR fusions in 3 cases of pediatric glioma.	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('BCOR', 'Gene', (93, 97))	('CREBBP', 'Gene', (44, 50))	('CREBBP', 'Gene', '1387', (55, 61))	('glioma', 'Disease', (130, 136))	('BCOR', 'Gene', '54880', (93, 97))	('fusions', 'Var', (98, 105))	('EP300', 'Gene', (87, 92))	('BCOR', 'Gene', (39, 43))	('CREBBP-BCOR', 'Gene', (55, 66))	('EP300', 'Gene', '2033', (87, 92))	('BCOR', 'Gene', '54880', (62, 66))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('CREBBP', 'Gene', '1387', (44, 50))	('CREBBP-BCOR', 'Gene', '1387;54880', (55, 66))	('BCOR', 'Gene', '54880', (39, 43))	('CREBBP', 'Gene', (55, 61))	('BCOR', 'Gene', (62, 66))
487160	32493417	The extent of the BCOR segment of the chimeric transcripts was variable among the reported cases (Supplementary Fig.	('BCOR', 'Gene', (18, 22))	('chimeric', 'Var', (38, 46))	('BCOR', 'Gene', '54880', (18, 22))
487166	32493417	Gene fusions have been described in a diversity of CNS tumors similar to other tumor families, including hematopoietic neoplasms and sarcomas.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CNS tumors', 'Disease', (51, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('sarcomas', 'Disease', 'MESH:D012509', (133, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (133, 141))	('hematopoietic neoplasms', 'Disease', (105, 128))	('sarcomas', 'Disease', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Gene fusions', 'Var', (0, 12))	('CNS tumors', 'Disease', 'MESH:D016543', (51, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('tumor', 'Disease', (79, 84))	('CNS tumor', 'Phenotype', 'HP:0100006', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (55, 60))	('hematopoietic neoplasms', 'Disease', 'MESH:D019337', (105, 128))	('neoplasms', 'Phenotype', 'HP:0002664', (119, 128))	('described', 'Reg', (23, 32))	('hematopoietic neoplasms', 'Phenotype', 'HP:0004377', (105, 128))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
487167	32493417	For example, a tandem duplication event linking BRAF to a nearby gene, KIAA1549, is a recurrent event seen in a majority of pilocytic astrocytomas and represents the predominant neoplastic driver in such cases.	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('KIAA1549', 'Gene', (71, 79))	('KIAA1549', 'Gene', '57670', (71, 79))	('tandem duplication event', 'Var', (15, 39))	('pilocytic astrocytomas', 'Disease', (124, 146))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (124, 146))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
487168	32493417	For example, those infiltrating gliomas with FGFR-TACC fusions may present with other oncogenic alterations including CDKN2A loss, CDK4 amplification, MDM2 amplification and/or TERT promoter mutations.	('CDKN2A', 'Gene', (118, 124))	('CDK4', 'Gene', (131, 135))	('loss', 'NegReg', (125, 129))	('amplification', 'Var', (156, 169))	('gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('gliomas', 'Disease', (32, 39))	('CDKN2A', 'Gene', '1029', (118, 124))	('TERT', 'Gene', '7015', (177, 181))	('CDK4', 'Gene', '1019', (131, 135))	('gliomas', 'Disease', 'MESH:D005910', (32, 39))	('MDM2', 'Gene', '4193', (151, 155))	('MDM2', 'Gene', (151, 155))	('FGFR-TACC', 'Gene', (45, 54))	('fusions', 'Var', (55, 62))	('present', 'Reg', (67, 74))	('amplification', 'Var', (136, 149))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('TERT', 'Gene', (177, 181))
487172	32493417	Recent in vivo studies suggest that the PUFD domain is essential for a tumor suppressor function of BCOR and that loss of BCOR promotes leukemogenesis.	('promotes', 'PosReg', (127, 135))	('BCOR', 'Gene', '54880', (100, 104))	('BCOR', 'Gene', '54880', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('loss', 'Var', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('BCOR', 'Gene', (122, 126))	('tumor', 'Disease', (71, 76))	('BCOR', 'Gene', (100, 104))	('leukemogenesis', 'Disease', (136, 150))
487173	32493417	Moreover, next-generation sequencing studies have revealed various BCOR alterations in a broad range of neoplastic diseases.	('alterations', 'Var', (72, 83))	('neoplastic diseases', 'Disease', 'MESH:D009386', (104, 123))	('neoplastic diseases', 'Disease', (104, 123))	('BCOR', 'Gene', (67, 71))	('BCOR', 'Gene', '54880', (67, 71))
487174	32493417	In CNS tumors, loss of function BCOR mutations (e.g., nonsense, frameshift, splice sites and deletions) have been described in medulloblastoma, high-grade pediatric gliomas and astroblastomas.	('medulloblastoma', 'Disease', 'MESH:D008527', (127, 142))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('medulloblastoma', 'Phenotype', 'HP:0002885', (127, 142))	('BCOR', 'Gene', '54880', (32, 36))	('medulloblastoma', 'Disease', (127, 142))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('BCOR', 'Gene', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('astroblastomas', 'Disease', (177, 191))	('CNS tumors', 'Disease', 'MESH:D016543', (3, 13))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('splice sites', 'Var', (76, 88))	('CNS tumor', 'Phenotype', 'HP:0100006', (3, 12))	('frameshift', 'Var', (64, 74))	('loss of function', 'NegReg', (15, 31))	('astroblastomas', 'Disease', 'MESH:D018302', (177, 191))	('nonsense', 'Var', (54, 62))	('deletions', 'Var', (93, 102))	('gliomas', 'Disease', (165, 172))	('CNS tumors', 'Disease', (3, 13))
487176	32493417	Moreover, since the BCOR gene is located on the X-chromosome, the BCOR gene in the index case is present as only one allele and the fusion event would lead to a complete loss of putative tumor-suppressor activity mediated by the PUFD.	('BCOR', 'Gene', (66, 70))	('BCOR', 'Gene', '54880', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('BCOR', 'Gene', '54880', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('loss', 'NegReg', (170, 174))	('tumor', 'Disease', (187, 192))	('fusion', 'Var', (132, 138))	('BCOR', 'Gene', (20, 24))
487184	32493417	In cancer, CREBBP/EP300 is targeted by both mutations and structural alterations.	('CREBBP', 'Gene', '1387', (11, 17))	('EP300', 'Gene', (18, 23))	('EP300', 'Gene', '2033', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('CREBBP', 'Gene', (11, 17))	('structural alterations', 'Var', (58, 80))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
487187	32493417	Given that the CREBBP component of the fusion transcript in our case retains only exon 31 and consequently lacks most of the functional domains, loss of CREBBP through this gene fusion potentially promotes gliomagenesis.	('CREBBP', 'Gene', (15, 21))	('exon 31', 'MPA', (82, 89))	('promotes', 'PosReg', (197, 205))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('lacks', 'NegReg', (107, 112))	('CREBBP', 'Gene', '1387', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('loss', 'Var', (145, 149))	('CREBBP', 'Gene', '1387', (15, 21))	('functional domains', 'MPA', (125, 143))	('glioma', 'Disease', (206, 212))	('CREBBP', 'Gene', (153, 159))
487191	32493417	While the pathogenic impact of most reported gene fusions is gain-of-function, such as constitutive kinase activation and abnormal activity of transcriptional factors, fusions resulting in loss of function of tumor suppressors have been identified as well.	('tumor', 'Disease', (209, 214))	('gain-of-function', 'PosReg', (61, 77))	('transcriptional', 'Protein', (143, 158))	('loss of function', 'NegReg', (189, 205))	('activity', 'MPA', (131, 139))	('fusions', 'Var', (50, 57))	('constitutive', 'MPA', (87, 99))	('fusions', 'Var', (168, 175))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('activation', 'PosReg', (107, 117))
487192	32493417	The APC-COMMD10 fusion in colorectal cancer is one example wherein fusion-mediated truncation leads to a loss-of-function of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('truncation', 'Var', (83, 93))	('colorectal cancer', 'Disease', (26, 43))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('APC', 'Disease', 'MESH:D011125', (4, 7))	('APC', 'Disease', (4, 7))	('tumor', 'Disease', (125, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('COMMD10', 'Gene', '51397', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('COMMD10', 'Gene', (8, 15))	('fusion', 'Var', (16, 22))	('loss-of-function', 'NegReg', (105, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))
487193	32493417	suggested that the lack of functional domains in APC resulting from the APC-COMMD10 gene fusion can lead to tumorigenesis where loss of APC is known to be a critical event in the development of colon cancer.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('fusion', 'Var', (89, 95))	('colon cancer', 'Disease', 'MESH:D015179', (194, 206))	('COMMD10', 'Gene', '51397', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('APC', 'Disease', 'MESH:D011125', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('APC', 'Disease', 'MESH:D011125', (49, 52))	('tumor', 'Disease', (108, 113))	('colon cancer', 'Disease', (194, 206))	('APC', 'Disease', (136, 139))	('lead to', 'Reg', (100, 107))	('APC', 'Disease', (49, 52))	('APC', 'Disease', 'MESH:D011125', (72, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (194, 206))	('COMMD10', 'Gene', (76, 83))	('APC', 'Disease', (72, 75))
487196	32493417	A fusion involving CREBBP with BCORL1 has been described in ossifying fibromyxoid tumors, with a similar breakpoint region to that seen in our case, though with a distinct predicted fusion transcript that preserves the HAT domain of CREBBP.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('BCORL1', 'Gene', '63035', (31, 37))	('CREBBP', 'Gene', (19, 25))	('CREBBP', 'Gene', '1387', (233, 239))	('HAT domain', 'MPA', (219, 229))	('CREBBP', 'Gene', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BCORL1', 'Gene', (31, 37))	('described', 'Reg', (47, 56))	('CREBBP', 'Gene', '1387', (19, 25))	('ossifying fibromyxoid tumors', 'Disease', 'MESH:D018214', (60, 88))	('ossifying fibromyxoid tumors', 'Disease', (60, 88))	('fusion', 'Var', (2, 8))
487204	32493417	Given that CNS tumors with previously reported BCOR alterations, such as BCOR ex15 ITD, EP300-BCOR fusions, and loss-of-function mutations predominantly arise in pediatric or young adult patients, expanding analysis to larger cohorts enriched in pediatric patients would be warranted and may increase the chances of detecting further events involving CREBBP and/or BCOR.	('BCOR', 'Gene', '54880', (73, 77))	('ex15 ITD', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CREBBP', 'Gene', (351, 357))	('BCOR', 'Gene', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('patients', 'Species', '9606', (187, 195))	('CNS tumors', 'Disease', 'MESH:D016543', (11, 21))	('BCOR', 'Gene', '54880', (365, 369))	('BCOR', 'Gene', '54880', (47, 51))	('EP300', 'Gene', '2033', (88, 93))	('loss-of-function', 'NegReg', (112, 128))	('CREBBP', 'Gene', '1387', (351, 357))	('BCOR', 'Gene', (365, 369))	('BCOR', 'Gene', '54880', (94, 98))	('BCOR', 'Gene', (47, 51))	('CNS tumor', 'Phenotype', 'HP:0100006', (11, 20))	('EP300', 'Gene', (88, 93))	('BCOR', 'Gene', (94, 98))	('mutations', 'Var', (129, 138))	('patients', 'Species', '9606', (256, 264))	('CNS tumors', 'Disease', (11, 21))
487243	31059555	The KSHV genome also contains four genes with partial sequence homology to cellular interferon regulatory factors (IRFs): an unspliced mRNA transcribed from the viral open reading frame (ORF) K9 encodes viral interferon regulatory factor 1 (vIRF1), while spliced mRNAs generated from ORF K10/K10.1, ORF K10.5/10.6 and ORF K11/K11.1 yield vIRF 4, 3 and 2, respectively.	('KSHV', 'Species', '37296', (4, 8))	('vIRF1', 'Gene', (241, 246))	('ORF K11/K11.1', 'Var', (318, 331))	('interferon', 'Gene', (84, 94))	('interferon', 'Gene', '3439', (209, 219))	('KS', 'Phenotype', 'HP:0100726', (4, 6))	('ORF K10/K10.1', 'Var', (284, 297))	('viral interferon regulatory factor 1', 'Gene', (203, 239))	('rat', 'Species', '10116', (273, 276))	('ORF K10.5/10.6', 'Var', (299, 313))	('vIRF1', 'Gene', '4961464', (241, 246))	('interferon', 'Gene', (209, 219))	('interferon', 'Gene', '3439', (84, 94))	('viral interferon regulatory factor 1', 'Gene', '4961464', (203, 239))
487251	31059555	PML NBs are known to restrict the replication of several virus families, which have, in turn, evolved mechanisms to counteract this PML-mediated antiviral restriction.	('restrict', 'NegReg', (21, 29))	('PML', 'Gene', (132, 135))	('replication', 'MPA', (34, 45))	('PML', 'Gene', '5371', (0, 3))	('NBs', 'Var', (4, 7))	('PML', 'Gene', '5371', (132, 135))	('PML', 'Gene', (0, 3))	('NBs', 'Chemical', 'MESH:D009556', (4, 7))
487265	31059555	This KSHV-induced increase in PML and Daxx protein levels and in the number of PML NBs is reminiscent of the effect of IFN treatment, which is shown in Fig 1D and has been described in many previous studies.	('Daxx', 'Gene', (38, 42))	('increase', 'PosReg', (18, 26))	('IFN', 'Gene', '3439', (119, 122))	('NBs', 'Chemical', 'MESH:D009556', (83, 86))	('Daxx', 'Gene', '1616', (38, 42))	('KSHV-induced', 'Var', (5, 17))	('IFN', 'Gene', (119, 122))	('PML', 'Gene', '5371', (79, 82))	('KS', 'Phenotype', 'HP:0100726', (5, 7))	('PML', 'Gene', (30, 33))	('KSHV', 'Species', '37296', (5, 9))	('PML', 'Gene', (79, 82))	('PML', 'Gene', '5371', (30, 33))
487277	31059555	Both monoclonal antibodies recognized the same repeated epitope (QGPMQSEG) located at position aa347-354 and aa405-412 within the repeated sequence ELLCETASPQGPMQSEGGEEGSTES in the regions R1 and R2 of vIRF2, as illustrated in Fig 3B and S1 Fig.	('QGPMQSEG', 'Gene', (65, 73))	('vIRF2', 'Gene', (202, 207))	('vIRF2', 'Gene', '4961491', (202, 207))	('aa347-354', 'Var', (95, 104))	('rat', 'Species', '10116', (218, 221))	('aa405-412', 'Var', (109, 118))
487288	31059555	Our observation that vIRF2 is found both in the nucleus and cytoplasm of KSHV-infected cells, is in keeping with overexpression studies that used an expression vector for the spliced K11.1/K11 cDNA.	('expression', 'Species', '29278', (117, 127))	('vIRF2', 'Gene', (21, 26))	('K11.1/K11', 'Var', (183, 192))	('expression', 'Species', '29278', (149, 159))	('vIRF2', 'Gene', '4961491', (21, 26))	('KS', 'Phenotype', 'HP:0100726', (73, 75))	('KSHV-infected', 'Disease', 'MESH:C537372', (73, 86))	('KSHV-infected', 'Disease', (73, 86))
487290	31059555	As a first step we overexpressed vIRF2 in the KSHV-infected immortalized endothelial cell line HuARLT.rKSHV.219 via lentiviral transduction and induced the lytic cycle.	('KSHV-infected', 'Disease', (46, 59))	('KSHV-infected', 'Disease', 'MESH:C537372', (46, 59))	('induced', 'PosReg', (144, 151))	('lytic cycle', 'CPA', (156, 167))	('KSHV', 'Species', '37296', (103, 107))	('KS', 'Phenotype', 'HP:0100726', (103, 105))	('KSHV', 'Species', '37296', (46, 50))	('KS', 'Phenotype', 'HP:0100726', (46, 48))	('vIRF2', 'Gene', (33, 38))	('vIRF2', 'Gene', '4961491', (33, 38))	('HuARLT.rKSHV.219', 'Var', (95, 111))
487291	31059555	We could observe a strong inhibition of KSHV early lytic protein expression upon vIRF2 overexpression, as judged by the reduced expression of the KSHV early lytic protein K-bZIP (Fig 4A).	('overexpression', 'Var', (87, 101))	('vIRF2', 'Gene', '4961491', (81, 86))	('KSHV', 'Species', '37296', (146, 150))	('KSHV early lytic protein', 'Gene', (40, 64))	('expression', 'Species', '29278', (65, 75))	('inhibition', 'NegReg', (26, 36))	('KS', 'Phenotype', 'HP:0100726', (146, 148))	('KSHV', 'Species', '37296', (40, 44))	('expression', 'Species', '29278', (128, 138))	('expression', 'MPA', (65, 75))	('expression', 'MPA', (128, 138))	('KS', 'Phenotype', 'HP:0100726', (40, 42))	('expression', 'Species', '29278', (91, 101))	('reduced', 'NegReg', (120, 127))	('vIRF2', 'Gene', (81, 86))
487296	31059555	Interestingly, the knockdown with any of these three siRNAs led to an increased early lytic gene expression, as shown here for the early lytic proteins K-bZIP and ORF45 (Fig 4B).	('increased', 'PosReg', (70, 79))	('knockdown', 'Var', (19, 28))	('early lytic gene', 'Gene', (80, 96))	('ORF45', 'Gene', '4961474', (163, 168))	('expression', 'Species', '29278', (97, 107))	('ORF45', 'Gene', (163, 168))	('expression', 'MPA', (97, 107))
487297	31059555	To verify a possible role of vIRF2 in lytic cycle regulation with another experimental approach, we used the BAC16 vector to generate a vIRF2 deletion mutant (KSHV.DeltavIRF2) by replacing the ORFs K11 and K11.1 with a kanamycin resistance cassette (Fig 4C).	('deletion mutant', 'Var', (142, 157))	('vIRF2', 'Gene', '4961491', (136, 141))	('vIRF2', 'Gene', (136, 141))	('mutant', 'Var', (151, 157))	('rat', 'Species', '10116', (129, 132))	('KS', 'Phenotype', 'HP:0100726', (159, 161))	('KSHV', 'Species', '37296', (159, 163))	('vIRF2', 'Gene', (29, 34))	('kanamycin', 'Chemical', 'MESH:D007612', (219, 228))	('vIRF2', 'Gene', (169, 174))	('vIRF2', 'Gene', '4961491', (29, 34))	('vIRF2', 'Gene', '4961491', (169, 174))
487309	31059555	Together, these results show that, in endothelial cells, the deletion of vIRF2 from the viral genome or its suppression by siRNA promotes early viral protein expression and, in the case of the vIRF2 deletion, the production of viral progeny.	('early viral protein expression', 'MPA', (138, 168))	('expression', 'Species', '29278', (158, 168))	('promotes', 'PosReg', (129, 137))	('deletion', 'Var', (61, 69))	('vIRF2', 'Gene', (73, 78))	('vIRF2', 'Gene', '4961491', (73, 78))	('production of viral progeny', 'MPA', (213, 240))	('vIRF2', 'Gene', (193, 198))	('vIRF2', 'Gene', '4961491', (193, 198))
487314	31059555	We observed an increase in the expression of the lytic proteins K-bZIP and ORF45 upon the transient knockdown of vIRF2 by siRNA (3) which targets vIRF2 mRNA at the C-terminal end (Fig 5A and Fig 3B).	('vIRF2', 'Gene', (113, 118))	('ORF45', 'Gene', (75, 80))	('knockdown', 'Var', (100, 109))	('vIRF2', 'Gene', '4961491', (113, 118))	('expression', 'Species', '29278', (31, 41))	('increase', 'PosReg', (15, 23))	('vIRF2', 'Gene', (146, 151))	('expression', 'MPA', (31, 41))	('vIRF2', 'Gene', '4961491', (146, 151))	('ORF45', 'Gene', '4961474', (75, 80))
487325	31059555	To further understand which forms and parts of the vIRF2 protein are necessary and/or sufficient for its regulatory function during KSHV replication, we generated four different KSHV mutants (Stop#1:Stop#4) by introducing double stop codons at different positions within the vIRF2 sequence in the BAC16 backbone using En passant mutagenesis (Fig 6A).	('KSHV', 'Species', '37296', (178, 182))	('KSHV', 'Species', '37296', (132, 136))	('vIRF2', 'Gene', (51, 56))	('mutants', 'Var', (183, 190))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('vIRF2', 'Gene', (275, 280))	('rat', 'Species', '10116', (157, 160))	('vIRF2', 'Gene', '4961491', (51, 56))	('KSHV', 'Gene', (178, 182))	('vIRF2', 'Gene', '4961491', (275, 280))	('KS', 'Phenotype', 'HP:0100726', (178, 180))
487332	31059555	In contrast, the KSHV.vIRF2.Stop mutants #1, #3 and #4 showed several bands of different molecular weight that were detected by the vIRF2 antibody (Fig 6B, lane 5, 7, 8).	('KS', 'Phenotype', 'HP:0100726', (17, 19))	('vIRF2', 'Gene', (132, 137))	('mutants', 'Var', (33, 40))	('vIRF2', 'Gene', '4961491', (132, 137))	('KSHV', 'Species', '37296', (17, 21))	('vIRF2', 'Gene', '4961491', (22, 27))	('vIRF2', 'Gene', (22, 27))
487334	31059555	Thus, the protein bands with the highest molecular weight observed in the case of the KSHV.vIRF2.Stop#1 and KSHV.vIRF2.Stop#4 mutants could initiate at a methionine in position aa47 of the vIRF2 sequence, and bands of lower apparent molecular weight could be translated from other internal methionine codons.	('vIRF2', 'Gene', '4961491', (91, 96))	('vIRF2', 'Gene', (113, 118))	('vIRF2', 'Gene', (189, 194))	('KSHV', 'Species', '37296', (108, 112))	('vIRF2', 'Gene', '4961491', (113, 118))	('methionine', 'Chemical', 'MESH:D008715', (290, 300))	('vIRF2', 'Gene', '4961491', (189, 194))	('methionine', 'Chemical', 'MESH:D008715', (154, 164))	('KS', 'Phenotype', 'HP:0100726', (108, 110))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('KSHV', 'Species', '37296', (86, 90))	('vIRF2', 'Gene', (91, 96))	('initiate', 'Reg', (140, 148))	('mutants', 'Var', (126, 133))
487335	31059555	The weak immunoreactive band at ~ 30 kDa, detected with the monoclonal antibody in the case of KSHV.vIRF2.Stop#3, suggests that either this antibody mainly detects epitope E2 in the second repeat in the context of the entire vIRF2 protein, in spite of reacting with epitopes E1 and E2 on the peptide array (S1 Fig) or the vIRF2 protein expressed by the Stop#3 mutant could be unstable.	('vIRF2', 'Gene', '4961491', (322, 327))	('vIRF2', 'Gene', (100, 105))	('vIRF2', 'Gene', '4961491', (100, 105))	('Stop#3', 'Gene', (353, 359))	('vIRF2', 'Gene', (225, 230))	('vIRF2', 'Gene', '4961491', (225, 230))	('KS', 'Phenotype', 'HP:0100726', (95, 97))	('KSHV', 'Species', '37296', (95, 99))	('vIRF2', 'Gene', (322, 327))	('mutant', 'Var', (360, 366))
487339	31059555	Interestingly, while the complete deletion of vIRF2 led to an increased expression of KSHV K-bZIP and ORF45 as noted before (Fig 4C, Fig 6C lane 2), KSHV.vIRF2 stop mutants #2-4 did not increase the levels of these lytic proteins, while Stop mutant #1 showed an increase in ORF45 but not K-bZIP expression in endothelial cells (Fig 6C).	('increased', 'PosReg', (62, 71))	('ORF45', 'Gene', '4961474', (274, 279))	('vIRF2', 'Gene', (154, 159))	('vIRF2', 'Gene', '4961491', (154, 159))	('ORF45', 'Gene', (274, 279))	('KSHV', 'Species', '37296', (86, 90))	('expression', 'MPA', (72, 82))	('KSHV', 'Species', '37296', (149, 153))	('ORF45', 'Gene', '4961474', (102, 107))	('vIRF2', 'Gene', '4961491', (46, 51))	('vIRF2', 'Gene', (46, 51))	('expression', 'Species', '29278', (295, 305))	('KSHV', 'Gene', (86, 90))	('ORF45', 'Gene', (102, 107))	('expression', 'Species', '29278', (72, 82))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('KS', 'Phenotype', 'HP:0100726', (149, 151))	('deletion', 'Var', (34, 42))	('levels', 'MPA', (199, 205))
487365	31059555	In this experiment, transduction of vIRF2 led to an increase in IFIT1 and 3 protein expression (S3B Fig).	('IFIT1', 'Gene', (64, 69))	('vIRF2', 'Gene', '4961491', (36, 41))	('transduction', 'Var', (20, 32))	('increase', 'PosReg', (52, 60))	('IFIT1', 'Gene', '3434', (64, 69))	('expression', 'Species', '29278', (84, 94))	('vIRF2', 'Gene', (36, 41))
487369	31059555	In contrast, Stop#1- and Stop#2-infected cells, as well as their revertants, maintained the expression of IFIT1, indicating that the truncated vIRF2 proteins expressed by these mutants (Fig 6A) are sufficient to induce IFIT1 (S3C Fig).	('IFIT1', 'Gene', '3434', (106, 111))	('IFIT1', 'Gene', (219, 224))	('vIRF2', 'Gene', (143, 148))	('induce', 'PosReg', (212, 218))	('vIRF2', 'Gene', '4961491', (143, 148))	('mutants', 'Var', (177, 184))	('proteins', 'Protein', (149, 157))	('IFIT1', 'Gene', '3434', (219, 224))	('expression', 'Species', '29278', (92, 102))	('IFIT1', 'Gene', (106, 111))	('expression', 'MPA', (92, 102))
487370	31059555	As we could show that vIRF2 expression leads to an increased expression of the IFIT proteins, we wondered if this might correlate with the ability of vIRF2 to regulate early lytic viral protein expression during de novo infection.	('vIRF2', 'Gene', '4961491', (150, 155))	('expression', 'Species', '29278', (28, 38))	('increased', 'PosReg', (51, 60))	('expression', 'Species', '29278', (194, 204))	('IFIT proteins', 'Protein', (79, 92))	('expression', 'Var', (28, 38))	('vIRF2', 'Gene', (150, 155))	('expression', 'Species', '29278', (61, 71))	('vIRF2', 'Gene', '4961491', (22, 27))	('expression', 'MPA', (61, 71))	('vIRF2', 'Gene', (22, 27))
487378	31059555	Silencing IFIT1 during KSHV lytic reactivation (Fig 8A, left) as well as during de novo infection (Fig 8A, right) increased the expression of the KSHV early lytic protein K-bZIP.	('KS', 'Phenotype', 'HP:0100726', (23, 25))	('IFIT1', 'Gene', (10, 15))	('KSHV', 'Species', '37296', (146, 150))	('increased', 'PosReg', (114, 123))	('IFIT1', 'Gene', '3434', (10, 15))	('KS', 'Phenotype', 'HP:0100726', (146, 148))	('expression', 'Species', '29278', (128, 138))	('KSHV', 'Species', '37296', (23, 27))	('expression', 'MPA', (128, 138))	('Silencing', 'Var', (0, 9))
487379	31059555	IFIT2 knockdown affected K-bZIP expression only during KSHV de novo infection (Fig 8B and S4A Fig) and silencing of IFIT3 increased K-bZIP expression only during lytic reactivation (Fig 8C and S4B Fig).	('silencing', 'Var', (103, 112))	('IFIT3', 'Gene', (116, 121))	('affected', 'Reg', (16, 24))	('KSHV', 'Species', '37296', (55, 59))	('KS', 'Phenotype', 'HP:0100726', (55, 57))	('IFIT3', 'Gene', '3437', (116, 121))	('expression', 'Species', '29278', (139, 149))	('K-bZIP expression', 'MPA', (25, 42))	('expression', 'Species', '29278', (32, 42))	('K-bZIP expression', 'MPA', (132, 149))	('increased', 'PosReg', (122, 131))
487382	31059555	We found that a transient PML knockdown increases KSHV lytic protein expression, as shown for the early lytic protein K-bZIP (Fig 8D).	('expression', 'Species', '29278', (69, 79))	('PML', 'Gene', (26, 29))	('KSHV lytic protein', 'Gene', (50, 68))	('expression', 'MPA', (69, 79))	('KSHV', 'Species', '37296', (50, 54))	('knockdown', 'Var', (30, 39))	('KS', 'Phenotype', 'HP:0100726', (50, 52))	('increases', 'PosReg', (40, 49))	('PML', 'Gene', '5371', (26, 29))
487400	31059555	Some of them likely result from translational initiation at internal start codons, as they are produced by a KSHV mutant that had two stop codons inserted immediately after the predicted start codon for the vIRF2 ORF in exon K11.1 (Fig 6, Stop#1).	('KSHV', 'Gene', (109, 113))	('mutant', 'Var', (114, 120))	('result from', 'Reg', (20, 31))	('KSHV', 'Species', '37296', (109, 113))	('KS', 'Phenotype', 'HP:0100726', (109, 111))	('vIRF2', 'Gene', (207, 212))	('vIRF2', 'Gene', '4961491', (207, 212))
487403	31059555	Using transient knockdown experiments with different vIRF2 siRNAs, as well as a KSHV mutant lacking the vIRF2 gene, we could show that vIRF2 restricts the expression of early lytic KSHV proteins both after reactivation from latency (Fig 4) and following de novo infection (Fig 5).	('KSHV', 'Species', '37296', (181, 185))	('KS', 'Phenotype', 'HP:0100726', (181, 183))	('expression', 'Species', '29278', (155, 165))	('KS', 'Phenotype', 'HP:0100726', (80, 82))	('KSHV', 'Species', '37296', (80, 84))	('expression', 'MPA', (155, 165))	('KSHV', 'Gene', (181, 185))	('vIRF2', 'Gene', '4961491', (104, 109))	('restricts', 'NegReg', (141, 150))	('vIRF2', 'Gene', (104, 109))	('vIRF2', 'Gene', (135, 140))	('vIRF2', 'Gene', '4961491', (135, 140))	('vIRF2', 'Gene', (53, 58))	('mutant', 'Var', (85, 91))	('vIRF2', 'Gene', '4961491', (53, 58))
487424	31059555	The HRP-conjugated secondary antibodies rabbit anti-mouse IgG (P0447) and goat anti-rabbit IgG (P0448) were purchased from Dako.	('P0448', 'Var', (96, 101))	('goat', 'Species', '9925', (74, 78))	('rabbit', 'Species', '9986', (84, 90))	('mouse', 'Species', '10090', (52, 57))	('rabbit', 'Species', '9986', (40, 46))	('P0447', 'Var', (63, 68))
487475	31059555	Experiments in this study were performed with hybridoma culture supernatant of vIRF2/K11 clone #30F9 and #31A2 (mouse IgG2b/kappa) at a dilution of 1:10 in PBS-T.	('IgG2b', 'Gene', (118, 123))	('vIRF2', 'Gene', (79, 84))	('vIRF2', 'Gene', '4961491', (79, 84))	('#31A2', 'Var', (105, 110))	('PBS-T', 'Disease', 'MESH:D011535', (156, 161))	('IgG2b', 'Gene', '16016', (118, 123))	('PBS-T', 'Disease', (156, 161))	('mouse', 'Species', '10090', (112, 117))
487488	31059555	To map the epitope of the two K11 antibody clones #30F9 and #31A2, the membranes were wetted with a few drops of ethanol and blocked in 5% milk in PBS-T buffer for 2 h at RT.	('PBS-T', 'Disease', 'MESH:D011535', (147, 152))	('PBS-T', 'Disease', (147, 152))	('ethanol', 'Chemical', 'MESH:D000431', (113, 120))	('#31A2', 'Var', (60, 65))
487489	31059555	The membranes were incubated with the antibody clones #30F9 or #31A2 (diluted 1:10 in 5% milk PBS-T) over night at 4 C gently mixing.	('PBS-T', 'Disease', (94, 99))	('PBS-T', 'Disease', 'MESH:D011535', (94, 99))	('#31A2', 'Var', (63, 68))	('over night', 'Phenotype', 'HP:0000662', (101, 111))
487517	31059555	All the KSHV BAC16 mutants used in this study showed only the mutations introduced by mutagenesis and did not contain any additional changes in their genomic sequence.	('KSHV BAC16', 'Gene', (8, 18))	('mutagenesis', 'Var', (86, 97))	('KS', 'Phenotype', 'HP:0100726', (8, 10))	('KSHV', 'Species', '37296', (8, 12))	('mutants', 'Var', (19, 26))
487636	27877194	5-year actuarial local control for all patients in the brachytherapy arm was 82%, significantly better than 69% local control for patients who received surgery alone.	('patients', 'Species', '9606', (130, 138))	('local control', 'CPA', (17, 30))	('brachytherapy', 'Var', (55, 68))	('patients', 'Species', '9606', (39, 47))
487643	27877194	Treatment time is significantly shorter with brachytherapy compared to EBRT, a consideration that may be especially important for palliative treatment or patients who have a substantial travel time to come for treatment.	('shorter', 'NegReg', (32, 39))	('EBRT', 'Chemical', '-', (71, 75))	('brachytherapy', 'Var', (45, 58))	('patients', 'Species', '9606', (154, 162))
487681	23638435	Class IA PI3Ks are the most commonly implicated in cell division and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cell division', 'CPA', (51, 64))	('implicated', 'Reg', (37, 47))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PI3Ks', 'Var', (9, 14))
487689	23638435	At the membrane, PKB/Akt is phosphorylated at Thr308 by PDK1 and at Ser473 by the mammalian target of Rapamycin (mTOR)C2 complex.	('mammalian target of Rapamycin', 'Gene', '2475', (82, 111))	('PKB', 'Gene', '2185', (17, 20))	('PKB', 'Gene', (17, 20))	('Thr308', 'Var', (46, 52))	('mammalian target of Rapamycin', 'Gene', (82, 111))	('Thr308', 'Chemical', '-', (46, 52))	('Ser473', 'Chemical', '-', (68, 74))	('PDK1', 'Gene', '5163', (56, 60))	('PDK1', 'Gene', (56, 60))
487690	23638435	Key downstream cellular processes induced by Akt include increased cell metabolism and glycogen synthesis via inhibition of the FOXO (forkhead) family and glycogen synthase kinase 3 (GSK3); blockade of apoptosis via inhibition of p53, NF-kappaB, and BAD (Bcl2-antagonist of cell death); and increased protein synthesis and cell proliferation via activation of the mTOR complex 1 (mTOR-raptor kinase complex, or mTORC1) (Carnero,).	('mTORC1', 'Gene', '382056', (411, 417))	('protein synthesis', 'MPA', (301, 318))	('increased', 'PosReg', (291, 300))	('p53', 'Gene', '7157', (230, 233))	('glycogen', 'Chemical', 'MESH:D006003', (87, 95))	('p53', 'Gene', (230, 233))	('Bcl2', 'Gene', (255, 259))	('glycogen', 'Chemical', 'MESH:D006003', (155, 163))	('cell proliferation', 'CPA', (323, 341))	('Bcl2', 'Gene', '596', (255, 259))	('apoptosis', 'CPA', (202, 211))	('increased', 'PosReg', (57, 66))	('blockade', 'Var', (190, 198))	('glycogen synthesis', 'MPA', (87, 105))	('cell metabolism', 'CPA', (67, 82))	('activation', 'PosReg', (346, 356))	('NF-kappaB, and BAD', 'Gene', '4790', (235, 253))	('mTORC1', 'Gene', (411, 417))	('inhibition', 'NegReg', (216, 226))
487692	23638435	The commonest are activating point mutations of PI3K, inactivation of the tumor suppressor PTEN, and amplification of the Akt gene.	('Akt gene', 'Gene', (122, 130))	('amplification', 'Var', (101, 114))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PI3K', 'Protein', (48, 52))	('tumor', 'Disease', (74, 79))	('activating', 'PosReg', (18, 28))	('PTEN', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (91, 95))	('inactivation', 'Var', (54, 66))	('point mutations', 'Var', (29, 44))
487693	23638435	Gain of function mutations of PI3K have been observed in many human adult cancers, including ovarian, breast, gastric, and hepatocellular carcinoma.	('breast', 'Disease', (102, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('human', 'Species', '9606', (62, 67))	('gastric', 'Disease', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('ovarian', 'Disease', (93, 100))	('PI3K', 'Gene', (30, 34))	('adult cancers', 'Disease', (68, 81))	('adult cancers', 'Disease', 'MESH:C535836', (68, 81))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('hepatocellular carcinoma', 'Disease', (123, 147))	('mutations', 'Var', (17, 26))	('Gain of function', 'PosReg', (0, 16))
487694	23638435	These include increased copy numbers and activating somatic mutations of PI3KCA, the gene encoding the p110alpha catalytic subunit of PI3K (Samuels and Ericson,; Ligresti et al.,).	('increased', 'PosReg', (14, 23))	('p110alpha', 'Gene', (103, 112))	('copy', 'MPA', (24, 28))	('activating', 'PosReg', (41, 51))	('PI3KCA', 'Gene', (73, 79))	('mutations', 'Var', (60, 69))	('p110alpha', 'Gene', '5290', (103, 112))
487697	23638435	Other known genetic aberrations involving PI3K include deletion and somatic mutations of PIK3R1, the gene encoding the p85 regulatory subunit, have been noted in colon and ovarian carcinomas, and glioblastoma.	('PIK3R1', 'Gene', (89, 95))	('p85', 'Gene', (119, 122))	('mutations', 'Var', (76, 85))	('PIK3R1', 'Gene', '5295', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (172, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('noted', 'Reg', (153, 158))	('glioblastoma', 'Disease', (196, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (196, 208))	('p85', 'Gene', '5295', (119, 122))	('glioblastoma', 'Phenotype', 'HP:0012174', (196, 208))	('deletion', 'Var', (55, 63))	('colon and ovarian carcinomas', 'Disease', 'MESH:D010051', (162, 190))
487699	23638435	Inactivating mutations of PTEN are encountered in lung, kidney, endometrial and breast carcinomas, melanomas, and glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (114, 127))	('melanomas', 'Disease', 'MESH:D008545', (99, 108))	('kidney', 'Disease', (56, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('melanomas', 'Disease', (99, 108))	('Inactivating mutations', 'Var', (0, 22))	('endometrial', 'Disease', (64, 75))	('breast carcinomas', 'Disease', 'MESH:D001943', (80, 97))	('breast carcinomas', 'Disease', (80, 97))	('glioblastomas', 'Phenotype', 'HP:0012174', (114, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('encountered', 'Reg', (35, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('PTEN', 'Gene', (26, 30))	('breast carcinomas', 'Phenotype', 'HP:0003002', (80, 97))	('glioblastomas', 'Disease', (114, 127))	('lung', 'Disease', (50, 54))	('PTEN', 'Gene', '5728', (26, 30))
487701	23638435	Germline mutations of PTEN are associated with the PTEN hamartoma-tumor syndromes (PHTS), a family of hamartomatous polyposis syndromes including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome (Chow and Baker,).	('Germline mutations', 'Var', (0, 18))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', 'MESH:D006223', (163, 196))	('PTEN', 'Gene', (22, 26))	('Proteus-like syndrome', 'Disease', 'MESH:D016715', (220, 241))	('PTEN', 'Gene', (51, 55))	('Proteus syndrome', 'Disease', 'MESH:D016715', (198, 214))	('hamartomatous polyposis syndromes', 'Disease', (102, 135))	('associated', 'Reg', (31, 41))	('PHTS', 'Gene', (83, 87))	('PTEN', 'Gene', '5728', (22, 26))	('hamartoma-tumor', 'Disease', 'MESH:D006222', (56, 71))	('Cowden syndrome', 'Disease', 'MESH:D006223', (146, 161))	('Proteus-like syndrome', 'Disease', (220, 241))	('PTEN', 'Gene', '5728', (51, 55))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', (163, 196))	('hamartomatous polyposis', 'Phenotype', 'HP:0004390', (102, 125))	('Cowden syndrome', 'Disease', (146, 161))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('hamartoma', 'Phenotype', 'HP:0010566', (56, 65))	('hamartomatous polyposis syndromes', 'Disease', 'MESH:D010580', (102, 135))	('hamartoma', 'Phenotype', 'HP:0010566', (102, 111))	('hamartoma-tumor', 'Disease', (56, 71))	('PHTS', 'Gene', '116372', (83, 87))	('Proteus syndrome', 'Disease', (198, 214))
487702	23638435	Akt gene amplification has been observed in cases of gastric carcinoma, glioblastoma, and gliosarcoma.	('amplification', 'Var', (9, 22))	('observed', 'Reg', (32, 40))	('gastric carcinoma', 'Disease', (53, 70))	('gliosarcoma', 'Disease', 'MESH:D018316', (90, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (53, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('gastric carcinoma', 'Disease', 'MESH:D013274', (53, 70))	('glioblastoma', 'Disease', (72, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('gliosarcoma', 'Disease', (90, 101))	('Akt', 'Gene', (0, 3))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
487704	23638435	An activating somatic mutation of Akt1 (Akt-E17K) has been reported in human breast, colorectal, and ovarian cancers.	('Akt1', 'Gene', (34, 38))	('E17K', 'SUBSTITUTION', 'None', (44, 48))	('ovarian cancers', 'Phenotype', 'HP:0100615', (101, 116))	('ovarian cancers', 'Disease', (101, 116))	('colorectal', 'Disease', 'MESH:D015179', (85, 95))	('ovarian cancers', 'Disease', 'MESH:D010051', (101, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('activating', 'PosReg', (3, 13))	('Akt1', 'Gene', '207', (34, 38))	('colorectal', 'Disease', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast', 'Disease', (77, 83))	('E17K', 'Var', (44, 48))	('human', 'Species', '9606', (71, 76))
487705	23638435	This mutation induces plasma membrane localization, downstream signaling, and transforms cells, and induces leukemia in mice.	('mice', 'Species', '10090', (120, 124))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('leukemia', 'Disease', 'MESH:D007938', (108, 116))	('downstream signaling', 'MPA', (52, 72))	('induces', 'Reg', (100, 107))	('induces', 'Reg', (14, 21))	('leukemia', 'Disease', (108, 116))	('transforms', 'MPA', (78, 88))	('plasma membrane localization', 'MPA', (22, 50))	('mutation', 'Var', (5, 13))	('cells', 'CPA', (89, 94))
487716	23638435	In an analysis of 39 samples of high-risk tumors, high levels of PI3Kp85 and PI3Kp110 expression were seen in the cytoplasm in 54% of cases (Izycka-Swieszewska et al.,).	('p85', 'Gene', '5295', (69, 72))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('p85', 'Gene', (69, 72))	('PI3Kp110 expression', 'Var', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
487717	23638435	However, activating gene mutations of PI3KCA and the loss of function mutations of tumor suppressor PTEN are very rarely present in NB, even though they are commonly seen in other human cancers.	('PTEN', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutations', 'Var', (25, 34))	('mutations', 'Var', (70, 79))	('PTEN', 'Gene', '5728', (100, 104))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('PI3KCA', 'Gene', (38, 44))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('human', 'Species', '9606', (180, 185))	('activating', 'PosReg', (9, 19))	('NB', 'Phenotype', 'HP:0003006', (132, 134))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('loss of function', 'NegReg', (53, 69))
487719	23638435	found homozygous deletions of PTEN in only 2 of 41 (5%) primary tumors, and in none of 12 cell lines.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('deletions', 'Var', (17, 26))	('PTEN', 'Gene', (30, 34))	('PTEN', 'Gene', '5728', (30, 34))
487728	23638435	Our laboratory is presently investigating the significance of differential phosphorylation levels of Akt and mTOR in NB cell lines and xenografts, as well as differential phosphorylation at the key activation sites Thr308 and Ser473.	('Akt', 'Protein', (101, 104))	('NB', 'Phenotype', 'HP:0003006', (117, 119))	('phosphorylation', 'MPA', (171, 186))	('Thr308', 'Var', (215, 221))	('Ser473', 'Chemical', '-', (226, 232))	('mTOR', 'Gene', (109, 113))	('Ser473', 'Var', (226, 232))	('Thr308', 'Chemical', '-', (215, 221))	('phosphorylation', 'MPA', (75, 90))
487737	23638435	Other common translocations include t(21;22), t(7;22), and t(17;22), involving the ERG, ETV1, and E1AF genes, respectively.	('ETV1', 'Gene', '2115', (88, 92))	('ERG', 'Gene', '2078', (83, 86))	('t(21;22', 'Var', (36, 43))	('ERG', 'Gene', (83, 86))	('E1AF', 'Gene', '2118', (98, 102))	('ETV1', 'Gene', (88, 92))	('E1AF', 'Gene', (98, 102))
487743	23638435	PI3K inhibition sensitizes these cells to apoptosis by FGF-2 (fibroblast growth factor 2) - a growth and differentiation factor that induces growth arrest in ESFT cells (Hotfilder et al.,).	('FGF-2', 'Gene', '2247', (55, 60))	('PI3K', 'Var', (0, 4))	('inhibition', 'Var', (5, 15))	('growth arrest', 'Phenotype', 'HP:0001510', (141, 154))	('sensitizes', 'Reg', (16, 26))	('fibroblast growth factor 2', 'Gene', '2247', (62, 88))	('FGF-2', 'Gene', (55, 60))	('growth arrest', 'Disease', 'MESH:D006323', (141, 154))	('fibroblast growth factor 2', 'Gene', (62, 88))	('growth arrest', 'Disease', (141, 154))
487749	23638435	PI3K inhibition may serve to decrease chemotherapy resistance, in addition to its direct anticancer effects.	('chemotherapy resistance', 'CPA', (38, 61))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PI3K inhibition', 'Var', (0, 15))	('decrease', 'NegReg', (29, 37))
487750	23638435	PI3K/mTOR inhibitors Wortmannin and LY294002 sensitized ESFT cells in culture to increased apoptosis by various common chemotherapeutic agents.	('LY294002', 'Chemical', 'MESH:C085911', (36, 44))	('Wortmannin', 'Chemical', 'MESH:D000077191', (21, 31))	('apoptosis', 'CPA', (91, 100))	('LY294002', 'Var', (36, 44))	('increased', 'PosReg', (81, 90))
487751	23638435	Doxorubicin-induced apoptosis was enhanced when PI3K was inhibited in TC-71 and TC-32 ESFT cells, as evidenced by increased DNA fragmentation, increased caspase-3 activity, and on TUNEL assay (Toretsky et al.,; Benini et al.,).	('increased', 'PosReg', (143, 152))	('DNA fragmentation', 'CPA', (124, 141))	('enhanced', 'PosReg', (34, 42))	('inhibited', 'NegReg', (57, 66))	('caspase-3', 'Gene', (153, 162))	('PI3K', 'Var', (48, 52))	('increased', 'PosReg', (114, 123))	('activity', 'MPA', (163, 171))	('TC-71', 'CellLine', 'CVCL:2213', (70, 75))	('caspase-3', 'Gene', '836', (153, 162))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('TC-32', 'CellLine', 'CVCL:7151', (80, 85))	('Doxorubicin-induced', 'MPA', (0, 19))
487753	23638435	Inhibition of pAkt with LY294002 enhanced Actinomycin D-induced caspase-dependent cell apoptosis as determined by PARP cleavage assays.	('caspase-dependent cell apoptosis', 'CPA', (64, 96))	('Actinomycin D', 'Chemical', 'MESH:D003609', (42, 55))	('LY294002', 'Var', (24, 32))	('Actinomycin D-induced', 'MPA', (42, 63))	('PARP', 'Gene', '1302', (114, 118))	('LY294002', 'Chemical', 'MESH:C085911', (24, 32))	('PARP', 'Gene', (114, 118))	('enhanced', 'PosReg', (33, 41))
487759	23638435	Up to 80% of alveolar tumors possess the t(2;13)(q35;q14) or t(1;13)(p36;q14) chromosomal translocations, involving the FOXO1 (FKHR) gene on chromosome 13 and the PAX 3 or PAX 7 genes, respectively (Shapiro et al.,).	('FKHR', 'Gene', '2308', (127, 131))	('t(1;13)(p36;q14', 'Var', (61, 76))	('PAX 7', 'Gene', (172, 177))	('FOXO1', 'Gene', (120, 125))	('FOXO1', 'Gene', '2308', (120, 125))	('alveolar tumors', 'Disease', (13, 28))	('alveolar tumors', 'Disease', 'MESH:D002282', (13, 28))	('PAX 3', 'Gene', '5077', (163, 168))	('t(2;13)(q35;q14', 'Var', (41, 56))	('PAX 7', 'Gene', '5081', (172, 177))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('FKHR', 'Gene', (127, 131))	('PAX 3', 'Gene', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (41, 57))
487762	23638435	PI3K activation induces phosphorylation, nuclear export, and transcriptional inactivation of FOXO1, FOXO3, FOXO4, and FOXO6.	('FOXO6', 'Gene', (118, 123))	('nuclear export', 'MPA', (41, 55))	('FOXO4', 'Gene', '4303', (107, 112))	('FOXO6', 'Gene', '100132074', (118, 123))	('transcriptional', 'MPA', (61, 76))	('FOXO1', 'Gene', '2308', (93, 98))	('FOXO3', 'Gene', (100, 105))	('FOXO1', 'Gene', (93, 98))	('phosphorylation', 'MPA', (24, 39))	('PI3K activation', 'Var', (0, 15))	('FOXO4', 'Gene', (107, 112))	('FOXO3', 'Gene', '2309', (100, 105))
487770	23638435	In RMS cell lines, PAX3-FOXO1 inhibition induced PTEN upregulation.	('PAX3', 'Gene', '5077', (19, 23))	('PTEN', 'Gene', '5728', (49, 53))	('RMS', 'Phenotype', 'HP:0002859', (3, 6))	('PAX3', 'Gene', (19, 23))	('inhibition', 'Var', (30, 40))	('FOXO1', 'Gene', '2308', (24, 29))	('upregulation', 'PosReg', (54, 66))	('FOXO1', 'Gene', (24, 29))	('PTEN', 'Gene', (49, 53))
487777	23638435	IGF-2 induction of Akt is regulated by differential phosphorylation at Ser473, rather than at Thr308 where high levels of Akt phosphorylation are seen in all RMS cell lines.	('RMS', 'Phenotype', 'HP:0002859', (158, 161))	('IGF-2', 'Gene', '3481', (0, 5))	('Ser473', 'Var', (71, 77))	('Ser473', 'Chemical', '-', (71, 77))	('Thr308', 'Chemical', '-', (94, 100))	('Akt', 'Pathway', (19, 22))	('IGF-2', 'Gene', (0, 5))	('phosphorylation', 'MPA', (52, 67))
487779	23638435	In an autocrine loop, the PAX3-FOXO1 fusion transcript transactivates the IGF-1R promoter, further potentiating the effects of IGF on PI3K/Akt activation.	('potentiating', 'PosReg', (99, 111))	('transactivates', 'MPA', (55, 69))	('PI3K/Akt activation', 'Pathway', (134, 153))	('PAX3', 'Gene', '5077', (26, 30))	('IGF-1R', 'Gene', '3480', (74, 80))	('PAX3', 'Gene', (26, 30))	('IGF-1R', 'Gene', (74, 80))	('FOXO1', 'Gene', (31, 36))	('FOXO1', 'Gene', '2308', (31, 36))	('fusion', 'Var', (37, 43))
487785	23638435	In a series of 59 pediatric patients, PTEN deletions were observed in 12 cases (Freeman et al.,).	('deletions', 'Var', (43, 52))	('patients', 'Species', '9606', (28, 36))	('PTEN', 'Gene', (38, 42))	('PTEN', 'Gene', '5728', (38, 42))
487786	23638435	In a series of 98 primary adult osteosarcomas, 40 were found to have at least 1 gene mutation, and among these, 3 novel mutations involving PI3KCA were observed.	('osteosarcomas', 'Disease', 'MESH:D012516', (32, 45))	('osteosarcomas', 'Phenotype', 'HP:0002669', (32, 45))	('mutation', 'Var', (85, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('osteosarcoma', 'Phenotype', 'HP:0002669', (32, 44))	('osteosarcomas', 'Disease', (32, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
487787	23638435	Yet, samples without PI3KCA mutations have been found to have high levels of pAkt and p4EBP1, suggesting that alternate mechanisms exist for the hyperactivation of PI3K in osteosarcoma (Choy et al.,).	('4EBP1', 'Gene', (87, 92))	('hyperactivation', 'PosReg', (145, 160))	('osteosarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('osteosarcoma', 'Disease', (172, 184))	('osteosarcoma', 'Disease', 'MESH:D012516', (172, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('mutations', 'Var', (28, 37))	('4EBP1', 'Gene', '1978', (87, 92))
487789	23638435	The PI3K/Akt pathway has been shown to play an important role in cell cycle regulation and apoptosis of osteosarcoma cancer stem-like cells, with dose-dependent decrease in pAkt expression seen following PI3K inhibition with LY204002.	('PI3K inhibition', 'Var', (204, 219))	('osteosarcoma cancer', 'Disease', (104, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('apoptosis', 'CPA', (91, 100))	('decrease', 'NegReg', (161, 169))	('cell cycle', 'CPA', (65, 75))	('pAkt', 'MPA', (173, 177))	('osteosarcoma', 'Phenotype', 'HP:0002669', (104, 116))	('LY204002', 'Chemical', '-', (225, 233))	('PI3K/Akt pathway', 'Pathway', (4, 20))	('osteosarcoma cancer', 'Disease', 'MESH:D012516', (104, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('LY204002', 'Var', (225, 233))
487794	23638435	Alendronate, an amino-bisphosphonate commonly used in clinical practice, inhibits Akt phosphorylation at Ser473 and Thr308 in osteosarcoma cell lines.	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('osteosarcoma', 'Disease', (126, 138))	('Alendronate', 'Chemical', 'MESH:D019386', (0, 11))	('Thr308', 'Var', (116, 122))	('amino-bisphosphonate', 'Chemical', '-', (16, 36))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('inhibits', 'NegReg', (73, 81))	('Ser473', 'Chemical', '-', (105, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Akt', 'Pathway', (82, 85))	('Thr308', 'Chemical', '-', (116, 122))
487797	23638435	Everolimus inhibition alone induced marked decrease in the rate of cell cycle phases and mitosis, but further significant additive effects were seen with addition of Zoledronic acid, resulting in downregulation of mTOR downstream signaling involving 4EBP1 and decreased Ras isoprenylation and GTP binding.	('decrease', 'NegReg', (43, 51))	('mTOR downstream signaling', 'MPA', (214, 239))	('decreased', 'NegReg', (260, 269))	('GTP binding', 'Interaction', (293, 304))	('mitosis', 'Disease', (89, 96))	('Zoledronic acid', 'Chemical', 'MESH:D000077211', (166, 181))	('4EBP1', 'Gene', '1978', (250, 255))	('Ras isoprenylation', 'MPA', (270, 288))	('GTP', 'Chemical', 'MESH:D006160', (293, 296))	('inhibition', 'Var', (11, 21))	('downregulation', 'NegReg', (196, 210))	('mitosis', 'Disease', 'None', (89, 96))	('4EBP1', 'Gene', (250, 255))	('Everolimus', 'Chemical', 'MESH:D000068338', (0, 10))
487812	23638435	In preclinical trials, MK-2206 increased the efficacy of etoposide or rapamycin in NB cell lines (by MTS assay) (Li et al.,).	('rapamycin', 'Chemical', 'MESH:D020123', (70, 79))	('increased', 'PosReg', (31, 40))	('etoposide', 'Chemical', 'MESH:D005047', (57, 66))	('efficacy', 'MPA', (45, 53))	('MK-2206', 'Var', (23, 30))	('NB', 'Phenotype', 'HP:0003006', (83, 85))	('MK-2206', 'Chemical', 'MESH:C548887', (23, 30))
487815	23638435	Based on favorable preclinical evidence (Maira et al.,; Serra et al.,; Brachmann et al.,; Maira,; Bendell et al.,; Koul et al.,), pediatric preclinical testing is underway for two of these agents: NVP-BKM-120, a selective inhibitor of PI3K, and NVP-BEZ-235 a dual mTOR and PI3K inhibitor (Federico,).	('BKM-120', 'Chemical', 'MESH:C571178', (201, 208))	('NVP-BKM-120', 'Var', (197, 208))	('NVP-BEZ-235', 'Gene', (245, 256))
487827	23638435	The most recent mTOR inhibitor under evaluation in a phase I clinical trial is Ridaforolimus, both alone (NCT01431534) and in potential combination with Dalotuzumab (NCT01431547).	('combination', 'Interaction', (136, 147))	('NCT01431534', 'Var', (106, 117))	('Dalotuzumab', 'Chemical', 'MESH:C569480', (153, 164))	('Ridaforolimus', 'Chemical', 'MESH:C515074', (79, 92))
487837	23638435	While IGF-1R antagonists showed more preclinical promise than clinical efficacy as single agent therapy, they may be useful in combination therapy (Wagner and Maki,).	('IGF-1R', 'Gene', (6, 12))	('antagonists', 'Var', (13, 24))	('IGF-1R', 'Gene', '3480', (6, 12))
487843	23638435	A recent review summarized abnormalities in the PI3K/Akt/mTOR signaling pathway in hematologic malignancies and reviewed the results of preclinical and clinical research supporting the use of these agents for pediatric patients with these cancers (Barrett et al.,).	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('hematologic malignancies', 'Disease', (83, 107))	('cancers', 'Disease', (239, 246))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('abnormalities', 'Var', (27, 40))	('patients', 'Species', '9606', (219, 227))	('PI3K/Akt/mTOR signaling pathway', 'Pathway', (48, 79))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('hematologic malignancies', 'Disease', 'MESH:D019337', (83, 107))
487844	23638435	Recent preclinical investigation indicates that mTOR inhibition may also disrupt leukemia/stromal interactions, leading to antitumor effect by a different mechanism (Zeng et al.,).	('mTOR', 'Protein', (48, 52))	('inhibition', 'Var', (53, 63))	('leukemia', 'Disease', 'MESH:D007938', (81, 89))	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('leukemia', 'Disease', (81, 89))	('tumor', 'Disease', (127, 132))	('disrupt', 'NegReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
487845	23638435	In tuberous sclerosis, the associated inactivating mutations of TSC1 and TSC2 result in constitutive activation of the mTOR pathway independent of upstream PI3K/Akt stimulation.	('inactivating mutations', 'Var', (38, 60))	('TSC1', 'Gene', '7248', (64, 68))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (3, 21))	('TSC2', 'Gene', '7249', (73, 77))	('activation', 'PosReg', (101, 111))	('TSC2', 'Gene', (73, 77))	('TSC1', 'Gene', (64, 68))	('tuberous sclerosis', 'Disease', (3, 21))	('mTOR pathway', 'Pathway', (119, 131))
487847	23638435	The development of targeted PI3K therapies will likely lead to the addition of these antagonists to existing therapy options, alone or in combination with background treatments (chemotherapy, surgery, radiotherapy), and eventually offer enhanced treatment schemes to children with solid tumors.	('solid tumors', 'Disease', (281, 293))	('PI3K', 'Var', (28, 32))	('solid tumors', 'Disease', 'MESH:D009369', (281, 293))	('children', 'Species', '9606', (267, 275))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))
487852	23638435	Lastly, the activation of alternative survival pathways such as deregulated KRAS has been shown to bypass Everolimus-mediated mTOR inhibition (Delbaldo et al.,).	('deregulated', 'Var', (64, 75))	('KRAS', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (76, 80))	('Everolimus-mediated', 'MPA', (106, 125))	('Everolimus', 'Chemical', 'MESH:D000068338', (106, 116))
487910	31751681	The relationship of SD-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset.	('TTF1', 'Gene', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('mutations', 'Var', (383, 392))	('NSCC', 'Disease', (439, 443))	('sarcomatoid areas', 'Disease', (107, 124))	('SD-TSTs', 'Chemical', '-', (20, 27))	('TTF1', 'Gene', '7270', (185, 189))	('p40', 'Gene', (193, 196))	('sarcomatoid areas', 'Disease', 'MESH:C538614', (107, 124))	('patient', 'Species', '9606', (261, 268))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('tumor', 'Disease', (348, 353))	('mutations', 'Var', (411, 420))	('p40', 'Gene', '3578', (193, 196))
487917	31751681	A prototypical example is inactivation of SMARCB1 (INI1) in pediatric malignant rhabdoid tumors (MRTs).	('SMARCB1', 'Gene', (42, 49))	('inactivation', 'Var', (26, 38))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('malignant rhabdoid tumors', 'Disease', (70, 95))	('INI1', 'Gene', (51, 55))	('INI1', 'Gene', '6598', (51, 55))	('SMARCB1', 'Gene', '6598', (42, 49))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (70, 95))
487920	31751681	In addition to MRTs and SCCOHTs: the tumors in which SMARCA4/B1 alterations are virtually pathognomonic events occurring in a distinctively simple genomic background : the loss of SMARCA4, SMARCB1, and other SWI/SNF components has been implicated in the process of de-differentiation in tumors of various sites, including carcinomas of endometrium, bladder, gastrointestinal tract, and other organs, and other tumor types such as melanoma.	('SMARCB1', 'Gene', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (410, 415))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('carcinomas', 'Disease', (322, 332))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('SMARCA4', 'Gene', '6597', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('SMARCA4', 'Gene', (53, 60))	('tumor', 'Disease', (287, 292))	('tumors', 'Disease', (37, 43))	('melanoma', 'Disease', 'MESH:D008545', (430, 438))	('gastrointestinal tract', 'Disease', (358, 380))	('loss', 'Var', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('carcinomas', 'Disease', 'MESH:D009369', (322, 332))	('carcinomas', 'Phenotype', 'HP:0030731', (322, 332))	('SMARCA4', 'Gene', (180, 187))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('implicated', 'Reg', (236, 246))	('bladder', 'Disease', (349, 356))	('tumor', 'Disease', (410, 415))	('tumor', 'Disease', (37, 42))	('melanoma', 'Disease', (430, 438))	('melanoma', 'Phenotype', 'HP:0002861', (430, 438))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('SMARCB1', 'Gene', '6598', (189, 196))	('tumors', 'Disease', (287, 293))	('SMARCA4', 'Gene', '6597', (53, 60))
487921	31751681	Among pulmonary tumors, SMARCA4 mutations and loss of expression occur in approximately 5% of non-small cell carcinomas (NSCC), predominantly adenocarcinomas, associated with aggressive clinical behavior.	('pulmonary tumors', 'Phenotype', 'HP:0100526', (6, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('pulmonary tumors', 'Disease', (6, 22))	('SMARCA4', 'Gene', (24, 31))	('non-small cell carcinomas', 'Disease', 'MESH:D002289', (94, 119))	('mutations', 'Var', (32, 41))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (98, 119))	('loss of expression', 'NegReg', (46, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('pulmonary tumor', 'Phenotype', 'HP:0100526', (6, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('pulmonary tumors', 'Disease', 'MESH:D008175', (6, 22))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (175, 203))	('SMARCA4', 'Gene', '6597', (24, 31))	('adenocarcinomas', 'Disease', 'MESH:D000230', (142, 157))	('adenocarcinomas', 'Disease', (142, 157))	('non-small cell carcinomas', 'Disease', (94, 119))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
487923	31751681	The initial landmark study comprised 19 patients with thoracic tumors characterized by undifferentiated round cell or rhabdoid morphology and SMARCA4 mutations with concomitant loss of expression.	('rhabdoid', 'CPA', (118, 126))	('thoracic tumors', 'Disease', (54, 69))	('expression', 'MPA', (185, 195))	('patients', 'Species', '9606', (40, 48))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('SMARCA4', 'Gene', (142, 149))	('thoracic tumors', 'Disease', 'MESH:D013899', (54, 69))	('mutations', 'Var', (150, 159))	('SMARCA4', 'Gene', '6597', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
487929	31751681	Despite the phenotypic similarity of SDTS with MRT and SCCOHT, several features identified in prior studies were unusual for bona fide MRT-type sarcomas, including (1) history of smoking in most patients, (2) complex genomes with frequent TP53 mutations and presence of mutations typical of smoking-related NSCCs (KRAS, KEAP1, STK11) in a subset of tumors, and (3) focal expression of NSCC lineage markers TTF1 or p40 in several cases.	('sarcomas', 'Phenotype', 'HP:0100242', (144, 152))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('sarcomas', 'Disease', (144, 152))	('KEAP1', 'Gene', '9817', (320, 325))	('KRAS', 'Gene', '3845', (314, 318))	('KEAP1', 'Gene', (320, 325))	('TP53', 'Gene', '7157', (239, 243))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('p40', 'Gene', (414, 417))	('TTF1', 'Gene', '7270', (406, 410))	('tumors', 'Disease', (349, 355))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('KRAS', 'Gene', (314, 318))	('mutations', 'Var', (270, 279))	('patients', 'Species', '9606', (195, 203))	('STK11', 'Gene', (327, 332))	('mutations', 'Var', (244, 253))	('tumors', 'Disease', 'MESH:D009369', (349, 355))	('TTF1', 'Gene', (406, 410))	('TP53', 'Gene', (239, 243))	('STK11', 'Gene', '6794', (327, 332))	('presence', 'Reg', (258, 266))	('p40', 'Gene', '3578', (414, 417))	('sarcomas', 'Disease', 'MESH:D012509', (144, 152))
487937	31751681	Second, eight cases were identified by means of a retrospective re-review of thoracic tumors harboring SMARCA4 truncating mutations or deletions in cBioPortal database of MSK-IMPACT next-generation sequencing (NGS) results.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('thoracic tumors', 'Disease', (77, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('SMARCA4', 'Gene', (103, 110))	('SMARCA4', 'Gene', '6597', (103, 110))	('thoracic tumors', 'Disease', 'MESH:D013899', (77, 92))	('truncating mutations', 'Var', (111, 131))	('deletions', 'Var', (135, 144))
487940	31751681	In addition, as a control group, 45 conventional lung NSCCs (comprising predominantly adenocarcinomas) with SMARCA4 truncating mutations and SMARCA4 loss by immunohistochemistry (IHC) (i.e., SD-NSCC) were selected from the retrospective search of cBioPortal.	('loss', 'NegReg', (149, 153))	('adenocarcinomas', 'Disease', 'MESH:D000230', (86, 101))	('truncating mutations', 'Var', (116, 136))	('SMARCA4', 'Gene', (141, 148))	('SMARCA4', 'Gene', (108, 115))	('SMARCA4', 'Gene', '6597', (141, 148))	('SMARCA4', 'Gene', '6597', (108, 115))	('adenocarcinomas', 'Disease', (86, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
487947	31751681	A total of 16 SD-TSTs and 45 SD-NSCCs were analyzed using MSK-IMPACT (a Hybrid Capture-based NGS platform) for somatic mutations in 341 (v3), 410 (v4), or 468 (v5) cancer genes, as previously described.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('SD-NSCCs', 'Disease', 'MESH:D029461', (29, 37))	('341', 'Var', (132, 135))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('SD-TSTs', 'Chemical', '-', (14, 21))	('mutations', 'Var', (119, 128))	('SD-NSCCs', 'Disease', (29, 37))
487948	31751681	Two older, retrospectively identified SD-TSTs had been analyzed by Sequenom mass spectrometry genotyping for hotspot mutations in key lung NSCC oncogenes.	('SD-TSTs', 'Chemical', '-', (38, 45))	('mutations', 'Var', (117, 126))	('lung', 'Disease', (134, 138))
487949	31751681	Using NGS results, all silent and nonsilent mutations were used to identify different mutational signatures according to the distribution of the six substitution classes (C>A, C>G, C>T, T>A, T>C, T>G) and their trinucleotide context; for each sample, a weight corresponding to the percentage of mutations explained by each of 30 mutational signatures was calculated, as previously described.	('C>T', 'Var', (181, 184))	('T>A', 'Var', (186, 189))	('C>A', 'Var', (171, 174))	('T>C', 'Var', (191, 194))	('trinucleotide', 'Chemical', '-', (211, 224))	('C>G', 'Var', (176, 179))
487981	31751681	Notably, tumors with retained SMARCA2 exhibited identical sarcomatoid morphology and lacked claudin-4 as other SD-TSTs.	('retained', 'Var', (21, 29))	('SMARCA2', 'Gene', (30, 37))	('SD-TSTs', 'Chemical', '-', (111, 118))	('SMARCA2', 'Gene', '6595', (30, 37))	('lacked', 'NegReg', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('claudin-4', 'Gene', '1364', (92, 101))	('sarcomatoid', 'Disease', 'MESH:C538614', (58, 69))	('sarcomatoid morphology', 'Phenotype', 'HP:0100242', (58, 80))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('claudin-4', 'Gene', (92, 101))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('sarcomatoid', 'Disease', (58, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
487983	31751681	The combination of strong synaptophysin expression, high Ki67, and frequent crush artifact with geographic necrosis closely resembled the appearance of neuroendocrine carcinomas, resulting in an initial diagnosis of large cell or small cell neuroendocrine carcinomas in five cases (23%) (Supplementary Table 2).	('high Ki67', 'Var', (52, 61))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (152, 177))	('neuroendocrine carcinomas', 'Disease', (241, 266))	('necrosis', 'Disease', (107, 115))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (241, 266))	('neuroendocrine carcinomas', 'Disease', (152, 177))	('synaptophysin', 'Gene', (26, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('large cell', 'Disease', (216, 226))	('synaptophysin', 'Gene', '6855', (26, 39))	('necrosis', 'Disease', 'MESH:D009336', (107, 115))	('men', 'Species', '9606', (294, 297))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (152, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (256, 266))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (241, 266))
487993	31751681	The most striking difference was the substantially larger primary tumor size of SD-TSTs compared with SD-NSCCs (mean = 9.2 cm versus 3.2 cm, respectively; p < 0.0001).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SD-TSTs', 'Chemical', '-', (80, 87))	('larger', 'PosReg', (51, 57))	('tumor', 'Disease', (66, 71))	('SD-TSTs', 'Var', (80, 87))	('SD-NSCCs', 'Disease', (102, 110))	('SD-NSCCs', 'Disease', 'MESH:D029461', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
487996	31751681	This revealed that overall survival of patients with SD-TSTs was considerably worse than that for patients with SD-NSCC (median survival = 5.2 mo versus 20.7 mo, respectively; p = 0.004) (Fig.	('SD-TSTs', 'Chemical', '-', (53, 60))	('patients', 'Species', '9606', (39, 47))	('SD-TSTs', 'Var', (53, 60))	('patients', 'Species', '9606', (98, 106))	('worse', 'NegReg', (78, 83))
487999	31751681	Tumors analyzed by NGS harbored on average 16 nonsynonymous mutations per case (range = 4-34).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('nonsynonymous mutations', 'Var', (46, 69))
488001	31751681	Overall, 50% of cases with molecular analysis (9/18) harbored alterations typical of smoking-associated NSCC, including STK11 (n = 6), KEAP1 (n = 4), or KRAS (n = 5); three cases harbored concurrent KRAS/STK11/KEAP1 mutations.	('KRAS', 'Gene', '3845', (199, 203))	('STK11', 'Gene', '6794', (204, 209))	('STK11', 'Gene', (120, 125))	('KEAP1', 'Gene', (135, 140))	('KEAP1', 'Gene', '9817', (135, 140))	('KEAP1', 'Gene', '9817', (210, 215))	('KRAS', 'Gene', (153, 157))	('STK11', 'Gene', '6794', (120, 125))	('KRAS', 'Gene', '3845', (153, 157))	('smoking-associated NSCC', 'Disease', (85, 108))	('KEAP1', 'Gene', (210, 215))	('STK11', 'Gene', (204, 209))	('alterations', 'Var', (62, 73))	('KRAS', 'Gene', (199, 203))
488002	31751681	KRAS mutations comprised 2 G12C, 2 G12V, and Q61H alterations.	('G12V', 'SUBSTITUTION', 'None', (35, 39))	('G12C', 'SUBSTITUTION', 'None', (27, 31))	('G12V', 'Var', (35, 39))	('Q61H', 'Var', (45, 49))	('Q61H', 'SUBSTITUTION', 'None', (45, 49))	('KRAS', 'Gene', (0, 4))	('G12C', 'Var', (27, 31))	('KRAS', 'Gene', '3845', (0, 4))
488003	31751681	In addition, three cases harbored NF1 mutations : another alteration seen in NSCC with predominance in smokers.	('mutations', 'Var', (38, 47))	('harbored', 'Reg', (25, 33))	('NF1', 'Gene', '4763', (34, 37))	('NF1', 'Gene', (34, 37))
488004	31751681	For comparison, review of published NGS data for 933 soft tissue sarcomas in cBioPortal revealed that mutations in KRAS, STK11, or KEAP1 are either absent or extremely rare in those tumors (Supplementary Fig.	('men', 'Species', '9606', (196, 199))	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('KEAP1', 'Gene', '9817', (131, 136))	('KRAS', 'Gene', (115, 119))	('tumors', 'Disease', (182, 188))	('sarcomas', 'Disease', (65, 73))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('KRAS', 'Gene', '3845', (115, 119))	('mutations', 'Var', (102, 111))	('KEAP1', 'Gene', (131, 136))	('STK11', 'Gene', (121, 126))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (53, 73))	('STK11', 'Gene', '6794', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
488006	31751681	SMARCA4 alterations comprised nonsense mutations (n = 7), splice site mutations (n = 4), and deletions (n = 3) (Supplementary Fig.	('SMARCA4', 'Gene', (0, 7))	('splice', 'MPA', (58, 64))	('SMARCA4', 'Gene', '6597', (0, 7))	('alterations', 'Var', (8, 19))	('men', 'Species', '9606', (118, 121))	('deletions', 'Var', (93, 102))	('nonsense mutations', 'Var', (30, 48))
488007	31751681	By FACETS, SMARCA4 mutations were accompanied by loss of heterozygosity (LOH) in all cases, which was primarily copy-neutral (i.e., deletion of wild-type allele accompanied by duplication of mutant allele).	('deletion', 'Var', (132, 140))	('loss', 'NegReg', (49, 53))	('SMARCA4', 'Gene', (11, 18))	('SMARCA4', 'Gene', '6597', (11, 18))	('mutations', 'Var', (19, 28))	('heterozygosity', 'MPA', (57, 71))	('duplication', 'MPA', (176, 187))
488008	31751681	LOH was detected in both cases that lacked detectable SMARCA4 mutations.	('SMARCA4', 'Gene', (54, 61))	('SMARCA4', 'Gene', '6597', (54, 61))	('mutations', 'Var', (62, 71))
488009	31751681	FISH for SMARCA4 locus was performed on 20 SD-TSTs (14 with NGS and six without NGS), revealing detectable alterations in only seven cases (35%) (Supplementary Table 7).	('NGS', 'Var', (60, 63))	('SD-TSTs', 'Chemical', '-', (43, 50))	('men', 'Species', '9606', (152, 155))	('SMARCA4', 'Gene', (9, 16))	('SMARCA4', 'Gene', '6597', (9, 16))
488010	31751681	All SMARCA4 alterations detected by NGS were somatic, given that the MSK-IMPACT bioinformatic pipeline filters out germline variants found in the patient's paired normal DNA.	('alterations', 'Var', (12, 23))	('patient', 'Species', '9606', (146, 153))	('SMARCA4', 'Gene', (4, 11))	('SMARCA4', 'Gene', '6597', (4, 11))
488025	31751681	In this series, the relationship of SD-TST with NSCC was supported by the following observations: (1) documentation of a NSCC component in five of 22 SD-TSTs; (2) focal expression of NSCC lineage markers, TTF1 or p40, in four additional cases; (3) smoking history in all except one patient, accompanied by radiologic evidence of emphysema, and (4) genomic alterations characteristic of smoking-related NSCC, including a dominant smoking signature, high TMB (average = 14.2 mutations per megabase) and smoking-associated NSCC-type mutations (KRAS, STK11, KEAP1) in a subset of cases.	('TST', 'Gene', (153, 156))	('p40', 'Gene', '3578', (213, 216))	('emphysema', 'Disease', 'MESH:D004646', (329, 338))	('STK11', 'Gene', '6794', (547, 552))	('men', 'Species', '9606', (106, 109))	('p40', 'Gene', (213, 216))	('emphysema', 'Disease', (329, 338))	('TST', 'Gene', (39, 42))	('TST', 'Gene', '7263', (153, 156))	('TTF1', 'Gene', '7270', (205, 209))	('KRAS', 'Gene', '3845', (541, 545))	('high', 'Disease', (448, 452))	('KEAP1', 'Gene', '9817', (554, 559))	('SD-TSTs', 'Chemical', '-', (150, 157))	('STK11', 'Gene', (547, 552))	('mutations', 'Var', (473, 482))	('TST', 'Gene', '7263', (39, 42))	('KRAS', 'Gene', (541, 545))	('KEAP1', 'Gene', (554, 559))	('emphysema', 'Phenotype', 'HP:0002097', (329, 338))	('TMB', 'Chemical', '-', (453, 456))	('patient', 'Species', '9606', (282, 289))	('TTF1', 'Gene', (205, 209))
488026	31751681	Furthermore, the pattern of metastatic spread for SD-TSTs was more typical of carcinoma than sarcoma, involving the lymph nodes, bones, and adrenal glands.	('carcinoma', 'Disease', 'MESH:D009369', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('sarcoma', 'Disease', (93, 100))	('SD-TSTs', 'Chemical', '-', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('SD-TSTs', 'Var', (50, 57))	('carcinoma', 'Disease', (78, 87))	('metastatic spread', 'CPA', (28, 45))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
488030	31751681	A similar concept of "epithelial-rhabdoid transition" or "rhabdoid/round cell de-differentiation" is a well-recognized phenomenon in tumors of various sites, which has been recently linked to inactivation of SWI/SNF components superimposed on the genomic alterations of the parent neoplasm.	('inactivation', 'Var', (192, 204))	('linked', 'Reg', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('neoplasm', 'Disease', 'MESH:D009369', (281, 289))	('tumors', 'Disease', (133, 139))	('men', 'Species', '9606', (124, 127))	('rhabdoid/round cell de-differentiation', 'CPA', (58, 96))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('neoplasm', 'Disease', (281, 289))	('neoplasm', 'Phenotype', 'HP:0002664', (281, 289))
488037	31751681	Marker expression in SD-TSTs is also distinctive, comprising negative or low keratin expression, consistent lack of epithelial adhesion molecule claudin-4, codeficiency with the second major catalytic subunit of SWI/SNF complex SMARCA2 (BRM) in most cases, and frequent but variable expression of stem cell markers.	('negative', 'NegReg', (61, 69))	('BRM', 'Gene', '6595', (237, 240))	('deficiency', 'Disease', 'MESH:D007153', (158, 168))	('keratin', 'Protein', (77, 84))	('BRM', 'Gene', (237, 240))	('claudin-4', 'Gene', '1364', (145, 154))	('SMARCA2', 'Gene', '6595', (228, 235))	('lack', 'NegReg', (108, 112))	('claudin-4', 'Gene', (145, 154))	('SD-TSTs', 'Chemical', '-', (21, 28))	('low', 'NegReg', (73, 76))	('SD-TSTs', 'Var', (21, 28))	('SMARCA2', 'Gene', (228, 235))	('deficiency', 'Disease', (158, 168))
488052	31751681	However, the fact that most SD-TSTs lack evidence of carcinomatous components may suggest that SMARCA4/A2 co-inactivation tends to occur as an early event in the pathogenesis of SD-TSTs, in line with prior suggestion that the timing of SWI/SNF inactivation may determine the extent of residual carcinomatous components.	('carcinomatous', 'Disease', (294, 307))	('carcinomatous', 'Disease', 'MESH:D055756', (53, 66))	('carcinomatous', 'Disease', (53, 66))	('SD-TSTs', 'Disease', (178, 185))	('SD-TSTs', 'Chemical', '-', (178, 185))	('co-inactivation', 'Var', (106, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('SD-TSTs', 'Chemical', '-', (28, 35))	('carcinomatous', 'Disease', 'MESH:D055756', (294, 307))	('SMARCA4', 'Gene', (95, 102))	('SMARCA4', 'Gene', '6597', (95, 102))
488062	31751681	In such cases, truncated SMARCA4 could be partially expressed and detected by the SMARCA4 antibody that recognizes the N-terminal epitope.	('SMARCA4', 'Gene', '6597', (82, 89))	('SMARCA4', 'Gene', (25, 32))	('SMARCA4', 'Gene', '6597', (25, 32))	('truncated', 'Var', (15, 24))	('SMARCA4', 'Gene', (82, 89))
488069	31751681	Although our NGS panel did not encompass the SMARCA2 gene, prior studies in SCCOHT found a consistent lack of mutations, suggesting epigenetic or post-translational regulation.	('SMARCA2', 'Gene', (45, 52))	('SMARCA2', 'Gene', '6595', (45, 52))	('epigenetic', 'Var', (132, 142))
488070	31751681	Our findings regarding overall mutation profiles of SD-TSTs in smokers are notable for the parallels with SD-NSCC, including the high TMB (defined as > 13.8 mutations per megabase) and the presence of classic smoking-associated NSCC mutations involving KRAS, SKT11, and KEAP1 in a subset of cases.	('KEAP1', 'Gene', (270, 275))	('SD-NSCC', 'Disease', (106, 113))	('TMB', 'Chemical', '-', (134, 137))	('SD-TSTs', 'Gene', (52, 59))	('SKT11', 'Gene', (259, 264))	('TMB', 'MPA', (134, 137))	('KRAS', 'Gene', (253, 257))	('KEAP1', 'Gene', '9817', (270, 275))	('KRAS', 'Gene', '3845', (253, 257))	('mutations', 'Var', (233, 242))	('smoking-associated NSCC', 'Disease', (209, 232))	('NSCC', 'Disease', (228, 232))	('SD-TSTs', 'Chemical', '-', (52, 59))
488071	31751681	Apparent enrichment in NF1 mutations may be of interest given their previously reported association with undifferentiated histology in NSCC.	('mutations', 'Var', (27, 36))	('NF1', 'Gene', (23, 26))	('men', 'Species', '9606', (15, 18))	('association', 'Reg', (88, 99))	('NF1', 'Gene', '4763', (23, 26))	('NSCC', 'Disease', (135, 139))
488078	31751681	First, we confirm that SD-TSTs are associated with exceptionally poor prognosis (median survival = 5.2 mo) and show that the prognosis is substantially worse than that for SD-NSCCs.	('SD-NSCCs', 'Disease', 'MESH:D029461', (172, 180))	('SD-TSTs', 'Chemical', '-', (23, 30))	('SD-TSTs', 'Var', (23, 30))	('SD-NSCCs', 'Disease', (172, 180))	('poor', 'NegReg', (65, 69))
488100	31751681	However, consistent history of smoking, radiologic evidence of emphysema, and:most importantly:presence of genomic smoking signature and NSCC-type alterations in such tumors support their pulmonary origin.	('emphysema', 'Phenotype', 'HP:0002097', (63, 72))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('emphysema', 'Disease', (63, 72))	('emphysema', 'Disease', 'MESH:D004646', (63, 72))	('pulmonary origin', 'CPA', (188, 204))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('alterations', 'Var', (147, 158))
488107	31751681	In particular, inhibitors of Enhancer of Zeste Homolog 2 histone methyltransferase have emerged as promising therapeutic agents for MRTs and SCCOHTs, with activity linked to SMARCB1 or dual SMARCA4/A2 inactivation.	('SMARCB1', 'Gene', '6598', (174, 181))	('SMARCA4', 'Gene', (190, 197))	('SMARCB1', 'Gene', (174, 181))	('SMARCA4', 'Gene', '6597', (190, 197))	('SCCOHTs', 'Disease', (141, 148))	('inhibitors', 'Var', (15, 25))	('MRTs', 'Disease', (132, 136))
488306	33401376	Immunohistochemically, all cases showed smooth muscle actin (SMA) positivity in spindle cells, while desmin, beta catenin, cytokeratin, and CD34 were negative, resulting in a diagnosis of LGMS.	('desmin', 'Gene', '1674', (101, 107))	('LGMS', 'Disease', (188, 192))	('beta catenin', 'Gene', (109, 121))	('beta catenin', 'Gene', '1499', (109, 121))	('positivity', 'Var', (66, 76))	('CD34', 'Gene', (140, 144))	('CD34', 'Gene', '947', (140, 144))	('desmin', 'Gene', (101, 107))
488437	32204368	However, beta catenin staining and mutations are frequent along with many other acquired mutations, making these aggressive tumors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('aggressive tumors', 'Disease', 'MESH:D001523', (113, 130))	('beta catenin', 'Gene', (9, 21))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('aggressive tumors', 'Disease', (113, 130))	('beta catenin', 'Gene', '1499', (9, 21))	('mutations', 'Var', (35, 44))
488445	32204368	These tumors do not produce AFP but are associated with mutations or deletions of the INI1 or SMARCA4 gene on chromosome 22.	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('SMARCA4', 'Gene', (94, 101))	('tumors', 'Disease', (6, 12))	('deletions', 'Var', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('SMARCA4', 'Gene', '6597', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('INI1', 'Gene', (86, 90))	('associated', 'Reg', (40, 50))	('INI1', 'Gene', '6598', (86, 90))
488507	32204368	However, the anaplastic variant of HB was not associated with inferior post-transplant outcomes.	('post', 'Gene', '159371', (71, 75))	('post', 'Gene', (71, 75))	('HB', 'Phenotype', 'HP:0002884', (35, 37))	('anaplastic', 'Var', (13, 23))
488544	32204368	However, chemotherapeutic agents, including cisplatin, facilitate tumor cell death by enhancing the anti-tumor response.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('death', 'Disease', 'MESH:D003643', (77, 82))	('death', 'Disease', (77, 82))	('facilitate', 'PosReg', (55, 65))	('tumor', 'Disease', (66, 71))	('cisplatin', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('enhancing', 'PosReg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (105, 110))
488552	32204368	The tumor landscape may reveal novel druggable mutations, novel pathways for alternative chemotherapy, or changes in tumor clonality after primary chemotherapy that may help select more effective second line agents.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('mutations', 'Var', (47, 56))	('changes', 'Reg', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
488555	32204368	Among other findings, whole exome sequencing (WES) studies of HB implicate the well-known wingless integration-1 (Wnt)-beta-catenin signaling pathways, aberrant ubiquitin ligase signaling, and mutations that cause impaired function of tumor suppressors or critical transcription factors.	('beta-catenin', 'Gene', '1499', (119, 131))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('ubiquitin ligase signaling', 'MPA', (161, 187))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('implicate', 'Reg', (65, 74))	('mutations', 'Var', (193, 202))	('aberrant', 'Var', (152, 160))	('tumor', 'Disease', (235, 240))	('beta-catenin', 'Gene', (119, 131))	('HB', 'Phenotype', 'HP:0002884', (62, 64))
488559	32204368	This panel also looks for specific mutations in EGFR, ALK, BRAF, ERBB2, and BRCA1/2 genes which indicate response to specific agents in non-small-cell lung cancer, melanoma, breast, ovarian, and colon cancer.	('ALK', 'Gene', (54, 57))	('EGFR', 'Gene', '1956', (48, 52))	('BRCA1/2', 'Gene', (76, 83))	('lung cancer', 'Disease', (151, 162))	('ERBB2', 'Gene', '2064', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('BRCA1/2', 'Gene', '672;675', (76, 83))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (140, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('EGFR', 'Gene', (48, 52))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('colon cancer', 'Phenotype', 'HP:0003003', (195, 207))	('ERBB2', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('melanoma, breast, ovarian, and colon cancer', 'Disease', 'MESH:D008545', (164, 207))	('ALK', 'Gene', '238', (54, 57))	('indicate', 'Reg', (96, 104))	('mutations', 'Var', (35, 44))
488564	32204368	The components of this assay range from variants in 300-500 common cancer-associated genes (Guardant360 or Guardant Omni, Guardant Health), to custom panels that incorporate 16 unique clonal somatic variants individualized to each tumor (Signatera, Natera).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('cancer', 'Disease', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('variants', 'Var', (40, 48))
488574	32204368	HB hepatoblastoma  HCC Hepatocellular carcinoma  SEER Surveillance, Epidemiology and End-Results  SRTR Scientific Registry for Transplant Recipients  AFP alphafetoprotein  HCN-NOS Hepatocellular neoplasm NOS  SCU small cell undifferentiated hepatoblastoma  N:: C nuclear to cytoplasmic ratio  PHITT Pediatric Hepatic International Tumor Trial  SIOPEL Societe Internationale d'Oncologie Pediatrique:Epithelial Liver Tumor Study Group   PRETEXT Pretreatment Extent of Tumor  POSTTEXT Post-treatment extent of Tumor  COG Cooperative Oncology group  JCCG Japan Children's Cancer Group  MRT malignant rhabdoid tumor  PLADO Cisplatin and doxorubicin  C5VD combination of cisplatin/5-flurouricil/vincristine/doxorubicin  EFS event-free survival  PLUTO Pediatric Liver Unresectable Tumours Observatory  TMB tumor mutation burden  Mut mutations  ctDNA circulating tumor DN  MHC major histocompatibility complex	('POST', 'Gene', (473, 477))	('tumor', 'Disease', (799, 804))	('POST', 'Gene', '159371', (473, 477))	('HCN-NOS Hepatocellular neoplasm NOS  SCU small cell undifferentiated hepatoblastoma  N', 'Disease', 'MESH:D018197', (172, 258))	('Cisplatin', 'Chemical', 'MESH:D002945', (618, 627))	('tumor', 'Disease', 'MESH:D009369', (799, 804))	('Cancer', 'Disease', (568, 574))	('vincristine', 'Chemical', 'MESH:D014750', (689, 700))	('Tumor', 'Phenotype', 'HP:0002664', (507, 512))	('tumor', 'Phenotype', 'HP:0002664', (855, 860))	('mutation', 'Var', (805, 813))	('neoplasm', 'Phenotype', 'HP:0002664', (195, 203))	('Post', 'Gene', (482, 486))	('tumor', 'Disease', (605, 610))	('Tumor', 'Phenotype', 'HP:0002664', (331, 336))	('Children', 'Species', '9606', (557, 565))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (23, 47))	('Oncology', 'Phenotype', 'HP:0002664', (530, 538))	('Post', 'Gene', '159371', (482, 486))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('Cancer', 'Disease', 'MESH:D009369', (568, 574))	('tumor', 'Disease', 'MESH:D009369', (605, 610))	('TMB tumor', 'Disease', (795, 804))	('Tumor', 'Phenotype', 'HP:0002664', (466, 471))	('tumor', 'Phenotype', 'HP:0002664', (799, 804))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (586, 610))	('doxorubicin', 'Chemical', 'MESH:D004317', (632, 643))	('Liver Tumor', 'Phenotype', 'HP:0002896', (409, 420))	('Tumours', 'Phenotype', 'HP:0002664', (774, 781))	('HB hepatoblastoma  HCC Hepatocellular carcinoma', 'Disease', (0, 47))	('malignant rhabdoid tumor', 'Disease', (586, 610))	('cisplatin', 'Chemical', 'MESH:D002945', (665, 674))	('HB', 'Phenotype', 'HP:0002884', (0, 2))	('HB hepatoblastoma  HCC Hepatocellular carcinoma', 'Disease', 'MESH:D018197', (0, 47))	('Liver Tumor', 'Disease', 'MESH:D008113', (409, 420))	('Hepatocellular neoplasm', 'Phenotype', 'HP:0001402', (180, 203))	('PLADO', 'Chemical', '-', (612, 617))	('Tumor', 'Phenotype', 'HP:0002664', (415, 420))	('tumor', 'Phenotype', 'HP:0002664', (605, 610))	('tumor', 'Disease', (855, 860))	('Liver Tumor', 'Disease', (409, 420))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (3, 17))	('C5V', 'Chemical', '-', (645, 648))	('TMB tumor', 'Disease', 'MESH:D009369', (795, 804))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (241, 255))	('HCC', 'Phenotype', 'HP:0001402', (19, 22))	('doxorubicin', 'Chemical', 'MESH:D004317', (701, 712))	('tumor', 'Disease', 'MESH:D009369', (855, 860))	('COG', 'Chemical', '-', (514, 517))	('Cancer', 'Phenotype', 'HP:0002664', (568, 574))
488624	31667169	Accumulating evidence suggests that, in addition to its role as a staging tool, laparoscopic liver resection provides better quality of care, improves patient outcomes by minimizing blood loss and postoperative pain or morbidity, and shortens hospital stay relative to open surgery.	('better', 'PosReg', (118, 124))	('pain', 'Phenotype', 'HP:0012531', (211, 215))	('patient', 'Species', '9606', (151, 158))	('minimizing', 'NegReg', (171, 181))	('hospital', 'MPA', (243, 251))	('quality of', 'MPA', (125, 135))	('postoperative pain', 'Disease', 'MESH:D010149', (197, 215))	('laparoscopic', 'Var', (80, 92))	('blood loss', 'Disease', 'MESH:D006473', (182, 192))	('postoperative pain', 'Disease', (197, 215))	('improves', 'PosReg', (142, 150))	('shortens', 'NegReg', (234, 242))	('blood loss', 'Disease', (182, 192))
488686	30027144	In pediatric solid tumors, structural variants are more common than recurrent point mutations.	('common', 'Reg', (56, 62))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (3, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('pediatric solid tumors', 'Disease', (3, 25))	('structural variants', 'Var', (27, 46))
488688	30027144	Copy number changes seen by ultralow passage whole-genome sequencing enabled detection of ctDNA in patients with osteosarcoma, neuroblastoma, alveolar rhabdomyosarcoma, and Wilms tumor.	('Wilms tumor', 'Disease', (173, 184))	('Copy number changes', 'Var', (0, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('osteosarcoma', 'Disease', (113, 125))	('neuroblastoma', 'Disease', (127, 140))	('alveolar rhabdomyosarcoma', 'Disease', (142, 167))	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('ctDNA', 'Gene', (90, 95))	('neuroblastoma', 'Phenotype', 'HP:0003006', (127, 140))	('Wilms tumor', 'Disease', 'MESH:D009396', (173, 184))	('detection', 'Reg', (77, 86))	('patients', 'Species', '9606', (99, 107))	('neuroblastoma', 'Disease', 'MESH:D009447', (127, 140))	('Wilms tumor', 'Phenotype', 'HP:0002667', (173, 184))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (151, 167))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (142, 167))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (142, 167))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))
488702	30027144	Many ctDNA assays have been developed to detect highly recurrent hot-spot mutations that frequently drive adult malignancies.	('malignancies', 'Disease', 'MESH:D009369', (112, 124))	('mutations', 'Var', (74, 83))	('malignancies', 'Disease', (112, 124))
488703	30027144	However, recent comprehensive sequencing efforts in pediatric cancers show that pediatric solid tumors are rarely driven by highly recurrent single-nucleotide variants.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pediatric solid tumors', 'Disease', (80, 102))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (80, 102))	('pediatric cancers', 'Disease', 'MESH:D009369', (52, 69))	('pediatric cancers', 'Disease', (52, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('single-nucleotide variants', 'Var', (141, 167))
488704	30027144	Instead, structural variants, including chromosomal copy number changes and DNA translocations, are common somatic events in these tumor types.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('DNA', 'CPA', (76, 79))	('chromosomal copy number changes', 'Var', (40, 71))
488741	30027144	In three of the four patients with Ewing sarcoma for which no copy number change could be detected by ULP-WGS in the tumor (MRD0006, MRD0041, MRD0047), TranSS-Seq was able to detect an EWSR1-fusion in the tumor and cell-free DNA (Data Supplement).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('MRD0006', 'Var', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('tumor', 'Disease', (117, 122))	('MRD0047', 'Var', (142, 149))	('EWSR1', 'Gene', '2130', (185, 190))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('EWSR1', 'Gene', (185, 190))	('Ewing sarcoma', 'Disease', (35, 48))	('MRD0041', 'Var', (133, 140))	('detect', 'Reg', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
488742	30027144	In the fourth patient (MRD0007), TranSS-Seq detected an EWSR1/FLI fusion in the tumor but not in cell-free DNA (Data Supplement).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('EWSR1', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('FLI', 'Gene', '2314', (62, 65))	('FLI', 'Gene', (62, 65))	('tumor', 'Disease', (80, 85))	('fusion', 'Var', (66, 72))	('detected', 'Reg', (44, 52))	('patient', 'Species', '9606', (14, 21))	('EWSR1', 'Gene', '2130', (56, 61))
488743	30027144	Finally, in all three patients with Ewing sarcoma for which the tumor biopsy specimen detected a segmental copy number change but ULP-WGS was unable to detect ctDNA from the same patient (MRD0019, MRD0023, MRD0046), TranSS-Seq detected low levels of ctDNA, suggesting that TranSS-Seq may have greater sensitivity for ctDNA than ULP-WGS in Ewing sarcoma (Data Supplement).	('tumor', 'Disease', (64, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Ewing sarcoma', 'Disease', (339, 352))	('patient', 'Species', '9606', (179, 186))	('patients', 'Species', '9606', (22, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (36, 49))	('MRD0046', 'Var', (206, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (345, 352))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (339, 352))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (339, 352))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('patient', 'Species', '9606', (22, 29))	('Ewing sarcoma', 'Disease', (36, 49))
488752	30027144	However, four patients with tumor necrosis < 70% (MRD0031, MRD0036, MRD0040, MRD0054) had detectable ctDNA in at least one sample collected after initiation of chemotherapy (Fig 4D; Data Supplement).	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor necrosis', 'Disease', (28, 42))	('MRD0054', 'Var', (77, 84))	('MRD0040', 'Var', (68, 75))	('MRD0031', 'Var', (50, 57))	('patients', 'Species', '9606', (14, 22))	('MRD0036', 'Var', (59, 66))	('tumor necrosis', 'Disease', 'MESH:D009336', (28, 42))
488754	30027144	Recent studies demonstrate that mutations in STAG2 and TP53 may be associated with a worse outcome in Ewing sarcoma.	('STAG2', 'Gene', (45, 50))	('Ewing sarcoma', 'Disease', (102, 115))	('STAG2', 'Gene', '10735', (45, 50))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 115))	('mutations', 'Var', (32, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (102, 115))	('associated', 'Reg', (67, 77))
488755	30027144	A frame-shift mutation in STAG2 was detected by ctDNA from one patient (MRD0023), and a mutation in TP53 was detected in another patient (MRD0003; Data Supplement).	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (100, 104))	('frame-shift mutation', 'Var', (2, 22))	('STAG2', 'Gene', '10735', (26, 31))	('patient', 'Species', '9606', (63, 70))	('STAG2', 'Gene', (26, 31))	('patient', 'Species', '9606', (129, 136))
488757	30027144	The FOXO1 fluorescent in situ hybridization probe, which is used in the diagnostic work-up of alveolar rhabdomyosarcoma, confirms a FOXO1 rearrangement but not the fusion partner.	('FOXO1', 'Gene', (132, 137))	('FOXO1', 'Gene', (4, 9))	('alveolar rhabdomyosarcoma', 'Disease', (94, 119))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (94, 119))	('rearrangement', 'Var', (138, 151))	('FOXO1', 'Gene', '2308', (4, 9))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (103, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (94, 119))	('FOXO1', 'Gene', '2308', (132, 137))
488759	30027144	In our study, all patients with ctDNA were found to have a PAX3/FOXO1 translocation (Data Supplement).	('ctDNA', 'Disease', (32, 37))	('FOXO1', 'Gene', '2308', (64, 69))	('translocation', 'Var', (70, 83))	('FOXO1', 'Gene', (64, 69))	('PAX3', 'Gene', '5077', (59, 63))	('PAX3', 'Gene', (59, 63))	('patients', 'Species', '9606', (18, 26))
488760	30027144	In osteosarcoma, copy number gains of chromosome arm 8q are associated with a poor outcome.	('osteosarcoma', 'Disease', (3, 15))	('copy number gains', 'Var', (17, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))
488761	30027144	ULP-WGS detected copy number gains in 8q in seven of nine osteosarcoma samples with detectable ctDNA (Fig 1C; Data Supplement).	('osteosarcoma', 'Disease', (58, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('copy number gains', 'Var', (17, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))
488762	30027144	Amplification of MYCN is a well-established marker of poor prognosis in neuroblastoma.	('MYCN', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('neuroblastoma', 'Disease', (72, 85))	('MYCN', 'Gene', '4613', (17, 21))	('neuroblastoma', 'Phenotype', 'HP:0003006', (72, 85))	('neuroblastoma', 'Disease', 'MESH:D009447', (72, 85))
488764	30027144	These were the only two patients with neuroblastoma with fluorescent in situ hybridization-confirmed MYCN amplification in our cohort.	('neuroblastoma', 'Phenotype', 'HP:0003006', (38, 51))	('MYCN', 'Gene', (101, 105))	('amplification', 'Var', (106, 119))	('MYCN', 'Gene', '4613', (101, 105))	('neuroblastoma', 'Disease', 'MESH:D009447', (38, 51))	('patients', 'Species', '9606', (24, 32))	('neuroblastoma', 'Disease', (38, 51))
488765	30027144	Finally, in Wilms tumor, copy number gains of 1q were associated with poor prognosis in favorable histology tumors.	('copy number gains of 1q', 'Var', (25, 48))	('Wilms tumor', 'Disease', (12, 23))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('Wilms tumor', 'Phenotype', 'HP:0002667', (12, 23))	('Wilms tumor', 'Disease', 'MESH:D009396', (12, 23))
488774	30027144	We first applied ULP-WGS to detect copy number changes in cell-free DNA and found that the majority of patients with pediatric solid tumors had detectable levels of ctDNA.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('pediatric solid tumors', 'Disease', (117, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (117, 139))	('patients', 'Species', '9606', (103, 111))	('copy number changes', 'Var', (35, 54))	('ctDNA', 'MPA', (165, 170))
488779	30027144	One recent study used a combination of ddPCR and hybrid capture sequencing to detect EWSR1 translocations in Ewing sarcoma and desmoplastic small round-cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('EWSR1', 'Gene', '2130', (85, 90))	('Ewing sarcoma', 'Disease', (109, 122))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('translocations', 'Var', (91, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('EWSR1', 'Gene', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('desmoplastic small round-cell tumors', 'Disease', 'MESH:D058405', (127, 163))	('desmoplastic small round-cell tumors', 'Disease', (127, 163))
488780	30027144	Results showed that it is feasible to detect EWSR1 translocations directly from the plasma of these patients without first sequencing the tumor sample.	('detect', 'Reg', (38, 44))	('translocations', 'Var', (51, 65))	('EWSR1', 'Gene', (45, 50))	('tumor', 'Disease', (138, 143))	('EWSR1', 'Gene', '2130', (45, 50))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
488793	30027144	With the emergence of new sequencing modifications that improve sensitivity and decrease sequencing errors, we believe that ctDNA profiling by next-generation sequencing approaches will improve our understanding of tumor heterogeneity and patterns of somatic evolution in pediatric solid tumors.	('sequencing', 'MPA', (89, 99))	('sensitivity', 'MPA', (64, 75))	('tumor', 'Disease', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (272, 294))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('modifications', 'Var', (37, 50))	('tumor', 'Disease', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('pediatric solid tumors', 'Disease', (272, 294))
488800	28141799	We retrospectively analysed all specimens tested for EWSR1 rearrangements by fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) over a 7-year period.	('EWSR1', 'Gene', (53, 58))	('EWSR1', 'Gene', '2130', (53, 58))	('rearrangements', 'Var', (59, 73))
488801	28141799	In total, 210 (27.9%) specimens were FISH-positive for EWSR1 rearrangement compared to 111 (14.4%) that showed EWSR1 fusion transcripts with RT-PCR.	('rearrangement', 'Var', (61, 74))	('EWSR1', 'Gene', (55, 60))	('EWSR1', 'Gene', (111, 116))	('fusion transcripts', 'Var', (117, 135))	('EWSR1', 'Gene', '2130', (55, 60))	('EWSR1', 'Gene', '2130', (111, 116))
488805	28141799	FISH is more sensitive for identifying EWSR1 rearrangements than RT-PCR.	('EWSR1', 'Gene', (39, 44))	('EWSR1', 'Gene', '2130', (39, 44))	('rearrangements', 'Var', (45, 59))
488807	28141799	FISH and RT-PCR should be used as complementary modalities in diagnosing EWSR1-rearranged neoplasms, but as tumour groups harbouring EWSR1 rearrangements are increasingly characterised and because given translocations involving EWSR1 and its partner genes are not always specific for tumour types, it is critical that these are evaluated by specialist soft tissue surgical pathologists noting the morphologic and immunohistochemical context.	('tumour', 'Disease', (108, 114))	('EWSR1', 'Gene', '2130', (133, 138))	('tumour', 'Disease', 'MESH:D009369', (284, 290))	('neoplasms', 'Phenotype', 'HP:0002664', (90, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (90, 98))	('EWSR1', 'Gene', (73, 78))	('tumour', 'Disease', (284, 290))	('neoplasms', 'Disease', 'MESH:D009369', (90, 99))	('EWSR1', 'Gene', (133, 138))	('EWSR1', 'Gene', (228, 233))	('neoplasms', 'Disease', (90, 99))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('EWSR1', 'Gene', '2130', (73, 78))	('EWSR1', 'Gene', '2130', (228, 233))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('translocations', 'Var', (203, 217))
488810	28141799	A proportion of soft tissue tumours harbours characteristic, reproducible genetic abnormalities, including chromosomal translocations that result in the fusion of two separate genes, of which there are almost 100 uniquely identified in sarcoma; molecular techniques are therefore a crucial and routine adjunct to diagnosis.	('soft tissue tumour', 'Phenotype', 'HP:0031459', (16, 34))	('chromosomal translocations', 'Var', (107, 133))	('soft tissue tumours', 'Disease', 'MESH:D012983', (16, 35))	('genetic abnormalities', 'Disease', (74, 95))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('sarcoma', 'Disease', 'MESH:D012509', (236, 243))	('soft tissue tumours', 'Disease', (16, 35))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('sarcoma', 'Disease', (236, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('genetic abnormalities', 'Disease', 'MESH:D030342', (74, 95))	('fusion', 'MPA', (153, 159))
488814	28141799	EWSR1 rearrangements can be easily detected in the routine setting by fluorescence in situ hybridisation (FISH) with break-apart probes, and corresponding fusion transcripts by reverse transcription-PCR (RT-PCR) studies, usually using commercial probes and primers respectively.	('EWSR1', 'Gene', (0, 5))	('EWSR1', 'Gene', '2130', (0, 5))	('rearrangements', 'Var', (6, 20))
488817	28141799	Prior to EWSR1 rearrangement testing, diagnoses were made from morphology and immunohistochemistry by one or two (KT and CF) soft tissue specialist (consultant/attending) pathologists.	('rearrangement testing', 'Var', (15, 36))	('EWSR1', 'Gene', (9, 14))	('EWSR1', 'Gene', '2130', (9, 14))
488826	28141799	A total of 812 specimens from 762 patients were analysed for EWSR1 rearrangement by either FISH, RT-PCR or both modalities.	('EWSR1', 'Gene', (61, 66))	('EWSR1', 'Gene', '2130', (61, 66))	('patients', 'Species', '9606', (34, 42))	('rearrangement', 'Var', (67, 80))
488827	28141799	Routine FISH was performed on 753 (97.5%) samples, of which 210 (27.9%) were positive for an EWSR1 rearrangement and 524 (69.6%) were negative.	('rearrangement', 'Var', (99, 112))	('EWSR1', 'Gene', '2130', (93, 98))	('positive', 'Reg', (77, 85))	('EWSR1', 'Gene', (93, 98))
488841	28141799	The final interpretations were of small round cell tumour, possibly Ewing sarcoma with variant partner gene, or in the case with cellular atypia, of possible atypical Ewing sarcoma.	('Ewing sarcoma', 'Disease', (68, 81))	('variant', 'Var', (87, 94))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (167, 180))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (167, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (68, 81))	('tumour', 'Disease', (51, 57))	('Ewing sarcoma', 'Disease', (167, 180))
488846	28141799	An EWSR1 rearrangement was less prevalent in EMC, AFH, PPMS, myoepithelial neoplasms, LGFMS and SEF.	('myoepithelial neoplasms', 'Disease', 'MESH:D009208', (61, 84))	('PPMS', 'Disease', (55, 59))	('neoplasms', 'Phenotype', 'HP:0002664', (75, 84))	('EMC', 'Disease', (45, 48))	('myoepithelial neoplasms', 'Phenotype', 'HP:0031492', (61, 84))	('EWSR1', 'Gene', '2130', (3, 8))	('prevalent', 'Reg', (32, 41))	('LGFMS', 'Disease', (86, 91))	('AFH', 'Disease', (50, 53))	('rearrangement', 'Var', (9, 22))	('myoepithelial neoplasms', 'Disease', (61, 84))	('neoplasm', 'Phenotype', 'HP:0002664', (75, 83))	('EWSR1', 'Gene', (3, 8))
488852	28141799	Although overall FISH testing was more reliable, the additional RT-PCR testing was useful in identifying a fusion transcript containing an EWSR1 rearrangement in FISH-negative cases, particularly for Ewing sarcoma (four cases, 3.6%), DRSCT (two cases, 9.1%), AFH (four cases, 20.0%), CCSLGT (one case, 20.0%) and LGFMS and SEF (six cases, 31.6%).	('Ewing sarcoma', 'Disease', 'MESH:C563168', (200, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('EWSR1', 'Gene', (139, 144))	('DRSCT', 'Disease', (234, 239))	('SEF', 'Disease', (323, 326))	('EWSR1', 'Gene', '2130', (139, 144))	('CCSLGT', 'Disease', (284, 290))	('rearrangement', 'Var', (145, 158))	('LGFMS', 'Disease', (313, 318))	('Ewing sarcoma', 'Disease', (200, 213))	('AFH', 'Disease', (259, 262))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (200, 213))
488856	28141799	It is now clear though that the spectrum of gene fusions associated with soft tissue tumours is far wider than previously anticipated.	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('soft tissue tumours', 'Disease', (73, 92))	('gene fusions', 'Var', (44, 56))	('soft tissue tumours', 'Disease', 'MESH:D012983', (73, 92))	('soft tissue tumour', 'Phenotype', 'HP:0031459', (73, 91))	('associated', 'Reg', (57, 67))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
488857	28141799	Our study exemplifies the widespread nature of EWSR1 rearrangements in soft tissue tumours and the need to correlate positive molecular findings with morphology and immunohistochemistry.	('EWSR1', 'Gene', '2130', (47, 52))	('soft tissue tumours', 'Disease', 'MESH:D012983', (71, 90))	('soft tissue tumour', 'Phenotype', 'HP:0031459', (71, 89))	('soft tissue tumours', 'Disease', (71, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('EWSR1', 'Gene', (47, 52))	('rearrangements', 'Var', (53, 67))
488867	28141799	The t(11;22)(q24;q12) rearrangement leading to EWSR1-FLI1 fusion is the commonest (in ~85%), with about 10% harbouring t(21;22)(q22;q12) leading to EWSR1-ERG fusion.	('EWSR1', 'Gene', '2130', (47, 52))	('EWSR1', 'Gene', (148, 153))	('t(11;22)(q24;q12', 'Var', (4, 20))	('leading to', 'Reg', (36, 46))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (119, 136))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 21))	('t(21;22)(q22;q12', 'Var', (119, 135))	('leading to', 'Reg', (137, 147))	('EWSR1', 'Gene', '2130', (148, 153))	('ERG', 'Gene', '2078', (154, 157))	('EWSR1', 'Gene', (47, 52))	('ERG', 'Gene', (154, 157))
488868	28141799	However, as there are numerous variant fusions (present in less than 1%), ancillary molecular analysis can be negative in tumours displaying typical morphologic and immunohistochemical features of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (197, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (197, 210))	('fusions', 'Var', (39, 46))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (197, 210))	('variant fusions', 'Var', (31, 46))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('tumours', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
488870	28141799	Furthermore, a group of primitive round cell tumours with histologic appearances similar to Ewing sarcomas remain unclassifiable, lacking specific clinical and immunohistochemical features and molecular evidence of EWSR1 gene rearrangements or other small round cell tumour-associated gene rearrangements such as SS18, DDIT3 or FOXO1.	('tumour', 'Disease', (267, 273))	('Ewing sarcomas', 'Disease', (92, 106))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (92, 106))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('cell tumours', 'Disease', 'MESH:C538614', (40, 52))	('tumour', 'Disease', (45, 51))	('cell tumours', 'Disease', (40, 52))	('EWSR1', 'Gene', '2130', (215, 220))	('rearrangements', 'Var', (226, 240))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('DDIT3', 'Gene', (319, 324))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('FOXO1', 'Gene', (328, 333))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('EWSR1', 'Gene', (215, 220))	('tumour', 'Phenotype', 'HP:0002664', (267, 273))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (92, 106))	('SS18', 'Gene', (313, 317))	('tumour', 'Disease', 'MESH:D009369', (267, 273))
488873	28141799	CIC-DUX4 fusions have been demonstrated in up to two thirds of EWSR1 rearrangement-negative undifferentiated round cell sarcomas of pediatric and young adult patients, with expression profiling demonstrating a distinct gene signature and suggesting a distinct pathogenesis from Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (278, 291))	('DUX4', 'Gene', (4, 8))	('fusions', 'Var', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (284, 291))	('sarcomas', 'Disease', (120, 128))	('EWSR1', 'Gene', '2130', (63, 68))	('DUX4', 'Gene', '100288687', (4, 8))	('Ewing sarcoma', 'Disease', (278, 291))	('rearrangement-negative', 'Var', (69, 91))	('demonstrated', 'Reg', (27, 39))	('patients', 'Species', '9606', (158, 166))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('EWSR1', 'Gene', (63, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (278, 291))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
488877	28141799	Finally, 13 'unclassifiable' neoplasms which did not show typical histologic or immunohistochemical features of Ewing sarcoma showed EWSR1 rearrangement with FISH but no identifiable partner, that is, they did not harbour detectable EWSR1-related fusion transcripts with the primers available (Table 5) (Figure 2).	('Ewing sarcoma', 'Disease', (112, 125))	('EWSR1', 'Gene', '2130', (133, 138))	('neoplasms', 'Phenotype', 'HP:0002664', (29, 38))	('EWSR1', 'Gene', (233, 238))	('EWSR1', 'Gene', '2130', (233, 238))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (112, 125))	('neoplasms', 'Disease', (29, 38))	('EWSR1', 'Gene', (133, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (112, 125))	('neoplasm', 'Phenotype', 'HP:0002664', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('neoplasms', 'Disease', 'MESH:D009369', (29, 38))	('rearrangement', 'Var', (139, 152))
488882	28141799	It is unclear whether any of these neoplasms could represent specific, as yet uncharacterised tumour types harbouring EWSR1 rearrangements with unknown partner genes, or if these EWSR1 rearrangements might be non-reproducible and a function of the intrinsic genetic instability of the tumours.	('tumour', 'Disease', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (285, 292))	('tumours', 'Disease', (285, 292))	('neoplasm', 'Phenotype', 'HP:0002664', (35, 43))	('neoplasms', 'Disease', 'MESH:D009369', (35, 44))	('EWSR1', 'Gene', '2130', (179, 184))	('neoplasms', 'Disease', (35, 44))	('neoplasms', 'Phenotype', 'HP:0002664', (35, 44))	('tumour', 'Phenotype', 'HP:0002664', (285, 291))	('EWSR1', 'Gene', (118, 123))	('rearrangements', 'Var', (124, 138))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Disease', 'MESH:D009369', (285, 291))	('EWSR1', 'Gene', (179, 184))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('tumours', 'Disease', 'MESH:D009369', (285, 292))	('tumour', 'Disease', (285, 291))	('EWSR1', 'Gene', '2130', (118, 123))
488883	28141799	It seems, however, that 'unclassifiable' EWSR1-rearranged neoplasms represent only a small proportion of cases in this study; from these relatively small numbers there were no identifiably recurrent morphologic patterns or immunoprofiles, so the hypothesis of these representing malignant tumours in which EWSR1 rearrangement was present due to inherent genetic instability rather than as a driver mechanism for pathogenesis appears more likely.	('EWSR1', 'Gene', (41, 46))	('neoplasms', 'Disease', 'MESH:D009369', (58, 67))	('neoplasms', 'Disease', (58, 67))	('neoplasm', 'Phenotype', 'HP:0002664', (58, 66))	('EWSR1', 'Gene', (306, 311))	('tumour', 'Phenotype', 'HP:0002664', (289, 295))	('EWSR1', 'Gene', '2130', (41, 46))	('EWSR1', 'Gene', '2130', (306, 311))	('tumours', 'Phenotype', 'HP:0002664', (289, 296))	('neoplasms', 'Phenotype', 'HP:0002664', (58, 67))	('malignant tumours', 'Disease', 'MESH:D009369', (279, 296))	('malignant tumours', 'Disease', (279, 296))	('rearrangement', 'Var', (312, 325))
488885	28141799	FISH had shown heterozygous deletion or unbalanced split signals for EWSR1, suggesting unbalanced translocations or rearrangements, but these were in keeping with false-positive results owing to the proximity of the SMARCB1 and EWSR1 genes on chromosome 22, whereby large SMARCB1 deletions can involve the EWSR1 locus.	('EWSR1', 'Gene', (69, 74))	('EWSR1', 'Gene', (306, 311))	('EWSR1', 'Gene', '2130', (69, 74))	('EWSR1', 'Gene', (228, 233))	('EWSR1', 'Gene', '2130', (306, 311))	('SMARCB1', 'Gene', (216, 223))	('EWSR1', 'Gene', '2130', (228, 233))	('deletions', 'Var', (280, 289))	('SMARCB1', 'Gene', (272, 279))
488886	28141799	Care should therefore be taken in the interpretation of FISH for EWSR1 rearrangement with INI1-deficient neoplasms, and in general the FISH patterns for these tumours have been complex, differing from the more uniform and simple split signals of typical EWSR1-rearranged neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (271, 280))	('EWSR1', 'Gene', '2130', (65, 70))	('INI1-deficient neoplasms', 'Disease', (90, 114))	('neoplasms', 'Disease', (105, 114))	('tumours', 'Disease', (159, 166))	('neoplasms', 'Disease', (271, 280))	('EWSR1', 'Gene', '2130', (254, 259))	('neoplasm', 'Phenotype', 'HP:0002664', (105, 113))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('EWSR1', 'Gene', (65, 70))	('neoplasm', 'Phenotype', 'HP:0002664', (271, 279))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('neoplasms', 'Phenotype', 'HP:0002664', (271, 280))	('rearrangement', 'Var', (71, 84))	('INI1-deficient neoplasms', 'Disease', 'MESH:D009369', (90, 114))	('EWSR1', 'Gene', (254, 259))	('neoplasms', 'Disease', 'MESH:D009369', (105, 114))
488893	26848860	A pathognomonic reciprocal chromosomal translocation results in a fusion gene coding for a protein which derives its N-terminus from a FUS/EWS/TAF15 (FET) protein family member, commonly EWS, and C-terminus containing the DNA-binding domain of an ETS transcription factor, commonly FLI1.	('FUS', 'Gene', (135, 138))	('EWS', 'Gene', (187, 190))	('EWS', 'Gene', '2130', (187, 190))	('FLI1', 'Gene', (282, 286))	('results in', 'Reg', (53, 63))	('FUS', 'Gene', '2521', (135, 138))	('FLI1', 'Gene', '2313', (282, 286))	('TAF15', 'Gene', (143, 148))	('EWS', 'Gene', '2130', (139, 142))	('EWS', 'Gene', (139, 142))	('translocation', 'Var', (39, 52))	('TAF15', 'Gene', '8148', (143, 148))
488895	26848860	As the primary genomic lesion and a protein which is not expressed in normal cells, disrupting EWS-FLI function is an attractive therapeutic strategy for Ewing sarcoma.	('Ewing sarcoma', 'Disease', (154, 167))	('FLI', 'Gene', (99, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (154, 167))	('EWS', 'Gene', (95, 98))	('EWS', 'Gene', '2130', (95, 98))	('disrupting', 'Var', (84, 94))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (154, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('FLI', 'Gene', '2314', (99, 102))
488908	26848860	Indeed, Ewing sarcoma tumor samples showed recurrent, though low frequency, mutations only in the cohesin complex subunit STAG2 (21.5%), the tumor suppressor TP53 (6.2%) and homozygous deletion of the cyclin-dependent kinase inhibitor CDKN2A (13.8%).	('TP53', 'Gene', '7157', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('TP53', 'Gene', (158, 162))	('mutations', 'Var', (76, 85))	('CDKN2A', 'Gene', (235, 241))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (8, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Ewing sarcoma tumor', 'Disease', 'MESH:C563168', (8, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('CDKN2A', 'Gene', '1029', (235, 241))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('STAG2', 'Gene', (122, 127))	('Ewing sarcoma tumor', 'Disease', (8, 27))	('STAG2', 'Gene', '10735', (122, 127))
488909	26848860	It appears possible Ewing sarcoma cells require large-scale epigenetic alteration to maintain malignant programming which disrupts normal developmental processes.	('epigenetic alteration', 'Var', (60, 81))	('Ewing sarcoma', 'Disease', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (20, 33))
488917	26848860	EWS-FLI expression affects the transcriptome, epigenome, and proteome to reprogram cells into a malignant developmental limbo.	('proteome', 'MPA', (61, 69))	('affects', 'Reg', (19, 26))	('expression', 'Var', (8, 18))	('FLI', 'Gene', '2314', (4, 7))	('transcriptome', 'MPA', (31, 44))	('epigenome', 'MPA', (46, 55))	('FLI', 'Gene', (4, 7))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
488923	26848860	Notably, disruption of either epigenetic mechanisms or alternative splicing mechanisms delay tumor growth in xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('delay', 'NegReg', (87, 92))	('epigenetic mechanisms', 'Var', (30, 51))	('alternative splicing mechanisms', 'Var', (55, 86))	('disruption', 'Var', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
488926	26848860	LSD1 (also known as KDM1A, AOF2 and BHC110), is a flavin adenine dinucleotide (FAD) dependent amine oxidase with important epigenetic eraser function, specifically catalyzing oxidative demethylation of mono- and dimethyl-lysine at histone H3 lysines 4 and 9 (H3K4me1/2 and H3K9me1/2), generating formaldehyde and hydrogen peroxide.	('H3K9me1/2', 'Var', (273, 282))	('-lysine', 'Chemical', 'MESH:D008239', (220, 227))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (313, 330))	('flavin adenine dinucleotide', 'Chemical', 'MESH:D005182', (50, 77))	('AOF2', 'Gene', '23028', (27, 31))	('formaldehyde', 'MPA', (296, 308))	('lysines', 'Chemical', 'MESH:D008239', (242, 249))	('formaldehyde', 'Chemical', 'MESH:D005557', (296, 308))	('mono', 'Chemical', 'MESH:C106553', (202, 206))	('KDM1A', 'Gene', '23028', (20, 25))	('BHC110', 'Gene', (36, 42))	('BHC110', 'Gene', '23028', (36, 42))	('KDM1A', 'Gene', (20, 25))	('AOF2', 'Gene', (27, 31))	('LSD1', 'Gene', (0, 4))	('FAD', 'Chemical', 'MESH:D005182', (79, 82))	('H3K4me1/2', 'Var', (259, 268))	('hydrogen peroxide', 'MPA', (313, 330))
488927	26848860	In addition, LSD1 is reported to demethylate modified lysines on a myriad of non-histone proteins such as DNMT1 (residue K1096), E2F1 (K185 residue), MYPT1 (residue K442), p53 (K370 residue) and STAT3 (K140 residue).	('K140 residue', 'Var', (202, 214))	('K185 residue', 'Var', (135, 147))	('DNMT1', 'Gene', (106, 111))	('MYPT1', 'Gene', '4659', (150, 155))	('STAT3', 'Gene', '6774', (195, 200))	('residue K442', 'Var', (157, 169))	('demethylate', 'Chemical', '-', (33, 44))	('lysines', 'Chemical', 'MESH:D008239', (54, 61))	('STAT3', 'Gene', (195, 200))	('MYPT1', 'Gene', (150, 155))	('demethylate', 'Var', (33, 44))	('residue K1096', 'Var', (113, 126))	('K370 residue', 'Var', (177, 189))
488929	26848860	As such, the epigenetic effects of LSD1 are implicated in diverse biologic processes pertinent to adipogenesis, chromosome segregation, cell proliferation, embryonic development, epithelial-mesenchymal transition (EMT), hematopoiesis, and regulation of stem cell pluripotency.	('hematopoiesis', 'Disease', (220, 233))	('epithelial-mesenchymal transition', 'CPA', (179, 212))	('implicated', 'Reg', (44, 54))	('LSD1', 'Gene', (35, 39))	('chromosome segregation', 'CPA', (112, 134))	('hematopoiesis', 'Disease', 'MESH:C536227', (220, 233))	('epigenetic effects', 'Var', (13, 31))	('embryonic', 'CPA', (156, 165))	('cell proliferation', 'CPA', (136, 154))
488940	26848860	This binding conformation is critical for the demethylation of mono- and di-methyl modifications, though the catalytic mechanism precludes activity against trimethylated lysine.	('mono', 'Chemical', 'MESH:C106553', (63, 67))	('mono-', 'Var', (63, 68))	('trimethylated lysine', 'Chemical', '-', (156, 176))	('di-methyl modifications', 'Var', (73, 96))	('demethylation', 'MPA', (46, 59))
488943	26848860	LSD1 was observed to demethylate the H3K9me1/2 marks in association with the androgen receptor, promoting target gene expression.	('androgen receptor', 'Gene', '367', (77, 94))	('demethylate', 'Var', (21, 32))	('promoting', 'PosReg', (96, 105))	('target gene expression', 'MPA', (106, 128))	('androgen receptor', 'Gene', (77, 94))	('H3K9me1/2', 'Protein', (37, 46))	('demethylate', 'Chemical', '-', (21, 32))
488950	26848860	Stabilization of E2F1 in p53-deficient tumor cells through demethylation at K185 inhibits DNA-damage induced cell death.	('inhibits', 'NegReg', (81, 89))	('deficient tumor', 'Disease', (29, 44))	('DNA-damage induced', 'MPA', (90, 108))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('demethylation', 'Var', (59, 72))	('E2F1', 'Gene', (17, 21))	('deficient tumor', 'Disease', 'MESH:D009369', (29, 44))	('death', 'Disease', 'MESH:D003643', (114, 119))	('death', 'Disease', (114, 119))
488951	26848860	In an interesting link between the chromatin and DNA methylation machinery, LSD1 is critical for the maintenance of global DNA methylation patterns through regulation of DNMT1 stability during gastrulation in mouse embryos via demethylation at K1096.	('DNMT1', 'Gene', (170, 175))	('demethylation at K1096', 'Var', (227, 249))	('mouse', 'Species', '10090', (209, 214))	('stability', 'MPA', (176, 185))
488976	26848860	Co-treatment of glioblastoma cells with tranylcypromine and vorinostat led to a marked (6-fold) increase in caspase 3 activity.	('tranylcypromine', 'Chemical', 'MESH:D014191', (40, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('caspase 3', 'Gene', (108, 117))	('activity', 'MPA', (118, 126))	('tranylcypromine', 'Var', (40, 55))	('caspase 3', 'Gene', '836', (108, 117))	('vorinostat', 'Chemical', 'MESH:D000077337', (60, 70))	('increase', 'PosReg', (96, 104))	('glioblastoma', 'Disease', (16, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
488997	26848860	ORY-1001 (structure undisclosed), a trans-2-phenylcyclopropylamine-based LSD1 inactivator (IC50 < 20nM) from Oryzon Genomics is reported to be 1,000 times more potent than TCP and highly selective over related enzymes, including LSD2.	('LSD2', 'Gene', '221656', (229, 233))	('trans-2-phenylcyclopropylamine', 'Chemical', 'MESH:D014191', (36, 66))	('ORY-1001', 'Chemical', '-', (0, 8))	('TCP', 'Chemical', 'MESH:D014191', (172, 175))	('more', 'PosReg', (155, 159))	('ORY-1001', 'Var', (0, 8))	('potent', 'MPA', (160, 166))	('LSD2', 'Gene', (229, 233))
489000	26848860	The recent screening of 165 cancer cell lines of varying histology by Mohammad et al., revealed that the anti-proliferative activity of GSK2879552 was largely restricted to SCLC and AML cell lines (EC50 2-240nM), with genomic analyses revealing elevated MYC expression or amplification was correlated with resistance to GSK2879552, whereas global DNA hypomethylation was correlated with sensitivity.	('resistance', 'MPA', (306, 316))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('elevated', 'PosReg', (245, 253))	('expression', 'MPA', (258, 268))	('GSK2879552', 'Chemical', 'MESH:C000602008', (320, 330))	('MYC', 'Protein', (254, 257))	('AML', 'Disease', (182, 185))	('GSK2879552', 'Var', (320, 330))	('SCLC', 'Gene', (173, 177))	('AML', 'Disease', 'MESH:D015470', (182, 185))	('amplification', 'MPA', (272, 285))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('SCLC', 'Gene', '7864', (173, 177))	('AML', 'Phenotype', 'HP:0004808', (182, 185))	('anti-proliferative activity', 'MPA', (105, 132))	('cancer', 'Disease', (28, 34))	('GSK2879552', 'Chemical', 'MESH:C000602008', (136, 146))	('GSK2879552', 'Var', (136, 146))
489012	26848860	Indeed, deregulation of the FLI transcription factor through N-terminal fusion with other strong activation domains, like VP16, shows transforming activity, highlighting an important role for transcriptional activation in Ewing sarcoma tumorigenesis.	('N-terminal fusion', 'Var', (61, 78))	('transforming activity', 'MPA', (134, 155))	('Ewing sarcoma tumor', 'Disease', (222, 241))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (222, 235))	('FLI', 'Gene', '2314', (28, 31))	('Ewing sarcoma tumor', 'Disease', 'MESH:C563168', (222, 241))	('deregulation', 'Var', (8, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('VP16', 'Gene', '3054', (122, 126))	('FLI', 'Gene', (28, 31))	('VP16', 'Gene', (122, 126))
489030	26848860	For both HDAC and LSD1 inhibition, the effects on cell viability and transcription were mitigated in the context of RNAi-mediated EWS-FLI depletion, suggesting a disease-specific function for these enzymes .	('LSD1', 'Gene', (18, 22))	('FLI', 'Gene', '2314', (134, 137))	('inhibition', 'Var', (23, 33))	('FLI', 'Gene', (134, 137))	('HDAC', 'Gene', (9, 13))	('HDAC', 'Gene', '9734', (9, 13))	('mitigated', 'NegReg', (88, 97))	('EWS', 'Gene', '2130', (130, 133))	('EWS', 'Gene', (130, 133))
489033	26848860	In our hands, HCI-2509 showed more pronounced effects on global H3K9 methylation status in Ewing sarcoma, though the genomic implications of this result as well as a narrowed focus on H3K4 at regions of interest remain the work of continued studies.	('HCI-2509', 'Var', (14, 22))	('Ewing sarcoma', 'Disease', (91, 104))	('HCI-2509', 'Chemical', '-', (14, 22))	('H3K9', 'Protein', (64, 68))	('methylation status', 'MPA', (69, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('effects', 'Reg', (46, 53))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('global', 'MPA', (57, 63))
489095	25089183	A positive trend favouring pazopanib was also recorded in overall survival (12.5 months versus 10.7 months), without reaching a statistical significance (P = 0.25).	('pazopanib', 'Chemical', 'MESH:C516667', (27, 36))	('overall survival', 'MPA', (58, 74))	('pazopanib', 'Var', (27, 36))
489171	32884743	Despite adequate treatment protocol, patients with high-grade STS are still at risk for recurrence and distant metastasis.	('recurrence', 'CPA', (88, 98))	('high-grade', 'Var', (51, 61))	('patients', 'Species', '9606', (37, 45))	('STS', 'Phenotype', 'HP:0030448', (62, 65))	('distant metastasis', 'CPA', (103, 121))
489224	32884743	Lower overall one-year and three-year survival rates (85.2% and 33% respectively) were observed in patients with mGPS 1.	('patients', 'Species', '9606', (99, 107))	('Lower', 'NegReg', (0, 5))	('mGPS 1', 'Var', (113, 119))
489226	32884743	Multivariate analysis showed that mGPS was the only independent prognostic factor for OS in soft tissue sarcoma patients (HR = 2.138; CI = 1.187-3.851).	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (92, 111))	('patients', 'Species', '9606', (112, 120))	('mGPS', 'Var', (34, 38))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (92, 111))	('soft tissue sarcoma', 'Disease', (92, 111))
489252	32884743	Furthermore in their study, majority of anemia were found in patients with concomitant worse prognosis factor like high tumor grade, deep tumor, bigger tumor size, and older age.	('high', 'Var', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('deep tumor', 'Disease', 'MESH:D057887', (133, 143))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('patients', 'Species', '9606', (61, 69))	('anemia', 'Disease', 'MESH:D000740', (40, 46))	('tumor', 'Disease', (152, 157))	('anemia', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('deep tumor', 'Disease', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('anemia', 'Phenotype', 'HP:0001903', (40, 46))	('tumor', 'Disease', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
489254	32884743	Low Hb levels are also associated with poor tumor oxygenation of up to 50-60% of tumors.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('poor tumor oxygenation', 'Phenotype', 'HP:0012418', (39, 61))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Low Hb levels', 'Phenotype', 'HP:0020062', (0, 13))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (81, 86))	('Low', 'Var', (0, 3))
489286	32884743	Microscopic positive margins were associated with high LR and low disease free survival rates.	('low disease', 'Disease', (62, 73))	('Microscopic', 'Var', (0, 11))	('LR', 'Chemical', '-', (55, 57))	('low disease', 'Disease', 'MESH:D009800', (62, 73))
489301	31096717	We also found that high MAGE-A3 mRNA and protein expression is associated with worse overall survival in UPS/MFS.	('MAGE-A3', 'Gene', (24, 31))	('high', 'Var', (19, 23))	('worse', 'NegReg', (79, 84))	('UPS', 'Disease', 'MESH:D017118', (105, 108))	('MAGE-A3', 'Gene', '4102', (24, 31))	('UPS', 'Disease', (105, 108))	('overall survival', 'MPA', (85, 101))
489307	31096717	In addition, presence of this antigen has been associated with worse prognosis in colorectal cancer, gastric cancer, non-small cell lung cancer, cutaneous squamous cell carcinoma and diffuse large B-cell lymphoma.	('colorectal cancer', 'Disease', (82, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (117, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (197, 212))	('associated', 'Reg', (47, 57))	('diffuse large B-cell lymphoma', 'Disease', (183, 212))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (121, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cutaneous squamous cell carcinoma', 'Disease', (145, 178))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (117, 143))	('presence', 'Var', (13, 21))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (145, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('gastric cancer', 'Disease', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('non-small cell lung cancer', 'Disease', (117, 143))	('lymphoma', 'Phenotype', 'HP:0002665', (204, 212))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (145, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))
489311	31096717	Neurological toxicities were observed when administering anti-MAGE-A3 T-cell receptor (TCR)-engineered T cells recognizing epitopes in MAGE-A3, -A9 and -A12, potentially due to expression of MAGE-A12 in the human brain.	('MAGE-A3', 'Gene', (135, 142))	('MAGE-A3', 'Gene', '4102', (135, 142))	('MAGE-A3', 'Gene', '4102', (62, 69))	('A3 T', 'Mutation', 'c.3A>T', (67, 71))	('human', 'Species', '9606', (207, 212))	('Neurological toxicities', 'Disease', 'MESH:D020258', (0, 23))	('Neurological toxicities', 'Disease', (0, 23))	('epitopes', 'Var', (123, 131))	('MAGE-A3', 'Gene', (62, 69))
489338	31096717	High expression was more likely to seen in recurrences (56%, n = 24/43), than primary tumors (30%, n = 13/44) or metastases (31%, n = 6/19) (p = 0.03).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('High expression', 'Var', (0, 15))	('primary tumors', 'Disease', 'MESH:D009369', (78, 92))	('recurrences', 'Disease', (43, 54))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('metastases', 'Disease', (113, 123))	('metastases', 'Disease', 'MESH:D009362', (113, 123))	('primary tumors', 'Disease', (78, 92))
489339	31096717	Utilizing our UPS TMA, we show that MAGEA3 protein expression (>=90 extent %, n = 43 vs. <90%, n = 63) is associated with an adverse survival (p < 0.05; Figure 3D).	('UPS TMA', 'Disease', (14, 21))	('MAGEA3', 'Gene', (36, 42))	('>=90 extent %', 'Var', (63, 76))	('MAGEA3', 'Gene', '4102', (36, 42))	('UPS TMA', 'Disease', 'MESH:D017118', (14, 21))
489382	30552129	A recurrent novel MGA-NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma NUTM1-rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy.	('NUTM1', 'Gene', (22, 27))	('sarcoma', 'Disease', (87, 94))	('fusion', 'Var', (28, 34))	('NUTM1', 'Gene', '256646', (172, 177))	('MGA', 'Gene', (18, 21))	('NUTM1', 'Gene', (172, 177))	('gene fusion', 'Var', (152, 163))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('MGA', 'Gene', '23269', (18, 21))	('aggressive disease', 'Disease', (238, 256))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('aggressive disease', 'Disease', 'MESH:D001523', (238, 256))	('NUTM1', 'Gene', '256646', (95, 100))	('NUTM1', 'Gene', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NUTM1', 'Gene', '256646', (22, 27))	('tumors', 'Disease', (112, 118))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
489384	30552129	In this report, we describe the characterization of two cases of high-grade spindle cell sarcoma harboring a novel MGA-NUTM1 fusion.	('NUTM1', 'Gene', '256646', (119, 124))	('NUTM1', 'Gene', (119, 124))	('fusion', 'Var', (125, 131))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))
489385	30552129	Whole-genome sequencing identified the presence of complex rearrangements resulting in a MGA-NUTM1 fusion gene in the absence of other significant somatic mutations.	('fusion gene', 'Var', (99, 110))	('NUTM1', 'Gene', (93, 98))	('resulting in', 'Reg', (74, 86))	('NUTM1', 'Gene', '256646', (93, 98))
489398	30552129	The advent of next-generation sequencing platforms that enable the identification of therapeutically relevant and targetable mutations and their incorporation into clinical diagnostics and treatment planning have offered renewed insight into the biology and potential curative approaches to rare and incurable cancers.	('mutations', 'Var', (125, 134))	('cancers', 'Phenotype', 'HP:0002664', (310, 317))	('cancers', 'Disease', 'MESH:D009369', (310, 317))	('cancers', 'Disease', (310, 317))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))
489400	30552129	As a result of this screening effort, we identified two cases with a primary diagnosis of high-grade spindle cell sarcoma harboring novel MGA-NUTM1 fusions.	('fusions', 'Var', (148, 155))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('sarcoma', 'Disease', (114, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('NUTM1', 'Gene', '256646', (142, 147))	('NUTM1', 'Gene', (142, 147))
489429	30552129	Assessment of the contribution of known mutation signatures from COSMIC  in the mutation spectrum of the substitution data showed that a majority of mutations were assigned to S-1 (aging-related, clock-like), S-3 (associated with biallelic inactivation of BRCA1 and BRCA2), and S-8 (unknown etiology).	('BRCA1', 'Gene', (256, 261))	('mutations', 'Var', (149, 158))	('BRCA2', 'Gene', (266, 271))	('S-1 (aging-related, clock-like), S-3', 'Gene', '6188', (176, 212))	('BRCA1', 'Gene', '672', (256, 261))	('associated', 'Reg', (214, 224))	('BRCA2', 'Gene', '675', (266, 271))
489430	30552129	However, the tumor did not exhibit other genomic features indicative of BRCA1/BRCA2 deficiency:namely, an excess of microhomology-mediated deletions, short <10-kilobases (kb), or long >100-kb tandem duplications:precluding the possibility of a "BRCAness" phenotype.	('tumor', 'Disease', (13, 18))	('short <10-kilobases', 'Var', (150, 169))	('BRCA1/BRCA2 deficiency', 'Disease', (72, 94))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('long >100-kb tandem', 'Var', (179, 198))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('microhomology-mediated', 'Var', (116, 138))	('BRCA1/BRCA2 deficiency', 'Disease', 'OMIM:604370', (72, 94))
489431	30552129	Case 1 revealed only two somatic changes of potential functional impact: a clonal copy-number gain on Chromosome 15 from intron 2/7 of NUTM1 (Chr 15:34,639,000) to intron 22/24 of MGA (Chr 15:42,057,000), and a subclonal frameshift deletion in NF2 (p.H195fs*12) (Table 1).	('frameshift deletion', 'Var', (221, 240))	('NF2', 'Gene', (244, 247))	('p.H195fs*12', 'Var', (249, 260))	('gain', 'PosReg', (94, 98))	('NF2', 'Gene', '4771', (244, 247))	('NUTM1', 'Gene', '256646', (135, 140))	('p.H195fs*12', 'Mutation', 'p.H195fsX12', (249, 260))	('NUTM1', 'Gene', (135, 140))
489434	30552129	Analysis of the WGS data identified a total of 1389 somatic alterations (1047 single-nucleotide substitutions, 302 indels, and 40 rearrangements) confirming a relatively low mutation burden (3.6 x 10-4 subs/Mb) in this tumor (Fig.	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('single-nucleotide substitutions', 'Var', (78, 109))
489435	30552129	After reviewing all genomic alterations of Case 2, the only somatic alteration of potential functional impact was the MGA-NUTM1 fusion created by a complex structural variant including multiple rearrangement breakpoints between intron 2/7 of NUTM1 and intron 22/24 of MGA (Table 1; Fig.	('NUTM1', 'Gene', '256646', (122, 127))	('NUTM1', 'Gene', (122, 127))	('variant', 'Var', (167, 174))	('NUTM1', 'Gene', '256646', (242, 247))	('NUTM1', 'Gene', (242, 247))
489438	30552129	Tissue from initial diagnosis exhibited a complex break-apart signal pattern consistent with a rearrangement at the NUTM1 locus.	('NUTM1', 'Gene', '256646', (116, 121))	('NUTM1', 'Gene', (116, 121))	('rearrangement', 'Var', (95, 108))
489442	30552129	Analysis of RNA-seq data for fusion genes unequivocally identified an in-frame chimeric transcript containing exons 1-22 of MGA (NM_001164273.1) and exons 3-8 of NUTM1 (NM_175741.2) in both cases (Fig.	('NUTM1', 'Gene', '256646', (162, 167))	('NUTM1', 'Gene', (162, 167))	('NM_175741.2', 'Var', (169, 180))	('NM_001164273.1', 'Var', (129, 143))
489452	30552129	We describe the genetic and histologic characterization of two cases of high-grade spindle cell sarcoma harboring a novel MGA-NUTM1 fusion.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('NUTM1', 'Gene', '256646', (126, 131))	('NUTM1', 'Gene', (126, 131))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('fusion', 'Var', (132, 138))	('sarcoma', 'Disease', (96, 103))
489455	30552129	There appear to be a group of spindle cell sarcomas harboring NUTM1 rearrangement that are completely distinct from NCs.	('rearrangement', 'Var', (68, 81))	('NUTM1', 'Gene', '256646', (62, 67))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('NUTM1', 'Gene', (62, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcomas', 'Disease', (43, 51))
489456	30552129	These tumors harbored BCORL1-NUTM1 and CIC-NUTM1 rearrangements.	('NUTM1', 'Gene', '256646', (43, 48))	('NUTM1', 'Gene', (43, 48))	('CIC-NUTM1', 'Gene', (39, 48))	('BCORL1', 'Gene', (22, 28))	('rearrangements', 'Var', (49, 63))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('BCORL1', 'Gene', '63035', (22, 28))	('NUTM1', 'Gene', '256646', (29, 34))	('NUTM1', 'Gene', (29, 34))	('CIC-NUTM1', 'Gene', '23152;256646', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
489466	30552129	Therefore, it will be imperative to fully characterize tumors of ambiguous lineage for the presence of NUTM1 gene rearrangements and tissue lineage markers in order to identify this unique subset of NUTM1-rearranged tumors with associated mesenchymal markers and institute prompt multimodality therapies to maximize the chances of long-term cure.	('NUTM1', 'Gene', '256646', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NUTM1', 'Gene', '256646', (103, 108))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('NUTM1', 'Gene', (199, 204))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('NUTM1', 'Gene', (103, 108))	('rearrangements', 'Var', (114, 128))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
489467	30552129	In summary, we describe two cases of NUTM1-rearranged tumors with a novel MGA-NUTM1 fusion gene occurring within the context of a histologically defined high-grade spindle cell sarcoma and in the absence of epithelial differentiation.	('NUTM1', 'Gene', (37, 42))	('NUTM1', 'Gene', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('sarcoma', 'Disease', (177, 184))	('fusion gene', 'Var', (84, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('NUTM1', 'Gene', '256646', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('NUTM1', 'Gene', '256646', (78, 83))	('tumors', 'Disease', (54, 60))
489477	30552129	For each mutation we calculated corrected VAF (aka cancer cell fraction) as previously described, using the mutant allele burden, tumor purity, and locus-specific copy number in the tumor and matched normal.	('mutation', 'Var', (9, 17))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mutant', 'Var', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('aka cancer', 'Disease', 'MESH:D009369', (47, 57))	('aka cancer', 'Disease', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
489491	24358232	In this study, quantitative and profound analyses of magnetic resonance imaging (MRI) were developed to evaluate these as imaging biomarkers for MK1775 and Gem in an osteosarcoma xenotransplant model at early time-points following treatment.	('MK1775', 'Chemical', 'MESH:C549567', (145, 151))	('MK1775', 'Var', (145, 151))	('Gem', 'Gene', (156, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (166, 178))	('osteosarcoma', 'Disease', (166, 178))	('osteosarcoma', 'Disease', 'MESH:D012516', (166, 178))	('Gem', 'Gene', '2669', (156, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))
489505	24358232	In a subsequent study, we observed that MK1775 led to cell death in all sarcoma cells and tumor explants independent of their p53 status and showed strong synergistic interaction with gemcitabine.	('sarcoma', 'Disease', (72, 79))	('cell death', 'CPA', (54, 64))	('interaction', 'Interaction', (167, 178))	('p53', 'Gene', '7157', (126, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('MK1775', 'Chemical', 'MESH:C549567', (40, 46))	('gemcitabine', 'Chemical', 'MESH:C056507', (184, 195))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('MK1775', 'Var', (40, 46))	('p53', 'Gene', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
489506	24358232	Furthermore, we demonstrated that in a patient-derived osteosarcoma xenotransplant mouse model, MK1775 alone, and in combination with gemcitabine, caused marked terminal differentiation, apoptotic cell death and increased DNA damage by day 14.	('MK1775', 'Chemical', 'MESH:C549567', (96, 102))	('patient', 'Species', '9606', (39, 46))	('MK1775', 'Var', (96, 102))	('DNA', 'MPA', (222, 225))	('mouse', 'Species', '10090', (83, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('osteosarcoma', 'Disease', (55, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('terminal differentiation', 'CPA', (161, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('increased', 'PosReg', (212, 221))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('apoptotic cell death', 'CPA', (187, 207))
489530	24358232	At a tumor volume of 500 mm3, mice were randomly assigned to the following treatment groups with N = 4 and thus 8 tumors per group: (1) control; (2) MK1775 (30 mg/kg.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('MK1775', 'Chemical', 'MESH:C549567', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MK1775', 'Var', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (114, 119))	('tumors', 'Disease', (114, 120))	('tumor', 'Disease', (5, 10))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
489556	24358232	The MK1775 group grew similar to the controls up until day 11, but appear to have decreased tumor volumes by day 14.	('MK1775', 'Chemical', 'MESH:C549567', (4, 10))	('MK1775', 'Var', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('decreased tumor', 'Disease', 'MESH:D009369', (82, 97))	('decreased tumor', 'Disease', (82, 97))
489562	24358232	Statistically, significant differences in ADC were established for the controls compared to Gem and Combo on day 2, as well as controls and Combo, and MK1775 and Combo, on day 9 (Table 1B).	('MK1775', 'Chemical', 'MESH:C549567', (151, 157))	('Gem', 'Gene', '2669', (92, 95))	('MK1775', 'Var', (151, 157))	('differences', 'Reg', (27, 38))	('Gem', 'Gene', (92, 95))	('ADC', 'MPA', (42, 45))
489574	24358232	Entropy is a texture-based statistical measure of the randomness in an ADC histogram such that a large variation in ADC is associated with higher entropy values.	('entropy values', 'MPA', (146, 160))	('randomness', 'Disease', 'MESH:C562757', (54, 64))	('randomness', 'Disease', (54, 64))	('variation', 'Var', (103, 112))	('ADC', 'MPA', (116, 119))	('higher', 'PosReg', (139, 145))
489612	24358232	Interestingly, while MK1775 did not induce significant apoptosis or elevated ADC values at day 4, our studies have shown that when administered for a prolonged time period (i.e.	('MK1775', 'Var', (21, 27))	('ADC values', 'MPA', (77, 87))	('MK1775', 'Chemical', 'MESH:C549567', (21, 27))
489614	24358232	In conclusion, therapeutic effects of Gem, administered solely or in combination with MK1775, induced significant tumor growth control by day 4, which was presaged by significant elevations in mean tumor ADC, ADC distribution and entropy by 24 hours following therapy.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Gem', 'Gene', (38, 41))	('MK1775', 'Chemical', 'MESH:C549567', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MK1775', 'Var', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('elevations', 'PosReg', (179, 189))	('Gem', 'Gene', '2669', (38, 41))	('tumor', 'Disease', (114, 119))	('entropy', 'MPA', (230, 237))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('ADC distribution', 'MPA', (209, 225))	('tumor', 'Disease', (198, 203))
489624	22619566	22 primary STS patients (cohort A/B 15/7).	('A/B 15', 'Var', (32, 38))	('A/B 15', 'SUBSTITUTION', 'None', (32, 38))	('primary STS', 'Disease', (3, 14))
489647	22619566	The risk for developing distant metastases with a high-grade STS is directly proportional to tumor size (34% for 5.1-10 cm, 43% for 10.1-15 cm, and 58% for 15.1-20 cm).	('5.1-10 cm', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('metastases', 'Disease', (32, 42))	('metastases', 'Disease', 'MESH:D009362', (32, 42))
489649	22619566	A meta-analysis of 3,322 multiple myeloma patients treated with thalidomide alone, dexamethasone alone, combination therapy, or nonthalidomide/dexamethasone regimens showed that thalidomide was associated with a 2.6-fold increased risk for VTE while thalidomide with dexamethasone had an 8-fold increased risk.	('dexamethasone', 'Chemical', 'MESH:D003907', (267, 280))	('multiple myeloma', 'Phenotype', 'HP:0006775', (25, 41))	('dexamethasone', 'Chemical', 'MESH:D003907', (143, 156))	('dexamethasone', 'Chemical', 'MESH:D003907', (83, 96))	('VTE', 'Disease', (240, 243))	('nonthalidomide', 'Chemical', '-', (128, 142))	('thalidomide', 'Var', (178, 189))
489653	22619566	with an initial VTE incidence of 28.6% in multiple myeloma patients receiving pegylated doxorubicin, vincristine, dexamethasone, and thalidomide.	('multiple myeloma', 'Phenotype', 'HP:0006775', (42, 58))	('vincristine', 'Chemical', 'MESH:D014750', (101, 112))	('pegylated', 'Var', (78, 87))	('multiple myeloma', 'Disease', (42, 58))
489746	32549298	In case of positivity for SARS-CoV-2, the patient was addressed to hospitals of the COVID-19 network of our region if symptoms were consistent or to COVID-19-committed hospital in case urgent surgery was needed, while home isolation and transfer to the GP was recommend if surgery was not urgent and if symptoms were mild or absent.	('COVID-19', 'Disease', 'MESH:C000657245', (84, 92))	('tr', 'Gene', '2149', (237, 239))	('COVID-19', 'Disease', (149, 157))	('positivity', 'Var', (11, 21))	('COVID-19', 'Disease', (84, 92))	('patient', 'Species', '9606', (42, 49))	('SARS-CoV-2', 'Gene', (26, 36))	('SARS-CoV-2', 'Species', '2697049', (26, 36))	('COVID-19', 'Disease', 'MESH:C000657245', (149, 157))
489810	31310216	Moreover, mucosal, anal and fluid swab samples were clearly positive for viral genomes and the high viral load in the mucosa of the eye and in the lacrimal glands might be explained by Kaposi sarcoma in unusual locations.	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (185, 199))	('viral genomes', 'Var', (73, 86))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (185, 199))	('Kaposi sarcoma', 'Disease', (185, 199))	('positive', 'Reg', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
489854	22761622	Immunohistochemical analysis often reveals positivity for vimentin, S100 protein and CD99; meanwhile, actin, cytokeratin, and EMA are typically negative.	('S100', 'Gene', (68, 72))	('vimentin', 'Gene', (58, 66))	('CD99', 'Gene', (85, 89))	('S100', 'Gene', '6271', (68, 72))	('positivity', 'Var', (43, 53))	('CD99', 'Gene', '4267', (85, 89))	('vimentin', 'Gene', '7431', (58, 66))
489890	32005258	Mutation of exon 3 of CTNNB1, which encodes beta-catenin, has also been identified in some pilomatrical neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('CTNNB1', 'Gene', (22, 28))	('pilomatrical neoplasms', 'Disease', (91, 113))	('pilomatrical neoplasms', 'Disease', 'MESH:D009369', (91, 113))	('identified', 'Reg', (72, 82))	('Mutation', 'Var', (0, 8))	('CTNNB1', 'Gene', '1499', (22, 28))	('beta-catenin', 'Gene', (44, 56))	('beta-catenin', 'Gene', '1499', (44, 56))
489891	32005258	In addition, LEF1-1, further downstream effector of aberrant beta-catenin in Wnt pathway, has been recently tested as a diagnostic marker for pilomatrical tumors (sensitivity = 100%, specificity = 56%).	('beta-catenin', 'Gene', '1499', (61, 73))	('pilomatrical tumors', 'Disease', 'MESH:D009369', (142, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('LEF1-1', 'Gene', (13, 19))	('pilomatrical tumors', 'Disease', (142, 161))	('aberrant', 'Var', (52, 60))	('beta-catenin', 'Gene', (61, 73))	('LEF1-1', 'Gene', '51176', (13, 19))
489930	32005258	CTNNB1 gene mutation, which is considered to force beta-catenin expression, has been indicated in the development of follicular tumors; a mutation at exon 3 of the CTNNB1 gene was also found in 61% to 100%.	('CTNNB1', 'Gene', '1499', (0, 6))	('beta-catenin', 'Gene', '1499', (51, 63))	('follicular tumors', 'Disease', 'MESH:C572845', (117, 134))	('CTNNB1', 'Gene', (0, 6))	('CTNNB1', 'Gene', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('follicular tumors', 'Disease', (117, 134))	('CTNNB1', 'Gene', '1499', (164, 170))	('mutation', 'Var', (12, 20))	('beta-catenin', 'Gene', (51, 63))
489936	32005258	Although the beta-catenin and LEF-1 expression in our case are different from previous reports of pilomatrical tumors, aberrant beta-catenin expression in sarcomatous component was concordant with previous reports of pilomatrical CS.	('aberrant', 'Var', (119, 127))	('pilomatrical CS', 'Disease', 'MESH:D002296', (217, 232))	('beta-catenin', 'Gene', '1499', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('beta-catenin', 'Gene', (128, 140))	('sarcomatous component', 'Disease', 'MESH:D018316', (155, 176))	('LEF-1', 'Gene', '51176', (30, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcomatous component', 'Disease', (155, 176))	('beta-catenin', 'Gene', '1499', (128, 140))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('pilomatrical tumors', 'Disease', 'MESH:D009369', (98, 117))	('expression', 'MPA', (141, 151))	('beta-catenin', 'Gene', (13, 25))	('pilomatrical CS', 'Disease', (217, 232))	('pilomatrical tumors', 'Disease', (98, 117))	('LEF-1', 'Gene', (30, 35))
489937	32005258	Furthermore, previous report of pilomatrical CS investigating both beta-catenin expression and CTNNB1 gene exon 3 mutation showed aberrant beta-catenin expression in the tumor without mutation, which is consistent with our case.	('CTNNB1', 'Gene', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('pilomatrical CS', 'Disease', (32, 47))	('beta-catenin', 'Gene', '1499', (67, 79))	('beta-catenin', 'Gene', (139, 151))	('tumor', 'Disease', (170, 175))	('pilomatrical CS', 'Disease', 'MESH:D002296', (32, 47))	('CTNNB1', 'Gene', '1499', (95, 101))	('beta-catenin', 'Gene', (67, 79))	('mutation', 'Var', (114, 122))	('beta-catenin', 'Gene', '1499', (139, 151))
489938	32005258	These results suggest the presence of alteration other than CTNNB1 exons 3-5 mutation or other mechanism which activates Wnt pathway during carcinogengesis of pilomatrical CS.	('activates', 'PosReg', (111, 120))	('pilomatrical CS', 'Disease', (159, 174))	('CTNNB1', 'Gene', (60, 66))	('pilomatrical CS', 'Disease', 'MESH:D002296', (159, 174))	('mutation', 'Var', (77, 85))	('Wnt pathway', 'Pathway', (121, 132))	('CTNNB1', 'Gene', '1499', (60, 66))
489940	32005258	The association of p16 overexpression and deletion of the p16 gene (CDKN2a, 9p21) with high grade histology and unfavorable prognosis have been recently reported in various cancers.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('p16', 'Gene', (19, 22))	('overexpression', 'PosReg', (23, 37))	('CDKN2a', 'Gene', (68, 74))	('cancers', 'Disease', (173, 180))	('p16', 'Gene', (58, 61))	('CDKN2a', 'Gene', '1029', (68, 74))	('p16', 'Gene', '1029', (19, 22))	('p16', 'Gene', '1029', (58, 61))	('deletion', 'Var', (42, 50))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
489950	32005258	In addition, we observed positivity of AE1/AE3 and P63, not only in the epithelial component but also partially in the sarcomatous component.	('sarcomatous component', 'Disease', 'MESH:D018316', (119, 140))	('positivity', 'Var', (25, 35))	('P63', 'Gene', '8626', (51, 54))	('AE3', 'Gene', '6508', (43, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('AE3', 'Gene', (43, 46))	('P63', 'Gene', (51, 54))	('AE1', 'Gene', (39, 42))	('sarcomatous component', 'Disease', (119, 140))	('AE1', 'Gene', '6521', (39, 42))
489969	29057176	As a result, we conclude that conversion to sirolimus likely reduces NMSC in post-renal transplantation patients.	('post-renal transplant', 'Phenotype', 'HP:0003774', (77, 98))	('NMSC', 'Disease', (69, 73))	('reduces', 'NegReg', (61, 68))	('patients', 'Species', '9606', (104, 112))	('sirolimus', 'Chemical', 'MESH:D020123', (44, 53))	('post-renal transplantation', 'Phenotype', 'HP:0003774', (77, 103))	('conversion', 'Var', (30, 40))
489991	29057176	However, there is also conflicting evidence suggesting that, while conversion from CNIs to sirolimus is associated with improvement in glomerular filtration rate and reduction in risk of malignancy and NMSC, conversion is also associated with higher risk of rejection and mortality.	('NMSC', 'Disease', (202, 206))	('glomerular filtration rate', 'MPA', (135, 161))	('reduction', 'NegReg', (166, 175))	('rejection', 'Disease', (258, 267))	('malignancy', 'Disease', 'MESH:D009369', (187, 197))	('conversion', 'Var', (208, 218))	('conversion', 'Var', (67, 77))	('improvement', 'PosReg', (120, 131))	('malignancy', 'Disease', (187, 197))	('sirolimus', 'Chemical', 'MESH:D020123', (91, 100))
489993	29057176	As for the risk of skin cancer, CNI withdrawal and conversion to sirolimus after renal transplantation have been associated with reduced risk of different types of NMSCs such as SCC, BCC, and Kaposi's sarcoma in multiple clinical trials.	('sirolimus', 'Chemical', 'MESH:D020123', (65, 74))	('BCC', 'Phenotype', 'HP:0002671', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('skin cancer', 'Phenotype', 'HP:0008069', (19, 30))	('skin cancer', 'Disease', (19, 30))	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('skin cancer', 'Disease', 'MESH:D012878', (19, 30))	('SCC', 'Gene', '6317', (178, 181))	('conversion', 'Var', (51, 61))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (192, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (192, 208))	("Kaposi's sarcoma", 'Disease', (192, 208))	('CNI withdrawal', 'Disease', (32, 46))	('CNI withdrawal', 'Disease', 'MESH:D013375', (32, 46))	('SCC', 'Gene', (178, 181))	('BCC', 'Disease', (183, 186))	('reduced', 'NegReg', (129, 136))
490015	29057176	The attrition rate was thus 36% in the sirolimus group and 11% in the control group.	('attrition', 'MPA', (4, 13))	('sirolimus', 'Var', (39, 48))	('sirolimus', 'Chemical', 'MESH:D020123', (39, 48))
490025	29057176	While the results of this study are promising that conversion to sirolimus improves NMSC outcomes, the high dropout rate among sirolimus patients makes the practicality of this alternative less convincing.	('sirolimus', 'Chemical', 'MESH:D020123', (65, 74))	('sirolimus', 'Chemical', 'MESH:D020123', (127, 136))	('NMSC outcomes', 'Disease', (84, 97))	('patients', 'Species', '9606', (137, 145))	('improves', 'PosReg', (75, 83))	('conversion', 'Var', (51, 61))
490037	29057176	The attrition rate was thus 79% in the sirolimus group and 49% in the control group.	('attrition', 'MPA', (4, 13))	('sirolimus', 'Var', (39, 48))	('sirolimus', 'Chemical', 'MESH:D020123', (39, 48))
490086	29057176	Conversion to sirolimus also exhibited a nonsignificant decrease in development of BCC [Hazard Ratio = 0.56 (95% CI: 0.30 to 1.1, p = 0.076)].	('BCC', 'Phenotype', 'HP:0002671', (83, 86))	('BCC', 'Disease', (83, 86))	('decrease', 'NegReg', (56, 64))	('sirolimus', 'Chemical', 'MESH:D020123', (14, 23))	('Conversion', 'Var', (0, 10))
490110	29057176	This contrasted the results of the studies with initial sirolimus therapy which showed no reduced cancer risk in the sirolimus group compared to control (p = 0.65).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('sirolimus', 'Chemical', 'MESH:D020123', (117, 126))	('sirolimus', 'Chemical', 'MESH:D020123', (56, 65))	('sirolimus', 'Var', (117, 126))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))
490119	29057176	In renal transplant recipients being treated with sirolimus, there was a 29% reduced incidence of cancer when compared to patients being treated with another immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('sirolimus', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('sirolimus', 'Chemical', 'MESH:D020123', (50, 59))	('patients', 'Species', '9606', (122, 130))	('reduced', 'NegReg', (77, 84))	('cancer', 'Disease', (98, 104))
490121	29057176	When looking at RCTs alone, sirolimus use was associated with a 51% decrease in NMSC incidence (Incidence Rates Ratio = 0.49, 95% CI: 0.32-0.76).	('NMSC', 'Disease', (80, 84))	('decrease', 'NegReg', (68, 76))	('sirolimus', 'Chemical', 'MESH:D020123', (28, 37))	('sirolimus', 'Var', (28, 37))
490125	29057176	There are multiple studies examining if conversion to sirolimus in post-renal transplantation patients can reduce the risk of skin cancer, especially NMSC.	('patients', 'Species', '9606', (94, 102))	('post-renal transplant', 'Phenotype', 'HP:0003774', (67, 88))	('skin cancer', 'Phenotype', 'HP:0008069', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('sirolimus', 'Chemical', 'MESH:D020123', (54, 63))	('skin cancer', 'Disease', (126, 137))	('reduce', 'NegReg', (107, 113))	('skin cancer', 'Disease', 'MESH:D012878', (126, 137))	('conversion', 'Var', (40, 50))	('NMSC', 'Disease', (150, 154))	('post-renal transplantation', 'Phenotype', 'HP:0003774', (67, 93))
490126	29057176	In some clinical trials or meta-analyses, conversion to sirolimus from CNIs shows promising hope of reducing NMSC and improving survival.	('sirolimus', 'Chemical', 'MESH:D020123', (56, 65))	('conversion', 'Var', (42, 52))	('improving', 'PosReg', (118, 127))	('reducing', 'NegReg', (100, 108))	('NMSC', 'Disease', (109, 113))	('survival', 'CPA', (128, 136))
490127	29057176	However, in other studies, there seems to be no convincing evidence that conversion to sirolimus can significantly decrease the development of NMSC.	('sirolimus', 'Chemical', 'MESH:D020123', (87, 96))	('conversion', 'Var', (73, 83))	('development', 'CPA', (128, 139))	('NMSC', 'Disease', (143, 147))	('decrease', 'NegReg', (115, 123))
490128	29057176	From the selected articles in our review, larger trials and meta-analysis came to the conclusion that conversion to sirolimus in post-renal transplantation patients reduces skin cancer rates, while smaller scale studies tend to yield no clinically significant data.	('patients', 'Species', '9606', (156, 164))	('post-renal transplant', 'Phenotype', 'HP:0003774', (129, 150))	('skin cancer', 'Disease', 'MESH:D012878', (173, 184))	('reduces', 'NegReg', (165, 172))	('conversion', 'Var', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('skin cancer', 'Phenotype', 'HP:0008069', (173, 184))	('sirolimus', 'Chemical', 'MESH:D020123', (116, 125))	('skin cancer', 'Disease', (173, 184))	('post-renal transplantation', 'Phenotype', 'HP:0003774', (129, 155))
490129	29057176	Generally, conversion to sirolimus tends to be more effective in reducing NMSC over a short rather than long timeframe.	('reducing', 'NegReg', (65, 73))	('sirolimus', 'Chemical', 'MESH:D020123', (25, 34))	('NMSC', 'Disease', (74, 78))	('conversion', 'Var', (11, 21))
490130	29057176	Although there are some inconsistencies in the conclusions, we tend to conclude that conversion to sirolimus reduces NMSC risk in post-renal transplantation patients.	('post-renal transplant', 'Phenotype', 'HP:0003774', (130, 151))	('post-renal transplantation', 'Phenotype', 'HP:0003774', (130, 156))	('NMSC', 'Disease', (117, 121))	('conversion', 'Var', (85, 95))	('patients', 'Species', '9606', (157, 165))	('sirolimus', 'Chemical', 'MESH:D020123', (99, 108))	('reduces', 'NegReg', (109, 116))
490131	29057176	Further, there are exciting reports that conversion to sirolimus can even potentially lead to clinical remission in Kaposi's sarcoma.	('conversion', 'Var', (41, 51))	('sirolimus', 'Chemical', 'MESH:D020123', (55, 64))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (116, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (116, 132))	("Kaposi's sarcoma", 'Disease', (116, 132))	('lead to', 'Reg', (86, 93))
490240	32860002	Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions Fusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors.	('TRK', 'Gene', (132, 135))	('TRK', 'Gene', (84, 87))	('NTRK1', 'Gene', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('fusions Fusions', 'Var', (136, 151))	('TRK', 'Gene', (28, 31))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (43, 61))	('TRK', 'Gene', '4914', (181, 184))	('TRK', 'Gene', '4914', (163, 166))	('NTRK3', 'Gene', '4916', (180, 185))	('TRK', 'Gene', '4914', (132, 135))	('TRK', 'Gene', (170, 173))	('TRK', 'Gene', '4914', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NTRK2', 'Gene', '4915', (169, 174))	('NTRK3', 'Gene', (180, 185))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (235, 256))	('TRK', 'Gene', '4914', (28, 31))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('mesenchymal neoplasms', 'Disease', (235, 256))	('mesenchymal tumors', 'Disease', (43, 61))	('neoplasm', 'Phenotype', 'HP:0002664', (247, 255))	('TRK', 'Gene', '4914', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('neoplasms', 'Phenotype', 'HP:0002664', (247, 256))	('NTRK2', 'Gene', (169, 174))	('malignant tumors', 'Disease', (287, 303))	('malignant tumors', 'Disease', 'MESH:D009369', (287, 303))	('TRK', 'Gene', (181, 184))	('TRK', 'Gene', (163, 166))	('NTRK1', 'Gene', '4914', (162, 167))	('Fusions', 'Var', (144, 151))
490253	32860002	The presence of NTRK1-3 fusions has been identified as an agnostic marker for treatment response with a selective small-molecule inhibitor of the TRK kinases (TKI) in solid tumors.	('TRK', 'Gene', (146, 149))	('TRK', 'Gene', '4914', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('TRK', 'Gene', (17, 20))	('TKI', 'Gene', (159, 162))	('TRK', 'Gene', '4914', (17, 20))	('NTRK1-3', 'Gene', (16, 23))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('NTRK1-3', 'Gene', '4914;4915;4916', (16, 23))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('fusions', 'Var', (24, 31))
490254	32860002	The ETV6-NTRK3 gene fusion has been described in sporadic solid tumors, including congenital infantile fibrosarcoma (IFS), congenital "cellular" mesoblastic nephroma, secretory breast carcinoma, and carcinoma of the salivary gland (mammary analog secretory carcinoma) in more than 90% of cases and fusion detection has been used as diagnostic confirmation.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('fusion', 'Var', (20, 26))	('ETV6', 'Gene', '2120', (4, 8))	('carcinoma', 'Disease', (257, 266))	('carcinoma', 'Disease', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma of the salivary', 'Disease', (199, 224))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (103, 115))	('tumors', 'Disease', (64, 70))	('carcinoma of the salivary', 'Disease', 'MESH:D012468', (199, 224))	('breast carcinoma', 'Disease', 'MESH:D001943', (177, 193))	('carcinoma', 'Disease', (199, 208))	('carcinoma of the salivary gland', 'Phenotype', 'HP:0100684', (199, 230))	('carcinoma', 'Disease', 'MESH:D009369', (257, 266))	('congenital infantile fibrosarcoma', 'Disease', 'MESH:D005354', (82, 115))	('described', 'Reg', (36, 45))	('sporadic', 'Disease', (49, 57))	('carcinoma', 'Disease', 'MESH:D009369', (184, 193))	('IFS', 'Chemical', '-', (117, 120))	('ETV6', 'Gene', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('nephroma', 'Disease', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('carcinoma', 'Disease', 'MESH:D009369', (199, 208))	('congenital infantile fibrosarcoma', 'Disease', (82, 115))	('breast carcinoma', 'Phenotype', 'HP:0003002', (177, 193))	('breast carcinoma', 'Disease', (177, 193))	('NTRK3', 'Gene', '4916', (9, 14))	('mesoblastic nephroma', 'Phenotype', 'HP:0100881', (145, 165))	('NTRK3', 'Gene', (9, 14))	('nephroma', 'Disease', 'MESH:D018201', (157, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
490257	32860002	In addition, NTRK fusions were detected in other more common cancer types, such as papillary thyroid carcinoma, gastrointestinal stromal tumor (GIST), gliomas, non-small cell lung cancer (NSCLC), colorectal carcinoma (most frequently found in MSI-high carcinoma associated with MLH1 promoter hypermethylation), as well as malignant melanomas, uterine sarcomas, and pancreatic adenocarcinomas, however in less than 1% of all solid tumors overall.	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (83, 110))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (430, 436))	('lung cancer', 'Disease', (175, 186))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D000230', (365, 391))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (351, 358))	('colorectal carcinoma', 'Disease', (196, 216))	('MLH1', 'Gene', '4292', (278, 282))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (365, 391))	('TRK', 'Gene', '4914', (14, 17))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (196, 216))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (93, 110))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (112, 142))	('tumors', 'Disease', 'MESH:D009369', (430, 436))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('pancreatic adenocarcinomas', 'Disease', (365, 391))	('malignant melanomas', 'Disease', 'MESH:D008545', (322, 341))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (112, 142))	('malignant melanomas', 'Disease', (322, 341))	('cancer', 'Disease', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (381, 390))	('NSCLC', 'Disease', (188, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (61, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('promoter hypermethylation', 'Var', (283, 308))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('gastrointestinal stromal tumor', 'Disease', (112, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gliomas', 'Disease', (151, 158))	('MSI-high carcinoma', 'Disease', 'MESH:D009369', (243, 261))	('sarcomas', 'Disease', 'MESH:D012509', (351, 359))	('MSI-high carcinoma', 'Disease', (243, 261))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (83, 110))	('tumors', 'Phenotype', 'HP:0002664', (430, 436))	('GIST', 'Phenotype', 'HP:0100723', (144, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (351, 359))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('sarcomas', 'Disease', (351, 359))	('malignant melanomas', 'Phenotype', 'HP:0002861', (322, 341))	('MLH1', 'Gene', (278, 282))	('TRK', 'Gene', (14, 17))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('papillary thyroid carcinoma', 'Disease', (83, 110))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (430, 435))
490260	32860002	At the moment, RNA-based NGS screening approaches are the most reliable method to detect NTRK1-3 fusions also with unknown partners.	('NTRK1-3', 'Gene', '4914;4915;4916', (89, 96))	('NTRK1-3', 'Gene', (89, 96))	('fusions', 'Var', (97, 104))
490281	32860002	IHC positive cases with available FFPE material were sent for RNA-based analysis with Archer FusionPlex Sarcoma Panel to assess specific NTRK1, NTRK2, and NTRK3 rearrangements for the production of NTRK fusion transcripts.	('NTRK1', 'Gene', (137, 142))	('NTRK3', 'Gene', '4916', (155, 160))	('NTRK2', 'Gene', '4915', (144, 149))	('Sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('Archer FusionPlex Sarcoma', 'Disease', (86, 111))	('NTRK3', 'Gene', (155, 160))	('rearrangements', 'Var', (161, 175))	('NTRK2', 'Gene', (144, 149))	('Archer FusionPlex Sarcoma', 'Disease', 'MESH:D012509', (86, 111))	('TRK', 'Gene', (199, 202))	('NTRK1', 'Gene', '4914', (137, 142))	('TRK', 'Gene', '4914', (199, 202))	('TRK', 'Gene', (145, 148))	('TRK', 'Gene', '4914', (145, 148))	('TRK', 'Gene', (138, 141))	('TRK', 'Gene', '4914', (138, 141))	('TRK', 'Gene', (156, 159))	('TRK', 'Gene', '4914', (156, 159))
490310	32860002	Staining for ALK, CD68 and CD163 were observed, whereas CD34, EMA, SMA, S100, and SOX10 were negative.	('ALK', 'Gene', (13, 16))	('SOX10', 'Gene', (82, 87))	('CD163', 'Gene', '9332', (27, 32))	('SOX10', 'Gene', '6663', (82, 87))	('SMA', 'Gene', '6606', (67, 70))	('SMA', 'Gene', (67, 70))	('CD163', 'Gene', (27, 32))	('ALK', 'Gene', '238', (13, 16))	('CD68', 'Var', (18, 22))	('S100', 'Gene', (72, 76))	('S100', 'Gene', '6271', (72, 76))
490311	32860002	Based on the unusual morphology for benign fibrous histiocytoma, the ALK expression by IHC and the fact that "epithelioid fibrous histiocytoma (EFH)" commonly demonstrate ALK fusions, NGS testing was performed and revealed IRF2BP2-NTRK1 fusion (Fig.	('NTRK1', 'Gene', '4914', (231, 236))	('IRF2BP2', 'Gene', (223, 230))	('benign fibrous histiocytoma', 'Disease', (36, 63))	('ALK', 'Gene', '238', (69, 72))	('IRF2BP2', 'Gene', '359948', (223, 230))	('fusion', 'Var', (237, 243))	('NTRK1', 'Gene', (231, 236))	('benign fibrous histiocytoma', 'Disease', 'MESH:D018219', (36, 63))	('ALK', 'Gene', (171, 174))	('fibrous histiocytoma', 'Disease', 'MESH:D018219', (43, 63))	('histiocytoma', 'Phenotype', 'HP:0012315', (130, 142))	('ALK', 'Gene', (69, 72))	('fibrous histiocytoma', 'Disease', (122, 142))	('ALK', 'Gene', '238', (171, 174))	('fibrous histiocytoma', 'Disease', 'MESH:D018219', (122, 142))	('histiocytoma', 'Phenotype', 'HP:0012315', (51, 63))
490320	32860002	Molecular analysis showed TMB3-NTRK1 fusion (Fig.	('fusion', 'Var', (37, 43))	('NTRK1', 'Gene', '4914', (31, 36))	('NTRK1', 'Gene', (31, 36))
490326	32860002	A growing body of evidence recognizes the oncogenic role of chromosomal translocations involving NTRK genes found infrequently across a wide range of solid neoplasms.	('TRK', 'Gene', (98, 101))	('neoplasms', 'Disease', 'MESH:D009369', (156, 165))	('TRK', 'Gene', '4914', (98, 101))	('neoplasms', 'Disease', (156, 165))	('neoplasm', 'Phenotype', 'HP:0002664', (156, 164))	('chromosomal translocations', 'Var', (60, 86))	('neoplasms', 'Phenotype', 'HP:0002664', (156, 165))
490331	32860002	Recently, the locally aggressive LFLNT has been described, a tumor entity habouring NTRK-fusions, with similar morphology as dermatofibrosarcoma protuberans and co-expression of CD34, S100 and pan-TRK.	('CD34', 'Var', (178, 182))	('TRK', 'Gene', (197, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('locally aggressive LFLNT', 'Disease', (14, 38))	('S100', 'Gene', '6271', (184, 188))	('TRK', 'Gene', '4914', (197, 200))	('TRK', 'Gene', (85, 88))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (132, 144))	('TRK', 'Gene', '4914', (85, 88))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (125, 156))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('S100', 'Gene', (184, 188))	('tumor', 'Disease', (61, 66))	('dermatofibrosarcoma protuberans', 'Disease', (125, 156))
490339	32860002	The principal mechanism of NTRK1/2/3 gene fusions includes a fusion of the 3  region of the NTRK gene containing the NTRK kinase domain with the critical tyrosine docking site with a 5  fusion partner gene which is highly variable.	('TRK', 'Gene', (118, 121))	('tyrosine', 'Chemical', 'MESH:D014443', (154, 162))	('TRK', 'Gene', '4914', (93, 96))	('TRK', 'Gene', '4914', (118, 121))	('NTRK1/2/3', 'Gene', '4914;4915;4916', (27, 36))	('fusion', 'Interaction', (61, 67))	('NTRK1/2/3', 'Gene', (27, 36))	('TRK', 'Gene', (28, 31))	('TRK', 'Gene', (93, 96))	('fusions', 'Var', (42, 49))	('TRK', 'Gene', '4914', (28, 31))
490341	32860002	Various molecular assays can detect NTRK rearrangements.	('rearrangements', 'Var', (41, 55))	('TRK', 'Gene', (37, 40))	('TRK', 'Gene', '4914', (37, 40))
490349	32860002	Tumors harboring NTRK1 rearrangements usually show strong, diffuse cytoplasmic staining.	('NTRK1', 'Gene', (17, 22))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('rearrangements', 'Var', (23, 37))	('NTRK1', 'Gene', '4914', (17, 22))
490350	32860002	Nuclear staining (at least focal) has been described in tumors harboring NTRK3 fusions and may be used as a surrogate of the presence of NTRK3 fusions, however, the staining in these tumors can be weak.	('NTRK3', 'Gene', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NTRK3', 'Gene', '4916', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('Nuclear staining', 'MPA', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('NTRK3', 'Gene', (73, 78))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('NTRK3', 'Gene', '4916', (137, 142))	('tumors', 'Disease', (183, 189))	('fusions', 'Var', (79, 86))
490355	32860002	False-positive staining with TRK antibodys can occur in non-NTRK fused tumors, mainly tumors with neural and smooth muscle differentiation, and some others namely: GIST, leiomyosarcoma, glioblastoma, neuroblastoma, a primitive myxoid mesenchymal tumor of infancy, synovial sarcoma, Ewing sarcoma, and fibrous hamartoma of infancy, SFT, soft tissue round cell sarcomas with YWHAE rearrangements, BCOR internal tandem duplications (ITD) and BCOR-CCNB3 fusions and clear cell sarcomas of the kidney (another BCOR family tumor) as well as ossifying fibromyxoid tumors with ZC3H7B-BCOR fusion.	('neuroblastoma', 'Disease', (200, 213))	('TRK', 'Gene', (29, 32))	('TRK', 'Gene', (61, 64))	('CCNB3', 'Gene', (444, 449))	('Ewing sarcoma', 'Disease', (282, 295))	('neuroblastoma', 'Disease', 'MESH:D009447', (200, 213))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (264, 280))	('fibrous hamartoma', 'Disease', 'MESH:D006222', (301, 318))	('leiomyosarcoma', 'Disease', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (557, 562))	('CCNB3', 'Gene', '85417', (444, 449))	('ZC3H7B', 'Gene', (569, 575))	('ossifying fibromyxoid tumors', 'Disease', 'MESH:D018214', (535, 563))	('sarcoma', 'Phenotype', 'HP:0100242', (288, 295))	('BCOR', 'Gene', '54880', (439, 443))	('fusions', 'Var', (450, 457))	('TRK', 'Gene', '4914', (29, 32))	('YWHAE', 'Gene', (373, 378))	('tumor', 'Disease', (557, 562))	('sarcomas', 'Disease', 'MESH:D012509', (473, 481))	('TRK', 'Gene', '4914', (61, 64))	('tumors', 'Disease', 'MESH:D009369', (557, 563))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('BCOR', 'Gene', '54880', (505, 509))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('BCOR', 'Gene', (395, 399))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (282, 295))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (282, 295))	('tumor', 'Disease', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (517, 522))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (557, 563))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', (86, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (473, 481))	('sarcomas of the kidney', 'Disease', 'MESH:D012509', (473, 495))	('glioblastoma', 'Disease', (186, 198))	('sarcomas', 'Disease', (473, 481))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (264, 280))	('sarcomas of the kidney', 'Disease', (473, 495))	('sarcoma', 'Phenotype', 'HP:0100242', (473, 480))	('sarcomas', 'Disease', 'MESH:D012509', (359, 367))	('BCOR', 'Gene', (576, 580))	('sarcomas', 'Disease', (359, 367))	('tumors', 'Phenotype', 'HP:0002664', (557, 563))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (170, 184))	('neuroblastoma', 'Phenotype', 'HP:0003006', (200, 213))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (359, 366))	('synovial sarcoma', 'Disease', (264, 280))	('BCOR', 'Gene', (439, 443))	('fibrous hamartoma', 'Disease', (301, 318))	('GIST', 'Phenotype', 'HP:0100723', (164, 168))	('YWHAE', 'Gene', '7531', (373, 378))	('tumor', 'Disease', (517, 522))	('BCOR', 'Gene', '54880', (395, 399))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('fibrous hamartoma', 'Phenotype', 'HP:0100882', (301, 318))	('tumor', 'Disease', 'MESH:D009369', (517, 522))	('BCOR', 'Gene', (505, 509))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', (71, 76))	('BCOR', 'Gene', '54880', (576, 580))	('hamartoma', 'Phenotype', 'HP:0010566', (309, 318))	('tumor', 'Phenotype', 'HP:0002664', (557, 562))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('sarcomas', 'Phenotype', 'HP:0100242', (359, 367))	('ZC3H7B', 'Gene', '23264', (569, 575))	('ossifying fibromyxoid tumors', 'Disease', (535, 563))
490364	32860002	To date, most of the fusions described in mesenchymal neoplasms involve NTRK1 and NTRK3 genes and include different fusion partner genes, most common being ETV6, LMNA, and TPM3.	('LMNA', 'Gene', '4000', (162, 166))	('neoplasms', 'Phenotype', 'HP:0002664', (54, 63))	('mesenchymal neoplasms', 'Disease', (42, 63))	('NTRK1', 'Gene', (72, 77))	('TPM3', 'Gene', '7170', (172, 176))	('NTRK3', 'Gene', '4916', (82, 87))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (42, 63))	('ETV6', 'Gene', '2120', (156, 160))	('ETV6', 'Gene', (156, 160))	('fusions', 'Var', (21, 28))	('LMNA', 'Gene', (162, 166))	('NTRK1', 'Gene', '4914', (72, 77))	('neoplasm', 'Phenotype', 'HP:0002664', (54, 62))	('TPM3', 'Gene', (172, 176))	('NTRK3', 'Gene', (82, 87))
490395	33192158	Cytogenetic and molecular characterization of DSRCT has identified a unique chromosomal rearrangement, t(11; 22) (p13; q12), associated with this tumor.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('DSRCT', 'Disease', (46, 51))	('t(11; 22) (p13; q12', 'Var', (103, 122))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
490499	33192158	Later, the same author published a study which included children and adults, showing significantly longer mOS for patients who had CR0 or CR1 and HIPEC versus CR2 and HIPEC (63 vs. 27 months).	('longer', 'PosReg', (99, 105))	('CR2', 'Species', '2498238', (159, 162))	('mOS', 'Gene', '17451', (106, 109))	('children', 'Species', '9606', (56, 64))	('mOS', 'Gene', (106, 109))	('patients', 'Species', '9606', (114, 122))	('CR0', 'Var', (131, 134))	('CR1', 'Var', (138, 141))
490507	33192158	Furthermore, only 4 patients had the diagnosis confirmed by fluorescence in situ hybridization (FISH) for EWSR1 gene rearrangement, and the identification of the EWSR1-WT1 fusion transcript by reverse transcription-polymerase chain reaction (RT-PCR) was not performed in any case.	('WT1', 'Gene', '7490', (168, 171))	('EWSR1', 'Gene', '2130', (106, 111))	('EWSR1', 'Gene', (162, 167))	('WT1', 'Gene', (168, 171))	('rearrangement', 'Var', (117, 130))	('patients', 'Species', '9606', (20, 28))	('EWSR1', 'Gene', '2130', (162, 167))	('EWSR1', 'Gene', (106, 111))
490617	31311568	The WWTR1-CAMTA1 mutation is found in EHE, which is absent in PHE/ESH.	('CAMTA1', 'Gene', '23261', (10, 16))	('ESH', 'Chemical', '-', (66, 69))	('EHE', 'Disease', (38, 41))	('mutation', 'Var', (17, 25))	('PHE', 'Chemical', '-', (62, 65))	('WWTR1', 'Gene', (4, 9))	('WWTR1', 'Gene', '25937', (4, 9))	('CAMTA1', 'Gene', (10, 16))
490636	31311568	Among them, inhibitors of mammalian target of rapamycin (mTOR) show major efficiency in cases of progressive metastatic and relapsing multifocal PHE/ESH resistant to multiagent chemotherapy.	('inhibitors', 'Var', (12, 22))	('mammalian target of rapamycin', 'Gene', '2475', (26, 55))	('mammalian target of rapamycin', 'Gene', (26, 55))	('ESH', 'Chemical', '-', (149, 152))	('PHE', 'Chemical', '-', (145, 148))
490648	30975996	A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression.	('cohesin-mutant', 'Gene', (100, 114))	('STAG2', 'Gene', '10735', (18, 23))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('Cohesin', 'Gene', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cohesin-mutant', 'Var', (100, 114))	('STAG2', 'Gene', (18, 23))
490649	30975996	Genomic analyses have identified that the cohesin subunit STAG2 is frequently inactivated by mutations in cancer.	('STAG2', 'Gene', (58, 63))	('STAG2', 'Gene', '10735', (58, 63))	('mutations', 'Var', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cohesin subunit', 'Protein', (42, 57))	('cancer', 'Disease', (106, 112))	('inactivated', 'NegReg', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
490651	30975996	Here we show that STAG2 is essential for DNA replication fork progression, whereby STAG2 inactivation in non-transformed cells leads to replication fork stalling and collapse with disruption of interaction between the cohesin ring and the replication machinery as well as failure to establish SMC3 acetylation.	('STAG2', 'Gene', (83, 88))	('SMC3', 'Gene', (293, 297))	('replication fork stalling', 'CPA', (136, 161))	('STAG2', 'Gene', '10735', (18, 23))	('STAG2', 'Gene', '10735', (83, 88))	('inactivation', 'Var', (89, 101))	('cohesin ring', 'Protein', (218, 230))	('collapse', 'NegReg', (166, 174))	('interaction', 'Interaction', (194, 205))	('SMC3', 'Gene', '9126', (293, 297))	('STAG2', 'Gene', (18, 23))
490652	30975996	As a consequence, STAG2 mutation confers synthetic lethality with DNA double-strand break repair genes and increased sensitivity to select cytotoxic chemotherapeutic agents and PARP or ATR inhibitors.	('STAG2', 'Gene', '10735', (18, 23))	('synthetic lethality', 'MPA', (41, 60))	('sensitivity', 'MPA', (117, 128))	('increased', 'PosReg', (107, 116))	('PARP', 'Gene', '142', (177, 181))	('ATR', 'Gene', '545', (185, 188))	('ATR', 'Gene', (185, 188))	('mutation', 'Var', (24, 32))	('STAG2', 'Gene', (18, 23))	('PARP', 'Gene', (177, 181))
490653	30975996	These studies identify a critical role for STAG2 in replication fork procession and elucidate a potential therapeutic strategy for cohesin-mutant cancers.	('cohesin-mutant', 'Gene', (131, 145))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('STAG2', 'Gene', (43, 48))	('cohesin-mutant', 'Var', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('rat', 'Species', '10116', (120, 123))	('STAG2', 'Gene', '10735', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('replication fork', 'CPA', (52, 68))
490654	30975996	Here the authors show another role of cohesin in replication fork progression, suggesting a potential therapeutic strategy for cohesin-mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('cohesin-mutant', 'Var', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rat', 'Species', '10116', (116, 119))	('cohesin-mutant', 'Gene', (127, 141))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
490656	30975996	Cohesin genes were originally identified in yeast as mutants that displayed premature separation of sister chromatids, and were later identified as being highly conserved from yeast to mammals.	('premature separation', 'Phenotype', 'HP:0001622', (76, 96))	('yeast', 'Species', '4932', (44, 49))	('mutants', 'Var', (53, 60))	('yeast', 'Species', '4932', (176, 181))	('Cohesin genes', 'Gene', (0, 13))	('rat', 'Species', '10116', (90, 93))
490661	30975996	However, the extent to which cohesin is essential for DNA replication is largely unknown, as is the effect that cohesin gene mutations in human cancers might have on stability and procession of replication forks.	('mutations', 'Var', (125, 134))	('cohesin gene', 'Gene', (112, 124))	('human', 'Species', '9606', (138, 143))	('stability', 'MPA', (166, 175))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('have', 'Reg', (158, 162))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
490663	30975996	Germline mutations in the cohesin subunits or in genes responsible for cohesin loading (e.g., NIPBL) or regulation (e.g., HDAC8 and ESCO2) cause a spectrum of severe developmental syndromes characterized by facial dysmorphism, growth retardation, mental retardation, and limb anomalies.	('Germline mutations', 'Var', (0, 18))	('severe developmental syndromes', 'Disease', (159, 189))	('ESCO2', 'Gene', (132, 137))	('facial dysmorphism', 'Disease', 'None', (207, 225))	('growth retardation', 'Disease', 'MESH:D006130', (227, 245))	('NIPBL', 'Gene', '25836', (94, 99))	('NIPBL', 'Gene', (94, 99))	('facial dysmorphism', 'Phenotype', 'HP:0001999', (207, 225))	('growth retardation', 'Disease', (227, 245))	('facial dysmorphism', 'Disease', (207, 225))	('HDAC8', 'Gene', '55869', (122, 127))	('HDAC8', 'Gene', (122, 127))	('limb anomalies', 'Disease', (271, 285))	('limb anomalies', 'Phenotype', 'HP:0040064', (271, 285))	('mental retardation', 'Phenotype', 'HP:0001249', (247, 265))	('cause', 'Reg', (139, 144))	('mental retardation', 'Disease', 'MESH:D008607', (247, 265))	('ESCO2', 'Gene', '157570', (132, 137))	('growth retardation', 'Phenotype', 'HP:0001510', (227, 245))	('limb anomalies', 'Disease', 'MESH:D017880', (271, 285))	('mental retardation', 'Disease', (247, 265))
490666	30975996	However, subsequent studies have not observed similar defects in sister chromatid cohesion, calling into question the functional consequence of cohesin mutations in the germline of affected patients.	('cohesin', 'Gene', (144, 151))	('patients', 'Species', '9606', (190, 198))	('mutations', 'Var', (152, 161))
490667	30975996	Genome-wide transcriptional profiling in cells derived from Cornelia de Lange syndrome patients with NIPBL or SMC1A mutations versus normal subjects has revealed a conserved pattern of transcriptional dysregulation.	('Cornelia de Lange syndrome', 'Disease', 'MESH:D003635', (60, 86))	('Cornelia de Lange syndrome', 'Disease', (60, 86))	('SMC1A', 'Gene', '8243', (110, 115))	('transcriptional dysregulation', 'MPA', (185, 214))	('NIPBL', 'Gene', '25836', (101, 106))	('mutations', 'Var', (116, 125))	('SMC1A', 'Gene', (110, 115))	('NIPBL', 'Gene', (101, 106))	('patients', 'Species', '9606', (87, 95))
490669	30975996	Recent genomic analyses of human cancer have identified that the cohesin genes, and STAG2 in particular, are frequent targets of mutational inactivation in a select subset of tumor types that include glioblastoma, urothelial carcinoma, Ewing sarcoma, and myeloid leukemia.	('Ewing sarcoma', 'Disease', (236, 249))	('cancer', 'Disease', (33, 39))	('human', 'Species', '9606', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutational inactivation', 'Var', (129, 152))	('urothelial carcinoma', 'Disease', (214, 234))	('STAG2', 'Gene', '10735', (84, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (200, 212))	('myeloid leukemia', 'Disease', (255, 271))	('tumor', 'Disease', (175, 180))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (236, 249))	('STAG2', 'Gene', (84, 89))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (236, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('glioblastoma', 'Disease', (200, 212))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (214, 234))	('glioblastoma', 'Phenotype', 'HP:0012174', (200, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('myeloid leukemia', 'Disease', 'MESH:D007951', (255, 271))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (255, 271))	('cohesin genes', 'Gene', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('leukemia', 'Phenotype', 'HP:0001909', (263, 271))
490670	30975996	STAG2 has been identified as one of only 12 genes that are significantly mutated in four or more human cancer types by The Cancer Genome Atlas, in which STAG2 mutation defines molecular subgroups of these tumor types with distinct clinical outcomes.	('STAG2', 'Gene', '10735', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (97, 102))	('STAG2', 'Gene', (153, 158))	('STAG2', 'Gene', '10735', (153, 158))	('mutation', 'Var', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('STAG2', 'Gene', (0, 5))
490671	30975996	Initial studies in glioblastoma cell lines suggested a role for STAG2 mutations as a cause of chromosomal instability and aneuploidy during tumorigenesis.	('chromosomal instability', 'MPA', (94, 117))	('glioblastoma', 'Disease', (19, 31))	('mutations', 'Var', (70, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (19, 31))	('aneuploidy', 'Disease', 'MESH:D000782', (122, 132))	('STAG2', 'Gene', '10735', (64, 69))	('cause', 'Reg', (85, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('chromosomal instability', 'Phenotype', 'HP:0040012', (94, 117))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('aneuploidy', 'Disease', (122, 132))	('STAG2', 'Gene', (64, 69))	('tumor', 'Disease', (140, 145))
490672	30975996	However, the majority of urothelial carcinomas, Ewing sarcomas, and myeloid leukemias harboring STAG2 mutations are actually diploid or near-diploid tumors, suggesting that cohesin mutations in cancer likely promote tumorigenesis by mechanisms unrelated to chromosome segregation.	('STAG2', 'Gene', '10735', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cohesin', 'Gene', (173, 180))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (48, 61))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('tumor', 'Disease', (216, 221))	('promote', 'PosReg', (208, 215))	('STAG2', 'Gene', (96, 101))	('diploid tumors', 'Disease', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('urothelial carcinomas', 'Disease', (25, 46))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('mutations', 'Var', (181, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (25, 46))	('leukemias', 'Phenotype', 'HP:0001909', (76, 85))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (68, 84))	('diploid tumors', 'Disease', 'MESH:C548012', (141, 155))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (48, 62))	('myeloid leukemias', 'Disease', (68, 85))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('Ewing sarcomas', 'Disease', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (48, 62))	('cancer', 'Disease', (194, 200))	('myeloid leukemias', 'Disease', 'MESH:D007951', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('tumor', 'Disease', (149, 154))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (68, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))
490673	30975996	The exact reasons why inactivating cohesin mutations are selected for during cancer development and progression are still uncertain.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (43, 52))	('inactivating', 'Var', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cohesin', 'Protein', (35, 42))
490674	30975996	In one recent study, STAG2 mutations were found to be acquired after therapy with RAF inhibitors in BRAF-mutant melanomas as a mechanism of therapeutic resistance.	('mutations', 'Var', (27, 36))	('melanomas', 'Disease', (112, 121))	('RAF', 'Gene', '22882', (82, 85))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('RAF', 'Gene', '22882', (101, 104))	('BRAF', 'Gene', '673', (100, 104))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('RAF', 'Gene', (101, 104))	('STAG2', 'Gene', '10735', (21, 26))	('BRAF', 'Gene', (100, 104))	('acquired', 'Reg', (54, 62))	('RAF', 'Gene', (82, 85))	('STAG2', 'Gene', (21, 26))
490675	30975996	However, the majority of STAG2 mutations in glioblastoma, urothelial carcinoma, and Ewing sarcoma are clonal events that likely arise early during tumor development.	('Ewing sarcoma', 'Disease', (84, 97))	('STAG2', 'Gene', (25, 30))	('tumor', 'Disease', (147, 152))	('mutations', 'Var', (31, 40))	('glioblastoma', 'Disease', (44, 56))	('glioblastoma', 'Disease', 'MESH:D005909', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('STAG2', 'Gene', '10735', (25, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (58, 78))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('urothelial carcinoma', 'Disease', (58, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
490676	30975996	The therapeutic consequences of cohesin mutations in these cancers are largely unknown at present, as are methodologies for treating cohesin-mutant cancers using a precision medicine approach.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cohesin', 'Gene', (32, 39))	('cohesin-mutant', 'Var', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (40, 49))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cohesin-mutant', 'Gene', (133, 147))	('cancers', 'Disease', (59, 66))
490679	30975996	Deficiency of STAG2 results in disruption of the interaction of cohesin with the replication machinery, leading to stalling and collapse of replication forks, as well as failure to establish SMC3 acetylation.	('disruption', 'NegReg', (31, 41))	('STAG2', 'Gene', (14, 19))	('SMC3', 'Gene', (191, 195))	('stalling', 'CPA', (115, 123))	('STAG2', 'Gene', '10735', (14, 19))	('interaction', 'Interaction', (49, 60))	('collapse', 'CPA', (128, 136))	('SMC3', 'Gene', '9126', (191, 195))	('cohesin', 'Protein', (64, 71))	('acetylation', 'MPA', (196, 207))	('replication forks', 'CPA', (140, 157))	('Deficiency', 'Var', (0, 10))
490681	30975996	Our data provide the preclinical rationale for targeted therapy-based clinical trials for cohesin mutant cancers.	('cohesin', 'Gene', (90, 97))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('rat', 'Species', '10116', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutant', 'Var', (98, 104))
490682	30975996	To study the function of STAG2 in non-transformed human cells, we used the CRISPR/Cas9 system to inactivate the STAG2 gene in hTERT-immortalized retinal pigmented epithelial (RPE) cells.	('hTERT', 'Gene', (126, 131))	('STAG2', 'Gene', (25, 30))	('retinal pigmented epithelial', 'Disease', 'MESH:C537835', (145, 173))	('STAG2', 'Gene', '10735', (25, 30))	('STAG2', 'Gene', (112, 117))	('STAG2', 'Gene', '10735', (112, 117))	('hTERT', 'Gene', '7015', (126, 131))	('human', 'Species', '9606', (50, 55))	('inactivate', 'Var', (97, 107))	('retinal pigmented epithelial', 'Disease', (145, 173))
490690	30975996	Together, these data indicate that acute STAG2 inactivation in non-transformed human cells leads to an intra-S-phase cell cycle arrest and senescence.	('inactivation', 'Var', (47, 59))	('human', 'Species', '9606', (79, 84))	('senescence', 'CPA', (139, 149))	('STAG2', 'Gene', (41, 46))	('STAG2', 'Gene', '10735', (41, 46))	('intra-S-phase cell cycle arrest', 'CPA', (103, 134))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (117, 134))
490692	30975996	In contrast, no decreased proliferation or death was observed following STAG1 depletion.	('STAG1', 'Gene', '10274', (72, 77))	('depletion', 'Var', (78, 87))	('STAG1', 'Gene', (72, 77))	('rat', 'Species', '10116', (33, 36))
490698	30975996	Upon STAG2 depletion, RPAp34 accumulated at stalled replication foci, similar to that observed upon replication block with aphidicolin (Fig.	('accumulated', 'PosReg', (29, 40))	('STAG2', 'Gene', (5, 10))	('STAG2', 'Gene', '10735', (5, 10))	('RPAp34', 'Gene', (22, 28))	('RPAp34', 'Gene', '6118', (22, 28))	('aphidicolin', 'Chemical', 'MESH:D016590', (123, 134))	('depletion', 'Var', (11, 20))
490703	30975996	In order to assess the cell cycle specificity of the interaction between cohesin and replication factors, immunoprecipitation was performed using SMC3 antibodies on RPE cells either asynchronously proliferating (+DMSO vehicle), arrested in G1 phase using the cyclin-dependent kinases 4/6 (CDK4/6) inhibitor palbociclib, arrested in S phase using the DNA polymerase inhibitor aphidicolin, or arrested in mitosis using the microtubule polymerization inhibitor colcemid.	('SMC3', 'Gene', (146, 150))	('mitosis', 'Disease', (403, 410))	('rat', 'Species', '10116', (204, 207))	('cyclin-dependent kinases 4/6', 'Gene', '1019;1021', (259, 287))	('mitosis', 'Disease', 'None', (403, 410))	('palbociclib', 'Chemical', 'MESH:C500026', (307, 318))	('antibodies', 'Var', (151, 161))	('DMSO', 'Chemical', 'MESH:D004121', (213, 217))	('CDK4/6', 'Gene', '1019;1021', (289, 295))	('aphidicolin', 'Chemical', 'MESH:D016590', (375, 386))	('cyclin-dependent kinases 4/6', 'Gene', (259, 287))	('SMC3', 'Gene', '9126', (146, 150))	('CDK4/6', 'Gene', (289, 295))
490708	30975996	We next studied how STAG2 inactivation perturbs the association of cohesin with the replication machinery.	('inactivation', 'Var', (26, 38))	('cohesin', 'Protein', (67, 74))	('association', 'Interaction', (52, 63))	('STAG2', 'Gene', '10735', (20, 25))	('STAG2', 'Gene', (20, 25))	('perturbs', 'NegReg', (39, 47))
490709	30975996	shRNA depletion of STAG2 caused a complete disruption of cohesin interaction with PCNA, the sliding clamp essential for normal processivity of DNA replication, and also reduced association with DNA polymerases PolD and PolE (Fig.	('PCNA', 'Gene', (82, 86))	('disruption', 'NegReg', (43, 53))	('interaction', 'Interaction', (65, 76))	('STAG2', 'Gene', (19, 24))	('reduced', 'NegReg', (169, 176))	('STAG2', 'Gene', '10735', (19, 24))	('PCNA', 'Gene', '5111', (82, 86))	('cohesin', 'Protein', (57, 64))	('depletion', 'Var', (6, 15))	('association', 'Interaction', (177, 188))
490710	30975996	In contrast, STAG2 depletion resulted in increased association of cohesin with the single-stranded DNA binding protein RPAp34, and also enhanced binding with the MCM helicase complex and multiple replication licensing factors including Geminin, a negative regulator of DNA replication known to be essential for preventing genome reduplication.	('depletion', 'Var', (19, 28))	('enhanced', 'PosReg', (136, 144))	('increased', 'PosReg', (41, 50))	('Geminin', 'Gene', (236, 243))	('STAG2', 'Gene', '10735', (13, 18))	('binding', 'Interaction', (145, 152))	('association', 'Interaction', (51, 62))	('RPAp34', 'Gene', '6118', (119, 125))	('RPAp34', 'Gene', (119, 125))	('MCM', 'Protein', (162, 165))	('STAG2', 'Gene', (13, 18))	('cohesin', 'Protein', (66, 73))	('Geminin', 'Gene', '51053', (236, 243))
490712	30975996	Biallelic germline mutations in the ESCO2 gene are the cause of Roberts syndrome, a cohesinopathy characterized by tetraphocomelia (symmetrical limb reduction), craniofacial anomalies, growth retardation, mental retardation, and cardiac and renal abnormalities (Online Mendelian Inheritance in Man #268300).	('Roberts syndrome', 'Disease', (64, 80))	('cohesinopathy', 'Disease', 'None', (84, 97))	('mental retardation', 'Phenotype', 'HP:0001249', (205, 223))	('tetraphocomelia', 'Disease', 'MESH:C564771', (115, 130))	('mental retardation', 'Disease', 'MESH:D008607', (205, 223))	('Man', 'Species', '9606', (294, 297))	('tetraphocomelia', 'Disease', (115, 130))	('ESCO2', 'Gene', (36, 41))	('cohesinopathy', 'Disease', (84, 97))	('cardiac and renal abnormalities', 'Disease', 'MESH:D007674', (229, 260))	('craniofacial anomalies', 'Disease', 'MESH:D019465', (161, 183))	('mental retardation', 'Disease', (205, 223))	('growth retardation', 'Disease', 'MESH:D006130', (185, 203))	('growth retardation', 'Disease', (185, 203))	('cause', 'Reg', (55, 60))	('limb reduction', 'Phenotype', 'HP:0009826', (144, 158))	('renal abnormalities', 'Phenotype', 'HP:0000077', (241, 260))	('Roberts syndrome', 'Disease', 'MESH:C535687', (64, 80))	('Biallelic germline mutations', 'Var', (0, 28))	('ESCO2', 'Gene', '157570', (36, 41))	('tetraphocomelia', 'Phenotype', 'HP:0030721', (115, 130))	('craniofacial anomalies', 'Disease', (161, 183))	('growth retardation', 'Phenotype', 'HP:0001510', (185, 203))
490714	30975996	shRNA depletion of STAG2 in RPE cells abolished SMC3 acetylation (Fig.	('acetylation', 'MPA', (53, 64))	('abolished', 'NegReg', (38, 47))	('SMC3', 'Gene', (48, 52))	('STAG2', 'Gene', (19, 24))	('STAG2', 'Gene', '10735', (19, 24))	('depletion', 'Var', (6, 15))	('SMC3', 'Gene', '9126', (48, 52))
490716	30975996	To evaluate the consequence of replication fork stalling induced by STAG2 inactivation, we investigated whether this may lead to replication fork collapse and DNA double-strand breaks.	('replication fork', 'CPA', (129, 145))	('inactivation', 'Var', (74, 86))	('replication fork', 'CPA', (31, 47))	('STAG2', 'Gene', '10735', (68, 73))	('lead', 'Reg', (121, 125))	('DNA double-strand breaks', 'MPA', (159, 183))	('STAG2', 'Gene', (68, 73))
490717	30975996	We observed accumulation of 53BP1 foci, a marker of DNA double-strand breaks but not normal replication sites, in the three non-transformed human cell lines upon shRNA depletion of STAG2 (Fig.	('human', 'Species', '9606', (140, 145))	('53BP1', 'Gene', (28, 33))	('STAG2', 'Gene', '10735', (181, 186))	('53BP1', 'Gene', '7158', (28, 33))	('depletion', 'Var', (168, 177))	('accumulation', 'PosReg', (12, 24))	('STAG2', 'Gene', (181, 186))
490720	30975996	Commensurate with induction of 53BP1 foci accumulation, STAG2 depletion in multiple non-transformed human cell lines resulted in activation of DNA damage checkpoint signaling, as evidenced by a robust increase in phosphorylated isoforms of ATM, ATR, BRCA1, Chk2, and p53 proteins, as well as upregulation of the cell cycle checkpoint inhibitor p21WAF1/CIP1 (Fig.	('STAG2', 'Gene', '10735', (56, 61))	('rat', 'Species', '10116', (8, 11))	('53BP1', 'Gene', (31, 36))	('Chk2', 'Gene', (257, 261))	('BRCA1', 'Gene', '672', (250, 255))	('ATM', 'Gene', (240, 243))	('CIP1', 'Gene', '1026', (352, 356))	('ATR', 'Gene', (245, 248))	('BRCA1', 'Gene', (250, 255))	('STAG2', 'Gene', (56, 61))	('DNA', 'MPA', (143, 146))	('activation', 'PosReg', (129, 139))	('CIP1', 'Gene', (352, 356))	('phosphorylated isoforms', 'MPA', (213, 236))	('proteins', 'Protein', (271, 279))	('upregulation', 'PosReg', (292, 304))	('increase', 'PosReg', (201, 209))	('cell', 'CPA', (312, 316))	('Chk2', 'Gene', '11200', (257, 261))	('p53', 'Gene', '7157', (267, 270))	('ATR', 'Gene', '545', (245, 248))	('ATM', 'Gene', '472', (240, 243))	('human', 'Species', '9606', (100, 105))	('p53', 'Gene', (267, 270))	('depletion', 'Var', (62, 71))	('53BP1', 'Gene', '7158', (31, 36))
490722	30975996	While acute inactivation of STAG2 in non-transformed human cells results in cell cycle arrest, STAG2 homozygous deletion or inactivating truncating mutations are commonly selected for during the development of glioblastoma, urothelial carcinoma, Ewing sarcoma, acute myeloid leukemia, and other human cancer types, whereby this genetic inactivation likely functions to promote some aspect of tumor survival or growth.	('promote', 'PosReg', (369, 376))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('tumor', 'Disease', (392, 397))	('glioblastoma', 'Disease', 'MESH:D005909', (210, 222))	('acute myeloid leukemia', 'Disease', (261, 283))	('STAG2', 'Gene', '10735', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (392, 397))	('human', 'Species', '9606', (295, 300))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (224, 244))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (246, 259))	('leukemia', 'Phenotype', 'HP:0001909', (275, 283))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (246, 259))	('cancer', 'Disease', (301, 307))	('glioblastoma', 'Disease', (210, 222))	('STAG2', 'Gene', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('inactivating truncating mutations', 'Var', (124, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (210, 222))	('STAG2', 'Gene', '10735', (28, 33))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (261, 283))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (267, 283))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('cell cycle arrest', 'CPA', (76, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (261, 283))	('human', 'Species', '9606', (53, 58))	('STAG2', 'Gene', (28, 33))	('Ewing sarcoma', 'Disease', (246, 259))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('growth', 'CPA', (410, 416))	('urothelial carcinoma', 'Disease', (224, 244))
490723	30975996	Multiple studies have noted a strong association of STAG2 inactivation and TP53 mutation in Ewing sarcoma, whereby the combination of these two genetic alterations is significantly associated with poor prognosis relative to STAG2 and TP53 wildtype tumors.	('STAG2', 'Gene', '10735', (224, 229))	('tumors', 'Disease', (248, 254))	('TP53', 'Gene', (234, 238))	('STAG2', 'Gene', (224, 229))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('TP53', 'Gene', (75, 79))	('association', 'Interaction', (37, 48))	('rat', 'Species', '10116', (156, 159))	('STAG2', 'Gene', '10735', (52, 57))	('inactivation', 'Var', (58, 70))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('mutation', 'Var', (80, 88))	('TP53', 'Gene', '7157', (234, 238))	('STAG2', 'Gene', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('TP53', 'Gene', '7157', (75, 79))	('Ewing sarcoma', 'Disease', (92, 105))
490726	30975996	We observed a bypass of the intra-S-phase cell cycle arrest and cellular senescence induced by STAG2 inactivation alone (Fig.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (42, 59))	('cellular senescence', 'CPA', (64, 83))	('STAG2', 'Gene', (95, 100))	('inactivation', 'Var', (101, 113))	('STAG2', 'Gene', '10735', (95, 100))
490728	30975996	1a, b), we were able to produce STAG2 knockout clones at high efficiency in p53-depleted RPE cells and multiple Ewing sarcoma cell lines harboring inactivating TP53 mutations (Fig.	('Ewing sarcoma', 'Disease', (112, 125))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('TP53', 'Gene', '7157', (160, 164))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (112, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('STAG2', 'Gene', (32, 37))	('STAG2', 'Gene', '10735', (32, 37))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (112, 125))	('TP53', 'Gene', (160, 164))	('mutations', 'Var', (165, 174))
490729	30975996	These results demonstrate that the intra-S-phase cell cycle arrest induced by STAG2 inactivation is p53 dependent and help to explain the frequent co-occurrence of STAG2 and TP53 mutation in Ewing sarcoma.	('STAG2', 'Gene', '10735', (164, 169))	('TP53', 'Gene', (174, 178))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (191, 204))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (191, 204))	('p53', 'Gene', '7157', (100, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('rat', 'Species', '10116', (21, 24))	('STAG2', 'Gene', (78, 83))	('STAG2', 'Gene', '10735', (78, 83))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('STAG2', 'Gene', (164, 169))	('inactivation', 'Var', (84, 96))	('Ewing sarcoma', 'Disease', (191, 204))	('TP53', 'Gene', '7157', (174, 178))	('p53', 'Gene', (100, 103))
490730	30975996	In order the explore the mechanism by which TP53 inactivation allows bypass of the intra-S-phase arrest in STAG2 mutant cells, we performed immunoprecipitation reactions using SMC3 antibodies to study the binding of cohesin with the DNA replication machinery in STAG2-depleted RPE cells with and without simultaneous shRNA knockdown of p53.	('SMC3', 'Gene', (176, 180))	('STAG2', 'Gene', (262, 267))	('SMC3', 'Gene', '9126', (176, 180))	('STAG2', 'Gene', (107, 112))	('STAG2', 'Gene', '10735', (262, 267))	('STAG2', 'Gene', '10735', (107, 112))	('p53', 'Gene', '7157', (336, 339))	('TP53', 'Gene', '7157', (44, 48))	('binding', 'Interaction', (205, 212))	('mutant', 'Var', (113, 119))	('TP53', 'Gene', (44, 48))	('p53', 'Gene', (336, 339))
490732	30975996	However, simultaneous TP53 knockdown did not block the enhanced interaction of cohesin with RPAp34 or CDC6.	('knockdown', 'Var', (27, 36))	('RPAp34', 'Gene', (92, 98))	('RPAp34', 'Gene', '6118', (92, 98))	('CDC6', 'Gene', '990', (102, 106))	('TP53', 'Gene', '7157', (22, 26))	('CDC6', 'Gene', (102, 106))	('interaction', 'Interaction', (64, 75))	('TP53', 'Gene', (22, 26))	('cohesin', 'Protein', (79, 86))
490733	30975996	Thus, while p53 is a critical regulator of replication fork procession in STAG2 mutant cells, there are perturbations of the interaction between cohesin and replication factors (e.g., RPAp34 and CDC6) that are independent of p53 control.	('RPAp34', 'Gene', '6118', (184, 190))	('RPAp34', 'Gene', (184, 190))	('mutant', 'Var', (80, 86))	('STAG2', 'Gene', (74, 79))	('p53', 'Gene', (225, 228))	('interaction', 'Interaction', (125, 136))	('STAG2', 'Gene', '10735', (74, 79))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', '7157', (225, 228))	('CDC6', 'Gene', '990', (195, 199))	('CDC6', 'Gene', (195, 199))	('cohesin', 'Protein', (145, 152))
490735	30975996	We have previously used homologous recombination to correct the endogenous STAG2 mutant allele in the H4 human glioblastoma cell line.	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('STAG2', 'Gene', (75, 80))	('STAG2', 'Gene', '10735', (75, 80))	('mutant', 'Var', (81, 87))	('human', 'Species', '9606', (105, 110))	('glioblastoma', 'Disease', (111, 123))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))
490737	30975996	Additionally, we found that the levels of SMC3 acetylation were impaired in cancer cells lines harboring STAG2 inactivation (H4 parental and TC-106 STAG2 knockout cells) relative to their STAG2 wildtype counterparts (H4 STAG2 knock-in and TC-106 parental cells) (Fig.	('SMC3', 'Gene', (42, 46))	('STAG2', 'Gene', (220, 225))	('STAG2', 'Gene', '10735', (220, 225))	('TC-106', 'Chemical', '-', (141, 147))	('STAG2', 'Gene', (148, 153))	('STAG2', 'Gene', '10735', (148, 153))	('impaired', 'NegReg', (64, 72))	('STAG2', 'Gene', '10735', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('levels', 'MPA', (32, 38))	('STAG2', 'Gene', (105, 110))	('inactivation', 'Var', (111, 123))	('STAG2', 'Gene', '10735', (105, 110))	('TC-106', 'Chemical', '-', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('SMC3', 'Gene', '9126', (42, 46))	('STAG2', 'Gene', (188, 193))
490738	30975996	These results indicate that STAG2 is critical for SMC3 acetylation independent of p53 function, and that cancer cells with concomitant STAG2 and TP53 inactivation escape cellular senescence despite abrogation of SMC3 acetylation.	('inactivation', 'Var', (150, 162))	('cancer', 'Disease', (105, 111))	('STAG2', 'Gene', '10735', (135, 140))	('TP53', 'Gene', '7157', (145, 149))	('p53', 'Gene', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SMC3', 'Gene', '9126', (50, 54))	('STAG2', 'Gene', (135, 140))	('abrogation', 'NegReg', (198, 208))	('SMC3', 'Gene', (212, 216))	('cellular senescence', 'CPA', (170, 189))	('STAG2', 'Gene', '10735', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('escape', 'PosReg', (163, 169))	('TP53', 'Gene', (145, 149))	('STAG2', 'Gene', (28, 33))	('SMC3', 'Gene', (50, 54))	('SMC3', 'Gene', '9126', (212, 216))	('p53', 'Gene', '7157', (82, 85))
490739	30975996	Two recent studies have both demonstrated that STAG2 mutant cancer cells have a critical dependence on STAG1.	('rat', 'Species', '10116', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('STAG1', 'Gene', (103, 108))	('cancer', 'Disease', (60, 66))	('STAG2', 'Gene', (47, 52))	('STAG2', 'Gene', '10735', (47, 52))	('mutant', 'Var', (53, 59))	('STAG1', 'Gene', '10274', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
490740	30975996	We observed no significant growth inhibition or cell death upon lentiviral shRNA knockdown of >99% of STAG1 protein in hTERT-immortalized primary human cells with wildtype STAG2, whereas shRNA knockdown of >99% of SMC3, SMC1A, and RAD21 proteins resulted in cell death (Fig.	('STAG2', 'Gene', (172, 177))	('STAG2', 'Gene', '10735', (172, 177))	('hTERT', 'Gene', (119, 124))	('RAD21', 'Gene', (231, 236))	('RAD21', 'Gene', '5885', (231, 236))	('SMC3', 'Gene', '9126', (214, 218))	('SMC3', 'Gene', (214, 218))	('knockdown', 'Var', (193, 202))	('SMC1A', 'Gene', (220, 225))	('cell death', 'CPA', (258, 268))	('STAG1', 'Gene', '10274', (102, 107))	('human', 'Species', '9606', (146, 151))	('hTERT', 'Gene', '7015', (119, 124))	('SMC1A', 'Gene', '8243', (220, 225))	('STAG1', 'Gene', (102, 107))
490741	30975996	In order to investigate the genetic dependencies for these core cohesin genes in cancer cells harboring inactivating STAG2 mutations, lentiviral shRNA transduction using two independent shRNA sequences for each cohesin subunit was performed in four pairs of isogenic STAG2 human cell lines (H4 glioblastoma, 42MGBA glioblastoma, TC-106 Ewing sarcoma, and RPE primary epithelial cells with hTERT overexpression and TP53 depletion).	('hTERT', 'Gene', '7015', (389, 394))	('TP53', 'Gene', '7157', (414, 418))	('cancer', 'Disease', (81, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (315, 327))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TC-106', 'Chemical', '-', (329, 335))	('sarcoma', 'Phenotype', 'HP:0100242', (342, 349))	('STAG2', 'Gene', '10735', (117, 122))	('Ewing sarcoma', 'Disease', (336, 349))	('glioblastoma', 'Disease', (315, 327))	('STAG2', 'Gene', '10735', (267, 272))	('hTERT', 'Gene', (389, 394))	('glioblastoma', 'Phenotype', 'HP:0012174', (315, 327))	('STAG2', 'Gene', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (294, 306))	('STAG2', 'Gene', (267, 272))	('TP53', 'Gene', (414, 418))	('glioblastoma', 'Disease', (294, 306))	('glioblastoma', 'Phenotype', 'HP:0012174', (294, 306))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (336, 349))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (336, 349))	('human', 'Species', '9606', (273, 278))	('mutations', 'Var', (123, 132))
490742	30975996	In keeping with the two recent studies, STAG1 depletion had no significant growth inhibition on STAG2 proficient cells, whereas STAG1 depletion uniformly resulted in cell death across all four of the STAG2 deficient cells (Fig.	('depletion', 'Var', (46, 55))	('STAG2', 'Gene', (96, 101))	('STAG2', 'Gene', '10735', (96, 101))	('STAG1', 'Gene', '10274', (128, 133))	('resulted in', 'Reg', (154, 165))	('depletion', 'Var', (134, 143))	('STAG2', 'Gene', (200, 205))	('STAG2', 'Gene', '10735', (200, 205))	('STAG1', 'Gene', '10274', (40, 45))	('STAG1', 'Gene', (128, 133))	('cell death', 'CPA', (166, 176))	('STAG1', 'Gene', (40, 45))
490744	30975996	Given the large burden of collapsed replication forks and DNA double-strand breaks in STAG2 deficient cells, we hypothesized that STAG2 mutational inactivation might create a synthetic lethality with factors critical for DNA damage repair.	('STAG2', 'Gene', '10735', (130, 135))	('STAG2', 'Gene', '10735', (86, 91))	('STAG2', 'Gene', (86, 91))	('mutational', 'Var', (136, 146))	('STAG2', 'Gene', (130, 135))	('synthetic lethality', 'CPA', (175, 194))
490749	30975996	Together, these results highlight a critical dependency for DNA double-strand break repair, but not excision repair, in STAG2 mutant cells.	('STAG2', 'Gene', '10735', (120, 125))	('STAG2', 'Gene', (120, 125))	('mutant', 'Var', (126, 132))
490750	30975996	Given this finding, we speculated that STAG2 mutant cells may show increased sensitivity to ionizing radiation via synergizing with the replication fork disruption to cause a catastrophic accumulation of DNA double-strand breaks.	('mutant', 'Var', (45, 51))	('DNA double-strand breaks', 'MPA', (204, 228))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (67, 110))	('STAG2', 'Gene', (39, 44))	('STAG2', 'Gene', '10735', (39, 44))	('increased', 'PosReg', (67, 76))	('sensitivity', 'MPA', (77, 88))
490753	30975996	These results further highlight the dependency for DNA double-strand break repair, but not excision repair, in STAG2 mutant cells.	('STAG2', 'Gene', '10735', (111, 116))	('mutant', 'Var', (117, 123))	('STAG2', 'Gene', (111, 116))
490754	30975996	While STAG2 mutational activation is known to be frequent in glioblastoma, Ewing sarcoma, and urothelial carcinoma, the effect of STAG2 status on the response to cytotoxic chemotherapy agents routinely used in the treatment of these cancer types is largely unknown.	('STAG2', 'Gene', '10735', (130, 135))	('urothelial carcinoma', 'Disease', (94, 114))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Ewing sarcoma', 'Disease', (75, 88))	('glioblastoma', 'Disease', (61, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('mutational', 'Var', (12, 22))	('cancer', 'Disease', (233, 239))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (94, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('STAG2', 'Gene', (130, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('STAG2', 'Gene', (6, 11))	('STAG2', 'Gene', '10735', (6, 11))
490759	30975996	Cyclophosphamide treatment significantly reduced colony formation in STAG2 mutant cells relative to their STAG2 wildtype counterparts in all four isogenic pairs (Supplementary Fig.	('STAG2', 'Gene', (69, 74))	('reduced', 'NegReg', (41, 48))	('STAG2', 'Gene', '10735', (69, 74))	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (0, 16))	('STAG2', 'Gene', (106, 111))	('mutant', 'Var', (75, 81))	('STAG2', 'Gene', '10735', (106, 111))	('colony formation', 'CPA', (49, 65))
490761	30975996	However, methods to therapeutically target cohesin-mutant cancers are currently unknown.	('cohesin-mutant', 'Var', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('cohesin-mutant', 'Protein', (43, 57))
490762	30975996	Herein we have identified an essential role for the STAG2 gene in stability of the replication fork that creates a targetable synthetic lethality in STAG2 mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('STAG2', 'Gene', (52, 57))	('cancers', 'Disease', (162, 169))	('STAG2', 'Gene', '10735', (52, 57))	('stability', 'MPA', (66, 75))	('STAG2', 'Gene', (149, 154))	('STAG2', 'Gene', '10735', (149, 154))	('mutant', 'Var', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
490763	30975996	In order to study the fundamental cellular processes controlled by STAG2, we used multiple genetic mechanisms to inactivate STAG2 function in primary non-transformed human cells.	('function', 'MPA', (130, 138))	('inactivate', 'Var', (113, 123))	('STAG2', 'Gene', (124, 129))	('human', 'Species', '9606', (166, 171))	('STAG2', 'Gene', '10735', (124, 129))	('STAG2', 'Gene', '10735', (67, 72))	('STAG2', 'Gene', (67, 72))
490765	30975996	In contrast, inactivation of the cohesin ring subunits SMC1A, SMC3, and RAD21 is not compatible with viability in both primary non-transformed human cells and human cancer cell lines.	('RAD21', 'Gene', (72, 77))	('RAD21', 'Gene', '5885', (72, 77))	('SMC1A', 'Gene', '8243', (55, 60))	('human', 'Species', '9606', (143, 148))	('inactivation', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('cancer', 'Disease', (165, 171))	('SMC1A', 'Gene', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('SMC3', 'Gene', (62, 66))	('SMC3', 'Gene', '9126', (62, 66))
490766	30975996	The reason why cohesin mutations in human cancers most commonly affect STAG2 and less commonly the other cohesin subunits has been unknown.	('cancers', 'Disease', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (23, 32))	('STAG2', 'Gene', (71, 76))	('STAG2', 'Gene', '10735', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('affect', 'Reg', (64, 70))	('human', 'Species', '9606', (36, 41))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
490768	30975996	However, our findings indicate that truncating mutations in cohesin ring subunits are uncommon in human cancers because these are required genes for cell viability.	('truncating mutations', 'Var', (36, 56))	('cohesin ring subunits', 'Protein', (60, 81))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('human', 'Species', '9606', (98, 103))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
490769	30975996	In contrast, truncating loss of function mutations in STAG2 are likely selected for in human cancers because STAG2 inactivation is not an essential gene, but instead is a critical regulator of cohesin function that when subverted promotes tumorigenesis without perturbing the essential functions of the core cohesin ring.	('mutations', 'Var', (41, 50))	('cancers', 'Disease', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('loss of function', 'NegReg', (24, 40))	('human', 'Species', '9606', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('promotes', 'PosReg', (230, 238))	('STAG2', 'Gene', '10735', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('STAG2', 'Gene', (109, 114))	('tumor', 'Disease', (239, 244))	('STAG2', 'Gene', (54, 59))	('STAG2', 'Gene', '10735', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
490775	30975996	These findings indicate that the interaction of the cohesin ring with the pre-replication complex and the active replication machinery during S phase is a complex and dynamic process, which is perturbed by the absence of STAG2.	('cohesin', 'Protein', (52, 59))	('STAG2', 'Gene', (221, 226))	('STAG2', 'Gene', '10735', (221, 226))	('absence', 'Var', (210, 217))	('interaction', 'Interaction', (33, 44))
490781	30975996	These results show that SMC3 acetylation is not required for DNA replication in cancer cells with TP53 mutation, but instead suggest that SMC3 acetylation is critical for controlling activation of an S-phase checkpoint that ensures establishment of sister chromatid cohesion during DNA synthesis.	('SMC3', 'Gene', '9126', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('SMC3', 'Gene', '9126', (24, 28))	('SMC3', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (98, 102))	('mutation', 'Var', (103, 111))	('SMC3', 'Gene', (138, 142))	('cancer', 'Disease', (80, 86))	('TP53', 'Gene', (98, 102))
490782	30975996	These results also help to explain the frequent co-occurrence of STAG2 and TP53 mutations in human cancers including Ewing sarcoma.	('STAG2', 'Gene', (65, 70))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (117, 130))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (117, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('mutations', 'Var', (80, 89))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('STAG2', 'Gene', '10735', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('Ewing sarcoma', 'Disease', (117, 130))	('TP53', 'Gene', '7157', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TP53', 'Gene', (75, 79))
490783	30975996	STAG2 mutation disrupts stability of the replication fork leading to fork collapse and DNA double-strand breaks, which in normal cells with intact TP53 leads to checkpoint activation and senescence.	('stability', 'MPA', (24, 33))	('TP53', 'Gene', (147, 151))	('DNA double-strand', 'MPA', (87, 104))	('STAG2', 'Gene', '10735', (0, 5))	('senescence', 'CPA', (187, 197))	('checkpoint activation', 'MPA', (161, 182))	('mutation', 'Var', (6, 14))	('fork collapse', 'CPA', (69, 82))	('TP53', 'Gene', '7157', (147, 151))	('STAG2', 'Gene', (0, 5))	('disrupts', 'NegReg', (15, 23))
490784	30975996	However, in cells with concurrent TP53 inactivation, the fork collapse and DNA double-strand breaks induced by STAG2 deficiency likely promotes tumorigenesis by facilitating oncogenic structural variants such as gene amplifications, deletions, and rearrangements.	('tumor', 'Disease', (144, 149))	('DNA double-strand breaks', 'MPA', (75, 99))	('TP53', 'Gene', (34, 38))	('fork collapse', 'CPA', (57, 70))	('STAG2 deficiency', 'Disease', (111, 127))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('deletions', 'Var', (233, 242))	('rearrangements', 'Var', (248, 262))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('STAG2 deficiency', 'Disease', 'MESH:D007153', (111, 127))	('promotes', 'PosReg', (135, 143))	('inactivation', 'Var', (39, 51))	('TP53', 'Gene', '7157', (34, 38))
490785	30975996	Indeed, an increased quantity of chromosomal structural variants is found in STAG2 mutant versus STAG2 wildtype Ewing sarcomas.	('mutant', 'Var', (83, 89))	('STAG2', 'Gene', '10735', (97, 102))	('STAG2', 'Gene', (97, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('Ewing sarcomas', 'Disease', (112, 126))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (112, 126))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (112, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('STAG2', 'Gene', (77, 82))	('STAG2', 'Gene', '10735', (77, 82))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (112, 126))
490786	30975996	We find that a consequence of the replication fork instability caused by STAG2 inactivation in human cells is a critical dependence on DNA double-strand break repair factors.	('human', 'Species', '9606', (95, 100))	('inactivation', 'Var', (79, 91))	('STAG2', 'Gene', '10735', (73, 78))	('STAG2', 'Gene', (73, 78))	('replication fork instability', 'CPA', (34, 62))
490787	30975996	STAG2 deficient cells show profound sensitivity to depletion of genes involved in homologous recombination and non-homologous end-joining, but not excision repair pathways.	('depletion', 'MPA', (51, 60))	('STAG2', 'Gene', '10735', (0, 5))	('deficient', 'Var', (6, 15))	('sensitivity', 'Reg', (36, 47))	('STAG2', 'Gene', (0, 5))
490788	30975996	Additionally, we find that STAG2 mutant cancer cells have increased sensitivity to ionizing radiation and cytotoxic chemotherapeutic agents (e.g., cyclophosphamide and etoposide) that function by inducing DNA double-strand breaks.	('DNA double-strand breaks', 'MPA', (205, 229))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (58, 101))	('inducing', 'Reg', (196, 204))	('increased', 'PosReg', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('STAG2', 'Gene', '10735', (27, 32))	('cancer', 'Disease', (40, 46))	('mutant', 'Var', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (147, 163))	('etoposide', 'Chemical', 'MESH:D005047', (168, 177))	('sensitivity', 'MPA', (68, 79))	('STAG2', 'Gene', (27, 32))
490791	30975996	These findings have significant treatment implications for STAG2 mutant cancers, suggesting a greater benefit from radiation therapy and chemotherapeutic agents that induce DNA double-strand breaks.	('STAG2', 'Gene', (59, 64))	('mutant', 'Var', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('STAG2', 'Gene', '10735', (59, 64))
490792	30975996	In summary, STAG2 mutations are a frequent characteristic of a few of the most common human cancers including glioblastoma, urothelial carcinoma, and Ewing sarcoma.	('Ewing sarcoma', 'Disease', (150, 163))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (124, 144))	('STAG2', 'Gene', (12, 17))	('STAG2', 'Gene', '10735', (12, 17))	('cancers', 'Disease', (92, 99))	('glioblastoma', 'Disease', (110, 122))	('urothelial carcinoma', 'Disease', (124, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (150, 163))	('glioblastoma', 'Disease', 'MESH:D005909', (110, 122))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))	('mutations', 'Var', (18, 27))
490793	30975996	Here we show that cohesin has critical functions at the DNA replication fork regulated by STAG2, and that the replication fork instability caused by STAG2 inactivation creates a targetable synthetic lethality in cohesin-mutant cancers.	('synthetic lethality', 'CPA', (189, 208))	('replication fork instability', 'MPA', (110, 138))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('STAG2', 'Gene', (90, 95))	('STAG2', 'Gene', (149, 154))	('inactivation', 'Var', (155, 167))	('STAG2', 'Gene', '10735', (90, 95))	('cohesin-mutant', 'Var', (212, 226))	('STAG2', 'Gene', '10735', (149, 154))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cohesin-mutant', 'Gene', (212, 226))	('cancers', 'Disease', (227, 234))	('cancers', 'Disease', 'MESH:D009369', (227, 234))
490794	30975996	Together with other recent studies showing enhanced PARP inhibitor sensitivity in cohesin-deficient cells, these studies lay the foundation for clinical trials of targeted agents in STAG2 mutant cancers.	('PARP', 'Gene', '142', (52, 56))	('enhanced', 'PosReg', (43, 51))	('STAG2', 'Gene', (182, 187))	('STAG2', 'Gene', '10735', (182, 187))	('PARP', 'Gene', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('mutant', 'Var', (188, 194))
490806	30975996	hTERT-immortalized RPE cells, hTERT-immortalized RPE shTP53 cells, hTERT-immortalized BJ cells, EW2 Ewing sarcoma cells, TC-71 Ewing sarcoma cells, and TC-106 Ewing sarcoma cells were used for CRISPR induced mutagenesis of the STAG2 gene.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Ewing sarcoma', 'Disease', (100, 113))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (159, 172))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (159, 172))	('hTERT', 'Gene', (0, 5))	('TP53', 'Gene', '7157', (55, 59))	('TC-71', 'CellLine', 'CVCL:2213', (121, 126))	('hTERT', 'Gene', '7015', (30, 35))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (127, 140))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (127, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('STAG2', 'Gene', '10735', (227, 232))	('TC-106', 'Chemical', '-', (152, 158))	('hTERT', 'Gene', '7015', (67, 72))	('Ewing sarcoma', 'Disease', (159, 172))	('hTERT', 'Gene', (30, 35))	('STAG2', 'Gene', (227, 232))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (100, 113))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (100, 113))	('TP53', 'Gene', (55, 59))	('Ewing sarcoma', 'Disease', (127, 140))	('mutagenesis', 'Var', (208, 219))	('BJ', 'CellLine', 'CVCL:6573', (86, 88))	('hTERT', 'Gene', '7015', (0, 5))	('hTERT', 'Gene', (67, 72))
490811	30975996	Cell lysate was prepared from individual clones found to have Cas9 induced frameshift mutations predicted to cause premature truncation of the encoded STAG2 protein, and immunoblots were performed using a monoclonal antibody raised against an epitope at the C-terminus of the STAG2 protein (clone J-12, Santa Cruz sc-81852) as described in detail below.	('STAG2', 'Gene', '10735', (151, 156))	('STAG2', 'Gene', (151, 156))	('STAG2', 'Gene', (276, 281))	('STAG2', 'Gene', '10735', (276, 281))	('frameshift mutations', 'Var', (75, 95))
491007	26913028	Appropriate regulation of latent and lytic gene expression is extremely critical for viral persistence and spread, disturbances in the regulation of these mechanisms can lead to a development of cancers.	('disturbances', 'Var', (115, 127))	('lead to', 'Reg', (170, 177))	('men', 'Species', '9606', (187, 190))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
491011	26913028	KSHV infection of endothelial cells lays a foundation for the development of Kaposi's Sarcoma (KS), a highly vascularised tumor of endothelial origin, and the infection of B cells can cause a rare but aggressive B cell tumor, PEL.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('men', 'Species', '9606', (69, 72))	('vascularised tumor', 'Phenotype', 'HP:0100742', (109, 127))	('Sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('tumor', 'Disease', (219, 224))	('PEL', 'Disease', (226, 229))	("Kaposi's Sarcoma", 'Disease', 'MESH:D012514', (77, 93))	('cause', 'Reg', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('KSHV infection', 'Disease', 'MESH:C537372', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	("Kaposi's Sarcoma", 'Phenotype', 'HP:0100726', (77, 93))	('KSHV infection', 'Disease', (0, 14))	("Kaposi's Sarcoma", 'Disease', (77, 93))	('tumor', 'Disease', (122, 127))	('infection', 'Var', (159, 168))
491012	26913028	A variant of MCD is another disease associated with KSHV infection.	('MCD', 'Disease', 'MESH:D012514', (13, 16))	('MCD', 'Disease', (13, 16))	('KSHV infection', 'Disease', (52, 66))	('variant', 'Var', (2, 9))	('KSHV infection', 'Disease', 'MESH:C537372', (52, 66))
491056	26913028	Increased risk of developing KS and PEL associated with low CD4+ T cell count indicates that immune suppression associated with HIV co-infection plays essential roles in KSHV induced pathologies.	('low', 'Var', (56, 59))	('HIV co-infection', 'Disease', 'MESH:D060085', (128, 144))	('low CD4+ T cell', 'Phenotype', 'HP:0005407', (56, 71))	('KSHV', 'Species', '37296', (170, 174))	('CD4', 'Gene', (60, 63))	('HIV co-infection', 'Disease', (128, 144))	('PEL', 'Disease', (36, 39))	('CD4', 'Gene', '920', (60, 63))
491112	26913028	Indeed, a couple of studies have demonstrated that EBV co-infected PEL cell lines are more tumorigenic compared to the EBV negative PEL cell lines.	('EBV', 'Var', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('EBV', 'Species', '10376', (119, 122))	('more', 'PosReg', (86, 90))	('tumor', 'Disease', (91, 96))	('EBV', 'Species', '10376', (51, 54))
491120	26913028	While EBV-ZTA suppresses the lytic reactivation of only KSHV, expression of EBV-LMP1 suppresses the lytic replication of both, EBV and KSHV.	('lytic reactivation', 'MPA', (29, 47))	('EBV', 'Species', '10376', (76, 79))	('EBV-LMP1', 'Gene', (76, 84))	('suppresses', 'NegReg', (85, 95))	('KSHV', 'Species', '37296', (56, 60))	('KSHV', 'Species', '37296', (135, 139))	('lytic replication', 'CPA', (100, 117))	('EBV-LMP1', 'Gene', '17494204', (76, 84))	('EBV', 'Species', '10376', (127, 130))	('expression', 'Var', (62, 72))	('EBV', 'Species', '10376', (6, 9))	('suppresses', 'NegReg', (14, 24))
491158	26913028	Since HHV-6 infection is ubiquitous, reactivation of HHV-6 in the context of immune-suppression may contribute to a progression of KSHV associated pathologies by further augmenting KSHV lytic replication.	('KSHV', 'Species', '37296', (181, 185))	('HHV-6 infection', 'Disease', 'MESH:C537372', (6, 21))	('men', 'Species', '9606', (173, 176))	('reactivation', 'Var', (37, 49))	('KSHV', 'Species', '37296', (131, 135))	('HHV-6', 'Species', '10368', (53, 58))	('augmenting', 'PosReg', (170, 180))	('HHV-6 infection', 'Disease', (6, 21))	('KSHV lytic replication', 'CPA', (181, 203))	('contribute', 'Reg', (100, 110))	('HHV-6', 'Gene', (53, 58))	('KSHV', 'Gene', (131, 135))	('HHV-6', 'Species', '10368', (6, 11))
491166	26913028	Oral cavity KS lesions may be seen in all variants of KS but they are more common with AIDS-KS.	('variants', 'Var', (42, 50))	('AIDS-KS', 'Disease', 'MESH:D000163', (87, 94))	('common', 'Reg', (75, 81))	('AIDS-KS', 'Disease', (87, 94))	('Oral cavity KS lesions', 'Disease', (0, 22))
491167	26913028	A couple of studies have indicated that co-infection of periodontal pathogenic microbiota has a potential to enhance KSHV infectivity and promote lytic replication of the virus.	('KSHV', 'Species', '37296', (117, 121))	('infectivity', 'MPA', (122, 133))	('co-infection', 'Var', (40, 52))	('promote', 'PosReg', (138, 145))	('lytic replication', 'CPA', (146, 163))	('enhance', 'PosReg', (109, 116))	('KSHV', 'Protein', (117, 121))
491180	26913028	Currently, five species of Plasmodium are known to infect humans of which, P. falciparum causes the most severe form of the disease and is accountable for nearly 85% of all malaria cases worldwide.	('P. falciparum', 'Species', '5833', (75, 88))	('malaria', 'Disease', (173, 180))	('humans', 'Species', '9606', (58, 64))	('causes', 'Reg', (89, 95))	('Plasmodium', 'Species', '5833', (27, 37))	('P. falciparum', 'Var', (75, 88))	('malaria', 'Disease', 'MESH:D008288', (173, 180))
491186	26913028	As mentioned earlier, a healthy host immune system suppresses KSHV lytic replication, however, impairment of B-cell and T-cell immunity resulting from repeated infections of malarial parasite can lead to viral reactivation and thus could potentially enhance the infectivity and/or transmission of KSHV.	('infections of malarial', 'Disease', (160, 182))	('repeated infections', 'Phenotype', 'HP:0002719', (151, 170))	('infections of malarial', 'Disease', 'MESH:D007239', (160, 182))	('infectivity', 'CPA', (262, 273))	('KSHV', 'Species', '37296', (62, 66))	('lead to', 'Reg', (196, 203))	('men', 'Species', '9606', (101, 104))	('viral reactivation', 'MPA', (204, 222))	('transmission', 'CPA', (281, 293))	('impairment', 'Var', (95, 105))	('KSHV', 'Species', '37296', (297, 301))	('enhance', 'PosReg', (250, 257))	('men', 'Species', '9606', (3, 6))
491194	26913028	found that cross-linking of CD36 with a recombinant peptide derived from CD36 binding domain of pfEMP-1 antigen could revoke KSHV latency, presumably through activation of some of the signal transduction pathways that lead to an activation of KSHV-RTA promoter.	('RTA', 'Gene', '4961526', (248, 251))	('KSHV latency', 'Disease', (125, 137))	('KSHV', 'Species', '37296', (125, 129))	('CD36', 'Species', '42374', (28, 32))	('CD36', 'Species', '42374', (73, 77))	('activation', 'PosReg', (158, 168))	('pfEMP-1', 'Gene', (96, 103))	('revoke', 'PosReg', (118, 124))	('RTA', 'Gene', (248, 251))	('KSHV', 'Species', '37296', (243, 247))	('cross-linking', 'Var', (11, 24))
491203	21979944	Ewing's sarcoma family tumors (ESFTs), which include peripheral primitive neuroectodermal tumors (PNETs), are characterized by chromosomal translocations that generate fusions between the EWS gene and ETS-family transcription factors, most commonly FLI1.	("Ewing's sarcoma family tumors", 'Disease', (0, 29))	('PNETs', 'Phenotype', 'HP:0030065', (98, 103))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	("Ewing's sarcoma family tumors", 'Disease', 'MESH:C563168', (0, 29))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (74, 96))	('peripheral primitive neuroectodermal tumors', 'Phenotype', 'HP:0030067', (53, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('EWS', 'Gene', (188, 191))	('fusions', 'Var', (168, 175))	('neuroectodermal tumors', 'Disease', (74, 96))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (74, 96))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (64, 96))
491207	21979944	Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly resembling that of human Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (150, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('human', 'Species', '9606', (144, 149))	('Mosaic expression', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('zebrafish', 'Species', '7955', (58, 67))	('human', 'Species', '9606', (25, 30))	('EWS-FLI1', 'Gene', (31, 39))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (150, 165))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	("Ewing's sarcoma", 'Disease', (150, 165))	('caused', 'Reg', (68, 74))
491208	21979944	The incidence of tumors increased in a p53 mutant background, suggesting that the p53 pathway suppresses EWS-FLI1-driven tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', (121, 126))	('mutant', 'Var', (43, 49))	('EWS-FLI1-driven', 'Gene', (105, 120))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('suppresses', 'NegReg', (94, 104))	('increased', 'PosReg', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
491212	21979944	Chromosomal translocations that create fusion oncogenes have long been recognized as a cause of human cancers such as leukemias and sarcomas, and recently have been described in prostate and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('leukemias', 'Disease', 'MESH:D007938', (118, 127))	('leukemias', 'Phenotype', 'HP:0001909', (118, 127))	('sarcomas', 'Disease', 'MESH:D012509', (132, 140))	('human', 'Species', '9606', (96, 101))	('Chromosomal translocations', 'Var', (0, 26))	('leukemias', 'Disease', (118, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('cause', 'Reg', (87, 92))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('sarcomas', 'Disease', (132, 140))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('prostate and lung cancer', 'Disease', 'MESH:D011471', (178, 202))
491214	21979944	In Ewing's sarcoma, a malignant bone tumor that most commonly occurs in adolescents and young adults, the discovery of a characteristic chromosomal translocation t(11;22)(q24;q12) marked a turning point in the understanding of the biology of the disease.	('bone tumor', 'Disease', (32, 42))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (3, 18))	('bone tumor', 'Phenotype', 'HP:0010622', (32, 42))	("Ewing's sarcoma", 'Disease', (3, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('bone tumor', 'Disease', 'MESH:D001859', (32, 42))	('t(11;22)(q24;q12', 'Var', (162, 178))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (3, 18))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (162, 179))
491221	21979944	The discovery of EWS-ETS translocations in Ewing's sarcoma family tumors (ESFTs) creates an opportunity for the development of targeted therapy of Ewing's sarcoma, either through direct inhibition of EWS-FLI1, or through the discovery of critical downstream effectors that might themselves be candidates for targeted therapy.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	("Ewing's sarcoma", 'Disease', (147, 162))	('EWS-FLI1', 'Gene', (200, 208))	('inhibition', 'NegReg', (186, 196))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (147, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('EWS-ETS', 'Gene', (17, 24))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (43, 58))	("Ewing's sarcoma family tumors", 'Disease', (43, 72))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (147, 162))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (43, 58))	('translocations', 'Var', (25, 39))	("Ewing's sarcoma family tumors", 'Disease', 'MESH:C563168', (43, 72))
491225	21979944	Mouse mesenchymal progenitor cells are one type of cell that tolerates EWS-FLI1 expression and generate Ewing's-like tumors when transplanted into mice.	('mice', 'Species', '10090', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	("Ewing's-like tumors", 'Phenotype', 'HP:0012254', (104, 123))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('generate', 'Reg', (95, 103))	("Ewing's-like tumors", 'Disease', (104, 123))	('EWS-FLI1', 'Gene', (71, 79))	('tolerates', 'Var', (61, 70))	('Mouse', 'Species', '10090', (0, 5))	("Ewing's-like tumors", 'Disease', 'MESH:C563168', (104, 123))	('expression', 'Var', (80, 90))
491227	21979944	Thus, the molecular characteristics that are required for EWS-FLI1 responsiveness, as well as the downstream mechanisms by which EWS-FLI1 gives rise to tumors, remain to be elucidated.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('gives rise', 'Reg', (138, 148))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('EWS-FLI1', 'Var', (129, 137))
491228	21979944	Several mouse models of EWS-FLI1 transgenic expression have been reported.	('EWS-FLI1', 'Gene', (24, 32))	('transgenic expression', 'Var', (33, 54))	('mouse', 'Species', '10090', (8, 13))
491230	21979944	Recently, EWS-FLI1 was conditionally expressed in mice under the control of a primitive mesenchymal cell promoter, resulting in limb defects and accelerated development of undifferentiated sarcoma when introduced into the p53 mutant background.	('limb defects', 'Disease', 'MESH:D017880', (128, 140))	('mutant', 'Var', (226, 232))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (172, 196))	('limb defects', 'Disease', (128, 140))	('development', 'CPA', (157, 168))	('undifferentiated sarcoma', 'Disease', (172, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('EWS-FLI1', 'Gene', (10, 18))	('mice', 'Species', '10090', (50, 54))	('accelerated', 'PosReg', (145, 156))
491233	21979944	Here, we report that expression of human EWS-FLI1 in zebrafish causes tumors strongly resembling human Ewing's sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (103, 118))	('human', 'Species', '9606', (35, 40))	('expression', 'Var', (21, 31))	('human', 'Species', '9606', (97, 102))	("Ewing's sarcoma", 'Disease', (103, 118))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('EWS-FLI1', 'Gene', (41, 49))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (103, 118))	('causes', 'Reg', (63, 69))	('zebrafish', 'Species', '7955', (53, 62))
491238	21979944	From over 300 wild-type embryos injected with the three different EWS-FLI1 transgenes and raised to adulthood, we identified two fish with tumors.	('transgenes', 'Var', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('EWS-FLI1', 'Gene', (66, 74))
491246	21979944	Mutations in tp53 occur in a subset of primary Ewing's tumors and research suggests that EWS-FLI1 can induce a p53-dependent growth arrest.	("Ewing's tumor", 'Phenotype', 'HP:0012254', (47, 60))	('p53-dependent', 'MPA', (111, 124))	('induce', 'Reg', (102, 108))	('growth arrest', 'Phenotype', 'HP:0001510', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	("Ewing's tumors", 'Disease', (47, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (47, 61))	('EWS-FLI1', 'Gene', (89, 97))	('Mutations', 'Var', (0, 9))	('tp53', 'Gene', '30590', (13, 17))	("Ewing's tumors", 'Disease', 'MESH:C563168', (47, 61))	('growth arrest', 'Disease', (125, 138))	('growth arrest', 'Disease', 'MESH:D006323', (125, 138))	('tp53', 'Gene', (13, 17))
491247	21979944	Additionally, mutation of tp53 has been shown to be a sensitized background for the development of other tumors in the zebrafish, including rhabdomyosarcoma and melanoma models, as well as in a mouse model of EWS-FLI1-driven tumor development.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('zebrafish', 'Species', '7955', (119, 128))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (140, 156))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (225, 230))	('mouse', 'Species', '10090', (194, 199))	('tp53', 'Gene', '30590', (26, 30))	('mutation', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('rhabdomyosarcoma and melanoma', 'Disease', 'MESH:D012208', (140, 169))	('tumor', 'Disease', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tp53', 'Gene', (26, 30))
491248	21979944	Zebrafish with a mutation in tp53 are predisposed to develop malignant peripheral nerve sheath tumors (MPNSTs), composed of spindle cells with abundant cytoplasm.	('malignant peripheral nerve sheath tumors', 'Disease', (61, 101))	('tp53', 'Gene', '30590', (29, 33))	('mutation', 'Var', (17, 25))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (61, 101))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (61, 101))	('MPNSTs', 'Phenotype', 'HP:0100697', (103, 109))	('develop', 'PosReg', (53, 60))	('tp53', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('Zebrafish', 'Species', '7955', (0, 9))
491251	21979944	From 6 to 19 months of age, we identified 48 tumors from approximately 150 tp53 mutant zebrafish injected with one of the three EWS-FLI1 transposons (Table 1).	('tp53', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('zebrafish', 'Species', '7955', (87, 96))	('mutant', 'Var', (80, 86))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tp53', 'Gene', '30590', (75, 79))
491255	21979944	The identification of both solid and diffuse tumors suggests that EWS-FLI1 can induce the formation of at least two tumor types in the zebrafish.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('induce', 'Reg', (79, 85))	('zebrafish', 'Species', '7955', (135, 144))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('formation', 'CPA', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('EWS-FLI1', 'Var', (66, 74))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
491256	21979944	The small round blue cell morphology was not identified in any tumors occurring in uninjected tp53 mutants.	('tp53', 'Gene', '30590', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tp53', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutants', 'Var', (99, 106))
491257	21979944	Therefore, this histological phenotype is associated with the presence of EWS-FLI1 and is consistent with the pathology of human Ewing's sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (129, 144))	('EWS-FLI1', 'Gene', (74, 82))	('associated', 'Reg', (42, 52))	('human', 'Species', '9606', (123, 128))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (129, 144))	("Ewing's sarcoma", 'Disease', (129, 144))	('presence', 'Var', (62, 70))
491263	21979944	Following dissection and manual dissociation of two SRBCTs derived from tp53 mutants, approximately 1 million cells were injected intraperitoneally into irradiated wild-type adult zebrafish.	('zebrafish', 'Species', '7955', (180, 189))	('mutants', 'Var', (77, 84))	('tp53', 'Gene', '30590', (72, 76))	('tp53', 'Gene', (72, 76))
491274	21979944	Both primary tumors were derived from tp53 mutant fish, but formed new tumors in the recipient wild-type hosts.	('tp53', 'Gene', (38, 42))	('tumors', 'Disease', (13, 19))	('primary tumors', 'Disease', 'MESH:D009369', (5, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutant', 'Var', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', (71, 77))	('tp53', 'Gene', '30590', (38, 42))	('primary tumors', 'Disease', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
491279	21979944	We conclude that the SRBCTs were caused by the presence of the transgene, but that the MPNSTs were attributable to the mutation in tp53.	('mutation', 'Var', (119, 127))	('caused by', 'Reg', (33, 42))	('tp53', 'Gene', '30590', (131, 135))	('transgene', 'Var', (63, 72))	('tp53', 'Gene', (131, 135))	('SRBCTs', 'Disease', (21, 27))	('presence', 'Var', (47, 55))	('MPNSTs', 'Phenotype', 'HP:0100697', (87, 93))
491285	21979944	Using a mutation in the conserved tumor suppressor p53 as a sensitized genetic background that is likely to affect the expression of many genes that contribute to tumor initiation or development.	('p53', 'Gene', (51, 54))	('expression', 'MPA', (119, 129))	('tumor initiation', 'Disease', 'MESH:D009369', (163, 179))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('affect', 'Reg', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor initiation', 'Disease', (163, 179))	('tumor', 'Disease', (163, 168))	('mutation', 'Var', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
491287	21979944	Increased variation might be expected from mosaic integration of the transgene and differences in the tissue of origin, because two tumors presented in the abdominal cavity and one tumor presented in the eye.	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('mosaic', 'Var', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('presented', 'Reg', (139, 148))
491303	21979944	Three datasets were generated using gene expression profiling following the knockdown of EWS-FLI1 in the Ewing's sarcoma cell lines.	('knockdown', 'Var', (76, 85))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (105, 120))	('EWS-FLI1', 'Gene', (89, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (105, 120))	("Ewing's sarcoma", 'Disease', (105, 120))
491321	21979944	We observed that the GFP-positive transgenic progeny exhibited developmental dysmorphology, including reduced head development and eye size, as well as severe pericardial edema and subsequent lethality (Fig.	('eye size', 'CPA', (131, 139))	('GFP-positive', 'Gene', (21, 33))	('pericardial edema', 'Disease', (159, 176))	('developmental dysmorphology', 'Disease', 'MESH:D003147', (63, 90))	('edema', 'Phenotype', 'HP:0000969', (171, 176))	('pericardial edema', 'Disease', 'MESH:D004487', (159, 176))	('reduced head', 'Phenotype', 'HP:0000252', (102, 114))	('head development', 'CPA', (110, 126))	('transgenic', 'Var', (34, 44))	('reduced', 'NegReg', (102, 109))	('pericardial edema', 'Phenotype', 'HP:0001698', (159, 176))	('lethality', 'CPA', (192, 201))	('developmental dysmorphology', 'Disease', (63, 90))
491332	21979944	The identification of both solid and infiltrating tumors suggests that EWS-FLI1 can induce the formation of both of these tumor types in the zebrafish.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('zebrafish', 'Species', '7955', (141, 150))	('induce', 'Reg', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (50, 55))	('EWS-FLI1', 'Var', (71, 79))
491335	21979944	Although EWS-FLI1-associated leukemia is not observed in humans, a closely related fusion of TLS-ERG is associated with acute myeloid leukemia.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (120, 142))	('leukemia', 'Disease', 'MESH:D007938', (134, 142))	('TLS', 'Gene', (93, 96))	('leukemia', 'Disease', (134, 142))	('ERG', 'Gene', '2078', (97, 100))	('humans', 'Species', '9606', (57, 63))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('TLS', 'Gene', '2521', (93, 96))	('acute myeloid leukemia', 'Disease', (120, 142))	('associated', 'Reg', (104, 114))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (126, 142))	('ERG', 'Gene', (97, 100))	('leukemia', 'Phenotype', 'HP:0001909', (29, 37))	('fusion', 'Var', (83, 89))	('leukemia', 'Disease', 'MESH:D007938', (29, 37))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (120, 142))	('leukemia', 'Disease', (29, 37))
491336	21979944	Rare cases of pre-B-cell lymphoblastic leukemia with the EWS-FLI1 translocation have also been reported.	('EWS-FLI1', 'Gene', (57, 65))	('translocation', 'Var', (66, 79))	('lymphoblastic leukemia', 'Disease', (25, 47))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (25, 47))	('leukemia', 'Phenotype', 'HP:0001909', (39, 47))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (25, 47))
491337	21979944	These cases suggest a connection between EWS translocation proteins and cancers of the hematopoietic lineage.	('EWS', 'Protein', (41, 44))	('translocation', 'Var', (45, 58))	('connection', 'Reg', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
491349	21979944	Mutation of tp53 provided a sensitized background for the formation of SRBCTs in zebrafish.	('zebrafish', 'Species', '7955', (81, 90))	('tp53', 'Gene', '30590', (12, 16))	('Mutation', 'Var', (0, 8))	('tp53', 'Gene', (12, 16))
491350	21979944	Although mutations in tp53 occur in only a subset of Ewing's sarcomas, the p53 pathway might also be inhibited by other mechanisms.	('inhibited', 'NegReg', (101, 110))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (53, 69))	('mutations', 'Var', (9, 18))	('p53 pathway', 'Pathway', (75, 86))	("Ewing's sarcomas", 'Disease', (53, 69))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (53, 68))	('tp53', 'Gene', '30590', (22, 26))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (53, 69))	('tp53', 'Gene', (22, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
491351	21979944	Interestingly, the solid SRBCTs that we identified most frequently arose in proximity to the eye and abdomen, the locations in which MPNSTs also develop in tp53 mutant zebrafish.	('mutant', 'Var', (161, 167))	('arose', 'Reg', (67, 72))	('zebrafish', 'Species', '7955', (168, 177))	('tp53', 'Gene', '30590', (156, 160))	('MPNSTs', 'Phenotype', 'HP:0100697', (133, 139))	('tp53', 'Gene', (156, 160))
491353	21979944	An alternative possibility is that the tumors originate as a result of the loss of p53, but that the presence of EWS-FLI1 drives the tumor cells to a less differentiated, more primitive state, which results in the SRBCT histology.	('drives', 'PosReg', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('EWS-FLI1', 'Gene', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('presence', 'Var', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('results in', 'Reg', (199, 209))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (39, 44))	('tumors', 'Disease', (39, 45))
491356	21979944	By comparing the gene expression profiles to MPNSTs, we eliminated those genes that are generally affected in tumors and also those genes that might be changed because of the absence of p53.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('absence', 'Var', (175, 182))	('eliminated', 'NegReg', (56, 66))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('MPNSTs', 'Phenotype', 'HP:0100697', (45, 51))
491374	21979944	For mutation of tp53, the allele TP53zdf1 was used.	('tp53', 'Gene', (16, 20))	('tp53', 'Gene', '30590', (16, 20))	('mutation', 'Var', (4, 12))
491391	21979944	For microarray experiments, MPNST samples were taken from tumors in three uninjected tp53 mutant adults.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mutant', 'Var', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tp53', 'Gene', '30590', (85, 89))	('tp53', 'Gene', (85, 89))
491398	21979944	Expression profiling of Ewing's sarcoma and rhabdomyosarcoma, GEO GSE967; expression profiling of human mesenchymal tumors, Array Express: E-MEXP-353; knockdown of EWS-FLI1 in Ewing's cell lines and expression profiling of Ewing's tumors and Bone Marrow Stem Cells, GEO: GSE7007.	("Ewing's sarcoma", 'Disease', (24, 39))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (44, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (44, 60))	("Ewing's tumors", 'Phenotype', 'HP:0012254', (223, 237))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('EWS-FLI1', 'Gene', (164, 172))	('GSE7007', 'Chemical', '-', (271, 278))	("Ewing's tumors", 'Disease', 'MESH:C563168', (223, 237))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (24, 39))	("Ewing's tumors", 'Disease', (223, 237))	('GSE967', 'Chemical', '-', (66, 72))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (104, 122))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (24, 39))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('rhabdomyosarcoma', 'Disease', (44, 60))	("Ewing's tumor", 'Phenotype', 'HP:0012254', (223, 236))	('mesenchymal tumors', 'Disease', (104, 122))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('human', 'Species', '9606', (98, 103))	('knockdown', 'Var', (151, 160))
491399	21979944	Additional BMSC samples, E-MEXP-215; siRNA knockdown of EWS-FLI1 in Ewing's cell lines, Array Express: E-GEOD-14543; knockdown of EWS-FLI1 in Ewing's cell lines, from http://www.huntsmancancer.org/publicweb/content/lessnick/mscSupplementalSmith2006_files/mscSupplemental-Smith-2006.html.	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('knockdown', 'Var', (117, 126))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
491405	21979944	Cancers caused by fusion oncogenes resulting from chromosomal translocations (such as the EWS-FLI1 protein that can cause Ewing's sarcoma) are promising candidates for targeted therapies, because they contain a unique protein that is not found in healthy tissues.	("Ewing's sarcoma", 'Disease', (122, 137))	('cause', 'Reg', (116, 121))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (122, 137))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('caused', 'Reg', (8, 14))	('chromosomal translocations', 'Var', (50, 76))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (122, 137))	('EWS-FLI1', 'Gene', (90, 98))
491410	21979944	First, adult fish expressing EWS-FLI1 in a subset of cells develop tumors that resemble human Ewing's sarcoma.	('develop', 'PosReg', (59, 66))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (94, 109))	("Ewing's sarcoma", 'Disease', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('human', 'Species', '9606', (88, 93))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (94, 109))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('EWS-FLI1', 'Var', (29, 37))	('tumors', 'Disease', (67, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
491411	21979944	Second, embryos that express EWS-FLI1 exhibit developmental defects, revealing specific signaling pathways that are altered in the presence of EWS-FLI1.	('EWS-FLI1', 'Var', (29, 37))	('developmental defects', 'Disease', 'MESH:D003147', (46, 67))	('altered', 'Reg', (116, 123))	('developmental defects', 'Disease', (46, 67))
491437	23563009	Molecular genetic analysis of the tumor using RT-PCR demonstrated the (t11:22)(q24;q12) chromosomal translocation characteristic of the EFTs:irrefutable evidence of a primary vaginal Ewing sarcoma.	('tumor', 'Disease', (34, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (183, 196))	('vaginal Ewing sarcoma', 'Disease', 'MESH:C563168', (175, 196))	('t11:22)(q24;q12) chromosomal translocation', 'Var', (71, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('vaginal Ewing sarcoma', 'Disease', (175, 196))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
491452	23563009	The remaining 10% exhibit variant translocations involving the EWSR1 gene on chromosome region 22q12 such as t(21;22)(q22;q12), t(7:22)(p22;q12) or t(2:22) (q33;q12) resulting in different fusion proteins: EWSR1-ERG, EWSR1-ETV1 or EWSR1-FEV, respectively.	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (109, 126))	('EWSR1', 'Gene', (206, 211))	('ERG', 'Gene', (212, 215))	('t(21;22)(q22;q12', 'Var', (109, 125))	('ETV1', 'Gene', (223, 227))	('EWSR1', 'Gene', (231, 236))	('t(7:22)(p22;q12', 'Var', (128, 143))	('fusion proteins', 'MPA', (189, 204))	('EWSR1', 'Gene', '2130', (206, 211))	('EWSR1', 'Gene', '2130', (63, 68))	('EWSR1', 'Gene', '2130', (217, 222))	('ERG', 'Gene', '2078', (212, 215))	('t(7:22)(p22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (128, 144))	('ETV1', 'Gene', '2115', (223, 227))	('t(2:22) (q33;q12', 'Var', (148, 164))	('EWSR1', 'Gene', '2130', (231, 236))	('EWSR1', 'Gene', (63, 68))	('EWSR1', 'Gene', (217, 222))
491560	27143930	The observed malfunction comprised the restriction in adduction and internal rotation of both upper arms, and it was the consequence of the resection of the upper part of the sternum en bloc with the attached head and anterior part of the clavicles for chondrosarcoma (Figure 6).	('chondrosarcoma', 'Disease', 'MESH:D002813', (253, 267))	('restriction', 'NegReg', (39, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('chondrosarcoma', 'Disease', (253, 267))	('resection', 'Var', (140, 149))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (253, 267))
491611	24852265	In previous work, we showed that knockdown of c-Jun by RNA interference impaired the in vitro proliferation and in vivo growth of a DDLPS cell line (LP6) with genomic amplification of the c-Jun locus.	('in vitro proliferation', 'CPA', (85, 107))	('impaired', 'NegReg', (72, 80))	('knockdown', 'Var', (33, 42))	('c-Jun', 'Gene', (46, 51))	('LP6', 'Chemical', '-', (149, 152))	('RNA interference', 'MPA', (55, 71))
491615	24852265	Finally, we provide evidence that c-Jun genomic amplification and overexpression may have similar functional consequences in other types of soft tissue sarcoma.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (140, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (140, 159))	('c-Jun', 'MPA', (34, 39))	('soft tissue sarcoma', 'Disease', (140, 159))	('genomic amplification', 'Var', (40, 61))
491632	24852265	Cell lines were established from dedifferentiated liposarcoma (LP6, LPS141, LPS510, LPS12), well differentiated liposarcoma (T449, T778), leiomyosarcoma (LMS03), unclassified sarcomas (USCS2, USCS5) and Alveolar Soft Part Sarcoma (ASPS-KY).	('LPS12', 'Var', (84, 89))	('LPS510', 'Chemical', '-', (76, 82))	('LP6', 'Chemical', '-', (63, 66))	('sarcomas', 'Disease', (175, 183))	('Alveolar Soft Part Sarcoma', 'Disease', (203, 229))	('liposarcoma', 'Disease', 'MESH:D008080', (112, 123))	('liposarcoma', 'Disease', (50, 61))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (138, 152))	('LPS510', 'Var', (76, 82))	('LPS12', 'Chemical', '-', (84, 89))	('LMS03', 'CellLine', 'CVCL:5H98', (154, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (138, 152))	('dedifferentiated', 'Disease', (33, 49))	('Soft Part Sarcoma', 'Phenotype', 'HP:0030448', (212, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('Sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('Alveolar Soft Part Sarcoma', 'Phenotype', 'HP:0012218', (203, 229))	('liposarcoma', 'Disease', (112, 123))	('liposarcoma', 'Phenotype', 'HP:0012034', (50, 61))	('Alveolar Soft Part Sarcoma', 'Disease', 'MESH:D018234', (203, 229))	('leiomyosarcoma', 'Disease', (138, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (175, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('liposarcoma', 'Disease', 'MESH:D008080', (50, 61))	('LPS141', 'Chemical', '-', (68, 74))	('liposarcoma', 'Phenotype', 'HP:0012034', (112, 123))	('sarcomas', 'Disease', 'MESH:D012509', (175, 183))	('LP6', 'Var', (63, 66))
491649	24852265	However, we did not observe an increase in the expression of adipocytic genes (such as PPARG2, CFD (adipsin) and CEBPA) after c-Jun knockdown by either exon array or qRT-PCR.	('PPARG2', 'Gene', '5468', (87, 93))	('CFD', 'Gene', (95, 98))	('knockdown', 'Var', (132, 141))	('adipsin', 'Gene', (100, 107))	('CEBPA', 'Gene', (113, 118))	('c-Jun', 'MPA', (126, 131))	('PPARG2', 'Gene', (87, 93))	('adipocytic genes', 'Gene', (61, 77))	('adipsin', 'Gene', '1675', (100, 107))	('CEBPA', 'Gene', '1050', (113, 118))	('CFD', 'Gene', '1675', (95, 98))
491651	24852265	These data raise the possibility that c-Jun might promote cell migration specifically in the context of amplification or overexpression, whereas c-Jun might stimulate proliferation in most liposarcomas.	('c-Jun', 'Var', (145, 150))	('liposarcoma', 'Phenotype', 'HP:0012034', (189, 200))	('cell migration', 'CPA', (58, 72))	('promote', 'PosReg', (50, 57))	('c-Jun', 'Protein', (38, 43))	('stimulate', 'PosReg', (157, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('liposarcomas', 'Phenotype', 'HP:0012034', (189, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('liposarcomas', 'Disease', 'MESH:D008080', (189, 201))	('proliferation', 'CPA', (167, 180))	('liposarcomas', 'Disease', (189, 201))
491653	24852265	Cell cycle analysis revealed that c-Jun knockdown caused a G1 phase arrest in four liposarcoma cell lines (Fig.	('liposarcoma', 'Disease', 'MESH:D008080', (83, 94))	('liposarcoma', 'Phenotype', 'HP:0012034', (83, 94))	('G1 phase arrest', 'CPA', (59, 74))	('knockdown', 'Var', (40, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('c-Jun', 'MPA', (34, 39))	('liposarcoma', 'Disease', (83, 94))
491655	24852265	Western blot analysis revealed increased expression of the cyclin-dependent kinase inhibitor p21 after c-Jun knockdown in all liposarcoma cell lines tested (Fig.	('increased', 'PosReg', (31, 40))	('expression', 'MPA', (41, 51))	('p21', 'Gene', (93, 96))	('liposarcoma', 'Disease', (126, 137))	('knockdown', 'Var', (109, 118))	('p21', 'Gene', '644914', (93, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('liposarcoma', 'Phenotype', 'HP:0012034', (126, 137))	('liposarcoma', 'Disease', 'MESH:D008080', (126, 137))
491658	24852265	We next investigated the possibility that c-Jun knockdown might impair cell migration in liposarcoma.	('c-Jun', 'Protein', (42, 47))	('liposarcoma', 'Disease', (89, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('liposarcoma', 'Phenotype', 'HP:0012034', (89, 100))	('liposarcoma', 'Disease', 'MESH:D008080', (89, 100))	('cell migration', 'CPA', (71, 85))	('impair', 'NegReg', (64, 70))	('knockdown', 'Var', (48, 57))
491661	24852265	Importantly, levels of these genes did not change in response to shRNAs targeting the oncogenes MDM2 and CDK4, suggesting that their response to c-Jun knockdown is not simply an indirect effect of proliferation arrest.	('proliferation arrest', 'Disease', (197, 217))	('proliferation arrest', 'Disease', 'MESH:D006323', (197, 217))	('CDK4', 'Gene', (105, 109))	('CDK4', 'Gene', '1019', (105, 109))	('MDM2', 'Gene', '4193', (96, 100))	('MDM2', 'Gene', (96, 100))	('knockdown', 'Var', (151, 160))
491665	24852265	We first used a cell exclusion zone assay to measure the effect of c-Jun knockdown on LP6 cell migration.	('LP6', 'Chemical', '-', (86, 89))	('knockdown', 'Var', (73, 82))	('LP6 cell migration', 'CPA', (86, 104))
491667	24852265	At baseline, the migration capacity of LP6 was higher than that of LPS141 and other DDLPS cell lines (Fig.	('migration capacity', 'CPA', (17, 35))	('LPS141', 'Chemical', '-', (67, 73))	('higher', 'PosReg', (47, 53))	('LP6', 'Var', (39, 42))	('LP6', 'Chemical', '-', (39, 42))
491668	24852265	c-Jun knockdown in LP6 cell lines reduced migration capacity by 40-50 % (Fig.	('c-Jun', 'Protein', (0, 5))	('reduced', 'NegReg', (34, 41))	('migration capacity', 'CPA', (42, 60))	('knockdown', 'Var', (6, 15))	('LP6', 'Chemical', '-', (19, 22))
491672	24852265	Furthermore, we observed a >2 fold decrease in the velocity of LP6 cells upon c-Jun knockdown (p<0.0001, Fig.	('LP6', 'Chemical', '-', (63, 66))	('knockdown', 'Var', (84, 93))	('decrease', 'NegReg', (35, 43))	('velocity', 'CPA', (51, 59))	('c-Jun', 'Protein', (78, 83))
491675	24852265	This suggests that genomic amplification of c-Jun can enhance liposarcoma invasiveness.	('liposarcoma invasiveness', 'Disease', 'MESH:D008080', (62, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('liposarcoma invasiveness', 'Disease', (62, 86))	('genomic amplification', 'Var', (19, 40))	('enhance', 'PosReg', (54, 61))	('c-Jun', 'Protein', (44, 49))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))
491677	24852265	We infected four non-amplified LPS cell lines (3 DDLPS: LPS141, LPS510 and LPS12 and 1 WDLPS T449) with lentivirus expressing either c-Jun or RFP (negative control).	('c-Jun', 'Var', (133, 138))	('LPS12', 'Chemical', '-', (75, 80))	('RFP', 'Gene', (142, 145))	('LPS510', 'Chemical', '-', (64, 70))	('RFP', 'Gene', '2358', (142, 145))	('LPS141', 'Chemical', '-', (56, 62))
491678	24852265	c-Jun overexpression in LPS141, LPS12 and LPS510 significantly upregulated the expression of 351, 653 and 2283 genes and reduced the expression of 509, 891 and 1923 genes by more than two fold respectively.	('expression', 'MPA', (133, 143))	('LPS12', 'Var', (32, 37))	('LPS12', 'Chemical', '-', (32, 37))	('expression', 'MPA', (79, 89))	('LPS510', 'Chemical', '-', (42, 48))	('reduced', 'NegReg', (121, 128))	('LPS141', 'Chemical', '-', (24, 30))	('c-Jun', 'MPA', (0, 5))	('upregulated', 'PosReg', (63, 74))	('overexpression', 'PosReg', (6, 20))	('LPS510', 'Var', (42, 48))	('LPS141', 'Var', (24, 30))
491681	24852265	We found that c-Jun overexpressing LPS141 cells were significantly more migratory than controls, with closure space of 93% and 45% at 3 days, respectively (Fig.	('LPS141', 'Var', (35, 41))	('more', 'PosReg', (67, 71))	('c-Jun', 'Protein', (14, 19))	('migratory', 'CPA', (72, 81))	('overexpressing', 'PosReg', (20, 34))	('LPS141', 'Chemical', '-', (35, 41))
491682	24852265	Single cell tracking experiments demonstrated that c-Jun overexpression increased the velocity of LPS141, LPS510 and T449 cells by 2 to 4 fold (Fig.	('velocity', 'MPA', (86, 94))	('LPS510', 'Chemical', '-', (106, 112))	('LPS141', 'Chemical', '-', (98, 104))	('LPS510', 'Var', (106, 112))	('c-Jun', 'MPA', (51, 56))	('LPS141', 'Var', (98, 104))	('overexpression increased', 'PosReg', (57, 81))
491689	24852265	Autotaxin mRNA levels in LP6 cells are more than 130 fold higher than in LPS141 cells (non-amplified) (data not shown).	('LP6', 'Chemical', '-', (25, 28))	('LPS141', 'Chemical', '-', (73, 79))	('mRNA levels', 'MPA', (10, 21))	('Autotaxin', 'Gene', (0, 9))	('Autotaxin', 'Gene', '5168', (0, 9))	('higher', 'PosReg', (58, 64))	('LP6', 'Var', (25, 28))
491694	24852265	Furthermore, single cell tracking experiments revealed that autotaxin knockdown reduced LP6 cell velocity by 30% compared to control cells, but had no effect on the velocity of LPS141 cells (Fig.	('LPS141', 'Chemical', '-', (177, 183))	('knockdown', 'Var', (70, 79))	('reduced', 'NegReg', (80, 87))	('LP6 cell velocity', 'CPA', (88, 105))	('LP6', 'Chemical', '-', (88, 91))	('autotaxin', 'Protein', (60, 69))
491695	24852265	In contrast, autotaxin knockdown significantly reduced the velocity of LPS141 cells overexpressing c-Jun (Fig.	('LPS141', 'Chemical', '-', (71, 77))	('velocity', 'MPA', (59, 67))	('knockdown', 'Var', (23, 32))	('autotaxin', 'Protein', (13, 22))	('reduced', 'NegReg', (47, 54))
491697	24852265	We have previously shown that c-Jun knockdown impairs the ability of LP6 cells to form subcutaneous tumors, suggesting that c-Jun amplification plays a role in augmenting in vivo tumorigenesis.	('subcutaneous tumors', 'Disease', 'MESH:D013352', (87, 106))	('c-Jun', 'MPA', (124, 129))	('impairs', 'NegReg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('LP6', 'Chemical', '-', (69, 72))	('tumor', 'Disease', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('knockdown', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('subcutaneous tumors', 'Disease', (87, 106))	('augmenting', 'PosReg', (160, 170))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (87, 106))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (179, 184))
491700	24852265	We injected LPS141 and LPS510 cells (control and c-Jun-overexpressing) subcutaneously into the flanks of nude mice.	('LPS141', 'Chemical', '-', (12, 18))	('nude mice', 'Species', '10090', (105, 114))	('LPS141', 'Var', (12, 18))	('LPS510', 'Chemical', '-', (23, 29))	('LPS510', 'Var', (23, 29))
491710	24852265	Analysis of LMS03 migration in Boyden chambers revealed a decreased migratory capacity upon c-Jun knockdown (Fig.	('knockdown', 'Var', (98, 107))	('c-Jun', 'MPA', (92, 97))	('decreased', 'NegReg', (58, 67))	('migratory capacity', 'CPA', (68, 86))	('LMS03', 'CellLine', 'CVCL:5H98', (12, 17))
491711	24852265	Interestingly, the velocity of USCS5 cells, whose c-Jun levels are approximately as low as LPS141 cells, was not affected by c-Jun knockdown (Fig.	('knockdown', 'Var', (131, 140))	('c-Jun levels', 'MPA', (50, 62))	('c-Jun knockdown', 'Var', (125, 140))	('LPS141', 'Chemical', '-', (91, 97))
491713	24852265	c-Jun knockdown led to a decline in ENPP2 mRNA levels in the three cell lines (LMS03, ASPS-KY, USCS2) with intermediate to high levels of basal c-Jun expression (Fig.	('decline', 'NegReg', (25, 32))	('mRNA levels', 'MPA', (42, 53))	('ENPP2', 'Gene', (36, 41))	('LMS03', 'CellLine', 'CVCL:5H98', (79, 84))	('knockdown', 'Var', (6, 15))	('ENPP2', 'Gene', '5168', (36, 41))
491714	24852265	Furthermore, knockdown of ENPP2 via shRNA (Fig.	('ENPP2', 'Gene', '5168', (26, 31))	('knockdown', 'Var', (13, 22))	('ENPP2', 'Gene', (26, 31))
491717	24852265	Histologically, LMS03 and USCS2 were high-grade spindle cell sarcomas, whereas ASPS-KY tumors exhibited a typical organoid arrangement of neoplastic cells separated by thin walled vascular channels (Fig.	('LMS03', 'Var', (16, 21))	('sarcomas', 'Disease', (61, 69))	('LMS03', 'CellLine', 'CVCL:5H98', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ASPS-KY tumors', 'Disease', 'MESH:D018234', (79, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('USCS2', 'Var', (26, 31))	('sarcomas', 'Disease', 'MESH:D012509', (61, 69))	('ASPS-KY tumors', 'Disease', (79, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
491718	24852265	Stable knockdown of c-Jun reduced the tumorigenicity of LMS03 and ASPS-KY cells.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('c-Jun', 'Gene', (20, 25))	('LMS03', 'CellLine', 'CVCL:5H98', (56, 61))	('reduced', 'NegReg', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('knockdown', 'Var', (7, 16))
491730	24852265	Cell migration and invasion were significantly impaired in cells with genomic amplification (LP6 and LMS003) or c-Jun upregulation by undetermined mechanisms (ASPS and USCS2).	('c-Jun', 'MPA', (112, 117))	('Cell migration', 'CPA', (0, 14))	('upregulation', 'PosReg', (118, 130))	('invasion', 'CPA', (19, 27))	('genomic amplification', 'Var', (70, 91))	('impaired', 'NegReg', (47, 55))	('LP6', 'Chemical', '-', (93, 96))
491740	24852265	Taken together, our data suggest that tumors with high levels of c-Jun (via amplification or other mechanisms) are likely to be more aggressive than c-Jun-low tumors, and a formal study with a large sample number is clearly warranted to address this point.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('c-Jun', 'MPA', (65, 70))	('high levels', 'Var', (50, 61))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('aggressive', 'CPA', (133, 143))
491742	24852265	There is a need for additional studies to determine whether inhibitors of ENPP2 (and other c-Jun targets) display efficacy in the treatment of c-Jun-amplified soft tissue sarcomas.	('ENPP2', 'Gene', (74, 79))	('sarcomas', 'Disease', (171, 179))	('soft tissue sarcoma', 'Disease', (159, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (159, 179))	('inhibitors', 'Var', (60, 70))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('ENPP2', 'Gene', '5168', (74, 79))	('c-Jun-amplified', 'MPA', (143, 158))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (159, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (159, 178))
491859	25587363	The differentiation of a parapharyngeal salivary gland adenoma is important for the surgical removal because an intraoperative disruption of an adenoma may lead to an uncontrollable local tumor dissemination.	('tumor', 'Disease', (188, 193))	('uncontrollable', 'MPA', (167, 181))	('lead to', 'Reg', (156, 163))	('adenoma', 'Disease', 'MESH:D000236', (55, 62))	('adenoma', 'Disease', 'MESH:D000236', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('adenoma', 'Disease', (144, 151))	('disruption', 'Var', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('adenoma', 'Disease', (55, 62))
491905	25587363	For example, the deviation of the nasal septum and the deformation of the medial wall of the maxillary sinus are signs of a slow tumor growth and support the probability of a benign lesion.	('nasal septum', 'Phenotype', 'HP:0005322', (34, 46))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('deformation', 'Var', (55, 66))	('tumor', 'Disease', (129, 134))	('deviation', 'Var', (17, 26))
492185	31761563	First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect", thereby inhibiting sarcoma cell proliferation.	('FBP2', 'Gene', (17, 21))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('glycolysis', 'MPA', (43, 53))	('sarcoma', 'Disease', (111, 118))	('inhibiting', 'NegReg', (100, 110))	('antagonizes', 'NegReg', (22, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('elevated', 'PosReg', (34, 42))	('cytosolic', 'Var', (7, 16))
492189	31761563	demonstrate that the loss of fructose-1,6-bisphosphatase 2 (FBP2) is a common metabolic feature of soft tissue sarcomas (STSs).	('loss', 'Var', (21, 25))	('fructose-1,6-bisphosphatase 2', 'Gene', '8789', (29, 58))	('sarcomas', 'Disease', 'MESH:D012509', (111, 119))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (99, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('STSs', 'Phenotype', 'HP:0030448', (121, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcomas', 'Disease', (111, 119))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (99, 119))	('FBP2', 'Gene', (60, 64))
492190	31761563	Restoration of FBP2 in STS cells suppresses sarcoma growth through two mechanisms, including inhibiting glycolysis and restraining mitochondrial biogenesis by inhibiting c-Myc-driven transcriptional activity.	('suppresses', 'NegReg', (33, 43))	('c-Myc', 'Gene', '4609', (170, 175))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('Restoration', 'Var', (0, 11))	('c-Myc', 'Gene', (170, 175))	('restraining', 'NegReg', (119, 130))	('sarcoma', 'Disease', (44, 51))	('FBP2', 'Gene', (15, 19))	('inhibiting', 'NegReg', (159, 169))	('inhibiting', 'NegReg', (93, 103))	('mitochondrial biogenesis', 'MPA', (131, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('glycolysis', 'MPA', (104, 114))
492197	31761563	A broad array of oncogenes and tumor suppressors that regulate metabolic pathways are mutated in sarcomas, such as PIK3CA (catalytic subunit of phosphatidylinositol 3-kinase), TP53, and NF1.	('mutated', 'Var', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('metabolic pathways', 'Pathway', (63, 81))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('NF1', 'Gene', (186, 189))	('TP53', 'Gene', '7157', (176, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('tumor', 'Disease', (31, 36))	('NF1', 'Gene', '4763', (186, 189))	('TP53', 'Gene', (176, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (97, 105))	('PIK3CA', 'Gene', (115, 121))	('PIK3CA', 'Gene', '5290', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
492205	31761563	Several mechanisms are implicated in downregulating FBP1, including transcription factor repression, epigenetic silencing and proteasome degradation.	('transcription', 'MPA', (68, 81))	('FBP1', 'Gene', '2203', (52, 56))	('epigenetic silencing', 'Var', (101, 121))	('proteasome degradation', 'MPA', (126, 148))	('downregulating', 'NegReg', (37, 51))	('FBP1', 'Gene', (52, 56))
492211	31761563	Isotope tracing and unbiased mass spectrometry analyses of liposarcoma, fibrosarcoma and UPS cells demonstrated that glycolysis and TCA cycle activity are inhibited by FBP2 restoration.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (72, 84))	('fibrosarcoma', 'Disease', 'MESH:D005354', (72, 84))	('activity', 'MPA', (142, 150))	('TCA', 'Chemical', 'MESH:D014238', (132, 135))	('FBP2', 'Gene', (168, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('liposarcoma', 'Disease', (59, 70))	('restoration', 'Var', (173, 184))	('fibrosarcoma', 'Disease', (72, 84))	('inhibited', 'NegReg', (155, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('TCA', 'Enzyme', (132, 135))	('glycolysis', 'MPA', (117, 127))	('liposarcoma', 'Disease', 'MESH:D008080', (59, 70))	('liposarcoma', 'Phenotype', 'HP:0012034', (59, 70))
492212	31761563	Both FBP1 and FBP2 isozymes share a consensus nuclear localization sequence (NLS), and a nucleus-excluded FBP2 mutant has no effect on mitochondrial biogenesis and OXPHOS, indicating that nuclear FBP2 regulates mitochondrial function independent of its enzymatic activity.	('OXPHOS', 'MPA', (164, 170))	('FBP2', 'Gene', (106, 110))	('mitochondrial function', 'MPA', (211, 233))	('FBP1', 'Gene', (5, 9))	('mutant', 'Var', (111, 117))	('mitochondrial biogenesis', 'MPA', (135, 159))	('FBP1', 'Gene', '2203', (5, 9))	('regulates', 'Reg', (201, 210))
492226	31761563	In addition, FBP2 re-expression in SW872, HT1080 and KP250 cells dramatically impaired anchorage-independent growth in 3D soft agar colony assays (Figure 2B).	('SW872', 'CellLine', 'CVCL:1730', (35, 40))	('HT1080', 'CellLine', 'CVCL:0317', (42, 48))	('impaired', 'NegReg', (78, 86))	('anchorage-independent growth', 'CPA', (87, 115))	('re-expression', 'Var', (18, 31))	('FBP2', 'Gene', (13, 17))
492227	31761563	We also exploited a doxycycline (dox)-inducible system to restore FBP2 expression in LPS246 cells (LPS246 TetO-FBP2) and identified dox concentrations that produced FBP2 protein in LPS246 TetO-FBP2 cells comparable to control HSMM cells (Figure S3E).	('LPS246', 'Var', (181, 187))	('expression', 'MPA', (71, 81))	('doxycycline', 'Chemical', 'MESH:D004318', (20, 31))	('LPS246', 'Chemical', '-', (181, 187))	('dox', 'Chemical', 'MESH:D004318', (132, 135))	('FBP2', 'Gene', (66, 70))	('dox', 'Chemical', 'MESH:D004318', (33, 36))	('dox', 'Chemical', 'MESH:D004318', (20, 23))	('LPS246', 'Chemical', '-', (99, 105))	('LPS246', 'Chemical', '-', (85, 91))
492228	31761563	To further evaluate the role of FBP2 in tumor growth and maintenance in vivo, highly immunodeficient NSG mice were injected subcutaneously with LPS246 TetO-FBP2 cells and tumors allowed to grow to 100 mm3.	('immunodeficient', 'Disease', 'MESH:D007153', (85, 100))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('immunodeficient', 'Disease', (85, 100))	('LPS246', 'Chemical', '-', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('LPS246', 'Var', (144, 150))	('mice', 'Species', '10090', (105, 109))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
492229	31761563	Subsequent dox-induced FBP2 expression decreased tumor growth (volume and mass) without affecting mouse body weight (Figure 2C-E, Figure S3F).	('dox', 'Chemical', 'MESH:D004318', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('decreased tumor', 'Disease', (39, 54))	('expression', 'Var', (28, 38))	('mouse', 'Species', '10090', (98, 103))	('FBP2', 'Gene', (23, 27))	('decreased tumor', 'Disease', 'MESH:D002303', (39, 54))
492234	31761563	Since FBP2 is a rate-limiting enzyme in gluconeogenesis, FBP2 re-expression is likely to antagonize glycolysis and therefore reduce glucose uptake.	('glucose uptake', 'MPA', (132, 146))	('glucose', 'Chemical', 'MESH:D005947', (132, 139))	('reduce', 'NegReg', (125, 131))	('antagonize', 'NegReg', (89, 99))	('glycolysis', 'MPA', (100, 110))	('re-expression', 'Var', (62, 75))	('FBP2', 'Gene', (57, 61))
492236	31761563	FBP2 significantly decreased glucose uptake and lactate secretion without affecting glutamine uptake in LPS224, LPS246, T1000, HT1080, and KP250 cells cultured in 10 mM glucose (Figure 3A-C).	('glucose uptake', 'MPA', (29, 43))	('FBP2', 'Gene', (0, 4))	('glucose', 'Chemical', 'MESH:D005947', (169, 176))	('glucose', 'Chemical', 'MESH:D005947', (29, 36))	('glutamine', 'Chemical', 'MESH:D005973', (84, 93))	('lactate secretion', 'MPA', (48, 65))	('LPS246', 'Var', (112, 118))	('LPS224', 'Chemical', '-', (104, 110))	('decreased', 'NegReg', (19, 28))	('HT1080', 'CellLine', 'CVCL:0317', (127, 133))	('LPS246', 'Chemical', '-', (112, 118))	('lactate', 'Chemical', 'MESH:D019344', (48, 55))
492238	31761563	Analysis of culture media confirmed reduced [1,2-13C]glucose uptake and M1- and M2-labeled 13C-lactate secretion in FBP2-expressing LPS246 cells (Figure 3E-F), indicating decreased conversion of glucose to lactate.	('13C-lactate', 'Chemical', '-', (91, 102))	('decreased', 'NegReg', (171, 180))	('FBP2-expressing', 'Gene', (116, 131))	('LPS246', 'Var', (132, 138))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('lactate', 'Chemical', 'MESH:D019344', (95, 102))	('reduced', 'NegReg', (36, 43))	('lactate', 'Chemical', 'MESH:D019344', (206, 213))	('LPS246', 'Chemical', '-', (132, 138))	('conversion of glucose to lactate', 'MPA', (181, 213))	('1,2-13C', 'Chemical', '-', (45, 52))	('M2-labeled 13C-lactate secretion', 'MPA', (80, 112))	('glucose', 'Chemical', 'MESH:D005947', (195, 202))
492240	31761563	Interestingly, we found that FBP2 re-expression reduced PPP flux (Figure 3G), which is important for the synthesis of ribonucleotides and NADPH.	('ribonucleotides', 'Chemical', 'MESH:D012265', (118, 133))	('reduced', 'NegReg', (48, 55))	('NADPH', 'Gene', (138, 143))	('NADPH', 'Gene', '1666', (138, 143))	('re-expression', 'Var', (34, 47))	('FBP2', 'Gene', (29, 33))	('PPP flux', 'MPA', (56, 64))
492244	31761563	In both cell lines, ectopic FBP2 expression significantly reduced steady-state abundance of metabolites in glycolysis (glucose-6-phosphate, pyruvate, lactate) (Figure S4A), serine metabolism (serine and glycine) (Figure S4B) and the TCA cycle (citrate, alpha-ketoglutarate, fumarate, malate, oxaloacetate) (Figure S4C).	('oxaloacetate', 'Chemical', 'MESH:D062907', (292, 304))	('citrate', 'Chemical', 'MESH:D019343', (244, 251))	('expression', 'Var', (33, 43))	('serine', 'Chemical', 'MESH:D012694', (192, 198))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('malate', 'MPA', (284, 290))	('glycine', 'Chemical', 'MESH:D005998', (203, 210))	('pyruvate', 'Chemical', 'MESH:D019289', (140, 148))	('TCA', 'Chemical', 'MESH:D014238', (233, 236))	('malate', 'Chemical', 'MESH:C030298', (284, 290))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (253, 272))	('FBP2', 'Gene', (28, 32))	('serine', 'Chemical', 'MESH:D012694', (173, 179))	('ectopic', 'Var', (20, 27))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))	('reduced', 'NegReg', (58, 65))	('fumarate', 'Chemical', 'MESH:D005650', (274, 282))
492246	31761563	To investigate whether the growth inhibitory effect of FBP2 is dependent on its enzymatic activity, we generated a catalytically inactive FBP2 mutant by replacing a glycine residue at position 260 with arginine (FBP2G260R) as previously described (Figure S5A).	('FBP2', 'Gene', (138, 142))	('replacing', 'Var', (153, 162))	('mutant', 'Var', (143, 149))	('glycine residue at position 260 with arginine', 'Mutation', 'p.R260G', (165, 210))
492247	31761563	Upon wild-type FBP2 and FBP2G260R expression at comparable levels in LPS246 cells (Figure S5B), FBP2G260R inhibited cell growth, although to a lesser extent than wild-type FBP2 (Figure S5C), implying that FBP2 has catalytic activity-independent cellular functions.	('inhibited', 'NegReg', (106, 115))	('FBP2G260R', 'Var', (96, 105))	('LPS246', 'Chemical', '-', (69, 75))	('FBP2G260R', 'Gene', (24, 33))	('cell growth', 'CPA', (116, 127))
492250	31761563	By replacing four lysine residues in the NLS with alanine, we generated a nucleus-excluded form of FBP2 without disrupting its catalytic activity (Figure 4C-D), and FBP24KA expression in LPS246 cells decreased cell proliferation albeit, not as dramatically as wild-type FBP2, suggesting that nuclear FBP2 contributes functionally to its growth inhibitory properties (Figure 4E-F).	('FBP2', 'Gene', (99, 103))	('lysine', 'Chemical', 'MESH:D008239', (18, 24))	('cell proliferation', 'CPA', (210, 228))	('decreased', 'NegReg', (200, 209))	('alanine', 'Chemical', 'MESH:D000409', (50, 57))	('FBP24KA', 'Var', (165, 172))	('LPS246', 'Chemical', '-', (187, 193))	('replacing', 'Var', (3, 12))
492255	31761563	We confirmed differential expression of several genes involved in OXPHOS (MT-ND1, MT-MYB, MT-CO1 and MT-ATP6) by qRT-PCR analysis and found that FBP2, but not FBP24KA, significantly decreased their expression (Figure 4J).	('MT-ND1', 'Gene', (74, 80))	('MT-CO1', 'Gene', (90, 96))	('decreased', 'NegReg', (182, 191))	('MT-CO1', 'Gene', '4512', (90, 96))	('MT-ND1', 'Gene', '4535', (74, 80))	('MT-ATP6', 'Gene', (101, 108))	('FBP2', 'Var', (145, 149))	('expression', 'MPA', (198, 208))	('MT-ATP6', 'Gene', '4508', (101, 108))
492258	31761563	Decreased mitochondrial biogenesis in FBP2-expressing LPS246 cells was further confirmed by transmission electron microscopy, indicated by reduced number of mitochondria and swollen mitochondria with disorganized cristae (Figure 5D).	('reduced number of mitochondria', 'Phenotype', 'HP:0040013', (139, 169))	('FBP2-expressing', 'Gene', (38, 53))	('Decreased', 'NegReg', (0, 9))	('number of mitochondria', 'MPA', (147, 169))	('mitochondrial biogenesis', 'MPA', (10, 34))	('reduced', 'NegReg', (139, 146))	('LPS246', 'Var', (54, 60))	('LPS246', 'Chemical', '-', (54, 60))
492259	31761563	Consistently, LPS246 xenograft sections exhibited reduced staining of Vdac (voltage-dependent anion channel) and Tomm20 (a constitutively expressed mitochondrial protein) in dox-treated tumors, supporting decreased mitochondrial mass caused by FBP2 expression (Figure 5E).	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('LPS246', 'Var', (14, 20))	('FBP2', 'Gene', (244, 248))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('LPS246', 'Chemical', '-', (14, 20))	('expression', 'Var', (249, 259))	('decreased mitochondrial mass', 'Phenotype', 'HP:0040013', (205, 233))	('staining', 'MPA', (58, 66))	('tumors', 'Disease', (186, 192))	('decreased', 'NegReg', (205, 214))	('mitochondrial mass', 'MPA', (215, 233))	('reduced', 'NegReg', (50, 57))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('dox', 'Chemical', 'MESH:D004318', (174, 177))	('Tomm20', 'Gene', '9804', (113, 119))	('Tomm20', 'Gene', (113, 119))
492261	31761563	Collectively, these data demonstrate that nuclear FBP2 inhibits mitochondrial biogenesis in LPS246 cells.	('mitochondrial biogenesis', 'MPA', (64, 88))	('inhibits', 'NegReg', (55, 63))	('FBP2', 'Gene', (50, 54))	('nuclear', 'Var', (42, 49))	('LPS246', 'Chemical', '-', (92, 98))
492263	31761563	We observed increased apoptosis in dox-treated LPS246 TetO-FBP2 cells cultured in galactose medium (Figure 6A, S6A) compared to vehicle-treated cells, indicating that mitochondrial OXPHOS is critically impaired upon FBP2 induction.	('LPS246', 'Chemical', '-', (47, 53))	('apoptosis', 'CPA', (22, 31))	('mitochondrial OXPHOS', 'MPA', (167, 187))	('LPS246', 'Var', (47, 53))	('TetO-FBP2', 'Gene', (54, 63))	('galactose medium', 'Chemical', '-', (82, 98))	('dox', 'Chemical', 'MESH:D004318', (35, 38))
492264	31761563	Furthermore, oxygen consumption rates (OCR) and ATP production were lower in FBP2-expressing LPS246 cells compared to controls (Figure 6B, 6D, S6B).	('FBP2-expressing', 'Gene', (77, 92))	('oxygen', 'Chemical', 'MESH:D010100', (13, 19))	('lower', 'NegReg', (68, 73))	('ATP production', 'MPA', (48, 62))	('LPS246', 'Var', (93, 99))	('oxygen consumption rates', 'MPA', (13, 37))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('LPS246', 'Chemical', '-', (93, 99))
492266	31761563	Loss of ATP-generating capacity stimulated glycolytic compensation in both LPS246 TetO-FBP2 and TetO-FBP24KA cells, as indicated by extracellular acidification rate (ECAR) (Figure S6D).	('LPS246', 'Chemical', '-', (75, 81))	('stimulated', 'PosReg', (32, 42))	('extracellular acidification rate', 'MPA', (132, 164))	('glycolytic compensation', 'MPA', (43, 66))	('Loss', 'NegReg', (0, 4))	('LPS246', 'Var', (75, 81))	('ATP', 'Chemical', 'MESH:D000255', (8, 11))	('ATP-generating capacity', 'MPA', (8, 31))
492267	31761563	Interestingly, ECAR was lower in both FBP2- and FBP24KA-expressing LPS246 cells than control cells (Figure S6D), indicating inhibition of glycolysis by each protein.	('inhibition', 'NegReg', (124, 134))	('ECAR', 'MPA', (15, 19))	('lower', 'NegReg', (24, 29))	('LPS246', 'Var', (67, 73))	('FBP2-', 'Var', (38, 43))	('LPS246', 'Chemical', '-', (67, 73))	('glycolysis', 'MPA', (138, 148))	('FBP24KA-expressing LPS246', 'Var', (48, 73))
492275	31761563	In contrast, ectopic FBP24KA expression had no effect on M1 and M2 enrichment of TCA intermediates and products compared with control cells (Figure S6E-H), further indicating that it is nuclear FBP2 that restrains mitochondrial function and metabolism.	('TCA', 'Chemical', 'MESH:D014238', (81, 84))	('ectopic', 'Var', (13, 20))	('restrains', 'NegReg', (204, 213))	('FBP24KA', 'Gene', (21, 28))	('metabolism', 'MPA', (241, 251))	('mitochondrial function', 'MPA', (214, 236))
492277	31761563	Quantitative RT-PCR analyses revealed significant downregulation of NRF1 and TFAM expression upon FBP2 restoration (Figure 7A).	('FBP2', 'Gene', (98, 102))	('downregulation', 'NegReg', (50, 64))	('TFAM', 'Gene', '7019', (77, 81))	('expression', 'MPA', (82, 92))	('TFAM', 'Gene', (77, 81))	('restoration', 'Var', (103, 114))	('NRF1', 'Gene', (68, 72))	('NRF1', 'Gene', '4899', (68, 72))
492278	31761563	Ectopic expression of TFAM or NRF1 reversed the suppression of target genes associated with OXPHOS (MT-ND1, MT-CYB, MT-CO1 and MT-ATP) (Figure 7B-C, Figure S7A-B), and partially restored mitochondrial mass (Figure 7D, Figure S7C).	('NRF1', 'Gene', '4899', (30, 34))	('TFAM', 'Gene', (22, 26))	('MT-ND1', 'Gene', '4535', (100, 106))	('TFAM', 'Gene', '7019', (22, 26))	('restored', 'NegReg', (178, 186))	('ATP', 'Chemical', 'MESH:D000255', (130, 133))	('NRF1', 'Gene', (30, 34))	('Ectopic expression', 'Var', (0, 18))	('MT-CYB', 'Gene', '4519', (108, 114))	('MT-CYB', 'Gene', (108, 114))	('MT-ND1', 'Gene', (100, 106))	('MT-CO1', 'Gene', (116, 122))	('suppression', 'MPA', (48, 59))	('mitochondrial mass', 'MPA', (187, 205))	('MT-CO1', 'Gene', '4512', (116, 122))
492279	31761563	Moreover, ectopic TFAM or NRF1 expression partially reversed cell apoptosis (Figure 7E, Figure S7D) and proliferation (Figure 7F, Figure S7E) in dox-treated LPS246 TetO-FBP2 cells.	('dox', 'Chemical', 'MESH:D004318', (145, 148))	('cell apoptosis', 'CPA', (61, 75))	('proliferation', 'CPA', (104, 117))	('NRF1', 'Gene', (26, 30))	('LPS246', 'Chemical', '-', (157, 163))	('TFAM', 'Gene', '7019', (18, 22))	('TFAM', 'Gene', (18, 22))	('ectopic', 'Var', (10, 17))	('reversed', 'NegReg', (52, 60))	('expression', 'Var', (31, 41))	('NRF1', 'Gene', '4899', (26, 30))
492283	31761563	To ascertain that FBP2 diminishes c-Myc transcriptional activity, we measured c-Myc luciferase-reporter intensity and found FBP2 decreased c-Myc functionality (Figure 7G).	('diminishes', 'NegReg', (23, 33))	('c-Myc', 'Gene', (34, 39))	('c-Myc', 'Gene', '4609', (139, 144))	('c-Myc', 'Gene', (139, 144))	('FBP2', 'Var', (124, 128))	('c-Myc', 'Gene', '4609', (78, 83))	('c-Myc', 'Gene', (78, 83))	('c-Myc', 'Gene', '4609', (34, 39))	('decreased', 'NegReg', (129, 138))
492284	31761563	Transcript levels of c-Myc target genes (CCND2, eIF2A, NPM1, PSAT1) were also decreased in FBP2-expressing cells (Figure 7H).	('CCND2', 'Gene', '894', (41, 46))	('c-Myc', 'Gene', (21, 26))	('PSAT1', 'Gene', '29968', (61, 66))	('PSAT1', 'Gene', (61, 66))	('decreased', 'NegReg', (78, 87))	('eIF2A', 'Gene', (48, 53))	('FBP2-expressing', 'Var', (91, 106))	('Transcript levels', 'MPA', (0, 17))	('NPM1', 'Gene', (55, 59))	('c-Myc', 'Gene', '4609', (21, 26))	('CCND2', 'Gene', (41, 46))	('eIF2A', 'Gene', '83939', (48, 53))	('NPM1', 'Gene', '4869', (55, 59))
492304	31761563	Previous studies uncovered frequently mutated genes in STS, including TP53, NF1 and PIK3CA, further confirmed by recent large-scale analyses of 206 adult soft tissue sarcomas representing 6 major subtypes using multi-platform molecular profiling.	('mutated', 'Var', (38, 45))	('PIK3CA', 'Gene', '5290', (84, 90))	('NF1', 'Gene', '4763', (76, 79))	('TP53', 'Gene', '7157', (70, 74))	('sarcomas', 'Disease', 'MESH:D012509', (166, 174))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (154, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (166, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('TP53', 'Gene', (70, 74))	('sarcomas', 'Disease', (166, 174))	('PIK3CA', 'Gene', (84, 90))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (154, 174))	('NF1', 'Gene', (76, 79))
492306	31761563	Furthermore, PIK3CA mutations, among the most frequent somatic mutations found in STS along with gain of function mutations in c-KIT and PDGFRalpha, are implicated in activation of the AKT/mTOR pathway, stimulating a shift towards aerobic glycolysis.	('PDGFRalpha', 'Gene', '5156', (137, 147))	('AKT', 'Gene', (185, 188))	('shift towards aerobic glycolysis', 'MPA', (217, 249))	('c-KIT', 'Gene', (127, 132))	('PIK3CA', 'Gene', (13, 19))	('stimulating', 'Reg', (203, 214))	('mutations', 'Var', (114, 123))	('PDGFRalpha', 'Gene', (137, 147))	('activation', 'PosReg', (167, 177))	('c-KIT', 'Gene', '3815', (127, 132))	('PIK3CA', 'Gene', '5290', (13, 19))	('AKT', 'Gene', '207', (185, 188))	('gain of function', 'PosReg', (97, 113))	('mutations', 'Var', (20, 29))	('mTOR', 'Gene', (189, 193))	('mTOR', 'Gene', '2475', (189, 193))
492309	31761563	Furthermore, FBP2 restoration reduces PPP activity needed for ribonucleotide production and reducing equivalents in the form of NADPH.	('reducing', 'NegReg', (92, 100))	('PPP activity needed for ribonucleotide production', 'MPA', (38, 87))	('restoration', 'Var', (18, 29))	('NADPH', 'Gene', (128, 133))	('reduces', 'NegReg', (30, 37))	('NADPH', 'Gene', '1666', (128, 133))	('ribonucleotide', 'Chemical', 'MESH:D012265', (62, 76))	('FBP2', 'Gene', (13, 17))
492313	31761563	Of note, nuclear FBP2 also plays a role in suppressing glycolysis, as nucleus-excluded FBP24KA exhibited less potent inhibition of glucose uptake and lactate secretion than wild-type FBP2, as indicated by [1,2-13C]glucose labeling experiments (e.g.	('glycolysis', 'MPA', (55, 65))	('suppressing', 'NegReg', (43, 54))	('lactate secretion', 'MPA', (150, 167))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('less', 'NegReg', (105, 109))	('glucose', 'Chemical', 'MESH:D005947', (131, 138))	('glucose', 'Chemical', 'MESH:D005947', (214, 221))	('inhibition', 'NegReg', (117, 127))	('glucose uptake', 'MPA', (131, 145))	('FBP24KA', 'Var', (87, 94))	('1,2-13C', 'Chemical', '-', (206, 213))
492314	31761563	26% decrease in glucose consumption by FBP2 versus 14% by FBP24KA).	('glucose', 'Chemical', 'MESH:D005947', (16, 23))	('FBP2', 'Var', (39, 43))	('glucose consumption', 'MPA', (16, 35))	('decrease', 'NegReg', (4, 12))
492316	31761563	c-Myc regulates virtually all genes involved in glycolysis, including the essential glycolytic enzymes LDHA, PDK1 and ENO1, consistent with our observation that nuclear FBP2 also contributes to changes in glucose catabolism.	('PDK1', 'Gene', (109, 113))	('glucose', 'Chemical', 'MESH:D005947', (205, 212))	('changes', 'Reg', (194, 201))	('LDHA', 'Gene', (103, 107))	('ENO1', 'Gene', (118, 122))	('ENO1', 'Gene', '2023', (118, 122))	('regulates', 'Reg', (6, 15))	('LDHA', 'Gene', '3939', (103, 107))	('glucose catabolism', 'MPA', (205, 223))	('nuclear', 'Var', (161, 168))	('c-Myc', 'Gene', '4609', (0, 5))	('FBP2', 'Gene', (169, 173))	('PDK1', 'Gene', '5163', (109, 113))	('c-Myc', 'Gene', (0, 5))
492324	31761563	Recent isotope tracing analysis of human ccRCC confirmed enhanced glycolysis and suppressed glucose oxidation by the TCA cycle in these tumors, likely due to HIF stabilization caused by frequent von Hippel-Lindau (VHL) mutations.	('tumors', 'Disease', (136, 142))	('suppressed', 'NegReg', (81, 91))	('suppressed glucose oxidation', 'Phenotype', 'HP:0040270', (81, 109))	('VHL', 'Gene', (214, 217))	('human', 'Species', '9606', (35, 40))	('TCA cycle', 'Enzyme', (117, 126))	('TCA', 'Chemical', 'MESH:D014238', (117, 120))	('enhanced', 'PosReg', (57, 65))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('von Hippel-Lindau', 'Gene', (195, 212))	('glucose oxidation', 'MPA', (92, 109))	('glucose', 'Chemical', 'MESH:D005947', (92, 99))	('VHL', 'Gene', '7428', (214, 217))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('von Hippel-Lindau', 'Gene', '7428', (195, 212))	('glycolysis', 'MPA', (66, 76))	('mutations', 'Var', (219, 228))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
492339	31761563	We have not delineated consequences of FBP2 loss during sarcoma initiation thus far; future studies will assess Fbp2 deletion in genetically engineered mouse models of STS, such as a "KP" UPS model.	('Fbp2', 'Gene', '14120', (112, 116))	('sarcoma initiation', 'Disease', 'MESH:D012509', (56, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('mouse', 'Species', '10090', (152, 157))	('Fbp2', 'Gene', (112, 116))	('sarcoma initiation', 'Disease', (56, 74))	('deletion', 'Var', (117, 125))
492356	31761563	The FBP24KA and FBP2G260R mutants were generated using Q5 Site-Directed Mutagenesis Kit (NEB, E0554).	('Kit', 'Gene', '3815', (84, 87))	('Kit', 'Gene', (84, 87))	('FBP24KA', 'Var', (4, 11))	('FBP2G260R', 'Var', (16, 25))
492357	31761563	Multiple cultures of LPS246, T449, T778, T1000, HT1080, and KP250 cells were plated in 60 mm plates at a density of 8 x 104 cells supplemented with either DMEM containing 1% FBS or glucose-free DMEM supplemented with 10% FBS and 5 mM D-(+)-Glucose (Sigma-Aldrich, G8270).	('LPS246', 'Var', (21, 27))	('T778', 'Var', (35, 39))	('DMEM', 'Chemical', '-', (155, 159))	('LPS246', 'Chemical', '-', (21, 27))	('Glucose', 'Chemical', 'MESH:D005947', (240, 247))	('DMEM', 'Chemical', '-', (194, 198))	('HT1080', 'CellLine', 'CVCL:0317', (48, 54))	('T449', 'Var', (29, 33))	('glucose', 'Chemical', 'MESH:D005947', (181, 188))
492365	31761563	Pre-designed Taqman primers were obtained from Life Technologies for the following genes: 18S (HS03928985_G1), MT-ND1 (HS02596873_S1), MT-MYB (HS02596867_S1), MT-CO1 (HS02596864_G1), and MT-ATP6 (HS02596862_G1).	('HS03928985_G1', 'Var', (95, 108))	('MT-ND1', 'Gene', '4535', (111, 117))	('HS02596864_G1', 'Var', (167, 180))	('HS02596867_S1', 'Var', (143, 156))	('MT-CO1', 'Gene', (159, 165))	('HS02596873_S1', 'Var', (119, 132))	('HS02596862_G1', 'Var', (196, 209))	('MT-ND1', 'Gene', (111, 117))	('MT-CO1', 'Gene', '4512', (159, 165))	('MT-ATP6', 'Gene', (187, 194))	('MT-ATP6', 'Gene', '4508', (187, 194))
492377	31761563	Vector control 293T cells, or 293T cells expressing FBP2, FBP24KA or FBP2G260R were harvested in lysis buffer used for western blot analysis.	('293T', 'CellLine', 'CVCL:0063', (30, 34))	('FBP2G260R', 'Var', (69, 78))	('FBP2', 'Var', (52, 56))	('FBP24KA', 'Var', (58, 65))	('293T', 'CellLine', 'CVCL:0063', (15, 19))
492381	31761563	LPS246 TetO-FBP2 (PBS or Dox treated) and LPS246 TetO-FBP24KA (PBS or Dox treated) cells were seeded in 6-well plates at a density of 1.5 x 105 per well.	('LPS246', 'Var', (0, 6))	('LPS246 TetO-FBP24KA', 'Var', (42, 61))	('Dox', 'Chemical', 'MESH:D004317', (70, 73))	('LPS246', 'Chemical', '-', (42, 48))	('LPS246', 'Chemical', '-', (0, 6))	('PBS', 'Chemical', 'MESH:D007854', (63, 66))	('PBS', 'Chemical', 'MESH:D007854', (18, 21))	('Dox', 'Chemical', 'MESH:D004317', (25, 28))
492395	31761563	LPS246 tumors were fixed in 4% paraformaldehyde (PFA)/PBS overnight at 4  C. Fixed tissues were dehydrated in 30% sucrose solution and embedded in OCT for frozen sectioning.	('LPS246', 'Var', (0, 6))	('PBS', 'Chemical', 'MESH:D007854', (54, 57))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('sucrose', 'Chemical', 'MESH:D013395', (114, 121))	('LPS246', 'Chemical', '-', (0, 6))	('OCT', 'Gene', (147, 150))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (31, 47))	('OCT', 'Gene', '5362', (147, 150))	('PFA', 'Chemical', 'MESH:C003043', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
492422	31761563	6 replicates were set up for each of the following groups: (1) LPS246 TetO-FBP2 + Veh; (2) LPS246 TetO-FBP2 + Dox; (3) LPS246 TetO-FBP24KA + Veh; (4) LPS246 TetO-FBP24KA + Dox.	('Dox', 'Chemical', 'MESH:D004317', (172, 175))	('LPS246', 'Chemical', '-', (91, 97))	('LPS246', 'Chemical', '-', (150, 156))	('Dox', 'Chemical', 'MESH:D004317', (110, 113))	('LPS246', 'Var', (63, 69))	('LPS246', 'Chemical', '-', (119, 125))	('LPS246', 'Chemical', '-', (63, 69))	('LPS246', 'Var', (91, 97))	('LPS246 TetO-FBP24KA', 'Var', (119, 138))	('LPS246 TetO-FBP24KA', 'Var', (150, 169))
492430	31761563	Here, Celeste Simon and her colleagues show that fructose-1,6-bisphosphatase 2 (FBP2) is lost in many STS subtypes, and FBP2 re-expression dramatically inhibits sarcoma growth.	('sarcoma', 'Disease', (161, 168))	('FBP2', 'Gene', (120, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('lost', 'NegReg', (89, 93))	('inhibits', 'NegReg', (152, 160))	('FBP2', 'Gene', (80, 84))	('fructose-1,6-bisphosphatase 2', 'Gene', '8789', (49, 78))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('re-expression', 'Var', (125, 138))
492432	31761563	Both these aspects of FBP2 starve the cancer of energy, providing a rationale for why loss of FBP2 is so often seen in STSs and why its re-expression is a therapeutic option.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('loss', 'Var', (86, 90))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('FBP2', 'Gene', (94, 98))	('cancer', 'Disease', (38, 44))	('STSs', 'Phenotype', 'HP:0030448', (119, 123))
492485	21804475	Osteosarcoma tumorigenesis is associated with vital genetic alterations, including the inactivation of tumor suppressor genes; gain, loss, or rearrangement of chromosomal regions; and misregulated signal transduction pathways.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('chromosomal', 'Protein', (159, 170))	('misregulated', 'Reg', (184, 196))	('tumor', 'Disease', (103, 108))	('inactivation', 'Var', (87, 99))	('loss', 'NegReg', (133, 137))	('rearrangement', 'Var', (142, 155))	('Osteosarcoma', 'Disease', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('gain', 'PosReg', (127, 131))
492489	21804475	Overexpression of HER2/neu, alteration in receptor activator of NF-kB (RANK) signaling in pagetic patients, and mutations in the RECQL4 gene in Rothmund-Thomson syndrome patients are linked with the occurrence of osteosarcoma.	('osteosarcoma', 'Disease', (213, 225))	('RECQL4', 'Gene', '9401', (129, 135))	('osteosarcoma', 'Disease', 'MESH:D012516', (213, 225))	('alteration', 'Var', (28, 38))	('mutations', 'Var', (112, 121))	('HER2/neu', 'Gene', '2064', (18, 26))	('RANK', 'Gene', (71, 75))	('receptor activator of NF-kB', 'Gene', '8792', (42, 69))	('RECQL4', 'Gene', (129, 135))	('receptor activator of NF-kB', 'Gene', (42, 69))	('Rothmund-Thomson syndrome', 'Disease', 'MESH:D011038', (144, 169))	('RANK', 'Gene', '8792', (71, 75))	('linked', 'Reg', (183, 189))	('patients', 'Species', '9606', (170, 178))	('osteosarcoma', 'Phenotype', 'HP:0002669', (213, 225))	('patients', 'Species', '9606', (98, 106))	('Rothmund-Thomson syndrome', 'Disease', (144, 169))	('HER2/neu', 'Gene', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))
492491	21804475	Further, alterations in RANK signaling are associated with Paget's disease of the bone.	("Paget's disease", 'Disease', (59, 74))	('RANK', 'Gene', (24, 28))	('alterations', 'Var', (9, 20))	('RANK', 'Gene', '8792', (24, 28))	("Paget's disease", 'Disease', 'MESH:C537701', (59, 74))	('associated', 'Reg', (43, 53))
492516	21804475	Studies conducted by Yuan et al have demonstrated that a combination of interferon-gamma and conventional chemotherapeutic agents such as doxorubicin may be used for the management of osteosarcoma with functional p53.	('interferon-gamma', 'Gene', '3458', (72, 88))	('interferon-gamma', 'Gene', (72, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('p53', 'Var', (213, 216))	('osteosarcoma', 'Phenotype', 'HP:0002669', (184, 196))	('osteosarcoma', 'Disease', (184, 196))	('osteosarcoma', 'Disease', 'MESH:D012516', (184, 196))	('doxorubicin', 'Chemical', 'MESH:D004317', (138, 149))	('functional p53', 'Var', (202, 216))
492536	21804475	Recently, a study on AZD2171, a specific inhibitor of the VEGF receptor, has shown encouraging results, with AZD2171 showing an inhibitory effect on solid osteosarcoma tumor xenografts.	('VEGF', 'Gene', (58, 62))	('osteosarcoma', 'Phenotype', 'HP:0002669', (155, 167))	('VEGF', 'Gene', '7422', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('osteosarcoma tumor', 'Disease', (155, 173))	('osteosarcoma tumor', 'Disease', 'MESH:D012516', (155, 173))	('inhibitory effect', 'NegReg', (128, 145))	('AZD2171', 'Chemical', 'MESH:C500926', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('AZD2171', 'Var', (109, 116))	('AZD2171', 'Chemical', 'MESH:C500926', (21, 28))
492543	21804475	Therefore, the inhibitors of RANKL are potential drug candidates, as they have been shown to exhibit antitumor effects with fewer adverse effects.	('RANKL', 'Gene', '8600', (29, 34))	('RANKL', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('inhibitors', 'Var', (15, 25))
492634	21804475	A study by Miyaji et al revealed that monoclonal antibody against PTHLH induced differentiation and apoptosis of chondrosarcoma cells in vitro; this occurred because of downregulation of its downstream target BCL2 - the antiapoptotic protein.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('BCL2', 'Gene', (209, 213))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (113, 127))	('differentiation', 'CPA', (80, 95))	('monoclonal antibody', 'Var', (38, 57))	('PTHLH', 'Gene', '5744', (66, 71))	('PTHLH', 'Gene', (66, 71))	('induced', 'Reg', (72, 79))	('chondrosarcoma', 'Disease', 'MESH:D002813', (113, 127))	('chondrosarcoma', 'Disease', (113, 127))	('downregulation', 'NegReg', (169, 183))	('apoptosis', 'CPA', (100, 109))	('BCL2', 'Gene', '596', (209, 213))
492674	21804475	Recently, translocations on chromosome 22, t(21;22)(q22;q12) and t(7;22)(p22;q12), involving the EWS gene have also been identified as diagnostic factors.	('t(7;22)(p22;q12', 'Var', (65, 80))	('translocations', 'Var', (10, 24))	('EWS', 'Gene', (97, 100))	('t(7;22)(p22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (65, 81))	('EWS', 'Gene', '2130', (97, 100))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (43, 60))	('t(21;22)(q22;q12', 'Var', (43, 59))
492689	21804475	The inhibition of EWS-Fli1 by antisense oligonucleotides or small interfering RNAs (SiRNAs) has proven to be useful in arresting cell growth in vivo.	('EWS', 'Gene', '2130', (18, 21))	('EWS', 'Gene', (18, 21))	('oligonucleotides', 'Chemical', 'MESH:D009841', (40, 56))	('Fli1', 'Gene', '2313', (22, 26))	('cell growth', 'CPA', (129, 140))	('Fli1', 'Gene', (22, 26))	('antisense oligonucleotides', 'Var', (30, 56))	('inhibition', 'NegReg', (4, 14))	('arresting', 'NegReg', (119, 128))
492702	21804475	These cells underwent growth arrest, thereby suggesting that growth arrest-abrogating collaborative mutations are essential for tumorigenesis.	('mutations', 'Var', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('underwent', 'Reg', (12, 21))	('growth arrest-', 'Phenotype', 'HP:0031164', (61, 75))	('growth arrest', 'Phenotype', 'HP:0001510', (22, 35))	('growth arrest', 'Phenotype', 'HP:0001510', (61, 74))	('tumor', 'Disease', (128, 133))	('growth arrest', 'CPA', (22, 35))
492703	21804475	Adenoviral transfection of wild-type p53 in the ESFT cell line and RH1 containing mutp53 resulted in decreased viability and increased sensitivity to the chemotherapeutic agents cisplatin and doxorubicin.	('doxorubicin', 'MPA', (192, 203))	('ES', 'Phenotype', 'HP:0012254', (48, 50))	('increased', 'PosReg', (125, 134))	('RH1', 'CellLine', 'CVCL:C355', (67, 70))	('decreased', 'NegReg', (101, 110))	('doxorubicin', 'Chemical', 'MESH:D004317', (192, 203))	('sensitivity to the chemotherapeutic', 'MPA', (135, 170))	('mutp53', 'Var', (82, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
492718	21804475	Alterations in these pathways lead to enhanced tumor growth via the suppression of apoptosis.	('enhanced', 'PosReg', (38, 46))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('apoptosis', 'CPA', (83, 92))	('suppression', 'NegReg', (68, 79))	('tumor', 'Disease', (47, 52))
492719	21804475	The inactivation of EWS/ETS could serve as a promising therapeutic target due to its role in tumorigenesis as well as its specificity for transformed cells alone.	('EWS', 'Gene', (20, 23))	('inactivation', 'Var', (4, 16))	('EWS', 'Gene', '2130', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
492738	32766799	These findings suggest that Medicaid insurance or no insurance is associated with the presence of metastases at the time of diagnosis among adults with soft-tissue sarcomas, suggesting a diagnostic delay, but there is no such association for adults with bone sarcomas.	('Medicaid insurance', 'Var', (28, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (164, 172))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (152, 172))	('sarcomas', 'Disease', 'MESH:D012509', (259, 267))	('bone sarcomas', 'Disease', 'MESH:D012509', (254, 267))	('sarcomas', 'Disease', (164, 172))	('metastases', 'Disease', (98, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (259, 267))	('bone sarcomas', 'Disease', (254, 267))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (152, 171))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('bone sarcoma', 'Phenotype', 'HP:0002669', (254, 266))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('sarcomas', 'Disease', (259, 267))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('bone sarcomas', 'Phenotype', 'HP:0002669', (254, 267))	('sarcomas', 'Disease', 'MESH:D012509', (164, 172))
492759	32766799	Of note, a genome-wide association study of osteosarcoma identified 2 germline genetic variants that were associated with an increased risk of metastases.	('metastases', 'Disease', 'MESH:D009362', (143, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('associated', 'Reg', (106, 116))	('variants', 'Var', (87, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (44, 56))	('metastases', 'Disease', (143, 153))	('osteosarcoma', 'Disease', (44, 56))	('osteosarcoma', 'Disease', 'MESH:D012516', (44, 56))
493148	26735287	Multifocal signal abnormalities were seen in seven limbs on T1-GRE sequences but not on T2-FSE images.	('T1-GRE', 'Var', (60, 66))	('Multifocal signal abnormalities', 'Disease', (0, 31))	('Multifocal signal abnormalities', 'Disease', 'None', (0, 31))
493175	26735287	Methods: Contrast-enhanced CT studies of PPID free horses, divided in three different age groups:young (<5 years), adult (5-15 years), and aged (>15 years); three different size groups:small (<250 kg), average (250-550 kg), and large (>550 kg); and two gender groups:male, female, were reviewed.	('horses', 'Species', '9796', (51, 57))	('250-550 kg', 'Var', (211, 221))	('<250 kg', 'Var', (192, 199))	('>550 kg', 'Var', (235, 242))
493177	26735287	Findings: Twenty-one horses and ponies were included in the study: 10 young (<5 years), five adults (5-15 years), and six aged (>15 years)/three small (<250 kg), 11 average (250-550 kg), and seven large (>550 kg)/eight male and 13 female.	('horses', 'Species', '9796', (21, 27))	('<250 kg', 'Var', (152, 159))	('>550 kg', 'Var', (204, 211))	('250-550 kg', 'Var', (174, 184))
493366	26735287	Importantly, high ICCR was significantly (rs = 0.1986, P = 0.006) correlated to cerebellar herniation.	('correlated', 'Reg', (66, 76))	('high', 'Var', (13, 17))	('cerebellar herniation', 'Disease', (80, 101))	('cerebellar herniation', 'Disease', 'MESH:D004677', (80, 101))	('hernia', 'Phenotype', 'HP:0100790', (91, 97))
493426	26735287	Right ventricle/LVCT in T, SA, and 4C views were significantly increased in group A (T: 0.873 +- 0.101; SA: 0.866 +- 0.065; 4C: 0.881 +- 0.065) compared to group C (T: 0.657 +- 0.114, P < 0.05; SA: 0.669 +- 0.068, P < 0.05; 4C: 0.710 +- 0.075, P < 0.05).	('LV', 'Disease', 'MESH:C535509', (16, 18))	('increased', 'PosReg', (63, 72))	('T: 0.873 +- 0.101;', 'Var', (85, 103))
493446	26735287	Evaluated CT parameters are: type and morphology of the aberrant subclavian arteries, presence of concurrent vascular abnormalities, reason, and degree of esophageal constriction.	('vascular abnormalities', 'Disease', (109, 131))	('vascular abnormalities', 'Disease', 'MESH:D000783', (109, 131))	('vascular abnormalities', 'Phenotype', 'HP:0002597', (109, 131))	('aberrant', 'Var', (56, 64))
493448	26735287	Aberrant left subclavian artery (LSA) was diagnosed in 4/13 cases (all of them scanned because of a suspected vascular ring anomaly) concurrently with persistent right aortic arch (PRAA) with left ligamentum arteriosum that was considered the only cause of esophageal constriction in 3/4 cases.	('Aberrant', 'Var', (0, 8))	('vascular ring anomaly', 'Disease', (110, 131))	('vascular ring', 'Phenotype', 'HP:0010775', (110, 123))	('vascular ring anomaly', 'Disease', 'MESH:D000073872', (110, 131))	('right aortic arch', 'Phenotype', 'HP:0012020', (162, 179))
493623	26735287	Presence of LTV is a predisposition for early disc degeneration in some young dogs.	('disc degeneration', 'Phenotype', 'HP:0008419', (46, 63))	('disc degeneration', 'Disease', (46, 63))	('disc degeneration', 'Disease', 'MESH:D055959', (46, 63))	('LTV', 'Gene', (12, 15))	('dogs', 'Species', '9615', (78, 82))	('early', 'Disease', (40, 45))	('Presence', 'Var', (0, 8))
493836	29371980	Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor.	('HGNET-BCOR', 'Gene', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (110, 131))	('BCOR', 'Gene', '54880', (32, 36))	('alteration', 'Var', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BCOR', 'Gene', '54880', (167, 171))	('neuroepithelial tumor', 'Disease', (110, 131))	('BCOR', 'Gene', (32, 36))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (110, 131))	('BCOR', 'Gene', (167, 171))	('HGNET-BCOR', 'Gene', '54880', (184, 194))	('BCOR', 'Gene', '54880', (190, 194))	('HGNET-BCOR', 'Gene', '54880', (26, 36))	('tumor of the central nervous system', 'Phenotype', 'HP:0100006', (126, 161))	('BCOR', 'Gene', (190, 194))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (55, 71))	('malignant tumor', 'Disease', (214, 229))	('malignant tumor', 'Disease', 'MESH:D018198', (214, 229))	('HGNET-BCOR', 'Gene', (184, 194))
493844	29371980	Meanwhile, an increase in the concentration of circulating tumor DNA carrying a BCOR internal tandem duplication was observed.	('tumor', 'Disease', (59, 64))	('BCOR', 'Gene', (80, 84))	('BCOR', 'Gene', '54880', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('internal tandem duplication', 'Var', (85, 112))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('increase', 'PosReg', (14, 22))
493846	29371980	In P2, we detected a larger tandem duplication and greater activation of the Sonic hedgehog pathway than in P1.	('Sonic hedgehog', 'Gene', '6469', (77, 91))	('Sonic hedgehog', 'Gene', (77, 91))	('activation', 'PosReg', (59, 69))	('tandem duplication', 'Var', (28, 46))
493851	29371980	HGNET-BCOR is characterized by somatic internal tandem duplication (ITD) in the C-terminus of BCL-6 co-repressor (BCOR) associated with an upregulation of BCOR expression.	('BCOR', 'Gene', (155, 159))	('expression', 'MPA', (160, 170))	('HGNET-BCOR', 'Gene', '54880', (0, 10))	('BCOR', 'Gene', '54880', (6, 10))	('BCOR', 'Gene', (114, 118))	('upregulation', 'PosReg', (139, 151))	('BCOR', 'Gene', '54880', (155, 159))	('HGNET-BCOR', 'Gene', (0, 10))	('BCL-6 co-repressor', 'Gene', (94, 112))	('BCOR', 'Gene', '54880', (114, 118))	('internal tandem duplication', 'Var', (39, 66))	('BCL-6 co-repressor', 'Gene', '54880', (94, 112))	('BCOR', 'Gene', (6, 10))
493879	29371980	We have previously described that the primary tumor and the metastases of P1 did not carry SMO missense mutations.	('missense mutations', 'Var', (95, 113))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('tumor', 'Disease', (46, 51))	('metastases', 'Disease', (60, 70))	('SMO', 'Gene', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
493885	29371980	These results suggest that ATO decreases the expression of target genes of the SHH pathway, thus inhibiting cell proliferation.	('SHH', 'Gene', (79, 82))	('decreases', 'NegReg', (31, 40))	('ATO', 'Chemical', 'MESH:D000077237', (27, 30))	('expression', 'MPA', (45, 55))	('ATO', 'Var', (27, 30))	('cell proliferation', 'CPA', (108, 126))	('SHH', 'Gene', '6469', (79, 82))	('inhibiting', 'NegReg', (97, 107))
493894	29371980	These data indicate that ATO induces the expression of proteins that may allow the cellular recovery from stress, thus restoring protein homeostasis and promoting cell survival.	('proteins', 'Protein', (55, 63))	('expression', 'MPA', (41, 51))	('ATO', 'Chemical', 'MESH:D000077237', (25, 28))	('cell survival', 'CPA', (163, 176))	('promoting', 'PosReg', (153, 162))	('protein homeostasis', 'MPA', (129, 148))	('ATO', 'Var', (25, 28))	('restoring', 'PosReg', (119, 128))
493895	29371980	Co-targeting these stress-induced survival pathways may better manipulate cancer cell sensitivity to ATO therapy.	('ATO', 'Chemical', 'MESH:D000077237', (101, 104))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('Co-targeting', 'Var', (0, 12))	('cancer', 'Disease', (74, 80))	('manipulate', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
493941	29371980	CNS HGNET-BCOR is characterized by tandem duplication in exon 15 of the BCOR gene.	('BCOR', 'Gene', (72, 76))	('HGNET-BCOR', 'Gene', '54880', (4, 14))	('BCOR', 'Gene', '54880', (10, 14))	('tandem duplication in', 'Var', (35, 56))	('BCOR', 'Gene', '54880', (72, 76))	('HGNET-BCOR', 'Gene', (4, 14))	('BCOR', 'Gene', (10, 14))
493978	29371980	Here we show that ATO reduced the transcription of GLI target genes in a primary culture of HGNET-BCOR.	('HGNET-BCOR', 'Gene', (92, 102))	('ATO', 'Var', (18, 21))	('transcription', 'MPA', (34, 47))	('GLI', 'Gene', '2735', (51, 54))	('HGNET-BCOR', 'Gene', '54880', (92, 102))	('reduced', 'NegReg', (22, 29))	('ATO', 'Chemical', 'MESH:D000077237', (18, 21))	('GLI', 'Gene', (51, 54))
494015	29371980	The presence of the wt BCOR allele in the P2 patient (female) could be related to the better prognosis compared to the P1 patient (male).	('patient', 'Species', '9606', (122, 129))	('BCOR', 'Gene', (23, 27))	('patient', 'Species', '9606', (45, 52))	('BCOR', 'Gene', '54880', (23, 27))	('presence', 'Var', (4, 12))
494030	29371980	The CNS HGNET-BCOR diagnosis in P2 was based on targeted next-generation sequencing results from the UCSF500 Cancer Panel, which we have previously described, that detected an internal tandem duplication in exon 15 of the BCOR gene and absence of genetic alterations that are commonly seen in medulloblastomas.	('BCOR', 'Gene', '54880', (14, 18))	('medulloblastoma', 'Phenotype', 'HP:0002885', (293, 308))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('internal tandem duplication in exon', 'Var', (176, 211))	('HGNET-BCOR', 'Gene', '54880', (8, 18))	('medulloblastomas', 'Disease', 'MESH:D008527', (293, 309))	('BCOR', 'Gene', (222, 226))	('HGNET-BCOR', 'Gene', (8, 18))	('medulloblastomas', 'Disease', (293, 309))	('BCOR', 'Gene', '54880', (222, 226))	('BCOR', 'Gene', (14, 18))
494056	29371980	APL acute promyelocytic leukemia ATO arsenic trioxide BCOR BCL-6 co-repressor CNS HGNET-BCOR high-grade neuroepithelial tumor of the central nervous system with BCOR alteration ct threshold cycle ctDNA circulating DNA CR complete remission CSF cerebrospinal fluid DOX doxorubicin ICE ifosfamide, carboplatin, etoposide ITD internal tandem duplication I2VAd ifosfamide, vincristine, dactinomycin C PD progressive disease PE Plating efficiency TPM Transcripts per Kilobase Million	('etoposide', 'Chemical', 'MESH:D005047', (309, 318))	('BCOR', 'Gene', '54880', (161, 165))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (37, 53))	('neuroepithelial tumor', 'Disease', 'MESH:D018302', (104, 125))	('HGNET-BCOR', 'Gene', (82, 92))	('dactinomycin C', 'Chemical', '-', (382, 396))	('leukemia', 'Phenotype', 'HP:0001909', (24, 32))	('carboplatin', 'Chemical', 'MESH:D016190', (296, 307))	('BCOR', 'Gene', (161, 165))	('BCOR', 'Gene', '54880', (88, 92))	('APL', 'Disease', (0, 3))	('tumor of the central nervous system', 'Phenotype', 'HP:0100006', (120, 155))	('DOX', 'Chemical', 'MESH:D004317', (264, 267))	('BCOR', 'Gene', (88, 92))	('BCL-6 co-repressor', 'Gene', (59, 77))	('I2VAd', 'Chemical', '-', (351, 356))	('BCOR', 'Gene', '54880', (54, 58))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (4, 32))	('HGNET-BCOR', 'Gene', '54880', (82, 92))	('ifosfamide', 'Chemical', 'MESH:D007069', (357, 367))	('BCOR', 'Gene', (54, 58))	('doxorubicin', 'Chemical', 'MESH:D004317', (268, 279))	('APL', 'Phenotype', 'HP:0004836', (0, 3))	('ifosfamide', 'Chemical', 'MESH:D007069', (284, 294))	('vincristine', 'Chemical', 'MESH:D014750', (369, 380))	('APL', 'Disease', 'MESH:D015473', (0, 3))	('neuroepithelial tumor', 'Phenotype', 'HP:0030063', (104, 125))	('BCL-6 co-repressor', 'Gene', '54880', (59, 77))	('internal tandem duplication', 'Var', (323, 350))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (10, 32))	('CR', 'Chemical', '-', (218, 220))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('neuroepithelial tumor', 'Disease', (104, 125))
494105	28679123	Pharmacological blockade of VEGFR-2 stabilizes endothelial barrier function and suppresses tumor cell extravasation in vivo, emphasizing the importance of VEGFR-2 signaling in tumor invasion and metastasis.	('blockade', 'Var', (16, 24))	('stabilizes', 'Reg', (36, 46))	('VEGFR-2', 'Gene', '3791', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('VEGFR-2', 'Gene', '3791', (155, 162))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('endothelial', 'MPA', (47, 58))	('VEGFR-2', 'Gene', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('VEGFR-2', 'Gene', (155, 162))	('tumor', 'Disease', (91, 96))	('suppresses', 'NegReg', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
494106	28679123	VEGFR-2 activation can be inhibited using a number of pharmacodynamic approaches, including receptor blockade (ramucirumab), ligand capture (bevacizumab, also known as avastin), and small-molecule inhibition (sorafenib, sunitinib, apatinib, and cediranib).	('avastin', 'Chemical', 'MESH:D000068258', (168, 175))	('activation', 'PosReg', (8, 18))	('inhibited', 'NegReg', (26, 35))	('VEGFR-2', 'Gene', (0, 7))	('ligand', 'MPA', (125, 131))	('small-molecule inhibition', 'Var', (182, 207))	('apatinib', 'Chemical', 'MESH:C553458', (231, 239))	('cediranib', 'Chemical', 'MESH:C500926', (245, 254))	('ramucirumab', 'Chemical', 'MESH:C543333', (111, 122))	('sorafenib', 'Chemical', 'MESH:D000077157', (209, 218))	('bevacizumab', 'Chemical', 'MESH:D000068258', (141, 152))	('VEGFR-2', 'Gene', '3791', (0, 7))	('sunitinib', 'Chemical', 'MESH:D000077210', (220, 229))
494111	28679123	Although VEGF inhibitors demonstrate potent advantages in cancer therapy, their impacts on overall survival are unclear.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('VEGF', 'Gene', (9, 13))	('advantages', 'PosReg', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('VEGF', 'Gene', '7422', (9, 13))	('cancer', 'Disease', (58, 64))	('inhibitors', 'Var', (14, 24))
494112	28679123	Resistance to therapy is associated with highly aggressive cancer phenotypes; therefore, no increase in overall survival has been observed.	('Resistance', 'Var', (0, 10))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
494266	26799834	F3879-1G, in 90% RPMI 1640, 5% 1X phosphate buffered saline, and 5% ultrafiltered water) and 5 mul of 1 U/mul Thrombin (Biovision, cat.	('RPMI 1640', 'Chemical', '-', (17, 26))	('F3879-1G', 'Var', (0, 8))	('water', 'Chemical', 'MESH:D014867', (82, 87))	('phosphate buffered saline', 'Chemical', '-', (34, 59))	('Thrombin', 'Gene', (110, 118))	('Thrombin', 'Gene', '2147', (110, 118))
494373	33467731	Moreover, decreasing sphingosine 1-phosphate levels (S1P) by FTY720 (Fingolimod) impaired acid-induced tumor survival and migration.	('FTY720', 'Var', (61, 67))	('S1P', 'Gene', '13609', (53, 56))	('migration', 'CPA', (122, 131))	('Fingolimod', 'Chemical', 'MESH:D000068876', (69, 79))	('sphingosine 1-phosphate levels', 'MPA', (21, 51))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('sphingosine 1-phosphate', 'Chemical', 'MESH:C060506', (21, 44))	('impaired', 'NegReg', (81, 89))	('S1P', 'Gene', (53, 56))	('decreasing', 'NegReg', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('FTY720', 'Chemical', 'MESH:D000068876', (61, 67))
494375	33467731	Finally, when we treated osteosarcoma xenografts with FTY720 combined with low-serine/glycine diet, both lipid accumulation (as measured by magnetic resonance imaging) and tumor growth were greatly inhibited.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('FTY720', 'Chemical', 'MESH:D000068876', (54, 60))	('glycine', 'Chemical', 'MESH:D005998', (86, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (25, 37))	('lipid', 'Chemical', 'MESH:D008055', (105, 110))	('osteosarcoma', 'Disease', (25, 37))	('tumor', 'Disease', (172, 177))	('osteosarcoma', 'Disease', 'MESH:D012516', (25, 37))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('lipid accumulation', 'MPA', (105, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('FTY720', 'Var', (54, 60))	('inhibited', 'NegReg', (198, 207))
494395	33467731	Overall, our findings suggest that impinging the sphingolipid pathway can improve acid-resistant cell disposal, with the potential for clinical translation.	('sphingolipid pathway', 'Pathway', (49, 69))	('improve', 'PosReg', (74, 81))	('sphingolipid', 'Chemical', 'MESH:D013107', (49, 61))	('acid-resistant cell disposal', 'MPA', (82, 110))	('impinging', 'Var', (35, 44))
494401	33467731	In 143B, notably, at pH 6.8, we also noted a strong reduction in the number of cells (Figure S3A).	('reduction', 'NegReg', (52, 61))	('pH', 'Gene', '5053', (21, 23))	('143B', 'Var', (3, 7))	('number of cells', 'CPA', (69, 84))
494407	33467731	In conclusion, our results suggest that acidity is a considerable source of stress that causes lipid accumulation, does not cause cell death and leads to enhanced cell migration.	('lipid', 'Chemical', 'MESH:D008055', (95, 100))	('enhanced', 'PosReg', (154, 162))	('cell migration', 'CPA', (163, 177))	('acidity', 'Var', (40, 47))	('death', 'Disease', 'MESH:D003643', (135, 140))	('lipid accumulation', 'MPA', (95, 113))	('death', 'Disease', (135, 140))
494415	33467731	We found that, although the relative expression of genes encoding mitochondrial complex I (i.e., NDUFA9 and NDUFAB1) was similar in cells grown under acidic and neutral conditions (Figure S6A), a significant decrease in oxygen consumption rate (OCR), with reductions both in basal and maximal respiration, occurred only under acidity (Figure 2A,B (143B cells) and Figure S6B (HOS cells)).	('HOS', 'Gene', '23291', (376, 379))	('NDUFAB1', 'Gene', '4706', (108, 115))	('oxygen', 'Chemical', 'MESH:D010100', (220, 226))	('reductions', 'NegReg', (256, 266))	('NDUFA9', 'Gene', '4704', (97, 103))	('maximal respiration', 'MPA', (285, 304))	('Figure S6B', 'Var', (364, 374))	('NDUFAB1', 'Gene', (108, 115))	('oxygen consumption rate', 'MPA', (220, 243))	('NDUFA9', 'Gene', (97, 103))	('decrease', 'NegReg', (208, 216))	('HOS', 'Gene', (376, 379))
494427	33467731	SPHK1 was significantly upregulated in acid-treated spheroids, whereas SPHK2 was unchanged (Figure 3D).	('spheroids', 'Chemical', '-', (52, 61))	('SPHK2', 'Gene', '56848', (71, 76))	('SPHK1', 'Gene', (0, 5))	('SPHK1', 'Gene', '8877', (0, 5))	('upregulated', 'PosReg', (24, 35))	('acid-treated', 'Var', (39, 51))	('SPHK2', 'Gene', (71, 76))
494429	33467731	Consistent with these findings, intracellular S1P levels were significantly increased under acidity in 143B spheroids (Figure 3E), and mildly, although not significantly, also in HOS spheroids (Figure S7A).	('S1P', 'Gene', (46, 49))	('HOS spheroids', 'Disease', (179, 192))	('increased', 'PosReg', (76, 85))	('HOS spheroids', 'Disease', 'MESH:C535326', (179, 192))	('143B spheroids', 'Chemical', '-', (103, 117))	('acidity', 'Var', (92, 99))	('S1P', 'Gene', '13609', (46, 49))
494430	33467731	Overall, our data revealed that oncogenic lipids are greatly upregulated by acidity.	('acidity', 'Var', (76, 83))	('lipids', 'Chemical', 'MESH:D008055', (42, 48))	('upregulated', 'PosReg', (61, 72))	('oncogenic lipids', 'MPA', (32, 48))
494433	33467731	Both myriocin and FTY720 were able to impair S1P accumulation in 143B spheroids under acidity, with a greater effect shown by FTY720 (Figure 3E).	('S1P', 'Gene', (45, 48))	('FTY720', 'Var', (126, 132))	('FTY720', 'Chemical', 'MESH:D000068876', (126, 132))	('impair', 'NegReg', (38, 44))	('S1P', 'Gene', '13609', (45, 48))	('FTY720', 'Var', (18, 24))	('143B spheroids', 'Chemical', '-', (65, 79))	('FTY720', 'Chemical', 'MESH:D000068876', (18, 24))	('myriocin', 'Chemical', 'MESH:C001996', (5, 13))
494435	33467731	FTY720 also greatly impaired LD formation under acidic conditions (Figure 3G, acidity and Figure S7B, neutrality).	('LD formation', 'CPA', (29, 41))	('impaired', 'NegReg', (20, 28))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('FTY720', 'Var', (0, 6))
494437	33467731	By contrast, the results with FTY720 suggest that the sphingomyelinase pathway is prevalent under acidic conditions as a source for LD accumulation and for S1P synthesis.	('FTY720', 'Var', (30, 36))	('sphingomyelinase', 'Disease', (54, 70))	('S1P', 'Gene', (156, 159))	('FTY720', 'Chemical', 'MESH:D000068876', (30, 36))	('sphingomyelinase', 'Disease', 'MESH:D052536', (54, 70))	('S1P', 'Gene', '13609', (156, 159))
494439	33467731	Conversely, FTY720 significantly impaired tumor cell migration under acidity but had no effect under neutral conditions (Figure 3H).	('impaired tumor', 'Disease', (33, 47))	('impaired tumor', 'Disease', 'MESH:D060825', (33, 47))	('FTY720', 'Chemical', 'MESH:D000068876', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('FTY720', 'Var', (12, 18))
494440	33467731	Overall, these data demonstrate that acidity induces a marked overexpression of components of the sphingolipid pathway, with specific enhancement of the sphingomyelinase pathway over the de novo pathway and S1P accumulation.	('sphingolipid', 'Chemical', 'MESH:D013107', (98, 110))	('S1P', 'Gene', (207, 210))	('enhancement', 'PosReg', (134, 145))	('acidity', 'Var', (37, 44))	('overexpression', 'PosReg', (62, 76))	('sphingolipid pathway', 'Pathway', (98, 118))	('sphingomyelinase', 'Disease', (153, 169))	('sphingomyelinase', 'Disease', 'MESH:D052536', (153, 169))	('S1P', 'Gene', '13609', (207, 210))	('de novo pathway', 'Pathway', (187, 202))
494441	33467731	Moreover, we showed that FTY720 can effectively inhibit the acid-induced S1P accumulation and reduce the survival and migration of OS cells under acidic conditions.	('S1P', 'Gene', (73, 76))	('FTY720', 'Chemical', 'MESH:D000068876', (25, 31))	('FTY720', 'Var', (25, 31))	('S1P', 'Gene', '13609', (73, 76))	('reduce', 'NegReg', (94, 100))	('inhibit', 'NegReg', (48, 55))
494443	33467731	In 143B, the concentration of S1P in the supernatant showed an increased trend in acid-treated spheroids compared to those growing in neutral conditions (Figure S7D).	('S1P', 'Gene', '13609', (30, 33))	('concentration', 'MPA', (13, 26))	('increased', 'PosReg', (63, 72))	('spheroids', 'Chemical', '-', (95, 104))	('S1P', 'Gene', (30, 33))	('acid-treated', 'Var', (82, 94))
494451	33467731	Next, we found that FTY720 significantly increased the percentage of apoptotic cells (Figure 4B), whereas myriocin was not effective, suggesting that S1P mediates the anti-apoptotic response to acidity.	('S1P', 'Gene', '13609', (150, 153))	('FTY720', 'Var', (20, 26))	('increased', 'PosReg', (41, 50))	('FTY720', 'Chemical', 'MESH:D000068876', (20, 26))	('myriocin', 'Chemical', 'MESH:C001996', (106, 114))	('S1P', 'Gene', (150, 153))
494456	33467731	The above-reported results suggest that FTY720 treatment impairs tumor cell survival in acidic condition by inhibiting S1P-induced anti-apoptotic signaling.	('FTY720', 'Chemical', 'MESH:D000068876', (40, 46))	('impairs tumor', 'Disease', (57, 70))	('S1P', 'Gene', '13609', (119, 122))	('S1P', 'Gene', (119, 122))	('inhibiting', 'NegReg', (108, 118))	('impairs tumor', 'Disease', 'MESH:D060825', (57, 70))	('FTY720', 'Var', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
494461	33467731	We thus used intraperitoneal treatment with FTY720 alone or combined with serine/glycine restriction (Figure 5A).	('FTY720', 'Var', (44, 50))	('FTY720', 'Chemical', 'MESH:D000068876', (44, 50))	('serine/glycine restriction', 'MPA', (74, 100))	('glycine', 'Chemical', 'MESH:D005998', (81, 88))	('serine', 'Chemical', 'MESH:D012694', (74, 80))
494466	33467731	Adversely, FTY720 treatment alone had little effect on tumor growth or fat fraction (Figure 5C,D), as its main target is the acidic cell population, which represents only a fraction of the tumor mass.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (189, 194))	('fat fraction', 'MPA', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('FTY720', 'Chemical', 'MESH:D000068876', (11, 17))	('FTY720', 'Var', (11, 17))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
494467	33467731	By contrast, the combination of the reduced serine/glycine diet and FTY720 significantly inhibited tumor growth and percentage of fat fraction at a greater extent than low serine diet alone (Figure 5C).	('tumor', 'Disease', (99, 104))	('serine/glycine', 'MPA', (44, 58))	('low serine diet', 'Phenotype', 'HP:0012279', (168, 183))	('FTY720', 'Var', (68, 74))	('glycine', 'Chemical', 'MESH:D005998', (51, 58))	('FTY720', 'Chemical', 'MESH:D000068876', (68, 74))	('inhibited', 'NegReg', (89, 98))	('serine', 'Chemical', 'MESH:D012694', (172, 178))	('percentage of fat fraction', 'MPA', (116, 142))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('serine', 'Chemical', 'MESH:D012694', (44, 50))
494468	33467731	To confirm that intraperitoneal FTY720 treatment successfully targeted the tumor and that the observed growth-inhibition was specifically due to the FTY720 effect at the tumor site, we performed untargeted lipid profiling of the extracted tumors from FTY720- and vehicle-treated mice.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('growth-inhibition', 'CPA', (103, 120))	('FTY720', 'Var', (149, 155))	('tumor', 'Disease', (170, 175))	('FTY720', 'Chemical', 'MESH:D000068876', (32, 38))	('tumor', 'Disease', (75, 80))	('tumors', 'Disease', (239, 245))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (239, 244))	('FTY720', 'Chemical', 'MESH:D000068876', (149, 155))	('FTY720-', 'Var', (251, 258))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mice', 'Species', '10090', (279, 283))	('FTY720', 'Chemical', 'MESH:D000068876', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lipid', 'Chemical', 'MESH:D008055', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))
494469	33467731	A signal at 308.25 m/z corresponding to FTY720 was clearly detected in the tumor and only in the treatment group (Figure S8C).	('FTY720', 'Chemical', 'MESH:D000068876', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('FTY720', 'Var', (40, 46))	('tumor', 'Disease', (75, 80))
494472	33467731	In particular, as shown in Table 1 and Figure S8F, the single treatment with FTY720 significantly affected the sphingolipid pathway, providing additional evidence that this drug has the potential to be used as anticancer treatment to target the downstream pro-survival effects induced by intratumoral acidity and mediated by lipid accumulation and sphingolipid pathway activation in OS cells.	('sphingolipid pathway', 'Pathway', (348, 368))	('activation', 'PosReg', (369, 379))	('cancer', 'Disease', (214, 220))	('affected', 'Reg', (98, 106))	('lipid', 'Chemical', 'MESH:D008055', (325, 330))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('sphingolipid pathway', 'Pathway', (111, 131))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('lipid', 'Chemical', 'MESH:D008055', (355, 360))	('sphingolipid', 'Chemical', 'MESH:D013107', (111, 123))	('tumor', 'Disease', (293, 298))	('sphingolipid', 'Chemical', 'MESH:D013107', (348, 360))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lipid', 'Chemical', 'MESH:D008055', (118, 123))	('FTY720', 'Chemical', 'MESH:D000068876', (77, 83))	('FTY720', 'Var', (77, 83))
494493	33467731	S1P accumulation is known to activate oncogenic signaling and, through an autocrine circuit, it inhibits apoptosis, induces cell proliferation and/or migration and increases drug resistance.	('drug resistance', 'CPA', (174, 189))	('inhibits', 'NegReg', (96, 104))	('accumulation', 'Var', (4, 16))	('increases', 'PosReg', (164, 173))	('drug resistance', 'Phenotype', 'HP:0020174', (174, 189))	('apoptosis', 'CPA', (105, 114))	('S1P', 'Gene', '13609', (0, 3))	('cell proliferation', 'CPA', (124, 142))	('S1P', 'Gene', (0, 3))	('activate', 'PosReg', (29, 37))	('oncogenic', 'CPA', (38, 47))	('induces', 'PosReg', (116, 123))
494495	33467731	Subsequently, to confirm the role of S1P in OS cells surviving in an acidic TME, we used FTY720, a modulator of the sphingomyelin pathway and of S1P receptor.	('S1P', 'Gene', '13609', (37, 40))	('FTY720', 'Chemical', 'MESH:D000068876', (89, 95))	('FTY720', 'Var', (89, 95))	('sphingomyelin', 'Chemical', 'MESH:D013109', (116, 129))	('S1P', 'Gene', (37, 40))	('sphingomyelin pathway', 'Pathway', (116, 137))	('S1P', 'Gene', '13609', (145, 148))	('S1P', 'Gene', (145, 148))
494496	33467731	FTY720 is FDA approved for the treatment of multiple sclerosis, and it is currently under trial for the treatment of breast carcinoma, glioblastoma and anaplastic astrocytoma (NCT03941743 and NCT02490930).	('breast carcinoma', 'Phenotype', 'HP:0003002', (117, 133))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('glioblastoma and anaplastic astrocytoma', 'Disease', 'MESH:D001254', (135, 174))	('multiple sclerosis', 'Disease', (44, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('NCT02490930', 'Var', (192, 203))	('multiple sclerosis', 'Disease', 'MESH:D009103', (44, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (163, 174))	('breast carcinoma', 'Disease', 'MESH:D001943', (117, 133))	('breast carcinoma', 'Disease', (117, 133))	('NCT03941743', 'Var', (176, 187))
494497	33467731	FTY720 has several anticancer effects but its activity in OS has not been explored so far.	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('FTY720', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
494498	33467731	Despite being considered an S1P receptor modulator, FTY720 is also able to induce changes in the enzymes of the sphingolipid pathway, including SPHK1, thus providing an explanation for the reduction of S1P seen in our model.	('sphingolipid', 'Chemical', 'MESH:D013107', (112, 124))	('SPHK1', 'Gene', (144, 149))	('FTY720', 'Chemical', 'MESH:D000068876', (52, 58))	('FTY720', 'Var', (52, 58))	('changes', 'Reg', (82, 89))	('S1P', 'Gene', '13609', (202, 205))	('enzymes', 'MPA', (97, 104))	('sphingolipid pathway', 'Pathway', (112, 132))	('SPHK1', 'Gene', '8877', (144, 149))	('S1P', 'Gene', '13609', (28, 31))	('reduction', 'NegReg', (189, 198))	('S1P', 'Gene', (202, 205))	('S1P', 'Gene', (28, 31))
494499	33467731	FTY720 inhibited LD and S1P accumulation in acid-treated spheroids, and, as a consequence, impaired cell survival and migration.	('impaired', 'NegReg', (91, 99))	('spheroids', 'Chemical', '-', (57, 66))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('cell survival', 'CPA', (100, 113))	('FTY720', 'Var', (0, 6))	('S1P', 'Gene', '13609', (24, 27))	('inhibited', 'NegReg', (7, 16))	('S1P', 'Gene', (24, 27))
494501	33467731	Indeed, we found that FTY720 treatment in acid-stressed cells blocked the expression of TRAF and BIRC2/3, possibly by blocking S1P.	('expression', 'MPA', (74, 84))	('blocking', 'NegReg', (118, 126))	('S1P', 'Gene', '13609', (127, 130))	('BIRC2', 'Gene', '329', (97, 102))	('TRAF', 'Gene', (88, 92))	('FTY720', 'Chemical', 'MESH:D000068876', (22, 28))	('S1P', 'Gene', (127, 130))	('blocked', 'NegReg', (62, 69))	('FTY720', 'Var', (22, 28))	('BIRC2', 'Gene', (97, 102))
494509	33467731	We sought to administer FTY720 in combination with a low serine/glycine diet in order to impair both the de novo synthesis and the recycling pathway that, according to in vitro data, are activated, respectively, by the neutral and acidic area of the tumor microenvironment.	('de novo synthesis', 'MPA', (105, 122))	('impair', 'NegReg', (89, 95))	('FTY720', 'Var', (24, 30))	('recycling pathway', 'Pathway', (131, 148))	('FTY720', 'Chemical', 'MESH:D000068876', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (250, 255))	('serine', 'Chemical', 'MESH:D012694', (57, 63))	('glycine', 'Chemical', 'MESH:D005998', (64, 71))
494513	33467731	In OS xenografts, combining FTY720 to a serine/glycine restrictive diet significantly affected the sphingomyelin pathway, tumor growth and fat fraction.	('serine', 'Chemical', 'MESH:D012694', (40, 46))	('FTY720', 'Var', (28, 34))	('FTY720', 'Chemical', 'MESH:D000068876', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('sphingomyelin', 'Chemical', 'MESH:D013109', (99, 112))	('restrictive diet', 'Phenotype', 'HP:0000723', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('affected', 'Reg', (86, 94))	('sphingomyelin pathway', 'Pathway', (99, 120))	('fat fraction', 'MPA', (139, 151))	('tumor', 'Disease', (122, 127))	('glycine', 'Chemical', 'MESH:D005998', (47, 54))
494547	33467731	The antibodies were as follow: anti-LC3 1:1000 (Cell Signaling, #2775s); anti-p62 1:1000 (BD, #610833); anti TBP 1:1000 (Santa Cruz, #sc-204, Santa Cruz, CA, USA).	('TBP 1', 'Gene', (109, 114))	('TBP 1', 'Gene', '7132', (109, 114))	('p62 1', 'Gene', '55729', (78, 83))	('anti-LC3', 'Var', (31, 39))	('p62 1', 'Gene', (78, 83))
494575	33467731	The following adduct species were searched: [M + H]+, [M + NH4]+, [M + H - H2O]+, [M + Na]+, and [M + K]+.	('[M + NH4]+', 'Var', (54, 64))	('[M + K]+', 'Var', (97, 105))	('[M + Na]+', 'Var', (82, 91))	('H2O', 'Chemical', '-', (75, 78))	('[M + H - H2O]+', 'Var', (66, 80))
494603	33467731	As serine uptake supports the Warburg effect, the therapeutic utility of the S1P inhibitor FTY720 could be supplemented by dietary restriction of serine/glycine.	('S1P', 'Gene', '13609', (77, 80))	('serine', 'Chemical', 'MESH:D012694', (3, 9))	('S1P', 'Gene', (77, 80))	('serine uptake', 'MPA', (3, 16))	('Warburg effect', 'CPA', (30, 44))	('glycine', 'Chemical', 'MESH:D005998', (153, 160))	('serine', 'Chemical', 'MESH:D012694', (146, 152))	('FTY720', 'Chemical', 'MESH:D000068876', (91, 97))	('FTY720', 'Var', (91, 97))
494606	33467731	In the latter case, FTY720 would impinge on the acid-resistant tumor subpopulation that normally resists anti-proliferative strategies.	('tumor', 'Disease', (63, 68))	('FTY720', 'Var', (20, 26))	('FTY720', 'Chemical', 'MESH:D000068876', (20, 26))	('impinge', 'Reg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
494671	33362974	In our study, the positive immunohistochemistry showed the following: vimentin (12/14, 85.7%), SMA (33/36, 91.7%), CD34 (7/11, 63.6%), Bcl-2 (14/18, 77.8%), beta-catenin (12/18, 66.7%), CK (5/10, 50%), ALK (+) (10/14, 71.4%), and EMA (1/12, 8.3%), respectively.	('vimentin', 'Gene', '7431', (70, 78))	('beta-catenin', 'Gene', '1499', (157, 169))	('CD34', 'Var', (115, 119))	('vimentin', 'Gene', (70, 78))	('Bcl-2', 'Gene', (135, 140))	('Bcl-2', 'Gene', '596', (135, 140))	('ALK', 'Gene', (202, 205))	('EMA', 'CPA', (230, 233))	('beta-catenin', 'Gene', (157, 169))	('ALK', 'Gene', '238', (202, 205))	('CK', 'Gene', '51727', (186, 188))
494684	33362974	As the table shows, patients with age <=25 (p = 0.03), initial admission (p = 0.003), Ki-67 >=5% (p = 0.007), multicentricity (p = 0.015), metastatic pathology (p = 0.008) and piecemeal surgical treatment (p = 0.001) had lower DFS.	('age', 'Gene', (34, 37))	('lower', 'NegReg', (221, 226))	('metastatic pathology', 'CPA', (139, 159))	('patients', 'Species', '9606', (20, 28))	('DFS', 'MPA', (227, 230))	('multicentricity', 'Var', (110, 125))	('Ki-67', 'Chemical', '-', (86, 91))	('age', 'Gene', '5973', (34, 37))
494703	33362974	The Ki-67 labeling index could be relevant to detecting tumor multiplication, knowing that a mesenchymal neoplasm with a high degree of Ki-67 tended to proliferate more rapidly.	('Ki-67', 'Var', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Ki-67', 'Chemical', '-', (136, 141))	('tumor', 'Disease', (56, 61))	('Ki-67', 'Chemical', '-', (4, 9))	('neoplasm', 'Disease', (105, 113))	('proliferate', 'CPA', (152, 163))	('neoplasm', 'Phenotype', 'HP:0002664', (105, 113))	('neoplasm', 'Disease', 'MESH:D009369', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
494790	30621224	Expression of mutated form of c-Kit is usually observed in gastrointestinal stromal tumors (GISTs), and GISTs usually respond to imatinib mesylate.	('mutated', 'Var', (14, 21))	('c-Kit', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('observed', 'Reg', (47, 55))	('c-Kit', 'Gene', '3815', (30, 35))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (59, 90))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (59, 90))	('GISTs', 'Phenotype', 'HP:0100723', (104, 109))	('respond', 'Reg', (118, 125))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (129, 146))	('GISTs', 'Phenotype', 'HP:0100723', (92, 97))	('gastrointestinal stromal tumors', 'Disease', (59, 90))
494808	30621224	Rogorafenib is a multikinase inhibitor targeting tumor cells, vasculature, angiogenesis, and the tumor microenvironment by blocking the activity of several protein kinases, including those involved in the regulation of angiogenesis (VEGFR-1, VEGFR-2, and VEGFR-3, and TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, and BRAFV600E), and tumor microenvironment (PDGFR and FGFR).	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('VEGFR-1', 'Gene', (233, 240))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('VEGFR-3', 'Gene', (255, 262))	('VEGFR-2', 'Gene', '3791', (242, 249))	('activity', 'MPA', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('RET', 'Gene', '5979', (293, 296))	('tumor', 'Disease', (97, 102))	('KIT', 'Var', (288, 291))	('VEGFR-1', 'Gene', '2321', (233, 240))	('BRAFV600E', 'Mutation', 'rs113488022', (315, 324))	('VEGFR-2', 'Gene', (242, 249))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('PDGFR', 'Gene', (355, 360))	('PDGFR', 'Gene', '5159', (355, 360))	('BRAF', 'Gene', '673', (315, 319))	('tumor', 'Disease', (49, 54))	('Rogorafenib', 'Chemical', '-', (0, 11))	('TIE2', 'Gene', (268, 272))	('BRAF', 'Gene', (315, 319))	('TIE2', 'Gene', '7010', (268, 272))	('RET', 'Gene', (293, 296))	('RAF-1', 'Gene', '5894', (298, 303))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('VEGFR-3', 'Gene', '2324', (255, 262))	('BRAF', 'Gene', '673', (305, 309))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('RAF-1', 'Gene', (298, 303))	('BRAF', 'Gene', (305, 309))	('tumor', 'Disease', (331, 336))	('blocking', 'NegReg', (123, 131))	('angiogenesis', 'CPA', (219, 231))	('protein kinases', 'Enzyme', (156, 171))
494822	30621224	TRC105 inhibits angiogenesis, tumor growth, and metastases in preclinical models and complements the activity of multi-kinase VEGFRI.	('angiogenesis', 'CPA', (16, 28))	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('inhibits', 'NegReg', (7, 15))	('VEGF', 'Gene', '7422', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TRC105', 'Var', (0, 6))	('VEGF', 'Gene', (126, 130))	('tumor', 'Disease', (30, 35))	('metastases', 'Disease', (48, 58))
494838	30621224	Eribulin inhibits microtubule polymerization through a specific binding site on beta-tubulin and has tubulin-based antimitotic effect and disrupts mitotic spindle formation by arresting the cells in G2-phase and M-phase.	('binding', 'Interaction', (64, 71))	('arresting', 'Reg', (176, 185))	('Eribulin', 'Chemical', 'MESH:C490954', (0, 8))	('G2-phase', 'CPA', (199, 207))	('M-phase', 'CPA', (212, 219))	('beta-tubulin', 'Protein', (80, 92))	('microtubule polymerization', 'MPA', (18, 44))	('antimitotic effect', 'MPA', (115, 133))	('disrupts', 'NegReg', (138, 146))	('mitotic spindle formation', 'CPA', (147, 172))	('inhibits', 'NegReg', (9, 17))	('Eribulin', 'Var', (0, 8))
494845	30621224	The study demonstrated a statistically significant improvement of two months in overall survival in patients treated with eribulin, compared with patients treated with dacarbazine, although no significant improvement in progression-free survival rates was observed.	('improvement', 'PosReg', (51, 62))	('overall survival', 'MPA', (80, 96))	('eribulin', 'Var', (122, 130))	('dacarbazine', 'Chemical', 'MESH:D003606', (168, 179))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (146, 154))
494922	26555224	Genome-wide association studies (GWAS) have led to the identification of over a thousand genomic regions that harbor sequence variants affecting risk for numerous diseases and other phenotypic traits.	('affecting', 'Reg', (135, 144))	('numerous diseases', 'Disease', (154, 171))	('variants', 'Var', (126, 134))	('numerous diseases', 'Disease', 'MESH:D004194', (154, 171))
494935	26555224	The promoter region of the UGT1A1 gene was first sequenced in patients with Gilbert's syndrome who were found to be homozygous for the UGT1A1*28 variant.	("Gilbert's syndrome", 'Disease', 'MESH:D005878', (76, 94))	('UGT1A1', 'Gene', '54658', (27, 33))	('UGT1A1', 'Gene', '54658', (135, 141))	('UGT1A1', 'Gene', (27, 33))	('UGT1A1', 'Gene', (135, 141))	("Gilbert's syndrome", 'Disease', (76, 94))	('patients', 'Species', '9606', (62, 70))	('variant', 'Var', (145, 152))
494937	26555224	The UGT1A1*28 variant was associated with significantly decreased UGT1A1 expression levels.	('UGT1A1', 'Gene', '54658', (4, 10))	('UGT1A1', 'Gene', '54658', (66, 72))	('UGT1A1', 'Gene', (4, 10))	('expression levels', 'MPA', (73, 90))	('decreased', 'NegReg', (56, 65))	('UGT1A1', 'Gene', (66, 72))	('variant', 'Var', (14, 21))
494943	26555224	The activation of LXRalpha by GW3965, a liver X receptor agonist (activator) of human LXRalpha, induced the expression of SULT2A1 at mRNA, protein and enzymatic levels.	('LXRalpha', 'Gene', (86, 94))	('GW3965', 'Var', (30, 36))	('LXRalpha', 'Gene', '10062', (18, 26))	('LXRalpha', 'Gene', '10062', (86, 94))	('SULT2A1', 'Gene', (122, 129))	('GW3965', 'Chemical', 'MESH:C473027', (30, 36))	('human', 'Species', '9606', (80, 85))	('expression', 'MPA', (108, 118))	('SULT2A1', 'Gene', '6822', (122, 129))	('LXRalpha', 'Gene', (18, 26))
494947	26555224	Mutation of this putative DR4 in the context of the 500 bp promoter abolished the transactivation by LXRalpha.	('abolished', 'NegReg', (68, 77))	('transactivation by', 'MPA', (82, 100))	('LXRalpha', 'Gene', (101, 109))	('DR4', 'Gene', (26, 29))	('Mutation', 'Var', (0, 8))	('LXRalpha', 'Gene', '10062', (101, 109))	('DR4', 'Gene', '3126', (26, 29))
494952	26555224	Ewing's sarcoma patients with higher SLFN11 expression showed better tumor-free survival rate.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	("Ewing's sarcoma", 'Disease', (0, 15))	('expression', 'MPA', (44, 54))	('higher', 'Var', (30, 36))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('tumor', 'Disease', (69, 74))	('SLFN11', 'Gene', (37, 43))	('better', 'PosReg', (62, 68))	('patients', 'Species', '9606', (16, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('SLFN11', 'Gene', '91607', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))
494956	26555224	To determine the relative contribution of the putative FLI1-binding site(s) to the EWS-FLI1-induced SLFN11 promoter activity, three SLFN11 promoter mutations were tested by site-directed mutagenesis (mt+91, mt+181, mt+201).	('SLFN11', 'Gene', (100, 106))	('EWS', 'Gene', '2130', (83, 86))	('SLFN11', 'Gene', (132, 138))	('FLI1', 'Gene', (55, 59))	('EWS', 'Gene', (83, 86))	('FLI1', 'Gene', '2313', (87, 91))	('FLI1', 'Gene', (87, 91))	('FLI1', 'Gene', '2313', (55, 59))	('SLFN11', 'Gene', '91607', (100, 106))	('mt+181', 'Var', (207, 213))	('SLFN11', 'Gene', '91607', (132, 138))	('mt+91', 'Var', (200, 205))	('mt+201', 'Var', (215, 221))
494957	26555224	Luciferase reporter assays showed that individual mutations at positions +91 and +201 reduced SLFN11 promoter activity by more than 80%, whereas the +181 mutation had no significant effect.	('reduced', 'NegReg', (86, 93))	('promoter activity', 'MPA', (101, 118))	('SLFN11', 'Gene', (94, 100))	('mutations', 'Var', (50, 59))	('SLFN11', 'Gene', '91607', (94, 100))
494958	26555224	SLFN11 promoter activity in 293T/EWS-FLI1 cells was also suppressed by approximately 90% for mt+91 and 50% for mt+201, whereas mt+181 did not affect SLFN11 promoter activity.	('SLFN11', 'Gene', (149, 155))	('SLFN11', 'Gene', '91607', (0, 6))	('293T', 'CellLine', 'CVCL:0063', (28, 32))	('mt+201', 'Var', (111, 117))	('EWS', 'Gene', '2130', (33, 36))	('EWS', 'Gene', (33, 36))	('SLFN11', 'Gene', '91607', (149, 155))	('FLI1', 'Gene', (37, 41))	('mt+91', 'Var', (93, 98))	('promoter activity', 'MPA', (7, 24))	('FLI1', 'Gene', '2313', (37, 41))	('SLFN11', 'Gene', (0, 6))	('suppressed', 'NegReg', (57, 67))
494978	26555224	Notably, mutation of DR4-1 completely abolished its response to PXR, whereas the DR4-2 mutant only exhibited a moderate decrease in PXR-based activation.	('mutation', 'Var', (9, 17))	('abolished', 'NegReg', (38, 47))	('DR4', 'Gene', '3126', (21, 24))	('DR4', 'Gene', (81, 84))	('PXR', 'Gene', (64, 67))	('decrease', 'NegReg', (120, 128))	('PXR', 'Gene', '8856', (64, 67))	('mutant', 'Var', (87, 93))	('PXR', 'Gene', (132, 135))	('DR4', 'Gene', (21, 24))	('DR4', 'Gene', '3126', (81, 84))	('PXR', 'Gene', '8856', (132, 135))
494979	26555224	Functional analysis further revealed that SLC13A5 induction was positively correlated with rifampin-mediated fat accumulation in human primary hepatocytes, whereas knockdown of SLC13A5 significantly decreased lipid content in HepG2 cells.	('lipid content', 'MPA', (209, 222))	('lipid', 'Chemical', 'MESH:D008055', (209, 214))	('decreased', 'NegReg', (199, 208))	('SLC13A5', 'Gene', (42, 49))	('rifampin', 'Chemical', 'MESH:D012293', (91, 99))	('HepG2', 'CellLine', 'CVCL:0027', (226, 231))	('SLC13A5', 'Gene', '284111', (42, 49))	('knockdown', 'Var', (164, 173))	('SLC13A5', 'Gene', (177, 184))	('human', 'Species', '9606', (129, 134))	('SLC13A5', 'Gene', '284111', (177, 184))	('rifampin-mediated fat accumulation', 'MPA', (91, 125))
494983	26555224	Two linked SNPs (rs5758550 and rs133333) were identified in an enhancer region located approximately 115 kb downstream of the CYP2D6 gene that are associated with greater than twofold increased CYP2D6 transcription.	('CYP2D6', 'Gene', '1565', (126, 132))	('CYP2D6', 'Gene', (126, 132))	('rs5758550', 'Mutation', 'rs5758550', (17, 26))	('increased', 'PosReg', (184, 193))	('rs133333', 'Var', (31, 39))	('transcription', 'MPA', (201, 214))	('CYP2D6', 'Gene', '1565', (194, 200))	('rs133333', 'Mutation', 'rs133333', (31, 39))	('rs5758550', 'Var', (17, 26))	('CYP2D6', 'Gene', (194, 200))
494986	26555224	The previously identified enhancer region was confirmed as having robust effects on CYP2D6 expression, and reporter gene assays identified rs5758550 as the regulatory SNP involved in increasing CYP2D6 transcription.	('CYP2D6', 'Gene', (84, 90))	('effects', 'Reg', (73, 80))	('rs5758550', 'Var', (139, 148))	('transcription', 'MPA', (201, 214))	('CYP2D6', 'Gene', '1565', (194, 200))	('CYP2D6', 'Gene', '1565', (84, 90))	('increasing', 'PosReg', (183, 193))	('CYP2D6', 'Gene', (194, 200))	('rs5758550', 'Mutation', 'rs5758550', (139, 148))
494987	26555224	CRISPR-mediated deletion in HepG2 cells of the enhancer region surrounding rs5758550 resulted in 70% decreased CYP2D6 expression.	('rs5758550', 'Mutation', 'rs5758550', (75, 84))	('deletion', 'Var', (16, 24))	('CYP2D6', 'Gene', '1565', (111, 117))	('decreased', 'NegReg', (101, 110))	('rs5758550', 'Var', (75, 84))	('CYP2D6', 'Gene', (111, 117))	('HepG2', 'CellLine', 'CVCL:0027', (28, 33))
494988	26555224	The minor allele of the SNP rs5758550 (G) was shown to increase enhancer activity in HepG2 cells.	('increase', 'PosReg', (55, 63))	('rs5758550', 'Mutation', 'rs5758550', (28, 37))	('enhancer activity', 'MPA', (64, 81))	('HepG2', 'CellLine', 'CVCL:0027', (85, 90))	('rs5758550', 'Var', (28, 37))
494989	26555224	Combined, these studies show robust effects of both the enhancer element and the SNP rs5758550 on CYP2D6 expression.	('CYP2D6', 'Gene', '1565', (98, 104))	('enhancer', 'PosReg', (56, 64))	('rs5758550', 'Mutation', 'rs5758550', (85, 94))	('CYP2D6', 'Gene', (98, 104))	('rs5758550', 'Var', (85, 94))	('expression', 'MPA', (105, 115))
494991	26555224	A haplotype of VKORC1 gene carrying the minor allele for five SNPs located in the promoter and intragenic regions, including the promoter SNP -1639G>A (rs9923231, Supplementary Table 1), was associated with lower mRNA expression and lower warfarin maintenance dose.	('VKORC1', 'Gene', (15, 21))	('VKORC1', 'Gene', '79001', (15, 21))	('warfarin maintenance dose', 'MPA', (239, 264))	('lower', 'NegReg', (233, 238))	('mRNA expression', 'MPA', (213, 228))	('-1639G>A', 'Mutation', 'rs9923231', (142, 150))	('warfarin', 'Chemical', 'MESH:D014859', (239, 247))	('rs9923231', 'Mutation', 'rs9923231', (152, 161))	('lower', 'NegReg', (207, 212))	('rs9923231', 'Var', (152, 161))
494992	26555224	However, how and where the SNP -1639G>A reduces promoter activity was not known.	('reduces', 'NegReg', (40, 47))	('SNP -1639G>A', 'Var', (27, 39))	('promoter activity', 'MPA', (48, 65))	('-1639G>A', 'Mutation', 'rs9923231', (31, 39))
494996	26555224	ChIP with antibodies against H3K4me3 or acetyl-Histone H3 (Lys 4) (H3K4ac) revealed preferential association of the promoter -1639G allele with active chromatin, consistent with enhanced mRNA expression.	('Lys', 'Chemical', 'MESH:D008239', (59, 62))	('enhanced', 'PosReg', (178, 186))	('acetyl-Histone', 'Chemical', '-', (40, 54))	('promoter -1639G', 'Var', (116, 131))	('association', 'Interaction', (97, 108))	('mRNA expression', 'MPA', (187, 202))
494997	26555224	The minor -1639A allele is thought to generate a suppressor E-box-binding site, which could lead to lower VKORC1 expression, and a lower effective dose of warfarin.	('expression', 'MPA', (113, 123))	('warfarin', 'Chemical', 'MESH:D014859', (155, 163))	('VKORC1', 'Gene', (106, 112))	('lower', 'NegReg', (100, 105))	('VKORC1', 'Gene', '79001', (106, 112))	('lower', 'NegReg', (131, 136))	('minor -1639A', 'Var', (4, 16))
494998	26555224	Thus, the common variant in the VKORC1 promoter region (-1639G>A, rs9923231) can explain much of the variability in average dose requirements among Caucasians, and it is incorporated in the warfarin-dosing algorithm to improve warfarin treatment outcome.	('rs9923231', 'Var', (66, 75))	('-1639G>A', 'Var', (56, 64))	('VKORC1', 'Gene', '79001', (32, 38))	('warfarin', 'Chemical', 'MESH:D014859', (227, 235))	('improve', 'PosReg', (219, 226))	('warfarin', 'Chemical', 'MESH:D014859', (190, 198))	('rs9923231', 'Mutation', 'rs9923231', (66, 75))	('VKORC1', 'Gene', (32, 38))	('-1639G>A', 'Mutation', 'rs9923231', (56, 64))
494999	26555224	SNPs associated with chemotherapeutic agent-induced cytotoxicity for six different anticancer agents were systematically evaluated for their genomic regions and their functional class, such as coding (consisting of missense, nonsense or frameshift polymorphisms), noncoding (such as 3' UTRs or splice sites) or eQTLs.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('nonsense', 'Var', (225, 233))	('cytotoxicity', 'Disease', 'MESH:D064420', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('missense', 'Var', (215, 223))	('cytotoxicity', 'Disease', (52, 64))
495000	26555224	For example, the SNP rs1649942 is associated with sensitivity for both carboplatin and cisplatin, and with the transcriptional expression level of 39 genes throughout the genome.	('transcriptional expression level', 'MPA', (111, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('associated', 'Reg', (34, 44))	('SNP rs1649942', 'Var', (17, 30))	('rs1649942', 'Mutation', 'rs1649942', (21, 30))	('sensitivity', 'MPA', (50, 61))	('carboplatin', 'Chemical', 'MESH:D016190', (71, 82))	('cisplatin', 'MPA', (87, 96))
495002	26555224	RNA-seq and ChIP-seq were performed by using antibodies against PXR and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control.	('PXR', 'Gene', (64, 67))	('human', 'Species', '9606', (138, 143))	('rifampin', 'Chemical', 'MESH:D012293', (169, 177))	('p300', 'Gene', (103, 107))	('PXR', 'Gene', '8856', (64, 67))	('H3K27ac', 'Var', (118, 125))	('H3K4me1', 'Var', (109, 116))	('p300', 'Gene', '2033', (103, 107))
495105	24298557	The indispensable role of a downstream pseudoknot in efficient -1 frameshifting has been established in a large number of RNA viruses including members from the retroviridae family, coronaviridae family (such as SARS CoV), totiviridae family, and Luteoviridae family.	('SARS', 'Gene', (212, 216))	('SARS CoV', 'Species', '227859', (212, 220))	('frameshifting', 'Var', (66, 79))	('SARS', 'Gene', '6301', (212, 216))
495119	24298557	While pseudoknots were detected shortly downstream from the frame-shift or read-through sites in most of the viral sequences using the default ranges of stem and loop lengths, the default search did miss some known cases, such as the frameshift stimulator pseudoknot in human coronavirus 229E that has a 164 nt L2.	('human coronavirus 229E', 'Species', '11137', (270, 292))	('pseudoknot', 'Var', (256, 266))	('frameshift stimulator', 'Reg', (234, 255))
495137	20601955	PIK3CA mutations in myxoid/round-cell liposarcomas were associated with AKT activation and poor clinical outcomes.	('AKT', 'Gene', '207', (72, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('AKT', 'Gene', (72, 75))	('PIK3CA', 'Gene', (0, 6))	('liposarcomas', 'Phenotype', 'HP:0012034', (38, 50))	('PIK3CA', 'Gene', '5290', (0, 6))	('liposarcomas', 'Disease', 'MESH:D008080', (38, 50))	('liposarcoma', 'Phenotype', 'HP:0012034', (38, 49))	('liposarcomas', 'Disease', (38, 50))	('activation', 'PosReg', (76, 86))	('myxoid/round-cell liposarcoma', 'Phenotype', 'HP:0012268', (20, 49))	('mutations', 'Var', (7, 16))
495139	20601955	Finally, we found that shRNA-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation.	('knockdown', 'Var', (35, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('CDK4', 'Gene', (115, 119))	('YEATS4', 'Gene', '8089', (124, 130))	('liposarcoma', 'Disease', (92, 103))	('CDK4', 'Gene', '1019', (115, 119))	('liposarcoma', 'Disease', 'MESH:D008080', (92, 103))	('cell proliferation', 'CPA', (142, 160))	('YEATS4', 'Gene', (124, 130))	('liposarcoma', 'Phenotype', 'HP:0012034', (92, 103))	('decreased', 'NegReg', (132, 141))
495142	20601955	Subtypes with simple, near-diploid karyotypes bear few chromosomal rearrangements but have pathognomonic alterations: translocations in myxoid/round-cell liposarcoma (MRC) [t(12;16)(q13;p11), t(12;22)(q13;q12)] and synovial sarcomas (SS) [t(X;18)(p11;q11)]; activating mutations in KIT or PDGFRA in gastrointestinal stromal tumors (GIST).	('gastrointestinal stromal tumors', 'Disease', (299, 330))	('liposarcoma', 'Disease', (154, 165))	('GIST', 'Phenotype', 'HP:0100723', (332, 336))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (215, 232))	('myxoid/round-cell liposarcoma', 'Phenotype', 'HP:0012268', (136, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('synovial sarcomas', 'Disease', (215, 232))	('KIT', 'Gene', (282, 285))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (173, 190))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('SS', 'Phenotype', 'HP:0100242', (234, 236))	('liposarcoma', 'Phenotype', 'HP:0012034', (154, 165))	('synovial sarcomas', 'Disease', 'MESH:D013584', (215, 232))	('mutations', 'Var', (269, 278))	('activating', 'PosReg', (258, 268))	('PDGFRA', 'Gene', (289, 295))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (215, 231))	('MRC', 'Phenotype', 'HP:0012268', (167, 170))	('PDGFRA', 'Gene', '5156', (289, 295))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (192, 209))	('liposarcoma', 'Disease', 'MESH:D008080', (154, 165))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (299, 330))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (299, 330))	('sarcomas', 'Phenotype', 'HP:0100242', (224, 232))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (239, 255))	('MRC', 'CellLine', 'CVCL:0440', (167, 170))
495148	20601955	To study the genomic alterations in sarcomas, we initially analyzed 47 tumor/normal DNA pairs encompassing six soft tissue sarcoma subtypes by sequencing 722 protein-coding and microRNA genes, followed by verifying discovered mutations with mass spectrometry-based genotyping (see Methods, Supplementary Figure 1A, and Supplementary Table 2).	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (123, 139))	('sarcoma subtypes', 'Disease', (123, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutations', 'Var', (226, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('tumor', 'Disease', (71, 76))	('sarcomas', 'Disease', (36, 44))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (111, 130))
495149	20601955	The results revealed 28 somatic non-synonymous coding point mutations and 9 somatic insertions/deletions (indels) involving 21 genes in total (Table 2 and Supplementary Figure 1B).	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (155, 178))	('insertions/deletions', 'Var', (84, 104))	('Supplementary Figure 1B', 'Disease', (155, 178))
495150	20601955	We extended the analysis to an additional 160 tumors, where we genotyped each of the mutations found above and re-sequenced exons of NF1 and ERBB4 in pleomorphic liposarcoma and myxofibrosarcoma, PIK3CA and KIT in myxoid/round cell liposarcoma, and CDH1 in dedifferentiated liposarcoma; this revealed nine additional mutations (Table 2 and Supplementary Table 3).	('liposarcoma', 'Disease', (274, 285))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PIK3CA', 'Gene', (196, 202))	('NF1', 'Gene', '4763', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('liposarcoma', 'Disease', (162, 173))	('pleomorphic liposarcoma and myxofibrosarcoma', 'Disease', 'MESH:D008080', (150, 194))	('liposarcoma', 'Disease', (232, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (278, 285))	('ERBB4', 'Gene', '2066', (141, 146))	('NF1', 'Gene', (133, 136))	('liposarcoma', 'Phenotype', 'HP:0012034', (274, 285))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('tumors', 'Disease', (46, 52))	('CDH1', 'Gene', '999', (249, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('ERBB4', 'Gene', (141, 146))	('liposarcoma', 'Phenotype', 'HP:0012034', (162, 173))	('KIT', 'Gene', (207, 210))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (214, 243))	('PIK3CA', 'Gene', '5290', (196, 202))	('liposarcoma', 'Phenotype', 'HP:0012034', (232, 243))	('liposarcoma', 'Disease', 'MESH:D008080', (274, 285))	('mutations', 'Var', (85, 94))	('CDH1', 'Gene', (249, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('liposarcoma', 'Disease', 'MESH:D008080', (162, 173))	('liposarcoma', 'Disease', 'MESH:D008080', (232, 243))
495151	20601955	KIT was frequently mutated in GISTs and unexpectedly, in one myxoid/round cell liposarcoma sample (Supplementary Note).	('liposarcoma', 'Phenotype', 'HP:0012034', (79, 90))	('liposarcoma', 'Disease', 'MESH:D008080', (79, 90))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (61, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('GIST', 'Phenotype', 'HP:0100723', (30, 34))	('mutated', 'Var', (19, 26))	('liposarcoma', 'Disease', (79, 90))	('KIT', 'Gene', (0, 3))
495153	20601955	Additional genes, including protein and lipid kinases, as well as known or candidate tumor suppressor genes, were found mutated in just one sample for each sarcoma subtype (Table 2, Figure 1, and Supplementary Note).	('tumor', 'Disease', (85, 90))	('protein', 'Enzyme', (28, 35))	('sarcoma subtype', 'Disease', (156, 171))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('sarcoma subtype', 'Disease', 'MESH:D012509', (156, 171))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutated', 'Var', (120, 127))
495154	20601955	Further studies will be needed to establish the functional impact of these mutations in sarcoma.	('sarcoma', 'Disease', (88, 95))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('mutations', 'Var', (75, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
495155	20601955	Below, we focus on three major specific genomic findings with therapeutic implications: point mutation and deletion of NF1 in a subset of soft tissue sarcomas, point mutation of PIK3CA in myxoid/round cell liposarcoma, and the complex pattern of amplification of chromosome 12q in dedifferentiated liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (206, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (302, 309))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (138, 158))	('NF1', 'Gene', (119, 122))	('liposarcoma', 'Disease', (298, 309))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('point mutation', 'Var', (160, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('liposarcoma', 'Disease', 'MESH:D008080', (206, 217))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))	('PIK3CA', 'Gene', (178, 184))	('sarcomas', 'Disease', (150, 158))	('liposarcoma', 'Phenotype', 'HP:0012034', (298, 309))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (188, 217))	('liposarcoma', 'Disease', (206, 217))	('liposarcoma', 'Disease', 'MESH:D008080', (298, 309))	('deletion', 'Var', (107, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('NF1', 'Gene', '4763', (119, 122))	('PIK3CA', 'Gene', '5290', (178, 184))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (138, 157))	('point mutation', 'Var', (88, 102))
495157	20601955	While germline and somatic inactivation of NF1 is associated with malignant peripheral nerve sheath tumors and GISTs in Neurofibromatosis type 1 patients, no somatic NF1 alterations have been reported in other sarcomas.	('NF1', 'Gene', '4763', (166, 169))	('malignant peripheral nerve sheath tumors', 'Disease', (66, 106))	('Neurofibromatosis type 1', 'Gene', (120, 144))	('NF1', 'Gene', (166, 169))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (120, 137))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('GISTs', 'Disease', (111, 116))	('sarcomas', 'Disease', 'MESH:D012509', (210, 218))	('sarcomas', 'Phenotype', 'HP:0100242', (210, 218))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('sarcomas', 'Disease', (210, 218))	('germline', 'Var', (6, 14))	('NF1', 'Gene', '4763', (43, 46))	('patients', 'Species', '9606', (145, 153))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (66, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('associated', 'Reg', (50, 60))	('NF1', 'Gene', (43, 46))	('Neurofibromatosis type 1', 'Gene', '4763', (120, 144))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (66, 106))	('GIST', 'Phenotype', 'HP:0100723', (111, 115))
495159	20601955	Two of the mutations, R304* and Q369*, were previously reported as germline mutations in patients with Neurofibromatosis type 1, while the other four mutations (three missense and one nonsense) have not been previously reported.	('Neurofibromatosis type 1', 'Gene', (103, 127))	('Neurofibromatosis type 1', 'Gene', '4763', (103, 127))	('R304*', 'Var', (22, 27))	('patients', 'Species', '9606', (89, 97))	('R304*', 'SUBSTITUTION', 'None', (22, 27))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (103, 120))	('Q369*', 'Var', (32, 37))	('Q369*', 'SUBSTITUTION', 'None', (32, 37))
495160	20601955	In some tumors, biallelic inactivation was evident, with heterozygous point mutations accompanied by deletion of the wild-type allele and correspondingly reduced gene expression compared to normal adipose tissue in most cases (Figure 2B).	('deletion', 'Var', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('point mutations', 'Var', (70, 85))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('reduced', 'NegReg', (154, 161))	('gene expression', 'MPA', (162, 177))
495161	20601955	Together, these data indicate a diverse pattern of NF1 aberrations in myxofibrosarcomas and pleomorphic liposarcomas.	('liposarcoma', 'Phenotype', 'HP:0012034', (104, 115))	('aberrations', 'Var', (55, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('liposarcomas', 'Phenotype', 'HP:0012034', (104, 116))	('myxofibrosarcomas and pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (70, 116))	('NF1', 'Gene', (51, 54))	('NF1', 'Gene', '4763', (51, 54))
495164	20601955	Nucleotide substitutions in PIK3CA were initially detected in 4 of 21 myxoid/round-cell liposarcomas (MRCs).	('liposarcomas', 'Phenotype', 'HP:0012034', (88, 100))	('PIK3CA', 'Gene', (28, 34))	('liposarcomas', 'Disease', 'MESH:D008080', (88, 100))	('MRC', 'Phenotype', 'HP:0012268', (102, 105))	('myxoid/round-cell liposarcoma', 'Phenotype', 'HP:0012268', (70, 99))	('liposarcomas', 'Disease', (88, 100))	('liposarcoma', 'Phenotype', 'HP:0012034', (88, 99))	('detected', 'Reg', (50, 58))	('MRC', 'CellLine', 'CVCL:0440', (102, 105))	('PIK3CA', 'Gene', '5290', (28, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('Nucleotide substitutions', 'Var', (0, 24))
495165	20601955	We measured the frequency of point mutations in PIK3CA in this subtype by genotyping an independent cohort of 50 MRCs for 13 common sites of PIK3CA mutation, including those discovered in our initial sequencing; mutations were detected in 9 additional patients (in total, 13 of 71).	('patients', 'Species', '9606', (252, 260))	('PIK3CA', 'Gene', (48, 54))	('MRC', 'Phenotype', 'HP:0012268', (113, 116))	('MRC', 'CellLine', 'CVCL:0440', (113, 116))	('point', 'Var', (29, 34))	('PIK3CA', 'Gene', (141, 147))	('PIK3CA', 'Gene', '5290', (48, 54))	('PIK3CA', 'Gene', '5290', (141, 147))	('mutation', 'Var', (148, 156))
495166	20601955	The mutations were clustered in two domains, the helical domain (E542K and E545K) and the kinase domain (H1047L and H1047R) (Table 2); both these domains are also mutated in epithelial tumors.	('E545K', 'Var', (75, 80))	('E542K', 'Mutation', 'rs121913273', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('H1047R', 'Var', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('epithelial tumors', 'Disease', (174, 191))	('H1047L', 'Mutation', 'rs121913279', (105, 111))	('E542K', 'Var', (65, 70))	('H1047L', 'Var', (105, 111))	('epithelial tumors', 'Disease', 'MESH:D002277', (174, 191))	('H1047R', 'Mutation', 'rs121913279', (116, 122))	('E545K', 'Mutation', 'rs104886003', (75, 80))
495167	20601955	MRC patients whose tumors harbored mutations in PIK3CA had a shorter duration of disease-specific survival than did those with wildtype PIK3CA (p=0.036, log-rank test).	('tumors', 'Disease', (19, 25))	('shorter', 'NegReg', (61, 68))	('PIK3CA', 'Gene', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('disease-specific survival', 'CPA', (81, 106))	('PIK3CA', 'Gene', (48, 54))	('PIK3CA', 'Gene', '5290', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MRC', 'Phenotype', 'HP:0012268', (0, 3))	('PIK3CA', 'Gene', '5290', (48, 54))	('patients', 'Species', '9606', (4, 12))	('MRC', 'CellLine', 'CVCL:0440', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (35, 44))
495168	20601955	Similar to observations in breast cancers, patients with helical-domain PIK3CA mutations had worse outcomes than those with kinase-domain mutations (Figure 3A).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('helical-domain', 'Var', (57, 71))	('patients', 'Species', '9606', (43, 51))	('breast cancers', 'Phenotype', 'HP:0003002', (27, 41))	('PIK3CA', 'Gene', (72, 78))	('breast cancers', 'Disease', 'MESH:D001943', (27, 41))	('breast cancers', 'Disease', (27, 41))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('PIK3CA', 'Gene', '5290', (72, 78))	('mutations', 'Var', (79, 88))
495169	20601955	As both helical- and kinase-domain PIK3CA mutants are believed to activate Akt, although through different mechanisms, we assessed Akt activation in MRC tumors harboring wildtype and mutated PIK3CA.	('helical-', 'Protein', (8, 16))	('mutants', 'Var', (42, 49))	('MRC tumors', 'Disease', (149, 159))	('Akt', 'Gene', '207', (75, 78))	('PIK3CA', 'Gene', '5290', (191, 197))	('mutated', 'Var', (183, 190))	('Akt', 'Gene', (131, 134))	('MRC tumors', 'Disease', 'MESH:D009369', (149, 159))	('Akt', 'Gene', (75, 78))	('activate', 'PosReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('kinase-domain', 'Var', (21, 34))	('PIK3CA', 'Gene', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('MRC', 'Phenotype', 'HP:0012268', (149, 152))	('PIK3CA', 'Gene', '5290', (35, 41))	('PIK3CA', 'Gene', (191, 197))	('Akt', 'Gene', '207', (131, 134))
495170	20601955	Of note, only E545K helical-domain mutations were associated with increased Akt phosphorylation relative to wildtype, both at serine-473 and threonine-308 (TORC2 and PDK1 phosphorylation sites, respectively), and with increased phosphorylation of Akt substrates PRAS40 and S6 kinase (Figure 3B).	('TORC2', 'Gene', (156, 161))	('serine', 'Chemical', 'MESH:D012694', (126, 132))	('increased', 'PosReg', (66, 75))	('threonine', 'Chemical', 'MESH:D013912', (141, 150))	('Akt', 'Gene', (76, 79))	('helical-domain', 'Protein', (20, 34))	('E545K', 'Mutation', 'rs104886003', (14, 19))	('increased', 'PosReg', (218, 227))	('phosphorylation', 'MPA', (228, 243))	('E545K', 'Var', (14, 19))	('Akt', 'Gene', '207', (247, 250))	('PRAS40', 'Gene', '84335', (262, 268))	('PDK1', 'Gene', '5163', (166, 170))	('Akt', 'Gene', '207', (76, 79))	('Akt', 'Gene', (247, 250))	('TORC2', 'Gene', '200186', (156, 161))	('PRAS40', 'Gene', (262, 268))	('PDK1', 'Gene', (166, 170))
495171	20601955	Surprisingly, tumors with H1047R kinase-domain mutations did not have similar increases in Akt phosphorylation or activation (Figure 3B).	('Akt', 'Gene', '207', (91, 94))	('H1047R kinase-domain', 'Var', (26, 46))	('Akt', 'Gene', (91, 94))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('activation', 'MPA', (114, 124))	('H1047R', 'Mutation', 'rs121913279', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('increases', 'PosReg', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
495172	20601955	However, H1047R-mutant tumors exhibited variably higher levels of PTEN, a negative regulator of PI3K activity, which may partly explain lower Akt activity.	('lower', 'NegReg', (136, 141))	('Akt', 'Gene', (142, 145))	('tumors', 'Disease', (23, 29))	('PTEN', 'Gene', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('activity', 'MPA', (146, 154))	('PTEN', 'Gene', '5728', (66, 70))	('H1047R', 'Mutation', 'rs121913279', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('H1047R-mutant', 'Var', (9, 22))	('Akt', 'Gene', '207', (142, 145))	('higher', 'PosReg', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
495173	20601955	In addition, we detected a single MRC tumor with homozygous PTEN deletion and high Akt phosphorylation levels (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Akt', 'Gene', (83, 86))	('PTEN', 'Gene', (60, 64))	('MRC tumor', 'Disease', (34, 43))	('MRC tumor', 'Disease', 'MESH:D009369', (34, 43))	('PTEN', 'Gene', '5728', (60, 64))	('MRC', 'Phenotype', 'HP:0012268', (34, 37))	('Akt', 'Gene', '207', (83, 86))	('deletion', 'Var', (65, 73))
495174	20601955	Further studies are needed to determine the relationship between activated PI3K signaling (resulting from PIK3CA mutations) and the pathognomonic t(12;16)(q13;p11) translocation in this subtype.	('PIK3CA', 'Gene', (106, 112))	('PIK3CA', 'Gene', '5290', (106, 112))	('mutations', 'Var', (113, 122))	('activated', 'PosReg', (65, 74))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (146, 163))
495175	20601955	In addition to sequencing, we characterized the spectrum of genomic aberrations in soft tissue sarcoma with 250K single nucleotide polymorphism (SNP) arrays for somatic copy number alterations (SCNAs: n=207; Figure 1 and Supplementary Figure 2A) and loss-of-heterozygosity (LOH) (n=200; Supplementary Figure 2B) and with oligonucleotide gene expression arrays (n=149) (see Methods).	('single nucleotide polymorphism', 'Var', (113, 143))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('sarcoma', 'Disease', (95, 102))	('oligonucleotide', 'Chemical', 'MESH:D009841', (321, 336))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (83, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('loss-of-heterozygosity', 'NegReg', (250, 272))
495178	20601955	The alteration with the highest prevalence in any subtype was chromosome 12q amplification in dedifferentiated liposarcoma (~90%; Figure 1 and Figure 4A).	('chromosome 12q amplification', 'Var', (62, 90))	('liposarcoma', 'Phenotype', 'HP:0012034', (111, 122))	('liposarcoma', 'Disease', 'MESH:D008080', (111, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('liposarcoma', 'Disease', (111, 122))
495181	20601955	To determine whether the effect of gene knockdown on cell proliferation was specific for dedifferentiated liposarcoma, we compared our results to a pooled shRNA screen of ~9500 genes in 12 cancer cell lines of different types which included 58 of the 99 genes whose knock-down reduced proliferation.	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('liposarcoma', 'Disease', (106, 117))	('proliferation', 'MPA', (285, 298))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('liposarcoma', 'Disease', 'MESH:D008080', (106, 117))	('reduced', 'NegReg', (277, 284))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))	('knock-down', 'Var', (266, 276))	('cancer', 'Disease', (189, 195))
495183	20601955	27 of the 99 genes whose knockdown reduced proliferation were amplified in at least one of the three dedifferentiated liposarcoma cell lines used in our study (Supplementary Figure 3).	('liposarcoma', 'Disease', 'MESH:D008080', (118, 129))	('reduced', 'NegReg', (35, 42))	('liposarcoma', 'Phenotype', 'HP:0012034', (118, 129))	('liposarcoma', 'Disease', (118, 129))	('proliferation', 'MPA', (43, 56))	('knockdown', 'Var', (25, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
495185	20601955	We confirmed that sustained knockdown of CDK4 (>10 days) inhibited proliferation when we assayed two of the three cell lines we screened (see Methods, Figure 4B).	('inhibited', 'NegReg', (57, 66))	('proliferation', 'CPA', (67, 80))	('CDK4', 'Gene', (41, 45))	('knockdown', 'Var', (28, 37))	('CDK4', 'Gene', '1019', (41, 45))
495186	20601955	Furthermore, pharmacological inhibition of CDK4 in dedifferentiated liposarcoma cells with PD0332991, a selective CDK4/CDK6 inhibitor currently in clinical trials, induced G1 arrest in the same two cell lines (Figure 4C).	('CDK6', 'Gene', (119, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('CDK4', 'Gene', (114, 118))	('CDK6', 'Gene', '1021', (119, 123))	('liposarcoma', 'Disease', (68, 79))	('CDK4', 'Gene', (43, 47))	('liposarcoma', 'Phenotype', 'HP:0012034', (68, 79))	('CDK4', 'Gene', '1019', (114, 118))	('induced', 'Reg', (164, 171))	('CDK4', 'Gene', '1019', (43, 47))	('liposarcoma', 'Disease', 'MESH:D008080', (68, 79))	('PD0332991', 'Chemical', 'MESH:C500026', (91, 100))	('arrest', 'Disease', 'MESH:D006323', (175, 181))	('PD0332991', 'Var', (91, 100))	('arrest', 'Disease', (175, 181))
495188	20601955	Interestingly, another gene whose knockdown reduced proliferation of cells in which it was amplified was YEATS4 (GAS41), encoding a putative transcription factor that represses the p53 tumor suppressor network during normal cell proliferation.	('tumor', 'Disease', (185, 190))	('p53', 'Gene', (181, 184))	('p53', 'Gene', '7157', (181, 184))	('GAS41', 'Gene', '8089', (113, 118))	('GAS41', 'Gene', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('YEATS4', 'Gene', '8089', (105, 111))	('represses', 'NegReg', (167, 176))	('reduced', 'NegReg', (44, 51))	('knockdown', 'Var', (34, 43))	('YEATS4', 'Gene', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
495189	20601955	YEATS4, frequently co-amplified with MDM2 (Figure 4A), was transcriptionally upregulated both in tumors relative to normal adipose tissue and in tumors with amplification compared to those copy-neutral for the locus (Supplementary Figure 3).	('transcriptionally', 'MPA', (59, 76))	('YEATS4', 'Gene', '8089', (0, 6))	('upregulated', 'PosReg', (77, 88))	('MDM2', 'Gene', '4193', (37, 41))	('YEATS4', 'Gene', (0, 6))	('MDM2', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('amplification', 'Var', (157, 170))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
495193	20601955	This dataset provides the most comprehensive database of sarcoma genome alterations to date, revealing genes and signaling pathways not previously associated with this group of diseases.	('signaling pathways', 'Pathway', (113, 131))	('alterations', 'Var', (72, 83))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('genes', 'Gene', (103, 108))	('sarcoma', 'Disease', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
495195	20601955	For instance, the PIK3CA mutations found in MRC constitute the first report of such mutations in a mesenchymal cancer.	('mutations', 'Var', (25, 34))	('MRC', 'Phenotype', 'HP:0012268', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('MRC', 'CellLine', 'CVCL:0440', (44, 47))	('PIK3CA', 'Gene', (18, 24))	('mesenchymal cancer', 'Disease', (99, 117))	('PIK3CA', 'Gene', '5290', (18, 24))	('mesenchymal cancer', 'Disease', 'MESH:C535700', (99, 117))
495196	20601955	These mutations identify a subset of tumors that might respond to treatment with PI3K inhibitors currently in clinical trials.	('tumors', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (6, 15))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
495197	20601955	Our results also provide further rationale for use of CDK4 inhibitors in dedifferentiated liposarcoma and suggest the use of mTOR inhibitors in NF1-deficient sarcomas, since loss of NF1 function appears to cause mTOR pathway activation.	('mTOR', 'Gene', '2475', (125, 129))	('CDK4', 'Gene', '1019', (54, 58))	('NF1', 'Gene', (182, 185))	('liposarcoma', 'Disease', (90, 101))	('NF1', 'Gene', (144, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('loss', 'Var', (174, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('activation', 'PosReg', (225, 235))	('NF1-deficient sarcomas', 'Disease', 'MESH:C537392', (144, 166))	('NF1-deficient sarcomas', 'Disease', (144, 166))	('liposarcoma', 'Phenotype', 'HP:0012034', (90, 101))	('mTOR', 'Gene', (212, 216))	('liposarcoma', 'Disease', 'MESH:D008080', (90, 101))	('mTOR', 'Gene', (125, 129))	('CDK4', 'Gene', (54, 58))	('inhibitors', 'Var', (59, 69))	('NF1', 'Gene', '4763', (182, 185))	('NF1', 'Gene', '4763', (144, 147))	('mTOR', 'Gene', '2475', (212, 216))
495203	33498287	In the majority of cases the aetiology is unknown; however, two genetic mutations are associated with OS: a mutation of the retinoblastoma gene, and an autosomic recessive mutation of p53 in Li-Fraumeni syndrome.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (191, 211))	('p53', 'Gene', (184, 187))	('associated', 'Reg', (86, 96))	('OS', 'Disease', (102, 104))	('retinoblastoma', 'Gene', (124, 138))	('retinoblastoma', 'Gene', '5925', (124, 138))	('p53', 'Gene', '7157', (184, 187))	('OS', 'Phenotype', 'HP:0002669', (102, 104))	('retinoblastoma', 'Phenotype', 'HP:0009919', (124, 138))	('Li-Fraumeni syndrome', 'Disease', (191, 211))	('mutation', 'Var', (108, 116))
495283	33498287	Finally, due to the delay between the planning and jig manufacture, there is a possibility for disease progression and therefore a mismatch between the planned resection and tumour margins, resulting in intralesional resections.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('tumour', 'Disease', (174, 180))	('disease progression', 'CPA', (95, 114))	('mismatch', 'Var', (131, 139))
495320	33494434	Several murine tumour models have also demonstrated the reversibility of TIS, during which epigenetic modelling reprograms TIS cells to acquire enhanced plasticity and stem cell features.	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Disease', (15, 21))	('enhanced', 'PosReg', (144, 152))	('epigenetic modelling', 'Var', (91, 111))	('plasticity', 'CPA', (153, 163))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('murine', 'Species', '10090', (8, 14))
495321	33494434	Drug inhibition of the Bcl-2 family anti-apoptotic proteins represents one type of senolytic that has demonstrated the ability to specifically induce apoptosis in RT and PARP inhibitor-induced senescent cells and to improve the aging-related functional decline of various organs following senescent cell clearance.	('functional decline of various organs', 'CPA', (242, 278))	('apoptosis', 'CPA', (150, 159))	('induce', 'Reg', (143, 149))	('improve', 'PosReg', (216, 223))	('Bcl-2', 'Gene', (23, 28))	('Bcl-2', 'Gene', '596', (23, 28))	('PARP', 'Gene', '1302', (170, 174))	('PARP', 'Gene', (170, 174))	('Drug inhibition', 'Var', (0, 15))
495327	33494434	Cell viability measured by flow cytometry showed only a slight increase in cell death 48 h after RT: less than 10% of STS93, STS109 and STS117 cells underwent apoptosis or necrosis compared to untreated controls basal level (Figure 1C).	('necrosis', 'Disease', (172, 180))	('necrosis', 'Disease', 'MESH:D009336', (172, 180))	('STS93', 'Var', (118, 123))	('STS109', 'Chemical', '-', (125, 131))	('apoptosis', 'CPA', (159, 168))
495340	33494434	After exposure to 8 Gy, we measured a strong and progressive increase of both IL-6 and IL-8 over time in STS109 and STS117, while STS93 showed no significant induction of IL-6 or IL-8 at the RNA level (Figure 2D).	('STS117', 'Var', (116, 122))	('IL-8', 'Gene', '3576', (179, 183))	('IL-6', 'Gene', (78, 82))	('STS109', 'Chemical', '-', (105, 111))	('IL-6', 'Gene', (171, 175))	('IL-8', 'Gene', (179, 183))	('IL-6', 'Gene', '3569', (78, 82))	('STS109', 'Var', (105, 111))	('IL-8', 'Gene', '3576', (87, 91))	('IL-8', 'Gene', (87, 91))	('increase', 'PosReg', (61, 69))	('IL-6', 'Gene', '3569', (171, 175))
495341	33494434	When cytokine secretions of IL-6 and IL-8 were detected in the supernatant, all three cell lines showed an increased IL-8 secretion from irradiated condition, whereas IL-6 secretion was detected only for STS109 and STS117 (Figure 2E).	('STS109', 'Chemical', '-', (204, 210))	('IL-6', 'Gene', '3569', (28, 32))	('IL-8', 'Gene', '3576', (37, 41))	('STS117', 'Var', (215, 221))	('increased', 'PosReg', (107, 116))	('secretion', 'MPA', (122, 131))	('STS109', 'Var', (204, 210))	('IL-8', 'Gene', (37, 41))	('IL-6', 'Gene', (167, 171))	('IL-8', 'Gene', '3576', (117, 121))	('IL-6', 'Gene', '3569', (167, 171))	('IL-6', 'Gene', (28, 32))	('IL-8', 'Gene', (117, 121))
495345	33494434	At the mRNA level, BCL-XL increased significantly in STS109 and STS117, but not in STS93 during senescence establishment (Figure 3A).	('STS117', 'Var', (64, 70))	('STS109', 'Chemical', '-', (53, 59))	('BCL-XL', 'Gene', '598', (19, 25))	('STS109', 'Var', (53, 59))	('increased', 'PosReg', (26, 35))	('BCL-XL', 'Gene', (19, 25))
495347	33494434	This was consistent with protein levels, with STS109 and STS117 showing an increased BCL-XL level over time in addition to present higher basal levels than STS93 (Figure 3B and Figure S1).	('STS117', 'Var', (57, 63))	('BCL-XL', 'Gene', (85, 91))	('basal levels', 'MPA', (138, 150))	('STS109', 'Var', (46, 52))	('STS109', 'Chemical', '-', (46, 52))	('BCL-XL', 'Gene', '598', (85, 91))	('increased', 'PosReg', (75, 84))	('higher', 'PosReg', (131, 137))
495348	33494434	While BCL2 expression is stronger in STS93, proteins analysis revealed an increase in both STS93 and STS109 with RT.	('BCL2', 'Gene', '596', (6, 10))	('STS109', 'Var', (101, 107))	('STS109', 'Chemical', '-', (101, 107))	('BCL2', 'Gene', (6, 10))	('increase', 'PosReg', (74, 82))	('stronger', 'PosReg', (25, 33))	('STS93', 'Var', (91, 96))
495355	33494434	To confirm that ABT-199 and ABT-263 reduced cell viability through induction of apoptosis, we used a fluorescent reporter of caspases 3 and 7 activity in our cell lines in real-time imaging.	('ABT-263', 'Var', (28, 35))	('ABT-199', 'Chemical', 'MESH:C579720', (16, 23))	('ABT-199', 'Var', (16, 23))	('reduced', 'NegReg', (36, 43))	('apoptosis', 'CPA', (80, 89))	('cell viability', 'CPA', (44, 58))	('ABT-263', 'Chemical', 'MESH:C528561', (28, 35))
495358	33494434	In a study from Teicher et al., sarcoma cell lines exposure to ABT-199 or ABT-263 also revealed resistance of this pathology to these compounds.	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('sarcoma', 'Disease', (32, 39))	('ABT-263', 'Chemical', 'MESH:C528561', (74, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('ABT-263', 'Var', (74, 81))	('ABT-199', 'Gene', (63, 70))	('ABT-199', 'Chemical', 'MESH:C579720', (63, 70))
495360	33494434	However, IC50 of ABT-199 were approximately twenty times higher than ABT-263 (Figure 4F,G), which supported the need for a BCL-XL and/or BCL-W-selective counterpart to recapitulate ABT-263 efficacy.	('BCL-XL', 'Gene', (123, 129))	('BCL-W', 'Gene', (137, 142))	('BCL-W', 'Gene', '599', (137, 142))	('ABT-199', 'Chemical', 'MESH:C579720', (17, 24))	('IC50', 'MPA', (9, 13))	('ABT-199', 'Var', (17, 24))	('BCL-XL', 'Gene', '598', (123, 129))	('ABT-263', 'Chemical', 'MESH:C528561', (181, 188))	('ABT-263', 'Chemical', 'MESH:C528561', (69, 76))
495363	33494434	According to IC50's, STS117 was the most sensitive cell line for both drugs and STS109, as already mentioned, presents a different kinetic which was attested by higher IC50 for both drugs (Figure 4F,G).	('IC50', 'MPA', (168, 172))	('STS109', 'Chemical', '-', (80, 86))	('higher', 'PosReg', (161, 167))	('STS109', 'Var', (80, 86))
495368	33494434	Both STS93 and STS117 formed suitable spheroid structures, whereas STS109 cells did not aggregate and could not be tested using 3D models.	('STS117', 'Var', (15, 21))	('spheroid structures', 'CPA', (38, 57))	('STS109', 'Chemical', '-', (67, 73))
495371	33494434	STS117 spheroids responded more drastically to ABT-263 than ABT-199 according to their size (Figure 5B).	('ABT-263', 'Chemical', 'MESH:C528561', (47, 54))	('ABT-263', 'Var', (47, 54))	('ABT-199', 'Chemical', 'MESH:C579720', (60, 67))	('responded', 'Reg', (17, 26))
495374	33494434	Overall, our results demonstrated that the combination of Bcl-2 inhibitors and RT efficiently enhances cytotoxicity and cell death.	('Bcl-2', 'Gene', '596', (58, 63))	('enhances', 'PosReg', (94, 102))	('cell death', 'CPA', (120, 130))	('cytotoxicity', 'Disease', 'MESH:D064420', (103, 115))	('inhibitors', 'Var', (64, 74))	('combination', 'Interaction', (43, 54))	('cytotoxicity', 'Disease', (103, 115))	('Bcl-2', 'Gene', (58, 63))
495385	33494434	Even if ABT-263 has been proven to be more potent in our work (Figure 4) as well as in previous reports, ABT-199 seems to be more suitable for clinical administration.	('ABT-199', 'Chemical', 'MESH:C579720', (105, 112))	('ABT-263', 'Chemical', 'MESH:C528561', (8, 15))	('ABT-199', 'Var', (105, 112))	('ABT-263', 'Gene', (8, 15))
495389	33494434	In addition to ABT-199 and ABT-263, other Bcl-2 family inhibitors have been evaluated in clinical trials for cancer treatment, including molecules targeting MCL-1 (A-1210477, S63845, AMG 176, AZD5991).	('Bcl-2', 'Gene', (42, 47))	('A-1210477', 'Var', (164, 173))	('Bcl-2', 'Gene', '596', (42, 47))	('L', 'Gene', '21832', (159, 160))	('ABT-199', 'Chemical', 'MESH:C579720', (15, 22))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ABT-263', 'Chemical', 'MESH:C528561', (27, 34))	('S63845', 'Var', (175, 181))
495391	33494434	Notably, STS109 response to both ABT-199 and ABT-263 may indicate a partial resistance, reflected by a slower rate of cell death that may possibly rely on MCL-1 expression.	('ABT-199', 'Chemical', 'MESH:C579720', (33, 40))	('STS109', 'Chemical', '-', (9, 15))	('ABT-199', 'Gene', (33, 40))	('STS109', 'Var', (9, 15))	('L', 'Gene', '21832', (157, 158))	('ABT-263', 'Chemical', 'MESH:C528561', (45, 52))	('ABT-263', 'Gene', (45, 52))
495392	33494434	Among them, STS93 and STS109 carry wild type TP53 gene while STS117 carries mutated TP53.	('TP53', 'Gene', (45, 49))	('STS117', 'Var', (61, 67))	('STS109', 'Chemical', '-', (22, 28))	('mutated', 'Var', (76, 83))	('STS109', 'Var', (22, 28))	('TP53', 'Gene', '7157', (84, 88))	('TP53', 'Gene', (84, 88))	('STS93', 'Var', (12, 17))	('TP53', 'Gene', '7157', (45, 49))
495393	33494434	The complete senescence phenotype of STS93 and STS109 was in line with the senescence-associated growth arrest that generally relies on p53/p21.	('p21', 'Gene', (140, 143))	('growth arrest', 'Phenotype', 'HP:0001510', (97, 110))	('p53', 'Gene', '7157', (136, 139))	('p21', 'Gene', '644914', (140, 143))	('STS109', 'Chemical', '-', (47, 53))	('growth arrest', 'Disease', (97, 110))	('STS109', 'Var', (47, 53))	('STS93', 'Var', (37, 42))	('growth arrest', 'Disease', 'MESH:D006323', (97, 110))	('p53', 'Gene', (136, 139))
495395	33494434	In the absence of strong senescence markers (Figure 2), we suspect that STS117 undergo mitotic catastrophe, which is the main cellular response to RT-induced DNA damage, especially in the absence of functional check points such as p53 and can drive cells toward cell death by either apoptosis or necrosis or toward senescence.	('necrosis', 'Disease', 'MESH:D009336', (296, 304))	('necrosis', 'Disease', (296, 304))	('apoptosis', 'CPA', (283, 292))	('drive', 'Reg', (243, 248))	('p53', 'Gene', (231, 234))	('cell death', 'CPA', (262, 272))	('undergo', 'Reg', (79, 86))	('p53', 'Gene', '7157', (231, 234))	('senescence', 'CPA', (315, 325))	('STS117', 'Var', (72, 78))	('mitotic catastrophe', 'CPA', (87, 106))
495444	33494434	Antibodies used in western blotting include BCL2 (C124), BCLXL (clone 54H6) and HRP-coupled secondary.	('HRP-coupled', 'Protein', (80, 91))	('BCLXL', 'Gene', '598', (57, 62))	('BCL2', 'Gene', '596', (44, 48))	('C124', 'Var', (50, 54))	('BCLXL', 'Gene', (57, 62))	('BCL2', 'Gene', (44, 48))
495462	33494434	A recent clinical trial suggested the de-escalation in the dose of RT in the pre-operative treatment of radiosensitive myxoid liposarcoma is safe and does not impair local control.	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (119, 137))	('de-escalation', 'Var', (38, 51))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (119, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('myxoid liposarcoma', 'Disease', (119, 137))	('liposarcoma', 'Phenotype', 'HP:0012034', (126, 137))
495490	22420726	The unifying criterion for inclusion in the Ewing family of tumors is the presence of a nonrandom translocation, most commonly t(11;22)(q24;q12), which juxtaposes a portion of the EWS gene on chromosome 22q with the FLI-1 gene on 11q.	('t(11;22)(q24;q12', 'Var', (127, 143))	('EWS', 'Gene', (180, 183))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (127, 144))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
495551	22420726	Standard cytogenetics can be informative, especially in those tumors with variant translocations (see below).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('variant translocations', 'Var', (74, 96))
495554	22420726	However, detection of variant fusions by RT-PCR requires use of multiple primers and can be labor intensive.	('C', 'Chemical', 'MESH:D002244', (45, 46))	('labor', 'Disease', (92, 97))	('labor', 'Disease', 'MESH:D048949', (92, 97))	('variant fusions', 'Var', (22, 37))
495557	22420726	Furthermore, because of the growing number of variant fusions in EWS/pPNET, standard molecular testing may be negative.	('EWS/pPNET', 'Gene', (65, 74))	('EWS/pPNET', 'Gene', '2130', (65, 74))	('variant fusions', 'Var', (46, 61))
495560	22420726	The spectrum of differential diagnosis of EWS/pPNET includes several other entities that share with EWS/pPNET the classic small round cell morphology or the fusion of the EWS gene with different partner genes (Table 2).	('EWS/pPNET', 'Gene', (42, 51))	('EWS/pPNET', 'Gene', (100, 109))	('fusion', 'Var', (157, 163))	('EWS/pPNET', 'Gene', '2130', (42, 51))	('EWS/pPNET', 'Gene', '2130', (100, 109))	('EWS', 'Gene', (171, 174))
495582	22420726	The most frequent translocation, t(11;22) (q24;q12) fuses EWS (EWSR1) to FLI1 (Fig.	('FLI1', 'Gene', '2313', (73, 77))	('FLI1', 'Gene', (73, 77))	('EWSR1', 'Gene', '2130', (63, 68))	('EWSR1', 'Gene', (63, 68))	('t(11;22) (q24;q12', 'Var', (33, 50))
495584	22420726	Approximately 10% of EWS/pPNET exhibit a 2nd translocation, t(21;22) (q22;q12) (Fig.	('EWS/pPNET', 'Gene', '2130', (21, 30))	('EWS/pPNET', 'Gene', (21, 30))	('t(21;22) (q22;q12', 'Var', (60, 77))
495586	22420726	The remaining 5% of EWS/pPNET exhibit variant translocations (Table 3).	('variant', 'Var', (38, 45))	('EWS/pPNET', 'Gene', (20, 29))	('EWS/pPNET', 'Gene', '2130', (20, 29))
495589	22420726	Rare EWS/pPNET have fusions involving the EWS homolog FUS (TLS) of the TET family, with t(16:21) (p11;24) and FUS-ERG fusion and with t(2;16) (q35;p11) and FUS-FEV fusion.	('FUS', 'Gene', (156, 159))	('FUS', 'Gene', '2521', (110, 113))	('FUS', 'Gene', '2521', (156, 159))	('p11', 'Gene', (98, 101))	('ERG', 'Gene', '2078', (114, 117))	('p11', 'Gene', (147, 150))	('EWS/pPNET', 'Gene', (5, 14))	('ERG', 'Gene', (114, 117))	('FUS', 'Gene', (54, 57))	('FUS', 'Gene', '2521', (54, 57))	('EWS/pPNET', 'Gene', '2130', (5, 14))	('p11', 'Gene', '6281', (98, 101))	('p11', 'Gene', '6281', (147, 150))	('FEV', 'Gene', (160, 163))	('fusions', 'Var', (20, 27))	('FEV', 'Gene', '54738', (160, 163))	('FUS', 'Gene', (110, 113))
495594	22420726	EWS/FLI-1 and the other EWS/ETS fusions have been classified as oncogenes because they can transform immortalized murine NIH3T3 cells.	('murine', 'Species', '10090', (114, 120))	('fusions', 'Var', (32, 39))	('NIH3T3', 'CellLine', 'CVCL:0594', (121, 127))	('EWS/ETS', 'Gene', (24, 31))	('transform', 'Reg', (91, 100))	('EWS/FLI-1', 'Gene', (0, 9))
495605	22420726	Early studies showed that the EWS/FLI-1 fusion transcript blocks differentiation of pluripotent murine mesenchymal progenitor cells, in agreement with recent data showing that EWS/FLI-1 silencing restores a pluripotent mesenchymal cell phenotype in EWS/pPNET cells.	('EWS/FLI-1', 'Gene', (176, 185))	('blocks', 'NegReg', (58, 64))	('differentiation', 'CPA', (65, 80))	('silencing', 'Var', (186, 195))	('restores', 'PosReg', (196, 204))	('EWS/pPNET', 'Gene', (249, 258))	('pluripotent', 'MPA', (207, 218))	('EWS/pPNET', 'Gene', '2130', (249, 258))	('EWS/FLI-1', 'Gene', (30, 39))	('murine', 'Species', '10090', (96, 102))
495607	22420726	Other recent studies have shown that ectopic expression of EWS/FLI-1 in human fibroblasts and rhabdomyosarcoma cells induces neuronal and epithelial differentiation and upregulates genes involved in neural crest development, supporting the notion that the neural features in EWS/pPNET may merely be the result of EWS/FLI-1 expression and not signify origin from a neural progenitor cell.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (94, 110))	('upregulates', 'PosReg', (169, 180))	('rhabdomyosarcoma', 'Disease', (94, 110))	('EWS/pPNET', 'Gene', (275, 284))	('ectopic expression', 'Var', (37, 55))	('genes', 'Gene', (181, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('induces', 'PosReg', (117, 124))	('human', 'Species', '9606', (72, 77))	('EWS/pPNET', 'Gene', '2130', (275, 284))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (94, 110))	('EWS/FLI-1', 'Gene', (59, 68))
495612	22420726	Mutations in p53 and deletions in p16INK4a/p14ARF (CDKN2A) are present in 10% and 25%, respectively, of EWS/pPNET and are associated with a poor prognosis.	('CDKN2A', 'Gene', '1029', (51, 57))	('p14ARF', 'Gene', (43, 49))	('EWS/pPNET', 'Gene', (104, 113))	('p14ARF', 'Gene', '1029', (43, 49))	('deletions', 'Var', (21, 30))	('EWS/pPNET', 'Gene', '2130', (104, 113))	('Mutations', 'Var', (0, 9))	('p16INK4a', 'Gene', (34, 42))	('p53', 'Gene', (13, 16))	('CDKN2A', 'Gene', (51, 57))	('p16INK4a', 'Gene', '1029', (34, 42))	('p53', 'Gene', '7157', (13, 16))
495652	22420726	For example, a chest wall tumor exhibiting small round cell morphology and desmin positivity but lacking desmoplasia was reported with a fusion transcript between EWS and another zing finger family gene, ZNF278.	('fusion transcript', 'Var', (137, 154))	('desmin', 'Gene', '1674', (75, 81))	('EWS', 'Gene', (163, 166))	('ZNF278', 'Gene', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('ZNF278', 'Gene', '23598', (204, 210))	('desmin positivity', 'Phenotype', 'HP:0100300', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('desmin', 'Gene', (75, 81))
495653	22420726	Whether this tumor represents DSRCT with a variant fusion is currently unclear.	('tumor', 'Disease', (13, 18))	('DSRCT', 'Disease', (30, 35))	('variant', 'Var', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('DSRCT', 'Disease', 'MESH:D058405', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
495654	22420726	The most frequent EWS/WT-1 fusion consists of the 1st 7 exons of the EWS and the last 3 exons of the WT-1 gene.	('WT-1', 'Gene', (22, 26))	('WT-1', 'Gene', '7490', (22, 26))	('fusion', 'Var', (27, 33))	('WT-1', 'Gene', (101, 105))	('EWS/WT-1', 'Gene', '7490', (18, 26))	('EWS/WT-1', 'Gene', (18, 26))	('WT-1', 'Gene', '7490', (101, 105))
495662	22420726	A reverse staining pattern for WT-1, negative for the C-terminus and positive with the N-terminus antibody, has been reported in association with a rare fusion transcript characterized by deletion of WT1 exons 9 and 10.	('WT1', 'Gene', (200, 203))	('deletion', 'Var', (188, 196))	('WT-1', 'Gene', (31, 35))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('WT1', 'Gene', '7490', (200, 203))	('WT-1', 'Gene', '7490', (31, 35))
495673	22420726	Unlike other EWS-related chromosomal translocations, there are 2 isoforms of the EWS/WT-1 fusion, which are defined by the insertion or deletion of 3 amino acids in the region between zinc fingers 3 and 4 of WT-1.	('WT-1', 'Gene', '7490', (208, 212))	('WT-1', 'Gene', (85, 89))	('insertion', 'Var', (123, 132))	('EWS/WT-1', 'Gene', '7490', (81, 89))	('deletion', 'Var', (136, 144))	('WT-1', 'Gene', '7490', (85, 89))	('EWS/WT-1', 'Gene', (81, 89))	('amino', 'Chemical', 'MESH:D000596', (150, 155))	('WT-1', 'Gene', (208, 212))
495674	22420726	For example, only the isoform with the deletion of amino acids exhibits DNA binding and transforming activity in vitro.	('N', 'Chemical', 'MESH:D009584', (73, 74))	('DNA binding', 'Interaction', (72, 83))	('transforming activity', 'CPA', (88, 109))	('deletion of amino acids', 'Var', (39, 62))	('amino', 'Chemical', 'MESH:D000596', (51, 56))
495675	22420726	The function of the EWS/WT-1 fusion protein can also be altered by phosphorylation.	('phosphorylation', 'Var', (67, 82))	('function', 'MPA', (4, 12))	('altered', 'Reg', (56, 63))	('EWS/WT-1', 'Gene', (20, 28))	('EWS/WT-1', 'Gene', '7490', (20, 28))
495684	31977292	The SWI/SNF complex mutations in gynecologic cancers: molecular mechanisms and models The SWI/SNF (Mating Type SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression.	('gene expression', 'MPA', (267, 282))	('chromatin structure', 'MPA', (235, 254))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('control', 'Reg', (259, 266))	('SWI/SNF', 'Gene', (90, 97))	('modulate', 'Reg', (226, 234))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('interact', 'Interaction', (174, 182))	('Sucrose', 'Chemical', 'MESH:D013395', (118, 125))	('cancers', 'Disease', (45, 52))	('mutations', 'Var', (20, 29))
495685	31977292	Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI/SNF complexes in a wide spectrum of cancer types, including gynecologic cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('mutations', 'Var', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (168, 174))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
495686	31977292	These SWI/SNF mutations occur at different stages of tumour development and are restricted to unique histologic types of gynecologic cancer.	('SWI/SNF', 'Gene', (6, 13))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('occur', 'Reg', (24, 29))	('tumour', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
495687	31977292	Thus, the SWI/SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression.	('promote', 'PosReg', (91, 98))	('SWI/SNF', 'Gene', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('progression', 'CPA', (133, 144))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (18, 27))
495688	31977292	In this review, we will summarize the current knowledge of SWI/SNF mutations in gynecologic cancer development to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.	('SWI/SNF', 'Gene', (59, 66))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
495693	31977292	In addition to finding common well-studied tumor suppressors and oncogenes, genomic analysis of gynecologic cancers has identified frequent mutations of genes encoding subunits of the SWI/SNF (Mating Type SWItch/Sucrose Non-Fermentable) chromatin remodeling complex.	('died', 'Disease', 'MESH:D003643', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Sucrose', 'Chemical', 'MESH:D013395', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (140, 149))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumor', 'Disease', (43, 48))	('died', 'Disease', (38, 42))	('cancers', 'Disease', (108, 115))
495694	31977292	Some mutations, such as SMARCA4/BRG1, occur as a germline event and function as a classic tumor suppressor and key driver in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (136, 158))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (125, 145))	('BRG1', 'Gene', (32, 36))	('hypercalcemic type', 'Disease', (160, 178))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('carcinoma of the ovary', 'Disease', (136, 158))	('mutations', 'Var', (5, 14))	('BRG1', 'Gene', '6597', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
495695	31977292	Other mutations occur either early during the transformation or as a late event during the progression of gynecologic cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('occur', 'Reg', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (6, 15))
495696	31977292	These studies suggest specific roles of mutations in the SWI/SNF complex during multiple steps of gynecologic cancer development.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (40, 49))	('roles', 'Reg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('SWI/SNF', 'Gene', (57, 64))
495697	31977292	In this review, we will summarize the current knowledge of SWI/SNF mutations in gynecologic cancer development to provide insights into both molecular pathogenesis and the potential treatment implications of these disease.	('SWI/SNF', 'Gene', (59, 66))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
495707	31977292	The BAF complex displayed a strong enrichment in active enhancers (H3K27ac and H3K4me1) and primed enhancers (H3K4me1), suggestive of their key roles in enhancer regulation, whereas the PBAF complex had the strongest presence in active promoters (H3K27ac and H3K4me3).	('H3K4me3', 'Var', (259, 266))	('BAF', 'Chemical', '-', (187, 190))	('H3K4me1', 'Var', (79, 86))	('enhancers', 'PosReg', (56, 65))	('H3K27ac', 'Var', (67, 74))	('BAF', 'Chemical', '-', (4, 7))	('H3K27ac', 'Var', (247, 254))
495709	31977292	Given its pivotal role in regulating diverse pathways, it is not surprising that mutations impacting SWI/SNF function occur in a broad spectrum of cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('occur', 'Reg', (118, 123))	('SWI/SNF', 'Gene', (101, 108))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('mutations impacting', 'Var', (81, 100))	('function', 'MPA', (109, 117))	('cancers', 'Disease', (147, 154))
495710	31977292	Indeed, data from The Cancer Genome Atlas (TCGA) has shown that mutations of the SWI/SNF subunits are found in about 20% of all cancers, a rate that approaches the frequency of TP53 mutations.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('Cancer', 'Disease', (22, 28))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancers', 'Disease', (128, 135))	('Cancer', 'Disease', 'MESH:D009369', (22, 28))	('TP53', 'Gene', '7157', (177, 181))	('found', 'Reg', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', (177, 181))	('SWI/SNF', 'Gene', (81, 88))
495715	31977292	Mutations in the SWI/SNF complexes have been reported in multiple types of gynecologic cancers (Figure.	('cancers', 'Disease', (87, 94))	('SWI/SNF', 'Gene', (17, 24))	('reported', 'Reg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
495716	31977292	These mutations, which impact different subunits of the complex, arise at different stages of tumor development and thus may play distinct roles in each tumor type.	('play', 'Reg', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('mutations', 'Var', (6, 15))
495717	31977292	In contrast, the inactivating mutations of SMARCA4, SMARCB1 or ARID1A/B genes are late events in the development of endometrial cancer that may promote disease progression.	('SMARCB1', 'Gene', '6598', (52, 59))	('endometrial cancer', 'Disease', 'MESH:D016889', (116, 134))	('inactivating mutations', 'Var', (17, 39))	('SMARCB1', 'Gene', (52, 59))	('promote', 'PosReg', (144, 151))	('endometrial cancer', 'Disease', (116, 134))	('ARID1A/B', 'Gene', '8289', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('endometrial cancer', 'Phenotype', 'HP:0012114', (116, 134))	('ARID1A/B', 'Gene', (63, 71))	('SMARCA4', 'Gene', (43, 50))
495718	31977292	In this section, we will summarize the current understanding of SWI/SNF mutations in gynecologic cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('mutations', 'Var', (72, 81))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SWI/SNF', 'Gene', (64, 71))
495730	31977292	We and others have discovered that, unlike most common ovarian malignancies, the genome of SCCOHT is diploid with inactivating germline and/or somatic mutations of the SMARCA4 gene as the only recurrent feature and the likely driver event in ~90% of SCCOHT tumors.	('inactivating', 'Var', (114, 126))	('SCCOHT tumors', 'Disease', (250, 263))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('SMARCA4', 'Gene', (168, 175))	('ovarian malignancies', 'Disease', 'MESH:D010049', (55, 75))	('SCCOHT tumors', 'Disease', 'MESH:D009369', (250, 263))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('ovarian malignancies', 'Phenotype', 'HP:0100615', (55, 75))	('ovarian malignancies', 'Disease', (55, 75))	('mutations', 'Var', (151, 160))
495732	31977292	Through IHC analysis of over 3000 primary gynecologic tumors, we further demonstrated that loss of SMARCA4, either alone or together with SMARCA2, is highly sensitive and specific for the diagnosis of SCCOHT, thus providing a definitive tool for SCCOHT diagnosis.	('SMARCA4', 'Gene', (99, 106))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('SMARCA2', 'Gene', (138, 145))	('SMARCA2', 'Gene', '6595', (138, 145))	('SCCOHT', 'Disease', (201, 207))	('loss', 'Var', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
495734	31977292	SCCOHTs share both histological and genetic similarities to malignant rhabdoid tumors of the kidney, soft tissues and brain, which are tumors caused by mutations in SMARCB1.	('SMARCB1', 'Gene', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('mutations', 'Var', (152, 161))	('malignant rhabdoid tumors of the kidney', 'Disease', (60, 99))	('malignant rhabdoid tumors of the kidney', 'Disease', 'MESH:D018335', (60, 99))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('SMARCB1', 'Gene', '6598', (165, 172))	('caused by', 'Reg', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
495746	31977292	Research from our group and others has shown that somatic mutations in the ARID1A gene, encoding an accessory subunit of the SWI/SNF chromatin remodeling complex, commonly occur in both CCOC and ENOC, resulting in complete loss of ARID1A protein expression in ~50% of CCOC and 30% of ENOC.	('mutations', 'Var', (58, 67))	('CCOC', 'Chemical', '-', (186, 190))	('occur', 'Reg', (172, 177))	('ARID1A', 'Gene', (231, 237))	('CCOC', 'Chemical', '-', (268, 272))	('ARID1A', 'Gene', (75, 81))	('loss', 'NegReg', (223, 227))
495750	31977292	Moreover, ARID1A loss is significantly associated with genetic alterations that activate the PI3K/AKT signaling pathway in CCOC, such as PTEN loss and/or gain-of-function mutations of PIK3CA gene, suggesting a cooperative role of ARID1A inactivation and PI3K/AKT activation in malignant transformation of premalignant lesions.	('PTEN loss', 'Disease', (137, 146))	('AKT', 'Gene', '207', (259, 262))	('malignant transformation of premalignant lesions', 'Disease', (277, 325))	('CCOC', 'Chemical', '-', (123, 127))	('gain-of-function', 'PosReg', (154, 170))	('ARID1A', 'Gene', (10, 16))	('AKT', 'Gene', '207', (98, 101))	('PTEN loss', 'Disease', 'MESH:D006223', (137, 146))	('AKT', 'Gene', (259, 262))	('PIK3CA', 'Gene', (184, 190))	('activate', 'PosReg', (80, 88))	('mutations', 'Var', (171, 180))	('loss', 'NegReg', (17, 21))	('CCOC', 'Disease', (123, 127))	('AKT', 'Gene', (98, 101))	('malignant transformation of premalignant lesions', 'Disease', 'MESH:D009369', (277, 325))
495753	31977292	The genomic landscapes of sporadic EECs and HGSECs have been elucidated by TCGA and ourselves, in which mutations of ARID1A occurs in about 30-50% of low grade EEC, 40-60% of high grade EEC and a much lower frequency in HGSEC and endometrial carcinosarcoma.	('mutations', 'Var', (104, 113))	('HGSEC', 'Disease', (220, 225))	('EEC', 'Chemical', '-', (160, 163))	('endometrial carcinosarcoma', 'Phenotype', 'HP:0012114', (230, 256))	('EEC', 'Phenotype', 'HP:0012114', (160, 163))	('EEC', 'Phenotype', 'HP:0012114', (186, 189))	('endometrial carcinosarcoma', 'Disease', 'MESH:D002296', (230, 256))	('EEC', 'Chemical', '-', (35, 38))	('ARID1A', 'Gene', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('low grade EEC', 'Disease', (150, 163))	('occurs', 'Reg', (124, 130))	('endometrial carcinosarcoma', 'Disease', (230, 256))	('EEC', 'Phenotype', 'HP:0012114', (35, 38))	('EEC', 'Chemical', '-', (186, 189))
495757	31977292	Mutation of ARID1A was observed in 22% (7/32) of CCEC along with protein loss, in agreement with an earlier report by Fadare et al..	('loss', 'NegReg', (73, 77))	('CCEC', 'Disease', (49, 53))	('observed', 'Reg', (23, 31))	('Mutation', 'Var', (0, 8))	('ARID1A', 'Gene', (12, 18))	('CCEC', 'Chemical', '-', (49, 53))	('protein', 'MPA', (65, 72))
495758	31977292	Thus, ARID1A mutations occurs at differential frequencies in most common types of endometrial carcinomas, with a significant enrichment in EEC.	('EEC', 'Chemical', '-', (139, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (82, 103))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (82, 104))	('EEC', 'Phenotype', 'HP:0012114', (139, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('EEC', 'Disease', (139, 142))	('endometrial carcinomas', 'Disease', (82, 104))	('ARID1A', 'Gene', (6, 12))	('mutations', 'Var', (13, 22))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (82, 104))
495764	31977292	Patients with Lynch syndrome, one of the most prevalent hereditary cancer predisposition syndromes arising from a germline mutation in one of the four microsatellite repair genes (MLH1, MSH2, MSH6, PMS2), have a 40-60% lifetime risk of developing ECs.	('Lynch syndrome', 'Disease', (14, 28))	('hereditary cancer', 'Disease', 'MESH:D009369', (56, 73))	('arising from', 'Reg', (99, 111))	('mutation', 'Var', (123, 131))	('MLH1', 'Gene', (180, 184))	('MLH1', 'Gene', '4292', (180, 184))	('Lynch syndrome', 'Disease', 'MESH:D003123', (14, 28))	('hereditary cancer', 'Disease', (56, 73))	('PMS2', 'Gene', '5395', (198, 202))	('MSH6', 'Gene', '2956', (192, 196))	('ECs', 'Disease', (247, 250))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('PMS2', 'Gene', (198, 202))	('MSH2', 'Gene', (186, 190))	('MSH6', 'Gene', (192, 196))	('MSH2', 'Gene', '4436', (186, 190))
495768	31977292	This discrepancy may be attributed to the size and origin of different Lynch syndrome kindreds that may carry distinct mutations of mismatch repair genes.	('Lynch syndrome', 'Disease', 'MESH:D003123', (71, 85))	('Lynch syndrome', 'Disease', (71, 85))	('mutations', 'Var', (119, 128))
495779	31977292	These include inactivating mutations in SMARCA4 resulting in loss of SMARCA4 protein in 30-40% of DDEC, inactivation of SMARCB1 resulting in loss of SMARCB1 protein in 2-7% of DDEC, or co-inactivation of ARID1A and ARID1B resulting in concurrent loss of ARID1A and ARID1B proteins in 28% of DDEC.	('ARID1B', 'Gene', '57492', (265, 271))	('inactivating mutations', 'Var', (14, 36))	('SMARCB1', 'Gene', (149, 156))	('ARID1B', 'Gene', (265, 271))	('ARID1B', 'Gene', '57492', (215, 221))	('loss', 'NegReg', (141, 145))	('loss', 'NegReg', (61, 65))	('SMARCA4', 'Gene', (69, 76))	('inactivation', 'Var', (104, 116))	('protein', 'Protein', (77, 84))	('ARID1B', 'Gene', (215, 221))	('co-inactivation', 'Var', (185, 200))	('SMARCB1', 'Gene', (120, 127))	('loss', 'NegReg', (246, 250))	('SMARCB1', 'Gene', '6598', (120, 127))	('SMARCA4', 'Gene', (40, 47))	('protein', 'Protein', (157, 164))	('SMARCB1', 'Gene', '6598', (149, 156))
495782	31977292	Furthermore, mutational loss of SMARCA4, SMARCB1 or ARID1A/ARID1B is often associated with loss of the expression of SMARCA2 protein, the alternative ATPase of the SWI/SNF complex, through non-genetic mechanisms.	('ATPase', 'Gene', (150, 156))	('SMARCB1', 'Gene', (41, 48))	('mutational loss', 'Var', (13, 28))	('ARID1B', 'Gene', (59, 65))	('expression', 'MPA', (103, 113))	('protein', 'Protein', (125, 132))	('ARID1B', 'Gene', '57492', (59, 65))	('SMARCA4', 'Gene', (32, 39))	('loss', 'NegReg', (91, 95))	('SMARCA2', 'Gene', (117, 124))	('SMARCA2', 'Gene', '6595', (117, 124))	('ATPase', 'Gene', '1769', (150, 156))	('SMARCB1', 'Gene', '6598', (41, 48))
495783	31977292	Such SWI/SNF mutations are also implicated in undifferentiated carcinomas of ovary, urinary tract, gastrointestinal tract and kidney, suggesting that the SWI/SNF deficiency acquired during tumor progression may be a widespread mechanism that promotes cancer dedifferentiation.	('tumor', 'Disease', (189, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('SNF deficiency', 'Phenotype', 'HP:0025457', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('implicated', 'Reg', (32, 42))	('SNF deficiency', 'Disease', 'MESH:D007153', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('undifferentiated carcinomas of ovary', 'Disease', 'MESH:D010051', (46, 82))	('undifferentiated carcinomas of ovary', 'Disease', (46, 82))	('SNF deficiency', 'Disease', (158, 172))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (251, 257))	('SWI/SNF', 'Gene', (5, 12))	('promotes', 'PosReg', (242, 250))
495792	31977292	discovered SMARCA4 mutations and/or protein loss in 5 cases of undifferentiated uterine sarcoma with a median age of diagnosis of 33 years old, close to that of SCCOHT.	('SMARCA4', 'Gene', (11, 18))	('mutations', 'Var', (19, 28))	('loss', 'NegReg', (44, 48))	('protein', 'Protein', (36, 43))	('undifferentiated uterine sarcoma', 'Disease', 'MESH:D002277', (63, 95))	('undifferentiated uterine sarcoma', 'Disease', (63, 95))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (80, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
495805	31977292	studied the clinicopathologic, IHC, and molecular genetic features of 14 SMARCB1-deficient vulvar neoplasms and uncovered that the proximal-type epithelioid sarcoma was the predominant subtype with SMARCB1 deficiency, followed by myoepithelial carcinoma.	('died', 'Disease', (3, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('SMARCB1', 'Gene', (73, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (98, 107))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (233, 253))	('SMARCB1', 'Gene', '6598', (198, 205))	('deficiency', 'Var', (206, 216))	('SMARCB1', 'Gene', (198, 205))	('SMARCB1-deficient vulvar neoplasms', 'Disease', (73, 107))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('myoepithelial carcinoma', 'Disease', (230, 253))	('vulvar neoplasms', 'Phenotype', 'HP:0030416', (91, 107))	('died', 'Disease', 'MESH:D003643', (3, 7))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (230, 253))	('SMARCB1-deficient vulvar neoplasms', 'Disease', 'MESH:D014846', (73, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('SMARCB1', 'Gene', '6598', (73, 80))	('sarcoma', 'Disease', (157, 164))
495809	31977292	Despite this, future study of a large number of cases are required to fully characterize the clinicopathologic, immunophenotypic and genomic features of these two entities and address whether SMARCB1 inactivation is the only recurrent driver event, as seen in epithelioid sarcomas at other anatomic sites.	('sarcomas', 'Phenotype', 'HP:0100242', (272, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('sarcomas', 'Disease', (272, 280))	('SMARCB1', 'Gene', '6598', (192, 199))	('SMARCB1', 'Gene', (192, 199))	('inactivation', 'Var', (200, 212))	('sarcomas', 'Disease', 'MESH:D012509', (272, 280))
495814	31977292	Supporting this, analysis of transcriptomic profiles from the ARID1A wild-type and mutant CCOC failed to identify a canonical signaling process that was distinct between wild-type and ARID1A mutant tumors.	('CCOC', 'Chemical', '-', (90, 94))	('mutant', 'Var', (83, 89))	('CCOC', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Disease', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
495815	31977292	found that loss of ARID1A was significantly correlated with advanced FIGO stage and high CA125 levels and a shorter progression-free survival in 60 patients of CCOC that received platinum-based chemotherapy.	('CCOC', 'Chemical', '-', (160, 164))	('patients', 'Species', '9606', (148, 156))	('CA125', 'Gene', '94025', (89, 94))	('loss', 'Var', (11, 15))	('ARID1A', 'Gene', (19, 25))	('shorter', 'NegReg', (108, 115))	('FIGO', 'Disease', (69, 73))	('CA125', 'Gene', (89, 94))	('platinum', 'Chemical', 'MESH:D010984', (179, 187))	('progression-free survival', 'CPA', (116, 141))
495828	31977292	demonstrated that ARID1A mutations correlated with a better outcome in endometrial carcinoma.	('mutations', 'Var', (25, 34))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (71, 92))	('ARID1A', 'Gene', (18, 24))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (71, 92))	('endometrial carcinoma', 'Disease', (71, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
495830	31977292	further investigated whether such correlation reflects the enrichment of ARID1A mutations in MSI tumor.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('ARID1A', 'Gene', (73, 79))
495831	31977292	It was unveiled that ARID1A mutation status was not significantly associated with survival in patients with MSI tumors, but was associated with a better prognosis in patients with MSS tumors, implying that ARID1A mutation status may predict patient outcome in MSS endometrial cancer.	('mutation', 'Var', (28, 36))	('MSS tumors', 'Disease', (180, 190))	('predict', 'Reg', (233, 240))	('patients', 'Species', '9606', (94, 102))	('MSI tumors', 'Disease', (108, 118))	('patient', 'Species', '9606', (94, 101))	('patient', 'Species', '9606', (166, 173))	('endometrial cancer', 'Phenotype', 'HP:0012114', (264, 282))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('MSS endometrial cancer', 'Disease', 'MESH:D016889', (260, 282))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('MSI tumors', 'Disease', 'MESH:D009369', (108, 118))	('MSS endometrial cancer', 'Disease', (260, 282))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('patient', 'Species', '9606', (241, 248))	('ARID1A', 'Gene', (21, 27))	('MSS tumors', 'Disease', 'MESH:D013132', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (166, 174))
495833	31977292	Although DDEC displayed a worse outcome than grade 3 endometrial cancer, our initial comparison between 15 DDEC with intact SMARCA4/SMARCB1 and 15 DDEC with loss of SMARCA4 or SMARCB1 did not identify significant differences in disease-specific survival.	('SMARCB1', 'Gene', '6598', (176, 183))	('SMARCB1', 'Gene', (132, 139))	('SMARCA4', 'Gene', (165, 172))	('SMARCB1', 'Gene', '6598', (132, 139))	('SMARCB1', 'Gene', (176, 183))	('endometrial cancer', 'Disease', (53, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('intact', 'Var', (117, 123))	('endometrial cancer', 'Phenotype', 'HP:0012114', (53, 71))	('loss', 'NegReg', (157, 161))	('endometrial cancer', 'Disease', 'MESH:D016889', (53, 71))
495869	31977292	Given the strong association of ARID1A loss and PIK3CA or PTEN mutations in endometriosis-associated ovarian cancer, it is plausible that such mutations may be present in this endometriosis cell line.	('mutations', 'Var', (63, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('endometriosis', 'Phenotype', 'HP:0030127', (176, 189))	('PIK3CA', 'Gene', (48, 54))	('endometriosis', 'Disease', 'MESH:D004715', (76, 89))	('loss', 'NegReg', (39, 43))	('endometriosis-associated ovarian cancer', 'Disease', 'MESH:D004715', (76, 115))	('endometriosis', 'Disease', (176, 189))	('endometriosis', 'Disease', (76, 89))	('endometriosis', 'Disease', 'MESH:D004715', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('endometriosis-associated ovarian cancer', 'Disease', (76, 115))	('ARID1A', 'Gene', (32, 38))	('endometriosis', 'Phenotype', 'HP:0030127', (76, 89))	('PTEN', 'Gene', '19211', (58, 62))	('PTEN', 'Gene', (58, 62))
495874	31977292	Since within the normal uterine environment, endometrial epithelial progenitor cells undergo terminal differentiation with a preference towards secretory cells, it is speculated that the local ovarian microenvironment of each patient, which holds distinct differentiation pressure, may determine the differentiation of ARID1A-deficient biopotential premalignant progenitor cells of endometriotic cysts and together with accumulated additional mutations or epigenetic changes to drive their malignant transformation towards either ENOC or CCOC, respectively (Figure 4).	('CCOC', 'Chemical', '-', (538, 542))	('patient', 'Species', '9606', (226, 233))	('epigenetic changes', 'Var', (456, 474))	('determine', 'Reg', (286, 295))	('CCOC', 'Disease', (538, 542))	('malignant transformation', 'CPA', (490, 514))	('ARID1A-deficient', 'Gene', (319, 335))	('ENOC', 'Disease', (530, 534))	('mutations', 'Var', (443, 452))
495876	31977292	Recently, we and others have demonstrated that TOV112D and OVK18, two ENOC cell lines, are likely DDEC cell lines derived from dedifferentiated carcinomas of the ovary based on their lack of expression of both SMARCA4 and SMARCA2 and histological reevaluation of original tumor material (Karnezis et al., manuscript in preparation).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (272, 277))	('SMARCA2', 'Gene', (222, 229))	('SMARCA2', 'Gene', '6595', (222, 229))	('TOV112D', 'Var', (47, 54))	('SMARCA4', 'Gene', (210, 217))	('carcinomas of the ovary', 'Disease', (144, 167))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas of the ovary', 'Disease', 'MESH:D010051', (144, 167))	('OVK18', 'Gene', (59, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
495878	31977292	As ARID1A/ARID1B-dual deficient DDEC has intact PBAF and GBAF complexes and SMARCB1-deficient DDEC has functional GBAF complex, whereas SMARCA4-deficient DDEC loses ATPase activity of all SWI/SNF complexes completely (Figure 5), it is plausible to propose that inactivation of the BAF complexes is sufficient to stall the differentiation of cancer initiating cells and drive histological dedifferentiation.	('ARID1B', 'Gene', (10, 16))	('BAF', 'Chemical', '-', (115, 118))	('stall', 'NegReg', (312, 317))	('BAF', 'Chemical', '-', (281, 284))	('ARID1B', 'Gene', '57492', (10, 16))	('BAF', 'Chemical', '-', (49, 52))	('cancer', 'Disease', (341, 347))	('SMARCB1', 'Gene', '6598', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('SMARCB1', 'Gene', (76, 83))	('SMARCA4-deficient DDEC loses', 'Disease', 'MESH:D011504', (136, 164))	('SMARCA4-deficient DDEC loses', 'Disease', (136, 164))	('GBAF', 'Chemical', '-', (114, 118))	('GBAF', 'Chemical', '-', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('histological dedifferentiation', 'CPA', (375, 405))	('activity', 'MPA', (172, 180))	('ATPase', 'Gene', (165, 171))	('inactivation', 'Var', (261, 273))	('BAF', 'Chemical', '-', (58, 61))	('drive', 'Reg', (369, 374))	('ATPase', 'Gene', '1769', (165, 171))
495882	31977292	Efforts from several teams have attempted to determine whether inactivation of ARID1A is sufficient to drive the development of ovarian cancer and whether co-existing mutations are required to synergize with ARID1A loss to promote tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('ovarian cancer', 'Disease', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('inactivation', 'Var', (63, 75))	('loss', 'NegReg', (215, 219))	('drive', 'Reg', (103, 108))	('tumor', 'Disease', (231, 236))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('ARID1A', 'Gene', (79, 85))	('ARID1A', 'Gene', (208, 214))	('promote', 'PosReg', (223, 230))	('ovarian cancer', 'Disease', 'MESH:D010051', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
495883	31977292	reported that adenoviral-mediated co-depletion of Pten and Arid1a in ovarian surface epithelium of the Ptenfl/fl;Arid1afl/fl mice induces ovarian hyperplasia as early as 2 months after genetic depletion, which drives the development of undifferentiated or endometrioid carcinoma of the ovary in 6/13 mice examined at 6 months and 7/9 mice at 8-9 months.	('Pten', 'Gene', (50, 54))	('Pten', 'Gene', '19211', (50, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('ovarian hyperplasia', 'Disease', 'MESH:D006965', (138, 157))	('mice', 'Species', '10090', (334, 338))	('ovarian hyperplasia', 'Disease', (138, 157))	('undifferentiated or endometrioid carcinoma of the ovary', 'Disease', 'MESH:D010051', (236, 291))	('mice', 'Species', '10090', (125, 129))	('co-depletion', 'Var', (34, 46))	('Pten', 'Gene', (103, 107))	('Arid1afl/fl', 'Var', (113, 124))	('mice', 'Species', '10090', (300, 304))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (256, 278))	('induces', 'Reg', (130, 137))	('Arid1a', 'Gene', (59, 65))	('Pten', 'Gene', '19211', (103, 107))
495884	31977292	Noteworthy, inactivation of one or both alleles of Arid1a in ovarian surface epithelium prolonged the survival of tumor-bearing Apc/Pten-deficient mice and promoted cancer cell differentiation to more closely resemble the histology of human ovarian endometrioid cancer.	('Pten', 'Gene', '19211', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('inactivation', 'Var', (12, 24))	('mice', 'Species', '10090', (147, 151))	('Arid1a', 'Gene', (51, 57))	('survival', 'CPA', (102, 110))	('tumor', 'Disease', (114, 119))	('Apc', 'Gene', (128, 131))	('promoted', 'PosReg', (156, 164))	('cancer', 'Disease', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Apc', 'Gene', '11789', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('human ovarian endometrioid cancer', 'Disease', (235, 268))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (249, 268))	('human ovarian endometrioid cancer', 'Disease', 'MESH:D016889', (235, 268))	('prolonged', 'PosReg', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('Pten', 'Gene', (132, 136))
495885	31977292	found that inactivation of Arid1a and expression of Pik3ca H1047R activating mutation in ovarian surface epithelium of the Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R mice rapidly develop primary ovarian tumor with a 7.5 week latency and clear cell carcinoma-like histopathology.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('Pik3ca', 'Gene', '18706', (145, 151))	('H1047R', 'SUBSTITUTION', 'None', (152, 158))	('ovarian tumor', 'Phenotype', 'HP:0100615', (188, 201))	('primary', 'CPA', (180, 187))	('Pik3ca', 'Gene', (52, 58))	('H1047R', 'Var', (59, 65))	('Pik3ca', 'Gene', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('develop', 'PosReg', (172, 179))	('ovarian tumor', 'Disease', (188, 201))	('clear cell carcinoma', 'Disease', (230, 250))	('inactivation', 'Var', (11, 23))	('ovarian tumor', 'Disease', 'MESH:D010051', (188, 201))	('Pik3ca', 'Gene', '18706', (52, 58))	('H1047R', 'SUBSTITUTION', 'None', (59, 65))	('H1047R', 'Var', (152, 158))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (230, 250))	('mice', 'Species', '10090', (159, 163))	('Arid1a', 'Gene', (27, 33))
495886	31977292	In contrast, mice with deletion of Pten or Arid1a or activation of Pik3ca.H1047R alone did not develop ovarian lesions except that activation of Pik3ca.H1047R led to development of hyperplasia in ovarian surface epithelium.	('Pten', 'Gene', (35, 39))	('mice', 'Species', '10090', (13, 17))	('Pik3ca', 'Gene', (67, 73))	('Pik3ca', 'Gene', '18706', (145, 151))	('Pten', 'Gene', '19211', (35, 39))	('deletion', 'Var', (23, 31))	('ovarian lesions', 'Disease', 'MESH:D010049', (103, 118))	('ovarian lesions', 'Disease', (103, 118))	('hyperplasia', 'Disease', 'MESH:D006965', (181, 192))	('Pik3ca', 'Gene', '18706', (67, 73))	('ovarian lesions', 'Phenotype', 'HP:0100615', (103, 118))	('Arid1a', 'Gene', (43, 49))	('ovarian surface epithelium', 'CPA', (196, 222))	('hyperplasia', 'Disease', (181, 192))	('Pik3ca', 'Gene', (145, 151))
495892	31977292	As ARID1A is also frequently mutated in endometrial carcinomas, inactivation of Arid1a, alone or in combination with genetic mutations of other genes (such as Pten, Pik3ca), in specific mouse cre strains in which the cre expression is driven by endometrial tissue specific promoters (i.e.	('inactivation', 'Var', (64, 76))	('Arid1a', 'Gene', (80, 86))	('Pten', 'Gene', (159, 163))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (40, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Pten', 'Gene', '19211', (159, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (40, 61))	('endometrial carcinomas', 'Disease', (40, 62))	('mouse', 'Species', '10090', (186, 191))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (40, 62))	('Pik3ca', 'Gene', (165, 171))	('Pik3ca', 'Gene', '18706', (165, 171))
495896	31977292	These putative tissue-specific GEMMs will open the opportunity for better understanding how inactivation of ARID1A interacts with other genetic mutations as well as ovarian microenvironment to drive transformation of precursor cells through comparison of the gene expression profiles and epigenetic states of tumor cells to those of the precursor cells that can be identified by lineage tracking markers.	('inactivation', 'Var', (92, 104))	('tumor', 'Disease', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('ARID1A', 'Gene', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
495897	31977292	reported that inactivation of Smarca4 using a Wap-cre line, which activates cre expression in granulosa cells of mouse ovary and multiple lineages of mouse uterus, led to frequent development of ovarian cyst and a low incidence of endometrial cancer.	('ovarian cyst', 'Disease', 'MESH:D010048', (195, 207))	('Wap', 'Gene', (46, 49))	('ovarian cyst', 'Phenotype', 'HP:0000138', (195, 207))	('inactivation', 'Var', (14, 26))	('Smarca4', 'Gene', (30, 37))	('ovarian cyst', 'Disease', (195, 207))	('endometrial cancer', 'Disease', (231, 249))	('endometrial cancer', 'Phenotype', 'HP:0012114', (231, 249))	('Wap', 'Gene', '22373', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('mouse', 'Species', '10090', (113, 118))	('led to', 'Reg', (164, 170))	('mouse', 'Species', '10090', (150, 155))	('endometrial cancer', 'Disease', 'MESH:D016889', (231, 249))	('activates', 'PosReg', (66, 75))
495899	31977292	Therefore, inactivation of Smarca4 cannot drive the transformation of ovarian granulosa cells, but has the ability to transform unknown lineage in uterus.	('transform', 'Reg', (118, 127))	('ovarian granulosa', 'Disease', (70, 87))	('ovarian granulosa', 'Disease', 'MESH:D010049', (70, 87))	('inactivation', 'Var', (11, 23))	('Smarca4', 'Gene', (27, 34))
495903	31977292	Furthermore, additional inactivation of Smarca4 or the BAF complex through dual inactivation of Arid1a/Arid1b will likely promote the development of undifferentiated cancer resembling human DDEC in GEMMs of well differentiated endometrial cancer, such as Pgr-Cre:Ptenfl/fl GEMM mice.	('undifferentiated cancer', 'Disease', 'MESH:D009369', (149, 172))	('promote', 'PosReg', (122, 129))	('Pgr', 'Gene', (255, 258))	('human', 'Species', '9606', (184, 189))	('endometrial cancer', 'Phenotype', 'HP:0012114', (227, 245))	('Smarca4', 'Gene', (40, 47))	('BAF', 'Chemical', '-', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('Arid1b', 'Gene', (103, 109))	('endometrial cancer', 'Disease', (227, 245))	('Arid1b', 'Gene', '57492', (103, 109))	('Pten', 'Gene', (263, 267))	('Pten', 'Gene', '19211', (263, 267))	('endometrial cancer', 'Disease', 'MESH:D016889', (227, 245))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('inactivation', 'Var', (24, 36))	('mice', 'Species', '10090', (278, 282))	('Pgr', 'Gene', '5241', (255, 258))	('undifferentiated cancer', 'Disease', (149, 172))
495904	31977292	These models will offer great opportunities for better understanding the context-specific tumor suppressive roles of distinct SWI/SNF mutations in gynecologic cancers.	('cancers', 'Disease', (159, 166))	('SWI/SNF', 'Gene', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('mutations', 'Var', (134, 143))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
495905	31977292	Although SWI/SNF gene mutations occur in nearly 20% of all human cancers, most SWI/SNF gene mutations are loss of function mutations, including nonsense, frameshift and large deletions, that lead to concurrent loss of their protein expression.	('human', 'Species', '9606', (59, 64))	('loss of function', 'NegReg', (106, 122))	('protein expression', 'MPA', (224, 242))	('loss', 'NegReg', (210, 214))	('SWI/SNF gene', 'Gene', (79, 91))	('large deletions', 'Var', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (92, 101))	('frameshift', 'Var', (154, 164))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('nonsense', 'Var', (144, 152))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))
495906	31977292	Consequently, many efforts have been invested to identify synthetic lethal targets that are conferred by these SWI/SNF mutations on cancer cells, which has been summarized in details in several reviews.	('cancer', 'Disease', (132, 138))	('SWI/SNF', 'Gene', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
495919	31977292	Mutations of several SWI/SNF subunits have been discovered in multiple gynecologic cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('discovered', 'Reg', (48, 58))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('SWI/SNF', 'Gene', (21, 28))
495920	31977292	The frequency and inactivating nature of these mutations supports that the SWI/SNF complexes are bona fide tumor suppressors in gynecologic tissues, which also define unique vulnerabilities that warrants further clinical investigations.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (47, 56))	('SWI/SNF', 'Gene', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
495921	31977292	These SWI/SNF mutations may function as either the sole driver event (SCCOHT), a malignant transformation-permitting early event (CCOC/ENOC/EEC) or a late progression event (DDEC) in distinct gynecologic cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('SWI/SNF', 'Gene', (6, 13))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('CCOC', 'Chemical', '-', (130, 134))	('EEC', 'Chemical', '-', (140, 143))	('EEC', 'Phenotype', 'HP:0012114', (140, 143))	('mutations', 'Var', (14, 23))
495923	31977292	The SWI/SNF mutations appears to have a value in predicting the worse outcome of DDEC patients even though a large number of cases are required to validate its clinical utility.	('DDEC', 'Disease', (81, 85))	('mutations', 'Var', (12, 21))	('SWI/SNF', 'Gene', (4, 11))	('patients', 'Species', '9606', (86, 94))
495925	31977292	Furthermore, the pathogenic roles of the SWI/SNF mutations are far beyond being fully understood in gynecologic cancers.	('mutations', 'Var', (49, 58))	('SWI/SNF', 'Gene', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
495926	31977292	The fact that specific subunits are mutated in specific gynecologic malignancies implies that the SWI/SNF complexes function in context-specific manners.	('mutated', 'Var', (36, 43))	('malignancies', 'Disease', (68, 80))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))
495930	31977292	The understanding of SWI/SNF complex mutations and their cellular interactions will be pivotal to developing novel treatment strategies for these gynecologic malignancies, particularly those which portend poor prognoses and often only have conventional platinum-based chemotherapy as a therapeutic option.	('SWI/SNF complex', 'Gene', (21, 36))	('malignancies', 'Disease', 'MESH:D009369', (158, 170))	('gynecologic', 'Disease', (146, 157))	('malignancies', 'Disease', (158, 170))	('mutations', 'Var', (37, 46))	('platinum', 'Chemical', 'MESH:D010984', (253, 261))
496075	25633333	150-153  C;  -64.5 (c 0.44, MeOH); positive ion ESI-MS m/z: 502 [M+NH4]+, 507 [M+Na]+; negative ion ESI-MS m/z: 483 [M-H]-, 519 [M+Cl]-.	('507 [M+Na]+', 'Var', (74, 85))	('NH4', 'Chemical', '-', (67, 70))	('519 [M+Cl]-', 'Var', (124, 135))	('MeOH', 'Chemical', '-', (28, 32))
496077	25633333	161-163  C;  +20.4 (c 0.44, MeOH); positive ion ESI-MS m/z: 507 [M+Na]+; negative ion ESI-MS m/z: 483 [M-H]-, 519 [M+Cl]-, 529 [M+HCO2]-.	('519 [M+Cl]-', 'Var', (110, 121))	('529 [M+HCO2]-', 'Var', (123, 136))	('HCO2', 'Chemical', '-', (130, 134))	('ESI-MS', 'Var', (86, 92))	('MeOH', 'Chemical', '-', (28, 32))
496105	25633333	113-115  C,  +76.5 (c 1.00, MeOH); positive ion ESI-MS m/z: 302 [M+NH4]+, 307 [M+Na]+, 323 [M+K]+; negative ion ESI-MS m/z: 283 [M-H]-, 319 [M+Cl]-, 329 [M+HCO2]-.	('319 [M+Cl]-', 'Var', (136, 147))	('302 [M+NH4]+', 'Var', (60, 72))	('HCO2', 'Chemical', '-', (156, 160))	('329 [M+HCO2]-', 'Var', (149, 162))	('MeOH', 'Chemical', '-', (28, 32))	('NH4', 'Chemical', '-', (67, 70))	('307 [M+Na]+', 'Var', (74, 85))
496107	25633333	13C-NMR (100 MHz, CD3OD) delta: 139.8, 129.4 (2C), 129.2 (2C), 128.9, all Ph-C6 in PhCH2; 99.2 (C-1), 81.0 (C-2), 74.3 (C-3), 74.0 (PhCH2), 73.3 (C-5), 71.8 (C-4), 62.6 (C-6), 55.4 (OCH3).	('13C', 'Chemical', '-', (0, 3))	('Ph-C6', 'Var', (74, 79))	('C-4', 'Gene', (158, 161))	('C-3', 'Gene', (120, 123))	('C6', 'Chemical', 'MESH:C117224', (77, 79))	('C-5', 'Gene', '727', (146, 149))	('PhCH2', 'Chemical', '-', (83, 88))	('C-2', 'Gene', '717', (108, 111))	('C-3', 'Gene', '718', (120, 123))	('C-1', 'Gene', '3217', (96, 99))	('C-6', 'Gene', '729', (170, 173))	('PhCH2', 'Chemical', '-', (132, 137))	('C-6', 'Gene', (170, 173))	('C-2', 'Gene', (108, 111))	('d', 'Chemical', 'MESH:D003903', (25, 26))	('C-5', 'Gene', (146, 149))	('C-4', 'Gene', '720', (158, 161))	('C-1', 'Gene', (96, 99))
496126	25633333	This mixture was further separated by preparative HPLC on a Capcell Pak C18 column (MG II S5, 2.0 x 25.0 cm), eluted by 30% MeOH, to obtain 11 (0.76 g, 0.0015 mol; tR = 36.0 min) and 12 (0.55 g, 0.0011 mol; tR = 23.0 min) in yields of 22.7% and 17.2%, respectively.	('d', 'Chemical', 'MESH:D003903', (33, 34))	('d', 'Chemical', 'MESH:D003903', (181, 182))	('d', 'Chemical', 'MESH:D003903', (243, 244))	('0.55 g', 'Var', (187, 193))	('d', 'Chemical', 'MESH:D003903', (115, 116))	('0.76 g', 'Var', (144, 150))	('MeOH', 'Chemical', '-', (124, 128))	('d', 'Chemical', 'MESH:D003903', (229, 230))
496169	25633333	13C-NMR (100 MHz, CDCl3) delta: 137.1, 129.4, 128.5 (2C), 126.4 (2C), all Ph-C6 in PhCH; 102.1 (PhCH), 99.9 (C-1), 81.0 (C-4), 72.9 (C-2), 71.8 (C-3), 69.0 (C-6), 62.4 (C-5), 55.7 (OCH3).	('13C', 'Chemical', '-', (0, 3))	('C-6', 'Gene', '729', (157, 160))	('Ph-C6', 'Var', (74, 79))	('C-4', 'Gene', '720', (121, 124))	('C6', 'Chemical', 'MESH:C117224', (77, 79))	('C-2', 'Gene', (133, 136))	('C-5', 'Gene', '727', (169, 172))	('C-3', 'Gene', (145, 148))	('C-3', 'Gene', '718', (145, 148))	('C-2', 'Gene', '717', (133, 136))	('C-4', 'Gene', (121, 124))	('C-1', 'Gene', (109, 112))	('d', 'Chemical', 'MESH:D003903', (25, 26))	('C-1', 'Gene', '3217', (109, 112))	('C-5', 'Gene', (169, 172))	('CDCl3', 'Chemical', '-', (18, 23))	('C-6', 'Gene', (157, 160))
496188	25633333	An amorphous powder (CH2Cl2-MeOH), positive ion ESI-MS m/z: 297 [M+H]+, 314 [M+NH4]+, 319 [M+Na]+; negative ion ESI-MS m/z: 341 [M+HCO2]-.	('d', 'Chemical', 'MESH:D003903', (16, 17))	('314 [M+NH4]+', 'Var', (72, 84))	('HCO2', 'Chemical', '-', (131, 135))	('319 [M+Na]+', 'Var', (86, 97))	('NH4', 'Chemical', '-', (79, 82))	('CH2Cl2-MeOH', 'Chemical', '-', (21, 32))
496193	25633333	Ethyl 4,6-O-benzylidene-beta-d-glucopyranoside (17b): positive ion ESI-MS m/z: 297 [M+H]+, 314 [M+NH4]+, 615 [2M+Na]+.	('17b', 'Chemical', '-', (48, 51))	('297 [M+H]+', 'Var', (79, 89))	('NH4', 'Chemical', '-', (98, 101))	('314 [M+NH4]+', 'Var', (91, 103))	('Ethyl 4,6-O-benzylidene-beta-d-glucopyranoside', 'Chemical', '-', (0, 46))
496387	22966471	To our best knowledge, metastatic synovial sarcoma associated with desmin positivity, which may mimic myogenic tumor, has not been reported; particularly within the abdominal cavity which may cause diagnostic difficulties.	('positivity', 'Var', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (34, 50))	('desmin positivity', 'Phenotype', 'HP:0100300', (67, 84))	('associated', 'Reg', (51, 61))	('synovial sarcoma', 'Disease', (34, 50))	('synovial sarcoma', 'Disease', 'MESH:D013584', (34, 50))	('myogenic tumor', 'Disease', 'MESH:D009369', (102, 116))	('desmin', 'Gene', (67, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('myogenic tumor', 'Disease', (102, 116))	('desmin', 'Gene', '1674', (67, 73))
496398	32461620	Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases.	('KMT2A', 'Gene', '4297', (32, 37))	('YAP1', 'Gene', (90, 94))	('KMT2A', 'Gene', '4297', (95, 100))	('Sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('KMT2A', 'Gene', (114, 119))	('YAP1', 'Gene', '10413', (101, 105))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('men', 'Species', '9606', (206, 209))	('Sarcomas', 'Disease', (128, 136))	('sarcoma', 'Disease', (4, 11))	('KMT2A', 'Gene', (32, 37))	('KMT2A', 'Gene', (95, 100))	('YAP1', 'Gene', (101, 105))	('VIM', 'Gene', '7431', (110, 113))	('men', 'Species', '9606', (47, 50))	('KMT2A', 'Gene', '4297', (114, 119))	('VIM', 'Gene', (110, 113))	('Sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('YAP1', 'Gene', '10413', (90, 94))	('fusions', 'Var', (120, 127))
496399	32461620	Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (5, 24))	('KMT2A', 'Gene', (37, 42))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (153, 165))	('sarcomas', 'Disease', (17, 25))	('sclerosing epithelioid fibrosarcoma', 'Disease', 'MESH:D005354', (130, 165))	('KMT2A', 'Gene', '4297', (37, 42))	('fusions', 'Var', (43, 50))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (5, 25))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('sclerosing epithelioid fibrosarcoma', 'Disease', (130, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
496402	32461620	In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('KMT2A', 'Gene', (44, 49))	('sarcomas', 'Disease', (126, 134))	('KMT2A', 'Gene', '4297', (44, 49))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))	('variants', 'Var', (61, 69))
496404	32461620	Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]).	('KMT2A', 'Gene', (57, 62))	('YAP1', 'Gene', (83, 87))	('YAP1', 'Gene', '10413', (83, 87))	('KMT2A', 'Gene', '4297', (57, 62))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('fusions', 'Var', (63, 70))	('sarcomas', 'Disease', (43, 51))
496405	32461620	Notably, a complex rearrangement with YAP1 consistent with YAP1-KMT2A-YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1-KMT2A-YAP1 fusion and concurrent deletions of corresponding exons in KMT2A.	('YAP1', 'Gene', '10413', (175, 179))	('men', 'Species', '9606', (28, 31))	('KMT2A', 'Gene', '4297', (238, 243))	('KMT2A', 'Gene', '4297', (64, 69))	('YAP1', 'Gene', (175, 179))	('KMT2A', 'Gene', (169, 174))	('YAP1', 'Gene', '10413', (38, 42))	('YAP1', 'Gene', '10413', (70, 74))	('deletions', 'Var', (202, 211))	('YAP1', 'Gene', (38, 42))	('KMT2A', 'Gene', '4297', (131, 136))	('YAP1', 'Gene', '10413', (164, 168))	('KMT2A', 'Gene', (238, 243))	('YAP1', 'Gene', '10413', (59, 63))	('YAP1', 'Gene', (70, 74))	('KMT2A', 'Gene', (64, 69))	('CxxC-binding domain', 'MPA', (137, 156))	('YAP1', 'Gene', (164, 168))	('YAP1', 'Gene', (59, 63))	('KMT2A', 'Gene', '4297', (169, 174))	('KMT2A', 'Gene', (131, 136))
496408	32461620	Our cohort also included two sarcomas with VIM-KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells.	('ARID1A', 'Gene', '8289', (122, 128))	('ARID1A', 'Gene', (122, 128))	('VIM', 'Gene', '7431', (43, 46))	('SMARCB1', 'Gene', '6598', (109, 116))	('KMT2A', 'Gene', (47, 52))	('mutations', 'Var', (88, 97))	('SMARCB1', 'Gene', (109, 116))	('VIM', 'Gene', (43, 46))	('KMT2A', 'Gene', '4297', (47, 52))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('CTNNB1', 'Gene', '1499', (101, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('sarcomas', 'Disease', (29, 37))	('CTNNB1', 'Gene', (101, 107))
496411	32461620	Cases also include rare spindle-to-round cell sarcomas with VIM-KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners.	('KMT2A', 'Gene', (132, 137))	('tumors', 'Disease', (82, 88))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('VIM', 'Gene', (60, 63))	('YAP1', 'Gene', (153, 157))	('VIM', 'Gene', '7431', (162, 165))	('KMT2A', 'Gene', '4297', (64, 69))	('sarcomas', 'Disease', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('VIM', 'Gene', (162, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('fusions', 'Var', (138, 145))	('KMT2A', 'Gene', '4297', (132, 137))	('KMT2A', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('YAP1', 'Gene', '10413', (153, 157))	('fusions', 'Var', (70, 77))	('VIM', 'Gene', '7431', (60, 63))
496412	32461620	Sarcomas are mesenchymal tumors driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mesenchymal tumors', 'Disease', (13, 31))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (13, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('men', 'Species', '9606', (97, 100))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('gene rearrangements', 'Var', (83, 102))	('Sarcomas', 'Disease', (0, 8))
496414	32461620	Recently, oncogenic rearrangements involving Lysine methyltransferase 2A (KMT2A), a frequent fusion partner in some acute leukemias, have been reported in solid tumors, including types B2 and B3 thymomas and soft tissue sarcomas.	('KMT2A', 'Gene', (74, 79))	('tumors', 'Disease', (161, 167))	('sarcomas', 'Disease', 'MESH:D012509', (220, 228))	('acute leukemias', 'Disease', 'MESH:D015470', (116, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (220, 228))	('acute leukemias', 'Disease', (116, 131))	('Lysine methyltransferase 2A', 'Gene', '4297', (45, 72))	('thymomas', 'Disease', 'MESH:D013945', (195, 203))	('sarcomas', 'Disease', (220, 228))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (208, 228))	('acute leukemias', 'Phenotype', 'HP:0002488', (116, 131))	('reported', 'Reg', (143, 151))	('thymomas', 'Disease', (195, 203))	('rearrangements', 'Var', (20, 34))	('KMT2A', 'Gene', '4297', (74, 79))	('B2 and B3', 'Gene', '28907;680', (185, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('leukemias', 'Phenotype', 'HP:0001909', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('men', 'Species', '9606', (29, 32))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (208, 227))	('Lysine methyltransferase 2A', 'Gene', (45, 72))
496415	32461620	first described two soft tissue sarcomas with KMT2A rearrangements, one each to the partners yes-associated protein 1 (YAP1) and vimentin (VIM).	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (20, 40))	('KMT2A', 'Gene', '4297', (46, 51))	('men', 'Species', '9606', (131, 134))	('vimentin', 'Gene', '7431', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('vimentin', 'Gene', (129, 137))	('YAP1', 'Gene', (119, 123))	('VIM', 'Gene', '7431', (139, 142))	('yes-associated protein 1', 'Gene', (93, 117))	('VIM', 'Gene', (139, 142))	('KMT2A', 'Gene', (46, 51))	('rearrangements', 'Var', (52, 66))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('yes-associated protein 1', 'Gene', '10413', (93, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (20, 39))	('men', 'Species', '9606', (61, 64))	('sarcomas', 'Disease', (32, 40))	('YAP1', 'Gene', '10413', (119, 123))
496417	32461620	In this study, we described an index patient with a sarcoma that showed sclerosing epithelioid fibrosarcoma-like morphology and harbored rearrangements in KMT2A and YAP1.	('rearrangements', 'Var', (137, 151))	('sarcoma', 'Disease', (100, 107))	('YAP1', 'Gene', (165, 169))	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('KMT2A', 'Gene', '4297', (155, 160))	('YAP1', 'Gene', '10413', (165, 169))	('sarcoma', 'Disease', (52, 59))	('patient', 'Species', '9606', (37, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sclerosing epithelioid fibrosarcoma', 'Disease', (72, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('men', 'Species', '9606', (146, 149))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (95, 107))	('sclerosing epithelioid fibrosarcoma', 'Disease', 'MESH:D005354', (72, 107))	('KMT2A', 'Gene', (155, 160))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))
496420	32461620	Next-generation sequencing-based anchored multiplex PCR was performed for targeted RNA fusion transcript detection as described, and targeted sequencing of genomic DNA was performed using Illumina (San Diego, CA) for detection of single nucleotide variants, insertion/deletion (indel), and copy number alterations (lists of gene targets in Supplementary Table 1).	('men', 'Species', '9606', (346, 349))	('single nucleotide variants', 'Var', (230, 256))	('insertion/deletion', 'Var', (258, 276))	('copy number alterations', 'Var', (290, 313))
496428	32461620	Sequences were analyzed for genomic alterations including short variant alterations, copy number alterations, and gene rearrangements as described.	('copy number alterations', 'Var', (85, 108))	('men', 'Species', '9606', (128, 131))	('short variant alterations', 'Var', (58, 83))
496430	32461620	For sequence alignment of transcripts, the reference sequences for KMT2A and YAP1 used were NM_005933 and NM_006106, respectively; to be consistent with prior literature, the nomenclature was converted to NM_001197104 and NM_001130145, respectively.	('YAP1', 'Gene', '10413', (77, 81))	('men', 'Species', '9606', (18, 21))	('NM_001197104', 'Var', (205, 217))	('KMT2A', 'Gene', (67, 72))	('NM_006106', 'Var', (106, 115))	('men', 'Species', '9606', (177, 180))	('KMT2A', 'Gene', '4297', (67, 72))	('NM_001130145', 'Var', (222, 234))	('YAP1', 'Gene', (77, 81))
496431	32461620	After exclusion of hematologic-related myeloid/monocytic sarcoma, this cohort of non-hematologic soft tissue sarcomas harboring KMT2A fusions comprised 33 cases.	('KMT2A', 'Gene', (128, 133))	('KMT2A', 'Gene', '4297', (128, 133))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('fusions', 'Var', (134, 141))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (97, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('sarcoma', 'Disease', (109, 116))	('sarcoma', 'Disease', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcomas', 'Disease', (109, 117))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (97, 116))
496446	32461620	We identified 33 (0.2%) soft tissue sarcomas beyond the index case that harbored KMT2A rearrangements.	('men', 'Species', '9606', (96, 99))	('rearrangements', 'Var', (87, 101))	('KMT2A', 'Gene', (81, 86))	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('KMT2A', 'Gene', '4297', (81, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (24, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('sarcomas', 'Disease', (36, 44))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (24, 44))
496447	32461620	This cohort included 15 additional soft tissue sarcomas with complex rearrangements between YAP1 and KMT2A (Table 1), two soft tissue sarcomas with VIM-KMT2A (Supplementary Table 2, patients #S1-S2), and 16 soft tissue sarcomas with KMT2A fusions to unique non-YAP1 non-VIM partners (Supplementary Table 2, patients #S3-S18).	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (35, 55))	('VIM', 'Gene', (148, 151))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (122, 141))	('KMT2A', 'Gene', (233, 238))	('patients', 'Species', '9606', (182, 190))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('patients', 'Species', '9606', (307, 315))	('KMT2A', 'Gene', (152, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (122, 142))	('sarcomas', 'Disease', (47, 55))	('sarcomas', 'Disease', (134, 142))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (207, 226))	('KMT2A', 'Gene', '4297', (101, 106))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (207, 227))	('YAP1', 'Gene', '10413', (261, 265))	('YAP1', 'Gene', '10413', (92, 96))	('sarcomas', 'Disease', 'MESH:D012509', (219, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('VIM', 'Gene', '7431', (270, 273))	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('YAP1', 'Gene', (261, 265))	('sarcomas', 'Disease', (219, 227))	('VIM', 'Gene', (270, 273))	('men', 'Species', '9606', (78, 81))	('YAP1', 'Gene', (92, 96))	('KMT2A', 'Gene', '4297', (233, 238))	('KMT2A', 'Gene', (101, 106))	('KMT2A', 'Gene', '4297', (152, 157))	('men', 'Species', '9606', (165, 168))	('fusions', 'Var', (239, 246))	('men', 'Species', '9606', (290, 293))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (35, 54))	('VIM', 'Gene', '7431', (148, 151))
496455	32461620	Accompanying pathology reports specified that immunohistochemistry for MUC4 was negative in all four tumors tested, and that break-apart FISH for EWSR1 rearrangements was negative in all four tested cases.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('EWSR1', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('MUC4', 'Gene', (71, 75))	('EWSR1', 'Gene', '2130', (146, 151))	('MUC4', 'Gene', '4585', (71, 75))	('rearrangements', 'Var', (152, 166))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('negative', 'NegReg', (80, 88))	('men', 'Species', '9606', (161, 164))	('tumors', 'Disease', (101, 107))
496456	32461620	Fusions between YAP1 and KMT2A were detected by RNA-based assays in all 16 sarcomas, six of which were additionally confirmed by orthogonal DNA-based assays (Table 1).	('Fusions', 'Var', (0, 7))	('sarcomas', 'Disease', (75, 83))	('KMT2A', 'Gene', '4297', (25, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))	('detected', 'Reg', (36, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('KMT2A', 'Gene', (25, 30))	('sarcomas', 'Disease', 'MESH:D012509', (75, 83))	('YAP1', 'Gene', '10413', (16, 20))	('YAP1', 'Gene', (16, 20))
496459	32461620	Of these, eight tumors had separate KMT2A deletions of exons 4-6 detected at the DNA and/or RNA level (Table 1).	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('KMT2A', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('KMT2A', 'Gene', '4297', (36, 41))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('deletions', 'Var', (42, 51))	('tumors', 'Disease', (16, 22))
496461	32461620	In one of these two tumors, separate KMT2A deletion of exon 5-6 was detected.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('KMT2A', 'Gene', (37, 42))	('deletion', 'Var', (43, 51))	('KMT2A', 'Gene', '4297', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
496468	32461620	Both tumors harbored concurrent mutations in CTNNB1, SMARCB1, and ARID1A (Supplementary Table 2).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('CTNNB1', 'Gene', '1499', (45, 51))	('SMARCB1', 'Gene', '6598', (53, 60))	('ARID1A', 'Gene', '8289', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CTNNB1', 'Gene', (45, 51))	('ARID1A', 'Gene', (66, 72))	('SMARCB1', 'Gene', (53, 60))	('mutations', 'Var', (32, 41))	('men', 'Species', '9606', (80, 83))	('harbored', 'Reg', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
496470	32461620	Sixteen tumors of diverse histologic subtypes were identified with KMT2A fusion to nonrecurrent partners (Supplementary Table 2, patients #S3-S18).	('men', 'Species', '9606', (112, 115))	('patients', 'Species', '9606', (129, 137))	('KMT2A', 'Gene', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('KMT2A', 'Gene', '4297', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('fusion', 'Var', (73, 79))
496475	32461620	Pathogenic TP53 mutation was the most common co-occurring mutation, present in seven (44%) tumors in this group.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutation', 'Var', (16, 24))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('Pathogenic', 'Reg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
496477	32461620	In this study, we described 34 soft tissue sarcomas with KMT2A rearrangements.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (31, 51))	('KMT2A', 'Gene', (57, 62))	('men', 'Species', '9606', (72, 75))	('KMT2A', 'Gene', '4297', (57, 62))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('rearrangements', 'Var', (63, 77))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (31, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcomas', 'Disease', (43, 51))
496479	32461620	We found that YAP1-KMT2A rearrangements are complex in configuration, showing two reciprocally oriented breakpoints and often concurrent KMT2A exon deletions, altogether in keeping with a complex YAP1-KMT2A-YAP1 fusion.	('YAP1', 'Gene', (196, 200))	('KMT2A', 'Gene', (19, 24))	('YAP1', 'Gene', '10413', (196, 200))	('KMT2A', 'Gene', (201, 206))	('YAP1', 'Gene', (14, 18))	('YAP1', 'Gene', '10413', (14, 18))	('KMT2A', 'Gene', '4297', (19, 24))	('KMT2A', 'Gene', '4297', (201, 206))	('YAP1', 'Gene', (207, 211))	('KMT2A', 'Gene', (137, 142))	('deletions', 'Var', (148, 157))	('YAP1', 'Gene', '10413', (207, 211))	('KMT2A', 'Gene', '4297', (137, 142))	('men', 'Species', '9606', (34, 37))
496480	32461620	We also described the features of VIM-KMT2A sarcomas as well as sarcomas of diverse histologic subtypes that harbored unique nonrecurrent KMT2A fusions of unclear significance.	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('KMT2A', 'Gene', '4297', (38, 43))	('VIM', 'Gene', '7431', (34, 37))	('sarcomas', 'Disease', 'MESH:D012509', (44, 52))	('sarcomas', 'Disease', 'MESH:D012509', (64, 72))	('KMT2A', 'Gene', (138, 143))	('KMT2A', 'Gene', (38, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('fusions', 'Var', (144, 151))	('VIM', 'Gene', (34, 37))	('KMT2A', 'Gene', '4297', (138, 143))	('sarcomas', 'Disease', (44, 52))	('sarcomas', 'Disease', (64, 72))
496495	32461620	In prior studies, concurrent KMT2A and YAP1 rearrangements were noted in only one tumor tested by both break-apart fluorescence in situ hybridization (FISH) probes; negative FISH results for KMT2A and/or YAP1 were common in cases where the fusion was confirmed by sequencing.	('KMT2A', 'Gene', (29, 34))	('YAP1', 'Gene', '10413', (39, 43))	('KMT2A', 'Gene', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('KMT2A', 'Gene', '4297', (29, 34))	('KMT2A', 'Gene', '4297', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('YAP1', 'Gene', (204, 208))	('YAP1', 'Gene', '10413', (204, 208))	('men', 'Species', '9606', (53, 56))	('YAP1', 'Gene', (39, 43))	('tumor', 'Disease', (82, 87))	('rearrangements', 'Var', (44, 58))
496497	32461620	While KMT2A is frequently included on the sequencing panels for hematolymphoid neoplasms, it is less often covered on solid tumor sequencing panels due to the low prevalence of KMT2A structural alterations in solid tumors, including sarcomas.	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('KMT2A', 'Gene', '4297', (6, 11))	('tumors', 'Disease', (215, 221))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('hematolymphoid neoplasms', 'Disease', (64, 88))	('KMT2A', 'Gene', (177, 182))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('hematolymphoid neoplasms', 'Disease', 'MESH:D009369', (64, 88))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('structural alterations', 'Var', (183, 205))	('KMT2A', 'Gene', (6, 11))	('neoplasms', 'Phenotype', 'HP:0002664', (79, 88))	('tumor', 'Disease', (215, 220))	('sarcomas', 'Disease', 'MESH:D012509', (233, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('sarcomas', 'Phenotype', 'HP:0100242', (233, 241))	('neoplasm', 'Phenotype', 'HP:0002664', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('sarcomas', 'Disease', (233, 241))	('KMT2A', 'Gene', '4297', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
496503	32461620	Deletion between 5' YAP and 3' KMT2A could also generate an in-frame fusion but would not account for the two sets of fusion breakpoints observed.	('in-frame fusion', 'MPA', (60, 75))	('KMT2A', 'Gene', '4297', (31, 36))	('KMT2A', 'Gene', (31, 36))	('generate', 'Reg', (48, 56))	('Deletion', 'Var', (0, 8))
496504	32461620	We detected two sets of reciprocally oriented breakpoints involving KMT2A and YAP1 in every fully evaluated case, along with frequent concurrent exon deletion of KMT2A involving the same exons implicated in the complex fusion.	('KMT2A', 'Gene', '4297', (162, 167))	('exon deletion', 'Var', (145, 158))	('KMT2A', 'Gene', (68, 73))	('YAP1', 'Gene', (78, 82))	('KMT2A', 'Gene', (162, 167))	('YAP1', 'Gene', '10413', (78, 82))	('KMT2A', 'Gene', '4297', (68, 73))
496516	32461620	Interestingly, CCN2 encodes for a matricellular protein that is ubiquitously overexpressed in fibrotic diseases, and overexpression in fibroblasts is sufficient to cause fibrosis in tissues of multiple types.	('CCN2', 'Gene', '1490', (15, 19))	('overexpression', 'Var', (117, 131))	('cause', 'Reg', (164, 169))	('fibrotic diseases', 'Disease', 'MESH:D003141', (94, 111))	('fibrosis', 'Disease', 'MESH:D005355', (170, 178))	('fibrosis', 'Disease', (170, 178))	('CCN2', 'Gene', (15, 19))	('fibrotic diseases', 'Disease', (94, 111))
496522	32461620	In the remaining sarcomas with KMT2A fusions to non-YAP1 non-VIM partners, none of the gene partners were recurrent or previously described, and these sarcomas harbored diverse histologic diagnoses.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcomas', 'Disease', (151, 159))	('KMT2A', 'Gene', '4297', (31, 36))	('VIM', 'Gene', '7431', (61, 64))	('sarcomas', 'Disease', (17, 25))	('YAP1', 'Gene', (52, 56))	('YAP1', 'Gene', '10413', (52, 56))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('fusions', 'Var', (37, 44))	('VIM', 'Gene', (61, 64))	('KMT2A', 'Gene', (31, 36))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('harbored', 'Reg', (160, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
496524	32461620	The rarity of nonrecurrent KMT2A fusions in histologically diverse sets of sarcomas underscores the importance of correlating molecular results with clinicopathologic parameters when reaching the diagnosis.	('sarcomas', 'Disease', (75, 83))	('fusions', 'Var', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('KMT2A', 'Gene', (27, 32))	('sarcomas', 'Disease', 'MESH:D012509', (75, 83))	('KMT2A', 'Gene', '4297', (27, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
496525	32461620	Given their rarity and the frequent presence of diverse co-occurring mutations, these nonrecurrent KMT2A fusions may represent sequelae of genomic instability rather than bona fide oncogenic drivers.	('fusions', 'Var', (105, 112))	('KMT2A', 'Gene', '4297', (99, 104))	('KMT2A', 'Gene', (99, 104))
496526	32461620	In conclusion, in a comprehensive genomic profiling database of 14,680 sarcomas, KMT2A rearrangements were observed in 0.2% of cases.	('men', 'Species', '9606', (96, 99))	('rearrangements', 'Var', (87, 101))	('KMT2A', 'Gene', (81, 86))	('KMT2A', 'Gene', '4297', (81, 86))	('sarcomas', 'Disease', 'MESH:D012509', (71, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('observed', 'Reg', (107, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('sarcomas', 'Disease', (71, 79))
496527	32461620	Most KMT2A fusions involved complex rearrangements with YAP1, consistent with a YAP1-KMT2A-YAP1 fusion configuration.	('involved', 'Reg', (19, 27))	('rearrangements', 'MPA', (36, 50))	('KMT2A', 'Gene', (5, 10))	('men', 'Species', '9606', (45, 48))	('KMT2A', 'Gene', '4297', (5, 10))	('YAP1', 'Gene', (56, 60))	('KMT2A', 'Gene', (85, 90))	('YAP1', 'Gene', (80, 84))	('YAP1', 'Gene', '10413', (80, 84))	('YAP1', 'Gene', '10413', (56, 60))	('KMT2A', 'Gene', '4297', (85, 90))	('YAP1', 'Gene', '10413', (91, 95))	('fusions', 'Var', (11, 18))	('YAP1', 'Gene', (91, 95))
496530	32461620	Other unique and nonrecurrent KMT2A fusions occurred in sarcomas of diverse histologic subtypes with unclear significance.	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('KMT2A', 'Gene', (30, 35))	('occurred', 'Reg', (44, 52))	('fusions', 'Var', (36, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('KMT2A', 'Gene', '4297', (30, 35))	('sarcomas', 'Disease', (56, 64))
496531	32461620	Identification of sarcomas with pathogenic KMT2A fusions raises a possibility of targeted therapies which are actively being pursued in KMT2A-rearranged leukemias.	('sarcomas', 'Disease', 'MESH:D012509', (18, 26))	('leukemias', 'Phenotype', 'HP:0001909', (153, 162))	('KMT2A', 'Gene', (43, 48))	('leukemias', 'Disease', (153, 162))	('pathogenic', 'Reg', (32, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcomas', 'Disease', (18, 26))	('KMT2A', 'Gene', (136, 141))	('leukemias', 'Disease', 'MESH:D007938', (153, 162))	('KMT2A', 'Gene', '4297', (43, 48))	('KMT2A', 'Gene', '4297', (136, 141))	('fusions', 'Var', (49, 56))
496607	28325298	Therefore, their etiology could be explained in part by other oncogenic mechanisms such as chromosomal rearrangements, supporting the possible implication of fusion genes in the development of pediatric cancers.	('pediatric cancers', 'Disease', (193, 210))	('pediatric cancers', 'Disease', 'MESH:D009369', (193, 210))	('fusion genes', 'Var', (158, 170))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
496609	28325298	In this review, we discuss the molecular mechanisms of fusion genes and their particularities in pediatric cancers, as well as their relevance in murine models and in the clinical setting.	('murine', 'Species', '10090', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('fusion genes', 'Var', (55, 67))	('pediatric cancers', 'Disease', (97, 114))	('pediatric cancers', 'Disease', 'MESH:D009369', (97, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
496618	28325298	previously reported that 8%-10% of pediatric cancers are associated with germline alterations leading to a cancer predisposition (Table 1).	('pediatric cancers', 'Disease', 'MESH:D009369', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('pediatric cancers', 'Disease', (35, 52))	('alterations', 'Var', (82, 93))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (107, 113))	('associated', 'Reg', (57, 67))	('leading to', 'Reg', (94, 104))
496621	28325298	Other factors such as epigenetics and immune system deregulation have also been identified as being responsible for tumorigenesis.	('immune system deregulation', 'Phenotype', 'HP:0002958', (38, 64))	('deregulation', 'Var', (52, 64))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('epigenetics', 'Var', (22, 33))	('tumor', 'Disease', (116, 121))
496622	28325298	highlighted that pediatric cancers usually harbor fewer genetic mutations than adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('pediatric cancers', 'Disease', 'MESH:D009369', (17, 34))	('adult cancers', 'Disease', (79, 92))	('fewer', 'NegReg', (50, 55))	('pediatric cancers', 'Disease', (17, 34))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('adult cancers', 'Disease', 'MESH:C535836', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('genetic mutations', 'Var', (56, 73))
496626	28325298	A possible hypothesis of their etiology could be the presence of chromosome rearrangements, which is one of the first mechanisms described to be responsible for carcinogenesis.	('chromosome rearrangements', 'Var', (65, 90))	('carcinogenesis', 'Disease', (161, 175))	('carcinogenesis', 'Disease', 'MESH:D063646', (161, 175))
496627	28325298	These rearrangements can lead, in some cases, to fusion genes, which are the juxtaposition of two previously separate genes localized on the same (intra-chromosomal) or two different (inter-chromosomal) chromosomes.	('intra-chromosomal', 'Disease', (147, 164))	('fusion genes', 'Var', (49, 61))	('intra-chromosomal', 'Disease', 'MESH:D002869', (147, 164))	('lead', 'Reg', (25, 29))
496629	28325298	It has also been shown in adult cancers that some tumors with driving fusions have a much lower mutational burden compared to tumors without fusions.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('adult cancers', 'Disease', (26, 39))	('adult cancers', 'Disease', 'MESH:C535836', (26, 39))	('lower', 'NegReg', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('mutational burden', 'MPA', (96, 113))	('fusions', 'Var', (70, 77))
496630	28325298	Thus, pediatric cancers appear to be the consequence of chromosomal rearrangements rather than mutation events.	('chromosomal rearrangements', 'Var', (56, 82))	('pediatric cancers', 'Disease', 'MESH:D009369', (6, 23))	('pediatric cancers', 'Disease', (6, 23))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
496631	28325298	We should keep in mind that a recurrence of alterations (mutations and copy-number alterations) of genes involved in embryogenesis and epigenetic regulation are also described in pediatric cancers but will not be discussed here.	('pediatric cancers', 'Disease', 'MESH:D009369', (179, 196))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('pediatric cancers', 'Disease', (179, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('copy-number alterations', 'Var', (71, 94))
496634	28325298	Fusion genes were primarily discovered in leukemia and other hematological diseases.	('Fusion genes', 'Var', (0, 12))	('leukemia', 'Disease', (42, 50))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('discovered', 'Reg', (28, 38))	('leukemia', 'Disease', 'MESH:D007938', (42, 50))	('hematological diseases', 'Disease', 'MESH:D006402', (61, 83))	('hematological diseases', 'Disease', (61, 83))
496636	28325298	Twenty years later in the early 1980s, molecular studies of the translocation revealed a fusion between the 3' part of the ABL1 gene in chromosome 9 and the 5' part of the BCR1 gene in chromosome 22.	('fusion', 'Var', (89, 95))	('ABL1', 'Gene', (123, 127))	('BCR1', 'Gene', '613', (172, 176))	('ABL1', 'Gene', '25', (123, 127))	('BCR1', 'Gene', (172, 176))
496640	28325298	After this time, it became clear that fusions can drive cancer development and are potential therapeutic targets in anti-cancer treatment in a very specific manner.	('drive', 'PosReg', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (121, 127))	('fusions', 'Var', (38, 45))
496642	28325298	It should be noted that most of the studies and discoveries to date were made among adult patients; nevertheless, some pediatric cancers have been described to also harbor fusion genes that are involved in patients' diagnosis and/or targeted treatments (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('pediatric cancers', 'Disease', 'MESH:D009369', (119, 136))	('pediatric cancers', 'Disease', (119, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('fusion genes', 'Var', (172, 184))	('patients', 'Species', '9606', (206, 214))	('harbor', 'Reg', (165, 171))	('patients', 'Species', '9606', (90, 98))
496644	28325298	Fusion genes leading to abnormal protein expression were first described in adult tumors.	('adult tumors', 'Disease', (76, 88))	('Fusion', 'Var', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('adult tumors', 'Disease', 'MESH:C538052', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('protein expression', 'MPA', (33, 51))
496645	28325298	Among the best-known examples are the fusions involving immunoglobulin genes and the MYC proto-oncogene, found in various hematological malignancies.	('hematological malignancies', 'Disease', (122, 148))	('hematological malignancies', 'Disease', 'MESH:D019337', (122, 148))	('MYC', 'Gene', '4609', (85, 88))	('hematological malignancies', 'Phenotype', 'HP:0004377', (122, 148))	('MYC', 'Gene', (85, 88))	('immunoglobulin genes', 'Gene', (56, 76))	('fusions', 'Var', (38, 45))
496646	28325298	Several translocations were found to be responsible for the fusion of MYC with other genes: t(8;14) led to IGH-MYC fusion, t(2;8) gave IGK-MYC, and t(8;22) resulted in IGL-MYC.	('MYC', 'Gene', (172, 175))	('resulted in', 'Reg', (156, 167))	('led to', 'Reg', (100, 106))	('MYC', 'Gene', '4609', (111, 114))	('IGH', 'Gene', (107, 110))	('IGL', 'Gene', '3535', (168, 171))	('MYC', 'Gene', '4609', (139, 142))	('MYC', 'Gene', (111, 114))	('IGK', 'Gene', '50802', (135, 138))	('MYC', 'Gene', (70, 73))	('t(8', 'Var', (148, 151))	('MYC', 'Gene', (139, 142))	('MYC', 'Gene', '4609', (172, 175))	('t(8;14', 'Var', (92, 98))	('IGL', 'Gene', (168, 171))	('MYC', 'Gene', '4609', (70, 73))	('IGK', 'Gene', (135, 138))	('IGH', 'Gene', '3492', (107, 110))
496649	28325298	Indeed, the fusion results in constitutive activation of the MYC oncogene, increasing cell proliferation and tumorigenicity.	('fusion', 'Var', (12, 18))	('increasing', 'PosReg', (75, 85))	('activation', 'PosReg', (43, 53))	('MYC', 'Gene', '4609', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cell proliferation', 'CPA', (86, 104))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MYC', 'Gene', (61, 64))	('tumor', 'Disease', (109, 114))
496650	28325298	Another often-mentioned example is the fusion TMPRSS2-ERG found in 50% of prostate cancers, affecting chromosome 21.	('prostate cancers', 'Phenotype', 'HP:0012125', (74, 90))	('prostate cancers', 'Disease', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('TMPRSS2', 'Gene', '7113', (46, 53))	('ERG', 'Gene', '2078', (54, 57))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('TMPRSS2', 'Gene', (46, 53))	('prostate cancers', 'Disease', 'MESH:D011471', (74, 90))	('ERG', 'Gene', (54, 57))	('affecting', 'Reg', (92, 101))	('fusion', 'Var', (39, 45))
496653	28325298	To date, several chimeric oncoproteins have been identified in blood malignancies but very few are described in carcinomas.	('oncoproteins', 'Protein', (26, 38))	('identified', 'Reg', (49, 59))	('blood malignancies', 'Disease', (63, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('carcinomas', 'Disease', (112, 122))	('chimeric', 'Var', (17, 25))	('carcinomas', 'Disease', 'MESH:D002277', (112, 122))	('blood malignancies', 'Disease', 'MESH:D009369', (63, 81))
496655	28325298	Concerning pediatric cancers, EWS-FLI1 fusion is found in 85% of Ewing's sarcoma, which results in a chimeric oncoprotein between the amino terminus of EWS and the carboxy terminus of FLI, giving aberrant transcriptional activity.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (65, 80))	('FLI', 'Gene', (184, 187))	('results in', 'Reg', (88, 98))	('FLI', 'Gene', '2314', (34, 37))	("Ewing's sarcoma", 'Disease', (65, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('pediatric cancers', 'Disease', 'MESH:D009369', (11, 28))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (65, 80))	('pediatric cancers', 'Disease', (11, 28))	('FLI', 'Gene', (34, 37))	('transcriptional activity', 'MPA', (205, 229))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('oncoprotein', 'Protein', (110, 121))	('FLI', 'Gene', '2314', (184, 187))	('chimeric', 'MPA', (101, 109))	('fusion', 'Var', (39, 45))
496659	28325298	Inactivation of the tumor suppressor gene can occur through different mechanisms: the fusion can either act as the second hit (e.g., CDKN2A or NF1 genes) or lead to a dominant effect on the wild-type protein (e.g., PAX5 fusions) or even provoke haploinsufficiency of the disrupted protein (e.g., RUNX1 fusions).	('protein', 'Protein', (281, 288))	('PAX5', 'Gene', (215, 219))	('haploinsufficiency', 'Disease', (245, 263))	('RUNX1', 'Gene', '861', (296, 301))	('lead to', 'Reg', (157, 164))	('CDKN2A', 'Gene', (133, 139))	('fusion', 'Var', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('NF1', 'Gene', (143, 146))	('CDKN2A', 'Gene', '1029', (133, 139))	('NF1', 'Gene', '4763', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('provoke', 'Reg', (237, 244))	('haploinsufficiency', 'Disease', 'MESH:D058495', (245, 263))	('PAX5', 'Gene', '5079', (215, 219))	('RUNX1', 'Gene', (296, 301))	('tumor', 'Disease', (20, 25))
496666	28325298	Another example of fusions belonging to the first category are PAX3/7-FKHR fusions found in alveolar rhabdomyosarcomas due to the translocation t(2;13)(q35;q14) or, less commonly, t(1;13)(p36;p14), leading to PAX3-FOXO1 (55%-70%) or PAX7-FOXO1 (10%-22%) fusion genes, respectively.	('FOXO1', 'Gene', (214, 219))	('FOXO1', 'Gene', '2308', (214, 219))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (92, 117))	('t(2;13)(q35;q14', 'Var', (144, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('PAX7', 'Gene', (233, 237))	('FOXO1', 'Gene', '2308', (238, 243))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (101, 117))	('alveolar rhabdomyosarcomas', 'Disease', (92, 118))	('t(1;13)(p36;p14', 'Var', (180, 195))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (92, 118))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (92, 118))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (144, 160))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (101, 118))	('t(1;13)(p36;p14)', 'STRUCTURAL_ABNORMALITY', 'None', (180, 196))	('PAX7', 'Gene', '5081', (233, 237))	('FOXO1', 'Gene', (238, 243))
496677	28325298	Finally, the reciprocal translocation t(X,18; p11,q11), which is found in all cases of synovial sarcoma, leads to fusions involving the SYT gene (also named SSX18; namely, SYT-SSX1 or SYT-SSX2 fusions).	('fusions', 'Var', (114, 121))	('SSX1', 'Gene', (176, 180))	('SSX2', 'Gene', '6757', (188, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('synovial sarcoma', 'Disease', 'MESH:D013584', (87, 103))	('SSX1', 'Gene', '6756', (157, 161))	('p11', 'Gene', '6281', (46, 49))	('SSX2', 'Gene', (188, 192))	('SSX1', 'Gene', (157, 161))	('synovial sarcoma', 'Disease', (87, 103))	('SSX1', 'Gene', '6756', (176, 180))	('SYT', 'Gene', (136, 139))	('leads to', 'Reg', (105, 113))	('p11', 'Gene', (46, 49))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (87, 103))
496681	28325298	ASPSCR1-TFE3 [t(X;17)(p11.2;q25)] and, more generally, TFE3 fusions are found in more than 95% of patients with alveolar soft-part sarcoma and in a subset of patients with renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (172, 192))	('TFE3', 'Gene', (8, 12))	('alveolar soft-part sarcoma', 'Disease', (112, 138))	('TFE3', 'Gene', '7030', (55, 59))	('ASPSCR1', 'Gene', (0, 7))	('fusions', 'Var', (60, 67))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (172, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (14, 32))	('patients', 'Species', '9606', (98, 106))	('alveolar soft-part sarcoma', 'Disease', 'MESH:D018234', (112, 138))	('soft-part sarcoma', 'Phenotype', 'HP:0030448', (121, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('patients', 'Species', '9606', (158, 166))	('TFE3', 'Gene', '7030', (8, 12))	('renal cell carcinoma', 'Disease', (172, 192))	('TFE3', 'Gene', (55, 59))	('ASPSCR1', 'Gene', '79058', (0, 7))
496685	28325298	The FGFR1-TACC1 and FGFR3-TACC3 fusions were first identified in glioblastoma multiforme (GBM; also known as grade IV astrocytoma).	('FGFR3', 'Gene', '2261', (20, 25))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (65, 88))	('TACC3', 'Gene', (26, 31))	('fusions', 'Var', (32, 39))	('TACC1', 'Gene', '6867', (10, 15))	('identified', 'Reg', (51, 61))	('FGFR1', 'Gene', (4, 9))	('astrocytoma', 'Disease', 'MESH:D001254', (118, 129))	('FGFR3', 'Gene', (20, 25))	('astrocytoma', 'Disease', (118, 129))	('FGFR1', 'Gene', '2260', (4, 9))	('TACC1', 'Gene', (10, 15))	('astrocytoma', 'Phenotype', 'HP:0009592', (118, 129))	('glioblastoma multiforme', 'Disease', (65, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('TACC3', 'Gene', '10460', (26, 31))
496691	28325298	The first experiments showing its therapeutic potential involved targeting cells transfected with the KIAA1549-BRAF fusion using the BRAF inhibitor vemurafenib (PLX4032), a selective BRAFV600E inhibitor, as BRAF mutations also result in MAPK signaling activation.	('BRAF', 'Gene', (207, 211))	('KIAA1549-BRAF', 'Disease', (102, 115))	('BRAF', 'Gene', '673', (207, 211))	('BRAF', 'Gene', '673', (133, 137))	('activation', 'PosReg', (252, 262))	('KIAA1549-BRAF', 'Disease', 'None', (102, 115))	('BRAF', 'Gene', (133, 137))	('BRAFV600E', 'Mutation', 'rs113488022', (183, 192))	('vemurafenib', 'Chemical', 'MESH:D000077484', (148, 159))	('PLX4032', 'Chemical', 'MESH:D000077484', (161, 168))	('BRAF', 'Gene', '673', (183, 187))	('mutations', 'Var', (212, 221))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (183, 187))	('BRAF', 'Gene', (111, 115))	('MAPK signaling', 'Pathway', (237, 251))
496692	28325298	Although the anti-tumor effects of vemurafenib in BRAF (V600E)-mutated cells are well demonstrated, the treatment of cell lines expressing KIAA1549-BRAF with PLX4032 resulted in activation of the MAPK pathway, leading to increased cell proliferation in vitro and tumor growth in vivo.	('KIAA1549-BRAF', 'Disease', 'None', (139, 152))	('vemurafenib', 'Chemical', 'MESH:D000077484', (35, 46))	('activation', 'PosReg', (178, 188))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (263, 268))	('BRAF', 'Gene', '673', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cell proliferation in vitro', 'CPA', (231, 258))	('BRAF', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('PLX4032', 'Chemical', 'MESH:D000077484', (158, 165))	('KIAA1549-BRAF', 'Disease', (139, 152))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('MAPK pathway', 'Pathway', (196, 208))	('BRAF', 'Gene', '673', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('BRAF', 'Gene', (50, 54))	('increased', 'PosReg', (221, 230))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('PLX4032', 'Var', (158, 165))
496694	28325298	In BRAF (V600E)-mutated tumors, the level of RAS may not be sufficient to transactivate wild-type BRAF.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('V600E)-mutated', 'Var', (9, 23))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('BRAF', 'Gene', '673', (3, 7))	('BRAF', 'Gene', (3, 7))
496700	28325298	This is being currently explored in patients carrying KIAA1549-BRAF fusions (NCT01089101 and NCT02124772).	('patients', 'Species', '9606', (36, 44))	('KIAA1549-BRAF', 'Disease', 'None', (54, 67))	('NCT02124772', 'Var', (93, 104))	('NCT01089101', 'Var', (77, 88))	('KIAA1549-BRAF', 'Disease', (54, 67))
496703	28325298	ALK is a tyrosine kinase receptor; therefore, the fusion gives a chimeric oncoprotein with a constitutively activated kinase.	('oncoprotein', 'Protein', (74, 85))	('chimeric', 'MPA', (65, 73))	('ALK', 'Gene', (0, 3))	('fusion', 'Var', (50, 56))	('ALK', 'Gene', '238', (0, 3))
496706	28325298	Promising results have also been reported in pediatric patients with anaplastic large cell lymphoma (NCT00939770 and NCT01742286) (B. Geoerger et al., 2015, J. Clin.	('lymphoma', 'Disease', 'MESH:D008223', (91, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('cell lymphoma', 'Phenotype', 'HP:0012191', (86, 99))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (69, 99))	('NCT01742286', 'Var', (117, 128))	('lymphoma', 'Disease', (91, 99))	('patients', 'Species', '9606', (55, 63))	('NCT00939770', 'Var', (101, 112))
496707	28325298	Finally, and more recently, NTRK fusions involving either NTRK1, 2, or 3 located on chromosome 1 q21-q22 have raised great interest in the clinical setting, as they are found in different neoplasms in adults and children.	('neoplasm', 'Phenotype', 'HP:0002664', (188, 196))	('neoplasms', 'Disease', 'MESH:D009369', (188, 197))	('neoplasms', 'Disease', (188, 197))	('NTRK1', 'Gene', (58, 63))	('fusions', 'Var', (33, 40))	('NTRK1', 'Gene', '4914', (58, 63))	('children', 'Species', '9606', (212, 220))	('neoplasms', 'Phenotype', 'HP:0002664', (188, 197))
496709	28325298	Among childhood neoplasms harboring NTRK fusions are found soft-tissue sarcoma, congenital infantile fibrosarcoma, glioblastoma, low-grade glioma, pilocytic astrocytoma, congenital mesoblastic nephroma, acute myeloid leukemia, and various other tumor types.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('congenital infantile fibrosarcoma', 'Disease', (80, 113))	('glioma', 'Disease', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('neoplasms', 'Disease', 'MESH:D009369', (16, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (115, 127))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (59, 78))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('acute myeloid leukemia', 'Disease', (203, 225))	('congenital mesoblastic nephroma', 'Disease', 'MESH:D018201', (170, 201))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (147, 168))	('neoplasms', 'Disease', (16, 25))	('glioblastoma', 'Disease', (115, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (101, 113))	('pilocytic astrocytoma', 'Disease', (147, 168))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('congenital mesoblastic nephroma', 'Disease', (170, 201))	('tumor', 'Disease', (245, 250))	('fusions', 'Var', (41, 48))	('sarcoma', 'Disease', (106, 113))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (203, 225))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (203, 225))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('congenital infantile fibrosarcoma', 'Disease', 'MESH:D005354', (80, 113))	('neoplasms', 'Phenotype', 'HP:0002664', (16, 25))	('leukemia', 'Phenotype', 'HP:0001909', (217, 225))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (209, 225))	('sarcoma', 'Disease', (71, 78))	('congenital mesoblastic nephroma', 'Phenotype', 'HP:0100881', (170, 201))	('neoplasm', 'Phenotype', 'HP:0002664', (16, 24))
496711	28325298	Indeed, fusions specific to a cancerous disease are ideal for diagnostic purposes and for subgroup classifications; therefore, they can also be used as prognostic biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancerous disease', 'Disease', 'MESH:D009369', (30, 47))	('fusions', 'Var', (8, 15))	('cancerous disease', 'Disease', (30, 47))
496731	28325298	Interestingly, when TP53 was simultaneously deleted, EWS-FLI1 promoted tumor formation.	('TP53', 'Gene', (20, 24))	('EWS-FLI1', 'Gene', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('promoted', 'PosReg', (62, 70))	('tumor', 'Disease', (71, 76))	('TP53', 'Gene', '7157', (20, 24))	('deleted', 'Var', (44, 51))
496733	28325298	In myxoid liposarcoma, previous studies demonstrated that the introduction of the FUS-CHOP transgene into the mouse genome led to the development of liposarcomas, but its specific expression in differentiated aP2-expressing adipocytes did not result in tumor formation, suggesting the importance of the "stage of differentiation" in driving the tumors.	('liposarcomas', 'Disease', 'MESH:D008080', (149, 161))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (3, 21))	('liposarcoma', 'Phenotype', 'HP:0012034', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (345, 350))	('FUS', 'Gene', (82, 85))	('myxoid liposarcoma', 'Disease', (3, 21))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('liposarcomas', 'Phenotype', 'HP:0012034', (149, 161))	('mouse', 'Species', '10090', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (345, 351))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (3, 21))	('CHOP', 'Gene', '1649', (86, 90))	('FUS', 'Gene', '2521', (82, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('aP2', 'Gene', (209, 212))	('liposarcomas', 'Disease', (149, 161))	('tumors', 'Disease', (345, 351))	('tumor', 'Disease', (253, 258))	('liposarcoma', 'Phenotype', 'HP:0012034', (10, 21))	('CHOP', 'Gene', (86, 90))	('introduction', 'Var', (62, 74))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('aP2', 'Gene', '21418', (209, 212))	('tumors', 'Disease', 'MESH:D009369', (345, 351))	('led to', 'Reg', (123, 129))
496735	28325298	The addition of TP53 or INK4A/ARF disruption increased the frequency of alveolar rhabdomyosarcoma (RMS), emphasizing the fact that additional mutations to PAX3-FHKR fusion might be necessary to generate alveolar RMS.	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (72, 97))	('INK4A', 'Gene', (24, 29))	('alveolar RMS', 'Disease', 'MESH:D002282', (203, 215))	('RMS', 'Phenotype', 'HP:0002859', (99, 102))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (81, 97))	('alveolar rhabdomyosarcoma', 'Disease', (72, 97))	('alveolar RMS', 'Disease', (203, 215))	('increased', 'PosReg', (45, 54))	('ARF', 'Disease', 'MESH:D058186', (30, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('RMS', 'Phenotype', 'HP:0002859', (212, 215))	('ARF', 'Disease', (30, 33))	('disruption', 'Var', (34, 44))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (72, 97))	('TP53', 'Gene', '7157', (16, 20))	('INK4A', 'Gene', '1029', (24, 29))	('TP53', 'Gene', (16, 20))
496748	28325298	This type of strategy offers promising opportunities for targeted therapy, since it specifically targets fusion transcripts only expressed in tumor cells, without affecting other genes.	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('fusion', 'Var', (105, 111))
496803	23864989	It is now believed that presence of HHV-8 is necessary but not sufficient to cause KS.	('presence', 'Var', (24, 32))	('cause', 'Reg', (77, 82))	('HHV-8', 'Gene', (36, 41))	('KS', 'Phenotype', 'HP:0100726', (83, 85))	('HHV-8', 'Species', '37296', (36, 41))
496881	21486722	An aggregated Poisson model was used to estimate incidence rate ratios (IRR) of different CD4 categories (0 - 50 cells/mul, 51 - 100 cells/mul, 101 - 200 cells/mul, 201 - 350 cells/mul, 351 - 700 cells/mul and > 700 cells/mul) in comparison to the reference population, adjusted for HIV-infection status and age.	('51 - 100 cells/mul', 'Var', (124, 142))	('0 - 50 cells/mul', 'Var', (106, 122))	('CD4', 'Gene', (90, 93))	('101 - 200 cells/mul', 'Var', (144, 163))	('HIV-infection', 'Disease', 'MESH:D015658', (283, 296))	('CD4', 'Gene', '920', (90, 93))	('201 - 350 cells/mul', 'Var', (165, 184))	('HIV-infection', 'Disease', (283, 296))	('351 - 700 cells/mul', 'Var', (186, 205))
496909	21486722	The protective effect of HAART was most pronounced in infection-related types of cancer, where HAART reduced the risk for cancer by 76%.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('HAART', 'Var', (95, 100))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (81, 87))	('reduced', 'NegReg', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
496926	21486722	also reported a significant impact of CD4-cell counts on the risk of lung cancer, which was approximately ten-fold increased in patients with CD4 cell-counts < 50/mul.	('CD4', 'Gene', (38, 41))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('CD4', 'Gene', '920', (38, 41))	('CD4', 'Gene', (142, 145))	('CD4', 'Gene', '920', (142, 145))	('< 50/mul', 'Var', (158, 166))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
496987	32483396	The tumor growth timespan for SW982 is two to three times longer than other soft-tissue sarcoma cell lines we have experience with, including the EGFR negative cell line, MES-SA.	('tumor', 'Disease', (4, 9))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (76, 95))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('MES-SA', 'Chemical', '-', (171, 177))	('SW982', 'CellLine', 'CVCL:1734', (30, 35))	('longer', 'PosReg', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('SW982', 'Var', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('sarcoma', 'Disease', (88, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
497029	21493893	Human MSCs derived from adipose tissues became immortalized and spontaneously transformed after long-term culture, possibly due to augmented chromosome instability associated with dysregulation of telomere activity and cell cycle related genes.	('Human', 'Species', '9606', (0, 5))	('chromosome', 'MPA', (141, 151))	('augmented', 'PosReg', (131, 140))	('MSC', 'Gene', '17681', (6, 9))	('chromosome instability', 'Phenotype', 'HP:0040012', (141, 163))	('MSC', 'Gene', (6, 9))	('dysregulation', 'Var', (180, 193))
497094	21493893	We demonstrate that culture-expanded BM-MSCs possess chromosomal aberrations even at passage 4 of culture, and transplantation of these cells induces malignant tumors in mouse diabetic neuropathy and MI models.	('transplantation', 'Var', (111, 126))	('malignant tumors', 'Disease', (150, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('diabetic neuropathy', 'Disease', 'MESH:D003929', (176, 195))	('MI', 'Phenotype', 'HP:0001658', (200, 202))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (53, 76))	('neuropathy', 'Phenotype', 'HP:0009830', (185, 195))	('malignant tumors', 'Disease', 'MESH:D018198', (150, 166))	('MSC', 'Gene', '17681', (40, 43))	('MSC', 'Gene', (40, 43))	('mouse', 'Species', '10090', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('induces', 'Reg', (142, 149))	('rat', 'Species', '10116', (10, 13))	('rat', 'Species', '10116', (69, 72))	('diabetic neuropathy', 'Disease', (176, 195))
497311	30481590	Recently, several studies have shown that missense mutations of EWSR1 genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).	('dementia', 'Disease', (204, 212))	('FTD', 'Disease', (214, 217))	('frontotemporal dementia', 'Phenotype', 'HP:0002145', (189, 212))	('dementia', 'Disease', 'MESH:D003704', (204, 212))	('nervous system disorders', 'Phenotype', 'HP:0000707', (116, 140))	('ALS', 'Disease', 'MESH:D008113', (180, 183))	('central nervous system disorders', 'Disease', (108, 140))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (149, 178))	('central nervous system disorders', 'Disease', 'MESH:D002493', (108, 140))	('missense mutations', 'Var', (42, 60))	('FTD', 'Disease', 'MESH:C563003', (214, 217))	('dementia', 'Phenotype', 'HP:0000726', (204, 212))	('amyotrophic lateral sclerosis', 'Disease', (149, 178))	('ALS', 'Disease', (180, 183))	('central nervous system disorders', 'Phenotype', 'HP:0002011', (108, 140))	('associated', 'Reg', (92, 102))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (149, 178))	('EWSR1', 'Gene', (64, 69))
497313	30481590	Ewsr1 deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis.	('abnormal meiosis', 'Phenotype', 'HP:0031515', (125, 141))	('leads to', 'Reg', (22, 30))	('abnormal meiosis', 'Disease', (125, 141))	('Ewsr1', 'Gene', (0, 5))	('deficiency', 'Var', (6, 16))	('Ewsr1', 'Gene', '14030', (0, 5))	('premature senescence', 'CPA', (31, 51))	('rat', 'Species', '10116', (96, 99))	('abnormal meiosis', 'Disease', 'OMIM:270960', (125, 141))
497314	30481590	In this context, the current review overviews a large body of evidence and discusses on what EWSR1 genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway.	('mutations', 'Var', (107, 116))	('EWSR1', 'Gene', (93, 98))	('epigenetic pathway', 'Pathway', (205, 223))	('brain diseases', 'Disease', (137, 151))	('associated', 'Reg', (121, 131))	('brain diseases', 'Disease', 'MESH:D001927', (137, 151))	('cellular function', 'MPA', (179, 196))	('modulates', 'Reg', (169, 178))
497327	30481590	Importantly, recent studies have shown that mutations of TET family genes are closely linked to certain neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) (or termed as frontotemporal lobar degeneration [FTLD]), and essential tremor.	('FTD', 'Disease', 'MESH:C563003', (202, 205))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (104, 131))	('dementia', 'Disease', (192, 200))	('frontotemporal lobar degeneration', 'Phenotype', 'HP:0006892', (221, 254))	('frontotemporal dementia', 'Phenotype', 'HP:0002145', (177, 200))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (140, 169))	('dementia', 'Disease', 'MESH:D003704', (192, 200))	('tremor', 'Phenotype', 'HP:0001337', (278, 284))	('ALS', 'Disease', (171, 174))	('neurodegenerative disorders', 'Disease', (104, 131))	('FTD', 'Disease', (202, 205))	('FTLD', 'Disease', 'MESH:D057174', (256, 260))	('FTLD', 'Disease', (256, 260))	('frontotemporal lobar degeneration', 'Disease', (221, 254))	('TET', 'Chemical', 'MESH:C010349', (57, 60))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (140, 169))	('amyotrophic lateral sclerosis', 'Disease', (140, 169))	('linked', 'Reg', (86, 92))	('tremor', 'Disease', (278, 284))	('essential tremor', 'Phenotype', 'HP:0030186', (268, 284))	('ALS', 'Disease', 'MESH:D008113', (171, 174))	('dementia', 'Phenotype', 'HP:0000726', (192, 200))	('rat', 'Species', '10116', (115, 118))	('TET family genes', 'Gene', (57, 73))	('tremor', 'Disease', 'MESH:D014202', (278, 284))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (104, 131))	('mutations', 'Var', (44, 53))	('rat', 'Species', '10116', (248, 251))
497328	30481590	It has been shown that epigenetic modifications and signatures contribute to the pathogenesis of many human disorders.	('human', 'Species', '9606', (102, 107))	('contribute', 'Reg', (63, 73))	('human disorders', 'Disease', (102, 117))	('epigenetic modifications', 'Var', (23, 47))
497329	30481590	Despite the strong association between EWSR1 mutations in cancers and neurodegenerative disorders, its epigenetic roles are not well known.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (70, 97))	('neurodegenerative disorders', 'Disease', (70, 97))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (70, 97))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('EWSR1', 'Gene', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
497331	30481590	Mutations in TET family genes encoding FUS, EWSR1, and TAF15 have recently been demonstrated to be associated with several neurodegenerative disorders including ALS, FTD/FTLD, and essential tremor that causes involuntary and rhythmic shaking (Figure 1).	('neurodegenerative disorders', 'Disease', (123, 150))	('FTLD', 'Disease', (170, 174))	('FTLD', 'Disease', 'MESH:D057174', (170, 174))	('TAF15', 'Gene', (55, 60))	('rat', 'Species', '10116', (87, 90))	('involuntary', 'MPA', (209, 220))	('tremor', 'Phenotype', 'HP:0001337', (190, 196))	('Mutations', 'Var', (0, 9))	('rat', 'Species', '10116', (134, 137))	('EWSR1', 'Gene', (44, 49))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (123, 150))	('TET family', 'Gene', (13, 23))	('ALS', 'Disease', (161, 164))	('FTD', 'Disease', 'MESH:C563003', (166, 169))	('FUS', 'Gene', (39, 42))	('essential tremor', 'Phenotype', 'HP:0030186', (180, 196))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (123, 150))	('tremor', 'Disease', (190, 196))	('associated', 'Reg', (99, 109))	('TET', 'Chemical', 'MESH:C010349', (13, 16))	('causes', 'Reg', (202, 208))	('tremor', 'Disease', 'MESH:D014202', (190, 196))	('FTD', 'Disease', (166, 169))	('ALS', 'Disease', 'MESH:D008113', (161, 164))
497335	30481590	The findings of TET mutations in ALS and FTD pathology have made a shift in understanding the pathological mechanisms, from RBP aggregation to problem of RNA metabolism.	('ALS', 'Disease', (33, 36))	('RBP', 'Gene', '19662', (124, 127))	('TET', 'Gene', (16, 19))	('FTD', 'Disease', (41, 44))	('RBP', 'Gene', (124, 127))	('TET', 'Chemical', 'MESH:C010349', (16, 19))	('ALS', 'Disease', 'MESH:D008113', (33, 36))	('FTD', 'Disease', 'MESH:C563003', (41, 44))	('Th', 'Gene', '21823', (0, 2))	('mutations', 'Var', (20, 29))
497336	30481590	Here, we focus on mutations of EWSR1 and other members of TET family underlying ALS and FTD pathogenesis.	('FTD', 'Disease', (88, 91))	('EWSR1', 'Gene', (31, 36))	('TET', 'Chemical', 'MESH:C010349', (58, 61))	('ALS', 'Disease', 'MESH:D008113', (80, 83))	('FTD', 'Disease', 'MESH:C563003', (88, 91))	('ALS', 'Disease', (80, 83))	('mutations', 'Var', (18, 27))
497338	30481590	Over 50 mutations in the FUS gene have been identified in ALS, and about two-thirds of mutations are missense changes clustering in exons 13-15, encoding the last RRG-rich domain and a PY nuclear localization signal (Figure 1).	('ALS', 'Disease', (58, 61))	('mutations', 'Var', (8, 17))	('FUS', 'Gene', (25, 28))	('missense changes', 'Var', (101, 117))	('ALS', 'Disease', 'MESH:D008113', (58, 61))	('mutations', 'Var', (87, 96))
497339	30481590	The majority of the C-terminal mutant FUS proteins show cytoplasmic redistribution due to the defects of transportin-mediated nuclear import, resulting in a loss of nuclear function and an aggregation of cytoplasmic FUS proteins.	('cytoplasmic FUS proteins', 'MPA', (204, 228))	('C-terminal mutant', 'Var', (20, 37))	('nuclear function', 'MPA', (165, 181))	('aggregation', 'MPA', (189, 200))	('transportin-mediated nuclear import', 'MPA', (105, 140))	('FUS', 'Gene', (38, 41))	('loss', 'NegReg', (157, 161))	('defects', 'NegReg', (94, 101))	('Th', 'Gene', '21823', (0, 2))
497341	30481590	It has been documented that mutations in FUS account for less than 1% of sALS, whereas 35 different pathogenic FUS mutations have been reported in fALS in only 2 years.	('ALS', 'Disease', 'MESH:D008113', (148, 151))	('ALS', 'Disease', 'MESH:D008113', (74, 77))	('ALS', 'Disease', (148, 151))	('FUS', 'Gene', (41, 44))	('mutations', 'Var', (28, 37))	('ALS', 'Disease', (74, 77))
497345	30481590	used the models of human induced pluripotent stem cells (hiPSCs) and hiPSC derived motor neurons, and observed the FUS mislocalization in motor neurons that express mutant FUS, which is correlated with the findings in ALS patients.	('mutant', 'Var', (165, 171))	('ALS', 'Disease', (218, 221))	('patients', 'Species', '9606', (222, 230))	('ALS', 'Disease', 'MESH:D008113', (218, 221))	('human', 'Species', '9606', (19, 24))	('FUS', 'Gene', (172, 175))
497346	30481590	Nonetheless, it remains unsolved how the mutations in FUS cause the development of ALS.	('mutations', 'Var', (41, 50))	('ALS', 'Disease', 'MESH:D008113', (83, 86))	('FUS', 'Gene', (54, 57))	('cause', 'Reg', (58, 63))	('ALS', 'Disease', (83, 86))
497349	30481590	In contrast to FUS, a few EWSR1 mutations have been found in sALS patients.	('found', 'Reg', (52, 57))	('ALS', 'Disease', (62, 65))	('mutations', 'Var', (32, 41))	('EWSR1', 'Gene', (26, 31))	('ALS', 'Disease', 'MESH:D008113', (62, 65))	('patients', 'Species', '9606', (66, 74))
497351	30481590	Two missense mutations, G511A and P552L, were identified in 2 sALS cases out of 817 samples and none in 1082 control individuals, suggesting their potential cause for ALS pathogenicity (Figure 1).	('ALS', 'Disease', 'MESH:D008113', (63, 66))	('cause', 'Reg', (157, 162))	('P552L', 'Mutation', 'rs149288880', (34, 39))	('ALS', 'Disease', (167, 170))	('G511A', 'Mutation', 'rs80356719', (24, 29))	('ALS', 'Disease', (63, 66))	('P552L', 'Var', (34, 39))	('G511A', 'Var', (24, 29))	('ALS', 'Disease', 'MESH:D008113', (167, 170))
497352	30481590	G511A and P552L are located in the last RGG domain of EWSR1.	('P552L', 'Var', (10, 15))	('G511A', 'Var', (0, 5))	('G511A', 'Mutation', 'rs80356719', (0, 5))	('P552L', 'Mutation', 'rs149288880', (10, 15))
497353	30481590	Intriguingly, both ALS-linked mutant EWSR1 proteins result in a formation of cytoplasmic EWSR1 inclusion in primary motor neurons cultured from mouse spinal cord and rat embryos, whereas wild-type (WT) EWSR1 primarily reside in the nucleus.	('ALS', 'Disease', (19, 22))	('mouse', 'Species', '10090', (144, 149))	('rat', 'Species', '10116', (166, 169))	('proteins', 'Protein', (43, 51))	('EWSR1', 'Gene', (37, 42))	('ALS', 'Disease', 'MESH:D008113', (19, 22))	('EWSR1', 'Gene', (89, 94))	('result in', 'Reg', (52, 61))	('mutant', 'Var', (30, 36))
497355	30481590	Interestingly, ALS-associated mutant EWSR1 proteins show increased proclivity to form aggregated proteins than WT EWSR1, which suggests the possibility of these mutations causing accelerated aggregation in the affected motor neurons.	('aggregation', 'MPA', (191, 202))	('proclivity', 'MPA', (67, 77))	('ALS', 'Disease', 'MESH:D008113', (15, 18))	('accelerated', 'PosReg', (179, 190))	('proteins', 'Protein', (43, 51))	('mutations', 'Var', (161, 170))	('increased', 'PosReg', (57, 66))	('EWSR1', 'Gene', (37, 42))	('rat', 'Species', '10116', (185, 188))	('mutant', 'Var', (30, 36))	('ALS', 'Disease', (15, 18))
497356	30481590	Furthermore, overexpression of mutant EWSR1 in Drosophila causes neurodegeneration in the nervous system.	('neurodegeneration', 'Disease', (65, 82))	('mutant', 'Var', (31, 37))	('neurodegeneration', 'Disease', 'MESH:D019636', (65, 82))	('Drosophila', 'Species', '7227', (47, 57))	('causes', 'Reg', (58, 64))	('overexpression', 'PosReg', (13, 27))	('neurodegeneration', 'Phenotype', 'HP:0002180', (65, 82))	('EWSR1', 'Gene', (38, 43))
497357	30481590	Both in vitro and in vivo data support that mutant EWSR1 is able to confer neurodegeneration in similar manner to FUS, TAF15 and TDP43.	('EWSR1', 'Gene', (51, 56))	('TDP43', 'Gene', '230908', (129, 134))	('TDP43', 'Gene', (129, 134))	('neurodegeneration', 'Phenotype', 'HP:0002180', (75, 92))	('neurodegeneration', 'Disease', (75, 92))	('neurodegeneration', 'Disease', 'MESH:D019636', (75, 92))	('mutant', 'Var', (44, 50))
497359	30481590	Therefore, whether mutations in EWSR1 contribute significantly to the pathogenesis of fALS or not awaits further investigation.	('ALS', 'Disease', 'MESH:D008113', (87, 90))	('mutations', 'Var', (19, 28))	('contribute', 'Reg', (38, 48))	('EWSR1', 'Gene', (32, 37))	('ALS', 'Disease', (87, 90))	('Th', 'Gene', '21823', (0, 2))
497360	30481590	To date, there is very little data on EWSR1 mutations in FTD pathology.	('mutations', 'Var', (44, 53))	('FTD', 'Disease', (57, 60))	('EWSR1', 'Gene', (38, 43))	('FTD', 'Disease', 'MESH:C563003', (57, 60))
497363	30481590	TAF15 gene mutations are observed in both sALS and fALS patients (Figure 1).	('patients', 'Species', '9606', (56, 64))	('mutations', 'Var', (11, 20))	('ALS', 'Disease', (43, 46))	('ALS', 'Disease', 'MESH:D008113', (52, 55))	('TAF15', 'Gene', (0, 5))	('ALS', 'Disease', (52, 55))	('observed', 'Reg', (25, 33))	('ALS', 'Disease', 'MESH:D008113', (43, 46))
497364	30481590	Using a yeast functional screening, missense variants in TAF15 gene (G391E, R408C and G473E) were found in sALS cases, while absent in a large number of healthy individuals.	('yeast', 'Species', '4932', (8, 13))	('G391E', 'Var', (69, 74))	('TAF15', 'Gene', (57, 62))	('ALS', 'Disease', 'MESH:D008113', (108, 111))	('found', 'Reg', (98, 103))	('G391E', 'Mutation', 'rs375783267', (69, 74))	('ALS', 'Disease', (108, 111))	('missense', 'Var', (36, 44))	('R408C', 'Mutation', 'rs200175347', (76, 81))	('R408C', 'Var', (76, 81))	('G473E', 'Mutation', 'rs777993379', (86, 91))	('G473E', 'Var', (86, 91))
497365	30481590	The ALS-associated mutant TAF15 proteins also accelerate TAF15 aggregation in primary spinal cord neurons.	('rat', 'Species', '10116', (52, 55))	('TAF15 aggregation', 'MPA', (57, 74))	('TAF15', 'Gene', (26, 31))	('ALS', 'Disease', (4, 7))	('proteins', 'Protein', (32, 40))	('mutant', 'Var', (19, 25))	('Th', 'Gene', '21823', (0, 2))	('accelerate', 'PosReg', (46, 56))	('ALS', 'Disease', 'MESH:D008113', (4, 7))
497366	30481590	Notably, mutant TAF15 proteins confer neurodegeneration in Drosophila with more severe phenotypes than WT TAF15.	('neurodegeneration', 'Disease', (38, 55))	('neurodegeneration', 'Disease', 'MESH:D019636', (38, 55))	('mutant', 'Var', (9, 15))	('neurodegeneration', 'Phenotype', 'HP:0002180', (38, 55))	('proteins', 'Protein', (22, 30))	('Drosophila', 'Species', '7227', (59, 69))	('TAF15', 'Gene', (16, 21))
497367	30481590	In sALS cases, mutant TAF15 was mislocalized to the cytoplasm of motor neurons in the spinal cord.	('mutant', 'Var', (15, 21))	('ALS', 'Disease', (4, 7))	('TAF15', 'Gene', (22, 27))	('ALS', 'Disease', 'MESH:D008113', (4, 7))
497368	30481590	Mutations of TAF15 (A31T and R395Q) were also discovered in fALS cases that belong to three unrelated pedigrees, while not in over 1100 healthy cases.	('R395Q', 'Var', (29, 34))	('TAF15', 'Gene', (13, 18))	('ALS', 'Disease', (61, 64))	('A31T', 'Var', (20, 24))	('R395Q', 'Mutation', 'rs71381481', (29, 34))	('ALS', 'Disease', 'MESH:D008113', (61, 64))	('A31T', 'Mutation', 'rs771188948', (20, 24))
497369	30481590	These studies suggest that further investigations are needed to identify whether TAF15 genetic mutations are the cause of ALS pathogenesis.	('cause', 'Reg', (113, 118))	('TAF15', 'Gene', (81, 86))	('ALS', 'Disease', (122, 125))	('ALS', 'Disease', 'MESH:D008113', (122, 125))	('genetic mutations', 'Var', (87, 104))	('Th', 'Gene', '21823', (0, 2))
497385	30481590	A mechanistic study shows that Ewsr1 deficiency halts brown preadipocyte differentiation due to loss of Bmp7, a critical brown adipogenic factor during BAT development.	('Bmp7', 'Gene', (104, 108))	('brown preadipocyte differentiation', 'CPA', (54, 88))	('halts', 'NegReg', (48, 53))	('Ewsr1', 'Gene', (31, 36))	('Ewsr1', 'Gene', '14030', (31, 36))	('loss', 'NegReg', (96, 100))	('deficiency', 'Var', (37, 47))	('Bmp7', 'Gene', '12162', (104, 108))
497390	30481590	identified that Ewsr1 deficiency leads to a rapid degradation of PGC-1alpha by increasing ubiquitination and proteolysis of PGC-1alpha via proteasome pathway.	('Ewsr1', 'Gene', '14030', (16, 21))	('degradation', 'MPA', (50, 61))	('increasing', 'PosReg', (79, 89))	('proteolysis', 'MPA', (109, 120))	('ubiquitination', 'MPA', (90, 104))	('PGC-1alpha', 'Gene', '19017', (124, 134))	('PGC-1alpha', 'Gene', '19017', (65, 75))	('PGC-1alpha', 'Gene', (65, 75))	('PGC-1alpha', 'Gene', (124, 134))	('Ewsr1', 'Gene', (16, 21))	('deficiency', 'Var', (22, 32))
497399	30481590	further determined that gamma-irradiation (7 Gy) exacerbates the death of Ewsr1 mutant mice compared to Ewsr1 WT mice.	('exacerbates', 'PosReg', (49, 60))	('mutant', 'Var', (80, 86))	('mice', 'Species', '10090', (87, 91))	('death', 'Disease', 'MESH:D003643', (65, 70))	('death', 'Disease', (65, 70))	('Ewsr1', 'Gene', (104, 109))	('Ewsr1', 'Gene', (74, 79))	('mice', 'Species', '10090', (113, 117))	('Ewsr1', 'Gene', '14030', (104, 109))	('Ewsr1', 'Gene', '14030', (74, 79))
497400	30481590	Upon irradiation, Ewsr1 mutant mice lived up to 60 days while littermate control mice (Ewsr1+/+ and Ewsr1+/-) survived beyond 120 days.	('mutant', 'Var', (24, 30))	('mice', 'Species', '10090', (81, 85))	('Ewsr1', 'Gene', (18, 23))	('Ewsr1', 'Gene', (100, 105))	('Ewsr1', 'Gene', (87, 92))	('Ewsr1', 'Gene', '14030', (18, 23))	('mice', 'Species', '10090', (31, 35))	('Ewsr1', 'Gene', '14030', (87, 92))	('Ewsr1', 'Gene', '14030', (100, 105))
497403	30481590	Accordingly, it seems unlikely that the early onset of senescence in Ewsr1 mutant cells is due to telomere attrition.	('Ewsr1', 'Gene', '14030', (69, 74))	('Ewsr1', 'Gene', (69, 74))	('mutant', 'Var', (75, 81))
497404	30481590	The other molecular pathways via p53 and RB may be involved in the cellular senescence of Ewsr1 mutant cells.	('p53', 'Gene', '22060', (33, 36))	('mutant', 'Var', (96, 102))	('Ewsr1', 'Gene', '14030', (90, 95))	('involved', 'Reg', (51, 59))	('p53', 'Gene', (33, 36))	('Ewsr1', 'Gene', (90, 95))	('Th', 'Gene', '21823', (0, 2))	('cellular senescence', 'CPA', (67, 86))
497411	30481590	These findings indicate that EWSR1 plays a significant role in maintaining the hematopoietic stem cell lineage and its deficiency may trigger aging processes in a cell type-specific manner.	('deficiency', 'Var', (119, 129))	('trigger', 'Reg', (134, 141))	('aging processes', 'CPA', (142, 157))	('EWSR1', 'Gene', (29, 34))	('Th', 'Gene', '21823', (0, 2))	('hematopoietic stem cell lineage', 'CPA', (79, 110))
497419	30481590	This finding indicates that Ewsr1 deficiency downregulates TH level and, in turn, reduces PPP1R1B/DARPP-32 phosphorylation.	('DARPP-32', 'Gene', (98, 106))	('TH level', 'MPA', (59, 67))	('PPP1R1B', 'Gene', '19049', (90, 97))	('deficiency', 'Var', (34, 44))	('Ewsr1', 'Gene', (28, 33))	('TH', 'Chemical', 'MESH:D013910', (59, 61))	('Ewsr1', 'Gene', '14030', (28, 33))	('downregulates', 'NegReg', (45, 58))	('PPP1R1B', 'Gene', (90, 97))	('DARPP-32', 'Gene', '19049', (98, 106))	('Th', 'Gene', '21823', (0, 2))	('reduces', 'NegReg', (82, 89))
497421	30481590	Taken togehter, these results suggest that Ewsr1 deficiency deregulates dopaminergic signaling pathways by reducing TH and PPP1R1B/DARPP-32 activity and subsequently leads to motor dysfunction.	('Ewsr1', 'Gene', '14030', (43, 48))	('TH', 'Chemical', 'MESH:D013910', (116, 118))	('motor dysfunction', 'Disease', (175, 192))	('PPP1R1B', 'Gene', (123, 130))	('dopamine', 'Chemical', 'MESH:D004298', (72, 80))	('reducing', 'NegReg', (107, 115))	('deficiency', 'Var', (49, 59))	('leads to', 'Reg', (166, 174))	('DARPP-32', 'Gene', (131, 139))	('DARPP-32', 'Gene', '19049', (131, 139))	('motor dysfunction', 'Disease', 'MESH:D000068079', (175, 192))	('deregulates', 'Reg', (60, 71))	('dopaminergic signaling pathways', 'Pathway', (72, 103))	('activity', 'MPA', (140, 148))	('Ewsr1', 'Gene', (43, 48))	('PPP1R1B', 'Gene', '19049', (123, 130))
497426	30481590	Interestingly, both miR29b and miR-18b directly target collagen IV alpha 1 (Col4a1) and connective tissue growth factor (CTGF) mRNAs and reduce their mRNA levels by negatively regulating the post-transcriptional pathway in Ewsr1 KO mouse MEFs.	('negatively', 'NegReg', (165, 175))	('miR29b', 'Var', (20, 26))	('miR-18b', 'Gene', '100124431', (31, 38))	('MEFs', 'CellLine', 'CVCL:9115', (238, 242))	('mRNA levels', 'MPA', (150, 161))	('Ewsr1', 'Gene', '14030', (223, 228))	('CTGF', 'Gene', '14219', (121, 125))	('connective tissue growth factor', 'Gene', (88, 119))	('connective tissue growth factor', 'Gene', '14219', (88, 119))	('miR-18b', 'Gene', (31, 38))	('CTGF', 'Gene', (121, 125))	('Col4a1', 'Gene', (76, 82))	('regulating', 'Reg', (176, 186))	('post-transcriptional pathway', 'Pathway', (191, 219))	('Col4a1', 'Gene', '12826', (76, 82))	('reduce', 'NegReg', (137, 143))	('Ewsr1', 'Gene', (223, 228))	('target', 'Reg', (48, 54))	('mouse', 'Species', '10090', (232, 237))
497428	30481590	In contrast, loss of Drosha function restores Col4a1 and CTGF protein levels by normalizing miR-29b, and miR18b expression in Ewsr1 KO mouse MEFs.	('normalizing', 'NegReg', (80, 91))	('Ewsr1', 'Gene', (126, 131))	('CTGF', 'Gene', '14219', (57, 61))	('restores', 'PosReg', (37, 45))	('Ewsr1', 'Gene', '14030', (126, 131))	('Col4a1', 'Gene', '12826', (46, 52))	('miR18b', 'Gene', '100124431', (105, 111))	('mouse', 'Species', '10090', (135, 140))	('Drosha', 'Gene', '14000', (21, 27))	('miR-29b', 'MPA', (92, 99))	('miR18b', 'Gene', (105, 111))	('MEFs', 'CellLine', 'CVCL:9115', (141, 145))	('Drosha', 'Gene', (21, 27))	('loss', 'Var', (13, 17))	('Col4a1', 'Gene', (46, 52))	('CTGF', 'Gene', (57, 61))	('expression', 'MPA', (112, 122))
497430	30481590	This evidence proves a novel epigenetic role of EWSR1 in miRNA biogenesis and dermal morphogenesis.	('EWSR1', 'Gene', (48, 53))	('miRNA biogenesis', 'MPA', (57, 73))	('epigenetic', 'Var', (29, 39))	('Th', 'Gene', '21823', (0, 2))	('dermal morphogenesis', 'CPA', (78, 98))
497434	30481590	Two novel findings were identified as follows: First, Ewsr1 deficiency up regulates microprocessor complexes and miR125a and miR351.	('miR351', 'Gene', (125, 131))	('deficiency', 'Var', (60, 70))	('Ewsr1', 'Gene', (54, 59))	('miR125a', 'Gene', (113, 120))	('Ewsr1', 'Gene', '14030', (54, 59))	('miR125a', 'Gene', '387235', (113, 120))	('microprocessor complexes', 'Enzyme', (84, 108))	('up regulates', 'PosReg', (71, 83))	('miR351', 'Gene', '723910', (125, 131))
497439	30481590	UVRAG suppresses cancer cell growth by promoting autophagy, its deficiency leads to decrease of autophagy and uncontrolled cell proliferation.	('decrease', 'NegReg', (84, 92))	('autophagy', 'CPA', (96, 105))	('deficiency', 'Var', (64, 74))	('rat', 'Species', '10116', (135, 138))	('uncontrolled cell proliferation', 'CPA', (110, 141))	('autophagy', 'CPA', (49, 58))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('suppresses', 'NegReg', (6, 16))	('promoting', 'PosReg', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
497440	30481590	Based on the previous finding that DROSHA level is elevated by Ewsr1 deficiency, it is hypothesized that DROSHA-miRNA dependent pathway may be involved in UVRAG expression.	('DROSHA', 'Gene', (105, 111))	('DROSHA', 'Gene', '14000', (35, 41))	('involved', 'Reg', (143, 151))	('Ewsr1', 'Gene', (63, 68))	('deficiency', 'Var', (69, 79))	('Ewsr1', 'Gene', '14030', (63, 68))	('DROSHA', 'Gene', '14000', (105, 111))	('elevated', 'PosReg', (51, 59))	('DROSHA', 'Gene', (35, 41))
497441	30481590	Our group found that Uvrag mRNA is inversely correlated with elevated DROSHA levels in the cytoplasm of Ewsr1 null (-/-) MEFs.	('DROSHA', 'Gene', '14000', (70, 76))	('null', 'Var', (110, 114))	('elevated', 'PosReg', (61, 69))	('Uvrag', 'Gene', '78610', (21, 26))	('DROSHA', 'Gene', (70, 76))	('MEFs', 'CellLine', 'CVCL:9115', (121, 125))	('Ewsr1', 'Gene', (104, 109))	('Ewsr1', 'Gene', '14030', (104, 109))	('Uvrag', 'Gene', (21, 26))
497456	30481590	Interestingly, transcriptional activation of protein kinase PKC-ss (PRKCB) is directly regulated by the chimeric EWSR1-FLI1 protein in EWS.	('PRKCB', 'Gene', (68, 73))	('transcriptional activation', 'MPA', (15, 41))	('PRKCB', 'Gene', '18751', (68, 73))	('protein', 'Protein', (124, 131))	('protein kinase PKC-ss', 'Enzyme', (45, 66))	('EWSR1-FLI1', 'Gene', (113, 123))	('regulated', 'Reg', (87, 96))	('chimeric', 'Var', (104, 112))
497468	30481590	In this context, it is proposed that LSD1 inhibition may block the function of EWS-ETS proteins.	('EWS-ETS proteins', 'Protein', (79, 95))	('inhibition', 'Var', (42, 52))	('LSD1', 'Gene', (37, 41))	('block', 'NegReg', (57, 62))	('LSD1', 'Gene', '99982', (37, 41))	('function', 'MPA', (67, 75))
497471	30481590	We overviewed that i) genetic mutations of EWSR1 are associated with neurodegeneration, ii) EWSR1 deficiency leads to epigenetic alteration such as miRNA processing, and iii) EWSR1, as if "Jack of all trades, master of none", plays diverse molecular functions and its deficiency affects many cellular functions including autophagy and mitochondrial activity.	('deficiency', 'Var', (98, 108))	('miRNA processing', 'MPA', (148, 164))	('neurodegeneration', 'Disease', 'MESH:D019636', (69, 86))	('rat', 'Species', '10116', (80, 83))	('mitochondrial activity', 'CPA', (335, 357))	('genetic mutations', 'Var', (22, 39))	('epigenetic alteration', 'MPA', (118, 139))	('deficiency', 'Var', (268, 278))	('rat', 'Species', '10116', (133, 136))	('EWSR1', 'Gene', (92, 97))	('mutations', 'Var', (30, 39))	('EWSR1', 'Gene', (43, 48))	('associated', 'Reg', (53, 63))	('neurodegeneration', 'Phenotype', 'HP:0002180', (69, 86))	('affects', 'Reg', (279, 286))	('autophagy', 'CPA', (321, 330))	('leads to', 'Reg', (109, 117))	('neurodegeneration', 'Disease', (69, 86))
497474	30481590	(2017) developed a strategy using the combination of CRISPR-Cas9 genome editing and homology-directed repair to select human mesenchymal stem cells containing the EWSR1-WT1 translocation with fusion transcript expression under the control of the EWSR1 promoter and conditionally using Cre recombinase.	('WT1', 'Gene', '7490', (169, 172))	('rat', 'Species', '10116', (21, 24))	('fusion transcript', 'Var', (192, 209))	('WT1', 'Gene', (169, 172))	('human', 'Species', '9606', (119, 124))
497481	30481590	These data imply that sarcomagenesis can be induced via the cooperation of EWS-FLI1 and inactivation of the p53 tumor suppressor pathway.	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('p53', 'Gene', (108, 111))	('induced', 'Reg', (44, 51))	('sarcomagenesis', 'Disease', (22, 36))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('EWS-FLI1', 'Gene', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('p53', 'Gene', '22060', (108, 111))	('tumor', 'Disease', (112, 117))	('sarcomagenesis', 'Disease', 'None', (22, 36))	('Th', 'Gene', '21823', (0, 2))	('inactivation', 'Var', (88, 100))	('rat', 'Species', '10116', (65, 68))
497484	30481590	Missense mutations of EWSR1 genes are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).	('dementia', 'Disease', (109, 117))	('FTD', 'Disease', (119, 122))	('associated', 'Reg', (38, 48))	('ALS', 'Disease', (85, 88))	('dementia', 'Disease', 'MESH:D003704', (109, 117))	('frontotemporal dementia', 'Phenotype', 'HP:0002145', (94, 117))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (54, 83))	('EWSR1', 'Gene', (22, 27))	('FTD', 'Disease', 'MESH:C563003', (119, 122))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (54, 83))	('amyotrophic lateral sclerosis', 'Disease', (54, 83))	('ALS', 'Disease', 'MESH:D008113', (85, 88))	('dementia', 'Phenotype', 'HP:0000726', (109, 117))	('Missense mutations', 'Var', (0, 18))
497485	30481590	EWSR1 deficiency also contributes to hematopoietic stem cell senescence EWSR1 participates in mitochondria function and cellular energy homeostasis by modulating the stability of PGC-1alpha (Peroxisome proliferator-activated receptor gamma Coactivator) protein EWSR1 deficiency deregulates dopaminergic signaling pathways by reducing TH and PPP1R1B/DARPP-32 activity and leads to motor dysfunction.	('DARPP-32', 'Gene', (349, 357))	('leads to', 'Reg', (371, 379))	('motor dysfunction', 'Disease', (380, 397))	('deregulates', 'Reg', (278, 289))	('PGC-1alpha', 'Gene', '19017', (179, 189))	('activity', 'MPA', (358, 366))	('EWSR1', 'Gene', (261, 266))	('PGC-1alpha', 'Gene', (179, 189))	('dopaminergic signaling pathways', 'Pathway', (290, 321))	('PPP1R1B', 'Gene', '19049', (341, 348))	('motor dysfunction', 'Disease', 'MESH:D000068079', (380, 397))	('rat', 'Species', '10116', (209, 212))	('TH', 'Chemical', 'MESH:D013910', (334, 336))	('PPP1R1B', 'Gene', (341, 348))	('dopamine', 'Chemical', 'MESH:D004298', (290, 298))	('reducing', 'NegReg', (325, 333))	('DARPP-32', 'Gene', '19049', (349, 357))	('deficiency', 'Var', (267, 277))
497542	22315235	Arsenic trioxide demonstrated in vitro cytotoxicity against medulloblastoma cell lines with activation of Hh pathway through SMO mutations, and showed modest tumor growth delay against a Ptch-mutant mouse model when treatment was initiated after tumors were palpable.	('mouse', 'Species', '10090', (199, 204))	('SMO', 'Gene', '319757', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (246, 252))	('SMO', 'Gene', (125, 128))	('Arsenic trioxide', 'Chemical', 'MESH:D000077237', (0, 16))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('medulloblastoma', 'Phenotype', 'HP:0002885', (60, 75))	('medulloblastoma', 'Disease', 'MESH:D008527', (60, 75))	('cytotoxicity', 'Disease', (39, 51))	('medulloblastoma', 'Disease', (60, 75))	('growth delay', 'Phenotype', 'HP:0001510', (164, 176))	('cytotoxicity', 'Disease', 'MESH:D064420', (39, 51))	('tumor', 'Disease', (246, 251))	('Ptch', 'Gene', '19206', (187, 191))	('tumor', 'Disease', (158, 163))	('activation', 'PosReg', (92, 102))	('mutations', 'Var', (129, 138))	('Hh pathway', 'Pathway', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('Ptch', 'Gene', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))
497564	22315235	By contrast, arsenic trioxide induces partial differentiation of APL cells at concentrations of 0.1 to 0.5 muM, and it causes degradation of PML-RARalpha at concentrations as low as 0.1 muM.	('APL', 'Phenotype', 'HP:0004836', (65, 68))	('RARalpha', 'Gene', '5914', (145, 153))	('partial differentiation', 'CPA', (38, 61))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (13, 29))	('muM', 'Gene', '56925', (107, 110))	('arsenic', 'Var', (13, 20))	('PML', 'Gene', '5371', (141, 144))	('RARalpha', 'Gene', (145, 153))	('muM', 'Gene', '56925', (186, 189))	('muM', 'Gene', (107, 110))	('PML', 'Gene', (141, 144))	('degradation', 'MPA', (126, 137))	('muM', 'Gene', (186, 189))
497583	32551227	A 34-year-old G5P2002 woman who presented to labor and delivery at 30 weeks and 4 days gestation with several days of abdominal pain and tightness.	('abdominal pain', 'Disease', 'MESH:D015746', (118, 132))	('woman', 'Species', '9606', (22, 27))	('pain', 'Phenotype', 'HP:0012531', (128, 132))	('tightness', 'Disease', 'MESH:C536920', (137, 146))	('G5P2002', 'Var', (14, 21))	('labor', 'Disease', (45, 50))	('abdominal pain', 'Phenotype', 'HP:0002027', (118, 132))	('tightness', 'Disease', (137, 146))	('abdominal pain', 'Disease', (118, 132))	('labor', 'Disease', 'MESH:D048949', (45, 50))
497607	32551227	Histologically, it demonstrates epithelioid morphology with deletion of SMARCB1/INI-1.	('SMARCB1', 'Gene', (72, 79))	('deletion', 'Var', (60, 68))	('INI-1', 'Gene', '6598', (80, 85))	('INI-1', 'Gene', (80, 85))	('epithelioid morphology', 'CPA', (32, 54))	('SMARCB1', 'Gene', '6598', (72, 79))
497615	32551227	Rhabdoid tumor is identified histologically by the presence of rhabdoid tumor cells with round vesicular nuclei, prominent nucleoli, and eosinophilic inclusions within the cytoplasm, and usually with deletion of the SMARCB1/INI-1 gene on chromosome 22q11.	('Rhabdoid tumor', 'Disease', (0, 14))	('rhabdoid tumor', 'Disease', (63, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('deletion', 'Var', (200, 208))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('INI-1', 'Gene', '6598', (224, 229))	('INI-1', 'Gene', (224, 229))	('SMARCB1', 'Gene', '6598', (216, 223))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (63, 77))	('SMARCB1', 'Gene', (216, 223))	('Rhabdoid tumor', 'Disease', 'MESH:D018335', (0, 14))
497695	31528854	Low-grade ESS is often associated with JAZF1-SUZ12 (formerly JAZF1-JJAZ1) fusion gene re-arrangement and Wnt signaling.	('JAZF1', 'Gene', (61, 66))	('JAZF1', 'Gene', (39, 44))	('fusion gene re-arrangement', 'Var', (74, 100))	('SUZ12', 'Gene', '23512', (45, 50))	('JAZF1', 'Gene', '221895', (39, 44))	('SUZ12', 'Gene', (45, 50))	('ESS', 'Disease', (10, 13))	('JJAZ1', 'Gene', '23512', (67, 72))	('JAZF1', 'Gene', '221895', (61, 66))	('JJAZ1', 'Gene', (67, 72))	('associated', 'Reg', (23, 33))
497728	30173244	The early stage of a primary tumor was defined as T1 in IRSG and T1+T2 in non-RMS, and the advanced stage was defined as T2 in IRSG and T3+T4 in non-RMS.	('RMS', 'Phenotype', 'HP:0002859', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('RMS', 'Phenotype', 'HP:0002859', (149, 152))	('IRSG', 'Disease', (56, 60))	('T3+T4', 'Var', (136, 141))	('tumor', 'Disease', (29, 34))	('T1+T2', 'Var', (65, 70))
497761	30173244	Similarly, our univariate analysis revealed that patients with lymph node metastasis had worse DMFS and OS.	('worse', 'NegReg', (89, 94))	('DMFS', 'Disease', (95, 99))	('OS', 'Chemical', '-', (104, 106))	('DMFS', 'Chemical', '-', (95, 99))	('lymph node metastasis', 'Var', (63, 84))	('patients', 'Species', '9606', (49, 57))
497819	29137020	Molecular cytogenetic analysis can help the diagnosis of ASPS, because an ASPL-TFE3 (novel gene-transcription factor) translocation, which caused by a unique chromosomal rearrangement der(17)t(X;17)(p11;q25), has been identified.	('ASPS', 'Gene', '79058', (57, 61))	('caused by', 'Reg', (139, 148))	('der(17)t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (184, 207))	('TFE3', 'Gene', '7030', (79, 83))	('ASPL', 'Gene', '79058', (74, 78))	('ASPL', 'Gene', (74, 78))	('ASPS', 'Phenotype', 'HP:0012218', (57, 61))	('ASPS', 'Gene', (57, 61))	('TFE3', 'Gene', (79, 83))	('der(17)t(X;17)(p11;q25', 'Var', (184, 206))
498063	24218512	Based on prior studies, we assessed antibodies targeting CD221 (insulin-like growth factor receptor), and CD99 (MIC2) using flow cytometric analysis after in vitro immunofluorescent staining.	('MIC2', 'Gene', '4267', (112, 116))	('CD221', 'Gene', (57, 62))	('CD99', 'Var', (106, 110))	('CD221', 'Gene', '3480', (57, 62))	('MIC2', 'Gene', (112, 116))
498071	24218512	Mice with A673 (CD99+) xenograft tumors between 50-150 mm3 were injected with either 64Cu-DN16 or an isotype-matched 64Cu-IgG probe.	('A673', 'Var', (10, 14))	('64Cu-DN16', 'Chemical', '-', (85, 94))	('64Cu', 'Chemical', 'MESH:C000615411', (85, 89))	('xenograft tumors', 'Disease', (23, 39))	('64Cu', 'Chemical', 'MESH:C000615411', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('Mice', 'Species', '10090', (0, 4))	('xenograft tumors', 'Disease', 'MESH:D009369', (23, 39))	('64Cu-DN16', 'Var', (85, 94))
498072	24218512	Both probes showed distribution through the blood pool (Figure 2A), but only the 64Cu-DN16 probe demonstrated strong avidity for A673 xenografts with a statistically significant difference (p=0.001) in maximum SUV values comparing the 64Cu-DN16 probe to 64Cu-IgG (Figure 2A).	('64Cu-DN16', 'Chemical', '-', (81, 90))	('64Cu', 'Chemical', 'MESH:C000615411', (254, 258))	('avidity', 'MPA', (117, 124))	('64Cu', 'Chemical', 'MESH:C000615411', (235, 239))	('SUV values', 'MPA', (210, 220))	('64Cu-DN16', 'Var', (235, 244))	('64Cu-DN16', 'Chemical', '-', (235, 244))	('64Cu', 'Chemical', 'MESH:C000615411', (81, 85))
498076	24218512	In contrast to the 18F-FDG results (Figure 2B), uptake of the 64Cu-DN16 radiotracer was restricted to the CD99+ TC32 tumors (Figure 2C).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('64Cu-DN16', 'Chemical', '-', (62, 71))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('CD99+', 'Var', (106, 111))	('uptake', 'MPA', (48, 54))	('18F-FDG', 'Chemical', 'MESH:D019788', (19, 26))
498078	24218512	Together, these results demonstrate that the 64Cu-DN16 is highly specific for CD99 expressing tumors.	('CD99', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('64Cu-DN16', 'Var', (45, 54))	('64Cu-DN16', 'Chemical', '-', (45, 54))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
498088	24218512	Together, these results demonstrate that preclinical PET imaging with the 64Cu-DN16 probe improves signal-to-background ratio and enables detection of 1-2 mm CD99+ micrometastatic lesions that are below the threshold of detection using 18F-FDG.	('64Cu-DN16', 'Gene', (74, 83))	('micrometastatic lesions', 'CPA', (164, 187))	('CD99+', 'Var', (158, 163))	('64Cu-DN16', 'Chemical', '-', (74, 83))	('improves', 'PosReg', (90, 98))	('18F-FDG', 'Chemical', 'MESH:D019788', (236, 243))	('signal-to-background ratio', 'MPA', (99, 125))
498121	24218512	Finally, the current results suggest that an anti-CD99 antibody may have utility not only for delivering imaging moieties to CD99+ tumors, but also for delivering therapeutic payloads.	('CD99+', 'Var', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('delivering imaging moieties', 'MPA', (94, 121))
498205	24409320	1 H MR images (fast-spin echo with TR = 2000 ms, effective TE 39-48 ms, echo train length 8) were obtained from 1 mm or 2 mm thick slices with a field of view 40 mmx40 mm and matrix size 256x256, corresponding to an in-plane spatial resolution of 0.16 mm.	('256x256', 'Var', (187, 194))	('H MR', 'Disease', 'MESH:C564570', (2, 6))	('H MR', 'Disease', (2, 6))
498267	24409320	The mice injected with higher number of tumour cells (1-5x105) had a median time of 31 days until reaching protocol limits, whereas those mice injected with lower number of cells (1x103-1x104) had a median time of 44 days before being culled.	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('mice', 'Species', '10090', (4, 8))	('tumour', 'Disease', (40, 46))	('mice', 'Species', '10090', (138, 142))	('1-5x105', 'Var', (54, 61))
498275	24409320	On dissection, 2 mice which were transplanted with 25% transduced TC-71 cells were found to have additional ovarian tumours not detected by bioluminescent imaging and likely to have arisen from non-transduced cells injected.	('mice', 'Species', '10090', (17, 21))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('TC-71', 'Gene', (66, 71))	('transduced', 'Var', (55, 65))	('additional ovarian tumours', 'Disease', 'MESH:D010051', (97, 123))	('TC-71', 'CellLine', 'CVCL:2213', (66, 71))	('additional ovarian tumours', 'Disease', (97, 123))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
498327	22384167	LAGE-1 is a cancer testis antigen 90% homologous to NY-ESO-1, sharing the 157-165 A*0201 NY-ESO-1 epitope with its transcript variant, LAGE-1s.	('LAGE-1', 'Gene', '30848', (0, 6))	('NY-ESO-1', 'Gene', (89, 97))	('LAGE-1', 'Gene', '30848', (135, 141))	('NY-ESO-1', 'Gene', (52, 60))	('cancer testis antigen 90', 'Gene', (12, 36))	('NY-ESO-1', 'Gene', '246100', (52, 60))	('cancer testis', 'Phenotype', 'HP:0010788', (12, 25))	('157-165 A*0201', 'Var', (74, 88))	('cancer testis antigen 90', 'Gene', '9585', (12, 36))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('LAGE-1', 'Gene', (0, 6))	('LAGE-1', 'Gene', (135, 141))	('NY-ESO-1', 'Gene', '246100', (89, 97))
498332	22384167	Finally, using NY-ESO-1/LAGE-1s and PRAME specific effectors that we generated from sarcoma patients, we evaluated the ability of these T cells to lyse A*0201 expressing chondrosarcoma cell lines in vitro both with and without 5-Aza-dC treatment.	('5-Aza-dC', 'Chemical', '-', (227, 235))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('chondrosarcoma', 'Disease', (170, 184))	('sarcoma', 'Disease', (177, 184))	('chondrosarcoma', 'Disease', 'MESH:D002813', (170, 184))	('LAGE-1', 'Gene', (24, 30))	('sarcoma', 'Disease', (84, 91))	('NY-ESO-1', 'Gene', '246100', (15, 23))	('patients', 'Species', '9606', (92, 100))	('NY-ESO-1', 'Gene', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('A*0201', 'Var', (152, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('LAGE-1', 'Gene', '30848', (24, 30))	('PRAME', 'Gene', '23532', (36, 41))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (170, 184))	('PRAME', 'Gene', (36, 41))
498334	22384167	However, in all four of the chondrosarcoma cell lines tested, NY-ESO-1 and PRAME expression could be induced following treatment with 5-Aza-dC including in cell lines where expression was absent or barely detectable.	('NY-ESO-1', 'Gene', '246100', (62, 70))	('NY-ESO-1', 'Gene', (62, 70))	('chondrosarcoma', 'Disease', (28, 42))	('5-Aza-dC', 'Var', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (28, 42))	('induced', 'Reg', (101, 108))	('PRAME', 'Gene', '23532', (75, 80))	('5-Aza-dC', 'Chemical', '-', (134, 142))	('PRAME', 'Gene', (75, 80))	('expression', 'MPA', (81, 91))	('chondrosarcoma', 'Disease', 'MESH:D002813', (28, 42))
498335	22384167	Furthermore, NY-ESO-1/LAGE-1s and PRAME specific CD8+ effector T cells were able to specifically recognize and lyse A*0201 expressing chondrosarcoma cell lines following 5-Aza-dC treatment.	('PRAME', 'Gene', '23532', (34, 39))	('LAGE-1', 'Gene', (22, 28))	('lyse', 'Reg', (111, 115))	('PRAME', 'Gene', (34, 39))	('5-Aza-dC', 'Chemical', '-', (170, 178))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (134, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('LAGE-1', 'Gene', '30848', (22, 28))	('CD8', 'Gene', (49, 52))	('A*0201 expressing', 'Var', (116, 133))	('CD8', 'Gene', '925', (49, 52))	('NY-ESO-1', 'Gene', '246100', (13, 21))	('chondrosarcoma', 'Disease', (134, 148))	('chondrosarcoma', 'Disease', 'MESH:D002813', (134, 148))	('NY-ESO-1', 'Gene', (13, 21))
498345	22384167	The transcript variant LAGE-1s shares the A*0201 epitope, SLLMWITQC , with NY-ESO-1 and is thus an equivalent target for NY-ESO-1 directed therapy.	('A*0201', 'Var', (42, 48))	('NY-ESO-1', 'Gene', '246100', (121, 129))	('variant', 'Var', (15, 22))	('LAGE-1', 'Gene', (23, 29))	('NY-ESO-1', 'Gene', (121, 129))	('LAGE-1', 'Gene', '30848', (23, 29))	('NY-ESO-1', 'Gene', '246100', (75, 83))	('NY-ESO-1', 'Gene', (75, 83))
498365	22384167	NY-ESO-1/LAGE-1s and PRAME specific effectors were generated in our lab from sarcoma patients who were HLA typed under IRB approved protocol (FCRC protocol #1765) and found to express A*0201.	('NY-ESO-1', 'Gene', (0, 8))	('PRAME', 'Gene', '23532', (21, 26))	('PRAME', 'Gene', (21, 26))	('LAGE-1', 'Gene', '30848', (9, 15))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('A*0201', 'Var', (184, 190))	('patients', 'Species', '9606', (85, 93))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('NY-ESO-1', 'Gene', '246100', (0, 8))	('LAGE-1', 'Gene', (9, 15))
498390	22384167	NY-ESO expression increased following 5-Aza-dC treatment in each of the four cell lines.	('increased', 'PosReg', (18, 27))	('expression', 'MPA', (7, 17))	('5-Aza-dC', 'Var', (38, 46))	('5-Aza-dC', 'Chemical', '-', (38, 46))	('NY-ESO', 'Gene', (0, 6))
498394	22384167	Both of these cell lines had multiple log fold increases in NY-ESO-1 expression following 5-Aza-dC treatment.	('5-Aza-dC', 'Chemical', '-', (90, 98))	('NY-ESO-1', 'Gene', '246100', (60, 68))	('expression', 'MPA', (69, 79))	('NY-ESO-1', 'Gene', (60, 68))	('increases', 'PosReg', (47, 56))	('5-Aza-dC', 'Var', (90, 98))
498397	22384167	However PRAME expression was increased significantly following 5-Aza-dC treatment including the cell lines FS, which had increased expression above the level of the reference sample.	('increased', 'PosReg', (29, 38))	('expression', 'MPA', (14, 24))	('PRAME', 'Gene', '23532', (8, 13))	('5-Aza-dC', 'Var', (63, 71))	('PRAME', 'Gene', (8, 13))	('5-Aza-dC', 'Chemical', '-', (63, 71))
498400	22384167	The cell line FS does not express LAGE-1s but expression was induced following 5-Aza-dC treatment.	('LAGE-1', 'Gene', (34, 40))	('induced', 'Reg', (61, 68))	('5-Aza-dC', 'Var', (79, 87))	('LAGE-1', 'Gene', '30848', (34, 40))	('expression', 'MPA', (46, 56))	('5-Aza-dC', 'Chemical', '-', (79, 87))
498406	22384167	High resolution class I typing of all four chondrosarcoma cell lines and revealed that the FS and JJ cell lines both were positive for A*0201.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (43, 57))	('positive', 'Reg', (122, 130))	('A*0201', 'Var', (135, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('chondrosarcoma', 'Disease', (43, 57))	('chondrosarcoma', 'Disease', 'MESH:D002813', (43, 57))
498411	22384167	The use of 5-Aza-dC was found to significantly enhance NY-ESO/LAGE-1s mediated killing in the FS cell line compared to cells treated with vehicle alone.	('enhance', 'PosReg', (47, 54))	('5-Aza-dC', 'Chemical', '-', (11, 19))	('LAGE-1', 'Gene', (62, 68))	('5-Aza-dC', 'Var', (11, 19))	('LAGE-1', 'Gene', '30848', (62, 68))
498415	22384167	Following treatment with 5-Aza-dC, increased lysis was seen with both cell lines (Figure 2C and 2D).	('5-Aza-dC', 'Var', (25, 33))	('increased', 'PosReg', (35, 44))	('lysis', 'MPA', (45, 50))	('5-Aza-dC', 'Chemical', '-', (25, 33))
498417	22384167	Using both NY-ESO-1 and PRAME specific effectors, lysis of 5-Aza-dC treated JJ and FS was inhibited by peptide pulsed cold targets at the 30:1 cold to hot target ratio and to lesser extent at the 10:1 cold to hot target ratio compared with unpulsed controls.	('NY-ESO-1', 'Gene', '246100', (11, 19))	('PRAME', 'Gene', (24, 29))	('NY-ESO-1', 'Gene', (11, 19))	('peptide', 'Var', (103, 110))	('inhibited', 'NegReg', (90, 99))	('PRAME', 'Gene', '23532', (24, 29))	('5-Aza-dC', 'Chemical', '-', (59, 67))	('lysis', 'MPA', (50, 55))
498433	21085683	Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing's sarcoma stem cells that survive standard chemotherapy.	('Inhibiting', 'Var', (0, 10))	('EWS-FLI1', 'Gene', (15, 23))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (114, 129))	("Ewing's sarcoma", 'Disease', (114, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (114, 129))	('patient', 'Species', '9606', (84, 91))
498437	21085683	The origin of CSCs remains controversial, but whether they are derived directly from normal tissue stem cells, or from differentiated cells that have acquired stem cell properties through genetic mutations, these cells, like normal stem cells, can undergo asymmetric division and are capable of self renewal as well as giving rise to a population of differentiated tumor cells.	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('tumor', 'Disease', (365, 370))	('asymmetric division', 'CPA', (256, 275))	('giving rise to', 'Reg', (319, 333))	('self renewal', 'CPA', (295, 307))	('mutations', 'Var', (196, 205))
498444	21085683	Moreover, transduction of mesenchymal stem cells with EWS-FLI1 causes the development of tumors with an ESFT phenotype.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('EWS-FLI1', 'Gene', (54, 62))	('ESFT', 'Disease', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('transduction', 'Var', (10, 22))	('causes', 'Reg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
498489	21085683	In contrast, only 9 out of 13 of the mice injected with 800,000 ALDHlow cells and none of the mice injected with 80,000 or fewer ALDHlow cells developed a tumor, suggesting that this population was relatively depleted of tumor initiating cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (155, 160))	('mice', 'Species', '10090', (94, 98))	('ALDHlow cells', 'Var', (64, 77))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('mice', 'Species', '10090', (37, 41))
498518	21085683	At each doxorubicin dose we detected both larger and more numerous colonies arising from ALDHhigh compared with ALDHlow cells (Figure 12A).	('ALDHhigh', 'Var', (89, 97))	('doxorubicin', 'Chemical', 'MESH:D004317', (8, 19))	('colonies', 'CPA', (67, 75))
498525	21085683	In contrast, ALDHhigh cells obtained from TC71, SK-ES, RD-ES, and MHH-ES were relatively resistant to doxorubicin when compared to ALDHlow cells (Figure 10, left panels).	('TC71', 'Var', (42, 46))	('TC71', 'CellLine', 'CVCL:2213', (42, 46))	('doxorubicin', 'Chemical', 'MESH:D004317', (102, 113))	('resistant to doxorubicin', 'MPA', (89, 113))
498526	21085683	To fully assess whether YK-4-279 eradicates ESFT stem cell activity, ALDHhigh and ALDHlow TC71cells were plated in soft agar in the presence or absence of YK-4-279.	('agar', 'Chemical', 'MESH:D000362', (120, 124))	('TC71', 'CellLine', 'CVCL:2213', (90, 94))	('ESFT stem cell activity', 'CPA', (44, 67))	('eradicates', 'NegReg', (33, 43))	('YK-4-279', 'Var', (24, 32))
498527	21085683	Thus, ALDHhigh cells retain sensitivity to YK-4-279 induced EWS-FLI1 inhibition, as reflected by both direct cytotoxicity and by loss of clonogenic activity.	('YK-4-279', 'Var', (43, 51))	('EWS-FLI1', 'Gene', (60, 68))	('cytotoxicity', 'Disease', (109, 121))	('loss', 'NegReg', (129, 133))	('clonogenic activity', 'CPA', (137, 156))	('cytotoxicity', 'Disease', 'MESH:D064420', (109, 121))	('inhibition', 'NegReg', (69, 79))
498575	21085683	The sections were incubated overnight at 4 C in a humidor with monoclonal antibody to ALDH1 (1:100; BD bioscience, clone 44), diluted with 1% goat serum, 0.2% BSA and 0.3% Triton X-100 in PBS (pH 7.4), followed by washing with PBS.	('ALDH1', 'Gene', (86, 91))	('ALDH1', 'Gene', '216', (86, 91))	('PBS', 'Chemical', 'MESH:D007854', (188, 191))	('Triton X-100', 'Chemical', 'MESH:D017830', (172, 184))	('1:100;', 'Var', (93, 99))	('PBS', 'Chemical', 'MESH:D007854', (227, 230))	('goat', 'Species', '9925', (142, 146))
498662	32547975	Deep tissue cultures grew multidrug-resistant Klebsiella pneumoniae.	('Klebsiella pneumoniae', 'Disease', (46, 67))	('Klebsiella pneumoniae', 'Species', '573', (46, 67))	('multidrug-resistant', 'Var', (26, 45))
498678	30206211	However, we show that inhibitors of MDM2 and CDK4 antagonize each other in their cytotoxicity towards sarcoma cells.	('MDM2', 'Gene', (36, 40))	('cytotoxicity', 'Disease', (81, 93))	('inhibitors', 'Var', (22, 32))	('antagonize', 'Reg', (50, 60))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('CDK4', 'Gene', (45, 49))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
498681	30206211	Pharmacological inhibitors of CDK4 have proven to be effective in cancer treatment, leading to the Food and Drug Administration (FDA) approval of Palbociclib (PD0332991), Ribociclib (LEE011) and Abemaciclib (LY2835319).	('PD0332991', 'Chemical', 'MESH:C500026', (159, 168))	('LY2835319', 'Chemical', '-', (208, 217))	('PD0332991', 'Var', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('LY2835319', 'Var', (208, 217))	('LEE011', 'Var', (183, 189))	('Palbociclib', 'Chemical', 'MESH:C500026', (146, 157))	('CDK4', 'Gene', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
498685	30206211	This has spurred the search for optimized combinations of MDM2 inhibitors with other cancer drugs.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('inhibitors', 'Var', (63, 73))	('MDM2', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
498687	30206211	These tumors contain amplifications of the MDM2 gene in more than 90% of all cases, and liposarcoma-derived cell lines undergo apoptosis when treated with MDM2-antagonizing drugs.	('undergo', 'Reg', (119, 126))	('liposarcoma', 'Disease', (88, 99))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('MDM2', 'Gene', (43, 47))	('amplifications', 'Var', (21, 35))	('apoptosis', 'CPA', (127, 136))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('liposarcoma', 'Disease', 'MESH:D008080', (88, 99))	('liposarcoma', 'Phenotype', 'HP:0012034', (88, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
498689	30206211	The amplification of the MDM2 gene in sarcomas is often associated with CDK4 amplifications.	('CDK4', 'Gene', (72, 76))	('amplifications', 'Var', (77, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('sarcomas', 'Disease', (38, 46))	('MDM2', 'Gene', (25, 29))	('associated', 'Reg', (56, 66))	('amplification', 'Var', (4, 17))	('sarcomas', 'Disease', 'MESH:D012509', (38, 46))
498690	30206211	Other examples of tumors containing both amplifications include melanomas and parosteal osteosarcomas.	('amplifications', 'Var', (41, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('melanomas and parosteal osteosarcomas', 'Disease', 'MESH:D012516', (64, 101))	('osteosarcomas', 'Phenotype', 'HP:0002669', (88, 101))	('osteosarcoma', 'Phenotype', 'HP:0002669', (88, 100))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
498691	30206211	The co-amplification of both genes might constitute tumor cell addiction to the simultaneous activity of both gene products.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('co-amplification', 'Var', (4, 20))
498694	30206211	Here we show that the inhibition of CDK4 attenuates MDM2 inhibitor-induced activity of p53, leading to decreased rather than synergistic cytotoxicity.	('inhibition', 'Var', (22, 32))	('CDK4', 'Protein', (36, 40))	('attenuates', 'NegReg', (41, 51))	('cytotoxicity', 'Disease', (137, 149))	('decreased', 'NegReg', (103, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (137, 149))	('activity', 'MPA', (75, 83))	('MDM2', 'Gene', (52, 56))
498701	30206211	For treatment of cells, neocarzinostatin (NCS, 0.5 mg/mL, Sigma-Aldrich), Nutlin-3a (Sigma N6287 and BOC life sciences 675576-98-4), Palbociclib (PD0332991 isethionate, Sigma PZ0199), Ribociclib (LEE011, Selleckchem S7440), Abemaciclib (LY2835219, Selleckchem S7158) and MG-132 (Calbiochem 474791) were diluted in pre-warmed medium and added to the cells for the indicated periods of time.	('PD0332991', 'Chemical', 'MESH:C500026', (146, 155))	('Palbociclib', 'Chemical', 'MESH:C500026', (133, 144))	('LEE011', 'Var', (196, 202))	('Nutlin', 'Chemical', '-', (74, 80))	('PD0332991', 'Var', (146, 155))	('LY2835219', 'Var', (237, 246))	('LY2835219', 'Chemical', 'MESH:C000590451', (237, 246))
498710	30206211	This was followed by transfer on a nitrocellulose membrane and visualization with the following antibodies: pH2AX (S139) (9718, Cell Signalling), Beta-Actin (ab8227, Abcam), p21 (2947, Cell Signalling), pRb (S807/811) (9308, Cell Signalling), Rb (9309, Cell Signalling), MDM2 (OP 46, Calbiochem), p53 (DO-1, sc-126, Santa Cruz), p53-HRP (DO-1, sc-126, Santa Cruz), CDK4 (ab68266 abcam; DCS-35, sc-23896, Santa Cruz), p53 K382ac (2525, Cell Signalling) and Cyclin D1 (ab134175, Abcam).	('pRb', 'Gene', '5925', (203, 206))	('p21', 'Gene', (174, 177))	('Cyclin D1', 'Gene', (456, 465))	('Rb', 'Chemical', 'MESH:D012413', (243, 245))	('Beta-Actin', 'Gene', '396797', (146, 156))	('p21', 'Gene', '1026', (174, 177))	('Rb', 'Chemical', 'MESH:D012413', (204, 206))	('p53 K382ac', 'Var', (417, 427))	('pRb', 'Gene', (203, 206))	('Beta-Actin', 'Gene', (146, 156))
498722	30206211	For IP, the following antibodies were used: p53 (DO-1, sc-126, Santa Cruz), IgG (ab46540, Abcam), H3K27ac (C15410196, Diagenode), RNA Polymerase II (MABI0601, MBL Life Sciences; sc-17798, Santa Cruz; sc-899, Santa Cruz).	('MBL', 'Gene', (159, 162))	('MBL', 'Gene', '50639', (159, 162))	('C15410196', 'Var', (107, 116))
498725	30206211	We treated SJSA cells (osteosarcoma cells with amplifications of MDM2 and CKD4, cf.	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('CKD4', 'Var', (74, 78))	('MDM2', 'Gene', (65, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (23, 35))	('amplifications', 'Var', (47, 61))	('osteosarcoma', 'Disease', (23, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (23, 35))
498728	30206211	S1b), and PD0332991 abolished the phosphorylation of the CDK4 substrate pRb at Serine 807/811 (Fig.	('PD0332991', 'Var', (10, 19))	('phosphorylation', 'MPA', (34, 49))	('abolished', 'NegReg', (20, 29))	('pRb', 'Gene', '5925', (72, 75))	('pRb', 'Gene', (72, 75))	('Serine', 'Chemical', 'MESH:D012694', (79, 85))	('PD0332991', 'Chemical', 'MESH:C500026', (10, 19))
498743	30206211	To determine whether the impairment of p53 target gene expression was specific to Palbociclib or whether it was due to inhibition of CDK4/6 kinase activity, in general, we treated SJSA cells with alternate, FDA-approved CDK4/6 inhibitors, namely LEE011 (Ribociclib) and LY2835219 (Abemaciclib), alone or in combination with Nutlin.	('LY2835219', 'Chemical', 'MESH:C000590451', (270, 279))	('CDK4/6', 'Gene', '1019;1021', (133, 139))	('Palbociclib', 'Chemical', 'MESH:C500026', (82, 93))	('CDK4/6', 'Gene', '1019;1021', (220, 226))	('CDK4/6', 'Gene', (133, 139))	('LEE011', 'Var', (246, 252))	('Nutlin', 'Chemical', '-', (324, 330))	('CDK4/6', 'Gene', (220, 226))	('LY2835219', 'Var', (270, 279))
498747	30206211	Strikingly, Palbociclib pretreatment strongly decreased the accumulation of p53 and its target gene product p21 in response to NCS (Fig.	('accumulation', 'MPA', (60, 72))	('p53', 'Protein', (76, 79))	('p21', 'Gene', '1026', (108, 111))	('p21', 'Gene', (108, 111))	('decreased', 'NegReg', (46, 55))	('Palbociclib', 'Chemical', 'MESH:C500026', (12, 23))	('NCS', 'Var', (127, 130))
498748	30206211	Hence, CDK4 inhibition can also interfere with the p53-inducing ability of DNA damaging drugs, giving rise to caution when combining CDK4 inhibitors with conventional chemotherapy in cancer treatment.	('inhibition', 'Var', (12, 22))	('cancer', 'Disease', (183, 189))	('p53-inducing ability', 'MPA', (51, 71))	('interfere', 'NegReg', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('CDK4', 'Protein', (7, 11))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
498749	30206211	This revealed corresponding changes in p53-induced p21, i.e., induction by MDM2 knockdown alone, but far less induction by the simultaneous depletion of MDM2 and CDK4 (Fig.	('p53-induced', 'Gene', (39, 50))	('knockdown', 'Var', (80, 89))	('p21', 'Gene', '1026', (51, 54))	('p21', 'Gene', (51, 54))	('MDM2', 'Gene', (75, 79))	('changes', 'Reg', (28, 35))
498750	30206211	Moreover, to exclude any role of the p53 kinase HIPK2 in this context, we performed a parallel experiment replacing CDK4 inhibitors with the HIPK2 inhibitor A64 (PubChem Substance ID 329826044) but did not observe any detectable change in p53 activity (Fig.	('HIPK2', 'Gene', '28996', (48, 53))	('HIPK2', 'Gene', (48, 53))	('A64', 'Chemical', '-', (157, 160))	('CDK4', 'Gene', (116, 120))	('inhibitors', 'Var', (121, 131))	('HIPK2', 'Gene', '28996', (141, 146))	('HIPK2', 'Gene', (141, 146))
498759	30206211	We conclude that, when cells are subjected to MDM2 inhibition, a CDK4/6 inhibitor specifically attenuates the expression of p53-responsive genes more than any other distinguishable group of genes except the cell cycle regulators.	('p53-responsive genes', 'Gene', (124, 144))	('inhibitor', 'Var', (72, 81))	('CDK4/6', 'Gene', '1019;1021', (65, 71))	('expression', 'MPA', (110, 120))	('attenuates', 'NegReg', (95, 105))	('CDK4/6', 'Gene', (65, 71))
498762	30206211	To mechanistically understand how CDK4/6 inhibition reduces the activity of p53 as a transcription factor, we performed immunoblot analysis to detect the acetylation of p53 on Lys 382, an activating modification of p53.	('CDK4/6', 'Gene', '1019;1021', (34, 40))	('Lys', 'Chemical', 'MESH:D008239', (176, 179))	('acetylation', 'MPA', (154, 165))	('p53', 'Gene', (169, 172))	('reduces', 'NegReg', (52, 59))	('inhibition', 'Var', (41, 51))	('activity', 'MPA', (64, 72))	('CDK4/6', 'Gene', (34, 40))
498763	30206211	Surprisingly, we observed that the acetylation of p53 was even stronger when PD0332991 was combined with Nutlin than Nutlin alone (Fig.	('Nutlin', 'Chemical', '-', (105, 111))	('p53', 'Protein', (50, 53))	('PD0332991', 'Chemical', 'MESH:C500026', (77, 86))	('combined', 'Interaction', (91, 99))	('stronger', 'PosReg', (63, 71))	('PD0332991', 'Var', (77, 86))	('Nutlin', 'Chemical', '-', (117, 123))	('acetylation', 'MPA', (35, 46))
498766	30206211	We observed that CDK4/6 inhibition mostly reduced pre-mRNA levels proximal to the promoters of p53-responsive genes in response to Nutlin (Fig.	('reduced', 'NegReg', (42, 49))	('CDK4/6', 'Gene', '1019;1021', (17, 23))	('p53-responsive', 'Gene', (95, 109))	('response', 'MPA', (119, 127))	('inhibition', 'Var', (24, 34))	('pre-mRNA levels proximal to the', 'MPA', (50, 81))	('CDK4/6', 'Gene', (17, 23))	('Nutlin', 'Chemical', '-', (131, 137))
498772	30206211	In conclusion, CDK4/6 inhibition interferes with the recruitment of RNA Polymerase II by p53, thereby diminishing the initiation of transcription at p53 target genes.	('inhibition', 'Var', (22, 32))	('CDK4/6', 'Gene', (15, 21))	('interferes', 'NegReg', (33, 43))	('RNA Polymerase II', 'Protein', (68, 85))	('recruitment', 'Interaction', (53, 64))	('diminishing', 'NegReg', (102, 113))	('CDK4/6', 'Gene', '1019;1021', (15, 21))	('initiation of transcription', 'MPA', (118, 145))
498784	30206211	In cells where accumulated MDM2 leads to the degradation of hypophosphorylated Rb, apoptosis can be induced, but when Rb remains, the cells merely arrest.	('degradation', 'MPA', (45, 56))	('MDM2', 'Var', (27, 31))	('Rb', 'Chemical', 'MESH:D012413', (79, 81))	('apoptosis', 'CPA', (83, 92))	('hypophosphorylated', 'MPA', (60, 78))	('Rb', 'Chemical', 'MESH:D012413', (118, 120))
498793	30206211	The DNA damaging drug Trabectedin, currently used in second line for treating soft tissue sarcoma, was also reported to synergize with the MDM2 inhibitor RG7112, perhaps as a result of p53 accumulation (through MDM2 inhibition) and activating p53 modifications (through DNA damage response).	('p53', 'Gene', (185, 188))	('sarcoma', 'Disease', (90, 97))	('modifications', 'Var', (247, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('accumulation', 'PosReg', (189, 201))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (78, 97))	('p53', 'Gene', (243, 246))	('activating', 'PosReg', (232, 242))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
498794	30206211	In preclinical investigations and cell culture, MDM2 antagonists also cooperated efficiently with mitogen-activated protein kinase kinase (MEK) or phosphatidylinositol-3 kinase (PI3K) inhibitors, BH3 mimetics, BCR-ABL antagonists, and histone deacetylase inhibitors.	('mitogen-activated protein kinase kinase', 'Gene', '5609', (98, 137))	('phosphatidylinositol-3 kinase', 'Gene', (147, 176))	('antagonists', 'Var', (53, 64))	('BCR-ABL', 'Gene', '25', (210, 217))	('MDM2', 'Gene', (48, 52))	('BCR-ABL', 'Gene', (210, 217))	('MEK', 'Gene', (139, 142))	('phosphatidylinositol-3 kinase', 'Gene', '5290', (147, 176))	('MEK', 'Gene', '5609', (139, 142))	('mitogen-activated protein kinase kinase', 'Gene', (98, 137))
498800	30206211	Thus, combining CDK4 inhibitors with DNA damaging chemotherapy might turn out to protect non-cancerous tissue in a patient, giving rise to a potential strategy for avoiding undesired general toxicities.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('CDK4', 'Protein', (16, 20))	('toxicities', 'Disease', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('inhibitors', 'Var', (21, 31))	('patient', 'Species', '9606', (115, 122))	('toxicities', 'Disease', 'MESH:D064420', (191, 201))
498809	30158829	To ensure inclusion of only ES or PNET tumors, codes for Askin tumors (code 9365; n=15) and CNS PNET (code 9473; n=1621) were excluded.	('Askin tumors', 'Disease', 'MESH:C563168', (57, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ES', 'Phenotype', 'HP:0012254', (28, 30))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('code 9365', 'Var', (71, 80))	('code 9473', 'Var', (102, 111))	('Askin tumors', 'Disease', (57, 69))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
498889	27994217	Sporadic DF demonstrates mutations in the CTNNB1 gene in 80% of cases, whereas hereditary tumors show genetic abnormalities most frequently in the adenomatous polyposis coli (APC) gene on 5q21-q22.	('mutations', 'Var', (25, 34))	('genetic abnormalities', 'Disease', 'MESH:D030342', (102, 123))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (147, 173))	('hereditary tumors', 'Disease', 'MESH:D009386', (79, 96))	('hereditary tumors', 'Disease', (79, 96))	('APC', 'Gene', (175, 178))	('APC', 'Phenotype', 'HP:0005227', (175, 178))	('adenomatous polyposis coli', 'Disease', (147, 173))	('APC', 'Gene', '324', (175, 178))	('DF', 'Phenotype', 'HP:0100245', (9, 11))	('genetic abnormalities', 'Disease', (102, 123))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CTNNB1', 'Gene', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CTNNB1', 'Gene', '1499', (42, 48))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (147, 168))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (147, 173))
498893	27994217	FAP is inherited in an autosomal dominant manner, with 80% showing mutations in the APC gene.	('APC', 'Gene', '324', (84, 87))	('FAP', 'Disease', 'MESH:C567782', (0, 3))	('mutations', 'Var', (67, 76))	('FAP', 'Disease', (0, 3))	('APC', 'Phenotype', 'HP:0005227', (84, 87))	('APC', 'Gene', (84, 87))
498991	25563490	The most reliable criteria for the immunohistochemical diagnosis of CCH when only paraffin sections are available are CD18 and MHCII positivity coupled with negative labelling for the lymphocytic markers CD3 and CD79alpha (Fernandez et al.).	('positivity', 'Var', (133, 143))	('CCH', 'Chemical', '-', (68, 71))	('CD18', 'Gene', '16414', (118, 122))	('CD79alpha', 'Gene', (212, 221))	('CCH', 'Disease', (68, 71))	('CD79alpha', 'Gene', '484483', (212, 221))	('paraffin', 'Chemical', 'MESH:D010232', (82, 90))	('CD18', 'Gene', (118, 122))	('MHCII', 'Gene', (127, 132))
499131	25563490	As previously reported, most of the lymphocytes infiltrating CCHs were CD3+ and CD8+, whereas B-lymphocytes and CD4 lymphocytes were encountered less frequently (Moore et al.).	('CCH', 'Chemical', '-', (61, 64))	('CCHs', 'Disease', (61, 65))	('CD8+', 'Var', (80, 84))	('rat', 'Species', '10116', (54, 57))	('CD3+', 'Var', (71, 75))	('CD4', 'Gene', '403931', (112, 115))	('CD4', 'Gene', (112, 115))
499137	25563490	The mechanism of tumour regression is connected with CD8+ lymphocytes, which cause the apoptosis or necrosis of tumour cells (Barry and Bleackley).	('necrosis of tumour', 'Disease', 'MESH:D009336', (100, 118))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour regression', 'Disease', 'MESH:D009365', (17, 34))	('apoptosis', 'CPA', (87, 96))	('necrosis of tumour', 'Disease', (100, 118))	('CD8+ lymphocytes', 'Var', (53, 69))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('tumour regression', 'Disease', (17, 34))
499221	23178492	Downregulation of LOX and TGFBR2 were not off-target RNAi effects because the gene expression changes mediated by EWS/FLI knockdown were reversed by re-expression of an RNAi-resistant EWS/FLI cDNA in multiple Ewing sarcoma cell lines (Figure 1B; S1B).	('FLI', 'Gene', '2314', (188, 191))	('FLI', 'Gene', '2314', (118, 121))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (209, 222))	('Ewing sarcoma', 'Disease', (209, 222))	('FLI', 'Gene', (188, 191))	('knockdown', 'Var', (122, 131))	('expression', 'Species', '29278', (83, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (209, 222))	('expression', 'Species', '29278', (152, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('TGFBR2', 'Gene', (26, 32))	('TGFBR2', 'Gene', '21813', (26, 32))	('FLI', 'Gene', (118, 121))
499234	23178492	We next sought to identify the key domains required for transcriptional repression mediated by EWS/FLI by knocking-down endogenous EWS/FLI and re-introducing mutant forms of the protein (Figures S3A-S3E), followed by evaluation of endogenous LOX and TGFBR2 expression.	('FLI', 'Gene', (135, 138))	('expression', 'Species', '29278', (257, 267))	('FLI', 'Gene', (99, 102))	('knocking-down', 'Var', (106, 119))	('TGFBR2', 'Gene', (250, 256))	('TGFBR2', 'Gene', '21813', (250, 256))	('FLI', 'Gene', '2314', (135, 138))	('mutant', 'Var', (158, 164))	('FLI', 'Gene', '2314', (99, 102))
499235	23178492	We found that the DNA binding mutant R2L2 failed to repress LOX or TGFBR2, but the mutant Delta89-C, lacking the carboxyl-terminal 89 amino acids of EWS/FLI retained full repressive capability at these loci (Figures 3A, 3B, S3A-S3C).	('FLI', 'Gene', (153, 156))	('repressive', 'MPA', (171, 181))	('mutant Delta89-C', 'Var', (83, 99))	('TGFBR2', 'Gene', (67, 73))	('Delta89-C', 'Var', (90, 99))	('TGFBR2', 'Gene', '21813', (67, 73))	('lacking', 'NegReg', (101, 108))	('FLI', 'Gene', '2314', (153, 156))	('Delta89', 'Mutation', 'c.del89', (90, 97))
499236	23178492	In contrast, the Delta22 mutant, lacking nearly all of the EWS portion of EWS/FLI, did not repress LOX or TGFBR2 when introduced in place of full-length EWS/FLI (Figures 3A, 3B, S3A-S3C).	('FLI', 'Gene', '2314', (78, 81))	('TGFBR2', 'Gene', (106, 112))	('FLI', 'Gene', '2314', (157, 160))	('TGFBR2', 'Gene', '21813', (106, 112))	('FLI', 'Gene', (78, 81))	('FLI', 'Gene', (157, 160))	('Delta22 mutant', 'Var', (17, 31))	('Delta22', 'Mutation', 'c.del22', (17, 24))
499238	23178492	We then used a previously-described panel of deletion mutants to further refine the location of the repression domain within EWS/FLI (Figures 3B; S3C-S3E).	('deletion mutants', 'Var', (45, 61))	('mutants', 'Var', (54, 61))	('FLI', 'Gene', '2314', (129, 132))	('FLI', 'Gene', (129, 132))
499241	23178492	Consistent with this observation, EWS/FLI mutants that retained transcriptional repressive function also retained the ability to activate the critical EWS/FLI upregulated target genes NKX2.2 and NR0B1, while mutants deficient in transcriptional repression also failed to transactivate these genes (Figures 3E, 3F).	('NR0B1', 'Gene', (195, 200))	('activate', 'PosReg', (129, 137))	('mutants', 'Var', (42, 49))	('FLI', 'Gene', '2314', (155, 158))	('FLI', 'Gene', '2314', (38, 41))	('NKX2.2', 'Gene', (184, 190))	('FLI', 'Gene', (38, 41))	('transcriptional repressive function', 'MPA', (64, 99))	('FLI', 'Gene', (155, 158))	('upregulated', 'PosReg', (159, 170))
499242	23178492	Importantly, the mutants that mediate both transcriptional repression and activation also rescue oncogenic transformation of Ewing sarcoma cells following EWS/FLI knockdown, while those that are inactive in repression and activation do not (Figure 3G).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('Ewing sarcoma', 'Disease', (125, 138))	('rescue', 'PosReg', (90, 96))	('FLI', 'Gene', '2314', (159, 162))	('oncogenic transformation', 'CPA', (97, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('FLI', 'Gene', (159, 162))	('mutants', 'Var', (17, 24))
499245	23178492	This construct was previously shown to effectively transactivate a reporter construct and induce oncogenic transformation of NIH3T3 cells.	('NIH3T3', 'CellLine', 'CVCL:0594', (125, 131))	('transactivate', 'Var', (51, 64))	('oncogenic transformation', 'CPA', (97, 121))	('induce', 'Reg', (90, 96))
499265	23178492	These data were consistent with siRNA experiments that showed that knock-down of HDAC2 or HDAC3, but not HDAC1, derepressed both LOX and TGFBR2 (Figures S5C, S5D).	('HDAC2', 'Gene', (81, 86))	('HDAC3', 'Gene', (90, 95))	('derepressed', 'NegReg', (112, 123))	('S5D', 'Mutation', 'p.S5D', (158, 161))	('knock-down', 'Var', (67, 77))	('TGFBR2', 'Gene', (137, 143))	('TGFBR2', 'Gene', '21813', (137, 143))	('LOX', 'Gene', (129, 132))
499266	23178492	If HDAC2 and/or HDAC3 were truly involved in EWS/FLI-mediated transcriptional repression, we would predict that these proteins would interact with EWS/FLI mutants that mediate transcriptional repression, but not with inactive mutants.	('involved', 'Reg', (33, 41))	('mutants', 'Var', (155, 162))	('FLI', 'Gene', '2314', (151, 154))	('transcriptional', 'MPA', (176, 191))	('FLI', 'Gene', (151, 154))	('FLI', 'Gene', '2314', (49, 52))	('FLI', 'Gene', (49, 52))	('interact', 'Interaction', (133, 141))
499267	23178492	To test this, we knocked-down endogenous EWS/FLI in Ewing sarcoma cells and rescued with RNAi-resistant cDNAs encoding wild-type EWS/FLI, the Delta22 mutant (that does not mediate transcriptional repression), or mutant 9 (that retains transcriptional repression activity).	('Delta22', 'Mutation', 'c.del22', (142, 149))	('Delta22', 'Var', (142, 149))	('FLI', 'Gene', (133, 136))	('knocked-down', 'Var', (17, 29))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))	('FLI', 'Gene', '2314', (45, 48))	('Ewing sarcoma', 'Disease', (52, 65))	('FLI', 'Gene', (45, 48))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('FLI', 'Gene', '2314', (133, 136))
499268	23178492	We found that wild-type EWS/FLI and mutant 9 both bind HDAC2 and HDAC3, while the Delta22 mutant does not (Figure 5F).	('HDAC3', 'Gene', (65, 70))	('bind', 'Interaction', (50, 54))	('FLI', 'Gene', '2314', (28, 31))	('Delta22', 'Mutation', 'c.del22', (82, 89))	('HDAC2', 'Protein', (55, 60))	('mutant', 'Var', (36, 42))	('FLI', 'Gene', (28, 31))
499273	23178492	In contrast, ~50% knockdown of the NuRD complex component Chromodomain Helicase DNA-Binding Protein 4 (CHD4) resulted in significant upregulation of both LOX and TGFBR2 (Figure 6A).	('knockdown', 'Var', (18, 27))	('CHD4', 'Gene', (103, 107))	('TGFBR2', 'Gene', (162, 168))	('upregulation', 'PosReg', (133, 145))	('TGFBR2', 'Gene', '21813', (162, 168))	('LOX', 'Gene', (154, 157))
499276	23178492	We found that full-length EWS/FLI and the repressive mutant 9 allele bind both CHD4 and MTA2 NuRD complex components in co-immunoprecipitation experiments, while the non-repressive Delta22 protein does not (Figure 6B).	('FLI', 'Gene', '2314', (30, 33))	('Delta22', 'Mutation', 'c.del22', (181, 188))	('FLI', 'Gene', (30, 33))	('mutant', 'Var', (53, 59))
499282	23178492	De-repression of LOX and TGFBR2 was absolutely dependent on the expression of EWS/FLI, as the effect was lost following knockdown of the fusion protein (Figures 6E, 6F), and was not observed in the EWS/FLI-deficient cell line HEK 293 (Figure S6I).	('FLI', 'Gene', '2314', (82, 85))	('FLI', 'Gene', (82, 85))	('TGFBR2', 'Gene', (25, 31))	('TGFBR2', 'Gene', '21813', (25, 31))	('FLI', 'Gene', '2314', (202, 205))	('FLI', 'Gene', (202, 205))	('knockdown', 'Var', (120, 129))	('De-repression', 'NegReg', (0, 13))	('HEK 293', 'CellLine', 'CVCL:0045', (226, 233))	('lost', 'NegReg', (105, 109))	('expression', 'Species', '29278', (64, 74))
499283	23178492	Dose-dependent increases in expression of both LOX and TGFBR2 with siRNA knock-down of LSD1 in A673 cells confirmed the specificity of the effect observed with the small-molecule inhibitors (Figure S6J).	('LSD1', 'Gene', (87, 91))	('expression', 'Species', '29278', (28, 38))	('LSD1', 'Gene', '23028', (87, 91))	('expression', 'MPA', (28, 38))	('TGFBR2', 'Gene', (55, 61))	('TGFBR2', 'Gene', '21813', (55, 61))	('increases', 'PosReg', (15, 24))	('knock-down', 'Var', (73, 83))
499296	23178492	In support of this argument, we validated previous data suggesting an important role for inhibition of TGFBR2 in Ewing sarcoma development, and extended these data by demonstrating a critical role for the inhibition of LOX expression as well.	('expression', 'Species', '29278', (223, 233))	('inhibition', 'Var', (89, 99))	('TGFBR2', 'Gene', (103, 109))	('Ewing sarcoma', 'Disease', (113, 126))	('TGFBR2', 'Gene', '21813', (103, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (113, 126))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (113, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))
499312	23178492	This suggests that there may be EWS/FLI-associated sub-complexes of the NuRD co-repressor in Ewing sarcoma cells that contains HDAC3 instead of HDAC1.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (93, 106))	('HDAC3', 'Var', (127, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (93, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Ewing sarcoma', 'Disease', (93, 106))	('FLI', 'Gene', '2314', (36, 39))	('FLI', 'Gene', (36, 39))
499325	23178492	HDAC inhibition has already been shown to block Ewing sarcoma cell growth, transformation, and survival in ex vivo settings.	('HDAC', 'Gene', (0, 4))	('inhibition', 'Var', (5, 15))	('block Ewing sarcoma', 'Disease', 'MESH:C563168', (42, 61))	('block Ewing sarcoma', 'Disease', (42, 61))	('transformation', 'CPA', (75, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (48, 61))	('survival', 'CPA', (95, 103))
499326	23178492	Our data show that LSD1 specific inhibitors also block growth and survival of multiple Ewing sarcoma patient-derived cell lines.	('block', 'NegReg', (49, 54))	('growth', 'CPA', (55, 61))	('LSD1', 'Gene', (19, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('LSD1', 'Gene', '23028', (19, 23))	('Ewing sarcoma', 'Disease', (87, 100))	('survival', 'CPA', (66, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (87, 100))	('patient', 'Species', '9606', (101, 108))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (87, 100))	('inhibitors', 'Var', (33, 43))
499327	23178492	Of note, a recent report documented LSD1 expression in Ewing sarcoma tumors, and demonstrated that inhibition of LSD1 activity (with a monoamine oxidase inhibitor) blocked Ewing sarcoma cell growth in tissue culture.	('inhibition', 'Var', (99, 109))	('blocked', 'NegReg', (164, 171))	('Ewing sarcoma', 'Disease', (172, 185))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (55, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('activity', 'MPA', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('LSD1', 'Gene', (36, 40))	('LSD1', 'Gene', '23028', (36, 40))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (55, 68))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (55, 68))	('Ewing sarcoma tumors', 'Disease', (55, 75))	('LSD1', 'Gene', (113, 117))	('LSD1', 'Gene', '23028', (113, 117))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (172, 185))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (172, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('expression', 'Species', '29278', (41, 51))
499333	23178492	The Luc-RNAi, EF-2-RNAi, EWS/FLI, Delta22, R2L2, mutants 2, 3 and 9 have been described previously.	('FLI', 'Gene', (29, 32))	('Delta22', 'Mutation', 'c.del22', (34, 41))	('FLI', 'Gene', '2314', (29, 32))	('mutants', 'Var', (49, 56))
499344	23178492	The following antibodies were used for immunodetection: M2-anti-FLAG (HRP; Sigma A8592), anti-FLI-1 (Santa-Cruz sc-356X), anti-alpha-Tubulin (Calbiochem CP06), anti-HDAC1 (Santa-Cruz sc-7872), anti-HDAC2 (Santa-Cruz sc-7899), anti-HDAC3 (Santa-Cruz sc-11417), anti-CHD4/Mi2 beta (BETHYL Laboratories Inc. A301-081A), anti-MTA-2 (Abcam A8106), anti-LOX (Santa-Cruz sc-66947), anti-EWS (Santa-Cruz sc-48404), anti-REST (Santa-Cruz sc-374611), anti-NcoR (Abcam ab80856), anti-LSD1 (Cell Signaling C69G12), anti-NKX2.2 (Santa-Cruz sc-15015) and anti-NR0B1 (Abcam ab24552).	('FLI', 'Gene', '2314', (94, 97))	('LSD1', 'Gene', (473, 477))	('anti-NR0B1', 'Var', (541, 551))	('FLI', 'Gene', (94, 97))	('LSD1', 'Gene', '23028', (473, 477))
499345	23178492	Directed ChIPs were performed as previously described using anti-FLI-1 and anti-ELK-1 antibodies (sc-356X and sc-355 respectively; Santa Cruz Biotechnology, Inc.).	('FLI', 'Gene', '2314', (65, 68))	('FLI', 'Gene', (65, 68))	('sc-356X', 'Var', (98, 105))	('sc-355', 'Var', (110, 116))
499347	23178492	Nuclear extracts were prepared from 293EBNA cells transfected with 3X-FLAG wild-type EWS/FLI, 3X-FLAG deletion mutants of EWS/FLI, or empty vector control expression plasmids.	('FLI', 'Gene', '2314', (89, 92))	('expression', 'Species', '29278', (155, 165))	('FLI', 'Gene', '2314', (126, 129))	('FLI', 'Gene', (89, 92))	('FLI', 'Gene', (126, 129))	('deletion mutants', 'Var', (102, 118))	('293EBNA', 'CellLine', 'CVCL:6974', (36, 43))
499365	32381079	The (X;18)(p11;q11) translocation results in fusion of the homologous gene at Xp11 (SSX1, SSX2, or SSX4) and the SYT gene on chromosome 18.	('SSX2', 'Gene', (90, 94))	('SSX1', 'Gene', (84, 88))	('fusion', 'Var', (45, 51))	('SSX4', 'Gene', '6759', (99, 103))	('SYT', 'Gene', (113, 116))	('SSX4', 'Gene', (99, 103))	('results in', 'Reg', (34, 44))	('SSX1', 'Gene', '6756', (84, 88))	('SSX2', 'Gene', '6757', (90, 94))	('SYT', 'Gene', '6760', (113, 116))
499367	32381079	SS18 rearrangement is a recognized aberration in SS.	('SS18', 'Gene', (0, 4))	('SS18', 'Gene', '6760', (0, 4))	('rearrangement', 'Var', (5, 18))
499378	32381079	Fluorescence in situ hybridization (FISH) revealed positivity for SS18(SYT)(18q11.2) in 68% of the interphase nuclei.	('positivity', 'Var', (51, 61))	('SYT', 'Gene', (71, 74))	('SS18', 'Gene', '6760', (66, 70))	('SYT', 'Gene', '6760', (71, 74))	('SS18', 'Gene', (66, 70))
499414	31882401	Inhibition of Haspin kinase promotes cell-intrinsic and extrinsic anti-tumor activity Melanoma patients resistant to RAF/MEK-inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease.	('cell-intrinsic', 'MPA', (37, 51))	('RAF', 'Gene', '22882', (117, 120))	('patients', 'Species', '9606', (95, 103))	('Melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('RAF', 'Gene', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Haspin', 'Gene', (14, 20))	('promotes', 'PosReg', (28, 36))	('MEK', 'Gene', (121, 124))	('Melanoma', 'Disease', 'MESH:D008545', (86, 94))	('MEK', 'Gene', '5609', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Inhibition', 'Var', (0, 10))	('Melanoma', 'Disease', (86, 94))	('tumor', 'Disease', (71, 76))
499419	31882401	In murine models, CX-6258 induced a potent cGAS-dependent type-I-interferon response in tumor cells, increased IFNgamma-producing CD8+ T-cells and reduced Treg frequency in vivo.	('Treg frequency', 'CPA', (155, 169))	('reduced', 'NegReg', (147, 154))	('CD8', 'Gene', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('increased', 'PosReg', (101, 110))	('CX-6258', 'Chemical', 'MESH:C000607921', (18, 25))	('cGAS-dependent type-I-interferon response', 'MPA', (43, 84))	('CD8', 'Gene', '925', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CX-6258', 'Var', (18, 25))	('murine', 'Species', '10090', (3, 9))	('tumor', 'Disease', (88, 93))
499424	31882401	About half of melanomas harbor BRAF mutations, which sensitizes tumors to RAF/MEK inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('MEK', 'Gene', (78, 81))	('MEK', 'Gene', '5609', (78, 81))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (36, 45))	('RAF', 'Gene', (32, 35))	('RAF', 'Gene', '22882', (32, 35))	('RAF', 'Gene', '22882', (74, 77))	('RAF', 'Gene', (74, 77))	('melanomas harbor BRAF', 'Disease', 'MESH:C537062', (14, 35))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('melanomas harbor BRAF', 'Disease', (14, 35))
499431	31882401	CDK4/6 inhibitors, for example, enhance anti-tumor immunity by increasing responsiveness to ICIs and/or by activation of NK cells.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('NK cells', 'CPA', (121, 129))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('inhibitors', 'Var', (7, 17))	('responsiveness to ICIs', 'MPA', (74, 96))	('increasing', 'PosReg', (63, 73))	('enhance', 'PosReg', (32, 39))	('CDK4/6', 'Gene', (0, 6))	('activation', 'PosReg', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
499485	31882401	Taqman assays (ThermoFisher) for Ifna1 (#Mm00439552_s1) and Ifnb1 (#Mm03030145_gH) were run on a QuantStudio 6 Flex (Applied Biosystems) with TaqMan  gene expression MasterMix (ThermoFisher).	('#Mm03030145_gH', 'Var', (67, 81))	('Ifnb1', 'Gene', '3456', (60, 65))	('Ifna1', 'Gene', (33, 38))	('Ifnb1', 'Gene', (60, 65))	('#Mm00439552_s1', 'Var', (40, 54))	('Ifna1', 'Gene', '3439', (33, 38))
499486	31882401	Gapdh (Mm99999915_g1) and Actb (Mm00607939_s1) were used as reference genes for normalization.	('Mm99999915_g1', 'Var', (7, 20))	('Actb', 'Gene', (26, 30))	('Actb', 'Gene', '60', (26, 30))	('Mm00607939_s1', 'Var', (32, 45))	('Gapdh', 'Gene', '2597', (0, 5))	('Gapdh', 'Gene', (0, 5))
499489	31882401	After washing cells were stained with secondary anti-Rabbit Alexa488 or anti-human Alex647 (ThermoFisher).	('Alex647', 'Gene', (83, 90))	('Alexa488', 'Chemical', '-', (60, 68))	('anti-human', 'Var', (72, 82))	('Alex647', 'Chemical', '-', (83, 90))	('human', 'Species', '9606', (77, 82))
499507	31882401	Thereafter surface antigens were stained in PBS supplemented with 3% FBS and 2mM EDTA for 30 minutes on ice using anti-CD45-BV510 (30-F11, Biolegend), anti-CD3-PE-Cy5 (145-2C11, Biolegend), anti-CD4-BV605 (RM4-5, Biolegend), anti-CD8a-BV785 (53-6.7, Biolegend), anti-NKp46-PE (145-29A1.4, Biolegend), anti-CD14-APC (Sa14.2, Biolegend), anti-CD45R-APC (RA3-6B2, Biolegend), anti-F4/80-APC (BM8, Biolegend).	('PBS', 'Chemical', 'MESH:D007854', (44, 47))	('anti-F4/80-APC', 'Var', (373, 387))	('CD8a', 'Gene', (230, 234))	('CD4', 'Gene', (341, 344))	('NKp46', 'Gene', '9437', (267, 272))	('CD4', 'Gene', '920', (195, 198))	('CD45R', 'Gene', (341, 346))	('CD14', 'Gene', (306, 310))	('CD45', 'Gene', (119, 123))	('CD14', 'Gene', '929', (306, 310))	('NKp46', 'Gene', (267, 272))	('CD45', 'Gene', '5788', (119, 123))	('CD4', 'Gene', (195, 198))	('CD45', 'Gene', (341, 345))	('CD45', 'Gene', '5788', (341, 345))	('CD4', 'Gene', '920', (119, 122))	('CD8a', 'Gene', '925', (230, 234))	('CD4', 'Gene', (119, 122))	('CD4', 'Gene', '920', (341, 344))	('CD45R', 'Gene', '5788', (341, 346))
499525	31882401	Both S and RMR cell lines were treated with 1 muM drug for three days and viable cell numbers were inferred from ATP levels in cell extracts; by this measure, CX-6258 was highly active in both A375-S and A375-RMR cells, as well as UACC62-S and UACC62-RMR (Figure 1A and B, Supplementary Figure 1H, EC50 ~100 nM in A375 and ~300 nM in UACC62).	('EC50', 'Var', (298, 302))	('ATP', 'Chemical', 'MESH:D000255', (113, 116))	('UACC62', 'Chemical', '-', (334, 340))	('active', 'MPA', (178, 184))	('UACC62', 'Chemical', '-', (244, 250))	('A375-S', 'CellLine', 'CVCL:Y439', (193, 199))	('CX-6258', 'Chemical', 'MESH:C000607921', (159, 166))	('muM', 'Gene', '56925', (46, 49))	('CX-6258', 'Gene', (159, 166))	('UACC62', 'Chemical', '-', (231, 237))	('A375', 'CellLine', 'CVCL:0132', (193, 197))	('A375', 'CellLine', 'CVCL:0132', (314, 318))	('A375', 'CellLine', 'CVCL:0132', (204, 208))	('muM', 'Gene', (46, 49))
499526	31882401	When we corrected for differences in A375 and UACC62 proliferation rates using the normalized growth rate inhibition (GR) metric, CX-6258 was equally potent in both cell lines with GR50 ~200 nM and GRmax ~1 muM (Figure 1C-D).	('A375', 'CellLine', 'CVCL:0132', (37, 41))	('muM', 'Gene', '56925', (207, 210))	('UACC62', 'Chemical', '-', (46, 52))	('muM', 'Gene', (207, 210))	('CX-6258', 'Chemical', 'MESH:C000607921', (130, 137))	('CX-6258', 'Var', (130, 137))
499527	31882401	To assess activity in vivo, we generated xenografts of A375-S and A375-RMR in nude mice (n=5/group) and treated animals for five days with either vehicle control or CX-6258 (100 mg/kg) by daily oral gavage.	('A375-S', 'CellLine', 'CVCL:Y439', (55, 61))	('CX-6258', 'Chemical', 'MESH:C000607921', (165, 172))	('A375', 'CellLine', 'CVCL:0132', (66, 70))	('A375', 'CellLine', 'CVCL:0132', (55, 59))	('A375-S', 'Var', (55, 61))	('nude mice', 'Species', '10090', (78, 87))	('A375-RMR', 'Var', (66, 74))
499528	31882401	CX-6258 significantly reduced tumor growth in both types of tumor (A375-S vs. A375-S plus CX-6258; p= 0.02; A375-RMR vs. A375-RMR plus CX-6258, p = 0.01, by 2-way ANOVA) demonstrating oral bioavailability (Figure 1E).	('CX-6258', 'Chemical', 'MESH:C000607921', (0, 7))	('A375-S', 'CellLine', 'CVCL:Y439', (67, 73))	('A375', 'CellLine', 'CVCL:0132', (108, 112))	('CX-6258', 'Chemical', 'MESH:C000607921', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('A375', 'CellLine', 'CVCL:0132', (121, 125))	('A375-S', 'CellLine', 'CVCL:Y439', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('CX-6258', 'Chemical', 'MESH:C000607921', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('reduced', 'NegReg', (22, 29))	('A375', 'CellLine', 'CVCL:0132', (67, 71))	('tumor', 'Disease', (60, 65))	('A375-RMR', 'Var', (108, 116))	('tumor', 'Disease', (30, 35))	('A375', 'CellLine', 'CVCL:0132', (78, 82))	('A375-S', 'Var', (78, 84))
499529	31882401	Nude mice treated with CX-6258 did not display weight loss suggesting in vivo tolerability of the compound (Supplementary Figure 1I).	('Nude mice', 'Species', '10090', (0, 9))	('weight loss', 'Disease', (47, 58))	('weight loss', 'Phenotype', 'HP:0001824', (47, 58))	('CX-6258', 'Chemical', 'MESH:C000607921', (23, 30))	('weight loss', 'Disease', 'MESH:D015431', (47, 58))	('CX-6258', 'Var', (23, 30))
499536	31882401	Cell counts were not reduced in cells treated with CX-6258 at 100 nM compared to DMSO treated cells (mean difference 0.04%, adjusted p>0.99 ANOVA) while doses of 300 nM to 10 muM resulted in modest reduction of cell numbers (Figure 1I).	('CX-6258', 'Chemical', 'MESH:C000607921', (51, 58))	('reduction', 'NegReg', (198, 207))	('muM', 'Gene', (175, 178))	('DMSO', 'Chemical', 'MESH:D004121', (81, 85))	('cell numbers', 'CPA', (211, 223))	('CX-6258', 'Var', (51, 58))	('Cell counts', 'CPA', (0, 11))	('muM', 'Gene', '56925', (175, 178))
499537	31882401	Thus, CX-6258 is active against melanoma cells and modestly toxic against human TILs and neurons in vitro.	('CX-6258', 'Chemical', 'MESH:C000607921', (6, 13))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('CX-6258', 'Var', (6, 13))	('human', 'Species', '9606', (74, 79))
499538	31882401	CX-6258 is annotated as an inhibitor of PIM-kinases, a family of kinases that act downstream of the JAK/STAT pathway.	('CX-6258', 'Chemical', 'MESH:C000607921', (0, 7))	('CX-6258', 'Var', (0, 7))	('PIM', 'Gene', '5292', (40, 43))	('JAK', 'Gene', '3716', (100, 103))	('STAT', 'Gene', '6774', (104, 108))	('JAK', 'Gene', (100, 103))	('STAT', 'Gene', (104, 108))	('PIM', 'Gene', (40, 43))
499540	31882401	As previously described, CX-6258 bound PIM1-3 but also bound MYLK4 and HASPIN with high affinity (Figure 1J, Supplementary Figure 1K).	('CX-6258', 'Chemical', 'MESH:C000607921', (25, 32))	('CX-6258', 'Var', (25, 32))	('MYLK4', 'Gene', '340156', (61, 66))	('bound', 'Interaction', (55, 60))	('PIM1-3', 'Gene', '5292;11040;415116', (39, 45))	('HASPIN', 'Gene', (71, 77))	('bound', 'Interaction', (33, 38))	('HASPIN', 'Gene', '83903', (71, 77))	('MYLK4', 'Gene', (61, 66))	('PIM1-3', 'Gene', (39, 45))
499542	31882401	Despite having partially overlapping target spectra, GR50 values for AZD1206, PIM447, and SGI1776 in A375 were ~30-fold higher (> 3 muM) than CX-6258 (Figure 1L) demonstrating that CX-6258 has higher activity in cell-based assays.	('CX-6258', 'Chemical', 'MESH:C000607921', (181, 188))	('AZD1206', 'Var', (69, 76))	('higher', 'PosReg', (120, 126))	('CX-6258', 'Chemical', 'MESH:C000607921', (142, 149))	('PIM447', 'Var', (78, 84))	('SGI1776', 'Var', (90, 97))	('GR50', 'MPA', (53, 57))	('A375', 'CellLine', 'CVCL:0132', (101, 105))	('muM', 'Gene', '56925', (132, 135))	('PIM447', 'Chemical', '-', (78, 84))	('muM', 'Gene', (132, 135))	('AZD1206', 'Chemical', '-', (69, 76))
499546	31882401	Furthermore, none of these KOs altered GR values for CX-6258 suggesting that PIM kinases and MYLK4 are not the relevant cellular targets of CX-6258 in melanoma cells (Figure 2E and F).	('PIM', 'Gene', (77, 80))	('CX-6258', 'Var', (140, 147))	('MYLK4', 'Gene', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('CX-6258', 'Chemical', 'MESH:C000607921', (53, 60))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('PIM', 'Gene', '5292', (77, 80))	('CX-6258', 'Chemical', 'MESH:C000607921', (140, 147))	('MYLK4', 'Gene', '340156', (93, 98))
499547	31882401	Consistent with a PIM kinase-independent mode of action, exposure of cells to CX-6258 did not reduce the levels of BAD phosphorylation, a known downstream target of PIM kinases suggesting that PIMs are not the cellular target of CX-6258 or that other pathways compensate for the loss of PIM activity in melanoma cells (Figure 2G).	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanoma', 'Disease', 'MESH:D008545', (303, 311))	('PIM', 'Gene', (287, 290))	('CX-6258', 'Var', (78, 85))	('PIM', 'Gene', '5292', (287, 290))	('BAD phosphorylation', 'MPA', (115, 134))	('PIM', 'Gene', (165, 168))	('PIM', 'Gene', '5292', (165, 168))	('PIM', 'Gene', '5292', (18, 21))	('PIM', 'Gene', '5292', (193, 196))	('PIM', 'Gene', (18, 21))	('activity', 'MPA', (291, 299))	('CX-6258', 'Chemical', 'MESH:C000607921', (229, 236))	('PIM', 'Gene', (193, 196))	('CX-6258', 'Chemical', 'MESH:C000607921', (78, 85))	('melanoma', 'Disease', (303, 311))
499549	31882401	We observed no significant differences in A375-S and A375-RMR at drug concentrations as high as 1 muM (Figure 2H).	('muM', 'Gene', (98, 101))	('A375-RMR', 'Var', (53, 61))	('A375', 'CellLine', 'CVCL:0132', (42, 46))	('A375', 'CellLine', 'CVCL:0132', (53, 57))	('muM', 'Gene', '56925', (98, 101))	('A375-S', 'CellLine', 'CVCL:Y439', (42, 48))
499551	31882401	These data suggest that neither PIM kinases and MYLK4, nor components of signal transduction pathways required for the growth of melanoma cells are responsible for the anti-proliferative effects of CX-6258.	('MYLK4', 'Gene', (48, 53))	('PIM', 'Gene', '5292', (32, 35))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('anti-proliferative', 'CPA', (168, 186))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('CX-6258', 'Chemical', 'MESH:C000607921', (198, 205))	('PIM', 'Gene', (32, 35))	('MYLK4', 'Gene', '340156', (48, 53))	('CX-6258', 'Var', (198, 205))
499554	31882401	Treatment of melanoma cells lines with CX-6258 reduced H3pT3 in a dose dependent fashion (EC50 ~ 150 nM) (Figure 2L and Supplementary Figure 2A).	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('CX-6258', 'Chemical', 'MESH:C000607921', (39, 46))	('H3', 'Chemical', '-', (55, 57))	('reduced', 'NegReg', (47, 54))	('CX-6258', 'Var', (39, 46))	('H3pT3', 'Protein', (55, 60))
499555	31882401	Additionally, transfection of A375-S with previously validated siRNA against HASPIN (Supplementary Figure 2B) resulted in significant reduction in cell numbers as compared to a non-targeting siRNA (-63.86%, p<0.0001, t test) (Figure 2M).	('HASPIN', 'Gene', '83903', (77, 83))	('reduction', 'NegReg', (134, 143))	('siRNA', 'Var', (63, 68))	('A375-S', 'CellLine', 'CVCL:Y439', (30, 36))	('HASPIN', 'Gene', (77, 83))	('cell numbers', 'CPA', (147, 159))
499556	31882401	Together, these results suggest that HASPIN is a key cellular target of CX-6258 and responsible for its anti-tumor activity, while preserving viability of human TILs and neurons.	('CX-6258', 'Chemical', 'MESH:C000607921', (72, 79))	('CX-6258', 'Var', (72, 79))	('human', 'Species', '9606', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('HASPIN', 'Gene', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('HASPIN', 'Gene', '83903', (37, 43))	('tumor', 'Disease', (109, 114))
499557	31882401	To study the effects of CX-6258 on cell division we performed EdU incorporation assays and found that CX-6258 caused dose-dependent arrest in G2/M in A375 and UACC62 cells (Figure 3A and B, and Supplementary Figure 3A).	('CX-6258', 'Chemical', 'MESH:C000607921', (102, 109))	('A375', 'CellLine', 'CVCL:0132', (150, 154))	('CX-6258', 'Chemical', 'MESH:C000607921', (24, 31))	('arrest', 'Disease', 'MESH:D006323', (132, 138))	('CX-6258', 'Var', (102, 109))	('UACC62', 'Chemical', '-', (159, 165))	('G2/M', 'Protein', (142, 146))	('arrest', 'Disease', (132, 138))	('EdU', 'Chemical', '-', (62, 65))
499561	31882401	Geminin accumulates during S/G2 and M phases of the cell cycle and is rapidly degraded by the Anaphase Promoting Complex (APC) at the metaphase to anaphase transition; the levels of geminin therefore identify cell cycle stages.	('Geminin', 'Gene', '51053', (0, 7))	('Geminin', 'Gene', (0, 7))	('geminin', 'Gene', (182, 189))	('geminin', 'Gene', '51053', (182, 189))	('S/G2', 'Var', (27, 31))	('S/G2', 'SUBSTITUTION', 'None', (27, 31))
499568	31882401	Treatment with either 0.1 muM or 0.3 muM CX-6258 led to a significant accumulation of cells with post-mitotic micronuclei after 48 h (8.274 % vs. 50.9% for DMSO vs. 0.1 muM, adjusted p value 0.01; 8.274 % vs. 57.8% for DMSO vs. 0.3 muM, p value 0.005; one-way ANOVA; Figure 3D).	('muM', 'Gene', (26, 29))	('0.3', 'Var', (33, 36))	('CX-6258', 'Gene', (41, 48))	('CX-6258', 'Chemical', 'MESH:C000607921', (41, 48))	('muM', 'Gene', '56925', (169, 172))	('muM', 'Gene', '56925', (232, 235))	('accumulation', 'PosReg', (70, 82))	('muM', 'Gene', '56925', (37, 40))	('muM', 'Gene', (169, 172))	('muM', 'Gene', '56925', (26, 29))	('DMSO', 'Chemical', 'MESH:D004121', (219, 223))	('muM', 'Gene', (232, 235))	('DMSO', 'Chemical', 'MESH:D004121', (156, 160))	('muM', 'Gene', (37, 40))
499578	31882401	We conclude that inhibition of HASPIN results in DNA damage and the formation of micronuclei that are prone to rupture.	('DNA damage', 'MPA', (49, 59))	('micronuclei', 'CPA', (81, 92))	('HASPIN', 'Gene', (31, 37))	('HASPIN', 'Gene', '83903', (31, 37))	('inhibition', 'Var', (17, 27))	('rupture', 'Disease', (111, 118))	('results in', 'Reg', (38, 48))	('rupture', 'Disease', 'MESH:D012421', (111, 118))
499580	31882401	UACC62 cells are cGAS-proficient (Supplementary Figure 3J) and we found that exposure of these cells to CX-6258 at concentrations that still allowed cell division (~0.3 x GRmax; 0.3 muM) triggered micronuclei formation (DMSO vs. 0.3 muM, adjusted p value <0.0001, ANOVA) and resulted in recruitment of cGAS specifically to micronuclei (Figure 3I-K, Supplementary Figure 3K).	('UACC62', 'Chemical', '-', (0, 6))	('muM', 'Gene', (182, 185))	('muM', 'Gene', (233, 236))	('CX-6258', 'Chemical', 'MESH:C000607921', (104, 111))	('recruitment', 'MPA', (287, 298))	('DMSO', 'Chemical', 'MESH:D004121', (220, 224))	('CX-6258', 'Var', (104, 111))	('micronuclei formation', 'CPA', (197, 218))	('muM', 'Gene', '56925', (182, 185))	('muM', 'Gene', '56925', (233, 236))	('cGAS', 'Protein', (302, 306))
499586	31882401	To confirm that cGAS was necessary for IFN induction, we used CRISPR-Cas9 to knockout cGAS in CT26 cells (Supplementary Figure 3L) and observed an ~5-fold reduction in basal IFNbeta1 levels (adjusted p value <0.001, ANOVA) with no significant induction of IFNalpha and IFNbeta by CX-6258 (Figure 3M-N).	('cGAS', 'Gene', (86, 90))	('knockout', 'Var', (77, 85))	('CX-6258', 'Chemical', 'MESH:C000607921', (280, 287))	('CT26', 'CellLine', 'CVCL:7254', (94, 98))	('reduction', 'NegReg', (155, 164))
499587	31882401	Thus, CX-6258 triggers a type I IFN response in a cGAS-dependent manner.	('triggers', 'Reg', (14, 22))	('type I IFN response', 'MPA', (25, 44))	('CX-6258', 'Var', (6, 13))	('CX-6258', 'Chemical', 'MESH:C000607921', (6, 13))
499589	31882401	Rates of tumor growth were variable (n=5/group), but tumor volumes at day 14 were not significantly different in CX-6258-treated mice and vehicle-only controls (Supplementary Figure 4A and B).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (9, 14))	('CX-6258-treated', 'Var', (113, 128))	('tumor', 'Disease', (53, 58))	('mice', 'Species', '10090', (129, 133))	('CX-6258', 'Chemical', 'MESH:C000607921', (113, 120))
499591	31882401	To see if adaptive immunity might enhance the effects of CX-6258, CT26 cells were engrafted in immune-competent BALB/c animals and cohorts of 8 animals were exposed to CX-6258, anti-PD-1 antibody, or a phased combination of CX-6258 plus anti-PD-1 (see study design in Figure 4A).	('CX-6258', 'Chemical', 'MESH:C000607921', (168, 175))	('CX-6258', 'Var', (168, 175))	('CX-6258', 'Chemical', 'MESH:C000607921', (224, 231))	('CT26', 'CellLine', 'CVCL:7254', (66, 70))	('effects', 'MPA', (46, 53))	('CX-6258', 'Chemical', 'MESH:C000607921', (57, 64))
499592	31882401	Animals treated with high dose CX-6258 alone exhibited a significant reduction in tumor growth as compared to vehicle-only controls (adjusted p value= 0.02, 2-way ANOVA); PD-1 alone did not reach statistical significance (adjusted p value=0.36).	('CX-6258', 'Chemical', 'MESH:C000607921', (31, 38))	('CX-6258', 'Var', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('reduction', 'NegReg', (69, 78))	('tumor', 'Disease', (82, 87))
499593	31882401	Phased combination of anti-PD-1 and CX-6258 led to a less variable and significant delay in tumor outgrowth (adjusted p value < 0.002, 2-way ANOVA) (Figure 4B and C).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('delay', 'NegReg', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CX-6258', 'Chemical', 'MESH:C000607921', (36, 43))	('tumor', 'Disease', (92, 97))	('anti-PD-1', 'Gene', (22, 31))	('CX-6258', 'Var', (36, 43))
499595	31882401	Thus, the anti-tumor activity of CX-6258 is substantially enhanced by the presence of an adaptive immune system, being substantially greater in immune-competent than in nude mice.	('greater', 'PosReg', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('nude mice', 'Species', '10090', (169, 178))	('enhanced', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('CX-6258', 'Chemical', 'MESH:C000607921', (33, 40))	('CX-6258', 'Var', (33, 40))
499596	31882401	We hypothesized that response to CX-6258 (either alone or in phased combination with anti-PD-1 therapy) could be due to modulation of the tumor microenvironment (TME).	('tumor', 'Disease', (138, 143))	('CX-6258', 'Chemical', 'MESH:C000607921', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('CX-6258', 'Var', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
499599	31882401	Compared to vehicle-only controls, CX-6258-alone increased infiltration of CD3+ T lymphocytes into the TME (31% vs. 43%, adjusted p=0.04, ANOVA) (Supplementary Figure 4I).	('increased', 'PosReg', (49, 58))	('CX-6258-alone', 'Var', (35, 48))	('CX-6258', 'Chemical', 'MESH:C000607921', (35, 42))	('infiltration of CD3+ T lymphocytes', 'CPA', (59, 93))
499601	31882401	Significant reduction in Tregs was observed in tumors treated with CX-6258 (30.57% vs. 18.8% of CD4+, adjusted p value = 0.008, ANOVA) or anti-PD-1 therapy (30.57% vs. 19.63% of CD4+, adjusted p value = 0.01, ANOVA) as compared to vehicle-only controls and this reduction was most pronounced in animals receiving the phased combination (30.57% vs. 10.97% of CD4+, adjusted p value < 0.001, ANOVA) (Figure 4D).	('Tregs', 'Chemical', '-', (25, 30))	('tumors', 'Disease', (47, 53))	('CD4', 'Gene', (96, 99))	('CD4', 'Gene', '920', (178, 181))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('reduction', 'NegReg', (12, 21))	('CD4', 'Gene', (358, 361))	('CD4', 'Gene', '920', (96, 99))	('Tregs', 'CPA', (25, 30))	('CD4', 'Gene', '920', (358, 361))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CX-6258', 'Chemical', 'MESH:C000607921', (67, 74))	('CX-6258', 'Var', (67, 74))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('CD4', 'Gene', (178, 181))
499604	31882401	These data suggest that CX-6258 modulates the immune environment in tumors to favour a more consistent response to immune checkpoint blockade.	('tumors', 'Disease', (68, 74))	('CX-6258', 'Chemical', 'MESH:C000607921', (24, 31))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('CX-6258', 'Var', (24, 31))	('favour', 'PosReg', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('modulates', 'Reg', (32, 41))
499605	31882401	HASPIN inhibition may therefore promote anti-tumor activity by directly inhibiting tumor growth and also improving anti-tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('HASPIN', 'Gene', (0, 6))	('tumor', 'Disease', (83, 88))	('HASPIN', 'Gene', '83903', (0, 6))	('tumor', 'Disease', (45, 50))	('inhibiting', 'NegReg', (72, 82))	('improving', 'PosReg', (105, 114))	('inhibition', 'Var', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('promote', 'PosReg', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', (120, 125))
499611	31882401	CX-6258 inhibited cell growth in all MM cell lines tested with EC50 < 1 muM (Figure 4E).	('CX-6258', 'Chemical', 'MESH:C000607921', (0, 7))	('inhibited', 'NegReg', (8, 17))	('CX-6258', 'Var', (0, 7))	('muM', 'Gene', '56925', (72, 75))	('cell growth in', 'CPA', (18, 32))	('muM', 'Gene', (72, 75))
499613	31882401	Additionally, CX-6258 inhibited formation of ES spheroids; in this assay, cells are grown on a low-adherent surface to induce formation of sarcoma-spheres.	('ES', 'Phenotype', 'HP:0012254', (45, 47))	('inhibited', 'NegReg', (22, 31))	('CX-6258', 'Chemical', 'MESH:C000607921', (14, 21))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('CX-6258', 'Var', (14, 21))	('sarcoma', 'Disease', (139, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('spheroids', 'Chemical', '-', (48, 57))
499614	31882401	In SKES1, CX-6258 prevented the formation of spheroids at 5 nM; in RDES and SKNEP1 there was a significant reduction of spheroid formation at 500 nM and 1muM, respectively (Figure 4G).	('ES', 'Phenotype', 'HP:0012254', (69, 71))	('CX-6258', 'Chemical', 'MESH:C000607921', (10, 17))	('SKES1', 'CellLine', 'CVCL:B526', (3, 8))	('CX-6258', 'Var', (10, 17))	('prevented', 'NegReg', (18, 27))	('ES', 'Phenotype', 'HP:0012254', (5, 7))	('SKNEP1', 'Var', (76, 82))	('spheroid formation', 'MPA', (120, 138))	('muM', 'Gene', '56925', (154, 157))	('spheroids', 'Chemical', '-', (45, 54))	('reduction', 'NegReg', (107, 116))	('muM', 'Gene', (154, 157))
499615	31882401	Treatment of ES cell lines with CX-6258 also led to induction of IFNalpha1 and IFNbeta1 across all lines (Figure 4H).	('IFNalpha1', 'Gene', (65, 74))	('induction', 'Reg', (52, 61))	('CX-6258', 'Chemical', 'MESH:C000607921', (32, 39))	('IFNbeta1', 'Gene', (79, 87))	('ES', 'Phenotype', 'HP:0012254', (13, 15))	('CX-6258', 'Var', (32, 39))
499618	31882401	We show that the small-molecule CX-6258 blocks cell proliferation and induces cell death of both RMI-sensitive and RMI-resistant (RMR) BRAF-mutated melanoma lines, most likely by inhibiting HASPIN kinase, which promotes errors in mitotic chromosome segregation.	('RMI', 'Chemical', '-', (97, 100))	('blocks', 'NegReg', (40, 46))	('BRAF', 'Gene', '673', (135, 139))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('inhibiting', 'NegReg', (179, 189))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('BRAF', 'Gene', (135, 139))	('RMI', 'Chemical', '-', (115, 118))	('cell death', 'CPA', (78, 88))	('HASPIN', 'Gene', (190, 196))	('induces', 'Reg', (70, 77))	('CX-6258', 'Chemical', 'MESH:C000607921', (32, 39))	('HASPIN', 'Gene', '83903', (190, 196))	('CX-6258', 'Var', (32, 39))	('cell proliferation', 'CPA', (47, 65))
499619	31882401	Primary human TILs and neurons differentiated in vitro are substantially less sensitive to CX-6258 than tumor cells, suggesting a potential therapeutic window for future clinical application.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('less', 'NegReg', (73, 77))	('CX-6258', 'Chemical', 'MESH:C000607921', (91, 98))	('human', 'Species', '9606', (8, 13))	('CX-6258', 'Var', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
499620	31882401	CX-6258 has in vivo activity in immunocompetent mice and results in significant modulation of the tumor immune environment, including reduction in Tregs and increase in cytotoxic CD8+ T cells, thereby contributing to a more consistent response to immunotherapy.	('CX-6258', 'Chemical', 'MESH:C000607921', (0, 7))	('CX-6258', 'Var', (0, 7))	('CD8', 'Gene', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mice', 'Species', '10090', (48, 52))	('Tregs', 'CPA', (147, 152))	('reduction', 'NegReg', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CD8', 'Gene', '925', (179, 182))	('Tregs', 'Chemical', '-', (147, 152))	('tumor', 'Disease', (98, 103))	('increase', 'PosReg', (157, 165))	('modulation', 'Reg', (80, 90))
499621	31882401	CX-6258 is annotated as an inhibitor of the PIM kinase family.	('PIM', 'Gene', '5292', (44, 47))	('CX-6258', 'Var', (0, 7))	('PIM', 'Gene', (44, 47))	('CX-6258', 'Chemical', 'MESH:C000607921', (0, 7))
499622	31882401	However, using unbiased kinase inhibitor profiling, we identified MYLK4 and HASPIN as additional high affinity targets of CX-6258.	('MYLK4', 'Gene', '340156', (66, 71))	('CX-6258', 'Chemical', 'MESH:C000607921', (122, 129))	('MYLK4', 'Gene', (66, 71))	('HASPIN', 'Gene', (76, 82))	('CX-6258', 'Var', (122, 129))	('HASPIN', 'Gene', '83903', (76, 82))
499623	31882401	Overexpression of PIMs did not alter the proliferation rates of cell lines in which CX-6258 was active nor did knockdown of PIM1, PIM2 or MYLK4 alter sensitivity to CX-6258.	('knockdown', 'Var', (111, 120))	('CX-6258', 'Chemical', 'MESH:C000607921', (165, 172))	('MYLK4', 'Gene', (138, 143))	('PIM', 'Gene', (130, 133))	('PIM', 'Gene', '5292', (130, 133))	('PIM', 'Gene', '5292', (124, 127))	('PIM2', 'Gene', '11040', (130, 134))	('PIM', 'Gene', '5292', (18, 21))	('PIM2', 'Gene', (130, 134))	('PIM', 'Gene', (124, 127))	('PIM', 'Gene', (18, 21))	('CX-6258', 'Chemical', 'MESH:C000607921', (84, 91))	('PIM1', 'Gene', '5292', (124, 128))	('PIM1', 'Gene', (124, 128))	('MYLK4', 'Gene', '340156', (138, 143))
499625	31882401	In contrast, knockdown of HASPIN phenocopied CX-6258 with respect to cell proliferation; HASPIN knockdown also resulted in mitotic mis-segregation and formation of micronuclei and increased the number of double-stranded DNA breaks.	('double-stranded DNA breaks', 'MPA', (204, 230))	('knockdown', 'Var', (96, 105))	('HASPIN', 'Gene', '83903', (26, 32))	('CX-6258', 'Chemical', 'MESH:C000607921', (45, 52))	('HASPIN', 'Gene', '83903', (89, 95))	('micronuclei', 'CPA', (164, 175))	('increased', 'PosReg', (180, 189))	('HASPIN', 'Gene', (26, 32))	('mitotic mis-segregation', 'CPA', (123, 146))	('resulted in', 'Reg', (111, 122))	('HASPIN', 'Gene', (89, 95))
499626	31882401	CX-6258 also caused dose-dependent reductions in Histone H3 phosphorylation at Threonine 3, the only known phosphorylation site dependent on HASPIN.	('reductions', 'NegReg', (35, 45))	('CX-6258', 'Chemical', 'MESH:C000607921', (0, 7))	('HASPIN', 'Gene', (141, 147))	('CX-6258', 'Var', (0, 7))	('Histone H3 phosphorylation at Threonine 3', 'MPA', (49, 90))	('HASPIN', 'Gene', '83903', (141, 147))	('Threonine', 'Chemical', 'MESH:D013912', (79, 88))	('H3', 'Chemical', '-', (57, 59))
499627	31882401	Our data strongly suggests that HASPIN is a biologically significant target of CX-6258 in cancer cells, although they do not rule out a secondary role for PIMs or MYLK4.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CX-6258', 'Chemical', 'MESH:C000607921', (79, 86))	('MYLK4', 'Gene', '340156', (163, 168))	('PIM', 'Gene', '5292', (155, 158))	('MYLK4', 'Gene', (163, 168))	('CX-6258', 'Var', (79, 86))	('PIM', 'Gene', (155, 158))	('HASPIN', 'Gene', (32, 38))	('HASPIN', 'Gene', '83903', (32, 38))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
499631	31882401	These micronuclei stain positive with CREST antibodies suggesting that they arise through errors in mitotic chromosome segregation and not just DSB formation.	('CREST', 'Gene', (38, 43))	('errors', 'Var', (90, 96))	('CREST', 'Gene', '26039', (38, 43))	('positive', 'Reg', (24, 32))	('mitotic chromosome segregation', 'CPA', (100, 130))	('ES', 'Phenotype', 'HP:0012254', (40, 42))
499633	31882401	MCF10A breast cancer cell lines exposed to ionizing radiation for 3 to 6 days also develop micronuclei as a consequence of double-stranded DNA-breaks.	('micronuclei', 'CPA', (91, 102))	('MCF10A', 'CellLine', 'CVCL:0598', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('develop', 'PosReg', (83, 90))	('breast cancer', 'Disease', (7, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('double-stranded DNA-breaks', 'Var', (123, 149))
499639	31882401	Chromosomal instability (CIN) resulting from errors in mitotic segregation has been associated with increased metastatic potential through tonic STING activation resulting in an immunosuppressive tumor environment.	('metastatic potential', 'CPA', (110, 130))	('increased', 'PosReg', (100, 109))	('errors', 'Var', (45, 51))	('tumor', 'Disease', (196, 201))	('CIN', 'Disease', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('STING', 'Gene', (145, 150))	('mitotic segregation', 'Gene', (55, 74))	('Chromosomal instability', 'Disease', (0, 23))	('CIN', 'Disease', 'MESH:D007674', (25, 28))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('CIN', 'Phenotype', 'HP:0040012', (25, 28))	('STING', 'Gene', '340061', (145, 150))
499643	31882401	Reduction of Tregs mediated by inhibitors of cell cycle or mitosis has been observed in the context of CDK4/6 inhibitors, and may indicate differential yet poorly defined sensitivity of Tregs to anti-proliferative compounds, including HASPIN inhibitors.	('HASPIN', 'Gene', '83903', (235, 241))	('Tregs', 'Chemical', '-', (186, 191))	('Tregs', 'CPA', (13, 18))	('cell cycle', 'CPA', (45, 55))	('CDK4/6', 'Gene', '1019;1021', (103, 109))	('Tregs', 'Chemical', '-', (13, 18))	('Reduction', 'NegReg', (0, 9))	('mitosis', 'CPA', (59, 66))	('CDK4/6', 'Gene', (103, 109))	('HASPIN', 'Gene', (235, 241))	('inhibitors', 'Var', (110, 120))
499650	31882401	While our study provides evidence that inhibition of HASPINs' role in mitosis is the primary mechanism to promote anti-proliferative activity and enhanced immunogenicity, it is possible that other, currently unknown downstream targets of HASPIN could contribute to these effects.	('inhibition', 'Var', (39, 49))	('immunogenicity', 'CPA', (155, 169))	('promote', 'PosReg', (106, 113))	('HASPIN', 'Gene', (238, 244))	('HASPIN', 'Gene', (53, 59))	('enhanced', 'PosReg', (146, 154))	('HASPIN', 'Gene', '83903', (238, 244))	('anti-proliferative activity', 'CPA', (114, 141))	('HASPIN', 'Gene', '83903', (53, 59))
499655	31882401	Haspin Kinase inhibition by CX-6258 is a novel and potent strategy for RAF/MEK-inhibitor resistant melanoma and potentially other tumor types.	('tumor', 'Disease', (130, 135))	('Haspin', 'Gene', (0, 6))	('CX-6258', 'Chemical', 'MESH:C000607921', (28, 35))	('Haspin', 'Gene', '83903', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('CX-6258', 'Var', (28, 35))	('RAF', 'Gene', '22882', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('RAF', 'Gene', (71, 74))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('MEK', 'Gene', (75, 78))	('MEK', 'Gene', '5609', (75, 78))
499657	30473623	SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal models.	('sarcoma', 'Phenotype', 'HP:0100242', (334, 341))	('Patients', 'Species', '9606', (82, 90))	('Mocetinostat', 'Var', (35, 47))	('Metastatic Leiomyosarcoma', 'Disease', 'MESH:D007890', (96, 121))	('cytotoxicity', 'Disease', (309, 321))	('Leiomyosarcoma', 'Phenotype', 'HP:0100243', (107, 121))	('cytotoxicity', 'Disease', 'MESH:D064420', (309, 321))	('HDAC', 'Gene', '9734', (244, 248))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('sarcoma', 'Disease', (114, 121))	('enhance', 'PosReg', (280, 287))	('sarcoma', 'Disease', 'MESH:D012509', (334, 341))	('HDAC', 'Gene', (244, 248))	('reverse', 'PosReg', (255, 262))	('sarcoma', 'Disease', (334, 341))	('chemoresistance', 'CPA', (263, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('reduce', 'NegReg', (327, 333))	('Metastatic Leiomyosarcoma', 'Disease', (96, 121))
499676	30473623	Deregulation of HDAC activity can cause malignant diseases in humans.	('malignant diseases', 'Disease', 'MESH:D009369', (40, 58))	('Deregulation', 'Var', (0, 12))	('malignant diseases', 'Disease', (40, 58))	('cause', 'Reg', (34, 39))	('HDAC', 'Gene', (16, 20))	('HDAC', 'Gene', '9734', (16, 20))	('humans', 'Species', '9606', (62, 68))
499678	30473623	Anticancer activity of HDACi is mediated by regulating aberrant gene expression at the transcriptional level in cancer cells.	('regulating', 'Reg', (44, 54))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('aberrant', 'Var', (55, 63))	('HDAC', 'Gene', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('HDAC', 'Gene', '9734', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (4, 10))
499679	30473623	These gene expression changes lead to inhibition of proliferation, induction of apoptosis, and/or cell differentiation in cancer cells in vitro and in vivo.	('proliferation', 'CPA', (52, 65))	('changes', 'Var', (22, 29))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('inhibition', 'NegReg', (38, 48))	('cell differentiation', 'CPA', (98, 118))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('apoptosis', 'CPA', (80, 89))
499680	30473623	Inhibitors of histone deacetylase (HDACi) have demonstrated preclinical activity in sarcoma models, and there have been anecdotes of patients with sarcoma responding to HDACi therapy.	('HDAC', 'Gene', (35, 39))	('HDAC', 'Gene', (169, 173))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('Inhibitors', 'Var', (0, 10))	('HDAC', 'Gene', '9734', (169, 173))	('sarcoma', 'Disease', (84, 91))	('HDAC', 'Gene', '9734', (35, 39))	('patients', 'Species', '9606', (133, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('sarcoma', 'Disease', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
499757	26918731	In GIST cells with KIT mutations, selinexor induced G1- arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib.	('selinexor', 'Chemical', 'MESH:C585161', (34, 43))	('AKT', 'Gene', (110, 113))	('imatinib', 'Chemical', 'MESH:D000068877', (139, 147))	('arrest', 'Disease', (56, 62))	('mutations', 'Var', (23, 32))	('KIT', 'Gene', (19, 22))	('AKT', 'Gene', '207', (110, 113))	('arrest', 'Disease', 'MESH:D006323', (56, 62))
499766	26918731	Although their role in tumor development or progression remains to be elucidated, recurrent mutations in XPO1 have been identified in chronic lymphoblastic leukemia.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('chronic lymphoblastic leukemia', 'Disease', 'MESH:D015451', (134, 164))	('leukemia', 'Phenotype', 'HP:0001909', (156, 164))	('chronic lymphoblastic leukemia', 'Disease', (134, 164))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (142, 164))	('tumor', 'Disease', (23, 28))	('identified', 'Reg', (120, 130))	('XPO1', 'Gene', '7514', (105, 109))	('chronic lymphoblastic leukemia', 'Phenotype', 'HP:0005550', (134, 164))	('XPO1', 'Gene', (105, 109))
499767	26918731	The classic XPO1 inhibitor Leptomycin B is cytotoxic in vitro and in vivo, and disrupts mitotic progression and chromosome segregation.	('XPO1', 'Gene', '7514', (12, 16))	('XPO1', 'Gene', (12, 16))	('mitotic progression', 'CPA', (88, 107))	('Leptomycin B', 'Chemical', 'MESH:C038753', (27, 39))	('chromosome segregation', 'CPA', (112, 134))	('disrupts', 'NegReg', (79, 87))	('Leptomycin', 'Var', (27, 37))
499772	26918731	Effective small molecule targeted therapies have been established only in a small subset of this group with defined molecular backgrounds, such as imatinib for mutated KIT in gastrointestinal stromal tumors (GIST).	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (175, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (175, 206))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (175, 205))	('mutated', 'Var', (160, 167))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('KIT', 'Gene', (168, 171))	('imatinib', 'Chemical', 'MESH:D000068877', (147, 155))	('gastrointestinal stromal tumors', 'Disease', (175, 206))
499788	26918731	In most models, selinexor-treated tumors tended to be less cellular but demonstrated little appreciable difference in morphology when compared with control tumors, like PG47 (GIST) representatively shown in Figure 3.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', (156, 162))	('less', 'NegReg', (54, 58))	('selinexor-treated', 'Var', (16, 33))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('selinexor', 'Chemical', 'MESH:C585161', (16, 25))
499792	26918731	Cell lines from several sarcoma subtypes with defined molecular backgrounds, such as GIST with KIT mutations and dedifferentiated LPS with MDM2 and CDK4 amplification, were treated with selinexor to investigate potential mechanisms of action.	('MDM2', 'Gene', (139, 143))	('CDK4', 'Gene', '1019', (148, 152))	('LPS', 'Disease', 'MESH:C536528', (130, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('KIT', 'Gene', (95, 98))	('mutations', 'Var', (99, 108))	('selinexor', 'Chemical', 'MESH:C585161', (186, 195))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (24, 40))	('sarcoma subtypes', 'Disease', (24, 40))	('LPS', 'Disease', (130, 133))	('CDK4', 'Gene', (148, 152))	('MDM2', 'Gene', '4193', (139, 143))
499793	26918731	We investigated the mechanism of action of selinexor with particular attention to the phosphorylation status of KIT and its downstream pathways using a KIT-mutant cell line, GIST-T1, and its imatinib-resistant subclone, GIST-T1/829, which contains a secondary mutation in KIT.	('imatinib', 'Chemical', 'MESH:D000068877', (191, 199))	('selinexor', 'Chemical', 'MESH:C585161', (43, 52))	('mutation', 'Var', (260, 268))	('KIT', 'Gene', (272, 275))
499796	26918731	In cell cycle analyses, selinexor induced G1-arrest in a dose-dependent manner irrespective of the presence of secondary KIT mutation, while imatinib induced G1-arrest only in the naive GIST-T1 line and showed little activity against GIST-T1/829 (Figure 4A).	('G1-arrest', 'Disease', 'MESH:D006323', (158, 167))	('selinexor', 'Chemical', 'MESH:C585161', (24, 33))	('G1-arrest', 'Disease', (158, 167))	('G1-arrest', 'Disease', 'MESH:D006323', (42, 51))	('imatinib', 'Chemical', 'MESH:D000068877', (141, 149))	('G1-arrest', 'Disease', (42, 51))	('mutation', 'Var', (125, 133))
499800	26918731	To address this hypothesis, we tested the in vitro effects of selinexor in a dedifferentiated LPS cell line, LP6, which harbors high copy number of MDM2, and compared it to the effects of a classic MDM2 inhibitor, Nutlin-3a, which was used as a positive control.	('LPS', 'Disease', (94, 97))	('MDM2', 'Gene', (198, 202))	('selinexor', 'Chemical', 'MESH:C585161', (62, 71))	('MDM2', 'Gene', '4193', (198, 202))	('LPS', 'Disease', 'MESH:C536528', (94, 97))	('tested', 'Reg', (31, 37))	('LP6', 'Chemical', '-', (109, 112))	('MDM2', 'Gene', '4193', (148, 152))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (214, 223))	('MDM2', 'Gene', (148, 152))	('high copy number', 'Var', (128, 144))
499801	26918731	Selinexor increased the G1 population in cell cycle analysis (Figure 5A), and increased the Annexin V-positive population (Figure 5B), indicating that it induced both G1-arrest and apoptosis in LP6 cells at 100 nM, equivalent to the IC50 in LP6 in the cell viability assay (Table 1 and Figure 1).	('G1 population', 'MPA', (24, 37))	('G1-arrest', 'Disease', (167, 176))	('LP6', 'Chemical', '-', (241, 244))	('induced', 'Reg', (154, 161))	('cell cycle analysis', 'CPA', (41, 60))	('Selinexor', 'Var', (0, 9))	('Selinexor', 'Chemical', 'MESH:C585161', (0, 9))	('apoptosis', 'CPA', (181, 190))	('increased', 'PosReg', (78, 87))	('Annexin V', 'Gene', '308', (92, 101))	('LP6', 'Chemical', '-', (194, 197))	('G1-arrest', 'Disease', 'MESH:D006323', (167, 176))	('increased', 'PosReg', (10, 19))	('Annexin V', 'Gene', (92, 101))
499808	26918731	To address if G1-arrest and apoptosis induced by selinexor in LPS are dependent on the status of p53, we analyzed the activity of selinexor in two other models: a p53 mutant LPS line, LPS510 and the LP6 line with p53-knocked down by siRNA treatment.	('LPS', 'Disease', 'MESH:C536528', (174, 177))	('LP6', 'Chemical', '-', (199, 202))	('LPS', 'Disease', 'MESH:C536528', (62, 65))	('G1-arrest', 'Disease', 'MESH:D006323', (14, 23))	('p53', 'Gene', '7157', (97, 100))	('mutant', 'Var', (167, 173))	('p53', 'Gene', '7157', (213, 216))	('LPS510', 'Chemical', '-', (184, 190))	('p53', 'Gene', (97, 100))	('G1-arrest', 'Disease', (14, 23))	('p53', 'Gene', (213, 216))	('selinexor', 'Chemical', 'MESH:C585161', (130, 139))	('LPS', 'Disease', (184, 187))	('p53', 'Gene', '7157', (163, 166))	('LPS', 'Disease', (62, 65))	('LPS', 'Disease', (174, 177))	('p53', 'Gene', (163, 166))	('selinexor', 'Chemical', 'MESH:C585161', (49, 58))	('LPS', 'Disease', 'MESH:C536528', (184, 187))
499813	26918731	Similarly, siRNA-mediated knockdown of RB in LP6 did not result in any significant change in cell cycle arrest induced by selinexor (Supplementary Figure 3), suggesting that its mechanism of action is also independent of RB, in contrast with the RB-dependent effects of CDK inhibitors.	('arrest', 'Disease', 'MESH:D006323', (104, 110))	('RB', 'Chemical', 'MESH:D012413', (39, 41))	('RB', 'Chemical', 'MESH:D012413', (246, 248))	('LP6', 'Chemical', '-', (45, 48))	('arrest', 'Disease', (104, 110))	('knockdown', 'Var', (26, 35))	('cell cycle', 'CPA', (93, 103))	('RB', 'Chemical', 'MESH:D012413', (221, 223))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))	('selinexor', 'Chemical', 'MESH:C585161', (122, 131))
499819	26918731	In general, in the experiments presented here, selinexor appeared to exhibit a growth arrest rather than cytotoxic activity as indicated by the curves in Figure 2 and histological findings in Figure 3.	('selinexor', 'Var', (47, 56))	('selinexor', 'Chemical', 'MESH:C585161', (47, 56))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('arrest', 'Disease', (86, 92))
499828	26918731	We hypothesized that selinexor could inhibit nuclear to cytoplasmic shuttling of MDM2, and subsequently stabilize p53, and investigated the activity of selinexor in vitro using the LPS lines with MDM2 amplification (LP6, LPS141 and LPS12) and with mutant p53 (LPS510).	('nuclear to cytoplasmic shuttling', 'MPA', (45, 77))	('p53', 'Gene', (114, 117))	('MDM2', 'Gene', '4193', (196, 200))	('LPS', 'Disease', 'MESH:C536528', (221, 224))	('p53', 'Gene', '7157', (255, 258))	('LPS', 'Disease', 'MESH:C536528', (260, 263))	('p53', 'Gene', (255, 258))	('LPS', 'Disease', 'MESH:C536528', (181, 184))	('mutant', 'Var', (248, 254))	('selinexor', 'Chemical', 'MESH:C585161', (21, 30))	('LPS', 'Disease', (232, 235))	('inhibit', 'NegReg', (37, 44))	('MDM2', 'Gene', (81, 85))	('selinexor', 'Chemical', 'MESH:C585161', (152, 161))	('LPS', 'Disease', 'MESH:C536528', (232, 235))	('LP6', 'Var', (216, 219))	('LP6', 'Chemical', '-', (216, 219))	('p53', 'Gene', '7157', (114, 117))	('LPS', 'Disease', (221, 224))	('MDM2', 'Gene', '4193', (81, 85))	('LPS510', 'Chemical', '-', (260, 266))	('MDM2', 'Gene', (196, 200))	('LPS', 'Disease', (260, 263))	('LPS', 'Disease', (181, 184))
499831	26918731	The results in a similar experiment using the p53-mutant LPS510 line and p53-knockdown in LP6 indicated that selinexor was capable of inducing both G1-arrest and apoptosis irrespective of the mutation status or expression of p53 in LPS lines.	('selinexor', 'Chemical', 'MESH:C585161', (109, 118))	('LPS', 'Disease', 'MESH:C536528', (57, 60))	('p53', 'Gene', (73, 76))	('p53', 'Gene', (46, 49))	('selinexor', 'Var', (109, 118))	('p53', 'Gene', (225, 228))	('LPS', 'Disease', (232, 235))	('p53', 'Gene', '7157', (73, 76))	('LPS510', 'Chemical', '-', (57, 63))	('LP6', 'Chemical', '-', (90, 93))	('p53', 'Gene', '7157', (46, 49))	('G1-arrest', 'Disease', (148, 157))	('p53', 'Gene', '7157', (225, 228))	('G1-arrest', 'Disease', 'MESH:D006323', (148, 157))	('LPS', 'Disease', 'MESH:C536528', (232, 235))	('apoptosis', 'CPA', (162, 171))	('inducing', 'PosReg', (134, 142))	('LPS', 'Disease', (57, 60))
499870	26918731	Transcript levels were quantified using TaqMan Gene Expression Master Mix (TP53, Hs01034249_m1; CDKN1A (gene encoding p21), Hs00355782_m1; MDM2, Hs01066930_m1; GAPDH, Hs99999905_m1; ACTB, Hs99999903_m1; Applied Biosystems) on a 7900HT Fast Real-Time PCR System and normalized to the average of ACTB and GAPDH.	('MDM2', 'Gene', (139, 143))	('TP53', 'Gene', '7157', (75, 79))	('p21', 'Gene', '1026', (118, 121))	('ACTB', 'Gene', (294, 298))	('Hs99999903_m1', 'Var', (188, 201))	('p21', 'Gene', (118, 121))	('GAPDH', 'Gene', '2597', (303, 308))	('ACTB', 'Gene', '60', (294, 298))	('GAPDH', 'Gene', (303, 308))	('GAPDH', 'Gene', '2597', (160, 165))	('CDKN1A', 'Gene', (96, 102))	('Hs00355782_m1', 'Var', (124, 137))	('ACTB', 'Gene', (182, 186))	('CDKN1A', 'Gene', '1026', (96, 102))	('ACTB', 'Gene', '60', (182, 186))	('GAPDH', 'Gene', (160, 165))	('TP53', 'Gene', (75, 79))	('MDM2', 'Gene', '4193', (139, 143))
499877	27336789	Mesenchymal progenitor cells (MPCs) transformed with the signature EWS-FLI1 translocation, the hallmark of Ewing's sarcoma family tumors, exhibited increased sensitivity to the PARP inhibitor olaparib as compared to MPCs transformed with a different translocation (Figure 4E).	('olaparib', 'Chemical', 'MESH:C531550', (192, 200))	('increased', 'PosReg', (148, 157))	("Ewing's sarcoma family tumors", 'Disease', (107, 136))	('EWS-FLI1', 'Gene', (67, 75))	('PARP', 'Gene', '142', (177, 181))	('EWS-FLI1', 'Gene', '2130;2313', (67, 75))	('translocation', 'Var', (76, 89))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (107, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('PARP', 'Gene', (177, 181))	("Ewing's sarcoma family tumors", 'Disease', 'MESH:C563168', (107, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('sensitivity', 'MPA', (158, 169))
499878	27336789	Knockdown mediated by siRNA of EWS-FLI1 abrogated this sensitivity to olaparib (Figure 4F).	('sensitivity to olaparib', 'MPA', (55, 78))	('Knockdown', 'Var', (0, 9))	('EWS-FLI1', 'Gene', (31, 39))	('abrogated', 'NegReg', (40, 49))	('olaparib', 'Chemical', 'MESH:C531550', (70, 78))	('EWS-FLI1', 'Gene', '2130;2313', (31, 39))
499882	27336789	The ability to accurately capture a large number of known clinically relevant drug response biomarkers as well as preferential cancer type sensitivities known to occur in the clinic, such as decreased sensitivity to BRAF inhibitors in BRAF mutant colorectal cancers relative to melanomas, demonstrated the effectiveness of this large-scale pharmacogenomic approach.	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('sensitivity', 'MPA', (201, 212))	('colorectal cancers', 'Disease', 'MESH:D015179', (247, 265))	('mutant', 'Var', (240, 246))	('decreased', 'NegReg', (191, 200))	('cancer', 'Disease', (127, 133))	('BRAF', 'Gene', '673', (235, 239))	('melanomas', 'Disease', 'MESH:D008545', (278, 287))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRAF', 'Gene', (235, 239))	('melanomas', 'Disease', (278, 287))	('cancer', 'Disease', (258, 264))	('rat', 'Species', '10116', (296, 299))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('colorectal cancers', 'Disease', (247, 265))	('BRAF', 'Gene', '673', (216, 220))	('rat', 'Species', '10116', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('BRAF', 'Gene', (216, 220))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('melanomas', 'Phenotype', 'HP:0002861', (278, 287))
499884	27336789	Garnett and colleagues identified an unexpected highly significant association between the EWS-FLI1 translocation and sensitivity to the PARP inhibitor olaparib.	('PARP', 'Gene', (137, 141))	('EWS-FLI1', 'Gene', (91, 99))	('EWS-FLI1', 'Gene', '2130;2313', (91, 99))	('translocation', 'Var', (100, 113))	('PARP', 'Gene', '142', (137, 141))	('olaparib', 'Chemical', 'MESH:C531550', (152, 160))	('significant association', 'Reg', (55, 78))
499890	27336789	This makes PARP1 an interesting therapeutic target in the context of malignancies with deficient HR, such as BRCA1 and BRCA2 mutant breast and ovarian cancers.	('PARP1', 'Gene', (11, 16))	('BRCA1', 'Gene', (109, 114))	('deficient HR', 'Disease', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutant', 'Var', (125, 131))	('deficient HR', 'Disease', 'MESH:D001919', (87, 99))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('ovarian cancers', 'Phenotype', 'HP:0100615', (143, 158))	('BRCA2', 'Gene', (119, 124))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (132, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('malignancies', 'Disease', (69, 81))	('BRCA1', 'Gene', '672', (109, 114))	('PARP1', 'Gene', '142', (11, 16))	('BRCA2', 'Gene', '675', (119, 124))
499897	27336789	In Figure 4E, the hypothesis that mouse mesenchymal progenitor cells (MPCs) that had been transformed with the EWS-FLI1 translocation would confer sensitivity to olaparib was tested.	('translocation', 'Var', (120, 133))	('mouse', 'Species', '10090', (34, 39))	('EWS-FLI1', 'Gene', '2130;2313', (111, 119))	('olaparib', 'Chemical', 'MESH:C531550', (162, 170))	('EWS-FLI1', 'Gene', (111, 119))
499907	27336789	Further, they reported that transforming a cell line (in this case, PC3 cells) with the EWS-FLI1 translocation conferred sensitivity to treatment with olaparib, and that siRNA mediated knockdown of EWS-FLI1 inhibited transwell migration of ESFT derived cell lines, but not osteosarcoma cell lines.	('inhibited', 'NegReg', (207, 216))	('conferred', 'Reg', (111, 120))	('EWS-FLI1', 'Gene', (198, 206))	('sensitivity to treatment with olaparib', 'MPA', (121, 159))	('EWS-FLI1', 'Gene', (88, 96))	('PC3', 'CellLine', 'CVCL:0035', (68, 71))	('osteosarcoma', 'Disease', 'MESH:D012516', (273, 285))	('olaparib', 'Chemical', 'MESH:C531550', (151, 159))	('EWS-FLI1', 'Gene', '2130;2313', (88, 96))	('translocation', 'Var', (97, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (278, 285))	('EWS-FLI1', 'Gene', '2130;2313', (198, 206))	('knockdown', 'Var', (185, 194))	('rat', 'Species', '10116', (230, 233))	('osteosarcoma', 'Disease', (273, 285))	('transwell migration of ESFT derived cell lines', 'CPA', (217, 263))	('osteosarcoma', 'Phenotype', 'HP:0002669', (273, 285))
499909	27336789	Additional work then demonstrated that, similar to breast and ovarian cancers harboring BRCA1/2 mutations, Ewing's sarcomas may also have defects in DNA repair mechanisms, rendering them sensitive to PARP inhibition.	("Ewing's sarcomas", 'Disease', (107, 123))	('defects', 'NegReg', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (107, 123))	('PARP', 'Gene', '142', (200, 204))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (51, 77))	('rat', 'Species', '10116', (28, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (107, 122))	('ovarian cancers', 'Phenotype', 'HP:0100615', (62, 77))	('BRCA1/2', 'Gene', (88, 95))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (107, 123))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('PARP', 'Gene', (200, 204))	('BRCA1/2', 'Gene', '672;675', (88, 95))	('DNA repair mechanisms', 'MPA', (149, 170))	('mutations', 'Var', (96, 105))
499949	27336789	Coat culture dishes for cells with fibronectin (0.0001% in PBS) for 3 hr at 37 C (or 4 C overnight) before plating.	('PBS', 'Chemical', '-', (59, 62))	('0.0001%', 'Var', (48, 55))	('fibronectin', 'Gene', (35, 46))	('fibronectin', 'Gene', '2335', (35, 46))
499987	27336789	Data to be collected: Unpaired two-tailed t-test of olaparib IC50 values of siControl transfected cells compared to siEF1 transfected cells.	('IC50 values', 'MPA', (61, 72))	('siControl', 'Gene', (76, 85))	('transfected', 'Var', (86, 97))	('olaparib', 'Gene', (52, 60))	('olaparib', 'Chemical', 'MESH:C531550', (52, 60))
499988	27336789	o Viability assay: siControl transfected cells treated with DMSO compared to siEF1 transfected cells treated with DMSO.	('DMSO', 'Chemical', 'MESH:D004121', (60, 64))	('DMSO', 'Chemical', 'MESH:D004121', (114, 118))	('DMSO', 'Var', (60, 64))	('siControl', 'Gene', (19, 28))
499998	27336789	While this finding is indeed an important part of the original study it does not embody a large part of the original conclusions: The original paper demonstrated that a drug screen performed across a large collection of cell lines was able to capture accurately a large number of known clinically relevant drug response biomarkers as well as preferential cancer type sensitivities known to occur in the clinic (for example that BRAF mutant colorectal cancers are less responsive to BRAF inhibitor than melanomas).	('cancer', 'Disease', 'MESH:D009369', (451, 457))	('colorectal cancers', 'Disease', 'MESH:D015179', (440, 458))	('BRAF', 'Gene', '673', (428, 432))	('melanomas', 'Disease', 'MESH:D008545', (502, 511))	('BRAF', 'Gene', (428, 432))	('melanomas', 'Disease', (502, 511))	('cancer', 'Disease', (355, 361))	('cancers', 'Phenotype', 'HP:0002664', (451, 458))	('rat', 'Species', '10116', (156, 159))	('cancer', 'Disease', (451, 457))	('BRAF', 'Gene', (482, 486))	('BRAF', 'Gene', '673', (482, 486))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('colorectal cancers', 'Disease', (440, 458))	('cancer', 'Phenotype', 'HP:0002664', (451, 457))	('mutant', 'Var', (433, 439))	('melanomas', 'Phenotype', 'HP:0002861', (502, 511))	('rat', 'Species', '10116', (255, 258))	('cancer', 'Disease', 'MESH:D009369', (355, 361))
500006	27336789	The DoTc2-4510 cell line (uterus tissue that is mutant for BRCA2 and wild-type for BRCA1) was already included as a positive control and we have added the MES-SA cell line (uterus tissue that is wild-type for BRCA1 and BRCA2) as a negative control in the revised Registered Report.	('BRCA1', 'Gene', '672', (209, 214))	('BRCA2', 'Gene', '675', (59, 64))	('MES-SA', 'Chemical', '-', (155, 161))	('mutant', 'Var', (48, 54))	('BRCA2', 'Gene', '675', (219, 224))	('BRCA1', 'Gene', '672', (83, 88))	('BRCA1', 'Gene', (209, 214))	('BRCA1', 'Gene', (83, 88))	('BRCA2', 'Gene', (59, 64))	('BRCA2', 'Gene', (219, 224))
500023	27219337	Interestingly, inactivation of the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway was recently found to be involved in some of its above described antitumoral effects.	('AKT', 'Gene', '207', (72, 75))	('phosphatidylinositol 3-kinase', 'Gene', (35, 64))	('tumor', 'Disease', (164, 169))	('AKT', 'Gene', (72, 75))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (35, 64))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('inactivation', 'Var', (15, 27))
500025	27219337	Once activated by PI3K, AKT moves from the cell membrane to the cytoplasm and/or nucleus, where it promotes cell cycle progression and prevents apoptosis in several ways, thereby controlling essential cellular regulator proteins (e.g., cyclin D, c-Myc or beta-catenin) and cyclin-dependent kinase (CDK) inhibitors (e.g., p21/WAF1).	('beta-catenin', 'Gene', (255, 267))	('prevents', 'NegReg', (135, 143))	('AKT', 'Gene', (24, 27))	('beta-catenin', 'Gene', '1499', (255, 267))	('WAF1', 'Gene', (325, 329))	('cell cycle progression', 'CPA', (108, 130))	('PI3K', 'Var', (18, 22))	('promotes', 'PosReg', (99, 107))	('apoptosis', 'CPA', (144, 153))	('c-Myc', 'Gene', '4609', (246, 251))	('p21', 'Gene', '1026', (321, 324))	('p21', 'Gene', (321, 324))	('c-Myc', 'Gene', (246, 251))	('AKT', 'Gene', '207', (24, 27))	('WAF1', 'Gene', '1026', (325, 329))
234850	27219337	Cell populations in the different phases of cell cycle (sub-G1 (cell death), G0/G1, S/G2/M peaks) were determined based on their DNA content in a Beckman Coulter Epics XL flow cytometer.	('S/G2', 'Var', (84, 88))	('S/G2', 'SUBSTITUTION', 'None', (84, 88))	('DNA', 'MPA', (129, 132))
500083	27219337	Previous work has suggested that inhibition of AKT could be a desirable therapeutic approach for treatment of STS, in particular, synovial sarcoma.	('AKT', 'Gene', (47, 50))	('inhibition', 'Var', (33, 43))	('synovial sarcoma', 'Disease', (130, 146))	('AKT', 'Gene', '207', (47, 50))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (130, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('STS', 'Phenotype', 'HP:0030448', (110, 113))	('synovial sarcoma', 'Disease', 'MESH:D013584', (130, 146))
500085	27219337	suggested that the overexpression of several tyrosine kinase receptors that signal through AKT contributes to the proliferation of these tumor cells through beta-catenin stabilization, since mutations in APC (Adenomatous Polyposis Coli) or beta-catenin, which would promote its nuclear accumulation, are rare in synovial sarcoma.	('beta-catenin', 'Gene', (240, 252))	('beta-catenin', 'Gene', '1499', (240, 252))	('synovial sarcoma', 'Disease', (312, 328))	('synovial sarcoma', 'Disease', 'MESH:D013584', (312, 328))	('Adenomatous Polyposis Coli', 'Disease', 'MESH:D011125', (209, 235))	('mutations', 'Var', (191, 200))	('Adenomatous Polyposis Coli', 'Phenotype', 'HP:0005227', (209, 235))	('AKT', 'Gene', (91, 94))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (312, 328))	('beta-catenin', 'Gene', (157, 169))	('APC', 'Disease', 'MESH:D011125', (204, 207))	('APC', 'Disease', (204, 207))	('beta-catenin', 'Gene', '1499', (157, 169))	('Adenomatous Polyposis Coli', 'Disease', (209, 235))	('tumor', 'Disease', (137, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (321, 328))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('AKT', 'Gene', '207', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
500091	27219337	The SK-UT-1 cells used in our study differ from SW982 cells as the former have mutations in the PI3KCA and PTEN genes (phosphatase and tensin homologe, deleted on chromosome 10; http://cancer.sanger.ac.uk/cell_lines/sample/), which should lead to a higher basal AKT activation.	('PTEN', 'Gene', (107, 111))	('basal', 'MPA', (256, 261))	('SK-UT-1', 'CellLine', 'CVCL:0533', (4, 11))	('PTEN', 'Gene', '5728', (107, 111))	('AKT', 'Gene', (262, 265))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('activation', 'PosReg', (266, 276))	('PI3KCA', 'Gene', (96, 102))	('higher', 'PosReg', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('SW982', 'CellLine', 'CVCL:1734', (48, 53))	('AKT', 'Gene', '207', (262, 265))	('cancer', 'Disease', (185, 191))	('mutations', 'Var', (79, 88))
500105	27219337	Although the role of p21 in apoptosis is complex and depends on the cellular context, it was shown that expression of p21 protected tumor cells from DXR-induced apoptosis.	('DXR', 'Chemical', 'MESH:D004317', (149, 152))	('p21', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('p21', 'Gene', '1026', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('p21', 'Gene', (118, 121))	('tumor', 'Disease', (132, 137))	('p21', 'Gene', '1026', (21, 24))	('expression', 'Var', (104, 114))
500136	21499557	Similarly, familial retinoblastoma has been known to be associated with inherited mutations of retinoblastoma gene.	('retinoblastoma', 'Gene', (95, 109))	('retinoblastoma', 'Gene', '5925', (20, 34))	('familial retinoblastoma', 'Disease', 'MESH:D012175', (11, 34))	('retinoblastoma', 'Phenotype', 'HP:0009919', (95, 109))	('retinoblastoma', 'Gene', '5925', (95, 109))	('retinoblastoma', 'Gene', (20, 34))	('retinoblastoma', 'Phenotype', 'HP:0009919', (20, 34))	('associated', 'Reg', (56, 66))	('mutations', 'Var', (82, 91))	('familial retinoblastoma', 'Disease', (11, 34))
500147	21499557	In addition, trabectedin compared to end-stage treatment was estimated to result in a 14 months of additional survival and 9 to 10 months of additional quality-adjusted survival compared to end-stage treatment alone.	('trabectedin', 'Var', (13, 24))	('additional', 'PosReg', (99, 109))	('trabectedin', 'Chemical', 'MESH:D000077606', (13, 24))
500151	21499557	Deficiencies in homologous recombination repair render the cell quite sensitive to the toxic effects of trabectedin, thus BRCA1/2 or other Fanconi gene deficiency would render the tumor cells sensitive.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('trabectedin', 'Chemical', 'MESH:D000077606', (104, 115))	('Fanconi gene deficiency', 'Disease', 'MESH:D005198', (139, 162))	('BRCA1/2', 'Gene', '672;675', (122, 129))	('Deficiencies', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Fanconi gene deficiency', 'Disease', (139, 162))	('tumor', 'Disease', (180, 185))	('BRCA1/2', 'Gene', (122, 129))	('sensitive', 'MPA', (70, 79))
500154	21499557	Tumor cells having p53 mutations appear more sensitive to trabectedin compared to those with wt p53.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('mutations', 'Var', (23, 32))	('p53', 'Gene', '7157', (19, 22))	('p53', 'Gene', (19, 22))	('sensitive', 'MPA', (45, 54))	('trabectedin', 'Chemical', 'MESH:D000077606', (58, 69))
500516	23700373	Li-Fraumeni syndrome results from germline mutations in the TP53 suppressor gene.	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('results from', 'Reg', (21, 33))	('germline mutations', 'Var', (34, 52))	('TP53', 'Gene', '7157', (60, 64))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('TP53', 'Gene', (60, 64))
500517	23700373	Sarcoma patients are more likely to have TP53 germline mutations, and sarcoma represents 25% of tumors in TP53 mutation carriers.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('sarcoma', 'Disease', (70, 77))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('germline mutations', 'Var', (46, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('tumors', 'Disease', (96, 102))	('Sarcoma', 'Disease', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))	('patients', 'Species', '9606', (8, 16))
500518	23700373	Retinoblastoma develops through germline mutations in the RB1 tumor suppressor gene, and retinoblastoma survivors have shown an increased risk of sarcoma compared to the general population.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RB1', 'Gene', '5925', (58, 61))	('germline mutations', 'Var', (32, 50))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('retinoblastoma', 'Phenotype', 'HP:0009919', (89, 103))	('sarcoma', 'Disease', (146, 153))	('tumor', 'Disease', (62, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('retinoblastoma', 'Disease', 'MESH:D012175', (89, 103))	('retinoblastoma', 'Disease', (89, 103))	('Retinoblastoma', 'Disease', 'MESH:D012175', (0, 14))	('RB1', 'Gene', (58, 61))	('Retinoblastoma', 'Disease', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
500519	23700373	Werner syndrome is an autosomal inherited disease caused by a mutation in the DNA helicase gene, WRN.	('autosomal inherited disease', 'Disease', (22, 49))	('caused by', 'Reg', (50, 59))	('WRN', 'Gene', '7486', (97, 100))	('WRN', 'Gene', (97, 100))	('autosomal inherited disease', 'Disease', 'MESH:D030342', (22, 49))	('Werner syndrome', 'Disease', 'MESH:D014898', (0, 15))	('mutation', 'Var', (62, 70))	('Werner syndrome', 'Disease', (0, 15))
500526	23700373	Diamond Black fan anemia is an inherited red blood disorder where 40% of patients have mutations in genes important in ribosomal function.	('anemia', 'Disease', 'MESH:D000740', (18, 24))	('anemia', 'Phenotype', 'HP:0001903', (18, 24))	('mutations', 'Var', (87, 96))	('inherited red blood disorder', 'Disease', 'MESH:D030342', (31, 59))	('inherited red blood disorder', 'Disease', (31, 59))	('patients', 'Species', '9606', (73, 81))	('anemia', 'Disease', (18, 24))
500578	23700373	The genes, or their pathways are mutated in the majority of osteosarcomas, but targeting these aberrations has proved to be difficult.	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('mutated', 'Var', (33, 40))	('osteosarcomas', 'Phenotype', 'HP:0002669', (60, 73))	('osteosarcomas', 'Disease', (60, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('osteosarcomas', 'Disease', 'MESH:D012516', (60, 73))
500584	23700373	Other compounds that may be translated into upcoming trials include mammalian target of rapamycin (mTOR) inhibitors, PI3K pathway inhibitors, anti-microtubular agents, cell cycle protein inhibitors, disruptors of osteoclast activity (receptor activator of nuclear factor-kappaB ligand inhibitors and bisphosphonates), immune strategies, and other targeted agents.	('osteoclast activity', 'CPA', (213, 232))	('mammalian target of rapamycin', 'Gene', '2475', (68, 97))	('mammalian target of rapamycin', 'Gene', (68, 97))	('disruptors', 'Var', (199, 209))	('bisphosphonates', 'Chemical', 'MESH:D004164', (300, 315))	('PI3K', 'Gene', (117, 121))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', (99, 103))
500586	23700373	More than 90% of patients display rearrangement of the EWS gene, most often to FLI1.	('FLI1', 'Gene', (79, 83))	('EWS', 'Gene', '2130', (55, 58))	('EWS', 'Gene', (55, 58))	('rearrangement', 'Var', (34, 47))	('FLI1', 'Gene', '2313', (79, 83))	('patients', 'Species', '9606', (17, 25))
500603	23700373	Mithramycin (ongoing study NCT01610570) is an older antibiotic identified in a drug screen, and YK-4-279 disrupts the EWS/FLI1 interaction with a binding partner, RNA helicase A.	('FLI1', 'Gene', (122, 126))	('EWS', 'Gene', '2130', (118, 121))	('EWS', 'Gene', (118, 121))	('binding', 'Interaction', (146, 153))	('YK-4-279', 'Var', (96, 104))	('RNA helicase A', 'Gene', (163, 177))	('Mithramycin', 'Chemical', 'MESH:D008926', (0, 11))	('disrupts', 'NegReg', (105, 113))	('FLI1', 'Gene', '2313', (122, 126))	('RNA helicase A', 'Gene', '1660', (163, 177))	('interaction', 'Interaction', (127, 138))
500631	23700373	Synovial sarcoma is characterized by the presence of a translocation between SYT on the X chromosome and SSX1, SSX2, or SSX4 on chromosome 18.	('SSX2', 'Gene', (111, 115))	('SSX1', 'Gene', (105, 109))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('SSX4', 'Gene', '6759', (120, 124))	('SSX4', 'Gene', (120, 124))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('SYT', 'Gene', (77, 80))	('sarcoma', 'Disease', (9, 16))	('SYT', 'Gene', '6760', (77, 80))	('translocation', 'Var', (55, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SSX2', 'Gene', '6757', (111, 115))	('SSX1', 'Gene', '6756', (105, 109))
500644	23700373	NF1 affects 1 in 3500 people and is characterized by a mutation in NF1, a tumor suppressor gene whose protein product, neurofibromin, is an RAS-GTPase activating protein, which negatively regulates RAS.	('RAS', 'Protein', (198, 201))	('NF1', 'Gene', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('negatively regulates', 'NegReg', (177, 197))	('neurofibromin', 'Gene', (119, 132))	('NF1', 'Gene', '4763', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('people', 'Species', '9606', (22, 28))	('tumor', 'Disease', (74, 79))	('NF1', 'Gene', (0, 3))	('mutation', 'Var', (55, 63))	('neurofibromin', 'Gene', '4763', (119, 132))	('NF1', 'Gene', '4763', (0, 3))
500652	23700373	Based on the current knowledge of neurofibromatosis and MPNST, it could be predicted that inhibiting pathways downstream of RAS such as MEK/ERK and PI3K/AKT/mTOR may be promising therapeutic strategies.	('neurofibroma', 'Phenotype', 'HP:0001067', (34, 46))	('MEK', 'Gene', (136, 139))	('AKT', 'Gene', '207', (153, 156))	('MEK', 'Gene', '5609', (136, 139))	('neurofibromatosis', 'Disease', (34, 51))	('inhibiting', 'Var', (90, 100))	('neurofibromatosis', 'Disease', 'MESH:C537392', (34, 51))	('AKT', 'Gene', (153, 156))	('ERK', 'Gene', '2048', (140, 143))	('MPNST', 'Phenotype', 'HP:0100697', (56, 61))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (34, 51))	('mTOR', 'Gene', (157, 161))	('ERK', 'Gene', (140, 143))	('mTOR', 'Gene', '2475', (157, 161))
500655	23700373	Mutations in the TP53 gene, inactivation of the PTEN gene, and mTOR activation have been observed in a subset of tumors.	('mTOR', 'Gene', (63, 67))	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('inactivation', 'Var', (28, 40))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('TP53', 'Gene', '7157', (17, 21))	('mTOR', 'Gene', '2475', (63, 67))	('TP53', 'Gene', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
500660	23700373	Loss of cell cycle regulation is inferred by the frequency of p53 inactivation and alterations in RB1 function.	('RB1', 'Gene', '5925', (98, 101))	('function', 'MPA', (102, 110))	('Loss', 'NegReg', (0, 4))	('inactivation', 'Var', (66, 78))	('RB1', 'Gene', (98, 101))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('cell cycle regulation', 'CPA', (8, 29))	('alterations', 'Reg', (83, 94))
500682	23700373	Well- differentiated and dedifferentiated liposarcomas frequently exhibit abnormalities in chromosome 12, and approximately 95% of dedifferentiated liposarcomas display up-regulation of HDM2 and CDK4.	('liposarcomas', 'Disease', 'MESH:D008080', (148, 160))	('up-regulation', 'PosReg', (169, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('CDK4', 'Gene', (195, 199))	('liposarcomas', 'Phenotype', 'HP:0012034', (148, 160))	('liposarcoma', 'Phenotype', 'HP:0012034', (148, 159))	('abnormalities', 'Var', (74, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('liposarcomas', 'Disease', 'MESH:D008080', (42, 54))	('CDK4', 'Gene', '1019', (195, 199))	('liposarcomas', 'Disease', (148, 160))	('dedifferentiated liposarcomas', 'Phenotype', 'HP:0012034', (131, 160))	('liposarcomas', 'Phenotype', 'HP:0012034', (42, 54))	('HDM2', 'Gene', (186, 190))	('liposarcoma', 'Phenotype', 'HP:0012034', (42, 53))	('dedifferentiated liposarcomas', 'Phenotype', 'HP:0012034', (25, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('HDM2', 'Gene', '4193', (186, 190))	('liposarcomas', 'Disease', (42, 54))
500683	23700373	Recent early-phase studies involving inhibitors of HDM2 and CDK4 have yielded modest results in terms of response and survivorship, although these Phase I studies, which aim to determine an adequate dose, are not powered for response analysis.	('inhibitors', 'Var', (37, 47))	('CDK4', 'Gene', (60, 64))	('HDM2', 'Gene', (51, 55))	('HDM2', 'Gene', '4193', (51, 55))	('survivorship', 'CPA', (118, 130))	('CDK4', 'Gene', '1019', (60, 64))
500685	23700373	Retrospective analyses of responders have shown that trabectedin induces fat maturation similar to that seen with doxorubicin-based regimens and radiation.	('trabectedin', 'Var', (53, 64))	('fat maturation', 'CPA', (73, 87))	('doxorubicin', 'Chemical', 'MESH:D004317', (114, 125))
500690	23700373	Many patients with MPNST have a uniform first hit of a neurofibromin mutation.	('MPNST', 'Disease', (19, 24))	('patients', 'Species', '9606', (5, 13))	('neurofibromin', 'Gene', '4763', (55, 68))	('MPNST', 'Phenotype', 'HP:0100697', (19, 24))	('mutation', 'Var', (69, 77))	('neurofibromin', 'Gene', (55, 68))
500764	32823999	For these domains, patients treated with palliative intent had worse functioning, worse global HRQoL and higher insomnia scores than patients treated with curative intent.	('patients', 'Species', '9606', (19, 27))	('worse', 'NegReg', (63, 68))	('higher', 'PosReg', (105, 111))	('palliative', 'Var', (41, 51))	('patients', 'Species', '9606', (133, 141))	('global HRQoL', 'MPA', (88, 100))	('insomnia', 'Disease', (112, 120))	('worse', 'NegReg', (82, 87))	('insomnia', 'Phenotype', 'HP:0100785', (112, 120))	('functioning', 'MPA', (69, 80))	('insomnia', 'Disease', 'MESH:D007319', (112, 120))
500919	31550266	Importantly, in preclinical models of ES, reversible inhibitors of LSD1 also demonstrate some promise in halting tumor cell propagation.	('inhibitors', 'Var', (53, 63))	('tumor', 'Disease', (113, 118))	('ES', 'Disease', 'MESH:D012512', (38, 40))	('halting', 'NegReg', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('LSD1', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LSD1', 'Gene', '23028', (67, 71))
500922	31550266	SP2509 does not interfere with FAD binding as it interacts with the H3 pocket region of LSD1 which functions as an allosteric site, suggesting that SP2509 may act as an allosteric inhibitor.	('interacts', 'Interaction', (49, 58))	('SP2509', 'Var', (0, 6))	('LSD1', 'Gene', (88, 92))	('SP2509', 'Var', (148, 154))	('LSD1', 'Gene', '23028', (88, 92))	('FAD', 'Chemical', 'MESH:D005182', (31, 34))
500924	31550266	HDAC inhibitors have been shown to possess direct antineoplastic activity as well as to enhance the efficacy of other anticancer agents.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('cancer', 'Disease', (122, 128))	('inhibitors', 'Var', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('efficacy', 'MPA', (100, 108))	('antineoplastic activity', 'CPA', (50, 73))	('enhance', 'PosReg', (88, 95))
500925	31550266	There is also evidence that inhibition of HDAC inhibition attenuates LSD1 activity in vivo.	('HDAC', 'Gene', (42, 46))	('LSD1', 'Gene', (69, 73))	('attenuates', 'NegReg', (58, 68))	('HDAC', 'Gene', '9734', (42, 46))	('LSD1', 'Gene', '23028', (69, 73))	('inhibition', 'Var', (28, 38))	('activity', 'MPA', (74, 82))
500961	31550266	Combinations SP2509+romidepson, SP2509+doxorubicin, and SP2509+vincristine all produced FAs more statistically significant than SP2509+etoposide.	('doxorubicin', 'Chemical', 'MESH:D004317', (39, 50))	('etoposide', 'Chemical', 'MESH:D005047', (135, 144))	('SP2509+vincristine', 'Chemical', 'MESH:C000594309', (56, 74))	('FAs', 'Chemical', 'MESH:D053222', (88, 91))	('SP2509+vincristine', 'Var', (56, 74))	('SP2509+romidepson', 'Chemical', 'MESH:C000594309', (13, 30))	('SP2509+doxorubicin', 'Var', (32, 50))	('SP2509+romidepson', 'Var', (13, 30))
500963	31550266	When the same analysis was performed with romidepsin combinations, we found romidepsin+doxorubicin, romidepsin+SN-38, and romidepsin+vincristine to have the most statistically significant FAs (Fig 2D).	('N', 'Chemical', 'MESH:D009584', (112, 113))	('FAs', 'Chemical', 'MESH:D053222', (188, 191))	('romidepsin', 'Chemical', 'MESH:C087123', (122, 132))	('romidepsin+SN-38', 'Var', (100, 116))	('romidepsin', 'Chemical', 'MESH:C087123', (42, 52))	('romidepsin+vincristine', 'Chemical', 'MESH:C087123', (122, 144))	('FAs', 'Disease', (188, 191))	('romidepsin', 'Chemical', 'MESH:C087123', (100, 110))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))	('romidepsin', 'Chemical', 'MESH:C087123', (76, 86))
500965	31550266	Interestingly, nearly all the combinations produced higher FA values than those produced with romidepsin+SP2509.	('FA values', 'MPA', (59, 68))	('romidepsin', 'Chemical', 'MESH:C087123', (94, 104))	('higher', 'PosReg', (52, 58))	('combinations', 'Var', (30, 42))
500967	31550266	Except for SP2509+vincristine, FA values trended lower than the other cell lines, though this is likely due more to A673's sensitivity to vincristine.	('SP2509+vincristine', 'Chemical', 'MESH:C000594309', (11, 29))	('lower', 'NegReg', (49, 54))	('SP2509+vincristine', 'Var', (11, 29))	('vincristine', 'Chemical', 'MESH:D014750', (18, 29))	('end', 'Disease', (43, 46))	('vincristine', 'Chemical', 'MESH:D014750', (138, 149))	('end', 'Disease', 'MESH:D007676', (43, 46))
500969	31550266	The distribution of CI values for SP2509 combinations was similar in RD-ES and TC-71 with median values between 0.5 and 0.8 (Fig 2E).	('SP2509 combinations', 'Var', (34, 53))	('ES', 'Disease', 'MESH:D012512', (72, 74))	('combinations', 'Var', (41, 53))
500974	31550266	The combination of SP2509 with romidepsin itself was rather effective, producing median FA values near and above 0.7 across all cell lines except TC-71, with maximum FA values of 1.0 reached in all 4 ES models (Fig 2A, 2B, 2C, 2D, 2G and 2I).	('romidepsin', 'Chemical', 'MESH:C087123', (31, 41))	('combination', 'Interaction', (4, 15))	('SP2509', 'Var', (19, 25))	('ES', 'Disease', 'MESH:D012512', (200, 202))
500976	31550266	SP2509 and any of doxorubicin, etoposide or SN-38 demonstrated an average FA of at least 0.87, with FA as high as 0.95 observed in two cell lines and average CIs of 0.5 or lower (Fig 2A, 2C, 2E and 2Giii,iv, S2 Table).	('etoposide', 'Chemical', 'MESH:D005047', (31, 40))	('SP2509', 'Var', (0, 6))	('lower', 'NegReg', (172, 177))	('SN-38', 'Gene', (44, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (18, 29))	('N', 'Chemical', 'MESH:D009584', (45, 46))
500981	31550266	TC32 has a functional p53 gene while A673 has a frameshift mutation rendering p53 nonfunctional.	('frameshift mutation', 'Var', (48, 67))	('end', 'Disease', (69, 72))	('end', 'Disease', 'MESH:D007676', (69, 72))	('p53', 'Gene', (22, 25))	('A673', 'Var', (37, 41))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', '7157', (78, 81))	('nonfunctional', 'MPA', (82, 95))
500982	31550266	Conversely, A673 is wild type for STAG2 whereas TC32 has a frameshift mutation in STAG2 (Table 1).	('STAG2', 'Gene', (34, 39))	('frameshift mutation', 'Var', (59, 78))	('A673', 'Var', (12, 16))	('STAG2', 'Gene', (82, 87))	('STAG2', 'Gene', '10735', (82, 87))	('STAG2', 'Gene', '10735', (34, 39))
500983	31550266	We found that the effects on viability from SN-38 were more delayed than any of the other agents.	('viability', 'CPA', (29, 38))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('delayed', 'NegReg', (60, 67))	('SN-38', 'Var', (44, 49))
500987	31550266	Importantly, at concentrations well below Cmax (Table 3, S1A Fig), combinations of VIT+SP2509 were able to reduce cell viability by over 90% at the highest-tested concentrations and by over 80% at half the topmost concentrations.	('combinations', 'Var', (67, 79))	('VIT', 'Chemical', 'MESH:D014750', (83, 86))	('VIT+SP2509', 'Gene', (83, 93))	('cell viability', 'CPA', (114, 128))	('reduce', 'NegReg', (107, 113))
500989	31550266	In TC32, there is a tendency towards higher potency when SP2509 is added last, but this is within the bounds of experimental variability.	('end', 'Disease', 'MESH:D007676', (21, 24))	('TC32', 'Gene', (3, 7))	('potency', 'MPA', (44, 51))	('higher', 'PosReg', (37, 43))	('SP2509', 'Var', (57, 63))	('end', 'Disease', (21, 24))
500990	31550266	Overall, addition of SP2509 increased the FA but only slightly, most likely due to the already efficacious treatment of VIT alone.	('increased', 'PosReg', (28, 37))	('SP2509', 'Var', (21, 27))	('VIT', 'Chemical', 'MESH:D014750', (120, 123))
500998	31550266	Importantly, when SP2509 is combined with current second-line conventional chemotherapy regimen vincristine, irinotecan, temozolomide (VIT) in vitro, cell viability is considerably decreased even at concentrations well below Cmax.	('VIT', 'Chemical', 'MESH:D014750', (135, 138))	('vincristine', 'Chemical', 'MESH:D014750', (96, 107))	('SP2509', 'Var', (18, 24))	('irinotecan', 'Chemical', 'MESH:C051890', (109, 119))	('cell viability', 'CPA', (150, 164))	('temozolomide', 'Chemical', 'MESH:C047246', (121, 133))	('decreased', 'NegReg', (181, 190))
501000	31550266	If indeed SP2509 is acting as an LSD1 inhibitor, LSD1 is required for heterochromatin formation.	('LSD1', 'Gene', '23028', (49, 53))	('LSD1', 'Gene', (33, 37))	('SP2509', 'Var', (10, 16))	('LSD1', 'Gene', '23028', (33, 37))	('LSD1', 'Gene', (49, 53))
501004	31550266	Inhibition of the EWS-FLI1 fusion protein has been shown to decrease EWS-FLI1-mediated generation of microtubule-associated proteins leaving cells more susceptible to microtubule depolymerization by vincristine.	('EWS', 'Gene', '2130', (18, 21))	('EWS', 'Gene', (18, 21))	('decrease', 'NegReg', (60, 68))	('EWS', 'Gene', (69, 72))	('EWS', 'Gene', '2130', (69, 72))	('FLI1', 'Gene', '2313', (73, 77))	('FLI1', 'Gene', (73, 77))	('vincristine', 'Chemical', 'MESH:D014750', (199, 210))	('generation of microtubule-associated proteins', 'MPA', (87, 132))	('Inhibition', 'Var', (0, 10))	('FLI1', 'Gene', (22, 26))	('FLI1', 'Gene', '2313', (22, 26))
501005	31550266	Real time quantitative PCR for the EWS/ETS gene product as well as the native FLI1 showed the lowest expression of EWS/ETS in A673, followed by TC32 and then TC-71 (RD-ES was not tested).	('EWS', 'Gene', '2130', (35, 38))	('EWS', 'Gene', (35, 38))	('ES', 'Disease', 'MESH:D012512', (168, 170))	('FLI1', 'Gene', '2313', (78, 82))	('EWS', 'Gene', '2130', (115, 118))	('EWS', 'Gene', (115, 118))	('FLI1', 'Gene', (78, 82))	('lowest', 'NegReg', (94, 100))	('expression', 'MPA', (101, 111))	('A673', 'Var', (126, 130))
501018	31550266	HDACs are involved in a broad number of biological pathways, and interruption of their function can result in a plethora of transcriptional and functional consequences.	('HDAC', 'Gene', (0, 4))	('biological pathways', 'Pathway', (40, 59))	('HDAC', 'Gene', '9734', (0, 4))	('transcriptional', 'MPA', (124, 139))	('interruption', 'Var', (65, 77))	('involved', 'Reg', (10, 18))	('plethora', 'Phenotype', 'HP:0001050', (112, 120))
501020	31550266	Of additional interest is the fact that we also saw synergistic activity when SP2509 was paired with romidepsin.	('romidepsin', 'Chemical', 'MESH:C087123', (101, 111))	('synergistic activity', 'MPA', (52, 72))	('paired', 'Interaction', (89, 95))	('SP2509', 'Var', (78, 84))
501024	31550266	In particular we discovered that combinations of SP2509 with currently utilized conventional chemotherapies demonstrate largely synergistic activity against ES cell lines.	('SP2509', 'Var', (49, 55))	('ES', 'Disease', 'MESH:D012512', (157, 159))	('combinations', 'Interaction', (33, 45))
501054	31550266	Minor comments for consideration Introduction 1) As synergism with SP2509 was the main premise for this study, the authors should explain why SP2509 was chosen over other LSD1 inhibitors (GSK2879552 and ORY-1001).	('SP2509', 'Var', (142, 148))	('GSK2879552', 'Var', (188, 198))	('LSD1', 'Gene', '23028', (171, 175))	('LSD1', 'Gene', (171, 175))
501055	31550266	It would be helpful to state in the introduction that SP2509 is currently in Phase I clinical testing for Ewing sarcoma patients (NCT03600649) and that Ewing sarcoma cell lines are resistant to reversible inhibitors (Romo-Morales et al., Pediatric Blood & Cancer, 2019).	('SP2509', 'Var', (54, 60))	('Cancer', 'Phenotype', 'HP:0002664', (256, 262))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('Ewing sarcoma', 'Disease', (106, 119))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('patients', 'Species', '9606', (120, 128))	('Ewing sarcoma', 'Disease', (152, 165))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (152, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (106, 119))
501064	31550266	2) Although not used for clinical settings in Ewing sarcoma, SP2509 has been shown to synergise with docetaxel in prostate cancer (Gupta et al., 2016).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('docetaxel', 'Chemical', 'MESH:C067311', (101, 110))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (46, 59))	('Ewing sarcoma', 'Disease', (46, 59))	('prostate cancer', 'Disease', (114, 129))	('SP2509', 'Var', (61, 67))
501073	31550266	Minor comments: Page 3 line 44 sentence unclear - most commonly t(11;22)(q24;12) between the amino ... - "12" should be q12 is missing and that fuses would be better than "between" ********** 6.	('Page 3', 'Gene', '139793', (16, 22))	('Page 3', 'Gene', (16, 22))	('********** 6', 'Var', (181, 193))
501084	31550266	Reviewer Comments: Reviewer 1: Minor comments for consideration Introduction 1) As synergism with SP2509 was the main premise for this study, the authors should explain why SP2509 was chosen over other LSD1 inhibitors (GSK2879552 and ORY-1001).	('LSD1', 'Gene', (202, 206))	('SP2509', 'Var', (173, 179))	('GSK2879552', 'Var', (219, 229))	('LSD1', 'Gene', '23028', (202, 206))
501103	31550266	26 Aug 2019  [EXSCINDED] Small Molecule Inhibition of Lysine-Specific Demethylase 1 (LSD1) and Histone Deactylase (HDAC) Alone and in Combination in Ewing Sarcoma Cell Lines PONE-D-19-18074R1 Dear Dr. Reed, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('Sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('Lysine-Specific Demethylase 1', 'Gene', (54, 83))	('Lysine-Specific Demethylase 1', 'Gene', '23028', (54, 83))	('PONE-D-19-18074R1', 'Chemical', 'MESH:C039200', (174, 191))	('LSD1', 'Gene', '23028', (85, 89))	('HDAC', 'Gene', (115, 119))	('HDAC', 'Gene', '9734', (115, 119))	('Ewing Sarcoma Cell Lines', 'Disease', 'MESH:D012512', (149, 173))	('LSD1', 'Gene', (85, 89))	('Small', 'Var', (25, 30))	('N', 'Chemical', 'MESH:D009584', (176, 177))	('Ewing Sarcoma Cell Lines', 'Disease', (149, 173))	('Inhibition', 'NegReg', (40, 50))
501115	31252633	Aberrant expression of p53, inactivation of cell cycle inhibitors, loss of beta-catenin, and increased VEGFR1 were more frequent in AS.	('beta-catenin', 'Gene', '1499', (75, 87))	('VEGFR1', 'Gene', '2321', (103, 109))	('Aberrant', 'Var', (0, 8))	('increased', 'PosReg', (93, 102))	('inactivation', 'Var', (28, 40))	('VEGFR1', 'Gene', (103, 109))	('cell', 'Protein', (44, 48))	('expression', 'MPA', (9, 19))	('loss', 'NegReg', (67, 71))	('beta-catenin', 'Gene', (75, 87))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('increased VEGFR1', 'Phenotype', 'HP:0030269', (93, 109))
501119	31252633	The AS-rich cluster was characterized by high caveolin-1 positivity, abnormal p53, high Ki-67 index, and inactivated p27.	('Ki-67', 'CPA', (88, 93))	('abnormal', 'Var', (69, 77))	('positivity', 'MPA', (57, 67))	('caveolin-1', 'Gene', (46, 56))	('p53', 'Gene', (78, 81))	('p27', 'Gene', (117, 120))	('p27', 'Gene', '3429', (117, 120))	('caveolin-1', 'Gene', '857', (46, 56))	('inactivated', 'NegReg', (105, 116))	('p53', 'Gene', '7157', (78, 81))
501127	31252633	After the establishment of the pathogenic role of HHV8 in KS, the presence of HHV8 in tissues became the essential diagnostic criterion for KS.	('presence', 'Var', (66, 74))	('HHV8', 'Gene', (78, 82))	('HHV8', 'Species', '37296', (78, 82))	('HHV8', 'Species', '37296', (50, 54))
501149	31252633	Aberrant p53 expression (implying abnormal p53 status) was found only in the AS and HE groups, with no positive KS and BG cases.	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('BG', 'Chemical', 'MESH:C064976', (119, 121))
501162	31252633	Cluster 1 was characterized by 1) high expression of caveolin-1, expression of p53, high Ki-67 index, and expression of c-kit, 2) frequent inactivation of p27, and 3) low expression of galectin-3 and CD34.	('expression', 'MPA', (171, 181))	('c-kit', 'Gene', (120, 125))	('p53', 'Gene', (79, 82))	('CD34', 'Gene', (200, 204))	('p53', 'Gene', '7157', (79, 82))	('CD34', 'Gene', '947', (200, 204))	('galectin-3', 'Gene', '3958', (185, 195))	('low', 'NegReg', (167, 170))	('p27', 'Gene', '3429', (155, 158))	('caveolin-1', 'Gene', (53, 63))	('galectin-3', 'Gene', (185, 195))	('p27', 'Gene', (155, 158))	('expression', 'MPA', (65, 75))	('caveolin-1', 'Gene', '857', (53, 63))	('low expression of galectin-3', 'Phenotype', 'HP:0032205', (167, 195))	('expression', 'MPA', (39, 49))	('inactivation', 'Var', (139, 151))	('c-kit', 'Gene', '3815', (120, 125))
501179	31252633	Abnormal p53 signaling has been reported in hepatic AS, and inactivated p16 was shown to induce endothelial cell dysfunction that led to AS in an in vitro study.	('induce', 'Reg', (89, 95))	('p16', 'Gene', '1029', (72, 75))	('inactivated', 'Var', (60, 71))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p16', 'Gene', (72, 75))	('endothelial', 'Disease', (96, 107))
501188	31252633	The triggers for cellular proliferation in BG are hypoxia, inflammation, or genetic mutations.	('genetic mutations', 'Var', (76, 93))	('hypoxia', 'Disease', 'MESH:D000860', (50, 57))	('hypoxia', 'Disease', (50, 57))	('BG', 'Chemical', 'MESH:C064976', (43, 45))	('inflammation', 'Disease', 'MESH:D007249', (59, 71))	('inflammation', 'Disease', (59, 71))
501209	31252633	Thus, vascular tumors mimicking Kaposi sarcoma can be categorized into three clusters: cluster 1, altered expression of tumor suppressor genes (p53, p27) with a high proliferative index, enriched AS; cluster 2: high CD44 expression with a low proliferative index suggesting stem cell differentiation, mixed diagnosis; and cluster 3: lymphatic differentiation with activated Rb pathway, enriched KS.	('CD44', 'Gene', '960', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('p27', 'Gene', '3429', (149, 152))	('p27', 'Gene', (149, 152))	('CD44', 'Gene', (216, 220))	('vascular tumors', 'Disease', 'MESH:D019043', (6, 21))	('lymphatic differentiation', 'CPA', (333, 358))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('p53', 'Gene', '7157', (144, 147))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (32, 46))	('expression', 'MPA', (106, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('tumor', 'Disease', (120, 125))	('p53', 'Gene', (144, 147))	('Kaposi sarcoma', 'Disease', (32, 46))	('high', 'Var', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (15, 20))	('expression', 'MPA', (221, 231))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (32, 46))	('vascular tumors', 'Disease', (6, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('vascular tumor', 'Phenotype', 'HP:0100742', (6, 20))	('vascular tumors', 'Phenotype', 'HP:0100742', (6, 21))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('altered', 'Reg', (98, 105))
501251	27806299	Strikingly, we found that over 82.9%, 94.6% and 94.0% of peak summits identified in H1-ESC, H9-ESC, and H7-ESC, respectively, intersected a repetitive element.	('H9-ESC', 'CellLine', 'CVCL:1240', (92, 98))	('H7-ESC', 'CellLine', 'CVCL:9772', (104, 110))	('H1-ESC', 'Var', (84, 90))	('H7-ESC', 'Var', (104, 110))
501253	27806299	Simple repeats and short interspersed nucleotide elements (SINEs) were selectively enriched among FAIRE peaks in hESC, relative to their genomic prevalence.	('SINEs', 'Disease', 'MESH:D031368', (59, 64))	('Simple repeats', 'Var', (0, 14))	('SINEs', 'Disease', (59, 64))	('short interspersed nucleotide elements', 'Var', (19, 57))	('hESC', 'Disease', (113, 117))
501254	27806299	83% of unaligned sequences from H1-ESC were repetitive in nature, enriched for SINEs, simple repeats, and LINEs (Table S2).	('SINEs', 'Disease', 'MESH:D031368', (79, 84))	('SINEs', 'Disease', (79, 84))	('simple repeats', 'Var', (86, 100))	('H1-ESC', 'Gene', (32, 38))
501255	27806299	After normalizing for repeat length and sequencing depth, signal in hESC at simple repeats and SINEs greatly exceeded that of differentiated control cells (Figure 1E).	('SINEs', 'Disease', (95, 100))	('SINEs', 'Disease', 'MESH:D031368', (95, 100))	('simple repeats', 'Var', (76, 90))
501256	27806299	Taken together, read, signal and peak-based detection approaches consistently identify the selective enrichment of simple repeats and SINEs by FAIRE in hESCs.	('SINEs', 'Disease', (134, 139))	('SINEs', 'Disease', 'MESH:D031368', (134, 139))	('simple repeats', 'Var', (115, 129))
501258	27806299	Further, using the ENCODE mappability track, we found that the majority (51%) of FAIRE positive SINEs contain enough sequence diversity to map 50 bp reads in over 50% of the repeat length and contain bps near the 5' and 3' ends that have an average mappability score > 0.5 (Figure S1D, E).	('bps', 'Var', (200, 203))	('mappability', 'MPA', (249, 260))	('SINEs', 'Disease', 'MESH:D031368', (96, 101))	('SINEs', 'Disease', (96, 101))
501265	27806299	Leveraging publicly available data, we compared FAIRE and DNase signal at simple repeats and SINEs at FAIRE peaks (from Figure 1C).	('FAIRE', 'MPA', (48, 53))	('SINEs', 'Disease', 'MESH:D031368', (93, 98))	('SINEs', 'Disease', (93, 98))	('DNase signal', 'MPA', (58, 70))	('simple repeats', 'Var', (74, 88))
501266	27806299	Conversely, the few repeats that demonstrated DNase signal lacked FAIRE enrichment (1099 and 2033 simple repeats and SINEs, respectively).	('SINEs', 'Disease', 'MESH:D031368', (117, 122))	('simple repeats', 'Var', (98, 112))	('SINEs', 'Disease', (117, 122))
501270	27806299	Associated modifications differed from those at FAIRE-enriched SINEs as well as TSS and CTCF sites (Figure 4A).	('CTCF', 'Gene', '10664', (88, 92))	('modifications', 'Var', (11, 24))	('SINEs', 'Disease', 'MESH:D031368', (63, 68))	('SINEs', 'Disease', (63, 68))	('CTCF', 'Gene', (88, 92))
501271	27806299	H3K56ac and H2AK5ac were most associated with simple repeats.	('associated', 'Reg', (30, 40))	('H2AK5ac', 'Chemical', '-', (12, 19))	('H3K56ac', 'Var', (0, 7))	('H2AK5ac', 'Var', (12, 19))	('simple repeats', 'Disease', (46, 60))
501272	27806299	Signals for these modifications were centered over the repeat and demonstrated a magnitude similar or greater than that found at TSS and CTCF sites.	('CTCF', 'Gene', (137, 141))	('modifications', 'Var', (18, 31))	('CTCF', 'Gene', '10664', (137, 141))
501273	27806299	H4K8ac and H2A.Z were most associated with SINEs and show subtle but center-weighted enrichment (Figures 4C and S4B).	('H2A.Z', 'Gene', '3015', (11, 16))	('associated', 'Reg', (27, 37))	('SINEs', 'Disease', 'MESH:D031368', (43, 48))	('H4K8ac', 'Var', (0, 6))	('SINEs', 'Disease', (43, 48))	('H2A.Z', 'Gene', (11, 16))
501274	27806299	Overall, these data indicate that FAIRE-enriched simple repeats and SINEs are characterized by distinctly marked nucleosomes.	('simple repeats', 'Var', (49, 63))	('SINEs', 'Disease', (68, 73))	('SINEs', 'Disease', 'MESH:D031368', (68, 73))
501290	27806299	Clustering cell lineages based on FAIRE signal at simple repeats demonstrated a distinct pattern from that observed based on signal at SINEs.	('simple repeats', 'Var', (50, 64))	('SINEs', 'Disease', 'MESH:D031368', (135, 140))	('SINEs', 'Disease', (135, 140))
501297	27806299	We and others have previously shown that the resulting oncoprotein, EWSR1-FLI1, targets a subset of simple repeats distinct from the parental protein FLI1.	('FLI1', 'Gene', '2313', (150, 154))	('simple repeats', 'Var', (100, 114))	('EWSR1', 'Gene', '2130', (68, 73))	('FLI1', 'Gene', '2313', (74, 78))	('FLI1', 'Gene', (74, 78))	('EWSR1', 'Gene', (68, 73))	('FLI1', 'Gene', (150, 154))
501300	27806299	We first tested for the enrichment of repeat classes in accessible chromatin in tumor cells and primary BM-MSC and found that they shared a high degree of enrichment at simple repeats, relative to other repetitive element classes (Figure 6A).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('simple repeats', 'Var', (169, 183))	('tested', 'Reg', (9, 15))
501311	27806299	Moreover, in BM-MSC, ATAC enrichment was noted at these sites only after EWSR1-FLI1 was transduced (Figure 6D and.	('FLI1', 'Gene', (79, 83))	('FLI1', 'Gene', '2313', (79, 83))	('EWSR1', 'Gene', (73, 78))	('ATAC', 'Gene', (21, 25))	('EWSR1', 'Gene', '2130', (73, 78))	('transduced', 'Var', (88, 98))	('ATAC', 'Gene', '6375', (21, 25))
501320	27806299	Although not addressed in this study, our analysis of these data also demonstrated enrichment of repetitive elements in mESC compared to MEF (data not shown).	('mESC', 'Disease', (120, 124))	('repetitive elements', 'Var', (97, 116))	('MEF', 'Gene', '2000', (137, 140))	('MEF', 'Gene', (137, 140))
501325	27806299	Our results greatly extend previous reports suggesting that Alu repeats may serve to pattern nucleosomes.	('Alu', 'Chemical', '-', (60, 63))	('pattern nucleosomes', 'MPA', (85, 104))	('Alu', 'Var', (60, 63))
501330	27806299	Simple repeats, when bound by EWSR1-FLI1, gain enhancer activity to regulate the transcription of multiple genes known to be important for Ewing Sarcoma.	('EWSR1', 'Gene', '2130', (30, 35))	('Simple repeats', 'Var', (0, 14))	('Sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (139, 152))	('Ewing Sarcoma', 'Gene', (139, 152))	('FLI1', 'Gene', '2313', (36, 40))	('FLI1', 'Gene', (36, 40))	('EWSR1', 'Gene', (30, 35))	('gain enhancer', 'PosReg', (42, 55))	('Ewing Sarcoma', 'Gene', '2130', (139, 152))	('regulate', 'MPA', (68, 76))	('transcription', 'MPA', (81, 94))
501341	27806299	After 3-4 days adherent cells were selected by magnetic depletion according to manufacturer's instructions (MACS) with CD11b/Mac-1 (BD #555387) and CD45 (BD #555481).	('CD11b', 'Gene', (119, 124))	('CD45', 'Gene', (148, 152))	('BD #555387', 'Var', (132, 142))	('CD45', 'Gene', '5788', (148, 152))	('Mac-1', 'Gene', '3684', (125, 130))	('Mac-1', 'Gene', (125, 130))	('CD11b', 'Gene', '3684', (119, 124))
501363	21867429	Currently, we are using the Cre-loxP system to delete genes, such as p53, in a cell-type specific manner in mice in order to study mechanisms of acute radiation injury and late effects of radiation.	('radiation injury', 'Disease', 'MESH:D011832', (151, 167))	('p53', 'Gene', (69, 72))	('mice', 'Species', '10090', (108, 112))	('radiation injury', 'Disease', (151, 167))	('delete', 'Var', (47, 53))
501373	21867429	Indeed, he generated some of the first mice with deletions in tumor suppressor genes, including Rb, NF1, and p53.	('NF1', 'Gene', '18015', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('p53', 'Gene', (109, 112))	('deletions', 'Var', (49, 58))	('NF1', 'Gene', (100, 103))	('mice', 'Species', '10090', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
501379	21867429	This particular point mutation is frequently observed in a number of human cancers such as pancreatic cancer, non-small cell lung cancer, and colon cancer.	('colon cancer', 'Disease', (142, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (110, 136))	('point mutation', 'Var', (16, 30))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (114, 136))	('observed', 'Reg', (45, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (110, 136))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))	('human', 'Species', '9606', (69, 74))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('pancreatic cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('non-small cell lung cancer', 'Disease', (110, 136))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
501380	21867429	These mice contain a transcription/ translation "STOP cassette," which is flanked by loxP sites, upstream of the mutant Kras allele.	('mice', 'Species', '10090', (6, 10))	('mutant', 'Var', (113, 119))	('Kras', 'Gene', '16653', (120, 124))	('Kras', 'Gene', (120, 124))
501393	21867429	However, in the presence of tamoxifen, Cre can enter the nucleus, delete the STOP cassette, and restore wild-type p53 expression from its endogenous promoter.	('wild-type', 'MPA', (104, 113))	('delete', 'Var', (66, 72))	('restore', 'PosReg', (96, 103))	('tamoxifen', 'Chemical', 'MESH:D013629', (28, 37))	('expression', 'MPA', (118, 128))
501397	21867429	Scott Lowe's lab utilized in vivo shRNA to knock down p53 in a mouse model of liver cancer and demonstrated that loss of p53 function was required for tumor maintenance in a model of hepatocellular carcinoma.	('liver cancer', 'Disease', (78, 90))	('mouse', 'Species', '10090', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (183, 207))	('p53', 'Gene', (121, 124))	('knock', 'Var', (43, 48))	('tumor', 'Disease', (151, 156))	('hepatocellular carcinoma', 'Disease', (183, 207))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (183, 207))	('p53', 'Gene', (54, 57))	('loss', 'NegReg', (113, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('function', 'MPA', (125, 133))	('liver cancer', 'Phenotype', 'HP:0002896', (78, 90))	('liver cancer', 'Disease', 'MESH:D006528', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
501400	21867429	When the Evan's lab treated these mice with tamoxifen to turn on p53, they also observed regression of the thymic lymphomas.	('mice', 'Species', '10090', (34, 38))	("Evan's lab", 'Disease', (9, 19))	('lymphomas', 'Disease', (114, 123))	("Evan's lab", 'Disease', 'MESH:C536380', (9, 19))	('tamoxifen', 'Chemical', 'MESH:D013629', (44, 53))	('lymphomas', 'Disease', 'MESH:D008223', (114, 123))	('p53', 'Var', (65, 68))	('lymphomas', 'Phenotype', 'HP:0002665', (114, 123))	('turn', 'Var', (57, 61))
501401	21867429	More recently, Wang and colleagues compared the effect of restoring wild-type p53 (p53LSL mice) in tumors with no p53 or R172H mutant p53.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('R172H', 'Var', (121, 126))	('p53', 'Gene', (134, 137))	('mice', 'Species', '10090', (90, 94))	('LSL', 'Gene', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('LSL', 'Gene', '7839', (86, 89))	('R172H', 'Mutation', 'p.R172H', (121, 126))	('tumors', 'Disease', (99, 105))
501402	21867429	They confirmed that restoration of wild-type p53 in p53 null tumors caused tumor regression.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('p53', 'Gene', (52, 55))	('null', 'Var', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (75, 80))
501403	21867429	Interestingly, they observed that restoring p53 in tumors that also express R172H mutant p53 did not cause tumor regression, but instead halted tumor growth.	('tumor', 'Disease', (144, 149))	('R172H', 'Var', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('halted', 'NegReg', (137, 143))	('tumor', 'Disease', (51, 56))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('p53', 'Gene', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('p53', 'MPA', (44, 47))	('R172H', 'Mutation', 'p.R172H', (76, 81))
501404	21867429	Taken together, these results collectively demonstrate that loss of p53 function is required not only for tumor initiation, but also for tumor maintenance.	('tumor', 'Disease', (137, 142))	('tumor initiation', 'Disease', (106, 122))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('loss', 'Var', (60, 64))	('p53', 'Gene', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor initiation', 'Disease', 'MESH:D009369', (106, 122))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (106, 111))
501414	21867429	For example, we utilized Tie2Cre mice to delete Bax specifically within hematopoietic cells and endothelial cells.	('Bax', 'Gene', '12028', (48, 51))	('Bax', 'Gene', (48, 51))	('mice', 'Species', '10090', (33, 37))	('delete', 'Var', (41, 47))
501415	21867429	When Bax was deleted in Tie2+ cells in Bak-/- mice (i.e., Tie2Cre; Bak-/-; BaxFL/-), they were protected from the hematopoietic syndrome following WBI.	('deleted', 'Var', (13, 20))	('Bak', 'Gene', (67, 70))	('hematopoietic syndrome', 'Disease', 'MESH:D019337', (114, 136))	('Bax', 'Gene', (75, 78))	('Bak', 'Gene', '12018', (39, 42))	('Bax', 'Gene', (5, 8))	('Bak', 'Gene', (39, 42))	('Bak', 'Gene', '12018', (67, 70))	('mice', 'Species', '10090', (46, 50))	('protected', 'Reg', (95, 104))	('Bax', 'Gene', '12028', (5, 8))	('Bax', 'Gene', '12028', (75, 78))	('hematopoietic syndrome', 'Disease', (114, 136))
501416	21867429	However, neither single Bak-/- or Bax-/- mice nor the compound mutant Tie2Cre; Bak-/-; BaxFL/- mice were protected from SBI, indicating that the intrinisic pathway of apoptosis in Tie2+ cells does not regulate the GI syndrome after SBI.	('SBI', 'Disease', (120, 123))	('GI syndrome', 'Disease', 'MESH:D005767', (214, 225))	('mice', 'Species', '10090', (95, 99))	('Bak', 'Gene', '12018', (79, 82))	('mutant', 'Var', (63, 69))	('GI syndrome', 'Disease', (214, 225))	('mice', 'Species', '10090', (41, 45))	('Bax', 'Gene', '12028', (34, 37))	('Bak', 'Gene', '12018', (24, 27))	('Bax', 'Gene', '12028', (87, 90))	('Bax', 'Gene', (34, 37))	('Tie2Cre', 'Gene', (70, 77))	('Bak', 'Gene', (24, 27))	('Bax', 'Gene', (87, 90))	('Bak', 'Gene', (79, 82))
501417	21867429	We also utilized VillinCre mice to delete Bax specifically in GI epithelial cells in Bak-/- mice (i.e., VillinCre; Bak-/-; BaxFL/-).	('delete', 'Var', (35, 41))	('Bak', 'Gene', (115, 118))	('Bax', 'Gene', '12028', (42, 45))	('mice', 'Species', '10090', (27, 31))	('Bak', 'Gene', (85, 88))	('Bax', 'Gene', (123, 126))	('Bak', 'Gene', '12018', (115, 118))	('Bax', 'Gene', (42, 45))	('Bax', 'Gene', '12028', (123, 126))	('Bak', 'Gene', '12018', (85, 88))	('mice', 'Species', '10090', (92, 96))
501422	21867429	Although some investigators had reported that deletion of p53 did not affect the GI syndrome, others found that mice lacking p53 are sensitized to the GI syndrome.	('sensitized', 'Reg', (133, 143))	('deletion', 'Var', (46, 54))	('GI syndrome', 'Disease', (81, 92))	('GI syndrome', 'Disease', 'MESH:D005767', (151, 162))	('p53', 'Gene', (125, 128))	('GI syndrome', 'Disease', (151, 162))	('p53', 'Gene', (58, 61))	('GI syndrome', 'Disease', 'MESH:D005767', (81, 92))	('mice', 'Species', '10090', (112, 116))
501424	21867429	We deleted p53 in the GI epithelium with VillinCre and observed that VillinCre; p53FL/- mice were sensitized to the GI syndrome.	('p53', 'Gene', (11, 14))	('deleted', 'Var', (3, 10))	('GI syndrome', 'Disease', 'MESH:D005767', (116, 127))	('p53FL/-', 'Var', (80, 87))	('GI syndrome', 'Disease', (116, 127))	('sensitized', 'Reg', (98, 108))	('mice', 'Species', '10090', (88, 92))
501446	23671688	The oncogenic potential of different adenovirus types has been widely studied in rodents, in which adenovirus inoculation can induce multiple tumors such as undifferentiated sarcomas, adenocarcinomas and neuroectodermal tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('adenovirus', 'Species', '28282', (37, 47))	('inoculation', 'Var', (110, 121))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (204, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('multiple tumors', 'Disease', 'MESH:D009369', (133, 148))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (204, 226))	('adenovirus', 'Species', '28282', (99, 109))	('neuroectodermal tumors', 'Disease', (204, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('induce', 'PosReg', (126, 132))	('undifferentiated sarcomas', 'Disease', (157, 182))	('adenocarcinomas', 'Disease', 'MESH:D000230', (184, 199))	('multiple tumors', 'Disease', (133, 148))	('adenocarcinomas', 'Disease', (184, 199))	('adenovirus inoculation', 'Var', (99, 121))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (157, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))
501463	23671688	A previous study provided evidence for the presence of HAdV DNA in different brain tumors while several specimens from other pediatric tumor entities investigated revealed HAdV-negative findings.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('brain tumors', 'Phenotype', 'HP:0030692', (77, 89))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (135, 140))	('brain tumors', 'Disease', 'MESH:D001932', (77, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('brain tumors', 'Disease', (77, 89))	('HAdV', 'Var', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
501467	23671688	The adenoviral tumorigenicity may be attributable to the transforming capacity mediated by several viral oncogenes.	('adenoviral', 'Var', (4, 14))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (15, 20))
501511	23671688	HQ413315.1, HQ003817.1, FJ349096.1 and JO1917.1) (Figure 2B).	('FJ349096.1', 'Var', (24, 34))	('HQ413315.1', 'Var', (0, 10))	('JO1917.1', 'CellLine', 'CVCL:9I02', (39, 47))	('JO1917.1', 'Var', (39, 47))	('HQ003817.1', 'Var', (12, 22))
501534	23671688	Moreover, HAdVs are well known to induce sarcomas in rodents since decades.	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcomas', 'Disease', (41, 49))	('HAdVs', 'Var', (10, 15))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
501536	23671688	By using a specific qRT-PCR assay we screened a subset of 64 human sarcoma specimens and detected HAdV E1A and/or hexon in 35% of the tested liposarcoma and in 18% of the leiomyosarcoma specimens.	('HAdV E1A', 'Var', (98, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('sarcoma', 'Disease', (145, 152))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('leiomyosarcoma', 'Disease', (171, 185))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (171, 185))	('sarcoma', 'Disease', (67, 74))	('hexon', 'MPA', (114, 119))	('liposarcoma', 'Disease', (141, 152))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (171, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('human', 'Species', '9606', (61, 66))	('sarcoma', 'Disease', (178, 185))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('liposarcoma', 'Phenotype', 'HP:0012034', (141, 152))	('liposarcoma', 'Disease', 'MESH:D008080', (141, 152))
501698	30915424	Several studies have confirmed a characteristic 11-22 chromosomal translocation in Ewing's sarcoma in 85% of cases.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (83, 98))	('11-22 chromosomal translocation', 'Var', (48, 79))	("Ewing's sarcoma", 'Disease', (83, 98))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (83, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))
501715	30915424	Patterns of focal/multifocal uptake of 18F-FDG on a background of diffuse uptake at FDG PET/CT should be considered positive for bone marrow involvement.	('bone marrow involvement', 'Disease', (129, 152))	('bone marrow involvement', 'Disease', 'MESH:D001855', (129, 152))	('18F-FDG', 'Var', (39, 46))	('18F-FDG', 'Chemical', 'MESH:D019788', (39, 46))
501946	29228722	Specifically, in the case of HS, advanced stage, high MIB-1 (>= 20%), and lesions greater than 3.5 cm are considered to indicate poor prognosis.	('MIB-1', 'Gene', '57534', (54, 59))	('high', 'Var', (49, 53))	('MIB-1', 'Gene', (54, 59))
501949	29228722	The BRAFV600E mutation is present in many malignant tumors, e.g., malignant melanoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('malignant melanoma', 'Phenotype', 'HP:0002861', (66, 84))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('malignant melanoma', 'Disease', 'MESH:D008545', (66, 84))	('malignant melanoma', 'Disease', (66, 84))	('malignant tumors', 'Disease', (42, 58))	('malignant tumors', 'Disease', 'MESH:D018198', (42, 58))
501952	29228722	The clinical characteristics, prognostic factors, and frequency of the BRAFV600E mutation in histiocytic and dendritic cell neoplasms have not been reported in a large number of cases.	('neoplasms', 'Phenotype', 'HP:0002664', (124, 133))	('neoplasm', 'Phenotype', 'HP:0002664', (124, 132))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (109, 133))	('BRAFV600E', 'Var', (71, 80))	('BRAFV600E', 'Mutation', 'rs113488022', (71, 80))	('dendritic cell neoplasm', 'Phenotype', 'HP:0020178', (109, 132))	('dendritic cell neoplasms', 'Disease', (109, 133))
502025	29228722	In previous reports of HS, MIB-1 >= 20%, a lesion of greater than 3.5 cm, and advanced stage have been reported to indicate a poor prognosis.	('MIB-1', 'Gene', '57534', (27, 32))	('>= 20%', 'Var', (33, 39))	('MIB-1', 'Gene', (27, 32))
502032	29228722	It has been reported that age may greatly influence the frequency of the BRAFV600E mutation in LCH, as it was more frequently found in children than in adults.	('LCH', 'Gene', (95, 98))	('children', 'Species', '9606', (135, 143))	('BRAFV600E', 'Var', (73, 82))	('BRAFV600E', 'Mutation', 'rs113488022', (73, 82))
502077	26534966	Other inclusion criteria included adequate performance and end organ function, specifically Karnofsky or Lansky score >50%, hemoglobin concentration >8g/dL, absolute granulocyte count >1000/mm3, platelet count >75,000/mm3, aspartate transaminase (AST) and alanine transaminase (ALT) <=2.5-fold the upper limit of normal (ULN), as well as bilirubin and serum creatinine within normal limits.	('>1000/mm3', 'Var', (184, 193))	('bilirubin', 'MPA', (338, 347))	('alanine transaminase', 'MPA', (256, 276))	('AST', 'Gene', (247, 250))	('serum creatinine', 'MPA', (352, 368))	('AST', 'Gene', '26503', (247, 250))	('creatinine', 'Chemical', 'MESH:D003404', (358, 368))	('aspartate transaminase', 'Gene', '26503', (223, 245))	('bilirubin', 'Chemical', 'MESH:D001663', (338, 347))	('aspartate transaminase', 'Gene', (223, 245))
502079	26534966	NCI 08-C-0007 (NCT01445379) opened as a single center phase 1 study at the National Institutes of Health Clinical Center and was subsequently expanded to include enrollment at Memorial Sloan-Kettering Cancer Center and Dana-Farber Cancer Institute.	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Cancer', 'Disease', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer', 'Disease', 'MESH:D009369', (231, 237))	('NCT01445379', 'Var', (15, 26))	('Dana-Farber Cancer', 'Disease', 'MESH:D055577', (219, 237))	('Dana-Farber Cancer', 'Disease', (219, 237))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('Cancer', 'Disease', (201, 207))
502090	26534966	Peripheral blood mononuclear cells were isolated and stained for CD3, CD4, CD8, HLA-DR, foxP3, CD19, CD20 and ki67 in a CLIA certified clinical laboratory.	('CLIA', 'Disease', 'None', (120, 124))	('CLIA', 'Disease', (120, 124))	('CD8', 'Gene', '925', (75, 78))	('foxP3', 'Gene', '50943', (88, 93))	('foxP3', 'Gene', (88, 93))	('CD4', 'Gene', (70, 73))	('CD19', 'Gene', (95, 99))	('CD20', 'Gene', '54474', (101, 105))	('CD20', 'Gene', (101, 105))	('CD4', 'Gene', '920', (70, 73))	('CD19', 'Gene', '930', (95, 99))	('CD8', 'Gene', (75, 78))	('CD3', 'Var', (65, 68))
502161	26534966	Melanomas in adults have multiple mutations that may be serve as neoantigens for T cell response, and recent data suggests that mutated proteins may be important for immune responses to non-melanoma tumors.	('important', 'Reg', (152, 161))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('mutated', 'Var', (128, 135))	('Melanomas', 'Disease', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('non-melanoma tumors', 'Disease', (186, 205))	('non-melanoma tumors', 'Disease', 'MESH:D008545', (186, 205))	('mutations', 'Var', (34, 43))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('proteins', 'Protein', (136, 144))
502278	23150839	Mutation of the WT1 gene is implicated in Wilm's tumours; however, in this case we found cytoplasmic staining with nucleus sparing.	("Wilm's tumours", 'Disease', 'MESH:D009396', (42, 56))	("Wilm's tumours", 'Phenotype', 'HP:0002667', (42, 56))	('Mutation', 'Var', (0, 8))	("Wilm's tumours", 'Disease', (42, 56))	("Wilm's tumour", 'Phenotype', 'HP:0002667', (42, 55))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('WT1', 'Gene', '7490', (16, 19))	('implicated', 'Reg', (28, 38))	('WT1', 'Gene', (16, 19))
502293	21609503	Deregulation of epigenetic mechanisms underlying chromatin modifications during stem cell differentiation has been suggested to contribute to soft tissue sarcoma pathogenesis.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (142, 161))	('Deregulation', 'Var', (0, 12))	('epigenetic', 'Var', (16, 26))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('contribute', 'Reg', (128, 138))
502296	21609503	EZH2 deregulated expression/function in soft tissue sarcomas has been recently reported.	('expression/function', 'MPA', (17, 36))	('deregulated', 'Var', (5, 16))	('EZH2', 'Gene', '2146', (0, 4))	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (40, 59))	('EZH2', 'Gene', (0, 4))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (40, 60))	('sarcomas', 'Disease', (52, 60))
502301	21609503	A series of chromosomal translocations have been identified as hallmarks of most STSs, such as t(X;18)(p11.2;q11.2) in synovial sarcoma, t(11;22)(q24;q12) in Ewing's sarcoma, t(2;13)(q35;q14) and t(1;13)(p36;q14) in alveolar rhabdomyosarcoma (RMS).	("Ewing's sarcoma", 'Disease', (158, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('t(1;13)(p36;q14', 'Var', (196, 211))	('alveolar rhabdomyosarcoma', 'Disease', (216, 241))	('RMS', 'Phenotype', 'HP:0002859', (243, 246))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (137, 154))	('t(2;13)(q35;q14', 'Var', (175, 190))	('synovial sarcoma', 'Disease', (119, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('t(X;18)(p11.2;q11.2', 'Var', (95, 114))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (225, 241))	('synovial sarcoma', 'Disease', 'MESH:D013584', (119, 135))	('t(11;22)(q24;q12', 'Var', (137, 153))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (216, 241))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (158, 173))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (216, 241))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (119, 135))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (175, 191))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (158, 173))	('STSs', 'Phenotype', 'HP:0030448', (81, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (95, 115))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (196, 212))
502316	21609503	EZH2 methylates lysine 27 of histone H3, thus generating the H3K27-trimethylated epigenetic mark that is recognized by the PRC1 complex for further, long-term chromatin modifications (Figure 1a).	('PRC1', 'Gene', '9055', (123, 127))	('EZH2', 'Gene', '2146', (0, 4))	('methylates', 'Var', (5, 15))	('EZH2', 'Gene', (0, 4))	('H3K27-trimethylated epigenetic mark', 'MPA', (61, 96))	('lysine', 'Chemical', 'MESH:D008239', (16, 22))	('PRC1', 'Gene', (123, 127))
502319	21609503	Moreover, the abundance of EZH2 molecules induces the formation of more repressor complexes and, by altering the balance between different PcG components, may lead to the formation of tumor-specific PRC complexes that show differential substrate specificities.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('balance between different', 'MPA', (113, 138))	('more', 'PosReg', (67, 71))	('altering', 'Reg', (100, 108))	('EZH2', 'Gene', (27, 31))	('abundance', 'Var', (14, 23))	('EZH2', 'Gene', '2146', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('repressor complexes', 'MPA', (72, 91))	('lead to', 'Reg', (159, 166))	('formation', 'MPA', (54, 63))	('PRC', 'Protein', (199, 202))
502321	21609503	EZH2 aberrant overexpression may be one of the molecular lesions occurring in differentiating mesenchymal stem cells (MSCs), which are thought to be the cells of origin of STS.	('EZH2', 'Gene', (0, 4))	('overexpression', 'PosReg', (14, 28))	('EZH2', 'Gene', '2146', (0, 4))	('aberrant', 'Var', (5, 13))
502322	21609503	It has been proposed that the presence of EZH2 in tumors with embryonal features and stem-cell phenotype, such as STS, may explain their undifferentiated and immature character.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('STS', 'Disease', (114, 117))	('EZH2', 'Gene', '2146', (42, 46))	('EZH2', 'Gene', (42, 46))	('presence', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
502325	21609503	More recently, it has been reported that a diagnosis of alveolar RMS can be made only in the presence of two specific molecular aberrations, namely t(2;13)(q35;q14) and/or t(1;13)(p36;q14) chromosomal translocations resulting in PAX3-FKHR and the rarer PAX7-FKHR oncogenic fusion proteins, respectively.	('oncogenic fusion proteins', 'Protein', (263, 288))	('t(1;13)(p36;q14) chromosomal', 'Var', (172, 200))	('resulting in', 'Reg', (216, 228))	('PAX7', 'Gene', (253, 257))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (172, 188))	('PAX3', 'Gene', (229, 233))	('FKHR', 'Gene', (234, 238))	('alveolar RMS', 'Disease', (56, 68))	('FKHR', 'Gene', '2308', (234, 238))	('PAX3', 'Gene', '5077', (229, 233))	('alveolar RMS', 'Disease', 'MESH:D002282', (56, 68))	('FKHR', 'Gene', '2308', (258, 262))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (148, 164))	('RMS', 'Phenotype', 'HP:0002859', (65, 68))	('PAX7', 'Gene', '5081', (253, 257))	('t(2;13)(q35;q14', 'Var', (148, 163))	('FKHR', 'Gene', (258, 262))
502343	21609503	Altogether, these findings provide evidence for a key role of EZH2-mediated epigenetic changes in RMS pathogenesis, which involve also mutual interactions with microRNAs.	('RMS', 'Phenotype', 'HP:0002859', (98, 101))	('EZH2', 'Gene', '2146', (62, 66))	('EZH2', 'Gene', (62, 66))	('interactions', 'Interaction', (142, 154))	('epigenetic changes', 'Var', (76, 94))	('RMS', 'Disease', (98, 101))
502345	21609503	It is characterized by the typical translocation t(X;18)(p11;q11) that generates the fusion between the synovial sarcoma translocation, chromosome 18 (SS18 or SYT) gene on chromosome 18 and either synovial sarcoma, X breakpoint 1, 2 or 4 (SSX1, SSX2 or SSX4) genes on the X chromosome.	('fusion', 'Var', (85, 91))	('SSX4', 'Gene', (253, 257))	('SSX2', 'Gene', (245, 249))	('synovial sarcoma', 'Disease', (104, 120))	('SYT', 'Gene', (159, 162))	('SSX2', 'Gene', '6757', (245, 249))	('SSX4', 'Gene', '6759', (253, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('synovial sarcoma', 'Disease', 'MESH:D013584', (104, 120))	('SS18', 'Gene', (151, 155))	('synovial sarcoma', 'Disease', (197, 213))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (104, 120))	('SYT', 'Gene', '6760', (159, 162))	('synovial sarcoma', 'Disease', 'MESH:D013584', (197, 213))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 65))	('SSX1', 'Gene', '6756', (239, 243))	('SS18', 'Gene', '6760', (151, 155))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (197, 213))	('SSX1', 'Gene', (239, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
502347	21609503	In particular, SYT-SSX2 fusion protein induces downstream target-gene deregulation through epigenetic mechanisms.	('fusion', 'Var', (24, 30))	('SSX2', 'Gene', '6757', (19, 23))	('SSX2', 'Gene', (19, 23))	('SYT', 'Gene', (15, 18))	('SYT', 'Gene', '6760', (15, 18))	('induces', 'Reg', (39, 46))
502352	21609503	Ewing's sarcoma is an embryonal malignancy characterized by the t(11;22)(q24;q12) translocation which generates chimerical Ewing sarcoma (EWS)/ETS fusion transcription factors.	('EWS', 'Phenotype', 'HP:0012254', (138, 141))	('EWS', 'Gene', '2130', (138, 141))	('EWS', 'Gene', (138, 141))	("Ewing's sarcoma", 'Disease', (0, 15))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (64, 81))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('embryonal malignancy', 'Disease', 'MESH:D009369', (22, 42))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (123, 136))	('Ewing sarcoma', 'Disease', (123, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('embryonal malignancy', 'Phenotype', 'HP:0002898', (22, 42))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('chimerical', 'Var', (112, 122))	('embryonal malignancy', 'Disease', (22, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))
502363	21609503	Increasing attention is focusing on epigenetic therapies that have provided promising results in clinical trials for some human tumors.	('human', 'Species', '9606', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('epigenetic therapies', 'Var', (36, 56))	('tumors', 'Disease', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))
502364	21609503	The clinical effectiveness of epigenetic therapies in human malignancies has been recently proved by the observation that, in a randomized phase III trial, the DNA hypomethylating agent azacytidine prolonged overall survival of myelodysplastic syndrome (MDS) patients compared to other standard therapies.	('MDS', 'Phenotype', 'HP:0002863', (254, 257))	('malignancies', 'Disease', (60, 72))	('MDS', 'Disease', (254, 257))	('MDS', 'Disease', 'MESH:D009190', (254, 257))	('patients', 'Species', '9606', (259, 267))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (228, 252))	('azacytidine', 'Var', (186, 197))	('overall survival', 'MPA', (208, 224))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (228, 252))	('azacytidine', 'Chemical', 'MESH:D001374', (186, 197))	('myelodysplastic syndrome', 'Disease', (228, 252))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('prolonged', 'PosReg', (198, 207))	('human', 'Species', '9606', (54, 59))
502365	21609503	The potential efficacy of epigenetic therapy in STS is supported by preclinical studies employing HDAC inhibitors.	('HDAC', 'Gene', '9734', (98, 102))	('HDAC', 'Gene', (98, 102))	('epigenetic therapy', 'Var', (26, 44))
502369	21609503	DZNep has been shown to act by causing depletion of PRC2 subunits with subsequent reactivation of PRC2-silenced genes.	('PRC2', 'Gene', (52, 56))	('depletion', 'MPA', (39, 48))	('reactivation', 'MPA', (82, 94))	('DZNep', 'Chemical', '-', (0, 5))	('DZNep', 'Var', (0, 5))
502374	21609503	Indeed, the clinical response to azacytidine in terms of prolongation of survival in MDS patients does not appear to be directly correlated with methylation of specific tumor suppressor genes, though methylation status has been shown to correlate with poor survival.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('MDS', 'Disease', (85, 88))	('MDS', 'Disease', 'MESH:D009190', (85, 88))	('tumor', 'Disease', (169, 174))	('patients', 'Species', '9606', (89, 97))	('methylation', 'Var', (200, 211))	('azacytidine', 'Chemical', 'MESH:D001374', (33, 44))	('MDS', 'Phenotype', 'HP:0002863', (85, 88))
502376	21609503	Despite these unresolved questions, epigenetic therapy is a promising approach for targeted anticancer therapies in pediatric STS.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epigenetic therapy', 'Var', (36, 54))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
502378	21609503	In the future, modulation of EZH2 activity may provide a new line of intervention that could be combined with epigenetic drugs acting on other molecular targets and/or conventional cytotoxic agents to treat these aggressive pediatric tumors.	('activity', 'MPA', (34, 42))	('aggressive pediatric tumors', 'Disease', 'MESH:D063766', (213, 240))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('modulation', 'Var', (15, 25))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('aggressive pediatric tumors', 'Disease', (213, 240))
502423	33775935	reported a novel CTNNB1-USP6 fusion in IVF, showing that IVF is a USP6-induced neoplasm and should be included in USP6-rearranged lesions.	('USP6', 'Gene', '9098', (24, 28))	('neoplasm', 'Disease', (79, 87))	('USP6', 'Gene', (24, 28))	('neoplasm', 'Phenotype', 'HP:0002664', (79, 87))	('CTNNB1', 'Gene', (17, 23))	('USP6', 'Gene', '9098', (66, 70))	('USP6', 'Gene', (66, 70))	('neoplasm', 'Disease', 'MESH:D009369', (79, 87))	('CTNNB1', 'Gene', '1499', (17, 23))	('IVF', 'Disease', 'MESH:C537182', (39, 42))	('USP6', 'Gene', '9098', (114, 118))	('IVF', 'Disease', (39, 42))	('USP6', 'Gene', (114, 118))	('IVF', 'Disease', 'MESH:C537182', (57, 60))	('IVF', 'Disease', (57, 60))	('fusion', 'Var', (29, 35))
502472	32366852	Alterations of genes involved in the DNA damage repair pathway have been associated with sarcoma risk and prognosis.	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (73, 83))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))
502483	32366852	Moreover, a recent international study has shown that germline variants in several genes encoding proteins involved in DNA repair such as BRCA2, ATM, ATR, and ERCC2, contributed significantly to sarcoma risk.	('ERCC2', 'Gene', '2068', (159, 164))	('sarcoma', 'Disease', (195, 202))	('BRCA2', 'Gene', '675', (138, 143))	('ATM', 'Gene', '472', (145, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('ATR', 'Gene', (150, 153))	('ERCC2', 'Gene', (159, 164))	('contributed', 'Reg', (166, 177))	('germline variants', 'Var', (54, 71))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('BRCA2', 'Gene', (138, 143))	('ATM', 'Gene', (145, 148))
502488	32366852	All the cell lines had impaired TP53 pathway has a result of TP53 mutation/deletion or MDM2 amplification except for two cell lines (IB114 and IB128).	('mutation/deletion', 'Var', (66, 83))	('amplification', 'Var', (92, 105))	('TP53 pathway', 'Pathway', (32, 44))	('MDM2', 'Gene', '4193', (87, 91))	('MDM2', 'Gene', (87, 91))	('TP53', 'Gene', (61, 65))
502498	32366852	Importantly, in all the cell lines tested, VE-822 reduced the level of gemcitabine-induced CHK1 phosphorylation, the downstream ATR target (Fig.	('CHK1', 'Gene', (91, 95))	('VE-822', 'Chemical', 'MESH:C000598331', (43, 49))	('CHK1', 'Gene', '1111', (91, 95))	('reduced', 'NegReg', (50, 57))	('gemcitabine', 'Chemical', 'MESH:C056507', (71, 82))	('VE-822', 'Var', (43, 49))
502505	32366852	After three weeks of treatment we observed a significant effect on progression free survival (evaluated as the time span from the treatment start and the doubling of the initial tumor volume), median time to doubling was 14.5 days for combination, 9.9 days for VE-822 (p = 0.0014) 10.3 days for gemcitabine, and 8.4 days for the vehicle (Fig.	('progression free survival', 'CPA', (67, 92))	('gemcitabine', 'Chemical', 'MESH:C056507', (295, 306))	('tumor', 'Disease', (178, 183))	('VE-822', 'Var', (261, 267))	('VE-822', 'Chemical', 'MESH:C000598331', (261, 267))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('combination', 'Var', (235, 246))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
502507	32366852	Cancer cells are characterized by defects in DDR which results in increased mutational load, replication stress and genome instability.	('defects', 'Var', (34, 41))	('increased', 'PosReg', (66, 75))	('genome instability', 'CPA', (116, 134))	('DDR', 'Gene', (45, 48))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutational load', 'MPA', (76, 91))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('stress', 'Disease', (105, 111))	('stress', 'Disease', 'MESH:D000079225', (105, 111))
502522	32366852	When the activity of ATR is inhibited, maintenance of genome integrity becomes dependent on functional TP53, with TP53 being essential for arresting cell cycle progression to permit repair.	('TP53', 'Var', (114, 118))	('arrest', 'Disease', (139, 145))	('arrest', 'Disease', 'MESH:D006323', (139, 145))	('cell cycle progression', 'CPA', (149, 171))
502523	32366852	Several studies have confirmed such synthetically lethal interaction by deleting ATR in TP53-deficient mice and by inhibiting its activity in tumor cell lines, which resulted in death induction of cells harboring TP53 defects.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('ATR', 'Gene', (81, 84))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Disease', (142, 147))	('death', 'Disease', 'MESH:D003643', (178, 183))	('death', 'Disease', (178, 183))	('defects', 'Var', (218, 225))	('inhibiting', 'NegReg', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('activity', 'MPA', (130, 138))	('deleting', 'Var', (72, 80))
502525	32366852	However, our results indicate that defective TP53 as result of deletion or mutation or MDM2 gene amplification do not confer greater sensitivity of STS cells to VE-822.	('amplification', 'Var', (97, 110))	('TP53', 'Gene', (45, 49))	('STS', 'Phenotype', 'HP:0030448', (148, 151))	('mutation', 'Var', (75, 83))	('defective', 'Var', (35, 44))	('MDM2', 'Gene', '4193', (87, 91))	('VE-822', 'Chemical', 'MESH:C000598331', (161, 167))	('MDM2', 'Gene', (87, 91))	('deletion', 'Var', (63, 71))	('sensitivity', 'MPA', (133, 144))
502532	32366852	Moreover, VE-822 synergized with gemcitabine to induce apoptosis in STS cells and does not only inhibit gemcitabine induced checkpoint activation, but also pre-existing CHK1 phosphorylation and/or CHK1 protein levels in general, while enhancing gemcitabine-induced DNA damage.	('gemcitabine', 'Chemical', 'MESH:C056507', (245, 256))	('CHK1', 'Gene', '1111', (169, 173))	('CHK1', 'Gene', '1111', (197, 201))	('VE-822', 'Var', (10, 16))	('gemcitabine', 'Chemical', 'MESH:C056507', (104, 115))	('STS', 'Phenotype', 'HP:0030448', (68, 71))	('checkpoint activation', 'MPA', (124, 145))	('apoptosis', 'CPA', (55, 64))	('CHK1', 'Gene', (169, 173))	('gemcitabine-induced DNA damage', 'MPA', (245, 275))	('VE-822', 'Chemical', 'MESH:C000598331', (10, 16))	('inhibit', 'NegReg', (96, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (33, 44))	('enhancing', 'PosReg', (235, 244))	('CHK1', 'Gene', (197, 201))
502544	32366852	The blots were probed overnight at 4  C with an anti-phospho-CHK1 (S296, ab79758, 1/1000 Abcam), and an anti-CHK1 (Ab47574, 1/500, Abcam) primary antibody diluted in PBST (100 mM phosphate, 27 mM KCl, 1.37 M NaCl, pH 7.4 after 1X dilution; 0.2% Tween-20) with 5% BSA.	('CHK1', 'Gene', (61, 65))	('KCl', 'Chemical', 'MESH:D011189', (196, 199))	('CHK1', 'Gene', '1111', (109, 113))	('CHK1', 'Gene', '1111', (61, 65))	('phosphate', 'Chemical', 'MESH:D010710', (179, 188))	('S296', 'Var', (67, 71))	('Tween-20', 'Chemical', 'MESH:D011136', (245, 253))	('CHK1', 'Gene', (109, 113))	('PBS', 'Chemical', 'MESH:D007854', (166, 169))	('Ab47574', 'Var', (115, 122))	('NaCl', 'Chemical', 'MESH:D012965', (208, 212))
502559	24868227	IPT-like variant tumors occur almost exclusively in the liver and spleen and are consistently associated with Epstein-Barr virus (EBV).	('Epstein-Barr virus', 'Disease', (110, 128))	('IPT-like', 'Gene', (0, 8))	('variant', 'Var', (9, 16))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('associated', 'Reg', (94, 104))	('EBV', 'Species', '10376', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
502588	24868227	Immunohistochemical studies showed that these large cells expressed CD21, CD23, CD35, CD45, p53, D2-40, and epithelial membrane antigen and weakly expressed estrogen receptors, but not CD34, CD68, CD117, DOG-1, S-100 protein, pan-cytokeratin, and progesterone receptors.	('CD45', 'Gene', (86, 90))	('CD68', 'Gene', (191, 195))	('D2-40', 'Var', (97, 102))	('p53', 'Gene', '403869', (92, 95))	('DOG', 'Species', '9615', (204, 207))	('estrogen receptors', 'Protein', (157, 175))	('CD23', 'Gene', '2208', (74, 78))	('CD35', 'Gene', '1378', (80, 84))	('CD45', 'Gene', '490255', (86, 90))	('p53', 'Gene', (92, 95))	('CD21', 'Gene', (68, 72))	('CD35', 'Gene', (80, 84))	('CD23', 'Gene', (74, 78))	('CD21', 'Gene', '1380', (68, 72))	('CD68', 'Gene', '489476', (191, 195))
502614	24868227	Most notably, this variant is consistently associated with EBV, in contrast to the conventional type, which is only very rarely associated with EBV.	('EBV', 'Species', '10376', (144, 147))	('variant', 'Var', (19, 26))	('EBV', 'Disease', (59, 62))	('associated', 'Reg', (43, 53))	('EBV', 'Species', '10376', (59, 62))
502615	24868227	The universal association of EBV with IPT-like variant of FDC sarcomas is strongly suggestive of a pathogenetic role; EBV-induced cytokines and monokines are known to lead to vascular proliferation, inflammation and damage of the blood vessels, which may explain the unusual presentations of prominent vascular changes in our case.	('vascular changes', 'Phenotype', 'HP:0002597', (302, 318))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('FDC sarcomas', 'Disease', 'MESH:C536231', (58, 70))	('vascular proliferation', 'CPA', (175, 197))	('FDC sarcoma', 'Phenotype', 'HP:0031350', (58, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('lead to', 'Reg', (167, 174))	('EBV', 'Species', '10376', (118, 121))	('damage', 'CPA', (216, 222))	('EBV', 'Species', '10376', (29, 32))	('EBV-induced', 'Var', (118, 129))	('inflammation', 'Disease', 'MESH:D007249', (199, 211))	('FDC sarcomas', 'Disease', (58, 70))	('inflammation', 'Disease', (199, 211))	('cytokines', 'Var', (130, 139))
502636	24868227	In our case, in addition to EBER-positivity, there were essentially no eosinophils and the tumor cells expressed all FDC markers including CD21, CD23, CD35, and D2-40.	('CD35', 'Gene', '1378', (151, 155))	('CD23', 'Gene', '2208', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CD35', 'Gene', (151, 155))	('CD21', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CD23', 'Gene', (145, 149))	('CD21', 'Gene', '1380', (139, 143))	('tumor', 'Disease', (91, 96))	('D2-40', 'Var', (161, 166))
502641	24868227	In the current World Helath Organization (WHO) classification of GI tumors, IPT and IPT-like FDC sarcoma can be distinguished by the expression of FDC markers and EBER-positivity in the later tumors.	('FDC sarcoma', 'Disease', (93, 104))	('GI tumors', 'Disease', (65, 74))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', (192, 198))	('FDC sarcoma', 'Disease', 'MESH:C536231', (93, 104))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('GI tumors', 'Disease', 'MESH:D009369', (65, 74))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('IPT', 'Disease', (76, 79))	('FDC sarcoma', 'Phenotype', 'HP:0031350', (93, 104))	('EBER-positivity', 'Var', (163, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('GI tumors', 'Phenotype', 'HP:0007378', (65, 74))
502658	23401762	Suboptimal coverage can lead to prosthesis infection, subsequent hardware exposure, or loss with eventual amputation.	('Suboptimal', 'Var', (0, 10))	('lead to', 'Reg', (24, 31))	('hardware exposure', 'CPA', (65, 82))	('infection', 'Disease', (43, 52))	('infection', 'Disease', 'MESH:D007239', (43, 52))
502914	31914093	AVS, AVK, and inhomogeneity were significantly higher in soft tissue sarcomas (P < .05).	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (57, 76))	('inhomogeneity', 'Var', (14, 27))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (57, 77))	('higher', 'PosReg', (47, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (57, 77))	('soft tissue sarcomas', 'Disease', (57, 77))
502978	29642934	In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('substitutions', 'Var', (121, 134))	('generating', 'Reg', (55, 65))	('APOBEC3B', 'Gene', (17, 25))	('mutation load', 'MPA', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('increases', 'PosReg', (26, 35))
502981	29642934	We used information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine associations of the prevalence of APOBEC-like motifs and mutational loads with expression of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT and with cell line chemosensitivity to 255 antitumor drugs.	('Cancer Cell Line Encyclopedia', 'Disease', (29, 58))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (79, 95))	('APOBEC3A', 'Gene', '200315', (220, 228))	('tumor', 'Disease', (307, 312))	('REV1', 'Gene', (240, 244))	('Cancer', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('Cancer', 'Disease', (99, 105))	('APOBEC3B', 'Gene', (230, 238))	('associations', 'Interaction', (127, 139))	('UNG', 'Gene', (246, 249))	('mutational loads', 'Var', (184, 200))	('Cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('FHIT', 'Gene', (255, 259))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (29, 58))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('APOBEC-like motifs', 'Gene', (161, 179))	('FHIT', 'Gene', '2272', (255, 259))	('UNG', 'Gene', '7374', (246, 249))	('APOBEC3A', 'Gene', (220, 228))	('Cancer', 'Disease', (29, 35))	('REV1', 'Gene', '51455', (240, 244))
502984	29642934	The strongest correlations of gene expression levels with mutational loads or with measures of prevalence of APOBEC-like motif counts and kataegis clusters were observed for REV1, UNG, and APOBEC3A.	('APOBEC3A', 'Gene', '200315', (189, 197))	('UNG', 'Gene', '7374', (180, 183))	('REV1', 'Gene', '51455', (174, 178))	('UNG', 'Gene', (180, 183))	('REV1', 'Gene', (174, 178))	('correlations', 'Interaction', (14, 26))	('APOBEC3A', 'Gene', (189, 197))	('mutational', 'Var', (58, 68))
502985	29642934	Sensitivity or resistance of cell lines to JQ1, palbociclib, bicalutamide, 17-AAG, TAE684, MEK inhibitors refametinib, PD-0325901, and trametinib and a number of other agents was correlated with candidate gene expression levels or with abundance of APOBEC-like motif clusters in specific cancers or across cancer types.	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('AAG', 'Gene', '4350', (78, 81))	('cancer', 'Disease', (288, 294))	('cancers', 'Disease', (288, 295))	('bicalutamide', 'Chemical', 'MESH:C053541', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('MEK', 'Gene', '5609', (91, 94))	('refametinib', 'Chemical', 'MESH:C544830', (106, 117))	('PD-0325901', 'Var', (119, 129))	('MEK', 'Gene', (91, 94))	('AAG', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancers', 'Disease', 'MESH:D009369', (288, 295))	('TAE684', 'Chemical', 'MESH:C516714', (83, 89))	('cancer', 'Disease', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('palbociclib', 'Chemical', 'MESH:C500026', (48, 59))	('PD-0325901', 'Chemical', 'MESH:C506614', (119, 129))	('trametinib', 'Chemical', 'MESH:C560077', (135, 145))
502991	29642934	APOBEC3B is an endogenous mutagen which generates DNA substitutions, most frequently C to T, via a process that involves cytosine to uracil deamination of single-stranded DNA, most commonly in the 5'-TCW-3' (where W is either A or T) sequence context.	('cytosine to uracil', 'MPA', (121, 139))	('APOBEC3B', 'Gene', (0, 8))	('substitutions', 'Var', (54, 67))	('cytosine', 'Chemical', 'MESH:D003596', (121, 129))	('uracil', 'Chemical', 'MESH:D014498', (133, 139))
502992	29642934	In multiple human cancer categories, increased APOBEC3B gene expression has been associated with genome-wide hypermutation and with kataegis, a mutagenic process that generates clusters of closely spaced, single-strand-specific DNA substitutions, which are predominantly C to T. Clusters of APOBEC3B mutations are often localized at breakpoints of chromosomal rearrangements.	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('APOBEC3B', 'Gene', (47, 55))	('mutations', 'Var', (300, 309))	('APOBEC3B', 'Gene', (291, 299))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('increased', 'PosReg', (37, 46))	('human', 'Species', '9606', (12, 17))	('cancer', 'Disease', (18, 24))	('expression', 'MPA', (61, 71))
502993	29642934	Increased APOBEC3B gene expression, germline polymorphisms in the APOBEC3 genome region, and higher degree of abundance of APOBEC3B mutational signatures have been associated with increased cancer risk and patient survival.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('germline polymorphisms', 'Var', (36, 58))	('APOBEC3B', 'Gene', (123, 131))	('expression', 'MPA', (24, 34))	('patient', 'Species', '9606', (206, 213))	('Increased', 'PosReg', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('APOBEC3B gene', 'Gene', (10, 23))	('APOBEC3', 'Gene', (66, 73))
502995	29642934	According to various reports, in addition to the C>T transitions, these patterns may include possible C>G and, in some specific cancer types such as ovarian carcinomas, C>A transversions, as well as a possible 5'-TC(A or G)-3' sequence context, so that possible mutational motifs could be represented as 5'-T(C>K)W-3', 5'-T(C>D)R-3', or 5'-T(C>D)D-3', where K is [G or T], W is [A or T], R is [A or G], and D is [A or G or T] according to the IUB-IUPAC ambiguity codes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (149, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('D is [A', 'Var', (407, 414))	('ovarian carcinomas', 'Disease', (149, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (149, 167))	('R is [A', 'Var', (388, 395))	('W is [A', 'Var', (373, 380))	('cancer', 'Disease', (128, 134))
502996	29642934	Below, we present these sequence motifs in the 5' to 3' direction as T(C>K)W, T(C>D)R, and T(C>D)D. While APOBEC3B plays a prominent role in cancer mutagenesis, several other AID/APOBEC family members also have mutagenic roles and affect DNA integrity.	('T(C>D)R', 'Var', (78, 85))	('DNA integrity', 'CPA', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutagenic', 'CPA', (211, 220))	('APOBEC3B', 'Gene', (106, 114))	('affect', 'Reg', (231, 237))	('T(C>D)D.', 'Var', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('AID', 'Gene', '57379', (175, 178))	('AID', 'Gene', (175, 178))	('cancer', 'Disease', (141, 147))
502999	29642934	An APOBEC3A-APOBEC3B fusion transcript may be produced due to a germline deletion polymorphism, which results in the complete loss of the coding part of the APOBEC3B gene and abolishes APOBEC3B gene expression; this deletion polymorphism produces a fusion product of the APOBEC3A gene with the 3'-UTR of APOBEC3B gene, and it has been associated with an increased risk of several types of cancer.	('APOBEC3B', 'Gene', (304, 312))	('associated with', 'Reg', (335, 350))	('APOBEC3A', 'Gene', '200315', (271, 279))	('expression', 'MPA', (199, 209))	('APOBEC3A', 'Gene', '200315', (3, 11))	('APOBEC3B', 'Gene', (157, 165))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('deletion polymorphism', 'Var', (216, 237))	('abolishes', 'NegReg', (175, 184))	('produces', 'Reg', (238, 246))	('APOBEC3B gene', 'Gene', (185, 198))	('APOBEC3A', 'Gene', (271, 279))	('loss', 'NegReg', (126, 130))	('cancer', 'Disease', (389, 395))	('APOBEC3A', 'Gene', (3, 11))
503003	29642934	Based on the strong evidence for APOBEC-associated mutagenesis in a variety of cancer types, it is important to learn whether such mutagenic processes may affect cancer response to therapy, in order to exploit potential pathways involved in sensitivity and to avoid potential mechanisms of resistance.	('APOBEC-associated', 'Gene', (33, 50))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('affect', 'Reg', (155, 161))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutagenesis', 'Var', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
503004	29642934	Some studies suggested a potential role of APOBEC mutagenesis in tumor resistance to therapy, with a possible resistance mechanism explained by increased tumor heterogeneity when APOBEC3B activity is elevated.	('tumor', 'Disease', (65, 70))	('APOBEC3B', 'Gene', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mutagenesis', 'Var', (50, 61))	('activity', 'MPA', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (154, 159))
503008	29642934	Experimental in vitro overexpression of APOBEC3B in the 293-A3B and 293-GFP cell lines with inactivated p53 resulted in an increase in APOBEC mutagenesis and kataegic events, which were accompanied by cell hypersensitivity to small-molecule DNA damage response inhibitors including ATR (VX-970 and AZD673), CHEK1 (SAR020106), CHEK2 (CCT241553), PARP (olaparib and BMN-673), and WEE1 (AZD1775) inhibitors, as well as by sensitivity to combinations of cisplatin/ATR inhibitor, ATR/PARP inhibitor, and PARP/WEE1 inhibitor.	('PARP', 'Gene', '142', (499, 503))	('p53', 'Gene', '7157', (104, 107))	('WEE1', 'Gene', (504, 508))	('ATR', 'Gene', (460, 463))	('SAR', 'Gene', (314, 317))	('ATR', 'Gene', (475, 478))	('PARP', 'Gene', (499, 503))	('WEE1', 'Gene', (378, 382))	('ATR', 'Gene', '545', (282, 285))	('inhibitors', 'MPA', (393, 403))	('p53', 'Gene', (104, 107))	('APOBEC3B', 'Gene', (40, 48))	('hypersensitivity', 'Disease', (206, 222))	('293-GFP', 'CellLine', 'CVCL:0045', (68, 75))	('PARP', 'Gene', '142', (479, 483))	('PARP', 'Gene', '142', (345, 349))	('increase', 'PosReg', (123, 131))	('SAR', 'Gene', '1757', (314, 317))	('APOBEC', 'Gene', (135, 141))	('CHEK2', 'Gene', (326, 331))	('PARP', 'Gene', (345, 349))	('PARP', 'Gene', (479, 483))	('hypersensitivity', 'Disease', 'MESH:D004342', (206, 222))	('inactivated', 'Var', (92, 103))	('WEE1', 'Gene', '7465', (504, 508))	('ATR', 'Gene', '545', (460, 463))	('kataegic events', 'CPA', (158, 173))	('ATR', 'Gene', '545', (475, 478))	('CHEK1', 'Gene', '1111', (307, 312))	('CHEK2', 'Gene', '11200', (326, 331))	('293-A3B', 'CellLine', 'CVCL:6910', (56, 63))	('WEE1', 'Gene', '7465', (378, 382))	('ATR', 'Gene', (282, 285))	('CHEK1', 'Gene', (307, 312))
503027	29642934	To examine possible associations of expression levels of APOBEC3A and APOBEC3B with the germline APOBEC3B gene deletion, we downloaded the copy number status of the APOBEC3B gene from the CCLE web resource of the Broad Institute.	('APOBEC3A', 'Gene', (57, 65))	('APOBEC3B', 'Gene', (165, 173))	('CCLE', 'Chemical', '-', (188, 192))	('APOBEC3B', 'Gene', (97, 105))	('deletion', 'Var', (111, 119))	('APOBEC3A', 'Gene', '200315', (57, 65))
503054	29642934	Many earlier studies reported elevated expression and activity of APOBEC3B and APOBEC3A in bladder cancer and of APOBEC3B in head and neck cancer patients.	('APOBEC3A', 'Gene', (79, 87))	('APOBEC3B', 'Var', (113, 121))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('APOBEC3A', 'Gene', '200315', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('bladder cancer', 'Disease', (91, 105))	('head and neck cancer', 'Phenotype', 'HP:0012288', (125, 145))	('elevated', 'PosReg', (30, 38))	('neck cancer', 'Disease', 'MESH:D006258', (134, 145))	('activity', 'MPA', (54, 62))	('neck cancer', 'Disease', (134, 145))	('expression', 'MPA', (39, 49))	('APOBEC3B', 'Gene', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('patients', 'Species', '9606', (146, 154))
503055	29642934	APOBEC-derived mutagenesis is considered to be the predominant mutation source in 65% of invasive bladder cancers in the TCGA dataset.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('invasive bladder', 'Phenotype', 'HP:0100645', (89, 105))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (89, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('mutagenesis', 'Var', (15, 26))	('invasive bladder cancers', 'Disease', (89, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('bladder cancers', 'Phenotype', 'HP:0009725', (98, 113))
503056	29642934	Similarly, a genomic signature attributed to APOBEC3 activity was reported in a subset of patients with all melanoma subtypes, although C>T transitions attributed to APOBEC activity could be confounded with UV-induced substitutions in many melanoma cells.	('C>T', 'Var', (136, 139))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (240, 248))	('melanoma subtypes', 'Disease', (108, 125))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('melanoma subtypes', 'Disease', 'MESH:D008545', (108, 125))	('melanoma', 'Disease', (240, 248))	('patients', 'Species', '9606', (90, 98))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('APOBEC3', 'Gene', (45, 52))
503057	29642934	Increased expression and activity of both APOBEC3A and APOBEC3B were also reported in multiple myeloma patients, most commonly in those with the t(14:16) translocation, which was associated with poor survival.	('multiple myeloma', 'Phenotype', 'HP:0006775', (86, 102))	('multiple myeloma', 'Disease', 'MESH:D009101', (86, 102))	('multiple myeloma', 'Disease', (86, 102))	('expression', 'MPA', (10, 20))	('APOBEC3A', 'Gene', '200315', (42, 50))	('Increased', 'PosReg', (0, 9))	('APOBEC3B', 'Gene', (55, 63))	('activity', 'MPA', (25, 33))	('patients', 'Species', '9606', (103, 111))	('APOBEC3A', 'Gene', (42, 50))	('t(14:16) translocation', 'Var', (145, 167))
503060	29642934	Because abrogated FHIT activity may increase the levels of mutagenesis both as a standalone mechanism and synergistically with APOBEC3B, we note that cell lines from several cancer types including head and neck (4.85) and sarcoma (4.87) had a considerably lower mean FHIT expression than the pan-cancer average (5.74).	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('expression', 'MPA', (272, 282))	('sarcoma', 'Disease', 'MESH:D012509', (222, 229))	('levels of mutagenesis', 'MPA', (49, 70))	('sarcoma', 'Disease', (222, 229))	('FHIT', 'Gene', (267, 271))	('increase', 'PosReg', (36, 44))	('cancer', 'Disease', (174, 180))	('activity', 'MPA', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('lower', 'NegReg', (256, 261))	('abrogated', 'Var', (8, 17))	('FHIT', 'Gene', '2272', (267, 271))	('FHIT', 'Gene', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', (296, 302))	('FHIT', 'Gene', '2272', (18, 22))
503075	29642934	Prevalence of mutation counts and single nucleotide positions in the combined analysis of all cancer categories and within individual cancer types in the 325 cell lines with available WES data is provided in Table 3.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('single nucleotide positions', 'Var', (34, 61))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutation counts', 'Var', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
503078	29642934	However, clusters of mutations in genome regions have been reported to provide a more robust representation of mutational processes in tumor genomes that do average mutation rates at single positions.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('mutations', 'Var', (21, 30))
503083	29642934	For the most specific APOBEC motif, T(C>K)W, the highest mean number of motifs per cell line was observed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC; mean = 736 motifs per cell line), followed by bladder cancer (mean = 716 motifs), and melanoma (mean = 642 motifs; Fig.	('T(C>K)W', 'Var', (36, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('melanoma', 'Disease', (267, 275))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (118, 173))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('bladder cancer', 'Phenotype', 'HP:0009725', (227, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('bladder cancer', 'Disease', 'MESH:D001749', (227, 241))	('bladder cancer', 'Disease', (227, 241))
503085	29642934	The highest mean number of the 5/1000 kataegis clusters with the T(C>K)W motif was observed in bladder cancer (mean = 0.33 clusters per cell line), followed by mature B cell lymphoma (MATBCL; mean = 0.28 clusters), and NSCLC (mean = 0.19 clusters; Fig.	('NSCLC', 'Disease', (219, 224))	('SCLC', 'Phenotype', 'HP:0030357', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('B cell lymphoma', 'Disease', 'MESH:D016393', (167, 182))	('NSCLC', 'Disease', 'MESH:D002289', (219, 224))	('B cell lymphoma', 'Disease', (167, 182))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (167, 182))	('lymphoma', 'Phenotype', 'HP:0002665', (174, 182))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('T(C>K)W', 'Var', (65, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))
503088	29642934	The highest mean number of the 5/1000 kataegis clusters with the T(C>D)R motif was observed for THCA (mean = 1.00 cluster), followed by MATBCL (mean = 0.83 clusters) and the liver hepatocellular carcinoma (LIHC; mean = 0.76; Fig.	('liver hepatocellular carcinoma', 'Disease', (174, 204))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (180, 204))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (174, 204))	('T(C>D)R motif', 'Var', (65, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('THCA', 'Chemical', '-', (96, 100))
503091	29642934	The highest numbers of 5/1000 kataegis clusters with the T(C>D)D motif were observed in LIHC (mean = 2.65 clusters), renal cell carcinoma (RCC; mean = 2.50 clusters), and UCEC (mean = 2.50 clusters; Fig.	('renal cell carcinoma', 'Disease', (117, 137))	('T(C>D)D', 'Var', (57, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (117, 137))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('LIHC', 'Disease', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('UCEC', 'Disease', (171, 175))	('RCC', 'Disease', (139, 142))
503092	29642934	When 6/10000 kataegis clusters (data not shown), the two cancer types with the highest mean numbers of kataegis clusters were LIHC (mean = 0.76 clusters for T(C>K)W, 1.24 clusters for T(C>D)R, and 3.24 clusters for the T(C>D)D motif) and RCC (mean = 0.38, 0.88, and 2.13 clusters, respectively).	('T(C>D)R', 'Var', (184, 191))	('RCC', 'Phenotype', 'HP:0005584', (238, 241))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('RCC', 'Disease', (238, 241))	('cancer', 'Disease', (57, 63))	('T(C>K)W', 'Var', (157, 164))	('T(C>D)D motif', 'Var', (219, 232))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
503093	29642934	Our findings for bladder cancer, melanoma, non-small cell lung cancer, uterine corpus endometrial carcinoma, and prostate adenocarcinoma were consistent with previous reports which suggested the roles for APOBEC3 mutagenesis in those cancer types.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('APOBEC3', 'Gene', (205, 212))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('non-small cell lung cancer', 'Disease', (43, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (17, 31))	('bladder cancer', 'Disease', (17, 31))	('cancer', 'Disease', (25, 31))	('prostate adenocarcinoma', 'Disease', (113, 136))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (86, 107))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (17, 31))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (86, 107))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (43, 69))	('cancer', 'Disease', (63, 69))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (113, 136))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (47, 69))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (43, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('endometrial carcinoma', 'Disease', (86, 107))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (234, 240))	('mutagenesis', 'Var', (213, 224))
503094	29642934	In contrast, APOBEC3B was reported to be less likely to play a role in mutagenesis of renal cell carcinoma cell lines, suggesting that high prevalence of mutation clusters in the RCC cell lines observed in our study could be generated by molecular factors other than APOBEC3B.	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (86, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('mutation', 'Var', (154, 162))	('renal cell carcinoma', 'Disease', (86, 106))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (86, 106))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
503095	29642934	The increased prevalence of mutagenic clusters in mature B cell lymphoma cell lines may be explained by the effects of translesion synthesis DNA polymerase eta.	('lymphoma', 'Phenotype', 'HP:0002665', (64, 72))	('mutagenic', 'Var', (28, 37))	('DNA polymerase eta', 'Gene', '5429', (141, 159))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (57, 72))	('DNA polymerase eta', 'Gene', (141, 159))	('B cell lymphoma', 'Disease', 'MESH:D016393', (57, 72))	('B cell lymphoma', 'Disease', (57, 72))
503096	29642934	It is also possible that some of the mutations in MATBCL could be explained by a partial overlap of the motifs examined in our study with a characteristic signature for another member of the APOBEC family, the activation-induced cytidine deaminase (AID), which has been linked to mutagenesis in MATBCL.	('MATBCL', 'Gene', (50, 56))	('activation-induced cytidine deaminase', 'Gene', '57379', (210, 247))	('mutagenesis', 'Var', (280, 291))	('mutations', 'Var', (37, 46))	('AID', 'Gene', '57379', (249, 252))	('AID', 'Gene', (249, 252))	('activation-induced cytidine deaminase', 'Gene', (210, 247))
503104	29642934	Among individual cancer types, we observed a strong (rho between - 0.738 and - 0.902) and statistically significant (padj < 0.05) negative correlation of the frequencies of C>T, C>G, and C>K substitutions and overall nucleotide substitution counts with REV1 expression in sarcoma and UNG expression in melanoma (Table 5).	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('melanoma', 'Disease', (302, 310))	('sarcoma', 'Disease', (272, 279))	('negative', 'NegReg', (130, 138))	('expression', 'MPA', (258, 268))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('REV1', 'Gene', '51455', (253, 257))	('C>G', 'Var', (178, 181))	('C>K', 'Var', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('REV1', 'Gene', (253, 257))	('C>T', 'Var', (173, 176))	('cancer', 'Disease', (17, 23))	('UNG', 'Gene', '7374', (284, 287))	('sarcoma', 'Disease', 'MESH:D012509', (272, 279))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('UNG', 'Gene', (284, 287))
503107	29642934	APOBEC3B expression also had the strongest correlation with mutation counts in RCC as opposed to other cancer categories; however, such correlations for APOBEC3B were somewhat weaker and less significant (rho <= 0.86, padj >= 0.16) than those for APOBEC3A (data not shown).	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('APOBEC3B', 'Var', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('APOBEC3A', 'Gene', '200315', (247, 255))	('APOBEC3B', 'Gene', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('APOBEC3A', 'Gene', (247, 255))	('cancer', 'Disease', (103, 109))	('weaker', 'NegReg', (176, 182))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
503109	29642934	A large proportion of C>T and C>G substitutions in melanoma cell lines were likely generated via mutagenic processes related to UV radiation exposure.	('C>G substitutions', 'Var', (30, 47))	('C>T', 'Var', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('substitutions', 'Var', (34, 47))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
503110	29642934	However, the role for APOBEC3 in melanoma mutagenesis has also been established in a subset of melanomas, and experimental evidence has suggested an important role of APOBEC3A generating mutations specific to skin lesions.	('APOBEC3A', 'Gene', '200315', (167, 175))	('melanomas', 'Disease', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('APOBEC3', 'Gene', (22, 29))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('mutations', 'Var', (187, 196))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('skin lesions', 'Disease', (209, 221))	('APOBEC3A', 'Gene', (167, 175))	('melanomas', 'Disease', 'MESH:D008545', (95, 104))	('skin lesions', 'Disease', 'MESH:D012871', (209, 221))
503111	29642934	Among the correlations of gene expression levels with APOBEC-like motif counts and measures of kataegis, significant or nearly significant correlations were observed for UNG expression with kataegis measures (rho between - 0.81 and - 0.80, 0.039 <= padj <= 0.063, n = 17, Ntests = 475) of the T(C>D)D motif in melanoma, and for APOBEC3A expression with motif counts and kataegis measures in renal cell carcinoma (rho between 0.93 and 0.98, 0.008 <= padj <= 0.087 with n = 8 and Ntests = 510 for the T(C>D)R and T(C>D)D motifs; data not shown).	('renal cell carcinoma', 'Disease', 'MESH:C538614', (391, 411))	('APOBEC3A', 'Gene', '200315', (328, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (402, 411))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (391, 411))	('melanoma', 'Disease', (310, 318))	('melanoma', 'Disease', 'MESH:D008545', (310, 318))	('APOBEC3A', 'Gene', (328, 336))	('T(C>D)R', 'Var', (499, 506))	('renal cell carcinoma', 'Disease', (391, 411))	('UNG', 'Gene', '7374', (170, 173))	('UNG', 'Gene', (170, 173))
503116	29642934	Expression of REV1 in the non-small cell lung cancer cell lines was significantly positively correlated with log(IC50) of MEK (mitogen-activated protein kinase) inhibitors PD-0325901, RDEA119, and trametinib, as well as AKT inhibitor VIII, XIAP inhibitor embelin, PI3Kbeta inhibitor AZD6482, and a cyclin-dependent kinase (CDK) 4/6 inhibitor PD-0332991, or palbociclib (Table 6; 0.348 <= rho <= 0.405, padj <= 0.0436, n >= 100, Ntests = 26,610).	('XIAP', 'Gene', '331', (240, 244))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (26, 52))	('AKT', 'Gene', (220, 223))	('PD-0325901', 'Chemical', 'MESH:C506614', (172, 182))	('trametinib', 'Chemical', 'MESH:C560077', (197, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('VIII', 'Gene', (234, 238))	('non-small cell lung cancer', 'Disease', (26, 52))	('REV1', 'Gene', '51455', (14, 18))	('PI3Kbeta', 'Gene', (264, 272))	('mitogen-activated protein kinase', 'Gene', '5609', (127, 159))	('XIAP', 'Gene', (240, 244))	('MEK', 'Gene', '5609', (122, 125))	('PD-0325901', 'Var', (172, 182))	('AKT', 'Gene', '207', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('REV1', 'Gene', (14, 18))	('cyclin-dependent kinase (CDK) 4/6', 'Gene', '1019;1021', (298, 331))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (26, 52))	('palbociclib', 'Chemical', 'MESH:C500026', (357, 368))	('PI3Kbeta', 'Gene', '5291', (264, 272))	('MEK', 'Gene', (122, 125))	('VIII', 'Gene', '1351', (234, 238))	('mitogen-activated protein kinase', 'Gene', (127, 159))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (30, 52))
503118	29642934	PD-0325901 has an in vitro inhibiting effect in NSCLC; however, a phase II clinical trial of that antitumor agent in NSCLC patients did not meet the primary efficacy end point.	('NSCLC', 'Disease', (117, 122))	('NSCLC', 'Disease', (48, 53))	('SCLC', 'Phenotype', 'HP:0030357', (49, 53))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('PD-0325901', 'Var', (0, 10))	('inhibiting', 'NegReg', (27, 37))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('SCLC', 'Phenotype', 'HP:0030357', (118, 122))	('PD-0325901', 'Chemical', 'MESH:C506614', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
503120	29642934	In melanoma cell lines, FHIT expression was associated with chemoresistance to the ALK inhibitor TAE684 (Table 6; rho = 0.621, padj = 0.0326, n = 38, Ntests = 26,610).	('expression', 'Var', (29, 39))	('ALK', 'Gene', '238', (83, 86))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('chemoresistance', 'CPA', (60, 75))	('FHIT', 'Gene', (24, 28))	('TAE684', 'Chemical', 'MESH:C516714', (97, 103))	('ALK', 'Gene', (83, 86))	('FHIT', 'Gene', '2272', (24, 28))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('associated with', 'Reg', (44, 59))
503133	29642934	Among notable correlations, the combined length of clusters with the T(C>D)D motif had a strong correlation (5 <= n <= 7, Ntests = 1834) with chemoresistance to bicalutamide, a nonsteroidal antiandrogen drug, in the pancreatic adenocarcinoma and breast cancer cell lines (Table 7; Fig.	('breast cancer', 'Disease', (246, 259))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (216, 241))	('chemoresistance', 'CPA', (142, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('pancreatic adenocarcinoma', 'Disease', (216, 241))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (216, 241))	('T(C>D)D', 'Var', (69, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('bicalutamide', 'Chemical', 'MESH:C053541', (161, 173))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('correlation', 'Reg', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
503134	29642934	As discussed above, we did not observe a statistically significant correlation between expression of any candidate gene and the prevalence of T(C>D)D or any other motif in breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('T(C>D)D', 'Var', (142, 149))	('breast cancer', 'Disease', (172, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))
503135	29642934	Sequence variation of breast cancer genomes is shaped by a diversity of mutational processes, and further investigation is needed to establish whether the T(C>D)D motif in the breast cancer cell lines is predominantly generated by APOBEC3B and APOBEC3A and/or requires an additional role or REV1, UNG, and FHIT, or whether it involves other molecular mechanisms.	('APOBEC3B', 'Gene', (231, 239))	('FHIT', 'Gene', '2272', (306, 310))	('APOBEC3A', 'Gene', (244, 252))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('APOBEC3A', 'Gene', '200315', (244, 252))	('UNG', 'Gene', '7374', (297, 300))	('T(C>D)D', 'Var', (155, 162))	('REV1', 'Gene', '51455', (291, 295))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('REV1', 'Gene', (291, 295))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('UNG', 'Gene', (297, 300))	('breast cancer', 'Disease', (176, 189))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('FHIT', 'Gene', (306, 310))
503138	29642934	To our knowledge, no relationship between the abundance of APOBEC-like signatures and sensitivity to this agent has been reported, although HER2-enriched cell lines have been reported to have high levels of APOBEC mutagenesis and to be among the breast cancer categories that are likely to be sensitive to bicalutamide.	('breast cancer', 'Disease', (246, 259))	('APOBEC', 'Protein', (207, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('bicalutamide', 'Chemical', 'MESH:C053541', (306, 318))	('mutagenesis', 'Var', (214, 225))	('HER2', 'Gene', (140, 144))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('HER2', 'Gene', '2064', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
503145	29642934	Similarly, log(IC50) of the hedgehog signaling pathway inhibitor vismodegib and of the PPARgamma/PPARdelta inhibitor FH535 were associated with the overall counts of the T(C>D)R motif.	('PPARgamma', 'Gene', '5468', (87, 96))	('hedgehog signaling pathway', 'Pathway', (28, 54))	('PPARdelta', 'Gene', (97, 106))	('associated', 'Reg', (128, 138))	('FH535', 'Chemical', 'MESH:C575430', (117, 122))	('PPARdelta', 'Gene', '5467', (97, 106))	('PPARgamma', 'Gene', (87, 96))	('T(C>D)R motif', 'Var', (170, 183))
503146	29642934	The overall counts of the T(C>D)D motif were associated with log(IC50) of the PKCB inhibitor LY317615, whereas the length of its predicted kataegis regions was associated with log(IC50) of the Aurora kinase A/B inhibitor Genentech Cpd10, a DNA-damaging agent gemcitabine, and, as discussed above, with a nonsteroidal antiandrogen agent bicalutamide (Table 7).	('LY317615', 'Var', (93, 101))	('PKCB', 'Gene', (78, 82))	('LY317615', 'Chemical', 'MESH:C504878', (93, 101))	('Aurora kinase A/B', 'Gene', '6790;9212', (193, 210))	('Aurora kinase A/B', 'Gene', (193, 210))	('bicalutamide', 'Chemical', 'MESH:C053541', (336, 348))	('inhibitor LY317615', 'Var', (83, 101))	('PKCB', 'Gene', '5579', (78, 82))	('gemcitabine', 'Chemical', 'MESH:C056507', (259, 270))
503150	29642934	The bimodal distribution of APOBEC3B is likely due to several reasons which include previously reported differences in expression levels of this gene among specific cancer types and individual cell lines within specific cancer categories, along with the germline deletion polymorphism that results in the loss the APOBEC3B gene in a subset of the samples.	('expression levels', 'MPA', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (165, 171))	('loss', 'NegReg', (305, 309))	('APOBEC3B', 'Gene', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('germline deletion polymorphism', 'Var', (254, 284))	('cancer', 'Disease', (220, 226))	('APOBEC3B', 'Gene', (314, 322))
503155	29642934	2f, a strong correlation between APOBEC3A and APOBEC3B expression levels (Table 2) appeared to be independent from the APOBEC3B deletion polymorphism which removes the coding area of the APOBEC3B gene and creates a fusion transcript of APOBEC3A with the 3'-UTR of the APOBEC3 gene, although earlier reports suggest that this transcript increases APOBEC3A levels due to the increase in stability of the fusion transcript.	('APOBEC3A', 'Gene', '200315', (236, 244))	('APOBEC3A', 'Gene', '200315', (346, 354))	('creates', 'Reg', (205, 212))	('coding', 'MPA', (168, 174))	('stability', 'MPA', (385, 394))	('APOBEC3A', 'Gene', (236, 244))	('APOBEC3A', 'Gene', (33, 41))	('APOBEC3A', 'Gene', (346, 354))	('increase', 'PosReg', (373, 381))	('APOBEC3A', 'Gene', '200315', (33, 41))	('APOBEC3B', 'Gene', (187, 195))	('increases', 'PosReg', (336, 345))	('polymorphism', 'Var', (137, 149))	('removes', 'NegReg', (156, 163))	('deletion', 'Var', (128, 136))
503157	29642934	Mutagenesis in cancer cells generated due to the activity of APOBEC family members, and in particular of APOBEC3B, has been a subject of many recent studies.	('activity', 'MPA', (49, 57))	('cancer', 'Disease', (15, 21))	('Mutagenesis', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('APOBEC3B', 'Gene', (105, 113))	('APOBEC family', 'Gene', (61, 74))
503162	29642934	While we found an increased number of APOBEC-like motifs in mature B cell lymphoma, we did not include the AID gene expression in our analysis because both the mutational sequence specificity of AID and the biological context in which AID mutations occur are different from those of APOBEC3B and APOBEC3A.	('AID', 'Gene', '57379', (107, 110))	('AID', 'Gene', (107, 110))	('APOBEC3A', 'Gene', (296, 304))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('mutations', 'Var', (239, 248))	('APOBEC3A', 'Gene', '200315', (296, 304))	('AID', 'Gene', '57379', (235, 238))	('AID', 'Gene', (235, 238))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (67, 82))	('B cell lymphoma', 'Disease', 'MESH:D016393', (67, 82))	('B cell lymphoma', 'Disease', (67, 82))	('AID', 'Gene', '57379', (195, 198))	('AID', 'Gene', (195, 198))
503165	29642934	AID deaminates cytosines within the characteristic WRC motif, or more broadly the WRCY/RGYW motif, with several other AID motif variants having been reported.	('deaminates', 'Var', (4, 14))	('cytosines', 'MPA', (15, 24))	('cytosine', 'Chemical', 'MESH:D003596', (15, 23))	('AID', 'Gene', '57379', (118, 121))	('AID', 'Gene', (118, 121))	('variants', 'Var', (128, 136))	('AID', 'Gene', '57379', (0, 3))	('AID', 'Gene', (0, 3))
503170	29642934	Expression levels of APOBEC3A, APOBEC3B, APOBEC3D, APOBEC3G, and APOBEC3H in tumor specimens from cancer patients were associated with varying clinical responses to chemotherapy and with overall patient survival, and possible suggested mechanisms of such associations, which may also involve other APOBEC genes, include immune targeting of increased mutation diversity due to higher levels of APOBEC mutagenesis, associated inflammation, PD-L1 expression on tumor-infiltrating mononuclear cells, and the degree of T lymphocyte infiltration.	('patient', 'Species', '9606', (105, 112))	('PD-L1', 'Gene', (438, 443))	('tumor', 'Disease', 'MESH:D009369', (458, 463))	('APOBEC3A', 'Gene', '200315', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('PD-L1', 'Gene', '29126', (438, 443))	('cancer', 'Disease', (98, 104))	('APOBEC3D', 'Gene', (41, 49))	('associated', 'Reg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('APOBEC3G', 'Gene', (51, 59))	('inflammation', 'Disease', 'MESH:D007249', (424, 436))	('tumor', 'Phenotype', 'HP:0002664', (458, 463))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('APOBEC3H', 'Gene', '164668', (65, 73))	('APOBEC3H', 'Gene', (65, 73))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (350, 358))	('APOBEC3A', 'Gene', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('inflammation', 'Disease', (424, 436))	('higher', 'PosReg', (376, 382))	('APOBEC3G', 'Gene', '60489', (51, 59))	('APOBEC3D', 'Gene', '140564', (41, 49))	('patient', 'Species', '9606', (195, 202))	('tumor', 'Disease', (458, 463))	('APOBEC', 'Gene', (393, 399))	('tumor', 'Disease', (77, 82))
503187	29642934	When using measures of kataegis clusters, we observed correlations of the combined length of kataegis clusters of the least specific T(C>D)D motif with sensitivity to various agents in breast, pancreatic adenocarcinoma, and colon adenocarcinoma and rectum adenocarcinoma cancer cell lines.	('T(C>D)D motif', 'Var', (133, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (193, 218))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('correlations', 'Reg', (54, 66))	('least', 'NegReg', (118, 123))	('colon adenocarcinoma and rectum adenocarcinoma cancer', 'Disease', 'MESH:D012004', (224, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('sensitivity', 'MPA', (152, 163))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (193, 218))	('pancreatic adenocarcinoma', 'Disease', (193, 218))
503228	25844809	Eleven different entities were included, among them the most common and clinically relevant subtypes and tumors with specific translocations or complex genetic changes.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('translocations', 'Var', (126, 140))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
503232	25844809	MET FISH amplification and copy number gain were present in 4% of the tumors (15/413).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('copy number gain', 'Var', (27, 43))
503243	25844809	For some sarcoma subtypes tumor specific molecular aberrations such as gene translocations, amplifications or mutations have been identified, however, their exploitation as therapeutic targets has been limited.	('gene translocations', 'Var', (71, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcoma subtypes tumor', 'Disease', 'MESH:D012509', (9, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('sarcoma subtypes tumor', 'Disease', (9, 31))	('amplifications', 'Var', (92, 106))
503244	25844809	The best example for molecular targeted therapy in mesenchymal tumors is treatment with tyrosine kinase inhibitors in gastrointestinal stromal tumors (GIST) which carry activating KIT or PDGFRA (platelet derived growth factor receptor alpha) mutations in approximately 90%.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('platelet derived growth factor receptor alpha', 'Gene', '5156', (195, 240))	('platelet derived growth factor receptor alpha', 'Gene', (195, 240))	('KIT', 'Gene', (180, 183))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('gastrointestinal stromal tumors', 'Disease', (118, 149))	('mutations', 'Var', (242, 251))	('PDGFRA', 'Gene', '5156', (187, 193))	('PDGFRA', 'Gene', (187, 193))	('mesenchymal tumors', 'Disease', (51, 69))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (51, 69))	('activating', 'PosReg', (169, 179))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (118, 149))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (118, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
503247	25844809	MET is a transmembrane tyrosine kinase receptor and is also known as hepatocyte growth factor receptor (HGFR).	('hepatocyte growth factor receptor', 'Gene', '4233', (69, 102))	('HGFR', 'Gene', '4233', (104, 108))	('hepatocyte growth factor receptor', 'Gene', (69, 102))	('HGFR', 'Gene', (104, 108))	('MET', 'Var', (0, 3))
503250	25844809	Improper activation may lead to tumorigenesis, tumor angiogenesis, invasion and metastasis.	('metastasis', 'CPA', (80, 90))	('invasion', 'CPA', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('lead to', 'Reg', (24, 31))	('activation', 'MPA', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (47, 52))	('Improper', 'Var', (0, 8))
503258	25844809	Few sarcoma subgroups are already enrolled in clinical trials for ARQ 197 (Tivantinib) and PF-02341066 (Crizotinib).	('sarcoma', 'Disease', (4, 11))	('ARQ 197', 'Gene', (66, 73))	('PF-02341066', 'Var', (91, 102))	('Tivantinib', 'Chemical', 'MESH:C551661', (75, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Crizotinib', 'Chemical', 'MESH:D000077547', (104, 114))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))
503261	25844809	However, a systematic and comprehensive prevalence study of MET and HGF alterations in soft tissue sarcomas has not yet been published.	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('HGF', 'Gene', (68, 71))	('alterations', 'Var', (72, 83))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (87, 107))	('soft tissue sarcomas', 'Disease', (87, 107))	('HGF', 'Gene', '3082', (68, 71))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (87, 107))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (87, 106))	('MET', 'Gene', (60, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
503265	25844809	Our results were obtained by up-to-date biomarker assays and provide first comprehensive epidemiologic data for ongoing and upcoming clinical trials with MET/HGF inhibitors in soft tissue sarcomas and GIST.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (176, 196))	('HGF', 'Gene', (158, 161))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (176, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('HGF', 'Gene', '3082', (158, 161))	('soft tissue sarcomas', 'Disease', (176, 196))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (176, 195))	('inhibitors', 'Var', (162, 172))	('sarcomas', 'Phenotype', 'HP:0100242', (188, 196))
503285	25844809	Strong staining intensity was defined by the level of MET and HGF expression in the H441 and EBC-1 cell lines and in breast carcinoma tissue, respectively.	('breast carcinoma', 'Phenotype', 'HP:0003002', (117, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('HGF', 'Gene', (62, 65))	('HGF', 'Gene', '3082', (62, 65))	('breast carcinoma', 'Disease', 'MESH:D001943', (117, 133))	('MET', 'Var', (54, 57))	('breast carcinoma', 'Disease', (117, 133))
503314	25844809	15% of those tumors with complex karyotype and only 1% of tumors with specific aberrations were HGF immunopositive.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HGF', 'Gene', (96, 99))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('HGF', 'Gene', '3082', (96, 99))	('complex karyotype', 'Var', (25, 42))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
503328	25844809	The other 12 positive cases were tumors with low level copy number gains (defined by >=4.0 MET signals/cell in >=40% of tumor cells).	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('copy number gains', 'Var', (55, 72))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (33, 39))	('tumor', 'Disease', (120, 125))
503331	25844809	Low level copy number gain was seen in angiosarcomas (4/37, 11%), undifferentiated pleomorphic sarcomas (3/32, 9%), dedifferentiated liposarcomas (2/67, 3%), pleomorphic liposarcomas (1/10, 10%), leiomyosarcomas (1/65, 2%) and myxoid liposarcomas (1/27, 4%).	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('liposarcomas', 'Phenotype', 'HP:0012034', (133, 145))	('copy number', 'Var', (10, 21))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (158, 182))	('liposarcomas', 'Disease', 'MESH:D008080', (234, 246))	('liposarcoma', 'Phenotype', 'HP:0012034', (133, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (227, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (66, 103))	('undifferentiated pleomorphic sarcomas', 'Disease', (66, 103))	('angiosarcomas', 'Disease', 'MESH:D006394', (39, 52))	('liposarcomas', 'Disease', 'MESH:D008080', (170, 182))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (196, 211))	('liposarcomas', 'Disease', (133, 145))	('leiomyosarcomas', 'Disease', (196, 211))	('liposarcomas', 'Phenotype', 'HP:0012034', (234, 246))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('myxoid liposarcomas', 'Disease', (227, 246))	('liposarcomas', 'Phenotype', 'HP:0012034', (170, 182))	('liposarcoma', 'Phenotype', 'HP:0012034', (234, 245))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (196, 211))	('pleomorphic liposarcomas', 'Disease', (158, 182))	('angiosarcomas', 'Phenotype', 'HP:0200058', (39, 52))	('liposarcoma', 'Phenotype', 'HP:0012034', (170, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (227, 246))	('angiosarcomas', 'Disease', (39, 52))	('liposarcomas', 'Disease', (234, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('liposarcomas', 'Disease', (170, 182))	('liposarcomas', 'Disease', 'MESH:D008080', (133, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))	('gain', 'PosReg', (22, 26))
503338	25844809	Furthermore, all tumors with low level gene copy number gains could be confirmed showing a homogeneous signal distribution.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('gene copy number gains', 'Var', (39, 61))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
503342	25844809	Two tumors had focally more than >=15 MET gene copies/cell in >=10% of tumor cells and one tumor had a focal MET/CEN7 ratio >=2.0.	('tumor', 'Disease', (4, 9))	('MET gene copies/cell', 'Var', (38, 58))	('tumors', 'Disease', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (91, 96))	('CEN7', 'Chemical', '-', (113, 117))
503357	25844809	Among the most promising approaches are tyrosine kinase inhibitors (i.e., small molecules) as well as anti-MET and anti-HGF antibodies.	('HGF', 'Gene', (120, 123))	('anti-MET', 'Var', (102, 110))	('HGF', 'Gene', '3082', (120, 123))	('tyrosine kinase inhibitors', 'MPA', (40, 66))
503361	25844809	Notably, none of the more than 150 liposarcoma samples of any type (i.e., atypical lipomatous tumor, dedifferentiated, myxoid and pleomorphic liposarcoma) showed MET amplification, MET copy number gain or MET or HGF overexpression.	('liposarcoma', 'Phenotype', 'HP:0012034', (142, 153))	('pleomorphic liposarcoma', 'Disease', (130, 153))	('liposarcoma', 'Disease', (35, 46))	('MET', 'MPA', (205, 208))	('liposarcoma', 'Disease', 'MESH:D008080', (142, 153))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('myxoid', 'Disease', (119, 125))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (130, 153))	('liposarcoma', 'Phenotype', 'HP:0012034', (35, 46))	('lipomatous tumor', 'Phenotype', 'HP:0012031', (83, 99))	('lipomatous tumor', 'Disease', 'MESH:D008080', (83, 99))	('HGF', 'Gene', '3082', (212, 215))	('MET amplification', 'Var', (162, 179))	('overexpression', 'PosReg', (216, 230))	('liposarcoma', 'Disease', (142, 153))	('liposarcoma', 'Disease', 'MESH:D008080', (35, 46))	('MET copy number', 'Var', (181, 196))	('lipomatous tumor', 'Disease', (83, 99))	('HGF', 'Gene', (212, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('gain', 'PosReg', (197, 201))
503366	25844809	We demonstrate that a subset of angiosarcomas and undifferentiated pleomorphic sarcomas (UPS) harbor MET amplifications, MET copy number gains or show MET/HGF overexpression.	('MET copy number gains', 'Var', (121, 142))	('overexpression', 'PosReg', (159, 173))	('HGF', 'Gene', '3082', (155, 158))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('angiosarcomas', 'Phenotype', 'HP:0200058', (32, 45))	('HGF', 'Gene', (155, 158))	('MET amplifications', 'Var', (101, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('angiosarcomas and undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D006394', (32, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))
503374	25844809	It might as well be possible that the poor correlation of MET amplification and gene copy number alteration with IHC reflects a specific feature of sarcomas since the similar observation has recently been reported by another group.	('sarcomas', 'Disease', 'MESH:D012509', (148, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('IHC', 'Disease', (113, 116))	('gene copy number alteration', 'Var', (80, 107))	('sarcomas', 'Disease', (148, 156))	('MET', 'Var', (58, 61))
503388	25844809	In some other tumor entities such as gastric carcinomas 1+ staining has previously been judged as predictively relevant positive staining.	('tumor', 'Disease', (14, 19))	('gastric carcinomas', 'Disease', 'MESH:D013274', (37, 55))	('1+ staining', 'Var', (56, 67))	('gastric carcinomas', 'Disease', (37, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
503403	25844809	On the other hand, we could clearly demonstrate that 96% of all sarcomas in our cohort do not harbor any significant increase in MET gene copy numbers ("MET negatives").	('MET gene copy numbers', 'Var', (129, 150))	('sarcomas', 'Disease', 'MESH:D012509', (64, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcomas', 'Disease', (64, 72))
503410	25844809	Based on preliminary data in NSCLC patients with high-level MET amplification seem to be most likely to benefit from MET-targeted therapy.	('benefit', 'PosReg', (104, 111))	('high-level MET amplification', 'Var', (49, 77))	('NSCLC', 'Disease', (29, 34))	('patients', 'Species', '9606', (35, 43))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))
503412	25844809	In summary, we investigated a comprehensive series of more than 400 adult-type sarcomas for MET and HGF overexpression as well as for MET gene amplification.	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('MET gene amplification', 'Var', (134, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Disease', (79, 87))	('HGF', 'Gene', (100, 103))	('HGF', 'Gene', '3082', (100, 103))	('overexpression', 'PosReg', (104, 118))
503449	25745287	Negativity of cytokeratin ruled out the possibility of poorly differentiated carcinoma.	('Negativity', 'Var', (0, 10))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('carcinoma', 'Disease', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))
503466	22927549	Using the 3'methylcholanthrene (MCA) model of sarcomagenesis, we previously found that the immune system in WT mice could edit tumors more effectively than the immune system in RAG2-/- mice (which lack adaptive immunity), but we did not assess whether tumors from RAG2-/- mice were edited by the innate immune system.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MCA', 'Chemical', 'MESH:D008748', (32, 35))	('tumors', 'Disease', (127, 133))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('edit', 'Var', (122, 126))	('mice', 'Species', '10090', (185, 189))	('mice', 'Species', '10090', (272, 276))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('mice', 'Species', '10090', (111, 115))	('sarcoma', 'Disease', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('tumors', 'Disease', (252, 258))
503468	22927549	Toward this end, we set out to quantitate tumor editing in WT versus RAG2-/- versus RAG2-/-x gammac-/- mice.	('tumor editing', 'Disease', (42, 55))	('tumor editing', 'Disease', 'MESH:D009369', (42, 55))	('mice', 'Species', '10090', (103, 107))	('RAG2-/-', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
503470	22927549	If cells of the innate immune system could hinder tumor growth, then we would expect RAG2-/-x gammac-/- mice to demonstrate increased tumor incidence and decreased tumor editing compared with RAG2-/- mice.	('tumor', 'Disease', (164, 169))	('decreased tumor editing', 'Disease', 'MESH:D009369', (154, 177))	('increased', 'PosReg', (124, 133))	('mice', 'Species', '10090', (104, 108))	('rat', 'Species', '10116', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('RAG2-/-x', 'Var', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('mice', 'Species', '10090', (200, 204))	('tumor', 'Disease', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('decreased tumor editing', 'Disease', (154, 177))	('tumor', 'Disease', (134, 139))
503471	22927549	Indeed, when we compared MCA-induced sarcoma incidence and tumor cell immunogenicity between the groups of mice, we found both increased incidence and immunogenicity of MCA-induced sarcomas in RAG2-/-x gammac-/- mice compared with RAG2-/- mice, which, consistent with previous results, had increased incidence and immunogenicity of tumors compared with WT mice.	('mice', 'Species', '10090', (212, 216))	('tumor', 'Disease', (59, 64))	('mice', 'Species', '10090', (356, 360))	('sarcoma', 'Disease', 'MESH:D012509', (181, 188))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('sarcomas', 'Disease', 'MESH:D012509', (181, 189))	('MCA', 'Chemical', 'MESH:D008748', (169, 172))	('sarcoma', 'Disease', (181, 188))	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('sarcomas', 'Disease', (181, 189))	('sarcoma', 'Disease', 'MESH:D012509', (37, 44))	('mice', 'Species', '10090', (107, 111))	('MCA', 'Chemical', 'MESH:D008748', (25, 28))	('sarcoma', 'Disease', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (332, 338))	('RAG2-/-x gammac-/-', 'Var', (193, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('MCA-induced', 'Gene', (169, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('mice', 'Species', '10090', (239, 243))	('tumor', 'Disease', (332, 337))	('tumors', 'Disease', 'MESH:D009369', (332, 338))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('increased', 'PosReg', (127, 136))
503472	22927549	When transplanted into RAG2-/- recipients, RAG2-/-x gammac-/- regressor sarcoma cell lines formed tumors that became heavily infiltrated with M1 macrophages.	('sarcoma', 'Disease', (72, 79))	('rat', 'Species', '10116', (131, 134))	('tumors', 'Disease', (98, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('RAG2-/-x', 'Var', (43, 51))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))
503474	22927549	In contrast, in the absence of gammac and IFN-gamma function, RAG2-/-x gammac-/- regressors were infiltrated with more M2 macrophages, which can promote tumor formation.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('rat', 'Species', '10116', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('promote', 'PosReg', (145, 152))	('RAG2-/-x', 'Var', (62, 70))
503478	22927549	1 shows that the incidence of sarcomas was higher in RAG2-/-x gammac-/- mice compared with RAG2-/- mice at all doses tested.	('mice', 'Species', '10090', (99, 103))	('gammac-/-', 'Var', (62, 71))	('higher', 'PosReg', (43, 49))	('sarcomas', 'Disease', (30, 38))	('RAG2-/-x gammac-/-', 'Var', (53, 71))	('mice', 'Species', '10090', (72, 76))	('sarcomas', 'Disease', 'MESH:D012509', (30, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
503480	22927549	In addition, at MCA doses of 25 or 100 microg, RAG2-/-x gammac-/- mice developed sarcomas slightly faster than RAG2-/- mice, indicating that the innate immune system in RAG2-/- mice controlled MCA-induced tumor outgrowth to some extent.	('mice', 'Species', '10090', (119, 123))	('sarcomas', 'Disease', (81, 89))	('MCA', 'Chemical', 'MESH:D008748', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('MCA', 'Chemical', 'MESH:D008748', (16, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('RAG2-/-x', 'Var', (47, 55))	('mice', 'Species', '10090', (66, 70))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('developed', 'PosReg', (71, 80))	('mice', 'Species', '10090', (177, 181))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
503484	22927549	When we examined groups of MCA-induced sarcoma cell lines generated from WT, RAG2-/-, and RAG2-/-x gammac-/- mice, we found that the proportion of regressor MCA-induced sarcoma cell lines was 0/9 WT, 3/10 RAG2-/-, and 6/10 RAG2-/-x gammac-/- (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (169, 176))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('rat', 'Species', '10116', (62, 65))	('sarcoma', 'Disease', (169, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('MCA', 'Chemical', 'MESH:D008748', (157, 160))	('MCA', 'Chemical', 'MESH:D008748', (27, 30))	('sarcoma', 'Disease', (39, 46))	('mice', 'Species', '10090', (109, 113))	('RAG2-/-x gammac-/-', 'Var', (223, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('RAG2-/-', 'Var', (205, 212))
503499	22927549	Because regressor cell lines generated from RAG2-/-x gammac-/- mice displayed the highest levels of immunogenicity and, subsequently, the lowest levels of immunoediting compared with RAG2-/- and WT mice, we hypothesized that the innate immune system of RAG2-/- mice could edit these tumor cell lines in vivo.	('levels', 'MPA', (90, 96))	('RAG2-/-x', 'Var', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('mice', 'Species', '10090', (63, 67))	('rat', 'Species', '10116', (33, 36))	('mice', 'Species', '10090', (261, 265))	('immunogenicity', 'MPA', (100, 114))	('tumor', 'Disease', (283, 288))	('mice', 'Species', '10090', (198, 202))
503500	22927549	We tested this by transplanting two independent sarcoma cell lines generated from RAG2-/-x gammac-/- mice into either RAG2-/- or RAG2-/-x gammac-/- mice.	('rat', 'Species', '10116', (71, 74))	('sarcoma', 'Disease', (48, 55))	('tested', 'Reg', (3, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('RAG2-/-x', 'Var', (82, 90))	('mice', 'Species', '10090', (148, 152))	('mice', 'Species', '10090', (101, 105))	('sarcoma', 'Disease', 'MESH:D012509', (48, 55))
503503	22927549	These results suggest a higher level of editing by the innate immune system in RAG2-/- versus RAG2-/-x gammac-/- mice but also indicate that there is some level of measurable tumor sculpting in RAG2-/-x gammac-/- mice, which could be caused by residual immune function or a nonimmunological editing process.	('tumor', 'Disease', (175, 180))	('mice', 'Species', '10090', (213, 217))	('RAG2-/-x gammac-/-', 'Var', (194, 212))	('editing', 'MPA', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
503511	22927549	Strikingly, we observed significantly higher numbers of MHC class II-positive cells in tumors growing in RAG2-/- versus RAG2-/-x gammac-/- hosts (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RAG2-/-', 'Var', (105, 112))	('MHC class II-positive', 'Protein', (56, 77))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('higher', 'PosReg', (38, 44))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
503512	22927549	This was likely caused by increased MHC class II induction rather than an increase in macrophages, as no differences were detected in the total number of macrophages infiltrating tumors growing in either RAG2-/- or RAG2-/-x gammac-/- hosts, as detected by the tissue macrophage marker CD68 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('increased MHC', 'Phenotype', 'HP:0025548', (26, 39))	('MHC class II', 'Protein', (36, 48))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('increased', 'PosReg', (26, 35))	('CD68', 'Gene', '12514', (285, 289))	('rat', 'Species', '10116', (59, 62))	('rat', 'Species', '10116', (172, 175))	('RAG2-/-', 'Var', (204, 211))	('CD68', 'Gene', (285, 289))
503516	22927549	We therefore transplanted a regressor cell line derived from a RAG2-/-x gammac-/- mouse into RAG2-/- recipients treated either with the neutralizing H22 IFN-gamma-specific monoclonal antibody (mAb), an NK1.1 specific monoclonal antibody (PK136), or a control mAb (PIP).	('PIP', 'Gene', (264, 267))	('NK1.1', 'Gene', '17059', (202, 207))	('neutralizing', 'Var', (136, 148))	('H22 IFN-gamma-specific', 'Protein', (149, 171))	('NK1.1', 'Gene', (202, 207))	('mouse', 'Species', '10090', (82, 87))	('PIP', 'Gene', '18716', (264, 267))
503533	22927549	Conversely, M2 macrophage percentages were slightly increased in tumors isolated from RAG2-/- mice treated with anti-IFN-gamma (36%) and RAG2-/-x gammac-/- mice (37%), but not anti-NK1.1-treated mice (27%) compared with control RAG2-/- mice (28%; Fig.	('mice', 'Species', '10090', (236, 240))	('mice', 'Species', '10090', (195, 199))	('anti-IFN-gamma', 'Var', (112, 126))	('increased', 'PosReg', (52, 61))	('M2 macrophage percentages', 'CPA', (12, 37))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('NK1.1', 'Gene', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mice', 'Species', '10090', (94, 98))	('mice', 'Species', '10090', (156, 160))	('RAG2-/-', 'Gene', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('NK1.1', 'Gene', '17059', (181, 186))
503542	22927549	Macrophages sorted from tumors transplanted into RAG2-/- hosts that were identified as M1-type MHC class IIhi, Ly6Clo, CD206lo, F4/80hi displayed high levels of both TNF and iNOS transcript compared with macrophages sorted from RAG2-/-x gammac-/- that were identified as M2-type MHC class IIlo, Ly6Clo, CD206hi, F4/80hi and displayed higher transcript levels of arginase, eCAD, and Gas3.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('iNOS', 'Gene', '18126', (174, 178))	('tumors', 'Disease', (24, 30))	('eCAD', 'Gene', (372, 376))	('F4/80', 'Gene', '13733', (312, 317))	('iNOS', 'Gene', (174, 178))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('Gas3', 'Gene', '18858', (382, 386))	('CD206', 'Gene', '17533', (303, 308))	('F4/80', 'Gene', (312, 317))	('Ly6Clo', 'Chemical', '-', (295, 301))	('eCAD', 'Gene', '12550', (372, 376))	('Gas3', 'Gene', (382, 386))	('CD206', 'Gene', '17533', (119, 124))	('Ly6Clo', 'Chemical', '-', (111, 117))	('Ly6Clo', 'Var', (295, 301))	('arginase', 'MPA', (362, 370))	('CD206', 'Gene', (303, 308))	('Ly6Clo', 'Var', (111, 117))	('TNF', 'Gene', (166, 169))	('F4/80', 'Gene', '13733', (128, 133))	('CD206', 'Gene', (119, 124))	('transcript levels', 'MPA', (341, 358))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('F4/80', 'Gene', (128, 133))	('higher', 'PosReg', (334, 340))	('TNF', 'Gene', '21926', (166, 169))
503544	22927549	We hypothesized that CD40 agonist treatment would activate macrophages in tumors growing in RAG2-/-x gammac-/- mice, thereby leading to editing of cancer cells in vivo.	('leading to', 'Reg', (125, 135))	('macrophages', 'CPA', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mice', 'Species', '10090', (111, 115))	('CD40', 'Var', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('activate', 'PosReg', (50, 58))	('cancer', 'Disease', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
503547	22927549	We then analyzed the quantity of M1 macrophages in harvested tumor cell suspensions and found that M1 macrophage percentages were doubled in mice treated with CD40 agonist (36%) compared with control treatment (18%; Fig.	('CD40', 'Var', (159, 163))	('M1 macrophage percentages', 'CPA', (99, 124))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
503564	22927549	In our studies, we have defined CD45+CD11b+MHC class IIhiCD206loLy6Clo cells as M1 macrophages based not only on their phenotype but also on their classical requirement for IFN-gamma for their generation.	('rat', 'Species', '10116', (197, 200))	('CD45+CD11b+MHC', 'Var', (32, 46))	('Ly6Clo', 'Chemical', '-', (64, 70))	('CD206', 'Gene', (57, 62))	('CD206', 'Gene', '17533', (57, 62))
503566	22927549	The administration of reagents that increased M1 percentages, such as CD40 agonist, enhanced editing, whereas treatments that decreased M1 percentages, such as NK cell depletion and anti-IFN-gamma mAb blocked editing.	('rat', 'Species', '10116', (12, 15))	('enhanced', 'PosReg', (84, 92))	('CD40', 'Var', (70, 74))	('editing', 'MPA', (93, 100))
503576	22927549	Similarly, we have found that CD40 agonist treatment of RAG2-/-x gammac-/- mice can induce tumor editing in the absence of adaptive immunity and NK cells, thereby suggesting that macrophages are sufficient for tumor editing.	('mice', 'Species', '10090', (75, 79))	('tumor editing', 'Disease', 'MESH:D009369', (210, 223))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor editing', 'Disease', (210, 223))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CD40', 'Var', (30, 34))	('induce', 'Reg', (84, 90))	('tumor editing', 'Disease', (91, 104))	('tumor editing', 'Disease', 'MESH:D009369', (91, 104))
503580	22927549	Therefore, we considered the possibility that there might be increased NK cell killing of MCA-induced sarcoma cells from RAG2-/-x gammac-/- versus RAG2-/- or WT mice.	('mice', 'Species', '10090', (161, 165))	('increased', 'PosReg', (61, 70))	('NK cell killing', 'CPA', (71, 86))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('MCA-induced', 'Disease', (90, 101))	('sarcoma', 'Disease', (102, 109))	('RAG2-/-x', 'Var', (121, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('MCA', 'Chemical', 'MESH:D008748', (90, 93))
503591	22927549	Other studies have implicated calreticulin exposure as a key initiator of innate immune responses to tumor cells, leading to antigen presentation and productive adaptive antitumor responses, and the blockade of these pathways could be a mechanism of tumor escape.	('tumor', 'Disease', (174, 179))	('leading', 'PosReg', (114, 121))	('calreticulin', 'Gene', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (250, 255))	('blockade', 'Var', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('antigen presentation', 'MPA', (125, 145))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('productive', 'PosReg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('calreticulin', 'Gene', '12317', (30, 42))
503601	22927549	In brief, cohorts of C57BL/6-strain WT (Taconic), RAG2-/-, RAG1-/-, and RAG2-/-x gammac-/- mice were injected with MCA dissolved in peanut oil at various doses.	('mice', 'Species', '10090', (91, 95))	('RAG1', 'Gene', (59, 63))	('MCA', 'Chemical', 'MESH:D008748', (115, 118))	('C57BL/6-strain', 'Var', (21, 35))	('peanut', 'Species', '3818', (132, 138))	('RAG1', 'Gene', '19373', (59, 63))
503613	22927549	Microsatellite analysis confirmed that these mice were virtually congenic at the NK-C locus and contained ~22 cM of C57BL/6 sequence encompassing the following genes/markers: D6MIT261, D6MIT105, D6MIT018, D6MIT111, Nkrp1a, Nkrp1c, CD69, Nkg2d, Nkg2a, and Ly49a.	('Ly49a', 'Gene', '16627', (255, 260))	('mice', 'Species', '10090', (45, 49))	('Nkrp1c', 'Gene', '17059', (223, 229))	('Nkg2a', 'Gene', '16641', (244, 249))	('D6MIT105', 'Gene', (185, 193))	('Nkrp1a', 'Gene', '17057', (215, 221))	('Nkg2d', 'Gene', '27007', (237, 242))	('D6MIT018', 'Var', (195, 203))	('CD69', 'Gene', (231, 235))	('MIT261', 'CellLine', 'CVCL:D526', (177, 183))	('D6MIT105', 'Gene', '61437', (185, 193))	('Nkg2d', 'Gene', (237, 242))	('D6MIT261', 'Var', (175, 183))	('CD69', 'Gene', '12515', (231, 235))	('Nkg2a', 'Gene', (244, 249))	('Nkrp1a', 'Gene', (215, 221))	('Nkrp1c', 'Gene', (223, 229))	('D6MIT111', 'Var', (205, 213))	('Ly49a', 'Gene', (255, 260))
503623	22927549	with 200 microg of either control hamster IgG (PIP), anti-NK1.1 (PK136), or anti-IFN-gamma (H22) on days -2 and 0 and every 4 d after until tumor harvest.	('NK1.1', 'Gene', '17059', (58, 63))	('PIP', 'Gene', '18716', (47, 50))	('NK1.1', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('anti-IFN-gamma', 'Var', (76, 90))	('PIP', 'Gene', (47, 50))	('hamster', 'Species', '10034', (34, 41))	('tumor', 'Disease', (140, 145))
503671	22690347	In addition, nodules of malignant hepatoid tumour were admixed with the undifferentiated areas (Figure 3(d)) and stained positively for HepPar-1, polyclonal carcinomembryonic antigen, and AE1/AE3.	('AE1', 'Gene', '6521', (188, 191))	('AE1', 'Gene', (188, 191))	('polyclonal', 'Var', (146, 156))	('malignant hepatoid tumour', 'Disease', (24, 49))	('AE3', 'Gene', '6508', (192, 195))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('AE3', 'Gene', (192, 195))	('malignant hepatoid tumour', 'Disease', 'MESH:D009369', (24, 49))	('HepPar-1', 'Protein', (136, 144))
503814	33393133	Prior studies have suggested that the pharmacokinetic properties of liposomal doxorubicin confer a higher drug concentration in the endothelial venules and therefore efficacy in AS.	('AS', 'Gene', '112935892', (178, 180))	('higher', 'PosReg', (99, 105))	('doxorubicin', 'Chemical', 'MESH:D004317', (78, 89))	('AS', 'Phenotype', 'HP:0200058', (178, 180))	('liposomal', 'Var', (68, 77))	('drug concentration in the endothelial venules', 'MPA', (106, 151))	('pharmacokinetic', 'MPA', (38, 53))
503842	26994145	Thirty patients (51% of total) had clinically actionable mutations, of which 24 (41%) had a mutation that was currently targetable in a clinical trial setting, 4 patients (7%) had a change in diagnosis, and 7 patients (12%) had a reportable germline mutation.	('patients', 'Species', '9606', (162, 170))	('change', 'Reg', (182, 188))	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (7, 15))
503843	26994145	We found a remarkably high number of clinically actionable mutations in 51% of the patients, and 12% with significant germline mutations.	('patients', 'Species', '9606', (83, 91))	('mutations', 'Var', (59, 68))	('actionable', 'Reg', (48, 58))
503848	26994145	Given the need for improved therapeutic strategies for these patients, we undertook a study to determine the utility and feasibility of performing comprehensive genomic analyses to identify clinically actionable mutations in pediatric and young adult patients with refractory or relapsed solid tumors.	('solid tumors', 'Disease', (288, 300))	('solid tumors', 'Disease', 'MESH:D009369', (288, 300))	('patients', 'Species', '9606', (61, 69))	('refractory', 'Disease', (265, 275))	('patients', 'Species', '9606', (251, 259))	('mutations', 'Var', (212, 221))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
503850	26994145	For example, the presence of the PAX3-FOXO1 fusion in rhabdomyosarcoma not only contributes the diagnosis of fusion-positive rhabdomyosarcoma, but also imparts a poorer prognosis.	('PAX3', 'Gene', '5077', (33, 37))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (125, 141))	('fusion', 'Var', (44, 50))	('PAX3', 'Gene', (33, 37))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (54, 70))	('rhabdomyosarcoma', 'Disease', (54, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('FOXO1', 'Gene', '2308', (38, 43))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (125, 141))	('FOXO1', 'Gene', (38, 43))	('contributes', 'PosReg', (80, 91))	('presence', 'Var', (17, 25))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (54, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('rhabdomyosarcoma', 'Disease', (125, 141))
503861	26994145	We defined actionable mutations as: 1) a reportable germline mutation including nonsense or frameshift indels of a cancer consensus gene or pathogenic or likely pathogenic mutation of an American College of Medical Genetics (ACMG) gene, 2) genomics alterations that changed the patient's diagnosis, or 3) a somatic event (including single nucleotide variant, indel, amplification, deletion, or a fusion gene), which may be targeted and patient treated with FDA approved drugs or in the context of existing clinical trials according to the NCI-adult MATCH- Criteria (Supplementary Table 1).	('single nucleotide variant', 'Var', (332, 357))	('indel', 'Var', (359, 364))	('changed', 'Reg', (266, 273))	('patient', 'Species', '9606', (436, 443))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer consensus', 'Disease', 'MESH:D009369', (115, 131))	('deletion', 'Var', (381, 389))	('amplification', 'Var', (366, 379))	('patient', 'Species', '9606', (278, 285))	('cancer consensus', 'Disease', (115, 131))	('frameshift indels', 'Var', (92, 109))
503862	26994145	All actionable mutations for which clinical decisions were made the mutations were validated with the same tumor from the pathology laboratory and the sequencing was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.	('mutations', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))
503873	26994145	The number of somatic point mutations differed by diagnosis: metastatic melanoma had the highest number of somatic variants per sample, while atypical teratoid rhabdoid tumors and fusion gene-driven cancers had the lowest number of SNVs per sample, similar to what has been described in the literature (Fig.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('melanoma', 'Disease', (72, 80))	('teratoid rhabdoid tumors', 'Disease', 'MESH:C000597569', (151, 175))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('variants', 'Var', (115, 123))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('teratoid rhabdoid tumors', 'Disease', (151, 175))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancers', 'Disease', (199, 206))
503874	26994145	In keeping with previous genomics studies of relapsed pediatric cancers by our group and others, mutations increased with respect to tumor time (Fig.	('mutations', 'Var', (97, 106))	('pediatric cancers', 'Disease', (54, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('increased', 'PosReg', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('pediatric cancers', 'Disease', 'MESH:D009369', (54, 71))
503876	26994145	For Ewing sarcoma, we previously reported an average mutation rate of 6-7 somatic protein altering mutations per tumor, whereas in our current study with relapsed samples, we found approximately 3 times the rate with an average somatic protein altering mutation rate of 15.	('tumor', 'Disease', (113, 118))	('Ewing sarcoma', 'Disease', (4, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('altering', 'Reg', (90, 98))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (4, 17))
503878	26994145	The somatic SNVs were enriched for cancer pathways including signaling, transcription factors, splicing, DNA repair and epigenetic modifiers.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('epigenetic', 'Var', (120, 130))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))
503879	26994145	As expected from the demographics of children and AYA patients seen at the POB, who were primarily diagnosed with sarcomas, 26 (44%) of the patient's tumors had gene fusions.	('patient', 'Species', '9606', (54, 61))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('patients', 'Species', '9606', (54, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('patient', 'Species', '9606', (140, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', (114, 122))	('children', 'Species', '9606', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('gene fusions', 'Var', (161, 173))
503880	26994145	In the germline, 12 patients (20%) had nonsense or frameshift indels of cancer genes, with one patient harboring a non-frameshift 2 base substitution, and an additional 5 patients with rare non-synonymous SNVs.	('patient', 'Species', '9606', (95, 102))	('patient', 'Species', '9606', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('nonsense', 'Var', (39, 47))	('patients', 'Species', '9606', (171, 179))	('frameshift indels', 'Var', (51, 68))	('patient', 'Species', '9606', (20, 27))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
503883	26994145	In an adolescent patient with melanoma (NCI0072), we discovered a germline frameshift mutation in ATM, but interestingly, this patient's tumor had only one detected somatic alteration of BRAF (V600E), which is a known driver mutation.	('tumor', 'Disease', (137, 142))	('patient', 'Species', '9606', (127, 134))	('BRAF', 'Gene', '673', (187, 191))	('V600E', 'Mutation', 'rs113488022', (193, 198))	('patient', 'Species', '9606', (17, 24))	('ATM', 'Gene', (98, 101))	('frameshift mutation', 'Var', (75, 94))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('melanoma', 'Disease', (30, 38))	('ATM', 'Gene', '472', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('BRAF', 'Gene', (187, 191))
503885	26994145	Although neither of these germline mutations alone was considered reportable by ACMG guidelines because these are variants of unknown significance, the mutation found in the TSC2 gene (T246A; see Table 1) is reported as a Human Gene Mutation Database (HGMD) disease-causing mutation (CM087814).	('Human', 'Species', '9606', (222, 227))	('T246A', 'Mutation', 'rs137854123', (185, 190))	('HGMD', 'Disease', 'None', (252, 256))	('TSC2', 'Gene', (174, 178))	('HGMD', 'Disease', (252, 256))	('T246A', 'Var', (185, 190))	('TSC2', 'Gene', '7249', (174, 178))	('mutation', 'Var', (152, 160))
503886	26994145	Our results indicate that children with melanomas who have germline mutation have a low somatic burden compared with the high mutational burden seen in adult melanomas.	('melanomas', 'Disease', (40, 49))	('low', 'NegReg', (84, 87))	('adult melanomas', 'Disease', (152, 167))	('melanomas', 'Disease', (158, 167))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('somatic burden', 'MPA', (88, 102))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('germline mutation', 'Var', (59, 76))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('adult melanomas', 'Disease', 'MESH:D008545', (152, 167))	('children', 'Species', '9606', (26, 34))	('melanomas', 'Phenotype', 'HP:0002861', (158, 167))	('melanomas', 'Disease', 'MESH:D008545', (158, 167))
503887	26994145	Two patients (NCI0152, and NCI0226) had germline TP53 mutations, and had loss of heterozygosity (LOH) with complete loss of the wild type allele in the tumor, rendering the mutations likely pathogenic and reportable.	('loss', 'NegReg', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('TP53', 'Gene', '7157', (49, 53))	('NCI0152', 'CellLine', 'CVCL:8B52', (14, 21))	('TP53', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', (152, 157))	('patients', 'Species', '9606', (4, 12))	('heterozygosity', 'MPA', (81, 95))
503889	26994145	The remaining ACMG reportable mutations were found in a patient with neuroblastoma (NCI0010) that had frameshift mutations in two cancer predisposition genes: BRCA1 (ovarian and breast cancer) and PMS2 (Lynch syndrome and mismatch repair cancer syndrome).	('cancer syndrome', 'Disease', 'MESH:D009369', (238, 253))	('frameshift mutations', 'Var', (102, 122))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (166, 191))	('Lynch syndrome', 'Disease', (203, 217))	('PMS2', 'Gene', (197, 201))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', (238, 244))	('cancer syndrome', 'Disease', (238, 253))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('patient', 'Species', '9606', (56, 63))	('neuroblastoma', 'Disease', (69, 82))	('Lynch syndrome', 'Disease', 'MESH:D003123', (203, 217))	('neuroblastoma', 'Phenotype', 'HP:0003006', (69, 82))	('BRCA1', 'Gene', '672', (159, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('mutations', 'Var', (30, 39))	('neuroblastoma', 'Disease', 'MESH:D009447', (69, 82))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('BRCA1', 'Gene', (159, 164))	('PMS2', 'Gene', '5395', (197, 201))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
503890	26994145	Another patient with a neuroendocrine tumor (NET) had a frame shift mutation in PTEN (R14fs) which is associated with hamartoma tumor syndromes.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('PTEN', 'Gene', (80, 84))	('neuroendocrine tumor', 'Disease', (23, 43))	('PTEN', 'Gene', '5728', (80, 84))	('R14fs', 'Mutation', 'rs587776671', (86, 91))	('hamartoma tumor', 'Disease', 'MESH:D006222', (118, 133))	('hamartoma tumor', 'Disease', (118, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('hamartoma', 'Phenotype', 'HP:0010566', (118, 127))	('frame shift mutation', 'Var', (56, 76))	('patient', 'Species', '9606', (8, 15))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (23, 43))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (23, 43))
503892	26994145	In summary, we report 7/59 (12%) patients with reportable germline mutations, which is considerably higher than the 2-4% in expected incidental findings, but corresponds to a similar rate described in recently published reports in germline mutations for both cancer predisposition genes in pediatric cancer and in whole exome sequencing of trios across clinical indications.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('patients', 'Species', '9606', (33, 41))	('pediatric cancer', 'Disease', (290, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('germline mutations', 'Var', (58, 76))	('pediatric cancer', 'Disease', 'MESH:D009369', (290, 306))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (300, 306))	('cancer', 'Disease', (259, 265))
503902	26994145	Instead, we identified a germline TP53 (p.R175H) mutation.	('p.R175H', 'Var', (40, 47))	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))	('p.R175H', 'Mutation', 'rs28934578', (40, 47))
503908	26994145	Of note, two of these patients had germline mutations in TSC1 and TSC2 (NCI0211), and RET (NCI0228) that would make them eligible for the NCI Adult-MATCH trial; as germline DNA is not currently sequenced on their study, and it is not possible to distinguish germline from somatic mutations if only the tumor DNA is sequenced.	('RET', 'Gene', '5979', (86, 89))	('TSC2', 'Gene', '7249', (66, 70))	('TSC1', 'Gene', '7248', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('TSC1', 'Gene', (57, 61))	('TSC2', 'Gene', (66, 70))	('tumor', 'Disease', (302, 307))	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (44, 53))	('RET', 'Gene', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
503916	26994145	The development of new mutations during tumor progression has been previously reported by our group, where we showed that RAS pathway mutations were enriched for in the relapsed setting, and that many of these mutations were not present in diagnostic samples, indicating tumor evolution or selection during tumor progression.	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (271, 276))	('RAS pathway', 'Pathway', (122, 133))	('tumor', 'Disease', (307, 312))	('mutations', 'Var', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (271, 276))
503917	26994145	Similarly, in our study, there was one notable example (NCI0167), who presented with a refractory Ewing sarcoma lung metastasis, which was fully resected and found to have two likely driver mutations, an EWSR1-FLI1 fusion and a PIK3CA (p.D1017G) somatic mutation.	('FLI1', 'Gene', (210, 214))	('Ewing sarcoma lung metastasis', 'Disease', (98, 127))	('FLI1', 'Gene', '2313', (210, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('Ewing sarcoma lung metastasis', 'Disease', 'MESH:C563168', (98, 127))	('EWSR1', 'Gene', (204, 209))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (98, 111))	('EWSR1', 'Gene', '2130', (204, 209))	('p.D1017G', 'Mutation', 'rs762414334', (236, 244))	('p.D1017G', 'Var', (236, 244))	('PIK3CA', 'Gene', (228, 234))	('PIK3CA', 'Gene', '5290', (228, 234))
503927	26994145	In addition, WTS and WES showed that both relapsed tumors acquired a secondary mutation in the ALK coding region, c.T3512C, p.I1171T (Supplementary Fig.	('p.I1171T', 'Mutation', 'rs1057519698', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ALK', 'Gene', (95, 98))	('c.T3512C', 'Mutation', 'c.3512T>C', (114, 122))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('ALK', 'Gene', '238', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('c.T3512C', 'Var', (114, 122))	('p.I1171T', 'Var', (124, 132))
503928	26994145	Both the fusion gene and the ALK c.T3512C mutation was confirmed by RT-PCR and Sanger sequencing.	('c.T3512C', 'Mutation', 'c.3512T>C', (33, 41))	('ALK', 'Gene', (29, 32))	('c.T3512C', 'Var', (33, 41))	('ALK', 'Gene', '238', (29, 32))
503932	26994145	A liver metastasis taken post-ceritinib treatment contained the same ALK mutation (c.T3512C) but no other somatic mutations were identified that could be implicated in the relapse.	('c.T3512C', 'Mutation', 'c.3512T>C', (83, 91))	('ALK', 'Gene', '238', (69, 72))	('c.T3512C', 'Var', (83, 91))	('ALK', 'Gene', (69, 72))	('ceritinib', 'Chemical', 'MESH:C586847', (30, 39))
503944	26994145	Our results are in accordance with a recent pediatric study which reported that 8.5% of children with cancer have pathogenic or likely pathogenic germline mutations.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('germline mutations', 'Var', (146, 164))	('pathogenic', 'Reg', (114, 124))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('children', 'Species', '9606', (88, 96))
503948	26994145	In this study we found, in keeping with two recent studies in neuroblastoma, refractory or relapsed pediatric cancers not only have an increased number of mutations but also contain a higher percentage of actionable somatic mutations, coming close to the number found in adult cancers at diagnosis.	('mutations', 'Var', (155, 164))	('neuroblastoma', 'Phenotype', 'HP:0003006', (62, 75))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('adult cancers', 'Disease', (271, 284))	('adult cancers', 'Disease', 'MESH:C535836', (271, 284))	('pediatric cancers', 'Disease', 'MESH:D009369', (100, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('pediatric cancers', 'Disease', (100, 117))	('neuroblastoma', 'Disease', 'MESH:D009447', (62, 75))	('refractory', 'Disease', (77, 87))	('neuroblastoma', 'Disease', (62, 75))
503951	26994145	Furthermore, we found a total of 40 clinically actionable mutations in 30 patients (51% of total), including germline findings, changes in diagnosis, and possible application of targeted therapy.	('actionable', 'Reg', (47, 57))	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (74, 82))
503953	26994145	We show here that the use of WES as part of a comprehensive multi-omics platform allows for the detection of unexpected actionable germline and somatic tumor mutations which may be missed if panel sequencing or single-omics platforms are utilized.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))
503957	26994145	BRAF V600E and vemurafenib).	('V600E', 'Mutation', 'rs113488022', (5, 10))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('vemurafenib', 'Chemical', 'MESH:D000077484', (15, 26))
503960	26994145	The actionability of the germline mutations in TSC1 and TSC2 (NCI0211; malignant melanoma) is controversial.	('TSC1', 'Gene', '7248', (47, 51))	('TSC2', 'Gene', '7249', (56, 60))	('TSC1', 'Gene', (47, 51))	('TSC2', 'Gene', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('germline mutations', 'Var', (25, 43))	('malignant melanoma', 'Phenotype', 'HP:0002861', (71, 89))	('malignant melanoma', 'Disease', 'MESH:D008545', (71, 89))	('malignant melanoma', 'Disease', (71, 89))
503961	26994145	In the setting of a congenital melanoma with a low somatic mutational burden and no other actionable mutations, combined with predicted damaging germline mutations in two TSC genes, in which one (TSC2), was reported as a causal mutation in HGMD (CM087814, we concluded this would be considered actionable.	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('TSC', 'Gene', (171, 174))	('TSC', 'Gene', (196, 199))	('HGMD', 'Disease', (240, 244))	('HGMD', 'Disease', 'None', (240, 244))	('TSC', 'Gene', '7248;7249', (171, 174))	('congenital melanoma', 'Disease', (20, 39))	('congenital melanoma', 'Disease', 'MESH:D008545', (20, 39))	('CM087814', 'Var', (246, 254))	('TSC2', 'Gene', '7249', (196, 200))	('TSC2', 'Gene', (196, 200))	('TSC', 'Gene', '7248;7249', (196, 199))
503975	26852677	Therefore, we focused on the biological effects and the enhancement of drug effects brought by this low-intensity ultrasound energy and reported on the efficacy against a uterine sarcoma model, by implementing the basic studies, for the first time, including the concomitant use of low-intensity ultrasound irradiation, as an expected new antiangiogenic therapy for cancer treatment.	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('low-intensity', 'Var', (100, 113))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Disease', (366, 372))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (171, 186))	('enhancement of drug effects', 'Phenotype', 'HP:0020173', (56, 83))	('sarcoma', 'Disease', 'MESH:D012509', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('sarcoma', 'Disease', (179, 186))
504029	26852677	Although surgical resection or panhysterectomy using a laser scalpel is currently common for in situ carcinomas and microinvasive cancer, modifying the current vaginal probe for diagnosis may make it possible to irradiate the uterine cervix within the scope of sufficient ultrasound.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('situ carcinomas', 'Disease', 'MESH:D002278', (96, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('situ carcinomas', 'Disease', (96, 111))	('modifying', 'Var', (138, 147))	('uterine cervix', 'Phenotype', 'HP:0030160', (226, 240))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
504037	33076370	SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line As most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies.	('Knockout', 'Var', (5, 13))	('Chondrosarcoma', 'Phenotype', 'HP:0006765', (92, 106))	('SOX9', 'Gene', '6662', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('Chondrosarcoma', 'Disease', 'MESH:D002813', (92, 106))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (184, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (318, 325))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (311, 325))	('Changes', 'Reg', (37, 44))	('SOX9', 'Gene', (250, 254))	('Polyploidy', 'Disease', (22, 32))	('Chondrosarcoma', 'Disease', (92, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Tumor', 'Phenotype', 'HP:0002664', (60, 65))	('SOX9', 'Gene', (0, 4))	('SOX9', 'Gene', '6662', (250, 254))	('chondrosarcoma', 'Disease', (184, 198))	('chondrosarcoma', 'Disease', 'MESH:D002813', (184, 198))	('Polyploidy', 'Disease', 'MESH:D011123', (22, 32))	('chondrosarcoma', 'Disease', 'MESH:D002813', (311, 325))	('Induces', 'Reg', (14, 21))	('chondrosarcoma', 'Disease', (311, 325))
504040	33076370	CRISPR/Cas9-mediated knockout of SOX9 in a human chondrosarcoma cell line (HTB94) results in reduced proliferation, clonogenicity and migration, accompanied by an inability to activate MMP13.	('HTB94', 'CellLine', 'CVCL:1S02', (75, 80))	('chondrosarcoma', 'Disease', 'MESH:D002813', (49, 63))	('rat', 'Species', '10116', (108, 111))	('chondrosarcoma', 'Disease', (49, 63))	('reduced', 'NegReg', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('proliferation', 'CPA', (101, 114))	('rat', 'Species', '10116', (137, 140))	('knockout', 'Var', (21, 29))	('MMP13', 'Gene', (185, 190))	('migration', 'CPA', (134, 143))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (49, 63))	('MMP13', 'Gene', '4322', (185, 190))	('SOX9', 'Gene', (33, 37))	('clonogenicity', 'CPA', (116, 129))	('human', 'Species', '9606', (43, 48))
504041	33076370	In contrast, adhesion, apoptosis and polyploidy formation are favored after SOX9 deletion, probably involving BCL2 and survivin.	('BCL2', 'Gene', '596', (110, 114))	('favored', 'PosReg', (62, 69))	('apoptosis', 'CPA', (23, 32))	('deletion', 'Var', (81, 89))	('BCL2', 'Gene', (110, 114))	('SOX9', 'Gene', (76, 80))	('polyploidy', 'Disease', (37, 47))	('adhesion', 'CPA', (13, 21))	('polyploidy', 'Disease', 'MESH:D011123', (37, 47))
504058	33076370	The latest studies emphasize the direct crosstalk between SOX9 and a mutation of isocitrate dehydrogenase (IDH) 1.	('crosstalk', 'Reg', (40, 49))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (81, 113))	('mutation', 'Var', (69, 77))
504059	33076370	IDH1 mutations are found in ~50% of all chondrosarcoma patients and are involved in malignant transformation.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (40, 54))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (55, 63))	('involved', 'Reg', (72, 80))	('chondrosarcoma', 'Disease', 'MESH:D002813', (40, 54))	('IDH1', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('chondrosarcoma', 'Disease', (40, 54))	('IDH1', 'Gene', '3417', (0, 4))
504062	33076370	The analysis of chondrosarcoma cells after the knockdown and knockout of SOX9 was performed to determine the subsequent molecular impact on the carcinogenic properties, downstream targets of SOX9 and therapeutic resistance mechanisms.	('SOX9', 'Gene', (73, 77))	('carcinogenic', 'Disease', 'MESH:D063646', (144, 156))	('knockout', 'Var', (61, 69))	('carcinogenic', 'Disease', (144, 156))	('chondrosarcoma', 'Disease', 'MESH:D002813', (16, 30))	('chondrosarcoma', 'Disease', (16, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (16, 30))
504073	33076370	According to the data shown in Figure 1, we assumed an important role for SOX9 in tumor development, progression and differentiation/dedifferentiation status, and we hypothesized that the reduction or depletion of SOX9 potentially influences cancerogenic characteristics in chondrosarcoma.	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (274, 288))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('chondrosarcoma', 'Disease', (274, 288))	('reduction', 'NegReg', (188, 197))	('depletion', 'Var', (201, 210))	('SOX9', 'Gene', (214, 218))	('tumor', 'Disease', (82, 87))	('chondrosarcoma', 'Disease', 'MESH:D002813', (274, 288))	('influences', 'Reg', (231, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))
504076	33076370	Two single-cell-derived colonies (clones 8 and 11) with complete SOX9 knockout were selected and sequenced (Supplementary Figure S3B) to verify the generated mutations.	('SOX9', 'Gene', (65, 69))	('knockout', 'Var', (70, 78))	('rat', 'Species', '10116', (152, 155))
504088	33076370	Whereas SOX9 knockdown cells did not show a significant difference in migration compared to control cells (Figure 4A), SOX9 knockout clone 8 and 11 left a significantly wider gap in the cell layer one day after scratch introduction, indicating a reduced migration rate when Sox9 was depleted (Figure 4B).	('rat', 'Species', '10116', (257, 260))	('reduced', 'NegReg', (246, 253))	('rat', 'Species', '10116', (213, 216))	('migration rate', 'CPA', (254, 268))	('knockout', 'Var', (124, 132))	('rat', 'Species', '10116', (264, 267))	('rat', 'Species', '10116', (73, 76))	('SOX9', 'Gene', (119, 123))
504102	33076370	Infection with the oncolytic virus (T-VEC) revealed that SOX9 knockout clone 11 retained significantly more viable cells after T-VEC infection with an MOI (multiplicity of infection) of 10, and SOX9 knockout clone 8 showed the same result by trend (Figure 6C), implying a lower potential efficiency of this anticancer therapy in chondrosarcoma cells without SOX9 expression.	('Infection', 'Disease', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (329, 343))	('infection', 'Disease', (172, 181))	('cancer', 'Disease', (311, 317))	('T-VEC infection', 'Disease', 'MESH:D007239', (127, 142))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('infection', 'Disease', 'MESH:D007239', (172, 181))	('more', 'PosReg', (103, 107))	('T-VEC infection', 'Disease', (127, 142))	('knockout', 'Var', (62, 70))	('Infection', 'Disease', 'MESH:D007239', (0, 9))	('chondrosarcoma', 'Disease', (329, 343))	('chondrosarcoma', 'Disease', 'MESH:D002813', (329, 343))	('infection', 'Disease', (133, 142))	('SOX9', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('infection', 'Disease', 'MESH:D007239', (133, 142))
504103	33076370	Notably, stem cell homeostasis and the dysregulation of tissue differentiation pathways can critically contribute to the onset and progression of cancer.	('dysregulation', 'Var', (39, 52))	('cancer', 'Disease', (146, 152))	('tissue differentiation pathways', 'Pathway', (56, 87))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('stem cell homeostasis', 'CPA', (9, 30))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('contribute', 'Reg', (103, 113))
504116	33076370	One driver of this genetic stability and structural normality is probably SOX9, as the depletion of the transcription factor revealed a massive increase in the proportion of polyploid and aneuploid cells (super-4N) in our experiments.	('aneuploid', 'Disease', 'MESH:D000782', (188, 197))	('polyploid', 'Var', (174, 183))	('aneuploid', 'Disease', (188, 197))	('depletion', 'MPA', (87, 96))	('increase', 'PosReg', (144, 152))
504125	33076370	However, both SOX9 knockdown and knockout cells exhibit a strong increase in apoptosis, accompanied by a reduction of the anti-apoptosis mediator BCL-2 suggesting a potential direct connection between SOX9 and BCL-2 during chondrosarcoma progression to a dedifferentiated stage.	('increase', 'PosReg', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('chondrosarcoma', 'Disease', (223, 237))	('SOX9', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('apoptosis', 'MPA', (77, 86))	('BCL-2', 'Gene', (146, 151))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (223, 237))	('BCL-2', 'Gene', '596', (210, 215))	('BCL-2', 'Gene', '596', (146, 151))	('reduction', 'NegReg', (105, 114))	('BCL-2', 'Gene', (210, 215))	('chondrosarcoma', 'Disease', 'MESH:D002813', (223, 237))
504127	33076370	They reported that a transient siRNA-based SOX9 knockdown in a chordoma cell line leads to enhanced apoptotic activity.	('apoptotic activity', 'CPA', (100, 118))	('chordoma', 'Phenotype', 'HP:0010762', (63, 71))	('chordoma', 'Gene', '121775', (63, 71))	('enhanced', 'PosReg', (91, 99))	('chordoma', 'Gene', (63, 71))	('knockdown', 'Var', (48, 57))
504128	33076370	As the suppression of apoptosis by the acquisition of mutations is considered to be a hallmark of cancer, we concluded that SOX9 drives the accumulation of mutations, genetic and chromosomal modifications and thereby functions as a critical oncogene in chondrosarcoma cancer progression.	('chondrosarcoma cancer', 'Disease', (253, 274))	('cancer', 'Disease', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('SOX9', 'Gene', (124, 128))	('cancer', 'Disease', (98, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('chondrosarcoma cancer', 'Disease', 'MESH:D009369', (253, 274))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (253, 267))
504130	33076370	Our present results demonstrate that the knockdown and knockout of SOX9 in HTB94 cells drastically reduced the proliferation rate and hampered clonogenicity and migratory ability.	('hampered', 'NegReg', (134, 142))	('rat', 'Species', '10116', (125, 128))	('proliferation rate', 'CPA', (111, 129))	('rat', 'Species', '10116', (118, 121))	('knockout', 'Var', (55, 63))	('rat', 'Species', '10116', (27, 30))	('reduced', 'NegReg', (99, 106))	('rat', 'Species', '10116', (164, 167))	('HTB94', 'CellLine', 'CVCL:1S02', (75, 80))	('SOX9', 'Gene', (67, 71))
504137	33076370	Thus, cleaving type II collagen by MMP13 may favor invasion and motility potential in chondrosarcoma.	('MMP13', 'Gene', (35, 40))	('favor', 'PosReg', (45, 50))	('chondrosarcoma', 'Disease', (86, 100))	('chondrosarcoma', 'Disease', 'MESH:D002813', (86, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('motility potential', 'CPA', (64, 82))	('cleaving', 'Var', (6, 14))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (86, 100))	('MMP13', 'Gene', '4322', (35, 40))
504146	33076370	showed for intrahepatic cholangiocarcinoma cells, that SOX9 knockdown or knockout did not impact the efficiency of Cisplatin.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (11, 42))	('Cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('intrahepatic cholangiocarcinoma', 'Disease', (11, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('SOX9', 'Gene', (55, 59))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (24, 42))	('knockdown', 'Var', (60, 69))	('knockout', 'Var', (73, 81))
504151	33076370	Here, we provide results for the first time showing that the loss of SOX9 in chondrosarcoma cells increases the resistance against the oncolytic virus therapy using T-VEC (Talimogen laherparepvec).	('chondrosarcoma', 'Phenotype', 'HP:0006765', (77, 91))	('SOX9', 'Gene', (69, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('chondrosarcoma', 'Disease', (77, 91))	('chondrosarcoma', 'Disease', 'MESH:D002813', (77, 91))	('increases', 'PosReg', (98, 107))	('loss', 'Var', (61, 65))
504155	33076370	As we observed a clear difference in the proliferative behavior in the SOX9 knockout clones compared to the control chondrosarcoma cells, we assumed a potentially different sensitivity to oncolytic virus treatment.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('difference', 'Reg', (23, 33))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (116, 130))	('SOX9', 'Gene', (71, 75))	('proliferative behavior', 'CPA', (41, 63))	('different', 'Reg', (163, 172))	('chondrosarcoma', 'Disease', 'MESH:D002813', (116, 130))	('chondrosarcoma', 'Disease', (116, 130))	('knockout', 'Var', (76, 84))	('rat', 'Species', '10116', (48, 51))
504162	33076370	(GSE51588 , GSE1919 , GSE117999 , E-MTAB-5564 .	('GSE1919', 'Chemical', '-', (12, 19))	('GSE117999', 'Var', (22, 31))	('GSE51588', 'Var', (1, 9))	('E-MTAB', 'Chemical', '-', (34, 40))	('GSE1919', 'Var', (12, 19))
504178	33076370	After electrophoretic separation, the proteins were transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA, USA) and blocked with 5% dried milk (Carl Roth, Karlsruhe, Germany) and subsequently incubated with the following primary antibody for 16 h at 4  C or 1 h at room temperature: rabbit polyclonal anti-SOX9 (#AB5545, 1:2000; Merck, Darmstadt, Germany), rabbit polyclonal anti-Bcl-2 (#2872, 1:1000; Cell Signaling Technology (CST), Danvers, MA, USA), rabbit polyclonal anti-Survivin (#2808, 1:1000; Cell Signaling Technology (CST), Danvers, MA, USA).	('CS', 'Gene', '1431', (438, 440))	('Bcl-2', 'Gene', '596', (389, 394))	('Rad', 'Gene', '6236', (97, 100))	('rat', 'Species', '10116', (284, 287))	('Rad', 'Gene', (97, 100))	('Bcl-2', 'Gene', (389, 394))	('rat', 'Species', '10116', (26, 29))	('CS', 'Gene', '1431', (538, 540))	('#2808', 'Var', (496, 501))
504211	33076370	SOX9 knockout results in reduced proliferation, clonogenicity and migration, whereas adhesion, apoptosis and genetic instability were favored, involving cell survival mediators like BCL-2 and survivin.	('reduced', 'NegReg', (25, 32))	('migration', 'CPA', (66, 75))	('knockout', 'Var', (5, 13))	('SOX9', 'Gene', (0, 4))	('BCL-2', 'Gene', '596', (182, 187))	('apoptosis', 'CPA', (95, 104))	('rat', 'Species', '10116', (40, 43))	('clonogenicity', 'CPA', (48, 61))	('BCL-2', 'Gene', (182, 187))	('proliferation', 'CPA', (33, 46))	('favored', 'PosReg', (134, 141))	('genetic instability', 'CPA', (109, 128))	('rat', 'Species', '10116', (69, 72))	('adhesion', 'CPA', (85, 93))
504241	31676322	Other adverse prognostic variables include absence of skin lesions, multilineage involvement with KIT Asp816Val, mutations in genes other than KIT (eg, SRSF2, ASXL1, or RUNX1), increased amounts of beta2-microglobulin in serum, and raised amounts of alkaline phosphatase.	('ASXL1', 'Gene', (159, 164))	('skin lesions', 'Disease', (54, 66))	('KIT', 'Gene', '3815', (143, 146))	('mutations', 'Var', (113, 122))	('raised amounts of alkaline phosphatase', 'Phenotype', 'HP:0003155', (232, 270))	('beta2-microglobulin', 'Gene', '567', (198, 217))	('KIT', 'Gene', (98, 101))	('increased amounts of beta2-microglobulin', 'Phenotype', 'HP:0025346', (177, 217))	('beta2-microglobulin', 'Gene', (198, 217))	('Asp816Val', 'Var', (102, 111))	('RUNX1', 'Gene', (169, 174))	('SRSF2', 'Gene', '6427', (152, 157))	('RUNX1', 'Gene', '861', (169, 174))	('increased', 'PosReg', (177, 186))	('Asp816Val', 'SUBSTITUTION', 'None', (102, 111))	('KIT', 'Gene', (143, 146))	('SRSF2', 'Gene', (152, 157))	('amounts', 'MPA', (187, 194))	('ASXL1', 'Gene', '171023', (159, 164))	('absence of skin', 'Phenotype', 'HP:0001057', (43, 58))	('skin lesions', 'Disease', 'MESH:D012871', (54, 66))	('KIT', 'Gene', '3815', (98, 101))	('raised', 'PosReg', (232, 238))	('amounts of alkaline phosphatase', 'MPA', (239, 270))
504254	31676322	We excluded from the analysis of prognostic factors children (aged <17 years) with cutaneous mastocytosis because no bone marrow studies were available for most patients and because of the different disease biology of this group (in most patients, no KIT Asp816Val mutation is found).	('cutaneous mastocytosis', 'Phenotype', 'HP:0200151', (83, 105))	('mastocytosis', 'Phenotype', 'HP:0100495', (93, 105))	('Asp816Val', 'SUBSTITUTION', 'None', (255, 264))	('patients', 'Species', '9606', (238, 246))	('cutaneous mastocytosis', 'Disease', 'MESH:D034701', (83, 105))	('children', 'Species', '9606', (52, 60))	('Asp816Val', 'Var', (255, 264))	('patients', 'Species', '9606', (161, 169))	('KIT', 'Gene', '3815', (251, 254))	('cutaneous mastocytosis', 'Disease', (83, 105))	('KIT', 'Gene', (251, 254))
504255	31676322	We also excluded patients with mast cell sarcoma because of the rarity of the disease and its unique pathology and pathogenesis (usually KIT Asp816Val is not detectable in mast cell sarcoma).	('Asp816Val', 'SUBSTITUTION', 'None', (141, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('mast cell sarcoma', 'Disease', (172, 189))	('mast cell sarcoma', 'Disease', (31, 48))	('KIT', 'Gene', '3815', (137, 140))	('patients', 'Species', '9606', (17, 25))	('KIT', 'Gene', (137, 140))	('Asp816Val', 'Var', (141, 150))	('mast cell sarcoma', 'Disease', 'MESH:D012515', (172, 189))	('mast cell sarcoma', 'Disease', 'MESH:D012515', (31, 48))
504299	31676322	Significant differences were also observed in progression-free survival at 10 years: 96 3% (95% CI 92 2-98 3) in lowrisk patients, 86 7% (77 9-92 2) in int-1 patients, 76 3% (52 2-89 4) in int-2 patients, and 61 1% (42 0-75 6) in patients with advanced systemic mastocytosis (figure 3B).	('int-2', 'Gene', (189, 194))	('int-1', 'Gene', (152, 157))	('int-2', 'Gene', '2248', (189, 194))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (253, 274))	('systemic mastocytosis', 'Disease', (253, 274))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (195, 203))	('int-1', 'Gene', '7471', (152, 157))	('patients', 'Species', '9606', (158, 166))	('lowrisk', 'Var', (113, 120))	('patients', 'Species', '9606', (121, 129))	('mastocytosis', 'Phenotype', 'HP:0100495', (262, 274))
504305	31676322	Patients with scores from -1 to 0 points (no risk factors) were grouped in advanced systemic mastocytosis 1 (referred to as AdvSM-1), those with a score of 1 point (one risk factor) were in the advanced systemic mastocytosis 2 (AdvSM-2) group, individuals with scores of 2-3 points (two or three risk factors) were grouped in advanced systemic mastocytosis 3 (AdvSM-3), and patients with a score of 4 or 5 points (four or five risk factors) were included in the advanced systemic mastocytosis 4 (AdvSM-4) group.	('mastocytosis', 'Phenotype', 'HP:0100495', (93, 105))	('mastocytosis', 'Phenotype', 'HP:0100495', (344, 356))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (84, 105))	('systemic mastocytosis', 'Disease', (84, 105))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (335, 356))	('mastocytosis', 'Phenotype', 'HP:0100495', (480, 492))	('systemic mastocytosis', 'Disease', (335, 356))	('Patients', 'Species', '9606', (0, 8))	('scores', 'Var', (14, 20))	('patients', 'Species', '9606', (374, 382))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (203, 224))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (471, 492))	('mastocytosis', 'Phenotype', 'HP:0100495', (212, 224))	('systemic mastocytosis', 'Disease', (203, 224))	('systemic mastocytosis', 'Disease', (471, 492))
504306	31676322	Overall survival of patients in risk groups AdvSM-1 and AdvSM-2 was similar to that of patients with non-advanced mastocytosis in the int-1 and int-2 risk groups, respectively (figure 3C).	('int-2', 'Gene', (144, 149))	('AdvSM-2', 'Var', (56, 63))	('int-1', 'Gene', '7471', (134, 139))	('mastocytosis', 'Phenotype', 'HP:0100495', (114, 126))	('int-2', 'Gene', '2248', (144, 149))	('AdvSM-1', 'Var', (44, 51))	('patients', 'Species', '9606', (20, 28))	('int-1', 'Gene', (134, 139))	('mastocytosis', 'Disease', 'MESH:D008415', (114, 126))	('mastocytosis', 'Disease', (114, 126))	('patients', 'Species', '9606', (87, 95))
504352	31676322	Elevated beta2-microglobulin, multilineage involvement, the KIT Asp816Val allele burden, and mutations in additional genes are of prognostic importance.	('Asp816Val', 'Var', (64, 73))	('mutations', 'Var', (93, 102))	('beta2-microglobulin', 'Gene', '567', (9, 28))	('KIT', 'Gene', '3815', (60, 63))	('Elevated', 'PosReg', (0, 8))	('KIT', 'Gene', (60, 63))	('beta2-microglobulin', 'Gene', (9, 28))	('Asp816Val', 'SUBSTITUTION', 'None', (64, 73))	('Elevated beta2-microglobulin', 'Phenotype', 'HP:0025346', (0, 28))
504354	31676322	Moreover, KIT Asp816Val is often analysed by conventional PCR but not by quantitative PCR.	('Asp816Val', 'SUBSTITUTION', 'None', (14, 23))	('Asp816Val', 'Var', (14, 23))	('KIT', 'Gene', '3815', (10, 13))	('KIT', 'Gene', (10, 13))
504356	31676322	Moreover, molecular abnormalities are preferentially detected in patients who have advanced systemic mastocytosis, such as systemic mastocytosis with an associated haematological neoplasm, and are, therefore, not always WHO-independent variables.	('systemic mastocytosis', 'Disease', 'MESH:D034721', (92, 113))	('neoplasm', 'Phenotype', 'HP:0002664', (179, 187))	('mastocytosis', 'Phenotype', 'HP:0100495', (101, 113))	('systemic mastocytosis', 'Disease', (92, 113))	('mastocytosis', 'Phenotype', 'HP:0100495', (132, 144))	('haematological neoplasm', 'Disease', 'MESH:D019337', (164, 187))	('haematological neoplasm', 'Disease', (164, 187))	('molecular abnormalities', 'Var', (10, 33))	('detected', 'Reg', (53, 61))	('systemic mastocytosis', 'Disease', 'MESH:D034721', (123, 144))	('patients', 'Species', '9606', (65, 73))	('systemic mastocytosis', 'Disease', (123, 144))	('haematological neoplasm', 'Phenotype', 'HP:0004377', (164, 187))
504375	31676322	Several prognostic variables have been identified, including absence of skin lesions, multilineage involvement with KIT Asp816Val, mutations in genes other than KIT, raised amounts of beta2-microglobulin in serum, or increased alkaline phosphatase.	('skin lesions', 'Disease', (72, 84))	('mutations', 'Var', (131, 140))	('beta2-microglobulin', 'Gene', '567', (184, 203))	('Asp816Val', 'Var', (120, 129))	('skin lesions', 'Disease', 'MESH:D012871', (72, 84))	('absence of skin', 'Phenotype', 'HP:0001057', (61, 76))	('raised', 'PosReg', (166, 172))	('increased alkaline phosphatase', 'Phenotype', 'HP:0003155', (217, 247))	('alkaline phosphatase', 'MPA', (227, 247))	('raised amounts of beta2-microglobulin', 'Phenotype', 'HP:0025346', (166, 203))	('KIT', 'Gene', '3815', (116, 119))	('KIT', 'Gene', '3815', (161, 164))	('Asp816Val', 'SUBSTITUTION', 'None', (120, 129))	('beta2-microglobulin', 'Gene', (184, 203))	('KIT', 'Gene', (116, 119))	('KIT', 'Gene', (161, 164))	('increased', 'PosReg', (217, 226))
504382	31676322	In these scores, multilineage involvement of leukocytes with KIT Asp816Val, the KIT Asp816Val allele burden, or mutations in additional genes were included as prognostic variables.	('Asp816Val', 'Var', (84, 93))	('KIT', 'Gene', '3815', (80, 83))	('KIT', 'Gene', '3815', (61, 64))	('Asp816Val', 'SUBSTITUTION', 'None', (84, 93))	('KIT', 'Gene', (80, 83))	('Asp816Val', 'Var', (65, 74))	('KIT', 'Gene', (61, 64))	('Asp816Val', 'SUBSTITUTION', 'None', (65, 74))
504508	31214596	For instance, fibrosarcomas induced by 3-methylcholanthrene and UV-light induced sarcomas grow more rapidly in older animals compared to young animals and this may be related to an age-related decline in cytotoxic T-cell function.	('sarcomas', 'Disease', (81, 89))	('fibrosarcomas', 'Disease', 'MESH:D005354', (14, 27))	('3-methylcholanthrene', 'Var', (39, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('fibrosarcomas', 'Disease', (14, 27))	('sarcomas', 'Disease', 'MESH:D012509', (19, 27))	('3-methylcholanthrene', 'Chemical', 'MESH:D008748', (39, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('sarcomas', 'Disease', (19, 27))	('UV-light', 'Gene', (64, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
504522	30891023	N6-Methyladenosine and Viral Infection N6-methyladenosine (m6A), as a dynamic posttranscriptional RNA modification, recently gave rise to the field of viral epitranscriptomics.	('m6A', 'Gene', '56339', (59, 62))	('N6-Methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (39, 57))	('m6A', 'Gene', (59, 62))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (39, 57))
504526	30891023	The expression of viral genes, the replication of virus and the generation of progeny virions are influenced by m6A modifications in viral RNAs during virus infection.	('virus infection', 'Disease', 'MESH:D015658', (151, 166))	('expression', 'MPA', (4, 14))	('replication', 'CPA', (35, 46))	('m6A', 'Gene', (112, 115))	('influenced by', 'Reg', (98, 111))	('modifications', 'Var', (116, 129))	('virus infection', 'Disease', (151, 166))	('viral genes', 'Gene', (18, 29))	('m6A', 'Gene', '56339', (112, 115))
504527	30891023	Meanwhile, the decorations of m6A in host mRNAs can make viral infections more likely to happen or can enhance the resistance of host to virus infection.	('viral infections', 'Disease', (57, 73))	('viral infections', 'Disease', 'MESH:D001102', (57, 73))	('enhance', 'PosReg', (103, 110))	('decorations', 'Var', (15, 26))	('m6A', 'Gene', (30, 33))	('host to virus infection', 'Disease', 'MESH:D006086', (129, 152))	('resistance', 'CPA', (115, 125))	('m6A', 'Gene', '56339', (30, 33))	('host to virus infection', 'Disease', (129, 152))
504533	30891023	The most prevalent modification of internal messenger RNA in eukaryotes and in nuclear-replicating viruses is the addition of a methyl group to the N6 position of adenosine, known as m6A.	('addition', 'Var', (114, 122))	('m6A', 'Gene', (183, 186))	('adenosine', 'Chemical', 'MESH:D000241', (163, 172))	('m6A', 'Gene', '56339', (183, 186))	('internal messenger RNA', 'MPA', (35, 57))	('methyl group', 'MPA', (128, 140))
504539	30891023	m6A has been reported to control the fate of modified RNAs at multiple steps, including RNA splicing, mRNA stability, cap-independent translation, and miRNA biogenesis.	('m6A', 'Gene', '56339', (0, 3))	('modified', 'Var', (45, 53))	('control', 'Reg', (25, 32))	('m6A', 'Gene', (0, 3))	('mRNA stability', 'MPA', (102, 116))
504556	30891023	These researchers verified that m6A negatively regulated HCV infection by using m6A-abrogating mutations in HCV E1.	('m6A', 'Gene', (80, 83))	('HCV infection', 'Disease', (57, 70))	('m6A', 'Gene', (32, 35))	('HCV E1', 'Gene', (108, 114))	('HCV infection', 'Disease', 'MESH:D006526', (57, 70))	('m6A', 'Gene', '56339', (32, 35))	('mutations', 'Var', (95, 104))	('m6A', 'Gene', '56339', (80, 83))	('negatively', 'NegReg', (36, 46))
504562	30891023	As the core methyltransferase subunit, METTL3 is a strongly conserved protein and has been demonstrated to selectively methylate the GAC or AAC motifs in synthetic single-stranded RNA in vitro.	('METTL3', 'Gene', '56339', (39, 45))	('AAC', 'Var', (140, 143))	('METTL3', 'Gene', (39, 45))	('methylate', 'Var', (119, 128))
504566	30891023	As a regulatory subunit of the m6A methyltransferase complex, WTAP allows METTL3/METTL14 to interact with messenger RNAs in the nucleus to improve m6A modification efficiency.	('METTL3', 'Gene', (74, 80))	('improve', 'PosReg', (139, 146))	('METTL14', 'Gene', '57721', (81, 88))	('m6A', 'Gene', '56339', (147, 150))	('WTAP', 'Gene', '9589', (62, 66))	('m6A', 'Gene', '56339', (31, 34))	('WTAP', 'Gene', (62, 66))	('modification', 'Var', (151, 163))	('interact', 'Interaction', (92, 100))	('METTL14', 'Gene', (81, 88))	('m6A', 'Gene', (147, 150))	('m6A', 'Gene', (31, 34))	('METTL3', 'Gene', '56339', (74, 80))
504574	30891023	found that FTO could efficiently demethylate m6A in RNA in vitro.	('m6A', 'Gene', '56339', (45, 48))	('FTO', 'Gene', '79068', (11, 14))	('demethylate', 'Chemical', '-', (33, 44))	('FTO', 'Gene', (11, 14))	('demethylate', 'Var', (33, 44))	('m6A', 'Gene', (45, 48))
504575	30891023	They used siRNA mediated knockdown of FTO and then detected an increased level of m6A in mRNA, whereas the overexpression of FTO resulted in a decreased level of m6A in human HeLa cells.	('FTO', 'Gene', (125, 128))	('m6A', 'Gene', (162, 165))	('increased', 'PosReg', (63, 72))	('FTO', 'Gene', '79068', (38, 41))	('mRNA', 'MPA', (89, 93))	('HeLa', 'CellLine', 'CVCL:0030', (175, 179))	('level', 'MPA', (73, 78))	('m6A', 'Gene', (82, 85))	('m6A', 'Gene', '56339', (162, 165))	('FTO', 'Gene', '79068', (125, 128))	('human', 'Species', '9606', (169, 174))	('FTO', 'Gene', (38, 41))	('m6A', 'Gene', '56339', (82, 85))	('knockdown', 'Var', (25, 34))
504578	30891023	The function of m6A modification on target mRNAs is thought to be mediated by "reader" proteins.	('modification', 'Var', (20, 32))	('m6A', 'Gene', '56339', (16, 19))	('m6A', 'Gene', (16, 19))
504610	30891023	in both the IAV mRNA and vRNA strands, and it was demonstrated that m6A modification increases viral RNA expression in cis.	('IAV', 'Species', '11320', (12, 15))	('modification', 'Var', (72, 84))	('m6A', 'Gene', (68, 71))	('viral RNA expression', 'MPA', (95, 115))	('m6A', 'Gene', '56339', (68, 71))	('increases', 'PosReg', (85, 94))
504612	30891023	One method used a non-toxic dose of DAA treatment (an inhibitor of m6A addition), and the other used knockout of METTL3 through gene editing with CRISPR/Cas.	('knockout', 'Var', (101, 109))	('METTL3', 'Gene', (113, 119))	('m6A', 'Gene', (67, 70))	('DAA', 'Chemical', 'MESH:C018258', (36, 39))	('m6A', 'Gene', '56339', (67, 70))	('METTL3', 'Gene', '56339', (113, 119))
504615	30891023	Moreover, they used synonymous mutations to remove m6A on both strands of the hemagglutinin (HA) segment, and found that IAV HA m6A mutants revealed reduced pathogenicity in mice.	('m6A', 'Gene', (128, 131))	('mutations', 'Var', (31, 40))	('pathogenicity', 'MPA', (157, 170))	('m6A', 'Gene', '56339', (51, 54))	('mice', 'Species', '10090', (174, 178))	('m6A', 'Gene', '56339', (128, 131))	('mutants', 'Var', (132, 139))	('reduced', 'NegReg', (149, 156))	('IAV', 'Species', '11320', (121, 124))	('m6A', 'Gene', (51, 54))
504627	30891023	To further confirm this conclusion, mutations in the E1 gene of HCV to inactivate m6A modification were constructed marked as HCV-E1mut.	('m6A', 'Gene', '56339', (82, 85))	('m6A', 'Gene', (82, 85))	('mutations', 'Var', (36, 45))
504632	30891023	Like the role of m6A in regulating the HCV life cycle, the knockdown of host methyltransferases METTL3 and METTL14 increased ZIKV production while the silencing of demethylases ALKBH5 and FTO suppressed ZIKV production.	('ZIKV', 'Species', '64320', (203, 207))	('demethylase', 'Gene', (164, 175))	('suppressed', 'NegReg', (192, 202))	('ALKBH5', 'Gene', (177, 183))	('METTL3', 'Gene', '56339', (96, 102))	('demethylase', 'Gene', '8932', (164, 175))	('METTL14', 'Gene', (107, 114))	('knockdown', 'Var', (59, 68))	('silencing', 'Var', (151, 160))	('ALKBH5', 'Gene', '54890', (177, 183))	('increased', 'PosReg', (115, 124))	('ZIKV production', 'MPA', (203, 218))	('FTO', 'Gene', '79068', (188, 191))	('m6A', 'Gene', '56339', (17, 20))	('METTL3', 'Gene', (96, 102))	('ZIKV', 'Species', '64320', (125, 129))	('FTO', 'Gene', (188, 191))	('METTL14', 'Gene', '57721', (107, 114))	('m6A', 'Gene', (17, 20))	('ZIKV production', 'MPA', (125, 140))
504633	30891023	The difference was that the m6A machinery decreased HCV production by affecting the assembly of virus, yet m6A modification inhibited ZIKV production by impacting replication of ZIKV.	('ZIKV', 'Gene', (178, 182))	('m6A', 'Gene', (28, 31))	('impacting', 'NegReg', (153, 162))	('m6A', 'Gene', (107, 110))	('decreased', 'NegReg', (42, 51))	('modification', 'Var', (111, 123))	('ZIKV production', 'MPA', (134, 149))	('assembly of virus', 'MPA', (84, 101))	('m6A', 'Gene', '56339', (28, 31))	('ZIKV', 'Species', '64320', (178, 182))	('m6A', 'Gene', '56339', (107, 110))	('decreased HCV', 'Phenotype', 'HP:0025066', (42, 55))	('HCV production', 'MPA', (52, 66))	('replication', 'MPA', (163, 174))	('affecting', 'Reg', (70, 79))	('inhibited', 'NegReg', (124, 133))	('ZIKV', 'Species', '64320', (134, 138))
504639	30891023	The Cao group demonstrated in 2017 that knockdown of the m6A eraser ALKBH5 noticeably increased the production of type I interferons triggered by VSV infection.	('production of type I interferons', 'MPA', (100, 132))	('increased', 'PosReg', (86, 95))	('Cao', 'Chemical', 'MESH:C016538', (4, 7))	('VSV infection', 'Disease', 'MESH:D007239', (146, 159))	('knockdown', 'Var', (40, 49))	('ALKBH5', 'Gene', '54890', (68, 74))	('m6A', 'Gene', (57, 60))	('ALKBH5', 'Gene', (68, 74))	('m6A', 'Gene', '56339', (57, 60))	('VSV infection', 'Disease', (146, 159))
504640	30891023	This finding suggested that m6A modifications might play a negative role in the life cycle of VSV.	('m6A', 'Gene', (28, 31))	('life cycle', 'CPA', (80, 90))	('negative', 'NegReg', (59, 67))	('m6A', 'Gene', '56339', (28, 31))	('modifications', 'Var', (32, 45))	('VSV', 'Disease', (94, 97))
504643	30891023	In effect, elimination of the m6A modification suppressed the exportation of mRNA from the nucleus and induced retention of the mRNA encoding proteins in the nucleus such as those involved in circadian rhythm; this phenomenon was well verified in this article.	('suppressed', 'NegReg', (47, 57))	('retention', 'MPA', (111, 120))	('m6A', 'Gene', (30, 33))	('modification', 'Var', (34, 46))	('m6A', 'Gene', '56339', (30, 33))	('exportation of mRNA from the nucleus', 'MPA', (62, 98))
504647	30891023	The genomic copy numbers of EV71 RNA were significantly decreased by silencing METTL3 gene and increased by FTO gene depletion.	('METTL3', 'Gene', '56339', (79, 85))	('FTO', 'Gene', '79068', (108, 111))	('decreased', 'NegReg', (56, 65))	('EV71', 'Species', '39054', (28, 32))	('METTL3', 'Gene', (79, 85))	('depletion', 'Var', (117, 126))	('EV71 RNA', 'Gene', (28, 36))	('FTO', 'Gene', (108, 111))	('increased', 'PosReg', (95, 104))	('silencing', 'Var', (69, 78))
504648	30891023	When two m6A sites were mutated in the EV71 RNA, the virus titer was significantly decreased.	('EV71', 'Species', '39054', (39, 43))	('mutated', 'Var', (24, 31))	('m6A', 'Gene', (9, 12))	('virus titer', 'MPA', (53, 64))	('decreased', 'NegReg', (83, 92))	('m6A', 'Gene', '56339', (9, 12))
504655	30891023	During KSHV latent infection, most of the viral genome is suppressed through DNA methylation, repressive histone modifications and other regulatory mechanisms which negatively regulate gene expression.	('KS', 'Phenotype', 'HP:0100726', (7, 9))	('KSHV', 'Species', '37296', (7, 11))	('histone', 'Protein', (105, 112))	('suppressed', 'NegReg', (58, 68))	('DNA methylation', 'Var', (77, 92))	('KSHV', 'Gene', (7, 11))
504656	30891023	Three recent studies revealed that the KSHV life cycle was affected by RNA N6-adenosine methylation epigenetic modification.	('adenosine', 'Chemical', 'MESH:D000241', (78, 87))	('affected', 'Reg', (59, 67))	('KSHV', 'Species', '37296', (39, 43))	('KS', 'Phenotype', 'HP:0100726', (39, 41))	('methylation epigenetic modification', 'Var', (88, 123))	('KSHV life cycle', 'CPA', (39, 54))	('RNA', 'Var', (71, 74))
504677	30891023	The authors observed that the mutant virus replicated more slowly than wild type SV40 when they inactivated most of the m6A addition sites on the SV40 late mRNAs using synonymous mutations.	('SV40', 'Species', '1891767', (146, 150))	('inactivated', 'NegReg', (96, 107))	('SV40', 'Species', '1891767', (81, 85))	('replicated', 'MPA', (43, 53))	('m6A', 'Gene', (120, 123))	('slowly', 'NegReg', (59, 65))	('mutant', 'Var', (30, 36))	('m6A', 'Gene', '56339', (120, 123))
504718	30450193	Gain-of-function mutations in the growth factor receptor genes for KIT (CD117) and platelet-derived growth factor alpha (PDGFRA) drive tumor development in 85-90% of GISTs to promote constitutive activation of growth factor signaling pathways that cause uncontrolled cell proliferation.	('CD117', 'Gene', '3815', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('PDGFRA', 'Gene', (121, 127))	('CD117', 'Gene', (72, 77))	('PDGFRA', 'Gene', '5156', (121, 127))	('tumor', 'Disease', (135, 140))	('GISTs', 'Phenotype', 'HP:0100723', (166, 171))	('constitutive', 'MPA', (183, 195))	('promote', 'PosReg', (175, 182))	('Gain-of-function', 'PosReg', (0, 16))	('growth factor signaling pathways', 'Pathway', (210, 242))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
504727	30450193	The most common mutations found in untreated GISTs are in the juxtamembrane region, specifically in exon 11 (70%) and exon 9 (15%), with up to another 10% of primary mutations being found in PDGFRA .	('PDGFRA', 'Gene', (191, 197))	('GISTs', 'Phenotype', 'HP:0100723', (45, 50))	('PDGFRA', 'Gene', '5156', (191, 197))	('mutations', 'Var', (16, 25))
504728	30450193	The most common PDGFRA mutation is the D842V substitution in the activation loop of PDGFRA.	('D842V', 'Mutation', 'rs121908585', (39, 44))	('PDGFRA', 'Gene', '5156', (84, 90))	('PDGFRA', 'Gene', (84, 90))	('PDGFRA', 'Gene', '5156', (16, 22))	('D842V', 'Var', (39, 44))	('PDGFRA', 'Gene', (16, 22))
504729	30450193	Tumors harboring this mutation are refractory to nearly all available treatment options and are associated with poor outcomes with a short PFS of only 2.8 months with imatinib .	('mutation', 'Var', (22, 30))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('imatinib', 'Chemical', 'MESH:D000068877', (167, 175))
504731	30450193	Development of mutations in the ATP-binding pocket or activation loop decreases the drug's binding affinity, leading to TKI resistance.	('TKI', 'Disease', (120, 123))	('decreases', 'NegReg', (70, 79))	('mutations', 'Var', (15, 24))	('leading to', 'Reg', (109, 119))	('binding', 'Interaction', (91, 98))	('ATP', 'Chemical', 'MESH:D000255', (32, 35))
504732	30450193	The most commonly found secondary resistance mutations are encoded in exons 13 and 14 of the ATP-binding pocket and in exons 17 and 18 of the activation loop.	('mutations', 'Var', (45, 54))	('ATP', 'Chemical', 'MESH:D000255', (93, 96))	('secondary resistance', 'MPA', (24, 44))
504733	30450193	About 14% of tumors have primary resistance to imatinib (progression within the first 6 months of treatment), while in 40-50% of tumors secondary resistance due to acquired mutations in KIT or PDGFRA develops after about 2 years on imatinib treatment , .	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('secondary resistance', 'MPA', (136, 156))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('KIT', 'Gene', (186, 189))	('imatinib', 'Chemical', 'MESH:D000068877', (232, 240))	('mutations', 'Var', (173, 182))	('PDGFRA', 'Gene', '5156', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PDGFRA', 'Gene', (193, 199))	('imatinib', 'Chemical', 'MESH:D000068877', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('primary resistance to imatinib', 'MPA', (25, 55))
504736	30450193	Selection of agents based on the initiating and acquired resistance mutations in KIT and PDGFRA will hopefully expand systemic options beyond the three currently approved TKIs.	('mutations', 'Var', (68, 77))	('PDGFRA', 'Gene', '5156', (89, 95))	('PDGFRA', 'Gene', (89, 95))	('KIT', 'Gene', (81, 84))
504737	30450193	Currently, no approved treatment options are available for the highly resistant PDGFRA D842V exon 18 activation loop mutation.	('PDGFRA', 'Gene', (80, 86))	('D842V', 'Var', (87, 92))	('D842V', 'Mutation', 'rs121908585', (87, 92))	('PDGFRA', 'Gene', '5156', (80, 86))
504740	30450193	BLU-285, also known as avapritinib, and DCC-2618 are highly potent and selective inhibitors of mutant KIT and PDGFRA, with demonstrated activity against PDGFRA D842V mutations along with secondary KIT resistance mutations.	('BLU-285', 'Chemical', '-', (0, 7))	('avapritinib', 'Chemical', '-', (23, 34))	('PDGFRA', 'Gene', (110, 116))	('D842V mutations', 'Var', (160, 175))	('DCC-2618', 'Chemical', '-', (40, 48))	('PDGFRA', 'Gene', (153, 159))	('D842V', 'Mutation', 'rs121908585', (160, 165))	('PDGFRA', 'Gene', '5156', (110, 116))	('mutant', 'Var', (95, 101))	('PDGFRA', 'Gene', '5156', (153, 159))	('KIT', 'Gene', (102, 105))
504741	30450193	BLU-285 is a selective inhibitor of KIT and PDGFRA activation loop mutants .	('BLU-285', 'Chemical', '-', (0, 7))	('KIT', 'Gene', (36, 39))	('mutants', 'Var', (67, 74))	('PDGFRA', 'Gene', '5156', (44, 50))	('PDGFRA', 'Gene', (44, 50))
504742	30450193	While BLU-285 demonstrated strong activity against clinically relevant single mutations in either the activation loop or the ATP-binding pocket of KIT and PDGFRA, tumor sensitivity was increased in the setting of dual mutants of the juxtamembrane and ATP-binding pocket and protein regions (e.g.	('activity', 'MPA', (34, 42))	('BLU-285', 'Chemical', '-', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('PDGFRA', 'Gene', (155, 161))	('ATP', 'Chemical', 'MESH:D000255', (251, 254))	('PDGFRA', 'Gene', '5156', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (163, 168))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('KIT', 'Gene', (147, 150))	('increased', 'PosReg', (185, 194))
504743	30450193	In a phase I study of BLU-285, all 31 patients with D842V PDGFRA GISTs demonstrated a tumor response .	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('PDGFRA', 'Gene', (58, 64))	('GISTs', 'Phenotype', 'HP:0100723', (65, 70))	('D842V', 'Mutation', 'rs121908585', (52, 57))	('PDGFRA', 'Gene', '5156', (58, 64))	('tumor', 'Disease', (86, 91))	('D842V', 'Var', (52, 57))	('patients', 'Species', '9606', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('BLU-285', 'Chemical', '-', (22, 29))
504747	30450193	DCC-2618 showed partial metabolic response in 69% of patients with KIT or PDGFRA mutants .	('DCC-2618', 'Chemical', '-', (0, 8))	('patients', 'Species', '9606', (53, 61))	('KIT', 'Gene', (67, 70))	('partial', 'NegReg', (16, 23))	('mutants', 'Var', (81, 88))	('PDGFRA', 'Gene', '5156', (74, 80))	('PDGFRA', 'Gene', (74, 80))
504801	30450193	In TGCTs/PVNS, a translocation involving the colony-stimulating factor (CSF1) gene promotes proliferative inflammation of the synovium through the recruitment of tumor-associated macrophage cells expressing the CSF1 receptor (CSF1R) , .	('CSF1', 'Gene', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('CSF1', 'Gene', '1435', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('CSF1 receptor', 'Gene', (211, 224))	('CSF1R', 'Gene', '1436', (226, 231))	('translocation', 'Var', (17, 30))	('proliferative inflammation of the synovium', 'CPA', (92, 134))	('tumor', 'Disease', (162, 167))	('CSF1', 'Gene', '1435', (226, 230))	('inflammation of the synovium', 'Phenotype', 'HP:0100769', (106, 134))	('promotes', 'PosReg', (83, 91))	('CSF1R', 'Gene', (226, 231))	('CSF1', 'Gene', (226, 230))	('CSF1 receptor', 'Gene', '1436', (211, 224))	('CSF1', 'Gene', (72, 76))	('CSF1', 'Gene', '1435', (72, 76))
504813	30450193	These are being explored particularly in synovial and myxoid/round cell liposarcoma where >80% of tumors express the antigen (NCT03520959) - .	('liposarcoma', 'Phenotype', 'HP:0012034', (72, 83))	('liposarcoma', 'Disease', 'MESH:D008080', (72, 83))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NCT03520959) -', 'Var', (126, 140))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (54, 83))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('liposarcoma', 'Disease', (72, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))
504837	29996478	The WWTR1 gene encodes the Transcriptional Co-activator with a PDZ-motif (TAZ), and the fusion results in constitutive activation of the TAZ transcriptome, which, as detailed below, drives a transformed phenotype, resistance to anoikis, and increased colony formation in soft agar.	('increased', 'PosReg', (241, 250))	('WWTR1', 'Gene', '25937', (4, 9))	('drives', 'PosReg', (182, 188))	('activation', 'PosReg', (119, 129))	('TAZ transcriptome', 'Gene', (137, 154))	('resistance to anoikis', 'CPA', (214, 235))	('WWTR1', 'Gene', (4, 9))	('colony formation in soft agar', 'CPA', (251, 280))	('fusion', 'Var', (88, 94))	('transformed phenotype', 'CPA', (191, 212))
504839	29996478	Unregulated TAZ expression also contributes to metastasis in other, more common cancers.	('Unregulated', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('contributes to', 'Reg', (32, 46))	('metastasis', 'CPA', (47, 57))	('TAZ', 'Gene', (12, 15))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
504874	29996478	However, identification of the WWTR1-CAMTA1 and YAP-TFE3 fusions is diagnostic and gives clinicians a potentially targetable therapeutic marker.	('WWTR1', 'Gene', (31, 36))	('WWTR1', 'Gene', '25937', (31, 36))	('TFE3', 'Gene', '7030', (52, 56))	('YAP', 'Gene', (48, 51))	('fusions', 'Var', (57, 64))	('TFE3', 'Gene', (52, 56))	('YAP', 'Gene', '10413', (48, 51))
504882	29996478	The WWTR1-CAMATA1 gene fusion joins the amino terminus of WWTR1 with the carboxyl terminus of CAMTA1 and is under the transcriptional control of the WWTR1 promoter.	('WWTR1', 'Gene', '25937', (4, 9))	('WWTR1', 'Gene', (149, 154))	('fusion', 'Var', (23, 29))	('WWTR1', 'Gene', '25937', (149, 154))	('WWTR1', 'Gene', (4, 9))	('WWTR1', 'Gene', (58, 63))	('WWTR1', 'Gene', '25937', (58, 63))
504888	29996478	All variants identified to date contain the TEAD binding domain, 14-3-3 binding motif, and all or most of the WW domain of TAZ fused to the CAMTA1 transactivation domain (TAD), TIG domain, ankyrin repeats, and IQ domains.	('TEAD', 'Gene', (44, 48))	('TAZ', 'Gene', (123, 126))	('TEAD', 'Gene', '7003', (44, 48))	('variants', 'Var', (4, 12))
504892	29996478	Consistently, the fusion activates a TEAD-responsive transcriptional reporter construct.	('TEAD', 'Gene', (37, 41))	('fusion', 'Var', (18, 24))	('activates', 'PosReg', (25, 34))	('TEAD', 'Gene', '7003', (37, 41))
504893	29996478	Furthermore, the oncogenic properties of the fusion require TEAD binding since S51A mutation, which prevents TEADs from binding TAZ, prevented the fusion from promoting cellular transformation.	('prevented', 'NegReg', (133, 142))	('TEAD', 'Gene', (109, 113))	('promoting', 'PosReg', (159, 168))	('TEAD', 'Gene', (60, 64))	('S51A mutation', 'Var', (79, 92))	('TEAD', 'Gene', '7003', (109, 113))	('S51A', 'Mutation', 'p.S51A', (79, 83))	('TEAD', 'Gene', '7003', (60, 64))	('cellular transformation', 'CPA', (169, 192))
504897	29996478	Inappropriate TAZ transcriptional activation and/or Hippo pathway dysregulation drives tumor development, progression, and metastasis in many cancer types.	('drives', 'Reg', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('metastasis in many cancer', 'Disease', (123, 148))	('metastasis in many cancer', 'Disease', 'MESH:D009362', (123, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', (87, 92))	('progression', 'CPA', (106, 117))	('Hippo', 'Gene', (52, 57))	('dysregulation', 'Var', (66, 79))	('activation', 'PosReg', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('TAZ transcriptional', 'Gene', (14, 33))
504899	29996478	Indeed, aberrant YAP/TAZ activity can promote the formation and progression of osteosarcoma, rhabdomyosarcoma, and soft-tissue sarcomas.	('sarcomas', 'Disease', (127, 135))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (93, 109))	('aberrant', 'Var', (8, 16))	('YAP', 'Gene', '10413', (17, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('progression', 'CPA', (64, 75))	('osteosarcoma', 'Phenotype', 'HP:0002669', (79, 91))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (115, 134))	('formation', 'CPA', (50, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('promote', 'PosReg', (38, 45))	('YAP', 'Gene', (17, 20))	('rhabdomyosarcoma', 'Disease', (93, 109))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (115, 135))	('osteosarcoma', 'Disease', (79, 91))	('osteosarcoma', 'Disease', 'MESH:D012516', (79, 91))	('sarcomas', 'Disease', 'MESH:D012509', (127, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (93, 109))
504900	29996478	In addition, evidence suggests that many of the most common sarcoma types have genetic alterations in the Hippo pathway or increased YAP or TAZ protein expression.	('increased', 'PosReg', (123, 132))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('Hippo pathway', 'Pathway', (106, 119))	('YAP', 'Gene', '10413', (133, 136))	('TAZ protein', 'Protein', (140, 151))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('expression', 'MPA', (152, 162))	('YAP', 'Gene', (133, 136))	('genetic alterations', 'Var', (79, 98))
504907	29996478	Since the WWTR1-CAMATA1 fusion that drives EHE results in activation of a TAZ-like transcriptional program, it is not surprising that many clinical features of EHEs are also associated with TAZ activation in other cancer types and/or pathological processes.	('EHE', 'Phenotype', 'HP:0032060', (43, 46))	('WWTR1', 'Gene', '25937', (10, 15))	('EHE', 'Phenotype', 'HP:0032060', (160, 163))	('cancer', 'Disease', (214, 220))	('fusion', 'Var', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('TAZ-like transcriptional program', 'Pathway', (74, 106))	('EHEs', 'Disease', (160, 164))	('activation', 'PosReg', (58, 68))	('WWTR1', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
504951	29996478	Clearly, a reliable genetically engineered mouse model of EHE would facilitate the identification of target genes as well as provide a system to test novel small molecule, biological, gene silencing/editing, or other putative therapies.	('EHE', 'Phenotype', 'HP:0032060', (58, 61))	('gene silencing/editing', 'Var', (184, 206))	('mouse', 'Species', '10090', (43, 48))	('silencing/editing', 'Var', (189, 206))
504952	29996478	It is worth noting that inhibitors of the tankyrase class of PARP enzymes represent a potentially promising method of reducing YAP/TAZ activity in EHE.	('YAP', 'Gene', (127, 130))	('PARP', 'Gene', (61, 65))	('EHE', 'Phenotype', 'HP:0032060', (147, 150))	('reducing', 'NegReg', (118, 126))	('inhibitors', 'Var', (24, 34))	('tankyrase', 'Gene', '8658', (42, 51))	('YAP', 'Gene', '10413', (127, 130))	('PARP', 'Gene', '142', (61, 65))	('tankyrase', 'Gene', (42, 51))
504954	29996478	Conversely, knock down of AMOTL2 in canine kidney cells resulted in increased YAP/TAZ nuclear localization.	('AMOTL2', 'Gene', (26, 32))	('canine', 'Species', '9615', (36, 42))	('YAP', 'Gene', '10413', (78, 81))	('knock down', 'Var', (12, 22))	('AMOTL2', 'Gene', '485669', (26, 32))	('increased', 'PosReg', (68, 77))	('YAP', 'Gene', (78, 81))
504957	29996478	They further reported that tankyrase inhibitors reduced the growth rate of YAP-transformed cultured cells.	('inhibitors', 'Var', (37, 47))	('YAP', 'Gene', '10413', (75, 78))	('reduced', 'NegReg', (48, 55))	('YAP', 'Gene', (75, 78))	('tankyrase', 'Gene', '8658', (27, 36))	('tankyrase', 'Gene', (27, 36))	('growth rate', 'CPA', (60, 71))
504965	29996478	Finally, hypermethylation of Hippo-related promoters, such as LATS1 and LATS2 and MST1 and MST2, can contribute to tumor growth and aggressiveness in many cancers, including sarcomas.	('aggressiveness', 'Phenotype', 'HP:0000718', (132, 146))	('sarcomas', 'Disease', (174, 182))	('MST2', 'Gene', '6788', (91, 95))	('tumor', 'Disease', (115, 120))	('hypermethylation', 'Var', (9, 25))	('LATS2', 'Gene', (72, 77))	('LATS2', 'Gene', '26524', (72, 77))	('MST1', 'Gene', (82, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('MST2', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('contribute', 'Reg', (101, 111))	('aggressiveness in many cancers', 'Disease', 'MESH:D009369', (132, 162))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('MST1', 'Gene', '4485', (82, 86))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('LATS1', 'Gene', (62, 67))	('LATS1', 'Gene', '9113', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('aggressiveness in many cancers', 'Disease', (132, 162))	('sarcomas', 'Disease', 'MESH:D012509', (174, 182))	('sarcomas', 'Phenotype', 'HP:0100242', (174, 182))
505017	25608963	Approximately 10% of ES cases have other analogous translocations such as t(21;22)(q22;q12) and t(7;22)(q22;q12); therefore, cytogenetic and molecular techniques are useful to distinguish ES/PNET from other tumors.	('t(7;22)(q22;q12)', 'Var', (96, 112))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (74, 91))	('tumors', 'Disease', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('t(7;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (96, 112))	('PNET', 'Phenotype', 'HP:0030065', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('ES', 'Phenotype', 'HP:0012254', (188, 190))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('ES/PNET', 'Disease', (188, 195))	('ES', 'Phenotype', 'HP:0012254', (21, 23))
505174	21034938	The successor IRSG-V/Children's Oncology Group Soft Tissue Committee protocols D9602 (for low-risk patients) and D9803 (for intermediate-risk patients) advocated considering to perform an SLP at approximately week 12 after beginning chemotherapy in patients with localized, gross residual sarcoma, in an attempt to reduce the dose of subsequent RT to the primary site.	('sarcoma', 'Disease', (289, 296))	('patients', 'Species', '9606', (249, 257))	('Oncology', 'Phenotype', 'HP:0002664', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (289, 296))	('patients', 'Species', '9606', (99, 107))	('D9803', 'Var', (113, 118))	('patients', 'Species', '9606', (142, 150))	('sarcoma', 'Disease', 'MESH:D012509', (289, 296))	('D9803', 'CellLine', 'CVCL:D654', (113, 118))	('Children', 'Species', '9606', (21, 29))
505280	26969300	Inhibition of SOX2 induces cell apoptosis and G1/S arrest in Ewing's sarcoma through the PI3K/Akt pathway Ewing's sarcoma is an aggressive bone and soft tissue tumor with a high incidence in children and adolescents.	("Ewing's sarcoma", 'Disease', (106, 121))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (148, 165))	('Akt', 'Gene', (94, 97))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (106, 121))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (61, 76))	('children', 'Species', '9606', (191, 199))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('S arrest', 'Disease', (49, 57))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (61, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('S arrest', 'Disease', 'MESH:D006323', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Inhibition', 'Var', (0, 10))	("Ewing's sarcoma", 'Disease', (61, 76))	('Akt', 'Gene', '207', (94, 97))	('tumor', 'Disease', (160, 165))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (106, 121))
505298	26969300	Ewing's sarcoma is characterized by unique chromosomal translocations; the most common is t(11;22) (q24;q12) generating the EWS/FLI1 fusion gene that accounts for 85 % of all cases.	("Ewing's sarcoma", 'Disease', (0, 15))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('FLI1', 'Gene', '2313', (128, 132))	('FLI1', 'Gene', (128, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('t(11;22) (q24;q12', 'Var', (90, 107))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))
505305	26969300	For example, repression of SOX2 was found to induce cell apoptosis via cleavage of caspase-3 and activation of specific pro-apoptotic factors, and inhibit G1/S transition by regulating cyclin E in prostate cancer and cyclin D1 in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('breast cancer', 'Disease', (230, 243))	('regulating', 'Reg', (174, 184))	('cyclin D1', 'Gene', '595', (217, 226))	('cyclin E', 'MPA', (185, 193))	('repression', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('activation', 'PosReg', (97, 107))	('caspase-3', 'Gene', '836', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('inhibit', 'NegReg', (147, 154))	('prostate cancer', 'Disease', 'MESH:D011471', (197, 212))	('prostate cancer', 'Phenotype', 'HP:0012125', (197, 212))	('caspase-3', 'Gene', (83, 92))	('prostate cancer', 'Disease', (197, 212))	('G1/S transition', 'CPA', (155, 170))	('cleavage', 'MPA', (71, 79))	('induce', 'PosReg', (45, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('cell apoptosis', 'CPA', (52, 66))	('SOX2', 'Gene', (27, 31))	('cyclin D1', 'Gene', (217, 226))
505317	26969300	Antibodies against SOX2 (3579), p-Akt (4060), cyclin-E (4136) and cleaved-caspase-3 (9661) for immunohistochemistry were purchased from Cell Signaling Technology (Beverly, MA, USA).	('caspase-3', 'Gene', (74, 83))	('4060', 'Var', (39, 43))	('Akt', 'Gene', '207', (34, 37))	('4136', 'Var', (56, 60))	('3579', 'Var', (25, 29))	('caspase-3', 'Gene', '836', (74, 83))	('Akt', 'Gene', (34, 37))
505329	26969300	Antibodies against SOX2 (3579, 1:1000), PI3K (11189, 1:500), p-Akt (9271, 1:500), Fas (4233, 1:500), Bad (9239, 1:500), Bcl-2 (2872, 1:1000), XIAP (2042, 1:1000), Caspase-8 (9746, 1:500), Caspase-9 (9508, 1:1000), Caspase-3 (9662, 1:1000), PARP (9542, 1:1000), Cyclin-E (4129, 1:500) and Cyclin-D1 (2922, 1:1000) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('Caspase-9', 'Gene', '842', (188, 197))	('4129', 'Var', (271, 275))	('Caspase-8', 'Gene', '841', (163, 172))	('XIAP', 'Gene', (142, 146))	('XIAP', 'Gene', '331', (142, 146))	('Cyclin-D1', 'Gene', (288, 297))	('Caspase-9', 'Gene', (188, 197))	('Caspase-8', 'Gene', (163, 172))	('PARP', 'Gene', (240, 244))	('Caspase-3', 'Gene', (214, 223))	('Akt', 'Gene', '207', (63, 66))	('Cyclin-D1', 'Gene', '595', (288, 297))	('Caspase-3', 'Gene', '836', (214, 223))	('Bcl-2', 'Gene', (120, 125))	('Bcl-2', 'Gene', '596', (120, 125))	('PARP', 'Gene', '142', (240, 244))	('Akt', 'Gene', (63, 66))
505347	26969300	In order to confirm the relationship between SOX2 and EWS/FLI1 in Ewing's sarcoma, two small interfering RNAs (siRNAs) were used to knockdown EWS/FLI1 in A673 and RD-ES cells.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (66, 81))	('FLI1', 'Gene', (58, 62))	('knockdown', 'Var', (132, 141))	("Ewing's sarcoma", 'Disease', (66, 81))	('FLI1', 'Gene', (146, 150))	('FLI1', 'Gene', '2313', (58, 62))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (66, 81))	('FLI1', 'Gene', '2313', (146, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
505354	26969300	In order to determine whether overexpression of SOX2 advanced the growth capacity of Ewing's sarcoma cells, two different siRNAs against SOX2 were used to knockdown expression of SOX2 in A673 and RD-ES cell lines.	("Ewing's sarcoma", 'Disease', (85, 100))	('knockdown', 'Var', (155, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (85, 100))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (85, 100))	('growth capacity', 'CPA', (66, 81))	('SOX2', 'Gene', (179, 183))
505356	26969300	Both SOX2 mRNA and protein expressions were significantly downregulated in the silenced cells (siSOX2-#1 and siSOX2-#2) compared to control cells (Fig.	('siSOX2-#', 'Var', (95, 103))	('siSOX2', 'Chemical', '-', (95, 101))	('siSOX2', 'Chemical', '-', (109, 115))	('SOX2', 'Gene', (5, 9))	('downregulated', 'NegReg', (58, 71))
505358	26969300	The MTT cell viability assays showed that knockdown of SOX2 reduced cell viability by approximately 30 % in both cell lines compared to controls (Fig.	('cell viability', 'CPA', (68, 82))	('SOX2', 'Gene', (55, 59))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('reduced', 'NegReg', (60, 67))	('knockdown', 'Var', (42, 51))
505359	26969300	The effect of SOX2 knockdown on cell cycle distribution in Ewing's sarcoma cells was investigated by flow cytometry in A673 and RD-ES cell lines as an indication of proliferative capacity.	('SOX2', 'Gene', (14, 18))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (59, 74))	('knockdown', 'Var', (19, 28))	("Ewing's sarcoma", 'Disease', (59, 74))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (59, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))
505361	26969300	Expressions of cyclin-dependent kinase (CKD) inhibitors p21 and p27 were markedly increased after knockdown of SOX2 compared to control cells; expression of cyclin-E was decreased; however, there was no significant change in expression of cyclin-D1 (Fig.	('p27', 'Gene', '3429', (64, 67))	('cyclin-D1', 'Gene', (239, 248))	('expression', 'MPA', (143, 153))	('p27', 'Gene', (64, 67))	('p21', 'Gene', '1026', (56, 59))	('knockdown', 'Var', (98, 107))	('p21', 'Gene', (56, 59))	('decreased', 'NegReg', (170, 179))	('increased', 'PosReg', (82, 91))	('cyclin-D1', 'Gene', '595', (239, 248))	('Expressions', 'MPA', (0, 11))
505363	26969300	To investigate whether knockdown of SOX2 induced apoptosis in Ewing's sarcoma cells, flow cytometric and TUNEL assays were performed in A673 and RD-ES cell lines.	("Ewing's sarcoma", 'Disease', (62, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (62, 77))	('knockdown', 'Var', (23, 32))	('SOX2', 'Gene', (36, 40))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (62, 77))
505364	26969300	Similarly, the TUNEL assay showed an increase in apoptotic cells, as evidenced by enhanced fluorescence, in both cell lines following knockdown of SOX2, confirming that inhibition of SOX2 induced apoptosis in Ewing's sarcoma cells (Fig.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (209, 224))	('enhanced', 'PosReg', (82, 90))	('SOX2', 'Gene', (183, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (209, 224))	("Ewing's sarcoma", 'Disease', (209, 224))	('inhibition', 'Var', (169, 179))
505366	26969300	PARP plays a central role in DNA repair; however, cleavage of PARP results in loss-of-function and can be induced following activation of caspase-3 via cleavage.	('caspase-3', 'Gene', (138, 147))	('PARP', 'Gene', (0, 4))	('caspase-3', 'Gene', '836', (138, 147))	('cleavage', 'Var', (152, 160))	('PARP', 'Gene', (62, 66))	('cleavage', 'Var', (50, 58))	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', '142', (62, 66))	('loss-of-function', 'NegReg', (78, 94))
505371	26969300	These results indicated that inhibition of SOX2 induced activation of both extrinsic cell death receptor and intrinsic mitochondrial apoptotic pathways, leading to apoptosis in Ewing's sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (177, 192))	('apoptosis', 'CPA', (164, 173))	("Ewing's sarcoma", 'Disease', (177, 192))	('intrinsic mitochondrial apoptotic pathways', 'Pathway', (109, 151))	('SOX2', 'Gene', (43, 47))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (177, 192))	('extrinsic cell death receptor', 'Pathway', (75, 104))	('activation', 'PosReg', (56, 66))	('inhibition', 'Var', (29, 39))
505374	26969300	To verify this supposition, the expressions of PI3K, Akt and p-Akt proteins in A673 and RD-ES cells following knockdown of SOX2 were examined by Western blotting.	('knockdown', 'Var', (110, 119))	('Akt', 'Gene', '207', (53, 56))	('Akt', 'Gene', '207', (63, 66))	('Akt', 'Gene', (53, 56))	('Akt', 'Gene', (63, 66))
505377	26969300	To further demonstrate that SOX2 was implicated in the proliferation and progression of Ewing's sarcoma, we reactivated the PI3K/Akt pathway after knockdown of SOX2 by overexpressing Akt using plasmids.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('reactivated', 'PosReg', (108, 119))	('Akt', 'Gene', (183, 186))	('Akt', 'Gene', '207', (129, 132))	('Akt', 'Gene', '207', (183, 186))	('SOX2', 'Gene', (160, 164))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (88, 103))	('Akt', 'Gene', (129, 132))	("Ewing's sarcoma", 'Disease', (88, 103))	('knockdown', 'Var', (147, 156))	('overexpressing', 'PosReg', (168, 182))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (88, 103))
505379	26969300	Four test groups were prepared: untreated controls (-/-), SOX2 knockdown (+/-), Akt overexpression (-/+), and cotransfection of siSOX2 + Akt plasmid (+/+).	('SOX2', 'Gene', (58, 62))	('overexpression', 'PosReg', (84, 98))	('Akt', 'Gene', '207', (80, 83))	('Akt', 'Gene', '207', (137, 140))	('Akt', 'Gene', (80, 83))	('Akt', 'Gene', (137, 140))	('knockdown', 'Var', (63, 72))	('siSOX2', 'Chemical', '-', (128, 134))
505382	26969300	Inhibition of Akt phosphorylation through knockdown of SOX2 was found to elevate protein expressions of pro-apoptotic factors Bad and Fas, induce cleavage of caspase-9 and caspase-3, promote expression of p21 and p27, and suppress expression of cyclin-E compared to the corresponding levels in untreated controls.	('p27', 'Gene', '3429', (213, 216))	('p27', 'Gene', (213, 216))	('Inhibition', 'NegReg', (0, 10))	('caspase-9', 'Gene', (158, 167))	('cleavage', 'MPA', (146, 154))	('Fas', 'Gene', (134, 137))	('promote', 'PosReg', (183, 190))	('Akt', 'Gene', (14, 17))	('p21', 'Gene', (205, 208))	('protein expressions', 'MPA', (81, 100))	('Akt', 'Gene', '207', (14, 17))	('expression', 'MPA', (191, 201))	('expression', 'MPA', (231, 241))	('knockdown', 'Var', (42, 51))	('SOX2', 'Gene', (55, 59))	('caspase-3', 'Gene', '836', (172, 181))	('suppress', 'NegReg', (222, 230))	('cyclin-E', 'Protein', (245, 253))	('caspase-3', 'Gene', (172, 181))	('caspase-9', 'Gene', '842', (158, 167))	('p21', 'Gene', '1026', (205, 208))	('elevate', 'PosReg', (73, 80))	('induce', 'Reg', (139, 145))
505387	26969300	The results showed that rate of tumor growth and the sizes of the tumors were significantly lower in the siSOX2 group compared to those in the control groups (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('siSOX2', 'Chemical', '-', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('siSOX2', 'Var', (105, 111))	('tumor', 'Disease', (32, 37))	('lower', 'NegReg', (92, 97))	('rate', 'CPA', (24, 28))
505388	26969300	These findings confirmed that inhibition of SOX2 could significantly repress tumorigenesis in Ewing's sarcoma in vivo.	('inhibition', 'Var', (30, 40))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (94, 109))	('repress', 'NegReg', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	("Ewing's sarcoma", 'Disease', (94, 109))	('SOX2', 'Protein', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (94, 109))	('tumor', 'Disease', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
505389	26969300	As observed in vitro, the results confirmed that SOX2 regulated apoptotic and cell cycle factors via mediation of PI3K/Akt signaling: IHC showed that positive staining for pro-proliferation factors (SOX2, p-Akt and cyclin-E) was lower in xenograft tissues from the siSOX2 group compared to those from the siNC group.	('Akt', 'Gene', '207', (207, 210))	('siSOX2', 'Var', (265, 271))	('Akt', 'Gene', '207', (119, 122))	('Akt', 'Gene', (207, 210))	('Akt', 'Gene', (119, 122))	('lower', 'NegReg', (229, 234))	('siSOX2', 'Chemical', '-', (265, 271))	('cyclin-E', 'Protein', (215, 223))	('siNC', 'Chemical', '-', (305, 309))
505392	26969300	This confirmed that silencing SOX2 inhibited PI3K/Akt signaling in vivo.	('Akt', 'Gene', '207', (50, 53))	('Akt', 'Gene', (50, 53))	('inhibited', 'NegReg', (35, 44))	('silencing', 'Var', (20, 29))	('SOX2', 'Gene', (30, 34))
505393	26969300	Similarly, silencing SOX2 elevated protein expressions of pro-apoptotic factors Fas and cleaved-caspase-8 (mediators in the cell death receptor pathway), Bad and cleaved-caspase-9 (mediators in the mitochondrial apoptotic pathway), as well as cleaved-caspase-3 (activated by the cell death receptor and mitochondrial apoptotic pathway) and cleaved-PARP, demonstrating that SOX2 inhibition induced cell apoptosis.	('silencing', 'Var', (11, 20))	('PARP', 'Gene', (348, 352))	('caspase-9', 'Gene', (170, 179))	('caspase-8', 'Gene', (96, 105))	('caspase-3', 'Gene', '836', (251, 260))	('PARP', 'Gene', '142', (348, 352))	('caspase-8', 'Gene', '841', (96, 105))	('protein expressions', 'MPA', (35, 54))	('elevated', 'PosReg', (26, 34))	('caspase-9', 'Gene', '842', (170, 179))	('SOX2', 'Gene', (21, 25))	('cell apoptosis', 'CPA', (397, 411))	('caspase-3', 'Gene', (251, 260))
505394	26969300	In addition, protein expressions of cell cycle regulators p21 and p27 were increased after injection of siSOX2, whereas expression of cyclin-E was decreased, indicating that knockdown of SOX2 suppressed G1/S phase transition (Fig.	('protein expressions', 'MPA', (13, 32))	('p21', 'Gene', (58, 61))	('suppressed', 'NegReg', (192, 202))	('siSOX2', 'Gene', (104, 110))	('G1/S phase transition', 'CPA', (203, 224))	('p27', 'Gene', '3429', (66, 69))	('p27', 'Gene', (66, 69))	('p21', 'Gene', '1026', (58, 61))	('siSOX2', 'Chemical', '-', (104, 110))	('knockdown', 'Var', (174, 183))	('increased', 'PosReg', (75, 84))
505399	26969300	Consistent with previous reports, we found that silencing EWS/FLI1 in these cell lines with siRNAs significantly suppressed expression of SOX2, verifying that SOX2 was a downstream target of EWS/FLI1.	('FLI1', 'Gene', (195, 199))	('SOX2', 'MPA', (138, 142))	('silencing', 'Var', (48, 57))	('suppressed', 'NegReg', (113, 123))	('FLI1', 'Gene', (62, 66))	('FLI1', 'Gene', '2313', (62, 66))	('expression', 'MPA', (124, 134))	('FLI1', 'Gene', '2313', (195, 199))
505407	26969300	Consistent with these reports, we found that silencing SOX2 resulted in morphologic changes and a significant increase in apoptotic cells in Ewing's sarcoma.	('silencing', 'Var', (45, 54))	('apoptotic cells', 'CPA', (122, 137))	('SOX2', 'Gene', (55, 59))	('increase', 'PosReg', (110, 118))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (141, 156))	('morphologic changes', 'CPA', (72, 91))	("Ewing's sarcoma", 'Disease', (141, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (141, 156))
505411	26969300	Our observations confirmed that these actions were replicated in Ewing's sarcoma: silencing SOX2 promoted apoptosis in Ewing's sarcoma cells via activation of caspase-8 and caspase-9, and stimulated pro-apoptotic factors while repressing anti-apoptotic factors in both the extrinsic and intrinsic pathways.	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('stimulated', 'PosReg', (188, 198))	('pro-apoptotic factors', 'MPA', (199, 220))	('caspase-8', 'Gene', '841', (159, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('activation', 'PosReg', (145, 155))	('caspase-9', 'Gene', (173, 182))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (65, 80))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (119, 134))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (65, 80))	('extrinsic', 'Pathway', (273, 282))	('apoptosis', 'CPA', (106, 115))	('intrinsic pathways', 'Pathway', (287, 305))	('silencing', 'Var', (82, 91))	('caspase-8', 'Gene', (159, 168))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (119, 134))	("Ewing's sarcoma", 'Disease', (65, 80))	('SOX2', 'Gene', (92, 96))	("Ewing's sarcoma", 'Disease', (119, 134))	('caspase-9', 'Gene', '842', (173, 182))	('promoted', 'PosReg', (97, 105))
505415	26969300	Activation of Akt via phosphorylation has been shown to directly downregulate pro-apoptotic proteins, such as Bad and caspase-9, indirectly mediate the Fas death receptor, and target CDK inhibitors involved in cell cycle regulation, including p21 and p27, thereby promoting cell survival and growth.	('Akt', 'Gene', (14, 17))	('promoting', 'PosReg', (264, 273))	('growth', 'CPA', (292, 298))	('caspase-9', 'Gene', (118, 127))	('p27', 'Gene', (251, 254))	('mediate', 'Reg', (140, 147))	('p27', 'Gene', '3429', (251, 254))	('phosphorylation', 'Var', (22, 37))	('p21', 'Gene', '1026', (243, 246))	('downregulate', 'NegReg', (65, 77))	('Akt', 'Gene', '207', (14, 17))	('caspase-9', 'Gene', '842', (118, 127))	('p21', 'Gene', (243, 246))	('cell survival', 'CPA', (274, 287))
505416	26969300	The present study identified SOX2 as an upstream regulator in the PI3K/Akt pathway in Ewing's sarcoma; knockdown of SOX2 reduced expression of PI3K and abolished phosphorylation of Akt to p-Akt in vitro; whereas overexpression of Akt counteracted the variations of downstream proteins caused by silencing of SOX2, thereby negating the effects of SOX2 inhibition on the cell cycle progression and apoptosis.	('Akt', 'Gene', '207', (71, 74))	("Ewing's sarcoma", 'Disease', (86, 101))	('Akt', 'Gene', '207', (230, 233))	('abolished', 'NegReg', (152, 161))	('PI3K', 'Pathway', (143, 147))	('Akt', 'Gene', (190, 193))	('Akt', 'Gene', (181, 184))	('Akt', 'Gene', '207', (190, 193))	('expression', 'MPA', (129, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('reduced', 'NegReg', (121, 128))	('Akt', 'Gene', '207', (181, 184))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (86, 101))	('knockdown', 'Var', (103, 112))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (86, 101))	('Akt', 'Gene', (71, 74))	('phosphorylation', 'MPA', (162, 177))	('SOX2', 'Gene', (116, 120))	('Akt', 'Gene', (230, 233))
505421	26969300	By establishing Ewing's sarcoma xenograft models in mice, we were able to demonstrate that treatment with siRNAs against SOX2 could substantially reduce tumor growth of Ewing's sarcoma in vivo.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('SOX2', 'Gene', (121, 125))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (169, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (16, 31))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (169, 184))	("Ewing's sarcoma", 'Disease', (16, 31))	("Ewing's sarcoma", 'Disease', (169, 184))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (16, 31))	('reduce', 'NegReg', (146, 152))	('siRNAs', 'Var', (106, 112))
505422	26969300	Furthermore, variations of the factors that had been identified in vitro, including SOX2, regulators of the PI3K/Akt signaling pathway, apoptotic proteins and G1/S transitional mediators, were also verified in xenograft tissue samples.	('Akt', 'Gene', '207', (113, 116))	('Akt', 'Gene', (113, 116))	('variations', 'Var', (13, 23))
505484	22951631	Alcohol/drug abuse diagnoses were captured by ICD-9 codes 291, 292, 303-305.0, 305.2-305.5, overweight or obesity diagnoses were captured by ICD-9 codes 278, 259.9, V85 as well as KP internal weight/height files, and tobacco use was captured by ICD-9 codes 305.1, V15, V65, 649, as well as KP internal social history files.	('drug abuse', 'Disease', (8, 18))	('overweight', 'Phenotype', 'HP:0025502', (92, 102))	('obesity', 'Phenotype', 'HP:0001513', (106, 113))	('tobacco', 'Species', '4097', (217, 224))	('V65', 'Var', (269, 272))	('codes 278', 'Var', (147, 156))	('V15', 'Var', (264, 267))	('drug abuse', 'Disease', 'MESH:D019966', (8, 18))	('obesity', 'Disease', 'MESH:D009765', (106, 113))	('obesity', 'Disease', (106, 113))	('V85', 'Var', (165, 168))
505504	22951631	In the unadjusted analyses, ART use was significantly associated with a lower rate of ADC, yet, a higher rate of infection-related NADCs, largely driven by anal cancer (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ART', 'Chemical', '-', (28, 31))	('ADC', 'Disease', (86, 89))	('anal cancer', 'Phenotype', 'HP:0032186', (156, 167))	('ART use', 'Var', (28, 35))	('lower', 'NegReg', (72, 77))	('higher', 'PosReg', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('NADC', 'Chemical', '-', (131, 135))	('cancer', 'Disease', (161, 167))
505526	22951631	PI agents have been shown to confer a broad-spectrum of anti-cancer properties.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('PI agents', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
505528	22951631	In addition to direct cytotoxicity, some PI drugs also demonstrate the ability to induce cell cycle arrest.	('PI drugs', 'Var', (41, 49))	('cell cycle arrest', 'CPA', (89, 106))	('cytotoxicity', 'Disease', (22, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (89, 106))	('cytotoxicity', 'Disease', 'MESH:D064420', (22, 34))
505552	22951631	Another possibility is residual confounding by sexual orientation since MSM have a known increased risk of anal cancer, and MSM may also contribute the longest duration of PIs.	('anal cancer', 'Phenotype', 'HP:0032186', (107, 118))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('MSM', 'Var', (124, 127))	('PIs', 'Chemical', '-', (172, 175))
505641	22966215	Assessment of outcome: we awarded one star if the assessment tool was a well-known and widely used validated tool, for example, SF-36, EORTC QLQ C-30, TESS, MSTS87, and MSTS93 (abbreviations under Table 2).	('TESS', 'Gene', (151, 155))	('MSTS93', 'Var', (169, 175))	('TESS', 'Gene', '26136', (151, 155))
505777	33057440	Using two different transformed mouse models and tumorigenic full KSHV genome-bearing cells, including KSHV-Bac16 based mutant system with a vGPCR deletion, we demostrate that vGPCR upregulates COX-2 expression and activity, signaling through selective MAPK cascades.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('KSHV', 'Species', '37296', (103, 107))	('vGPCR', 'Gene', (141, 146))	('activity', 'MPA', (215, 223))	('vGPCR', 'Gene', '4961465', (141, 146))	('mouse', 'Species', '10090', (32, 37))	('expression', 'MPA', (200, 210))	('KS', 'Phenotype', 'HP:0100726', (66, 68))	('rat', 'Species', '10116', (166, 169))	('upregulates', 'PosReg', (182, 193))	('KS', 'Phenotype', 'HP:0100726', (103, 105))	('vGPCR', 'Gene', (176, 181))	('COX-2', 'Gene', (194, 199))	('tumor', 'Disease', (49, 54))	('expression', 'Species', '29278', (200, 210))	('deletion', 'Var', (147, 155))	('vGPCR', 'Gene', '4961465', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('KSHV', 'Species', '37296', (66, 70))	('COX-2', 'Gene', '5743', (194, 199))
505778	33057440	We show that vGPCR expression triggers signaling pathways that upregulate COX-2 levels due to a dual effect upon both its gene promoter region and, in mature mRNA, the 3'UTR region that control mRNA stability.	('COX-2', 'Gene', (74, 79))	('expression', 'Var', (19, 29))	('vGPCR', 'Gene', '4961465', (13, 18))	('COX-2', 'Gene', '5743', (74, 79))	('triggers', 'Reg', (30, 38))	('mRNA stability', 'MPA', (194, 208))	('upregulate', 'PosReg', (63, 73))	('gene promoter region', 'MPA', (122, 142))	('expression', 'Species', '29278', (19, 29))	('vGPCR', 'Gene', (13, 18))
505779	33057440	Inhibition of COX-2 in vGPCR-transformed cells impairs vGPCR-driven angiogenesis and treatment with the COX-2-selective inhibitory drug Celecoxib produces a significant decrease in tumor growth, pointing to COX-2 activity as critical for vGPCR oncogenicity in vivo and indicating that COX-2-mediated angiogenesis could play a role in KS tumorigenesis.	('vGPCR', 'Gene', '4961465', (238, 243))	('COX-2', 'Gene', (104, 109))	('tumor', 'Disease', (337, 342))	('impairs', 'NegReg', (47, 54))	('vGPCR', 'Gene', (55, 60))	('COX-2', 'Gene', (207, 212))	('vGPCR', 'Gene', '4961465', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('COX-2', 'Gene', (14, 19))	('COX-2', 'Gene', (285, 290))	('COX-2', 'Gene', '5743', (104, 109))	('COX-2', 'Gene', '5743', (207, 212))	('COX-2', 'Gene', '5743', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('COX-2', 'Gene', '5743', (285, 290))	('Celecoxib', 'Chemical', 'MESH:D000068579', (136, 145))	('KS', 'Phenotype', 'HP:0100726', (334, 336))	('Inhibition', 'Var', (0, 10))	('decrease', 'NegReg', (169, 177))	('tumor', 'Disease', (181, 186))	('vGPCR', 'Gene', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('vGPCR', 'Gene', (23, 28))	('vGPCR', 'Gene', '4961465', (23, 28))
505801	33057440	Moreover, Cyclooxygenase-2 (COX-2), is one of the host genes that is highly induced upon KSHV de novo infection of human microvascular endothelial cells (HMVEC-d) and human foreskin fibroblast (HFF) cells, and COX-2 silencing or chemical inhibition significantly reduces the proliferation and invasiveness of KSHV-infected endothelial cells.	('KSHV', 'Species', '37296', (89, 93))	('KSHV', 'Species', '37296', (309, 313))	('COX-2', 'Gene', '5743', (210, 215))	('HFF', 'CellLine', 'CVCL:3285', (194, 197))	('Cyclooxygenase-2', 'Gene', '5743', (10, 26))	('Cyclooxygenase-2', 'Gene', (10, 26))	('invasiveness of KSHV-infected', 'Disease', (293, 322))	('human', 'Species', '9606', (167, 172))	('reduces', 'NegReg', (263, 270))	('COX-2', 'Gene', (28, 33))	('KS', 'Phenotype', 'HP:0100726', (89, 91))	('infection', 'Disease', (102, 111))	('infection', 'Disease', 'MESH:D007239', (102, 111))	('proliferation', 'CPA', (275, 288))	('invasiveness of KSHV-infected', 'Disease', 'MESH:D007239', (293, 322))	('chemical inhibition', 'Var', (229, 248))	('silencing', 'Var', (216, 225))	('COX-2', 'Gene', '5743', (28, 33))	('COX-2', 'Gene', (210, 215))	('rat', 'Species', '10116', (282, 285))	('KS', 'Phenotype', 'HP:0100726', (309, 311))	('human', 'Species', '9606', (115, 120))
505811	33057440	Moreover, using KS biopsies we show that COX-2 is overexpressed in KSHV-infected cells of KS lesions, defining COX-2 as a potential target for preventing and treating KSHV-oncogenesis.	('COX-2', 'Gene', (41, 46))	('COX-2', 'Gene', (111, 116))	('COX-2', 'Gene', '5743', (41, 46))	('KSHV-infected', 'Disease', (67, 80))	('COX-2', 'Gene', '5743', (111, 116))	('KS', 'Phenotype', 'HP:0100726', (90, 92))	('overexpressed', 'PosReg', (50, 63))	('KS', 'Phenotype', 'HP:0100726', (67, 69))	('KSHV', 'Species', '37296', (67, 71))	('KS', 'Phenotype', 'HP:0100726', (16, 18))	('lesions', 'Var', (93, 100))	('KS', 'Phenotype', 'HP:0100726', (167, 169))	('KSHV', 'Species', '37296', (167, 171))	('KSHV-infected', 'Disease', 'MESH:D007239', (67, 80))
505825	33057440	We found that vGPCR-expressing cells treated with the ERK1/2 inhibitor PD98059 showed a marked decrease in the levels of COX-2 activity.	('decrease', 'NegReg', (95, 103))	('COX-2', 'Gene', (121, 126))	('vGPCR', 'Gene', (14, 19))	('PD98059', 'Chemical', 'MESH:C093973', (71, 78))	('COX-2', 'Gene', '5743', (121, 126))	('vGPCR', 'Gene', '4961465', (14, 19))	('PD98059', 'Var', (71, 78))
505829	33057440	The vGPCR-triggered activation of ERK1/2 was confirmed by using the MAPK pharmacological inhibitor to MAPKK MEK1, PD98059 which impairs ERK1/2 MAPK signaling and significantly reduced and almost completely abolished ERK1/2 activation in vGPCR expressing cells.	('vGPCR', 'Gene', (237, 242))	('ERK1/2 activation', 'MPA', (216, 233))	('reduced', 'NegReg', (176, 183))	('abolished', 'NegReg', (206, 215))	('vGPCR', 'Gene', '4961465', (4, 9))	('vGPCR', 'Gene', '4961465', (237, 242))	('MEK1', 'Gene', '5604', (108, 112))	('PD98059', 'Var', (114, 121))	('impairs', 'NegReg', (128, 135))	('PD98059', 'Chemical', 'MESH:C093973', (114, 121))	('MEK1', 'Gene', (108, 112))	('vGPCR', 'Gene', (4, 9))	('ERK1/2 MAPK signaling', 'MPA', (136, 157))
505839	33057440	Pharmacological inhibition of the ERK1/2 signaling pathway was achieved by adding the specific inhibitor of the MAPKK MEK1 PD98059 (Fig 2C).	('MEK1', 'Gene', '5604', (118, 122))	('PD98059', 'Var', (123, 130))	('MEK1', 'Gene', (118, 122))	('PD98059', 'Chemical', 'MESH:C093973', (123, 130))	('ERK1/2 signaling pathway', 'Pathway', (34, 58))
505840	33057440	Cells were transfected with constitutively active or dominant negative (kinase-dead) MEK1 mutants (MEKEE and MEKAA, respectively).	('MEK', 'Gene', '5609', (85, 88))	('MEK', 'Gene', '5609', (99, 102))	('mutants', 'Var', (90, 97))	('MEK1', 'Gene', '5604', (85, 89))	('negative', 'NegReg', (62, 70))	('MEK1', 'Gene', (85, 89))	('MEK', 'Gene', (85, 88))	('MEK', 'Gene', (109, 112))	('MEK', 'Gene', '5609', (109, 112))	('MEK', 'Gene', (99, 102))
505841	33057440	While activation of the MEK1-ERK1/2 axis increased COX-2 promoter activity per se, both the pharmacological inhibitor and the dominant negative MEK1 mutant showed a reduction of vGPCR induced luciferase activity.	('COX-2', 'Gene', (51, 56))	('vGPCR', 'Gene', (178, 183))	('increased', 'PosReg', (41, 50))	('COX-2', 'Gene', '5743', (51, 56))	('mutant', 'Var', (149, 155))	('MEK1', 'Gene', '5604', (24, 28))	('MEK1', 'Gene', '5604', (144, 148))	('vGPCR', 'Gene', '4961465', (178, 183))	('MEK1', 'Gene', (24, 28))	('MEK1', 'Gene', (144, 148))	('reduction', 'NegReg', (165, 174))	('activity', 'MPA', (203, 211))
505850	33057440	to "swap" Bac36 for the Bac16-delta vGPCR mutant or its revertant in mECK36 cells that have lost the Bac36 episome by lack of antibiotic selection (KSHV-negative cells, mEC) (See Materials and methods), to generate the cell lines mECK16-DeltavGPCR and mECK16-revertant, respectively.	('mEC', 'Gene', (169, 172))	('mEC', 'Gene', '56838', (169, 172))	('mEC', 'Gene', '56838', (69, 72))	('mutant', 'Var', (42, 48))	('vGPCR', 'Gene', '4961465', (242, 247))	('mEC', 'Gene', (252, 255))	('mEC', 'Gene', '56838', (252, 255))	('Bac36 episome', 'MPA', (101, 114))	('KSHV', 'Species', '37296', (148, 152))	('vGPCR', 'Gene', '4961465', (36, 41))	('mEC', 'Gene', (230, 233))	('mEC', 'Gene', '56838', (230, 233))	('vGPCR', 'Gene', (242, 247))	('KS', 'Phenotype', 'HP:0100726', (148, 150))	('rat', 'Species', '10116', (210, 213))	('mEC', 'Gene', (69, 72))	('vGPCR', 'Gene', (36, 41))	('lost', 'NegReg', (92, 96))
505851	33057440	Fig 3D and 3H show a sharp drop in COX-2 mRNA and protein expression when mECK36 cells lose the KSHV episome indicating that, as shown in other infection systems, KSHV induces COX-2 upregulation.	('infection', 'Disease', (144, 153))	('COX-2', 'Gene', (35, 40))	('drop', 'NegReg', (27, 31))	('mEC', 'Gene', (74, 77))	('expression', 'Species', '29278', (58, 68))	('COX-2', 'Gene', '5743', (176, 181))	('KSHV', 'Species', '37296', (96, 100))	('infection', 'Disease', 'MESH:D007239', (144, 153))	('COX-2', 'Gene', '5743', (35, 40))	('KSHV', 'MPA', (96, 100))	('mEC', 'Gene', '56838', (74, 77))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('KS', 'Phenotype', 'HP:0100726', (163, 165))	('KSHV', 'Species', '37296', (163, 167))	('KSHV', 'Var', (163, 167))	('lose', 'NegReg', (87, 91))	('upregulation', 'PosReg', (182, 194))	('COX-2', 'Gene', (176, 181))
505852	33057440	We found a similar drop in COX-2 expression between Bac16-revertant bearing cells and the vGPCR deletion mutant (Fig 3E and 3H).	('deletion mutant', 'Var', (96, 111))	('COX-2', 'Gene', '5743', (27, 32))	('vGPCR', 'Gene', (90, 95))	('expression', 'Species', '29278', (33, 43))	('expression', 'MPA', (33, 43))	('drop', 'NegReg', (19, 23))	('vGPCR', 'Gene', '4961465', (90, 95))	('COX-2', 'Gene', (27, 32))
505853	33057440	Since LANA and vFLIP has been shown to activate COX-2 and in order to rule out effects in COX-2 regulation due to downregulation of these viral genes caused by vGPCR deletion in the Bac16 mutant, we assessed their expression levels by qRT-PCR.	('COX-2', 'Gene', '5743', (48, 53))	('deletion', 'Var', (166, 174))	('vFLIP', 'Gene', (15, 20))	('COX-2', 'Gene', (90, 95))	('COX-2', 'Gene', '5743', (90, 95))	('vGPCR', 'Gene', '4961465', (160, 165))	('Bac16', 'Gene', (182, 187))	('LANA', 'Gene', (6, 10))	('expression', 'Species', '29278', (214, 224))	('vGPCR', 'Gene', (160, 165))	('COX-2', 'Gene', (48, 53))	('LANA', 'Gene', '4961527', (6, 10))	('vFLIP', 'Gene', '4961494', (15, 20))
505854	33057440	Interestingly, vGPCR deletion mutant showed more expression of LANA and similar expression levels of vFLIP than mECK16 revertant cells (S1 Fig).	('vGPCR', 'Gene', '4961465', (15, 20))	('more', 'PosReg', (44, 48))	('expression', 'Species', '29278', (49, 59))	('mEC', 'Gene', (112, 115))	('mEC', 'Gene', '56838', (112, 115))	('expression', 'MPA', (49, 59))	('expression', 'Species', '29278', (80, 90))	('vGPCR', 'Gene', (15, 20))	('LANA', 'Gene', (63, 67))	('vFLIP', 'Gene', '4961494', (101, 106))	('expression', 'MPA', (80, 90))	('deletion mutant', 'Var', (21, 36))	('vFLIP', 'Gene', (101, 106))	('LANA', 'Gene', '4961527', (63, 67))
505855	33057440	Taken together these results reinforce the idea that the effects on COX-2 downregulation in the Bac16 mutant are due to vGPCR deletion.	('mutant', 'Var', (102, 108))	('downregulation', 'NegReg', (74, 88))	('vGPCR', 'Gene', '4961465', (120, 125))	('COX-2', 'Gene', '5743', (68, 73))	('deletion', 'Var', (126, 134))	('Bac16', 'Gene', (96, 101))	('COX-2', 'Gene', (68, 73))	('vGPCR', 'Gene', (120, 125))
505870	33057440	On the other hand, vessel density in the group inoculated with vGPCR-transformed cells pre-treated with NS398 did not show significant differences compared to group injected with NIH3T3 control cells (Fig 5B).	('NS398', 'Chemical', 'MESH:C080955', (104, 109))	('NIH3T3', 'CellLine', 'CVCL:0594', (179, 185))	('vGPCR', 'Gene', '4961465', (63, 68))	('NS398', 'Var', (104, 109))	('vGPCR', 'Gene', (63, 68))
505871	33057440	This indicates that treatment of the cells with NS398 before inoculation abolished the angiogenic response induced by vGPCR expression, suggesting that a COX-2 dependent pathway has a major contribution to in vivo angiogenesis mediated by vGPCR signaling in NIH3T3 cells.	('vGPCR', 'Gene', '4961465', (118, 123))	('vGPCR', 'Gene', '4961465', (239, 244))	('NS398', 'Var', (48, 53))	('abolished', 'NegReg', (73, 82))	('angiogenesis', 'CPA', (214, 226))	('NIH3T3', 'CellLine', 'CVCL:0594', (258, 264))	('expression', 'Species', '29278', (124, 134))	('vGPCR', 'Gene', (118, 123))	('COX-2', 'Gene', (154, 159))	('vGPCR', 'Gene', (239, 244))	('NS398', 'Chemical', 'MESH:C080955', (48, 53))	('COX-2', 'Gene', '5743', (154, 159))	('angiogenic response', 'MPA', (87, 106))
505887	33057440	Tumors from animals treated with Celecoxib produced significantly lower levels of VEGF than tumors from untreated animals (Fig 7B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('Celecoxib', 'Chemical', 'MESH:D000068579', (33, 42))	('VEGF', 'MPA', (82, 86))	('Celecoxib', 'Var', (33, 42))	('lower', 'NegReg', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
505889	33057440	We found that COX-2 inhibitors caused a dramatic reduction in VEGF secretion of NIH3T3-vGPCR without affecting cell growth (Fig 7C).	('COX-2', 'Gene', '5743', (14, 19))	('reduction', 'NegReg', (49, 58))	('vGPCR', 'Gene', (87, 92))	('inhibitors', 'Var', (20, 30))	('VEGF secretion', 'MPA', (62, 76))	('NIH3T3', 'CellLine', 'CVCL:0594', (80, 86))	('vGPCR', 'Gene', '4961465', (87, 92))	('COX-2', 'Gene', (14, 19))
505890	33057440	Taken together our results suggest that COX-2 inhibition blocks tumor angiogenesis at least partly by inhibiting VEGF secretion by vGPCR expressing cells.	('VEGF secretion', 'MPA', (113, 127))	('inhibition', 'Var', (46, 56))	('tumor', 'Disease', (64, 69))	('inhibiting', 'NegReg', (102, 112))	('vGPCR', 'Gene', (131, 136))	('COX-2', 'Gene', (40, 45))	('COX-2', 'Gene', '5743', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('vGPCR', 'Gene', '4961465', (131, 136))	('blocks', 'NegReg', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
505898	33057440	Using this insight, we have identified molecular signaling components of the cascades that are triggered by expression of the virus-encoded oncogene vGPCR and mediate its tumorigenic capabilities.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('expression', 'Species', '29278', (108, 118))	('vGPCR', 'Gene', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('vGPCR', 'Gene', '4961465', (149, 154))	('expression', 'Var', (108, 118))
505905	33057440	We found that inhibition of COX-2 in cells with the NSAID NS398 impairs vGPCR-driven angiogenesis, in this intradermal angiogenic assay the cells are treated with the inhibitors and not the animals.	('NSAID NS398', 'Var', (52, 63))	('COX-2', 'Gene', (28, 33))	('COX-2', 'Gene', '5743', (28, 33))	('impairs', 'NegReg', (64, 71))	('vGPCR', 'Gene', (72, 77))	('NS398', 'Var', (58, 63))	('vGPCR', 'Gene', '4961465', (72, 77))	('NS398', 'Chemical', 'MESH:C080955', (58, 63))	('inhibition', 'NegReg', (14, 24))
505909	33057440	Tumors from animals treated with Celecoxib showed a significant decrease in total and mature vasculature that correlated with a decrease in tumor cell VEGF production.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('decrease', 'NegReg', (64, 72))	('Celecoxib', 'Chemical', 'MESH:D000068579', (33, 42))	('Celecoxib', 'Var', (33, 42))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('decrease', 'NegReg', (128, 136))	('tumor', 'Disease', (140, 145))
505947	33057440	KSHV vGPCR-deleted mutant and its revertant in the Bac16 platform were kindly provided by Drs.	('KSHV', 'Species', '37296', (0, 4))	('vGPCR', 'Gene', '4961465', (5, 10))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('mutant', 'Var', (19, 25))	('vGPCR', 'Gene', (5, 10))
505951	33057440	NS398 (10 muM), PD98059 (20 muM) and SB220025 (10 uM) and SB203580 (10uM) were from Calbiochem (San Diego, California) and Celecoxib (Celebrex ) was from Pharmacia, Pfizer Inc (New York, New York).	('Celebrex', 'Chemical', 'MESH:D000068579', (134, 142))	('SB220025', 'Chemical', 'MESH:C110631', (37, 45))	('SB203580', 'Var', (58, 66))	('NS398', 'Chemical', 'MESH:C080955', (0, 5))	('SB203580', 'Chemical', 'MESH:C093642', (58, 66))	('PD98059', 'Var', (16, 23))	('Celecoxib', 'Chemical', 'MESH:D000068579', (123, 132))	('PD98059', 'Chemical', 'MESH:C093973', (16, 23))
505978	33057440	Briefly: after blocking, samples were incubated ON with anti-CD31 (Pharmingen, San Diego, CA), anti-alpha-SMA (Sigma, San Louis, Missouri) or isotype-matched control antibodies as indicated.	('CD31', 'Gene', (61, 65))	('CD31', 'Gene', '5175', (61, 65))	('anti-alpha-SMA', 'Var', (95, 109))
505990	32089919	Morcellation has also been associated with dissemination of benign pathologic processes such as endometriosis and leiomyomas.	('associated', 'Reg', (27, 37))	('endometriosis and leiomyomas', 'Disease', 'MESH:D004715', (96, 124))	('dissemination', 'Disease', (43, 56))	('endometriosis', 'Phenotype', 'HP:0030127', (96, 109))	('Morcellation', 'Var', (0, 12))
506029	32089919	Recent molecular studies show identical ARID1A and PIK3CA mutations as well as loss of PTEN heterozygosity in endometriosis lesions adjacent to clear cell and endometrioid adenocarcinomas as well as in the carcinomas themselves.	('mutations', 'Var', (58, 67))	('heterozygosity', 'Var', (92, 106))	('PTEN', 'Gene', '5728', (87, 91))	('carcinomas', 'Disease', (206, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('carcinomas', 'Disease', 'MESH:D002277', (177, 187))	('PIK3CA', 'Gene', (51, 57))	('endometriosis', 'Phenotype', 'HP:0030127', (110, 123))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D018269', (159, 187))	('ARID1A', 'Gene', (40, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('carcinomas', 'Disease', 'MESH:D002277', (206, 216))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (159, 186))	('carcinomas', 'Disease', (177, 187))	('endometriosis lesions', 'Disease', (110, 131))	('ARID1A', 'Gene', '8289', (40, 46))	('loss', 'NegReg', (79, 83))	('PTEN', 'Gene', (87, 91))	('endometriosis lesions', 'Disease', 'MESH:D004715', (110, 131))	('PIK3CA', 'Gene', '5290', (51, 57))	('endometrioid adenocarcinomas', 'Disease', (159, 187))
506036	32089919	Interestingly, similar JAZF1-SUZ12, EPC1-PHF1 fusions, and PHF1 rearrangements have been reported in both uterine and extrauterine endometrial stromal sarcomas, including those associated with endometriosis.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('endometriosis', 'Phenotype', 'HP:0030127', (193, 206))	('endometrial stromal sarcomas', 'Disease', (131, 159))	('fusions', 'Var', (46, 53))	('SUZ12', 'Gene', (29, 34))	('rearrangements', 'Var', (64, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('PHF1', 'Gene', (59, 63))	('SUZ12', 'Gene', '23512', (29, 34))	('reported', 'Reg', (89, 97))	('PHF1', 'Gene', (41, 45))	('PHF1', 'Gene', '5252', (59, 63))	('JAZF1', 'Gene', '221895', (23, 28))	('EPC1', 'Gene', '80314', (36, 40))	('endometriosis', 'Disease', 'MESH:D004715', (193, 206))	('EPC1', 'Gene', (36, 40))	('uterine and', 'Disease', (106, 117))	('JAZF1', 'Gene', (23, 28))	('endometriosis', 'Disease', (193, 206))	('PHF1', 'Gene', '5252', (41, 45))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (131, 159))
506038	32089919	's finding of somatic cancer-driver hotspot mutations in KRAS, ERBB2, PIK3CA, and CTNNB1 and heterozygous PTEN loss in archived endometriotic lesions.	('hotspot', 'PosReg', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('endometriotic lesions', 'Disease', 'MESH:D051437', (128, 149))	('CTNNB1', 'Gene', (82, 88))	('cancer', 'Disease', (22, 28))	('ERBB2', 'Gene', '2064', (63, 68))	('PIK3CA', 'Gene', (70, 76))	('ERBB2', 'Gene', (63, 68))	('KRAS', 'Gene', (57, 61))	('mutations', 'Var', (44, 53))	('PTEN', 'Gene', (106, 110))	('CTNNB1', 'Gene', '1499', (82, 88))	('PTEN', 'Gene', '5728', (106, 110))	('KRAS', 'Gene', '3845', (57, 61))	('endometriotic lesions', 'Disease', (128, 149))	('PIK3CA', 'Gene', '5290', (70, 76))
506042	32089919	Regardless of the true incidence of occult malignancies following surgery for benign gynecologic conditions, the use of power morcellation has been associated with the upstaging of the occult cancers, the consequences of which can be devastating for the individual patient.	('occult cancers', 'Disease', 'MESH:D009369', (185, 199))	('power morcellation', 'Var', (120, 138))	('upstaging', 'PosReg', (168, 177))	('occult cancers', 'Disease', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('use', 'Var', (113, 116))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('occult malignancies', 'Disease', (36, 55))	('patient', 'Species', '9606', (265, 272))	('occult malignancies', 'Disease', 'MESH:D009382', (36, 55))
506054	32021270	Bone marrow aspirate and biopsy had been conducted in May 2017, which demonstrated 5.5% blasts expressing CD13, CD33, CD34, CD117 and MPO, and the cytogenetic analysis demonstrated t(8;21)(q22;q22), and molecular studies showed a positive RUNX1-RUNX1T1 rearrangement.	('MPO', 'Gene', (134, 137))	('CD13', 'Gene', '290', (106, 110))	('CD33', 'Gene', '945', (112, 116))	('CD33', 'Gene', (112, 116))	('RUNX1T1', 'Gene', (245, 252))	('t(8;21)(q22;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (181, 197))	('CD34', 'Gene', '947', (118, 122))	('t(8;21)(q22;q22', 'Var', (181, 196))	('CD117', 'Gene', '3815', (124, 129))	('RUNX1', 'Gene', (239, 244))	('RUNX1', 'Gene', '861', (239, 244))	('CD13', 'Gene', (106, 110))	('rearrangement', 'Var', (253, 266))	('CD34', 'Gene', (118, 122))	('RUNX1', 'Gene', (245, 250))	('CD117', 'Gene', (124, 129))	('RUNX1T1', 'Gene', '862', (245, 252))	('RUNX1', 'Gene', '861', (245, 250))	('MPO', 'Gene', '4353', (134, 137))
506056	32021270	Emergency cranial CT demonstrated a circular hyperdense mass (54mmx37mm), which was surrounded by hypodense peritumoral edema in the left cerebellar hemisphere, and the density of the lesions was uniform and the margin was clear.	('edema', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('54mmx37mm', 'Var', (62, 71))	('edema', 'Disease', 'MESH:D004487', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('edema', 'Phenotype', 'HP:0000969', (120, 125))	('tumor', 'Disease', (112, 117))
506068	32021270	Bone marrow aspirate and biopsy had been conducted in May 2017, which demonstrated 5.5% blasts expressing CD13, CD33, CD34, CD117 and MPO, and the cytogenetic analysis demonstrated t(8;21)(q22;q22), and molecular studies showed a positive RUNX1-RUNX1T1 rearrangement, but negative for c-KIT, FLT3, NPM1, or CEBPA mutations.	('MPO', 'Gene', (134, 137))	('CEBPA', 'Gene', (307, 312))	('FLT3', 'Gene', (292, 296))	('CD13', 'Gene', '290', (106, 110))	('c-KIT', 'Gene', (285, 290))	('NPM1', 'Gene', '4869', (298, 302))	('c-KIT', 'Gene', '3815', (285, 290))	('CD33', 'Gene', '945', (112, 116))	('CD33', 'Gene', (112, 116))	('FLT3', 'Gene', '2322', (292, 296))	('RUNX1T1', 'Gene', (245, 252))	('t(8;21)(q22;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (181, 197))	('CD34', 'Gene', '947', (118, 122))	('CD117', 'Gene', '3815', (124, 129))	('RUNX1', 'Gene', (239, 244))	('NPM1', 'Gene', (298, 302))	('RUNX1', 'Gene', '861', (239, 244))	('CD13', 'Gene', (106, 110))	('rearrangement', 'Var', (253, 266))	('CD34', 'Gene', (118, 122))	('RUNX1', 'Gene', (245, 250))	('CEBPA', 'Gene', '1050', (307, 312))	('CD117', 'Gene', (124, 129))	('RUNX1T1', 'Gene', '862', (245, 252))	('RUNX1', 'Gene', '861', (245, 250))	('MPO', 'Gene', '4353', (134, 137))
506102	32021270	The lipophilic idarubicin and high-dose cytarabine both can quickly pass through the blood-brain barrier, and penetrate into tumor cells and dissolve tumor cells, thus effectively control the progression of the disease.	('cytarabine', 'Chemical', 'MESH:D003561', (40, 50))	('control', 'Reg', (180, 187))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('progression', 'MPA', (192, 203))	('tumor', 'Disease', (125, 130))	('lipophilic', 'Var', (4, 14))	('idarubicin', 'Chemical', 'MESH:D015255', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
506145	29780156	The chimeric fusion oncogene EWS-FLI1 is considered a therapeutic target for Ewing sarcoma based on the causal association with the translocation of the EWS gene.	('Ewing sarcoma', 'Gene', '2130', (77, 90))	('Ewing sarcoma', 'Gene', (77, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('EWS', 'Gene', (29, 32))	('EWS', 'Gene', '2130', (153, 156))	('FLI1', 'Gene', (33, 37))	('EWS', 'Gene', (153, 156))	('EWS', 'Gene', '2130', (29, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('translocation', 'Var', (132, 145))	('FLI1', 'Gene', '2313', (33, 37))
506181	28454538	We have also previously demonstrated the therapeutic effect of recombining hydrophilic and hydrophobic mistletoe constituents in the viscumTT extract for Ewing sarcoma (Twardziok et al., 2016, manuscript accepted 07/2016) and acute leukaemia cells in vitro and in vivo cancer models.	('TT', 'Chemical', '-', (139, 141))	('Ewing sarcoma', 'Disease', (154, 167))	('leukaemia', 'Disease', 'MESH:D007938', (232, 241))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('acute leukaemia', 'Phenotype', 'HP:0002488', (226, 241))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (154, 167))	('rat', 'Species', '10116', (31, 34))	('recombining', 'Var', (63, 74))	('leukaemia', 'Disease', (232, 241))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (154, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
506198	28454538	Normalisation and identification of differentially expressed genes was performed using DE-Seq software (Bioconductor open source software) to calculate fold-change relative to untreated control cells, false discovery rate (FDR) and p value using the negative binomial distribution, with p <= 0.05 considered as significant.	('rat', 'Species', '10116', (217, 220))	('fold-change', 'MPA', (152, 163))	('p value', 'Var', (232, 239))
506226	28454538	Primary antibodies were directed against p-MAPK14 (Thr180/Tyr182, #9211 Cell Signaling Technology, Danvers, MA, USA), LC3B (#2775 Cell Signaling Technology), EIF2AK3 (#3192, Cell Signaling Technology), p-MAPK8 (sc-6254, Santa Cruz biotechnology, Dallas, TX, USA), HSPA5 (#G8918, Sigma-Aldrich) and ss-actin conjugated directly to peroxidase (#A3854, Sigma-Aldrich).	('MAPK14', 'Gene', '1432', (43, 49))	('Thr180', 'Chemical', '-', (51, 57))	('Tyr182', 'Chemical', '-', (58, 64))	('EIF2AK3', 'Gene', '9451', (158, 165))	('HSPA5', 'Gene', '3309', (264, 269))	('MAPK8', 'Gene', '5599', (204, 209))	('LC3B', 'Gene', '81631', (118, 122))	('EIF2AK3', 'Gene', (158, 165))	('HSPA5', 'Gene', (264, 269))	('MAPK8', 'Gene', (204, 209))	('LC3B', 'Gene', (118, 122))	('#G8918', 'Var', (271, 277))	('MAPK14', 'Gene', (43, 49))
506227	28454538	To measure the impact of TLR4 signalling, MAPK14 and MAPK8 activation or oxidative stress on apoptotic induction, TC-71 cells were pre-incubated with specific inhibitors for 1 h followed by an incubation with ~ IC50 extract concentrations for 24 h. Specific inhibitor treatment included 5-50 muM SB203580 (Cell Signaling Technology), 1 muM - 25 muM SP600125 (Sigma-Aldrich), 1-10 mM N-acetylcysteine (NAC, Sigma-Aldrich), 0.1-10 mug mL-1 LPS-RS (InvivoGen, San Diego, CA, USA).	('muM', 'Gene', '56925', (292, 295))	('muM', 'Gene', (336, 339))	('rat', 'Species', '10116', (231, 234))	('SP600125', 'Chemical', 'MESH:C432165', (349, 357))	('MAPK14', 'Gene', (42, 48))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (383, 399))	('MAPK8', 'Gene', '5599', (53, 58))	('muM', 'Gene', (292, 295))	('MAPK14', 'Gene', '1432', (42, 48))	('NAC', 'Chemical', 'MESH:D000111', (401, 404))	('muM', 'Gene', '56925', (345, 348))	('oxidative stress', 'Phenotype', 'HP:0025464', (73, 89))	('MAPK8', 'Gene', (53, 58))	('SB203580', 'Chemical', 'MESH:C093642', (296, 304))	('SB203580', 'Var', (296, 304))	('muM', 'Gene', '56925', (336, 339))	('muM', 'Gene', (345, 348))	('TC-71', 'CellLine', 'CVCL:2213', (114, 119))
506260	28454538	In order to further analyse the role of stress-mediated MAPK or TLR signalling and oxidative stress in mistletoe-mediated apoptosis of Ewing sarcoma cells, TC-71 cells were treated with viscumTT, viscum or TT for 24 h in the absence or presence of the SB203580 MAPK14 inhibitor, the SP600125 MAPK8 inhibitor, the LPS-RS TLR4 inhibitor or the antioxidant NAC.	('SB203580', 'Chemical', 'MESH:C093642', (252, 260))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (135, 148))	('TC-71', 'CellLine', 'CVCL:2213', (156, 161))	('SB203580', 'Var', (252, 260))	('MAPK8', 'Gene', (292, 297))	('MAPK14', 'Gene', (261, 267))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (135, 148))	('TT', 'Chemical', '-', (192, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('SP600125', 'Var', (283, 291))	('SP600125', 'Chemical', 'MESH:C432165', (283, 291))	('oxidative stress', 'Phenotype', 'HP:0025464', (83, 99))	('Ewing sarcoma', 'Disease', (135, 148))	('MAPK14', 'Gene', '1432', (261, 267))	('TT', 'Chemical', '-', (206, 208))	('MAPK8', 'Gene', '5599', (292, 297))	('NAC', 'Chemical', 'MESH:D000111', (354, 357))
506263	28454538	Higher MAPK8 and MAPK14 inhibitor concentrations (up to 50 muM SB203580 and 25 muM SP600125), as well as higher concentrations of the other used inhibitors (Table 3), all increased apoptosis in TC-71 cells.	('MAPK8', 'Gene', (7, 12))	('MAPK14', 'Gene', (17, 23))	('muM', 'Gene', '56925', (59, 62))	('muM', 'Gene', '56925', (79, 82))	('MAPK14', 'Gene', '1432', (17, 23))	('SB203580', 'Var', (63, 71))	('rat', 'Species', '10116', (119, 122))	('apoptosis', 'CPA', (181, 190))	('muM', 'Gene', (59, 62))	('muM', 'Gene', (79, 82))	('SB203580', 'Chemical', 'MESH:C093642', (63, 71))	('rat', 'Species', '10116', (41, 44))	('SP600125', 'Chemical', 'MESH:C432165', (83, 91))	('increased', 'PosReg', (171, 180))	('TC-71', 'CellLine', 'CVCL:2213', (194, 199))	('MAPK8', 'Gene', '5599', (7, 12))
506300	28454538	Notably, the applied MAPK14 and MAPK8 inhibitors (up to 10 muM SB203580, 5 muM SP600125) were not able to inhibit the activation of the kinases and to prevent the induction of apoptosis by viscumTT or viscum.	('SP600125', 'Chemical', 'MESH:C432165', (79, 87))	('muM', 'Gene', '56925', (59, 62))	('MAPK14', 'Gene', (21, 27))	('kinases', 'Pathway', (136, 143))	('SB203580', 'Var', (63, 71))	('MAPK8', 'Gene', '5599', (32, 37))	('MAPK8', 'Gene', (32, 37))	('prevent', 'NegReg', (151, 158))	('muM', 'Gene', (59, 62))	('inhibit', 'NegReg', (106, 113))	('muM', 'Gene', '56925', (75, 78))	('SB203580', 'Chemical', 'MESH:C093642', (63, 71))	('MAPK14', 'Gene', '1432', (21, 27))	('apoptosis', 'CPA', (176, 185))	('TT', 'Chemical', '-', (195, 197))	('muM', 'Gene', (75, 78))	('SP600125', 'Var', (79, 87))
506302	28454538	Others have used superior concentrations (up to 30 muM SB203580 or SP600125) to achieve a block in mistletoe mediated apoptosis induction without a loss of cell viability in leukaemia and hepatocarcinoma cells suggesting that higher concentrations might be necessary to effectively block apoptosis.	('muM', 'Gene', '56925', (51, 54))	('SP600125', 'Chemical', 'MESH:C432165', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('leukaemia and hepatocarcinoma', 'Disease', 'MESH:D007938', (174, 203))	('rat', 'Species', '10116', (33, 36))	('SP600125', 'Var', (67, 75))	('SB203580', 'Var', (55, 63))	('SB203580', 'Chemical', 'MESH:C093642', (55, 63))	('muM', 'Gene', (51, 54))	('rat', 'Species', '10116', (240, 243))
506329	28191313	Chromosomal translocation with fusion of the SYT and SSX genes has been described and is currently used as a diagnostic marker, although the full impact of the fusion is unknown.	('SSX', 'Gene', (53, 56))	('SYT', 'Gene', '6760', (45, 48))	('SSX', 'Gene', '6757', (53, 56))	('Chromosomal', 'Disease', (0, 11))	('fusion', 'Var', (31, 37))	('SYT', 'Gene', (45, 48))
506346	28191313	The chromosomal translocation t(X;18)(p11.2;q11.2) fuses the SS18 (SYT) gene to the SSX gene (predominantly SSX1 or SSX2) and is regarded as a founding event in the oncogenic development of synovial sarcoma.	('SSX', 'Gene', '6757', (84, 87))	('SSX', 'Gene', '6757', (116, 119))	('SSX1', 'Gene', '6756', (108, 112))	('SYT', 'Gene', '6760', (67, 70))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 50))	('SSX', 'Gene', (108, 111))	('SSX1', 'Gene', (108, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('SS18', 'Gene', '6760', (61, 65))	('SSX', 'Gene', (84, 87))	('SSX', 'Gene', (116, 119))	('SSX2', 'Gene', (116, 120))	('synovial sarcoma', 'Disease', (190, 206))	('SSX2', 'Gene', '6757', (116, 120))	('synovial sarcoma', 'Disease', 'MESH:D013584', (190, 206))	('fuses', 'Var', (51, 56))	('SYT', 'Gene', (67, 70))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (190, 206))	('SS18', 'Gene', (61, 65))	('SSX', 'Gene', '6757', (108, 111))
506356	28191313	Some have reported that the SYT-SSX1 fusion approximately doubles the risk of metastatic tumor development compared with SYT-SSX2.	('SYT', 'Gene', (121, 124))	('SSX1', 'Gene', (32, 36))	('SSX2', 'Gene', (125, 129))	('SYT', 'Gene', '6760', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('SYT', 'Gene', '6760', (121, 124))	('SSX1', 'Gene', '6756', (32, 36))	('SSX2', 'Gene', '6757', (125, 129))	('fusion', 'Var', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('SYT', 'Gene', (28, 31))
506357	28191313	Intriguingly, a similar pattern was evident in a survival study demonstrating a median survival of 6.1 years for SS patients with an SYT-SSX1 fusion gene compared with 13.7 years for those with SYT-SSX2.	('SSX2', 'Gene', '6757', (198, 202))	('fusion gene', 'Var', (142, 153))	('SSX1', 'Gene', '6756', (137, 141))	('patients', 'Species', '9606', (116, 124))	('SSX2', 'Gene', (198, 202))	('SSX1', 'Gene', (137, 141))	('SYT', 'Gene', (194, 197))	('SYT', 'Gene', (133, 136))	('SYT', 'Gene', '6760', (194, 197))	('SYT', 'Gene', '6760', (133, 136))
506361	28191313	A whole blood microRNA signature shows that SS patients demonstrate significant upregulation of seven microRNAs (miR-99a-5p, miR-146b-5p, miR-148b-3p, miR-195-5p, miR-223-3p, miR-500b-3p and miR-505-3p) compared with patients in remission and healthy controls.	('miR-195-5p', 'Var', (151, 161))	('miR-148b-3p', 'Var', (138, 149))	('miR-223-3p', 'Var', (163, 173))	('patients', 'Species', '9606', (217, 225))	('upregulation', 'PosReg', (80, 92))	('miR-99a-5p', 'Var', (113, 123))	('patients', 'Species', '9606', (47, 55))	('miR-146b-5p', 'Var', (125, 136))
506397	28191313	In colon cancer, SCRN1 expression promoted exocytosis secretion of MMP2 and MMP, while silencing this gene reduced MMP2 secretion, inhibited cell proliferation and decreased invasion capability.	('silencing', 'Var', (87, 96))	('MMP2', 'Gene', '4313', (115, 119))	('decreased', 'NegReg', (164, 173))	('MMP2', 'Gene', '4313', (67, 71))	('reduced', 'NegReg', (107, 114))	('MMP', 'MPA', (76, 79))	('SCRN1', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cell proliferation', 'CPA', (141, 159))	('MMP2', 'Gene', (115, 119))	('promoted', 'PosReg', (34, 42))	('SCRN1', 'Gene', '9805', (17, 22))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('invasion capability', 'CPA', (174, 193))	('inhibited', 'NegReg', (131, 140))	('MMP2', 'Gene', (67, 71))	('colon cancer', 'Disease', (3, 15))
506401	28191313	Metastasis-free survival was significantly higher (62.8% vs. 16.7%) in the SS patient group with SCRN1 positive tumors compared to that with SCRN1 negative tumors (p = 0.0012).	('SCRN1', 'Gene', '9805', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('patient', 'Species', '9606', (78, 85))	('higher', 'PosReg', (43, 49))	('Metastasis', 'Disease', (0, 10))	('Metastasis', 'Disease', 'MESH:D009362', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('positive', 'Var', (103, 111))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('SCRN1', 'Gene', (141, 146))	('SCRN1', 'Gene', (97, 102))	('tumors', 'Disease', (156, 162))	('tumors', 'Disease', (112, 118))	('SCRN1', 'Gene', '9805', (97, 102))
506406	28191313	Importantly, high expression of EZH2 is predictive of developing distant metastasis even in the better-differentiated MPSS and BPSS subtypes.	('distant metastasis', 'CPA', (65, 83))	('high expression', 'Var', (13, 28))	('EZH2', 'Gene', '2146', (32, 36))	('EZH2', 'Gene', (32, 36))	('developing', 'PosReg', (54, 64))
506410	28191313	showed that EZH2 knockdown is sufficient to reduce distant metastasis in vivo.	('distant metastasis', 'CPA', (51, 69))	('reduce', 'NegReg', (44, 50))	('knockdown', 'Var', (17, 26))	('EZH2', 'Gene', '2146', (12, 16))	('EZH2', 'Gene', (12, 16))
506424	28191313	Tumor cells expressing CXCR4 that detach from the primary tumor and enter the circulatory system can migrate toward organs that express its ligand CXCL12.	('CXCL12', 'Gene', (147, 153))	('tumor', 'Disease', (58, 63))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('migrate', 'CPA', (101, 108))	('CXCL12', 'Gene', '6387', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('CXCR4', 'Var', (23, 28))
506426	28191313	A study of SS patients found that 5-year overall survival (OS) rates were 47% for those with positive CXCR4 staining, and 86% (P = 0.0003) for those with negative CXCR4 staining.	('patients', 'Species', '9606', (14, 22))	('overall survival', 'CPA', (41, 57))	('positive', 'Var', (93, 101))	('CXCR4', 'MPA', (102, 107))
506428	28191313	Importantly, it was found that SS cultures contain a subpopulation of cells expressing high levels of CXCR4 that also express high levels stem cell markers (NANOG, OCT4, SOX2), and these cells have an increased tumor initiating capacity in xenographic mouse models.	('NANOG', 'Gene', '71950', (157, 162))	('CXCR4', 'Var', (102, 107))	('increased', 'PosReg', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('NANOG', 'Gene', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('mouse', 'Species', '10090', (252, 257))	('OCT4', 'Gene', (164, 168))	('OCT4', 'Gene', '18999', (164, 168))
506517	23255356	Key findings from recent clinical trials include safe reduction in therapy for low risk rhabdomyosarcoma (RMS), validation of FOXO1 fusion as a prognostic factor, a modest improvement in outcome for high-risk RMS, and a biologically-designed non-cytotoxic therapy for pediatric desmoid tumor.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (88, 104))	('therapy', 'MPA', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('rhabdomyosarcoma', 'Disease', (88, 104))	('FOXO1', 'Gene', (126, 131))	('reduction', 'NegReg', (54, 63))	('FOXO1', 'Gene', '2308', (126, 131))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (88, 104))	('desmoid tumor', 'Phenotype', 'HP:0100245', (278, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('desmoid tumor', 'Disease', (278, 291))	('fusion', 'Var', (132, 138))	('desmoid tumor', 'Disease', 'MESH:C535944', (278, 291))
506557	23255356	A small minority of DTs occur in children with a germline adenomatous polyposis coli (APC) gene mutation.	('DTs', 'Disease', (20, 23))	('mutation', 'Var', (96, 104))	('APC', 'Disease', 'MESH:D011125', (86, 89))	('APC', 'Disease', (86, 89))	('children', 'Species', '9606', (33, 41))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (58, 84))
506559	23255356	Risk factors for local recurrence/progression include inadequate surgical resection, beta-catenin mutation, and age < 18 years.	('beta-catenin', 'Gene', (85, 97))	('local recurrence/progression', 'CPA', (17, 45))	('mutation', 'Var', (98, 106))	('beta-catenin', 'Gene', '1499', (85, 97))
506563	23255356	The clinical activity of irinotecan, particularly when combined with vincristine (as predicted by xenograft models) was confirmed in ARST0121 (phase II study of recurrent RMS) and in D9802 and ARST0431, both phase II window studies of metastatic RMS.	('irinotecan', 'Chemical', 'MESH:D000077146', (25, 35))	('vincristine', 'Chemical', 'MESH:D014750', (69, 80))	('D9802', 'Var', (183, 188))	('clinical activity', 'MPA', (4, 21))
506578	23255356	Rarelygenetic alterations confer unique sensitivity to a molecularly targeted agent, such as the COLIA1-PDGFbeta fusion in dermatofibrosarcoma protuberans leading to imatinib sensitivity or activating ALK-related translocations in inflammatory myofibroblastic tumor leading to crizotinib sensitivity.	('alterations', 'Var', (14, 25))	('tumor', 'Disease', (260, 265))	('imatinib', 'Chemical', 'MESH:D000068877', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('activating', 'Reg', (190, 200))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (244, 265))	('dermatofibrosarcoma protuberans', 'Disease', (123, 154))	('ALK', 'Gene', '238', (201, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('ALK', 'Gene', (201, 204))	('imatinib sensitivity', 'MPA', (166, 186))	('sensitivity', 'MPA', (40, 51))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (123, 154))	('fusion', 'Var', (113, 119))	('leading to', 'Reg', (155, 165))	('crizotinib sensitivity', 'MPA', (277, 299))	('crizotinib', 'Chemical', 'MESH:D000077547', (277, 287))	('COLIA1-PDGFbeta', 'Gene', (97, 112))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (130, 142))
506579	23255356	However, the more commonly described molecular events that define a NRSTS histologic subtype, including the SYT-SSX fusion in synovial sarcoma and NF1 mutations in MPNST, are not obvious targets for pharmacologic inhibition.	('synovial sarcoma', 'Disease', 'MESH:D013584', (126, 142))	('SYT', 'Gene', (108, 111))	('MPNST', 'Gene', (164, 169))	('SYT', 'Gene', '6760', (108, 111))	('synovial sarcoma', 'Disease', (126, 142))	('NF1', 'Gene', (147, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (126, 142))	('NF1', 'Gene', '4763', (147, 150))	('mutations', 'Var', (151, 160))
506584	23255356	DT is associated with germ-line APC mutations, and frequent somatic mutations in APC or beta-catenin (CTNNB1), which encodes a downstream effector of APC; either alteration leads increased beta-catenin protein activity.	('beta-catenin', 'Gene', (189, 201))	('APC', 'Disease', (32, 35))	('APC', 'Disease', 'MESH:D011125', (150, 153))	('APC', 'Disease', (150, 153))	('APC', 'Disease', (81, 84))	('associated', 'Reg', (6, 16))	('CTNNB1', 'Gene', (102, 108))	('mutations', 'Var', (36, 45))	('beta-catenin', 'Gene', '1499', (189, 201))	('beta-catenin', 'Gene', (88, 100))	('CTNNB1', 'Gene', '1499', (102, 108))	('mutations', 'Var', (68, 77))	('APC', 'Disease', 'MESH:D011125', (32, 35))	('increased', 'PosReg', (179, 188))	('APC', 'Disease', 'MESH:D011125', (81, 84))	('beta-catenin', 'Gene', '1499', (88, 100))
506585	23255356	APC mutation enhances the activity of the peroxisome proliferator-activated receptor delta, which is blocked by non-steroidal anti-inflammatory agents.	('activity', 'MPA', (26, 34))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('enhances', 'PosReg', (13, 21))	('mutation', 'Var', (4, 12))	('APC', 'Disease', (0, 3))	('peroxisome proliferator-activated receptor delta', 'Gene', '5467', (42, 90))	('peroxisome proliferator-activated receptor delta', 'Gene', (42, 90))
506586	23255356	Pharmacological or genetic cyclooxygenase-2 inhibition suppressed intestinal polyp formation in patients with germ-line APC mutations and in mice with mutations in the orthologous mouse Apc gene.	('mutations', 'Var', (124, 133))	('Apc', 'Gene', (186, 189))	('APC', 'Disease', 'MESH:D011125', (120, 123))	('APC', 'Disease', (120, 123))	('mouse', 'Species', '10090', (180, 185))	('Apc', 'Gene', '11789', (186, 189))	('inhibition suppressed', 'NegReg', (44, 65))	('intestinal polyp formation', 'MPA', (66, 92))	('mice', 'Species', '10090', (141, 145))	('patients', 'Species', '9606', (96, 104))	('cyclooxygenase-2', 'Gene', '5743', (27, 43))	('intestinal polyp', 'Phenotype', 'HP:0005266', (66, 82))	('mutations', 'Var', (151, 160))	('cyclooxygenase-2', 'Gene', (27, 43))
506594	23255356	Even after adjusting for prognostic groups within patients with metastatic disease, the EFS on ARST0431 was superior to prior COG and international studies, particularly for patients with more "favorable" metastatic disease, including ERMS and those with lower metastatic risk scores as defined by Oberlin.	('COG', 'Chemical', '-', (126, 129))	('patients', 'Species', '9606', (50, 58))	('ARST0431', 'Var', (95, 103))	('more', 'PosReg', (188, 192))	('patients', 'Species', '9606', (174, 182))
506612	23255356	Potential agents that could be tested in high-risk RMS include crizotinib, a dual ALK and c-met inhibitor.	('ALK', 'Gene', (82, 85))	('c-met', 'Gene', (90, 95))	('crizotinib', 'Var', (63, 73))	('c-met', 'Gene', '4233', (90, 95))	('ALK', 'Gene', '238', (82, 85))	('crizotinib', 'Chemical', 'MESH:D000077547', (63, 73))
506613	23255356	ALK amplification is common in RMS, particularly ARMS and metastatic ERMS.	('ARMS', 'Disease', (49, 53))	('RMS', 'Disease', (31, 34))	('metastatic ERMS', 'Disease', (58, 73))	('amplification', 'Var', (4, 17))	('ALK', 'Gene', (0, 3))	('common', 'Reg', (21, 27))	('ALK', 'Gene', '238', (0, 3))
506645	22619567	Efficacy of Phosphatidylinositol-3 Kinase Inhibitors in a Primary Mouse Model of Undifferentiated Pleomorphic Sarcoma Recent advances in sarcoma genomics have identified novel mutations in the PI3K pathway in human sarcomas.	('Mouse', 'Species', '10090', (66, 71))	('human', 'Species', '9606', (209, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('mutations', 'Var', (176, 185))	('Sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('PI3K pathway', 'Pathway', (193, 205))	('sarcoma', 'Disease', 'MESH:D012509', (215, 222))	('sarcomas', 'Disease', 'MESH:D012509', (215, 223))	('sarcoma', 'Disease', (215, 222))	('sarcoma', 'Disease', 'MESH:D012509', (137, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('Sarcoma', 'Disease', (110, 117))	('sarcomas', 'Disease', (215, 223))	('Sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('Phosphatidylinositol-3 Kinase', 'Gene', '18708', (12, 41))	('Phosphatidylinositol-3 Kinase', 'Gene', (12, 41))	('sarcoma', 'Disease', (137, 144))
506646	22619567	Here, we use a mouse model of primary soft-tissue sarcoma for preclinical testing of doxorubicin and inhibitors of the PI3K pathway: BKM120 (PI3K inhibitor) and BEZ235 (a dual PI3K/mTOR inhibitor).	('mTOR', 'Gene', '56717', (181, 185))	('doxorubicin', 'Chemical', 'MESH:D004317', (85, 96))	('BKM120', 'Chemical', 'MESH:C571178', (133, 139))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('BEZ235', 'Chemical', 'MESH:C531198', (161, 167))	('sarcoma', 'Disease', (50, 57))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (42, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('PI3K pathway', 'Pathway', (119, 131))	('mouse', 'Species', '10090', (15, 20))	('BKM120', 'Var', (133, 139))	('mTOR', 'Gene', (181, 185))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (38, 57))
506648	22619567	Treatment with BKM120 elicited a partial response in 50% of tumors (n = 10), which was also seen in combination with doxorubicin (n = 10).	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', (60, 66))	('BKM120', 'Var', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('doxorubicin', 'Chemical', 'MESH:D004317', (117, 128))	('BKM120', 'Chemical', 'MESH:C571178', (15, 21))
506649	22619567	Additionally, BKM120 treatment produced a robust delay in tumor growth kinetics.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('BKM120 treatment', 'Var', (14, 30))	('delay', 'NegReg', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('BKM120', 'Chemical', 'MESH:C571178', (14, 20))
506651	22619567	Combining BEZ235 with doxorubicin (n = 10) increased the complete response rate to 50% (P = 0.035).	('doxorubicin', 'Chemical', 'MESH:D004317', (22, 33))	('BEZ235', 'Var', (10, 16))	('BEZ235', 'Chemical', 'MESH:C531198', (10, 16))	('increased', 'PosReg', (43, 52))
506659	22619567	Genomic analyses of sarcomas with complex karyotypes have recently identified novel mutations that may be targeted by molecularly directed therapies.	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcomas', 'Disease', (20, 28))	('mutations', 'Var', (84, 93))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
506660	22619567	One of the most frequent somatic mutations is found in the PIK3CA gene, which encodes the catalytic subunit of phosphatidylinositol-3 kinase (PI3K).	('PIK3CA', 'Gene', (59, 65))	('phosphatidylinositol-3 kinase', 'Gene', (111, 140))	('phosphatidylinositol-3 kinase', 'Gene', '18708', (111, 140))	('mutations', 'Var', (33, 42))
506665	22619567	We have previously utilized the Cre-loxP system in mice to activate conditional mutations in Kras and Trp53 (LSL-KrasG12D; p53flox/flox) by intramuscular delivery of Cre recombinase to generate high-grade primary soft-tissue sarcomas.	('p53flox/flox', 'Var', (123, 135))	('mice', 'Species', '10090', (51, 55))	('mutations', 'Var', (80, 89))	('sarcomas', 'Disease', 'MESH:D012509', (225, 233))	('Trp53', 'Gene', '22059', (102, 107))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (217, 232))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (213, 233))	('sarcomas', 'Phenotype', 'HP:0100242', (225, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('Kras', 'Gene', (93, 97))	('sarcomas', 'Disease', (225, 233))	('Trp53', 'Gene', (102, 107))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (213, 232))
506668	22619567	Here, we use this model to test the response of primary mouse sarcomas to doxorubicin and to inhibition of the PI3K pathway with BKM120 (PI3K inhibitor) and BEZ235 (dual inhibitor of PI3K and mTOR), both provided by Novartis.	('Novartis', 'Disease', (216, 224))	('inhibition', 'NegReg', (93, 103))	('sarcomas', 'Disease', 'MESH:D012509', (62, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('BKM120', 'Chemical', 'MESH:C571178', (129, 135))	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('PI3K pathway', 'Pathway', (111, 123))	('BEZ235', 'Chemical', 'MESH:C531198', (157, 163))	('mouse', 'Species', '10090', (56, 61))	('sarcomas', 'Disease', (62, 70))	('mTOR', 'Gene', (192, 196))	('Novartis', 'Disease', 'None', (216, 224))	('BKM120', 'Var', (129, 135))	('mTOR', 'Gene', '56717', (192, 196))
506670	22619567	Therefore, the juxtaposition of the pan-PI3K inhibitor (BKM120) and the PI3K/mTOR dual inhibitor (BEZ235) may reveal important information about the design of future molecularly targeted therapies for soft-tissue sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (213, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('BKM120', 'Var', (56, 62))	('BEZ235', 'Chemical', 'MESH:C531198', (98, 104))	('sarcomas', 'Disease', (213, 221))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (201, 220))	('BKM120', 'Chemical', 'MESH:C571178', (56, 62))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (205, 220))	('mTOR', 'Gene', (77, 81))	('mTOR', 'Gene', '56717', (77, 81))	('sarcomas', 'Disease', 'MESH:D012509', (213, 221))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (201, 221))
506673	22619567	The BEZ235-treated cells exhibited decreased levels of phospho-S6, a molecule downstream of the mTOR pathway (Figure 1).	('levels', 'MPA', (45, 51))	('mTOR', 'Gene', (96, 100))	('mTOR', 'Gene', '56717', (96, 100))	('BEZ235', 'Chemical', 'MESH:C531198', (4, 10))	('BEZ235-treated', 'Var', (4, 18))	('decreased', 'NegReg', (35, 44))	('phospho-S6', 'MPA', (55, 65))
506674	22619567	Additionally, the BKM120-treated cells demonstrated decreased levels of phospho-S6, showing the PI3K pathway was inhibited through inhibition of this downstream target.	('levels', 'MPA', (62, 68))	('inhibited', 'NegReg', (113, 122))	('decreased', 'NegReg', (52, 61))	('phospho-S6', 'MPA', (72, 82))	('BKM120-treated', 'Var', (18, 32))	('PI3K pathway', 'Pathway', (96, 108))	('BKM120', 'Chemical', 'MESH:C571178', (18, 24))	('inhibition', 'NegReg', (131, 141))
506675	22619567	These data suggest that BEZ235 treatment in mouse sarcoma cells effectively inhibits targets of the mTOR pathway and BKM120 treatment results in inhibition of PI3K pathway targets.	('mTOR', 'Gene', '56717', (100, 104))	('BKM120', 'Var', (117, 123))	('mouse', 'Species', '10090', (44, 49))	('BEZ235', 'Chemical', 'MESH:C531198', (24, 30))	('targets', 'MPA', (85, 92))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('inhibition', 'NegReg', (145, 155))	('inhibits', 'NegReg', (76, 84))	('sarcoma', 'Disease', (50, 57))	('BKM120', 'Chemical', 'MESH:C571178', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('PI3K pathway', 'Pathway', (159, 171))	('mTOR', 'Gene', (100, 104))	('BEZ235', 'Var', (24, 30))
506678	22619567	Tumors were generated by intramuscular delivery of an adenovirus that expresses Cre recombinase into compound mutant mice with conditional mutations in both oncogenic Kras (LSL-KrasG12D) and mutant Trp53 (p53flox/flox).	('Trp53', 'Gene', '22059', (198, 203))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (139, 148))	('mice', 'Species', '10090', (117, 121))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutant', 'Var', (191, 197))	('Trp53', 'Gene', (198, 203))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
506688	22619567	Mice with tumors 150-300 mm3 in volume were treated with BKM120 (50 mg/kg, administered 5 days/week) for 4-7 weeks.	('BKM120', 'Chemical', 'MESH:C571178', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('BKM120', 'Var', (57, 63))	('Mice', 'Species', '10090', (0, 4))
506689	22619567	Treatment with either BKM120 or BKM120 with doxorubicin delayed tumor growth in comparison to vehicle alone (Figure 3, Table 1).	('BKM120', 'Chemical', 'MESH:C571178', (32, 38))	('BKM120', 'Chemical', 'MESH:C571178', (22, 28))	('tumor', 'Disease', (64, 69))	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('BKM120', 'Var', (22, 28))	('BKM120', 'Var', (32, 38))	('delayed', 'NegReg', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
506691	22619567	The combination of BKM120 with doxorubicin had a partial response rate of 60% (n = 6/10), which was similar to BKM120 single-agent treatment (P = 0.343).	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('BKM120', 'Chemical', 'MESH:C571178', (111, 117))	('doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('BKM120', 'Var', (19, 25))	('combination', 'Interaction', (4, 15))
506695	22619567	Tumors treated with BKM120 required 18.0 days (range 10-35 days) to triple in volume (P = 0.0133, compared to vehicle alone).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('triple', 'PosReg', (68, 74))	('BKM120', 'Chemical', 'MESH:C571178', (20, 26))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BKM120', 'Var', (20, 26))
506696	22619567	The combination of BKM120 with doxorubicin had the greatest time to triple the tumor volume of 19.4 days (range 12-27 days), but this was not statistically different than BKM120 alone (P = 0.657).	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('tumor', 'Disease', (79, 84))	('BKM120', 'Chemical', 'MESH:C571178', (171, 177))	('triple', 'PosReg', (68, 74))	('doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('BKM120', 'Var', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('combination', 'Interaction', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
506699	22619567	Tumor growth was delayed in mice receiving BEZ235 or BEZ235 with doxorubicin in comparison to vehicle alone (Figure 5, Table 3).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('delayed', 'NegReg', (17, 24))	('mice', 'Species', '10090', (28, 32))	('BEZ235', 'Var', (53, 59))	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))	('BEZ235', 'Var', (43, 49))	('BEZ235', 'Chemical', 'MESH:C531198', (53, 59))	('Tumor growth', 'CPA', (0, 12))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
506700	22619567	Complete tumor response was observed in 11.1% of the BEZ235-treated mice (n = 1/9), and 22.2% of tumors responded partially to treatment (n = 2/9).	('mice', 'Species', '10090', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (9, 14))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('BEZ235-treated', 'Var', (53, 67))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('BEZ235', 'Chemical', 'MESH:C531198', (53, 59))
506705	22619567	To assess toxicity of BEZ235 or BKM120, we measured the weight of mice with tumors treated with doxorubicin, BKM120, or BKM120 and doxorubicin.	('BKM120', 'Chemical', 'MESH:C571178', (32, 38))	('doxorubicin', 'Chemical', 'MESH:D004317', (131, 142))	('BKM120', 'Chemical', 'MESH:C571178', (109, 115))	('BKM120', 'Chemical', 'MESH:C571178', (120, 126))	('toxicity', 'Disease', 'MESH:D064420', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mice', 'Species', '10090', (66, 70))	('toxicity', 'Disease', (10, 18))	('tumors', 'Disease', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('BKM120', 'Var', (109, 115))	('BKM120', 'Var', (120, 126))	('BEZ235', 'Chemical', 'MESH:C531198', (22, 28))
506708	22619567	In contrast, animals receiving the combined BEZ235 and doxorubicin regimen showed significant weight loss, with 50% of animals losing >10% of their body weight.	('BEZ235', 'Chemical', 'MESH:C531198', (44, 50))	('weight loss', 'Disease', 'MESH:D015431', (94, 105))	('weight loss', 'Disease', (94, 105))	('losing', 'NegReg', (127, 133))	('weight loss', 'Phenotype', 'HP:0001824', (94, 105))	('BEZ235', 'Var', (44, 50))	('doxorubicin', 'Chemical', 'MESH:D004317', (55, 66))
506710	22619567	Twenty percent of BKM120-treated animals lost 10-15% of body weight, and no animal lost greater than 15% of initial weight.	('body weight', 'CPA', (56, 67))	('BKM120', 'Chemical', 'MESH:C571178', (18, 24))	('BKM120-treated', 'Var', (18, 32))	('lost', 'NegReg', (41, 45))
506712	22619567	Tumors were generated by injection of Adenovirus-expressing Cre recombinase (University of Iowa, Vector core) into the lower left leg of p53flox/flox; LSL-KrasG12D compound mutant mice as previously described.	('p53flox/flox', 'Var', (137, 149))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (180, 184))
506716	22619567	BEZ235 (Novartis) or BKM120 (Novartis) was dissolved in NMP 10% (1-methyl-2-pyrrolidone)/PEG300 90%.	('BKM120', 'Var', (21, 27))	('Novartis', 'Disease', 'None', (8, 16))	('Novartis', 'Disease', (8, 16))	('Novartis', 'Disease', 'None', (29, 37))	('BKM120', 'Chemical', 'MESH:C571178', (21, 27))	('NMP', 'Chemical', 'MESH:C038678', (56, 59))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('1-methyl-2-pyrrolidone', 'Chemical', 'MESH:C038678', (65, 87))	('Novartis', 'Disease', (29, 37))	('PEG300', 'Chemical', '-', (89, 95))
506728	22619567	For days 11-20, the vehicle-alone, doxorubicin-alone, BKM120-alone, BKM120+doxorubicin, BEZ235-alone, BEZ2235+doxorubicin cohorts were measured an average of 2.2, 2.3, 2.6, 2.7, 2.2, and 1.0 times, respectively.	('doxorubicin', 'Chemical', 'MESH:D004317', (75, 86))	('BKM120', 'Chemical', 'MESH:C571178', (54, 60))	('BEZ2235+doxorubicin', 'Var', (102, 121))	('BKM120', 'Chemical', 'MESH:C571178', (68, 74))	('BEZ2235', 'Chemical', '-', (102, 109))	('doxorubicin', 'Chemical', 'MESH:D004317', (110, 121))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))	('BEZ235', 'Chemical', 'MESH:C531198', (88, 94))	('BKM120+doxorubicin', 'Var', (68, 86))
506729	22619567	None of these measurement intervals were statistically different, with the exception of the BEZ235+doxorubicin tumors during days 11-20 (P < 0.001), which resulted from the loss of mice during this time window.	('mice', 'Species', '10090', (181, 185))	('doxorubicin', 'Chemical', 'MESH:D004317', (99, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('BEZ235+doxorubicin', 'Var', (92, 110))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('BEZ235', 'Chemical', 'MESH:C531198', (92, 98))
506731	22619567	Tumor-bearing mice receiving treatment with doxorubicin alone, BKM120 alone, or BKM120+doxorubicin were also monitored for changes in body weight.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BKM120+doxorubicin', 'Var', (80, 98))	('BKM120', 'Var', (63, 69))	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('mice', 'Species', '10090', (14, 18))	('BKM120', 'Chemical', 'MESH:C571178', (63, 69))	('BKM120', 'Chemical', 'MESH:C571178', (80, 86))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))	('body weight', 'CPA', (134, 145))
416861	22619567	Cells were washed once with cold PBS (Sigma) and lysed for 10 minutes on ice with RIPA buffer (Sigma), supplemented with phosphatase inhibitors (Sigma, P5726 and P0044).	('P5726', 'Var', (152, 157))	('PBS', 'Disease', 'MESH:D011535', (33, 36))	('PBS', 'Disease', (33, 36))	('RIPA buffer', 'Chemical', '-', (82, 93))	('Sigma', 'Var', (145, 150))	('P0044', 'Var', (162, 167))
506736	22619567	To our knowledge, this is the first study to use PI3K inhibitors and standard-of-care chemotherapies in a primary mouse model of soft-tissue sarcoma.	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (133, 148))	('sarcoma', 'Disease', (141, 148))	('PI3K', 'Var', (49, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('mouse', 'Species', '10090', (114, 119))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (129, 148))
506741	22619567	This suggests that inhibition of PI3K alone is sufficient to see a robust delay in tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('inhibition', 'Var', (19, 29))	('tumor', 'Disease', (83, 88))	('PI3K', 'Var', (33, 37))	('delay', 'NegReg', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
506742	22619567	Combining BKM120 with doxorubicin increased benefits, although these did not reach statistical significance.	('benefits', 'MPA', (44, 52))	('BKM120', 'Var', (10, 16))	('doxorubicin', 'Chemical', 'MESH:D004317', (22, 33))	('BKM120', 'Chemical', 'MESH:C571178', (10, 16))
506743	22619567	The average time to tumor tripling for BKM120 and doxorubicin was 1.4 days more than BKM120 alone, which is similar to the 1.2-day increase for doxorubicin alone compared to vehicle.	('doxorubicin', 'Chemical', 'MESH:D004317', (50, 61))	('BKM120', 'Chemical', 'MESH:C571178', (85, 91))	('doxorubicin', 'Chemical', 'MESH:D004317', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('BKM120', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('BKM120', 'Chemical', 'MESH:C571178', (39, 45))	('tumor', 'Disease', (20, 25))
506747	22619567	However, severe toxicity was observed in half of the animals given the combined BEZ235/doxorubicin treatment.	('toxicity', 'Disease', 'MESH:D064420', (16, 24))	('toxicity', 'Disease', (16, 24))	('BEZ235/doxorubicin', 'Var', (80, 98))	('BEZ235', 'Chemical', 'MESH:C531198', (80, 86))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))
506748	22619567	Of note, BKM120 alone or BKM120/doxorubicin treatment was better tolerated than BEZ235.	('BKM120/doxorubicin', 'Var', (25, 43))	('BKM120', 'Var', (9, 15))	('BKM120', 'Chemical', 'MESH:C571178', (25, 31))	('BEZ235', 'Chemical', 'MESH:C531198', (80, 86))	('BKM120', 'Chemical', 'MESH:C571178', (9, 15))	('doxorubicin', 'Chemical', 'MESH:D004317', (32, 43))
506763	22619567	An interesting observation from our study was the striking difference in tumor response based on initial size of the treated tumors with BEZ235.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('BEZ235', 'Var', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('BEZ235', 'Chemical', 'MESH:C531198', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (73, 78))
506769	22619567	The LSL-KrasG12D; p53flox/flox sarcomas are driven by overactive Kras, which may increase sensitivity to PI3K inhibition.	('LSL-KrasG12D; p53flox/flox', 'Var', (4, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('sarcomas', 'Disease', (31, 39))	('sensitivity', 'MPA', (90, 101))	('overactive', 'PosReg', (54, 64))	('increase', 'PosReg', (81, 89))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('Kras', 'Protein', (65, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
506770	22619567	Therefore, these results may only be applicable to patients with mutations in PI3K-sensitive pathways.	('PI3K-sensitive pathways', 'Pathway', (78, 101))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (65, 74))
506771	22619567	PI3K inhibitors have shown efficacy against a wide array of cancers in a laboratory setting.	('array of cancers', 'Disease', 'MESH:D009369', (51, 67))	('array of cancers', 'Disease', (51, 67))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('PI3K inhibitors', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
506772	22619567	BEZ235 decreased cell proliferation of breast cancer cell lines with PIK3CA mutations and cisplatin-resistant human ovarian cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('mutations', 'Var', (76, 85))	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('cell proliferation', 'CPA', (17, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('decreased', 'NegReg', (7, 16))	('ovarian cancer', 'Disease', (116, 130))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (110, 115))	('PIK3CA', 'Gene', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))	('breast cancer', 'Disease', (39, 52))
506773	22619567	Additionally, BEZ235 suppressed growth of xenograft models of breast cancer, rhabdomyosarcoma, metastatic melanoma, gastric cancer, hepatocellular carcinoma, renal cell carcinoma, prostate cancer, primary effusion lymphoma, glioma, and non-small-cell lung cancer.	('prostate cancer', 'Disease', (180, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (132, 156))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (77, 93))	('BEZ235', 'Var', (14, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (158, 178))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (77, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (132, 156))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('gastric cancer', 'Disease', (116, 130))	('lung cancer', 'Disease', (251, 262))	('breast cancer', 'Disease', (62, 75))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('glioma', 'Disease', (224, 230))	('lymphoma', 'Phenotype', 'HP:0002665', (214, 222))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (197, 222))	('suppressed', 'NegReg', (21, 31))	('glioma', 'Disease', 'MESH:D005910', (224, 230))	('hepatocellular carcinoma', 'Disease', (132, 156))	('renal cell carcinoma', 'Disease', (158, 178))	('gastric cancer', 'Disease', 'MESH:D013274', (116, 130))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (158, 178))	('BEZ235', 'Chemical', 'MESH:C531198', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (251, 262))	('growth', 'MPA', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('primary effusion lymphoma', 'Disease', (197, 222))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (197, 222))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('prostate cancer', 'Disease', 'MESH:D011471', (180, 195))	('rhabdomyosarcoma', 'Disease', (77, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (251, 262))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (180, 195))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))
506774	22619567	BEZ235 has also shown activity in genetically engineered mouse models, including Kras-initiated ovarian carcinoma.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('BEZ235', 'Var', (0, 6))	('Kras-initiated ovarian carcinoma', 'Disease', 'MESH:D010051', (81, 113))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('activity', 'MPA', (22, 30))	('mouse', 'Species', '10090', (57, 62))	('Kras-initiated ovarian carcinoma', 'Disease', (81, 113))
506775	22619567	Alternatively, single-agent BEZ235 therapy was not effective in a primary NSCLC mouse model, but combining BEZ235 with a MEK inhibitor did inhibit tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('MEK', 'Gene', '17242', (121, 124))	('BEZ235', 'Chemical', 'MESH:C531198', (28, 34))	('inhibit', 'NegReg', (139, 146))	('BEZ235', 'Var', (107, 113))	('mouse', 'Species', '10090', (80, 85))	('MEK', 'Gene', (121, 124))	('BEZ235', 'Chemical', 'MESH:C531198', (107, 113))	('NSCLC', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
506777	22619567	In this study, patients are prescreened for molecular alterations in PIK3CA and/or PTEN.	('PTEN', 'Gene', '5728', (83, 87))	('patients', 'Species', '9606', (15, 23))	('PIK3CA', 'Gene', (69, 75))	('molecular alterations', 'Var', (44, 65))	('PTEN', 'Gene', (83, 87))
506791	28988646	The ORR in the STS cohort was 18% and clinical activity was variable by histologic subtype: 40% ORR in UPS (1 CR+3PR/10), 2 PR/10 in LPS, 1PR/10 in SS and 0/10 in LMS.	('ORR', 'Var', (96, 99))	('STS', 'Phenotype', 'HP:0030448', (15, 18))	('LMS', 'Phenotype', 'HP:0100243', (163, 166))	('LPS', 'Phenotype', 'HP:0012034', (133, 136))	('LPS', 'Disease', (133, 136))	('SS', 'Phenotype', 'HP:0012570', (148, 150))	('LPS', 'Disease', 'MESH:C536528', (133, 136))
506875	28988646	To our knowledge, SARC028 is the first prospective multi-centre open-label phase 2 study of immune checkpoint blockade in patients with advanced soft tissue and bone sarcomas, pembrolizumab monotherapy was associated with clinically meaningful and sustained objective responses in 18% in STS, while the response rate was only 5% in BS.	('BS', 'Phenotype', 'HP:0002669', (332, 334))	('soft tissue and bone sarcomas', 'Phenotype', 'HP:0030448', (145, 174))	('STS', 'Phenotype', 'HP:0030448', (288, 291))	('pembrolizumab', 'Chemical', 'MESH:C582435', (176, 189))	('bone sarcomas', 'Disease', 'MESH:D012509', (161, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (166, 174))	('bone sarcomas', 'Disease', (161, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('patients', 'Species', '9606', (122, 130))	('monotherapy', 'Var', (190, 201))	('bone sarcomas', 'Phenotype', 'HP:0002669', (161, 174))
506896	28988646	Mifarmutide has been shown to increase immune cell infiltration into osteosarcoma metastases, a critical step to improve the efficacy of anti-PD-1 antibodies.	('Mifarmutide', 'Chemical', '-', (0, 11))	('Mifarmutide', 'Var', (0, 11))	('osteosarcoma metastases', 'Disease', (69, 92))	('immune cell infiltration into', 'CPA', (39, 68))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('osteosarcoma metastases', 'Disease', 'MESH:D009362', (69, 92))	('PD-1', 'Gene', (142, 146))	('increase', 'PosReg', (30, 38))	('PD-1', 'Gene', '5133', (142, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
507007	32547189	Apatinib is an active anti-angiogenesis tyrosine kinase inhibitor (TKI), which more selectively inhibits vascular endothelial growth factor receptor 2 with an IC50 of 0.001 muM in vitro while synchronously inhibiting c-kit (0.429 muM), PDGFR-alpha (>1 muM), Ret (0.013 muM), c-src (0.53 muM), EGFR (>10 muM), HER2 (>10 muM), and FGFR1 (>10 muM).	('vascular endothelial growth factor receptor 2', 'Gene', (105, 150))	('EGFR', 'Gene', '1956', (293, 297))	('Ret', 'Gene', '5979', (258, 261))	('PDGFR-alpha', 'Gene', '5156', (236, 247))	('HER2', 'Gene', '2064', (309, 313))	('c-src', 'Gene', (275, 280))	('c-kit', 'Gene', (217, 222))	('FGFR1', 'Gene', '2260', (329, 334))	('c-src', 'Gene', '6714', (275, 280))	('PDGFR-alpha', 'Gene', (236, 247))	('vascular endothelial growth factor receptor 2', 'Gene', '3791', (105, 150))	('EGFR', 'Gene', (293, 297))	('HER2', 'Gene', (309, 313))	('0.53', 'Var', (282, 286))	('inhibits', 'NegReg', (96, 104))	('FGFR1', 'Gene', (329, 334))	('c-kit', 'Gene', '3815', (217, 222))	('Apatinib', 'Chemical', 'MESH:C553458', (0, 8))	('inhibiting', 'NegReg', (206, 216))	('Ret', 'Gene', (258, 261))
507061	32547189	Signaling pathways suggested to have a role in CS include Hedgehog (Hh), Src, PI3k-Akt-mTOR, mutations in isocitrate dehydrogenase 1/2, and angiogenesis.	('mTOR', 'Gene', '2475', (87, 91))	('mutations', 'Var', (93, 102))	('Akt', 'Gene', (83, 86))	('CS', 'Phenotype', 'HP:0006765', (47, 49))	('angiogenesis', 'CPA', (140, 152))	('Src', 'Gene', (73, 76))	('Akt', 'Gene', '207', (83, 86))	('Src', 'Gene', '6714', (73, 76))	('Signaling pathways', 'Pathway', (0, 18))	('isocitrate', 'Gene', (106, 116))	('mTOR', 'Gene', (87, 91))
507103	30221671	As a result, besides cancer-associated pathways, KEGG pathways associated with nervous system diseases, such as Parkinson's disease, Huntington's disease, were also significantly enriched in several network modules (Table II).	('KEGG', 'Var', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	("Huntington's disease", 'Disease', (133, 153))	("Parkinson's disease", 'Disease', (112, 131))	("Huntington's disease", 'Disease', 'MESH:D006816', (133, 153))	("Parkinson's disease", 'Disease', 'MESH:D010300', (112, 131))	('nervous system diseases', 'Disease', (79, 102))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('nervous system diseases', 'Disease', 'MESH:D009422', (79, 102))
507134	30221671	Overexpressed RACGAP1 was associated with poor disease-free and overall survival, and may act as an independent predictive marker for lymph node metastasis, recurrence and poor prognosis of colorectal cancer.	('RACGAP1', 'Gene', '29127', (14, 21))	('Overexpressed', 'Var', (0, 13))	('colorectal cancer', 'Disease', 'MESH:D015179', (190, 207))	('colorectal cancer', 'Disease', (190, 207))	('colorectal cancer', 'Phenotype', 'HP:0003003', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('lymph node metastasis', 'CPA', (134, 155))	('RACGAP1', 'Gene', (14, 21))	('overall survival', 'CPA', (64, 80))	('poor', 'NegReg', (42, 46))	('disease-free', 'CPA', (47, 59))
507207	23275778	Polymerase chain reaction investigation for specific translocations included t(9;22), t(9;17) (extraskeletal myxoid chondrosarcoma), t(11;22), t(21;22) (Ewing's sarcoma), and t(X;18) (synovial sarcoma) and revealed no positive results.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (116, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (153, 168))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (184, 200))	('synovial sarcoma', 'Disease', 'MESH:D013584', (184, 200))	("Ewing's sarcoma", 'Disease', (153, 168))	('t(9;22', 'Var', (77, 83))	('t(11;22', 'Var', (133, 140))	('t(X;18', 'Var', (175, 181))	('extraskeletal myxoid chondrosarcoma', 'Disease', (95, 130))	('t(21;22', 'Var', (143, 150))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (95, 130))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (153, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('t(9;17', 'Var', (86, 92))	('synovial sarcoma', 'Disease', (184, 200))
507258	33924080	CDKN2A deletion/mutation or CDK4 amplification was associated with worse median OS (p = 0.06), while a RB1 deletion/mutation was associated with better median PFS (p = 0.05), and these two genomic alterations were mutually exclusive.	('CDKN2A', 'Gene', '1029', (0, 6))	('CDK4', 'Gene', '1019', (28, 32))	('RB1', 'Gene', (103, 106))	('amplification', 'Var', (33, 46))	('RB1', 'Gene', '5925', (103, 106))	('deletion/mutation', 'Var', (107, 124))	('deletion/mutation', 'Var', (7, 24))	('CDK4', 'Gene', (28, 32))	('CDKN2A', 'Gene', (0, 6))
507278	33924080	showed that genomic alteration of the CDKN2A pathway was associated with worse prognosis in patients with STS.	('genomic alteration', 'Var', (12, 30))	('CDKN2A', 'Gene', '1029', (38, 44))	('CDKN2A', 'Gene', (38, 44))	('patients', 'Species', '9606', (92, 100))
507279	33924080	In this study we also explored the association of genomic alterations with outcomes and found that the patients with the genomic alteration of CDKN2A pathway were associated with worse OS.	('worse OS', 'Disease', (179, 187))	('CDKN2A', 'Gene', (143, 149))	('patients', 'Species', '9606', (103, 111))	('CDKN2A', 'Gene', '1029', (143, 149))	('genomic alteration', 'Var', (121, 139))
507280	33924080	In addition, we found that RB1 deletion/mutation was associated with better PFS.	('RB1', 'Gene', '5925', (27, 30))	('PFS', 'Disease', (76, 79))	('deletion/mutation', 'Var', (31, 48))	('RB1', 'Gene', (27, 30))
507281	33924080	We also found that genomic alteration of CDKN2A pathway and RB1 deletion/mutation were mutually exclusive.	('deletion/mutation', 'Var', (64, 81))	('RB1', 'Gene', (60, 63))	('CDKN2A', 'Gene', (41, 47))	('CDKN2A', 'Gene', '1029', (41, 47))	('RB1', 'Gene', '5925', (60, 63))
507304	33924080	The most common genomic alterations were CDKN2A deletion or mutation or CDK4 amplification (N = 15), RB1 deletion or mutation (N = 18), and TP53 deletion or mutation or MDM2 amplification (N = 37).	('CDK4', 'Gene', (72, 76))	('mutation', 'Var', (60, 68))	('deletion', 'Var', (105, 113))	('amplification', 'PosReg', (77, 90))	('TP53', 'Gene', (140, 144))	('CDK4', 'Gene', '1019', (72, 76))	('RB1', 'Gene', (101, 104))	('mutation', 'Var', (157, 165))	('CDKN2A', 'Gene', (41, 47))	('RB1', 'Gene', '5925', (101, 104))	('MDM2', 'Gene', '4193', (169, 173))	('mutation', 'Var', (117, 125))	('MDM2', 'Gene', (169, 173))	('deletion', 'Var', (48, 56))	('CDKN2A', 'Gene', '1029', (41, 47))	('TP53', 'Gene', '7157', (140, 144))	('deletion', 'Var', (145, 153))
507305	33924080	More patients treated with the 14-day regimen had CDKN2A deletion/mutation or CDK amplification than patients treated with 21-day regimen (11 versus 4, p = 0.08, Table 1).	('CDK', 'Gene', '1019', (50, 53))	('CDKN2A', 'Gene', (50, 56))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (5, 13))	('CDK', 'Gene', (50, 53))	('CDK', 'Gene', '1019', (78, 81))	('CDKN2A', 'Gene', '1029', (50, 56))	('deletion/mutation', 'Var', (57, 74))	('CDK', 'Gene', (78, 81))
507330	33924080	TP53 deletion/mutation/MDM2 amplification, CDKN2A deletion/mutation/CDK4 amplification, and RB1 deletion/mutation were the most common genomic alterations.	('RB1', 'Gene', '5925', (92, 95))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('CDKN2A', 'Gene', (43, 49))	('MDM2', 'Gene', '4193', (23, 27))	('MDM2', 'Gene', (23, 27))	('CDK4', 'Gene', (68, 72))	('CDKN2A', 'Gene', '1029', (43, 49))	('CDK4', 'Gene', '1019', (68, 72))	('RB1', 'Gene', (92, 95))	('deletion/mutation', 'Var', (96, 113))
507331	33924080	Interestingly, we found that for all the patients with a CDKN2A deletion/mutation or CDK4 amplification, there was absence of RB1 deletion or mutation, and for all the patients whose tumor harbored a RB1 deletion or mutation, there was absence of CDKN2A deletion/mutation or CDK4 amplification, indicating that these two types of genomic alterations are mutually exclusive.	('deletion/mutation', 'Var', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('CDK4', 'Gene', (85, 89))	('RB1', 'Gene', '5925', (200, 203))	('CDK4', 'Gene', '1019', (275, 279))	('RB1', 'Gene', (126, 129))	('CDKN2A', 'Gene', (57, 63))	('CDKN2A', 'Gene', (247, 253))	('mutation', 'Var', (216, 224))	('CDK4', 'Gene', '1019', (85, 89))	('deletion', 'Var', (204, 212))	('RB1', 'Gene', '5925', (126, 129))	('CDKN2A', 'Gene', '1029', (57, 63))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Disease', (183, 188))	('CDKN2A', 'Gene', '1029', (247, 253))	('mutation', 'Var', (142, 150))	('absence', 'NegReg', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('RB1', 'Gene', (200, 203))	('deletion', 'Var', (130, 138))	('CDK4', 'Gene', (275, 279))	('patients', 'Species', '9606', (168, 176))
507332	33924080	Consistent with this finding, 40% of patients with CDKN2A/CDK4 alteration had de-differentiated liposarcoma (26.7% LMS, 20% UPS, and 13.3% osteosarcoma), while 83.3% of patients with a Rb1 alteration had leiomyosarcoma.	('UPS', 'Disease', (124, 127))	('CDKN2A', 'Gene', (51, 57))	('leiomyosarcoma', 'Disease', (204, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('patients', 'Species', '9606', (37, 45))	('LMS', 'Disease', (115, 118))	('LMS', 'Phenotype', 'HP:0100243', (115, 118))	('liposarcoma', 'Disease', (96, 107))	('CDK4', 'Gene', (58, 62))	('osteosarcoma', 'Disease', (139, 151))	('osteosarcoma', 'Disease', 'MESH:D012516', (139, 151))	('CDKN2A', 'Gene', '1029', (51, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Rb1', 'Gene', '5925', (185, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (204, 218))	('CDK4', 'Gene', '1019', (58, 62))	('patients', 'Species', '9606', (169, 177))	('liposarcoma', 'Phenotype', 'HP:0012034', (96, 107))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (204, 218))	('alteration', 'Var', (63, 73))	('Rb1', 'Gene', (185, 188))	('liposarcoma', 'Disease', 'MESH:D008080', (96, 107))
507333	33924080	One out of 15 (6.7%) patients with a CDKN2A deletion/mutation or CDK4 amplification obtained a PR, while 12 out of 52 (23.1%) patients without a CDKN2A deletion/mutation or CDK4 amplification had PR/CR, though not statistically significant (p = 0.16).	('CDKN2A', 'Gene', '1029', (145, 151))	('CDKN2A', 'Gene', (37, 43))	('amplification', 'Var', (70, 83))	('PR/CR', 'Disease', (196, 201))	('CDK4', 'Gene', (173, 177))	('deletion/mutation', 'Var', (44, 61))	('CDKN2A', 'Gene', '1029', (37, 43))	('CDK4', 'Gene', '1019', (173, 177))	('patients', 'Species', '9606', (21, 29))	('patients', 'Species', '9606', (126, 134))	('CDK4', 'Gene', (65, 69))	('CDK4', 'Gene', '1019', (65, 69))	('CDKN2A', 'Gene', (145, 151))
507334	33924080	However, patients without a CDKN2A deletion/mutation or CDK4 amplification had nearly statistically significant, longer OS compared to patients with a CDKN2A deletion/mutation or CDK4 amplification (17.6 versus 10.1 months, Figure 3, p = 0.06).	('patients', 'Species', '9606', (9, 17))	('CDK4', 'Gene', '1019', (56, 60))	('CDK4', 'Gene', (56, 60))	('patients', 'Species', '9606', (135, 143))	('CDK4', 'Gene', (179, 183))	('CDKN2A', 'Gene', (28, 34))	('CDKN2A', 'Gene', (151, 157))	('deletion/mutation', 'Var', (158, 175))	('CDKN2A', 'Gene', '1029', (151, 157))	('CDK4', 'Gene', '1019', (179, 183))	('deletion/mutation', 'Var', (35, 52))	('CDKN2A', 'Gene', '1029', (28, 34))
507335	33924080	Six out of 18 (33.3%) patients with a RB1 deletion/mutation obtained PR/CR, compared to seven out of 49 (14.3%) patients without a RB1 deletion/mutation, though not statistically significant (p = 0.08).	('PR/CR', 'MPA', (69, 74))	('RB1', 'Gene', (38, 41))	('RB1', 'Gene', '5925', (38, 41))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (112, 120))	('RB1', 'Gene', (131, 134))	('RB1', 'Gene', '5925', (131, 134))	('deletion/mutation', 'Var', (42, 59))
507336	33924080	However, patients with a RB1 deletion/mutation had statistically significant longer PFS compared to patients without a RB1 deletion/mutation (6.2 versus 3.2 months, Figure 4, p = 0.05), though the OS was not significantly different.	('patients', 'Species', '9606', (9, 17))	('longer', 'PosReg', (77, 83))	('deletion/mutation', 'Var', (29, 46))	('RB1', 'Gene', '5925', (25, 28))	('patients', 'Species', '9606', (100, 108))	('RB1', 'Gene', (119, 122))	('RB1', 'Gene', (25, 28))	('PFS', 'MPA', (84, 87))	('RB1', 'Gene', '5925', (119, 122))
507337	33924080	There were no statistically significant differences on RR, PFS, or OS between patients with or without a TP53 deletion/mutation or MDM2 amplification.	('MDM2', 'Gene', (131, 135))	('patients', 'Species', '9606', (78, 86))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('deletion/mutation', 'Var', (110, 127))	('MDM2', 'Gene', '4193', (131, 135))
507340	33924080	The SARC002 randomized phase II trial that enrolled the patients who had received zero to three lines of chemotherapy demonstrated superior efficacy with G-D combination (RR 16%, PFS 6 months, and OS 17.9 months) compared to G alone (RR 8%, PFS 3 months, and OS 11.5 months), which further established the G-D combination as a standard first- or second-line chemotherapy option.	('patients', 'Species', '9606', (56, 64))	('D', 'Chemical', 'MESH:D000077143', (156, 157))	('D', 'Chemical', 'MESH:D000077143', (308, 309))	('G-D combination', 'Var', (154, 169))	('efficacy', 'MPA', (140, 148))
507354	33924080	G was initially thought to be potentially associated with better survival when given by FDR compared to a 30-min infusion in patients with metastatic pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('better', 'PosReg', (58, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('D', 'Chemical', 'MESH:D000077143', (89, 90))	('pancreatic cancer', 'Disease', (150, 167))	('FDR', 'Var', (88, 91))	('patients', 'Species', '9606', (125, 133))
507355	33924080	In fact, some studies have shown that FDR was associated with more hematologic toxicities compared to a 30-min infusion.	('hematologic toxicities', 'Disease', 'MESH:D006402', (67, 89))	('FDR', 'Var', (38, 41))	('hematologic toxicities', 'Disease', (67, 89))	('D', 'Chemical', 'MESH:D000077143', (39, 40))
507358	33924080	In addition, our data showed RB1 deletion or mutation was associated with better PFS.	('deletion', 'Var', (33, 41))	('RB1', 'Gene', (29, 32))	('PFS', 'Disease', (81, 84))	('mutation', 'Var', (45, 53))	('RB1', 'Gene', '5925', (29, 32))
507359	33924080	This is consistent with our additional finding that all patients with a RB1 deletion or mutation did not harbor a CDKN2A deletion/mutation or CDK4 amplification and that all patients with a CDKN2A deletion/mutation or CDK4 amplification did not harbor a RB1 deletion/mutation, suggesting that the genomic alterations in these two pathways are mutually exclusive, consistent with the previous study on Rb1 pathway alteration in 31 tumor types using The Cancer Genome Atlas (TCGA) database.	('patients', 'Species', '9606', (56, 64))	('RB1', 'Gene', (254, 257))	('CDK4', 'Gene', '1019', (142, 146))	('Cancer', 'Disease', 'MESH:D009369', (452, 458))	('RB1', 'Gene', (72, 75))	('CDKN2A', 'Gene', (114, 120))	('Rb1', 'Gene', '5925', (401, 404))	('CDK4', 'Gene', (218, 222))	('RB1', 'Gene', '5925', (254, 257))	('RB1', 'Gene', '5925', (72, 75))	('CDKN2A', 'Gene', (190, 196))	('mutation', 'Var', (88, 96))	('CDKN2A', 'Gene', '1029', (114, 120))	('Cancer', 'Phenotype', 'HP:0002664', (452, 458))	('tumor', 'Disease', (430, 435))	('CDK4', 'Gene', '1019', (218, 222))	('Rb1', 'Gene', (401, 404))	('tumor', 'Disease', 'MESH:D009369', (430, 435))	('CDK4', 'Gene', (142, 146))	('Cancer', 'Disease', (452, 458))	('deletion', 'Var', (76, 84))	('CDKN2A', 'Gene', '1029', (190, 196))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (430, 435))
507361	33924080	A study showed mutation in INK4A deletion was associated with worse outcomes in Ewing sarcoma.	('mutation', 'Var', (15, 23))	('INK4A', 'Gene', (27, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('associated', 'Reg', (46, 56))	('deletion', 'Var', (33, 41))	('Ewing sarcoma', 'Disease', (80, 93))	('INK4A', 'Gene', '1029', (27, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
507376	33924080	Note p = 0.01 indicating better PFS for patients treated with 14-day G-D regimen compared to 21-day regimen.	('G-D', 'Var', (69, 72))	('better', 'PosReg', (25, 31))	('patients', 'Species', '9606', (40, 48))	('D', 'Chemical', 'MESH:D000077143', (71, 72))	('PFS', 'MPA', (32, 35))
507455	28265395	Therefore, we hypothesize that aberrant wound healing or inflammation from the uveal schwannoma, rather than direct extension of schwannoma, induced the subsequent orbital rhabdomyosarcoma within this canine patient.	('uveal schwannoma', 'Disease', (79, 95))	('rat', 'Species', '10116', (97, 100))	('schwannoma', 'Disease', (85, 95))	('patient', 'Species', '9606', (208, 215))	('schwannoma', 'Disease', 'MESH:D009442', (85, 95))	('canine', 'Species', '9615', (201, 207))	('aberrant', 'Var', (31, 39))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (172, 188))	('schwannoma', 'Phenotype', 'HP:0100008', (129, 139))	('induced', 'Reg', (141, 148))	('orbital rhabdomyosarcoma', 'Disease', (164, 188))	('schwannoma', 'Disease', (129, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('aberrant wound healing', 'Phenotype', 'HP:0001058', (31, 53))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('uveal schwannoma', 'Disease', 'MESH:D009442', (79, 95))	('orbital rhabdomyosarcoma', 'Phenotype', 'HP:0500092', (164, 188))	('orbital rhabdomyosarcoma', 'Disease', 'MESH:C537605', (164, 188))	('schwannoma', 'Disease', 'MESH:D009442', (129, 139))	('schwannoma', 'Phenotype', 'HP:0100008', (85, 95))	('inflammation', 'Disease', (57, 69))
507459	28265395	It has been hypothesized that sarcomas can arise from wound healing when there are gene mutations of the proliferating cells due to rapid duplication; however, this process remains uncertain 13, 14, 15, 16.	('sarcomas', 'Disease', (30, 38))	('mutations', 'Var', (88, 97))	('rat', 'Species', '10116', (112, 115))	('sarcomas', 'Disease', 'MESH:D012509', (30, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
507462	28265395	SMR has also been reported to histologically stimulate cutaneous malignancies such as squamous cell carcinoma and rhabdomyosarcoma in humans 27, 28, 29.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (114, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 109))	('cutaneous malignancies', 'Disease', (55, 77))	('squamous cell carcinoma', 'Disease', (86, 109))	('humans', 'Species', '9606', (134, 140))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (114, 130))	('cutaneous malignancies', 'Phenotype', 'HP:0008069', (55, 77))	('stimulate', 'PosReg', (45, 54))	('SMR', 'Var', (0, 3))	('cutaneous malignancies', 'Disease', 'MESH:C562393', (55, 77))	('rhabdomyosarcoma', 'Disease', (114, 130))
507497	24114123	Over the past 10 years, epigenetic regulation of gene expression has been shown to play an important role in the biology of multiple hematologic malignancies and solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (162, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('epigenetic regulation', 'Var', (24, 45))	('hematologic malignancies', 'Disease', 'MESH:D019337', (133, 157))	('hematologic malignancies', 'Disease', (133, 157))	('solid tumors', 'Disease', (162, 174))	('play', 'Reg', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
507667	28382648	Patients who underwent an upfront gross total resection (GTR) experienced better PFS and OS (both P<0.0001).	('better', 'PosReg', (74, 80))	('Patients', 'Species', '9606', (0, 8))	('gross', 'Var', (34, 39))	('PFS', 'CPA', (81, 84))
507678	28382648	Additionally, recurrent loss of function alterations in NFKBIA and CDKN2A and copy number gains in chromosome 9p24 (site of CD274 [also termed PD-L1] and PDCD1LG2 [also termed PD-L2, CD273]) have been identified, indicating potential molecular targets.	('PDCD1LG2', 'Gene', '80380', (154, 162))	('CD274', 'Gene', (124, 129))	('NFKBIA', 'Gene', (56, 62))	('CDKN2A', 'Gene', (67, 73))	('PDCD1LG2', 'Gene', (154, 162))	('gains', 'PosReg', (90, 95))	('CD273', 'Gene', '80380', (183, 188))	('NFKBIA', 'Gene', '4792', (56, 62))	('CDKN2A', 'Gene', '1029', (67, 73))	('CD273', 'Gene', (183, 188))	('PD-L1', 'Gene', (143, 148))	('CD274', 'Gene', '29126', (124, 129))	('alterations', 'Var', (41, 52))	('PD-L1', 'Gene', '29126', (143, 148))	('PD-L2', 'Gene', (176, 181))	('PD-L2', 'Gene', '80380', (176, 181))
507703	28382648	Both tumours contained TP53 mutations (c.743G>A p.R248Q, exon 7 and c.839G>A p.R280K, exon 8).	('c.839G>A p.R280K', 'Var', (68, 84))	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('c.839G>A', 'Mutation', 'rs121912660', (68, 76))	('c.743G>A', 'Mutation', 'rs11540652', (39, 47))	('p.R280K', 'Mutation', 'rs121912660', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('contained', 'Reg', (13, 22))	('tumours', 'Disease', (5, 12))	('p.R248Q', 'Mutation', 'rs11540652', (48, 55))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('c.743G>A p.R248Q', 'Var', (39, 55))
507704	28382648	One sample also contained a PTEN mutation (c.388C>T p.R130, exon 5).	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (28, 32))	('c.388C>T', 'Mutation', 'rs121909224', (43, 51))	('c.388C>T p.R130', 'Var', (43, 58))
507720	28382648	Patients who underwent an upfront gross total resection (GTR; n=27) experienced significantly longer PFS and OS (Figure 3A-B).	('PFS', 'CPA', (101, 104))	('Patients', 'Species', '9606', (0, 8))	('gross', 'Var', (34, 39))	('longer', 'PosReg', (94, 100))
507778	28382648	We identified TP53 and PTEN gene mutations in 2 patients with FDCS.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (33, 42))	('PTEN', 'Gene', (23, 27))	('FDCS', 'Disease', (62, 66))	('PTEN', 'Gene', '5728', (23, 27))	('patients', 'Species', '9606', (48, 56))
507946	25302783	These results implied that the PFPE markedly induced DNA damage in S180 cells.	('S180', 'CellLine', 'CVCL:2874', (67, 71))	('DNA damage', 'MPA', (53, 63))	('PE', 'Chemical', '-', (33, 35))	('PFPE', 'Var', (31, 35))	('induced', 'Reg', (45, 52))
507954	25302783	These results demonstrated that PFPE markedly increased the intracellular ROS level.	('PE', 'Chemical', '-', (34, 36))	('PFPE', 'Var', (32, 36))	('increased', 'PosReg', (46, 55))	('intracellular ROS level', 'MPA', (60, 83))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))
507955	25302783	Furthermore, our in vivo studies showed that the PFPE caused a significant decline in the sarcoma weight compared with the model control group (p<0.01) (Figure 7).	('sarcoma weight', 'Disease', (90, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('PE', 'Chemical', '-', (51, 53))	('sarcoma weight', 'Disease', 'MESH:D015431', (90, 104))	('decline', 'NegReg', (75, 82))	('PFPE', 'Var', (49, 53))
507963	25302783	Moreover, PFPE had no or little cytotoxicity in HEK-293 cells.	('HEK-293', 'CellLine', 'CVCL:0045', (48, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (32, 44))	('PFPE', 'Var', (10, 14))	('PE', 'Chemical', '-', (12, 14))	('cytotoxicity', 'Disease', (32, 44))
507964	25302783	Thus, the present study suggests that PFPE has a potential application as a natural anti-tumor agent.	('PFPE', 'Var', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PE', 'Chemical', '-', (40, 42))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
507965	25302783	Defects in apoptosis are the critical step in the resistance to therapy in many types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('Defects', 'Var', (0, 7))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('apoptosis', 'CPA', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
507969	25302783	As evidenced by Annexin V-FITC/PI double staining, we found that the proportion of early and late apoptotic cells increased significantly after the PFPE treatment (Figure 2).	('Annexin V', 'Gene', '11747', (16, 25))	('increased', 'PosReg', (114, 123))	('PFPE', 'Var', (148, 152))	('Annexin V', 'Gene', (16, 25))	('PE', 'Chemical', '-', (150, 152))
507970	25302783	Staining with DAPI then clearly showed that the PFPE caused fragmented punctate blue nuclear fluorescence and condensed chromatin in S180 cells (Figure 3), which are the morphological characteristics of apoptosis.	('condensed chromatin', 'CPA', (110, 129))	('S180', 'CellLine', 'CVCL:2874', (133, 137))	('DAPI', 'Chemical', 'MESH:C007293', (14, 18))	('PFPE', 'Var', (48, 52))	('caused', 'Reg', (53, 59))	('PE', 'Chemical', '-', (50, 52))	('fragmented punctate blue nuclear fluorescence', 'MPA', (60, 105))
507971	25302783	As shown in Figure 4, PFPE caused obvious DNA fragmentation in S180 cells, which is also a typical biochemical feature of apoptosis.	('PE', 'Chemical', '-', (24, 26))	('DNA fragmentation', 'CPA', (42, 59))	('PFPE', 'Var', (22, 26))	('S180', 'CellLine', 'CVCL:2874', (63, 67))
507972	25302783	The data in this study suggest that the PFPE could induce apoptosis in S180 cells, and the cytotoxic effects were associated with apoptosis, implying that the extract has great potential in anti-cancer drug screening.	('PE', 'Chemical', '-', (42, 44))	('S180', 'CellLine', 'CVCL:2874', (71, 75))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('induce', 'PosReg', (51, 57))	('apoptosis', 'CPA', (58, 67))	('PFPE', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
507978	25302783	Consistent with in vitro findings, the in vivo study provides information that the PFPE significantly reduced the S180 sarcoma weight at the indicated dose (Figure 7), showing its specific role in anticancer therapy.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('S180 sarcoma', 'Disease', (114, 126))	('cancer', 'Disease', (201, 207))	('PFPE', 'Var', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('sarcoma weight', 'Disease', (119, 133))	('S180 sarcoma', 'Disease', 'MESH:D012509', (114, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('reduced', 'NegReg', (102, 109))	('PE', 'Chemical', '-', (85, 87))	('sarcoma weight', 'Disease', 'MESH:D015431', (119, 133))
507983	25302783	As illustrated in our work, PFPE could efficiently inhibit tumor growth and also has lower immune organ toxicity.	('lower immune organ', 'Phenotype', 'HP:0002721', (85, 103))	('tumor', 'Disease', (59, 64))	('lower', 'NegReg', (85, 90))	('toxicity', 'Disease', 'MESH:D064420', (104, 112))	('toxicity', 'Disease', (104, 112))	('PFPE', 'Var', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inhibit', 'NegReg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('PE', 'Chemical', '-', (30, 32))
507997	25255370	However, how and why KSHV alters host cell metabolism remains poorly understood.	('KS', 'Phenotype', 'HP:0100726', (21, 23))	('alters', 'Reg', (26, 32))	('KSHV', 'Var', (21, 25))	('host cell metabolism', 'MPA', (33, 53))	('KSHV', 'Species', '37296', (21, 25))
508000	25255370	KSHV microRNAs expression decreases oxygen consumption, increase lactate secretion and glucose uptake, stabilize HIF1alpha and decreases mitochondria copy number.	('oxygen', 'Chemical', 'MESH:D010100', (36, 42))	('KSHV', 'Species', '37296', (0, 4))	('increase lactate secretion', 'Disease', 'MESH:D007775', (56, 82))	('expression', 'Var', (15, 25))	('HIF1alpha', 'Gene', (113, 122))	('KSHV microRNAs', 'Gene', (0, 14))	('oxygen consumption', 'MPA', (36, 54))	('decreases', 'NegReg', (26, 35))	('glucose', 'Chemical', 'MESH:D005947', (87, 94))	('HIF1alpha', 'Gene', '3091', (113, 122))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('microRNAs', 'Gene', (5, 14))	('increase lactate secretion', 'Disease', (56, 82))	('decreases mitochondria copy number', 'Disease', (127, 161))	('glucose uptake', 'MPA', (87, 101))	('stabilize', 'Reg', (103, 112))	('increase lactate', 'Phenotype', 'HP:0002151', (56, 72))	('decreases mitochondria copy number', 'Disease', 'MESH:C564971', (127, 161))
508007	25255370	Our work demonstrates that KSHV microRNAs can alter cell metabolism through coherent control of independent pathways, a key feature of microRNA-mediated control of cellular functions.	('KS', 'Phenotype', 'HP:0100726', (27, 29))	('KSHV', 'Gene', (27, 31))	('microRNAs', 'Var', (32, 41))	('cell metabolism', 'MPA', (52, 67))	('independent pathways', 'Pathway', (96, 116))	('alter', 'Reg', (46, 51))	('KSHV', 'Species', '37296', (27, 31))
508022	25255370	Cancer cells metabolism is a result of the modulation of intracellular signaling pathways that are disrupted by mutated oncogenes and tumor suppressors.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('metabolism', 'MPA', (13, 23))	('mutated', 'Var', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
508042	25255370	Since over expression of exogenous miRNAs in cells can have non-specific effects, we created a mutated version of the miRK12-3, which is one of the most expressed among the KSHV miRNAs (Figure S1E and F), and used it as a control for expression of the KSHV miRNA cluster.	('mutated', 'Var', (95, 102))	('KS', 'Phenotype', 'HP:0100726', (173, 175))	('KSHV', 'Species', '37296', (173, 177))	('miRK12-3', 'Gene', (118, 126))	('KSHV', 'Species', '37296', (252, 256))	('KS', 'Phenotype', 'HP:0100726', (252, 254))
508049	25255370	We monitored glucose uptake into cells by measuring the uptake of the fluorescently labeled deoxyglucose analog 6-NBDG and found increased uptake of ~30% in cells expressing miR-LEC (Figure 1C), but not in those expressing latent proteins (Figure S1J).	('uptake', 'MPA', (139, 145))	('glucose', 'Chemical', 'MESH:D005947', (97, 104))	('6-NBDG', 'Chemical', 'MESH:C045400', (112, 118))	('increased', 'PosReg', (129, 138))	('miR-LEC', 'Var', (174, 181))	('deoxyglucose', 'Chemical', 'MESH:D003847', (92, 104))	('glucose', 'Chemical', 'MESH:D005947', (13, 20))
508051	25255370	KSHV express additional two miRNAs out of the cluster; miR-K10-10 and miR-K12-12.	('KSHV', 'Species', '37296', (0, 4))	('miR-K10-10', 'Var', (55, 65))	('miR-K12-12', 'Var', (70, 80))	('KS', 'Phenotype', 'HP:0100726', (0, 2))
508058	25255370	As shown in figure 1E, in miR-LEC HIF1alpha protein is overexpressed by ~3 fold compared to the control cells.	('miR-LEC', 'Var', (26, 33))	('HIF1alpha', 'Gene', (34, 43))	('overexpressed', 'PosReg', (55, 68))	('HIF1alpha', 'Gene', '3091', (34, 43))
508061	25255370	Taken together these results suggest that expression of the miRNA cluster in LEC is sufficient to change glucose metabolism from oxidative phosphorylation to aerobic glycolysis and this might occur due to HIF1alpha stabilization.	('HIF1alpha', 'Gene', '3091', (205, 214))	('change', 'Reg', (98, 104))	('glucose', 'Chemical', 'MESH:D005947', (105, 112))	('miRNA cluster', 'Var', (60, 73))	('aerobic glycolysis', 'MPA', (158, 176))	('expression', 'Var', (42, 52))	('glucose metabolism', 'MPA', (105, 123))	('LEC', 'Gene', (77, 80))	('HIF1alpha', 'Gene', (205, 214))
508063	25255370	Having found that expression of KSHV miRNAs reduces oxidative phosphorylation, we next tested their effect on mitochondrial function.	('oxidative phosphorylation', 'MPA', (52, 77))	('miRNAs', 'Var', (37, 43))	('KSHV', 'Species', '37296', (32, 36))	('KS', 'Phenotype', 'HP:0100726', (32, 34))	('reduces', 'NegReg', (44, 51))	('tested', 'Reg', (87, 93))	('expression', 'Var', (18, 28))	('KSHV', 'Gene', (32, 36))
508071	25255370	EGLN1 was suggested to be targeted by miR-K12-2 and miR-K12-11 in both BC-1 and BC-3 PEL cell lines through a CLIP experiment, while EGLN2 is predicted by the different algorithms to be targets by multiple miRNAs (miR-K12-2, miR-K12-3, miR-K12-6, miR-K12-7, miR-K12-8, miR-K12-9 and miR-K12-11).	('miR-K12-9', 'Var', (269, 278))	('miR-K12-3', 'Var', (225, 234))	('miR-K12-7', 'Var', (247, 256))	('EGLN1', 'Gene', (0, 5))	('miR-K12-2', 'Var', (214, 223))	('PEL', 'Phenotype', 'HP:0030069', (85, 88))	('miR-K12-11', 'Var', (52, 62))	('miR-K12-2', 'Var', (38, 47))	('EGLN1', 'Gene', '54583', (0, 5))	('miR-K12-6', 'Var', (236, 245))	('miR-K12-8', 'Var', (258, 267))	('miR-K12-11', 'Var', (283, 293))
508080	25255370	As the mitochondrial heat shock protein HSPA9 was suggested to be a target of multiple viral miRNAs in both CLIP studies (miR-K12-3 and miR-K12-4) and by all three algorithms (miR-K12-3, 4, 5, 6, 7, 10 and 11), and it was shown to be the most down-regulated among the genes we tested, we focused on it for further studies.	('down-regulated', 'NegReg', (243, 257))	('miR-K12-3', 'Var', (122, 131))	('HSPA9', 'Gene', (40, 45))	('HSPA9', 'Gene', '3313', (40, 45))	('miR-K12-4', 'Var', (136, 145))	('shock', 'Phenotype', 'HP:0031273', (26, 31))	('miR-K12-3, 4, 5, 6, 7, 10 and 11', 'Gene', '9149;10859;10288;406904', (176, 208))
508083	25255370	EGLN2 and HSPA9 mRNA and protein levels were significantly reduced in miR-LEC comparing to the controls cells (Figure 3A and B and Figure S3E).	('miR-LEC', 'Var', (70, 77))	('HSPA9', 'Gene', (10, 15))	('HSPA9', 'Gene', '3313', (10, 15))	('reduced', 'NegReg', (59, 66))
508087	25255370	This showed that, as predicted, each one of these genes is targeted by more than one of the KSHV miRNAs (miR-K12-1, 3, 8, and 11 for EGLN2 and miR-K12-1, 3, 4, 6, 8, 9 and 11 for HSPA9).	('miR-K12-1, 3, 4, 6, 8, 9 and 11', 'Gene', '4961486', (143, 174))	('KS', 'Phenotype', 'HP:0100726', (92, 94))	('KSHV', 'Gene', (92, 96))	('HSPA9', 'Gene', '3313', (179, 184))	('KSHV', 'Species', '37296', (92, 96))	('HSPA9', 'Gene', (179, 184))	('miR-K12-1, 3, 8, and 11', 'Gene', '4961486', (105, 128))	('EGLN2', 'Var', (133, 138))
508089	25255370	miR-K12-4 on HSPA9).	('HSPA9', 'Gene', '3313', (13, 18))	('HSPA9', 'Gene', (13, 18))	('miR-K12-4', 'Var', (0, 9))
508092	25255370	We found that knockdown of each of these genes led to stabilization of HIF1alpha, decreased oxygen consumption and reduced mitochondrial volume (Figure 4A-C).	('stabilization', 'MPA', (54, 67))	('oxygen consumption', 'MPA', (92, 110))	('HIF1alpha', 'Gene', '3091', (71, 80))	('reduced', 'NegReg', (115, 122))	('reduced mitochondrial volume', 'Phenotype', 'HP:0040013', (115, 143))	('knockdown', 'Var', (14, 23))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('decreased', 'NegReg', (82, 91))	('mitochondrial volume', 'MPA', (123, 143))	('HIF1alpha', 'Gene', (71, 80))
508093	25255370	Because knockdown of EGLN2 and HSPA9 caused HIF1alpha stabilization, we next investigated whether the observed metabolic phenotype depends on HIF1alpha.	('HSPA9', 'Gene', (31, 36))	('HSPA9', 'Gene', '3313', (31, 36))	('EGLN2', 'Gene', (21, 26))	('HIF1alpha', 'Gene', (44, 53))	('knockdown', 'Var', (8, 17))	('HIF1alpha', 'Gene', '3091', (44, 53))	('HIF1alpha', 'Gene', (142, 151))	('HIF1alpha', 'Gene', '3091', (142, 151))
508094	25255370	We therefore expressed the HIF1alpha P402A/P564A stable mutant in LEC (Figure S4D).	('P402A', 'Var', (37, 42))	('P402A', 'SUBSTITUTION', 'None', (37, 42))	('LEC', 'Gene', (66, 69))	('P564A', 'Var', (43, 48))	('P564A', 'SUBSTITUTION', 'None', (43, 48))	('HIF1alpha', 'Gene', (27, 36))	('HIF1alpha', 'Gene', '3091', (27, 36))
508097	25255370	We achieved overexpression of both EGLN2 and HSPA9, alongside viral miRNA expression, by using constructs that lacked 3'UTRs (Figure S5A).	('HSPA9', 'Gene', '3313', (45, 50))	('overexpression', 'PosReg', (12, 26))	('HSPA9', 'Gene', (45, 50))	('EGLN2', 'Var', (35, 40))
508099	25255370	As expected, overexpression of EGLN2 prevented HIF1alpha stabilization by the miRNA cluster (Figure 5A).	('EGLN2', 'Var', (31, 36))	('HIF1alpha', 'Gene', (47, 56))	('prevented', 'NegReg', (37, 46))	('HIF1alpha', 'Gene', '3091', (47, 56))
508100	25255370	More importantly, we found that both EGLN2 and HSPA9 overexpression significantly reduced the effect of the viral miRNA cluster on oxygen consumption and mitochondrial volume (Figure 5B and C).	('effect', 'MPA', (94, 100))	('HSPA9', 'Gene', (47, 52))	('mitochondrial', 'MPA', (154, 167))	('oxygen', 'Chemical', 'MESH:D010100', (131, 137))	('HSPA9', 'Gene', '3313', (47, 52))	('reduced', 'NegReg', (82, 89))	('EGLN2', 'Var', (37, 42))	('oxygen consumption', 'MPA', (131, 149))
508105	25255370	In contrast to high oxygen conditions, where both control and miR-LEC growth rates were similar (Figure S6A), when cells were exposed to hypoxia, miR-LEC had a significant growth advantage in the first 24 hours (Figure 6A).	('miR-LEC', 'Var', (146, 153))	('hypoxia', 'Disease', 'MESH:D000860', (137, 144))	('oxygen', 'Chemical', 'MESH:D010100', (20, 26))	('hypoxia', 'Disease', (137, 144))	('growth advantage', 'CPA', (172, 188))
508107	25255370	When we tested the effect of knocking down EGLN2 and HSPA9, we found that only EGLN2 silencing improved the initial response of LEC to hypoxia (Figure 6B and Figure S6B).	('hypoxia', 'Disease', (135, 142))	('hypoxia', 'Disease', 'MESH:D000860', (135, 142))	('EGLN2', 'Gene', (79, 84))	('HSPA9', 'Gene', (53, 58))	('HSPA9', 'Gene', '3313', (53, 58))	('improved', 'PosReg', (95, 103))	('silencing', 'Var', (85, 94))	('initial response', 'MPA', (108, 124))
508110	25255370	U2OS were infected with lentiviruses to express the miRNA cluster or the specific hairpins for EGLN2 and HSPA9 knockdown.	('knockdown', 'Var', (111, 120))	('miRNA', 'Gene', (52, 57))	('U2OS', 'CellLine', 'CVCL:0042', (0, 4))	('HSPA9', 'Gene', '3313', (105, 110))	('HSPA9', 'Gene', (105, 110))
508112	25255370	We found that, similarly to the growth advantage under hypoxic conditions, expression of the KSHV miRNA cluster and knock down of EGLN2 led to enhanced growth in 3D cultures, as shown by increased spheroid area (Figure S6D-E) and cell number (Figure 6F).	('EGLN2', 'Gene', (130, 135))	('growth', 'MPA', (152, 158))	('KSHV', 'Gene', (93, 97))	('enhanced', 'PosReg', (143, 151))	('spheroid area', 'CPA', (197, 210))	('KSHV', 'Species', '37296', (93, 97))	('cell number', 'CPA', (230, 241))	('hypoxic conditions', 'Disease', (55, 73))	('increased', 'PosReg', (187, 196))	('KS', 'Phenotype', 'HP:0100726', (93, 95))	('knock down', 'Var', (116, 126))	('hypoxic conditions', 'Disease', 'MESH:D009135', (55, 73))
508124	25255370	Interestingly, when we overexpressed EGLN2 and HSPA9 in BCBCL1 and KLEC.219, we found that while HSPA9 did not show a significant effect, EGLN2 overexpression caused a small increase in lytic phase activation (Figure S7D and F).	('HSPA9', 'Gene', (97, 102))	('EGLN2', 'Var', (138, 143))	('HSPA9', 'Gene', '3313', (97, 102))	('HSPA9', 'Gene', (47, 52))	('lytic', 'MPA', (186, 191))	('increase', 'PosReg', (174, 182))	('overexpression', 'PosReg', (144, 158))	('HSPA9', 'Gene', '3313', (47, 52))
508125	25255370	Respectively, knocking down HIF1alpha gave similar results; activation of the lytic phase indicated by increase in RFP positive cells and KSHV copy number in cell infected with media from these cells (Figure S7 E-F).	('increase', 'PosReg', (103, 111))	('knocking', 'Var', (14, 22))	('HIF1alpha', 'Gene', (28, 37))	('KSHV', 'Species', '37296', (138, 142))	('KS', 'Phenotype', 'HP:0100726', (138, 140))	('activation', 'PosReg', (60, 70))	('HIF1alpha', 'Gene', '3091', (28, 37))	('RFP positive', 'Protein', (115, 127))	('KSHV', 'Gene', (138, 142))	('lytic phase', 'CPA', (78, 89))
508128	25255370	Among those it was shown that KSHV alter its host cell energy metabolism, but neither the mechanism by which this is achieved nor the biological benefit, are understood.	('KSHV', 'Species', '37296', (30, 34))	('KSHV', 'Var', (30, 34))	('KS', 'Phenotype', 'HP:0100726', (30, 32))	('alter', 'Reg', (35, 40))	('host cell energy metabolism', 'MPA', (45, 72))
508132	25255370	We identified and confirmed two new targets for the KSHV miRNAs, EGLN2 and HSPA9, and show that KSHV alters host cell energy metabolism through down-regulation of these genes.	('host cell energy metabolism', 'MPA', (108, 135))	('alters', 'Reg', (101, 107))	('KSHV', 'Species', '37296', (96, 100))	('KSHV', 'Var', (96, 100))	('KSHV', 'Species', '37296', (52, 56))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('HSPA9', 'Gene', (75, 80))	('HSPA9', 'Gene', '3313', (75, 80))	('down-regulation', 'NegReg', (144, 159))	('KSHV', 'Gene', (52, 56))
508133	25255370	We suggest a two-armed mechanism by which KSHV changes cellular energy metabolism; the first is based on activation of the transcription factor HIF and the subsequent up-regulation of its metabolically relevant target genes.	('KS', 'Phenotype', 'HP:0100726', (42, 44))	('KSHV', 'Species', '37296', (42, 46))	('KSHV', 'Var', (42, 46))	('changes', 'Reg', (47, 54))	('activation', 'PosReg', (105, 115))	('cellular energy metabolism', 'MPA', (55, 81))	('up-regulation', 'PosReg', (167, 180))
508137	25255370	In addition, adjustments to energy metabolism have been suggested to give cancer cells many advantages with respect to proliferation and growth.	('advantages', 'PosReg', (92, 102))	('adjustments', 'Var', (13, 24))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('energy metabolism', 'MPA', (28, 45))	('growth', 'CPA', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('proliferation', 'CPA', (119, 132))
508142	25255370	Various types of cancer cells have been shown to overexpress HIF due to intratumoral hypoxia or as a result of genetic alterations that have occurred as part of their oncogenic program (reviewed in).	('hypoxia', 'Disease', 'MESH:D000860', (85, 92))	('genetic alterations', 'Var', (111, 130))	('hypoxia', 'Disease', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('overexpress', 'PosReg', (49, 60))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('alterations', 'Var', (119, 130))	('tumor', 'Disease', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
508149	25255370	This could be the reason that over expression of EGLN2 and HSPA9 failed to rescue the miRNAs phenotype, since other proteins from the import machinery are still down regulated.	('down regulated', 'NegReg', (161, 175))	('HSPA9', 'Gene', (59, 64))	('HSPA9', 'Gene', '3313', (59, 64))	('EGLN2', 'Var', (49, 54))
508150	25255370	It has been previously shown that knockout of the mitochondrial HSP70 (HSPA9), as well as other essential proteins in the import machinery, is lethal to cells.	('HSP70', 'Gene', '3308', (64, 69))	('HSPA9', 'Gene', (71, 76))	('HSPA9', 'Gene', '3313', (71, 76))	('knockout', 'Var', (34, 42))	('HSP70', 'Gene', (64, 69))
508213	23966622	Combining poly(ADP-ribose) polymerase 1 (PARP-1) inhibition and radiation in Ewing sarcoma results in lethal DNA damage Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly FLI1.	('poly(ADP-ribose) polymerase 1', 'Gene', '142', (10, 39))	('Ewing sarcoma', 'Disease', (77, 90))	('EWS', 'Gene', '2130', (190, 193))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (120, 133))	('ES', 'Phenotype', 'HP:0012254', (136, 138))	('FLI1', 'Gene', (245, 249))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (120, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('FLI1', 'Gene', '2313', (245, 249))	('inhibition', 'Var', (49, 59))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (120, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('PARP-1', 'Gene', '142', (41, 47))	('Ewing sarcomas', 'Disease', (120, 134))	('EWS', 'Gene', (190, 193))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (120, 134))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('poly(ADP-ribose) polymerase 1', 'Gene', (10, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('PARP-1', 'Gene', (41, 47))
508220	23966622	In conclusion, PARP-1 inhibition in ES amplifies the level and duration of DNA damage caused by RT leading to synergistic increases in apoptosis and cell death in a EWS-FLI1 dependent manner.	('inhibition', 'Var', (22, 32))	('apoptosis', 'CPA', (135, 144))	('DNA damage', 'MPA', (75, 85))	('PARP-1', 'Gene', (15, 21))	('EWS-FLI1', 'Gene', (165, 173))	('ES', 'Phenotype', 'HP:0012254', (36, 38))	('cell death', 'CPA', (149, 159))	('EWS-FLI1', 'Gene', '2130;2313', (165, 173))	('increases', 'PosReg', (122, 131))
508224	23966622	Aberrant transcription from the EWS/ETS fusion gene products induces transformation through induction or repression of target genes involved in controlling cell growth, signal transduction, and differentiation.	('Aberrant transcription', 'Var', (0, 22))	('induces', 'Reg', (61, 68))	('repression', 'NegReg', (105, 115))	('transformation', 'CPA', (69, 83))	('EWS', 'Gene', '2130', (32, 35))	('EWS', 'Gene', (32, 35))
508233	23966622	In the presence of PARP-1 inhibition, SSBs accumulate and are converted to double strand breaks (DSBs) during replication.	('double strand breaks', 'MPA', (75, 95))	('DSBs', 'Chemical', '-', (97, 101))	('converted', 'Reg', (62, 71))	('inhibition', 'Var', (26, 36))	('SSBs', 'Chemical', '-', (38, 42))	('PARP-1', 'Gene', (19, 25))	('SSBs', 'MPA', (38, 42))	('accumulate', 'PosReg', (43, 53))
508235	23966622	Given that radiation kills cancer cells primarily through DNA damage, it is not surprising that PARP-1 inhibitors are radiosensitisers in a variety of cell lines with enhancement ratios of up to 1.7.	('PARP-1', 'Gene', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('inhibitors', 'Var', (103, 113))	('DNA damage', 'MPA', (58, 68))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
508236	23966622	Non-toxic doses of PARP-1 inhibitors have been demonstrated to increase the efficacy of radiation in several xenograft tumor models.	('increase', 'PosReg', (63, 71))	('tumor', 'Disease', (119, 124))	('inhibitors', 'Var', (26, 36))	('PARP-1', 'Gene', (19, 25))	('efficacy', 'CPA', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
508242	23966622	Both these cell lines harbor t(11;22) leading to expression of the EWS-FLI1 fusion protein.	('EWS-FLI1', 'Gene', (67, 75))	('t(11;22', 'Var', (29, 36))	('EWS-FLI1', 'Gene', '2130;2313', (67, 75))	('expression', 'MPA', (49, 59))
508261	23966622	Antibodies used were anti-gammaH2AX (Millipore), m cleaved caspase-3 (Cell Signaling), anti-TUNEL (ApoptoTag Peroxidase kit, Millipore), and anti-PCNA (Santa Cruz Biotechnology).	('anti-gammaH2AX', 'Var', (21, 35))	('PCNA', 'Gene', (146, 150))	('gammaH2AX', 'Chemical', '-', (26, 35))	('PCNA', 'Gene', '5111', (146, 150))
508286	23966622	Efficient PARP-1 knockdown in RD-ES and SK-N-MC cells was confirmed by Western blot analysis (Fig.	('PARP-1', 'Gene', (10, 16))	('knockdown', 'Var', (17, 26))	('ES', 'Phenotype', 'HP:0012254', (33, 35))	('SK-N-MC', 'CellLine', 'CVCL:0530', (40, 47))	('RD-ES', 'Chemical', '-', (30, 35))
508287	23966622	When the proliferation of RD-ES and SK-N-MC cells with shRNA silencing of PARP-1 was compared to that of control cells transduced with scrambled shRNA, there was a dramatic reduction in proliferation which was somewhat greater in magnitude than following treatment with olaparib (500 nM) (Fig.	('reduction', 'NegReg', (173, 182))	('ES', 'Phenotype', 'HP:0012254', (29, 31))	('proliferation', 'CPA', (186, 199))	('silencing', 'Var', (61, 70))	('SK-N-MC', 'CellLine', 'CVCL:0530', (36, 43))	('PARP-1', 'Gene', (74, 80))	('RD-ES', 'Chemical', '-', (26, 31))	('olaparib', 'Chemical', 'MESH:C531550', (270, 278))
508289	23966622	In RD-ES and SK-N-MC cells, inhibition of PARP-1 with olaparib (50-100 nM) or PARP-1 shRNA potentiated the ability of radiation in blocking colony formation (Fig.	('SK-N-MC', 'CellLine', 'CVCL:0530', (13, 20))	('ES', 'Phenotype', 'HP:0012254', (6, 8))	('RD-ES', 'Chemical', '-', (3, 8))	('potentiated', 'PosReg', (91, 102))	('blocking', 'NegReg', (131, 139))	('inhibition', 'Var', (28, 38))	('PARP-1', 'Gene', (78, 84))	('colony formation', 'CPA', (140, 156))	('olaparib', 'Chemical', 'MESH:C531550', (54, 62))	('PARP-1', 'Gene', (42, 48))
508298	23966622	Activation of PARP-1 leads to a number of DNA damage responses including activation of ataxia telangiectasia-mutated (ATM), which is involved in double-strand break repair by homologous recombination and activation of DNA-protein kinase catalytic subunit (DNA-PKcs), which is involved in double-strand break repair by nonhomologous end-joining.	('ATM', 'Gene', (118, 121))	('activation', 'PosReg', (73, 83))	('PARP-1', 'Gene', (14, 20))	('telangiectasia', 'Phenotype', 'HP:0001009', (94, 108))	('DNA damage responses', 'MPA', (42, 62))	('ATM', 'Gene', '472', (118, 121))	('DNA-PKcs', 'Gene', '5591', (256, 264))	('ataxia', 'Phenotype', 'HP:0001251', (87, 93))	('Activation', 'Var', (0, 10))	('ataxia telangiectasia-mutated', 'Gene', '472', (87, 116))	('DNA-PKcs', 'Gene', (256, 264))	('ataxia telangiectasia-mutated', 'Gene', (87, 116))
508302	23966622	We examined apoptosis in our Ewing sarcoma cell lines following radiation combined with PARP-1 inhibition.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (29, 42))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (29, 42))	('inhibition', 'Var', (95, 105))	('PARP-1', 'Gene', (88, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('Ewing sarcoma', 'Disease', (29, 42))
508309	23966622	The combination of olaparib (500 nM) and radiation led to a synergistic increase in cell death in Ewing sarcoma cell lines, with 46% of RD-ES and 49% of SK-N-MC cells dying from this combination, while cell death in non-Ewing sarcoma cells increased only to 16-22%.	('Ewing sarcoma', 'Disease', (98, 111))	('olaparib', 'Chemical', 'MESH:C531550', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('increase', 'PosReg', (72, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('dying', 'NegReg', (167, 172))	('non-Ewing sarcoma', 'Disease', (216, 233))	('SK-N-MC', 'CellLine', 'CVCL:0530', (153, 160))	('ES', 'Phenotype', 'HP:0012254', (139, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (98, 111))	('non-Ewing sarcoma', 'Disease', 'MESH:C563168', (216, 233))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (98, 111))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (220, 233))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (220, 233))	('RD-ES', 'Chemical', '-', (136, 141))	('cell death', 'CPA', (84, 94))	('500 nM', 'Var', (29, 35))
508323	23966622	We examined proliferation and clonogenic survival of shA673-1C cells in response to olaparib and found decreased proliferation with increasing doses of olaparib, but this effect was lost in the presence of doxycycline and knockdown of EWS-FLI1 (Fig.	('doxycycline', 'Chemical', 'MESH:D004318', (206, 217))	('EWS-FLI1', 'Gene', (235, 243))	('decreased', 'NegReg', (103, 112))	('knockdown', 'Var', (222, 231))	('EWS-FLI1', 'Gene', '2130;2313', (235, 243))	('proliferation', 'CPA', (113, 126))	('proliferation', 'CPA', (12, 25))	('olaparib', 'Chemical', 'MESH:C531550', (152, 160))	('olaparib', 'Chemical', 'MESH:C531550', (84, 92))	('clonogenic survival', 'CPA', (30, 49))
508324	23966622	We also examined the effect of combining olaparib (500 nM) and radiation (4 Gy) on the proliferation and clonogenic survival of shA673-1C cells.	('500', 'Var', (51, 54))	('clonogenic survival', 'CPA', (105, 124))	('olaparib', 'Chemical', 'MESH:C531550', (41, 49))
508327	23966622	Of note, the silencing of EWS-FLI alone in shA673-1C cells reduced proliferation by 24% and colony formation by 27% (data now shown).	('FLI', 'Gene', '2314', (30, 33))	('FLI', 'Gene', (30, 33))	('reduced', 'NegReg', (59, 66))	('colony formation', 'CPA', (92, 108))	('EWS', 'Gene', (26, 29))	('proliferation', 'CPA', (67, 80))	('EWS', 'Gene', '2130', (26, 29))	('silencing', 'Var', (13, 22))
508334	23966622	Nearly all Ewing sarcomas and ESFT have a characteristic chromosomal translocation, which fuses the EWS gene to an ETS family member such as FLI1 or ERG, and the transcriptional program initiated by EWS-ETS translocations results in a high sensitivity to PARP-1 inhibition.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (11, 25))	('EWS', 'Gene', (199, 202))	('EWS', 'Gene', '2130', (199, 202))	('ERG', 'Gene', '2078', (149, 152))	('results in', 'Reg', (222, 232))	('high sensitivity to PARP-1 inhibition', 'MPA', (235, 272))	('FLI1', 'Gene', (141, 145))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (11, 25))	('translocations', 'Var', (207, 221))	('FLI1', 'Gene', '2313', (141, 145))	('Ewing sarcomas', 'Disease', (11, 25))	('ERG', 'Gene', (149, 152))	('ES', 'Phenotype', 'HP:0012254', (30, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (11, 24))	('EWS', 'Gene', '2130', (100, 103))	('EWS', 'Gene', (100, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))
508338	23966622	The same group also found that PARP-1 inhibition can potentiate the DNA-damaging effects of chemotherapy in EWS-FLI1 or EWS-ERG driven Ewing sarcoma cells.	('EWS-FLI1', 'Gene', '2130;2313', (108, 116))	('EWS', 'Gene', '2130', (108, 111))	('EWS', 'Gene', (108, 111))	('EWS', 'Gene', '2130', (120, 123))	('ERG', 'Gene', '2078', (124, 127))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (135, 148))	('DNA-damaging effects', 'MPA', (68, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (135, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('ERG', 'Gene', (124, 127))	('inhibition', 'Var', (38, 48))	('Ewing sarcoma', 'Disease', (135, 148))	('potentiate', 'PosReg', (53, 63))	('EWS', 'Gene', (120, 123))	('EWS-FLI1', 'Gene', (108, 116))	('PARP-1', 'Gene', (31, 37))
508342	23966622	Cells may respond to DNA damage by initiating apoptosis within hours of radiation injury, or DNA damage may lead to death through abnormal chromosomal segregation during mitosis.	('apoptosis', 'CPA', (46, 55))	('radiation injury', 'Disease', (72, 88))	('mitosis', 'Disease', (170, 177))	('mitosis', 'Disease', 'None', (170, 177))	('radiation injury', 'Disease', 'MESH:D011832', (72, 88))	('initiating', 'Reg', (35, 45))	('damage', 'Var', (97, 103))	('lead to', 'Reg', (108, 115))	('abnormal chromosomal segregation', 'CPA', (130, 162))	('death', 'CPA', (116, 121))
508344	23966622	Dysfunction of p53 related machinery prevents cells from initiating rapid apoptotic death in response to radiation, and predisposes to premature entry into M phase, before DNA damage is repaired.	('Dysfunction', 'Var', (0, 11))	('prevents', 'NegReg', (37, 45))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('rapid apoptotic death', 'MPA', (68, 89))	('premature entry', 'MPA', (135, 150))
508347	23966622	PARP-1 is most closely associated with the base excision repair pathway, but the sensitivity of Ewing sarcomas to the combination of radiation and PARP-1 inhibition would suggest a defect in other mechanisms of DNA repair such that PARP-1 inhibition leads to unrepaired and lethal DNA damage.	('defect', 'NegReg', (181, 187))	('inhibition', 'Var', (239, 249))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (96, 110))	('PARP-1', 'Gene', (232, 238))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (96, 110))	('Ewing sarcomas', 'Disease', (96, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('PARP-1', 'Gene', (147, 153))
508349	23966622	We found that PARP-1 silencing with shRNA was not as effective as PARP-1 inhibition with olaparib in enhancing the effects of radiation on DNA damage (as measured by levels of gammaH2AX) and on apoptosis (as measured by levels of cleaved caspase 3).	('apoptosis', 'CPA', (194, 203))	('DNA damage', 'MPA', (139, 149))	('olaparib', 'Chemical', 'MESH:C531550', (89, 97))	('gammaH2AX', 'Chemical', '-', (176, 185))	('silencing', 'Var', (21, 30))
508352	23966622	An example of the first strategy is the use of PARP-1 inhibitors in BRCA-mutated cancers where defects or inhibition of BRCA 1/2 or PARP-1 has little or no effect, but deletion of both genes is cytotoxic (a.k.a synthetic lethality) .	('BRCA', 'Gene', (120, 124))	('cancers where defects', 'Disease', (81, 102))	('BRCA 1/2', 'Gene', '672;675', (120, 128))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BRCA 1/2', 'Gene', (120, 128))	('BRCA', 'Gene', '672', (68, 72))	('BRCA', 'Gene', '672', (120, 124))	('deletion', 'Var', (168, 176))	('BRCA', 'Gene', (68, 72))	('cancers where defects', 'Disease', 'MESH:D009369', (81, 102))
508353	23966622	PARP-1 inhibition leads to conversion of single strand DNA breaks to double strand breaks, and BRCA mutation leads to defects in homologous recombination and the ability to repair double strand breaks.	('BRCA', 'Gene', (95, 99))	('homologous', 'MPA', (129, 139))	('defects', 'NegReg', (118, 125))	('mutation', 'Var', (100, 108))	('ability', 'MPA', (162, 169))	('single strand DNA breaks', 'MPA', (41, 65))	('BRCA', 'Gene', '672', (95, 99))	('conversion', 'MPA', (27, 37))	('inhibition', 'NegReg', (7, 17))	('PARP-1', 'Gene', (0, 6))
508363	23966622	Other investigators have found that PARP-1 inhibition and radiation inhibits tumor vasculature.	('inhibition', 'Var', (43, 53))	('PARP-1', 'Protein', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('inhibits', 'NegReg', (68, 76))
508377	22848594	The predicted targets are consistently enriched for miRNA binding site motifs in their 3'UTR.	('motifs', 'Var', (71, 77))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))
508388	22848594	Misregulation of miRNA expression has been linked to many types of cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('Misregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('linked', 'Reg', (43, 49))	('expression', 'Species', '29278', (23, 33))
508395	22848594	Results show that upon introduction (or knockdown) of a miRNA, the synthesis of hundreds of proteins is affected, but effects are mild, with few proteins decreasing by more than 50%.	('decreasing', 'NegReg', (154, 164))	('knockdown', 'Var', (40, 49))	('affected', 'Reg', (104, 112))	('synthesis of hundreds of proteins', 'MPA', (67, 100))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))
508426	22848594	This malignant pediatric tumor is characterized by specific fusions between EWS and ETS family genes.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('EWS', 'Gene', (76, 79))	('fusions', 'Var', (60, 67))	('ETS family', 'Gene', (84, 94))	('pediatric tumor', 'Disease', 'MESH:D063766', (15, 30))	('pediatric tumor', 'Disease', (15, 30))
508675	32046545	Immunohistochemistry showed positive staining of CD3, CD5, CD43, CD38, CD138, CD21, CD23, CD20, CD79, BCL2, and Ki-67 (<10%) in the large cells, with negative staining of CK, CD10, CD56, cyclin D1, SOX11, and IgG4.	('BCL2', 'Gene', (102, 106))	('CD5', 'Gene', (181, 184))	('cyclin D1', 'Gene', '595', (187, 196))	('CD38', 'Gene', (65, 69))	('CD56', 'Gene', (181, 185))	('CD79', 'Var', (96, 100))	('CD23', 'Gene', '2208', (84, 88))	('CD138', 'Gene', '6382', (71, 76))	('CD43', 'Gene', (59, 63))	('CD5', 'Gene', '921', (54, 57))	('CD56', 'Gene', '4684', (181, 185))	('CD5', 'Gene', '921', (181, 184))	('CD3', 'Gene', (49, 52))	('SOX11', 'Gene', (198, 203))	('CD20', 'Gene', (90, 94))	('CD21', 'Gene', (78, 82))	('CD138', 'Gene', (71, 76))	('CD10', 'Gene', '4311', (175, 179))	('CD43', 'Gene', '6693', (59, 63))	('CD20', 'Gene', '54474', (90, 94))	('CD38', 'Gene', '952', (65, 69))	('BCL2', 'Gene', '596', (102, 106))	('CD21', 'Gene', '1380', (78, 82))	('CD10', 'Gene', (175, 179))	('SOX11', 'Gene', '6664', (198, 203))	('cyclin D1', 'Gene', (187, 196))	('CD5', 'Gene', (54, 57))	('CD23', 'Gene', (84, 88))
508707	32046545	However, other infections were present among five of the eight adult patients in our study, including cholangitis, chronic urinary tract infection, and chronic hepatitis C. Notably, only one patient had acute cellular rejection, suggesting that exposure to HHV-8/EBV instead of strengthening of immunosuppression may be a key risk factor.	('infection', 'Disease', 'MESH:D007239', (137, 146))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (152, 169))	('hepatitis', 'Phenotype', 'HP:0012115', (160, 169))	('patients', 'Species', '9606', (69, 77))	('patient', 'Species', '9606', (191, 198))	('HHV-8', 'Species', '37296', (257, 262))	('infections', 'Disease', 'MESH:D007239', (15, 25))	('infections', 'Disease', (15, 25))	('cholangitis', 'Disease', 'MESH:D002761', (102, 113))	('infection', 'Disease', (15, 24))	('infection', 'Disease', 'MESH:D007239', (15, 24))	('chronic hepatitis C', 'Disease', 'MESH:D019698', (152, 171))	('cholangitis', 'Disease', (102, 113))	('patient', 'Species', '9606', (69, 76))	('HHV-8/EBV', 'Var', (257, 266))	('cholangitis', 'Phenotype', 'HP:0030151', (102, 113))	('EBV', 'Species', '10376', (263, 266))	('urinary tract infection', 'Phenotype', 'HP:0000010', (123, 146))	('chronic hepatitis C', 'Disease', (152, 171))	('infection', 'Disease', (137, 146))
508739	31350293	The genetic characteristic of PMS is often the (2; 22) (q33; q12) translocation with the EWSR1-CREB1 fusion gene.	('EWSR1', 'Gene', '2130', (89, 94))	('2;', 'Var', (48, 50))	('CREB1', 'Gene', '1385', (95, 100))	('PMS', 'Disease', 'MESH:D045888', (30, 33))	('PMS', 'Disease', (30, 33))	('EWSR1', 'Gene', (89, 94))	('CREB1', 'Gene', (95, 100))
508750	31350293	The diagnosis of PMS is morphological and confirmed by the presence of EWSR1 translocation.	('PMS', 'Disease', (17, 20))	('EWSR1', 'Gene', (71, 76))	('PMS', 'Disease', 'MESH:D045888', (17, 20))	('EWSR1', 'Gene', '2130', (71, 76))	('presence', 'Var', (59, 67))
508752	27631520	To date, only YWHAE-NUTM2 rearrangements are associated with distinctive high-grade morphology and aggressive clinical behavior.	('YWHAE', 'Gene', (14, 19))	('associated', 'Reg', (45, 55))	('rearrangements', 'Var', (26, 40))	('YWHAE', 'Gene', '7531', (14, 19))	('aggressive clinical behavior', 'CPA', (99, 127))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (99, 127))
508767	27631520	While PHF1 rearrangements have been reportedly associated with sex-cord differentiation, other gene fusions found in LG-ESS have not been linked with variant morphologic features.	('PHF1', 'Gene', (6, 10))	('rearrangements', 'Var', (11, 25))	('PHF1', 'Gene', '5252', (6, 10))	('LG-ESS', 'Chemical', '-', (117, 123))	('associated', 'Reg', (47, 57))	('sex-cord differentiation', 'CPA', (63, 87))
508768	27631520	JAZF1-SUZ12 gene fusions are only extraordinarily encountered in the fibromyxoid variant.	('SUZ12', 'Gene', (6, 11))	('fibromyxoid variant', 'Disease', (69, 88))	('JAZF1', 'Gene', (0, 5))	('fusions', 'Var', (17, 24))	('SUZ12', 'Gene', '23512', (6, 11))	('JAZF1', 'Gene', '221895', (0, 5))
508772	27631520	The term, HG-ESS, was recently reintroduced into the classification of endometrial stromal tumors based on the discovery of the t(10;17) translocation resulting in fusion of YWHAE and NUTM2 genes.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('YWHAE', 'Gene', (174, 179))	('fusion', 'Var', (164, 170))	('endometrial stromal tumors', 'Disease', 'MESH:D036821', (71, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('NUTM2', 'Gene', (184, 189))	('endometrial stromal tumors', 'Disease', (71, 97))	('YWHAE', 'Gene', '7531', (174, 179))
508841	27631520	Case 1 was subjected to MSK-IMPACT sequencing at a median sequencing depth of coverage of 924X and was found to have an in frame fusion between ZC3H7B exon 10 (NM_017590) and BCOR exon 7 (NM_001123385) (t(X;22)(p11.4;q13.2)(chrX:c.3146::chr22:c.1525)) (Figure 7).	('ZC3H7B', 'Gene', (144, 150))	('BCOR', 'Gene', '54880', (175, 179))	('t(X;22)(p11.4;q13.2)', 'STRUCTURAL_ABNORMALITY', 'None', (203, 223))	('ZC3H7B', 'Gene', '23264', (144, 150))	('NM_017590', 'Var', (160, 169))	('BCOR', 'Gene', (175, 179))	('NM_001123385', 'Var', (188, 200))
508842	27631520	Genomic testing of case 2 by Foundation One also revealed a ZC3H7B-BCOR fusion in addition to amplification of CDK4, MDM2, FRS2 genes, HDAC4-HABP2 fusion, and seven variants of unknown significance.	('ZC3H7B', 'Gene', (60, 66))	('CDK4', 'Gene', (111, 115))	('HDAC4', 'Gene', '9759', (135, 140))	('HDAC4', 'Gene', (135, 140))	('CDK4', 'Gene', '1019', (111, 115))	('FRS2', 'Gene', '10818', (123, 127))	('HABP2', 'Gene', '3026', (141, 146))	('ZC3H7B', 'Gene', '23264', (60, 66))	('fusion', 'Var', (72, 78))	('HABP2', 'Gene', (141, 146))	('BCOR', 'Gene', (67, 71))	('BCOR', 'Gene', '54880', (67, 71))	('MDM2', 'Gene', '4193', (117, 121))	('FRS2', 'Gene', (123, 127))	('MDM2', 'Gene', (117, 121))
508843	27631520	This also revealed an in-frame fusion between ZC3H7B exon 10 (NM_017590) and BCOR exon 7 (NM_001123385).	('ZC3H7B', 'Gene', '23264', (46, 52))	('NM_001123385', 'Var', (90, 102))	('NM_017590', 'Var', (62, 71))	('BCOR', 'Gene', (77, 81))	('BCOR', 'Gene', '54880', (77, 81))	('ZC3H7B', 'Gene', (46, 52))
508844	27631520	In cases 1 and 2, FISH confirmed gene rearrangements in both ZC3H7B and BCOR (Figure 8).	('gene rearrangements', 'Var', (33, 52))	('BCOR', 'Gene', (72, 76))	('ZC3H7B', 'Gene', '23264', (61, 67))	('BCOR', 'Gene', '54880', (72, 76))	('ZC3H7B', 'Gene', (61, 67))
508845	27631520	FISH for YWHAE and JAZF1 rearrangements were also performed on case 2 at the original institution and were both negative by report.	('YWHAE', 'Gene', '7531', (9, 14))	('JAZF1', 'Gene', (19, 24))	('rearrangements', 'Var', (25, 39))	('JAZF1', 'Gene', '221895', (19, 24))	('YWHAE', 'Gene', (9, 14))
508846	27631520	In this report, we describe for the first time the association of ZC3H7B-BCOR fusion resulting from t(X;22)(p11.4;q13.2) in tumors with extensive myxoid change and focal fascicular architecture mimicking myxoid LMS and thus representing a potential diagnostic pitfall.	('fusion', 'Var', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('t(X;22)(p11.4;q13.2)', 'STRUCTURAL_ABNORMALITY', 'None', (100, 120))	('BCOR', 'Gene', '54880', (73, 77))	('association', 'Interaction', (51, 62))	('ZC3H7B', 'Gene', (66, 72))	('myxoid LMS', 'Disease', (204, 214))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('LMS', 'Phenotype', 'HP:0100243', (211, 214))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('ZC3H7B', 'Gene', '23264', (66, 72))	('BCOR', 'Gene', (73, 77))
508848	27631520	Detection of the ZC3H7B-BCOR fusion prompted a re-review of the histopathology of the uterine primary and recurrences, and in all cases, a diagnosis of ESS with extensive myxoid features was ultimately rendered based on the molecular genetic findings, involvement of the endometrium, and characteristic pattern of myometrial invasion.	('ZC3H7B', 'Gene', (17, 23))	('BCOR', 'Gene', '54880', (24, 28))	('fusion', 'Var', (29, 35))	('ZC3H7B', 'Gene', '23264', (17, 23))	('BCOR', 'Gene', (24, 28))
508856	27631520	Although this translocation was not characterized in their study and the morphologic description of these 2 cases was not available in their report, both tumors likely harbor ZC3H7B-BCOR rearrangements based on their cytogenetic profiles.	('ZC3H7B', 'Gene', (175, 181))	('tumors', 'Disease', (154, 160))	('BCOR', 'Gene', '54880', (182, 186))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('ZC3H7B', 'Gene', '23264', (175, 181))	('rearrangements', 'Var', (187, 201))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('harbor', 'Reg', (168, 174))	('BCOR', 'Gene', (182, 186))
508865	27631520	The investigation for BCOR and ZC3H7B rearrangements in histologically classified myxoid LMS would be an interesting endeavour and merits further study.	('rearrangements', 'Var', (38, 52))	('ZC3H7B', 'Gene', (31, 37))	('BCOR', 'Gene', (22, 26))	('ZC3H7B', 'Gene', '23264', (31, 37))	('LMS', 'Phenotype', 'HP:0100243', (89, 92))	('BCOR', 'Gene', '54880', (22, 26))
508869	27631520	While germline mutations in BCOR result in the syndromic diseases, oculo-facio-cardio-dental syndrome and Lenz microphthalmia, somatic BCOR mutations have been reported in various hematolymphoid malignancies, retinoblastoma, medulloblastoma , central nervous system primitive neuroectodermal tumors, rhabdomyosarcoma, and clear cell sarcoma of the kidney.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (300, 316))	('cardio-dental syndrome', 'Disease', (79, 101))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (300, 316))	('hematolymphoid malignancies', 'Disease', 'MESH:D009369', (180, 207))	('retinoblastoma', 'Disease', 'MESH:D012175', (209, 223))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (276, 298))	('sarcoma', 'Phenotype', 'HP:0100242', (333, 340))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('sarcoma', 'Phenotype', 'HP:0100242', (309, 316))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (276, 298))	('syndromic diseases', 'Disease', 'MESH:D030342', (47, 65))	('BCOR', 'Gene', '54880', (135, 139))	('reported', 'Reg', (160, 168))	('Lenz microphthalmia', 'Disease', 'MESH:C537464', (106, 125))	('dental syndrome', 'Phenotype', 'HP:0000164', (86, 101))	('neuroectodermal tumors', 'Disease', (276, 298))	('retinoblastoma', 'Phenotype', 'HP:0009919', (209, 223))	('BCOR', 'Gene', (135, 139))	('result in', 'Reg', (33, 42))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (333, 354))	('mutations', 'Var', (140, 149))	('retinoblastoma', 'Disease', (209, 223))	('rhabdomyosarcoma', 'Disease', (300, 316))	('medulloblastoma', 'Phenotype', 'HP:0002885', (225, 240))	('medulloblastoma', 'Disease', 'MESH:D008527', (225, 240))	('Lenz microphthalmia', 'Disease', (106, 125))	('syndromic diseases', 'Disease', (47, 65))	('cardio-dental syndrome', 'Disease', 'MESH:D059347', (79, 101))	('medulloblastoma', 'Disease', (225, 240))	('BCOR', 'Gene', '54880', (28, 32))	('hematolymphoid malignancies', 'Disease', (180, 207))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (266, 298))	('sarcoma of the kidney', 'Disease', (333, 354))	('BCOR', 'Gene', (28, 32))	('microphthalmia', 'Phenotype', 'HP:0000568', (111, 125))
508871	27631520	has reported ZC3H7B-BCOR, MEAF6-PHF1 and EPC1-PHF1 fusions in a subset of ossifying fibromyxoid tumors (OFMT); these genetic rearrangements have also been reported in ESS.	('PHF1', 'Gene', '5252', (46, 50))	('PHF1', 'Gene', '5252', (32, 36))	('fibromyxoid tumors', 'Disease', 'MESH:D009369', (84, 102))	('BCOR', 'Gene', '54880', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ZC3H7B', 'Gene', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('EPC1', 'Gene', '80314', (41, 45))	('fibromyxoid tumors', 'Disease', (84, 102))	('EPC1', 'Gene', (41, 45))	('MEAF6', 'Gene', (26, 31))	('MEAF6', 'Gene', '64769', (26, 31))	('ZC3H7B', 'Gene', '23264', (13, 19))	('PHF1', 'Gene', (32, 36))	('fusions', 'Var', (51, 58))	('BCOR', 'Gene', (20, 24))	('PHF1', 'Gene', (46, 50))
508872	27631520	Notably, ZC3H7B-BCOR rearrangements were identified in 2 OFMT, both of which displayed malignant features and were S100-negative.	('identified', 'Reg', (41, 51))	('S100', 'Gene', '6271', (115, 119))	('rearrangements', 'Var', (21, 35))	('BCOR', 'Gene', (16, 20))	('ZC3H7B', 'Gene', (9, 15))	('BCOR', 'Gene', '54880', (16, 20))	('S100', 'Gene', (115, 119))	('ZC3H7B', 'Gene', '23264', (9, 15))
508873	27631520	Rearrangements in BCOR have also been identified in undifferentiated small blue round cell tumors, undifferentiated spindle cell sarcomas that lack EWS rearrangements, and a single case of acute promyelocytic leukemia.	('BCOR', 'Gene', (18, 22))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('Rearrangements', 'Var', (0, 14))	('identified', 'Reg', (38, 48))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (189, 217))	('leukemia', 'Phenotype', 'HP:0001909', (209, 217))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (189, 217))	('BCOR', 'Gene', '54880', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('sarcomas', 'Disease', 'MESH:D012509', (129, 137))	('acute promyelocytic leukemia', 'Disease', (189, 217))	('small', 'Disease', (69, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcomas', 'Disease', (129, 137))
508874	27631520	The presence of BCOR rearrangements across diverse tumor types suggests the likely role of BCOR driving tumourigenesis.	('BCOR', 'Gene', '54880', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('rearrangements', 'Var', (21, 35))	('tumor', 'Disease', (51, 56))	('BCOR', 'Gene', (16, 20))	('BCOR', 'Gene', (91, 95))	('BCOR', 'Gene', '54880', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
508919	23243527	Immunohistochemistry was positive for CD45 (weakly +), CD34 (+) (Figure 3), CD117 (+), CD33 (+), MPO (+), CD43 (bright +), and Bcl-2 (+).	('CD33', 'Gene', '945', (87, 91))	('CD34', 'Gene', '947', (55, 59))	('CD33', 'Gene', (87, 91))	('CD45', 'Gene', '5788', (38, 42))	('CD43', 'Gene', '6693', (106, 110))	('CD117', 'Gene', '3815', (76, 81))	('CD43', 'Gene', (106, 110))	('MPO (+', 'Var', (97, 103))	('CD117', 'Gene', (76, 81))	('bright +', 'Gene', '1820', (112, 120))	('CD34', 'Gene', (55, 59))	('CD45', 'Gene', (38, 42))	('bright +', 'Gene', (112, 120))
508956	23243527	The chromosomal abnormalities that have been reported in conjunction with these extramedullary sarcomas include t(8,21), inv(16), t(9,11), 11q23, del(16q), and trisomy 8.	('11q23', 'Var', (139, 144))	('del(16q', 'Var', (146, 153))	('inv', 'Disease', (121, 124))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (4, 29))	('chromosomal abnormalities', 'Disease', (4, 29))	('sarcomas', 'Disease', 'MESH:D012509', (95, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('trisomy', 'Disease', (160, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('sarcomas', 'Disease', (95, 103))
508957	23243527	Interestingly, the patient presented in this paper did not have any of these listed abnormalities; however, he did have a balanced translocation involving chromosomes 2 and 17, which to our knowledge has not been reported in association with myeloid sarcomas.	('patient', 'Species', '9606', (19, 26))	('myeloid sarcomas', 'Disease', (242, 258))	('sarcomas', 'Phenotype', 'HP:0100242', (250, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('myeloid sarcomas', 'Disease', 'MESH:D023981', (242, 258))	('balanced translocation', 'Var', (122, 144))
509034	29861296	Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest.	('BAF47', 'Gene', (44, 49))	('enhancer activation', 'MPA', (59, 78))	('restores', 'PosReg', (50, 58))	('reassembly', 'Var', (30, 40))	('BAF47', 'Gene', '6598', (44, 49))	('SS18-SSX', 'Gene', (20, 28))	('SS18-SSX', 'Gene', '6760', (20, 28))
509041	29861296	Recent exome sequencing studies have revealed the major contribution of these regulators to human disease, demonstrating that genes encoding BAF complex subunits are recurrently mutated in >20% of human cancers as well as a number of intellectual disability syndromes.	('intellectual disability', 'Phenotype', 'HP:0001249', (234, 257))	('intellectual disability syndromes', 'Disease', (234, 267))	('BAF', 'Gene', (141, 144))	('intellectual disability syndromes', 'Disease', 'MESH:D008607', (234, 267))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('mutated', 'Var', (178, 185))	('human', 'Species', '9606', (197, 202))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('human', 'Species', '9606', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
509043	29861296	Over the past several years, sequencing studies have demonstrated cancer-specific loss-of-function BAF complex gene mutations, such as PBRM1 mutations in clear cell renal cell carcinoma and SMARCE1 mutations in clear cell meningioma, highlighting distinct, cell-type-specific routes toward oncogenesis.	('BAF complex gene', 'Gene', (99, 115))	('SMARCE1', 'Gene', '6605', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PBRM1', 'Gene', '55193', (135, 140))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (154, 185))	('SMARCE1', 'Gene', (190, 197))	('loss-of-function', 'NegReg', (82, 98))	('cancer', 'Disease', (66, 72))	('mutations', 'Var', (198, 207))	('PBRM1', 'Gene', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('meningioma', 'Disease', (222, 232))	('mutations', 'Var', (141, 150))	('meningioma', 'Disease', 'MESH:D008579', (222, 232))	('meningioma', 'Phenotype', 'HP:0002858', (222, 232))	('mutations', 'Var', (116, 125))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (154, 185))	('clear cell renal cell carcinoma', 'Disease', (154, 185))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (165, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
509057	29861296	To define the consequences of SS18-SSX protein expression and complex incorporation on the targeting of BAF complexes genome wide, we performed fusion-specific (shSSX) knockdown compared with scrambled hairpin control (shCt) in the Aska SS cell line.	('SS18-SSX', 'Gene', (30, 38))	('SS18-SSX', 'Gene', '6760', (30, 38))	('SSX', 'Gene', (35, 38))	('knockdown', 'Var', (168, 177))	('SSX', 'Gene', '6757', (163, 166))	('SSX', 'Gene', '6757', (35, 38))	('SSX', 'Gene', (163, 166))
509058	29861296	Upon knockdown of SS18-SSX1, protein levels of WT SS18 and BAF47 are rescued (Figures 1A and S1A-S1C), as shown previously.	('SS18-SSX', 'Gene', (18, 26))	('SSX1', 'Gene', '6756', (23, 27))	('SS18-SSX', 'Gene', '6760', (18, 26))	('BAF47', 'Gene', '6598', (59, 64))	('SS18', 'Gene', (50, 54))	('SSX1', 'Gene', (23, 27))	('knockdown', 'Var', (5, 14))	('protein levels', 'MPA', (29, 43))	('BAF47', 'Gene', (59, 64))	('SS18', 'Gene', '6760', (18, 22))	('rescued', 'PosReg', (69, 76))	('SS18', 'Gene', '6760', (50, 54))	('SS18', 'Gene', (18, 22))
509071	29861296	Changes in BAF complex peak width and locus-specific occupancy directed by SS18-SSX incorporation are exemplified at the SOX8 and CAV1 loci in SS and fibroblast lines (Figure 1K).	('SOX8', 'Gene', (121, 125))	('CAV1', 'Gene', (130, 134))	('incorporation', 'Var', (84, 97))	('SS18-SSX', 'Gene', (75, 83))	('SS18-SSX', 'Gene', '6760', (75, 83))	('SOX8', 'Gene', '30812', (121, 125))	('CAV1', 'Gene', '857', (130, 134))
509076	29861296	We found that 528 genes (92.9%) were concordantly regulated in the same direction across the three cell lines upon SS18-SSX knockdown (Figures 2C and 2D).	('knockdown', 'Var', (124, 133))	('SS18-SSX', 'Gene', (115, 123))	('regulated', 'Reg', (50, 59))	('SS18-SSX', 'Gene', '6760', (115, 123))
509079	29861296	Comparing defined shCt-only and shSSX-only SS18 peaks (Figure 1D) with transcriptional changes, we found that significantly changed targets of SS18-SSX-containing BAF complexes (n = 394) are disproportionately downregulated, whereas the significantly changed targets of SS18 WT (n = 176) are disproportionately upregulated upon fusion knockdown (Figure 2G).	('SS18', 'Gene', '6760', (143, 147))	('SS18', 'Gene', '6760', (43, 47))	('SSX', 'Gene', (148, 151))	('SS18', 'Gene', (270, 274))	('upregulated', 'PosReg', (311, 322))	('SS18', 'Gene', (43, 47))	('SSX', 'Gene', '6757', (34, 37))	('knockdown', 'Var', (335, 344))	('SS18', 'Gene', (143, 147))	('SSX', 'Gene', (34, 37))	('downregulated', 'NegReg', (210, 223))	('SS18', 'Gene', '6760', (270, 274))	('SS18-SSX', 'Gene', (143, 151))	('SS18-SSX', 'Gene', '6760', (143, 151))	('SSX', 'Gene', '6757', (148, 151))
509085	29861296	We identified 978 genes that are targets of SS18-SSX in both Aska and SYO1; however, we found that only 87 of these genes are primary targets activated by the SS18-SSX fusion in both cell lines (Figures 2J, 2K, and S2K).	('SS18-SSX', 'Gene', (159, 167))	('SS18-SSX', 'Gene', '6760', (159, 167))	('fusion', 'Var', (168, 174))	('SS18-SSX', 'Gene', (44, 52))	('SYO1', 'Gene', '55027', (70, 74))	('SS18-SSX', 'Gene', '6760', (44, 52))	('SYO1', 'Gene', (70, 74))
509090	29861296	The SS mutational burden (median = 0.589 mutations/kb exome) is slightly higher than that of MRT (median = 0.067 mutation/kb exome), which has the lowest mutational burden of any cancer sequenced to date.	('mutations/kb', 'Var', (41, 53))	('cancer', 'Disease', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))
509096	29861296	These results demonstrate globally similar transcriptional profiles among SS18-SSX1 and SS18-SSX2 cases, and establish that SSX1/2 expression in SS tumors results exclusively from the fusion gene.	('SSX2', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('results', 'Reg', (155, 162))	('fusion gene', 'Var', (184, 195))	('SS18-SSX', 'Gene', (88, 96))	('SS18-SSX', 'Gene', (74, 82))	('SSX1', 'Gene', '6756', (79, 83))	('SS18-SSX', 'Gene', '6760', (74, 82))	('SS18-SSX', 'Gene', '6760', (88, 96))	('SSX1', 'Gene', '6756', (124, 128))	('SSX1', 'Gene', (79, 83))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('SSX2', 'Gene', '6757', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('SSX1', 'Gene', (124, 128))
509111	29861296	Given previous findings that BAF complexes target to SOX2 at which H3K27me3 levels are reduced in an SS cell line, we performed ChIP-seq for H3K27me3 as well as for the PRC2 subunit SUZ12 in Aska cells.	('SUZ12', 'Gene', '23512', (182, 187))	('H3K27me3 levels', 'MPA', (67, 82))	('reduced', 'NegReg', (87, 94))	('SUZ12', 'Gene', (182, 187))	('SOX2', 'Gene', '6657', (53, 57))	('SOX2', 'Gene', (53, 57))	('H3K27me3', 'Var', (141, 149))
509113	29861296	SS18-SSX knockdown results in retargeting of BAF complexes away from SUZ12 and H3K27me3 sites, suggesting that SS18-SSX is responsible for mediating this co-occupancy (Figures 4B and S5B).	('retargeting', 'NegReg', (30, 41))	('SS18-SSX', 'Gene', (111, 119))	('SS18-SSX', 'Gene', '6760', (111, 119))	('SS18-SSX', 'Gene', '6760', (0, 8))	('knockdown', 'Var', (9, 18))	('SUZ12', 'Gene', '23512', (69, 74))	('SUZ12', 'Gene', (69, 74))	('S5B', 'Gene', '5711', (183, 186))	('S5B', 'Gene', (183, 186))	('SS18-SSX', 'Gene', (0, 8))	('BAF complexes', 'Protein', (45, 58))
509125	29861296	Importantly, we found that suppression of SS18-SSX, and hence restoration of WT BAF complex composition and retargeting, resulted in a gain of repressed bivalent genes (dually marked by H3K4me3 and H3K27me3) (Figure 4E), owing to increases in H3K27me3, while H3K4me3 targets remain constant (Figure S5H).	('H3K4me3', 'Var', (186, 193))	('H3K27me3', 'Protein', (243, 251))	('repressed', 'MPA', (143, 152))	('H3K27me3', 'Var', (198, 206))	('H3K4me3', 'Chemical', 'MESH:C024755', (186, 193))	('H3K4me3', 'Chemical', 'MESH:C024755', (259, 266))	('SS18-SSX', 'Gene', '6760', (42, 50))	('bivalent genes', 'Gene', (153, 167))	('gain', 'PosReg', (135, 139))	('increases', 'PosReg', (230, 239))	('SS18-SSX', 'Gene', (42, 50))	('suppression', 'NegReg', (27, 38))
509126	29861296	We found substantial increases in bivalent (and hence repressed) genes upon fusion knockdown--from 21.5% (62/289) to 45.3% (131/289)--the greatest increase of any promoter category, among primary SS18-SSX targets, while secondary genes did not exhibit similar changes (Figure 4F).	('bivalent', 'Gene', (34, 42))	('increases', 'PosReg', (21, 30))	('knockdown--', 'Var', (83, 94))	('increase', 'PosReg', (147, 155))	('SS18-SSX', 'Gene', (196, 204))	('SS18-SSX', 'Gene', '6760', (196, 204))
509132	29861296	We have previously shown that SS18-SSX drives two concurrent changes in BAF complex composition: (1) the gain of 78aa of SSX to the SS18 subunit, and (2) destabilization of the BAF47 subunit, raising the possibility that these tumors are driven in a manner similar to MRT by loss of BAF47 (Figures 5A, S6A, and S6B).	('BAF47', 'Gene', (177, 182))	('SS18', 'Gene', '6760', (132, 136))	('SS18-SSX', 'Gene', (30, 38))	('gain', 'PosReg', (105, 109))	('SSX', 'Gene', '6757', (35, 38))	('78aa', 'MPA', (113, 117))	('loss', 'Var', (275, 279))	('SS18', 'Gene', '6760', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('S6A', 'Mutation', 'p.S6A', (302, 305))	('SSX', 'Gene', (35, 38))	('BAF47', 'Gene', (283, 288))	('BAF47', 'Gene', '6598', (177, 182))	('SSX', 'Gene', '6757', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('changes', 'Reg', (61, 68))	('tumors', 'Disease', (227, 233))	('destabilization', 'NegReg', (154, 169))	('S6B', 'Chemical', 'MESH:C012008', (311, 314))	('SSX', 'Gene', (121, 124))	('SS18', 'Gene', (132, 136))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('BAF47', 'Gene', '6598', (283, 288))	('SS18-SSX', 'Gene', '6760', (30, 38))	('SS18', 'Gene', (30, 34))
509137	29861296	This experimental system enables us to examine the effects SS18-SSX knockdown in the presence or absence of BAF47 restoration, and thereby decouple the role of each event in SS cell chromatin regulation, gene expression, and proliferation.	('BAF47', 'Gene', '6598', (108, 113))	('knockdown', 'Var', (68, 77))	('BAF47', 'Gene', (108, 113))	('SS18-SSX', 'Gene', (59, 67))	('SS18-SSX', 'Gene', '6760', (59, 67))
509139	29861296	We observed that SS18-SSX-mediated targeting to broad sites was abated upon knockdown of SS18-SSX in BAF47Delta cells in a manner similar to that in the WT cell setting (Figure 5C).	('knockdown', 'Var', (76, 85))	('BAF47Delta', 'Gene', '6598', (101, 111))	('BAF47Delta', 'Gene', (101, 111))	('SS18-SSX', 'Gene', (17, 25))	('SS18-SSX', 'Gene', '6760', (17, 25))	('abated', 'NegReg', (64, 70))	('SS18-SSX', 'Gene', (89, 97))	('SS18-SSX', 'Gene', '6760', (89, 97))
509140	29861296	In the WT context, SS18-SSX knockdown restored BAF complex targeting to distal sites to mediate accessibility and enhancer activation (Figures 5C, 5D, S6C, and S6D).	('enhancer activation', 'PosReg', (114, 133))	('SS18-SSX', 'Gene', (19, 27))	('SS18-SSX', 'Gene', '6760', (19, 27))	('accessibility', 'MPA', (96, 109))	('knockdown', 'Var', (28, 37))	('BAF', 'Protein', (47, 50))
509149	29861296	These results suggest that BAF47 plays a role in restoring WT gene regulation, likely by enabling active displacement and retargeting of oncogenic BAF complexes to normal sites upon SS18-SSX knockdown, as observed by ChIP-seq (Figure 5H).	('SS18-SSX', 'Gene', '6760', (182, 190))	('restoring', 'PosReg', (49, 58))	('BAF47', 'Gene', '6598', (27, 32))	('WT gene regulation', 'MPA', (59, 77))	('BAF47', 'Gene', (27, 32))	('knockdown', 'Var', (191, 200))	('SS18-SSX', 'Gene', (182, 190))
509154	29861296	SS18-SSX-mediated eviction of BAF47 results in enhancer decommissioning, but rescue of these enhancers upon SS18-SSX knockdown is dispensable for proliferative arrest, suggesting that the key mechanism driving SS is the oncogenic gene activation at bivalent genes by the highly unique genome-wide targeting of BAF complexes by the SSX 78 amino acids (Figure 6B).	('enhancer decommissioning', 'MPA', (47, 71))	('SSX', 'Gene', (331, 334))	('SS18-SSX', 'Gene', (108, 116))	('BAF47', 'Gene', (30, 35))	('SS18-SSX', 'Gene', '6760', (108, 116))	('SSX', 'Gene', '6757', (331, 334))	('SSX', 'Gene', '6757', (113, 116))	('SSX', 'Gene', '6757', (5, 8))	('eviction', 'Var', (18, 26))	('SSX', 'Gene', (113, 116))	('SSX', 'Gene', (5, 8))	('activation', 'PosReg', (235, 245))	('BAF47', 'Gene', '6598', (30, 35))	('SS18-SSX', 'Gene', (0, 8))	('SS18-SSX', 'Gene', '6760', (0, 8))
509161	29861296	Consequently, this suggests that altering H3K4 methylation levels may modulate SS18-SSX-mediated activation of bivalent genes and provides the motivation to explore inhibiting H3K4me3 placement by MLL2/COMPASS complexes to silence oncogenic gene expression in SS.	('SS18-SSX', 'Gene', '6760', (79, 87))	('modulate', 'Reg', (70, 78))	('MLL2', 'Gene', '9757', (197, 201))	('activation', 'PosReg', (97, 107))	('oncogenic gene', 'Gene', (231, 245))	('H3K4me3', 'Chemical', 'MESH:C024755', (176, 183))	('bivalent genes', 'Gene', (111, 125))	('MLL2', 'Gene', (197, 201))	('silence', 'NegReg', (223, 230))	('inhibiting', 'NegReg', (165, 175))	('H3K4', 'Protein', (42, 46))	('altering', 'Var', (33, 41))	('methylation', 'MPA', (47, 58))	('SS18-SSX', 'Gene', (79, 87))
509165	29861296	In addition, following SS18-SSX knockdown, we did not observe increases in terminal myogenic marker expression, but did find activation of some genes implicated in myogenesis.	('activation', 'PosReg', (125, 135))	('terminal myogenic marker expression', 'MPA', (75, 110))	('genes', 'MPA', (144, 149))	('knockdown', 'Var', (32, 41))	('SS18-SSX', 'Gene', (23, 31))	('SS18-SSX', 'Gene', '6760', (23, 31))
509237	29861296	Mammalian SWI/SNF (BAF) complexes are mutated in over 20% of human cancers, with both gain- and loss-of-function perturbations each implicated in malignancy.	('Mammalian', 'Species', '9606', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('loss-of-function', 'NegReg', (96, 112))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('gain-', 'PosReg', (86, 91))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('perturbations', 'Var', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('malignancy', 'Disease', (146, 156))	('human', 'Species', '9606', (61, 66))
509252	31281207	In the non-L-sarcoma patients, trabectedin resulted in 0.413 less life years and 0.266 less QALYs, at the increased cost of $4,698.	('trabectedin', 'Chemical', 'MESH:D000077606', (31, 42))	('LYs', 'Chemical', '-', (94, 97))	('life years', 'CPA', (66, 76))	('trabectedin', 'Var', (31, 42))	('QALYs', 'MPA', (92, 97))	('non-L-sarcoma', 'Disease', (7, 20))	('patients', 'Species', '9606', (21, 29))	('less', 'NegReg', (61, 65))	('non-L-sarcoma', 'Disease', 'MESH:D012509', (7, 20))	('less', 'NegReg', (87, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))
509333	31281207	The total QALY loss due to adverse events was 0.00153 for trabectedin and 0.00352 for ifosfamide, with costs of $1,119 and $1,841, respectively.	('QALY', 'MPA', (10, 14))	('ifosfamide', 'Chemical', 'MESH:D007069', (86, 96))	('loss', 'NegReg', (15, 19))	('0.00352', 'Var', (74, 81))	('trabectedin', 'Chemical', 'MESH:D000077606', (58, 69))
509341	31281207	For OS, high ECOG performance score at baseline showed an association with reduced survival in both univariate and multivariate tests, with a HR of 1.91 (95% CI, 1.06-3.45) and p value 0.032, in the multivariate analysis.	('high', 'Var', (8, 12))	('OS', 'Chemical', '-', (4, 6))	('reduced', 'NegReg', (75, 82))	('ECOG performance', 'Gene', (13, 29))	('survival', 'MPA', (83, 91))
509398	31281207	comparing trabectedin vs. dacarbazine in pretreated metastatic L-sarcoma patients, patients on trabectedin in the current study in a real-life setting had a higher median PFS (4.2 vs. 5.2 months, respectively), whereas OS was slightly lower (12.4 months vs. 11.8 months, respectively).	('OS', 'Chemical', '-', (219, 221))	('dacarbazine', 'Chemical', 'MESH:D003606', (26, 37))	('trabectedin', 'Chemical', 'MESH:D000077606', (10, 21))	('PFS', 'MPA', (171, 174))	('L-sarcoma', 'Disease', 'MESH:D012509', (63, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('L-sarcoma', 'Disease', (63, 72))	('higher', 'PosReg', (157, 163))	('trabectedin', 'Chemical', 'MESH:D000077606', (95, 106))	('patients', 'Species', '9606', (83, 91))	('trabectedin', 'Var', (95, 106))	('patients', 'Species', '9606', (73, 81))
509426	29142354	Her chest X-ray showed left lung opacification and lesions in the right lung and was suspected to have malignancy and referred for fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) scan.	('malignancy', 'Disease', 'MESH:D009369', (103, 113))	('lung opacification', 'Phenotype', 'HP:0031457', (28, 46))	('malignancy', 'Disease', (103, 113))	('left lung opacification', 'CPA', (23, 46))	('lesions', 'Var', (51, 58))	('FDG', 'Chemical', 'MESH:D019788', (200, 203))	('fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (131, 149))
509533	25687875	To identify patients with newly diagnosed extremity STS from the KNCI database, the following ICD-10 diagnostic codes were searched: "malignant neoplasm of the peripheral nerves and autonomic nervous system" (ICD-10 diagnostic code: C47.1 for upper extremity and C47.2 for lower extremity) or "malignant neoplasm of other connective and soft tissues" (C49.1 for upper extremity and C49.2 for lower extremity).	('lower extremity', 'Phenotype', 'HP:0006385', (273, 288))	('C47.2', 'CellLine', 'CVCL:L675', (263, 268))	('patients', 'Species', '9606', (12, 20))	('STS', 'Phenotype', 'HP:0030448', (52, 55))	('neoplasm', 'Phenotype', 'HP:0002664', (144, 152))	('C47.1', 'Var', (233, 238))	('neoplasm', 'Phenotype', 'HP:0002664', (304, 312))	('neoplasm', 'Disease', 'MESH:D009369', (144, 152))	('C47.2', 'Var', (263, 268))	('neoplasm', 'Disease', (304, 312))	('neoplasm of the peripheral nerves', 'Phenotype', 'HP:0100007', (144, 177))	('lower extremity', 'Phenotype', 'HP:0006385', (392, 407))	('neoplasm', 'Disease', 'MESH:D009369', (304, 312))	('C49.1', 'CellLine', 'CVCL:6519', (352, 357))	('C49.2', 'Var', (382, 387))	('neoplasm', 'Disease', (144, 152))
509535	25687875	To identify patients who were newly diagnosed and treated for extremity STS from the HIRA database, with the following ICD-10 diagnostic codes were searched: C47.1, C47.2, C49.1, and C49.2.	('C47.2', 'Var', (165, 170))	('C47.1', 'Var', (158, 163))	('patients', 'Species', '9606', (12, 20))	('STS', 'Phenotype', 'HP:0030448', (72, 75))	('C49.2', 'Var', (183, 188))	('C47.2', 'CellLine', 'CVCL:L675', (165, 170))	('C49.1', 'CellLine', 'CVCL:6519', (172, 177))	('C49.1', 'Var', (172, 177))
509546	25687875	The "procedure for STS" included STS-related surgery (removal of malignant soft tissue tumor [ICD-10 procedure code: N0232], limb-salvage procedure for malignant tumor removal [NA282 for thigh, scapula, and upper arm; NA283 for forearm and lower leg; and NA284 for hand and foot], and removal of a malignant neurogenic tumor [S4616]), a radiotherapy-related procedure (teletherapy [HD051-056], rotational irradiation [HD057-059], three-dimensional conformal therapy [HD061], body stereotactic radiosurgery [HD111, 112]), and/or a chemotherapy-related procedure (chemotherapy administration [KK151-156, 158, KK059]).	('malignant soft tissue tumor', 'Disease', (65, 92))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('neurogenic tumor', 'Disease', 'MESH:D009369', (308, 324))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('malignant tumor', 'Disease', 'MESH:D018198', (152, 167))	('NA284', 'Var', (255, 260))	('STS', 'Phenotype', 'HP:0030448', (33, 36))	('malignant tumor', 'Disease', (152, 167))	('STS', 'Phenotype', 'HP:0030448', (19, 22))	('neurogenic tumor', 'Disease', (308, 324))	('NA283', 'Var', (218, 223))	('malignant soft tissue', 'Phenotype', 'HP:0100242', (65, 86))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (75, 92))	('men', 'Species', '9606', (438, 441))	('malignant soft tissue tumor', 'Disease', 'MESH:D012983', (65, 92))	('malignant neurogenic tumor', 'Phenotype', 'HP:0100697', (298, 324))	('lower leg', 'Phenotype', 'HP:0006385', (240, 249))
509547	25687875	Additionally, cases with both a diagnostic code for STS and a procedure code for the removal of a benign soft tissue tumor (N0233, N0234, and S4615), and with a claim date that preceded the earliest claim date for STS diagnosis by < 6 months and at the same anatomical site, were regarded as involving an unplanned excision, and were included in the analysis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('STS', 'Phenotype', 'HP:0030448', (52, 55))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (105, 122))	('tumor', 'Disease', (117, 122))	('STS', 'Phenotype', 'HP:0030448', (214, 217))	('N0233', 'Var', (124, 129))	('S4615', 'Var', (142, 147))	('N0234', 'Var', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
509669	33204876	Body-mass-index and waist-to-hip ratio were positively associated with endometrial cancer in postmenopausal women and women of all ages, respectively, whereas parity was inversely related.	('women', 'Species', '9606', (108, 113))	('endometrial cancer', 'Phenotype', 'HP:0012114', (71, 89))	('women', 'Species', '9606', (118, 123))	('Body-mass-index', 'Var', (0, 15))	('age', 'Gene', '5973', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('endometrial cancer', 'Disease', (71, 89))	('associated with', 'Reg', (55, 70))	('cancer in postmenopausal women', 'Phenotype', 'HP:0008209', (83, 113))	('endometrial cancer', 'Disease', 'MESH:D016889', (71, 89))	('age', 'Gene', (131, 134))
509701	33204876	A higher parity on the other hand is a directly related risk factor to pelvic floor issues, but has been shown to have a protective influence against endometrial cancer.	('pelvic floor issues', 'Disease', (71, 90))	('endometrial cancer', 'Disease', 'MESH:D016889', (150, 168))	('parity', 'Var', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('endometrial cancer', 'Disease', (150, 168))	('endometrial cancer', 'Phenotype', 'HP:0012114', (150, 168))
509757	31817510	In good agreement with very limited cDC involvement in CD8+ T cell priming during EBV infection, mutant EBV viruses that lack EBV-encoded small non-coding RNAs (EBERs) as the main pathogen-associated molecular pattern (PAMP) that was described to activate cDCs, replicate to the same viral loads in HIS mice and expand CD8+ T cells to the same extent as wild-type EBV.	('EBV', 'Disease', 'MESH:D020031', (104, 107))	('activate', 'PosReg', (247, 255))	('CD8', 'Gene', (319, 322))	('expand', 'PosReg', (312, 318))	('CD8', 'Gene', '925', (319, 322))	('EBV', 'Disease', 'MESH:D020031', (82, 85))	('mutant', 'Var', (97, 103))	('mice', 'Species', '10090', (303, 307))	('EBV', 'Disease', 'MESH:D020031', (126, 129))	('EBV', 'Disease', (82, 85))	('cDCs', 'Gene', (256, 260))	('CD8', 'Gene', (55, 58))	('EBV', 'Disease', 'MESH:D020031', (364, 367))	('EBV', 'Disease', (126, 129))	('CD8', 'Gene', '925', (55, 58))	('EBV', 'Disease', (364, 367))	('EBV', 'Disease', (104, 107))
509767	31817510	Deficiencies in IFN-gamma production in response to IL-12 production (mutations in IL-12p40, IL-12 receptor beta1, IRF8, ISG15, and NEMO) and in IFN-gamma detection (mutations in IFN-gamma receptor 1 and 2, STAT1, IRF8, and CYBB) do not predispose for uncontrolled EBV pathology, but instead sensitize for mycobacterium associated pathologies.	('CYBB', 'Gene', (224, 228))	('IL-12p40', 'Gene', (83, 91))	('Deficiencies', 'Var', (0, 12))	('IRF8', 'Gene', (115, 119))	('IFN-gamma', 'Gene', '3458', (145, 154))	('IFN-gamma', 'Gene', (145, 154))	('response', 'MPA', (40, 48))	('mycobacterium associated pathologies', 'Disease', (306, 342))	('IFN-gamma', 'Gene', '3458', (16, 25))	('IFN-gamma', 'Gene', (16, 25))	('ISG15', 'Gene', (121, 126))	('EBV', 'Disease', 'MESH:D020031', (265, 268))	('sensitize', 'Reg', (292, 301))	('EBV', 'Disease', (265, 268))	('IFN-gamma', 'Gene', '3458', (179, 188))	('IFN-gamma', 'Gene', (179, 188))
509768	31817510	In contrast, IFN-gamma receptor 1 and STAT4 deficiencies lead to KSHV pathology.	('IFN-gamma', 'Gene', (13, 22))	('KSHV pathology', 'Disease', (65, 79))	('KSHV', 'Species', '37296', (65, 69))	('lead to', 'Reg', (57, 64))	('STAT4', 'Gene', '6775', (38, 43))	('STAT4', 'Gene', (38, 43))	('deficiencies', 'Var', (44, 56))	('IFN-gamma', 'Gene', '3458', (13, 22))
509772	31817510	These include mutations in IFN-alpha/beta receptor, STAT1, IRF7, and TYK2 and predispose for alpha-herpesvirus, e.g., herpes simplex virus (HSV) and associated encephalitis.	('IFN-alpha', 'Gene', '111654', (27, 36))	('encephalitis', 'Phenotype', 'HP:0002383', (160, 172))	('STAT1', 'Gene', (52, 57))	('herpesvirus', 'Species', '39059', (99, 110))	('TYK2', 'Gene', (69, 73))	('herpes simplex', 'Phenotype', 'HP:0012302', (118, 132))	('encephalitis', 'Disease', (160, 172))	('IRF7', 'Gene', (59, 63))	('herpes simplex virus', 'Disease', (118, 138))	('encephalitis', 'Disease', 'MESH:D004660', (160, 172))	('alpha-herpesvirus', 'Protein', (93, 110))	('predispose', 'Reg', (78, 88))	('IFN-alpha', 'Gene', (27, 36))	('mutations', 'Var', (14, 23))
509850	30066758	Early initiation of continuous antiretroviral therapy in HIV patients is known to decrease the risk of disease progression, especially with viral RNA suppression and subsequent increase in CD4 T-lymphocyte count., Treatment adherence should also be discussed at length with the patient, since lack of perfect adherence has been shown to be a risk factor (up to 20-fold) that favors dissemination of the disease and systemic manifestations.	('men', 'Species', '9606', (219, 222))	('patient', 'Species', '9606', (61, 68))	('CD4', 'Gene', (189, 192))	('dissemination of the disease', 'Disease', 'MESH:D009103', (382, 410))	('patients', 'Species', '9606', (61, 69))	('CD4', 'Gene', '920', (189, 192))	('dissemination of the disease', 'Disease', (382, 410))	('HIV', 'Species', '12721', (57, 60))	('patient', 'Species', '9606', (278, 285))	('lack', 'Var', (293, 297))	('favors', 'PosReg', (375, 381))
509920	20579347	It is well known that HIV-positive patients with CD4+ lymphocyte counts less than 200 cells/ml are severely immunocompromised and the HIV-positive patient with viral load greater than 10,000 copies/ml show active viremia.	('CD4', 'Gene', (49, 52))	('patient', 'Species', '9606', (147, 154))	('viremia', 'Disease', 'MESH:D014766', (213, 220))	('viremia', 'Phenotype', 'HP:0020071', (213, 220))	('CD4', 'Gene', '920', (49, 52))	('HIV', 'Species', '12721', (22, 25))	('patient', 'Species', '9606', (35, 42))	('lymphocyte counts less than 200', 'Phenotype', 'HP:0001888', (54, 85))	('CD4+ lymphocyte counts less than 200', 'Phenotype', 'HP:0005407', (49, 85))	('active viremia', 'Phenotype', 'HP:0032248', (206, 220))	('patients', 'Species', '9606', (35, 43))	('less', 'Var', (72, 76))	('HIV', 'Species', '12721', (134, 137))	('viremia', 'Disease', (213, 220))
509975	33080721	2B-H) were as follows: 34betaE12 (Epithelium+, 200x), Bcl-2(+, 200x), CD99 (+, 200x), CK-pan((Epithelium+, 200x), EMA(Epithelium+, 200x), Ki-67(+60%, 200x), and Vimentin(+, 200x).	('Vimentin', 'Gene', '7431', (161, 169))	('+60%', 'Var', (144, 148))	('+, 200x', 'Var', (76, 83))	('Epithelium+', 'Var', (118, 129))	('CK', 'Gene', '51727', (86, 88))	('CD99', 'Gene', '4267', (70, 74))	('Bcl-2', 'Gene', '596', (54, 59))	('Bcl-2', 'Gene', (54, 59))	('(Epithelium+', 'Var', (93, 105))	('Vimentin', 'Gene', (161, 169))	('CD99', 'Gene', (70, 74))
509998	33080721	Since >90% of SS has t (x; 18) (p11; q11) chromosome translocations, resulting in the fusion of genes SS18-SSX1 or SS18-SSX2, histopathological HE and immunohistochemical staining are very effective in the diagnosis of PRSS.	('SS18', 'Gene', '6760', (102, 106))	('SSX2', 'Gene', '6757', (120, 124))	('SS18', 'Gene', (115, 119))	('PRSS', 'Disease', (219, 223))	('SS18', 'Gene', (102, 106))	('fusion', 'Var', (86, 92))	('HE', 'Chemical', 'MESH:D006371', (144, 146))	('SSX2', 'Gene', (120, 124))	('SSX1', 'Gene', '6756', (107, 111))	('SS18', 'Gene', '6760', (115, 119))	('SSX1', 'Gene', (107, 111))
510121	30563222	EWSR1-FLI1 t(11;22)(q24;q12) and EWSR1-ERG t(21;22)(q22;q12) fusions accounts for 85% and 5-10% of the cases respectively.	('ERG', 'Gene', (39, 42))	('FLI1', 'Gene', (6, 10))	('FLI1', 'Gene', '2313', (6, 10))	('EWSR1', 'Gene', '2130', (0, 5))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (43, 60))	('t(11;22)(q24;q12', 'Var', (11, 27))	('EWSR1', 'Gene', (33, 38))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (11, 28))	('fusions', 'Var', (61, 68))	('ERG', 'Gene', '2078', (39, 42))	('EWSR1', 'Gene', (0, 5))	('EWSR1', 'Gene', '2130', (33, 38))
510152	30563222	In two cluster groups, the average expression activity is increasing from the non-SP over SP to the MSC samples, while in the remaining group the SP samples have a stronger activity window.	('non-SP', 'Var', (78, 84))	('expression activity', 'MPA', (35, 54))	('SP', 'Chemical', '-', (146, 148))	('SP', 'Chemical', '-', (90, 92))	('increasing', 'PosReg', (58, 68))	('SP', 'Chemical', '-', (82, 84))
510245	30563222	and with a stronger pathway focus and cancer relevance in Zhou et al., exposes, by comparing SET-1 candidates with factors mentioned in those two publications, that mainly G1/S phase alterations might be enhanced by the SP cells.	('SP', 'Chemical', '-', (220, 222))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('SET-1', 'Gene', '9739', (93, 98))	('SP cells', 'Var', (220, 228))	('enhanced', 'PosReg', (204, 212))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('G1/S phase alterations', 'CPA', (172, 194))	('cancer', 'Disease', (38, 44))	('SET-1', 'Gene', (93, 98))
510250	30563222	Several other regulatory levels like the already mentioned microRNA miR-130B or epigenetic alterations of the transcriptional control might influence cellular expression.	('miR-130B', 'Gene', (68, 76))	('epigenetic alterations', 'Var', (80, 102))	('influence', 'Reg', (140, 149))	('microRNA', 'Var', (59, 67))	('cellular expression', 'MPA', (150, 169))	('miR-130B', 'Gene', '406920', (68, 76))
510255	30563222	All these details might point towards the fact that the SP cells stabilize their presumed stemness character, amongst other mechanisms, by epigenetic regulatory circuits via HDAC9.	('SP', 'Chemical', '-', (56, 58))	('epigenetic regulatory circuits', 'Var', (139, 169))	('HDAC9', 'Gene', '9734', (174, 179))	('HDAC9', 'Gene', (174, 179))	('stabilize', 'PosReg', (65, 74))
510403	26380169	alpha-SMA alpha-smooth muscle actin BCS Breast-conserving surgery CNB Core needle biopsy MFH Malignant fibrous histiocytoma PIS Post-irradiation sarcoma RT Radiation therapy	('sarcoma', 'Disease', (145, 152))	('Malignant fibrous histiocytoma PIS', 'Disease', (93, 127))	('PIS', 'Chemical', '-', (124, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('histiocytoma', 'Phenotype', 'HP:0012315', (111, 123))	('MFH', 'Var', (89, 92))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('alpha-SMA', 'Chemical', '-', (0, 9))
510415	25482329	They are characterized genetically by amplification of chromosome 12q, with resultant increased expression of MDM2 and CDK4.	('increased', 'PosReg', (86, 95))	('CDK4', 'Gene', (119, 123))	('expression', 'MPA', (96, 106))	('CDK4', 'Gene', '1019', (119, 123))	('MDM2', 'Gene', '4193', (110, 114))	('MDM2', 'Gene', (110, 114))	('amplification', 'Var', (38, 51))
510527	25482329	MSKCC studied 55 patients with unresectable liposarcomas and found increased survival (26 versus 4 months) in patients receiving partial resection compared to biopsy alone.	('liposarcomas', 'Disease', 'MESH:D008080', (44, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('liposarcomas', 'Phenotype', 'HP:0012034', (44, 56))	('partial resection', 'Var', (129, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('liposarcomas', 'Disease', (44, 56))	('increased', 'PosReg', (67, 76))	('patients', 'Species', '9606', (17, 25))	('liposarcoma', 'Phenotype', 'HP:0012034', (44, 55))	('survival', 'MPA', (77, 85))	('patients', 'Species', '9606', (110, 118))
510528	25482329	The majority of benefit for partial resection was seen in patients with primary disease, and patients undergoing partial resection of local recurrence showed significantly decreased survival compared to after partial resection of primary disease (17 versus 46 months).	('patients', 'Species', '9606', (93, 101))	('decreased', 'NegReg', (172, 181))	('primary disease', 'Disease', (72, 87))	('partial', 'Var', (28, 35))	('patients', 'Species', '9606', (58, 66))	('survival', 'MPA', (182, 190))
510548	25482329	During this trial, use of brachytherapy to the upper abdomen was associated with grade 3 toxicity in nearly 40% of patients including two deaths and one life-threatening illness.	('patients', 'Species', '9606', (115, 123))	('deaths', 'Disease', 'MESH:D003643', (138, 144))	('deaths', 'Disease', (138, 144))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('toxicity', 'Disease', (89, 97))	('brachytherapy', 'Var', (26, 39))
510575	25482329	Targeted agents, especially inhibitors of CDK4 and MDM2 for well- and de-differentiated liposarcomas, have recently been developed and show promise in early clinical trials.	('CDK4', 'Gene', '1019', (42, 46))	('liposarcomas', 'Phenotype', 'HP:0012034', (88, 100))	('liposarcomas', 'Disease', 'MESH:D008080', (88, 100))	('liposarcomas', 'Disease', (88, 100))	('MDM2', 'Gene', '4193', (51, 55))	('MDM2', 'Gene', (51, 55))	('liposarcoma', 'Phenotype', 'HP:0012034', (88, 99))	('inhibitors', 'Var', (28, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('CDK4', 'Gene', (42, 46))
510592	25482329	There remains a risk of delayed recurrence (five years after resection) particularly for low grade tumors.	('low grade', 'Var', (89, 98))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
510609	31803974	 PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours Although adoptive T-cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited.	('PTPN2', 'Gene', (1, 6))	('tumour', 'Disease', 'MESH:D009369', (245, 251))	('promotes', 'PosReg', (39, 47))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', (245, 251))	('solid tumours', 'Disease', (96, 109))	('tumour', 'Disease', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('malignancies', 'Disease', 'MESH:D009369', (200, 212))	('Alt', 'Gene', (110, 113))	('malignancies', 'Disease', (200, 212))	('solid tumours', 'Disease', 'MESH:D009369', (239, 252))	('CAR', 'Gene', (73, 76))	('solid tumours', 'Disease', 'MESH:D009369', (96, 109))	('PTPN2', 'Gene', '19255', (1, 6))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('CAR', 'Gene', '12355', (73, 76))	('deletion', 'Var', (19, 27))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('Alt', 'Gene', '76282', (110, 113))	('solid tumours', 'Disease', (239, 252))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
510610	31803974	Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('deletion', 'Var', (27, 35))	('enhances', 'PosReg', (47, 55))	('efficacy', 'CPA', (90, 98))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('PTPN2', 'Gene', (21, 26))	('cancer', 'Disease', (56, 62))
510611	31803974	T-cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53.	('tumour', 'Disease', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('tumour', 'Disease', 'MESH:D009369', (43, 49))	('PTPN2', 'Gene', (16, 21))	('tumour', 'Disease', (43, 49))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('tumours', 'Disease', (43, 50))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('prevented', 'NegReg', (33, 42))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('mice', 'Species', '10090', (67, 71))	('deficiency', 'Var', (22, 32))
510613	31803974	Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR T-cell activation and homing to CXCL9/10-expressing tumours to eradicate HER-2+ mammary tumours in vivo.	('tumours', 'Disease', (289, 296))	('tumours', 'Phenotype', 'HP:0002664', (289, 296))	('increased', 'PosReg', (116, 125))	('homing', 'CPA', (259, 265))	('tumours', 'Disease', 'MESH:D009369', (289, 296))	('deletion', 'Var', (16, 24))	('tumours', 'Disease', (325, 332))	('tumour', 'Phenotype', 'HP:0002664', (289, 295))	('STAT-5', 'Gene', (191, 197))	('CAR T-cell activation', 'CPA', (233, 254))	('STAT-5', 'Gene', '20850', (191, 197))	('Src', 'Gene', (148, 151))	('activation', 'MPA', (130, 140))	('tumours', 'Phenotype', 'HP:0002664', (325, 332))	('tumours', 'Disease', 'MESH:D009369', (325, 332))	('LCK', 'Gene', '16818', (166, 169))	('enhancing', 'PosReg', (218, 227))	('tumour', 'Phenotype', 'HP:0002664', (325, 331))	('LCK', 'Gene', (166, 169))	('PTPN2', 'Gene', (10, 15))	('Src', 'Gene', '20779', (148, 151))
510620	31803974	PTPN2 also antagonises cytokine signalling required for T-cell function, homeostasis and differentiation by dephosphorylating and inactivating Janus-activated kinase (JAK)-1 and JAK-3, and their target substrates signal transducer and activator of transcription (STAT)-1, STAT-3 and STAT-5 in a cell context-dependent manner (ten Hoeve et al, 2002; Simoncic et al, 2002; Wiede et al, 2017a,b).	('dephosphorylating', 'Var', (108, 125))	('JAK-3', 'Gene', '16453', (178, 183))	('antagonises', 'NegReg', (11, 22))	('inactivating', 'NegReg', (130, 142))	('PTPN2', 'Gene', (0, 5))	('STAT-3', 'Gene', '20848', (272, 278))	('STAT-5', 'Gene', (283, 289))	('STAT-3', 'Gene', (272, 278))	('signal transducer', 'MPA', (213, 230))	('STAT-5', 'Gene', '20850', (283, 289))	('Janus-activated', 'Protein', (143, 158))	('JAK-3', 'Gene', (178, 183))
510621	31803974	By dephosphorylating LCK, PTPN2 sets the threshold for productive TCR signalling and prevents overt responses to self-antigen in the context of T-cell homeostasis and antigen cross-presentation to establish peripheral T-cell tolerance (Wiede et al, 2014a,b).	('overt responses to self-antigen', 'MPA', (94, 125))	('establish', 'Reg', (197, 206))	('LCK', 'Gene', (21, 24))	('LCK', 'Gene', '16818', (21, 24))	('PTPN2', 'Gene', (26, 31))	('prevents', 'NegReg', (85, 93))	('peripheral T-cell tolerance', 'CPA', (207, 234))	('dephosphorylating', 'Var', (3, 20))	('TCR signalling', 'MPA', (66, 80))
510623	31803974	In humans, PTPN2 deficiency is accompanied by the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease (Consortium, 2007, Long et al, 2011).	("Crohn's disease", 'Phenotype', 'HP:0100280', (107, 122))	('diabetes', 'Disease', (72, 80))	("Crohn's disease", 'Disease', (107, 122))	('deficiency', 'Var', (17, 27))	('arthritis', 'Phenotype', 'HP:0001369', (93, 102))	('diabetes', 'Disease', 'MESH:D003920', (72, 80))	("Crohn's disease", 'Disease', 'MESH:D003424', (107, 122))	('humans', 'Species', '9606', (3, 9))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (82, 102))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (65, 80))	('PTPN2', 'Gene', (11, 16))	('rheumatoid arthritis', 'Disease', (82, 102))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (82, 102))	('accompanied', 'Reg', (31, 42))
510625	31803974	Whole-body PD-1 deletion results in spontaneous lupus-like autoimmunity in C57BL/6 mice (Nishimura et al, 1999) and accelerated type 1 diabetes onset in NOD mice (Wang et al, 2005), whereas CTLA4 deletion in C57BL/6 mice results in marked lymphoproliferation, autoreactivity and early lethality (Tivol et al, 1995; Waterhouse et al, 1995).	('diabetes onset', 'Disease', 'MESH:D003922', (135, 149))	('autoimmunity', 'Disease', 'MESH:D001327', (59, 71))	('CTLA4', 'Gene', '12477', (190, 195))	('mice', 'Species', '10090', (157, 161))	('mice', 'Species', '10090', (216, 220))	('autoreactivity', 'CPA', (260, 274))	('deletion', 'Var', (16, 24))	('early lethality', 'CPA', (279, 294))	('deletion', 'Var', (196, 204))	('accelerated', 'PosReg', (116, 127))	('mice', 'Species', '10090', (83, 87))	('PD-1', 'Gene', (11, 15))	('diabetes onset', 'Disease', (135, 149))	('CTLA4', 'Gene', (190, 195))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (128, 143))	('autoimmunity', 'Phenotype', 'HP:0002960', (59, 71))	('autoimmunity', 'Disease', (59, 71))	('lymphoproliferation', 'CPA', (239, 258))
510626	31803974	Although PD-1 and/or CTLA4 blockade can be accompanied by the development of immune-related toxicities, antibodies targeting these receptors have nonetheless shown marked therapeutic efficacy in various tumours, including melanomas, non-small-cell lung carcinomas, renal cancers and Hodgkin lymphoma (Pardoll, 2012; Ribas & Wolchok, 2018).	('tumours', 'Disease', (203, 210))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('Alt', 'Gene', (0, 3))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('tumours', 'Phenotype', 'HP:0002664', (203, 210))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('tumours', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('non-small-cell lung carcinomas', 'Disease', 'MESH:D002289', (233, 263))	('renal cancers', 'Disease', (265, 278))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('Hodgkin lymphoma', 'Disease', (283, 299))	('antibodies', 'Var', (104, 114))	('PD-1', 'Gene', (9, 13))	('non-small-cell lung carcinomas', 'Disease', (233, 263))	('CTLA4', 'Gene', (21, 26))	('melanomas', 'Disease', 'MESH:D008545', (222, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (253, 263))	('toxicities', 'Disease', 'MESH:D064420', (92, 102))	('melanomas', 'Disease', (222, 231))	('Alt', 'Gene', '76282', (0, 3))	('renal cancers', 'Disease', 'MESH:D007680', (265, 278))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (283, 299))	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (233, 263))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (283, 299))	('lymphoma', 'Phenotype', 'HP:0002665', (291, 299))	('toxicities', 'Disease', (92, 102))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (237, 263))	('CTLA4', 'Gene', '12477', (21, 26))
510628	31803974	First we determined the impact of deleting PTPN2 in T cells on tumour formation in mice heterozygous for p53, the most commonly mutated tumour suppressor in the human genome (Hollstein et al, 1991).	('human', 'Species', '9606', (161, 166))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('deleting', 'Var', (34, 42))	('tumour', 'Disease', (136, 142))	('PTPN2', 'Gene', (43, 48))	('mice', 'Species', '10090', (83, 87))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour', 'Disease', (63, 69))
510629	31803974	In humans, inheritance of one mutant allele of p53 results in a broad-based cancer predisposition syndrome known as Li-Fraumeni syndrome (Malkin et al, 1990).	('Li-Fraumeni syndrome', 'Disease', (116, 136))	('inheritance', 'Var', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('humans', 'Species', '9606', (3, 9))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (116, 136))	('cancer', 'Disease', (76, 82))	('p53', 'Gene', (47, 50))	('mutant', 'Var', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('results in', 'Reg', (51, 61))
510630	31803974	In mice, p53 heterozygosity results in lymphomas and sarcomas, as well as lung adenocarcinomas and hepatomas in 44% of mice by 17 months of age with the majority of tumours exhibiting p53 loss of heterozygosity (LOH) (Jacks, Jacks et al, 1994).	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('lung adenocarcinomas', 'Disease', (74, 94))	('heterozygosity', 'Var', (13, 27))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (74, 94))	('p53', 'Gene', (184, 187))	('p53', 'Gene', (9, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('carcinomas and hepatomas', 'Disease', 'MESH:D006528', (84, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('loss of', 'NegReg', (188, 195))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('mice', 'Species', '10090', (3, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('tumours', 'Disease', (165, 172))	('lymphomas and sarcomas', 'Disease', 'MESH:D012509', (39, 61))	('mice', 'Species', '10090', (119, 123))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('results in', 'Reg', (28, 38))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (74, 94))	('lymphomas', 'Phenotype', 'HP:0002665', (39, 48))
510632	31803974	Upon necropsy 15/28 (54%), Ptpn2 fl/fl;p53 +/- mice developed various tumours including thymomas, lymphomas, sarcomas, carcinomas and hepatomas (Fig 1A; Appendix Fig S1; Appendix Table EV1) as reported previously for p53 heterozygous mice (Jacks et al, 1994).	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('sarcomas', 'Disease', (109, 117))	('Ptpn2 fl/fl', 'Var', (27, 38))	('mice', 'Species', '10090', (234, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('lymphomas', 'Disease', 'MESH:D008223', (98, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('tumours', 'Disease', (70, 77))	('lymphomas', 'Phenotype', 'HP:0002665', (98, 107))	('developed', 'PosReg', (52, 61))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('thymomas', 'Disease', 'MESH:D013945', (88, 96))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('lymphomas', 'Disease', (98, 107))	('thymomas', 'Disease', (88, 96))	('carcinomas and hepatomas', 'Disease', 'MESH:D006528', (119, 143))	('mice', 'Species', '10090', (47, 51))
510633	31803974	In addition, 6/28 mice exhibited splenomegaly accompanied by the accumulation of CD19+IgMhiCD5hiB220int B1 cells consistent with the development of B-cell leukaemias (Fig 1B), whereas CD3-negative CD4+CD8+ double-positive cells reminiscent of T-cell leukaemic blasts (FSC-Ahi) were evident in the thymi or peripheral lymphoid organs of 5/28 mice (Fig 1A and B; Appendix Table EV1).	('CD3', 'Gene', (184, 187))	('CD3', 'Gene', '12501', (184, 187))	('B-cell leukaemias', 'Disease', (148, 165))	('accumulation', 'PosReg', (65, 77))	('splenomegaly', 'Disease', (33, 45))	('splenomegaly', 'Phenotype', 'HP:0001744', (33, 45))	('mice', 'Species', '10090', (18, 22))	('CD4', 'Gene', (197, 200))	('T-cell leukaemic blasts', 'Disease', 'MESH:D001753', (243, 266))	('mice', 'Species', '10090', (341, 345))	('T-cell leukaemic blasts', 'Disease', (243, 266))	('CD8', 'Gene', (201, 204))	('CD19+IgMhiCD5hiB220int B1', 'Var', (81, 106))	('splenomegaly', 'Disease', 'MESH:D013163', (33, 45))	('CD8', 'Gene', '925', (201, 204))	('CD4', 'Gene', '12504', (197, 200))	('B-cell leukaemias', 'Disease', 'MESH:D015448', (148, 165))
510637	31803974	Accordingly, we determined whether PTPN2 deficiency might exacerbate inflammation in p53 +/- mice.	('exacerbate', 'PosReg', (58, 68))	('inflammation', 'Disease', (69, 81))	('deficiency', 'Var', (41, 51))	('mice', 'Species', '10090', (93, 97))	('PTPN2', 'Gene', (35, 40))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))
510638	31803974	We found that inflammation, as assessed by measuring the pro-inflammatory cytokines IL-6, TNF and IFNgamma in serum, was elevated in Lck-Cre;Ptpn2 fl/fl;p53 +/- mice (Appendix Fig S2A), as seen in aged Lck-Cre;Ptpn2 fl/fl mice (Appendix Fig S2B), but this did not exceed that occurring in Ptpn2 fl/fl;p53 +/- littermate controls.	('inflammation', 'Disease', (14, 26))	('mice', 'Species', '10090', (161, 165))	('mice', 'Species', '10090', (222, 226))	('IL-6', 'Gene', (84, 88))	('IL-6', 'Gene', '16193', (84, 88))	('TNF', 'MPA', (90, 93))	('IFNgamma', 'MPA', (98, 106))	('inflammation', 'Disease', 'MESH:D007249', (14, 26))	('Lck-Cre;Ptpn2 fl/fl;p53 +/-', 'Var', (133, 160))	('elevated', 'PosReg', (121, 129))
510640	31803974	However, lymphocytic infiltrates and fibrosis were also evident in the livers of tumour-bearing Ptpn2 fl/fl;p53 +/- mice (Appendix Fig S2C).	('mice', 'Species', '10090', (116, 120))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('Ptpn2', 'Gene', (96, 101))	('tumour', 'Disease', (81, 87))	('lymphocytic infiltrates', 'CPA', (9, 32))	('fl/fl;p53 +/-', 'Var', (102, 115))	('fibrosis', 'Disease', 'MESH:D005355', (37, 45))	('fibrosis', 'Disease', (37, 45))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
510641	31803974	Taken together, these results indicate that PTPN2 deficiency in T cells can prevent the formation of tumours induced by p53 LOH without exacerbating inflammation.	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('inflammation', 'Disease', 'MESH:D007249', (149, 161))	('tumours', 'Disease', (101, 108))	('deficiency in T', 'Disease', (50, 65))	('PTPN2', 'Gene', (44, 49))	('LOH', 'Var', (124, 127))	('inflammation', 'Disease', (149, 161))	('deficiency in T cells', 'Phenotype', 'HP:0005403', (50, 71))	('deficiency in T', 'Disease', 'MESH:D001260', (50, 65))	('p53', 'Gene', (120, 123))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('prevent', 'NegReg', (76, 83))
510642	31803974	At least one mechanism by which PTPN2 deficiency might prevent tumour formation in p53 +/- mice might be through the promotion of T-cell-mediated tumour immunosurveillance.	('mice', 'Species', '10090', (91, 95))	('promotion', 'PosReg', (117, 126))	('tumour', 'Disease', (146, 152))	('PTPN2', 'Gene', (32, 37))	('tumour immunosurveillance', 'Disease', 'MESH:D009369', (146, 171))	('deficiency', 'Var', (38, 48))	('tumour immunosurveillance', 'Disease', (146, 171))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('prevent', 'NegReg', (55, 62))	('tumour', 'Disease', (63, 69))
510644	31803974	Whereas AT3-OVA cells grew readily in Ptpn2 fl/fl mice, tumour growth was markedly repressed in Lck-Cre;Ptpn2 fl/fl mice so that tumour progression was prevented in 5/13 mice and eradicated in 2/8 of the remaining mice after tumours had developed.	('tumours', 'Disease', (225, 232))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('mice', 'Species', '10090', (116, 120))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('fl/fl', 'Var', (110, 115))	('mice', 'Species', '10090', (50, 54))	('mice', 'Species', '10090', (170, 174))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', (225, 231))	('Ptpn2 fl/fl', 'Var', (104, 115))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('OVA', 'Gene', '282665', (12, 15))	('tumour', 'Disease', (56, 62))	('prevented', 'NegReg', (152, 161))	('OVA', 'Gene', (12, 15))	('mice', 'Species', '10090', (214, 218))
510648	31803974	To directly assess the influence of PTPN2 deficiency on T-cell-mediated immunosurveillance, we next isolated tumour-infiltrating CD8+ T cells from Ptpn2 fl/fl versus Lck-Cre;Ptpn2 fl/fl mice and assessed their activation by measuring IFNgamma production ex vivo upon re-challenge with tumour cells isolated from AT3-OVA tumours that had developed in Ptpn2 fl/fl mice (Fig 1F).	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('IFNgamma production', 'MPA', (234, 253))	('tumour', 'Disease', (109, 115))	('mice', 'Species', '10090', (362, 366))	('tumours', 'Phenotype', 'HP:0002664', (320, 327))	('CD8', 'Gene', (129, 132))	('tumour', 'Phenotype', 'HP:0002664', (320, 326))	('tumour', 'Disease', 'MESH:D009369', (320, 326))	('mice', 'Species', '10090', (186, 190))	('tumour', 'Disease', (320, 326))	('AT3-OVA tumours', 'Disease', 'MESH:D009369', (312, 327))	('OVA tumour', 'Phenotype', 'HP:0100615', (316, 326))	('deficiency', 'Var', (42, 52))	('AT3-OVA tumours', 'Disease', (312, 327))	('Ptpn2 fl/fl', 'Var', (350, 361))	('CD8', 'Gene', '925', (129, 132))	('PTPN2', 'Gene', (36, 41))	('tumour', 'Phenotype', 'HP:0002664', (285, 291))	('tumour', 'Disease', 'MESH:D009369', (285, 291))	('tumour', 'Disease', (285, 291))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
510649	31803974	Ptpn2 fl/fl tumour-infiltrating CD8+ T cells remained largely unresponsive when re-challenged (Fig 1F), consistent with tolerisation.	('CD8', 'Gene', '925', (32, 35))	('tumour', 'Disease', (12, 18))	('unresponsive', 'MPA', (62, 74))	('Ptpn2', 'Gene', (0, 5))	('CD8', 'Gene', (32, 35))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('fl/fl', 'Var', (6, 11))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
510651	31803974	To explore the cellular mechanisms by which PTPN2 deficiency might enhance immunosurveillance, we determined whether PTPN2 deletion might promote the tumour-specific activity of adoptively transferred CD8+ T cells expressing the OT-1 TCR specific for the ovalbumin (OVA) peptide SIINFEKL.	('OVA', 'Gene', (266, 269))	('immunosurveillance', 'CPA', (75, 93))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Disease', (150, 156))	('deletion', 'Var', (123, 131))	('PTPN2', 'Gene', (44, 49))	('enhance', 'PosReg', (67, 74))	('promote', 'PosReg', (138, 145))	('CD8', 'Gene', (201, 204))	('PTPN2', 'Gene', (117, 122))	('CD8', 'Gene', '925', (201, 204))	('OVA', 'Gene', '282665', (266, 269))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('deficiency', 'Var', (50, 60))
510654	31803974	Our previous studies have shown that PTPN2 deficiency enhances TCR-instigated responses and negates the need for CD4+ T-cell help in the context of antigen cross-presentation (Wiede et al, 2014b).	('CD4', 'Gene', '12504', (113, 116))	('TCR-instigated responses', 'MPA', (63, 87))	('enhances', 'PosReg', (54, 62))	('PTPN2', 'Gene', (37, 42))	('CD4', 'Gene', (113, 116))	('negates', 'NegReg', (92, 99))	('deficiency', 'Var', (43, 53))
510656	31803974	To this end, naive OT-1;Ptpn2 fl/fl or OT-1;Lck-Cre;Ptpn2 fl/fl CD8+ T cells were adoptively transferred into immunocompetent and non-irradiated congenic C57BL/6 hosts bearing syngeneic tumours arising from AT-3-OVA cells inoculated into the mammary fat pad (Fig 2A).	('fl/fl', 'Var', (58, 63))	('CD8', 'Gene', (64, 67))	('OVA', 'Gene', (212, 215))	('OVA', 'Gene', '282665', (212, 215))	('syngeneic tumours', 'Disease', (176, 193))	('CD8', 'Gene', '925', (64, 67))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('syngeneic tumours', 'Disease', 'MESH:D009369', (176, 193))
510664	31803974	Taken together, these results are consistent with PTPN2 deficiency increasing the functional activity and attenuating the tolerisation of naive CD8+ T cells to suppress tumour growth.	('tolerisation', 'CPA', (122, 134))	('functional activity', 'MPA', (82, 101))	('tumour', 'Disease', (169, 175))	('suppress', 'NegReg', (160, 168))	('PTPN2', 'Gene', (50, 55))	('CD8', 'Gene', (144, 147))	('deficiency', 'Var', (56, 66))	('attenuating', 'NegReg', (106, 117))	('CD8', 'Gene', '925', (144, 147))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('increasing', 'PosReg', (67, 77))
510665	31803974	Next, we determined whether PTPN2 deficiency might promote T-cell-mediated immunosurveillance and anti-tumour activity in a different tumour setting (Fig 2F-I).	('deficiency', 'Var', (34, 44))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', (134, 140))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('promote', 'PosReg', (51, 58))	('T-cell-mediated immunosurveillance', 'CPA', (59, 93))	('tumour', 'Disease', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('PTPN2', 'Gene', (28, 33))
510670	31803974	These findings are consistent with PTPN2 deficiency promoting the differentiation of circulating naive OT-1 T cells into TRMs to prevent tumour formation.	('promoting', 'PosReg', (52, 61))	('differentiation', 'CPA', (66, 81))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('tumour', 'Disease', (137, 143))	('deficiency', 'Var', (41, 51))	('PTPN2', 'Gene', (35, 40))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
510676	31803974	Given our findings on PTPN2 in T-cell-mediated immunosurveillance and anti-tumour immunity, we determined whether targeting PTPN2 might enhance the function of CAR T cells in solid tumours.	('PTPN2', 'Gene', (124, 129))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('targeting', 'Var', (114, 123))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('solid tumours', 'Disease', 'MESH:D009369', (175, 188))	('tumour', 'Disease', (75, 81))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('tumours', 'Phenotype', 'HP:0002664', (181, 188))	('function', 'MPA', (148, 156))	('tumour', 'Disease', (181, 187))	('solid tumours', 'Disease', (175, 188))	('enhance', 'PosReg', (136, 143))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
510679	31803974	Consistent with PTPN2's role in setting thresholds for TCR-instigated responses (Wiede et al, 2011, 2014a,b), we found that PTPN2 deficiency resulted in tenfold lower concentrations of TCR crosslinking antibodies (alpha-CD3epsilon) being required for the maximal generation of CD8+ HER-2 CAR T cells in vitro, with the resulting CAR T cells being predominated by the effector/memory (CD44hiCD62Llo) subset (Fig EV1A).	('PTPN2', 'Gene', (124, 129))	('lower', 'NegReg', (161, 166))	('deficiency', 'Var', (130, 140))	('CD8', 'Gene', (277, 280))	('CD8', 'Gene', '925', (277, 280))	('concentrations', 'MPA', (167, 181))	('CD62L', 'Gene', (390, 395))	('CD62L', 'Gene', '20343', (390, 395))
510684	31803974	Taken together, these results are consistent with PTPN2 deficiency enhancing not only the generation, but also the antigen-specific activation and cytotoxicity of CAR T cells in vitro.	('enhancing', 'PosReg', (67, 76))	('antigen-specific activation', 'MPA', (115, 142))	('generation', 'CPA', (90, 100))	('PTPN2', 'Gene', (50, 55))	('cytotoxicity of CAR T', 'Disease', 'MESH:D056733', (147, 168))	('deficiency', 'Var', (56, 66))	('cytotoxicity of CAR T', 'Disease', (147, 168))
510685	31803974	PTPN2 dephosphorylates and inactivates the SFK LCK to tune TCR signalling so that T cells can differentially respond to self versus non-self (Wiede et al, 2011, 2014a,b, 2017a).	('TCR signalling', 'MPA', (59, 73))	('respond', 'Reg', (109, 116))	('LCK', 'Gene', (47, 50))	('SFK', 'Gene', (43, 46))	('inactivates', 'Var', (27, 38))	('LCK', 'Gene', '16818', (47, 50))	('PTPN2', 'Gene', (0, 5))
510687	31803974	Accordingly, we assessed the influence of PTPN2 deficiency on the activation of LCK in CAR T cells by monitoring for the phosphorylation of Y394 (using antibodies specific for Y418-phosphorylated SFKs).	('Y394', 'Var', (140, 144))	('LCK', 'Gene', '16818', (80, 83))	('phosphorylation', 'MPA', (121, 136))	('deficiency', 'Var', (48, 58))	('LCK', 'Gene', (80, 83))	('PTPN2', 'Gene', (42, 47))
510688	31803974	PTPN2 deficiency significantly increased SFK Y418 phosphorylation in CD8+ HER-2 CAR T cells (Figs EV2A and 3A).	('phosphorylation', 'MPA', (50, 65))	('increased', 'PosReg', (31, 40))	('increased SFK', 'Phenotype', 'HP:0003236', (31, 44))	('Y418', 'Var', (45, 49))	('deficiency', 'Var', (6, 16))	('SFK', 'Gene', (41, 44))	('PTPN2', 'Gene', (0, 5))	('CD8', 'Gene', (69, 72))	('CD8', 'Gene', '925', (69, 72))
510689	31803974	We have shown previously that the enhanced TCR-induced T-cell activation resulting from PTPN2 deficiency is accompanied by the increased expression of the interleukin (IL)-2 receptor chains CD25 (IL-2 receptor alpha chain) and CD122 (IL-2/15 receptor beta chain) and IL-2 induced STAT-5 signalling (Wiede et al, 2011, 2014b).	('CD25', 'Gene', '16184', (190, 194))	('TCR-induced T-cell activation', 'CPA', (43, 72))	('CD25', 'Gene', (190, 194))	('enhanced', 'PosReg', (34, 42))	('IL-2/15 receptor beta', 'Gene', (234, 255))	('PTPN2', 'Gene', (88, 93))	('IL-2', 'MPA', (267, 271))	('expression', 'MPA', (137, 147))	('CD122', 'Gene', '16185', (227, 232))	('CD122', 'Gene', (227, 232))	('IL-2/15 receptor beta', 'Gene', '16185', (234, 255))	('deficiency', 'Var', (94, 104))	('STAT-5', 'Gene', (280, 286))	('increased', 'PosReg', (127, 136))	('STAT-5', 'Gene', '20850', (280, 286))
510695	31803974	The persistent increased STAT-5 signalling despite correcting IL-2/15 receptor levels is consistent with previous studies showing that STAT-5 can also serve as direct a bona fide substrate of PTPN2 and that PTPN2 deficiency promotes cytokine-induced STAT-5 signalling in thymocytes/T cells (Simoncic et al, 2002; Tiganis & Bennett, 2007; Wiede et al, 2011, 2014a, 2017a; Gurzov et al, 2014).	('STAT-5', 'Gene', '20850', (250, 256))	('PTPN2', 'Gene', (207, 212))	('deficiency', 'Var', (213, 223))	('STAT-5', 'Gene', (25, 31))	('promotes', 'PosReg', (224, 232))	('STAT-5', 'Gene', '20850', (25, 31))	('increased', 'PosReg', (15, 24))	('STAT-5', 'Gene', (135, 141))	('STAT-5', 'Gene', '20850', (135, 141))	('STAT-5', 'Gene', (250, 256))
510696	31803974	Irrespective, these results are consistent with PTPN2 deficiency enhancing the antigen-specific activation and function of CAR T cells through the promotion of LCK signalling.	('deficiency', 'Var', (54, 64))	('promotion', 'PosReg', (147, 156))	('enhancing', 'PosReg', (65, 74))	('function', 'MPA', (111, 119))	('antigen-specific activation', 'MPA', (79, 106))	('PTPN2', 'Gene', (48, 53))	('LCK', 'Gene', (160, 163))	('LCK', 'Gene', '16818', (160, 163))
510707	31803974	Taken together, these results demonstrate that PTPN2 deficiency promotes the LCK-dependent activation of CAR T cells and overcomes the immunosuppressive tumour microenvironment to eradicate solid tumours in vivo.	('solid tumours', 'Disease', 'MESH:D009369', (190, 203))	('promotes', 'PosReg', (64, 72))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('PTPN2', 'Gene', (47, 52))	('tumours', 'Phenotype', 'HP:0002664', (196, 203))	('solid tumours', 'Disease', (190, 203))	('deficiency', 'Var', (53, 63))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('immunosuppressive tumour', 'Disease', 'MESH:D009369', (135, 159))	('LCK', 'Gene', '16818', (77, 80))	('immunosuppressive tumour', 'Disease', (135, 159))	('LCK', 'Gene', (77, 80))	('activation', 'MPA', (91, 101))
510710	31803974	These results are consistent with PTPN2-deficient HER-2 CAR T cells completely eliminating HER-2-expressing tumours and eliciting a selective pressure so that any re-emerging tumours downregulate HER-2.	('eliminating', 'NegReg', (79, 90))	('tumours', 'Disease', (108, 115))	('HER-2-expressing', 'Protein', (91, 107))	('PTPN2-deficient', 'Var', (34, 49))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Disease', 'MESH:D009369', (175, 182))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('HER-2', 'Protein', (196, 201))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('downregulate', 'NegReg', (183, 195))	('tumours', 'Disease', (175, 182))
510717	31803974	By contrast, the growth of HER-2-negative mammary E0771 tumours was not affected.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('E0771', 'Var', (50, 55))
510718	31803974	These results are consistent with PTPN2 deficiency in HER-2 CAR T cells promoting CAR T-cell memory and recall to prevent the re-emergence of HER-2+ tumours, including those that may arise at distant metastatic sites.	('deficiency', 'Var', (40, 50))	('promoting', 'PosReg', (72, 81))	('tumours', 'Disease', (149, 156))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('PTPN2', 'Gene', (34, 39))	('prevent', 'NegReg', (114, 121))	('CAR T-cell memory', 'CPA', (82, 99))	('recall', 'CPA', (104, 110))	('tumours', 'Disease', 'MESH:D009369', (149, 156))
510720	31803974	In part, the increased CAR T-cell abundance may reflect the expansion of CAR T cells after they engage tumour antigen, as PTPN2 deficiency increased the antigen-specific proliferation of HER-2 CAR T cells in vitro (Figs 6B and EV3A).	('HER-2', 'Protein', (187, 192))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('increased', 'PosReg', (139, 148))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('PTPN2', 'Gene', (122, 127))	('deficiency', 'Var', (128, 138))	('tumour', 'Disease', (103, 109))	('antigen-specific proliferation', 'CPA', (153, 183))
510725	31803974	The ligands for CXCR3 are increased in many tumours and associated with the intralesional accumulation of TILs and improved outcome (Slaney et al, 2014; Nagarsheth et al, 2017) and Cxcl9 and Cxcl10 (Cxcl11 is not expressed in C57BL/6 mice; Sierro et al, 2007) were elevated in the HER-2-E0771 tumours analysed at 10 days after implantation (Fig 6E).	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('elevated', 'PosReg', (265, 273))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('outcome', 'MPA', (124, 131))	('mice', 'Species', '10090', (234, 238))	('Cxcl10', 'Gene', (191, 197))	('Cxcl9', 'Gene', '17329', (181, 186))	('Cxcl10', 'Gene', '15945', (191, 197))	('ligands', 'MPA', (4, 11))	('Cxcl11', 'Gene', (199, 205))	('tumours', 'Disease', (293, 300))	('Cxcl9', 'Gene', (181, 186))	('Cxcl11', 'Gene', '56066', (199, 205))	('increased', 'PosReg', (26, 35))	('tumours', 'Phenotype', 'HP:0002664', (293, 300))	('tumours', 'Disease', 'MESH:D009369', (293, 300))	('CXCR3', 'Gene', (16, 21))	('HER-2-E0771', 'Var', (281, 292))	('CXCR3', 'Gene', '12766', (16, 21))	('tumours', 'Disease', (44, 51))	('improved', 'PosReg', (115, 123))	('tumour', 'Phenotype', 'HP:0002664', (293, 299))
510726	31803974	Moreover, consistent with the potential for increased homing, we found that PTPN2-deficient CXCR3hi CAR T cells accumulated in HER-2-E0771 tumours within 3 days of adoptive transfer (Fig 6F), prior to any effects on tumour burden (Fig 4A).	('CXCR3', 'Gene', (92, 97))	('PTPN2-deficient', 'Gene', (76, 91))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumour burden', 'Disease', 'MESH:D009369', (216, 229))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('CXCR3', 'Gene', '12766', (92, 97))	('HER-2-E0771', 'Var', (127, 138))	('tumours', 'Disease', (139, 146))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('accumulated', 'PosReg', (112, 123))	('tumour burden', 'Disease', (216, 229))
510732	31803974	Since IL-2-induced STAT-5 signalling was only partially corrected in Lck-Cre;Ptpn2 fl/fl;Lck +/- CAR T cells (Fig EV2F), we also crossed the Lck-Cre;Ptpn2 fl/fl mice onto the Stat5 fl/+ background so that we could independently correct the increased STAT-5 signalling (Fig 6G and H).	('STAT-5', 'Gene', '20850', (250, 256))	('STAT-5', 'Gene', '20850', (19, 25))	('mice', 'Species', '10090', (161, 165))	('Lck-Cre', 'Var', (69, 76))	('STAT-5', 'Gene', (250, 256))	('Stat5', 'Gene', (175, 180))	('Stat5', 'Gene', '20850', (175, 180))	('STAT-5', 'Gene', (19, 25))
510734	31803974	By contrast, Stat5 heterozygosity completely corrected the enhanced IL-2- and IL-15-induced STAT-5 signalling and almost completely corrected the increased CXCR3 (Fig 6G and H).	('CXCR3', 'Gene', (156, 161))	('IL-15', 'Gene', '16168', (78, 83))	('increased', 'PosReg', (146, 155))	('CXCR3', 'Gene', '12766', (156, 161))	('enhanced', 'PosReg', (59, 67))	('Stat5', 'Gene', (13, 18))	('STAT-5', 'Gene', (92, 98))	('STAT-5', 'Gene', '20850', (92, 98))	('heterozygosity', 'Var', (19, 33))	('IL-15', 'Gene', (78, 83))	('Stat5', 'Gene', '20850', (13, 18))
510739	31803974	The repression of CAR T-cell infiltration was also evident in resected tumours at day 16 with Lck-Cre;Ptpn2 fl/fl;Stat5 fl/+ CAR T-cell cytotoxicity markers (TNF, IFNgamma; induced by PMA/ionomycin ex vivo) being reduced to those in Ptpn2 fl/fl control CAR T cells (Fig 7C).	('tumours', 'Phenotype', 'HP:0002664', (71, 78))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('Ptpn2', 'Var', (102, 107))	('CAR T-cell cytotoxicity', 'Disease', (125, 148))	('tumours', 'Disease', (71, 78))	('CAR T-cell cytotoxicity', 'Disease', 'MESH:D056733', (125, 148))	('Stat5', 'Gene', '20850', (114, 119))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('PMA', 'Gene', '18849', (184, 187))	('ionomycin', 'Chemical', 'MESH:D015759', (188, 197))	('PMA', 'Gene', (184, 187))	('Stat5', 'Gene', (114, 119))
510750	31803974	PTPN2 deficiency did not exacerbate systemic inflammation, as assessed by monitoring for lymphocytic infiltrates in non-lymphoid tissues, including the lungs and livers (Appendix Fig S5E) or for circulating IL-6, IFNgamma, TNF and IL-10 over time (Fig EV4A).	('IL-6', 'Gene', (207, 211))	('IL-10', 'Gene', (231, 236))	('exacerbate', 'Reg', (25, 35))	('IL-6', 'Gene', '16193', (207, 211))	('systemic inflammation', 'Disease', (36, 57))	('deficiency', 'Var', (6, 16))	('PTPN2', 'Gene', (0, 5))	('systemic inflammation', 'Disease', 'MESH:D007249', (36, 57))	('IL-10', 'Gene', '16153', (231, 236))
510762	31803974	Therefore, targeting PTPN2 may not only enhance the antigen-specific activation and function of CAR T cells, but also limit "on-target off-tumour" toxicities by driving the homing of CXCR3-expressing CAR T cells to CXCL9/10/11-expressing tumours.	('driving', 'Reg', (161, 168))	('CXCR3', 'Gene', '12766', (183, 188))	('tumours', 'Disease', 'MESH:D009369', (238, 245))	('tumour" toxicities', 'Disease', (139, 157))	('limit', 'NegReg', (118, 123))	('tumours', 'Disease', (238, 245))	('tumours', 'Phenotype', 'HP:0002664', (238, 245))	('tumour" toxicities', 'Disease', 'MESH:D064420', (139, 157))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('targeting', 'Var', (11, 20))	('enhance', 'PosReg', (40, 47))	('CXCR3', 'Gene', (183, 188))	('homing', 'CPA', (173, 179))	('antigen-specific activation', 'MPA', (52, 79))	('PTPN2', 'Gene', (21, 26))	('function', 'MPA', (84, 92))
510763	31803974	Taken together, our results demonstrate that PTPN2 deletion in murine CD8+ CAR T cells dramatically enhances their recruitment into the tumour site, as well as their antigen-specific activation and ability to overcome the immunosuppressive tumour microenvironment to effectively suppress the growth of solid tumours without promoting overt morbidity.	('tumour', 'Disease', 'MESH:D009369', (308, 314))	('solid tumours', 'Disease', (302, 315))	('tumour', 'Disease', (308, 314))	('murine', 'Species', '10090', (63, 69))	('suppress', 'NegReg', (279, 287))	('CD8', 'Gene', '925', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('solid tumours', 'Disease', 'MESH:D009369', (302, 315))	('immunosuppressive tumour', 'Disease', (222, 246))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumour', 'Disease', (136, 142))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('enhances', 'PosReg', (100, 108))	('deletion', 'Var', (51, 59))	('tumour', 'Disease', (240, 246))	('PTPN2', 'Gene', (45, 50))	('tumour', 'Phenotype', 'HP:0002664', (308, 314))	('tumours', 'Phenotype', 'HP:0002664', (308, 315))	('CD8', 'Gene', (70, 73))	('immunosuppressive tumour', 'Disease', 'MESH:D009369', (222, 246))
510767	31803974	To assess whether targeting of PTPN2 might enhance the cytotoxic potential of human CAR T cells, we took advantage of human CAR T cells targeting the Lewis Y (LY) antigen (Westwood et al, 2008; Peinert et al, 2010) that is overexpressed in many human cancers, including 80% of lung adenocarcinomas, 25% of ovarian carcinomas and 25% of colorectal adenocarcinomas (Fig 8A).	('cytotoxic potential', 'CPA', (55, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('ovarian carcinomas', 'Disease', (306, 324))	('carcinomas', 'Phenotype', 'HP:0030731', (352, 362))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (306, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('targeting', 'Var', (18, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (287, 297))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (336, 362))	('human', 'Species', '9606', (245, 250))	('human', 'Species', '9606', (78, 83))	('PTPN2', 'Gene', (31, 36))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (277, 297))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('lung adenocarcinomas', 'Disease', (277, 297))	('cancers', 'Disease', (251, 258))	('colorectal adenocarcinomas', 'Disease', (336, 362))	('human', 'Species', '9606', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('carcinomas', 'Phenotype', 'HP:0030731', (314, 324))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (277, 297))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (306, 324))
510769	31803974	Taken together, these results are consistent with PTPN2 targeting increasing the potential therapeutic efficacy of human CAR T cells as seen in our pre-clinical models.	('human', 'Species', '9606', (115, 120))	('increasing', 'PosReg', (66, 76))	('PTPN2', 'Gene', (50, 55))	('targeting', 'Var', (56, 65))
510770	31803974	Whole-body, T-cell- or hematopoietic compartment-specific PTPN2 deletion in mice results in systemic inflammation, overt autoreactivity and morbidity (You-Ten et al, 1997; Wiede et al, 2011, 2012, 2017b, 2019).	('overt autoreactivity', 'MPA', (115, 135))	('results in', 'Reg', (81, 91))	('deletion', 'Var', (64, 72))	('systemic inflammation', 'Disease', (92, 113))	('systemic inflammation', 'Disease', 'MESH:D007249', (92, 113))	('mice', 'Species', '10090', (76, 80))	('PTPN2', 'Gene', (58, 63))	('morbidity', 'CPA', (140, 149))
510773	31803974	Ptpn2 knockdown enhanced the tumour antigen-specific activation/cytotoxic potential and killing capacity of HER-2 CAR T cells ex vivo (Fig EV5C-E) and markedly repressed the growth of HER-2-E0771 mammary tumours in vivo (Fig 8C).	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('tumour', 'Disease', (204, 210))	('tumour', 'Disease', (29, 35))	('repressed', 'NegReg', (160, 169))	('tumours', 'Disease', 'MESH:D009369', (204, 211))	('tumours', 'Disease', (204, 211))	('killing capacity', 'CPA', (88, 104))	('tumours', 'Phenotype', 'HP:0002664', (204, 211))	('growth', 'CPA', (174, 180))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('Ptpn2', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('knockdown', 'Var', (6, 15))	('enhanced', 'PosReg', (16, 24))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
510774	31803974	The repression of tumour growth was accompanied by the significant infiltration of mCherry+ CD8+ HER-2 CAR T cells into tumours (Fig 8D); infiltrating HER-2 T cells exhibited increased cytotoxic capacity (as assessed by IFNgamma and TNF expression after PMA/ionomycin treatment ex vivo) (Fig EV5F).	('ionomycin', 'Chemical', 'MESH:D015759', (258, 267))	('CD8', 'Gene', (92, 95))	('PMA', 'Gene', (254, 257))	('HER-2 T', 'CellLine', 'CVCL:J973', (151, 158))	('HER-2', 'Var', (151, 156))	('tumours', 'Disease', (120, 127))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('cytotoxic capacity', 'CPA', (185, 203))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('expression', 'MPA', (237, 247))	('CD8', 'Gene', '925', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumour', 'Disease', (120, 126))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('increased', 'PosReg', (175, 184))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumour', 'Disease', (18, 24))	('PMA', 'Gene', '18849', (254, 257))	('TNF', 'Gene', (233, 236))
510775	31803974	By contrast, mCherry+ CD8+ HER-2 CAR T-cell numbers in the spleen were not affected by Ptpn2 knockdown (Fig 8D).	('knockdown', 'Var', (93, 102))	('CD8', 'Gene', (22, 25))	('Ptpn2', 'Gene', (87, 92))	('CD8', 'Gene', '925', (22, 25))
510777	31803974	Importantly, we found that Ptpn2 deletion led to the effective eradication of HER-2-E0771 mammary tumours (Fig 8F) and this was accompanied by the increased infiltration of mCherry+ HER-2 CAR T cells into HER-2-E0771 mammary tumours (Fig 8G) in vivo.	('Ptpn2', 'Gene', (27, 32))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumours', 'Disease', (225, 232))	('eradication', 'NegReg', (63, 74))	('deletion', 'Var', (33, 41))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('HER-2-E0771', 'Gene', (78, 89))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('increased infiltration', 'PosReg', (147, 169))
510778	31803974	These results demonstrate that CRISPR-Cas9 genome editing can be used to efficiently ablate PTPN2 to enhance the therapeutic efficacy of CAR T cells in solid cancer.	('therapeutic efficacy', 'CPA', (113, 133))	('PTPN2', 'Gene', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('ablate', 'Var', (85, 91))	('cancer', 'Disease', (158, 164))	('enhance', 'PosReg', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
510785	31803974	Consistent with this, our studies herein demonstrate that the deletion of PTPN2 in T cells enhances cancer immunosurveillance and the anti-tumour activity of adoptively transferred T cells.	('tumour', 'Disease', (139, 145))	('PTPN2', 'Gene', (74, 79))	('enhances', 'PosReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('deletion', 'Var', (62, 70))	('tumour', 'Disease', 'MESH:D009369', (139, 145))
510786	31803974	In particular, our studies demonstrate that the deletion of PTPN2 not only drives the homing of CAR T cells to solid tumours, but also their activation to eradicate tumours in an otherwise immunosuppressive tumour microenvironment.	('drives', 'PosReg', (75, 81))	('tumours', 'Disease', (117, 124))	('solid tumours', 'Disease', (111, 124))	('immunosuppressive tumour', 'Disease', 'MESH:D009369', (189, 213))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('PTPN2', 'Gene', (60, 65))	('immunosuppressive tumour', 'Disease', (189, 213))	('homing', 'CPA', (86, 92))	('tumours', 'Disease', 'MESH:D009369', (117, 124))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('solid tumours', 'Disease', 'MESH:D009369', (111, 124))	('deletion', 'Var', (48, 56))	('activation', 'PosReg', (141, 151))	('tumours', 'Disease', (165, 172))
510787	31803974	Therefore, targeting PTPN2 may provide a means for enhancing the anti-tumour activity of T cells and extending the utility of CAR T cells beyond haematological malignancies to solid cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('malignancies to solid cancers', 'Disease', (160, 189))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('enhancing', 'PosReg', (51, 60))	('targeting', 'Var', (11, 20))	('malignancies to solid cancers', 'Disease', 'MESH:D009369', (160, 189))	('PTPN2', 'Gene', (21, 26))	('tumour', 'Disease', (70, 76))
510789	31803974	This was reliant on PTPN2 deficiency driving the IFNgamma-induced and STAT-1-mediated expression of antigen-presentation pathway genes and T-cell chemoattractants, such as Cxcl9 in tumour cells (Manguso et al, 2017).	('deficiency', 'Var', (26, 36))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('STAT-1', 'Gene', (70, 76))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('PTPN2', 'Gene', (20, 25))	('Cxcl9', 'Gene', (172, 177))	('tumour', 'Disease', (181, 187))	('STAT-1', 'Gene', '20846', (70, 76))	('Cxcl9', 'Gene', '17329', (172, 177))
510790	31803974	In humans, CXCL9 expression is generally associated with increased CD8+ T-cell infiltrates and improved overall survival and response to chemotherapy (Nagarsheth et al, 2017).	('overall survival', 'CPA', (104, 120))	('response to chemotherapy', 'CPA', (125, 149))	('CXCL9 expression', 'Var', (11, 27))	('improved', 'PosReg', (95, 103))	('humans', 'Species', '9606', (3, 9))	('increased', 'PosReg', (57, 66))	('CD8', 'Gene', (67, 70))	('CD8', 'Gene', '925', (67, 70))
510791	31803974	Our own studies indicate that the deletion of PTPN2 in CAR T cells drives the expression of CXCR3 and the trafficking of CAR T cells to CXCL9/10-expressing mammary tumours.	('PTPN2', 'Gene', (46, 51))	('CXCR3', 'Gene', (92, 97))	('expression', 'MPA', (78, 88))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('drives', 'Reg', (67, 73))	('CXCR3', 'Gene', '12766', (92, 97))	('deletion', 'Var', (34, 42))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('tumours', 'Disease', (164, 171))	('trafficking', 'MPA', (106, 117))
510796	31803974	Second, we have shown that the inducible deletion of PTPN2 in the hematopoietic compartment of adult non-autoimmune-prone C57BL/6 mice is sufficient to promote the development of systemic inflammation and autoimmunity (Wiede et al, 2017b), whereas PTPN2 deletion in T cells in autoimmune-prone NOD1 mice markedly accelerates type 1 diabetes onset, as well as other autoimmune and inflammatory disorders, including colitis (Wiede et al, 2019).	('mice', 'Species', '10090', (299, 303))	('diabetes onset', 'Disease', 'MESH:D003922', (332, 346))	('inflammatory disorders', 'Disease', (380, 402))	('colitis', 'Disease', (414, 421))	('NOD1', 'Gene', (294, 298))	('deletion', 'Var', (254, 262))	('inflammatory disorders', 'Disease', 'MESH:D009220', (380, 402))	('promote', 'PosReg', (152, 159))	('NOD1', 'Gene', '107607', (294, 298))	('colitis', 'Disease', 'MESH:D003092', (414, 421))	('autoimmunity', 'Phenotype', 'HP:0002960', (205, 217))	('systemic inflammation and autoimmunity', 'Disease', 'MESH:D007249', (179, 217))	('mice', 'Species', '10090', (130, 134))	('PTPN2', 'Gene', (53, 58))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (325, 340))	('colitis', 'Phenotype', 'HP:0002583', (414, 421))	('diabetes onset', 'Disease', (332, 346))	('deletion', 'Var', (41, 49))	('accelerates', 'PosReg', (313, 324))	('PTPN2', 'Gene', (248, 253))
510797	31803974	Third, we and others have shown that the deletion of PTPN2 in some solid tumours can enhance tumorigenicity (Shields et al, 2013; Lee et al, 2017; Grohmann et al, 2018).	('PTPN2', 'Gene', (53, 58))	('solid tumours', 'Disease', 'MESH:D009369', (67, 80))	('tumorigenicity', 'CPA', (93, 107))	('deletion', 'Var', (41, 49))	('solid tumours', 'Disease', (67, 80))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('enhance', 'PosReg', (85, 92))
510798	31803974	For example, PTPN2 deletion in the liver can facilitate the STAT-3-dependent development of hepatocellular carcinoma in obesity (Grohmann et al, 2018).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('hepatocellular carcinoma in obesity', 'Disease', (92, 127))	('STAT-3', 'Gene', '20848', (60, 66))	('obesity', 'Phenotype', 'HP:0001513', (120, 127))	('STAT-3', 'Gene', (60, 66))	('facilitate', 'PosReg', (45, 55))	('deletion', 'Var', (19, 27))	('hepatocellular carcinoma in obesity', 'Disease', 'MESH:D009765', (92, 127))	('PTPN2', 'Gene', (13, 18))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))
510800	31803974	Our studies demonstrate that the deletion of PTPN2 enhances the function of CAR T cells by promoting antigen-induced LCK activation and cytokine-induced STAT-5 signalling.	('deletion', 'Var', (33, 41))	('LCK', 'Gene', (117, 120))	('LCK', 'Gene', '16818', (117, 120))	('STAT-5', 'Gene', (153, 159))	('enhances', 'PosReg', (51, 59))	('STAT-5', 'Gene', '20850', (153, 159))	('promoting', 'PosReg', (91, 100))	('function', 'MPA', (64, 72))	('PTPN2', 'Gene', (45, 50))
510813	31803974	This is in keeping the lack or HER2 expression in the colon in HER2 TG mice and our findings demonstrating that PTPN2 deficiency only promotes the antigen-induced activation of CAR T cells.	('mice', 'Species', '10090', (71, 75))	('CAR T cells', 'CPA', (177, 188))	('activation', 'PosReg', (163, 173))	('promotes', 'PosReg', (134, 142))	('HER2', 'Gene', '13866', (63, 67))	('PTPN2', 'Gene', (112, 117))	('HER2', 'Gene', '13866', (31, 35))	('HER2', 'Gene', (63, 67))	('HER2', 'Gene', (31, 35))	('deficiency', 'Var', (118, 128))	('antigen-induced', 'MPA', (147, 162))
510817	31803974	The C57BL/6 mouse mammary carcinoma cell line E0771 (a gift from Robin Anderson, Peter MacCallum Cancer Centre) (Johnstone et al, 2015) and the C57BL/6 mouse sarcoma cell line 24JK (a gift from Patrick Hwu, NIH, Bethesda, Maryland, USA) (Shiloni et al, 1993) were genetically engineered to express truncated human HER-2 (HER-2-E0771) as described previously (Kershaw et al, 2004).	('truncated', 'Var', (298, 307))	('Robin', 'Species', '9188', (65, 70))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (18, 35))	('sarcoma', 'Disease', 'MESH:D012509', (158, 165))	('mouse', 'Species', '10090', (152, 157))	('carcinoma', 'Disease', 'MESH:D002277', (26, 35))	('mouse', 'Species', '10090', (12, 17))	('Peter MacCallum Cancer', 'Disease', 'MESH:D009369', (81, 103))	('Peter MacCallum Cancer', 'Disease', (81, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (308, 313))	('sarcoma', 'Disease', (158, 165))	('carcinoma', 'Disease', (26, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
510825	31803974	Ptpn2 fl/fl and Lck-Cre;Ptpn2 fl/fl mice and the corresponding OT-1 TCR transgenic mice were described previously (Wiede et al, 2011).	('mice', 'Species', '10090', (83, 87))	('fl/fl', 'Var', (30, 35))	('mice', 'Species', '10090', (36, 40))	('Ptpn2', 'Gene', (24, 29))	('transgenic mice', 'Species', '10090', (72, 87))
510831	31803974	Antibodies against p-(Y701) STAT1 (clone 58D6), p-(Y694) STAT5 (D47E7) XP  and STAT1 were from Cell Signaling.	('STAT1', 'Gene', (79, 84))	('STAT1', 'Gene', (28, 33))	('STAT5', 'Gene', '20850', (57, 62))	('STAT1', 'Gene', '20846', (79, 84))	('D47E7', 'CellLine', 'CVCL:0553', (64, 69))	('STAT5', 'Gene', (57, 62))	('STAT1', 'Gene', '20846', (28, 33))	('p-(Y701', 'Var', (19, 26))
510846	31803974	Lymphocytes (0.5 x 107/ml) were cultured overnight with anti-CD3epsilon (0.5 mug/ml) and anti-CD28 (0.5 mug/ml) in the presence of 100 IU/ml human IL-2 and 0.2 ng/ml murine IL-7 in complete T-cell medium [RPMI supplemented with 10% FBS, l-glutamine (2 mM), penicillin (100 units/ml)/streptomycin (100 mug/ml), non-essential amino acids, Na-pyruvate (1 mM), HEPES (10 mM) and 2-mercaptoethanol (50 muM)].	('2-mercaptoethanol', 'Chemical', 'MESH:D008623', (375, 392))	('Na-pyruvate', 'MPA', (337, 348))	('l-glutamine', 'Chemical', 'None', (237, 248))	('murine', 'Species', '10090', (166, 172))	('HEPES', 'Chemical', 'MESH:D006531', (357, 362))	('Na-pyruvate', 'Chemical', 'MESH:D012964', (337, 348))	('streptomycin', 'Chemical', 'MESH:D013307', (283, 295))	('human', 'Species', '9606', (141, 146))	('HEPES', 'MPA', (357, 362))	('penicillin', 'Chemical', 'MESH:D010406', (257, 267))	('IL-7', 'Gene', (173, 177))	('IL-7', 'Gene', '16196', (173, 177))	('anti-CD28', 'Var', (89, 98))
510856	31803974	Cell surface phenotyping of transduced cells was determined by staining with BV785-conjugated anti-human CD3 (UCHT1, BioLegend), BV605-conjugated anti-human CD4 (OKT-4, BioLegend) and PE-Cy7-conjugated anti-human CD8 (SK1, BioLegend).	('CD4', 'Gene', (157, 160))	('CD8', 'Gene', (213, 216))	('CD4', 'Gene', '12504', (157, 160))	('BV605-conjugated', 'Var', (129, 145))	('CD8', 'Gene', '925', (213, 216))	('human', 'Species', '9606', (151, 156))	('CD3', 'Gene', '12501', (105, 108))	('SK1', 'Gene', (218, 221))	('human', 'Species', '9606', (207, 212))	('SK1', 'Gene', '103985', (218, 221))	('CD3', 'Gene', (105, 108))	('human', 'Species', '9606', (99, 104))
510894	31803974	For detection of HER-2, 30-mum sections throughout the entire rostral-caudal extent of the cerebellum from C57BL/6 or HER-2 TG C57BL/6 mice were subjected to antigen retrieval and incubated in blocking buffer (as described above).	('HER-2 TG', 'Gene', '100710', (118, 126))	('C57BL/6', 'Var', (107, 114))	('HER-2 TG', 'Gene', (118, 126))	('mice', 'Species', '10090', (135, 139))
510906	31803974	CAR T cells were transfected with Ptpn2 siRNA (300 nM) conjugated to FITC or GFP siRNA (300 nM) conjugated to FITC 2 days prior to adoptive T-cell therapy using the Mouse T-cell Nucleofector  Kit (Lonza Bioscience) according to the manufacturer's instructions.	('300', 'Var', (88, 91))	('300 nM', 'Var', (47, 53))	('Mouse T-', 'CellLine', 'CVCL:0594', (165, 173))	('FITC', 'Chemical', 'MESH:D016650', (69, 73))	('Ptpn2', 'Gene', (34, 39))	('FITC', 'Chemical', 'MESH:D016650', (110, 114))
510918	31803974	All protocols were approved by the Monash University School of Biomedical Sciences Animal Ethics Committee (Ethics number: MARP/2012/124) or the Peter MacCallum Animal Ethics and Experimentation Committee (Ethics numbers: E570, E582 and E604).	('E582', 'Var', (228, 232))	('E604', 'Chemical', 'MESH:C520671', (237, 241))	('E604', 'Var', (237, 241))
510997	30045945	use genome-scale CRISPR-Cas9 screening technology to identify druggable targets for TP53 wild-type Ewing sarcoma and discover reactivation of p53 through inhibition of MDM2, MDM4, Wip1, or USP7 as therapeutic strategies for the disease.	('p53', 'Gene', (142, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('Ewing sarcoma', 'Disease', (99, 112))	('inhibition', 'Var', (154, 164))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (99, 112))	('reactivation', 'Var', (126, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (99, 112))	('MDM2', 'Gene', (168, 172))	('TP53', 'Gene', (84, 88))
510999	30045945	The majority of tumors express wild-type TP53, and thus, therapies targeting the p53 pathway would benefit most patients.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Protein', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('patients', 'Species', '9606', (112, 120))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('p53 pathway', 'Pathway', (81, 92))	('tumors', 'Disease', (16, 22))	('wild-type', 'Var', (31, 40))
511002	30045945	The USP7 inhibitor, P5091, and the Wip1/PPM1D inhibitor, GSK2830371, decreased the viability of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('GSK2830371', 'Chemical', 'MESH:C587624', (57, 67))	('viability', 'CPA', (83, 92))	('decreased', 'NegReg', (69, 78))	('P5091', 'Var', (20, 25))	('Ewing sarcoma', 'Disease', (96, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))	('P5091', 'Chemical', 'MESH:C576408', (20, 25))
511003	30045945	The combination of ATSP-7041 with P5091, GSK2830371, and chemotherapeutic agents showed synergistic action on the p53 pathway.	('P5091', 'Chemical', 'MESH:C576408', (34, 39))	('ATSP-7041', 'Chemical', 'MESH:C584947', (19, 28))	('p53 pathway', 'Pathway', (114, 125))	('GSK2830371', 'Chemical', 'MESH:C587624', (41, 51))	('GSK2830371', 'Var', (41, 51))	('P5091', 'Var', (34, 39))	('ATSP-7041', 'Gene', (19, 28))
511004	30045945	The effects of the inhibitors, including the specific USP7 inhibitor XL-188, were rescued by concurrent TP53 knockout, highlighting the essentiality of intact p53 for the observed cytotoxic activities.	('knockout', 'Var', (109, 117))	('XL-188', 'Chemical', '-', (69, 75))	('TP53', 'Gene', (104, 108))
511008	30045945	The defining event in Ewing sarcoma is a somatic chromosomal translocation, most commonly between chromosomes 11 and 22, causing a fusion between the EWSR1 (Ewing sarcoma breakpoint region 1) gene and an ETS family gene FLI1 (Friend leukemia virus integration 1).	('FLI1', 'Gene', (220, 224))	('FLI1', 'Gene', '2313', (220, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('Friend leukemia virus integration 1', 'Gene', (226, 261))	('EWSR1', 'Gene', '2130', (150, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('leukemia', 'Phenotype', 'HP:0001909', (233, 241))	('Friend leukemia virus integration 1', 'Gene', '2313', (226, 261))	('causing', 'Reg', (121, 128))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (22, 35))	('Ewing sarcoma breakpoint region 1', 'Gene', (157, 190))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (157, 190))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (22, 35))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (157, 170))	('EWSR1', 'Gene', (150, 155))	('fusion', 'Var', (131, 137))	('Ewing sarcoma', 'Disease', (22, 35))
511013	30045945	Although the majority of patient tumors retain wild-type TP53, there has been a historic bias against studying p53 dependent genes in this disease.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('patient', 'Species', '9606', (25, 32))	('TP53', 'Var', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (33, 39))
511014	30045945	The vast majority of Ewing sarcoma cell lines harbor TP53 mutations, and patient-derived Ewing sarcoma xenografts have only recently been established.	('mutations', 'Var', (58, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('Ewing sarcoma', 'Disease', (89, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))	('Ewing sarcoma', 'Disease', (21, 34))	('patient', 'Species', '9606', (73, 80))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('TP53', 'Gene', (53, 57))
511015	30045945	Consequently, models with TP53 mutations have been overrepresented in Ewing sarcoma studies in the past.	('TP53', 'Gene', (26, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('mutations', 'Var', (31, 40))	('Ewing sarcoma', 'Disease', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (70, 83))
511016	30045945	Therefore, we sought to identify druggable dependencies in TP53 wild-type Ewing sarcoma models, which better recapitulate the more common disease biology.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (74, 87))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (74, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('TP53', 'Var', (59, 63))	('Ewing sarcoma', 'Disease', (74, 87))
511023	30045945	ATSP-7041 showed anti-tumor efficacy in vivo in several Ewing sarcoma models.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('ATSP-7041', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('ATSP-7041', 'Chemical', 'MESH:C584947', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Ewing sarcoma', 'Disease', (56, 69))	('tumor', 'Disease', (22, 27))
511024	30045945	Furthermore, ATSP-7041 synergized with some standard-of-care Ewing sarcoma chemotherapeutic agents.	('Ewing sarcoma', 'Disease', (61, 74))	('ATSP-7041', 'Var', (13, 22))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (61, 74))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (61, 74))	('ATSP-7041', 'Chemical', 'MESH:C584947', (13, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))
511027	30045945	The response to TP53 disruption was consistent with the annotated mutation status in 97% of cell lines, including all of the Ewing sarcoma cell lines in this screen.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('disruption', 'Var', (21, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Ewing sarcoma', 'Disease', (125, 138))	('TP53', 'Gene', (16, 20))
511029	30045945	In Ewing sarcoma, MDM2, MDM4, USP7, and PPM1D were preferential dependencies in the TP53 wild-type cell lines (Fig.	('MDM2', 'Var', (18, 22))	('Ewing sarcoma', 'Disease', (3, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('MDM4', 'Var', (24, 28))
511035	30045945	Given the disrupted p53-MDM2 axis in the TP53 mutant lines, there was no increase in MDM2 protein following RG7388 treatment of A673 and EWS502 cells, irrespective of infection with MDM2 or control sgRNAs (Fig.	('TP53', 'Gene', (41, 45))	('MDM2 protein', 'Protein', (85, 97))	('mutant', 'Var', (46, 52))	('EWS', 'Gene', '2130', (137, 140))	('EWS', 'Gene', (137, 140))
511040	30045945	ATSP-7041 is a stapled peptide, dual inhibitor of MDM2 and MDM4.	('MDM2', 'Gene', (50, 54))	('MDM4', 'Gene', (59, 63))	('ATSP-7041', 'Var', (0, 9))	('ATSP-7041', 'Chemical', 'MESH:C584947', (0, 9))
511041	30045945	We observed concentration-dependent increases in MDM2, p53, and p21 protein levels after ATSP-7041 treatment of TP53 wild-type Ewing sarcoma cell lines (Fig.	('p21 protein', 'Gene', '16653', (64, 75))	('MDM2', 'MPA', (49, 53))	('ATSP-7041', 'Gene', (89, 98))	('p21 protein', 'Gene', (64, 75))	('ATSP-7041', 'Chemical', 'MESH:C584947', (89, 98))	('p53', 'MPA', (55, 58))	('Ewing sarcoma', 'Disease', (127, 140))	('TP53', 'Var', (112, 116))	('increases', 'PosReg', (36, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (127, 140))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (127, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
511043	30045945	TC32 cells were pretreated with the MDM2 inhibitor RG7388 to increase p53 protein levels and then cell lysates were treated with vehicle, ATSP-7041 or RG7388, followed by MDM4 immunoprecipitation and p53 and MDM4 Western blot analysis.	('p53 protein levels', 'MPA', (70, 88))	('RG7388', 'Var', (51, 57))	('ATSP-7041', 'Chemical', 'MESH:C584947', (138, 147))	('increase', 'PosReg', (61, 69))
511044	30045945	Whereas RG7388 was unable to dissociate the inhibitory p53-MDM4 complexes formed in response to selective inhibition of MDM2 in Ewing sarcoma cells, ATSP-7041 exposure decreased the level of p53-MDM4 interaction (Fig.	('ATSP-7041', 'Chemical', 'MESH:C584947', (149, 158))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('decreased', 'NegReg', (168, 177))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('p53-MDM4 interaction', 'MPA', (191, 211))	('MDM2', 'Gene', (120, 124))	('Ewing sarcoma', 'Disease', (128, 141))	('inhibition', 'NegReg', (106, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('ATSP-7041', 'Var', (149, 158))
511046	30045945	ATSP-7041 selectively reduced the viability of five TP53 wild-type Ewing sarcoma cell lines at low micromolar concentrations (Fig.	('viability', 'CPA', (34, 43))	('ATSP-7041', 'Var', (0, 9))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('ATSP-7041', 'Chemical', 'MESH:C584947', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('reduced', 'NegReg', (22, 29))	('Ewing sarcoma', 'Disease', (67, 80))
511051	30045945	We next sought to evaluate the activity of ATSP-7041 Ewing sarcoma in vivo.	('ATSP-7041', 'Var', (43, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (53, 66))	('ATSP-7041', 'Chemical', 'MESH:C584947', (43, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('Ewing sarcoma', 'Disease', (53, 66))
511064	30045945	5 A) and observed reduced viability of TP53 wild-type compared with mutant Ewing sarcoma cell lines (Fig.	('Ewing sarcoma', 'Disease', (75, 88))	('reduced', 'NegReg', (18, 25))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('TP53', 'Var', (39, 43))	('viability', 'MPA', (26, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('mutant', 'Var', (68, 74))
511065	30045945	Similarly, the disruption of PPM1D by CRISPR-Cas9 in TC32, TC138, A673, and EWS502 led to reduced protein levels of Wip1 (Fig.	('A673', 'Var', (66, 70))	('reduced', 'NegReg', (90, 97))	('EWS', 'Gene', '2130', (76, 79))	('EWS', 'Gene', (76, 79))	('TC138', 'Gene', (59, 64))	('TC138', 'Chemical', '-', (59, 64))	('protein levels of Wip1', 'MPA', (98, 120))	('TC32', 'Gene', (53, 57))	('disruption', 'Var', (15, 25))
511066	30045945	5 C) and a decrease in viability of the TP53 wild-type compared with the TP53 mutant Ewing sarcoma cell lines (Fig.	('viability', 'CPA', (23, 32))	('Ewing sarcoma', 'Disease', (85, 98))	('TP53', 'Gene', (73, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('decrease', 'NegReg', (11, 19))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('mutant', 'Var', (78, 84))
511067	30045945	Given the selective effects of genetic disruption of USP7 and PPM1D on the viability of wild-type TP53 Ewing sarcoma, we tested the pharmacologic activities of their respective small inhibitors, P5091 and GSK2830371.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (103, 116))	('effects', 'Reg', (20, 27))	('P5091', 'Chemical', 'MESH:C576408', (195, 200))	('USP7', 'Gene', (53, 57))	('Ewing sarcoma', 'Disease', (103, 116))	('PPM1D', 'Gene', (62, 67))	('P5091', 'Var', (195, 200))	('tested', 'Reg', (121, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('GSK2830371', 'Chemical', 'MESH:C587624', (205, 215))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (103, 116))	('genetic disruption', 'Var', (31, 49))
511068	30045945	P5091 increased p53 and p21 protein levels in a time-dependent fashion in the wild-type TP53 cells, TC32 and TC138 (Fig.	('increased', 'PosReg', (6, 15))	('p21 protein', 'Gene', '16653', (24, 35))	('P5091', 'Var', (0, 5))	('TC138', 'Chemical', '-', (109, 114))	('p21 protein', 'Gene', (24, 35))	('P5091', 'Chemical', 'MESH:C576408', (0, 5))
511070	30045945	Annexin V staining likewise demonstrated P5091-induced cell death in TP53 wild-type Ewing sarcoma cell lines (Fig.	('Ewing sarcoma', 'Disease', (84, 97))	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('P5091-induced', 'Var', (41, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('P5091', 'Chemical', 'MESH:C576408', (41, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('cell death', 'CPA', (55, 65))
511071	30045945	GSK2830371 reduced the protein levels of Wip1 in a time-dependent manner and triggered a surge in phosphorylation of Serine 15 of p53, the primary p53 dephosphorylation target site of Wip1 (Fig.	('reduced', 'NegReg', (11, 18))	('protein levels', 'MPA', (23, 37))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('GSK2830371', 'Var', (0, 10))	('phosphorylation of Serine 15', 'MPA', (98, 126))	('Serine', 'Chemical', 'MESH:D012694', (117, 123))
511072	30045945	There was a notable increase in susceptibility of TP53 wild-type Ewing sarcoma cell lines to micromolar concentrations of GSK2830371, as compared with the TP53 mutated cell lines (Fig.	('GSK2830371', 'Chemical', 'MESH:C587624', (122, 132))	('GSK2830371', 'Var', (122, 132))	('Ewing sarcoma', 'Disease', (65, 78))	('susceptibility', 'MPA', (32, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (65, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))	('increase', 'PosReg', (20, 28))
511073	30045945	GSK2830371-induced cell death in TP53 wild-type Ewing sarcoma cell lines was likewise observed by Annexin V staining (Fig.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (48, 61))	('Ewing sarcoma', 'Disease', (48, 61))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('Annexin V', 'Gene', '308', (98, 107))	('GSK2830371-induced', 'Var', (0, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (48, 61))	('Annexin V', 'Gene', (98, 107))
511074	30045945	Given the promising single-agent activity of GSK2830371 and P5091 in reactivating the p53 pathway, we next evaluated the therapeutic potential of combining these molecules with ATSP-7041.	('p53 pathway', 'Pathway', (86, 97))	('ATSP-7041', 'Chemical', 'MESH:C584947', (177, 186))	('P5091', 'Var', (60, 65))	('GSK2830371', 'Chemical', 'MESH:C587624', (45, 55))	('reactivating', 'MPA', (69, 81))	('P5091', 'Chemical', 'MESH:C576408', (60, 65))	('GSK2830371', 'Var', (45, 55))
511075	30045945	Because MDM2, MDM4, USP7, and PPM1D all scored as top dependencies in TP53 wild-type Ewing sarcoma, we reasoned that chemically inhibiting these proteins in combination could provide the most effective mechanism to trigger p53-mediated cell death in Ewing sarcoma.	('MDM4', 'Var', (14, 18))	('Ewing sarcoma', 'Disease', (85, 98))	('PPM1D', 'Var', (30, 35))	('USP7', 'Var', (20, 24))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (250, 263))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (250, 263))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('MDM2', 'Var', (8, 12))	('Ewing sarcoma', 'Disease', (250, 263))
511076	30045945	Indeed, we found that the combination of ATSP-7041 with P5091 exhibited synergy in TC32 and TC138 and additivity in CHLA258 cells, as assessed by the Chou-Talalay combination index for Loewe additivity model (Fig.	('P5091', 'Var', (56, 61))	('TC138', 'Gene', (92, 97))	('combination', 'Interaction', (26, 37))	('CHLA258', 'CellLine', 'CVCL:A058', (116, 123))	('TC32', 'Protein', (83, 87))	('P5091', 'Chemical', 'MESH:C576408', (56, 61))	('TC138', 'Chemical', '-', (92, 97))	('ATSP-7041', 'Var', (41, 50))	('Loewe', 'Chemical', '-', (185, 190))	('synergy', 'MPA', (72, 79))	('ATSP-7041', 'Chemical', 'MESH:C584947', (41, 50))
511077	30045945	Western blot analysis revealed that P5091 decreased the level of MDM2 protein that is otherwise induced by ATSP-7041 as a result of the surge in p53 and counter-up-regulation of MDM2 (Fig.	('p53', 'Protein', (145, 148))	('decreased', 'NegReg', (42, 51))	('level of', 'MPA', (56, 64))	('ATSP-7041', 'Chemical', 'MESH:C584947', (107, 116))	('MDM2', 'Protein', (65, 69))	('surge', 'PosReg', (136, 141))	('P5091', 'Var', (36, 41))	('P5091', 'Chemical', 'MESH:C576408', (36, 41))
511080	30045945	Western blot assays revealed that the combination of ATSP-7041 and GSK2830371 increased the phosphorylation of p53 at Serine 15 in two Ewing sarcoma cell lines (Fig.	('ATSP-7041', 'Var', (53, 62))	('GSK2830371', 'Var', (67, 77))	('Serine', 'Chemical', 'MESH:D012694', (118, 124))	('phosphorylation', 'MPA', (92, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (135, 148))	('p53', 'Protein', (111, 114))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (135, 148))	('ATSP-7041', 'Chemical', 'MESH:C584947', (53, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('increased', 'PosReg', (78, 87))	('Ewing sarcoma', 'Disease', (135, 148))	('GSK2830371', 'Chemical', 'MESH:C587624', (67, 77))
511088	30045945	These data support further consideration of adding a stapled peptide dual inhibitor of MDM2/MDM4 to standard chemotherapy regimens in patients with TP53 wild-type Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (163, 176))	('TP53', 'Var', (148, 152))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (163, 176))	('patients', 'Species', '9606', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('MDM2/MDM4', 'Gene', (87, 96))	('Ewing sarcoma', 'Disease', (163, 176))
511089	30045945	While these data suggest that TP53 wild-type Ewing sarcoma cancer cell lines are more sensitive to loss of MDM2, MDM4, PPM1D, and USP7 than TP53 mutated ones, we next generated isogenic cell lines with TP53 loss to more definitively support this hypothesis.	('TP53', 'Gene', (202, 206))	('loss', 'NegReg', (207, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MDM4', 'Var', (113, 117))	('Ewing sarcoma cancer', 'Disease', (45, 65))	('loss', 'Var', (99, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('PPM1D', 'Var', (119, 124))	('Ewing sarcoma cancer', 'Disease', 'MESH:C563168', (45, 65))	('MDM2', 'Gene', (107, 111))
511091	30045945	Treatment of TP53 knockout cells revealed that loss of TP53 fully rescues the cytotoxic effect of ATSP-7041, indicating on-target activity of the drug (Fig.	('cytotoxic effect', 'CPA', (78, 94))	('ATSP-7041', 'Gene', (98, 107))	('TP53', 'Gene', (55, 59))	('ATSP-7041', 'Chemical', 'MESH:C584947', (98, 107))	('rescues', 'PosReg', (66, 73))	('loss', 'Var', (47, 51))
511096	30045945	Strikingly, TP53 knockout completely reversed the cytotoxic effect of XL-188 (Fig.	('TP53', 'Gene', (12, 16))	('cytotoxic effect', 'MPA', (50, 66))	('XL-188', 'Chemical', '-', (70, 76))	('knockout', 'Var', (17, 25))
511098	30045945	Collectively, these data validate the hypothesis that in Ewing sarcoma, MDM2, MDM4, PPM1D, and USP7 dependencies are mediated by functional p53 and exert their cytotoxic effects, singly and in combination, by reactivating the p53 tumor suppressor pathway.	('mediated by', 'Reg', (117, 128))	('tumor', 'Disease', (230, 235))	('Ewing sarcoma', 'Disease', (57, 70))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('cytotoxic effects', 'CPA', (160, 177))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('MDM2', 'Var', (72, 76))	('p53', 'Protein', (140, 143))	('MDM4', 'Var', (78, 82))	('reactivating', 'PosReg', (209, 221))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
511100	30045945	Loss of p53, either by genetic deletion, mutation, or protein interaction-based suppression, is a key oncogenic event in tumorigenesis.	('p53', 'Gene', (8, 11))	('suppression', 'NegReg', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('Loss', 'NegReg', (0, 4))	('mutation', 'Var', (41, 49))	('protein', 'Protein', (54, 61))	('genetic deletion', 'Var', (23, 39))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
511101	30045945	Whereas TP53 is mutated in ~50% of human tumors, a large subset of pediatric cancers exhibit a low frequency of TP53 mutations, implicating negative regulation of p53 through protein interactions as a pathogenic mechanism.	('protein', 'Protein', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (117, 126))	('pediatric cancers', 'Disease', 'MESH:D009369', (67, 84))	('negative', 'NegReg', (140, 148))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('human', 'Species', '9606', (35, 40))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('interactions', 'Interaction', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('pediatric cancers', 'Disease', (67, 84))	('TP53', 'Gene', (112, 116))
511102	30045945	Indeed, several recent studies indicate that the TP53 mutation rate in Ewing sarcoma is very low.	('mutation', 'Var', (54, 62))	('Ewing sarcoma', 'Disease', (71, 84))	('TP53', 'Gene', (49, 53))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (71, 84))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (71, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))
511105	30045945	We leveraged data from 33 cancer cell lines and identified MDM2, MDM4, PPM1D, and USP7 as anti-correlated with TP53 dependency scores in Ewing sarcoma and across all cancer cell lines in the dataset.	('USP7', 'Var', (82, 86))	('Ewing sarcoma', 'Disease', (137, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('cancer', 'Disease', (166, 172))	('MDM4', 'Var', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (26, 32))	('MDM2', 'Var', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('PPM1D', 'Var', (71, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('anti-correlated', 'NegReg', (90, 105))
511115	30045945	High Wip1 levels or PPM1D amplification have been found to correlate with poor prognosis in a variety of cancer types.	('PPM1D amplification', 'Var', (20, 39))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (105, 111))
511117	30045945	MDM2 inhibition by RG7112 and RG7388 is being investigated in clinical trials as single agents or combination treatments for several malignancies.	('malignancies', 'Disease', (133, 145))	('RG7388', 'Var', (30, 36))	('inhibition', 'NegReg', (5, 15))	('MDM2', 'Gene', (0, 4))	('RG7112', 'Var', (19, 25))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))
511118	30045945	While early clinical trials testing RG7112 in patients with leukemia and advanced solid tumors have shown promise, coexpression of MDM4 can cause resistance.	('solid tumors', 'Disease', (82, 94))	('resistance', 'MPA', (146, 156))	('patients', 'Species', '9606', (46, 54))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('cause', 'Reg', (140, 145))	('solid tumors', 'Disease', 'MESH:D009369', (82, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('MDM4', 'Gene', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('coexpression', 'Var', (115, 127))	('leukemia', 'Disease', (60, 68))	('leukemia', 'Disease', 'MESH:D007938', (60, 68))
511121	30045945	ATSP-7041 is a mechanistically validated stapled peptide inhibitor of both MDM2 and MDM4.	('ATSP-7041', 'Chemical', 'MESH:C584947', (0, 9))	('ATSP-7041', 'Var', (0, 9))	('MDM4', 'Gene', (84, 88))	('MDM2', 'Gene', (75, 79))
511123	30045945	ALRN-6924 is currently in phase 1/2 evaluation for TP53 wild-type solid tumors and lymphomas in adults (NCT02264613) and in phase 1 evaluation for acute myeloid leukemia and for myelodysplastic syndrome (NCT02909972).	('myeloid leukemia', 'Phenotype', 'HP:0012324', (153, 169))	('lymphomas', 'Disease', (83, 92))	('myelodysplastic syndrome', 'Disease', (178, 202))	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('lymphomas', 'Disease', 'MESH:D008223', (83, 92))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (178, 202))	('leukemia', 'Phenotype', 'HP:0001909', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('lymphomas', 'Phenotype', 'HP:0002665', (83, 92))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (147, 169))	('ALRN-6924', 'Gene', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('solid tumors', 'Disease', (66, 78))	('NCT02264613', 'Var', (104, 115))	('acute myeloid leukemia', 'Disease', (147, 169))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (178, 202))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (147, 169))
511127	30045945	Therefore, we consider a dual MDM2/MDM4 inhibitor strategy to potentially be the most effective and rapidly translatable approach to reactivate p53 in patients with Ewing sarcoma.	('Ewing sarcoma', 'Disease', (165, 178))	('patients', 'Species', '9606', (151, 159))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (165, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (165, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('p53', 'Gene', (144, 147))	('reactivate', 'Var', (133, 143))
511131	30045945	These mechanistic data support the addition of ATSP-7041 or other p53 reactivating agents to chemotherapy regimens.	('ATSP-7041', 'Chemical', 'MESH:C584947', (47, 56))	('ATSP-7041', 'Var', (47, 56))	('p53', 'Gene', (66, 69))
511135	30045945	For example, in the case of ATSP-7041 and P5091 treatment, the addition of P5091 suppresses the counter up-regulation of MDM2.	('P5091', 'Chemical', 'MESH:C576408', (42, 47))	('suppresses', 'NegReg', (81, 91))	('P5091', 'Var', (75, 80))	('P5091', 'Var', (42, 47))	('ATSP-7041', 'Chemical', 'MESH:C584947', (28, 37))	('P5091', 'Chemical', 'MESH:C576408', (75, 80))	('counter up-regulation', 'MPA', (96, 117))	('MDM2', 'Gene', (121, 125))
511136	30045945	The combination of ATSP-7041 with GSK2830371 increases the level of pSer15 p53 more than with either molecule alone.	('level', 'MPA', (59, 64))	('increases', 'PosReg', (45, 54))	('GSK2830371', 'Chemical', 'MESH:C587624', (34, 44))	('ATSP-7041', 'Chemical', 'MESH:C584947', (19, 28))	('pSer15 p53', 'MPA', (68, 78))	('GSK2830371', 'Var', (34, 44))	('combination', 'Interaction', (4, 15))	('ATSP-7041', 'Var', (19, 28))
511137	30045945	Based on our findings that inhibitors of these targets have synergistic anti-cancer activity, we suggest that systematic analysis of correlated dependencies in genetic screens can inform new, effective, and potentially rapidly translatable drug combinations.	('inhibitors', 'Var', (27, 37))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
511140	30045945	Here, we show that in Ewing sarcoma a key target of USP7 is the p53 pathway, as demonstrated by TP53 knockout experiments and the notable synergism of ATSP-7041 and P5091.	('P5091', 'Chemical', 'MESH:C576408', (165, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('synergism', 'Reg', (138, 147))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (22, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (22, 35))	('P5091', 'Var', (165, 170))	('p53 pathway', 'Pathway', (64, 75))	('ATSP-7041', 'Chemical', 'MESH:C584947', (151, 160))	('Ewing sarcoma', 'Disease', (22, 35))
511144	30045945	While the phosphatase has been shown to target a variety of proteins in different disease contexts, it appears to act through p53 in Ewing sarcoma, as indicated by TP53 knockout experiments and the synergistic elevation of phosphorylated p53 at serine 15 when GSK2830371 was combined with ATSP-7041.	('serine', 'Chemical', 'MESH:D012694', (245, 251))	('phosphorylated', 'MPA', (223, 237))	('GSK2830371', 'Chemical', 'MESH:C587624', (260, 270))	('ATSP-7041', 'Chemical', 'MESH:C584947', (289, 298))	('Ewing sarcoma', 'Disease', (133, 146))	('GSK2830371', 'Var', (260, 270))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (133, 146))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (133, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('elevation', 'PosReg', (210, 219))
511156	30045945	RG7388 (ApexBio Technology), GSK2830371 (Selleck Chemicals), P5091 (Sigma-Aldrich), doxorubicin (Cell Signaling), etoposide (Selleck Chemicals), and vincristine (Selleck Chemicals) were solubilized in DMSO.	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('GSK2830371', 'Var', (29, 39))	('P5091', 'Var', (61, 66))	('etoposide', 'Chemical', 'MESH:D005047', (114, 123))	('DMSO', 'Chemical', 'MESH:D004121', (201, 205))	('doxorubicin', 'MPA', (84, 95))	('vincristine', 'Chemical', 'MESH:D014750', (149, 160))	('etoposide', 'MPA', (114, 123))	('P5091', 'Chemical', 'MESH:C576408', (61, 66))	('GSK2830371', 'Chemical', 'MESH:C587624', (29, 39))
511161	30045945	Primary antibodies used included anti-MDM2 (ab178938; Abcam), anti-MDM2 (86934; Cell Signaling), anti-MDM4 (A300-287A; Bethyl Laboratories), anti-p53 (2527S; Cell Signaling), anti-p21 (2946S; Cell Signaling), anti-Vinculin (18058; Abcam), anti-Wip1 (A300-664A; Bethyl Laboratories), anti-pSer15-p53 (9284; Cell Signaling), anti-USP7 (A300-033A; Bethyl Laboratories), and anti-Tubulin (cp06; CalBiochem).	('anti-p21', 'Var', (175, 183))	('A300-664A', 'Var', (250, 259))	('anti-Wip1', 'Var', (239, 248))	('9284', 'Var', (300, 304))	('Vinculin', 'Gene', (214, 222))	('anti-MDM4', 'Var', (97, 106))	('Vinculin', 'Gene', '7414', (214, 222))	('A300-033A', 'Var', (334, 343))
511162	30045945	Viability assays were performed after Ewing sarcoma cell lines were infected with sgRNAs targeting TP53, MDM2, MDM4, PPM1D, or USP7 or treated with ATSP-7041, ATSP-7342, GSK2830371, P5091, XL-188, or vehicle control.	('ATSP-7041', 'Chemical', 'MESH:C584947', (148, 157))	('PPM1D', 'Var', (117, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('MDM4', 'Var', (111, 115))	('GSK2830371', 'Var', (170, 180))	('sgRNAs', 'Gene', (82, 88))	('ATSP', 'Chemical', '-', (148, 152))	('ATSP', 'Chemical', '-', (159, 163))	('P5091', 'Chemical', 'MESH:C576408', (182, 187))	('Ewing sarcoma', 'Disease', (38, 51))	('TP53', 'Var', (99, 103))	('XL-188', 'Chemical', '-', (189, 195))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('MDM2', 'Var', (105, 109))	('targeting TP53', 'Var', (89, 103))	('P5091', 'Var', (182, 187))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))	('GSK2830371', 'Chemical', 'MESH:C587624', (170, 180))
511164	30045945	Ewing sarcoma cells lines were assessed for induction of cell death after 2 d of treatment with ATSP-7041 or P5091, or after 3 d of treatment with GSK2830371.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('GSK2830371', 'Chemical', 'MESH:C587624', (147, 157))	('Ewing sarcoma', 'Disease', (0, 13))	('ATSP-7041', 'Var', (96, 105))	('P5091', 'Var', (109, 114))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('ATSP-7041', 'Chemical', 'MESH:C584947', (96, 105))	('P5091', 'Chemical', 'MESH:C576408', (109, 114))
511167	30045945	TaqMan probes included RPL13A (Hs04194366_g1; ThermoFisher Scientific), CDKN1A (Hs00355782_m1; Thermo Fisher Scientific), and MDM2 (Hs01066930_m1; ThermoFisher Scientific).	('Hs01066930_m1', 'Var', (132, 145))	('Hs04194366_g1;', 'Var', (31, 45))	('RPL13A', 'Gene', '23521', (23, 29))	('CDKN1A', 'Gene', (72, 78))	('RPL13A', 'Gene', (23, 29))	('CDKN1A', 'Gene', '1026', (72, 78))	('Hs00355782_m1', 'Var', (80, 93))
511329	21160411	Our results were consistent with another recent study of survival after NHL that directly compared those with and without HIV-infection in the cART era and found 40% 2-year survival for patients with HIV and 70% for those without HIV.	('HIV', 'Var', (200, 203))	('HIV-infection', 'Disease', 'MESH:D015658', (122, 135))	('patients', 'Species', '9606', (186, 194))	('HIV-infection', 'Disease', (122, 135))
511431	32493236	Age >= 40 years old (OR 2.826, 95%CI 1.326-5.461), tumor size >=7 cm (OR 6.930, 95% CI 2.872-16.724), neutrophil-to-lymphocyte ratio (NLR) >= 2.8 (OR 3.032, 95%CI 1.288-7.13), number of platelet >=298 x 109/L (OR 3.688, 95%CI 1.452-9.266) and lactate dehydrogenase (LDH) >= 193 U/L (OR 6.479, 95%CI 2.658-15.792) were independent predictors of ULMS.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lactate', 'Chemical', 'MESH:D019344', (243, 250))	('tumor', 'Disease', (51, 56))	('>= 193', 'Var', (271, 277))	('ULMS', 'Disease', (344, 348))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
511432	32493236	Age >= 40 years old, tumor size >=7 cm, LDH >= 193 U/L, NLR >= 2.8 and number of platelet >=298 x 109/L were independent predictors of ULMS.	('>= 193', 'Var', (44, 50))	('tumor', 'Disease', (21, 26))	('ULMS', 'Disease', (135, 139))	('LDH', 'MPA', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
511436	32493236	Morcellation may lead to intraperitoneal spread of tumor cells, thus making prognosis of undiagnosed ULMS patients worse.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ULMS', 'Disease', (101, 105))	('lead to', 'Reg', (17, 24))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (106, 114))	('Morcellation', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
511452	32493236	The cutoff value of each factor was determined according to ROC curves, with age >= 40 years old, tumor size >=7 cm, LDH >= 193 U/L, NLR >= 2.8 and number of platelet >=298 x 109/L.	('>= 193 U/L', 'Var', (121, 131))	('LDH', 'MPA', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('>=7', 'Var', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
511509	28683124	Furthermore, hybrid reconstruction is demonstrated to enhance spatial resolution within material decomposition results and to improve low-contrast detectability by as much as 2.6 times relative to reconstruction with PCD data only.	('spatial resolution', 'MPA', (62, 80))	('improve', 'PosReg', (126, 133))	('PCD', 'Chemical', '-', (217, 220))	('low-contrast detectability', 'MPA', (134, 160))	('low-contrast detectability', 'Phenotype', 'HP:0032109', (134, 160))	('enhance', 'PosReg', (54, 61))	('hybrid', 'Var', (13, 19))
511583	28683124	Redefining the data fidelity terms (Eq 1) as a function of xL,e and xS,e, f(xL,e,xS,e), we introduce rank and sparsity constraints on the solution to the hybrid reconstruction problem:    XL  * denotes the nuclear norm, or the sum of singular values of the matrix XL, which is a convex proxy for column rank.	('Eq 1', 'Gene', (36, 40))	('Eq 1', 'Gene', '56429', (36, 40))	('XL  *', 'Var', (188, 193))
511680	28683124	With respect to the Gaussian kernels used to approximate the point spread function in the algebraic forward model (Hybrid data fidelity sub-section), this yielded the following parameter values: FWHMPCD = 0.254 mm; FWHMEID = 0.176 mm; sigmar = 0.078 mm.	('EID', 'Chemical', '-', (219, 222))	('PCD', 'Chemical', '-', (199, 202))	('FWHMEID = 0.176 mm', 'Var', (215, 233))	('FWHMPCD = 0.254 mm', 'Var', (195, 213))
511727	28683124	Given these changes, the purpose of the PCD only control experiment is to establish a base-line for the resolution enhancement and denoising performance improvements afforded by the incorporation of EID data into the PCD reconstruction problem.	('resolution', 'MPA', (104, 114))	('improvements', 'PosReg', (153, 165))	('PCD', 'Chemical', '-', (40, 43))	('enhancement', 'PosReg', (115, 126))	('PCD', 'Chemical', '-', (217, 220))	('EID', 'Chemical', '-', (199, 202))	('denoising', 'MPA', (131, 140))	('changes', 'Var', (12, 19))
511730	28683124	The in vivo experiment was conducted in an adult mouse model of soft-tissue sarcoma (LSL-KrasG12D/+Trp53FL/FL conditional mutants) with sarcoma tumor growth initiated by intramuscular injection of adenovirus expressing Cre recombinase (see).	('mutants', 'Var', (122, 129))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (64, 83))	('mouse', 'Species', '10090', (49, 54))	('sarcoma tumor', 'Disease', 'MESH:D012509', (136, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcoma tumor', 'Disease', (136, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (64, 83))	('soft-tissue sarcoma', 'Disease', (64, 83))
511798	28683124	Comparing the PCD only results with the hybrid results, an artifact is seen in the iodine map of the hybrid decomposition which is not present in the PCD only decomposition (2).	('iodine map', 'MPA', (83, 93))	('PCD', 'Chemical', '-', (14, 17))	('iodine', 'Chemical', 'MESH:D007455', (83, 89))	('hybrid', 'Var', (101, 107))	('PCD', 'Chemical', '-', (150, 153))
511906	22408374	Consequently, HAT inactivation has been associated with tumorigenesis and aberrant HDAC activity has been related to the development and maintenance of human tumors, including CTCL.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HDAC', 'Gene', (83, 87))	('human', 'Species', '9606', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('associated', 'Reg', (40, 50))	('tumors', 'Disease', (158, 164))	('CTCL', 'Gene', (176, 180))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('inactivation', 'Var', (18, 30))	('tumor', 'Disease', (56, 61))	('related', 'Reg', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (158, 163))	('HDAC', 'Gene', '9734', (83, 87))	('CTCL', 'Gene', '64061', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('CTCL', 'Phenotype', 'HP:0012192', (176, 180))	('aberrant', 'Var', (74, 82))
511909	22408374	Ecke and co-workers observed that combined 5-aza-2'deoxycytidine (a DNA methylation inhibitor) and valproic acid (a HDAC inhibitor) efficiently prevented medulloblastoma and rhabdomyosarcoma formation in patched mutant mice.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (174, 190))	('medulloblastoma', 'Disease', 'MESH:D008527', (154, 169))	('mutant', 'Var', (212, 218))	('prevented', 'NegReg', (144, 153))	('medulloblastoma', 'Phenotype', 'HP:0002885', (154, 169))	('mice', 'Species', '10090', (219, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (174, 190))	('rhabdomyosarcoma', 'Disease', (174, 190))	('medulloblastoma', 'Disease', (154, 169))	('HDAC', 'Gene', (116, 120))	('HDAC', 'Gene', '9734', (116, 120))
511912	22408374	While Sakimura and colleagues noted that depsipeptide inhibited chondrosarcoma cell growth, up-regulated the expression of aggrecan and alpha2 chain of type XI collagen (COL11A2) mRNA, and induced differentiation to a hypertrophic cell phenotype.	('inhibited', 'NegReg', (54, 63))	('expression', 'MPA', (109, 119))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (64, 78))	('depsipeptide', 'Chemical', 'MESH:D047630', (41, 53))	('depsipeptide', 'Var', (41, 53))	('COL11A2', 'Gene', '1302', (170, 177))	('hypertrophic', 'Disease', 'MESH:D006984', (218, 230))	('differentiation', 'CPA', (197, 212))	('hypertrophic cell', 'Phenotype', 'HP:0003712', (218, 235))	('up-regulated', 'PosReg', (92, 104))	('induced', 'Reg', (189, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('chondrosarcoma', 'Disease', 'MESH:D002813', (64, 78))	('COL11A2', 'Gene', (170, 177))	('chondrosarcoma', 'Disease', (64, 78))	('hypertrophic', 'Disease', (218, 230))
511949	32708128	Finally, patients with hemoglobin <12 g/dL had a shorter median survival time of 4.1 months (95% CI, 0.8-24.2) than that of patients with hemoglobin >=12 g/dL (21.8 months; 95% CI, 7.6-33.2; p = 0.001) (Figure S1f).	('patients', 'Species', '9606', (124, 132))	('patients', 'Species', '9606', (9, 17))	('shorter', 'NegReg', (49, 56))	('hemoglobin', 'Var', (23, 33))
512004	32708128	In our study population, the H-risk patients could be identified by the following clinical metabolic cut-off values: citrulline <= 33.7 microM, hemoglobin <= 12.4 g/dL and PS >= 1.	('<= 33.7', 'Var', (128, 135))	('patients', 'Species', '9606', (36, 44))	('citrulline', 'Chemical', 'MESH:D002956', (117, 127))	('citrulline', 'MPA', (117, 127))	('PS', 'Chemical', '-', (172, 174))	('hemoglobin', 'MPA', (144, 154))
512075	29480840	PNETs of the genital tract are rare; they can share some genetic rearrangements such as translocations involving the EWS-FLI1 genes, as in peripheral PNET or also CIC-DUX4.	('DUX4', 'Gene', '100288687', (167, 171))	('EWS', 'Gene', (117, 120))	('CIC', 'Gene', (163, 166))	('EWS', 'Gene', '2130', (117, 120))	('PNETs', 'Phenotype', 'HP:0030065', (0, 5))	('FLI1', 'Gene', (121, 125))	('FLI1', 'Gene', '2313', (121, 125))	('translocations', 'Var', (88, 102))	('peripheral PNET', 'Disease', (139, 154))	('CIC', 'Gene', '23152', (163, 166))	('DUX4', 'Gene', (167, 171))
512081	29480840	In the case series of uterine PNETs collected by Euscher et al, CD99 was positive in 7 of 9 cases tested for the marker; all 12 cases were tested for the typical EWSR1 rearrangement, but yielded negative results.	('tested', 'Reg', (139, 145))	('CD99', 'Gene', (64, 68))	('EWSR1', 'Gene', (162, 167))	('PNETs', 'Phenotype', 'HP:0030065', (30, 35))	('rearrangement', 'Var', (168, 181))	('CD99', 'Gene', '4267', (64, 68))	('EWSR1', 'Gene', '2130', (162, 167))
512105	29480840	The new immunohistochemistry is also summarized in Table 2; FISH (fluorescence in situ hybridization) study demonstrated negativity for EWS (Ewing sarcoma), a 22q12 translocation, WT1, and CIC rearrangement (with BAC Bacteria Artificial Chromosome probe library RP11).	('Ewing sarcoma', 'Gene', '2130', (141, 154))	('22q12 translocation', 'Var', (159, 178))	('CIC', 'Gene', (189, 192))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (141, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('WT1', 'Gene', '7490', (180, 183))	('CIC', 'Gene', '23152', (189, 192))	('Ewing sarcoma', 'Gene', (141, 154))	('rearrangement', 'Var', (193, 206))	('WT1', 'Gene', (180, 183))	('EWS', 'Gene', '2130', (136, 139))	('EWS', 'Gene', (136, 139))
512121	29480840	EWSR1 can often form a chimeric couple with FLI 1 (11q24) (85%) or ERG (21q22) (5-10%).	('11q24', 'Var', (51, 56))	('EWSR1', 'Gene', '2130', (0, 5))	('ERG', 'Var', (67, 70))	('FLI 1', 'Gene', (44, 49))	('EWSR1', 'Gene', (0, 5))	('form', 'Reg', (16, 20))	('FLI 1', 'Gene', '2313', (44, 49))
512130	29480840	Most MRTs, including tumors arising in the brain, called atypical teratoid/rhabdoid tumors [AT/RTs], host inactivating mutations in SMARCB1 (INI-1; SNF5; BAF47).	('SMARCB1', 'Gene', (132, 139))	('SMARCB1', 'Gene', '6598', (132, 139))	('SNF5', 'Gene', (148, 152))	('AT', 'Disease', 'None', (92, 94))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('BAF47', 'Gene', '6598', (154, 159))	('inactivating mutations', 'Var', (106, 128))	('rhabdoid tumors', 'Disease', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (75, 90))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumors', 'Disease', (21, 27))	('SNF5', 'Gene', '6598', (148, 152))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('BAF47', 'Gene', (154, 159))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('INI-1', 'Gene', '6598', (141, 146))	('INI-1', 'Gene', (141, 146))
512131	29480840	Other MRTs of the ovaries, without the SMARCB1 alteration, harbor a similar mutation involving the SMARCA4 gene (also called BRG1) as also occurs in SCCOHT, so both can be denominated MRTOs.	('SMARCA4', 'Gene', (99, 106))	('SMARCA4', 'Gene', '6597', (99, 106))	('BRG1', 'Gene', '6597', (125, 129))	('SMARCB1', 'Gene', '6598', (39, 46))	('ovaries', 'Disease', 'MESH:D010051', (18, 25))	('SMARCB1', 'Gene', (39, 46))	('ovaries', 'Disease', (18, 25))	('mutation', 'Var', (76, 84))	('BRG1', 'Gene', (125, 129))
512216	27267837	RESULTS: The growth of patient derived tumor cells was significantly reduced by exposure to 1.0 muM AZD2014 compared with control (control versus AZD2014, mean growth = 100.0% vs 16.04%, difference = 83.96%, 95% CI = 70.01% to 97.92%, P = .0435).	('AZD2014', 'Var', (100, 107))	('muM', 'Gene', '56925', (96, 99))	('reduced', 'NegReg', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('AZD2014', 'Chemical', 'MESH:C585537', (100, 107))	('AZD2014', 'Chemical', 'MESH:C585537', (146, 153))	('muM', 'Gene', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('growth', 'CPA', (13, 19))	('patient', 'Species', '9606', (23, 30))
512217	27267837	Similarly, 1.0 muM BEZ235 profoundly inhibited tumor cell growth in vitro when compared to control (control versus BEZ235, mean growth = 100.0% vs 7.308%, difference = 92.69%, 95% CI = 78.87% to 106.5%, P < .0001).	('muM', 'Gene', (15, 18))	('BEZ235', 'Chemical', 'MESH:C531198', (19, 25))	('inhibited', 'NegReg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('BEZ235', 'Chemical', 'MESH:C531198', (115, 121))	('muM', 'Gene', '56925', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BEZ235', 'Var', (19, 25))	('tumor', 'Disease', (47, 52))
512218	27267837	Despite the presence of CDK4 amplification in the patient-derived tumor cells, LEE011 did not considerably inhibit cell proliferation when compared with control (control vs LEE011, mean growth = 100.0% vs 80.23%, difference = 19.77%, 95% CI = 1.828% to 37.72%, P = .0377).	('inhibit', 'NegReg', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('amplification', 'Var', (29, 42))	('LEE011', 'Var', (79, 85))	('tumor', 'Disease', (66, 71))	('cell proliferation', 'CPA', (115, 133))	('LEE011', 'Chemical', 'MESH:C000589651', (79, 85))	('CDK4', 'Gene', '1019', (24, 28))	('CDK4', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('LEE011', 'Chemical', 'MESH:C000589651', (173, 179))	('patient', 'Species', '9606', (50, 57))
512219	27267837	The immunoblot analysis showed that BEZ235 treatment decreased pAKT, pmTOR and pERK whereas AZD2014 decreased only pmTOR.	('BEZ235', 'Chemical', 'MESH:C531198', (36, 42))	('mTOR', 'Gene', (70, 74))	('mTOR', 'Gene', '2475', (70, 74))	('pERK', 'Gene', (79, 83))	('AKT', 'Gene', '207', (64, 67))	('pERK', 'Gene', '9451', (79, 83))	('mTOR', 'Gene', (116, 120))	('AZD2014', 'Chemical', 'MESH:C585537', (92, 99))	('mTOR', 'Gene', '2475', (116, 120))	('decreased', 'NegReg', (53, 62))	('AKT', 'Gene', (64, 67))	('BEZ235', 'Var', (36, 42))
512220	27267837	CONCLUSION: Taken together, upregulation of mTOR/AKT pathway in sarcoma patient derived cells was considerably inhibited by the treatment of AZD2014 and BEZ235 with downregulation of AKT pathway (greater extent for BEZ235).	('AKT', 'Gene', (49, 52))	('AZD2014', 'Var', (141, 148))	('AZD2014', 'Chemical', 'MESH:C585537', (141, 148))	('AKT', 'Gene', (183, 186))	('mTOR', 'Gene', (44, 48))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('patient', 'Species', '9606', (72, 79))	('downregulation', 'NegReg', (165, 179))	('mTOR', 'Gene', '2475', (44, 48))	('BEZ235', 'Var', (153, 159))	('sarcoma', 'Disease', (64, 71))	('inhibited', 'NegReg', (111, 120))	('AKT', 'Gene', '207', (49, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('BEZ235', 'Chemical', 'MESH:C531198', (153, 159))	('BEZ235', 'Chemical', 'MESH:C531198', (215, 221))	('upregulation', 'PosReg', (28, 40))	('AKT', 'Gene', '207', (183, 186))
512250	27267837	Thirty micrograms of proteins were subjected to sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis on 10% gels and then electrotransferred to nitrocellulose membranes incubated with the following specific antibodies: Cyclin D1 (sc-718) (M-20) from Santa Cruz (USA) and PI3K (#4255) (p110alpha), phospho-mTOR (#2971) (Ser2448), mTOR (#2983) (7C10), phospho-Akt (#4060) (Ser473), Akt (#9272), phospho-ERK1/2 (#4370) (Thr202/Tyr204), ERK1/2 (#9102) from Cell Signaling Technologies (Beverly, MA, USA).	('mTOR', 'Gene', '2475', (316, 320))	('Cyclin D1', 'Gene', '595', (230, 239))	('Cyclin D1', 'Gene', (230, 239))	('#2983', 'Var', (346, 351))	('Ser473', 'Var', (382, 388))	('#9102', 'Var', (452, 457))	('Akt', 'Gene', (369, 372))	('#4370) (Thr202/Tyr204', 'Var', (420, 441))	('Akt', 'Gene', (391, 394))	('p110alpha', 'Gene', (296, 305))	('p110alpha', 'Gene', '5290', (296, 305))	('mTOR', 'Gene', (340, 344))	('Akt', 'Gene', '207', (369, 372))	('mTOR', 'Gene', (316, 320))	('Thr202/Tyr204', 'Var', (428, 441))	('Akt', 'Gene', '207', (391, 394))	('#4060) (Ser473', 'Var', (374, 388))	('mTOR', 'Gene', '2475', (340, 344))	('#9272', 'Var', (396, 401))
512267	27267837	Based on the initial results from 3-dimentionsal multi-drug testing, we tested the anti-tumor effect of AZD2014 (TORC1/TORC2 inhibitor), BEZ235 (mTOR/PIK3 inhibitor), lapatinib (HER1, HER2 inhibitor), LEE011 (CDK4 inhibitor), pazopanib which showed IC 50 less than 3.0 muM, in vitro cell viability assay.	('PIK3', 'Gene', (150, 154))	('BEZ235', 'Chemical', 'MESH:C531198', (137, 143))	('HER2', 'Gene', '2064', (184, 188))	('pazopanib', 'Chemical', 'MESH:C516667', (226, 235))	('PIK3', 'Gene', '5294', (150, 154))	('AZD2014', 'Gene', (104, 111))	('TORC1', 'Gene', '23373', (113, 118))	('LEE011', 'Chemical', 'MESH:C000589651', (201, 207))	('AZD2014', 'Chemical', 'MESH:C585537', (104, 111))	('mTOR', 'Gene', (145, 149))	('HER1', 'Gene', (178, 182))	('CDK4', 'Gene', (209, 213))	('tumor', 'Disease', (88, 93))	('HER2', 'Gene', (184, 188))	('TORC2', 'Gene', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('muM', 'Gene', '56925', (269, 272))	('mTOR', 'Gene', '2475', (145, 149))	('muM', 'Gene', (269, 272))	('CDK4', 'Gene', '1019', (209, 213))	('lapatinib', 'Chemical', 'MESH:D000077341', (167, 176))	('TORC1', 'Gene', (113, 118))	('TORC2', 'Gene', '200186', (119, 124))	('HER1', 'Gene', '1956', (178, 182))	('LEE011', 'Var', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tested', 'Reg', (72, 78))
512268	27267837	In accordance to the results from the 3-dimensional culture assay, we confirmed that the cells were very sensitive to AZD2014 and BEZ235 while the cells were relatively resistant to lapatinib, LEE011 and pazopanib.	('BEZ235', 'Chemical', 'MESH:C531198', (130, 136))	('lapatinib', 'Chemical', 'MESH:D000077341', (182, 191))	('AZD2014', 'Var', (118, 125))	('AZD2014', 'Chemical', 'MESH:C585537', (118, 125))	('pazopanib', 'Chemical', 'MESH:C516667', (204, 213))	('BEZ235', 'Var', (130, 136))	('LEE011', 'Chemical', 'MESH:C000589651', (193, 199))
512269	27267837	The growth of tumor cells was significantly reduced by exposure to 1.0 muM AZD2014 compared with control (control versus AZD2014, mean growth = 100.0% vs 16.04%, difference = 83.96%, 95% CI = 70.01% to 97.92%, P = .0435).	('muM', 'Gene', (71, 74))	('tumor', 'Disease', (14, 19))	('AZD2014', 'Chemical', 'MESH:C585537', (121, 128))	('AZD2014', 'Var', (75, 82))	('AZD2014', 'Chemical', 'MESH:C585537', (75, 82))	('reduced', 'NegReg', (44, 51))	('muM', 'Gene', '56925', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
512270	27267837	In contrast, despite of the presence of CDK4 amplification (Table 1) in the patient-derived tumor cells, LEE011 did not considerably inhibit cell proliferation when compared with control (control versus LEE011, mean growth = 100.0% vs 80.23%, difference = 19.77%, 95% CI = 1.828% to 37.72%, P = .0377).	('LEE011', 'Var', (105, 111))	('CDK4', 'Gene', (40, 44))	('LEE011', 'Chemical', 'MESH:C000589651', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('CDK4', 'Gene', '1019', (40, 44))	('LEE011', 'Chemical', 'MESH:C000589651', (203, 209))	('inhibit', 'NegReg', (133, 140))	('cell proliferation', 'CPA', (141, 159))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('patient', 'Species', '9606', (76, 83))
512272	27267837	AZD2014, a pharmacologically much "cleaner" TORC1/TORC2 inhibitor, also down-regulated pmTOR and PI3K but not pAKT.	('TORC2', 'Gene', (50, 55))	('AKT', 'Gene', '207', (111, 114))	('TORC2', 'Gene', '200186', (50, 55))	('mTOR', 'Gene', (88, 92))	('down-regulated', 'NegReg', (72, 86))	('AZD2014', 'Chemical', 'MESH:C585537', (0, 7))	('mTOR', 'Gene', '2475', (88, 92))	('AKT', 'Gene', (111, 114))	('TORC1', 'Gene', '23373', (44, 49))	('AZD2014', 'Var', (0, 7))	('TORC1', 'Gene', (44, 49))
512273	27267837	Upon exposure to AZD2014 and BEZ235, cyclin D1 was virtually undetectable whereas lapatinib, LEE011 and pazopanib did not have any effect on its expression.	('undetectable', 'NegReg', (61, 73))	('cyclin D1', 'Gene', '595', (37, 46))	('cyclin D1', 'Gene', (37, 46))	('BEZ235', 'Var', (29, 35))	('AZD2014', 'Chemical', 'MESH:C585537', (17, 24))	('pazopanib', 'Chemical', 'MESH:C516667', (104, 113))	('lapatinib', 'Chemical', 'MESH:D000077341', (82, 91))	('BEZ235', 'Chemical', 'MESH:C531198', (29, 35))	('AZD2014', 'Var', (17, 24))	('LEE011', 'Chemical', 'MESH:C000589651', (93, 99))
512274	27267837	Taken together, upregulation of mTOR/AKT pathway in pazopanib-resistant tumor derived cells was considerably inhibited by the treatment of AZD2014 and BEZ235 with downregulation of AKT pathway (greater extent for BEZ235).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('BEZ235', 'Var', (151, 157))	('BEZ235', 'Chemical', 'MESH:C531198', (213, 219))	('AKT', 'Gene', (181, 184))	('tumor', 'Disease', (72, 77))	('upregulation', 'PosReg', (16, 28))	('AKT', 'Gene', '207', (37, 40))	('inhibited', 'NegReg', (109, 118))	('BEZ235', 'Chemical', 'MESH:C531198', (151, 157))	('mTOR', 'Gene', (32, 36))	('AZD2014', 'Var', (139, 146))	('mTOR', 'Gene', '2475', (32, 36))	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('AKT', 'Gene', '207', (181, 184))	('AKT', 'Gene', (37, 40))	('AZD2014', 'Chemical', 'MESH:C585537', (139, 146))	('downregulation', 'NegReg', (163, 177))
512275	27267837	In contrast, LEE011 did not have significant inhibitory effect on CDK4-amplified sarcoma cells in this particular case.	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('LEE011', 'Chemical', 'MESH:C000589651', (13, 19))	('sarcoma', 'Disease', (81, 88))	('CDK4', 'Gene', (66, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('LEE011', 'Var', (13, 19))	('CDK4', 'Gene', '1019', (66, 70))
512279	27267837	The genomic profiling of these cells using targeted deep sequencing showed FGFR1 (N457K), PIK3R1 (M56I), BRCA1 (Q309R) mutations and CDK4/MDM2/KIT amplifications and a PTEN deletion (Table 1).	('BRCA1', 'Gene', (105, 110))	('PTEN', 'Gene', (168, 172))	('deletion', 'Var', (173, 181))	('FGFR1', 'Gene', (75, 80))	('N457K', 'Mutation', 'rs779707422', (82, 87))	('PTEN', 'Gene', '5728', (168, 172))	('PIK3R1', 'Gene', '5295', (90, 96))	('CDK4', 'Gene', (133, 137))	('FGFR1', 'Gene', '2260', (75, 80))	('PIK3R1', 'Gene', (90, 96))	('Q309R) mutations', 'Var', (112, 128))	('CDK4', 'Gene', '1019', (133, 137))	('MDM2', 'Gene', '4193', (138, 142))	('M56I', 'Mutation', 'rs3730089', (98, 102))	('BRCA1', 'Gene', '672', (105, 110))	('MDM2', 'Gene', (138, 142))	('Q309R', 'Mutation', 'rs1799950', (112, 117))
512283	27267837	The AKT pathway was significantly downregulated upon drug treatment with AZD2014 or BEZ235.	('AKT', 'Gene', (4, 7))	('downregulated', 'NegReg', (34, 47))	('AKT', 'Gene', '207', (4, 7))	('AZD2014', 'Var', (73, 80))	('AZD2014', 'Chemical', 'MESH:C585537', (73, 80))	('BEZ235', 'Chemical', 'MESH:C531198', (84, 90))	('BEZ235', 'Var', (84, 90))
512287	27267837	Moreover, BEZ235 also inhibits mTOR catalytic activity .	('mTOR', 'Gene', (31, 35))	('mTOR', 'Gene', '2475', (31, 35))	('BEZ235', 'Chemical', 'MESH:C531198', (10, 16))	('BEZ235', 'Var', (10, 16))	('inhibits', 'NegReg', (22, 30))
512290	27267837	In contrast, AZD2014 is a highly specific mTORC1 and mTORC2 inhibitor.	('mTORC2', 'Gene', (53, 59))	('AZD2014', 'Chemical', 'MESH:C585537', (13, 20))	('mTORC2', 'Gene', '74343', (53, 59))	('mTORC1', 'Gene', '382056', (42, 48))	('mTORC1', 'Gene', (42, 48))	('AZD2014', 'Var', (13, 20))
512293	27267837	We have sequenced the PDX models generated from PDCs with targeted sequencing and found FGFR1 (N457K), PIK3R1 (M56I), BRCA1 (Q309R) mutations, which are currently not reported to be associated with AKT pathway activation.	('Q309R) mutations', 'Var', (125, 141))	('FGFR1', 'Gene', (88, 93))	('FGFR1', 'Gene', '2260', (88, 93))	('M56I', 'Mutation', 'rs3730089', (111, 115))	('PIK3R1', 'Gene', '5295', (103, 109))	('mutations', 'Var', (132, 141))	('N457K', 'Mutation', 'rs779707422', (95, 100))	('PIK3R1', 'Gene', (103, 109))	('Q309R', 'Mutation', 'rs1799950', (125, 130))	('BRCA1', 'Gene', '672', (118, 123))	('AKT', 'Gene', '207', (198, 201))	('N457K', 'Var', (95, 100))	('BRCA1', 'Gene', (118, 123))	('AKT', 'Gene', (198, 201))
512296	27267837	Recently, a phase II trial of the CDK4 inhibitor PD0332991 in patients with CDK4-amplified liposarcoma have shown a progression free survival at 12 weeks to be 66% and one partial response.	('CDK4', 'Gene', '1019', (76, 80))	('CDK4', 'Gene', (76, 80))	('liposarcoma', 'Disease', (91, 102))	('PD0332991', 'Chemical', 'MESH:C500026', (49, 58))	('liposarcoma', 'Disease', 'MESH:D008080', (91, 102))	('PD0332991', 'Var', (49, 58))	('liposarcoma', 'Phenotype', 'HP:0012034', (91, 102))	('CDK4', 'Gene', (34, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('patients', 'Species', '9606', (62, 70))	('CDK4', 'Gene', '1019', (34, 38))
512297	27267837	In our cell line model with CDK4 amplification, the activity of CDK4 inhibitor was modest.	('CDK4', 'Gene', '1019', (28, 32))	('CDK4', 'Gene', (64, 68))	('amplification', 'Var', (33, 46))	('activity', 'MPA', (52, 60))	('CDK4', 'Gene', '1019', (64, 68))	('CDK4', 'Gene', (28, 32))
512300	27267837	Taken together, the mTOR/AKT pathway in pazopanib-resistant tumor derived cells was considerably inhibited by the treatment with AZD2014 or BEZ235 with downregulation of AKT pathway (to a greater extent for BEZ235).	('AKT', 'Gene', (25, 28))	('pazopanib', 'Chemical', 'MESH:C516667', (40, 49))	('downregulation', 'NegReg', (152, 166))	('mTOR', 'Gene', '2475', (20, 24))	('BEZ235', 'Chemical', 'MESH:C531198', (140, 146))	('AKT', 'Gene', '207', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('BEZ235', 'Chemical', 'MESH:C531198', (207, 213))	('AZD2014', 'Chemical', 'MESH:C585537', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('AKT', 'Gene', (170, 173))	('AKT', 'Gene', '207', (25, 28))	('inhibited', 'NegReg', (97, 106))	('AZD2014', 'Var', (129, 136))	('tumor', 'Disease', (60, 65))	('BEZ235', 'Var', (140, 146))	('mTOR', 'Gene', (20, 24))
512339	21092139	Besides making the readership aware of the rarity of location and age of this present case, this report distinctly highlights the great value of a molecular analysis of an SYT associated genetic alteration in the diagnosis of synovial sarcoma occurring at rare sites especially when immunochemical results are equivocal.	('SYT', 'Gene', '6760', (172, 175))	('synovial sarcoma', 'Disease', (226, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (226, 242))	('genetic alteration', 'Var', (187, 205))	('SYT', 'Gene', (172, 175))	('synovial sarcoma', 'Disease', 'MESH:D013584', (226, 242))
512341	21092139	The detection of a reciprocal translocation between chromosomes X and 18 t(X:18) has led to the identification of an SS18 gene(also known as SYT) rearrangement being involved in the formation of a SYT-SSX fusion protein in synovial sarcomas.	('SYT', 'Gene', (141, 144))	('SSX', 'Gene', (201, 204))	('SYT', 'Gene', (197, 200))	('SS', 'Phenotype', 'HP:0012570', (201, 203))	('SYT', 'Gene', '6760', (141, 144))	('SS', 'Phenotype', 'HP:0012570', (117, 119))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (223, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('SSX', 'Gene', '6757', (201, 204))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (223, 239))	('SS18', 'Gene', '6760', (117, 121))	('rearrangement', 'Var', (146, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (232, 240))	('synovial sarcomas', 'Disease', 'MESH:D013584', (223, 240))	('involved', 'Reg', (166, 174))	('synovial sarcomas', 'Disease', (223, 240))	('SYT', 'Gene', '6760', (197, 200))	('SS18', 'Gene', (117, 121))
512417	20403160	For all sarcoma types with mutation, a molecular biology was systematically assessed (FISH technic, PCR or DNA sequencing) to characterize the genetic alteration and confirm the diagnose.	('mutation', 'Var', (27, 35))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('sarcoma', 'Disease', (8, 15))
512440	20403160	The most frequent discrepancy was related to the grade of the tumor: either no grading by the diagnostic pathologist while the expert attributed grade 3 (n = 33, 20%), or misinterpretation of the grading with grade 3 attributed by the diagnostic pathologist and grade 1 by the expert (n = 3, 2%).	('misinterpretation', 'Var', (171, 188))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
512564	23249693	A role for the CXCR4-CXCL12 axis in Ewing sarcoma growth was suggested by our observations that i) CXCR4 expression correlated positively with tumor volume at diagnosis (p = 0.013), ii) CXCL12 was present within the microenvironment of virtually all cases, iii) CXCL12 induced proliferation of CXCR4-positive Ewing sarcoma cell lines, which could be abrogated by AMD3100.	('CXCR4', 'Gene', '7852', (15, 20))	('tumor', 'Disease', (143, 148))	('CXCR4', 'Gene', '7852', (294, 299))	('CXCR4', 'Gene', '7852', (99, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('CXCR4', 'Gene', (15, 20))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('CXCR4', 'Gene', (99, 104))	('CXCR4', 'Gene', (294, 299))	('sarcoma', 'Phenotype', 'HP:0100242', (315, 322))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (309, 322))	('CXCL12', 'Var', (262, 268))	('proliferation', 'CPA', (277, 290))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
512582	23249693	Recently, high CXCR4 gene expression was reported to associate with metastatic phenotype in EWS  .	('CXCR4', 'Gene', '7852', (15, 20))	('CXCR4', 'Gene', (15, 20))	('associate', 'Reg', (53, 62))	('high', 'Var', (10, 14))	('metastatic phenotype', 'CPA', (68, 88))
512583	23249693	Moreover, CXCL12 has been demonstrated to contribute to neovascularization and EWS tumor growth in a mouse xenograft model  .	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('neovascularization', 'CPA', (56, 74))	('tumor', 'Disease', (83, 88))	('mouse', 'Species', '10090', (101, 106))	('CXCL12', 'Var', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
512623	23249693	As demonstrated in Figure  3D, stimulation with 100ng/ml CXCL12 for seven days significantly increased cell numbers in cell lines expressing substantial levels of constitutive CXCR4 (CADO-ES, EW3, IOR/BER; repeated measures ANOVA with Bonferroni's multiple comparison post hoc test, p < 0.001), whereas no effects were observed in cell lines with minimal levels of constitutive CXCR4 expression (SK-ES-1, SK-N-MC, STA-ET2.1).	('SK-N-MC', 'CellLine', 'CVCL:0530', (405, 412))	('CXCL12', 'Var', (57, 63))	('cell numbers', 'CPA', (103, 115))	('increased', 'PosReg', (93, 102))	('CXCR4', 'Gene', '7852', (378, 383))	('SK-ES', 'Chemical', '-', (396, 401))	('CXCR4', 'Gene', '7852', (176, 181))	('CADO-ES', 'Chemical', '-', (183, 190))	('STA', 'Chemical', 'MESH:C009695', (414, 417))	('CXCR4', 'Gene', (378, 383))	('CXCR4', 'Gene', (176, 181))
512658	23249693	Successful inhibition of EWS proliferation by AMD3100, one of several CXCR4-specific antagonists that are currently being evaluated for treatment of patients with both hematological and solid tumors   indicates that disruption of the CXCR4-CXCL12 axis may indeed interfere with EWS progression.	('EWS proliferation', 'CPA', (25, 42))	('interfere', 'NegReg', (263, 272))	('patients', 'Species', '9606', (149, 157))	('solid tumors', 'Disease', 'MESH:D009369', (186, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('EWS', 'Disease', (278, 281))	('inhibition', 'NegReg', (11, 21))	('CXCR4', 'Gene', '7852', (234, 239))	('disruption', 'Var', (216, 226))	('CXCR4', 'Gene', '7852', (70, 75))	('CXCR4', 'Gene', (234, 239))	('solid tumors', 'Disease', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('AMD3100', 'Gene', (46, 53))	('CXCR4', 'Gene', (70, 75))
512676	31871807	CCS can be differentiated from MM by molecular biology testing, such as RT-PCR and FISH, and by characteristic chromosomal abnormalities and the genetic translocation t(12;22)(q13;q12).	('t(12;22)(q13;q12', 'Var', (167, 183))	('CCS', 'Disease', (0, 3))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (167, 184))
512711	30606223	Furthermore, of interest, VLIUS increases tumor killing of chemotherapy drug trabectedin in a time dependent fashion.	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('VLIUS', 'Var', (26, 31))	('increases tumor', 'Disease', (32, 47))	('increases tumor', 'Disease', 'MESH:D009369', (32, 47))
512769	30606223	Of interest, despite the intrinsic peculiarity of each line, VLIUS significantly increases DNA delivery in tumor HT29 and HCT116 lines without any significant effect in normal cells (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('DNA delivery', 'MPA', (91, 103))	('VLIUS', 'Var', (61, 66))	('HT29', 'CellLine', 'CVCL:0320', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('increases', 'PosReg', (81, 90))
512780	30606223	In particular, US has been noted causing the process of sonoporation thus producing transient pores in the cancer cell membranes through which molecules are able to enter the cell.	('producing', 'Reg', (74, 83))	('pores', 'MPA', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('sonoporation', 'Var', (56, 68))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
512782	30606223	The underlying hypothesis is to deliver genetic materials into specific tumor sites sparing the non-targeted areas.	('tumor', 'Disease', (72, 77))	('genetic materials', 'Var', (40, 57))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))
512929	23799912	Therefore, the ADAM10-dependent cleavage of N-cadherin modulates cell-cell adhesion, as well as signal transduction.	('signal transduction', 'MPA', (96, 115))	('ADAM10', 'Gene', (15, 21))	('N-cadherin', 'Gene', '1000', (44, 54))	('modulates', 'Reg', (55, 64))	('cell-cell adhesion', 'CPA', (65, 83))	('cleavage', 'Var', (32, 40))	('ADAM10', 'Gene', '102', (15, 21))	('N-cadherin', 'Gene', (44, 54))
513011	23799912	In the present study, we confirmed that, poor overall survival was associated with high sN-CAD and high histological grade in the univariate analysis.	('high', 'Var', (99, 103))	('overall', 'MPA', (46, 53))	('poor', 'NegReg', (41, 45))	('sN-CAD', 'Chemical', '-', (88, 94))	('high', 'Var', (83, 87))
513039	20979627	ARTEMIS stabilizes the genome and modulates proliferative responses in multipotent mesenchymal cells Unrepaired DNA double-stranded breaks (DSBs) cause chromosomal rearrangements, loss of genetic information, neoplastic transformation or cell death.	('modulates', 'Reg', (34, 43))	('loss', 'NegReg', (180, 184))	('genetic', 'MPA', (188, 195))	('chromosomal rearrangements', 'CPA', (152, 178))	('DSBs', 'Chemical', '-', (140, 144))	('cell death', 'CPA', (238, 248))	('double-stranded breaks', 'Var', (116, 138))	('neoplastic transformation', 'CPA', (209, 234))
513041	20979627	NHEJ defects lead to severe combined immunodeficiency (SCID) and lymphoid cancer predisposition in both mice and humans.	('lymphoid cancer', 'Disease', (65, 80))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (21, 53))	('lymphoid cancer', 'Disease', 'MESH:D009369', (65, 80))	('mice', 'Species', '10090', (104, 108))	('lead to', 'Reg', (13, 20))	('humans', 'Species', '9606', (113, 119))	('immunodeficiency', 'Phenotype', 'HP:0002721', (37, 53))	('defects', 'Var', (5, 12))	('SCID', 'Disease', 'MESH:D053632', (55, 59))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (28, 53))	('SCID', 'Disease', (55, 59))	('immunodeficiency', 'Disease', 'MESH:D007153', (37, 53))	('NHEJ', 'Gene', (0, 4))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('immunodeficiency', 'Disease', (37, 53))	('SCID', 'Phenotype', 'HP:0004430', (55, 59))
513053	20979627	Mutations in Art underlie human radiosensitive severe combined immunodeficiency (RS-SCID) and SCID-A, primary immunodeficiencies associated with hypersensitivity to DNA-damaging agents and variable lymphoma predisposition.	('immunodeficiency', 'Phenotype', 'HP:0002721', (63, 79))	('associated', 'Reg', (129, 139))	('SCID', 'Disease', 'MESH:D053632', (84, 88))	('lymphoma', 'Disease', 'MESH:D008223', (198, 206))	('hypersensitivity', 'Disease', (145, 161))	('immunodeficiencies', 'Disease', 'MESH:D007153', (110, 128))	('SCID', 'Disease', (94, 98))	('human', 'Species', '9606', (26, 31))	('immunodeficiencies', 'Phenotype', 'HP:0002721', (110, 128))	('RS-SCID', 'Gene', '64421', (81, 88))	('SCID', 'Phenotype', 'HP:0004430', (94, 98))	('SCID', 'Disease', (84, 88))	('SCID', 'Phenotype', 'HP:0004430', (84, 88))	('hypersensitivity', 'Disease', 'MESH:D004342', (145, 161))	('Mutations', 'Var', (0, 9))	('lymphoma', 'Disease', (198, 206))	('immunodeficiency', 'Disease', (63, 79))	('lymphoma', 'Phenotype', 'HP:0002665', (198, 206))	('RS-SCID', 'Gene', (81, 88))	('immunodeficiencies', 'Disease', (110, 128))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (47, 79))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (54, 79))	('immunodeficiency', 'Disease', 'MESH:D007153', (63, 79))	('Art', 'Gene', (13, 16))	('SCID', 'Disease', 'MESH:D053632', (94, 98))
513058	20979627	Our previous data suggested that patients with mutations in Art or other NHEJ factors may also be at risk for a host of nonlymphoid cancers, especially sarcomas, even if the immunodeficiency can be corrected by bone marrow transplantation or gene therapy.	('host of nonlymphoid cancers', 'Disease', (112, 139))	('Art', 'Gene', (60, 63))	('patients', 'Species', '9606', (33, 41))	('NHEJ factors', 'Gene', (73, 85))	('sarcomas', 'Disease', 'MESH:D012509', (152, 160))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('sarcomas', 'Disease', (152, 160))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (123, 138))	('immunodeficiency', 'Phenotype', 'HP:0002721', (174, 190))	('immunodeficiency', 'Disease', 'MESH:D007153', (174, 190))	('risk', 'Reg', (101, 105))	('host of nonlymphoid cancers', 'Disease', 'MESH:D009369', (112, 139))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('immunodeficiency', 'Disease', (174, 190))
513062	20979627	In the context of a lymphoma study, we previously observed that deficiency for ARTEMIS in mice can be associated with increased incidence of certain nonlymphoid tumors, including sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('deficiency', 'Var', (64, 74))	('lymphoma', 'Disease', (20, 28))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('sarcomas', 'Disease', (179, 187))	('lymphoma', 'Disease', 'MESH:D008223', (20, 28))	('ARTEMIS', 'Gene', (79, 86))	('mice', 'Species', '10090', (90, 94))	('nonlymphoid tumors', 'Disease', 'MESH:D009369', (149, 167))	('lymphoma', 'Phenotype', 'HP:0002665', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('sarcomas', 'Disease', 'MESH:D012509', (179, 187))	('nonlymphoid tumors', 'Disease', (149, 167))
513065	20979627	Of the 750 ArtDelta/Delta Trp53Delta/+ mice, 46 (6.1%) developed tumors of any kind.	('Trp53', 'Gene', '22059', (26, 31))	('developed', 'PosReg', (55, 64))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('ArtDelta/Delta', 'Var', (11, 25))	('ArtDelta', 'Chemical', '-', (11, 19))	('mice', 'Species', '10090', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Trp53', 'Gene', (26, 31))
513066	20979627	This is similar to, but slightly lower than, the overall tumor incidence (17%) previously reported for ArtDelta/Delta Trp53Delta/+ mice.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ArtDelta/Delta', 'Var', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Trp53', 'Gene', (118, 123))	('mice', 'Species', '10090', (131, 135))	('tumor', 'Disease', (57, 62))	('ArtDelta', 'Chemical', '-', (103, 111))	('Trp53', 'Gene', '22059', (118, 123))
513069	20979627	Whereas the fraction of mice ultimately developing sarcomas was similar in our ArtDelta/Delta Trp53Delta/+ and Trp53Delta/+ control mice, a higher fraction of ArtDelta/Delta Trp53Delta/+ animals developed sarcomas over the initial 60-week observation period (Figure 1a).	('sarcomas', 'Disease', 'MESH:D012509', (205, 213))	('Trp53', 'Gene', (111, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (205, 213))	('Trp53', 'Gene', '22059', (174, 179))	('mice', 'Species', '10090', (132, 136))	('ArtDelta', 'Chemical', '-', (79, 87))	('Trp53', 'Gene', '22059', (94, 99))	('sarcomas', 'Disease', (205, 213))	('Trp53', 'Gene', (174, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('Trp53', 'Gene', (94, 99))	('developed', 'PosReg', (195, 204))	('sarcomas', 'Disease', 'MESH:D012509', (51, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('sarcomas', 'Disease', (51, 59))	('mice', 'Species', '10090', (24, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('ArtDelta/Delta', 'Var', (79, 93))	('Trp53', 'Gene', '22059', (111, 116))	('ArtDelta', 'Chemical', '-', (159, 167))
513071	20979627	Histopathological analysis after hematoxylin and eosin (H&E) staining revealed a range of sarcoma subtypes occurring in ArtDelta/Delta Trp53Delta/+, including chondrosarcoma, osteosarcoma and rhabdomyosarcoma (Figure 1b).	('eosin', 'Chemical', 'MESH:D004801', (49, 54))	('chondrosarcoma', 'Disease', (159, 173))	('chondrosarcoma', 'Disease', 'MESH:D002813', (159, 173))	('Trp53', 'Gene', (135, 140))	('ArtDelta', 'Chemical', '-', (120, 128))	('including', 'Disease', (149, 158))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (90, 106))	('sarcoma subtypes', 'Disease', (90, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (175, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (159, 173))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (192, 208))	('osteosarcoma and rhabdomyosarcoma', 'Disease', 'MESH:D012516', (175, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('H&E', 'Chemical', '-', (56, 59))	('hematoxylin', 'Chemical', 'MESH:D006416', (33, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('in ArtDelta/Delta', 'Var', (117, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('Trp53', 'Gene', '22059', (135, 140))
513075	20979627	While we cannot rule out chromosomal instability in some Art-deficient sarcomas, the spectral karyotypes we did analyze were reminiscent of human sarcoma karyotypes, which commonly show aneuploidization without consistent or clonal translocations.	('Art-deficient sarcomas', 'Disease', 'MESH:C535388', (57, 79))	('human', 'Species', '9606', (140, 145))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('sarcoma', 'Disease', (146, 153))	('chromosomal instability', 'Phenotype', 'HP:0040012', (25, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Art-deficient sarcomas', 'Disease', (57, 79))	('sarcoma', 'Disease', (71, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('aneuploidization', 'Var', (186, 202))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))
513077	20979627	In this context, the observed aneuploidization may be indicative of a defect in normal proliferation or growth control in the pretransformed or early transformed sarcoma cells of origin.	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('growth control', 'CPA', (104, 118))	('sarcoma', 'Disease', (162, 169))	('defect', 'NegReg', (70, 76))	('aneuploidization', 'Var', (30, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))
513083	20979627	This revealed approximately the same rate (20%) of spontaneously occurring aneuploidy in ArtDelta/Delta and WT MSCs (Figures 2a-c).	('ArtDelta/Delta', 'Var', (89, 103))	('aneuploidy', 'Disease', (75, 85))	('ArtDelta', 'Chemical', '-', (89, 97))	('aneuploidy', 'Disease', 'MESH:D000782', (75, 85))
513085	20979627	However, ArtDelta/Delta MSCs also exhibited a higher frequency of spontaneous chromosomal structural lesions, that is, breaks, fragments, or translocations, than their WT counterparts (17% versus 7%, respectively) (Figures 2a and 2b).	('ArtDelta/Delta MSCs', 'Var', (9, 28))	('ArtDelta', 'Chemical', '-', (9, 17))	('breaks', 'CPA', (119, 125))	('translocations', 'CPA', (141, 155))	('fragments', 'CPA', (127, 136))
513101	20979627	Conversely, both ArtDelta/Delta and WT exhibited nearly identical increases in LipidTOX positivity at both 7 and 14 days of adipogenic culture (Figure 3c, black lines).	('increases', 'PosReg', (66, 75))	('ArtDelta', 'Chemical', '-', (17, 25))	('ArtDelta/Delta', 'Var', (17, 31))	('LipidTOX positivity', 'MPA', (79, 98))	('LipidTOX', 'Chemical', '-', (79, 87))
513109	20979627	This analysis revealed no overt differences between ArtDelta/Delta and WT MSCs or MEFs, although the ArtDelta/Delta MEFs showed a slightly faster initial expansion than their counterpart WT MEFs (Figure 4a).	('ArtDelta', 'Chemical', '-', (52, 60))	('initial', 'MPA', (146, 153))	('ArtDelta', 'Chemical', '-', (101, 109))	('MEFs', 'CellLine', 'CVCL:9115', (82, 86))	('MEFs', 'CellLine', 'CVCL:9115', (116, 120))	('faster', 'PosReg', (139, 145))	('MEFs', 'CellLine', 'CVCL:9115', (190, 194))	('ArtDelta/Delta', 'Var', (101, 115))
513115	20979627	ArtDelta/Delta fibroblasts expectedly showed IR hypersensitivity relative to WT fibroblasts, especially at intermediate doses (Figure 4c).	('ArtDelta/Delta', 'Var', (0, 14))	('ArtDelta', 'Chemical', '-', (0, 8))	('hypersensitivity', 'Disease', 'MESH:D004342', (48, 64))	('hypersensitivity', 'Disease', (48, 64))
513118	20979627	As in the colony formation assay, we observed the relative IR hypersensitivity in ArtDelta/Delta MEFs, but not MSCs, relative to the corresponding WT cells.	('hypersensitivity in', 'Disease', 'MESH:D004342', (62, 81))	('ArtDelta', 'Chemical', '-', (82, 90))	('ArtDelta/Delta MEFs', 'Var', (82, 101))	('MEFs', 'CellLine', 'CVCL:9115', (97, 101))	('hypersensitivity in', 'Disease', (62, 81))
513125	20979627	By contrast, ArtDelta/Delta MEFs showed elevated mitotic index in unirradiated cultures relative to WT MEFs, but did not exhibit a sustained increase in mitotic index following irradiation as in WT cells (Figures 5f and 5g).	('mitotic index', 'MPA', (49, 62))	('elevated', 'PosReg', (40, 48))	('ArtDelta', 'Chemical', '-', (13, 21))	('ArtDelta/Delta', 'Var', (13, 27))	('MEFs', 'CellLine', 'CVCL:9115', (103, 107))	('MEFs', 'CellLine', 'CVCL:9115', (28, 32))
513132	20979627	This confirmed that Art-mutant MSC cultures were significantly more resistant to serum withdrawal than WT MSC, with ArtDelta/Delta cultures exhibiting greater than fourfold higher survival than WT cultures (Figures 6c and 6d).	('ArtDelta/Delta', 'Var', (116, 130))	('ArtDelta', 'Chemical', '-', (116, 124))	('more', 'PosReg', (63, 67))	('Art-mutant', 'Var', (20, 30))	('resistant', 'MPA', (68, 77))	('higher', 'PosReg', (173, 179))
513144	20979627	Moreover, alteration in normal growth factor responsiveness is a general hallmark of tumorigenesis in numerous cell types.	('alteration', 'Var', (10, 20))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
513150	20979627	Previous studies have shown that ArtDelta/Delta Trp53Delta/+ mice are susceptible to tumorigenesis with shorter latency and an altered spectrum relative to Trp53Delta/+ mice.	('tumor', 'Disease', (85, 90))	('Trp53', 'Gene', '22059', (156, 161))	('mice', 'Species', '10090', (61, 65))	('Trp53', 'Gene', (48, 53))	('ArtDelta', 'Chemical', '-', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Trp53', 'Gene', '22059', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mice', 'Species', '10090', (169, 173))	('spectrum', 'MPA', (135, 143))	('susceptible', 'Reg', (70, 81))	('Trp53', 'Gene', (156, 161))	('ArtDelta/Delta', 'Var', (33, 47))	('altered', 'Reg', (127, 134))
513154	20979627	Rather, we propose that defects in proliferation control following cellular stress can render Art-defective (and perhaps other NHEJ-deficient) MSCs or MMSs preneoplastic.	('Art-defective', 'Disease', (94, 107))	('MSCs', 'Disease', (143, 147))	('proliferation', 'CPA', (35, 48))	('NHEJ-deficient', 'Disease', (127, 141))	('NHEJ-deficient', 'Disease', 'MESH:D007153', (127, 141))	('defects', 'Var', (24, 31))
513159	20979627	Whereas Art deficiency did not lead to overt defects in either the number or differentiation function of primary bone marrow-derived MSCs, lack of Art did result in aberrant proliferative responses to cellular stress conditions such as ionizing radiation or serum deprivation, conditions that are normally cytostatic to WT MSCs and MMSs.	('Art deficiency', 'Disease', (8, 22))	('result in aberrant', 'Reg', (155, 173))	('ionizing radiation', 'Disease', (236, 254))	('Art', 'Gene', (147, 150))	('Art deficiency', 'Disease', 'MESH:C535388', (8, 22))	('proliferative', 'CPA', (174, 187))	('ionizing radiation', 'Disease', 'MESH:D004194', (236, 254))	('lack', 'Var', (139, 143))
513166	20979627	However, it is possible that the pathways identified by our differential gene expression analysis influence the exact checkpoint functions of ARTEMIS, perhaps in a cell type-dependent fashion, and may thus account for the phenotypic differences we observe in ArtDelta/Delta MSCs versus other cell types.	('influence', 'Reg', (98, 107))	('ArtDelta', 'Chemical', '-', (259, 267))	('ArtDelta/Delta', 'Var', (259, 273))	('checkpoint functions', 'MPA', (118, 138))
513167	20979627	Here we have identified BMP, WNT, and growth factor signaling pathways as differentially affected in serum-starved WT versus ArtDelta/Delta MSCs.	('ArtDelta', 'Chemical', '-', (125, 133))	('affected', 'Reg', (89, 97))	('ArtDelta/Delta', 'Var', (125, 139))	('BMP', 'Pathway', (24, 27))	('growth factor signaling pathways', 'Pathway', (38, 70))	('WNT', 'Pathway', (29, 32))
513216	33260631	Galant et al., in 64 subcutaneous soft tissue masses, demonstrated that malignant tumors have a higher tendency to develop a close relationship with the fascia than benign lesions and that an obtuse angle between the fascia and the mass, or a lesion crossing the fascia, strongly suggests malignancy.	('soft', 'Gene', (34, 38))	('soft', 'Gene', '25886', (34, 38))	('malignant tumors', 'Disease', 'MESH:D009369', (72, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('fascia than benign lesions', 'Disease', (153, 179))	('malignancy', 'Disease', 'MESH:D009369', (289, 299))	('develop', 'PosReg', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('malignancy', 'Disease', (289, 299))	('obtuse', 'Var', (192, 198))	('close', 'Interaction', (125, 130))	('fascia than benign lesions', 'Disease', 'MESH:D009369', (153, 179))	('malignant tumors', 'Disease', (72, 88))	('subcutaneous soft tissue masses', 'Phenotype', 'HP:0001482', (21, 52))
513221	33260631	Without distinguishing between superficial and deep masses, two studies (respectively, on 54 and 216 ST lesions) demonstrated that inhomogeneous perfusion, due to central tumoral necrosis, and arterial uptake were associated with high risk of malignancy, whereas size and the relationship with the muscular fascia were predictive factors just in one study and not in the other.	('inhomogeneous', 'Var', (131, 144))	('tumoral necrosis', 'Phenotype', 'HP:0010885', (171, 187))	('muscular fascia', 'Disease', 'MESH:D009135', (298, 313))	('arterial', 'MPA', (193, 201))	('tumoral necrosis', 'Disease', (171, 187))	('tumoral necrosis', 'Disease', 'MESH:D009336', (171, 187))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('malignancy', 'Disease', 'MESH:D009369', (243, 253))	('muscular fascia', 'Disease', (298, 313))	('malignancy', 'Disease', (243, 253))
513321	26730359	The following pulse sequences were used for all patients as part of our standard institutional protocol: T1-weighted spin-echo (400-700/8-16 [repetition time ms/echo time ms]) and fat-suppressed T2-weighted fast spin-echo (2000-5000/80-100, with an echo train length of 8) sequences, followed by in-phase (100-165/4.6; flip angle, 30 ) and out-of-phase (100-165/2.3; flip angle, 30 ) fast multiplanar spoiled gradient-echo sequences acquired using Dixon technique.	('2000-5000/80-100', 'Var', (223, 239))	('patients', 'Species', '9606', (48, 56))	('400-700/8-16', 'Var', (128, 140))	('100-165/2.3', 'Var', (354, 365))
513335	26730359	This was due to hemorrhage and illuminates an important caveat when using this technique: in the acute phase, blood products can result in an increase in signal intensity on OP imaging.	('increase', 'PosReg', (142, 150))	('blood products', 'Var', (110, 124))	('hemorrhage', 'Disease', (16, 26))	('hemorrhage', 'Disease', 'MESH:D006470', (16, 26))	('signal intensity on OP imaging', 'MPA', (154, 184))
513539	28415158	Recurrence was noted in 30% of ALK-1 positive and 37.5% of ALK-1 negative cases, whereas metastasis to the lung, liver, and pelvic bone was noted in the ALK-1 positive group only.	('positive', 'Var', (37, 45))	('ALK-1', 'Gene', '94', (31, 36))	('ALK-1', 'Gene', (31, 36))	('ALK-1', 'Gene', '94', (153, 158))	('ALK-1', 'Gene', (153, 158))	('ALK-1', 'Gene', '94', (59, 64))	('ALK-1', 'Gene', (59, 64))
513549	28415158	Inflammatory myofibroblastic tumors expressing RANBP2 and ALK rearrangement (RANBP2-ALK) fusion usually display high grade epithelioid/round cell morphology with nuclear membrane staining pattern and predict poor prognosis.	('RANBP2', 'Gene', '5903', (47, 53))	('RANBP2', 'Gene', (77, 83))	('fusion', 'Var', (89, 95))	('RANBP2', 'Gene', (47, 53))	('ALK', 'Gene', (84, 87))	('RANBP2', 'Gene', '5903', (77, 83))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (13, 34))	('ALK', 'Gene', (58, 61))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (13, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (13, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('ALK', 'Gene', '238', (84, 87))	('myofibroblastic tumors', 'Disease', (13, 35))	('ALK', 'Gene', '238', (58, 61))
513583	28415158	ALK-1 positive tumors (55.6%) included five females and five males and the mean age was 23.8 years (range, 3 to 44 years), compared with the mean age of (four females and four males) 27.1 years (range, 18 to 41 years) for ALK-1 negative cases.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('positive', 'Var', (6, 14))	('ALK-1', 'Gene', (222, 227))	('ALK-1', 'Gene', '94', (222, 227))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('ALK-1', 'Gene', '94', (0, 5))	('ALK-1', 'Gene', (0, 5))	('tumors', 'Disease', (15, 21))
513584	28415158	Recurrence was noted in 3/10 ALK-1 positive (30%) and 3/8 ALK-1 negative (37.5%) cases, whereas metastasis to the lung, liver and pelvic bone was noted in the ALK-1 positive group (Tables 4, 5).	('ALK-1', 'Gene', '94', (159, 164))	('ALK-1', 'Gene', (159, 164))	('ALK-1', 'Gene', '94', (29, 34))	('ALK-1', 'Gene', (29, 34))	('positive', 'Var', (35, 43))	('ALK-1', 'Gene', '94', (58, 63))	('ALK-1', 'Gene', (58, 63))
513608	28415158	ALK gene rearrangement was demonstrated in all the tested cases of epithelioid variant of inflammatory myofibroblastic tumors by fluorescence in situ hybridization (FISH).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('inflammatory myofibroblastic tumors', 'Disease', (90, 125))	('epithelioid variant', 'Disease', (67, 86))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (103, 124))	('ALK', 'Gene', (0, 3))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (103, 125))	('rearrangement', 'Var', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (90, 125))	('ALK', 'Gene', '238', (0, 3))
513727	26825914	In our study, the combined use of DDP + IFO + ADM can effectively control tumor cell proliferation.	('ADM', 'Chemical', 'MESH:D004317', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('DDP', 'Chemical', 'MESH:D002945', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('IFO', 'Chemical', 'MESH:D007069', (40, 43))	('DDP', 'Var', (34, 37))
513773	22674423	The mean volume circulated during the 30-minute infusion, which was calculated only in patients at Duke University Medical Center, was lower for the UE group (1250 mL; n = 11) than for the LE group (1867 mL; n = 73; P < .001).	('LE', 'Phenotype', 'HP:0006385', (189, 191))	('lower', 'NegReg', (135, 140))	('patients', 'Species', '9606', (87, 95))	('1250 mL', 'Var', (159, 166))
513794	22674423	It is noteworthy that correcting the melphalan dose for IBW is associated with less toxicity.	('toxicity', 'Disease', 'MESH:D064420', (84, 92))	('melphalan', 'Chemical', 'MESH:D008558', (37, 46))	('correcting', 'Var', (22, 32))	('toxicity', 'Disease', (84, 92))
513876	22916018	Fatty acid synthesis is required for the survival of latently infected endothelial cells, as inhibition of key enzymes in this pathway led to apoptosis of infected cells.	('Fatty acid', 'Chemical', 'MESH:D005227', (0, 10))	('inhibition', 'Var', (93, 103))	('apoptosis', 'CPA', (142, 151))
513884	22916018	Many metabolic pathways that are altered in most tumor cells were also altered by KSHV.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('altered', 'Reg', (71, 78))	('metabolic pathways', 'Pathway', (5, 23))	('KSHV', 'Species', '37296', (82, 86))	('KSHV', 'Var', (82, 86))
513887	22916018	In summary, we found that a directly oncogenic virus alters the same host metabolic pathways that are dysregulated in many cancer cells and that inhibition of these pathways can be used to kill off infected cells, thereby providing novel therapeutic targets for KSHV and ultimately KS tumors.	('host metabolic pathways', 'Pathway', (69, 92))	('alters', 'Reg', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('KSHV', 'Disease', (262, 266))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('KSHV', 'Species', '37296', (262, 266))	('virus', 'Var', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('KS tumors', 'Disease', (282, 291))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (123, 129))	('KS tumors', 'Disease', 'MESH:D009369', (282, 291))	('inhibition', 'Var', (145, 155))
513889	22916018	These alterations are thought to provide cancer cells with the necessary energy and substrates for rapid cell division.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('alterations', 'Var', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))
513912	22916018	To determine if KSHV induces other metabolic changes similar to cancer cells, we performed a global screen to detect metabolites in mock- and KSHV-infected cells at 48 and 96 hours post infection (hpi).	('KSHV-infected', 'Disease', 'MESH:C537372', (142, 155))	('KSHV', 'Species', '37296', (142, 146))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('hours post infection', 'Disease', (175, 195))	('hours post infection', 'Disease', 'MESH:D020178', (175, 195))	('KSHV', 'Species', '37296', (16, 20))	('KSHV-infected', 'Disease', (142, 155))	('KSHV', 'Var', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
513914	22916018	Metabolites of several pathways commonly dysregulated in tumor cells were altered by KSHV, including glycolysis, amino acid metabolism, the pentose phosphate pathway and lipogenesis.	('pentose phosphate', 'Chemical', 'MESH:D010428', (140, 157))	('glycolysis', 'MPA', (101, 111))	('pentose phosphate pathway', 'Pathway', (140, 165))	('amino acid metabolism', 'MPA', (113, 134))	('Metabolites of', 'MPA', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('KSHV', 'Var', (85, 89))	('altered', 'Reg', (74, 81))	('tumor', 'Disease', (57, 62))	('KSHV', 'Species', '37296', (85, 89))	('lipogenesis', 'MPA', (170, 181))
513924	22916018	Inhibitors of FAS led to greatly increased apoptotic death of latently infected cells, as compared to their mock-infected counterparts.	('apoptotic death', 'CPA', (43, 58))	('FAS', 'Gene', (14, 17))	('Inhibitors', 'Var', (0, 10))	('increased', 'PosReg', (33, 42))	('FAS', 'Chemical', '-', (14, 17))
513927	22916018	Inhibition of fatty acid synthesis provides a potential therapeutic target for KSHV and ultimately KS tumors.	('KSHV', 'Species', '37296', (79, 83))	('fatty acid', 'Chemical', 'MESH:D005227', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('KS tumors', 'Disease', 'MESH:D009369', (99, 108))	('KS tumors', 'Disease', (99, 108))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('KSHV', 'Disease', (79, 83))
513946	22916018	Of note, many of the metabolites that are increased by infection, are increased to higher levels at 96 hours as compared to 48 hours post infection.	('increased', 'PosReg', (70, 79))	('metabolites', 'MPA', (21, 32))	('hours post infection', 'Disease', (127, 147))	('hours post infection', 'Disease', 'MESH:D020178', (127, 147))	('infection', 'Var', (55, 64))
513971	22916018	Inhibitors of FAS have been shown to selectively kill cancer cells and inhibit tumor cell growth.	('FAS', 'Gene', (14, 17))	('kill', 'PosReg', (49, 53))	('tumor', 'Disease', (79, 84))	('inhibit', 'NegReg', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('FAS', 'Chemical', '-', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
513979	22916018	Fatty acid inhibitor C75 specifically inhibits fatty acid synthase (FASN), thereby preventing the catalysis of acetyl-CoA and malonyl-CoA into palmitic acid (fig.	('FASN', 'Gene', (68, 72))	('C75', 'Var', (21, 24))	('preventing', 'NegReg', (83, 93))	('fatty acid synthase', 'Gene', (47, 66))	('FASN', 'Gene', '2194', (68, 72))	('inhibits', 'NegReg', (38, 46))	('malonyl-CoA', 'Chemical', 'MESH:D008316', (126, 137))	('Fatty acid', 'Chemical', 'MESH:D005227', (0, 10))	('fatty acid synthase', 'Gene', '2194', (47, 66))	('palmitic acid', 'Chemical', 'MESH:D019308', (143, 156))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (111, 121))
513982	22916018	Treatment with C75 for 24 hours induces a significantly larger dose-dependent increase in cell death in KSHV versus mock-infected cells (fig.	('increase', 'PosReg', (78, 86))	('cell death', 'CPA', (90, 100))	('C75', 'Var', (15, 18))	('KSHV', 'Species', '37296', (104, 108))
513983	22916018	After normalizing for the basal death rate in the absence of drug, 70% of KSHV-infected cells die due to 4 microg/mL C75 treatment, while only 13% of mock-infected cells die due to identical C75 treatment.	('KSHV-infected', 'Disease', 'MESH:C537372', (74, 87))	('KSHV-infected', 'Disease', (74, 87))	('C75', 'Var', (117, 120))
513989	22916018	Treatment of KSHV-infected cells with TOFA or C75 led to high levels of Caspase 3 and PARP cleavage (fig.	('Caspase 3', 'Gene', '836', (72, 81))	('KSHV-infected', 'Disease', 'MESH:C537372', (13, 26))	('PARP', 'Gene', '142', (86, 90))	('PARP', 'Gene', (86, 90))	('C75', 'Var', (46, 49))	('KSHV-infected', 'Disease', (13, 26))	('TOFA', 'Chemical', 'MESH:C014289', (38, 42))	('Caspase 3', 'Gene', (72, 81))
513991	22916018	These results demonstrate that inhibition of fatty acid synthesis induces cell death by apoptosis specifically in KSHV-infected endothelial cells but not in mock-infected cells.	('apoptosis', 'CPA', (88, 97))	('cell death', 'CPA', (74, 84))	('fatty acid', 'Chemical', 'MESH:D005227', (45, 55))	('KSHV-infected', 'Disease', (114, 127))	('fatty acid synthesis', 'MPA', (45, 65))	('KSHV-infected', 'Disease', 'MESH:C537372', (114, 127))	('inhibition', 'Var', (31, 41))
513993	22916018	Inhibition of ACC1 by TOFA could lead to apoptosis through inhibition of the synthesis of necessary downstream metabolites or through increased accumulation of precursors that could potentially be harmful to the cell.	('inhibition', 'NegReg', (59, 69))	('lead to', 'Reg', (33, 40))	('TOFA', 'Gene', (22, 26))	('TOFA', 'Chemical', 'MESH:C014289', (22, 26))	('accumulation of precursors', 'MPA', (144, 170))	('ACC1', 'Gene', (14, 18))	('apoptosis', 'CPA', (41, 50))	('Inhibition', 'Var', (0, 10))	('synthesis of necessary downstream metabolites', 'MPA', (77, 122))	('ACC1', 'Gene', '31', (14, 18))	('increased', 'PosReg', (134, 143))
514010	22916018	A number of enveloped lytic viruses have been shown to be inhibited by a block in FAS.	('FAS', 'Chemical', '-', (82, 85))	('block', 'Var', (73, 78))	('enveloped lytic viruses', 'Protein', (12, 35))	('inhibited', 'NegReg', (58, 67))	('FAS', 'Protein', (82, 85))
514012	22916018	Interestingly, treatment of EBV infected cells with fatty acid synthase (FASN) inhibitors C75 and cerulenin lead to reduced immediate-early and early gene expression.	('EBV', 'Species', '10376', (28, 31))	('fatty acid synthase', 'Gene', (52, 71))	('FASN', 'Gene', (73, 77))	('C75', 'Var', (90, 93))	('fatty acid synthase', 'Gene', '2194', (52, 71))	('FASN', 'Gene', '2194', (73, 77))	('cerulenin', 'Chemical', 'MESH:D002569', (98, 107))	('reduced', 'NegReg', (116, 123))
514020	22916018	Inhibition of FAS led to high levels of apoptosis in KSHV latently infected cells, while the same concentration of inhibitors had little effect on the mock-infected cells.	('FAS', 'Chemical', '-', (14, 17))	('FAS', 'Protein', (14, 17))	('KSHV', 'Species', '37296', (53, 57))	('Inhibition', 'Var', (0, 10))
514023	22916018	Importantly, apoptosis is also induced in many cancer cells following inhibition of FAS.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('FAS', 'Chemical', '-', (84, 87))	('cancer', 'Disease', (47, 53))	('apoptosis', 'CPA', (13, 22))	('inhibition', 'Var', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('induced', 'Reg', (31, 38))	('FAS', 'Protein', (84, 87))
514044	22916018	Antibodies recognizing cleaved Caspase-3 (Cell Signaling), Poly-A Ribose Polymerase (Cell Signaling) ORF 59 (Advanced Biotechnology inc.) were used at 1:1000 dilutions as specified by the manufacturer and antibodies to beta-Actin (Sigma) was used at 1:10,000.	('beta-Actin', 'Gene', '728378', (219, 229))	('Poly-A', 'Var', (59, 65))	('Caspase-3', 'Protein', (31, 40))	('beta-Actin', 'Gene', (219, 229))	('ORF 59', 'Gene', (101, 107))
514051	22916018	For lytic replication, fixed cells were incubated with antibody to ORF 59 followed by incubation with fluor-conjugated secondary antibodies(goat anti-rabbit Alexa Fluor 488 and goat anti-mouse Alexa Fluor594 Molecular Probes/Invitrogen.	('goat', 'Species', '9925', (177, 181))	('goat', 'Species', '9925', (140, 144))	('Alexa Fluor594', 'Chemical', '-', (193, 207))	('rabbit', 'Species', '9986', (150, 156))	('mouse', 'Species', '10090', (187, 192))	('antibody', 'Var', (55, 63))	('Alexa Fluor 488', 'Chemical', '-', (157, 172))	('ORF 59', 'Gene', (67, 73))
514148	21896345	The majority of patients also experienced greater toxicity following post-transplant EOCH than was experienced with the EPOCH-F regimen, despite the same or lower doses of cytotoxic drugs administered post-transplant.	('EOCH', 'Var', (85, 89))	('patients', 'Species', '9606', (16, 24))	('toxicity', 'Disease', 'MESH:D064420', (50, 58))	('toxicity', 'Disease', (50, 58))
514149	21896345	Mucositis was a common and severe side effect, occurring in 5 of 12 patients (3 grade 3, 1 grade 2, 1 grade 1) receiving post-transplant EOCH, whereas mucositis (grade 2) occurred in only 1 of 30 patients receiving EPOCH-F pre-transplant.	('mucositis', 'Disease', (151, 160))	('mucositis', 'Disease', 'MESH:D052016', (151, 160))	('patients', 'Species', '9606', (196, 204))	('patients', 'Species', '9606', (68, 76))	('Mucositis', 'Disease', (0, 9))	('EOCH', 'Var', (137, 141))	('Mucositis', 'Disease', 'MESH:D052016', (0, 9))
514175	21896345	We postulate that immune priming due to alloreactivity effects result in both enhanced effects of chemotherapy and/or radiation therapy targeting both normal and tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('alloreactivity effects', 'Var', (40, 62))	('tumor', 'Disease', (162, 167))	('effects', 'MPA', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('enhanced', 'PosReg', (78, 86))
514200	21184173	Engraftment was confirmed by identifying the H-2Kb IL-1beta-type specific polymorphism.	('H-2Kb', 'Gene', (45, 50))	('polymorphism', 'Var', (74, 86))	('H-2Kb', 'Gene', '14972', (45, 50))
514264	21184173	To confirm engraftment of transplanted H-2Kb/d BM cells, we assessed a strain-specific DNA polymorphism in the IL-1beta gene.	('IL-1beta', 'Gene', (111, 119))	('H-2Kb', 'Gene', '14972', (39, 44))	('polymorphism', 'Var', (91, 103))	('H-2Kb', 'Gene', (39, 44))
514268	21184173	DNA extracted from the spleens (lane 1) and blood (lane 2) of transplanted mice demonstrated both the H-2Kb and H-2Kd IL-1beta polymorphisms, whereas DNA extracted from the spleens (lane 3), livers (lane 4), or blood (lane 5) of non-transplanted nude mice demonstrated only the H-2Kd IL-1beta polymorphism.	('mice', 'Species', '10090', (75, 79))	('mice', 'Species', '10090', (251, 255))	('H-2Kb', 'Gene', '14972', (102, 107))	('H-2Kd', 'Gene', (112, 117))	('nude mice', 'Species', '10090', (246, 255))	('H-2Kd', 'Gene', '14972', (112, 117))	('rat', 'Species', '10116', (263, 266))	('polymorphisms', 'Var', (127, 140))	('H-2Kb', 'Gene', (102, 107))	('H-2Kd', 'Gene', (278, 283))	('IL-1beta', 'Gene', (118, 126))	('H-2Kd', 'Gene', '14972', (278, 283))	('rat', 'Species', '10116', (87, 90))
514344	21184173	Therefore, the presence of VEGF165 in the lung microenvironment will result in the chemotaxis and retention of BM cells in the lungs.	('retention', 'CPA', (98, 107))	('chemotaxis', 'CPA', (83, 93))	('presence', 'Var', (15, 23))	('VEGF', 'Gene', '22339', (27, 31))	('VEGF', 'Gene', (27, 31))	('result in', 'Reg', (69, 78))
514369	21253554	This highlights the importance of molecular classification in these tumours and genetic alterations now considered an integral part of the WHO classification.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('tumours', 'Disease', (68, 75))	('genetic', 'Var', (80, 87))
514385	21253554	MDM2 amplification is a key feature of WD/DDLPS and is amplified and overexpressed in a number of other cancers, highlighting its importance in tumorigenesis (as reviewed).	('WD', 'Disease', 'MESH:D006527', (39, 41))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('amplification', 'Var', (5, 18))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
514391	21253554	Therapeutically this is important, as MDM2 inhibitors aim to reactivate p53 and thus allow it to actively induce cell death in response to appropriate stressors.	('induce', 'Reg', (106, 112))	('response to appropriate stressors', 'MPA', (127, 160))	('cell death', 'CPA', (113, 123))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('MDM2', 'Gene', '4193', (38, 42))	('MDM2', 'Gene', (38, 42))	('reactivate', 'Var', (61, 71))
514393	21253554	Amplification of MDM2 and mutation of p53 appear to be mutually exclusive events in WDLPS, but have been reported in DDLPS.	('WD', 'Disease', 'MESH:D006527', (84, 86))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('mutation', 'Var', (26, 34))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))
514394	21253554	p53 mutations have been associated with the de-differentiation process from WDLPS to DDLPS.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('de-differentiation process', 'CPA', (44, 70))	('associated with', 'Reg', (24, 39))	('WD', 'Disease', 'MESH:D006527', (76, 78))	('mutations', 'Var', (4, 13))	('DDLPS', 'Disease', (85, 90))
514396	21253554	Retroperitoneal WD/DDLPS demonstrate mutual exclusivity between MDM2 amplification and p53 mutation.	('mutation', 'Var', (91, 99))	('WD', 'Disease', 'MESH:D006527', (16, 18))	('MDM2', 'Gene', '4193', (64, 68))	('MDM2', 'Gene', (64, 68))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))
514397	21253554	In non-retroperitoneal DDLPS, p53 mutations occur in the absence of MDM2 amplification suggesting involvement in the de-differentiation process.	('MDM2', 'Gene', '4193', (68, 72))	('MDM2', 'Gene', (68, 72))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('involvement', 'Reg', (98, 109))	('mutations', 'Var', (34, 43))	('non-retroperitoneal DDLPS', 'Disease', (3, 28))
514403	21253554	Coamplification of MDM2 and CDK4 is a common feature of WD/DDLPS and may result in proliferation through combined effects upon p53 and the cell cycle.	('CDK4', 'Gene', '1019', (28, 32))	('MDM2', 'Gene', '4193', (19, 23))	('proliferation', 'CPA', (83, 96))	('MDM2', 'Gene', (19, 23))	('p53', 'Gene', (127, 130))	('Coamplification', 'Var', (0, 15))	('effects', 'Reg', (114, 121))	('combined', 'Interaction', (105, 113))	('WD', 'Disease', 'MESH:D006527', (56, 58))	('p53', 'Gene', '7157', (127, 130))	('CDK4', 'Gene', (28, 32))	('result in', 'Reg', (73, 82))
514413	21253554	that showed mice expressing C-terminal truncated HMGA2 developed lipomas.	('C-terminal truncated', 'Var', (28, 48))	('lipoma', 'Phenotype', 'HP:0012032', (65, 71))	('lipomas', 'Phenotype', 'HP:0012032', (65, 72))	('developed', 'PosReg', (55, 64))	('mice', 'Species', '10090', (12, 16))	('lipomas', 'Disease', 'MESH:D008067', (65, 72))	('HMGA2', 'Gene', (49, 54))	('lipomas', 'Disease', (65, 72))
514421	21253554	WDLPS and DDLPS have shown co-amplification of 1q21-q22 and/or 12q21-q22, along with amplification of chromosome 1(1q21-q23).	('WD', 'Disease', 'MESH:D006527', (0, 2))	('12q21-q22', 'Var', (63, 72))	('1q21-q22', 'Var', (47, 55))
514436	21253554	MLPS is characterised by the recurrent translocation t(12;16)(q13;p11) that results in the FUS-CHOP gene fusion that is present in over 95% of cases.	('MLPS', 'Disease', 'None', (0, 4))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 70))	('MLPS', 'Disease', (0, 4))	('FUS-CHOP', 'Protein', (91, 99))	('t(12;16)(q13;p11', 'Var', (53, 69))	('results in', 'Reg', (76, 86))
514443	21253554	Understanding how the FUS-CHOP fusion causes MLPS and uncovering any further molecular abnormalities in the disease will aid in development of novel targeted therapies.	('molecular abnormalities in the disease', 'Disease', 'MESH:D030342', (77, 115))	('MLPS', 'Disease', 'None', (45, 49))	('causes', 'Reg', (38, 44))	('molecular abnormalities in the disease', 'Disease', (77, 115))	('fusion', 'Var', (31, 37))	('FUS-CHOP', 'Gene', (22, 30))	('MLPS', 'Disease', (45, 49))
514464	21253554	In a small clinical cohort, specific Akt phosphorylation was observed in the RC variant and 2 treated cases that harboured PTEN mutations, implicating RTK pathways signaling through Akt in MLPS.	('Akt', 'Gene', '207', (37, 40))	('variant', 'Var', (80, 87))	('RC', 'Chemical', '-', (77, 79))	('Akt', 'Gene', '207', (182, 185))	('MLPS', 'Disease', 'None', (189, 193))	('observed', 'Reg', (61, 69))	('Akt', 'Gene', (37, 40))	('PTEN', 'Gene', (123, 127))	('Akt', 'Gene', (182, 185))	('PTEN', 'Gene', '5728', (123, 127))	('MLPS', 'Disease', (189, 193))
514467	21253554	PI3K can activate many proteins including the protein serine-threonine kinase Akt, which when phosphorylated causes downstream activation and ultimately cell growth, cell cycle entry, and subsequently survival.	('cell growth', 'CPA', (153, 164))	('PI3K', 'Var', (0, 4))	('cell cycle entry', 'CPA', (166, 182))	('Akt', 'Gene', '207', (78, 81))	('proteins', 'Protein', (23, 31))	('Akt', 'Gene', (78, 81))	('survival', 'CPA', (201, 209))	('activation', 'PosReg', (127, 137))	('activate', 'PosReg', (9, 17))
514469	21253554	A recent study showed 18% of MLPS patients (n = 71) had PIK3CA mutations in either the helical (E542K and E545K) or kinase (H1047L and H1047R) domain.	('MLPS', 'Disease', (29, 33))	('E545K', 'Mutation', 'rs104886003', (106, 111))	('E545K', 'Var', (106, 111))	('H1047L', 'Mutation', 'rs121913279', (124, 130))	('E542K', 'Mutation', 'rs121913273', (96, 101))	('PIK3CA', 'Gene', (56, 62))	('H1047R', 'Mutation', 'rs121913279', (135, 141))	('H1047L', 'Var', (124, 130))	('patients', 'Species', '9606', (34, 42))	('MLPS', 'Disease', 'None', (29, 33))	('PIK3CA', 'Gene', '5290', (56, 62))	('H1047R', 'Var', (135, 141))	('E542K', 'Var', (96, 101))
514470	21253554	The presence of a PIK3CA mutation was associated with a shortened disease specific survival.	('disease specific survival', 'CPA', (66, 91))	('mutation', 'Var', (25, 33))	('shortened', 'NegReg', (56, 65))	('PIK3CA', 'Gene', (18, 24))	('PIK3CA', 'Gene', '5290', (18, 24))
514471	21253554	also showed one tumour with a homozygous PTEN mutation.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (16, 22))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('PTEN', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('PTEN', 'Gene', '5728', (41, 45))
514477	21253554	described that 60% of PLPS have a deletion of 13q14.2-q14.3, a region that includes the tumour suppressor RB1.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('RB1', 'Gene', '5925', (106, 109))	('PLPS', 'Disease', (22, 26))	('deletion', 'Var', (34, 42))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('RB1', 'Gene', (106, 109))
514480	21253554	additional deletions in PLPS include 17p13 and 17q11.2, where p53 and the sarcoma associated tumour suppressor gene, neurofibromatosis type 1 (NF-1) are located.	('NF-1', 'Gene', (143, 147))	('tumour', 'Disease', (93, 99))	('PLPS', 'Gene', (24, 28))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (117, 134))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('deletions', 'Var', (11, 20))	('neurofibromatosis type 1', 'Gene', (117, 141))	('neurofibromatosis type 1', 'Gene', '4763', (117, 141))	('NF-1', 'Gene', '4763', (143, 147))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('sarcoma', 'Disease', (74, 81))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
514481	21253554	showed 16.7% of PLPS cases had mutations identified in p53, which are rarely seen in MLPS and WD/DDLPS.	('mutations', 'Var', (31, 40))	('MLPS', 'Disease', 'None', (85, 89))	('p53', 'Gene', (55, 58))	('PLPS', 'Disease', (16, 20))	('p53', 'Gene', '7157', (55, 58))	('MLPS', 'Disease', (85, 89))	('WD', 'Disease', 'MESH:D006527', (94, 96))
514483	21253554	Given MDM2 is consistently amplified in WD/DDLPS, and sensitivity to MDM2 antagonists (such as Nutlin-3a) is predicted by MDM2 amplification and an intact wild-type p53, it is an appealing therapeutic target.	('p53', 'Gene', (165, 168))	('WD', 'Disease', 'MESH:D006527', (40, 42))	('p53', 'Gene', '7157', (165, 168))	('MDM2', 'Gene', '4193', (122, 126))	('MDM2', 'Gene', (122, 126))	('MDM2', 'Gene', '4193', (6, 10))	('MDM2', 'Gene', (6, 10))	('MDM2', 'Gene', '4193', (69, 73))	('MDM2', 'Gene', (69, 73))	('amplification', 'Var', (127, 140))	('sensitivity', 'MPA', (54, 65))
514485	21253554	Nutlin-3a was heralded as one of the most promising MDM2 antagonists when it was shown to activate wild type p53 and induce cell cycle arrest and apoptosis in cancer cell lines.	('cancer', 'Disease', (159, 165))	('arrest', 'Disease', 'MESH:D006323', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('antagonists', 'Var', (57, 68))	('arrest', 'Disease', (135, 141))	('induce', 'PosReg', (117, 123))	('activate', 'PosReg', (90, 98))	('p53', 'Gene', (109, 112))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('MDM2', 'Gene', '4193', (52, 56))	('p53', 'Gene', '7157', (109, 112))	('MDM2', 'Gene', (52, 56))	('apoptosis', 'CPA', (146, 155))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (124, 141))
514486	21253554	These cell lines included osteosarcoma with amplified MDM2.	('MDM2', 'Gene', '4193', (54, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('osteosarcoma', 'Disease', (26, 38))	('MDM2', 'Gene', (54, 58))	('osteosarcoma', 'Disease', 'MESH:D012516', (26, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('amplified', 'Var', (44, 53))
514496	21253554	Two oral MDM2 inhibitors have recently entered the clinical setting, JNJ-26854165 (Ortho Biotech; Johnson & Johnson) and R7112 (Hoffmann-La Roche).	('MDM2', 'Gene', '4193', (9, 13))	('MDM2', 'Gene', (9, 13))	('and', 'Var', (117, 120))
514499	21253554	Of relevant interest, an MDM2 antagonist RO5045337 is about to recruit for a Phase I trial in liposarcoma patients.	('liposarcoma', 'Disease', 'MESH:D008080', (94, 105))	('liposarcoma', 'Phenotype', 'HP:0012034', (94, 105))	('MDM2', 'Gene', '4193', (25, 29))	('MDM2', 'Gene', (25, 29))	('patients', 'Species', '9606', (106, 114))	('liposarcoma', 'Disease', (94, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('RO5045337', 'Chemical', '-', (41, 50))	('RO5045337', 'Var', (41, 50))
514509	21253554	Newer generation CDK inhibitors include PD0332991, P27600, ZK 304709, R 547 and P1446A05.	('CDK', 'Enzyme', (17, 20))	('ZK 304709', 'Var', (59, 68))	('P27600', 'Var', (51, 57))	('P1446A05', 'Var', (80, 88))	('PD0332991', 'Chemical', 'MESH:C500026', (40, 49))	('PD0332991', 'Var', (40, 49))	('R 547', 'Var', (70, 75))
514511	21253554	PD0332991 is one of two more selective CDK inhibitors specific for CDK4 and CDK6.	('CDK4', 'Gene', (67, 71))	('CDK4', 'Gene', '1019', (67, 71))	('PD0332991', 'Chemical', 'MESH:C500026', (0, 9))	('CDK6', 'Gene', (76, 80))	('PD0332991', 'Var', (0, 9))	('CDK6', 'Gene', '1021', (76, 80))
514513	21253554	PD0332991 is available in Phase I and Phase II trials for solid and haematological malignancy.	('malignancy', 'Disease', (83, 93))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('PD0332991', 'Var', (0, 9))	('PD0332991', 'Chemical', 'MESH:C500026', (0, 9))
514514	21253554	Finally, P1446A05 is the only single CDK4 selective inhibitor available.	('CDK4', 'Gene', '1019', (37, 41))	('CDK4', 'Gene', (37, 41))	('P1446A05', 'Var', (9, 17))
514528	21253554	Trabectedin does not appear to effect transcription of FUS-CHOP, but has been shown to dissociate the aberrant transcription factor from promoters of its target genes resulting in removal of the differentiation block by activating a differentiation cascade through the C/EBPs.	('C/EBP', 'Gene', '1050', (269, 274))	('differentiation', 'MPA', (195, 210))	('activating', 'Reg', (220, 230))	('aberrant', 'Var', (102, 110))	('removal', 'NegReg', (180, 187))	('dissociate', 'NegReg', (87, 97))	('C/EBP', 'Gene', (269, 274))	('differentiation', 'CPA', (233, 248))
514529	21253554	It has been suggested that these breaks are repaired by homologous recombination (HR), as HR-deficient cells, such as BRCA2 mutants, are 100 fold more sensitive to Trabectedin.	('HR-deficient', 'Disease', (90, 102))	('mutants', 'Var', (124, 131))	('BRCA2', 'Gene', (118, 123))	('HR-deficient', 'Disease', 'MESH:D001919', (90, 102))	('more', 'PosReg', (146, 150))	('sensitive', 'MPA', (151, 160))	('BRCA2', 'Gene', '675', (118, 123))
514534	21253554	The high frequency of PIK3CA and PTEN mutations suggests a role for PI3K inhibitors in MLPS.	('PIK3CA', 'Gene', '5290', (22, 28))	('PTEN', 'Gene', (33, 37))	('MLPS', 'Disease', 'None', (87, 91))	('PTEN', 'Gene', '5728', (33, 37))	('mutations', 'Var', (38, 47))	('PIK3CA', 'Gene', (22, 28))	('MLPS', 'Disease', (87, 91))
514535	21253554	The nonisoform-specific PI3K inhibitors Wortmannin, and LY294002 have been widely used in biological research but are not particularly suited to clinical work due to their lack of specificity, Wortmannin's instability and LY294002's low potency (as reviewed).	('LY294002', 'Chemical', 'MESH:C085911', (222, 230))	('LY294002', 'Var', (56, 64))	('Wortmannin', 'Chemical', 'MESH:D000077191', (193, 203))	('LY294002', 'Var', (222, 230))	('LY294002', 'Chemical', 'MESH:C085911', (56, 64))	('Wortmannin', 'Chemical', 'MESH:D000077191', (40, 50))
514537	21253554	In lung cancer cell lines and xenograft models, PIK3CA mutants are more sensitive to GDC-0941.	('lung cancer', 'Disease', (3, 14))	('mutants', 'Var', (55, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('PIK3CA', 'Gene', (48, 54))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('PIK3CA', 'Gene', '5290', (48, 54))	('GDC-0941', 'Chemical', 'MESH:C532162', (85, 93))	('sensitive', 'MPA', (72, 81))
514538	21253554	Similarly, PIK3CA mutant and PTEN-null tumours were sensitive to PX-866 in xenograft models, and phase I clinical trials for solid tumours are currently underway.	('solid tumours', 'Disease', 'MESH:D009369', (125, 138))	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('PTEN', 'Gene', (29, 33))	('solid tumours', 'Disease', (125, 138))	('tumours', 'Disease', (131, 138))	('mutant', 'Var', (18, 24))	('PTEN', 'Gene', '5728', (29, 33))	('tumours', 'Disease', 'MESH:D009369', (39, 46))	('tumours', 'Disease', (39, 46))	('PIK3CA', 'Gene', (11, 17))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('PIK3CA', 'Gene', '5290', (11, 17))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('PX-866', 'Chemical', 'MESH:C496788', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))
514540	21253554	Both H1047R and E545K PI3K mutant cells are sensitive to Everolimus.	('E545K PI3K', 'Var', (16, 26))	('H1047R', 'Var', (5, 11))	('sensitive to Everolimus', 'MPA', (44, 67))	('Everolimus', 'Chemical', 'MESH:D000068338', (57, 67))	('H1047R', 'Mutation', 'rs121913279', (5, 11))	('PI3K', 'Var', (22, 26))	('E545K', 'Mutation', 'rs104886003', (16, 21))
514541	21253554	PIK3CA mutated MLPS represents an ideal candidate for PI3K inhibition.	('MLPS', 'Disease', (15, 19))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('MLPS', 'Disease', 'None', (15, 19))	('mutated', 'Var', (7, 14))
514570	30828621	The search was then limited to the following primary sites codes (based on the American Joint Committee on Cancer): maxillary sinus (C31.0), ethmoid sinus (C31.1), frontal sinus (C31.2), and sphenoid sinus (C31.3).	('C31.2', 'Var', (179, 184))	('Cancer', 'Disease', (107, 113))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('maxillary sinus', 'Disease', (116, 131))	('frontal sinus', 'Disease', (164, 177))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('ethmoid sinus', 'Disease', (141, 154))
514747	24999758	Ewing sarcoma is the second most common malignancy of bone and soft tissues in children and young adults and is characterized by a chromosomal translocation that generates a fusion oncogene between EWS and an Ets family transcription factor, most commonly Fli-1.- EWS-Fli-1 fusion accounts for 85% of Ewing sarcoma cases.	('fusion', 'Var', (274, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', (301, 314))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (301, 314))	('sarcoma', 'Phenotype', 'HP:0100242', (307, 314))	('malignancy of bone', 'Phenotype', 'HP:0010622', (40, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('malignancy', 'Disease', (40, 50))
514767	24999758	Online HPLC separation of the digests was accomplished with an Eksigent/AB Sciex NanoLC-Ultra 2-D HPLC system: column, PicoFrit (New Objective; 75 mum i.d.)	('PicoFrit', 'Var', (119, 127))	('mum', 'Gene', '56925', (147, 150))	('mum', 'Gene', (147, 150))
514770	24999758	Dynamic exclusion settings were: repeat count, 1; repeat duration, 30 s; exclusion list size, 500; exclusion duration, 30 s. Three 15-cm plates of 293 cells were transfected with BioID-EWS-Fli-1 (Myc tag and BirA R118G mutant fused to the N-terminus of EWS-Fli-1).	('Myc', 'Gene', '4609', (196, 199))	('EWS-Fli-1', 'Gene', (253, 262))	('Myc', 'Gene', (196, 199))	('BirA', 'Var', (208, 212))	('R118G', 'Mutation', 'rs375393848', (213, 218))
514781	24999758	In the BioID approach, a bait protein is fused to a mutated BirA biotinylase (BirA R118G) which promiscuously biotinylates the lysine residues of proteins in the vicinity (within 20-30 nm).	('lysine residues', 'MPA', (127, 142))	('R118G', 'SUBSTITUTION', 'None', (83, 88))	('proteins', 'Protein', (146, 154))	('R118G', 'Var', (83, 88))
514806	23316192	The average distribution of kappa to lambda-bearing B cells in humans is approximately 65:35%, and aberration from this ratio is indicative of lymphoproliferative disorders, reflecting dominance of one clone.	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (143, 172))	('aberration', 'Var', (99, 109))	('lymphoproliferative disorder', 'Phenotype', 'HP:0005523', (143, 171))	('lymphoproliferative disorders', 'Disease', (143, 172))	('humans', 'Species', '9606', (63, 69))	('lymphoproliferative disorders', 'Disease', 'MESH:D008232', (143, 172))
514820	23316192	Deletions of the two fragile site tumor suppressors, WWOX and FHIT, were also recently reported in PEL.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('WWOX', 'Gene', '51741', (53, 57))	('reported', 'Reg', (87, 95))	('WWOX', 'Gene', (53, 57))	('FHIT', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('FHIT', 'Gene', '2272', (62, 66))	('Deletions', 'Var', (0, 9))	('PEL', 'Disease', (99, 102))
514841	23316192	During plasmablast differentiation, IgM memory B cells acquire phenotypic markers such as Ki67+, IgM+, and CD27+, similar to MCD.	('Ki67+', 'Var', (90, 95))	('CD27', 'Gene', '939', (107, 111))	('CD27', 'Gene', (107, 111))
514849	23316192	Moreover, impaired GC formation and class switch recombination resulting from vFLIP expression suggests that inhibition of the adaptive response is a means of escaping immune surveillance.	('vFLIP', 'Gene', '4961494', (78, 83))	('expression', 'Var', (84, 94))	('GC formation', 'CPA', (19, 31))	('vFLIP', 'Gene', (78, 83))	('class switch recombination', 'CPA', (36, 62))	('impaired', 'NegReg', (10, 18))
514864	23316192	Furthermore, stimulation of Toll-like receptors (TLRs) 7 and 8 by microbes can also reactivate KSHV from latently infected cells (; stimulation of these pattern recognition receptors generates an anti-viral state, and expressed lytic proteins have many functions which antagonize the host immune system.	('KSHV', 'Species', '37296', (95, 99))	('anti-viral state', 'MPA', (196, 212))	('stimulation', 'Var', (132, 143))
514871	23316192	For recent reviews describing up-to-date targets of PI3K/AKT/mTOR signaling, their regulation, and relevance to malignancies, please refer to and  The PI3K are lipid kinases that phosphorylate the 3'-hydroxyl of the inositol ring of phosphoinositide, a component of the interior side of eukaryotic cell membranes.	("3'-hydroxyl", 'Chemical', '-', (197, 208))	('PI3K', 'Var', (151, 155))	('malignancies', 'Disease', (112, 124))	('inositol', 'Chemical', 'MESH:D007294', (216, 224))	('AKT', 'Gene', '207', (57, 60))	('malignancies', 'Disease', 'MESH:D009369', (112, 124))	('phosphoinositide', 'Chemical', 'MESH:D010716', (233, 249))	('AKT', 'Gene', (57, 60))	('lipid', 'Chemical', 'MESH:D008055', (160, 165))
514875	23316192	PI(3,4,5)P3 production by PI3K allows for pleckstrin homology (PH)-domain containing proteins to localize to the plasma membrane.	('localize', 'MPA', (97, 105))	('pleckstrin', 'Protein', (42, 52))	('PI(3,4,5)P3', 'Chemical', 'MESH:C118303', (0, 11))	('PI3K', 'Var', (26, 30))
514877	23316192	The regulatory subunits are p85alpha, p85beta, p55alpha, p55gamma and p50alpha.	('p85beta', 'Gene', (38, 45))	('p85alpha', 'Gene', '5295', (28, 36))	('p55alpha', 'Var', (47, 55))	('p55gamma', 'Gene', '8503', (57, 65))	('p50alpha', 'Var', (70, 78))	('p85beta', 'Gene', '5296', (38, 45))	('p85alpha', 'Gene', (28, 36))	('p55gamma', 'Gene', (57, 65))
514881	23316192	PTEN is one of the most frequently lost tumor suppressors in various cancers.Mutations or deletions in PTEN cause hyperactivation of PI3K signaling, leading to increased cell proliferation as well as evasion of apoptosis.	('PTEN', 'Gene', (103, 107))	('deletions', 'Var', (90, 99))	('PI3K signaling', 'Pathway', (133, 147))	('apoptosis', 'CPA', (211, 220))	('PTEN', 'Gene', '5728', (103, 107))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('evasion', 'MPA', (200, 207))	('hyperactivation', 'PosReg', (114, 129))	('increased', 'PosReg', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cell proliferation', 'CPA', (170, 188))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('cancers', 'Disease', (69, 76))
514884	23316192	Once AKT is localized to the cell membrane through its PH-domain, it is phosphorylated on Threonine308 by phosphoinositide-dependent kinase 1 (PDK1), and serine473 through the mTORC2 complex (, both of which are activating modifications.	('mTORC2', 'Gene', '74343', (176, 182))	('phosphoinositide-dependent kinase 1', 'Gene', (106, 141))	('serine473', 'Chemical', '-', (154, 163))	('PDK1', 'Gene', '5163', (143, 147))	('PDK1', 'Gene', (143, 147))	('AKT', 'Gene', '207', (5, 8))	('serine473', 'Var', (154, 163))	('Threonine308', 'Chemical', '-', (90, 102))	('AKT', 'Gene', (5, 8))	('mTORC2', 'Gene', (176, 182))	('phosphoinositide-dependent kinase 1', 'Gene', '5163', (106, 141))
514887	23316192	Phosphorylation of the FOXO transcription factors sequesters them within the cytoplasm, thus preventing them from transcriptionally activating target pro-apoptotic genes such as Fas ligand and Bim.	('FOXO transcription factors', 'Gene', (23, 49))	('preventing', 'NegReg', (93, 103))	('Fas ligand', 'Gene', '356', (178, 188))	('Phosphorylation', 'Var', (0, 15))	('transcriptionally activating', 'MPA', (114, 142))	('Fas ligand', 'Gene', (178, 188))
514918	23316192	Deregulated signaling may result from inactivation of negative regulator phosphatases, e.g., TSC2 or PTEN, or from mutations in catalytic domains of kinases, e.g., PIK3CA.	('mutations', 'Var', (115, 124))	('inactivation', 'NegReg', (38, 50))	('PIK3CA', 'Gene', (164, 170))	('PTEN', 'Gene', (101, 105))	('TSC2', 'Gene', '7249', (93, 97))	('PTEN', 'Gene', '5728', (101, 105))	('TSC2', 'Gene', (93, 97))	('PIK3CA', 'Gene', '5290', (164, 170))	('Deregulated signaling', 'MPA', (0, 21))
514932	23316192	FAK, Src, and PI3K are also phosphorylated following infection of THP-1 monocytes, as are NF-kappaB and ERK-1/2.	('Src', 'Gene', (5, 8))	('Src', 'Gene', '6714', (5, 8))	('PI3K', 'Var', (14, 18))	('THP-1', 'Gene', '2736', (66, 71))	('THP-1', 'Gene', (66, 71))	('infection of T', 'Disease', 'MESH:D001260', (53, 67))	('infection of T', 'Disease', (53, 67))	('FAK', 'Gene', (0, 3))	('FAK', 'Gene', '5747', (0, 3))	('NF-kappaB', 'Gene', '4790', (90, 99))	('NF-kappaB', 'Gene', (90, 99))	('ERK-1/2', 'Gene', (104, 111))	('ERK-1/2', 'Gene', '5595;5594', (104, 111))
514933	23316192	PI3K and Rho GTPase activation collectively induces other Rho GTPase family members, which precipitate the formation of subcellular structures such as lamellipodia (through Rac), stress fibers (through RhoA), and filopodia (through Cdc42).	('RhoA', 'Gene', '387', (202, 206))	('PI3K', 'Var', (0, 4))	('Rac', 'Gene', '207', (173, 176))	('Cdc42', 'Gene', '998', (232, 237))	('lamellipodia', 'Disease', 'None', (151, 163))	('Rac', 'Gene', (173, 176))	('stress fibers', 'CPA', (179, 192))	('Rho', 'Gene', (58, 61))	('Cdc42', 'Gene', (232, 237))	('activation', 'PosReg', (20, 30))	('RhoA', 'Gene', (202, 206))	('precipitate', 'Reg', (91, 102))	('induces', 'Reg', (44, 51))	('filopodia', 'CPA', (213, 222))	('lamellipodia', 'Disease', (151, 163))
514943	23316192	A physiological consequence of K1-mediated alteration of the cellular transcription program is the development of tumors similar to spindle-cell sarcomatoid tumor and malignant plasmablastic lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (191, 199))	('malignant plasmablastic lymphoma', 'Disease', (167, 199))	('cellular', 'MPA', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('alteration', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('sarcomatoid tumor', 'Disease', 'MESH:C538614', (145, 162))	('sarcomatoid tumor', 'Phenotype', 'HP:0100242', (145, 162))	('malignant plasmablastic lymphoma', 'Disease', 'MESH:D000069293', (167, 199))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('sarcomatoid tumor', 'Disease', (145, 162))	('K1-mediated', 'Var', (31, 42))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
514944	23316192	The regulatory p85 subunit modulates PI3K activity, and tyrosine-phosphorylation of p85 results in activation of PI3K.	('activity', 'MPA', (42, 50))	('tyrosine', 'Chemical', 'MESH:D014443', (56, 64))	('PI3K', 'Pathway', (37, 41))	('PI3K', 'Pathway', (113, 117))	('modulates', 'Reg', (27, 36))	('tyrosine-phosphorylation', 'Var', (56, 80))	('activation', 'PosReg', (99, 109))	('p85', 'Gene', '5295', (84, 87))	('p85', 'Gene', '5295', (15, 18))	('p85', 'Gene', (84, 87))	('p85', 'Gene', (15, 18))
514947	23316192	In B lymphocytes, ectopic K1 expression was found to activate AKT signaling in two simultaneous ways: K1 expression induced AKT phosphorylation on Thr308 and Ser473, and also inactivation of the negative regulator PTEN.	('inactivation', 'NegReg', (175, 187))	('AKT', 'Gene', (62, 65))	('Thr308', 'Chemical', '-', (147, 153))	('AKT', 'Gene', '207', (124, 127))	('AKT', 'Gene', (124, 127))	('PTEN', 'Gene', (214, 218))	('PTEN', 'Gene', '5728', (214, 218))	('Ser473', 'Var', (158, 164))	('Ser473', 'Chemical', '-', (158, 164))	('AKT', 'Gene', '207', (62, 65))	('Thr308', 'Var', (147, 153))	('ectopic', 'Var', (18, 25))	('activate', 'PosReg', (53, 61))
514964	23316192	In various mouse models, vGPCR expression leads to formation of vascular tumors and KS-like angioproliferative lesions, with cell surface markers and circulating cytokine profiles resembling KS.	('mouse', 'Species', '10090', (11, 16))	('vascular tumors', 'Phenotype', 'HP:0100742', (64, 79))	('vascular tumors', 'Disease', 'MESH:D019043', (64, 79))	('vGPCR', 'Gene', (25, 30))	('leads to', 'Reg', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('vascular tumors', 'Disease', (64, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('KS-like', 'Disease', (84, 91))	('vGPCR', 'Gene', '4961465', (25, 30))	('expression', 'Var', (31, 41))
514978	23316192	Inhibiting paracrine mTOR activity in non-expressing cells abrogated the tumor-promoting activities of vGPCR-expressing cells in vivo.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Inhibiting', 'Var', (0, 10))	('vGPCR', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('vGPCR', 'Gene', '4961465', (103, 108))	('tumor', 'Disease', (73, 78))	('abrogated', 'NegReg', (59, 68))
514981	23316192	In particular, the tissue-restricted gamma isoform of PI3K is crucial for relaying vGPCR signaling downstream to AKT/mTOR in endothelial cells.	('vGPCR', 'Gene', (83, 88))	('AKT', 'Gene', '207', (113, 116))	('vGPCR', 'Gene', '4961465', (83, 88))	('AKT', 'Gene', (113, 116))	('PI3K', 'Var', (54, 58))
514984	23316192	Ectopic vGPCR expression in B cells activates several transcription factors: AP-1, CREB, NF-AT, and NF-kappaB, thereby promoting cell survival, although the mechanisms of activation of these transcription factors differ.	('vGPCR', 'Gene', '4961465', (8, 13))	('AP-1', 'Gene', (77, 81))	('CREB', 'Gene', (83, 87))	('NF-kappaB', 'Gene', '4790', (100, 109))	('activates', 'PosReg', (36, 45))	('vGPCR', 'Gene', (8, 13))	('cell survival', 'CPA', (129, 142))	('Ectopic', 'Var', (0, 7))	('AP-1', 'Gene', '2353', (77, 81))	('CREB', 'Gene', '1385', (83, 87))	('promoting', 'PosReg', (119, 128))	('NF-kappaB', 'Gene', (100, 109))
514988	23316192	Pharmacologic and genetic ablation of Src family kinases abolished AP-1 and CREB transcriptional activity, confirming that these transcription factors are activated by vGPCR through a Galphai-PI3K/AKT-Src signaling axis.	('CREB', 'Gene', '1385', (76, 80))	('AP-1', 'Gene', (67, 71))	('vGPCR', 'Gene', (168, 173))	('AKT', 'Gene', '207', (197, 200))	('vGPCR', 'Gene', '4961465', (168, 173))	('Src', 'Gene', (38, 41))	('AKT', 'Gene', (197, 200))	('ablation', 'Var', (26, 34))	('Src', 'Gene', (201, 204))	('Src', 'Gene', '6714', (38, 41))	('Src', 'Gene', '6714', (201, 204))	('CREB', 'Gene', (76, 80))	('AP-1', 'Gene', '2353', (67, 71))	('abolished', 'NegReg', (57, 66))	('activated', 'PosReg', (155, 164))
515001	23316192	Thus, KSHV vIL-6 circumvents the requirement for a second receptor, thereby subverting cellular checks against uncontrolled, exuberant signaling.	('KSHV', 'Species', '37296', (6, 10))	('KSHV', 'Var', (6, 10))	('subverting', 'NegReg', (76, 86))	('vIL-6', 'Chemical', '-', (11, 16))
515013	23316192	Activated AKT promotes the expression of Prox1, a lymphatic transcription factor necessary for VEGFR-3 induction, and Prox1 itself is known to potentiate the lymphatic reprogramming of endothelial cells upon de novo KSHV infection.	('lymphatic reprogramming of endothelial cells', 'CPA', (158, 202))	('VEGF', 'Gene', '7422', (95, 99))	('AKT', 'Gene', (10, 13))	('KSHV infection', 'Disease', (216, 230))	('potentiate', 'PosReg', (143, 153))	('Prox1', 'Var', (118, 123))	('promotes', 'PosReg', (14, 22))	('Prox1', 'Gene', (41, 46))	('expression', 'MPA', (27, 37))	('VEGF', 'Gene', (95, 99))	('AKT', 'Gene', '207', (10, 13))	('KSHV infection', 'Disease', 'MESH:C537372', (216, 230))
515014	23316192	Furthermore, STAT3 amplifies this signaling cascade by activating gp130 receptor expression.	('gp130', 'Gene', (66, 71))	('gp130', 'Gene', '3572', (66, 71))	('activating', 'PosReg', (55, 65))	('STAT3', 'Var', (13, 18))	('expression', 'MPA', (81, 91))
515027	23316192	Normally, S6 and eIF4B are activated by p70 S6 kinase, itself regulated by upstream mTOR signaling; eIF4B is also a target of the p90 S6 kinase, regulated by MAPK signaling.	('p70', 'Var', (40, 43))	('eIF4B', 'Gene', '1975', (17, 22))	('eIF4B', 'Gene', '1975', (100, 105))	('eIF4B', 'Gene', (17, 22))	('eIF4B', 'Gene', (100, 105))	('activated', 'PosReg', (27, 36))
515041	23316192	As described above, K1-dependent, AKT-mediated sequestration of FOXO transcription factors and inactivation of Bad can protect B cells from apoptosis.	('AKT', 'Gene', (34, 37))	('apoptosis', 'CPA', (140, 149))	('FOXO transcription factors', 'Gene', (64, 90))	('Bad', 'Gene', (111, 114))	('AKT', 'Gene', '207', (34, 37))	('inactivation', 'Var', (95, 107))
515047	23316192	Additionally, K1 expression in primary HUVECs endows replicative immortality, primarily through the ALT pathway.	('replicative immortality', 'CPA', (53, 76))	('HUVEC', 'CellLine', 'CVCL:2959', (39, 44))	('K1 expression', 'Var', (14, 27))	('ALT pathway', 'Pathway', (100, 111))
515051	23316192	KSHV vGPCR induces VEGF and VEGF receptor 2 secretion in endothelial cells.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('VEGF', 'Gene', (28, 32))	('vGPCR', 'Gene', '4961465', (5, 10))	('secretion', 'MPA', (44, 53))	('induces', 'Reg', (11, 18))	('VEGF', 'Gene', (19, 23))	('VEGF', 'Gene', '7422', (28, 32))	('vGPCR', 'Gene', (5, 10))	('VEGF', 'Gene', '7422', (19, 23))
515052	23316192	Moreover, K1 expression in epithelial and endothelial cells also induces secretion of VEGF and the invasion factor matrix metalloprotease-9 (MMP-9; discussed below), as does KSHV infection of endothelial cells (.	('VEGF', 'Gene', (86, 90))	('induces', 'Reg', (65, 72))	('KSHV infection', 'Disease', 'MESH:C537372', (174, 188))	('VEGF', 'Gene', '7422', (86, 90))	('K1 expression', 'Var', (10, 23))	('KSHV infection', 'Disease', (174, 188))
515070	23316192	The ability to escape immune surveillance is a frequent consequence of genetic instability and aberrant signaling in tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('genetic instability', 'Var', (71, 90))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('aberrant', 'Var', (95, 103))
515071	23316192	KSHV-associated tumors are even more adept at hiding from the immune system as viral protein expression can subvert various aspects of the innate and adaptive immune response.	('KSHV', 'Species', '37296', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('viral', 'Var', (79, 84))	('KSHV-associated', 'Gene', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('subvert', 'NegReg', (108, 115))
515080	23316192	Because aberrant PI3K/AKT/mTOR signaling is a characteristic of almost all human cancers, a plethora of small molecule inhibitors exist that target various nodes of this pathway.	('AKT', 'Gene', '207', (22, 25))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('plethora', 'Phenotype', 'HP:0001050', (92, 100))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('AKT', 'Gene', (22, 25))	('aberrant', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))
515087	23316192	Specifically, rapamycin is effective at halting the proliferation of PEL in cell culture, and in a xenograft model of PEL, rapamycin inhibits tumor formation and induces tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('proliferation', 'CPA', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (142, 147))	('halting', 'NegReg', (40, 47))	('rapamycin', 'Var', (123, 132))	('induces', 'PosReg', (162, 169))	('tumor', 'Disease', (170, 175))	('rapamycin', 'Chemical', 'MESH:D020123', (123, 132))	('rapamycin', 'Chemical', 'MESH:D020123', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('inhibits', 'NegReg', (133, 141))
515090	23316192	A class of AKT inhibitors called alkyl-lysophospholipids (e.g., miltefosine and perifosine) also inhibited PEL cell proliferation both in vitro and in vivo .	('AKT', 'Gene', (11, 14))	('miltefosine', 'Chemical', 'MESH:C039128', (64, 75))	('AKT', 'Gene', '207', (11, 14))	('inhibited', 'NegReg', (97, 106))	('perifosine', 'Chemical', 'MESH:C105905', (80, 90))	('PEL cell proliferation', 'CPA', (107, 129))	('alkyl-lysophospholipids', 'Chemical', '-', (33, 56))	('miltefosine', 'Var', (64, 75))
515091	23316192	Moreover, NVP-BEZ235, a dual inhibitor of both PI3K and mTOR kinases, is a potent inhibitor of PEL cell proliferation and tumor formation in xenograft mouse models.	('mouse', 'Species', '10090', (151, 156))	('NVP-BEZ235', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('PEL cell proliferation', 'CPA', (95, 117))	('inhibitor', 'NegReg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('BEZ235', 'Chemical', 'MESH:C531198', (14, 20))	('tumor', 'Disease', (122, 127))
515120	32421448	In addition, they allow for the detection of hitherto unknown gene fusions, which may add to our current understanding of the genetic drivers of sarcoma and help inform and refine current classification schemes.	('sarcoma', 'Disease', (145, 152))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('fusions', 'Var', (67, 74))
515126	32421448	The discovery of characteristic loss-of-function mutations in SUZ12 or EED, encoding components of the polycomb repressive complex 2 (PRC2), and subsequent loss of trimethylation at lysine 27 of histone 3 (H3K27me3) led to the introduction of H3K27me3 immunohistochemistry as a useful diagnostic marker.	('mutations', 'Var', (49, 58))	('H3K27me3', 'Var', (243, 251))	('SUZ12', 'Gene', '23512', (62, 67))	('loss', 'NegReg', (156, 160))	('SUZ12', 'Gene', (62, 67))	('trimethylation', 'MPA', (164, 178))	('lysine', 'Chemical', 'MESH:D008239', (182, 188))	('EED', 'Gene', '8726', (71, 74))	('loss-of-function', 'NegReg', (32, 48))	('EED', 'Gene', (71, 74))
515130	32421448	As demonstrated recently, SMARCB1 loss in epithelioid MPNST results from inactivating mutations of SMARCB1 on chromosome 22.	('inactivating mutations', 'Var', (73, 95))	('SMARCB1', 'Gene', '6598', (26, 33))	('SMARCB1', 'Gene', '6598', (99, 106))	('SMARCB1', 'Gene', (26, 33))	('SMARCB1', 'Gene', (99, 106))	('loss', 'NegReg', (34, 38))
515132	32421448	SMARCB1 inactivation and SMARCB1 protein loss can be found in a wide range of benign and malignant mesenchymal neoplasms, including 40% of epithelioid schwannomas, which rarely give rise to epithelioid MPNST.	('epithelioid schwannomas', 'Phenotype', 'HP:0032060', (139, 162))	('schwannomas', 'Disease', 'MESH:D009442', (151, 162))	('malignant mesenchymal neoplasms', 'Disease', (89, 120))	('malignant mesenchymal neoplasms', 'Disease', 'MESH:C535700', (89, 120))	('neoplasm', 'Phenotype', 'HP:0002664', (111, 119))	('SMARCB1', 'Gene', (25, 32))	('inactivation', 'Var', (8, 20))	('benign', 'Disease', (78, 84))	('SMARCB1', 'Gene', '6598', (25, 32))	('SMARCB1', 'Gene', '6598', (0, 7))	('schwannomas', 'Phenotype', 'HP:0100008', (151, 162))	('protein', 'Protein', (33, 40))	('SMARCB1', 'Gene', (0, 7))	('neoplasms', 'Phenotype', 'HP:0002664', (111, 120))	('loss', 'NegReg', (41, 45))	('schwannomas', 'Disease', (151, 162))
515138	32421448	These tumors harbor characteristic t(4;19)(q35;q13) or t(10;19)(q26;q13), resulting mostly in CIC-DUX4 fusion (Table 2); rare cases with alternate CIC-FOXO4 fusion have been reported.	('DUX4', 'Gene', '100288687', (98, 102))	('FOXO4', 'Gene', '4303', (151, 156))	('CIC', 'Gene', (94, 97))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (35, 51))	('t(10;19)(q26;q13', 'Var', (55, 71))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('DUX4', 'Gene', (98, 102))	('tumors', 'Disease', (6, 12))	('CIC', 'Gene', '23152', (147, 150))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('CIC', 'Gene', (147, 150))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (55, 72))	('CIC', 'Gene', '23152', (94, 97))	('FOXO4', 'Gene', (151, 156))
515141	32421448	In contrast, diffuse membranous expression of CD99 and nuclear expression of the transcription factor NKX2.2 and the presence of EWSR1 rearrangement by FISH would favor a diagnosis of Ewing sarcoma (Fig.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (184, 197))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (184, 197))	('NKX2.2', 'Gene', (102, 108))	('CD99', 'Gene', '4267', (46, 50))	('rearrangement', 'Var', (135, 148))	('EWSR1', 'Gene', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('NKX2.2', 'Gene', '4821', (102, 108))	('Ewing sarcoma', 'Disease', (184, 197))	('CD99', 'Gene', (46, 50))	('EWSR1', 'Gene', '2130', (129, 134))
515142	32421448	Another distinct type of round cell sarcoma lacking EWSR1 rearrangement initially reported in 2012 with predilection for bone and soft tissue of male children is characterized by BCOR-CCNB3 rearrangement resulting from inv(X)(p11) (i.e., X-chromosomal paracentric inversion; Tables 1 and 2).	('EWSR1', 'Gene', (52, 57))	('CCNB3', 'Gene', '85417', (184, 189))	('CCNB3', 'Gene', (184, 189))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('BCOR', 'Gene', '54880', (179, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('inv(X)(p11)', 'Gene', '6281', (219, 230))	('EWSR1', 'Gene', '2130', (52, 57))	('soft', 'Gene', '25886', (130, 134))	('sarcoma', 'Disease', (36, 43))	('inv(X)(p11', 'Gene', (219, 229))	('BCOR', 'Gene', (179, 183))	('rearrangement', 'Var', (190, 203))	('children', 'Species', '9606', (150, 158))	('soft', 'Gene', (130, 134))
515149	32421448	Rearrangements of ALK at 2p23 are identified in about 50% of cases, particularly when arising in younger patients.	('ALK', 'Gene', '238', (18, 21))	('Rearrangements', 'Var', (0, 14))	('patients', 'Species', '9606', (105, 113))	('ALK', 'Gene', (18, 21))
515151	32421448	ALK rearrangement results in upregulation of ALK expression, which is detectable by immunohistochemistry (Fig.	('ALK', 'Gene', '238', (45, 48))	('rearrangement', 'Var', (4, 17))	('upregulation', 'PosReg', (29, 41))	('expression', 'MPA', (49, 59))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', (45, 48))	('ALK', 'Gene', '238', (0, 3))
515155	32421448	However, ALK expression is also found, for instance, in subsets of epithelioid and spindle cell rhabdomyosarcomas with TFCP2 fusion lacking ALK rearrangement, suggesting that ALK staining is not always associated with ALK rearrangement.	('ALK', 'Gene', (9, 12))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (96, 112))	('ALK', 'Gene', (218, 221))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (96, 113))	('ALK', 'Gene', (175, 178))	('rhabdomyosarcomas', 'Disease', (96, 113))	('ALK', 'Gene', (140, 143))	('TFCP2', 'Gene', (119, 124))	('epithelioid', 'Disease', (67, 78))	('fusion', 'Var', (125, 131))	('ALK', 'Gene', '238', (9, 12))	('ALK', 'Gene', '238', (218, 221))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (96, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('ALK', 'Gene', '238', (140, 143))	('TFCP2', 'Gene', '7024', (119, 124))	('ALK', 'Gene', '238', (175, 178))
515162	32421448	The discovery of recurrent t(1;3)(p36.3; q25) translocation in 2011 in approximately 90% of cases resulting in WWTR1-CAMTA1 fusion, led to the development of a highly specific and sensitive CAMTA1 immunohistochemical stain for the diagnosis of EHE in distinction from histologic mimics (Tables 1 and 2).	('WWTR1', 'Gene', (111, 116))	('resulting in', 'Reg', (98, 110))	('WWTR1', 'Gene', '25937', (111, 116))	('EHE', 'Disease', (244, 247))	('CAMTA1', 'Gene', '23261', (190, 196))	('translocation', 'Var', (46, 59))	('CAMTA1', 'Gene', (117, 123))	('EHE', 'Phenotype', 'HP:0032060', (244, 247))	('CAMTA1', 'Gene', (190, 196))	('CAMTA1', 'Gene', '23261', (117, 123))
515163	32421448	A small subset (< 10% of cases) lack WWTR1-CAMTA1 fusion and instead harbor alternate YAP1-TFE3 fusion resulting from t(X;11)(p11;q22) (Tables 1 and 2).	('CAMTA1', 'Gene', (43, 49))	('TFE3', 'Gene', (91, 95))	('WWTR1', 'Gene', (37, 42))	('WWTR1', 'Gene', '25937', (37, 42))	('t(X;11)(p11;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (118, 134))	('CAMTA1', 'Gene', '23261', (43, 49))	('YAP1', 'Gene', (86, 90))	('t(X;11)(p11;q22', 'Var', (118, 133))	('lack', 'NegReg', (32, 36))	('YAP1', 'Gene', '10413', (86, 90))	('TFE3', 'Gene', '7030', (91, 95))
515166	32421448	Pseudomyogenic hemangioendothelioma (PHE), another vascular neoplasm of intermediate biologic potential, was recently found to harbor recurrent SERPINE1-FOSB fusion resulting from t(7;19)(q22;q13); rare cases of PHE with alternate ACTB-FOSB fusion have been described.FOSB rearrangement leading to FOSB overexpression can be detected by recently introduced FOSB immunohistochemistry, which is positive in 96% of cases of PHE (Table 1).	('FOSB', 'Gene', '2354', (268, 272))	('FOSB', 'Gene', '2354', (236, 240))	('FOSB', 'Gene', '2354', (298, 302))	('t(7;19)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (180, 196))	('vascular neoplasm', 'Disease', (51, 68))	('neoplasm', 'Phenotype', 'HP:0002664', (60, 68))	('FOSB', 'Gene', (268, 272))	('rearrangement', 'Var', (273, 286))	('PHE', 'Chemical', '-', (421, 424))	('ACTB', 'Gene', (231, 235))	('ACTB', 'Gene', '60', (231, 235))	('FOSB', 'Gene', (236, 240))	('FOSB', 'Gene', (298, 302))	('vascular neoplasm', 'Disease', 'MESH:D019043', (51, 68))	('vascular neoplasm', 'Phenotype', 'HP:0100742', (51, 68))	('SERPINE1', 'Gene', (144, 152))	('FOSB', 'Gene', '2354', (153, 157))	('PHE', 'Chemical', '-', (212, 215))	('Pseudomyogenic hemangioendothelioma', 'Disease', (0, 35))	('FOSB', 'Gene', '2354', (357, 361))	('overexpression', 'PosReg', (303, 317))	('SERPINE1', 'Gene', '5054', (144, 152))	('Pseudomyogenic hemangioendothelioma', 'Disease', 'MESH:D006390', (0, 35))	('PHE', 'Chemical', '-', (37, 40))	('FOSB', 'Gene', (153, 157))	('FOSB', 'Gene', (357, 361))
515167	32421448	However, subsets of other vascular neoplasms may harbor FOSB rearrangement, such as the "cellular variant" of epithelioid hemangioma (i.e., ZFP36-FOSB or WWTR1-FOSB), with positive FOSB staining demonstrated in approximately 50% of cases.	('FOSB', 'Gene', (56, 60))	('rearrangement', 'Var', (61, 74))	('WWTR1', 'Gene', (154, 159))	('FOSB', 'Gene', (181, 185))	('vascular neoplasms', 'Disease', (26, 44))	('hemangioma', 'Disease', 'MESH:D006391', (122, 132))	('FOSB', 'Gene', '2354', (146, 150))	('ZFP36', 'Gene', '7538', (140, 145))	('neoplasm', 'Phenotype', 'HP:0002664', (35, 43))	('hemangioma', 'Disease', (122, 132))	('neoplasms', 'Phenotype', 'HP:0002664', (35, 44))	('FOSB', 'Gene', (146, 150))	('FOSB', 'Gene', '2354', (160, 164))	('vascular neoplasm', 'Phenotype', 'HP:0100742', (26, 43))	('vascular neoplasms', 'Disease', 'MESH:D019043', (26, 44))	('vascular neoplasms', 'Phenotype', 'HP:0100742', (26, 44))	('WWTR1', 'Gene', '25937', (154, 159))	('FOSB', 'Gene', '2354', (56, 60))	('FOSB', 'Gene', (160, 164))	('hemangioma', 'Phenotype', 'HP:0001028', (122, 132))	('epithelioid hemangioma', 'Phenotype', 'HP:0032060', (110, 132))	('FOSB', 'Gene', '2354', (181, 185))	('ZFP36', 'Gene', (140, 145))
515171	32421448	3G-I), which can be detected by immunohistochemical staining for MYC and by genomic evidence of high-level copy number gain at 8q24.21.	('MYC', 'Gene', '4609', (65, 68))	('MYC', 'Gene', (65, 68))	('copy number gain', 'Var', (107, 123))
515175	32421448	As an example, various solid tumors (including rare benign and malignant mesenchymal neoplasms) harbor fusions of NTRK1, NTRK2, or NTRK3 encoding neurotrophic tyrosine kinases NTRK1-3 (i.e., TRKA-C), which are generally believed to be mutually exclusive with other genomic aberrations.	('fusions', 'Var', (103, 110))	('TRK', 'Gene', (132, 135))	('neoplasms', 'Phenotype', 'HP:0002664', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('NTRK1', 'Gene', '4914', (176, 181))	('NTRK1-3', 'Gene', '4914;4915;4916', (176, 183))	('TRK', 'Gene', (115, 118))	('NTRK1', 'Gene', '4914', (114, 119))	('TRK', 'Gene', (177, 180))	('TRK', 'Gene', '4914', (132, 135))	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))	('NTRK1', 'Gene', (176, 181))	('NTRK2', 'Gene', '4915', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('NTRK1', 'Gene', (114, 119))	('TRK', 'Gene', (122, 125))	('tumors', 'Disease', (29, 35))	('TRK', 'Gene', (191, 194))	('TRK', 'Gene', '4914', (115, 118))	('TRK', 'Gene', '4914', (177, 180))	('NTRK3', 'Gene', '4916', (131, 136))	('NTRK3', 'Gene', (131, 136))	('TRK', 'Gene', '4914', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('NTRK2', 'Gene', (121, 126))	('TRK', 'Gene', '4914', (191, 194))	('NTRK1-3', 'Gene', (176, 183))	('malignant mesenchymal neoplasms', 'Disease', 'MESH:C535700', (63, 94))	('malignant mesenchymal neoplasms', 'Disease', (63, 94))
515177	32421448	A recently introduced "pan-TRK" immunohistochemical stain has been shown to be highly sensitive but not entirely specific for tumors with NTRK fusions and can be expressed, for instance, in ALK-rearranged tumors.	('ALK', 'Gene', (190, 193))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('TRK', 'Gene', (139, 142))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('TRK', 'Gene', '4914', (139, 142))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ALK', 'Gene', '238', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('TRK', 'Gene', (27, 30))	('fusions', 'Var', (143, 150))	('TRK', 'Gene', '4914', (27, 30))	('tumors', 'Disease', (205, 211))
515179	32421448	A recent retrospective analysis evaluated the performance of immunohistochemistry and DNA-based NGS to detect NTRK fusions relative to RNA-based NGS.	('fusions', 'Var', (115, 122))	('TRK', 'Gene', (111, 114))	('TRK', 'Gene', '4914', (111, 114))
515180	32421448	Among a total of 33,997 patients, the authors identified 87 patients with oncogenic NTRK1-3 fusions in solid tumors.	('NTRK1-3', 'Gene', '4914;4915;4916', (84, 91))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('patients', 'Species', '9606', (60, 68))	('fusions', 'Var', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('patients', 'Species', '9606', (24, 32))	('tumors', 'Disease', (109, 115))	('NTRK1-3', 'Gene', (84, 91))
515181	32421448	The reported sensitivity and specificity for detection of NTRK fusions were 81.1% and 99.9% for DNA-based sequencing and 87.9% and 81.1% for immunohistochemistry, respectively.	('TRK', 'Gene', (59, 62))	('TRK', 'Gene', '4914', (59, 62))	('fusions', 'Var', (63, 70))
515182	32421448	Specifically, immunohistochemistry showed 96% to 100% sensitivity for fusions of NTRK1 and NTRK2 but only 79% sensitivity for NTRK3.	('NTRK3', 'Gene', (126, 131))	('NTRK2', 'Gene', (91, 96))	('NTRK1', 'Gene', '4914', (81, 86))	('NTRK3', 'Gene', '4916', (126, 131))	('NTRK2', 'Gene', '4915', (91, 96))	('NTRK1', 'Gene', (81, 86))	('fusions', 'Var', (70, 77))
515184	32421448	Lipofibromatosis-like neural tumor, which harbors morphologic resemblance to lipofibromatosis but exhibits locally aggressive behavior in children and young adults, has recurrent NTRK1 rearrangement and expresses pan-TRK (Fig.	('TRK', 'Gene', (180, 183))	('NTRK1', 'Gene', (179, 184))	('lipofibromatosis', 'Disease', (77, 93))	('Lipofibromatosis-like neural tumor', 'Disease', (0, 34))	('children', 'Species', '9606', (138, 146))	('TRK', 'Gene', '4914', (180, 183))	('rearrangement', 'Var', (185, 198))	('lipofibromatosis', 'Disease', 'None', (77, 93))	('aggressive behavior', 'Phenotype', 'HP:0000718', (115, 134))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('NTRK1', 'Gene', '4914', (179, 184))	('TRK', 'Gene', (217, 220))	('Lipofibromatosis-like neural tumor', 'Disease', 'MESH:C536408', (0, 34))	('TRK', 'Gene', '4914', (217, 220))
515254	32421448	Tailoring radiation dose and volumes to tumor subtypes:as defined not only by histology but also by biology:will further amplify the potential impact of RT on patients with sarcoma.	('Tailoring', 'Var', (0, 9))	('sarcoma', 'Disease', (173, 180))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('amplify', 'PosReg', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patients', 'Species', '9606', (159, 167))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))
515336	29056442	Prior taxane/platinum use (2-year SAR rate, 62.1% versus 39.7%, P =0.019), absence of prior whole pelvic irradiation (52.2% versus 31.6%, P = 0.004), distant recurrence (54.6% versus 26.8%, P = 0.001), and disease-free interval >=6 months (61.9% versus 40.0%, P = 0.002) were statistically associated with improved SAR with taxane/platinum regimen as the first-line salvage chemotherapy.	('SAR', 'Species', '2698737', (315, 318))	('taxane', 'Chemical', 'MESH:C080625', (324, 330))	('SAR', 'Species', '2698737', (34, 37))	('absence', 'Var', (75, 82))	('platinum', 'Chemical', 'MESH:D010984', (331, 339))	('improved', 'PosReg', (306, 314))	('SAR', 'MPA', (315, 318))	('platinum', 'Chemical', 'MESH:D010984', (13, 21))	('taxane', 'Chemical', 'MESH:C080625', (6, 12))
515377	29056442	Survival after recurrence was higher in TP regimen compared to non-TP regimen.	('higher', 'PosReg', (30, 36))	('Survival', 'MPA', (0, 8))	('TP', 'Chemical', '-', (67, 69))	('TP', 'Chemical', '-', (40, 42))	('TP regimen', 'Var', (40, 50))
515635	31164132	Hematological tests showed leukocytosis (12.9 x 103 muL) with thrombocytosis (664 x 103 muL), elevated erythrocyte sedimentation rate (87 mm/hr) along with increased C-reactive protein level (86.2 mg/L).	('leukocytosis', 'Disease', (27, 39))	('C-reactive protein', 'Gene', (166, 184))	('C-reactive protein', 'Gene', '1401', (166, 184))	('664 x', 'Var', (78, 83))	('elevated', 'PosReg', (94, 102))	('thrombocytosis', 'Disease', (62, 76))	('elevated erythrocyte sedimentation', 'Phenotype', 'HP:0003565', (94, 128))	('increased', 'PosReg', (156, 165))	('elevated erythrocyte', 'Phenotype', 'HP:0001901', (94, 114))	('thrombocytosis', 'Phenotype', 'HP:0001894', (62, 76))	('leukocytosis', 'Disease', 'MESH:D007964', (27, 39))	('leukocytosis', 'Phenotype', 'HP:0001974', (27, 39))	('thrombocytosis', 'Disease', 'MESH:D013922', (62, 76))	('increased C-reactive protein level', 'Phenotype', 'HP:0011227', (156, 190))	('erythrocyte sedimentation', 'Phenotype', 'HP:0003565', (103, 128))
515640	31164132	Computerized tomography (CT) also detected a large heterogeneous solid mass (131 x 129 mm) in the lower-mid portion of the right kidney with the extension to the hilum causing renal parenchymal destruction.	('renal parenchyma', 'Disease', 'MESH:D007674', (176, 192))	('renal parenchyma', 'Disease', (176, 192))	('heterogeneous', 'MPA', (51, 64))	('131 x 129 mm', 'Var', (77, 89))
515687	29808414	There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability.	('chromosomal instability', 'Phenotype', 'HP:0040012', (150, 173))	('aggressiveness', 'Disease', (98, 112))	('aggressiveness', 'Phenotype', 'HP:0000718', (98, 112))	('aggressiveness', 'Disease', 'MESH:D001523', (98, 112))	('chromosomal instability', 'Var', (150, 173))
515743	29808414	If epithelial origin of the lesion is confirmed (CK+ , S100-, vimentin +- and LCA-), a combination of CK7 and CK20 will give a first indication of the organ in which the tumour is most likely to have originated.	('CK+', 'Var', (49, 52))	('CK20', 'Gene', (110, 114))	('CK20', 'Gene', '54474', (110, 114))	('tumour', 'Disease', (170, 176))	('S100-, vimentin +- and LCA-', 'Gene', (55, 82))	('S100-, vimentin +- and LCA-)', 'Gene', '5788', (55, 83))	('CK7', 'Gene', (102, 105))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('CK7', 'Gene', '3855', (102, 105))	('tumour', 'Disease', 'MESH:D009369', (170, 176))
515771	29808414	The main objection to using massively parallel sequencing in CUP arises from the belief that the potential drug response conferred by a given mutation depends on the type of tumour in which the mutation is found.	('mutation', 'Var', (142, 150))	('tumour', 'Disease', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))
515825	29808414	The most common mutations were in TP53, KRAS, and PIK3CA.	('TP53', 'Gene', (34, 38))	('PIK3CA', 'Gene', '5290', (50, 56))	('common', 'Reg', (9, 15))	('KRAS', 'Gene', (40, 44))	('mutations', 'Var', (16, 25))	('KRAS', 'Gene', '3845', (40, 44))	('PIK3CA', 'Gene', (50, 56))	('TP53', 'Gene', '7157', (34, 38))
515826	29808414	EGFR abnormalities, ERBB2 alterations, and BRAF V600E mutations were found in 5.9, 3.6, and 1.6% of cases, respectively.	('EGFR', 'Gene', (0, 4))	('V600E', 'Var', (48, 53))	('BRAF', 'Gene', '673', (43, 47))	('ERBB2', 'Gene', '2064', (20, 25))	('abnormalities', 'Var', (5, 18))	('BRAF', 'Gene', (43, 47))	('alterations', 'Var', (26, 37))	('ERBB2', 'Gene', (20, 25))	('V600E', 'Mutation', 'rs113488022', (48, 53))	('EGFR', 'Gene', '1956', (0, 4))
515828	29808414	As well as MMR mutations, other promising biomarkers that may help with immunotherapy, such as tumour mutational burden, are being tested intensively and may play an important role in CUP treatment strategies.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('mutations', 'Var', (15, 24))	('men', 'Species', '9606', (193, 196))	('tumour', 'Disease', (95, 101))	('MMR', 'Gene', (11, 14))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
515838	28816792	Cytogenetic and mutation profiling of the leukemia cells revealed the DNA-topoisomerase-II-inhibitor-associated t(9;11)(p22;q23) translocation and clonal KRAS and BRAF mutations.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('KRAS', 'Gene', '3845', (154, 158))	('t(9;11)(p22;q23) translocation', 'Var', (112, 142))	('leukemia', 'Disease', (42, 50))	('t(9;11)(p22;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 128))	('leukemia', 'Disease', 'MESH:D007938', (42, 50))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('KRAS', 'Gene', (154, 158))	('mutations', 'Var', (168, 177))
515855	28816792	Flow cytometry confirmed the diagnosis of M4-5 AML.	('M4-5', 'Var', (42, 46))	('AML', 'Phenotype', 'HP:0004808', (47, 50))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('AML', 'Disease', (47, 50))
515865	28816792	Cytogenetic evaluation revealed 46, XX, t(9;11)(p22;q23) and FISH studies showed a MLL-gene rearrangement signal pattern in 96.0% of nuclei.	('t(9;11)(p22;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (40, 56))	('t(9;11)(p22;q23', 'Var', (40, 55))	('MLL', 'Gene', (83, 86))	('MLL', 'Gene', '4297', (83, 86))
515866	28816792	Institutional cancer mutation profile testing (Ion-AmpliSeqTMCancer-HotSpot-Panel-V2; Life Technologies, Carlsbad, CA) revealed mutations in KRAS (c.182_183delinsGC, p. Q61R) and BRAF (c.1799T > A, p.V600E) with allelic frequencies of 36% and 5.4%, respectively (Fig.	('cancer', 'Disease', (14, 20))	('Q61R', 'SUBSTITUTION', 'None', (169, 173))	('p.V600E', 'Mutation', 'rs113488022', (198, 205))	('KRAS', 'Gene', (141, 145))	('KRAS', 'Gene', '3845', (141, 145))	('c.182_183delinsGC', 'Mutation', 'rs121913240', (147, 164))	('BRAF', 'Gene', '673', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('p.V600E', 'Var', (198, 205))	('BRAF', 'Gene', (179, 183))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('Q61R', 'Var', (169, 173))	('c.1799T > A', 'Mutation', 'rs113488022', (185, 196))
515876	28816792	DNA-topoisomerase-II-inhibitor-associated (epipodophyllotoxin/anthracycline) t-MDS/AML usually develops 1.5 to 3 years after exposure and is associated with balanced translocations involving chromosome bands 11q23 (most common), 21q22, t(8;21) (q22q22), t(3;21), inv(16)(p13q22), t(8;16), t(15;17)(q22,12), and t(9;22).	('t(8;16', 'Var', (280, 286))	('AML', 'Disease', (83, 86))	('t(3;21', 'Var', (254, 260))	('AML', 'Phenotype', 'HP:0004808', (83, 86))	('associated', 'Reg', (141, 151))	('epipodophyllotoxin', 'Chemical', 'MESH:D011034', (43, 61))	('MDS', 'Phenotype', 'HP:0002863', (79, 82))	('AML', 'Disease', 'MESH:D015470', (83, 86))	('MDS', 'Disease', (79, 82))	('MDS', 'Disease', 'MESH:D009190', (79, 82))
515882	28816792	No mutations in FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, or FANCL were detected and our patient had no physical features suggestive of Fanconi anemia.	('Fanconi anemia', 'Disease', 'MESH:D005199', (137, 151))	('FANCC', 'Gene', '2176', (23, 28))	('FANCF', 'Gene', '2188', (45, 50))	('FANCD2', 'Gene', '2177', (30, 36))	('FANCG', 'Gene', '2189', (52, 57))	('FANCC', 'Gene', (23, 28))	('FANCA', 'Gene', '2175', (16, 21))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (137, 151))	('FANCF', 'Gene', (45, 50))	('FANCL', 'Gene', (62, 67))	('FANCA', 'Gene', (16, 21))	('FANCL', 'Gene', '55120', (62, 67))	('FANCE', 'Gene', (38, 43))	('FANCG', 'Gene', (52, 57))	('FANCE', 'Gene', '2178', (38, 43))	('anemia', 'Phenotype', 'HP:0001903', (145, 151))	('Fanconi anemia', 'Disease', (137, 151))	('FANCD2', 'Gene', (30, 36))	('patient', 'Species', '9606', (90, 97))	('mutations', 'Var', (3, 12))
515884	28816792	The mechanism of secondary malignancy is proposed to be the result of a stimulated blast proliferation following DNA damage to hematopoietic stem cells.	('blast proliferation', 'CPA', (83, 102))	('malignancy', 'Disease', 'MESH:D009369', (27, 37))	('malignancy', 'Disease', (27, 37))	('damage', 'Var', (117, 123))	('stimulated', 'PosReg', (72, 82))
515888	28816792	Notably, t-MDS/AML with RAS/BRAF mutations is associated with a very short survival (median survival 1-month, P = 0.017).	('BRAF', 'Gene', '673', (28, 32))	('AML', 'Disease', 'MESH:D015470', (15, 18))	('AML', 'Disease', (15, 18))	('mutations', 'Var', (33, 42))	('AML', 'Phenotype', 'HP:0004808', (15, 18))	('MDS', 'Phenotype', 'HP:0002863', (11, 14))	('BRAF', 'Gene', (28, 32))	('MDS', 'Disease', (11, 14))	('MDS', 'Disease', 'MESH:D009190', (11, 14))
515889	28816792	We did an English language search in Ovid, Google Scholar, and PubMed using the keywords "t-AML" and "KRAS and BRAF" and found only one report of concurrent KRAS-13D and BRAF-V600E subclonal disease t-MDS/AML in a 69-year-old female who received primary therapy for small cell lung cancer, diagnosed with t-AML 11 months into her primary therapy.	('MDS', 'Disease', 'MESH:D009190', (201, 204))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (266, 288))	('BRAF', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (111, 115))	('V600E', 'SUBSTITUTION', 'None', (175, 180))	('MDS', 'Disease', (201, 204))	('AML', 'Disease', 'MESH:D015470', (205, 208))	('AML', 'Phenotype', 'HP:0004808', (205, 208))	('AML', 'Disease', (205, 208))	('small cell lung cancer', 'Disease', 'MESH:D055752', (266, 288))	('AML', 'Disease', 'MESH:D015470', (307, 310))	('KRAS', 'Gene', '3845', (102, 106))	('BRAF', 'Gene', '673', (170, 174))	('small cell lung cancer', 'Disease', (266, 288))	('KRAS', 'Gene', '3845', (157, 161))	('MDS', 'Phenotype', 'HP:0002863', (201, 204))	('BRAF', 'Gene', (170, 174))	('AML', 'Disease', (307, 310))	('AML', 'Disease', 'MESH:D015470', (92, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('AML', 'Phenotype', 'HP:0004808', (307, 310))	('AML', 'Phenotype', 'HP:0004808', (92, 95))	('KRAS', 'Gene', (157, 161))	('AML', 'Disease', (92, 95))	('KRAS', 'Gene', (102, 106))	('V600E', 'Var', (175, 180))
515892	28816792	In the case of our patient, the early and aggressive disease may have been the result of the MLL-MLLT3 gene fusion and the concurrent mutations in KRAS and BRAF.	('KRAS', 'Gene', '3845', (147, 151))	('aggressive disease', 'Disease', (42, 60))	('patient', 'Species', '9606', (19, 26))	('BRAF', 'Gene', (156, 160))	('MLLT3', 'Gene', (97, 102))	('MLLT3', 'Gene', '4300', (97, 102))	('aggressive disease', 'Disease', 'MESH:D001523', (42, 60))	('MLL', 'Gene', '4297', (93, 96))	('MLL', 'Gene', (97, 100))	('result', 'Reg', (79, 85))	('mutations', 'Var', (134, 143))	('MLL', 'Gene', '4297', (97, 100))	('MLL', 'Gene', (93, 96))	('KRAS', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (156, 160))
515894	28978183	Noncoding RNA in drug resistant sarcoma Sarcomas are a group of malignant tumors that arise from mesenchymal origin.	('Sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('malignant tumors', 'Disease', (64, 80))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('sarcoma', 'Disease', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('malignant tumors', 'Disease', 'MESH:D018198', (64, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Noncoding RNA', 'Var', (0, 13))	('Sarcomas', 'Disease', (40, 48))	('Sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
515897	28978183	Sarcoma biology has traditionally focused on genomic and epigenomic deregulation of protein-coding genes to identify the therapeutic potential for reversing drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (157, 172))	('Sarcoma', 'Disease', (0, 7))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('deregulation', 'Var', (68, 80))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
515910	28978183	ncRNAs have emerged as a class of cellular regulators involved in biological processes such as proliferation, differentiation, apoptosis and cell cycle, whereas mutations and dysregulation of ncRNAs have been linked to diverse human diseases, including sarcomas.	('sarcomas', 'Disease', (253, 261))	('dysregulation', 'Var', (175, 188))	('human', 'Species', '9606', (227, 232))	('ncRNA', 'Gene', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('sarcomas', 'Phenotype', 'HP:0100242', (253, 261))	('sarcomas', 'Disease', 'MESH:D012509', (253, 261))	('ncRNA', 'Gene', (192, 197))	('mutations', 'Var', (161, 170))	('ncRNA', 'Gene', '220202', (192, 197))	('ncRNA', 'Gene', '220202', (0, 5))	('linked', 'Reg', (209, 215))
515923	28978183	However, recent studies have revealed that ncRNAs could be deregulated or mutated in many human cancers and they play an important role in pathological processes, including in tumorigenesis, metastasis and treatment resistance.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ncRNA', 'Gene', (43, 48))	('role', 'Reg', (131, 135))	('tumor', 'Disease', (176, 181))	('play', 'Reg', (113, 117))	('metastasis', 'CPA', (191, 201))	('human', 'Species', '9606', (90, 95))	('mutated', 'Var', (74, 81))	('treatment resistance', 'CPA', (206, 226))	('ncRNA', 'Gene', '220202', (43, 48))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
515925	28978183	Mutations, amplifications or deletions within oncogenes and/or tumor suppressors were considered to be associated with the development of drug resistance.	('tumor', 'Disease', (63, 68))	('oncogenes', 'Gene', (46, 55))	('associated', 'Reg', (103, 113))	('drug resistance', 'Phenotype', 'HP:0020174', (138, 153))	('amplifications', 'Var', (11, 25))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('deletions', 'Var', (29, 38))
515927	28978183	ncRNAs, mainly in the form of miRs and lncRNAs, have been linked to sarcoma drug resistance through abnormal gene regulation related to the activity of drug efflux transporters; the activation of drug target mutations or changes; DNA repair and cell cycle arrest; apoptosis and cell-survival pathways; cancer stem cells (CSCs) and autophagy involved signaling pathways.	('miR', 'Gene', (30, 33))	('linked', 'Reg', (58, 64))	('changes', 'Var', (221, 228))	('mutations', 'Var', (208, 217))	('DNA repair', 'CPA', (230, 240))	('drug resistance', 'Phenotype', 'HP:0020174', (76, 91))	('cell cycle arrest', 'CPA', (245, 262))	('cancer', 'Disease', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('autophagy', 'CPA', (331, 340))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('sarcoma', 'Disease', (68, 75))	('drug efflux transporters', 'MPA', (152, 176))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (245, 262))	('ncRNA', 'Gene', (0, 5))	('activation', 'PosReg', (182, 192))	('apoptosis', 'CPA', (264, 273))	('ncRNA', 'Gene', '220202', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('activity', 'MPA', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('miR', 'Gene', '220972', (30, 33))	('ncRNA', 'Gene', (40, 45))	('ncRNA', 'Gene', '220202', (40, 45))	('cell-survival', 'CPA', (278, 291))
515932	28978183	Mutation patterns or aberrant expressions of miRs have been detected in sarcoma and have been associated with clinical features such as progression, metastasis and drug resistance.	('sarcoma', 'Disease', (72, 79))	('expressions', 'MPA', (30, 41))	('aberrant', 'Var', (21, 29))	('drug resistance', 'Phenotype', 'HP:0020174', (164, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('detected', 'Reg', (60, 68))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('associated', 'Reg', (94, 104))	('Mutation patterns', 'Var', (0, 17))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))
515956	28978183	Inhibition of DTL induced G2-arrest and decreased cell proliferation.	('DTL', 'Gene', (14, 17))	('G2-arrest', 'Disease', 'MESH:D006323', (26, 35))	('G2-arrest', 'Disease', (26, 35))	('Inhibition', 'Var', (0, 10))	('decreased', 'NegReg', (40, 49))	('DTL', 'Gene', '51514', (14, 17))	('cell proliferation', 'CPA', (50, 68))
515962	28978183	Treatment with a PLK1 inhibitor potently induced G2-M cell cycle arrest and apoptosis in liposarcoma cells, indicating that miR-143 could be a therapeutic target for the reversal of drug resistance.	('inhibitor', 'Var', (22, 31))	('drug resistance', 'Phenotype', 'HP:0020174', (182, 197))	('G2-M cell cycle arrest', 'CPA', (49, 71))	('liposarcoma', 'Disease', (89, 100))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('PLK1', 'Gene', (17, 21))	('PLK1', 'Gene', '5347', (17, 21))	('induced', 'Reg', (41, 48))	('liposarcoma', 'Disease', 'MESH:D008080', (89, 100))	('liposarcoma', 'Phenotype', 'HP:0012034', (89, 100))	('miR-143', 'Gene', '406935', (124, 131))	('apoptosis', 'CPA', (76, 85))	('miR-143', 'Gene', (124, 131))
515975	28978183	Loss of miR-34a is mainly caused by inactivating mutations of p53, genetic alterations of the region Chr1p36 (which contains the coding region for miR-34a), or epigenetic changes.	('epigenetic changes', 'Var', (160, 178))	('miR-34a', 'Gene', '407040', (8, 15))	('p53', 'Gene', (62, 65))	('genetic alterations', 'Var', (67, 86))	('miR-34a', 'Gene', (8, 15))	('Loss', 'NegReg', (0, 4))	('inactivating mutations', 'Var', (36, 58))	('miR-34a', 'Gene', '407040', (147, 154))	('miR-34a', 'Gene', (147, 154))	('p53', 'Gene', '7157', (62, 65))
515993	28978183	Loss of miR-497 induced drug resistance through targeting vascular endothelial growth factor A (VEGFA) in osteosarcoma.	('induced', 'Reg', (16, 23))	('osteosarcoma', 'Disease', (106, 118))	('vascular endothelial growth factor A', 'Gene', (58, 94))	('VEGFA', 'Gene', (96, 101))	('miR-497', 'Gene', (8, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (106, 118))	('drug resistance', 'Phenotype', 'HP:0020174', (24, 39))	('targeting', 'Reg', (48, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('vascular endothelial growth factor A', 'Gene', '7422', (58, 94))	('VEGFA', 'Gene', '7422', (96, 101))	('miR-497', 'Gene', '574456', (8, 15))	('drug resistance', 'MPA', (24, 39))	('Loss', 'Var', (0, 4))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
515995	28978183	With depletive VEGFA, decreased miR-497 induced Akt activation, resulting in resistance to CDDP.	('CDDP', 'Chemical', 'MESH:D002945', (91, 95))	('Akt', 'Gene', (48, 51))	('VEGFA', 'Gene', '7422', (15, 20))	('depletive', 'Var', (5, 14))	('resistance to CDDP', 'MPA', (77, 95))	('VEGFA', 'Gene', (15, 20))	('Akt', 'Gene', '207', (48, 51))	('miR-497', 'Gene', '574456', (32, 39))	('miR-497', 'Gene', (32, 39))	('decreased', 'NegReg', (22, 31))	('activation', 'PosReg', (52, 62))
516016	28978183	CSCs in sarcoma can also induce evasion of apoptosis through p53 and Rb pathways to resist chemotherapeutic drugs.	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('CSCs', 'Var', (0, 4))	('evasion', 'MPA', (32, 39))	('induce', 'Reg', (25, 31))	('p53', 'Gene', (61, 64))	('apoptosis', 'MPA', (43, 52))	('sarcoma', 'Disease', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('p53', 'Gene', '7157', (61, 64))	('Rb pathways', 'Pathway', (69, 80))
516020	28978183	Recent findings have suggested that dysregulated miRs are closely connected to autophagy modulation and cancer drug resistance (Figure 4).	('autophagy modulation', 'CPA', (79, 99))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('dysregulated', 'Var', (36, 48))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('connected', 'Reg', (66, 75))	('drug resistance', 'Phenotype', 'HP:0020174', (111, 126))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
516021	28978183	Thus, inhibition of autophagy can re-sensitize resistant cancer cells and enhance cytotoxicity of chemotherapeutic agents.	('autophagy', 'CPA', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cytotoxicity', 'Disease', (82, 94))	('inhibition', 'Var', (6, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('enhance', 'PosReg', (74, 81))
516039	28978183	The misregulated lncRNAs can function as decoys, scaffolds, signals or guides for specific regulatory modules, resulting in a gene expression profile in favor of cancer drug resistance development (Table 3).	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('misregulated', 'Var', (4, 16))	('drug resistance', 'Phenotype', 'HP:0020174', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('ncRNA', 'Gene', (18, 23))	('ncRNA', 'Gene', '220202', (18, 23))	('gene expression profile', 'MPA', (126, 149))
516041	28978183	This lncRNA-mRNA co-expression network identified that upregulated expression of lncRNA EST00000563280 and downregulated expression of lncRNA NR-036444 could stimulate the expression of Pgp to transport the drugs out of the cell, leading to drug resistance to DOX in osteosarcoma (Figure 2).	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('osteosarcoma', 'Disease', (267, 279))	('osteosarcoma', 'Disease', 'MESH:D012516', (267, 279))	('drug resistance', 'Phenotype', 'HP:0020174', (241, 256))	('ncRNA', 'Gene', (82, 87))	('stimulate', 'PosReg', (158, 167))	('ncRNA', 'Gene', '220202', (82, 87))	('leading to', 'Reg', (230, 240))	('Pgp', 'Gene', (186, 189))	('Pgp', 'Gene', '283871', (186, 189))	('ncRNA', 'Gene', (136, 141))	('ncRNA', 'Gene', '220202', (136, 141))	('DOX', 'Chemical', 'MESH:D004317', (260, 263))	('osteosarcoma', 'Phenotype', 'HP:0002669', (267, 279))	('EST00000563280', 'Var', (88, 102))	('transport the drugs out of the cell', 'MPA', (193, 228))	('ncRNA', 'Gene', (6, 11))	('expression', 'MPA', (172, 182))	('upregulated', 'PosReg', (55, 66))	('downregulated', 'NegReg', (107, 120))	('drug resistance to DOX', 'MPA', (241, 263))	('ncRNA', 'Gene', '220202', (6, 11))
516047	28978183	The novel lncRNA EST00000563280, termed osteosarcoma DOX-resistance related upregulated lncRNA (ODRUL), was the most upregulated lncRNA in DOX-resistant osteosarcoma cells.	('osteosarcoma DOX-resistance related upregulated lncRNA', 'Gene', '103752587', (40, 94))	('DOX', 'Chemical', 'MESH:D004317', (139, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (153, 165))	('osteosarcoma', 'Phenotype', 'HP:0002669', (40, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('ODRUL', 'Gene', (96, 101))	('ncRNA', 'Gene', (130, 135))	('ncRNA', 'Gene', (11, 16))	('ncRNA', 'Gene', '220202', (130, 135))	('ncRNA', 'Gene', '220202', (11, 16))	('ODRUL', 'Gene', '103752587', (96, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('ncRNA', 'Gene', (89, 94))	('osteosarcoma', 'Disease', (153, 165))	('osteosarcoma', 'Disease', (40, 52))	('ncRNA', 'Gene', '220202', (89, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (153, 165))	('osteosarcoma', 'Disease', 'MESH:D012516', (40, 52))	('upregulated', 'PosReg', (117, 128))	('EST00000563280', 'Var', (17, 31))	('DOX', 'Chemical', 'MESH:D004317', (53, 56))
516057	28978183	Recent evidence has confirmed that the selective modulation of miR activity could improve responses to chemotherapy.	('improve', 'PosReg', (82, 89))	('modulation', 'Var', (49, 59))	('responses to chemotherapy', 'CPA', (90, 115))	('activity', 'MPA', (67, 75))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))
516058	28978183	The rationale for developing miR therapies is based on the premise that aberrant expression of miRs play key roles in the development of resistance to chemotherapy and that correcting these miR deficiencies by either antagonizing or restoring miR function may provide a therapeutic benefit.	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', '220972', (243, 246))	('miR', 'Gene', (95, 98))	('miR', 'Gene', (243, 246))	('resistance to chemotherapy', 'MPA', (137, 163))	('miR', 'Gene', (29, 32))	('miR', 'Gene', '220972', (29, 32))	('function', 'MPA', (247, 255))	('antagonizing', 'Var', (217, 229))	('aberrant', 'Var', (72, 80))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (190, 193))	('restoring', 'PosReg', (233, 242))
516060	28978183	Inhibition of these miRs may increase chemoresponse to antitumor therapy.	('tumor', 'Disease', (59, 64))	('increase', 'PosReg', (29, 37))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
516061	28978183	For example, miR-21 promotes drug resistance in sarcoma, and inhibition of miR-21 may function to reverse drug resistance in osteosarcoma cells.	('drug resistance', 'MPA', (29, 44))	('sarcoma', 'Disease', (48, 55))	('miR-21', 'Gene', '406991', (75, 81))	('osteosarcoma', 'Disease', (125, 137))	('osteosarcoma', 'Disease', 'MESH:D012516', (125, 137))	('drug resistance', 'Phenotype', 'HP:0020174', (29, 44))	('miR-21', 'Gene', (13, 19))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('promotes', 'PosReg', (20, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('sarcoma', 'Disease', (130, 137))	('drug resistance', 'MPA', (106, 121))	('miR-21', 'Gene', (75, 81))	('drug resistance', 'Phenotype', 'HP:0020174', (106, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('inhibition', 'Var', (61, 71))	('miR-21', 'Gene', '406991', (13, 19))	('sarcoma', 'Disease', 'MESH:D012509', (48, 55))
516077	28978183	Functional analysis indicated that miR-34a increased tumor sensitivity to the effects of DOX and vincristine in Ewing's sarcoma cells, and that restoration of miR-34a activity may be useful to decrease malignancy.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('activity', 'MPA', (167, 175))	('DOX', 'Chemical', 'MESH:D004317', (89, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('miR-34a', 'Gene', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('increased', 'PosReg', (43, 52))	('decrease', 'NegReg', (193, 201))	('restoration', 'Var', (144, 155))	('miR-34a', 'Gene', '407040', (35, 42))	('malignancy', 'Disease', 'MESH:D009369', (202, 212))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (112, 127))	('miR-34a', 'Gene', (159, 166))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (112, 127))	('miR-34a', 'Gene', '407040', (159, 166))	('malignancy', 'Disease', (202, 212))	('tumor', 'Disease', (53, 58))	('vincristine', 'Chemical', 'MESH:D014750', (97, 108))	("Ewing's sarcoma", 'Disease', (112, 127))
516106	28978183	A rising strategy to solve gene specificity limitations is the technology of genome editing by clustered regulatory interspaced short palindromic repeats-associated endonuclease 9 (CRISPR-Cas9), which is a rapid and efficient way to generate total or partial downregulation of specific genes, including ncRNAs, by the targeted interruption of the promoter and the chosen sequence through insertion of polyadenylation signals.	('polyadenylation signals', 'Var', (401, 424))	('ncRNA', 'Gene', '220202', (303, 308))	('insertion', 'Var', (388, 397))	('interruption', 'NegReg', (327, 339))	('downregulation', 'NegReg', (259, 273))	('ncRNA', 'Gene', (303, 308))
516107	28978183	Furthermore, CRISPR-Cas9 can be applied to achieve ncRNA overexpression from its endogenous locus by inserting a strong promoter upstream of the ncRNA sequence or by targeting transcriptional activator complexes to the promoter.	('overexpression', 'PosReg', (57, 71))	('ncRNA', 'Gene', '220202', (145, 150))	('ncRNA', 'Gene', '220202', (51, 56))	('ncRNA', 'Gene', (145, 150))	('targeting', 'Reg', (166, 175))	('ncRNA', 'Gene', (51, 56))	('inserting', 'Var', (101, 110))
516133	25884933	Treating patients with adjuvant radiotherapy as opposed to neo-adjuvant radiotherapy has been linked to a higher risk of developing acute toxic skin effects (68% vs. 36% of patients), as well as being linked to an increased likelihood of developing joint stiffness, subcutaneous fibrosis and soft tissue oedema.	('patients', 'Species', '9606', (9, 17))	('radiotherapy', 'Var', (32, 44))	('joint stiffness', 'Phenotype', 'HP:0001387', (249, 264))	('patients', 'Species', '9606', (173, 181))	('acute toxic skin effects', 'MPA', (132, 156))	('fibrosis', 'Disease', (279, 287))	('adjuvant radiotherapy', 'Var', (23, 44))	('oedema', 'Phenotype', 'HP:0000969', (304, 310))	('soft tissue oedema', 'Disease', (292, 310))	('fibrosis', 'Disease', 'MESH:D005355', (279, 287))	('joint stiffness', 'Disease', 'MESH:C535724', (249, 264))	('joint stiffness', 'Disease', (249, 264))	('soft tissue oedema', 'Disease', 'MESH:D004487', (292, 310))	('neo-', 'Chemical', '-', (59, 63))	('subcutaneous fibrosis', 'Phenotype', 'HP:0007618', (266, 287))
516233	32967883	Blockade of PD-1 can stimulate antitumour immune responses.	('PD-1', 'Gene', '9825', (12, 16))	('Blockade', 'Var', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('stimulate', 'PosReg', (21, 30))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('PD-1', 'Gene', (12, 16))	('tumour', 'Disease', (35, 41))
516234	32967883	Significant responses have been obtained in several sarcomas (NCT01343043; NCT02107963; NCT01953900) with acceptable tolerance.	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('NCT01343043', 'Var', (62, 73))	('NCT02107963; NCT01953900', 'Var', (75, 99))	('sarcomas', 'Disease', (52, 60))	('NCT01953900', 'Var', (88, 99))
516247	32967883	Impact of biomarkers (PD1/PDL1 immunostaining in tumour and microenvironment, C reactive protein (CRP), albumin, neutrophils/lymphocytes, mutational load at baseline and Circulating tumour (ct)DNA at baseline, 6 months and relapse) on PFS as previously described.	('mutational', 'Var', (138, 148))	('PDL1', 'Gene', (26, 30))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('C reactive protein', 'Gene', (78, 96))	('albumin', 'Gene', '213', (104, 111))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('C reactive protein', 'Gene', '1401', (78, 96))	('CRP', 'Gene', (98, 101))	('PD1', 'Gene', (22, 25))	('PFS', 'Disease', (235, 238))	('albumin', 'Gene', (104, 111))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', (182, 188))	('PD1', 'Gene', '9825', (22, 25))	('CRP', 'Gene', '1401', (98, 101))	('PDL1', 'Gene', '29126', (26, 30))	('tumour', 'Disease', (49, 55))
516248	32967883	Impact of biomarkers (PD1/PDL1 immunostaining in tumour and microenvironment, CRP, albumin, neutrophils/lymphocytes, mutational load at baseline and ctDNA at baseline, 6 months and relapse) on response rate as previously described.	('mutational', 'Var', (117, 127))	('PDL1', 'Gene', (26, 30))	('albumin', 'Gene', (83, 90))	('albumin', 'Gene', '213', (83, 90))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('CRP', 'Gene', (78, 81))	('CRP', 'Gene', '1401', (78, 81))	('PD1', 'Gene', (22, 25))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('PD1', 'Gene', '9825', (22, 25))	('PDL1', 'Gene', '29126', (26, 30))	('tumour', 'Disease', (49, 55))
516252	32967883	Demonstrate adequate organ function: absolute neutrophil count >=1500/mL; platelets >=1 00 000; haemoglobin >=9 g/dL or >=5.6 mmol/L; serum creatinine <=1.5 times the upper limit of normal (ULN) OR measured or calculated creatinine clearance with MDRD equation >=50 mL/min for subject with creatinine levels >1.5 times the institutional ULN; serum total bilirubin <=1.5 times the ULN OR direct bilirubin <=ULN for subjects with total bilirubin levels >1.5 ULN; AST (SGOT) and ALT (SGPT) <=2.5 times the ULN OR <=5 times the ULN for subjects with liver metastases.	('creatinine', 'Chemical', 'MESH:D003404', (140, 150))	('metastases', 'Disease', 'MESH:D009362', (552, 562))	('AST', 'Gene', (461, 464))	('AST', 'Gene', '26503', (461, 464))	('direct bilirubin', 'MPA', (387, 403))	('<=2.5', 'Var', (487, 492))	('creatinine', 'Chemical', 'MESH:D003404', (221, 231))	('metastases', 'Disease', (552, 562))	('creatinine', 'Chemical', 'MESH:D003404', (290, 300))
516586	25612511	A recent study identified rearrangements of ROS1 (another tyrosine kinase receptor) in a subset of ALK-negative inflammatory myofibroblastic tumors.	('ROS1', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('ALK', 'Gene', (99, 102))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (112, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (125, 146))	('inflammatory myofibroblastic tumors', 'Disease', (112, 147))	('ALK', 'Gene', '238', (99, 102))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (125, 147))	('rearrangements', 'Var', (26, 40))
516587	25612511	Immunohistochemistry for ROS1 has been shown to correlate with ROS1 rearrangement in lung adenocarcinomas.	('ROS1', 'Gene', (25, 29))	('rearrangement', 'Var', (68, 81))	('ROS1', 'Gene', (63, 67))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('correlate', 'Reg', (48, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('lung adenocarcinomas', 'Disease', (85, 105))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (85, 105))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (85, 105))
516588	25612511	The purpose of this study was to determine whether immunohistochemistry for ROS1 could predict ROS1 rearrangement in inflammatory myofibroblastic tumor.	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (130, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ROS1', 'Gene', (95, 99))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (117, 151))	('rearrangement', 'Var', (100, 113))	('inflammatory myofibroblastic tumor', 'Disease', (117, 151))
516589	25612511	In total, 30 inflammatory myofibroblastic tumors were evaluated, including 21 ALK-positive tumors (10 confirmed to harbor ALK rearrangements, with TPM3, CLTC, RANPB2, and FN1 fusion partners) and 9 ALK-negative tumors (including 2 known to harbor ROS1 rearrangements).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('ALK', 'Gene', (78, 81))	('ALK', 'Gene', (198, 201))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('TPM3', 'Gene', (147, 151))	('CLTC', 'Gene', '1213', (153, 157))	('rearrangements', 'Var', (126, 140))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (13, 48))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('ALK', 'Gene', '238', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CLTC', 'Gene', (153, 157))	('FN1', 'Gene', '2335', (171, 174))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (26, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('ALK', 'Gene', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('inflammatory myofibroblastic tumors', 'Disease', (13, 48))	('tumors', 'Disease', (91, 97))	('TPM3', 'Gene', '7170', (147, 151))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (26, 47))	('tumors', 'Disease', (42, 48))	('FN1', 'Gene', (171, 174))	('ALK', 'Gene', '238', (198, 201))	('ALK', 'Gene', '238', (78, 81))
516593	25612511	Expression of ROS1 correlates with ROS1 gene rearrangement in inflammatory myofibroblastic tumor.	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (75, 96))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (62, 96))	('inflammatory myofibroblastic tumor', 'Disease', (62, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ROS1', 'Gene', (35, 39))	('gene rearrangement', 'Var', (40, 58))
516599	25612511	Around 50% of inflammatory myofibroblastic tumors harbor rearrangements involving the ALK (anaplastic lymphoma kinase) gene; diverse fusion partners have been identified.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (91, 110))	('ALK', 'Gene', '238', (86, 89))	('anaplastic lymphoma kinase', 'Gene', (91, 117))	('inflammatory myofibroblastic tumors', 'Disease', (14, 49))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('ALK', 'Gene', (86, 89))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (27, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (27, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (14, 49))	('rearrangements', 'Var', (57, 71))	('anaplastic lymphoma kinase', 'Gene', '238', (91, 117))
516602	25612511	ALK staining is therefore both a helpful diagnostic marker and a predictive marker for targeted therapy in this tumor type, similar to the small subset of lung adenocarcinomas with ALK rearrangements.	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('rearrangements', 'Var', (185, 199))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (155, 175))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (155, 175))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('ALK', 'Gene', '238', (0, 3))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (155, 174))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', (181, 184))	('ALK', 'Gene', '238', (181, 184))	('tumor', 'Disease', (112, 117))	('lung adenocarcinomas', 'Disease', (155, 175))
516604	25612511	Using a massively parallel (next generation) DNA sequencing strategy, a member of our group recently discovered that a subset of ALK-negative inflammatory myofibroblastic tumors harbors rearrangements involving ROS1 (v-ros avian UR2 sarcoma virus oncogene homolog 1), which encodes a tyrosine kinase receptor similar to ALK.	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (142, 177))	('v-ros avian UR2 sarcoma virus oncogene homolog 1', 'Gene', '6098', (217, 265))	('ALK', 'Gene', '238', (320, 323))	('ALK', 'Gene', (129, 132))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (155, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('inflammatory myofibroblastic tumors', 'Disease', (142, 177))	('rearrangements', 'Var', (186, 200))	('ALK', 'Gene', '238', (129, 132))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (155, 176))	('ALK', 'Gene', (320, 323))	('ROS1', 'Gene', (211, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('v-ros avian UR2 sarcoma virus oncogene homolog 1', 'Gene', (217, 265))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
516605	25612511	Immunohistochemistry for ROS1 has been shown to correlate with ROS1 rearrangement in lung adenocarcinoma.	('ROS1', 'Gene', (25, 29))	('rearrangement', 'Var', (68, 81))	('ROS1', 'Gene', (63, 67))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('lung adenocarcinoma', 'Disease', (85, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (85, 104))
516607	25612511	Archival tumor samples from 30 inflammatory myofibroblastic tumors were evaluated, including 21 ALK-positive tumors (10 previously confirmed to harbor ALK rearrangements) and 9 ALK-negative tumors (including 2 known to harbor ROS1 rearrangements).	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumors', 'Disease', (190, 196))	('tumor', 'Disease', (60, 65))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (31, 66))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (44, 66))	('ALK', 'Gene', '238', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (109, 115))	('ALK', 'Gene', (177, 180))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('inflammatory myofibroblastic tumors', 'Disease', (31, 66))	('ALK', 'Gene', '238', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('rearrangements', 'Var', (155, 169))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (44, 65))	('tumor', 'Disease', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ALK', 'Gene', (96, 99))	('ALK', 'Gene', '238', (151, 154))	('tumors', 'Disease', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('ALK', 'Gene', (151, 154))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', (109, 114))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
516611	25612511	A lung adenocarcinoma with confirmed ROS1 rearrangement served as a positive control.	('rearrangement', 'Var', (42, 55))	('A lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 21))	('A lung adenocarcinoma', 'Disease', (0, 21))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (2, 21))
516613	25612511	However, if a ROS1 rearrangement has occurred, one copy of the red probe will be separated from the adjacent green probe by >= 1 signal diameter, or the 5' (green) probe signal will be lost, as previously described for lung adenocarcinomas.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (219, 239))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (219, 239))	('lost', 'NegReg', (185, 189))	('ROS1', 'Gene', (14, 18))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (219, 238))	('carcinomas', 'Phenotype', 'HP:0030731', (229, 239))	('lung adenocarcinomas', 'Disease', (219, 239))	('rearrangement', 'Var', (19, 32))
516616	25612511	The sample was subjected to targeted next generation sequencing using a cancer genomic assay to detect sequence and copy number variations in 275 oncogenes and tumor suppressor genes.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('copy number variations', 'Var', (116, 138))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', (160, 165))	('oncogenes', 'Gene', (146, 155))	('cancer', 'Disease', (72, 78))
516617	25612511	Polymerase chain reaction (PCR) and reverse transcriptase (RT)-PCR were then performed using primers that flank the breakpoints in the known YWHAE-ROS1 and TFG-ROS1 fusions.	('fusions', 'Var', (165, 172))	('TFG-ROS1', 'Gene', (156, 164))	('YWHAE-ROS1', 'Gene', (141, 151))	('YWHAE-ROS1', 'Gene', '7531;6098', (141, 151))
516624	25612511	Alternatively, DNA isolated from formalin-fixed paraffin-embedded tissue samples known to harbor YWHAE-ROS1 or TFG-ROS1 fusions was used as a positive control in an attempt to identify the exact breakpoint by PCR.	('paraffin', 'Chemical', 'MESH:D010232', (48, 56))	('formalin', 'Chemical', 'MESH:D005557', (33, 41))	('YWHAE-ROS1', 'Gene', (97, 107))	('YWHAE-ROS1', 'Gene', '7531;6098', (97, 107))	('fusions', 'Var', (120, 127))	('TFG-ROS1', 'Gene', (111, 119))
516632	25612511	Ten of these tumors were previously confirmed to harbor ALK gene rearrangements (by FISH, next-generation sequencing, or reverse transcriptase-polymerase chain reaction), 7 with known fusion partners (4 RANBP2 and 1 each TPM3, CLTC, and FN1).	('CLTC', 'Gene', (227, 231))	('TPM3', 'Gene', (221, 225))	('tumors', 'Disease', (13, 19))	('FN1', 'Gene', '2335', (237, 240))	('RANBP2', 'Gene', '5903', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('RANBP2', 'Gene', (203, 209))	('ALK', 'Gene', '238', (56, 59))	('rearrangements', 'Var', (65, 79))	('TPM3', 'Gene', '7170', (221, 225))	('FN1', 'Gene', (237, 240))	('CLTC', 'Gene', '1213', (227, 231))	('ALK', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
516633	25612511	Immunohistochemistry for ROS1 was positive in 3 ALK-negative inflammatory myofibroblastic tumors (including both tumors with previously identified ROS1 rearrangements) (Table 2; Figures 1 and 2), whereas all ALK-positive inflammatory myofibroblastic tumors were negative for ROS1 (Figure 3).	('tumors', 'Disease', (113, 119))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (234, 256))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('rearrangements', 'Var', (152, 166))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (74, 96))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (221, 256))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('positive', 'Reg', (34, 42))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (61, 96))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (234, 255))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (74, 95))	('inflammatory myofibroblastic tumors', 'Disease', (221, 256))	('ALK', 'Gene', '238', (208, 211))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('inflammatory myofibroblastic tumors', 'Disease', (61, 96))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('ALK', 'Gene', (208, 211))	('ROS1', 'Gene', (25, 29))	('ALK', 'Gene', '238', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('ALK', 'Gene', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', 'MESH:D009369', (250, 256))
516640	25612511	RT-PCR and PCR were performed using primers that flank breakpoints in known YWHAE-ROS1 and TFG-ROS1 fusions.	('fusions', 'Var', (100, 107))	('TFG-ROS1', 'Gene', (91, 99))	('YWHAE-ROS1', 'Gene', (76, 86))	('YWHAE-ROS1', 'Gene', '7531;6098', (76, 86))
516641	25612511	Therefore, we also performed PCR using primers that bind directly to the breakpoints in tumors harboring known YWHAE-ROS1 and TFG-ROS1 fusions.	('YWHAE-ROS1', 'Gene', '7531;6098', (111, 121))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('YWHAE-ROS1', 'Gene', (111, 121))	('fusions', 'Var', (135, 142))	('TFG-ROS1', 'Gene', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
516649	25612511	ROS1 rearrangements were recently identified in a subset of ALK-negative inflammatory myofibroblastic tumors, suggesting a new diagnostic marker for this group of neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (163, 172))	('ALK', 'Gene', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('ROS1', 'Gene', (0, 4))	('inflammatory myofibroblastic tumors', 'Disease', (73, 108))	('neoplasms', 'Disease', 'MESH:D009369', (163, 172))	('neoplasms', 'Disease', (163, 172))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (86, 108))	('neoplasm', 'Phenotype', 'HP:0002664', (163, 171))	('ALK', 'Gene', '238', (60, 63))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (86, 107))	('identified', 'Reg', (34, 44))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (73, 108))	('rearrangements', 'Var', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
516651	25612511	We showed that ROS1 expression is limited to tumors with ROS1 rearrangements.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('rearrangements', 'Var', (62, 76))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('ROS1', 'Gene', (57, 61))
516654	25612511	The prevalence of ROS1 rearrangement in inflammatory myofibroblastic tumor is unknown.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (53, 74))	('inflammatory myofibroblastic tumor', 'Disease', (40, 74))	('ROS1', 'Gene', (18, 22))	('rearrangement', 'Var', (23, 36))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (40, 74))
516658	25612511	ALK rearrangements are found in hematopoietic (anaplastic large cell lymphoma), mesenchymal (inflammatory myofibroblastic tumor), epithelial (lung adenocarcinoma and rare renal cell carcinomas), and melanocytic neoplasms (Spitz tumors).	('Spitz tumors', 'Disease', (222, 234))	('lymphoma', 'Disease', (69, 77))	('lymphoma', 'Disease', 'MESH:D008223', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('neoplasm', 'Phenotype', 'HP:0002664', (211, 219))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (142, 161))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (199, 220))	('neoplasms', 'Phenotype', 'HP:0002664', (211, 220))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (199, 220))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (93, 127))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (171, 192))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('melanocytic neoplasms', 'Disease', (199, 220))	('Spitz tumors', 'Disease', 'MESH:D018332', (222, 234))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (106, 127))	('lung adenocarcinoma and rare renal cell carcinomas', 'Disease', 'MESH:C538614', (142, 192))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('inflammatory myofibroblastic tumor', 'Disease', (93, 127))	('cell lymphoma', 'Phenotype', 'HP:0012191', (64, 77))	('ALK', 'Gene', '238', (0, 3))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (47, 77))	('rearrangements', 'Var', (4, 18))	('ALK', 'Gene', (0, 3))
516659	25612511	ROS1 rearrangements have not yet been identified in hematopoietic tumors, but are found in these other lineages, as well as in a subset of glioblastomas.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('glioblastomas', 'Disease', 'MESH:D005909', (139, 152))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (52, 72))	('ROS1', 'Gene', (0, 4))	('glioblastomas', 'Disease', (139, 152))	('found', 'Reg', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('glioblastomas', 'Phenotype', 'HP:0012174', (139, 152))	('hematopoietic tumors', 'Disease', (52, 72))	('rearrangements', 'Var', (5, 19))
516667	25612511	Most inflammatory myofibroblastic tumors with ALK rearrangements show a cytoplasmic pattern of staining by immunohistochemistry, although the fusion partners are diverse.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (5, 40))	('ALK', 'Gene', '238', (46, 49))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (18, 40))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (18, 39))	('rearrangements', 'Var', (50, 64))	('inflammatory myofibroblastic tumors', 'Disease', (5, 40))	('ALK', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
516671	25612511	Similar to the situation in lung adenocarcinomas, the identification of ROS1 rearrangements in inflammatory myofibroblastic tumors provides a new potential therapeutic option for some patients with aggressive variants of this tumor type.	('tumor', 'Disease', (124, 129))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (95, 130))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('ROS1', 'Gene', (72, 76))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (108, 130))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('inflammatory myofibroblastic tumors', 'Disease', (95, 130))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (108, 129))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('rearrangements', 'Var', (77, 91))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (28, 48))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('patients', 'Species', '9606', (184, 192))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (28, 48))	('lung adenocarcinomas', 'Disease', (28, 48))	('tumor', 'Disease', (226, 231))
516673	25612511	Similarly, a member of our group recently reported that crizotinib provided symptomatic improvement, as well as radiologic response, in a patient with advanced ROS1-rearranged inflammatory myofibroblastic tumor.	('crizotinib', 'Var', (56, 66))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (176, 210))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (189, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('patient', 'Species', '9606', (138, 145))	('inflammatory myofibroblastic tumor', 'Disease', (176, 210))	('crizotinib', 'Chemical', 'MESH:D000077547', (56, 66))
516674	25612511	In summary, expression of ROS1 correlates with ROS1 gene rearrangement in inflammatory myofibroblastic tumors.	('ROS1', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (74, 109))	('gene rearrangement', 'Var', (52, 70))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (87, 108))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (87, 109))	('inflammatory myofibroblastic tumors', 'Disease', (74, 109))	('expression', 'MPA', (12, 22))	('ROS1', 'Protein', (26, 30))
516788	26240736	Expression of both cytokeratins and viamentin is seen in most synovial sarcoma with biphasic histology with cytokeratin and viamentin and epithelial and mesenchymal components.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (62, 78))	('synovial sarcoma', 'Disease', 'MESH:D013584', (62, 78))	('viamentin', 'Chemical', '-', (124, 133))	('cytokeratin', 'Var', (108, 119))	('synovial sarcoma', 'Disease', (62, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('viamentin', 'Chemical', '-', (36, 45))
516791	26240736	Some cases have demonstrated presence of chromosomal abnormality that include t (X; 18)(p1;p1) X2, del (1) t (1;8)(q10;q10), del-(4),-13,-14,-16,+17,+18,+4,+7,+8 and del (13;15)(q10;q10).	('chromosomal abnormality', 'Disease', (41, 64))	('presence of chromosomal abnormality', 'Phenotype', 'HP:0040012', (29, 64))	('del-(4', 'Var', (125, 131))	('chromosomal abnormality', 'Disease', 'MESH:D002869', (41, 64))	('t (X; 18)(', 'Var', (78, 88))	('del (1) t (1;8)(q10;q10', 'Var', (99, 122))	('del (13;15)(q10;q10', 'Var', (166, 185))
517066	32804276	177Lu is a favorable isotope for theranostic application with a half-life of 6.7 days, a maximal tissue penetration of 2 mm, and a low energy emission (Ebeta-max 0.49) that causes damage to neighboring healthy cells.	('177Lu', 'Var', (0, 5))	('damage', 'CPA', (180, 186))	('causes', 'Reg', (173, 179))	('177Lu', 'Chemical', 'MESH:C000615061', (0, 5))
517126	32804276	For conjugates, the binding to TEM-1 positive cells was respectively 8654, 8095, 8321 at 2 mug/ml for 10, 20, and 40 equivalents of DOTA; 7714, 7679, 7454 at 0.2 mug/ml for 10, 20, and 40 equivalents of DOTA and 58.6 for the isotype control (Fig.	('8095', 'Var', (75, 79))	('binding', 'Interaction', (20, 27))	('7454', 'Var', (150, 154))	('7714', 'Var', (138, 142))	('DOTA', 'Chemical', 'MESH:C071349', (203, 207))	('DOTA', 'Chemical', 'MESH:C071349', (132, 136))	('8654', 'Var', (69, 73))
517148	32804276	The fusion of scFvs to the IgG Fc constant domains adds significant size, avidity, and stability to the targeting moiety and would be expected to lead to improved blood pharmacokinetics.	('improved', 'PosReg', (154, 162))	('scFv', 'Gene', (14, 18))	('stability', 'MPA', (87, 96))	('improved blood pharmacokinetics', 'Phenotype', 'HP:0020171', (154, 185))	('scFv', 'Gene', '652070', (14, 18))	('fusion', 'Var', (4, 10))	('size', 'MPA', (68, 72))	('avidity', 'MPA', (74, 81))	('blood pharmacokinetics', 'MPA', (163, 185))
517167	32804276	Moreover, at high DOTA conjugation ratios, the possibility of DOTA attachment to important residues in the antigen-targeting variable domains of the antibody increases, potentially compromising the immunoreactivity of the molecule.	('DOTA', 'Chemical', 'MESH:C071349', (62, 66))	('DOTA', 'Chemical', 'MESH:C071349', (18, 22))	('attachment', 'Reg', (67, 77))	('compromising', 'NegReg', (181, 193))	('DOTA', 'Var', (62, 66))	('immunoreactivity of the molecule', 'MPA', (198, 230))	('increases', 'PosReg', (158, 167))
517168	32804276	Elevated uptake in the liver can also indicate a lower stability of the radiolabeling such as trans-chelation to transferrin.	('stability', 'MPA', (55, 64))	('lower', 'NegReg', (49, 54))	('trans-chelation', 'Var', (94, 109))	('transferrin', 'Gene', '22041', (113, 124))	('transferrin', 'Gene', (113, 124))	('uptake', 'MPA', (9, 15))
517176	32804276	We have performed SPECT/CT imaging experiments on an scFv-Fc antibody that binds both human and mouse TEM-1, and generated data showing that TEM-1 was either absent or present at negligible levels in normal mouse organs and that [177Lu]Lu-1C1m-Fc was able to efficiently target a TEM-1 positive tumor in vivo.	('177Lu', 'Chemical', 'MESH:C000615061', (230, 235))	('mouse', 'Species', '10090', (96, 101))	('human', 'Species', '9606', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('[177Lu]Lu-1C1m-Fc', 'Var', (229, 246))	('TEM-1', 'Gene', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('scFv', 'Gene', (53, 57))	('mouse', 'Species', '10090', (207, 212))	('scFv', 'Gene', '652070', (53, 57))	('tumor', 'Disease', (295, 300))
517179	32804276	The highly specific expression of TEM-1 in several types of solids tumors suggests that [177Lu]Lu-1C1m-Fc could prove a potentially useful and safe tool for molecular imaging and theranostic applications.	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('177Lu', 'Chemical', 'MESH:C000615061', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('[177Lu]Lu-1C1m-Fc', 'Var', (88, 105))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
517324	31338321	For instance, the role of maintenance of Imatinib in advanced gastrointestinal stromal tumors (GISTs) has been well-established and Imatinib interruption in long-lasting responders results in a high risk of rapid progression.	('gastrointestinal stromal tumors', 'Disease', (62, 93))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (62, 93))	('rapid progression', 'MPA', (207, 224))	('Imatinib', 'Chemical', 'MESH:D000068877', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (62, 93))	('interruption', 'Var', (141, 153))	('Imatinib', 'Chemical', 'MESH:D000068877', (132, 140))	('GISTs', 'Phenotype', 'HP:0100723', (95, 100))
517335	31338321	In fact, the enthusiasm for Olaratumab (a novel anti platelet derived growth factor receptor antibody) rapidly deflated after the recent Lilly press release about the results of the phase III trial: Olaratumab in association with Doxorubicin demonstrated no significant increase in overall survival vs. Doxorubicin alone.	('Olaratumab', 'Chemical', 'MESH:C000589393', (199, 209))	('Olaratumab', 'Var', (199, 209))	('overall survival', 'MPA', (282, 298))	('Olaratumab', 'Chemical', 'MESH:C000589393', (28, 38))	('Doxorubicin', 'Chemical', 'MESH:D004317', (230, 241))	('deflated', 'NegReg', (111, 119))	('Doxorubicin', 'Chemical', 'MESH:D004317', (303, 314))
517412	29292843	Conversely, when endosialin expression is knocked down, PDGF-BB-induced pericyte proliferation is blocked.	('blocked', 'NegReg', (98, 105))	('PD', 'Disease', 'MESH:D010300', (56, 58))	('endosialin', 'Gene', (17, 27))	('knocked down', 'Var', (42, 54))	('pericyte proliferation', 'CPA', (72, 94))	('endosialin', 'Gene', '57124', (17, 27))
517414	29292843	Blocking of endosialin may also have anti-angiogenic effects via prevention of vascular remodeling leading to decreased tumor blood flow.	('endosialin', 'Gene', '57124', (12, 22))	('decreased tumor', 'Disease', 'MESH:D009369', (110, 125))	('Blocking', 'Var', (0, 8))	('decreased tumor', 'Disease', (110, 125))	('anti-angiogenic effects', 'CPA', (37, 60))	('vascular remodeling', 'CPA', (79, 98))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('endosialin', 'Gene', (12, 22))
517554	28786880	All tumors were centrally examined for degree of cytologic atypia, morphology (spindled, epithelioid, myxoid), mitotic index per 10 high power fields, atypical mitotic figures, tumor cell necrosis, ischemic necrosis, tumor interface (circumscribed or infiltrative) and margin status.	('tumor', 'Disease', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mitotic index', 'CPA', (111, 124))	('tumor cell necrosis', 'Disease', (177, 196))	('ischemic necrosis', 'Phenotype', 'HP:0010885', (198, 215))	('tumor', 'Disease', (217, 222))	('ischemic necrosis', 'Disease', (198, 215))	('atypical', 'Var', (151, 159))	('ischemic necrosis', 'Disease', 'MESH:D007511', (198, 215))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (177, 182))	('tumor cell necrosis', 'Disease', 'MESH:D009336', (177, 196))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))
517563	28786880	A review of 32 vulvar SMTs led to identification of 3 main risk determinants based on tumor recurrence: gross size >= 5 cm, mitotic index >= 5 figures/10 high power fields (HPFs) and infiltrative tumor interface.	('>= 5', 'Var', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('>= 5', 'Var', (115, 119))	('tumor', 'Disease', (196, 201))	('gross', 'Var', (104, 109))	('tumor', 'Disease', (86, 91))	('mitotic index', 'CPA', (124, 137))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
517671	28786880	Recurrence in each patient occurred at differing intervals: metastasis to lung at 1 month in 1 patient, metastasis to lung at 36 months in another patient and extensive local recurrence of the pelvis at 41 months in the remaining patient.	('patient', 'Species', '9606', (19, 26))	('patient', 'Species', '9606', (95, 102))	('patient', 'Species', '9606', (147, 154))	('patient', 'Species', '9606', (230, 237))	('metastasis', 'Var', (104, 114))	('metastasis', 'CPA', (60, 70))
517742	28786880	Additionally, if molecular genetic or cytogenetic testing is pursued, t(17;22)(q22;q13) which results in COL1A1-PDGFB fusion, is diagnostic of dermatofibrosarcoma protuberans and is not found in SMTs.	('results in', 'Reg', (94, 104))	('PDGFB', 'Gene', '5155', (112, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('COL1A1', 'Gene', (105, 111))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (70, 87))	('dermatofibrosarcoma protuberans', 'Disease', (143, 174))	('PDGFB', 'Gene', (112, 117))	('t(17;22)(q22;q13', 'Var', (70, 86))	('COL1A1', 'Gene', '1277', (105, 111))	('fusion', 'Var', (118, 124))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (143, 174))
517795	27488020	Treatment of breast cancer 2 (BRCA2)-mutant follicular dendritic cell sarcoma with a poly ADP-ribose polymerase (PARP) inhibitor: a case report Follicular dendritic cell sarcoma is a rare tumour with clinical behaviour covering a spectrum from indolent to aggressive disease.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('breast cancer 2', 'Gene', '675', (13, 28))	('tumour', 'Disease', (188, 194))	('Follicular dendritic cell sarcoma', 'Disease', 'MESH:D054740', (144, 177))	('-mutant', 'Var', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('dendritic cell sarcoma', 'Disease', 'MESH:D054740', (55, 77))	('aggressive disease', 'Disease', (256, 274))	('PARP', 'Gene', '142', (113, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('PARP', 'Gene', (113, 117))	('aggressive disease', 'Disease', 'MESH:D001523', (256, 274))	('Follicular dendritic cell sarcoma', 'Disease', (144, 177))	('dendritic cell sarcoma', 'Disease', 'MESH:D054740', (155, 177))	('dendritic cell sarcoma', 'Disease', (55, 77))	('BRCA2', 'Gene', (30, 35))	('breast cancer 2', 'Gene', (13, 28))	('poly ADP-ribose polymerase', 'Gene', '142', (85, 111))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('poly ADP-ribose polymerase', 'Gene', (85, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('BRCA2', 'Gene', '675', (30, 35))
517799	27488020	Mutation testing by Caris molecular intelligence demonstrated a breast cancer 2 gene mutation and further treatment with carboplatin and veliparib achieved disease stabilisation.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('veliparib', 'Chemical', 'MESH:C521013', (137, 146))	('breast cancer 2', 'Gene', '675', (64, 79))	('carboplatin', 'Chemical', 'MESH:D016190', (121, 132))	('mutation', 'Var', (85, 93))	('breast cancer 2', 'Gene', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
517808	27488020	Other FDC markers such as R4/23, Ki-M4, Ki-M4p, Ki-FDC1 may also be positive as well as vimentin, CD68, S100, fascin but these may be nonspecific.	('R4/23', 'Var', (26, 31))	('Ki-M4', 'Var', (33, 38))	('fascin', 'Gene', (110, 116))	('Ki-M4p', 'Var', (40, 46))	('fascin', 'Gene', '6624', (110, 116))	('vimentin', 'Gene', '7431', (88, 96))	('S100', 'Gene', '6271', (104, 108))	('S100', 'Gene', (104, 108))	('vimentin', 'Gene', (88, 96))	('CD68', 'Gene', (98, 102))	('CD68', 'Gene', '968', (98, 102))	('Ki-FDC1', 'Var', (48, 55))
517814	27488020	have reported v-Raf murine sarcoma viral oncogene homolog B (BRAF)V600E mutations in 5 from 27 (18.5 %) cases tested.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (14, 59))	('BRAF', 'Gene', '109880', (61, 65))	('V600E', 'Var', (66, 71))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (14, 59))	('BRAF', 'Gene', (61, 65))	('V600E', 'Mutation', 'rs113488022', (66, 71))
517815	27488020	Phosphatase and tension homolog (PTEN), RET and TP53 mutations have also been documented in FDCS presenting as a thyroid mass.	('TP53', 'Gene', '7157', (48, 52))	('RET', 'Gene', (40, 43))	('PTEN', 'Gene', (33, 37))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('RET', 'Gene', '5979', (40, 43))	('PTEN', 'Gene', '5728', (33, 37))	('FDCS', 'Disease', (92, 96))	('thyroid mass', 'Disease', (113, 125))
517816	27488020	The PTEN and TP53 mutations were similar to those previously described in other malignancies, though the functional significance of the RET mutation was unknown.	('RET', 'Gene', '5979', (136, 139))	('PTEN', 'Gene', '5728', (4, 8))	('TP53', 'Gene', (13, 17))	('RET', 'Gene', (136, 139))	('malignancies', 'Disease', 'MESH:D009369', (80, 92))	('TP53', 'Gene', '7157', (13, 17))	('PTEN', 'Gene', (4, 8))	('malignancies', 'Disease', (80, 92))	('mutations', 'Var', (18, 27))
517829	27488020	An E1493 fs BRCA2 mutation was demonstrated and confirmed as a germline mutation.	('E1493 fs', 'Mutation', 'rs80359454', (3, 11))	('BRCA2', 'Gene', (12, 17))	('BRCA2', 'Gene', '675', (12, 17))	('E1493 fs', 'Var', (3, 11))
517832	27488020	Due to the finding of a BRCA2 mutation, it was decided to treat with the combination of carboplatin and a poly ADP-ribose polymerase (PARP) inhibitor.	('BRCA2', 'Gene', '675', (24, 29))	('PARP', 'Gene', (134, 138))	('mutation', 'Var', (30, 38))	('poly ADP-ribose polymerase', 'Gene', (106, 132))	('PARP', 'Gene', '142', (134, 138))	('poly ADP-ribose polymerase', 'Gene', '142', (106, 132))	('BRCA2', 'Gene', (24, 29))	('carboplatin', 'Chemical', 'MESH:D016190', (88, 99))
517842	27488020	This case report describes the use of a PARP inhibitor in combination with carboplatin in the treatment of a FDCS with a BRCA2 mutation.	('carboplatin', 'Chemical', 'MESH:D016190', (75, 86))	('BRCA2', 'Gene', (121, 126))	('mutation', 'Var', (127, 135))	('BRCA2', 'Gene', '675', (121, 126))	('PARP', 'Gene', '142', (40, 44))	('FDCS', 'Disease', (109, 113))	('PARP', 'Gene', (40, 44))
517843	27488020	This is the first report of FDCS with a BRCA2 mutation and also the first report of the use of molecularly targeted therapy in this disease.	('BRCA2', 'Gene', (40, 45))	('mutation', 'Var', (46, 54))	('FDCS', 'Disease', (28, 32))	('BRCA2', 'Gene', '675', (40, 45))
517845	27488020	Female carriers of a mutation have a 45 and 20 % lifetime risk of breast cancer and ovarian cancer respectively.	('ovarian cancer', 'Disease', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutation', 'Var', (21, 29))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))
517846	27488020	BRCA2 mutation is also associated with prostate and pancreatic cancers and melanoma.	('BRCA2', 'Gene', '675', (0, 5))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (52, 70))	('prostate', 'Disease', (39, 47))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('mutation', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('BRCA2', 'Gene', (0, 5))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('pancreatic cancers', 'Disease', 'MESH:D010190', (52, 70))	('pancreatic cancers', 'Disease', (52, 70))	('associated', 'Reg', (23, 33))
517847	27488020	PARP inhibition in patients with a BRCA mutation demonstrates the concept of synthetic lethality.	('mutation', 'Var', (40, 48))	('patients', 'Species', '9606', (19, 27))	('PARP', 'Gene', (0, 4))	('BRCA', 'Gene', (35, 39))	('BRCA', 'Gene', '672', (35, 39))	('PARP', 'Gene', '142', (0, 4))
517849	27488020	Thus in cancer cells with BRCA2 mutation that already display a deficiency in DNA repair, inhibition of PARP1 activity leads to an accumulation of single strand breaks that are converted to double strand breaks that can not be repaired and result in cell death.	('inhibition', 'NegReg', (90, 100))	('cancer', 'Disease', (8, 14))	('deficiency', 'Disease', 'MESH:D007153', (64, 74))	('PARP1', 'Gene', '142', (104, 109))	('activity', 'MPA', (110, 118))	('PARP1', 'Gene', (104, 109))	('single strand breaks', 'MPA', (147, 167))	('BRCA2', 'Gene', (26, 31))	('accumulation', 'PosReg', (131, 143))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('deficiency', 'Disease', (64, 74))	('mutation', 'Var', (32, 40))	('BRCA2', 'Gene', '675', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
517852	27488020	Veliparib has demonstrated activity in phase I and II studies in BRCA 1/2 mutated ovarian and breast cancers both as a single agent and in combination with carboplatin as well as in patients with brain metastases in combination with whole brain irradiation.	('brain metastases', 'Disease', (196, 212))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('ovarian and breast cancers', 'Disease', 'MESH:D010051', (82, 108))	('BRCA 1/2', 'Gene', '672;675', (65, 73))	('Veliparib', 'Chemical', 'MESH:C521013', (0, 9))	('breast cancers', 'Phenotype', 'HP:0003002', (94, 108))	('carboplatin', 'Chemical', 'MESH:D016190', (156, 167))	('mutated', 'Var', (74, 81))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('BRCA 1/2', 'Gene', (65, 73))	('brain metastases', 'Disease', 'MESH:D009362', (196, 212))
517853	27488020	In this FDCS case, activity is seen both in the setting of a BRCA2 mutation as well as activity in combination with carboplatin.	('BRCA2', 'Gene', '675', (61, 66))	('carboplatin', 'Chemical', 'MESH:D016190', (116, 127))	('mutation', 'Var', (67, 75))	('BRCA2', 'Gene', (61, 66))
517857	27488020	Thus, with the identification of both a BRCA2 mutation and ERCC1 negativity, this case clearly demonstrates the benefit of molecular profiling in optimising therapy for this rare tumour and avoiding aggressive protocols from which the patient was unlikely to derive benefit.	('patient', 'Species', '9606', (235, 242))	('ERCC1', 'Gene', (59, 64))	('ERCC1', 'Gene', '2067', (59, 64))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('BRCA2', 'Gene', (40, 45))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('mutation', 'Var', (46, 54))	('BRCA2', 'Gene', '675', (40, 45))	('tumour', 'Disease', (179, 185))
517870	25258541	CTCs were identified by cytomorphology and characterized by dual-color immunocytochemistry using antivimentin or anti-Pan CK, and anti-CD45.	('CD45', 'Gene', (135, 139))	('vimentin', 'Gene', '7431', (101, 109))	('vimentin', 'Gene', (101, 109))	('anti-Pan', 'Var', (113, 121))	('CD45', 'Gene', '5788', (135, 139))
517883	25258541	On average, more than 50% of patients with high-grade STS develop tumor relapse and die due to tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('develop', 'PosReg', (58, 65))	('patients', 'Species', '9606', (29, 37))	('tumor', 'Disease', (66, 71))	('high-grade', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (95, 100))
517909	25258541	We also performed dual-color immunocytochemistry replacing vimentin by anti-Pan CK (1:1,000, clone AE1/AE3; Dako), an epithelial-related marker.	('vimentin', 'Gene', (59, 67))	('vimentin', 'Gene', '7431', (59, 67))	('AE3', 'Gene', (103, 106))	('AE3', 'Gene', '6508', (103, 106))	('anti-Pan', 'Var', (71, 79))	('AE1', 'Gene', '6521', (99, 102))	('AE1', 'Gene', (99, 102))
517971	25258541	cfDNA-marker detection is bound to the presence of mutations in the cfDNA, is spread from the tumor even when the tumor mass is not invasive, may derive from necrotic or apoptotic cells (thus not be involved in the invasion process and more sensitive to antitumor treatments), and may contain "early" mutations that may not be the end point of cancer transformation or a hallmark of cancer, but only one of the first steps of carcinogenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', (383, 389))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (344, 350))	('tumor', 'Disease', (258, 263))	('hallmark of cancer', 'Disease', 'MESH:D009369', (371, 389))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('carcinogenesis', 'Disease', (426, 440))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('carcinogenesis', 'Disease', 'MESH:D063646', (426, 440))	('tumor', 'Disease', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('hallmark of cancer', 'Disease', (371, 389))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (383, 389))	('cfDNA', 'Gene', (68, 73))	('necrotic', 'Disease', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (94, 99))	('necrotic', 'Disease', 'MESH:D009336', (158, 166))
518057	29978507	For each simulation run, we report the mean bias (Bias), averages of the standard error estimates (ASE), empirical standard deviations (ESE), and empirical coverage probabilities (Cov) of the cause-1 quantile regression coefficients betak(tau), k = 1, 2, 3.	('betak', 'Var', (233, 238))	('ASE', 'Gene', '415', (99, 102))	('ASE', 'Gene', (99, 102))
518074	29978507	It can be seen that the effects of chemotherapy are positive roughly for tau < 0.2, which is statistically significant, while tau <= 0.1, and negative for tau >= 0.2 in reducing sarcoma-related death.	('tau < 0.2', 'Var', (73, 82))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('reducing', 'NegReg', (169, 177))	('sarcoma', 'Disease', (178, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
518097	27557498	Inhibition of RNR in Ewing sarcoma cells caused apoptosis in vitro and attenuated tumor growth in an in vivo, xenograft model.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('Ewing sarcoma', 'Disease', (21, 34))	('RNR', 'Gene', (14, 17))	('attenuated tumor', 'Disease', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Inhibition', 'Var', (0, 10))	('attenuated tumor', 'Disease', 'MESH:C538265', (71, 87))	('apoptosis', 'CPA', (48, 57))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (21, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (21, 34))
518131	27557498	Treatment of the Ewing sarcoma cells with ciclopirox resulted in the downregulation of ~45 genes in each of the cell lines (Fold > 2 and FDR < 0.05; Supplementary Table 3) (Figure 1B).	('ciclopirox', 'Var', (42, 52))	('Ewing sarcoma', 'Disease', (17, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (17, 30))	('ciclopirox', 'Chemical', 'MESH:D000077768', (42, 52))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (17, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('downregulation', 'NegReg', (69, 83))
518133	27557498	As predicted, CMAP analysis with these downregulated genes identified ciclopirox and 5109870 as significant hits (Figure 1D and 1E).	('CMAP', 'Chemical', '-', (14, 18))	('5109870', 'Var', (85, 92))	('ciclopirox', 'Chemical', 'MESH:D000077768', (70, 80))	('ciclopirox', 'Var', (70, 80))
518145	27557498	RRM2 is highly expressed in Ewing sarcoma cells compared to other cancer types (p-value < 0.01; Supplementary Figure 3) and treatment of Ewing sarcoma cells with ciclopirox resulted in a significant reduction in deoxyribonucleotide levels, as predicted if RRM2 is a target of ciclopirox (Figure 2C).	('RRM2', 'Gene', '6241', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Ewing sarcoma', 'Disease', (28, 41))	('RRM2', 'Gene', (256, 260))	('Ewing sarcoma', 'Disease', (137, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('RRM2', 'Gene', (0, 4))	('ciclopirox', 'Chemical', 'MESH:D000077768', (162, 172))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('reduction', 'NegReg', (199, 208))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (28, 41))	('ciclopirox', 'Chemical', 'MESH:D000077768', (276, 286))	('ciclopirox', 'Var', (162, 172))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (137, 150))	('deoxyribonucleotide levels', 'MPA', (212, 238))	('deoxyribonucleotide', 'Chemical', 'MESH:D003854', (212, 231))	('RRM2', 'Gene', '6241', (256, 260))	('cancer', 'Disease', (66, 72))
518146	27557498	Similarly, treatment of Ewing sarcoma cells with ciclopirox caused an increase in single-strand DNA (ssDNA), which is an indicator of impaired DNA replication (Figure 2D).	('increase', 'PosReg', (70, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('Ewing sarcoma', 'Disease', (24, 37))	('ciclopirox', 'Var', (49, 59))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (24, 37))	('ciclopirox', 'Chemical', 'MESH:D000077768', (49, 59))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (24, 37))	('single-strand DNA', 'MPA', (82, 99))
518149	27557498	Treatment of Ewing sarcoma cell lines with ciclopirox for 72 hours caused a significant reduction in growth (Figure 3A), with IC50 values ranging from 500 nM to 3 muM.	('growth', 'MPA', (101, 107))	('ciclopirox', 'Chemical', 'MESH:D000077768', (43, 53))	('Ewing sarcoma', 'Disease', (13, 26))	('muM', 'Gene', '56925', (163, 166))	('reduction', 'NegReg', (88, 97))	('muM', 'Gene', (163, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('ciclopirox', 'Var', (43, 53))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))
518160	27557498	In addition to the effects on cell cycle, we also noted significant morphologic changes, suggestive of cell death, in the Ewing sarcoma cells treated with 10 muM ciclopirox (Figure 4A), which is a drug concentration that significantly impairs the viability of all of the Ewing sarcoma cell lines (Figure 3B) and is an achievable serum concentration of the drug in vivo.	('changes', 'Reg', (80, 87))	('impairs', 'NegReg', (235, 242))	('Ewing sarcoma', 'Disease', (122, 135))	('Ewing sarcoma', 'Disease', (271, 284))	('viability', 'CPA', (247, 256))	('muM', 'Gene', (158, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('ciclopirox', 'Var', (162, 172))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (122, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (122, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (271, 284))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (271, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('ciclopirox', 'Chemical', 'MESH:D000077768', (162, 172))	('muM', 'Gene', '56925', (158, 161))
518163	27557498	Treatment of Ewing sarcoma cells with ciclopirox also resulted in an increase in the percentage of cells positive for annexin-V and propidium iodide (Figure 4C and 4D).	('annexin-V', 'Gene', (118, 127))	('propidium iodide', 'Chemical', 'MESH:D011419', (132, 148))	('increase', 'PosReg', (69, 77))	('ciclopirox', 'Var', (38, 48))	('Ewing sarcoma', 'Disease', (13, 26))	('ciclopirox', 'Chemical', 'MESH:D000077768', (38, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))	('annexin-V', 'Gene', '308', (118, 127))
518166	27557498	We then used siRNA to knockdown RRM2 in Ewing sarcoma cells to complement the small-molecule studies.	('Ewing sarcoma', 'Disease', (40, 53))	('RRM2', 'Gene', (32, 36))	('knockdown', 'Var', (22, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (40, 53))	('RRM2', 'Gene', '6241', (32, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
518167	27557498	Two different siRNAs, a "pool" set consisting of four unique siRNAs (si_RRM2_pool) and a well-validated siRNA used in clinical trials (si_RRM2_R2B), were used to knockdown RRM2 (Figure 5A).	('RRM2', 'Gene', '6241', (138, 142))	('RRM2', 'Gene', (138, 142))	('RRM2', 'Gene', '6241', (172, 176))	('RRM2', 'Gene', (172, 176))	('RRM2', 'Gene', '6241', (72, 76))	('RRM2', 'Gene', (72, 76))	('knockdown', 'Var', (162, 171))
518169	27557498	Deconvolution of the si_RRM2_pool set showed that siRRM2_1 and siRRM2_3 were most effective at depleting RRM2 (Figure 5E) and that knockdown efficiency correlated with growth inhibition (Figure 5F).	('RRM2', 'Gene', '6241', (24, 28))	('RRM2', 'Gene', (24, 28))	('knockdown', 'Var', (131, 140))	('RRM2', 'Gene', '6241', (65, 69))	('RRM2', 'Gene', (65, 69))	('RRM2', 'Gene', '6241', (52, 56))	('RRM2', 'Gene', (52, 56))	('growth', 'MPA', (168, 174))	('RRM2', 'Gene', '6241', (105, 109))	('RRM2', 'Gene', (105, 109))
518172	27557498	More genes were deregulated by ciclopirox than the RRM2 siRNA, which likely reflects off-target effects of the drug.	('RRM2', 'Gene', (51, 55))	('RRM2', 'Gene', '6241', (51, 55))	('deregulated', 'Reg', (16, 27))	('ciclopirox', 'Var', (31, 41))	('ciclopirox', 'Chemical', 'MESH:D000077768', (31, 41))
518174	27557498	Notably, expression of this siRNA-resistant RRM2 gene in Ewing sarcoma cells rescued the growth defect (Figure 5I) and caspase-3/7 activation (Figure 5J) caused by transfection of si_RRM2_3 and knockdown of endogenous RRM2.	('activation', 'PosReg', (131, 141))	('rescued', 'PosReg', (77, 84))	('Ewing sarcoma', 'Disease', (57, 70))	('caspase-3', 'Gene', '836', (119, 128))	('knockdown', 'Var', (194, 203))	('RRM2', 'Gene', '6241', (183, 187))	('RRM2', 'Gene', (183, 187))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('growth defect', 'Disease', 'MESH:D006130', (89, 102))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('RRM2', 'Gene', (218, 222))	('caspase-3', 'Gene', (119, 128))	('growth defect', 'Disease', (89, 102))	('RRM2', 'Gene', '6241', (44, 48))	('RRM2', 'Gene', (44, 48))	('RRM2', 'Gene', '6241', (218, 222))
518177	27557498	All four siRNAs in the pool showed effective knockdown of RRM1 (Supplementary Figure 6B) and significant inhibition of Ewing sarcoma cell growth (Supplementary Figure 6C).	('RRM1', 'Gene', '6240', (58, 62))	('inhibition', 'NegReg', (105, 115))	('Ewing sarcoma', 'Disease', (119, 132))	('RRM1', 'Gene', (58, 62))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (119, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (119, 132))	('knockdown', 'Var', (45, 54))
518178	27557498	The Ewing sarcoma cells were more sensitive to RNR inhibition and knockdown than the other cell lines we tested.	('Ewing sarcoma', 'Disease', (4, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (4, 17))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (4, 17))	('knockdown', 'Var', (66, 75))
518179	27557498	Notably, Ewing sarcoma cell lines are also known to be sensitive to PARP-1 inhibitors and combinations of PARP-1 inhibitors with DNA-damaging agents.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (9, 22))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (9, 22))	('inhibitors', 'Var', (75, 85))	('PARP-1', 'Gene', '142', (106, 112))	('combinations', 'Interaction', (90, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('PARP-1', 'Gene', (106, 112))	('Ewing sarcoma', 'Disease', (9, 22))	('PARP-1', 'Gene', (68, 74))	('PARP-1', 'Gene', '142', (68, 74))
518183	27557498	To test whether SLFN11 expression modulates the sensitivity of Ewing sarcoma cells to RRM2 knockdown we used siRNA to knockdown both SLFN11 and RRM2 in Ewing sarcoma cells (Figure 6B).	('SLFN11', 'Gene', '91607', (133, 139))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (152, 165))	('RRM2', 'Gene', '6241', (144, 148))	('RRM2', 'Gene', (144, 148))	('modulates', 'Reg', (34, 43))	('knockdown', 'Var', (118, 127))	('SLFN11', 'Gene', '91607', (16, 22))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('RRM2', 'Gene', (86, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('SLFN11', 'Gene', (16, 22))	('Ewing sarcoma', 'Disease', (63, 76))	('RRM2', 'Gene', '6241', (86, 90))	('SLFN11', 'Gene', (133, 139))	('Ewing sarcoma', 'Disease', (152, 165))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
518184	27557498	Notably, the toxicity from knockdown of RRM2 was partially rescued by co-knockdown of SLFN11 (Figure 6C).	('toxicity', 'Disease', 'MESH:D064420', (13, 21))	('SLFN11', 'Gene', (86, 92))	('knockdown', 'Var', (27, 36))	('toxicity', 'Disease', (13, 21))	('SLFN11', 'Gene', '91607', (86, 92))	('RRM2', 'Gene', '6241', (40, 44))	('RRM2', 'Gene', (40, 44))
518185	27557498	Additionally, knockdown of SLFN11 also partially rescued Ewing sarcoma cells from the effects of ciclopirox on cell viability (Figure 6D).	('SLFN11', 'Gene', (27, 33))	('Ewing sarcoma', 'Disease', (57, 70))	('SLFN11', 'Gene', '91607', (27, 33))	('ciclopirox', 'Chemical', 'MESH:D000077768', (97, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (57, 70))	('knockdown', 'Var', (14, 23))	('rescued', 'NegReg', (49, 56))
518199	27557498	We used a doxycycline-inducible, siRNA-resistant, RRM2 transgene to demonstrate that the reduced viability and induction of apoptosis caused by siRNA knockdown of RRM2 is an on-target effect.	('RRM2', 'Gene', (163, 167))	('siRNA', 'Gene', (144, 149))	('viability', 'CPA', (97, 106))	('knockdown', 'Var', (150, 159))	('RRM2', 'Gene', (50, 54))	('RRM2', 'Gene', '6241', (50, 54))	('RRM2', 'Gene', '6241', (163, 167))	('reduced', 'NegReg', (89, 96))	('apoptosis', 'CPA', (124, 133))	('doxycycline', 'Chemical', 'MESH:D004318', (10, 21))
518201	27557498	Additionally, because multiple inhibitors of RNR are currently used in clinical oncology, we show that ciclopirox inhibits the in vivo growth of Ewing sarcoma cells in a xenograft model.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (145, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (145, 158))	('ciclopirox', 'Var', (103, 113))	('growth', 'CPA', (135, 141))	('inhibits', 'NegReg', (114, 122))	('ciclopirox', 'Chemical', 'MESH:D000077768', (103, 113))	('Ewing sarcoma', 'Disease', (145, 158))	('oncology', 'Phenotype', 'HP:0002664', (80, 88))
518207	27557498	Furthermore, in vitro and in vivo work has demonstrated synergy between RRM1 and RRM2 inhibitors.	('RRM2', 'Gene', (81, 85))	('synergy', 'Interaction', (56, 63))	('RRM1', 'Gene', '6240', (72, 76))	('RRM1', 'Gene', (72, 76))	('inhibitors', 'Var', (86, 96))	('RRM2', 'Gene', '6241', (81, 85))
518218	27557498	However, inhibition or suppression of RNR in cancer cells is known to cause senescence.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('senescence', 'Disease', (76, 86))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('suppression', 'NegReg', (23, 34))	('RNR', 'Protein', (38, 41))	('cancer', 'Disease', (45, 51))	('inhibition', 'Var', (9, 19))
518220	27557498	has shown that knockdown of RRM2 triggers aberrant DNA replication, activation of the DNA damage response and cellular senescence in primary cells and cancer cell lines, including melanoma and ovarian cancer.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('RRM2', 'Gene', (28, 32))	('cancer', 'Disease', (201, 207))	('knockdown', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('DNA replication', 'CPA', (51, 66))	('RRM2', 'Gene', '6241', (28, 32))	('melanoma and ovarian cancer', 'Disease', 'MESH:D010051', (180, 207))	('activation', 'PosReg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cellular senescence', 'CPA', (110, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (193, 207))	('DNA damage', 'MPA', (86, 96))
518221	27557498	In Ewing sarcoma cells, however, we show that inhibition of RNR leads to apoptosis.	('RNR', 'Gene', (60, 63))	('inhibition', 'Var', (46, 56))	('Ewing sarcoma', 'Disease', (3, 16))	('apoptosis', 'CPA', (73, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))
518222	27557498	An aberrant response to DNA damage is well described in Ewing sarcoma tumors, although the mechanism is unclear.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (56, 76))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('response to DNA damage', 'MPA', (12, 34))	('aberrant', 'Var', (3, 11))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Ewing sarcoma tumors', 'Disease', (56, 76))
518228	27557498	Notably, PARP inhibitors can cause replication stress by a "trapping" mechanism whereby the inhibitor stabilizes a PARP-DNA complex that interferes with DNA replication.	('PARP', 'Gene', (9, 13))	('interferes', 'NegReg', (137, 147))	('PARP', 'Gene', '142', (9, 13))	('PARP', 'Gene', '142', (115, 119))	('PARP', 'Gene', (115, 119))	('inhibitors', 'Var', (14, 24))	('cause', 'Reg', (29, 34))	('DNA replication', 'MPA', (153, 168))
518250	27557498	For the microarray experiments, RNA was collected from three biological replicates of cells treated with DMSO, ciclopirox (10 muM), si_NT, and si_RRM2_R2B using an RNeasy kit (Qiagen).	('DMSO', 'Chemical', 'MESH:D004121', (105, 109))	('muM', 'Gene', '56925', (126, 129))	('muM', 'Gene', (126, 129))	('RRM2', 'Gene', '6241', (146, 150))	('RRM2', 'Gene', (146, 150))	('ciclopirox', 'Chemical', 'MESH:D000077768', (111, 121))	('si_NT', 'Var', (132, 137))
518261	27557498	The sequences for si_RRM2_R2B and si_NT were 5'-GAUUUAGCCAAGAAGUUCAGA-3' and 5'-UAGCGACUAAACACAUCAAUU-3', respectively.	('RRM2', 'Gene', '6241', (21, 25))	('RRM2', 'Gene', (21, 25))	('si_NT', 'Var', (34, 39))
518274	26402468	The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone.	('NVP-AEW541', 'Var', (16, 26))	('Akt', 'Gene', (56, 59))	('buparlisib', 'Chemical', 'MESH:C571178', (115, 125))	('induced', 'Reg', (85, 92))	('reduced', 'NegReg', (40, 47))	('Akt', 'Gene', '207', (56, 59))	('apoptosis', 'CPA', (93, 102))
518275	26402468	Additionally, the combination of buparlisib with the MEK1/2 inhibitor trametinib resulted in synergy in sarcoma cell lines possessing MAPK pathway mutations.	('mutations', 'Var', (147, 156))	('synergy in sarcoma', 'Disease', (93, 111))	('synergy in sarcoma', 'Disease', 'MESH:D012509', (93, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('MEK1/2', 'Gene', '5604;5605', (53, 59))	('trametinib', 'Chemical', 'MESH:C560077', (70, 80))	('MEK1/2', 'Gene', (53, 59))	('buparlisib', 'Chemical', 'MESH:C571178', (33, 43))	('MAPK pathway', 'Pathway', (134, 146))	('combination', 'Interaction', (18, 29))
518286	26402468	Additionally, mTOR (mammalian target of rapamycin) inhibition induces activation of Akt in cancer cell lines and patient tumors.	('mTOR', 'Gene', '2475', (14, 18))	('patient', 'Species', '9606', (113, 120))	('Akt', 'Gene', '207', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Disease', (91, 97))	('tumors', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('mammalian target of rapamycin', 'Gene', '2475', (20, 49))	('Akt', 'Gene', (84, 87))	('mammalian target of rapamycin', 'Gene', (20, 49))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('inhibition', 'Var', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('activation', 'PosReg', (70, 80))	('mTOR', 'Gene', (14, 18))
518288	26402468	Akt is activated upon phosphoinositide 3-kinase (PI3K)-mediated modulation of phospholipids within the plasma membrane.	('phosphoinositide 3-kinase', 'Gene', '5290', (22, 47))	('phosphoinositide 3-kinase', 'Gene', (22, 47))	('Akt', 'Gene', '207', (0, 3))	('phospholipids', 'Chemical', 'MESH:D010743', (78, 91))	('activated', 'PosReg', (7, 16))	('Akt', 'Gene', (0, 3))	('modulation', 'Var', (64, 74))
518289	26402468	Three classes of PI3Ks are activated by various stimuli and modify distinct lipid substrates.	('lipid', 'Chemical', 'MESH:D008055', (76, 81))	('PI3Ks', 'Var', (17, 22))	('modify', 'Reg', (60, 66))
518292	26402468	In general, class IA PI3Ks act downstream of growth factor receptor tyrosine kinases to phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2) and generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) at the cell membrane to create a docking site for signaling proteins.	('PIP2', 'Chemical', 'MESH:D019269', (141, 145))	('PIP3', 'Chemical', '-', (202, 206))	('docking', 'Interaction', (241, 248))	('PI3Ks', 'Var', (21, 26))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (102, 139))	('phosphatidylinositol-3,4,5-trisphosphate', 'Chemical', 'MESH:C060974', (160, 200))	('phosphorylate', 'MPA', (88, 101))
518294	26402468	Accumulation of PIP3 recruits Akt to the cell membrane, where it is first phosphorylated within the activation loop at threonine 308 by phosphoinositide-dependent protein kinase 1 (PDK1).	('threonine', 'Chemical', 'MESH:D013912', (119, 128))	('Akt', 'Gene', '207', (30, 33))	('phosphoinositide-dependent protein kinase 1', 'Gene', '5163', (136, 179))	('phosphoinositide-dependent protein kinase 1', 'Gene', (136, 179))	('PIP3', 'Chemical', '-', (16, 20))	('PDK1', 'Gene', '5163', (181, 185))	('PDK1', 'Gene', (181, 185))	('Akt', 'Gene', (30, 33))	('PIP3', 'Var', (16, 20))
518297	26402468	In cancer, this pathway can be constitutively activated, most commonly by loss of PTEN or an activating mutation in the PIK3CA gene that encodes the p110alpha catalytic subunit of PI3K.	('PIK3CA', 'Gene', (120, 126))	('p110alpha', 'Gene', (149, 158))	('p110alpha', 'Gene', '5290', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('PIK3CA', 'Gene', '5290', (120, 126))	('loss', 'NegReg', (74, 78))	('activating', 'PosReg', (93, 103))	('cancer', 'Disease', (3, 9))	('mutation', 'Var', (104, 112))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
518300	26402468	Early phase I studies of the pan-class I PI3K inhibitor buparlisib demonstrated a clinical benefit in breast cancer, leading to a multi-center phase III trial to evaluate progression free survival in patients stratified by PI3K pathway activating mutations.	('breast cancer', 'Disease', (102, 115))	('PI3K pathway', 'Pathway', (223, 235))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('patients', 'Species', '9606', (200, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('buparlisib', 'Chemical', 'MESH:C571178', (56, 66))	('buparlisib', 'Gene', (56, 66))	('mutations', 'Var', (247, 256))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
518306	26402468	It is at least 50-fold more specific to PI3K than other protein kinases and potently blocks activation of Akt and other downstream signaling proteins.	('blocks', 'NegReg', (85, 91))	('Akt', 'Gene', '207', (106, 109))	('PI3K', 'Var', (40, 44))	('activation', 'MPA', (92, 102))	('Akt', 'Gene', (106, 109))
518318	26402468	The primary antibodies used for these studies were rabbit anti-PTEN, rabbit anti-phospho-Akt (Ser473), rabbit anti-phospho-Akt (Thr308), mouse anti-Akt (pan), rabbit anti-phospho-p44/42 MAPK (Erk1/2) (T202/T204 on Erk1, T185/T187 on Erk2), mouse anti-p44/42 MAPK (Erk1/2), mouse anti-phospho-p70 S6 Kinase (Thr389), rabbit anti-p70 S6 Kinase, rabbit anti-phospho-4E-BP1 (Thr37/46), rabbit anti-4E-BP1, rabbit anti-STAT3 (Y705), mouse anti-STAT3, and rabbit anti-cleaved PARP from Cell Signaling Technology; and mouse anti-beta-actin from Sigma.	('PTEN', 'Gene', '5728', (63, 67))	('STAT3', 'Gene', '6774', (414, 419))	('rabbit', 'Species', '9986', (69, 75))	('mouse', 'Species', '10090', (137, 142))	('Erk1', 'Gene', '5595', (214, 218))	('T185/T187', 'Var', (220, 229))	('Erk1/2', 'Gene', (192, 198))	('p44', 'Gene', '79084', (251, 254))	('Erk1', 'Gene', (214, 218))	('mouse', 'Species', '10090', (428, 433))	('p44', 'Gene', (179, 182))	('Erk1/2', 'Gene', (264, 270))	('rabbit', 'Species', '9986', (51, 57))	('4E-BP1', 'Gene', '1978', (363, 369))	('4E-BP1', 'Gene', '1978', (394, 400))	('Akt', 'Gene', (148, 151))	('p44', 'Gene', '79084', (179, 182))	('rabbit', 'Species', '9986', (343, 349))	('Akt', 'Gene', (123, 126))	('PARP', 'Gene', '142', (470, 474))	('Akt', 'Gene', '207', (148, 151))	('rabbit', 'Species', '9986', (103, 109))	('Erk1/2', 'Gene', '5595;5594', (192, 198))	('rabbit', 'Species', '9986', (159, 165))	('Erk1/2', 'Gene', '5595;5594', (264, 270))	('rabbit', 'Species', '9986', (382, 388))	('Erk2', 'Gene', '5594', (233, 237))	('Akt', 'Gene', '207', (123, 126))	('PARP', 'Gene', (470, 474))	('Erk1', 'Gene', '5595', (192, 196))	('T202/T204', 'Var', (201, 210))	('Akt', 'Gene', (89, 92))	('Erk2', 'Gene', (233, 237))	('4E-BP1', 'Gene', (363, 369))	('mouse', 'Species', '10090', (273, 278))	('Erk1', 'Gene', '5595', (264, 268))	('mouse', 'Species', '10090', (511, 516))	('Erk1', 'Gene', (192, 196))	('STAT3', 'Gene', (439, 444))	('4E-BP1', 'Gene', (394, 400))	('PTEN', 'Gene', (63, 67))	('Erk1', 'Gene', (264, 268))	('rabbit', 'Species', '9986', (316, 322))	('mouse', 'Species', '10090', (240, 245))	('STAT3', 'Gene', (414, 419))	('Akt', 'Gene', '207', (89, 92))	('p44', 'Gene', (251, 254))	('STAT3', 'Gene', '6774', (439, 444))	('rabbit', 'Species', '9986', (402, 408))	('rabbit', 'Species', '9986', (450, 456))
518330	26402468	The breast cancer cell line MCF-7 and prostate cancer cell line LNCaP were also included since they display increased Akt phosphorylation due the presence of PIK3CA and PTEN mutations, respectively.	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF-7', 'CellLine', 'CVCL:0031', (28, 33))	('PIK3CA', 'Gene', (158, 164))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('increased', 'PosReg', (108, 117))	('PTEN', 'Gene', (169, 173))	('Akt', 'Gene', (118, 121))	('breast cancer', 'Disease', (4, 17))	('prostate cancer', 'Disease', (38, 53))	('PIK3CA', 'Gene', '5290', (158, 164))	('LNCaP', 'CellLine', 'CVCL:0395', (64, 69))	('PTEN', 'Gene', '5728', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (174, 183))	('Akt', 'Gene', '207', (118, 121))
518332	26402468	The ES cell line A673, which harbors a B-RAF mutation and thus expected to have less dependence on PI3K/Akt signaling, displayed low phospho-Akt levels.	('ES', 'Phenotype', 'HP:0012254', (4, 6))	('Akt', 'Gene', (104, 107))	('low', 'NegReg', (129, 132))	('B-RAF', 'Gene', (39, 44))	('mutation', 'Var', (45, 53))	('B-RAF', 'Gene', '673', (39, 44))	('Akt', 'Gene', '207', (141, 144))	('Akt', 'Gene', '207', (104, 107))	('Akt', 'Gene', (141, 144))
518333	26402468	Conversely, the RMS cell line RD displayed high levels of Akt phosphorylation despite possessing a MAPK pathway mutation (Fig 1A and 1B).	('mutation', 'Var', (112, 120))	('MAPK pathway', 'Pathway', (99, 111))	('Akt', 'Gene', '207', (58, 61))	('RMS', 'Phenotype', 'HP:0002859', (16, 19))	('Akt', 'Gene', (58, 61))
518349	26402468	Akt phosphorylation increased at threonine 308 and serine 473 (Fig 3A), indicating a reactivation mechanism that is upstream of both PDK1 and mTORC2.	('mTORC2', 'Gene', (142, 148))	('increased', 'PosReg', (20, 29))	('PDK1', 'Gene', '5163', (133, 137))	('serine 473', 'Var', (51, 61))	('PDK1', 'Gene', (133, 137))	('phosphorylation', 'MPA', (4, 19))	('threonine', 'Chemical', 'MESH:D013912', (33, 42))	('serine', 'Chemical', 'MESH:D012694', (51, 57))	('Akt', 'Gene', '207', (0, 3))	('threonine 308', 'Var', (33, 46))	('Akt', 'Gene', (0, 3))	('mTORC2', 'Gene', '74343', (142, 148))
518363	26402468	MCF-7 cells containing the E545K PIK3CA mutation displayed a lower IC50 of 173 nM, despite having a similar phospho-Akt IC50 (S1B-S1D Fig, S1 Table).	('lower', 'NegReg', (61, 66))	('50 (S', 'Species', '1214577', (122, 127))	('PIK3CA', 'Gene', '5290', (33, 39))	('MCF-7', 'CellLine', 'CVCL:0031', (0, 5))	('E545K', 'Mutation', 'rs104886003', (27, 32))	('Akt', 'Gene', '207', (116, 119))	('E545K', 'Var', (27, 32))	('Akt', 'Gene', (116, 119))	('PIK3CA', 'Gene', (33, 39))	('IC50 of 173 nM', 'MPA', (67, 81))
518367	26402468	This agrees with a prior study that demonstrated increased buparlisib sensitivity only in cell lines with an activating PIK3CA mutation.	('PIK3CA', 'Gene', (120, 126))	('mutation', 'Var', (127, 135))	('buparlisib', 'Chemical', 'MESH:C571178', (59, 69))	('PIK3CA', 'Gene', '5290', (120, 126))	('activating', 'PosReg', (109, 119))
518381	26402468	We also measured the effects of combining buparlisib and NVP-AEW541 on Akt phosphorylation and induction of apoptosis (Fig 6C and 6D).	('Akt', 'Gene', '207', (71, 74))	('buparlisib', 'Chemical', 'MESH:C571178', (42, 52))	('NVP-AEW541', 'Var', (57, 67))	('Akt', 'Gene', (71, 74))	('apoptosis', 'CPA', (108, 117))
518383	26402468	Furthermore, this response persisted up to 24 hours, indicating IGF1R inhibition can prevent Akt reactivation that was observed with buparlisib treatment alone (Fig 6D).	('Akt', 'Gene', (93, 96))	('prevent', 'NegReg', (85, 92))	('IGF1R', 'Gene', (64, 69))	('inhibition', 'Var', (70, 80))	('IGF1R', 'Gene', '3480', (64, 69))	('Akt', 'Gene', '207', (93, 96))	('buparlisib', 'Chemical', 'MESH:C571178', (133, 143))
518385	26402468	While PTEN status did not correlate with sensitivity to buparlisib as a single agent, it appears lower PTEN expression may render cells more sensitive to buparlisib when combined with other agents that inhibit Akt signaling.	('PTEN', 'Gene', (103, 107))	('PTEN', 'Gene', '5728', (103, 107))	('sensitive', 'MPA', (141, 150))	('buparlisib', 'Chemical', 'MESH:C571178', (154, 164))	('PTEN', 'Gene', '5728', (6, 10))	('more', 'PosReg', (136, 140))	('buparlisib', 'Chemical', 'MESH:C571178', (56, 66))	('Akt', 'Gene', '207', (210, 213))	('lower', 'NegReg', (97, 102))	('PTEN', 'Gene', (6, 10))	('Akt', 'Gene', (210, 213))	('expression', 'Var', (108, 118))
518388	26402468	MAPK mutations in sarcoma cell lines as well as increased Erk activity after buparlisib treatment suggested the addition of an agent targeting the MAPK pathway may also increase buparlisib efficacy.	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('increased', 'PosReg', (48, 57))	('buparlisib', 'Chemical', 'MESH:C571178', (178, 188))	('sarcoma', 'Disease', (18, 25))	('buparlisib', 'Chemical', 'MESH:C571178', (77, 87))	('activity', 'MPA', (62, 70))	('Erk', 'Gene', '5594', (58, 61))	('MAPK', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('mutations', 'Var', (5, 14))	('increase', 'PosReg', (169, 177))	('efficacy', 'MPA', (189, 197))	('Erk', 'Gene', (58, 61))
518389	26402468	Buparlisib was combined with the MEK1/2 inhibitor trametinib in cell lines with (A673, RD) and without (TC-32, A4573) mutations in the MAPK pathway.	('trametinib', 'Chemical', 'MESH:C560077', (50, 60))	('MAPK pathway', 'Pathway', (135, 147))	('mutations', 'Var', (118, 127))	('MEK1/2', 'Gene', '5604;5605', (33, 39))	('MEK1/2', 'Gene', (33, 39))	('Buparlisib', 'Chemical', 'MESH:C571178', (0, 10))	('TC-32', 'Chemical', '-', (104, 109))
518397	26402468	Reactivation of Akt within 24 hours of buparlisib treatment suggests possible removal of negative feedback inhibition.	('Reactivation', 'Var', (0, 12))	('Akt', 'Gene', '207', (16, 19))	('Akt', 'Gene', (16, 19))	('buparlisib', 'Chemical', 'MESH:C571178', (39, 49))
518398	26402468	Transient inhibition of Akt phosphorylation was also observed with dual PI3K/mTOR inhibitor NVP-BEZ235, which was thought to be a result of loss of negative feedback through IRS1.	('IRS1', 'Gene', (174, 178))	('inhibition', 'NegReg', (10, 20))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (92, 102))	('mTOR', 'Gene', '2475', (77, 81))	('NVP-BEZ235', 'Var', (92, 102))	('mTOR', 'Gene', (77, 81))	('Akt', 'Gene', '207', (24, 27))	('IRS1', 'Gene', '3667', (174, 178))	('loss', 'NegReg', (140, 144))	('Akt', 'Gene', (24, 27))
518401	26402468	Since IGF1R functions upstream of IRS1, inhibition at this point of the pathway can prevent IRS1 activation that can occur through release of negative feedback.	('inhibition', 'Var', (40, 50))	('activation', 'PosReg', (97, 107))	('IRS1', 'Gene', (34, 38))	('IRS1', 'Gene', '3667', (92, 96))	('IGF1R', 'Gene', (6, 11))	('IRS1', 'Gene', (92, 96))	('IGF1R', 'Gene', '3480', (6, 11))	('IRS1', 'Gene', '3667', (34, 38))
518407	26402468	Further investigation of the direct correlation between phospho-Akt levels over time and PI3K-dependent buparlisib cytotoxicity is warranted to fully define the role of Akt reactivation in resistance to buparlisib treatment.	('buparlisib', 'Chemical', 'MESH:C571178', (203, 213))	('Akt', 'Gene', (169, 172))	('cytotoxicity', 'Disease', 'MESH:D064420', (115, 127))	('Akt', 'Gene', '207', (64, 67))	('buparlisib', 'Chemical', 'MESH:C571178', (104, 114))	('Akt', 'Gene', (64, 67))	('PI3K-dependent', 'Var', (89, 103))	('cytotoxicity', 'Disease', (115, 127))	('Akt', 'Gene', '207', (169, 172))
518410	26402468	For example, cell lines with low PTEN expression displayed increased synergy when combined with an IGF1R inhibitor.	('IGF1R', 'Gene', (99, 104))	('PTEN', 'Gene', (33, 37))	('IGF1R', 'Gene', '3480', (99, 104))	('PTEN', 'Gene', '5728', (33, 37))	('expression', 'Var', (38, 48))	('combined', 'Interaction', (82, 90))	('increased', 'PosReg', (59, 68))	('synergy', 'MPA', (69, 76))
518412	26402468	Combination of buparlisib with trametinib only resulted in synergy in cell lines that harbored RAS or RAF mutations.	('synergy', 'MPA', (59, 66))	('trametinib', 'Chemical', 'MESH:C560077', (31, 41))	('buparlisib', 'Chemical', 'MESH:C571178', (15, 25))	('mutations', 'Var', (106, 115))	('RAS', 'Gene', (95, 98))	('RAF', 'Gene', (102, 105))	('RAF', 'Gene', '22882', (102, 105))
518415	26402468	The pan PI3K inhibitor SAR245408 demonstrated cytotoxic activity in a panel of pediatric tumor cell lines, including sarcomas, with a median relative IC50 of 10.9 muM.	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('muM', 'Gene', '56925', (163, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcomas', 'Disease', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cytotoxic', 'CPA', (46, 55))	('SAR245408', 'Chemical', 'MESH:C581157', (23, 32))	('muM', 'Gene', (163, 166))	('SAR245408', 'Var', (23, 32))	('tumor', 'Disease', (89, 94))
518421	26402468	Additionally, two recent studies investigated the pre-clinical activity NVP-BEZ235 and NVP-BYL719, a p110alpha specific PI3K inhibitor, in osteosarcoma.	('p110alpha', 'Gene', (101, 110))	('NVP-BEZ235', 'Var', (72, 82))	('p110alpha', 'Gene', '5290', (101, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('NVP-BYL719', 'Var', (87, 97))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (72, 82))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('osteosarcoma', 'Disease', (139, 151))	('osteosarcoma', 'Disease', 'MESH:D012516', (139, 151))
518423	26402468	Furthermore, combining NVP-BYL719 and the chemotherapeutic agent ifosfamide synergistically inhibited tumor growth.	('inhibited', 'NegReg', (92, 101))	('ifosfamide', 'Chemical', 'MESH:D007069', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('NVP-BYL719', 'Var', (23, 33))
518424	26402468	Overall, this promising pre-clinical data supports the rationale for clinical investigation of PI3K inhibitors in bone and soft tissue sarcomas.	('PI3K', 'Gene', (95, 99))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (123, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (123, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('inhibitors', 'Var', (100, 110))	('soft tissue sarcomas', 'Disease', (123, 143))
518438	26402468	The utility of buparlisib as an effective therapeutic agent is also influenced by the prevalence of activating PIK3CA mutations in sarcoma since increased single agent sensitivity is observed for tumors harboring these mutations.	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('mutations', 'Var', (118, 127))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('PIK3CA', 'Gene', (111, 117))	('sarcoma', 'Disease', (131, 138))	('activating', 'PosReg', (100, 110))	('buparlisib', 'Chemical', 'MESH:C571178', (15, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('PIK3CA', 'Gene', '5290', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
518439	26402468	Based on our data and recently published studies, PI3K mutations in sarcoma are rare.	('sarcoma', 'Disease', (68, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('PI3K', 'Var', (50, 54))
518440	26402468	examined 55 ES tumors and 31 cell lines for PI3K mutations and only one cell line contained a PIK3CA G118D mutation.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('mutations', 'Var', (49, 58))	('G118D', 'Var', (101, 106))	('G118D', 'Mutation', 'rs587777790', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('ES', 'Phenotype', 'HP:0012254', (12, 14))	('PIK3CA', 'Gene', (94, 100))	('tumors', 'Disease', (15, 21))	('PIK3CA', 'Gene', '5290', (94, 100))
518442	26402468	However, 24% of the tumors had mutations in the PI3K/mTOR pathway, including 5 PTEN deletions, suggesting the pathway rather than specific mutations plays a role in tumorigenesis.	('tumor', 'Disease', (165, 170))	('tumors', 'Disease', (20, 26))	('mutations', 'Var', (31, 40))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('mTOR', 'Gene', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('PTEN', 'Gene', '5728', (79, 83))	('mTOR', 'Gene', '2475', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('PTEN', 'Gene', (79, 83))	('tumor', 'Disease', (20, 25))	('deletions', 'Var', (84, 93))
518443	26402468	PIK3CA mutations have a higher rate in rhabdomyosarcoma, where a recent study identified a frequency of 5.4% in a sample of 147 tumors.	('rhabdomyosarcoma', 'Disease', (39, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('PIK3CA', 'Gene', (0, 6))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (39, 55))	('mutations', 'Var', (7, 16))
518452	32002485	Genetic analysis of the Ewing's sarcoma was fluorescence in situ hybridization positive for EWSR/FLI1 rearrangement.	('rearrangement', 'Var', (102, 115))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (24, 39))	('FLI1', 'Gene', (97, 101))	("Ewing's sarcoma", 'Disease', (24, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('FLI1', 'Gene', '2313', (97, 101))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (24, 39))
518493	31496726	Whole exome sequencing of the tissue identified the genetic alterations profile of PAS: copy number variation (CNV) of KIT and mutations of TP53, PIK3CA, IL7R and ATR.	('copy number variation', 'Var', (88, 109))	('PAS', 'Chemical', '-', (83, 86))	('IL7R', 'Gene', '3575', (154, 158))	('PIK3CA', 'Gene', '5290', (146, 152))	('TP53', 'Gene', (140, 144))	('IL7R', 'Gene', (154, 158))	('KIT', 'Gene', (119, 122))	('ATR', 'Gene', '545', (163, 166))	('PIK3CA', 'Gene', (146, 152))	('mutations', 'Var', (127, 136))	('ATR', 'Gene', (163, 166))	('TP53', 'Gene', '7157', (140, 144))
518521	31496726	These tumors also overexpress MDM2 and mutant P53 (Figure 3).	('P53', 'Gene', '7157', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('MDM2', 'Gene', '4193', (30, 34))	('MDM2', 'Gene', (30, 34))	('tumors', 'Disease', (6, 12))	('overexpress', 'PosReg', (18, 29))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutant', 'Var', (39, 45))	('P53', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
518527	31496726	In targeted drug-related genes, KIT copy number variation (CNV) and TP53 and PIK3CA mutations were found.	('PIK3CA', 'Gene', (77, 83))	('KIT', 'Gene', (32, 35))	('PIK3CA', 'Gene', '5290', (77, 83))	('mutations', 'Var', (84, 93))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))
518528	31496726	The PIK3CA gene had missense mutations at the encoding sequence NM_006218.4:c.1345C>A (p.P449T.)	('PIK3CA', 'Gene', (4, 10))	('p.P449T', 'Mutation', 'p.P449T', (87, 94))	('NM_006218.4:c.1345C>A', 'Mutation', 'c.1345C>A', (64, 85))	('PIK3CA', 'Gene', '5290', (4, 10))	('c.1345C>A', 'Var', (76, 85))
518529	31496726	The TP53 gene had mutations in the encoding sequence NM_000546.5:c.329G>C (p.R110P) in exon 4 with an abundance of 62.1.	('NM_000546.5:c.329G>C', 'Mutation', 'rs11540654', (53, 73))	('TP53', 'Gene', (4, 8))	('p.R110P', 'Mutation', 'rs11540654', (75, 82))	('c.329G>C', 'Var', (65, 73))	('TP53', 'Gene', '7157', (4, 8))
518532	31496726	The following drug metabolism-related polymorphisms were detected: NAD(P)H quinone dehydrogenase 1 (NQO1) (rs1800566 GA), UDP glucuronosyltransferase family 1 member A1 (UGT1A1) (rs4148323 GG), methylenetetrahydrofolate reductase (MTHFR) (rs1801133 GG), and cytochrome P450 family 19 subfamily a member 1 (CYP19A1) (rs4646 AA).	('MTHFR', 'Gene', (231, 236))	('NQO1', 'Gene', (100, 104))	('UDP glucuronosyltransferase family 1 member A1', 'Gene', (122, 168))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (194, 229))	('CYP19A1', 'Gene', '1588', (306, 313))	('rs4148323', 'Mutation', 'rs4148323', (179, 188))	('rs4148323 GG', 'Var', (179, 191))	('rs1801133', 'Mutation', 'rs1801133', (239, 248))	('cytochrome P450 family 19 subfamily a member 1', 'Gene', (258, 304))	('cytochrome P450 family 19 subfamily a member 1', 'Gene', '1588', (258, 304))	('UDP glucuronosyltransferase family 1 member A1', 'Gene', '54658', (122, 168))	('methylenetetrahydrofolate reductase', 'Gene', (194, 229))	('rs4646', 'Mutation', 'rs4646', (316, 322))	('CYP19A1', 'Gene', (306, 313))	('MTHFR', 'Gene', '4524', (231, 236))	('detected', 'Reg', (57, 65))	('rs1800566 GA', 'Var', (107, 119))	('UGT1A1', 'Gene', (170, 176))	('NAD(P)H quinone dehydrogenase 1', 'Gene', '1728', (67, 98))	('rs1801133 GG', 'Var', (239, 251))	('rs1800566', 'Mutation', 'rs1800566', (107, 116))	('UGT1A1', 'Gene', '54658', (170, 176))	('NQO1', 'Gene', '1728', (100, 104))
518533	31496726	Two other mutations were identified in this patient, namely, NM_001184.4:c.1732G>A (p.V578I) in the rad3-related protein (ATR) gene and NM_002185.5:c.731C>T (p.T244I) in the interleukin 7 receptor (IL7R) gene.	('IL7R', 'Gene', (198, 202))	('patient', 'Species', '9606', (44, 51))	('p.T244I', 'Mutation', 'rs6897932', (158, 165))	('interleukin 7 receptor', 'Gene', '3575', (174, 196))	('ATR', 'Gene', '545', (122, 125))	('ATR', 'Gene', (122, 125))	('p.V578I', 'Mutation', 'rs748979139', (84, 91))	('NM_002185.5:c.731C>T', 'Var', (136, 156))	('IL7R', 'Gene', '3575', (198, 202))	('NM_001184.4:c.1732G>A', 'Mutation', 'rs748979139', (61, 82))	('c.1732G>A', 'Var', (73, 82))	('interleukin 7 receptor', 'Gene', (174, 196))	('NM_002185.5:c.731C>T', 'Mutation', 'rs6897932', (136, 156))
518535	31496726	Although the MTHFR rs1801133 polymorphism indicated that the patient might be sensitive to pemetrexed, the patient received a chemotherapy regimen of pemetrexed.	('MTHFR', 'Gene', '4524', (13, 18))	('pemetrexed', 'Chemical', 'MESH:D000068437', (91, 101))	('patient', 'Species', '9606', (61, 68))	('rs1801133', 'Var', (19, 28))	('pemetrexed', 'Chemical', 'MESH:D000068437', (150, 160))	('rs1801133', 'Mutation', 'rs1801133', (19, 28))	('MTHFR', 'Gene', (13, 18))	('patient', 'Species', '9606', (107, 114))
518583	31496726	This sequencing contained targeted therapy-related genes, including KIT CNV, PIK3CA and TP53 mutations.	('PIK3CA', 'Gene', (77, 83))	('mutations', 'Var', (93, 102))	('PIK3CA', 'Gene', '5290', (77, 83))	('TP53', 'Gene', '7157', (88, 92))	('KIT CNV', 'Gene', (68, 75))	('TP53', 'Gene', (88, 92))
518585	31496726	Since the MTHFR rs1801133 polymorphism indicated that the patient might be sensitive to pemetrexed, the patient received a chemotherapy regimen of pemetrexed.	('MTHFR', 'Gene', '4524', (10, 15))	('patient', 'Species', '9606', (58, 65))	('rs1801133', 'Var', (16, 25))	('rs1801133', 'Mutation', 'rs1801133', (16, 25))	('pemetrexed', 'Chemical', 'MESH:D000068437', (147, 157))	('patient', 'Species', '9606', (104, 111))	('MTHFR', 'Gene', (10, 15))	('pemetrexed', 'Chemical', 'MESH:D000068437', (88, 98))
518594	31496726	Genomic analysis showed that the amplification of MDM2, KIT, and PDFGRA in PAS and patients could benefit from therapies targeting PDGFRA or MDM2.	('MDM2', 'Gene', (50, 54))	('amplification', 'Var', (33, 46))	('KIT', 'Gene', (56, 59))	('benefit', 'Reg', (98, 105))	('PDGFRA', 'Gene', (131, 137))	('PDFGRA', 'Gene', (65, 71))	('PAS', 'Chemical', '-', (75, 78))	('patients', 'Species', '9606', (83, 91))	('PDGFRA', 'Gene', '5156', (131, 137))	('PAS', 'Disease', (75, 78))	('MDM2', 'Gene', '4193', (141, 145))	('MDM2', 'Gene', '4193', (50, 54))	('MDM2', 'Gene', (141, 145))
518595	31496726	Several investigators have reported that pulmonary artery sarcoma has MDM2 amplification and PDGFRalpha overexpression in PAS.	('pulmonary artery sarcoma', 'Disease', (41, 65))	('pulmonary artery sarcoma', 'Disease', 'MESH:D000071079', (41, 65))	('PDGFR', 'Gene', (93, 98))	('amplification', 'Var', (75, 88))	('PAS', 'Chemical', '-', (122, 125))	('MDM2', 'Gene', '4193', (70, 74))	('MDM2', 'Gene', (70, 74))	('overexpression', 'PosReg', (104, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('PDGFR', 'Gene', '5159', (93, 98))
518600	31496726	Strikingly, whole exome sequencing of the tissue of this patient identified genetic alterations to the profile of PAS: KIT CNV and mutation of TP53, PIK3CA, IL7R, ATR.	('TP53', 'Gene', (143, 147))	('PAS', 'Chemical', '-', (114, 117))	('IL7R', 'Gene', '3575', (157, 161))	('patient', 'Species', '9606', (57, 64))	('IL7R', 'Gene', (157, 161))	('alterations', 'Reg', (84, 95))	('PIK3CA', 'Gene', (149, 155))	('PAS', 'Disease', (114, 117))	('TP53', 'Gene', '7157', (143, 147))	('ATR', 'Gene', '545', (163, 166))	('ATR', 'Gene', (163, 166))	('KIT CNV', 'Gene', (119, 126))	('PIK3CA', 'Gene', '5290', (149, 155))	('mutation', 'Var', (131, 139))
518609	30294322	Genetic Alterations of TRAF Proteins in Human Cancers The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors.	('Cancers', 'Disease', 'MESH:D009369', (46, 53))	('Cancers', 'Phenotype', 'HP:0002664', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Human', 'Species', '9606', (40, 45))	('TNF', 'Gene', (90, 93))	('TNF', 'Gene', (244, 247))	('tumor necrosis', 'Disease', (58, 72))	('TNF', 'Gene', '7124', (244, 247))	('regulate', 'Reg', (161, 169))	('TNF', 'Gene', '7124', (90, 93))	('Alterations', 'Var', (8, 19))	('tumor necrosis', 'Disease', 'MESH:D009336', (58, 72))	('signal transduction', 'MPA', (174, 193))	('Cancers', 'Disease', (46, 53))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
518612	30294322	Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('loss-of-function', 'NegReg', (41, 57))	('gain-', 'PosReg', (31, 36))	('TRAF', 'Gene', (91, 95))	('human', 'Species', '9606', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('genetic alterations', 'Var', (58, 77))
518614	30294322	Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('genetic alterations', 'Var', (102, 121))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TRAF proteins', 'Gene', (125, 138))
518618	30294322	With the rapid progress made in next-generation deep sequencing technology and the tremendous efforts put forth on whole genome/exome/transcriptome sequencing and copy number variation (CNV) analyses of cancers at the post-genome era, it has become increasingly clear that genetic alterations of TRAF proteins are commonly present in various human cancers.	('TRAF', 'Gene', (296, 300))	('cancers', 'Disease', 'MESH:D009369', (348, 355))	('cancers', 'Phenotype', 'HP:0002664', (348, 355))	('cancers', 'Disease', (348, 355))	('present', 'Reg', (323, 330))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('genetic alterations', 'Var', (273, 292))	('human', 'Species', '9606', (342, 347))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
518620	30294322	Moreover, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('TRAF proteins', 'Gene', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('genetic alterations', 'Var', (99, 118))
518622	30294322	According to the TCGA and COSMIC datasets of sample size n > 100, the frequency of genetic alterations of TRAF1 is generally <4% in human cancers (Figure 1A).	('genetic alterations', 'Var', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('TRAF1', 'Gene', (106, 111))	('human', 'Species', '9606', (132, 137))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
518623	30294322	The eight human cancers with relatively higher genetic alterations of TRAF1 are pancreatic cancer (3.7%), skin cutaneous melanoma (2.9%) (TCGA, PanCancer Atlas), esophageal cancer (2.8%) (TCGA, PanCancer Atlas), stomach cancer (2.7%), sarcoma (2.4%), ovarian cancer (2.3%) (TCGA, Provisional), lung cancer (2.3%), and prostate cancer (2%) (TCGA, Provisional).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (106, 129))	('lung cancer', 'Disease', (294, 305))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('stomach cancer', 'Disease', (212, 226))	('skin cutaneous melanoma', 'Disease', (106, 129))	('pancreatic cancer', 'Disease', (80, 97))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('ovarian cancer', 'Disease', (251, 265))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (251, 265))	('esophageal cancer', 'Disease', (162, 179))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('sarcoma', 'Disease', (235, 242))	('lung cancer', 'Disease', 'MESH:D008175', (294, 305))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('stomach cancer', 'Disease', 'MESH:D013274', (212, 226))	('prostate cancer', 'Disease', 'MESH:D011471', (318, 333))	('prostate cancer', 'Phenotype', 'HP:0012125', (318, 333))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('stomach cancer', 'Phenotype', 'HP:0012126', (212, 226))	('prostate cancer', 'Disease', (318, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (294, 305))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('genetic alterations', 'Var', (47, 66))	('TRAF1', 'Gene', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('ovarian cancer', 'Disease', 'MESH:D010051', (251, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
518624	30294322	Deep deletion (copy loss) is less common but also detected in several types of human cancers (Figure 1).	('human', 'Species', '9606', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('detected', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Deep deletion', 'Var', (0, 13))
518626	30294322	To date, there are 139 different mutations of the TRAF1 gene detected in human cancers, comprising 80% (111/139) mutations that alter the protein sequence of TRAF1 and 20% (28/139) coding silent mutations (Table 1).	('cancers', 'Disease', (79, 86))	('alter', 'Reg', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TRAF1', 'Gene', (50, 55))	('human', 'Species', '9606', (73, 78))	('mutations', 'Var', (113, 122))	('silent', 'NegReg', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('TRAF1', 'Gene', (158, 163))	('protein sequence', 'MPA', (138, 154))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
518627	30294322	Only 29% (32/111) of the coding-altering mutations of TRAF1 are recurrent and have been detected in at least two patients with various cancers.	('mutations', 'Var', (41, 50))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('patients', 'Species', '9606', (113, 121))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('TRAF1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('coding-altering', 'Reg', (25, 40))
518628	30294322	Interestingly, missense mutations of two specific amino acids are detected in more than three patients: R70C or H in the linker between the Zinc finger and the coiled-coil domain, and M182I of the coiled-coil (also known as TRAF-N) domain of the TRAF1 protein (Figure 3).	('patients', 'Species', '9606', (94, 102))	('TRAF1', 'Gene', (246, 251))	('coiled-coil', 'MPA', (197, 208))	('M182I', 'Mutation', 'p.M182I', (184, 189))	('missense', 'Var', (15, 23))	('R70C', 'Var', (104, 108))	('R70C', 'Mutation', 'p.R70C', (104, 108))	('M182I', 'Var', (184, 189))
518629	30294322	The R70 mutations are detected in 4 patients with stomach, colon, and colorectal cancers (TCGA).	('patients', 'Species', '9606', (36, 44))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('colon', 'Disease', (59, 64))	('R70 mutations', 'Var', (4, 17))	('colorectal cancers', 'Disease', 'MESH:D015179', (70, 88))	('stomach', 'Disease', (50, 57))	('colorectal cancers', 'Disease', (70, 88))	('detected', 'Reg', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
518630	30294322	M182I is documented in 4 patients with melanoma and chronic lymphocytic leukemia (CLL).	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (52, 80))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (52, 80))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('M182I', 'Var', (0, 5))	('patients', 'Species', '9606', (25, 33))	('leukemia', 'Phenotype', 'HP:0001909', (72, 80))	('CLL', 'Phenotype', 'HP:0005550', (82, 85))	('chronic lymphocytic leukemia', 'Disease', (52, 80))	('M182I', 'Mutation', 'p.M182I', (0, 5))
518631	30294322	The functional significance of R70C/H and M182I mutations of TRAF1 remains to be determined.	('R70C', 'Mutation', 'p.R70C', (31, 35))	('TRAF1', 'Gene', (61, 66))	('R70C/H', 'Var', (31, 37))	('M182I', 'Var', (42, 47))	('M182I', 'Mutation', 'p.M182I', (42, 47))
518636	30294322	Gene amplification is the most common TRAF1 genetic alteration in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('Gene amplification', 'Var', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TRAF1', 'Gene', (38, 43))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
518639	30294322	In this case, TRAF1 upregulation might be the result of epigenetic alterations and/or aberrant activation of NF-kappaB1/2, as TRAF1 is a direct target gene of NF-kappaB.	('NF-kappaB1', 'Gene', '18033', (109, 119))	('activation', 'PosReg', (95, 105))	('NF-kappaB1', 'Gene', (109, 119))	('upregulation', 'PosReg', (20, 32))	('TRAF1', 'Gene', (14, 19))	('epigenetic alterations', 'Var', (56, 78))
518649	30294322	In line with the evidence of TRAF1 overexpression in HLs and NHLs, TRAF1 deficiency inhibits the spontaneous development of small B cell lymphoma in a transgenic mouse model that expresses the human lymphoma-associated NF-kappaB2 mutant p80HT specifically in lymphocytes (p80HT tg mice) (Table 2).	('B cell lymphoma', 'Phenotype', 'HP:0012191', (130, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('p80HT', 'Var', (237, 242))	('spontaneous development', 'CPA', (97, 120))	('small B cell lymphoma', 'Disease', 'MESH:D016393', (124, 145))	('mutant p80HT', 'Var', (230, 242))	('NHLs, TRAF1 deficiency inhibits', 'Disease', 'MESH:C565433', (61, 92))	('HL', 'CellLine', 'CVCL:2492', (62, 64))	('human', 'Species', '9606', (193, 198))	('NHLs', 'Phenotype', 'HP:0012539', (61, 65))	('HL', 'CellLine', 'CVCL:2492', (53, 55))	('cell lymphoma', 'Phenotype', 'HP:0012191', (132, 145))	('HLs', 'Phenotype', 'HP:0012189', (62, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (199, 207))	('lymphoma', 'Disease', (137, 145))	('small B cell lymphoma', 'Disease', (124, 145))	('mice', 'Species', '10090', (281, 285))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('mouse', 'Species', '10090', (162, 167))	('NF-kappaB2', 'Gene', '18034', (219, 229))	('transgenic', 'Species', '10090', (151, 161))	('NF-kappaB2', 'Gene', (219, 229))	('lymphoma', 'Disease', (199, 207))	('HLs', 'Phenotype', 'HP:0012189', (53, 56))	('lymphoma', 'Disease', 'MESH:D008223', (199, 207))	('small B cell', 'Phenotype', 'HP:0010976', (124, 136))
518654	30294322	The frequency of genetic alterations of TRAF2 is generally <6% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 180.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF2', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
518655	30294322	The eight human cancers with relatively higher genetic alterations of TRAF2 are prostate cancer (5.5%), ovarian cancer (5.1%) (TCGA, Provisional), uterine cancer (4.4%) (TCGA, PanCancer Atlas), esophageal cancer (3.9%) (TCGA, PanCancer Atlas), skin cutaneous melanoma (3.4%) (TCGA, PanCancer Atlas), head and neck squamous cell carcinoma (HNSCC, 3.2%) (TCGA, Provisional), bladder cancer (3.2%) (TCGA, PanCancer Atlas), and stomach cancer (3.1%).	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (89, 95))	('stomach cancer', 'Disease', (424, 438))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('Cancer', 'Phenotype', 'HP:0002664', (405, 411))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (309, 337))	('neck squamous cell carcinoma', 'Disease', (309, 337))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('cancer', 'Disease', (16, 22))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('esophageal cancer', 'Disease', (194, 211))	('cancer', 'Disease', 'MESH:D009369', (432, 438))	('bladder cancer', 'Disease', 'MESH:D001749', (373, 387))	('bladder cancer', 'Disease', (373, 387))	('cancer', 'Disease', (381, 387))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TRAF2', 'Gene', (70, 75))	('prostate cancer', 'Disease', (80, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (373, 387))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (244, 267))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (314, 337))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (205, 211))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('stomach cancer', 'Disease', 'MESH:D013274', (424, 438))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('stomach cancer', 'Phenotype', 'HP:0012126', (424, 438))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (249, 267))	('skin cutaneous melanoma', 'Disease', (244, 267))	('genetic alterations', 'Var', (47, 66))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (155, 161))	('ovarian cancer', 'Disease', (104, 118))	('alterations', 'Var', (55, 66))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('cancer', 'Disease', (432, 438))	('uterine cancer', 'Phenotype', 'HP:0010784', (147, 161))
518656	30294322	Notably, although not cataloged in TCGA, mutations of TRAF2 are recognized as one of the most frequent somatic mutations in mantle cell lymphoma (MCL, 6.1%, 10/165) and diffuse large B-cell lymphoma (DLBCL, 6%, 6/101) (Figure 1B).	('mutations', 'Var', (41, 50))	('MCL', 'Disease', (146, 149))	('cell lymphoma', 'Phenotype', 'HP:0012191', (185, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('cell lymphoma', 'Phenotype', 'HP:0012191', (131, 144))	('cell lymphoma', 'Disease', 'MESH:D016399', (185, 198))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (124, 144))	('TRAF2', 'Gene', (54, 59))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (183, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('mantle cell lymphoma', 'Disease', (124, 144))	('MCL', 'Disease', 'OMIM:150800', (146, 149))	('cell lymphoma', 'Disease', (185, 198))	('cell lymphoma', 'Disease', 'MESH:D016399', (131, 144))
518658	30294322	Truncation and fusion of TRAF2 are relatively rare but also detected in human cancers (Figure 1).	('fusion', 'Var', (15, 21))	('TRAF2', 'Gene', (25, 30))	('Truncation', 'Var', (0, 10))	('human', 'Species', '9606', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('detected', 'Reg', (60, 68))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
518659	30294322	There are 237 different mutations of TRAF2 detected in human cancers, comprising 86% (205/237) mutations that change the protein sequence of TRAF2 and 14% (32/237) coding silent mutations (Table 1).	('TRAF2', 'Gene', (37, 42))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('protein sequence', 'MPA', (121, 137))	('TRAF2', 'Gene', (141, 146))
518660	30294322	Notably, 45% (92/205) of the coding-altering mutations of TRAF2 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (45, 54))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (112, 120))	('coding-altering', 'Reg', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TRAF2', 'Gene', (58, 63))
518661	30294322	Interestingly, four mutation hotspots of TRAF2 are detected in more than 5 cancer patients, specifically P9, G10, R372, and Q457 (Figure 3).	('TRAF2', 'Gene', (41, 46))	('detected', 'Reg', (51, 59))	('Q457', 'Var', (124, 128))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('G10', 'Var', (109, 112))	('patients', 'Species', '9606', (82, 90))	('P9', 'Gene', '11340', (105, 107))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('R372', 'Var', (114, 118))
518662	30294322	In particular, the frameshift deletion occurred at P9 (P9fs*77) is found in 16 patients with colon cancer, colorectal cancer (CRC), uterine cancer, stomach cancer, and sarcoma, and an additional missense mutation at P9 (P9S) is also detected in a CRC patient (TCGA).	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('CRC', 'Phenotype', 'HP:0003003', (126, 129))	('found', 'Reg', (67, 72))	('frameshift deletion', 'Var', (19, 38))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('P9', 'Gene', '11340', (51, 53))	('P9 (P9S', 'Gene', '11340', (216, 223))	('stomach cancer', 'Disease', (148, 162))	('colon cancer', 'Disease', (93, 105))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('P9', 'Gene', '11340', (216, 218))	('patient', 'Species', '9606', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CRC', 'Disease', (247, 250))	('CRC', 'Phenotype', 'HP:0003003', (247, 250))	('cancer', 'Disease', (118, 124))	('stomach cancer', 'Disease', 'MESH:D013274', (148, 162))	('patient', 'Species', '9606', (251, 258))	('stomach cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('P9', 'Gene', '11340', (55, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('sarcoma', 'Disease', (168, 175))	('cancer', 'Disease', (156, 162))	('uterine cancer', 'Phenotype', 'HP:0010784', (132, 146))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', (107, 124))	('patients', 'Species', '9606', (79, 87))	('P9', 'Gene', '11340', (220, 222))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('colon cancer', 'Disease', 'MESH:D015179', (93, 105))
518663	30294322	The amino acid right next to P9, G10, also exhibits similar frameshift deletion (G10fs*76) or insertion (G10fs*70) or missense mutation (G10D) in five patients with colon cancer, CRC, gallbladder cancer, and glioblastoma (TCGA).	('G10fs*76', 'Var', (81, 89))	('G10fs*70', 'Mutation', 'p.G10fsX70', (105, 113))	('G10D', 'Var', (137, 141))	('G10D', 'Mutation', 'p.G10D', (137, 141))	('CRC', 'Disease', (179, 182))	('colon cancer', 'Disease', (165, 177))	('frameshift', 'Reg', (60, 70))	('gallbladder cancer', 'Disease', (184, 202))	('CRC', 'Phenotype', 'HP:0003003', (179, 182))	('G10fs*70', 'Var', (105, 113))	('G10fs*76', 'Mutation', 'p.G10fsX76', (81, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (208, 220))	('colon cancer', 'Phenotype', 'HP:0003003', (165, 177))	('P9', 'Gene', '11340', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('glioblastoma', 'Disease', (208, 220))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('gallbladder cancer', 'Disease', 'MESH:D005706', (184, 202))	('glioblastoma', 'Phenotype', 'HP:0012174', (208, 220))	('patients', 'Species', '9606', (151, 159))	('colon cancer', 'Disease', 'MESH:D015179', (165, 177))
518665	30294322	Another amino acid of the TRAF-C domain, Q457, shows complex mutations, including a truncation (Q457*), a frameshift insertion (Q457fs*277), and missense mutations (Q457K or L) in six patients of HNSCC, oral squamous cell carcinoma (OSCC), stomach cancer, melanoma, and breast cancer (TCGA; COSMIC).	('Q457*', 'SUBSTITUTION', 'None', (96, 101))	('Q457fs*277', 'Var', (128, 138))	('stomach cancer', 'Phenotype', 'HP:0012126', (240, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (270, 283))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('Q457K', 'Var', (165, 170))	('melanoma', 'Disease', (256, 264))	('Q457K', 'Mutation', 'p.Q457K', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (270, 283))	('breast cancer', 'Disease', (270, 283))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('Q457*', 'Var', (96, 101))	('missense', 'Var', (145, 153))	('truncation', 'MPA', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Q457fs*277', 'Mutation', 'p.Q457fsX277', (128, 138))	('stomach cancer', 'Disease', (240, 254))	('melanoma', 'Disease', 'MESH:D008545', (256, 264))	('HNSCC', 'Disease', (196, 201))	('patients', 'Species', '9606', (184, 192))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('oral squamous cell carcinoma', 'Disease', (203, 231))	('stomach cancer', 'Disease', 'MESH:D013274', (240, 254))
518666	30294322	Frameshift mutations occurring at P9 and G10 are functionally equivalent to deletion of TRAF2.	('deletion', 'Var', (76, 84))	('P9', 'Gene', '11340', (34, 36))	('TRAF2', 'Gene', (88, 93))	('G10', 'Var', (41, 44))	('Frameshift mutations', 'Var', (0, 20))
518669	30294322	Functional contribution of these TRAF2 fusions to cancer pathogenesis is currently unclear.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('TRAF2', 'Gene', (33, 38))	('fusions', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
518670	30294322	Inactivating mutations of TRAF2 are frequently detected in human MCL and DLBCL, resulting in elevated activation of NF-kappaB1 and NF-kappaB2 in malignant B cells.	('elevated activation', 'PosReg', (93, 112))	('human', 'Species', '9606', (59, 64))	('NF-kappaB1', 'Gene', '18033', (116, 126))	('NF-kappaB1', 'Gene', (116, 126))	('Inactivating mutations', 'Var', (0, 22))	('MCL', 'Disease', 'OMIM:150800', (65, 68))	('TRAF2', 'Gene', (26, 31))	('NF-kappaB2', 'Gene', (131, 141))	('MCL', 'Disease', (65, 68))	('NF-kappaB2', 'Gene', '18034', (131, 141))
518673	30294322	Similarly in TRAF2DN-tg mice that express a dominant negative form of TRAF2 specifically in lymphocytes (Igh-TRAF2DN), inhibition of TRAF2 also leads to splenomegaly and lymphadenopathy due to constitutive NF-kappaB2 activation and increased numbers of B cells.	('splenomegaly and lymphadenopathy', 'Disease', 'MESH:C536897', (153, 185))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (170, 185))	('leads to', 'Reg', (144, 152))	('mice', 'Species', '10090', (24, 28))	('NF-kappaB2', 'Gene', (206, 216))	('inhibition', 'Var', (119, 129))	('TRAF2', 'Gene', (133, 138))	('Igh', 'Gene', (105, 108))	('increased', 'PosReg', (232, 241))	('NF-kappaB2', 'Gene', '18034', (206, 216))	('Igh', 'Gene', '111507', (105, 108))	('splenomegaly', 'Phenotype', 'HP:0001744', (153, 165))	('activation', 'PosReg', (217, 227))	('negative', 'NegReg', (53, 61))	('TRAF2', 'Gene', (70, 75))
518674	30294322	Remarkably, TRAF2DN/Bcl-2 double-transgenic mice spontaneously develop small B cell lymphoma progressing to leukemia with many similarities to human CLL (Table 2).	('human', 'Species', '9606', (143, 148))	('small B cell', 'Phenotype', 'HP:0010976', (71, 83))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (77, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('cell lymphoma', 'Phenotype', 'HP:0012191', (79, 92))	('CLL', 'Phenotype', 'HP:0005550', (149, 152))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('develop', 'PosReg', (63, 70))	('leukemia', 'Disease', 'MESH:D007938', (108, 116))	('transgenic mice', 'Species', '10090', (33, 48))	('leukemia', 'Disease', (108, 116))	('small B cell lymphoma', 'Disease', (71, 92))	('TRAF2DN/Bcl-2', 'Var', (12, 25))	('small B cell lymphoma', 'Disease', 'MESH:D016393', (71, 92))
518676	30294322	Genetic alterations of TRAF2 are detected in 1-2% of human liver cancers, including deletion, mutation and amplification (TCGA, PanCancer Atlas).	('liver cancer', 'Phenotype', 'HP:0002896', (59, 71))	('liver cancers', 'Phenotype', 'HP:0002896', (59, 72))	('deletion', 'Var', (84, 92))	('TRAF2', 'Gene', (23, 28))	('liver cancers', 'Disease', (59, 72))	('liver cancers', 'Disease', 'MESH:D006528', (59, 72))	('amplification', 'MPA', (107, 120))	('detected', 'Reg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('human', 'Species', '9606', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutation', 'Var', (94, 102))
518678	30294322	In line with human evidence, deletion of both TRAF2 and RIP1 in liver parenchymal cells (LPC) leads to spontaneous development of hepatocellular carcinoma, which results from extensive hepatocyte apoptosis due to hyperactivation of caspase-8 but impaired NF-kappaB activation induced by TNFalpha (Table 2).	('RIP1', 'Gene', (56, 60))	('deletion', 'Var', (29, 37))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (130, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('TRAF2', 'Gene', (46, 51))	('human', 'Species', '9606', (13, 18))	('RIP1', 'Gene', '8737', (56, 60))	('impaired', 'NegReg', (246, 254))	('caspase-8', 'Gene', '841', (232, 241))	('hyperactivation', 'PosReg', (213, 228))	('caspase-8', 'Gene', (232, 241))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('activation', 'PosReg', (265, 275))	('hepatocyte apoptosis', 'CPA', (185, 205))	('NF-kappaB', 'Protein', (255, 264))	('hepatocellular carcinoma', 'Disease', (130, 154))
518680	30294322	Induced TRAF2 deletion in adult mice results in rapid lethality, in conjunction with increased hepatic necroptosome assembly (Table 2).	('TRAF2', 'Gene', (8, 13))	('rapid lethality', 'MPA', (48, 63))	('mice', 'Species', '10090', (32, 36))	('increased', 'PosReg', (85, 94))	('deletion', 'Var', (14, 22))	('hepatic necroptosome assembly', 'MPA', (95, 124))
518682	30294322	Genetic alterations of TRAF2 are detected in 3-4% of human HNSCC and melanoma (Figure 1A).	('Genetic alterations', 'Var', (0, 19))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('TRAF2', 'Gene', (23, 28))	('human HNSCC', 'Disease', (53, 64))	('detected', 'Reg', (33, 41))	('human', 'Species', '9606', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
518686	30294322	Further in support of a role for TRAF2 in skin tumorigenesis, mutations of the TRAF2-deubiquitinating enzyme CYLD are identified in patients with familial cylindromatosis, a condition that results in benign tumors of skin appendages, and CYLD-/- mice are highly susceptible to chemically induced skin tumors.	('TRAF2-deubiquitinating', 'Gene', (79, 101))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', (207, 213))	('patients', 'Species', '9606', (132, 140))	('tumors', 'Disease', (301, 307))	('familial cylindromatosis', 'Disease', (146, 170))	('skin tumor', 'Phenotype', 'HP:0008069', (42, 52))	('skin tumor', 'Phenotype', 'HP:0008069', (296, 306))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', 'MESH:D009369', (301, 307))	('CYLD', 'Gene', (109, 113))	('mutations', 'Var', (62, 71))	('CYLD', 'Gene', (238, 242))	('skin tumors', 'Disease', (296, 307))	('tumors of skin', 'Phenotype', 'HP:0008069', (207, 221))	('tumors of skin appendages', 'Phenotype', 'HP:0012842', (207, 232))	('familial cylindromatosis', 'Disease', 'MESH:C536611', (146, 170))	('tumor', 'Disease', (301, 306))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (47, 52))	('CYLD', 'Gene', '1540', (109, 113))	('CYLD', 'Gene', '1540', (238, 242))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('skin tumors', 'Disease', 'MESH:D012878', (296, 307))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('skin tumors', 'Phenotype', 'HP:0008069', (296, 307))	('mice', 'Species', '10090', (246, 250))
518687	30294322	Similarly, genetic alterations of TRAF2 are also identified in 2.7% (12/439) of human colon cancers (TCGA, PanCancer Atlas).	('colon cancers', 'Disease', (86, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('colon cancers', 'Phenotype', 'HP:0003003', (86, 99))	('identified', 'Reg', (49, 59))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('colon cancers', 'Disease', 'MESH:D015179', (86, 99))	('human', 'Species', '9606', (80, 85))	('TRAF2', 'Gene', (34, 39))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('genetic alterations', 'Var', (11, 30))
518690	30294322	Interestingly, myeloid cell-specific ablation of TRAF2 markedly exacerbates DSS-induced colitis in mice due to enhanced TLR-induced proinflammatory cytokine expression in macrophages.	('mice', 'Species', '10090', (99, 103))	('colitis', 'Phenotype', 'HP:0002583', (88, 95))	('ablation', 'Var', (37, 45))	('enhanced', 'PosReg', (111, 119))	('colitis', 'Disease', 'MESH:D003092', (88, 95))	('exacerbates', 'PosReg', (64, 75))	('colitis', 'Disease', (88, 95))	('TLR-induced proinflammatory cytokine expression', 'MPA', (120, 167))	('TRAF2', 'Gene', (49, 54))
518693	30294322	It is also noteworthy that genetic alterations of TRAF2 are detected in 2.6% (7/265) of human sarcomas (TCGA) and TRAF2-/- mice display decreased viability of skeletal muscle tissue because of defective TNFalpha-induced NF-kappaB activation in myotubes (Table 2).	('sarcomas', 'Disease', (94, 102))	('alterations', 'Var', (35, 46))	('defective', 'NegReg', (193, 202))	('TRAF2-/', 'Gene', '7186', (114, 121))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('viability', 'CPA', (146, 155))	('TRAF2', 'Gene', (50, 55))	('TNFalpha-induced NF-kappaB', 'Protein', (203, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('activation', 'PosReg', (230, 240))	('human', 'Species', '9606', (88, 93))	('genetic alterations', 'Var', (27, 46))	('TRAF2-/', 'Gene', (114, 121))	('decreased', 'NegReg', (136, 145))	('mice', 'Species', '10090', (123, 127))
518694	30294322	Additionally, specific deletion of TRAF2 in T cells results in decreased numbers of CD8 naive and memory T cells as well as NKT cells, due to impaired IL-15-induced signaling in these cells (Table 2).	('memory T', 'Disease', 'MESH:D008569', (98, 106))	('CD8', 'Gene', '925', (84, 87))	('deletion', 'Var', (23, 31))	('decreased', 'NegReg', (63, 72))	('memory T', 'Disease', (98, 106))	('IL-15-induced signaling', 'MPA', (151, 174))	('CD8', 'Gene', (84, 87))	('impaired', 'NegReg', (142, 150))	('TRAF2', 'Gene', (35, 40))
518696	30294322	Potential causal roles of TRAF2 dysregulation in muscle or T cell tumorigenesis remain to be elucidated.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('dysregulation', 'Var', (32, 45))	('tumor', 'Disease', (66, 71))	('muscle', 'CPA', (49, 55))	('TRAF2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
518703	30294322	Importantly, suppression of TRAF2 in cancer cells harboring a TRAF2 copy number gain inhibits proliferation, NF-kappaB activation, anchorage-independent growth, and tumorigenesis.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('inhibits', 'NegReg', (85, 93))	('copy number', 'Var', (68, 79))	('cancer', 'Disease', (37, 43))	('gain', 'PosReg', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('activation', 'PosReg', (119, 129))	('proliferation', 'CPA', (94, 107))	('TRAF2', 'Gene', (28, 33))	('NF-kappaB', 'Protein', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('anchorage-independent growth', 'CPA', (131, 159))	('TRAF2', 'Gene', (62, 67))	('suppression', 'NegReg', (13, 24))	('tumor', 'Disease', (165, 170))
518705	30294322	Thus, TRAF2 is required for the maintenance of the malignant state in certain cancer cells containing TRAF2 amplification or overexpression, and TRAF2 protein levels also regulate the sensitivity of cancer cells to chemotherapy and radiotherapy.	('amplification', 'Var', (108, 121))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('regulate', 'Reg', (171, 179))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('TRAF2', 'Gene', (102, 107))	('sensitivity', 'MPA', (184, 195))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
518710	30294322	The frequency of genetic alterations of TRAF3 is generally <6% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 250.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF3', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
518711	30294322	The eight human cancers with relatively higher genetic alterations of TRAF3 are HNSCC (5.4%), lung cancer (5.3%) (TCGA, PanCancer Atlas), cervical cancer (4.7%) (TCGA, PanCancer Atlas), uterine cancer (4.5%) (TCGA, PanCancer Atlas), stomach cancer (4.1%) (TCGA, PanCancer Atlas), bladder cancer (3.6%), ovarian cancer (3.4%) (TCGA, PanCancer Atlas), and skin cutaneous melanoma (3.4%) (TCGA, PanCancer Atlas).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', (311, 317))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('bladder cancer', 'Disease', 'MESH:D001749', (280, 294))	('bladder cancer', 'Disease', (280, 294))	('cancer', 'Disease', (288, 294))	('lung cancer', 'Disease', (94, 105))	('Cancer', 'Phenotype', 'HP:0002664', (265, 271))	('bladder cancer', 'Phenotype', 'HP:0009725', (280, 294))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('stomach cancer', 'Disease', (233, 247))	('HNSCC', 'Disease', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (303, 317))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (354, 377))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('genetic alterations', 'Var', (47, 66))	('skin cutaneous melanoma', 'Disease', (354, 377))	('stomach cancer', 'Disease', 'MESH:D013274', (233, 247))	('stomach cancer', 'Phenotype', 'HP:0012126', (233, 247))	('TRAF3', 'Gene', (70, 75))	('ovarian cancer', 'Disease', (303, 317))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('melanoma', 'Phenotype', 'HP:0002861', (369, 377))	('uterine cancer', 'Phenotype', 'HP:0010784', (186, 200))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (359, 377))	('cancer', 'Disease', (99, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (303, 317))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
518712	30294322	Interestingly however, a subgroup among the 279 cases of HNSCC cataloged in TCGA, the human papilloma virus-positive (HPV+) HNSCC tumors, has much higher frequency (22%, 8/36) of deep deletions and truncations of TRAF3 than the HPV- HNSCC tumors (Figure 1B).	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('human papilloma virus', 'Species', '10566', (86, 107))	('papilloma', 'Phenotype', 'HP:0012740', (92, 101))	('HPV', 'Species', '10566', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('HNSCC tumors', 'Disease', 'MESH:C535575', (233, 245))	('HNSCC tumors', 'Disease', (233, 245))	('HPV', 'Species', '10566', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('HNSCC tumors', 'Disease', 'MESH:C535575', (124, 136))	('deep deletions', 'Var', (179, 193))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('HNSCC tumors', 'Disease', (124, 136))	('truncations', 'MPA', (198, 209))
518713	30294322	Notably, although not cataloged in TCGA, deletions and mutations of TRAF3 are recognized as one of the most frequent genetic alterations in a variety of B cell malignancies, including gastric marginal zone lymphoma (MZL, 21%), multiple myeloma (MM, 17%), HL (15%), DLBCL (14.3%), splenic MZL (10%), and Waldenstrom's macroglobulinemia (WM, 5.3%) (Figure 1B).	('B cell malignancies', 'Disease', (153, 172))	('gastric marginal zone lymphoma', 'Disease', (184, 214))	("Waldenstrom's macroglobulinemia", 'Disease', 'MESH:D008258', (303, 334))	('TRAF3', 'Gene', (68, 73))	("Waldenstrom's macroglobulinemia", 'Disease', (303, 334))	('gastric marginal zone lymphoma', 'Phenotype', 'HP:0045038', (184, 214))	('multiple myeloma', 'Phenotype', 'HP:0006775', (227, 243))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('splenic MZL', 'Disease', (280, 291))	('mutations', 'Var', (55, 64))	('multiple myeloma', 'Disease', 'MESH:D009101', (227, 243))	("Waldenstrom's macroglobulinemia", 'Phenotype', 'HP:0005508', (303, 334))	('gastric marginal zone lymphoma', 'Disease', 'MESH:D018442', (184, 214))	('deletions', 'Var', (41, 50))	('B cell malignancies', 'Disease', 'MESH:D015448', (153, 172))	('multiple myeloma', 'Disease', (227, 243))	('HL', 'CellLine', 'CVCL:2492', (255, 257))	('DLBCL', 'Disease', (265, 270))	('MM', 'Disease', 'MESH:D009101', (245, 247))
518715	30294322	Truncation and fusion of TRAF3 are less common but also detected in several different types of human cancers (Figure 1).	('fusion', 'Var', (15, 21))	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('detected', 'Reg', (56, 64))	('cancers', 'Disease', (101, 108))	('Truncation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('TRAF3', 'Gene', (25, 30))
518716	30294322	There are 280 different mutations of TRAF3 detected in human cancers, comprising 90% (253/280) mutations that change the protein sequence of TRAF3 and 10% (27/280) coding silent mutations (Table 1).	('TRAF3', 'Gene', (37, 42))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('protein sequence', 'MPA', (121, 137))	('TRAF3', 'Gene', (141, 146))
518717	30294322	Approximately 43% (108/253) of the coding-altering mutations of TRAF3 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (51, 60))	('coding-altering', 'Reg', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TRAF3', 'Gene', (64, 69))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (118, 126))
518718	30294322	Five mutation hotspots of TRAF3 are identified in more than 5 cancer patients, specifically N16, N285, K286, R310, and R376 (Figure 3).	('K286', 'Chemical', '-', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('K286', 'Var', (103, 107))	('TRAF3', 'Gene', (26, 31))	('N285', 'Var', (97, 101))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('patients', 'Species', '9606', (69, 77))	('R310', 'Var', (109, 113))	('R376', 'Var', (119, 123))	('N16', 'Var', (92, 95))
518719	30294322	TRAF3 mutations at N16 have the highest patient count, including the missense mutation (N16T) identified in 10 patients with HNSCC (COSMIC) and the frameshift deletion (N16fs*3) detected in a patient with splenic MZL.	('mutations at N16', 'Var', (6, 22))	('patient', 'Species', '9606', (40, 47))	('patient', 'Species', '9606', (192, 199))	('frameshift deletion', 'Var', (148, 167))	('TRAF3', 'Gene', (0, 5))	('N16T', 'SUBSTITUTION', 'None', (88, 92))	('N16fs*3', 'Var', (169, 176))	('patient', 'Species', '9606', (111, 118))	('N16T', 'Var', (88, 92))	('patients', 'Species', '9606', (111, 119))
518720	30294322	Mutations at the two consecutive amino acids N285 and K286 of the coiled-coil domain of TRAF3 exhibit the most complex pattern.	('TRAF3', 'Gene', (88, 93))	('coiled-coil domain', 'MPA', (66, 84))	('K286', 'Var', (54, 58))	('K286', 'Chemical', '-', (54, 58))
518721	30294322	N285 contains frameshift deletion (N285fs*38), frameshift insertion (N285fs*13) and missense mutation (N285S) identified in 8 patients with HNSCC, MZL, NPC, CRC, stomach cancer and uterine cancer (TCGA; COSMIC).	('N285fs*38', 'Var', (35, 44))	('cancer', 'Disease', (170, 176))	('stomach cancer', 'Disease', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('patients', 'Species', '9606', (126, 134))	('N285S', 'Mutation', 'p.N285S', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('N285fs*38', 'Mutation', 'p.N285fsX38', (35, 44))	('N285fs', 'Mutation', 'p.N285fsX', (69, 75))	('frameshift deletion (N285fs*38', 'Var', (14, 44))	('uterine cancer', 'Phenotype', 'HP:0010784', (181, 195))	('MZL', 'Disease', (147, 150))	('stomach cancer', 'Disease', 'MESH:D013274', (162, 176))	('N285fs', 'Mutation', 'p.N285fsX', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('stomach cancer', 'Phenotype', 'HP:0012126', (162, 176))	('N285S', 'Var', (103, 108))	('NPC', 'Disease', (152, 155))	('HNSCC', 'Disease', (140, 145))	('cancer', 'Disease', (189, 195))	('N285fs*13', 'Var', (69, 78))	('frameshift insertion (N285fs*13', 'Var', (47, 78))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('CRC', 'Disease', (157, 160))	('CRC', 'Phenotype', 'HP:0003003', (157, 160))
518722	30294322	Similarly, K286 exhibits frameshift deletion (K286fs*7 or fs*11) and truncation (K286*) detected in six patients with B cell malignancies, including MM, CLL and WM.	('K286', 'Chemical', '-', (81, 85))	('K286*', 'Var', (81, 86))	('B cell malignancies', 'Disease', (118, 137))	('K286', 'Var', (11, 15))	('B cell malignancies', 'Disease', 'MESH:D015448', (118, 137))	('K286', 'Chemical', '-', (11, 15))	('detected', 'Reg', (88, 96))	('K286', 'Chemical', '-', (46, 50))	('K286fs', 'Mutation', 'p.K286fsX', (46, 52))	('CLL', 'Phenotype', 'HP:0005550', (153, 156))	('K286fs*7', 'Var', (46, 54))	('MM', 'Disease', 'MESH:D009101', (149, 151))	('fs*11', 'Gene', (58, 63))	('truncation', 'MPA', (69, 79))	('CLL', 'Disease', (153, 156))	('K286*', 'SUBSTITUTION', 'None', (81, 86))	('patients', 'Species', '9606', (104, 112))
518723	30294322	A third amino acid of the coiled-coil domain, R310, is consistently targeted by truncation (R310*) as detected in 8 patients with DLBCL, MM, HNSCC, cervical cancer and uterine cancer (TCGA).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MM', 'Disease', 'MESH:D009101', (137, 139))	('R310*', 'SUBSTITUTION', 'None', (92, 97))	('HNSCC', 'Disease', (141, 146))	('DLBCL', 'Disease', (130, 135))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('R310*', 'Var', (92, 97))	('cancer', 'Disease', (157, 163))	('R310', 'Var', (46, 50))	('detected', 'Reg', (102, 110))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('uterine cancer', 'Phenotype', 'HP:0010784', (168, 182))
518725	30294322	Many of these truncations, frameshifts and missense mutations have been shown to result in inactivation of TRAF3 by disrupting its interaction with NIK, thereby inducing constitutive NF-kappaB2 activation.	('missense mutations', 'Var', (43, 61))	('inducing', 'Reg', (161, 169))	('NIK', 'Gene', (148, 151))	('NF-kappaB2', 'Gene', '18034', (183, 193))	('activation', 'PosReg', (194, 204))	('frameshifts', 'Var', (27, 38))	('disrupting', 'NegReg', (116, 126))	('inactivation', 'MPA', (91, 103))	('NIK', 'Gene', '9020', (148, 151))	('interaction', 'Interaction', (131, 142))	('NF-kappaB2', 'Gene', (183, 193))	('TRAF3', 'Gene', (107, 112))
518726	30294322	Thus, most of the recurrent genetic alterations of TRAF3 identified in human cancers cause complete loss or inactivation of the TRAF3 protein.	('TRAF3', 'Gene', (51, 56))	('genetic alterations', 'Var', (28, 47))	('TRAF3', 'Gene', (128, 133))	('complete loss', 'Disease', 'MESH:D003638', (91, 104))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('inactivation', 'NegReg', (108, 120))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('protein', 'Protein', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('complete loss', 'Disease', (91, 104))	('human', 'Species', '9606', (71, 76))
518729	30294322	Similar to TRAF2 and also consistent with the frequent deletions and inactivating mutations of TRAF3 identified in human B cell malignancies (Figure 1B), a tumor suppressive role for TRAF3 in B lymphocytes has been demonstrated by in vivo evidence obtained from mouse models.	('B cell malignancies', 'Disease', (121, 140))	('B cell malignancies', 'Disease', 'MESH:D015448', (121, 140))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mouse', 'Species', '10090', (262, 267))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('human', 'Species', '9606', (115, 120))	('TRAF3', 'Gene', (95, 100))	('tumor', 'Disease', (156, 161))	('deletions', 'Var', (55, 64))
518735	30294322	Intriguingly, lymphocyte-specific TRAF3 transgenic mice also develop plasmacytosis, autoimmunity, inflammation, and cancers, which are likely caused by hyper-responsiveness of B cells to antigens and TLR agonists.	('autoimmunity', 'Phenotype', 'HP:0002960', (84, 96))	('autoimmunity', 'Disease', (84, 96))	('transgenic mice', 'Species', '10090', (40, 55))	('inflammation', 'Disease', 'MESH:D007249', (98, 110))	('plasmacytosis', 'Disease', (69, 82))	('plasmacytosis', 'Phenotype', 'HP:0030150', (69, 82))	('TRAF3', 'Gene', (34, 39))	('transgenic', 'Var', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('inflammation', 'Disease', (98, 110))	('autoimmunity', 'Disease', 'MESH:D001327', (84, 96))	('cancers', 'Disease', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('develop', 'PosReg', (61, 68))
518737	30294322	Interestingly, specific deletion of TRAF3 from myeloid cells (granulocytes, monocytes, and macrophages) leads to spontaneous development of histiocytic sarcomas derived from TRAF3-/- tissue-resident macrophages in aging mice.	('TRAF3-/-', 'Gene', '22031', (174, 182))	('TRAF3-/-', 'Gene', (174, 182))	('TRAF3', 'Gene', (36, 41))	('leads to', 'Reg', (104, 112))	('mice', 'Species', '10090', (220, 224))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('histiocytic sarcomas', 'Disease', (140, 160))	('deletion', 'Var', (24, 32))	('histiocytic sarcomas', 'Disease', 'MESH:D054747', (140, 160))
518743	30294322	Transgenic expression of human TLR7/TLR8 in mice deficient for endogenous TLR7/TLR8 drives inflammation and proliferative histiocytosis, which can be reversed by compound deletion of MyD88.	('Transgenic', 'Species', '10090', (0, 10))	('inflammation', 'Disease', 'MESH:D007249', (91, 103))	('compound deletion', 'Var', (162, 179))	('inflammation', 'Disease', (91, 103))	('human', 'Species', '9606', (25, 30))	('MyD88', 'Gene', (183, 188))	('MyD88', 'Gene', '17874', (183, 188))	('histiocytosis', 'Phenotype', 'HP:0100727', (122, 135))	('TLR7/TLR8', 'Gene', (31, 40))	('proliferative histiocytosis', 'MPA', (108, 135))	('mice', 'Species', '10090', (44, 48))	('drives', 'PosReg', (84, 90))
518744	30294322	Collectively, the above in vivo evidence indicates that TRAF3 is a tumor suppressor in macrophages and that dysregulation of the TLR-MyD88-TRAF3-Dok3 axis in macrophages plays causal roles in the pathogenesis of histiocytic sarcoma.	('histiocytic sarcoma', 'Disease', (212, 231))	('Dok3', 'Gene', '27261', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('Dok3', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MyD88', 'Gene', (133, 138))	('tumor', 'Disease', (67, 72))	('dysregulation', 'Var', (108, 121))	('MyD88', 'Gene', '17874', (133, 138))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (212, 231))	('TRAF3', 'Gene', (56, 61))
518745	30294322	However, because histiocytic sarcoma in humans is a rare malignancy with sparse pathologic and cytogenetic data, potential TRAF3 genetic alterations in human histiocytic sarcomas require future investigation.	('malignancy', 'Disease', (57, 67))	('histiocytic sarcoma', 'Disease', (17, 36))	('histiocytic sarcomas', 'Disease', (158, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('humans', 'Species', '9606', (40, 46))	('TRAF3', 'Gene', (123, 128))	('genetic alterations', 'Var', (129, 148))	('human', 'Species', '9606', (152, 157))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (158, 177))	('malignancy', 'Disease', 'MESH:D009369', (57, 67))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (17, 36))	('histiocytic sarcomas', 'Disease', 'MESH:D054747', (158, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('human', 'Species', '9606', (40, 45))
518751	30294322	In line with the in vivo data, mutations and deletions of TRAF3 are detected in 2.3% (10/439) of human colon cancers (TCGA, PanCancer Atlas).	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('colon cancers', 'Phenotype', 'HP:0003003', (103, 116))	('colon cancers', 'Disease', 'MESH:D015179', (103, 116))	('human', 'Species', '9606', (97, 102))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deletions', 'Var', (45, 54))	('detected', 'Reg', (68, 76))	('TRAF3', 'Gene', (58, 63))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('colon cancers', 'Disease', (103, 116))
518758	30294322	Silencing of TRAF3 in ALCL cells not only results in aberrant activation of the NIK-NF-kappaB2 pathway, but also affects the continued PI3K-AKT and JAK-STAT signaling.	('AKT', 'Gene', (140, 143))	('NF-kappaB2', 'Gene', '18034', (84, 94))	('ALCL', 'Phenotype', 'HP:0012193', (22, 26))	('NIK', 'Gene', (80, 83))	('affects', 'Reg', (113, 120))	('TRAF3', 'Gene', (13, 18))	('AKT', 'Gene', '207', (140, 143))	('NF-kappaB2', 'Gene', (84, 94))	('Silencing', 'Var', (0, 9))	('activation', 'PosReg', (62, 72))	('JAK-STAT', 'MPA', (148, 156))	('NIK', 'Gene', '9020', (80, 83))
518763	30294322	The frequency of genetic alterations of TRAF4 is generally <11% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 100.	('cancers', 'Disease', (73, 80))	('TRAF4', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('genetic alterations', 'Var', (17, 36))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
518764	30294322	The eight human cancers with relatively higher genetic alterations of TRAF4 are pancreatic cancer (10.1%), bladder cancer (7.3%), breast cancer (5.5%), uterine cancer (5.1%) (TCGA, PanCancer Atlas), esophageal cancer (3.2%) (TCGA, Provisional), lung cancer (2.6%), melanoma (2.5%), and ovarian cancer (2.4%) (TCGA, PanCancer Atlas).	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('pancreatic cancer', 'Disease', (80, 97))	('TRAF4', 'Gene', (70, 75))	('cancer', 'Disease', (137, 143))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('Cancer', 'Phenotype', 'HP:0002664', (318, 324))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('lung cancer', 'Disease', (245, 256))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('uterine cancer', 'Phenotype', 'HP:0010784', (152, 166))	('cancer', 'Disease', (294, 300))	('ovarian cancer', 'Disease', 'MESH:D010051', (286, 300))	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))	('lung cancer', 'Disease', 'MESH:D008175', (245, 256))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('genetic alterations', 'Var', (47, 66))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('ovarian cancer', 'Disease', (286, 300))	('bladder cancer', 'Disease', (107, 121))	('breast cancer', 'Disease', (130, 143))	('cancer', 'Disease', (115, 121))	('esophageal cancer', 'Disease', (199, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (286, 300))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (210, 216))
518765	30294322	Deep deletion, truncation and fusion of TRAF4 are relatively rare in human cancers.	('truncation', 'Var', (15, 25))	('fusion', 'Var', (30, 36))	('TRAF4', 'Gene', (40, 45))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Deep deletion', 'Var', (0, 13))
518766	30294322	There are 123 different mutations of TRAF4 detected in human cancers, comprising 85% (105/123) mutations that cause changes in the amino acid sequence of TRAF4 and 15% (18/123) coding silent mutations (Table 1).	('TRAF4', 'Gene', (154, 159))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('changes', 'Reg', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('amino acid sequence', 'MPA', (131, 150))	('silent', 'NegReg', (184, 190))	('TRAF4', 'Gene', (37, 42))
518767	30294322	About 42% (44/105) of the coding-altering mutations of the TRAF4 gene are recurrent and detected in at least two cancer patients, including mostly missense mutations (89%, 39/44), 3 truncations, 1 frameshift deletion, and 1 in frame deletion (Table 1 and Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('frameshift deletion', 'Var', (197, 216))	('TRAF4', 'Gene', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('truncations', 'MPA', (182, 193))	('detected', 'Reg', (88, 96))	('cancer', 'Disease', (113, 119))	('missense mutations', 'Var', (147, 165))	('coding-altering', 'Reg', (26, 41))	('patients', 'Species', '9606', (120, 128))	('mutations', 'Var', (42, 51))
518768	30294322	Only two specific amino acids, R448 and R452 located at the C-terminal TRAF-C domain, are mutated in more than 3 patients (Figure 3).	('R452', 'Var', (40, 44))	('patients', 'Species', '9606', (113, 121))	('R448', 'Var', (31, 35))
518769	30294322	For R448, mixed missense mutations (R448Q or L) and a truncation (R448*) are identified in 4 patients with prostate cancer, uterine cancer, HNSCC, and OSCC.	('prostate cancer', 'Disease', (107, 122))	('cancer', 'Disease', (132, 138))	('R448Q', 'Mutation', 'p.R448Q', (36, 41))	('R448*', 'SUBSTITUTION', 'None', (66, 71))	('patients', 'Species', '9606', (93, 101))	('uterine cancer', 'Phenotype', 'HP:0010784', (124, 138))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('R448Q or L', 'Var', (36, 46))	('OSCC', 'Disease', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HNSCC', 'Disease', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('R448*', 'Var', (66, 71))
518770	30294322	For R452, missense mutations (R452W or Q or L) are detected in four patients with uterine, colorectal and lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('detected', 'Reg', (51, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('uterine', 'Disease', (82, 89))	('R452W', 'Var', (30, 35))	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (91, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (68, 76))	('lung cancers', 'Phenotype', 'HP:0100526', (106, 118))	('R452', 'Var', (4, 8))	('R452W', 'Mutation', 'p.R452W', (30, 35))
518772	30294322	Available human evidence indicates that gene amplification is the most common TRAF4 genetic alteration in cancers and that TRAF4 expression is ubiquitously elevated in many human cancers.	('TRAF4', 'Gene', (78, 83))	('human', 'Species', '9606', (10, 15))	('expression', 'MPA', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('human', 'Species', '9606', (173, 178))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('gene amplification', 'Var', (40, 58))	('cancers', 'Disease', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
518775	30294322	Interestingly, TRAF4-/- dendritic cells (DCs) derived from the null mice exhibit reduced in vivo and in vitro migration.	('mice', 'Species', '10090', (68, 72))	('TRAF4-/-', 'Var', (15, 23))	('reduced', 'NegReg', (81, 88))
518777	30294322	TRAF4 deficiency substantially diminishes IL-17A-induced ERK5 activation and epidermal hyperplasia in mice.	('TRAF4 deficiency', 'Phenotype', 'HP:0040209', (0, 16))	('mice', 'Species', '10090', (102, 106))	('epidermal hyperplasia', 'Disease', (77, 98))	('TRAF4', 'Gene', (0, 5))	('diminishes', 'NegReg', (31, 41))	('deficiency', 'Var', (6, 16))	('ERK5', 'Protein', (57, 61))	('IL-17A-induced', 'MPA', (42, 56))	('epidermal hyperplasia', 'Disease', 'MESH:D006965', (77, 98))
518778	30294322	In the DMBA/TPA-induced skin cancer model, TRAF4-/- mice exhibit remarkably reduced tumor incidence and tumor numbers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('skin cancer', 'Phenotype', 'HP:0008069', (24, 35))	('tumor', 'Disease', (104, 109))	('mice', 'Species', '10090', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('skin cancer', 'Disease', (24, 35))	('tumor', 'Disease', (84, 89))	('reduced', 'NegReg', (76, 83))	('DMBA', 'Chemical', 'MESH:C082386', (7, 11))	('TPA', 'Chemical', '-', (12, 15))	('skin cancer', 'Disease', 'MESH:D012878', (24, 35))	('TRAF4-/-', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
518785	30294322	The frequency of genetic alterations of TRAF5 is generally <13% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 140.	('cancers', 'Disease', (73, 80))	('TRAF5', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('genetic alterations', 'Var', (17, 36))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
518786	30294322	The eight human cancers with relatively higher genetic alterations of TRAF5 are breast cancer (12.2%), liver cancer (8.4%) (TCGA, Provisional), uterine cancer (6.4%) (TCGA, PanCancer Atlas), lung cancer (5.3%) (TCGA, Provisional), ovarian cancer (5.1%) (TCGA, Provisional), melanoma (4.0%) (TCGA, Provisional), esophageal cancer (3.8%) (TCGA, Provisional), and prostate cancer (3.3%).	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('TRAF5', 'Gene', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('uterine cancer', 'Phenotype', 'HP:0010784', (144, 158))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (16, 23))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('cancer', 'Disease', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (311, 328))	('ovarian cancer', 'Disease', 'MESH:D010051', (231, 245))	('cancer', 'Disease', (322, 328))	('cancer', 'Disease', (109, 115))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('melanoma', 'Disease', (274, 282))	('liver cancer', 'Disease', 'MESH:D006528', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (370, 376))	('cancer', 'Disease', (196, 202))	('genetic alterations', 'Var', (47, 66))	('esophageal cancer', 'Disease', (311, 328))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('liver cancer', 'Phenotype', 'HP:0002896', (103, 115))	('prostate cancer', 'Disease', 'MESH:D011471', (361, 376))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('prostate cancer', 'Phenotype', 'HP:0012125', (361, 376))	('ovarian cancer', 'Disease', (231, 245))	('liver cancer', 'Disease', (103, 115))	('lung cancer', 'Disease', (191, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('prostate cancer', 'Disease', (361, 376))	('ovarian cancer', 'Phenotype', 'HP:0100615', (231, 245))
518787	30294322	Deep deletion, truncation and fusion of TRAF5 are rare events in human cancers.	('truncation', 'Var', (15, 25))	('fusion', 'Var', (30, 36))	('TRAF5', 'Gene', (40, 45))	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Deep deletion', 'Var', (0, 13))
518788	30294322	There are 188 different mutations of TRAF5 detected in human cancers, comprising 85% (160/188) mutations that alter the amino acid sequence of TRAF5 and 15% (28/188) coding silent mutations (Table 1).	('silent', 'NegReg', (173, 179))	('TRAF5', 'Gene', (143, 148))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('amino acid sequence', 'MPA', (120, 139))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TRAF5', 'Gene', (37, 42))
518789	30294322	Approximately 36% (57/160) of the coding-altering mutations of TRAF5 are recurrent in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('mutations', 'Var', (50, 59))	('TRAF5', 'Gene', (63, 68))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('coding-altering', 'Reg', (34, 49))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('recurrent', 'Reg', (73, 82))
518790	30294322	Mutations of three specific amino acids, R164, T232, and A548, are detected in more than three patients (Figure 3).	('A548', 'Var', (57, 61))	('R164', 'Var', (41, 45))	('T232', 'Var', (47, 51))	('patients', 'Species', '9606', (95, 103))
518791	30294322	Complex alterations of R164 of the zinc finger motif, including truncation (R164*) and missense mutations (R164Q or L), are detected in six patients with uterine, colon and bile duct cancers and DLBCL (TCGA).	('R164*', 'Var', (76, 81))	('R164', 'Var', (23, 27))	('detected', 'Reg', (124, 132))	('colon and bile duct cancers', 'Disease', 'MESH:D001650', (163, 190))	('truncation', 'MPA', (64, 74))	('DLBCL', 'Disease', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('uterine', 'Disease', (154, 161))	('missense mutations (R164Q or L', 'Var', (87, 117))	('R164Q', 'Mutation', 'p.R164Q', (107, 112))	('patients', 'Species', '9606', (140, 148))	('R164*', 'SUBSTITUTION', 'None', (76, 81))	('bile duct cancers', 'Phenotype', 'HP:0030153', (173, 190))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
518792	30294322	Another missense mutation of the zinc finger motif, T232M, is detected in four patients with colon, breast, and prostate cancers (TCGA; COSMIC).	('detected', 'Reg', (62, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('breast', 'Disease', (100, 106))	('T232M', 'Var', (52, 57))	('T232M', 'Mutation', 'p.T232M', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('prostate cancers', 'Phenotype', 'HP:0012125', (112, 128))	('prostate cancers', 'Disease', (112, 128))	('colon', 'Disease', (93, 98))	('patients', 'Species', '9606', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('prostate cancers', 'Disease', 'MESH:D011471', (112, 128))
518793	30294322	Missense mutation A548V of the TRAF-C domain is identified in four patients with uterine, cervical, stomach, and breast cancers (TCGA).	('Missense mutation A548V', 'Var', (0, 23))	('identified', 'Reg', (48, 58))	('breast cancers', 'Disease', (113, 127))	('breast cancers', 'Disease', 'MESH:D001943', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('stomach', 'Disease', (100, 107))	('A548V', 'Var', (18, 23))	('patients', 'Species', '9606', (67, 75))	('uterine', 'Disease', (81, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cervical', 'Disease', (90, 98))	('A548V', 'Mutation', 'p.A548V', (18, 23))	('TRAF-C domain', 'Gene', (31, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (113, 127))
518794	30294322	Although not cataloged in TCGA, TRAF5 mutations are detected in 5% (5/101) of human DLBCL.	('detected', 'Reg', (52, 60))	('mutations', 'Var', (38, 47))	('human', 'Species', '9606', (78, 83))	('TRAF5', 'Gene', (32, 37))	('DLBCL', 'Disease', (84, 89))
518797	30294322	Consistent with human evidence, B cells of TRAF5-/- mice show defects in CD40-induced proliferation and up-regulation of surface molecules and activation markers as well as CD40 plus IL-4-induced Ig production (Table 2).	('up-regulation', 'PosReg', (104, 117))	('activation', 'MPA', (143, 153))	('CD40', 'Var', (173, 177))	('human', 'Species', '9606', (16, 21))	('mice', 'Species', '10090', (52, 56))	('surface molecules', 'MPA', (121, 138))	('CD40-induced', 'Gene', (73, 85))	('IL-4', 'Gene', (183, 187))	('defects', 'NegReg', (62, 69))	('IL-4', 'Gene', '16189', (183, 187))
518800	30294322	TRAF5 deficiency reverses the CD40-LMP1-induced enlargement of the spleen and lymph nodes, decreases the serum levels of IL-6 and autoantibodies that are elevated by CD40-LMP1-tg expression, and also inhibits LMP1-mediated JNK activation in B lymphocytes (Table 2).	('JNK', 'Gene', (223, 226))	('enlargement of the spleen', 'Phenotype', 'HP:0001744', (48, 73))	('LMP1', 'Gene', '17494204', (35, 39))	('TRAF5', 'Gene', (0, 5))	('LMP1', 'Gene', (35, 39))	('enlargement of the spleen', 'Disease', (48, 73))	('JNK', 'Gene', '5599', (223, 226))	('deficiency', 'Var', (6, 16))	('LMP1', 'Gene', '17494204', (209, 213))	('inhibits', 'NegReg', (200, 208))	('enlargement of the spleen', 'Disease', 'MESH:D013163', (48, 73))	('LMP1', 'Gene', (171, 175))	('serum levels of IL-6', 'MPA', (105, 125))	('elevated', 'PosReg', (154, 162))	('LMP1', 'Gene', '17494204', (171, 175))	('LMP1', 'Gene', (209, 213))	('decreases', 'NegReg', (91, 100))	('reverses', 'NegReg', (17, 25))
518802	30294322	Additionally, available in vivo evidence indicates the importance of TRAF5 in the survival, proliferation and differentiation of different T cell subsets as detailed in Table 2, suggesting that TRAF5 malfunction may contribute to T cell malignancies.	('malfunction', 'Var', (200, 211))	('T cell malignancies', 'Phenotype', 'HP:0005517', (230, 249))	('T cell malignancies', 'Disease', 'MESH:D018273', (230, 249))	('T cell malignancies', 'Disease', (230, 249))	('contribute', 'Reg', (216, 226))	('TRAF5', 'Gene', (194, 199))
518803	30294322	However, the evidence of TRAF5 alterations in human T cell lymphomas/leukemias is still lacking.	('alterations', 'Var', (31, 42))	('leukemias', 'Disease', (69, 78))	('lymphomas', 'Phenotype', 'HP:0002665', (59, 68))	('T cell lymphomas', 'Disease', 'MESH:D016399', (52, 68))	('leukemia', 'Phenotype', 'HP:0001909', (69, 77))	('T cell lymphomas', 'Disease', (52, 68))	('leukemias', 'Disease', 'MESH:D007938', (69, 78))	('human', 'Species', '9606', (46, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (52, 67))	('TRAF5', 'Gene', (25, 30))	('cell lymphoma', 'Phenotype', 'HP:0012191', (54, 67))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (52, 68))	('leukemias', 'Phenotype', 'HP:0001909', (69, 78))
518807	30294322	The frequency of genetic alterations of TRAF6 is generally <7% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 120.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TRAF6', 'Gene', (40, 45))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
518808	30294322	The eight human cancers with relatively higher genetic alterations of TRAF6 are breast cancer (6.9%), uterine cancer (4.5%) (TCGA, PanCancer Atlas), stomach cancer (4.1%), HNSCC (3.6%), lung cancer (3.4%), bladder cancer (3.1%), sarcoma (3%) (TCGA, Provisional), and ovarian cancer (2.8%) (TCGA, Provisional).	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('TRAF6', 'Gene', (70, 75))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('ovarian cancer', 'Disease', (267, 281))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('sarcoma', 'Disease', (229, 236))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (267, 281))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancer', 'Disease', (191, 197))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', (214, 220))	('stomach cancer', 'Disease', 'MESH:D013274', (149, 163))	('stomach cancer', 'Phenotype', 'HP:0012126', (149, 163))	('cancer', 'Disease', (16, 22))	('uterine cancer', 'Phenotype', 'HP:0010784', (102, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('bladder cancer', 'Disease', 'MESH:D001749', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder cancer', 'Disease', (206, 220))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (157, 163))	('genetic alterations', 'Var', (47, 66))	('lung cancer', 'Disease', (186, 197))	('cancer', 'Disease', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('ovarian cancer', 'Disease', 'MESH:D010051', (267, 281))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('HNSCC', 'Disease', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('stomach cancer', 'Disease', (149, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
518809	30294322	Although not listed in TCGA, TRAF6 amplification is recognized as one of the most frequent genomic alterations in human lung cancer (9.2%, 24/261) and OSCC (10%, 2/20).	('amplification', 'Var', (35, 48))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TRAF6', 'Gene', (29, 34))	('human', 'Species', '9606', (114, 119))	('OSCC', 'Disease', (151, 155))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))
518811	30294322	TRAF6 overexpression is also identified as a prognostic factor for breast and esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('overexpression', 'Var', (6, 20))	('breast and esophageal cancers', 'Disease', 'MESH:D001943', (67, 96))	('TRAF6', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
518812	30294322	Deep deletion of TRAF6 is less common but also detected in several different types of human cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('detected', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Deep deletion', 'Var', (0, 13))	('TRAF6', 'Gene', (17, 22))
518813	30294322	Truncation and fusion of TRAF6 are rare in human cancers.	('fusion', 'Var', (15, 21))	('TRAF6', 'Gene', (25, 30))	('Truncation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('human', 'Species', '9606', (43, 48))
518814	30294322	There are 178 different mutations of TRAF6 detected in human cancers, comprising 85% (152/178) mutations that alter the protein sequence of TRAF6 and 15% (26/178) coding silent mutations (Table 1).	('protein sequence', 'MPA', (120, 136))	('human', 'Species', '9606', (55, 60))	('TRAF6', 'Gene', (37, 42))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TRAF6', 'Gene', (140, 145))
518815	30294322	Only 27% (41/152) of the coding-altering mutations of TRAF6 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('TRAF6', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (108, 116))	('coding-altering', 'Reg', (25, 40))
518816	30294322	Mutations of only two specific amino acids, R335 and P398, are detected in more than three patients (Figure 3).	('P398', 'Var', (53, 57))	('patients', 'Species', '9606', (91, 99))	('R335', 'Var', (44, 48))
518817	30294322	A truncation (R335*) and missense mutation (R335Q) at R335 within the coiled-coil domain of TRAF6 are detected in five patients with colon and uterine cancers (TCGA).	('uterine cancers', 'Phenotype', 'HP:0010784', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('R335*', 'SUBSTITUTION', 'None', (14, 19))	('patients', 'Species', '9606', (119, 127))	('TRAF6', 'Gene', (92, 97))	('colon and uterine cancers', 'Disease', 'MESH:D015179', (133, 158))	('detected', 'Reg', (102, 110))	('R335Q', 'Mutation', 'p.R335Q', (44, 49))	('uterine cancer', 'Phenotype', 'HP:0010784', (143, 157))	('R335Q', 'Var', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('R335*', 'Var', (14, 19))
518819	30294322	Functional significance of these TRAF6 recurrent mutations in cancer pathogenesis remains to be elucidated.	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TRAF6', 'Gene', (33, 38))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
518821	30294322	However, available in vivo evidence supports potential contributions of TRAF6 dysregulation in tumorigenesis.	('dysregulation', 'Var', (78, 91))	('TRAF6', 'Gene', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
518822	30294322	Consistent with the genetic alterations (mainly amplification and mutation) and frequent overexpression of TRAF6 detected in human epithelial cancers such as breast cancer and uterine cancer (Figure 1A), deletion of TRAF6 in mice results in loss of NF-kappaB activity in epithelia and vasculature during mouse development (Table 2).	('cancer', 'Disease', (184, 190))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('uterine cancer', 'Phenotype', 'HP:0010784', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('breast cancer', 'Disease', (158, 171))	('NF-kappaB', 'Protein', (249, 258))	('mice', 'Species', '10090', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('TRAF6', 'Gene', (216, 221))	('cancer', 'Disease', (142, 148))	('loss', 'NegReg', (241, 245))	('cancers', 'Disease', (142, 149))	('deletion', 'Var', (204, 212))	('activity', 'MPA', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('human', 'Species', '9606', (125, 130))	('cancer', 'Disease', (165, 171))	('mouse', 'Species', '10090', (304, 309))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
518824	30294322	In line with the in vivo data, knockdown of TRAF6 or inhibition of TRAF6 E3 ligase activity suppresses the survival, proliferation, migration, and metastasis of many human epithelial cancers, including breast, lung, liver, and colon cancers as well as HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('colon cancers', 'Disease', 'MESH:D015179', (227, 240))	('colon cancers', 'Disease', (227, 240))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', (183, 190))	('inhibition', 'NegReg', (53, 63))	('proliferation', 'CPA', (117, 130))	('human', 'Species', '9606', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('TRAF6', 'Gene', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('breast', 'Disease', (202, 208))	('liver', 'Disease', (216, 221))	('migration', 'CPA', (132, 141))	('survival', 'CPA', (107, 115))	('HNSCC', 'Disease', (252, 257))	('metastasis', 'CPA', (147, 157))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('suppresses', 'NegReg', (92, 102))	('activity', 'MPA', (83, 91))	('lung', 'Disease', (210, 214))	('colon cancers', 'Phenotype', 'HP:0003003', (227, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))	('cancers', 'Disease', (233, 240))	('knockdown', 'Var', (31, 40))
518826	30294322	Hematopoietic-specific deletion of TRAF6 in mice leads to decreased tonic IKKbeta-NF-kappaB activation, impaired hematopoietic stem cell (HSC) self-renewal and loss of hematopoietic stem/progenitor cells (HSPCs) in the bone marrow (BM) (Table 2).	('impaired hematopoietic', 'Disease', (104, 126))	('IKKbeta-NF-kappaB', 'Protein', (74, 91))	('deletion', 'Var', (23, 31))	('loss', 'NegReg', (160, 164))	('tonic', 'MPA', (68, 73))	('TRAF6', 'Gene', (35, 40))	('decreased', 'NegReg', (58, 67))	('impaired hematopoietic', 'Disease', 'MESH:D019337', (104, 126))	('activation', 'MPA', (92, 102))	('mice', 'Species', '10090', (44, 48))
518828	30294322	In the lymphoid lineage, TRAF6 mutations have been detected in 2.1% human DLBCL (TCGA) and 2.4% human cutaneous T cell lymphoma (CTCL).	('detected', 'Reg', (51, 59))	('mutations', 'Var', (31, 40))	('human', 'Species', '9606', (68, 73))	('TRAF6', 'Gene', (25, 30))	('human', 'Species', '9606', (96, 101))	('lymphoma', 'Phenotype', 'HP:0002665', (119, 127))	('cutaneous T cell lymphoma', 'Disease', 'MESH:D016410', (102, 127))	('cutaneous T cell lymphoma', 'Disease', (102, 127))	('cell lymphoma', 'Phenotype', 'HP:0012191', (114, 127))	('cutaneous T cell lymphoma', 'Phenotype', 'HP:0012192', (102, 127))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (112, 127))	('CTCL', 'Phenotype', 'HP:0012192', (129, 133))
518833	30294322	T-TRAF6-/- mice also exhibit increased Th17 differentiation due to enhanced sensitivity of CD4 T cells to TGFbeta signaling, but have defects in generating CD8 memory T cells caused by defective AMPK activation in activated CD8 T cells.	('memory T', 'Disease', (160, 168))	('CD8', 'Gene', (156, 159))	('T-TRAF6-/-', 'Var', (0, 10))	('defects', 'NegReg', (134, 141))	('AMPK activation', 'MPA', (195, 210))	('defective', 'NegReg', (185, 194))	('increased', 'PosReg', (29, 38))	('sensitivity', 'MPA', (76, 87))	('mice', 'Species', '10090', (11, 15))	('CD8', 'Gene', (224, 227))	('CD8', 'Gene', '925', (224, 227))	('CD8', 'Gene', '925', (156, 159))	('CD4', 'Gene', (91, 94))	('memory T', 'Disease', 'MESH:D008569', (160, 168))	('CD4', 'Gene', '920', (91, 94))	('Th17 differentiation', 'CPA', (39, 59))	('enhanced', 'PosReg', (67, 75))
518836	30294322	Furthermore, inhibition of the IRAK1/4-TRAF6 axis sensitizes human T cell ALL (T-ALL) to chemotherapies.	('IRAK1', 'Gene', '3654', (31, 36))	('IRAK1', 'Gene', (31, 36))	('inhibition', 'Var', (13, 23))	('sensitizes', 'Reg', (50, 60))	('T cell ALL (T-ALL)', 'Disease', 'MESH:D054218', (67, 85))	('human', 'Species', '9606', (61, 66))
518840	30294322	In skeletal muscle, TRAF6 deficiency prevents muscle loss and cancer cachexia in response to transplanted tumor growth, improves regeneration of myofibers upon injury and reduces skeletal muscle atrophy upon starvation through regulating NF-kappaB activation/ubiquitin-proteasome/autophagy-lysosomal systems, Akt/FoxO3a/AMPK activation and Notch signaling, respectively.	('Akt', 'Gene', (309, 312))	('muscle loss', 'Disease', 'MESH:D009133', (46, 57))	('regeneration of myofibers', 'CPA', (129, 154))	('muscle atrophy', 'Disease', 'MESH:D009133', (188, 202))	('skeletal muscle atrophy', 'Phenotype', 'HP:0003202', (179, 202))	('injury', 'Disease', 'MESH:D014947', (160, 166))	('Akt', 'Gene', '207', (309, 312))	('TRAF6', 'Gene', (20, 25))	('tumor', 'Disease', (106, 111))	('FoxO3a', 'Gene', (313, 319))	('muscle loss', 'Disease', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('regulating', 'Reg', (227, 237))	('FoxO3a', 'Gene', '2309', (313, 319))	('muscle atrophy', 'Disease', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cachexia', 'Phenotype', 'HP:0004326', (69, 77))	('cancer cachexia', 'Disease', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('deficiency', 'Var', (26, 36))	('cancer cachexia', 'Disease', 'MESH:D002100', (62, 77))	('NF-kappaB', 'Protein', (238, 247))	('improves', 'PosReg', (120, 128))	('injury', 'Disease', (160, 166))	('muscle loss', 'Phenotype', 'HP:0003202', (46, 57))	('reduces', 'NegReg', (171, 178))
518841	30294322	In line with the mouse data, genetic alterations of TRAF6, including amplification, mutation and deletion, are detected in 1% of human glioblastoma and 3% of human sarcoma (TCGA).	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('TRAF6', 'Gene', (52, 57))	('detected', 'Reg', (111, 119))	('mouse', 'Species', '10090', (17, 22))	('human', 'Species', '9606', (158, 163))	('amplification', 'MPA', (69, 82))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('human', 'Species', '9606', (129, 134))	('glioblastoma', 'Disease', (135, 147))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('deletion', 'Var', (97, 105))	('mutation', 'Var', (84, 92))
518845	30294322	Interestingly, the importance of TRAF6-dependent oncogenic pathways in human cancers is also underscored by the findings that TRAF6 mRNA is the direct target of tumor suppressive mi-RNAs, including miR-146a, and miR-141-3p.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('miR-146a', 'Var', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mi-RNAs', 'Var', (179, 186))	('miR-141-3p', 'Var', (212, 222))	('TRAF6', 'Gene', (126, 131))	('tumor', 'Disease', (161, 166))	('human', 'Species', '9606', (71, 76))
518852	30294322	The frequency of genetic alterations of TRAF7 is generally <7% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 150.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF7', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
518853	30294322	The eight human cancers with relatively higher genetic alterations of TRAF7 are breast cancer (6%), prostate cancer (5.1%), stomach cancer (4.8%) (8), sarcoma (3.8%) (TCGA, Provisional), esophageal cancer (3.3%) (TCGA, PanCancer Atlas), uterine cancer (3.2%) (TCGA, PanCancer Atlas), melanoma (3.1%) (TCGA, PanCancer Atlas), and liver cancer (2.4%) (TCGA, PanCancer Atlas).	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (335, 341))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('stomach cancer', 'Disease', (124, 138))	('Cancer', 'Phenotype', 'HP:0002664', (359, 365))	('breast cancer', 'Disease', (80, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('liver cancer', 'Phenotype', 'HP:0002896', (329, 341))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('TRAF7', 'Gene', (70, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('liver cancer', 'Disease', (329, 341))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', (198, 204))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('cancer', 'Disease', (16, 22))	('melanoma', 'Disease', (284, 292))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophageal cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (310, 316))	('uterine cancer', 'Phenotype', 'HP:0010784', (237, 251))	('cancer', 'Disease', (87, 93))	('stomach cancer', 'Disease', 'MESH:D013274', (124, 138))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('stomach cancer', 'Phenotype', 'HP:0012126', (124, 138))	('cancer', 'Disease', (245, 251))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('genetic alterations', 'Var', (47, 66))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Cancer', 'Phenotype', 'HP:0002664', (269, 275))	('liver cancer', 'Disease', 'MESH:D006528', (329, 341))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (132, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('melanoma', 'Disease', 'MESH:D008545', (284, 292))	('prostate cancer', 'Disease', (100, 115))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('sarcoma', 'Disease', (151, 158))
518854	30294322	However, it should be noted that although not yet cataloged in TCGA, the rate of TRAF7 mutation is overwhelmingly high in patients with adenomatoid tumors of the male and female genital tracts (100%, 31/31), secretory meningiomas (97%, 29/30), intraneural perineuriomas (62.5%, 10/16), and meningiomas 23% (182/775) (Figure 1B).	('meningiomas', 'Disease', 'MESH:D008579', (290, 301))	('meningiomas', 'Disease', 'MESH:D008579', (218, 229))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('meningiomas', 'Phenotype', 'HP:0002858', (290, 301))	('meningioma', 'Phenotype', 'HP:0002858', (218, 228))	('intraneural perineuriomas', 'Disease', (244, 269))	('meningiomas', 'Phenotype', 'HP:0002858', (218, 229))	('meningioma', 'Phenotype', 'HP:0002858', (290, 300))	('TRAF7', 'Gene', (81, 86))	('high', 'Reg', (114, 118))	('meningiomas', 'Disease', (290, 301))	('patients', 'Species', '9606', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('meningiomas', 'Disease', (218, 229))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (136, 154))	('mutation', 'Var', (87, 95))	('adenomatoid tumors', 'Disease', (136, 154))	('intraneural perineuriomas', 'Disease', 'MESH:D018317', (244, 269))
518855	30294322	In particular, high frequencies (15-26%) of TRAF7 mutations has been reproducibly detected in multiple studies, and knowledge of TRAF7 mutations has contributed significantly to improving the diagnosis, classification, prognosis, and treatment of patients with meningiomas.	('meningiomas', 'Disease', (261, 272))	('TRAF7', 'Gene', (129, 134))	('mutations', 'Var', (50, 59))	('meningiomas', 'Disease', 'MESH:D008579', (261, 272))	('meningiomas', 'Phenotype', 'HP:0002858', (261, 272))	('improving', 'PosReg', (178, 187))	('TRAF7', 'Gene', (44, 49))	('patients', 'Species', '9606', (247, 255))	('meningioma', 'Phenotype', 'HP:0002858', (261, 271))
518856	30294322	Additionally, deletion of TRAF7 is detected in 67% (18/27) of malignant mesothelioma patients' malignant cells in pleural fluids.	('detected', 'Reg', (35, 43))	('TRAF7', 'Gene', (26, 31))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (62, 84))	('patients', 'Species', '9606', (85, 93))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (62, 84))	('deletion', 'Var', (14, 22))	('malignant mesothelioma', 'Disease', (62, 84))
518857	30294322	Truncation and fusion of TRAF7 are rarely detected in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('Truncation', 'Var', (0, 10))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))	('TRAF7', 'Gene', (25, 30))
518859	30294322	Over half (53%, 174/326) of the TRAF7 coding-altering mutations are recurrently detected in at least two cancer patients.	('TRAF7', 'Gene', (32, 37))	('cancer', 'Disease', (105, 111))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('coding-altering', 'Reg', (38, 53))
518860	30294322	Of particular interest, missense mutations of six specific amino acids located within the C-terminal WD40 repeats, N520, H521, G536, S561, K615, and R641, are identified as mutation hotspots of TRAF7 detected in more than 15 cancer patients (Figure 3).	('H521', 'Var', (121, 125))	('TRAF7', 'Gene', (194, 199))	('R641', 'Var', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('missense', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('G536', 'Var', (127, 131))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Disease', (225, 231))	('N520', 'Var', (115, 119))	('S561', 'Var', (133, 137))	('K615', 'Var', (139, 143))
518861	30294322	N520 mutations (N520S, H, Y, or T) are found in 31 patients with meningioma, mesothelioma, sarcoma and colon cancer.	('meningioma', 'Disease', 'MESH:D008579', (65, 75))	('mesothelioma', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('N520', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('found', 'Reg', (39, 44))	('sarcoma and colon cancer', 'Disease', 'MESH:D015179', (91, 115))	('N520S', 'Mutation', 'p.N520S', (16, 21))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('meningioma', 'Phenotype', 'HP:0002858', (65, 75))	('patients', 'Species', '9606', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('meningioma', 'Disease', (65, 75))	('N520S', 'Var', (16, 21))
518862	30294322	Mutations of the next amino acid H521 (H521R or N) are identified in 15 patients with adenomatoid tumor, perineurioma, and meningioma.	('H521', 'Gene', (33, 37))	('perineurioma', 'Disease', 'MESH:D018317', (105, 117))	('meningioma', 'Disease', (123, 133))	('H521R', 'Mutation', 'p.H521R', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Mutations', 'Var', (0, 9))	('meningioma', 'Disease', 'MESH:D008579', (123, 133))	('meningioma', 'Phenotype', 'HP:0002858', (123, 133))	('adenomatoid tumor', 'Disease', 'MESH:D018254', (86, 103))	('adenomatoid tumor', 'Disease', (86, 103))	('perineurioma', 'Disease', (105, 117))	('patients', 'Species', '9606', (72, 80))
518863	30294322	G536 mutations (G536S or V) are detected in 16 patients with meningioma, pancreatic cancer, mesothelioma and stomach cancer.	('G536S', 'Mutation', 'p.G536S', (16, 21))	('meningioma', 'Disease', (61, 71))	('pancreatic cancer', 'Disease', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('G536', 'Var', (0, 4))	('stomach cancer', 'Phenotype', 'HP:0012126', (109, 123))	('patients', 'Species', '9606', (47, 55))	('meningioma', 'Phenotype', 'HP:0002858', (61, 71))	('detected', 'Reg', (32, 40))	('meningioma', 'Disease', 'MESH:D008579', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mesothelioma and stomach cancer', 'Disease', 'MESH:D013274', (92, 123))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
518864	30294322	S561 mutations (S561R, N or T) are identified in 19 patients with adenomatoid tumor, perineurioma and meningioma.	('S561R', 'Mutation', 'p.S561R', (16, 21))	('perineurioma and meningioma', 'Disease', 'MESH:D018317', (85, 112))	('S561', 'Gene', (0, 4))	('meningioma', 'Phenotype', 'HP:0002858', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('adenomatoid tumor', 'Disease', 'MESH:D018254', (66, 83))	('adenomatoid tumor', 'Disease', (66, 83))	('S561R', 'Var', (16, 21))	('patients', 'Species', '9606', (52, 60))
518865	30294322	K615E mutations are detected in 15 patients with meningioma and OSCC.	('detected', 'Reg', (20, 28))	('meningioma', 'Disease', 'MESH:D008579', (49, 59))	('K615E', 'Mutation', 'p.K615E', (0, 5))	('OSCC', 'Disease', (64, 68))	('meningioma', 'Disease', (49, 59))	('patients', 'Species', '9606', (35, 43))	('meningioma', 'Phenotype', 'HP:0002858', (49, 59))	('K615E', 'Var', (0, 5))
518866	30294322	R641 mutations (R641H, C, P, or L) are detected in 24 patients with uterine, bile duct, colon, stomach and lung cancers and meningioma (TCGA, PanCancer Atlas).	('colon', 'Disease', (88, 93))	('meningioma', 'Disease', 'MESH:D008579', (124, 134))	('meningioma', 'Phenotype', 'HP:0002858', (124, 134))	('bile duct', 'Disease', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('patients', 'Species', '9606', (54, 62))	('lung cancers', 'Disease', (107, 119))	('R641H', 'Mutation', 'p.R641H', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('R641H', 'Var', (16, 21))	('detected', 'Reg', (39, 47))	('uterine', 'Disease', (68, 75))	('stomach', 'Disease', (95, 102))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('meningioma', 'Disease', (124, 134))	('lung cancers', 'Disease', 'MESH:D008175', (107, 119))	('lung cancers', 'Phenotype', 'HP:0100526', (107, 119))
518867	30294322	Although the functional significance of most TRAF7 mutations is currently unclear, the exceptionally high recurrence and clustering of missense mutations implicate TRAF7 malfunction as a critical pathogenic event in relevant human cancers.	('TRAF7', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (231, 238))	('human', 'Species', '9606', (225, 230))	('TRAF7', 'Gene', (164, 169))	('missense mutations', 'Var', (135, 153))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
518871	30294322	recently reported that de novo missense mutations in TRAF7 cause developmental abnormalities and other clinical symptoms in seven unrelated patients, including developmental delay (5/5), congenital heart defects (6/7), limb and digital anomalies (7/7), and dysmorphic facial features (7/7).	('developmental abnormalities', 'Disease', 'MESH:D006130', (65, 92))	('developmental delay', 'Phenotype', 'HP:0001263', (160, 179))	('developmental delay', 'Disease', (160, 179))	('dysmorphic facial features', 'Phenotype', 'HP:0001999', (257, 283))	('TRAF7', 'Gene', (53, 58))	('congenital heart defects', 'Disease', 'MESH:D006330', (187, 211))	('dysmorphic facial', 'Disease', 'None', (257, 274))	('cause', 'Reg', (59, 64))	('heart defects', 'Phenotype', 'HP:0030680', (198, 211))	('missense mutations', 'Var', (31, 49))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (65, 92))	('patients', 'Species', '9606', (140, 148))	('developmental abnormalities', 'Disease', (65, 92))	('congenital heart defects', 'Disease', (187, 211))	('dysmorphic facial', 'Disease', (257, 274))	('congenital heart defects', 'Phenotype', 'HP:0001627', (187, 211))	('digital anomalies', 'Phenotype', 'HP:0011297', (228, 245))
518872	30294322	TRAF7 mutations identified in this study include a recurrent R655Q mutation found in four patients, and another 3 single mutations each identified in one patient, including K346E, R371G, and T601A.	('R371G', 'Var', (180, 185))	('R655Q', 'Mutation', 'p.R655Q', (61, 66))	('patient', 'Species', '9606', (154, 161))	('R371G', 'Mutation', 'p.R371G', (180, 185))	('T601A', 'Var', (191, 196))	('K346E', 'Mutation', 'p.K346E', (173, 178))	('T601A', 'Mutation', 'c.601T>A', (191, 196))	('K346E', 'Var', (173, 178))	('TRAF7', 'Gene', (0, 5))	('patient', 'Species', '9606', (90, 97))	('patients', 'Species', '9606', (90, 98))	('R655Q', 'Var', (61, 66))
518873	30294322	Interestingly, R371 recurrent mutations are also detected in human cancers (Figure 3).	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('detected', 'Reg', (49, 57))	('cancers', 'Disease', (67, 74))	('R371 recurrent', 'Var', (15, 29))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (61, 66))
518874	30294322	K346 is a ubiquitination site of TRAF7.	('K346', 'Chemical', '-', (0, 4))	('TRAF7', 'Gene', (33, 38))	('K346', 'Var', (0, 4))
518875	30294322	Both K346 and R371 are located in the coiled-coil domain of TRAF7 that is important for TRAF7 homodimerization.	('K346', 'Chemical', '-', (5, 9))	('R371', 'Var', (14, 18))	('K346', 'Var', (5, 9))	('TRAF7', 'Gene', (60, 65))
518876	30294322	The recurrent R655Q mutation has also been previously identified as a de novo event in an autism patient.	('autism', 'Phenotype', 'HP:0000717', (90, 96))	('autism', 'Disease', 'MESH:D001321', (90, 96))	('R655Q', 'Var', (14, 19))	('autism', 'Disease', (90, 96))	('R655Q', 'Mutation', 'p.R655Q', (14, 19))	('patient', 'Species', '9606', (97, 104))
518877	30294322	Both T601 and R665 are located in the C-terminal WD40 repeats of TRAF7, which contain most mutation hotspots of TRAF7 detected in human cancers (Figure 3) and are known to mediate the interaction of TRAF7 with MEKK3 or c-Myb.	('c-Myb', 'Gene', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('MEKK3', 'Protein', (210, 215))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('TRAF7', 'Gene', (112, 117))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('T601', 'Var', (5, 9))	('TRAF7', 'Gene', (65, 70))	('interaction', 'Interaction', (184, 195))	('R665', 'Var', (14, 18))	('c-Myb', 'Gene', '4602', (219, 224))	('human', 'Species', '9606', (130, 135))
518878	30294322	further revealed that transfection of the R665Q, T601A, or R371G mutants of TRAF7 into HEK293T cells results in significantly reduced levels of ERK1/2 phosphorylation, both basal and in response to TNFalpha signaling.	('TRAF7', 'Gene', (76, 81))	('reduced', 'NegReg', (126, 133))	('HEK293T', 'CellLine', 'CVCL:0063', (87, 94))	('ERK1/2', 'Gene', '5595;5594', (144, 150))	('T601A', 'Mutation', 'c.601T>A', (49, 54))	('R665Q', 'Var', (42, 47))	('phosphorylation', 'MPA', (151, 166))	('R665Q', 'Mutation', 'p.R665Q', (42, 47))	('R371G', 'Var', (59, 64))	('T601A', 'Var', (49, 54))	('R371G', 'Mutation', 'p.R371G', (59, 64))	('ERK1/2', 'Gene', (144, 150))
518879	30294322	Consistent with this biochemical evidence, conditional ERK2-/- mice show a phenotype mirroring that observed in the seven patients with TRAF7 mutations, including craniofacial abnormalities, cardiovascular malformations and limb defects.	('mutations', 'Var', (142, 151))	('mice', 'Species', '10090', (63, 67))	('ERK2', 'Gene', '26413', (55, 59))	('TRAF7', 'Gene', (136, 141))	('patients', 'Species', '9606', (122, 130))	('ERK2', 'Gene', (55, 59))	('cardiovascular malformations', 'Phenotype', 'HP:0030680', (191, 219))	('craniofacial abnormalities', 'Disease', (163, 189))	('craniofacial abnormalities', 'Disease', 'MESH:D019465', (163, 189))	('cardiovascular malformations and limb defects', 'Disease', 'MESH:D018376', (191, 236))
518880	30294322	These highly interesting findings warrant further investigation of the in vivo functions of TRAF7 mutations in cancer pathogenesis using animal models.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TRAF7', 'Gene', (92, 97))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
518881	30294322	In addition to the above TRAF7-ERK1/2 pathway revealed by studying TRAF7 mutants of patients with developmental defects, the following TRAF7 signaling pathways have been proposed based on in vitro studies.	('patients', 'Species', '9606', (84, 92))	('ERK1/2', 'Gene', (31, 37))	('ERK1/2', 'Gene', '5595;5594', (31, 37))	('mutants', 'Var', (73, 80))	('TRAF7', 'Gene', (67, 72))	('developmental defects', 'Disease', 'MESH:D009436', (98, 119))	('developmental defects', 'Disease', (98, 119))
518882	30294322	(1) Transfection of tumor-derived TRAF7 mutants (H521R, Y538S, or S561R) but not WT TRAF7 in 293T cells causes increased phosphorylation of RelA and expression of the NF-kappaB target gene L1CAM, which is also elevated in adenomatoid tumors.	('tumor', 'Disease', (234, 239))	('293T', 'CellLine', 'CVCL:0063', (93, 97))	('RelA', 'Gene', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('H521R', 'Mutation', 'p.H521R', (49, 54))	('L1CAM', 'Gene', '3897', (189, 194))	('H521R', 'Var', (49, 54))	('S561R', 'Mutation', 'p.S561R', (66, 71))	('Y538S', 'Mutation', 'p.Y538S', (56, 61))	('RelA', 'Gene', '5970', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (222, 240))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('expression', 'MPA', (149, 159))	('L1CAM', 'Gene', (189, 194))	('Y538S', 'Var', (56, 61))	('TRAF7', 'Gene', (34, 39))	('increased', 'PosReg', (111, 120))	('phosphorylation', 'MPA', (121, 136))	('adenomatoid tumors', 'Disease', (222, 240))	('tumor', 'Disease', (20, 25))
518883	30294322	(2) Overexpression of TRAF7 or TNFalpha induces caspase-dependent apoptosis in HEK293 and HeLa cells via the TRAF7-MEKK3-NF-kappaB/p38/JNK-AP1/CHOP pathway, in which TRAF7 interacts with MEKK3 and potentiates the kinase activity of MEKK3.	('induces', 'Reg', (40, 47))	('CHOP', 'Gene', '1649', (143, 147))	('TNFalpha', 'Gene', (31, 39))	('HeLa', 'CellLine', 'CVCL:0030', (90, 94))	('MEKK3', 'Protein', (187, 192))	('JNK', 'Gene', (135, 138))	('potentiates', 'PosReg', (197, 208))	('TRAF7', 'Var', (22, 27))	('p38', 'Gene', (131, 134))	('CHOP', 'Gene', (143, 147))	('JNK', 'Gene', '5599', (135, 138))	('HEK293', 'CellLine', 'CVCL:0045', (79, 85))	('p38', 'Gene', '5594', (131, 134))	('AP1', 'Gene', (139, 142))	('MEKK3', 'Enzyme', (232, 237))	('AP1', 'Gene', '2353', (139, 142))	('caspase-dependent apoptosis', 'CPA', (48, 75))	('kinase activity', 'MPA', (213, 228))	('interacts', 'Interaction', (172, 181))
518892	30294322	TRAF7 mutations or downregulated protein levels may lead to aberrant NF-kappaB activation or altered signaling of ERK1/2, p38, JNK, c-FLIP, c-Myb, or p53 to drive tumorigenesis.	('NF-kappaB', 'Protein', (69, 78))	('c-FLIP', 'Gene', '8837', (132, 138))	('ERK1/2', 'Gene', (114, 120))	('p53', 'Gene', '7157', (150, 153))	('ERK1/2', 'Gene', '5595;5594', (114, 120))	('tumor', 'Disease', (163, 168))	('c-Myb', 'Gene', '4602', (140, 145))	('c-Myb', 'Gene', (140, 145))	('JNK', 'Gene', (127, 130))	('JNK', 'Gene', '5599', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('p53', 'Gene', (150, 153))	('activation', 'PosReg', (79, 89))	('p38', 'Gene', (122, 125))	('lead', 'Reg', (52, 56))	('mutations', 'Var', (6, 15))	('drive', 'PosReg', (157, 162))	('altered', 'Reg', (93, 100))	('c-FLIP', 'Gene', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('signaling', 'MPA', (101, 110))	('p38', 'Gene', '5594', (122, 125))	('TRAF7', 'Gene', (0, 5))	('downregulated', 'NegReg', (19, 32))
518893	30294322	Further studies are required to clarify the roles and mechanisms of TRAF7 alterations in cancer pathogenesis.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('TRAF7', 'Gene', (68, 73))	('alterations', 'Var', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
518895	30294322	Although the frequency of the genetic alterations of each TRAF is generally low (usually <5%), their combined rate is substantially increased to 10-35% in many types of human cancers (Figure 4) (TCGA).	('increased', 'PosReg', (132, 141))	('genetic alterations', 'Var', (30, 49))	('human', 'Species', '9606', (169, 174))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
518896	30294322	For example, the combined frequency of gene amplification of all seven TRAFs is 35% (709/2015) in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gene amplification', 'Var', (39, 57))
518897	30294322	The combined frequency of genetic alterations of all seven TRAFs is 23% (71/311) in ovarian cancer (TCGA, Provisional), 19% (77/408) in bladder cancer, 19% (45/240) in uterine cancer, 17% (81/469) in lung cancer (TCGA, PanCancer Atlas), 15% (41/265) in oesophageal cancer, 14% (48/353) in liver cancer (TCGA, PanCancer Atlas), 13% (35/279) in HNSCC, 13% (36/278) in cervical cancer (TCGA, PanCancer Atlas), 13% (58/438) in melanoma (TCGA, PanCancer Atlas), 12% (46/389) in colon cancer (TCGA, PanCancer Atlas), and 10% (106/1013) in prostate cancer.	('ovarian cancer', 'Disease', (84, 98))	('Cancer', 'Phenotype', 'HP:0002664', (496, 502))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (479, 485))	('cancer', 'Disease', (295, 301))	('liver cancer', 'Disease', 'MESH:D006528', (289, 301))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('cancer', 'Disease', (542, 548))	('cancer', 'Disease', (144, 150))	('colon cancer', 'Disease', 'MESH:D015179', (473, 485))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('HNSCC', 'Disease', (343, 348))	('alterations', 'Var', (34, 45))	('oesophageal cancer', 'Disease', (253, 271))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('uterine cancer', 'Phenotype', 'HP:0010784', (168, 182))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('Cancer', 'Phenotype', 'HP:0002664', (392, 398))	('Cancer', 'Phenotype', 'HP:0002664', (312, 318))	('prostate cancer', 'Disease', 'MESH:D011471', (533, 548))	('melanoma', 'Phenotype', 'HP:0002861', (423, 431))	('liver cancer', 'Phenotype', 'HP:0002896', (289, 301))	('colon cancer', 'Disease', (473, 485))	('prostate cancer', 'Phenotype', 'HP:0012125', (533, 548))	('liver cancer', 'Disease', (289, 301))	('prostate cancer', 'Disease', (533, 548))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('oesophageal cancer', 'Disease', 'MESH:D009369', (253, 271))	('cancer', 'Disease', (265, 271))	('melanoma', 'Disease', 'MESH:D008545', (423, 431))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (479, 485))	('cancer', 'Disease', 'MESH:D009369', (542, 548))	('lung cancer', 'Disease', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('Cancer', 'Phenotype', 'HP:0002664', (442, 448))	('colon cancer', 'Phenotype', 'HP:0003003', (473, 485))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', (375, 381))	('melanoma', 'Disease', (423, 431))
518900	30294322	Given the often mutually exclusive genetic alterations of different TRAFs in the same cancer, it is very likely that all seven TRAFs may have non-overlapping and distinct contributions to different aspects or at different stages of the initiation, progression and metastasis of the same cancer.	('genetic alterations', 'Var', (35, 54))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('alterations', 'Var', (43, 54))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
518914	30294322	In particular, consistent with the high frequency of TRAF3 deletions and mutations in HPV+ HNSCC, overexpression of TRAF3 inhibits the growth, migration and chemoresistance of HPV+ HNSCC by decreasing HPV E6 oncoprotein and increasing p53 and RB tumor suppressors.	('deletions', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('chemoresistance', 'CPA', (157, 172))	('RB tumor', 'Disease', (243, 251))	('growth', 'CPA', (135, 141))	('HPV', 'Species', '10566', (201, 204))	('HPV E6 oncoprotein', 'Protein', (201, 219))	('HPV', 'Species', '10566', (176, 179))	('p53', 'Gene', '7157', (235, 238))	('decreasing', 'NegReg', (190, 200))	('HPV', 'Species', '10566', (86, 89))	('TRAF3', 'Gene', (53, 58))	('inhibits', 'NegReg', (122, 130))	('HPV+ HNSCC', 'Gene', (86, 96))	('RB tumor', 'Disease', 'MESH:D012175', (243, 251))	('TRAF3', 'Gene', (116, 121))	('increasing', 'PosReg', (224, 234))	('p53', 'Gene', (235, 238))	('mutations', 'Var', (73, 82))
518918	30294322	Specific deletion of TRAF3 from myeloid cells leads to development of B lymphomas and liver cancer in mice.	('mice', 'Species', '10090', (102, 106))	('B lymphoma', 'Phenotype', 'HP:0012191', (70, 80))	('deletion', 'Var', (9, 17))	('B lymphomas', 'Phenotype', 'HP:0012191', (70, 81))	('liver cancer', 'Phenotype', 'HP:0002896', (86, 98))	('lymphomas', 'Phenotype', 'HP:0002665', (72, 81))	('TRAF3', 'Gene', (21, 26))	('B lymphomas and liver cancer', 'Disease', 'MESH:D006528', (70, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))
518919	30294322	Similarly, lymphocyte-specific TRAF3 transgenic mice develop autoimmunity, inflammation and cancers (such as squamous cell carcinomas of the tongue, salivary gland tumors, and hepatoma).	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (109, 133))	('salivary gland tumors', 'Disease', (149, 170))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (109, 133))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('hepatoma', 'Disease', 'MESH:D006528', (176, 184))	('squamous cell carcinomas of the tongue', 'Phenotype', 'HP:0030413', (109, 147))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('autoimmunity', 'Disease', (61, 73))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('develop', 'PosReg', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('squamous cell carcinomas', 'Disease', (109, 133))	('transgenic', 'Var', (37, 47))	('inflammation', 'Disease', (75, 87))	('transgenic mice', 'Species', '10090', (37, 52))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('salivary gland tumors', 'Disease', 'MESH:D008949', (149, 170))	('autoimmunity', 'Disease', 'MESH:D001327', (61, 73))	('TRAF3', 'Gene', (31, 36))	('autoimmunity', 'Phenotype', 'HP:0002960', (61, 73))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('hepatoma', 'Disease', (176, 184))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (149, 170))	('cancers', 'Disease', (92, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))
518926	30294322	In this article, we have analyzed the current evidence of genetic alterations of the TRAF family in human cancers.	('human', 'Species', '9606', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('genetic alterations', 'Var', (58, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
518927	30294322	The results revealed that genetic alterations of all seven TRAF genes are present in various human cancers and that recurrent mutations of each TRAF gene have been detected in cancer patients.	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Disease', (99, 105))	('cancers', 'Disease', (99, 106))	('genetic alterations', 'Var', (26, 45))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (183, 191))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('TRAF genes', 'Gene', (59, 69))	('detected', 'Reg', (164, 172))	('present', 'Reg', (74, 81))
518928	30294322	In particular, loss-of-function genetic alterations of TRAF2 and TRAF3 are frequently detected in B cell malignancies, and the rates of missense mutations of TRAF7 are overwhelmingly high in adenomatoid tumors, secretory meningiomas and perineuriomas.	('TRAF2', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('missense mutations', 'Var', (136, 154))	('meningiomas and perineuriomas', 'Disease', 'MESH:D018317', (221, 250))	('meningioma', 'Phenotype', 'HP:0002858', (221, 231))	('B cell malignancies', 'Disease', 'MESH:D015448', (98, 117))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('genetic alterations', 'Var', (32, 51))	('B cell malignancies', 'Disease', (98, 117))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (191, 209))	('adenomatoid tumors', 'Disease', (191, 209))	('TRAF3', 'Gene', (65, 70))	('TRAF7', 'Gene', (158, 163))	('meningiomas', 'Phenotype', 'HP:0002858', (221, 232))	('loss-of-function', 'NegReg', (15, 31))
518929	30294322	Gain-of-function alterations (gene amplification and overexpression) are common for TRAF1, TRAF4, TRAF5, and TRAF6 in human cancers, and are also identified for TRAF2 in epithelial cancers.	('TRAF4', 'Gene', (91, 96))	('TRAF5', 'Gene', (98, 103))	('cancers', 'Disease', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('TRAF1', 'Gene', (84, 89))	('overexpression', 'PosReg', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Gain-of-function', 'PosReg', (0, 16))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('human', 'Species', '9606', (118, 123))	('TRAF6', 'Gene', (109, 114))	('alterations', 'Var', (17, 28))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
518930	30294322	Corroborating human evidence, direct causal roles of TRAF genetic alterations (except TRAF7) in tumorigenesis have been demonstrated in vivo with genetically engineered mouse models that have each TRAF gene deleted or overexpressed in specific cell types.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('human', 'Species', '9606', (14, 19))	('TRAF', 'Gene', (53, 57))	('tumor', 'Disease', (96, 101))	('mouse', 'Species', '10090', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('genetic alterations', 'Var', (58, 77))
518931	30294322	Importantly, however, the functional significance of most TRAF point mutations identified in human cancers remains to be assessed in future studies.	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('point mutations', 'Var', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TRAF', 'Gene', (58, 62))
518942	29371919	NU7441 increased the cytotoxicity of etoposide, doxorubicin and radiation.	('increased', 'PosReg', (7, 16))	('cytotoxicity', 'Disease', (21, 33))	('doxorubicin', 'MPA', (48, 59))	('etoposide', 'Chemical', 'MESH:D005047', (37, 46))	('radiation', 'CPA', (64, 73))	('NU7441', 'Chemical', 'MESH:C499693', (0, 6))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('doxorubicin', 'Chemical', 'MESH:D004317', (48, 59))	('NU7441', 'Var', (0, 6))
518955	29371919	Homologous recombination repair (HRR) and non-homologous end joining (NHEJ) repair DSB lesions, with NHEJ being the most important repair pathway in the G0 and G1 phase of the cell cycle.	('DSB', 'Disease', (83, 86))	('DSB', 'Chemical', '-', (83, 86))	('lesions', 'Var', (87, 94))
518960	29371919	Inhibitors of PARP1 have been shown to increase the antitumor activity of temozolomide and topotecan in preclinical studies, including models of pediatric cancers.	('PARP1', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (56, 61))	('Inhibitors', 'Var', (0, 10))	('increase', 'PosReg', (39, 47))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('pediatric cancers', 'Disease', 'MESH:D009369', (145, 162))	('pediatric cancers', 'Disease', (145, 162))	('temozolomide', 'Chemical', 'MESH:D000077204', (74, 86))	('PARP1', 'Gene', '142', (14, 19))	('topotecan', 'Chemical', 'MESH:D019772', (91, 100))
518964	29371919	Ewing sarcoma (ES) cells are characterized by translocations involving the EWS gene from chromosome 22 and a member of the ETS family of transcription factors, most commonly the FLI1 gene on chromosome 11.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('FLI1', 'Gene', '2313', (178, 182))	('FLI1', 'Gene', (178, 182))	('Ewing sarcoma', 'Disease', (0, 13))	('translocations', 'Var', (46, 60))	('EWS', 'Gene', '2130', (75, 78))	('EWS', 'Gene', (75, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))
518967	29371919	In 2012, cells harboring the EWS-FLI1 translocation have been characterized as being particularly sensitive to PARP-inhibition by a high-throughput screening approach, and ES cells and xenografts were sensitive to the PARP-inhibitor olaparib.	('sensitive', 'Reg', (98, 107))	('translocation', 'Var', (38, 51))	('EWS-FLI1', 'Gene', (29, 37))	('EWS-FLI1', 'Gene', '2130;2313', (29, 37))	('olaparib', 'Chemical', 'MESH:C531550', (233, 241))	('PARP-inhibition', 'MPA', (111, 126))
519007	29371919	Temozolomide was slightly more cytotoxic in DNA-PK deficient V3 cells, but the DRF was only 1.6.	('more', 'PosReg', (26, 30))	('cytotoxic', 'CPA', (31, 40))	('DNA-PK', 'Gene', '5591', (44, 50))	('deficient', 'Var', (51, 60))	('DNA-PK', 'Gene', (44, 50))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
519011	29371919	After DSB induction by ionizing radiation (10 Gy), there was a strong increase in signal intensity of phosphorylated DNA-PK at serine2056; a marker for DNA-PK activation.	('serine2056', 'Var', (127, 137))	('serine2056', 'Chemical', '-', (127, 137))	('DNA-PK', 'Gene', (117, 123))	('increase', 'PosReg', (70, 78))	('signal intensity', 'MPA', (82, 98))	('DSB', 'Chemical', '-', (6, 9))	('DNA-PK', 'Gene', '5591', (117, 123))	('DNA-PK', 'Gene', (152, 158))	('DNA-PK', 'Gene', '5591', (152, 158))	('Gy', 'Chemical', 'MESH:C022013', (46, 48))
519012	29371919	In both cell lines, co-treatment of the cells with NU7441 revealed inhibition of DNA-PK activity in a concentration dependent manner, with a maximal inhibition at 1.0 microM NU7441 in both cell lines (Figure 1D).	('DNA-PK', 'Gene', '5591', (81, 87))	('inhibition', 'NegReg', (67, 77))	('NU7441', 'Var', (51, 57))	('NU7441', 'Chemical', 'MESH:C499693', (174, 180))	('activity', 'MPA', (88, 96))	('rat', 'Species', '10116', (109, 112))	('NU7441', 'Chemical', 'MESH:C499693', (51, 57))	('DNA-PK', 'Gene', (81, 87))	('NU7441', 'Var', (174, 180))
519014	29371919	Using standard clonogenic assays on TC-71 and VH-64 cells, NU7441 alone was not toxic at 1.0 muM.	('TC-71', 'CellLine', 'CVCL:2213', (36, 41))	('NU7441', 'Var', (59, 65))	('muM', 'Gene', '56925', (93, 96))	('muM', 'Gene', (93, 96))	('NU7441', 'Chemical', 'MESH:C499693', (59, 65))	('VH-64', 'CellLine', 'CVCL:9672', (46, 51))
519015	29371919	In TC-71 cells, the NU7441 LD50 was 12 muM (n = 5 clonogenic assays, Figure 5A, left panel), and in VH-64 cells the LD50 was 16 muM (n = 1 clonogenic assay).	('muM', 'Gene', '56925', (39, 42))	('muM', 'Gene', (39, 42))	('NU7441', 'Chemical', 'MESH:C499693', (20, 26))	('muM', 'Gene', '56925', (128, 131))	('TC-71', 'CellLine', 'CVCL:2213', (3, 8))	('muM', 'Gene', (128, 131))	('VH-64', 'CellLine', 'CVCL:9672', (100, 105))	('NU7441', 'Var', (20, 26))
519016	29371919	As predicted from the data presented in Supplementary Figure 3, NU7441 markedly potentiated the cytotoxicity of doxorubicin, etoposide and ionizing radiation when used at 1 muM (Figure 5A).	('muM', 'Gene', (173, 176))	('ionizing', 'CPA', (139, 147))	('NU7441', 'Chemical', 'MESH:C499693', (64, 70))	('etoposide', 'Chemical', 'MESH:D005047', (125, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (96, 108))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('muM', 'Gene', '56925', (173, 176))	('cytotoxicity', 'Disease', (96, 108))	('NU7441', 'Var', (64, 70))	('potentiated', 'PosReg', (80, 91))
519017	29371919	NU7441 enhanced the cytotoxicity of doxorubicin 2-fold at the LD50 concentration (doxorubicin alone: LD50 = 12-13 nM; doxorubicin with 1 muM NU7441 LD50 = 6 nM), and for both cell lines this effect was highly significant (2-way ANOVA p = 0.0008 for TC-71, p < 0.0001 for VH-64 cells).	('muM', 'Gene', '56925', (137, 140))	('doxorubicin', 'Chemical', 'MESH:D004317', (36, 47))	('TC-71', 'CellLine', 'CVCL:2213', (249, 254))	('muM', 'Gene', (137, 140))	('doxorubicin', 'Chemical', 'MESH:D004317', (82, 93))	('cytotoxicity', 'Disease', (20, 32))	('rat', 'Species', '10116', (74, 77))	('enhanced', 'PosReg', (7, 15))	('NU7441', 'Chemical', 'MESH:C499693', (141, 147))	('NU7441', 'Chemical', 'MESH:C499693', (0, 6))	('cytotoxicity', 'Disease', 'MESH:D064420', (20, 32))	('VH-64', 'CellLine', 'CVCL:9672', (271, 276))	('NU7441', 'Var', (0, 6))	('doxorubicin', 'Chemical', 'MESH:D004317', (118, 129))
519018	29371919	Potentiation of etoposide cytotoxicity by NU7441 was even greater (3-7 fold), with LD50 values for etoposide alone being 0.1 muM in VH-64 and 0.28 muM in TC-71 cells, reduced to 0.04 muM by NU7441, the effect again being highly significant in both cell lines (2-way ANOVA p < 0.0001).	('VH-64', 'CellLine', 'CVCL:9672', (132, 137))	('TC-71', 'CellLine', 'CVCL:2213', (154, 159))	('cytotoxicity', 'Disease', (26, 38))	('muM', 'Gene', (147, 150))	('muM', 'Gene', '56925', (183, 186))	('NU7441', 'Chemical', 'MESH:C499693', (42, 48))	('etoposide', 'Chemical', 'MESH:D005047', (16, 25))	('muM', 'Gene', '56925', (125, 128))	('muM', 'Gene', (183, 186))	('muM', 'Gene', (125, 128))	('etoposide', 'Chemical', 'MESH:D005047', (99, 108))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('NU7441', 'Chemical', 'MESH:C499693', (190, 196))	('muM', 'Gene', '56925', (147, 150))	('NU7441', 'Var', (42, 48))
519019	29371919	In addition, NU7441 potentiated the effects of ionizing radiation in both cell lines, causing a 3-fold reduction in cell survival (ionizing radiation alone LD50 = 1.0-1.3 Gy, ionizing radiation in presence of NU7441 LD50 = 0.36-0.4 Gy; 2-way ANOVA p < 0.0001).	('Gy', 'Chemical', 'MESH:C022013', (171, 173))	('NU7441', 'Chemical', 'MESH:C499693', (13, 19))	('NU7441', 'Chemical', 'MESH:C499693', (209, 215))	('NU7441', 'Var', (209, 215))	('reduction', 'NegReg', (103, 112))	('NU7441', 'Var', (13, 19))	('Gy', 'Chemical', 'MESH:C022013', (232, 234))	('cell survival', 'CPA', (116, 129))
519021	29371919	Dysregulation of the DNA damage response has emerged over the past decade as both a contributor to genomic instability and thus carcinogenesis, but also as a possible therapeutic opportunity, either for overcoming drug resistance or for exploiting synthetic lethality.	('carcinogenesis', 'Disease', (128, 142))	('contributor', 'Reg', (84, 95))	('Dysregulation', 'Var', (0, 13))	('drug resistance', 'Phenotype', 'HP:0020174', (214, 229))	('genomic instability', 'CPA', (99, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (128, 142))
519024	29371919	Pilot data in DNA-PKcs deficient and proficient cells demonstrated that sensitivity to both ionizing radiation and drugs commonly used in treatment strategies for Ewing sarcoma (doxorubicin, etoposide) was greater in the DNA-PKcs deficient cells (Supplementary Figure 1).	('greater', 'PosReg', (206, 213))	('DNA-PKcs', 'Gene', (14, 22))	('DNA-PKcs', 'Gene', '5591', (221, 229))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (163, 176))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (163, 176))	('sensitivity to', 'MPA', (72, 86))	('deficient', 'Var', (230, 239))	('DNA-PKcs', 'Gene', (221, 229))	('rat', 'Species', '10116', (150, 153))	('rat', 'Species', '10116', (61, 64))	('etoposide', 'Chemical', 'MESH:D005047', (191, 200))	('doxorubicin', 'Chemical', 'MESH:D004317', (178, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('Ewing sarcoma', 'Disease', (163, 176))	('DNA-PKcs', 'Gene', '5591', (14, 22))
519025	29371919	Inhibitors of DNA-PKcs have been used in vitro in colon cancer models and CLL blasts to enhance sensitivity to radio- and chemo-therapeutic treatments, but pediatric malignancies so far have not been studied.	('DNA-PKcs', 'Gene', (14, 22))	('colon cancer', 'Disease', 'MESH:D015179', (50, 62))	('colon cancer', 'Disease', (50, 62))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('malignancies', 'Disease', 'MESH:D009369', (166, 178))	('colon cancer', 'Phenotype', 'HP:0003003', (50, 62))	('DNA-PKcs', 'Gene', '5591', (14, 22))	('malignancies', 'Disease', (166, 178))	('enhance', 'PosReg', (88, 95))
519026	29371919	The inhibitor NU7441 has improved potency and specificity over its predecessors NU7026 and LY294002, with an IC50 of 14 nM and a > 100 fold specificity for DNA-PK over other PI3 kinase family members.	('improved', 'PosReg', (25, 33))	('NU7441', 'Chemical', 'MESH:C499693', (14, 20))	('NU7441', 'Var', (14, 20))	('NU7026', 'Chemical', 'MESH:C479235', (80, 86))	('LY294002', 'Chemical', 'MESH:C085911', (91, 99))	('LY294002', 'Var', (91, 99))	('potency', 'MPA', (34, 41))	('DNA-PK', 'Gene', (156, 162))	('specificity', 'MPA', (46, 57))	('DNA-PK', 'Gene', '5591', (156, 162))
519027	29371919	The expression and activity of DNA-PKcs was confirmed in ES cell lines, and concentration dependent inhibition by NU7441 was demonstrated.	('rat', 'Species', '10116', (83, 86))	('rat', 'Species', '10116', (132, 135))	('NU7441', 'Var', (114, 120))	('DNA-PKcs', 'Gene', '5591', (31, 39))	('activity', 'MPA', (19, 27))	('inhibition', 'NegReg', (100, 110))	('NU7441', 'Chemical', 'MESH:C499693', (114, 120))	('DNA-PKcs', 'Gene', (31, 39))
519028	29371919	In in vitro assays, NU7441 was shown to sensitize ES cells to etoposide, doxorubicin and ionizing radiation with DRF50 values of 2.7-6.7, 2.1-2.2 and 2.8-3.4, respectively, all combinations being significantly different to the respective DNA-damaging agent alone in 2-sided ANOVA analyses.	('etoposide', 'Chemical', 'MESH:D005047', (62, 71))	('NU7441', 'Chemical', 'MESH:C499693', (20, 26))	('sensitize', 'Reg', (40, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (73, 84))	('NU7441', 'Var', (20, 26))
519029	29371919	There are currently two DNA-PK inhibitors (MSC2490484A: DNA-PK inhibitor, trials NCT02316197 and NCT02516813; CC-115: dual DNA-PK and TOR kinase inhibitor, trial NCT01353625) undergoing testing in Phase I clinical trials in adult patients, including those with Ewing sarcoma, as single agents and for MSC2490484A also as a radio-/chemo-sensitizing agent.	('DNA-PK', 'Gene', (123, 129))	('DNA-PK', 'Gene', '5591', (24, 30))	('DNA-PK', 'Gene', (56, 62))	('DNA-PK', 'Gene', '5591', (123, 129))	('DNA-PK', 'Gene', '5591', (56, 62))	('Ewing sarcoma', 'Disease', (261, 274))	('patients', 'Species', '9606', (230, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (267, 274))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (261, 274))	('DNA-PK', 'Gene', (24, 30))	('MSC2490484A', 'Var', (301, 312))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (261, 274))
519045	29371919	NCT01858168, NCT02392793); however, systemic toxicity, especially myelosuppression, is anticipated.	('myelosuppression', 'Disease', (66, 82))	('toxicity', 'Disease', 'MESH:D064420', (45, 53))	('toxicity', 'Disease', (45, 53))	('myelosuppression', 'Disease', 'MESH:D001855', (66, 82))	('NCT02392793', 'Var', (13, 24))
519053	29371919	The DNA-PK inhibitor NU7441 was synthesized at the Northern Institute for Cancer Research as described previously and dissolved at 2 mM in DMSO.	('NU7441', 'Var', (21, 27))	('DMSO', 'Chemical', 'MESH:D004121', (139, 143))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))	('DNA-PK', 'Gene', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('NU7441', 'Chemical', 'MESH:C499693', (21, 27))	('DNA-PK', 'Gene', '5591', (4, 10))
519098	29371919	daily x5 for 6 cycles was selected as it had been well tolerated previously and had shown significant delays in tumor growth in a BRCA1 and BRCA2 mutated mouse models.	('mouse', 'Species', '10090', (154, 159))	('BRCA1', 'Gene', (130, 135))	('mutated', 'Var', (146, 153))	('delays', 'NegReg', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('BRCA2', 'Gene', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('rat', 'Species', '10116', (59, 62))	('tumor', 'Disease', (112, 117))
519100	29371919	ATCC American Type Culture Collection BER Base excision repair BRCA Breast Cancer CLL Chronic lymphocytic leukemia DMEM Dulbecco's Modified Eagle's Medium DMSO Dimethylsulfonic acid DNA Deoxyribonucleic acid DNAPK DNA dependent protein kinase DNA-PKcs DNA dependent protein kinase catalytic subunit DRF50 Dose reduction factor ratio of two LD50 results (cells treated with cytotoxic alone and corresponding cells treated with cytotoxic plus inhibitor) DSB DNA-double strand breaks gammaH2AX phosphorylated histone H2AX EFS Event-free survival e.g.	('Chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (86, 114))	('histone H2AX', 'Gene', '3014', (506, 518))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rat', 'Species', '10116', (327, 330))	('BRCA', 'Gene', (63, 67))	('Dimethylsulfonic acid', 'Chemical', '-', (160, 181))	('DMEM', 'Chemical', '-', (115, 119))	('Breast Cancer', 'Disease', 'MESH:D001943', (68, 81))	('Chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (86, 114))	('DNA-PKcs', 'Gene', '5591', (243, 251))	('Breast Cancer', 'Disease', (68, 81))	('gammaH2AX', 'Var', (481, 490))	('Breast Cancer', 'Phenotype', 'HP:0003002', (68, 81))	('Chronic lymphocytic leukemia', 'Disease', (86, 114))	('DMSO', 'Chemical', 'MESH:D004121', (155, 159))	("Dulbecco's Modified Eagle's Medium", 'Chemical', '-', (120, 154))	('DSB', 'Chemical', '-', (452, 455))	('gammaH2AX', 'Chemical', '-', (481, 490))	('BRCA', 'Gene', '672', (63, 67))	('histone H2AX', 'Gene', (506, 518))	('leukemia', 'Phenotype', 'HP:0001909', (106, 114))	('DNA-PKcs', 'Gene', (243, 251))
519254	33405052	There are two genetic types, CTNNB1 mutations and FAP mutations.	('FAP', 'Gene', (50, 53))	('CTNNB1', 'Gene', '1499', (29, 35))	('mutations', 'Var', (36, 45))	('CTNNB1', 'Gene', (29, 35))	('FAP', 'Gene', '2191', (50, 53))
519291	32087612	Diagnosis of RMS was based on morphology and both desmin and myogenin positivity on immunohistochemistry (IHC).	('RMS', 'Phenotype', 'HP:0002859', (13, 16))	('myogenin', 'Gene', '4656', (61, 69))	('desmin', 'Gene', '1674', (50, 56))	('positivity', 'Var', (70, 80))	('desmin', 'Gene', (50, 56))	('myogenin', 'Gene', (61, 69))	('RMS', 'Disease', (13, 16))
519303	32087612	Two additional poorly differentiated tumors, initially diagnosed as ERMS (positive for both desmin and myogenin), were reviewed as MRT with SMARCB1/INI1 loss on IHC and confirmed SMARCB1/INI1 mutation on RNAseq (Figure 1).	('INI1', 'Gene', '6598', (187, 191))	('RMS', 'Phenotype', 'HP:0002859', (69, 72))	('myogenin', 'Gene', '4656', (103, 111))	('SMARCB1', 'Gene', (140, 147))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('SMARCB1', 'Gene', '6598', (179, 186))	('SMARCB1', 'Gene', '6598', (140, 147))	('desmin', 'Gene', (92, 98))	('SMARCB1', 'Gene', (179, 186))	('mutation', 'Var', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('desmin', 'Gene', '1674', (92, 98))	('loss', 'NegReg', (153, 157))	('INI1', 'Gene', (187, 191))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('myogenin', 'Gene', (103, 111))	('INI1', 'Gene', '6598', (148, 152))	('INI1', 'Gene', (148, 152))
519307	32087612	These easily recognized tumors were suspected to harbor a VGLL2 rearrangement.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('VGLL2', 'Gene', '245806', (58, 63))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('VGLL2', 'Gene', (58, 63))	('rearrangement', 'Var', (64, 77))
519314	32087612	One additional FOXO1-negative ARMS had PAX3-positive rearrangement on FISH but no gene fusion was diagnosed on RNAseq.	('PAX3', 'Gene', '5077', (39, 43))	('rearrangement', 'Var', (53, 66))	('RMS', 'Phenotype', 'HP:0002859', (31, 34))	('PAX3', 'Gene', (39, 43))	('FOXO1', 'Gene', (15, 20))	('FOXO1', 'Gene', '2308', (15, 20))
519315	32087612	Among the eight SRMS, all three "fibromatous-like" SRMS had VGLL2-related fusion, with NCOA2 (n = 2) or CITED2 partner (n = 1).	('fusion', 'Var', (74, 80))	('RMS', 'Phenotype', 'HP:0002859', (17, 20))	('VGLL2', 'Gene', (60, 65))	('NCOA2', 'Gene', '10499', (87, 92))	('CITED2', 'Gene', (104, 110))	('RMS', 'Phenotype', 'HP:0002859', (52, 55))	('NCOA2', 'Gene', (87, 92))	('CITED2', 'Gene', '10370', (104, 110))	('VGLL2', 'Gene', '245806', (60, 65))
519316	32087612	Three "fibrosarcoma-like" SRMS presented three rearranged genes previously described in other sarcomas: TPM3-NTRK1, SYPL1-BRAF, and TOP2B-RAF1.	('TPM3', 'Gene', '7170', (104, 108))	('RAF1', 'Gene', '5894', (138, 142))	('RMS', 'Phenotype', 'HP:0002859', (27, 30))	('rearranged', 'Var', (47, 57))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('RAF1', 'Gene', (138, 142))	('TPM3', 'Gene', (104, 108))	('sarcomas', 'Disease', (94, 102))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (7, 19))	('SYPL1', 'Gene', (116, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('fibrosarcoma', 'Disease', 'MESH:D005354', (7, 19))	('BRAF', 'Gene', '673', (122, 126))	('NTRK1', 'Gene', '4914', (109, 114))	('BRAF', 'Gene', (122, 126))	('TOP2B', 'Gene', '7155', (132, 137))	('fibrosarcoma', 'Disease', (7, 19))	('SYPL1', 'Gene', '6856', (116, 121))	('NTRK1', 'Gene', (109, 114))	('TOP2B', 'Gene', (132, 137))
519319	32087612	Two out the three "rhabdomyoma-like" ERMS had PTCH1 deletion on CGH array, including one with unknown BANZ1-FANCC fusion.	('FANCC', 'Gene', (108, 113))	('rhabdomyoma', 'Disease', (19, 30))	('PTCH1', 'Gene', '5727', (46, 51))	('FANCC', 'Gene', '2176', (108, 113))	('RMS', 'Phenotype', 'HP:0002859', (38, 41))	('rhabdomyoma', 'Phenotype', 'HP:0009730', (19, 30))	('rhabdomyoma', 'Disease', 'MESH:D012207', (19, 30))	('PTCH1', 'Gene', (46, 51))	('deletion', 'Var', (52, 60))
519322	32087612	Except for one SRMS with VGLL2 fusion identified on frozen sample and not in FFPE sample, there were no discrepancies in results from the analysis of FFPE and frozen specimens.	('fusion', 'Var', (31, 37))	('RMS', 'Phenotype', 'HP:0002859', (16, 19))	('VGLL2', 'Gene', '245806', (25, 30))	('VGLL2', 'Gene', (25, 30))
519325	32087612	The group 1 was composed of the ARMS (2/19, 10%), the group 2 contained ERMS (5/19, 26%), the group 3, the "VGLL2-fusion" cluster, consisted of all six SRMS and six ERMS (including the two RMS with PTCH1 deletion).	('deletion', 'Var', (204, 212))	('RMS', 'Phenotype', 'HP:0002859', (189, 192))	('RMS', 'Phenotype', 'HP:0002859', (153, 156))	('PTCH1', 'Gene', '5727', (198, 203))	('VGLL2', 'Gene', '245806', (108, 113))	('RMS', 'Phenotype', 'HP:0002859', (166, 169))	('RMS', 'Phenotype', 'HP:0002859', (73, 76))	('RMS', 'Phenotype', 'HP:0002859', (33, 36))	('PTCH1', 'Gene', (198, 203))	('VGLL2', 'Gene', (108, 113))
519349	32087612	Spindle cell/sclerosing RMS have been redefined in the WHO 2013 classification as a stand-alone pathologic entity, distinct from ERMS.22 However, the definition criteria of SRMS are not consensual, because "spindle cells" are observed in different types of RMS-like ERMS, RMS with VGLL2 rearrangement or with MyoD1 mutation.	('RMS-like', 'Disease', (257, 265))	('VGLL2', 'Gene', (281, 286))	('RMS', 'Phenotype', 'HP:0002859', (257, 260))	('MyoD1', 'Gene', (309, 314))	('MyoD1', 'Gene', '4654', (309, 314))	('RMS', 'Phenotype', 'HP:0002859', (130, 133))	('mutation', 'Var', (315, 323))	('RMS', 'Phenotype', 'HP:0002859', (24, 27))	('VGLL2', 'Gene', '245806', (281, 286))	('RMS', 'Phenotype', 'HP:0002859', (267, 270))	('rearrangement', 'Var', (287, 300))	('RMS', 'Phenotype', 'HP:0002859', (174, 177))
519359	32087612	Notably, we observed a significant number of early progressions (11%) when compared with RMS in older patients (2%).38 All occurred in fusion-negative non-highly differentiated ERMS and despite intensive chemotherapy, lead to death.	('RMS', 'Phenotype', 'HP:0002859', (178, 181))	('RMS', 'Phenotype', 'HP:0002859', (89, 92))	('lead to', 'Reg', (218, 225))	('death', 'Disease', 'MESH:D003643', (226, 231))	('death', 'Disease', (226, 231))	('patients', 'Species', '9606', (102, 110))	('non-highly', 'Var', (151, 161))	('occurred', 'Reg', (123, 131))
519369	32087612	In conclusion, biopathology findings of our work support the different prognosis of this heterogeneous population of infantile RMS with VGLL2 rearranged SRMS having a very good outcome while ARMS but also ERMS having a clinically aggressive course.	('RMS', 'Phenotype', 'HP:0002859', (192, 195))	('rearranged', 'Var', (142, 152))	('RMS', 'Phenotype', 'HP:0002859', (127, 130))	('VGLL2', 'Gene', (136, 141))	('RMS', 'Phenotype', 'HP:0002859', (206, 209))	('infantile RMS', 'Disease', (117, 130))	('RMS', 'Phenotype', 'HP:0002859', (154, 157))	('VGLL2', 'Gene', '245806', (136, 141))
519370	32087612	Fusion-positive SRMS appear to behave as intermediate malignancy tumor and may benefit from more conservative strategies in the future.	('malignancy tumor', 'Disease', 'MESH:D009369', (54, 70))	('SRMS', 'Disease', (16, 20))	('RMS', 'Phenotype', 'HP:0002859', (17, 20))	('Fusion-positive', 'Var', (0, 15))	('malignancy tumor', 'Disease', (54, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
519521	27148438	Tumours cause local destruction of bone and may be associated with a soft tissue mass or pathological fracture.	('fracture', 'Disease', (102, 110))	('destruction of bone', 'Phenotype', 'HP:0002797', (20, 39))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('soft tissue mass', 'Phenotype', 'HP:0031459', (69, 85))	('pathological fracture', 'Phenotype', 'HP:0002756', (89, 110))	('Tumours', 'Var', (0, 7))	('local destruction of bone', 'CPA', (14, 39))	('associated', 'Reg', (51, 61))	('soft', 'Disease', (69, 73))	('fracture', 'Disease', 'MESH:D050723', (102, 110))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
519617	27148438	Amputation may still be indicated if tumours fail to show a radiological response and/or resection of the tumour and the contaminated area cannot safely leave a useful limb.	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumour', 'Disease', (37, 43))	('tumours', 'Disease', 'MESH:D009369', (37, 44))	('tumours', 'Disease', (37, 44))	('tumour', 'Disease', (106, 112))	('resection', 'Var', (89, 98))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
519636	27148438	Impaired renal function can cause delayed clearance of methotrexate resulting in mucositis and nephrotoxicity and therefore close monitoring is required.	('methotrexate', 'Chemical', 'MESH:D008727', (55, 67))	('clearance', 'MPA', (42, 51))	('nephrotoxicity', 'Disease', (95, 109))	('mucositis', 'Disease', (81, 90))	('nephrotoxicity', 'Disease', 'MESH:D007674', (95, 109))	('Impaired', 'Var', (0, 8))	('mucositis', 'Disease', 'MESH:D052016', (81, 90))
519649	27148438	18FDG PET is more reliable than standard imaging in evaluating response to neoadjuvant chemotherapy in craniofacial bone sarcomas and may correlate better with outcome than histological response.	('18FDG PET', 'Var', (0, 9))	('craniofacial bone sarcomas', 'Disease', (103, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('craniofacial bone sarcomas', 'Disease', 'MESH:D019465', (103, 129))	('bone sarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('18FDG', 'Chemical', 'MESH:D019788', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('bone sarcomas', 'Phenotype', 'HP:0002669', (116, 129))
519761	24672293	Our hypothesis is that systemic delivery of VSVDeltaM51 can demonstrate tumor-specific killing of resistant EWS cells, as well as a significant decrease of tumor burden in EWS bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EWS', 'Phenotype', 'HP:0012254', (108, 111))	('tumor', 'Disease', (72, 77))	('decrease', 'NegReg', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('VSVDeltaM51', 'Var', (44, 55))	('mice', 'Species', '10090', (184, 188))	('EWS', 'Phenotype', 'HP:0012254', (172, 175))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
519764	24672293	EWS xenograft mice model bearing either lung or subcutaneous tumors was established to evaluate the antitumor specific oncolytic effect of VSVDeltaM51 after local and systemic delivery.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('subcutaneous tumors', 'Disease', (48, 67))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', (104, 109))	('VSVDeltaM51', 'Var', (139, 150))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (48, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('EWS', 'Phenotype', 'HP:0012254', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (48, 67))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
519766	24672293	In vivo, VSVDeltaM51 selectively infected and killed EWS and led to significant delay in tumor growth.	('VSVDeltaM51', 'Var', (9, 20))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('EWS', 'Phenotype', 'HP:0012254', (53, 56))	('delay', 'NegReg', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
519777	24672293	Over 85% of EWS cells possess an aberrant chromosomal translocation involving chromosomes 11 and 22, which produces the oncogenic chimeric fusion protein EWS/FLI1.	('FLI1', 'Gene', '2313', (158, 162))	('EWS', 'Phenotype', 'HP:0012254', (12, 15))	('EWS', 'Phenotype', 'HP:0012254', (154, 157))	('produces', 'Reg', (107, 115))	('chromosomal translocation', 'Var', (42, 67))	('FLI1', 'Gene', (158, 162))
519817	24672293	Confirmed tumor cultures were then washed with PBS, and VSVDeltaM51 was diluted in PBS in multiplicity of infection (MOI) ratios of 1, 0.1 and 0.01, and was allowed to incubate at 37 C for 45 minutes prior to the addition of 10 mL of DMEM with 10% FBS.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('DMEM', 'Chemical', '-', (234, 238))	('infection', 'Disease', 'MESH:D007239', (106, 115))	('FBS', 'Disease', (248, 251))	('VSVDeltaM51', 'Var', (56, 67))	('tumor', 'Disease', (10, 15))	('PBS', 'Chemical', '-', (47, 50))	('FBS', 'Disease', 'MESH:D005198', (248, 251))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('PBS', 'Chemical', '-', (83, 86))	('infection', 'Disease', (106, 115))
519819	24672293	To confirm CD99 expression, cells were incubated with CD99 polyclonal antibody conjugated to fluorescein or corresponding isotype control and processed through a Fluorescent Activated Cell Sorter (FACS) (R&D Systems Catalog number FAB3968F, or isotype control Catalog number IC108F).	('CD99', 'Gene', (54, 58))	('number', 'Var', (224, 230))	('CD99', 'Gene', '4267', (11, 15))	('fluorescein', 'Chemical', 'MESH:D019793', (93, 104))	('CD99', 'Gene', '4267', (54, 58))	('CD99', 'Gene', (11, 15))
519848	24672293	To determine the susceptibility of EWS cells to VSVDeltaM51 infection, a representative tissue sample obtained from the patient's proximal humerus lesion was incubated with VSVDeltaM51 encoding the green fluorescent protein (GFP) gene.	('VSVDeltaM51', 'Var', (173, 184))	('patient', 'Species', '9606', (120, 127))	('VSVDeltaM51 infection', 'Disease', 'MESH:D007239', (48, 69))	('VSVDeltaM51 infection', 'Disease', (48, 69))	('EWS', 'Phenotype', 'HP:0012254', (35, 38))
519855	24672293	VSVDeltaM51 encoding red fluorescent protein, RFP, was used to monitor its replication.	('red fluorescent protein', 'Gene', (21, 44))	('RFP', 'Gene', '5987', (46, 49))	('RFP', 'Gene', (46, 49))	('VSVDeltaM51', 'Var', (0, 11))	('red fluorescent protein', 'Gene', '5987', (21, 44))
519859	24672293	Using trypan blue, a quantitative assay was used to measure the amount of tumor cell death caused by VSVDeltaM51 at various time points.	('trypan blue', 'Chemical', 'MESH:D014343', (6, 17))	('VSVDeltaM51', 'Var', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor cell death', 'Disease', (74, 90))	('tumor cell death', 'Disease', 'MESH:D003643', (74, 90))
519867	24672293	These results provide a proof of principle that VSVDeltaM51 is able to selectively infect and replicate at the tumor site despite its systemic administration.	('VSVDeltaM51', 'Var', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('infect', 'Reg', (83, 89))
519868	24672293	Microperfusion studies performed on subcutaneous tumors harvested from VSVDeltaM51 treated mice also indicated profound loss of blood flow to the tumor (Figure 6(b)).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mice', 'Species', '10090', (91, 95))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (36, 55))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('blood flow', 'MPA', (128, 138))	('VSVDeltaM51', 'Var', (71, 82))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (36, 55))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('loss', 'NegReg', (120, 124))	('subcutaneous tumors', 'Disease', (36, 55))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
519870	24672293	VSVDeltaM51 treatment also led to tumor cell death that was confirmed by the abundant presence of the apoptotic marker active caspase 3 (Figure 6(c)).	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor cell death', 'Disease', 'MESH:D003643', (34, 50))	('VSVDeltaM51', 'Var', (0, 11))	('tumor cell death', 'Disease', (34, 50))	('caspase 3', 'Gene', (126, 135))	('caspase 3', 'Gene', '836', (126, 135))
519871	24672293	Also, a significant delay in tumor growth (P < 0.005) was subsequently observed after either the intratumoral or intravenous routes of VSVDeltaM51 administration (Figure 7).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('delay', 'NegReg', (20, 25))	('VSVDeltaM51', 'Var', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
519883	24672293	Some of these studies have demonstrated VSVDeltaM51 to be a potent oncolytic viral agent, killing malignant carcinoma cells while leaving normal tissues unharmed.	('VSVDeltaM51', 'Var', (40, 51))	('carcinoma', 'Disease', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinoma', 'Disease', 'MESH:D002277', (108, 117))
519884	24672293	Our research is the first to highlight the antitumor effect of VSVDeltaM51 against a resistant EWS model.	('EWS', 'Phenotype', 'HP:0012254', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('VSVDeltaM51', 'Var', (63, 74))	('tumor', 'Disease', (47, 52))
519888	24672293	We hypothesized that VSVDeltaM51 can demonstrate tumor-specific killing of resistant EWS after systemic delivery, as well as a significant decrease of tumor burden in EWS bearing mice.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mice', 'Species', '10090', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (151, 156))	('EWS', 'Phenotype', 'HP:0012254', (85, 88))	('tumor', 'Disease', (49, 54))	('EWS', 'Phenotype', 'HP:0012254', (167, 170))	('VSVDeltaM51', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('decrease', 'NegReg', (139, 147))
519893	24672293	This naturally inherent tumor targeting ability of VSVDeltaM51 makes it a favorable oncolytic viral agent.	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('VSVDeltaM51', 'Var', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
519900	24672293	Indeed, in our in vivo model, VSVDeltaM51 caused significant delay in tumor growth prolonging survival.	('delay', 'NegReg', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('VSVDeltaM51', 'Var', (30, 41))	('survival', 'CPA', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
519924	23109999	It is also necessary to perform further evaluation such as immunohistochemistry or molecular studies for detection of SYT-SSX fusion transcripts, which is essential for avoiding misdiagnosis.	('fusion transcripts', 'Var', (126, 144))	('SYT', 'Gene', (118, 121))	('SSX', 'Gene', '6757', (122, 125))	('SYT', 'Gene', '6760', (118, 121))	('SSX', 'Gene', (122, 125))
519971	23109999	The t(X;18)(p11.2;q11.2) translocation is found in about 90% of synovial sarcomas and it is considered a pathogenic factor of this tumor.	('t(X;18)(p11.2;q11.2', 'Var', (4, 23))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 24))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('synovial sarcomas', 'Disease', 'MESH:D013584', (64, 81))	('synovial sarcomas', 'Disease', (64, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (64, 80))	('tumor', 'Disease', (131, 136))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (64, 81))
519981	32086342	Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined.	('RABL6A', 'Gene', (46, 52))	('RABL6A', 'Chemical', '-', (46, 52))	('human', 'Species', '9606', (90, 95))	('silencing', 'Var', (36, 45))	('p27', 'Gene', '3429', (60, 63))	('p27', 'Gene', (60, 63))
519984	32086342	Silencing RABL6A caused MPNST cell death and G1 arrest that coincided with p27 upregulation, CDK downregulation and RB1 activation.	('arrest', 'Disease', 'MESH:D006323', (48, 54))	('p27', 'Gene', (75, 78))	('CDK', 'CPA', (93, 96))	('upregulation', 'PosReg', (79, 91))	('arrest', 'Disease', (48, 54))	('RABL6A', 'Gene', (10, 16))	('activation', 'PosReg', (120, 130))	('p27', 'Gene', '3429', (75, 78))	('death', 'Disease', 'MESH:D003643', (35, 40))	('RABL6A', 'Chemical', '-', (10, 16))	('RB1', 'Gene', (116, 119))	('death', 'Disease', (35, 40))	('Silencing', 'Var', (0, 9))	('downregulation', 'NegReg', (97, 111))
519986	32086342	Importantly, reactivation of RB1 using a CDK4/6 inhibitor (palbociclib) killed MPNST cells in vitro in a RABL6A-dependent manner and suppressed MPNST growth in vivo.	('CDK4/6', 'Gene', (41, 47))	('suppressed', 'NegReg', (133, 143))	('killed', 'NegReg', (72, 78))	('palbociclib', 'Chemical', 'MESH:C500026', (59, 70))	('RABL6A', 'Chemical', '-', (105, 111))	('CDK4/6', 'Gene', '1019;1021', (41, 47))	('RB1', 'Gene', (29, 32))	('reactivation', 'Var', (13, 25))	('MPNST growth', 'CPA', (144, 156))
520001	32086342	Inactivation of CDKN2A, the locus encoding p16INK4a, is the hallmark event associated with PNF-to-MPNST malignant transformation in NF1 patients.	('NF1', 'Gene', '4763', (132, 135))	('p16INK4a', 'Gene', (43, 51))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('p16INK4a', 'Gene', '1029', (43, 51))	('patients', 'Species', '9606', (136, 144))	('associated', 'Reg', (75, 85))	('Inactivation', 'Var', (0, 12))	('NF1', 'Gene', (132, 135))
520002	32086342	In fact, loss of CDKN2A and the adjacent CDKN2B gene (which encodes a related p15INK4b protein) is the only known molecular change that defines the transitional lesion between PNFs and MPNSTs, called atypical neurofibromatosis neoplasm of unidentified biologic potential (ANNUBP).	('neurofibromatosis', 'Phenotype', 'HP:0001067', (209, 226))	('p15INK4b', 'Gene', (78, 86))	('neoplasm', 'Phenotype', 'HP:0002664', (227, 235))	('loss', 'Var', (9, 13))	('CDKN2A', 'Gene', (17, 23))	('p15INK4b', 'Gene', '1030', (78, 86))	('atypical neurofibromatosis', 'Phenotype', 'HP:0007524', (200, 226))	('CDKN2A', 'Gene', '1029', (17, 23))	('CDKN2B', 'Gene', (41, 47))	('neurofibroma', 'Phenotype', 'HP:0001067', (209, 221))	('neurofibromatosis neoplasm', 'Disease', 'MESH:C537392', (209, 235))	('CDKN2B', 'Gene', '1030', (41, 47))	('neurofibromatosis neoplasm', 'Disease', (209, 235))
520006	32086342	For example, RABL6A promotes ERK signaling, activates AKT by inhibiting tumor suppressive protein phosphatase 2A (PP2A), and inhibits p53 by enhancing its degradation via Mdm2-mediated ubiquitination.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inhibiting', 'NegReg', (61, 71))	('Mdm2', 'Gene', (171, 175))	('ERK', 'Gene', (29, 32))	('PP2A', 'Gene', '5524', (114, 118))	('AKT', 'Gene', (54, 57))	('degradation', 'MPA', (155, 166))	('promotes', 'PosReg', (20, 28))	('enhancing', 'PosReg', (141, 150))	('inhibits', 'NegReg', (125, 133))	('RABL6A', 'Var', (13, 19))	('p53', 'Gene', '7157', (134, 137))	('PP2A', 'Gene', (114, 118))	('tumor', 'Disease', (72, 77))	('AKT', 'Gene', '207', (54, 57))	('RABL6A', 'Chemical', '-', (13, 19))	('activates', 'PosReg', (44, 53))	('Mdm2', 'Gene', '4193', (171, 175))	('phosphatase 2A', 'Gene', '5524', (98, 112))	('phosphatase 2A', 'Gene', (98, 112))	('p53', 'Gene', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('ERK', 'Gene', '5594', (29, 32))
520008	32086342	Because disruptions in the RB1 pathway are key to MPNST development, this study sought to define the role of RABL6A in MPNST pathogenesis.	('disruptions', 'Var', (8, 19))	('RB1 pathway', 'Pathway', (27, 38))	('RABL6A', 'Chemical', '-', (109, 115))
520009	32086342	Here, we show that RABL6A protein expression and signaling is significantly upregulated in MPNSTs versus matched, benign neurofibromas (NFs) from the same NF1 patients.	('benign neurofibromas', 'Disease', 'MESH:D009455', (114, 134))	('expression', 'MPA', (34, 44))	('RABL6A', 'Gene', (19, 25))	('neurofibroma', 'Phenotype', 'HP:0001067', (121, 133))	('RABL6A', 'Chemical', '-', (19, 25))	('MPNSTs', 'Var', (91, 97))	('benign neurofibromas', 'Disease', (114, 134))	('signaling', 'MPA', (49, 58))	('neurofibromas', 'Phenotype', 'HP:0001067', (121, 134))	('protein', 'Protein', (26, 33))	('upregulated', 'PosReg', (76, 87))	('NF1', 'Gene', (155, 158))	('patients', 'Species', '9606', (159, 167))	('NF1', 'Gene', '4763', (155, 158))
520037	32086342	Lentiviruses encoding RABL6A shRNAs (KD1 and KD2), p27 shRNA, and empty vector (CON) were produced by lipofection of viral constructs in HEK293T cells and infected into target cells using established methods.	('RABL6A', 'Chemical', '-', (22, 28))	('infected', 'Disease', 'MESH:D007239', (155, 163))	('RABL6A', 'Var', (22, 28))	('p27', 'Gene', '3429', (51, 54))	('p27', 'Gene', (51, 54))	('HEK293T', 'CellLine', 'CVCL:0063', (137, 144))	('infected', 'Disease', (155, 163))
520047	32086342	3686), and cleaved PARP (no.	('PARP', 'Gene', (19, 23))	('cleaved', 'Var', (11, 18))	('PARP', 'Gene', '1302', (19, 23))
520051	32086342	NA934 and NA935) from Sigma; and CDK2 (no.	('NA934', 'Var', (0, 5))	('NA935', 'Var', (10, 15))	('CDK2', 'Gene', (33, 37))	('CDK2', 'Gene', '1017', (33, 37))
520104	32086342	Strikingly, while the RABL6 transcript is not increased in MPNSTs, IPA revealed that the RABL6A pathway is activated in MPNSTs (Figure 1G) consistent with elevated RABL6A protein levels.	('RABL6', 'Gene', '55684', (22, 27))	('elevated RABL6A protein levels', 'Phenotype', 'HP:0003240', (155, 185))	('MPNSTs', 'Var', (120, 126))	('RABL6', 'Gene', (22, 27))	('RABL6', 'Gene', '55684', (89, 94))	('RABL6', 'Gene', '55684', (164, 169))	('RABL6A', 'Chemical', '-', (164, 170))	('RABL6A', 'Chemical', '-', (89, 95))	('elevated', 'PosReg', (155, 163))	('RABL6', 'Gene', (89, 94))	('RABL6', 'Gene', (164, 169))	('activated', 'PosReg', (107, 116))
520118	32086342	In pancreatic neuroendocrine tumor cells, RABL6A promotes G1 to S phase progression through multiple mechanisms that include inactivation of the RB1 tumor suppressor.	('RB1', 'Gene', (145, 148))	('G1 to S phase progression', 'CPA', (58, 83))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (14, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('promotes', 'PosReg', (49, 57))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (3, 34))	('inactivation', 'Var', (125, 137))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (29, 34))	('RABL6A', 'Chemical', '-', (42, 48))	('RABL6A', 'Gene', (42, 48))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (3, 34))	('pancreatic neuroendocrine tumor', 'Disease', (3, 34))
520122	32086342	Consistent with the rise in p27 protein levels, loss of RABL6A led to decreased phosphorylation of RB1 at CDK4/6 targeted sites (S807/811) (Figure 3, C and D; Supplemental Figure 2, A and B).	('rise', 'PosReg', (20, 24))	('loss', 'Var', (48, 52))	('CDK4/6', 'Gene', '1019;1021', (106, 112))	('decreased', 'NegReg', (70, 79))	('p27', 'Gene', (28, 31))	('p27', 'Gene', '3429', (28, 31))	('CDK4/6', 'Gene', (106, 112))	('phosphorylation', 'MPA', (80, 95))	('RB1', 'Protein', (99, 102))	('RABL6A', 'Chemical', '-', (56, 62))	('RABL6A', 'Gene', (56, 62))
520130	32086342	Western analyses confirmed effective knockdown of both RABL6A and p27 (Figure 4B; Supplemental Figure 4, D and E).	('p27', 'Gene', '3429', (66, 69))	('p27', 'Gene', (66, 69))	('knockdown', 'Var', (37, 46))	('RABL6A', 'Gene', (55, 61))	('RABL6A', 'Chemical', '-', (55, 61))
520142	32086342	As shown in Figure 5B, palbociclib caused significant death in MPNST cells concomitant with RB1 activation (i.e., reduced phosphorylation at S807/811).	('death', 'Disease', 'MESH:D003643', (54, 59))	('death', 'Disease', (54, 59))	('palbociclib', 'Var', (23, 34))	('reduced', 'NegReg', (114, 121))	('phosphorylation', 'MPA', (122, 137))	('RB1', 'Gene', (92, 95))	('palbociclib', 'Chemical', 'MESH:C500026', (23, 34))	('activation', 'PosReg', (96, 106))
520149	32086342	Importantly, palbociclib induces arrest (not death) in NHSCs (Figure 5D, left) that mirrors effective activation of RB1 due to reduced phosphorylation (Figure 5D, right).	('RB1', 'Protein', (116, 119))	('palbociclib', 'Var', (13, 24))	('arrest', 'Disease', 'MESH:D006323', (33, 39))	('NHSCs', 'Disease', (55, 60))	('activation', 'PosReg', (102, 112))	('death', 'Disease', 'MESH:D003643', (45, 50))	('death', 'Disease', (45, 50))	('phosphorylation', 'MPA', (135, 150))	('arrest', 'Disease', (33, 39))	('reduced', 'NegReg', (127, 134))	('palbociclib', 'Chemical', 'MESH:C500026', (13, 24))
520172	32086342	A major limitation of cancer therapy is drug resistance, and with CDK4/6 inhibitors acquired tumor resistance is often mediated by increased CDK2 activity.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('increased', 'PosReg', (131, 140))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('activity', 'MPA', (146, 154))	('cancer', 'Disease', (22, 28))	('tumor', 'Disease', (93, 98))	('CDK4/6', 'Gene', '1019;1021', (66, 72))	('drug resistance', 'Phenotype', 'HP:0020174', (40, 55))	('CDK2', 'Gene', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('inhibitors', 'Var', (73, 83))	('CDK2', 'Gene', '1017', (141, 145))	('CDK4/6', 'Gene', (66, 72))
520180	32086342	Palbociclib and dinaciclib were likewise synergistic in S462 cells (Supplemental Figure 8) and patient-derived MT1 and MT2 cultures (Supplemental Figure 5C).	('patient', 'Species', '9606', (95, 102))	('MT2', 'Gene', '4502', (119, 122))	('dinaciclib', 'Chemical', 'MESH:C553669', (16, 26))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('MT1', 'Gene', (111, 114))	('MT2', 'Gene', (119, 122))	('MT1', 'Gene', '644314', (111, 114))	('dinaciclib', 'Var', (16, 26))
520184	32086342	However, mice treated with dinaciclib or dinaciclib plus palbociclib suffered from diarrhea.	('dinaciclib', 'Chemical', 'MESH:C553669', (27, 37))	('diarrhea', 'Phenotype', 'HP:0002014', (83, 91))	('dinaciclib', 'Var', (41, 51))	('diarrhea', 'Disease', 'MESH:D003967', (83, 91))	('diarrhea', 'Disease', (83, 91))	('palbociclib', 'Chemical', 'MESH:C500026', (57, 68))	('mice', 'Species', '10090', (9, 13))	('dinaciclib', 'Chemical', 'MESH:C553669', (41, 51))	('suffered', 'Reg', (69, 77))
520187	32086342	Combining palbociclib and dinaciclib also caused the greatest accumulation of active, hypo-phosphorylated RB1 (Figure 7, E and G).	('palbociclib', 'Chemical', 'MESH:C500026', (10, 21))	('dinaciclib', 'Chemical', 'MESH:C553669', (26, 36))	('accumulation', 'PosReg', (62, 74))	('active', 'MPA', (78, 84))	('RB1', 'Gene', (106, 109))	('dinaciclib', 'Var', (26, 36))
520204	32086342	Silencing RABL6A in three different MPNST cell lines caused upregulation of p27 and activation of RB1 coincident with cellular arrest and death.	('arrest', 'Disease', (127, 133))	('activation', 'PosReg', (84, 94))	('RABL6A', 'Gene', (10, 16))	('upregulation', 'PosReg', (60, 72))	('death', 'Disease', 'MESH:D003643', (138, 143))	('death', 'Disease', (138, 143))	('RB1', 'Gene', (98, 101))	('p27', 'Gene', (76, 79))	('RABL6A', 'Chemical', '-', (10, 16))	('p27', 'Gene', '3429', (76, 79))	('Silencing', 'Var', (0, 9))	('arrest', 'Disease', 'MESH:D006323', (127, 133))
520205	32086342	Conversely, silencing p27 in RABL6A depleted cells restored RB1 phosphorylation, cellular viability and cell cycle progression into S phase where levels of DNA synthesis paralleled those of control cells.	('cellular viability', 'CPA', (81, 99))	('phosphorylation', 'MPA', (64, 79))	('RABL6A', 'Chemical', '-', (29, 35))	('restored', 'PosReg', (51, 59))	('cell cycle progression', 'CPA', (104, 126))	('silencing', 'Var', (12, 21))	('p27', 'Gene', '3429', (22, 25))	('p27', 'Gene', (22, 25))	('RB1', 'Protein', (60, 63))
520208	32086342	Earlier work found that p27 inactivation in MPNSTs confers reduced survival, predicting that elevated RABL6A in MPNSTs may likewise connote worse outcomes.	('reduced', 'NegReg', (59, 66))	('p27', 'Gene', '3429', (24, 27))	('survival', 'MPA', (67, 75))	('inactivation', 'Var', (28, 40))	('RABL6A', 'Chemical', '-', (102, 108))	('p27', 'Gene', (24, 27))	('RABL6A', 'Gene', (102, 108))	('elevated', 'PosReg', (93, 101))
520212	32086342	Inactivation of p27 is common in aggressive human cancers and occurs through gene mutation, transcriptional silencing, and/or dysregulation of the protein through phosphorylation changes that dictate cytoplasmic mislocalization, ubiquitination and proteasomal degradation .	('transcriptional silencing', 'Var', (92, 117))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('gene mutation', 'Var', (77, 90))	('dysregulation', 'Var', (126, 139))	('aggressive human cancers', 'Disease', (33, 57))	('proteasomal degradation', 'MPA', (248, 271))	('dictate', 'Reg', (192, 199))	('changes', 'Reg', (179, 186))	('aggressive human cancers', 'Disease', 'MESH:D009369', (33, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('p27', 'Gene', '3429', (16, 19))	('p27', 'Gene', (16, 19))	('phosphorylation', 'MPA', (163, 178))	('ubiquitination', 'MPA', (229, 243))	('Inactivation', 'Var', (0, 12))	('cytoplasmic mislocalization', 'MPA', (200, 227))
520214	32086342	Following RABL6A depletion, we observed little to moderate upregulation of p27 mRNA coincident with a robust rise in p27 protein levels that surpassed the fold induction of its mRNA.	('p27', 'Gene', (75, 78))	('depletion', 'Var', (17, 26))	('p27', 'Gene', '3429', (117, 120))	('p27', 'Gene', (117, 120))	('rise', 'PosReg', (109, 113))	('RABL6A', 'Chemical', '-', (10, 16))	('upregulation', 'PosReg', (59, 71))	('p27', 'Gene', '3429', (75, 78))
520217	32086342	RABL6A is essential for AKT activation in pancreatic neuroendocrine tumors and here we showed it promotes CDK2 expression, supporting the prospect that RABL6A may destabilize p27 protein by enhancing its phosphorylation at AKT and/or CDK2 specific sites.	('AKT', 'Gene', (24, 27))	('p27', 'Gene', '3429', (175, 178))	('p27', 'Gene', (175, 178))	('AKT', 'Gene', (223, 226))	('RABL6A', 'Var', (152, 158))	('CDK2', 'Gene', (234, 238))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (42, 74))	('CDK2', 'Gene', '1017', (106, 110))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (42, 73))	('destabilize', 'NegReg', (163, 174))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (53, 73))	('enhancing', 'PosReg', (190, 199))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (53, 74))	('CDK2', 'Gene', (106, 110))	('RABL6A', 'Chemical', '-', (152, 158))	('pancreatic neuroendocrine tumors', 'Disease', (42, 74))	('expression', 'MPA', (111, 121))	('AKT', 'Gene', '207', (24, 27))	('phosphorylation', 'MPA', (204, 219))	('RABL6A', 'Chemical', '-', (0, 6))	('AKT', 'Gene', '207', (223, 226))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('promotes', 'PosReg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('protein', 'Protein', (179, 186))	('CDK2', 'Gene', '1017', (234, 238))
520221	32086342	Nearly all patients with advanced or metastatic liposarcoma have CDK4 amplification, and a phase 2 trial of palbociclib in those patients (NCT01209598) was encouraging with favorable progression-free survival and occasional tumor response .	('liposarcoma', 'Phenotype', 'HP:0012034', (48, 59))	('liposarcoma', 'Disease', 'MESH:D008080', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('patients', 'Species', '9606', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('palbociclib', 'Chemical', 'MESH:C500026', (108, 119))	('tumor', 'Disease', (224, 229))	('liposarcoma', 'Disease', (48, 59))	('CDK4', 'Gene', (65, 69))	('patients', 'Species', '9606', (11, 19))	('CDK4', 'Gene', '1019', (65, 69))	('amplification', 'Var', (70, 83))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
520225	32086342	In both sNF96.2 and S462 tumor models, palbociclib caused a pronounced G1 arrest but emerging resistance (regrowth of arrested tumors or presence of high Ki-67 regions) was evident near the end of treatment.	('arrested tumors', 'Disease', (118, 133))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('arrest', 'Disease', 'MESH:D006323', (118, 124))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('palbociclib', 'Var', (39, 50))	('arrested tumors', 'Disease', 'MESH:D006323', (118, 133))	('Ki-67', 'Gene', '17345', (154, 159))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('arrest', 'Disease', (118, 124))	('palbociclib', 'Chemical', 'MESH:C500026', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Ki-67', 'Gene', (154, 159))	('arrest', 'Disease', (74, 80))
520227	32086342	Hyperactivation of CDK5 might also confer resistance to CDK4/6 inhibitors since it can inactivate RB1 via S807/811 phosphorylation.	('CDK5', 'Gene', (19, 23))	('CDK4/6', 'Gene', '1019;1021', (56, 62))	('CDK5', 'Gene', '1020', (19, 23))	('inactivate', 'NegReg', (87, 97))	('S807/811', 'Var', (106, 114))	('CDK4/6', 'Gene', (56, 62))	('RB1', 'Protein', (98, 101))
520232	32086342	S100 expression was greatest in tumors treated with the combination of palbociclib plus dinaciclib compared to either drug alone, which correlated with increased RB1 activation.	('expression', 'MPA', (5, 15))	('palbociclib', 'Var', (71, 82))	('activation', 'PosReg', (166, 176))	('dinaciclib', 'Chemical', 'MESH:C553669', (88, 98))	('increased', 'PosReg', (152, 161))	('S100', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('RB1', 'Protein', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('palbociclib', 'Chemical', 'MESH:C500026', (71, 82))	('tumors', 'Disease', (32, 38))	('dinaciclib', 'Var', (88, 98))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
520233	32086342	The ability of CDK2 and CDK4/6 inhibitors to promote tumor reversion to a less aggressive, more targetable tumor type has not to our knowledge been described.	('CDK2', 'Gene', '1017', (15, 19))	('CDK4/6', 'Gene', '1019;1021', (24, 30))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CDK4/6', 'Gene', (24, 30))	('promote', 'PosReg', (45, 52))	('tumor', 'Disease', (53, 58))	('CDK2', 'Gene', (15, 19))	('inhibitors', 'Var', (31, 41))
520235	32086342	Further investigation is needed to better understand how inhibition of RB1-directed CDKs may potentially promote MPNST cell re-differentiation and to identify additional drugs that may enhance it further.	('CDKs', 'Gene', (84, 88))	('promote', 'PosReg', (105, 112))	('inhibition', 'Var', (57, 67))	('MPNST cell re-differentiation', 'CPA', (113, 142))	('RB1-directed', 'Gene', (71, 83))	('CDKs', 'Gene', '983;1017;1019;1020;1021;1025;5127', (84, 88))
520243	32086342	Moreover, this drug combination was found to activate a senescence-associated secretory phenotype which promotes NK cell-mediated cytotoxicity and prolonged tumor control in lung cancer models with mutant Ras .	('tumor', 'Disease', (157, 162))	('lung cancer', 'Disease', (174, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cytotoxicity', 'Disease', (130, 142))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('activate', 'PosReg', (45, 53))	('Ras', 'Gene', (205, 208))	('mutant', 'Var', (198, 204))	('promotes', 'PosReg', (104, 112))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('cytotoxicity', 'Disease', 'MESH:D064420', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('senescence-associated secretory phenotype', 'MPA', (56, 97))
520248	32086342	Currently, there are no effective therapies for MPNSTs, yet RB1 pathway mutations that hyperactivate CDK4/6 and CDK2 kinases are defining events in MPNST pathogenesis.	('mutations', 'Var', (72, 81))	('RB1 pathway', 'Gene', (60, 71))	('CDK4/6', 'Gene', (101, 107))	('CDK4/6', 'Gene', '1019;1021', (101, 107))	('CDK2', 'Gene', '1017', (112, 116))	('CDK2', 'Gene', (112, 116))	('hyperactivate', 'PosReg', (87, 100))
520255	29328472	The results indicated that CPX may inhibit ES growth by affecting vasculature development and DNA replication.	('CPX', 'Chemical', 'MESH:D000077768', (27, 30))	('DNA replication', 'CPA', (94, 109))	('ES growth', 'CPA', (43, 52))	('ES', 'Phenotype', 'HP:0012254', (43, 45))	('affecting', 'Reg', (56, 65))	('vasculature development', 'CPA', (66, 89))	('CPX', 'Var', (27, 30))	('inhibit', 'NegReg', (35, 42))
520262	29328472	A common biomarker target in ES is Ewing sarcoma breakpoint region 1-Friend leukemia integration 1 (EWS-FLI1), a fusion gene induced by t(11;22) (q24;q12) chromosome translocation, which has been reported as an independent prognosis determinant in ES.	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (35, 48))	('ES', 'Phenotype', 'HP:0012254', (248, 250))	('ES', 'Phenotype', 'HP:0012254', (29, 31))	('t(11;22) (q24;q12', 'Var', (136, 153))	('Ewing sarcoma breakpoint region 1-Friend leukemia', 'Disease', 'MESH:C563168', (35, 84))	('EWS-FLI1', 'Gene', (100, 108))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('EWS-FLI1', 'Gene', '2130;2313', (100, 108))	('Ewing sarcoma breakpoint region 1-Friend leukemia', 'Disease', (35, 84))
520276	29328472	In addition, two sub-data sets of GSE61944, including GSM1517562, which was obtained through EWS-FLI1 chromatin immune precipitation followed by high-throughput sequencing (ChIP-seq) in A673, and GSM1517568, which was from A673 whole-cell extracts, were used for the identification of EWS-FLI1 specific binding sites (peaks).	('EWS-FLI1', 'Gene', '2130;2313', (93, 101))	('GSE61944', 'Var', (34, 42))	('GSM1517562', 'Chemical', '-', (54, 64))	('GSM1517568', 'Chemical', '-', (196, 206))	('binding', 'Interaction', (303, 310))	('EWS-FLI1', 'Gene', (285, 293))	('EWS-FLI1', 'Gene', '2130;2313', (285, 293))	('EWS-FLI1', 'Gene', (93, 101))
520285	29328472	This observation was probably due to the knockdown of EWS-FLI1 resulting in upregulated expression of tumor suppressor genes.	('EWS-FLI1', 'Gene', (54, 62))	('tumor', 'Disease', (102, 107))	('expression', 'MPA', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('EWS-FLI1', 'Gene', '2130;2313', (54, 62))	('upregulated', 'PosReg', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('knockdown', 'Var', (41, 50))
520304	29328472	EWS-FLI1 is a fusion transcript structure caused by chromosome translocation of t(11;22) (q24;q12), which was previously demonstrated to be closely associated with the initiation and progression of ES.	('chromosome translocation', 'Var', (52, 76))	('EWS-FLI1', 'Gene', (0, 8))	('ES', 'Phenotype', 'HP:0012254', (198, 200))	('associated', 'Reg', (148, 158))	('caused by', 'Reg', (42, 51))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))
520312	29328472	DEGs in the CPX-treated A673 cell lines were associated with tissue development, particularly vascular development.	('associated', 'Reg', (45, 55))	('tissue development', 'CPA', (61, 79))	('vascular development', 'CPA', (94, 114))	('CPX', 'Chemical', 'MESH:D000077768', (12, 15))	('DEGs', 'Var', (0, 4))
520320	29328472	The amplification of MYCN is closely associated with a number of cancer types, including ES.	('MYCN', 'Gene', (21, 25))	('MYCN', 'Gene', '4613', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('amplification', 'Var', (4, 17))	('associated', 'Reg', (37, 47))	('ES', 'Phenotype', 'HP:0012254', (89, 91))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
520336	28974986	An extension of this theory would be that alteration(s) in mesenchymal stem cell genetics can give rise to several sarcomas, including osteosarcoma, Ewing's sarcoma, synovial sarcoma, chondrosarcoma, rhabdomyosarcoma, fibrosarcoma and liposarcoma.	('liposarcoma', 'Disease', (235, 246))	("Ewing's sarcoma", 'Disease', (149, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('fibrosarcoma', 'Disease', 'MESH:D005354', (218, 230))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (184, 198))	('rhabdomyosarcoma', 'Disease', (200, 216))	('fibrosarcoma', 'Disease', (218, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('alteration', 'Var', (42, 52))	('liposarcoma', 'Phenotype', 'HP:0012034', (235, 246))	('osteosarcoma', 'Phenotype', 'HP:0002669', (135, 147))	('give rise to', 'Reg', (94, 106))	('synovial sarcoma', 'Disease', (166, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (200, 216))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('synovial sarcoma', 'Disease', 'MESH:D013584', (166, 182))	('liposarcoma', 'Disease', 'MESH:D008080', (235, 246))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (149, 164))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (200, 216))	('sarcomas', 'Disease', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (149, 164))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (166, 182))	('chondrosarcoma', 'Disease', (184, 198))	('chondrosarcoma', 'Disease', 'MESH:D002813', (184, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (218, 230))	('osteosarcoma', 'Disease', (135, 147))	('osteosarcoma', 'Disease', 'MESH:D012516', (135, 147))
520340	28974986	From a molecular point of view, sarcomas may be broadly classified into two types: (1) sarcomas with simple karyotypes characterized by chromosomal translocations or specific mutations; and (2) sarcomas with complex aneuploidy karyotypes, consisting of numerous losses, gains and amplifications.	('amplifications', 'Var', (280, 294))	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('losses', 'NegReg', (262, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('gains', 'Var', (270, 275))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcomas', 'Disease', (87, 95))	('sarcomas', 'Disease', 'MESH:D012509', (194, 202))	('mutations', 'Var', (175, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('chromosomal translocations', 'Var', (136, 162))	('sarcomas', 'Disease', (32, 40))	('sarcomas', 'Disease', (194, 202))
520418	28974986	This results in double-strand DNA damage followed by a G2/M cell cycle arrest and ultimately apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('arrest', 'Disease', 'MESH:D006323', (71, 77))	('results in', 'Reg', (5, 15))	('double-strand', 'Var', (16, 29))	('arrest', 'Disease', (71, 77))	('apoptosis', 'CPA', (93, 102))
520434	28974986	In this regard, eribulin has been found to be especially efficacious in patients with tumours harbouring beta-tubulin mutations that are refractory to taxanes.	('beta-tubulin', 'Protein', (105, 117))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (118, 127))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('taxanes', 'Chemical', 'MESH:D043823', (151, 158))	('tumours', 'Disease', (86, 93))	('patients', 'Species', '9606', (72, 80))
520435	28974986	In preclinical models, eribulin was shown to induce an irreversible mitotic arrest, apoptosis and tumour regression in multiple cancer cell lines with a mean IC50 that is 2-4-fold more potent than vinblastine and paclitaxel.	('eribulin', 'Var', (23, 31))	('tumour regression in multiple cancer', 'Disease', (98, 134))	('arrest', 'Disease', 'MESH:D006323', (76, 82))	('apoptosis', 'CPA', (84, 93))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('vinblastine', 'Chemical', 'MESH:D014747', (197, 208))	('arrest', 'Disease', (76, 82))	('tumour regression in multiple cancer', 'Disease', 'MESH:D009369', (98, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('paclitaxel', 'Chemical', 'MESH:D017239', (213, 223))
520458	28974986	Approximately 95% of GISTs arising in adults constitutively express active c-KIT; of these patients, 80% have c-KIT gene mutations which result in ligand-independent constitutive activation of the receptor.	('patients', 'Species', '9606', (91, 99))	('mutations', 'Var', (121, 130))	('c-KIT', 'Gene', '3815', (75, 80))	('constitutive', 'MPA', (166, 178))	('c-KIT', 'Gene', (110, 115))	('activation', 'PosReg', (179, 189))	('c-KIT', 'Gene', (75, 80))	('c-KIT', 'Gene', '3815', (110, 115))
520467	28974986	While most mutations that result in ligand-independent constitutive activation of c-KIT occur in exon 11, there are some less frequent mutations present in exon 9, 13 or 17.	('activation', 'PosReg', (68, 78))	('mutations', 'Var', (11, 20))	('c-KIT', 'Gene', '3815', (82, 87))	('c-KIT', 'Gene', (82, 87))
520468	28974986	These more rare mutations appear to have a different underlying mechanism that results in uncontrolled c-KIT signalling and are less responsive to imatinib treatment.	('c-KIT', 'Gene', (103, 108))	('results', 'Reg', (79, 86))	('mutations', 'Var', (16, 25))	('c-KIT', 'Gene', '3815', (103, 108))	('imatinib', 'Chemical', 'MESH:D000068877', (147, 155))
520469	28974986	Hirota and colleagues also identified mutations causing constitutively active PDGFRs in a minority of GIST cases which induce cytogenetic changes associated with tumour progression.	('cytogenetic', 'MPA', (126, 137))	('tumour', 'Disease', (162, 168))	('PDGFR', 'Gene', (78, 83))	('PDGFR', 'Gene', '5159', (78, 83))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (38, 47))	('tumour', 'Disease', 'MESH:D009369', (162, 168))	('induce', 'Reg', (119, 125))
520470	28974986	Similar to the rare c-KIT mutations, these mutations are characterized by insensitivity to imatinib but they are more sensitive to sunitinib, which inhibits multiple receptor tyrosine kinases including c-KIT, PDGFR, VEGFR, RET (rearranged during transfection) and FLT3 (fms-related tyrosine kin-ase-3).	('mutations', 'Var', (26, 35))	('c-KIT', 'Gene', (20, 25))	('c-KIT', 'Gene', '3815', (20, 25))	('RET', 'Gene', '5979', (223, 226))	('rearranged during transfection', 'Gene', (228, 258))	('imatinib', 'Chemical', 'MESH:D000068877', (91, 99))	('inhibits', 'NegReg', (148, 156))	('rearranged during transfection', 'Gene', '5979', (228, 258))	('VEGFR', 'Gene', '3791', (216, 221))	('FLT3', 'Gene', (264, 268))	('c-KIT', 'Gene', (202, 207))	('sunitinib', 'Chemical', 'MESH:D000077210', (131, 140))	('VEGFR', 'Gene', (216, 221))	('c-KIT', 'Gene', '3815', (202, 207))	('fms-related tyrosine kin-ase-3', 'Gene', '2322', (270, 300))	('RET', 'Gene', (223, 226))	('FLT3', 'Gene', '2322', (264, 268))	('fms-related tyrosine kin-ase-3', 'Gene', (270, 300))	('mutations', 'Var', (43, 52))	('PDGFR', 'Gene', (209, 214))	('tyrosine kinase', 'Gene', (175, 190))	('PDGFR', 'Gene', '5159', (209, 214))	('tyrosine kinase', 'Gene', '7294', (175, 190))
520504	28974986	Unfortunately, most patients who initially respond to IGFR-1 inhibitors develop resistance to the therapy and suffer from relapse or recurrence within several months.	('resistance', 'MPA', (80, 90))	('inhibitors', 'Var', (61, 71))	('IGFR-1', 'Gene', '100132417', (54, 60))	('develop', 'Reg', (72, 79))	('patients', 'Species', '9606', (20, 28))	('IGFR-1', 'Gene', (54, 60))
520506	28974986	Alterations in the mammalian target of rapamycin (mTOR) pathway are commonly associated with sarcoma formation.	('mammalian target of rapamycin', 'Gene', '2475', (19, 48))	('mammalian target of rapamycin', 'Gene', (19, 48))	('Alterations', 'Var', (0, 11))	('mTOR', 'Gene', (50, 54))	('sarcoma', 'Disease', (93, 100))	('mTOR', 'Gene', '2475', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('associated', 'Reg', (77, 87))
520510	28974986	In the latter trial, compared to the placebo, tumour progression was only marginally delayed in patients on ridaforolimus and the median benefit of progression-free survival was low (17.7 weeks for ridaforolimus versus 14.6 weeks for placebo).	('ridaforolimus', 'Chemical', 'MESH:C515074', (198, 211))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', (46, 52))	('ridaforolimus', 'Var', (108, 121))	('patients', 'Species', '9606', (96, 104))	('ridaforolimus', 'Var', (198, 211))	('ridaforolimus', 'Chemical', 'MESH:C515074', (108, 121))	('delayed', 'NegReg', (85, 92))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
520517	28974986	Encouraging results have, however, been observed for palbociclib, a selective CDK4/6 inhibitor, in liposarcoma patients with amplified CDK4.	('CDK4/6', 'Gene', '1019;1021', (78, 84))	('liposarcoma', 'Disease', (99, 110))	('CDK4', 'Gene', (135, 139))	('CDK4', 'Gene', (78, 82))	('amplified', 'Var', (125, 134))	('CDK4', 'Gene', '1019', (135, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('CDK4/6', 'Gene', (78, 84))	('CDK4', 'Gene', '1019', (78, 82))	('liposarcoma', 'Phenotype', 'HP:0012034', (99, 110))	('liposarcoma', 'Disease', 'MESH:D008080', (99, 110))	('palbociclib', 'Chemical', 'MESH:C500026', (53, 64))	('patients', 'Species', '9606', (111, 119))
520519	28974986	Histone deacetylase (HDAC) inhibitors can induce transcription of key cell cycle regulators including the CDKI p21 which leads to growth arrest and apoptosis in sarcoma cell lines.	('sarcoma', 'Disease', (161, 168))	('arrest', 'Disease', (137, 143))	('HDAC', 'Gene', '9734', (21, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('induce', 'PosReg', (42, 48))	('growth arrest', 'Phenotype', 'HP:0001510', (130, 143))	('p21', 'Gene', (111, 114))	('leads to', 'Reg', (121, 129))	('inhibitors', 'Var', (27, 37))	('Histone deacetylase', 'Gene', '9734', (0, 19))	('p21', 'Gene', '644914', (111, 114))	('transcription', 'MPA', (49, 62))	('Histone deacetylase', 'Gene', (0, 19))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('apoptosis', 'CPA', (148, 157))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('HDAC', 'Gene', (21, 25))
520528	28974986	In a phase I study, sarcoma patients with MDM2-amplified liposarcoma treated with RG7112 showed a significant reduction in tumour growth.	('tumour growth', 'Disease', (123, 136))	('sarcoma', 'Disease', (20, 27))	('RG7112', 'Var', (82, 88))	('reduction', 'NegReg', (110, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('liposarcoma', 'Phenotype', 'HP:0012034', (57, 68))	('MDM2-amplified liposarcoma', 'Disease', 'MESH:D008080', (42, 68))	('tumour growth', 'Disease', 'MESH:D006130', (123, 136))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('MDM2-amplified liposarcoma', 'Disease', (42, 68))	('patients', 'Species', '9606', (28, 36))	('sarcoma', 'Disease', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
520530	28974986	Aberrant expression of AURKA has been implicated in many cancers and contributes to chromosome instability and phosphorylation-mediated ubiquitylation and degradation of the tumour suppressor p53.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('Aberrant expression', 'Var', (0, 19))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('AURKA', 'Gene', '6790', (23, 28))	('chromosome instability', 'CPA', (84, 106))	('p53', 'Gene', '7157', (192, 195))	('cancers', 'Disease', (57, 64))	('tumour', 'Disease', (174, 180))	('contributes', 'Reg', (69, 80))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('phosphorylation-mediated ubiquitylation', 'MPA', (111, 150))	('AURKA', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('implicated', 'Reg', (38, 48))	('p53', 'Gene', (192, 195))	('degradation', 'MPA', (155, 166))	('chromosome instability', 'Phenotype', 'HP:0040012', (84, 106))
520698	25630954	As demonstrated in Table II, patients under age 18, patients with an LDH less than or equal to 200 and patients with metastatic disease limited to the lungs had improved OS; however, none of these factors reached statistical significance.	('OS', 'MPA', (170, 172))	('patients', 'Species', '9606', (29, 37))	('less than', 'Var', (73, 82))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (52, 60))	('improved', 'PosReg', (161, 169))
520727	24891666	Pleomorphism excluded a diagnosis of myxofibrosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('myxofibrosarcoma', 'Disease', (37, 53))	('Pleomorphism', 'Var', (0, 12))	('myxofibrosarcoma', 'Disease', 'None', (37, 53))
520734	23967402	The main hypothesis was that sparing a person's limb, as opposed to amputating it, would result in a better quality of life.	('person', 'Species', '9606', (39, 45))	('quality of life', 'CPA', (108, 123))	('sparing', 'Var', (29, 36))
520820	23967402	For the MMPI, the limb-preservation patients scored significantly higher than the patients that had amputations in the K scale, also referred to as the defensiveness scale.	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (82, 90))	('limb-preservation', 'CPA', (18, 35))	('defensiveness', 'Disease', (152, 165))	('MMPI', 'Var', (8, 12))	('higher', 'PosReg', (66, 72))	('defensiveness', 'Disease', 'None', (152, 165))
520848	32010455	Although lipomas are benign in nature, lipomatous lesions that are deep to the fascia could be intra or inter-muscular lipomas, or atypical lipomatous tumours such as well-differentiated lipomas like liposarcomas with amplification of the MDM2 gene.	('lipomas', 'Disease', (187, 194))	('lipomas', 'Disease', 'MESH:D008067', (187, 194))	('lipomatous tumours', 'Disease', 'MESH:C537029', (140, 158))	('lipoma', 'Phenotype', 'HP:0012032', (9, 15))	('inter-muscular lipomas', 'Disease', (104, 126))	('lipomas like liposarcomas', 'Disease', (187, 212))	('fascia', 'Disease', (79, 85))	('inter-muscular lipomas', 'Disease', 'MESH:D008067', (104, 126))	('amplification', 'Var', (218, 231))	('lipoma', 'Phenotype', 'HP:0012032', (39, 45))	('lipomas', 'Phenotype', 'HP:0012032', (9, 16))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('lipoma', 'Phenotype', 'HP:0012032', (119, 125))	('lipomas', 'Phenotype', 'HP:0012032', (119, 126))	('lipomas', 'Disease', 'MESH:D008067', (9, 16))	('lipomatous lesions', 'Disease', 'MESH:C537029', (39, 57))	('MDM2', 'Gene', (239, 243))	('lipomas', 'Disease', (9, 16))	('lipomas', 'Disease', (119, 126))	('lipomatous tumours', 'Disease', (140, 158))	('lipomas', 'Disease', 'MESH:D008067', (119, 126))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('lipoma', 'Phenotype', 'HP:0012032', (140, 146))	('liposarcomas', 'Phenotype', 'HP:0012034', (200, 212))	('MDM2', 'Gene', '4193', (239, 243))	('fascia', 'Disease', 'None', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('lipomatous lesions', 'Disease', (39, 57))	('lipoma', 'Phenotype', 'HP:0012032', (187, 193))	('lipomas', 'Phenotype', 'HP:0012032', (187, 194))	('lipomas like liposarcomas', 'Disease', 'MESH:D008067', (187, 212))
520867	32010455	Desmoid tumours are benign but locally aggressive fibroblastic neoplasms that arise sporadically due to mutations leading to increased beta-catenin protein level and activity.	('mutations', 'Var', (104, 113))	('increased', 'PosReg', (125, 134))	('aggressive fibroblastic neoplasms', 'Disease', 'MESH:D001523', (39, 72))	('Desmoid tumours', 'Disease', (0, 15))	('activity', 'MPA', (166, 174))	('Desmoid tumours', 'Disease', 'MESH:C535944', (0, 15))	('beta-catenin', 'Gene', (135, 147))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('beta-catenin', 'Gene', '1499', (135, 147))	('aggressive fibroblastic neoplasms', 'Disease', (39, 72))	('neoplasms', 'Phenotype', 'HP:0002664', (63, 72))	('Desmoid tumours', 'Phenotype', 'HP:0100245', (0, 15))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))
520871	32010455	Little is known about the prognostic factors that can differentiate between indolent and aggressive cases; however, mutations in the beta-catenin gene have been shown to have prognostic value and may predict the risk of recurrence.	('beta-catenin', 'Gene', '1499', (133, 145))	('prognostic', 'MPA', (175, 185))	('predict', 'Reg', (200, 207))	('mutations', 'Var', (116, 125))	('beta-catenin', 'Gene', (133, 145))
520917	32010455	The cytogenetic abnormality t(X:18)(p11;q11) is found in 95% of patients with synovial sarcoma.	('synovial sarcoma', 'Disease', (78, 94))	('patients', 'Species', '9606', (64, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('t(X:18)(p11;q11', 'Var', (28, 43))	('synovial sarcoma', 'Disease', 'MESH:D013584', (78, 94))	('t(X:18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (28, 44))
520949	31510956	Stimulated MMP-2 production in co-culture of cancer cells and fibroblasts was completely suppressed by siRNA knockdown of CD73, but not by CD99 knockdown.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('CD73', 'Gene', (122, 126))	('suppressed', 'NegReg', (89, 99))	('MMP-2', 'Gene', (11, 16))	('CD99', 'Gene', '4267', (139, 143))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('knockdown', 'Var', (109, 118))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('MMP-2', 'Gene', '4313', (11, 16))	('CD99', 'Gene', (139, 143))
520965	31510956	Previously, we reported that synthetic peptides carrying a partial ECI construct of emmprin sequence without chitobiose could inhibit emmprin activity.	('inhibit', 'NegReg', (126, 133))	('emmprin activity', 'MPA', (134, 150))	('emmprin', 'Gene', (84, 91))	('peptides', 'Chemical', 'MESH:D010455', (39, 47))	('partial ECI construct', 'Var', (59, 80))
520972	31510956	Co-culture experiments were performed as previously described using fibroblasts (ST353i) and tumor cells (FU-EPS-1).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('ST353i', 'Var', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
520980	31510956	Three bands detected in co-culture of tumor cells and fibroblasts (75-100 kDa, 100-140 kDa, and 220 kDa) and a single band (220 kDa) detected in tumor cells alone were analyzed (Additional file 1: Figure.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('75-100 kDa', 'Var', (67, 77))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
521029	31510956	The PLA signals were quantified by using Image Tool analysis, which confirmed that the signal intensity was clearly decreased by CD73 siRNA vs. control siRNA (Additional file 3: Figure.	('N', 'Chemical', 'MESH:D009584', (137, 138))	('signal intensity', 'MPA', (87, 103))	('CD73', 'Var', (129, 133))	('decreased', 'NegReg', (116, 125))	('N', 'Chemical', 'MESH:D009584', (155, 156))
521036	31510956	By contrast, upon adding anti-CD73 neutralizing antibodies to co-cultured fibroblasts and tumor cells, MMP-2 production in the supernatant was clearly suppressed, compared with the control (Fig.	('MMP-2', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('suppressed', 'NegReg', (151, 161))	('anti-CD73', 'Gene', (25, 34))	('anti-CD73', 'Var', (25, 34))	('MMP-2', 'Gene', '4313', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
521037	31510956	These data show that MMP-2 production from fibroblasts is suppressed by anti-CD73 neutralizing antibodies (Fig.	('MMP-2', 'Gene', '4313', (21, 26))	('anti-CD73', 'Var', (72, 81))	('suppressed', 'NegReg', (58, 68))	('MMP-2', 'Gene', (21, 26))
521051	31510956	In this study, we have for the first time reported that CD73 forms a complex with emmprin and regulates the production of MMP-2 from fibroblasts, although there has been a previous report providing evidence that suppression of CD73 leads to down-regulation of MMP-2.	('MMP-2', 'Gene', (260, 265))	('regulates', 'Reg', (94, 103))	('MMP-2', 'Gene', (122, 127))	('MMP-2', 'Gene', '4313', (260, 265))	('MMP-2', 'Gene', '4313', (122, 127))	('complex', 'Interaction', (69, 76))	('suppression', 'Var', (212, 223))	('down-regulation', 'NegReg', (241, 256))	('CD73', 'Gene', (227, 231))	('production', 'MPA', (108, 118))
521060	31510956	CD73 is also known as ecto-5'-nucleotidase (ecto5'-NT).	('CD73', 'Var', (0, 4))	("ecto-5'-nucleotidase", 'Gene', (22, 42))	('N', 'Chemical', 'MESH:D009584', (51, 52))	("ecto-5'-nucleotidase", 'Gene', '4907', (22, 42))
521088	31510956	While the CD99-emmprin complex was detected, inhibition of CD99 expression did not suppress MMP-2 production by fibroblasts.	('MMP-2', 'Gene', '4313', (92, 97))	('CD99', 'Gene', '4267', (10, 14))	('CD99', 'Gene', (59, 63))	('CD99', 'Gene', (10, 14))	('inhibition', 'Var', (45, 55))	('CD99', 'Gene', '4267', (59, 63))	('MMP-2', 'Gene', (92, 97))
521176	30574289	The der(17)t(X;17)(p11;q25) hints to rearrangement and fusion of ASPL and TFE3 genes.	('TFE3', 'Gene', (74, 78))	('der(17)t(X;17)(p11;q25', 'Var', (4, 26))	('ASPL', 'Gene', '79058', (65, 69))	('TFE3', 'Gene', '7030', (74, 78))	('ASPL', 'Gene', (65, 69))	('der(17)t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 27))
521193	30574289	Apart from this, identification of mutations and homozygous deletions of the SMARCB1 (INI1) gene or absence of nuclear staining for INI1 are commonly encountered in rhabdoid tumors, but absent in ASPS.	('SMARCB1', 'Gene', '6598', (77, 84))	('ASPS', 'Gene', '79058', (196, 200))	('SMARCB1', 'Gene', (77, 84))	('encountered', 'Reg', (150, 161))	('rhabdoid tumors', 'Disease', (165, 180))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (165, 180))	('homozygous deletions', 'Var', (49, 69))	('INI1', 'Gene', (132, 136))	('ASPS', 'Gene', (196, 200))	('INI1', 'Gene', '6598', (132, 136))	('INI1', 'Gene', (86, 90))	('INI1', 'Gene', '6598', (86, 90))	('mutations', 'Var', (35, 44))
521199	30574289	A comparable but common t(X;17)(p11;q25) translocation and ASPSCR1/TFE3 fusion transcripts have also been acknowledged in a type of renal cell carcinoma developing in pediatric and young adult patients.	('t(X;17)(p11;q25', 'Var', (24, 39))	('patients', 'Species', '9606', (193, 201))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (132, 152))	('TFE3', 'Gene', (67, 71))	('ASPSCR1', 'Gene', (59, 66))	('t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (24, 40))	('type of renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 152))	('fusion', 'Var', (72, 78))	('TFE3', 'Gene', '7030', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('type of renal cell carcinoma', 'Disease', (124, 152))	('ASPSCR1', 'Gene', '79058', (59, 66))
521228	29865280	Parvovirus H-1PV triggers several distinct cell death processes, including apoptosis and the cytosolic relocation and activation of lysosomal cathepsins.	('cell death', 'CPA', (43, 53))	('activation', 'PosReg', (118, 128))	('H-1PV', 'Var', (11, 16))	('apoptosis', 'CPA', (75, 84))	('lysosomal cathepsins', 'Enzyme', (132, 152))	('Parvovirus H-1PV', 'Species', '10799', (0, 16))	('cytosolic relocation', 'CPA', (93, 113))	('triggers', 'Reg', (17, 25))
521406	27672565	High throughput methods has revealed gene copy number variations, such as - 1q-, 18q-, 20-, 16q+ along with mutation in TP53, CDKN2A and STAT2 and concurrent presence of STAT2 and TP53 reported as poor prognostic.	('STAT2', 'Gene', (170, 175))	('STAT2', 'Gene', '6773', (137, 142))	('CDKN2A', 'Gene', (126, 132))	('TP53', 'Gene', '7157', (180, 184))	('TP53', 'Gene', (180, 184))	('mutation', 'Var', (108, 116))	('STAT2', 'Gene', '6773', (170, 175))	('CDKN2A', 'Gene', '1029', (126, 132))	('16q+ along', 'Var', (92, 102))	('STAT2', 'Gene', (137, 142))	('20-', 'Var', (87, 90))	('18q-', 'Var', (81, 85))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
521412	27672565	Then comes the role of anthracyclines and addition of doxorubicin resulted in improved survival in 342 localized ESFT along with additional benefit of whole lung irradiation (WLI) in metastasis prevention in Intergroup Ewing's Sarcoma Study 1 (IESS-1).	('survival', 'MPA', (87, 95))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (219, 234))	('anthracyclines', 'Chemical', 'MESH:D018943', (23, 37))	('doxorubicin', 'Chemical', 'MESH:D004317', (54, 65))	('Sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	("Ewing's Sarcoma", 'Disease', (219, 234))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (219, 234))	('improved', 'PosReg', (78, 86))	('anthracyclines', 'Var', (23, 37))
521467	27672565	The other potential targeted therapies include - PARP1 inhibitor olaparib in combination with temozolamide showed in-vivo and in-vitro activity, anti-GD2 ganglioside (a neuroendocrine marker present in ESFT cells) chimeric antigen, and anti-CD99 monoclonal antibody are in preclinical study periods.	('PARP1', 'Gene', '142', (49, 54))	('CD99', 'Gene', '4267', (241, 245))	('PARP1', 'Gene', (49, 54))	('GD2 ganglioside', 'Chemical', 'MESH:C019403', (150, 165))	('olaparib', 'Chemical', 'MESH:C531550', (65, 73))	('temozolamide', 'Chemical', '-', (94, 106))	('activity', 'MPA', (135, 143))	('anti-GD2', 'Var', (145, 153))	('inhibitor', 'Var', (55, 64))	('CD99', 'Gene', (241, 245))
521500	27366153	A powerful causal-effect relation between specific gene alterations and OS initiation came from studies of human hereditary disorders characterized by a predisposition to the development of OS.	('OS', 'Phenotype', 'HP:0002669', (190, 192))	('OS initiation', 'Disease', (72, 85))	('alterations', 'Var', (56, 67))	('hereditary disorders', 'Disease', 'MESH:D030342', (113, 133))	('human', 'Species', '9606', (107, 112))	('OS', 'Phenotype', 'HP:0002669', (72, 74))	('hereditary disorders', 'Disease', (113, 133))
521502	27366153	The strongest genetic association for sporadic and hereditary OS is with the retinoblastoma (RB) and the P53 tumor suppressor genes; meanwhile other relevant alterations include mutations in other cell cycle regulators, oncogenes, and DNA helicases.	('retinoblastoma (RB', 'Gene', (77, 95))	('hereditary OS', 'Disease', (51, 64))	('retinoblastoma', 'Phenotype', 'HP:0009919', (77, 91))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('DNA helicases', 'Protein', (235, 248))	('retinoblastoma (RB)', 'Gene', '5925', (77, 96))	('sporadic', 'Disease', (38, 46))	('RB', 'Phenotype', 'HP:0009919', (93, 95))	('OS', 'Phenotype', 'HP:0002669', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', (109, 114))
521503	27366153	Li-Fraumeni and hereditary retinoblastoma syndromes are caused by heterozygous germ-line mutations of P53 and RB, respectively, and patients presenting with these disorders have a higher predisposition to a range of cancers, including OS.	('P53 and RB', 'Gene', '7157', (102, 112))	('Li-Fraumeni and hereditary retinoblastoma syndromes', 'Disease', 'MESH:D016864', (0, 51))	('OS', 'Phenotype', 'HP:0002669', (235, 237))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('retinoblastoma', 'Phenotype', 'HP:0009919', (27, 41))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('mutations', 'Var', (89, 98))	('cancers', 'Disease', (216, 223))	('RB', 'Phenotype', 'HP:0009919', (110, 112))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('patients', 'Species', '9606', (132, 140))	('caused by', 'Reg', (56, 65))
521504	27366153	Importantly, mutations in P53 and/or RB genes and other components of their pathways are also common in sporadic OS, suggesting a relevant role for alterations in these tumor suppression genes or their related signaling pathways in OS development.	('P53', 'Gene', (26, 29))	('RB', 'Phenotype', 'HP:0009919', (37, 39))	('OS', 'Phenotype', 'HP:0002669', (232, 234))	('common', 'Reg', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('OS', 'Phenotype', 'HP:0002669', (113, 115))	('sporadic OS', 'Disease', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('RB', 'Gene', '5925', (37, 39))	('tumor', 'Disease', (169, 174))	('mutations', 'Var', (13, 22))
521508	27366153	Notably, RB mutation strongly reduced the latency required for sarcoma formation in P53-deficient mice, although it decreased the proportion of OS formed.	('sarcoma', 'Disease', (63, 70))	('RB', 'Phenotype', 'HP:0009919', (9, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('latency', 'MPA', (42, 49))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('OS', 'Phenotype', 'HP:0002669', (144, 146))	('reduced', 'NegReg', (30, 37))	('RB', 'Gene', '5925', (9, 11))	('mutation', 'Var', (12, 20))	('decreased', 'NegReg', (116, 125))	('mice', 'Species', '10090', (98, 102))
521509	27366153	It was reported that RB is needed to promote the osteogenic differentiation program of mesenchymal stem/stromal cells (MSCs) and, therefore, it could be speculated that RB mutations synergize with P53 inactivation in OS formation only when mutations occur in osteogenic-committed cell types; meanwhile it could favor other sarcoma phenotypes when mutated in more immature cell types (see below).	('RB', 'Gene', '5925', (21, 23))	('mutations', 'Var', (172, 181))	('osteogenic differentiation program', 'CPA', (49, 83))	('sarcoma', 'Disease', (323, 330))	('sarcoma', 'Phenotype', 'HP:0100242', (323, 330))	('RB', 'Gene', '5925', (169, 171))	('RB', 'Phenotype', 'HP:0009919', (21, 23))	('inactivation', 'NegReg', (201, 213))	('favor', 'PosReg', (311, 316))	('OS', 'Phenotype', 'HP:0002669', (217, 219))	('sarcoma', 'Disease', 'MESH:D012509', (323, 330))	('RB', 'Phenotype', 'HP:0009919', (169, 171))
521510	27366153	Other genes involved in P53 or RB signaling have also been found to be mutated in sporadic OS.	('sporadic OS', 'Disease', (82, 93))	('RB', 'Gene', '5925', (31, 33))	('OS', 'Phenotype', 'HP:0002669', (91, 93))	('mutated', 'Var', (71, 78))	('RB', 'Phenotype', 'HP:0009919', (31, 33))
521511	27366153	For example, the INK4A/ARF locus, which encodes for P16INK4A and P19ARF genes, is deleted in approximately 10% of OS.	('INK4A/ARF', 'Gene', (17, 26))	('deleted', 'Var', (82, 89))	('OS', 'Phenotype', 'HP:0002669', (114, 116))	('INK4A/ARF', 'Gene', '1029', (17, 26))
521512	27366153	P16INK4A and P19ARF proteins contribute to the stabilization of RB and P53 proteins through the inhibition of cyclin-dependent kinase 4 (CDK4) and mouse double minute 2 homolog (MDM2) repressors, respectively.	('P53', 'Gene', (71, 74))	('mouse', 'Species', '10090', (147, 152))	('P16INK4A', 'Var', (0, 8))	('cyclin-dependent kinase 4', 'Gene', '12567', (110, 135))	('stabilization', 'MPA', (47, 60))	('RB', 'Phenotype', 'HP:0009919', (64, 66))	('cyclin-dependent kinase 4', 'Gene', (110, 135))	('proteins', 'Protein', (75, 83))	('P19ARF', 'Var', (13, 19))	('inhibition', 'NegReg', (96, 106))	('RB', 'Gene', '5925', (64, 66))	('proteins', 'Protein', (20, 28))
521513	27366153	In addition, the absence of expression of P16INK4A correlated with a decreased survival in pediatric OS, while the amplification of MDM2 has been associated with the development of metastases in OS.	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('OS', 'Phenotype', 'HP:0002669', (101, 103))	('amplification', 'Var', (115, 128))	('absence', 'NegReg', (17, 24))	('P16INK4A', 'Var', (42, 50))	('expression', 'MPA', (28, 38))	('decreased', 'NegReg', (69, 78))	('OS', 'Phenotype', 'HP:0002669', (195, 197))	('metastases', 'Disease', (181, 191))	('associated', 'Reg', (146, 156))	('survival', 'MPA', (79, 87))	('MDM2', 'Gene', (132, 136))
521514	27366153	The amplification and/or increased expression of other cell cycle genes, such as Cyclins D1 and E, have also been reported in OS, further highlighting an important role of defective cell cycle regulation in OS development.	('cell cycle genes', 'Gene', (55, 71))	('defective cell cycle regulation', 'Phenotype', 'HP:0011018', (172, 203))	('increased', 'PosReg', (25, 34))	('Cyclins D1 and E', 'Gene', '595', (81, 97))	('OS', 'Phenotype', 'HP:0002669', (207, 209))	('reported', 'Reg', (114, 122))	('expression', 'MPA', (35, 45))	('OS', 'Phenotype', 'HP:0002669', (126, 128))	('amplification', 'Var', (4, 17))
521517	27366153	Transgenic mice overexpressing C-FOS developed OS, further suggesting a role in OS pathogenesis.	('developed', 'Reg', (37, 46))	('C-FOS', 'Var', (31, 36))	('OS', 'Phenotype', 'HP:0002669', (47, 49))	('OS', 'Phenotype', 'HP:0002669', (34, 36))	('Transgenic mice', 'Species', '10090', (0, 15))	('OS', 'Phenotype', 'HP:0002669', (80, 82))
521522	27366153	Confirming the heterogeneity of OS, an exome sequencing-based study showed that identified candidate OS-driver genes were associated with the development of a small set of tumors, suggesting that multiple oncogenic pathways drive the characteristic chromosomal instability during OS development.	('associated', 'Reg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('OS', 'Phenotype', 'HP:0002669', (101, 103))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('OS', 'Phenotype', 'HP:0002669', (280, 282))	('OS', 'Phenotype', 'HP:0002669', (32, 34))	('chromosomal instability', 'Var', (249, 272))	('chromosomal instability', 'Phenotype', 'HP:0040012', (249, 272))
521523	27366153	However, the overall mutation signatures in these tumors were reminiscent of BRCA1/2 deficient tumors, a finding with possible therapeutic implications.	('deficient tumors', 'Disease', (85, 101))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('deficient tumors', 'Disease', 'MESH:D009369', (85, 101))	('BRCA1/2', 'Gene', (77, 84))	('BRCA1/2', 'Gene', '672;675', (77, 84))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('mutation', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumors', 'Disease', (95, 101))
521525	27366153	Likewise, genomic analysis indicated that ossification factor genes such as MET, TWIST, and APC are frequently mutated in pediatric high-grade OS and these alterations correlated to a worse outcome, thus suggesting a role in OS development.	('APC', 'Disease', 'MESH:D011125', (92, 95))	('correlated to', 'Reg', (168, 181))	('mutated', 'Var', (111, 118))	('OS', 'Phenotype', 'HP:0002669', (225, 227))	('APC', 'Disease', (92, 95))	('TWIST', 'Gene', '7291', (81, 86))	('MET', 'Gene', (76, 79))	('OS', 'Phenotype', 'HP:0002669', (143, 145))	('TWIST', 'Gene', (81, 86))	('ossification factor genes', 'Gene', (42, 67))
521526	27366153	Other genetic and epigenetic alterations likely involved in OS pathogenesis include mutations in RECQL4 DNA helicase associated with the OS-predisposing Rothmund Thomson syndrome, amplification/mutation in the osteogenic factor RUNX2, loss of heterozygosity of FGFR2 and BUB3, enhanced telomerase activity, deletion of PRKAR1A, and reduced expression of WWOX or hypermethylation of HIC1 in P53 mutated tumors among others.	('PRKAR1A', 'Gene', (319, 326))	('FGFR2', 'Gene', '2263', (261, 266))	('HIC1', 'Gene', (382, 386))	('RECQL4', 'Gene', '9401', (97, 103))	('Thomson syndrome', 'Disease', (162, 178))	('hypermethylation', 'MPA', (362, 378))	('BUB3', 'Gene', (271, 275))	('amplification/mutation', 'Var', (180, 202))	('BUB3', 'Gene', '9184', (271, 275))	('Thomson syndrome', 'Disease', 'MESH:D011038', (162, 178))	('tumors', 'Phenotype', 'HP:0002664', (402, 408))	('RECQL4', 'Gene', (97, 103))	('OS', 'Phenotype', 'HP:0002669', (60, 62))	('PRKAR1A', 'Gene', '5573', (319, 326))	('HIC1', 'Gene', '3090', (382, 386))	('deletion', 'Var', (307, 315))	('telomerase', 'Enzyme', (286, 296))	('tumor', 'Phenotype', 'HP:0002664', (402, 407))	('WWOX', 'Gene', (354, 358))	('enhanced', 'PosReg', (277, 285))	('loss of heterozygosity', 'Var', (235, 257))	('tumors', 'Disease', (402, 408))	('mutations', 'Var', (84, 93))	('OS', 'Phenotype', 'HP:0002669', (137, 139))	('reduced', 'NegReg', (332, 339))	('RUNX2', 'Gene', (228, 233))	('FGFR2', 'Gene', (261, 266))	('OS-predisposing', 'Disease', (137, 152))	('expression', 'MPA', (340, 350))	('tumors', 'Disease', 'MESH:D009369', (402, 408))	('RUNX2', 'Gene', '860', (228, 233))	('activity', 'MPA', (297, 305))	('WWOX', 'Gene', '51741', (354, 358))	('P53', 'Gene', (390, 393))
521527	27366153	The cell-of-origin concept refers to the normal cell type that acquires the first cancer-promoting mutations and initiates tumor formation.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (123, 128))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
521529	27366153	Both translocation- and non-translocation-associated sarcomas have been modeled by introducing relevant mutations into MSC.	('mutations', 'Var', (104, 113))	('MSC', 'Gene', (119, 122))	('sarcomas', 'Disease', 'MESH:D012509', (53, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('sarcomas', 'Disease', (53, 61))
521530	27366153	In the case of OS, most of the cell-of-origin models are based on mutated P53, alone or in combination with RB inactivation, in the mesenchymal/osteogenic lineage of mouse models or in murine MSC.	('mutated', 'Var', (66, 73))	('P53', 'Gene', (74, 77))	('RB', 'Gene', '5925', (108, 110))	('OS', 'Phenotype', 'HP:0002669', (15, 17))	('mouse', 'Species', '10090', (166, 171))	('RB', 'Phenotype', 'HP:0009919', (108, 110))	('mesenchymal/osteogenic lineage of', 'CPA', (132, 165))	('murine', 'Species', '10090', (185, 191))
521531	27366153	By crossing mice with conditional (floxed) alleles of P53 and/or RB with mice that have the CRE recombinase gene under the control of different tissue-restricted promoters, several groups were able to generate OS development in vivo.	('OS development', 'CPA', (210, 224))	('generate', 'Reg', (201, 209))	('RB', 'Gene', '5925', (65, 67))	('mice', 'Species', '10090', (73, 77))	('RB', 'Phenotype', 'HP:0009919', (65, 67))	('mice', 'Species', '10090', (12, 16))	('P53', 'Var', (54, 57))	('OS', 'Phenotype', 'HP:0002669', (210, 212))
521532	27366153	Thus, the inactivation of P53 and/or RB in early mesenchymal progenitors of embryonic limb buds through PRX1-driven CRE expression (PRX1-CRE) resulted in sarcoma development, presenting an OS incidence of 60% in P53 -/- mice and 20-30% in P53 -/- RB -/- mice, where most of the alternate tumors formed poorly differentiated soft tissue sarcomas.	('mice', 'Species', '10090', (220, 224))	('RB', 'Gene', '5925', (37, 39))	('OS', 'Phenotype', 'HP:0002669', (189, 191))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('RB', 'Phenotype', 'HP:0009919', (247, 249))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (154, 161))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (324, 343))	('embryonic limb', 'Disease', 'MESH:D017880', (76, 90))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (324, 344))	('inactivation', 'Var', (10, 22))	('sarcoma', 'Disease', 'MESH:D012509', (336, 343))	('sarcomas', 'Disease', 'MESH:D012509', (336, 344))	('sarcoma', 'Disease', (336, 343))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (336, 344))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('embryonic limb', 'Disease', (76, 90))	('RB', 'Gene', '5925', (247, 249))	('RB', 'Phenotype', 'HP:0009919', (37, 39))	('sarcomas', 'Disease', (336, 344))	('mice', 'Species', '10090', (254, 258))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('resulted in', 'Reg', (142, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (336, 343))	('tumors', 'Disease', (288, 294))
521533	27366153	Meanwhile, the inactivation of these cell cycle regulators in osteoblast precursors [OSX1 (Osterix)-CRE] resulted in a higher incidence of OS formation in both P53 -/- (100%) and P53 -/- RB -/- mice (between 53 and 100%).	('RB', 'Phenotype', 'HP:0009919', (187, 189))	('OS', 'Phenotype', 'HP:0002669', (139, 141))	('OS formation', 'CPA', (139, 151))	('OS', 'Phenotype', 'HP:0002669', (85, 87))	('RB', 'Gene', '5925', (187, 189))	('mice', 'Species', '10090', (194, 198))	('inactivation', 'Var', (15, 27))
521534	27366153	Similarly, ShRNA-mediated depletion of P53, together with CRE-mediated inactivation of RB in osteoblast precursors (OSX1 restricted), resulted in a delayed and consistent formation of OS, presenting a higher degree of osteoblastic differentiation than other CRE-based models.	('OS', 'Phenotype', 'HP:0002669', (184, 186))	('P53', 'Gene', (39, 42))	('depletion', 'Var', (26, 35))	('RB', 'Gene', '5925', (87, 89))	('OS', 'Phenotype', 'HP:0002669', (116, 118))	('RB', 'Phenotype', 'HP:0009919', (87, 89))	('inactivation', 'Var', (71, 83))	('osteoblastic differentiation', 'CPA', (218, 246))
521538	27366153	Notably, the activation of NOTCH in mesenchymal progenitors or in osteoblast precursors produces embryonic lethality.	('activation', 'PosReg', (13, 23))	('NOTCH', 'Var', (27, 32))	('osteoblast precursors', 'CPA', (66, 87))	('embryonic lethality', 'Disease', 'MESH:D020964', (97, 116))	('embryonic lethality', 'Disease', (97, 116))
521542	27366153	P53 -/- and P53 -/- RB -/- adipose-derived-MSC (ASC) or BM-derived-MSC (BM-MSC) give rise to leiomyosarcoma-like tumors when injected subcutaneously into immunodeficient mice.	('immunodeficient', 'Disease', 'MESH:D007153', (154, 169))	('leiomyosarcoma-like tumors', 'Disease', (93, 119))	('immunodeficient', 'Disease', (154, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (93, 107))	('RB', 'Phenotype', 'HP:0009919', (20, 22))	('leiomyosarcoma-like tumors', 'Disease', 'MESH:D007890', (93, 119))	('mice', 'Species', '10090', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('P53 -/-', 'Var', (0, 7))	('RB', 'Gene', '5925', (20, 22))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
521543	27366153	Otherwise, when BM-MSCs were differentiated along the osteoblastic lineage before CRE-mediated deletion of P53 and RB, they generated OS-like tumors upon subcutaneous injection into immunodeficient mice, whereas P53 -/- RB -/- ASC-derived osteogenic progenitors did not display tumorigenic potential.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('deletion', 'Var', (95, 103))	('immunodeficient', 'Disease', 'MESH:D007153', (182, 197))	('immunodeficient', 'Disease', (182, 197))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('RB', 'Phenotype', 'HP:0009919', (115, 117))	('P53 and RB', 'Gene', '7157', (107, 117))	('RB', 'Gene', '5925', (220, 222))	('tumors', 'Disease', (142, 148))	('tumor', 'Disease', (278, 283))	('tumor', 'Disease', (142, 147))	('RB', 'Gene', '5925', (115, 117))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('OS', 'Phenotype', 'HP:0002669', (134, 136))	('RB', 'Phenotype', 'HP:0009919', (220, 222))	('generated', 'Reg', (124, 133))	('mice', 'Species', '10090', (198, 202))
521545	27366153	Nevertheless, orthotopic (intrabone or periosteal) inoculation of P53 -/- and P53 -/- RB -/- BM-MSC and ASC undifferentiated MSC consistently generated osteoblastic OS displaying human OS radiographic and histological features alongside metastatic potential.	('human', 'Species', '9606', (179, 184))	('RB', 'Gene', '5925', (86, 88))	('human OS', 'CPA', (179, 187))	('osteoblastic OS', 'Disease', 'MESH:C567932', (152, 167))	('OS', 'Phenotype', 'HP:0002669', (165, 167))	('osteoblastic OS', 'Disease', (152, 167))	('generated', 'PosReg', (142, 151))	('RB', 'Phenotype', 'HP:0009919', (86, 88))	('OS', 'Phenotype', 'HP:0002669', (185, 187))	('P53 -/-', 'Var', (66, 73))
521548	27366153	Furthermore, evidence of undifferentiated MSC as cell-of-origin for OS comes from the introduction of other oncogenic events into undifferentiated BM-MSC, like the expression of C-MYC in a P16INK4A -/- P19ARF -/- genetic background or the aneuploidization accompanied by the loss of the INKAA locus, resulting in OS development.	('aneuploidization', 'Var', (239, 255))	('C-MYC', 'Gene', (178, 183))	('OS', 'Phenotype', 'HP:0002669', (68, 70))	('OS development', 'CPA', (313, 327))	('C-MYC', 'Gene', '4609', (178, 183))	('OS', 'Phenotype', 'HP:0002669', (313, 315))	('loss', 'NegReg', (275, 279))	('INKAA', 'Gene', (287, 292))
521551	27366153	In this regard this type of tumors could be related to fibrodysplasia ossificans progressiva, a rare genetic disorder of connective tissue characterized by the presence of activating mutations in the ACVR1 gene, which encode a BMP type I receptor.	('fibrodysplasia', 'Disease', (55, 69))	('BMP', 'Gene', '649', (227, 230))	('ACVR1', 'Gene', '90', (200, 205))	('mutations', 'Var', (183, 192))	('tumors', 'Disease', (28, 34))	('activating', 'PosReg', (172, 182))	('genetic disorder', 'Disease', 'MESH:D030342', (101, 117))	('BMP', 'Gene', (227, 230))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('disorder of connective tissue', 'Phenotype', 'HP:0003549', (109, 138))	('fibrodysplasia', 'Disease', 'MESH:D009221', (55, 69))	('genetic disorder', 'Disease', (101, 117))	('ACVR1', 'Gene', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
521578	27366153	BYL719, a specific PI3Kalpha inhibitor, induces cell cycle arrest and inhibition of cell migration in OS cells, and, therefore, has been postulated to be useful for multidrug therapeutic approaches.	('inhibition', 'NegReg', (70, 80))	('arrest', 'Disease', (59, 65))	('BYL719', 'Var', (0, 6))	('OS', 'Phenotype', 'HP:0002669', (102, 104))	('induces', 'PosReg', (40, 47))	('cell migration in OS cells', 'CPA', (84, 110))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (48, 65))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
521579	27366153	Moreover, another PI3K inhibitor, LY294002, induces cell cycle arrest and apoptosis in OS-CSC.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('apoptosis', 'CPA', (74, 83))	('LY294002', 'Var', (34, 42))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('OS-CSC', 'Disease', (87, 93))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('arrest', 'Disease', (63, 69))	('induces', 'PosReg', (44, 51))	('OS', 'Phenotype', 'HP:0002669', (87, 89))
521580	27366153	In addition, aberrant active WNT/beta-catenin signaling has been described in the OS-CSC population and has been associated with SOX2 overexpression and tumorigenicity.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('overexpression', 'PosReg', (134, 148))	('SOX2', 'Gene', '6657', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('OS', 'Phenotype', 'HP:0002669', (82, 84))	('SOX2', 'Gene', (129, 133))	('beta-catenin', 'Gene', (33, 45))	('beta-catenin', 'Gene', '1499', (33, 45))	('OS-CSC', 'Disease', (82, 88))	('associated', 'Reg', (113, 123))	('aberrant', 'Var', (13, 21))
521583	27366153	Likewise, NOTCH signaling has been associated with ALDH activity and increased metastatic potential in OS cells.	('metastatic potential', 'CPA', (79, 99))	('NOTCH signaling', 'Var', (10, 25))	('increased', 'PosReg', (69, 78))	('ALDH', 'Gene', '11670', (51, 55))	('associated', 'Reg', (35, 45))	('ALDH', 'Gene', (51, 55))	('OS', 'Phenotype', 'HP:0002669', (103, 105))
521588	27366153	Moreover, TGF-beta signaling activation has been involved in the induction of stemness, tumorigenicity, metastatic potential, and chemoresistance in nonstem OS cells, and, conversely, the blocking of this signaling resulted in the inhibition of this dedifferentiation process of nonstem cell populations, thereby highlighting TGF-beta as a potential therapeutic target.	('metastatic potential', 'CPA', (104, 124))	('TGF-beta', 'Gene', (10, 18))	('blocking', 'Var', (188, 196))	('activation', 'PosReg', (29, 39))	('stemness', 'CPA', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibition', 'NegReg', (231, 241))	('chemoresistance', 'CPA', (130, 145))	('TGF-beta', 'Gene', '7040', (326, 334))	('OS', 'Phenotype', 'HP:0002669', (157, 159))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('dedifferentiation process', 'CPA', (250, 275))	('TGF-beta', 'Gene', '7040', (10, 18))	('TGF-beta', 'Gene', (326, 334))	('tumor', 'Disease', (88, 93))
521592	27366153	On the other hand, high levels of miR-133a and CD133 correlated with poor prognosis in OS and the inhibition of miR-133a associated with chemotherapy suppressed lung metastasis and prolonged survival in preclinical models of OS.	('inhibition', 'Var', (98, 108))	('prolonged', 'PosReg', (181, 190))	('suppressed', 'NegReg', (150, 160))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('OS', 'Phenotype', 'HP:0002669', (225, 227))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('CD133', 'Gene', (47, 52))	('lung metastasis', 'CPA', (161, 176))	('survival', 'CPA', (191, 199))	('OS', 'Phenotype', 'HP:0002669', (87, 89))	('CD133', 'Gene', '8842', (47, 52))
521596	27366153	Thus, besides inhibiting proliferation, invasion, and metastatic potential in OS cells, the hypoglycemic agent metformin also induces a marked reduction of the self-renewal and differentiation potential of CSC subpopulations and sensitizes OS cell to cisplatin.	('invasion', 'CPA', (40, 48))	('proliferation', 'CPA', (25, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (251, 260))	('OS', 'Phenotype', 'HP:0002669', (78, 80))	('metastatic potential', 'CPA', (54, 74))	('metformin', 'Var', (111, 120))	('reduction', 'NegReg', (143, 152))	('inhibiting', 'NegReg', (14, 24))	('metformin', 'Chemical', 'MESH:D008687', (111, 120))	('OS', 'Phenotype', 'HP:0002669', (240, 242))
521609	27366153	In addition, inhibition of transcription factors presenting altered activity offers a promising choice since they are pivotal points in signaling pathways and therefore their inhibition may block several routes involved in tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('inhibition', 'Var', (13, 23))	('block', 'NegReg', (190, 195))	('inhibition', 'NegReg', (175, 185))	('activity', 'MPA', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (223, 228))
521610	27366153	In this regard, inhibition of SP1 was able to eliminate CSCs in soft tissue sarcoma models.	('CSCs', 'Disease', (56, 60))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('eliminate', 'NegReg', (46, 55))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (64, 83))	('SP1', 'Gene', (30, 33))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('inhibition', 'Var', (16, 26))
521611	27366153	In the most likely scenario, OS development is initiated by different cell types along the mesenchymal-osteogenic lineage targeted with relevant oncogenic lesions, like the inactivation of the tumor suppressor genes P53 and RB, and highly influenced by bone microenvironment signals.	('OS', 'Phenotype', 'HP:0002669', (29, 31))	('oncogenic lesions', 'Disease', (145, 162))	('OS development', 'CPA', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('P53 and RB', 'Gene', '7157', (216, 226))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('oncogenic lesions', 'Disease', 'MESH:D000074723', (145, 162))	('RB', 'Phenotype', 'HP:0009919', (224, 226))	('tumor', 'Disease', (193, 198))	('inactivation', 'Var', (173, 185))
521612	27366153	During tumor evolution, CSC subpopulations emerge after the accumulation of further epigenetic and/or genetic alterations in a subset of tumor cells.	('tumor', 'Disease', (137, 142))	('epigenetic', 'Var', (84, 94))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('genetic alterations', 'Var', (102, 121))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
521664	26911328	There were higher proportion of patients with tumors located in the extremities and head/neck, MFH, grade III, positive margin and the usage of chemotherapy in RT group, while the no RT group had a higher rate of patients with tumors located in retroperitoneum, liposarcoma, grade I and negative margin.	('liposarcoma', 'Disease', 'MESH:D008080', (262, 273))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MFH', 'Gene', '27086', (95, 98))	('liposarcoma', 'Phenotype', 'HP:0012034', (262, 273))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('liposarcoma', 'Disease', (262, 273))	('positive margin', 'Var', (111, 126))	('patients', 'Species', '9606', (213, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('MFH', 'Gene', (95, 98))	('grade III', 'Var', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
521720	26911328	The metastasis after local recurrence significantly increased in patients with high-grade and deep tumors.	('increased', 'PosReg', (52, 61))	('high-grade', 'Var', (79, 89))	('deep tumors', 'Disease', 'MESH:D057887', (94, 105))	('patients', 'Species', '9606', (65, 73))	('deep tumors', 'Disease', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('metastasis', 'CPA', (4, 14))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
521880	33526082	Translocation of 'FUS-CREB3L1' fusion gene is reported in about 5% of the LGFMS cases.	('CREB3L1', 'Gene', (22, 29))	('LGFMS', 'Disease', (74, 79))	('Translocation', 'Var', (0, 13))	('CREB3L1', 'Gene', '90993', (22, 29))
521888	27499902	We identified non-synonymous somatic mutations in 90% of the cases, with 27 of 30 cases (90%) harbouring TP53 alterations.	('alterations', 'Var', (110, 121))	('non-synonymous', 'Var', (14, 28))	('harbouring', 'Reg', (94, 104))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))
521889	27499902	The PI3K pathway was the most commonly mutated signalling pathway with mutations identified in PIK3CA, PTEN, PIK3R1, and/or PIK3R2 in two-thirds of the cases.	('PTEN', 'Gene', (103, 107))	('mutated', 'Reg', (39, 46))	('PIK3CA', 'Gene', (95, 101))	('PTEN', 'Gene', '5728', (103, 107))	('PIK3CA', 'Gene', '5290', (95, 101))	('PIK3R2', 'Gene', (124, 130))	('PIK3R2', 'Gene', '5296', (124, 130))	('mutations', 'Var', (71, 80))	('PI3K pathway', 'Pathway', (4, 16))	('PIK3R1', 'Gene', (109, 115))	('PIK3R1', 'Gene', '5295', (109, 115))
521890	27499902	Mutations in FBXW7, PPP2R1A, ARID1A and KRAS were demonstrated in a minority of cases.	('PPP2R1A', 'Gene', (20, 27))	('FBXW7', 'Gene', '55294', (13, 18))	('PPP2R1A', 'Gene', '5518', (20, 27))	('KRAS', 'Gene', (40, 44))	('FBXW7', 'Gene', (13, 18))	('ARID1A', 'Gene', '8289', (29, 35))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (40, 44))	('ARID1A', 'Gene', (29, 35))
521892	27499902	Furthermore, the same TP53 alterations and/or PI3K pathway mutations seen in the primary tumours were also identified in the metastatic sites.	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('primary tumours', 'Disease', (81, 96))	('PI3K pathway', 'Pathway', (46, 58))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('TP53', 'Gene', '7157', (22, 26))	('mutations', 'Var', (59, 68))	('primary tumours', 'Disease', 'MESH:D009369', (81, 96))	('TP53', 'Gene', (22, 26))	('alterations', 'Var', (27, 38))
521895	27499902	Our results provide insights into the oncogenesis of uterine carcinosarcoma and identify targetable mutations that represent early oncogenic events.	('mutations', 'Var', (100, 109))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (53, 75))	('carcinosarcoma', 'Disease', (61, 75))	('carcinosarcoma', 'Disease', 'MESH:D002296', (61, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
521905	27499902	A number of prior studies compared patterns of X-chromosome inactivation, microsatellite instability (MSI), types of TP53 and KRAS mutations and loss of heterozygosity (LOH) status between the carcinoma and sarcoma elements and demonstrated shared molecular features in the majority of cases 12, 13, 14, 15.	('KRAS', 'Gene', '3845', (126, 130))	('mutations', 'Var', (131, 140))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (193, 214))	('MSI', 'Disease', (102, 105))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('loss', 'Var', (145, 149))	('microsatellite instability', 'MPA', (74, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('KRAS', 'Gene', (126, 130))	('MSI', 'Disease', 'None', (102, 105))
521942	27499902	Overall, there appeared to be good concordance in the detection of mutations in FFPE tumour tissue.	('FFPE tumour', 'Disease', (80, 91))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('FFPE tumour', 'Disease', 'MESH:D009369', (80, 91))	('mutations', 'Var', (67, 76))
521943	27499902	TP53 mutations were present in the majority of carcinosarcoma (24 of 30) (80%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('carcinosarcoma', 'Disease', (47, 61))	('mutations', 'Var', (5, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('carcinosarcoma', 'Disease', 'MESH:D002296', (47, 61))
521944	27499902	Most of the tumours harbouring missense TP53 mutations showed diffuse nuclear p53 immunostaining, with the exception of two cases (7 and 21) that harboured TP53 deletions and showed diffuse nuclear p53 immunostaining (Table 2).	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('missense', 'Var', (31, 39))	('mutations', 'Var', (45, 54))	('tumours', 'Disease', (12, 19))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('TP53', 'Gene', '7157', (40, 44))	('p53', 'Gene', (78, 81))	('showed', 'Reg', (55, 61))	('TP53', 'Gene', (40, 44))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('p53', 'Gene', '7157', (78, 81))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))
521945	27499902	Cases 19 and 30 both demonstrated TP53 mutations (frameshift and nonsense) in the sarcoma component but not the carcinoma component of the tumour, and both displayed a wild-type pattern of p53 immunostaining in both components of the tumour.	('tumour', 'Disease', (139, 145))	('carcinoma component of the tumour', 'Disease', (112, 145))	('TP53', 'Gene', (34, 38))	('p53', 'Gene', '7157', (189, 192))	('tumour', 'Disease', (234, 240))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('frameshift', 'Var', (50, 60))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcoma component', 'Disease', 'MESH:D012509', (82, 99))	('carcinoma component of the tumour', 'Disease', 'MESH:D009369', (112, 145))	('nonsense', 'Var', (65, 73))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('sarcoma component', 'Disease', (82, 99))	('TP53', 'Gene', '7157', (34, 38))	('p53', 'Gene', (189, 192))
521946	27499902	Loss of nuclear p53 immunohistochemistry was detected in 5 cases with indel or nonsense mutations, and 3 additional tumours (cases 17, 18 and 29) displayed abnormal patterns of staining with no detectable mutations (Table 2 and supplementary material Table 2).	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('indel', 'Var', (70, 75))	('p53', 'Gene', (16, 19))	('Loss', 'NegReg', (0, 4))	('additional tumours', 'Disease', 'MESH:D009369', (105, 123))	('p53', 'Gene', '7157', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('nonsense mutations', 'Var', (79, 97))	('additional tumours', 'Disease', (105, 123))
521948	27499902	In the primary tumours, mutations involving genes that encode the kinase or regulatory proteins of the PI3K pathway were identified in 20 of 30 tumours (67%), where multiple PI3K pathway proteins were mutated in 6 tumours.	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('identified', 'Reg', (121, 131))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('tumours', 'Disease', (15, 22))	('primary tumours', 'Disease', (7, 22))	('tumours', 'Disease', 'MESH:D009369', (214, 221))	('tumours', 'Disease', (214, 221))	('primary tumours', 'Disease', 'MESH:D009369', (7, 22))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('mutations', 'Var', (24, 33))	('tumours', 'Disease', (144, 151))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
521949	27499902	PIK3CA mutations were found in 12 of 30 (40%) tumours, which were scattered throughout the different functional domains of PIK3CA (Figure 3).	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('PIK3CA', 'Gene', (123, 129))	('tumours', 'Disease', (46, 53))	('found', 'Reg', (22, 27))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (123, 129))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (7, 16))
521950	27499902	PTEN mutations, most commonly missense in type, were observed in eight tumours (27%).	('missense', 'Var', (30, 38))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('observed', 'Reg', (53, 61))	('tumours', 'Disease', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
521951	27499902	PIK3R1 mutations were found in five tumours (17%), while only one tumour demonstrated a PIK3R2 mutation.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('tumour', 'Disease', (36, 42))	('PIK3R1', 'Gene', '5295', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('PIK3R1', 'Gene', (0, 6))	('found', 'Reg', (22, 27))	('tumours', 'Disease', (36, 43))	('PIK3R2', 'Gene', (88, 94))	('PIK3R2', 'Gene', '5296', (88, 94))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', (66, 72))	('mutations', 'Var', (7, 16))
521952	27499902	Of note in this cohort, PIK3CA mutations were rarely found with concurrent PIK3R1 or PIK3R2 mutations.	('PIK3R1', 'Gene', (75, 81))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('mutations', 'Var', (92, 101))	('PIK3CA', 'Gene', '5290', (24, 30))	('PIK3R2', 'Gene', (85, 91))	('PIK3R1', 'Gene', '5295', (75, 81))	('PIK3R2', 'Gene', '5296', (85, 91))
521953	27499902	One tumour (case 20) with a PIK3CA mutation also harboured an AKT3 (E167D) mutation, while case 18 harboured an AKT3 (M336I) mutation at low frequency (5%) without concurrent PI3K pathway mutations.	('AKT3', 'Gene', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('PIK3CA', 'Gene', (28, 34))	('AKT3', 'Gene', '10000', (62, 66))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('AKT3', 'Gene', (112, 116))	('PIK3CA', 'Gene', '5290', (28, 34))	('M336I', 'Mutation', 'rs773792621', (118, 123))	('mutation', 'Var', (35, 43))	('tumour', 'Disease', (4, 10))	('E167D', 'Mutation', 'rs755369410', (68, 73))	('AKT3', 'Gene', '10000', (112, 116))
521956	27499902	By immunohistochemistry, only two cases showed loss of BAF250 (ARID1A), which corresponded to the presence of frameshift and nonsense mutations (Table 2).	('BAF250', 'Gene', (55, 61))	('frameshift', 'Var', (110, 120))	('nonsense mutations', 'Var', (125, 143))	('ARID1A', 'Gene', '8289', (63, 69))	('ARID1A', 'Gene', (63, 69))	('loss', 'NegReg', (47, 51))	('BAF250', 'Gene', '8289', (55, 61))
521958	27499902	A somatic MED12 mutation (D23Y) was identified in one tumour, which has been previously documented in a case of endometrial carcinoma 27; however, it was not the typical hotspot MED12 mutation found in uterine smooth muscle tumours 20, 21.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('D23Y', 'Var', (26, 30))	('muscle tumours', 'Disease', 'MESH:D009217', (217, 231))	('muscle tumours', 'Disease', (217, 231))	('MED12', 'Gene', (10, 15))	('MED12', 'Gene', (178, 183))	('tumours', 'Phenotype', 'HP:0002664', (224, 231))	('endometrial carcinoma', 'Disease', (112, 133))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('tumour', 'Disease', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (112, 133))	('D23Y', 'Mutation', 'p.D23Y', (26, 30))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (112, 133))	('MED12', 'Gene', '9968', (178, 183))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('MED12', 'Gene', '9968', (10, 15))
521961	27499902	A somatic POLE exonuclease domain mutation (M444K) was identified in one tumour (case 30), which was reported in an ultra-mutated endometrial carcinoma in a prior study 17.	('endometrial carcinoma', 'Disease', (130, 151))	('tumour', 'Disease', (73, 79))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (130, 151))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('M444K', 'Mutation', 'p.M444K', (44, 49))	('M444K', 'Var', (44, 49))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (130, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
521962	27499902	In keeping with the ultra-mutator phenotype, this tumour also possessed 11 point mutations involving eight other genes.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('point mutations', 'Var', (75, 90))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Disease', (50, 56))
521967	27499902	Two cases exhibited additional mutation(s) in the sarcoma component compared to the carcinoma component: case 19 with a TP53 missense mutation, and case 27 with PIK3R2, CHD4 mutations, and a POLE non-exonuclease domain mutation.	('CHD4', 'Gene', (169, 173))	('carcinoma component', 'Disease', (84, 103))	('PIK3R2', 'Gene', '5296', (161, 167))	('missense mutation', 'Var', (125, 142))	('mutation', 'Var', (31, 39))	('sarcoma component', 'Disease', 'MESH:D012509', (50, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('carcinoma component', 'Disease', 'MESH:C562869', (84, 103))	('mutations', 'Var', (174, 183))	('CHD4', 'Gene', '1108', (169, 173))	('sarcoma component', 'Disease', (50, 67))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))	('PIK3R2', 'Gene', (161, 167))
521968	27499902	In contrast, two cases displayed additional mutation(s) in the carcinoma component compared to the sarcoma component: case 8 with an ARID1A mutation, and case 14 with PPP2R1A, FBXW7 and SPOP mutations.	('ARID1A', 'Gene', '8289', (133, 139))	('ARID1A', 'Gene', (133, 139))	('sarcoma component', 'Disease', (99, 116))	('mutation', 'Var', (44, 52))	('carcinoma component', 'Disease', 'MESH:C562869', (63, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('SPOP', 'Gene', '8405', (186, 190))	('mutation', 'Var', (140, 148))	('FBXW7', 'Gene', '55294', (176, 181))	('SPOP', 'Gene', (186, 190))	('carcinoma component', 'Disease', (63, 82))	('FBXW7', 'Gene', (176, 181))	('sarcoma component', 'Disease', 'MESH:D012509', (99, 116))	('PPP2R1A', 'Gene', (167, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('PPP2R1A', 'Gene', '5518', (167, 174))
521969	27499902	Overall, there was complete concordance or partial overlap in mutations identified in the carcinoma and the sarcoma components in 11 of 12 cases, hence indicating clonal relatedness between the carcinoma and the sarcoma components.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('sarcoma component', 'Disease', (212, 229))	('carcinoma', 'Disease', 'MESH:D002277', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Disease', 'MESH:D002277', (194, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma component', 'Disease', 'MESH:D012509', (108, 125))	('carcinoma', 'Disease', (90, 99))	('sarcoma component', 'Disease', (108, 125))	('carcinoma', 'Disease', (194, 203))	('sarcoma component', 'Disease', 'MESH:D012509', (212, 229))	('mutations', 'Var', (62, 71))
521973	27499902	For case 22, the carcinoma and the sarcoma components of the uterine primary all harboured the same PTEN, PIK3R1 and TP53 (frameshift) mutations with loss of p53 immunostaining.	('PTEN', 'Gene', (100, 104))	('PTEN', 'Gene', '5728', (100, 104))	('PIK3R1', 'Gene', '5295', (106, 112))	('p53', 'Gene', '7157', (158, 161))	('carcinoma', 'Disease', (17, 26))	('PIK3R1', 'Gene', (106, 112))	('TP53', 'Gene', '7157', (117, 121))	('sarcoma component', 'Disease', 'MESH:D012509', (35, 52))	('TP53', 'Gene', (117, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('mutations', 'Var', (135, 144))	('frameshift) mutations', 'Var', (123, 144))	('sarcoma components of the uterine', 'Phenotype', 'HP:0010784', (35, 68))	('sarcoma component', 'Disease', (35, 52))	('carcinoma', 'Disease', 'MESH:D002277', (17, 26))	('loss', 'NegReg', (150, 154))	('p53', 'Gene', (158, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
521974	27499902	In contrast, the metastatic tumour (bilateral ovaries and peritoneal deposits) displayed no evidence of PTEN, PIK3R1 mutations, and harboured a different TP53 missense mutation with diffuse nuclear p53 immunostaining (Figure 2E-F).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('TP53', 'Gene', (154, 158))	('missense mutation', 'Var', (159, 176))	('PIK3R1', 'Gene', (110, 116))	('bilateral ovaries', 'Disease', (36, 53))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('PIK3R1', 'Gene', '5295', (110, 116))	('p53', 'Gene', (198, 201))	('tumour', 'Disease', (28, 34))	('bilateral ovaries', 'Disease', 'MESH:D010051', (36, 53))	('p53', 'Gene', '7157', (198, 201))	('bilateral ovaries', 'Phenotype', 'HP:0010463', (36, 53))	('PTEN', 'Gene', (104, 108))	('TP53', 'Gene', '7157', (154, 158))	('PTEN', 'Gene', '5728', (104, 108))
521977	27499902	Additional immunohistochemistry analysis demonstrated nuclear WT1 positivity in the ovarian tumour but not the uterine tumour (Figure 2E-F) 28.	('uterine tumour', 'Phenotype', 'HP:0010784', (111, 125))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('ovarian tumour', 'Disease', (84, 98))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Disease', (92, 98))	('WT1', 'Gene', '7490', (62, 65))	('WT1', 'Gene', (62, 65))	('ovarian tumour', 'Phenotype', 'HP:0100615', (84, 98))	('positivity', 'Var', (66, 76))	('tumour', 'Disease', (119, 125))	('ovarian tumour', 'Disease', 'MESH:D010051', (84, 98))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
521980	27499902	We have previously identified different molecular types of uterine carcinosarcomas with some tumours showing endometrial serous carcinoma-like mutation profiles (characterized by the presence of TP53 mutation with PPP2R1A and/or FBXW7 mutations and in the absence of PTEN, CTNNB1, KRAS or ARID1A mutations) and other tumours showing endometrioid carcinoma-like mutation profiles (characterized by the presence of PTEN, CTNNB1, KRAS and/or ARID1A mutations) 16.	('ARID1A', 'Gene', (439, 445))	('KRAS', 'Gene', (427, 431))	('CTNNB1', 'Gene', (419, 425))	('PTEN', 'Gene', (267, 271))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('ARID1A', 'Gene', (289, 295))	('KRAS', 'Gene', '3845', (281, 285))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (333, 355))	('CTNNB1', 'Gene', (273, 279))	('FBXW7', 'Gene', (229, 234))	('TP53', 'Gene', (195, 199))	('ARID1A', 'Gene', '8289', (439, 445))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('KRAS', 'Gene', (281, 285))	('ARID1A', 'Gene', '8289', (289, 295))	('PTEN', 'Gene', '5728', (267, 271))	('PPP2R1A', 'Gene', '5518', (214, 221))	('mutation', 'Var', (200, 208))	('carcinosarcomas', 'Disease', 'MESH:D002296', (67, 82))	('tumours', 'Disease', (317, 324))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (333, 355))	('PTEN', 'Gene', (413, 417))	('mutations', 'Var', (235, 244))	('endometrial serous carcinoma', 'Disease', (109, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('tumours', 'Phenotype', 'HP:0002664', (317, 324))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('FBXW7', 'Gene', '55294', (229, 234))	('PPP2R1A', 'Gene', (214, 221))	('TP53', 'Gene', '7157', (195, 199))	('tumours', 'Disease', 'MESH:D009369', (317, 324))	('CTNNB1', 'Gene', '1499', (419, 425))	('tumours', 'Disease', (93, 100))	('endometrioid carcinoma', 'Disease', (333, 355))	('PTEN', 'Gene', '5728', (413, 417))	('carcinosarcomas', 'Disease', (67, 82))	('CTNNB1', 'Gene', '1499', (273, 279))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (109, 137))	('tumour', 'Phenotype', 'HP:0002664', (317, 323))	('KRAS', 'Gene', '3845', (427, 431))	('mutations', 'Var', (446, 455))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
521989	27499902	This is evident in the cases where the two histologic components were separately analysed; all cases with detectable mutations shared at least one somatic mutation in common between the carcinoma and the sarcoma components.	('carcinoma', 'Disease', 'MESH:D002277', (186, 195))	('mutations', 'Var', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('sarcoma component', 'Disease', 'MESH:D012509', (204, 221))	('carcinoma', 'Disease', (186, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('sarcoma component', 'Disease', (204, 221))
521992	27499902	There were four tumours that showed differences in mutations in additional to shared mutations between the two components.	('mutations', 'Var', (51, 60))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumours', 'Disease', (16, 23))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
521993	27499902	These included two cases with additional mutations found in the sarcoma component and two cases with additional mutations found in the carcinoma component.	('mutations', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinoma component', 'Disease', 'MESH:C562869', (135, 154))	('sarcoma component', 'Disease', 'MESH:D012509', (64, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('sarcoma component', 'Disease', (64, 81))	('carcinoma component', 'Disease', (135, 154))
522000	27499902	We have identified mutations involving PI3K pathway in two-thirds of uterine carcinosarcoma examined, most commonly involving PIK3CA and PTEN.	('PIK3CA', 'Gene', (126, 132))	('carcinosarcoma', 'Disease', (77, 91))	('mutations', 'Var', (19, 28))	('PI3K pathway', 'Pathway', (39, 51))	('PIK3CA', 'Gene', '5290', (126, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('PTEN', 'Gene', (137, 141))	('carcinosarcoma', 'Disease', 'MESH:D002296', (77, 91))	('PTEN', 'Gene', '5728', (137, 141))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (69, 91))
522001	27499902	In contrast to prior studies on uterine carcinosarcomas 29, 30, our present analyses identified both traditional PIK3CA hotspots (exons 9 and 20) mutations as well as mutations in the adaptor binding domain, helical domain, and C2 domain which can also enhance kinase enzymatic activity 31, 32.	('mutations', 'Var', (146, 155))	('PIK3CA', 'Gene', (113, 119))	('carcinosarcomas', 'Disease', 'MESH:D002296', (40, 55))	('PIK3CA', 'Gene', '5290', (113, 119))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (32, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('mutations', 'Var', (167, 176))	('carcinosarcomas', 'Disease', (40, 55))	('enhance', 'PosReg', (253, 260))	('kinase enzymatic activity', 'MPA', (261, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
522002	27499902	When present, these PI3K pathway mutations were found in the carcinoma and sarcoma components of the primary tumour, as well as in the metastatic tumour.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Disease', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (33, 42))	('tumour', 'Disease', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('found', 'Reg', (48, 53))	('PI3K pathway', 'Pathway', (20, 32))	('carcinoma and sarcoma components of the primary tumour', 'Disease', 'MESH:D012509', (61, 115))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
522003	27499902	This indicates that these PI3K pathway mutations occur relatively early in the tumourigenesis of carcinosarcoma and likely represent important oncogenic driver events that could be targeted with PIK3CA/mTOR inhibitors 33, 34, 35.	('carcinosarcoma', 'Disease', (97, 111))	('PIK3CA', 'Gene', (195, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('PIK3CA', 'Gene', '5290', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (39, 48))	('carcinosarcoma', 'Disease', 'MESH:D002296', (97, 111))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('mTOR', 'Gene', '2475', (202, 206))	('PI3K pathway', 'Pathway', (26, 38))	('mTOR', 'Gene', (202, 206))	('tumour', 'Disease', (79, 85))
522004	27499902	We also observed a very high frequency of TP53 alterations (90%) in this series of uterine carcinosarcomas, which is supported by previous literature 5, 12, 16.	('TP53', 'Gene', '7157', (42, 46))	('carcinosarcomas', 'Disease', 'MESH:D002296', (91, 106))	('TP53', 'Gene', (42, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (98, 106))	('carcinosarcomas', 'Disease', (91, 106))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (83, 105))	('alterations', 'Var', (47, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
522006	27499902	In keeping with prior studies, MMR protein deficiency that suggests underlying microsatellite instability was rarely observed in our present series of uterine carcinosarcoma 12, 24.	('carcinosarcoma', 'Disease', (159, 173))	('carcinosarcoma', 'Disease', 'MESH:D002296', (159, 173))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (151, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('MMR protein deficiency', 'Disease', (31, 53))	('MMR protein deficiency', 'Disease', 'MESH:C536143', (31, 53))	('microsatellite', 'Var', (79, 93))
522007	27499902	A recent study demonstrated frequent mutations in chromatin remodelling genes (ARID1A, ARID1B, MLL3, SPOP) with the identification of 4 mismatch repair deficient tumour in a cohort of 17 uterine and five ovarian carcinosarcomas 36.	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('mismatch', 'Var', (136, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('SPOP', 'Gene', '8405', (101, 105))	('MLL3', 'Gene', (95, 99))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (204, 227))	('deficient tumour', 'Disease', (152, 168))	('ARID1B', 'Gene', (87, 93))	('mutations', 'Var', (37, 46))	('SPOP', 'Gene', (101, 105))	('ARID1A', 'Gene', '8289', (79, 85))	('ARID1A', 'Gene', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('ovarian carcinosarcomas', 'Disease', (204, 227))	('MLL3', 'Gene', '58508', (95, 99))	('ARID1B', 'Gene', '57492', (87, 93))	('deficient tumour', 'Disease', 'MESH:D009369', (152, 168))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (204, 227))
522008	27499902	While these results are overall different from our present cohort, a closer examination reveals that nearly all of the identified ARID1A, ARID1B and MLL3 mutations were found in the four MMR-deficient uterine carcinosarcomas and in four of the five ovarian carcinosarcomas.	('ARID1A', 'Gene', (130, 136))	('ovarian carcinosarcomas', 'Disease', 'MESH:D002296', (249, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('MLL3', 'Gene', '58508', (149, 153))	('ARID1A', 'Gene', '8289', (130, 136))	('found', 'Reg', (169, 174))	('MLL3', 'Gene', (149, 153))	('carcinosarcomas', 'Disease', 'MESH:D002296', (209, 224))	('ovarian carcinosarcomas', 'Phenotype', 'HP:0025318', (249, 272))	('carcinosarcomas', 'Disease', 'MESH:D002296', (257, 272))	('sarcomas', 'Phenotype', 'HP:0100242', (216, 224))	('deficient uterine', 'Phenotype', 'HP:0000013', (191, 208))	('ARID1B', 'Gene', (138, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (264, 272))	('carcinosarcomas', 'Disease', (209, 224))	('mutations', 'Var', (154, 163))	('ARID1B', 'Gene', '57492', (138, 144))	('carcinosarcomas', 'Disease', (257, 272))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (201, 223))	('ovarian carcinosarcomas', 'Disease', (249, 272))
522009	27499902	We did, however, identify a few cases in our cohort with ARID1A mutations and one with an SPOP mutation.	('SPOP', 'Gene', '8405', (90, 94))	('SPOP', 'Gene', (90, 94))	('mutations', 'Var', (64, 73))	('ARID1A', 'Gene', '8289', (57, 63))	('ARID1A', 'Gene', (57, 63))
522022	27499902	Further studies are needed to investigate whether there is increased propensity for POLE-mutated endometrioid carcinoma to display spindle cell elements.	('POLE-mutated', 'Var', (84, 96))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (97, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (97, 119))	('endometrioid carcinoma', 'Disease', (97, 119))
522032	25826089	PLK1 is a critical determinant of tumor cell sensitivity to CPT11 and its inhibition enhances the drug antitumor efficacy in squamous cell carcinoma models sensitive and resistant to camptothecins Intrinsic and acquired tumor drug resistance limits the therapeutic efficacy of camptothecins (CPTs).	('drug', 'MPA', (98, 102))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('camptothecins', 'Chemical', 'MESH:D002166', (183, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('tumor', 'Disease', (34, 39))	('camptothecins', 'Chemical', 'MESH:D002166', (277, 290))	('drug resistance', 'Phenotype', 'HP:0020174', (226, 241))	('PLK1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 148))	('CPT11', 'Var', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PLK1', 'Gene', '5347', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('squamous cell carcinoma', 'Disease', (125, 148))	('CPTs', 'Chemical', 'MESH:D002166', (292, 296))	('inhibition', 'NegReg', (74, 84))	('enhances', 'PosReg', (85, 93))
522033	25826089	Downregulation of the mitotic kinase PLK1 was found associated with apoptosis induced by SN38 (CPT11 active metabolite).	('SN38', 'Var', (89, 93))	('Downregulation', 'NegReg', (0, 14))	('apoptosis', 'CPA', (68, 77))	('CPT11', 'Chemical', 'MESH:D000077146', (95, 100))	('SN38', 'Chemical', 'MESH:D000077146', (89, 93))
522034	25826089	We investigated the role of PLK1 in the cell response to CPTs in squamous cell carcinoma (SCC) and pediatric sarcoma cell lines and explored the therapeutic potential of the combination of CPT11 and the PLK1 inhibitor BI2536 in CPT-sensitive and -resistant tumor models.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('CPT', 'Chemical', 'MESH:D002166', (228, 231))	('pediatric sarcoma cell lines', 'Disease', (99, 127))	('SCC', 'Gene', '6317', (90, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('CPT', 'Chemical', 'MESH:D002166', (189, 192))	('tumor', 'Disease', (257, 262))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 88))	('SCC', 'Gene', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('BI2536', 'Var', (218, 224))	('CPTs', 'Chemical', 'MESH:D002166', (57, 61))	('squamous cell carcinoma', 'Disease', (65, 88))	('pediatric sarcoma cell lines', 'Disease', 'MESH:D063766', (99, 127))	('CPT11', 'Chemical', 'MESH:D000077146', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('BI2536', 'Chemical', 'MESH:C518477', (218, 224))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('CPT11', 'Gene', (189, 194))	('CPT', 'Chemical', 'MESH:D002166', (57, 60))
522036	25826089	The ability to activate an efficient G2/M cell cycle checkpoint allowing PLK1 ubiquitination and degradation was found associated with SN38-induced apoptosis in SCC cells.	('ubiquitination', 'MPA', (78, 92))	('SCC', 'Gene', (161, 164))	('SCC', 'Phenotype', 'HP:0002860', (161, 164))	('SN38-induced', 'Var', (135, 147))	('SN38', 'Chemical', 'MESH:D000077146', (135, 139))	('degradation', 'MPA', (97, 108))	('SCC', 'Gene', '6317', (161, 164))	('PLK1', 'Protein', (73, 77))
522037	25826089	However, the synergistic interaction between SN38 and BI2536 enhanced apoptosis in cell lines both sensitive and resistant to SN38-induced apoptotic cell death.	('SN38', 'Gene', (45, 49))	('enhanced', 'PosReg', (61, 69))	('BI2536', 'Chemical', 'MESH:C518477', (54, 60))	('SN38', 'Chemical', 'MESH:D000077146', (45, 49))	('SN38', 'Chemical', 'MESH:D000077146', (126, 130))	('apoptosis', 'CPA', (70, 79))	('BI2536', 'Var', (54, 60))
522038	25826089	A well-tolerated CPT11/BI2536 cotreatment resulted in improved antitumor effect against SCC xenografts in mice compared to single agent treatments.	('mice', 'Species', '10090', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cotreatment', 'Var', (30, 41))	('BI2536', 'Chemical', 'MESH:C518477', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CPT11/BI2536', 'Gene', (17, 29))	('SCC', 'Gene', (88, 91))	('improved', 'PosReg', (54, 62))	('tumor', 'Disease', (67, 72))	('CPT11', 'Chemical', 'MESH:D000077146', (17, 22))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
522048	25826089	Drug induced double-strand breaks also trigger a DNA damage response characterized by activation of serine-threonine kinases driving the ATM-CHK2 and ATR-CHK1 mediated checkpoint pathways and cell cycle arrest at the G1/S and G2/M cell cycle phase transitions.	('CHK2', 'Gene', '11200', (141, 145))	('double-strand breaks', 'Var', (13, 33))	('CHK1', 'Gene', (154, 158))	('ATR', 'Gene', (150, 153))	('serine-threonine kinases', 'Enzyme', (100, 124))	('trigger', 'Reg', (39, 46))	('ATR', 'Gene', '545', (150, 153))	('ATM', 'Gene', (137, 140))	('checkpoint pathways', 'Pathway', (168, 187))	('ATM', 'Gene', '472', (137, 140))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (192, 209))	('CHK1', 'Gene', '1111', (154, 158))	('activation', 'PosReg', (86, 96))	('CHK2', 'Gene', (141, 145))	('G2/M cell cycle phase transitions', 'CPA', (226, 259))	('DNA damage response', 'MPA', (49, 68))	('cell cycle arrest', 'CPA', (192, 209))
522055	25826089	Among several small molecule PLK1 inhibitors developed in preclinical studies, a few, including the dihypteridinones BI2536 and BI6727 (volasertib), have entered clinical evaluation.	('PLK1', 'Gene', (29, 33))	('BI6727', 'Var', (128, 134))	('BI2536', 'Var', (117, 123))	('dihypteridinones BI2536', 'Chemical', '-', (100, 123))	('volasertib', 'Chemical', 'MESH:C541363', (136, 146))	('BI6727', 'Chemical', 'MESH:C541363', (128, 134))
522056	25826089	In a previous study, we observed that an early and significant apoptosis induction by the CPT ST1968 was associated with a marked reduction of PLK1 levels in human squamous and ovarian cancer cell lines.	('CPT', 'Chemical', 'MESH:D002166', (90, 93))	('human', 'Species', '9606', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('ovarian cancer', 'Disease', (177, 191))	('ST1968', 'Var', (94, 100))	('reduction', 'NegReg', (130, 139))	('apoptosis', 'CPA', (63, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (177, 191))	('PLK1 levels', 'MPA', (143, 154))	('CPT', 'Gene', (90, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (177, 191))
522057	25826089	Here, we explored the role of PLK1 in the sensitivity of cell lines of different tumor types to SN38 and evaluated pharmacological inhibition of PLK1 in preclinical models as an approach to enhance CPT11 antitumor activity and overcome drug resistance.	('pharmacological inhibition', 'Var', (115, 141))	('PLK1', 'Gene', (145, 149))	('CPT11', 'Chemical', 'MESH:D000077146', (198, 203))	('drug resistance', 'MPA', (236, 251))	('CPT11', 'Protein', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (208, 213))	('enhance', 'PosReg', (190, 197))	('drug resistance', 'Phenotype', 'HP:0020174', (236, 251))	('SN38', 'Chemical', 'MESH:D000077146', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
522059	25826089	To this aim, we examined the effect of treatment with SN38, the active metabolite of CPT11, in squamous cell carcinoma (SCC) cell lines previously characterized for sensitivity to the CPTs.	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('SN38', 'Chemical', 'MESH:D000077146', (54, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('CPT11', 'Chemical', 'MESH:D000077146', (85, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('CPTs', 'Chemical', 'MESH:D002166', (184, 188))	('squamous cell carcinoma', 'Disease', (95, 118))	('SN38', 'Var', (54, 58))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 118))	('SCC', 'Gene', (120, 123))
522060	25826089	Loss of PLK1 was observed after exposure to SN38 in CaSki cells, sensitive to CPT-induced apoptosis, and not in SiHa cells which are intrinsically resistant to SN38-induced apoptotic cell death as evidenced by Tunel assay performed on both SCC cell lines after treatment at equitoxic and equimolar concentrations (Suppl.	('SiHa', 'CellLine', 'CVCL:0032', (112, 116))	('SCC', 'Gene', (240, 243))	('SN38', 'Chemical', 'MESH:D000077146', (160, 164))	('PLK1', 'Gene', (8, 12))	('Suppl', 'Chemical', '-', (314, 319))	('SCC', 'Phenotype', 'HP:0002860', (240, 243))	('SN38', 'Chemical', 'MESH:D000077146', (44, 48))	('SCC', 'Gene', '6317', (240, 243))	('Loss', 'NegReg', (0, 4))	('CaSki', 'CellLine', 'CVCL:1100', (52, 57))	('CPT', 'Chemical', 'MESH:D002166', (78, 81))	('SN38', 'Var', (44, 48))
522064	25826089	1C, in the Ewing's sarcoma cells TC71 exposed to drug concentrations around the IC50 and IC80 (and Suppl.	("Ewing's sarcoma", 'Disease', (11, 26))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (11, 26))	('TC71', 'CellLine', 'CVCL:2213', (33, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('IC80', 'Var', (89, 93))	('Suppl', 'Chemical', '-', (99, 104))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (11, 26))
522067	25826089	Apoptosis induction was further confirmed by a marked increase in the number of TUNEL-positive cells after SN38 treatment (Fig.	('SN38', 'Var', (107, 111))	('increase', 'PosReg', (54, 62))	('SN38', 'Chemical', 'MESH:D000077146', (107, 111))
522069	25826089	Table 2), exposure to SN38 did not result in modulation of PLK1 protein levels or in apoptotic cell death (Suppl.Fig.	('PLK1', 'Protein', (59, 63))	('SN38', 'Var', (22, 26))	('SN38', 'Chemical', 'MESH:D000077146', (22, 26))	('Suppl', 'Chemical', '-', (107, 112))
522077	25826089	Accordingly, the analysis of cell cycle distribution and of nuclear morphology evidenced a persistent drug-induced accumulation of SiHa cells with a 4N DNA content despite a low expression of cyclin B1 and phospho-Ser10 histone H3 (Fig.	('cyclin B1', 'Gene', '891', (192, 201))	('cyclin B1', 'Gene', (192, 201))	('Ser10', 'Chemical', '-', (214, 219))	('expression', 'MPA', (178, 188))	('low', 'NegReg', (174, 177))	('accumulation', 'PosReg', (115, 127))	('phospho-Ser10', 'Var', (206, 219))	('SiHa', 'CellLine', 'CVCL:0032', (131, 135))
522081	25826089	Moreover, Cdc25A appeared coherently modulated with PLK1 also in the in vivo setting in SCC from mice treated with CPT11 (Suppl.	('CPT11', 'Chemical', 'MESH:D000077146', (115, 120))	('modulated', 'Reg', (37, 46))	('mice', 'Species', '10090', (97, 101))	('SCC', 'Gene', (88, 91))	('Suppl', 'Chemical', '-', (122, 127))	('CPT11', 'Var', (115, 120))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
522084	25826089	3A shows that, in SiHa cells, PLK1 knockdown by siRNA resulted in a marked inhibition of cell growth (about 60%) and in the accumulation of mitotic and apoptotic cells.	('knockdown', 'Var', (35, 44))	('inhibition', 'NegReg', (75, 85))	('accumulation', 'PosReg', (124, 136))	('SiHa', 'CellLine', 'CVCL:0032', (18, 22))	('PLK1', 'Gene', (30, 34))
522086	25826089	cyclin B1, phospho-Ser10 histone H3 and MPM-2) and by the accumulation of cells with 4N DNA content.	('Ser10', 'Chemical', '-', (19, 24))	('phospho-Ser10', 'Var', (11, 24))	('MPM-2', 'Gene', (40, 45))	('cyclin B1', 'Gene', '891', (0, 9))	('cyclin B1', 'Gene', (0, 9))
522090	25826089	3B, an increased CPT-induced antiproliferative activity was observed in PLK1 silenced SiHa cells, with a marked reduction of the IC50 (1muM in cells with control siRNA vs <0.1 muM in cells with PLK1 siRNA).	('PLK1', 'Gene', (72, 76))	('silenced', 'Var', (77, 85))	('antiproliferative activity', 'MPA', (29, 55))	('reduction', 'NegReg', (112, 121))	('SiHa', 'CellLine', 'CVCL:0032', (86, 90))	('CPT', 'Chemical', 'MESH:D002166', (17, 20))
522093	25826089	As in SiHa cells, PLK1 dowmodulation by siRNA was able to enhance the antiproliferative and proapoptotic effects of SN38 (Fig.	('enhance', 'PosReg', (58, 65))	('PLK1', 'Gene', (18, 22))	('SN38', 'Var', (116, 120))	('SiHa', 'CellLine', 'CVCL:0032', (6, 10))	('antiproliferative', 'CPA', (70, 87))	('dowmodulation', 'Var', (23, 36))	('SN38', 'Chemical', 'MESH:D000077146', (116, 120))	('proapoptotic', 'CPA', (92, 104))
522097	25826089	BI2536, a highly selective PLK1 inhibitor displayed comparable antiproliferative effects on both CPT-resistant and -sensitive cell lines (Suppl.	('Suppl', 'Chemical', '-', (138, 143))	('CPT', 'Chemical', 'MESH:D002166', (97, 100))	('BI2536', 'Var', (0, 6))	('CPT-resistant', 'Disease', (97, 110))	('antiproliferative', 'MPA', (63, 80))	('BI2536', 'Chemical', 'MESH:C518477', (0, 6))
522098	25826089	Similarly to the behavior observed in PLK1-silenced SiHa cells, PLK1 inhibition by BI2536 resulted in increased accumulation of cells with G2/M DNA content and mitosis (Fig.	('cells with G2/M DNA content', 'MPA', (128, 155))	('mitosis', 'Disease', (160, 167))	('mitosis', 'Disease', 'None', (160, 167))	('PLK1', 'Gene', (64, 68))	('increased accumulation', 'PosReg', (102, 124))	('BI2536', 'Var', (83, 89))	('SiHa', 'CellLine', 'CVCL:0032', (52, 56))	('BI2536', 'Chemical', 'MESH:C518477', (83, 89))	('inhibition', 'NegReg', (69, 79))
522104	25826089	Again, in this system, the sequential exposure to SN38 and BI2536 resulted in a synergistic interaction (Suppl.	('synergistic interaction', 'MPA', (80, 103))	('SN38', 'Chemical', 'MESH:D000077146', (50, 54))	('BI2536', 'Var', (59, 65))	('resulted in', 'Reg', (66, 77))	('Suppl', 'Chemical', '-', (105, 110))	('SN38', 'Var', (50, 54))	('BI2536', 'Chemical', 'MESH:C518477', (59, 65))
522106	25826089	These findings indicated that inhibition of PLK1 enzymatic activity could enhance apoptosis in tumor cell lines characterized by intrinsic or acquired resistance to CPTs.	('CPTs', 'Chemical', 'MESH:D002166', (165, 169))	('inhibition', 'Var', (30, 40))	('apoptosis', 'CPA', (82, 91))	('PLK1', 'Protein', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('enhance', 'PosReg', (74, 81))
522107	25826089	The antitumor efficacy of CPT11 and BI2536 cotreatment was assessed in nude mice bearing SCC xenografts in a sequential schedule resembling the in vitro treatments (i.e.	('BI2536', 'Chemical', 'MESH:C518477', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('SCC', 'Gene', '6317', (89, 92))	('nude mice', 'Species', '10090', (71, 80))	('CPT11', 'Chemical', 'MESH:D000077146', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('BI2536', 'Var', (36, 42))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
522111	25826089	In both SCC models, BI2536 administered as single agent at the 25 mg/kg dose, produced a moderate but significant inhibition of tumor growth (69% TVI, P<0.01, CaSki; 52% TVI, P<0.05, SiHa).	('BI2536', 'Var', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('inhibition', 'NegReg', (114, 124))	('BI2536', 'Chemical', 'MESH:C518477', (20, 26))	('TVI', 'Chemical', '-', (146, 149))	('SCC', 'Gene', (8, 11))	('SCC', 'Phenotype', 'HP:0002860', (8, 11))	('SiHa', 'CellLine', 'CVCL:0032', (183, 187))	('TVI', 'Chemical', '-', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CaSki', 'CellLine', 'CVCL:1100', (159, 164))	('tumor', 'Disease', (128, 133))	('SCC', 'Gene', '6317', (8, 11))
522112	25826089	In mice bearing CaSki tumors, the combination of CPT11 and BI2536 resulted in a significant implementation of TVI.	('CaSki tumors', 'Disease', (16, 28))	('implementation', 'PosReg', (92, 106))	('CPT11', 'Chemical', 'MESH:D000077146', (49, 54))	('CPT11', 'Gene', (49, 54))	('TVI', 'Chemical', '-', (110, 113))	('mice', 'Species', '10090', (3, 7))	('CaSki tumors', 'Disease', 'MESH:D009369', (16, 28))	('BI2536', 'Var', (59, 65))	('CaSki tumor', 'Phenotype', 'HP:0010891', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('BI2536', 'Chemical', 'MESH:C518477', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('TVI', 'CPA', (110, 113))
522118	25826089	The combination of CPT with an almost ineffective dose of BI2536 resulted in a marked improvement of the antitumor activity with 99% TVI, 7/8 complete responses and 6/8 cured mice.	('improvement', 'PosReg', (86, 97))	('mice', 'Species', '10090', (175, 179))	('BI2536', 'Var', (58, 64))	('TVI', 'CPA', (133, 136))	('CPT', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('BI2536', 'Chemical', 'MESH:C518477', (58, 64))	('CPT', 'Chemical', 'MESH:D002166', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('combination', 'Interaction', (4, 15))	('TVI', 'Chemical', '-', (133, 136))	('tumor', 'Disease', (109, 114))
522119	25826089	Western blot analysis of A431 tumor specimens following a single administration of CPT11, followed by BI2536, revealed an increased PARP cleavage, indicating that the combination treatment was able to promote apoptosis also in vivo (Fig.	('promote', 'PosReg', (201, 208))	('BI2536', 'Var', (102, 108))	('PARP', 'Gene', '142', (132, 136))	('A431', 'CellLine', 'CVCL:0037', (25, 29))	('apoptosis', 'CPA', (209, 218))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BI2536', 'Chemical', 'MESH:C518477', (102, 108))	('PARP', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CPT11', 'Chemical', 'MESH:D000077146', (83, 88))	('tumor', 'Disease', (30, 35))	('CPT11', 'Gene', (83, 88))
522122	25826089	Of note, the CPT11-BI2536 cotreatment was well tolerated (body weight loss <10% and no lethal toxicity).	('body weight', 'CPA', (58, 69))	('CPT11-BI2536', 'Var', (13, 25))	('BI2536', 'Chemical', 'MESH:C518477', (19, 25))	('weight loss', 'Phenotype', 'HP:0001824', (63, 74))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('CPT11', 'Chemical', 'MESH:D000077146', (13, 18))	('toxicity', 'Disease', (94, 102))
522124	25826089	In this study, we provided preclinical rationale and mechanistic insights into a drug combinatory approach based on the use of PLK1 inhibitors to improve CPT-based antitumor therapies.	('inhibitors', 'Var', (132, 142))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('CPT', 'Chemical', 'MESH:D002166', (154, 157))	('PLK1', 'Gene', (127, 131))	('improve', 'PosReg', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
522135	25826089	Indeed, it has been reported that cells expressing a mutant form of PLK1 resistant to APC/CCdh1-mediated ubiquitination display a greater tendency to escape DNA damage checkpoint and enter mitosis despite the presence of DNA damage foci.	('enter mitosis', 'Disease', 'MESH:D004751', (183, 196))	('PLK1', 'Gene', (68, 72))	('APC', 'Disease', 'MESH:D011125', (86, 89))	('enter mitosis', 'Disease', (183, 196))	('APC', 'Disease', (86, 89))	('escape DNA damage checkpoint', 'MPA', (150, 178))	('mutant', 'Var', (53, 59))
522138	25826089	The dihydropteridinone BI2536 was the first PLK1 inhibitor investigated in patients with solid tumors, whereas current clinical studies favor the structurally related BI6727 (Volasertib, now entering Phase III) endowed with an improved pharmacokinetic profile.	('BI2536', 'Var', (23, 29))	('dihydropteridinone', 'Chemical', '-', (4, 22))	('solid tumors', 'Disease', (89, 101))	('patients', 'Species', '9606', (75, 83))	('BI2536', 'Chemical', 'MESH:C518477', (23, 29))	('BI6727', 'Var', (167, 173))	('solid tumors', 'Disease', 'MESH:D009369', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('BI6727', 'Chemical', 'MESH:C541363', (167, 173))
522139	25826089	Pharmacological inhibition of PLK1 by BI2536 treatment in SCC cells resulted in the typical "Polo phenotype" characterized by perturbed mitoses and apoptotic nuclei.	('SCC', 'Gene', (58, 61))	('apoptotic nuclei', 'CPA', (148, 164))	('BI2536', 'Var', (38, 44))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('SCC', 'Gene', '6317', (58, 61))	('BI2536', 'Chemical', 'MESH:C518477', (38, 44))	('PLK1', 'Gene', (30, 34))	('perturbed', 'NegReg', (126, 135))
522140	25826089	Such phenotype resembled that observed following PLK1 RNA interference in the CPT-resistant SiHa cells, indicating that the impairment of the mitotic kinase enzymatic activity was sufficient to promote cell death.	('mitotic kinase', 'Enzyme', (142, 156))	('SiHa', 'CellLine', 'CVCL:0032', (92, 96))	('promote', 'PosReg', (194, 201))	('cell death', 'CPA', (202, 212))	('impairment', 'Var', (124, 134))	('CPT', 'Chemical', 'MESH:D002166', (78, 81))
522141	25826089	Accordingly, the combination treatment with SN38 and BI2536 resulted in a synergistic inhibition of cell growth and a marked enhancement of the apoptotic response.	('cell growth', 'CPA', (100, 111))	('BI2536', 'Chemical', 'MESH:C518477', (53, 59))	('apoptotic response', 'CPA', (144, 162))	('enhancement', 'PosReg', (125, 136))	('SN38', 'Chemical', 'MESH:D000077146', (44, 48))	('BI2536', 'Var', (53, 59))	('SN38', 'Var', (44, 48))	('inhibition', 'NegReg', (86, 96))
522143	25826089	Importantly, a striking enhancement of antitumor activity was obtained by CPT11 and BI2536 administered in combination to SCC xenografts bearing mice in a well-tolerated sequential schedule.	('enhancement', 'PosReg', (24, 35))	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('CPT11', 'Gene', (74, 79))	('CPT11', 'Chemical', 'MESH:D000077146', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('SCC', 'Gene', '6317', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('BI2536', 'Var', (84, 90))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Disease', (43, 48))	('BI2536', 'Chemical', 'MESH:C518477', (84, 90))
522147	25826089	Of note, we performed our study in a panel of cell lines defective for p53 function as a consequence of gene mutation or Human Papilloma Virus (HPV) infection (http://p53.fr),.	('gene mutation', 'Var', (104, 117))	('p53', 'Gene', (71, 74))	('consequence', 'Reg', (89, 100))	('p53', 'Gene', '7157', (71, 74))	('Papilloma Virus (HPV) infection', 'Disease', 'MESH:D030361', (127, 158))	('Papilloma', 'Phenotype', 'HP:0012740', (127, 136))	('p53', 'Gene', '7157', (167, 170))	('p53', 'Gene', (167, 170))
522156	25826089	The PLK1 inhibitor BI2536 (Axon Medchem B.V., Groningen, The Netherlands), was dissolved and diluted in DMSO (0.5% final concentration in culture medium).	('PLK1', 'Gene', (4, 8))	('BI2536', 'Chemical', 'MESH:C518477', (19, 25))	('DMSO', 'Chemical', 'MESH:D004121', (104, 108))	('BI2536', 'Var', (19, 25))
522166	25826089	The antibodies used in the study were: anti-PLK1, anti-cleaved caspase-3, anti-cleaved PARP-1, anti-phospho-Histone H3 (Ser10) (Cell Signaling Technology); anti-vinculin (Sigma); anti-Cdc25A, anti-cyclin-B1 and -cyclin-D (Santa Cruz Biotechnology); anti-vinculin, anti-actin and anti-tubulin (Sigma); anti-RPA-2 (Neomarker, Union City, CS, USA), anti-gammaH2AX (Upstate Biotechnology, Lake Placid, NY, USA), anti-ubiquitin (Abcam, Cambridge, United Kingdom).	('anti-gammaH2AX', 'Var', (346, 360))	('PARP-1', 'Gene', (87, 93))	('vinculin', 'Gene', (161, 169))	('vinculin', 'Gene', '7414', (254, 262))	('RPA-2', 'Gene', (306, 311))	('PARP-1', 'Gene', '142', (87, 93))	('anti-ubiquitin', 'Protein', (408, 422))	('vinculin', 'Gene', (254, 262))	('Ser10', 'Chemical', '-', (120, 125))	('RPA-2', 'Gene', '6118', (306, 311))	('vinculin', 'Gene', '7414', (161, 169))
522167	25826089	Quantitative real-time PCR (qRT-PCR) was performed by the TaqMan PCR Kit (Applied Biosystems, Foster City, CA) according to manufacturer's instructions using TaqMan probes PLK1, Hs00153444_m1; GAPDH, Hs02758991_g1.	('GAPDH', 'Gene', '2597', (193, 198))	('GAPDH', 'Gene', (193, 198))	('Hs00153444_m1', 'Var', (178, 191))	('Hs02758991_g1', 'Var', (200, 213))
522295	25002954	In the molecular study of the study, there is sure rearrangement in the SYT-SSX gene (Figure 1E-I).	('SYT', 'Gene', (72, 75))	('SSX', 'Gene', (76, 79))	('SYT', 'Gene', '6760', (72, 75))	('rearrangement', 'Var', (51, 64))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('SSX', 'Gene', '6757', (76, 79))
522313	25002954	In comparison with other authors who reported this rare tumor, we can detect the rearrangement in the SYT-SSX-Gene which supports the diagnosis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('SS', 'Phenotype', 'HP:0012570', (106, 108))	('SYT', 'Gene', '6760', (102, 105))	('SSX', 'Gene', '6757', (106, 109))	('SYT', 'Gene', (102, 105))	('SSX', 'Gene', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('rearrangement', 'Var', (81, 94))
522355	31915021	FUS gene rearrangements have also been reported in some myoepitheliomas.	('myoepitheliomas', 'Disease', (56, 71))	('myoepitheliomas', 'Disease', 'MESH:D009208', (56, 71))	('rearrangements', 'Var', (9, 23))	('FUS', 'Gene', (0, 3))	('reported', 'Reg', (39, 47))	('FUS', 'Gene', '2521', (0, 3))
522458	26322224	Like other camptothecins such as topotecan, SN-38 mediates cytotoxicity by stabilizing the DNA-topoisomerase I complex created during replication.	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('SN-38', 'Var', (44, 49))	('SN-38', 'Chemical', 'MESH:D000077146', (44, 49))	('stabilizing', 'MPA', (75, 86))	('cytotoxicity', 'Disease', (59, 71))	('topotecan', 'Chemical', 'MESH:D019772', (33, 42))	('camptothecins', 'Chemical', 'MESH:D002166', (11, 24))	('DNA-topoisomerase', 'Protein', (91, 108))
522486	26322224	In adult studies, patients with the UGT1A1*28 polymorphism have increased toxicity from irinotecan.	('irinotecan', 'Chemical', 'MESH:D000077146', (88, 98))	('toxicity', 'Disease', (74, 82))	('polymorphism', 'Var', (46, 58))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))	('UGT1A1', 'Gene', '54658', (36, 42))	('patients', 'Species', '9606', (18, 26))	('increased', 'PosReg', (64, 73))	('UGT1A1', 'Gene', (36, 42))
522523	26322224	This is consistent with the proposed mechanism in which temozolomide-induced methylation of DNA causes localization of topoisomerase I-DNA complexes that are more susceptible to the cytotoxic effects of irinotecan.	('DNA', 'Gene', (92, 95))	('methylation', 'Var', (77, 88))	('localization', 'MPA', (103, 115))	('causes', 'Reg', (96, 102))	('irinotecan', 'Chemical', 'MESH:D000077146', (203, 213))	('temozolomide', 'Chemical', 'MESH:D000077204', (56, 68))
522541	26322224	A third example is the use of inhibitors against the DNA repair protein poly(ADP-ribose) polymerase (PARP).	('DNA repair protein', 'Gene', '442459', (53, 71))	('PARP', 'Gene', '142', (101, 105))	('inhibitors', 'Var', (30, 40))	('poly(ADP-ribose) polymerase', 'Gene', '142', (72, 99))	('poly(ADP-ribose) polymerase', 'Gene', (72, 99))	('PARP', 'Gene', (101, 105))	('DNA repair protein', 'Gene', (53, 71))
522628	25761890	Using dual-recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells.	('mice', 'Species', '10090', (68, 72))	('primary sarcomas', 'Disease', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('tumor', 'Disease', (121, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('mutations', 'Var', (95, 104))	('rat', 'Species', '10116', (42, 45))	('primary sarcomas', 'Disease', 'MESH:D012509', (48, 64))
522629	25761890	We selectively mutated the proapoptotic gene Bax or the DNA damage-response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (164, 184))	('Atm', 'Gene', '11920', (81, 84))	('sarcomas', 'Disease', 'MESH:D012509', (176, 184))	('Bax', 'Gene', '12028', (45, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('mutated', 'Var', (15, 22))	('manipulate', 'Reg', (100, 110))	('sarcomas', 'Disease', (176, 184))	('Atm', 'Gene', (81, 84))	('Bax', 'Gene', (45, 48))
522630	25761890	Bax deletion from endothelial cells did not affect radiation-induced cell death in tumor endothelial cells or sarcoma response to radiation therapy.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('sarcoma', 'Disease', (110, 117))	('Bax', 'Gene', '12028', (0, 3))	('tumor', 'Disease', (83, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('Bax', 'Gene', (0, 3))	('deletion', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
522631	25761890	Although Atm deletion increased endothelial cell death after radiation therapy, deletion of Atm from endothelial cells failed to enhance sarcoma eradication.	('sarcoma eradication', 'Disease', (137, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('deletion', 'Var', (80, 88))	('Atm', 'Gene', '11920', (9, 12))	('endothelial cell death', 'CPA', (32, 54))	('Atm', 'Gene', '11920', (92, 95))	('sarcoma eradication', 'Disease', 'MESH:D012509', (137, 156))	('deletion', 'Var', (13, 21))	('Atm', 'Gene', (9, 12))	('increased', 'PosReg', (22, 31))	('Atm', 'Gene', (92, 95))	('Al', 'Chemical', 'MESH:D000535', (0, 2))
522632	25761890	In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('increased', 'PosReg', (46, 55))	('sarcoma eradication', 'Disease', (56, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('deletion', 'Var', (13, 21))	('Atm', 'Gene', '11920', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('sarcoma eradication', 'Disease', 'MESH:D012509', (56, 75))	('Atm', 'Gene', (25, 28))
522635	25761890	These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.	('inhibiting', 'Var', (27, 37))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('rat', 'Species', '10116', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ATM kinase', 'Enzyme', (38, 48))
522649	25761890	To investigate the contribution of endothelial cells to the radiation response of primary sarcomas, we developed the technology to contemporaneously mutate different genes specifically in the tumor cells versus the endothelial cells of primary sarcomas.	('tumor', 'Disease', (192, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (244, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('primary sarcomas', 'Disease', 'MESH:D012509', (236, 252))	('primary sarcomas', 'Disease', (236, 252))	('primary sarcomas', 'Disease', 'MESH:D012509', (82, 98))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('primary sarcomas', 'Disease', (82, 98))	('mutate', 'Var', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
522650	25761890	In this system, an adenovirus expressing FlpO (adeno-FlpO) activates a conditional allele of oncogenic Kras (FSF- KrasG12D) and deletes both copies of a conditional allele of p53 (p53FRT), while a tissue-specific Cre driver mutates floxed alleles specifically in endothelial cells.	('p53', 'Gene', (175, 178))	('p53', 'Gene', '22060', (175, 178))	('Kras', 'Gene', '16653', (114, 118))	('p53', 'Gene', (180, 183))	('adeno-FlpO', 'Chemical', '-', (47, 57))	('p53', 'Gene', '22060', (180, 183))	('FlpO', 'Var', (41, 45))	('Kras', 'Gene', (103, 107))	('Kras', 'Gene', '16653', (103, 107))	('activates', 'PosReg', (59, 68))	('deletes', 'NegReg', (128, 135))	('Kras', 'Gene', (114, 118))
522651	25761890	We recently used this dual recombinase technology to demonstrate that selectively sensitizing endothelial cells to mitotic cell death by deleting the DNA damage response gene ataxia telangiectasia mutated (Atm) prolongs sarcoma growth delay after SBRT.	('growth delay', 'Phenotype', 'HP:0001510', (228, 240))	('ataxia', 'Phenotype', 'HP:0001251', (175, 181))	('Atm', 'Gene', (206, 209))	('deleting', 'Var', (137, 145))	('sarcoma growth delay', 'Disease', (220, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('prolongs', 'PosReg', (211, 219))	('ataxia telangiectasia mutated', 'Gene', '11920', (175, 204))	('sarcoma growth delay', 'Disease', 'MESH:D006130', (220, 240))	('ataxia telangiectasia mutated', 'Gene', (175, 204))	('rat', 'Species', '10116', (60, 63))	('Atm', 'Gene', '11920', (206, 209))	('telangiectasia', 'Phenotype', 'HP:0001009', (182, 196))
522659	25761890	Because apoptosis of tumor endothelial cells is dependent on Bax in transplanted tumor models, we used (i) dual recombinase technology to initiate primary sarcomas in conditional FSF-KrasG12D; p53FRT/FRT (KPFRT) mice with adeno-FlpO and (ii) VE-Cadherin-Cre to delete Bax floxed alleles (BaxFL) specifically in endothelial cells.	('mice', 'Species', '10090', (212, 216))	('tumor', 'Disease', (21, 26))	('p53', 'Gene', (193, 196))	('Bax', 'Gene', (288, 291))	('Kras', 'Gene', (183, 187))	('p53', 'Gene', '22060', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('VE-Cadherin', 'Gene', (242, 253))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('adeno-FlpO', 'Chemical', '-', (222, 232))	('Bax', 'Gene', '12028', (268, 271))	('Kras', 'Gene', '16653', (183, 187))	('primary sarcomas', 'Disease', (147, 163))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('Bax', 'Gene', '12028', (61, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Bax', 'Gene', '12028', (288, 291))	('Bax', 'Gene', (268, 271))	('delete', 'Var', (261, 267))	('VE-Cadherin', 'Gene', '12562', (242, 253))	('Bax', 'Gene', (61, 64))	('primary sarcomas', 'Disease', 'MESH:D012509', (147, 163))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
522660	25761890	We recently demonstrated that this approach efficiently deletes floxed alleles in endothelial cells of primary sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('rat', 'Species', '10116', (19, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('floxed', 'Var', (64, 70))	('deletes floxed', 'Var', (56, 70))	('primary sarcomas', 'Disease', 'MESH:D012509', (103, 119))	('primary sarcomas', 'Disease', (103, 119))
522661	25761890	We confirmed by quantitative polymerase chain reaction (qPCR) that VE-Cadherin-Cre efficiently deleted Bax in endothelial cells (fig.	('Bax', 'Gene', (103, 106))	('VE-Cadherin', 'Gene', '12562', (67, 78))	('Bax', 'Gene', '12028', (103, 106))	('VE-Cadherin', 'Gene', (67, 78))	('deleted', 'Var', (95, 102))
522662	25761890	We next investigated the effect of Bax deletion specifically in endothelial cells on sarcoma initiation and growth by generating primary sarcomas in KPFRT; VE-Cadherin-Cre; BaxFL/+ (KPFRTVBaxFL/+) and KPFRT; VE-Cadherin-Cre; BaxFL/FL (KPFRTVBaxFL/FL) mice.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Bax', 'Gene', (225, 228))	('mice', 'Species', '10090', (251, 255))	('primary sarcomas', 'Disease', 'MESH:D012509', (129, 145))	('Bax', 'Gene', '12028', (173, 176))	('generating', 'Reg', (118, 128))	('Bax', 'Gene', '12028', (188, 191))	('VE-Cadherin', 'Gene', (156, 167))	('sarcoma initiation', 'Disease', (85, 103))	('deletion', 'Var', (39, 47))	('VE-Cadherin', 'Gene', '12562', (208, 219))	('sarcoma initiation', 'Disease', 'MESH:D012509', (85, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('Bax', 'Gene', (173, 176))	('Bax', 'Gene', '12028', (241, 244))	('Bax', 'Gene', '12028', (35, 38))	('primary sarcomas', 'Disease', (129, 145))	('Bax', 'Gene', (188, 191))	('Bax', 'Gene', '12028', (225, 228))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('VE-Cadherin', 'Gene', (208, 219))	('VE-Cadherin', 'Gene', '12562', (156, 167))	('rat', 'Species', '10116', (122, 125))	('Bax', 'Gene', (35, 38))	('Bax', 'Gene', (241, 244))
522663	25761890	In contrast to previous reports with tumor cells transplanted into Bax null mice, we observed no change in primary sarcoma initiation or growth in mice with deletion of Bax specifically in endothelial cells (fig.	('mice', 'Species', '10090', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('sarcoma initiation', 'Disease', 'MESH:D012509', (115, 133))	('deletion', 'Var', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Bax', 'Gene', (169, 172))	('tumor', 'Disease', (37, 42))	('Bax', 'Gene', '12028', (169, 172))	('Bax', 'Gene', '12028', (67, 70))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('sarcoma initiation', 'Disease', (115, 133))	('Bax', 'Gene', (67, 70))
522664	25761890	To determine if Bax deletion from endothelial cells protected tumor endothelial cells from radiation in an autochthonous model system, we irradiated the sarcomas in KPFRTVBaxFL/+ and KPFRTVBaxFL/FL mice with a single dose of 20 Gy using fluoroscopy-guided radiation therapy and examined endothelial cell death via TUNEL staining at various time points after irradiation.	('Bax', 'Gene', '12028', (171, 174))	('Bax', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Bax', 'Gene', '12028', (189, 192))	('tumor', 'Disease', (62, 67))	('sarcomas', 'Disease', 'MESH:D012509', (153, 161))	('Bax', 'Gene', (171, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('Bax', 'Gene', '12028', (16, 19))	('deletion', 'Var', (20, 28))	('mice', 'Species', '10090', (198, 202))	('Bax', 'Gene', (189, 192))	('sarcomas', 'Disease', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
522667	25761890	Furthermore, deletion of Bax did not affect endothelial cell death, suggesting that endothelial cells in primary sarcomas do not undergo Bax-mediated apoptosis after irradiation.	('Bax', 'Gene', '12028', (137, 140))	('Bax', 'Gene', '12028', (25, 28))	('primary sarcomas', 'Disease', 'MESH:D012509', (105, 121))	('not', 'NegReg', (125, 128))	('deletion', 'Var', (13, 21))	('primary sarcomas', 'Disease', (105, 121))	('Bax', 'Gene', (25, 28))	('Bax', 'Gene', (137, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))
522673	25761890	Because the pro-apoptotic genes Bax and Bcl-2 homologous antagonist killer (Bak)can be redundant for executing programmed cell death in some settings, we also deleted the Bax gene from the endothelial cells of Bak null (Bak-/-) mice.	('Bax', 'Gene', (32, 35))	('Bax', 'Gene', '12028', (171, 174))	('Bak', 'Gene', (76, 79))	('Bak', 'Gene', '12018', (210, 213))	('Bak', 'Gene', '12018', (220, 223))	('Bax', 'Gene', (171, 174))	('Bak', 'Gene', '12018', (76, 79))	('deleted', 'Var', (159, 166))	('Bcl-2', 'Gene', (40, 45))	('Bak', 'Gene', (220, 223))	('Bax', 'Gene', '12028', (32, 35))	('Bak', 'Gene', (210, 213))	('Bcl-2', 'Gene', '12043', (40, 45))	('mice', 'Species', '10090', (228, 232))
522674	25761890	Primary sarcomas in KPFRT; VE-Cadherin-Cre; Bak-/-; BaxFL/+ (KPFRTVBak-/-BaxFL/+) and KPFRT; VE- Cadherin-Cre; Bak-/-; BaxFL/FL (KPFRTVBak-/-BaxFL/FL) mice developed at the same time after injection of adeno-FlpO and grew at the same rate in the absence of radiation (fig.	('Bax', 'Gene', '12028', (141, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('VE- Cadherin', 'Gene', '12562', (93, 105))	('Bax', 'Gene', (73, 76))	('VE- Cadherin', 'Gene', (93, 105))	('Bak', 'Gene', (135, 138))	('Bak', 'Gene', (111, 114))	('Bax', 'Gene', (119, 122))	('VE-Cadherin', 'Gene', (27, 38))	('Primary sarcomas', 'Disease', (0, 16))	('adeno-FlpO', 'Var', (202, 212))	('Bax', 'Gene', (141, 144))	('Bak', 'Gene', (67, 70))	('Bak', 'Gene', (44, 47))	('Bak', 'Gene', '12018', (111, 114))	('Bak', 'Gene', '12018', (135, 138))	('Bax', 'Gene', '12028', (52, 55))	('rat', 'Species', '10116', (234, 237))	('Primary sarcomas', 'Disease', 'MESH:D012509', (0, 16))	('mice', 'Species', '10090', (151, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('Bax', 'Gene', '12028', (73, 76))	('Bak', 'Gene', '12018', (67, 70))	('VE-Cadherin', 'Gene', '12562', (27, 38))	('Bak', 'Gene', '12018', (44, 47))	('Bax', 'Gene', (52, 55))	('adeno-FlpO', 'Chemical', '-', (202, 212))	('Bax', 'Gene', '12028', (119, 122))
522679	25761890	We showed recently that deleting Atm specifically in endothelial cells radiosensitizes these cells in autochthonous sarcomas, causing them to undergo a delayed mitotic cell death that increases tumor growth delay after radiation therapy with 20 Gy.	('sarcomas', 'Disease', (116, 124))	('increases tumor', 'Disease', (184, 199))	('increases tumor', 'Disease', 'MESH:D009369', (184, 199))	('sarcomas', 'Disease', 'MESH:D012509', (116, 124))	('Atm', 'Gene', '11920', (33, 36))	('delayed mitotic cell death', 'CPA', (152, 178))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('autochthonous sarcomas', 'Phenotype', 'HP:0031549', (102, 124))	('deleting', 'Var', (24, 32))	('Atm', 'Gene', (33, 36))	('growth delay', 'Phenotype', 'HP:0001510', (200, 212))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('causing', 'Reg', (126, 133))
522680	25761890	To determine whether Atm deletion increased endothelial cell death after a curative dose of radiation, we treated primary sarcomas in KPFRT; VE-Cadherin-Cre; AtmFL/+ (KPFRTVAtmFL/+) and KPFRT; VE-Cadherin-Cre; AtmFL/FL (KPFRTVAtmFL/FL) mice with 50 Gy.	('Atm', 'Gene', (210, 213))	('VE-Cadherin', 'Gene', '12562', (193, 204))	('Atm', 'Gene', '11920', (21, 24))	('mice', 'Species', '10090', (236, 240))	('rat', 'Species', '10116', (77, 80))	('Atm', 'Gene', '11920', (226, 229))	('Atm', 'Gene', '11920', (210, 213))	('increased', 'PosReg', (34, 43))	('Atm', 'Gene', (158, 161))	('VE-Cadherin', 'Gene', (193, 204))	('VE-Cadherin', 'Gene', '12562', (141, 152))	('primary sarcomas', 'Disease', (114, 130))	('Atm', 'Gene', (173, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('Atm', 'Gene', (21, 24))	('Atm', 'Gene', '11920', (158, 161))	('deletion', 'Var', (25, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('VE-Cadherin', 'Gene', (141, 152))	('primary sarcomas', 'Disease', 'MESH:D012509', (114, 130))	('Atm', 'Gene', (226, 229))	('Atm', 'Gene', '11920', (173, 176))
522681	25761890	Consistent with our previous results, deletion of Atm significantly increased endothelial cell death 24 h after irradiation (Fig.	('Atm', 'Gene', '11920', (50, 53))	('endothelial cell death', 'CPA', (78, 100))	('deletion', 'Var', (38, 46))	('Atm', 'Gene', (50, 53))	('increased', 'PosReg', (68, 77))
522692	25761890	P7KPloxP mice develop sarcomas after administration of systemic tamoxifen.	('sarcomas', 'Disease', (22, 30))	('tamoxifen', 'Chemical', 'MESH:D013629', (64, 73))	('develop', 'Reg', (14, 21))	('sarcomas', 'Disease', 'MESH:D012509', (22, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('mice', 'Species', '10090', (9, 13))	('P7KPloxP', 'Var', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('rat', 'Species', '10116', (45, 48))
522693	25761890	In contrast to the KPloxPAtmFL/FL mice injected with adeno-Cre, intramuscular injection of P7KPloxPAtmFL/FL mice with 4-hydroxy-tamoxifen generated primary sarcomas at the site of injection with efficient deletion of both Atm alleles (fig.	('deletion', 'Var', (205, 213))	('mice', 'Species', '10090', (34, 38))	('primary sarcomas', 'Disease', (148, 164))	('Atm', 'Gene', '11920', (99, 102))	('Atm', 'Gene', '11920', (222, 225))	('4-hydroxy-tamoxifen', 'Chemical', '-', (118, 137))	('rat', 'Species', '10116', (142, 145))	('mice', 'Species', '10090', (108, 112))	('Atm', 'Gene', '11920', (25, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('Atm', 'Gene', (99, 102))	('Atm', 'Gene', (222, 225))	('Atm', 'Gene', (25, 28))	('primary sarcomas', 'Disease', 'MESH:D012509', (148, 164))
522694	25761890	To determine if Atm deletion sensitized sarcoma cells to radiation, we irradiated cell lines isolated from sarcomas in P7KPloxPAtmFL/+ and P7KPloxPAtmFL/FL mice.	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('Atm', 'Gene', '11920', (16, 19))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('sarcoma', 'Disease', (107, 114))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('Atm', 'Gene', (16, 19))	('Atm', 'Gene', '11920', (127, 130))	('sarcoma', 'Disease', (40, 47))	('sarcomas', 'Disease', (107, 115))	('deletion', 'Var', (20, 28))	('sensitized', 'Reg', (29, 39))	('Atm', 'Gene', '11920', (147, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('mice', 'Species', '10090', (156, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Atm', 'Gene', (127, 130))	('Atm', 'Gene', (147, 150))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))
522697	25761890	Deletion of Atm in tumor cells significantly improved local control of primary sarcomas (Fig.	('Atm', 'Gene', '11920', (12, 15))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('improved', 'PosReg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('primary sarcomas', 'Disease', 'MESH:D012509', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('primary sarcomas', 'Disease', (71, 87))	('local control', 'CPA', (54, 67))	('Atm', 'Gene', (12, 15))	('tumor', 'Disease', (19, 24))	('Deletion', 'Var', (0, 8))
522701	25761890	Deletion of the Atm gene freom tumor cells increased the probability of tumor eradication after SBRT, suggesting that therapeutic targeting of the ATM protein could improve tumor response to radiation therapy.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('Atm', 'Gene', '11920', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (72, 77))	('improve', 'PosReg', (165, 172))	('tumor', 'Disease', (31, 36))	('Atm', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('increased', 'PosReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('Deletion', 'Var', (0, 8))
522706	25761890	Pretreatment of the mice with BEZ235 significantly decreased autophosphorylation of mouse Atm and phosphorylation of the Atm target Kap1 in primary sarcomas after irradiation with 20 Gy (fig.	('autophosphorylation', 'MPA', (61, 80))	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('phosphorylation', 'MPA', (98, 113))	('Atm', 'Gene', (90, 93))	('Atm', 'Gene', '11920', (90, 93))	('Kap1', 'Gene', (132, 136))	('mice', 'Species', '10090', (20, 24))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('Atm', 'Gene', (121, 124))	('decreased', 'NegReg', (51, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('primary sarcomas', 'Disease', 'MESH:D012509', (140, 156))	('mouse', 'Species', '10090', (84, 89))	('Atm', 'Gene', '11920', (121, 124))	('Kap1', 'Gene', '21849', (132, 136))	('BEZ235', 'Var', (30, 36))	('primary sarcomas', 'Disease', (140, 156))
522709	25761890	Next, we monitored tumor growth in KPloxP mice treated with BEZ235 alone or in combination with focal 20 Gy irradiation.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('BEZ235', 'Var', (60, 66))	('BEZ235', 'Chemical', 'MESH:C531198', (60, 66))
522713	25761890	We showed previously that deletion of Atm radiosensitizes p53 null cardiac endothelial cells but not cardiac endothelial cells with intact p53.	('p53', 'Gene', '22060', (139, 142))	('p53', 'Gene', '22060', (58, 61))	('Atm', 'Gene', (38, 41))	('radiosensitizes', 'NegReg', (42, 57))	('deletion', 'Var', (26, 34))	('p53', 'Gene', (139, 142))	('Atm', 'Gene', '11920', (38, 41))	('p53', 'Gene', (58, 61))
522715	25761890	BEZ235 shifted the myocardial necrosis-free survival curve to the left in VPFL/FL mice but did not promote the development of radiation-induced myocardial necrosis in VPFL/+ mice (Fig.	('mice', 'Species', '10090', (82, 86))	('myocardial necrosis', 'Disease', (19, 38))	('mice', 'Species', '10090', (174, 178))	('BEZ235', 'Var', (0, 6))	('myocardial necrosis', 'Disease', (144, 163))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('myocardial necrosis', 'Phenotype', 'HP:0001700', (19, 38))	('myocardial necrosis', 'Disease', 'MESH:D009202', (19, 38))	('myocardial necrosis', 'Phenotype', 'HP:0001700', (144, 163))	('myocardial necrosis', 'Disease', 'MESH:D009202', (144, 163))
522717	25761890	However, taken together with the genetic studies, these experiments with a pharmacological inhibitor of ATM suggest that inhibiting ATM may preferentially radiosensitize sarcomas compared with quiescent normal tissues, such as the heart.	('ATM', 'Gene', (132, 135))	('sarcomas', 'Disease', 'MESH:D012509', (170, 178))	('inhibiting', 'Var', (121, 131))	('radiosensitize', 'CPA', (155, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcomas', 'Disease', (170, 178))	('preferentially', 'PosReg', (140, 154))
522721	25761890	In contrast, radiosensitizing of tumor cells increased the probability of sarcoma eradication by SBRT.	('radiosensitizing', 'Var', (13, 29))	('increased', 'PosReg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('sarcoma eradication', 'Disease', 'MESH:D012509', (74, 93))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('sarcoma eradication', 'Disease', (74, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
522737	25761890	Instead, targeting tumor cells with radiosensitizers, such as inhibitors of ATM, might be a more promising treatment approach to achieve local control.	('ATM', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('inhibitors', 'Var', (62, 72))	('tumor', 'Disease', (19, 24))
522777	25761890	Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed using Taqman universal PCR master mix (Applied Biosystems) and TaqMan Gene Expression Assay Mix (Applied Biosystems) for Bax (Mm00432050_m1) or Hprt (Mm0446968_m1).	('Bax', 'Gene', '12028', (206, 209))	('Bax', 'Gene', (206, 209))	('Mm0446968_m1', 'Var', (235, 247))	('Mm00432050_m1', 'Var', (211, 224))
522781	25761890	Deletion of Atm was verified by PCR using primers flanking the 3' loxP site: sense 5'-GGGCTACGAAATGAGACACACAC-3' and anti-sense 5'-CTTCCCCTGTTCAAAAGCCACTC-3' and primers flanking the recombined loxP site: sense 5'-TGAGTTCAAATCCCAGGAGCCAG-3' and anti-sense 5'-CTTCCCCTGTTCAAAAGCCACTC-3'.	('Atm', 'Gene', '11920', (12, 15))	('Atm', 'Gene', (12, 15))	("anti-sense 5'-CTTCCCCTGTTCAAAAGCCACTC-3", 'Var', (245, 284))
522859	23474110	An RTOG atlas for GTV and CTV definition aiming at improving target volume consistency was subsequently developed and the current consensus is to combine the edema volume (in this case, the STAPLE95) and the anatomical expansion (in this case the CTV2cm or CTV3cm) to form the clinical target volume (to which a PTV margin would be added).	('CTV3cm', 'Var', (257, 263))	('edema', 'Disease', (158, 163))	('CTV2cm', 'Var', (247, 253))	('GTV', 'Chemical', '-', (18, 21))	('edema', 'Disease', 'MESH:D004487', (158, 163))	('edema', 'Phenotype', 'HP:0000969', (158, 163))
522880	21702998	However, in STS patients with complete tumor resection (R0), high PAI-1 and uPAR-del4/5 mRNA levels were associated with a distinctly increased risk of tumor-related death (RR = 6.55, P = 0.054 and RR = 6.00, P = 0.088, respectively).	('PAI-1', 'Gene', '5054', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('STS', 'Phenotype', 'HP:0030448', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('high', 'Var', (61, 65))	('uPAR', 'Gene', '5329', (76, 80))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Disease', (152, 157))	('mRNA levels', 'MPA', (88, 99))	('PAI-1', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('uPAR', 'Gene', (76, 80))
522881	21702998	Strikingly, R0 patients with both high PAI-1 and uPAR-del4/5 mRNA expression levels showed a significant, 19-fold increased risk of tumor-related death (P = 0.044) compared to the low expression group.	('patients', 'Species', '9606', (15, 23))	('mRNA expression', 'MPA', (61, 76))	('uPAR', 'Gene', '5329', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PAI-1', 'Gene', '5054', (39, 44))	('high', 'Var', (34, 38))	('tumor', 'Disease', (132, 137))	('uPAR', 'Gene', (49, 53))	('PAI-1', 'Gene', (39, 44))
522894	21702998	Whereas wild-type uPAR consists of three structurally homologous domains, in the uPAR-del4/5 variant the complete domain II of uPAR is deleted, and the uPAR-del4/5 protein does not interact with either of its ligands uPA or vitronectin.	('uPA', 'Gene', (152, 155))	('uPA', 'Gene', '5328', (152, 155))	('uPAR', 'Gene', (152, 156))	('uPAR', 'Gene', (127, 131))	('uPAR', 'Gene', (81, 85))	('uPA', 'Gene', (127, 130))	('uPA', 'Gene', '5328', (127, 130))	('interact', 'Interaction', (181, 189))	('uPAR', 'Gene', '5329', (18, 22))	('uPAR', 'Gene', '5329', (152, 156))	('vitronectin', 'Gene', (224, 235))	('uPAR', 'Gene', '5329', (127, 131))	('uPAR', 'Gene', '5329', (81, 85))	('vitronectin', 'Gene', '7448', (224, 235))	('variant', 'Var', (93, 100))	('uPA', 'Gene', '5328', (81, 84))	('uPA', 'Gene', (81, 84))	('uPAR', 'Gene', (18, 22))	('uPA', 'Gene', (18, 21))	('uPA', 'Gene', '5328', (217, 220))	('uPA', 'Gene', (217, 220))	('uPA', 'Gene', '5328', (18, 21))
522897	21702998	In sarcomas, high expression of uPA and uPAR antigen as detected by immunohistochemistry has been reported to be an independent prognostic factor for metastasis-free survival and overall survival in chondrosarcoma patients.	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('chondrosarcoma', 'Disease', (199, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('uPA', 'Gene', '5328', (32, 35))	('uPA', 'Gene', (40, 43))	('patients', 'Species', '9606', (214, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (206, 213))	('high', 'Var', (13, 17))	('sarcomas', 'Disease', (3, 11))	('chondrosarcoma', 'Disease', 'MESH:D002813', (199, 213))	('uPA', 'Gene', '5328', (40, 43))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (199, 213))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('uPAR', 'Gene', '5329', (40, 44))	('uPAR', 'Gene', (40, 44))	('metastasis-free survival', 'CPA', (150, 174))	('uPA', 'Gene', (32, 35))
522943	21702998	We found an association between high PAI-1 and uPAR-del4/5 mRNA expression levels and an increased risk of tumor-related death for R0 patients using multivariate Cox regression analysis with relative risks (RR) of 6.55 (95%CI = 1.0-44.5) and 6.00 (95%CI = 0.8-47.1), respectively, with a trend towards significance (P = 0.054 and P = 0.088, respectively; Table 3).	('high', 'Var', (32, 36))	('uPAR', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('PAI-1', 'Gene', '5054', (37, 42))	('patients', 'Species', '9606', (134, 142))	('uPAR', 'Gene', '5329', (47, 51))	('Cox', 'Gene', '1351', (162, 165))	('Cox', 'Gene', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('PAI-1', 'Gene', (37, 42))	('mRNA expression levels', 'MPA', (59, 81))
522949	21702998	R0 patients with high PAI-1/uPAR-del4/5 (n = 30) revealed a significant 19-fold increased risk of tumor-related death (RR = 19.1, 95%CI = 1.1-335.3, P = 0.044) compared to R0 patients who showed low PAI-1/uPAR-del4/5 mRNA expression levels (n = 13).	('uPAR', 'Gene', '5329', (28, 32))	('PAI-1', 'Gene', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('high', 'Var', (17, 21))	('uPAR', 'Gene', '5329', (205, 209))	('PAI-1', 'Gene', '5054', (22, 27))	('uPAR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (3, 11))	('PAI-1', 'Gene', '5054', (199, 204))	('tumor', 'Disease', (98, 103))	('uPAR', 'Gene', (205, 209))	('PAI-1', 'Gene', (22, 27))
522972	21702998	have reported that patients with high PAI-1 mRNA expression have a reduced 10-year disease-free survival and overall survival rate, and PAI-1 mRNA expression might reveal additional clinically relevant information compared to PAI-1 protein levels.	('overall survival rate', 'CPA', (109, 130))	('high', 'Var', (33, 37))	('PAI-1', 'Gene', (136, 141))	('patients', 'Species', '9606', (19, 27))	('PAI-1', 'Gene', (226, 231))	('mRNA expression', 'MPA', (44, 59))	('PAI-1', 'Gene', (38, 43))	('disease-free survival', 'CPA', (83, 104))	('reduced', 'NegReg', (67, 74))	('PAI-1', 'Gene', '5054', (136, 141))	('PAI-1', 'Gene', '5054', (226, 231))	('PAI-1', 'Gene', '5054', (38, 43))
522973	21702998	In other studies that have analyzed PAI-1 mRNA expression in different sets of breast cancer patients, high PAI-1 mRNA levels were found to be significantly associated with shorter metastasis-free or overall survival, whereas uPA mRNA levels had no prognostic relevance.	('metastasis-free', 'CPA', (181, 196))	('mRNA levels', 'MPA', (114, 125))	('PAI-1', 'Gene', (36, 41))	('PAI-1', 'Gene', '5054', (108, 113))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('PAI-1', 'Gene', '5054', (36, 41))	('shorter', 'NegReg', (173, 180))	('overall survival', 'CPA', (200, 216))	('uPA', 'Gene', (226, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('uPA', 'Gene', '5328', (226, 229))	('PAI-1', 'Gene', (108, 113))	('high', 'Var', (103, 107))	('patients', 'Species', '9606', (93, 101))
522981	21702998	In the present study, uPA, PAI-1 and uPAR-wt mRNA values did not differ significantly between tumors in relation to clinical and histomorphological parameters, except for a significant relationship between high PAI-1 mRNA expression and tumor grade and between PAI-1 and uPAR-wt mRNA levels and the histological STS subtype, which has also been reported by others.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mRNA expression', 'MPA', (217, 232))	('high', 'Var', (206, 210))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('uPAR', 'Gene', '5329', (271, 275))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('PAI-1', 'Gene', '5054', (261, 266))	('uPA', 'Gene', (22, 25))	('uPA', 'Gene', '5328', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PAI-1', 'Gene', (261, 266))	('tumors', 'Disease', (94, 100))	('uPAR', 'Gene', (37, 41))	('uPA', 'Gene', '5328', (37, 40))	('uPA', 'Gene', (37, 40))	('PAI-1', 'Gene', '5054', (211, 216))	('STS', 'Phenotype', 'HP:0030448', (312, 315))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('PAI-1', 'Gene', (211, 216))	('PAI-1', 'Gene', '5054', (27, 32))	('tumor', 'Disease', (237, 242))	('uPAR', 'Gene', (271, 275))	('tumor', 'Disease', (94, 99))	('PAI-1', 'Gene', (27, 32))	('uPA', 'Gene', (271, 274))	('uPA', 'Gene', '5328', (271, 274))	('uPAR', 'Gene', '5329', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (237, 242))
522988	21702998	Moreover, by using combined PAI-1 and uPAR-del4/5 mRNA expression values, R0-resected patients with high PAI-1/uPAR-del4/5 mRNA values had a significant, 19-fold increased risk of tumor-related death compared to R0-resected patients who displayed low PAI-1/uPAR-del4/5 expression levels.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('PAI-1', 'Gene', (105, 110))	('uPAR', 'Gene', '5329', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('PAI-1', 'Gene', '5054', (251, 256))	('uPAR', 'Gene', (257, 261))	('PAI-1', 'Gene', (251, 256))	('PAI-1', 'Gene', (28, 33))	('tumor', 'Disease', (180, 185))	('uPAR', 'Gene', (38, 42))	('high', 'Var', (100, 104))	('PAI-1', 'Gene', '5054', (105, 110))	('PAI-1', 'Gene', '5054', (28, 33))	('uPAR', 'Gene', (111, 115))	('patients', 'Species', '9606', (224, 232))	('uPAR', 'Gene', '5329', (257, 261))	('uPAR', 'Gene', '5329', (38, 42))	('patients', 'Species', '9606', (86, 94))
522994	21702998	In addition, in STS patients with complete tumor resection high PAI-1 or uPAR-del4/5 mRNA levels are associated with a distinctly shortened disease-associated survival of STS patients.	('uPAR', 'Gene', '5329', (73, 77))	('STS', 'Phenotype', 'HP:0030448', (16, 19))	('shortened', 'NegReg', (130, 139))	('PAI-1', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mRNA levels', 'MPA', (85, 96))	('uPAR', 'Gene', (73, 77))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (20, 28))	('disease-associated survival', 'CPA', (140, 167))	('PAI-1', 'Gene', '5054', (64, 69))	('STS', 'Phenotype', 'HP:0030448', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
523187	33158916	We hypothesized that combination strategies would significantly augment anti-sarcoma effects in highly relevant human and dog translational models.	('combination', 'Var', (21, 32))	('augment', 'NegReg', (64, 71))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('sarcoma', 'Disease', (77, 84))	('dog', 'Species', '9615', (122, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('human', 'Species', '9606', (112, 117))
523221	33158916	Overall, we observed variability in baseline ALC and CD3+ T cell counts, while CD8+ T cell counts (0.4+-0.2x103 cells/microL) and NK cells counts in particular (0.2+-0.03x103 cells/microL) were more uniform (figure 1C).	('CD3+ T cell', 'CPA', (53, 64))	('CD8', 'Gene', (79, 82))	('CD8', 'Gene', '925', (79, 82))	('ALC', 'MPA', (45, 48))	('0.2+-0.03x103', 'Var', (161, 174))
523238	33158916	CD8 infiltration was associated with improved DRFS (HR=0.76; 95% CI=0.59 to 0.98; p=0.036) after adjustment of other covariates (online supplemental table 1).	('DRFS', 'Disease', (46, 50))	('infiltration', 'Var', (4, 16))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('improved', 'PosReg', (37, 45))
523244	33158916	Among TIL populations, CD3+ T cells were predominant (52%+-5.7%), followed by CD8+ T cells (22%+-5.6%), and then NK cells (19%+-3.4%) (figure 3D).	('CD8', 'Gene', (78, 81))	('CD3+', 'Var', (23, 27))	('CD8', 'Gene', '925', (78, 81))
523285	33158916	Notably, while TIGIT expression was not associated with survival in STS, high expression of CD155 was associated with significantly worse overall survival (log-rank p=0.04) (figure 7E).	('overall survival', 'MPA', (138, 154))	('CD155', 'Gene', '5817', (92, 97))	('CD155', 'Gene', (92, 97))	('STS', 'Phenotype', 'HP:0030448', (68, 71))	('worse', 'NegReg', (132, 137))	('high', 'Var', (73, 77))
523292	33158916	Overall, we observed a significant increase in CD107a expression in NK cells following IL-15 plus TIGIT blockade compared with IL-15 alone after exposure to both A673 (42%+-1.1% vs 58%+-1.9%, p=0.0003) and SK-LMS targets (30%+-0.7% vs 45%+-1.1%, p=0.0001) (figure 7I).	('expression', 'MPA', (54, 64))	('increase', 'PosReg', (35, 43))	('CD107a', 'Gene', '3916', (47, 53))	('SK-LMS', 'CellLine', 'CVCL:0628', (206, 212))	('CD107a', 'Gene', (47, 53))	('blockade', 'Var', (104, 112))	('IL-15', 'Gene', (87, 92))
523366	32454786	Adult patients (>=18 years old) with bone sarcoma diagnosed between 2004 and 2012 were identified using topographical codes (C40.0-C40.3, C40.8-C41.4, C41.8, C41.9) designated by International Classification of Disease for Oncology, Third Edition [ICD-O-3].	('bone sarcoma', 'Phenotype', 'HP:0002669', (37, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('C41.9', 'Var', (158, 163))	('C41.9', 'CellLine', 'CVCL:2253', (158, 163))	('C40.0-C40.3', 'Var', (125, 136))	('bone sarcoma', 'Disease', (37, 49))	('Oncology', 'Phenotype', 'HP:0002664', (223, 231))	('C41.8', 'Var', (151, 156))	('C40.8-C41.4', 'Var', (138, 149))
523385	32066914	Heritable retinoblastoma survivors are at increased risk due to germline inactivation of the retinoblastoma gene.	('retinoblastoma', 'Gene', (10, 24))	('retinoblastoma', 'Gene', '5925', (10, 24))	('germline inactivation', 'Var', (64, 85))	('retinoblastoma', 'Gene', '5925', (93, 107))	('retinoblastoma', 'Gene', (93, 107))	('retinoblastoma', 'Phenotype', 'HP:0009919', (10, 24))	('retinoblastoma', 'Phenotype', 'HP:0009919', (93, 107))
523401	32066914	The morphological tumour type was ascertained from code 92603 (ES) or 91803 (OS) using the ICD-O WHO (World Health Organization) morphological classification of cancers, which has been used in Sweden since 1993.	('91803', 'Var', (70, 75))	('ES', 'Phenotype', 'HP:0012254', (63, 65))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('OS', 'Phenotype', 'HP:0002669', (77, 79))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumour', 'Disease', (18, 24))
523498	33983928	Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans.	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (77, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('dog', 'Species', '9615', (117, 120))	('aggressive hematopoietic malignancy', 'Disease', (154, 189))	('Histiocytic sarcoma', 'Disease', 'MESH:D054747', (128, 147))	('humans', 'Species', '9606', (256, 262))	('variants', 'Var', (52, 60))	('Histiocytic sarcoma', 'Disease', (128, 147))	('hematopoietic malignancy', 'Phenotype', 'HP:0004377', (165, 189))	('hematopoietic malignancies', 'Disease', (77, 103))	('associated', 'Reg', (61, 71))	('aggressive hematopoietic malignancy', 'Disease', 'MESH:D019337', (154, 189))
523502	33983928	These data highlight the PI3K pathway gene PIK3R6 on CFA5, and proximal candidate regulatory variants that are strongly associated with histiocytic sarcoma and predicted to impact transcription factor binding.	('impact', 'Reg', (173, 179))	('transcription factor', 'Gene', (180, 200))	('associated with', 'Reg', (120, 135))	('PIK3R6', 'Gene', (43, 49))	('CFA5', 'Chemical', '-', (53, 57))	('variants', 'Var', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('transcription factor', 'Gene', '490153', (180, 200))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (136, 155))	('PI3K pathway', 'Pathway', (25, 37))	('histiocytic sarcoma', 'Disease', (136, 155))
523508	33983928	The first includes variants in regulatory regions at the tumor suppressor PIK3R6 locus that are strongly associated with histiocytic sarcoma and likely confer risk for other hematopoietic cancers.	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (121, 140))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('histiocytic sarcoma', 'Disease', (121, 140))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('hematopoietic cancers', 'Disease', 'MESH:D009369', (174, 195))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('PIK3R6', 'Gene', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('hematopoietic cancers', 'Disease', (174, 195))	('associated', 'Reg', (105, 115))	('tumor', 'Disease', (57, 62))	('variants', 'Var', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
523527	33983928	We advance beyond previous cancer and complex disease studies in the dog, analyzing whole genome, transcriptome, and ChIP sequencing data to identify putative regulatory variants associated with histiocytic sarcoma susceptibility in FCRs that may also confer risk for hematopoietic cancers in other breeds.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('dog', 'Species', '9615', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('variants', 'Var', (170, 178))	('hematopoietic cancers', 'Disease', 'MESH:D009369', (268, 289))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (195, 214))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('hematopoietic cancers', 'Disease', (268, 289))	('cancer', 'Disease', (282, 288))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('histiocytic sarcoma', 'Disease', (195, 214))
523555	33983928	Variants demonstrating significant ASE in two or more FCRs were identified in seven genes: CD68, MPDU1, CHD3, BORCS6, NDEL1, and PIK3R6 (Fig 5 and S6 Table).	('Variants', 'Var', (0, 8))	('CD68', 'Gene', (91, 95))	('NDEL1', 'Gene', '489495', (118, 123))	('MPDU1', 'Gene', '489477', (97, 102))	('BORCS6', 'Gene', (110, 116))	('PIK3R6', 'Gene', (129, 135))	('CHD3', 'Gene', '479489', (104, 108))	('CD68', 'Gene', '489476', (91, 95))	('CHD3', 'Gene', (104, 108))	('NDEL1', 'Gene', (118, 123))	('BORCS6', 'Gene', '608122', (110, 116))	('MPDU1', 'Gene', (97, 102))
523556	33983928	Both NudE Neurodevelopment Protein 1 Like 1 (NDEL1) and Phosphoinositide-3-kinase regulatory subunit 6 (PIK3R6) lie within the minimal 631 kb shared risk haplotype and contain variants demonstrating significant ASE in at least six of seven FCRs.	('NDEL1', 'Gene', '489495', (45, 50))	('Phosphoinositide-3-kinase regulatory subunit 6', 'Gene', (56, 102))	('variants', 'Var', (176, 184))	('NDEL1', 'Gene', (45, 50))	('Neurodevelopment Protein 1 Like 1', 'Gene', (10, 43))	('PIK3R6', 'Gene', (104, 110))	('Phosphoinositide-3-kinase regulatory subunit 6', 'Gene', '608225', (56, 102))	('Neurodevelopment Protein 1 Like 1', 'Gene', '489495', (10, 43))
523564	33983928	We next sought to identify potential pathogenic variants within the CFA5 631 kb risk haplotype.	('CFA5', 'Gene', (68, 72))	('variants', 'Var', (48, 56))	('pathogenic', 'Reg', (37, 47))	('CFA5', 'Chemical', '-', (68, 72))
523567	33983928	A total of 284 variants matched the segregation pattern of the CFA5 risk haplotype in the four FCR and four golden retriever WGS.	('variants', 'Var', (15, 23))	('CFA5', 'Chemical', '-', (63, 67))	('CFA5', 'Gene', (63, 67))
523568	33983928	A conservative allele frequency threshold of 50% in 1090 genomes from 233 other breed dogs (S8 Table) was applied to eliminate variants common across many breeds, resulting in 218 variants, none of which were unique to FCRs and golden retrievers (S9 Table).	('variants', 'Var', (127, 135))	('dogs', 'Species', '9615', (86, 90))	('variants', 'Var', (180, 188))
523569	33983928	The CanFam3.1 reference genome contains six gaps, totaling approximately 3 kb, within the critical interval, which may mask variants relevant to histiocytic sarcoma susceptibility.	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (145, 164))	('histiocytic sarcoma', 'Disease', (145, 164))	('variants', 'Var', (124, 132))	('mask', 'NegReg', (119, 123))
523570	33983928	To identify promoter and enhancer regions in canine cell types relevant to cancers investigated herein, ChIP-seq data from peripheral blood mononuclear cells from seven dogs were generated for two histone marks, H3K4me1 and H3K4me3, to identify canine promoters and enhancers (See Methods, S10 Table).	('H3K4me1', 'Var', (212, 219))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('canine', 'Species', '9615', (245, 251))	('cancers', 'Disease', (75, 82))	('H3K4me3', 'Var', (224, 231))	('dogs', 'Species', '9615', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('canine', 'Species', '9615', (45, 51))
523573	33983928	The 98 variants were phased, allowing us to generate haplotypes in retriever and spaniel breeds, the latter of which were included because the retriever and spaniel clades share a recent common ancestor, yet the spaniel is not at risk for histiocytic sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (239, 258))	('variants', 'Var', (7, 15))	('histiocytic sarcoma', 'Disease', (239, 258))
523574	33983928	To further explore candidate pathogenic variants, we selected regulatory regions from blood ChIP-seq data surrounding NDEL1 and PIK3R6, candidates from ASE analysis, to interrogate variants for possible transcription factor binding motif alterations.	('NDEL1', 'Gene', '489495', (118, 123))	('transcription factor', 'Gene', '490153', (203, 223))	('transcription factor', 'Gene', (203, 223))	('variants', 'Var', (40, 48))	('NDEL1', 'Gene', (118, 123))	('PIK3R6', 'Gene', (128, 134))
523575	33983928	Regulatory elements at PIK3R6 and PIK3R5 contained 92% of the 98 variants overlapping ChIP-seq within the 631 kb shared haplotype (Fig 5 and S9 Table).	('PIK3R6', 'Gene', (23, 29))	('PIK3R5', 'Gene', '612805', (34, 40))	('variants', 'Var', (65, 73))	('PIK3R5', 'Gene', (34, 40))
523576	33983928	Five of the 98 WGS variants had significant scores in two transcription factor (TF) motif programs (See Methods), suggestive of a difference in binding affinity between the FCR risk and non-risk alleles (S11 Table); all were within PIK3R5/6 regions.	('PIK3R5', 'Gene', (232, 238))	('PIK3R5', 'Gene', '612805', (232, 238))	('transcription factor', 'Gene', '490153', (58, 78))	('FCR', 'Disease', (173, 176))	('scores', 'Reg', (44, 50))	('binding affinity', 'Interaction', (144, 160))	('transcription factor', 'Gene', (58, 78))	('variants', 'Var', (19, 27))	('difference', 'Reg', (130, 140))
523577	33983928	An additional variant (CFA5:33528647), significant in one TF binding affinity program (FIMO, Padj = 0.0067) and demonstrating a difference in SP1 and KLF5 binding affinity between risk and non-risk variants in sTRAP (log(P) = 0.5), was chosen for Sanger sequencing because it is within a human PIK3R6 regulatory region in the GeneHancer promoter- and enhancer-gene interaction database where SP1 and KLF5 are reported to bind.	('KLF5', 'Gene', (150, 154))	('human', 'Species', '9606', (288, 293))	('KLF5', 'Gene', '688', (150, 154))	('CFA5', 'Chemical', '-', (23, 27))	('binding', 'Interaction', (155, 162))	('KLF5', 'Gene', (400, 404))	('KLF5', 'Gene', '688', (400, 404))	('variants', 'Var', (198, 206))
523579	33983928	The remaining five variants were significantly associated with histiocytic sarcoma (S12 Table).	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (63, 82))	('histiocytic sarcoma', 'Disease', (63, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('associated', 'Reg', (47, 57))	('variants', 'Var', (19, 27))
523580	33983928	Variants at CFA5:33531780 and 33576022 had the lowest P-values of 4.2x10-5 and 4.6x10-5, respectively (lead SNP P = 1.8x10-4, Table 3), and were located in ChIP-seq regulatory regions upstream of PIK3R6.	('CFA5', 'Chemical', '-', (12, 16))	('lowest', 'NegReg', (47, 53))	('P-values', 'MPA', (54, 62))	('CFA5:33531780', 'Var', (12, 25))	('CFA5:33531780', 'Gene', (12, 25))	('33576022', 'Var', (30, 38))
523583	33983928	Additional genotyping of the five candidate variants within this region, reveals that they are present in ~75% of FCRs with lymphoma (B-cell n = 3, T-cell n = 4, and unspecified subtype n = 13; Table 1), and are in complete LD with the lead histiocytic sarcoma GWAS SNP (r2 = 1), consistent with our hypothesis.	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (241, 260))	('lymphoma', 'Disease', 'MESH:D008223', (124, 132))	('histiocytic sarcoma', 'Disease', (241, 260))	('lymphoma', 'Disease', (124, 132))	('sarcoma GWAS SNP', 'Disease', 'MESH:D012509', (253, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('unspecified', 'Species', '32644', (166, 177))	('variants', 'Var', (44, 52))	('sarcoma GWAS SNP', 'Disease', (253, 269))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))
523585	33983928	CFA5:33576022, 33587141, and 33594214.	('33587141', 'Var', (15, 23))	('CFA5:33576022', 'Var', (0, 13))	('CFA5', 'Chemical', '-', (0, 4))	('33594214', 'Var', (29, 37))
523587	33983928	In aggregate, these data provide strong support that one or more of the three variants located on the CFA5 risk haplotype are likely to confer susceptibility to histiocytic sarcoma and B-cell lymphoma in both retriever breeds.	('histiocytic sarcoma', 'Disease', (161, 180))	('B-cell lymphoma', 'Disease', (185, 200))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (185, 200))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (185, 200))	('susceptibility', 'Reg', (143, 157))	('CFA5', 'Gene', (102, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('CFA5', 'Chemical', '-', (102, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (161, 180))	('variants', 'Var', (78, 86))
523596	33983928	In our data, the maximum haplotype sharing is observed here among FCR cases (Fig 2C), as well as in the closely-related golden retriever breed, where cases diagnosed with B-cell lymphoma share the same risk haplotype (Fig 4).	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (171, 186))	('lymphoma', 'Phenotype', 'HP:0002665', (178, 186))	('B-cell lymphoma', 'Disease', (171, 186))	('haplotype sharing', 'Var', (25, 42))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (171, 186))
523597	33983928	When genotypes for the CFA5 lead SNP were included as a covariate in our FCR histiocytic sarcoma GWAS, we also observed top SNPs proximal to CFA11:44 Mb and CFA2:29 Mb peaks (S4 Table) as described in the published Bernese mountain dog GWAS.	('CFA2:29 Mb', 'Var', (157, 167))	('dog', 'Species', '9615', (232, 235))	('CFA5', 'Chemical', '-', (23, 27))	('sarcoma GWAS', 'Disease', (89, 101))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (77, 96))	('sarcoma GWAS', 'Disease', 'MESH:D012509', (89, 101))	('histiocytic sarcoma', 'Disease', (77, 96))	('CFA11:44 Mb', 'Var', (141, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))
523600	33983928	PIK3R6 has a tumor suppressive role; knockdown increases PI3Kgamma signaling and the potential for cells to metastasize.	('tumor', 'Disease', (13, 18))	('cells', 'CPA', (99, 104))	('PI3Kgamma', 'Gene', '5294', (57, 66))	('PI3Kgamma', 'Gene', (57, 66))	('knockdown', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('PIK3R6', 'Gene', (0, 6))	('increases', 'PosReg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
523601	33983928	The PI3K/Akt pathway is commonly activated in cancers, and somatic mutations in PIK3CD and PI3KCA, which encode other PI3K isoforms, have recently been detected in a subset of primary human histiocytic sarcoma tumors as well as secondary tumors and their co-occurring lymphomas, although mutations in PI3Kgamma genes have not yet been reported.	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('lymphomas', 'Disease', 'MESH:D008223', (268, 277))	('sarcoma tumors', 'Disease', 'MESH:D012509', (202, 216))	('lymphomas', 'Phenotype', 'HP:0002665', (268, 277))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('human', 'Species', '9606', (184, 189))	('tumors', 'Disease', (238, 244))	('PI3KCA', 'Gene', (91, 97))	('sarcoma tumors', 'Disease', (202, 216))	('PI3Kgamma', 'Gene', (301, 310))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('histiocytic sarcoma', 'Disease', (190, 209))	('lymphomas', 'Disease', (268, 277))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('detected', 'Reg', (152, 160))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('PIK3CD', 'Gene', '5293', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (268, 276))	('PI3Kgamma', 'Gene', '5294', (301, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('Akt', 'Gene', (9, 12))	('tumors', 'Disease', (210, 216))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (190, 209))	('mutations', 'Var', (67, 76))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('PIK3CD', 'Gene', (80, 86))	('Akt', 'Gene', '207', (9, 12))
523602	33983928	PIK3R6 was downregulated in B-cell lymphoma tumors from golden retrievers that harbored the CFA5:29 Mb hemangiosarcoma risk haplotype in this breed.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('hemangiosarcoma', 'Disease', 'MESH:D006394', (103, 118))	('CFA5', 'Chemical', '-', (92, 96))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (28, 43))	('downregulated', 'NegReg', (11, 24))	('B-cell lymphoma tumors', 'Disease', 'MESH:D016393', (28, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('lymphoma', 'Phenotype', 'HP:0002665', (35, 43))	('PIK3R6', 'Gene', (0, 6))	('CFA5:29', 'Var', (92, 99))	('B-cell lymphoma tumors', 'Disease', (28, 50))	('hemangiosarcoma', 'Disease', (103, 118))
523603	33983928	Our ASE results suggest that variants on the CFA5:33 Mb haplotype may impact PIK3R6 regulation.	('CFA5:33', 'Gene', (45, 52))	('CFA5', 'Chemical', '-', (45, 49))	('variants', 'Var', (29, 37))	('PIK3R6 regulation', 'MPA', (77, 94))	('impact', 'Reg', (70, 76))
523604	33983928	Our ChIP-seq and WGS analyses identified five candidate variants strongly associated with histiocytic sarcoma in FCRs and predicted to impact TF binding sites proximal to PIK3R6.	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (90, 109))	('histiocytic sarcoma', 'Disease', (90, 109))	('binding sites', 'Interaction', (145, 158))	('variants', 'Var', (56, 64))	('associated with', 'Reg', (74, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('impact', 'Reg', (135, 141))
523605	33983928	While these variants were also detected in FCRs and golden retrievers with lymphoma and golden retrievers with histiocytic sarcoma, supporting the hypothesis that variants within the shared risk haplotype underly susceptibility to both diseases in the retrievers, we note that sample sizes were small.	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('lymphoma', 'Disease', 'MESH:D008223', (75, 83))	('susceptibility', 'Reg', (213, 227))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (111, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('histiocytic sarcoma', 'Disease', (111, 130))	('variants', 'Var', (12, 20))	('variants', 'Var', (163, 171))	('lymphoma', 'Disease', (75, 83))
523609	33983928	The deleterious cancer alleles may have increased in frequency in the FCR as a hitchhiking event with nearby variants that control the desirable skull shape phenotype.	('variants', 'Var', (109, 117))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('desirable skull shape', 'Phenotype', 'HP:0002678', (135, 156))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
523624	33983928	Candidate genes at both loci, PIK3R6 and TNFAIP6, have tumor suppressive and metastatic roles in other cancers, and mutations in members of the PI3K and tumor necrosis factor pathways have been identified in human histiocytic sarcoma and lymphoma tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('lymphoma tumors', 'Disease', 'MESH:D008223', (238, 253))	('PI3K', 'Pathway', (144, 148))	('histiocytic sarcoma', 'Disease', (214, 233))	('human', 'Species', '9606', (208, 213))	('lymphoma', 'Phenotype', 'HP:0002665', (238, 246))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (153, 158))	('tumor necrosis factor', 'Gene', (153, 174))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (247, 252))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (214, 233))	('mutations', 'Var', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('lymphoma tumors', 'Disease', (238, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Disease', (55, 60))	('PIK3R6', 'Gene', (30, 36))	('identified', 'Reg', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor necrosis factor', 'Gene', '7124', (153, 174))	('TNFAIP6', 'Gene', (41, 48))
523628	33983928	DNA samples from FCRs diagnosed with lymphoma were included for variant genotyping, as well as golden retrievers with lymphoma or histiocytic sarcoma (S13 Table and S1 Text).	('lymphoma', 'Disease', 'MESH:D008223', (37, 45))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('lymphoma', 'Phenotype', 'HP:0002665', (37, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (130, 149))	('lymphoma', 'Disease', (118, 126))	('variant', 'Var', (64, 71))	('lymphoma', 'Disease', 'MESH:D008223', (118, 126))	('lymphoma', 'Disease', (37, 45))	('histiocytic sarcoma', 'Disease', (130, 149))
523637	33983928	Variants were filtered for concordance with associated risk haplotypes in FCRs and genomes of four golden retrievers diagnosed with lymphoma (S1 Text).	('lymphoma', 'Disease', 'MESH:D008223', (132, 140))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('Variants', 'Var', (0, 8))	('lymphoma', 'Disease', (132, 140))
523641	33983928	Transcription Factor Binding Affinity Prediction (sTRAP) predicts binding affinity of each transcription factor in a given matrix to wild-type and mutant sequence, compares affinity values between the two, and calculates which TF has the greatest difference in affinity resulting from the sequence change.	('mutant', 'Var', (147, 153))	('Transcription Factor', 'Gene', (0, 20))	('change', 'Var', (298, 304))	('transcription factor', 'Gene', (91, 111))	('binding', 'Interaction', (66, 73))	('affinity', 'MPA', (261, 269))	('transcription factor', 'Gene', '490153', (91, 111))	('Transcription Factor', 'Gene', '490153', (0, 20))
523704	33920505	Several studies reported that, in a variety of different solid tumors (lung, gastric, colorectal, head-neck and renal cell carcinoma), the presence of NK cells in the TME correlated with improved patient outcome.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('solid tumors', 'Disease', (57, 69))	('gastric', 'Disease', (77, 84))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('patient', 'Species', '9606', (196, 203))	('improved', 'PosReg', (187, 195))	('presence', 'Var', (139, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (112, 132))	('head-neck and renal cell carcinoma', 'Disease', 'MESH:D000077195', (98, 132))	('solid tumors', 'Disease', 'MESH:D009369', (57, 69))	('colorectal', 'Disease', 'MESH:D015179', (86, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('lung', 'Disease', (71, 75))	('colorectal', 'Disease', (86, 96))
523714	33920505	Indeed, they express co-stimulatory molecules (e.g., CD40, CD80 and CD86), produce antibodies and cytokines, function as APC, initiate T-cell priming, promote T-cell expansion and memory differentiation and directly kill tumor cells through FasL-Fas interaction and the secretion of cytotoxic granules (e.g., granzyme B).	('CD8', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('CD40', 'Var', (53, 57))	('CD8', 'Gene', (59, 62))	('granzyme B', 'Gene', (309, 319))	('kill', 'NegReg', (216, 220))	('secretion', 'MPA', (270, 279))	('T-cell priming', 'CPA', (135, 149))	('FasL', 'Gene', (241, 245))	('initiate', 'PosReg', (126, 134))	('FasL', 'Gene', '356', (241, 245))	('promote', 'PosReg', (151, 158))	('T-cell expansion', 'CPA', (159, 175))	('CD8', 'Gene', '925', (68, 71))	('tumor', 'Disease', (221, 226))	('CD8', 'Gene', '925', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('memory differentiation', 'CPA', (180, 202))	('APC', 'Disease', 'MESH:D011125', (121, 124))	('granzyme B', 'Gene', '3002', (309, 319))	('APC', 'Disease', (121, 124))
523734	33920505	As a consequence of the use of drugs targeting such molecules, including anti-CD47, anti-SIRPalpha and anti-LILRB1 monoclonal antibodies, the recognition pathways are blocked and phagocytosis of macrophages is enhanced.	('LILRB1', 'Gene', (108, 114))	('LILRB1', 'Gene', '10859', (108, 114))	('SIRPalpha', 'Gene', '140885', (89, 98))	('enhanced', 'PosReg', (210, 218))	('recognition pathways', 'Pathway', (142, 162))	('anti-CD47', 'Var', (73, 82))	('blocked', 'NegReg', (167, 174))	('SIRPalpha', 'Gene', (89, 98))	('phagocytosis of macrophages', 'CPA', (179, 206))
523753	33920505	As expected, tumors with the highest proportion of PD-L1 positivity showed the poorest survival.	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('poorest', 'NegReg', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('positivity', 'Var', (57, 67))	('PD-L1', 'Gene', (51, 56))
523757	33920505	TAIC were represented by macrophages (20% of samples) and lymphocytes (72%), with a significant prevalence of macrophage infiltration in PD-L1-positive (51%) compared to PD-L1-negative tumors (17%).	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('macrophage infiltration', 'CPA', (110, 133))	('PD-L1-negative tumors', 'Disease', (170, 191))	('PD-L1-positive', 'Var', (137, 151))	('PD-L1-negative tumors', 'Disease', 'MESH:D010300', (170, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
523766	33920505	Although the presence of TIL had a positive clinical impact in high-risk NB patients, Melaiu and coworkers correlated a worse prognosis in NB patients with the presence of PD1+ and LAG3+ TIL and a high density of PD-L1+ and HLA class I+ tumor cells in the TME.	('patients', 'Species', '9606', (76, 84))	('tumor', 'Disease', (237, 242))	('NB', 'Phenotype', 'HP:0003006', (139, 141))	('LAG3', 'Gene', (181, 185))	('LAG3', 'Gene', '3902', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('PD1+', 'Var', (172, 176))	('NB', 'Phenotype', 'HP:0003006', (73, 75))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
523767	33920505	The authors identified two PD-L1/HLA-I combinations, irrespective of T cell infiltration level, MYCN amplification status, stage of disease and age at diagnosis: the first, characterized by high HLA-I and low/negative PD-L1, was associated with a good prognosis, whereas the second, represented by low HLA-I and high/negative PD-L1, correlated with a poor prognosis.	('MYCN', 'Gene', (96, 100))	('PD-L1', 'Var', (218, 223))	('low/negative PD-L1', 'Var', (205, 223))	('MYCN', 'Gene', '4613', (96, 100))	('high HLA-I', 'Var', (190, 200))
523773	33920505	reported that patients with testicular germ cell tumors had the worst prognosis in the presence of PD-L1hi tumor cells and PD-L1low TILs.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('germ cell tumors', 'Phenotype', 'HP:0100728', (39, 55))	('PD-L1low TILs', 'Var', (123, 136))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PD-L1hi', 'Var', (99, 106))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (14, 22))
523774	33920505	On the contrary, PD-L1low tumor cells and PD-L1hi TILs predicted a better prognosis.	('PD-L1low', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('PD-L1hi', 'Var', (42, 49))
523779	33920505	More importantly, high PD-L1 expression was significantly associated with worse overall survival, regardless of sex, age, tumor size, histology, site, surgical outcome and adjuvant treatment, thus envisaging that, similarly to other pediatric tumors, the PD-1/PD-L1 axis may represent a potential therapeutic target for the treatment of young STS patients.	('tumors', 'Disease', (243, 249))	('PD-L1', 'Gene', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('overall survival', 'MPA', (80, 96))	('STS', 'Phenotype', 'HP:0030448', (343, 346))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('high', 'Var', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('worse', 'NegReg', (74, 79))	('expression', 'MPA', (29, 39))	('tumor', 'Disease', (122, 127))	('patients', 'Species', '9606', (347, 355))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
523783	33920505	Furthermore, infiltration of PD-1+ lymphocytes was mainly observed in synovial sarcomas (18%), whereas a high infiltration of CD8+ lymphocytes was detected mostly in osteosarcomas (35%) and correlated with a worse event-free survival.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (70, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('CD8', 'Gene', (126, 129))	('CD8', 'Gene', '925', (126, 129))	('osteosarcomas', 'Disease', (166, 179))	('osteosarcoma', 'Phenotype', 'HP:0002669', (166, 178))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (70, 87))	('osteosarcomas', 'Phenotype', 'HP:0002669', (166, 179))	('synovial sarcomas', 'Disease', 'MESH:D013584', (70, 87))	('osteosarcomas', 'Disease', 'MESH:D012516', (166, 179))	('synovial sarcomas', 'Disease', (70, 87))	('observed', 'Reg', (58, 66))	('PD-1+', 'Var', (29, 34))
523796	33920505	Similarly, it has been demonstrated that combined therapy using anti-PD-1 and anti-TIGIT or anti-TIM-3 antibodies significantly prolonged mice survival compared to untreated mice and mice treated with single therapies.	('anti-PD-1', 'Var', (64, 73))	('mice survival', 'CPA', (138, 151))	('mice', 'Species', '10090', (174, 178))	('mice', 'Species', '10090', (138, 142))	('mice', 'Species', '10090', (183, 187))	('prolonged', 'PosReg', (128, 137))
523797	33920505	In addition, it was reported that a significant increase in the therapeutic effect of anti-PD-L1 antibodies was obtained by associating an agonist of Toll-like receptor 3 (TLR3), that activated DC and increased infiltration of immune effector cells within the tumor, or standard chemotherapy.	('activated', 'PosReg', (184, 193))	('infiltration of', 'CPA', (211, 226))	('tumor', 'Disease', (260, 265))	('increased', 'PosReg', (201, 210))	('TLR3', 'Gene', (172, 176))	('TLR3', 'Gene', '7098', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('Toll-like receptor 3', 'Gene', (150, 170))	('Toll-like receptor 3', 'Gene', '7098', (150, 170))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('anti-PD-L1 antibodies', 'Var', (86, 107))	('increase', 'PosReg', (48, 56))	('antibodies', 'Var', (97, 107))	('therapeutic', 'MPA', (64, 75))
523799	33920505	This resulted in increased T lymphocyte infiltration in an orthotopic preclinical model of glioblastoma, although the survival of mice was significantly prolonged by combined therapy using GMCI and anti-PD-L1 antibodies.	('increased', 'PosReg', (17, 26))	('mice', 'Species', '10090', (130, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('combined', 'Interaction', (166, 174))	('anti-PD-L1', 'Var', (198, 208))	('increased T lymphocyte', 'Phenotype', 'HP:0100828', (17, 39))	('GMCI', 'Chemical', '-', (189, 193))	('prolonged', 'PosReg', (153, 162))	('T lymphocyte infiltration', 'CPA', (27, 52))	('glioblastoma', 'Disease', (91, 103))
523804	33920505	Phase I and, to a lesser extent, phase II clinical trials are in progress and are mainly recruiting pediatric patients with glioblastoma or different solid tumors that are treated with anti-PD1 drugs in combination with conventional therapies, radio-chemotherapies or surgery.	('solid tumors', 'Disease', (150, 162))	('anti-PD1', 'Var', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('glioblastoma', 'Disease', (124, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('solid tumors', 'Disease', 'MESH:D009369', (150, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('patients', 'Species', '9606', (110, 118))
523812	33920505	The role of CTLA-4 in the control of auto-reactive T cells has been demonstrated in CTLA-4 deficient mice, who developed a lethal form of lymphoproliferative disorder.	('deficient', 'Var', (91, 100))	('CTLA-4', 'Gene', (84, 90))	('lymphoproliferative disorder', 'Phenotype', 'HP:0005523', (138, 166))	('mice', 'Species', '10090', (101, 105))	('lymphoproliferative disorder', 'Disease', (138, 166))	('developed', 'Reg', (111, 120))	('lymphoproliferative disorder', 'Disease', 'MESH:D008232', (138, 166))
523819	33920505	Similar effects were observed in an orthotopic model of glioblastoma, in which anti-CTLA-4 alone displayed only marginal effects in terms of reduction in tumor growth and prolonged overall survival.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('prolonged', 'PosReg', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('overall survival', 'CPA', (181, 197))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('anti-CTLA-4', 'Var', (79, 90))	('glioblastoma', 'Disease', (56, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))	('reduction', 'NegReg', (141, 150))	('tumor', 'Disease', (154, 159))
523820	33920505	However, once administered a combination of anti-CTLA-4 and anti-PD-1 antibodies, therapeutic effects were improved due to the increased infiltration of effector T cells, paralleled by a decreased infiltration of Treg.	('therapeutic effects', 'CPA', (82, 101))	('anti-PD-1', 'Var', (60, 69))	('anti-CTLA-4', 'Var', (44, 55))	('improved', 'PosReg', (107, 115))	('anti-CTLA-4', 'Gene', (44, 55))	('infiltration', 'CPA', (137, 149))	('Treg', 'Chemical', '-', (213, 217))	('Treg', 'CPA', (213, 217))	('decreased', 'NegReg', (187, 196))	('increased', 'PosReg', (127, 136))
523821	33920505	Similar results were obtained in an orthotopic model of glioblastoma where the highest curative effect was obtained using a combination of anti-CTLA-4 and anti-PD-1 antibodies in addition to oncolytic viruses.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('anti-PD-1', 'Var', (155, 164))	('glioblastoma', 'Disease', (56, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))	('anti-CTLA-4', 'Var', (139, 150))
523823	33920505	These studies confirm that CTLA-4 blocking may revert tumor-mediated immunosuppression, thus rendering more effective other immunotherapeutic strategies.	('CTLA-4', 'Gene', (27, 33))	('revert', 'NegReg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('blocking', 'Var', (34, 42))	('more', 'PosReg', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
523826	33920505	To date, four clinical trials involving children affected by NB and nine in glioblastoma patients are currently ongoing using anti-CTLA-4 antibodies in combination with standard therapies or other drugs (, accessed on 28 March 2021).	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('anti-CTLA-4', 'Var', (126, 137))	('children', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (89, 97))	('glioblastoma', 'Disease', (76, 88))	('NB', 'Phenotype', 'HP:0003006', (61, 63))
523831	33920505	B7-H3 plays a role in cancer progression not only by mediating immune evasion, but also by promoting migration, angiogenesis, gene regulation via epigenetic mechanisms and enrichment of cancer stem cells.	('mediating', 'Reg', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('epigenetic', 'Var', (146, 156))	('migration', 'CPA', (101, 110))	('angiogenesis', 'CPA', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (22, 28))	('B7-H3', 'Gene', (0, 5))	('immune evasion', 'MPA', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('gene', 'MPA', (126, 130))	('promoting', 'PosReg', (91, 100))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
523832	33920505	Recent pre-clinical studies suggested that B7-H3 over-expression impacts drug resistance, since B7-H3 depletion enhanced the chemo-sensitivity of cancer cells to chemotherapeutic drugs in melanoma and breast cancer.	('enhanced', 'PosReg', (112, 120))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (208, 214))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (188, 214))	('B7-H3', 'Var', (96, 101))	('drug resistance', 'Phenotype', 'HP:0020174', (73, 88))	('chemo-sensitivity', 'MPA', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('impacts', 'Reg', (65, 72))	('drug resistance', 'MPA', (73, 88))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
523848	33920505	Moreover, they setup an orthotopic preclinical model of glioblastoma and observed that combined therapy using anti-LAG-3 and anti-PD-1 antibodies was more effective in terms of increased overall survival than the single therapy.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('combined', 'Interaction', (87, 95))	('overall survival', 'CPA', (187, 203))	('anti-PD-1', 'Var', (125, 134))	('increased', 'PosReg', (177, 186))	('anti-LAG-3', 'Var', (110, 120))	('glioblastoma', 'Disease', (56, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))
523849	33920505	In addition, high LAG-3 expression correlated with a worse prognosis of STS patients.	('patients', 'Species', '9606', (76, 84))	('STS', 'Phenotype', 'HP:0030448', (72, 75))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('LAG-3', 'Gene', (18, 23))
523850	33920505	To date, two clinical trials are ongoing using anti-LAG-3 antibodies as a therapeutic strategy for children affected by glioblastoma.	('glioblastoma', 'Disease', (120, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('anti-LAG-3', 'Var', (47, 57))	('children', 'Species', '9606', (99, 107))
523852	33920505	TIM-3 was first identified in Th1 and cytotoxic CD8+ T cells in 2002 and afterwards several studies reported an association between TIM-3 gene polymorphisms and the risk of developing autoimmune diseases (i.e.	('autoimmune diseases', 'Phenotype', 'HP:0002960', (184, 203))	('polymorphisms', 'Var', (143, 156))	('autoimmune diseases', 'Disease', (184, 203))	('CD8', 'Gene', (48, 51))	('TIM-3', 'Gene', (132, 137))	('autoimmune diseases', 'Disease', 'MESH:D001327', (184, 203))	('CD8', 'Gene', '925', (48, 51))
523864	33920505	In a preclinical model of glioma, the treatment with anti-TIM-3 and anti-Ceacam-1 significantly increased the overall survival of mice, but the best results were obtained combining the two antibodies (Figure 4).	('mice', 'Species', '10090', (130, 134))	('increased', 'PosReg', (96, 105))	('glioma', 'Disease', (26, 32))	('anti-TIM-3', 'Var', (53, 63))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('anti-Ceacam-1', 'Var', (68, 81))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
523888	33920505	Preclinical studies using glioma cells revealed that the treatment of mice with IDO inhibitors prolonged survival and limited tumor growth, with a higher effect when used in combination with TMZ.	('IDO', 'Gene', (80, 83))	('inhibitors', 'Var', (84, 94))	('tumor', 'Disease', (126, 131))	('TMZ', 'Chemical', 'MESH:D000077204', (191, 194))	('limited', 'NegReg', (118, 125))	('glioma', 'Disease', (26, 32))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('survival', 'CPA', (105, 113))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('prolonged', 'PosReg', (95, 104))
523889	33920505	Superimposable results were obtained using tumor cells with knockdown of IDO, as well as using the IDO inhibitor PCC0208009.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('knockdown', 'Var', (60, 69))	('tumor', 'Disease', (43, 48))	('IDO', 'Gene', (73, 76))
523890	33920505	Moreover, the pharmacological inhibition of IDO increased the anti-tumor effects of radiotherapy.	('increased', 'PosReg', (48, 57))	('IDO', 'Gene', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('pharmacological', 'Var', (14, 29))	('tumor', 'Disease', (67, 72))
524006	28323337	Recent advances in molecular testing have led to the exciting possibility that treatment choices might be directed on the basis of the identification of so-called actionable mutations in a patient's individual tumor.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('patient', 'Species', '9606', (189, 196))	('mutations', 'Var', (174, 183))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
524132	25687849	In the subset analysis with patients who received RT with or without surgery (n=48), surgical resection did not significantly improve OS (p=0.161) and PFS (p=0.068) compared to RT without surgery.	('patients', 'Species', '9606', (28, 36))	('PFS', 'MPA', (151, 154))	('surgical resection', 'Var', (85, 103))	('OS', 'Chemical', '-', (134, 136))
524189	32148436	In conclusion, ablation of sarcoma metastases can provide an extended systemic chemotherapy-free interval of greater than 1 year.	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('sarcoma metastases', 'Disease', 'MESH:D009362', (27, 45))	('sarcoma metastases', 'Disease', (27, 45))	('ablation', 'Var', (15, 23))
524190	32148436	Ablation of sarcoma metastases may improve patient quality of life by extending the chemotherapy-free interval.	('chemotherapy-free interval', 'CPA', (84, 110))	('patient', 'Species', '9606', (43, 50))	('Ablation', 'Var', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('sarcoma metastases', 'Disease', (12, 30))	('improve', 'PosReg', (35, 42))	('sarcoma metastases', 'Disease', 'MESH:D009362', (12, 30))
524202	32148436	Ablation is minimally invasive, lacks treatment-specific toxicity, and provides a lower-morbidity treatment option compared to surgical resection.	('toxicity', 'Disease', (57, 65))	('Ablation', 'Var', (0, 8))	('men', 'Species', '9606', (103, 106))	('men', 'Species', '9606', (43, 46))	('toxicity', 'Disease', 'MESH:D064420', (57, 65))
524355	31277155	We found only 2 gene expression Datasets of GSE16354 and GSE22522 can be used for further analyzing by synthesis.	('GSE', 'Chemical', '-', (57, 60))	('GSE22522', 'Var', (57, 65))	('GSE16354', 'Var', (44, 52))	('GSE', 'Chemical', '-', (44, 47))
524357	31277155	There were 24 samples in GSE16354, 6 blood vessel endothelial cells (BECs) control samples compared with KSHV 72 hours post infection of blood vessel endothelial cells (BEC); and 6 LECs control samples compared with KSHV 72 hours post infection of LECs.	('KS', 'Phenotype', 'HP:0100726', (216, 218))	('KS', 'Phenotype', 'HP:0100726', (105, 107))	('KSHV', 'Species', '37296', (105, 109))	('GSE', 'Chemical', '-', (25, 28))	('infection', 'Disease', (124, 133))	('infection', 'Disease', 'MESH:D007239', (124, 133))	('infection', 'Disease', (235, 244))	('GSE16354', 'Var', (25, 33))	('infection', 'Disease', 'MESH:D007239', (235, 244))	('KSHV', 'Species', '37296', (216, 220))
524390	31277155	In Mi et al's study, DEPDC1 was found have a higher expression in the mitotic phase during the cell cycle, and siRNA-mediated knockdown of DEPDC1 would make an effect of mitotic arrest and defects.	('DEPDC1', 'Gene', '55635', (21, 27))	('DEPDC1', 'Gene', (139, 145))	('mitotic arrest and defects', 'Disease', 'MESH:D006323', (170, 196))	('DEPDC1', 'Gene', '55635', (139, 145))	('expression', 'MPA', (52, 62))	('DEPDC1', 'Gene', (21, 27))	('higher', 'PosReg', (45, 51))	('knockdown', 'Var', (126, 135))
524647	30853364	Likewise, the risk for occult endometrial carcinoma was 0.18% (95% CI: 0.12-0.24%) in women undergoing laparoscopic supracervical hysterectomy versus 1.35% (95% CI: 1.25-1.45%) in women who underwent a total abdominal hysterectomy.	('women', 'Species', '9606', (180, 185))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (30, 51))	('laparoscopic', 'Var', (103, 115))	('occult endometrial carcinoma', 'Disease', 'MESH:D016889', (23, 51))	('occult endometrial carcinoma', 'Disease', (23, 51))	('women', 'Species', '9606', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
524668	30853364	Meta-analysis performed by the Agency for Healthcare Research and Quality (AHRQ) estimated that 0 021% (95% credible interval: 0-0.094%) of women in prospective studies and 0.085% (95% credible interval: 0.047-0.127%) in retrospective studies had unexpected leiomyosarcoma.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (258, 272))	('0.085', 'Var', (173, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('leiomyosarcoma', 'Disease', (258, 272))	('women', 'Species', '9606', (140, 145))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (258, 272))
524746	31652801	In fact, mutations, translocations, and deletions occurring within some subunits of SWI/SNF complex were found in ~20% of human tumors, making the complex one of the most commonly affected hallmarks in cancer.	('human', 'Species', '9606', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('hallmarks in cancer', 'Disease', 'MESH:D009369', (189, 208))	('deletions', 'Var', (40, 49))	('mutations', 'Var', (9, 18))	('found', 'Reg', (105, 110))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('SWI/SNF', 'Gene', (84, 91))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('translocations', 'Var', (20, 34))	('hallmarks in cancer', 'Disease', (189, 208))
524748	31652801	Mutations in the SWI/SNF complex are usually associated with loss of protein function, with SMARCB1/BAF47, SMARCA4/BRG1, and ARID1A/BAF250A subunits of the complex being characterized by very high mutation frequencies and a strong relation to disease development.	('men', 'Species', '9606', (258, 261))	('SWI/SNF', 'Gene', (17, 24))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('BRG1', 'Gene', (115, 119))	('BAF250A', 'Gene', '8289', (132, 139))	('BAF47', 'Gene', '6598', (100, 105))	('protein', 'Protein', (69, 76))	('BAF47', 'Gene', (100, 105))	('SMARCB1', 'Gene', '6598', (92, 99))	('BRG1', 'Gene', '6597', (115, 119))	('Mutations', 'Var', (0, 9))	('SMARCA4', 'Gene', (107, 114))	('SMARCA4', 'Gene', '6597', (107, 114))	('SMARCB1', 'Gene', (92, 99))	('loss', 'NegReg', (61, 65))	('BAF250A', 'Gene', (132, 139))
524749	31652801	The roles of mutations in the individual BAF-complex subunits in the development of various human diseases will be discussed later.	('BAF', 'Gene', (41, 44))	('men', 'Species', '9606', (76, 79))	('mutations', 'Var', (13, 22))	('BAF', 'Gene', '8815', (41, 44))	('human', 'Species', '9606', (92, 97))
524753	31652801	The most frequent gene translocation associated with ESFT is t(11;22) (q24;q12) translocation, where fusion of EWS gene on 22q12 with FLI1 gene on 11q24 will produce EWS-FLI1 hybrid protein, and this fusion transcript will lead to increased transcription capacity compared with FLI1 alone.	('fusion', 'Var', (101, 107))	('FLI1', 'Gene', (134, 138))	('transcription capacity', 'MPA', (241, 263))	('FLI1', 'Gene', (278, 282))	('EWS', 'Gene', '2130', (166, 169))	('EWS', 'Gene', (166, 169))	('FLI1', 'Gene', '2313', (278, 282))	('EWS', 'Gene', (111, 114))	('increased', 'PosReg', (231, 240))	('FLI1', 'Gene', (170, 174))	('EWS', 'Gene', '2130', (111, 114))	('FLI1', 'Gene', '2313', (170, 174))	('produce', 'Reg', (158, 165))	('FLI1', 'Gene', '2313', (134, 138))
524755	31652801	Mutations within these pathways lead to tumor progression and unstable EWS-FLI1 expression.	('lead to', 'Reg', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('EWS', 'Gene', '2130', (71, 74))	('EWS', 'Gene', (71, 74))	('tumor', 'Disease', (40, 45))	('Mutations', 'Var', (0, 9))	('expression', 'MPA', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('FLI1', 'Gene', (75, 79))	('FLI1', 'Gene', '2313', (75, 79))
524762	31652801	In addition, the prion domain of EWSR1 at the N-terminus provides the BAF complex with a gain of function that is recruited to GGAA repeats microsatellites, and when this occurs, the closed chromatin is remodeled for activation of enhancer and oncogenic transcription.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('oncogenic transcription', 'CPA', (244, 267))	('recruited', 'PosReg', (114, 123))	('BAF', 'Gene', '8815', (70, 73))	('gain of function', 'PosReg', (89, 105))	('BAF', 'Gene', (70, 73))	('prion', 'Species', '36469', (17, 22))	('EWS', 'Gene', (33, 36))	('EWS', 'Gene', '2130', (33, 36))	('microsatellites', 'Var', (140, 155))	('enhancer', 'CPA', (231, 239))
524767	31652801	Furthermore, the mRNA regions affected by alternative splicing predominantly encodes IDPRs.	('alternative splicing', 'Var', (42, 62))	('IDPRs', 'Disease', (85, 90))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('encodes', 'Reg', (77, 84))
524791	31652801	Human Brahma-related gene-1 (BRG1, also known as BAF190A, or SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4 (ATP-dependent helicase SMARCA4), UniProt ID: P51532; 1,647 residues) encoded by the SMARCA4 gene is the central catalytic subunit of numerous chromatin-modifying enzymatic complexes, including BAF.	('P51532', 'Chemical', 'MESH:D010695', (201, 207))	('Human', 'Species', '9606', (0, 5))	('BRG1', 'Gene', (29, 33))	('SMARCA4', 'Gene', (240, 247))	('helicase', 'Gene', (170, 178))	('ATP', 'Chemical', 'MESH:D000255', (156, 159))	('BAF', 'Gene', '8815', (49, 52))	('SMARCA4', 'Gene', '6597', (179, 186))	('BAF190A', 'Gene', (49, 56))	('BAF', 'Gene', '8815', (349, 352))	('helicase', 'Gene', '164045', (170, 178))	('SMARCA4', 'Gene', '6597', (240, 247))	('P51532', 'Var', (201, 207))	('SMARCA4', 'Gene', (179, 186))	('BAF', 'Gene', (49, 52))	('BAF190A', 'Gene', '6597', (49, 56))	('BRG1', 'Gene', '6597', (29, 33))	('SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4', 'Gene', '6597', (61, 154))	('BAF', 'Gene', (349, 352))
524797	31652801	The sections below briefly describe mutations in, and deregulations of, SMARCA4/BRG1 associated with the development of human diseases.	('human', 'Species', '9606', (120, 125))	('BRG1', 'Gene', (80, 84))	('SMARCA4', 'Gene', (72, 79))	('BRG1', 'Gene', '6597', (80, 84))	('mutations', 'Var', (36, 45))	('SMARCA4', 'Gene', '6597', (72, 79))	('deregulations', 'Var', (54, 67))	('men', 'Species', '9606', (112, 115))	('associated', 'Reg', (85, 95))
524799	31652801	Furthermore, mutations in BRG1 were found in 5-10% of cases of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('BRG1', 'Gene', (26, 30))	('found', 'Reg', (36, 41))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('BRG1', 'Gene', '6597', (26, 30))	('mutations', 'Var', (13, 22))
524803	31652801	In almost all SCCOHT tumors, inactivating mutations leading to loss of BRG1/SMARCA4 expression have been exclusively found, and mutations of this protein were observed in 91% of cases.	('mutations', 'Var', (128, 137))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('BRG1', 'Gene', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('BRG1', 'Gene', '6597', (71, 75))	('SMARCA4', 'Gene', (76, 83))	('SMARCA4', 'Gene', '6597', (76, 83))	('loss', 'NegReg', (63, 67))	('expression', 'MPA', (84, 94))
524804	31652801	Blood neoplasm (Burkitt lymphoma) is linked to mutations in the BRG1/SMARCA4 and BAF250A/ARID1A tumor suppressor genes, with the nonsense and frame-shift mutations leading to loss of function constituting almost 30% of the genetic events occurring with BAF250A/ARID1A.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('neoplasm', 'Phenotype', 'HP:0002664', (6, 14))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (16, 32))	('SMARCA4', 'Gene', '6597', (69, 76))	('BAF250A', 'Gene', '8289', (81, 88))	('BAF250A', 'Gene', (81, 88))	('mutations', 'Var', (47, 56))	('nonsense', 'Var', (129, 137))	('BRG1', 'Gene', '6597', (64, 68))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('Blood neoplasm', 'Phenotype', 'HP:0004377', (0, 14))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (16, 32))	('neoplasm', 'Disease', 'MESH:D009369', (6, 14))	('frame-shift mutations', 'Var', (142, 163))	('BRG1', 'Gene', (64, 68))	('loss of function', 'NegReg', (175, 191))	('tumor', 'Disease', (96, 101))	('SMARCA4', 'Gene', (69, 76))	('BAF250A', 'Gene', '8289', (253, 260))	('linked', 'Reg', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('neoplasm', 'Disease', (6, 14))	('BAF250A', 'Gene', (253, 260))	('Burkitt lymphoma', 'Disease', (16, 32))
524805	31652801	Group 3 and 4 pediatric medulloblastomas also linked to mutation in the BRG1/SMARCA4 gene represent a significant clinical challenge due to poor prognosis and lack of targeted therapy.	('pediatric medulloblastomas', 'Disease', (14, 40))	('pediatric medulloblastomas', 'Disease', 'MESH:D008527', (14, 40))	('BRG1', 'Gene', (72, 76))	('BRG1', 'Gene', '6597', (72, 76))	('linked', 'Reg', (46, 52))	('mutation', 'Var', (56, 64))	('SMARCA4', 'Gene', (77, 84))	('SMARCA4', 'Gene', '6597', (77, 84))
524813	31652801	Although mutated BRCA1 exposes individuals to the risk of breast cancer, it was also shown that BRCA1 could interact with the BRG1 subunit of a SWI/SNF complex.	('BRCA1', 'Gene', '672', (17, 22))	('interact', 'Interaction', (108, 116))	('BRCA1', 'Gene', '672', (96, 101))	('BRCA1', 'Gene', (17, 22))	('mutated', 'Var', (9, 16))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('BRG1', 'Gene', (126, 130))	('BRCA1', 'Gene', (96, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('BRG1', 'Gene', '6597', (126, 130))	('N', 'Chemical', 'MESH:D009584', (149, 150))
524814	31652801	Furthermore, a mutant form of BRG1 interfered with the transcriptional control mediated by BRCA1.	('BRCA1', 'Gene', (91, 96))	('transcriptional control', 'MPA', (55, 78))	('interfered', 'NegReg', (35, 45))	('BRG1', 'Gene', (30, 34))	('BRCA1', 'Gene', '672', (91, 96))	('mutant', 'Var', (15, 21))	('BRG1', 'Gene', '6597', (30, 34))
524815	31652801	Other tumors associated with BRG1 mutations are melanomas, colorectal cancer, oral cancer, and hepatocellular carcinoma, with BRG1 mutations being present in 5-10% of cases in melanoma and colorectal cancer, and increased expression of BRG1 mRNA identified in both oral cancer and hepatocellular carcinoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (189, 206))	('oral cancer', 'Disease', (78, 89))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('BRG1', 'Gene', (29, 33))	('melanoma', 'Disease', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('BRG1', 'Gene', (236, 240))	('hepatocellular carcinoma', 'Disease', (95, 119))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', (48, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('increased', 'PosReg', (212, 221))	('oral cancer', 'Disease', 'MESH:D009062', (265, 276))	('N', 'Chemical', 'MESH:D009584', (243, 244))	('oral cancer', 'Disease', (265, 276))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (281, 305))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('colorectal cancer', 'Disease', 'MESH:D015179', (189, 206))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('associated', 'Reg', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('colorectal cancer', 'Disease', (189, 206))	('melanomas', 'Disease', (48, 57))	('tumors', 'Disease', (6, 12))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (281, 305))	('BRG1', 'Gene', '6597', (126, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('mutations', 'Var', (131, 140))	('colorectal cancer', 'Disease', (59, 76))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('BRG1', 'Gene', '6597', (29, 33))	('BRG1', 'Gene', (126, 130))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('BRG1', 'Gene', '6597', (236, 240))	('hepatocellular carcinoma', 'Disease', (281, 305))	('oral cancer', 'Disease', 'MESH:D009062', (78, 89))	('mutations', 'Var', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
524816	31652801	Another malady linked to the mutated BRG1 is Coffin-Siris syndrome (CSS), a disease characterized by growth and developmental abnormalities as well as craniofacial features, such as sparse scalp hair, bushy eye brows, wide and prominent mouth, body hirsutism, absent or hypoplastic nails of fifth fingers, or toes with absent hypoplastic phalanges.	('hypoplastic nails of fifth fingers', 'Disease', 'MESH:C565090', (270, 304))	('developmental abnormalities', 'Disease', (112, 139))	('wide and prominent mouth', 'Phenotype', 'HP:0000154', (218, 242))	('BRG1', 'Gene', (37, 41))	('bushy eye brows', 'Disease', 'MESH:D000853', (201, 216))	('developmental abnormalities', 'Disease', 'MESH:D006130', (112, 139))	('absent', 'NegReg', (260, 266))	('absent hypoplastic phalanges', 'Disease', 'MESH:C536903', (319, 347))	('mutated', 'Var', (29, 36))	('hypoplastic nails', 'Phenotype', 'HP:0001792', (270, 287))	('body hirsutism', 'Disease', (244, 258))	('absent or hypoplastic nails', 'Phenotype', 'HP:0008386', (260, 287))	('hirsutism', 'Phenotype', 'HP:0001007', (249, 258))	('toes with absent', 'Phenotype', 'HP:0010760', (309, 325))	('Coffin-Siris syndrome', 'Disease', (45, 66))	('absent hypoplastic phalanges', 'Disease', (319, 347))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (45, 66))	('sparse scalp hair', 'Phenotype', 'HP:0002209', (182, 199))	('wide', 'Disease', (218, 222))	('hypoplastic phalanges', 'Phenotype', 'HP:0009803', (326, 347))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (112, 139))	('prominent mouth', 'Disease', (227, 242))	('hypoplastic nails of fifth fingers', 'Disease', (270, 304))	('bushy eye brows', 'Disease', (201, 216))	('body hirsutism', 'Disease', 'MESH:D006628', (244, 258))	('fifth fingers', 'Phenotype', 'HP:0009237', (291, 304))	('prominent mouth', 'Disease', 'MESH:C538270', (227, 242))	('BRG1', 'Gene', '6597', (37, 41))
524818	31652801	Chromatin remodeling subunit SMARCA4/BRG1 has been found to be mutated in 11% of CSS patients, containing missense mutations with gain-of-function or dominant-negative effects.	('SMARCA4', 'Gene', '6597', (29, 36))	('missense mutations', 'Var', (106, 124))	('CSS', 'Disease', (81, 84))	('gain-of-function', 'PosReg', (130, 146))	('BRG1', 'Gene', (37, 41))	('patients', 'Species', '9606', (85, 93))	('BRG1', 'Gene', '6597', (37, 41))	('SMARCA4', 'Gene', (29, 36))
524819	31652801	Besides CSS, other neurodevelopmental disorders, such as Hirschsprung disease, autism spectrum disorder, and schizophrenia, have been associated with mutations in BRG1/BRM subunit of the BAF chromatin remodeling complex like.	('neurodevelopmental disorders', 'Disease', (19, 47))	('autism spectrum disorder', 'Disease', 'MESH:D002659', (79, 103))	('schizophrenia', 'Disease', (109, 122))	('BRG1', 'Gene', '6597', (163, 167))	('BRG1', 'Gene', (163, 167))	('associated', 'Reg', (134, 144))	('autism', 'Phenotype', 'HP:0000717', (79, 85))	('BRM', 'Gene', (168, 171))	('schizophrenia', 'Disease', 'MESH:D012559', (109, 122))	('mutations', 'Var', (150, 159))	('BAF', 'Gene', (187, 190))	('schizophrenia', 'Phenotype', 'HP:0100753', (109, 122))	('neurodevelopmental disorders', 'Disease', 'MESH:D002658', (19, 47))	('CSS', 'Disease', (8, 11))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (57, 77))	('autism spectrum disorder', 'Disease', (79, 103))	('BRM', 'Gene', '6595', (168, 171))	('neurodevelopmental disorders', 'Phenotype', 'HP:0012759', (19, 47))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (79, 103))	('BAF', 'Gene', '8815', (187, 190))	('Hirschsprung disease', 'Disease', (57, 77))	('Hirschsprung disease', 'Disease', 'MESH:D006627', (57, 77))	('developmental disorder', 'Phenotype', 'HP:0001263', (24, 46))
524820	31652801	Furthermore, SMARCA4/BRG1 mutations have been also linked to microphthalmia, a developmental disorder in which one or both eyes are abnormally small and have anatomic malformations.	('SMARCA4', 'Gene', (13, 20))	('linked', 'Reg', (51, 57))	('SMARCA4', 'Gene', '6597', (13, 20))	('anatomic malformations', 'Disease', (158, 180))	('developmental disorder', 'Disease', (79, 101))	('microphthalmia', 'Phenotype', 'HP:0000568', (61, 75))	('mutations', 'Var', (26, 35))	('developmental disorder', 'Phenotype', 'HP:0001263', (79, 101))	('anatomic malformations', 'Disease', 'MESH:D020763', (158, 180))	('BRG1', 'Gene', (21, 25))	('microphthalmia', 'Disease', 'MESH:D008850', (61, 75))	('developmental disorder', 'Disease', 'MESH:D002658', (79, 101))	('microphthalmia', 'Disease', (61, 75))	('BRG1', 'Gene', '6597', (21, 25))
524823	31652801	Among these functional domains and motifs are QLQ domain (residues 171-206) involved in protein-protein interactions, DNA-binding HSA domain (residues 460-532), BRK domain (residues 611-656), helicase (residues 766-1246) containing DEXHc ATP binding domain (residues 766-931) and helicase C-terminal domain HELICc (residues 1081-1246), and bromodomain (residues 1455-1566) interacting with acetylated lysines (Figure 5A).	('residues', 'Var', (258, 266))	('residues', 'Var', (142, 150))	('helicase', 'Gene', '164045', (280, 288))	('acetylated lysines', 'Chemical', 'MESH:C083300', (390, 408))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('helicase', 'Gene', '164045', (192, 200))	('interacting', 'Interaction', (373, 384))	('residues 171-206', 'Var', (58, 74))	('acetylated lysines', 'MPA', (390, 408))	('residues 1081-1246', 'Var', (315, 333))	('residues 1455-1566', 'Var', (353, 371))	('helicase', 'Gene', (280, 288))	('residues 766-1246', 'Var', (202, 219))	('involved', 'Reg', (76, 84))	('helicase', 'Gene', (192, 200))	('ATP', 'Chemical', 'MESH:D000255', (238, 241))	('residues 611-656', 'Var', (173, 189))
524824	31652801	BRG1 also contains the Snf2 ATP coupling domain (residues 1321-1389), and several established functional regions, such as residues 1-282, necessary for interaction with SS18L1/CREST, RNA binding region interacting with lncRNA Evf2 (residues 462-748), and two regions sufficient for interaction with DLX1 (residues 837-916, and 1247-1446).	('Evf2', 'Gene', '285987', (226, 230))	('CREST', 'Gene', (176, 181))	('SS18L1', 'Gene', '26039', (169, 175))	('Snf2', 'Gene', (23, 27))	('residues 1321-1389', 'Var', (49, 67))	('Evf2', 'Gene', (226, 230))	('ATP', 'Chemical', 'MESH:D000255', (28, 31))	('Snf2', 'Gene', '6595', (23, 27))	('BRG1', 'Gene', '6597', (0, 4))	('N', 'Chemical', 'MESH:D009584', (184, 185))	('interaction', 'Interaction', (282, 293))	('N', 'Chemical', 'MESH:D009584', (223, 224))	('SS18L1', 'Gene', (169, 175))	('BRG1', 'Gene', (0, 4))	('DLX1', 'Gene', (299, 303))	('interaction', 'Interaction', (152, 163))	('residues 462-748', 'Var', (232, 248))	('CREST', 'Gene', '26039', (176, 181))	('DLX1', 'Gene', '1745', (299, 303))
524825	31652801	There are also several regions with compositional biases, such as the poly-Lys region (residues 578-588) and three poly-Glu regions (residues 663-672, 1360-1364, and 1571-1584).	('residues 578-588', 'Var', (87, 103))	('1360-1364', 'Var', (151, 160))	('poly-Lys', 'Chemical', 'MESH:C026591', (70, 78))	('poly-Glu', 'Chemical', 'MESH:C023843', (115, 123))	('residues 663-672', 'Var', (133, 149))
524826	31652801	Structural information is currently available for bromodomain by itself (see Figure 5B) and for a fragment of C-tail (residues 1591-1602) complexed with the Brd3 ET domain (see Figure 5C).	('Brd3', 'Gene', (157, 161))	('men', 'Species', '9606', (102, 105))	('Brd3', 'Gene', '8019', (157, 161))	('residues 1591-1602', 'Var', (118, 136))
524830	31652801	Similarly, the protein interacting QLQ domain (residues 171-206) is a part of a long N-terminal MoRF (residues 21-231).	('MoRF', 'Gene', '23522', (96, 100))	('residues 21-231', 'Var', (102, 117))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('MoRF', 'Gene', (96, 100))	('residues 171-206', 'Var', (47, 63))
524831	31652801	Similarly, the 34-residue-long MoRF (residues 475-508) represents a large portion of the HSA domain spanning residues 460-532.	('MoRF', 'Gene', (31, 35))	('MoRF', 'Gene', '23522', (31, 35))	('residues 475-508', 'Var', (37, 53))
524833	31652801	Finally, BRG1 might exist in five experimentally validated isoforms generated by alternative splicing (AS), and there are 29 computationally mapped potential isoforms.	('men', 'Species', '9606', (40, 43))	('alternative splicing', 'Var', (81, 101))	('BRG1', 'Gene', (9, 13))	('BRG1', 'Gene', '6597', (9, 13))
524836	31652801	Note that all AS-induced sequence changes are concentrated within the intrinsically disordered C-terminal region of BRG1.	('BRG1', 'Gene', '6597', (116, 120))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('changes', 'Var', (34, 41))	('BRG1', 'Gene', (116, 120))
524837	31652801	In fact, the missing 1259-1291 region includes one of the MoRFs (residues 1263-1282), changes at W1,388 affect another MoRF (residues 1381-1398), and elimination of S1,475 might affect yet another MoRF (residues 1458-1474).	('affect', 'Reg', (104, 110))	('MoRF', 'Gene', (119, 123))	('MoRFs', 'Chemical', 'MESH:C055328', (58, 63))	('MoRF', 'Gene', '23522', (119, 123))	('MoRF', 'Gene', '23522', (58, 62))	('MoRF', 'Gene', (58, 62))	('MoRF', 'Gene', (197, 201))	('MoRF', 'Gene', '23522', (197, 201))	('elimination', 'Var', (150, 161))	('affect', 'Reg', (178, 184))
524841	31652801	Human protein brahma homolog (BRM, also known as BAF190B, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2 (ATP-dependent helicase SMARCA2), or probable global transcription activator SNF2L2, UniProt ID: P51531) is a 1590 residue-long catalytic subunit of the multiprotein chromatin-remodeling SWI/SNF complexes.	('BRM', 'Gene', (30, 33))	('Human', 'Species', '9606', (0, 5))	('P51531', 'Chemical', 'MESH:D010695', (249, 255))	('N', 'Chemical', 'MESH:D009584', (230, 231))	('SNF2L2', 'Gene', '6595', (229, 235))	('P51531', 'Var', (249, 255))	('SMARCA2', 'Gene', (176, 183))	('helicase', 'Gene', '164045', (167, 175))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('BRM', 'Gene', '6595', (30, 33))	('SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2', 'Gene', '6595', (58, 151))	('BAF190B', 'Gene', '6595', (49, 56))	('BAF190B', 'Gene', (49, 56))	('SNF2L2', 'Gene', (229, 235))	('SMARCA2', 'Gene', '6595', (176, 183))	('helicase', 'Gene', (167, 175))	('N', 'Chemical', 'MESH:D009584', (344, 345))	('ATP', 'Chemical', 'MESH:D000255', (153, 156))
524842	31652801	BRM is encoded by the SMARCA2 gene, and has domain organization similar to that of BRG1, containing a QLQ domain (residues 173-208), an HSA domain (residues 436-508), a helicase ATP-binding domain (residues 736-901), a helicase C-terminal domain (residues 1054-1216), and a bromodomain (residues 1419-1489).	('residues 1054-1216', 'Var', (247, 265))	('SMARCA2', 'Gene', (22, 29))	('SMARCA2', 'Gene', '6595', (22, 29))	('BRG1', 'Gene', '6597', (83, 87))	('BRM', 'Gene', (0, 3))	('helicase', 'Gene', '164045', (169, 177))	('ATP', 'Chemical', 'MESH:D000255', (178, 181))	('residues 436-508', 'Var', (148, 164))	('residues 173-208', 'Var', (114, 130))	('helicase', 'Gene', (169, 177))	('helicase', 'Gene', '164045', (219, 227))	('residues 736-901', 'Var', (198, 214))	('BRM', 'Gene', '6595', (0, 3))	('BRG1', 'Gene', (83, 87))	('helicase', 'Gene', (219, 227))
524844	31652801	These include two poly-Gln regions (residues 216-238 and 245-253), a poly-Arg region (residues 559-562), and three poly-Glu regions (residues 643-650, 1291-1301, and 1518-1529).	('1291-1301', 'Var', (151, 160))	('residues 559-562', 'Var', (86, 102))	('residues 216-238', 'Var', (36, 52))	('poly-Gln', 'Chemical', 'MESH:C544323', (18, 26))	('1518-1529', 'Var', (166, 175))	('residues 643-650', 'Var', (133, 149))	('poly-Arg', 'Chemical', 'MESH:C056211', (69, 77))	('poly-Glu', 'Chemical', 'MESH:C023843', (115, 123))
524846	31652801	Multiple mutations in the SMARCA2 gene were identified in Nicolaides-Baraitser syndrome (NCBRS), which is a rare disease characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints, and broad distal phalanges.	('seizures', 'Disease', 'MESH:D012640', (195, 203))	('mutations', 'Var', (9, 18))	('seizures', 'Phenotype', 'HP:0001250', (195, 203))	('sparse hair', 'Disease', (220, 231))	('brachydactyly', 'Phenotype', 'HP:0001156', (265, 278))	('brachydactyly', 'Disease', 'MESH:D059327', (265, 278))	('short stature', 'Disease', 'MESH:D006130', (205, 218))	('Nicolaides-Baraitser syndrome', 'Disease', 'MESH:C536116', (58, 87))	('short stature', 'Disease', (205, 218))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('broad distal phalanges', 'Phenotype', 'HP:0009836', (309, 331))	('SMARCA2', 'Gene', (26, 33))	('SMARCA2', 'Gene', '6595', (26, 33))	('mental retardation', 'Phenotype', 'HP:0001249', (145, 163))	('mental retardation', 'Disease', 'MESH:D008607', (145, 163))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('Nicolaides-Baraitser syndrome', 'Disease', (58, 87))	('retardation with absent or limited speech', 'Phenotype', 'HP:0001344', (152, 193))	('brachydactyly', 'Disease', (265, 278))	('severe mental retardation', 'Phenotype', 'HP:0010864', (138, 163))	('mental retardation', 'Disease', (145, 163))	('short stature', 'Phenotype', 'HP:0004322', (205, 218))	('sparse hair', 'Phenotype', 'HP:0008070', (220, 231))	('seizures', 'Disease', (195, 203))	('identified', 'Reg', (44, 54))
524847	31652801	These SMARCA2 gene mutations cause BRM substitutions at Ala752, Arg755, Ile756, His851, Asp852, Lys852, Arg854, Asn854, Gly855, Arg881, Val881, Leu883, Tyr939, Ser946, Phe946, Cys1105, Pro1105, Pro1135, Arg1146, Val1158, Gly1159, Leu1159, Gln1159, His1162, Pro1188, Val1201, Cys1202, Gly1205, and Trp1213.	('Asn854', 'Chemical', 'MESH:C073821', (112, 118))	('Cys1202', 'Chemical', 'MESH:C577765', (275, 282))	('Ser946', 'Var', (160, 166))	('Arg1146', 'Chemical', 'MESH:C050547', (203, 210))	('SMARCA2', 'Gene', (6, 13))	('Arg854', 'Var', (104, 110))	('Pro1105', 'Gene', '56063', (185, 192))	('Gly1205', 'Var', (284, 291))	('His1162', 'Var', (248, 255))	('Val1158', 'Var', (212, 219))	('Gly855', 'Var', (120, 126))	('BRM', 'Gene', (35, 38))	('Gly1159', 'Var', (221, 228))	('Leu883', 'Chemical', 'MESH:C054472', (144, 150))	('SMARCA2', 'Gene', '6595', (6, 13))	('Ser', 'Chemical', 'MESH:C530429', (160, 163))	('Val1158', 'Chemical', 'MESH:C515245', (212, 219))	('Asp852', 'Var', (88, 94))	('Lys852', 'Var', (96, 102))	('Lys', 'Chemical', 'MESH:C026591', (96, 99))	('Phe946', 'Chemical', 'MESH:C086976', (168, 174))	('Cys1202', 'Var', (275, 282))	('Trp1213', 'Chemical', 'MESH:C113730', (297, 304))	('Ile756', 'Var', (72, 78))	('Arg881', 'Chemical', 'MESH:C035755', (128, 134))	('Val881', 'Var', (136, 142))	('Arg854', 'Chemical', 'MESH:C073821', (104, 110))	('Leu1159', 'Chemical', 'MESH:C006272', (230, 237))	('Asn854', 'Var', (112, 118))	('His851', 'Var', (80, 86))	('Gln1159', 'Var', (239, 246))	('Pro1135', 'Var', (194, 201))	('Arg755', 'Var', (64, 70))	('BRM', 'Gene', '6595', (35, 38))	('Ala752', 'Var', (56, 62))	('Leu1159', 'Var', (230, 237))	('Leu883', 'Var', (144, 150))	('Arg755', 'Chemical', 'MESH:C439606', (64, 70))	('Val1201', 'Var', (266, 273))	('Ala', 'Chemical', 'MESH:C026593', (56, 59))	('Val881', 'Chemical', 'MESH:C035755', (136, 142))	('Pro1188', 'Chemical', 'MESH:C073897', (257, 264))	('Tyr939', 'Chemical', 'MESH:C066169', (152, 158))	('Cys1105', 'Var', (176, 183))	('Cys1105', 'Chemical', 'MESH:C541937', (176, 183))	('Gln1159', 'Chemical', 'MESH:C006272', (239, 246))	('Pro1105', 'Gene', (185, 192))	('Tyr939', 'Var', (152, 158))	('Pro1188', 'Var', (257, 264))	('Asp852', 'Chemical', 'MESH:D005907', (88, 94))	('Gly1159', 'Chemical', 'MESH:C006272', (221, 228))	('Phe946', 'Var', (168, 174))	('Arg1146', 'Var', (203, 210))	('Trp1213', 'Var', (297, 304))	('Arg881', 'Var', (128, 134))
524848	31652801	Single nucleotide polymorphisms (SNPs) in this gene are also associated with schizophrenia.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('schizophrenia', 'Disease', 'MESH:D012559', (77, 90))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('schizophrenia', 'Disease', (77, 90))	('associated', 'Reg', (61, 71))	('schizophrenia', 'Phenotype', 'HP:0100753', (77, 90))
524849	31652801	According to the BioMuta database of single-nucleotide variations (SNVs) in cancer , mutations in the SMARCA2 gene are linked to melanoma, malignant glioma, thyroid carcinoma, and blastoma, as well as to uterine, urinary bladder, stomach, colorectal, kidney, ovarian, breast, liver, cervical, and lung cancer.	('SMARCA2', 'Gene', (102, 109))	('blastoma', 'Disease', (180, 188))	('SMARCA2', 'Gene', '6595', (102, 109))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (157, 174))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (302, 308))	('uterine', 'Disease', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('colorectal, kidney, ovarian, breast, liver', 'Disease', 'MESH:D010051', (239, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('linked', 'Reg', (119, 125))	('lung cancer', 'Disease', (297, 308))	('mutations', 'Var', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('blastoma', 'Disease', 'MESH:D018202', (180, 188))	('urinary bladder', 'Disease', (213, 228))	('cancer', 'Disease', (76, 82))	('stomach', 'Disease', (230, 237))	('lung cancer', 'Disease', 'MESH:D008175', (297, 308))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (157, 174))	('malignant glioma', 'Disease', 'MESH:D005910', (139, 155))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('malignant glioma', 'Disease', (139, 155))	('melanoma', 'Disease', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('thyroid carcinoma', 'Disease', (157, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (297, 308))	('cervical', 'Disease', (283, 291))
524850	31652801	X-ray crystal structure was solved for a construct containing helicase ATP-binding domain (residues 705-955) with N-terminally attached maltose binding protein (MBP) tag (PDB ID: 6EG3).	('N', 'Chemical', 'MESH:D009584', (114, 115))	('MBP', 'Gene', '4155', (161, 164))	('maltose binding protein', 'Gene', '4155', (136, 159))	('helicase', 'Gene', (62, 70))	('maltose binding protein', 'Gene', (136, 159))	('MBP', 'Gene', (161, 164))	('residues', 'Var', (91, 99))	('helicase', 'Gene', '164045', (62, 70))	('ATP', 'Chemical', 'MESH:D000255', (71, 74))
524865	31652801	Furthermore, BAF155 has a tumor suppressor activity in some tumors, such as colorectal cancer and ovarian carcinoma, as mutations of SMARCC1/BAF155 were also linked to the development of these tumors.	('men', 'Species', '9606', (179, 182))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (98, 115))	('ovarian carcinoma', 'Disease', (98, 115))	('SMARCC1', 'Gene', '6599', (133, 140))	('mutations', 'Var', (120, 129))	('BAF155', 'Gene', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Disease', (60, 65))	('BAF155', 'Gene', '6599', (141, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('SMARCC1', 'Gene', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (98, 115))	('BAF155', 'Gene', (13, 19))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (193, 198))	('BAF155', 'Gene', '6599', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumors', 'Disease', (60, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('colorectal cancer', 'Disease', (76, 93))	('tumors', 'Disease', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('linked to', 'Reg', (158, 167))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
524869	31652801	Human BAF155 (UniProt ID: Q92922) contains two functional domains, SWIRM (residues 449-546) that mediates specific PPIs required for the assembly of chromatin-protein complexes, and SANT (residues 618-669), which is another PPI module that can bind to tails of histone proteins.	('N', 'Chemical', 'MESH:D009584', (184, 185))	('BAF155', 'Gene', '6599', (6, 12))	('Human', 'Species', '9606', (0, 5))	('residues 449-546', 'Var', (74, 90))	('residues', 'Var', (188, 196))	('Q92922', 'Chemical', 'MESH:C000295', (26, 32))	('BAF155', 'Gene', (6, 12))
524870	31652801	Furthermore, there are several regions with amino acid composition biases in this protein, such as poly-Pro (residues 329-336), Glu-rich (residues 769-863), poly-Ala (residues 867-878), and Pro-rich regions (residues 977-1105).	('poly-Ala', 'Chemical', 'MESH:C022266', (157, 165))	('residues 329-336', 'Var', (109, 125))	('poly-Pro', 'Chemical', 'MESH:C008982', (99, 107))	('residues 867-878', 'Var', (167, 183))	('residues 769-863', 'Var', (138, 154))	('residues 977-1105', 'Var', (208, 225))	('Glu', 'Chemical', 'MESH:C094686', (128, 131))
524871	31652801	Structure is currently known for the SWIRM domain complexed with the with the repeat 1 (RPT1) domain of BAF47 (residues 183-289; PDB ID: 5GJK) and for the SANT domain (residues 610-675; PDB ID: 1RYU) (see Figure 7A,B).	('N', 'Chemical', 'MESH:D009584', (157, 158))	('BAF47', 'Gene', (104, 109))	('BAF47', 'Gene', '6598', (104, 109))	('residues 610-675;', 'Var', (168, 185))	('residues 183-289', 'Var', (111, 127))
524878	31652801	It has a domain organization similar to that of BAF155, containing SWIRM and SANT domains (residues 424-521 and 596-647, respectively), as well as a coiled-coil domain (residues 907-934).	('residues 424-521', 'Var', (91, 107))	('BAF155', 'Gene', '6599', (48, 54))	('596-647', 'Var', (112, 119))	('coiled-coil', 'MPA', (149, 160))	('residues 907-934', 'Var', (169, 185))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('BAF155', 'Gene', (48, 54))	('SWIRM', 'MPA', (67, 72))
524879	31652801	It also has regions with amino acid composition biases, such as poly-Glu (residues 186-189), Glu-rich (residues 747-855), poly-Ala (residues 861-870), poly-Gln (residues 956-960), and Pro-rich regions (residues 961-1213).	('poly-Gln', 'Chemical', 'MESH:C544323', (151, 159))	('poly-Glu', 'Chemical', 'MESH:C023843', (64, 72))	('poly-Ala', 'Chemical', 'MESH:C022266', (122, 130))	('residues 747-855', 'Var', (103, 119))	('residues 861-870', 'Var', (132, 148))	('Glu', 'Chemical', 'MESH:C094686', (69, 72))	('residues 956-960', 'Var', (161, 177))	('residues 186-189', 'Var', (74, 90))	('residues 961-1213', 'Var', (202, 219))	('Glu', 'Chemical', 'MESH:C094686', (93, 96))
524880	31652801	SMARCC2 is one of the genes mutations that are associated with a rare and clinically and genetically heterogeneous disorder, Coffin-Siris syndrome.	('SMARCC2', 'Gene', (0, 7))	('SMARCC2', 'Gene', '6601', (0, 7))	('Coffin-Siris syndrome', 'Disease', (125, 146))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (125, 146))	('associated', 'Reg', (47, 57))	('mutations', 'Var', (28, 37))
524881	31652801	Furthermore, according to the BioMuta database of single-nucleotide variations (SNVs) in cancer, mutations in this gene are associated with liver, cancer, colorectal, stomach, lung, breast, and uterine cancers, as well as with melanoma and multiple other tumors.	('mutations', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumors', 'Disease', (255, 261))	('lung', 'Disease', (176, 180))	('cancer', 'Disease', (89, 95))	('colorectal', 'Disease', 'MESH:D015179', (155, 165))	('uterine cancers', 'Phenotype', 'HP:0010784', (194, 209))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('liver', 'Disease', (140, 145))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('associated', 'Reg', (124, 134))	('stomach', 'Disease', (167, 174))	('colorectal', 'Disease', (155, 165))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('melanoma', 'Disease', (227, 235))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('uterine cancer', 'Phenotype', 'HP:0010784', (194, 208))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancer', 'Disease', (202, 208))	('cancers', 'Disease', (202, 209))	('cancer', 'Disease', (147, 153))
524892	31652801	Mutations in the SMARCB1 gene are associated with Coffin-Siris syndrome 3 (CSS3), Schwannomatosis 1 (SWNTS1), rhabdoid tumor predisposition syndrome 1 (RTPS1), as well as familial multiple meningioma, familial rhabdoid tumor, and neurofibromatosis type 3.	('rhabdoid tumor', 'Disease', 'MESH:D018335', (110, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('RTPS1', 'Gene', '6598', (152, 157))	('neurofibromatosis', 'Disease', (230, 247))	('Mutations', 'Var', (0, 9))	('SMARCB1', 'Gene', (17, 24))	('SMARCB1', 'Gene', '6598', (17, 24))	('RTPS1', 'Gene', (152, 157))	('neurofibromatosis', 'Disease', 'MESH:D017253', (230, 247))	('Schwannomatosis', 'Disease', 'MESH:C536641', (82, 97))	('rhabdoid tumor', 'Disease', (110, 124))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (210, 224))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('associated', 'Reg', (34, 44))	('familial multiple meningioma', 'Disease', (171, 199))	('familial rhabdoid tumor', 'Disease', 'MESH:D018335', (201, 224))	('familial multiple meningioma', 'Disease', 'MESH:D008579', (171, 199))	('Coffin-Siris syndrome', 'Disease', (50, 71))	('Schwannomatosis', 'Disease', (82, 97))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (230, 247))	('familial rhabdoid tumor', 'Disease', (201, 224))	('meningioma', 'Phenotype', 'HP:0002858', (189, 199))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (50, 71))
524893	31652801	Furthermore, according to BioMuta , SNV mutations in SMARCB1 are found in various cancers, including uterine, lung, kidney, and stomach cancers.	('N', 'Chemical', 'MESH:D009584', (37, 38))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', (82, 89))	('found', 'Reg', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('stomach cancers', 'Disease', 'MESH:D013274', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('uterine', 'Disease', (101, 108))	('lung', 'Disease', (110, 114))	('mutations', 'Var', (40, 49))	('kidney', 'Disease', (116, 122))	('stomach cancers', 'Disease', (128, 143))	('stomach cancers', 'Phenotype', 'HP:0012126', (128, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('SMARCB1', 'Gene', '6598', (53, 60))	('SMARCB1', 'Gene', (53, 60))
524894	31652801	Human BAF47 can be divided into several functional regions with specific activities, such as DNA-binding region (residues 1-113), HIV-1 integrase binding region (residues 183-243) that overlaps with MYC-binding region (residues 186-245), and PPP1R15A-interacting region (residues 304-318).	('Human', 'Species', '9606', (0, 5))	('BAF47', 'Gene', '6598', (6, 11))	('MYC', 'Gene', (199, 202))	('BAF47', 'Gene', (6, 11))	('residues 183-243', 'Var', (162, 178))	('PPP1R15A', 'Gene', '23645', (242, 250))	('MYC', 'Gene', '4609', (199, 202))	('PPP1R15A', 'Gene', (242, 250))	('HIV-1', 'Species', '11676', (130, 135))	('N', 'Chemical', 'MESH:D009584', (94, 95))
524906	31652801	Similar to BRG1, mutations and deregulation of BAF250A is associated with cancer pathogenesis.	('associated', 'Reg', (58, 68))	('deregulation', 'Var', (31, 43))	('BRG1', 'Gene', '6597', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('BAF250A', 'Gene', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('BAF250A', 'Gene', '8289', (47, 54))	('mutations', 'Var', (17, 26))	('BRG1', 'Gene', (11, 15))
524907	31652801	For example, Burkitt lymphoma has been linked to mutations in the genes coding for both BRG1 and BAF250A, with nonsense and frame-shift mutations in BAF250A that lead to loss of function constituting almost 30% of genetic events associated with this blood neoplasm.	('BAF250A', 'Gene', (97, 104))	('blood neoplasm', 'Phenotype', 'HP:0004377', (250, 264))	('neoplasm', 'Disease', 'MESH:D009369', (256, 264))	('mutations', 'Var', (49, 58))	('BRG1', 'Gene', (88, 92))	('Burkitt lymphoma', 'Disease', (13, 29))	('BAF250A', 'Gene', '8289', (149, 156))	('BAF250A', 'Gene', '8289', (97, 104))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (13, 29))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('linked', 'Reg', (39, 45))	('BRG1', 'Gene', '6597', (88, 92))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (13, 29))	('BAF250A', 'Gene', (149, 156))	('loss of function', 'NegReg', (170, 186))	('neoplasm', 'Disease', (256, 264))	('neoplasm', 'Phenotype', 'HP:0002664', (256, 264))	('frame-shift mutations', 'Var', (124, 145))
524908	31652801	Mutations in ARID1A encoding BAF250A associated with the loss of BAF250 function have been linked to ovarian clear cell carcinoma (OCCC), which is a rare form of cancer, accounting for approximately 5-10% of all ovarian carcinomas in North America, with a higher percentage in East Asia.	('ovarian carcinomas', 'Disease', (212, 230))	('BAF250A', 'Gene', (29, 36))	('cancer', 'Disease', (162, 168))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (212, 230))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D010051', (101, 129))	('N', 'Chemical', 'MESH:D009584', (234, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('BAF250', 'Gene', '8289', (65, 71))	('BAF250', 'Gene', (65, 71))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (37, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('BAF250', 'Gene', '8289', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('BAF250', 'Gene', (29, 35))	('loss', 'NegReg', (57, 61))	('ovarian clear cell carcinoma', 'Disease', (101, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (220, 230))	('ARID1A', 'Gene', (13, 19))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (212, 229))	('linked', 'Reg', (91, 97))	('BAF250A', 'Gene', '8289', (29, 36))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (212, 230))
524910	31652801	Mutations in ARID1A with loss of BAF250 function have been also linked to the development of the subtypes of endometrioid carcinoma.	('BAF250', 'Gene', '8289', (33, 39))	('endometrioid carcinoma', 'Disease', (109, 131))	('ARID1A', 'Gene', (13, 19))	('BAF250', 'Gene', (33, 39))	('Mutations', 'Var', (0, 9))	('men', 'Species', '9606', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('linked', 'Reg', (64, 70))	('function', 'MPA', (40, 48))	('endometrioid carcinoma', 'Disease', 'MESH:D018269', (109, 131))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (109, 131))
524911	31652801	In OCCC and endometrioid ovarian cancer, ARID1A mutations may be heterozygous or biallelic, with biallelic mutations being associated with BAF250A loss of function or loss of protein expression.	('BAF250A', 'Gene', (139, 146))	('OCCC and endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (3, 39))	('loss of function', 'NegReg', (147, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('ARID1A', 'Gene', (41, 47))	('loss', 'NegReg', (167, 171))	('BAF250A', 'Gene', '8289', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (48, 57))	('protein expression', 'MPA', (175, 193))
524912	31652801	ARID1A mutations are also present in more than 10% of liver cancer cases.	('liver cancer', 'Phenotype', 'HP:0002896', (54, 66))	('ARID1A', 'Gene', (0, 6))	('present', 'Reg', (26, 33))	('liver cancer', 'Disease', 'MESH:D006528', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('liver cancer', 'Disease', (54, 66))	('mutations', 'Var', (7, 16))
524913	31652801	During initiation of the tumors, deletion of ARID1A was protective, causing a delay in the onset of hepatocellular carcinoma in mice, while it was also noticed that loss of ARID1A led to acceleration of colorectal cancer in mice.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('initiation of the tumors', 'Disease', (7, 31))	('deletion', 'Var', (33, 41))	('loss', 'Var', (165, 169))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('mice', 'Species', '10090', (224, 228))	('hepatocellular carcinoma', 'Disease', (100, 124))	('acceleration', 'PosReg', (187, 199))	('mice', 'Species', '10090', (128, 132))	('initiation of the tumors', 'Disease', 'MESH:D009369', (7, 31))	('ARID1A', 'Gene', (173, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('ARID1A', 'Gene', (45, 51))	('colorectal cancer', 'Disease', (203, 220))
524915	31652801	In addition to the aforementioned pathologies, genome sequencing and comparative genomic hybridization (CGH) studies have detected ARID1A mutations or deletions in a share of additional cancer subtypes, such as gastric cancer (29%), breast cancer (4-13%), pancreatic cancer (33-45%), transitional cell carcinoma of the bladder (13%), Waldenstrom's macroglobulinemia (17%), and uterine cancer.	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	("Waldenstrom's macroglobulinemia", 'Disease', 'MESH:D008258', (334, 365))	("Waldenstrom's macroglobulinemia", 'Disease', (334, 365))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('cancer', 'Disease', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (256, 273))	('transitional cell carcinoma of the bladder', 'Phenotype', 'HP:0006740', (284, 326))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('men', 'Species', '9606', (24, 27))	('cancer', 'Disease', (267, 273))	('gastric cancer', 'Disease', (211, 225))	("Waldenstrom's macroglobulinemia", 'Phenotype', 'HP:0005508', (334, 365))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('carcinoma of the bladder', 'Disease', 'MESH:D001749', (302, 326))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Disease', (219, 225))	('cancer', 'Disease', (186, 192))	('mutations', 'Var', (138, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (256, 273))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('carcinoma of the bladder', 'Disease', (302, 326))	('breast cancer', 'Disease', (233, 246))	('deletions', 'Var', (151, 160))	('ARID1A', 'Gene', (131, 137))	('cancer', 'Disease', (385, 391))	('pancreatic cancer', 'Disease', (256, 273))	('uterine cancer', 'Phenotype', 'HP:0010784', (377, 391))
524918	31652801	There are also four LXXL motifs (residues 295-299, 1709-1713, 1967-1971, and 2085-2089) and four regions of amino acid composition biases, including two poly-Glu regions (residues 479-482 and 561-567), a poly-Ser region (residues 998-1001), and a Glu-rich region (residues 1317-1404).	('poly-Glu', 'Chemical', 'MESH:C023843', (153, 161))	('poly-Ser', 'Chemical', 'MESH:C530429', (204, 212))	('residues 479-482', 'Var', (171, 187))	('residues 295-299', 'Var', (33, 49))	('Glu', 'Chemical', 'MESH:C094686', (158, 161))	('2085-2089', 'Var', (77, 86))	('1709-1713', 'Var', (51, 60))	('Glu', 'Chemical', 'MESH:C094686', (247, 250))	('residues 998-1001', 'Var', (221, 238))
524919	31652801	In addition to the canonical form, BAF250 may exist in two AS-generated isoforms, with missing residues 1367-1583 (isoform-1) or 1-383 (isoform-2).	('BAF250', 'Gene', '8289', (35, 41))	('BAF250', 'Gene', (35, 41))	('1-383', 'Var', (129, 134))	('missing residues 1367-1583', 'Var', (87, 113))
524928	31652801	In line with this conclusion, ARID1B was found to be mutated in more than 10% of patients with OCCC.	('ARID1B', 'Gene', '57492', (30, 36))	('patients', 'Species', '9606', (81, 89))	('mutated', 'Var', (53, 60))	('ARID1B', 'Gene', (30, 36))	('OCCC', 'Disease', (95, 99))
524929	31652801	ARID1B mutations were found in 5-10% of cases of colorectal cancer, which is the chief cause of morbidity and mortality all over the world, accounting for over 9% of all cancer incidence, and being the third most common cancer worldwide and the fourth most common cause of death.	('death', 'Disease', 'MESH:D003643', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('ARID1B', 'Gene', (0, 6))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('death', 'Disease', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('found', 'Reg', (22, 27))	('colorectal cancer', 'Disease', (49, 66))	('cancer', 'Disease', (60, 66))	('ARID1B', 'Gene', '57492', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('cancer', 'Disease', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (7, 16))
524931	31652801	ARID1B mutations are also found in 5-10% of cases of gastric cancer, which is one of the most common cancers and the second most common cause of cancer deaths worldwide.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('ARID1B', 'Gene', (0, 6))	('cancers', 'Disease', (101, 108))	('cancer deaths', 'Disease', 'MESH:D003643', (145, 158))	('gastric cancer', 'Disease', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('ARID1B', 'Gene', '57492', (0, 6))	('found', 'Reg', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('cancer deaths', 'Disease', (145, 158))	('mutations', 'Var', (7, 16))
524933	31652801	Finally, ARID1B can be mutated in hepatocellular carcinoma (HCC), which is a complex disease and a main cause of death in high endemic areas of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (34, 58))	('HCC', 'Gene', '619501', (60, 63))	('hepatocellular carcinoma', 'Disease', (34, 58))	('death', 'Disease', 'MESH:D003643', (113, 118))	('death', 'Disease', (113, 118))	('ARID1B', 'Gene', (9, 15))	('hepatitis B virus (HBV) or hepatitis C virus (HCV) infection', 'Disease', 'MESH:D006526', (144, 204))	('complex disease', 'Disease', (77, 92))	('mutated', 'Var', (23, 30))	('complex disease', 'Disease', 'MESH:D007105', (77, 92))	('ARID1B', 'Gene', '57492', (9, 15))	('hepatitis', 'Phenotype', 'HP:0012115', (171, 180))	('hepatitis', 'Phenotype', 'HP:0012115', (144, 153))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (34, 58))	('HCC', 'Gene', (60, 63))
524936	31652801	In addition to ARID domain (residues 1041-1159) human BAF250B contains two LXXL motifs (residues 419-423 and 2036-2040), a nuclear localization signal (residues 1358-1,77), and 14 regions with amino acid composition biases, such as two Ala-rich segments (residues 2-47 and 329-493), two Ser-rich fragments (residues 35-57 and 684-771), two Gln-rich regions (residues 107-131 and 574-633), two poly-Ser segments (residues 1034-1037 and 1441-1444), a His-rich (residues 81-114), a poly-Gln (residues 114-131), a poly-Ala (residues 932-935), and a poly-Pro region (residues 1833-1836), as well as 261- and 139-residue-long Gly-rich and Pro-rich regions (residues 141-401 and 1459-1597, respectively).	('Ser', 'Chemical', 'MESH:C530429', (398, 401))	('residues', 'Var', (459, 467))	('BAF250B', 'Gene', (54, 61))	('residues', 'Var', (562, 570))	('poly-Gln', 'Chemical', 'MESH:C544323', (479, 487))	('Ser', 'Chemical', 'MESH:C530429', (287, 290))	('men', 'Species', '9606', (248, 251))	('human', 'Species', '9606', (48, 53))	('residues 114-131', 'Var', (489, 505))	('poly-Pro', 'Chemical', 'MESH:C008982', (545, 553))	('Gln', 'Chemical', 'MESH:C544323', (484, 487))	('Ala', 'Chemical', 'MESH:C026593', (515, 518))	('men', 'Species', '9606', (405, 408))	('Ala', 'Chemical', 'MESH:C026593', (236, 239))	('Gln', 'Chemical', 'MESH:C544323', (340, 343))	('BAF250B', 'Gene', '57492', (54, 61))	('poly-Ser', 'Chemical', 'MESH:C530429', (393, 401))	('men', 'Species', '9606', (300, 303))	('poly-Ala', 'Chemical', 'MESH:C022266', (510, 518))
524938	31652801	Similar to BAF250A, ARID domain (residues 1041-1159) of BAF250B was the only protein region with a known structure (see Figure 11A).	('residues 1041-1159', 'Var', (33, 51))	('BAF250B', 'Gene', (56, 63))	('BAF250B', 'Gene', '57492', (56, 63))	('BAF250A', 'Gene', (11, 18))	('BAF250A', 'Gene', '8289', (11, 18))
524943	31652801	A comparison of the data summarized in Figure 11 with the description of alternative splicing-generated alterations in the BAF250B amino acid sequence indicates that AS might affect the potential disorder-based functionality of this protein.	('BAF250B', 'Gene', '57492', (123, 130))	('alterations', 'Var', (104, 115))	('alternative splicing-generated', 'Var', (73, 103))	('disorder-based functionality', 'MPA', (196, 224))	('affect', 'Reg', (175, 181))	('BAF250B', 'Gene', (123, 130))
524944	31652801	For example, isoform-4 was missing 11 MoRFs and multiple phosphorylation and ubiquitination sites, whereas sequence changes in isoform-2 might affect two MoRFs (residues 543-578 and 583-604), and isoform-3 might change the local phosphorylation predisposition of this protein and introduce a new MoRF.	('MoRFs', 'Chemical', 'MESH:C055328', (154, 159))	('MoRFs', 'Chemical', 'MESH:C055328', (38, 43))	('MoRF', 'Gene', (154, 158))	('MoRF', 'Gene', '23522', (154, 158))	('MoRF', 'Gene', (38, 42))	('MoRF', 'Gene', '23522', (38, 42))	('local phosphorylation predisposition', 'MPA', (223, 259))	('change', 'Reg', (212, 218))	('MoRF', 'Gene', (296, 300))	('MoRF', 'Gene', '23522', (296, 300))	('583-604', 'Var', (182, 189))	('changes', 'Var', (116, 123))	('residues 543-578', 'Var', (161, 177))	('affect', 'Reg', (143, 149))
524950	31652801	SMARCE1 mutations have been found in the germline of families with a history of meningiomas and sporadic tumors.	('meningiomas', 'Disease', (80, 91))	('meningioma', 'Phenotype', 'HP:0002858', (80, 90))	('SMARCE1', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('sporadic tumors', 'Disease', 'MESH:D020821', (96, 111))	('meningiomas', 'Disease', 'MESH:D008579', (80, 91))	('SMARCE1', 'Gene', '6605', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('meningiomas', 'Phenotype', 'HP:0002858', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('sporadic tumors', 'Disease', (96, 111))
524952	31652801	Germline SMARCE1 mutations were identified in 14% (9/63) of the solitary meningioma patients younger than 25 years, with all the affected individuals suffering from meningiomas of the clear cell type.	('SMARCE1', 'Gene', (9, 16))	('meningioma', 'Disease', 'MESH:D008579', (165, 175))	('SMARCE1', 'Gene', '6605', (9, 16))	('meningioma', 'Phenotype', 'HP:0002858', (73, 83))	('meningioma', 'Disease', 'MESH:D008579', (73, 83))	('patients', 'Species', '9606', (84, 92))	('meningiomas', 'Disease', 'MESH:D008579', (165, 176))	('meningiomas', 'Phenotype', 'HP:0002858', (165, 176))	('meningioma', 'Disease', (165, 175))	('meningioma', 'Phenotype', 'HP:0002858', (165, 175))	('mutations', 'Var', (17, 26))	('meningiomas', 'Disease', (165, 176))	('meningioma', 'Disease', (73, 83))
524953	31652801	Heterozygous loss of function mutations was also found in 4/9 individuals and loss of protein was found in all tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('loss', 'NegReg', (78, 82))	('mutations', 'Var', (30, 39))
524954	31652801	SMARCE1 mutations are thought to be involved other types of cancer, including breast, ovarian, and prostate.	('ovarian', 'Disease', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('SMARCE1', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('SMARCE1', 'Gene', '6605', (0, 7))	('prostate', 'Disease', (99, 107))	('involved', 'Reg', (36, 44))	('breast', 'Disease', (78, 84))
524958	31652801	No structural information is available for this protein, which contains a long coiled-coil region (residues 220-319), as well as Pro-rich and Glu-rich regions (residues 5-65 and 320-411, respectively).	('coiled-coil', 'MPA', (79, 90))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('residues 5-65', 'Var', (160, 173))	('residues 220-319', 'Var', (99, 115))	('Glu', 'Chemical', 'MESH:C094686', (142, 145))
524964	31652801	BAF180 acts as a tumor suppressor by functioning within the tumor suppressor pathways causing genetic inactivation in tumors, and also plays a role in tissue maintenance.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('BAF180', 'Gene', (0, 6))	('tumors', 'Disease', (118, 124))	('tumor', 'Disease', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('genetic inactivation', 'Var', (94, 114))	('tumor', 'Disease', (60, 65))	('BAF180', 'Gene', '55193', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
524965	31652801	Mutations in the PBRM1 gene are related to renal carcinoma.	('related', 'Reg', (32, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('PBRM1', 'Gene', (17, 22))	('renal carcinoma', 'Disease', (43, 58))	('renal carcinoma', 'Disease', 'MESH:D002292', (43, 58))	('renal carcinoma', 'Phenotype', 'HP:0005584', (43, 58))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', '55193', (17, 22))
524969	31652801	Heterozygous or biallelic inactivating mutations were found in 41% of clear cell tumor cases and mutations were found in more than 10% of renal cell carcinoma cases.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (138, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('Heterozygous', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('found', 'Reg', (54, 59))	('biallelic inactivating mutations', 'Var', (16, 48))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('renal cell carcinoma', 'Disease', (138, 158))	('tumor', 'Disease', (81, 86))
524976	31652801	Mutations in PBRM1 lead to loss of protein expression in 32% of cases of intrahepatic cholangiocarcinoma (n = 108).	('PBRM1', 'Gene', (13, 18))	('protein expression', 'MPA', (35, 53))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (73, 104))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', '55193', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('intrahepatic cholangiocarcinoma', 'Disease', (73, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('loss', 'NegReg', (27, 31))
524977	31652801	Human BAF180 includes eight functional domains, such as bromodomains 1 through to 6 (residues 64-134, 200-270, 400-470, 538-608, 676-746, and 792-862), as well as domains BAH1 and BAH2 (residues 956-1074 and 1156-1272).	('Human', 'Species', '9606', (0, 5))	('400-470', 'Var', (111, 118))	('residues 956-1074', 'Var', (186, 203))	('538-608', 'Var', (120, 127))	('residues 64-134', 'Var', (85, 100))	('792-862', 'Var', (142, 149))	('BAF180', 'Gene', (6, 12))	('BAF180', 'Gene', '55193', (6, 12))
524980	31652801	The highest level of disorder was found in the C-terminal region (residues 1300-1689), which also included the remaining MoRFs and additional PTM sites.	('residues 1300-1689', 'Var', (66, 84))	('MoRFs', 'Chemical', 'MESH:C055328', (121, 126))	('disorder', 'MPA', (21, 29))
524983	31652801	B-cell CLL/lymphoma 7 protein family members A, B, and C (BCL7A, BCL7B, and BCL7C, UniProt IDs: Q4VC05, Q9BQE9, and Q8WUZ0, respectively) are relatively short proteins (of 210, 202, and 217 residues, respectively) encoded correspondingly by genes BCL7A, BCL7B, and BCL7C.	('BCL7A', 'Gene', (247, 252))	('B-cell CLL/lymphoma', 'Phenotype', 'HP:0012191', (0, 19))	('BCL7B', 'Gene', '9275', (254, 259))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('BCL7A', 'Gene', '605', (58, 63))	('Q8WUZ0', 'Var', (116, 122))	('BCL7C', 'Gene', (76, 81))	('BCL7C', 'Gene', '9274', (76, 81))	('Q9BQE9', 'Var', (104, 110))	('BCL7B', 'Gene', (65, 70))	('BCL7A', 'Gene', '605', (247, 252))	('lymphoma', 'Disease', (11, 19))	('BCL7C', 'Gene', '9274', (265, 270))	('lymphoma', 'Disease', 'MESH:D008223', (11, 19))	('BCL7C', 'Gene', (265, 270))	('Q4VC05', 'Var', (96, 102))	('BCL7B', 'Gene', (254, 259))	('BCL7A', 'Gene', (58, 63))	('BCL7B', 'Gene', '9275', (65, 70))
524988	31652801	As per BioMuta annotations, among several tumors associated with non-synonymous SNVs in the BCL7A gene, the most abundant are uterine, hematologic, liver, and colorectal cancers.	('colorectal cancers', 'Disease', (159, 177))	('non-synonymous SNVs', 'Var', (65, 84))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('SNVs', 'Var', (80, 84))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('colorectal cancers', 'Disease', 'MESH:D015179', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('hematologic', 'Disease', (135, 146))	('uterine', 'Disease', (126, 133))	('abundant', 'Reg', (113, 121))	('BCL7A', 'Gene', (92, 97))	('liver', 'Disease', (148, 153))	('BCL7A', 'Gene', '605', (92, 97))
524989	31652801	Mutations in the BCL7B gene can be related to lung tumor development or progression.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lung tumor', 'Disease', (46, 56))	('BCL7B', 'Gene', (17, 22))	('BCL7B', 'Gene', '9275', (17, 22))	('lung tumor', 'Disease', 'MESH:D008175', (46, 56))	('Mutations', 'Var', (0, 9))	('progression', 'CPA', (72, 83))	('related', 'Reg', (35, 42))	('lung tumor', 'Phenotype', 'HP:0100526', (46, 56))	('men', 'Species', '9606', (64, 67))
524990	31652801	Aberrations of this gene are also linked to the Williams-Beuren syndrome (WBS) and, according to BioMuta, to liver and uterine cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('WBS', 'Disease', 'MESH:D018980', (74, 77))	('liver', 'Disease', (109, 114))	('linked', 'Reg', (34, 40))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('uterine cancer', 'Phenotype', 'HP:0010784', (119, 133))	('WBS', 'Disease', (74, 77))	('cancers', 'Disease', (127, 134))	('Williams-Beuren syndrome', 'Disease', 'MESH:D018980', (48, 72))	('Aberrations', 'Var', (0, 11))	('uterine cancers', 'Phenotype', 'HP:0010784', (119, 134))	('Williams-Beuren syndrome', 'Disease', (48, 72))
524992	31652801	Alterations in the human BCL7C gene are associated with the Sezary syndrome, which is a leukemic form of cutaneous T-cell lymphoma.	('leukemic', 'Disease', (88, 96))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (115, 130))	('Alterations', 'Var', (0, 11))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (105, 130))	('cell lymphoma', 'Phenotype', 'HP:0012191', (117, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('leukemic', 'Disease', 'MESH:D007938', (88, 96))	('BCL7C', 'Gene', '9274', (25, 30))	('Sezary syndrome', 'Disease', (60, 75))	('BCL7C', 'Gene', (25, 30))	('cutaneous T-cell lymphoma', 'Disease', (105, 130))	('Sezary syndrome', 'Disease', 'MESH:D012751', (60, 75))	('human', 'Species', '9606', (19, 24))	('associated', 'Reg', (40, 50))	('cutaneous T-cell lymphoma', 'Disease', 'MESH:D016410', (105, 130))
524994	31652801	Human BCL7C contains a Pro-rich region (residues 108-217), whereas there are no segments with the compositional biases in BCL7A and BCL7B proteins.	('Human', 'Species', '9606', (0, 5))	('BCL7C', 'Gene', '9274', (6, 11))	('BCL7C', 'Gene', (6, 11))	('men', 'Species', '9606', (83, 86))	('residues 108-217', 'Var', (40, 56))	('BCL7B', 'Gene', (132, 137))	('BCL7B', 'Gene', '9275', (132, 137))	('BCL7A', 'Gene', '605', (122, 127))	('BCL7A', 'Gene', (122, 127))
524995	31652801	All three BCL7 family members contain several isoforms generated by alternative splicing.	('alternative splicing', 'Var', (68, 88))	('BCL7', 'Gene', '605', (10, 14))	('BCL7', 'Gene', (10, 14))
524997	31652801	Human BCL7B has four isoforms, where isoform 2 is missing residues 1-60 and has changed N-terminal region (residues 61-88), KSNSSAAREPNGFPSDASANSSLLLEFQ   MPGPWLCPEFLLRKMTTLSCCLCSVWFS, isoform 3 contains K   F substitution at position 163 and is missing residues 164-202, whereas residues 89-145 are missing in isoform 4.	('BCL7B', 'Gene', (6, 11))	('Human', 'Species', '9606', (0, 5))	('BCL7B', 'Gene', '9275', (6, 11))	('N', 'Chemical', 'MESH:D009584', (88, 89))	('residues', 'MPA', (254, 262))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('changed', 'Reg', (80, 87))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('missing', 'NegReg', (246, 253))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('substitution', 'Var', (210, 222))
524998	31652801	In BCL7C, isoform 2 is different from the canonical form by changed residues 177-217 (DSGVRMTRRALHEKGLKTEPLRRLLPRRGLRTNVRPSSMAVPDTRAPGGGS KAPRAPRTI PQGKGR).	('changed', 'Var', (60, 67))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('BCL7C', 'Gene', '9274', (3, 8))	('BCL7C', 'Gene', (3, 8))
525017	31652801	Due to the involvement of BCL11A in regulation of HbF, mutations in the human BCL11A gene can be associated with the pathogenesis of intellectual developmental disorder with persistence of fetal hemoglobin (IDPFH).	('BCL11A', 'Gene', '53335', (78, 84))	('IDPFH', 'Chemical', 'None', (207, 212))	('intellectual developmental disorder', 'Disease', 'MESH:D001037', (133, 168))	('mutations', 'Var', (55, 64))	('men', 'Species', '9606', (18, 21))	('fetal hemoglobin', 'Disease', (189, 205))	('developmental disorder', 'Phenotype', 'HP:0001263', (146, 168))	('human', 'Species', '9606', (72, 77))	('men', 'Species', '9606', (153, 156))	('intellectual developmental disorder', 'Disease', (133, 168))	('BCL11A', 'Gene', '53335', (26, 32))	('BCL11A', 'Gene', (26, 32))	('associated', 'Reg', (97, 107))	('BCL11A', 'Gene', (78, 84))
525018	31652801	Furthermore, according to the BioMuta database, mutations in this gene are related to a wide spectrum of tumors, such as uterine, lung, esophageal, stomach, hematologic, pancreatic, breast, colorectal, and liver cancers, as well as malignant glioma, blastoma, and melanoma.	('tumors', 'Disease', (105, 111))	('blastoma', 'Disease', 'MESH:D018202', (250, 258))	('breast', 'Disease', (182, 188))	('stomach', 'Disease', (148, 155))	('malignant glioma', 'Disease', (232, 248))	('malignant glioma', 'Disease', 'MESH:D005910', (232, 248))	('liver cancers', 'Disease', (206, 219))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('related', 'Reg', (75, 82))	('colorectal', 'Disease', (190, 200))	('pancreatic', 'Disease', 'MESH:D010195', (170, 180))	('blastoma', 'Disease', (250, 258))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('melanoma', 'Disease', 'MESH:D008545', (264, 272))	('hematologic', 'Disease', (157, 168))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('pancreatic', 'Disease', (170, 180))	('liver cancers', 'Disease', 'MESH:D006528', (206, 219))	('colorectal', 'Disease', 'MESH:D015179', (190, 200))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('esophageal', 'Disease', (136, 146))	('liver cancer', 'Phenotype', 'HP:0002896', (206, 218))	('uterine', 'Disease', (121, 128))	('liver cancers', 'Phenotype', 'HP:0002896', (206, 219))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('lung', 'Disease', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('melanoma', 'Disease', (264, 272))
525019	31652801	Mutations of BCL11B were found in 5.7-12.7% of cases of T-cell acute lymphoblastic leukemia (TALL), which is responsible for almost 15% and 25% of acute lymphoblastic leukemia in pediatrics and adult cohorts, correspondingly.	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (56, 91))	('BCL11B', 'Gene', (13, 19))	('T-cell acute lymphoblastic leukemia', 'Disease', (56, 91))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (147, 175))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (153, 175))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (56, 91))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (63, 91))	('acute lymphoblastic leukemia', 'Disease', (147, 175))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('Mutations', 'Var', (0, 9))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (147, 175))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (63, 91))	('found', 'Reg', (25, 30))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (69, 91))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))
525023	31652801	Human BCL11A protein contains a region required for nuclear body formation and recruitment of SUMO1 (residues 1-210), as well as Pro-rich and Glu-rich regions (residues 260-373 and 481-509, respectively).	('BCL11A', 'Gene', '53335', (6, 12))	('Human', 'Species', '9606', (0, 5))	('men', 'Species', '9606', (86, 89))	('SUMO1', 'Gene', '7341', (94, 99))	('residues 260-373', 'Var', (160, 176))	('BCL11A', 'Gene', (6, 12))	('Glu', 'Chemical', 'MESH:C094686', (142, 145))	('SUMO1', 'Gene', (94, 99))
525024	31652801	In human BCL11B, there are Glu- and Gly-rich regions (residues 529-553 and 569-661, respectively) and six zinc finger motifs of C2H2-type (residues 221-251, 427-454, 455-482, 796-823, 824-853, and 854-884).	('human', 'Species', '9606', (3, 8))	('residues 221-251', 'Var', (139, 155))	('427-454', 'Var', (157, 164))	('BCL11B', 'Gene', (9, 15))	('Glu', 'Chemical', 'MESH:C094686', (27, 30))	('455-482', 'Var', (166, 173))
525036	31652801	Aberrations in the SS18 gene are linked to synovial sarcoma, which is an aggressive subtype of soft tissue sarcomas, and although it is named "synovial", it arises from the mesenchyme.	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('synovial sarcoma', 'Disease', (43, 59))	('SS18', 'Gene', (19, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('linked', 'Reg', (33, 39))	('sarcomas', 'Disease', (107, 115))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (43, 59))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (95, 115))	('Aberrations', 'Var', (0, 11))	('synovial sarcoma', 'Disease', 'MESH:D013584', (43, 59))	('SS18', 'Gene', '6760', (19, 23))
525038	31652801	Synovial sarcoma is a gene fusion-driven cancer, in which the underlying event is the chromosomal translocation t(X,18; p11, q11) that creates fusion of SS18 to SSX1 and SSX2.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SS18', 'Gene', (153, 157))	('SSX2', 'Gene', (170, 174))	('p11', 'Gene', (120, 123))	('SSX1', 'Gene', '6756', (161, 165))	('fusion', 'Var', (143, 149))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('Synovial sarcoma', 'Disease', (0, 16))	('SSX1', 'Gene', (161, 165))	('p11', 'Gene', '6281', (120, 123))	('Synovial sarcoma', 'Disease', 'MESH:D013584', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SS18', 'Gene', '6760', (153, 157))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('SSX2', 'Gene', '6757', (170, 174))
525041	31652801	Translocations of the SS18 gene with SSX1 or SSX2 were found in 90% of the tumors (total n = 32).	('found', 'Reg', (55, 60))	('SSX1', 'Gene', '6756', (37, 41))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('Translocations', 'Var', (0, 14))	('SSX1', 'Gene', (37, 41))	('SSX2', 'Gene', '6757', (45, 49))	('SS18', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SSX2', 'Gene', (45, 49))	('tumors', 'Disease', (75, 81))	('SS18', 'Gene', '6760', (22, 26))
525042	31652801	Human SSXT protein contain two imperfect tandem repeats of 13 amino acids (residues 344-369) in addition to a poly-Pro region (residues 95-99), and four SH2 binding motifs (residues 50-53, 374-377, 392-401, and 412-416).	('Human', 'Species', '9606', (0, 5))	('residues 50-53', 'Var', (173, 187))	('binding', 'Interaction', (157, 164))	('SSXT', 'Gene', '6760', (6, 10))	('poly-Pro', 'Chemical', 'MESH:C008982', (110, 118))	('SSXT', 'Gene', (6, 10))
525050	31652801	Similar to ARID1A and ARID1B, mutations in the ARID2 gene are linked to hepatocellular carcinoma.	('ARID1B', 'Gene', '57492', (22, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('hepatocellular carcinoma', 'Disease', (72, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('ARID2', 'Gene', '196528', (47, 52))	('ARID1B', 'Gene', (22, 28))	('ARID2', 'Gene', (47, 52))	('mutations', 'Var', (30, 39))	('linked', 'Reg', (62, 68))
525051	31652801	Heterozygous inactivating mutations in the ARID2 gene are found in 14% (total n = 43) of the HCV-associated tumors and mutations were found in 5-10% of cases.	('Heterozygous inactivating mutations', 'Var', (0, 35))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('HCV', 'Species', '11103', (93, 96))	('ARID2', 'Gene', '196528', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('ARID2', 'Gene', (43, 48))	('found', 'Reg', (58, 63))
525052	31652801	Aberrations in ARID were also observed in melanoma, which is a malignant tumor that affects the skin, particularly melanocytes.	('melanoma', 'Disease', (42, 50))	('tumor that affects the skin', 'Phenotype', 'HP:0008069', (73, 100))	('ARID', 'Gene', (15, 19))	('malignant tumor', 'Disease', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('malignant tumor', 'Disease', 'MESH:D009369', (63, 78))	('observed', 'Reg', (30, 38))	('Aberrations', 'Var', (0, 11))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
525060	31652801	Heterozygous loss of function mutations in the ARID2 gene is present in 7% of tumors (total n = 121), and mutations were found in 5-10% of cases.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('ARID2', 'Gene', '196528', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ARID2', 'Gene', (47, 52))	('mutations', 'Var', (30, 39))
525061	31652801	Another tumor commonly associated with the mutations in ARID2 is lung cancer, which is the most diagnosed cancer and the chief cause of death in men from cancer, while for women it is the fourth most common cancer to be diagnosed and the second cause of death from cancer.	('men', 'Species', '9606', (145, 148))	('death', 'Disease', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('death', 'Disease', (254, 259))	('cancer', 'Disease', (106, 112))	('ARID2', 'Gene', '196528', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('men', 'Species', '9606', (174, 177))	('associated', 'Reg', (23, 33))	('death', 'Disease', 'MESH:D003643', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ARID2', 'Gene', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('death', 'Disease', 'MESH:D003643', (254, 259))	('tumor', 'Disease', (8, 13))	('women', 'Species', '9606', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancer', 'Disease', (154, 160))	('lung cancer', 'Disease', (65, 76))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
525064	31652801	In lung cancer, biallelic inactivating mutations in the ARID2 gene were found in 5% in cases of non-small cell lung carcinoma (n = 82).	('found', 'Reg', (72, 77))	('lung cancer', 'Disease', (3, 14))	('ARID2', 'Gene', (56, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('non-small cell lung carcinoma', 'Disease', (96, 125))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (100, 125))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('biallelic inactivating mutations', 'Var', (16, 48))	('ARID2', 'Gene', '196528', (56, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (96, 125))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (96, 125))
525065	31652801	Finally, ARID2 mutations were found in 5-10% of the colorectal cancer cases.	('ARID2', 'Gene', '196528', (9, 14))	('ARID2', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (15, 24))	('found', 'Reg', (30, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('colorectal cancer', 'Disease', (52, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
525066	31652801	Human BAF200 includes the ARID domain (residues 13-105), LXXLL motif (residues 313-317), two ARM repeats (residues 163-207 and 263-454), Gln-rich region (residues 793-1128), and zinc-finger motif of C2H2 type (residues 1632-1657).	('Human', 'Species', '9606', (0, 5))	('residues 313-317', 'Var', (70, 86))	('residues 1632-1657', 'Var', (210, 228))	('residues 793-1128', 'Var', (154, 171))	('BAF200', 'Gene', '196528', (6, 12))	('residues', 'Var', (39, 47))	('residues 163-207', 'Var', (106, 122))	('Gln', 'Chemical', 'MESH:C544323', (137, 140))	('BAF200', 'Gene', (6, 12))
525069	31652801	Note that region 1784-1835 that includes one MoRF (residues 1812-1818) was missing in isoform 2.	('MoRF', 'Gene', '23522', (45, 49))	('residues 1812-1818', 'Var', (51, 69))	('MoRF', 'Gene', (45, 49))	('N', 'Chemical', 'MESH:D009584', (0, 1))
525074	31652801	Although they are characterized by 37.1% sequence identity (53.0% sequence similarity), and although they both contain bromodomains (residues 148-218 and 153-223 in BRD7 and BRD9, respectively) with very similar structural organizations, these two proteins have rather different functions.	('BRD9', 'Gene', '65980', (174, 178))	('BRD7', 'Gene', '29117', (165, 169))	('BRD7', 'Gene', (165, 169))	('residues 148-218', 'Var', (133, 149))	('BRD9', 'Gene', (174, 178))
525080	31652801	According to BioMuta, non-synonymous single-nucleotide variations (nsSNVs) in the BRD7 gene are linked to bladder, breast, colorectal, liver, lung, urinary, and uterine cancers, as well as melanoma.	('cancers', 'Disease', (169, 176))	('BRD7', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('uterine cancer', 'Phenotype', 'HP:0010784', (161, 175))	('urinary', 'Disease', (148, 155))	('uterine cancers', 'Phenotype', 'HP:0010784', (161, 176))	('linked', 'Reg', (96, 102))	('lung', 'Disease', (142, 146))	('colorectal', 'Disease', 'MESH:D015179', (123, 133))	('breast', 'Disease', (115, 121))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('bladder', 'Disease', (106, 113))	('non-synonymous single-nucleotide variations', 'Var', (22, 65))	('BRD7', 'Gene', '29117', (82, 86))	('colorectal', 'Disease', (123, 133))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('liver', 'Disease', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
525084	31652801	BRD9 also possesses a Lys-rich region (residues 64-95) and bromodomain (residues 153-223).	('Lys-rich region', 'MPA', (22, 37))	('residues 64-95', 'Var', (39, 53))	('Lys', 'Chemical', 'MESH:C026591', (22, 25))	('BRD9', 'Gene', '65980', (0, 4))	('BRD9', 'Gene', (0, 4))	('residues 153-223', 'Var', (72, 88))
525097	31652801	As per BioMuta, non-synonymous single-nucleotide variations (nsSNVs) in the SMARCD1 gene are linked to colorectal, liver, and uterine cancer.	('SMARCD1', 'Gene', (76, 83))	('SMARCD1', 'Gene', '6602', (76, 83))	('linked', 'Reg', (93, 99))	('cancer', 'Disease', (134, 140))	('colorectal', 'Disease', 'MESH:D015179', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('non-synonymous single-nucleotide variations', 'Var', (16, 59))	('uterine cancer', 'Phenotype', 'HP:0010784', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('liver', 'Disease', (115, 120))	('colorectal', 'Disease', (103, 113))
525098	31652801	nsSNVs in SMARCD2 can be associated with melanoma and liver, colorectal, stomach, and uterine cancers, whereas mutations in SMARCD3 can cause liver, uterine and colorectal cancer, or melanoma.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('colorectal', 'Disease', 'MESH:D015179', (61, 71))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('colorectal cancer', 'Disease', (161, 178))	('cause', 'Reg', (136, 141))	('associated', 'Reg', (25, 35))	('SMARCD3', 'Gene', (124, 131))	('colorectal', 'Disease', (161, 171))	('SMARCD2', 'Gene', '6603', (10, 17))	('mutations', 'Var', (111, 120))	('liver', 'Disease', (54, 59))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('SMARCD3', 'Gene', '6604', (124, 131))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('cancers', 'Disease', (94, 101))	('uterine cancer', 'Phenotype', 'HP:0010784', (86, 100))	('stomach', 'Disease', (73, 80))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('uterine cancers', 'Phenotype', 'HP:0010784', (86, 101))	('colorectal', 'Disease', 'MESH:D015179', (161, 171))	('colorectal', 'Disease', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('SMARCD2', 'Gene', (10, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('liver', 'Disease', (142, 147))	('nsSNVs', 'Var', (0, 6))	('uterine', 'Disease', (149, 156))
525099	31652801	The common structural feature of these three proteins is the presence of the SWIB domain (residues 291-390, 307-382, and 259-334 in BAF60A, BAF60B, and BAF60C, respectively).	('BAF60C', 'Gene', (152, 158))	('BAF60A', 'Gene', (132, 138))	('BAF60A', 'Gene', '6602', (132, 138))	('BAF60C', 'Gene', '6604', (152, 158))	('BAF60B', 'Gene', '6603', (140, 146))	('259-334', 'Var', (121, 128))	('307-382', 'Var', (108, 115))	('residues 291-390', 'Var', (90, 106))	('BAF60B', 'Gene', (140, 146))
525101	31652801	Although human BAF60A contains a poly-Lys region (residues 124-127), and although there is a long Pro-rich segment (residues 10-129) in BAF60B, human BAF60C includes no regions with amino acid composition bias.	('human', 'Species', '9606', (144, 149))	('BAF60B', 'Gene', '6603', (136, 142))	('BAF60C', 'Gene', (150, 156))	('men', 'Species', '9606', (110, 113))	('human', 'Species', '9606', (9, 14))	('BAF60A', 'Gene', (15, 21))	('BAF60A', 'Gene', '6602', (15, 21))	('BAF60C', 'Gene', '6604', (150, 156))	('residues 124-127', 'Var', (50, 66))	('residues', 'Var', (116, 124))	('BAF60B', 'Gene', (136, 142))	('poly-Lys', 'Chemical', 'MESH:C026591', (33, 41))
525115	31652801	Mutations in the PHF10 gene are associated with uterine cancer and melanoma.	('PHF10', 'Gene', '55274', (17, 22))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('PHF10', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (32, 42))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('uterine cancer', 'Phenotype', 'HP:0010784', (48, 62))
525118	31652801	In AS-produced isoforms 2 and 3, residues 321-330 are missing and residue K226 is changed to ICGKRYK NRPGLSYHYTHTHLAEEEGEENAERHALPFHRKNNHKQ, and in addition, isoform 3 is missing residues 1-82.	('residues 321-330', 'Var', (33, 49))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('missing', 'NegReg', (54, 61))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('N', 'Chemical', 'MESH:D009584', (135, 136))
525119	31652801	Similar to PHF10/BAF45A, DPF1/BAF45B contains two zinc-finger motifs of the PHD type (residues 254-311 and 308-368).	('BAF45A', 'Gene', '55274', (17, 23))	('DPF1', 'Gene', (25, 29))	('BAF45B', 'Gene', '8193', (30, 36))	('PHF10', 'Gene', '55274', (11, 16))	('BAF45A', 'Gene', (17, 23))	('DPF1', 'Gene', '8193', (25, 29))	('PHF10', 'Gene', (11, 16))	('308-368', 'Var', (107, 114))	('residues 254-311', 'Var', (86, 102))	('BAF45B', 'Gene', (30, 36))
525120	31652801	Mutations in the DPF1 gene are linked to the pathogenesis of uterine, liver, and lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('linked', 'Reg', (31, 37))	('DPF1', 'Gene', '8193', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancers', 'Disease', 'MESH:D008175', (81, 93))	('lung cancers', 'Phenotype', 'HP:0100526', (81, 93))	('uterine', 'Disease', (61, 68))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('liver', 'Disease', (70, 75))	('lung cancers', 'Disease', (81, 93))	('DPF1', 'Gene', (17, 21))
525123	31652801	nsSNVs in the DPF2 gene are linked to Coffin-Siris syndrome 7 (CSS7), melanoma, blastoma, and liver, lung, and uterine cancers.	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('liver', 'Disease', (94, 99))	('uterine cancer', 'Phenotype', 'HP:0010784', (111, 125))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('DPF2', 'Gene', (14, 18))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('cancers', 'Disease', (119, 126))	('DPF2', 'Gene', '5977', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('blastoma', 'Disease', 'MESH:D018202', (80, 88))	('melanoma', 'Disease', (70, 78))	('Coffin-Siris syndrome', 'Disease', (38, 59))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (38, 59))	('lung', 'Disease', (101, 105))	('uterine cancers', 'Phenotype', 'HP:0010784', (111, 126))	('linked', 'Reg', (28, 34))	('blastoma', 'Disease', (80, 88))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('nsSNVs', 'Var', (0, 6))
525128	31652801	nsSNVs in the DPF3 gene are associated with blastoma, melanoma, stomach, liver, lung, and uterine cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('uterine cancer', 'Phenotype', 'HP:0010784', (90, 104))	('associated', 'Reg', (28, 38))	('nsSNVs', 'Var', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('lung', 'Disease', (80, 84))	('DPF3', 'Gene', (14, 18))	('blastoma', 'Disease', (44, 52))	('melanoma', 'Disease', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('cancer', 'Disease', (98, 104))	('DPF3', 'Gene', '8110', (14, 18))	('stomach', 'Disease', (64, 71))	('liver', 'Disease', (73, 78))	('blastoma', 'Disease', 'MESH:D018202', (44, 52))
525129	31652801	Similar to DPF2/BAF45D, this protein contains a zinc-finger domain of C2H2 type (residues 198-221) and two zinc-finger motifs of the PHD type (residues 259-319 and 316-366).	('residues 198-221', 'Var', (81, 97))	('BAF45D', 'Gene', (16, 22))	('DPF2', 'Gene', (11, 15))	('DPF2', 'Gene', '5977', (11, 15))	('BAF45D', 'Gene', '5977', (16, 22))
525148	31652801	ACTL6A mutations have been found in patients with intellectual disability of variable severity, developmental delay, dysmorphic features, and digit abnormalities.	('intellectual disability', 'Disease', (50, 73))	('patients', 'Species', '9606', (36, 44))	('ACTL6A', 'Gene', '86', (0, 6))	('digit abnormalities', 'Disease', (142, 161))	('men', 'Species', '9606', (103, 106))	('digit abnormalities', 'Phenotype', 'HP:0011297', (142, 161))	('intellectual disability', 'Phenotype', 'HP:0001249', (50, 73))	('developmental delay', 'Phenotype', 'HP:0001263', (96, 115))	('found', 'Reg', (27, 32))	('dysmorphic features', 'Disease', (117, 136))	('ACTL6A', 'Gene', (0, 6))	('developmental delay', 'Disease', (96, 115))	('mutations', 'Var', (7, 16))
525153	31652801	According to the BioMuta database, non-synonymous single-nucleotide variations (nsSNVs) in the ACTL6B gene were found in liver, lung, and uterine cancers, and this gene was significantly down-regulated in esophageal cancer.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('ACTL6B', 'Gene', (95, 101))	('uterine cancer', 'Phenotype', 'HP:0010784', (138, 152))	('found', 'Reg', (112, 117))	('lung', 'Disease', (128, 132))	('esophageal cancer', 'Disease', (205, 222))	('ACTL6B', 'Gene', '51412', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('uterine cancers', 'Phenotype', 'HP:0010784', (138, 153))	('non-synonymous single-nucleotide variations', 'Var', (35, 78))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('liver', 'Disease', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('down-regulated', 'NegReg', (187, 201))
525161	31652801	Since actin is one of the most abundant, if not the most abundant eukaryotic protein, it is not surprising that mutations in ACTB genes are linked to numerous diseases, such as dystonia, juvenile-onset (DJO), Baraitser-Winter syndrome 1 (BRWS1), inherited myopathy, combined and complex dystonia, developmental malformations-deafness-dystonia syndrome, as well as multiple tumors, such as melanoma, blastoma, and hematologic, lung, urinary, uterine, bladder, kidney, and colorectal cancers.	('dystonia', 'Disease', 'MESH:D004421', (287, 295))	('myopathy', 'Disease', (256, 264))	('myopathy', 'Phenotype', 'HP:0003198', (256, 264))	('tumors', 'Phenotype', 'HP:0002664', (373, 379))	('colorectal cancers', 'Disease', 'MESH:D015179', (471, 489))	('mutations', 'Var', (112, 121))	('Baraitser-Winter syndrome', 'Disease', 'MESH:C536208', (209, 234))	('hematologic', 'Disease', (413, 424))	('bladder', 'Disease', (450, 457))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('combined', 'Disease', (266, 274))	('blastoma', 'Disease', 'MESH:D018202', (399, 407))	('uterine', 'Disease', (441, 448))	('tumors', 'Disease', (373, 379))	('Baraitser-Winter syndrome', 'Disease', (209, 234))	('deafness', 'Phenotype', 'HP:0000365', (325, 333))	('urinary', 'Disease', (432, 439))	('dystonia', 'Disease', (334, 342))	('lung', 'Disease', (426, 430))	('kidney', 'Disease', (459, 465))	('melanoma', 'Disease', 'MESH:D008545', (389, 397))	('dystonia', 'Disease', (177, 185))	('tumors', 'Disease', 'MESH:D009369', (373, 379))	('cancers', 'Phenotype', 'HP:0002664', (482, 489))	('colorectal cancer', 'Phenotype', 'HP:0003003', (471, 488))	('blastoma', 'Disease', (399, 407))	('dystonia', 'Disease', (287, 295))	('colorectal cancers', 'Disease', (471, 489))	('myopathy', 'Disease', 'MESH:D009135', (256, 264))	('dystonia', 'Phenotype', 'HP:0001332', (334, 342))	('linked', 'Reg', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (482, 488))	('developmental malformations-deafness-dystonia syndrome', 'Disease', 'MESH:C535808', (297, 351))	('ACTB', 'Gene', '60', (125, 129))	('ACTB', 'Gene', (125, 129))	('dystonia', 'Phenotype', 'HP:0001332', (177, 185))	('dystonia', 'Phenotype', 'HP:0001332', (287, 295))	('dystonia', 'Disease', 'MESH:D004421', (334, 342))	('dystonia', 'Disease', 'MESH:D004421', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (389, 397))	('melanoma', 'Disease', (389, 397))
525163	31652801	Aberrations in F-actin polymerization were also linked to intellectual and developmental disabilities (IDD) and autism spectrum disorders (ASD).	('linked', 'Reg', (48, 54))	('developmental disabilities', 'Disease', 'MESH:D002658', (75, 101))	('intellectual and developmental disabilities', 'Phenotype', 'HP:0001263', (58, 101))	('ASD', 'Disease', 'MESH:D001321', (139, 142))	('IDD', 'Disease', (103, 106))	('IDD', 'Disease', 'MESH:C535531', (103, 106))	('ASD', 'Disease', (139, 142))	('autism spectrum disorders', 'Phenotype', 'HP:0000729', (112, 137))	('autism', 'Phenotype', 'HP:0000717', (112, 118))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (112, 136))	('autism spectrum disorders', 'Disease', 'MESH:D002659', (112, 137))	('Aberrations', 'Var', (0, 11))	('autism spectrum disorders', 'Disease', (112, 137))	('developmental disabilities', 'Disease', (75, 101))	('F-actin', 'Protein', (15, 22))
525177	31652801	Alterations (nsSNVs) in the BICRA gene are associated with various tumors, such as melanoma, blastoma, and thyroid carcinoma, as well as stomach, breast, liver, lung, colorectal, and uterine cancers.	('lung', 'Disease', (161, 165))	('blastoma', 'Disease', (93, 101))	('Alterations', 'Var', (0, 11))	('colorectal', 'Disease', (167, 177))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (107, 124))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('thyroid carcinoma', 'Disease', (107, 124))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('uterine cancer', 'Phenotype', 'HP:0010784', (183, 197))	('cancers', 'Disease', (191, 198))	('uterine cancers', 'Phenotype', 'HP:0010784', (183, 198))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('stomach', 'Disease', (137, 144))	('colorectal', 'Disease', 'MESH:D015179', (167, 177))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (107, 124))	('liver', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('breast', 'Disease', (146, 152))	('blastoma', 'Disease', 'MESH:D018202', (93, 101))	('associated', 'Reg', (43, 53))	('tumors', 'Disease', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('BICRA', 'Gene', (28, 33))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
525183	31652801	These include three poly-Pro segments (residues 935-940, 1333-1337, and 1345-1355), a poly-Gly region (residues 88-96), and a poly-Ser region (residues 1265-1276).	('residues 935-940', 'Var', (39, 55))	('poly-Gly', 'Chemical', 'MESH:C409505', (86, 94))	('men', 'Species', '9606', (32, 35))	('poly-Pro', 'Chemical', 'MESH:C008982', (20, 28))	('1333-1337', 'Var', (57, 66))	('1345-1355', 'Var', (72, 81))	('poly-Ser', 'Chemical', 'MESH:C530429', (126, 134))
525188	31652801	It was also shown that GLTSCR1 or GLTSCR1L knockouts in the metastatic prostate cancer cell line PC3 led to the loss of proliferation and colony-forming abilities.	('proliferation', 'CPA', (120, 133))	('colony-forming abilities', 'CPA', (138, 162))	('GLTSCR1L', 'Gene', '23506', (34, 42))	('prostate cancer', 'Disease', (71, 86))	('PC3', 'Gene', '3853', (97, 100))	('GLTSCR1', 'Gene', '29998', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GLTSCR1', 'Gene', (23, 30))	('knockouts', 'Var', (43, 52))	('loss', 'NegReg', (112, 116))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('GLTSCR1', 'Gene', '29998', (23, 30))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('GLTSCR1', 'Gene', (34, 41))	('PC3', 'Gene', (97, 100))	('GLTSCR1L', 'Gene', (34, 42))
525192	31652801	Non-synonymous single-nucleotide variations (nsSNVs) in the BICRAL gene are linked to blastoma, malignant glioma, and melanoma, as well as to stomach, uterine, pancreatic, colorectal, liver, and lung cancers, whereas significant down-regulation of the BICRAL gene was observed in urinary bladder cancer, head and neck cancer, lung squamous cell carcinoma, breast cancer, thyroid cancer, and esophageal cancer.	('lung cancers', 'Disease', (195, 207))	('blastoma', 'Disease', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (356, 369))	('colorectal', 'Disease', 'MESH:D015179', (172, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('lung cancers', 'Phenotype', 'HP:0100526', (195, 207))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (326, 354))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('bladder cancer', 'Phenotype', 'HP:0009725', (288, 302))	('melanoma', 'Disease', (118, 126))	('thyroid cancer', 'Disease', 'MESH:D013964', (371, 385))	('breast cancer', 'Disease', 'MESH:D001943', (356, 369))	('esophageal cancer', 'Disease', 'MESH:D004938', (391, 408))	('down-regulation', 'NegReg', (229, 244))	('Non-synonymous', 'Var', (0, 14))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('breast cancer', 'Disease', (356, 369))	('urinary bladder cancer', 'Disease', (280, 302))	('head and neck cancer', 'Phenotype', 'HP:0012288', (304, 324))	('thyroid cancer', 'Phenotype', 'HP:0002890', (371, 385))	('single-nucleotide variations', 'Var', (15, 43))	('esophageal cancer', 'Disease', (391, 408))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (331, 354))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (326, 354))	('lung squamous cell carcinoma', 'Disease', (326, 354))	('pancreatic', 'Disease', 'MESH:D010195', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('blastoma', 'Disease', 'MESH:D018202', (86, 94))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (280, 302))	('BICRAL', 'Gene', (60, 66))	('liver', 'Disease', (184, 189))	('colorectal', 'Disease', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('linked', 'Reg', (76, 82))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('head and neck cancer', 'Disease', 'MESH:D006258', (304, 324))	('stomach', 'Disease', (142, 149))	('lung cancers', 'Disease', 'MESH:D008175', (195, 207))	('pancreatic', 'Disease', (160, 170))	('malignant glioma', 'Disease', (96, 112))	('uterine', 'Disease', (151, 158))	('thyroid cancer', 'Disease', (371, 385))	('malignant glioma', 'Disease', 'MESH:D005910', (96, 112))
525223	30923682	A 67-year-old woman, G18P18, presented to the emergency department with a bleeding mass that had acutely prolapsed out of the vagina.	('bleeding', 'Disease', 'MESH:D006470', (74, 82))	('woman', 'Species', '9606', (14, 19))	('bleeding', 'Disease', (74, 82))	('G18P18', 'Var', (21, 27))
525236	30923682	A 67-year-old woman, G18P18, presented to the emergency department after an acute expulsion of a mass out of the vagina that was associated with pain and bleeding (Fig.	('pain', 'Phenotype', 'HP:0012531', (145, 149))	('G18P18', 'Var', (21, 27))	('woman', 'Species', '9606', (14, 19))	('pain', 'Disease', 'MESH:D010146', (145, 149))	('pain', 'Disease', (145, 149))	('bleeding', 'Disease', 'MESH:D006470', (154, 162))	('bleeding', 'Disease', (154, 162))
525320	28031738	The clinical and pathological parameters examined for prognostic value within the group undergoing IOBRT were tumor size (divided into two groups: < 10 and > 10 cm), histological malignancy grade of tumor (low grade G1 vs. high grade G2 or G3), histological tumor type (liposarcoma vs. others), sex, one-time resection with a contiguous organ (zero additional organs, one organ, and more than one organ), number of previous operations (zero, one, or more than one), and subsequent EBRT.	('tumor', 'Disease', (258, 263))	('liposarcoma', 'Disease', 'MESH:D008080', (270, 281))	('malignancy', 'Disease', 'MESH:D009369', (179, 189))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('EBRT', 'Chemical', '-', (481, 485))	('tumor', 'Disease', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('malignancy', 'Disease', (179, 189))	('liposarcoma', 'Disease', (270, 281))	('low grade G1', 'Var', (206, 218))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('IOBRT', 'Chemical', '-', (99, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('histological malignancy', 'Phenotype', 'HP:0002664', (166, 189))	('tumor', 'Disease', (110, 115))	('liposarcoma', 'Phenotype', 'HP:0012034', (270, 281))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
525428	26849082	The difference may also reflect the changing ethnic composition of the US population as persons of self-described Hispanic ethnicity have the highest incidence rates of ALL and the incidence rate of ALL in this ethnic group is increasing compared to all other racial and ethnic groups (SEER.cancer.gov).	('persons', 'Species', '9606', (88, 95))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('incidence rates', 'MPA', (150, 165))	('Hispanic ethnicity', 'Var', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
525436	26849082	A single susceptibility locus was identified on chromosome 10p14, signified by two SNPs within the GATA3 gene with genome-wide significant associations: rs3824662.	('rs3824662', 'Var', (153, 162))	('rs3824662', 'Mutation', 'rs3824662', (153, 162))	('GATA3', 'Gene', (99, 104))	('associations', 'Interaction', (139, 151))	('GATA3', 'Gene', '2625', (99, 104))
525437	26849082	The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYA patients.	('patients', 'Species', '9606', (148, 156))	('Philadelphia chromosome', 'Disease', (50, 73))	('susceptibility', 'Reg', (107, 121))	('rs3824662', 'Mutation', 'rs3824662', (19, 28))	('rs3824662', 'Var', (19, 28))
525440	26849082	These alterations include aneuploidy (e.g., high hyperdiploidy (HeH) or hypodiploidy) and chromosomal rearrangements that commonly disrupt hematopoietic regulators or aberrantly active oncogenes and tyrosine kinases (e.g., ETV6-RUNX - t(12;21); TCF3-PBX1 - t(1;19); BCR-ABL1 - t(9;22), and translocation of the 11q23 gene MLL - frequently t(4;11) and other variants) in B-ALL and rearrangement of TAL1, TLX1, and TLX3 in T-ALL.	('PBX1', 'Gene', (250, 254))	('disrupt', 'Reg', (131, 138))	('BCR-ABL1', 'Gene', (266, 274))	('ETV6', 'Gene', (223, 227))	('tyrosine kinase', 'Gene', '7294', (199, 214))	('translocation', 'Var', (290, 303))	('TAL1', 'Gene', (397, 401))	('PBX1', 'Gene', '5087', (250, 254))	('high hyperdiploidy (HeH) or hypodiploidy', 'Disease', 'MESH:D008228', (44, 84))	('BCR-ABL1', 'Gene', '613;25', (266, 274))	('11q23', 'Gene', (311, 316))	('TLX1', 'Gene', (403, 407))	('ETV6', 'Gene', '2120', (223, 227))	('TCF3', 'Gene', (245, 249))	('TLX3', 'Gene', (413, 417))	('rearrangement', 'Var', (380, 393))	('MLL', 'Gene', '4297', (322, 325))	('MLL', 'Gene', (322, 325))	('TAL1', 'Gene', '6886', (397, 401))	('TLX1', 'Gene', '3195', (403, 407))	('TCF3', 'Gene', '6929', (245, 249))	('TLX3', 'Gene', '30012', (413, 417))	('tyrosine kinase', 'Gene', (199, 214))
525441	26849082	Several of these genetic alterations are typically associated with a significantly increased risk of treatment failure and relapse on current treatment regimens (e.g., MLL rearrangements, BCR-ABL1, and low hypo-diploidy).	('MLL', 'Gene', '4297', (168, 171))	('hypo-diploidy', 'Disease', (206, 219))	('MLL', 'Gene', (168, 171))	('rearrangements', 'Var', (172, 186))	('treatment failure', 'Disease', (101, 118))	('low', 'CPA', (202, 205))	('relapse', 'CPA', (123, 130))	('BCR-ABL1', 'Gene', (188, 196))	('associated', 'Reg', (51, 61))	('treatment failure', 'Disease', 'MESH:D016609', (101, 118))	('genetic alterations', 'Var', (17, 36))	('BCR-ABL1', 'Gene', '613;25', (188, 196))	('hypo-diploidy', 'Disease', 'MESH:D052456', (206, 219))
525442	26849082	Importantly, as shown in Figure 2, the frequency of genomic rearrangements is associated with a superior outcome (e.g., ETV6-RUNX1- t(12;21) and high hyper-diploidy in pediatric ALL decrease in AYA ALL patients, while those genetic abnormalities associated with a poorer outcome (BCR- ABL1 - t(9;22), MLL rearrangements) and Ph-like ALL increase.	('RUNX1', 'Gene', (125, 130))	('increase', 'PosReg', (337, 345))	('ETV6', 'Gene', '2120', (120, 124))	('genetic abnormalities', 'Disease', 'MESH:D030342', (224, 245))	('ABL1', 'Gene', (285, 289))	('RUNX1', 'Gene', '861', (125, 130))	('BCR', 'Gene', (280, 283))	('decrease', 'NegReg', (182, 190))	('high hyper-diploidy', 'Var', (145, 164))	('patients', 'Species', '9606', (202, 210))	('genetic abnormalities', 'Disease', (224, 245))	('BCR', 'Gene', '613', (280, 283))	('ETV6', 'Gene', (120, 124))	('MLL', 'Gene', (301, 304))	('ABL1', 'Gene', '25', (285, 289))	('MLL', 'Gene', '4297', (301, 304))
525450	26849082	However, while Ph- like ALL cases lack the classic Ph chromosome translocation, they contain one or more of a complex array of novel genomic mutations in genes encoding tyrosine kinases or genes which regulating tyrosine kinase signaling pathways.	('tyrosine kinase', 'Gene', '7294', (212, 227))	('mutations', 'Var', (141, 150))	('tyrosine kinase', 'Gene', (212, 227))	('tyrosine kinase', 'Gene', '7294', (169, 184))	('tyrosine kinase', 'Gene', (169, 184))
525451	26849082	Nearly 50% of pediatric Ph-like ALL cases are characterized by novel genomic rearrangements of CRLF2 such as IGH-CRLF2, P2RY8-CRLF2 and about half of CRLF2-rearranged cases also have mutations of the JAK family of tyrosine kinases, which cooperate to promote leukemogenesis.	('CRLF2', 'Gene', (113, 118))	('P2RY8', 'Gene', (120, 125))	('tyrosine kinase', 'Gene', (214, 229))	('mutations', 'Var', (183, 192))	('IGH', 'Gene', '3492', (109, 112))	('promote', 'PosReg', (251, 258))	('tyrosine kinase', 'Gene', '7294', (214, 229))	('IGH', 'Gene', (109, 112))	('CRLF2', 'Gene', '64109', (150, 155))	('P2RY8', 'Gene', '286530', (120, 125))	('leukemogenesis', 'Disease', (259, 273))	('CRLF2', 'Gene', '64109', (126, 131))	('CRLF2', 'Gene', '64109', (95, 100))	('CRLF2', 'Gene', '64109', (113, 118))	('CRLF2', 'Gene', (150, 155))	('CRLF2', 'Gene', (95, 100))	('CRLF2', 'Gene', (126, 131))
525452	26849082	Using transcriptomic sequencing methods, these investigators have recently also discovered that Ph-like ALL cases lacking CRLF2 genomic rearrangements or JAK mutations have a complex and heterogeneous spectrum of mutations in the SH2B3, IL7R genes or cryptic translocations and gene fusions involving a number of unique partner genes fused to several different tyrosine kinases including ABL1, ABL2, PDGFRB1/2, JAK2, EPOR, and CSF1R.	('EPOR', 'Gene', '2057', (417, 421))	('EPOR', 'Gene', (417, 421))	('CSF1R', 'Gene', (427, 432))	('tyrosine kinase', 'Gene', (361, 376))	('CRLF2', 'Gene', (122, 127))	('JAK2', 'Gene', '3717', (411, 415))	('tyrosine kinase', 'Gene', '7294', (361, 376))	('SH2B3', 'Gene', '10019', (230, 235))	('mutations', 'Var', (213, 222))	('ABL1', 'Gene', (388, 392))	('PDGFRB', 'Gene', '5159', (400, 406))	('JAK2', 'Gene', (411, 415))	('CRLF2', 'Gene', '64109', (122, 127))	('PDGFRB', 'Gene', (400, 406))	('ABL1', 'Gene', '25', (388, 392))	('SH2B3', 'Gene', (230, 235))	('IL7R', 'Gene', '3575', (237, 241))	('IL7R', 'Gene', (237, 241))	('ABL2', 'Gene', '27', (394, 398))	('CSF1R', 'Gene', '1436', (427, 432))	('ABL2', 'Gene', (394, 398))
525454	26849082	In addition to the discovery of the Ph-like ALL subgroup, this team of investigators have also discovered a large spectrum of additional novel, and potentially targetable, mutations in high-risk ALL including NRAS and KRAS.	('mutations', 'Var', (172, 181))	('KRAS', 'Gene', (218, 222))	('KRAS', 'Gene', '3845', (218, 222))	('NRAS', 'Gene', (209, 213))	('NRAS', 'Gene', '4893', (209, 213))
525458	26849082	IKZF1 alterations, a marker of poor outcome in childhood ALL, were enriched in BCR-ABL1 and Ph-like ALL (70% and 77%, respectively) compared to non Ph-like patients (26%), and correlated with inferior 5 year EFS in adolescents and young adults.	('patients', 'Species', '9606', (156, 164))	('alterations', 'Var', (6, 17))	('IKZF1', 'Gene', '10320', (0, 5))	('BCR-ABL1', 'Gene', '613;25', (79, 87))	('IKZF1', 'Gene', (0, 5))	('BCR-ABL1', 'Gene', (79, 87))
525459	26849082	Interestingly, different genetic abnormalities were observed in children vs. AYA Ph-like ALL cases with a higher frequency of fusions involving ABL class genes such as ABL1, ABL2, CSF1R, and PDGFRB in children and a higher frequency of JAK2 translocations in AYA patients.	('JAK2', 'Gene', '3717', (236, 240))	('ABL class', 'Gene', (144, 153))	('children', 'Species', '9606', (201, 209))	('ABL1', 'Gene', (168, 172))	('patients', 'Species', '9606', (263, 271))	('JAK2', 'Gene', (236, 240))	('ABL2', 'Gene', (174, 178))	('PDGFRB', 'Gene', '5159', (191, 197))	('CSF1R', 'Gene', '1436', (180, 185))	('genetic abnormalities', 'Disease', 'MESH:D030342', (25, 46))	('PDGFRB', 'Gene', (191, 197))	('fusions', 'Var', (126, 133))	('children', 'Species', '9606', (64, 72))	('ABL2', 'Gene', '27', (174, 178))	('genetic abnormalities', 'Disease', (25, 46))	('ABL1', 'Gene', '25', (168, 172))	('CSF1R', 'Gene', (180, 185))
525467	26849082	Genetic susceptibility is a risk factor for developing a melanoma.	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('Genetic', 'Var', (0, 7))	('melanoma', 'Disease', (57, 65))
525486	26849082	Adult melanoma typically contains complex genotypic abnormalities including frequent deletions of chromosomes 9p (the most common aberration in melanoma harboring p16), 6q, 10q and 8p and gains of chromosomes 1q, 6p, 7q, 8q, 6p, 17q and 20q.	('p16', 'Gene', '1029', (163, 166))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('deletions', 'Var', (85, 94))	('p16', 'Gene', (163, 166))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('melanoma', 'Disease', (6, 14))	('gains', 'PosReg', (188, 193))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
525492	26849082	Somatic mutations in BRAF are the most common genetic alterations occurring in up to 60% of adult cutaneous malignant melanomas and common benign melanocytic nevi (80%).	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (146, 162))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('melanomas', 'Disease', 'MESH:D008545', (118, 127))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('Somatic mutations', 'Var', (0, 17))	('melanomas', 'Disease', (118, 127))	('malignant melanomas', 'Phenotype', 'HP:0002861', (108, 127))	('nevi', 'Phenotype', 'HP:0003764', (158, 162))
525493	26849082	Smaller series of pediatric melanomas show 87% pediatric/AYA conventional melanoma harbor activating BRAF mutations.	('melanoma', 'Disease', (28, 36))	('BRAF', 'Gene', (101, 105))	('pediatric melanomas', 'Disease', 'MESH:D008545', (18, 37))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('activating', 'Reg', (90, 100))	('melanoma', 'Disease', (74, 82))	('mutations', 'Var', (106, 115))	('pediatric melanomas', 'Disease', (18, 37))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('BRAF', 'Gene', '673', (101, 105))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
525494	26849082	Similarly, spitzoid melanomas show BRAF and NRAS mutations in majority of the cases whereas no HRAS mutations were detected.	('BRAF', 'Gene', (35, 39))	('HRAS', 'Gene', (95, 99))	('mutations', 'Var', (49, 58))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (11, 29))	('NRAS', 'Gene', (44, 48))	('spitzoid melanomas', 'Disease', (11, 29))	('NRAS', 'Gene', '4893', (44, 48))	('HRAS', 'Gene', '3265', (95, 99))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('BRAF', 'Gene', '673', (35, 39))
525495	26849082	In contrast, Spitz nevi frequently harbor HRAS mutations, but completely lack BRAF and NRAS mutations.	('Spitz nevi', 'Disease', (13, 23))	('harbor', 'Reg', (35, 41))	('NRAS', 'Gene', '4893', (87, 91))	('HRAS', 'Gene', '3265', (42, 46))	('BRAF', 'Gene', '673', (78, 82))	('HRAS', 'Gene', (42, 46))	('lack', 'NegReg', (73, 77))	('BRAF', 'Gene', (78, 82))	('mutations', 'Var', (47, 56))	('nevi', 'Phenotype', 'HP:0003764', (19, 23))	('NRAS', 'Gene', (87, 91))
525496	26849082	Thus, the presence of HRAS mutations would favor the diagnosis of Spitz nevus and the combined BRAF and NRAS mutational analysis would strongly argue for the diagnosis of spitzoid melanoma.	('mutations', 'Var', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('nevus', 'Phenotype', 'HP:0003764', (72, 77))	('NRAS', 'Gene', '4893', (104, 108))	('BRAF', 'Gene', '673', (95, 99))	('spitzoid melanoma', 'Disease', 'MESH:D008545', (171, 188))	('spitzoid melanoma', 'Disease', (171, 188))	('BRAF', 'Gene', (95, 99))	('Spitz nevus', 'Disease', (66, 77))	('HRAS', 'Gene', '3265', (22, 26))	('favor', 'PosReg', (43, 48))	('NRAS', 'Gene', (104, 108))	('presence', 'Var', (10, 18))	('HRAS', 'Gene', (22, 26))
525497	26849082	However, studies examining BRAF/NRAS mutations in a large series of spitzoid melanocytic lesions are needed to confirm these data and to clarify the inconsistencies between published studies.	('NRAS', 'Gene', (32, 36))	('NRAS', 'Gene', '4893', (32, 36))	('spitzoid melanocytic lesions', 'Disease', (68, 96))	('BRAF', 'Gene', '673', (27, 31))	('mutations', 'Var', (37, 46))	('spitzoid melanocytic lesions', 'Disease', 'MESH:D009508', (68, 96))	('BRAF', 'Gene', (27, 31))
525498	26849082	For those lesions that do not have mutation of any of these three genes, mutation analysis in other genes such as PTEN, CDKN2A, and TP53 may increase the sensitivity of mutation analysis to enable the diagnosis.	('sensitivity', 'MPA', (154, 165))	('increase', 'PosReg', (141, 149))	('CDKN2A', 'Gene', (120, 126))	('TP53', 'Gene', '7157', (132, 136))	('PTEN', 'Gene', (114, 118))	('TP53', 'Gene', (132, 136))	('PTEN', 'Gene', '5728', (114, 118))	('CDKN2A', 'Gene', '1029', (120, 126))	('mutation analysis', 'Var', (73, 90))
525500	26849082	Copy number loss at the 9p21 chromosomal locus containing cyclin-dependent kinase inhibitor 2A tumor suppressor gene (CDKN2A) is frequently seen in melanoma, but not in conventional Spitz nevi.	('CDKN2A', 'Gene', (118, 124))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('CDKN2A', 'Gene', '1029', (118, 124))	('melanoma', 'Disease', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('nevi', 'Phenotype', 'HP:0003764', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('Copy number loss', 'Var', (0, 16))
525510	26849082	It is likely that the use of CGH, FISH, and PCR- based LOH assessing chromosomal aberrations, mutations in the BRAF, NRAS, and HRAS genes, next generation sequencing and immunohistochemical approaches (e.g.	('HRAS', 'Gene', (127, 131))	('NRAS', 'Gene', (117, 121))	('mutations', 'Var', (94, 103))	('NRAS', 'Gene', '4893', (117, 121))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (69, 92))	('BRAF', 'Gene', '673', (111, 115))	('HRAS', 'Gene', '3265', (127, 131))	('BRAF', 'Gene', (111, 115))
525517	26849082	At present, it is unknown whether specific inhibitors are effective in NRAS mutated melanomas in children, or HRAS mutated spitzoid tumors.	('spitzoid tumors', 'Disease', 'MESH:D009369', (123, 138))	('melanomas', 'Disease', (84, 93))	('spitzoid tumors', 'Disease', (123, 138))	('children', 'Species', '9606', (97, 105))	('NRAS', 'Gene', (71, 75))	('mutated', 'Var', (76, 83))	('HRAS', 'Gene', (110, 114))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('NRAS', 'Gene', '4893', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('HRAS', 'Gene', '3265', (110, 114))
525521	26849082	The total incidence of non-Kaposi soft tissue sarcomas increases steadily with age, mostly for non-fusion gene related FPS.	('sarcomas increases', 'Disease', (46, 64))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (34, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('non-fusion gene', 'Var', (95, 110))	('Kaposi soft tissue sarcomas', 'Phenotype', 'HP:0100726', (27, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('sarcomas increases', 'Disease', 'MESH:D012509', (46, 64))
525539	26849082	A tumor-specific fusion protein is an ideal target that is not expressed in normal cells and appears to be required for the oncogenesis of most fusion positive FPS; however, the ability to target these fusions has remained a challenge.	('fusion positive', 'Var', (144, 159))	('tumor', 'Disease', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('tumor', 'Disease', 'MESH:D009369', (2, 7))
525551	26849082	AYA CRC exhibits a greater frequency of mucinous histology, signet ring cells, high microsatellite instability (MSI- H), and a higher incidence of mutations in mismatch repair (MMR) genes.	('mutations', 'Var', (147, 156))	('MSI', 'Disease', (112, 115))	('mucinous', 'Disease', (40, 48))	('MMR) genes', 'Gene', (177, 187))	('microsatellite instability', 'MPA', (84, 110))	('MSI', 'Disease', 'None', (112, 115))	('signet ring cells', 'CPA', (60, 77))
525572	26849082	Whole genome analysis with deep sequencing could also help to identify mutations or polymorphic patterns that could be linked to susceptibility to early onset breast cancer.	('polymorphic patterns', 'Var', (84, 104))	('mutations', 'Var', (71, 80))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('linked', 'Reg', (119, 125))
525601	24484617	Even in sarcoma cases that are characterized by specific genetic alterations, using targeted agents have not always led to clinical benefit despite the presence and overexpression of the molecular target.	('alterations', 'Var', (65, 76))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('sarcoma', 'Disease', (8, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('overexpression', 'PosReg', (165, 179))
525638	24484617	NAB-paclitaxel may act as a "Trojan horse," with the albumin encapsulation serving to direct the paclitaxel chemotherapeutic agent to tumor cells via binding to SPARC.	('NAB-paclitaxel', 'Chemical', '-', (0, 14))	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('SPARC', 'Protein', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('paclitaxel', 'Chemical', 'MESH:D017239', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('horse', 'Species', '9796', (36, 41))	('NAB-paclitaxel', 'Var', (0, 14))	('tumor', 'Disease', (134, 139))	('binding', 'Interaction', (150, 157))
525693	21286027	The monoclonal antibodies used were the following: S100 (1:800; Dako, Glostrup, Demark), vimentin (1:200; Dako), CD45 (1:100; Leica, Newcastle-upon-Tyne, UK), CK (1:600; Leica), myeloperoxidase (1:200; Leica), HMB45 (1:150; Leica), CD1a (1:20; Leica), CD20 (1:200; Leica), CD21 (1:60; Leica), CD23 (1:100; Leica), CD31 (1:300; Leica), CD34 (1:20; Leica), CD56 (1:150; Leica), CK5 (1:300; Leica), WT-1 (1:40; Leica), calretrenin (1:100; Leica), CD68 (1:600; DiNonA, Iksan, Korea), CD3 (1:300; Neo, Fremont, USA), CD35 (1:50; Cell marque, Rocklin, CA, USA), and CK6 (1:50; Thermo, Fremont, CA, USA).	('CD31', 'Gene', (314, 318))	('CD20', 'Gene', (252, 256))	('1:300', 'Var', (485, 490))	('CD45', 'Gene', (113, 117))	('S100', 'Gene', (51, 55))	('CD56', 'Gene', (355, 359))	('CD68', 'Gene', '968', (444, 448))	('S100', 'Gene', '6271', (51, 55))	('CK5', 'Gene', (376, 379))	('CD45', 'Gene', '5788', (113, 117))	('CD1a', 'Gene', '909', (232, 236))	('CD21', 'Gene', '1380', (273, 277))	('CD20', 'Gene', '54474', (252, 256))	('CD56', 'Gene', '4684', (355, 359))	('CD68', 'Gene', (444, 448))	('CD34', 'Gene', (335, 339))	('vimentin', 'Gene', '7431', (89, 97))	('vimentin', 'Gene', (89, 97))	('myeloperoxidase', 'Gene', (178, 193))	('myeloperoxidase', 'Gene', '4353', (178, 193))	('CK5', 'Gene', '3852', (376, 379))	('CD1a', 'Gene', (232, 236))	('CD23', 'Gene', (293, 297))	('CD31', 'Gene', '5175', (314, 318))	('CD23', 'Gene', '2208', (293, 297))	('CD35', 'Gene', '1378', (512, 516))	('CD35', 'Gene', (512, 516))	('CD34', 'Gene', '947', (335, 339))	('CD21', 'Gene', (273, 277))
525695	21286027	3), vimentin, and CD68, but negative for cytokeratin (epithelial cell marker), myeloperoxidase (myeloid cell marker), HMB45 (melanoma marker), CD1a (LCS marker), CD3 (T-cell marker), CD20 (B-cell marker), CD21, CD23, CD35 (FDCS marker), CD31 (vascular endothelial cell marker), CD34 (myeloid stem cell marker), CD56 (neuroendocrine cell marker), CK5, CK6, WT-1, and calretrenin (mesothelioma marker).	('vimentin', 'Gene', (4, 12))	('mesothelioma', 'Disease', 'MESH:D008654', (379, 391))	('CD35', 'Gene', '1378', (217, 221))	('CD68', 'Gene', (18, 22))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('myeloperoxidase', 'Gene', (79, 94))	('CD35', 'Gene', (217, 221))	('CK5', 'Gene', (346, 349))	('CD23', 'Gene', '2208', (211, 215))	('myeloperoxidase', 'Gene', '4353', (79, 94))	('CK6', 'Var', (351, 354))	('CD1a', 'Gene', '909', (143, 147))	('CD31', 'Gene', '5175', (237, 241))	('CD21', 'Gene', (205, 209))	('CD20', 'Gene', (183, 187))	('CK5', 'Gene', '3852', (346, 349))	('CD34', 'Gene', (278, 282))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('CD1a', 'Gene', (143, 147))	('CD21', 'Gene', '1380', (205, 209))	('CD20', 'Gene', '54474', (183, 187))	('CD31', 'Gene', (237, 241))	('CD56', 'Gene', (311, 315))	('CD68', 'Gene', '968', (18, 22))	('CD56', 'Gene', '4684', (311, 315))	('vimentin', 'Gene', '7431', (4, 12))	('mesothelioma', 'Disease', (379, 391))	('CD23', 'Gene', (211, 215))	('CD34', 'Gene', '947', (278, 282))
525717	30895378	DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2.	('undifferentiated round cell sarcomas', 'Disease', (227, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('Ewing sarcoma', 'Gene', '2130', (165, 178))	('EwS', 'Gene', '2130', (180, 183))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('undifferentiated round cell sarcomas', 'Disease', 'MESH:D002277', (227, 263))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('EWSR1', 'Gene', '2130', (200, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('NFATc2', 'Gene', (70, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (165, 178))	('EWSR1', 'Gene', '2130', (276, 281))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (165, 178))	('EwS', 'Phenotype', 'HP:0012254', (180, 183))	('EWSR1', 'Gene', '2130', (64, 69))	('EWSR1', 'Gene', (200, 205))	('Ewing sarcoma', 'Gene', (89, 102))	('NFATc2', 'Gene', (323, 329))	('NFATc2', 'Gene', '4773', (70, 76))	('EwS', 'Gene', (180, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (255, 263))	('fusions', 'Var', (215, 222))	('Ewing sarcoma', 'Gene', (165, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('EWSR1', 'Gene', (276, 281))	('Ewing sarcoma', 'Gene', '2130', (89, 102))	('Ewing-like sarcoma', 'Disease', (40, 58))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (40, 58))	('NFATc2', 'Gene', '4773', (323, 329))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (40, 58))	('EWSR1', 'Gene', (64, 69))
525721	30895378	Unsupervised clustering and t-distributed stochastic neighbor embedding analysis of DNA-methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes.	('fusion', 'Var', (175, 181))	('EwS', 'Gene', (213, 216))	('EWSR1', 'Gene', (162, 167))	('NFATc2', 'Gene', '4773', (168, 174))	('EwS', 'Phenotype', 'HP:0012254', (213, 216))	('EwS', 'Gene', '2130', (213, 216))	('EWSR1', 'Gene', '2130', (162, 167))	('NFATc2', 'Gene', (168, 174))
525739	30895378	These URCS carry fusions between EWSR1 and members outside the ETS gene family, which often occur between EWSR1 and NFATc2.	('EWSR1', 'Gene', '2130', (106, 111))	('NFATc2', 'Gene', '4773', (116, 122))	('EWSR1', 'Gene', (33, 38))	('fusions', 'Var', (17, 24))	('NFATc2', 'Gene', (116, 122))	('EWSR1', 'Gene', (106, 111))	('EWSR1', 'Gene', '2130', (33, 38))
525744	30895378	To address this issue further, we performed comparative, genome-wide DNA methylation profiling and cytogenetic analyses of five URCS with EWSR1-NFATc2 fusion.	('EWSR1', 'Gene', (138, 143))	('NFATc2', 'Gene', '4773', (144, 150))	('EWSR1', 'Gene', '2130', (138, 143))	('fusion', 'Var', (151, 157))	('NFATc2', 'Gene', (144, 150))
525747	30895378	In one previously published case, detection by next generation sequencing and FISH analysis failed due to poor RNA quality, though the copy number profile revealed amplifications involving the EWSR1 locus.	('amplifications', 'Var', (164, 178))	('EWSR1', 'Gene', (193, 198))	('EWSR1', 'Gene', '2130', (193, 198))
525752	30895378	The methylation data of the control group and of two URCS with EWSR1-NFATc2 fusions have been previously reported.	('methylation', 'MPA', (4, 15))	('NFATc2', 'Gene', (69, 75))	('fusions', 'Var', (76, 83))	('EWSR1', 'Gene', '2130', (63, 68))	('NFATc2', 'Gene', '4773', (69, 75))	('EWSR1', 'Gene', (63, 68))
525765	30895378	URCS with EWSR1-NFATc2 fusion formed a homogeneous methylation class by both clustering (Figure 2 a) and t-SNE analyses (Figure 2 b), which also kept stable when varying the number of CpGs used for this analysis.	('EWSR1', 'Gene', (10, 15))	('fusion', 'Var', (23, 29))	('methylation', 'MPA', (51, 62))	('EWSR1', 'Gene', '2130', (10, 15))	('NFATc2', 'Gene', (16, 22))	('NFATc2', 'Gene', '4773', (16, 22))
525766	30895378	The methylation profiles of URCS with EWSR1-NFATc2 fusion were distinct from the methylation class of EwS, which formed a homogeneous methylation cluster irrespective of their various TET-ETS gene fusion variants.	('EwS', 'Gene', (102, 105))	('NFATc2', 'Gene', '4773', (44, 50))	('EWSR1', 'Gene', '2130', (38, 43))	('fusion', 'Var', (51, 57))	('EwS', 'Phenotype', 'HP:0012254', (102, 105))	('NFATc2', 'Gene', (44, 50))	('EwS', 'Gene', '2130', (102, 105))	('TET', 'Chemical', 'MESH:C010349', (184, 187))	('EWSR1', 'Gene', (38, 43))
525773	30895378	We here describe a distinct DNA methylation signature for URCS with EWSR1-NFATc2 fusion, which is clearly distinguishable from the DNA methylation signature of EwS.	('NFATc2', 'Gene', '4773', (74, 80))	('fusion', 'Var', (81, 87))	('EWSR1', 'Gene', '2130', (68, 73))	('EwS', 'Phenotype', 'HP:0012254', (160, 163))	('EwS', 'Gene', '2130', (160, 163))	('NFATc2', 'Gene', (74, 80))	('EWSR1', 'Gene', (68, 73))	('EwS', 'Gene', (160, 163))
525775	30895378	This concept has recently been fueled by gene expression studies, which revealed major differences between URCS with EWSR1-NFATc2 fusion and EwS with canonical TET-ETS gene fusions.	('EwS', 'Phenotype', 'HP:0012254', (141, 144))	('fusion', 'Var', (130, 136))	('EwS', 'Gene', '2130', (141, 144))	('EWSR1', 'Gene', (117, 122))	('NFATc2', 'Gene', '4773', (123, 129))	('EWSR1', 'Gene', '2130', (117, 122))	('EwS', 'Gene', (141, 144))	('TET', 'Chemical', 'MESH:C010349', (160, 163))	('NFATc2', 'Gene', (123, 129))
525781	30895378	Epithelial marker expression has been consistently described in URCS with EWSR1-NFATc2 fusion, which is rarely observed in EwS.	('EwS', 'Gene', (123, 126))	('Epithelial', 'MPA', (0, 10))	('described', 'Reg', (51, 60))	('NFATc2', 'Gene', (80, 86))	('EWSR1', 'Gene', (74, 79))	('EwS', 'Phenotype', 'HP:0012254', (123, 126))	('EwS', 'Gene', '2130', (123, 126))	('NFATc2', 'Gene', '4773', (80, 86))	('EWSR1', 'Gene', '2130', (74, 79))	('fusion', 'Var', (87, 93))
525784	30895378	However, it has not been proven yet whether similar functional consequences may emerge from the EWSR1-NFATc2 fusion compared to TET-ETS gene fusions.	('NFATc2', 'Gene', (102, 108))	('EWSR1', 'Gene', (96, 101))	('NFATc2', 'Gene', '4773', (102, 108))	('TET', 'Chemical', 'MESH:C010349', (128, 131))	('EWSR1', 'Gene', '2130', (96, 101))	('fusion', 'Var', (109, 115))
525789	30895378	From a clinical perspective, URCS with EWSR1-NFATc2 fusion predominantly occurred as intraosseous lesions, had a striking male predominance and occurred in patients with a slightly higher age at diagnosis compared to EwS.	('patients', 'Species', '9606', (156, 164))	('occurred', 'Reg', (73, 81))	('EwS', 'Phenotype', 'HP:0012254', (217, 220))	('NFATc2', 'Gene', (45, 51))	('URCS', 'Disease', (29, 33))	('EwS', 'Gene', '2130', (217, 220))	('EwS', 'Gene', (217, 220))	('fusion', 'Var', (52, 58))	('EWSR1', 'Gene', (39, 44))	('NFATc2', 'Gene', '4773', (45, 51))	('EWSR1', 'Gene', '2130', (39, 44))
525792	30895378	Due to the exceptional rarity of URCS with EWSR1-NFATc2 fusion, clinical data regarding the biological behavior is very limited.	('URCS', 'Disease', (33, 37))	('NFATc2', 'Gene', (49, 55))	('fusion', 'Var', (56, 62))	('EWSR1', 'Gene', (43, 48))	('NFATc2', 'Gene', '4773', (49, 55))	('EWSR1', 'Gene', '2130', (43, 48))
525796	30895378	Despite the growing evidence that URCS with EWSR1-NFATc2 fusion may be distinct from EwS, their origin has not yet been resolved.	('EWSR1', 'Gene', '2130', (44, 49))	('EwS', 'Phenotype', 'HP:0012254', (85, 88))	('EwS', 'Gene', '2130', (85, 88))	('NFATc2', 'Gene', (50, 56))	('EWSR1', 'Gene', (44, 49))	('fusion', 'Var', (57, 63))	('EwS', 'Gene', (85, 88))	('NFATc2', 'Gene', '4773', (50, 56))
525801	30895378	However, myoepithelial tumors often carry EWSR1 gene fusions with a growing number of non-ETS fusion partner genes, e.g.	('fusions', 'Var', (53, 60))	('EWSR1', 'Gene', '2130', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (9, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('myoepithelial tumors', 'Disease', (9, 29))	('EWSR1', 'Gene', (42, 47))
525803	30895378	Most recently, a subcutaneous lesion with a phenotype matching with myoepithelial tumors has been described in a young female patient, which carried a EWSR1-NFATc2 fusion and additionally had amplifications in the EWSR1 and NFATc2 regions.	('subcutaneous lesion', 'Disease', (17, 36))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('NFATc2', 'Gene', (224, 230))	('EWSR1', 'Gene', (151, 156))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (68, 88))	('amplifications', 'Var', (192, 206))	('fusion', 'Var', (164, 170))	('myoepithelial tumors', 'Disease', (68, 88))	('patient', 'Species', '9606', (126, 133))	('NFATc2', 'Gene', '4773', (157, 163))	('EWSR1', 'Gene', '2130', (151, 156))	('EWSR1', 'Gene', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('NFATc2', 'Gene', '4773', (224, 230))	('subcutaneous lesion', 'Phenotype', 'HP:0001482', (17, 36))	('EWSR1', 'Gene', '2130', (214, 219))	('NFATc2', 'Gene', (157, 163))
525807	30895378	In conclusion, DNA methylation profiling segregates URCS with EWSR1-NFATc2 fusion from EwS with canonical TET-ETS fusions.	('NFATc2', 'Gene', (68, 74))	('TET', 'Chemical', 'MESH:C010349', (106, 109))	('fusion', 'Var', (75, 81))	('EwS', 'Phenotype', 'HP:0012254', (87, 90))	('EWSR1', 'Gene', (62, 67))	('NFATc2', 'Gene', '4773', (68, 74))	('EwS', 'Gene', '2130', (87, 90))	('EwS', 'Gene', (87, 90))	('EWSR1', 'Gene', '2130', (62, 67))
525817	32085455	Failure to respond to treatment as well as drug resistance to anti-cancer drugs are critical challenges in clinical oncology that can be ascribed to factors like genetic mutation, oncogenic amplification, and other changes in the tumor cell machinery that result in changes in the uptake capability, metabolism of drugs, and removal of drugs and drug metabolites from the cells.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', (230, 235))	('changes', 'Reg', (215, 222))	('cancer', 'Disease', (67, 73))	('uptake capability', 'MPA', (281, 298))	('changes', 'Reg', (266, 273))	('oncology', 'Phenotype', 'HP:0002664', (116, 124))	('metabolism of drugs', 'MPA', (300, 319))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))	('removal of drugs', 'MPA', (325, 341))	('genetic mutation', 'Var', (162, 178))
525915	32085455	The small molecule p53 activator, NSC59984, is not a clinically approved drug, but targets p53 mutant cells, which many GBM tumor cells are.	('GBM', 'Disease', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('GBM', 'Disease', 'MESH:D005909', (120, 123))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('tumor', 'Disease', (124, 129))	('p53', 'Gene', (91, 94))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (91, 94))	('p53', 'Gene', '7157', (19, 22))	('mutant', 'Var', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
526110	29854355	Approximately 90% of synovial sarcomas harbor the SYT-SSX fusion gene as a result of the translocation.	('translocation', 'Var', (89, 102))	('SSX', 'Gene', '6757', (54, 57))	('SSX', 'Gene', (54, 57))	('SYT', 'Gene', (50, 53))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (21, 38))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (21, 37))	('synovial sarcomas', 'Disease', 'MESH:D013584', (21, 38))	('synovial sarcomas', 'Disease', (21, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('SYT', 'Gene', '6760', (50, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (30, 38))
526126	25243408	Using material from cohorts of genetically diagnosed Ewing sarcoma with EWSR1 chromosomal translocations, confocal images of tissue microarrays were segmented with level sets and watershed algorithms.	('EWSR1', 'Gene', (72, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (53, 66))	('chromosomal translocations', 'Var', (78, 104))	('water', 'Chemical', 'MESH:D014867', (179, 184))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('EWSR1', 'Gene', '2130', (72, 77))	('Ewing sarcoma', 'Disease', (53, 66))
526164	25243408	Monoclonal rabbit antibodies pS6 (#4857), Foxo3a (#2497; #9467), EGR1 (#4154) and pMAPK (#4370) were purchased from New England Biolabs (UK).	('rabbit', 'Species', '9986', (11, 17))	('#2497; #9467', 'Var', (50, 62))	('#4857', 'Var', (34, 39))	('pS6', 'Gene', '338413', (29, 32))	('Foxo3a', 'Gene', '2309', (42, 48))	('Foxo3a', 'Gene', (42, 48))	('EGR1', 'Gene', '1958', (65, 69))	('#4370', 'Var', (89, 94))	('pS6', 'Gene', (29, 32))	('#4154', 'Var', (71, 76))	('EGR1', 'Gene', (65, 69))
526170	25243408	Reduction in either signal intensity or altered cellular distribution in response to IGF2 were confirmed by addition of inhibitors with a range of concentrations (maximal inhibitory concentration); rapamycin (10nM), LY294002 (10 microM) and U0126 (10 microM), for pS6 (signal reduction), Foxo3a (nuclear localization) and EGR1 (cytoplasmic localization), respectively.	('Foxo3a', 'Gene', '2309', (288, 294))	('Foxo3a', 'Gene', (288, 294))	('LY294002', 'Var', (216, 224))	('U0126', 'Chemical', 'MESH:C113580', (241, 246))	('pS6', 'Gene', (264, 267))	('rapamycin', 'Chemical', 'MESH:D020123', (198, 207))	('IGF2', 'Gene', '3481', (85, 89))	('U0126', 'Var', (241, 246))	('LY294002', 'Chemical', 'MESH:C085911', (216, 224))	('pS6', 'Gene', '338413', (264, 267))	('EGR1', 'Gene', (322, 326))	('Reduction', 'NegReg', (0, 9))	('altered', 'Reg', (40, 47))	('signal intensity', 'MPA', (20, 36))	('IGF2', 'Gene', (85, 89))	('EGR1', 'Gene', '1958', (322, 326))	('cellular distribution', 'MPA', (48, 69))
526238	25243408	Error rates were lower (<4.0) in the RSF with Ki67, Ki67 combined with DAPI and Ki67 combined with EGR1, Foxo3a and pS6 markers (Table 2, Figure 4a).	('pS6', 'Gene', (116, 119))	('EGR1', 'Gene', '1958', (99, 103))	('Foxo3a', 'Gene', '2309', (105, 111))	('lower', 'NegReg', (17, 22))	('pS6', 'Gene', '338413', (116, 119))	('Ki67', 'Var', (52, 56))	('Ki67', 'Chemical', '-', (52, 56))	('RSF', 'Chemical', '-', (37, 40))	('Error', 'MPA', (0, 5))	('Ki67', 'Chemical', '-', (46, 50))	('Ki67', 'Var', (80, 84))	('Ki67', 'Chemical', '-', (80, 84))	('EGR1', 'Gene', (99, 103))	('Ki67', 'Var', (46, 50))	('Foxo3a', 'Gene', (105, 111))	('DAPI', 'Chemical', 'MESH:C007293', (71, 75))
526243	25243408	This also enabled us to better understand the variation in performance by visualising the change in predicted output, as summarised by four of the cross-validation predictions for the CD99 negative (low cytoplasmic labelling) Ki67 RSF (Figure 5).	('Ki67', 'Chemical', '-', (226, 230))	('Ki67', 'Var', (226, 230))	('RSF', 'Chemical', '-', (231, 234))	('CD99', 'Gene', '4267', (184, 188))	('negative', 'NegReg', (189, 197))	('CD99', 'Gene', (184, 188))
526258	25243408	Variation includes fundamental differences in tumour cells attributed to different driver mutations, and to the differences in clinical outcome attributed to non-standardised diagnosis, stage of disease and treatment modalities.	('tumour', 'Disease', (46, 52))	('mutations', 'Var', (90, 99))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
526264	25243408	Our unbiased pipeline with RSF verified Ki67 as a potentially informative prognostic biomarker in terms of patient survival, but only it appears in a subset of cells with lower CD99 labelling than in the total cell population.	('CD99', 'Gene', (177, 181))	('CD99', 'Gene', '4267', (177, 181))	('Ki67', 'Chemical', '-', (40, 44))	('patient', 'Species', '9606', (107, 114))	('Ki67', 'Var', (40, 44))	('RSF', 'Chemical', '-', (27, 30))	('lower', 'NegReg', (171, 176))
526286	22745043	Pemetrexed (LY231514; ALIMTA ; pemetrexed disodium; Eli Lilly and Company, Indianapolis, Indiana), is a novel folate antimetabolite that inhibits several folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyl transferase (GARFT), and to a lesser degree, aminoimidazole carboxamide formyl transferase.	('GARFT', 'Gene', '2618', (296, 301))	('thymidylate synthase', 'Gene', (190, 210))	('DHFR', 'Gene', (242, 246))	('GARFT', 'Gene', (296, 301))	('LY231514', 'Chemical', 'MESH:D000068437', (12, 20))	('thymidylate synthase', 'Gene', '7298', (190, 210))	('dihydrofolate reductase', 'Gene', (217, 240))	('glycinamide ribonucleotide formyl transferase', 'Gene', (249, 294))	('LY231514;', 'Var', (12, 21))	('folate', 'Chemical', 'MESH:D005492', (154, 160))	('DHFR', 'Gene', '1719', (242, 246))	('folate-dependent enzymes', 'Enzyme', (154, 178))	('folate', 'Chemical', 'MESH:D005492', (224, 230))	('TS', 'Gene', '7298', (212, 214))	('pemetrexed disodium', 'Chemical', 'MESH:D000068437', (31, 50))	('dihydrofolate reductase', 'Gene', '1719', (217, 240))	('inhibits', 'NegReg', (137, 145))	('Pemetrexed', 'Chemical', 'MESH:D000068437', (0, 10))	('glycinamide ribonucleotide formyl transferase', 'Gene', '2618', (249, 294))	('folate', 'Chemical', 'MESH:D005492', (110, 116))	('aminoimidazole carboxamide formyl transferase', 'Enzyme', (328, 373))
526298	22745043	Secondary aims included further assessment of pemetrexed toxicities in children, as well as an exploration of a potential correlation between the presence of a polymorphism in the TS gene and/or gene promoter and pemetrexed toxicity.	('pemetrexed', 'Chemical', 'MESH:D000068437', (46, 56))	('toxicities', 'Disease', 'MESH:D064420', (57, 67))	('toxicity', 'Disease', 'MESH:D064420', (224, 232))	('presence', 'Var', (146, 154))	('pemetrexed', 'Chemical', 'MESH:D000068437', (213, 223))	('toxicity', 'Disease', (224, 232))	('polymorphism', 'Var', (160, 172))	('toxicities', 'Disease', (57, 67))	('children', 'Species', '9606', (71, 79))	('TS', 'Gene', '7298', (180, 182))
526340	22745043	Similarly, two regions containing a single nucleotide polymorphism (SNP) in the methylenetetrahydrofolate reductase (MTHFR) gene were amplified with specific primers and sequenced in the Mayo AGTC core lab.	('single nucleotide polymorphism', 'Var', (36, 66))	('MTHFR', 'Gene', '4524', (117, 122))	('Mayo', 'Species', '162683', (187, 191))	('methylenetetrahydrofolate reductase', 'Gene', (80, 115))	('MTHFR', 'Gene', (117, 122))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (80, 115))
526360	22745043	DNA from 62 patients was analyzed for the presence of genetic variations in the TS and MTHFR genes, looking specifically for variable numbers of tandem repeats, deletions, or SNPs (Table I).	('patients', 'Species', '9606', (12, 20))	('deletions', 'Var', (161, 170))	('MTHFR', 'Gene', '4524', (87, 92))	('TS', 'Gene', '7298', (80, 82))	('MTHFR', 'Gene', (87, 92))
526363	22745043	Four patients were homozygous and 30 heterozygous for a 6bp deletion 447bp downstream of the TS transcription stop codon, which has been suggested to alter the TS mRNA stability.	('TS', 'Gene', '7298', (160, 162))	('patients', 'Species', '9606', (5, 13))	('alter', 'Reg', (150, 155))	('deletion', 'Var', (60, 68))	('TS', 'Gene', '7298', (93, 95))
526364	22745043	(20) Five patients were homozygous and 27 heterozygous for a variant allele at amino acid position 222Val of the MTHFR gene, which is associated with an elevated homocysteine levels under conditions of impaired folate status, and thus might be expected to result increased toxicity with pemetrexed.	('MTHFR', 'Gene', '4524', (113, 118))	('homocysteine', 'Chemical', 'MESH:D006710', (162, 174))	('pemetrexed', 'Chemical', 'MESH:D000068437', (287, 297))	('elevated', 'PosReg', (153, 161))	('MTHFR', 'Gene', (113, 118))	('variant', 'Var', (61, 68))	('increased', 'PosReg', (263, 272))	('elevated homocysteine', 'Phenotype', 'HP:0002160', (153, 174))	('homocysteine levels', 'MPA', (162, 181))	('patients', 'Species', '9606', (10, 18))	('impaired folate status', 'Phenotype', 'HP:0100507', (202, 224))	('folate', 'Chemical', 'MESH:D005492', (211, 217))	('toxicity', 'Disease', 'MESH:D064420', (273, 281))	('toxicity', 'Disease', (273, 281))
526365	22745043	Four patients were homozygous and 23 heterozygous for a variant allele at amino acid position 429Ala of the MTHFR gene, which is associated with decreased MTHFR activity.	('variant', 'Var', (56, 63))	('patients', 'Species', '9606', (5, 13))	('MTHFR', 'Gene', '4524', (155, 160))	('MTHFR', 'Gene', '4524', (108, 113))	('decreased', 'NegReg', (145, 154))	('MTHFR', 'Gene', (155, 160))	('MTHFR', 'Gene', (108, 113))	('activity', 'MPA', (161, 169))
526468	30505937	The most profound effects were in A673 with only a transient effect on response rates in TC71.	('TC71', 'Gene', (89, 93))	('rat', 'Species', '10116', (80, 83))	('effects', 'Reg', (18, 25))	('A673', 'Var', (34, 38))
526469	30505937	Interestingly, A673 was more dependent than TC71 on macrophages for its tumorigenesis.	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('A673', 'Var', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))
526475	30505937	The characteristic translocation between chromosomes 11 and 22, resulting in the EWS/FLI fusion protein, or similar translocations between EWS and other members of the ETS family of transcription factors, are pathognomonic oncogenes that aberrantly regulate gene expression.	('EWS', 'Gene', '14030', (139, 142))	('regulate', 'Reg', (249, 257))	('EWS', 'Gene', '14030', (81, 84))	('EWS', 'Gene', (139, 142))	('EWS', 'Gene', (81, 84))	('translocation', 'Var', (19, 32))
526495	30505937	We treated athymic nude mice previously implanted with A673 xenograft tumors with a combination of intravenous and intraperitoneal Clodrosome or liposome control prior to two intratumoral doses of rRp450, a herpes simplex type 1 virus attenuated by deletion of the virus gene encoding the large subunit of ribonucleotide reductase, or PBS control (Figure 1A).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('xenograft tumors', 'Disease', (60, 76))	('deletion', 'Var', (249, 257))	('nude mice', 'Species', '10090', (19, 28))	('Clodrosome', 'Chemical', '-', (131, 141))	('tumor', 'Disease', (70, 75))	('PBS', 'Chemical', 'MESH:D007854', (335, 338))	('tumor', 'Disease', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('herpes simplex', 'Phenotype', 'HP:0012302', (207, 221))	('rat', 'Species', '10116', (178, 181))	('xenograft tumors', 'Disease', 'MESH:D009369', (60, 76))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
526497	30505937	When we depleted macrophages with Clodrosome prior to rRp450 injection, however, we found that the majority of A673 xenografts shrank to CR (8/14 CR).	('A673', 'Var', (111, 115))	('shrank', 'CPA', (127, 133))	('Clodrosome', 'Chemical', '-', (34, 44))
526501	30505937	We used flow cytometry to analyze leukocyte populations (see gating strategy in Figure S1) in mouse spleens and rRp450-infected A673 tumors, and found that Clodrosome induced significant depletion of both M1-like (CD11c+/CD206-) and M2-like (CD11c+/CD206+) splenic macrophages (Figure 2A).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('rat', 'Species', '10116', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('depletion', 'MPA', (187, 196))	('rRp450-infected A673 tumors', 'Disease', (112, 139))	('mouse', 'Species', '10090', (94, 99))	('rRp450-infected A673 tumors', 'Disease', 'MESH:D009369', (112, 139))	('CD11c+/CD206-', 'Var', (214, 227))	('CD11c+/CD206+', 'Var', (242, 255))	('Clodrosome', 'Chemical', '-', (156, 166))
526509	30505937	Interestingly, the few tumors that formed 10 days after A673 implantation in the Clodrosome-treated mice acquired tumor macrophages comparable with the liposome control-treated tumors (Figure 3D); this finding may be due to variability in Clodrosome stability or the ability of residual macrophages in the flank to assist in tumor formation.	('mice', 'Species', '10090', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Clodrosome', 'Chemical', '-', (81, 91))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (177, 182))	('Clodrosome', 'Chemical', '-', (239, 249))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumors', 'Disease', (23, 29))	('A673', 'Var', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (325, 330))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))
526557	30505937	Here we report that xenograft models of Ewing sarcoma are variably dependent on macrophages for tumorigenesis, and systemic strategies to diminish macrophages enhance the antitumor response to oncolytic herpes virotherapy without changes in the kinetics of virus replication.	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Ewing sarcoma', 'Disease', (40, 53))	('diminish', 'Var', (138, 146))	('tumor', 'Disease', (96, 101))	('enhance', 'PosReg', (159, 166))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (40, 53))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (40, 53))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
526561	30505937	Although IL-12 expressing oHSV has been shown to induce phosphorylated signal transducer and activator of transcription 1 (p-STAT1)+/inducible nitric oxide synthase (iNOS)+ M1-like macrophage polarization, the additional inhibition of immune checkpoint signaling was required to improve oncolytic virus (OV) antitumor efficacy in glioblastoma models.	('inducible nitric oxide synthase', 'Gene', (133, 164))	('oHSV', 'Var', (26, 30))	('STAT1', 'Gene', '20846', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('STAT1', 'Gene', (125, 130))	('IL-12', 'Gene', (9, 14))	('signal transducer and activator of transcription 1', 'Gene', '20846', (71, 121))	('oHSV', 'Chemical', '-', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('glioblastoma', 'Disease', (330, 342))	('induce', 'PosReg', (49, 55))	('inducible nitric oxide synthase', 'Gene', '18126', (133, 164))	('glioblastoma', 'Disease', 'MESH:D005909', (330, 342))	('tumor', 'Disease', (312, 317))	('glioblastoma', 'Phenotype', 'HP:0012174', (330, 342))
526588	30505937	The oncolytic virus rRp450, attenuated by insertion of the rat cytochrome p450 CYP2B1 gene into the viral ribonucleotide reductase ICP6 gene, was provided by E. Antonio Chiocca (Brigham and Women's Hospital, Boston, MA, USA).	('attenuated', 'NegReg', (28, 38))	('CYP2B1', 'Gene', (79, 85))	('CYP2B1', 'Gene', '24300', (79, 85))	('Women', 'Species', '9606', (190, 195))	('insertion', 'Var', (42, 51))	('rat', 'Species', '10116', (59, 62))
526598	30505937	A8301 or equal volume of plain DMSO was diluted in PBS to 6 mg/kg A8301 and administered intraperitoneally thrice weekly as described in the figure legends.	('A8301', 'Var', (66, 71))	('A8301', 'Chemical', '-', (0, 5))	('PBS', 'Chemical', 'MESH:D007854', (51, 54))	('DMSO', 'Chemical', 'MESH:D004121', (31, 35))	('A8301', 'Var', (0, 5))	('A8301', 'Chemical', '-', (66, 71))
526817	26396606	This stems from the fact that similar genetic aberrations occur in these cell population namely identical p53 mutations, homozygous p16 deletion, PTEN mutation, and co-amplification of MDM2 and CDK4.	('genetic aberrations', 'Disease', 'MESH:D030342', (38, 57))	('p53', 'Gene', '7157', (106, 109))	('PTEN', 'Gene', (146, 150))	('mutations', 'Var', (110, 119))	('CDK4', 'Gene', (194, 198))	('PTEN', 'Gene', '5728', (146, 150))	('p16', 'Gene', '1029', (132, 135))	('CDK4', 'Gene', '1019', (194, 198))	('mutation', 'Var', (151, 159))	('MDM2', 'Gene', '4193', (185, 189))	('MDM2', 'Gene', (185, 189))	('genetic aberrations', 'Disease', (38, 57))	('p16', 'Gene', (132, 135))	('deletion', 'Var', (136, 144))	('p53', 'Gene', (106, 109))
526845	26396606	Younger age, good preoperative KPS (which ensures that the patient undergoes the entire treatment modalities) and gross total excision as opposed to lesser degree of excision are associated with better survival, facts that are similar to the GBMs.	('better', 'PosReg', (195, 201))	('gross', 'Var', (114, 119))	('patient', 'Species', '9606', (59, 66))	('survival', 'CPA', (202, 210))	('KPS', 'CPA', (31, 34))	('GBM', 'Phenotype', 'HP:0012174', (242, 245))
527037	31007895	Aldoxorubicin showed a significant prolongation of the PFS (5.6 vs 2.7 months; p = 0.02) and the 6-months PFS rate (46% vs 23%; p = 0.02).	('prolongation of the PFS', 'Disease', (35, 58))	('prolongation of the PFS', 'Disease', 'MESH:D011273', (35, 58))	('Aldoxorubicin', 'Chemical', 'MESH:C575867', (0, 13))	('Aldoxorubicin', 'Var', (0, 13))
527042	31007895	However, in the subcohort of l-sarcomas (leiomyosarcomas and liposarcomas, 57.5%) aldoxorubicin could improve PFS (5.3 vs 2.9 months; p = 0.007) and the disease control rate (41.7 vs 27%; p = 0.016).	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('sarcomas', 'Disease', (31, 39))	('sarcomas', 'Disease', (48, 56))	('liposarcoma', 'Phenotype', 'HP:0012034', (61, 72))	('improve', 'PosReg', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (82, 95))	('liposarcomas', 'Phenotype', 'HP:0012034', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('aldoxorubicin', 'Var', (82, 95))	('disease control', 'CPA', (153, 168))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (41, 55))	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('leiomyosarcomas and liposarcomas', 'Disease', 'MESH:D007890', (41, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcomas', 'Disease', (65, 73))	('PFS', 'MPA', (110, 113))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
527045	31007895	Palbociclib, a selective CDK4/CDK6-inhibitor, and DS-3032b, a MDM2-inhibitor, have both been investigated for the treatment of well- and de-differentiated liposarcomas (WDLS/DDLS).	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('CDK6', 'Gene', (30, 34))	('DS-3032b', 'Var', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('CDK6', 'Gene', '1021', (30, 34))	('liposarcomas', 'Phenotype', 'HP:0012034', (155, 167))	('MDM2', 'Gene', '4193', (62, 66))	('CDK4', 'Gene', (25, 29))	('MDM2', 'Gene', (62, 66))	('liposarcomas', 'Disease', 'MESH:D008080', (155, 167))	('liposarcomas', 'Disease', (155, 167))	('CDK4', 'Gene', '1019', (25, 29))	('DS-3032b', 'Chemical', '-', (50, 58))	('liposarcoma', 'Phenotype', 'HP:0012034', (155, 166))
527053	31007895	Hence, TRC105 is able to suppress angiogenesis and might enhance the activity of bevacizumab or other tyrosine multi-kinase inhibitors such as pazopanib.	('activity', 'MPA', (69, 77))	('pazopanib', 'Chemical', 'MESH:C516667', (143, 152))	('bevacizumab', 'Chemical', 'MESH:D000068258', (81, 92))	('TRC105', 'Var', (7, 13))	('angiogenesis', 'CPA', (34, 46))	('suppress', 'NegReg', (25, 33))	('enhance', 'PosReg', (57, 64))
527103	31001265	In addition, knockdown of CD99 in EWS tumor cells reduced in vivo tumor growth in mouse xenograft experiments.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mouse', 'Species', '10090', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CD99', 'Gene', (26, 30))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('reduced', 'NegReg', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('knockdown', 'Var', (13, 22))
527106	31001265	CD99 was also found to be highly expressed in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and stem cells and anti-CD99 monoclonal antibodies show antileukemic activity in AML xenograft models.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (88, 104))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (46, 74))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (112, 137))	('AML', 'Disease', 'MESH:D015470', (106, 109))	('MDS', 'Disease', 'MESH:D009190', (139, 142))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (46, 74))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (82, 104))	('AML', 'Disease', (106, 109))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (82, 104))	('CD99', 'Gene', (0, 4))	('MDS', 'Disease', (139, 142))	('anti-CD99', 'Gene', (164, 173))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (52, 74))	('anti-CD99', 'Var', (164, 173))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (112, 137))	('myelodysplastic syndromes', 'Disease', (112, 137))	('AML', 'Disease', 'MESH:D015470', (226, 229))	('acute myeloid leukemia', 'Disease', (82, 104))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))	('antileukemic activity', 'CPA', (201, 222))	('acute lymphoblastic leukemia', 'Disease', (46, 74))	('AML', 'Disease', (226, 229))
527272	31001265	Indeed, when antibodies against CD99 were present in the sera of the mice, tumor growth of osteosarcoma (Os-P0107) was significantly inhibited compared to control vaccinated mice (**P < 0.01; Figure 2F).	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('mice', 'Species', '10090', (174, 178))	('antibodies', 'Var', (13, 23))	('tumor growth of osteosarcoma', 'Disease', 'MESH:D012516', (75, 103))	('inhibited', 'NegReg', (133, 142))	('mice', 'Species', '10090', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('Os-P0107', 'Chemical', '-', (105, 113))	('tumor growth of osteosarcoma', 'Disease', (75, 103))	('CD99', 'Gene', (32, 36))
527283	31001265	In the CD99 low CT26 tumor model also a significantly lower vessel density (*P < 0.05) was found in tumors of CD99 vaccinated mice (Figures 2J,K).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CT26', 'CellLine', 'CVCL:7254', (16, 20))	('low CT26', 'Var', (12, 20))	('mice', 'Species', '10090', (126, 130))	('vessel', 'MPA', (60, 66))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (100, 105))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('lower', 'NegReg', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
527285	31001265	As illustrated in Figure 2E (lower panels) and Figure 2H, a significantly lower pericyte coverage was found in TRXtr-mCD99 vaccinated tumor tissue (red bars) compared to TRXtr vaccinated tumor tissue (blue bars) (*P < 0.05, Figure 2H, left panel).	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('vaccinated', 'Var', (123, 133))	('rat', 'Species', '10116', (9, 12))	('pericyte coverage', 'CPA', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('TRXtr', 'Chemical', '-', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (187, 192))	('TRXtr', 'Chemical', '-', (170, 175))	('mCD99', 'Gene', '673094', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lower', 'NegReg', (74, 79))	('mCD99', 'Gene', (117, 122))	('tumor', 'Disease', (134, 139))
527286	31001265	Furthermore, tumors of CD99 vaccinated mice were found to have more vessel without pericytes than control vaccinated mice (*P < 0.05, Figure 2H, right panel).	('tumors', 'Disease', (13, 19))	('vessel without pericytes', 'CPA', (68, 92))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('CD99 vaccinated', 'Var', (23, 38))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mice', 'Species', '10090', (117, 121))	('more', 'PosReg', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mice', 'Species', '10090', (39, 43))
527299	31001265	In activated HUVEC (HUVEC+; n = 9), EW7 (n = 11), and EWS-RDES (RDES; n = 3) expression of total CD99 (k + l primers; all variants) is downregulated on mRNA level (Figure 3B).	('expression', 'Species', '29278', (77, 87))	('variants', 'Var', (122, 130))	('downregulated', 'NegReg', (135, 148))	('CD99', 'Gene', (97, 101))
527318	31001265	It also induces complement-dependent cytotoxicity (CDC) where the antibodies activate the complement system which leads to the formation of the membrane attack complex (MAC) and subsequent lysis of the target cell.	('membrane attack complex', 'MPA', (144, 167))	('cytotoxicity', 'Disease', (37, 49))	('activate', 'PosReg', (77, 85))	('lysis', 'CPA', (189, 194))	('pen', 'Gene', '30052', (29, 32))	('pen', 'Gene', (29, 32))	('leads to', 'Reg', (114, 122))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('antibodies', 'Var', (66, 76))	('induces', 'Reg', (8, 15))
527330	31001265	Neutralization of VEGF results in a more quiescent vasculature with more pericyte coverage and improved vascular flow.	('vascular flow', 'CPA', (104, 117))	('more', 'PosReg', (68, 72))	('Neutralization', 'Var', (0, 14))	('improved', 'PosReg', (95, 103))	('VEGF', 'Gene', '22339', (18, 22))	('quiescent vasculature', 'MPA', (41, 62))	('pericyte coverage', 'CPA', (73, 90))	('more', 'PosReg', (36, 40))	('VEGF', 'Gene', (18, 22))
527333	31001265	As, the target CD99 is a transmembrane molecule tissue bound frustrated phagocytosis will occur and not only the endothelial cells will be destroyed but everything in their vicinity as well, including pericytes.	('CD99', 'Var', (15, 19))	('rat', 'Species', '10116', (66, 69))	('phagocytosis', 'CPA', (72, 84))
527336	31001265	In addition, we monitored the body weight and health condition of CD99 vaccinated mice, with constantly high anti-mCD99 antibody levels in their sera, and control vaccinated mice, for a period of 45 weeks.	('mice', 'Species', '10090', (82, 86))	('mCD99', 'Gene', (114, 119))	('mice', 'Species', '10090', (174, 178))	('mCD99', 'Gene', '673094', (114, 119))	('CD99', 'Var', (66, 70))	('high', 'PosReg', (104, 108))
527352	31001265	In conclusion targeting of CD99 by vaccination inhibits tumor growth in different murine tumor models and is safe.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CD99', 'Gene', (27, 31))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('targeting', 'Var', (14, 23))	('murine', 'Species', '10090', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('inhibits', 'NegReg', (47, 55))
527511	30719261	In a recent single German institution study of Harati et al., which has included 164 patients with somatic LMS of the soft tissues, high histologic grade (p = 0.001), size >5 cm (p = 0.002), and subfascial localization (p = 0.002) were associated with significantly diminished disease-specific survival (DSS) in univariate analysis.	('disease-specific survival', 'CPA', (277, 302))	('diminished', 'NegReg', (266, 276))	('patients', 'Species', '9606', (85, 93))	('DSS', 'Chemical', '-', (304, 307))	('high', 'Var', (132, 136))
527533	29502955	Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion leading to irreversible mesenchymal differentiation.	('binds', 'Interaction', (21, 26))	('SSX1', 'Gene', (16, 20))	('mesenchymal differentiation', 'CPA', (212, 239))	('expression', 'MPA', (52, 62))	('KDM2B', 'Var', (4, 9))	('activates', 'PosReg', (42, 51))	('developmentally regulated genes', 'Gene', (66, 97))	('SSX1', 'Gene', '6756', (16, 20))
527535	29502955	show that SS18-SSX fusions characteristic of synovial sarcoma associate with KDM2B, a non-canonical polycomb repressive complex 1, to aberrantly activate the expression of developmentally regulated transcription factors that are normally targets of polycomb mediated gene repression.	('SSX', 'Gene', (15, 18))	('SSX', 'Gene', '6757', (15, 18))	('expression', 'MPA', (158, 168))	('fusions', 'Var', (19, 26))	('synovial sarcoma', 'Disease', (45, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('activate', 'PosReg', (145, 153))	('KDM2B', 'Gene', (77, 82))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (45, 61))	('synovial sarcoma', 'Disease', 'MESH:D013584', (45, 61))
527538	29502955	While the presence of such fusions further underscores the key relationship between cancer genetics and epigenetics during tumorigenesis, the mechanisms by which most chimeric oncoproteins drive oncogenesis remain poorly understood.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Disease', (123, 128))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('fusions', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
527541	29502955	Accordingly, aberrant expression of the translocated gene product in the myoblast lineage of mice produces tumors that histologically and molecularly resemble the human disease.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('aberrant expression', 'Var', (13, 32))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('human', 'Species', '9606', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mice', 'Species', '10090', (93, 97))
527552	29502955	Efforts to elucidate how cancer-causing mutations sustain the transformed state often reveal potential mechanisms of oncogenesis and rational strategies for therapeutic intervention.	('reveal', 'Reg', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('oncogenesis', 'CPA', (117, 128))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
527564	29502955	Confirming an on-target effect, a non-targetable KDM2B cDNA restored the proliferation of synovial sarcoma cells expressing KDM2B shRNAs (Figure S1E).	('KDM2B', 'Var', (124, 129))	('synovial sarcoma', 'Disease', 'MESH:D013584', (90, 106))	('proliferation', 'CPA', (73, 86))	('synovial sarcoma', 'Disease', (90, 106))	('restored', 'PosReg', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (90, 106))
527567	29502955	Immunohistochemistry of a large panel of human sarcomas revealed that synovial sarcoma cells express high levels of KDM2B (Figure 2A,B).	('sarcomas', 'Disease', (47, 55))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (70, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('synovial sarcoma', 'Disease', 'MESH:D013584', (70, 86))	('human', 'Species', '9606', (41, 46))	('KDM2B', 'Var', (116, 121))	('synovial sarcoma', 'Disease', (70, 86))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
527571	29502955	This cell fate transition was irreversible: cells harboring GFP-coupled, doxycycline (Dox)-inducible shRNAs targeting either SS18-SSX or KDM2B showed proliferative arrest and mesenchymal differentiation upon Dox addition, which was maintained upon shRNA silencing following Dox withdrawal (Figures 2H,I and Figures S2D-E).	('doxycycline', 'Chemical', 'MESH:D004318', (73, 84))	('Dox', 'Chemical', 'MESH:D004318', (86, 89))	('arrest', 'Disease', (164, 170))	('SSX', 'Gene', '6757', (130, 133))	('mesenchymal differentiation', 'CPA', (175, 202))	('SSX', 'Gene', (130, 133))	('Dox', 'Chemical', 'MESH:D004318', (208, 211))	('KDM2B', 'Var', (137, 142))	('Dox', 'Chemical', 'MESH:D004318', (274, 277))	('arrest', 'Disease', 'MESH:D006323', (164, 170))
527572	29502955	Apparently, SS18-SSX or KDM2B inhibition disrupts synovial sarcoma maintenance by triggering proliferative arrest and differentiation into a more mesenchymal cell fate.	('disrupts synovial sarcoma', 'Disease', 'MESH:D013584', (41, 66))	('arrest', 'Disease', 'MESH:D006323', (107, 113))	('KDM2B', 'Gene', (24, 29))	('inhibition', 'Var', (30, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('triggering', 'Reg', (82, 92))	('differentiation', 'CPA', (118, 133))	('arrest', 'Disease', (107, 113))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (50, 66))	('disrupts synovial sarcoma', 'Disease', (41, 66))	('SSX', 'Gene', '6757', (17, 20))	('SSX', 'Gene', (17, 20))
527575	29502955	Tumor xenografts expressing KDM2B shRNAs displayed markedly impaired tumor growth, closely mimicking the effects seen by RNAi-mediated downregulation of SS18-SSX (Figures 3B,C).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('KDM2B shRNAs', 'Var', (28, 40))	('SSX', 'Gene', (158, 161))	('SSX', 'Gene', '6757', (158, 161))	('impaired tumor', 'Disease', 'MESH:D015417', (60, 74))	('impaired tumor', 'Disease', (60, 74))
527577	29502955	Therefore, human synovial sarcoma cells also require KDM2B for tumor maintenance in vivo.	('tumor', 'Disease', (63, 68))	('human', 'Species', '9606', (11, 16))	('KDM2B', 'Var', (53, 58))	('synovial sarcoma', 'Disease', (17, 33))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (17, 33))	('synovial sarcoma', 'Disease', 'MESH:D013584', (17, 33))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
527582	29502955	Accordingly, expression of a JmjC-defective mutant (KDM2BH211A/H222A) or of a JmjC-deficient short KDM2B isoform was as effective as wild-type KDM2B at rescuing the proliferative arrest produced by KDM2B knockdown (Figures S3C-G).	('arrest', 'Disease', 'MESH:D006323', (179, 185))	('knockdown', 'Var', (204, 213))	('arrest', 'Disease', (179, 185))	('H222A', 'Mutation', 'p.H222A', (63, 68))	('KDM2BH211A/H222A', 'Var', (52, 68))	('rescuing', 'PosReg', (152, 160))
527588	29502955	We infer that KDM2B sustains synovial sarcoma through its PRC1.1-associated activity.	('synovial sarcoma', 'Disease', (29, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (29, 45))	('PRC1.1-associated activity', 'MPA', (58, 84))	('synovial sarcoma', 'Disease', 'MESH:D013584', (29, 45))	('sustains', 'PosReg', (20, 28))	('KDM2B', 'Var', (14, 19))
527593	29502955	Immunofluorescence and immunoblotting confirmed that the HA epitope was depleted by SS18-SSX1 knockdown (Figures 5B and 5C).	('knockdown', 'Var', (94, 103))	('HA epitope', 'MPA', (57, 67))	('SSX1', 'Gene', '6756', (89, 93))	('SSX1', 'Gene', (89, 93))	('depleted', 'NegReg', (72, 80))
527596	29502955	Like BRG1, KDM2B, BCOR, and PCGF1 were detected in anti-HA IPs of lysates from the HA tagged but not the parental cell line.	('BCOR', 'Gene', (18, 22))	('BRG1', 'Gene', (5, 9))	('PCGF1', 'Gene', (28, 33))	('BRG1', 'Gene', '6597', (5, 9))	('PCGF1', 'Gene', '84759', (28, 33))	('BCOR', 'Gene', '63035', (18, 22))	('KDM2B', 'Var', (11, 16))
527600	29502955	This signal was SS18-SSX1/2-specific and dependent: a strong PLA signal was observed in other synovial sarcoma lines using SS18 and KDM2B antibodies but not in MCF7 cells lacking the fusion (Figure S4B), and this signal was abolished upon SS18-SSX1 knockdown using an SSX targeting siRNA (Figure S4C).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (94, 110))	('SSX1', 'Gene', '6756', (21, 25))	('SSX1', 'Gene', '6756', (244, 248))	('SSX1', 'Gene', (21, 25))	('SSX', 'Gene', (21, 24))	('SSX1', 'Gene', (244, 248))	('SSX', 'Gene', (244, 247))	('SSX', 'Gene', (268, 271))	('SSX1/2', 'Gene', (21, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('KDM2B antibodies', 'Var', (132, 148))	('MCF7', 'CellLine', 'CVCL:0031', (160, 164))	('SSX1/2', 'Gene', '6756;6757', (21, 27))	('synovial sarcoma', 'Disease', (94, 110))	('PLA signal', 'MPA', (61, 71))	('synovial sarcoma', 'Disease', 'MESH:D013584', (94, 110))	('SS18', 'Var', (123, 127))	('SSX', 'Gene', '6757', (21, 24))	('SSX', 'Gene', '6757', (244, 247))	('SSX', 'Gene', '6757', (268, 271))
527601	29502955	KDM2B co-immunoprecipitated with epitope-tagged versions of SSX1, but not SS18, in ectopic overexpression assays (Figure 5G), whereas deletion of the C-terminal SSX1 repressive domain (SSXRD) in the context of the SS18-SSX1 fusion abolished this interaction (Figure S4D).	('SSX', 'Gene', (219, 222))	('SSX1', 'Gene', '6756', (161, 165))	('SSX', 'Gene', '6757', (60, 63))	('SSX1', 'Gene', '6756', (219, 223))	('SSX1', 'Gene', (60, 64))	('SSX', 'Gene', (60, 63))	('SSX', 'Gene', '6757', (161, 164))	('SSX1', 'Gene', (161, 165))	('SSX', 'Gene', (161, 164))	('deletion', 'Var', (134, 142))	('SSX1', 'Gene', (219, 223))	('SSX', 'Gene', '6757', (185, 188))	('SSX', 'Gene', (185, 188))	('abolished', 'NegReg', (231, 240))	('SSX', 'Gene', '6757', (219, 222))	('interaction', 'Interaction', (246, 257))	('SSX1', 'Gene', '6756', (60, 64))
527608	29502955	Consistent with the ability of KDM2B to bind to and recruit proteins to CpG islands, SS18-SSX1 and KDM2B were bound predominantly to CpG-rich promoters (Figure 6C) and overlapped with annotated CGIs (Figure 6D, and Figure S5B) that are more hypomethylated in synovial sarcoma compared to normal fat or other sarcoma types (Figure 6E-F and Figure S5C).	('SSX1', 'Gene', (90, 94))	('S5B', 'Gene', (222, 225))	('sarcoma', 'Disease', (268, 275))	('sarcoma', 'Disease', 'MESH:D012509', (308, 315))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('S5B', 'Gene', '5711', (222, 225))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (259, 275))	('synovial sarcoma', 'Disease', 'MESH:D013584', (259, 275))	('KDM2B', 'Var', (99, 104))	('SSX1', 'Gene', '6756', (90, 94))	('sarcoma', 'Disease', (308, 315))	('sarcoma', 'Phenotype', 'HP:0100242', (308, 315))	('synovial sarcoma', 'Disease', (259, 275))	('sarcoma', 'Disease', 'MESH:D012509', (268, 275))
527615	29502955	Transcriptional profiling of synovial sarcoma cells expressing either SS18-SSX1 or KDM2B shRNAs revealed a strong correlation between genes that were highly bound by both SS18-SSX1 and KDM2B and whose expression was significantly repressed upon SS18-SSX1 knockdown (Figure S5F).	('synovial sarcoma', 'Disease', (29, 45))	('SSX1', 'Gene', (176, 180))	('knockdown', 'Var', (255, 264))	('SSX1', 'Gene', '6756', (75, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('SSX1', 'Gene', (250, 254))	('SSX1', 'Gene', (75, 79))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (29, 45))	('SSX1', 'Gene', '6756', (176, 180))	('synovial sarcoma', 'Disease', 'MESH:D013584', (29, 45))	('KDM2B', 'Var', (185, 190))	('KDM2B', 'Var', (83, 88))	('bound', 'Interaction', (157, 162))	('SSX1', 'Gene', '6756', (250, 254))
527618	29502955	Apparently, the SS18-SSX1/KDM2B collaboration produces the neural-like gene expression signature that is a hallmark of synovial sarcoma, and its disruption restores a more mesenchymal cell fate.	('SSX1', 'Gene', '6756', (21, 25))	('synovial sarcoma', 'Disease', (119, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('SSX1', 'Gene', (21, 25))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (119, 135))	('synovial sarcoma', 'Disease', 'MESH:D013584', (119, 135))	('more mesenchymal cell fate', 'CPA', (167, 193))	('disruption', 'Var', (145, 155))	('restores', 'PosReg', (156, 164))
527620	29502955	To test this hypothesis, we profiled SS18-SSX1 and BRG1 occupancy following either SS18-SSX1 or KDM2B knockdown.	('BRG1', 'Gene', '6597', (51, 55))	('SSX1', 'Gene', (88, 92))	('BRG1', 'Gene', (51, 55))	('SSX1', 'Gene', '6756', (42, 46))	('knockdown', 'Var', (102, 111))	('occupancy', 'MPA', (56, 65))	('SSX1', 'Gene', (42, 46))	('SSX1', 'Gene', '6756', (88, 92))
527621	29502955	As expected, SS18-SSX knockdown reduced the HA-SS18-SSX1 and BRG1 (i.e.	('reduced', 'NegReg', (32, 39))	('SSX', 'Gene', (18, 21))	('knockdown', 'Var', (22, 31))	('BRG1', 'Gene', (61, 65))	('SSX1', 'Gene', '6756', (52, 56))	('BRG1', 'Gene', '6597', (61, 65))	('SSX', 'Gene', '6757', (52, 55))	('SSX', 'Gene', '6757', (18, 21))	('SSX1', 'Gene', (52, 56))	('SSX', 'Gene', (52, 55))
527623	29502955	More importantly, KDM2B depletion also reduced SS18-SSX1 and BRG1 binding to loci co-occupied by SS18-SSX1/KDM2B but not loci bound by SS18-SSX1 alone (Figure 7A-C and Figure S7B-D).	('SSX1', 'Gene', '6756', (102, 106))	('SSX1', 'Gene', '6756', (140, 144))	('binding', 'Interaction', (66, 73))	('depletion', 'Var', (24, 33))	('SSX1', 'Gene', '6756', (52, 56))	('BRG1', 'Gene', (61, 65))	('SSX1', 'Gene', (102, 106))	('KDM2B depletion', 'Var', (18, 33))	('SSX1', 'Gene', (140, 144))	('reduced', 'NegReg', (39, 46))	('BRG1', 'Gene', '6597', (61, 65))	('SSX1', 'Gene', (52, 56))
527627	29502955	As predicted both SS18-SSX1 and KDM2B knockdown resulted in reduced ATAC-Seq signals at regions that were previously occupied by SS18-SSX1 (Figure 7E).	('SSX1', 'Gene', '6756', (23, 27))	('ATAC-Seq signals', 'MPA', (68, 84))	('SSX1', 'Gene', '6756', (134, 138))	('SSX1', 'Gene', (23, 27))	('reduced', 'NegReg', (60, 67))	('SSX1', 'Gene', (134, 138))	('KDM2B', 'Gene', (32, 37))	('knockdown', 'Var', (38, 47))
527629	29502955	Surprisingly, SS18-SSX1 and, to a lesser extent, KDM2B knockdown also produced increases in BRG1 signals at a series of new loci associated with genes involved in skeleton and muscle development, including several of the mesenchymal genes we previously noted as upregulated by SS18-SSX1 or KDM2B knockdown (e.g.	('knockdown', 'Var', (55, 64))	('SSX1', 'Gene', (19, 23))	('increases', 'PosReg', (79, 88))	('KDM2B knockdown', 'Var', (290, 305))	('BRG1', 'Gene', (92, 96))	('SSX1', 'Gene', '6756', (282, 286))	('mesenchymal genes', 'Gene', (221, 238))	('BRG1', 'Gene', '6597', (92, 96))	('upregulated', 'PosReg', (262, 273))	('SSX1', 'Gene', '6756', (19, 23))	('KDM2B knockdown', 'Var', (49, 64))	('SSX1', 'Gene', (282, 286))	('knockdown', 'Var', (296, 305))
527633	29502955	Consequently, KDM2B inhibition triggers cell cycle arrest and terminal differentiation by releasing SS18-SSX1 gene activation complexes and allowing the formation of a repressive chromatin environment at target loci.	('KDM2B', 'Gene', (14, 19))	('SSX1', 'Gene', (105, 109))	('arrest', 'Disease', 'MESH:D006323', (51, 57))	('inhibition', 'Var', (20, 30))	('arrest', 'Disease', (51, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (40, 57))	('releasing', 'PosReg', (90, 99))	('triggers', 'Reg', (31, 39))	('formation', 'MPA', (153, 162))	('allowing', 'Reg', (140, 148))	('terminal differentiation', 'CPA', (62, 86))	('SSX1', 'Gene', '6756', (105, 109))
527637	29502955	KDM2B inhibition reverses this program by releasing SS18-SSX1 from chromatin, thereby enabling target gene silencing, re-acquisition of a mesenchymal-like expression program, and irreversible proliferative arrest (Figure 8).	('KDM2B', 'Gene', (0, 5))	('SSX1', 'Gene', '6756', (57, 61))	('SSX1', 'Gene', (57, 61))	('releasing', 'PosReg', (42, 51))	('enabling', 'PosReg', (86, 94))	('mesenchymal-like expression program', 'CPA', (138, 173))	('arrest', 'Disease', (206, 212))	('inhibition', 'Var', (6, 16))	('arrest', 'Disease', 'MESH:D006323', (206, 212))
527647	29502955	We show that, in synovial sarcoma cells, SS18-SSX1 achieves the same end via an entirely different mechanism - by targeting KDM2B PRC1.1 complexes, the SS18-SSX1 fusion facilitates mislocalization of SWI/SNF complexes to polycomb target genes where, as previously described, it opposes polycomb-mediated repressive activity.	('SSX1', 'Gene', (46, 50))	('SSX1', 'Gene', '6756', (157, 161))	('synovial sarcoma', 'Disease', (17, 33))	('facilitates', 'PosReg', (169, 180))	('mislocalization', 'MPA', (181, 196))	('SSX1', 'Gene', (157, 161))	('SSX1', 'Gene', '6756', (46, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (17, 33))	('fusion', 'Var', (162, 168))	('synovial sarcoma', 'Disease', 'MESH:D013584', (17, 33))
527649	29502955	Our results do not rule out the possibility that altered SWI/SNF composition or gene repression mechanisms contribute to the oncogenic activity of SS18-SSX fusions.	('oncogenic activity', 'CPA', (125, 143))	('SSX', 'Gene', '6757', (152, 155))	('SSX', 'Gene', (152, 155))	('fusions', 'Var', (156, 163))
527652	29502955	Most of those genes were also occupied by BRG1 and KDM2B, though the magnitude of SS18-SSX1 binding was substantially reduced compared to targets that are directly activated by SS18-SSX1.	('binding', 'Interaction', (92, 99))	('BRG1', 'Gene', '6597', (42, 46))	('KDM2B', 'Var', (51, 56))	('reduced', 'NegReg', (118, 125))	('SSX1', 'Gene', '6756', (87, 91))	('SSX1', 'Gene', '6756', (182, 186))	('SSX1', 'Gene', (182, 186))	('BRG1', 'Gene', (42, 46))	('SSX1', 'Gene', (87, 91))
527653	29502955	Perhaps other factors such as transcription factor availability, alterations in the balance of PcG to SWI/SNF activity at particular loci, or increased accessibility to transcriptional repressors ultimately dictate the expression output at SS18-SSX1/2 target genes.	('alterations', 'Var', (65, 76))	('dictate', 'Reg', (207, 214))	('SSX1/2', 'Gene', (245, 251))	('SSX1/2', 'Gene', '6756;6757', (245, 251))	('expression output', 'MPA', (219, 236))
527663	29502955	Indeed, like KDM2B, other PRC1.1-specifc complex proteins BCOR and PCGF1 co-immunoprecipitate with SS18-SSX1, and their disruption phenocopies KDM2B loss on synovial sarcoma cell proliferation and cell fate.	('BCOR', 'Gene', (58, 62))	('KDM2B', 'Gene', (143, 148))	('PCGF1', 'Gene', (67, 72))	('synovial sarcoma', 'Disease', (157, 173))	('loss', 'NegReg', (149, 153))	('disruption', 'Var', (120, 130))	('PCGF1', 'Gene', '84759', (67, 72))	('BCOR', 'Gene', '63035', (58, 62))	('SSX1', 'Gene', '6756', (104, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (157, 173))	('SSX1', 'Gene', (104, 108))	('cell fate', 'CPA', (197, 206))	('synovial sarcoma', 'Disease', 'MESH:D013584', (157, 173))
527665	29502955	Additionally, in-frame internal tandem duplications (ITDs) in the PUFD domain of BCOR that interacts with PCGF1 have recently been found in up to 85% of pediatric clear cell sarcoma of the kidney and in a class of primitive neuroectodermal tumors (CNS-PNET).	('found', 'Reg', (131, 136))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (224, 246))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (174, 195))	('PCGF1', 'Gene', (106, 111))	('BCOR', 'Gene', '63035', (81, 85))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (174, 195))	('neuroectodermal tumors', 'Disease', (224, 246))	('PCGF1', 'Gene', '84759', (106, 111))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (224, 246))	('internal tandem duplications', 'Var', (23, 51))	('sarcoma of the kidney', 'Disease', (174, 195))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (214, 246))	('BCOR', 'Gene', (81, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
527666	29502955	The repercussions of these mutations on PRC1.1 complex activity are currently unknown, but their presence suggests that alterations in developmental programs controlled by this non-canonical complex broadly contribute to cancer and in particular, pediatric malignancies.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('pediatric malignancies', 'Disease', 'MESH:D063766', (247, 269))	('pediatric malignancies', 'Disease', (247, 269))	('contribute', 'Reg', (207, 217))	('cancer', 'Disease', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))
527675	29502955	Cells were maintained in a humidified incubator at 373 C with 5% CO2, grown in DMEM supplemented with 10% FBS and 1003IU/ml penicillin-streptomycin.	('streptomycin', 'Chemical', 'MESH:D013307', (135, 147))	('DMEM', 'Chemical', '-', (79, 83))	('FBS', 'Disease', 'MESH:D005198', (106, 109))	('1003IU/ml', 'Var', (114, 123))	('penicillin', 'Chemical', 'MESH:D010406', (124, 134))	('CO2', 'Chemical', '-', (65, 68))	('FBS', 'Disease', (106, 109))
527699	29502955	Using election criteria that required an shRNA depletion averaging greater than twofold at Tf, at least two shRNAs targeting the same gene and for scoring to be specific to M5SS1 cells, and not in C2C12, 14 shRNAs were identified (hSS18, KDM2B (FBXL10), BRD3, BRD7 and PADI4.	('FBXL10', 'Gene', '84678', (245, 251))	('hSS18', 'Gene', '6760', (231, 236))	('PADI4', 'Gene', '23569', (269, 274))	('KDM2B', 'Var', (238, 243))	('PADI4', 'Gene', (269, 274))	('C2C12', 'CellLine', 'CVCL:0188', (197, 202))	('FBXL10', 'Gene', (245, 251))	('BRD3', 'Gene', (254, 258))	('BRD7', 'Gene', (260, 264))	('BRD3', 'Gene', '8019', (254, 258))	('BRD7', 'Gene', '29117', (260, 264))	('hSS18', 'Gene', (231, 236))
527714	29502955	Synovial sarcoma cell lines were transduced with lentiCas9-Blast (Addgene #52962) and selected using 5ug/ml of blasticidin to generate stable Cas9-expressing cell lines.	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('lentiCas9-Blast', 'Var', (49, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('blasticidin', 'Chemical', 'MESH:C004500', (111, 122))
527720	29502955	For experiments using transient expression in 293T cells, gene fragments encoding HA tagged versions of SS18, SSX1 wild type versions, SS18-SSX1 C-terminal deletions mutants and GFP fusions, were cloned into EcoRI and XhoI sites in MSCV-puro or pLVX-puro plasmids.	('SSX1', 'Gene', '6756', (140, 144))	('mutants', 'Var', (166, 173))	('SSX1', 'Gene', '6756', (110, 114))	('293T', 'CellLine', 'CVCL:0063', (46, 50))	('SSX1', 'Gene', (140, 144))	('SSX1', 'Gene', (110, 114))	('MSCV', 'Species', '258023', (232, 236))	('SS18', 'Gene', (104, 108))
527732	29502955	The following antibodies were used for immunoblotting: beta-ACTIN (ac-15, Sigma), KDM2B (Millipore, 09-864) HA-tag (Cell Signaling, 3724) and Myc-tag (Cell Signaling, 2276).	('beta-ACTIN', 'Gene', (55, 65))	('KDM2B', 'Var', (82, 87))	('Myc', 'Gene', '4609', (142, 145))	('HA-tag', 'Var', (108, 114))	('beta-ACTIN', 'Gene', '728378', (55, 65))	('Myc', 'Gene', (142, 145))
527741	29502955	Sonicated lysates were centrifuged, and incubated overnight at 4 C with specific antibodies (BRG1 Abcam 110641; KDM2B Millipore 17-10264, HA-tag Abcam 9110; H3K27me3 Millipore 07-449).	('H3K27me3', 'Var', (157, 165))	('BRG1', 'Gene', (93, 97))	('BRG1', 'Gene', '6597', (93, 97))	('HA-tag', 'Var', (138, 144))
527750	29502955	Once ChIP-Seq peaks were identified from HA-SS18/SSX and H3K27me3 ChIP-Seq experiments with individual shRNA expression, all peaks were combined and merged if the maximum distance between peak centers were smaller than 100 bp.	('SSX', 'Gene', (49, 52))	('H3K27me3', 'Var', (57, 65))	('SSX', 'Gene', '6757', (49, 52))
527751	29502955	The peaks with lower than 50 tag counts of HA-SS18/SSX or H3K27me3 were excluded from further analyses, which finally yielded union peaks of HA-SS18-SSX (n=10,984) and H3K27me3 (n=13,226) ChIP-Seq experiments.	('SSX', 'Gene', (51, 54))	('H3K27me3', 'Var', (168, 176))	('SSX', 'Gene', '6757', (51, 54))	('SSX', 'Gene', '6757', (149, 152))	('SSX', 'Gene', (149, 152))
527753	29502955	If the normalized tag counts of KDM2B were lower than 20, they were considered as HA-SS18/SSX(+) KDM2B(-) regions (n=451), and, if not, considered as HA-SSX/SSX (+) KDM2B (+) regions (n=10,533).	('HA-SSX/SSX', 'Gene', '6757', (150, 160))	('SSX', 'Gene', '6757', (153, 156))	('SSX', 'Gene', (153, 156))	('KDM2B', 'Var', (32, 37))	('SSX', 'Gene', (157, 160))	('SSX', 'Gene', '6757', (157, 160))	('SSX', 'Gene', '6757', (90, 93))	('HA-SSX/SSX', 'Gene', (150, 160))	('SSX', 'Gene', (90, 93))	('lower', 'NegReg', (43, 48))
527769	29502955	Somatic gene fusions are hallmarks of soft tissue sarcomas but little is known about how they exert their oncogenic effects.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (38, 58))	('soft tissue sarcomas', 'Disease', (38, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (38, 58))	('Somatic gene fusions', 'Var', (0, 20))
527771	29502955	Accordingly, KDM2B inhibition recapitulates the consequences of SS18-SSX1 inhibition resulting in loss of the synovial sarcoma-specific gene signature and irreversible acquisition of mesenchymal-like features.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (110, 126))	('loss of the synovial sarcoma', 'Disease', (98, 126))	('inhibition', 'Var', (74, 84))	('loss of the synovial sarcoma', 'Disease', 'MESH:D013584', (98, 126))	('inhibition', 'Var', (19, 29))	('SSX1', 'Gene', '6756', (69, 73))	('acquisition', 'PosReg', (168, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('mesenchymal-like features', 'CPA', (183, 208))	('SSX1', 'Gene', (69, 73))
527946	26472273	Stereo versions with the median as reference base line are available as IMSLP MP3 files 15CHP192st, 16SHSY5Y192st, 17SIMA192st, and 18SKNMC192st.	('16SHSY5Y192st', 'Var', (100, 113))	('15CHP192st', 'Var', (88, 98))	('SKNMC192', 'CellLine', 'CVCL:0530', (134, 142))	('16SHSY5Y192', 'CellLine', 'CVCL:0019', (100, 111))
527970	26472273	The melodies are available as IMSLP MP3 files 28CD19aEx288, 29CD19bEx288, 30CD19cEx288, 31HDLM2Ex288, 32L428Ex288, 33L540Ex288, and 34MedHLEx288.	('33L540Ex288', 'Var', (115, 126))	('CD19', 'Gene', '930', (76, 80))	('CD19', 'Gene', '930', (62, 66))	('CD19', 'Gene', (48, 52))	('CD19', 'Gene', '930', (48, 52))	('31HDLM2Ex288', 'Var', (88, 100))	('HL', 'CellLine', 'CVCL:2492', (137, 139))	('32L428Ex288', 'Var', (102, 113))	('CD19', 'Gene', (62, 66))	('CD19', 'Gene', (76, 80))
527971	26472273	These versions are available as IMSLP MP3 files 35CD19aEx288st, 36CD19bEx288st, 37CD19cEx288st, 38HDLM2Ex288st, 39L428Ex288st, and 40L540Ex288st.	('CD19', 'Gene', '930', (66, 70))	('CD19', 'Gene', (50, 54))	('38HDLM2Ex288st', 'Var', (96, 110))	('39L428Ex288st', 'Var', (112, 125))	('CD19', 'Gene', '930', (50, 54))	('CD19', 'Gene', (82, 86))	('40L540Ex288st', 'Var', (131, 144))	('CD19', 'Gene', '930', (82, 86))	('CD19', 'Gene', (66, 70))
528001	25628840	Present study investigated that the IL36 gene therapy effects on the regression of tumor masses in mouse model.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mouse', 'Species', '10090', (99, 104))	('IL36', 'Gene', (36, 40))	('gene therapy', 'Var', (41, 53))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
528010	25628840	IL36 gene therapy has therapeutic effects on the regression of tumor masses in fibro sarcoma mouse model.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('sarcoma', 'Disease', (85, 92))	('regression', 'CPA', (49, 59))	('mouse', 'Species', '10090', (93, 98))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('IL36', 'Gene', (0, 4))	('gene therapy', 'Var', (5, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
528071	25628840	So gene therapy with IL36 has effect in the regression of tumor masses (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('gene therapy', 'Var', (3, 15))	('IL36', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('regression', 'CPA', (44, 54))
528074	25628840	The results of real-time PCR indicated that the expression of IL36 and IFN-gamma was enhanced in group treated with IL36 in comparison to the control group (Figure 3).	('IFN-gamma', 'Gene', '15978', (71, 80))	('IL36', 'Var', (116, 120))	('enhanced', 'PosReg', (85, 93))	('expression', 'MPA', (48, 58))	('IL36', 'Protein', (62, 66))	('IFN-gamma', 'Gene', (71, 80))
528075	25628840	The results of immunoblotting showed that the expression of IL36 and IFN-gamma was enhanced in group treated with IL36 in comparison to the control group (Figure 4).	('IFN-gamma', 'Gene', (69, 78))	('IL36', 'Gene', (60, 64))	('enhanced', 'PosReg', (83, 91))	('IFN-gamma', 'Gene', '15978', (69, 78))	('expression', 'MPA', (46, 56))	('IL36', 'Var', (114, 118))
528095	25628840	We demonstrated that the local IL36 gene delivery into tumor tissue is an immune response to the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('gene delivery', 'Var', (36, 49))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (97, 102))	('IL36', 'Gene', (31, 35))
528096	25628840	Therefore, gene delivery by Lipofectamine could be a useful non-viral vector system in cancer gene therapy.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('gene', 'Var', (11, 15))	('Lipofectamine', 'Chemical', 'MESH:C086724', (28, 41))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
528099	24596823	Though the most of the prominent mass was removed during surgery, there was massive bleeding due to tearing of internal iliac vein while dissecting the ureter close to vessels.	('tearing', 'Phenotype', 'HP:0009926', (100, 107))	('bleeding', 'Disease', 'MESH:D006470', (84, 92))	('tearing', 'Var', (100, 107))	('bleeding', 'Disease', (84, 92))	('iliac vein', 'Phenotype', 'HP:0009780', (120, 130))	('ureter close to vessels', 'Phenotype', 'HP:0012571', (152, 175))
528229	23689977	In agreement with these observations, previous research suggests that the mobilization of fatty acids may occur prior to the onset of weight loss, indicating that alterations in lipid metabolism are an important early event in the development of cachexia.	('alterations', 'Var', (163, 174))	('cachexia', 'Phenotype', 'HP:0004326', (246, 254))	('lipid', 'Chemical', 'MESH:D008055', (178, 183))	('fatty acids', 'Chemical', 'MESH:D005227', (90, 101))	('cachexia', 'Disease', 'MESH:D002100', (246, 254))	('weight loss', 'Phenotype', 'HP:0001824', (134, 145))	('cachexia', 'Disease', (246, 254))	('weight loss', 'Disease', 'MESH:D015431', (134, 145))	('mobilization of fatty acids', 'MPA', (74, 101))	('rat', 'Species', '10116', (167, 170))	('weight loss', 'Disease', (134, 145))
528280	23172349	The conditions that are assumed to be direct consequences of HIV/AIDS are: Kaposi's sarcoma, Burkitt's tumour, and any other malignant neoplasm of lymphoid, haematopoietic and related tissue, classifiable to C46 or C81-96; and any infectious diseases classifiable to A00-B19, B25-B49, B58-B64, B99 or J12-J18.	('B99', 'Gene', '51512', (294, 297))	('B19', 'Gene', '59271', (271, 274))	('J12-J18', 'Var', (301, 308))	('AIDS', 'Disease', 'MESH:D000163', (65, 69))	('HIV', 'Disease', 'MESH:D015658', (61, 64))	('infectious diseases', 'Disease', 'MESH:D003141', (231, 250))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('infectious diseases', 'Disease', (231, 250))	('B25-B49', 'Var', (276, 283))	('B19', 'Gene', (271, 274))	('HIV', 'Disease', (61, 64))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (75, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('B58-B64', 'Var', (285, 292))	("Burkitt's tumour", 'Phenotype', 'HP:0030080', (93, 109))	('malignant neoplasm of lymphoid', 'Disease', 'MESH:D008223', (125, 155))	('neoplasm of lymphoid', 'Phenotype', 'HP:0002665', (135, 155))	('malignant neoplasm of lymphoid', 'Disease', (125, 155))	("Burkitt's tumour", 'Disease', 'MESH:D002051', (93, 109))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (75, 91))	('AIDS', 'Disease', (65, 69))	('neoplasm', 'Phenotype', 'HP:0002664', (135, 143))	("Kaposi's sarcoma", 'Disease', (75, 91))	('B99', 'Gene', (294, 297))	("Burkitt's tumour", 'Disease', (93, 109))
528385	21044309	They identified mutated genes in cancer from their effect on connected sub-networks of differentially expressed genes.	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutated', 'Var', (16, 23))
528397	21044309	Delattre and colleagues showed that it is associated in more than 80% of cases with the t(11;22)(q24;q12) chromosomal translocation.	('associated', 'Reg', (42, 52))	('t(11;22)(q24;q12', 'Var', (88, 104))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (88, 105))
528405	21044309	In this paper, Ewing cells were profiled upon EWS-FLI1 knocked down (with retroviral-mediated RNAi EF-2-RNAi construct) and then rescued based on a tetracycline-inducible EWS-FLI1 cDNA.	('EWS-FLI1', 'Gene', '2130;2313', (46, 54))	('EWS-FLI1', 'Gene', (171, 179))	('tetracycline', 'Chemical', 'MESH:D013752', (148, 160))	('EWS-FLI1', 'Gene', '2130;2313', (171, 179))	('knocked', 'Var', (55, 62))	('EWS-FLI1', 'Gene', (46, 54))
528418	21044309	This set of significant variations was complemented with variations over non-transcriptional products, including the variation of EWS-FLI1 protein and variations of 'phenotypic' nodes (representing apoptosis, cell migration, cell cycle anaphase, -G2, -M and -S phases).	('cell cycle anaphase', 'CPA', (225, 244))	('-G2', 'CPA', (246, 249))	('apoptosis', 'CPA', (198, 207))	('EWS-FLI1', 'Gene', (130, 138))	('variation', 'Var', (117, 126))	('protein', 'Protein', (139, 146))	('EWS-FLI1', 'Gene', '2130;2313', (130, 138))	('cell migration', 'CPA', (209, 223))
528421	21044309	According to the Identification of significantly responding genes performed above, genes and proteins which are anti-correlated to EWS-FLI1 and are up-regulated upon the oncogene silencing have '+' as a sign of variation, while correlated genes and proteins have '-' as a sign of variation.	('EWS-FLI1', 'Gene', (131, 139))	("'+'", 'PosReg', (194, 197))	('EWS-FLI1', 'Gene', '2130;2313', (131, 139))	('up-regulated', 'PosReg', (148, 160))	('oncogene silencing', 'Var', (170, 188))	('silencing', 'Var', (179, 188))
528460	21044309	A discrepancy appeared since these new data suggest that IGFBP3 protein is induced upon silencing of EWS-FLI1.	('IGFBP3', 'Gene', '3486', (57, 63))	('EWS-FLI1', 'Gene', '2130;2313', (101, 109))	('silencing', 'Var', (88, 97))	('induced', 'PosReg', (75, 82))	('IGFBP3', 'Gene', (57, 63))	('protein', 'Protein', (64, 71))	('EWS-FLI1', 'Gene', (101, 109))
528469	21044309	In this case, the variation of the IGF2 protein must be '-', as it is stated in the prediction listing (see Table 2 and Additional file 5: Results of the constraint-based analysis).	('IGF2', 'Gene', (35, 39))	('IGF2', 'Gene', '3481', (35, 39))	('variation', 'Var', (18, 27))	('protein', 'Protein', (40, 47))
528475	21044309	The BioQuali analysis of the network with respect to this set of variations resulted in an inconsistent diagnosis, indicating that regulations are missing over IGF1 to explain the new set of observations.	('mis', 'Gene', (147, 150))	('IGF1', 'Gene', '3479', (160, 164))	('variations', 'Var', (65, 75))	('IGF1', 'Gene', (160, 164))	('mis', 'Gene', '268', (147, 150))
528492	20532208	Our analysis furthermore demonstrates that such patterns are not characterized by the absence of activating histone modifications, as H3K9/K14-ac and H3K4-me3 marks were prominently detected at several loci, including the promoter of the lytic cycle transactivator Rta.	('K14', 'Gene', '3861', (139, 142))	('H3K4-me3 marks', 'Var', (150, 164))	('K14', 'Gene', (139, 142))
528506	20532208	Furthermore, the ORF50 promoter was reported to be subject to DNA methylation in latently infected PEL cells whereas the latent ORF73 promoter remained unmethylated, and it has therefore been suggested that CpG methylation may actively repress Rta expression during latency.	('Rta', 'Gene', (244, 247))	('methylation', 'Var', (211, 222))	('PEL', 'Phenotype', 'HP:0030069', (99, 102))	('ORF73', 'Gene', (128, 133))	('expression', 'MPA', (248, 258))	('ORF50', 'Gene', '4961526', (17, 22))	('repress', 'NegReg', (236, 243))	('ORF73', 'Gene', '4961527', (128, 133))	('ORF50', 'Gene', (17, 22))
528514	20532208	However, concomitant with the appearance of these modifications, latent genomes were also subject to profound tri-methylation of lysine 27 of histone H3 (H3K27), a modification which can suppress transcription even in the presence of activating marks.	('transcription', 'MPA', (196, 209))	('suppress', 'NegReg', (187, 195))	('tri-methylation', 'MPA', (110, 125))	('modifications', 'Var', (50, 63))	('lysine', 'Chemical', 'MESH:D008239', (129, 135))
528515	20532208	In mammals, DNA methylation occurs almost exclusively by methylation of cytidine residues at CpG dinucleotides and is generally associated with transcriptional repression (reviewed in).	('methylation', 'Var', (57, 68))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (93, 110))	('associated', 'Reg', (128, 138))	('transcriptional', 'MPA', (144, 159))	('cytidine', 'Chemical', 'MESH:D003562', (72, 80))
528522	20532208	As promoter activity was furthermore repressed by DNA methylation in an in vitro assay, it was suggested that CpG methylation actively suppresses expression of the lytic switch gene Rta during KSHV latency.	('suppresses', 'NegReg', (135, 145))	('Rta', 'Gene', (182, 185))	('KSHV', 'Species', '37296', (193, 197))	('KS', 'Phenotype', 'HP:0100726', (193, 195))	('methylation', 'Var', (114, 125))	('expression', 'MPA', (146, 156))
528537	20532208	127301 to 128901, harbors the major latency promoter upstream of ORF73.	('ORF73', 'Gene', '4961527', (65, 70))	('127301', 'Var', (0, 6))	('ORF73', 'Gene', (65, 70))
528552	20532208	The recognition sequence of TaqI contains a CpG motif, and as only methylated cytosine residues are preserved during bisulfite conversion, absence of DNA methylation at the restriction site leads to TaqI resistance.	('absence', 'Var', (139, 146))	('cytosine', 'Chemical', 'MESH:D003596', (78, 86))	('CpG motif', 'MPA', (44, 53))	('bisulfite', 'Chemical', 'MESH:C042345', (117, 126))	('leads to', 'Reg', (190, 198))	('TaqI resistance', 'MPA', (199, 214))
528563	20532208	The results clearly confirmed our MeDIP results and revealed near complete CpG methylation of the ORF50 promoter region in the HBL6 line, but no or only sporadic methylation in all other cells.	('ORF50', 'Gene', '4961526', (98, 103))	('ORF50', 'Gene', (98, 103))	('methylation', 'Var', (79, 90))
528578	20532208	Interestingly, while the highest density of CpG motifs within the KSHV genome is found at the terminal repeats (TR, see rightmost region of the KSHV map), this is also the region which showed the highest levels of H3K9/K14-ac and H3K4-me3 enrichment.	('KS', 'Phenotype', 'HP:0100726', (66, 68))	('KSHV', 'Species', '37296', (66, 70))	('K14', 'Gene', '3861', (219, 222))	('H3K4-me3', 'Var', (230, 238))	('KS', 'Phenotype', 'HP:0100726', (144, 146))	('K14', 'Gene', (219, 222))	('KSHV', 'Species', '37296', (144, 148))
528583	20532208	Therefore, we analyzed two modifications commonly associated with silent chromatin: Tri-methylation of lysine 9 of histone H3 (H3K9-me3), which is a hallmark of constitutive heterochromatin, and tri-methylation of lysine 27 (H3K27-me3), a modification which is typically seen in facultative heterochromatin.	('H3K27-me3', 'Gene', (225, 234))	('lysine', 'Chemical', 'MESH:D008239', (214, 220))	('tri-methylation', 'Var', (195, 210))	('lysine', 'Chemical', 'MESH:D008239', (103, 109))	('Tri-methylation', 'MPA', (84, 99))
528584	20532208	33000 to 46000 (ORF19-ORF25) and 100400 to 114400 (ORF64- ORF67).	('ORF19', 'Gene', (16, 21))	('100400 to 114400', 'Var', (33, 49))	('ORF19', 'Gene', '79783', (16, 21))
528585	20532208	While the H3K9-me3 modification was most prominently detected in BCBL1 cells, SLKp cells did display a markedly less distinct pattern, and the modification was barely detectable in SLK-5dpi cultures.	('SLK', 'Gene', '9748', (78, 81))	('SLK', 'Gene', (78, 81))	('SLK', 'Gene', '9748', (181, 184))	('H3K9-me3', 'Var', (10, 18))	('SLK', 'Gene', (181, 184))
528588	20532208	H3K27 tri-methylation is carried out by EZH2, the enzymatic subunit of the polycomb PRC2 complex, leading to the recruitment of polycomb PRC1 complexes and thus gene silencing.	('PRC1', 'Gene', '9055', (137, 141))	('recruitment', 'PosReg', (113, 124))	('gene', 'MPA', (161, 165))	('H3K27', 'Var', (0, 5))	('PRC1', 'Gene', (137, 141))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))
528589	20532208	Tri-methylation of H3K27 has been shown to play important roles in developmental and differentiation processes, cell cycle regulation, mammalian X chromosome inactivation, stem cell identity and cancer.	('Tri-methylation', 'Var', (0, 15))	('cell cycle regulation', 'CPA', (112, 133))	('mammalian', 'Species', '9606', (135, 144))	('play', 'Reg', (43, 47))	('cancer', 'Disease', (195, 201))	('H3K27', 'Protein', (19, 24))	('stem cell identity', 'CPA', (172, 190))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('roles', 'Reg', (58, 63))	('mammalian X chromosome', 'CPA', (135, 157))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
528590	20532208	As shown at the top of each panel in Figure 7, our analysis revealed that latent KSHV episomes in the BCBL1 and SLKp lines as well as SLK-5dpi cells were subject to abundant H3K27 tri-methylation.	('KSHV', 'Gene', (81, 85))	('tri-methylation', 'Var', (180, 195))	('SLK', 'Gene', '9748', (112, 115))	('episomes', 'Var', (86, 94))	('SLK', 'Gene', (112, 115))	('H3K27', 'Protein', (174, 179))	('SLK', 'Gene', '9748', (134, 137))	('SLK', 'Gene', (134, 137))	('KS', 'Phenotype', 'HP:0100726', (81, 83))	('KSHV', 'Species', '37296', (81, 85))
528591	20532208	The modification was detected virtually across the complete genome, although most regions which had been found enriched in H3K9/K14-ac and H3K4-me3 modifications tended to be tri-methylated at H3K27 to a lesser extend (compare with Figure 6, see also correlation coefficients in Table 1).	('K14', 'Gene', (128, 131))	('tri-methylated', 'MPA', (175, 189))	('K14', 'Gene', '3861', (128, 131))	('modifications', 'Var', (148, 161))
528593	20532208	Importantly, in contrast to H3K9-me3, the H3K27-me3 patterns were already present 5 days after de novo infection of SLK cultures.	('infection', 'Disease', (103, 112))	('infection', 'Disease', 'MESH:D007239', (103, 112))	('SLK', 'Gene', '9748', (116, 119))	('H3K27-me3', 'Var', (42, 51))	('SLK', 'Gene', (116, 119))
528597	20532208	As all of the KSHV-infected lines investigated here contain multiple copies of the viral episome, it may appear possible that the simultaneous detection of activating marks and the H3K27-me3 modification could be due to the existence of distinct, but separate episome populations.	('KSHV-infected', 'Disease', 'MESH:C537372', (14, 27))	('KSHV-infected', 'Disease', (14, 27))	('H3K27-me3', 'Var', (181, 190))	('KS', 'Phenotype', 'HP:0100726', (14, 16))
528608	20532208	In order to investigate whether a reduction of H3K27-me3 also results in an increase of the number of lytically reactivated cells in the absence of chemical inducers, we next generated BCBL1 and SLK cells which were stably transduced with a retrovirus that expresses the H3K27-me3-specific demethylase JMJD3.	('JMJD3', 'Gene', '23135', (302, 307))	('H3K27-me3', 'Var', (47, 56))	('SLK', 'Gene', '9748', (195, 198))	('reduction', 'NegReg', (34, 43))	('JMJD3', 'Gene', (302, 307))	('SLK', 'Gene', (195, 198))
528622	20532208	Whatever the mode of deposition, loci with lower levels of H3K27-me3 are ultimately confined to those regions which carry activating H3K9/K14-ac and H3K4-me3 marks which, clearly, are present not only on latency promoters.	('activating', 'PosReg', (122, 132))	('K14', 'Gene', (138, 141))	('H3K27-me3', 'Var', (59, 68))	('K14', 'Gene', '3861', (138, 141))	('H3K4-me3', 'Var', (149, 157))
528626	20532208	The onset of widespread H3K27 methylation then may lead to the silencing of the ORF50 promoter, establishing a poised state of repression which can be easily reverted upon reactivation.	('ORF50', 'Gene', (80, 85))	('methylation', 'Var', (30, 41))	('silencing', 'MPA', (63, 72))	('lead to', 'Reg', (51, 58))	('poised state', 'MPA', (111, 123))	('H3K27', 'Protein', (24, 29))	('ORF50', 'Gene', '4961526', (80, 85))
528627	20532208	In contrast to DNA methylation or polycomb-associated H3K27-me3 marks, H3K9/K14-ac and H3K4-me3 modifications are therefore not considered inheritable (and, therefore in a strict sense also do not represent epigenetic modifications).	('K14', 'Gene', (76, 79))	('H3K4-me3', 'Var', (87, 95))	('K14', 'Gene', '3861', (76, 79))
528628	20532208	Thus, even if Rta is indeed responsible for the initial establishment of H3K27-me3 and H3K9/K14-ac marks, due to its rapid eradication upon establishment of latent expression patterns it cannot be responsible for their long-term maintenance.	('K14', 'Gene', '3861', (92, 95))	('K14', 'Gene', (92, 95))	('H3K27-me3', 'Var', (73, 82))
528629	20532208	There are, however, also a few loci which are rich in H3K9/K14-ac and H3K4-me3 marks, but display very little H3K27 tri-methylation or DNA methylation.	('DNA methylation', 'MPA', (135, 150))	('K14', 'Gene', (59, 62))	('H3K27', 'Protein', (110, 115))	('K14', 'Gene', '3861', (59, 62))	('tri-methylation', 'Var', (116, 131))	('H3K4-me3', 'Var', (70, 78))
528630	20532208	These include not only the constitutively active latency promoter upstream of ORF73 as well as the locus encoding the KSHV miRNA-cluster, but also ORFs K5/K6/K7/nut-1, the region upstream of three of the four vIRFs (vIRF1/K9, vIRF-3 and vIRF-4) and the complete K15 gene region at the right end of the viral genome.	('vIRF-4', 'Gene', '4961495', (237, 243))	('ORF73', 'Gene', '4961527', (78, 83))	('vIRF-4', 'Gene', (237, 243))	('vIRF1/K9, vIRF-3', 'Gene', '4961464;4961493', (216, 232))	('KS', 'Phenotype', 'HP:0100726', (118, 120))	('K15', 'Gene', '4961473', (262, 265))	('KSHV', 'Species', '37296', (118, 122))	('ORF73', 'Gene', (78, 83))	('ORFs K5/K6/K7/nut-1', 'Var', (147, 166))	('K15', 'Gene', (262, 265))
528636	20532208	If continuous transcriptional initiation is required to maintain H3K9/K14-ac and H3K4-me3 marks, then additional factors may exist which stall RNA polymerase II at these loci.	('K14', 'Gene', (70, 73))	('RNA polymerase II', 'Enzyme', (143, 160))	('K14', 'Gene', '3861', (70, 73))	('H3K4-me3 marks', 'Var', (81, 95))
528642	20532208	With regard to PEL cells, more lines will have to be studied to conclude whether absence or presence of methylation marks at the ORF50 promoter has an impact on the percentage of spontaneously reactivated cells and/or the response of such lines to chemical agents which induce the lytic cycle.	('ORF50', 'Gene', '4961526', (129, 134))	('response', 'MPA', (222, 230))	('PEL', 'Phenotype', 'HP:0030069', (15, 18))	('ORF50', 'Gene', (129, 134))	('spontaneously reactivated cells', 'CPA', (179, 210))	('impact', 'Reg', (151, 157))	('methylation marks', 'Var', (104, 121))
528644	20532208	It is thus very conceivable that DNA methylation may represent an additional, functionally important block which augments repressive histone marks and re-inforces latent expression patterns during long-term latency in vivo, but which may be of lesser consequence in in vitro models of viral infection.	('augments', 'NegReg', (113, 121))	('methylation', 'Var', (37, 48))	('latent expression patterns', 'MPA', (163, 189))	('viral infection', 'Disease', 'MESH:D001102', (285, 300))	('repressive histone marks', 'MPA', (122, 146))	('viral infection', 'Disease', (285, 300))
528667	20532208	After bisulfite conversion, the site is only preserved if the original CpG motif was methylated (note that the bisulfite conversion creates additional TaqI sites at methylated CpG motifs which are flanked by C and A residues, as the C in position -1 is converted to a T by the bisulfite reaction).	('bisulfite', 'Chemical', 'MESH:C042345', (277, 286))	('CpG', 'Gene', (176, 179))	('bisulfite', 'Chemical', 'MESH:C042345', (6, 15))	('methylated', 'Var', (165, 175))	('bisulfite', 'Chemical', 'MESH:C042345', (111, 120))
528672	20532208	Material from 1x106 cells was pre-cleared with salmon-sperm DNA protein-A agarose beads (Upstate) to reduce non-specific background and subjected to immunoprecipitation using 2 to 10 microg of antibodies specific for the histone modifications H3K9/K14-Ac (Upstate: #06-599), H3K4-me3 (Upstate: #04-745), H3K9-me3 (Upstate: #17-625) or H3K27-me3 (Upstate: #07-449).	('K14', 'Gene', (248, 251))	('agarose', 'Chemical', 'MESH:D012685', (74, 81))	('H3K27-me3', 'Var', (335, 344))	('H3K9-me3', 'Var', (304, 312))	('K14', 'Gene', '3861', (248, 251))	('H3K4-me3', 'Var', (275, 283))
528691	20532208	500 ng of MeDIP-input or ChIP-input controls, 500 ng of immunoprecipitated ChIP material and all of the MeDIP material were labeled with Cy3 and Cy5 using Agilent Genomic DNA Labeling Kit PLUS according to Agilent's recommendations.	('Cy5', 'Chemical', 'MESH:C085321', (145, 148))	('Cy3', 'Var', (137, 140))	('Cy5', 'Var', (145, 148))	('Cy3', 'Chemical', '-', (137, 140))
528705	26349414	In addition, more recent exploitation of advances in stem cell and developmental biology has provided key insights into the cellular origins of ES and the role of epigenetic deregulation in tumor initiation and maintenance.	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor initiation', 'Disease', 'MESH:D009369', (190, 206))	('ES', 'Phenotype', 'HP:0012254', (144, 146))	('tumor initiation', 'Disease', (190, 206))	('epigenetic deregulation', 'Var', (163, 186))
528717	26349414	In ~85-90% of ES cases, a somatic reciprocal t(11;22)(q24;q12) chromosomal translocation is observed that fuses EWSR1 to the FLI1 ETS family gene to generate EWSR1-FLI1 fusion transcripts.	('ES', 'Phenotype', 'HP:0012254', (14, 16))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (45, 62))	('fuses', 'Var', (106, 111))	('EWS', 'Gene', '2130', (112, 115))	('EWS', 'Gene', (112, 115))	('EWS', 'Gene', '2130', (158, 161))	('EWS', 'Gene', (158, 161))
528721	26349414	In addition to such FET-ETS gene fusions, cases of so-called "ES-like" tumors are described in which EWS is fused to non-ETS proteins, and others that contain translocations without similarity to EWS-based fusions, such the t(4;19)(q35;q13) generated CIC-DUX4 fusion.	('ES', 'Phenotype', 'HP:0012254', (62, 64))	('EWS-', 'Gene', (196, 200))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (224, 240))	('t(4;19)(q35;q13', 'Var', (224, 239))	('CIC-DUX4', 'Chemical', '-', (251, 259))	('EWS', 'Gene', (101, 104))	('EWS', 'Gene', '2130', (101, 104))	('EWS-', 'Gene', '2130', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', (71, 77))	('EWS', 'Gene', '2130', (196, 199))	('EWS', 'Gene', (196, 199))	('CIC-DUX4 fusion', 'MPA', (251, 266))
528725	26349414	Fluorescence in situ hybridization (FISH) using an EWS "break-apart" probe or dual color EWS and FLI1 probes is also utilized, but must take into account other EWS-rearranged tumors, such as desmoplastic round cell tumor, myxoid chondrosarcomas, myxoid liposarcoma, or clear cell sarcoma Given the above variant fusions, the absence of molecular confirmation of EWS-FLI1 and EWS-ERG fusions may not rule out the diagnosis of ES.	('tumors', 'Disease', (175, 181))	('EWS', 'Gene', (51, 54))	('EWS', 'Gene', (375, 378))	('sarcoma', 'Disease', 'MESH:D012509', (236, 243))	('desmoplastic round cell tumor', 'Disease', 'MESH:D058405', (191, 220))	('EWS-', 'Gene', (362, 366))	('variant', 'Var', (304, 311))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('EWS', 'Gene', (89, 92))	('liposarcoma', 'Phenotype', 'HP:0012034', (253, 264))	('sarcoma', 'Disease', (236, 243))	('EWS-FLI1', 'Gene', (362, 370))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('EWS-', 'Gene', '2130', (160, 164))	('EWS-', 'Gene', '2130', (375, 379))	('EWS', 'Gene', '2130', (362, 365))	('EWS', 'Gene', (160, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (236, 244))	('sarcoma', 'Disease', 'MESH:D012509', (257, 264))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (246, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('EWS', 'Gene', '2130', (51, 54))	('EWS', 'Gene', '2130', (375, 378))	('sarcoma', 'Disease', (257, 264))	('sarcoma', 'Disease', 'MESH:D012509', (280, 287))	('EWS-FLI1', 'Gene', '2130;2313', (362, 370))	('myxoid liposarcoma', 'Disease', (246, 264))	('EWS-', 'Gene', (375, 379))	('sarcoma', 'Disease', (280, 287))	('ES', 'Phenotype', 'HP:0012254', (425, 427))	('EWS-', 'Gene', (160, 164))	('EWS', 'Gene', '2130', (89, 92))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (222, 244))	('myxoid chondrosarcomas', 'Disease', (222, 244))	('desmoplastic round cell tumor', 'Disease', (191, 220))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('EWS-', 'Gene', '2130', (362, 366))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (246, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('is a', 'Gene', (109, 113))	('EWS', 'Gene', (362, 365))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (229, 244))	('EWS', 'Gene', '2130', (160, 163))	('is a', 'Gene', '312', (109, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (280, 287))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
528726	26349414	Additional chromosomal abnormalities in ES include gains of chromosome 8 in up to 50% of cases, chromosome 12 and 1q gains in 25%, gains in chromosome 20 in 10-20%, and 1p36 losses.	('chromosome 12', 'Gene', (96, 109))	('gains', 'PosReg', (51, 56))	('chromosome', 'Gene', (60, 70))	('chromosomal abnormalities', 'Disease', (11, 36))	('losses', 'NegReg', (174, 180))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (11, 36))	('ES', 'Phenotype', 'HP:0012254', (40, 42))	('gains', 'Var', (131, 136))	('1p36', 'Gene', (169, 173))	('gains', 'PosReg', (117, 122))
528728	26349414	Finally, mutations in TP53 and CDKN2A are detected in 10-20% of cases and may be associated with aggressive disease.	('associated with', 'Reg', (81, 96))	('aggressive disease', 'Disease', (97, 115))	('mutations', 'Var', (9, 18))	('CDKN2A', 'Gene', (31, 37))	('aggressive disease', 'Disease', 'MESH:D001523', (97, 115))	('TP53', 'Gene', (22, 26))	('detected', 'Reg', (42, 50))
528730	26349414	EWS-ETS chimeric proteins are oncogenic in NIH3T3 fibroblasts  and function as aberrant transcription factors binding to ETS consensus sequences of target genes.	('chimeric', 'Var', (8, 16))	('EWS-', 'Gene', (0, 4))	('binding', 'Interaction', (110, 117))	('EWS-', 'Gene', '2130', (0, 4))	('NIH3T3', 'CellLine', 'CVCL:0594', (43, 49))
528731	26349414	Among early reported targets of EWS-ETS mediated transcriptional activation are stromelysin 1, cytochrome P-450 F1, cytokeratin 15, manic fringe, E2-C, Id2, PIM3, uridine phosphorylase, and p21WAF1/CIP1.	('manic', 'Disease', (132, 137))	('manic', 'Disease', 'MESH:D001714', (132, 137))	('manic', 'Phenotype', 'HP:0100754', (132, 137))	('EWS-', 'Gene', '2130', (32, 36))	('EWS-', 'Gene', (32, 36))	('p21WAF1/CIP1', 'Var', (190, 202))
528736	26349414	Another mechanism of IGF pathway deregulation in ES appears to be through EWS-FLI1 repression of microRNAs that otherwise negatively regulate the expression of IGF1 and the IGF1 receptor (IGF1R).	('repression', 'NegReg', (83, 93))	('ES', 'Phenotype', 'HP:0012254', (49, 51))	('EWS-FLI1', 'Gene', (74, 82))	('regulate', 'Reg', (133, 141))	('IGF pathway', 'Pathway', (21, 32))	('deregulation', 'Var', (33, 45))	('IGF1R', 'Gene', (188, 193))	('IGF1', 'Gene', (160, 164))	('EWS-FLI1', 'Gene', '2130;2313', (74, 82))	('negatively', 'NegReg', (122, 132))	('expression', 'MPA', (146, 156))
528741	26349414	Coordinated regulation of gene expression via epigenetic mechanisms is essential for normal development and these regulatory elements are frequently disturbed in both adult and pediatric tumors.	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('pediatric tumors', 'Disease', 'MESH:D063766', (177, 193))	('epigenetic', 'Var', (46, 56))	('pediatric tumors', 'Disease', (177, 193))	('disturbed', 'Reg', (149, 158))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
528744	26349414	EZH2 represses transcription by methylating histone 3 at lysine residue 27 (H3K27me3) and alterations in H3K27me3 promote oncogenesis.	('alterations', 'Var', (90, 101))	('me3', 'Gene', '10873', (110, 113))	('me3', 'Gene', (110, 113))	('oncogenesis', 'CPA', (122, 133))	('lysine', 'Chemical', 'MESH:D008239', (57, 63))	('me3', 'Gene', '10873', (81, 84))	('me3', 'Gene', (81, 84))	('transcription', 'MPA', (15, 28))	('promote', 'PosReg', (114, 121))
528746	26349414	The net effect of these polycombdependent modifications is repression of differentiation and maintenance of stemness, two driving forces in the process of malignant transformation.	('modifications', 'Var', (42, 55))	('differentiation', 'CPA', (73, 88))	('stemness', 'Disease', 'MESH:D020295', (108, 116))	('stemness', 'Disease', (108, 116))	('repression', 'NegReg', (59, 69))
528752	26349414	LSD1 is over-expressed by ES and inhibition of LSD1 in ES by genetic or pharmacologic means results in de-repression of EWS-ETS-suppressed genes and inhibition of tumorigenicity.	('inhibition', 'Var', (33, 43))	('EWS-', 'Gene', (120, 124))	('inhibition', 'NegReg', (149, 159))	('ES', 'Phenotype', 'HP:0012254', (55, 57))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('EWS-', 'Gene', '2130', (120, 124))	('de-repression', 'NegReg', (103, 116))	('tumor', 'Disease', (163, 168))	('LSD1', 'Gene', (47, 51))	('ES', 'Phenotype', 'HP:0012254', (26, 28))
528753	26349414	Interestingly, LSD1 inhibition also leads to down-regulation of EWS-FLI1-induced genes demonstrating the complex interplay between chromatin activating and chromatin repressive marks and revealing the central role that EWS-ETS proteins play in disrupting this balance.	(', LSD', 'Gene', '1776', (13, 18))	('inhibition', 'Var', (20, 30))	('EWS-FLI1', 'Gene', (64, 72))	('EWS-', 'Gene', (219, 223))	('EWS-FLI1', 'Gene', '2130;2313', (64, 72))	('EWS-', 'Gene', '2130', (64, 68))	('EWS-', 'Gene', '2130', (219, 223))	('down-regulation', 'NegReg', (45, 60))	('EWS-', 'Gene', (64, 68))
528756	26349414	Studies of chromatin structure in ES cells as well as EWS-FLI1 transduced endothelial cells revealed that the fusion can alter nucleosome occupancy, especially in regions adjacent to its own binding sites.	('nucleosome occupancy', 'MPA', (127, 147))	('EWS-FLI1', 'Gene', (54, 62))	('EWS-FLI1', 'Gene', '2130;2313', (54, 62))	('fusion', 'Var', (110, 116))	('alter', 'Reg', (121, 126))	('ES', 'Phenotype', 'HP:0012254', (34, 36))
528779	26349414	mutations or structural variations) may occur after the metastatic clones have migrated from the primary tumor.	('structural variations', 'Var', (13, 34))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutations', 'Var', (0, 9))	('tumor', 'Disease', (105, 110))
528780	26349414	This has major implications for precision medicine, as actionable mutations identified in primary tumors may have no relevance to metastasis, the major cause of death in that patient population.	('mutations', 'Var', (66, 75))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('patient', 'Species', '9606', (175, 182))	('primary tumors', 'Disease', (90, 104))	('metastasis', 'CPA', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('primary tumors', 'Disease', 'MESH:D009369', (90, 104))
528788	26349414	In addition, ERBB4 overexpression enhanced migration and invasion of ES cells in vitro and increased lung metastases in vivo.	('invasion', 'CPA', (57, 65))	('enhanced', 'PosReg', (34, 42))	('ERBB4', 'Gene', '2066', (13, 18))	('ES', 'Phenotype', 'HP:0012254', (69, 71))	('lung metastases', 'Disease', (101, 116))	('lung metastases', 'Disease', 'MESH:D009362', (101, 116))	('ERBB4', 'Gene', (13, 18))	('overexpression', 'Var', (19, 33))	('migration', 'CPA', (43, 52))	('increased', 'PosReg', (91, 100))
528807	26349414	With respect to targeting the aforementioned downstream hubs of EWS-ETS action, early preclinical studies with inhibitors of LSD1, HDAC, and DNA methyltransferases, suggest that targeting epigenetic deregulation will provide therapeutic benefit.	('epigenetic deregulation', 'Var', (188, 211))	('EWS-', 'Gene', (64, 68))	('EWS-', 'Gene', '2130', (64, 68))	('LSD1', 'Gene', (125, 129))
528808	26349414	In addition, epigenetic instability and evolution of cell lines in culture can result in considerable biologic drift that can mask or even erase key physiologic features of the primary tumor.	('tumor', 'Disease', (185, 190))	('epigenetic instability', 'Var', (13, 35))	('biologic', 'MPA', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('mask', 'NegReg', (126, 130))	('key physiologic features', 'MPA', (145, 169))	('erase', 'NegReg', (139, 144))	('result in', 'Reg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
528834	25688366	The chromosomal translocations that result in the fusion of the amino transactivation domain of TET proteins with the DNA-binding domain of ETS-related transcription factor proteins are the common determinants of cancer.	('TET', 'Chemical', '-', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('fusion', 'Var', (50, 56))	('cancer', 'Disease', (213, 219))
528835	25688366	Modulation of EWS/FLI1 expression is a therapeutic goal that may influence the course of the disease.	('Modulation', 'Var', (0, 10))	('course', 'MPA', (79, 85))	('FLI', 'Gene', '2314', (18, 21))	('influence', 'Reg', (65, 74))	('FLI', 'Gene', (18, 21))	('EWS', 'Phenotype', 'HP:0012254', (14, 17))
528843	25688366	The EWS gene is target of tumor-specific chromosomal translocations in Ewing's sarcoma family of tumours, myxoid liposarcoma, malignant melanoma of soft parts, desmoplastic small round cell tumor, small round cell sarcoma, acute leukaemia, extraskeletal myxoid chondrosarcoma, and others (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('acute leukaemia', 'Phenotype', 'HP:0002488', (223, 238))	('myxoid liposarcoma', 'Disease', (106, 124))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (254, 275))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (160, 195))	('desmoplastic small round cell tumor', 'Disease', (160, 195))	('EWS', 'Phenotype', 'HP:0012254', (4, 7))	('chromosomal translocations', 'Var', (41, 67))	('tumours', 'Disease', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('myxoid chondrosarcoma', 'Disease', (254, 275))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (106, 124))	('malignant melanoma of soft parts', 'Disease', 'MESH:D008545', (126, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('malignant melanoma', 'Phenotype', 'HP:0002861', (126, 144))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (71, 86))	('tumours', 'Disease', 'MESH:D009369', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('malignant melanoma of soft parts', 'Disease', (126, 158))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (261, 275))	('liposarcoma', 'Phenotype', 'HP:0012034', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('acute leukaemia', 'Disease', 'MESH:D007938', (223, 238))	('acute leukaemia', 'Disease', (223, 238))	('small round cell sarcoma', 'Disease', (197, 221))	('EWS', 'Gene', (4, 7))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (106, 124))
528848	25688366	The EWS/ATF1 fusion protein in soft tissue clear cell sarcoma is composed of the EAD (residues 1-325), fused to the C-terminal region of ATF1 (residues 66-271).	('clear cell sarcoma', 'Disease', (43, 61))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (43, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('residues 1-325', 'Var', (86, 100))	('EWS', 'Phenotype', 'HP:0012254', (4, 7))
528870	25688366	ESFT cells express the histone acetyl transferases PCAF, CBP, and p300.	('CBP', 'Gene', (57, 60))	('PCAF', 'Gene', (51, 55))	('p300', 'Var', (66, 70))	('PCAF', 'Gene', '8850', (51, 55))
528871	25688366	The CTD of EWS/FLI1 is acetylated by CBP, PCAF, and P300: four lysines are major sites for acetylation (K240, K252, K380, and K397), thus modulating its function.	('lysines', 'Chemical', 'MESH:D008239', (63, 70))	('K252', 'Var', (110, 114))	('function', 'MPA', (153, 161))	('modulating', 'Reg', (138, 148))	('P300', 'Gene', '2033', (52, 56))	('K240', 'Var', (104, 108))	('EWS', 'Phenotype', 'HP:0012254', (11, 14))	('K397', 'Var', (126, 130))	('K380', 'Var', (116, 120))	('P300', 'Gene', (52, 56))
528887	25688366	EWS/FLI1 protein-protein interaction partners in transcription are hsRBP7, RHA, BARD1, C-JUN, SAP1a, and CBP/p300.	('BARD1', 'Gene', (80, 85))	('interaction', 'Interaction', (25, 36))	('CBP/p300', 'Var', (105, 113))	('C-JUN', 'Gene', '3725', (87, 92))	('protein-protein', 'Protein', (9, 24))	('EWS', 'Phenotype', 'HP:0012254', (0, 3))	('hsRBP7', 'Gene', (67, 73))	('C-JUN', 'Gene', (87, 92))	('BARD1', 'Gene', '580', (80, 85))
528895	25688366	Disruption of the EWS and YB-1 interaction by CPT may alter the local recruitment of the splicing machinery, affecting MDM2 exon splicing.	('EWS', 'Phenotype', 'HP:0012254', (18, 21))	('affecting', 'Reg', (109, 118))	('CPT', 'Gene', (46, 49))	('alter', 'Reg', (54, 59))	('interaction', 'Interaction', (31, 42))	('MDM2', 'Gene', '4193', (119, 123))	('MDM2', 'Gene', (119, 123))	('local recruitment', 'MPA', (64, 81))	('Disruption', 'Var', (0, 10))
528896	25688366	Treatment with the transcription elongation inhibitor camptothecin leads to substantial exon skipping, and a subset of these events were recapitulated by knockdown of EWS or of its interacting protein YB-1.	('exon skipping', 'MPA', (88, 101))	('knockdown', 'Var', (154, 163))	('camptothecin', 'Chemical', 'MESH:D002166', (54, 66))	('EWS', 'Phenotype', 'HP:0012254', (167, 170))	('EWS', 'Gene', (167, 170))
528898	25688366	EWS depletion results in alternative splicing changes of genes involved in DNA-repair and genotoxic stress signaling, including ABL1, CHEK2, and MAP4 K2.	('CHEK2', 'Gene', (134, 139))	('ABL1', 'Gene', '25', (128, 132))	('ABL1', 'Gene', (128, 132))	('MAP4 K2', 'Gene', (145, 152))	('EWS', 'Phenotype', 'HP:0012254', (0, 3))	('CHEK2', 'Gene', '11200', (134, 139))	('MAP4 K2', 'Gene', '5871', (145, 152))	('alternative', 'Var', (25, 36))
528904	25688366	An alteration of EWS in Ewing's sarcoma alters the dynamics of Pol II over the CCND1 protooncogene encoding cyclin D1, leading to an increase in its transcription and to an alteration of splicing that results in high levels of the oncogenic cyclin D1b splice isoform.	('CCND1', 'Gene', '595', (79, 84))	('alters', 'Reg', (40, 46))	('high levels', 'MPA', (212, 223))	('results in', 'Reg', (201, 211))	('cyclin D1', 'Gene', (108, 117))	('alteration', 'Reg', (173, 183))	('dynamics', 'MPA', (51, 59))	('oncogenic cyclin D1b splice isoform', 'MPA', (231, 266))	('alteration', 'Var', (3, 13))	('EWS', 'Phenotype', 'HP:0012254', (17, 20))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (24, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('transcription', 'MPA', (149, 162))	('increase', 'PosReg', (133, 141))	('CCND1', 'Gene', (79, 84))	('splicing', 'MPA', (187, 195))
528931	25688366	Inhibiting the interaction of mutant cancer-specific TFs with the normal cellular binding partners, required for their oncogenic activity, provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents for Ewing's Tumor.	('Inhibiting', 'NegReg', (0, 10))	('Tumor', 'Phenotype', 'HP:0002664', (257, 262))	("Ewing's Tumor", 'Disease', 'MESH:C563168', (249, 262))	('TFs', 'Protein', (53, 56))	("Ewing's Tumor", 'Disease', (249, 262))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('interaction', 'Interaction', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('mutant', 'Var', (30, 36))	("Ewing's Tumor", 'Phenotype', 'HP:0012254', (249, 262))
528933	25688366	Neuropeptide Y (NPY) and two of its receptors, Y1R and Y5R, are upregulated by EWS/FLI1 and abundantly expressed in ES cells.	('Y1R', 'Var', (47, 50))	('NPY', 'Gene', (16, 19))	('upregulated', 'PosReg', (64, 75))	('EWS/FLI1', 'Gene', (79, 87))	('Neuropeptide Y', 'Gene', '4852', (0, 14))	('NPY', 'Gene', '4852', (16, 19))	('EWS', 'Phenotype', 'HP:0012254', (79, 82))	('Y5R', 'Var', (55, 58))	('Neuropeptide Y', 'Gene', (0, 14))
528936	25688366	The upregulation of HSPA5/BIP and other chaperones indicates that YB-1 depletion may lead to induction of ER stress, possibly due to unfolded protein accumulation, or conversely that YB-1 reduces ER stress.	('HSPA5', 'Gene', '3309', (20, 25))	('depletion', 'Var', (71, 80))	('HSPA5', 'Gene', (20, 25))	('BIP', 'Gene', '3309', (26, 29))	('ER stress', 'MPA', (106, 115))	('BIP', 'Gene', (26, 29))	('ER stress', 'MPA', (196, 205))	('upregulation', 'PosReg', (4, 16))	('YB-1', 'Gene', (66, 70))	('reduces', 'NegReg', (188, 195))
528955	33562337	Moreover, the low pressure and flow in the isolated limb (1000-1500 mL during the procedure, in HILP up to 10 times higher) allows for increased drug exposure of the tissues while avoiding systemic toxicity by minimal to no leakage of the cytotoxic infusate to the systemic circulation.	('low pressure', 'Phenotype', 'HP:0002615', (14, 26))	('increased', 'PosReg', (135, 144))	('toxicity', 'Disease', (198, 206))	('1000-1500', 'Var', (58, 67))	('toxicity', 'Disease', 'MESH:D064420', (198, 206))	('drug exposure', 'MPA', (145, 158))
529003	33562337	In a clinical HILP study conducted at the MIA, subcutaneous microdialysis catheters (CMA60/CMA70; CMA, Solna, Sweden) were inserted into normal and tumour tissues before commencement of the procedure.	('tumour', 'Disease', (148, 154))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('CMA60/CMA70;', 'Var', (85, 97))
529067	32373408	These neoplasms exhibit a neural phenotype, express the MIC2-protein (CD99) and display the same chromosomal translocation t (11; 22) (q24; q12) in about 85% of the cases and hence, can be helpful in diagnosis and have a prognostic value   PNETs usually originate in soft tissues and bone.	('neoplasms', 'Disease', 'MESH:D009369', (6, 15))	('t (11; 22) (q24; q12', 'Var', (123, 143))	('neoplasms', 'Disease', (6, 15))	('CD99', 'Gene', '4267', (70, 74))	('MIC2-protein', 'Protein', (56, 68))	('neoplasms', 'Phenotype', 'HP:0002664', (6, 15))	('CD99', 'Gene', (70, 74))
529085	32373408	Gene studies have shown that the fusion of the FLI1 gene on chromosome 11 and the ERG gene on chromosome 22 to be associated with PNES.	('ERG', 'Gene', (82, 85))	('PNES', 'Disease', (130, 134))	('ES', 'Phenotype', 'HP:0012254', (132, 134))	('associated', 'Reg', (114, 124))	('ERG', 'Gene', '2078', (82, 85))	('FLI1', 'Gene', (47, 51))	('fusion', 'Var', (33, 39))	('FLI1', 'Gene', '2313', (47, 51))
529086	32373408	The products of the fusion genes resulting from the translocations are specific to the type of tumors.	('translocations', 'Var', (52, 66))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
529093	32373408	The combination of clinical signs and symptoms such as abdominal pain with an abdominal mass, jaundice, vomiting, dyspepsia, pathological characteristics like sheets of small round blue cells with hyperchromatic nuclei and scant cytoplasm; immune-histochemical features stained positive for CD99, O13, HBA71, 12E7, RFB1 and neural markers like Neuron Specific Enolase (NSE), Chromogranin A, Synaptophysin; cytogenetic analysis for MIC-2 gene and t [11;22] [q24; q12] suggest a diagnosis of PNETs.	('t [', 'Var', (446, 449))	('jaundice', 'Phenotype', 'HP:0000952', (94, 102))	('Synaptophysin', 'Gene', '6855', (391, 404))	('abdominal pain', 'Disease', (55, 69))	('Chromogranin A', 'Gene', (375, 389))	('dyspepsia', 'Disease', 'MESH:D004415', (114, 123))	('abdominal pain', 'Disease', 'MESH:D015746', (55, 69))	('dyspepsia', 'Phenotype', 'HP:0410281', (114, 123))	('pain', 'Phenotype', 'HP:0012531', (65, 69))	('abdominal mass', 'Phenotype', 'HP:0031500', (78, 92))	('Synaptophysin', 'Gene', (391, 404))	('jaundice', 'Disease', (94, 102))	('dyspepsia', 'Disease', (114, 123))	('PNETs', 'Disease', (490, 495))	('jaundice', 'Disease', 'MESH:D007565', (94, 102))	('Neuron Specific Enolase', 'Gene', '2026', (344, 367))	('NSE', 'Gene', '2026', (369, 372))	('Chromogranin A', 'Gene', '1113', (375, 389))	('vomiting', 'Disease', 'MESH:D014839', (104, 112))	('HBA71', 'Gene', (302, 307))	('MIC-2', 'Gene', (431, 436))	('CD99', 'Gene', (291, 295))	('NSE', 'Gene', (369, 372))	('HBA71', 'Gene', '4267', (302, 307))	('abdominal pain', 'Phenotype', 'HP:0002027', (55, 69))	('MIC-2', 'Gene', '4267', (431, 436))	('vomiting', 'Phenotype', 'HP:0002013', (104, 112))	('vomiting', 'Disease', (104, 112))	('Neuron Specific Enolase', 'Gene', (344, 367))	('CD99', 'Gene', '4267', (291, 295))
529175	31963599	Endothelial cells take up breast cancer (BC)-derived exosomes leading to an increase in migration, driven by the incorporation of miR-105, associated with migration and tight junction protein ZO-1.	('breast cancer', 'Disease', (26, 39))	('incorporation', 'Var', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('increase', 'PosReg', (76, 84))	('ZO-1', 'Gene', (192, 196))	('migration', 'CPA', (88, 97))	('miR-105', 'Chemical', '-', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('miR-105', 'Gene', (130, 137))	('ZO-1', 'Gene', '7082', (192, 196))	('BC', 'Disease', 'MESH:D001943', (41, 43))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))
529182	31963599	In rhabdomyosarcoma, the transfer of the miRNA cargo to fibroblasts induced an increase in proliferation, migration, invasion, and angiogenesis in vitro compared to exposition to exosome-free media.	('increase', 'PosReg', (79, 87))	('angiogenesis', 'CPA', (131, 143))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (3, 19))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (3, 19))	('transfer', 'Var', (25, 33))	('rhabdomyosarcoma', 'Disease', (3, 19))	('proliferation', 'CPA', (91, 104))	('migration', 'CPA', (106, 115))	('invasion', 'CPA', (117, 125))
529186	31963599	In glioma, the transfer of linc-CCAT2 to endothelial cells via glioma-derived exosomes resulted in the promotion of angiogenesis via the upregulation of VEGF, TGFbeta, and Bcl-2 as well as a reduction of apoptosis via Bax and caspase-3 in vitro.	('TGFbeta', 'Gene', '7039', (159, 166))	('Bax', 'Gene', (218, 221))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('glioma', 'Disease', (3, 9))	('Bax', 'Gene', '581', (218, 221))	('apoptosis', 'CPA', (204, 213))	('transfer', 'Var', (15, 23))	('promotion', 'PosReg', (103, 112))	('Bcl-2', 'Gene', (172, 177))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('CCAT2', 'Gene', '101805488', (32, 37))	('VEGF', 'Gene', '7422', (153, 157))	('CCAT2', 'Gene', (32, 37))	('Bcl-2', 'Gene', '596', (172, 177))	('caspase-3', 'Gene', '836', (226, 235))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('VEGF', 'Gene', (153, 157))	('caspase-3', 'Gene', (226, 235))	('glioma', 'Disease', (63, 69))	('reduction', 'NegReg', (191, 200))	('angiogenesis', 'CPA', (116, 128))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('upregulation', 'PosReg', (137, 149))	('TGFbeta', 'Gene', (159, 166))
529192	31963599	When miR-23a was transferred to endothelial cells via exosomes, this induced an accumulation of HIF1alpha in recipient cells, triggering a signalling cascade that resulted in an angiogenic response in endothelial cells and the destruction of thigh junctions via inhibition of ZO-1.	('thigh', 'Protein', (242, 247))	('ZO-1', 'Gene', (276, 280))	('signalling cascade', 'Pathway', (139, 157))	('triggering', 'Reg', (126, 136))	('ZO-1', 'Gene', '7082', (276, 280))	('angiogenic response', 'CPA', (178, 197))	('miR-23a', 'Var', (5, 12))	('HIF1alpha', 'Gene', (96, 105))	('HIF1alpha', 'Gene', '3091', (96, 105))	('accumulation', 'PosReg', (80, 92))	('resulted in', 'Reg', (163, 174))
529193	31963599	To confirm the role of this miR-23a in the angiogenic process, the inhibition of miR-23a in mice models reduced growth and angiogenesis in vivo.	('inhibition', 'Var', (67, 77))	('mice', 'Species', '10090', (92, 96))	('reduced', 'NegReg', (104, 111))	('miR-23a', 'Gene', (81, 88))
529199	31963599	This involvement of Rab27A in pro-metastatic changes was confirmed when knock-down of Rab27A in melanoma mice models resulted in decreased metastasis formation in vivo.	('metastasis formation', 'CPA', (139, 159))	('Rab27A', 'Gene', '11891', (86, 92))	('mice', 'Species', '10090', (105, 109))	('Rab27A', 'Gene', (20, 26))	('knock-down', 'Var', (72, 82))	('Rab27A', 'Gene', (86, 92))	('Rab27A', 'Gene', '11891', (20, 26))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('decreased', 'NegReg', (129, 138))	('melanoma', 'Disease', (96, 104))
529214	31963599	A study on senescent cells identified the transfer of EphA2 to active cancer cells, inducing a signalling cascade via EphA2/ephrin-A1 which resulted in an increased cellular proliferation in the recipient cell, thus promoting a tumorigenic transformation.	('EphA2', 'Gene', '1969', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('increased', 'PosReg', (155, 164))	('ephrin-A1', 'Gene', (124, 133))	('EphA2', 'Gene', (118, 123))	('inducing', 'Reg', (84, 92))	('signalling', 'MPA', (95, 105))	('EphA2', 'Gene', (54, 59))	('EphA2', 'Gene', '1969', (118, 123))	('tumorigenic transformation', 'CPA', (228, 254))	('transfer', 'Var', (42, 50))	('cancer', 'Disease', (70, 76))	('ephrin-A1', 'Gene', '1942', (124, 133))	('promoting', 'PosReg', (216, 225))	('cellular proliferation', 'CPA', (165, 187))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
529273	31963599	The main driving event is the translocation between the EWSR1 gene in chromosome 22 and a member of the ETS family of transcription factors, being in 85% of cases the FLI1 gene located on chromosome 11.	('EWSR1', 'Gene', (56, 61))	('EWSR1', 'Gene', '2130', (56, 61))	('FLI1', 'Gene', (167, 171))	('FLI1', 'Gene', '2313', (167, 171))	('translocation', 'Var', (30, 43))
529275	31963599	This results in an aberrant transcription factor fundamental for ES tumorigenic transformation.	('aberrant', 'Var', (19, 27))	('ES', 'Disease', 'MESH:D012512', (65, 67))	('results in', 'Reg', (5, 15))
529320	31963599	Moreover, miR-141 and miR-101 have been shown to inhibit the metastatic potential of CS via regulation of c-Src.	('miR-141', 'Gene', '406933', (10, 17))	('miR-101', 'Chemical', '-', (22, 29))	('c-Src', 'Gene', (106, 111))	('c-Src', 'Gene', '6714', (106, 111))	('miR-101', 'Var', (22, 29))	('CS', 'Disease', 'MESH:D002813', (85, 87))	('miR-141', 'Gene', (10, 17))	('inhibit', 'NegReg', (49, 56))
529351	29359803	Hallmark tumor suppressor gene mutations and pathognomonic gene fusions collectively account for approximately one-third of all sarcomas.	('mutations', 'Var', (31, 40))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomas', 'Disease', (128, 136))	('account', 'Reg', (85, 92))	('Hallmark tumor', 'Disease', 'MESH:D009369', (0, 14))	('Hallmark tumor', 'Disease', (0, 14))
529353	29359803	Specifically, alterations to mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes and polycomb repressive complexes cause disease-specific changes in chromatin architecture and gene expression across a number of sarcoma subtypes.	('alterations', 'Var', (14, 25))	('gene expression', 'MPA', (205, 220))	('sarcoma', 'Disease', (240, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('changes', 'Reg', (167, 174))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('ATP', 'Chemical', 'MESH:D000255', (65, 68))	('mammalian', 'Species', '9606', (29, 38))	('chromatin architecture', 'MPA', (178, 200))	('polycomb', 'Gene', (114, 122))	('polycomb', 'Gene', '40358', (114, 122))	('sarcoma', 'Disease', 'MESH:D012509', (240, 247))
529356	29359803	Sarcoma subtypes possess diverse genetic profiles ranging from a single pathognomonic genetic event, such as chromosomal translocations in synovial sarcoma and Ewing sarcoma, to extensive mutational burden and complex genomes.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (160, 173))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (139, 155))	('Sarcoma', 'Disease', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('synovial sarcoma', 'Disease', 'MESH:D013584', (139, 155))	('chromosomal translocations', 'Var', (109, 135))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (160, 173))	('Ewing sarcoma', 'Disease', (160, 173))	('synovial sarcoma', 'Disease', (139, 155))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
529363	29359803	This review explores the current understanding of recurrent genetic alterations to epigenetic transcriptional regulators across a set of molecularly well-characterized sarcoma subtypes and proposes clinical strategies for reversing their oncogenic capabilities (Table 1).	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('genetic alterations', 'Var', (60, 79))	('sarcoma', 'Disease', (168, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))
529369	29359803	The regulation of chromatin architecture, required for proper lineage-specific gene expression, occurs by controlling the DNA-histone interactions through a number of mechanisms that include DNA methylation, covalent modification of histones, and ATP-dependent chromatin remodeling.	('interactions', 'Interaction', (134, 146))	('ATP', 'Chemical', 'MESH:D000255', (247, 250))	('methylation', 'Var', (195, 206))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('N', 'Chemical', 'MESH:D009584', (192, 193))	('histones', 'Protein', (233, 241))
529382	29359803	SWI/SNF complexes were initially discovered via the identification of redundant phenotypes upon mutation of genes involved in mating type switching (SWI) and nutrient switching (SNF) regulation in yeast.	('N', 'Chemical', 'MESH:D009584', (5, 6))	('yeast', 'Species', '4932', (197, 202))	('SWI', 'Gene', (149, 152))	('mutation', 'Var', (96, 104))	('N', 'Chemical', 'MESH:D009584', (179, 180))
529383	29359803	Mutation of histone coding genes suppressed these phenotypes, indicating that these SWI/SNF proteins were involved in altering chromatin structure to regulate transcription.	('chromatin structure', 'MPA', (127, 146))	('Mutation', 'Var', (0, 8))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('regulate', 'Reg', (150, 158))	('transcription', 'MPA', (159, 172))	('altering', 'Reg', (118, 126))
529391	29359803	Mutations in SMARCB1 (BAF47) represented the first link between SWI/SNF complexes and cancer, upon the discovery by Delattre and co-workers that 98% of malignant rhabdoid tumors exhibit biallelic inactivation of SMARCB1.	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (152, 177))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('biallelic inactivation', 'Var', (186, 208))	('malignant rhabdoid tumors', 'Disease', (152, 177))	('Mutations', 'Var', (0, 9))	('SMARCB1', 'Gene', '6598', (13, 20))	('SMARCB1', 'Gene', '6598', (212, 219))	('N', 'Chemical', 'MESH:D009584', (69, 70))	('SMARCB1', 'Gene', (13, 20))	('SMARCB1', 'Gene', (212, 219))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (86, 92))
529392	29359803	Exome sequencing studies have further revealed that members of these complexes are mutated in over 20% of cancers and that certain subunits are recurrently mutated in specific cancer types.	('mutated', 'Var', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
529393	29359803	For example, ARID1A (BAF250A) is mutated in 46% of ovarian clear cell carcinoma cases; SMARCA4 (BRG1) is mutated in 10-35% of non-small cell lung cancer cases; and PBRM1 (BAF180) is mutated in 41% of clear cell renal cell carcinoma cases.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (126, 152))	('ARID1A', 'Gene', '8289', (13, 19))	('clear cell renal cell carcinoma', 'Disease', (200, 231))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (211, 231))	('BAF180', 'Gene', '55193', (171, 177))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('BRG1', 'Gene', '6597', (96, 100))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D010051', (51, 79))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (126, 152))	('BAF180', 'Gene', (171, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (200, 231))	('SMARCA4', 'Gene', (87, 94))	('BRG1', 'Gene', (96, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('PBRM1', 'Gene', '55193', (164, 169))	('mutated', 'Var', (105, 112))	('non-small cell lung cancer', 'Disease', (126, 152))	('BAF250A', 'Gene', '8289', (21, 28))	('ARID1A', 'Gene', (13, 19))	('PBRM1', 'Gene', (164, 169))	('mutated', 'Var', (33, 40))	('ovarian clear cell carcinoma', 'Disease', (51, 79))	('BAF250A', 'Gene', (21, 28))	('SMARCA4', 'Gene', '6597', (87, 94))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (200, 231))
529402	29359803	The EZH1/2 proteins are SET methyltransferases that produce mono-, di-, and tri-methylated H3K27 in a SAM-dependent manner.	('tri-methylated', 'Var', (76, 90))	('di-', 'Var', (67, 70))	('EZH1/2', 'Gene', '2145;2146', (4, 10))	('mono-', 'Var', (60, 65))	('H3K27', 'Protein', (91, 96))	('EZH1/2', 'Gene', (4, 10))
529404	29359803	While the potential role of cooperation between PRC1 and PRC2 complexes in transcriptional repression is still being fully elucidated, these two complexes modify chromatin through the placement of the H2AK119 ubiquitin and H3K27me3 marks to compact chromatin and inhibit transcription.	('transcription', 'MPA', (271, 284))	('inhibit', 'NegReg', (263, 270))	('C', 'Chemical', 'MESH:D002244', (50, 51))	('H2AK119', 'Var', (201, 208))	('C', 'Chemical', 'MESH:D002244', (59, 60))	('H3K27me3', 'Var', (223, 231))	('modify', 'Reg', (155, 161))
529430	29359803	Less common but related translocations in the remaining 10% of Ewing sarcoma cases form EWSR1 gene fusions with other members of the ETS family of transcription factors, including ERG, ETV1, E1AF, and FEV.	('Ewing sarcoma', 'Disease', 'MESH:D012512', (63, 76))	('E1AF', 'Gene', (191, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('ERG', 'Gene', '2078', (180, 183))	('ETV1', 'Gene', (185, 189))	('E1AF', 'Gene', '2118', (191, 195))	('ETV1', 'Gene', '2115', (185, 189))	('ERG', 'Gene', (180, 183))	('Ewing sarcoma', 'Disease', (63, 76))	('EWSR1', 'Gene', (88, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('translocations', 'Var', (24, 38))	('EWSR1', 'Gene', '2130', (88, 93))
529431	29359803	While exome sequencing studies have identified extensive mutations in dedicated subunits of mSWI/SNF complexes, the contribution of mSWI/SNF complexes in oncogenesis likely extends well beyond perturbation to mSWI/SNF complex members themselves.	('N', 'Chemical', 'MESH:D009584', (215, 216))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('mutations', 'Var', (57, 66))	('oncogenesis', 'Disease', (154, 165))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('mSWI/SNF', 'Gene', (92, 100))
529432	29359803	Indeed, mSWI/SNF complex mistargeting due to genetic alterations to transient protein interaction partners, such as transcription factors, represents one route to altered, cancer-specific gene activation.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('interaction', 'Interaction', (86, 97))	('activation', 'PosReg', (193, 203))	('alterations', 'Reg', (53, 64))	('genetic', 'Var', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('cancer', 'Disease', (172, 178))
529433	29359803	Ewing sarcoma is an example of such a malignancy where mSWI/SNF complexes acquire gained oncogenic function due to genetic perturbation to a protein interaction partner.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('gained', 'PosReg', (82, 88))	('mSWI/SNF complexes', 'Gene', (55, 73))	('protein', 'Protein', (141, 148))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (0, 13))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('Ewing sarcoma', 'Disease', (0, 13))	('oncogenic function', 'CPA', (89, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('genetic perturbation', 'Var', (115, 135))
529441	29359803	Biallelic inactivation of SMARCB1 (BAF47/hSNF5/ INI1) is the defining genetic alteration in a specific set of malignancies.	('hSNF5', 'Gene', (41, 46))	('malignancies', 'Disease', 'MESH:D009369', (110, 122))	('SMARCB1', 'Gene', '6598', (26, 33))	('Biallelic inactivation', 'Var', (0, 22))	('SMARCB1', 'Gene', (26, 33))	('malignancies', 'Disease', (110, 122))	('hSNF5', 'Gene', '6598', (41, 46))	('INI1', 'Gene', (48, 52))	('INI1', 'Gene', '6598', (48, 52))
529444	29359803	The genetic perturbation of BAF47 has also been documented and implicated in a number of other neoplasms including poorly differentiated chordoma, renal medullary carcinoma, and meningiomas and schwannomas in patients with schwannomatosis.	('chordoma', 'Phenotype', 'HP:0010762', (137, 145))	('renal medullary carcinoma', 'Disease', (147, 172))	('schwannomas', 'Phenotype', 'HP:0100008', (194, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('chordoma', 'Disease', (137, 145))	('BAF47', 'Gene', (28, 33))	('meningiomas', 'Phenotype', 'HP:0002858', (178, 189))	('schwannomatosis', 'Disease', 'MESH:C536641', (223, 238))	('renal medullary carcinoma', 'Disease', 'MESH:D018276', (147, 172))	('genetic perturbation', 'Var', (4, 24))	('patients', 'Species', '9606', (209, 217))	('meningiomas and schwannomas', 'Disease', 'MESH:D009442', (178, 205))	('neoplasms', 'Disease', 'MESH:D009369', (95, 104))	('neoplasms', 'Disease', (95, 104))	('implicated', 'Reg', (63, 73))	('schwannomatosis', 'Disease', (223, 238))	('chordoma', 'Disease', 'MESH:D002817', (137, 145))
529447	29359803	BAF47 has been well established as a tumor suppressor as conditional biallelic inactivation of Smarcb1 (Baf47) in a mouse model resulted in tumor formation in 100% of cases with a median onset of 11 weeks, representing the most rapid inception of tumorigenesis by deletion of a single gene currently documented.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('biallelic inactivation', 'Var', (69, 91))	('Smarcb1', 'Gene', (95, 102))	('Baf47', 'Gene', '20587', (104, 109))	('tumor', 'Disease', (37, 42))	('Smarcb1', 'Gene', '20587', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('Baf47', 'Gene', (104, 109))	('resulted in', 'Reg', (128, 139))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('mouse', 'Species', '10090', (116, 121))	('tumor', 'Disease', (140, 145))
529448	29359803	BAF47 is a stable subunit in both BAF and PBAF assembly forms of mSWI/SNF complexes, and the discovery of BAF47 loss in MRT was the first evidence that alterations to the composition of mSWI/SNF complexes perturbed their tumor suppressive functions.	('BAF47', 'Gene', (106, 111))	('alterations', 'Var', (152, 163))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('perturbed', 'NegReg', (205, 214))	('loss', 'NegReg', (112, 116))	('MRT', 'Disease', 'MESH:D018335', (120, 123))	('N', 'Chemical', 'MESH:D009584', (192, 193))	('MRT', 'Disease', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
529460	29359803	NF1 is an autosomal-dominant hereditary cancer syndrome that affects 1 in 3000 individuals due to a germline mutation that inactivates one allele of the NF1 gene.	('autosomal-dominant hereditary cancer syndrome', 'Disease', (10, 55))	('NF1', 'Gene', (153, 156))	('NF1', 'Gene', '4763', (153, 156))	('autosomal-dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (10, 55))	('inactivates', 'NegReg', (123, 134))	('NF1', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('NF1', 'Gene', '4763', (0, 3))	('mutation', 'Var', (109, 117))
529461	29359803	Acquisition of a second somatic mutation that silences the NF1 gene of the allele inherited from the unaffected parent is the key driver in developing neurofibroma, which forms benign tumors and increases the risk of developing the more aggressive MPNSTs.	('neurofibroma', 'Disease', (151, 163))	('neurofibroma', 'Disease', 'MESH:D009455', (151, 163))	('benign tumors', 'Disease', 'MESH:D009369', (177, 190))	('neurofibroma', 'Phenotype', 'HP:0001067', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('MPNSTs', 'Disease', 'MESH:D009442', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('benign tumors', 'Disease', (177, 190))	('silences', 'NegReg', (46, 54))	('NF1', 'Gene', (59, 62))	('MPNSTs', 'Disease', (248, 254))	('mutation', 'Var', (32, 40))	('NF1', 'Gene', '4763', (59, 62))
529463	29359803	While MRT and synovial sarcomas discussed above contain genetic alterations to mSWI/SNF members that result in gained and lost H3K27me3-mediated repression, respectively, MPNST-associated mutations in PRC2 complex components directly cause loss of the H3K27me3 mark.	('loss', 'NegReg', (240, 244))	('H3K27me3-mediated', 'Protein', (127, 144))	('MRT', 'Disease', (6, 9))	('N', 'Chemical', 'MESH:D009584', (173, 174))	('synovial sarcomas', 'Disease', 'MESH:D013584', (14, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('lost', 'NegReg', (122, 126))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('gained', 'PosReg', (111, 117))	('PRC2', 'Gene', (201, 205))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (14, 31))	('MRT', 'Disease', 'MESH:D018335', (6, 9))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('mutations', 'Var', (188, 197))	('synovial sarcomas', 'Disease', (14, 31))	('H3K27me3 mark', 'MPA', (252, 265))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (14, 30))	('C', 'Chemical', 'MESH:D002244', (203, 204))
529464	29359803	The genetic alterations to PRC2 complex members consist of loss-of-function mutations to EED or SUZ12 that result in decreased levels of the H3K27me3 mark detected by immunohistochemical staining of paraffin-embedded tumor samples from patients (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('mutations', 'Var', (76, 85))	('PRC2', 'Gene', (27, 31))	('SUZ12', 'Gene', '23512', (96, 101))	('EED', 'Gene', '8726', (89, 92))	('EED', 'Gene', (89, 92))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('patients', 'Species', '9606', (236, 244))	('decreased', 'NegReg', (117, 126))	('levels of', 'MPA', (127, 136))	('loss-of-function', 'NegReg', (59, 75))	('H3K27me3 mark', 'MPA', (141, 154))	('SUZ12', 'Gene', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (217, 222))
529470	29359803	Cases of MPNSTs display clinical and histological diversity due to divergent differentiations, yet possess and share a convergent set of genetically perturbed molecular pathways (stemming from NF1, CDKN2A, and PRC2 complex gene mutations).	('MPNSTs', 'Disease', (9, 15))	('perturbed', 'Reg', (149, 158))	('C', 'Chemical', 'MESH:D002244', (212, 213))	('NF1', 'Gene', '4763', (193, 196))	('CDKN2A', 'Gene', (198, 204))	('NF1', 'Gene', (193, 196))	('CDKN2A', 'Gene', '1029', (198, 204))	('MPNSTs', 'Disease', 'MESH:D009442', (9, 15))	('mutations', 'Var', (228, 237))	('C', 'Chemical', 'MESH:D002244', (198, 199))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('PRC2 complex', 'Gene', (210, 222))
529471	29359803	The wide range of genes silenced by PRC2 complexes to prevent aberrant differentiation toward an alternative cell lineage suggests a mechanism by which perturbation of PRC2 complexes can result in disruption of gene repression, allowing for the formation of tumors through activation of one of a number of differentiation pathways.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('perturbation', 'Var', (152, 164))	('tumors', 'Disease', (258, 264))	('PRC2', 'Gene', (168, 172))	('differentiation', 'CPA', (306, 321))	('allowing for', 'Reg', (228, 240))	('disruption', 'NegReg', (197, 207))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('activation', 'PosReg', (273, 283))	('gene repression', 'MPA', (211, 226))	('C', 'Chemical', 'MESH:D002244', (38, 39))
529472	29359803	Due to the contribution of loss-of-function genetic alterations to PRC2 complexes in driving tumorigenesis, MPNST is a unique setting where genes encoding PRC2 complex members act as tumor suppressors rather than oncogenes.	('C', 'Chemical', 'MESH:D002244', (69, 70))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('loss-of-function', 'NegReg', (27, 43))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('genetic alterations', 'Var', (44, 63))	('tumor', 'Disease', (183, 188))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('PRC2', 'Gene', (67, 71))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
529473	29359803	The discovery of actionable synthetic lethal dependencies resulting from an imbalance of mSWI/SNF and PcG complex activities in sarcomas presents an important foundation for the identification of targeted therapies.	('synthetic lethal dependencies', 'MPA', (28, 57))	('PcG', 'Gene', (102, 105))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('PcG', 'Gene', '40358', (102, 105))	('imbalance', 'Phenotype', 'HP:0002172', (76, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomas', 'Disease', (128, 136))	('imbalance', 'Var', (76, 85))
529480	29359803	Potent and specific EZH2 inhibition has been shown to attenuate BAF47-deficient solid tumor growth in preclinical models.	('BAF47-deficient solid tumor', 'Disease', (64, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EZH2', 'Gene', '2146', (20, 24))	('EZH2', 'Gene', (20, 24))	('BAF47-deficient solid tumor', 'Disease', 'MESH:D009369', (64, 91))	('inhibition', 'Var', (25, 35))	('attenuate', 'NegReg', (54, 63))
529487	29359803	Furthermore, while it is clear that loss of PRC2 function in MPNSTs results in gene activation, it remains to be determined whether a transcriptional activator, such as a SWI/SNF family chromatin remodeler, contributes to this activation.	('function', 'Var', (49, 57))	('MPNSTs', 'Disease', (61, 67))	('loss', 'NegReg', (36, 40))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('gene activation', 'MPA', (79, 94))	('PRC2', 'Gene', (44, 48))	('MPNSTs', 'Disease', 'MESH:D009442', (61, 67))	('N', 'Chemical', 'MESH:D009584', (176, 177))
529489	29359803	The SS18-SSX fusion results in novel mSWI/SNF targeting which suggests that this fusion interacts directly and uniquely with chromatin or a chromatin-associated protein.	('SSX', 'Gene', (9, 12))	('mSWI/SNF targeting', 'MPA', (37, 55))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('SSX', 'Gene', '6757', (9, 12))	('SS18', 'Gene', '6760', (4, 8))	('fusion', 'Var', (13, 19))	('SS18', 'Gene', (4, 8))
529770	31346406	The study of BLU-285 (avapritinib) in GIST, with a particular target for those patients with a D842V mutation in PDGFRa, has been one of the leading studies relying on new methods for genetic analysis.	('D842V', 'Var', (95, 100))	('avapritinib', 'Chemical', '-', (22, 33))	('BLU', 'Gene', (13, 16))	('PDGFRa', 'Gene', '5156', (113, 119))	('BLU', 'Gene', '51364', (13, 16))	('patients', 'Species', '9606', (79, 87))	('D842V', 'Mutation', 'rs121908585', (95, 100))	('PDGFRa', 'Gene', (113, 119))
529778	31346406	We now have a lot of information about mutations in sarcomas of all kinds for which there is no clinical treatment.	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('mutations', 'Var', (39, 48))	('sarcomas', 'Disease', (52, 60))
529779	31346406	The prospect of a targeted therapy to address mutations in myxofibrosarcoma, for example, is remote in the short to medium term.	('myxofibrosarcoma', 'Disease', (59, 75))	('myxofibrosarcoma', 'Disease', 'None', (59, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('mutations', 'Var', (46, 55))
529942	29250486	WDLS/DDLS tumors are particularly associated with aberrations in chromosome 12q13-15 involving oncogenes including CDK4 and MDM2.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('associated', 'Reg', (34, 44))	('CDK4', 'Gene', (115, 119))	('DDLS tumors', 'Disease', 'MESH:D009369', (5, 16))	('CDK4', 'Gene', '1019', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('aberrations', 'Var', (50, 61))	('DDLS tumors', 'Disease', (5, 16))	('WD', 'Disease', 'MESH:D006527', (0, 2))	('MDM2', 'Gene', '4193', (124, 128))	('MDM2', 'Gene', (124, 128))
530001	29250486	Amplification of the CDK4 oncogene is noted in over 90% of cases of WDLS/DDLS and two phase II trials have investigated the CDK4/CDK6 inhibitor palbociclib in patients with CDK4 amplification and advanced disease.	('CDK6', 'Gene', (129, 133))	('Amplification', 'Var', (0, 13))	('CDK6', 'Gene', '1021', (129, 133))	('CDK4', 'Gene', '1019', (124, 128))	('CDK4', 'Gene', (173, 177))	('WD', 'Disease', 'MESH:D006527', (68, 70))	('CDK4', 'Gene', '1019', (173, 177))	('CDK4', 'Gene', (21, 25))	('amplification', 'Var', (178, 191))	('CDK4', 'Gene', '1019', (21, 25))	('patients', 'Species', '9606', (159, 167))	('palbociclib', 'Chemical', 'MESH:C500026', (144, 155))	('CDK4', 'Gene', (124, 128))
530011	29250486	MDM2 regulates transcription and degradation of the tumor suppressor gene p53, and its amplification is therefore thought to reduce levels of p53 resulting in downregulation of its tumor suppressor pathway.	('regulates', 'Reg', (5, 14))	('tumor', 'Disease', (52, 57))	('p53', 'Gene', (74, 77))	('reduce', 'NegReg', (125, 131))	('transcription', 'MPA', (15, 28))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('p53', 'Gene', '7157', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('p53', 'Gene', (142, 145))	('levels', 'MPA', (132, 138))	('MDM2', 'Gene', (0, 4))	('amplification', 'Var', (87, 100))	('tumor', 'Disease', (181, 186))	('degradation', 'MPA', (33, 44))	('MDM2', 'Gene', '4193', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('p53', 'Gene', '7157', (74, 77))	('downregulation', 'NegReg', (159, 173))
530013	29250486	Biomarker assessment of RG7112 on MDM2 inhibition and p53 reactivation was the primary end point of this study.	('RG7112', 'Var', (24, 30))	('MDM2', 'Gene', '4193', (34, 38))	('p53', 'Gene', (54, 57))	('MDM2', 'Gene', (34, 38))	('p53', 'Gene', '7157', (54, 57))
530014	29250486	20 patients were analyzed as part of the study (11 with WDLS and 9 with DDLS), 14 patients had MDM2 amplification and 18 patients had tumors which were p53 wild type.	('tumors', 'Disease', (134, 140))	('amplification', 'Var', (100, 113))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('patients', 'Species', '9606', (82, 90))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('MDM2', 'Gene', '4193', (95, 99))	('MDM2', 'Gene', (95, 99))	('patients', 'Species', '9606', (3, 11))	('WD', 'Disease', 'MESH:D006527', (56, 58))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('patients', 'Species', '9606', (121, 129))
530018	29250486	Inhibition of angiogenesis pathways has produced therapeutic benefit in a number of cancer types.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('angiogenesis pathways', 'Pathway', (14, 35))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Inhibition', 'Var', (0, 10))
530036	29250486	A randomized phase 2b clinical trial published in 2015 showed statistically significant improvement in median PFS (5.6 vs 2.7 months) favoring aldoxorubicin over doxorubicin.	('aldoxorubicin', 'Chemical', 'MESH:C575867', (143, 156))	('PFS', 'MPA', (110, 113))	('aldoxorubicin', 'Var', (143, 156))	('doxorubicin', 'Chemical', 'MESH:D004317', (145, 156))	('doxorubicin', 'Chemical', 'MESH:D004317', (162, 173))
530044	29250486	There was a statistically significant increased median PFS of 5.32 months in those receiving aldoxorubicin vs 2.96 months in those who received IC.	('aldoxorubicin', 'Var', (93, 106))	('aldoxorubicin', 'Chemical', 'MESH:C575867', (93, 106))	('increased', 'PosReg', (38, 47))	('PFS', 'MPA', (55, 58))
530055	29250486	These proteins include tumor suppressor proteins which can be inactivated through nuclear exclusion in the presence of XPO1 overactivity.	('overactivity', 'Var', (124, 136))	('XPO1', 'Gene', '7514', (119, 123))	('XPO1', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))
530105	33671768	Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively.	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('altered', 'Reg', (93, 100))	('toxicity', 'Disease', (4, 12))	('gene', 'MPA', (75, 79))	('resulted in', 'Reg', (63, 74))	('epigenetic modifications', 'Var', (16, 40))	('gene expression', 'MPA', (101, 116))
530114	33671768	Inflammation is thus the most effective intrinsic factor required to repeatedly maintain the states of "tissue damage", "genetic instability", and "growth stimulation".	('Inflammation', 'Disease', 'MESH:D007249', (0, 12))	('genetic instability', 'Var', (121, 140))	('Inflammation', 'Disease', (0, 12))
530115	33671768	Moreover, epigenetic alterations such as aberrant DNA hypermethylation are involved in the inflammation-related cancers.	('involved', 'Reg', (75, 83))	('inflammation-related cancers', 'Disease', 'MESH:D009369', (91, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('aberrant DNA hypermethylation', 'Var', (41, 70))	('rat', 'Species', '10116', (25, 28))	('inflammation-related cancers', 'Disease', (91, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
530137	33671768	When mice were treated with 4-NQO and with ethanol in drinking water, they developed mast cell infiltration and had increased expressions of the inflammatory mediators, 5-lipoxygenase and cyclooxygenase-2 (COX-2), and, thereafter, developed oral dysplasia and squamous cell carcinoma.	('5-lipoxygenase', 'Gene', (169, 183))	('increased', 'PosReg', (116, 125))	('mice', 'Species', '10090', (5, 9))	('COX-2', 'Gene', (206, 211))	('4-NQO', 'Chemical', 'MESH:D015112', (28, 33))	('expressions', 'MPA', (126, 137))	('cyclooxygenase-2', 'Gene', '19225', (188, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (260, 283))	('water', 'Chemical', 'MESH:D014867', (63, 68))	('cyclooxygenase-2', 'Gene', (188, 204))	('rat', 'Species', '10116', (101, 104))	('5-lipoxygenase', 'Gene', '11689', (169, 183))	('mast cell infiltration', 'CPA', (85, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (260, 283))	('4-NQO', 'Var', (28, 33))	('COX-2', 'Gene', '19225', (206, 211))	('oral dysplasia', 'Disease', (241, 255))	('developed', 'PosReg', (231, 240))	('ethanol', 'Chemical', 'MESH:D000431', (43, 50))	('oral dysplasia', 'Disease', 'MESH:D020820', (241, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('squamous cell carcinoma', 'Disease', (260, 283))
530138	33671768	Overactivation of the inhibitor of nuclear factor kappa-B kinase (IKK) complex caused the activation of nuclear factor kappa-B (NF-kB), leading to severe inflammation.	('NF-kB', 'Gene', '81736', (128, 133))	('activation', 'PosReg', (90, 100))	('nuclear factor', 'Protein', (104, 118))	('leading to', 'Reg', (136, 146))	('IKK', 'Gene', (66, 69))	('NF-kB', 'Gene', (128, 133))	('IKK', 'Gene', '12675;16150', (66, 69))	('inflammation', 'Disease', 'MESH:D007249', (154, 166))	('inflammation', 'Disease', (154, 166))	('Overactivation', 'Var', (0, 14))
530139	33671768	In the oral epithelia of IKK subunit beta (IKKbeta) transgenic mice, produced in persistent lichenoid inflammation due to neutrophil, macrophage, and B cell infiltration, spontaneous oral squamous cell carcinomas were formed.	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('IKKbeta', 'Gene', '12675', (43, 50))	('IKK', 'Gene', '12675;16150', (43, 46))	('IKK', 'Gene', '12675;16150', (25, 28))	('lichenoid inflammation', 'Disease', 'MESH:D007249', (92, 114))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (188, 212))	('neu', 'Gene', '13866', (122, 125))	('lichenoid inflammation', 'Disease', (92, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (183, 212))	('rat', 'Species', '10116', (163, 166))	('lichenoid inflammation', 'Phenotype', 'HP:0031452', (92, 114))	('neu', 'Gene', (122, 125))	('IKKbeta', 'Gene', (43, 50))	('IKK', 'Gene', (43, 46))	('oral squamous cell carcinomas', 'Disease', (183, 212))	('transgenic', 'Var', (52, 62))	('transgenic mice', 'Species', '10090', (52, 67))	('IKK', 'Gene', (25, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
530142	33671768	Homozygous deletion of Toll-like receptor 2 (TLR2-/-) using 4-NQO in mice increased the number of tongue-infiltrating M2 macrophages and resulted in the development of tongue cancer.	('rat', 'Species', '10116', (111, 114))	('Toll-like receptor 2', 'Gene', '24088', (23, 43))	('resulted in', 'Reg', (137, 148))	('tongue cancer', 'Disease', (168, 181))	('increased', 'PosReg', (74, 83))	('TLR2-/-', 'Gene', (45, 52))	('Toll-like receptor 2', 'Gene', (23, 43))	('mice', 'Species', '10090', (69, 73))	('tongue cancer', 'Disease', 'MESH:D014062', (168, 181))	('men', 'Species', '9606', (160, 163))	('development of tongue', 'Phenotype', 'HP:0012730', (153, 174))	('deletion', 'Var', (11, 19))	('4-NQO', 'Chemical', 'MESH:D015112', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
530145	33671768	The link between inflammation and esophageal cancer is well-established; in particular, interleukin (IL)-1beta is overexpressed in Barrett's esophagus, and polymorphisms in the IL-1beta gene are associated with Barrett's esophagus.	("Barrett's esophagus", 'Disease', (211, 230))	('associated', 'Reg', (195, 205))	('IL-1beta', 'Gene', (177, 185))	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (211, 230))	('interleukin (IL)-1beta', 'Gene', (88, 110))	('interleukin (IL)-1beta', 'Gene', '16175', (88, 110))	('overexpressed', 'PosReg', (114, 127))	('inflammation', 'Disease', 'MESH:D007249', (17, 29))	("Barrett's esophagus", 'Disease', (131, 150))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (131, 150))	('polymorphisms', 'Var', (156, 169))	('inflammation', 'Disease', (17, 29))
530153	33671768	The C57BL/6 strain is considered to be carcinogenic-tolerant, while the BALB/c strain is moderately sensitive.	('carcinogenic-tolerant', 'Disease', 'MESH:D018149', (39, 60))	('carcinogenic-tolerant', 'Disease', (39, 60))	('C57BL/6', 'Var', (4, 11))	('rat', 'Species', '10116', (93, 96))
530155	33671768	The reason for the highest sensitivity of A/J mice to the development of lung tumors is that they have the K-ras intron 2 polymorphism and, thus, undergo activation of the K-ras oncogene.	('polymorphism', 'Var', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('men', 'Species', '9606', (65, 68))	('lung tumors', 'Disease', 'MESH:D008175', (73, 84))	('activation', 'PosReg', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mice', 'Species', '10090', (46, 50))	('lung tumors', 'Phenotype', 'HP:0100526', (73, 84))	('lung tumors', 'Disease', (73, 84))
530172	33671768	Most of the experimental adenocarcinomas exhibited mutations in K-ras, either in codon 12 or in codon 61.	('K-ras', 'Protein', (64, 69))	('mutations', 'Var', (51, 60))	('exhibited', 'Reg', (41, 50))	('men', 'Species', '9606', (18, 21))	('adenocarcinomas', 'Disease', 'MESH:D000230', (25, 40))	('adenocarcinomas', 'Disease', (25, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))
530173	33671768	Lung adenocarcinoma developed in mice treated with N-nitrosodimethylamine (NDMA) alone showed A-to-G transition (Q61R) at K-ras codon 61, whereas mice treated with NDMA and oropharyngeal administration of silica showed G-to-A transition (G12D) in codon 12.	('Q61R', 'Var', (113, 117))	('Q61R', 'Mutation', 'rs121913240', (113, 117))	('NDMA', 'Chemical', 'MESH:D004128', (75, 79))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('G12D', 'Mutation', 'rs121913529', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('mice', 'Species', '10090', (146, 150))	('NDMA', 'Chemical', 'MESH:D004128', (164, 168))	('mice', 'Species', '10090', (33, 37))	('rat', 'Species', '10116', (195, 198))	('min', 'Gene', (69, 72))	('min', 'Gene', (189, 192))	('silica', 'Chemical', 'MESH:D012822', (205, 211))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('N-nitrosodimethylamine', 'Chemical', 'MESH:D004128', (51, 73))	('min', 'Gene', '11789', (189, 192))	('min', 'Gene', '11789', (69, 72))
530174	33671768	Therefore, among the K-ras mutation profiles of lung cancer, the Q61R to G12D mutations can occur in an inflammatory environment.	('G12D', 'Mutation', 'rs121913529', (73, 77))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('Q61R to G12D', 'Var', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('Q61R', 'Mutation', 'rs121913240', (65, 69))
530175	33671768	Benzo[a]pyrene (B[a]P) is present in tobacco metabolites and is metabolized into epoxide, which induces DNA adducts and causes mutations due to ROS generation, which can together accelerate the process of lung tumorigenesis.	('Benzo[a]pyrene', 'Chemical', 'MESH:D001564', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tobacco', 'Species', '4097', (37, 44))	('rat', 'Species', '10116', (152, 155))	('accelerate', 'PosReg', (179, 189))	('epoxide', 'Chemical', 'MESH:D004852', (81, 88))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('lung', 'Disease', (205, 209))	('tumor', 'Disease', (210, 215))	('induces', 'Reg', (96, 103))	('ROS', 'Protein', (144, 147))	('B[a]P', 'Chemical', 'MESH:D001564', (16, 21))	('mutations', 'Var', (127, 136))	('DNA adducts', 'MPA', (104, 115))	('rat', 'Species', '10116', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
530176	33671768	C57BL/6 mice exposed to B[a]p with intratracheal LPS administration formed more lung tumors than mice exposed to B[a]p alone.	('lung tumors', 'Phenotype', 'HP:0100526', (80, 91))	('B[a]p', 'Var', (24, 29))	('lung tumors', 'Disease', 'MESH:D008175', (80, 91))	('rat', 'Species', '10116', (61, 64))	('mice', 'Species', '10090', (97, 101))	('rat', 'Species', '10116', (38, 41))	('min', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung tumors', 'Disease', (80, 91))	('min', 'Gene', '11789', (55, 58))	('mice', 'Species', '10090', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
530180	33671768	The homozygous conditional deletion of mitogen-induced gene 6 (Mig-6d/d) and mutated K-ras (K-RasG12D) occurs in transgenic mouse (Mig-6d/dK-RasG12D) in which a signaling molecule, Mig-6, is deleted and K-ras (G12D) is activated in lung Clara cells.	('Mig-6', 'Gene', '74155', (181, 186))	('Mig-6', 'Gene', (181, 186))	('Mig-6', 'Gene', '74155', (63, 68))	('G12D', 'Mutation', 'rs121913529', (97, 101))	('Mig-6', 'Gene', (63, 68))	('mouse', 'Species', '10090', (124, 129))	('Mig-6', 'Gene', '74155', (131, 136))	('deletion', 'Var', (27, 35))	('Mig-6', 'Gene', (131, 136))	('transgenic', 'Species', '10090', (113, 123))	('K-RasG12D', 'Gene', '16653', (139, 148))	('K-RasG12D', 'Gene', (139, 148))	('K-RasG12D', 'Gene', (92, 101))	('K-RasG12D', 'Gene', '16653', (92, 101))	('G12D', 'Mutation', 'rs121913529', (210, 214))	('G12D', 'Mutation', 'rs121913529', (144, 148))
530185	33671768	The conclusive evidence that H. pylori-induced chronic inflammation causes gastric cancer is validated by the fact that eradication suppresses the H. pylori-related inflammatory response and, as a result, inhibits gastric carcinogenesis.	('suppresses', 'NegReg', (132, 142))	('eradication', 'Var', (120, 131))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('H. pylori', 'Species', '210', (147, 156))	('gastric carcinogenesis', 'Disease', (214, 236))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('chronic inflammation', 'Disease', 'MESH:D007249', (47, 67))	('inhibits', 'NegReg', (205, 213))	('chronic inflammation', 'Disease', (47, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('inflammatory response', 'CPA', (165, 186))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (214, 236))	('H. pylori', 'Species', '210', (29, 38))
530195	33671768	The histological types of gastric cancer developed by H. pylori and MNU caused poorly differentiated, signet-ring cells and well-differentiated adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('H. pylori', 'Var', (54, 63))	('caused', 'Reg', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('MNU', 'Gene', (68, 71))	('adenocarcinoma', 'Disease', (144, 158))	('gastric cancer', 'Disease', (26, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (26, 40))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('MNU', 'Chemical', 'MESH:D008770', (68, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))	('signet-ring cells', 'Disease', (102, 119))	('poorly differentiated', 'CPA', (79, 100))	('H. pylori', 'Species', '210', (54, 63))
530215	33671768	The homozygous knock-in substitution of a glycoprotein 130 (gp130Y757F/Y757F) mouse carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and hyperactivates STAT1 and STAT3 signaling.	('Y757F', 'Mutation', 'p.Y757F', (71, 76))	('STAT3', 'Gene', (241, 246))	('STAT1', 'Gene', '20846', (231, 236))	('Y757F', 'Mutation', 'p.Y757F', (65, 70))	('hyperactivates', 'PosReg', (216, 230))	('STAT1', 'Gene', (231, 236))	('SOCS3', 'Gene', (206, 211))	('mouse', 'Species', '10090', (78, 83))	('SOCS3', 'Gene', '12702', (206, 211))	('gp130Y757F/Y757F', 'Var', (60, 76))	('STAT3', 'Gene', '20848', (241, 246))
530217	33671768	gp130Y757F/Y757F causes the development of those gastric cancer-accompanying hyperplasia, with histological features reminiscent of those intestinal-type and metaplastic gastric tumors in humans.	('men', 'Species', '9606', (35, 38))	('causes', 'Reg', (17, 23))	('gastric tumors', 'Disease', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('hyperplasia', 'Disease', (77, 88))	('humans', 'Species', '9606', (188, 194))	('hyperplasia', 'Disease', 'MESH:D006965', (77, 88))	('Y757F', 'Mutation', 'p.Y757F', (5, 10))	('gp130Y757F/Y757F', 'Var', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('min', 'Gene', (119, 122))	('min', 'Gene', '11789', (119, 122))	('gastric tumors', 'Disease', 'MESH:D013274', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('gastric tumors', 'Phenotype', 'HP:0006753', (170, 184))	('Y757F', 'Mutation', 'p.Y757F', (11, 16))	('gastric cancer', 'Disease', (49, 63))
530218	33671768	The stomach-specific expression of human IL-1beta in transgenic mice leads to gastric inflammation and cancer by the early recruitment of myeloid-derived suppressor cells, while T and B cells are not needed for this phenomenon.	('gastric inflammation', 'Disease', 'MESH:D013272', (78, 98))	('gastric inflammation', 'Disease', (78, 98))	('gastric inflammation', 'Phenotype', 'HP:0005263', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('human', 'Species', '9606', (35, 40))	('transgenic mice', 'Species', '10090', (53, 68))	('leads to', 'Reg', (69, 77))	('men', 'Species', '9606', (221, 224))	('IL-1beta', 'Gene', (41, 49))	('expression', 'Var', (21, 31))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('men', 'Species', '9606', (130, 133))
530221	33671768	Carriers of IL-1beta polymorphisms are at risk for human gastric cancer.	('IL-1beta', 'Gene', (12, 20))	('gastric cancer', 'Disease', (57, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('human', 'Species', '9606', (51, 56))	('risk', 'Reg', (42, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('polymorphisms', 'Var', (21, 34))
530232	33671768	HBsAg in hepatocytes induces liver regeneration due to induction of inflammation and the associated ROS, which impairs their ability to replicate and allows the activation of hepatic stem cells.	('induces', 'PosReg', (21, 28))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('HBsAg', 'Var', (0, 5))	('rat', 'Species', '10116', (41, 44))	('ROS', 'Gene', (100, 103))	('inflammation', 'Disease', (68, 80))	('ability', 'MPA', (125, 132))	('liver', 'Disease', (29, 34))	('impairs', 'NegReg', (111, 118))
530257	33671768	Deletion of the ATP7B gene, which is homologous to the Wilson's disease gene, has been identified in LEC rats.	("Wilson's disease", 'Disease', (55, 71))	('ATP7B', 'Gene', '24218', (16, 21))	('ATP7B', 'Gene', (16, 21))	('LEC', 'Gene', (101, 104))	('LEC', 'Gene', '6360', (101, 104))	("Wilson's disease", 'Disease', 'MESH:D006527', (55, 71))	('rats', 'Species', '10116', (105, 109))	('Deletion', 'Var', (0, 8))
530283	33671768	Aberrant lipogenesis in the liver, which is closely linked to obesity and metabolic syndrome, causes nonalcoholic fatty liver disease (NAFLD), which is observed in 75-100% of overweight and obese adults and children.	('overweight', 'Phenotype', 'HP:0025502', (175, 185))	('fatty liver', 'Phenotype', 'HP:0001397', (114, 125))	('lipogenesis', 'MPA', (9, 20))	('nonalcoholic fatty liver disease', 'Disease', (101, 133))	('metabolic syndrome', 'Disease', 'MESH:D024821', (74, 92))	('obese', 'Disease', (190, 195))	('Aberrant', 'Var', (0, 8))	('obesity', 'Phenotype', 'HP:0001513', (62, 69))	('children', 'Species', '9606', (207, 215))	('causes', 'Reg', (94, 100))	('obese', 'Disease', 'MESH:D009765', (190, 195))	('nonalcoholic fatty liver disease', 'Disease', 'MESH:D065626', (101, 133))	('Aberrant lipogenesis', 'Phenotype', 'HP:0009125', (0, 20))	('liver disease', 'Phenotype', 'HP:0001392', (120, 133))	('obesity', 'Disease', (62, 69))	('NAFLD', 'Gene', (135, 140))	('NAFLD', 'Gene', '22084', (135, 140))	('obesity', 'Disease', 'MESH:D009765', (62, 69))	('metabolic syndrome', 'Disease', (74, 92))
530287	33671768	MSG induced beta cell proliferation and caused islet hypertrophy, leading to the development of obesity and steatosis with the infiltration of neutrophils and the onset of diabetes mellitus.	('obesity', 'Phenotype', 'HP:0001513', (96, 103))	('diabetes mellitus', 'Disease', 'MESH:D003920', (172, 189))	('MSG', 'Var', (0, 3))	('hypertrophy', 'Disease', 'MESH:D006984', (53, 64))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (172, 189))	('rat', 'Species', '10116', (133, 136))	('men', 'Species', '9606', (88, 91))	('hypertrophy', 'Disease', (53, 64))	('neu', 'Gene', '13866', (143, 146))	('MSG', 'Chemical', 'MESH:D012970', (0, 3))	('islet', 'Disease', (47, 52))	('rat', 'Species', '10116', (29, 32))	('beta cell proliferation', 'CPA', (12, 35))	('obesity and steatosis', 'Disease', 'MESH:D009765', (96, 117))	('islet hypertrophy', 'Phenotype', 'HP:0004510', (47, 64))	('diabetes mellitus', 'Disease', (172, 189))	('steatosis', 'Phenotype', 'HP:0001397', (108, 117))	('neu', 'Gene', (143, 146))	('leading to', 'Reg', (66, 76))
530300	33671768	It is known that approximately half of human liver tumors have G-T (Q61K) mutations at codon 61 of the H-ras oncogene.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('liver tumors', 'Disease', 'MESH:D008113', (45, 57))	('G-T (Q61K', 'Var', (63, 72))	('H-ras', 'Gene', '3265', (103, 108))	('liver tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Q61K', 'Mutation', 'rs28933406', (68, 72))	('liver tumors', 'Phenotype', 'HP:0002896', (45, 57))	('H-ras', 'Gene', (103, 108))	('human', 'Species', '9606', (39, 44))
530307	33671768	DEN has been widely used as a potent hepatocarcinogenic initiator in rodent models in which it induces DNA adduct formation, resulting in DNA mutations.	('mutations', 'Var', (142, 151))	('carcinogenic', 'Disease', 'MESH:D063646', (43, 55))	('DEN', 'Chemical', 'MESH:D004052', (0, 3))	('carcinogenic', 'Disease', (43, 55))	('DNA adduct formation', 'MPA', (103, 123))	('DNA', 'Gene', (138, 141))	('induces', 'Reg', (95, 102))
530312	33671768	TAA stimulates the infiltration of inflammatory cells, hepatic macrophages, and CD3+ T cells.	('infiltration', 'CPA', (19, 31))	('TAA', 'Var', (0, 3))	('CD3', 'Gene', (80, 83))	('rat', 'Species', '10116', (25, 28))	('TAA', 'Chemical', 'MESH:D013853', (0, 3))	('CD3', 'Gene', '12501', (80, 83))
530316	33671768	CCl4 induced chronic hepatotoxicity, such as fatty change, fibrosis, and cirrhosis, and led to the development of hepatocellular adenomas and HCC.	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (114, 137))	('cirrhosis', 'Disease', (73, 82))	('chronic hepatotoxicity', 'Disease', 'MESH:D056487', (13, 35))	('chronic hepatotoxicity', 'Disease', (13, 35))	('fibrosis', 'Disease', (59, 67))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (114, 137))	('cirrhosis', 'Phenotype', 'HP:0001394', (73, 82))	('fatty', 'Disease', (45, 50))	('hepatocellular adenomas', 'Disease', (114, 137))	('fibrosis', 'Disease', 'MESH:D005355', (59, 67))	('CCl4', 'Var', (0, 4))	('cirrhosis', 'Disease', 'MESH:D005355', (73, 82))	('HCC', 'Disease', (142, 145))	('HCC', 'Phenotype', 'HP:0001402', (142, 145))	('men', 'Species', '9606', (106, 109))
530319	33671768	The hepatocyte-specific homozygous deletion of Atg5 (Atg5-/-) mice resulted in increased inflammation and fibrosis and led to the formation of hepatocellular adenomas in the liver that was infiltrated with neutrophils and macrophages.	('hepatocellular adenomas', 'Disease', (143, 166))	('increased', 'PosReg', (79, 88))	('Atg5', 'Gene', '11793', (47, 51))	('fibrosis', 'Disease', (106, 114))	('Atg5', 'Gene', '11793', (53, 57))	('mice', 'Species', '10090', (62, 66))	('led to', 'Reg', (119, 125))	('fibrosis', 'Disease', 'MESH:D005355', (106, 114))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (143, 166))	('inflammation', 'Disease', 'MESH:D007249', (89, 101))	('deletion', 'Var', (35, 43))	('rat', 'Species', '10116', (195, 198))	('neu', 'Gene', '13866', (206, 209))	('inflammation', 'Disease', (89, 101))	('neu', 'Gene', (206, 209))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (143, 166))	('Atg5', 'Gene', (47, 51))	('Atg5', 'Gene', (53, 57))
530323	33671768	The homozygous deletion of the farnesoid X receptor (Fxr-/-) in mice results in the accumulation of high levels of bile acids, which provokes inflammation-induced hepatocarcinogenesis with fibrosis and hepatosteatosis.	('provokes', 'Reg', (133, 141))	('high levels of bile acids', 'MPA', (100, 125))	('deletion', 'Var', (15, 23))	('inflammation-induced hepatocarcinogenesis', 'Disease', 'MESH:D007249', (142, 183))	('Fxr', 'Gene', (53, 56))	('Fxr', 'Gene', '20186', (53, 56))	('bile acids', 'Chemical', 'MESH:D001647', (115, 125))	('inflammation-induced hepatocarcinogenesis', 'Disease', (142, 183))	('high levels of bile acids', 'Phenotype', 'HP:0012202', (100, 125))	('steatosis', 'Phenotype', 'HP:0001397', (208, 217))	('accumulation', 'PosReg', (84, 96))	('mice', 'Species', '10090', (64, 68))	('fibrosis and hepatosteatosis', 'Disease', 'MESH:D005355', (189, 217))
530331	33671768	Due to the insufficient secretion of phospholipids into the bile, mice with a homozygous deletion of the Mdr2 P-glycoprotein (Mdr2-/-) gene develop nonsuppurative inflammatory cholangitis, which mainly contributes to B cells and stimulates tube proliferation, and most mice develop HCC.	('rat', 'Species', '10116', (156, 159))	('develop', 'PosReg', (140, 147))	('tube proliferation', 'CPA', (240, 258))	('rat', 'Species', '10116', (252, 255))	('HCC', 'Phenotype', 'HP:0001402', (282, 285))	('cholangitis', 'Disease', 'MESH:D002761', (176, 187))	('nonsuppurative inflammatory cholangitis', 'Phenotype', 'HP:0030987', (148, 187))	('Mdr2', 'Gene', (126, 130))	('phospholipids', 'Chemical', 'MESH:D010743', (37, 50))	('mice', 'Species', '10090', (66, 70))	('Mdr2', 'Gene', '18670', (105, 109))	('deletion', 'Var', (89, 97))	('cholangitis', 'Disease', (176, 187))	('mice', 'Species', '10090', (269, 273))	('Mdr2', 'Gene', (105, 109))	('cholangitis', 'Phenotype', 'HP:0030151', (176, 187))	('Mdr2', 'Gene', '18670', (126, 130))	('HCC', 'Disease', (282, 285))
530337	33671768	Oncogenic K-ras mutation represents the most frequent and earliest genetic alteration in PDAC patients, which highlights its role as a driver of PDAC.	('mutation', 'Var', (16, 24))	('K-ras', 'Protein', (10, 15))	('PDAC', 'Chemical', '-', (89, 93))	('patients', 'Species', '9606', (94, 102))	('PDAC', 'Chemical', '-', (145, 149))	('PDAC', 'Disease', (89, 93))	('PDAC', 'Phenotype', 'HP:0006725', (89, 93))	('rat', 'Species', '10116', (79, 82))	('Oncogenic', 'Var', (0, 9))	('PDAC', 'Phenotype', 'HP:0006725', (145, 149))
530352	33671768	DSS induces colonic inflammation and its associated dysplasia and carcinomas in guinea pigs, rabbits, hamsters, and mice with clinical and histopathological similarity to human ulcerative colitis (UC).	('dysplasia', 'Disease', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (177, 195))	('colonic inflammation', 'Disease', (12, 32))	('DSS', 'Chemical', 'MESH:D016264', (0, 3))	('colitis', 'Phenotype', 'HP:0002583', (188, 195))	('hamster', 'Species', '10034', (102, 109))	('UC', 'Phenotype', 'HP:0100279', (197, 199))	('mice', 'Species', '10090', (116, 120))	('ulcerative colitis', 'Disease', (177, 195))	('dysplasia', 'Disease', 'MESH:C536170', (52, 61))	('carcinomas', 'Disease', (66, 76))	('colonic inflammation', 'Disease', 'MESH:D007249', (12, 32))	('induces', 'Reg', (4, 11))	('DSS', 'Var', (0, 3))	('ulcerative colitis', 'Disease', 'MESH:D003093', (177, 195))	('rabbits', 'Species', '9986', (93, 100))	('human', 'Species', '9606', (171, 176))	('guinea pigs', 'Species', '10141', (80, 91))	('carcinomas', 'Disease', 'MESH:D009369', (66, 76))
530393	33671768	The Min/Min homozygous mutation of the adenomatous polyposis coli gene in mice is lethal, and mice with a heterozygous mutation (ApcMin/+) survive but develop adenomas throughout the small intestine and only rarely in the colon; however, in humans with hereditary familial adenomatous polyposis, adenomas occur in the colon, duodenum, and rectum.	('Min', 'Gene', '11789', (4, 7))	('familial adenomatous polyposis', 'Disease', (264, 294))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (39, 65))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (39, 65))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (264, 294))	('mice', 'Species', '10090', (94, 98))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (273, 294))	('adenomatous polyposis coli', 'Disease', (39, 65))	('Min', 'Gene', (8, 11))	('Min', 'Gene', '11789', (8, 11))	('mice', 'Species', '10090', (74, 78))	('Min', 'Phenotype', 'HP:0200008', (132, 135))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (39, 60))	('Min', 'Phenotype', 'HP:0200008', (4, 7))	('humans', 'Species', '9606', (241, 247))	('adenomas', 'Disease', 'MESH:D000236', (159, 167))	('adenomas', 'Disease', 'MESH:D000236', (296, 304))	('adenomas', 'Disease', (159, 167))	('adenomas', 'Disease', (296, 304))	('Min', 'Gene', (132, 135))	('mutation', 'Var', (23, 31))	('Min', 'Gene', '11789', (132, 135))	('Min', 'Gene', (4, 7))	('Min', 'Phenotype', 'HP:0200008', (8, 11))
530396	33671768	There are three mouse strains with different codon sites for APC mutations, and the difference in mutation is represented by the difference in tumorigenesis site and number.	('APC', 'Disease', 'MESH:D011125', (61, 64))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('APC', 'Disease', (61, 64))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (65, 74))
530408	33671768	The homozygous deletion of interleukin-10 (IL-10-/-) mice leads to enterocolitis, which is similar to human IBD.	('IL-10', 'Gene', '16153', (43, 48))	('mice', 'Species', '10090', (53, 57))	('deletion', 'Var', (15, 23))	('enterocolitis', 'Disease', (67, 80))	('IL-10', 'Gene', (43, 48))	('IBD', 'Disease', (108, 111))	('leads to', 'Reg', (58, 66))	('interleukin-10', 'Gene', '16153', (27, 41))	('IBD', 'Disease', 'MESH:D015212', (108, 111))	('colitis', 'Phenotype', 'HP:0002583', (73, 80))	('IBD', 'Phenotype', 'HP:0002037', (108, 111))	('enterocolitis', 'Phenotype', 'HP:0004387', (67, 80))	('interleukin-10', 'Gene', (27, 41))	('enterocolitis', 'Disease', 'MESH:D004760', (67, 80))	('human', 'Species', '9606', (102, 107))
530410	33671768	The treatment of IL-10-/- mice with AOM/DSS caused colitis and tumors as a result of microbial activation, but tumor development was suppressed under germ-free conditions.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('IL-10', 'Gene', (17, 22))	('AOM/DSS', 'Var', (36, 43))	('men', 'Species', '9606', (9, 12))	('tumors', 'Disease', (63, 69))	('colitis', 'Phenotype', 'HP:0002583', (51, 58))	('tumor', 'Disease', (63, 68))	('IL-10', 'Gene', '16153', (17, 22))	('activation', 'PosReg', (95, 105))	('tumor', 'Disease', (111, 116))	('AOM', 'Chemical', 'MESH:D001397', (36, 39))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('DSS', 'Chemical', 'MESH:D016264', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('microbial', 'CPA', (85, 94))	('mice', 'Species', '10090', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('colitis', 'Disease', (51, 58))	('men', 'Species', '9606', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('caused', 'Reg', (44, 50))	('colitis', 'Disease', 'MESH:D003092', (51, 58))
530414	33671768	C57BL/6-Ay mice show severe hyperphagia, polydipsia, impaired glucose tolerance, hyperinsulinemia, and hyperlipidemia.	('hyperlipidemia', 'Disease', 'MESH:D006949', (103, 117))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (81, 97))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (103, 117))	('polydipsia', 'Phenotype', 'HP:0001959', (41, 51))	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (53, 79))	('polydipsia', 'Disease', (41, 51))	('hyperphagia', 'Disease', (28, 39))	('C57BL/6-Ay', 'Var', (0, 10))	('impaired glucose tolerance', 'Disease', (53, 79))	('hyperphagia', 'Phenotype', 'HP:0002591', (28, 39))	('hyperinsulinemia', 'Disease', (81, 97))	('hyperphagia', 'Disease', 'MESH:D006963', (28, 39))	('mice', 'Species', '10090', (11, 15))	('hyperlipidemia', 'Disease', (103, 117))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (53, 79))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (81, 97))	('polydipsia', 'Disease', 'MESH:D059606', (41, 51))
530416	33671768	Since the diabetes (db) gene encodes the receptor for the obese (ob) gene product, leptin, mutations in the mouse db gene, cause leptin dysfunction, resulting in obesity and diabetes in a syndrome similar to that of human obesity.	('diabetes', 'Disease', (10, 18))	('human', 'Species', '9606', (216, 221))	('leptin dysfunction', 'Disease', (129, 147))	('obesity', 'Disease', 'MESH:D009765', (222, 229))	('leptin dysfunction', 'Disease', 'OMIM:614962', (129, 147))	('diabetes', 'Disease', (174, 182))	('obesity', 'Disease', (162, 169))	('leptin', 'Gene', (83, 89))	('obesity', 'Disease', 'MESH:D009765', (162, 169))	('obese (ob', 'Gene', (58, 67))	('leptin', 'Gene', '16846', (83, 89))	('obesity', 'Phenotype', 'HP:0001513', (222, 229))	('diabetes', 'Disease', 'MESH:D003920', (10, 18))	('leptin', 'Gene', '16846', (129, 135))	('leptin', 'Gene', (129, 135))	('mouse', 'Species', '10090', (108, 113))	('resulting in', 'Reg', (149, 161))	('diabetes', 'Disease', 'MESH:D003920', (174, 182))	('cause', 'Reg', (123, 128))	('obese (ob)', 'Gene', '16846', (58, 68))	('obesity', 'Disease', (222, 229))	('obesity', 'Phenotype', 'HP:0001513', (162, 169))	('mutations', 'Var', (91, 100))
530420	33671768	The homozygous deletion of lactoferrin (Lf-/-) mice showed higher susceptibility to AOM/DSS-induced colitis and developed dysplasia.	('DSS', 'Chemical', 'MESH:D016264', (88, 91))	('lactoferrin', 'Gene', '17002', (27, 38))	('colitis', 'Disease', 'MESH:D003092', (100, 107))	('deletion', 'Var', (15, 23))	('colitis', 'Disease', (100, 107))	('dysplasia', 'Disease', 'MESH:C536170', (122, 131))	('susceptibility', 'Reg', (66, 80))	('AOM', 'Chemical', 'MESH:D001397', (84, 87))	('colitis', 'Phenotype', 'HP:0002583', (100, 107))	('lactoferrin', 'Gene', (27, 38))	('dysplasia', 'Disease', (122, 131))	('higher', 'PosReg', (59, 65))	('mice', 'Species', '10090', (47, 51))	('developed', 'Reg', (112, 121))
530422	33671768	The homozygous deletion of Nrf2 (Nrf2-/-) mice treated with AOM/DSS demonstrates increased colitis and adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Nrf2', 'Gene', (33, 37))	('DSS', 'Chemical', 'MESH:D016264', (64, 67))	('Nrf2', 'Gene', '18024', (27, 31))	('deletion', 'Var', (15, 23))	('rat', 'Species', '10116', (75, 78))	('mice', 'Species', '10090', (42, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('colitis', 'Disease', 'MESH:D003092', (91, 98))	('Nrf2', 'Gene', (27, 31))	('adenocarcinomas', 'Disease', 'MESH:D000230', (103, 118))	('adenocarcinomas', 'Disease', (103, 118))	('colitis', 'Disease', (91, 98))	('AOM', 'Chemical', 'MESH:D001397', (60, 63))	('Nrf2', 'Gene', '18024', (33, 37))	('increased', 'PosReg', (81, 90))	('colitis', 'Phenotype', 'HP:0002583', (91, 98))
530425	33671768	The homozygous deletion of syndecan-1 (Sdc1-/-) mice results in an increased susceptibility to colitis-associated cancer induced by AOM/DSS through IL-6 and STAT3 signaling.	('Sdc1', 'Gene', '20969', (39, 43))	('deletion', 'Var', (15, 23))	('DSS', 'Chemical', 'MESH:D016264', (136, 139))	('colitis', 'Phenotype', 'HP:0002583', (95, 102))	('mice', 'Species', '10090', (48, 52))	('syndecan-1', 'Gene', (27, 37))	('AOM', 'Chemical', 'MESH:D001397', (132, 135))	('STAT3', 'Gene', '20848', (157, 162))	('colitis-associated cancer', 'Disease', (95, 120))	('Sdc1', 'Gene', (39, 43))	('colitis-associated cancer', 'Disease', 'MESH:D009369', (95, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('STAT3', 'Gene', (157, 162))	('syndecan-1', 'Gene', '20969', (27, 37))	('susceptibility', 'Reg', (77, 91))
530426	33671768	Salmonella, a Gram-negative bacterium, causes gastroenteritis and sepsis, as well as intestinal injury in both humans and animals.	('causes', 'Reg', (39, 45))	('gastroenteritis and sepsis', 'Disease', 'MESH:D018805', (46, 72))	('Salmonella', 'Species', '90371', (0, 10))	('Salmonella', 'Var', (0, 10))	('intestinal injury', 'Disease', (85, 102))	('sepsis', 'Phenotype', 'HP:0100806', (66, 72))	('intestinal injury', 'Disease', 'MESH:D007410', (85, 102))	('humans', 'Species', '9606', (111, 117))
530482	33671768	Fe-NTA induced severe acute nephrotoxicity and the infiltration of leukocytes into the proximal tubular epithelium, as well as the resulting oxidative stress and hyperproliferative response.	('oxidative stress', 'MPA', (141, 157))	('hyperproliferative response', 'CPA', (162, 189))	('Fe-NTA', 'Var', (0, 6))	('rat', 'Species', '10116', (174, 177))	('rat', 'Species', '10116', (57, 60))	('Fe-NTA', 'Chemical', 'MESH:C020326', (0, 6))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))	('nephrotoxicity', 'Disease', (28, 42))	('infiltration', 'CPA', (51, 63))	('nephrotoxicity', 'Disease', 'MESH:D007674', (28, 42))
530496	33671768	In response to the DMBA-initiated and TPA-promoted skin carcinogenesis protocols, benign papillomas occur much faster in heterozygous p53 gene deletion (p53+/-) mice compared to wild-type mice.	('mice', 'Species', '10090', (188, 192))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (51, 70))	('mice', 'Species', '10090', (161, 165))	('benign papillomas', 'Disease', 'MESH:D010212', (82, 99))	('papillomas', 'Phenotype', 'HP:0012740', (89, 99))	('faster', 'PosReg', (111, 117))	('TPA', 'Chemical', 'MESH:D013755', (38, 41))	('gene deletion', 'Var', (138, 151))	('papilloma', 'Phenotype', 'HP:0012740', (89, 98))	('skin carcinogenesis', 'Disease', (51, 70))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '22059', (153, 156))	('benign papillomas', 'Disease', (82, 99))	('p53', 'Gene', (134, 137))	('p53', 'Gene', '22059', (134, 137))	('DMBA', 'Chemical', 'MESH:D015127', (19, 23))
530498	33671768	UVB induces signature mutations characterized by C-T or CC-TT mutations at pyrimidine-pyrimidine sequences.	('pyrimidine', 'Chemical', 'MESH:C030986', (75, 85))	('C-T', 'Disease', 'MESH:C537418', (57, 60))	('mutations', 'Var', (62, 71))	('C-T', 'Disease', (49, 52))	('C-T', 'Disease', 'MESH:C537418', (49, 52))	('pyrimidine', 'Chemical', 'MESH:C030986', (86, 96))	('C-T', 'Disease', (57, 60))
530499	33671768	These mutations are detectable in several tumor-suppressor genes, particularly Patched 1 (Ptch1) and p53 in UVB-exposed skin sites.	('Ptch1', 'Gene', (90, 95))	('Ptch1', 'Gene', '19206', (90, 95))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '22059', (101, 104))	('mutations', 'Var', (6, 15))	('tumor-suppressor', 'Gene', '7248', (42, 58))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Patched 1', 'Gene', (79, 88))	('Patched 1', 'Gene', '19206', (79, 88))	('tumor-suppressor', 'Gene', (42, 58))
530500	33671768	Since the homozygous deletion of Ptch1 is embryonic, Ptch1+/- mice were used for mating with SKH-1 hairless mice.	('Ptch1', 'Gene', '19206', (33, 38))	('Ptch1', 'Gene', (33, 38))	('Ptch1', 'Gene', (53, 58))	('Ptch1', 'Gene', '19206', (53, 58))	('mice', 'Species', '10090', (62, 66))	('deletion', 'Var', (21, 29))	('mice', 'Species', '10090', (108, 112))
530506	33671768	Homozygous deletions in XP group A (XPA-/-) mice are sensitive to UVB and induced a severe inflammatory response.	('sensitive to UVB', 'MPA', (53, 69))	('XP group A', 'Gene', (24, 34))	('induced', 'Reg', (74, 81))	('deletions', 'Var', (11, 20))	('XPA', 'Gene', (36, 39))	('inflammatory response', 'CPA', (91, 112))	('XPA', 'Gene', '22590', (36, 39))	('mice', 'Species', '10090', (44, 48))
530531	33671768	Spontaneous sarcoma development by inflammation induced by foreign body implantation in mice with heterozygous deletion of p53 (p53+/-) is associated with a higher rate of incidence and shorter tumor latency than those in wild-type mice.	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '22059', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('sarcoma', 'Disease', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('p53', 'Gene', '22059', (123, 126))	('p53', 'Gene', (123, 126))	('tumor', 'Disease', (194, 199))	('inflammation', 'Disease', 'MESH:D007249', (35, 47))	('rat', 'Species', '10116', (164, 167))	('mice', 'Species', '10090', (88, 92))	('deletion', 'Var', (111, 119))	('men', 'Species', '9606', (27, 30))	('inflammation', 'Disease', (35, 47))	('mice', 'Species', '10090', (232, 236))
530535	33671768	Inflammation-related carcinogenesis models of each organ using laboratory animals were organized by the cause of inflammation:that is, chemical or irritant-induced inflammation (Table 1), surgery, hormone or diet-induced inflammation (Table 2), genetically modified host-induced inflammation (Table 3), infection-induced inflammation (Table 4), and foreign body-induced inflammation (Table 5).	('inflammation', 'Disease', 'MESH:D007249', (321, 333))	('inflammation', 'Disease', (221, 233))	('infection', 'Disease', (303, 312))	('infection', 'Disease', 'MESH:D007239', (303, 312))	('inflammation', 'Disease', 'MESH:D007249', (370, 382))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('foreign', 'Disease', (349, 356))	('inflammation', 'Disease', (321, 333))	('inflammation', 'Disease', (370, 382))	('inflammation', 'Disease', 'MESH:D007249', (279, 291))	('genetically', 'Var', (245, 256))	('inflammation', 'Disease', (164, 176))	('rat', 'Species', '10116', (67, 70))	('Inflammation', 'Disease', (0, 12))	('inflammation', 'Disease', (113, 125))	('Inflammation', 'Disease', 'MESH:D007249', (0, 12))	('irritant-', 'Phenotype', 'HP:0000737', (147, 156))	('inflammation', 'Disease', 'MESH:D007249', (221, 233))	('inflammation', 'Disease', (279, 291))
530545	33671768	The overall estimates have shown a 11% increase in the risk of all cancers for increased natural logarithm levels of CRP.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('natural logarithm levels', 'Var', (89, 113))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CRP', 'Gene', (117, 120))
530557	33671768	For instance, rheumatoid arthritis is not linked to cancer risk, even though the inflammatory regions in patients with rheumatoid arthritis show mutations in tumor-suppressor genes at similar frequencies to those of genes in the digestive tract tumors arising from chronic inflammatory reactions.	('rheumatoid arthritis', 'Disease', (14, 34))	('mutations', 'Var', (145, 154))	('digestive tract tumors', 'Phenotype', 'HP:0007378', (229, 251))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (14, 34))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (119, 139))	('tumor-suppressor', 'Gene', '7248', (158, 174))	('tumors', 'Disease', (245, 251))	('arthritis', 'Phenotype', 'HP:0001369', (130, 139))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (14, 34))	('tumor-suppressor', 'Gene', (158, 174))	('rheumatoid arthritis', 'Disease', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('arthritis', 'Phenotype', 'HP:0001369', (25, 34))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (119, 139))
530610	33482754	Among the 473 patients with lesions <=3 cm, 277 (58.56%) were female and the mean age was 46.04 +/- 16.9 years, and among the 240 patients with lesions <= 2 cm, 143 (59.58%) were female and the mean age was 44.87 +/- 16.72 years.	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (14, 22))	('<=3', 'Var', (36, 39))	('lesions <=3', 'Var', (28, 39))
530719	32508466	LOH from the short arms of chromosomes 3 and 9 at the 3p24.3, 9p22-p21 and 9p22 loci is evident in AFS; the allelic loss fraction was reported to be 74.6 compared with that of AF.9 These findings suggest that genetic changes may cause an AF to become malignant.	('short arms', 'Phenotype', 'HP:0009824', (13, 23))	('AF', 'Disease', 'MESH:D001281', (176, 178))	('p21', 'Gene', (67, 70))	('AF', 'Disease', 'MESH:D001281', (99, 101))	('p21', 'Gene', '644914', (67, 70))	('AF', 'Disease', 'MESH:D001281', (238, 240))	('genetic changes', 'Var', (209, 224))	('cause', 'Reg', (229, 234))
530767	31963219	Clinical data from European clinical practices also suggested that trabectedin could be beneficial for STS patients with chromosomal translocation, represented by myxoid liposarcoma.	('myxoid liposarcoma', 'Disease', (163, 181))	('trabectedin', 'Chemical', 'MESH:D000077606', (67, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('liposarcoma', 'Phenotype', 'HP:0012034', (170, 181))	('chromosomal translocation', 'Var', (121, 146))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (163, 181))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (163, 181))	('patients', 'Species', '9606', (107, 115))	('STS', 'Phenotype', 'HP:0030448', (103, 106))
530789	31963219	Encouraged by the success of molecular targeted therapies to GIST, research groups have pursued new treatment targets for STS, and the new candidates for molecular targeted therapies include many growth factor receptors that are overexpressed on the membranes of STS, proteins that are thought to regulate a signaling pathway of tumor progression, and fusion genes promoted by chromosomal translocations.	('chromosomal translocations', 'Var', (377, 403))	('proteins', 'Disease', 'MESH:D058495', (268, 276))	('regulate', 'Reg', (297, 305))	('STS', 'Phenotype', 'HP:0030448', (263, 266))	('fusion genes', 'Gene', (352, 364))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('STS', 'Phenotype', 'HP:0030448', (122, 125))	('overexpressed', 'PosReg', (229, 242))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('promoted', 'PosReg', (365, 373))	('proteins', 'Disease', (268, 276))	('tumor', 'Disease', (329, 334))
530792	31963219	Patients with an alveolar soft part sarcoma (ASPS), characterized by translocation t(X;17)(p11.2;q25) and known as a vascular-rich tumor, showed high responses to VEGF-targeted therapies in prospective trials, including trials of pazopanib.	('translocation', 'Var', (69, 82))	('tumor', 'Disease', (131, 136))	('VEGF', 'Gene', '7422', (163, 167))	('ASPS', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('vascular-rich tumor', 'Phenotype', 'HP:0100742', (117, 136))	('VEGF', 'Gene', (163, 167))	('Patients', 'Species', '9606', (0, 8))	('pazopanib', 'Chemical', 'MESH:C516667', (230, 239))	('ASPS', 'Gene', '79058', (45, 49))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (17, 43))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (83, 101))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (26, 43))	('ASPS', 'Phenotype', 'HP:0012218', (45, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('responses', 'MPA', (150, 159))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (17, 43))	('alveolar soft part sarcoma', 'Disease', (17, 43))
530798	31963219	Preclinical results encouraged the enrollment of STS patients in early-phase clinical trials of IGF1-R inhibitors, one of which is figitumumab, whose clinical efficacy against STSs including Ewing sarcoma was evaluated.	('patients', 'Species', '9606', (53, 61))	('IGF1-R', 'Gene', (96, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (191, 204))	('STS', 'Phenotype', 'HP:0030448', (49, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('inhibitors', 'Var', (103, 113))	('Ewing sarcoma', 'Disease', (191, 204))	('figitumumab', 'Chemical', 'MESH:C525021', (131, 142))	('IGF1-R', 'Gene', '3480', (96, 102))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (191, 204))	('STS', 'Phenotype', 'HP:0030448', (176, 179))
530807	31963219	Activation of the mTOR pathway due to TSC1/TSC2 mutation has been observed in PEComa.	('PEComa', 'Disease', (78, 84))	('mTOR pathway', 'Pathway', (18, 30))	('Activation', 'PosReg', (0, 10))	('mutation', 'Var', (48, 56))	('TSC1', 'Gene', '7248', (38, 42))	('TSC2', 'Gene', '7249', (43, 47))	('PEComa', 'Disease', 'MESH:D054973', (78, 84))	('TSC1', 'Gene', (38, 42))	('TSC2', 'Gene', (43, 47))
530813	31963219	The investigation of MDM2 inhibitors has been limited to preclinical and early-phase trials, but there are some phase 2 results for CDK4 inhibitors; liposarcomas showed modest responses to them.	('liposarcomas', 'Disease', 'MESH:D008080', (149, 161))	('CDK4', 'Gene', '1019', (132, 136))	('liposarcoma', 'Phenotype', 'HP:0012034', (149, 160))	('liposarcomas', 'Phenotype', 'HP:0012034', (149, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('liposarcomas', 'Disease', (149, 161))	('inhibitors', 'Var', (137, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('CDK4', 'Gene', (132, 136))
530828	31963219	Where such evidence is available, the preclinical expectancy did not correlate with the clinical results; e.g., for the IGF1-R targeted therapy.	('IGF1-R', 'Gene', '3480', (120, 126))	('targeted therapy', 'Var', (127, 143))	('IGF1-R', 'Gene', (120, 126))
530830	31963219	Regarding STS, the anaplastic lymphoma kinase (ALK) and neurotrophic receptor kinase (NTRK) rearranged fusion genes are good examples.	('rearranged fusion', 'Var', (92, 109))	('anaplastic lymphoma kinase', 'Gene', (19, 45))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (19, 38))	('ALK', 'Gene', (47, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (30, 38))	('STS', 'Phenotype', 'HP:0030448', (10, 13))	('ALK', 'Gene', '238', (47, 50))	('anaplastic lymphoma kinase', 'Gene', '238', (19, 45))
530833	31963219	Solid tumors (regardless of tumor origin) showed high responses to NTRK-targeted TKIs, and the NTRK-targeted TKIs were approved for the treatment of solid tumors with NTRK rearrangements, including STS.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (28, 33))	('solid tumors', 'Disease', 'MESH:D009369', (149, 161))	('Solid tumors', 'Disease', 'MESH:D009369', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('rearrangements', 'Var', (172, 186))	('STS', 'Phenotype', 'HP:0030448', (198, 201))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('NTRK', 'Gene', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('Solid tumors', 'Disease', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('solid tumors', 'Disease', (149, 161))	('tumor', 'Disease', (6, 11))
530855	31963219	ALK anaplastic lymphoma kinase  ASPS alveolar soft part sarcoma  CDK4 cyclin-dependent kinase 4  EMA European Medicines Agency  EORTC European Organisation for Research and Treatment of Cancer  FDA Food and Drug Administration  GIST gastrointestinal stromal tumor  IGF1-R insulin-like growth factor 1 receptor  IMT inflammatory myofibroblastic tumor  MDM2 murine double minute 2  MSI microsatellite instability  MPNST malignant peripheral nerve sheath tumor  mTOR mammalian target of rapamycin  NGS next generation sequencing  NTRK neurotrophic receptor kinase  OS overall survival  PDGFR platelet-derived growth factor receptor  PD-L1 programmed death ligand-1  PEComa perivascular epithelioid cell tumor  PFS progression-free survival  PI3K phosphatidylinositol 3-kinase  STS soft tissue sarcoma  TKI tyrosine kinase inhibitor  TMB tumor mutation burden  UPS undifferentiated pleomorphic sarcoma  VEGF vascular endothelial growth factor  XPO1 exportin-1	('anaplastic lymphoma kinase', 'Gene', '238', (4, 30))	('IGF1-R', 'Gene', '3480', (265, 271))	('programmed death ligand-1', 'Gene', (636, 661))	('mammalian target of rapamycin', 'Gene', '2475', (464, 493))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('myofibroblastic tumor', 'Disease', (328, 349))	('myofibroblastic tumor', 'Disease', 'MESH:D009369', (328, 349))	('epithelioid cell tumor', 'Phenotype', 'HP:0032060', (683, 705))	('tumor', 'Disease', (452, 457))	('mutation', 'Var', (840, 848))	('CDK4', 'Gene', '1019', (65, 69))	('XPO1', 'Gene', (940, 944))	('MSI', 'Disease', 'MESH:D053842', (380, 383))	('tumor', 'Disease', 'MESH:D009369', (452, 457))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('ALK', 'Gene', (0, 3))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (890, 897))	('tumor', 'Disease', (258, 263))	('burden  UPS undifferentiated pleomorphic sarcoma', 'Disease', (849, 897))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (233, 263))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (4, 23))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('XPO1', 'Gene', '7514', (940, 944))	('tumor', 'Disease', (700, 705))	('tumor', 'Disease', (344, 349))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (743, 772))	('vascular endothelial growth factor', 'Gene', (904, 938))	('tumor', 'Disease', 'MESH:D009369', (700, 705))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (778, 797))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('tumor', 'Disease', (834, 839))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (328, 349))	('programmed death ligand-1', 'Gene', '29126', (636, 661))	('IGF1-R', 'Gene', (265, 271))	('PEComa perivascular epithelioid cell tumor', 'Disease', (663, 705))	('tumor', 'Disease', 'MESH:D009369', (834, 839))	('VEGF', 'Gene', (899, 903))	('PD-L1', 'Gene', (630, 635))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (46, 63))	('PD-L1', 'Gene', '29126', (630, 635))	('PEComa perivascular epithelioid cell tumor', 'Disease', 'MESH:D054973', (663, 705))	('sheath tumor', 'Disease', 'MESH:D018317', (445, 457))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (37, 63))	('burden  UPS undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D017118', (849, 897))	('murine double minute 2', 'Gene', (356, 378))	('TMB', 'Chemical', '-', (830, 833))	('ASPS', 'Phenotype', 'HP:0012218', (32, 36))	('murine double minute 2', 'Gene', '4193', (356, 378))	('cyclin-dependent kinase 4', 'Gene', (70, 95))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (778, 797))	('CDK4', 'Gene', (65, 69))	('PDGFR', 'Gene', '5159', (583, 588))	('soft tissue sarcoma', 'Disease', (778, 797))	('STS', 'Phenotype', 'HP:0030448', (774, 777))	('VEGF', 'Gene', '7422', (899, 903))	('GIST gastrointestinal stromal tumor', 'Disease', (228, 263))	('MSI', 'Disease', (380, 383))	('ASPS alveolar soft part sarcoma', 'Disease', (32, 63))	('PDGFR', 'Gene', (583, 588))	('GIST gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (228, 263))	('tumor', 'Phenotype', 'HP:0002664', (452, 457))	('anaplastic lymphoma kinase', 'Gene', (4, 30))	('Cancer', 'Disease', (186, 192))	('vascular endothelial growth factor', 'Gene', '7422', (904, 938))	('Cancer', 'Disease', 'MESH:D009369', (186, 192))	('phosphatidylinositol 3-kinase', 'Gene', (743, 772))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('cyclin-dependent kinase 4', 'Gene', '1019', (70, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (790, 797))	('mammalian target of rapamycin', 'Gene', (464, 493))	('sheath tumor', 'Disease', (445, 457))	('tumor', 'Phenotype', 'HP:0002664', (700, 705))	('ALK', 'Gene', '238', (0, 3))	('ASPS alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (32, 63))	('tumor', 'Phenotype', 'HP:0002664', (834, 839))	('TMB', 'Gene', (830, 833))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (418, 457))
530860	28638727	Particularly, in CMS5 tumor-bearing mice, we detected specific immune responses to mutated mitogen-activated protein kinase 2 (ERK2), which has previously been identified as an immunogenic mutated-antigen.	('mutated', 'Var', (83, 90))	('ERK2', 'Gene', '26413', (127, 131))	('ERK2', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mitogen-activated protein kinase 2', 'Gene', (91, 125))	('mitogen-activated protein kinase 2', 'Gene', '26413', (91, 125))	('tumor', 'Disease', (22, 27))	('mice', 'Species', '10090', (36, 40))
530861	28638727	Furthermore, by combining this approach with whole-exome and transcriptome sequencing analyses, we identified an immunogenic neo-epitope derived from mutated staphylococcal nuclease domain-containing protein 1 (Snd1) in CMS7 tumor-bearing mice.	('CMS7 tumor', 'Disease', (220, 230))	('staphylococcal nuclease domain-containing protein 1', 'Gene', '56463', (158, 209))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('Snd1', 'Gene', '56463', (211, 215))	('Snd1', 'Gene', (211, 215))	('CMS7 tumor', 'Disease', 'MESH:D020294', (220, 230))	('mutated', 'Var', (150, 157))	('mice', 'Species', '10090', (239, 243))
530867	28638727	This concept is further supported by the fact that tumors with a high load of somatic mutations are more likely to respond to this therapy.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('respond', 'MPA', (115, 122))	('high load', 'Var', (65, 74))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
530868	28638727	A second line of evidence supporting the role of immune responses against mutated tumor antigens for cancer treatment comes from adoptive tumor-infiltrating lymphocyte (TIL) therapy that has been used for treating patients with melanoma and a patient with cholangiocarcinoma.	('patients', 'Species', '9606', (214, 222))	('tumor', 'Disease', (138, 143))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (256, 274))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cholangiocarcinoma', 'Disease', (256, 274))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('patient', 'Species', '9606', (214, 221))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (256, 274))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanoma', 'Disease', (228, 236))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutated', 'Var', (74, 81))	('patient', 'Species', '9606', (243, 250))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
530869	28638727	Collectively, these results indicate that mutated antigens are key target antigens recognized by autologous T cells, which can cause a substantial reduction in tumor burden.	('mutated', 'Var', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('reduction', 'NegReg', (147, 156))	('tumor', 'Disease', (160, 165))	('antigens', 'Protein', (50, 58))
530907	28638727	Based on this information, we tested whether immune responses to the mERK2-9m peptide became detectable following intra-peritoneal administration of anti-CTLA-4, PD-1 and GITR antibodies.	('mERK2-9', 'Gene', '26413;225724;23939;29857;332110', (69, 76))	('tested', 'Reg', (30, 36))	('GITR', 'Gene', (171, 175))	('PD-1', 'Gene', '18566', (162, 166))	('PD-1', 'Gene', (162, 166))	('anti-CTLA-4', 'Var', (149, 160))	('GITR', 'Gene', '21936', (171, 175))	('mERK2-9', 'Gene', (69, 76))
530917	28638727	In both mouse groups, we observed a significant increase in CXCL9 mRNA levels following the addition of only a single neo-epitope derived from mutated Snd1 (staphylococcal nuclease domain-containing protein 1) (Fig.	('CXCL9 mRNA levels', 'MPA', (60, 77))	('staphylococcal nuclease domain-containing protein 1', 'Gene', '56463', (157, 208))	('mouse', 'Species', '10090', (8, 13))	('mutated', 'Var', (143, 150))	('Snd1', 'Gene', '56463', (151, 155))	('Snd1', 'Gene', (151, 155))	('increase', 'PosReg', (48, 56))
530926	28638727	In addition, recent clinical studies have shown that the expression of these chemokines in tumor tissue before treatment was positively associated with a favorable clinical response to immunotherapies, such as a cancer vaccine targeting MAGE-A3, an immunogenic cancer/testis antigen, and an immunotherapy using an anti-CTLA-4 antibody for melanoma patients.	('patients', 'Species', '9606', (348, 356))	('cancer', 'Disease', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('melanoma', 'Disease', 'MESH:D008545', (339, 347))	('MAGE-A3', 'Gene', '4102', (237, 244))	('expression', 'Var', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('melanoma', 'Phenotype', 'HP:0002861', (339, 347))	('MAGE-A3', 'Gene', (237, 244))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('tumor', 'Disease', (91, 96))	('melanoma', 'Disease', (339, 347))	('associated with', 'Reg', (136, 151))
530928	28638727	To examine the feasibility of this approach for identifying immunogenic neo-epitopes, we used a murine CMS5 tumor model since our group has previously identified a mutated ERK2-derived neo-epitope (mERK2-9m) as a tumor rejection antigen of CMS5 tumors, by cDNA cloning from a CD8+ T-cell clone (C18), established from draining lymph node cells of CMS5 tumor-bearing mice.	('mERK2-9', 'Gene', (198, 205))	('CMS5 tumors', 'Disease', (240, 251))	('ERK2', 'Gene', '26413', (199, 203))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('ERK2', 'Gene', (172, 176))	('mutated', 'Var', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('mERK2-9', 'Gene', '26413;225724;23939;29857;332110', (198, 205))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('CD8', 'Gene', '925', (276, 279))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CMS5 tumors', 'Disease', 'MESH:C566415', (240, 251))	('tumor', 'Disease', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ERK2', 'Gene', '26413', (172, 176))	('ERK2', 'Gene', (199, 203))	('tumor', 'Disease', (245, 250))	('CD8', 'Gene', (276, 279))	('mice', 'Species', '10090', (366, 370))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('murine', 'Species', '10090', (96, 102))
530932	28638727	6, we successfully detected CD8+ T-cell immune response to a single neo-epitope (YAPCRGEF) derived from mutated Snd1 in the CMS7 tumor model even without the checkpoint antibody treatment.	('mutated', 'Var', (104, 111))	('CMS7 tumor', 'Disease', (124, 134))	('CD8', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Snd1', 'Gene', '56463', (112, 116))	('Snd1', 'Gene', (112, 116))	('CD8', 'Gene', '925', (28, 31))	('CMS7 tumor', 'Disease', 'MESH:D020294', (124, 134))
530934	28638727	However, under different conditions, our approach might be more sensitive compared with the IFNgamma ELISPOT assay, since we could not detect specific immune responses to mERK2-9m or the mutated Snd1-derived neo-epitope by the IFNgamma ELISPOT assay, in antibody-treated CMS5 tumor-bearing mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('mERK2-9', 'Gene', '26413;225724;23939;29857;332110', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('mutated', 'Var', (187, 194))	('mERK2-9', 'Gene', (171, 178))	('tumor', 'Disease', (276, 281))	('Snd1', 'Gene', '56463', (195, 199))	('Snd1', 'Gene', (195, 199))	('mice', 'Species', '10090', (290, 294))
530973	28638727	Human lymphocytes (1 x 106) were cultured in 200 muL X-VIVO 15 (Lonza, Walkersville, MD, USA) in 96-well V-bottom plates in the presence of anti-human CD119, anti-human IFNgamma, or mouse IgG1 isotype control (final 10 microg/mL) for 1 h before the addition of the EBNA3A246-254 peptide.	('Human', 'Species', '9606', (0, 5))	('anti-human', 'Var', (140, 150))	('CD119', 'Gene', '15979', (151, 156))	('mouse', 'Species', '10090', (182, 187))	('IgG1', 'Gene', '16017', (188, 192))	('human', 'Species', '9606', (145, 150))	('human', 'Species', '9606', (163, 168))	('CD119', 'Gene', (151, 156))	('IgG1', 'Gene', (188, 192))
530976	28638727	Somatic single nucleotide variants (SNVs) were detected from read count comparisons between normal and tumor samples using the Fisher exact test, and variants whose p-value was less than 10-10 were considered as statistically significant.	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('single nucleotide variants', 'Var', (8, 34))
530978	28638727	Briefly, all candidate neo-epitopes (8-10-mer) containing missense mutations were analyzed in silico for their binding affinities to either H-2Kd, H-2Dd or H-2Ld molecules based on the IEDB recommended method (Consensus) consisting of the Artificial Neural Network (ANN), the Stabilized Matrix Method (SMM), and the Scoring Matrices derived from Combinatorial Peptide Libraries (Comblib_Sidney2008) algorithms.	('H-2', 'Gene', '111364', (147, 150))	('H-2', 'Gene', '111364', (140, 143))	('H-2', 'Gene', (156, 159))	('mutations', 'Var', (67, 76))	('missense mutations', 'Var', (58, 76))	('binding', 'Interaction', (111, 118))	('H-2', 'Gene', (147, 150))	('H-2', 'Gene', '111364', (156, 159))	('Combinatorial Peptide Libraries (Comblib_Sidney2008) algorithms', 'Disease', 'MESH:C565529', (346, 409))	('H-2', 'Gene', (140, 143))
530979	28638727	Primers and probes were selected from the ABI TaqMan Gene Expression Assay catalog (for human targets: CXCL9, Hs00171065_m1; CXCL10, Hs01124251_g1; CXCL11, Hs04187682_g1; IFNgamma, Hs00989291_m1; TNFalpha, Hs01113624_g1; CCL3, Hs00234142_m1; CCL4, Hs00237011_m1; CCL5, Hs00174575_m1; TRAIL, Hs00921974_m1; and IL-13, Hs00174379_m1; for mouse targets: CXCL9, Mm00434946_m1; CXCL10, Mm00445235_m1; CXCL11, and Mm00444662_m1).	('CCL4', 'Gene', '20303', (242, 246))	('TNFalpha', 'Gene', '7124', (196, 204))	('CCL4', 'Gene', (242, 246))	('Mm00445235_m1', 'Var', (381, 394))	('human', 'Species', '9606', (88, 93))	('mouse', 'Species', '10090', (336, 341))	('Mm00444662_m1', 'Var', (408, 421))	('TNFalpha', 'Gene', (196, 204))	('Mm00434946_m1', 'Var', (358, 371))
531092	26415226	Next generation sequencing in synovial sarcoma reveals novel gene mutations Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior.	('mutations', 'Var', (66, 75))	('synovial sarcomas', 'Disease', (92, 109))	('synovial sarcomas', 'Disease', 'MESH:D013584', (92, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (92, 108))	('synovial sarcoma', 'Disease', (30, 46))	('SS', 'Phenotype', 'HP:0100242', (111, 113))	('synovial sarcoma', 'Disease', 'MESH:D013584', (92, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (92, 109))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (30, 46))	('synovial sarcoma', 'Disease', 'MESH:D013584', (30, 46))	('SS', 'Phenotype', 'HP:0012570', (111, 113))
531094	26415226	Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA).	('tumors', 'Disease', (42, 48))	('Copy number variation', 'Var', (0, 21))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
531096	26415226	Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4.	('CSMD3', 'Gene', (58, 63))	('mutations', 'Var', (11, 20))	('CSMD3', 'Gene', '114788', (58, 63))	('ERBB4', 'Gene', (74, 79))	('KDR', 'Gene', '3791', (53, 56))	('RNF213', 'Gene', (38, 44))	('MLH1', 'Gene', '4292', (65, 69))	('MLH1', 'Gene', (65, 69))	('SEPT9', 'Gene', '10801', (46, 51))	('KDR', 'Gene', (53, 56))	('RNF213', 'Gene', '57674', (38, 44))	('ERBB4', 'Gene', '2066', (74, 79))	('SEPT9', 'Gene', (46, 51))
531109	26415226	Interestingly, similar mutations are shared by different cancer types, and within one cancer type different genetic subtypes can be found, explaining its biologic behavior and/or therapy response.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
531110	26415226	In addition, differences in mutations have been observed between primary tumors and their metastases, thereby providing insight in tumor evolution and therapy resistance.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('metastases', 'Disease', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', (73, 78))	('tumors', 'Disease', (73, 79))	('mutations', 'Var', (28, 37))
531111	26415226	Sarcomas have also been subject to genetic screening, which has led to diagnostic implementation in several subtypes, including gene amplifications in well-differentiated and dedifferentiated liposarcomas or distinct chromosomal translocations in, among others, myxoid liposarcomas.	('liposarcomas', 'Disease', (269, 281))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('myxoid liposarcomas', 'Disease', (262, 281))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (262, 281))	('sarcomas', 'Phenotype', 'HP:0100242', (273, 281))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (262, 281))	('well-differentiated', 'Disease', (151, 170))	('liposarcomas', 'Disease', 'MESH:D008080', (192, 204))	('liposarcomas', 'Phenotype', 'HP:0012034', (192, 204))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('chromosomal translocations', 'Var', (217, 243))	('liposarcomas', 'Disease', (192, 204))	('liposarcomas', 'Phenotype', 'HP:0012034', (269, 281))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('sarcomas', 'Phenotype', 'HP:0100242', (196, 204))	('liposarcomas', 'Disease', 'MESH:D008080', (269, 281))	('Sarcomas', 'Disease', (0, 8))
531112	26415226	Additionally, the discovery and treatment of the targetable alterations in hot spot regions in the KIT or PDGFRA genes in gastrointestinal stromal tumors (GIST) has significantly improved overall survival of these patients.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('improved', 'PosReg', (179, 187))	('PDGFRA', 'Gene', '5156', (106, 112))	('gastrointestinal stromal tumors', 'Disease', (122, 153))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (122, 153))	('patients', 'Species', '9606', (214, 222))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (122, 153))	('KIT', 'Gene', (99, 102))	('alterations', 'Var', (60, 71))	('GIST', 'Phenotype', 'HP:0100723', (155, 159))	('PDGFRA', 'Gene', (106, 112))	('overall', 'MPA', (188, 195))
531113	26415226	A unique reciprocal translocation between chromosome X and 18 in over 95% of SS tumors was already reported in 1994, leading to fusions between one of the SSX genes (1, 2 or 4) and the SS18 (SYT) gene.	('SS tumors', 'Disease', (77, 86))	('fusions', 'Var', (128, 135))	('SYT', 'Gene', '6760', (191, 194))	('SS', 'Phenotype', 'HP:0012570', (77, 79))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SYT', 'Gene', (191, 194))	('SS', 'Phenotype', 'HP:0100242', (77, 79))	('SS', 'Phenotype', 'HP:0100242', (185, 187))	('SS18', 'Gene', '6760', (185, 189))	('SS', 'Phenotype', 'HP:0100242', (155, 157))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('SS', 'Phenotype', 'HP:0012570', (185, 187))	('SS tumors', 'Disease', 'MESH:D009369', (77, 86))	('SSX', 'Gene', '6757', (155, 158))	('SSX', 'Gene', (155, 158))	('SS18', 'Gene', (185, 189))	('SS', 'Phenotype', 'HP:0012570', (155, 157))
531116	26415226	As knockdown of the fusion protein leads to cell death in vitro and in vivo and introduction of the translocation in mice forms histologically alike tumors, the translocation is believed to act as the central oncogenic driver in SS.	('SS', 'Phenotype', 'HP:0012570', (229, 231))	('translocation', 'Var', (161, 174))	('alike tumors', 'Disease', 'MESH:D009369', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mice', 'Species', '10090', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('alike tumors', 'Disease', (143, 155))	('SS', 'Phenotype', 'HP:0100242', (229, 231))
531118	26415226	Secondly, Sanger sequencing of synovial sarcomas has revealed mutations in several cancer-related genes, including TP53, TERT, CDH1, CTNBB1, APC, HRAS, PTEN, PI3KCA, EGFR, BCL9, SETD2, TRRAP and PDGFRA (Table 1).	('BCL9', 'Gene', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('EGFR', 'Gene', '1956', (166, 170))	('APC', 'Disease', 'MESH:D011125', (141, 144))	('TRRAP', 'Gene', '8295', (185, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('APC', 'Disease', (141, 144))	('SETD2', 'Gene', (178, 183))	('CTNBB1', 'Gene', (133, 139))	('PDGFRA', 'Gene', '5156', (195, 201))	('PDGFRA', 'Gene', (195, 201))	('HRAS', 'Gene', '3265', (146, 150))	('SETD2', 'Gene', '29072', (178, 183))	('HRAS', 'Gene', (146, 150))	('TP53', 'Gene', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('mutations', 'Var', (62, 71))	('BCL9', 'Gene', '607', (172, 176))	('PTEN', 'Gene', (152, 156))	('EGFR', 'Gene', (166, 170))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (31, 48))	('TERT', 'Gene', (121, 125))	('synovial sarcomas', 'Disease', (31, 48))	('TERT', 'Gene', '7015', (121, 125))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (31, 47))	('CDH1', 'Gene', '999', (127, 131))	('revealed', 'Reg', (53, 61))	('TP53', 'Gene', '7157', (115, 119))	('PTEN', 'Gene', '5728', (152, 156))	('TRRAP', 'Gene', (185, 190))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('CDH1', 'Gene', (127, 131))	('cancer', 'Disease', (83, 89))	('synovial sarcomas', 'Disease', 'MESH:D013584', (31, 48))
531121	26415226	Besides several mutations of unknown function, driver mutations in TP53 and SETD2 were found in one sample each.	('SETD2', 'Gene', (76, 81))	('mutations', 'Var', (54, 63))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('SETD2', 'Gene', '29072', (76, 81))
531129	26415226	We included tumors with both histology and translocation subtypes (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('translocation', 'Var', (43, 56))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
531134	26415226	In total 77,995 variants were called in the 26 tumors (range 755 - 5713).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('variants', 'Var', (16, 24))
531136	26415226	Seven of these mutations were found in primary tumor samples derived from therapy naive patients.	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
531138	26415226	The mutations in the oncogenes KRAS and CCND1 genes are well-established oncogenic mutations in other cancer types.	('KRAS', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('KRAS', 'Gene', '3845', (31, 35))	('CCND1', 'Gene', (40, 45))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('mutations', 'Var', (4, 13))	('CCND1', 'Gene', '595', (40, 45))
531139	26415226	The sample harboring the CCND1 mutation was further evaluated by immunohistochemistry, showing abundant over-expression of the protein (Figure 2).	('CCND1', 'Gene', (25, 30))	('over-expression', 'PosReg', (104, 119))	('CCND1', 'Gene', '595', (25, 30))	('mutation', 'Var', (31, 39))
531140	26415226	The sample harboring the MLH1 mutation was also evaluated by immunohistochemistry for MLH1, MSH2, MSH6 or PMS2 expression in accordance to the effect of MLH1 in Lynch.	('MLH1', 'Gene', '4292', (153, 157))	('MSH2', 'Gene', (92, 96))	('MLH1', 'Gene', (153, 157))	('MSH2', 'Gene', '4436', (92, 96))	('MSH6', 'Gene', '2956', (98, 102))	('PMS2', 'Gene', '5395', (106, 110))	('mutation', 'Var', (30, 38))	('MLH1', 'Gene', '4292', (25, 29))	('MLH1', 'Gene', (25, 29))	('MSH6', 'Gene', (98, 102))	('MLH1', 'Gene', '4292', (86, 90))	('MLH1', 'Gene', (86, 90))	('PMS2', 'Gene', (106, 110))
531141	26415226	However, no lack of expression of any of these proteins was found (data not shown) in the tumor sample with the MLH1 mutation.	('MLH1', 'Gene', '4292', (112, 116))	('MLH1', 'Gene', (112, 116))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutation', 'Var', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
531144	26415226	In addition, we extended the sequencing with coding exons 1-5 of the CCND1 gene and coding exons 2-5 of the KRAS gene, as the mutations that we found in these genes are proven pathogenic and, therefore, these two genes were considered to be of particular interest.	('KRAS', 'Gene', (108, 112))	('CCND1', 'Gene', '595', (69, 74))	('KRAS', 'Gene', '3845', (108, 112))	('mutations', 'Var', (126, 135))	('CCND1', 'Gene', (69, 74))
531146	26415226	To this end, we compared the aligned number of reads per gene generated by NGS in tumor tissue with the aligned number of reads per gene in healthy tissue.	('tumor', 'Disease', (82, 87))	('NGS', 'Var', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))
531148	26415226	Interestingly, differences in copy number alterations were seen in 2 of the 4 paired tumor lesions (Figure 3B) with additional deletions, duplications and loss of earlier duplications between the primary tumor and its corresponding metastasis.	('tumor lesions', 'Disease', (85, 98))	('tumor', 'Disease', (85, 90))	('loss', 'NegReg', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('copy number', 'Var', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('deletions', 'Var', (127, 136))	('tumor', 'Disease', (204, 209))	('tumor lesions', 'Disease', 'MESH:D051437', (85, 98))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('duplications', 'Var', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
531150	26415226	An additional (partial) deletion of chromosome 6q was found in 2 other tumors of cohort 1.	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('deletion', 'Var', (24, 32))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
531151	26415226	Another recurrent finding was loss of heterozygosity (LOH) in 5 of the 6 tumor samples at 3q13.33.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('heterozygosity', 'Var', (38, 52))	('tumor', 'Disease', (73, 78))	('loss', 'NegReg', (30, 34))
531152	26415226	Overall, tumors with chromosomal aberrations were more frequently seen in adults (34.5%) compared to children (12.5%), however this was not significant (p = 0.07).	('chromosomal aberrations', 'Var', (21, 44))	('children', 'Species', '9606', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (21, 44))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (21, 43))
531156	26415226	Using a next generation sequencing platform, we detected pathogenic mutations that have so far not been reported in synovial sarcoma.	('synovial sarcoma', 'Disease', (116, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('mutations', 'Var', (68, 77))	('synovial sarcoma', 'Disease', 'MESH:D013584', (116, 132))
531161	26415226	Mutations at codon 287, by which the proline changes to threonine or serine, have been reported in endometrial carcinomas.	('threonine', 'Chemical', 'MESH:D013912', (56, 65))	('proline', 'Chemical', 'MESH:D011392', (37, 44))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (99, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('reported', 'Reg', (87, 95))	('proline changes to threonine', 'MPA', (37, 65))	('Mutations', 'Var', (0, 9))	('endometrial carcinomas', 'Disease', (99, 121))	('serine', 'Chemical', 'MESH:D012694', (69, 75))	('serine', 'MPA', (69, 75))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (99, 121))
531162	26415226	These mutations result in nuclear accumulation of the active Cyclin D1/CDK complex, which is refractory to rapid degradation via the 26S proteasome.	('Cyclin D1', 'Gene', '595', (61, 70))	('nuclear accumulation', 'MPA', (26, 46))	('result in', 'Reg', (16, 25))	('Cyclin D1', 'Gene', (61, 70))	('active', 'MPA', (54, 60))	('mutations', 'Var', (6, 15))
531163	26415226	In our cohort, we identified a c.859C > G (p.P287A) mutation and, concomitantly, we observed a cyclin D1 accumulation by immunohistochemistry.	('c.859C > G', 'Mutation', 'c.859C>G', (31, 41))	('p.P287A', 'Mutation', 'p.P287A', (43, 50))	('cyclin D1', 'Gene', '595', (95, 104))	('cyclin D1', 'Gene', (95, 104))	('c.859C > G', 'Var', (31, 41))
531165	26415226	The single nucleotide substitution c.34C > A that we found represents an activating mutation known to result in oncogenesis in several adenocarcinomas.	('adenocarcinomas', 'Disease', 'MESH:D000230', (135, 150))	('c.34C > A', 'Mutation', 'rs587782084', (35, 44))	('adenocarcinomas', 'Disease', (135, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('c.34C > A', 'Var', (35, 44))
531166	26415226	Non small cell lung cancer cell lines with this mutant had activated phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutant', 'Var', (48, 54))	('MEK', 'Gene', (182, 185))	('MEK', 'Gene', '5609', (182, 185))	('Non small cell lung cancer', 'Disease', 'MESH:D002289', (0, 26))	('mitogen-activated protein/extracellular signal-regulated kinase kinase', 'Gene', '5609', (110, 180))	('activated', 'PosReg', (59, 68))	('Non small cell lung cancer', 'Disease', (0, 26))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (4, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
531168	26415226	As all eight mutations are found in genes involved in different pathways, including regulation of EGFR degradation (SEPT9) or the EGFR-pathway (ERBB4), angiogenesis (KDR, RNF213), proliferation (CSMD3) and mismatch repair (MLH1) pathways, no uniform suitable therapeutic target has emerged.	('RNF213', 'Gene', (171, 177))	('ERBB4', 'Gene', '2066', (144, 149))	('ERBB4', 'Gene', (144, 149))	('MLH1', 'Gene', '4292', (223, 227))	('EGFR', 'Gene', (130, 134))	('KDR', 'Gene', '3791', (166, 169))	('CSMD3', 'Gene', '114788', (195, 200))	('EGFR', 'Gene', (98, 102))	('SEPT9', 'Gene', (116, 121))	('CSMD3', 'Gene', (195, 200))	('proliferation', 'Pathway', (180, 193))	('EGFR', 'Gene', '1956', (98, 102))	('mutations', 'Var', (13, 22))	('EGFR', 'Gene', '1956', (130, 134))	('angiogenesis', 'Pathway', (152, 164))	('SEPT9', 'Gene', '10801', (116, 121))	('KDR', 'Gene', (166, 169))	('RNF213', 'Gene', '57674', (171, 177))	('MLH1', 'Gene', (223, 227))
531169	26415226	The 5-year overall survival was significantly worse in patients whose tumor harbored an additional mutation, which should be further investigated in a larger cohort.	('overall survival', 'MPA', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('mutation', 'Var', (99, 107))	('worse', 'NegReg', (46, 51))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
531170	26415226	Mutations were more often found in adult tumors compared to tumors with an onset in patient younger than 18 years (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('adult tumors', 'Disease', 'MESH:C538052', (35, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('found', 'Reg', (26, 31))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('adult tumors', 'Disease', (35, 47))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('patient', 'Species', '9606', (84, 91))	('tumors', 'Disease', (60, 66))
531179	26415226	From this study we conclude that not only mutations or copy number changes may underlie the immense complexity of human cancers, including SS, and, based on our and previous results, also further epigenetic research might be a way to explore the genetic nature of SS.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('underlie', 'Reg', (79, 87))	('copy number changes', 'Var', (55, 74))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('SS', 'Phenotype', 'HP:0100242', (264, 266))	('SS', 'Phenotype', 'HP:0100242', (139, 141))	('SS', 'Phenotype', 'HP:0012570', (264, 266))	('SS', 'Phenotype', 'HP:0012570', (139, 141))	('mutations', 'Var', (42, 51))
531193	26415226	After blocking of endogenous peroxidase with 3% hydrogen peroxide in methanol, sections were incubated for 1h at room temperature (RT) with the primary antibody against Cyclin D1 (ILM 30442, clone SP4; 1:40 dilution; Immunologic), MLH1 (551092, clone G168-15; 1:40 dilution; BD Pharmingen), MSH2 (NA26, clone GB12; 1:40 dilution; Calbiochem), MSH6 (ab92471, clone EPR3945; 1:500 dilution; Abcam) or PMS2 (556415, clone A16-4; 1:100 dilution; BD Pharmingen).	('MLH1', 'Gene', '4292', (231, 235))	('MSH6', 'Gene', '2956', (343, 347))	('MLH1', 'Gene', (231, 235))	('Cyclin D1', 'Gene', '595', (169, 178))	('MSH2', 'Gene', (291, 295))	('MSH2', 'Gene', '4436', (291, 295))	('Cyclin D1', 'Gene', (169, 178))	('PMS2', 'Gene', (399, 403))	('556415', 'Var', (405, 411))	('MSH6', 'Gene', (343, 347))	('gain', 'Disease', (162, 166))	('gain', 'Disease', 'MESH:D015430', (162, 166))	('PMS2', 'Gene', '5395', (399, 403))	('ethanol', 'Chemical', 'MESH:D000431', (70, 77))
531242	25928192	Of note, one patient presented with paroxysmal symptoms of catecholamine excess and was found to have a hormone secreting left atrial paraganglioma linked to a succinate dehydrogenase mutation.	('atrial paraganglioma', 'Disease', (127, 147))	('catecholamine', 'Chemical', 'MESH:D002395', (59, 72))	('paraganglioma', 'Phenotype', 'HP:0002668', (134, 147))	('patient', 'Species', '9606', (13, 20))	('linked', 'Reg', (148, 154))	('presented', 'Reg', (21, 30))	('paroxysmal symptoms', 'MPA', (36, 55))	('catecholamine excess', 'MPA', (59, 79))	('catecholamine excess', 'Phenotype', 'HP:0003334', (59, 79))	('atrial paraganglioma', 'Disease', 'MESH:D010235', (127, 147))	('mutation', 'Var', (184, 192))
531270	25928192	Patients who underwent adjuvant combination chemotherapy or doxorubicin and radiation had a mean survival of 45.7 +- 16.4 months compared to 4.2 +- 1.4 months in patients who were treated with either radiation alone (median survival was 4 months) or mono-chemotherapy (median survival was 5 months) or who did not receive any adjuvant therapy.	('patients', 'Species', '9606', (162, 170))	('doxorubicin', 'Chemical', 'MESH:D004317', (60, 71))	('combination chemotherapy', 'Var', (32, 56))	('Patients', 'Species', '9606', (0, 8))	('doxorubicin', 'Var', (60, 71))
531303	31480474	Using data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR GENIE) database, we cataloged genetic alterations and assessed their clinical utility from thirteen patients with intimal sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (246, 253))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('sarcoma', 'Disease', (246, 253))	('Cancer', 'Disease', (45, 51))	('Neoplasia', 'Phenotype', 'HP:0002664', (87, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('patients', 'Species', '9606', (224, 232))	('Neoplasia', 'Disease', (87, 96))	('genetic alterations', 'Var', (154, 173))	('Neoplasia', 'Disease', 'MESH:D009369', (87, 96))
531304	31480474	Notable copy number alterations included amplification in MDM2, CDK4, PDGFRA, and NOTCH2, as well as copy number losses in CDKN2A and CDKN2B.	('NOTCH2', 'Gene', (82, 88))	('CDK4', 'Gene', (64, 68))	('PDGFRA', 'Gene', '5156', (70, 76))	('PDGFRA', 'Gene', (70, 76))	('NOTCH2', 'Gene', '4853', (82, 88))	('CDK4', 'Gene', '1019', (64, 68))	('CDKN2B', 'Gene', (134, 140))	('copy', 'MPA', (101, 105))	('CDKN2A', 'Gene', (123, 129))	('losses', 'NegReg', (113, 119))	('amplification', 'Var', (41, 54))	('MDM2', 'Gene', '4193', (58, 62))	('CDKN2A', 'Gene', '1029', (123, 129))	('MDM2', 'Gene', (58, 62))	('CDKN2B', 'Gene', '1030', (134, 140))
531305	31480474	Actionable alterations included mutations in ATM/ATR, PTCH1, and PDGFRB.	('PTCH1', 'Gene', (54, 59))	('PDGFRB', 'Gene', '5159', (65, 71))	('ATM', 'Gene', '472', (45, 48))	('PDGFRB', 'Gene', (65, 71))	('mutations', 'Var', (32, 41))	('ATR', 'Gene', (49, 52))	('ATR', 'Gene', '545', (49, 52))	('PTCH1', 'Gene', '5727', (54, 59))	('ATM', 'Gene', (45, 48))
531307	31480474	Co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion positive tumor and PDGFRB mutations in both fusion-positive cases.	('PDE4DIP', 'Gene', '9659', (67, 74))	('NOTCH2', 'Gene', '4853', (36, 42))	('mutations', 'Var', (115, 124))	('NOTCH2', 'Gene', '4853', (75, 81))	('PDE4DIP', 'Gene', (67, 74))	('PDGFRB', 'Gene', '5159', (108, 114))	('gain', 'PosReg', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('copy number', 'Var', (43, 54))	('PDGFRB', 'Gene', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NOTCH2', 'Gene', (36, 42))	('tumor', 'Disease', (98, 103))	('NOTCH2', 'Gene', (75, 81))
531321	31480474	They also discovered concurrent PDGFRalpha amplification and PDGFRbeta R709H mutation in intimal sarcoma.	('R709H', 'Mutation', 'p.R709H', (71, 76))	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('PDGFRbeta', 'Gene', '5159', (61, 70))	('PDGFRalpha', 'Gene', '5156', (32, 42))	('sarcoma', 'Disease', (97, 104))	('PDGFRbeta', 'Gene', (61, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('PDGFRalpha', 'Gene', (32, 42))	('R709H mutation', 'Var', (71, 85))
531322	31480474	The largest study of cardiac sarcomas analyzed tissue samples from 100 cases, and found intimal sarcomas to be the most frequent subtype of cardiac sarcoma, with amplification of MDM2 in all cases.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('cardiac sarcomas', 'Disease', (21, 37))	('cardiac sarcomas', 'Disease', 'MESH:D006331', (21, 37))	('MDM2', 'Gene', (179, 183))	('cardiac sarcomas', 'Phenotype', 'HP:0031350', (21, 37))	('cardiac sarcoma', 'Disease', 'MESH:D006331', (140, 155))	('amplification', 'Var', (162, 175))	('cardiac sarcoma', 'Disease', 'MESH:D006331', (21, 36))	('MDM2', 'Gene', '4193', (179, 183))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcomas', 'Disease', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))	('cardiac sarcoma', 'Phenotype', 'HP:0031350', (140, 155))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('cardiac sarcoma', 'Phenotype', 'HP:0031350', (21, 36))	('sarcomas', 'Disease', (96, 104))	('cardiac sarcoma', 'Disease', (140, 155))
531323	31480474	They also identified copy gains of CDK4, HMGA2, DDIT3, and GLI coinciding with 12q12-15 region via immunohistochemical analysis and confirmed with fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (RT PCR), and aCGH.	('12q12-15', 'Disease', (79, 87))	('CDK4', 'Gene', '1019', (35, 39))	('copy gains', 'Var', (21, 31))	('12q12-15', 'Disease', 'MESH:C567193', (79, 87))	('HMGA2', 'Gene', '8091', (41, 46))	('DDIT3', 'Gene', (48, 53))	('HMGA2', 'Gene', (41, 46))	('CDK4', 'Gene', (35, 39))
531324	31480474	Other findings included copy gains in 4q12 with KIT and PDGFRA, 7p12 with EGFR, and copy number loss of CDKN2A in 9p21.	('CDKN2A', 'Gene', '1029', (104, 110))	('KIT', 'Gene', (48, 51))	('copy gains', 'Var', (24, 34))	('PDGFRA', 'Gene', '5156', (56, 62))	('copy number loss', 'Var', (84, 100))	('PDGFRA', 'Gene', (56, 62))	('EGFR', 'Gene', '1956', (74, 78))	('CDKN2A', 'Gene', (104, 110))	('KIT', 'Gene', '3815', (48, 51))	('EGFR', 'Gene', (74, 78))
531325	31480474	Another study of IS, which was the first to propose PDGFRA as a molecular hallmark for intimal sarcomas, found copy number gains of PDGFRA, EGFR, and MDM2 in 8 patients using FISH and aCGH with consistent activation of PDGFR and EGFR confirmed by western blotting.	('EGFR', 'Gene', (140, 144))	('MDM2', 'Gene', '4193', (150, 154))	('EGFR', 'Gene', '1956', (229, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('PDGFRA', 'Gene', (52, 58))	('PDGFRA', 'Gene', '5156', (52, 58))	('PDGFRA', 'Gene', (132, 138))	('PDGFRA', 'Gene', '5156', (132, 138))	('copy number', 'Var', (111, 122))	('EGFR', 'Gene', '1956', (140, 144))	('EGFR', 'Gene', (229, 233))	('PDGFR', 'Gene', (219, 224))	('gains', 'PosReg', (123, 128))	('PDGFR', 'Gene', (52, 57))	('PDGFR', 'Gene', '5159', (219, 224))	('PDGFR', 'Gene', '5159', (52, 57))	('patients', 'Species', '9606', (160, 168))	('PDGFR', 'Gene', (132, 137))	('PDGFR', 'Gene', '5159', (132, 137))	('MDM2', 'Gene', (150, 154))	('sarcomas', 'Disease', 'MESH:D012509', (95, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('sarcomas', 'Disease', (95, 103))
531328	31480474	Conversely, cells with the most atypia and aberrancy were found to have over-amplification of PDGFRA, suggesting PDGFRA is needed for tumorigenesis and the biopsy site is crucial for molecular studies.	('PDGFRA', 'Gene', '5156', (113, 119))	('aberrancy', 'Var', (43, 52))	('over-amplification', 'MPA', (72, 90))	('PDGFRA', 'Gene', '5156', (94, 100))	('PDGFRA', 'Gene', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PDGFRA', 'Gene', (113, 119))	('tumor', 'Disease', (134, 139))
531329	31480474	Overall, these studies found recurrent amplification of PDGFRA, PDGFRB, CKD4, and MDM2, implicating their involvement in the tumorigenesis process.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('MDM2', 'Gene', '4193', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('amplification', 'Var', (39, 52))	('MDM2', 'Gene', (82, 86))	('PDGFRA', 'Gene', (56, 62))	('PDGFRA', 'Gene', '5156', (56, 62))	('CKD4', 'Gene', (72, 76))	('tumor', 'Disease', (125, 130))	('involvement', 'Reg', (106, 117))	('PDGFRB', 'Gene', '5159', (64, 70))	('PDGFRB', 'Gene', (64, 70))
531340	31480474	Copy number losses in CDKN2A and CDKN2B were observed in three tumors (25%).	('CDKN2B', 'Gene', (33, 39))	('CDKN2A', 'Gene', (22, 28))	('CDKN2B', 'Gene', '1030', (33, 39))	('CDKN2A', 'Gene', '1029', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('Copy number losses', 'Var', (0, 18))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('observed', 'Reg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
531341	31480474	Next-generation sequencing revealed 38 somatic nonsynonymous mutations (33 missense, four frame shift, one nonsense, and one splice region) in intimal sarcoma tumors from nine patients (see Table 2).	('patients', 'Species', '9606', (176, 184))	('missense', 'Var', (75, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcoma tumors', 'Disease', 'MESH:D012509', (151, 165))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('sarcoma tumors', 'Disease', (151, 165))	('nonsynonymous mutations', 'Var', (47, 70))	('frame shift', 'Var', (90, 101))
531342	31480474	Among these mutations, M772V (c.2314A > G) and D850V (c.2549A > T) were found in PDGFRB from two different primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('D850V', 'Mutation', 'p.D850V', (47, 52))	('c.2314A > G', 'Mutation', 'c.2314A>G', (30, 41))	('primary tumors', 'Disease', (107, 121))	('M772V (c.2314A > G', 'Var', (23, 41))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('PDGFRB', 'Gene', '5159', (81, 87))	('primary tumors', 'Disease', 'MESH:D001932', (107, 121))	('c.2549A > T', 'Mutation', 'c.2549A>T', (54, 65))	('D850V (c.2549A > T', 'Var', (47, 65))	('PDGFRB', 'Gene', (81, 87))	('M772V', 'Mutation', 'p.M772V', (23, 28))
531343	31480474	The primary tumor sample with the D850V mutation in PDGFRB had concurrent mutations in PTCH1 (c.961C > A), ATR (c.4704C > G), and CDKN1A (c.419_420delGA).	('CDKN1A', 'Gene', (130, 136))	('CDKN1A', 'Gene', '1026', (130, 136))	('PTCH1', 'Gene', (87, 92))	('ATR', 'Gene', '545', (107, 110))	('tumor', 'Disease', (12, 17))	('PDGFRB', 'Gene', '5159', (52, 58))	('PDGFRB', 'Gene', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('c.961C > A', 'Mutation', 'c.961C>A', (94, 104))	('D850V', 'Mutation', 'p.D850V', (34, 39))	('c.4704C > G', 'Mutation', 'c.4704C>G', (112, 123))	('c.4704C > G', 'Var', (112, 123))	('c.419_420delGA', 'Var', (138, 152))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('ATR', 'Gene', (107, 110))	('PTCH1', 'Gene', '5727', (87, 92))	('D850V', 'Var', (34, 39))	('c.961C > A', 'Var', (94, 104))	('c.419_420delGA', 'Mutation', 'c.419_420delGA', (138, 152))
531345	31480474	Interestingly, co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion tumor and PDGFRB mutations in both fusion-positive cases.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutations', 'Var', (121, 130))	('NOTCH2', 'Gene', (90, 96))	('NOTCH2', 'Gene', (51, 57))	('PDE4DIP', 'Gene', '9659', (82, 89))	('NOTCH2', 'Gene', '4853', (51, 57))	('PDGFRB', 'Gene', '5159', (114, 120))	('gain', 'PosReg', (70, 74))	('tumor', 'Disease', (104, 109))	('PDE4DIP', 'Gene', (82, 89))	('copy number', 'Var', (58, 69))	('PDGFRB', 'Gene', (114, 120))	('NOTCH2', 'Gene', '4853', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
531352	31480474	Our study confirmed the recurrence of copy number gains in MDM2 and CDK4 that coincide with the location 12q12-15, and PDGFRA in 4q12, as described in prior studies.	('PDGFRA', 'Gene', '5156', (119, 125))	('copy number gains', 'Var', (38, 55))	('CDK4', 'Gene', (68, 72))	('MDM2', 'Gene', '4193', (59, 63))	('MDM2', 'Gene', (59, 63))	('CDK4', 'Gene', '1019', (68, 72))	('12q12-15', 'Disease', (105, 113))	('PDGFRA', 'Gene', (119, 125))	('12q12-15', 'Disease', 'MESH:C567193', (105, 113))
531355	31480474	Our data support the use of NGS on intimal sarcomas to identify MDM2 amplification and consideration for such trials.	('MDM2', 'Gene', '4193', (64, 68))	('MDM2', 'Gene', (64, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('sarcomas', 'Disease', 'MESH:D012509', (43, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (43, 51))	('amplification', 'Var', (69, 82))	('sarcomas', 'Disease', (43, 51))
531356	31480474	Thirty-three percent were found to have PDGFRA amplification, but this can be explained by the choice of biopsy site due to intratumoral heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('amplification', 'Var', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('PDGFRA', 'Gene', (40, 46))	('PDGFRA', 'Gene', '5156', (40, 46))
531358	31480474	We also found novel somatic mutations in another receptor kinase gene such as ALK, which is known to be mutated or amplified in various other cancers such as lymphomas and non-small cell lung cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('lung cancers', 'Phenotype', 'HP:0100526', (187, 199))	('ALK', 'Gene', (78, 81))	('lymphomas', 'Phenotype', 'HP:0002665', (158, 167))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('non-small cell lung cancers', 'Disease', (172, 199))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (172, 199))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (176, 199))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('lymphomas', 'Disease', (158, 167))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('mutations', 'Var', (28, 37))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (172, 199))	('ALK', 'Gene', '238', (78, 81))	('lymphomas', 'Disease', 'MESH:D008223', (158, 167))
531359	31480474	However, the ALK E1460Q mutation is outside the tyrosine kinase domain and may not be relevant clinically.	('ALK', 'Gene', (13, 16))	('E1460Q', 'Mutation', 'p.E1460Q', (17, 23))	('ALK', 'Gene', '238', (13, 16))	('tyrosine', 'Chemical', 'None', (48, 56))	('E1460Q', 'Var', (17, 23))
531360	31480474	Other mutations identified include ATM/ATR, and PTCH1, a tumor suppressor that is part of the hedgehog signaling pathway involved in tumorigenesis.	('ATM', 'Gene', '472', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('ATR', 'Gene', '545', (39, 42))	('ATR', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PTCH1', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (133, 138))	('ATM', 'Gene', (35, 38))	('tumor', 'Disease', (57, 62))	('mutations', 'Var', (6, 15))	('PTCH1', 'Gene', '5727', (48, 53))
531361	31480474	A cell checkpoint kinase mutation, which is upstream from p53 in the signaling pathway, was also seen.	('p53', 'Gene', (58, 61))	('mutation', 'Var', (25, 33))	('p53', 'Gene', '7157', (58, 61))
531362	31480474	Additional findings of interest include fusion proteins involving NOTCH2-PDE4DIP and ARID2-MRPS30 and copy number gains in NOTCH2.	('copy number gains', 'Var', (102, 119))	('PDE4DIP', 'Gene', (73, 80))	('NOTCH2', 'Gene', (66, 72))	('NOTCH2', 'Gene', '4853', (123, 129))	('MRPS30', 'Gene', '10884', (91, 97))	('ARID2', 'Gene', '196528', (85, 90))	('NOTCH2', 'Gene', '4853', (66, 72))	('fusion', 'Protein', (40, 46))	('ARID2', 'Gene', (85, 90))	('PDE4DIP', 'Gene', '9659', (73, 80))	('MRPS30', 'Gene', (91, 97))	('NOTCH2', 'Gene', (123, 129))
531363	31480474	Irregular NOTCH2 signaling has been associated with the initiation and progression of multiple cancers including liver, brain, and gastric cancers along with lymphomas.	('Irregular', 'Var', (0, 9))	('multiple cancers', 'Disease', (86, 102))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('NOTCH2', 'Gene', (10, 16))	('lymphomas', 'Phenotype', 'HP:0002665', (158, 167))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('liver', 'Disease', (113, 118))	('multiple cancers', 'Disease', 'MESH:D009369', (86, 102))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('brain', 'Disease', (120, 125))	('lymphomas', 'Disease', 'MESH:D008223', (158, 167))	('gastric cancers', 'Disease', (131, 146))	('gastric cancers', 'Disease', 'MESH:D013274', (131, 146))	('NOTCH2', 'Gene', '4853', (10, 16))	('gastric cancers', 'Phenotype', 'HP:0012126', (131, 146))	('lymphomas', 'Disease', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('associated', 'Reg', (36, 46))
531364	31480474	In addition to NOTCH2, mutations in ARID2, a possible tumor suppressor, are also found in hepatocellular carcinomas.	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (90, 115))	('NOTCH2', 'Gene', '4853', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (90, 115))	('found', 'Reg', (81, 86))	('ARID2', 'Gene', '196528', (36, 41))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ARID2', 'Gene', (36, 41))	('NOTCH2', 'Gene', (15, 21))	('hepatocellular carcinomas', 'Disease', (90, 115))	('tumor', 'Disease', (54, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))
531369	31480474	Since we noted actionable alterations in MDM2, CDK4, PDGFRA, and NOTCH2, as well as copy number losses in CDKN2A and CDKN2B, our study has clinical implications.	('copy number', 'Var', (84, 95))	('NOTCH2', 'Gene', (65, 71))	('CDK4', 'Gene', (47, 51))	('alterations', 'Reg', (26, 37))	('CDKN2A', 'Gene', (106, 112))	('PDGFRA', 'Gene', (53, 59))	('MDM2', 'Gene', (41, 45))	('CDK4', 'Gene', '1019', (47, 51))	('CDKN2B', 'Gene', '1030', (117, 123))	('MDM2', 'Gene', '4193', (41, 45))	('PDGFRA', 'Gene', '5156', (53, 59))	('CDKN2A', 'Gene', '1029', (106, 112))	('NOTCH2', 'Gene', '4853', (65, 71))	('CDKN2B', 'Gene', (117, 123))	('losses', 'NegReg', (96, 102))
531391	24277455	In addition, SN38cooperates with trabectedin to augment the suppression of EWS-FLI1 downstream targets, leading to an improved therapeutic index in vivo.	('FLI1', 'Gene', (79, 83))	('suppression', 'MPA', (60, 71))	('FLI1', 'Gene', '2313', (79, 83))	('improved', 'PosReg', (118, 126))	('augment', 'PosReg', (48, 55))	('therapeutic index', 'MPA', (127, 144))	('EWS', 'Gene', '2130', (75, 78))	('EWS', 'Gene', (75, 78))	('SN38cooperates', 'Var', (13, 27))	('SN38', 'Chemical', 'MESH:D000077146', (13, 17))	('trabectedin', 'Chemical', 'MESH:D000077606', (33, 44))
531394	24277455	The molecular feature that drives the malignant phenotype in ES cells is the EWS-FLI1 transcription factor, generated by the t(11;22)(q24;q12) chromosomal translocation.	('EWS', 'Gene', '2130', (77, 80))	('EWS', 'Gene', (77, 80))	('ES', 'Phenotype', 'HP:0012254', (61, 63))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (125, 142))	('t(11;22)(q24;q12) chromosomal', 'Var', (125, 154))	('FLI1', 'Gene', (81, 85))	('FLI1', 'Gene', '2313', (81, 85))
531395	24277455	In addition, siRNA, antisense DNA and dominant negative methods have established that silencing of EWS-FLI1 leads to a substantial reduction in the ability of the cells to proliferate in vitro or establish tumors in vivo.	('reduction', 'NegReg', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('silencing', 'Var', (86, 95))	('FLI1', 'Gene', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('FLI1', 'Gene', '2313', (103, 107))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('EWS', 'Gene', '2130', (99, 102))	('EWS', 'Gene', (99, 102))
531407	24277455	Werner syndrome patients have notable DNA repair defects responsible for the complex phenotype as well as a predisposition to develop cancer and in particular sarcomas.	('particular sarcomas', 'Disease', (148, 167))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('patients', 'Species', '9606', (16, 24))	('particular sarcomas', 'Disease', 'MESH:D012509', (148, 167))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('Werner syndrome', 'Disease', 'MESH:D014898', (0, 15))	('Werner syndrome', 'Disease', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('defects', 'Var', (49, 56))
531438	24277455	Mice were removed from the experiment that did not establish tumors [(TC71: control cohort (n =1); TC32: trabectedin (n = 1), irinotecan cohorts (n =3)] or if the tumor ulcerated (TC32, control, n=1).	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('TC32', 'Var', (99, 103))	('TC32', 'CellLine', 'CVCL:7151', (180, 184))	('TC71', 'CellLine', 'CVCL:2213', (70, 74))	('irinotecan', 'Chemical', 'MESH:D000077146', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('trabectedin', 'Chemical', 'MESH:D000077606', (105, 116))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('TC32', 'CellLine', 'CVCL:7151', (99, 103))	('tumor', 'Disease', (61, 66))
531455	24277455	Furthermore, other DNA repair genes such as ATM, KU80 or DNA-PK (PRKDC) were not suppressed with EWS-FLI1 silencing.	('EWS', 'Gene', (97, 100))	('PRKDC', 'Gene', (65, 70))	('ATM', 'Gene', (44, 47))	('EWS', 'Gene', '2130', (97, 100))	('FLI1', 'Gene', '2313', (101, 105))	('FLI1', 'Gene', (101, 105))	('silencing', 'Var', (106, 115))	('DNA-PK', 'Gene', (57, 63))	('KU80', 'Gene', (49, 53))	('ATM', 'Gene', '472', (44, 47))	('PRKDC', 'Gene', '5591', (65, 70))	('DNA-PK', 'Gene', '5591', (57, 63))	('KU80', 'Gene', '7520', (49, 53))
531470	24277455	3B, treatment with both SN38 and trabectedin increased the mean number of foci per cell to 9 from 5 and 4, respectively (P = 0.03 (SN38 and Combination); P = 0.0009 trabectedin and Combination)).	('increased', 'PosReg', (45, 54))	('SN38', 'Var', (24, 28))	('to 9', 'Species', '1214577', (88, 92))	('SN38', 'Chemical', 'MESH:D000077146', (131, 135))	('trabectedin', 'Chemical', 'MESH:D000077606', (33, 44))	('SN38', 'Chemical', 'MESH:D000077146', (24, 28))	('trabectedin', 'Chemical', 'MESH:D000077606', (165, 176))
531475	24277455	The same effect was observed at lower concentrations of SN38, where 1 nM of SN38 led to the suppression of luciferase to 80% of control (95% CI = 76 to 84) a level that was further suppressed to 53% of control (95% CI = 47 to 57) when combined with 5 nM trabectedin (Fig.	('trabectedin', 'Chemical', 'MESH:D000077606', (254, 265))	('SN38', 'Chemical', 'MESH:D000077146', (56, 60))	('SN38', 'Chemical', 'MESH:D000077146', (76, 80))	('ser', 'Chemical', 'MESH:D012694', (22, 25))	('suppression', 'NegReg', (92, 103))	('SN38', 'Var', (76, 80))	('luciferase', 'Enzyme', (107, 117))
531481	24277455	Silencing of WRN in TC32 Ewing sarcoma cells led to a substantial reduction in viability from 73.3% (SEM +/- 2.4) confluence in wild type TC32 cells to 36.4% (SEM +/- 3.7) in WRN null cells (Fig.	('TC32', 'CellLine', 'CVCL:7151', (20, 24))	('TC32', 'CellLine', 'CVCL:7151', (138, 142))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (25, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Ewing sarcoma', 'Disease', (25, 38))	('WRN', 'Gene', (13, 16))	('viability', 'MPA', (79, 88))	('Silencing', 'Var', (0, 9))	('TC32', 'Gene', (20, 24))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (25, 38))	('reduction', 'NegReg', (66, 75))
531483	24277455	A similar effect was observed with siRNA targeting of WRN in TC71 Ewing sarcoma cellseven at 0.5 nM SN38 resulting in a decrease in percent confluence from 99% (SEM +/- 0.2) to 70% (SEM +/-3.5) (Fig.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (66, 79))	('percent confluence', 'CPA', (132, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('SN38', 'Var', (100, 104))	('ser', 'Chemical', 'MESH:D012694', (23, 26))	('decrease', 'NegReg', (120, 128))	('Ewing sarcoma', 'Disease', (66, 79))	('TC71', 'CellLine', 'CVCL:2213', (61, 65))	('SN38', 'Chemical', 'MESH:D000077146', (100, 104))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (66, 79))
531486	24277455	Indeed, treatment with the combination of trabectedin and SN38 led to a comparable increase of cells in S-phase to 59% (+/- 3.3) as well as an increase in the sub-Go apoptotic fraction from 4.1% (+/- 0.3) in the solvent control to 14.5% (+/- 0.4) (Figs.	('increase', 'PosReg', (83, 91))	('sub-Go apoptotic fraction', 'CPA', (159, 184))	('SN38', 'Chemical', 'MESH:D000077146', (58, 62))	('trabectedin', 'Chemical', 'MESH:D000077606', (42, 53))	('SN38', 'Var', (58, 62))	('increase', 'PosReg', (143, 151))	('cells in S-phase', 'CPA', (95, 111))
531503	24277455	The TC71 mice also showed an increase in survival that was roughly 6 times that of the control and triple that of the single agent treated mice even though dosing of drug occurred only in the first 10 to 11 days of the study.	('survival', 'CPA', (41, 49))	('increase', 'PosReg', (29, 37))	('TC71', 'Var', (4, 8))	('mice', 'Species', '10090', (139, 143))	('mice', 'Species', '10090', (9, 13))	('TC71', 'CellLine', 'CVCL:2213', (4, 8))
531518	24277455	The camptothecin, in turn, augmented the suppression of EWS-FLI1 targets, making the blockade of EWS-FLI1 achievable in vivo thus causing the regression of two established ES xenograft tumors with only 4 to 6 doses of drug at 1/10th the maximum tolerated dose of irinotecan used in other xenograft experiments with virtually no appreciable systemic toxicity.	('EWS', 'Gene', '2130', (56, 59))	('suppression', 'MPA', (41, 52))	('tumors', 'Disease', (185, 191))	('blockade', 'Var', (85, 93))	('regression', 'CPA', (142, 152))	('toxicity', 'Disease', (349, 357))	('irinotecan', 'Chemical', 'MESH:D000077146', (263, 273))	('EWS', 'Gene', (97, 100))	('FLI1', 'Gene', (101, 105))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('causing', 'Reg', (130, 137))	('FLI1', 'Gene', (60, 64))	('camptothecin', 'Chemical', 'MESH:D002166', (4, 16))	('EWS', 'Gene', (56, 59))	('FLI1', 'Gene', '2313', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('FLI1', 'Gene', '2313', (60, 64))	('ES', 'Phenotype', 'HP:0012254', (172, 174))	('EWS', 'Gene', '2130', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('toxicity', 'Disease', 'MESH:D064420', (349, 357))
531535	27799929	Additional studies are needed to determine the clinical and therapeutic context of complement defects and their possible effect on treatment outcome or the increased risk of infection.	('increased risk of infection', 'Phenotype', 'HP:0002719', (156, 183))	('defects', 'Var', (94, 101))	('infection', 'Disease', (174, 183))	('infection', 'Disease', 'MESH:D007239', (174, 183))	('complement defect', 'Phenotype', 'HP:0004431', (83, 100))
531586	27799929	In total, 24.8% (n = 166/669) of the time points analyzed showed a reduced functionality of the complement system in either the CP or the AP, or both (Figure 3A): specific CP defects were observed in 18.7% (n = 31/166) of all defects, whereas a reduction of the AP was seen in 45.2% (n = 75/166) of the time points (Figure 3B; Appendix C in Supplementary Material).	('CP defects', 'Disease', 'MESH:C566991', (172, 182))	('functionality', 'MPA', (75, 88))	('reduced', 'NegReg', (67, 74))	('CP defects', 'Disease', (172, 182))	('defects', 'Var', (226, 233))
531628	27799929	Nonetheless, we were able to show a correlation between MTX and ifosfamide and their direct negative effect on the complement system.	('ifosfamide', 'Chemical', 'MESH:D007069', (64, 74))	('negative', 'NegReg', (92, 100))	('MTX', 'Chemical', 'MESH:D008727', (56, 59))	('MTX', 'Var', (56, 59))	('complement system', 'MPA', (115, 132))
531705	24093066	The most frequent chromosomal abnormality associated with certain myeloid sarcomas has been observed to be t(8;21)(q22;q22), an abnormality that it shares with some AMLs.	('t(8;21)(q22;q22', 'Var', (107, 122))	('AML', 'Disease', (165, 168))	('associated', 'Reg', (42, 52))	('myeloid sarcomas', 'Disease', (66, 82))	('t(8;21)(q22;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (107, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('AML', 'Disease', 'MESH:D015470', (165, 168))	('myeloid sarcomas', 'Disease', 'MESH:D023981', (66, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
531720	24039573	Further analysis also identified that KSHV miRNAs can modulate activity or expression of upstream regulatory factors, resulting in suppressed activation of a protein involved in leukocyte recruitment (ICAM1) following lysophosphatidic acid treatment, as well as up-regulation of a pro-angiogenic protein (HIF1alpha), and up-regulation of a protein involved in stimulating angiogenesis (HMOX1).	('activity', 'MPA', (63, 71))	('HIF1alpha', 'Gene', (305, 314))	('HMOX1', 'Gene', (386, 391))	('ICAM1', 'Gene', (201, 206))	('miRNAs', 'Var', (43, 49))	('expression', 'MPA', (75, 85))	('activation', 'PosReg', (142, 152))	('modulate', 'Reg', (54, 62))	('KSHV', 'Species', '37296', (38, 42))	('HIF1alpha', 'Gene', '3091', (305, 314))	('HMOX1', 'Gene', '3162', (386, 391))	('KSHV', 'Gene', (38, 42))	('suppressed', 'NegReg', (131, 141))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (218, 239))	('up-regulation', 'PosReg', (321, 334))	('ICAM1', 'Gene', '3383', (201, 206))	('lysophosphatidic acid', 'MPA', (218, 239))	('up-regulation', 'PosReg', (262, 275))
531742	24039573	However, those proteins whose transcripts have seed-matching sites tend to have lower expression in the presence of KSHV miRNAs, as do the proteins from mRNAs with multiple seed-matching sites (Figure 2C-D).	('expression', 'MPA', (86, 96))	('lower', 'NegReg', (80, 85))	('KSHV', 'Var', (116, 120))	('KSHV', 'Species', '37296', (116, 120))
531750	24039573	For example, GRB2 protein expression was repressed by miR-K4-3p, -K4-5p, and -K9*.	('expression', 'MPA', (26, 36))	('protein', 'Protein', (18, 25))	('miR-K4-3p', 'Var', (54, 63))	('GRB2', 'Gene', (13, 17))	('GRB2', 'Gene', '2885', (13, 17))
531758	24039573	Therefore, we hypothesized that KSHV miRNA-mediated knockdown of ROCK2 would contribute to the decrease of ICAM1 expression induced by LPA as part of a host immune evasion strategy during latency.	('decrease', 'NegReg', (95, 103))	('expression', 'MPA', (113, 123))	('LPA', 'Chemical', 'MESH:C032881', (135, 138))	('ROCK2', 'Gene', (65, 70))	('ICAM1', 'Gene', '3383', (107, 112))	('KSHV', 'Species', '37296', (32, 36))	('ROCK2', 'Gene', '9475', (65, 70))	('knockdown', 'Var', (52, 61))	('ICAM1', 'Gene', (107, 112))
531761	24039573	In LPA-treated cells, ROCK2 protein was sufficiently repressed by both miR-K4-3p and siROCK2, but not reproducibly by miR-K10a.	('ROCK2', 'Gene', (22, 27))	('protein', 'Protein', (28, 35))	('ROCK2', 'Gene', '9475', (22, 27))	('ROCK2', 'Gene', (87, 92))	('miR-K4-3p', 'Var', (71, 80))	('ROCK2', 'Gene', '9475', (87, 92))	('LPA', 'Chemical', 'MESH:C032881', (3, 6))
531763	24039573	While there was a significant decrease in ICAM1 protein expression from LPA-treated cells also transfected with miR-K4-3p or siROCK2, there was a much more robust repression of ICAM1 expression by miR-K10a transfection (Figure 5A).	('ICAM1', 'Gene', '3383', (42, 47))	('LPA', 'Chemical', 'MESH:C032881', (72, 75))	('protein', 'Protein', (48, 55))	('ICAM1', 'Gene', (177, 182))	('decrease', 'NegReg', (30, 38))	('ROCK2', 'Gene', (127, 132))	('ICAM1', 'Gene', (42, 47))	('ROCK2', 'Gene', '9475', (127, 132))	('expression', 'MPA', (183, 193))	('ICAM1', 'Gene', '3383', (177, 182))	('miR-K4-3p', 'Var', (112, 121))	('miR-K10a transfection', 'Var', (197, 218))	('repression', 'NegReg', (163, 173))
531764	24039573	Based on these results, we hypothesized that miR-K10a represses ICAM1 up-regulation through a ROCK2-independent mechanism.	('ROCK2', 'Gene', '9475', (94, 99))	('up-regulation', 'PosReg', (70, 83))	('ICAM1', 'Gene', '3383', (64, 69))	('represses', 'NegReg', (54, 63))	('ICAM1', 'Gene', (64, 69))	('ROCK2', 'Gene', (94, 99))	('miR-K10a', 'Var', (45, 53))
531766	24039573	We confirmed an increase in phospho-STAT3 (Tyr705) using Western blot analysis upon LPA treatment and found decreased levels of phospho-STAT3 (Tyr705) in the presence of miR-K10a (Figure 5B).	('Tyr705', 'Chemical', '-', (143, 149))	('levels', 'MPA', (118, 124))	('STAT3', 'Gene', '6774', (36, 41))	('miR-K10a', 'Var', (170, 178))	('increase', 'PosReg', (16, 24))	('STAT3', 'Gene', '6774', (136, 141))	('decreased', 'NegReg', (108, 117))	('STAT3', 'Gene', (36, 41))	('LPA', 'Chemical', 'MESH:C032881', (84, 87))	('Tyr705', 'Chemical', '-', (43, 49))	('STAT3', 'Gene', (136, 141))
531767	24039573	While repression of total STAT3 protein levels with miR-K10a transfection in the absence of LPA was variable, STAT3 protein levels were repressed in LPA-treated cells upon transfection with miR-K10a mimics compared to control mimics.	('STAT3', 'Gene', '6774', (110, 115))	('miR-K10a', 'Var', (52, 60))	('STAT3', 'Gene', (110, 115))	('STAT3', 'Gene', '6774', (26, 31))	('STAT3', 'Gene', (26, 31))	('LPA', 'Chemical', 'MESH:C032881', (92, 95))	('miR-K10a mimics', 'Var', (190, 205))	('LPA', 'Chemical', 'MESH:C032881', (149, 152))
531768	24039573	TargetScan analysis found three potential miR-K10a binding sites in the STAT3 3'UTR (Table S2), and luciferase assays with the STAT3 3'UTR confirmed direct repression by miR-K10a (Figure 5C).	('STAT3', 'Gene', (72, 77))	('STAT3', 'Gene', (127, 132))	('binding', 'Interaction', (51, 58))	('miR-K10a', 'Var', (170, 178))	('STAT3', 'Gene', '6774', (127, 132))	('miR-K10a', 'Gene', (42, 50))	('STAT3', 'Gene', '6774', (72, 77))
531771	24039573	To determine if KSHV miRNAs play a role in this repression, HUVECs were transfected with miRNA inhibitors to miR-K4-3p and miR-K10a, then infected with KSHV, and analyzed for ICAM1 protein expression three days after infection.	('ICAM1', 'Gene', '3383', (175, 180))	('infection', 'Disease', (217, 226))	('infection', 'Disease', 'MESH:D007239', (217, 226))	('miR-K10a', 'Var', (123, 131))	('ICAM1', 'Gene', (175, 180))	('KSHV', 'Species', '37296', (152, 156))	('KSHV', 'Species', '37296', (16, 20))	('miR-K4-3p', 'Var', (109, 118))
531772	24039573	ICAM1 protein expression is modestly elevated (likely due to incomplete inhibition of target miRNAs) in HUVECs transfected with miR-K4-3p and miR-K10a inhibitors (Figure 5E).	('protein', 'Protein', (6, 13))	('ICAM1', 'Gene', '3383', (0, 5))	('elevated', 'PosReg', (37, 45))	('miR-K4-3p', 'Var', (128, 137))	('ICAM1', 'Gene', (0, 5))
531781	24039573	Inducing hypoxia in 293 cells (also HUVECs, data not shown) with the addition of a hypoxia mimic, cobalt chloride (data not shown), or inducing hypoxia with incubation in 1% oxygen, showed that miR-K7 can induce a 5-fold activation of endogenous HIF1alpha protein levels (Figure 6A).	('endogenous', 'MPA', (235, 245))	('hypoxia', 'Disease', (9, 16))	('oxygen', 'Chemical', 'MESH:D010100', (174, 180))	('hypoxia', 'Disease', 'MESH:D000860', (83, 90))	('HIF1alpha', 'Gene', '3091', (246, 255))	('activation', 'PosReg', (221, 231))	('cobalt chloride', 'Chemical', 'MESH:C018021', (98, 113))	('293 cells', 'CellLine', 'CVCL:0045', (20, 29))	('hypoxia', 'Disease', (144, 151))	('miR-K7', 'Var', (194, 200))	('hypoxia', 'Disease', 'MESH:D000860', (144, 151))	('hypoxia', 'Disease', (83, 90))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))	('HIF1alpha', 'Gene', (246, 255))
531782	24039573	We also observed that miR-K7 can increase HIF1alpha transcriptional activity through assays using a HIF-responsive luciferase reporter (Figure 6B).	('increase', 'PosReg', (33, 41))	('HIF1alpha', 'Gene', '3091', (42, 51))	('miR-K7', 'Var', (22, 28))	('HIF1alpha', 'Gene', (42, 51))
531785	24039573	We suspected that miR-K7 might increase HIF1alpha protein levels by repressing an inhibitor of HIF1alpha protein expression.	('HIF1alpha', 'Gene', (95, 104))	('HIF1alpha', 'Gene', (40, 49))	('HIF1alpha', 'Gene', '3091', (40, 49))	('miR-K7', 'Var', (18, 24))	('HIF1alpha', 'Gene', '3091', (95, 104))	('increase', 'PosReg', (31, 39))
531788	24039573	Protein levels of RBX1 were modestly repressed in hypoxic cells transfected with miR-K7 mimic compared to the negative control miRNA mimic (Figure 6D).	('miR-K7 mimic', 'Var', (81, 93))	('RBX1', 'Gene', '9978', (18, 22))	('Protein levels', 'MPA', (0, 14))	('RBX1', 'Gene', (18, 22))
531791	24039573	Taken together, these results suggest miR-K7 may repress additional inhibitors of HIF1alpha protein expression.	('HIF1alpha', 'Gene', '3091', (82, 91))	('repress', 'NegReg', (49, 56))	('inhibitors', 'MPA', (68, 78))	('HIF1alpha', 'Gene', (82, 91))	('miR-K7', 'Var', (38, 44))
531795	24039573	Under normoxia and miR-K11 expression, we observed an expected repression of BACH1 and a robust 4.5-fold activation of HMOX1 protein expression (Figure 6E).	('BACH1', 'Gene', '571', (77, 82))	('BACH1', 'Gene', (77, 82))	('activation', 'PosReg', (105, 115))	('HMOX1', 'Gene', (119, 124))	('protein', 'Protein', (125, 132))	('HMOX1', 'Gene', '3162', (119, 124))	('repression', 'NegReg', (63, 73))	('miR-K11', 'Var', (19, 26))
531810	24039573	We discovered that KSHV miRNAs, miR-K10a and miR-K4-3p, repress ICAM1 expression after induction by LPA, likely through ROCK2 and STAT3-associated pathways.	('miR-K10a', 'Var', (32, 40))	('ROCK2', 'Gene', (120, 125))	('miR-K4-3p', 'Var', (45, 54))	('ICAM1', 'Gene', '3383', (64, 69))	('repress', 'NegReg', (56, 63))	('STAT3', 'Gene', '6774', (130, 135))	('ROCK2', 'Gene', '9475', (120, 125))	('expression', 'MPA', (70, 80))	('ICAM1', 'Gene', (64, 69))	('KSHV', 'Species', '37296', (19, 23))	('STAT3', 'Gene', (130, 135))	('LPA', 'Chemical', 'MESH:C032881', (100, 103))
531811	24039573	Our data indicate that miR-K10a may be inhibiting LPA induction of ICAM1 by multiple mechanisms.	('ICAM1', 'Gene', '3383', (67, 72))	('LPA induction', 'MPA', (50, 63))	('ICAM1', 'Gene', (67, 72))	('LPA', 'Chemical', 'MESH:C032881', (50, 53))	('miR-K10a', 'Var', (23, 31))	('inhibiting', 'NegReg', (39, 49))
531812	24039573	First, the repression of a direct or indirect miRNA target of miR-K10a may be partially responsible for the decrease in LPA-induced STAT3 phosphorylation.	('STAT3', 'Gene', '6774', (132, 137))	('STAT3', 'Gene', (132, 137))	('repression', 'NegReg', (11, 21))	('LPA', 'Chemical', 'MESH:C032881', (120, 123))	('decrease', 'NegReg', (108, 116))	('miR-K10a', 'Var', (62, 70))
531814	24039573	Although STAT3 protein levels can be repressed by miR-K6-5p, unlike miR-K10a, it is not predicted to target the kinase (PTK2B/FAK) and it remains to be determined if miR-K6-5p can repress LPA-activation of ICAM1.	('miR-K6-5p', 'Var', (166, 175))	('miR-K6-5p', 'Var', (50, 59))	('STAT3', 'Gene', (9, 14))	('LPA', 'Chemical', 'MESH:C032881', (188, 191))	('PTK2B', 'Gene', (120, 125))	('ICAM1', 'Gene', '3383', (206, 211))	('FAK', 'Gene', (126, 129))	('FAK', 'Gene', '5747', (126, 129))	('PTK2B', 'Gene', '2185', (120, 125))	('repress', 'NegReg', (180, 187))	('ICAM1', 'Gene', (206, 211))	('LPA-activation', 'MPA', (188, 202))	('STAT3', 'Gene', '6774', (9, 14))
531815	24039573	Second, miR-K10a may directly inhibit STAT3alpha total protein levels in LPA-treated cells, as suggested by the results from the STAT3 3'UTR luciferase assays with miR-K10a.	('miR-K10a', 'Var', (8, 16))	('LPA', 'Chemical', 'MESH:C032881', (73, 76))	('STAT3', 'Gene', '6774', (129, 134))	('inhibit', 'NegReg', (30, 37))	('STAT3', 'Gene', (129, 134))	('STAT3', 'Gene', '6774', (38, 43))	('STAT3', 'Gene', (38, 43))	('miR-K10a', 'Var', (164, 172))
531816	24039573	While others have shown that low levels of the KSHV protein K5 can still down-regulate ICAM1 expression, we believe it is likely that during latent infection, the inhibition of ICAM1 is also due to the viral miRNAs, miR-K4-3p and miR-K10a.	('inhibition', 'NegReg', (163, 173))	('ICAM1', 'Gene', (177, 182))	('miR-K10a', 'Var', (230, 238))	('ICAM1', 'Gene', '3383', (87, 92))	('infection', 'Disease', (148, 157))	('expression', 'MPA', (93, 103))	('infection', 'Disease', 'MESH:D007239', (148, 157))	('down-regulate', 'NegReg', (73, 86))	('KSHV', 'Species', '37296', (47, 51))	('ICAM1', 'Gene', (87, 92))	('miR-K4-3p', 'Var', (216, 225))	('ICAM1', 'Gene', '3383', (177, 182))
531819	24039573	Since miR-K7 increases HIF1alpha protein levels, but did not inhibit some major repressors of HIF1alpha (Figure 6), this suggests miR-K7 is working through an alternative pathway.	('increases', 'PosReg', (13, 22))	('HIF1alpha', 'Gene', '3091', (23, 32))	('miR-K7', 'Var', (6, 12))	('HIF1alpha', 'Gene', (94, 103))	('HIF1alpha', 'Gene', (23, 32))	('HIF1alpha', 'Gene', '3091', (94, 103))
531822	24039573	Interestingly, analysis using MetaCore software reveals human genes involved in translation initiation are enriched in the proteins repressed by KSHV miRNAs in endothelial cells.	('miRNAs', 'Var', (150, 156))	('KSHV', 'Gene', (145, 149))	('KSHV', 'Species', '37296', (145, 149))	('human', 'Species', '9606', (56, 61))
531853	24039573	The following secondary antibodies conjugated to infrared (IR) fluorescing dyes were obtained from Li-Cor: goat anti-rabbit antibody IR800CW, goat anti-mouse antibody IR680, and goat anti-mouse antibody IR800CW.	('rabbit', 'Species', '9986', (117, 123))	('mouse', 'Species', '10090', (188, 193))	('IR800CW', 'Var', (203, 210))	('mouse', 'Species', '10090', (152, 157))	('goat', 'Species', '9925', (178, 182))	('goat', 'Species', '9925', (142, 146))	('goat', 'Species', '9925', (107, 111))	('IR800CW', 'Var', (133, 140))
531856	24039573	Mutations of the predicted miRNA binding sites within the 3'UTRs of ROCK2 and HMGCS1 were performed as previously described using the following primers and their reverse compliments: 5'-GCAGGCCTGCAAATACTGGCACAGAAATATAATCATACACCTTATTAACGGTGA-3' for HMGCS1 and 5'-CTATGAAAGCAGTCATTATTCAAGGTGATCGTAAAGATCCAGTGAAAACAAGACTGAAATAT-3 for ROCK2 mut1 and 5'-TTACGCAGGACATTCTTGCCGTAAAGACATGATCCCAGATAAGTGTGTGT-3' for ROCK2 mut2.	('ROCK2', 'Gene', (407, 412))	('ROCK2', 'Gene', '9475', (331, 336))	('HMGCS1', 'Gene', '3157', (248, 254))	('HMGCS1', 'Gene', (248, 254))	('ROCK2', 'Gene', '9475', (407, 412))	('ROCK2', 'Gene', (68, 73))	('Mutations', 'Var', (0, 9))	('ROCK2', 'Gene', '9475', (68, 73))	('HMGCS1', 'Gene', '3157', (78, 84))	('ROCK2', 'Gene', (331, 336))	('HMGCS1', 'Gene', (78, 84))
531878	23091626	GLV-1h109 virus was derived from the oncolytic vaccinia virus GLV-1h68 by replacing lacZ gene (beta-galactosidase) with GLAF-1 protein encoding gene at J2R locus.	('replacing', 'Var', (74, 83))	('lacZ', 'Gene', (84, 88))	('GLV-1h109', 'Chemical', '-', (0, 9))	('vaccinia virus GLV-1h68', 'Species', '502057', (47, 70))
531886	23091626	We have already shown that the recombinant Vaccinia virus strains (VACV) expressing the GLAF-1 antibody exhibited enhanced tumor inhibition and therapeutic potency, which was comparable to the results seen in combination therapy with separately injected bevacizumab and the parental virus GLV-1h68.	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('enhanced', 'PosReg', (114, 122))	('GLV-1h68', 'Species', '502057', (289, 297))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('bevacizumab', 'Chemical', 'MESH:D000068258', (254, 265))	('Vaccinia virus', 'Species', '10245', (43, 57))	('VACV', 'Species', '10245', (67, 71))	('therapeutic potency', 'CPA', (144, 163))	('GLAF-1', 'Var', (88, 94))
531903	23091626	For the viral replication assay, cells grown in 24-well plates were infected with either GLV-1h68 or GLV-1h109 at an MOI of 0.1.	('GLV-1h68', 'Species', '502057', (89, 97))	('GLV-1h109', 'Chemical', '-', (101, 110))	('ca', 'Species', '9615', (19, 21))	('GLV-1h68', 'Var', (89, 97))	('GLV-1h109', 'Var', (101, 110))
531946	23091626	VEGF levels in the supernatant of STSA-1 cells were 1556.92+-103.88 pg/106 cells (24 hours) and 2962.19+-465.84 pg/106 cells (48 hours), while that of DT08/40 cells were 170.85+-6.84 pg/106 cells (24 hours) and 183.30+-28.68 pg/106 cells (48 hours).	('1556.92+-103.88', 'Var', (52, 67))	('2962.19+-465.84', 'Var', (96, 111))	('DT08', 'Chemical', '-', (151, 155))
531954	23091626	The results demonstrated that the GLV-1h109 is oncolytic to both canine cancer cell lines, however the rate of oncolysis was faster in STSA-1 cells than DT08/40 cells.	('canine', 'Species', '9615', (65, 71))	('GLV-1h109', 'Chemical', '-', (34, 43))	('DT08', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('GLV-1h109', 'Var', (34, 43))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
531956	23091626	To determine whether variation in the rate of oncolysis was due to differences in the rate of replication, STSA-1 and DT08/40 cells were infected with either GLV-1h109 or GLV-1h68 at a MOI of 0.1.	('GLV-1h109', 'Chemical', '-', (158, 167))	('GLV-1h68', 'Species', '502057', (171, 179))	('DT08', 'Chemical', '-', (118, 122))	('GLV-1h109', 'Var', (158, 167))	('GLV-1h68', 'Var', (171, 179))	('ca', 'Species', '9615', (99, 101))
531957	23091626	The maximum viral titers (total) were observed at 48 hours post virus infection (hpvi) in STSA-1 cells for both GLV-1h68 (2.98x106 pfu/ml) and GLV-1h109 (3.01x106 pfu/ml) ( Fig.	('hours post virus infection', 'Disease', (53, 79))	('hours post virus infection', 'Disease', 'MESH:D020178', (53, 79))	('GLV-1h68', 'Species', '502057', (112, 120))	('GLV-1h109', 'Chemical', '-', (143, 152))	('viral titers', 'MPA', (12, 24))	('GLV-1h68', 'Var', (112, 120))	('mu', 'Species', '10090', (8, 10))
531958	23091626	In addition, GLV-1h68 and GLV-1h109 viruses can also efficiently infect and replicate in DT08/40 cells with a maximum yield of 1.23x106 pfu/ml and 1.56x106 pfu/ml at 72 hpvi respectively ( Fig.	('GLV-1h109', 'Var', (26, 35))	('GLV-1h109', 'Chemical', '-', (26, 35))	('replicate', 'CPA', (76, 85))	('infect', 'CPA', (65, 71))	('GLV-1h68', 'Var', (13, 21))	('mu', 'Species', '10090', (114, 116))	('ca', 'Species', '9615', (81, 83))	('ca', 'Species', '9615', (44, 46))	('GLV-1h68', 'Species', '502057', (13, 21))	('DT08', 'Chemical', '-', (89, 93))
531962	23091626	For this purpose, 106 STSA-1 or DT08/40 cells were infected either with GLV-1h109 or GLV-1h68 (control) at an MOI of 1.0 in 6 well plates.	('GLV-1h68', 'Species', '502057', (85, 93))	('DT08', 'Chemical', '-', (32, 36))	('GLV-1h109', 'Chemical', '-', (72, 81))	('GLV-1h68', 'Var', (85, 93))	('GLV-1h109', 'Var', (72, 81))
531987	23091626	In contrast, we found about 104-105 fold more GLV-1h109 pfu in solid tumors at this time point, which clearly shows that GLV-1h109 virus displays an enhanced tumor specific replication.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (69, 74))	('solid tumors', 'Disease', (63, 75))	('GLV-1h109', 'Chemical', '-', (121, 130))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('GLV-1h109', 'Chemical', '-', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('enhanced', 'PosReg', (149, 157))	('solid tumors', 'Disease', 'MESH:D009369', (63, 75))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('ca', 'Species', '9615', (178, 180))	('GLV-1h109', 'Var', (121, 130))
531988	23091626	Using fluorogenic probes activated specifically by virus-mediated glucuronidase (GusA), we have recently shown that the detection of GusA in the serum could be used to evaluate successful tumor colonization and/or transgene expression of oncolytic vaccinia virus in tumor-bearing mice.	('tumor', 'Disease', (188, 193))	('ca', 'Species', '9615', (42, 44))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('GusA', 'Chemical', '-', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mice', 'Species', '10090', (280, 284))	('transgene expression', 'Var', (214, 234))	('GusA', 'Chemical', '-', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (266, 271))	('vaccinia virus', 'Species', '10245', (248, 262))
532016	23091626	In these experimental settings we found a significant increase of Gr-1high CD11b+, Gr-1int CD11b+ and F4/80+CD45+ cells in the GLV-1h109 infected tumors compared with GLV-1h68- or PBS-injected tumors ( Fig.	('increase', 'PosReg', (54, 62))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('GLV-1h109 infected tumors', 'Disease', 'MESH:D009369', (127, 152))	('GLV-1h68', 'Species', '502057', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ca', 'Species', '9615', (49, 51))	('Gr-1int', 'Var', (83, 90))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('F4/80', 'Gene', '13733', (102, 107))	('F4/80', 'Gene', (102, 107))	('tumors', 'Disease', (193, 199))	('GLV-1h109 infected tumors', 'Disease', (127, 152))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('CD11b', 'Gene', '3684', (91, 96))	('CD11b', 'Gene', '3684', (75, 80))	('tumors', 'Disease', (146, 152))	('CD11b', 'Gene', (91, 96))	('CD11b', 'Gene', (75, 80))	('PBS', 'Chemical', 'MESH:D007854', (180, 183))
532028	23091626	We found also that GLV-1h109 more efficiently infects both tumor and host immune cells, compared to GLV-1h68 ( Table 2 ).	('tumor', 'Disease', (59, 64))	('GLV-1h109', 'Var', (19, 28))	('infects', 'Reg', (46, 53))	('GLV-1h68', 'Species', '502057', (100, 108))	('mu', 'Species', '10090', (76, 78))	('GLV-1h109', 'Chemical', '-', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
532043	23091626	The data have revealed that GLV-1h109 achieved a significant inhibition of tumor growth and damage of tumor tissues in both tested canine xenografts models.	('canine', 'Species', '9615', (131, 137))	('GLV-1h109', 'Chemical', '-', (28, 37))	('ca', 'Species', '9615', (56, 58))	('ca', 'Species', '9615', (131, 133))	('inhibition', 'NegReg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('GLV-1h109', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (75, 80))
532046	23091626	However, higher serum GLAF-1 concentration in STSA-1 xenografts might be due to the enhanced replication efficacy of GLV-1h109 in STSA-1 cells ( Fig.	('ca', 'Species', '9615', (109, 111))	('serum GLAF-1 concentration', 'MPA', (16, 42))	('GLV-1h109', 'Chemical', '-', (117, 126))	('replication', 'MPA', (93, 104))	('ca', 'Species', '9615', (98, 100))	('enhanced', 'PosReg', (84, 92))	('GLV-1h109', 'Var', (117, 126))	('higher', 'PosReg', (9, 15))
532061	23091626	On the other hand, a significant reduction of the blood vessel density of GLV-1h109 treated STSA-1 tumors was observed when compared to both controls; GLV-1h68 and PBS ( Fig.	('blood vessel density', 'CPA', (50, 70))	('ca', 'Species', '9615', (28, 30))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('GLV-1h109', 'Var', (74, 83))	('reduction', 'NegReg', (33, 42))	('GLV-1h68', 'Species', '502057', (151, 159))	('PBS', 'Chemical', 'MESH:D007854', (164, 167))	('STSA-1', 'Gene', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('GLV-1h109', 'Chemical', '-', (74, 83))	('tumors', 'Disease', (99, 105))
532062	23091626	A possible reason for this phenomenon may be that the GLV-1h109-treatment led to "vascular normalization" in tumor tissue, as described by Winker and colleagues.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('GLV-1h109', 'Chemical', '-', (54, 63))	('GLV-1h109-treatment', 'Var', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
532114	22606414	X; 18 translocation is a sensitive marker and is demonstrated in 70 to 90% of synovial sarcomas.	('synovial sarcomas', 'Disease', 'MESH:D013584', (78, 95))	('synovial sarcomas', 'Disease', (78, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('X; 18 translocation', 'Var', (0, 19))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (78, 95))
532171	31941033	We therefore analyzed expression profiling data and compared the expression levels of each of the 19 ALDH gene variants (Figure 3d).	('expression', 'MPA', (65, 75))	('ALDH', 'Gene', '11670', (101, 105))	('ALDH', 'Gene', (101, 105))	('variants', 'Var', (111, 119))
532172	31941033	However, the analysis revealed upregulated expression of some ALDH gene variants, especially ALDH6A1, which may account for the Aldefluor  assay results, as discussed later.	('Aldefluor', 'Chemical', '-', (128, 137))	('variants', 'Var', (72, 80))	('upregulated', 'PosReg', (31, 42))	('ALDH', 'Gene', '11670', (62, 66))	('ALDH', 'Gene', '11670', (93, 97))	('ALDH', 'Gene', (62, 66))	('expression', 'MPA', (43, 53))	('ALDH', 'Gene', (93, 97))
532185	31941033	Further analysis of 18 genes that correlate with mesenchymal stem cell senescence revealed a remarkably significant downregulation of 10 genes (ANKRD1, KRT34, KRT19, SERPINB2, KRTAP1-5, LOC730755, PLCB4, THBS1, OXTR, MRVI1), while none of the analyzed genes was significantly upregulated during serial xenotransplantation (Figure 6c).	('ANKRD1', 'Gene', (144, 150))	('ANKRD1', 'Gene', '107765', (144, 150))	('KRT19', 'Gene', '16669', (159, 164))	('PLCB4', 'Gene', '18798', (197, 202))	('KRTAP1-5', 'Gene', (176, 184))	('SERPINB2', 'Gene', (166, 174))	('downregulation', 'NegReg', (116, 130))	('PLCB4', 'Gene', (197, 202))	('KRT34', 'Gene', '16672', (152, 157))	('KRTAP1-5', 'Gene', '26560;100859929', (176, 184))	('OXTR', 'Gene', (211, 215))	('THBS1', 'Gene', (204, 209))	('MRVI1', 'Gene', '17540', (217, 222))	('KRT34', 'Gene', (152, 157))	('MRVI1', 'Gene', (217, 222))	('SERPINB2', 'Gene', '18788', (166, 174))	('THBS1', 'Gene', '21825', (204, 209))	('KRT19', 'Gene', (159, 164))	('LOC730755', 'Var', (186, 195))	('OXTR', 'Gene', '18430', (211, 215))
532227	31941033	Indeed, it has been demonstrated in hematopoietic cells that ALDH1A1 deficiency does not affect Aldefluor staining.	('deficiency', 'Var', (69, 79))	('ALDH1A1', 'Gene', (61, 68))	('Aldefluor', 'Chemical', '-', (96, 105))
532246	31941033	Corroborating the increase in the expression of CDH15 along with MYOD1 in our model of rhabdomyosarcoma CSCs, MYOD1 knockdown has been demonstrated to significantly downregulate CDH15 expression.	('increase', 'PosReg', (18, 26))	('MYOD1', 'Gene', '17927', (110, 115))	('CDH15', 'Gene', (178, 183))	('MYOD1', 'Gene', (65, 70))	('expression', 'MPA', (34, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('MYOD1', 'Gene', (110, 115))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('CDH15', 'Gene', (48, 53))	('knockdown', 'Var', (116, 125))	('CDH15', 'Gene', '12555', (178, 183))	('CDH15', 'Gene', '12555', (48, 53))	('downregulate', 'NegReg', (165, 177))	('rhabdomyosarcoma CSCs', 'Disease', 'MESH:D012208', (87, 108))	('expression', 'MPA', (184, 194))	('MYOD1', 'Gene', '17927', (65, 70))	('rhabdomyosarcoma CSCs', 'Disease', (87, 108))
532253	31941033	Importantly, SOX4 is highly expressed in embryonal rhabdomyosarcoma compared with normal muscle and knockdown of SOX4 leads to a significant decrease in MYOD1 levels and impaired rhabdomyosarcoma cell survival.	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (41, 67))	('knockdown', 'Var', (100, 109))	('MYOD1', 'Gene', '17927', (153, 158))	('SOX4', 'Gene', '20677', (113, 117))	('SOX4', 'Gene', '20677', (13, 17))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (51, 67))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (179, 195))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (41, 67))	('SOX4', 'Gene', (113, 117))	('MYOD1', 'Gene', (153, 158))	('impaired rhabdomyosarcoma', 'Disease', (170, 195))	('impaired rhabdomyosarcoma', 'Disease', 'MESH:D012208', (170, 195))	('SOX4', 'Gene', (13, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('embryonal rhabdomyosarcoma', 'Disease', (41, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('decrease', 'NegReg', (141, 149))
532262	31941033	In parallel to the results obtained in carcinomas, partial MET has been discussed as a process contributing to the metastasis and stemness of sarcomas, although this mechanism remains elusive.	('metastasis', 'CPA', (115, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('stemness of sarcomas', 'Disease', (130, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('partial MET', 'Var', (51, 62))	('carcinomas', 'Disease', (39, 49))	('carcinomas', 'Disease', 'MESH:D002277', (39, 49))	('contributing', 'Reg', (95, 107))	('stemness of sarcomas', 'Disease', 'MESH:D012509', (130, 150))
532272	31941033	Notably, N-cadherin downregulation is crucial for the migration of neural crest cells and smooth muscle cells, which offers an explanation for how partial MET, i.e., a loss of the typical mesenchymal marker, N-cadherin, may promote the progression of sarcomas towards a more aggressive phenotype.	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('loss', 'Var', (168, 172))	('sarcomas', 'Disease', (251, 259))	('N-cadherin', 'Gene', '12558', (9, 19))	('N-cadherin', 'Gene', '12558', (208, 218))	('N-cadherin', 'Gene', (9, 19))	('promote', 'PosReg', (224, 231))	('N-cadherin', 'Gene', (208, 218))	('sarcomas', 'Disease', 'MESH:D012509', (251, 259))	('sarcomas', 'Phenotype', 'HP:0100242', (251, 259))
532304	31941033	The immunoreactivity of tumor cells was graded as - (none), + (weak), ++ (medium), and +++ (strong).	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('+++', 'Var', (87, 90))
532314	31941033	This approach enabled us to identify several novel and promising rhabdomyosarcoma CSC-specific targets, e.g., ALDH6A1, SOX4, PAX3, CDH15, downregulated MIR145, or phosphorylated RYK, which warrant validation in subsequent mechanistic studies.	('MIR145', 'Gene', (152, 158))	('RYK', 'Gene', (178, 181))	('PAX3', 'Gene', '18505', (125, 129))	('SOX4', 'Gene', '20677', (119, 123))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (65, 81))	('SOX4', 'Gene', (119, 123))	('rhabdomyosarcoma CSC', 'Disease', 'MESH:D012208', (65, 85))	('downregulated', 'NegReg', (138, 151))	('RYK', 'Gene', '20187', (178, 181))	('CDH15', 'Gene', (131, 136))	('MIR145', 'Gene', '387163', (152, 158))	('ALDH6A1', 'Gene', (110, 117))	('CDH15', 'Gene', '12555', (131, 136))	('phosphorylated', 'Var', (163, 177))	('rhabdomyosarcoma CSC', 'Disease', (65, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('PAX3', 'Gene', (125, 129))
532321	31831742	CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors.	('CTDSP1/2-DNM3OS', 'Gene', (0, 15))	('CTDSP1/2-DNM3OS', 'Gene', '100628315;58190;10106', (0, 15))	('fusion genes', 'Var', (16, 28))	('DDLPS tumors', 'Disease', 'MESH:D009369', (59, 71))	('identified', 'Reg', (33, 43))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('DDLPS tumors', 'Disease', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
532323	31831742	The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('associated', 'Reg', (227, 237))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('associated', 'Reg', (153, 163))	('tumor', 'Disease', (169, 174))	('alterations', 'Var', (140, 151))
532326	31831742	To date, several analyses have unveiled genomic characteristics common to DDLPS, including the amplification of 12q13-15, that are also frequently found in WDLPS.	('WD', 'Disease', 'MESH:D006527', (156, 158))	('amplification', 'Var', (95, 108))	('12q13-15', 'Gene', (112, 120))	('DDLPS', 'Disease', (74, 79))
532327	31831742	These studies have also identified a number of genes within 12q13-15, including HOXC13, MDM2, HMGA2, CDK4, and CPM, as being key to the development of DDLPS and WDLPS; a number of additional genomic occurrences, such as the loss of 11q23 and the gain of 6q23 and 1p32, have been defined as genomic abnormalities that are specific to DDLPS.	('11q23', 'Gene', (232, 237))	('MDM2', 'Gene', '4193', (88, 92))	('HMGA2', 'Gene', (94, 99))	('CDK4', 'Gene', (101, 105))	('1p32', 'Gene', (263, 267))	('MDM2', 'Gene', (88, 92))	('HMGA2', 'Gene', '8091', (94, 99))	('HOXC13', 'Gene', '3229', (80, 86))	('CDK4', 'Gene', '1019', (101, 105))	('6q23', 'Gene', (254, 258))	('WD', 'Disease', 'MESH:D006527', (161, 163))	('HOXC13', 'Gene', (80, 86))	('gain', 'PosReg', (246, 250))	('CPM', 'Gene', (111, 114))	('CPM', 'Gene', '1368', (111, 114))	('loss', 'Var', (224, 228))
532328	31831742	Recently, the Cancer Genome Atlas (TCGA) Research Network has identified the characteristics of some types of soft-tissue sarcoma, including DDLPS with amplification of 12q13-15, through comprehensive genomic analysis and showed that the classification of DDLPS tumors based on the status of their somatic copy-number alterations (SCNA) and DNA methylation could predict clinical prognosis.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('Cancer', 'Disease', (14, 20))	('DDLPS', 'Disease', (141, 146))	('DDLPS tumors', 'Disease', 'MESH:D009369', (256, 268))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (110, 129))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('copy-number alterations', 'Var', (306, 329))	('DDLPS tumors', 'Disease', (256, 268))	('sarcoma', 'Disease', 'MESH:D012509', (122, 129))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('predict', 'Reg', (363, 370))	('sarcoma', 'Disease', (122, 129))	('Cancer', 'Disease', 'MESH:D009369', (14, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
532339	31831742	Base substitution analysis of synonymous and nonsynonymous SNVs with the adjacent 5' and 3' flanking nucleotides, in order to better understand the mutational processes involved, showed that nucleotide alterations from anyCG to anyTG were the most frequently detected in DDLPS (Fig.	('DDLPS', 'Disease', (271, 276))	('nucleotide alterations', 'Var', (191, 213))	('synonymous SNVs', 'Disease', (48, 63))	('detected', 'Reg', (259, 267))	('synonymous SNVs', 'Disease', 'None', (48, 63))
532353	31831742	4b), suggesting the possibility that DNM3OS fusions might serve as specific DDLPS markers to discriminate WDLPS cases with and without dedifferentiation potential.	('DNM3OS', 'Gene', (37, 43))	('DNM3OS', 'Gene', '100628315', (37, 43))	('fusions', 'Var', (44, 51))	('WD', 'Disease', 'MESH:D006527', (106, 108))
532354	31831742	In contrast, 15 SCNAs, including those involving the gain of 1p32.1, 5p15.33, 5q35.3, 19p13.3, 19q12, and Xq21.1 and the loss of 6q27, 9p24.3, 9p21.2, 9q34.11, 11p15.5, 11q24.3, 13q32.3, 13q34, and 18q22.1, were significantly associated with the disease-specific survival of patients with DDLPS (Supplementary Fig.	('9q34.11', 'Var', (151, 158))	('9p21.2', 'Var', (143, 149))	('disease-specific survival', 'CPA', (246, 271))	('Xq21.1', 'Var', (106, 112))	('associated with', 'Reg', (226, 241))	('DDLPS', 'Disease', (289, 294))	('loss', 'Var', (121, 125))	('6q27', 'Var', (129, 133))	('9p24.3', 'Var', (135, 141))	('gain', 'PosReg', (53, 57))	('5p15.33', 'Var', (69, 76))	('patients', 'Species', '9606', (275, 283))
532355	31831742	Among the recurrently mutated genes, mutations or the copy-number loss of TP53 was found to be accumulated in Cluster 3, particularly in three of the five DDLPS samples that did not have the high-level gain of 12q15 (Fig.	('mutations', 'Var', (37, 46))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('copy-number', 'Var', (54, 65))
532356	31831742	3a), indicating that the disruption of the MDM2/TP53 axis was the most decisive genomic event contributing to DDLPS development.	('TP53', 'Gene', '7157', (48, 52))	('DDLPS', 'Disease', (110, 115))	('MDM2', 'Gene', '4193', (43, 47))	('MDM2', 'Gene', (43, 47))	('TP53', 'Gene', (48, 52))	('contributing', 'Reg', (94, 106))	('disruption', 'Var', (25, 35))
532369	31831742	These results indicated that SCNAs and chromosomal rearrangements at chromosomes 1 and 12, but not somatic mutations, were common initial genomic events in both DD and WD and that additional copy-number alterations or chromosomal rearrangements were associated with the development of DD.	('SCNAs', 'Disease', (29, 34))	('WD', 'Disease', 'MESH:D006527', (168, 170))	('chromosomal rearrangements', 'Var', (39, 65))	('copy-number alterations', 'Var', (191, 214))	('associated', 'Reg', (250, 260))
532373	31831742	Of note, the expression levels of G0S2 and DGAT2 were remarkably decreased in DD compared with WD (Supplementary Table 10b), suggesting the involvement of the downregulation of G0S2 and DGAT2 in malignant transformation mediated by copy-number loss in DDLPS.	('expression levels', 'MPA', (13, 30))	('malignant transformation', 'CPA', (195, 219))	('G0S2', 'Gene', (177, 181))	('DGAT2', 'Gene', (186, 191))	('DGAT2', 'Gene', (43, 48))	('G0S2', 'Gene', '50486', (34, 38))	('WD', 'Disease', 'MESH:D006527', (95, 97))	('decreased', 'NegReg', (65, 74))	('DGAT2', 'Gene', '84649', (186, 191))	('G0S2', 'Gene', (34, 38))	('copy-number loss', 'Var', (232, 248))	('downregulation', 'NegReg', (159, 173))	('DGAT2', 'Gene', '84649', (43, 48))	('G0S2', 'Gene', '50486', (177, 181))
532377	31831742	Most of these studies focused on the fact that the copy-number gain of specific genes, including MDM2, HMGA2, and CDK4, were driver genomic alterations.	('CDK4', 'Gene', (114, 118))	('gain', 'PosReg', (63, 67))	('copy-number', 'Var', (51, 62))	('CDK4', 'Gene', '1019', (114, 118))	('HMGA2', 'Gene', '8091', (103, 108))	('MDM2', 'Gene', '4193', (97, 101))	('HMGA2', 'Gene', (103, 108))	('MDM2', 'Gene', (97, 101))
532382	31831742	The evidence that somatic mutations or the copy-number loss of TP53 were accumulated in Cluster 3 (Fig.	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))	('copy-number loss', 'Var', (43, 59))
532387	31831742	As CTDSP1 and CTDSP2 encode the C-terminal domain small phosphatases 1 and 2 and the knock-down of CTDSP2 in DDLPS cell lines inhibited cell proliferation, further analysis is essential to characterize the expression and function of the fusion protein.	('CTDSP1', 'Gene', (3, 9))	('CTDSP2', 'Gene', '10106', (99, 105))	('knock-down', 'Var', (85, 95))	('CTDSP2', 'Gene', (14, 20))	('inhibited', 'NegReg', (126, 135))	('CTDSP2', 'Gene', '10106', (14, 20))	('CTDSP2', 'Gene', (99, 105))	('cell proliferation', 'CPA', (136, 154))	('CTDSP1', 'Gene', '58190', (3, 9))
532394	31831742	Taken together, these lines of evidence suggest that the upregulation of DNM3OS mediated by chromosomal rearrangement could lead to the proliferation of tumor cells and contribute to DDLPS progression.	('DNM3OS', 'Gene', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('DNM3OS', 'Gene', '100628315', (73, 79))	('DDLPS', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('chromosomal rearrangement', 'Var', (92, 117))	('tumor', 'Disease', (153, 158))	('upregulation', 'PosReg', (57, 69))	('lead to', 'Reg', (124, 131))	('contribute', 'Reg', (169, 179))
532397	31831742	Because JUN amplification blocks adipogenesis and is oncogenic in liposarcomas, the upregulation of JUN that occurs as a result of 1p32.1 gain may play a pivotal role in DDLPS progression.	('1p32.1', 'Gene', (131, 137))	('blocks', 'NegReg', (26, 32))	('liposarcomas', 'Disease', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('gain', 'PosReg', (138, 142))	('DDLPS', 'Disease', (170, 175))	('upregulation', 'PosReg', (84, 96))	('amplification', 'Var', (12, 25))	('JUN', 'MPA', (100, 103))	('adipogenesis', 'MPA', (33, 45))	('liposarcomas', 'Phenotype', 'HP:0012034', (66, 78))	('liposarcomas', 'Disease', 'MESH:D008080', (66, 78))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))
532402	31831742	Second, the augmentation of the common SCNAs and the emergence of additional SCNAs and chromosomal rearrangements in chromosome 12, both of which did not occur in WD, may cause the malignant transformation of DD.	('malignant transformation', 'CPA', (181, 205))	('cause', 'Reg', (171, 176))	('chromosomal rearrangements', 'Var', (87, 113))	('common', 'CPA', (32, 38))	('WD', 'Disease', 'MESH:D006527', (163, 165))
532403	31831742	Previous comparative analysis between DDLPS and WDLPS identified the loss of 11q23 and the amplification of 6q23 and 1p32 as genomic abnormalities specific to DDLPS.	('DDLPS', 'Disease', (159, 164))	('loss', 'NegReg', (69, 73))	('11q23', 'Protein', (77, 82))	('amplification', 'Var', (91, 104))	('6q23', 'Gene', (108, 112))	('1p32', 'Gene', (117, 121))	('WD', 'Disease', 'MESH:D006527', (48, 50))	('DDLPS', 'Disease', (38, 43))
532406	31831742	Indeed, the current fusion analysis identified DNM3OS fusions only in DDLPS and not in WDLPS, and a previous microarray-based transcriptome analysis showed a distinct gene expression pattern in WD from DDLPS versus that from WDLPS.	('DDLPS', 'Disease', (70, 75))	('WD', 'Disease', 'MESH:D006527', (194, 196))	('WD', 'Disease', 'MESH:D006527', (225, 227))	('fusions', 'Var', (54, 61))	('DNM3OS', 'Gene', '100628315', (47, 53))	('DNM3OS', 'Gene', (47, 53))	('WD', 'Disease', 'MESH:D006527', (87, 89))
532409	31831742	This study identified 27 genes that were specifically gained or lost in DD, but not in WD, and were differentially expressed in accordance with the alteration in their copy number (Fig.	('alteration', 'Var', (148, 158))	('gained', 'PosReg', (54, 60))	('lost', 'NegReg', (64, 68))	('WD', 'Disease', 'MESH:D006527', (87, 89))
532411	31831742	As G0S2 regulates lipid metabolism and promotes apoptosis by binding to BCL2, and DGAT2 plays an important role in triacylglycerol biosynthesis and fat digestion and absorption, the copy-number loss and concomitant downregulation of G0S2 and DGAT2 most likely strongly induced the dedifferentiation and malignant transformation of adipogenic cells.	('DGAT2', 'Gene', (242, 247))	('promotes', 'PosReg', (39, 47))	('DGAT2', 'Gene', (82, 87))	('downregulation', 'NegReg', (215, 229))	('G0S2', 'Gene', '50486', (233, 237))	('G0S2', 'Gene', '50486', (3, 7))	('DGAT2', 'Gene', '84649', (242, 247))	('DGAT2', 'Gene', '84649', (82, 87))	('binding', 'Interaction', (61, 68))	('lipid', 'Chemical', 'MESH:D008055', (18, 23))	('G0S2', 'Gene', (3, 7))	('G0S2', 'Gene', (233, 237))	('induced', 'Reg', (269, 276))	('copy-number loss', 'Var', (182, 198))	('malignant transformation', 'CPA', (303, 327))	('BCL2', 'Gene', '596', (72, 76))	('regulates', 'Reg', (8, 17))	('triacylglycerol', 'Chemical', 'MESH:D014280', (115, 130))	('dedifferentiation', 'CPA', (281, 298))	('lipid metabolism', 'MPA', (18, 34))	('BCL2', 'Gene', (72, 76))	('apoptosis', 'CPA', (48, 57))
532413	31831742	During the second step of the malignant transformation, some of the tumor clones undergo further augmentation of the initial SCNAs and gain additional SCNAs and chromosomal rearrangements, including the DNM3OS-fusion genes and the loss of G0S2 and DGAT2, which contribute to the cell-cycle progression and impairment of adipogenesis.	('tumor', 'Disease', (68, 73))	('SCNAs', 'MPA', (151, 156))	('DGAT2', 'Gene', '84649', (248, 253))	('G0S2', 'Gene', (239, 243))	('SCNAs', 'MPA', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('loss', 'Var', (231, 235))	('adipogenesis', 'MPA', (320, 332))	('DNM3OS', 'Gene', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('augmentation', 'PosReg', (97, 109))	('gain', 'PosReg', (135, 139))	('DGAT2', 'Gene', (248, 253))	('cell-cycle progression', 'CPA', (279, 301))	('DNM3OS', 'Gene', '100628315', (203, 209))	('G0S2', 'Gene', '50486', (239, 243))
532414	31831742	Finally, additional SCNAs, including the gain of 1p32.1, 1q24.3, 4p16.3, and Xq21.1 and the loss of 9q34.11, 12q24.33, 13q32.3, and Xp22.33, occur, which were found to be involved in tumor progression and are associated with poor clinical outcomes.	('gain', 'PosReg', (41, 45))	('9q34.11', 'Gene', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('12q24.33', 'Var', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('loss', 'NegReg', (92, 96))	('tumor', 'Disease', (183, 188))	('4p16.3', 'Var', (65, 71))	('1q24.3', 'Var', (57, 63))	('Xq21.1', 'Var', (77, 83))	('Xp22.33', 'Var', (132, 139))	('1p32.1', 'Var', (49, 55))	('13q32.3', 'Var', (119, 126))
532426	31831742	The raw sequence data generated by the Illumina HiSeq2000 or HiSeq2500 sequencers were processed through an in-house pipeline used for the whole-exome analysis of paired cancer genomes at the Human Genome Center, Institute of Medical Science, University of Tokyo.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('Human', 'Species', '9606', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('HiSeq2500', 'Var', (61, 70))
532534	25328308	Double labeling indicated cytokeratin and vimentin positivity in individual spindle cells thus illustrating the versatility of the intermediate filament.	('vimentin', 'Gene', '7431', (42, 50))	('cytokeratin', 'Protein', (26, 37))	('positivity', 'Var', (51, 61))	('vimentin', 'Gene', (42, 50))
532618	24202325	Patients with R1 resections had worse DFS (HR 3.74, 95% CI: 0.98-14.34) and OS (HR 4.4, 95% CI: 1.11-17.4).	('DFS', 'MPA', (38, 41))	('Patients', 'Species', '9606', (0, 8))	('R1 resections', 'Var', (14, 27))
532659	24202325	A large retrospective series from MD Anderson, however, indicated that high grade tumors, radiation induced tumors, and involved margins were associated with a poorer disease free survival and overall survival at five years.	('high grade', 'Var', (71, 81))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('overall survival', 'CPA', (193, 209))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('disease free survival', 'CPA', (167, 188))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('poorer', 'NegReg', (160, 166))
532667	23204874	Pazopanib for the treatment of soft-tissue sarcoma Pazopanib is a multikinase inhibitor which potently inhibits the activity of major receptor tyrosine kinases, including vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, platelet-derived growth factor receptor-a, platelet-derived growth factor receptor-a, and c-Kit.	('vascular endothelial growth factor receptor-1', 'Gene', '2321', (171, 216))	('inhibits', 'NegReg', (103, 111))	('Pazopanib', 'Var', (51, 60))	('c-Kit', 'Gene', '3815', (402, 407))	('vascular endothelial growth factor receptor-2', 'Gene', '3791', (218, 263))	('c-Kit', 'Gene', (402, 407))	('vascular endothelial growth factor receptor-3', 'Gene', (265, 310))	('Pazopanib', 'Chemical', 'MESH:C516667', (51, 60))	('platelet-derived', 'Enzyme', (355, 371))	('vascular endothelial growth factor receptor-3', 'Gene', '2324', (265, 310))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('activity', 'MPA', (116, 124))	('sarcoma', 'Disease', (43, 50))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (31, 50))	('vascular endothelial growth factor receptor-1', 'Gene', (171, 216))	('platelet-derived', 'Enzyme', (312, 328))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('vascular endothelial growth factor receptor-2', 'Gene', (218, 263))
532669	23204874	In comparison with sunitinib or sorafenib, pazopanib has a similar toxicity profile and is generally well tolerated.	('pazopanib', 'Var', (43, 52))	('sunitinib', 'Chemical', 'MESH:D000077210', (19, 28))	('sorafenib', 'Chemical', 'MESH:D000077157', (32, 41))	('pazopanib', 'Chemical', 'MESH:C516667', (43, 52))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))	('toxicity', 'Disease', (67, 75))
532683	23204874	Compared with historical controls receiving second-line chemotherapy, pazopanib extended progression-free survival and overall survival in patients with STS.	('pazopanib', 'Var', (70, 79))	('extended', 'PosReg', (80, 88))	('progression-free survival', 'CPA', (89, 114))	('patients', 'Species', '9606', (139, 147))	('STS', 'Phenotype', 'HP:0030448', (153, 156))	('pazopanib', 'Chemical', 'MESH:C516667', (70, 79))	('overall survival', 'CPA', (119, 135))
532691	23204874	In comparison to sorafenib or sunitinib, the pharmacokinetic characteristics of pazopanib are similar, and, like other tyrosine kinase inhibitors, pazopanib is highly protein-bound.	('pazopanib', 'Chemical', 'MESH:C516667', (147, 156))	('protein-bound', 'Interaction', (167, 180))	('pazopanib', 'Chemical', 'MESH:C516667', (80, 89))	('pazopanib', 'Var', (147, 156))	('sunitinib', 'Chemical', 'MESH:D000077210', (30, 39))	('sorafenib', 'Chemical', 'MESH:D000077157', (17, 26))
532695	23204874	Pazopanib has a significantly lower percentage of renal elimination than sorafenib and sunitinib.	('renal elimination', 'MPA', (50, 67))	('lower', 'NegReg', (30, 35))	('sunitinib', 'Chemical', 'MESH:D000077210', (87, 96))	('sorafenib', 'Chemical', 'MESH:D000077157', (73, 82))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('lower percentage of renal elimination', 'Phenotype', 'HP:0012213', (30, 67))	('Pazopanib', 'Var', (0, 9))
532696	23204874	A phase I study reported by Hurwitz et al evaluated a variety of doses and schedules of pazopanib (50 mg and 100 mg three times a week, 50-2000 mg once a day, and 300 mg and 400 mg twice a day) in 63 patients with advanced-stage and refractory solid tumors.	('patients', 'Species', '9606', (200, 208))	('50 mg', 'Var', (99, 104))	('pazopanib', 'Gene', (88, 97))	('solid tumors', 'Disease', (244, 256))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('solid tumors', 'Disease', 'MESH:D009369', (244, 256))	('pazopanib', 'Chemical', 'MESH:C516667', (88, 97))
532720	23204874	The study showed 69% reduction in the risk of progression or death in patients who received pazopanib.	('patients', 'Species', '9606', (70, 78))	('pazopanib', 'Var', (92, 101))	('death', 'Disease', 'MESH:D003643', (61, 66))	('death', 'Disease', (61, 66))	('reduction', 'NegReg', (21, 30))	('pazopanib', 'Chemical', 'MESH:C516667', (92, 101))
532721	23204874	Patients receiving pazopanib had a higher progression-free survival than those receiving placebo (4.6 months versus 1.6 months, respectively; hazard ratio = 0.31; P < 0.0001).	('pazopanib', 'Var', (19, 28))	('progression-free survival', 'CPA', (42, 67))	('Patients', 'Species', '9606', (0, 8))	('pazopanib', 'Chemical', 'MESH:C516667', (19, 28))	('higher', 'PosReg', (35, 41))
532724	23204874	Similarly, grade 3-5 thromboembolic events (3% versus 2%) and left ventricular ejection fraction drop of >15% (8% versus 3%) were experienced in the pazopanib versus placebo arm, respectively.	('pazopanib', 'Var', (149, 158))	('thromboembolic', 'Disease', 'MESH:D013923', (21, 35))	('thromboembolic events', 'Phenotype', 'HP:0001907', (21, 42))	('left ventricular ejection fraction', 'MPA', (62, 96))	('drop', 'NegReg', (97, 101))	('left ventricular ejection fraction drop', 'Phenotype', 'HP:0005162', (62, 101))	('thromboembolic', 'Disease', (21, 35))	('pazopanib', 'Chemical', 'MESH:C516667', (149, 158))
532734	23204874	Due to its antiangiogenic activities, pazopanib has been related with hypertension, bleeding, venous and arterial thrombosis, and proteinuria.	('bleeding', 'Disease', 'MESH:D006470', (84, 92))	('bleeding', 'Disease', (84, 92))	('pazopanib', 'Chemical', 'MESH:C516667', (38, 47))	('related', 'Reg', (57, 64))	('thrombosis', 'Disease', (114, 124))	('antiangiogenic activities', 'MPA', (11, 36))	('hypertension', 'Disease', 'MESH:D006973', (70, 82))	('proteinuria', 'Disease', (130, 141))	('proteinuria', 'Phenotype', 'HP:0000093', (130, 141))	('arterial thrombosis', 'Phenotype', 'HP:0004420', (105, 124))	('pazopanib', 'Var', (38, 47))	('proteinuria', 'Disease', 'MESH:D011507', (130, 141))	('thrombosis', 'Disease', 'MESH:D013927', (114, 124))	('hypertension', 'Disease', (70, 82))	('hypertension', 'Phenotype', 'HP:0000822', (70, 82))
532735	23204874	Of note, some lethal hepatitis has been described with pazopanib, and elevations in transaminases and total bilirubin must be closely monitored.	('hepatitis', 'Disease', (21, 30))	('hepatitis', 'Phenotype', 'HP:0012115', (21, 30))	('elevations in transaminases', 'Phenotype', 'HP:0002910', (70, 97))	('transaminases', 'MPA', (84, 97))	('bilirubin', 'Chemical', 'MESH:D001663', (108, 117))	('total bilirubin', 'MPA', (102, 117))	('hepatitis', 'Disease', 'MESH:D056486', (21, 30))	('pazopanib', 'Chemical', 'MESH:C516667', (55, 64))	('pazopanib', 'Var', (55, 64))
532736	23204874	Patients with Gilbert's syndrome must be monitored because pazopanib inhibits UDP-glycosyltransferase- 1 family, polypeptide A1, an enzyme involved in the metabolism of bilirubin and hyperbilirubinemia induced by pazopanib that has been associated with a polymorphism of the gene for UDP-glycosyltransferase-1 family, polypeptide A1 found in patients with Gilbert's syndrome.	("Gilbert's syndrome", 'Disease', 'MESH:D005878', (14, 32))	('hyperbilirubinemia', 'Phenotype', 'HP:0002904', (183, 201))	('pazopanib', 'Chemical', 'MESH:C516667', (59, 68))	('pazopanib', 'Chemical', 'MESH:C516667', (213, 222))	('hyperbilirubinemia', 'Disease', 'MESH:D006932', (183, 201))	('hyperbilirubinemia', 'Disease', (183, 201))	('inhibits', 'NegReg', (69, 77))	('patients', 'Species', '9606', (342, 350))	("Gilbert's syndrome", 'Disease', (356, 374))	('Patients', 'Species', '9606', (0, 8))	('pazopanib', 'Var', (59, 68))	("Gilbert's syndrome", 'Disease', (14, 32))	('bilirubin', 'Chemical', 'MESH:D001663', (169, 178))	('UDP-glycosyltransferase-1 family, polypeptide A1', 'Gene', '54658', (284, 332))	('UDP-glycosyltransferase- 1 family, polypeptide A1', 'Gene', '54658', (78, 127))	("Gilbert's syndrome", 'Disease', 'MESH:D005878', (356, 374))	('bilirubin', 'Chemical', 'MESH:D001663', (188, 197))
532740	23204874	Important progress has been made in the understanding of molecular alterations, which, associated with sarcoma subtypes, enabled the identification of early mutational events during tumor progression such as translocations and mutation of tyrosine kinases.	('sarcoma subtypes', 'Disease', (103, 119))	('tumor', 'Disease', (182, 187))	('translocations', 'Var', (208, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('mutation', 'Var', (227, 235))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (103, 119))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
532853	31509746	These alterations may endow phenotypic differences in tumor clones, which are subjected to competition and selection.	('alterations', 'Var', (6, 17))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('endow', 'Reg', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
532871	31509746	Ras/mitogen-activated protein kinase (MAPK) signaling is commonly activated in human soft tissue sarcomas, including UPS, and inactivating p53 mutations or silencing of the p53 pathway is one of the most common mutations in UPS.	('Ras/mitogen-activated', 'MPA', (0, 21))	('silencing', 'NegReg', (156, 165))	('human', 'Species', '9606', (79, 84))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (85, 105))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (85, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('UPS', 'Disease', (117, 120))	('p53 pathway', 'Pathway', (173, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('p53', 'Gene', (139, 142))	('sarcomas', 'Disease', (97, 105))	('inactivating', 'Var', (126, 138))	('activated', 'PosReg', (66, 75))	('mutations', 'Var', (143, 152))
532872	31509746	Tumors formed by the activation of oncogenic KrasG12D and deletion of p53 were similar to human UPS in histology and molecular profile.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('p53', 'Gene', (70, 73))	('KrasG12D', 'Var', (45, 53))	('deletion', 'Var', (58, 66))	('human', 'Species', '9606', (90, 95))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('activation', 'PosReg', (21, 31))	('G12D', 'Mutation', 'rs121913529', (49, 53))
532874	31509746	We observed up to 8 distinct fluorescent protein combinations, labeling on average ~60% of cells in tumors (Figure S1C).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('combinations', 'Var', (49, 61))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('labeling', 'Reg', (63, 71))
532875	31509746	The expression of the R26R-Confetti allele did not affect tumor histology (Figures S1B).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('R26R-Confetti', 'Var', (22, 35))
532878	31509746	Because the R26R-Confetti alleles randomly labeled tumor cells with 6-8 colors, and a given tumor may theoretically have more than 8 clones, it is possible that different clones may be labeled by the same color.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('R26R-Confetti', 'Var', (12, 25))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
532882	31509746	The K-sgP53-Cas9 tumors were histologically similar to KP and KPCC tumors (Figure S1B).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('KPCC tumors', 'Disease', 'MESH:D009369', (62, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('K-sgP53-Cas9', 'Var', (4, 16))	('KPCC tumors', 'Disease', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
532929	31509746	We hypothesized that if metastases were due to neutral drift, then the metastases in each nude mouse engrafted with the same KPCC tumor would be formed by different clones, which can be observed by the expression of different fluorescent reporters.	('metastases', 'Disease', 'MESH:D009362', (24, 34))	('KPCC tumor', 'Disease', 'MESH:D009369', (125, 135))	('KPCC tumor', 'Disease', (125, 135))	('metastases', 'Disease', (71, 81))	('due', 'Reg', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('metastases', 'Disease', (24, 34))	('neutral drift', 'Var', (47, 60))	('mouse', 'Species', '10090', (95, 100))
532985	31509746	MCs were enriched for the downregulated gene signature associated with the knock out of retinoic acid receptors, the downstream transcription factors of retinoic acid signaling (Figure S7F).	('retinoic acid', 'Chemical', 'MESH:D014212', (153, 166))	('downregulated', 'NegReg', (26, 39))	('retinoic acid', 'Chemical', 'MESH:D014212', (88, 101))	('knock out', 'Var', (75, 84))	('MC', 'Chemical', '-', (0, 2))	('retinoic', 'Protein', (88, 96))
532986	31509746	In addition, the loss of ALDH1A2 copy number in human soft tissue sarcoma was correlated with decreased survival (Figure S7G).	('sarcoma', 'Disease', (66, 73))	('copy number', 'Var', (33, 44))	('survival', 'MPA', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('human', 'Species', '9606', (48, 53))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (54, 73))	('ALDH1A2', 'Gene', (25, 32))	('decreased', 'NegReg', (94, 103))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('loss', 'NegReg', (17, 21))
532989	31509746	To test this, we performed a competition assay by co-injecting GFP+ Aldh1a2-OE cells with red fluorescent protein (RFP)+ control cells at a 1:1 ratio through the tail vein of nude mice.	('RFP', 'Gene', '19720', (115, 118))	('Aldh1a2-OE', 'Gene', (68, 78))	('red fluorescent protein', 'Gene', (90, 113))	('red fluorescent protein', 'Gene', '19720', (90, 113))	('nude mice', 'Species', '10090', (175, 184))	('RFP', 'Gene', (115, 118))	('GFP+', 'Var', (63, 67))
532998	31509746	First, in our models, tumor clones were initiated with the same founder mutations, KrasG12D, and homozygous deletion of p53.	('G12D', 'Mutation', 'rs121913529', (87, 91))	('KrasG12D', 'Var', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('p53', 'Gene', (120, 123))
533003	31509746	In our previous work, we tested the expression of p53 in cells generated from sarcomas in the KP-sgP53-Cas9 model and found that p53 expression is lost as a result of the various indels.	('expression', 'MPA', (133, 143))	('sarcomas', 'Disease', (78, 86))	('lost', 'NegReg', (147, 151))	('sarcomas', 'Disease', 'MESH:D012509', (78, 86))	('tested', 'Reg', (25, 31))	('p53', 'Gene', (129, 132))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('indels', 'Var', (179, 185))
533004	31509746	Furthermore, because our results with the KPsgP53-Cas9 model mirror the results from the KPCC model, where p53 alleles were deleted by Cre-Lox recombination, we concluded that the sarcomas in the K-sgP53-Cas9 model had lost p53 function.	('p53', 'Protein', (224, 227))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('K-sgP53-Cas9', 'Var', (196, 208))	('lost', 'NegReg', (219, 223))	('Lox', 'Gene', (139, 142))	('Lox', 'Gene', '16948', (139, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('sarcomas', 'Disease', (180, 188))	('function', 'MPA', (228, 236))
533005	31509746	Based on the fluorescent reporter model and DNA barcoding, we showed that primary tumor progression is associated with the expansion of a dominant clone.	('primary tumor', 'Disease', 'MESH:D009369', (74, 87))	('primary tumor', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('expansion', 'Var', (123, 132))
533031	31509746	More recently, genetic knock out of RA receptors, the transcriptional factors downstream of RA signaling, is reported to inhibit cell adhesion to matrix substrates.	('inhibit', 'NegReg', (121, 128))	('RA', 'Chemical', 'MESH:D014212', (36, 38))	('knock out', 'Var', (23, 32))	('cell adhesion to matrix substrates', 'CPA', (129, 163))	('RA', 'Chemical', 'MESH:D014212', (92, 94))	('RA receptors', 'Protein', (36, 48))
533036	31509746	The expression of Reck is downregulated in breast cancer by hypermethylation and contributes to tumor invasion and angiogenesis.	('breast cancer', 'Disease', (43, 56))	('downregulated', 'NegReg', (26, 39))	('contributes', 'Reg', (81, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('angiogenesis', 'CPA', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Reck', 'Gene', '53614', (18, 22))	('Reck', 'Gene', (18, 22))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', (96, 101))	('hypermethylation', 'Var', (60, 76))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))
533103	31509746	PCR to check the recombination of LSL-KrasG12D and p53 deletion were performed as described previously.	('G12D', 'Mutation', 'rs121913529', (42, 46))	('p53', 'Gene', (51, 54))	('LSL-KrasG12D', 'Var', (34, 46))
533129	30083234	A rare malignant thyroid carcinosarcoma with aggressive behavior and DICER1 gene mutation: a case report with literature review Malignant biphasic tumor also known as carcinosarcoma is an uncommon neoplasm that is composed of both malignant epithelial and mesenchymal components.	('DICER1', 'Gene', '23405', (69, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('aggressive behavior', 'Phenotype', 'HP:0000718', (45, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('Malignant biphasic tumor', 'Disease', 'MESH:D018198', (128, 152))	('DICER1', 'Gene', (69, 75))	('thyroid carcinosarcoma', 'Phenotype', 'HP:0002890', (17, 39))	('neoplasm', 'Disease', 'MESH:D009369', (197, 205))	('carcinosarcoma', 'Disease', (167, 181))	('mutation', 'Var', (81, 89))	('neoplasm', 'Disease', (197, 205))	('carcinosarcoma', 'Disease', (25, 39))	('carcinosarcoma', 'Disease', 'MESH:D002296', (167, 181))	('malignant thyroid carcinosarcoma', 'Disease', (7, 39))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('carcinosarcoma', 'Disease', 'MESH:D002296', (25, 39))	('Malignant biphasic tumor', 'Disease', (128, 152))	('neoplasm', 'Phenotype', 'HP:0002664', (197, 205))	('malignant thyroid carcinosarcoma', 'Disease', 'MESH:D002296', (7, 39))
533136	30083234	Molecular analysis using a next-generation sequencing based assay revealed a DICER1 (E1705K) point mutation in neoplastic cells.	('DICER1', 'Gene', '23405', (77, 83))	('DICER1', 'Gene', (77, 83))	('E1705K', 'Var', (85, 91))	('E1705K', 'Mutation', 'p.E1705K', (85, 91))
533137	30083234	To our knowledge, the E1705K point mutation within the DICER1 gene is the first reported mutation in carcinosarcoma of the thyroid.	('E1705K point', 'Var', (22, 34))	('DICER1', 'Gene', (55, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('DICER1', 'Gene', '23405', (55, 61))	('E1705K', 'Mutation', 'p.E1705K', (22, 28))	('carcinosarcoma of the thyroid', 'Disease', (101, 130))	('carcinosarcoma of the thyroid', 'Disease', 'MESH:D002296', (101, 130))
533153	30083234	Next generation sequencing (NGS) analysis revealed a novel point mutation in the DICER1 gene (E1705K) in neoplastic cells.	('DICER1', 'Gene', '23405', (81, 87))	('E1705K', 'Var', (94, 100))	('E1705K', 'Mutation', 'p.E1705K', (94, 100))	('DICER1', 'Gene', (81, 87))
533182	30083234	However, an interesting finding in this case is the presence of a point mutation in DICER1 (E1705K) that has previously been associated with differentiated thyroid carcinoma.	('point mutation', 'Var', (66, 80))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (156, 173))	('thyroid carcinoma', 'Disease', (156, 173))	('associated', 'Reg', (125, 135))	('DICER1', 'Gene', (84, 90))	('DICER1', 'Gene', '23405', (84, 90))	('E1705K', 'Mutation', 'p.E1705K', (92, 98))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (156, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('E1705K', 'Var', (92, 98))
533183	30083234	Whether the DICER1 (E1705K) mutation is the underlying genetic event leading to the initiation of tumorigenesis or is downstream to other gene alterations in tumor development is largely unknown.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('E1705K', 'Var', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('DICER1', 'Gene', (12, 18))	('DICER1', 'Gene', '23405', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (98, 103))	('E1705K', 'Mutation', 'p.E1705K', (20, 26))
533184	30083234	Additional mutations of unknown significance were also detected in this tumor including FLCN (R239H), POLD1 (Q684H) and SYK (R217L).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FLCN', 'Gene', '201163', (88, 92))	('detected', 'Reg', (55, 63))	('R217L', 'Var', (125, 130))	('tumor', 'Disease', (72, 77))	('R239H', 'Var', (94, 99))	('SYK', 'Gene', (120, 123))	('POLD1', 'Gene', '5424', (102, 107))	('FLCN', 'Gene', (88, 92))	('SYK', 'Gene', '6850', (120, 123))	('POLD1', 'Gene', (102, 107))	('R239H', 'Mutation', 'rs753948488', (94, 99))	('R217L', 'Mutation', 'p.R217L', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Q684H', 'Mutation', 'rs144143245', (109, 114))	('Q684H', 'Var', (109, 114))
533189	30083234	Heterozygous germline DICER mutations are described in the so-called DICER1 syndrome, which leads to a predisposition to develop a variety of tumors in children, including pleuropulmonary blastoma, cystic nephroma, rhabdomyosarcoma, ovarian Sertoli-Leydig tumors and multinodular goiter.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('DICER1', 'Gene', '23405', (69, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('DICER', 'Gene', '23405', (22, 27))	('develop', 'PosReg', (121, 128))	('multinodular goiter', 'Disease', 'MESH:C564546', (267, 286))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (172, 196))	('tumors', 'Disease', 'MESH:D009369', (256, 262))	('DICER', 'Gene', (69, 74))	('DICER1', 'Gene', (69, 75))	('children', 'Species', '9606', (152, 160))	('DICER', 'Gene', (22, 27))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (215, 231))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('mutations', 'Var', (28, 37))	('goiter', 'Phenotype', 'HP:0000853', (280, 286))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (172, 196))	('multinodular goiter', 'Disease', (267, 286))	('cystic nephroma, rhabdomyosarcoma, ovarian Sertoli-Leydig tumors', 'Disease', 'MESH:D018310', (198, 262))	('Leydig tumors', 'Phenotype', 'HP:0100618', (249, 262))	('pleuropulmonary blastoma', 'Disease', (172, 196))	('multinodular goiter', 'Phenotype', 'HP:0005987', (267, 286))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumors', 'Disease', (256, 262))	('DICER', 'Gene', '23405', (69, 74))
533190	30083234	A recent case study reported that a germline DICER1 mutation (S1814 L) is associated with an increased risk of thyroid follicular carcinoma.	('thyroid follicular carcinoma', 'Phenotype', 'HP:0006731', (111, 139))	('S1814 L', 'Mutation', 'rs1060503625', (62, 69))	('DICER1', 'Gene', (45, 51))	('DICER1', 'Gene', '23405', (45, 51))	('thyroid follicular carcinoma', 'Disease', 'MESH:D018263', (111, 139))	('follicular carcinoma', 'Phenotype', 'HP:0031548', (119, 139))	('thyroid follicular carcinoma', 'Disease', (111, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('S1814 L', 'Var', (62, 69))	('associated', 'Reg', (74, 84))
533191	30083234	A somatic DICER1 hotspot mutation at E1705K was reported in a case of anaplastic sarcoma of the kidney and in approximately 60% of Sertoli-Leydig cell tumors.	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (139, 157))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('DICER1', 'Gene', (10, 16))	('DICER1', 'Gene', '23405', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (81, 102))	('E1705K', 'Mutation', 'p.E1705K', (37, 43))	('Sertoli-Leydig cell tumors', 'Disease', (131, 157))	('sarcoma of the kidney', 'Disease', (81, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('E1705K', 'Var', (37, 43))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (131, 157))
533193	30083234	The presence of a DICER1 mutation in this case provides further evidence that development of the carcinosarcoma may not be a random occurrence, but is a likely due to a specific genetic alteration.	('carcinosarcoma', 'Disease', (97, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('mutation', 'Var', (25, 33))	('DICER1', 'Gene', (18, 24))	('DICER1', 'Gene', '23405', (18, 24))	('carcinosarcoma', 'Disease', 'MESH:D002296', (97, 111))
533196	30083234	Other mutations that were identified in this tumor include POLD1 (Q684H), FLCN (R239H) and SYK (R217L).	('FLCN', 'Gene', '201163', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('SYK', 'Gene', '6850', (91, 94))	('R217L', 'Var', (96, 101))	('Q684H', 'Mutation', 'rs144143245', (66, 71))	('Q684H', 'Var', (66, 71))	('R239H', 'Var', (80, 85))	('tumor', 'Disease', (45, 50))	('FLCN', 'Gene', (74, 78))	('R239H', 'Mutation', 'rs753948488', (80, 85))	('R217L', 'Mutation', 'p.R217L', (96, 101))	('POLD1', 'Gene', (59, 64))	('POLD1', 'Gene', '5424', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('SYK', 'Gene', (91, 94))
533198	30083234	Germline mutations in the folliculin (FLCN) gene, encoding the folliculin tumor-suppressor protein, are reported to be associated with Birt Hogg Dube syndrome.	('Birt Hogg Dube syndrome', 'Disease', (135, 158))	('FLCN', 'Gene', (38, 42))	('Birt Hogg Dube syndrome', 'Disease', 'MESH:D058249', (135, 158))	('folliculin', 'Gene', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('folliculin', 'Gene', '201163', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('FLCN', 'Gene', '201163', (38, 42))	('Germline', 'Var', (0, 8))	('tumor', 'Disease', (74, 79))	('folliculin', 'Gene', (63, 73))	('folliculin', 'Gene', '201163', (26, 36))	('associated', 'Reg', (119, 129))
533201	30083234	The clinical significance of FLCN (R239H) and SYK (R217L) mutations in thyroid carcinosarcoma is unknown.	('thyroid carcinosarcoma', 'Disease', 'MESH:D002296', (71, 93))	('FLCN', 'Gene', '201163', (29, 33))	('SYK', 'Gene', '6850', (46, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('thyroid carcinosarcoma', 'Phenotype', 'HP:0002890', (71, 93))	('R239H', 'Var', (35, 40))	('thyroid carcinosarcoma', 'Disease', (71, 93))	('R239H', 'Mutation', 'rs753948488', (35, 40))	('FLCN', 'Gene', (29, 33))	('R217L', 'Mutation', 'p.R217L', (51, 56))	('SYK', 'Gene', (46, 49))
533203	30083234	P53 point mutations are present in 60-80% of anaplastic thyroid carcinomas.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (56, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (56, 74))	('P53', 'Gene', (0, 3))	('point mutations', 'Var', (4, 19))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (45, 73))	('P53', 'Gene', '7157', (0, 3))	('anaplastic thyroid carcinoma', 'Disease', (45, 73))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (45, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (56, 74))	('thyroid carcinomas', 'Disease', (56, 74))	('anaplastic thyroid carcinomas', 'Phenotype', 'HP:0011779', (45, 74))
533204	30083234	Patients develop anaplastic carcinoma from a pre or coexistent differentiated carcinoma after a multistep process of dedifferentiation associated with loss of the p53 oncogene suppressor.	('carcinoma', 'Disease', (28, 37))	('carcinoma', 'Disease', 'MESH:D002277', (78, 87))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('anaplastic carcinoma', 'Disease', 'MESH:D002277', (17, 37))	('Patients', 'Species', '9606', (0, 8))	('anaplastic carcinoma', 'Disease', (17, 37))	('carcinoma', 'Disease', 'MESH:D002277', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('carcinoma', 'Disease', (78, 87))	('develop', 'Reg', (9, 16))	('loss', 'Var', (151, 155))
533205	30083234	Due to the similarities between anaplastic carcinoma and carcinosarcoma of the thyroid gland, it has been proposed that p53 mutation may contribute to the pathogenesis of carcinosarcoma.	('carcinosarcoma', 'Disease', (171, 185))	('carcinosarcoma', 'Disease', (57, 71))	('anaplastic carcinoma', 'Disease', 'MESH:D002277', (32, 52))	('p53', 'Gene', '7157', (120, 123))	('carcinosarcoma of the thyroid', 'Disease', (57, 86))	('anaplastic carcinoma', 'Disease', (32, 52))	('carcinosarcoma of the thyroid', 'Disease', 'MESH:D002296', (57, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('contribute', 'Reg', (137, 147))	('mutation', 'Var', (124, 132))	('carcinosarcoma', 'Disease', 'MESH:D002296', (57, 71))	('carcinosarcoma', 'Disease', 'MESH:D002296', (171, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('p53', 'Gene', (120, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
533209	30083234	Other mutations reported in anaplastic thyroid carcinoma include RAS, BRAF, PTEN, TERT, and PIK3kinase which were not identified in this patient.	('TERT', 'Gene', (82, 86))	('RAS', 'Gene', (65, 68))	('patient', 'Species', '9606', (137, 144))	('PIK3', 'Gene', '5294', (92, 96))	('PTEN', 'Gene', (76, 80))	('PTEN', 'Gene', '5728', (76, 80))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (39, 56))	('anaplastic thyroid carcinoma', 'Disease', (28, 56))	('TERT', 'Gene', '7015', (82, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('PIK3', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (70, 74))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (28, 56))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (28, 56))	('mutations', 'Var', (6, 15))	('BRAF', 'Gene', (70, 74))
533218	30083234	A DICER1 (E1705K) gene mutation was identified in this patient.	('E1705K', 'Mutation', 'p.E1705K', (10, 16))	('E1705K', 'Var', (10, 16))	('DICER1', 'Gene', (2, 8))	('DICER1', 'Gene', '23405', (2, 8))	('patient', 'Species', '9606', (55, 62))
533267	27057137	The entire slide was scanned at 10x magnification, and the percentage of each degree of staining intensity in the tumor cells was determined: H-score = (%0+)+(%1+)+(%2+)+(%3+).	('tumor', 'Disease', (114, 119))	('%0+', 'Var', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))
533322	27057137	As noted above, HIF-2 expression has been reported to upregulate endosialin expression and also regulates CAIX expression.	('expression', 'Var', (22, 32))	('upregulate', 'PosReg', (54, 64))	('expression', 'MPA', (111, 121))	('CAIX', 'Gene', (106, 110))	('endosialin', 'Gene', (65, 75))	('expression', 'MPA', (76, 86))	('HIF-2', 'Gene', (16, 21))	('regulates', 'Reg', (96, 105))	('endosialin', 'Gene', '57124', (65, 75))	('CAIX', 'Gene', '768', (106, 110))
533342	22674894	Conditional deletion of Igf2fl/fl attenuated the rapid tumour onset promoted by homozygous deletion of p53fl/fl.	('Igf2fl/fl', 'Gene', (24, 33))	('deletion', 'Var', (91, 99))	('tumour onset', 'Disease', (55, 67))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('p53fl/fl', 'Var', (103, 111))	('tumour onset', 'Disease', 'MESH:D009369', (55, 67))	('attenuated', 'NegReg', (34, 44))
533343	22674894	Accelerated carcinoma and sarcoma tumour formation in p53+/- females with bi-allelic Igf2 expression was associated with reductions in p53 loss of heterozygosity and apoptosis.	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (12, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('bi-allelic', 'Var', (74, 84))	('Igf2', 'Gene', (85, 89))	('p53', 'Gene', (135, 138))	('loss of', 'NegReg', (139, 146))	('sarcoma tumour', 'Disease', (26, 40))	('sarcoma tumour', 'Disease', 'MESH:D012509', (26, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('Accelerated', 'PosReg', (0, 11))	('reductions', 'NegReg', (121, 131))	('apoptosis', 'CPA', (166, 175))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
533346	22674894	DNA damage, oncogene activation, telomere erosion, nucleotide depletion and hypoxia, can activate p53 cellular responses including cell-cycle arrest, apoptosis, senescence and DNA repair (Menendez et al,; Riley et al,; Vousden & Prives,).	('hypoxia', 'Disease', (76, 83))	('activate', 'PosReg', (89, 97))	('arrest', 'Disease', 'MESH:D006323', (142, 148))	('nucleotide', 'Var', (51, 61))	('apoptosis', 'CPA', (150, 159))	('telomere erosion', 'Var', (33, 49))	('DNA repair', 'CPA', (176, 186))	('arrest', 'Disease', (142, 148))	('p53', 'Gene', (98, 101))	('senescence', 'CPA', (161, 171))	('hypoxia', 'Disease', 'MESH:D000860', (76, 83))
533348	22674894	Individuals with Li-Fraumeni syndrome (LFS) develop early onset cancers, and in 30-50% of cases, the tumours are attributed to germ-line heterozygote mutation of p53 with associated loss of heterozygosity (LOH) of the wild-type (WT) allele (Malkin,; Srivastava et al,).	('loss of', 'NegReg', (182, 189))	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('p53', 'Gene', (162, 165))	('mutation', 'Var', (150, 158))	('tumours', 'Disease', (101, 108))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (17, 37))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('Li-Fraumeni syndrome', 'Disease', (17, 37))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
533350	22674894	A single nucleotide polymorphism (SNP) of the MDM2 (SNP 309) gene promoter regulates the relative expression level of this negative regulator of p53 (Bond et al,).	('single nucleotide polymorphism', 'Var', (2, 32))	('regulates', 'Reg', (75, 84))	('relative expression level', 'MPA', (89, 114))	('MDM2', 'Gene', '17246', (46, 50))	('MDM2', 'Gene', (46, 50))
533354	22674894	Mice with homozygous disruption of p53 (p53-/-) are viable except for an exencephalic phenotype in females (Armstrong et al,; Clarke et al,; Donehower et al,).	('p53', 'Gene', (35, 38))	('disruption', 'Var', (21, 31))	('exencephalic', 'Disease', (73, 85))	('exencephalic', 'Disease', 'MESH:D009436', (73, 85))	('Mice', 'Species', '10090', (0, 4))
533356	22674894	p53 heterozygosity markedly reduces lymphoma, sarcoma and epithelial tumour latency and mirrors the phenotype of LFS (Donehower et al,; Jacks et al,).	('p53', 'Gene', (0, 3))	('epithelial tumour latency', 'Disease', (58, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (36, 44))	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('reduces', 'NegReg', (28, 35))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('sarcoma', 'Disease', (46, 53))	('heterozygosity', 'Var', (4, 18))	('epithelial tumour latency', 'Disease', 'MESH:D000077216', (58, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('lymphoma', 'Disease', (36, 44))	('lymphoma', 'Disease', 'MESH:D008223', (36, 44))	('epithelial tumour', 'Phenotype', 'HP:0031492', (58, 75))
533359	22674894	Mutations can lead to gain of function, as p53R172H/+ and p53R270H/+ can increase in carcinomas and osteosarcoma in the former, and carcinoma metastasis in the latter (Lang et al,; Olive et al,).	('osteosarcoma', 'Phenotype', 'HP:0002669', (100, 112))	('increase', 'PosReg', (73, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('p53R172H/+', 'Var', (43, 53))	('carcinomas and osteosarcoma', 'Disease', 'MESH:D012516', (85, 112))	('carcinoma metastasis', 'Disease', (132, 152))	('carcinoma metastasis', 'Disease', 'MESH:D009362', (132, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('p53R270H/+', 'Var', (58, 68))	('Olive', 'Species', '4146', (181, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('gain', 'PosReg', (22, 26))
533361	22674894	Stabilization of mutant p53 is also required in tumours, and is frequently associated with aggressive tumour phenotypes that can be induced by similar modifiers to those that regulate WT p53 (Suh et al,).	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumours', 'Disease', (48, 55))	('p53', 'Gene', (24, 27))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('aggressive tumour', 'Disease', 'MESH:D001523', (91, 108))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('aggressive tumour', 'Disease', (91, 108))	('associated', 'Reg', (75, 85))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('mutant', 'Var', (17, 23))
533367	22674894	IGF2 mRNA over-expression increases ligand supply in common human cancers mainly due to loss of imprinting (LOI, bi-allelic expression; Foulstone et al,; Ito et al,).	('ligand supply', 'MPA', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mRNA', 'Var', (5, 9))	('over-expression increases', 'PosReg', (10, 35))	('loss', 'NegReg', (88, 92))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('imprinting', 'MPA', (96, 106))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('IGF2', 'Gene', (0, 4))	('human', 'Species', '9606', (60, 65))
533371	22674894	Targeted disruption of the paternal (p) allele of Igf2 (Igf2+m/-p) regulates whole organism growth (60% of the size of WT littermates; Burns & Hassan,; DeChiara et al,).	('regulates', 'Reg', (67, 76))	('Igf2+m/-p', 'Gene', '16002', (56, 65))	('Igf2+m/-p', 'Gene', (56, 65))	('whole organism growth', 'MPA', (77, 98))	('disruption', 'Var', (9, 19))	('Igf2', 'Gene', (50, 54))
533372	22674894	Maternal (m) disruption of the imprinting control region (ICR) and the H19 gene (H19Delta13kb/+p) subsequently referred to as H19-m/+p, results in bi-allelic Igf2 expression and an overgrowth phenotype of 128% of the size of WT littermates (Leighton et al,).	('overgrowth', 'PosReg', (181, 191))	('H19', 'Gene', (126, 129))	('H19', 'Gene', '14955', (71, 74))	('disruption', 'Var', (13, 23))	('H19', 'Gene', '14955', (81, 84))	('overgrowth', 'Phenotype', 'HP:0001548', (181, 191))	('results in', 'Reg', (136, 146))	('Igf2', 'Gene', (158, 162))	('H19', 'Gene', '14955', (126, 129))	('expression', 'MPA', (163, 173))	('H19', 'Gene', (81, 84))	('H19', 'Gene', (71, 74))
533374	22674894	Igf2 can be reactivated in mouse tumours by LOI, where it promotes tumour progression (Christofori et al,).	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('tumour', 'Disease', (33, 39))	('tumour', 'Disease', (67, 73))	('mouse', 'Species', '10090', (27, 32))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('promotes', 'PosReg', (58, 66))	('tumours', 'Disease', (33, 40))	('LOI', 'Var', (44, 47))	('Igf2', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (67, 73))
533375	22674894	DNA hypomethylation also results in increased Igf2 expression and tumour promotion (Gaudet et al,; Linhart et al,).	('Igf2', 'Gene', (46, 50))	('hypomethylation', 'Var', (4, 19))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('increased Igf2', 'Phenotype', 'HP:0030269', (36, 50))	('increased', 'PosReg', (36, 45))	('expression', 'MPA', (51, 61))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))
533385	22674894	This was only observed when breeding from double heterozygote mothers (Igf2+m/-p, p53+/-, Supporting Information Fig S1A and B) and appeared independent of the parental Igf2 dose (Supporting Information Fig S2).	('Supporting', 'PosReg', (90, 100))	('p53+/-', 'Var', (82, 88))	('Igf2+m/-p', 'Gene', '16002', (71, 80))	('Igf2+m/-p', 'Gene', (71, 80))
533386	22674894	The majority of implantation sites in double heterozygote (Igf2+m/-p, p53+/-) mothers appeared abnormal (Supporting Information Fig S1C).	('implantation sites', 'CPA', (16, 34))	('p53+/-', 'Var', (70, 76))	('Igf2+m/-p', 'Gene', '16002', (59, 68))	('Igf2+m/-p', 'Gene', (59, 68))
533387	22674894	Haemorrhage was observed within the maternal decidua at implantation sites in double heterozygote (Igf2+m/-p, p53+/-) mothers, and was less frequently observed in either p53+/- or Igf2+m/-p heterozygote mothers (Supporting Information Fig S1C and D).	('Igf2+m/-p', 'Gene', '16002', (180, 189))	('Igf2+m/-p', 'Gene', (180, 189))	('p53+/-', 'Var', (110, 116))	('Haemorrhage', 'Disease', 'MESH:D006470', (0, 11))	('Igf2+m/-p', 'Gene', '16002', (99, 108))	('Igf2+m/-p', 'Gene', (99, 108))	('Haemorrhage', 'Disease', (0, 11))
533388	22674894	At birth, either H19-m/+p, Igf2+m/-p or p53+/- alleles exhibited the expected Mendelian segregation (129, B6 and F1/F2, Supporting Information Tables S2 and S3).	('H19', 'Gene', (17, 20))	('Igf2+m/-p', 'Gene', (27, 36))	('Igf2+m/-p', 'Gene', '16002', (27, 36))	('H19', 'Gene', '14955', (17, 20))	('p53+/-', 'Var', (40, 46))	('129', 'Var', (101, 104))	('F1/F2', 'Var', (113, 118))
533391	22674894	Second, pre-natal and post-natal lethality occurred in homozygote null p53 combined with disruption of the paternal expressed allele of Igf2 (Igf2+m/-p, p53-/- and Igf2-m/-p, p53-/- mice).	('Igf2+m/-p', 'Gene', '16002', (142, 151))	('Igf2+m/-p', 'Gene', (142, 151))	('Igf2', 'Gene', (136, 140))	('mice', 'Species', '10090', (182, 186))	('disruption', 'Var', (89, 99))	('p53', 'Gene', (71, 74))
533397	22674894	In contrast, double heterozygote (Igf2+m/-p, p53+/-) female littermates survived beyond post-natal day 10, indicating the lethality could be rescued by loss of an allele of p53.	('Igf2+m/-p', 'Gene', '16002', (34, 43))	('loss', 'Var', (152, 156))	('p53', 'Gene', (173, 176))	('Igf2+m/-p', 'Gene', (34, 43))
533398	22674894	Morphological appearances of embryos appeared normal between E9.5 and E18.5, even though Igf2+m/-p embryos were smaller (Supporting Information Fig S3).	('E9.5', 'Var', (61, 65))	('Igf2+m/-p', 'Gene', (89, 98))	('Morphological appearances', 'CPA', (0, 25))	('Igf2+m/-p', 'Gene', '16002', (89, 98))	('E18.5', 'Var', (70, 75))
533399	22674894	Following delivery by caesarean section at E19.5, Igf2+m/-p females became increasingly cyanotic (Fig 2B).	('E19.5', 'Var', (43, 48))	('Igf2+m/-p', 'Gene', (50, 59))	('cyanotic', 'MPA', (88, 96))	('Igf2+m/-p', 'Gene', '16002', (50, 59))	('caesarean section', 'Phenotype', 'HP:0011410', (22, 39))
533400	22674894	Analysis of organ growth revealed that the mean wet weights of lungs from Igf2+m/-p females were significantly reduced compared either to WT, Igf2+m/-p males or double heterozygote females (Igf2+m/-p, p53+/-, Fig 2C and Supporting Information Fig S3B and C).	('Igf2+m/-p', 'Gene', '16002', (142, 151))	('Igf2+m/-p', 'Gene', (142, 151))	('Igf2+m/-p', 'Gene', '16002', (190, 199))	('Igf2+m/-p', 'Gene', (190, 199))	('p53+/-', 'Var', (201, 207))	('Igf2+m/-p', 'Gene', (74, 83))	('reduced', 'NegReg', (111, 118))	('Igf2+m/-p', 'Gene', '16002', (74, 83))	('wet weights', 'CPA', (48, 59))
533403	22674894	A specific gene expression signature was observed in progeny that were derived from double heterozygote fathers (Igf2+m/-p, p53+/-; Fig 3B).	('p53+/-', 'Var', (124, 130))	('Igf2+m/-p', 'Gene', (113, 122))	('Igf2+m/-p', 'Gene', '16002', (113, 122))
533405	22674894	Using PScan (Zambelli et al,) to locate putative p53 binding sites in the promoters of the 50 most differentially expressed genes between progeny that were derived from double heterozygote fathers (Igf2+m/-p, p53+/-) and controls, we detected 48/50 potential p53 regulated genes.	('Igf2+m/-p', 'Gene', '16002', (198, 207))	('p53+/-', 'Var', (209, 215))	('Igf2+m/-p', 'Gene', (198, 207))	('p53', 'Gene', (259, 262))
533410	22674894	The E9.5 'lethality (rescue) signature' (Fig 3C) contained 23 genes including those encoding transcription factors (Zmiz2, Tbx6), endocrine regulators (Sst), endocytosis (Necap2), metabolic enzymes (Pck2, Man1a, Pus7) and the extracellular matrix protein, fibronectin (Fn1).	('Pus7', 'Gene', '78697', (212, 216))	('Pck2', 'Gene', '74551', (199, 203))	('Zmiz2', 'Gene', (116, 121))	('Tbx6', 'Gene', (123, 127))	('Man1a', 'Gene', (205, 210))	('Tbx6', 'Gene', '21389', (123, 127))	('fibronectin', 'Gene', '14268', (256, 267))	('Pus7', 'Gene', (212, 216))	('Pck2', 'Gene', (199, 203))	('E9.5', 'Var', (4, 8))	('Fn1', 'Gene', '14268', (269, 272))	('endocytosis', 'MPA', (158, 169))	('fibronectin', 'Gene', (256, 267))	('Necap2', 'Gene', (171, 177))	('Man1a', 'Gene', '17155', (205, 210))	('Necap2', 'Gene', '66147', (171, 177))	('Fn1', 'Gene', (269, 272))	('Zmiz2', 'Gene', '52915', (116, 121))
533419	22674894	Heterozygosity of p53 (p53+/-) combined with bi-allelic expression of Igf2 (in this case associated with the 13 kb deletion of the H19 gene and ICR H19Delta13kb), resulted in accelerated tumour formation in B6, 129 or F2 backgrounds (Fig 4A-C).	('deletion', 'Var', (115, 123))	('tumour', 'Disease', (187, 193))	('H19', 'Gene', '14955', (131, 134))	('H19', 'Gene', (131, 134))	('H19', 'Gene', (148, 151))	('accelerated', 'PosReg', (175, 186))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('Igf2', 'Gene', (70, 74))	('p53+/-', 'Var', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('H19', 'Gene', '14955', (148, 151))
533421	22674894	Control p53+/- females and males had similar tumour latencies (Fig 4D) indicating that the acceleration in tumour formation in females was primarily due to the consequences of Delta13 kb deletion on the Igf2-H19 locus.	('tumour latencies', 'Disease', (45, 61))	('tumour latencies', 'Disease', 'MESH:D009369', (45, 61))	('H19', 'Gene', '14955', (208, 211))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('acceleration', 'PosReg', (91, 103))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('H19', 'Gene', (208, 211))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('Delta13', 'Mutation', 'c.del13', (176, 183))	('Delta13 kb deletion', 'Var', (176, 195))	('tumour', 'Disease', (45, 51))	('tumour', 'Disease', (107, 113))
533424	22674894	Inactivation of the remaining WT p53 allele by LOH is normally required for tumour formation.	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('Inactivation', 'Var', (0, 12))	('tumour', 'Disease', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))
533425	22674894	We next determined the frequency of p53 LOH, mutation and the presence of p53 protein by IHC in tumours and correlated this with latency and tumour spectrum in H19-m/+p, p53+/- (Fig 5A; Supporting Information Table S4).	('tumours', 'Disease', (96, 103))	('H19', 'Gene', '14955', (160, 163))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('p53', 'Gene', (36, 39))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', (141, 147))	('p53', 'Gene', (74, 77))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('mutation', 'Var', (45, 53))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('H19', 'Gene', (160, 163))	('protein', 'Protein', (78, 85))	('tumour', 'Disease', (96, 102))
533426	22674894	Overall, 70% (21/30) of tumours from p53+/- littermates had either LOH or mutation of p53 compared to 16.7% (2/12) of tumours in H19-m/+p, p53+/- (Fig 5A).	('tumours', 'Disease', (24, 31))	('mutation', 'Var', (74, 82))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumours', 'Disease', (118, 125))	('H19', 'Gene', '14955', (129, 132))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('H19', 'Gene', (129, 132))	('LOH', 'NegReg', (67, 70))	('p53', 'Gene', (86, 89))
533428	22674894	In contrast, the untargeted (intact) p53 allele was retained in sarcoma and carcinomas associated with bi-allelic expression of Igf2 (Fig 5B), although this was independent of sex (not shown).	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('associated', 'Reg', (87, 97))	('sarcoma and carcinomas', 'Disease', 'MESH:D012509', (64, 86))	('Igf2', 'Gene', (128, 132))	('bi-allelic expression', 'Var', (103, 124))
533431	22674894	For the tumours that arose in H19-m/+p, p53+/-, we detected 1/10 with mutations in the p53 DNA-binding domain (Supporting Information Table S4).	('mutations in', 'Var', (70, 82))	('p53', 'Gene', (87, 90))	('tumours', 'Disease', (8, 15))	('H19', 'Gene', '14955', (30, 33))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('p53+/-', 'Var', (40, 46))	('H19', 'Gene', (30, 33))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
533432	22674894	Our data suggested that bi-allelic expression of Igf2 and the associated disruption of the H19 locus may have reduced the selection pressure for inactivation of the remaining WT allele of p53 mainly in carcinoma and sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('reduced', 'NegReg', (110, 117))	('H19', 'Gene', '14955', (91, 94))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (202, 223))	('selection pressure for inactivation', 'MPA', (122, 157))	('H19', 'Gene', (91, 94))	('Igf2', 'Gene', (49, 53))	('bi-allelic expression', 'Var', (24, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('disruption', 'Var', (73, 83))
533433	22674894	To determine whether proliferation and apoptosis were modified in the accelerated tumour formation from bi-allelic H19-m/+p, p53+/- females, we performed immuno-labelling for Ki67 proliferative marker and cleaved caspase-3 apoptotic marker.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('p53+/-', 'Var', (125, 131))	('H19', 'Gene', '14955', (115, 118))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('H19', 'Gene', (115, 118))	('tumour', 'Disease', (82, 88))	('Ki67', 'Gene', (175, 179))	('accelerated', 'PosReg', (70, 81))	('Ki67', 'Gene', '17345', (175, 179))
533434	22674894	In contrast to Ki67 labelling, cleaved caspase-3 labelling was significantly reduced in solid tumours (carcinoma and sarcoma) from p53+/- mice when combined with bi-allelic Igf2 expression compared to tumours from mice with mono-allelic Igf2 expression (Fig 5D).	('tumours', 'Disease', (201, 208))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumours', 'Disease', 'MESH:D009369', (201, 208))	('solid tumours', 'Disease', 'MESH:D009369', (88, 101))	('Ki67', 'Gene', (15, 19))	('mice', 'Species', '10090', (138, 142))	('combined', 'Interaction', (148, 156))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('tumours', 'Disease', (94, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (103, 124))	('reduced', 'NegReg', (77, 84))	('Ki67', 'Gene', '17345', (15, 19))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumours', 'Disease', 'MESH:D009369', (94, 101))	('Igf2', 'Gene', (173, 177))	('cleaved caspase-3 labelling', 'MPA', (31, 58))	('p53+/-', 'Var', (131, 137))	('solid tumours', 'Disease', (88, 101))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('mice', 'Species', '10090', (214, 218))	('bi-allelic', 'Var', (162, 172))
533438	22674894	Injection of tamoxifen (1 mg) to mothers at E10.5 generated deletion alleles and the expected segregation of progeny (37 males and 28 females, Supporting Information Fig S10A).	('tamoxifen', 'Chemical', 'MESH:D013629', (13, 22))	('deletion alleles', 'Var', (60, 76))	('S10A', 'Var', (170, 174))	('S10A', 'SUBSTITUTION', 'None', (170, 174))
533441	22674894	By P30 the mean total body weights (BW) and that of the eviscerated carcass of Igf2Delta/Delta, p53Delta/Delta, R26CreER+/- progeny was significantly less than that of Igf2fl/fl, p53fl/fl littermates, indicating that at least in these tissues Igf2-dependent functional growth effects could be detected (Fig 6B).	('P30', 'Gene', '15289', (3, 6))	('less', 'NegReg', (150, 154))	('Igf2Delta/Delta', 'Var', (79, 94))	('P30', 'Gene', (3, 6))	('p53Delta/Delta', 'Var', (96, 110))
533442	22674894	Tamoxifen treatment of homozygous conditional null Igf2Delta/Delta, p53Delta/Delta mice with ROSA 26 driven Cre (R26CreER+/-), avoided the combined lethality observed using germ-line transmission to create Igf2-m/-p, p53-/-.	('ROSA 26', 'Gene', (93, 100))	('avoided', 'NegReg', (127, 134))	('mice', 'Species', '10090', (83, 87))	('ROSA 26', 'Gene', '14910', (93, 100))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('p53Delta/Delta', 'Var', (68, 82))	('combined lethality', 'MPA', (139, 157))
533443	22674894	Moreover, bi-allelic disruption of the Igf2 allele eliminated the potential for tumour specific re-expression of the imprinted Igf2 (silenced) maternal allele (LOI).	('tumour', 'Disease', (80, 86))	('bi-allelic disruption', 'Var', (10, 31))	('Igf2', 'Gene', (39, 43))	('Igf2', 'Gene', (127, 131))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('eliminated', 'NegReg', (51, 61))
533445	22674894	Importantly, the time-dependent onset of tumours mimicked that of the p53-/- germ-line modification (Supporting Information Fig S4).	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('p53-/-', 'Var', (70, 76))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))
533446	22674894	There was a significant shift in tumour spectrum of Igf2Deltam/+p, p53Delta/Delta, R26+/- mice relative to Igf2Delta/Delta, p53Delta/Delta, R26+/- mice with a reduction in lymphoma development relative to carcinoma and sarcoma (Fig 6D).	('reduction', 'NegReg', (159, 168))	('mice', 'Species', '10090', (147, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('tumour', 'Disease', (33, 39))	('lymphoma', 'Disease', (172, 180))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('lymphoma', 'Phenotype', 'HP:0002665', (172, 180))	('shift', 'Reg', (24, 29))	('mice', 'Species', '10090', (90, 94))	('lymphoma', 'Disease', 'MESH:D008223', (172, 180))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (205, 226))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('Igf2Deltam/+p', 'Var', (52, 65))
533450	22674894	Loss of miR-675 in the H19ncRNA can promote tumour formation, as can an increase in miR-483 within the Igf2 region (Gabory et al,; Veronese et al,; Yoshimizu et al,).	('increase', 'PosReg', (72, 80))	('promote', 'PosReg', (36, 43))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('miR-675', 'Gene', '735280', (8, 15))	('H19', 'Gene', '14955', (23, 26))	('tumour', 'Disease', (44, 50))	('miR-483', 'Gene', '723874', (84, 91))	('miR-483', 'Gene', (84, 91))	('H19', 'Gene', (23, 26))	('miR-675', 'Gene', (8, 15))	('Loss', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
533454	22674894	Thus, our observation that homozygote null p53 mice fail to survive to adulthood in the context of disruption of the paternal allele of Igf2 suggests Igf2 is required to rescue a p53 loss of function-dependent lethality.	('loss of function-dependent', 'NegReg', (183, 209))	('Igf2', 'Gene', (136, 140))	('disruption', 'Var', (99, 109))	('mice', 'Species', '10090', (47, 51))
533457	22674894	Female Igf2+m/-p, p53+/- progeny also survived, albeit at lower than expected numbers, indicating that loss of one allele of p53 from the genotype of the offspring was sufficient for a partial rescue of the female specific lethality.	('Igf2+m/-p', 'Gene', (7, 16))	('loss', 'Var', (103, 107))	('p53', 'Gene', (125, 128))	('female specific lethality', 'CPA', (207, 232))	('Igf2+m/-p', 'Gene', '16002', (7, 16))
533459	22674894	In Igf2-m/-p mice, the canalicular phase of lung maturation during late gestation appeared delayed, leading to lungs having poorly organized alveoli with thick septae and reduced airspaces (Silva et al,).	('mice', 'Species', '10090', (13, 17))	('airspaces', 'CPA', (179, 188))	('Igf2-m/-p', 'Var', (3, 12))	('late gestation', 'Phenotype', 'HP:0001622', (67, 81))	('reduced', 'NegReg', (171, 178))
533464	22674894	Homozygous knock-out of Man1a2 produced a surprisingly severe lung phenotype that resulted in neonatal lethality (Tremblay et al,).	('Man1a2', 'Gene', '17156', (24, 30))	('lung', 'Disease', (62, 66))	('neonatal lethality', 'Disease', 'OMIM:202370', (94, 112))	('resulted in', 'Reg', (82, 93))	('neonatal lethality', 'Disease', (94, 112))	('Man1a2', 'Gene', (24, 30))	('knock-out', 'Var', (11, 20))
533466	22674894	Deletion of the H19 locus (Leighton et al,) is an imperfect model of LOI for Igf2.	('H19', 'Gene', '14955', (16, 19))	('H19', 'Gene', (16, 19))	('Deletion', 'Var', (0, 8))
533469	22674894	Thus the consequences of the 13 kb deletion in the H19-m/+p model we utilized may also have had Igf2-independent gain of function effects on the p53 pathway.	('gain of function', 'PosReg', (113, 129))	('p53 pathway', 'Pathway', (145, 156))	('H19', 'Gene', (51, 54))	('deletion', 'Var', (35, 43))	('H19', 'Gene', '14955', (51, 54))
533478	22674894	In the chondrosarcoma model, a p53-dependent reduction of IGFBP levels may have accounted for a secondary increase in IGF2 ligand bio-availability, and hence dependence on Igf2.	('chondrosarcoma', 'Disease', (7, 21))	('chondrosarcoma', 'Disease', 'MESH:D002813', (7, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('ligand bio-availability', 'MPA', (123, 146))	('IGF2', 'Protein', (118, 122))	('IGFBP', 'Gene', (58, 63))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (7, 21))	('p53-dependent', 'Var', (31, 44))	('increase', 'PosReg', (106, 114))	('reduction', 'NegReg', (45, 54))
533480	22674894	These data suggest that regulation of the IGF2 ligand in tumour susceptibility syndromes associated with p53 (e.g.	('IGF2', 'Gene', (42, 46))	('p53', 'Var', (105, 108))	('tumour', 'Disease', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
533481	22674894	Li-Fraumeni, p53 and MDM2 associated SNPs) may be a potential strategy for tumour prevention.	('MDM2', 'Gene', '17246', (21, 25))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('p53', 'Var', (13, 16))	('tumour', 'Disease', (75, 81))	('MDM2', 'Gene', (21, 25))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
533485	22674894	To distinguish Igf2+m/-p from Igf2-m/+p, embryos with reduced CR length and low Igf2 expression with qPCR were designated as being Igf2+m/-p. Recombination of conditional alleles by R26CreER+/- was with Tamoxifen (1 mg, 5% v/v ethanol and 95% v/v corn-oil, Sigma, Poole, UK) injected I.P.	('expression', 'MPA', (85, 95))	('ethanol', 'Chemical', 'MESH:D000431', (227, 234))	('R26CreER+/-', 'Var', (182, 193))	('Igf2+m/-p', 'Gene', (131, 140))	('Igf2+m/-p', 'Gene', '16002', (131, 140))	('Igf2+m/-p', 'Gene', '16002', (15, 24))	('Igf2+m/-p', 'Gene', (15, 24))	('reduced', 'NegReg', (54, 61))	('CR length', 'CPA', (62, 71))	('corn', 'Species', '4577', (247, 251))	('Tamoxifen', 'Chemical', 'MESH:D013629', (203, 212))	('Igf2', 'Gene', (80, 84))	('low', 'NegReg', (76, 79))
533489	22674894	Inherited mutation of the p53 gene can predispose humans to early onset cancers (Li-Fraumeni syndrome, LFS), and this effect can be reproduced in the mouse.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('humans', 'Species', '9606', (50, 56))	('mutation', 'Var', (10, 18))	('p53', 'Gene', (26, 29))	('predispose', 'Reg', (39, 49))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (81, 101))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('mouse', 'Species', '10090', (150, 155))	('Li-Fraumeni syndrome', 'Disease', (81, 101))
533530	31370265	In contrast to osteosarcoma, Ewing sarcoma is characterized by a chromosomal translocation between the EWSR1 and FLI1 genes in 90% of cases, or by the fusion of EWSR1 with other transcription factors of the E26 Transformation-Specific (ETS) gene family in 10% of cases.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (29, 42))	('EWSR1', 'Gene', (103, 108))	('osteosarcoma', 'Disease', 'MESH:D012516', (15, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (29, 42))	('EWSR1', 'Gene', '2130', (161, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('fusion', 'Var', (151, 157))	('EWSR1', 'Gene', '2130', (103, 108))	('FLI1', 'Gene', '2313', (113, 117))	('osteosarcoma', 'Phenotype', 'HP:0002669', (15, 27))	('FLI1', 'Gene', (113, 117))	('Ewing sarcoma', 'Disease', (29, 42))	('EWSR1', 'Gene', (161, 166))	('osteosarcoma', 'Disease', (15, 27))
533555	31370265	On the other hand, M2-polarized macrophages have been associated with increased tumor growth and metastases in preclinical models of osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('M2-polarized', 'Var', (19, 31))	('increased', 'PosReg', (70, 79))	('metastases', 'Disease', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('tumor', 'Disease', (80, 85))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('osteosarcoma', 'Disease', (133, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))
533574	31370265	Unfortunately, the results do not recommend the use of zoledronate as no improvement in event-free survival was observed, zoledronate showing a trend to increase the risk of failure in osteosarcoma patients.	('failure', 'Disease', (174, 181))	('osteosarcoma', 'Disease', (185, 197))	('zoledronate', 'Chemical', 'MESH:D000077211', (122, 133))	('patients', 'Species', '9606', (198, 206))	('osteosarcoma', 'Phenotype', 'HP:0002669', (185, 197))	('zoledronate', 'Var', (122, 133))	('zoledronate', 'Chemical', 'MESH:D000077211', (55, 66))	('osteosarcoma', 'Disease', 'MESH:D012516', (185, 197))	('increase', 'PosReg', (153, 161))	('failure', 'Disease', 'MESH:D017093', (174, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))
533579	31370265	This signaling pathway is therefore finely regulated and mutations or deregulation of the Wnt signaling pathway are often associated with tumor development, chemoresistance, or relapse.	('associated', 'Reg', (122, 132))	('relapse', 'CPA', (177, 184))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('deregulation', 'Var', (70, 82))	('mutations', 'Var', (57, 66))	('Wnt signaling pathway', 'Pathway', (90, 111))	('chemoresistance', 'CPA', (157, 172))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
533604	31370265	However, other studies highlighted that inactivation of the Wnt/beta-catenin pathway plays a key role in osteosarcoma development.	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('beta-catenin', 'Gene', (64, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('beta-catenin', 'Gene', '1499', (64, 76))	('inactivation', 'Var', (40, 52))
533605	31370265	In particular, frequent deletions of genes involved in the Wnt signaling pathway genes have been described in osteosarcoma patients.	('described', 'Reg', (97, 106))	('osteosarcoma', 'Disease', (110, 122))	('patients', 'Species', '9606', (123, 131))	('deletions', 'Var', (24, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (110, 122))	('osteosarcoma', 'Disease', 'MESH:D012516', (110, 122))
533625	31370265	Most of these miRs downregulate antagonists of the Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', (55, 67))	('downregulate', 'NegReg', (19, 31))	('miRs', 'Var', (14, 18))	('beta-catenin', 'Gene', '1499', (55, 67))	('antagonists', 'Pathway', (32, 43))
533626	31370265	As an example, miR-552-5p is overexpressed in osteosarcoma tissues and cell lines compared to healthy tissue and osteoblasts respectively.	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('osteosarcoma', 'Disease', (46, 58))	('overexpressed', 'PosReg', (29, 42))	('osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('osteosarcoma', 'Disease', 'MESH:D012516', (46, 58))	('miR-552-5p', 'Var', (15, 25))
533628	31370265	On the other hand, some miRs that are able to restrain the expression of key intermediates or regulators of the Wnt/beta-catenin signaling pathway have been described to be downregulated, causing an aberrant activation of this pathway in osteosarcoma cells.	('downregulated', 'NegReg', (173, 186))	('activation', 'PosReg', (208, 218))	('miRs', 'Var', (24, 28))	('osteosarcoma cells', 'Disease', (238, 256))	('expression', 'MPA', (59, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (238, 250))	('beta-catenin', 'Gene', (116, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('osteosarcoma cells', 'Disease', 'MESH:D012516', (238, 256))	('beta-catenin', 'Gene', '1499', (116, 128))
533647	31370265	In addition, WNT974 appears to reduce the development of metastatic disease in vivo in a murine subcutaneous xenograft model and to delay the time of first lung metastasis establishment.	('murine', 'Species', '10090', (89, 95))	('WNT974', 'Var', (13, 19))	('reduce', 'NegReg', (31, 37))	('delay', 'NegReg', (132, 137))	('development of metastatic disease', 'CPA', (42, 75))
533648	31370265	WNT974 inhibits Wnt signaling pathways (canonical and non-canonical) and cell migration and dissemination, therefore demonstrated the role of the Wnt signaling pathway during Ewing sarcoma metastatic spread.	('rat', 'Species', '10116', (124, 127))	('Wnt signaling pathways', 'Pathway', (16, 38))	('Ewing sarcoma', 'Disease', (175, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('inhibits', 'NegReg', (7, 15))	('rat', 'Species', '10116', (81, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (175, 188))	('WNT974', 'Var', (0, 6))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (175, 188))
533676	31370265	Osteosarcoma patients with high VEGF expression levels exhibit both lower disease-free survival and lower overall survival.	('disease-free survival', 'CPA', (74, 95))	('lower', 'NegReg', (68, 73))	('patients', 'Species', '9606', (13, 21))	('VEGF', 'Gene', (32, 36))	('lower', 'NegReg', (100, 105))	('high', 'Var', (27, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('Osteosarcoma', 'Disease', (0, 12))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('overall survival', 'CPA', (106, 122))	('expression', 'MPA', (37, 47))
533677	31370265	Similarly, a genetic amplification of the VEGFA gene was detected in osteosarcoma and significantly associated with high microvessels density and low patient disease-free survival.	('low', 'NegReg', (146, 149))	('patient', 'Species', '9606', (150, 157))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('patient disease-free survival', 'CPA', (150, 179))	('associated', 'Reg', (100, 110))	('osteosarcoma', 'Disease', (69, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (69, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('VEGFA', 'Gene', '7422', (42, 47))	('detected', 'Reg', (57, 65))	('genetic amplification', 'Var', (13, 34))	('high microvessels', 'MPA', (116, 133))	('VEGFA', 'Gene', (42, 47))
533683	31370265	Moreover, defects in APC, resulting in constitutively active beta-catenin, induce the over-expression of VEGF.	('beta-catenin', 'Gene', '1499', (61, 73))	('APC', 'Phenotype', 'HP:0005227', (21, 24))	('APC', 'Disease', 'MESH:D011125', (21, 24))	('over-expression', 'MPA', (86, 101))	('APC', 'Disease', (21, 24))	('constitutively', 'MPA', (39, 53))	('beta-catenin', 'Gene', (61, 73))	('VEGF', 'Protein', (105, 109))	('defects', 'Var', (10, 17))
533701	31370265	The most relevant one has described that inhibitors of the Wnt signaling pathway re-sensitizes osteosarcoma cells to doxorubicin under hypoxic conditions.	('re-sensitizes', 'PosReg', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('osteosarcoma cells', 'Disease', 'MESH:D012516', (95, 113))	('Wnt signaling pathway', 'Pathway', (59, 80))	('inhibitors', 'Var', (41, 51))	('doxorubicin', 'Chemical', 'MESH:D004317', (117, 128))	('osteosarcoma cells', 'Disease', (95, 113))	('osteosarcoma', 'Phenotype', 'HP:0002669', (95, 107))
533721	31370265	Another important point is that cross regulations between TAMs and TILs play a key role in osteosarcoma development.	('TILs', 'Gene', (67, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('TAMs', 'Chemical', '-', (58, 62))	('cross regulations', 'Var', (32, 49))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('osteosarcoma', 'Disease', (91, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (91, 103))
533728	31370265	Thus, aberrant activation of the canonical Wnt signaling pathway in osteosarcoma cells seems to be highly involved in cell proliferation, induction of an EMT-like process, acquisition of stem cells properties of osteosarcoma CSCs as well as metastatic dissemination.	('metastatic dissemination', 'CPA', (241, 265))	('activation', 'PosReg', (15, 25))	('osteosarcoma', 'Phenotype', 'HP:0002669', (212, 224))	('osteosarcoma CSCs', 'Disease', 'MESH:D012516', (212, 229))	('involved', 'Reg', (106, 114))	('aberrant', 'Var', (6, 14))	('osteosarcoma CSCs', 'Disease', (212, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('EMT-like process', 'CPA', (154, 170))	('canonical Wnt signaling pathway', 'Pathway', (33, 64))	('osteosarcoma cells', 'Disease', 'MESH:D012516', (68, 86))	('rat', 'Species', '10116', (130, 133))	('cell proliferation', 'CPA', (118, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('osteosarcoma', 'Phenotype', 'HP:0002669', (68, 80))	('osteosarcoma cells', 'Disease', (68, 86))
533815	28391775	In that study, the number of previous lines of chemotherapy was a significant prognostic factor in the multivariate analysis for PFS with a significantly worse outcome in patients receiving pazopanib in the third- or fourth-line settings versus the first- or second-line settings.	('pazopanib', 'Var', (190, 199))	('patients', 'Species', '9606', (171, 179))	('PFS', 'Disease', (129, 132))	('pazopanib', 'Chemical', 'MESH:C516667', (190, 199))	('worse', 'NegReg', (154, 159))
533958	30508968	A similar trend was observed on SROC with AUCs of 0.9467 and 0.9859 for lung and bone metastases, respectively.	('bone metastases', 'Disease', 'MESH:D009362', (81, 96))	('bone metastases', 'Disease', (81, 96))	('0.9859', 'Var', (61, 67))
533984	28182004	The increase of LC3-II by tenovin-6 results in the inhibition of classical autophagy pathway by impairing lysosomal function without affecting the fusion between autophagosome and lysosome.	('inhibition', 'NegReg', (51, 61))	('impairing', 'NegReg', (96, 105))	('tenovin-6', 'Chemical', 'MESH:C574854', (26, 35))	('lysosomal function', 'CPA', (106, 124))	('tenovin-6', 'Var', (26, 35))	('increase', 'PosReg', (4, 12))	('classical autophagy pathway', 'Pathway', (65, 92))	('LC3-II', 'Protein', (16, 22))
534006	28182004	The increase of LC3B-II following tenovin-6 treatment was also markedly compromised in human A549 and Huh7 cells following knockdown of ATG5 (Figure 2b).	('Huh7', 'Gene', '284424', (102, 106))	('human', 'Species', '9606', (87, 92))	('tenovin-6', 'Chemical', 'MESH:C574854', (34, 43))	('LC3B', 'Gene', '81631', (16, 20))	('compromised', 'NegReg', (72, 83))	('A549', 'CellLine', 'CVCL:0023', (93, 97))	('knockdown', 'Var', (123, 132))	('increase', 'PosReg', (4, 12))	('Huh7', 'Gene', (102, 106))	('LC3B', 'Gene', (16, 20))
534061	28182004	Although we detected LC3B-II accumulation in cells treated with tenovin-6 from 0 to 48 h, we failed to detect consistent p53 activation based on the status of p53 acetylation (K382) and phosphorylation (Ser15), and induction of its downstream targets Puma, Bax and p21 in all the time points examined (Figures 6a and b).	('LC3B', 'Gene', (21, 25))	('p21', 'Gene', (265, 268))	('K382', 'Var', (176, 180))	('tenovin-6', 'Chemical', 'MESH:C574854', (64, 73))	('Ser15', 'Chemical', '-', (203, 208))	('phosphorylation', 'MPA', (186, 201))	('p21', 'Gene', '644914', (265, 268))	('LC3B', 'Gene', '81631', (21, 25))	('accumulation', 'PosReg', (29, 41))	('acetylation', 'MPA', (163, 174))
534062	28182004	p53 acetylation was clearly detected in OCI-Ly1 cells treated with doxorubicin (Figure 6b) but not in A549 and Huh7 cells following tenovin-6 treatment (Figures 6a and b).	('tenovin-6', 'Chemical', 'MESH:C574854', (132, 141))	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('detected', 'Reg', (28, 36))	('Huh7', 'Gene', (111, 115))	('doxorubicin', 'Var', (67, 78))	('Huh7', 'Gene', '284424', (111, 115))	('OCI-Ly1', 'CellLine', 'CVCL:1879', (40, 47))	('acetylation', 'MPA', (4, 15))	('p53', 'Protein', (0, 3))	('A549', 'CellLine', 'CVCL:0023', (102, 106))
534066	28182004	Loss of ATG5 (ATG5-/-) markedly increased p53 expression level and its acetylation status (K379 in mouse) (Figure 6c).	('mouse', 'Species', '10090', (99, 104))	('p53 expression level', 'MPA', (42, 62))	('increased', 'PosReg', (32, 41))	('Loss', 'Var', (0, 4))	('ATG5', 'Gene', (8, 12))
534069	28182004	As SIRT1 regulates the autophagic pathway, we examined whether knockdown of SIRT1 was sufficient to mimic the effect of tenovin-6 on LC3B-II accumulation.	('tenovin-6', 'Chemical', 'MESH:C574854', (120, 129))	('autophagic pathway', 'CPA', (23, 41))	('LC3B', 'Gene', '81631', (133, 137))	('knockdown', 'Var', (63, 72))	('regulates', 'Reg', (9, 18))	('LC3B', 'Gene', (133, 137))	('SIRT1', 'Gene', (76, 81))
534070	28182004	SIRT1 knockdown did not cause LC3B-II accumulation in A549, Huh7 and OCI-Ly1 cells; in contrast, it slightly reduced the LC3B-II levels (Figure 7a).	('LC3B', 'Gene', (30, 34))	('OCI-Ly1', 'CellLine', 'CVCL:1879', (69, 76))	('SIRT1', 'Gene', (0, 5))	('LC3B', 'Gene', (121, 125))	('Huh7', 'Gene', (60, 64))	('LC3B', 'Gene', '81631', (30, 34))	('A549', 'CellLine', 'CVCL:0023', (54, 58))	('reduced', 'NegReg', (109, 116))	('knockdown', 'Var', (6, 15))	('Huh7', 'Gene', '284424', (60, 64))	('LC3B', 'Gene', '81631', (121, 125))
534071	28182004	There was slight increase of SQSTM1/p62 in OCI-Ly1 but not in A549 and Huh7 cells following SIRT1 knockdown.	('SQSTM1', 'Gene', (29, 35))	('Huh7', 'Gene', '284424', (71, 75))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('SQSTM1', 'Gene', '8878', (29, 35))	('knockdown', 'Var', (98, 107))	('p62', 'Gene', '8878', (36, 39))	('p62', 'Gene', (36, 39))	('increase', 'PosReg', (17, 25))	('OCI-Ly1', 'CellLine', 'CVCL:1879', (43, 50))	('Huh7', 'Gene', (71, 75))
534076	28182004	SIRT2 was expressed in A549, Huh7, OCI-Ly1 and KMM cells, and did not have any significant change following SIRT1 knockdown, or knockout (Figures 7a and b).	('OCI-Ly1', 'CellLine', 'CVCL:1879', (35, 42))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('knockdown', 'Var', (114, 123))	('SIRT2', 'Gene', (0, 5))	('Huh7', 'Gene', (29, 33))	('Huh7', 'Gene', '284424', (29, 33))
534079	28182004	These results indicated that the effect of tenovin-6 on LC3B-II accumulation cannot be phenocopied by knockdown of SIRT1 or SIRT2 alone, or double knockdown of both SIRT1 and SIRT2.	('tenovin-6', 'Chemical', 'MESH:C574854', (43, 52))	('LC3B', 'Gene', '81631', (56, 60))	('LC3B', 'Gene', (56, 60))	('double knockdown', 'Var', (140, 156))	('accumulation', 'PosReg', (64, 76))
534088	28182004	In this study, we have shown that SIRT1 knockdown or knockout reduces the expression of LC3B, results that are consistent with results of aforementioned studies.	('expression', 'MPA', (74, 84))	('reduces', 'NegReg', (62, 69))	('knockout', 'Var', (53, 61))	('LC3B', 'Gene', '81631', (88, 92))	('knockdown', 'Var', (40, 49))	('LC3B', 'Gene', (88, 92))	('SIRT1', 'Gene', (34, 39))
534089	28182004	However, the results of SIRT1 knockdown or knockout are opposite to those of tenovin-6 treatment, which significantly increases LC3B accumulation.	('LC3B', 'Gene', '81631', (128, 132))	('tenovin-6', 'Chemical', 'MESH:C574854', (77, 86))	('knockout', 'Var', (43, 51))	('LC3B', 'Gene', (128, 132))	('SIRT1', 'Gene', (24, 29))	('increases', 'PosReg', (118, 127))	('knockdown', 'Var', (30, 39))
534090	28182004	In a recent study, tenovin-6 treatment was shown to increase LC3-II accumulation, whereas siRNA knockdown of SIRT1 or SIRT2 decreased or did not change LC3-II level in pediatric soft tissue sarcoma cells.	('knockdown', 'Var', (96, 105))	('LC3-II accumulation', 'MPA', (61, 80))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('increase', 'PosReg', (52, 60))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (178, 197))	('sarcoma', 'Disease', (190, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('tenovin-6', 'Chemical', 'MESH:C574854', (19, 28))
534096	28182004	In the autophagic condition with normal lysosomal function, the double-tagged LC3B can be used to distinguish autophagosomes from autolysosomes.	('LC3B', 'Gene', (78, 82))	('LC3B', 'Gene', '81631', (78, 82))	('double-tagged', 'Var', (64, 77))
534108	28182004	The antibodies used were: LC3B (#CTB-LC3-1-50, Cosmo Bio, San Diego, CA, USA), LC3A (#ab62720, Abcam, Cambridge, MA, USA), SQSTM1/p62 (#PM045, MBL, Woburn, MA, USA), ATG5 (#2630, CST, Danvers, MA, USA), LAMP1 (#ab25630, Abcam; #9091, CST), beta-actin (#sc-8432, Santa Cruz, Santa Cruz, CA, USA), p53 (DO-1 for human and sc-126 for mouse, Santa Cruz; #2524, CST), acetyl-p53 (K382) (#2524, CST), acetyl-p53 (K379) (#2570, CST), phospho-p53 (S15) (#9284, CST), SIRT1 (#8469, CST), SIRT2 (#12672, CST), Bax (#2772, CST), Puma (#4976, CST), p21 (#556430, BD Biosciences, Franklin Lakes, NJ, USA), goat anti-rabbit IgG-HRP (#SC-2030, Santa Cruz) and goat anti-mouse IgG-HRP (#SC-2005, Santa Cruz).	('LAMP1', 'Gene', '3916', (203, 208))	('goat', 'Species', '9925', (645, 649))	('beta-actin', 'Gene', '728378', (240, 250))	('LC3A', 'Gene', '84557', (79, 83))	('human', 'Species', '9606', (310, 315))	('mouse', 'Species', '10090', (331, 336))	('#12672', 'Var', (486, 492))	('LAMP1', 'Gene', (203, 208))	('#556430', 'Var', (542, 549))	('LC3B', 'Gene', (26, 30))	('mouse', 'Species', '10090', (655, 660))	('goat', 'Species', '9925', (593, 597))	('p21', 'Gene', (537, 540))	('rabbit', 'Species', '9986', (603, 609))	('MBL', 'Gene', (143, 146))	('LC3B', 'Gene', '81631', (26, 30))	('SQSTM1', 'Gene', (123, 129))	('p21', 'Gene', '644914', (537, 540))	('beta-actin', 'Gene', (240, 250))	('#4976', 'Var', (524, 529))	('p62', 'Gene', '8878', (130, 133))	('p62', 'Gene', (130, 133))	('LC3A', 'Gene', (79, 83))	('SQSTM1', 'Gene', '8878', (123, 129))	('MBL', 'Gene', '50639', (143, 146))
534187	23056514	Rabbit polyclonal anti-Phospho-Akt (Ser473), -Phospho-S6 (Ser240/244), -Phospho EGFR (Tyr 1068) were purchased from Cell Signaling.	('Tyr', 'Chemical', 'MESH:D014443', (86, 89))	('Ser240', 'Chemical', '-', (58, 64))	('Akt', 'Gene', (31, 34))	('Tyr 1068', 'Var', (86, 94))	('Ser473', 'Var', (36, 42))	('Ser240/244', 'Var', (58, 68))	('Ser473', 'Chemical', '-', (36, 42))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('Akt', 'Gene', '207', (31, 34))	('Rabbit', 'Species', '9986', (0, 6))
534207	23056514	However, although CD166, CD44 and CD90 were abundantly present in all three cell culture types analyzed, as expected for these broadly expressed mesenchymal antigens, the MSC-restricted markers CD146 and CD105 were considerably up-regulated in both sarco-spheres (Figure 1A) and adherent MSC-like cultures (Figure 1B) in comparison with LMS cells obtained under standard conditions (Figure 1C).	('CD166', 'Gene', '214', (18, 23))	('CD90', 'Gene', (34, 38))	('MSC', 'Gene', '9242', (288, 291))	('CD105', 'Var', (204, 209))	('MSC', 'Gene', (288, 291))	('CD146', 'Gene', '4162', (194, 199))	('CD146', 'Gene', (194, 199))	('CD44', 'Gene', '960', (25, 29))	('MSC', 'Gene', '9242', (171, 174))	('up-regulated', 'PosReg', (228, 240))	('CD166', 'Gene', (18, 23))	('CD44', 'Gene', (25, 29))	('MSC', 'Gene', (171, 174))	('CD90', 'Gene', '7070', (34, 38))
534239	23056514	Additionally, the equal frequency of Ki67+ cells (between 18 and 20% in all samples as evaluated by the observation of 10 high power fields), suggests an equal growth rate of the different tumors (Figure3D-F).	('growth', 'MPA', (160, 166))	('Ki67+', 'Var', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumors', 'Disease', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
534255	23056514	Accordingly, we investigated by DNA sequence the presence of genomic alterations in genes that may be linked to these altered pathways and contribute to the tumor chemoresistance.	('tumor', 'Disease', (157, 162))	('contribute', 'Reg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('genomic alterations', 'Var', (61, 80))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('linked', 'Reg', (102, 108))	('genes', 'Gene', (84, 89))
534258	23056514	Inhibition of EGFR could represent a promising strategy to achieve concomitant down-regulation of both downstream signaling pathways possibly leading to LMS stem-like cell killing, growth inhibition or chemosensitization.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('growth inhibition', 'CPA', (181, 198))	('Inhibition', 'Var', (0, 10))	('down-regulation', 'NegReg', (79, 94))	('LMS stem-like cell killing', 'CPA', (153, 179))
534272	23056514	In the absence of EGFR mutations in tumor cells (see Table S1), we hypothesized that receptor stimulation might depend on the production of high EGF levels in the tumor microenvironment.	('EGF', 'Gene', '1950', (18, 21))	('EGFR', 'Gene', '1956', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('EGFR', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', (163, 168))	('EGF', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('EGF', 'Gene', (145, 148))	('tumor', 'Disease', (36, 41))	('EGF', 'Gene', '1950', (145, 148))
534317	23056514	Previous studies showed that EGFR targeting combined with chemotherapy displayed marked antitumor activity against some sarcoma cell lines both in vitro and in vivo .	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('targeting', 'Var', (34, 43))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('tumor', 'Disease', (92, 97))	('sarcoma', 'Disease', (120, 127))
534318	23056514	Our results are in agreement with these studies and further point toward this treatment direction demonstrating for the first time the efficacy of EGFR targeting in chemosensitization of LMS stem-like cells.	('targeting', 'Var', (152, 161))	('EGFR', 'Gene', '1956', (147, 151))	('EGFR', 'Gene', (147, 151))
534397	33204660	Patients received a single intratumoral injection of NP on day 1, followed by IMRT starting 24 h later (day 2), 70 Gy in 35 fractions of 2 Gy.	('tumoral', 'Disease', 'MESH:D009369', (32, 39))	('NP', 'Chemical', 'MESH:D009405', (53, 55))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('70 Gy', 'Var', (112, 117))	('tumoral', 'Disease', (32, 39))
534447	33204660	Animal studies have shown that NBTXR3 + RT can prime an immune response which is not observed with RT alone, with an increase in CD8 + T cell infiltrates.	('immune response', 'CPA', (56, 71))	('prime', 'PosReg', (47, 52))	('increase', 'PosReg', (117, 125))	('CD8', 'Gene', (129, 132))	('CD8', 'Gene', '925', (129, 132))	('NBTXR3 + RT', 'Var', (31, 42))
534450	33204660	There was a larger increase in CD8 + T cells and CD8 and PD1 biomarkers in patients treated with NP + RT versus RT alone.	('patients', 'Species', '9606', (75, 83))	('increase', 'PosReg', (19, 27))	('CD8', 'Gene', (31, 34))	('CD8', 'Gene', (49, 52))	('CD8', 'Gene', '925', (31, 34))	('NP + RT', 'Var', (97, 104))	('CD8', 'Gene', '925', (49, 52))	('NP', 'Chemical', 'MESH:D009405', (97, 99))	('PD1', 'Gene', (57, 60))
534482	31413773	In mesenchymal tumors, high expression of PD-L1 mRNA is associated with shorter metastasis-free survival.	('PD-L1', 'Gene', '29126', (42, 47))	('high expression', 'Var', (23, 38))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (3, 21))	('shorter', 'NegReg', (72, 79))	('mesenchymal tumors', 'Disease', (3, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('metastasis-free survival', 'CPA', (80, 104))	('PD-L1', 'Gene', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
534499	31413773	The population of mesenchymal tumors had reportedly PD-L1 positivity in 38% of cases, substantially more than the non-mesenchymal tumor population which was PD-L1 positive in 19% of cases.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (18, 35))	('PD-L1', 'Gene', '29126', (52, 57))	('positivity', 'Var', (58, 68))	('mesenchymal tumor', 'Disease', (118, 135))	('PD-L1', 'Gene', (157, 162))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (118, 135))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (18, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PD-L1', 'Gene', '29126', (157, 162))	('mesenchymal tumors', 'Disease', (18, 36))	('PD-L1', 'Gene', (52, 57))
534510	31413773	Colony-stimulating factor 1 receptor (CSF1R) is well known to associate with macrophages and there is preclinical evidence that its blockade increases CD8-positive T-cell motility and tumor infiltration.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('increases', 'PosReg', (141, 150))	('CSF1R', 'Gene', '1436', (38, 43))	('CD8', 'Gene', (151, 154))	('Colony-stimulating factor 1 receptor', 'Gene', (0, 36))	('Colony-stimulating factor 1 receptor', 'Gene', '1436', (0, 36))	('CD8', 'Gene', '925', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('associate', 'Interaction', (62, 71))	('tumor', 'Disease', (184, 189))	('CSF1R', 'Gene', (38, 43))	('blockade', 'Var', (132, 140))
534515	31413773	Functional analysis in a responding patient demonstrated rapid in vivo expansion of neo-antigen-specific T-cell clones that were reactive to mutant neo-peptides found in the tumor.	('tumor', 'Disease', (174, 179))	('mutant', 'Var', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('patient', 'Species', '9606', (36, 43))
534516	31413773	These data support the hypothesis that the large proportion of mutant neo-antigens in mismatch repair-deficient (dMMR) makes them sensitive to immune checkpoint blockade, regardless of the malignant tumor tissues of origin.	('dMMR', 'Chemical', '-', (113, 117))	('malignant tumor', 'Disease', (189, 204))	('sensitive', 'Reg', (130, 139))	('mutant', 'Var', (63, 69))	('neo-antigens', 'Protein', (70, 82))	('malignant tumor', 'Disease', 'MESH:D018198', (189, 204))	('mismatch repair-deficient', 'Disease', (86, 111))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
534684	27536332	AF148805.2), BCBL-1 (HQ404500.1), DG-1 (JQ619843.1), and JSC-1 (GQ994935.1), were compared with the SPEL KSHV sequence.	('JQ619843.1', 'Var', (40, 50))	('BCBL-1', 'CellLine', 'CVCL:0165', (13, 19))	('HQ404500.1', 'Var', (21, 31))	('GQ994935.1', 'Var', (64, 74))	('KSHV', 'Species', '37296', (105, 109))
534711	27536332	The SNP in ORF56 leads to a non-synonymous mutation, with a change of a glycine or histidine in the 257 position of the protein.	('SNP', 'Var', (4, 7))	('leads to', 'Reg', (17, 25))	('glycine', 'Chemical', 'MESH:D005998', (72, 79))	('change', 'Reg', (60, 66))	('ORF56', 'Gene', (11, 16))	('glycine', 'MPA', (72, 79))	('histidine', 'Chemical', 'MESH:D006639', (83, 92))
534761	25970788	Hisaoka et al further reported that modulation of miR-let-7e and miR-99b reduced synovial sarcoma cell proliferation, suggesting a potential role for these miRNAs in STS.	('miR-99b', 'Gene', (65, 72))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('miR-99b', 'Gene', '407056', (65, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('reduced', 'NegReg', (73, 80))	('synovial sarcoma', 'Disease', (81, 97))	('miR', 'Gene', '220972', (65, 68))	('let-7e', 'Gene', '406887', (54, 60))	('miR', 'Gene', (65, 68))	('modulation', 'Var', (36, 46))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (81, 97))	('let-7e', 'Gene', (54, 60))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (156, 159))	('synovial sarcoma', 'Disease', 'MESH:D013584', (81, 97))
534771	25970788	Due to the number of miRNAs, screening assays were focused on the top 9 miRNAs (miR-15, 21, 128, 130a, 138, 139-5p, 224, 375 and 491-5p) most significantly correlated with DMFS, or known to modulate cellular adhesion and metastasis in other cancers.	('miR', 'Gene', '220972', (80, 83))	('138', 'Var', (103, 106))	('miR', 'Gene', (80, 83))	('DMFS', 'Disease', (172, 176))	('modulate', 'Reg', (190, 198))	('correlated', 'Reg', (156, 166))	('miR', 'Gene', '220972', (21, 24))	('DMFS', 'Chemical', '-', (172, 176))	('miR', 'Gene', (21, 24))	('224', 'Var', (116, 119))	('130a', 'Var', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('cancers', 'Disease', 'MESH:D009369', (241, 248))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (72, 75))	('cancers', 'Disease', (241, 248))
534772	25970788	Initial screening using migration and invasion assays suggested that knock-down of miR-128, miR-130a, miR-138 and miR-224 reduced migration and invasion of STS117 cells; hence these miRNAs were further evaluated for clonogenic survival following miRNA modulation.	('miR', 'Gene', (102, 105))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', '220972', (114, 117))	('reduced', 'NegReg', (122, 129))	('miR', 'Gene', (92, 95))	('knock-down', 'Var', (69, 79))	('miR', 'Gene', (83, 86))	('miR', 'Gene', (114, 117))	('miR', 'Gene', '220972', (246, 249))	('miR-224', 'Gene', (114, 121))	('miR-224', 'Gene', '407009', (114, 121))	('miR', 'Gene', '220972', (182, 185))	('invasion', 'CPA', (144, 152))	('migration', 'CPA', (130, 139))	('miR', 'Gene', (246, 249))	('miR', 'Gene', '220972', (102, 105))	('miR-130a', 'Gene', '406919', (92, 100))	('miR', 'Gene', (182, 185))	('miR-130a', 'Gene', (92, 100))
534773	25970788	The combined result of the assays indicated that miRNA-138 and miRNA-224 were the best candidates to interrogate further as these two miRNAs were individually associated with both DMFS and DFS (Supplementary Figure 2); moreover, in vitro experiments demonstrated that increased expression of miRNA-138 and -224 promoted cell invasion; conversely, their knock-down decreased invasion (Figure 1).	('increased', 'PosReg', (268, 277))	('decreased', 'NegReg', (364, 373))	('miRNA-224', 'Gene', '407009', (63, 72))	('promoted', 'PosReg', (311, 319))	('miR', 'Gene', '220972', (134, 137))	('miR', 'Gene', (134, 137))	('knock-down', 'Var', (353, 363))	('miR', 'Gene', '220972', (292, 295))	('miR', 'Gene', (292, 295))	('invasion', 'CPA', (374, 382))	('cell invasion', 'CPA', (320, 333))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (49, 52))	('miR', 'Gene', (63, 66))	('miR', 'Gene', '220972', (49, 52))	('DMFS', 'Chemical', '-', (180, 184))	('miRNA-224', 'Gene', (63, 72))
534774	25970788	However, while knock-down of miRNA-138 had no effect on clonogenic survival (Supplementary Figure 3), or cell cycle (data not shown); miRNA-224 was cytotoxic (Supplementary Figure 3).	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('miR', 'Gene', '220972', (134, 137))	('miR', 'Gene', (134, 137))	('clonogenic survival', 'CPA', (56, 75))	('miRNA-224', 'Gene', (134, 143))	('knock-down', 'Var', (15, 25))	('miRNA-224', 'Gene', '407009', (134, 143))	('cell cycle', 'CPA', (105, 115))
534781	25970788	Western blot analysis demonstrated the anticipated reduction of RHOC protein level post-miR-138 transfection (Supplementary Figure 4B).	('miR', 'Gene', (88, 91))	('RHOC', 'Gene', '389', (64, 68))	('reduction', 'NegReg', (51, 60))	('RHOC', 'Gene', (64, 68))	('transfection', 'Var', (96, 108))	('miR', 'Gene', '220972', (88, 91))
534827	25970788	In light of the similar cellular morphology between breast and sarcoma cells following miR-138 and RHOA modulation, we postulated that our six miRNA signature might also be relevant for breast malignancies, and explored its value using the TCGA BRCA dataset.	('sarcoma', 'Disease', (63, 70))	('miR', 'Gene', '220972', (143, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('modulation', 'Var', (104, 114))	('breast malignancies', 'Disease', (186, 205))	('miR', 'Gene', (143, 146))	('RHOA', 'Gene', '387', (99, 103))	('BRCA', 'Gene', '672', (245, 249))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('breast malignancies', 'Disease', 'MESH:D001943', (186, 205))	('RHOA', 'Gene', (99, 103))	('miR', 'Gene', (87, 90))	('BRCA', 'Gene', (245, 249))	('miR', 'Gene', '220972', (87, 90))
534872	25970788	Cell lines were tested and authenticated using Short Tandem Repeat (STR) profiling of the following loci for each cell line: Amelogenin, CSF1PO, D13S317, D16S539, D18S51, D19S433, D21S11, D2S1338, D3S1358, D5S818, D7S820, D8S1179, FGA, THO1, TPOX, and vWA.	('CSF1PO', 'Var', (137, 143))	('FGA', 'Gene', (231, 234))	('D3S1358', 'Var', (197, 204))	('D21S11', 'Var', (180, 186))	('D16S539', 'Var', (154, 161))	('D18S51', 'Var', (163, 169))	('TPOX', 'Disease', (242, 246))	('THO1', 'Gene', (236, 240))	('D5S818', 'Var', (206, 212))	('D8S1179', 'Var', (222, 229))	('D2S1338', 'Var', (188, 195))	('D13S317', 'Var', (145, 152))	('THO1', 'Gene', '9984', (236, 240))	('D19S433', 'Var', (171, 178))	('FGA', 'Gene', '2243', (231, 234))	('D7S820', 'Var', (214, 220))
534880	25970788	This analytical method thereby accounted for any cytotoxic effects from pre-miR or LNA transfections.	('miR', 'Gene', (76, 79))	('accounted', 'Reg', (31, 40))	('transfections', 'Var', (87, 100))	('miR', 'Gene', '220972', (76, 79))
534957	25962382	The MSTS scores were lower in patients with reconstruction of the flexor tendons than those with extensor tendon reconstruction.	('patients', 'Species', '9606', (30, 38))	('reconstruction', 'Var', (44, 58))	('lower', 'NegReg', (21, 26))	('MSTS scores', 'MPA', (4, 15))
535037	24448245	Authenticity for LM7, K7, K7M3, LM-8, HOS, MG-263, OS-D, OS-O, SKNBE-2, LM7-GFP and OS-25 cells were validated using STR DNA Fingerprinting before experimentation at characterized cell line core facility, MD Anderson Cancer Center.	('SKNBE-2', 'CellLine', 'CVCL:0528', (63, 70))	('K7M3', 'Var', (26, 30))	('LM7', 'CellLine', 'CVCL:0515', (17, 20))	('Cancer', 'Phenotype', 'HP:0002664', (217, 223))	('HOS', 'CellLine', 'CVCL:0312', (38, 41))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (205, 223))	('LM7', 'CellLine', 'CVCL:0515', (72, 75))	('OS-25', 'CellLine', 'CVCL:2860', (84, 89))	('MD Anderson Cancer', 'Disease', (205, 223))	('LM-8', 'CellLine', 'CVCL:6669', (32, 36))	('MG-263', 'CellLine', 'CVCL:1154', (43, 49))
535091	24448245	Angiosarcoma derived CTC were tested for mutations in TP53 and FLT4 genes that were detectable in primary tumors, however only TP53 mutation was detectable in CTC (Fig.	('mutations', 'Var', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Angiosarcoma', 'Disease', (0, 12))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Angiosarcoma', 'Disease', 'MESH:D006394', (0, 12))	('FLT4', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (54, 58))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (0, 12))	('FLT4', 'Gene', '2324', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (54, 58))	('TP53', 'Gene', (127, 131))
535094	24448245	Since MDM-2 and KRAS have been previously shown to be amplified in metastatic osteosarcoma patients and from our results, amplification in CTC is associated with metastasis, it is tempting to speculate that the detection of this amplification in CTC can predict the onset of metastatic lesions at distant sites and also can prove to be an important tool to predict the therapeutic efficacy of the anti-cancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (402, 408))	('osteosarcoma', 'Disease', 'MESH:D012516', (78, 90))	('metastatic lesions at distant sites', 'CPA', (275, 310))	('metastasis', 'Disease', (162, 172))	('patients', 'Species', '9606', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('amplification', 'Var', (122, 135))	('CTC', 'Gene', (139, 142))	('MDM-2', 'Gene', (6, 11))	('KRAS', 'Gene', (16, 20))	('cancer', 'Disease', (402, 408))	('cancer', 'Disease', 'MESH:D009369', (402, 408))	('associated', 'Reg', (146, 156))	('KRAS', 'Gene', '3845', (16, 20))	('MDM-2', 'Gene', '4193', (6, 11))	('osteosarcoma', 'Disease', (78, 90))	('osteosarcoma', 'Phenotype', 'HP:0002669', (78, 90))
535098	24448245	We hypothesized that inhibiting specific phosphatases can enhance phosphorylation of vimentin, thereby increasing vimentin translocation to cell surface.	('enhance', 'PosReg', (58, 65))	('vimentin', 'Gene', '7431', (114, 122))	('inhibiting', 'Var', (21, 31))	('vimentin', 'Gene', (114, 122))	('specific', 'Protein', (32, 40))	('phosphorylation', 'MPA', (66, 81))	('phosphatases', 'Enzyme', (41, 53))	('increasing', 'PosReg', (103, 113))	('vimentin', 'Gene', '7431', (85, 93))	('vimentin', 'Gene', (85, 93))
535109	24448245	In summary, isolation of CSV positive CTC will provide an understanding about the metastatic precursor subpopulation and also help in providing novel diagnostics; treatment and prognostic options based on therapeutic monitoring in sarcoma patients and will play a potential role in clinical decision-making.	('CSV', 'Chemical', '-', (25, 28))	('isolation', 'Var', (12, 21))	('sarcoma', 'Disease', 'MESH:D012509', (231, 238))	('patients', 'Species', '9606', (239, 247))	('sarcoma', 'Disease', (231, 238))	('sarcoma', 'Phenotype', 'HP:0100242', (231, 238))	('CSV', 'Gene', (25, 28))
535168	30097600	In conclusion, high NLR is an independent marker of poor prognosis among patients with STS.	('high', 'Var', (15, 19))	('patients', 'Species', '9606', (73, 81))	('STS', 'Phenotype', 'HP:0030448', (87, 90))	('NLR', 'Gene', (20, 23))
535176	30097600	Amongst these indices, the NLR has been the most thoroughly investigated, and recent meta-analyses have shown that high NLR is correlated with poor survival across several cancer types besides sarcomas.	('high', 'Var', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('NLR', 'Gene', (120, 123))	('sarcomas', 'Disease', (193, 201))	('sarcomas', 'Disease', 'MESH:D012509', (193, 201))	('sarcomas', 'Phenotype', 'HP:0100242', (193, 201))	('poor', 'NegReg', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('cancer', 'Disease', (172, 178))
535200	30097600	In subgroup analysis according to histotype, NLR-high was associated with worse OS across different sarcoma subtypes (Fig.	('sarcoma', 'Disease', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('worse OS', 'Disease', (74, 82))	('NLR-high', 'Var', (45, 53))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))
535204	30097600	Specifically, we showed that a high NLR independently correlated with poor survival outcomes in patients across both localized and metastatic stages of disease.	('poor', 'NegReg', (70, 74))	('NLR', 'Gene', (36, 39))	('survival', 'MPA', (75, 83))	('patients', 'Species', '9606', (96, 104))	('high', 'Var', (31, 35))
535207	30097600	In line with our observations, previous studies have shown that high NLR in the pre-operative setting was associated with worse survival outcomes in non-metastatic soft tissue sarcomas.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (164, 184))	('high', 'Var', (64, 68))	('sarcomas', 'Disease', 'MESH:D012509', (176, 184))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (164, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('NLR', 'Gene', (69, 72))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (164, 183))	('sarcomas', 'Disease', (176, 184))	('soft tissue sarcoma', 'Disease', (164, 183))
535208	30097600	In a small study of 83 patients with miscellaneous surgically-excised soft tissue sarcomas by Idowu et al., high NLR >= 5 was an independently associated with poor OS.	('NLR', 'Gene', (113, 116))	('soft tissue sarcoma', 'Disease', (70, 89))	('patients', 'Species', '9606', (23, 31))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (70, 90))	('poor', 'Disease', (159, 163))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (70, 89))	('high', 'Var', (108, 112))	('sarcomas', 'Disease', 'MESH:D012509', (82, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (70, 89))	('sarcomas', 'Disease', (82, 90))
535209	30097600	examined the role of pre-treatment CRP levels and NLR in a cohort of 129 patients with non-metastatic disease, and observed significantly worse disease-specific survival outcomes for patients with both an elevated CRP level and high NLR, as compared to those with both a normal CRP level and low NLR.	('CRP', 'Gene', '1401', (35, 38))	('high', 'Var', (228, 232))	('CRP', 'Gene', '1401', (278, 281))	('elevated CRP', 'Phenotype', 'HP:0011227', (205, 217))	('worse', 'NegReg', (138, 143))	('patients', 'Species', '9606', (73, 81))	('CRP', 'Gene', (214, 217))	('CRP', 'Gene', '1401', (214, 217))	('patients', 'Species', '9606', (183, 191))	('CRP', 'Gene', (35, 38))	('CRP', 'Gene', (278, 281))	('disease-specific survival outcomes', 'CPA', (144, 178))
535212	30097600	The prognostic role of PLR has been investigated in a meta-analysis which concluded that high PLR was independently associated with worse OS in various solid tumors, as well as in a retrospective analysis of resected soft tissue sarcoma.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('solid tumors', 'Disease', 'MESH:D009369', (152, 164))	('high', 'Var', (89, 93))	('PLR', 'Gene', (94, 97))	('soft tissue sarcoma', 'Disease', (217, 236))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (217, 236))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (217, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('solid tumors', 'Disease', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('associated', 'Reg', (116, 126))
535213	30097600	Pre-operative LMR, but not NLR or PLR, has also been independently correlated with worse disease-free survival and disease-specific survival in one study on resected soft tissue sarcoma.	('disease-free', 'Disease', (89, 101))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (166, 185))	('worse', 'NegReg', (83, 88))	('LMR', 'Var', (14, 17))	('soft tissue sarcoma', 'Disease', (166, 185))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (166, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
535219	30097600	Furthermore, neutrophils may facilitate tumor immune escape by inhibition of cytotoxic T lymphocytes and lymphokine-activated killer cells.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('facilitate', 'PosReg', (29, 39))	('cytotoxic T lymphocytes', 'CPA', (77, 100))	('tumor', 'Disease', (40, 45))	('neutrophils', 'Var', (13, 24))	('inhibition', 'NegReg', (63, 73))
535234	26690869	In fact, ERG gene rearrangements represent the second most common molecular alteration, with EWSR1-ERG being identified in 5-10% of cases, while only a handful of reports document a FUS-ERG fusion.	('rearrangements', 'Var', (18, 32))	('ERG', 'Gene', '2078', (9, 12))	('FUS', 'Gene', (182, 185))	('ERG', 'Gene', (9, 12))	('FUS', 'Gene', '2521', (182, 185))	('ERG', 'Gene', '2078', (186, 189))	('ERG', 'Gene', (186, 189))	('ERG', 'Gene', '2078', (99, 102))	('ERG', 'Gene', (99, 102))
535235	26690869	In this study, we focus on ES with ERG gene abnormalities, specifically to investigate the prevalence and clinicopathologic features of FUS-ERG fusions in a large cohort of small blue round cell tumors (SBRCTs) and compare to the eight reported FUS-positive ES.	('cell tumors', 'Disease', 'MESH:D005935', (190, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('ES', 'Phenotype', 'HP:0012254', (258, 260))	('ES', 'Phenotype', 'HP:0012254', (27, 29))	('ERG', 'Gene', '2078', (35, 38))	('ERG', 'Gene', (140, 143))	('FUS', 'Gene', (245, 248))	('ERG', 'Gene', (35, 38))	('FUS', 'Gene', '2521', (245, 248))	('FUS', 'Gene', (136, 139))	('cell tumors', 'Disease', (190, 201))	('FUS', 'Gene', '2521', (136, 139))	('fusions', 'Var', (144, 151))	('abnormalities', 'Var', (44, 57))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('ERG', 'Gene', '2078', (140, 143))	('SBRCTs', 'Chemical', '-', (203, 209))
535236	26690869	Among the 85 SBRCTs tested, seven (8.2%) cases harbored FUS gene rearrangements; six fused to ERG and one with FEV.	('FUS', 'Gene', (56, 59))	('harbored', 'Reg', (47, 55))	('ERG', 'Gene', '2078', (94, 97))	('FUS', 'Gene', '2521', (56, 59))	('ERG', 'Gene', (94, 97))	('rearrangements', 'Var', (65, 79))	('fused', 'Reg', (85, 90))	('SBRCTs', 'Chemical', '-', (13, 19))
535243	26690869	The second most common molecular abnormality is the t(21;22)(q22;q12), which accounts for 5% of the cases, resulting in an EWSR1-ERG fusion.	('ERG', 'Gene', '2078', (129, 132))	('ERG', 'Gene', (129, 132))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (52, 69))	('t(21;22)(q22;q12', 'Var', (52, 68))
535247	26690869	However, only five cases of SBRCT with t(16;21)(q11.2;q22) resulting in FUS-ERG and two cases harboring FUS-FEV fusions have been described to date.	('FUS', 'Gene', (72, 75))	('FUS', 'Gene', '2521', (104, 107))	('t(16;21)(q11.2;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (39, 58))	('FUS', 'Gene', '2521', (72, 75))	('t(16;21)(q11.2', 'Var', (39, 53))	('ERG', 'Gene', '2078', (76, 79))	('ERG', 'Gene', (76, 79))	('FUS', 'Gene', (104, 107))
535251	26690869	Criteria of selection for the study were tumors that were negative for EWSR1, CIC, and BCOR-CCNB3 gene abnormalities by FISH.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('abnormalities', 'Var', (103, 116))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('BCOR-CCNB3', 'Gene', (87, 97))	('EWSR1', 'Gene', (71, 76))
535260	26690869	These cases were then screened for ERG gene abnormalities by FISH and found to be positive in six of the seven cases (Fig.	('abnormalities', 'Var', (44, 57))	('ERG', 'Gene', (35, 38))	('ERG', 'Gene', '2078', (35, 38))
535284	26690869	Only after the EWSR1-ERG fusion transcript was detected by FusionSeq and subsequently validated by RT-PCR, FISH was performed to confirm the ERG gene rearrangement (Fig.	('ERG', 'Gene', (21, 24))	('rearrangement', 'Var', (150, 163))	('ERG', 'Gene', '2078', (141, 144))	('ERG', 'Gene', (141, 144))	('ERG', 'Gene', '2078', (21, 24))
535285	26690869	As EWSR1 and ERG have opposite directions of transcription, the EWSR1-ERG fusion typically does not result through a simple balanced translocation, as seen with EWSR1-FLI1 or FUS-ERG fusion.	('fusion', 'Var', (74, 80))	('ERG', 'Gene', '2078', (179, 182))	('ERG', 'Gene', (179, 182))	('ERG', 'Gene', '2078', (70, 73))	('ERG', 'Gene', (70, 73))	('FUS', 'Gene', (175, 178))	('FUS', 'Gene', '2521', (175, 178))	('ERG', 'Gene', '2078', (13, 16))	('ERG', 'Gene', (13, 16))
535300	26690869	With the increased application of next generation sequencing and molecular screening, novel genetic alterations were described in tumors resembling ES.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('described', 'Reg', (117, 126))	('ES', 'Phenotype', 'HP:0012254', (148, 150))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('genetic alterations', 'Var', (92, 111))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
535304	26690869	Subsequently, a t(2;16) translocation resulting in an in-frame fusion of FUS-FEV was reported, involving FUS exon 10 to FEV exon 2.	('FUS', 'Gene', '2521', (73, 76))	('translocation', 'Var', (24, 37))	('FUS', 'Gene', (73, 76))	('FUS', 'Gene', (105, 108))	('FUS', 'Gene', '2521', (105, 108))
535309	26690869	Our findings confirm the rarity of FUS gene rearrangements in ES, with only seven (8.2%) cases harboring this genetic abnormality among 85 SBRCTs negative for all other known fusions.	('ES', 'Phenotype', 'HP:0012254', (62, 64))	('SBRCTs', 'Chemical', '-', (139, 145))	('genetic abnormality', 'Disease', (110, 129))	('FUS', 'Gene', (35, 38))	('genetic abnormality', 'Disease', 'MESH:D030342', (110, 129))	('FUS', 'Gene', '2521', (35, 38))	('rearrangements', 'Var', (44, 58))
535323	26690869	Furthermore, one of our cases showed FLI1 immunopositivity; aberrant FLI1 expression has been previously described in rare ES cases with EWSR1-ERG fusion.	('ERG', 'Gene', (143, 146))	('FLI1', 'Gene', (69, 73))	('ES', 'Phenotype', 'HP:0012254', (123, 125))	('ERG', 'Gene', '2078', (143, 146))	('aberrant', 'Var', (60, 68))
535329	26690869	In contrast, EWSR1-FLI1 or FUS-ERG fusions typically result from simple balanced translocation events, as the gene partners have similar directions of transcription.	('ERG', 'Gene', '2078', (31, 34))	('FUS', 'Gene', '2521', (27, 30))	('ERG', 'Gene', (31, 34))	('EWSR1-FLI1', 'Gene', (13, 23))	('FUS', 'Gene', (27, 30))	('fusions', 'Var', (35, 42))	('result from', 'Reg', (53, 64))
535330	26690869	In this study, the EWSR1-ERG fusion was confirmed by a fusion FISH assay in all four SBRCTs with ERG gene rearrangements and negative break-apart FISH for EWSR1 and FUS abnormalities.	('rearrangements', 'Var', (106, 120))	('ERG', 'Gene', '2078', (25, 28))	('ERG', 'Gene', (25, 28))	('ERG', 'Gene', '2078', (97, 100))	('FUS abnormalities', 'Disease', (165, 182))	('ERG', 'Gene', (97, 100))	('SBRCTs', 'Chemical', '-', (85, 91))	('FUS abnormalities', 'Disease', 'MESH:D000014', (165, 182))
535332	26690869	Our results show that in the setting of EWSR1-ERG fusions, standard break-apart FISH for EWSR1 will yield false negative results in half of the cases as a consequence of the complex rearrangement pattern between these two genes with inverse orientations, requiring often a multistep mechanism, with multiple, unbalanced breaks, inversions and insertions events.	('ERG', 'Gene', '2078', (46, 49))	('rearrangement', 'Var', (182, 195))	('ERG', 'Gene', (46, 49))	('EWSR1', 'Gene', (89, 94))	('insertions', 'Var', (343, 353))
535333	26690869	Alternatively, FISH for ERG gene rearrangements and/or 3-color FISH fusion assay for EWSR1 and ERG can be used to prevent this pitfall.	('ERG', 'Gene', '2078', (24, 27))	('ERG', 'Gene', (24, 27))	('rearrangements', 'Var', (33, 47))	('ERG', 'Gene', '2078', (95, 98))	('ERG', 'Gene', (95, 98))
535339	26690869	Thus adding CD31 immunostaining is required for any ERG-positive neoplasm, since CD31 is a highly reliable endothelial marker in angiosarcoma and has more specificity compared to ERG in this context.	('neoplasm', 'Disease', (65, 73))	('ERG', 'Gene', '2078', (179, 182))	('CD31', 'Var', (81, 85))	('neoplasm', 'Phenotype', 'HP:0002664', (65, 73))	('ERG', 'Gene', (179, 182))	('angiosarcoma', 'Disease', 'MESH:D006394', (129, 141))	('ERG', 'Gene', '2078', (52, 55))	('neoplasm', 'Disease', 'MESH:D009369', (65, 73))	('ERG', 'Gene', (52, 55))	('angiosarcoma', 'Disease', (129, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('angiosarcoma', 'Phenotype', 'HP:0200058', (129, 141))
535340	26690869	In conclusion, our study is the first molecular investigation to establish the prevalence of FUS gene rearrangements in a well-characterized cohort of SBRCT, which accounts for 8.2% of cases lacking all other known fusions.	('FUS', 'Gene', '2521', (93, 96))	('rearrangements', 'Var', (102, 116))	('FUS', 'Gene', (93, 96))
535415	27076350	In analyzing the factors associated with survival for the entire cohort (n=131), male gender (HR 2.00, p=0.012 Table 2), age above 60 (HR 2.00, p=0.009 Table 2), presence of metastases (HR 4.50, p<0.001 Table 2), R2 resection (HR 6.51, p<0.001 Table 2) or no resection (HR 8.24, p<0.001 Table 2), and high grade (HR 2.20, p=0.007 Table 2) were significantly associated with worse OS.	('metastases', 'Disease', (174, 184))	('high grade', 'CPA', (301, 311))	('metastases', 'Disease', 'MESH:D009362', (174, 184))	('R2 resection', 'Var', (213, 225))
535417	27076350	Patients who had R2 resection margins had significantly increased risk of death and similar survival to those who did not undergo surgery on Kaplan Meier (HR 6.66, p<0.001, Table 2; Figure 1A).	('R2 resection margins', 'Var', (17, 37))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', 'MESH:D003643', (74, 79))	('death', 'Disease', (74, 79))
535418	27076350	Resection of 5 or more organs increased risk of death compared to no organs resected (HR 6.25, p=0.005), but not any number of organs less than that.	('Resection', 'Var', (0, 9))	('death', 'Disease', (48, 53))	('death', 'Disease', 'MESH:D003643', (48, 53))
535419	27076350	High grade lesions had significantly increased risk of death (HR 2.01 p=0.022, Table 2).	('death', 'Disease', 'MESH:D003643', (55, 60))	('death', 'Disease', (55, 60))	('High grade lesions', 'Var', (0, 18))
535435	27076350	On multivariate analysis, margin status (R1 margin HR 4.28, p<0.001 Table 3), size of tumor >15cm (HR 4.38, p=0.024 Table 3) and presence of metastases (HR 6.61, p=0.003 Table 3) were associated with increased risk of recurrence.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('margin status', 'Var', (26, 39))	('tumor', 'Disease', (86, 91))	('metastases', 'Disease', 'MESH:D009362', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('metastases', 'Disease', (141, 151))
535460	27076350	Notably, grade is particularly important in predicting distal recurrence, indicating that high grade LMS is much more likely to have distant metastases than low or intermediate grade.	('metastases', 'Disease', 'MESH:D009362', (141, 151))	('LMS', 'Disease', (101, 104))	('high grade', 'Var', (90, 100))	('metastases', 'Disease', (141, 151))
535492	22575361	Co-expression of vimentin and epithelial markers such as cytokeratin, keratin, and epithelial membrane antigen are characteristic of ES and, more recently, loss of INI1.	('vimentin', 'Gene', (17, 25))	('Co-expression', 'MPA', (0, 13))	('cytokeratin', 'Protein', (57, 68))	('INI1', 'Gene', (164, 168))	('loss', 'Var', (156, 160))	('INI1', 'Gene', '6598', (164, 168))	('vimentin', 'Gene', '7431', (17, 25))	('keratin', 'Protein', (70, 77))
535662	33411764	Secondly, p53 expression augments the type I IFN response by inducing interferon regulatory factor 9, interferon-stimulated gene 15, toll-like receptor 3, and protein kinase R (PKR).	('expression', 'Var', (14, 24))	('IFN', 'Gene', '3439', (45, 48))	('expression', 'Species', '29278', (14, 24))	('augments', 'PosReg', (25, 33))	('PKR', 'Gene', '5610', (177, 180))	('inducing', 'PosReg', (61, 69))	('PKR', 'Gene', (177, 180))	('IFN', 'Gene', (45, 48))	('interferon', 'Protein', (70, 80))	('p53', 'Gene', (10, 13))
535663	33411764	Lastly, p53 is a target of PKR and is phosphorylated by PKR at Ser392, a site that is important for tetramer stabilization and transcriptional activity.	('p53', 'Gene', (8, 11))	('PKR', 'Gene', '5610', (27, 30))	('Ser392', 'Var', (63, 69))	('PKR', 'Gene', (27, 30))	('PKR', 'Gene', '5610', (56, 59))	('Ser392', 'Chemical', '-', (63, 69))	('PKR', 'Gene', (56, 59))
535678	33411764	A plasmid expressing the dominant-negative p53 R273H mutation, which abrogates DNA-binding, but still allows tetramerization -further referred to as p53-273 -was used as a positive control for all assays (complete inhibition of p53).	('allows', 'Reg', (102, 108))	('R273H', 'Mutation', 'rs28934576', (47, 52))	('tetramerization', 'MPA', (109, 124))	('R273H', 'Var', (47, 52))	('p53', 'Gene', (43, 46))	('abrogates', 'NegReg', (69, 78))	('DNA-binding', 'Interaction', (79, 90))
535687	33411764	Hit number three, KSHV orf45, is a KSHV immediate early protein that is also part of the virion and interferes with the innate response to KSHV at multiple levels.	('orf45', 'Gene', '4961474', (23, 28))	('interferes', 'NegReg', (100, 110))	('KSHV', 'Species', '37296', (35, 39))	('innate response to KSHV', 'MPA', (120, 143))	('KSHV', 'Var', (18, 22))	('KSHV', 'Species', '37296', (18, 22))	('KSHV', 'Species', '37296', (139, 143))	('orf45', 'Gene', (23, 28))
535697	33411764	KSHV orf10-induced p53-Luc ~5-fold compared to empty vector (EV) in mock-treated cells.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('orf10-induced', 'Gene', (5, 18))	('p53-Luc', 'MPA', (19, 26))	('EV', 'Chemical', '-', (61, 63))
535700	33411764	ZIKV NS2A inhibited p53 transcription induced by nutlin-3, but less efficiently than the dominant-negative p53-273 mutant, suggesting that ZIKV NS2A may interfere with DDR-induced activation of p53 as well as the signaling downstream of HDM2.	('interfere', 'NegReg', (153, 162))	('p53', 'Gene', (20, 23))	('DDR', 'Chemical', '-', (168, 171))	('ZIKV', 'Species', '64320', (0, 4))	('nutlin-3', 'Chemical', 'MESH:C482205', (49, 57))	('p53', 'Protein', (194, 197))	('inhibited', 'NegReg', (10, 19))	('ZIKV', 'Species', '64320', (139, 143))	('HDM2', 'Gene', '4193', (237, 241))	('HDM2', 'Gene', (237, 241))	('activation', 'PosReg', (180, 190))	('ZIKV', 'Var', (139, 143))
535701	33411764	KSHV orf10 again augmented the response to nutlin-3 compared to EV, suggesting that it acted directly on p53.	('KSHV', 'Species', '37296', (0, 4))	('response to nutlin-3', 'MPA', (31, 51))	('augmented', 'PosReg', (17, 26))	('KSHV orf10', 'Var', (0, 10))	('EV', 'Chemical', '-', (64, 66))	('orf10', 'Var', (5, 10))	('nutlin-3', 'Chemical', 'MESH:C482205', (43, 51))
535717	33411764	Furthermore, ZIKV NS2A expression significantly decreased nuclear accumulation of p21 in etoposide-treated cells by immunofluorescence (shown by arrows, Fig 2E, quantitation in Fig 2C).	('ZIKV NS2A', 'Gene', (13, 22))	('decreased', 'NegReg', (48, 57))	('expression', 'Var', (23, 33))	('p21', 'Protein', (82, 85))	('expression', 'Species', '29278', (23, 33))	('etoposide', 'Chemical', 'MESH:D005047', (89, 98))	('ZIKV', 'Species', '64320', (13, 17))	('nuclear accumulation', 'MPA', (58, 78))
535741	33411764	ZIKV NS2A increased the cytoplasmic localization of ATM in U2OS cells (shown by arrows, Fig 4D and 4E), but this phenotype was not observed in the U87MG glioma cell line (S2C and S2D Fig).	('U2OS', 'CellLine', 'CVCL:0042', (59, 63))	('ZIKV', 'Species', '64320', (0, 4))	('glioma', 'Disease', (153, 159))	('S2C', 'CellLine', 'CVCL:Z232', (171, 174))	('ZIKV', 'Var', (0, 4))	('NS2A', 'Gene', (5, 9))	('U87MG', 'CellLine', 'CVCL:0022', (147, 152))	('cytoplasmic localization of', 'MPA', (24, 51))	('glioma', 'Disease', 'MESH:D005910', (153, 159))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('increased', 'PosReg', (10, 19))
535742	33411764	Taken together, these observations suggest that ZIKV NS2A can affect the p53 signaling network at multiple non-exclusive nodes: (i) NS2A binds to p53, it traps p53 in the cytosol, prevents its nuclear translocation, and thereby dampens p53 transcriptional activity; and (ii) it inhibits DDR mediated by ATM under some circumstances.	('DDR', 'Chemical', '-', (287, 290))	('affect', 'Reg', (62, 68))	('binds', 'Interaction', (137, 142))	('p53 transcriptional activity', 'MPA', (236, 264))	('prevents', 'NegReg', (180, 188))	('DDR mediated by ATM', 'MPA', (287, 306))	('inhibits', 'NegReg', (278, 286))	('ZIKV', 'Species', '64320', (48, 52))	('dampens', 'NegReg', (228, 235))	('NS2A', 'Var', (132, 136))	('p53', 'MPA', (160, 163))	('nuclear translocation', 'MPA', (193, 214))	('p53 signaling network', 'Pathway', (73, 94))
535752	33411764	KSHV orf10 also increased accumulation of total p53 levels as measured by Western-Blot of the total cell population.	('KSHV orf10', 'Var', (0, 10))	('KSHV', 'Species', '37296', (0, 4))	('increased accumulation', 'PosReg', (16, 38))	('p53 levels', 'MPA', (48, 58))
535753	33411764	By individual cell analysis, KSHV orf10 expression increased phosphorylated p53 levels (Fig 5D and 5E, and quantitated in Fig 5C), consistent with the Western-Blot results.	('KSHV orf10', 'Gene', (29, 39))	('increased', 'PosReg', (51, 60))	('expression', 'Var', (40, 50))	('phosphorylated p53 levels', 'MPA', (61, 86))	('KSHV', 'Species', '37296', (29, 33))	('expression', 'Species', '29278', (40, 50))
535754	33411764	Furthermore, KSHV orf10 increased the levels of total p53 only in transfected, untreated cells (Fig 6A and 6B, shown by arrows).	('KSHV', 'Species', '37296', (13, 17))	('p53', 'Protein', (54, 57))	('increased', 'PosReg', (24, 33))	('KSHV orf10', 'Var', (13, 23))
535755	33411764	These experiments confirmed that KSHV orf10 augments p53 signaling in response to DNA damage and that KSHV orf10 stabilizes p53 in the absence of DNA damage signals.	('orf10', 'Var', (38, 43))	('augments', 'PosReg', (44, 52))	('p53', 'MPA', (124, 127))	('KSHV orf10', 'Var', (102, 112))	('stabilizes', 'NegReg', (113, 123))	('p53 signaling', 'MPA', (53, 66))	('KSHV', 'Species', '37296', (33, 37))	('response to DNA damage', 'MPA', (70, 92))	('KSHV', 'Species', '37296', (102, 106))	('KSHV orf10', 'Var', (33, 43))
535763	33411764	Furthermore, KSHV orf10 had no effect on the accumulation and phosphorylation of ATR and did not result in phosphorylation of gammaH2AX, suggesting that orf10 acts downstream of ATM and ATR.	('H2AX', 'Gene', (131, 135))	('phosphorylation', 'MPA', (62, 77))	('KSHV orf10', 'Var', (13, 23))	('accumulation', 'MPA', (45, 57))	('H2AX', 'Gene', '15270', (131, 135))	('KSHV', 'Species', '37296', (13, 17))	('ATR', 'Protein', (81, 84))
535764	33411764	This mechanism of action is consistent with the ability of KSHV orf10 to augment p53-dependent transcription in response to Nutlin-3 (Fig 1G), i.e., independent of ATM/ATR activation.	('KSHV', 'Species', '37296', (59, 63))	('p53-dependent', 'Gene', (81, 94))	('augment', 'PosReg', (73, 80))	('response to', 'MPA', (112, 123))	('KSHV orf10', 'Var', (59, 69))
535769	33411764	These observations prompted the hypothesis that orf10 interferes with p53 nuclear export because CRM1 is a p53 nuclear export receptor and the CRM1-Nup98 complex is necessary for CRM1-dependent nuclear export.	('Nup98', 'Gene', '4928', (148, 153))	('CRM1', 'Gene', (97, 101))	('p53 nuclear export', 'MPA', (70, 88))	('orf10', 'Var', (48, 53))	('Nup98', 'Gene', (148, 153))	('interferes', 'NegReg', (54, 64))
535770	33411764	Contrary to expectations, however, KSHV orf10 did not interact with CRM1, nor did KSHV orf10 inhibit CRM1-dependent nuclear export (S4B-S4E Fig).	('inhibit', 'NegReg', (93, 100))	('CRM1-dependent nuclear export', 'MPA', (101, 130))	('KSHV', 'Species', '37296', (35, 39))	('KSHV orf10', 'Var', (82, 92))	('KSHV', 'Species', '37296', (82, 86))
535779	33411764	Here, the nuclear extract fraction was used as input, as it contained the majority of KSHV orf10 and p53.	('p53', 'Var', (101, 104))	('KSHV orf10', 'Gene', (86, 96))	('KSHV', 'Species', '37296', (86, 90))
535780	33411764	p53 ubiquitination was reduced in the presence of KSHV orf10 as compared to control (Fig 6F, lane 2 compared to lane 1).	('KSHV orf10', 'Var', (50, 60))	('ubiquitination', 'MPA', (4, 18))	('KSHV', 'Species', '37296', (50, 54))	('reduced', 'NegReg', (23, 30))	('p53', 'Protein', (0, 3))
535781	33411764	As expected, the effect was very pronounced in the presence of the proteasome inhibitor MG132 but was also evident in the absence of MG132 (the arrow points to ubiquitinated species of p53 migrating above 100 kDa, Fig 6F, lane 4 compared to lane 3).	('MG132', 'Var', (88, 93))	('p53', 'Gene', (185, 188))	('MG132', 'Chemical', 'MESH:C072553', (133, 138))	('MG132', 'Chemical', 'MESH:C072553', (88, 93))
535794	33411764	Both sets of experiments demonstrated that USP24 expression was abolished and that U2OS cells deleted for USP24 are viable, most likely because loss of USP24 can be compensated for by cellular reprogramming or the presence of other, compensating USPs in the cell.	('loss', 'Var', (144, 148))	('USP24', 'Gene', (152, 157))	('expression', 'Species', '29278', (49, 59))	('U2OS', 'CellLine', 'CVCL:0042', (83, 87))	('expression', 'MPA', (49, 59))	('deleted', 'Var', (94, 101))	('USP24', 'Gene', (43, 48))	('USP24', 'Gene', (106, 111))	('abolished', 'NegReg', (64, 73))
535798	33411764	This is most evident in the quantitation table below, which shows induction of p53 and Ser15-phosphorylated p53 relative to untransfected control in USP24 wild-type, but not USP24 deleted cells under both etoposide-induced and normal conditions.	('USP24', 'Gene', (149, 154))	('p53', 'MPA', (79, 82))	('Ser15', 'Chemical', '-', (87, 92))	('induction', 'PosReg', (66, 75))	('etoposide', 'Chemical', 'MESH:D005047', (205, 214))	('deleted', 'Var', (180, 187))
535799	33411764	These data corroborate our hypothesis and further confirm USP24 role in KSHV orf10-dependent p53 induction.	('p53', 'Gene', (93, 96))	('KSHV', 'Gene', (72, 76))	('USP24', 'Var', (58, 63))	('KSHV', 'Species', '37296', (72, 76))
535808	33411764	Thus, inhibition by p53-273 is downstream of DDR induced activation (etoposide), and downstream of Nutlin-3 induced release of p53 from HDM2.	('HDM2', 'Gene', '4193', (136, 140))	('HDM2', 'Gene', (136, 140))	('DDR', 'Chemical', '-', (45, 48))	('activation', 'PosReg', (57, 67))	('inhibition', 'NegReg', (6, 16))	('p53-273', 'Var', (20, 27))	('etoposide', 'Chemical', 'MESH:D005047', (69, 78))
535827	33411764	ZIKV NS2A, but not DENV NS2A, led to decreased proliferation and premature differentiation of radial glial cells and impaired adherence junction formation in these cells.	('premature differentiation', 'CPA', (65, 90))	('NS2A', 'Var', (5, 9))	('adherence junction formation', 'CPA', (126, 154))	('ZIKV', 'Species', '64320', (0, 4))	('ZIKV NS2A', 'Var', (0, 9))	('proliferation', 'CPA', (47, 60))	('decreased', 'NegReg', (37, 46))	('impaired', 'NegReg', (117, 125))
535835	33411764	Hence, it is plausible to think that KSHV orf10 is part of a trimolecular complex leading to reduced p53 ubiquitination and increased activity.	('increased', 'PosReg', (124, 133))	('p53', 'Protein', (101, 104))	('reduced', 'NegReg', (93, 100))	('KSHV', 'Species', '37296', (37, 41))	('activity', 'MPA', (134, 142))	('KSHV orf10', 'Var', (37, 47))
535842	33411764	Considering that Nup98 is also important for nuclear export of p21 mRNA adds another layer of complexity.	('Nup98', 'Gene', (17, 22))	('Nup98', 'Gene', '4928', (17, 22))	('p21', 'Var', (63, 66))
535845	33411764	Depending on the context, p53 induces either apoptosis or cell cycle arrest.	('arrest', 'Disease', 'MESH:D006323', (69, 75))	('p53', 'Var', (26, 29))	('arrest', 'Disease', (69, 75))	('apoptosis', 'CPA', (45, 54))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (58, 75))	('induces', 'Reg', (30, 37))
535847	33411764	Consistent with this idea, early studies suggested that KSHV induces cell cycle arrest during lytic replication and that p53 and p21 were necessary for KSHV lytic replication.	('arrest', 'Disease', 'MESH:D006323', (80, 86))	('induces', 'Reg', (61, 68))	('KSHV', 'Species', '37296', (56, 60))	('KSHV', 'Var', (56, 60))	('arrest', 'Disease', (80, 86))	('KSHV', 'Species', '37296', (152, 156))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (69, 86))
535852	33411764	It showed that egress and secondary envelopment of HCMV virions was significantly reduced in p53 knock-out cells and that "adding back" p53 rescued the phenotype.	('reduced', 'NegReg', (82, 89))	('p53', 'Gene', (93, 96))	('knock-out', 'Var', (97, 106))	('HCMV', 'Species', '10359', (51, 55))
535853	33411764	P53 was critical for expression of the early replication protein UL44, the nuclear egress complex protein UL53, and the structural proteins pp28/UL99 and MCP/UL86, and loss of p53 altered the sub-cellular localization of the major tegument protein pp65/UL83 and the nuclear egress complex protein UL50.	('loss', 'Var', (168, 172))	('p53', 'Gene', (176, 179))	('expression', 'Species', '29278', (21, 31))	('UL53', 'Gene', '3077575', (106, 110))	('altered', 'Reg', (180, 187))	('P53', 'Gene', (0, 3))	('sub-cellular localization', 'MPA', (192, 217))	('P53', 'Gene', '7157', (0, 3))	('UL53', 'Gene', (106, 110))	('pp65/UL83', 'Protein', (248, 257))
535858	33411764	HCMV pUL38, but not pUL29/28, is able to regulate p53 transcriptional activity, resulting in selective suppression of p53 target genes.	('pUL29/28', 'Gene', 'None', (20, 28))	('pUL29/28', 'Gene', (20, 28))	('suppression', 'NegReg', (103, 114))	('regulate', 'Reg', (41, 49))	('p53', 'Gene', (50, 53))	('pUL38', 'Var', (5, 10))	('transcriptional activity', 'MPA', (54, 78))	('HCMV', 'Species', '10359', (0, 4))
535868	33411764	iSLK.219 cells were maintained in DMEM supplemented with 10% tetracycline-free FBS, G418 (250 mug/ml), hygromycin (400 mug/ml), and puromycin (10 mug/ml).	('250 mug/ml', 'Var', (90, 100))	('DMEM', 'Chemical', '-', (34, 38))	('tetracycline', 'Chemical', 'MESH:D013752', (61, 73))	('puromycin', 'Chemical', 'MESH:D011691', (132, 141))	('hygromycin', 'Chemical', 'MESH:C026273', (103, 113))	('400 mug/ml', 'Var', (115, 125))	('G418', 'Chemical', 'MESH:C010680', (84, 88))
535879	33411764	pOME0304, pOME0004, pOME0184, referred to as pDEST47-ZIKV NS2A-Flag, pDEST47-KSHV orf10-Flag, and pDEST47-KSHV orf57-Flag, respectively, express proteins fused to the C-terminal 3xFlag epitope (S1 Table).	('pOME0004', 'Var', (10, 18))	('orf57', 'Gene', '4961525', (111, 116))	('proteins', 'Protein', (145, 153))	('NS2A-Flag', 'Gene', (58, 67))	('NS2A-Flag', 'Gene', 'None', (58, 67))	('pOME0304', 'Var', (0, 8))	('ZIKV', 'Species', '64320', (53, 57))	('KSHV', 'Species', '37296', (77, 81))	('KSHV', 'Species', '37296', (106, 110))	('orf57', 'Gene', (111, 116))	('pOME0184', 'Var', (20, 28))
535885	33411764	For induction of endogenous p53 with etoposide or nutlin-3, U2OS cells were transfected with pGL13 and either pCMV-Neo-Bam, pCMV-Neo-Bam-p53R273H, or a vector expressing an orf of interest using Lipofectamine 2000.	('pCMV-Neo-Bam-p53R273H', 'Var', (124, 145))	('pGL13', 'Gene', (93, 98))	('pCMV-Neo-Bam', 'Var', (110, 122))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (195, 213))	('etoposide', 'Chemical', 'MESH:D005047', (37, 46))	('nutlin-3', 'Chemical', 'MESH:C482205', (50, 58))	('U2OS', 'CellLine', 'CVCL:0042', (60, 64))	('R273H', 'Mutation', 'rs28934576', (140, 145))
535897	33411764	The samples were washed with RIPA buffer and analyzed by immunoblotting with anti-ubiquitin Ab and anti-p53 Ab clone DO7.	('anti-ubiquitin', 'Var', (77, 91))	('RIPA buffer', 'Chemical', '-', (29, 40))	('anti-p53', 'Var', (99, 107))
535938	25745502	Immunohistochemical results revealed that the tumor cells were negative for SMA, desmin, keratin and melanoma cocktail, SOX10, BRAFV600E, CD31, and CD34.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('desmin', 'Gene', '1674', (81, 87))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('keratin', 'Protein', (89, 96))	('CD34', 'Gene', '947', (148, 152))	('BRAFV600E', 'Mutation', 'rs113488022', (127, 136))	('SOX10', 'Gene', '6663', (120, 125))	('CD31', 'Gene', '5175', (138, 142))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('tumor', 'Disease', (46, 51))	('SOX10', 'Gene', (120, 125))	('SMA', 'Protein', (76, 79))	('CD34', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('desmin', 'Gene', (81, 87))	('BRAFV600E', 'Var', (127, 136))	('negative', 'NegReg', (63, 71))	('CD31', 'Gene', (138, 142))
535959	25745502	Frequent findings in pulmonary artery intimal sarcomas are overexpression of MDM2 and gains and amplification of the 12q13-14 region.	('amplification', 'Var', (96, 109))	('pulmonary artery intimal sarcoma', 'Phenotype', 'HP:0005312', (21, 53))	('pulmonary artery intimal sarcomas', 'Phenotype', 'HP:0005312', (21, 54))	('MDM2', 'Gene', '4193', (77, 81))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('pulmonary artery intimal sarcoma', 'Disease', 'MESH:D000071079', (21, 53))	('MDM2', 'Gene', (77, 81))	('pulmonary artery intimal sarcoma', 'Disease', (21, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('gains', 'Var', (86, 91))	('overexpression', 'PosReg', (59, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('sarcomas', 'Disease', (46, 54))
536009	22045987	Every KSHV lytic mRNA was present at higher levels in KS biopsy specimens from the early ART, high-HIV, low-CD4 patients compared to post-ART KS samples from patients with undetectable HIV loads.	('KSHV', 'Species', '37296', (6, 10))	('high-HIV', 'Var', (94, 102))	('HIV', 'Species', '12721', (185, 188))	('KS', 'Phenotype', 'HP:0100726', (6, 8))	('CD4', 'Gene', (108, 111))	('CD4', 'Gene', '920', (108, 111))	('patients', 'Species', '9606', (112, 120))	('KS', 'Phenotype', 'HP:0100726', (142, 144))	('HIV', 'Species', '12721', (99, 102))	('patients', 'Species', '9606', (158, 166))	('KS', 'Phenotype', 'HP:0100726', (54, 56))
536010	22045987	2A) were orf26 and orf61.	('orf61', 'Var', (19, 24))	('orf26', 'Gene', (9, 14))	('orf26', 'Gene', '440829', (9, 14))
536074	31289294	The following biologically effective dose conversion factors for 2 Gy/fractions were used: alpha/beta = 10 Gy for PTV; alpha/beta = 3 Gy for OAR.	('PTV', 'Disease', (114, 117))	('alpha/beta =', 'Var', (119, 131))	('OAR', 'Disease', (141, 144))	('PTV', 'Chemical', '-', (114, 117))	('alpha/beta = 10 Gy', 'Var', (91, 109))
536152	27698882	It is also important to identify which tumor subtypes, specific translocations and patient profiles will benefit the most from treatment with trabectedin.	('benefit', 'PosReg', (105, 112))	('trabectedin', 'Chemical', 'MESH:D000077606', (142, 153))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patient', 'Species', '9606', (83, 90))	('tumor', 'Disease', (39, 44))	('translocations', 'Var', (64, 78))
536153	27698882	The Ewing's sarcoma family of tumors (ESFT) consists of a group of neoplasms with a number of characteristics in common, including the presence of small round cells, a shared neuroectodermal origin, an immunohistochemical panel positive for cluster of differentiation (CD)99 and the Ewing's sarcoma (EWS)-friend leukemia integration 1 (FLI1) transcription factor translocation t(11;22)(q24;q12), which occurs in 85% of cases.	('leukemia', 'Disease', (312, 320))	('EWS', 'Phenotype', 'HP:0012254', (300, 303))	('leukemia', 'Disease', 'MESH:D007938', (312, 320))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (377, 394))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (4, 19))	("Ewing's sarcoma", 'Disease', (283, 298))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (4, 19))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('neoplasms', 'Phenotype', 'HP:0002664', (67, 76))	('t(11;22)(q24;q12', 'Var', (377, 393))	('EWS', 'Gene', '2130', (300, 303))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Disease', (30, 36))	("Ewing's sarcoma", 'Disease', (4, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (283, 298))	('neoplasms', 'Disease', 'MESH:D009369', (67, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('FLI1', 'Gene', (336, 340))	('leukemia', 'Phenotype', 'HP:0001909', (312, 320))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('EWS', 'Gene', (300, 303))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (283, 298))	('FLI1', 'Gene', '2313', (336, 340))	('neoplasms', 'Disease', (67, 76))
536155	27698882	Other rarer translocations described include the genes ETS variant (ETV)1, ETV4 or fifth Ewing's sarcoma variant (FEV), forming t(7;22)(p22;q12), t(17;22)(q12;q12) or t(2;22)(q35;q12), respectively.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (89, 104))	('t(17;22)(q12;q12', 'Var', (146, 162))	('t(7;22)(p22;q12', 'Var', (128, 143))	('t(7;22)(p22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (128, 144))	('ETV4', 'Gene', '2118', (75, 79))	('ETV)1', 'Gene', '2115', (68, 73))	("Ewing's sarcoma", 'Disease', (89, 104))	('FEV', 'Gene', (114, 117))	('t(2;22)(q35;q12', 'Var', (167, 182))	('t(17;22)(q12;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (146, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('FEV', 'Gene', '54738', (114, 117))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (89, 104))	('t(2;22)(q35;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (167, 183))	('ETS', 'Gene', (55, 58))	('ETV4', 'Gene', (75, 79))
536156	27698882	Certain cases have translocations that involve the fused in sarcoma (FUS) gene, such as FUS-ERG t(16;21)(p11;q24) or FUS-FEV t(2;16)(q35;p11).	('FUS-FEV', 'Disease', (117, 124))	('t(16;21)(p11;q24', 'Var', (96, 112))	('FUS', 'Gene', (117, 120))	('ERG', 'Gene', (92, 95))	('FUS-FEV', 'Disease', 'None', (117, 124))	('FUS', 'Gene', '2521', (117, 120))	('fused in sarcoma', 'Gene', '2521', (51, 67))	('translocations', 'Var', (19, 33))	('FUS', 'Gene', (88, 91))	('FUS', 'Gene', '2521', (88, 91))	('t(2;16)(q35;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (125, 141))	('fused in sarcoma', 'Gene', (51, 67))	('ERG', 'Gene', '2078', (92, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('FUS', 'Gene', (69, 72))	('t(16;21)(p11;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (96, 113))	('FUS', 'Gene', '2521', (69, 72))
536185	27698882	Ewing's sarcoma belongs to a diverse group of small-round-cell tumors characterized by the same chromosomal translocation, t(11;22).	("Ewing's sarcoma", 'Disease', (0, 15))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('t(11;22', 'Var', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))
536207	27698882	It has been demonstrated in vitro that trabectedin is active against cell lines that express the EWS-FLI1 translocation.	('EWS', 'Phenotype', 'HP:0012254', (97, 100))	('EWS-FLI1', 'Gene', '2130;2313', (97, 105))	('trabectedin', 'Chemical', 'MESH:D000077606', (39, 50))	('translocation', 'Var', (106, 119))	('EWS-FLI1', 'Gene', (97, 105))
536233	22419563	We demonstrate the feasibility of ADOT by examples in which both known and unknown Ewing sarcoma translocations are identified from cell lines, tumour xenografts and FFPE primary tumours.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour xenografts and FFPE primary tumours', 'Disease', 'MESH:D009369', (144, 186))	('translocations', 'Var', (97, 111))	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('Ewing sarcoma', 'Disease', (83, 96))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (83, 96))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (83, 96))
536235	22419563	See accompanying article 10.1002/emmm.201200226 The identification of chromosomal translocations has important implications for understanding basic mechanisms of cancer development.	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('chromosomal translocations', 'Var', (70, 96))
536237	22419563	Transcription and splicing across this breakpoint results in an in-frame fusion transcript that encodes the EWS/FLI oncoprotein.	('splicing', 'Var', (18, 26))	('FLI', 'Gene', '2314', (112, 115))	('EWS', 'Gene', '2130', (108, 111))	('EWS', 'Gene', (108, 111))	('FLI', 'Gene', (112, 115))	('results in', 'Reg', (50, 60))
536239	22419563	While 85% of Ewing sarcoma cases are associated with translocations that encode EWS/FLI, six additional translocations (encoding EWS/ERG (ets-related gene), EWS/ETV1 (ets variant 1), EWS/ETV4 (ets variant 4), EWS/FEV (fifth Ewing variant), (translocated in liposarcoma) TLS/ERG or TLS/FEV) have been found in the remaining cases (Sankar & Lessnick,).	('FEV', 'Gene', '54738', (213, 216))	('Ewing sarcoma', 'Disease', (13, 26))	('liposarcoma', 'Disease', (257, 268))	('FEV', 'Gene', '54738', (285, 288))	('EWS', 'Gene', '2130', (80, 83))	('EWS', 'Gene', (129, 132))	('EWS', 'Gene', '2130', (157, 160))	('ERG', 'Gene', '2078', (133, 136))	('ERG', 'Gene', (274, 277))	('FEV', 'Gene', (213, 216))	('ETV1', 'Gene', (161, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('EWS', 'Gene', (183, 186))	('FEV', 'Gene', (285, 288))	('ERG', 'Gene', '2078', (274, 277))	('TLS', 'Gene', (281, 284))	('ETV4', 'Gene', (187, 191))	('associated', 'Reg', (37, 47))	('EWS', 'Gene', '2130', (209, 212))	('liposarcoma', 'Phenotype', 'HP:0012034', (257, 268))	('FLI', 'Gene', (84, 87))	('EWS', 'Gene', (80, 83))	('ETV1', 'Gene', '2115', (161, 165))	('TLS', 'Gene', (270, 273))	('translocations', 'Var', (53, 67))	('EWS', 'Gene', '2130', (129, 132))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (13, 26))	('EWS', 'Gene', (157, 160))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (13, 26))	('liposarcoma', 'Disease', 'MESH:D008080', (257, 268))	('FLI', 'Gene', '2314', (84, 87))	('TLS', 'Gene', '2521', (281, 284))	('ETV4', 'Gene', '2118', (187, 191))	('EWS', 'Gene', '2130', (183, 186))	('TLS', 'Gene', '2521', (270, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('EWS', 'Gene', (209, 212))	('ERG', 'Gene', (133, 136))
536245	22419563	Although there is debate on whether different fusion isoforms portend different outcomes (Le Deley et al,; van Doorninck et al,), detection of translocations at the exon level has important implications for diagnosis, prognosis and treatment of patients with Ewing sarcoma.	('patients', 'Species', '9606', (245, 253))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (259, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (259, 272))	('implications', 'Reg', (190, 202))	('Ewing sarcoma', 'Disease', (259, 272))	('translocations', 'Var', (143, 157))
536247	22419563	Current approaches routinely used to identify translocations and their products in cancer have many limitations.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('translocations', 'Var', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (83, 89))
536249	22419563	Western blot or immunohistochemical analysis can specifically detect the translocation fusion protein but are not often used clinically because of protein quantity, antibody quality or reproducibility issues.	('clinical', 'Species', '191496', (125, 133))	('detect', 'Reg', (62, 68))	('translocation', 'Var', (73, 86))
536253	22419563	This technique may be easily generalized to detect any translocation, both known and putative, in a wide variety of cancers.	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('translocation', 'Var', (55, 68))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
536254	22419563	We developed a novel technique, ADOT, to detect chromosomal translocations in cancer.	('chromosomal translocations', 'Var', (48, 74))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))
536258	22419563	To test the feasibility of this technique, we synthesized a pilot microarray that included oligonucleotides for all possible fusion transcripts between EWSR1 and either FLI or ERG, and tested this microarray with overexpressed EWS/FLI or EWS/ERG fusion transcripts.	('EWS', 'Gene', '2130', (227, 230))	('EWS', 'Gene', (227, 230))	('FLI', 'Gene', (231, 234))	('oligonucleotides', 'Chemical', 'MESH:D009841', (91, 107))	('EWS', 'Gene', '2130', (238, 241))	('EWS', 'Gene', (238, 241))	('EWS', 'Gene', (152, 155))	('EWSR1', 'Gene', (152, 157))	('EWS', 'Gene', '2130', (152, 155))	('ERG', 'Gene', '2078', (176, 179))	('ERG', 'Gene', '2078', (242, 245))	('fusion', 'Var', (125, 131))	('ERG', 'Gene', (242, 245))	('EWSR1', 'Gene', '2130', (152, 157))	('ERG', 'Gene', (176, 179))	('FLI', 'Gene', '2314', (169, 172))	('FLI', 'Gene', '2314', (231, 234))	('FLI', 'Gene', (169, 172))
536282	22419563	A673, EWS/FLI 7/6; RDES, EWS/FLI 7/5; TC466, EWS/ERG 7/8; Fig 3a and data not shown).	('EWS', 'Gene', (45, 48))	('EWS', 'Gene', (6, 9))	('EWS', 'Gene', '2130', (45, 48))	('ERG', 'Gene', '2078', (49, 52))	('FLI', 'Gene', (29, 32))	('TC466', 'Var', (38, 43))	('EWS', 'Gene', '2130', (6, 9))	('ERG', 'Gene', (49, 52))	('FLI', 'Gene', '2314', (10, 13))	('TC466', 'CellLine', 'CVCL:5064', (38, 43))	('FLI', 'Gene', (10, 13))	('A673', 'Var', (0, 4))	('FLI', 'Gene', '2314', (29, 32))	('EWS', 'Gene', '2130', (25, 28))	('EWS', 'Gene', (25, 28))
536299	22419563	PROBLEM: Identification of chromosomal translocations has important implications in the diagnosis, prognosis and treatment of patients with cancer.	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (126, 134))	('implications', 'Reg', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('chromosomal translocations', 'Var', (27, 53))
536301	22419563	RESULTS: In this report, we designed a novel technique ADOT and demonstrated its utility to accurately and sensitively identify translocations associated with cancers using poor-quality total RNA from biological specimen such as FFPE primary patient tumours.	('cancers', 'Disease', (159, 166))	('tumours', 'Phenotype', 'HP:0002664', (250, 257))	('tumours', 'Disease', 'MESH:D009369', (250, 257))	('translocations', 'Var', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumours', 'Disease', (250, 257))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('patient', 'Species', '9606', (242, 249))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
536302	22419563	IMPACT: Antibody detection of translocations bears promise as a discovery tool for identifying translocations in cancers, as well as a diagnostic tool for patients with translocation-associated tumours.	('tumours', 'Phenotype', 'HP:0002664', (194, 201))	('tumours', 'Disease', 'MESH:D009369', (194, 201))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('tumours', 'Disease', (194, 201))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('translocations', 'Var', (30, 44))	('translocations', 'Var', (95, 109))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('patients', 'Species', '9606', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
536303	22419563	We next tested whether ADOT can detect translocations in FFPE primary tumours specimens from patients.	('FFPE primary tumours', 'Disease', (57, 77))	('translocations', 'Var', (39, 53))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('FFPE primary tumours', 'Disease', 'MESH:D009369', (57, 77))	('patients', 'Species', '9606', (93, 101))
536307	22419563	Prior cytogenetic analysis of the fourth sample showed that it harboured a translocation between chromosomes 7 and 22 (data not shown), indicating the presence of EWS/ETV1, one of the rare Ewing sarcoma translocations not included in the design of the current microarray.	('translocation', 'Var', (75, 88))	('ETV1', 'Gene', (167, 171))	('ETV1', 'Gene', '2115', (167, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('presence', 'Reg', (151, 159))	('EWS', 'Gene', (163, 166))	('EWS', 'Gene', '2130', (163, 166))	('Ewing sarcoma', 'Disease', (189, 202))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (189, 202))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (189, 202))
536310	22419563	In some cases, identification of specific molecular abnormalities, such as chromosomal translocations, can provide the critical diagnostic tool to effectively classify specific tumours.	('molecular abnormalities', 'Disease', (42, 65))	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('tumours', 'Disease', (177, 184))	('molecular abnormalities', 'Disease', 'MESH:C567116', (42, 65))	('chromosomal translocations', 'Var', (75, 101))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))
536312	22419563	We developed a technique called ADOT to detect chromosomal translocations, and tested the approach using Ewing sarcoma as our model.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('chromosomal translocations', 'Var', (47, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('Ewing sarcoma', 'Disease', (105, 118))
536314	22419563	This study shows that ADOT can be used to detect translocations from cell lines, frozen tumours, and FFPE tumours.	('translocations', 'Var', (49, 63))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('tumours', 'Disease', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('FFPE tumours', 'Disease', (101, 113))	('tumours', 'Disease', (106, 113))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('FFPE tumours', 'Disease', 'MESH:D009369', (101, 113))
536317	22419563	Furthermore, there are additional translocations that have been identified in 'Ewing's-like tumours' that should be included (Sankar & Lessnick,).	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	("'Ewing's-like tumours'", 'Disease', 'MESH:C563168', (78, 100))	("'Ewing's-like tumours", 'Phenotype', 'HP:0012254', (78, 99))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('translocations', 'Var', (34, 48))	("'Ewing's-like tumours'", 'Disease', (78, 100))
536324	22419563	Furthermore, ADOT is capable of detecting known or unknown translocations in biological samples, including those most commonly encountered during the diagnostic work-up of a patient.	('patient', 'Species', '9606', (174, 181))	('detecting', 'Reg', (32, 41))	('translocations', 'Var', (59, 73))
536325	22419563	ADOT bears promise as a discovery tool for identifying fusion transcripts in cancers, as well as a diagnostic tool for patients with translocation-associated tumours.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (77, 84))	('patients', 'Species', '9606', (119, 127))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('ADOT', 'Gene', (0, 4))	('tumours', 'Disease', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('fusion transcripts', 'Var', (55, 73))
536344	22587874	IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge.	('IGF-1R', 'Gene', (0, 6))	('antagonists', 'Var', (7, 18))	('IGF-1R', 'Gene', '3480', (0, 6))	('clinical', 'Species', '191496', (60, 68))
536370	22587874	Metastasis at diagnosis conferred a 5 year relapse free survival (RFS) of 22% versus 55% for patients without initial metastasis (P < .0001).	('relapse free survival', 'CPA', (43, 64))	('patients', 'Species', '9606', (93, 101))	('Metastasis', 'Var', (0, 10))
536372	22587874	Members of the Ewing sarcoma/PNET family of tumours are characterized by rearrangements involving the EWS gene on chromosome 22q12 and fusion partners from the ETS oncogene family, most frequently FLI1 on chromosome 11q24 (85%) as demonstrated in Figure 1, or ERG on chromosome 21q22 (10%).	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (15, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (15, 28))	('rearrangements', 'Var', (73, 87))	('tumours', 'Disease', (44, 51))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('EWS gene', 'Gene', (102, 110))	('ERG', 'Gene', '2078', (260, 263))	('Ewing sarcoma', 'Disease', (15, 28))	('ERG', 'Gene', (260, 263))	('FLI1 on chromosome 11q24', 'Var', (197, 221))
536378	22587874	In most cases rearrangements occur with EWS intron 7 or 8: FLI1 introns 5 or 4 leading to either fusion of EWS intron 7 to Fli1 exon 6 (type I fusion [EF1]) documented in 51% of cases or exon 5 (type 2 fusion [EF2]) recorded in 27% of cases.	('FLI1', 'Gene', (59, 63))	('EWS intron', 'Gene', (107, 117))	('Fli1', 'Gene', '2313', (123, 127))	('Fli1', 'Gene', (123, 127))	('fusion', 'Var', (97, 103))
536382	22587874	In that study the association of type 1 EWS-FLI1 (fusion between exons 7 of EWS and 6 of FLI1) and non type 1 transcript translocations were correlated with disease characteristics, event free survival and overall survival.	('FLI1', 'Gene', (89, 93))	('correlated', 'Reg', (141, 151))	('association', 'Interaction', (18, 29))	('type 1 EWS-FLI1', 'Gene', '2313', (33, 48))	('type 1 EWS-FLI1', 'Gene', (33, 48))	('fusion', 'Var', (50, 56))
536423	22587874	EWS-FLI1 expression can be reduced by antisense oligonucleotides, antisense RNA (expressed from a vector) and small interfering RNA delivered by nanoparticles.	('reduced', 'NegReg', (27, 34))	('antisense oligonucleotides', 'Var', (38, 64))	('antisense RNA', 'Var', (66, 79))	('EWS-FLI1', 'Gene', (0, 8))	('expression', 'MPA', (9, 19))	('small interfering', 'Var', (110, 127))	('oligonucleotides', 'Chemical', 'MESH:D009841', (48, 64))
536424	22587874	EWS-FLI1 elimination through antisense cDNA and siRNA causes prolonged survival of ESFT xenograft bearing mice.	('mice', 'Species', '10090', (106, 110))	('survival', 'CPA', (71, 79))	('elimination', 'NegReg', (9, 20))	('EWS-FLI1', 'Gene', (0, 8))	('antisense cDNA', 'Var', (29, 43))	('ES', 'Chemical', 'MESH:D004540', (83, 85))	('prolonged', 'PosReg', (61, 70))
536428	22587874	One study combining EWS-FLI-1 antisense oligonucleotide and rapamycin efficiently induced the apoptotic death of EWS cells in culture through a caspase-dependent apoptotic process that involved restoration of the TGF beta-induced pro-apoptotic pathway in vivo.	('FLI-1', 'Gene', (24, 29))	('FLI-1', 'Gene', '2313', (24, 29))	('induced', 'Reg', (82, 89))	('apoptotic death', 'CPA', (94, 109))	('apoptotic process', 'CPA', (162, 179))	('rapamycin', 'Chemical', 'MESH:D020123', (60, 69))	('TGF beta', 'Gene', (213, 221))	('restoration', 'PosReg', (194, 205))	('antisense oligonucleotide', 'Var', (30, 55))	('oligonucleotide', 'Chemical', 'MESH:D009841', (40, 55))	('TGF beta', 'Gene', '7040', (213, 221))
536433	22587874	Furthermore, inhibition of Notch signalling induced neural differentiation in Ewing sarcoma cell lines however inhibition of Notch was associated with only a small change in tumour growth potential.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour growth', 'Disease', (174, 187))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('induced', 'Reg', (44, 51))	('tumour growth', 'Disease', 'MESH:D006130', (174, 187))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('inhibition', 'Var', (13, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('Notch signalling', 'Gene', (27, 43))	('neural differentiation', 'CPA', (52, 74))	('Ewing sarcoma', 'Disease', (78, 91))
536445	22587874	Therapeutics directed against IGF1R include either antibodies (for example, IgG1: R1507 and AMG479; IgG2: figitumumab) or else small molecule tyrosine kinase inhibitors.	('IGF1R', 'Gene', (30, 35))	('IGF1R', 'Gene', '3480', (30, 35))	('AMG', 'Gene', (92, 95))	('AMG', 'Gene', '265', (92, 95))	('R1507', 'Var', (82, 87))	('figitumumab', 'Chemical', 'MESH:C525021', (106, 117))
536446	22587874	Striking clinical responses for most IGF-1R inhibitors in Ewing sarcoma patients have been documented.	('inhibitors', 'Var', (44, 54))	('IGF-1R', 'Gene', '3480', (37, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('IGF-1R', 'Gene', (37, 43))	('clinical', 'Species', '191496', (9, 17))	('Ewing sarcoma', 'Disease', (58, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (58, 71))	('patients', 'Species', '9606', (72, 80))
536461	22587874	It is plausible that inhibition of IGF-1R ameliorates the negative feedback of IGF-1 on growth factor secretion at the pituitary level.	('IGF-1', 'Gene', (35, 40))	('growth factor secretion at the pituitary level', 'MPA', (88, 134))	('IGF-1', 'Gene', '3479', (79, 84))	('inhibition', 'Var', (21, 31))	('negative feedback', 'MPA', (58, 75))	('IGF-1', 'Gene', (79, 84))	('IGF-1R', 'Gene', '3480', (35, 41))	('ameliorates', 'PosReg', (42, 53))	('IGF-1', 'Gene', '3479', (35, 40))	('IGF-1R', 'Gene', (35, 41))
536465	22587874	A MD Anderson initiated phase I study of R1507, a monoclonal antibody to the insulin like growth factor receptor-1 (IGF1R), was conducted on 37 patients with advanced solid tumours.	('insulin', 'Gene', (77, 84))	('R1507', 'Var', (41, 46))	('insulin', 'Gene', '3630', (77, 84))	('IGF1R', 'Gene', (116, 121))	('solid tumours', 'Disease', 'MESH:D009369', (167, 180))	('patients', 'Species', '9606', (144, 152))	('IGF1R', 'Gene', '3480', (116, 121))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('solid tumours', 'Disease', (167, 180))
536468	22587874	In a phase II trial of 125 patients with recurrent or refractory Ewing sarcoma/PNET treated with R1507, 18 patients had a CR or PR (14.4%).	('Ewing sarcoma', 'Disease', (65, 78))	('patients', 'Species', '9606', (27, 35))	('R1507', 'Var', (97, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (65, 78))	('patients', 'Species', '9606', (107, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))
536472	22587874	113 patients were treated in a multi-centre phase II trial of R1507 in patients with recurrent or refractory Ewing sarcoma/PNET.	('Ewing sarcoma', 'Disease', (109, 122))	('R1507', 'Var', (62, 67))	('patients', 'Species', '9606', (71, 79))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('patients', 'Species', '9606', (4, 12))
536486	22587874	The authors found that both the MEK/MAPK inhibitors (PD98059 and U0126) and PI3K inhibitor (LY294002) decrease Ewing sarcoma/PNET cell survival by induction of G1 blockade.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('PD98059', 'Chemical', 'MESH:C093973', (53, 60))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('U0126', 'Chemical', 'MESH:C113580', (65, 70))	('MEK', 'Gene', '5609', (32, 35))	('LY294002', 'Chemical', 'MESH:C085911', (92, 100))	('decrease', 'NegReg', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('U0126', 'Var', (65, 70))	('Ewing sarcoma', 'Disease', (111, 124))	('PD98059', 'Var', (53, 60))	('MEK', 'Gene', (32, 35))	('LY294002', 'Var', (92, 100))	('G1 blockade', 'Protein', (160, 171))
536487	22587874	MEK/MAP blockade also increases Ewing sarcoma/PNET cell sensitivity to doxorubicin and reduces the cells migratory ability.	('Ewing sarcoma', 'Disease', (32, 45))	('MEK', 'Gene', (0, 3))	('reduces', 'NegReg', (87, 94))	('MEK', 'Gene', '5609', (0, 3))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (32, 45))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (32, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('cells migratory ability', 'CPA', (99, 122))	('blockade', 'Var', (8, 16))	('increases', 'PosReg', (22, 31))	('sensitivity to doxorubicin', 'MPA', (56, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (71, 82))
536495	22587874	Finally there also is the theoretical potential for combining IGR1R inhibitors with other drugs such as mTOR inhibitors with the prospect of enhanced treatment efficacy.	('mTOR', 'Gene', (104, 108))	('mTOR', 'Gene', '2475', (104, 108))	('inhibitors', 'Var', (68, 78))	('IGR1R', 'Gene', (62, 67))	('combining', 'Interaction', (52, 61))
536500	22587874	Tuberous sclerosis is caused by inactivating mutations of either of the TSC1 and TSC2 tumour suppressor genes that encode the cytoplasmic TSC1 (hamartin) and TSC2 (tuberin) proteins respectively.	('TSC2', 'Gene', (81, 85))	('TSC2 tumour', 'Disease', (81, 92))	('TSC1', 'Gene', (138, 142))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('TSC2', 'Gene', (158, 162))	('TSC1', 'Gene', '7248', (138, 142))	('TSC2 tumour', 'Disease', 'MESH:C566021', (81, 92))	('tuberin', 'Gene', '7249', (164, 171))	('inactivating mutations', 'Var', (32, 54))	('TSC2', 'Gene', '7249', (81, 85))	('tuberin', 'Gene', (164, 171))	('TSC1', 'Gene', (72, 76))	('Tuberous sclerosis', 'Disease', (0, 18))	('hamartin', 'Gene', '7248', (144, 152))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('hamartin', 'Gene', (144, 152))	('caused by', 'Reg', (22, 31))	('TSC1', 'Gene', '7248', (72, 76))	('TSC2', 'Gene', '7249', (158, 162))
536503	22587874	The use of rapamycin as a cytostatic treatment has been evaluated in Ewing sarcoma/PNET cell lines with heterogeneous EWS/FLI1 fusion genes.	('fusion genes', 'Var', (127, 139))	('EWS/FLI1', 'Gene', (118, 126))	('Ewing sarcoma', 'Disease', (69, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('rapamycin', 'Chemical', 'MESH:D020123', (11, 20))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (69, 82))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (69, 82))
536509	22587874	Evidently c-kit activating mutations were found not to be coincident with KIT protein expression in Ewing sarcoma/PNET.	('mutations', 'Var', (27, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (100, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (100, 113))	('c-kit', 'Gene', '3815', (10, 15))	('c-kit', 'Gene', (10, 15))	('Ewing sarcoma', 'Disease', (100, 113))	('activating', 'PosReg', (16, 26))
536514	22587874	Engagement of CD99 by a monoclonal antibody induces rapid tumour apoptosis through caspase independent mechanisms.	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('CD99', 'Gene', (14, 18))	('tumour', 'Disease', (58, 64))	('Engagement', 'Var', (0, 10))
536528	22587874	Although conceptually appealing, treatment efficacy may be ameliorated by cellular resistance due to TRAIL pathway signalling dysfunctions, such as imbalances in death/decoy receptors or c-FLIP up regulation.	('cellular resistance', 'CPA', (74, 93))	('imbalances', 'Var', (148, 158))	('up regulation', 'PosReg', (194, 207))	('death/decoy receptors', 'Protein', (162, 183))	('dysfunctions', 'Var', (126, 138))	('c-FLIP', 'Gene', '8837', (187, 193))	('c-FLIP', 'Gene', (187, 193))	('TRAIL', 'Gene', '8743', (101, 106))	('ameliorated', 'PosReg', (59, 70))	('TRAIL', 'Gene', (101, 106))	('imbalances', 'Phenotype', 'HP:0002172', (148, 158))
536531	22587874	Inhibition of histone deacetylase affects acetylation of histones and other proteins, resulting in transcriptional de-repression of tumour suppressor genes.	('tumour', 'Disease', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('histone deacetylase', 'Gene', '9734', (14, 33))	('histones', 'Protein', (57, 65))	('proteins', 'Protein', (76, 84))	('transcriptional', 'MPA', (99, 114))	('de-repression', 'NegReg', (115, 128))	('Inhibition', 'Var', (0, 10))	('histone deacetylase', 'Gene', (14, 33))	('affects', 'Reg', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('acetylation', 'MPA', (42, 53))
536535	22587874	HDAC inhibitors have also been shown to inhibit the growth of Ewing sarcoma/PNET cells in other reports.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('growth', 'CPA', (52, 58))	('inhibit', 'NegReg', (40, 47))	('inhibitors', 'Var', (5, 15))	('Ewing sarcoma', 'Disease', (62, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (62, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (62, 75))
536552	22587874	The paediatric preclinical testing program (PPTP) released results in 2010 of initial tests of the small molecule Aurora Kinase A (AURKA) inhibitor MLN8237 using the PPTP in vitro and in vivo panel.	('MLN8237', 'Var', (148, 155))	('AURKA', 'Gene', '6790', (131, 136))	('clinical', 'Species', '191496', (18, 26))	('AURKA', 'Gene', (131, 136))	('Aurora Kinase A', 'Gene', '6790', (114, 129))	('MLN8237', 'Chemical', 'MESH:C550258', (148, 155))	('Aurora Kinase A', 'Gene', (114, 129))
536554	22587874	MLN8237 inhibited the growth of the majority of the in vivo panel cell lines that included five Ewing sarcoma/PNET lines.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (96, 109))	('inhibited', 'NegReg', (8, 17))	('growth', 'MPA', (22, 28))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('MLN8237', 'Var', (0, 7))	('Ewing sarcoma', 'Disease', (96, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (96, 109))
536564	22587874	Nonetheless, the rapid accrual to the R1507 SARC Ewing sarcoma study showed that, with optimism and global collaboration, large numbers of patients can be accrued in short timeframes.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('R1507', 'Var', (38, 43))	('patients', 'Species', '9606', (139, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('Ewing sarcoma', 'Disease', (49, 62))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))
536718	30834285	There are certain factors that place patients with solid organ tumours at higher risk of developing TLS which include: large tumour burden, extensive metastases, highly proliferative tumour, high sensitivity to anticancer therapy, pre-existing nephropathy, or pretreatment hyperuricemia, hyperphosphatemia, or LDH >1500 IU/L2.	('nephropathy', 'Phenotype', 'HP:0000112', (244, 255))	('solid organ tumours', 'Disease', 'MESH:D019965', (51, 70))	('LDH >1500 IU/L2', 'Var', (310, 325))	('cancer', 'Disease', (215, 221))	('patients', 'Species', '9606', (37, 45))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (288, 305))	('metastases', 'Disease', 'MESH:D009362', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('solid organ tumours', 'Disease', (51, 70))	('nephropathy', 'Disease', (244, 255))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('metastases', 'Disease', (150, 160))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('hyperuricemia', 'Disease', (273, 286))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('nephropathy', 'Disease', 'MESH:D007674', (244, 255))	('hyperphosphatemia', 'Disease', (288, 305))	('TLS', 'Disease', (100, 103))	('tumour', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('hyperuricemia', 'Disease', 'MESH:D033461', (273, 286))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (288, 305))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('hyperuricemia', 'Phenotype', 'HP:0002149', (273, 286))	('tumour', 'Disease', (125, 131))	('tumour', 'Disease', (63, 69))
536734	30631245	Stratified survival analysis showed that radiation was associated with prolonged median OS for RPS that were high-grade (64.3 vs. 43.6 months, p < 0.001), less than 15 cm (104.1 vs. 84.2 months, p=0.007), and leiomyosarcomatous (104.8 vs. 61.8 months, p < 0.001).	('leiomyosarcomatous', 'Disease', (209, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('leiomyosarcomatous', 'Disease', 'None', (209, 227))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (209, 223))	('less than 15 cm', 'Var', (155, 170))	('RPS', 'Phenotype', 'HP:0006729', (95, 98))
536735	30631245	Perioperative radiation is independently associated with decreased mortality in patients with high-grade, less than 15 cm, and leiomyosarcomatous tumors.	('patients', 'Species', '9606', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('less than 15 cm', 'Var', (106, 121))	('leiomyosarcomatous tumors', 'Disease', (127, 152))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (127, 141))	('decreased', 'NegReg', (57, 66))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('leiomyosarcomatous tumors', 'Phenotype', 'HP:0100243', (127, 152))	('leiomyosarcomatous tumors', 'Disease', 'MESH:D009369', (127, 152))
536751	30631245	Patients with RPS were identified using International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) topography (C48.0) and histology (8800-8806, 8810-8815, 8830, 8840, 8850-8858, 8890-8896, 8900-8902, 8910-8912, and 8980-8982) codes.	('8800-8806', 'Var', (151, 160))	('8850-8858', 'Var', (185, 194))	('8810-8815', 'Var', (162, 171))	('8840', 'Var', (179, 183))	('Patients', 'Species', '9606', (0, 8))	('8890-8896', 'Var', (196, 205))	('RPS', 'Phenotype', 'HP:0006729', (14, 17))	('Oncology', 'Phenotype', 'HP:0002664', (85, 93))	('RPS', 'Disease', (14, 17))	('8830', 'Var', (173, 177))
536772	30631245	Overall median survival did not differ between treatment groups for low-grade RPS (p=0.354), liposarcomas (p=0.879), and RPS >=15 cm (p=0.899).	('RPS', 'Phenotype', 'HP:0006729', (78, 81))	('RPS >=15 cm', 'Var', (121, 132))	('liposarcoma', 'Phenotype', 'HP:0012034', (93, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('RPS', 'Phenotype', 'HP:0006729', (121, 124))	('liposarcomas', 'Phenotype', 'HP:0012034', (93, 105))	('liposarcomas', 'Disease', 'MESH:D008080', (93, 105))	('low-grade', 'Var', (68, 77))	('liposarcomas', 'Disease', (93, 105))
536777	30631245	However, our study clarifies those guidelines by identifying those patients with RPS most likely to benefit from radiation: small RPS, high-grade RPS, and leiomyosarcomas.	('patients', 'Species', '9606', (67, 75))	('RPS', 'Phenotype', 'HP:0006729', (130, 133))	('high-grade', 'Var', (135, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (162, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (155, 170))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (155, 170))	('RPS', 'Phenotype', 'HP:0006729', (146, 149))	('small RPS', 'Disease', (124, 133))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (155, 169))	('leiomyosarcomas', 'Disease', (155, 170))	('RPS', 'Phenotype', 'HP:0006729', (81, 84))
536800	30631245	This benefit is particularly evident in patients with high-grade, less than 15 cm, and leiomyosarcomatous tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('leiomyosarcomatous tumors', 'Phenotype', 'HP:0100243', (87, 112))	('leiomyosarcomatous tumors', 'Disease', 'MESH:D009369', (87, 112))	('patients', 'Species', '9606', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('less than 15 cm', 'Var', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (87, 101))	('leiomyosarcomatous tumors', 'Disease', (87, 112))
536827	30405839	In early studies, it was demonstrated that infection of cells by Fujinama sarcoma virus (FSV), HIV1, SV40, and polyomavirus promoted expression of glucose transporter 1(GLUT1) and GLUT3 or their membrane trafficking.	('HIV1', 'Gene', (95, 99))	('expression', 'MPA', (133, 143))	('SV40', 'Gene', (101, 105))	('polyomavirus', 'Var', (111, 123))	('GLUT1', 'Gene', '6513', (169, 174))	('glucose transporter', 'MPA', (147, 166))	('GLUT3', 'Gene', '6515', (180, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('polyomavirus', 'Species', '36362', (111, 123))	('membrane', 'MPA', (195, 203))	('promoted', 'PosReg', (124, 132))	('Fujinama sarcoma virus', 'Disease', (65, 87))	('GLUT3', 'Gene', (180, 185))	('glucose', 'Chemical', 'MESH:D005947', (147, 154))	('HIV1', 'Species', '11676', (95, 99))	('GLUT1', 'Gene', (169, 174))	('Fujinama sarcoma virus', 'Disease', 'MESH:D012509', (65, 87))
536831	30405839	Hepatitis B virus pre-S/S gene mutation increases oncogenic potential, and HBV pre-S2 mutant-induced mTOR activation facilitates the metabolic switch in HBV tumorigenesis.	('tumor', 'Disease', (157, 162))	('HBV', 'Species', '10407', (75, 78))	('HBV', 'Species', '10407', (153, 156))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('mTOR', 'Gene', (101, 105))	('metabolic switch', 'MPA', (133, 149))	('mTOR', 'Gene', '2475', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('activation facilitates', 'PosReg', (106, 128))	('mutation', 'Var', (31, 39))	('mutant-induced', 'Var', (86, 100))	('Hepatitis B virus', 'Species', '10407', (0, 17))	('HBV pre-S2', 'Gene', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('increases', 'PosReg', (40, 49))	('oncogenic potential', 'CPA', (50, 69))
536832	30405839	The pre-S2 mutant activates the mTOR/YY1/Myc/GLUT1 signaling cascade.	('mutant', 'Var', (11, 17))	('Myc', 'Gene', '4609', (41, 44))	('mTOR', 'Gene', '2475', (32, 36))	('YY1', 'Gene', (37, 40))	('mTOR', 'Gene', (32, 36))	('Myc', 'Gene', (41, 44))	('GLUT1', 'Gene', (45, 50))	('pre-S2', 'Gene', (4, 10))	('GLUT1', 'Gene', '6513', (45, 50))	('YY1', 'Gene', '7528', (37, 40))	('activates', 'PosReg', (18, 27))
536840	30405839	Loss of GLUT1 impairs the tumorigenic growth property of LMP1-expressing nasopharyngeal epithelial cells.	('GLUT1', 'Gene', '6513', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('LMP1', 'Gene', '9260', (57, 61))	('LMP1', 'Gene', (57, 61))	('impairs', 'NegReg', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Loss', 'Var', (0, 4))	('GLUT1', 'Gene', (8, 13))
536846	30405839	Inhibition of glycolysis induces apoptosis of KSHV-infected endothelial cells.	('apoptosis', 'CPA', (33, 42))	('KSHV-infected', 'Disease', (46, 59))	('KSHV-infected', 'Disease', 'MESH:C537372', (46, 59))	('Inhibition', 'Var', (0, 10))	('KS', 'Phenotype', 'HP:0100726', (46, 48))	('glycolysis', 'Enzyme', (14, 24))
536847	30405839	Aerobic glycolysis is usually essential to rapid growth of tumors; however, under glucose deprivation, KSHV inhibits glycolysis and oxidative phosphorylation, as opposed to inducing glycolysis.	('oxidative phosphorylation', 'MPA', (132, 157))	('KS', 'Phenotype', 'HP:0100726', (103, 105))	('KSHV', 'Species', '37296', (103, 107))	('KSHV', 'Var', (103, 107))	('glucose deprivation', 'Disease', 'MESH:D012892', (82, 101))	('inhibits', 'NegReg', (108, 116))	('tumors', 'Disease', (59, 65))	('glucose deprivation', 'Disease', (82, 101))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('glycolysis', 'MPA', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
536853	30405839	Human papilloma virus transfection leads to upregulation of MCT4 and CD147.	('MCT4', 'Gene', (60, 64))	('transfection', 'Var', (22, 34))	('Human papilloma virus', 'Species', '10566', (0, 21))	('upregulation', 'PosReg', (44, 56))	('papilloma', 'Phenotype', 'HP:0012740', (6, 15))	('MCT4', 'Gene', '9123', (60, 64))	('CD147', 'Protein', (69, 74))	('Human papilloma virus', 'Protein', (0, 21))
536867	30405839	Glucose consumption and lactate production is increased in HCV-infected cells.	('HCV', 'Species', '11103', (59, 62))	('Glucose consumption', 'Disease', (0, 19))	('increased', 'PosReg', (46, 55))	('HCV-infected', 'Var', (59, 71))	('Glucose consumption', 'Disease', 'MESH:D014397', (0, 19))	('lactate production', 'MPA', (24, 42))	('lactate', 'Chemical', 'MESH:D019344', (24, 31))
536869	30405839	Human papilloma virus16 E6/E7 facilitates the expression of HK2 through elevated c-Myc.	('elevated', 'PosReg', (72, 80))	('E6/E7', 'Var', (24, 29))	('HK2', 'Gene', (60, 63))	('HK2', 'Gene', '3099', (60, 63))	('Human papilloma virus', 'Species', '10566', (0, 21))	('papilloma', 'Phenotype', 'HP:0012740', (6, 15))	('c-Myc', 'Gene', '4609', (81, 86))	('c-Myc', 'Gene', (81, 86))	('expression', 'MPA', (46, 56))	('facilitates', 'PosReg', (30, 41))
536872	30405839	Liver kinase B1 is inactivated through mutation in many cancer types, including HPV-related cervical cancer.	('Liver kinase B1', 'Gene', '6794', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mutation', 'Var', (39, 47))	('cancer', 'Disease', (101, 107))	('cervical cancer', 'Disease', 'MESH:D002583', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Liver kinase B1', 'Gene', (0, 15))	('HPV', 'Species', '10566', (80, 83))	('cervical cancer', 'Disease', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('inactivated', 'NegReg', (19, 30))
536887	30405839	The dissociation of HIF-1alpha from VHL attenuates VHL-mediated HIF-1alpha ubiquitination and leads to HIF-1alpha accumulation.	('dissociation', 'Var', (4, 16))	('HIF-1alpha accumulation', 'Disease', (103, 126))	('HIF-1alpha', 'Gene', (103, 113))	('HIF-1alpha accumulation', 'Disease', 'MESH:C579880', (103, 126))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('HIF-1alpha', 'Gene', '3091', (20, 30))	('VHL attenuates VHL-mediated HIF-1alpha ubiquitination', 'Disease', 'MESH:D006623', (36, 89))	('leads to', 'Reg', (94, 102))	('HIF-1alpha', 'Gene', '3091', (103, 113))	('HIF-1alpha', 'Gene', (64, 74))	('HIF-1alpha', 'Gene', (20, 30))
536889	30405839	Thus, high-risk HPV E2-mediated Warburg effect or the modification of cell metabolism could play a role in carcinogenesis.	('play', 'Reg', (92, 96))	('Warburg effect', 'CPA', (32, 46))	('E2-mediated', 'Var', (20, 31))	('HPV', 'Species', '10566', (16, 19))	('carcinogenesis', 'Disease', (107, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (107, 121))	('cell metabolism', 'CPA', (70, 85))	('modification', 'Reg', (54, 66))
536900	30405839	Many viral oncoproteins, including mouse polyomavirus large T-antigen, HPV E6, and EBV nuclear antigen (EBNA) 3C, regulate the p53 pathway, suggesting that virus oncoprotein-mediated p53 inactivation may enhance glucose uptake and accelerate glycolysis in cancer cells.	('accelerate', 'PosReg', (231, 241))	('EBV nuclear antigen (EBNA) 3C', 'Gene', '17494198', (83, 112))	('mouse polyomavirus', 'Species', '1891730', (35, 53))	('EBV nuclear antigen (EBNA) 3C', 'Gene', (83, 112))	('glycolysis', 'MPA', (242, 252))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('p53', 'Gene', (183, 186))	('cancer', 'Disease', (256, 262))	('p53', 'Gene', '7157', (183, 186))	('inactivation', 'Var', (187, 199))	('glucose uptake', 'MPA', (212, 226))	('glucose', 'Chemical', 'MESH:D005947', (212, 219))	('HPV', 'Species', '10566', (71, 74))	('enhance', 'PosReg', (204, 211))	('regulate', 'Reg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
536904	30405839	The expression of KSHV miRNA decreases oxygen consumption and increases glucose uptake and lactate secretion, inducing aerobic glycolysis in infected cells.	('oxygen consumption', 'MPA', (39, 57))	('lactate secretion', 'MPA', (91, 108))	('lactate', 'Chemical', 'MESH:D019344', (91, 98))	('KSHV', 'Species', '37296', (18, 22))	('inducing', 'Reg', (110, 118))	('KS', 'Phenotype', 'HP:0100726', (18, 20))	('aerobic glycolysis', 'MPA', (119, 137))	('decreases', 'NegReg', (29, 38))	('increases glucose uptake', 'Disease', 'MESH:C536778', (62, 86))	('expression', 'Var', (4, 14))	('increases glucose uptake', 'Disease', (62, 86))	('KSHV', 'Gene', (18, 22))	('oxygen', 'Chemical', 'MESH:D010100', (39, 45))
536909	30405839	Inhibition of FGFR1 signaling attenuates LMP1-mediated aerobic glycolysis and malignant transformation of human nasopharyngeal epithelial cells.	('human', 'Species', '9606', (106, 111))	('FGFR1', 'Gene', (14, 19))	('LMP1', 'Gene', '9260', (41, 45))	('malignant transformation', 'CPA', (78, 102))	('Inhibition', 'Var', (0, 10))	('FGFR1', 'Gene', '2260', (14, 19))	('LMP1', 'Gene', (41, 45))	('attenuates', 'NegReg', (30, 40))
536919	30405839	Infection by KSHV is associated with primary effusion lymphoma (PEL), a unique subset of human B-cell non-Hodgkin lymphoma (B-NHL).	('human', 'Species', '9606', (89, 94))	('Hodgkin lymphoma', 'Disease', (106, 122))	('KS', 'Phenotype', 'HP:0100726', (13, 15))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (37, 62))	('KSHV', 'Gene', (13, 17))	('lymphoma', 'Phenotype', 'HP:0002665', (54, 62))	('associated with', 'Reg', (21, 36))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (106, 122))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (106, 122))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (102, 122))	('PEL', 'Phenotype', 'HP:0030069', (64, 67))	('Infection', 'Var', (0, 9))	('KSHV', 'Species', '37296', (13, 17))	('primary effusion lymphoma', 'Disease', (37, 62))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (37, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))
536926	30405839	Currently available data demonstrate that viruses potentiate tumor formation and progression through driving expression of oncogenes or reprogramming glucose metabolism via regulation of glucose uptake, glycolytic flux, and energy production.	('glucose uptake', 'MPA', (187, 201))	('progression', 'CPA', (81, 92))	('energy production', 'MPA', (224, 241))	('viruses', 'Var', (42, 49))	('glucose', 'Chemical', 'MESH:D005947', (187, 194))	('glucose', 'Chemical', 'MESH:D005947', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('regulation', 'Reg', (173, 183))	('oncogenes', 'Gene', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('glucose metabolism', 'MPA', (150, 168))	('glycolytic flux', 'MPA', (203, 218))	('tumor', 'Disease', (61, 66))	('potentiate', 'PosReg', (50, 60))
536933	29473967	WRR significantly improved RFS (hazard ratio [HR] 0.16, 95% CI 0.07-0.37; p < 0.0001), despite the fact that patients receiving WRR had higher-grade disease.	('patients', 'Species', '9606', (109, 117))	('improved', 'PosReg', (18, 26))	('WRR', 'Var', (0, 3))	('RFS', 'Chemical', '-', (27, 30))	('RFS', 'MPA', (27, 30))
536934	29473967	Tumor-positive margins upon WRR were strongly associated with both disease recurrence (HR 5.56; 95% CI 1.14-27.11, p = 0.034) and death from cancer (HR 6.16, 95% CI 1.25-30.29; p = 0.025).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('death', 'Disease', 'MESH:D003643', (130, 135))	('death', 'Disease', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('disease', 'Disease', (67, 74))	('Tumor-positive', 'Var', (0, 14))	('associated with', 'Reg', (46, 61))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
536973	29473967	While this was a small sample, positive surgical margins were strongly associated with both disease recurrence (HR 5.56, 95% CI 1.14-27.11; p = 0.034) and cancer-specific death (HR 6.16, 95% CI 1.25-30.29; p = 0.025).	('death', 'Disease', 'MESH:D003643', (171, 176))	('positive surgical', 'Var', (31, 48))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('death', 'Disease', (171, 176))	('disease recurrence', 'CPA', (92, 110))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
537012	27292183	Therefore, the evolution of these subpopulations through gaining new genetic and/or epigenetic alterations drives the evolution of tumors toward enhanced aggressiveness.	('aggressiveness', 'Disease', (154, 168))	('epigenetic alterations', 'Var', (84, 106))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aggressiveness', 'Phenotype', 'HP:0000718', (154, 168))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('genetic', 'Var', (69, 76))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('enhanced', 'PosReg', (145, 153))	('aggressiveness', 'Disease', 'MESH:D001523', (154, 168))
537024	27292183	Importantly, high expression and activity of members of the ALDH1 subgroup has been associated with poor prognosis and metastatic potential in several types of cancer.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('poor prognosis', 'CPA', (100, 114))	('cancer', 'Disease', (160, 166))	('high expression', 'Var', (13, 28))	('activity', 'MPA', (33, 41))	('metastatic potential', 'CPA', (119, 139))	('ALDH1', 'Gene', (60, 65))	('associated', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ALDH1', 'Gene', '11668', (60, 65))
537032	27292183	We have previously developed and characterized sarcoma models using human bone marrow MSCs (BM-MSCs) sequentially mutated with up to 6 oncogenic events [(1) hTERT overexpression; (2 & 3) P53 and Rb inactivation using E6 and E7 antigens of the HPV-16; (4) inactivation of PPA2 phosphatase with SV40 small T antigen (4 hits combination; MSC-4H); (5) expression of oncogenic H-RASv-12 (5 hits combination; MSC-5H); and (6) the expression of FUS-CHOP (FC)] (Table S1).	('human', 'Species', '9606', (68, 73))	('P53', 'Gene', '7157', (187, 190))	('mutated', 'Var', (114, 121))	('oncogenic', 'Gene', (362, 371))	('HPV-16', 'Species', '333760', (243, 249))	('FUS-CHOP', 'Gene', (438, 446))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('of PPA2', 'Enzyme', (268, 275))	('5H', 'Chemical', '-', (407, 409))	('P53', 'Gene', (187, 190))	('sarcoma', 'Disease', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
537044	27292183	We previously found that this collection of sequentially mutated MSCs lost their adipogenic potential during the transformation process, and MSC-4H, MSC-5H, T-5H and T-4H cells (regardless the expression of FUS-CHOP) displayed an impaired pattern of differentiation in which most cells of the culture presented a small amount of lipid droplets in their cytoplasm.	('lipid', 'Chemical', 'MESH:D008055', (329, 334))	('MSCs', 'Gene', (65, 69))	('5H', 'Chemical', '-', (153, 155))	('5H', 'Chemical', '-', (159, 161))	('T-5H', 'Chemical', '-', (157, 161))	('adipogenic potential', 'MPA', (81, 101))	('lost', 'NegReg', (70, 74))	('mutated', 'Var', (57, 64))
537066	27292183	Meanwhile, T-5H-FC#1 displayed a remarkable upregulation of two well-known CSC-promoting factors such as ALDH1A1 and SOX2 (Fig.	('ALDH1A1', 'Gene', '11668', (105, 112))	('T-5H-FC#1', 'Var', (11, 20))	('SOX2', 'Gene', (117, 121))	('CSC-promoting', 'Disease', (75, 88))	('upregulation', 'PosReg', (44, 56))	('SOX2', 'Gene', '20674', (117, 121))	('ALDH1A1', 'Gene', (105, 112))	('T-5H', 'Chemical', '-', (11, 15))
537067	27292183	Consistently, ALDH1A1 (fold regulation: 22.02) and SOX2 (38.88) were expressed in T-5H-FC#1-derived tumorspheres at higher levels than in those formed by MSC-5H-FC cells (Fig.	('5H', 'Chemical', '-', (158, 160))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ALDH1A1', 'Gene', (14, 21))	('SOX2', 'Gene', '20674', (51, 55))	('T-5H', 'Chemical', '-', (82, 86))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('T-5H-FC', 'Var', (82, 89))	('5H', 'Chemical', '-', (84, 86))	('ALDH1A1', 'Gene', '11668', (14, 21))	('SOX2', 'Gene', (51, 55))
537070	27292183	According to gene expression experiments, a western blotting analysis confirmed that SOX2 and ALDH1A1 protein levels were upregulated in T-5H-FC#1 tumorspheres at a greater level than in MSC-5H-FC tumorspheres (Fig.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('SOX2', 'Gene', '20674', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('ALDH1A1', 'Gene', (94, 101))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('T-5H', 'Chemical', '-', (137, 141))	('tumors', 'Disease', (197, 203))	('upregulated', 'PosReg', (122, 133))	('5H', 'Chemical', '-', (139, 141))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('protein levels', 'MPA', (102, 116))	('5H', 'Chemical', '-', (191, 193))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('ALDH1A1', 'Gene', '11668', (94, 101))	('T-5H-FC#1', 'Var', (137, 146))	('SOX2', 'Gene', (85, 89))
537071	27292183	Moreover, the immunofluorescence analysis of adherent cultures and tumorspheres that were allowed to attach to the substrate before fixation showed that T-5H-FC#1 adherent and tumorsphere cultures presented a significantly higher percentage of SOX2-positive stained nuclei than the respective nuclei of MSC-5H-FC cultures, with the nuclei of T-5H-FC#1 tumorspheres displaying the higher levels (Fig.	('T-5H-FC', 'Var', (153, 160))	('T-5H', 'Chemical', '-', (153, 157))	('T-5H', 'Chemical', '-', (342, 346))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Disease', (352, 358))	('tumors', 'Disease', 'MESH:D009369', (352, 358))	('5H', 'Chemical', '-', (155, 157))	('5H', 'Chemical', '-', (307, 309))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('SOX2', 'Gene', '20674', (244, 248))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('5H', 'Chemical', '-', (344, 346))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('tumors', 'Disease', (67, 73))	('SOX2', 'Gene', (244, 248))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('tumors', 'Disease', (176, 182))	('higher', 'PosReg', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
537073	27292183	Furthermore, in situ simultaneous immunofluorescent staining of SOX2 and ALDHA1 confirmed that T-5H-FC#1 tumorspheres displayed a higher proportion of cells presenting nuclear expression of SOX2 and a higher expression of cytosolic ALDH1A1 compared with MSC-5H-FC tumorspheres (Fig.	('tumors', 'Disease', (105, 111))	('nuclear expression', 'MPA', (168, 186))	('tumors', 'Disease', (264, 270))	('expression', 'MPA', (208, 218))	('ALDH', 'Gene', (73, 77))	('SOX2', 'Gene', '20674', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('ALDH1A1', 'Gene', '11668', (232, 239))	('ALDH', 'Gene', (232, 236))	('T-5H', 'Chemical', '-', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('SOX2', 'Gene', (64, 68))	('T-5H-FC#1', 'Var', (95, 104))	('SOX2', 'Gene', '20674', (190, 194))	('higher', 'PosReg', (130, 136))	('SOX2', 'Gene', (190, 194))	('5H', 'Chemical', '-', (258, 260))	('ALDH', 'Gene', '11670', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('ALDH', 'Gene', '11670', (232, 236))	('higher', 'PosReg', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('ALDH1A1', 'Gene', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('5H', 'Chemical', '-', (97, 99))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))
537078	27292183	These two isoforms were upregulated at greater levels in T-5H-O tumorspheres than in MSC-5H-O tumorspheres (Fig.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('5H-O', 'Chemical', '-', (59, 63))	('T-5H-O', 'Var', (57, 63))	('T-5H-O', 'Chemical', '-', (57, 63))	('upregulated', 'PosReg', (24, 35))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('5H-O', 'Chemical', '-', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
537081	27292183	To study the contributions of ALDH1A1 and ALDH1A3 to the ALDEFLUOR activity, we performed siRNA knockdown of both isoforms in T-5H-O cells.	('knockdown', 'Var', (96, 105))	('ALDH1A1', 'Gene', '11668', (30, 37))	('ALDH1A3', 'Gene', (42, 49))	('ALDH1A1', 'Gene', (30, 37))	('ALDH1A3', 'Gene', '56847', (42, 49))	('T-5H-O', 'Chemical', '-', (126, 132))
537105	27292183	On the one hand, tumorsphere cultures from the T-5H-FC#1 sarcoma-derived cell line are highly enriched in CSCs as seen by their highly increased capacity to initiate tumor formation in vivo.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Disease', (17, 23))	('T-5H', 'Chemical', '-', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('tumor', 'Disease', (166, 171))	('increased', 'PosReg', (135, 144))	('CSCs', 'Disease', (106, 110))	('T-5H-FC', 'Var', (47, 54))	('sarcoma', 'Disease', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
537108	27292183	These tumor-propagating subpopulations most likely appear and evolve through the accumulation of epigenetic alterations and are a source of intra-tumor heterogeneity.	('epigenetic alterations', 'Var', (97, 119))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('intra-tumor', 'Disease', 'MESH:D009369', (140, 151))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('accumulation', 'Reg', (81, 93))	('intra-tumor', 'Disease', (140, 151))	('tumor', 'Disease', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
537110	27292183	By analyzing the expression of several genes involved in the CSC phenotype in MSC-5H-FC and T-5H-FC#1 adherent and tumorsphere cultures, we found a group of genes highly enriched in T-5H-FC#1 vs. MSC-5H-FC tumorsphere cultures that are therefore progressively increased in tumorsphere-forming subpopulations during sarcoma progression.	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('sarcoma', 'Disease', 'MESH:D012509', (315, 322))	('5H', 'Chemical', '-', (94, 96))	('sarcoma', 'Disease', (315, 322))	('increased', 'PosReg', (260, 269))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Disease', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('T-5H-FC', 'Var', (182, 189))	('T-5H', 'Chemical', '-', (182, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (315, 322))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('T-5H', 'Chemical', '-', (92, 96))	('5H', 'Chemical', '-', (200, 202))	('5H', 'Chemical', '-', (184, 186))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Disease', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumors', 'Disease', (273, 279))	('5H', 'Chemical', '-', (82, 84))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (273, 279))
537112	27292183	Both factors were also upregulated at protein levels and their ALDEFLUOR activities were equally enhanced in T-5H vs. MSC-5H tumorspheres (Table 1).	('upregulated', 'PosReg', (23, 34))	('T-5H', 'Chemical', '-', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('ALDEFLUOR activities', 'MPA', (63, 83))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('enhanced', 'PosReg', (97, 105))	('5H', 'Chemical', '-', (111, 113))	('T-5H', 'Var', (109, 113))	('5H', 'Chemical', '-', (122, 124))
537119	27292183	These studies found that subpopulations with high activity of ALDH1 showed increased expression of pluripotency markers like SOX2, enhanced ability to grow as tumorspheres, increased tumorigenicity and strong chemo-resistance.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', (159, 165))	('increased', 'PosReg', (173, 182))	('pluripotency', 'Disease', (99, 111))	('ALDH1', 'Gene', '11668', (62, 67))	('high', 'Var', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('pluripotency', 'Disease', 'None', (99, 111))	('increased', 'PosReg', (75, 84))	('SOX2', 'Gene', '20674', (125, 129))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('ALDH1', 'Gene', (62, 67))	('expression', 'MPA', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('SOX2', 'Gene', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('enhanced', 'PosReg', (131, 139))
537136	27292183	Likewise, NOTCH signaling has been associated with ALDH activity and increased metastatic potential in osteosarcoma cells.	('metastatic potential', 'CPA', (79, 99))	('NOTCH signaling', 'Var', (10, 25))	('increased', 'PosReg', (69, 78))	('ALDH', 'Gene', '11670', (51, 55))	('associated', 'Reg', (35, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('ALDH', 'Gene', (51, 55))
537141	27292183	Human BM-MSCs sequentially mutated with up to 6 oncogenic events, and tumor lines derived from transformed BM-MSC-induced xenografts were previously generated and characterized (Table S1).	('Human', 'Species', '9606', (0, 5))	('mutated', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
537156	27292183	Upon removal, tumor samples were fixed in formol, embedded in paraffin, cut into 4-mum sections, and stained with hematoxylin and eosin (H&E) and anti-ALDH1A1 [(ab105920), 1:400 dilution] from Abcam (Cambridge, UK) as previously described.	('tumor', 'Disease', (14, 19))	('paraffin', 'Chemical', 'MESH:D010232', (62, 70))	('H&E', 'Chemical', '-', (137, 140))	('eosin', 'Chemical', 'MESH:D004801', (130, 135))	('ALDH1A1', 'Gene', '11668', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('and', 'Var', (142, 145))	('hematoxylin', 'Chemical', 'MESH:D006416', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('ALDH1A1', 'Gene', (151, 158))	('formol', 'Chemical', 'MESH:D005557', (42, 48))
537172	27292183	ALDH1A1 (J-008722-06-0002) and ALDH1A3 (J-009082-07-0002) On-Target plus siRNAs and siGenome RiSC-Free control siRNA (D-001220-01) were from Dharmacon (Lafayette, CO).	('J-009082-07-0002', 'Var', (40, 56))	('RiSC', 'Gene', '74617', (93, 97))	('J-008722-06-0002', 'Var', (9, 25))	('ALDH1A1', 'Gene', '11668', (0, 7))	('ALDH1A3', 'Gene', (31, 38))	('ALDH1A3', 'Gene', '56847', (31, 38))	('RiSC', 'Gene', (93, 97))	('ALDH1A1', 'Gene', (0, 7))
537212	25125819	Factors responsible for bad prognosis include tumor size (>5 cm), male gender, older age (>20 years), extensive tumor necrosis, high grade, large number of mitotic figures (>10/high powered fields), and recently SYT-SSX1 variant.	('high grade', 'CPA', (128, 138))	('SSX1', 'Gene', '6756', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('variant', 'Var', (221, 228))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SYT', 'Gene', '6760', (212, 215))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (46, 51))	('SSX1', 'Gene', (216, 220))	('SS', 'Phenotype', 'HP:0012570', (216, 218))	('tumor necrosis', 'Disease', 'MESH:D009336', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SYT', 'Gene', (212, 215))	('tumor', 'Disease', (112, 117))	('tumor necrosis', 'Disease', (112, 126))
537216	24963404	Imatinib: A Breakthrough of Targeted Therapy in Cancer Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers.	('human', 'Species', '9606', (134, 139))	('tyrosine kinase', 'Gene', (75, 90))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('Deregulated', 'Var', (55, 66))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('activity', 'MPA', (91, 99))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', (48, 54))	('tyrosine kinase', 'Gene', '7294', (75, 90))	('cancers', 'Disease', (140, 147))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
537220	24963404	Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT.	('CML', 'Phenotype', 'HP:0005506', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PDGFR', 'Gene', (135, 140))	('PDGFR', 'Gene', '5159', (135, 140))	('benefits', 'PosReg', (60, 68))	('abnormalities', 'Var', (118, 131))	('CML', 'Disease', (37, 40))	('c-KIT', 'Gene', (145, 150))	('tumors', 'Disease', (83, 89))	('Imatinib', 'Chemical', 'MESH:D000068877', (100, 108))	('Imatinib', 'Chemical', 'MESH:D000068877', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('c-KIT', 'Gene', '3815', (145, 150))	('CML', 'Disease', 'MESH:D015464', (37, 40))
537229	24963404	Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancers.	('activity', 'MPA', (31, 39))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('protein kinase', 'Enzyme', (16, 30))	('human', 'Species', '9606', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
537236	24963404	Inhibition of the BCR-ABL tyrosine kinase also stimulates its entry into the nucleus, where it is unable to perform any of its normal antiapoptotic functions.	('BCR-ABL', 'Gene', '25', (18, 25))	('stimulates', 'PosReg', (47, 57))	('tyrosine kinase', 'Gene', (26, 41))	('Inhibition', 'Var', (0, 10))	('tyrosine kinase', 'Gene', '7294', (26, 41))	('BCR-ABL', 'Gene', (18, 25))	('entry into the nucleus', 'MPA', (62, 84))
537261	24963404	Acquired resistance may be caused by mutations in the BCR-ABL kinase domain, amplification of the BCR-ABL fusion gene, overexpression of drug transporter genes, and overexpression of tyrosine kinases such as the SRC family kinases.	('amplification', 'MPA', (77, 90))	('BCR-ABL', 'Gene', (54, 61))	('BCR-ABL', 'Gene', '25', (54, 61))	('Acquired', 'MPA', (0, 8))	('BCR-ABL', 'Gene', (98, 105))	('overexpression', 'PosReg', (119, 133))	('tyrosine kinase', 'Gene', '7294', (183, 198))	('BCR-ABL', 'Gene', '25', (98, 105))	('mutations', 'Var', (37, 46))	('overexpression', 'PosReg', (165, 179))	('caused by', 'Reg', (27, 36))	('tyrosine kinase', 'Gene', (183, 198))
537266	24963404	GISTs are typically defined by the expression of c-KIT (CD117) in the tumor cells, as these activating KIT mutations are seen in 85-95% of GISTs.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('GISTs', 'Phenotype', 'HP:0100723', (0, 5))	('mutations', 'Var', (107, 116))	('CD117', 'Gene', '3815', (56, 61))	('c-KIT', 'Gene', (49, 54))	('tumor', 'Disease', (70, 75))	('CD117', 'Gene', (56, 61))	('GISTs', 'Phenotype', 'HP:0100723', (139, 144))	('c-KIT', 'Gene', '3815', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('activating', 'PosReg', (92, 102))
537267	24963404	About 3-5% of the remainder of KIT-negative GISTs contain PDGFRA mutations.	('PDGFRA', 'Gene', (58, 64))	('PDGFRA', 'Gene', '5156', (58, 64))	('contain', 'Reg', (50, 57))	('GISTs', 'Phenotype', 'HP:0100723', (44, 49))	('mutations', 'Var', (65, 74))
537273	24963404	However, in a phase II randomized trial examining dose selection in 946 patients with advanced GIST, patients whose tumors expressed an exon 9 KIT mutation, treated with a daily dose of 800 mg of Imatinib (versus 400 mg), experienced a significantly superior PFS (P = 0.0013) with a reduction of relative risk of 61%.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (101, 109))	('Imatinib', 'Chemical', 'MESH:D000068877', (196, 204))	('exon 9', 'Var', (136, 142))	('reduction', 'NegReg', (283, 292))	('superior', 'PosReg', (250, 258))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('PFS', 'MPA', (259, 262))	('patients', 'Species', '9606', (72, 80))
537281	24963404	At a median follow-up of 4.7 years, 5-year Imatinib-free survival (IFS) was 87 percent in the Imatinib arm compared to 84 percent in the control arm, 3-year RFS was 84 versus 66 percent, and 5-year overall survival was 100 versus 99 percent.	('Imatinib', 'Chemical', 'MESH:D000068877', (94, 102))	('Imatinib-free survival', 'MPA', (43, 65))	('Imatinib', 'Var', (94, 102))	('Imatinib', 'Chemical', 'MESH:D000068877', (43, 51))
537286	24963404	Other identified mechanisms of acquired resistance have included amplification of KIT and pharmacokinetic resistance that may involve altered activity of drug transporters, induction of the cytochrome P450 (CYP)3A4 isoenzyme, and poor patient compliance.	('patient', 'Species', '9606', (235, 242))	('KIT', 'MPA', (82, 85))	('drug', 'Enzyme', (154, 158))	('pharmacokinetic resistance', 'MPA', (90, 116))	('activity', 'MPA', (142, 150))	('altered', 'Reg', (134, 141))	('induction', 'Reg', (173, 182))	('amplification', 'Var', (65, 78))
537291	24963404	The formation of COL1A1-PDGFB fusion gene results in the constitutional upregulation of PDGFB expression, leading to continuous autocrine activation of PDGF receptor B (PDGFRB) which is a key pathogenetic factor.	('autocrine', 'MPA', (128, 137))	('PDGF receptor B', 'Gene', '5159', (152, 167))	('fusion', 'Var', (30, 36))	('upregulation', 'PosReg', (72, 84))	('PDGFB', 'Gene', '5155', (88, 93))	('PDGF receptor B', 'Gene', (152, 167))	('PDGFRB', 'Gene', '5159', (169, 175))	('PDGFB', 'Gene', (88, 93))	('PDGFB', 'Gene', '5155', (24, 29))	('PDGFRB', 'Gene', (169, 175))	('expression', 'MPA', (94, 104))	('COL1A1', 'Gene', (17, 23))	('COL1A1', 'Gene', '1277', (17, 23))	('activation', 'PosReg', (138, 148))	('PDGFB', 'Gene', (24, 29))
537302	24963404	While p190 protein is exclusively expressed in Ph-positive (Ph+) ALL, p210 protein is predominant in chronic myelogenous leukemia (CML).	('CML', 'Disease', (131, 134))	('CML', 'Phenotype', 'HP:0005506', (131, 134))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('chronic myelogenous leukemia', 'Disease', (101, 129))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (101, 129))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (101, 129))	('CML', 'Disease', 'MESH:D015464', (131, 134))	('p210 protein', 'Var', (70, 82))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (109, 129))	('p190', 'Gene', '8506', (6, 10))	('p190', 'Gene', (6, 10))
537319	24963404	Some HES patients are associated with a deletion in chromosome 4, which fuses the FIP1-like-1 gene (FIP1L1) to the PDGFRA gene, leading to FIP1L1-PDGFRA rearrangement.	('patients', 'Species', '9606', (9, 17))	('HES', 'Disease', (5, 8))	('deletion', 'Var', (40, 48))	('FIP1-like-1', 'Gene', '81608', (82, 93))	('PDGFRA', 'Gene', '5156', (115, 121))	('PDGFRA', 'Gene', (115, 121))	('HES', 'Disease', 'MESH:D017681', (5, 8))	('FIP1L1', 'Gene', '81608', (139, 145))	('PDGFRA', 'Gene', '5156', (146, 152))	('PDGFRA', 'Gene', (146, 152))	('FIP1L1', 'Gene', (100, 106))	('FIP1-like-1', 'Gene', (82, 93))	('rearrangement', 'Var', (153, 166))	('FIP1L1', 'Gene', '81608', (100, 106))	('FIP1L1', 'Gene', (139, 145))
537320	24963404	HES patients with a FIP1L1-PDGFRA rearrangement are now reclassified as chronic eosinophilic leukemia (CEL), as this gene has become a marker of disease clonality.	('rearrangement', 'Var', (34, 47))	('PDGFRA', 'Gene', '5156', (27, 33))	('PDGFRA', 'Gene', (27, 33))	('FIP1L1', 'Gene', '81608', (20, 26))	('HES', 'Disease', (0, 3))	('chronic eosinophilic leukemia', 'Disease', (72, 101))	('leukemia', 'Phenotype', 'HP:0001909', (93, 101))	('FIP1L1', 'Gene', (20, 26))	('HES', 'Disease', 'MESH:D017681', (0, 3))	('patients', 'Species', '9606', (4, 12))	('chronic eosinophilic leukemia', 'Disease', 'MESH:D004802', (72, 101))
537333	24963404	Mastocytosis is frequently associated with somatic gain-of-function point mutation with KIT.	('Mastocytosis', 'Disease', 'MESH:D008415', (0, 12))	('Mastocytosis', 'Disease', (0, 12))	('gain-of-function', 'PosReg', (51, 67))	('KIT', 'Gene', (88, 91))	('Mastocytosis', 'Phenotype', 'HP:0100495', (0, 12))	('point mutation', 'Var', (68, 82))
537334	24963404	The most common somatic point mutation is the KITD816V, resulting from substitution of valine for aspartic acid at codon 816 within KIT exon 17.	('valine', 'MPA', (87, 93))	('KITD816V', 'Mutation', 'rs121913507', (46, 54))	('substitution', 'Var', (71, 83))	('valine for aspartic acid at codon 816', 'Mutation', 'rs121913507', (87, 124))	('KITD816V', 'Var', (46, 54))
537346	24963404	None of the studies showed any significant correlation with the expression and/or mutations in Imatinib sensitive tyrosine kinase with outcome or response.	('tyrosine kinase', 'Gene', (114, 129))	('mutations', 'Var', (82, 91))	('Imatinib', 'Chemical', 'MESH:D000068877', (95, 103))	('tyrosine kinase', 'Gene', '7294', (114, 129))
537352	24963404	Recently, KIT-activating mutations were reported in 21% of mucosal melanomas, 11% of acral melanomas, and 16.7% of melanomas arising in chronically sun-damaged skin.	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('melanomas', 'Disease', (115, 124))	('mucosal melanomas', 'Disease', 'MESH:D008545', (59, 76))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))	('melanomas', 'Disease', (67, 76))	('mutations', 'Var', (25, 34))	('melanomas', 'Disease', (91, 100))	('mucosal melanomas', 'Disease', (59, 76))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('sun-damaged', 'Phenotype', 'HP:0000992', (148, 159))	('acral melanomas', 'Disease', 'MESH:D008545', (85, 100))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('acral melanomas', 'Phenotype', 'HP:0012060', (85, 100))	('KIT-activating', 'Gene', (10, 24))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('acral melanomas', 'Disease', (85, 100))
537356	24963404	Recent studies also illustrated the effectiveness of Imatinib in patients with advanced melanoma harboring mutations or amplification of the KIT protooncogene.	('Imatinib', 'Chemical', 'MESH:D000068877', (53, 61))	('mutations', 'Var', (107, 116))	('KIT protooncogene', 'Gene', (141, 158))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('amplification', 'Var', (120, 133))	('patients', 'Species', '9606', (65, 73))
537357	24963404	Of 50 patients with melanomas, 24 evaluable patients with KIT-mutant (n = 8), KIT-amplified melanoma (n = 11), or both (n = 5) were treated with Imatinib.	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('patients', 'Species', '9606', (44, 52))	('melanomas', 'Disease', (20, 29))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('KIT-amplified', 'Var', (78, 91))	('patients', 'Species', '9606', (6, 14))	('melanomas', 'Disease', 'MESH:D008545', (20, 29))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('melanoma', 'Disease', (20, 28))	('Imatinib', 'Chemical', 'MESH:D000068877', (145, 153))	('KIT-mutant', 'Var', (58, 68))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
537369	24963404	However, no correlation between c-KIT and PDGF mutations or any changes in the candidate cytokines with response was found.	('PD', 'Disease', 'MESH:D010300', (42, 44))	('c-KIT', 'Gene', (32, 37))	('c-KIT', 'Gene', '3815', (32, 37))	('mutations', 'Var', (47, 56))
537558	30871044	Moreover, an important aspect of the combination of HT to MNPs is to allow the release of the selected drug loaded on MNPs in cancer tissue when they are irradiated with an appropriate laser beam, thus increasing drug delivery efficiency and favoring intracellular drug incorporation, thanks also to the temperature-induced increase of cell membrane permeability.	('HT', 'Phenotype', 'HP:0001945', (52, 54))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cell membrane permeability', 'CPA', (336, 362))	('increase', 'PosReg', (324, 332))	('favoring', 'PosReg', (242, 250))	('cancer', 'Disease', (126, 132))	('intracellular', 'MPA', (251, 264))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('increasing', 'PosReg', (202, 212))	('release', 'MPA', (79, 86))	('MNPs', 'Var', (118, 122))	('drug delivery', 'MPA', (213, 226))
537575	30871044	Finally, in addition to elicit direct cytotoxicity, PDT provokes a variety of additional beneficial anti-tumor effects such as an acute inflammatory response, anti-vascular effects and an activation of the immune system.	('immune', 'CPA', (206, 212))	('acute inflammatory', 'MPA', (130, 148))	('anti-vascular effects', 'CPA', (159, 180))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cytotoxicity', 'Disease', (38, 50))	('PDT', 'Var', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('activation', 'PosReg', (188, 198))	('tumor', 'Disease', (105, 110))	('cytotoxicity', 'Disease', 'MESH:D064420', (38, 50))
537576	30871044	The non-specific concentration of PSs leads to irradiated injury of normal tissues as well as liver and kidney damage.	('PSs', 'Gene', (34, 37))	('kidney damage', 'Disease', 'MESH:D007674', (104, 117))	('leads to', 'Reg', (38, 46))	('non-specific concentration', 'Var', (4, 30))	('kidney damage', 'Phenotype', 'HP:0000112', (104, 117))	('kidney damage', 'Disease', (104, 117))	('irradiated', 'CPA', (47, 57))
537634	30871044	studies, showing that ZnPc/BSA-PDT (zinc phthalocyanine BSA conjugated) and PPZ-PDT (PEG-PMAN/ZnPC) were able to reduce tumor size when used intraoperatively; moreover they were able to reduce cell invasiveness in vitro.	('reduce', 'NegReg', (113, 119))	('PPZ-PDT', 'Var', (76, 83))	('cell invasiveness in vitro', 'CPA', (193, 219))	('tumor', 'Disease', (120, 125))	('zinc phthalocyanine', 'Chemical', 'MESH:C052159', (36, 55))	('PEG-PMAN', 'Chemical', '-', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('reduce', 'NegReg', (186, 192))	('ZnPc/BSA-PDT', 'Var', (22, 34))
537638	30871044	showed that AO-PDT has a strong cytocidal effect, not only on chemosensitive mouse OS cells, but also on MDR mouse OS cells.	('cytocidal effect', 'CPA', (32, 48))	('OS', 'Phenotype', 'HP:0002669', (115, 117))	('OS', 'Phenotype', 'HP:0002669', (83, 85))	('mouse', 'Species', '10090', (77, 82))	('AO-PDT', 'Var', (12, 18))	('mouse', 'Species', '10090', (109, 114))
537650	26259251	beta-catenin stabilization enhances SS18-SSX2-driven synovial sarcomagenesis and blocks the mesenchymal to epithelial transition beta-catenin is a master regulator in the cellular biology of development and neoplasia.	('beta-catenin', 'Gene', '12387', (0, 12))	('stabilization', 'Var', (13, 26))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (53, 69))	('SS', 'Phenotype', 'HP:0012570', (41, 43))	('neoplasia', 'Disease', 'MESH:D009369', (207, 216))	('beta-catenin', 'Gene', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('neoplasia', 'Disease', (207, 216))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (53, 76))	('SS18', 'Gene', '268996', (36, 40))	('blocks', 'NegReg', (81, 87))	('neoplasia', 'Phenotype', 'HP:0002664', (207, 216))	('synovial sarcomagenesis', 'Disease', (53, 76))	('SSX2', 'Gene', (41, 45))	('SS', 'Phenotype', 'HP:0012570', (36, 38))	('beta-catenin', 'Gene', '12387', (129, 141))	('SS18', 'Gene', (36, 40))	('SSX2', 'Gene', '6757', (41, 45))	('beta-catenin', 'Gene', (129, 141))	('enhances', 'PosReg', (27, 35))
537651	26259251	Its dysregulation is implicated as a driver of colorectal carcinogenesis and the epithelial-mesenchymal transition in other cancers.	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (47, 72))	('epithelial-mesenchymal transition', 'CPA', (81, 114))	('dysregulation', 'Var', (4, 17))	('colorectal carcinogenesis', 'Disease', (47, 72))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
537663	26259251	Canonical Wnt signal transduction, APC inactivating mutations, or mutations in the third exon of beta-catenin each result in the prevention of this phosphorylation, stabilizing beta-catenin and driving it to the nucleus.	('beta-catenin', 'Gene', (97, 109))	('stabilizing', 'PosReg', (165, 176))	('beta-catenin', 'Protein', (177, 189))	('APC', 'Disease', 'MESH:D011125', (35, 38))	('driving', 'Reg', (194, 201))	('APC', 'Disease', (35, 38))	('mutations in', 'Var', (66, 78))
537664	26259251	beta-catenin stabilizing mutations and APC silencing mutations have been identified in SSs.	('mutations', 'Var', (25, 34))	('APC', 'Disease', 'MESH:D011125', (39, 42))	('APC', 'Disease', (39, 42))	('SSs', 'Disease', (87, 90))	('SS', 'Phenotype', 'HP:0012570', (87, 89))	('beta-catenin', 'Protein', (0, 12))
537665	26259251	Genetic disruption of beta-catenin blunts synovial sarcomagenesis driven by SS18-SSX2 in the mouse Myf5Cre lineage, suggesting near necessity of Wnt/beta-catenin signaling to the transformation of that lineage.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (42, 58))	('SSX2', 'Gene', '6757', (81, 85))	('mouse', 'Species', '10090', (93, 98))	('SS', 'Phenotype', 'HP:0012570', (81, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('blunts synovial sarcomagenesis', 'Disease', 'MESH:D014949', (35, 65))	('Genetic disruption', 'Var', (0, 18))	('beta-catenin', 'Protein', (22, 34))	('blunts synovial sarcomagenesis', 'Disease', (35, 65))	('SSX2', 'Gene', (81, 85))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (42, 65))
537668	26259251	First, we injected an adeno-associated virus (AdCre) into the bilateral hindlimbs of 7 four-week-old mice of each of 3 genotypes, Rosa26hSS2/wt; Ctnnb1wt/wt, Rosa26wt/wt; Ctnnb1ex3fl/wt, and Rosa26hSS2/wt; Ctnnb1ex3fl/wt.	('Rosa26', 'Gene', '14910', (191, 197))	('SS', 'Phenotype', 'HP:0012570', (198, 200))	('Rosa26', 'Gene', '14910', (130, 136))	('Rosa26', 'Gene', '14910', (158, 164))	('adeno-associated virus', 'Species', '272636', (22, 44))	('Rosa26', 'Gene', (191, 197))	('Ctnnb1ex3fl/wt', 'Var', (171, 185))	('SS', 'Phenotype', 'HP:0012570', (137, 139))	('mice', 'Species', '10090', (101, 105))	('Rosa26', 'Gene', (130, 136))	('Ctnnb1wt/wt', 'Var', (145, 156))	('Rosa26', 'Gene', (158, 164))
537670	26259251	By 1 year, neither Rosa26hSS2, nor Ctnnb1ex3f l alone produced tumors (Figure 1B).	('SS', 'Phenotype', 'HP:0012570', (26, 28))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Rosa26hSS2', 'Var', (19, 29))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
537687	26259251	Rosa26hSS2/wt; Ctnnb1wt/wt mice also developed tumors, at longer latency and lower prevalence (Figure 3B).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('mice', 'Species', '10090', (27, 31))	('SS', 'Phenotype', 'HP:0012570', (7, 9))	('developed', 'PosReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('Rosa26hSS2/wt', 'Var', (0, 13))
537693	26259251	Nonetheless, differential expression highlighted not only Wnt/beta-catenin pathway target genes, but also a deepening of the TLE1-driven repression of SS18-SSX target genes and derangement of EMT-related genes (Figure 4A-4B).	('SS', 'Phenotype', 'HP:0012570', (156, 158))	('SSX', 'Gene', (156, 159))	('SSX', 'Gene', '6757', (156, 159))	('derangement', 'Var', (177, 188))	('TLE1', 'Gene', (125, 129))	('SS', 'Phenotype', 'HP:0012570', (151, 153))	('Wnt/beta-catenin pathway', 'Pathway', (58, 82))	('repression', 'NegReg', (137, 147))	('TLE1', 'Gene', '21885', (125, 129))	('EMT-related genes', 'Gene', (192, 209))
537694	26259251	To test the relationship between beta-catenin and TCF/LEF target genes highlighted in the comparison of tumors extends to SS cell lines, we knocked down CTNNB1/Ctnnb1 in human and mouse SS cell lines by siRNA.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('TCF/LEF', 'Gene', (50, 57))	('SS', 'Phenotype', 'HP:0012570', (122, 124))	('TCF/LEF', 'Gene', '3172', (50, 57))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('mouse', 'Species', '10090', (180, 185))	('knocked', 'Var', (140, 147))	('tumors', 'Disease', (104, 110))	('CTNNB1/Ctnnb1', 'Gene', (153, 166))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('human', 'Species', '9606', (170, 175))	('SS', 'Phenotype', 'HP:0012570', (186, 188))
537696	26259251	We have shown that stabilization of beta-catenin powerfully enhances synovial sarcomagenesis driven by SS18-SSX2, inducing an aggressively invasive tumor phenotype.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (69, 85))	('synovial sarcoma', 'Disease', 'MESH:D013584', (69, 85))	('stabilization', 'Var', (19, 32))	('SSX2', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('enhances', 'PosReg', (60, 68))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (69, 92))	('beta-catenin', 'Protein', (36, 48))	('inducing', 'Reg', (114, 122))	('SSX2', 'Gene', '6757', (108, 112))	('aggressively invasive tumor', 'Disease', 'MESH:D001523', (126, 153))	('SS', 'Phenotype', 'HP:0012570', (103, 105))	('synovial sarcoma', 'Disease', (69, 85))	('SS', 'Phenotype', 'HP:0012570', (108, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('aggressively invasive tumor', 'Disease', (126, 153))
537699	26259251	The mouse data also explain the role played by CTNNB1 stabilizing and APC inactivating mutations in up to 20 percent of human SSs.	('SSs', 'Disease', (126, 129))	('CTNNB1', 'Gene', (47, 53))	('human', 'Species', '9606', (120, 125))	('mouse', 'Species', '10090', (4, 9))	('SS', 'Phenotype', 'HP:0012570', (126, 128))	('inactivating mutations', 'Var', (74, 96))	('APC', 'Disease', 'MESH:D011125', (70, 73))	('APC', 'Disease', (70, 73))
537700	26259251	Notably, all such described tumors with these mutations were monophasic fibrous SSs, lacking epithelial differentiation.	('mutations', 'Var', (46, 55))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('SS', 'Phenotype', 'HP:0012570', (80, 82))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('monophasic fibrous SSs', 'Disease', (61, 83))
537705	26259251	One explanation for the observed enhanced suppression of these SS18-SSX target genes is that the antagonism of TLE1 by an increase in nuclear beta-catenin liberates TLE1 from TCF/LEF-bound promoters.	('antagonism', 'Var', (97, 107))	('TLE1', 'Gene', (111, 115))	('TLE1', 'Gene', '21885', (165, 169))	('SS', 'Phenotype', 'HP:0012570', (68, 70))	('TLE1', 'Gene', (165, 169))	('SSX', 'Gene', '6757', (68, 71))	('SSX', 'Gene', (68, 71))	('TCF/LEF', 'Gene', (175, 182))	('TLE1', 'Gene', '21885', (111, 115))	('TCF/LEF', 'Gene', '3172', (175, 182))	('SS', 'Phenotype', 'HP:0012570', (63, 65))	('increase', 'PosReg', (122, 130))	('nuclear beta-catenin', 'MPA', (134, 154))
537710	26259251	This hypothesis is highlighted by the nine month delay in TATCre-induced tumor formation in mice with Rosa26hSS2/wt; Ctnnb1wl/wt compared to mice with Rosa26hSS2/wt; Ctnnb1ex3fl/wt.	('Ctnnb1wl/wt', 'Var', (117, 128))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('SS', 'Phenotype', 'HP:0012570', (109, 111))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SS', 'Phenotype', 'HP:0012570', (158, 160))	('tumor', 'Disease', (73, 78))	('delay', 'NegReg', (49, 54))	('Rosa26hSS2/wt; Ctnnb1wl/wt', 'Var', (102, 128))	('mice', 'Species', '10090', (141, 145))	('mice', 'Species', '10090', (92, 96))
537712	26259251	Why SS18-SSX2 expression is more rapidly oncogenic in the Myf5Cre lineage than following TATCre injection may derive in part from the simply stochastic principle that an entire lineage throughout the mouse begins expressing the fusion oncogene following Myf5Cre expression, as opposed to one small area of a limb after TATCre injection.	('SS', 'Phenotype', 'HP:0012570', (9, 11))	('SSX2', 'Gene', (9, 13))	('mouse', 'Species', '10090', (200, 205))	('SS', 'Phenotype', 'HP:0012570', (4, 6))	('SSX2', 'Gene', '6757', (9, 13))	('Myf5Cre expression', 'Var', (254, 272))
537717	26259251	The dramatic enhancement of synovial sarcomagenesis from the stabilization of beta-catenin suggests that Wnt signaling can help a cell tolerate the presence of the SS18-SSX2 fusion oncoprotein.	('synovial sarcoma', 'Disease', 'MESH:D013584', (28, 44))	('SSX2', 'Gene', (169, 173))	('synovial sarcomagenesis', 'Phenotype', 'HP:0012570', (28, 51))	('stabilization', 'Var', (61, 74))	('SS', 'Phenotype', 'HP:0012570', (164, 166))	('synovial sarcoma', 'Disease', (28, 44))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (28, 44))	('enhancement', 'PosReg', (13, 24))	('SS', 'Phenotype', 'HP:0012570', (169, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('SSX2', 'Gene', '6757', (169, 173))
537719	26259251	APC inactivating and beta-catenin stabilizing mutations have been described in SS, but many other genetic, epigenetic, paracrine, and microenvironmental forces converge upon beta-catenin stabilization and may provide alternate means of enabling SS18-SSX-driven oncogenesis.	('mutations', 'Var', (46, 55))	('SSX', 'Gene', (250, 253))	('SS', 'Phenotype', 'HP:0012570', (250, 252))	('SS', 'Phenotype', 'HP:0012570', (245, 247))	('SSX', 'Gene', '6757', (250, 253))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('oncogenesis', 'CPA', (261, 272))	('APC', 'Disease', (0, 3))	('SS', 'Phenotype', 'HP:0012570', (79, 81))	('enabling', 'PosReg', (236, 244))
537745	25784831	The literature has predominantly focused on "classical OS" (COS); that is, extremity localized primary tumour, high-grade histology, age below 40 years, and no detectable metastasis at primary diagnosis.	('OS', 'Phenotype', 'HP:0002669', (61, 63))	('high-grade histology', 'Var', (111, 131))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('primary tumour', 'Disease', (95, 109))	('primary tumour', 'Disease', 'MESH:D009369', (95, 109))	('COS', 'Chemical', '-', (60, 63))	('OS', 'Phenotype', 'HP:0002669', (55, 57))
537795	24131748	They are defined by a balanced, reciprocal translocation involving fusion of the SYT gene at 18q11 to either SSX1 or SSX2 at Xp11, with very rare cases having a fusion partner of SSX4.	('SSX4', 'Gene', '6759', (179, 183))	('SYT', 'Gene', (81, 84))	('SSX4', 'Gene', (179, 183))	('fusion', 'Var', (67, 73))
537804	24131748	None of their 5 "S100 positive sarcomas" expressed SOX10, which led the authors to conclude that in the setting of a soft tissue neoplasm SOX10 is more specific for peripheral nerve sheath tumors than S100.	('peripheral nerve sheath tumors', 'Disease', (165, 195))	('peripheral nerve sheath tumors', 'Disease', 'MESH:D010524', (165, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('soft tissue neoplasm', 'Phenotype', 'HP:0031459', (117, 137))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('SOX10', 'Var', (138, 143))	('neoplasm', 'Phenotype', 'HP:0002664', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
537807	24131748	All 5 of our synovial sarcomas with interpretable BAF47 labeling had reduced nuclear positivity compared to endothelial cells, all 3 of our synovial sarcoma mimics had staining comparable to endothelia, and one of our conventional MPNST cases had reduced nuclear staining.	('BAF47', 'Gene', (50, 55))	('all 3', 'Gene', '5079', (127, 132))	('reduced', 'NegReg', (69, 76))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (13, 30))	('labeling', 'Var', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (13, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (140, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('nuclear positivity', 'MPA', (77, 95))	('all 3', 'Gene', (127, 132))
537815	23553791	Depletion of either IFN-gamma or TNF-alpha in OVX mice abolishes MSC impairment and the tendency toward malignant transformation with no NFkappaB-mediated oncogene activation.	('abolishes', 'NegReg', (55, 64))	('malignant transformation', 'CPA', (104, 128))	('NFkappaB', 'Gene', (137, 145))	('NFkappaB', 'Gene', '18033', (137, 145))	('MSC impairment', 'Disease', 'MESH:D009422', (65, 79))	('OVX', 'Chemical', '-', (46, 49))	('Depletion', 'Var', (0, 9))	('MSC impairment', 'Disease', (65, 79))	('TNF-alpha', 'Gene', (33, 42))	('mice', 'Species', '10090', (50, 54))
537889	23553791	Blockage of either IFN-gamma or TNF-alpha can abolish OVX-induced osteoporotic phenotype.	('Blockage', 'Var', (0, 8))	('OVX-induced', 'Disease', (54, 65))	('TNF-alpha', 'Protein', (32, 41))	('osteoporotic', 'Disease', 'MESH:D058866', (66, 78))	('OVX', 'Chemical', '-', (54, 57))	('abolish', 'NegReg', (46, 53))	('osteoporotic', 'Disease', (66, 78))
537894	23553791	Concentrations of both IFN-gamma and TNF-alpha in serum, bone marrow and derma, but not in subcutaneous fat, were markedly increased in OVX mice when compared with sham-operated mice by ELISA and immunohistochemical staining analysis (Fig.	('increased', 'PosReg', (123, 132))	('OVX', 'Var', (136, 139))	('mice', 'Species', '10090', (140, 144))	('mice', 'Species', '10090', (178, 182))	('TNF-alpha', 'Gene', (37, 46))	('OVX', 'Chemical', '-', (136, 139))
537909	23553791	To clarify this, we first systemically administered either IFN-gamma or TNF-alpha neutralizing antibody to OVX mice to test whether depletion of IFN-gamma or TNF-alpha could prevent OVX-induced MSC deficiency.	('depletion', 'Var', (132, 141))	('OVX', 'Chemical', '-', (107, 110))	('MSC deficiency', 'Disease', (194, 208))	('MSC deficiency', 'Disease', 'MESH:D007153', (194, 208))	('mice', 'Species', '10090', (111, 115))	('OVX', 'Chemical', '-', (182, 185))
537930	23553791	When NFkappaB expression was knocked down by IKKalpha siRNA, IFN-gamma/TNF-alpha-induced upregulation of SMAD7 and downregulation of p-SMAD1, RUNX2, and ALP were abolished, leading to the rescue of IFN-gamma/TNF-alpha-induced reduction of mineralized nodule formation in BMMSCs (Fig.	('ALP', 'Disease', (153, 156))	('knocked', 'Var', (29, 36))	('NFkappaB', 'Gene', '18033', (5, 13))	('RUNX2', 'Gene', '12393', (142, 147))	('ALP', 'Disease', 'MESH:D050197', (153, 156))	('MSC', 'Gene', '17681', (273, 276))	('MSC', 'Gene', (273, 276))	('RUNX2', 'Gene', (142, 147))	('reduction', 'NegReg', (226, 235))	('SMAD1', 'Gene', '17125', (135, 140))	('IKKalpha', 'Gene', (45, 53))	('IKKalpha', 'Gene', '12675', (45, 53))	('SMAD1', 'Gene', (135, 140))	('SMAD7', 'Gene', (105, 110))	('SMAD7', 'Gene', '17131', (105, 110))	('NFkappaB', 'Gene', (5, 13))
537933	23553791	Combination knockdown of IFNGRalpha and TNFR1 resulted in marked inhibition of IFN-gamma-/TNF-alpha-induced activation of NFkappaB pathway when compared with knockdown of TNFR1 alone, suggesting that IFN-gamma activates TNF-alpha-induced NFkappaB activation via IFNGRalpha (Supporting Information Fig.	('inhibition', 'NegReg', (65, 75))	('TNFR1', 'Gene', '21938', (40, 45))	('NFkappaB', 'Gene', (122, 130))	('knockdown', 'Var', (12, 21))	('TNFR1', 'Gene', '21938', (171, 176))	('NFkappaB', 'Gene', '18033', (122, 130))	('NFkappaB', 'Gene', (238, 246))	('activation', 'PosReg', (247, 257))	('TNFR1', 'Gene', (40, 45))	('NFkappaB', 'Gene', '18033', (238, 246))	('TNFR1', 'Gene', (171, 176))
537936	23553791	We confirmed the efficiency of IKKalpha, IFNGRalpha, TNFR1, STAT-1 and SMAD7 knockdown by their specific siRNAs using Western blot analysis (Supporting Information Fig.	('TNFR1', 'Gene', (53, 58))	('SMAD7', 'Gene', (71, 76))	('SMAD7', 'Gene', '17131', (71, 76))	('TNFR1', 'Gene', '21938', (53, 58))	('STAT-1', 'Gene', '20846', (60, 66))	('knockdown', 'Var', (77, 86))	('IKKalpha', 'Gene', '12675', (31, 39))	('STAT-1', 'Gene', (60, 66))	('IKKalpha', 'Gene', (31, 39))	('IFNGRalpha', 'Gene', (41, 51))
537937	23553791	Additionally, knockdown of SMAD7 expression by siRNA assay resulted in rescuing TNF-alpha-/IFN-gamma-induced reduction of mineralized nodule formation and downregulation of p-SMAD1, RUNX2, and ALP in BMMSCs and DMSCs, without affecting p-IkappaB and p-NFkappaB (Supporting Information Fig.	('RUNX2', 'Gene', '12393', (182, 187))	('ALP', 'Disease', 'MESH:D050197', (193, 196))	('NFkappaB', 'Gene', '18033', (252, 260))	('reduction', 'NegReg', (109, 118))	('mineralized nodule formation', 'CPA', (122, 150))	('MSC', 'Gene', (212, 215))	('MSC', 'Gene', '17681', (202, 205))	('ALP', 'Disease', (193, 196))	('DMSCs', 'Chemical', '-', (211, 216))	('NFkappaB', 'Gene', (252, 260))	('SMAD7', 'Gene', (27, 32))	('downregulation', 'NegReg', (155, 169))	('MSC', 'Gene', (202, 205))	('SMAD1', 'Gene', (175, 180))	('RUNX2', 'Gene', (182, 187))	('SMAD7', 'Gene', '17131', (27, 32))	('SMAD1', 'Gene', '17125', (175, 180))	('MSC', 'Gene', '17681', (212, 215))	('knockdown', 'Var', (14, 23))	('TNF-alpha-/IFN-gamma-induced', 'Gene', (80, 108))
537941	23553791	Moreover, either IFN-gamma or TNF-alpha neutralizing antibody treatment in vivo was sufficient to downregulate NFkappaB pathway in BMMSCs to the level observed in the sham-operated group (Fig.	('NFkappaB', 'Gene', '18033', (111, 119))	('downregulate', 'NegReg', (98, 110))	('MSC', 'Gene', '17681', (133, 136))	('men', 'Species', '9606', (67, 70))	('MSC', 'Gene', (133, 136))	('NFkappaB', 'Gene', (111, 119))	('neutralizing antibody', 'Var', (40, 61))
537945	23553791	Interestingly, ELISA showed that both IFN-gamma and TNF-alpha concentration in serum remained markedly higher in OVX mice when compared with sham-operated mice (Fig.	('TNF-alpha concentration', 'MPA', (52, 75))	('mice', 'Species', '10090', (117, 121))	('OVX', 'Chemical', '-', (113, 116))	('mice', 'Species', '10090', (155, 159))	('higher', 'PosReg', (103, 109))	('OVX', 'Var', (113, 116))
537947	23553791	To confirm that such higher susceptibility of tumorigenesis involves MSCs, we locally applied 3-methycholanthrene (MCA) as a carcinogen to induce osteosarcoma, and found that the MCA-treated OVX mice showed a higher incidence of sarcoma with earlier sarcoma occurrence in femurs when compared with sham-operated mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('OVX', 'Chemical', '-', (191, 194))	('sarcoma', 'Disease', (229, 236))	('MSC', 'Gene', '17681', (69, 72))	('3-methycholanthrene', 'Chemical', '-', (94, 113))	('MSC', 'Gene', (69, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('mice', 'Species', '10090', (195, 199))	('sarcoma', 'Disease', 'MESH:D012509', (250, 257))	('MCA-treated', 'Var', (179, 190))	('osteosarcoma', 'Disease', (146, 158))	('osteosarcoma', 'Disease', 'MESH:D012516', (146, 158))	('sarcoma', 'Disease', (250, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('mice', 'Species', '10090', (312, 316))	('MCA', 'Chemical', '-', (179, 182))	('tumor', 'Disease', (46, 51))	('MCA', 'Chemical', '-', (115, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (250, 257))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (146, 158))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('sarcoma', 'Disease', (151, 158))
537960	23553791	6C), but that knockdown of NFkappaB by IKKalpha siRNA assay was able to abolish the elevation in c-MYC and c-FOS (Fig.	('c-FOS', 'Gene', (107, 112))	('abolish', 'NegReg', (72, 79))	('NFkappaB', 'Gene', (27, 35))	('IKKalpha', 'Gene', (39, 47))	('c-FOS', 'Gene', '14281', (107, 112))	('IKKalpha', 'Gene', '12675', (39, 47))	('NFkappaB', 'Gene', '18033', (27, 35))	('c-MYC', 'MPA', (97, 102))	('knockdown', 'Var', (14, 23))
537982	23553791	Blockage of either IFN-gamma or TNF-alpha with their neutralizing antibodies in vivo is sufficient to effectively rescue MSC deficiency.	('Blockage', 'Var', (0, 8))	('TNF-alpha', 'Protein', (32, 41))	('MSC deficiency', 'Disease', (121, 135))	('MSC deficiency', 'Disease', 'MESH:D007153', (121, 135))
537992	23553791	In this study, we demonstrated that IFN-gamma binds its receptor IFNGR1 to strongly enhance TNF-alpha/TNFR1-upregulated NFkappaB, which, in turn, mediates inhibitory SMAD7 to downregulate the osteogenic master gene Runx2 and, hence, induce osteogenic deficiency in MSCs, both in vivo and in vitro.	('Runx2', 'Gene', '12393', (215, 220))	('induce', 'Reg', (233, 239))	('TNFR1', 'Gene', '21938', (102, 107))	('NFkappaB', 'Gene', (120, 128))	('SMAD7', 'Gene', (166, 171))	('downregulate', 'NegReg', (175, 187))	('SMAD7', 'Gene', '17131', (166, 171))	('NFkappaB', 'Gene', '18033', (120, 128))	('MSC', 'Gene', '17681', (265, 268))	('osteogenic deficiency', 'Disease', (240, 261))	('osteogenic deficiency', 'Disease', 'MESH:D012516', (240, 261))	('Runx2', 'Gene', (215, 220))	('IFNGR1', 'Gene', '15979', (65, 71))	('inhibitory', 'Var', (155, 165))	('enhance', 'PosReg', (84, 91))	('TNFR1', 'Gene', (102, 107))	('MSC', 'Gene', (265, 268))	('IFNGR1', 'Gene', (65, 71))
538038	23061012	Immunohistochemistry typically showed positivity toward S-100 [Figure 4], CD68 [Figure 5], and particularly lysozyme [Figure 6] and was negative for CD1a, CD21, langerin suggesting the final diagnosis as histiocytic sarcoma.	('langerin', 'Gene', (161, 169))	('CD1a', 'Gene', (149, 153))	('langerin', 'Gene', '50489', (161, 169))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (204, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('positivity', 'Var', (38, 48))	('CD21', 'Gene', (155, 159))	('S-100', 'Protein', (56, 61))	('histiocytic sarcoma', 'Disease', (204, 223))	('CD21', 'Gene', '1380', (155, 159))	('CD68', 'Gene', (74, 78))	('CD68', 'Gene', '968', (74, 78))	('CD1a', 'Gene', '909', (149, 153))	('S-100', 'Chemical', '-', (56, 61))	('lysozyme', 'Gene', (108, 116))	('lysozyme', 'Gene', '4069', (108, 116))
538061	32967265	EMC is an ultra-rare sarcoma sub-type, more often arising from the soft tissues, marked by specific molecular features consisting in rearrangement of the NR4A3 gene, identified in recent years and very useful to distinguish EMC from other mimics.	('sarcoma sub-type', 'Disease', 'MESH:D012509', (21, 37))	('NR4A3', 'Gene', (154, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('NR4A3', 'Gene', '8013', (154, 159))	('sarcoma sub-type', 'Disease', (21, 37))	('EMC', 'Disease', (0, 3))	('EMC', 'Disease', (224, 227))	('rearrangement', 'Var', (133, 146))
538080	32967265	Gene fusions involving NR4A3 and leading to NR4A3 constitutive expression have to date been described exclusively in EMC and are therefore considered a hallmark of this disease.	('NR4A3', 'Gene', '8013', (44, 49))	('Gene fusions', 'Var', (0, 12))	('described', 'Reg', (92, 101))	('constitutive expression', 'MPA', (50, 73))	('EMC', 'Disease', (117, 120))	('NR4A3', 'Gene', '8013', (23, 28))	('NR4A3', 'Gene', (23, 28))	('NR4A3', 'Gene', (44, 49))
538082	32967265	The positivity for NR4A3 rearrangements may be particularly helpful in the differential diagnosis of EMC mimics such as myoepithelioma and myoepithelial carcinoma.	('myoepithelioma and myoepithelial carcinoma', 'Disease', 'MESH:D009208', (120, 162))	('art', 'Gene', (48, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('positivity', 'Var', (4, 14))	('rearrangements', 'Var', (25, 39))	('art', 'Gene', '181', (48, 51))	('NR4A3', 'Gene', (19, 24))	('NR4A3', 'Gene', '8013', (19, 24))
538083	32967265	Typically, in EMC translocations, NR4A3 breaks in proximity to the ATG start site and translocates, with its whole coding sequence, downstream of the partner gene that, in general, contributes with a strong promoter and part of the N-terminus (Figure 2).	('art', 'Gene', (73, 76))	('NR4A3', 'Gene', (34, 39))	('translocations', 'Var', (18, 32))	('art', 'Gene', (221, 224))	('promoter', 'MPA', (207, 215))	('NR4A3', 'Gene', '8013', (34, 39))	('art', 'Gene', '181', (151, 154))	('EMC', 'Disease', (14, 17))	('art', 'Gene', '181', (73, 76))	('art', 'Gene', (151, 154))	('art', 'Gene', '181', (221, 224))
538094	32967265	However, the specific biological properties of the diverse NR4A3 fusion variants are poorly defined.	('NR4A3', 'Gene', '8013', (59, 64))	('variants', 'Var', (72, 80))	('NR4A3', 'Gene', (59, 64))
538129	32967265	Of note, in all these series, the pathologic diagnosis of EMC was not molecularly supported by the detection of NR4A3 translocation events.	('translocation events', 'Var', (118, 138))	('NR4A3', 'Gene', (112, 117))	('EMC', 'Disease', (58, 61))	('NR4A3', 'Gene', '8013', (112, 117))
538141	32967265	Insulin-like growth factor receptor 1 (IGFR1) inhibitors also showed a certain degree of clinical activity in EMC.	('Insulin-like growth factor receptor 1', 'Gene', (0, 37))	('inhibitors', 'Var', (46, 56))	('IGFR1', 'Gene', (39, 44))	('EMC', 'Disease', (110, 113))	('Insulin-like growth factor receptor 1', 'Gene', '100132417', (0, 37))	('IGFR1', 'Gene', '100132417', (39, 44))
538171	28390819	YWHAE-Rearranged High-Grade Endometrial Stromal Sarcoma: Two-Center Case Series and Response to Chemotherapy YWHAE-rearranged high-grade endometrial stromal sarcoma (HG-ESS) is a rare, recently defined uterine sarcoma harboring t(10;17)(q22;p13) resulting in YWHAE-NUTM2A/B fusion.	('YWHAE', 'Gene', (0, 5))	('Endometrial Stromal Sarcoma', 'Disease', (28, 55))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('Endometrial Stromal Sarcoma', 'Disease', 'MESH:D018203', (28, 55))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (202, 217))	('YWHAE', 'Gene', '7531', (0, 5))	('t(10;17)(q22;p13', 'Var', (228, 244))	('sarcoma', 'Disease', (157, 164))	('endometrial stromal sarcoma', 'Disease', (137, 164))	('Sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('YWHAE', 'Gene', (259, 264))	('sarcoma', 'Disease', 'MESH:D012509', (210, 217))	('NUTM2A/B', 'Gene', '728118;729262', (265, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('sarcoma', 'Disease', (210, 217))	('YWHAE', 'Gene', (109, 114))	('YWHAE', 'Gene', '7531', (259, 264))	('YWHAE', 'Gene', '7531', (109, 114))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (228, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('NUTM2A/B', 'Gene', (265, 273))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (137, 164))
538175	28390819	Cytogenetics or fluorescence in situ hybridization were performed in all cases to confirm rearrangement and, in conjunction with histopathology, a diagnosis of YWHAE-rearranged HG-ESS.	('YWHAE', 'Gene', (160, 165))	('rearrangement', 'Var', (90, 103))	('YWHAE', 'Gene', '7531', (160, 165))
538189	28390819	High-grade ESS (HG-ESS), harboring t(10;17)(q22;p13) resulting in YWHAE-NUTM2A/B fusion, is a recently described and more aggressive neoplasm with a poorer prognosis compared to its low-grade counterpart.	('YWHAE', 'Gene', '7531', (66, 71))	('aggressive neoplasm', 'Disease', 'MESH:D001523', (122, 141))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (35, 52))	('aggressive neoplasm', 'Disease', (122, 141))	('t(10;17)(q22;p13', 'Var', (35, 51))	('YWHAE', 'Gene', (66, 71))	('NUTM2A/B', 'Gene', (72, 80))	('neoplasm', 'Phenotype', 'HP:0002664', (133, 141))	('NUTM2A/B', 'Gene', '728118;729262', (72, 80))
538196	28390819	The fusion between BRD4 or BRD3 genes to NUTM1 on chromosome 15 has been well described as the causative lesion in NUT midline carcinoma.	('BRD4', 'Gene', (19, 23))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (115, 136))	('fusion', 'Var', (4, 10))	('NUTM1', 'Gene', '256646', (41, 46))	('NUT midline carcinoma', 'Disease', (115, 136))	('BRD4', 'Gene', '23476', (19, 23))	('BRD3', 'Gene', '8019', (27, 31))	('NUTM1', 'Gene', (41, 46))	('BRD3', 'Gene', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
538212	28390819	Pathology slides and reports were retrospectively reviewed by two gynecologic pathologists and t(10;17)(q22;p13) YWHAE rearrangement confirmed by cytogenetics or fluorescence in-situ hybridization (FISH) with break-apart probes flanking the YWHAE gene.	('YWHAE', 'Gene', (113, 118))	('rearrangement', 'Var', (119, 132))	('YWHAE', 'Gene', (241, 246))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (95, 112))	('YWHAE', 'Gene', '7531', (113, 118))	('YWHAE', 'Gene', '7531', (241, 246))
538237	28390819	The unique course and treatment responses of this malignancy merit pathologic evaluation to confirm the presence of the t(10;17)(q22;p13) translocation in cases of suspected HG-ESS.	('t(10;17)(q22;p13', 'Var', (120, 136))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (120, 137))	('HG-ESS', 'Disease', (174, 180))	('malignancy', 'Disease', 'MESH:D009369', (50, 60))	('malignancy', 'Disease', (50, 60))
538247	28390819	The pathogenic t(10;17) fusion of the YWHAE and NUTM2A/B genes leads to an oncoprotein of unclear function.	('YWHAE', 'Gene', (38, 43))	('fusion', 'Var', (24, 30))	('leads to', 'Reg', (63, 71))	('NUTM2A/B', 'Gene', (48, 56))	('pathogenic', 'Reg', (4, 14))	('oncoprotein', 'MPA', (75, 86))	('YWHAE', 'Gene', '7531', (38, 43))	('t(10;17', 'Gene', (15, 22))	('NUTM2A/B', 'Gene', '728118;729262', (48, 56))
538248	28390819	Limited investigation to date has determined that the fusion protein leads to abnormal localization of 14-3-3epsilon to the nucleus and enhanced cell growth and migration in vitro.	('fusion', 'Var', (54, 60))	('14-3-3epsilon', 'Gene', '7531', (103, 116))	('enhanced', 'PosReg', (136, 144))	('localization', 'MPA', (87, 99))	('14-3-3epsilon', 'Gene', (103, 116))
538267	27351911	Cell free circulating tumor DNA (ctDNA) has been explored as a biomarker in multiple cancer types in both plasma and serum, and most applications of this technology have focused on developing a "liquid biopsy", using ctDNA to detect de novo mutations and clonal evolution in heterogeneous tumors in order to direct therapy.	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (289, 294))	('cancer', 'Disease', (85, 91))	('tumors', 'Disease', (289, 295))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('tumor', 'Disease', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (241, 250))
538330	27351911	Using this information, we were able to sensitively detect tumor specific translocation breakpoint ptDNA fragments from patients and in a murine preclinical model.	('translocation breakpoint', 'Var', (74, 98))	('breakpoint', 'Var', (88, 98))	('tumor', 'Disease', (59, 64))	('clinical', 'Species', '191496', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('patients', 'Species', '9606', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('ptDNA', 'Gene', (99, 104))	('murine', 'Species', '10090', (138, 144))
538336	27351911	Moreover, since mutations detected by NGS are heterogeneous within tumors and can be affected by clonal evolution, there is advantage to focusing on the EWS-ETS breakpoint if the goal is to develop a biomarker of disease burden and to identify patients with radiographically undetectable disease.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (16, 25))	('affected', 'Reg', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EWS', 'Gene', '2130', (153, 156))	('EWS', 'Gene', (153, 156))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (244, 252))	('tumors', 'Disease', (67, 73))
538367	26339516	Reconstruction of Radiated Gluteal Defects following Sarcoma Resection with Pedicled Sensate Tensor Fascia Lata Flaps Sarcomas of the gluteal region often result in sizable defects following resection that are challenging to reconstruct due to their location, particularly in patients who have received radiation therapy.	('result in', 'Reg', (155, 164))	('patients', 'Species', '9606', (276, 284))	('Sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('Tensor Fascia Lata Flaps', 'Disease', 'MESH:D000070600', (93, 117))	('Sarcomas', 'Disease', (118, 126))	('Sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('defects', 'Var', (173, 180))	('Radiated Gluteal Defects', 'Disease', (18, 42))	('Sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('Sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('Radiated Gluteal Defects', 'Disease', 'MESH:D004194', (18, 42))	('Sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('Sarcoma', 'Disease', 'MESH:D012509', (118, 125))	('Sarcoma', 'Disease', (118, 125))	('Tensor Fascia Lata Flaps', 'Disease', (93, 117))	('Sarcoma', 'Disease', (53, 60))
538391	26339516	Tumor ablation resulted in a 22 x 17 cm defect spanning from the posterior aspect of the greater trochanter to the sacrotuberous ligament and included resection of the gluteus maximus muscle, thereby exposing the sciatic nerve.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sacrotuberous', 'Disease', 'None', (115, 128))	('defect', 'Var', (40, 46))	('exposing', 'Reg', (200, 208))	('greater trochanter', 'Phenotype', 'HP:0002822', (89, 107))	('sacrotuberous', 'Disease', (115, 128))
211338	32440057	ES tumors often express a balanced translocation involving the EWS gene on chromosome 22 and a member of the ETS family of transcription factors.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('EWS', 'Gene', '2130', (63, 66))	('EWS', 'Gene', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('balanced translocation', 'Var', (26, 48))
538502	32382331	The incidence of MS in mice and patients with TET2 deficiency was examined, and the efficiency of hypomethylating agents (HMAs) was also be evaluated.	('MS', 'Gene', '14013', (17, 19))	('patients', 'Species', '9606', (32, 40))	('HMAs', 'Chemical', '-', (122, 126))	('hypomethylating agents', 'Chemical', '-', (98, 120))	('TET2', 'Gene', (46, 50))	('deficiency', 'Var', (51, 61))	('mice', 'Species', '10090', (23, 27))
538503	32382331	A total of 93% of the TET2-/- mice developed myeloid malignancies, 5.5% of which were accompanied by MS (n=11).	('mice', 'Species', '10090', (30, 34))	('TET2-/-', 'Var', (22, 29))	('myeloid malignancies', 'Disease', (45, 65))	('developed', 'PosReg', (35, 44))	('MS', 'Gene', '14013', (101, 103))	('myeloid malignancies', 'Disease', 'MESH:D009369', (45, 65))
538507	32382331	In the clinical setting, 9.7% of MDS and 11.6% of AML patients with TET2 deficiency developed MS, which was higher compared with previous reports (1.5-9.1%).	('MS', 'Gene', '14013', (94, 96))	('AML', 'Disease', 'MESH:D015470', (50, 53))	('patients', 'Species', '9606', (54, 62))	('AML', 'Phenotype', 'HP:0004808', (50, 53))	('MDS', 'Disease', 'MESH:D009190', (33, 36))	('MDS', 'Phenotype', 'HP:0002863', (33, 36))	('AML', 'Disease', (50, 53))	('deficiency', 'Var', (73, 83))	('MDS', 'Disease', (33, 36))	('TET2', 'Gene', (68, 72))	('developed', 'Reg', (84, 93))
538510	32382331	These data indicate that TET2 deficiency plays a key role in MS and its prognostic significance requires further investigation.	('TET2', 'Gene', (25, 29))	('MS', 'Gene', '14013', (61, 63))	('deficiency', 'Var', (30, 40))
538511	32382331	HMAs may be a useful treatment for MS patients with TET2 mutations.	('MS', 'Gene', '14013', (35, 37))	('TET2', 'Gene', (52, 56))	('HMAs', 'Chemical', '-', (0, 4))	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (38, 46))
538518	32382331	A variety of chromosomal disorders and mutations, such as the most commonly reported t(8;21) translocation and 11q23 abnormalities, are associated with a higher incidence of MS both at presentation and at relapse, indicating a poor response and relapse risk.	('chromosomal disorders', 'Disease', 'MESH:D025063', (13, 34))	('translocation', 'Var', (93, 106))	('chromosomal disorders', 'Disease', (13, 34))	('t(8;21', 'Gene', (85, 91))	('11q23', 'Gene', (111, 116))	('MS', 'Gene', '14013', (174, 176))
538522	32382331	However, no randomized trials to date have addressed the optimal treatment for MS patients with ten-eleven translocation (TET)2 deficiency.	('TET)2', 'Gene', (122, 127))	('deficiency', 'Var', (128, 138))	('MS', 'Gene', '14013', (79, 81))	('patients', 'Species', '9606', (82, 90))
538524	32382331	In addition, loss-of-function mutations of TET2 have been detected in patients with MS.	('patients', 'Species', '9606', (70, 78))	('loss-of-function', 'NegReg', (13, 29))	('MS', 'Gene', '14013', (84, 86))	('mutations', 'Var', (30, 39))	('TET2', 'Gene', (43, 47))
538528	32382331	To determine the complete spectrum of MS caused by TET2 loss in vivo, a 2-year follow-up study on a cohort of 214 TET2-/- and 67 wild-type (WT) mice was conducted.	('TET2-/-', 'Var', (114, 121))	('TET2', 'Gene', (51, 55))	('loss', 'NegReg', (56, 60))	('mice', 'Species', '10090', (144, 148))	('MS', 'Gene', '14013', (38, 40))
538546	32382331	In addition, mice with sarcoma (n=5) were injected with 5-Aza-dC daily over a period of 4 weeks and followed up for an additional 8 weeks.	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (56, 64))	('mice', 'Species', '10090', (13, 17))	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('sarcoma', 'Disease', (23, 30))	('5-Aza-dC', 'Var', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))
538554	32382331	In particular, MS patients with TET2 deficiency were closely examined and the effect of decitabine was assessed.	('TET2', 'Gene', (32, 36))	('decitabine', 'Chemical', 'MESH:D000077209', (88, 98))	('MS', 'Gene', '14013', (15, 17))	('patients', 'Species', '9606', (18, 26))	('deficiency', 'Var', (37, 47))
538589	32382331	These data indicated the effectiveness of 5-Aza-dC for TET2-/- myeloid malignancies, and its potential value in the treatment MS. A total of 436 MDS and 354 AML patients were included in the present study (Tables I and II).	('MDS', 'Disease', (145, 148))	('MDS', 'Disease', 'MESH:D009190', (145, 148))	('MDS', 'Phenotype', 'HP:0002863', (145, 148))	('myeloid malignancies', 'Disease', (63, 83))	('AML', 'Disease', 'MESH:D015470', (157, 160))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (42, 50))	('patients', 'Species', '9606', (161, 169))	('MS', 'Gene', '14013', (126, 128))	('5-Aza-dC', 'Var', (42, 50))	('myeloid malignancies', 'Disease', 'MESH:D009369', (63, 83))	('AML', 'Disease', (157, 160))	('AML', 'Phenotype', 'HP:0004808', (157, 160))
538591	32382331	A total of 72 MDS patients (16.5%) and 52 AML patients (14.7%) harbored TET2 deficiency with complete information, among whom 8.7% (n=6) of MDS patients and 9.6% (n=5) of AML patients developed MS in the soft tissue (n=6), skin (n=2), oral cavity (n=3) and breast (n=2).	('MDS', 'Disease', (14, 17))	('patients', 'Species', '9606', (46, 54))	('AML', 'Disease', 'MESH:D015470', (42, 45))	('MDS', 'Disease', (140, 143))	('AML', 'Phenotype', 'HP:0004808', (42, 45))	('deficiency', 'Var', (77, 87))	('AML', 'Disease', (42, 45))	('harbored', 'Reg', (63, 71))	('MDS', 'Phenotype', 'HP:0002863', (14, 17))	('patients', 'Species', '9606', (18, 26))	('MDS', 'Phenotype', 'HP:0002863', (140, 143))	('MDS', 'Disease', 'MESH:D009190', (14, 17))	('TET2', 'Gene', (72, 76))	('AML', 'Disease', 'MESH:D015470', (171, 174))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (175, 183))	('AML', 'Phenotype', 'HP:0004808', (171, 174))	('MS', 'Gene', '14013', (194, 196))	('AML', 'Disease', (171, 174))	('MDS', 'Disease', 'MESH:D009190', (140, 143))
538595	32382331	Among MDS patients, those with TET2 mutation had relatively inferior outcomes (Fig.	('TET2', 'Gene', (31, 35))	('MDS', 'Phenotype', 'HP:0002863', (6, 9))	('mutation', 'Var', (36, 44))	('patients', 'Species', '9606', (10, 18))	('MDS', 'Disease', (6, 9))	('MDS', 'Disease', 'MESH:D009190', (6, 9))
538596	32382331	MDS patients with TET2 deficiency were administered with decitabine monotherapy or combined with CAG (G-CSF for priming, in combination with cytarabine of 10 mg/m2 q12 h for 14 days and aclarubicin of 20 mg/d for 4 days), and all AML patients received decitabine combined with DA (3 days of daunorubicin and 7 days of cytarabine).	('cytarabine', 'Chemical', 'MESH:D003561', (141, 151))	('MDS', 'Phenotype', 'HP:0002863', (0, 3))	('deficiency', 'Var', (23, 33))	('G-CSF', 'Gene', '1440', (102, 107))	('G-CSF', 'Gene', (102, 107))	('AML', 'Disease', 'MESH:D015470', (230, 233))	('patients', 'Species', '9606', (234, 242))	('aclarubicin', 'Chemical', 'MESH:D015250', (186, 197))	('patients', 'Species', '9606', (4, 12))	('decitabine', 'Chemical', 'MESH:D000077209', (252, 262))	('AML', 'Disease', (230, 233))	('MDS', 'Disease', 'MESH:D009190', (0, 3))	('AML', 'Phenotype', 'HP:0004808', (230, 233))	('DA', 'Chemical', 'MESH:C025953', (277, 279))	('TET2', 'Gene', (18, 22))	('CAG', 'Chemical', '-', (97, 100))	('MDS', 'Disease', (0, 3))	('cytarabine', 'Chemical', 'MESH:D003561', (318, 328))	('daunorubicin', 'Chemical', 'MESH:D003630', (291, 303))	('decitabine', 'Chemical', 'MESH:D000077209', (57, 67))
538597	32382331	Due to the limited-number of MS patients with TET2 deficiency (Table IV), we were unable to systematically assess the possible impact of TET2 on survival and further evaluate the efficacy of decitabine with or without chemotherapy for each cohort.	('patients', 'Species', '9606', (32, 40))	('MS', 'Gene', '14013', (29, 31))	('TET2', 'Gene', (46, 50))	('decitabine', 'Chemical', 'MESH:D000077209', (191, 201))	('deficiency', 'Var', (51, 61))
538601	32382331	These results suggest that decitabine monotherapy may be an effective and safe treatment option for MS patients with TET2 mutations (Table IV).	('decitabine', 'Chemical', 'MESH:D000077209', (27, 37))	('MS', 'Gene', '14013', (100, 102))	('TET2', 'Gene', (117, 121))	('mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (103, 111))
538606	32382331	Kaplan-Meier survival analysis revealed that TET2 deficiency may be an negative factor in hematological malignancies, but did not adversely affect the OS of the MS mice.	('TET2', 'Gene', (45, 49))	('MS', 'Gene', '14013', (161, 163))	('hematological malignancies', 'Phenotype', 'HP:0004377', (90, 116))	('mice', 'Species', '10090', (164, 168))	('negative', 'NegReg', (71, 79))	('hematological malignancies', 'Disease', (90, 116))	('hematological malignancies', 'Disease', 'MESH:D019337', (90, 116))	('deficiency', 'Var', (50, 60))
538608	32382331	The animal experiments demonstrated that TET2-deficient MS mice exhibited typical myeloid characteristics but not inferior survival, which indicated that TET2 mutations may not be an independent prognostic factor and may play a role with other possible co-mutations, which warrants further investigation.	('MS', 'Gene', '14013', (56, 58))	('play', 'Reg', (221, 225))	('mice', 'Species', '10090', (59, 63))	('mutations', 'Var', (159, 168))	('myeloid characteristics', 'CPA', (82, 105))	('TET2', 'Gene', (154, 158))
538609	32382331	As expected, 5-Aza-dC was successful in reducing the incidence of MS with TET2 mutation.	('TET2', 'Gene', (74, 78))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (13, 21))	('mutation', 'Var', (79, 87))	('MS', 'Gene', '14013', (66, 68))
538610	32382331	In the present study, the incidence of MS with TET2 deficiency was 11.6 and 9.7% for AML (n=6/52) and MDS patients (7/72), respectively, which is similar to the results of our animal experiment but higher than the 2.5-9.1% of patients with AML in other reports.	('AML', 'Phenotype', 'HP:0004808', (240, 243))	('AML', 'Disease', (240, 243))	('AML', 'Disease', 'MESH:D015470', (85, 88))	('MS', 'Gene', '14013', (39, 41))	('deficiency', 'Var', (52, 62))	('TET2', 'Gene', (47, 51))	('AML', 'Phenotype', 'HP:0004808', (85, 88))	('MDS', 'Disease', 'MESH:D009190', (102, 105))	('AML', 'Disease', (85, 88))	('patients', 'Species', '9606', (226, 234))	('AML', 'Disease', 'MESH:D015470', (240, 243))	('patients', 'Species', '9606', (106, 114))	('MDS', 'Phenotype', 'HP:0002863', (102, 105))	('MDS', 'Disease', (102, 105))
538621	32382331	To summarize, it was deduced that decitabine may be an effective and safe treatment option for MS patients with TET2 mutations.	('mutations', 'Var', (117, 126))	('patients', 'Species', '9606', (98, 106))	('MS', 'Gene', '14013', (95, 97))	('TET2', 'Gene', (112, 116))	('decitabine', 'Chemical', 'MESH:D000077209', (34, 44))
538622	32382331	Based on the results of the animal experiments and patient validation, it was concluded that TET2 deficiency plays a role in MS and its prognostic significance requires further investigation.	('deficiency', 'Var', (98, 108))	('TET2', 'Gene', (93, 97))	('patient', 'Species', '9606', (51, 58))	('MS', 'Gene', '14013', (125, 127))
538627	32382331	A larger sample size and more accurate studies are required to identify and interpret these differences and their implications, providing new insights into a potential target for therapeutic intervention in MS. To the best of our knowledge, the association of TET2 abnormalities with MS has not been previously explored.	('abnormalities', 'Var', (265, 278))	('MS', 'Gene', '14013', (284, 286))	('TET2', 'Gene', (260, 264))	('MS', 'Gene', '14013', (207, 209))
538629	32382331	In conclusion, TET2 deficiency appears to have an impact on MS and its prognostic significance must be further investigated, as it may be a potential treatment biomarker for MS patients.	('impact', 'Reg', (50, 56))	('deficiency', 'Var', (20, 30))	('patients', 'Species', '9606', (177, 185))	('TET2', 'Gene', (15, 19))	('MS', 'Gene', '14013', (60, 62))	('MS', 'Gene', '14013', (174, 176))
538631	32382331	A larger data registry and more controlled clinical correlative studies are required to more accurately assess the effect of TET2 deficiency on the prognosis, diagnosis, and therapeutic relevance of MS and the role of HMAs in the treatment of MS.	('HMAs', 'Chemical', '-', (218, 222))	('deficiency', 'Var', (130, 140))	('TET2', 'Gene', (125, 129))	('MS', 'Gene', '14013', (243, 245))	('MS', 'Gene', '14013', (199, 201))
538657	32382698	For cancers like BL (9687/3), HL (9650/3), NHL (9596/3), adult T-cell leukemia (9827/3), KS (9140/3), acute leukemia (9835/3 & 9861/3), chronic leukemia (9863/3 & 9823/3) and multiple myeloma (9732/3) where ICD-0-3 topographical code was not clear, we converted the IDC-0-3 morphological code to ICD10 topographical code for clarity.	('9827/3', 'Var', (80, 86))	('acute leukemia', 'Phenotype', 'HP:0002488', (102, 116))	('multiple myeloma', 'Phenotype', 'HP:0006775', (175, 191))	('adult T-cell leukemia', 'Disease', 'MESH:D015459', (57, 78))	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('myeloma', 'Disease', (184, 191))	('chronic leukemia', 'Phenotype', 'HP:0005558', (136, 152))	('adult T-cell leukemia', 'Disease', (57, 78))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('myeloma', 'Disease', 'MESH:D009101', (184, 191))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('acute leukemia', 'Disease', 'MESH:D015470', (102, 116))	('acute leukemia', 'Disease', (102, 116))	('9835/3 & 9861/3', 'Var', (118, 133))
538658	32382698	Although many studies have shown a variety of cancers associated with infectious agents, the attributable fraction (AF) standard formula was applied to a group of cancers classified as carcinogenic in the IARC monograph 100b  namely; cervix (C53), liver (C22.0), stomach (C16), Kaposi's sarcoma (C46), non-Hodgkin's lymphoma (C82-85, C96), Hodgkin's lymphoma (C81), nasopharynx (C11), oropharynx (C10), bladder (C67), vulva (C51), vagina (C52), penis (C60), anus (C21) and bile duct (C22.1).	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (302, 324))	('C10', 'Gene', '113246', (397, 400))	('C11', 'Gene', (379, 382))	('C51', 'Var', (425, 428))	('C10', 'Gene', (397, 400))	('C21', 'Gene', '79718', (464, 467))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (278, 294))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (306, 324))	("Hodgkin's lymphoma", 'Disease', (340, 358))	('lymphoma', 'Phenotype', 'HP:0002665', (350, 358))	('C60', 'Var', (452, 455))	("non-Hodgkin's lymphoma", 'Disease', (302, 324))	('C11', 'Gene', '1109', (379, 382))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('C53', 'Gene', '80279', (242, 245))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('C82', 'Gene', (326, 329))	('lymphoma', 'Phenotype', 'HP:0002665', (316, 324))	('AF', 'Disease', 'MESH:D001281', (116, 118))	('C67', 'Var', (412, 415))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('C82', 'Gene', '732', (326, 329))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('C21', 'Gene', (464, 467))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (340, 358))	('C53', 'Gene', (242, 245))
538722	32015927	Pathological examination revealed a T2 N0 M0 grade 1 invasive ductal carcinoma with 14 examined lymph nodes showing no evidence of metastases.	('invasive ductal carcinoma', 'Disease', 'MESH:D044584', (53, 78))	('metastases', 'Disease', (131, 141))	('metastases', 'Disease', 'MESH:D009362', (131, 141))	('T2 N0 M0', 'Var', (36, 44))	('invasive ductal carcinoma', 'Disease', (53, 78))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (62, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
538754	32015927	Similar to sarcomas arising at other locations, POSB tends to be locally aggressive tumours with a propensity to spread via the blood as opposed to the characteristic lymphatic spread observed in carcinoma of the breast.	('POSB', 'Var', (48, 52))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('aggressive tumours', 'Disease', 'MESH:D001523', (73, 91))	('sarcomas', 'Disease', (11, 19))	('aggressive tumours', 'Disease', (73, 91))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (196, 219))	('carcinoma of the breast', 'Disease', 'MESH:D001943', (196, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('carcinoma of the breast', 'Disease', (196, 219))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
538757	32015927	In the most extensive series of patients with POSB, 20 patients underwent axillary lymph node dissection, all of which were negative for metastases.	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('patients', 'Species', '9606', (32, 40))	('POSB', 'Var', (46, 50))	('axillary lymph node dissection', 'CPA', (74, 104))	('metastases', 'Disease', (137, 147))	('patients', 'Species', '9606', (55, 63))	('underwent', 'Reg', (64, 73))
538764	26289771	Ovarian Tumors related to Intronic Mutations in DICER1: A Report from the International Ovarian and Testicular Stromal Tumor Registry Germline DICER1 mutations have been described in individuals with pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumor (SLCT), sarcomas, multinodular goiter, thyroid carcinoma, cystic nephroma and other neoplastic conditions.	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (200, 224))	('Testicular Stromal Tumor', 'Disease', (100, 124))	('pleuropulmonary blastoma', 'Disease', (200, 224))	('Tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (240, 265))	('Tumor', 'Phenotype', 'HP:0002664', (119, 124))	('described', 'Reg', (170, 179))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (305, 322))	('Ovarian Tumors', 'Phenotype', 'HP:0100615', (0, 14))	('sarcomas', 'Disease', 'MESH:D012509', (274, 282))	('mutations', 'Var', (150, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (274, 282))	('goiter', 'Phenotype', 'HP:0000853', (297, 303))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('thyroid carcinoma', 'Disease', (305, 322))	('multinodular goiter', 'Disease', (284, 303))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (200, 224))	('sarcomas', 'Disease', (274, 282))	('multinodular goiter', 'Phenotype', 'HP:0005987', (284, 303))	('DICER1', 'Gene', '23405', (48, 54))	('PPB', 'Phenotype', 'HP:0100528', (226, 229))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (305, 322))	('ovarian Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (232, 265))	('ovarian Sertoli-Leydig cell tumor', 'Disease', (232, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('cystic nephroma', 'Disease', (324, 339))	('Testicular Stromal Tumor', 'Disease', 'MESH:D013736', (100, 124))	('DICER1', 'Gene', (48, 54))	('Ovarian Tumors', 'Disease', (0, 14))	('DICER1', 'Gene', '23405', (143, 149))	('multinodular goiter', 'Disease', 'MESH:C564546', (284, 303))	('cystic nephroma', 'Disease', 'MESH:D018201', (324, 339))	('Ovarian Tumors', 'Disease', 'MESH:D010051', (0, 14))	('SLCT', 'Phenotype', 'HP:0100619', (267, 271))	('Tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (248, 265))	('DICER1', 'Gene', (143, 149))
538765	26289771	Early results from the International Ovarian and Testicular Stromal Tumor Registry show germline DICER1 mutations in 48% of girls and women with SLCT.	('Testicular Stromal Tumor', 'Disease', 'MESH:D013736', (49, 73))	('mutations', 'Var', (104, 113))	('Tumor', 'Phenotype', 'HP:0002664', (68, 73))	('SLCT', 'Phenotype', 'HP:0100619', (145, 149))	('Testicular Stromal Tumor', 'Disease', (49, 73))	('DICER1', 'Gene', (97, 103))	('girls', 'Species', '9606', (124, 129))	('women', 'Species', '9606', (134, 139))	('DICER1', 'Gene', '23405', (97, 103))
538770	26289771	In rare patients, germline intronic mutations in DICER1 that are predicted to cause incorrect splicing can also contribute to the pathogenesis of SLCT.	('SLCT', 'Phenotype', 'HP:0100619', (146, 150))	('contribute', 'Reg', (112, 122))	('DICER1', 'Gene', (49, 55))	('DICER1', 'Gene', '23405', (49, 55))	('germline intronic mutations', 'Var', (18, 45))	('SLCT', 'Disease', (146, 150))	('patients', 'Species', '9606', (8, 16))
538771	26289771	Germline DICER1 mutations were first identified in children with pleuropulmonary blastoma (PPB), a rare but aggressive lung tumor of infancy and early childhood.	('children', 'Species', '9606', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PPB', 'Phenotype', 'HP:0100528', (91, 94))	('DICER1', 'Gene', (9, 15))	('mutations', 'Var', (16, 25))	('lung tumor', 'Disease', (119, 129))	('lung tumor', 'Disease', 'MESH:D008175', (119, 129))	('DICER1', 'Gene', '23405', (9, 15))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (65, 89))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (65, 89))	('pleuropulmonary blastoma', 'Disease', (65, 89))	('lung tumor', 'Phenotype', 'HP:0100526', (119, 129))
538772	26289771	Conditions which are now known to be associated with germline DICER1 mutations include PPB, Sertoli-Leydig cell tumor (SLCT), cystic nephroma, lung cysts, nodular hyperplasia and/or carcinoma of the thyroid gland, nasal chondromesenchymal hamartomas, embryonal rhabdomyosarcoma of the uterine cervix, ciliary body medulloepithelioma, renal sarcoma, pituitary blastoma, Wilms tumor and pineoblastoma.	('lung cyst', 'Phenotype', 'HP:0032445', (143, 152))	('cystic nephroma', 'Disease', 'MESH:D018201', (126, 141))	('Wilms tumor', 'Disease', 'MESH:D009396', (369, 380))	('renal sarcoma', 'Disease', 'MESH:D007674', (334, 347))	('nasal chondromesenchymal hamartomas', 'Disease', (214, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (270, 277))	('DICER1', 'Gene', (62, 68))	('PPB', 'Phenotype', 'HP:0100528', (87, 90))	('lung cysts', 'Disease', 'MESH:D008171', (143, 153))	('Wilms tumor', 'Phenotype', 'HP:0002667', (369, 380))	('uterine cervix', 'Phenotype', 'HP:0030160', (285, 299))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (251, 277))	('pineoblastoma', 'Disease', (385, 398))	('lung cysts', 'Disease', (143, 153))	('SLCT', 'Phenotype', 'HP:0100619', (119, 123))	('medulloepithelioma', 'Disease', (314, 332))	('carcinoma of the thyroid gland', 'Phenotype', 'HP:0100031', (182, 212))	('lung cysts', 'Phenotype', 'HP:0032445', (143, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('pituitary blastoma', 'Disease', 'MESH:D018202', (349, 367))	('nasal chondromesenchymal hamartomas', 'Disease', 'MESH:D006222', (214, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (340, 347))	('mutations', 'Var', (69, 78))	('Wilms tumor', 'Disease', (369, 380))	('renal sarcoma', 'Phenotype', 'HP:0008663', (334, 347))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (100, 117))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (251, 277))	('pituitary blastoma', 'Disease', (349, 367))	('carcinoma of the thyroid gland', 'Disease', (182, 212))	('Sertoli-Leydig cell tumor', 'Disease', (92, 117))	('DICER1', 'Gene', '23405', (62, 68))	('pineoblastoma', 'Phenotype', 'HP:0030408', (385, 398))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (261, 277))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (92, 117))	('medulloepithelioma', 'Phenotype', 'HP:0030071', (314, 332))	('Sertoli-Leydig cell tumor', 'Phenotype', 'HP:0100619', (92, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('pineoblastoma', 'Disease', 'MESH:D010871', (385, 398))	('hamartomas', 'Phenotype', 'HP:0010566', (239, 249))	('carcinoma of the thyroid gland', 'Disease', 'MESH:D013964', (182, 212))	('nodular hyperplasia', 'Disease', 'MESH:D020518', (155, 174))	('embryonal rhabdomyosarcoma', 'Disease', (251, 277))	('medulloepithelioma', 'Disease', 'MESH:D008527', (314, 332))	('cystic nephroma', 'Disease', (126, 141))	('renal sarcoma', 'Disease', (334, 347))	('nodular hyperplasia', 'Disease', (155, 174))	('PPB', 'Disease', (87, 90))
538774	26289771	Most tumors in DICER1 syndrome have one allele (often germline) harboring a nonsense or frame-shift mutation predicted to cause full loss of function (LOF) with the other allele harboring a missense mutation in the DICER1 RNase IIIb domain.	('nonsense', 'Var', (76, 84))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('frame-shift mutation', 'Var', (88, 108))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('loss', 'NegReg', (133, 137))	('DICER1', 'Gene', (215, 221))	('DICER1', 'Gene', (15, 21))	('missense mutation', 'Var', (190, 207))	('DICER1', 'Gene', '23405', (215, 221))	('DICER1', 'Gene', '23405', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
538775	26289771	This combination of mutations in both DICER1 alleles results in improperly cleaved 5p miRNAs from the pre-miRNA hairpin structures, leading to an abnormal ratio of 5p to 3p miRNAs and altering expression of downstream target mRNAs.	('DICER1', 'Gene', (38, 44))	('DICER1', 'Gene', '23405', (38, 44))	('leading to', 'Reg', (132, 142))	('cleaved', 'MPA', (75, 82))	('5p to 3p miRNAs', 'MPA', (164, 179))	('ratio', 'MPA', (155, 160))	('altering', 'Reg', (184, 192))	('expression', 'MPA', (193, 203))	('mutations', 'Var', (20, 29))
538776	26289771	Data from the International Ovarian and Testicular Stromal Tumor (OTST) Registry indicate that almost half of children and adults with SLCT have germline DICER1 mutations.	('DICER1', 'Gene', '23405', (154, 160))	('Tumor', 'Phenotype', 'HP:0002664', (59, 64))	('children', 'Species', '9606', (110, 118))	('SLCT', 'Phenotype', 'HP:0100619', (135, 139))	('Testicular Stromal Tumor', 'Disease', 'MESH:D013736', (40, 64))	('mutations', 'Var', (161, 170))	('Testicular Stromal Tumor', 'Disease', (40, 64))	('DICER1', 'Gene', (154, 160))
538777	26289771	We have also found biallelic somatic mutations in children with ovarian SLCT in absence of a germline mutation (unpublished OTST Registry data presented at Children's Oncology Group 2014 Fall Meeting).	('Fall', 'Phenotype', 'HP:0002527', (187, 191))	('biallelic', 'Var', (19, 28))	('ovarian SLCT', 'Disease', 'MESH:D010051', (64, 76))	('ovarian SLCT', 'Disease', (64, 76))	('SLCT', 'Phenotype', 'HP:0100619', (72, 76))	('children', 'Species', '9606', (50, 58))	('Children', 'Species', '9606', (156, 164))	('Oncology', 'Phenotype', 'HP:0002664', (167, 175))
538778	26289771	Here we report two young women with SLCT both of whom have a unique intronic loss of function germline mutation in DICER1 and tumor-specific RNase IIIb missense mutations.	('missense mutations', 'Var', (152, 170))	('loss of function', 'NegReg', (77, 93))	('DICER1', 'Gene', (115, 121))	('DICER1', 'Gene', '23405', (115, 121))	('SLCT', 'Phenotype', 'HP:0100619', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('women', 'Species', '9606', (25, 30))	('tumor', 'Disease', (126, 131))
538783	26289771	The participants described in this report were tested for germline DICER1 mutations using previously described methodology.	('DICER1', 'Gene', (67, 73))	('mutations', 'Var', (74, 83))	('participants', 'Species', '9606', (4, 16))	('DICER1', 'Gene', '23405', (67, 73))
538784	26289771	Initial testing for DICER1 mutations was performed by standard Sanger methods as described previously or by a commercial laboratory (Ambry Genetics, Aliso Viejo, CA).	('mutations', 'Var', (27, 36))	('Aliso', 'Species', '111540', (149, 154))	('DICER1', 'Gene', (20, 26))	('DICER1', 'Gene', '23405', (20, 26))
538800	26289771	Fourteen years following her original diagnosis, she was tested for germline DICER1 mutation.	('DICER1', 'Gene', '23405', (77, 83))	('DICER1', 'Gene', (77, 83))	('mutation', 'Var', (84, 92))
538801	26289771	Sequence results showed an intronic mutation in DICER1 (NM_177438.2:c.5096-12 G>A).	('c.5096-12 G>A', 'Var', (68, 81))	('NM_177438.2:c.5096-12 G>A', 'Mutation', 'c.5096-12G>A', (56, 81))	('DICER1', 'Gene', (48, 54))	('DICER1', 'Gene', '23405', (48, 54))
538803	26289771	The undifferentiated sarcoma showed the germline mutation and a somatic NM_177438.2:c.5125G>A; p.Asp1709Asn DICER1 RNase IIIb mutation.	('undifferentiated sarcoma', 'Disease', (4, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('DICER1', 'Gene', (108, 114))	('DICER1', 'Gene', '23405', (108, 114))	('p.Asp1709Asn', 'Var', (95, 107))	('NM_177438.2:c.5125G>A', 'Mutation', 'c.5125G>A', (72, 93))	('p.Asp1709Asn', 'Mutation', 'p.D1709N', (95, 107))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (4, 28))
538804	26289771	TP53 was also mutated in the sarcoma (NM_000546.4:c.821T>A; p.Val274Asp).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('p.Val274Asp', 'Mutation', 'rs1057520006', (60, 71))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('c.821T>A', 'Var', (50, 58))	('sarcoma', 'Disease', (29, 36))	('NM_000546.4:c.821T>A', 'Mutation', 'rs1057520006', (38, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))
538806	26289771	No TP53 mutations were detected in the SLCT.	('SLCT', 'Phenotype', 'HP:0100619', (39, 43))	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))
538809	26289771	Sequencing of this individual's SLCT showed the germline NM_177438.2:c.5096-12G>A and a somatic c.5126A>T; p.Asp1709Val.	('p.Asp1709Val', 'Mutation', 'p.D1709V', (107, 119))	('SLCT', 'Phenotype', 'HP:0100619', (32, 36))	('c.5096-12G>A', 'Var', (69, 81))	('c.5126A>T', 'Mutation', 'c.5126A>T', (96, 105))	('c.5126A>T; p.Asp1709Val', 'Var', (96, 119))	('NM_177438.2:c.5096-12G>A', 'Mutation', 'c.5096-12G>A', (57, 81))
538812	26289771	The NM_177438.2:c.5096-12 G>A germline mutation seen in these two patients results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction (Fig.	('NM_177438.2:c.5096-12 G>A', 'Mutation', 'c.5096-12G>A', (4, 29))	('duplication', 'MPA', (95, 106))	('c.5096-12 G>A', 'Var', (16, 29))	('patients', 'Species', '9606', (66, 74))
538813	26289771	Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein (NP803187.1:p.Asp1699AlaFS*8) disrupting the RNase IIIb domain.	('premature truncation', 'MPA', (96, 116))	('RNase IIIb domain', 'MPA', (177, 194))	('NP803187.1:p.Asp1699Ala', 'SUBSTITUTION', 'None', (133, 156))	('frameshift', 'Var', (81, 91))	('disrupting', 'NegReg', (162, 172))	('NP803187.1:p.Asp1699Ala', 'Var', (133, 156))
538814	26289771	Identification of germline DICER1 mutations has significant clinical importance, both for the individual with the mutation indicating risk for other sites of disease, and for relatives and potential offspring who may also carry the mutation.	('mutation', 'Var', (114, 122))	('DICER1', 'Gene', (27, 33))	('DICER1', 'Gene', '23405', (27, 33))	('mutations', 'Var', (34, 43))
538817	26289771	The finding of an underlying DICER1 mutation also has implications for surveillance for the primary ovarian tumor.	('ovarian tumor', 'Disease', 'MESH:D010051', (100, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('DICER1', 'Gene', (29, 35))	('DICER1', 'Gene', '23405', (29, 35))	('implications', 'Reg', (54, 66))	('ovarian tumor', 'Disease', (100, 113))	('ovarian tumor', 'Phenotype', 'HP:0100615', (100, 113))	('mutation', 'Var', (36, 44))
538819	26289771	Girls and women with DICER1 mutations remain at risk for metachronous ovarian tumors after the usual risk period for recurrence and should be followed with surveillance imaging, usually ultrasound, after the usual period for recurrence has ended.	('DICER1', 'Gene', (21, 27))	('Girls', 'Species', '9606', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('ovarian tumors', 'Phenotype', 'HP:0100615', (70, 84))	('DICER1', 'Gene', '23405', (21, 27))	('ovarian tumors', 'Disease', 'MESH:D010051', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('women', 'Species', '9606', (10, 15))	('mutations', 'Var', (28, 37))	('ovarian tumors', 'Disease', (70, 84))	('ovarian tumor', 'Phenotype', 'HP:0100615', (70, 83))
538820	26289771	Intronic mutations have been described in other familial cancer predisposition syndromes including defects in mismatch repair genes and Gorlin syndrome.	('Gorlin syndrome', 'Disease', (136, 151))	('described', 'Reg', (29, 38))	('familial cancer', 'Disease', (48, 63))	('defects', 'Var', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('familial cancer', 'Disease', 'MESH:D009369', (48, 63))	('mismatch repair genes', 'Gene', (110, 131))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (136, 151))	('Intronic mutations', 'Var', (0, 18))
538822	26289771	One caveat to this study is that 12 of 124 patients with PPB did not have detectable germline DICER1 mutations.	('mutations', 'Var', (101, 110))	('DICER1', 'Gene', (94, 100))	('patients', 'Species', '9606', (43, 51))	('PPB', 'Phenotype', 'HP:0100528', (57, 60))	('DICER1', 'Gene', '23405', (94, 100))
538823	26289771	While we predict that most of those 12 children will have tumor-specific biallelic mutations, we cannot rule out a deep intronic mutation not detected by our sequencing assay.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('children', 'Species', '9606', (39, 47))	('biallelic mutations', 'Var', (73, 92))
538825	26289771	Twenty individuals have tested positive for germline DICER1 mutations.	('DICER1', 'Gene', (53, 59))	('mutations', 'Var', (60, 69))	('DICER1', 'Gene', '23405', (53, 59))
538826	26289771	In this report, we describe the finding of a unique intronic mutation in two patients with SLCT, each with additional DICER1-related conditions.	('DICER1', 'Gene', (118, 124))	('SLCT', 'Disease', (91, 95))	('patients', 'Species', '9606', (77, 85))	('intronic mutation', 'Var', (52, 69))	('DICER1', 'Gene', '23405', (118, 124))	('SLCT', 'Phenotype', 'HP:0100619', (91, 95))
538829	26289771	Germline DICER1 mutations should be suspected in individuals with a personal or family history of SLCT but also in patients with juvenile granulosa cell tumor and gynandroblastoma or any ovarian stromal tumor or sarcoma and a personal or family history of nodular thyroid disease or thyroid carcinoma or other DICER1 related conditions.	('thyroid carcinoma', 'Disease', 'MESH:D013964', (283, 300))	('thyroid carcinoma', 'Disease', (283, 300))	('juvenile granulosa cell tumor', 'Disease', (129, 158))	('sarcoma', 'Disease', 'MESH:D012509', (212, 219))	('SLCT', 'Phenotype', 'HP:0100619', (98, 102))	('sarcoma', 'Disease', (212, 219))	('ovarian stromal tumor', 'Phenotype', 'HP:0031918', (187, 208))	('thyroid disease', 'Phenotype', 'HP:0000820', (264, 279))	('nodular thyroid disease', 'Disease', 'MESH:D020518', (256, 279))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (283, 300))	('mutations', 'Var', (16, 25))	('DICER1', 'Gene', '23405', (9, 15))	('nodular thyroid disease', 'Disease', (256, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('patients', 'Species', '9606', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('juvenile granulosa cell tumor', 'Disease', 'MESH:D006106', (129, 158))	('DICER1', 'Gene', (9, 15))	('DICER1', 'Gene', '23405', (310, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('gynandroblastoma or any ovarian stromal tumor', 'Disease', (163, 208))	('gynandroblastoma or any ovarian stromal tumor', 'Disease', 'MESH:C538459', (163, 208))	('SLCT', 'Disease', (98, 102))	('DICER1', 'Gene', (310, 316))	('nodular thyroid disease', 'Phenotype', 'HP:0005994', (256, 279))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
538830	26289771	Somatic testing of tumor tissue is the most sensitive way to detect DICER1 mutations which may be germline or tumor-specific.	('DICER1', 'Gene', (68, 74))	('DICER1', 'Gene', '23405', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
538831	26289771	When analyzing DICER1 mutations, it is necessary to consider the role of intronic mutations creating nonfunctional DICER1 protein.	('protein', 'Protein', (122, 129))	('DICER1', 'Gene', (115, 121))	('DICER1', 'Gene', '23405', (115, 121))	('DICER1', 'Gene', (15, 21))	('mutations', 'Var', (22, 31))	('nonfunctional', 'MPA', (101, 114))	('DICER1', 'Gene', '23405', (15, 21))
538847	26358060	Immunohistochemical stains will show positivity for smooth muscle actin and desmin in the majority of cases.	('positivity', 'Var', (37, 47))	('smooth muscle actin', 'Protein', (52, 71))	('desmin', 'Gene', '1674', (76, 82))	('desmin', 'Gene', (76, 82))
538917	26358060	A recurrent genetic aberration in EHE, including mediastinal cases, is translocation of the CAMTA1 gene on chromosome 1p and fusion with the WWTR1 gene on chromosome 3q.	('WWTR1', 'Gene', (141, 146))	('CAMTA1', 'Gene', (92, 98))	('EHE', 'Disease', (34, 37))	('WWTR1', 'Gene', '25937', (141, 146))	('EHE', 'Phenotype', 'HP:0032060', (34, 37))	('fusion', 'Var', (125, 131))	('CAMTA1', 'Gene', '23261', (92, 98))	('translocation', 'Var', (71, 84))
538955	26358060	The differential diagnosis is broad and includes eES/PNET with variant translocations and eES-like tumours unrelated to EWS (small blue round cell tumours), as well as synovial sarcomas and undifferentiated pleomorphic sarcomas with a small cell morphology.	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('variant translocations', 'Var', (63, 85))	('tumours', 'Disease', 'MESH:D009369', (147, 154))	('ES', 'Phenotype', 'HP:0012254', (50, 52))	('eES/PNET', 'Disease', (49, 57))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (168, 185))	('synovial sarcomas', 'Disease', (168, 185))	('cell tumours', 'Disease', 'MESH:C538614', (142, 154))	('cell tumours', 'Disease', (142, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (190, 227))	('undifferentiated pleomorphic sarcomas', 'Disease', (190, 227))	('synovial sarcomas', 'Disease', 'MESH:D013584', (168, 185))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (168, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('ES', 'Phenotype', 'HP:0012254', (91, 93))	('tumours', 'Disease', (99, 106))	('tumours', 'Disease', (147, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (177, 185))
538984	26358060	Variants of MPNST, which have also been reported in the mediastinum, may show divergent mesenchymal differentiation with components of skeletal muscle (rhabdomyosarcoma, the so-called Triton tumour), osteosarcoma and chondrosarcoma.	('MPNST', 'Phenotype', 'HP:0100697', (12, 17))	('rhabdomyosarcoma', 'Disease', (152, 168))	('Variants', 'Var', (0, 8))	('chondrosarcoma', 'Disease', (217, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('Triton tumour', 'Disease', (184, 197))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (152, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('Triton tumour', 'Disease', 'MESH:D009369', (184, 197))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (217, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('osteosarcoma', 'Disease', (200, 212))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (152, 168))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('osteosarcoma', 'Phenotype', 'HP:0002669', (200, 212))	('MPNST', 'Gene', (12, 17))	('osteosarcoma', 'Disease', 'MESH:D012516', (200, 212))	('chondrosarcoma', 'Disease', 'MESH:D002813', (217, 231))
539008	26358060	It is conceivable that a number of these tumours may not actually have a normal tissue counterpart but instead reflect the consequence of genetic aberrations in which translocations and other genetic errors culminate in histological patterns, which are not encountered in normal tissue.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('translocations', 'Var', (167, 181))	('culminate in', 'Reg', (207, 219))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))
539051	26358060	The diagnosis was supported by demonstration of a translocation involving the EWSR1 gene by FISH analysis; the partner gene was not identified.	('EWSR1', 'Gene', '2130', (78, 83))	('EWSR1', 'Gene', (78, 83))	('translocation', 'Var', (50, 63))
539082	32873768	Fluorescence in-situ hybridization showed positivity for CIC-DUX4 gene fusion, resulting in a final diagnosis of round cell sarcoma with CIC-DUX4 translocation.	('DUX4', 'Gene', (61, 65))	('DUX4', 'Gene', '100288687', (61, 65))	('sarcoma', 'Disease', (124, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('DUX4', 'Gene', (141, 145))	('CIC', 'Gene', '23152', (57, 60))	('sarcoma', 'Disease', 'MESH:D012509', (124, 131))	('CIC', 'Gene', '23152', (137, 140))	('DUX4', 'Gene', '100288687', (141, 145))	('CIC', 'Gene', (137, 140))	('CIC', 'Gene', (57, 60))	('fusion', 'Var', (71, 77))
539093	32873768	CIC-DUX fusion, common in CDS, has been found to result from t(4;19) (q35;q13) or t(10;19)(q26;q13) translocation.	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (82, 99))	('t(4;19) (q35;q13', 'Var', (61, 77))	('CDS', 'Gene', '1040', (26, 29))	('CIC', 'Gene', '23152', (0, 3))	('CDS', 'Gene', (26, 29))	('result from', 'Reg', (49, 60))	('CIC', 'Gene', (0, 3))
539215	31670911	One common feature of Ewing sarcoma tumors is the presence of a translocation involving EWSR1 and a member of the E26 transformation-specific (ETS) transcription factor family, most commonly FLI1 (about 85% of patients).1, 2, 3, 4 Although the genetic epidemiology of Ewing sarcoma is not entirely clear, race remains a known significant risk factor for Ewing sarcoma, with incidence in Caucasians nine times greater than in Africans (0.155 vs 0.017 per 105 individuals).5 Further supporting an element of genetic risk, despite an overall incidence of just one case per million, there are several reports of Ewing sarcoma observed in siblings.6, 7, 8, 9 Based on this evidence, genetic risk loci have been sought through multiple genome-wide association study efforts, but there is no consensus as to what degree these risk candidates contribute to Ewing sarcoma development.10, 11, 12 Other studies have investigated germline mutations in known cancer predisposition genes, finding a minority (11%) of patients to have pathogenic, or probably pathogenic, variants in TP53, RET, and PMS2 13; family history does not predict the presence of a syndrome in most patients.	('PMS2', 'Gene', '5395', (1083, 1087))	('RET', 'Gene', '5979', (1074, 1077))	('sarcoma', 'Phenotype', 'HP:0100242', (360, 367))	('cancer', 'Disease', (946, 952))	('Ewing sarcoma', 'Disease', (608, 621))	('FLI1', 'Gene', '2313', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (946, 952))	('EWSR1', 'Gene', '2130', (88, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (849, 862))	('TP53', 'Gene', (1068, 1072))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (22, 42))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (849, 862))	('variants', 'Var', (1056, 1064))	('RET', 'Gene', (1074, 1077))	('patients', 'Species', '9606', (210, 218))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('PMS2', 'Gene', (1083, 1087))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (268, 281))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (354, 367))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (268, 281))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (354, 367))	('patients', 'Species', '9606', (1003, 1011))	('pathogenic', 'Reg', (1020, 1030))	('sarcoma', 'Phenotype', 'HP:0100242', (855, 862))	('cancer', 'Disease', 'MESH:D009369', (946, 952))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (22, 35))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('EWSR1', 'Gene', (88, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (608, 621))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (608, 621))	('Ewing sarcoma tumors', 'Disease', (22, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (614, 621))	('TP53', 'Gene', '7157', (1068, 1072))	('Ewing sarcoma', 'Disease', (849, 862))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('patients', 'Species', '9606', (1159, 1167))	('Ewing sarcoma', 'Disease', (268, 281))	('FLI1', 'Gene', (191, 195))	('Ewing sarcoma', 'Disease', (354, 367))
539228	31670911	Ewing sarcoma patients who linked to at least three generations of genealogy in the UPDB were identified from UCR records based on the International Classification of Diseases for Oncology (ICD-O) Revision 3 with histology 9260 (n = 130), or 9364 (n = 13).	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('9364', 'Var', (242, 246))	('Oncology', 'Phenotype', 'HP:0002664', (180, 188))	('patients', 'Species', '9606', (14, 22))
539329	31553702	T2w fat saturated with fat-saturation and T1w post-Gadolinium showed a better performance than T1w images (p < 0.05).	('T2w', 'Var', (0, 3))	('T1w', 'Var', (42, 45))	('Gadolinium', 'Chemical', 'MESH:D005682', (51, 61))
539338	31553702	AUCs of this study, especially for T1w post-gadolinium and T2w fat saturated are better that 90%.	('T2w', 'Var', (59, 62))	('gadolinium', 'Chemical', 'MESH:D005682', (44, 54))	('T1w', 'Var', (35, 38))
539399	31404317	Suboptimal biopsies and positive resection margins are associated with local and distant disease recurrence in patients with hand STS.	('hand STS', 'Disease', (125, 133))	('Suboptimal', 'Var', (0, 10))	('STS', 'Phenotype', 'HP:0030448', (130, 133))	('patients', 'Species', '9606', (111, 119))
539424	31404317	Significant differences in toxicity have been reported with the use of postoperative EBRT compared to LSS alone with respect to edema, limb strength and range of motion.	('toxicity', 'Disease', 'MESH:D064420', (27, 35))	('edema', 'Disease', 'MESH:D004487', (128, 133))	('toxicity', 'Disease', (27, 35))	('edema', 'Phenotype', 'HP:0000969', (128, 133))	('EBRT', 'Chemical', '-', (85, 89))	('range of motion', 'CPA', (153, 168))	('SS', 'Phenotype', 'HP:0012570', (103, 105))	('edema', 'Disease', (128, 133))	('limb strength', 'CPA', (135, 148))	('EBRT', 'Var', (85, 89))
539448	31404317	According to this meta-analysis, administration of adjuvant anthracyclines and ifosfamide leads to a significant reduction in the risk of recurrence and death of 10 and 11%, respectively.	('reduction', 'NegReg', (113, 122))	('ifosfamide', 'Chemical', 'MESH:D007069', (79, 89))	('anthracyclines', 'Var', (60, 74))	('anthracyclines', 'Chemical', 'MESH:D018943', (60, 74))
539485	31404317	Trabectedin has been reported ineffective in ES, and pazopanib showed an inferior PFS and OS when compared to anthracyclines and to gemcitabine in a retrospective study.	('OS', 'Chemical', '-', (90, 92))	('pazopanib', 'Var', (53, 62))	('PFS', 'CPA', (82, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (132, 143))	('pazopanib', 'Chemical', 'MESH:C516667', (53, 62))	('inferior', 'NegReg', (73, 81))	('anthracyclines', 'Chemical', 'MESH:D018943', (110, 124))
539504	30524892	Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '22059', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('Kras', 'Gene', (63, 67))	('Kras', 'Gene', '16653', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('regulatory T cell responses', 'MPA', (121, 148))	('cancer', 'Disease', (76, 82))	('mutations', 'Var', (42, 51))
539506	30524892	Hence, we designed a panel of long peptides (LPs, 28-35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential.	('mutations', 'Var', (83, 92))	('gastrointestinal tumors', 'Disease', (130, 153))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (130, 153))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (130, 153))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('peptides', 'Chemical', 'MESH:D010455', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('LPs', 'Chemical', '-', (45, 48))	('TP35', 'Gene', (96, 100))	('KRAS', 'Gene', (105, 109))
539507	30524892	We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations.	('colorectal cancer', 'Disease', (95, 112))	('peptides', 'Chemical', 'MESH:D010455', (83, 91))	('patients', 'Species', '9606', (113, 121))	('increased numbers of T cells', 'Phenotype', 'HP:0100828', (9, 37))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('increased', 'PosReg', (9, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('tumors', 'Disease', (163, 169))	('patients', 'Species', '9606', (175, 183))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (144, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
539509	30524892	Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes.	('T cell responses', 'CPA', (75, 91))	('DR1', 'Gene', (145, 148))	('Kras[G12V]', 'Var', (22, 32))	('HLA-A', 'Gene', '3105', (138, 143))	('DR1', 'Gene', '13486', (145, 148))	('higher', 'PosReg', (68, 74))	('peptides', 'Chemical', 'MESH:D010455', (12, 20))	('HLA-A', 'Gene', (138, 143))	('G12V', 'Mutation', 'rs121913529', (27, 31))	('R248W', 'Mutation', 'rs121912651', (38, 43))	('p53[R248W]', 'Var', (34, 44))
539510	30524892	However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth.	('protein', 'Protein', (179, 186))	('LPs', 'Chemical', '-', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('syngeneic sarcoma', 'Disease', 'MESH:D012509', (125, 142))	('tumor', 'Disease', (224, 229))	('variants', 'Var', (187, 195))	('accelerated', 'PosReg', (212, 223))	('increased', 'PosReg', (67, 76))	('rat', 'Species', '10116', (218, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('syngeneic sarcoma', 'Disease', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
539511	30524892	In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity.	('delayed', 'NegReg', (33, 40))	('Kras/Tp53', 'Gene', (95, 104))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (79, 84))	('mutations', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
539512	30524892	Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors.	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('LP', 'Chemical', '-', (27, 29))	('TSAs', 'Gene', (69, 73))	('mutated', 'Var', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('polyvalent', 'MPA', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
539516	30524892	Mutated TSAs can be of different quality for the tumor.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Mutated', 'Var', (0, 7))	('tumor', 'Disease', (49, 54))
539517	30524892	Passenger mutations are expendable to sustain a malignant phenotype, which can result in Ag-loss variants of the tumor once a Darwinian selection pressure is imposed by therapeutic intervention.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('variants', 'Var', (97, 105))
539518	30524892	Important driver genes in colorectal and pancreatic tumorigenesis are mutated alleles of the oncogene KRAS and the tumor suppressor gene/oncogene TP53.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('colorectal', 'Disease', 'MESH:D015179', (26, 36))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (115, 120))	('colorectal', 'Disease', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('pancreatic', 'Disease', 'MESH:D010195', (41, 51))	('KRAS', 'Gene', (102, 106))	('pancreatic', 'Disease', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('mutated', 'Var', (70, 77))
539519	30524892	We and others proved the existence of both TA-specific CD4+ and CD8+ memory T cells (Tmem) in cancer patients prior to any immunotherapeutic intervention.	('CD8', 'Gene', (64, 67))	('patients', 'Species', '9606', (101, 109))	('CD8', 'Gene', '925', (64, 67))	('CD4+', 'Var', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
539532	30524892	Moreover, combining several TSAs in one vaccine might broaden the responses towards sub-dominant epitopes and thereby prevent or delay the tumor's escape from immune surveillance through emergence of Ag-loss variants.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('escape from immune surveillance', 'MPA', (147, 178))	('Ag-loss', 'Gene', (200, 207))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('broaden', 'PosReg', (54, 61))	('variants', 'Var', (208, 216))	('responses towards sub-dominant epitopes', 'MPA', (66, 105))	('prevent', 'NegReg', (118, 125))	('delay', 'NegReg', (129, 134))
539536	30524892	Then small clinical pilot studies (phase I/II) were launched exploring vaccination with mutated Kras and p53 peptides for their clinical benefit.	('p53', 'Gene', (105, 108))	('mutated', 'Var', (88, 95))	('Kras', 'Gene', (96, 100))	('peptides', 'Chemical', 'MESH:D010455', (109, 117))
539537	30524892	Vaccination trials with mutated Kras peptides in advanced-stage pancreatic cancer patients resulted in longer survival of immune responders compared to non-responding patients.	('mutated', 'Var', (24, 31))	('Kras', 'Gene', (32, 36))	('peptides', 'Chemical', 'MESH:D010455', (37, 45))	('survival', 'MPA', (110, 118))	('patients', 'Species', '9606', (82, 90))	('patients', 'Species', '9606', (167, 175))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('longer', 'PosReg', (103, 109))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))
539538	30524892	In a second study, immune responses against mutated peptides were detected in the majority of the patients.	('detected', 'Reg', (66, 74))	('peptides', 'Chemical', 'MESH:D010455', (52, 60))	('patients', 'Species', '9606', (98, 106))	('mutated', 'Var', (44, 51))	('immune responses', 'MPA', (19, 35))
539545	30524892	However, in this carefully designed randomized multi-center study IMA901 did not prolong overall survival in the IMA901 co-treated patient cohort.	('IMA901', 'Var', (66, 72))	('IMA901', 'Chemical', '-', (113, 119))	('patient', 'Species', '9606', (131, 138))	('IMA901', 'Chemical', '-', (66, 72))	('overall', 'MPA', (89, 96))
539548	30524892	In this study we combined the most frequent mutations in KRAS and TP53 found in gastrointestinal cancers and explored preexisting immune responses against these sequences in colorectal cancer (CRC) patients.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('gastrointestinal cancers', 'Disease', (80, 104))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (80, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (174, 191))	('patients', 'Species', '9606', (198, 206))	('TP53', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('colorectal cancer', 'Disease', (174, 191))	('KRAS', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CRC', 'Phenotype', 'HP:0003003', (193, 196))	('mutations', 'Var', (44, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (174, 191))
539550	30524892	To test for T cell responses against driver gene mutations of GI tumors we assembled a panel of long peptides comprising the most frequent KRAS and TP53 hotspot mutations found in CRC and pancreatic cancer.	('GI tumors', 'Disease', (62, 71))	('CRC', 'Disease', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('GI tumors', 'Disease', 'MESH:D009369', (62, 71))	('TP53', 'Gene', (148, 152))	('KRAS', 'Gene', (139, 143))	('peptides', 'Chemical', 'MESH:D010455', (101, 109))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (161, 170))	('CRC', 'Phenotype', 'HP:0003003', (180, 183))	('GI tumors', 'Phenotype', 'HP:0007378', (62, 71))	('pancreatic cancer', 'Disease', (188, 205))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))
539560	30524892	Along with T cell reactivity, paraffin-embedded tissue samples of the same patients' primary tumors and metastases (24 out of 26 patients, Supplementary Table 3) were sequenced for the abundance of TP53, KRAS, and BRAF mutations in relevant hotspot mutation site-comprising exons employing the QIAsymphony technology.	('TP53', 'Gene', (198, 202))	('metastases', 'Disease', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('patients', 'Species', '9606', (129, 137))	('metastases', 'Disease', 'MESH:D009362', (104, 114))	('BRAF', 'Gene', (214, 218))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (75, 83))	('KRAS', 'Gene', (204, 208))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('mutations', 'Var', (219, 228))	('paraffin', 'Chemical', 'MESH:D010232', (30, 38))
539562	30524892	Notably, the patient presented in Figure 1A carried the point mutation p53 R175H in his primary tumor and, indeed, T cells purified from PB were significantly more responsive against the peptide harboring the mutation R175H than towards the corresponding wt peptide.	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('peptide', 'Chemical', 'MESH:D010455', (187, 194))	('patient', 'Species', '9606', (13, 20))	('p53 R175H', 'Var', (71, 80))	('tumor', 'Disease', (96, 101))	('R175H', 'Mutation', 'rs28934578', (218, 223))	('R175H', 'Mutation', 'rs28934578', (75, 80))	('R175H', 'Var', (218, 223))	('responsive against', 'MPA', (164, 182))	('peptide', 'Chemical', 'MESH:D010455', (258, 265))	('more', 'PosReg', (159, 163))
539563	30524892	Compared to the negative assay control (human IgG) the patient showed T cell recall responses against several other wt (p53 R273/R282 wt, Braf V600 wt) and mutated (p53 R273C, p53 R248W) long peptides.	('peptides', 'Chemical', 'MESH:D010455', (192, 200))	('T cell recall responses', 'CPA', (70, 93))	('R248W', 'Mutation', 'rs121912651', (180, 185))	('p53 R248W', 'Var', (176, 185))	('p53 R273/R282', 'Var', (120, 133))	('patient', 'Species', '9606', (55, 62))	('p53 R273C', 'Var', (165, 174))	('R273C', 'Mutation', 'rs121913343', (169, 174))	('human', 'Species', '9606', (40, 45))
539569	30524892	The resulting response rates for wt and mutated peptides are comparable using t-test as well as the DFR(eq) method, ranging from roughly 15% for the p53 R175 wt peptides to around 50% for some of the mutated (p53 R248W/Q, Kras G12V) and wt (p53 G245/R248 wt, Braf wt) peptides.	('peptides', 'Chemical', 'MESH:D010455', (161, 169))	('R248W', 'Var', (213, 218))	('peptides', 'Chemical', 'MESH:D010455', (268, 276))	('R248W', 'SUBSTITUTION', 'None', (213, 218))	('rat', 'Species', '10116', (23, 26))	('peptides', 'Chemical', 'MESH:D010455', (48, 56))	('Kras G12V', 'Var', (222, 231))	('p53 G245/R248', 'Var', (241, 254))	('G12V', 'Mutation', 'rs121913529', (227, 231))
539571	30524892	However, 70% of patients responded against three or more mutated peptides simultaneously and only 30% against less than three.	('mutated', 'Var', (57, 64))	('patients', 'Species', '9606', (16, 24))	('peptides', 'Chemical', 'MESH:D010455', (65, 73))	('responded', 'Reg', (25, 34))
539572	30524892	Cumulative analysis of peptide-specific T cell recall responses (BM- and PB-derived responses pooled) demonstrated that IFN-gamma production and therewith T cell reactivity against mutated peptides was generally higher than against wt peptides (Figure 1C).	('peptide', 'Chemical', 'MESH:D010455', (235, 242))	('peptides', 'Chemical', 'MESH:D010455', (189, 197))	('IFN-gamma', 'Gene', '15978', (120, 129))	('T cell reactivity', 'CPA', (155, 172))	('peptide', 'Chemical', 'MESH:D010455', (23, 30))	('higher', 'PosReg', (212, 218))	('rat', 'Species', '10116', (109, 112))	('IFN-gamma', 'Gene', (120, 129))	('peptides', 'Chemical', 'MESH:D010455', (235, 243))	('mutated', 'Var', (181, 188))	('peptide', 'Chemical', 'MESH:D010455', (189, 196))
539574	30524892	Further, responses against mutated peptides were considered mutation-specific if they elicited significantly higher IFN-gamma spot counts than corresponding wt counterparts.	('peptides', 'Chemical', 'MESH:D010455', (35, 43))	('IFN-gamma', 'Gene', '15978', (116, 125))	('higher', 'PosReg', (109, 115))	('responses', 'MPA', (9, 18))	('mutated peptides', 'Var', (27, 43))	('IFN-gamma', 'Gene', (116, 125))
539575	30524892	The mutation-specific response rates for the mutated peptides (Supplementary Figure 2D) revealed, that the peptide representing the mutation p53 R175H was selectively recognized by 40% of patients and peptide p53 R248W by 20% of BM T cells and 10% of patients' PB T cells, respectively.	('p53 R175H', 'Var', (141, 150))	('peptide', 'Chemical', 'MESH:D010455', (107, 114))	('peptide', 'Chemical', 'MESH:D010455', (53, 60))	('peptide', 'Chemical', 'MESH:D010455', (201, 208))	('R175H', 'Mutation', 'rs28934578', (145, 150))	('patients', 'Species', '9606', (188, 196))	('peptide p53 R248W', 'Var', (201, 218))	('patients', 'Species', '9606', (251, 259))	('R248W', 'Mutation', 'rs121912651', (213, 218))	('peptides', 'Chemical', 'MESH:D010455', (53, 61))	('rat', 'Species', '10116', (31, 34))
539576	30524892	Of note, the peptides p53 R175H and p53 R248Q/W were possibly recognized in an HLA-A2-restricted context.	('peptides', 'Chemical', 'MESH:D010455', (13, 21))	('HLA-A', 'Gene', '3105', (79, 84))	('p53 R175H', 'Var', (22, 31))	('R248Q', 'SUBSTITUTION', 'None', (40, 45))	('HLA-A', 'Gene', (79, 84))	('R175H', 'Mutation', 'rs28934578', (26, 31))	('R248Q', 'Var', (40, 45))
539584	30524892	However, the acquisition of the respective mutations can give rise to neo-epitopes for most of the peptides (indicated in light and dark red, Supplementary Figure3A), some of which are strong binders, as it is the case for the mutated peptides p53 R248W and Kras G12V (red parts of the bars, Supplementary Figure 3A).	('give rise to', 'Reg', (57, 69))	('peptides', 'Chemical', 'MESH:D010455', (99, 107))	('G12V', 'Mutation', 'rs121913529', (263, 267))	('neo-epitopes', 'MPA', (70, 82))	('p53 R248W', 'Var', (244, 253))	('mutations', 'Var', (43, 52))	('peptides', 'Chemical', 'MESH:D010455', (235, 243))	('Kras G12V', 'Var', (258, 267))	('R248W', 'Mutation', 'rs121912651', (248, 253))
539588	30524892	Sequencing results revealed that 20 of the 24 tested patients (83%) carried KRAS and/or TP53 mutations in their primary tumors and/or metastasis (Figure 1D, Supplementary Table 3), whereas no BRAF mutations could be detected.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('KRAS', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('TP53', 'Gene', (88, 92))
539589	30524892	TP53 (75%, 18 patients) mutations were more abundant than KRAS mutations (29%, 7 patients).	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (14, 22))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (81, 89))
539590	30524892	Moreover, 11 patients' tumors and/or metastases (46% of all patients analyzed) harbored mutations that were included in the panel of long peptides.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('metastases', 'Disease', (37, 47))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (88, 97))	('harbored', 'Reg', (79, 87))	('patients', 'Species', '9606', (13, 21))	('peptides', 'Chemical', 'MESH:D010455', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('metastases', 'Disease', 'MESH:D009362', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
539591	30524892	Correlation of the ELISpot results with the abundance of TP53 and KRAS mutations identified in the patients' primary tumors and metastases revealed that patients carrying a mutation that was tested for by ELISpot assay, were more likely to be responsive against the respective mutated peptide and sometimes showed a concomitant response against the respective wt peptide, than patients carrying other mutations in their tumors (Figure 1E).	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (420, 426))	('responsive against the respective mutated peptide', 'MPA', (243, 292))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('tumors', 'Disease', (117, 123))	('patients', 'Species', '9606', (377, 385))	('mutations', 'Var', (71, 80))	('tumors', 'Disease', 'MESH:D009369', (420, 426))	('showed', 'Reg', (307, 313))	('KRAS', 'Gene', (66, 70))	('metastases', 'Disease', (128, 138))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('patients', 'Species', '9606', (99, 107))	('peptide', 'Chemical', 'MESH:D010455', (285, 292))	('TP53', 'Gene', (57, 61))	('patients', 'Species', '9606', (153, 161))	('peptide', 'Chemical', 'MESH:D010455', (363, 370))	('tumors', 'Phenotype', 'HP:0002664', (420, 426))	('more', 'PosReg', (225, 229))	('mutation', 'Var', (173, 181))
539593	30524892	Taken together, our data provide evidence for spontaneous immunogenicity of Tp53 and Kras hotspot mutations expressed in patients with primary and metastasized colorectal cancer.	('Kras hotspot', 'Gene', (85, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('Tp53', 'Gene', (76, 80))	('mutations', 'Var', (98, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('colorectal cancer', 'Disease', (160, 177))	('patients', 'Species', '9606', (121, 129))
539594	30524892	Since we identified the existence of memory T cell responses in CRC patients against wt and mutated peptide sequences derived from hotspot mutation sites of KRAS, TP53 and BRAF genes, we were encouraged to investigate the therapeutic potential of these sequences.	('mutation', 'Var', (139, 147))	('patients', 'Species', '9606', (68, 76))	('TP53', 'Gene', (163, 167))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('KRAS', 'Gene', (157, 161))	('BRAF', 'Gene', (172, 176))	('peptide', 'Chemical', 'MESH:D010455', (100, 107))
539605	30524892	Interestingly, the strongest responses were elicited by similar peptides in both, the human and the murine MHC context.	('MHC', 'Gene', (107, 110))	('peptides', 'Var', (64, 72))	('MHC', 'Gene', '3107', (107, 110))	('human', 'Species', '9606', (86, 91))	('murine', 'Species', '10090', (100, 106))	('peptides', 'Chemical', 'MESH:D010455', (64, 72))
539606	30524892	In C57BL/6 mice the mutated peptides p53 R248W/Q, p53 G245S, and Kras G12V/D/wt were repeatedly highly stimulatory (Supplementary Figure 4A).	('G12V', 'Mutation', 'rs121913529', (70, 74))	('peptides', 'Chemical', 'MESH:D010455', (28, 36))	('R248W', 'Var', (41, 46))	('G245S', 'Mutation', 'rs28934575', (54, 59))	('p53 G245S', 'Var', (50, 59))	('Kras G12V/D/wt', 'Var', (65, 79))	('mice', 'Species', '10090', (11, 15))	('stimulatory', 'PosReg', (103, 114))	('R248W', 'SUBSTITUTION', 'None', (41, 46))
539607	30524892	Similarly, the peptides p53 R248W/Q and Kras G12V/D/R excelled in the human MHC context of A2.DR1 dtg mice (Figure 2A).	('mice', 'Species', '10090', (102, 106))	('dtg', 'Chemical', 'MESH:C562325', (98, 101))	('MHC', 'Gene', (76, 79))	('R248W', 'Var', (28, 33))	('DR1', 'Gene', (94, 97))	('DR1', 'Gene', '13486', (94, 97))	('Kras G12V/D/R', 'Var', (40, 53))	('R248W', 'SUBSTITUTION', 'None', (28, 33))	('human', 'Species', '9606', (70, 75))	('MHC', 'Gene', '3107', (76, 79))	('G12V', 'Mutation', 'rs121913529', (45, 49))	('peptides', 'Chemical', 'MESH:D010455', (15, 23))
539613	30524892	All T cell responses from mutated and wt peptide vaccinated mice were accumulated in two groups, respectively, namely cytokine production induced by mutated (Figure 2B and C - column labeled with 'mut peptides') peptides and corresponding wt (Figure 2B and C - column labeled with 'wt peptides') peptides.	('peptide', 'Chemical', 'MESH:D010455', (296, 303))	('peptides', 'Chemical', 'MESH:D010455', (212, 220))	('peptide', 'Chemical', 'MESH:D010455', (201, 208))	('mutated', 'Var', (149, 156))	('peptides', 'Chemical', 'MESH:D010455', (285, 293))	('peptide', 'Chemical', 'MESH:D010455', (285, 292))	('peptides', 'Chemical', 'MESH:D010455', (201, 209))	('peptides', 'Chemical', 'MESH:D010455', (296, 304))	('peptide', 'Chemical', 'MESH:D010455', (212, 219))	('cytokine production', 'MPA', (118, 137))	('peptide', 'Chemical', 'MESH:D010455', (41, 48))	('mice', 'Species', '10090', (60, 64))
539614	30524892	The analysis was done for IFN-gamma secretion of splenic CD8+ (Figure 2A) and CD4+ (Figure 2B) T cells, which resulted in the same tendencies for both MHC contexts (for C57BL/6 data see Supplementary Figures 4 B and C).	('IFN-gamma', 'Gene', '15978', (26, 35))	('CD8', 'Gene', (57, 60))	('CD8', 'Gene', '925', (57, 60))	('MHC', 'Gene', (151, 154))	('IFN-gamma', 'Gene', (26, 35))	('MHC', 'Gene', '3107', (151, 154))	('CD4+', 'Var', (78, 82))
539615	30524892	Upon vaccination with mutated peptides the cumulative CD4+ and CD8+ T cell responses against mutated peptides were significantly higher than those towards wt peptides in A2.DR1 dtg mice (CD4+ p = 0.0015, and CD8+ p = 0.0040), whereas there were no significant differences between the percentages of IFN-gamma positive T cells towards wt and mutated peptides after vaccination with wt peptides.	('CD8', 'Gene', (208, 211))	('CD4+', 'CPA', (54, 58))	('peptides', 'Chemical', 'MESH:D010455', (384, 392))	('mice', 'Species', '10090', (181, 185))	('peptides', 'Chemical', 'MESH:D010455', (30, 38))	('IFN-gamma', 'Gene', (299, 308))	('CD8', 'Gene', '925', (208, 211))	('peptides', 'Chemical', 'MESH:D010455', (158, 166))	('DR1', 'Gene', (173, 176))	('higher', 'PosReg', (129, 135))	('mutated', 'Var', (22, 29))	('peptides', 'Chemical', 'MESH:D010455', (101, 109))	('IFN-gamma', 'Gene', '15978', (299, 308))	('CD8', 'Gene', (63, 66))	('DR1', 'Gene', '13486', (173, 176))	('CD8', 'Gene', '925', (63, 66))	('dtg', 'Chemical', 'MESH:C562325', (177, 180))	('peptides', 'Chemical', 'MESH:D010455', (349, 357))
539618	30524892	The same trend was found when analyzing intracellular TNF-alpha accumulation after vaccination with mutated peptides for splenic CD4+ T cells (Supplementary Figure 5B, (p = 0.0451)) and CD8+ T cell responses.	('mutated', 'Var', (100, 107))	('CD8', 'Gene', '925', (186, 189))	('TNF-alpha', 'Gene', '21926', (54, 63))	('peptides', 'Chemical', 'MESH:D010455', (108, 116))	('TNF-alpha', 'Gene', (54, 63))	('CD8', 'Gene', (186, 189))
539626	30524892	Furthermore, the presence of CD4+ T cells enhanced the in vitro responsiveness of co-cultured CD8+ T cells compared to CD8+ T cells re-stimulated on DCs in the absence of CD4+ T cells.	('CD8', 'Gene', (119, 122))	('CD4+ T cells', 'Var', (29, 41))	('CD8', 'Gene', '925', (119, 122))	('enhanced', 'PosReg', (42, 50))	('CD8', 'Gene', (94, 97))	('CD8', 'Gene', '925', (94, 97))	('absence of CD4+ T cells', 'Phenotype', 'HP:0005407', (160, 183))
539628	30524892	Taken together, the presence of CD4+ T cells in in vitro cultures enhanced CD8+ T cell in vitro IFN-gamma secretion and argues for the significance of Ag-specific T helper cells to sustain an efficient CTL response towards TSAs.	('IFN-gamma', 'Gene', (96, 105))	('CD8', 'Gene', '925', (75, 78))	('CD8', 'Gene', (75, 78))	('enhanced', 'PosReg', (66, 74))	('IFN-gamma', 'Gene', '15978', (96, 105))	('CD4+', 'Var', (32, 36))
539630	30524892	Therefore, A2.DR1 dtg mice were vaccinated with previously identified, highly immunogenic long mutated peptides (p53 R248W/Q and Kras G12V/D/R).	('DR1', 'Gene', (14, 17))	('R248W', 'Var', (117, 122))	('Kras G12V/D/R', 'Var', (129, 142))	('DR1', 'Gene', '13486', (14, 17))	('peptides', 'Chemical', 'MESH:D010455', (103, 111))	('dtg', 'Chemical', 'MESH:C562325', (18, 21))	('R248W', 'SUBSTITUTION', 'None', (117, 122))	('G12V', 'Mutation', 'rs121913529', (134, 138))	('mice', 'Species', '10090', (22, 26))
539633	30524892	Importantly, vaccination with highly immunogenic peptides elicited cytokine double-positive, poly-functional CD4+ as well as CD8+ T cells (Figure 3A, quadrant Q2 and Figure 3D).	('poly-functional', 'Var', (93, 108))	('peptides', 'Chemical', 'MESH:D010455', (49, 57))	('elicited', 'Reg', (58, 66))	('peptides', 'Var', (49, 57))	('CD4+', 'Gene', (109, 113))	('CD8', 'Gene', (125, 128))	('CD8', 'Gene', '925', (125, 128))
539634	30524892	In accordance with results shown above, the proportions of cytokine positive cells reacting towards the mutated peptides used for vaccination were higher than towards corresponding wt peptides as exemplarily shown for the whole peptide mixes and the p53R248W/p53R248wt peptide pair.	('peptide', 'Chemical', 'MESH:D010455', (228, 235))	('peptide', 'Chemical', 'MESH:D010455', (184, 191))	('peptide', 'Chemical', 'MESH:D010455', (112, 119))	('peptides', 'Chemical', 'MESH:D010455', (184, 192))	('higher', 'PosReg', (147, 153))	('peptide', 'Chemical', 'MESH:D010455', (269, 276))	('peptides', 'Chemical', 'MESH:D010455', (112, 120))	('p53R248W/p53R248wt', 'Var', (250, 268))
539637	30524892	p53 R248W) eliciting a strong IL-2 secretion relative to other peptides also displayed higher proportions of IFN-gamma secreting and cytokine double positive T cells.	('peptides', 'Chemical', 'MESH:D010455', (63, 71))	('p53 R248W', 'Var', (0, 9))	('IFN-gamma', 'Gene', '15978', (109, 118))	('IL-2 secretion', 'MPA', (30, 44))	('eliciting', 'Reg', (11, 20))	('IFN-gamma', 'Gene', (109, 118))	('R248W', 'Mutation', 'rs121912651', (4, 9))	('higher', 'PosReg', (87, 93))
539642	30524892	The p53 R248W peptide elicited the highest induction of granzyme B in CD8+ T cells (Figure 3E and F).	('induction', 'MPA', (43, 52))	('granzyme B', 'Gene', (56, 66))	('p53 R248W', 'Var', (4, 13))	('R248W', 'Mutation', 'rs121912651', (8, 13))	('CD8', 'Gene', (70, 73))	('peptide', 'Chemical', 'MESH:D010455', (14, 21))	('CD8', 'Gene', '925', (70, 73))	('granzyme B', 'Gene', '14939', (56, 66))
539643	30524892	Moreover, the proportions of granzyme B and CD107a positive CD4+ and CD8+ T cells were higher when they were re-stimulated with mutated mixed peptides and single mutated p53 R248W peptide pulsed DCs compared to re-stimulation with corresponding wt peptides, underlining once more the preponderance for mutation-specific CTL responses.	('R248W', 'Var', (174, 179))	('granzyme B', 'Gene', '14939', (29, 39))	('peptide', 'Chemical', 'MESH:D010455', (180, 187))	('CD107a', 'Gene', (44, 50))	('peptide', 'Chemical', 'MESH:D010455', (248, 255))	('peptides', 'Chemical', 'MESH:D010455', (248, 256))	('p53', 'Gene', (170, 173))	('peptides', 'Chemical', 'MESH:D010455', (142, 150))	('CD107a', 'Gene', '16783', (44, 50))	('CD8', 'Gene', (69, 72))	('granzyme B', 'Gene', (29, 39))	('CD8', 'Gene', '925', (69, 72))	('R248W', 'Mutation', 'rs121912651', (174, 179))	('peptide', 'Chemical', 'MESH:D010455', (142, 149))	('higher', 'PosReg', (87, 93))
539644	30524892	Hence, CD8+ and CD4+ T cell responses, elicited by mutated long-peptide vaccination with Kras G12V and p53 R248W peptides, showed a poly-functional cytokine response pattern and cytotoxic features by in vitro analysis.	('poly-functional cytokine response pattern', 'MPA', (132, 173))	('p53', 'Gene', (103, 106))	('R248W', 'Mutation', 'rs121912651', (107, 112))	('peptide', 'Chemical', 'MESH:D010455', (113, 120))	('G12V', 'Mutation', 'rs121913529', (94, 98))	('peptide', 'Chemical', 'MESH:D010455', (64, 71))	('CD8', 'Gene', (7, 10))	('CD8', 'Gene', '925', (7, 10))	('CD4+ T cell responses', 'CPA', (16, 37))	('Kras G12V', 'Var', (89, 98))	('peptides', 'Chemical', 'MESH:D010455', (113, 121))
539646	30524892	In the HLA-A2/HLA-DR1 restricted context this comparison identified the peptides p53 R248W and Kras G12V to be more immunogenic than their wt counterparts when used for vaccination as the proportions of IFN-gamma secreting CD8+ (Figure 4A) and CD4+ (Figure 4B) T cells upon in vitro re-stimulation were significantly increased in this context.	('p53 R248W', 'Var', (81, 90))	('DR1', 'Gene', (18, 21))	('CD8', 'Gene', '925', (223, 226))	('HLA', 'Gene', (7, 10))	('R248W', 'Mutation', 'rs121912651', (85, 90))	('HLA-A', 'Gene', '3105', (7, 12))	('peptides', 'Chemical', 'MESH:D010455', (72, 80))	('IFN-gamma', 'Gene', '15978', (203, 212))	('HLA', 'Gene', (14, 17))	('IFN-gamma', 'Gene', (203, 212))	('DR1', 'Gene', '13486', (18, 21))	('HLA', 'Gene', '3123', (7, 10))	('immunogenic', 'MPA', (116, 127))	('CD8', 'Gene', (223, 226))	('increased', 'PosReg', (317, 326))	('Kras G12V', 'Var', (95, 104))	('HLA', 'Gene', '3123', (14, 17))	('HLA-A', 'Gene', (7, 12))	('G12V', 'Mutation', 'rs121913529', (100, 104))
539647	30524892	Spontaneous responses against the peptides p53 R248W and Kras G12V were negligible, as IFN-gamma secretion of T cells purified from non-immunized animals did not exceed negative assay controls (depicted on the right-hand side panel of each graph in Figure 4A and 4B).	('peptides', 'Chemical', 'MESH:D010455', (34, 42))	('IFN-gamma', 'Gene', (87, 96))	('Kras G12V', 'Var', (57, 66))	('IFN-gamma', 'Gene', '15978', (87, 96))	('R248W', 'Mutation', 'rs121912651', (47, 52))	('G12V', 'Mutation', 'rs121913529', (62, 66))	('p53 R248W', 'Var', (43, 52))
539654	30524892	Although both wt and mutated 10-mers were not predicted to be strong binders, the mutated 10-mer peptide scored with a higher affinity for HLA-A2 than the corresponding wt 10-mer (NetMHC scores: 300.18 nM versus 506.91 nM, SYFPEITHI scores: 24 versus 22).	('peptide', 'Chemical', 'MESH:D010455', (97, 104))	('MHC', 'Gene', (183, 186))	('MHC', 'Gene', '3107', (183, 186))	('higher', 'PosReg', (119, 125))	('mers', 'Species', '1335626', (32, 36))	('affinity', 'Interaction', (126, 134))	('HLA-A', 'Gene', '3105', (139, 144))	('mutated 10-mer', 'Var', (82, 96))	('HLA-A', 'Gene', (139, 144))
539657	30524892	T cells purified from mice immunized with the two highly immunogenic mutated long peptides p53 R248W and Kras G12V were re-stimulated on DCs pulsed with putative wt and mutated short epitopes or respective long peptides.	('short epitopes', 'Disease', 'MESH:C537327', (177, 191))	('p53 R248W', 'Var', (91, 100))	('peptides', 'Chemical', 'MESH:D010455', (82, 90))	('short epitopes', 'Disease', (177, 191))	('Kras G12V', 'Var', (105, 114))	('peptides', 'Chemical', 'MESH:D010455', (211, 219))	('R248W', 'Mutation', 'rs121912651', (95, 100))	('mice', 'Species', '10090', (22, 26))	('G12V', 'Mutation', 'rs121913529', (110, 114))
539659	30524892	While the wt 10-mer peptide elicited a weak CD8+ T cell cytokine response, the corresponding mutated Kras G12V 10-mer peptide generated a strong response by IFN-gamma/IL-2 double-positive CD8+ T cells (Figure 4E).	('CD8', 'Gene', (44, 47))	('peptide', 'Chemical', 'MESH:D010455', (118, 125))	('IFN-gamma', 'Gene', '15978', (157, 166))	('CD8', 'Gene', (188, 191))	('CD8', 'Gene', '925', (44, 47))	('CD8', 'Gene', '925', (188, 191))	('rat', 'Species', '10116', (130, 133))	('G12V', 'Mutation', 'rs121913529', (106, 110))	('IFN-gamma', 'Gene', (157, 166))	('peptide', 'Chemical', 'MESH:D010455', (20, 27))	('mutated Kras G12V', 'Var', (93, 110))
539661	30524892	Additionally, the mutated predicted MHC class II 15-mer binder elicited significantly higher levels of IL-2 secretion in CD4+ T cells than the respective 15-mer wt peptide (Figure 4G).	('mutated', 'Var', (18, 25))	('levels', 'MPA', (93, 99))	('MHC', 'Gene', (36, 39))	('peptide', 'Chemical', 'MESH:D010455', (164, 171))	('MHC', 'Gene', '3107', (36, 39))	('higher', 'PosReg', (86, 92))
539665	30524892	Our findings collectively suggest that the predicted Kras G12V 10-mer and 15-mer peptides are indeed immunogenic HLA-I and II restricted epitopes within Kras.	('G12V', 'Mutation', 'rs121913529', (58, 62))	('peptides', 'Chemical', 'MESH:D010455', (81, 89))	('HLA', 'Gene', '3123', (113, 116))	('HLA', 'Gene', (113, 116))	('Kras G12V', 'Var', (53, 62))	('G12V', 'Var', (58, 62))
539670	30524892	Overlapping 9-mer, 10-mer and 15-mer p53 R248(W) wt and mutated peptides were tested in vitro for their potential to re-stimulate T cells purified from A2.DR1 dtg mice immunized with the mutated, long peptide p53 R248W and were compared to recall responses against the respective long peptides.	('peptide', 'Chemical', 'MESH:D010455', (201, 208))	('R248W', 'Mutation', 'rs121912651', (213, 218))	('DR1', 'Gene', (155, 158))	('p53 R248W', 'Var', (209, 218))	('peptide', 'Chemical', 'MESH:D010455', (64, 71))	('DR1', 'Gene', '13486', (155, 158))	('peptides', 'Chemical', 'MESH:D010455', (285, 293))	('dtg', 'Chemical', 'MESH:C562325', (159, 162))	('mice', 'Species', '10090', (163, 167))	('p53', 'Gene', (37, 40))	('peptide', 'Chemical', 'MESH:D010455', (285, 292))	('peptides', 'Chemical', 'MESH:D010455', (64, 72))
539672	30524892	However, 10-mer peptide SP-p53 R248W247-256 elicited significantly higher percentages of IFN-gamma/IL-2 double positive (Figure 4C) CD8+ T cells when compared to background controls (for whole 10-mer epitope mapping see Supplementary Figure 7B) although it did not score as a putative HLA-A2 ligand (Supplementary Table 5).	('SP-p53 R248W247-256', 'Var', (24, 43))	('peptide', 'Chemical', 'MESH:D010455', (16, 23))	('higher', 'PosReg', (67, 73))	('R248W', 'Mutation', 'rs121912651', (31, 36))	('IFN-gamma', 'Gene', '15978', (89, 98))	('HLA-A', 'Gene', '3105', (285, 290))	('CD8', 'Gene', '925', (132, 135))	('CD8', 'Gene', (132, 135))	('HLA-A', 'Gene', (285, 290))	('IFN-gamma', 'Gene', (89, 98))
539674	30524892	Five mutated 15-mer peptides, however, elicited stronger cytokine responses than all other 15-mers tested and were therefore chosen for revalidation in a third experiment in which they were tested against their corresponding wt 15-mer counterpart peptides (see Supplementary Figure 7C and D).	('peptides', 'Chemical', 'MESH:D010455', (247, 255))	('peptides', 'Chemical', 'MESH:D010455', (20, 28))	('cytokine responses', 'MPA', (57, 75))	('stronger', 'PosReg', (48, 56))	('mutated', 'Var', (5, 12))	('mers', 'Species', '1335626', (94, 98))	('elicited', 'Reg', (39, 47))
539675	30524892	Figure 4C highlights the potential minimal HLA-A2 and HLA-DRB1 ligands identified within the sequences of the long peptides p53 R248W and Kras G12V.	('HLA-DRB1', 'Gene', (54, 62))	('HLA-DRB1', 'Gene', '116749', (54, 62))	('HLA-A', 'Gene', (43, 48))	('peptides', 'Chemical', 'MESH:D010455', (115, 123))	('R248W', 'Mutation', 'rs121912651', (128, 133))	('G12V', 'Mutation', 'rs121913529', (143, 147))	('p53 R248W', 'Var', (124, 133))	('Kras G12V', 'Var', (138, 147))	('HLA-A', 'Gene', '3105', (43, 48))
539683	30524892	We therefore stably introduced a doxycycline (DOX)-inducible transgene for KRAS G12V and TP53 R248W joined by a linker and fused to an HA-tag into the Rosa26 locus of the cell line 2277-NS by site-directed recombination (Supplementary Figure 8D-G, Supplementary Figure 9).	('TP53', 'Gene', (89, 93))	('G12V', 'Mutation', 'rs121913529', (80, 84))	('R248W', 'Mutation', 'rs121912651', (94, 99))	('doxycycline', 'Chemical', 'MESH:D004318', (33, 44))	('KRAS G12V', 'Var', (75, 84))	('Rosa26', 'Gene', '14910', (151, 157))	('DOX', 'Chemical', 'MESH:D004318', (46, 49))	('Rosa26', 'Gene', (151, 157))
539686	30524892	CpG and poly(I:C) have been pre-dominantly used as adjuvants in clinical trials, because they not only ensure optimal DC priming but were also shown to increase the Teff/Treg ratios.	('increase', 'PosReg', (152, 160))	('rat', 'Species', '10116', (175, 178))	('Teff/Treg ratios', 'MPA', (165, 181))	('poly', 'Var', (8, 12))	('DC priming', 'MPA', (118, 128))
539688	30524892	Although previously found to lead to fatal sequestration and deletion of TAA-specific CTLs when used for vaccination with minimal epitopes, IFAs are superior adjuvants when used in combination with long synthetic peptides, that require processing by APCs.	('peptides', 'Chemical', 'MESH:D010455', (213, 221))	('lead to', 'Reg', (29, 36))	('rat', 'Species', '10116', (50, 53))	('deletion', 'Var', (61, 69))	('CTLs', 'Gene', (86, 90))	('IFA', 'Chemical', 'MESH:C114843', (140, 143))
539690	30524892	For tumor challenge experiments groups of age- and gender-matched A2.DR1 dtg mice were vaccinated with either mutated (Kras G12V, p53 R248W), wt (Kras G12 wt, p53 R248 wt), or irrelevant (murine IgG sequences comprising peptides IgG47-81, IgG273-304) peptides formulated in Montanide ISA720/CpG ODN 1668 in a preventive setting three times prior tumor inoculation.	('tumor', 'Disease', (4, 9))	('DR1', 'Gene', '13486', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mice', 'Species', '10090', (77, 81))	('tumor inoculation', 'Disease', (346, 363))	('Montanide ISA', 'Chemical', '-', (274, 287))	('dtg', 'Chemical', 'MESH:C562325', (73, 76))	('murine', 'Species', '10090', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('peptides', 'Chemical', 'MESH:D010455', (220, 228))	('DR1', 'Gene', (69, 72))	('peptides', 'Chemical', 'MESH:D010455', (251, 259))	('tumor', 'Disease', (346, 351))	('p53 R248W', 'Var', (130, 139))	('Kras G12V', 'Var', (119, 128))	('R248W', 'Mutation', 'rs121912651', (134, 139))	('tumor inoculation', 'Disease', 'MESH:D002372', (346, 363))	('G12V', 'Mutation', 'rs121913529', (124, 128))
539691	30524892	During the challenge experiments, mice were boosted twice with peptide/CpG ODN 1668 vaccinations, two weeks and four weeks after tumor inoculation (Figure 5A).	('tumor inoculation', 'Disease', (129, 146))	('mice', 'Species', '10090', (34, 38))	('ODN 1668', 'Gene', (75, 83))	('peptide/CpG', 'Var', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor inoculation', 'Disease', 'MESH:D002372', (129, 146))	('peptide', 'Chemical', 'MESH:D010455', (63, 70))
539693	30524892	One week after tumor inoculation (day 0) transgene expression was induced followed by two boost vaccinations (peptides + 50 microg CpG ODN 1668 in PBS - week 2, week 4 after tumor inoculation).	('transgene expression', 'Var', (41, 61))	('tumor inoculation', 'Disease', 'MESH:D002372', (174, 191))	('PBS', 'Chemical', 'MESH:D007854', (147, 150))	('peptides', 'Chemical', 'MESH:D010455', (110, 118))	('expression', 'Species', '29278', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor inoculation', 'Disease', (174, 191))	('tumor inoculation', 'Disease', 'MESH:D002372', (15, 32))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('peptides', 'Var', (110, 118))	('tumor inoculation', 'Disease', (15, 32))
539694	30524892	The tumor growth curves of the differentially vaccinated groups of mice reveal an unexpectedly accelerated tumor outgrowth starting day 14 post tumor-inoculation after vaccination with mutated (red curve) and wt (green curve) peptides (Figure 5B).	('mutated', 'Var', (185, 192))	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (144, 149))	('peptides', 'Chemical', 'MESH:D010455', (226, 234))	('rat', 'Species', '10116', (101, 104))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('accelerated', 'PosReg', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mice', 'Species', '10090', (67, 71))
539696	30524892	When testing for mutation-specific IFN-gamma responses in non-vaccinated tumor bearing mice (inoculated with either the parental cell line or the 2277-NS clone expressing specific mutations), recall responses especially against the mutated p53 R248W peptide were detected (Figure 5C, left panel; of note, the parental cell line used for genetic engineering harbors a mutation at position 248 of Tp53 (R248H), which might explain a p53 R248W cytokine response towards the parental cell line.)	('R248W', 'Mutation', 'rs121912651', (244, 249))	('mutation at', 'Var', (367, 378))	('Tp53', 'Gene', (395, 399))	('IFN-gamma', 'Gene', '15978', (35, 44))	('IFN-gamma', 'Gene', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('R248H', 'Mutation', 'p.R248H', (401, 406))	('peptide', 'Chemical', 'MESH:D010455', (250, 257))	('mice', 'Species', '10090', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('R248W', 'Mutation', 'rs121912651', (435, 440))
539697	30524892	This result suggests spontaneous immunogenicity of the introduced mutations in the tumor in vivo and argues for a natural processing of mutated tumor Ags.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
539698	30524892	Importantly, the percentages of tumor-induced IL-2/IFN-gamma double positive, mutated TA-specific T cells in non-vaccinated mice or in mice vaccinated with irrelevant peptides were much lower than those after vaccination in non-tumor bearing mice (Figure 5D, right panels and middle left panel, respectively), clearly indicating the effect of vaccination.	('peptides', 'Chemical', 'MESH:D010455', (167, 175))	('IFN-gamma', 'Gene', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('non-tumor', 'Disease', 'MESH:D009369', (224, 233))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mice', 'Species', '10090', (124, 128))	('IFN-gamma', 'Gene', '15978', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (135, 139))	('lower', 'NegReg', (186, 191))	('tumor', 'Disease', (228, 233))	('mutated', 'Var', (78, 85))	('tumor', 'Disease', (32, 37))	('mice', 'Species', '10090', (242, 246))	('non-tumor', 'Disease', (224, 233))
539699	30524892	The highest percentage of restimulated T cells reactive against p53 R248(W) or Kras G12(V) peptides was found in vaccinated tumor-bearing mice (Figure 5D, very left panel), suggesting that vaccination-induced effector T cell responses in tumor-bearing mice were not hampered but rather boosted in the presence of the tumor.	('mice', 'Species', '10090', (252, 256))	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('p53 R248', 'Var', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (124, 129))	('mice', 'Species', '10090', (138, 142))	('tumor', 'Disease', (238, 243))	('peptides', 'Chemical', 'MESH:D010455', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('rat', 'Species', '10116', (279, 282))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
539703	30524892	Notably, the number of splenic Treg cells was significantly increased in tumor-bearing animals vaccinated with mutated (red group) and wt (green group) peptides compared to tumor bearing mice vaccinated with irrelevant peptides (grey group) or to completely naive mice (square symbols group).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('peptides', 'Chemical', 'MESH:D010455', (219, 227))	('mutated', 'Var', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mice', 'Species', '10090', (264, 268))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (73, 78))	('mice', 'Species', '10090', (187, 191))	('peptides', 'Chemical', 'MESH:D010455', (152, 160))	('increased', 'PosReg', (60, 69))
539706	30524892	Whereas there were no obvious differences in suppression after re-stimulation with Kras peptides, an increased suppression of effector T cells by Treg cells derived from mutation vaccinated mice were detected after re-stimulation with mutated peptide p53 R248W.	('effector T cells', 'CPA', (126, 142))	('R248W', 'Mutation', 'rs121912651', (255, 260))	('suppression', 'NegReg', (111, 122))	('peptide', 'Chemical', 'MESH:D010455', (243, 250))	('peptide', 'Chemical', 'MESH:D010455', (88, 95))	('mice', 'Species', '10090', (190, 194))	('peptides', 'Chemical', 'MESH:D010455', (88, 96))	('mutated peptide p53 R248W', 'Var', (235, 260))
539708	30524892	We therefore conclude that vaccination with highly immunogenic wt and mutated long peptides like p53 R248W, harboring CD4+ T cell epitopes, might comprise the risk to induce a dominant, immune-inhibitory response by induction of Treg cells during preventive vaccination.	('induce', 'PosReg', (167, 173))	('p53 R248W', 'Var', (97, 106))	('R248W', 'Mutation', 'rs121912651', (101, 106))	('peptides', 'Chemical', 'MESH:D010455', (83, 91))
539710	30524892	Based on the observations above, we returned to our bank of A2.DR1 tumor cell lines and screened for lines with intrinsic Kras and Tp53 mutations that may be less immunogenic.	('DR1', 'Gene', (63, 66))	('DR1', 'Gene', '13486', (63, 66))	('Kras', 'Gene', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Tp53', 'Gene', (131, 135))	('mutations', 'Var', (136, 145))	('tumor', 'Disease', (67, 72))
539711	30524892	One cell line (sarcoma line 39) carrying an MCA-induced intrinsic Kras mutation at position G12 (Kras G12C) and a p53 mutation (p53 C176F) was chosen for further tumor challenge experiments (Figure 6A).	('C176F', 'Mutation', 'rs786202962', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('MCA', 'Chemical', 'MESH:D008748', (44, 47))	('tumor', 'Disease', (162, 167))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcoma', 'Disease', (15, 22))	('p53 C176F', 'Var', (128, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('G12C', 'Mutation', 'rs121913530', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
539713	30524892	Both of the mutated peptides elicited mutation-specific responses when compared to their wt counterparts in in vitro cytokine secretion assays with T cells from mutated peptides vaccinated mice (Figure 6C).	('peptides', 'Chemical', 'MESH:D010455', (20, 28))	('responses', 'MPA', (56, 65))	('mice', 'Species', '10090', (189, 193))	('mutated', 'Var', (12, 19))	('elicited mutation-specific', 'Reg', (29, 55))	('peptides', 'Chemical', 'MESH:D010455', (169, 177))
539714	30524892	The strength of the cytokine response towards the p53 peptide comprising the mutation C176F, however, was considerably lower than the response towards the strongly immunogenic peptide p53 R248W (Supplementary Figure 11).	('C176F', 'Var', (86, 91))	('lower', 'NegReg', (119, 124))	('peptide', 'Chemical', 'MESH:D010455', (54, 61))	('cytokine response towards the p53 peptide', 'MPA', (20, 61))	('C176F', 'Mutation', 'rs786202962', (86, 91))	('R248W', 'Mutation', 'rs121912651', (188, 193))	('peptide', 'Chemical', 'MESH:D010455', (176, 183))
539715	30524892	When challenging preventively vaccinated mice (peptides/Montanide ISA 720/CpG ODN 1668 vaccine formulations) with sarcoma line 39 a growth delay in mutated-peptide vaccinated animals was observed compared to non-vaccinated (Figure 6E) and also wt peptide vaccinated mice (Figure 6F).	('Montanide ISA', 'Chemical', '-', (56, 69))	('peptides', 'Chemical', 'MESH:D010455', (47, 55))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('peptide', 'Chemical', 'MESH:D010455', (156, 163))	('sarcoma', 'Disease', (114, 121))	('mice', 'Species', '10090', (41, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('peptide', 'Chemical', 'MESH:D010455', (247, 254))	('peptide', 'Chemical', 'MESH:D010455', (47, 54))	('mutated-peptide', 'Var', (148, 163))	('growth delay', 'Phenotype', 'HP:0001510', (132, 144))	('growth', 'MPA', (132, 138))	('delay', 'NegReg', (139, 144))	('mice', 'Species', '10090', (266, 270))
539716	30524892	Analyzing the frequency of peripheral Treg cells revealed that Treg levels were not elevated in tumor-bearing mice after vaccination with mutated peptides, only after vaccination with wt peptides, when compared to non-tumor-bearing mice (Figure 6G).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutated', 'Var', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('Treg levels', 'MPA', (63, 74))	('tumor', 'Disease', (96, 101))	('mice', 'Species', '10090', (110, 114))	('peptides', 'Chemical', 'MESH:D010455', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('peptides', 'Chemical', 'MESH:D010455', (146, 154))	('non-tumor', 'Disease', (214, 223))	('non-tumor', 'Disease', 'MESH:D009369', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (218, 223))	('mice', 'Species', '10090', (232, 236))
539717	30524892	In the present study we investigated the cancer immunotherapeutic potential of synthetic long peptide sequences comprising common driver gene mutations at hot-spot sites of GI cancers in the oncogene KRAS and the tumor suppressor gene TP53.	('tumor', 'Disease', (213, 218))	('GI cancers', 'Disease', (173, 183))	('mutations', 'Var', (142, 151))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('GI cancers', 'Disease', 'MESH:D009369', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('GI cancer', 'Phenotype', 'HP:0007378', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('peptide', 'Chemical', 'MESH:D010455', (94, 101))
539718	30524892	We identified mutation-specific T cell responses in non-vaccinated CRC patients, demonstrating their immunogenicity in vivo.	('CRC', 'Disease', (67, 70))	('patients', 'Species', '9606', (71, 79))	('rat', 'Species', '10116', (88, 91))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('T cell responses', 'CPA', (32, 48))	('mutation-specific', 'Var', (14, 31))
539719	30524892	Furthermore, we found in a humanized mouse model that vaccination with mixtures of long peptides comprising MHC class I and - II epitopes derived from mutant Kras and p53 protein variants simultaneously induce robust cytotoxic and T helper cell responses against multiple mutations.	('MHC', 'Gene', (108, 111))	('mutant', 'Var', (151, 157))	('T helper cell responses against multiple mutations', 'CPA', (231, 281))	('variants', 'Var', (179, 187))	('MHC', 'Gene', '3107', (108, 111))	('induce', 'PosReg', (203, 209))	('human', 'Species', '9606', (27, 32))	('Kras', 'Gene', (158, 162))	('mouse', 'Species', '10090', (37, 42))	('p53', 'Gene', (167, 170))	('peptides', 'Chemical', 'MESH:D010455', (88, 96))
539720	30524892	However, we also encountered an important caveat of this therapeutic approach by unraveling the induction of TSA specific Treg cells upon vaccination with strongly immunogenic wt and mutated MHC class II epitopes that could drastically hamper vaccine effectiveness.	('mutated', 'Var', (183, 190))	('hamper', 'NegReg', (236, 242))	('MHC', 'Gene', (191, 194))	('MHC', 'Gene', '3107', (191, 194))
539723	30524892	The responses against mutated peptides were overall higher than those against wt peptides arguing for mutation specificity of the tumor Ag specific T cell pool in CRC patients and for immunogenicity of the chosen mutations and long peptide sequences.	('peptides', 'Chemical', 'MESH:D010455', (30, 38))	('peptides', 'Chemical', 'MESH:D010455', (81, 89))	('peptide', 'Chemical', 'MESH:D010455', (232, 239))	('peptide', 'Chemical', 'MESH:D010455', (30, 37))	('peptide', 'Chemical', 'MESH:D010455', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('patients', 'Species', '9606', (167, 175))	('CRC', 'Phenotype', 'HP:0003003', (163, 166))	('mutated', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('higher', 'PosReg', (52, 58))	('tumor', 'Disease', (130, 135))	('responses', 'MPA', (4, 13))
539724	30524892	Our observations are in accordance with investigations defining the preexistence of intrinsic and vaccination-induced TC responses against wt and mutated Kras and p53 sequences in patients with gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (194, 218))	('mutated', 'Var', (146, 153))	('gastrointestinal cancers', 'Disease', (194, 218))	('p53', 'Gene', (163, 166))	('Kras', 'Gene', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('TC', 'Chemical', 'MESH:D013667', (118, 120))	('patients', 'Species', '9606', (180, 188))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
539725	30524892	Vaccination of HLA-transgenic A2.DR1 dtg mice with mixes of up to five different long peptides resulted in polyvalent CD4+ and CD8+ T cell responses against mutated Kras and p53 peptides.	('DR1', 'Gene', '13486', (33, 36))	('peptides', 'Chemical', 'MESH:D010455', (178, 186))	('HLA', 'Gene', '3123', (15, 18))	('CD8', 'Gene', (127, 130))	('mice', 'Species', '10090', (41, 45))	('HLA', 'Gene', (15, 18))	('Kras', 'Gene', (165, 169))	('peptides', 'Chemical', 'MESH:D010455', (86, 94))	('CD8', 'Gene', '925', (127, 130))	('transgenic', 'Species', '10090', (19, 29))	('p53', 'Gene', (174, 177))	('DR1', 'Gene', (33, 36))	('mutated', 'Var', (157, 164))	('dtg', 'Chemical', 'MESH:C562325', (37, 40))
539729	30524892	It circumvents the problem of selecting for tumor Ag-loss variants, broadens the immune response towards sub-dominant epitopes, and induces CD4+ T cell responses that are indispensable to prime and sustain an effective anti-tumor CTL response.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('broadens', 'PosReg', (68, 76))	('variants', 'Var', (58, 66))	('Ag-loss', 'Protein', (50, 57))	('immune response towards sub-dominant epitopes', 'MPA', (81, 126))	('Ag-loss', 'NegReg', (50, 57))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('CD4+ T cell', 'MPA', (140, 151))	('induces', 'Reg', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
539731	30524892	Mutated peptides generally elicited higher CD8+ and CD4+ T cell responses than the corresponding wt peptides implying that the mutation-comprising peptides were recognized as foreign Ags endowed with higher immunogenicity than wt sequences.	('peptides', 'Chemical', 'MESH:D010455', (147, 155))	('higher', 'PosReg', (36, 42))	('CD8', 'Gene', (43, 46))	('elicited', 'Reg', (27, 35))	('peptides', 'Chemical', 'MESH:D010455', (100, 108))	('CD8', 'Gene', '925', (43, 46))	('peptides', 'Chemical', 'MESH:D010455', (8, 16))	('Mutated', 'Var', (0, 7))
539732	30524892	Vaccination induced CD8+ but also CD4+ T cells displayed a poly-functional profile, characterized by simultaneous IFN-gamma and IL-2 expression and signs of cytotoxic activity in vitro.	('expression', 'MPA', (133, 143))	('CD4+', 'Var', (34, 38))	('IFN-gamma', 'Gene', (114, 123))	('CD8', 'Gene', (20, 23))	('CD8', 'Gene', '925', (20, 23))	('cytotoxic activity', 'CPA', (157, 175))	('IFN-gamma', 'Gene', '15978', (114, 123))	('expression', 'Species', '29278', (133, 143))
539734	30524892	In that study vaccination with a single mutated IDH-1 HLA-DRB1-restricted epitope elicited a TH1 effector CD4+ T cell response that was sufficient to delay the outgrowth of IDH-1 mutant sarcomas in A2.DR1 dtg mice.	('mice', 'Species', '10090', (209, 213))	('mutant', 'Var', (179, 185))	('HLA-DRB1', 'Gene', (54, 62))	('HLA-DRB1', 'Gene', '116749', (54, 62))	('outgrowth', 'CPA', (160, 169))	('delay', 'NegReg', (150, 155))	('IDH-1', 'Gene', (48, 53))	('DR1', 'Gene', (201, 204))	('sarcomas', 'Disease', 'MESH:D012509', (186, 194))	('DR1', 'Gene', '13486', (201, 204))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('TH1 effector CD4+ T cell response', 'MPA', (93, 126))	('sarcomas', 'Disease', (186, 194))	('IDH-1', 'Gene', '15926', (48, 53))	('IDH-1', 'Gene', (173, 178))	('dtg', 'Chemical', 'MESH:C562325', (205, 208))	('IDH-1', 'Gene', '15926', (173, 178))
539735	30524892	We further identified Kras G12V and p53 R248W as highly immunogenic mutated peptides in a human HLA-A2/HLA.DRB1 restricted context when used for active vaccination.	('p53 R248W', 'Var', (36, 45))	('HLA.DRB1', 'Gene', '3123', (103, 111))	('human', 'Species', '9606', (90, 95))	('peptides', 'Chemical', 'MESH:D010455', (76, 84))	('Kras G12V', 'Var', (22, 31))	('HLA.DRB1', 'Gene', (103, 111))	('HLA-A', 'Gene', '3105', (96, 101))	('HLA-A', 'Gene', (96, 101))	('R248W', 'Mutation', 'rs121912651', (40, 45))	('G12V', 'Mutation', 'rs121913529', (27, 31))
539736	30524892	Memory T cell responses against the very same mutations were also prominent in human CRC patients.	('Memory T cell responses', 'CPA', (0, 23))	('human', 'Species', '9606', (79, 84))	('mutations', 'Var', (46, 55))	('patients', 'Species', '9606', (89, 97))	('CRC patients', 'Disease', (85, 97))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))
539737	30524892	However, p53 R175H is another highly immunogenic mutation in CRC patients but was only weakly immunogenic after active immunization in the two mouse strains.	('mouse', 'Species', '10090', (143, 148))	('p53 R175H', 'Var', (9, 18))	('CRC', 'Disease', (61, 64))	('patients', 'Species', '9606', (65, 73))	('R175H', 'Mutation', 'rs28934578', (13, 18))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))
539742	30524892	After in vitro epitope mapping we further suggested the short peptides 10-mer p53246-256 R248W and 15-mer p53240-254 R248W as novel, overlapping HLA-A2 and HLA-DRB1-restricted mutated epitopes.	('HLA-A', 'Gene', (145, 150))	('HLA-DRB1', 'Gene', (156, 164))	('HLA-DRB1', 'Gene', '116749', (156, 164))	('R248W', 'Mutation', 'rs121912651', (117, 122))	('peptides', 'Chemical', 'MESH:D010455', (62, 70))	('p53246-256 R248W', 'Var', (78, 94))	('p53240-254 R248W', 'Var', (106, 122))	('HLA-A', 'Gene', '3105', (145, 150))	('R248W', 'Mutation', 'rs121912651', (89, 94))
539744	30524892	We anticipated that a long peptide multi-epitope vaccine, being able to elicit polyvalent, mutation-specific, multi-functional CTL and TH1 responses would delay or prevent the outgrowth of sarcoma lines over-expressing the respective mutations when used in a preventive treatment setting.	('over-expressing', 'PosReg', (203, 218))	('sarcoma', 'Disease', (189, 196))	('prevent', 'NegReg', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('delay', 'NegReg', (155, 160))	('peptide', 'Chemical', 'MESH:D010455', (27, 34))	('sarcoma', 'Disease', 'MESH:D012509', (189, 196))	('mutations', 'Var', (234, 243))	('outgrowth', 'CPA', (176, 185))
539745	30524892	Unexpectedly, vaccination with wt and mutated peptides in the engineered highly immunogenic TSA system rather accelerated tumor outgrowth instead of delaying it compared to mice vaccinated with irrelevant peptides.	('peptides', 'Var', (46, 54))	('rat', 'Species', '10116', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('peptides', 'Chemical', 'MESH:D010455', (46, 54))	('peptides', 'Chemical', 'MESH:D010455', (205, 213))	('rat', 'Species', '10116', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutated peptides', 'Var', (38, 54))	('accelerated', 'PosReg', (110, 121))	('tumor', 'Disease', (122, 127))	('mice', 'Species', '10090', (173, 177))
539747	30524892	In addition to increased numbers of cytokine responsive effector T cells, however, we detected significantly increased numbers of peripheral Treg cells in animals vaccinated with wt and mutated peptides during tumor challenge.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('increased numbers of cytokine responsive effector T', 'Phenotype', 'HP:0025625', (15, 66))	('peptides', 'Chemical', 'MESH:D010455', (194, 202))	('tumor', 'Disease', (210, 215))	('mutated', 'Var', (186, 193))	('increased', 'PosReg', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
539749	30524892	Here, mutation-specific vaccination delayed tumor outgrowth compared to vaccination with wt peptides.	('vaccination', 'Var', (24, 35))	('mutation-specific vaccination', 'Var', (6, 35))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('delayed', 'NegReg', (36, 43))	('peptides', 'Chemical', 'MESH:D010455', (92, 100))	('tumor', 'Disease', (44, 49))
539752	30524892	In contrast, the number of Treg cells in non-tumor-bearing mice vaccinated with highly immunogenic peptides compared to mice vaccinated with lower immunogenic or non-vaccinated mice was not elevated.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mice', 'Species', '10090', (59, 63))	('mice', 'Species', '10090', (120, 124))	('non-tumor', 'Disease', (41, 50))	('peptides', 'Chemical', 'MESH:D010455', (99, 107))	('peptides', 'Var', (99, 107))	('non-tumor', 'Disease', 'MESH:D009369', (41, 50))	('mice', 'Species', '10090', (177, 181))
539759	30524892	However, we cannot exclude the possibility that in the tumor model with lower immunogenic, endogenous mutations the systemic Ag load may have been lower than in the tumor model with over-expressed highly, immunogenic mutations which may have potentially influenced the degree of Treg cell stimulation and recruitment to the tumor.	('recruitment', 'CPA', (305, 316))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Treg cell stimulation', 'CPA', (279, 300))	('lower', 'NegReg', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', (324, 329))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('mutations', 'Var', (102, 111))	('systemic Ag load', 'MPA', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('influenced', 'Reg', (254, 264))	('tumor', 'Disease', 'MESH:D009369', (324, 329))	('tumor', 'Disease', (165, 170))
539762	30524892	In conclusion, we here showed that poly-functional CD8+ and CD4+ helper type 1 effector T cells responses can simultaneously be induced against multiple mutated TSAs in the context of long peptide vaccines.	('mutated', 'Var', (153, 160))	('CD8', 'Gene', (51, 54))	('TSAs', 'Protein', (161, 165))	('CD8', 'Gene', '925', (51, 54))	('peptide', 'Chemical', 'MESH:D010455', (189, 196))
539766	30524892	The most relevant mutations in TP53, KRAS and BRAF genes for colorectal and pancreatic cancer were chosen using the IARC TP53 Database (version R17, November 2013) and COSMIC database for somatic mutations in cancer (from the Sanger Institute, COSMIC v69 Release), respectively.	('BRAF', 'Gene', (46, 50))	('cancer', 'Disease', (87, 93))	('colorectal', 'Disease', 'MESH:D015179', (61, 71))	('TP53', 'Gene', (31, 35))	('pancreatic cancer', 'Disease', (76, 93))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('colorectal', 'Disease', (61, 71))	('KRAS', 'Gene', (37, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('cancer', 'Disease', (209, 215))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('mutations', 'Var', (18, 27))
539772	30524892	Exon sequencing was performed to screen for mutations in the TP53, KRAS and BRAF genes in CRC patients' tumors and metastasis.	('BRAF', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('patients', 'Species', '9606', (94, 102))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('KRAS', 'Gene', (67, 71))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', (61, 65))
539777	30524892	Afterwards, the non-adherent cell fraction was removed by repeated washing with RPMI-1640 and further cultured in X-Vivo-20 supplemented with 100 IU/ml interleukin 2 (rHu IL-2 (proleukine), Novartis, DA1318BG) and 60 IU/ml IL-4 (rHu IL-4, Miltenyi, 130-093-924).	('RPMI-1640', 'Chemical', '-', (80, 89))	('interleukin 2', 'Gene', '16183', (152, 165))	('Novartis', 'Disease', 'None', (190, 198))	('interleukin 2', 'Gene', (152, 165))	('IL-4', 'Gene', (233, 237))	('Novartis', 'Disease', (190, 198))	('IL-4', 'Gene', (223, 227))	('IL-4', 'Gene', '16189', (223, 227))	('rHu', 'Var', (167, 170))	('X-Vivo-20', 'Chemical', '-', (114, 123))	('IL-4', 'Gene', '16189', (233, 237))
539807	30524892	For the generation of 2277-NS mutant Tp53/Kras transgene expressing sublines, FRT expression vectors containing a hygromycin (InvitrogenTM, Life technologies, 10687-010) resistance gene, tet repressor gene (tetR) as well as a tetracycline-responsive CMV promoter were cloned upstream of the wt and mutant chimeric mutant Tp53/Kras transgenes' ORFs, respectively, for inducible transgene expression.	('expression', 'Species', '29278', (82, 92))	('expression', 'Species', '29278', (387, 397))	('rat', 'Species', '10116', (12, 15))	('mutant', 'Var', (314, 320))	('Tp53/Kras', 'Gene', (321, 330))	('expression vectors', 'Species', '29278', (82, 100))	('mutant', 'Var', (298, 304))	('hygromycin', 'Chemical', 'MESH:C026273', (114, 124))	('tetracycline', 'Chemical', 'MESH:D013752', (226, 238))
539836	30524892	For cytokine secretion assays cell surface was stained for 20 min on ice in the dark with the following directly fluorescent-labeled antibodies: anti-CD4-FITC (BD, 553047), anti-CD8-Pacific Blue (BD, 558106), IFNgamma-detector-PE (Secretion assay kit, Miltenyi, 130-090-516), IL-2-detector-APC (Secretion assay kit, Miltenyi, 130-090-987), anti-CD11c-PE-Cy7 (BD, 558079).	('CD8', 'Gene', (178, 181))	('CD8', 'Gene', '925', (178, 181))	('anti-CD4-FITC', 'Var', (145, 158))	('CD11c', 'Gene', '16411', (345, 350))	('CD11c', 'Gene', (345, 350))
539837	30524892	In case of combinations of secretion assay and intracellular cytokine stainings the surface markers were stained for with anti-CD4-V500 (BD, 560782), anti-CD8-Pacific Blue (BD, 558106), IFNgamma-detector-PE (Secretion assay kit, Miltenyi, 130-090-516) anti-CD11c-PE-Cy7 (BD, 558079).	('anti-CD4-V500', 'Var', (122, 135))	('CD11c', 'Gene', '16411', (257, 262))	('CD11c', 'Gene', (257, 262))	('CD8', 'Gene', (155, 158))	('CD8', 'Gene', '925', (155, 158))
539864	30524892	NuPAGE  10% or 4-12% Bis-Tris Precast Gels (1.0 mm, 10 or 15 wells; Novex  by Life TechnologiesTM, NP0302BOX or NP0321BOX) were used for SDS-PAGE.	('SDS', 'Chemical', 'MESH:D012967', (137, 140))	('Bis-Tris', 'Chemical', 'MESH:C026272', (21, 29))	('NP0302BOX', 'Var', (99, 108))	('NP0321BOX', 'Var', (112, 121))
539866	30524892	Blocking with either performed in 2.5% BSA (Sigma-Aldrich, A9418-50G) in PBS-T (PBS plus 0.1% Tween-20) or 5% milk powder in PBS-T depending on primary antibodies.	('A9418-50G', 'Var', (59, 68))	('PBS-T', 'Disease', 'MESH:D011535', (125, 130))	('PBS-T', 'Disease', 'MESH:D011535', (73, 78))	('A9418-50G', 'SUBSTITUTION', 'None', (59, 68))	('PBS-T', 'Disease', (125, 130))	('PBS-T', 'Disease', (73, 78))	('Tween-20', 'Chemical', 'MESH:D011136', (94, 102))	('PBS', 'Chemical', 'MESH:D007854', (73, 76))	('PBS', 'Chemical', 'MESH:D007854', (80, 83))	('PBS', 'Chemical', 'MESH:D007854', (125, 128))
539872	30524892	Received sequences were screened for mutations by alignment with corresponding wild-type sequences (Serial Cloner, SerialBasics and BLAST, NCBI) and analysis of sequencing histograms employing Chromas Lite software (Technelysium).	('mutations', 'Var', (37, 46))	('Chromas Lite', 'Disease', (193, 205))	('Chromas Lite', 'Disease', 'None', (193, 205))
539885	29352292	The presence of KSHV also significantly affected the cellular transcriptome profile.	('affected', 'Reg', (40, 48))	('cellular transcriptome profile', 'MPA', (53, 83))	('KSHV', 'Gene', (16, 20))	('KSHV', 'Species', '37296', (16, 20))	('KS', 'Phenotype', 'HP:0100726', (16, 18))	('presence', 'Var', (4, 12))
539895	29352292	Additionally, cellular genes involved in lipid and glucose metabolism disorder pathways are significantly affected by the presence of KSHV.	('KSHV', 'Species', '37296', (134, 138))	('cellular genes', 'Gene', (14, 28))	('affected', 'Reg', (106, 114))	('KSHV', 'Gene', (134, 138))	('glucose metabolism disorder', 'Disease', 'MESH:D044882', (51, 78))	('lipid', 'Chemical', 'MESH:D008055', (41, 46))	('lipid', 'MPA', (41, 46))	('glucose metabolism disorder', 'Disease', (51, 78))	('KS', 'Phenotype', 'HP:0100726', (134, 136))	('presence', 'Var', (122, 130))
539931	29352292	We found that KSHV has significantly impacted the cellular gene expression that were involved in the lipid and glucose metabolism disorder pathways.	('KSHV', 'Species', '37296', (14, 18))	('KSHV', 'Var', (14, 18))	('KS', 'Phenotype', 'HP:0100726', (14, 16))	('glucose metabolism disorder', 'Disease', 'MESH:D044882', (111, 138))	('cellular gene expression', 'MPA', (50, 74))	('lipid', 'Chemical', 'MESH:D008055', (101, 106))	('glucose metabolism disorder', 'Disease', (111, 138))	('impacted', 'Reg', (37, 45))
539971	29352292	Microarray data from external sets (GSE6489, GSE45590, GSE66682) was quantile normalized and log2-transformed before statistical evaluation by one-way ANOVA with correction for multiple testing to estimate FDR as previously described.	('GSE6489', 'Var', (36, 43))	('GSE6489', 'Chemical', '-', (36, 43))	('GSE45590', 'Var', (45, 53))	('GSE66682', 'Var', (55, 63))
540052	29352292	It is worth noting that patients p32 and p83 had been on ART for an extended period of time, suggesting that ART might have stimulated some recovery of innate and adaptive anti-KSHV or anti-tumor immune response, but still was insufficient to suppress the KS development.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('ART', 'Var', (109, 112))	('p32', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('p83', 'Gene', '23221', (41, 44))	('p83', 'Gene', (41, 44))	('insufficient', 'Disease', 'MESH:D000309', (227, 239))	('tumor', 'Disease', (190, 195))	('KS development', 'CPA', (256, 270))	('men', 'Species', '9606', (266, 269))	('insufficient', 'Disease', (227, 239))	('patients', 'Species', '9606', (24, 32))	('KSHV', 'Species', '37296', (177, 181))	('p32', 'Gene', '925', (33, 36))	('KS', 'Phenotype', 'HP:0100726', (177, 179))	('KS', 'Phenotype', 'HP:0100726', (256, 258))
540070	29352292	Interestingly, it had been reported that both ART and HIV-1 are capable of inducing lipid dysregulation, which is therefore a plausible cause for the decreased lipid metabolism observed in these epidemic KS patients.	('patients', 'Species', '9606', (207, 215))	('lipid metabolism', 'MPA', (160, 176))	('ART', 'Var', (46, 49))	('KS', 'Phenotype', 'HP:0100726', (204, 206))	('lipid dysregulation', 'MPA', (84, 103))	('HIV-1', 'Species', '11676', (54, 59))	('HIV-1', 'Gene', (54, 59))	('lipid', 'Chemical', 'MESH:D008055', (84, 89))	('inducing', 'Reg', (75, 83))	('decreased', 'NegReg', (150, 159))	('lipid', 'Chemical', 'MESH:D008055', (160, 165))
540086	26873726	In this current study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo.	('diminish', 'NegReg', (56, 64))	('tumor', 'Disease', (79, 84))	('renal and liver tumors', 'Disease', 'MESH:D058186', (106, 128))	('liver tumors', 'Phenotype', 'HP:0002896', (116, 128))	('UAB30', 'Var', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('UAB30', 'Chemical', 'MESH:C112106', (44, 49))	('liver tumor', 'Phenotype', 'HP:0002896', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
540088	26873726	Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment.	('human', 'Species', '9606', (42, 47))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (48, 62))	('decreased tumor', 'Disease', 'MESH:D009369', (116, 131))	('renal tumors', 'Disease', (77, 89))	('UAB30', 'Chemical', 'MESH:C112106', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('renal tumors', 'Disease', 'MESH:D007674', (77, 89))	('UAB30', 'Var', (185, 190))	('decreased tumor', 'Disease', (116, 131))	('renal tumor', 'Phenotype', 'HP:0009726', (77, 88))	('renal tumors', 'Phenotype', 'HP:0009726', (77, 89))	('human', 'Species', '9606', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('hepatoblastoma', 'Disease', (48, 62))	('increased', 'PosReg', (153, 162))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('animal survival', 'CPA', (163, 178))	('hepatoblastoma', 'Disease', 'MESH:D018197', (48, 62))	('murine', 'Species', '10090', (25, 31))
540098	26873726	UAB30 has minimal toxicity compared to other retinoids [ - ], and has recently been found to be effective in decreasing xenograft tumor growth in neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (146, 159))	('neuroblastoma', 'Disease', (146, 159))	('decreasing', 'NegReg', (109, 119))	('neuroblastoma', 'Phenotype', 'HP:0003006', (146, 159))	('toxicity', 'Disease', 'MESH:D064420', (18, 26))	('UAB30', 'Var', (0, 5))	('toxicity', 'Disease', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('UAB30', 'Chemical', 'MESH:C112106', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('retinoids', 'Chemical', 'MESH:D012176', (45, 54))	('tumor', 'Disease', (130, 135))
540100	26873726	These data in neuroblastoma, and the prior results with retinoids in adult renal and hepatic malignancies, led us to believe that UAB30 may have an effect upon tumorigenicity in rare pediatric renal and hepatic malignancies.	('hepatic malignancies', 'Phenotype', 'HP:0002896', (203, 223))	('neuroblastoma', 'Phenotype', 'HP:0003006', (14, 27))	('UAB30', 'Var', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('adult renal and hepatic malignancies', 'Disease', 'MESH:D007674', (69, 105))	('effect', 'Reg', (148, 154))	('UAB30', 'Chemical', 'MESH:C112106', (130, 135))	('pediatric renal and hepatic malignancies', 'Disease', 'MESH:D007674', (183, 223))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('retinoids', 'Chemical', 'MESH:D012176', (56, 65))	('neuroblastoma', 'Disease', 'MESH:D009447', (14, 27))	('hepatic malignancies', 'Phenotype', 'HP:0002896', (85, 105))	('tumor', 'Disease', (160, 165))	('neuroblastoma', 'Disease', (14, 27))
540101	26873726	We hypothesized that the treatment of the rare pediatric renal tumors, MRKT and renal Ewing sarcoma, and hepatoblastoma with UAB30 would impact tumor growth in vitro and in vivo.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('renal Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 99))	('pediatric renal tumors', 'Disease', (47, 69))	('impact', 'Reg', (137, 143))	('UAB30', 'Var', (125, 130))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (86, 99))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (144, 149))	('hepatoblastoma', 'Disease', (105, 119))	('hepatoblastoma', 'Disease', 'MESH:D018197', (105, 119))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('pediatric renal tumors', 'Disease', 'MESH:D007674', (47, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('UAB30', 'Chemical', 'MESH:C112106', (125, 130))	('renal Ewing sarcoma', 'Disease', (80, 99))	('renal tumor', 'Phenotype', 'HP:0009726', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('renal tumors', 'Phenotype', 'HP:0009726', (57, 69))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (105, 119))
540110	26873726	Rabbit anti-phospho ERK1/2 (05-797R), mouse anti-FAK (4.47) and anti-phospho Src (Y416, 05-677) was from Millipore (EMD Millipore, Billerica, MA).	('mouse', 'Species', '10090', (38, 43))	('05-797R', 'Var', (28, 35))	('Y416', 'Var', (82, 86))	('Rabbit', 'Species', '9986', (0, 6))
540152	26873726	Animals were followed until IACUC parameters for euthanasia were met (6 or 7 weeks, HuH6 and G401, respectively), at which point all animals were euthanized with CO2 and bilateral thoracotomy and the tumors harvested.	('CO2', 'Chemical', '-', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('G401', 'Var', (93, 97))	('HuH6', 'CellLine', 'CVCL:4381', (84, 88))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))
540164	26873726	1B, Supplemental Data Figure 1), indicating that UAB30 functioned as an RXR agonist.	('RXR', 'Gene', '6256', (72, 75))	('UAB30', 'Chemical', 'MESH:C112106', (49, 54))	('RXR', 'Gene', (72, 75))	('UAB30', 'Var', (49, 54))
540166	26873726	Human specimens were obtained from the tumor repository at our institution (IRB: X10093009; X110825022).	('Human', 'Species', '9606', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('X110825022', 'Var', (92, 102))	('tumor', 'Disease', (39, 44))
540170	26873726	The LD50 for UAB30 was calculated: G401, 30 +- 4 muM; SK-NEP-1, 22 +- 2 muM; and HuH6, 78 +- 9 muM.	('muM', 'Gene', '56925', (49, 52))	('NEP-1', 'Gene', '10436', (57, 62))	('NEP-1', 'Gene', (57, 62))	('muM', 'Gene', '56925', (72, 75))	('muM', 'Gene', (49, 52))	('muM', 'Gene', '56925', (95, 98))	('UAB30', 'Chemical', 'MESH:C112106', (13, 18))	('muM', 'Gene', (72, 75))	('G401', 'Var', (35, 39))	('HuH6', 'CellLine', 'CVCL:4381', (81, 85))	('muM', 'Gene', (95, 98))
540173	26873726	Reduction of total caspase 3 was detected by immunoblotting in all three cell lines at 100 muM UAB30 (Supplemental Data Figure 2) and activation of caspase 3 was significantly increased in all three cell lines (p <= 0.05) by treatment with UAB30 (50 muM) (Fig.	('caspase 3', 'Gene', (148, 157))	('increased', 'PosReg', (176, 185))	('caspase 3', 'Gene', '836', (148, 157))	('UAB30', 'Var', (95, 100))	('activation', 'PosReg', (134, 144))	('caspase 3', 'Gene', (19, 28))	('UAB30', 'Chemical', 'MESH:C112106', (95, 100))	('Reduction', 'NegReg', (0, 9))	('UAB30', 'Chemical', 'MESH:C112106', (240, 245))	('muM', 'Gene', '56925', (91, 94))	('muM', 'Gene', '56925', (250, 253))	('caspase 3', 'Gene', '836', (19, 28))	('muM', 'Gene', (91, 94))	('muM', 'Gene', (250, 253))
540177	26873726	UAB30 led to arrest in cell cycle G0/G1 progression in all cell lines with an increased percentage of cells in G1 (p <= 0.05) and decreased percentage of cells in S phase (p <= 0.05) (Fig.	('cell cycle G0/G1 progression', 'CPA', (23, 51))	('UAB30', 'Var', (0, 5))	('UAB30', 'Chemical', 'MESH:C112106', (0, 5))	('increased', 'PosReg', (78, 87))	('decreased', 'NegReg', (130, 139))
540178	26873726	After finding cell cycle arrest, we wished to determine if UAB30 would also affect cellular proliferation.	('affect', 'Reg', (76, 82))	('cell cycle arrest', 'CPA', (14, 31))	('UAB30', 'Var', (59, 64))	('UAB30', 'Chemical', 'MESH:C112106', (59, 64))	('cellular proliferation', 'CPA', (83, 105))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (14, 31))
540182	26873726	Together, these data indicated that UAB30 diminished cellular proliferation.	('cellular proliferation', 'CPA', (53, 75))	('UAB30', 'Chemical', 'MESH:C112106', (36, 41))	('UAB30', 'Var', (36, 41))	('diminished', 'NegReg', (42, 52))
540183	26873726	Next we wished to determine if UAB30 would alter other phenotypic features of the tumor cells.	('alter', 'Reg', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('UAB30', 'Var', (31, 36))	('UAB30', 'Chemical', 'MESH:C112106', (31, 36))
540189	26873726	The number of colonies detected at the end of the studies was decreased by 34% (p <= 0.01), 26% (p <= 0.05) and 86% (p <= 0.01) in the UAB30-treated G401, SK-NEP-1, and HuH6 cell lines, respectively, compared to controls (Fig.	('UAB30', 'Chemical', 'MESH:C112106', (135, 140))	('UAB30-treated', 'Var', (135, 148))	('decreased', 'NegReg', (62, 71))	('HuH6', 'CellLine', 'CVCL:4381', (169, 173))	('NEP-1', 'Gene', (158, 163))	('NEP-1', 'Gene', '10436', (158, 163))
540192	26873726	There was a significant decrease in the number of migrating cells beginning at 5 muM UAB30 when compared to controls (p <= 0.01) (Fig.	('UAB30', 'Var', (85, 90))	('UAB30', 'Chemical', 'MESH:C112106', (85, 90))	('decrease', 'NegReg', (24, 32))	('muM', 'Gene', '56925', (81, 84))	('muM', 'Gene', (81, 84))
540193	26873726	Representative photographs of the stained inserts demonstrate decreased migration following UAB30 treatment (Fig.	('decreased', 'NegReg', (62, 71))	('migration', 'CPA', (72, 81))	('UAB30', 'Chemical', 'MESH:C112106', (92, 97))	('UAB30', 'Var', (92, 97))
540194	26873726	The UAB30-treated cells showed a significant decrease in their migration across a monolayer scratch injury (Supplemental Data Figure 4A, B).	('UAB30', 'Chemical', 'MESH:C112106', (4, 9))	('decrease', 'NegReg', (45, 53))	('migration across a monolayer scratch injury', 'CPA', (63, 106))	('UAB30-treated', 'Var', (4, 17))
540201	26873726	The tumors in the G401 control-treated animals grew more rapidly and were significantly larger at seven weeks than the UAB30 treated animals (662 +- 189 mm3 vs. 36 +- 13 mm3, control vs. UAB30, p = 0.003) (Fig.	('UAB30', 'Chemical', 'MESH:C112106', (187, 192))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('larger', 'PosReg', (88, 94))	('UAB30', 'Chemical', 'MESH:C112106', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('G401', 'Var', (18, 22))	('grew', 'CPA', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
540203	26873726	Ki67 decreased in the UAB30 treated tumors, but differences were not statistically significant.	('UAB30', 'Var', (22, 27))	('Ki67', 'Chemical', '-', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('UAB30', 'Chemical', 'MESH:C112106', (22, 27))	('Ki67', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('decreased', 'NegReg', (5, 14))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
540205	26873726	An orthotopic nude mouse model was used to evaluate UAB30 upon the growth of renal Ewing sarcoma cells and their ability to form lung metastasis.	('renal Ewing sarcoma', 'Disease', (77, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('renal Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 96))	('mouse', 'Species', '10090', (19, 24))	('UAB30', 'Var', (52, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (83, 96))	('UAB30', 'Chemical', 'MESH:C112106', (52, 57))
540210	26873726	Animals treated with UAB30 had significantly smaller tumor weights (0.6 +- 0.1 g vs. 1.5 +- 0.2 g, UAB30 vs. control, p = 0.003) (Fig.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('UAB30', 'Var', (99, 104))	('smaller', 'NegReg', (45, 52))	('UAB30', 'Chemical', 'MESH:C112106', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('UAB30', 'Var', (21, 26))	('UAB30', 'Chemical', 'MESH:C112106', (21, 26))	('tumor', 'Disease', (53, 58))
540212	26873726	Animals that received UAB30 demonstrated less weight gain than the control animals, therefore, a tumor weight to animal weight ratio was calculated to determine if the lack of weight gain could explain the differences in tumor weight.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('weight gain', 'Phenotype', 'HP:0004324', (176, 187))	('UAB30', 'Var', (22, 27))	('weight gain', 'Phenotype', 'HP:0004324', (46, 57))	('weight gain', 'Disease', (176, 187))	('UAB30', 'Chemical', 'MESH:C112106', (22, 27))	('weight gain', 'Disease', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('lack of weight', 'Phenotype', 'HP:0004325', (168, 182))	('less', 'NegReg', (41, 45))	('weight gain', 'Disease', 'MESH:D015430', (176, 187))	('weight gain', 'Disease', 'MESH:D015430', (46, 57))
540213	26873726	The UAB30 treated animals had a significantly smaller ratio than the control animals (Supplemental Data Figure 5), which demonstrated that the treatment, rather than the smaller animal size, accounted for the decreased kidney tumor growth.	('UAB30', 'Var', (4, 9))	('decreased kidney tumor', 'Disease', (209, 231))	('decreased kidney', 'Phenotype', 'HP:0000089', (209, 225))	('UAB30', 'Chemical', 'MESH:C112106', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('kidney tumor', 'Phenotype', 'HP:0009726', (219, 231))	('decreased kidney tumor', 'Disease', 'MESH:D007680', (209, 231))
540226	26873726	There was a decrease in cell proliferation in the UAB30 treated animals compared to controls, but it did not reach statistical significance (80% vs. 58%, control vs. UAB30, p = 0.1).	('UAB30', 'Var', (50, 55))	('UAB30', 'Chemical', 'MESH:C112106', (50, 55))	('cell proliferation', 'CPA', (24, 42))	('UAB30', 'Chemical', 'MESH:C112106', (166, 171))	('decrease', 'NegReg', (12, 20))
540233	26873726	The RXR receptors have been documented in HCC cell lines, a primarily adult hepatic malignancy, so it was not completely unexpected that this nuclear receptor would be present in hepatoblastoma, and abnormalities in the RXR receptors have been highly associated with HCC progression.	('HCC', 'Gene', (267, 270))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (179, 193))	('RXR', 'Gene', (4, 7))	('hepatic malignancy', 'Disease', (76, 94))	('associated with', 'Reg', (251, 266))	('hepatoblastoma', 'Disease', (179, 193))	('HCC', 'Gene', '619501', (267, 270))	('hepatic malignancy', 'Disease', 'MESH:D056486', (76, 94))	('HCC', 'Gene', (42, 45))	('RXR', 'Gene', '6256', (4, 7))	('HCC', 'Phenotype', 'HP:0001402', (267, 270))	('HCC', 'Phenotype', 'HP:0001402', (42, 45))	('RXR', 'Gene', '6256', (220, 223))	('hepatoblastoma', 'Disease', 'MESH:D018197', (179, 193))	('HCC', 'Gene', '619501', (42, 45))	('hepatic malignancy', 'Phenotype', 'HP:0002896', (76, 94))	('abnormalities', 'Var', (199, 212))	('RXR', 'Gene', (220, 223))
540259	26873726	In the adult trials that have been conducted, the patients given UAB30 did not experience changes in appetite or weight loss.	('weight loss', 'Disease', (113, 124))	('patients', 'Species', '9606', (50, 58))	('weight loss', 'Phenotype', 'HP:0001824', (113, 124))	('appetite', 'CPA', (101, 109))	('UAB30', 'Var', (65, 70))	('UAB30', 'Chemical', 'MESH:C112106', (65, 70))	('weight loss', 'Disease', 'MESH:D015431', (113, 124))
540263	26873726	Therefore, we chose to incorporate this same model in our animal studies, looking at the ability of UAB30 to prevent tumor establishment or metastasis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('UAB30', 'Chemical', 'MESH:C112106', (100, 105))	('metastasis', 'CPA', (140, 150))	('UAB30', 'Var', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
540267	26873726	In addition, UAB30 led to changes in cellular phenotypes that resulted in cell cycle arrest and decreased migration and invasion in vitro.	('changes', 'Reg', (26, 33))	('decreased', 'NegReg', (96, 105))	('UAB30', 'Var', (13, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('cell cycle arrest', 'CPA', (74, 91))	('UAB30', 'Chemical', 'MESH:C112106', (13, 18))
540355	31964123	Overall, a significant increase in overall complication rate (100% vs. 28.0%, P=0.001) and hematoma (28.6% vs. 0.0%, P=0.042) was seen in the delayed reconstruction group.	('delayed', 'Var', (142, 149))	('hematoma', 'Disease', (91, 99))	('increase', 'PosReg', (23, 31))	('hematoma', 'Disease', 'MESH:D006406', (91, 99))	('complication', 'CPA', (43, 55))
540433	30816547	Several of these pathways were previously reported to be involved in tumor genesis or progression, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance (hsa01521), signaling pathways regulating stem cell pluripotency (hsa04550), extracellular matrix (ECM)-receptor interaction (hsa04512), focal adhesion (hsa04510), transcriptional misregulation in cancer (hsa05202) and the phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway (hsa04151).	('EGFR', 'Gene', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Disease', (383, 389))	('cancer', 'Disease', 'MESH:D009369', (383, 389))	('epidermal growth factor receptor', 'Gene', '1956', (109, 141))	('tumor', 'Disease', (69, 74))	('Akt', 'Gene', (462, 465))	('hsa04151', 'Var', (486, 494))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('hsa05202', 'Var', (391, 399))	('hsa04510', 'Var', (339, 347))	('EGFR', 'Gene', '1956', (143, 147))	('epidermal growth factor receptor', 'Gene', (109, 141))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('Akt', 'Gene', '207', (462, 465))	('involved', 'Reg', (57, 65))
540468	30816547	The dysregulation of CRK expression has been implicated in various aggressive human malignances, including synovial sarcoma, bladder cancer and breast cancer.	('human', 'Species', '9606', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('CRK', 'Gene', '1398', (21, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (107, 123))	('synovial sarcoma', 'Disease', 'MESH:D013584', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('dysregulation', 'Var', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('CRK', 'Gene', (21, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('implicated', 'Reg', (45, 55))	('synovial sarcoma', 'Disease', (107, 123))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))
540476	30816547	PIK3R2 was recently reported to be targeted by microRNA-126-3p and to suppress Kaposi's sarcoma cell proliferation.	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (79, 95))	("Kaposi's sarcoma", 'Disease', (79, 95))	('suppress', 'NegReg', (70, 78))	('PIK3R2', 'Gene', (0, 6))	('PIK3R2', 'Gene', '5296', (0, 6))	('microRNA-126-3p', 'Var', (47, 62))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (79, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
540628	28391003	An SYT rearrangement was detected in 98% of the tumours evaluated, but 17% were not tested.	('SYT', 'Gene', '6760', (3, 6))	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('rearrangement', 'Var', (7, 20))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('SYT', 'Gene', (3, 6))	('tumours', 'Disease', 'MESH:D009369', (48, 55))
540665	32560574	Almost 30% of adenocarcinomas of the lung are driven by an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('activating', 'PosReg', (59, 69))	('mutation', 'Var', (120, 128))	('KRAS', 'Gene', (114, 118))	('adenocarcinomas', 'Disease', 'MESH:D000230', (14, 29))	('adenocarcinomas', 'Disease', (14, 29))	('driven by', 'Reg', (46, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
540672	32560574	Somatic mutations in epidermal growth factor receptor (EGFR) and rearrangements in anaplastic lymphoma receptor tyrosine kinase (ALK), proto-oncogene tyrosine-protein kinase ROS (ROS) and RET proto-oncogene (RET) have been nominated as solid predictive biomarkers and attractive drug targets in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (295, 300))	('lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('ROS', 'Chemical', '-', (179, 182))	('ALK', 'Gene', (129, 132))	('anaplastic lymphoma receptor tyrosine kinase', 'Gene', '238', (83, 127))	('epidermal growth factor receptor', 'Gene', (21, 53))	('EGFR', 'Gene', (55, 59))	('anaplastic lymphoma receptor tyrosine kinase', 'Gene', (83, 127))	('rearrangements', 'Var', (65, 79))	('mutations', 'Var', (8, 17))	('epidermal growth factor receptor', 'Gene', '1956', (21, 53))	('ROS', 'Gene', (179, 182))	('ALK', 'Gene', '238', (129, 132))	('men', 'Species', '9606', (74, 77))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (83, 102))	('ROS', 'Chemical', '-', (174, 177))	('NSCLC', 'Disease', (295, 300))
540677	32560574	Oncogenic mutations in RAS proteins impair their ability for GTP hydrolysis, resulting in the accumulation of GTP-bound active RAS (Figure 1) and hyperactivation of downstream signaling cascades that lead to uncontrolled cell proliferation and survival.	('lead to', 'Reg', (200, 207))	('GTP', 'Chemical', 'MESH:D006160', (61, 64))	('hyperactivation', 'PosReg', (146, 161))	('uncontrolled cell proliferation', 'CPA', (208, 239))	('RAS', 'Protein', (127, 130))	('GTP', 'Chemical', 'MESH:D006160', (110, 113))	('GTP-bound active', 'MPA', (110, 126))	('ability', 'MPA', (49, 56))	('survival', 'CPA', (244, 252))	('rat', 'Species', '10116', (233, 236))	('RAS', 'Gene', (23, 26))	('accumulation', 'PosReg', (94, 106))	('mutations', 'Var', (10, 19))	('GTP hydrolysis', 'MPA', (61, 75))	('impair', 'NegReg', (36, 42))
540679	32560574	KRAS is the isoform most frequently altered in 86% of RAS mutant cancer cases, followed by NRAS 11% and HRAS 3%.	('mutant', 'Var', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('altered', 'Reg', (36, 43))	('RAS', 'Gene', (54, 57))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
540681	32560574	KRAS mutations account for approximately 30% of lung adenocarcinomas in Western countries and for 10-15% of cases in Asia.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (48, 68))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (48, 68))	('mutations', 'Var', (5, 14))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('KRAS', 'Gene', (0, 4))	('lung adenocarcinomas', 'Disease', (48, 68))
540682	32560574	The KRASG12C mutation is highly prevalent in patients suffering from lung adenocarcinoma (13% of total lung adenocarcinoma) and account for >50% of all KRAS mutant cases.	('KRASG12C', 'Var', (4, 12))	('lung adenocarcinoma', 'Disease', (69, 88))	('lung adenocarcinoma', 'Disease', (103, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (69, 88))	('KRASG12C', 'Chemical', '-', (4, 12))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('prevalent', 'Reg', (32, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('patients', 'Species', '9606', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))
540683	32560574	KRAS mutant lung cancers have worse outcomes in both early stage and advanced metastatic settings, illustrating the critical need for novel agents targeting KRAS-driven NSCLC.	('lung cancers', 'Phenotype', 'HP:0100526', (12, 24))	('rat', 'Species', '10116', (105, 108))	('NSCLC', 'Disease', (169, 174))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('lung cancers', 'Disease', (12, 24))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('mutant', 'Var', (5, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('lung cancers', 'Disease', 'MESH:D008175', (12, 24))	('KRAS', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
540688	32560574	Recent RNA sequencing efforts in KRAS+ NSCLC defined three expression clusters dominated by the co-mutations in serine/threonine kinase 11 (STK11, also known as liver kinase B1 (LKB1)) and tumor protein p53 (p53), inactivation of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) and low levels of thyroid transcription factor-1.	('inactivation', 'Var', (214, 226))	('2A/B', 'SUBSTITUTION', 'None', (264, 268))	('2A/B', 'Var', (264, 268))	('CDKN2A/B', 'Gene', (270, 278))	('NSCLC', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('thyroid transcription factor-1', 'Gene', '7080', (298, 328))	('co-mutations', 'Var', (96, 108))	('CDKN2A/B', 'Gene', '1029;1030', (270, 278))	('serine/threonine kinase 11', 'Gene', '6794', (112, 138))	('2A/B', 'Var', (274, 278))	('tumor', 'Disease', (189, 194))	('2A/B', 'SUBSTITUTION', 'None', (274, 278))	('low levels of thyroid', 'Phenotype', 'HP:0000821', (284, 305))	('liver kinase B1', 'Gene', '6794', (161, 176))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('thyroid transcription factor-1', 'Gene', (298, 328))	('liver kinase B1', 'Gene', (161, 176))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('serine/threonine kinase 11', 'Gene', (112, 138))
540689	32560574	KRAS/STK11 driven tumors were characterized by hypoxia-inducible factor-1 alpha-mediated metabolic reprogramming and adaptation to oxidative and endoplasmic reticulum stress and showed enrichment in Kelch-like ECH-associated protein 1 (KEAP1) mutations21.	('KEAP1', 'Gene', (236, 241))	('Kelch-like ECH-associated protein 1', 'Gene', (199, 234))	('hypoxia-inducible factor-1 alpha', 'Gene', (47, 79))	('men', 'Species', '9606', (191, 194))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (199, 234))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('KRAS/STK11', 'Gene', (0, 10))	('KEAP1', 'Gene', '9817', (236, 241))	('stress', 'Disease', 'MESH:D000079225', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('mutations21', 'Var', (243, 254))	('stress', 'Disease', (167, 173))	('hypoxia-inducible factor-1 alpha', 'Gene', '3091', (47, 79))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
540691	32560574	The presence of major co-mutations is of prognostic significance (e.g., STK11 or KEAP1 mutations are associated with worse overall survival) and of predictive value for therapeutic vulnerabilities.	('KEAP1', 'Gene', (81, 86))	('worse', 'NegReg', (117, 122))	('STK11', 'Gene', (72, 77))	('KEAP1', 'Gene', '9817', (81, 86))	('mutations', 'Var', (87, 96))
540692	32560574	To date, the most frequent KRAS mutations in NSCLC have been documented at codons 12 and 13.	('men', 'Species', '9606', (65, 68))	('NSCLC', 'Disease', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', (27, 31))
540693	32560574	Among those, glycine 12 to cysteine (G12C) and glycine 12 to valine (G12V) are the most common subtypes associated with a smoking history, whereas glycine 12 to aspartic acid (G12D) is mainly found in never smokers.	('smoking history', 'Disease', (122, 137))	('glycine 12 to aspartic acid', 'SUBSTITUTION', 'None', (147, 174))	('G12C', 'Chemical', '-', (37, 41))	('G12D', 'Chemical', '-', (176, 180))	('glycine 12 to valine', 'Var', (47, 67))	('G12V', 'Chemical', '-', (69, 73))	('associated', 'Reg', (104, 114))	('glycine 12 to aspartic acid', 'Var', (147, 174))	('glycine 12 to valine', 'SUBSTITUTION', 'None', (47, 67))	('glycine 12 to cysteine', 'Var', (13, 35))	('glycine 12 to cysteine', 'SUBSTITUTION', 'None', (13, 35))
540694	32560574	Each amino acid substitution differs in its binding affinity for downstream effectors: KRASG12D had higher affinity for PI3K/AKT signaling, whereas KRASG12C or KRASG12V led to low levels of phosphorylated AKT and increased RAL activation compared with other mutations or wildtype situation.	('PI3K/AKT signaling', 'MPA', (120, 138))	('RAL', 'Gene', '5898', (223, 226))	('low', 'NegReg', (176, 179))	('phosphorylated', 'MPA', (190, 204))	('KRASG12C', 'Chemical', '-', (148, 156))	('G12D', 'Chemical', '-', (91, 95))	('KRASG12C', 'Var', (148, 156))	('KRASG12V', 'Var', (160, 168))	('KRASG12D', 'Var', (87, 95))	('activation', 'PosReg', (227, 237))	('increased', 'PosReg', (213, 222))	('RAL', 'Gene', (223, 226))	('affinity', 'MPA', (107, 115))
540695	32560574	Two independent studies in metastatic patients and in those with surgically resected NSCLC are in favor with the idea that different codon variants may promote activation of distinct transcriptional networks which impact on prognosis and/or therapeutic susceptibilities: KRASG12C or KRASG12V positivity was associated with worse disease-free and overall survival when compared with other KRAS variants or wildtype protein, at least partly due to increased levels of epithelial to mesenchymal transition genes and lower levels of genes predicting KRAS dependency.	('NSCLC', 'Disease', (85, 90))	('overall survival', 'CPA', (346, 362))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('KRASG12C', 'Var', (271, 279))	('worse', 'NegReg', (323, 328))	('KRASG12C', 'Chemical', '-', (271, 279))	('patients', 'Species', '9606', (38, 46))	('disease-free', 'CPA', (329, 341))	('increased', 'PosReg', (446, 455))	('KRASG12V', 'Var', (283, 291))
540696	32560574	A common feature among KRAS mutant NSCLC is the metabolic rewiring of tumors towards anabolism.	('mutant', 'Var', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('NSCLC', 'Disease', (35, 40))	('metabolic', 'MPA', (48, 57))	('tumors', 'Disease', (70, 76))	('KRAS', 'Gene', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
540698	32560574	KRASG12D/G12D cells exhibited a glycolytic switch towards glutathione biosynthesis and a higher metastatic potential.	('glutathione biosynthesis', 'MPA', (58, 82))	('glutathione', 'Chemical', 'MESH:D005978', (58, 69))	('KRASG12D/G12D', 'Var', (0, 13))	('G12D', 'Chemical', '-', (9, 13))	('higher', 'PosReg', (89, 95))	('G12D', 'Chemical', '-', (4, 8))	('metastatic potential', 'CPA', (96, 116))
540699	32560574	These changes were recapitulated in spontaneous advanced murine lung tumors with a high frequency of KRASG12D copy gain (homozygous) but not in the corresponding early tumors (KRASG12D heterozygous).	('lung tumor', 'Phenotype', 'HP:0100526', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('murine', 'Species', '10090', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('lung tumors', 'Disease', (64, 75))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('lung tumors', 'Phenotype', 'HP:0100526', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumors', 'Disease', (69, 75))	('gain', 'PosReg', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('KRASG12D copy', 'Var', (101, 114))	('lung tumors', 'Disease', 'MESH:D008175', (64, 75))
540700	32560574	Tumors with KRASG12D allelic enrichment had lower survival rates than heterozygous tumors and were highly susceptible to the glycolytic inhibitor 2-deoxyglucose and the glutathione synthesis inhibitor buthionine sulfoximine.	('lower', 'NegReg', (44, 49))	('buthionine sulfoximine', 'MPA', (201, 223))	('men', 'Species', '9606', (35, 38))	('buthionine sulfoximine', 'Chemical', 'MESH:D019328', (201, 223))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('KRASG12D allelic enrichment', 'Var', (12, 39))	('tumors', 'Disease', (83, 89))	('glycolytic inhibitor 2-deoxyglucose', 'MPA', (125, 160))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('survival rates', 'CPA', (50, 64))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('glutathione', 'Chemical', 'MESH:D005978', (169, 180))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('rat', 'Species', '10116', (59, 62))	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (146, 160))
540709	32560574	Farnesyltransferase inhibitors (FTIs) represent the most well-known example of treatment failure in targeting mutant RAS.	('RAS', 'Gene', (117, 120))	('mutant', 'Var', (110, 116))	('men', 'Species', '9606', (84, 87))
540711	32560574	The second-generation FTI salirasib, at the dose and schedule applied in a phase II trial, exhibited insufficient activity in the treatment of KRAS mutant lung adenocarcinoma despite the promising preclinical data.	('lung adenocarcinoma', 'Disease', (155, 174))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (155, 174))	('activity', 'MPA', (114, 122))	('rat', 'Species', '10116', (15, 18))	('KRAS mutant', 'Var', (143, 154))	('men', 'Species', '9606', (135, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('FTI salirasib', 'Chemical', '-', (22, 35))
540713	32560574	Although Rce1 or Icmt1 deficiency in mouse embryonic fibroblasts impaired HRAS-mediated transformation, later studies provided puzzling results about loss of these enzymes: (i) absence of Rce1 in mouse hematopoietic cells accelerated KRASG12D-driven myeloproliferative disease, whereas inactivation of Icmt1 in the same mouse model had a protective effect; (ii) Icmt1 deficiency in the pancreas enhanced KRASG12D-driven neoplastic progression.	('Rce1', 'Gene', (188, 192))	('absence', 'Var', (177, 184))	('deficiency in the pancreas', 'Disease', (368, 394))	('G12D', 'Chemical', '-', (238, 242))	('rat', 'Species', '10116', (262, 265))	('deficiency in the pancreas', 'Disease', 'MESH:D010190', (368, 394))	('Rce1', 'Gene', '19671', (188, 192))	('deficiency in mouse embryonic', 'Disease', 'MESH:D004482', (23, 52))	('myeloproliferative disease', 'Phenotype', 'HP:0005547', (250, 276))	('rat', 'Species', '10116', (228, 231))	('accelerated', 'PosReg', (222, 233))	('deficiency in mouse embryonic', 'Disease', (23, 52))	('mouse', 'Species', '10090', (37, 42))	('KRASG12D-driven neoplastic progression', 'CPA', (404, 442))	('mouse', 'Species', '10090', (196, 201))	('enhanced', 'PosReg', (395, 403))	('myeloproliferative disease', 'Disease', 'MESH:D009196', (250, 276))	('myeloproliferative disease', 'Disease', (250, 276))	('Rce1', 'Gene', (9, 13))	('G12D', 'Chemical', '-', (408, 412))	('mouse', 'Species', '10090', (320, 325))	('Rce1', 'Gene', '19671', (9, 13))
540722	32560574	Unfortunately, these large-scale screens suffer from various limitations including high genetic complexity of KRAS mutant cells (large number of activating co-occurring alterations), experimental artefacts (e.g., choice of cell line, inconsistency of methodology), low magnitude of synthetic lethality effect and lack of validation.	('men', 'Species', '9606', (189, 192))	('mutant', 'Var', (115, 121))	('rat', 'Species', '10116', (173, 176))	('KRAS', 'Gene', (110, 114))
540723	32560574	The problematic can be exemplified as follows: (i) after its identification as a synthetic lethal partner using an RNAi screen in KRAS mutant cell lines, inhibition of STK33's kinase activity by the small molecule BRD-8899 proved ineffective; (ii) although three independent groups defined GATA2 as essential for survival of KRAS mutant NSCLC, Tessema et al.	('mutant', 'Var', (330, 336))	('NSCLC', 'Disease', (337, 342))	('GATA2', 'Gene', '2624', (290, 295))	('NSCLC', 'Disease', 'MESH:D002289', (337, 342))	('STK33', 'Gene', '65975', (168, 173))	('STK33', 'Gene', (168, 173))	('GATA2', 'Gene', (290, 295))
540725	32560574	Bortezomib, a proteosome inhibitor, was associated with modest anti-tumor activity and durable disease control in a small fraction of patients with KRASG12D mutant lung tumors.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('KRASG12D mutant', 'Var', (148, 163))	('G12D', 'Chemical', '-', (152, 156))	('Bortezomib', 'Chemical', 'MESH:D000069286', (0, 10))	('patients', 'Species', '9606', (134, 142))	('lung tumors', 'Disease', (164, 175))	('lung tumors', 'Phenotype', 'HP:0100526', (164, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('lung tumors', 'Disease', 'MESH:D008175', (164, 175))	('lung tumor', 'Phenotype', 'HP:0100526', (164, 174))
540726	32560574	Apart from chemotherapeutics, a possible combination partner could be MEK inhibition, currently the only targeted therapy with selectivity for KRAS mutations in the clinic (approved for B-RAFV600E-mutated NSCLC).	('mutations', 'Var', (148, 157))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('NSCLC', 'Disease', (205, 210))	('KRAS', 'Gene', (143, 147))	('B-RAF', 'Gene', '673', (186, 191))	('B-RAF', 'Gene', (186, 191))
540732	32560574	Consistently, a multi-tumor phase I trial reported that the CDK inhibitor abemaciclib (Verzenios, Lily; with greater selectivity to CDK4 than its close homolog CDK6) achieved a higher disease control rate in NSCLC patients with KRAS mutations than without.	('CDK6', 'Gene', '1021', (160, 164))	('patients', 'Species', '9606', (214, 222))	('rat', 'Species', '10116', (200, 203))	('KRAS', 'Gene', (228, 232))	('CDK6', 'Gene', (160, 164))	('CDK', 'Gene', (160, 163))	('multi-tumor', 'Disease', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CDK', 'Gene', '1019;12567;94201;1021;114483', (160, 163))	('achieved', 'PosReg', (166, 174))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('higher', 'PosReg', (177, 183))	('CDK', 'Gene', (132, 135))	('disease control rate', 'CPA', (184, 204))	('CDK', 'Gene', (60, 63))	('CDK', 'Gene', '1019;12567;94201;1021;114483', (132, 135))	('NSCLC', 'Disease', (208, 213))	('multi-tumor', 'Disease', 'MESH:D046589', (16, 27))	('CDK', 'Gene', '1019;12567;94201;1021;114483', (60, 63))	('mutations', 'Var', (233, 242))
540733	32560574	However, in a phase III trial comparing abemaciclib vs. erlotinib (an EGFR inhibitor) as second- or third-line treatment of advanced KRAS mutant NSCLC (NCT0215631), overall survival (the primary endpoint) did not differ between the two study arms.	('NSCLC', 'Disease', (145, 150))	('mutant', 'Var', (138, 144))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('KRAS', 'Gene', (133, 137))	('men', 'Species', '9606', (116, 119))	('erlotinib', 'Chemical', 'MESH:D000069347', (56, 65))
540734	32560574	Palbociclib (Ibrance, Pfizer), another U.S. Food and Drug Administration (FDA)-approved CDK4/6 inhibitor, is in clinical evaluation for KRAS mutant NSCLC either in combination with MEK inhibitors (NCT02022982, NCT03170206) or with the glutaminase inhibitor telaglenastat (CB-839) (NCT03965845).	('CDK4/6', 'Gene', (88, 94))	('CB-839', 'Chemical', 'MESH:C000593334', (272, 278))	('mutant', 'Var', (141, 147))	('NSCLC', 'Disease', (148, 153))	('NCT02022982', 'Var', (197, 208))	('telaglenastat', 'Chemical', '-', (257, 270))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('CDK4/6', 'Gene', '1019;1021', (88, 94))	('rat', 'Species', '10116', (66, 69))
540741	32560574	One explanation for this is that the most common subtype G12C exhibits more prominent engagement with MAPK signaling.	('engagement', 'MPA', (86, 96))	('G12C', 'Var', (57, 61))	('MAPK signaling', 'Pathway', (102, 116))	('men', 'Species', '9606', (92, 95))	('G12C', 'Chemical', '-', (57, 61))
540744	32560574	The multikinase inhibitor sorafenib exerts modest activity against RAF kinases yet efficacy in patients with KRAS mutant lung tumors is rather disappointing with an increase of 3 months in median progression-free survival (PFS).	('increase', 'PosReg', (165, 173))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (95, 103))	('lung tumors', 'Disease', 'MESH:D008175', (121, 132))	('lung tumor', 'Phenotype', 'HP:0100526', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('KRAS', 'Var', (109, 113))	('activity', 'MPA', (50, 58))	('sorafenib', 'Chemical', 'MESH:D000077157', (26, 35))	('rat', 'Species', '10116', (136, 139))	('lung tumors', 'Phenotype', 'HP:0100526', (121, 132))	('lung tumors', 'Disease', (121, 132))	('RAF kinases', 'Enzyme', (67, 78))
540746	32560574	Dabrafenib and vemurafenib, both type I B-RAF inhibitors, are potent in targeting B-RAF mutant NSCLC but show no benefit in patients with KRAS mutations.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('B-RAF', 'Gene', '673', (40, 45))	('patients', 'Species', '9606', (124, 132))	('B-RAF', 'Gene', (40, 45))	('B-RAF', 'Gene', (82, 87))	('mutant', 'Var', (88, 94))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('B-RAF', 'Gene', '673', (82, 87))	('vemurafenib', 'Chemical', 'MESH:D000077484', (15, 26))	('NSCLC', 'Disease', (95, 100))
540748	32560574	Ablation of C-RAF recapitulated the effects of disrupting KRAS and completely blocked tumor initiation without any significant toxicities observed in KRAS-driven lung tumor mouse models.	('KRAS', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('lung tumor', 'Phenotype', 'HP:0100526', (162, 172))	('tumor', 'Disease', (86, 91))	('blocked', 'NegReg', (78, 85))	('C-RAF', 'Protein', (12, 17))	('Ablation', 'Var', (0, 8))	('toxicities', 'Disease', 'MESH:D064420', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('lung tumor', 'Disease', 'MESH:D008175', (162, 172))	('mouse', 'Species', '10090', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('disrupting', 'Var', (47, 57))	('toxicities', 'Disease', (127, 137))	('tumor', 'Disease', (167, 172))	('lung tumor', 'Disease', (162, 172))
540749	32560574	In advanced tumors driven by KRASG12V/p53, systemic abrogation of C-RAF expression induced regression due to massive apoptosis by a mechanism independent of canonical MAPK signaling which is also essential for normal homeostasis79.	('C-RAF', 'Protein', (66, 71))	('abrogation', 'NegReg', (52, 62))	('KRASG12V/p53', 'Var', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('apoptosis', 'CPA', (117, 126))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
540752	32560574	The catalytic activity of C-RAF is not required for the KRAS-mediated transformation: three C-RAF inhibitors (MLN2480, GW5074, and PLX8394) designed to block the kinase activity but not the protein expression failed to yield any therapeutic effect.	('MLN2480', 'Var', (110, 117))	('C-RAF', 'Gene', (92, 97))	('GW5074', 'Var', (119, 125))	('PLX8394', 'Var', (131, 138))	('GW5074', 'Chemical', 'MESH:C489251', (119, 125))	('MLN2480', 'Chemical', 'MESH:C000626538', (110, 117))
540755	32560574	Individual MEK1/2 kinases are dispensable for the initiation of lung adenocarcinomas driven by KRASG12V, whereas complete elimination of MEK expression efficiently prevents tumor development.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('MEK1/2', 'Gene', '5604;5605', (11, 17))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('MEK1/2', 'Gene', (11, 17))	('lung adenocarcinomas', 'Disease', (64, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('men', 'Species', '9606', (186, 189))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (64, 84))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (64, 84))	('KRASG12V', 'Var', (95, 103))	('G12V', 'Chemical', '-', (99, 103))
540757	32560574	A phase II trial failed to show improvement in objective response rate (ORR) or PFS upon concomitant combination therapy of selumetinib (an allosteric MEK inhibitor) and erlotinib (an anti-EGFR inhibitor) over monotherapy in KRAS mutant and KRAS wildtype advanced NSCLC.	('NSCLC', 'Disease', (264, 269))	('erlotinib', 'Chemical', 'MESH:D000069347', (170, 179))	('mutant', 'Var', (230, 236))	('selumetinib', 'Chemical', 'MESH:C517975', (124, 135))	('NSCLC', 'Disease', 'MESH:D002289', (264, 269))	('men', 'Species', '9606', (39, 42))	('rat', 'Species', '10116', (66, 69))
540758	32560574	The ORR in the KRAS mutant arm was 0% for selumetinib alone and 10% for the combination.	('KRAS', 'Gene', (15, 19))	('selumetinib', 'Chemical', 'MESH:C517975', (42, 53))	('mutant', 'Var', (20, 26))
540762	32560574	In a randomized phase II trial, concomitant treatment with selumetinib plus docetaxel (a taxane chemotherapy) suggested an incremental survival advantage but with higher numbers of adverse events than with docetaxel alone in previously treated KRAS mutant NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('men', 'Species', '9606', (49, 52))	('docetaxel', 'Chemical', 'MESH:D000077143', (206, 215))	('men', 'Species', '9606', (128, 131))	('docetaxel', 'Chemical', 'MESH:D000077143', (76, 85))	('taxane', 'Chemical', 'MESH:C080625', (89, 95))	('mutant', 'Var', (249, 255))	('NSCLC', 'Disease', (256, 261))	('selumetinib', 'Chemical', 'MESH:C517975', (59, 70))	('KRAS', 'Gene', (244, 248))
540763	32560574	In a preclinical study using mouse models, simultaneous loss of either p53 or STK11, both clinically relevant tumor suppressors, markedly impaired the response of KRAS mutant tumors to docetaxel alone.	('docetaxel', 'Chemical', 'MESH:D000077143', (185, 194))	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('mutant', 'Var', (168, 174))	('loss', 'NegReg', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('p53', 'Gene', (71, 74))	('mouse', 'Species', '10090', (29, 34))	('response', 'MPA', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('KRAS mutant', 'Var', (163, 174))	('impaired', 'NegReg', (138, 146))	('STK11', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
540764	32560574	The addition of selumetinib offered substantial benefit for mice bearing KRAS and KRAS/p53 mutations, whereas KRAS/STK11 mutant mice displayed primary resistant to the therapy due to activation of parallel signaling pathways such as AKT and v-Src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC).	('SRC', 'Gene', (306, 309))	('KRAS', 'Gene', (73, 77))	('selumetinib', 'Gene', (16, 27))	('activation', 'PosReg', (183, 193))	('sarcoma', 'Disease', 'MESH:D012509', (253, 260))	('SRC', 'Gene', '20779', (306, 309))	('AKT', 'Pathway', (233, 236))	('selumetinib', 'Chemical', 'MESH:C517975', (16, 27))	('mice', 'Species', '10090', (128, 132))	('mutations', 'Var', (91, 100))	('sarcoma', 'Disease', (253, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('mice', 'Species', '10090', (60, 64))	('KRAS/p53', 'Gene', (82, 90))
540765	32560574	Trametinib is another selective and potent MEK inhibitor that has been clinically approved for B-RAF mutations, mainly to treat melanoma.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('B-RAF', 'Gene', '673', (95, 100))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('mutations', 'Var', (101, 110))	('B-RAF', 'Gene', (95, 100))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
540768	32560574	A phase II trial with KRAS-driven NSCLC reported a trend for worse PFS in G12C cohorts compared to non-G12C patients (NCT02642042).	('NSCLC', 'Disease', (34, 39))	('G12C', 'Chemical', '-', (103, 107))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('G12C', 'Var', (74, 78))	('PFS', 'MPA', (67, 70))	('G12C', 'Chemical', '-', (74, 78))	('patients', 'Species', '9606', (108, 116))	('worse', 'NegReg', (61, 66))
540770	32560574	However, the mTOR inhibitor ridaforolimus as monotherapy displayed little clinical benefit in a phase II trial in KRAS mutant NSCLC resulting only in a modest increase in PFS.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('PFS', 'MPA', (171, 174))	('KRAS', 'Gene', (114, 118))	('NSCLC', 'Disease', (126, 131))	('ridaforolimus', 'Chemical', 'MESH:C515074', (28, 41))	('mutant', 'Var', (119, 125))	('increase', 'PosReg', (159, 167))
540775	32560574	The KRAS/RHOA/FAK pathway plays an important role in the development of lung tumors bearing inactivated p53 or loss of CDKN2A.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('p53', 'Gene', (104, 107))	('loss', 'Var', (111, 115))	('FAK', 'Gene', '5747', (14, 17))	('lung tumors', 'Disease', 'MESH:D008175', (72, 83))	('lung tumor', 'Phenotype', 'HP:0100526', (72, 82))	('CDKN2A', 'Gene', (119, 125))	('men', 'Species', '9606', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CDKN2A', 'Gene', '1029', (119, 125))	('FAK', 'Gene', (14, 17))	('lung tumors', 'Phenotype', 'HP:0100526', (72, 83))	('lung tumors', 'Disease', (72, 83))
540776	32560574	A phase II trial of the FAK inhibitor defactinib failed to improve outcome in patients with KRAS mutant lung tumors (NCT01951690).	('KRAS mutant', 'Var', (92, 103))	('lung tumors', 'Disease', 'MESH:D008175', (104, 115))	('patients', 'Species', '9606', (78, 86))	('lung tumor', 'Phenotype', 'HP:0100526', (104, 114))	('defactinib', 'Chemical', 'MESH:C584510', (38, 48))	('FAK', 'Gene', '5747', (24, 27))	('FAK', 'Gene', (24, 27))	('lung tumors', 'Disease', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('lung tumors', 'Phenotype', 'HP:0100526', (104, 115))
540777	32560574	One reason behind might be co-occurring genetic events: FAK inhibitors have been documented to exert potent anti-tumor activity in NSCLC with KRASG12V mutation in association with CDKN2A deficiency but not in CDKN2A wildtype background.	('tumor', 'Disease', (113, 118))	('CDKN2A', 'Gene', '1029', (180, 186))	('NSCLC', 'Disease', (131, 136))	('FAK', 'Gene', '5747', (56, 59))	('mutation', 'Var', (151, 159))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('G12V', 'Chemical', '-', (146, 150))	('CDKN2A', 'Gene', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('men', 'Species', '9606', (85, 88))	('CDKN2A deficiency', 'Phenotype', 'HP:0032421', (180, 197))	('KRASG12V', 'Gene', (142, 150))	('CDKN2A', 'Gene', '1029', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('deficiency', 'Var', (187, 197))	('CDKN2A', 'Gene', (180, 186))	('FAK', 'Gene', (56, 59))
540778	32560574	A phase Ib dose-finding, pharmacokinetic trial has been initiated to determine the maximum tolerated dose of the FAK inhibitor GSK2256098 and the MEK1/2 inhibitor trametinib in combination in eligible patients having mesothelioma or other solid tumors with MAPK activation.	('patients', 'Species', '9606', (201, 209))	('GSK2256098', 'Chemical', 'MESH:C000600809', (127, 137))	('FAK', 'Gene', (113, 116))	('FAK', 'Gene', '5747', (113, 116))	('mesothelioma', 'Disease', (217, 229))	('rat', 'Species', '10116', (95, 98))	('trametinib', 'Chemical', 'MESH:C560077', (163, 173))	('MEK1/2', 'Gene', '5604;5605', (146, 152))	('solid tumors', 'Disease', 'MESH:D009369', (239, 251))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('MEK1/2', 'Gene', (146, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (217, 229))	('GSK2256098', 'Var', (127, 137))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('solid tumors', 'Disease', (239, 251))
540781	32560574	The use of heat shock protein 90 (HSP90) inhibitors in KRAS mutant NSCLC also appeared to be a promising approach as these molecules target many KRAS downstream effectors.	('KRAS', 'Gene', (55, 59))	('HSP90', 'Protein', (34, 39))	('heat shock protein 90', 'Gene', '3320', (11, 32))	('heat shock protein 90', 'Gene', (11, 32))	('shock', 'Phenotype', 'HP:0031273', (16, 21))	('NSCLC', 'Disease', (67, 72))	('mutant', 'Var', (60, 66))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
540782	32560574	The HSP90 inhibitor AUY922 attenuated intrinsic resistance to PI3K and MEK inhibitors by suppressing both PI3K/AKT/mTOR and RAF/MEK/ERK signaling in KRAS mutant NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('attenuated', 'NegReg', (27, 37))	('HSP90', 'Protein', (4, 9))	('intrinsic resistance', 'MPA', (38, 58))	('AUY922', 'Chemical', 'MESH:C528044', (20, 26))	('suppressing', 'NegReg', (89, 100))	('mutant', 'Var', (154, 160))	('PI3K/AKT/mTOR', 'Pathway', (106, 119))	('RAF/MEK/ERK signaling', 'Pathway', (124, 145))	('NSCLC', 'Disease', (161, 166))	('AUY922', 'Var', (20, 26))
540788	32560574	Activity of p90 ribosomal S6 kinase (p90RSK; a key activator of the mTOR pathway and an ERK downstream target) was increased in KRAS mutant NSCLC ganetespib resistant cells.	('KRAS', 'Gene', (128, 132))	('NSCLC ganetespib', 'Disease', (140, 156))	('increased', 'PosReg', (115, 124))	('NSCLC ganetespib', 'Disease', 'MESH:D002289', (140, 156))	('p90RSK', 'Gene', (37, 43))	('p90RSK', 'Gene', '6195', (37, 43))	('Activity', 'MPA', (0, 8))	('mutant', 'Var', (133, 139))
540789	32560574	While genetic or pharmacologic inhibition of p90RSK restored sensitivity to ganetespib, reactivation of p90RSK and its downstream target M-phase inducer phosphatase 3 (CDC25C) promoted bypass of the ganetespib induced G2/M arrest and led to acquired resistance to ganetespib and cross-resistance to docetaxel in KRAS mutant NSCLC.	('ganetespib', 'Chemical', 'MESH:C533237', (264, 274))	('NSCLC', 'Disease', 'MESH:D002289', (324, 329))	('cross-resistance', 'MPA', (279, 295))	('p90RSK', 'Gene', '6195', (104, 110))	('p90RSK', 'Gene', (45, 51))	('M arrest', 'Disease', 'MESH:D006323', (221, 229))	('NSCLC', 'Disease', (324, 329))	('ganetespib', 'Chemical', 'MESH:C533237', (199, 209))	('acquired resistance to ganetespib', 'MPA', (241, 274))	('M-phase inducer phosphatase 3', 'Gene', '995', (137, 166))	('docetaxel', 'Chemical', 'MESH:D000077143', (299, 308))	('M arrest', 'Disease', (221, 229))	('mutant', 'Var', (317, 323))	('p90RSK', 'Gene', '6195', (45, 51))	('p90RSK', 'Gene', (104, 110))	('CDC25C', 'Gene', (168, 174))	('M-phase inducer phosphatase 3', 'Gene', (137, 166))	('CDC25C', 'Gene', '995', (168, 174))	('ganetespib', 'Chemical', 'MESH:C533237', (76, 86))
540794	32560574	ARS-853, a potent G12C allele-specific inhibitor, reduced KRAS signaling and cancer cell growth in vitro.	('KRAS signaling', 'Pathway', (58, 72))	('ARS-853', 'Var', (0, 7))	('cancer', 'Disease', (77, 83))	('G12C', 'Chemical', '-', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('reduced', 'NegReg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ARS-853', 'Chemical', 'MESH:C000605991', (0, 7))
540795	32560574	These studies further illustrated that mutant RAS is not locked in a GTP-RAS constitutively active state: KRASG12C alteration enhances rapid nucleotide exchange (GDP-GTP) and thus leads to aberrant downstream signaling.	('leads to aberrant', 'Reg', (180, 197))	('KRASG12C', 'Chemical', '-', (106, 114))	('KRASG12C', 'Gene', (106, 114))	('rat', 'Species', '10116', (119, 122))	('GTP', 'Chemical', 'MESH:D006160', (69, 72))	('enhances', 'PosReg', (126, 134))	('rapid nucleotide exchange', 'MPA', (135, 160))	('GTP', 'Chemical', 'MESH:D006160', (166, 169))	('GDP-GTP', 'Chemical', '-', (162, 169))	('alteration', 'Var', (115, 125))	('downstream signaling', 'MPA', (198, 218))	('rat', 'Species', '10116', (28, 31))
540796	32560574	ARS-853 inactivated KRASG12C signaling by a trapping mechanism: KRASG12C was trapped in the GDP-RAS state, hindering further nucleotide exchange.	('KRASG12C', 'Chemical', '-', (64, 72))	('hindering', 'NegReg', (107, 116))	('KRASG12C', 'Chemical', '-', (20, 28))	('GDP-RAS', 'Chemical', '-', (92, 99))	('KRASG12C', 'Var', (64, 72))	('nucleotide exchange', 'MPA', (125, 144))	('ARS-853', 'Chemical', 'MESH:C000605991', (0, 7))
540800	32560574	Optimization of the cysteine conjugation and the molecular interactions within the drug-induced pocket has led to the development of oral KRASG12C inhibitors: ARS-1620/ARS-3248 (Wellspring Biosciences), AMG 510 (Amgen/Carmot Therapeutics) and MRTX849 (Mirati Therapeutics) induced regression of KRASG12C tumors; the latter three entered phase I clinical trials (NCT04006301, NCT03600883, NCT03785249, NCT04303780, NCT04330664).	('tumors', 'Disease', (304, 310))	('ARS', 'Gene', '6012', (168, 171))	('NCT04006301', 'Var', (362, 373))	('KRASG12C', 'Chemical', '-', (295, 303))	('ARS', 'Gene', '6012', (159, 162))	('rat', 'Species', '10116', (254, 257))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('AMG 510', 'Chemical', '-', (203, 210))	('KRASG12C', 'Gene', (295, 303))	('ARS', 'Gene', (168, 171))	('NCT04303780', 'Var', (401, 412))	('ARS', 'Gene', (159, 162))	('NCT03600883', 'Var', (375, 386))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('NCT04330664', 'Var', (414, 425))	('KRASG12C', 'Chemical', '-', (138, 146))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('cysteine', 'Chemical', 'MESH:D003545', (20, 28))	('men', 'Species', '9606', (125, 128))	('NCT03785249', 'Var', (388, 399))
540802	32560574	Different from the covalent inhibitors that specifically target mutant KRAS, AZD4785 is a KRAS antisense-oligonucleotide (ASO) targeting KRAS gene irrespective of its mutational status.	('AZD4785', 'Var', (77, 84))	('AZD4785', 'Chemical', '-', (77, 84))	('KRAS', 'Gene', (137, 141))	('ASO', 'Chemical', 'MESH:D016376', (122, 125))	('oligonucleotide', 'Chemical', 'MESH:D009841', (105, 120))
540803	32560574	AZD4785 potently depleted KRAS mRNA and protein, inhibited downstream effector pathways and led to anti-proliferative effects in mutant KRAS cells.	('rat', 'Species', '10116', (111, 114))	('AZD4785', 'Var', (0, 7))	('depleted', 'NegReg', (17, 25))	('AZD4785', 'Chemical', '-', (0, 7))	('anti-proliferative effects', 'CPA', (99, 125))	('KRAS', 'Protein', (26, 30))	('KRAS', 'Gene', (136, 140))	('downstream effector pathways', 'Pathway', (59, 87))	('inhibited', 'NegReg', (49, 58))	('mutant', 'Var', (129, 135))
540807	32560574	The underlying reason might be that AZD4785 does not distinguish between mutant and wildtype KRAS for degradation.	('mutant', 'Var', (73, 79))	('AZD4785', 'Chemical', '-', (36, 43))	('degradation', 'MPA', (102, 113))
540808	32560574	New optimism has been sparked by proteolysis-targeting chimeras (PROTACs) targeting KRASG12C mutants.	('mutants', 'Var', (93, 100))	('KRASG12C', 'Chemical', '-', (84, 92))	('KRASG12C', 'Gene', (84, 92))
540809	32560574	These bifunctional molecules simultaneously engage KRASG12C protein and an E3 ligase, forming a ternary complex, enabling the E3 ligase to ubiquitinate KRASG12C protein on proximal lysine residues.	('KRASG12C', 'Chemical', '-', (51, 59))	('KRASG12C', 'Var', (152, 160))	('enabling', 'PosReg', (113, 121))	('ubiquitinate', 'MPA', (139, 151))	('KRASG12C', 'Chemical', '-', (152, 160))	('lysine', 'Chemical', 'MESH:D008239', (181, 187))
540810	32560574	has reported a cysteine 12-directed covalent degrader molecule incorporating ARS-1620 and thalidomide to recruit the cereblon E3 ligase which degraded an artificial GFP-KRASG12C fusion protein in reporter cells but not endogenous KRASG12C in pancreatic and lung cancer cells.	('KRASG12C', 'Chemical', '-', (169, 177))	('rat', 'Species', '10116', (70, 73))	('pancreatic', 'Disease', 'MESH:D010195', (242, 252))	('ARS', 'Gene', (77, 80))	('cysteine', 'Chemical', 'MESH:D003545', (15, 23))	('KRASG12C', 'Chemical', '-', (230, 238))	('degraded', 'NegReg', (142, 150))	('lung cancer', 'Disease', (257, 268))	('pancreatic', 'Disease', (242, 252))	('lung cancer', 'Phenotype', 'HP:0100526', (257, 268))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('GFP-KRASG12C', 'Var', (165, 177))	('thalidomide', 'Chemical', 'MESH:D013792', (90, 101))	('ARS', 'Gene', '6012', (77, 80))	('lung cancer', 'Disease', 'MESH:D008175', (257, 268))
540813	32560574	LC-2 was identified as the most potent KRASG12C degrading PROTAC, incorporating MRTX849 and the VHL E3 ligase ligand, which resulted in rapid engagement and sustained degradation.	('KRASG12C', 'Chemical', '-', (39, 47))	('MRTX849', 'MPA', (80, 87))	('men', 'Species', '9606', (148, 151))	('engagement', 'MPA', (142, 152))	('PROTAC', 'MPA', (58, 64))	('LC-2', 'Chemical', '-', (0, 4))	('KRASG12C', 'Var', (39, 47))	('degradation', 'MPA', (167, 178))	('degrading', 'NegReg', (48, 57))	('rat', 'Species', '10116', (73, 76))
540814	32560574	KRASG12C degradation by LC-2 depended on both proteasome and neddylation (neddylation of cullin 2, a VHL adaptor protein, is required for assembly and function of the VHL E3 ligase complex) as pretreatment with epoxomicin or MLN4924, respectively, rescued KRASG12C levels.	('cullin 2', 'Gene', '8453', (89, 97))	('KRASG12C', 'Chemical', '-', (0, 8))	('KRASG12C', 'Chemical', '-', (256, 264))	('men', 'Species', '9606', (201, 204))	('KRASG12C levels', 'MPA', (256, 271))	('degradation', 'MPA', (9, 20))	('LC-2', 'Gene', (24, 28))	('cullin 2', 'Gene', (89, 97))	('MLN4924', 'Var', (225, 232))	('rescued', 'PosReg', (248, 255))	('LC-2', 'Chemical', '-', (24, 28))	('neddylation', 'MPA', (61, 72))	('KRASG12C', 'MPA', (0, 8))
540817	32560574	Total ERK was elevated in cells treated with the degrader molecule compared to vehicle controls at all time points indicating the initiation of a positive feedback loop upon KRASG12C degradation and pERK inhibition.	('KRASG12C', 'Chemical', '-', (174, 182))	('inhibition', 'NegReg', (204, 214))	('KRASG12C', 'Gene', (174, 182))	('ERK', 'MPA', (6, 9))	('degrader', 'Var', (49, 57))	('elevated', 'PosReg', (14, 22))
540819	32560574	Ligand development for other KRAS mutations is ongoing.	('KRAS', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('men', 'Species', '9606', (14, 17))
540821	32560574	The clinical failure of agents against the RAF/MEK/ERK pathway downstream of RAS in KRAS mutant cancers has led to explore the possibility of using combinations of targeted agents inhibiting the multiple pathways downstream of RAS.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('RAF/MEK/ERK pathway', 'Pathway', (43, 62))	('KRAS', 'Gene', (84, 88))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('mutant', 'Var', (89, 95))
540823	32560574	Preclinical studies have suggested combinations of mTOR and MEK inhibitors in KRAS mutant lung cancers but these attempts have proven challenging due to adverse events such as diarrhea, skin rash and fatigue.	('mutant', 'Var', (83, 89))	('skin rash', 'Disease', (186, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('lung cancers', 'Disease', 'MESH:D008175', (90, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('combinations', 'Interaction', (35, 47))	('fatigue', 'Disease', 'MESH:D005221', (200, 207))	('diarrhea', 'Phenotype', 'HP:0002014', (176, 184))	('lung cancers', 'Disease', (90, 102))	('skin rash', 'Disease', 'MESH:D005076', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('skin rash', 'Phenotype', 'HP:0000988', (186, 195))	('MEK', 'Gene', (60, 63))	('lung cancers', 'Phenotype', 'HP:0100526', (90, 102))	('diarrhea', 'Disease', (176, 184))	('KRAS', 'Gene', (78, 82))	('fatigue', 'Disease', (200, 207))	('diarrhea', 'Disease', 'MESH:D003967', (176, 184))	('fatigue', 'Phenotype', 'HP:0012378', (200, 207))
540824	32560574	investigated the dependence of MEK and mTOR inhibition in a panel of KRAS mutant and KRAS wildtype NSCLC cell lines and showed for the first time that inhibition of mTOR but not MEK contributes to the majority of the growth inhibition in this combination.	('mTOR', 'MPA', (165, 169))	('NSCLC', 'Disease', (99, 104))	('growth', 'MPA', (217, 223))	('mutant', 'Var', (74, 80))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
540826	32560574	recently reported that combinations of clinically approved mTOR inhibitors and chemotherapeutics synergized in inhibiting cell proliferation of KRAS mutant NSCLC cells in vitro and in vivo, and the efficacy of this approach correlated with the magnitude of mTOR activity induced by chemotherapy alone.	('mutant', 'Var', (149, 155))	('rat', 'Species', '10116', (134, 137))	('NSCLC', 'Disease', (156, 161))	('inhibiting', 'NegReg', (111, 121))	('KRAS', 'Gene', (144, 148))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('cell proliferation', 'CPA', (122, 140))
540828	32560574	This combination has been explored in patients with EGFR mutant pretreated NSCLC, triple-negative breast cancer, pancreatic cancer, colorectal cancer, malignant melanoma, NSCLC and other advanced solid tumors with KRAS, NRAS and/or B-RAF mutations; the results are not available yet.	('solid tumors', 'Disease', (196, 208))	('EGFR', 'Gene', (52, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('malignant melanoma', 'Disease', (151, 169))	('mutant', 'Var', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (38, 46))	('B-RAF', 'Gene', '673', (232, 237))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('NSCLC', 'Disease', (171, 176))	('solid tumors', 'Disease', 'MESH:D009369', (196, 208))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('malignant melanoma', 'Phenotype', 'HP:0002861', (151, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('B-RAF', 'Gene', (232, 237))	('malignant melanoma', 'Disease', 'MESH:D008545', (151, 169))	('pancreatic cancer', 'Disease', (113, 130))	('colorectal cancer', 'Disease', (132, 149))	('NSCLC', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))
540829	32560574	Another dose- and schedule-finding study evaluated MK-2206 (an allosteric inhibitor of pan-AKT) and selumetinib in patients with advanced treatment-refractory solid tumors (NCT01021748).	('patients', 'Species', '9606', (115, 123))	('selumetinib', 'Chemical', 'MESH:C517975', (100, 111))	('MK-2206', 'Chemical', 'MESH:C548887', (51, 58))	('MK-2206', 'Var', (51, 58))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('solid tumors', 'Disease', (159, 171))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('men', 'Species', '9606', (143, 146))	('solid tumors', 'Disease', 'MESH:D009369', (159, 171))
540831	32560574	Strikingly, no responses were documented in KRAS-mutated colorectal or small-bowel carcinoma, partly due to distinct biological context differences in these diseases.	('colorectal or small-bowel carcinoma', 'Disease', 'MESH:D015179', (57, 92))	('KRAS-mutated', 'Var', (44, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('colorectal or small-bowel carcinoma', 'Disease', (57, 92))	('men', 'Species', '9606', (34, 37))
540834	32560574	This combination is effective in half of KRAS-mutated NSCLC and cause potent tumor regression in xenograft and PDX models.	('KRAS-mutated', 'Var', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NSCLC', 'Disease', (54, 59))	('tumor', 'Disease', (77, 82))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
540836	32560574	reported that the MEK inhibitor trametinib provokes a compensatory response via FGFR-1-mediated adaptive resistance in KRAS mutant lung cancer cells.	('FGFR-1', 'Gene', (80, 86))	('trametinib', 'Chemical', 'MESH:C560077', (32, 42))	('FGFR-1', 'Gene', '2260', (80, 86))	('compensatory response', 'MPA', (54, 75))	('mutant', 'Var', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('lung cancer', 'Disease', (131, 142))	('adaptive', 'CPA', (96, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
540840	32560574	While each component of this triple drug combination has been found to cause adverse events in clinical trials, substitution of MEK inhibitor with the recently developed allele-specific KRASG12C inhibitor ARS-1620 allowed strong inhibition of KRASG12C positive tumors with low toxicity and markedly boosted the effects of ARS-1620 monotherapy.	('ARS', 'Gene', (205, 208))	('KRASG12C', 'Chemical', '-', (243, 251))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('toxicity', 'Disease', (277, 285))	('toxicity', 'Disease', 'MESH:D064420', (277, 285))	('ARS', 'Gene', '6012', (322, 325))	('substitution', 'Var', (112, 124))	('tumors', 'Disease', (261, 267))	('boosted', 'PosReg', (299, 306))	('inhibition', 'NegReg', (229, 239))	('MEK', 'Gene', (128, 131))	('ARS', 'Gene', (322, 325))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('ARS', 'Gene', '6012', (205, 208))	('KRASG12C', 'Chemical', '-', (186, 194))	('KRASG12C positive', 'Var', (243, 260))
540847	32560574	Patients with KRAS mutant lung adenocarcinomas showed significant treatment benefits, with 60% of patients showing tumor reductions:of which, 30% were partial responses.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('lung adenocarcinomas', 'Disease', (26, 46))	('patients', 'Species', '9606', (98, 106))	('men', 'Species', '9606', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('Patients', 'Species', '9606', (0, 8))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (26, 46))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (26, 46))	('tumor reductions', 'Disease', 'MESH:D007022', (115, 131))	('KRAS mutant', 'Var', (14, 25))	('tumor reductions', 'Disease', (115, 131))
540849	32560574	A multi-center, dose-escalation, phase I trial is ongoing to assess the maximum tolerated dose and the pharmacodynamic activity of the combination RO5126766 plus the FAK inhibitor defactinib in advanced solid tumors including KRAS+ NSCLC (NCT03875820).	('RO5126766', 'Var', (147, 156))	('FAK', 'Gene', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('rat', 'Species', '10116', (84, 87))	('solid tumors', 'Disease', (203, 215))	('RO5126766', 'Chemical', 'MESH:C577924', (147, 156))	('NSCLC', 'Disease', (232, 237))	('NSCLC', 'Disease', 'MESH:D002289', (232, 237))	('defactinib', 'Chemical', 'MESH:C584510', (180, 190))	('FAK', 'Gene', '5747', (166, 169))	('solid tumors', 'Disease', 'MESH:D009369', (203, 215))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
540851	32560574	A second study aims to test the safety of RO5126766 at different doses for patients with advanced KRAS+ lung cancer who have previously received treatment with a programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) inhibitor (NCT03681483).	('programmed cell death protein 1', 'Gene', (162, 193))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('RO5126766', 'Var', (42, 51))	('patients', 'Species', '9606', (75, 83))	('lung cancer', 'Disease', (104, 115))	('RO5126766', 'Chemical', 'MESH:C577924', (42, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('programmed cell death protein 1', 'Gene', '5133', (162, 193))	('men', 'Species', '9606', (150, 153))	('programmed cell death 1 ligand 1', 'Gene', '574058', (204, 236))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('programmed cell death 1 ligand 1', 'Gene', (204, 236))
540857	32560574	Strikingly, initial clinical trials using first-generation EGFR TKIs erlotinib or gefitinib have demonstrated little or no benefit to patients with KRAS mutations and the presence of mutant KRAS is used as a biomarker to exclude patients for EGFR TKI therapy.	('rat', 'Species', '10116', (52, 55))	('KRAS', 'Gene', (148, 152))	('patients', 'Species', '9606', (229, 237))	('mutations', 'Var', (153, 162))	('KRAS', 'Gene', (190, 194))	('mutant', 'Var', (183, 189))	('patients', 'Species', '9606', (134, 142))	('gefitinib', 'Chemical', 'MESH:D000077156', (82, 91))	('erlotinib', 'Chemical', 'MESH:D000069347', (69, 78))	('rat', 'Species', '10116', (104, 107))
540858	32560574	Two meta-analyses suggested that patients with KRAS-mutated tumors exhibited significantly lower response rates with EGFR TKI than those with KRAS wildtype tumors.	('lower', 'NegReg', (91, 96))	('KRAS-mutated', 'Var', (47, 59))	('patients', 'Species', '9606', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('rat', 'Species', '10116', (106, 109))	('response rates', 'MPA', (97, 111))	('tumors', 'Disease', (156, 162))	('tumors', 'Disease', (60, 66))
540860	32560574	The reason behind the negative treatment interaction between EGFR TKI and KRAS mutant tumors was believed to be that oncogenic mutations in KRAS lock the protein in a constitutively active state, conferring independence from upstream signaling by ERBB RTKs (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('men', 'Species', '9606', (36, 39))	('mutations', 'Var', (127, 136))	('KRAS', 'Gene', (140, 144))
540861	32560574	However, recent data provide evidence that this independence may not be definite: (i) in KRAS mutant NSCLC cell lines, activation of PI3K depends on basal activity of wildtype IGF1R, illustrating a model for how oncogenic and normal signal transduction coordinate; (ii) development of KRASG12D-driven pancreatic ductal adenocarcinoma is suppressed in the absence of EGFR; and (iii) induced expression of ERBB2 and ERBB3 provokes resistance to MEK inhibition in KRAS+ lung and colorectal cell lines.	('ERBB2', 'Gene', (404, 409))	('IGF1R', 'Gene', '3480', (176, 181))	('G12D', 'Chemical', '-', (289, 293))	('pancreatic ductal adenocarcinoma', 'Disease', (301, 333))	('expression', 'Var', (390, 400))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (301, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('NSCLC', 'Disease', (101, 106))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (301, 333))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('ERBB3', 'Gene', (414, 419))	('ERBB3', 'Gene', '2065', (414, 419))	('ERBB2', 'Gene', '2064', (404, 409))	('resistance to MEK inhibition', 'MPA', (429, 457))	('men', 'Species', '9606', (277, 280))	('rat', 'Species', '10116', (189, 192))	('IGF1R', 'Gene', (176, 181))
540862	32560574	Two preclinical studies further challenge this dogma, indicating that mutant KRAS demands activation of ERBB receptors to facilitate lung tumorigenesis.	('activation', 'PosReg', (90, 100))	('mutant', 'Var', (70, 76))	('lung tumor', 'Disease', (133, 143))	('KRAS', 'Gene', (77, 81))	('ERBB receptors', 'Protein', (104, 118))	('lung tumor', 'Disease', 'MESH:D008175', (133, 143))	('facilitate', 'PosReg', (122, 132))	('lung tumor', 'Phenotype', 'HP:0100526', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
540864	32560574	Deletion of EGFR in a mouse model of autochthonous lung cancer driven by KRASG12D reduced KRAS activity and transiently retarded tumor growth.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('transiently retarded tumor', 'Disease', 'MESH:D009422', (108, 134))	('KRAS activity', 'MPA', (90, 103))	('transiently retarded tumor', 'Disease', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mouse', 'Species', '10090', (22, 27))	('reduced', 'NegReg', (82, 89))	('EGFR', 'Gene', (12, 16))	('Deletion', 'Var', (0, 8))
540869	32560574	Taken together, these studies provide a solid ground to re-evaluate the use of pan-ERBB inhibitors in clinical trials in patients with KRAS mutant lung tumors.	('lung tumors', 'Disease', 'MESH:D008175', (147, 158))	('lung tumor', 'Phenotype', 'HP:0100526', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('lung tumors', 'Phenotype', 'HP:0100526', (147, 158))	('lung tumors', 'Disease', (147, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (121, 129))	('KRAS mutant', 'Var', (135, 146))
540871	32560574	Mutant KRAS activity causes increased proliferation in multiple models.	('increased', 'PosReg', (28, 37))	('proliferation', 'CPA', (38, 51))	('rat', 'Species', '10116', (45, 48))	('Mutant', 'Var', (0, 6))	('KRAS', 'Gene', (7, 11))
540873	32560574	In line, advanced-stage tumors in KRASG12D/+/p53-/- mice were hypersensitive to combined glucose and glutathione depletion, whereas low-grade tumors in the same model, with a glucose metabolism similar to that of normal tissues, failed to respond.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('KRASG12D/+/p53-/-', 'Var', (34, 51))	('mice', 'Species', '10090', (52, 56))	('glucose', 'Chemical', 'MESH:D005947', (89, 96))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('glutathione', 'Chemical', 'MESH:D005978', (101, 112))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('glucose', 'Chemical', 'MESH:D005947', (175, 182))
540877	32560574	Deletion of hexokinase 2 (Hk2) in lung cancer cells suppressed glucose derived ribonucleotides and impaired glutamine derived carbon utilization in anaplerosis.	('glucose', 'Chemical', 'MESH:D005947', (63, 70))	('carbon', 'Chemical', 'MESH:D002244', (126, 132))	('glutamine', 'Chemical', 'MESH:D005973', (108, 117))	('hexokinase 2', 'Gene', '3099', (12, 24))	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('glutamine derived carbon utilization', 'MPA', (108, 144))	('Deletion', 'Var', (0, 8))	('Hk2', 'Gene', (26, 29))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('suppressed', 'NegReg', (52, 62))	('impaired', 'NegReg', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('hexokinase 2', 'Gene', (12, 24))	('Hk2', 'Gene', '3099', (26, 29))	('anaplerosis', 'MPA', (148, 159))	('glucose derived ribonucleotides', 'MPA', (63, 94))
540879	32560574	In addition, silencing of pyruvate kinase isoenzyme M2 enhanced the efficacy of docetaxel and cisplatin (an alkylating agent) in human KRAS mutant lung cancer xenograft models.	('pyruvate', 'Chemical', 'MESH:D019289', (26, 34))	('enhanced', 'PosReg', (55, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('lung cancer', 'Disease', (147, 158))	('silencing', 'Var', (13, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('docetaxel', 'Chemical', 'MESH:D000077143', (80, 89))	('pyruvate kinase isoenzyme M2', 'Enzyme', (26, 54))	('efficacy', 'MPA', (68, 76))	('human', 'Species', '9606', (129, 134))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutant', 'Var', (140, 146))
540880	32560574	Ablation of lactate dehdryogenase-a enzyme (critical for interconversion of pyruvate to lactate and associated with aggressive outcome) repressed the formation of spontaneous KRASG12D-driven lung tumors.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('lactate', 'Chemical', 'MESH:D019344', (12, 19))	('lung tumors', 'Phenotype', 'HP:0100526', (191, 202))	('Ablation', 'Var', (0, 8))	('lactate', 'Chemical', 'MESH:D019344', (88, 95))	('pyruvate', 'Chemical', 'MESH:D019289', (76, 84))	('lung tumors', 'Disease', 'MESH:D008175', (191, 202))	('lung tumor', 'Phenotype', 'HP:0100526', (191, 201))	('G12D', 'Chemical', '-', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('lung tumors', 'Disease', (191, 202))
540883	32560574	This provides a logical rationale for why the inhibition of autophagy could improve the response to other agents and forms the basis for completed and ongoing clinical trials for NSCLC (NCT01649947, NCT00728845, NCT01497925, and NCT03057340).	('NSCLC', 'Disease', (179, 184))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('inhibition', 'NegReg', (46, 56))	('NCT01497925', 'Var', (212, 223))	('NCT03057340', 'Var', (229, 240))	('response', 'MPA', (88, 96))	('NCT01649947', 'Var', (186, 197))	('NCT00728845', 'Var', (199, 210))	('rat', 'Species', '10116', (24, 27))	('autophagy', 'CPA', (60, 69))	('improve', 'PosReg', (76, 83))
540884	32560574	In fact, in recent years, inhibition of autophagy has been widely explored as a potential therapeutic intervention for cancer, although the results are somehow contradictory.	('inhibition', 'Var', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('autophagy', 'CPA', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
540885	32560574	Tumors with KRAS substitutions were reported to depend on macroautophagy to cope with oncogene-induced metabolic stress in order to facilitate the maintenance of mitochondrial metabolism, cell survival and tumorigenic growth.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('metabolic stress', 'Disease', (103, 119))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mitochondrial metabolism', 'MPA', (162, 186))	('tumor', 'Disease', (206, 211))	('KRAS', 'Gene', (12, 16))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('facilitate', 'PosReg', (132, 142))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('metabolic stress', 'Disease', 'MESH:D000079225', (103, 119))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cell survival', 'CPA', (188, 201))	('substitutions', 'Var', (17, 30))
540886	32560574	: deletion of autophagy-related 7 potently blocked macroautophagy in several cancer lines with oncogenic KRAS alterations but failed to inhibit cell proliferation in vitro or tumorigenesis in vivo.	('alterations', 'Var', (110, 121))	('tumor', 'Disease', (175, 180))	('rat', 'Species', '10116', (156, 159))	('rat', 'Species', '10116', (114, 117))	('cancer', 'Disease', (77, 83))	('macroautophagy', 'CPA', (51, 65))	('KRAS', 'Gene', (105, 109))	('blocked', 'NegReg', (43, 50))	('deletion', 'Var', (2, 10))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('autophagy-related 7', 'Gene', '10533', (14, 33))	('autophagy-related 7', 'Gene', (14, 33))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
540887	32560574	On the other hand, it has been shown that inhibition of RAF/MEK/ERK cascade activates serine/threonine kinase 11/AMP-activated protein kinase/Unc-51-like autophagy activating kinase 1 (STK11/AMPK/ULK1) signaling axis, leading to autophagy induction.	('AMPK', 'Gene', (191, 195))	('activates', 'PosReg', (76, 85))	('Unc-51-like autophagy activating kinase 1', 'Gene', (142, 183))	('RAF/MEK/ERK cascade', 'Gene', (56, 75))	('serine/threonine kinase 11', 'Gene', '6794', (86, 112))	('inhibition', 'Var', (42, 52))	('ULK1', 'Gene', (196, 200))	('autophagy induction', 'CPA', (229, 248))	('AMPK', 'Gene', '5563', (191, 195))	('serine/threonine kinase 11', 'Gene', (86, 112))	('Unc-51-like autophagy activating kinase 1', 'Gene', '8408', (142, 183))	('ULK1', 'Gene', '8408', (196, 200))
540889	32560574	Three studies recently published simultaneously illustrated synergistic activity of concomitant inhibition of autophagy and MAPK pathway in patient-derived xenografts of KRAS mutant pancreatic ductal adenocarcinoma, NRAS mutant melanoma and B-RAF mutant colorectal tumor.	('B-RAF', 'Gene', '673', (241, 246))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('mutant', 'Var', (175, 181))	('mutant', 'Var', (247, 253))	('KRAS', 'Gene', (170, 174))	('autophagy', 'CPA', (110, 119))	('rat', 'Species', '10116', (54, 57))	('B-RAF', 'Gene', (241, 246))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (182, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanoma', 'Disease', (228, 236))	('pancreatic ductal adenocarcinoma', 'Disease', (182, 214))	('colorectal tumor', 'Disease', 'MESH:D015179', (254, 270))	('MAPK pathway', 'Pathway', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('patient', 'Species', '9606', (140, 147))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (182, 214))	('inhibition', 'NegReg', (96, 106))	('colorectal tumor', 'Disease', (254, 270))
540892	32560574	Based on these intriguing results, future investigations are required to address the potential therapeutic benefit of combined inhibition of autophagy and MAPK signaling for patients with KRAS-mutated NSCLC.	('autophagy', 'CPA', (141, 150))	('NSCLC', 'Disease', (201, 206))	('patients', 'Species', '9606', (174, 182))	('inhibition', 'NegReg', (127, 137))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))	('KRAS-mutated', 'Var', (188, 200))
540896	32560574	Mutant KRAS tumors also express unique dependencies in terms of fatty acid synthesis and oxidation, tricarboxylic acid cycle (TCA)-dependent glucose metabolism and branched-chain amino acid utilization, which can potentially be exploited therapeutically.	('glucose', 'Chemical', 'MESH:D005947', (141, 148))	('KRAS tumors', 'Disease', (7, 18))	('dependencies', 'MPA', (39, 51))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (100, 118))	('branched-chain amino acid utilization', 'MPA', (164, 201))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('fatty acid', 'Chemical', 'MESH:D005227', (64, 74))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('Mutant', 'Var', (0, 6))	('fatty acid synthesis', 'MPA', (64, 84))	('KRAS tumors', 'Disease', 'MESH:D009369', (7, 18))	('oxidation', 'MPA', (89, 98))
540897	32560574	Metabolic communication in tumors also adds a new layer of immunoregulation for immune evasion and its targeting is an encouraging strategy to enhance tumor immunogenicity.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('enhance', 'PosReg', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (27, 32))	('Metabolic', 'Var', (0, 9))	('tumor', 'Disease', (151, 156))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('rat', 'Species', '10116', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('immune evasion', 'MPA', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
540902	32560574	Immune checkpoint blockage using monoclonal antibodies against PD-1 and its main ligand PD-L1 has substantially improved the treatment landscape of advanced-stage NSCLC and made its most strong impact in the stage III and first-line stage IV settings.	('monoclonal', 'Var', (33, 43))	('PD-L1', 'Gene', (88, 93))	('Immune checkpoint blockage', 'Phenotype', 'HP:0002958', (0, 26))	('PD-1', 'Gene', (63, 67))	('NSCLC', 'Disease', (163, 168))	('treatment landscape', 'MPA', (125, 144))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('improved', 'PosReg', (112, 120))	('men', 'Species', '9606', (130, 133))
540907	32560574	Mutant KRAS was associated with increases in tumor infiltrating lymphocytes, PD-L1 expression and tumor mutational burden.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (45, 50))	('PD-L1', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Mutant', 'Var', (0, 6))	('rat', 'Species', '10116', (57, 60))	('expression', 'MPA', (83, 93))	('tumor', 'Disease', (98, 103))	('increases', 'PosReg', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('KRAS', 'Gene', (7, 11))
540910	32560574	In particular, co-alterations in STK11 and p53 (both associated with high tumor mutational burden) profoundly influence the tumor-immune contexture.	('high tumor', 'Disease', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('rat', 'Species', '10116', (22, 25))	('high tumor', 'Disease', 'MESH:D009369', (69, 79))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('influence', 'Reg', (110, 119))	('associated', 'Reg', (53, 63))	('tumor', 'Disease', (74, 79))	('p53', 'Gene', (43, 46))	('co-alterations', 'Var', (15, 29))	('STK11', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
540914	32560574	In fact, recent data demonstrated how anti-PD-1 antibodies failed to induce tumor regression in mice without STK11 but exposing them to an interleukin-6 antibody (a pro-inflammatory cytokine secreted by tumor-infiltrating neutrophils) or neutrophil-depleting antibody yielded T cell infiltration and therapeutic benefits.	('rat', 'Species', '10116', (289, 292))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('mice', 'Species', '10090', (96, 100))	('rat', 'Species', '10116', (215, 218))	('tumor', 'Disease', (76, 81))	('rat', 'Species', '10116', (28, 31))	('interleukin-6', 'Gene', '16193', (139, 152))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('antibodies', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('interleukin-6', 'Gene', (139, 152))	('T cell infiltration', 'CPA', (276, 295))	('therapeutic benefits', 'CPA', (300, 320))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
540915	32560574	Similarly, anti-angiogenics and epigenetic modifiers are also needed to be investigated in KRAS/STK11 NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('NSCLC', 'Disease', (102, 107))	('KRAS/STK11', 'Var', (91, 101))
540916	32560574	In addition, mutations in phosphatase and tensin homolog (PTEN) and KEAP1 have been nominated as potential drivers of de novo resistance to immune checkpoint inhibition in NSCLC.	('PTEN', 'Gene', '5728', (58, 62))	('NSCLC', 'Disease', (172, 177))	('KEAP1', 'Gene', (68, 73))	('KEAP1', 'Gene', '9817', (68, 73))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('resistance', 'MPA', (126, 136))	('mutations', 'Var', (13, 22))	('phosphatase and tensin homolog', 'Gene', '5728', (26, 56))	('PTEN', 'Gene', (58, 62))
540917	32560574	Co-mutation in KEAP1 was also associated with shorter duration of initial platinum-based chemotherapy and shorter overall survival from start of immune therapy in KRAS+ advanced NSCLC.	('NSCLC', 'Disease', (178, 183))	('overall survival', 'MPA', (114, 130))	('shorter', 'NegReg', (106, 113))	('rat', 'Species', '10116', (56, 59))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('platinum', 'Chemical', 'MESH:D010984', (74, 82))	('KEAP1', 'Gene', '9817', (15, 20))	('Co-mutation', 'Var', (0, 11))	('shorter', 'NegReg', (46, 53))	('KEAP1', 'Gene', (15, 20))
540918	32560574	In contrast, KRAS/p53 co-mutated NSCLC was characterized by an inflammatory response, immune-editing and expression of co-stimulatory and co-inhibitor molecules including PD-L1.	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('KRAS/p53 co-mutated', 'Var', (13, 32))	('NSCLC', 'Disease', (33, 38))	('co-mutated', 'Var', (22, 32))
540919	32560574	Indeed, KRAS/p53 co-mutations were associated with potent treatment response and improved progression-free and overall survival.	('improved', 'PosReg', (81, 89))	('men', 'Species', '9606', (63, 66))	('overall survival', 'CPA', (111, 127))	('co-mutations', 'Var', (17, 29))	('treatment response', 'CPA', (58, 76))	('KRAS/p53', 'Gene', (8, 16))
540920	32560574	Taken together, co-occurring somatic genomic alterations in KRAS+ NSCLC represent independent predictors for sensitivity to anti-PD-1/PD-L1 therapies.	('alterations', 'Var', (45, 56))	('rat', 'Species', '10116', (49, 52))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('NSCLC', 'Disease', (66, 71))
540923	32560574	A phase I study evaluates the combination of the CDK4/6 inhibitor abemaciclib with anti-PD-1 antibody pembrolizumab for KRAS mutant, PD-L1+ patients with stage IV NSCLC (NCT02779751).	('NSCLC', 'Disease', (163, 168))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('CDK4/6', 'Gene', '1019;1021', (49, 55))	('patients', 'Species', '9606', (140, 148))	('KRAS', 'Var', (120, 124))	('pembrolizumab', 'Chemical', 'MESH:C582435', (102, 115))	('CDK4/6', 'Gene', (49, 55))
540924	32560574	A second trial is recruiting patients to determine the side effects and best dose of pembrolizumab and the MEK inhibitor trametinib for recurrent KRAS-mutated NSCLC that is metastatic, unresectable or locally advanced (NCT03299088, NCT03225664).	('patients', 'Species', '9606', (29, 37))	('NCT03299088', 'Var', (219, 230))	('NCT03225664', 'Var', (232, 243))	('NSCLC', 'Disease', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('KRAS-mutated', 'Var', (146, 158))	('trametinib', 'Chemical', 'MESH:C560077', (121, 131))	('pembrolizumab', 'Chemical', 'MESH:C582435', (85, 98))
540925	32560574	Another phase I study focuses on the safety and tolerability of pembrolizumab infusion in combination with mRNA-5671/V941 (a KRAS vaccine) in patients with KRAS mutant advanced or metastatic NSCLC (NCT03948763).	('KRAS mutant advanced', 'Var', (156, 176))	('pembrolizumab', 'Chemical', 'MESH:C582435', (64, 77))	('NSCLC', 'Disease', (191, 196))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('patients', 'Species', '9606', (142, 150))
540941	32560574	reported that infusion of CD8+ T cells targeting KRASG12D results in regression of lung metastases and thus mediates effective anti-tumor activity in a patient with metastatic colorectal cancer.	('lung metastases', 'Disease', (83, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('lung metastases', 'Disease', 'MESH:D009362', (83, 98))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('CD8', 'Gene', '925', (26, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('KRASG12D', 'Var', (49, 57))	('tumor', 'Disease', (132, 137))	('colorectal cancer', 'Disease', (176, 193))	('G12D', 'Chemical', '-', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('patient', 'Species', '9606', (152, 159))	('regression', 'NegReg', (69, 79))	('CD8', 'Gene', (26, 29))
540945	32560574	A novel clinical trial is recruiting patients to determine the safety of administering peripheral blood lymphocytes transduced with anti-KRASG12D murine T cell receptor (TCR) with preparative lymphodepletion and high dose interleukin-2 (NCT03745326).	('interleukin-2', 'Gene', '16183', (222, 235))	('murine', 'Species', '10090', (146, 152))	('patients', 'Species', '9606', (37, 45))	('anti-KRASG12D', 'Var', (132, 145))	('rat', 'Species', '10116', (185, 188))	('interleukin-2', 'Gene', (222, 235))
540948	32560574	Future studies involving anti-mutant KRAS TCR in NSCLC are awaited.	('KRAS', 'Gene', (37, 41))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('anti-mutant', 'Var', (25, 36))	('NSCLC', 'Disease', (49, 54))
540949	32560574	Despite decades of research highlighting mutant KRAS as a central driver of tumorigenesis and clinical resistance, the development of therapeutics potently tackling KRAS aberrations has so far been unaccomplished.	('men', 'Species', '9606', (126, 129))	('KRAS', 'Gene', (48, 52))	('mutant', 'Var', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('rat', 'Species', '10116', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
540950	32560574	A striking breakthrough has been achieved with covalent inhibitors such as MRTX849 and AMG 510 as well as with LC-2, a degrader molecule against the endogenous protein, in patients with KRASG12C lung tumors.	('lung tumor', 'Phenotype', 'HP:0100526', (195, 205))	('LC-2', 'Chemical', '-', (111, 115))	('lung tumors', 'Disease', 'MESH:D008175', (195, 206))	('AMG 510', 'Gene', (87, 94))	('AMG 510', 'Chemical', '-', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('MRTX849', 'Gene', (75, 82))	('KRASG12C', 'Var', (186, 194))	('lung tumors', 'Phenotype', 'HP:0100526', (195, 206))	('lung tumors', 'Disease', (195, 206))	('patients', 'Species', '9606', (172, 180))	('KRASG12C', 'Chemical', '-', (186, 194))	('LC-2', 'Gene', (111, 115))
540951	32560574	Conventional (e.g., combined chemotherapy with targeted KRAS downstream agents) and novel tools based on improved understanding of the pathobiology of mutant KRAS (e.g., cellular co-dependencies, association with a vulnerability to immunotherapies) are appealing strategies but demand further clinical testing in patients.	('KRAS', 'Gene', (158, 162))	('patients', 'Species', '9606', (313, 321))	('mutant', 'Var', (151, 157))	('rat', 'Species', '10116', (265, 268))
540955	32560574	Co-existing genetic events and mutant KRAS allele copy number gains define distinct metabolic profiles and tumor microenvironment, both contributing to differential drug sensitivities in seemingly comparable tumors.	('mutant', 'Var', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('contributing to', 'Reg', (136, 151))	('KRAS', 'Gene', (38, 42))	('men', 'Species', '9606', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('gains', 'PosReg', (62, 67))
540959	32560574	A-RAF V-Raf murine sarcoma 3611 viral oncogene homolog 1  AKT Protein kinase B  ALK Anaplastic lymphoma receptor tyrosine kinase  AMPK AMP-activated protein kinase  APC/C Anaphase-promoting complex/cyclosome  ASK1 Apoptosis signal-regulating kinase 1   ASO Antisense-oligonucleotide  B-RAF V-Raf murine sarcoma viral oncogene homolog B  Bad BCL2-associated agonist of cell death  BCL-XL B-cell lymphoma-extra large  BCL2 B-cell lymphoma 2  BET Bromodomain and extraterminal domain  BRCA Breast cancer gene  C-RAF V-Raf-1 murine leukemia viral oncogene-like protein 1  CDC25C M-phase inducer phosphatase 3  CDK Cyclin-dependent kinase   CDKN2A/B Cyclin-dependent kinase inhibitor 2A/B  Chk1 Checkpoint kinase 1  CRISPR/Cas9 Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9  CSC Cancer stem-like cell  CTLA-4 Cytotoxic T-lymphocyte-associated protein 4  DDR1 Discoidin domain receptor 1  EGFR Epidermal growth factor receptor  ERK Extracellular regulated kinase  FAK Focal adhesion kinase  FDA U.S. Food and Drug Administration  FGFR Fibroblast growth factor receptor  FTI Farnesyltransferase inhibitor  G12C Glycine 12 to cysteine  G12D Glycine 12 to aspartic acid  G12V Glycine 12 to valine  GAP GTPase-activating protein  GATA2 GATA-binding protein 2  GDP Guanosine diphosphate  GEF Guanine nucleotide exchange factor  GGTase I Geranylgeranyltransferase I  GTP Guanosine triphosphate  HER2-4/ERBB2-4 Human epidermal growth factor receptors 2-4  HLA Human leukocyte antigen  HRAS Harvey rat sarcoma viral oncogene homolog  HSP90 Heat shock protein 90  ICMT1 Isoprenyl carboxyl methyltransferase  IGF1R Insulin-like growth factor 1 receptor  IKK IkappaB kinase  IkappaB Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor  JNK c-Jun N-terminal kinase  KEAP1 Kelch-like ECH-associated protein 1  KRAS Kirsten rat sarcoma viral oncogene homolog  LKB1 Liver kinase B1  MAP3K7 Mitogen-activated protein kinase kinase kinase 7  MAPK Mitogen-activated protein kinase  MEK Mitogen-activated protein kinase kinase  MHC II Major histocompatibility complex class II  mTOR Mechanistic target of rapamycin kinase  NF-kappaB Nuclear factor 'kappa-light-chain-enhancer' of activated B-cells  NRAS Neuroblastoma rat sarcoma viral oncogene homolog  NSCLC Non-small-cell lung cancer  ORR Objective response rate  p53 Tumor protein p53  p90RSK p90 ribosomal S6 kinase  PARP Poly(ADP-ribose)polymerase  PD-1 Programmed cell death protein 1  PD-L1 Programmed cell death 1 ligand 1  PDX Patient-derived xenograft  pERK Phosphorylated ERK  PFS Progression-free survival  PI3K Phosphoinositide 3-kinase  PLD1 Phospholipase D1  PLK1 Polo-like kinase 1  PROTAC Proteolysis-targeting chimera  PTEN Phosphatase and tensin homolog  PTPN11 Protein tyrosine phosphatase non-receptor type 11  RAC Ras-related C3 botulinum toxin substrate 1  RAF Rat fibrosarcoma  RAL Ras-like protein  RALGDS Ral guanine nucleotide dissociation stimulator  RBD RAS-binding domain  RCE1 RAS-converting enzyme 1  RET RET proto-oncogene  RHOA Ras homolog family member  RNAi RNA interference  ROCK2 Rho-associated coiled-coil containing protein kinase 2  ROS Proto-oncogene tyrosine-protein kinase ROS  RTK Receptor tyrosine kinase  SNAIL2 Snail family transcriptional repressor 2  SRC V-Src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog  STK11 Serine/threonine kinase 11  STK3 Serine/threonine-protein kinase 3  TBK1 TANK binding kinase 1  TCA Tricarboxylic acid cycle   TCR T cell receptor  Th17 T helper 17  TIAM1 T lymphoma invasion and metastasis-inducing protein 1  Tim-3 T cell immunoglobulin mucin-3  TKI Tyrosine kinase inhibitor  TPX2 Targeting protein for Xklp2  Treg Regulatory T cells  ULK1 Unc-51-like autophagy activating kinase 1  VHL von Hippel-Lindau disease tumor suppressor  WT1 Wilms tumor 1	('STK3', 'Gene', '6788', (3395, 3399))	('PTEN', 'Gene', (2728, 2732))	('B-cell lymphoma 2', 'Gene', (421, 438))	('GATA2', 'Gene', '2624', (1260, 1265))	('TPX2', 'Gene', '22974', (3662, 3666))	('CTLA-4', 'Gene', '1493', (837, 843))	('ULK1', 'Gene', (3721, 3725))	('G12V', 'Chemical', '-', (1202, 1206))	('Wilms tumor', 'Phenotype', 'HP:0002667', (3821, 3832))	('sarcoma', 'Phenotype', 'HP:0100242', (1873, 1880))	('RAL', 'Gene', (2915, 2918))	('Glycine 12 to valine', 'SUBSTITUTION', 'None', (1207, 1227))	('G12C', 'Chemical', '-', (1139, 1143))	('Glycine 12 to valine', 'Var', (1207, 1227))	('JNK', 'Gene', '116554', (1784, 1787))	('lymphoma', 'Phenotype', 'HP:0002665', (3541, 3549))	('TANK binding kinase 1', 'Gene', (3440, 3461))	('ROS', 'Chemical', '-', (3165, 3168))	('TANK binding kinase 1', 'Gene', '29110', (3440, 3461))	('APC', 'Disease', 'MESH:D011125', (165, 168))	('Programmed cell death protein 1', 'Gene', '100533201', (2450, 2481))	('RAL', 'Gene', '5898', (2893, 2896))	('rat', 'Species', '10116', (2863, 2866))	('shock', 'Phenotype', 'HP:0031273', (1571, 1576))	('Epidermal growth factor receptor', 'Gene', (928, 960))	('NRAS Neuroblastoma rat sarcoma', 'Disease', (2239, 2269))	('sarcoma', 'Disease', 'MESH:D012509', (1528, 1535))	('Unc-51-like autophagy activating kinase 1', 'Gene', '8408', (3726, 3767))	('Glycine 12 to aspartic acid', 'Var', (1173, 1200))	('sarcoma', 'Disease', (1528, 1535))	('Anaplastic lymphoma receptor tyrosine kinase', 'Gene', '238', (84, 128))	('PTPN11', 'Gene', '5781', (2765, 2771))	('lymphoma', 'Phenotype', 'HP:0002665', (428, 436))	('fibrosarcoma', 'Disease', 'MESH:D005354', (2879, 2891))	('T lymphoma invasion', 'Disease', 'MESH:D016399', (3539, 3558))	('Ral', 'Gene', '5898', (2922, 2925))	('ERBB2-4', 'Gene', '2064;2065;2066', (1430, 1437))	('Breast cancer', 'Phenotype', 'HP:0003002', (487, 500))	('Glycine 12 to cysteine', 'SUBSTITUTION', 'None', (1144, 1166))	('Ral', 'Gene', (2922, 2925))	('2A/B', 'SUBSTITUTION', 'None', (640, 644))	('sarcoma', 'Disease', 'MESH:D012509', (1873, 1880))	('epidermal growth factor receptors 2-4', 'Gene', '2064;2065;2066', (1444, 1481))	('KEAP1', 'Gene', '9817', (1813, 1818))	('leukemia', 'Disease', 'MESH:D007938', (528, 536))	('rat', 'Species', '10116', (1869, 1872))	('T lymphoma invasion', 'Disease', (3539, 3558))	('sarcoma', 'Disease', (1873, 1880))	('FAK', 'Gene', (998, 1001))	('RAL', 'Gene', (2893, 2896))	('Cancer', 'Phenotype', 'HP:0002664', (814, 820))	('SNAIL2', 'Gene', (3243, 3249))	('oligonucleotide', 'Chemical', 'MESH:D009841', (267, 282))	('lung cancer', 'Phenotype', 'HP:0100526', (2315, 2326))	('RCE1', 'Gene', '9986', (2994, 2998))	('HER2-4', 'Gene', (1423, 1429))	('AMPK', 'Gene', '5563', (130, 134))	('CDK', 'Gene', (606, 609))	('NSCLC Non-small-cell lung cancer', 'Disease', (2294, 2326))	('Human', 'Species', '9606', (1438, 1443))	('B-RAF', 'Gene', (284, 289))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (2244, 2257))	('Serine/threonine kinase 11', 'Gene', (3367, 3393))	('Liver kinase B1', 'Gene', '6794', (1910, 1925))	('MAP3K7', 'Gene', (1927, 1933))	('Wilms tumor 1', 'Gene', (3821, 3834))	('rat', 'Species', '10116', (1524, 1527))	('Glycine 12 to aspartic acid', 'SUBSTITUTION', 'None', (1173, 1200))	('BRCA Breast cancer', 'Disease', 'MESH:D001943', (482, 500))	('lymphoma', 'Phenotype', 'HP:0002665', (95, 103))	('death  BCL-XL B-cell lymphoma', 'Disease', 'MESH:D016393', (373, 402))	('GATA-binding protein 2', 'Gene', (1266, 1288))	('NRAS Neuroblastoma rat sarcoma', 'Disease', 'MESH:D009447', (2239, 2269))	('CDK', 'Gene', '1019;12567;94201;1021;114483', (636, 639))	('Apoptosis signal-regulating kinase 1', 'Gene', '26408', (214, 250))	('Protein tyrosine phosphatase non-receptor type 11', 'Gene', '5781', (2772, 2821))	('Discoidin domain receptor 1', 'Gene', '780', (894, 921))	('GTP', 'Chemical', 'MESH:D006160', (1395, 1398))	('murine', 'Species', '10090', (12, 18))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (1819, 1854))	('rat', 'Species', '10116', (2258, 2261))	('ROS', 'Chemical', '-', (3208, 3211))	('RCE1', 'Gene', (2994, 2998))	('von Hippel-Lindau disease tumor suppressor', 'Gene', '103313576', (3773, 3815))	('rat', 'Species', '10116', (463, 466))	('Serine/threonine kinase 11', 'Gene', '6794', (3367, 3393))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (84, 103))	('murine', 'Species', '10090', (296, 302))	('HER2-4', 'Gene', '2064;2065;2066', (1423, 1429))	('fibrosarcoma', 'Disease', (2879, 2891))	('ROCK2', 'Gene', (3103, 3108))	('2A/B', 'Var', (640, 644))	('Anaplastic lymphoma receptor tyrosine kinase', 'Gene', (84, 128))	('leukemia', 'Disease', (528, 536))	('G12D', 'Chemical', '-', (1168, 1172))	('2A/B', 'SUBSTITUTION', 'None', (679, 683))	('Human', 'Species', '9606', (1487, 1492))	('epidermal growth factor receptors 2-4', 'Gene', (1444, 1481))	('Targeting protein for Xklp2', 'Gene', '22974', (3667, 3694))	('ALK', 'Gene', '238', (80, 83))	('ULK1', 'Gene', '8408', (3721, 3725))	('ALK', 'Gene', (80, 83))	('sarcoma', 'Disease', (3308, 3315))	('SNAIL2', 'Gene', '6591', (3243, 3249))	('rat', 'Species', '10116', (1056, 1059))	('FAK', 'Gene', '5747', (998, 1001))	('TPX2', 'Gene', (3662, 3666))	('CDK', 'Gene', '1019;12567;94201;1021;114483', (606, 609))	('PLK1', 'Gene', '5347', (2665, 2669))	('GATA-binding protein 2', 'Gene', '2624', (1266, 1288))	('ERBB2-4', 'Gene', (1430, 1437))	('Targeting protein for Xklp2', 'Gene', (3667, 3694))	('sarcoma', 'Phenotype', 'HP:0100242', (2262, 2269))	('cancer', 'Phenotype', 'HP:0002664', (494, 500))	('Heat shock protein 90', 'Gene', (1566, 1587))	('MAP3K7', 'Gene', '6885', (1927, 1933))	('CTLA-4', 'Gene', (837, 843))	('ROCK2', 'Gene', '9475', (3103, 3108))	('Glycine 12 to cysteine', 'Var', (1144, 1166))	('murine', 'Species', '10090', (521, 527))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (2879, 2891))	('TBK1', 'Gene', '29110', (3435, 3439))	('JNK', 'Gene', (1784, 1787))	('M-phase inducer phosphatase 3', 'Gene', '995', (575, 604))	('CDC25C', 'Gene', (568, 574))	('PTPN11', 'Gene', (2765, 2771))	('TBK1', 'Gene', (3435, 3439))	('leukemia', 'Phenotype', 'HP:0001909', (528, 536))	('Serine', 'Chemical', 'MESH:D012694', (3367, 3373))	('CDC25C', 'Gene', '995', (568, 574))	('Phosphatase and tensin homolog', 'Gene', '5728', (2733, 2763))	('IGF1R', 'Gene', (1633, 1638))	('RAS-converting enzyme 1', 'Gene', '9986', (2999, 3022))	('sarcoma', 'Disease', (2884, 2891))	('SRC', 'Gene', '20779', (3292, 3295))	('Tumor', 'Phenotype', 'HP:0002664', (2361, 2366))	('Rat', 'CellLine', 'CVCL:0492', (2875, 2878))	('Heat shock protein 90', 'Gene', '299331', (1566, 1587))	('Kelch-like ECH-associated protein 1', 'Gene', (1819, 1854))	('2A/B', 'Var', (679, 683))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (2304, 2326))	('KEAP1', 'Gene', (1813, 1818))	('PARP', 'Gene', '142', (2412, 2416))	('PLD1', 'Gene', '5337', (2642, 2646))	('WT1', 'Gene', '7490', (3817, 3820))	('sarcoma', 'Disease', (2262, 2269))	('Epidermal growth factor receptor', 'Gene', '1956', (928, 960))	('p90RSK', 'Gene', (2380, 2386))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('Discoidin domain receptor 1', 'Gene', (894, 921))	('NSCLC Non-small-cell lung cancer', 'Disease', 'MESH:D002289', (2294, 2326))	('Poly(ADP-ribose)polymerase', 'Gene', '25591', (2417, 2443))	('sarcoma', 'Disease', 'MESH:D012509', (3308, 3315))	('von Hippel-Lindau disease tumor suppressor', 'Gene', (3773, 3815))	('STK3', 'Gene', (3395, 3399))	('PARP', 'Gene', (2412, 2416))	('Cancer', 'Disease', (814, 820))	('Programmed cell death protein 1', 'Gene', (2450, 2481))	('sarcoma', 'Phenotype', 'HP:0100242', (303, 310))	('Serine', 'Chemical', 'MESH:D012694', (3400, 3406))	('GATA2', 'Gene', (1260, 1265))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (387, 402))	('Liver kinase B1', 'Gene', (1910, 1925))	('Protein tyrosine phosphatase non-receptor type 11', 'Gene', (2772, 2821))	('Mitogen-activated protein kinase kinase kinase 7', 'Gene', (1934, 1982))	('tumor', 'Phenotype', 'HP:0002664', (3799, 3804))	('CDK', 'Gene', (636, 639))	('Cancer', 'Disease', 'MESH:D009369', (814, 820))	('PTEN', 'Gene', '5728', (2728, 2732))	('AMPK', 'Gene', (130, 134))	('RAS-converting enzyme 1', 'Gene', (2999, 3022))	('IGF1R', 'Gene', '3480', (1633, 1638))	('Mitogen-activated protein kinase kinase kinase 7', 'Gene', '6885', (1934, 1982))	('GTP', 'Chemical', 'MESH:D006160', (1233, 1236))	('PLD1', 'Gene', (2642, 2646))	('APC', 'Disease', (165, 168))	('p90RSK', 'Gene', '6195', (2380, 2386))	('Patient', 'Species', '9606', (2527, 2534))	('Apoptosis signal-regulating kinase 1', 'Gene', (214, 250))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (2926, 2944))	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('SRC', 'Gene', (3292, 3295))	('sarcoma', 'Disease', 'MESH:D012509', (2884, 2891))	('sarcoma', 'Disease', (19, 26))	('RAL', 'Gene', '5898', (2915, 2918))	('GDP', 'Chemical', 'MESH:D006153', (1290, 1293))	('sarcoma', 'Disease', 'MESH:D012509', (303, 310))	('M-phase inducer phosphatase 3', 'Gene', (575, 604))	('WT1', 'Gene', (3817, 3820))	('Rho-associated coiled-coil containing protein kinase 2', 'Gene', '9475', (3109, 3163))	('B-RAF', 'Gene', '673', (284, 289))	('PLK1', 'Gene', (2665, 2669))	('rat', 'Species', '10116', (2351, 2354))	('BRCA Breast cancer', 'Disease', (482, 500))	('B-cell lymphoma 2', 'Gene', '596', (421, 438))	('sarcoma', 'Disease', (303, 310))	('Unc-51-like autophagy activating kinase 1', 'Gene', (3726, 3767))	('sarcoma', 'Phenotype', 'HP:0100242', (1528, 1535))	('Poly(ADP-ribose)polymerase', 'Gene', (2417, 2443))	('tumor', 'Phenotype', 'HP:0002664', (3827, 3832))	('sarcoma', 'Disease', 'MESH:D012509', (2262, 2269))	('ASO', 'Chemical', 'MESH:D016376', (253, 256))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (421, 436))	('death  BCL-XL B-cell lymphoma', 'Disease', (373, 402))	('Wilms tumor 1', 'Gene', '7490', (3821, 3834))	('lymphoma', 'Phenotype', 'HP:0002665', (394, 402))	('cancer', 'Phenotype', 'HP:0002664', (2320, 2326))
540970	30701092	Furthermore, AJ-5 reduced autophagic flux as shown by reduced LC3II accumulation in the presence of bafilomycin A1 and a significant reduction in autophagosome flux J.	('LC3', 'Gene', '84557', (62, 65))	('LC3', 'Gene', (62, 65))	('AJ-5', 'Chemical', '-', (13, 17))	('reduction', 'NegReg', (133, 142))	('reduced', 'NegReg', (18, 25))	('autophagic flux', 'CPA', (26, 41))	('reduced', 'NegReg', (54, 61))	('AJ-5', 'Var', (13, 17))	('autophagosome flux J', 'CPA', (146, 166))	('bafilomycin A1', 'Chemical', 'MESH:C040929', (100, 114))
540991	30701092	We show that AJ-5 induces double-stranded DNA breaks (DSBs) which triggers the canonical DSBs ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (Chk2) pathway as well as the p38/mitogen-activated protein kinase (MAPK) stress signalling pathway leading to a G1 cell cycle arrest, reduction in autophagic flux and induction of apoptosis.	('ATM', 'Gene', '472', (149, 152))	('Chk2', 'Gene', '11200', (175, 179))	('apoptosis', 'CPA', (355, 364))	('MAPK', 'Gene', (242, 246))	('checkpoint kinase 2', 'Gene', '11200', (154, 173))	('G1 cell cycle arrest', 'CPA', (287, 307))	('AJ-5', 'Chemical', '-', (13, 17))	('p38/mitogen-activated protein kinase', 'Gene', '1432', (204, 240))	('MAPK', 'Gene', '1432', (242, 246))	('AJ-5', 'Var', (13, 17))	('ATM', 'Gene', (149, 152))	('ataxia telangiectasia', 'Disease', (94, 115))	('p38/mitogen-activated protein kinase', 'Gene', (204, 240))	('autophagic flux', 'CPA', (322, 337))	('Chk2', 'Gene', (175, 179))	('reduction', 'NegReg', (309, 318))	('telangiectasia', 'Phenotype', 'HP:0001009', (101, 115))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (290, 307))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (94, 115))	('checkpoint kinase 2', 'Gene', (154, 173))	('ataxia', 'Phenotype', 'HP:0001251', (94, 100))
540999	30701092	Interestingly, there is growing evidence that mesenchymal stem cells are the cell of origin for specific sarcoma types including RMS, and compared to the other non-malignant cells tested, the mesenchymal stem cells (A100021501) were the most sensitive to AJ-5.	('RMS', 'Phenotype', 'HP:0002859', (129, 132))	('sensitive', 'MPA', (242, 251))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('AJ-5', 'Chemical', '-', (255, 259))	('sarcoma', 'Disease', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('A100021501', 'Var', (216, 226))
541002	30701092	It is evident that AJ-5 significantly inhibits the ability of RMS cells to survive and proliferate.	('AJ-5', 'Var', (19, 23))	('inhibits', 'NegReg', (38, 46))	('RMS', 'Phenotype', 'HP:0002859', (62, 65))	('AJ-5', 'Chemical', '-', (19, 23))
541003	30701092	Importantly, the ability of the non-malignant C2C12 myoblasts to survive and proliferate was not significantly hindered after 24 h of 0.3 microM AJ-5 (Fig.	('C2C12', 'CellLine', 'CVCL:0188', (46, 51))	('0.3 microM AJ-5', 'Var', (134, 149))	('AJ-5', 'Var', (145, 149))	('AJ-5', 'Chemical', '-', (145, 149))
541005	30701092	2c shows that AJ-5 reduced the migratory ability of all RMS cells tested.	('migratory ability of all RMS cells', 'CPA', (31, 65))	('RMS', 'Phenotype', 'HP:0002859', (56, 59))	('AJ-5', 'Chemical', '-', (14, 18))	('reduced', 'NegReg', (19, 26))	('AJ-5', 'Var', (14, 18))
541008	30701092	gammaH2AX is a robust marker of DSBs and western blotting and immunocytochemistry revealed a dose-dependent increase in levels of gammaH2AX (Fig.	('gammaH2AX', 'Chemical', '-', (0, 9))	('increase', 'PosReg', (108, 116))	('gammaH2AX', 'Chemical', '-', (130, 139))	('gammaH2AX', 'Var', (130, 139))
541013	30701092	However, both the RMS cell lines used in this study harbour p53 mutations that result in high levels of inactive p53.	('p53', 'Gene', (113, 116))	('levels', 'MPA', (94, 100))	('RMS', 'Phenotype', 'HP:0002859', (18, 21))	('p53', 'Gene', (60, 63))	('mutations', 'Var', (64, 73))	('p53', 'Gene', '7157', (113, 116))	('p53', 'Gene', '7157', (60, 63))
541014	30701092	Importantly, p21 levels increased at the IC50 concentrations of AJ-5 and this response was particularly pronounced after 24 h of treatment (Fig.	('AJ-5', 'Chemical', '-', (64, 68))	('p21', 'Gene', '644914', (13, 16))	('IC50 concentrations', 'Var', (41, 60))	('p21', 'Gene', (13, 16))	('increased', 'PosReg', (24, 33))	('AJ-5', 'Gene', (64, 68))
541026	30701092	Importantly, caspases-8 and -9 were more robustly activated in RD cells treated with AJ-5 than those treated with IC50 doxorubicin, a drug commonly used in the treatment of RMS and used as a positive control in apoptosis assays (Fig.	('activated', 'PosReg', (50, 59))	('AJ-5', 'Chemical', '-', (85, 89))	('doxorubicin', 'Chemical', 'MESH:D004317', (119, 130))	('RMS', 'Phenotype', 'HP:0002859', (173, 176))	('AJ-5', 'Var', (85, 89))	('caspases-8 and -9', 'Gene', '841;842', (13, 30))
541064	30701092	This suggests that AJ-5 displays more potent anti-cancer activity at much lower concentrations over a shorter period than cisplatin in these RMS cells.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('RMS', 'Phenotype', 'HP:0002859', (141, 144))	('AJ-5', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('AJ-5', 'Chemical', '-', (19, 23))
541070	30701092	Taken together these findings support evidence that, compared to platinum compounds, palladium complexes display superior anti-cancer activity and that they may associate with fewer side effects.	('platinum', 'Chemical', 'MESH:D010984', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('palladium', 'Var', (85, 94))	('superior', 'PosReg', (113, 121))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('palladium', 'Chemical', 'MESH:D010165', (85, 94))
541074	30701092	4c reveal that AJ-5 induces not only a significant apoptotic population but also a significant cell population which could represent necrosis, programmed necrosis (necroptosis) and/or secondary necrosis which occurs when there is insufficient clearance of apoptotic cells.	('necrosis', 'Disease', 'MESH:D009336', (133, 141))	('necrosis', 'Disease', 'MESH:D009336', (194, 202))	('AJ-5', 'Chemical', '-', (15, 19))	('secondary necrosis', 'Phenotype', 'HP:0010885', (184, 202))	('necrosis', 'Disease', 'MESH:D009336', (154, 162))	('induces', 'Reg', (20, 27))	('AJ-5', 'Var', (15, 19))	('necrosis', 'Disease', (194, 202))	('apoptotic', 'CPA', (51, 60))	('necrosis', 'Disease', (133, 141))	('necrosis', 'Disease', (154, 162))
541081	30701092	It is important to note that AJ-5 induces autophagy PCD in melanoma and breast cancer cells, which suggests that the effect of palladium complexes on autophagy may be cancer type specific.	('AJ-5', 'Chemical', '-', (29, 33))	('palladium', 'Chemical', 'MESH:D010165', (127, 136))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (59, 85))	('PCD', 'Disease', (52, 55))	('PCD', 'Disease', 'MESH:D007619', (52, 55))	('autophagy', 'CPA', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('induces', 'Reg', (34, 41))	('cancer', 'Disease', (167, 173))	('AJ-5', 'Var', (29, 33))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
541094	30701092	Cells were seeded in 6-well plates and treated the following day with IC50, 1/2 IC50, 1/4 IC50 AJ-5 and vehicle.	('IC50', 'Var', (80, 84))	('AJ-5', 'Chemical', '-', (95, 99))	('IC50', 'Var', (70, 74))
541100	30701092	The membranes were incubated with primary antibodies: rabbit polyclonal antibodies to phospho-histone H2A.X (Ser139) (#2577), phospho-chk2 (Thr68) (#221), phospho-p38 MAPK (Thr180/Tyr182) (#9211), cleaved caspase-3 (Asp175) (#9661), PARP (#9542), caspase-9 (#9502), LC3B (#2775), p38 MAPK (#9212), rabbit monoclonal antibody to cleaved caspase-7 (Asp198) (D6H1) (#8438), mouse monoclonal antibodies to phospho-ATM (Ser1981) (D6H9) (#5883), Cyclin B1 (V152) (#4135), Caspase-8 (1C12) (#9746), SQSTM1/p62 (D5L7G) (#88588) from Cell Signaling Technology (Massachusetts, USA); mouse monoclonal antibody to p53 (DO-1) (sc-126), rabbit polyclonal antibodies to p21 (C-19) (sc-397), cyclin A (H-432) (sc-751), cyclin B1 (H-433)(sc-752), PARP-1 (H-250) (sc-7150) from Santa Cruz Biotechnology (Texas, USA); rabbit polyclonal antibody to p38 MAP kinase (M0800) from Sigma Aldrich.	('chk2', 'Gene', '11200', (134, 138))	('LC3B', 'Gene', '81631', (266, 270))	('p38', 'Gene', (163, 166))	('mouse', 'Species', '10090', (573, 578))	('p62', 'Gene', '8878', (499, 502))	('rabbit', 'Species', '9986', (623, 629))	('p62', 'Gene', (499, 502))	('Cyclin B1', 'Gene', (440, 449))	('PARP-1', 'Gene', (730, 736))	('Caspase-8', 'Gene', (466, 475))	('cyclin B1', 'Gene', (703, 712))	('cyclin B1', 'Gene', '891', (703, 712))	('rabbit', 'Species', '9986', (298, 304))	('SQSTM1', 'Gene', (492, 498))	('Cyclin B1', 'Gene', '891', (440, 449))	('caspase-7', 'Gene', '840', (336, 345))	('p53', 'Gene', '7157', (602, 605))	('p38', 'Gene', (280, 283))	('p38', 'Gene', (829, 832))	('cyclin A', 'Gene', '890', (676, 684))	('ATM', 'Gene', '472', (410, 413))	('p38', 'Gene', '1432', (163, 166))	('PARP', 'Gene', '142', (233, 237))	('MAPK', 'Gene', (167, 171))	('SQSTM1', 'Gene', '8878', (492, 498))	('mouse', 'Species', '10090', (371, 376))	('p53', 'Gene', (602, 605))	('caspase-9', 'Gene', '842', (247, 256))	('cyclin A', 'Gene', (676, 684))	('PARP', 'Gene', (233, 237))	('Caspase-8', 'Gene', '841', (466, 475))	('PARP', 'Gene', '142', (730, 734))	('PARP-1', 'Gene', '142', (730, 736))	('MAPK', 'Gene', '1432', (167, 171))	('PARP', 'Gene', (730, 734))	('MAPK', 'Gene', (284, 288))	('p38', 'Gene', '1432', (829, 832))	('chk2', 'Gene', (134, 138))	('p38', 'Gene', '1432', (280, 283))	('M0800', 'Var', (845, 850))	('caspase-7', 'Gene', (336, 345))	('ATM', 'Gene', (410, 413))	('p21', 'Gene', (655, 658))	('p21', 'Gene', '644914', (655, 658))	('rabbit', 'Species', '9986', (54, 60))	('MAPK', 'Gene', '1432', (284, 288))	('LC3B', 'Gene', (266, 270))	('rabbit', 'Species', '9986', (799, 805))	('caspase-9', 'Gene', (247, 256))
541192	28435644	Suddenly during physical activity, the patient presented a syncopal episode, so he was referred for cardiologic evaluation where transesophageal echocardiography was performed, reporting a left atrial mass (46x47 mm) protruding through the mitral valve orifice during ventricular diastole (Figure 1A) with pulmonary artery systolic pressure of 105 mmHg, consistent with severe pulmonary hypertension and a left ventricular ejection fraction of 62%.	('patient', 'Species', '9606', (39, 46))	('severe pulmonary hypertension', 'Phenotype', 'HP:0002092', (370, 399))	('ventricular diastole', 'Disease', (268, 288))	('pulmonary artery systolic', 'Disease', (306, 331))	('hypertension', 'Phenotype', 'HP:0000822', (387, 399))	('syncopal episode', 'Disease', (59, 75))	('syncopal episode', 'Disease', 'MESH:D013575', (59, 75))	('mitral valve', 'Phenotype', 'HP:0011564', (240, 252))	('46x47 mm', 'Var', (207, 215))	('pulmonary hypertension', 'Disease', (377, 399))	('pulmonary artery systolic', 'Disease', 'MESH:D000071079', (306, 331))	('pulmonary hypertension', 'Disease', 'MESH:D006976', (377, 399))	('ventricular diastole', 'Disease', 'MESH:C563897', (268, 288))
541263	25624891	Histological analysis revealed small round cells that were positive for MIC-2 expression and fluorescent in situ hybridization analysis detected a translocation involving Ewing sarcoma breakpoint region 1 at chromosome 22q12.	('MIC-2', 'Gene', '4267', (72, 77))	('Ewing sarcoma breakpoint region 1', 'Gene', (171, 204))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (171, 204))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (171, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('MIC-2', 'Gene', (72, 77))	('translocation', 'Var', (147, 160))
541266	25624891	The specific translocation t(11;22)(q24;q12) was identified in Ewing's sarcoma and PNET, however, various other translocation patterns may also be involved.	('PNET', 'Disease', (83, 87))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (63, 78))	("Ewing's sarcoma", 'Disease', (63, 78))	('t(11;22)(q24;q12', 'Var', (27, 43))	('PNET', 'Phenotype', 'HP:0030065', (83, 87))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (63, 78))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (27, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))
541376	32723378	Multi-target receptor tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors have also been shown to be effective against selective STS, although with a lower ORR and median-PFS than those of doxorubicin and docetaxel/ gemcitabine.	('receptor tyrosine kinase', 'Gene', '5979', (13, 37))	('doxorubicin', 'Chemical', 'MESH:D004317', (225, 236))	('ORR', 'MPA', (192, 195))	('docetaxel', 'Chemical', 'MESH:D000077143', (241, 250))	('inhibitors', 'Var', (99, 109))	('programmed cell death protein 1', 'Gene', (60, 91))	('lower', 'NegReg', (186, 191))	('PD-1', 'Gene', '5133', (93, 97))	('selective STS', 'Disease', (155, 168))	('gemcitabine', 'Chemical', 'MESH:C056507', (252, 263))	('PD-1', 'Gene', (93, 97))	('programmed cell death protein 1', 'Gene', '5133', (60, 91))	('receptor tyrosine kinase', 'Gene', (13, 37))
541379	32723378	Nab-paclitaxel has been shown to deliver a higher dose of paclitaxel to tumor lesions (compared to solvent-based paclitaxel formulations) and to decrease the incidence of serious toxicities, including severe allergic reactions.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('allergic reactions', 'Disease', 'MESH:D004342', (208, 226))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('higher', 'PosReg', (43, 49))	('decrease', 'NegReg', (145, 153))	('tumor', 'Disease', (72, 77))	('Nab-paclitaxel', 'Var', (0, 14))	('paclitaxel', 'Chemical', 'MESH:D017239', (58, 68))	('toxicities', 'Disease', 'MESH:D064420', (179, 189))	('paclitaxel', 'Chemical', 'MESH:D017239', (113, 123))	('toxicities', 'Disease', (179, 189))	('allergic reactions', 'Phenotype', 'HP:0012393', (208, 226))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('allergic reactions', 'Disease', (208, 226))	('Nab', 'Chemical', '-', (0, 3))
541381	32723378	Not only that, there is growing evidence that nab-paclitaxel is effective in the treatment of other malignant tumors, including STS.	('men', 'Species', '9606', (86, 89))	('nab', 'Chemical', '-', (46, 49))	('STS', 'Disease', (128, 131))	('nab-paclitaxel', 'Var', (46, 60))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('malignant tumors', 'Disease', (100, 116))	('malignant tumors', 'Disease', 'MESH:D009369', (100, 116))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))
541420	32723378	The nab-paclitaxel can pass through the leaky capillary junctions in the tumor bed more easily than through the normal vessels in healthy tissue, and is thus taken up selectively by tumor tissues and cells.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (182, 187))	('paclitaxel', 'Chemical', 'MESH:D017239', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('leaky capillary', 'Phenotype', 'HP:0030005', (40, 55))	('nab', 'Chemical', '-', (4, 7))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('nab-paclitaxel', 'Var', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
541422	32723378	Several previous studies have demonstrated that nab-paclitaxel has greater efficacy and a more favorable safety profile (compared with solvent-based paclitaxel) in many malignancies.	('paclitaxel', 'Chemical', 'MESH:D017239', (52, 62))	('malignancies', 'Disease', (169, 181))	('paclitaxel', 'Chemical', 'MESH:D017239', (149, 159))	('efficacy', 'MPA', (75, 83))	('malignancies', 'Disease', 'MESH:D009369', (169, 181))	('nab-paclitaxel', 'Var', (48, 62))	('nab', 'Chemical', '-', (48, 51))
541426	32723378	The toxicity of nab-paclitaxel/ gemcitabine is also lower than that of doxorubicin and docetaxel/ gemcitabine.	('nab', 'Chemical', '-', (16, 19))	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('docetaxel', 'Chemical', 'MESH:D000077143', (87, 96))	('lower', 'NegReg', (52, 57))	('toxicity', 'Disease', (4, 12))	('nab-paclitaxel/', 'Var', (16, 31))	('paclitaxel', 'Chemical', 'MESH:D017239', (20, 30))	('gemcitabine', 'Chemical', 'MESH:C056507', (32, 43))	('doxorubicin', 'Chemical', 'MESH:D004317', (71, 82))
541427	32723378	In addition, the results of this study demonstrate that the effectiveness of nab-paclitaxel/ gemcitabine is significantly greater than that of conventional paclitaxel and docetaxel in some subtypes of STS, such as epithelioid sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('greater', 'PosReg', (122, 129))	('effectiveness', 'MPA', (60, 73))	('nab', 'Chemical', '-', (77, 80))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (214, 233))	('epithelioid sarcoma', 'Disease', (214, 233))	('paclitaxel', 'Chemical', 'MESH:D017239', (156, 166))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('docetaxel', 'Chemical', 'MESH:D000077143', (171, 180))	('nab-paclitaxel/', 'Var', (77, 92))
541430	32723378	The results of our study indicate that nab-paclitaxel is more effective and has lower toxicity than conventional paclitaxel or docetaxel in STS.	('docetaxel', 'Chemical', 'MESH:D000077143', (127, 136))	('nab-paclitaxel', 'Var', (39, 53))	('nab', 'Chemical', '-', (39, 42))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('toxicity', 'Disease', 'MESH:D064420', (86, 94))	('toxicity', 'Disease', (86, 94))	('paclitaxel', 'Chemical', 'MESH:D017239', (113, 123))
541431	32723378	In view of the fact that nab-paclitaxel is superior to conventional paclitaxel in the treatment of many malignant tumors, nab-paclitaxel should not simply be considered as a drug with similar properties to paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (206, 216))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('paclitaxel', 'Chemical', 'MESH:D017239', (29, 39))	('men', 'Species', '9606', (91, 94))	('nab-paclitaxel', 'Var', (122, 136))	('malignant tumors', 'Disease', (104, 120))	('nab', 'Chemical', '-', (122, 125))	('nab', 'Chemical', '-', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('paclitaxel', 'Chemical', 'MESH:D017239', (126, 136))	('paclitaxel', 'Chemical', 'MESH:D017239', (68, 78))	('malignant tumors', 'Disease', 'MESH:D009369', (104, 120))
541436	32723378	Although this study has some limitations, including the small sample size, retrospective design and the lack of a control group, we can still conclude that nab-paclitaxel/ gemcitabine combination chemotherapy used in STS treatment demonstrates promising effectiveness with low toxicity, and is worthy of further study.	('nab', 'Chemical', '-', (156, 159))	('gemcitabine', 'Chemical', 'MESH:C056507', (172, 183))	('nab-paclitaxel/', 'Var', (156, 171))	('low toxicity', 'Disease', (273, 285))	('low toxicity', 'Disease', 'MESH:D009800', (273, 285))	('paclitaxel', 'Chemical', 'MESH:D017239', (160, 170))	('men', 'Species', '9606', (226, 229))
541438	32723378	In elderly sarcoma patients, where effective treatment is wanting due to poor tolerance, nab-paclitaxel may be of significant benefit.	('sarcoma', 'Disease', (11, 18))	('patients', 'Species', '9606', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('paclitaxel', 'Chemical', 'MESH:D017239', (93, 103))	('nab', 'Chemical', '-', (89, 92))	('men', 'Species', '9606', (50, 53))	('nab-paclitaxel', 'Var', (89, 103))	('sarcoma', 'Disease', 'MESH:D012509', (11, 18))
541495	29588868	It has become clear that this fusion is necessary for tumor growth, and targeting the mutant transcription itself or downstream targets is an attractive therapeutic strategy.	('mutant', 'Var', (86, 92))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
541502	29588868	Ewing sarcoma was frequently affected by mutations inSTAG2, a gene that has recently gained attention due to its importance in the biology of several cancer types.	('mutations', 'Var', (41, 50))	('affected', 'Reg', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('STAG2', 'Gene', (53, 58))	('STAG2', 'Gene', '10735', (53, 58))	('cancer', 'Disease', (150, 156))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
541663	25999349	ES is a member of Ewing's family tumors (ESFT) and it is associated in 85-90% of cases with the t(11;22)(q24:q12) chromosomal translocation that generates fusion of the 5' segment of the EWS gene with the 3' segment of the ETS family gene FLI-1.	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('EWS', 'Gene', '2130', (187, 190))	('EWS', 'Gene', (187, 190))	('ES', 'Phenotype', 'HP:0012254', (41, 43))	("Ewing's family tumors", 'Disease', (18, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('FLI-1', 'Gene', (239, 244))	("Ewing's family tumors", 'Disease', 'MESH:C563168', (18, 39))	('FLI-1', 'Gene', '2313', (239, 244))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('fusion', 'Var', (155, 161))	('t(11;22)(q24:q12)', 'STRUCTURAL_ABNORMALITY', 'None', (96, 113))
541675	25999349	In this work, we show both in vitro and in vivo evidence for the anti-ES activity of edelfosine, promoting apoptosis through the accumulation of edelfosine in the ER, leading to an ER stress response.	('ES', 'Phenotype', 'HP:0012254', (70, 72))	('promoting', 'PosReg', (97, 106))	('accumulation', 'PosReg', (129, 141))	('leading to', 'Reg', (167, 177))	('edelfosine', 'Chemical', 'MESH:C026659', (85, 95))	('edelfosine', 'Var', (145, 155))	('ER stress response', 'MPA', (181, 199))	('apoptosis', 'CPA', (107, 116))	('edelfosine', 'Chemical', 'MESH:C026659', (145, 155))
541687	25999349	The hFOB 1.19 cell line was established by stable transfection of fetal bone-derived osteoblast cells with a temperature-sensitive mutant of the SV40 T antigen.	('mutant', 'Var', (131, 137))	('hFOB', 'Chemical', '-', (4, 8))	('SV40', 'Gene', (145, 149))
541701	25999349	Phosphorylation of eIF2alpha was detected after only 3-h incubation (Figure 4B), suggesting that edelfosine elicits rapidly an ER stress response.	('edelfosine', 'Chemical', 'MESH:C026659', (97, 107))	('elicits', 'Reg', (108, 115))	('eIF2alpha', 'Gene', (19, 28))	('eIF2alpha', 'Gene', '83939', (19, 28))	('ER stress response', 'MPA', (127, 145))	('edelfosine', 'Var', (97, 107))
541720	25999349	Preincubation with the specific JNK inhibitor SP600125 highly reduced the edelfosine-induced apoptotic response in both CADO-ES1 and RD-ES cells (Figure 6A, lower).	('edelfosine-induced', 'MPA', (74, 92))	('SP600125', 'Chemical', 'MESH:C432165', (46, 54))	('SP600125', 'Var', (46, 54))	('ES', 'Phenotype', 'HP:0012254', (125, 127))	('JNK', 'Gene', (32, 35))	('edelfosine', 'Chemical', 'MESH:C026659', (74, 84))	('ES', 'Phenotype', 'HP:0012254', (136, 138))	('JNK', 'Gene', '5599', (32, 35))	('reduced', 'NegReg', (62, 69))
541721	25999349	Edelfosine treatment also induced ERK phosphorylation in both ES cell lines (Figure 6B, upper), but preincubation with the ERK inhibitor U0126 did not significantly affect the apoptotic response induced by edelfosine (Figure 6B, lower), even though U0126 by itself promoted a slight increase in apoptosis, particularly in CADO-ES1 cells (Figure 6B, lower).	('U0126', 'Chemical', 'MESH:C113580', (137, 142))	('ES', 'Phenotype', 'HP:0012254', (62, 64))	('U0126', 'Var', (249, 254))	('Edelfosine', 'Chemical', 'MESH:C026659', (0, 10))	('ERK', 'Gene', '5594', (123, 126))	('U0126', 'Chemical', 'MESH:C113580', (249, 254))	('ERK', 'Gene', '5594', (34, 37))	('ES', 'Phenotype', 'HP:0012254', (327, 329))	('ERK', 'Gene', (123, 126))	('edelfosine', 'Chemical', 'MESH:C026659', (206, 216))	('ERK', 'Gene', (34, 37))
541742	25999349	Interestingly, we have also found that the combination of metformin and edelfosine also potentiates apoptosis in CADO-ES1 cells (Figure 8).	('ES', 'Phenotype', 'HP:0012254', (118, 120))	('potentiates', 'PosReg', (88, 99))	('metformin', 'Chemical', 'MESH:D008687', (58, 67))	('edelfosine', 'Chemical', 'MESH:C026659', (72, 82))	('apoptosis', 'CPA', (100, 109))	('combination', 'Var', (43, 54))
541756	25999349	The generation of ROS is suggested to lead to the acquisition of apoptosis-promoting conditions, thus facilitating the triggering of an apoptotic response.	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('apoptotic', 'CPA', (136, 145))	('lead', 'Reg', (38, 42))	('ROS', 'Var', (18, 21))
541762	25999349	Perifosine has been recently found to induce apoptosis in human osteosarcoma cells.	('Perifosine', 'Chemical', 'MESH:C105905', (0, 10))	('osteosarcoma', 'Disease', 'MESH:D012516', (64, 76))	('human', 'Species', '9606', (58, 63))	('induce', 'PosReg', (38, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Perifosine', 'Var', (0, 10))	('apoptosis', 'CPA', (45, 54))	('osteosarcoma', 'Disease', (64, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (64, 76))
541951	21647361	Blockade of IGF-1R has been shown to cause inhibition of cancer cell proliferation, survival, and anchorage-independent growth in vitro, to inhibit tumourigenesis, and block tumour invasion and metastasis, and to sensitize cancer cells to chemotherapy and radiotherapy.	('block tumour invasion', 'Disease', 'MESH:D006327', (168, 189))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('anchorage-independent growth', 'CPA', (98, 126))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('inhibition', 'NegReg', (43, 53))	('cancer', 'Disease', (57, 63))	('Blockade', 'Var', (0, 8))	('IGF-1R', 'Gene', (12, 18))	('tumourigenesis', 'CPA', (148, 162))	('inhibit', 'NegReg', (140, 147))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('block tumour invasion', 'Disease', (168, 189))	('sensitize', 'Reg', (213, 222))	('cancer', 'Disease', (223, 229))	('survival', 'CPA', (84, 92))
541971	21647361	Potential grade 3 and 4 hematologic adverse events reported in the Phase II trial with ganitumumab and R1507 included thrombocytopenia, anemia, neutropenia, pain at the time of administration, hyponatremia, and hyperglycemia.	('pain', 'Disease', 'MESH:D010146', (157, 161))	('hyperglycemia', 'Disease', (211, 224))	('anemia', 'Disease', (136, 142))	('thrombocytopenia', 'Disease', (118, 134))	('hyperglycemia', 'Disease', 'MESH:D006943', (211, 224))	('hyponatremia', 'Phenotype', 'HP:0002902', (193, 205))	('ganitumumab', 'Chemical', '-', (87, 98))	('hyponatremia', 'Disease', (193, 205))	('neutropenia', 'Disease', (144, 155))	('pain', 'Disease', (157, 161))	('thrombocytopenia', 'Disease', 'MESH:D013921', (118, 134))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (118, 134))	('R1507', 'Var', (103, 108))	('hyponatremia', 'Disease', 'MESH:D007010', (193, 205))	('hyperglycemia', 'Phenotype', 'HP:0003074', (211, 224))	('anemia', 'Disease', 'MESH:D000740', (136, 142))	('ganitumumab', 'Gene', (87, 98))	('pain', 'Phenotype', 'HP:0012531', (157, 161))	('neutropenia', 'Disease', 'MESH:D009503', (144, 155))	('neutropenia', 'Phenotype', 'HP:0001875', (144, 155))	('anemia', 'Phenotype', 'HP:0001903', (136, 142))
541982	21647361	Thus, IGF-1R blockade could cause linear and somatic growth delay in a childhood and teenage population, as supported by the identification of patients with genetic defects in the IGF-1 axis such as IGF-1 deficiency.	('growth delay', 'Phenotype', 'HP:0001510', (53, 65))	('IGF-1 axis', 'Gene', (180, 190))	('IGF-1 deficiency', 'Disease', (199, 215))	('blockade', 'Var', (13, 21))	('genetic defects', 'Disease', 'MESH:D030342', (157, 172))	('genetic defects', 'Disease', (157, 172))	('IGF-1 deficiency', 'Disease', 'MESH:C564816', (199, 215))	('IGF-1R', 'Gene', (6, 12))
541984	21647361	Some of these novel IGF-1R TKIs (i.e., picropodophylin (PPP), GSK183870A, GSK1904529A, BMS-536924, NVP-AEW541) have already shown promising preclinical activity as single agents or in combination in different sarcoma models.	('picropodophylin', 'Chemical', '-', (39, 54))	('GSK183870A', 'Var', (62, 72))	('GSK1904529A', 'Var', (74, 85))	('IGF-1R', 'Gene', (20, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('PPP', 'Chemical', '-', (56, 59))	('BMS-536924', 'Var', (87, 97))
541991	21647361	Although initial reports suggested an association between the EWS/FLI-1 type 1 translocation and response in Ewing's sarcoma, the purported predictive value of translocation type has not been observed consistently.	('association', 'Interaction', (38, 49))	('FLI-1', 'Gene', '2313', (66, 71))	('FLI-1', 'Gene', (66, 71))	('translocation', 'Var', (79, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	("Ewing's sarcoma", 'Disease', (109, 124))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (109, 124))
542049	20808587	The incidence of complications was higher in the patients in which resection resulted in the loss of pelvic continuity than those patients in which resection did not result in the loss of pelvic continuity; 60% (15 patients) with loss of continuity and 37% (7 patients) without loss of continuity.	('patients', 'Species', '9606', (215, 223))	('loss', 'NegReg', (93, 97))	('patients', 'Species', '9606', (260, 268))	('patients', 'Species', '9606', (130, 138))	('resection', 'Var', (67, 76))	('patients', 'Species', '9606', (49, 57))	('pelvic continuity', 'CPA', (101, 118))	('loss', 'NegReg', (230, 234))
542080	32819423	PROSPERO CRD42019126906 Sarcomas are a relatively rare and highly heterogenous group of cancers originating from mesenchymal cells, haboring various histologies, and divergent natural history.	('Sarcomas', 'Disease', (24, 32))	('PROSPERO', 'Chemical', '-', (0, 8))	('Sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('CRD42019126906', 'Var', (9, 23))
542149	29955431	There was no evidence of expression of p53, as commonly observed in neoplasms with p53 mutations, in the case presented here.	('neoplasms', 'Disease', 'MESH:D009369', (68, 77))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '403869', (39, 42))	('neoplasms', 'Phenotype', 'HP:0002664', (68, 77))	('mutations', 'Var', (87, 96))	('p53', 'Gene', (39, 42))	('neoplasm', 'Phenotype', 'HP:0002664', (68, 76))	('p53', 'Gene', '403869', (83, 86))	('neoplasms', 'Disease', (68, 77))
542181	26859573	Histological examination revealed eradication of tumor only in G4 where mice were treated with S. typhimurium A1-R followed by DOX.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('DOX', 'Chemical', 'MESH:D004317', (127, 130))	('S. typhimurium', 'Var', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mice', 'Species', '10090', (72, 76))	('S. typhimurium', 'Species', '90371', (95, 109))
542182	26859573	Our present study indicates future clinical potential of combining S. typhimurium A1-R with chemotherapy such as DOX for soft tissue sarcoma patients.	('DOX', 'Chemical', 'MESH:D004317', (113, 116))	('sarcoma', 'Disease', 'MESH:D012509', (133, 140))	('S. typhimurium', 'Species', '90371', (67, 81))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (121, 140))	('sarcoma', 'Disease', (133, 140))	('S. typhimurium', 'Var', (67, 81))	('patients', 'Species', '9606', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
542194	26859573	S. typhimurium A1-R was able to inhibit or eradicate primary and metastatic tumors as monotherapy in nude mouse models of prostate, breast, lung, pancreatic, ovarian stomach, and cervical cancer, as well as sarcoma cell lines and glioma, all of which are highly aggressive tumor models.	('inhibit', 'NegReg', (32, 39))	('eradicate', 'NegReg', (43, 52))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('tumor', 'Disease', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('tumor', 'Disease', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('pancreatic', 'Disease', 'MESH:D010195', (146, 156))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('breast', 'Disease', (132, 138))	('S. typhimurium', 'Species', '90371', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('pancreatic', 'Disease', (146, 156))	('tumors', 'Disease', (76, 82))	('cervical cancer', 'Disease', 'MESH:D002583', (179, 194))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('cervical cancer', 'Disease', (179, 194))	('A1-R', 'Var', (15, 19))	('glioma', 'Disease', (230, 236))	('mouse', 'Species', '10090', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung', 'Disease', (140, 144))	('sarcoma', 'Disease', 'MESH:D012509', (207, 214))	('glioma', 'Disease', 'MESH:D005910', (230, 236))	('prostate', 'Disease', (122, 130))	('sarcoma', 'Disease', (207, 214))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('ovarian stomach', 'Disease', (158, 173))	('ovarian stomach', 'Disease', 'MESH:D013274', (158, 173))
542197	26859573	Pazopanib tended to reduce the tumor volume compared to the untreated mice, but there was no significant difference.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('tumor', 'Disease', (31, 36))	('reduce', 'NegReg', (20, 26))	('mice', 'Species', '10090', (70, 74))	('Pazopanib', 'Var', (0, 9))
216865	26859573	However, S. typhimurium A1-R significantly inhibited tumor growth compared to the untreated mice.	('inhibited', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('S. typhimurium', 'Species', '90371', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('S. typhimurium', 'Var', (9, 23))	('mice', 'Species', '10090', (92, 96))
432496	26859573	These results suggest tumor-targeting S. typhimurium A1-R is a promising treatment for chemo-resistant soft-tissue sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('sarcoma', 'Disease', (115, 122))	('S. typhimurium', 'Var', (38, 52))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (103, 122))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('tumor', 'Disease', (22, 27))	('S. typhimurium', 'Species', '90371', (38, 52))
542199	26859573	Since S. typhimurium A1-R is a facultative anaerobe, unlike C. novyi-NT, which is an obligate anaerobe, it was thought to have more broad application for cancer therapy.	('S. typhimurium A1-R', 'Var', (6, 25))	('C. novyi-NT', 'Species', '386415', (60, 71))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('S. typhimurium', 'Species', '90371', (6, 20))
542201	26859573	On the 25th day from initiation of treatment, tumor volume was significantly smaller in the animals treated with S. typhimurium A1-R (G2) (245.3 +- 141.6 mm3, p < 0.01); the animals treated with DOX (G3) (165.5 +- 247.7 mm3, p < 0.05); and the animals treated with S. typhimurium A1-R followed by DOX (G4) (138.4 +- 209.3 mm3, p < 0.01) compared to the untreated control animals (G1) (1460.3 +- 1136.6 mm3, Figure 2).	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('DOX', 'Chemical', 'MESH:D004317', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('S. typhimurium', 'Species', '90371', (265, 279))	('S. typhimurium A1-R', 'Var', (265, 284))	('tumor', 'Disease', (46, 51))	('DOX', 'Chemical', 'MESH:D004317', (297, 300))	('S. typhimurium', 'Species', '90371', (113, 127))	('smaller', 'NegReg', (77, 84))	('S. typhimurium A1-R', 'Var', (113, 132))
542207	26859573	In G2 treated with S. typhimurium A1-R forty to 60% of the tumor tissue consisted of viable tissue (Grade IIA or IIB), whereas the other part was replaced by necrosis or inflammatory cells (Figure 3C, 3D).	('necrosis', 'Disease', (158, 166))	('tumor', 'Disease', (59, 64))	('S. typhimurium', 'Species', '90371', (19, 33))	('necrosis', 'Disease', 'MESH:D009336', (158, 166))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('S. typhimurium A1-R', 'Var', (19, 38))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
542210	26859573	Tumors in G4, treated with the combination of S. typhimurium A1-R followed by DOX were considered eradicated.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('S. typhimurium', 'Species', '90371', (46, 60))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('DOX', 'Chemical', 'MESH:D004317', (78, 81))	('S. typhimurium', 'Var', (46, 60))
542213	26859573	The higher rate eradication of tumors by the combination of S. typhimurium and DOX may be attributable to the "decoy" effect of S. typhimurium A1-R, which induces quiescent cells to cycle, there by making them more susceptible to chemotheraphy than when the cancer cells are in G1/G0 which are the majority of cells in a solid tumor.	('susceptible', 'MPA', (215, 226))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('DOX', 'Chemical', 'MESH:D004317', (79, 82))	('solid tumor', 'Disease', (321, 332))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('solid tumor', 'Disease', 'MESH:D009369', (321, 332))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('S. typhimurium', 'Species', '90371', (128, 142))	('more', 'PosReg', (210, 214))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cycle', 'CPA', (182, 187))	('S. typhimurium', 'Species', '90371', (60, 74))	('cancer', 'Disease', (258, 264))	('S. typhimurium', 'Var', (128, 142))
542217	26859573	The fact that C. novyi-NT is an obligate anaerobe may preclude its systemic administration and may limit its treatment to i.t.	('C. novyi-NT', 'Var', (14, 25))	('treatment', 'MPA', (109, 118))	('C. novyi-NT', 'Species', '386415', (14, 25))	('limit', 'NegReg', (99, 104))
542221	26859573	The combination of S. typhimurium A1-R and subsequent DOX eradicated a soft tissue sarcoma in a PDOX mouse model.	('eradicated', 'NegReg', (58, 68))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (71, 90))	('sarcoma', 'Disease', (83, 90))	('S. typhimurium', 'Species', '90371', (19, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('mouse', 'Species', '10090', (101, 106))	('DOX', 'Chemical', 'MESH:D004317', (97, 100))	('DOX', 'Chemical', 'MESH:D004317', (54, 57))	('S. typhimurium A1-R', 'Var', (19, 38))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))
542246	25809532	Nab-paclitaxel was well tolerated in vivo, producing maximum weight loss of approximately 10% with recovery to baseline weight in the week following the third dose.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('weight loss', 'Phenotype', 'HP:0001824', (61, 72))	('Nab-paclitaxel', 'Var', (0, 14))	('weight', 'MPA', (61, 67))	('loss', 'NegReg', (68, 72))	('rat', 'Species', '10116', (28, 31))	('Nab', 'Chemical', '-', (0, 3))
542247	25809532	Nab-paclitaxel induced statistically significant differences in event-free survival (EFS) distribution compared to control in 19 of 20 (95%) of the solid tumors.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('solid tumors', 'Disease', 'MESH:D009369', (148, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('Nab-paclitaxel', 'Var', (0, 14))	('solid tumors', 'Disease', (148, 160))	('differences', 'Reg', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('event-free', 'MPA', (64, 74))	('Nab', 'Chemical', '-', (0, 3))
542259	25809532	Additionally, Cremophor EL may cause neutropenia and prolonged peripheral neuropathy associated with axonal swelling and degeneration, vesicular degeneration and demyelination.	('neutropenia', 'Disease', 'MESH:D009503', (37, 48))	('neutropenia', 'Phenotype', 'HP:0001875', (37, 48))	('prolonged peripheral neuropathy', 'Disease', (53, 84))	('demyelination', 'Phenotype', 'HP:0011096', (162, 175))	('Cremophor', 'Var', (14, 23))	('axonal swelling and degeneration, vesicular degeneration and demyelination', 'Disease', 'MESH:D009410', (101, 175))	('Cremophor EL', 'Chemical', 'MESH:C000515', (14, 26))	('cause', 'Reg', (31, 36))	('neutropenia', 'Disease', (37, 48))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (63, 84))	('prolonged peripheral neuropathy', 'Disease', 'MESH:D010523', (53, 84))	('associated', 'Reg', (85, 95))
542267	25809532	A Phase 3 clinical trial directly compared the antitumour activity and tolerability of nab-paclitaxel with those of paclitaxel in women with measurable metastatic breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('women', 'Species', '9606', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('paclitaxel', 'Chemical', 'MESH:D017239', (116, 126))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (87, 101))	('paclitaxel', 'Chemical', 'MESH:D017239', (91, 101))	('antitumour activity', 'CPA', (47, 66))	('nab-paclitaxel', 'Var', (87, 101))	('breast cancer', 'Disease', (163, 176))
542270	25809532	Both the objective response rates (33% versus 19%, p = 0.001) and the median time to progression (23.0 versus 16.9 weeks, p = 0.006) significantly favored nab-paclitaxel over paclitaxel.	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (155, 169))	('paclitaxel', 'Chemical', 'MESH:D017239', (159, 169))	('paclitaxel', 'Chemical', 'MESH:D017239', (175, 185))	('favored', 'PosReg', (147, 154))	('nab-paclitaxel', 'Var', (155, 169))	('rat', 'Species', '10116', (28, 31))
542295	25809532	Mass transitions of m/z 898.3 to 525.2 and 903.3 to 530.2 were optimized for paclitaxel and d5-paclitaxel, respectively.	('d5-paclitaxel', 'Var', (92, 105))	('paclitaxel', 'Chemical', 'MESH:D017239', (95, 105))	('paclitaxel', 'Chemical', 'MESH:D017239', (77, 87))	('d5-paclitaxel', 'Chemical', '-', (92, 105))	('903.3', 'Var', (43, 48))
542306	25809532	Nab-paxlitaxel was generally well tolerated, with a 0% toxicity rate in the treated groups (0 of 200), similar to that observed for control animals (0 of 200).	('toxicity', 'Disease', 'MESH:D064420', (55, 63))	('Nab-paxlitaxel', 'Chemical', '-', (0, 14))	('toxicity', 'Disease', (55, 63))	('rat', 'Species', '10116', (64, 67))	('Nab-paxlitaxel', 'Var', (0, 14))	('rat', 'Species', '10116', (38, 41))
542307	25809532	Nab-paxlitaxel induced significant differences in EFS distribution compared to control in 19 of 20 (95%) of the evaluable solid tumor xenografts (Table I).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (128, 133))	('Nab-paxlitaxel', 'Chemical', '-', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('EFS distribution', 'MPA', (50, 66))	('differences', 'Reg', (35, 46))	('Nab-paxlitaxel', 'Var', (0, 14))
542318	25809532	Similarly, there was no obvious relationship between SPARC expression and response, as expression was low in non-reponding models (NB-1691, TC-71, NB-1643) and responding models (Rh28, Rh30R, Rh36, Rh41, Rh65), whereas relatively high-level SPARC (mRNA ~ 9-fold the median for all models) was associated with Rh18 tumors that were non-responsive to nab-paclitaxeltreatment (Figure 4B).	('Rh41', 'Var', (198, 202))	('Rh28', 'Var', (179, 183))	('Rh30R', 'Var', (185, 190))	('SPARC', 'Gene', '6678', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('low', 'NegReg', (102, 105))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (349, 363))	('expression', 'MPA', (87, 97))	('tumors', 'Disease', (314, 320))	('SPARC', 'Gene', (241, 246))	('tumors', 'Disease', 'MESH:D009369', (314, 320))	('SPARC', 'Gene', '6678', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('Rh36', 'Var', (192, 196))	('SPARC', 'Gene', (53, 58))
542335	25809532	Of note, neither neuroblastoma or osteosarcoma models tested responded to the antimitotic agents vincristine or eribulin, which may suggest a common mechanism of resistance to these agents, for example expression of ABC transporters that may reduce intracellular levels of abraxane (e.g.	('neuroblastoma', 'Phenotype', 'HP:0003006', (17, 30))	('ABC', 'Gene', (216, 219))	('intracellular levels of abraxane', 'MPA', (249, 281))	('osteosarcoma', 'Phenotype', 'HP:0002669', (34, 46))	('neuroblastoma or osteosarcoma', 'Disease', 'MESH:D012516', (17, 46))	('ABC', 'Gene', '10058', (216, 219))	('neuroblastoma or osteosarcoma', 'Disease', (17, 46))	('expression', 'Var', (202, 212))	('vincristine', 'Chemical', 'MESH:D014750', (97, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('reduce', 'NegReg', (242, 248))
542349	25809532	High expression of SPARC and caveolin-1 have been postulated to increase sensitivity to nab-paclitaxel, although their role in predicting sensitivity remains an open question.	('High expression', 'Var', (0, 15))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (88, 102))	('caveolin-1', 'Gene', (29, 39))	('increase', 'PosReg', (64, 72))	('sensitivity to nab-paclitaxel', 'MPA', (73, 102))	('caveolin-1', 'Gene', '857', (29, 39))	('SPARC', 'Gene', '6678', (19, 24))	('SPARC', 'Gene', (19, 24))
542355	25809532	In conclusion, nab-paclitaxel showed high level in vivo activity against rhabdomyosarcoma and Ewing sarcoma xenograft models, but not in limited testing against neuroblastoma and osteosarcoma models resistant to vincristine.	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (15, 29))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('nab-paclitaxel', 'Var', (15, 29))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('osteosarcoma', 'Phenotype', 'HP:0002669', (179, 191))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (73, 89))	('vincristine', 'Chemical', 'MESH:D014750', (212, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('Ewing sarcoma', 'Disease', (94, 107))	('rhabdomyosarcoma', 'Disease', (73, 89))	('neuroblastoma and osteosarcoma', 'Disease', 'MESH:D012516', (161, 191))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (73, 89))	('neuroblastoma', 'Phenotype', 'HP:0003006', (161, 174))
542398	24497789	After injection of the ethiodized oil, the injection sites were gently massaged for one to two minutes in order to facilitate the migration of the ethiodized oil to the draining nodes.	('ethiodized oil', 'Chemical', 'MESH:D004998', (23, 37))	('facilitate', 'PosReg', (115, 125))	('ethiodized', 'Var', (147, 157))	('migration', 'CPA', (130, 139))	('ethiodized oil', 'Chemical', 'MESH:D004998', (147, 161))
542448	24497789	Metastasis could be found in 27 of 53 ethiodized oil retention nodes and five of 50 non-ethiodized oil retention nodes, while there were no metastatic foci in other non-ethiodized oil retention nodes when ethiodized oil retention nodes were negative for metastasis on a single rabbit basis.	('Metastasis', 'Disease', 'MESH:D009362', (0, 10))	('Metastasis', 'Disease', (0, 10))	('oil retention', 'Phenotype', 'HP:0000969', (49, 62))	('ethiodized oil', 'Chemical', 'MESH:D004998', (205, 219))	('ethiodized oil', 'Chemical', 'MESH:D004998', (169, 183))	('ethiodized oil', 'Chemical', 'MESH:D004998', (88, 102))	('oil retention', 'Phenotype', 'HP:0000969', (216, 229))	('oil retention', 'Phenotype', 'HP:0000969', (99, 112))	('rabbit', 'Species', '9986', (277, 283))	('ethiodized oil', 'Chemical', 'MESH:D004998', (38, 52))	('oil retention', 'Phenotype', 'HP:0000969', (180, 193))	('ethiodized oil', 'Var', (38, 52))
542449	24497789	Moreover, CT lymphography using ethiodized oil has an advantage of longer time window for sentinel node detection, compared to water soluble contrast agent such as iopamidol, which rapidly enhances and washes out of lymph nodes, giving a short time window for detection and making it impossible to directly match the resected nodes with the detected nodes on CT. After peritumoral injection of ethiodized oil, post-2h CT could demonstrate seven additional ethiodized oil retention nodes than post-1h CT in three rabbits, which could only be shown in post-2h CT. Also, the attenuation values of ethiodized oil retention nodes on post-2h CT were significantly higher than that on post-1h CT.	('ethiodized', 'MPA', (594, 604))	('2h', 'Chemical', 'MESH:D003903', (555, 557))	('post-2h', 'Var', (628, 635))	('ethiodized oil', 'Chemical', 'MESH:D004998', (394, 408))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('iopamidol', 'Chemical', 'MESH:D007479', (164, 173))	('2h', 'Chemical', 'MESH:D003903', (633, 635))	('1h', 'Chemical', '-', (683, 685))	('oil retention', 'Phenotype', 'HP:0000969', (605, 618))	('ethiodized oil', 'Chemical', 'MESH:D004998', (456, 470))	('water', 'Chemical', 'MESH:D014867', (127, 132))	('attenuation values', 'MPA', (572, 590))	('1h', 'Chemical', '-', (497, 499))	('tumor', 'Disease', (373, 378))	('ethiodized oil', 'Chemical', 'MESH:D004998', (32, 46))	('oil retention', 'Phenotype', 'HP:0000969', (467, 480))	('ethiodized oil', 'Chemical', 'MESH:D004998', (594, 608))	('tumor', 'Disease', 'MESH:D009369', (373, 378))	('2h', 'Chemical', 'MESH:D003903', (415, 417))	('rabbits', 'Species', '9986', (512, 519))	('higher', 'PosReg', (658, 664))
542590	20617134	Activating mutations in the KRAS gene impair the ability of the KRAS protein to switch between active and inactive states, leading to cell transformation and increased resistance to chemotherapy and biological therapies targeting epidermal growth factor receptors.	('KRAS', 'Gene', (28, 32))	('mutations', 'Var', (11, 20))	('resistance to chemotherapy', 'MPA', (168, 194))	('impair', 'NegReg', (38, 44))	('epidermal growth factor receptor', 'Gene', (230, 262))	('switch', 'MPA', (80, 86))	('epidermal growth factor receptor', 'Gene', '1956', (230, 262))	('ability', 'MPA', (49, 56))	('cell transformation', 'CPA', (134, 153))	('increased', 'PosReg', (158, 167))
542591	20617134	It also underlines the importance of activating mutations in the KRAS gene in relation to carcinogenesis and their importance as diagnostic biomarkers, providing clues regarding human cancer patients' prognosis and indicating potential therapeutic approaches.	('cancer', 'Disease', (184, 190))	('patients', 'Species', '9606', (191, 199))	('human', 'Species', '9606', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('KRAS', 'Gene', (65, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('activating', 'PosReg', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('carcinogenesis', 'Disease', (90, 104))	('mutations', 'Var', (48, 57))
542597	20617134	Aberrant p21 proteins were encoded by the altered KRAS gene and their expression in carcinoma tissue was causally linked to an abnormal state of activation.	('altered', 'Var', (42, 49))	('Aberrant', 'Var', (0, 8))	('linked', 'Reg', (114, 120))	('carcinoma', 'Disease', 'MESH:D002277', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('encoded by', 'Reg', (27, 37))	('KRAS', 'Gene', (50, 54))	('expression', 'MPA', (70, 80))	('p21', 'Gene', (9, 12))	('carcinoma', 'Disease', (84, 93))
542598	20617134	As a result of these effects, KRAS elicits changes in the cytoskeleton and consequently affects cell shape, adhesion and migration.	('rat', 'Species', '10116', (124, 127))	('migration', 'CPA', (121, 130))	('cell shape', 'CPA', (96, 106))	('affects', 'Reg', (88, 95))	('adhesion', 'CPA', (108, 116))	('cytoskeleton', 'MPA', (58, 70))	('changes', 'Reg', (43, 50))	('KRAS', 'Var', (30, 34))
542609	20617134	The KRAS protein also has intrinsic GTPase activity, stimulated by GAPs, which acts as a timer associated with direct interactions with the effectors.	('GTPase', 'Protein', (36, 42))	('stimulated', 'PosReg', (53, 63))	('activity', 'MPA', (43, 51))	('GTP', 'Chemical', 'MESH:D006160', (36, 39))	('GAPs', 'Var', (67, 71))
542610	20617134	Mutations found in an oncogenic form of the RAS p21 protein impair GTPase activity and make the KRAS protein unresponsive to GAP proteins.	('RAS', 'Chemical', 'MESH:D011883', (44, 47))	('impair', 'NegReg', (60, 66))	('GTPase', 'Protein', (67, 73))	('activity', 'MPA', (74, 82))	('Mutations', 'Var', (0, 9))	('RAS', 'Chemical', 'MESH:D011883', (97, 100))	('GTP', 'Chemical', 'MESH:D006160', (67, 70))	('unresponsive to GAP proteins', 'MPA', (109, 137))
542611	20617134	Mutated forms of p21 rapidly exchange GDP for GTP, which it prefers as a substrate, thus inducing the active state.	('active state', 'MPA', (102, 114))	('p21', 'Gene', (17, 20))	('GTP', 'MPA', (46, 49))	('GDP', 'MPA', (38, 41))	('GDP', 'Chemical', 'MESH:D006153', (38, 41))	('rat', 'Species', '10116', (78, 81))	('GTP', 'Chemical', 'MESH:D006160', (46, 49))	('Mutated', 'Var', (0, 7))	('exchange', 'Reg', (29, 37))	('inducing', 'PosReg', (89, 97))
542627	20617134	Treatment with farnesyl transferase inhibitors has been shown to inhibit anchorage-independent growth of both KRAS-transformed mouse fibroblasts and human tumour cells containing KRAS and NRAS mutations.	('mouse', 'Species', '10090', (127, 132))	('NRAS', 'Gene', '4893', (188, 192))	('inhibit', 'NegReg', (65, 72))	('NRAS', 'Gene', (188, 192))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (193, 202))	('human', 'Species', '9606', (149, 154))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('KRAS', 'Gene', (179, 183))	('anchorage-independent growth', 'CPA', (73, 101))	('tumour', 'Disease', (155, 161))
542632	20617134	Once the KRAS gene mutates, it acquires oncogenic properties (Table 1) and seems to be causally involved in the development of various human cancers.	('mutates', 'Var', (19, 26))	('KRAS', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('involved', 'Reg', (96, 104))	('human', 'Species', '9606', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('oncogenic properties', 'CPA', (40, 60))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
542634	20617134	Oncogenic mutations in the KRAS gene prevent the hydrolysis of GTP, thus permanently activating the RAS molecules.	('activating', 'PosReg', (85, 95))	('prevent', 'NegReg', (37, 44))	('RAS', 'Chemical', 'MESH:D011883', (100, 103))	('GTP', 'Chemical', 'MESH:D006160', (63, 66))	('RAS', 'Chemical', 'MESH:D011883', (28, 31))	('RAS molecules', 'Protein', (100, 113))	('hydrolysis of GTP', 'MPA', (49, 66))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (27, 31))
542635	20617134	Expression of a mutated KRAS gene in fibroblasts has been shown to augment metalloproteinase 2 (MMP2) expression in the matrix and enhance the invasion of cancer cells.	('MMP2', 'Gene', (96, 100))	('expression', 'MPA', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutated', 'Var', (16, 23))	('enhance', 'PosReg', (131, 138))	('MMP2', 'Gene', '4313', (96, 100))	('augment', 'PosReg', (67, 74))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('KRAS', 'Gene', (24, 28))
542636	20617134	Overexpression of this mutated form of KRAS also inhibits glycosylation of the integrin beta1-chain, resulting in altered polarisation and increased adhesiveness of colon cancer cells.	('adhesiveness of colon cancer', 'Disease', 'MESH:D015179', (149, 177))	('inhibits', 'NegReg', (49, 57))	('increased', 'PosReg', (139, 148))	('altered', 'Reg', (114, 121))	('colon cancer', 'Phenotype', 'HP:0003003', (165, 177))	('adhesiveness of colon cancer', 'Disease', (149, 177))	('mutated', 'Var', (23, 30))	('glycosylation', 'MPA', (58, 71))	('integrin beta1', 'Gene', (79, 93))	('integrin beta1', 'Gene', '3688', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('polarisation', 'MPA', (122, 134))
542646	20617134	Further, recent studies on lung adenocarcinoma suggest there is an association between the incidence of allelic losses in the 12p12-13 region and KRAS gene mutation.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (27, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('allelic losses', 'Var', (104, 118))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (27, 46))	('KRAS gene', 'Gene', (146, 155))	('12p12-13', 'Gene', (126, 134))	('lung adenocarcinoma', 'Disease', (27, 46))	('mutation', 'Var', (156, 164))
542647	20617134	Diagnostics of KRAS gene mutations in clinical setting is limited by two factors: first, in the time of testing, KRAS mutated tumour cells may be in minority, outbalanced by wild type tumour cells and wild type non-tumour cells present in the sample.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumour', 'Disease', 'MESH:D009369', (215, 221))	('tumour', 'Disease', (215, 221))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('mutated', 'Var', (118, 125))	('tumour', 'Disease', (126, 132))	('KRAS', 'Gene', (113, 117))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('tumour', 'Disease', (184, 190))
542668	20617134	In many cases KRAS protein expression is dramatically increased due to mutations in the KRAS gene sequence, thus making cells refractory to current therapies, such as those involving use of epidermal growth factor receptor inhibitors.	('epidermal growth factor receptor', 'Gene', '1956', (190, 222))	('increased', 'PosReg', (54, 63))	('expression', 'MPA', (27, 37))	('KRAS', 'Gene', (88, 92))	('mutations', 'Var', (71, 80))	('KRAS', 'Disease', (14, 18))	('epidermal growth factor receptor', 'Gene', (190, 222))
542669	20617134	Activating KRAS gene point mutations have been detected in many types of human tumours.	('Activating', 'PosReg', (0, 10))	('point mutations', 'Var', (21, 36))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('human', 'Species', '9606', (73, 78))	('KRAS gene', 'Gene', (11, 20))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumours', 'Disease', (79, 86))
542671	20617134	Mutations in the KRAS gene have important effects on the process of carcinogenesis, which depend on the cells and tissues involved.	('effects', 'Reg', (42, 49))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('carcinogenesis', 'Disease', (68, 82))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (17, 21))
542674	20617134	Allelic mutations result in amino acid changes, namely Gly to Asp, Ala, Arg, Ser, Val, or Cys in codon 12 and Gly to Asp in codon 13.	('Gly to', 'Var', (55, 61))	('Asp', 'Chemical', 'MESH:D001224', (62, 65))	('Cys', 'Chemical', 'MESH:D003545', (90, 93))	('Ala', 'Chemical', 'MESH:D000409', (67, 70))	('Val', 'MPA', (82, 85))	('Gly to Asp', 'Var', (110, 120))	('Cys', 'MPA', (90, 93))	('Gly to Asp in codon 13', 'Mutation', 'rs112445441', (110, 132))	('Arg', 'Chemical', 'MESH:D001120', (72, 75))	('Asp', 'Chemical', 'MESH:D001224', (117, 120))	('Gly', 'Chemical', 'MESH:D005998', (55, 58))	('Val', 'Chemical', 'MESH:D014633', (82, 85))	('Gly', 'Chemical', 'MESH:D005998', (110, 113))	('Ser', 'Chemical', 'MESH:D012694', (77, 80))	('Arg', 'MPA', (72, 75))	('Ser', 'MPA', (77, 80))
542675	20617134	Somatic missense mutations at positions 12, 13, 61, and 63 enable perturbation of the intrinsic GTPase activity of the KRAS protein, resulting in reductions in GTP hydrolysis capacity.	('GTP hydrolysis capacity', 'MPA', (160, 183))	('intrinsic', 'MPA', (86, 95))	('reductions', 'NegReg', (146, 156))	('GTPase', 'Enzyme', (96, 102))	('GTP', 'Chemical', 'MESH:D006160', (96, 99))	('GTP', 'Chemical', 'MESH:D006160', (160, 163))	('missense mutations', 'Var', (8, 26))
542676	20617134	Mutation in codon 12 of the KRAS gene causes the encoded KRAS protein to "freeze" in its active state for a much longer duration than its nonmutated counterpart.	('KRAS', 'Gene', (28, 32))	('Mutation', 'Var', (0, 8))	('rat', 'Species', '10116', (122, 125))
542677	20617134	Mutations resulting in the substitution of amino acids 116, 117, 119, and 146 reduce the nucleotide affinity of the KRAS protein, thereby affecting the rate of GDP/GTP exchange.	('GTP', 'Chemical', 'MESH:D006160', (164, 167))	('GDP/GTP exchange', 'MPA', (160, 176))	('reduce', 'NegReg', (78, 84))	('rat', 'Species', '10116', (152, 155))	('nucleotide affinity', 'MPA', (89, 108))	('substitution', 'Var', (27, 39))	('KRAS protein', 'Protein', (116, 128))	('rate', 'MPA', (152, 156))	('affecting', 'Reg', (138, 147))	('GDP', 'Chemical', 'MESH:D006153', (160, 163))
542679	20617134	Overexpression of KRAS can also be induced by the loss of p16INK4 (CDKN2A), p19INK4 (CDKN2D), or p53.	('CDKN2A', 'Gene', (67, 73))	('p53', 'Gene', (97, 100))	('KRAS', 'Gene', (18, 22))	('loss', 'NegReg', (50, 54))	('p53', 'Gene', '7157', (97, 100))	('CDKN2A', 'Gene', '1029', (67, 73))	('p19INK4', 'Var', (76, 83))	('induced', 'Reg', (35, 42))	('CDKN2D', 'Gene', '1032', (85, 91))	('CDKN2D', 'Gene', (85, 91))	('p16INK4', 'Gene', '1029', (58, 65))	('p16INK4', 'Gene', (58, 65))
542680	20617134	In addition, the radiosensitivity of tumour cells is altered by oncogenic RAS expression, probably as a result of the effect of the KRAS mutation on several intercommunicating pathways.	('KRAS', 'Gene', (132, 136))	('RAS', 'Chemical', 'MESH:D011883', (74, 77))	('tumour', 'Disease', (37, 43))	('oncogenic', 'Var', (64, 73))	('altered', 'Reg', (53, 60))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('RAS', 'Gene', (74, 77))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('RAS', 'Chemical', 'MESH:D011883', (133, 136))
542681	20617134	The prevalence of mutations in the KRAS gene at the time of diagnosis is highest in pancreatic cancers (>80% of cases), notably pancreatic adenocarcinomas predominantly harbour KRAS forms with a guanine to thymine transversion in codon 12.	('guanine', 'Chemical', 'MESH:D006147', (195, 202))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (84, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (128, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('pancreatic cancers', 'Disease', (84, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('thymine', 'Chemical', 'MESH:D013941', (206, 213))	('pancreatic adenocarcinomas', 'Disease', (128, 154))	('highest', 'Reg', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('harbour', 'Reg', (169, 176))	('KRAS', 'Gene', (35, 39))	('pancreatic cancers', 'Disease', 'MESH:D010190', (84, 102))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (128, 154))	('KRAS', 'Var', (177, 181))	('guanine to thymine transversion', 'Var', (195, 226))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('mutations', 'Var', (18, 27))
542682	20617134	Wei and colleagues examined samples collected from 30 patients with pancreatic cancer and found that 24 of them showed mutations at codon 12 and only one at codon 13.	('mutations at codon 12', 'Var', (119, 140))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (54, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('pancreatic cancer', 'Disease', (68, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
542683	20617134	However, concurrent KRAS mutations frequently occur in patients with pancreatic cancer.	('pancreatic cancer', 'Disease', (69, 86))	('mutations', 'Var', (25, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('occur', 'Reg', (46, 51))	('patients', 'Species', '9606', (55, 63))	('KRAS', 'Gene', (20, 24))
542684	20617134	A positive association has been found in patients with pancreatic cancer between tobacco exposure and mutations in the KRAS gene.	('tobacco', 'Species', '4097', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('pancreatic cancer', 'Disease', (55, 72))	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (102, 111))	('KRAS', 'Gene', (119, 123))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))
542686	20617134	The second highest incidence (about 50% of cases) of mutations in the KRAS gene is found in colon cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('KRAS', 'Gene', (70, 74))	('mutations', 'Var', (53, 62))	('colon cancers', 'Disease', (92, 105))	('colon cancers', 'Phenotype', 'HP:0003003', (92, 105))	('colon cancers', 'Disease', 'MESH:D015179', (92, 105))
542688	20617134	The first stage is characterized by the development of a small, benign tubular type of adenoma or polyp with sporadically detectable KRAS mutation(s).	('polyp', 'Disease', (98, 103))	('polyp', 'Disease', 'MESH:D011127', (98, 103))	('adenoma', 'Disease', 'MESH:D000236', (87, 94))	('KRAS', 'Gene', (133, 137))	('mutation', 'Var', (138, 146))	('adenoma', 'Disease', (87, 94))
542690	20617134	Mutations of the KRAS gene have been identified in tissues from both adenoma and carcinoma cases, but at much lower frequencies in colon adenoma tissues than in carcinoma tissues.	('carcinoma', 'Disease', (81, 90))	('colon adenoma', 'Disease', (131, 144))	('colon adenoma', 'Disease', 'MESH:D000236', (131, 144))	('carcinoma', 'Disease', 'MESH:D002277', (81, 90))	('adenoma and carcinoma', 'Disease', 'MESH:D000236', (69, 90))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('identified', 'Reg', (37, 47))	('KRAS', 'Gene', (17, 21))	('carcinoma', 'Disease', 'MESH:D002277', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Disease', (161, 170))
542693	20617134	Mutation from GGT (Gly) to GTT (Val) in codon 12 has been observed more frequently in primary metastatic carcinoma, suggesting that this mutation may confer a more aggressive phenotype in colorectal carcinoma.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (188, 208))	('Gly', 'Chemical', 'MESH:D005998', (19, 22))	('carcinoma', 'Disease', (199, 208))	('Mutation', 'Var', (0, 8))	('carcinoma', 'Disease', 'MESH:D002277', (105, 114))	('Val', 'Chemical', 'MESH:D014633', (32, 35))	('GGT', 'Gene', (14, 17))	('colorectal carcinoma', 'Disease', (188, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Disease', 'MESH:D002277', (199, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma', 'Disease', (105, 114))
542694	20617134	A mutation in codon 13, resulting in the substitution of Gly with Asp, observed in colon cancer has been shown to be associated with reduced survival rates.	('survival rates', 'CPA', (141, 155))	('colon cancer', 'Disease', (83, 95))	('Gly', 'MPA', (57, 60))	('Gly', 'Chemical', 'MESH:D005998', (57, 60))	('Asp', 'Chemical', 'MESH:D001224', (66, 69))	('Asp', 'MPA', (66, 69))	('rat', 'Species', '10116', (150, 153))	('substitution', 'Var', (41, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (83, 95))	('colon cancer', 'Disease', 'MESH:D015179', (83, 95))	('reduced', 'NegReg', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
542695	20617134	This kind of KRAS gene mutation has also been shown to occur more frequently in unstable, than in stable, colon tumours.	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('mutation', 'Var', (23, 31))	('colon tumours', 'Disease', 'MESH:D015179', (106, 119))	('KRAS gene', 'Gene', (13, 22))	('unstable', 'Disease', (80, 88))	('colon tumours', 'Disease', (106, 119))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))
542696	20617134	Losses of KRAS wild type alleles in both mouse and human lung adenocarcinomas and squamous carcinomas have been found in many studies, notably in 67% to 100% of chemically induced murine lung adenocarcinoma cases harbouring a mutant KRAS.	('mutant', 'Var', (226, 232))	('mouse', 'Species', '10090', (41, 46))	('lung adenocarcinoma', 'Disease', (187, 206))	('human', 'Species', '9606', (51, 56))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (57, 77))	('murine', 'Species', '10090', (180, 186))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (187, 206))	('lung adenocarcinomas', 'Disease', (57, 77))	('squamous carcinomas', 'Disease', (82, 101))	('KRAS', 'Gene', (233, 237))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (187, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (57, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous carcinomas', 'Disease', 'MESH:D002294', (82, 101))
542697	20617134	In humans, KRAS mutations appear in 10-30% of lung carcinoma cases, demonstrating strong associations with a history of smoking and poor prognosis.	('KRAS', 'Gene', (11, 15))	('associations', 'Interaction', (89, 101))	('lung carcinoma', 'Disease', 'MESH:D008175', (46, 60))	('rat', 'Species', '10116', (75, 78))	('mutations', 'Var', (16, 25))	('lung carcinoma', 'Disease', (46, 60))	('humans', 'Species', '9606', (3, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
542698	20617134	Among both current and former smokers, KRAS gene mutations have been identified in 30% of lung adenocarcinoma cases.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('mutations', 'Var', (49, 58))	('lung adenocarcinoma', 'Disease', (90, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (90, 109))	('identified', 'Reg', (69, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('KRAS gene', 'Gene', (39, 48))
542699	20617134	Further, although some researchers have found sporadic KRAS mutations in non-smokers with early onset of cancer, smoking history is an important factor and is correlated with increased occurrence of mutations in the KRAS gene in lung cancer cases.	('KRAS', 'Gene', (55, 59))	('correlated', 'Reg', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (234, 240))	('lung cancer', 'Disease', 'MESH:D008175', (229, 240))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('KRAS', 'Gene', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutations', 'Var', (199, 208))	('mutations', 'Var', (60, 69))	('lung cancer', 'Disease', (229, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))
542700	20617134	Mutations in the KRAS gene in codons 12 and 13 were detected in 21% of NSCLC (non-small cell lung cancer) tumour samples examined in the TRIBUTE III trial.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (78, 104))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('detected', 'Reg', (52, 60))	('non-small cell lung cancer', 'Disease', (78, 104))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (17, 21))	('tumour', 'Disease', (106, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('NSCLC', 'Disease', (71, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (82, 104))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (78, 104))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
542702	20617134	EGFR mutations are more often found in patients who have no history of smoking.	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (39, 47))	('found', 'Reg', (30, 35))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (0, 4))
542703	20617134	Although higher KRAS mutational frequency is primarily found in cancers of the pancreas, colon and lung, possible links between KRAS hyperactivity and human breast cancer have been explored recently.	('found', 'Reg', (55, 60))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancers of the pancreas', 'Disease', 'MESH:D010190', (64, 87))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers of the pancreas', 'Disease', (64, 87))	('breast cancer', 'Disease', (157, 170))	('hyperactivity', 'Disease', (133, 146))	('colon', 'Disease', (89, 94))	('hyperactivity', 'Disease', 'MESH:D006948', (133, 146))	('human', 'Species', '9606', (151, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancers of the pancreas', 'Phenotype', 'HP:0002894', (64, 87))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('hyperactivity', 'Phenotype', 'HP:0000752', (133, 146))	('KRAS', 'Gene', (16, 20))	('mutational', 'Var', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
542706	20617134	Two of the most important EGFR-specific TKIs are gefitinib (Iressa, ZD1839) and erlotinib (Tarceva).	('EGFR', 'Gene', (26, 30))	('erlotinib', 'Chemical', 'MESH:D000069347', (80, 89))	('gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))	('erlotinib', 'Var', (80, 89))	('EGFR', 'Gene', '1956', (26, 30))	('Tarceva', 'Chemical', 'MESH:D000069347', (91, 98))
542707	20617134	The first indications of the predictive strength of the association between the KRAS gene and therapeutic responses to the EGFR-TKI gefitinib were originally observed in NSCLC patients with tumours bearing the wild-type form of the KRAS gene and constitutively activated EGFR1 gene, due to activating mutations in exons 18 to 21 or high copy number/amplification of the EGFR1 gene.	('EGFR', 'Gene', (123, 127))	('patients', 'Species', '9606', (176, 184))	('high copy number/amplification', 'Var', (332, 362))	('EGFR', 'Gene', (370, 374))	('EGFR', 'Gene', (271, 275))	('tumours', 'Disease', 'MESH:D009369', (190, 197))	('tumours', 'Disease', (190, 197))	('mutations in', 'Var', (301, 313))	('NSCLC', 'Disease', (170, 175))	('gefitinib', 'Chemical', 'MESH:D000077156', (132, 141))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('EGFR', 'Gene', '1956', (123, 127))	('EGFR', 'Gene', '1956', (370, 374))	('EGFR', 'Gene', '1956', (271, 275))	('activating', 'PosReg', (290, 300))
542714	20617134	However, molecular analysis revealed that patients who have activating mutations in the KRAS gene (exon 1: codons 12, 13, or 61) with or without increases in EGFR copy numbers did not derive benefit from this therapy and had about a 96% chance of disease progression.	('activating', 'PosReg', (60, 70))	('EGFR', 'Gene', (158, 162))	('EGFR', 'Gene', '1956', (158, 162))	('mutations', 'Var', (71, 80))	('KRAS', 'Gene', (88, 92))	('patients', 'Species', '9606', (42, 50))	('disease progression', 'CPA', (247, 266))
542715	20617134	first observed the relationship between KRAS mutations and the outcome of erlotinib therapy in a randomized phase III clinical trial in which the drug was used, in combination with first line "gold standard" chemotherapy (carboplatin and paclitaxel), to treat advanced NSCLC patients.	('mutations', 'Var', (45, 54))	('carboplatin', 'Chemical', 'MESH:D016190', (222, 233))	('KRAS', 'Gene', (40, 44))	('NSCLC', 'Disease', (269, 274))	('paclitaxel', 'Chemical', 'MESH:D017239', (238, 248))	('erlotinib', 'Chemical', 'MESH:D000069347', (74, 83))	('NSCLC', 'Disease', 'MESH:D002289', (269, 274))	('patients', 'Species', '9606', (275, 283))
542716	20617134	Patients with the KRAS mutation exhibited a shorter time to progression (three months) and a shorter overall survival (four months) when treated with a combination of erlotinib and first line chemotherapy, such as treatment with cisplatin, compared to the group with wild-type KRAS, for whom the time-to-progression was 12 months.	('overall survival', 'MPA', (101, 117))	('mutation', 'Var', (23, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (229, 238))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (93, 100))	('erlotinib', 'Chemical', 'MESH:D000069347', (167, 176))	('KRAS mutation', 'Var', (18, 31))	('shorter', 'NegReg', (44, 51))
542718	20617134	However, in colorectal cancer, mutations in the KRAS gene are important predictive (as well as prognostic) biomarkers, since the effectiveness of treatment with cetuximab and panitumumab is impaired in tumours with the activating mutation.	('colorectal cancer', 'Disease', (12, 29))	('KRAS', 'Gene', (48, 52))	('mutations', 'Var', (31, 40))	('impaired', 'NegReg', (190, 198))	('effectiveness', 'MPA', (129, 142))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('panitumumab', 'Chemical', 'MESH:D000077544', (175, 186))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('tumours', 'Disease', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cetuximab', 'Chemical', 'MESH:D000068818', (161, 170))
542722	20617134	Interestingly, KRAS gene mutations also seem to provide strong predictive indication of therapeutic responses to other classes of tyrosine kinase inhibitors, as recently demonstrated for the imatinib mesylate (Glivec).	('mutations', 'Var', (25, 34))	('therapeutic responses', 'MPA', (88, 109))	('rat', 'Species', '10116', (177, 180))	('KRAS gene', 'Gene', (15, 24))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (191, 208))
542724	20617134	Further, drug resistance to imatinib is usually attributed to mutation of the imatinib-binding sites of these proteins, although amplification of the bcr-abl fusion gene or overexpression of multidrug resistance proteins may be involved in some cases.	('imatinib', 'Chemical', 'MESH:D000068877', (28, 36))	('drug resistance', 'Phenotype', 'HP:0020174', (196, 211))	('drug resistance', 'MPA', (9, 24))	('mutation', 'Var', (62, 70))	('imatinib', 'Chemical', 'MESH:D000068877', (78, 86))	('attributed', 'Reg', (48, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (9, 24))
542725	20617134	demonstrated that CML patients resistant to imatinib frequently expressed mutated KRAS proteins.	('expressed', 'Reg', (64, 73))	('KRAS proteins', 'Protein', (82, 95))	('CML', 'Disease', 'MESH:D015464', (18, 21))	('patients', 'Species', '9606', (22, 30))	('imatinib', 'Chemical', 'MESH:D000068877', (44, 52))	('mutated', 'Var', (74, 81))	('rat', 'Species', '10116', (7, 10))	('CML', 'Disease', (18, 21))
542729	20617134	Indeed, KRAS mutation status is the most important predictor of resistance to cetuximab or panitumumab; both the median progression-free survival of cetuximab-treated patients and overall survival was recently found to be superior in a KRAS wild-type group than in a KRAS mutant group (31 versus 10 weeks, and 16 versus 7 months, respectively).	('panitumumab', 'Chemical', 'MESH:D000077544', (91, 102))	('progression-free', 'CPA', (120, 136))	('patients', 'Species', '9606', (167, 175))	('cetuximab', 'Chemical', 'MESH:D000068818', (149, 158))	('superior', 'PosReg', (222, 230))	('cetuximab', 'Chemical', 'MESH:D000068818', (78, 87))	('KRAS', 'Var', (236, 240))
542732	20617134	Progression-free survival of patients with wild-type versus mutant KRAS gene tumours was 12 versus seven weeks, while response rates obtained in another study were 17% versus 0%.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('patients', 'Species', '9606', (29, 37))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('tumours', 'Disease', (77, 84))	('KRAS', 'Gene', (67, 71))	('rat', 'Species', '10116', (127, 130))	('mutant', 'Var', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
542733	20617134	These findings strongly indicate that KRAS gene status should be routinely tested as a critically important diagnostic biomarker to determine which patients will derive therapeutic benefit from EGFR1 inhibition.	('inhibition', 'Var', (200, 210))	('EGFR', 'Gene', '1956', (194, 198))	('EGFR', 'Gene', (194, 198))	('patients', 'Species', '9606', (148, 156))
542735	20617134	Surprisingly, the effects of KRAS gene mutations on tumour sensitivity to cytotoxic chemotherapies and radiation have only been explored in a few studies.	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('KRAS', 'Gene', (29, 33))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (39, 48))	('tumour', 'Disease', (52, 58))
542737	20617134	Similarly, the presence of oncogenic KRAS has been found to significantly increase the sensitivity of cells to a novel class of anticancer agents, cucurbitacins, in a p53- or p21-dependent manner.	('cancer', 'Disease', (132, 138))	('cucurbitacins', 'Chemical', 'MESH:D054728', (147, 160))	('presence', 'Var', (15, 23))	('increase', 'PosReg', (74, 82))	('sensitivity', 'MPA', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('KRAS', 'Var', (37, 41))	('p53', 'Gene', '7157', (167, 170))	('p53', 'Gene', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('oncogenic KRAS', 'Var', (27, 41))
542738	20617134	In contrast, an ovarian cancer cell line TOV-21G bearing a mutant allele of KRAS is reportedly significantly more sensitive to cisplatin and radiation, but not to paclitaxel or campthotecin, than the corresponding KRAS wild type line.	('sensitive', 'MPA', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('ovarian cancer', 'Disease', (16, 30))	('mutant', 'Var', (59, 65))	('KRAS', 'Gene', (76, 80))	('campthotecin', 'Chemical', '-', (177, 189))	('ovarian cancer', 'Disease', 'MESH:D010051', (16, 30))	('paclitaxel', 'Chemical', 'MESH:D017239', (163, 173))	('ovarian cancer', 'Phenotype', 'HP:0100615', (16, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('more', 'PosReg', (109, 113))
542739	20617134	However, results of clinical studies by Rosell and colleagues (1995) showed that patients with a mutation in the KRAS gene had poorer clinical responses to paclitaxel monotherapy than wild type controls, suggesting that KRAS gene status is a predictive marker of paclitaxel resistance.	('clinical responses to paclitaxel monotherapy', 'MPA', (134, 178))	('poorer', 'NegReg', (127, 133))	('paclitaxel', 'Chemical', 'MESH:D017239', (263, 273))	('patients', 'Species', '9606', (81, 89))	('paclitaxel', 'Chemical', 'MESH:D017239', (156, 166))	('KRAS', 'Gene', (113, 117))	('mutation', 'Var', (97, 105))
542740	20617134	In a phase III retrospective study on NSCLC patients (TRIBUTE), randomly treated with carboplatin and paclitaxel with erlotinib or placebo, patients with KRAS mutant tumours showed poorer clinical outcomes when treated with erlotinib plus chemotherapy compared to chemotherapy alone.	('NSCLC', 'Disease', (38, 43))	('patients', 'Species', '9606', (44, 52))	('tumours', 'Disease', (166, 173))	('erlotinib', 'Chemical', 'MESH:D000069347', (118, 127))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('mutant', 'Var', (159, 165))	('poorer', 'NegReg', (181, 187))	('erlotinib', 'Chemical', 'MESH:D000069347', (224, 233))	('carboplatin', 'Chemical', 'MESH:D016190', (86, 97))	('tumours', 'Disease', 'MESH:D009369', (166, 173))	('patients', 'Species', '9606', (140, 148))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('paclitaxel', 'Chemical', 'MESH:D017239', (102, 112))	('KRAS', 'Gene', (154, 158))
542741	20617134	An updated clinical trial (CRYSTAL) involving 540 metastatic colorectal cancer patients demonstrated that cetuximab in combination with FOLFIRI (folic acid, fluorouracil, and irinotecan) in first line therapy is highly effective against KRAS wild type, but not mutant, tumours.	('tumours', 'Disease', (269, 276))	('colorectal cancer', 'Disease', (61, 78))	('mutant', 'Var', (261, 267))	('irinotecan', 'Chemical', 'MESH:D000077146', (175, 185))	('FOLFIRI', 'Chemical', '-', (136, 143))	('rat', 'Species', '10116', (95, 98))	('KRAS wild type', 'Var', (237, 251))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('fluorouracil', 'Chemical', 'MESH:D005472', (157, 169))	('tumours', 'Phenotype', 'HP:0002664', (269, 276))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('patients', 'Species', '9606', (79, 87))	('folic acid', 'Chemical', 'MESH:D005492', (145, 155))	('cetuximab', 'Chemical', 'MESH:D000068818', (106, 115))	('cetuximab', 'Gene', (106, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('tumours', 'Disease', 'MESH:D009369', (269, 276))
542742	20617134	However, further analysis of the data showed that neither the response nor the progression-free survival of patients treated with chemotherapy alone were significantly affected by KRAS gene status, although the overall survival of patients with KRAS mutant tumours was significantly shorter than that of patients with KRAS wild type tumours.	('tumour', 'Phenotype', 'HP:0002664', (333, 339))	('type tumours', 'Disease', 'MESH:D009369', (328, 340))	('patients', 'Species', '9606', (231, 239))	('patients', 'Species', '9606', (304, 312))	('tumours', 'Phenotype', 'HP:0002664', (333, 340))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('KRAS', 'Gene', (245, 249))	('type tumours', 'Disease', (328, 340))	('tumours', 'Disease', 'MESH:D009369', (333, 340))	('tumours', 'Phenotype', 'HP:0002664', (257, 264))	('tumours', 'Disease', (333, 340))	('mutant', 'Var', (250, 256))	('tumours', 'Disease', 'MESH:D009369', (257, 264))	('patients', 'Species', '9606', (108, 116))	('shorter', 'NegReg', (283, 290))	('tumours', 'Disease', (257, 264))
542746	20617134	The predictive and prognostic significance of oncogenic KRAS seems to have been mixed in many studies, and the contributions of variations in the gene to clinical outcome appear to differ according to tumour types and therapeutic interventions.	('differ', 'Reg', (181, 187))	('tumour', 'Disease', (201, 207))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('variations', 'Var', (128, 138))	('tumour', 'Disease', 'MESH:D009369', (201, 207))
542748	20617134	Inhibition of KRAS expression by selected KRAS antisense oligonucleotides has been shown to be associated with significantly reduced secretion of VEGF-A165 into the medium of colorectal cancer cell cultures.	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('KRAS', 'Gene', (42, 46))	('VEGF', 'Gene', (146, 150))	('Inhibition', 'NegReg', (0, 10))	('oligonucleotides', 'Chemical', 'MESH:D009841', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colorectal cancer', 'Disease', (175, 192))	('reduced', 'NegReg', (125, 132))	('VEGF', 'Gene', '7422', (146, 150))	('antisense oligonucleotides', 'Var', (47, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('KRAS', 'Gene', (14, 18))
542749	20617134	In addition, in a cohort of patients with pancreatic tumours, 25/33 (76%) with KRAS mutations showed higher VEGF expression, and their median survival was shorter, than those with tumours expressing the wild-type allele.	('expression', 'MPA', (113, 123))	('VEGF', 'Gene', (108, 112))	('tumours', 'Disease', 'MESH:D009369', (180, 187))	('pancreatic tumours', 'Disease', (42, 60))	('higher', 'PosReg', (101, 107))	('tumours', 'Disease', (180, 187))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('shorter', 'NegReg', (155, 162))	('VEGF', 'Gene', '7422', (108, 112))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('mutations', 'Var', (84, 93))	('pancreatic tumours', 'Disease', 'MESH:D010190', (42, 60))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('patients', 'Species', '9606', (28, 36))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('KRAS', 'Gene', (79, 83))
542750	20617134	Similar findings have also been reported from a study of NSCLCs, in which higher VEGF expression was observed in 50% of tumours bearing a KRAS gene mutation.	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('NSCLC', 'Disease', (57, 62))	('VEGF', 'Gene', '7422', (81, 85))	('higher', 'PosReg', (74, 80))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('expression', 'MPA', (86, 96))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('KRAS gene', 'Gene', (138, 147))	('VEGF', 'Gene', (81, 85))	('tumours', 'Disease', (120, 127))	('mutation', 'Var', (148, 156))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
542751	20617134	Although these studies suggest that KRAS gene status could play an important role in responses to anti-VEGF targeted antiangiogenic therapy, a recent study by Hurwitz and Saini showed that groups of patients bearing either KRAS mutant or wild-type tumours derive therapeutic benefit from first line application of the anti-VEGF monoclonal antibody bevacizumab (Avastin).	('KRAS', 'Gene', (223, 227))	('VEGF', 'Gene', (323, 327))	('VEGF', 'Gene', (103, 107))	('bevacizumab', 'Chemical', 'MESH:D000068258', (348, 359))	('type tumours', 'Disease', 'MESH:D009369', (243, 255))	('mutant', 'Var', (228, 234))	('VEGF', 'Gene', '7422', (103, 107))	('VEGF', 'Gene', '7422', (323, 327))	('Avastin', 'Chemical', 'MESH:D000068258', (361, 368))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('type tumours', 'Disease', (243, 255))	('patients', 'Species', '9606', (199, 207))	('tumours', 'Phenotype', 'HP:0002664', (248, 255))
542752	20617134	Furthermore, although both groups of patients (i.e., those with wild-type KRAS and mutated KRAS genes) benefited from adding bevacizumab to chemotherapy, both progression-free survival and survival was better for wild-type KRAS patients, both with chemotherapy alone and with chemotherapy plus bevacizumab.	('mutated', 'Var', (83, 90))	('bevacizumab', 'Chemical', 'MESH:D000068258', (125, 136))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (228, 236))	('better', 'PosReg', (202, 208))	('bevacizumab', 'Chemical', 'MESH:D000068258', (294, 305))	('benefited', 'PosReg', (103, 112))	('KRAS', 'Gene', (91, 95))
542754	20617134	An optimal therapeutic drug should be able to specifically target the mutated KRAS gene or its product, have minimal systemic toxicity and be orally active.	('KRAS gene', 'Gene', (78, 87))	('toxicity', 'Disease', 'MESH:D064420', (126, 134))	('toxicity', 'Disease', (126, 134))	('mutated', 'Var', (70, 77))
542756	20617134	However, in addition to the cancer therapies mentioned above, several therapeutic agents and strategies can directly suppress the activating mutant form of the KRAS gene, and thus improve the efficiency of chemotherapy and biological therapy.	('biological therapy', 'CPA', (223, 241))	('mutant', 'Var', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('rat', 'Species', '10116', (95, 98))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('improve', 'PosReg', (180, 187))	('chemotherapy', 'CPA', (206, 218))	('KRAS gene', 'Gene', (160, 169))	('activating', 'MPA', (130, 140))	('suppress', 'NegReg', (117, 125))
542757	20617134	One possible approach for inhibiting KRAS expression is to use antisense oligonucleotides or viral constructs delivering antisense sequences in order to inactivate the mutant oncogene RNA message.	('inactivate', 'NegReg', (153, 163))	('RNA', 'Protein', (184, 187))	('mutant', 'Var', (168, 174))	('KRAS', 'Gene', (37, 41))	('oligonucleotides', 'Chemical', 'MESH:D009841', (73, 89))
542758	20617134	In addition, synthesis of mutated KRAS protein has been repressed by applying a small interfering adenovirus-mediated RNA (siRNA), and the specifically designed siRNA was shown to have prolonged anti-proliferative effects against various tumour cancer cell lines expressing mutated KRAS proteins.	('tumour cancer', 'Disease', (238, 251))	('KRAS', 'Gene', (282, 286))	('rat', 'Species', '10116', (207, 210))	('prolonged', 'PosReg', (185, 194))	('mutated', 'Var', (274, 281))	('anti-proliferative effects', 'CPA', (195, 221))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('tumour cancer', 'Disease', 'MESH:D009369', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
542761	20617134	Recently an interesting novel strategy employing farnesyltransferase inhibitors (FTIs) was shown to inhibit the biochemical transactivation initiated by the mutated KRAS gene.	('biochemical transactivation initiated', 'MPA', (112, 149))	('rat', 'Species', '10116', (32, 35))	('inhibit', 'NegReg', (100, 107))	('mutated', 'Var', (157, 164))	('KRAS', 'Gene', (165, 169))
542769	20617134	Overall, this review summarizes novel approaches allowing the management of cancers with or without KRAS mutations, and highlights the importance of early identification of somatic mutations in the KRAS gene in cancer biopsies.	('KRAS', 'Gene', (100, 104))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancers', 'Disease', (76, 83))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('KRAS', 'Gene', (198, 202))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
542797	31437624	TARGET datasets include large-scale genomic data including gene-expression, copy number variation, epigenetics, along with annotated clinical information for a selected set of pediatric cancers (https://ocg.cancer.gov/programs/target/data-matrix).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('copy number variation', 'Var', (76, 97))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
542828	31437624	Using 39 pedigrees, researchers were able to determine that the most common cause of LFS is inherited mutations in the tumor suppressor gene TP53.	('tumor', 'Disease', (119, 124))	('TP53', 'Gene', '7157', (141, 145))	('LFS', 'Disease', 'MESH:D016864', (85, 88))	('TP53', 'Gene', (141, 145))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cause', 'Reg', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LFS', 'Disease', (85, 88))
542848	31437624	analyzed the mutation landscape of 12 major cancer types and found that TP53 and PIK3CA were the most commonly mutated genes, ARID1A were frequently mutated in bladder urothelial carcinoma (BLCA), uterine corpus endometrial carcinoma (UCEC), lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and EGFR were frequently mutated in GBM and LUAD.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (278, 301))	('mutated', 'Var', (149, 156))	('PIK3CA', 'Gene', '5290', (81, 87))	('lung adenocarcinoma', 'Disease', (242, 261))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (212, 233))	('bladder urothelial carcinoma', 'Disease', (160, 188))	('LUAD', 'Phenotype', 'HP:0030078', (263, 267))	('EGFR', 'Gene', (314, 318))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (212, 233))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (273, 301))	('TP53', 'Gene', '7157', (72, 76))	('lung squamous cell carcinoma', 'Disease', (273, 301))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (160, 188))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GBM', 'Phenotype', 'HP:0012174', (346, 349))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (242, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (242, 261))	('PIK3CA', 'Gene', (81, 87))	('LUAD', 'Phenotype', 'HP:0030078', (354, 358))	('ARID1A', 'Gene', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('EGFR', 'Gene', '1956', (314, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('ARID1A', 'Gene', '8289', (126, 132))	('endometrial carcinoma', 'Disease', (212, 233))	('cancer', 'Disease', (44, 50))	('USC', 'Phenotype', 'HP:0002891', (304, 307))	('TP53', 'Gene', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
542849	31437624	In contrast, VHL and PBRM1 mutations were exclusive to kidney renal clear cell carcinoma (KIRC), and NPM1 and FLT3 mutations were exclusive to AML.	('mutations', 'Var', (27, 36))	('FLT3', 'Gene', (110, 114))	('NPM1', 'Gene', '4869', (101, 105))	('kidney renal clear cell carcinoma', 'Disease', (55, 88))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (55, 88))	('FLT3', 'Gene', '2322', (110, 114))	('PBRM1', 'Gene', (21, 26))	('VHL', 'Gene', (13, 16))	('PBRM1', 'Gene', '55193', (21, 26))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('VHL', 'Gene', '7428', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('AML', 'Disease', (143, 146))	('NPM1', 'Gene', (101, 105))	('AML', 'Phenotype', 'HP:0004808', (143, 146))
542850	31437624	Numerous pan-cancer analyses have been performed, including pan-cancer analyses of copy number alteration, enhancer expression, oncogenic signaling pathways, and transcriptional metabolic dysregulation.	('copy number alteration', 'Var', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('enhancer', 'PosReg', (107, 115))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
542860	31437624	To illustrate the integrative clustering analysis, we analyzed 241 sarcoma tumor samples from the TCGA SARC study that had somatic mutation, copy number, methylation and mRNA expression data using the recently developed iClusterBayes software.	('sarcoma tumor', 'Disease', 'MESH:D012509', (67, 80))	('sarcoma tumor', 'Disease', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('copy', 'Var', (141, 145))	('SARC', 'Phenotype', 'HP:0100242', (103, 107))	('mRNA expression', 'MPA', (170, 185))
542875	30577459	GISTs are usually associated with KIT and PDGFRalpha mutations and are sensitive to imatinib.	('PDGFRalpha', 'Gene', (42, 52))	('imatinib', 'Chemical', 'MESH:D000068877', (84, 92))	('mutations', 'Var', (53, 62))	('associated', 'Reg', (18, 28))	('KIT', 'Gene', (34, 37))	('PDGFRalpha', 'Gene', '5156', (42, 52))
542879	30577459	In-depth genomic profiling has shown that many sarcomas are generally driven by a chromosomal translocation event such as in synovial sarcoma or have copy number aberrations.	('synovial sarcoma', 'Disease', (125, 141))	('sarcomas', 'Disease', (47, 55))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (125, 141))	('synovial sarcoma', 'Disease', 'MESH:D013584', (125, 141))	('copy number aberrations', 'Var', (150, 173))	('driven by', 'Reg', (70, 79))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
542880	30577459	Some subtypes such as undifferentiated pleomorphic sarcoma (UPS) have a higher number of non-synonymous mutations and greater mutational burden.	('non-synonymous mutations', 'Var', (89, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (22, 58))	('UPS', 'Disease', 'MESH:D017118', (60, 63))	('undifferentiated pleomorphic sarcoma', 'Disease', (22, 58))	('UPS', 'Disease', (60, 63))
542886	30577459	To date, there are two FDA-approved therapeutic cancer vaccines: sipeleucel-T in prostate cancer and intravesical bacillus Calmette-Guerin (BCG) for non-muscular invasive bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (48, 54))	('invasive bladder', 'Phenotype', 'HP:0100645', (162, 178))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('prostate cancer', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('sipeleucel-T', 'Var', (65, 77))	('BCG', 'Species', '33892', (140, 143))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('sipeleucel-T', 'Chemical', '-', (65, 77))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (162, 185))	('non-muscular invasive bladder', 'Phenotype', 'HP:0000011', (149, 178))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('invasive bladder cancer', 'Disease', (162, 185))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('bacillus Calmette-Guerin', 'Species', '33892', (114, 138))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', (179, 185))
542907	30577459	Aberrant ganglioside antigen expression is also a rational tumour-specific target and vaccines have been tested in different tumour types including melanoma and sarcoma.	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('Aberrant', 'Var', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('melanoma and sarcoma', 'Disease', 'MESH:D008545', (148, 168))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (125, 131))	('tumour', 'Disease', (59, 65))	('ganglioside antigen', 'Protein', (9, 28))	('ganglioside', 'Chemical', 'MESH:D005732', (9, 20))
542912	30577459	Unique chromosomal translocation events that are ubiquitous within a sarcoma subtype such as the t(X;18)(p11;q11) translocation in synovial sarcoma or the t(12;16)(q13;p11) in myxoid/round cell liposarcoma are attractive vaccine targets as the newly-formed peptide will potentially create a tumour-specific neoantigen.	('tumour', 'Disease', 'MESH:D009369', (291, 297))	('sarcoma', 'Disease', 'MESH:D012509', (198, 205))	('tumour', 'Disease', (291, 297))	('synovial sarcoma', 'Disease', 'MESH:D013584', (131, 147))	('sarcoma', 'Disease', (198, 205))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (176, 205))	('liposarcoma', 'Disease', (194, 205))	('sarcoma', 'Disease', (69, 76))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (131, 147))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('sarcoma', 'Disease', (140, 147))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (155, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('liposarcoma', 'Phenotype', 'HP:0012034', (194, 205))	('translocation', 'Var', (114, 127))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (97, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('create', 'Reg', (282, 288))	('liposarcoma', 'Disease', 'MESH:D008080', (194, 205))	('synovial sarcoma', 'Disease', (131, 147))	('tumour', 'Phenotype', 'HP:0002664', (291, 297))
542988	30577459	LV305 has shown considerable activity in sarcoma.	('sarcoma', 'Disease', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('LV305', 'Var', (0, 5))	('activity', 'MPA', (29, 37))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))
543000	30577459	MN59 is an oil-in water adjuvant used in the influenza vaccine which activates cytokines and stimulates chemokine production but does not elicit a cellular immune response.	('activates', 'PosReg', (69, 78))	('MN59', 'Var', (0, 4))	('chemokine production', 'MPA', (104, 124))	('water', 'Chemical', 'MESH:D014867', (18, 23))	('oil', 'Chemical', 'MESH:D009821', (11, 14))	('cytokines', 'MPA', (79, 88))	('stimulates', 'PosReg', (93, 103))
543029	30577459	UPS, the subtype with the highest mutational burden, has a more robust T cell infiltrate, high PD-1 and PD-L1 expression and high expression of genes related to antigen presentation.	('expression', 'MPA', (130, 140))	('UPS', 'Disease', (0, 3))	('PD-1', 'Gene', (95, 99))	('PD-L1', 'Gene', '29126', (104, 109))	('expression', 'MPA', (110, 120))	('mutational', 'Var', (34, 44))	('T cell infiltrate', 'CPA', (71, 88))	('UPS', 'Disease', 'MESH:D017118', (0, 3))	('PD-L1', 'Gene', (104, 109))
543030	30577459	High PD-L1 expression in alveolar soft part sarcoma may contribute to immunosuppression and the limited response observed to vaccine therapy despite the presence of a T cell infiltrate.	('alveolar soft part sarcoma', 'Disease', (25, 51))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (25, 51))	('High', 'Var', (0, 4))	('PD-L1', 'Gene', (5, 10))	('PD-L1', 'Gene', '29126', (5, 10))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (25, 51))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (34, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('contribute', 'Reg', (56, 66))
543059	30577459	A trial combining CMB305-, LV305-, and NY-ESO-1-specific adoptive T cell therapy is currently recruiting.	('NY-ESO-1', 'Gene', '246100', (39, 47))	('LV305-', 'Var', (27, 33))	('CMB305', 'Chemical', '-', (18, 24))	('NY-ESO-1', 'Gene', (39, 47))
543176	28376845	The defining feature of the ESFT is a nonrandom chromosomal translocation and the most frequent is EWS-FLI1 fusion.	('FLI1', 'Gene', (103, 107))	('ES', 'Phenotype', 'HP:0012254', (28, 30))	('FLI1', 'Gene', '2313', (103, 107))	('ESFT', 'Disease', (28, 32))	('nonrandom', 'Var', (38, 47))	('EWS', 'Gene', '2130', (99, 102))	('EWS', 'Gene', (99, 102))	('frequent', 'Reg', (87, 95))
543238	25621678	The frequency of malignant change is increased in the polyostotic form of FD, especially in patients with McCune-Albright syndrome or Mazabraud syndrome.	('polyostotic', 'Var', (54, 65))	('malignant change', 'CPA', (17, 33))	('Mazabraud syndrome', 'Disease', (134, 152))	('patients', 'Species', '9606', (92, 100))	('malignant change', 'Phenotype', 'HP:0002664', (17, 33))	('Mazabraud syndrome', 'Disease', 'MESH:D013577', (134, 152))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (106, 130))	('FD', 'Disease', 'MESH:D004402', (74, 76))	('McCune-Albright syndrome', 'Disease', (106, 130))
543291	25621678	However, the frequency of malignant change is increased with the polyostotic form of FD.	('malignant change', 'CPA', (26, 42))	('FD', 'Disease', 'MESH:D004402', (85, 87))	('polyostotic', 'Var', (65, 76))	('malignant change', 'Phenotype', 'HP:0002664', (26, 42))
543364	32881345	Synovial sarcoma (SS) is a rare malignancy with unique molecular characteristic of translocation t(X;18)(p11.2;q11.2) in 90% of the patients resulting in fusion of SS18-SSX, which is the main oncogenic driver.	('fusion', 'Var', (154, 160))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (97, 117))	('SS', 'Phenotype', 'HP:0012570', (164, 166))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('Synovial sarcoma', 'Disease', (0, 16))	('Synovial sarcoma', 'Disease', 'MESH:D013584', (0, 16))	('malignancy', 'Disease', 'MESH:D009369', (32, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SS', 'Phenotype', 'HP:0012570', (18, 20))	('SS', 'Phenotype', 'HP:0012570', (169, 171))	('malignancy', 'Disease', (32, 42))	('SSX', 'Gene', '6757', (169, 172))	('patients', 'Species', '9606', (132, 140))	('SSX', 'Gene', (169, 172))
543409	32881345	Limb salvage surgery rate was 100% in NACRT group while it was reduced to 57.1% in the single modality neoadjuvant group.	('NACRT', 'Chemical', '-', (38, 43))	('Limb salvage surgery', 'CPA', (0, 20))	('NACRT', 'Var', (38, 43))
543429	32881345	Amongst these factors, Intralesional resection of the tumor is consistently associated with high risk of local and distant disease recurrence as well as poor OS.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('poor OS', 'Disease', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('Intralesional resection', 'Var', (23, 46))
543436	32881345	We found a high rate of suboptimal initial surgery for localized SS before getting referred to WA state sarcoma service.	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('suboptimal', 'Var', (24, 34))	('SS', 'Phenotype', 'HP:0012570', (65, 67))	('localized SS', 'Disease', (55, 67))
543462	33061452	A total of 72.9% of the cases revealed genetic EWSR1 recombination, including our 2 cases.	('EWSR1', 'Gene', (47, 52))	('revealed', 'Reg', (30, 38))	('recombination', 'Var', (53, 66))	('EWSR1', 'Gene', '2130', (47, 52))
543466	33061452	No earlier than Zambrano, other researchers also reported the resemblance of gastrointestinal tumors to CCS of soft tissue and gastrointestinal tumors occurring with EWSR1 genetic translocation.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (77, 100))	('gastrointestinal tumors', 'Disease', (77, 100))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (77, 100))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (127, 150))	('gastrointestinal tumors', 'Disease', (127, 150))	('EWSR1', 'Gene', (166, 171))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (127, 150))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('EWSR1', 'Gene', '2130', (166, 171))	('genetic translocation', 'Var', (172, 193))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
543515	33061452	Genetic recombination of EWSR1 was found in 72.9% of the patients.	('EWSR1', 'Gene', (25, 30))	('Genetic recombination', 'Var', (0, 21))	('patients', 'Species', '9606', (57, 65))	('EWSR1', 'Gene', '2130', (25, 30))	('found', 'Reg', (35, 40))
543544	33061452	These results suggest that patients with metastasis are more likely to experience recurrence and further metastasis and have a poor prognosis.	('metastasis', 'Var', (41, 51))	('patients', 'Species', '9606', (27, 35))	('recurrence', 'CPA', (82, 92))
543555	33061452	Binding of the SWI/SNF complex could induce nuclear localization, change the balance of tumor inhibitors and lead to similar changes in terms of SWI/SNF gene mutations.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('change', 'Reg', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('SWI/SNF gene', 'Gene', (145, 157))	('nuclear localization', 'MPA', (44, 64))	('induce', 'PosReg', (37, 43))	('Binding', 'Interaction', (0, 7))	('mutations', 'Var', (158, 167))	('tumor', 'Disease', (88, 93))	('changes', 'Reg', (125, 132))
543579	31182063	In normal human tissues, the N-acetylneuraminic acid (NeuAc) is the most common variant of sialic acid, while the presence of N-glycolylneuraminic acid (NeuGc) is limited due to an inactivating mutation in the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-NeuAc hydroxylase) gene .	('NeuAc', 'Chemical', 'MESH:D019158', (54, 59))	('CMP-NeuAc hydroxylase', 'Gene', '8418', (270, 291))	('N-acetylneuraminic acid', 'Chemical', 'MESH:D019158', (233, 256))	('human', 'Species', '9606', (10, 15))	('inactivating mutation', 'Var', (181, 202))	('NeuAc', 'Chemical', 'MESH:D019158', (274, 279))	('sialic acid', 'Chemical', 'MESH:D019158', (91, 102))	('CMP-NeuAc hydroxylase', 'Gene', (270, 291))	('N-acetylneuraminic acid', 'Chemical', 'MESH:D019158', (29, 52))	('N-glycolylneuraminic acid', 'Chemical', 'MESH:C032592', (126, 151))
543581	31182063	In particular, the aberrant expression of N-glycolyl GM3 ganglioside (NeuGcGM3) was previously reported by immunohistochemistry in a variety of malignant tumors, including pediatric and adult sarcomas.	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('expression', 'MPA', (28, 38))	('malignant tumors', 'Disease', (144, 160))	('malignant tumors', 'Disease', 'MESH:D018198', (144, 160))	('NeuGcGM3', 'Chemical', 'MESH:C044298', (70, 78))	('NeuGcGM3', 'Gene', (70, 78))	('adult sarcomas', 'Disease', 'MESH:D012509', (186, 200))	('N-glycolyl GM3 ganglioside', 'Chemical', '-', (42, 68))	('adult sarcomas', 'Disease', (186, 200))	('reported', 'Reg', (95, 103))	('aberrant', 'Var', (19, 27))	('pediatric', 'Disease', (172, 181))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
543617	31182063	In survival analysis, there was a statistically significant difference in the 5-year OS rates between high and low expression of NeuGcGM3 (45.4% vs. 82.3%; p = 0.016), while no significant relation was obtained with Disease-free survival (p = 0.346).	('high', 'Var', (102, 106))	('OS', 'Chemical', '-', (85, 87))	('low', 'NegReg', (111, 114))	('NeuGcGM3', 'Chemical', 'MESH:C044298', (129, 137))	('NeuGcGM3', 'Gene', (129, 137))
543622	31182063	Interestingly, the presence of this ganglioside was statistically significant increased in advanced clinical stages (p = 0.022), high histological grade tumors (p = 0.013) as well as in samples displaying an increased index of cell proliferation (p = 0.012) (Figs.	('presence', 'Var', (19, 27))	('cell proliferation', 'CPA', (227, 245))	('increased', 'PosReg', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('increased', 'PosReg', (78, 87))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('ganglioside', 'Chemical', 'MESH:D005732', (36, 47))
543631	31182063	In previous studies, NeuGc was the predominant sialic acid present on the plasmatic membrane of MG-63 sarcoma cells.	('MG', 'Chemical', 'MESH:D008274', (96, 98))	('sialic acid', 'Chemical', 'MESH:D019158', (47, 58))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('sarcoma', 'Disease', (102, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('NeuGc', 'Var', (21, 26))
543639	31182063	The presence of NeuGcGM3 was also related with age of sarcoma patients.	('NeuGcGM3', 'Chemical', 'MESH:C044298', (16, 24))	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('sarcoma', 'Disease', (54, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('related', 'Reg', (34, 41))	('presence', 'Var', (4, 12))	('NeuGcGM3', 'Gene', (16, 24))	('patients', 'Species', '9606', (62, 70))
543647	31182063	It is recognized that high histological grade sarcomas are characterized by an increase in the proliferation rates , occurrence of metastasis, and decreased survival rates.	('increase', 'PosReg', (79, 87))	('metastasis', 'CPA', (131, 141))	('sarcomas', 'Disease', (46, 54))	('sarcomas', 'Disease', 'MESH:D012509', (46, 54))	('decreased', 'NegReg', (147, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('survival rates', 'CPA', (157, 171))	('high histological', 'Var', (22, 39))	('proliferation rates', 'CPA', (95, 114))
543648	31182063	Moreover, the presence of NeuGcGM3 was significantly higher in tumors displaying an increased index of cell proliferation.	('NeuGcGM3', 'Chemical', 'MESH:C044298', (26, 34))	('presence', 'Var', (14, 22))	('NeuGcGM3', 'Gene', (26, 34))	('higher', 'PosReg', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
543650	31182063	Interestingly, the presence of NeuGcGM3 was increased in deep sarcomas when compared with superficial tumors, although only a tendency for statistical association was obtained.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('deep sarcomas', 'Disease', (57, 70))	('increased', 'Reg', (44, 53))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('NeuGcGM3', 'Chemical', 'MESH:C044298', (31, 39))	('NeuGcGM3', 'Gene', (31, 39))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('presence', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('deep sarcomas', 'Disease', 'MESH:D012509', (57, 70))
543653	31182063	Finally, the presence of NeuGcGM3 was significantly associated with advanced TNM stage, a clinicopathological feature also related with an adverse clinical outcome of patients.	('TNM', 'Gene', (77, 80))	('NeuGcGM3', 'Gene', (25, 33))	('NeuGcGM3', 'Chemical', 'MESH:C044298', (25, 33))	('associated', 'Reg', (52, 62))	('patients', 'Species', '9606', (167, 175))	('TNM', 'Gene', '10178', (77, 80))	('presence', 'Var', (13, 21))
543670	23967081	Fusion genes are found in haematological malignancies and soft tissue sarcomas as well as in epithelial tumours and are known to be one of the most prominent types of genetic alteration in cancer.	('Fusion genes', 'Var', (0, 12))	('haematological malignancies and soft tissue sarcomas', 'Disease', 'MESH:D012509', (26, 78))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (58, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('epithelial tumours', 'Disease', 'MESH:D000077216', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('found', 'Reg', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('epithelial tumours', 'Disease', (93, 111))	('cancer', 'Disease', (189, 195))
543673	23967081	However, the identification of specific fusion genes in various subtypes allows correct classification of the tumours for the purpose of treatment and, in some cases, also provides prognostic information.	('fusion', 'Var', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('provides', 'Reg', (172, 180))	('tumours', 'Disease', 'MESH:D009369', (110, 117))	('tumours', 'Disease', (110, 117))
543699	23967081	While FISH with break-apart probes readily identifies the vast majority of EWSR1 rearrangements, it does not provide any information on the fusion partner.	('rearrangements', 'Var', (81, 95))	('EWSR1', 'Gene', (75, 80))	('EWSR1', 'Gene', '14030', (75, 80))
543772	32806601	In general, neoadjuvant RT is associated with more acute wound complications while adjuvant RT is associated with higher rates of late toxicities and decreased limb function.	('neoadjuvant', 'Var', (12, 23))	('limb function', 'CPA', (160, 173))	('toxicities', 'Disease', (135, 145))	('decreased limb function', 'Phenotype', 'HP:0009826', (150, 173))	('toxicities', 'Disease', 'MESH:D064420', (135, 145))	('decreased', 'NegReg', (150, 159))	('rat', 'Species', '10116', (121, 124))
543780	32806601	Target coverage and protection of normal tissues appear to be superior for IMRT compared with 3D-CRT in STS of the extremity and the retroperitoneum.	('STS', 'Phenotype', 'HP:0030448', (104, 107))	('IMRT', 'Var', (75, 79))	('age', 'Gene', '5973', (12, 15))	('age', 'Gene', (12, 15))
543782	32806601	Though there has never been a prospective trial randomizing patients to IMRT vs. either 3D-CRT or BT, IMRT has been associated with lower rates of wound complications compared with historical 3D-CRT results (30.5 vs. 43%, respectively), but higher rates compared with BT (19% IMRT vs. 11% BT) though neither of these results were statistically significant.	('rat', 'Species', '10116', (138, 141))	('IMRT', 'Var', (102, 106))	('patients', 'Species', '9606', (60, 68))	('higher', 'PosReg', (241, 247))	('wound complications', 'CPA', (147, 166))	('lower', 'NegReg', (132, 137))	('rat', 'Species', '10116', (248, 251))
543809	32806601	showed a significantly higher incidence of fibrosis (48.2% vs. 31.5%), edema (23.2% vs. 15.1%) and fracture (23.2% vs. 17.8%) in adjuvant RT compared with neoadjuvant RT, respectively (all, p < 0.05).	('edema', 'Disease', (71, 76))	('fracture', 'Disease', (99, 107))	('edema', 'Disease', 'MESH:D004487', (71, 76))	('adjuvant RT', 'Var', (129, 140))	('edema', 'Phenotype', 'HP:0000969', (71, 76))	('fracture', 'Disease', 'MESH:D050723', (99, 107))	('fibrosis', 'Disease', 'MESH:D005355', (43, 51))	('fibrosis', 'Disease', (43, 51))
543864	32806601	Irradiation may induce microvascular damage and local tissue hypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (61, 68))	('hypoxia', 'Disease', (61, 68))	('Irradiation', 'Var', (0, 11))	('microvascular damage', 'Disease', (23, 43))	('induce', 'Reg', (16, 22))	('microvascular damage', 'Disease', 'MESH:D017566', (23, 43))
543898	32806601	Several recent clinical trials have been/are currently being conducted to investigate the ability of amifostine to reduce RT side effects in the rectum as part of prostate cancer treatment (NCT00040365), reduce head and neck side effects in the treatment of lymphoma (NCT00136474), or for reducing neuropathy from paclitaxel in a variety of settings (NCT00078845).	('prostate cancer', 'Disease', (163, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('reducing neuropathy', 'Disease', 'MESH:C536418', (289, 308))	('reduce head', 'Phenotype', 'HP:0000252', (204, 215))	('paclitaxel', 'Chemical', 'MESH:D017239', (314, 324))	('lymphoma', 'Disease', (258, 266))	('RT side effects', 'MPA', (122, 137))	('reducing neuropathy', 'Disease', (289, 308))	('amifostine', 'Chemical', 'MESH:D004999', (101, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (163, 178))	('neuropathy', 'Phenotype', 'HP:0009830', (298, 308))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))	('lymphoma', 'Disease', 'MESH:D008223', (258, 266))	('lymphoma', 'Phenotype', 'HP:0002665', (258, 266))	('head', 'MPA', (211, 215))	('reduce', 'NegReg', (115, 121))	('reduce', 'NegReg', (204, 210))	('NCT00040365', 'Var', (190, 201))
543910	32806601	In another mouse model combining fractionated RT with a mitochondrial-targeted tempol (GS-nitroxide, JP4-039), JP4-039 was able to protect bones from injury.	('mouse', 'Species', '10090', (11, 16))	('GS-nitroxide', 'Chemical', '-', (87, 99))	('JP4-039', 'Var', (111, 118))	('tempol', 'Chemical', 'MESH:C001803', (79, 85))	('bones from injury', 'CPA', (139, 156))
543916	32806601	In an in vivo model of radiogenic wound healing, pharmacological ascorbate was found to induce a significant acceleration in healing of radiogenic ulcers in mice treated with 10, 16, and 20 Gy of radiation.	('ulcers', 'Disease', (147, 153))	('ascorbate', 'Chemical', 'MESH:D001205', (65, 74))	('rat', 'Species', '10116', (115, 118))	('mice', 'Species', '10090', (157, 161))	('pharmacological', 'Var', (49, 64))	('acceleration', 'PosReg', (109, 121))	('ulcers', 'Disease', 'MESH:D014456', (147, 153))	('healing', 'MPA', (125, 132))
543924	32806601	GC4419 (previously known as M40419) is a small molecular weight mitochondria-specific SOD mimetic with a dismutation of superoxide rate constant of 1 x 107/mol/s; this compares favorably with the native MnSOD enzyme at 1.2 x 109/mol/s.	('SOD', 'Gene', (86, 89))	('rat', 'Species', '10116', (131, 134))	('MnSOD', 'Gene', (203, 208))	('M40419', 'Chemical', '-', (28, 34))	('SOD', 'Gene', (205, 208))	('MnSOD', 'Gene', '6648', (203, 208))	('GC4419', 'Var', (0, 6))	('SOD', 'Gene', '6647', (205, 208))	('SOD', 'Gene', '6647', (86, 89))	('superoxide', 'Chemical', 'MESH:D013481', (120, 130))	('GC4419', 'Chemical', 'MESH:C121876', (0, 6))	('dismutation of superoxide rate constant', 'MPA', (105, 144))
543925	32806601	Previous research showed that older fibroblasts have less migration ability compared with younger dermal fibroblasts, and GC4419 can restore the migration ability of the older dermal fibroblasts.	('GC4419', 'Var', (122, 128))	('rat', 'Species', '10116', (148, 151))	('restore', 'PosReg', (133, 140))	('migration', 'CPA', (145, 154))	('GC4419', 'Chemical', 'MESH:C121876', (122, 128))	('migration ability', 'CPA', (58, 75))	('rat', 'Species', '10116', (61, 64))
543926	32806601	In a phase Ib/IIa clinical trial in patients with head and neck cancer treated with >=60 Gy of radiation with concurrent cisplatin, GC4419 was found to have protective effects against oral mucositis.	('oral mucositis', 'Disease', 'MESH:D009059', (184, 198))	('head and neck cancer', 'Disease', 'MESH:D006258', (50, 70))	('oral mucositis', 'Disease', (184, 198))	('GC4419', 'Chemical', 'MESH:C121876', (132, 138))	('patients', 'Species', '9606', (36, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('head and neck cancer', 'Phenotype', 'HP:0012288', (50, 70))	('GC4419', 'Var', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
543953	32806601	Inhibition of the effects of TGF-beta by blocking its receptor has been found to reduce radiation fibrosis dramatically with fewer toxic effects.	('radiation fibrosis', 'Disease', 'MESH:D017564', (88, 106))	('reduce', 'NegReg', (81, 87))	('radiation fibrosis', 'Disease', (88, 106))	('TGF-beta', 'Gene', (29, 37))	('receptor', 'Protein', (54, 62))	('Inhibition', 'Var', (0, 10))	('TGF-beta', 'Gene', '7039', (29, 37))	('blocking', 'NegReg', (41, 49))
543954	32806601	Antisense TGF-beta oligonucleotides showed an anti-scarring effect in an in vivo model of wound healing and scarring.	('TGF-beta', 'Gene', (10, 18))	('oligonucleotides', 'Chemical', 'MESH:D009841', (19, 35))	('anti-scarring effect', 'CPA', (46, 66))	('scar', 'Phenotype', 'HP:0100699', (51, 55))	('scar', 'Phenotype', 'HP:0100699', (108, 112))	('TGF-beta', 'Gene', '7039', (10, 18))	('scarring', 'Phenotype', 'HP:0100699', (51, 59))	('scarring', 'Phenotype', 'HP:0100699', (108, 116))	('Antisense', 'Var', (0, 9))
543960	32806601	; data curation, N/A; writing:original draft preparation, C.M.C., M.M.H., E.J.S., S.N.R., B.J.M., J.E.G., M.C.C., M.M.M., and B.G.A.	('rat', 'Species', '10116', (9, 12))	('rat', 'Species', '10116', (50, 53))	('B.J.M.', 'Var', (90, 96))	('M.M.M.', 'Var', (114, 120))	('M.C.C.', 'Var', (106, 112))
543998	31439515	Morphological features of large round-to-ovoid cells, with evidence of hemophagocytosis instead of spindle cells, negativity for the CD23 and positivity for the CD68, favored HS.	('CD23', 'Gene', (133, 137))	('CD23', 'Gene', '2208', (133, 137))	('hemophagocytosis', 'CPA', (71, 87))	('hemophagocytosis', 'Phenotype', 'HP:0012156', (71, 87))	('positivity', 'Var', (142, 152))	('favored', 'PosReg', (167, 174))	('negativity', 'Var', (114, 124))	('CD68', 'Gene', '968', (161, 165))	('CD68', 'Gene', (161, 165))
544043	30109147	Typically magnetic therapy induces weak electrical currents in the tissues, which enhances surface potential of cells leading to enhanced blood circulation, oxygenation, nutrient supply and better removal of metabolic waste from the exposed body tissues.	('enhanced', 'PosReg', (129, 137))	('surface potential of cells', 'CPA', (91, 117))	('enhanced blood circulation', 'Phenotype', 'HP:0011028', (129, 155))	('oxygen', 'Chemical', 'MESH:D010100', (157, 163))	('nutrient supply', 'MPA', (170, 185))	('enhances', 'PosReg', (82, 90))	('magnetic', 'Var', (10, 18))	('removal of metabolic waste from the', 'MPA', (197, 232))	('blood circulation', 'CPA', (138, 155))	('oxygenation', 'CPA', (157, 168))
544051	30109147	At very high frequencies or amplitudes, induced currents can generate excessive heat in the tissues and cause thermal damage.	('heat', 'MPA', (80, 84))	('generate', 'Reg', (61, 69))	('currents', 'Var', (48, 56))	('cause', 'Reg', (104, 109))	('thermal damage', 'CPA', (110, 124))	('rat', 'Species', '10116', (65, 68))
544066	30109147	Furthermore, magnetic fields can induce Joule's heating and expand cancer tumor blood vessels.	('cancer tumor', 'Disease', (67, 79))	("Joule's heating", 'MPA', (40, 55))	('cancer tumor', 'Disease', 'MESH:D009369', (67, 79))	('expand', 'PosReg', (60, 66))	('magnetic', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer tumor blood vessels', 'Phenotype', 'HP:0100742', (67, 93))
544071	30109147	It has been observed that SMF interacts with the charged molecules (ions, proteins etc.)	('interacts', 'Interaction', (30, 39))	('SMF', 'Var', (26, 29))	('proteins', 'Protein', (74, 82))	('SMF', 'Chemical', '-', (26, 29))
544073	30109147	ROS (reactive oxygen species), RNS (reactive nitrogen species), which causes oxidative stress, genetic mutation, and apoptosis in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('oxidative stress', 'Phenotype', 'HP:0025464', (77, 93))	('cancer', 'Disease', (130, 136))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (5, 28))	('genetic mutation', 'Var', (95, 111))	('RNS', 'Var', (31, 34))	('oxidative stress', 'MPA', (77, 93))	('reactive nitrogen species', 'Chemical', 'MESH:D026361', (36, 61))	('causes', 'Reg', (70, 76))	('RNS', 'Chemical', 'MESH:D026361', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('apoptosis', 'CPA', (117, 126))
544104	30109147	This study demonstrated that 8.8 mT SMF enhances cytotoxic potency of Adriamycin on K562 cells due to decrease in the P-gp expression.	('P-gp', 'Gene', (118, 122))	('K562', 'CellLine', 'CVCL:0004', (84, 88))	('rat', 'Species', '10116', (18, 21))	('expression', 'MPA', (123, 133))	('enhances', 'PosReg', (40, 48))	('decrease', 'NegReg', (102, 110))	('SMF', 'Var', (36, 39))	('Adriamycin', 'Chemical', 'MESH:D004317', (70, 80))	('cytotoxic potency of Adriamycin', 'MPA', (49, 80))	('P-gp', 'Gene', '5243', (118, 122))	('SMF', 'Chemical', '-', (36, 39))
544128	30109147	Combined use of 100 muM Temozolomide (TMZ) and EMF (100 Hz, 100 G) on U87 and T98G (human brain cancer cells) found to enhance cellular apoptosis synergistically by upregulation of p53, Bax, Caspase-3 and downregulation of Bcl-2 and Cyclin-D1.	('enhance', 'PosReg', (119, 126))	('Bcl-2', 'Gene', '596', (223, 228))	('Bax', 'Gene', (186, 189))	('brain cancer', 'Disease', (90, 102))	('Bax', 'Gene', '581', (186, 189))	('Cyclin-D1', 'Gene', '595', (233, 242))	('downregulation', 'NegReg', (205, 219))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cyclin-D1', 'Gene', (233, 242))	('Caspase-3', 'Gene', (191, 200))	('upregulation', 'PosReg', (165, 177))	('p53', 'Gene', '7157', (181, 184))	('TMZ', 'Chemical', 'MESH:D000077204', (38, 41))	('brain cancer', 'Phenotype', 'HP:0030692', (90, 102))	('cellular apoptosis', 'CPA', (127, 145))	('brain cancer', 'Disease', 'MESH:D001932', (90, 102))	('human', 'Species', '9606', (84, 89))	('p53', 'Gene', (181, 184))	('Bcl-2', 'Gene', (223, 228))	('Temozolomide', 'Chemical', 'MESH:D000077204', (24, 36))	('T98G', 'Var', (78, 82))	('Caspase-3', 'Gene', '836', (191, 200))
544147	30109147	Maximum cell inhibition was found with SMF + Cisplatin treatment and the cells were found to halt in S phase.	('SMF + Cisplatin', 'Var', (39, 54))	('S phase', 'CPA', (101, 108))	('Cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cell', 'CPA', (8, 12))	('SMF', 'Chemical', '-', (39, 42))
544148	30109147	SMF is believed to change motion of Cisplatin molecules within and between the cells leading to increased intracellular drug levels.	('change', 'Reg', (19, 25))	('increased', 'PosReg', (96, 105))	('motion', 'MPA', (26, 32))	('SMF', 'Chemical', '-', (0, 3))	('Cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('SMF', 'Var', (0, 3))	('intracellular drug levels', 'MPA', (106, 131))
544269	30109147	This approach has been used in variety of treatment combinations such as LIU + drugs, LIU + drugs + microbubbles and LIU + drug loaded microbubbles.	('LIU + drug', 'Var', (117, 127))	('LIU +', 'Chemical', '-', (117, 122))	('LIU +', 'Chemical', '-', (73, 78))	('LIU', 'Var', (86, 89))	('LIU +', 'Chemical', '-', (86, 91))
544278	30109147	Further, it has been recently demonstrated that the use of MNPs as DDS can significantly enhance ultrasonic hyperthermia.	('enhance', 'PosReg', (89, 96))	('hyperthermia', 'Phenotype', 'HP:0001945', (108, 120))	('MNPs', 'Var', (59, 63))	('ultrasonic hyperthermia', 'Disease', 'MESH:D005334', (97, 120))	('rat', 'Species', '10116', (37, 40))	('DDS', 'Disease', (67, 70))	('DDS', 'Disease', 'MESH:D030321', (67, 70))	('ultrasonic hyperthermia', 'Disease', (97, 120))
544282	30109147	Such an enhancement in elevated cytotoxic temperature, using US + MNPs, enable achieving desired therapeutic goal with lower intensity and duration of US treatment.	('US + MNPs', 'Var', (61, 70))	('enhancement', 'PosReg', (8, 19))	('elevated cytotoxic temperature', 'MPA', (23, 53))	('rat', 'Species', '10116', (47, 50))	('rat', 'Species', '10116', (141, 144))
544283	30109147	Moreover, the presence of MNPs alone can effectively induce hyperthermia with AMF, as discussed earlier.	('presence', 'Var', (14, 22))	('hyperthermia', 'Disease', 'MESH:D005334', (60, 72))	('hyperthermia', 'Phenotype', 'HP:0001945', (60, 72))	('hyperthermia', 'Disease', (60, 72))	('induce', 'Reg', (53, 59))
544291	30109147	However, 5 nM SN38 showed a significant anti-proliferative effect compared to control on day 4 (Fig.	('rat', 'Species', '10116', (52, 55))	('SN38', 'Var', (14, 18))	('anti-proliferative effect', 'CPA', (40, 65))
544294	30109147	Similarly, the cytotoxicity of Doxorubicin (DOX) on human primary liver cancer (PLC) cells has been enhanced with LIU.	('cytotoxicity', 'Disease', (15, 27))	('enhanced', 'PosReg', (100, 108))	('human', 'Species', '9606', (52, 57))	('liver cancer', 'Disease', 'MESH:D006528', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cytotoxicity', 'Disease', 'MESH:D064420', (15, 27))	('liver cancer', 'Phenotype', 'HP:0002896', (66, 78))	('liver cancer', 'Disease', (66, 78))	('LIU', 'Chemical', '-', (114, 117))	('DOX', 'Chemical', 'MESH:D004317', (44, 47))	('Doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('LIU', 'Var', (114, 117))
544338	26216294	An oncogenic NTRK fusion in a soft tissue sarcoma patient with response to the tropomyosin-related kinase (TRK) inhibitor LOXO-101 Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('LOXO-101', 'Chemical', 'MESH:C000609083', (122, 130))	('TRK', 'Gene', '7170', (107, 110))	('induce', 'PosReg', (153, 159))	('TRK', 'Gene', (107, 110))	('engage', 'Reg', (190, 196))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', (206, 212))	('fusions', 'Var', (145, 152))	('tropomyosin-related kinase', 'Gene', '7170', (79, 105))	('TRK', 'Gene', '7170', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (30, 49))	('fusion', 'Var', (18, 24))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('TRK', 'Gene', (141, 144))	('sarcoma', 'Disease', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('TRK', 'Gene', '7170', (14, 17))	('tropomyosin-related kinase', 'Gene', (79, 105))	('TRK', 'Gene', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('patient', 'Species', '9606', (50, 57))
544342	26216294	The tumor of a 41-year old woman with soft tissue sarcoma metastatic to lung was found to harbor an LMNA-NTRK1 gene fusion encoding a functional LMNA-TRKA fusion oncoprotein as determined by an in situ proximity ligation assay.	('tumor', 'Disease', (4, 9))	('TRKA', 'Gene', (150, 154))	('fusion', 'Var', (116, 122))	('LMNA', 'Gene', '4000', (145, 149))	('TRKA', 'Gene', '4914', (150, 154))	('LMNA', 'Gene', (100, 104))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (38, 57))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (38, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('woman', 'Species', '9606', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('soft tissue sarcoma', 'Disease', (38, 57))	('LMNA', 'Gene', (145, 149))	('LMNA', 'Gene', '4000', (100, 104))
544349	26216294	TRK gene fusions follow the well-established paradigm of other oncogenic fusions, such as those involving ALK and ROS1 that have been shown to drive the growth of tumors and can be successfully inhibited in the clinic by targeted drugs.	('ALK', 'Gene', '238', (106, 109))	('fusions', 'Var', (9, 16))	('ALK', 'Gene', (106, 109))	('drive', 'PosReg', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TRK', 'Gene', (0, 3))	('ROS1', 'Gene', '6098', (114, 118))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('ROS1', 'Gene', (114, 118))	('TRK', 'Gene', '7170', (0, 3))
544350	26216294	Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways such as MAPK and AKT, as recently reviewed by Vaishnavi, et al..	('cancer', 'Disease', (29, 35))	('Oncogenic', 'Var', (0, 9))	('TRK', 'Gene', '7170', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('MAPK', 'Gene', (128, 132))	('AKT', 'Gene', '207', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('MAPK', 'Gene', '5595;5594;5595', (128, 132))	('TRK', 'Gene', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('fusions', 'Var', (14, 21))	('AKT', 'Gene', (137, 140))	('induce', 'PosReg', (22, 28))	('engage', 'Reg', (59, 65))
544353	26216294	This high variability observed in the 5' gene partner is similar to ROS1 where at least 25 different 5' partners have been identified, however, all studied variants seems to respond to targeted therapy.	('variants', 'Var', (156, 164))	('ROS1', 'Gene', '6098', (68, 72))	('respond', 'Reg', (174, 181))	('ROS1', 'Gene', (68, 72))
544366	26216294	We and others have previously demonstrated that cancer cells harboring oncogenic TRK can be inhibited in vitro and in vivo by drugs that target the TRK kinase family.	('oncogenic', 'Var', (71, 80))	('TRK', 'Gene', (81, 84))	('inhibited', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('TRK', 'Gene', '7170', (148, 151))	('TRK', 'Gene', '7170', (81, 84))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('TRK', 'Gene', (148, 151))
544367	26216294	To demonstrate activity of LOXO-101 in pre-clinical models harboring different variants of TRK oncogenes we performed proliferation assays in three cell line models harboring TRK gene fusions: CUTO-3.29 is derived from a patient with lung adenocarcinoma harboring the MPRIP-NTRK1 gene fusion, the KM12 cell line is a colorectal cancer cell line harboring the TPM3-NTRK1 fusion, and the MO-91 cell line is derived from an acute myeloid leukemia patient harboring the ETV6-NTRK3 fusion.	('TRK', 'Gene', (472, 475))	('fusion', 'Var', (370, 376))	('TRK', 'Gene', (91, 94))	('MPRIP', 'Gene', '23164', (268, 273))	('TPM3', 'Gene', '7170', (359, 363))	('myeloid leukemia', 'Disease', 'MESH:D007951', (427, 443))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (427, 443))	('colorectal cancer', 'Disease', 'MESH:D015179', (317, 334))	('lung adenocarcinoma', 'Disease', (234, 253))	('MPRIP', 'Gene', (268, 273))	('colorectal cancer', 'Disease', (317, 334))	('patient', 'Species', '9606', (221, 228))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (421, 443))	('TRK', 'Gene', '7170', (175, 178))	('patient', 'Species', '9606', (444, 451))	('leukemia', 'Phenotype', 'HP:0001909', (435, 443))	('TPM3', 'Gene', (359, 363))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (466, 483))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (234, 253))	('TRK', 'Gene', '7170', (365, 368))	('TRK', 'Gene', (175, 178))	('ETV6-NTRK3 fusion', 'Gene', (466, 483))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (234, 253))	('TRK', 'Gene', (365, 368))	('TRK', 'Gene', '7170', (275, 278))	('LOXO-101', 'Chemical', 'MESH:C000609083', (27, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (317, 334))	('TRK', 'Gene', '7170', (472, 475))	('TRK', 'Gene', '7170', (91, 94))	('myeloid leukemia', 'Disease', (427, 443))	('TRK', 'Gene', (275, 278))
544374	26216294	We next determined whether LOXO-101 could inhibit tumor growth in vivo.	('LOXO-101', 'Var', (27, 35))	('LOXO-101', 'Chemical', 'MESH:C000609083', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('inhibit', 'NegReg', (42, 49))	('tumor', 'Disease', (50, 55))
544377	26216294	Together, these and previously published results indicate that TRK fusions are constitutively activated, regulate critical downstream signaling pathways such as MAPK and AKT, and are inhibited by a highly-specific TRK inhibitor.	('regulate', 'Reg', (105, 113))	('TRK', 'Gene', '7170', (63, 66))	('MAPK', 'Gene', '5595;5594;5595', (161, 165))	('fusions', 'Var', (67, 74))	('MAPK', 'Gene', (161, 165))	('TRK', 'Gene', (214, 217))	('AKT', 'Gene', '207', (170, 173))	('downstream signaling pathways', 'Pathway', (123, 152))	('TRK', 'Gene', (63, 66))	('AKT', 'Gene', (170, 173))	('TRK', 'Gene', '7170', (214, 217))	('inhibited', 'NegReg', (183, 192))	('activated', 'PosReg', (94, 103))
544383	26216294	Subsequently, a break-apart fluorescence in situ hybridization (FISH) assay performed on the patient's tumor sample exhibited a predominantly single 3' NTRK1 (red fluorescence signal) pattern in 64% of tumor nuclei, consistent with a genomic alteration involving the NTRK1 gene locus, most likely secondary to a genomic deletion between the two genes given the location and orientation of both LMNA and NTRK1 on the large arm of chromosome 1 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (103, 108))	('NTRK1', 'Gene', (403, 408))	('NTRK1', 'Gene', (267, 272))	('patient', 'Species', '9606', (93, 100))	('LMNA', 'Gene', (394, 398))	('LMNA', 'Gene', '4000', (394, 398))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('deletion', 'Var', (320, 328))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
544386	26216294	In this assay we measured TRKA complexed with its preferred adaptor, SHC1, which binds to Y496 in the TRKA kinase domain (Supplementary Fig.	('TRKA', 'Gene', (102, 106))	('SHC1', 'Gene', (69, 73))	('TRKA', 'Gene', '4914', (102, 106))	('TRKA', 'Gene', '4914', (26, 30))	('Y496', 'Var', (90, 94))	('TRKA', 'Gene', (26, 30))	('SHC1', 'Gene', '6464', (69, 73))
544390	26216294	The TRK PLA detects functional signaling complexes in a FFPE tumor sample from a patient derived xenograft (PDX), CULC001, harboring the MPRIP-NTRK1 gene fusions but not the PDX CULC002, which does not harbor a known oncogenic driver mutation (Supplementary Fig.	('TRK', 'Gene', '7170', (4, 7))	('TRK', 'Gene', '7170', (144, 147))	('patient', 'Species', '9606', (81, 88))	('MPRIP', 'Gene', (137, 142))	('MPRIP', 'Gene', '23164', (137, 142))	('functional signaling complexes', 'MPA', (20, 50))	('fusions', 'Var', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TRK', 'Gene', (4, 7))	('TRK', 'Gene', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
544417	26216294	The genomic structures of these TRK fusions and the inferred protein structures have suggested that these genes are oncogenic drivers, and previously reported preclinical work in addition to that shown here support this hypothesis.	('TRK', 'Gene', (32, 35))	('fusions', 'Var', (36, 43))	('TRK', 'Gene', '7170', (32, 35))
544418	26216294	The first patient with a documented NTRK fusion in this clinical trial demonstrated substantial tumor regression when treated with a selective inhibitor of TRK, providing clinical validation of this molecular target.	('TRK', 'Gene', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TRK', 'Gene', '7170', (156, 159))	('tumor', 'Disease', (96, 101))	('patient', 'Species', '9606', (10, 17))	('fusion', 'Var', (41, 47))	('TRK', 'Gene', '7170', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('TRK', 'Gene', (156, 159))
544423	26216294	Although a significant proportion of sarcomas have known chromosomal translocations that are valuable for diagnostic purposes, these alterations have generally not informed treatment decisions and have often proven to be difficult therapeutic targets.	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('chromosomal translocations', 'Var', (57, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcomas', 'Disease', (37, 45))
544424	26216294	The majority of sarcoma-associated translocations involve genes encoding transcription factors, such as the pathognomonic EWS-FLI1 fusion of Ewing sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (16, 23))	('FLI1', 'Gene', (126, 130))	('translocations', 'Var', (35, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (141, 154))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (141, 154))	('involve', 'Reg', (50, 57))	('sarcoma', 'Disease', (16, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('Ewing sarcoma', 'Disease', (141, 154))	('sarcoma', 'Disease', (147, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('FLI1', 'Gene', '2313', (126, 130))
544425	26216294	Fusions involving kinases or growth factors have been identified in several sarcoma subtypes characterized by low metastatic potential, including dermatofibrosarcoma protuberans (DFSP).	('dermatofibrosarcoma protuberans', 'Disease', (146, 177))	('Fusions', 'Var', (0, 7))	('DFSP', 'Disease', (179, 183))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (153, 165))	('DFSP', 'Disease', 'MESH:D018223', (179, 183))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (146, 177))	('sarcoma', 'Disease', 'MESH:D012509', (158, 165))	('sarcoma', 'Disease', (76, 83))	('identified', 'Reg', (54, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcoma', 'Disease', (158, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))
544426	26216294	DFSP is driven by a COL1A1-PDGFB fusion in fibroblasts, resulting in unregulated production of mature PDGFB.	('DFSP', 'Disease', (0, 4))	('PDGFB', 'Gene', '5155', (102, 107))	('DFSP', 'Disease', 'MESH:D018223', (0, 4))	('COL1A1', 'Gene', (20, 26))	('COL1A1', 'Gene', '1277', (20, 26))	('PDGFB', 'Gene', (102, 107))	('PDGFB', 'Gene', '5155', (27, 32))	('fusion', 'Var', (33, 39))	('PDGFB', 'Gene', (27, 32))
544428	26216294	Similarly, inflammatory myofibroblastic tumors (IMT) harbor fusions involving ALK or ROS1 and treatment with crizotinib results in rapid clinical response.	('inflammatory myofibroblastic tumors', 'Disease', (11, 46))	('ROS1', 'Gene', (85, 89))	('ALK', 'Gene', (78, 81))	('ROS1', 'Gene', '6098', (85, 89))	('fusions', 'Var', (60, 67))	('crizotinib', 'Chemical', 'MESH:D000077547', (109, 119))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (24, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('ALK', 'Gene', '238', (78, 81))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (11, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
544430	26216294	The LMNA-NTRK1 gene fusion has been previously reported in Spitzoid nevi and is constitutively activated when expressed in cells resulting in activation of ERK1/2, AKT and PLCgamma demonstrating its oncogenicity.	('AKT', 'Gene', (164, 167))	('PLCgamma', 'Protein', (172, 180))	('ERK1/2', 'Pathway', (156, 162))	('fusion', 'Var', (20, 26))	('Spitzoid nevi', 'Disease', (59, 72))	('activation', 'PosReg', (142, 152))	('LMNA', 'Gene', (4, 8))	('AKT', 'Gene', '207', (164, 167))	('Spitzoid', 'Chemical', '-', (59, 67))	('nevi', 'Phenotype', 'HP:0003764', (68, 72))	('LMNA', 'Gene', '4000', (4, 8))	('reported', 'Reg', (47, 55))
544432	26216294	Foundation Medicine (FM) has previously tested 1272 soft tissue sarcoma samples with the FoundationOneHeme CGP test resulting in the detection of 8 NTRK1 or NTRK3 fusions, including the patient described in this case report (Table 1).	('soft tissue sarcoma', 'Disease', (52, 71))	('fusions', 'Var', (163, 170))	('NTRK1', 'Gene', (148, 153))	('detection', 'Reg', (133, 142))	('NTRK3', 'Gene', '4916', (157, 162))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (52, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (52, 71))	('patient', 'Species', '9606', (186, 193))	('NTRK3', 'Gene', (157, 162))
544436	26216294	Since this patient also had a CDKN2A/B deletion, we decided to examine whether co-occurrence of these two lesions was common in sarcomas.	('CDKN2A/B', 'Gene', (30, 38))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('deletion', 'Var', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('sarcomas', 'Disease', (128, 136))	('patient', 'Species', '9606', (11, 18))	('CDKN2A/B', 'Gene', '1029;1030', (30, 38))
544439	26216294	In this report, three different cell line models, each with different tumor histologies and TRK fusions, demonstrated dose-dependent inhibition by LOXO-101 in vitro.	('LOXO-101', 'Var', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('LOXO-101', 'Chemical', 'MESH:C000609083', (147, 155))	('TRK', 'Gene', (92, 95))	('tumor', 'Disease', (70, 75))	('inhibition', 'NegReg', (133, 143))	('TRK', 'Gene', '7170', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
544443	26216294	Finally, murine xenograft experiments with a colorectal cell line harboring an NTRK1 fusion demonstrated dose-dependent inhibition of tumor growth by LOXO-101.	('fusion', 'Var', (85, 91))	('NTRK1', 'Gene', (79, 84))	('murine', 'Species', '10090', (9, 15))	('LOXO-101', 'Chemical', 'MESH:C000609083', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('inhibition', 'NegReg', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
544444	26216294	The tumor regression and clinical response seen in this LMNA-NTRK1 fusion patient provides clinical validation of a new molecular target in oncology, and establishes that at least this NTRK1 fusion is a molecular driver of this patient's clinical disease.	('tumor', 'Disease', (4, 9))	('patient', 'Species', '9606', (74, 81))	('NTRK1', 'Gene', (185, 190))	('patient', 'Species', '9606', (228, 235))	('LMNA', 'Gene', '4000', (56, 60))	('oncology', 'Phenotype', 'HP:0002664', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('LMNA', 'Gene', (56, 60))	('clinical response', 'CPA', (25, 42))	('fusion', 'Var', (67, 73))
544452	26216294	CAS registry numbers for LOXO-101 include 1223403-58-4 and 1223405-08-0.	('LOXO-101', 'Chemical', 'MESH:C000609083', (25, 33))	('1223403-58-4', 'Var', (42, 54))	('1223405-08-0', 'Var', (59, 71))
544456	26216294	Sequence data from gDNA and cDNA were mapped to the reference human genome (hg19) and analyzed through a computational analysis pipeline to call genomic alterations present in the sample, including substitutions, short insertions and deletions, rearrangements and copy-number variants.	('copy-number variants', 'Var', (264, 284))	('short insertions', 'Var', (213, 229))	('human', 'Species', '9606', (62, 67))	('substitutions', 'Var', (198, 211))	('rearrangements', 'Var', (245, 259))
544462	26216294	Pleural fluid (CULC001) from a lung adenocarcinoma patient harboring an MRPIP-NTRK1 gene fusion was centrifuged and the resulting cell pellet was suspended in 5 ml ACK buffer (Lonza) for 2 min allowing for the complete lysis of red blood cells.	('lung adenocarcinoma', 'Disease', (31, 50))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('MRPIP-NTRK1', 'Gene', (72, 83))	('ACK', 'Gene', (164, 167))	('patient', 'Species', '9606', (51, 58))	('Pleural fluid', 'Phenotype', 'HP:0002202', (0, 13))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('gene fusion', 'Var', (84, 95))	('ACK', 'Gene', '10188', (164, 167))
544473	26216294	The following antibodies were used: TRK (C17F1) and ALK (D5F3) from Cell Signaling, SHC1 from Novus, and Grb2 (610111) from BD.	('Grb2', 'Gene', '2885', (105, 109))	('TRK', 'Gene', (36, 39))	('610111', 'Var', (111, 117))	('ALK', 'Gene', '238', (52, 55))	('SHC1', 'Gene', '6464', (84, 88))	('SHC1', 'Gene', (84, 88))	('TRK', 'Gene', '7170', (36, 39))	('Grb2', 'Gene', (105, 109))	('ALK', 'Gene', (52, 55))
544480	26216294	The following antibodies were used from Cell Signaling: pTRK Y490 (rabbit polyclonal, #9141), pERK1/2 XP T202/Y204 (#9101), total ERK1/2, pAKT S473 (rabbit mAb, #4060), and total AKT mouse clone D3A7 (#2920).	('AKT', 'Gene', (179, 182))	('rabbit', 'Species', '9986', (149, 155))	('AKT', 'Gene', '207', (139, 142))	('TRK', 'Gene', (57, 60))	('rabbit', 'Species', '9986', (67, 73))	('mouse', 'Species', '10090', (183, 188))	('AKT', 'Gene', (139, 142))	('AKT', 'Gene', '207', (179, 182))	('TRK', 'Gene', '7170', (57, 60))	('#9101', 'Var', (116, 121))	('#2920', 'Var', (201, 206))
544483	26216294	Confidence intervals for the detection rate of NTRK fusions in samples from sarcoma patients were calculated using the 1-sample proportions test.	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('patients', 'Species', '9606', (84, 92))	('TRK', 'Gene', '7170', (48, 51))	('sarcoma', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('TRK', 'Gene', (48, 51))	('fusions', 'Var', (52, 59))
544487	26216294	A patient with a metastatic soft tissue sarcoma with an LMNA-NTRK1 fusion had rapid and substantial tumor regression with a novel, highly-selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit inhibiting TRK fusions.	('TRK', 'Gene', '7170', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('soft tissue sarcoma', 'Disease', (28, 47))	('LMNA', 'Gene', '4000', (56, 60))	('LOXO-101', 'Chemical', 'MESH:C000609083', (163, 171))	('tumor', 'Disease', (100, 105))	('TRK', 'Gene', (148, 151))	('patient', 'Species', '9606', (2, 9))	('TRK', 'Gene', '7170', (148, 151))	('TRK', 'Gene', (233, 236))	('TRK', 'Gene', (62, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('LMNA', 'Gene', (56, 60))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (28, 47))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (28, 47))	('TRK', 'Gene', '7170', (233, 236))	('fusion', 'Var', (67, 73))
544489	26250552	A specific translocation in this sarcoma induces fusion of the SYT gene on chromosome 18 to the SSX genes on chromosome X, leading to proliferation of the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('SYT', 'Gene', '6760', (63, 66))	('translocation', 'Var', (11, 24))	('tumor', 'Disease', (155, 160))	('induces', 'Reg', (41, 48))	('SSX', 'Gene', '6757', (96, 99))	('sarcoma', 'Disease', (33, 40))	('leading to', 'Reg', (123, 133))	('fusion', 'Var', (49, 55))	('SSX', 'Gene', (96, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('proliferation', 'CPA', (134, 147))	('SYT', 'Gene', (63, 66))
544494	26250552	A panel of seven miRNAs (miR-99a-5p, miR-146b-5p, miR-148b-3p, miR-195-5p, miR-223-3p, miR-500b-3p and miR-505-3p) was further validated by qRT-PCR to be significantly upregulated in synovial sarcoma patients.	('miR-223', 'Gene', '407008', (75, 82))	('miR-146b', 'Gene', (37, 45))	('synovial sarcoma', 'Disease', (183, 199))	('miR-500b', 'Gene', (87, 95))	('synovial sarcoma', 'Disease', 'MESH:D013584', (183, 199))	('miR-500b', 'Gene', '100422911', (87, 95))	('miR-99a-5p', 'Var', (25, 35))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (183, 199))	('miR-146b', 'Gene', '574447', (37, 45))	('upregulated', 'PosReg', (168, 179))	('miR-195', 'Gene', '406971', (63, 70))	('miR-223', 'Gene', (75, 82))	('patients', 'Species', '9606', (200, 208))	('miR-195', 'Gene', (63, 70))	('miR-148b', 'Gene', '442892', (50, 58))	('miR-148b', 'Gene', (50, 58))	('miR-505', 'Gene', (103, 110))	('miR-505', 'Gene', '574508', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
544501	26250552	The cytogenetically defined translocation t(X; 18) (p11.2; q11.2) found in synovial sarcoma results in the fusion of the SYT gene on chromosome 18 to either SSX1, SSX2 or SSX4 on chromosome X, resulting in the formation of a SS18-SSX1, SS18-SSX2 or the rare SS18-SSX4 fusion transcript, which allow a very specific and sensitive molecular diagnosis of synovial sarcoma by fluorescence in situ hybridization (FISH) or quantitative and conventional reverse transcription-polymerase chain reaction (RT-PCR) of tumor tissue.	('SSX4', 'Gene', '6759', (263, 267))	('SSX1', 'Gene', '6756', (157, 161))	('SS18', 'Gene', (225, 229))	('synovial sarcoma', 'Disease', (75, 91))	('fusion', 'Var', (107, 113))	('synovial sarcoma', 'Disease', 'MESH:D013584', (352, 368))	('SSX1', 'Gene', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (507, 512))	('synovial sarcoma', 'Disease', 'MESH:D013584', (75, 91))	('SYT', 'Gene', (121, 124))	('SS18', 'Gene', '6760', (236, 240))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (352, 368))	('SSX4', 'Gene', (171, 175))	('SS18', 'Gene', '6760', (258, 262))	('p11', 'Gene', '8909', (52, 55))	('SS18', 'Gene', '6760', (225, 229))	('p11', 'Gene', (52, 55))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (75, 91))	('SSX2', 'Gene', (163, 167))	('SSX4', 'Gene', '6759', (171, 175))	('SYT', 'Gene', '6760', (121, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('tumor', 'Disease', (507, 512))	('SSX2', 'Gene', '6757', (163, 167))	('SSX2', 'Gene', (241, 245))	('SSX4', 'Gene', (263, 267))	('tumor', 'Disease', 'MESH:D009369', (507, 512))	('SSX1', 'Gene', '6756', (230, 234))	('SS18', 'Gene', (236, 240))	('sarcoma', 'Phenotype', 'HP:0100242', (361, 368))	('SSX2', 'Gene', '6757', (241, 245))	('SSX1', 'Gene', (230, 234))	('synovial sarcoma', 'Disease', (352, 368))	('SS18', 'Gene', (258, 262))
544510	26250552	Two patients with active synovial sarcoma presented the SS18-SSX2 fusion gene phenotype, while five presented the more common SS18-SSX1 phenotype.	('SSX1', 'Gene', (131, 135))	('SSX2', 'Gene', '6757', (61, 65))	('SS18', 'Gene', '6760', (126, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('SSX2', 'Gene', (61, 65))	('SS18', 'Gene', '6760', (56, 60))	('SS18', 'Gene', (126, 130))	('active synovial sarcoma', 'Disease', 'MESH:D013584', (18, 41))	('patients', 'Species', '9606', (4, 12))	('SSX1', 'Gene', '6756', (131, 135))	('active synovial sarcoma', 'Disease', (18, 41))	('fusion gene', 'Var', (66, 77))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (25, 41))	('SS18', 'Gene', (56, 60))
544515	26250552	Of the ten miRNAs, which met these criteria (miR-99a-5p, miR-146b-5p, miR-148b-3p, miR-183-3p, miR-195-5p, miR-223-3p, miR-500b-3p, miR-505-3p, miR-589-5p and miR-1225-5p), nine miRNAs showed an increased expression in tumor patients and one miRNA was decreased (Table 1).	('miR-1225-5p', 'Var', (159, 170))	('miR-146b', 'Gene', '574447', (57, 65))	('tumor', 'Disease', (219, 224))	('miR-500b', 'Gene', (119, 127))	('increased', 'PosReg', (195, 204))	('miR-500b', 'Gene', '100422911', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('miR-505', 'Gene', (132, 139))	('miR-505', 'Gene', '574508', (132, 139))	('miR-183', 'Gene', (83, 90))	('miR-223', 'Gene', '407008', (107, 114))	('miR-589', 'Gene', '693174', (144, 151))	('miR-195', 'Gene', '406971', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('patients', 'Species', '9606', (225, 233))	('miR-148b', 'Gene', '442892', (70, 78))	('miR-148b', 'Gene', (70, 78))	('miR-146b', 'Gene', (57, 65))	('miR-195', 'Gene', (95, 102))	('expression', 'MPA', (205, 215))	('miR-223', 'Gene', (107, 114))	('miR-99a-5p', 'Var', (45, 55))	('miR-589', 'Gene', (144, 151))	('miR-183', 'Gene', '406959', (83, 90))
544517	26250552	2): miR-99a-5p, miR-146b-5p, miR-148b-3p, miR-195-5p, miR-223-3p, miR-500b-3p and miR-505-3p.	('miR-500b', 'Gene', (66, 74))	('miR-505', 'Gene', (82, 89))	('miR-505', 'Gene', '574508', (82, 89))	('miR-195', 'Gene', (42, 49))	('miR-223', 'Gene', '407008', (54, 61))	('miR-500b', 'Gene', '100422911', (66, 74))	('miR-195', 'Gene', '406971', (42, 49))	('miR-148b', 'Gene', '442892', (29, 37))	('miR-99a-5p', 'Var', (4, 14))	('miR-148b', 'Gene', (29, 37))	('miR-146b', 'Gene', (16, 24))	('miR-223', 'Gene', (54, 61))	('miR-146b', 'Gene', '574447', (16, 24))
544520	26250552	MiR-99a-5p and miR-195-5p were not significantly deregulated (Fig.	('MiR-99a-5p', 'Chemical', '-', (0, 10))	('miR-195', 'Gene', (15, 22))	('miR-195', 'Gene', '406971', (15, 22))	('MiR-99a-5p', 'Var', (0, 10))
544521	26250552	Comparing the screening cohort of active synovial sarcoma patients to patients with active MPNST (n = 3), six of the analyzed miRNAs were shown to be significantly upregulated: miR-99a-5p, miR-146b-5p, miR-148b-3p, miR-223-3p, miR-500b-3p and miR-505-3p.	('patients', 'Species', '9606', (70, 78))	('miR-148b', 'Gene', (202, 210))	('patients', 'Species', '9606', (58, 66))	('miR-500b', 'Gene', (227, 235))	('miR-146b', 'Gene', (189, 197))	('miR-99a-5p', 'Var', (177, 187))	('active synovial sarcoma', 'Disease', 'MESH:D013584', (34, 57))	('miR-505', 'Gene', (243, 250))	('active synovial sarcoma', 'Disease', (34, 57))	('upregulated', 'PosReg', (164, 175))	('miR-223', 'Gene', '407008', (215, 222))	('miR-500b', 'Gene', '100422911', (227, 235))	('miR-146b', 'Gene', '574447', (189, 197))	('miR-505', 'Gene', '574508', (243, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('miR-223', 'Gene', (215, 222))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (41, 57))	('miR-148b', 'Gene', '442892', (202, 210))
544528	26250552	MiR-99a-5p and miR-223-3p were also expressed in higher quantities, however differences were not statistically significant (Fig.	('MiR-99a-5p', 'Chemical', '-', (0, 10))	('miR-223', 'Gene', (15, 22))	('miR-223', 'Gene', '407008', (15, 22))	('MiR-99a-5p', 'Var', (0, 10))
544551	26250552	MiR-99a-5p was the only miRNA being higher expressed in synovial sarcoma tissue than in whole blood.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (56, 72))	('MiR-99a-5p', 'Chemical', '-', (0, 10))	('higher expressed', 'PosReg', (36, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('synovial sarcoma', 'Disease', 'MESH:D013584', (56, 72))	('MiR-99a-5p', 'Var', (0, 10))	('synovial sarcoma', 'Disease', (56, 72))
544555	26250552	Interestingly, miR-99a-5p is the only miRNA being higher expressed both in synovial sarcoma tissue compared to whole blood cells (Fig.	('higher', 'PosReg', (50, 56))	('synovial sarcoma', 'Disease', (75, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (75, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (75, 91))	('miR-99a-5p', 'Var', (15, 25))
544556	26250552	5a) and synovial sarcoma cells compared to THP-1 and Jurkat cells (Additional file 6A), thus indicating that the high expression levels of miR-99a-5p in synovial sarcoma patients might not result from a miRNA expression shift of peripheral blood cells but might actually be related to the tumor itself.	('patients', 'Species', '9606', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('Jurkat cells', 'CellLine', 'CVCL:0065', (53, 65))	('synovial sarcoma', 'Disease', (153, 169))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (8, 24))	('synovial sarcoma', 'Disease', 'MESH:D013584', (8, 24))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (153, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('tumor', 'Disease', (289, 294))	('synovial sarcoma', 'Disease', 'MESH:D013584', (153, 169))	('expression levels', 'MPA', (118, 135))	('synovial sarcoma', 'Disease', (8, 24))	('miR-99a-5p', 'Var', (139, 149))	('THP-1', 'Gene', '2736', (43, 48))	('THP-1', 'Gene', (43, 48))
544557	26250552	However, miR-99a-5p shows overlapping expression values in whole blood of patients with active synovial sarcoma compared to the different control groups (Figs.	('active synovial sarcoma', 'Disease', 'MESH:D013584', (88, 111))	('active synovial sarcoma', 'Disease', (88, 111))	('expression', 'MPA', (38, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('patients', 'Species', '9606', (74, 82))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (95, 111))	('miR-99a-5p', 'Var', (9, 19))
544561	26250552	showed that silencing of miR-146b-5p resulted in more NFkappaB p65 DNA binding activity and TNFalpha.	('TNFalpha', 'Gene', '7124', (92, 100))	('miR-146b', 'Gene', '574447', (25, 33))	('silencing', 'Var', (12, 21))	('p65', 'Gene', (63, 66))	('more', 'PosReg', (49, 53))	('TNFalpha', 'Gene', (92, 100))	('p65', 'Gene', '5970', (63, 66))	('miR-146b', 'Gene', (25, 33))
544570	26250552	Although validated miRNAs were not always significantly different in patients with active disease compared to the different control groups, miR-146b-5p, miR-500b-3p and miR-505-3p allow discrimination of patients of active synovial sarcoma patients from the different control groups, showing clear cut-off-values at approximately 18.5 (miR-146b-5p), 17.5 (miR-500b-3p) and 11.5 (miR-505-3p) 2-DeltaDeltaCt; while miR-99-5p, miR-148b-3p, miR-195-5p and miR-223-3p show overlapping expression values.	('miR-500b', 'Gene', (153, 161))	('active disease', 'Disease', 'OMIM:612348', (83, 97))	('miR-500b', 'Gene', '100422911', (153, 161))	('patients', 'Species', '9606', (69, 77))	('miR-146b', 'Gene', (140, 148))	('active disease', 'Disease', (83, 97))	('patients', 'Species', '9606', (204, 212))	('miR-505', 'Gene', (169, 176))	('miR-195', 'Gene', '406971', (437, 444))	('miR-500b', 'Gene', (356, 364))	('miR-146b', 'Gene', (336, 344))	('miR-223', 'Gene', (452, 459))	('miR-505', 'Gene', '574508', (169, 176))	('miR-500b', 'Gene', '100422911', (356, 364))	('active synovial sarcoma', 'Disease', 'MESH:D013584', (216, 239))	('miR-146b', 'Gene', '574447', (140, 148))	('active synovial sarcoma', 'Disease', (216, 239))	('miR-195', 'Gene', (437, 444))	('patients', 'Species', '9606', (240, 248))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (223, 239))	('miR-146b', 'Gene', '574447', (336, 344))	('miR-99-5p', 'Var', (413, 422))	('miR-148b', 'Gene', '442892', (424, 432))	('miR-223', 'Gene', '407008', (452, 459))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('miR-148b', 'Gene', (424, 432))	('miR-505', 'Gene', (379, 386))	('miR-505', 'Gene', '574508', (379, 386))
544603	21872822	In addition to EWS/FLI, variant translocation fusions belonging to the TET/ETS family have been identified in Ewing's sarcoma.	('FLI', 'Gene', '2314', (19, 22))	('FLI', 'Gene', (19, 22))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (110, 125))	('identified', 'Reg', (96, 106))	("Ewing's sarcoma", 'Disease', (110, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (110, 125))	('variant translocation fusions', 'Var', (24, 53))	('TET', 'Chemical', '-', (71, 74))	('ETS', 'Chemical', '-', (75, 78))
544605	21872822	EWS fusions with non-ETS transcription factor family members have been described in sarcomas that are clearly distinct from Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (124, 139))	("Ewing's sarcoma", 'Disease', (124, 139))	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('ETS', 'Chemical', '-', (21, 24))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (124, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('described', 'Reg', (71, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcomas', 'Disease', (84, 92))	('fusions', 'Var', (4, 11))	('EWS', 'Gene', (0, 3))
544609	21872822	Non-random chromosomal translocations are often characteristic features of a number of bone and soft-tissue sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (108, 116))	('sarcomas', 'Phenotype', 'HP:0100242', (108, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcomas', 'Disease', (108, 116))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (96, 116))	('Non-random chromosomal translocations', 'Var', (0, 37))
544610	21872822	At the pathophysiologic level, many of these translocations behave as aberrant transcription factor oncogenes that play crucial roles in tumor development by deregulating target gene expression.	('tumor', 'Disease', (137, 142))	('deregulating', 'Reg', (158, 170))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('translocations', 'Var', (45, 59))
544626	21872822	The t(11;22) rearrangement creates a fusion between the Ewing's sarcoma breakpoint region 1 gene (EWSR1) on chromosome 22 and the Friend leukemia virus integration site 1 gene (FLI1) on chromosome 11 (Fig.	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('EWSR1', 'Gene', '2130', (98, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('rearrangement', 'Var', (13, 26))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (56, 71))	("Ewing's sarcoma", 'Disease', (56, 71))	('rat', 'Species', '10116', (157, 160))	('EWSR1', 'Gene', (98, 103))	('FLI1', 'Gene', '2313', (177, 181))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (56, 71))	('FLI1', 'Gene', (177, 181))	('fusion', 'Var', (37, 43))	('Friend leukemia', 'Disease', (130, 145))	('Friend leukemia', 'Disease', 'MESH:D007938', (130, 145))
544638	21872822	First, the translocation causes EWS/FLI to be constitutively expressed from the native EWSR1 promoter (FLI1 promoter expression is limited to hematopoietic and neural crest lineages, and is non-functional in Ewing's sarcoma cells).	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('FLI1', 'Gene', (103, 107))	('EWSR1', 'Gene', (87, 92))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (208, 223))	('FLI1', 'Gene', '2313', (103, 107))	("Ewing's sarcoma", 'Disease', (208, 223))	('translocation', 'Var', (11, 24))	('EWSR1', 'Gene', '2130', (87, 92))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (208, 223))	('FLI', 'Gene', '2314', (103, 106))	('FLI', 'Gene', (103, 106))	('FLI', 'Gene', '2314', (36, 39))	('FLI', 'Gene', (36, 39))
544655	21872822	However, that the DNA-binding property of EWS/FLI is indispensable to its oncogenic potential has been clearly demonstrated in patient-derived Ewing's sarcoma cells by the inability of DNA-binding mutant versions of EWS/FLI to rescue transformation when EWS/FLI is down-regulated via an RNAi approach, as well as the lack of any identified Ewing's sarcoma patient tumor sample expressing a DNA-binding deficient form of EWS/FLI.	("Ewing's sarcoma", 'Disease', (143, 158))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('FLI', 'Gene', (46, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	("Ewing's sarcoma", 'Disease', (340, 355))	('rat', 'Species', '10116', (118, 121))	('patient', 'Species', '9606', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (348, 355))	('FLI', 'Gene', (220, 223))	('FLI', 'Gene', '2314', (46, 49))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (143, 158))	('FLI', 'Gene', '2314', (220, 223))	('patient', 'Species', '9606', (356, 363))	('mutant', 'Var', (197, 203))	('FLI', 'Gene', (258, 261))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (143, 158))	('inability', 'NegReg', (172, 181))	('tumor', 'Disease', (364, 369))	('FLI', 'Gene', (424, 427))	('transformation', 'CPA', (234, 248))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (340, 355))	('FLI', 'Gene', '2314', (258, 261))	('down-regulated', 'NegReg', (265, 279))	('tumor', 'Disease', 'MESH:D009369', (364, 369))	('FLI', 'Gene', '2314', (424, 427))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (340, 355))
544658	21872822	In addition to regulating some target genes by binding to bona fide motifs used by ETS factors, EWS/FLI was also found to bind GGAA-microsatellite repeat sequences in promoters of target genes.	('FLI', 'Gene', '2314', (100, 103))	('FLI', 'Gene', (100, 103))	('GGAA-microsatellite', 'Var', (127, 146))	('bind', 'Interaction', (122, 126))	('ETS', 'Chemical', '-', (83, 86))
544659	21872822	Some of these genes (NR0B1, CAV1, and GSTM4) are necessary for EWS/FLI mediated oncogenesis, highlighting the importance of transcriptional regulation via microsatellite repeats in the pathogenesis of Ewing's sarcoma.	('NR0B1', 'Gene', (21, 26))	('microsatellite', 'Var', (155, 169))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (201, 216))	("Ewing's sarcoma", 'Disease', (201, 216))	('FLI', 'Gene', '2314', (67, 70))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (201, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('FLI', 'Gene', (67, 70))
544661	21872822	Identification of microsatellite repeats in EWS/FLI-bound chromatin is clearly an example of how advances can be made in unraveling the mechanism of disease pathogenesis using high-throughput genomic approaches.	('FLI', 'Gene', (48, 51))	('microsatellite repeats', 'Var', (18, 40))	('FLI', 'Gene', '2314', (48, 51))
544675	21872822	The second most common subtype (originally called a "type II" fusion) fuses exon 7 of EWSR1 to exon 5 of FLI1 (Fig.	('EWSR1', 'Gene', (86, 91))	('FLI1', 'Gene', (105, 109))	('EWSR1', 'Gene', '2130', (86, 91))	('FLI1', 'Gene', '2313', (105, 109))	('fuses', 'Var', (70, 75))
544677	21872822	There is data to suggest that the EWS/FLI type 1 fusion has reduced transactivation potential in Ewing's sarcoma cell lines when comparison to the other fusion subtypes and that this may have prognostic significance.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (97, 112))	('FLI', 'Gene', '2314', (38, 41))	("Ewing's sarcoma", 'Disease', (97, 112))	('transactivation potential', 'MPA', (68, 93))	('reduced', 'NegReg', (60, 67))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (97, 112))	('fusion', 'Var', (49, 55))	('FLI', 'Gene', (38, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))
544684	21872822	Many different members of the ETS family have been shown to be involved in oncogenesis, predominantly, by chromosomal translocations that fuse ETS members to a variety of amino-terminal partners.	('ETS', 'Chemical', '-', (30, 33))	('fuse', 'NegReg', (138, 142))	('involved', 'Reg', (63, 71))	('ETS', 'Chemical', '-', (143, 146))	('chromosomal translocations', 'Var', (106, 132))	('oncogenesis', 'Disease', (75, 86))
544687	21872822	These alternate translocations result in fusions of the EWSR1 gene with one of four different ETS genes including ERG (ETS-related gene), ETV1 (ETS-variant gene 1), ETV4 (ETS variant gene 4, also called E1AF) or FEV (fifth Ewing sarcoma variant) (Fig.	('ETS variant gene 4', 'Gene', (171, 189))	('ETV1', 'Gene', (138, 142))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (223, 236))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (223, 236))	('ETS variant gene 4', 'Gene', '2118', (171, 189))	('ETV4', 'Gene', (165, 169))	('ETS', 'Chemical', '-', (171, 174))	('ERG', 'Gene', (114, 117))	('EWSR1', 'Gene', '2130', (56, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('ETS-related gene', 'Gene', '2078', (119, 135))	('E1AF', 'Gene', (203, 207))	('ETS-variant gene 1', 'Gene', (144, 162))	('Ewing sarcoma', 'Disease', (223, 236))	('fusions', 'Var', (41, 48))	('E1AF', 'Gene', '2118', (203, 207))	('ETS', 'Chemical', '-', (119, 122))	('EWSR1', 'Gene', (56, 61))	('ETS-related gene', 'Gene', (119, 135))	('ETS-variant gene 1', 'Gene', '2115', (144, 162))	('ETS', 'Chemical', '-', (144, 147))	('ETS', 'Chemical', '-', (94, 97))	('result in', 'Reg', (31, 40))
544692	21872822	The most common of the alternate translocations is t(21;22)(q22;q12), found in approximately 10% of Ewing's sarcoma tumors.	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (100, 115))	("Ewing's sarcoma tumors", 'Disease', (100, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('t(21;22)(q22;q12', 'Var', (51, 67))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (51, 68))	("Ewing's sarcoma tumors", 'Disease', 'MESH:C563168', (100, 122))
544707	21872822	Although the carboxy-terminal ETS fusion partners have varied tissue-restricted expression patterns, tumor-specific expression of the fusions is accomplished by the strong EWSR1 gene promoter.	('EWSR1', 'Gene', (172, 177))	('ETS', 'Chemical', '-', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('EWSR1', 'Gene', '2130', (172, 177))	('fusions', 'Var', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
544710	21872822	This cooperative interaction has been established for ETS1-AP1, ERG-AP1 and also for EWS/FLI-AP1, further supporting the idea that various EWS/ETS fusions dysregulate a common target gene pool in Ewing's sarcoma.	('FLI', 'Gene', '2314', (89, 92))	('ETS', 'Chemical', '-', (54, 57))	("Ewing's sarcoma", 'Disease', (196, 211))	('AP1', 'Gene', (93, 96))	('fusions', 'Var', (147, 154))	('AP1', 'Gene', '2353', (93, 96))	('AP1', 'Gene', (68, 71))	('AP1', 'Gene', '2353', (68, 71))	('AP1', 'Gene', (59, 62))	('AP1', 'Gene', '2353', (59, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('EWS/ETS', 'Gene', (139, 146))	('ETS1', 'Gene', '2113', (54, 58))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (196, 211))	('FLI', 'Gene', (89, 92))	('ETS', 'Chemical', '-', (143, 146))	('dysregulate', 'Reg', (155, 166))	('ETS1', 'Gene', (54, 58))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (196, 211))	('rat', 'Species', '10116', (10, 13))
544711	21872822	A recurring feature of the various translocation fusions in Ewing's sarcoma is their mutual exclusivity, suggesting that these chimeric proteins can replace each other in the oncogenic pathways leading to Ewing's sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('oncogenic pathways', 'Pathway', (175, 193))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (205, 220))	('translocation', 'Var', (35, 48))	("Ewing's sarcoma", 'Disease', (205, 220))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (60, 75))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (205, 220))	("Ewing's sarcoma", 'Disease', (60, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (60, 75))
544713	21872822	All five fusions, however, did cause NIH3T3 cells to form tumors when injected into immunodeficient mice.	('immunodeficient', 'Disease', 'MESH:D007153', (84, 99))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('immunodeficient', 'Disease', (84, 99))	('tumors', 'Disease', (58, 64))	('fusions', 'Var', (9, 16))	('mice', 'Species', '10090', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('cause', 'Reg', (31, 36))	('NIH3T3', 'CellLine', 'CVCL:0594', (37, 43))
544715	21872822	One study found that 11 of 12 cases (92%) of Ewing's sarcomas harboring EWS/FEV, EWS/ETV1, or EWS/ETV4 presented with extraosseous tumors.	('extraosseous tumors', 'Disease', (118, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('EWS/ETV4', 'Var', (94, 102))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (45, 61))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('extraosseous tumors', 'Disease', 'MESH:D009369', (118, 137))	('presented', 'Reg', (103, 112))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (45, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('EWS/ETV1', 'Var', (81, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	("Ewing's sarcomas", 'Disease', (45, 61))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (45, 61))
544716	21872822	Whether this represents a unique aspect of the tumor biology of the rare EWS/ETS variants, or whether this represents a reporting bias, is unknown at this time.	('ETS', 'Chemical', '-', (77, 80))	('EWS/ETS', 'Gene', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('variants', 'Var', (81, 89))
544724	21872822	Indeed, identification of TLS/ERG and TLS/FEV translocation fusions supports the concept that all possible combinations of TET/ETS fusions might contribute to the development of Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (178, 193))	('TLS', 'Gene', '2521', (38, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (178, 193))	('TET', 'Chemical', '-', (123, 126))	('fusions', 'Var', (60, 67))	('ETS', 'Chemical', '-', (127, 130))	('TLS', 'Gene', (26, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('TLS', 'Gene', '2521', (26, 29))	('contribute', 'Reg', (145, 155))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (178, 193))	('TLS', 'Gene', (38, 41))
544726	21872822	One can also imagine the identification of novel TAF15/ETS fusions in Ewing's sarcoma, since members of the TET family of proteins behave in a similar fashion by contributing a strong amino-terminal transactivation domain when fused to members of the ETS family of transcription factors.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (70, 85))	('TAF15', 'Gene', '8148', (49, 54))	("Ewing's sarcoma", 'Disease', (70, 85))	('amino-terminal transactivation domain', 'MPA', (184, 221))	('ETS', 'Chemical', '-', (251, 254))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (70, 85))	('TET', 'Chemical', '-', (108, 111))	('TAF15', 'Gene', (49, 54))	('ETS', 'Chemical', '-', (55, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('fusions', 'Var', (59, 66))
544734	21872822	For example, it is possible that TET/ETS fusions also regulate gene expression by interfering with the normal function of TET family members or ETS family members via a "dominant-negative" mechanism.	('TET', 'Chemical', '-', (33, 36))	('interfering', 'NegReg', (82, 93))	('regulate', 'Reg', (54, 62))	('ETS', 'Chemical', '-', (37, 40))	('TET', 'Chemical', '-', (122, 125))	('function', 'MPA', (110, 118))	('ETS', 'Chemical', '-', (144, 147))	('gene expression', 'MPA', (63, 78))	('fusions', 'Var', (41, 48))
544737	21872822	Regardless of our lack of comprehensive understanding of how TET/ETS fusions function, there is general agreement that fusion of a TET family member to an ETS family member creates a fusion protein that mimics the domain structure of EWS/FLI.	('TET', 'Chemical', '-', (61, 64))	('fusion', 'Var', (119, 125))	('FLI', 'Gene', '2314', (238, 241))	('ETS', 'Chemical', '-', (65, 68))	('ETS', 'Chemical', '-', (155, 158))	('FLI', 'Gene', (238, 241))	('TET', 'Chemical', '-', (131, 134))
544747	21872822	Dephosphorylation of the wild-type protein causes functional activation and nuclear translocation, which then results in formation of a complex between NFATc2 and AP1 proteins (FOS and JUN).	('FOS', 'Gene', '2353', (177, 180))	('functional activation', 'MPA', (50, 71))	('NFATc2', 'Gene', '4773', (152, 158))	('complex', 'Interaction', (136, 143))	('FOS', 'Gene', (177, 180))	('AP1', 'Gene', (163, 166))	('NFATc2', 'Gene', (152, 158))	('nuclear', 'CPA', (76, 83))	('Dephosphorylation', 'Var', (0, 17))	('AP1', 'Gene', '2353', (163, 166))	('results in', 'Reg', (110, 120))
544749	21872822	In the case of the EWS/NFATc2 fusion, the normal tissue-restricted expression pattern of NFATc2 is overcome by fusion with the constitutively active EWSR1 gene promoter, as is the case for EWS/ETS fusions.	('fusion', 'Var', (30, 36))	('EWSR1', 'Gene', '2130', (149, 154))	('NFATc2', 'Gene', '4773', (23, 29))	('NFATc2', 'Gene', '4773', (89, 95))	('EWSR1', 'Gene', (149, 154))	('fusion', 'Var', (111, 117))	('expression', 'MPA', (67, 77))	('NFATc2', 'Gene', (23, 29))	('ETS', 'Chemical', '-', (193, 196))	('NFATc2', 'Gene', (89, 95))
544753	21872822	In addition to the EWS/NFATc2 fusion, fusions between EWS and other transcription factors have been described in "Ewing's-like tumors."	("Ewing's-like tumors", 'Disease', 'MESH:C563168', (114, 133))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('NFATc2', 'Gene', '4773', (23, 29))	('described', 'Reg', (100, 109))	("Ewing's-like tumors", 'Phenotype', 'HP:0012254', (114, 133))	('EWS', 'Gene', (54, 57))	("Ewing's-like tumors", 'Disease', (114, 133))	('NFATc2', 'Gene', (23, 29))	('fusions', 'Var', (38, 45))
544760	21872822	Histopathologically, tumor cells harboring the EWS/POU5F1 fusion displayed a highly undifferentiated phenotype, stained positive for vimentin and neuron specific enolase (resembling some features of Ewing's sarcoma), but were negative for CD99 staining (Table 1).	('CD99', 'Gene', (239, 243))	("Ewing's sarcoma", 'Disease', (199, 214))	('positive', 'Reg', (120, 128))	('tumor', 'Disease', (21, 26))	('fusion', 'Var', (58, 64))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (199, 214))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('neuron specific enolase', 'Gene', '2026', (146, 169))	('vimentin', 'Gene', '7431', (133, 141))	('CD99', 'Gene', '4267', (239, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('neuron specific enolase', 'Gene', (146, 169))	('vimentin', 'Gene', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('POU5F1', 'Gene', '5460', (51, 57))	('POU5F1', 'Gene', (51, 57))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (199, 214))
544774	21872822	While this is an important indicator of oncogenic potential, it appears that NIH3T3 cells expressing EWS/ETS fusions are a poor mimic of Ewing's sarcoma, as the gene expression pattern induced by the fusions in those cells does not recapitulate the gene expression pattern of bona fide Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (137, 152))	('ETS', 'Chemical', '-', (105, 108))	("Ewing's sarcoma", 'Disease', (137, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (286, 301))	("Ewing's sarcoma", 'Disease', (286, 301))	('fusions', 'Var', (109, 116))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (286, 301))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (137, 152))	('NIH3T3', 'CellLine', 'CVCL:0594', (77, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (294, 301))
544776	21872822	Considering the structural and functional disparities between EWS/ETS and EWS/SMARCA5, an important underlying question is whether the EWS/SMARCA5 fusion gives rise to Ewing's sarcoma, or does it give rise to a different tumor type that bears some resemblance to Ewing's sarcoma at the histopathological level, but is a completely different tumor at the molecular level?	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('gives rise to', 'Reg', (154, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (168, 183))	('fusion', 'Var', (147, 153))	('give rise to', 'Reg', (196, 208))	('ETS', 'Chemical', '-', (66, 69))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (168, 183))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (263, 278))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (341, 346))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (263, 278))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	("Ewing's sarcoma", 'Disease', (168, 183))	('EWS/SMARCA5 fusion', 'Var', (135, 153))	("Ewing's sarcoma", 'Disease', (263, 278))
544781	21872822	In AT/RT, loss of the SMARCB1 gene causes aberrant cell cycle progression, partly via the downregulation of p16INK4a, a tumor suppressor.	('loss', 'Var', (10, 14))	('p16INK4a', 'Gene', '1029', (108, 116))	('cell cycle progression', 'CPA', (51, 73))	('SMARCB1', 'Gene', '6598', (22, 29))	('SMARCB1', 'Gene', (22, 29))	('AT', 'Disease', 'None', (3, 5))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('aberrant cell cycle', 'Phenotype', 'HP:0011018', (42, 61))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('p16INK4a', 'Gene', (108, 116))	('downregulation', 'NegReg', (90, 104))	('causes', 'Reg', (35, 41))	('tumor', 'Disease', (120, 125))
544785	21872822	Perhaps any inactivation of the ISWI or the SWI/SNF chromatin remodeling complexes can cause tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('cause', 'Reg', (87, 92))	('SWI/SNF', 'Gene', (44, 51))	('inactivation', 'Var', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
544787	21872822	This inversion results in the fusion of the 5' portion of the EWSR1 gene to a newly identified zinc finger sarcoma gene (ZSG).	('ZSG', 'Gene', (121, 124))	('fusion', 'Var', (30, 36))	('results in', 'Reg', (15, 25))	('zinc finger sarcoma gene', 'Gene', '23598', (95, 119))	('EWSR1', 'Gene', (62, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('EWSR1', 'Gene', '2130', (62, 67))	('ZSG', 'Gene', '23598', (121, 124))	('zinc finger sarcoma gene', 'Gene', (95, 119))
544793	21872822	Additional analysis of the tumor from which this fusion was identified revealed a rearrangement of the second ZSG allele (in addition to the primary translocation), leading to complete loss of wild-type ZSG expression.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('rearrangement', 'Var', (82, 95))	('ZSG', 'Gene', (110, 113))	('tumor', 'Disease', (27, 32))	('ZSG', 'Gene', (203, 206))	('ZSG', 'Gene', '23598', (203, 206))	('ZSG', 'Gene', '23598', (110, 113))	('expression', 'MPA', (207, 217))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('loss', 'NegReg', (185, 189))
544799	21872822	Hence, the chimeric products EWS/WT1 and EWS/ZSG share similarities of being zinc finger proteins, lacking amino-terminal repression domains as a result of the translocations, and each occurs in tumors that lack CD99 expression.	('lacking', 'NegReg', (99, 106))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('CD99', 'Gene', (212, 216))	('EWS/WT1', 'Gene', (29, 36))	('amino-terminal repression domains', 'MPA', (107, 140))	('translocations', 'Var', (160, 174))	('occurs', 'Reg', (185, 191))	('ZSG', 'Gene', '23598', (45, 48))	('EWS/WT1', 'Gene', '7490;2130', (29, 36))	('CD99', 'Gene', '4267', (212, 216))	('ZSG', 'Gene', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
544802	21872822	In 2007 one sarcoma case was reported with a fusion of the EWSR1 gene with SP3, a gene of the Sp zinc finger family.	('EWSR1', 'Gene', (59, 64))	('SP3', 'Gene', '6670', (75, 78))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('EWSR1', 'Gene', '2130', (59, 64))	('sarcoma', 'Disease', (12, 19))	('fusion', 'Var', (45, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('SP3', 'Gene', (75, 78))
544805	21872822	A second longer chimeric EWS/SP3 fusion was also detected in the tumor, generated by the fusion of EWSR1 exon 8 and SP3 exon 6 with a 31 nucleotide sequence insertion to restore the reading frame.	('reading frame', 'MPA', (182, 195))	('SP3', 'Gene', (116, 119))	('fusion', 'Var', (89, 95))	('EWSR1', 'Gene', '2130', (99, 104))	('tumor', 'Disease', (65, 70))	('SP3', 'Gene', '6670', (29, 32))	('rat', 'Species', '10116', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('SP3', 'Gene', '6670', (116, 119))	('SP3', 'Gene', (29, 32))	('EWSR1', 'Gene', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
544811	21872822	This finding further highlights the importance of transactivating functions driven by aberrant fusion oncogenes in sarcomas and suggests that the EWS/zinc-finger fusion proteins participate in tumorigenesis through transcriptional deregulation.	('EWS/zinc-finger', 'Protein', (146, 161))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('-finger fusion', 'Phenotype', 'HP:0009700', (154, 168))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('transcriptional', 'MPA', (215, 230))	('participate', 'Reg', (178, 189))	('aberrant', 'Var', (86, 94))	('sarcomas', 'Disease', (115, 123))	('tumor', 'Disease', (193, 198))
544812	21872822	As was the question with the EWS/ZSG fusion discussed above, the question here again is whether EWS/SP3 fusions give rise to variant-small round cell tumor (SRCTs) or do they cause Ewing's-like tumors that share phenotypic resemblances, but are molecularly distinct, from Ewing's sarcoma?	('give rise to', 'Reg', (112, 124))	('ZSG', 'Gene', '23598', (33, 36))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (272, 287))	('cause', 'Reg', (175, 180))	("Ewing's-like tumors", 'Disease', (181, 200))	('SP3', 'Gene', '6670', (100, 103))	("Ewing's-like tumors", 'Disease', 'MESH:C563168', (181, 200))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (194, 199))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (272, 287))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('ZSG', 'Gene', (33, 36))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	("Ewing's sarcoma", 'Disease', (272, 287))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (150, 155))	('fusions', 'Var', (104, 111))	('SP3', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (280, 287))	("Ewing's-like tumors", 'Phenotype', 'HP:0012254', (181, 200))
544828	21872822	This model also did not give rise to sarcomas spontaneously and did so only when the p53 gene was simultaneously mutated.	('p53', 'Gene', (85, 88))	('sarcomas', 'Disease', 'MESH:D012509', (37, 45))	('sarcomas', 'Phenotype', 'HP:0100242', (37, 45))	('mutated', 'Var', (113, 120))	('p53', 'Gene', '7157', (85, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('sarcomas', 'Disease', (37, 45))
544831	21872822	This model further underscores the significance of cellular context and brings up an important concept that additional mutations may be required to cooperate with EWS/FLI in order to give rise to Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (196, 211))	('FLI', 'Gene', '2314', (167, 170))	('rat', 'Species', '10116', (153, 156))	('FLI', 'Gene', (167, 170))	('give rise to', 'Reg', (183, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (196, 211))	('mutations', 'Var', (119, 128))	("Ewing's sarcoma", 'Disease', (196, 211))
544841	21872822	Homologous recombination at site-specific sequences has been suggested as the potential mechanism of chromosomal translocations in human hematological malignancies such as lymphoid neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (181, 189))	('hematological malignancies', 'Disease', (137, 163))	('human', 'Species', '9606', (131, 136))	('lymphoid neoplasms', 'Disease', (172, 190))	('hematological malignancies', 'Disease', 'MESH:D019337', (137, 163))	('neoplasms', 'Phenotype', 'HP:0002664', (181, 190))	('lymphoid neoplasms', 'Disease', 'MESH:D008223', (172, 190))	('hematological malignancies', 'Phenotype', 'HP:0004377', (137, 163))	('lymphoid neoplasms', 'Phenotype', 'HP:0002665', (172, 190))	('Homologous', 'Var', (0, 10))
544843	21872822	This study suggested that the generation of chromosomal translocations in Ewing's sarcoma may be mediated by a mechanism of illegitimate recombination that initiates the translocation event independently on each chromosome before interchromosomal joining.	('mediated by', 'Reg', (97, 108))	('chromosomal translocations', 'Var', (44, 70))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (74, 89))	('rat', 'Species', '10116', (34, 37))	("Ewing's sarcoma", 'Disease', (74, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (74, 89))
544855	21872822	While the vast majority of Ewing's sarcomas would harbor EWS/FLI fusions, the ongoing identification of other TET/ETS fusions provided some support that "non-EWS/FLI containing Ewing's sarcomas" simply had one of the rare TET/ETS variants instead.	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (27, 43))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (27, 42))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (177, 192))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (27, 43))	('ETS', 'Chemical', '-', (226, 229))	('TET', 'Chemical', '-', (110, 113))	('ETS', 'Chemical', '-', (114, 117))	("Ewing's sarcomas", 'Disease', (27, 43))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (177, 193))	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('TET', 'Chemical', '-', (222, 225))	('FLI', 'Gene', (61, 64))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (177, 193))	('fusions', 'Var', (65, 72))	('FLI', 'Gene', (162, 165))	('FLI', 'Gene', '2314', (61, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (185, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	("Ewing's sarcomas", 'Disease', (177, 193))	('FLI', 'Gene', '2314', (162, 165))
544862	21872822	In this scenario, the non-TET/ETS fusions are indeed oncogenic, but they regulate a different set of target genes than the TET/ETS fusions do.	('TET', 'Chemical', '-', (26, 29))	('ETS', 'Chemical', '-', (30, 33))	('TET', 'Chemical', '-', (123, 126))	('ETS', 'Chemical', '-', (127, 130))	('regulate', 'Reg', (73, 81))	('non-TET/ETS fusions', 'Var', (22, 41))
544865	21872822	One conceptual possibility is that the various TET/ETS and non-TET/ETS fusions give rise to sarcomas that bear phenotypic resemblance but may occur in different cell types.	('ETS', 'Chemical', '-', (67, 70))	('sarcomas', 'Disease', (92, 100))	('TET', 'Chemical', '-', (47, 50))	('give rise to', 'Reg', (79, 91))	('fusions', 'Var', (71, 78))	('TET', 'Chemical', '-', (63, 66))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('ETS', 'Chemical', '-', (51, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
544868	21872822	Thus, although unlikely, it is possible that there are yet-to-be-discovered "driver" mutations in the Ewing's-like tumors that mediate oncogenesis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	("Ewing's-like tumors", 'Disease', (102, 121))	("Ewing's-like tumors", 'Disease', 'MESH:C563168', (102, 121))	('mutations', 'Var', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	("Ewing's-like tumors", 'Phenotype', 'HP:0012254', (102, 121))
544878	21872822	Thus, the non-TET/ETS fusions might modulate the expression of a limited set of genes, while other required genes might be "contributed" by the tumor cell-of-origin.	('tumor', 'Disease', (144, 149))	('modulate', 'Reg', (36, 44))	('non-TET/ETS fusions', 'Var', (10, 29))	('expression', 'MPA', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('TET', 'Chemical', '-', (14, 17))	('ETS', 'Chemical', '-', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
544885	21872822	The non-TET/ETS fusions may also be able to participate productively in such signaling pathways and thus contribute to "Ewing's-like" oncogenesis.	('contribute', 'Reg', (105, 115))	('participate', 'Reg', (44, 55))	('non-TET/ETS', 'Var', (4, 15))	('TET', 'Chemical', '-', (8, 11))	('ETS', 'Chemical', '-', (12, 15))
544887	21872822	If each of the rare TET/ETS and non-TET/ETS fusion variants occurs in 1% of cases or less, these will contribute to a very small portion, and a very small total number of tumors.	('TET', 'Chemical', '-', (36, 39))	('ETS', 'Chemical', '-', (40, 43))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('variants', 'Var', (51, 59))	('TET', 'Chemical', '-', (20, 23))	('ETS', 'Chemical', '-', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
544895	21872822	For example, if the non-TET/ETS tumors harbor specific mutations that inactivate important tumor suppressors, such observations may allow researchers to determine whether these tumor suppressors are inhibited by a TET/ETS fusion in Ewing's sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (232, 247))	('tumors', 'Disease', (32, 38))	('tumor', 'Disease', (91, 96))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (232, 247))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TET', 'Chemical', '-', (24, 27))	('ETS', 'Chemical', '-', (28, 31))	('tumor', 'Disease', (177, 182))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('mutations', 'Var', (55, 64))	('ETS', 'Chemical', '-', (218, 221))	('TET', 'Chemical', '-', (214, 217))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('inhibited', 'NegReg', (199, 208))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	("Ewing's sarcoma", 'Disease', (232, 247))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('inactivate', 'NegReg', (70, 80))
544896	21872822	Indeed, one significant problem in understanding the oncogenic program mediated by EWS/FLI and other TET/ETS fusions is that there are hundreds to thousands of genes dysregulated by the fusion.	('ETS', 'Chemical', '-', (105, 108))	('FLI', 'Gene', '2314', (87, 90))	('fusion', 'Var', (186, 192))	('FLI', 'Gene', (87, 90))	('TET', 'Chemical', '-', (101, 104))
544905	21872822	Large scale genomic approaches followed by detailed molecular and functional studies could be performed to dissect out the shared, as well as the divergent, mechanisms driven by the rare non-TET/ETS fusions.	('non-TET/ETS', 'Protein', (187, 198))	('ETS', 'Chemical', '-', (195, 198))	('fusions', 'Var', (199, 206))	('TET', 'Chemical', '-', (191, 194))
544938	33911779	Hornick and Fletcher reported a recurrent translocation t(7:19)(q22:q13) resulting in fusion of SERPINE1 and FOSB in their studies of PMH.	('FOSB', 'Gene', (109, 113))	('FOSB', 'Gene', '2354', (109, 113))	('fusion', 'Var', (86, 92))	('t(7:19)(q22:q13)', 'STRUCTURAL_ABNORMALITY', 'None', (56, 72))	('SERPINE1', 'Gene', '5054', (96, 104))	('SERPINE1', 'Gene', (96, 104))
544969	31615558	Reverse transcriptase-polymerase chain reaction showed the same-sized electrophoretic bands indicating JAZF1-SUZ12 gene fusion shared by the three uterine tumors and a focal tumor extension into the extrauterine vein.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('JAZF1', 'Gene', '221895', (103, 108))	('fusion', 'Var', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('uterine tumor', 'Phenotype', 'HP:0010784', (147, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('JAZF1', 'Gene', (103, 108))	('SUZ12', 'Gene', '23512', (109, 114))	('uterine tumors', 'Phenotype', 'HP:0010784', (147, 161))	('SUZ12', 'Gene', (109, 114))
544974	31615558	They are sorted by the 2014 World Health Organization (WHO) classification into four categories: endometrial stromal nodule, low-grade endometrial stromal sarcoma (ESS), high-grade ESS, and undifferentiated uterine sarcoma.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (207, 222))	('ESS', 'Disease', 'MESH:D018203', (164, 167))	('sarcoma', 'Disease', (155, 162))	('high-grade', 'Disease', (170, 180))	('low-grade', 'Var', (125, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcoma', 'Disease', 'MESH:D012509', (215, 222))	('ESS', 'Disease', 'MESH:D018203', (181, 184))	('ESS', 'Disease', (164, 167))	('endometrial stromal sarcoma', 'Disease', (135, 162))	('sarcoma', 'Disease', (215, 222))	('endometrial stromal nodule', 'Disease', (97, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('ESS', 'Disease', (181, 184))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (135, 162))
544997	31615558	The t (7;17) translocation resulting in fusion of the JAZF1 gene (on chromosome 7p15) to the SUZ12 gene (on 17q21) represents the most common chromosomal rearrangement in low-grade endometrial stromal tumors, being detected in approximately 30% of low-grade ESS and 50% of endometrial stromal nodules tested.	('fusion', 'Var', (40, 46))	('SUZ12', 'Gene', '23512', (93, 98))	('endometrial stromal tumors', 'Disease', (181, 207))	('JAZF1', 'Gene', (54, 59))	('SUZ12', 'Gene', (93, 98))	('ESS', 'Disease', 'MESH:D018203', (258, 261))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('JAZF1', 'Gene', '221895', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('endometrial stromal tumors', 'Disease', 'MESH:D036821', (181, 207))	('ESS', 'Disease', (258, 261))
545001	31615558	Immunohistochemically, the round-cell component usually shows > 70% cyclin D1 nuclear staining of the tumor cells with homogenous moderate to strong intensity, in contrast to the form of scattered positive cells (< 5%) in classic JAZF1 rearranged endometrial stromal tumors.	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('endometrial stromal tumors', 'Disease', (247, 273))	('rearranged', 'Var', (236, 246))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('JAZF1', 'Gene', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('cyclin D1', 'Gene', '595', (68, 77))	('tumor', 'Disease', (267, 272))	('JAZF1', 'Gene', '221895', (230, 235))	('cyclin D1', 'Gene', (68, 77))	('endometrial stromal tumors', 'Disease', 'MESH:D036821', (247, 273))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
545112	21173924	In 0.5-5% of seropositive transplant recipients reactivated HHV-8 leads to Kaposi sarcoma.	('reactivated', 'Var', (48, 59))	('Kaposi sarcoma', 'Disease', (75, 89))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (75, 89))	('HHV-8', 'Gene', (60, 65))	('HHV-8', 'Species', '37296', (60, 65))	('leads to', 'Reg', (66, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (75, 89))
545137	32875577	What 20 years of research has taught us about the TP53 p.R337H mutation The p53 tumor suppressor transcriptionally regulates a myriad of genes involved in cell cycle control, DNA repair, cell survival, and cell metabolism and represents one of the most well-studied inhibitors of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('p53', 'Gene', (76, 79))	('p.R337H', 'Var', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('TP53', 'Gene', '7157', (50, 54))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('p.R337H', 'Mutation', 'rs121912664', (55, 62))	('regulates', 'Reg', (115, 124))	('TP53', 'Gene', (50, 54))	('cell', 'MPA', (155, 159))	('tumor', 'Disease', (280, 285))	('myriad of genes', 'MPA', (127, 142))
545138	32875577	Since the discovery of TP53 in 1979, somatic mutations have been shown to be extremely common; more than 50% of human cancers carry loss-of-function mutations in TP53.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('mutations', 'Var', (149, 158))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('loss-of-function', 'NegReg', (132, 148))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('human', 'Species', '9606', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
545139	32875577	Inherited or germline TP53 mutations are rare and are involved in complex hereditary cancer predisposition disorders, and affected family members can develop diverse tumor types and multiple primary cancers at young ages.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('tumor', 'Disease', (166, 171))	('hereditary cancer', 'Disease', 'MESH:D009369', (74, 91))	('hereditary cancer', 'Disease', (74, 91))	('TP53', 'Gene', '7157', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('develop', 'PosReg', (150, 157))	('cancers', 'Disease', (199, 206))	('TP53', 'Gene', (22, 26))	('involved', 'Reg', (54, 62))
545140	32875577	In Brazil, a fascinating history of p53 and cancer predisposition began in the year 2000 with identification of the TP53 p.R337H mutation in close association with the development of adrenocortical tumors.	('TP53', 'Gene', (116, 120))	('adrenocortical tumors', 'Disease', (183, 204))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('p.R337H', 'Var', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('association', 'Reg', (147, 158))	('p.R337H', 'Mutation', 'rs121912664', (121, 128))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('TP53', 'Gene', '7157', (116, 120))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (183, 204))	('men', 'Species', '9606', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
545141	32875577	This review highlights the contributions of TP53 p.R337H research over the last 20 years, the findings of which have sparked passionate debate among researchers worldwide, to understanding cancer predisposition in Brazilian individuals and families.	('p.R337H', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('p.R337H', 'Mutation', 'rs121912664', (49, 56))	('TP53', 'Gene', '7157', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('TP53', 'Gene', (44, 48))	('cancer', 'Disease', (189, 195))
545142	32875577	This review highlights the impact of TP53 p.R337H research in cancer predisposition studies in the Brazilian population.	('p.R337H', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('p.R337H', 'Mutation', 'rs121912664', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))
545152	32875577	6   Acquired mutations in TP53 are frequent and are observed in ~50% of human cancers 7 ; they are most prevalent in small cell lung, colorectal, head/neck, and epithelial ovarian cancers (according to the International Agency for Research on Cancer [IARC] database).	('Cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('epithelial ovarian cancers', 'Disease', (161, 187))	('TP53', 'Gene', '7157', (26, 30))	('head/neck', 'Disease', (146, 155))	('prevalent', 'Reg', (104, 113))	('Cancer', 'Disease', (243, 249))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('ovarian cancer', 'Phenotype', 'HP:0100615', (172, 186))	('human', 'Species', '9606', (72, 77))	('colorectal', 'Disease', (134, 144))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (161, 187))	('small cell lung', 'Disease', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancers', 'Disease', (180, 187))	('ovarian cancers', 'Phenotype', 'HP:0100615', (172, 187))
545154	32875577	Furthermore, families harboring mutations in this domain have a distinct family history of cancer showing early onset and a higher incidence in comparison with families harboring mutations in other p53 domains.	('mutations', 'Var', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
545155	32875577	9 ,  10   The TP53 p.R337H variant located in the tetramerization domain of the p53 protein was first reported in a female pediatric patient with an ACT diagnosed at the age of 3 years.	('p.R337H', 'Mutation', 'rs121912664', (19, 26))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('patient', 'Species', '9606', (133, 140))	('p53', 'Gene', (80, 83))	('p.R337H', 'Var', (19, 26))
545163	32875577	13  The mutant p53-R337H protein functioned similarly to WT p53 in cell culture-based studies; however, a loss of heterozygosity with retention of the mutated allele in tumor cells and a high level of detectable nuclear p53 protein (in both tumor and normal cells) 10  suggested compromised functionality of this mutant protein.	('R337H', 'SUBSTITUTION', 'None', (19, 24))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('functionality', 'MPA', (291, 304))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mutant', 'Var', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('R337H', 'Var', (19, 24))	('tumor', 'Disease', (169, 174))	('heterozygosity', 'MPA', (114, 128))	('loss', 'NegReg', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
545168	32875577	14  To date, the most notable and well-characterized genetic risk factor for ACTs in South and Southeast Brazil is the presence of the germline TP53-R337H mutation.	('R337H', 'Var', (149, 154))	('TP53', 'Gene', (144, 148))	('TP53', 'Gene', '7157', (144, 148))	('R337H', 'SUBSTITUTION', 'None', (149, 154))
545169	32875577	13 ,  14    TP53 germline and somatic mutations found in association with human cancers have been compiled in the IARC database, 8  and to date, the germline TP53 p.R337H variant is the single most commonly reported mutation (Fig.	('human', 'Species', '9606', (74, 79))	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('TP53', 'Gene', '7157', (12, 16))	('p.R337H', 'Var', (163, 170))	('p.R337H', 'Mutation', 'rs121912664', (163, 170))	('TP53', 'Gene', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
545170	32875577	The founder concept for the TP53 p.R337H mutation was revisited because of the observed inheritance of this variant and no documented de novo mutation.	('p.R337H', 'Mutation', 'rs121912664', (33, 40))	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('p.R337H', 'Var', (33, 40))	('men', 'Species', '9606', (127, 130))
545171	32875577	13 ,  14  An analysis by Pinto et al 15  of 2 polymorphic markers at chromosome 17 in close proximity to the TP53 locus demonstrated an identical haplotype encompassing TP53, WRAP53, and EFNB3 (chr17:7,574,017-7,617,475; GRCh37/hg19) for Brazilian patients with ACTs carrying the TP53 p.R337H mutation that was distinct from the control group, and they thereby established the founder nature of this variant.	('EFNB3', 'Gene', '1949', (187, 192))	('EFNB3', 'Gene', (187, 192))	('TP53', 'Gene', '7157', (280, 284))	('TP53', 'Gene', '7157', (169, 173))	('TP53', 'Gene', '7157', (109, 113))	('p.R337H', 'Var', (285, 292))	('TP53', 'Gene', (280, 284))	('TP53', 'Gene', (169, 173))	('chr17:7,574,017-7,617,475', 'STRUCTURAL_ABNORMALITY', 'None', (194, 219))	('p.R337H', 'Mutation', 'rs121912664', (285, 292))	('TP53', 'Gene', (109, 113))	('patients', 'Species', '9606', (248, 256))	('WRAP53', 'Gene', (175, 181))	('WRAP53', 'Gene', '55135', (175, 181))
545172	32875577	Later, a study analyzing single-nucleotide polymorphisms in the TP53 locus showed that the p.R337H allele in Brazilian carriers shared a common TP53 sequence with the patient from Portugal with an ACT 11  and established the Caucasian origin of this allele.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('patient', 'Species', '9606', (167, 174))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('p.R337H', 'Var', (91, 98))	('p.R337H', 'Mutation', 'rs121912664', (91, 98))
545174	32875577	18   Most recently, a detailed analysis of whole-genome sequencing data from matched blood and tumor samples of children with ACTs from Brazil 19  revealed divergent haplotypes among p.R337H carriers (Fig.	('Brazil', 'Gene', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('p.R337H', 'Var', (183, 190))	('children', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p.R337H', 'Mutation', 'rs121912664', (183, 190))	('tumor', 'Disease', (95, 100))
545175	32875577	20  All evaluated p.R337H carriers in South and Southeast Brazil shared an identical TP53 sequence, including 1 copy (nonduplicate) of the 16-bp polymorphism in intron 3 (rs17878362), arginine at codon 72 (rs1042522), and the downstream TP53 variant that defines a Caucasian allele (rs9894946; Fig.	('TP53', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (237, 241))	('rs17878362', 'Mutation', 'rs17878362', (171, 181))	('rs9894946', 'Mutation', 'rs9894946', (283, 292))	('rs1042522', 'Mutation', 'rs1042522', (206, 215))	('TP53', 'Gene', (237, 241))	('rs1042522', 'Var', (206, 215))	('p.R337H', 'Var', (18, 25))	('TP53', 'Gene', '7157', (85, 89))	('rs9894946;', 'Var', (283, 293))	('p.R337H', 'Mutation', 'rs121912664', (18, 25))	('rs17878362', 'Var', (171, 181))	('arginine', 'Chemical', 'MESH:D001120', (184, 192))
545176	32875577	16 ,  19 ,  20  However, it was determined that the constitutive haplotype constructed on the same TP53 p.R337H variant, which occurs in the majority of Brazilian p.R337H carriers, is larger and has a nonsense mutation (p.E134*) in the putative tumor suppressor XAF1 in close proximity to the TP53 locus (Fig.	('XAF1', 'Gene', '54739', (262, 266))	('TP53', 'Gene', (99, 103))	('XAF1', 'Gene', (262, 266))	('p.R337H', 'Var', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('TP53', 'Gene', '7157', (293, 297))	('TP53', 'Gene', (293, 297))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('p.R337H', 'Mutation', 'rs121912664', (104, 111))	('p.E134*', 'Mutation', 'p.E134*', (220, 227))	('p.E134*', 'Var', (220, 227))	('tumor', 'Disease', (245, 250))	('TP53', 'Gene', '7157', (99, 103))	('p.R337H', 'Mutation', 'rs121912664', (163, 170))
545177	32875577	20  The XAF1 p.E134* in concert with the TP53 p.R337H allele leads to a more aggressive cancer phenotype than either variant alone, and this has clear implications for the clinical management of carriers.	('TP53', 'Gene', '7157', (41, 45))	('leads to', 'Reg', (61, 69))	('TP53', 'Gene', (41, 45))	('XAF1', 'Gene', '54739', (8, 12))	('men', 'Species', '9606', (187, 190))	('p.E134*', 'Var', (13, 20))	('XAF1', 'Gene', (8, 12))	('p.E134*', 'Mutation', 'p.E134*', (13, 20))	('aggressive cancer', 'Disease', 'MESH:D009369', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('p.R337H', 'Var', (46, 53))	('aggressive cancer', 'Disease', (77, 94))	('p.R337H', 'Mutation', 'rs121912664', (46, 53))
545179	32875577	21  Another study assessed the frequency of the TP53 p.R337H variant by screening 32,130 newborns from Sao Paulo State, and it found that 68 (0.21%) were carriers.	('TP53', 'Gene', (48, 52))	('TP53', 'Gene', '7157', (48, 52))	('p.R337H', 'Var', (53, 60))	('p.R337H', 'Mutation', 'rs121912664', (53, 60))
545180	32875577	22  These studies 21 ,  22  have established that the germline TP53 p.R337H variant is widespread in South and Southeast Brazil and occurs at a population frequency of 0.3%.	('TP53', 'Gene', (63, 67))	('p.R337H', 'Mutation', 'rs121912664', (68, 75))	('p.R337H', 'Var', (68, 75))	('TP53', 'Gene', '7157', (63, 67))
545181	32875577	Although these original studies have not addressed the constitutive haplotype, screening haplotype-defining variants in newborns (n = 42,538) with an unknown history of cancer from South Brazil showed that 69% of p.R337H carriers also have the XAF1 p.E134* variant in the same haplotype.	('XAF1', 'Gene', (244, 248))	('p.R337H', 'Var', (213, 220))	('p.E134*', 'Var', (249, 256))	('cancer', 'Disease', (169, 175))	('p.E134*', 'Mutation', 'p.E134*', (249, 256))	('p.R337H', 'Mutation', 'rs121912664', (213, 220))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('XAF1', 'Gene', '54739', (244, 248))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
545182	32875577	20   It is also important to consider that the TP53 p.R337H mutation can be observed outside the context of a founder mutation in an independent occurrence as observed in an adult patient with an ACT from Germany.	('p.R337H', 'Var', (52, 59))	('TP53', 'Gene', '7157', (47, 51))	('p.R337H', 'Mutation', 'rs121912664', (52, 59))	('patient', 'Species', '9606', (180, 187))	('TP53', 'Gene', (47, 51))
545183	32875577	23  These observations raise the question whether the TP53 p.R337H variant, constitutive haplotype, and associated polymorphisms influence the tumor phenotype.	('influence', 'Reg', (129, 138))	('tumor', 'Disease', (143, 148))	('p.R337H', 'Var', (59, 66))	('p.R337H', 'Mutation', 'rs121912664', (59, 66))	('TP53', 'Gene', '7157', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('TP53', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
545184	32875577	In addition to pediatric ACTs, 13 ,  14 ,  15 ,  17 ,  19 ,  21  the TP53 p.R337H variant is expressively associated with choroid plexus carcinoma (CPC) in the Brazilian population.	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (122, 146))	('p.R337H', 'Mutation', 'rs121912664', (74, 81))	('associated with', 'Reg', (106, 121))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (122, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('CPC', 'Phenotype', 'HP:0030392', (148, 151))	('choroid plexus carcinoma', 'Disease', (122, 146))	('p.R337H', 'Var', (74, 81))
545185	32875577	In a series of 29 patients with CPC or choroid plexus papilloma admitted to Pequeno Principe Hospital (Parana State) from 1992 to 2010, the p.R337H variant was observed in 14 of 22 patients (63.6%) with CPC but not in those with choroid plexus papilloma (n = 7).	('choroid plexus papilloma', 'Disease', 'MESH:D020288', (229, 253))	('p.R337H', 'Var', (140, 147))	('papilloma', 'Phenotype', 'HP:0012740', (54, 63))	('p.R337H', 'Mutation', 'rs121912664', (140, 147))	('CPC', 'Phenotype', 'HP:0030392', (203, 206))	('choroid plexus papilloma', 'Phenotype', 'HP:0200022', (229, 253))	('patients', 'Species', '9606', (181, 189))	('papilloma', 'Phenotype', 'HP:0012740', (244, 253))	('patients', 'Species', '9606', (18, 26))	('choroid plexus papilloma', 'Phenotype', 'HP:0200022', (39, 63))	('CPC', 'Phenotype', 'HP:0030392', (32, 35))	('choroid plexus papilloma', 'Disease', (39, 63))	('CPC', 'Disease', (203, 206))	('choroid plexus papilloma', 'Disease', (229, 253))	('choroid plexus papilloma', 'Disease', 'MESH:D020288', (39, 63))
545186	32875577	24   To determine the spectrum of pediatric malignancies associated with the TP53 p.R337H variant, 493 childhood cancer patients from Centro Infantil Boldrini, a referral institution in Southeast Brazil (Sao Paulo State), were genotyped for this variant.	('p.R337H', 'Mutation', 'rs121912664', (82, 89))	('malignancies', 'Disease', (44, 56))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('p.R337H', 'Var', (82, 89))
545187	32875577	Results confirmed the high association of this variant with ACT (65 of 70 cases [93%]) and CPC (9 of 13 patients [69%]).	('CPC', 'Disease', (91, 94))	('association', 'Interaction', (27, 38))	('variant', 'Var', (47, 54))	('ACT', 'Disease', (60, 63))	('CPC', 'Phenotype', 'HP:0030392', (91, 94))	('patients', 'Species', '9606', (104, 112))
545189	32875577	25  Moreover, the Centro Infantil Boldrini group identified the TP53 p.R337H mutation in 2 patients with concomitant ACT and neuroblastoma and investigated the frequency of this variant among patients with neuroblastoma treated at this referral institution.	('neuroblastoma', 'Disease', (125, 138))	('neuroblastoma', 'Disease', (206, 219))	('patients', 'Species', '9606', (91, 99))	('neuroblastoma', 'Phenotype', 'HP:0003006', (206, 219))	('p.R337H', 'Var', (69, 76))	('patients', 'Species', '9606', (192, 200))	('neuroblastoma', 'Phenotype', 'HP:0003006', (125, 138))	('p.R337H', 'Mutation', 'rs121912664', (69, 76))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('neuroblastoma', 'Disease', 'MESH:D009447', (125, 138))	('neuroblastoma', 'Disease', 'MESH:D009447', (206, 219))
545190	32875577	The TP53 p.R337H variant was identified in 7 of 83 available samples (8.4%) from a total of 178 patients with neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (110, 123))	('TP53', 'Gene', (4, 8))	('neuroblastoma', 'Disease', (110, 123))	('neuroblastoma', 'Phenotype', 'HP:0003006', (110, 123))	('p.R337H', 'Var', (9, 16))	('patients', 'Species', '9606', (96, 104))	('p.R337H', 'Mutation', 'rs121912664', (9, 16))	('TP53', 'Gene', '7157', (4, 8))
545192	32875577	27  Screening for the TP53 p.R337H mutation identified 11 of the 292 children with cancer (3.8%) as proband carriers (9 were diagnosed with an ACT [1 in the homozygous state], and 2 were diagnosed with a CPC) 27  and thereby confirmed previous studies.	('p.R337H', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('p.R337H', 'Mutation', 'rs121912664', (27, 34))	('TP53', 'Gene', '7157', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('CPC', 'Phenotype', 'HP:0030392', (204, 207))	('TP53', 'Gene', (22, 26))	('cancer', 'Disease', (83, 89))	('children', 'Species', '9606', (69, 77))
545193	32875577	12 ,  13 ,  19 ,  21 ,  24 ,  25  There were no TP53 p.R337H-positive carriers among probands with osteosarcoma (n = 21), leukemia (n = 77), or Wilms tumor (n = 34).	('osteosarcoma', 'Disease', 'MESH:D012516', (99, 111))	('TP53', 'Gene', '7157', (48, 52))	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('Wilms tumor', 'Phenotype', 'HP:0002667', (144, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('TP53', 'Gene', (48, 52))	('Wilms tumor', 'Disease', (144, 155))	('Wilms tumor', 'Disease', 'MESH:D009396', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('p.R337H-positive', 'Var', (53, 69))	('p.R337H', 'Mutation', 'rs121912664', (53, 60))	('osteosarcoma', 'Phenotype', 'HP:0002669', (99, 111))	('osteosarcoma', 'Disease', (99, 111))
545194	32875577	27   Pediatric ACT and CPC are extremely rare tumors, and the occurrence of metachronous ACT and CPC associated with TP53 alterations has been reported.	('CPC', 'Disease', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('associated', 'Reg', (101, 111))	('CPC', 'Phenotype', 'HP:0030392', (97, 100))	('tumors', 'Disease', (46, 52))	('metachronous ACT', 'Disease', (76, 92))	('alterations', 'Var', (122, 133))	('CPC', 'Phenotype', 'HP:0030392', (23, 26))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
545195	32875577	28 ,  29  However, the co-occurrence of both tumors in the context of the TP53 p.R337H variant has never been documented, although a metachronous ACT in a pediatric patient harboring this variant has been recognized.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('p.R337H', 'Var', (79, 86))	('men', 'Species', '9606', (114, 117))	('patient', 'Species', '9606', (165, 172))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('TP53', 'Gene', '7157', (74, 78))	('p.R337H', 'Mutation', 'rs121912664', (79, 86))	('TP53', 'Gene', (74, 78))
545196	32875577	30   Forty-five families from South and Southeast Brazil with family histories of cancer consistent with classic LFS or LFL criteria were screened for TP53 mutations.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', (151, 155))	('mutations', 'Var', (156, 165))	('LFS', 'Disease', 'MESH:D016864', (113, 116))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TP53', 'Gene', '7157', (151, 155))	('LFS', 'Disease', (113, 116))
545197	32875577	Of the 13 index cases (28.9%) with positive TP53 results, 6 harbored the p.R337H variant.	('harbored', 'Reg', (60, 68))	('p.R337H', 'Var', (73, 80))	('TP53', 'Gene', '7157', (44, 48))	('p.R337H', 'Mutation', 'rs121912664', (73, 80))	('TP53', 'Gene', (44, 48))
545198	32875577	31  Each of these p.R337H carriers was diagnosed with STS (x3), breast cancer, renal cell carcinoma, or pediatric ACT.	('p.R337H', 'Mutation', 'rs121912664', (18, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('diagnosed', 'Reg', (39, 48))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('pediatric ACT', 'Disease', (104, 117))	('p.R337H', 'Var', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('renal cell carcinoma', 'Disease', (79, 99))	('breast cancer', 'Disease', (64, 77))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (79, 99))
545200	32875577	31  A family history of cancer for p.R337H carriers included a wide spectrum of tumors, including breast and brain tumors, STSs, and ACTs.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Disease', (24, 30))	('tumors', 'Disease', (80, 86))	('STSs', 'Disease', (123, 127))	('STSs', 'Phenotype', 'HP:0030448', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('breast and brain tumors', 'Disease', 'MESH:D001943', (98, 121))	('brain tumors', 'Phenotype', 'HP:0030692', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('p.R337H', 'Var', (35, 42))	('tumors', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('brain tumor', 'Phenotype', 'HP:0030692', (109, 120))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('p.R337H', 'Mutation', 'rs121912664', (35, 42))	('ACTs', 'Disease', (133, 137))	('included', 'Reg', (52, 60))
545201	32875577	31  Achatz et al 31  suggested that the tumor spectrum observed in carriers of the TP53 p.R337H mutation is similar to that observed in LFS or LFL families carrying other TP53 mutations; nevertheless, as discussed in the profiled article, all p.R337H families in this study fulfilled LFL criteria rather than strict LFS criteria.	('TP53', 'Gene', (171, 175))	('TP53', 'Gene', '7157', (83, 87))	('LFL', 'Disease', (284, 287))	('LFS', 'Disease', (136, 139))	('p.R337H', 'Mutation', 'rs121912664', (88, 95))	('TP53', 'Gene', (83, 87))	('LFS', 'Disease', (316, 319))	('p.R337H', 'Mutation', 'rs121912664', (243, 250))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('TP53', 'Gene', '7157', (171, 175))	('LFS', 'Disease', 'MESH:D016864', (316, 319))	('LFS', 'Disease', 'MESH:D016864', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('p.R337H', 'Var', (243, 250))	('p.R337H', 'Var', (88, 95))
545202	32875577	31  Notably, these probands and family members were tested for the constitutive haplotype, and 5 of the 6 index cases testing positive for the TP53 p.R337H variant (the patients with STS [x3], breast cancer, and renal cell carcinoma) shared the extended haplotype cosegregating both TP53 and XAF1 mutated alleles.	('TP53', 'Gene', (143, 147))	('breast cancer', 'Disease', (193, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('patients', 'Species', '9606', (169, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('XAF1', 'Gene', (292, 296))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (212, 232))	('p.R337H', 'Var', (148, 155))	('TP53', 'Gene', '7157', (283, 287))	('renal cell carcinoma', 'Disease', (212, 232))	('TP53', 'Gene', '7157', (143, 147))	('XAF1', 'Gene', '54739', (292, 296))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('TP53', 'Gene', (283, 287))	('p.R337H', 'Mutation', 'rs121912664', (148, 155))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (212, 232))
545204	32875577	20   The tumor spectrum for individuals and family members associated with pathogenic germline TP53 variants is wide, but the tumors most closely associated with LFS (core cancers) include premenopausal breast cancer, STS, and osteosarcoma as well as brain tumors and ACTs.	('LFS', 'Disease', 'MESH:D016864', (162, 165))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('men', 'Species', '9606', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (189, 216))	('tumors', 'Disease', (126, 132))	('tumor', 'Disease', (257, 262))	('osteosarcoma', 'Disease', (227, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('tumor', 'Disease', (9, 14))	('osteosarcoma', 'Disease', 'MESH:D012516', (227, 239))	('STS', 'Disease', (218, 221))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('TP53', 'Gene', '7157', (95, 99))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('brain tumors', 'Phenotype', 'HP:0030692', (251, 263))	('breast cancer', 'Disease', (203, 216))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('brain tumors', 'Disease', 'MESH:D001932', (251, 263))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('brain tumor', 'Phenotype', 'HP:0030692', (251, 262))	('cancers', 'Disease', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('variants', 'Var', (100, 108))	('tumors', 'Disease', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('osteosarcoma', 'Phenotype', 'HP:0002669', (227, 239))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('brain tumors', 'Disease', (251, 263))	('LFS', 'Disease', (162, 165))	('associated', 'Reg', (146, 156))	('TP53', 'Gene', (95, 99))
545205	32875577	10  Palmero et al 32  tested for the p.R337H variant 750 asymptomatic women aged 40 to 69 years who were not selected on the basis of a family history of cancer but had participated in a breast cancer screening program in South Brazil (Rio Grande do Sul State).	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('p.R337H', 'Mutation', 'rs121912664', (37, 44))	('cancer', 'Disease', (194, 200))	('tested', 'Reg', (22, 28))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('p.R337H', 'Var', (37, 44))	('women', 'Species', '9606', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('breast cancer', 'Disease', (187, 200))
545207	32875577	32  Additional relatives were tested, and 3 harbored p.R337H: 1 developed breast cancer that was diagnosed at the age of 36 years, and the other 2 were asymptomatic carriers at the ages of 62 and 80 years.	('breast cancer', 'Disease', (74, 87))	('p.R337H', 'Var', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('p.R337H', 'Mutation', 'rs121912664', (53, 60))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('developed', 'PosReg', (64, 73))
545208	32875577	32  Another study (Rio de Janeiro State) screened for the TP53 p.R337H variant in 381 women with invasive breast cancer diagnosed between the ages of 20 and 60 years, including 87 diagnosed at or before the age of 40 years.	('TP53', 'Gene', '7157', (58, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('TP53', 'Gene', (58, 62))	('invasive breast cancer', 'Disease', (97, 119))	('p.R337H', 'Var', (63, 70))	('p.R337H', 'Mutation', 'rs121912664', (63, 70))	('invasive breast cancer', 'Disease', 'MESH:D001943', (97, 119))	('women', 'Species', '9606', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
545213	32875577	33   Breast cancer is the most common cancer in adult carriers of a germline TP53 mutation.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (12, 18))	('mutation', 'Var', (82, 90))	('Breast cancer', 'Disease', (5, 18))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', (38, 44))	('Breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('Breast cancer', 'Disease', 'MESH:D001943', (5, 18))
545215	32875577	34  In addition, breast cancer is predictive of a germline TP53 mutation when it is diagnosed at a younger age and in family members with LFS core tumors (other than breast cancer).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('LFS core tumors', 'Disease', (138, 153))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('TP53', 'Gene', (59, 63))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('LFS core tumors', 'Disease', 'MESH:D016864', (138, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('TP53', 'Gene', '7157', (59, 63))	('germline', 'Var', (50, 58))
545216	32875577	34  Recent studies have reported that breast cancers in carriers of TP53 variants are mostly ductal in histology, positive for hormone receptor and tyrosine kinase-type cell surface receptor HER2, and diagnosed at a very early age.	('hormone receptor', 'Gene', (127, 143))	('hormone receptor', 'Gene', '3164', (127, 143))	('breast cancers', 'Phenotype', 'HP:0003002', (38, 52))	('tyrosine kinase-type cell surface receptor HER2', 'Gene', '2064', (148, 195))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancers', 'Disease', 'MESH:D001943', (38, 52))	('breast cancers', 'Disease', (38, 52))	('variants', 'Var', (73, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('positive', 'Reg', (114, 122))	('tyrosine kinase-type cell surface receptor HER2', 'Gene', (148, 195))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))
545217	32875577	34  However, a Brazilian study of 78 patients with breast cancer demonstrated that the median age at breast cancer diagnosis in a group of p.R337H carriers (n = 66) was 42 years, which was older than the median age at diagnosis (30 years) for carriers of other nonfunctional germline TP53 mutations.	('p.R337H', 'Mutation', 'rs121912664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patients', 'Species', '9606', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('TP53', 'Gene', '7157', (284, 288))	('p.R337H', 'Var', (139, 146))	('TP53', 'Gene', (284, 288))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('breast cancer', 'Disease', (51, 64))
545218	32875577	35  In addition, most patients had a positive hormone receptor status, and in contrast to other studies, HER2+ breast cancer was very similar to that observed in noncarriers of TP53 variants.	('HER2', 'Gene', (105, 109))	('HER2', 'Gene', '2064', (105, 109))	('variants', 'Var', (182, 190))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('TP53', 'Gene', '7157', (177, 181))	('hormone receptor', 'Gene', (46, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('hormone receptor', 'Gene', '3164', (46, 62))	('breast cancer', 'Disease', (111, 124))	('TP53', 'Gene', (177, 181))
545220	32875577	However, sarcomas represent 17.4% of all cancers in TP53 germline mutation carriers and 36.8% of all cancers in patients younger than 20 years.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('germline mutation carriers', 'Var', (57, 83))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('TP53', 'Gene', '7157', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancers', 'Disease', (101, 108))	('patients', 'Species', '9606', (112, 120))	('TP53', 'Gene', (52, 56))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcomas', 'Disease', (9, 17))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
545222	32875577	36  In a recent study, the TP53 p.R337H mutation was screened in 502 patients diagnosed with sarcomas who were not selected by age or family history and were treated at Hospital de Cancer de Barretos (Sao Paulo State) between 2008 and 2016 (from a total of 701 patients with sarcomas).	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (275, 283))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('patients', 'Species', '9606', (69, 77))	('sarcomas', 'Disease', (275, 283))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('Cancer', 'Disease', (181, 187))	('p.R337H', 'Var', (32, 39))	('sarcomas', 'Disease', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('Cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Cancer', 'Disease', 'MESH:D009369', (181, 187))	('patients', 'Species', '9606', (261, 269))	('sarcomas', 'Disease', 'MESH:D012509', (275, 283))	('p.R337H', 'Mutation', 'rs121912664', (32, 39))
545223	32875577	The TP53 p.R337H variant was found in 40 samples (8%) and was confirmed to be germline in available blood DNA or normal tissue in 36 cases.	('p.R337H', 'Mutation', 'rs121912664', (9, 16))	('p.R337H', 'Var', (9, 16))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
545224	32875577	37  Although the total cohort study included 58 pediatric patients, the p.R337H variant was exclusively observed in adult cases, with the youngest patient diagnosed at the age of 18 years and the oldest diagnosed at the age of 84 years (22 cases [55%] were diagnosed in patients older than 50 years) 37 ; in contrast, in the IARC database, 8  67% of sarcomas in carriers of TP53 mutations were diagnosed before the age of 20 years.	('sarcoma', 'Phenotype', 'HP:0100242', (350, 357))	('carriers', 'Reg', (362, 370))	('TP53', 'Gene', (374, 378))	('p.R337H', 'Var', (72, 79))	('sarcomas', 'Disease', (350, 358))	('mutations', 'Var', (379, 388))	('patient', 'Species', '9606', (58, 65))	('patient', 'Species', '9606', (147, 154))	('patients', 'Species', '9606', (270, 278))	('p.R337H', 'Mutation', 'rs121912664', (72, 79))	('TP53', 'Gene', '7157', (374, 378))	('sarcomas', 'Disease', 'MESH:D012509', (350, 358))	('patients', 'Species', '9606', (58, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (350, 358))	('patient', 'Species', '9606', (270, 277))
545225	32875577	36  In addition, leiomyosarcoma accounted for 21 cases of sarcoma (52.5%) among p.R337H carriers, with 14 (67%) being diagnosed at an age older than 50 years.	('p.R337H', 'Mutation', 'rs121912664', (80, 87))	('sarcoma', 'Disease', (24, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcoma', 'Disease', 'MESH:D012509', (24, 31))	('p.R337H', 'Var', (80, 87))	('leiomyosarcoma', 'Disease', (17, 31))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (17, 31))	('sarcoma', 'Disease', (58, 65))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (17, 31))
545227	32875577	8 ,  36  Sarcoma was a second tumor in 7 of 8 p.R337H patients who developed multiple primary malignancies.	('Sarcoma', 'Disease', (9, 16))	('Sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('patients', 'Species', '9606', (54, 62))	('Sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('p.R337H', 'Mutation', 'rs121912664', (46, 53))	('malignancies', 'Disease', 'MESH:D009369', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('p.R337H', 'Var', (46, 53))	('tumor', 'Disease', (30, 35))	('malignancies', 'Disease', (94, 106))
545228	32875577	37  Furthermore, 30 p.R337H patients reported family members with cancer, and an excess of lung and breast cancer, malignant CNS tumors, colorectal and stomach cancer, leukemia, and ACTs was documented.	('malignant CNS tumors', 'Disease', 'MESH:D009369', (115, 135))	('lung', 'Disease', (91, 95))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('stomach cancer', 'Phenotype', 'HP:0012126', (152, 166))	('colorectal and stomach cancer', 'Disease', 'MESH:D015179', (137, 166))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (66, 72))	('cancer', 'Disease', (160, 166))	('leukemia', 'Disease', 'MESH:D007938', (168, 176))	('leukemia', 'Disease', (168, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('patients', 'Species', '9606', (28, 36))	('malignant CNS tumors', 'Disease', (115, 135))	('p.R337H', 'Var', (20, 27))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('breast cancer', 'Disease', (100, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p.R337H', 'Mutation', 'rs121912664', (20, 27))	('men', 'Species', '9606', (195, 198))
545229	32875577	37  Negative family histories of cancer were annotated for approximately 15% of the p.R337H patients with sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('p.R337H', 'Mutation', 'rs121912664', (84, 91))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('sarcomas', 'Disease', (106, 114))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('p.R337H', 'Var', (84, 91))	('sarcomas', 'Disease', 'MESH:D012509', (106, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))
545232	32875577	Nevertheless, 24 of the 40 sarcoma cases harboring the p.R337H variant were included in the analysis of the constitutive haplotype, and 98% shared the haplotype harboring mutations in both tumor suppressor TP53 and tumor suppressor XAF1.	('sarcoma', 'Disease', (27, 34))	('sarcoma', 'Disease', 'MESH:D012509', (27, 34))	('TP53', 'Gene', '7157', (206, 210))	('tumor', 'Disease', (189, 194))	('TP53', 'Gene', (206, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('p.R337H', 'Var', (55, 62))	('XAF1', 'Gene', '54739', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('p.R337H', 'Mutation', 'rs121912664', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (215, 220))	('XAF1', 'Gene', (232, 236))
545233	32875577	20   Because of the potential association between the p.R337H variant and breast cancer, a case-control study was conducted at the University of Sao Paulo Medical School of Ribeirao Preto (Sao Paulo State) to verify the prevalence of this variant in 28 unrelated female patients with breast cancer fulfilling the criteria for hereditary breast and ovarian cancer syndrome (HBOC) by genetic testing.	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (326, 371))	('breast cancer', 'Phenotype', 'HP:0003002', (284, 297))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (348, 362))	('patients', 'Species', '9606', (270, 278))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('p.R337H', 'Var', (54, 61))	('association', 'Interaction', (30, 41))	('breast cancer', 'Disease', 'MESH:D001943', (284, 297))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('p.R337H', 'Mutation', 'rs121912664', (54, 61))	('breast cancer', 'Disease', (284, 297))
545234	32875577	38  Two (7.1%) were positive for p.R337H and negative for BRCA1 and BRCA2 pathogenic mutations.	('p.R337H', 'Mutation', 'rs121912664', (33, 40))	('BRCA2', 'Gene', '675', (68, 73))	('positive', 'Reg', (20, 28))	('BRCA1', 'Gene', (58, 63))	('BRCA2', 'Gene', (68, 73))	('p.R337H', 'Var', (33, 40))	('BRCA1', 'Gene', '672', (58, 63))
545236	32875577	38  However, both patients met HBOC criteria on the basis of their personal histories and relatives diagnosed with breast cancer, 38  and this demonstrated that the p.R337H variant was significantly higher among women with HBOC-related breast cancer than the general Brazilian population.	('HBOC-related breast cancer', 'Disease', 'MESH:D061325', (223, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('p.R337H', 'Var', (165, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('p.R337H', 'Mutation', 'rs121912664', (165, 172))	('women', 'Species', '9606', (212, 217))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('patients', 'Species', '9606', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('higher', 'Reg', (199, 205))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('HBOC-related breast cancer', 'Disease', (223, 249))
545237	32875577	38  A second study analyzed 106 unrelated high-risk patients with HBOC from Northeast Brazil (Bahia State) for mutations in BRCA1, BRCA2, CHEK2, and TP53.	('mutations', 'Var', (111, 120))	('BRCA2', 'Gene', (131, 136))	('CHEK2', 'Gene', '11200', (138, 143))	('BRCA1', 'Gene', '672', (124, 129))	('CHEK2', 'Gene', (138, 143))	('TP53', 'Gene', '7157', (149, 153))	('BRCA2', 'Gene', '675', (131, 136))	('BRCA1', 'Gene', (124, 129))	('TP53', 'Gene', (149, 153))	('patients', 'Species', '9606', (52, 60))
545239	32875577	Two mutations of clinical significance were found in BRCA1 (p.R71G [c.211A>G; n = 5] and 3450del4 [c.3331_3334delCAAG; n = 4]), and 1 was found in TP53 (p.R337H [n = 1]).	('p.R71G', 'Mutation', 'rs80357382', (60, 66))	('TP53', 'Gene', (147, 151))	('3450del4', 'Mutation', 'c.3450del4', (89, 97))	('3450del4 [c.3331_3334delCAAG', 'Var', (89, 117))	('p.R71G [c.211A>G', 'Var', (60, 76))	('c.211A>G', 'Mutation', 'rs80357382', (68, 76))	('c.3331_3334delCAAG', 'Mutation', 'rs1323582820', (99, 117))	('BRCA1', 'Gene', '672', (53, 58))	('TP53', 'Gene', '7157', (147, 151))	('p.R337H', 'Mutation', 'rs121912664', (153, 160))	('BRCA1', 'Gene', (53, 58))
545240	32875577	39  The p.R337H carrier had a family history consistent with HBOC but not LFS or LFL syndrome.	('LFL syndrome', 'Disease', (81, 93))	('LFL syndrome', 'Disease', 'MESH:D016864', (81, 93))	('LFS', 'Disease', 'MESH:D016864', (74, 77))	('p.R337H', 'Var', (8, 15))	('HBOC', 'Disease', (61, 65))	('p.R337H', 'Mutation', 'rs121912664', (8, 15))	('LFS', 'Disease', (74, 77))
545241	32875577	39   The p.R337H variant was also documented in phyllodes breast tumors in South Brazil.	('men', 'Species', '9606', (38, 41))	('phyllodes', 'Chemical', '-', (48, 57))	('breast tumors', 'Phenotype', 'HP:0100013', (58, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('p.R337H', 'Var', (9, 16))	('breast tumors', 'Disease', 'MESH:D001943', (58, 71))	('p.R337H', 'Mutation', 'rs121912664', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('breast tumors', 'Disease', (58, 71))
545243	32875577	A DNA analysis from nontumoral tissue was possible in 2 positive cases, and both were associated with germline p.R337H mutations.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('associated', 'Reg', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('p.R337H', 'Var', (111, 118))	('tumor', 'Disease', (23, 28))	('p.R337H', 'Mutation', 'rs121912664', (111, 118))
545244	32875577	40  Positive cases were found in benign (n = 5) and malignant phyllodes breast tumors (n = 3); this suggests that this variant plays a role in phyllodes breast tumorigenesis.	('breast tumors', 'Disease', 'MESH:D001943', (72, 85))	('phyllodes', 'Chemical', '-', (62, 71))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('variant', 'Var', (119, 126))	('role', 'Reg', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('breast tumors', 'Phenotype', 'HP:0100013', (72, 85))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('phyllodes', 'Chemical', '-', (143, 152))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('breast tumors', 'Disease', (72, 85))
545245	32875577	40   Substantial clinical tumor heterogeneity and a wide range of tumor types have been observed at an increased frequency in TP53 p.R337H carriers.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('TP53', 'Gene', (126, 130))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('p.R337H', 'Var', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('p.R337H', 'Mutation', 'rs121912664', (131, 138))	('TP53', 'Gene', '7157', (126, 130))
545246	32875577	In an analysis of 45 unselected Brazilian patients (29 male) with non-small cell lung cancer treated at Hospital Julia Kubitschek (Minas Gerais State), 4 (8.9%) were p.R337H carriers.	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('p.R337H', 'Var', (166, 173))	('p.R337H', 'Mutation', 'rs121912664', (166, 173))	('Julia', 'Species', '33453', (113, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (66, 92))	('patients', 'Species', '9606', (42, 50))	('non-small cell lung cancer', 'Disease', (66, 92))
545248	32875577	41  In a study of 164 p.R337H carriers from 59 families followed at the A. C. Camargo Cancer Center (Sao Paulo State), 9 individuals (5.5%; 8 families) developed lung adenocarcinoma (mean age at diagnosis, 53 years).	('p.R337H', 'Mutation', 'rs121912664', (22, 29))	('lung adenocarcinoma', 'Disease', (162, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (162, 181))	('developed', 'Reg', (152, 161))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Cancer', 'Disease', (86, 92))	('p.R337H', 'Var', (22, 29))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (162, 181))	('Cancer', 'Disease', 'MESH:D009369', (86, 92))
545251	32875577	42  All 164 p.R337H patients had family histories of cancer, with 3 having more than 1 case of lung cancer.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('p.R337H', 'Var', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('p.R337H', 'Mutation', 'rs121912664', (12, 19))
545257	32875577	43  In addition, the same group reported a single case of colorectal carcinoma (diagnosed after the age of 50 years) among 101 cancer-affected p.R337H carriers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (58, 78))	('p.R337H', 'Mutation', 'rs121912664', (143, 150))	('p.R337H carriers', 'Var', (143, 159))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('colorectal carcinoma', 'Disease', (58, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
545258	32875577	44   Although the core cancers of LFS are seen in patients harboring the TP53 p.R337H variant, the clinical presentation appears to be distinct from the presentation observed in carriers of pathogenic TP53 alleles associated with LFS (Table 1).	('TP53', 'Gene', '7157', (73, 77))	('patients', 'Species', '9606', (50, 58))	('LFS', 'Disease', (34, 37))	('p.R337H', 'Mutation', 'rs121912664', (78, 85))	('TP53', 'Gene', '7157', (201, 205))	('LFS', 'Disease', (230, 233))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('TP53', 'Gene', (73, 77))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('TP53', 'Gene', (201, 205))	('LFS', 'Disease', 'MESH:D016864', (230, 233))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('LFS', 'Disease', 'MESH:D016864', (34, 37))	('p.R337H', 'Var', (78, 85))
545259	32875577	The TP53 p.R337H allele participates in a salt bridge within the dimerization domain, and structural studies have demonstrated that the stability of this mutant protein is pH dependent.	('p.R337H', 'Mutation', 'rs121912664', (9, 16))	('salt bridge within the', 'MPA', (42, 64))	('TP53', 'Gene', (4, 8))	('p.R337H', 'Var', (9, 16))	('participates', 'Reg', (24, 36))	('stability', 'MPA', (136, 145))	('TP53', 'Gene', '7157', (4, 8))
545263	32875577	In a different approach, chromatin immunoprecipitation sequencing studies in lymphocytes derived from carriers of TP53 p.R337H exposed to doxorubicin revealed a moderate decrease in p53 binding sites compared to the WT sequence and closer to lymphocytes derived from carriers of null TP53 variants; this suggests an impairment of the transcriptional response to DNA damage.	('doxorubicin', 'Chemical', 'MESH:D004317', (138, 149))	('TP53', 'Gene', (284, 288))	('p.R337H', 'Mutation', 'rs121912664', (119, 126))	('TP53', 'Gene', '7157', (114, 118))	('men', 'Species', '9606', (322, 325))	('p53', 'Protein', (182, 185))	('TP53', 'Gene', (114, 118))	('binding', 'Interaction', (186, 193))	('decrease', 'NegReg', (170, 178))	('TP53', 'Gene', '7157', (284, 288))	('p.R337H', 'Var', (119, 126))
545265	32875577	47   A recent study used human fibroblasts derived from skin biopsies of patients harboring the TP53 p.R337H and XAF1-E134* variants in homozygous and heterozygous states to evaluate p53 and cell cycle regulation pathways.	('TP53', 'Gene', (96, 100))	('XAF1', 'Gene', '54739', (113, 117))	('cell cycle regulation pathways', 'Pathway', (191, 221))	('human', 'Species', '9606', (25, 30))	('patients', 'Species', '9606', (73, 81))	('XAF1', 'Gene', (113, 117))	('p.R337H', 'Var', (101, 108))	('E134*', 'SUBSTITUTION', 'None', (118, 123))	('E134*', 'Var', (118, 123))	('p.R337H', 'Mutation', 'rs121912664', (101, 108))	('TP53', 'Gene', '7157', (96, 100))
545268	32875577	The generation of the p.R334H mouse model, which represents the human p.R337H homolog, is a major step in advancing our understanding of this TP53 variant.	('human', 'Species', '9606', (64, 69))	('p.R334H', 'Mutation', 'p.R334H', (22, 29))	('p.R334H', 'Var', (22, 29))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('p.R337H', 'Mutation', 'rs121912664', (70, 77))	('mouse', 'Species', '10090', (30, 35))
545269	32875577	Homozygous mutant mice developed normally and exhibited longevity and cancer incidence similar to those of WT mice.	('mutant', 'Var', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mice', 'Species', '10090', (18, 22))	('mice', 'Species', '10090', (110, 114))	('longevity', 'CPA', (56, 65))	('developed', 'CPA', (23, 32))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
545270	32875577	48  However, mutant mice were susceptible to developing liver tumors when they were exposed to the carcinogen diethylnitrosamine in a mutant allele dose-dependent manner.	('mutant', 'Var', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('susceptible', 'Reg', (30, 41))	('mice', 'Species', '10090', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('liver tumors', 'Disease', (56, 68))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (110, 128))	('liver tumors', 'Disease', 'MESH:D008113', (56, 68))	('liver tumors', 'Phenotype', 'HP:0002896', (56, 68))	('mutant', 'Var', (134, 140))
545271	32875577	48  This model, however, did not recapitulate the cancer phenotype observed in Brazilian carriers of the p.R337H variant, and this suggests that additional genetic and environmental factors modulate the cancer risk phenotype in carriers.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('p.R337H', 'Var', (105, 112))	('men', 'Species', '9606', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('p.R337H', 'Mutation', 'rs121912664', (105, 112))
545272	32875577	An assessment of cancer risk in TP53 p.R337H carriers includes individuals and families with no history of cancer over a lifetime, others showing an apparently sporadic pattern of cancer presentation, and those with a more aggressive cancer phenotype resembling LFS.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('TP53', 'Gene', '7157', (32, 36))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('men', 'Species', '9606', (9, 12))	('LFS', 'Disease', (262, 265))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('p.R337H', 'Var', (37, 44))	('LFS', 'Disease', 'MESH:D016864', (262, 265))	('cancer', 'Disease', (180, 186))	('aggressive cancer', 'Disease', 'MESH:D009369', (223, 240))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('TP53', 'Gene', (32, 36))	('cancer', 'Disease', (107, 113))	('p.R337H', 'Mutation', 'rs121912664', (37, 44))	('aggressive cancer', 'Disease', (223, 240))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (234, 240))
545273	32875577	It is important to note that an LFS diagnosis is determined by an evolving set of clinical classification criteria based on personal and family histories of cancer, with 70% of individuals who meet these criteria being positive for pathogenic TP53 variants.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('LFS', 'Disease', 'MESH:D016864', (32, 35))	('variants', 'Var', (248, 256))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('LFS', 'Disease', (32, 35))	('TP53', 'Gene', '7157', (243, 247))	('TP53', 'Gene', (243, 247))
545274	32875577	The TP53 p.R337H mutation represents a remarkable example of a reduced-penetrance allele, but still this disease-causing variant is present as a founder mutation in 0.3% of the population of Southeast and Southern Brazil.	('p.R337H', 'Mutation', 'rs121912664', (9, 16))	('p.R337H', 'Var', (9, 16))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
545275	32875577	The haplotype cosegregating both TP53 pR337H and XAF1 E134* mutant alleles likely contributes to a more aggressive cancer phenotype comparable to carriers of pathogenic TP53 variants but clearly distinct from the classic presentation of LFS.	('XAF1', 'Gene', (49, 53))	('E134*', 'Var', (54, 59))	('pR337H', 'Var', (38, 44))	('more', 'PosReg', (99, 103))	('LFS', 'Disease', (237, 240))	('aggressive cancer', 'Disease', 'MESH:D009369', (104, 121))	('TP53', 'Gene', '7157', (169, 173))	('TP53', 'Gene', '7157', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('aggressive cancer', 'Disease', (104, 121))	('TP53', 'Gene', (169, 173))	('TP53', 'Gene', (33, 37))	('LFS', 'Disease', 'MESH:D016864', (237, 240))	('contributes to', 'Reg', (82, 96))	('XAF1', 'Gene', '54739', (49, 53))	('E134*', 'SUBSTITUTION', 'None', (54, 59))
545276	32875577	Recognizing the constitutive haplotype in carriers of the p.R337 variant is of importance for stratifying carriers into high- and low-risk categories and thereby guiding physicians in counseling, targeted prevention, and earlier detection of tumors to improve outcomes.	('p.R337', 'Var', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))
545277	32875577	This review covers 20 years of clinical and basic research concerning a single TP53 mutant widespread in Brazil.	('mutant', 'Var', (84, 90))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))
545278	32875577	Although we have come far in understanding the biological roots, genetics, and biochemistry of the TP53 p.R337H variant, we still have to consolidate the contribution of haplotype-defining variants in cancer susceptibility in this population.	('TP53', 'Gene', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('p.R337H', 'Var', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('p.R337H', 'Mutation', 'rs121912664', (104, 111))	('TP53', 'Gene', '7157', (99, 103))
545279	32875577	Ongoing attention to not only cancer biology but also additional factors permissive to oncogenic stress is a priority in the context of the reduced-penetrant TP53 allele, as represented by the p.R337H allele.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('reduced-penetrant', 'NegReg', (140, 157))	('stress', 'Disease', (97, 103))	('stress', 'Disease', 'MESH:D000079225', (97, 103))	('p.R337H', 'Var', (193, 200))	('p.R337H', 'Mutation', 'rs121912664', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
545281	32875577	Emilia Modolo Pinto and Gerard P. Zambetti report a patent pending ("Genotyping Assays to Identify Mutations in XAF1").	('XAF1', 'Gene', '54739', (112, 116))	('XAF1', 'Gene', (112, 116))	('Mutations', 'Var', (99, 108))
545303	31019717	Polymerase chain reaction (PCR) demonstrated the presence of an SS18-SSX1 fusion confirming the diagnosis.	('fusion', 'Var', (74, 80))	('SS18', 'Gene', (64, 68))	('SSX1', 'Gene', '6756', (69, 73))	('SSX1', 'Gene', (69, 73))	('SS18', 'Gene', '6760', (64, 68))
545320	31019717	Synovial sarcoma is associated with the presence of the t(X;18)(p11.2;q11.2) translocation, which is described in >95% of the cases 7.	('associated', 'Reg', (20, 30))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (56, 76))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('t(X;18)(p11.2', 'Var', (56, 69))
545340	31019717	Poor prognostic features of synovial sarcoma include size >5 cm, male gender, age >20 years, extensive tumour necrosis, large number of mitotic figures, neurovascular invasion, and SS18-SSX1 variant 6.	('SS18', 'Gene', '6760', (181, 185))	('SSX1', 'Gene', (186, 190))	('synovial sarcoma', 'Disease', 'MESH:D013584', (28, 44))	('SSX1', 'Gene', '6756', (186, 190))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('synovial sarcoma', 'Disease', (28, 44))	('variant 6', 'Var', (191, 200))	('tumour necrosis', 'Disease', 'MESH:D009336', (103, 118))	('tumour necrosis', 'Disease', (103, 118))	('SS18', 'Gene', (181, 185))	('neurovascular invasion', 'CPA', (153, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (28, 44))
545367	27234989	Approval was based on the results of a randomized placebo-controlled Phase 3 (PALETTE) trial showing a significant, but modest, benefit in progression-free survival (PFS) for patients treated with pazopanib.	('patients', 'Species', '9606', (175, 183))	('progression-free survival', 'CPA', (139, 164))	('pazopanib', 'Var', (197, 206))	('pazopanib', 'Chemical', 'MESH:C516667', (197, 206))
545371	27234989	These include prolonged tumor growth stabilization, favorable outcomes in sarcomas with genetic mutations, durability of response:even upon treatment reinstitution after interruption of therapy, and absence of cumulative toxicity.	('sarcomas', 'Disease', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('genetic mutations', 'Var', (88, 105))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('sarcomas', 'Disease', 'MESH:D012509', (74, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (74, 82))	('toxicity', 'Disease', 'MESH:D064420', (221, 229))	('toxicity', 'Disease', (221, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
545387	27234989	The terminal half-life calculated using data from 14 Phase 1 and Phase 2 studies using non-linear mixed effects models was longer, in the range of 175 h. Of the five Phase 1 studies using trabectedin and one other chemotherapeutic agent, the most promising combination regimen in advanced soft tissue sarcomas (STS) and breast cancer was trabectedin with doxorubicin, with an overall response rate (ORR) of 18%, SD of 56%, and disease control rate (DCR) of 74%.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (289, 309))	('trabectedin', 'Chemical', 'MESH:D000077606', (338, 349))	('STS', 'Phenotype', 'HP:0030448', (311, 314))	('trabectedin', 'Var', (338, 349))	('soft tissue sarcomas', 'Disease', (289, 309))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('breast cancer', 'Disease', 'MESH:D001943', (320, 333))	('sarcoma', 'Phenotype', 'HP:0100242', (301, 308))	('trabectedin', 'Chemical', 'MESH:D000077606', (188, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (301, 309))	('breast cancer', 'Disease', (320, 333))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (289, 308))	('breast cancer', 'Phenotype', 'HP:0003002', (320, 333))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (289, 309))	('doxorubicin', 'Chemical', 'MESH:D004317', (355, 366))
545400	27234989	The Phase 3 randomized study comparing doxorubicin and trabectedin as first-line therapy for translocation-related sarcomas enrolled 121 patients and reported no significant difference in PFS or OS between the two arms of the trial, with the response rate by response criteria in solid tumors (RECIST) significantly higher in the doxorubicin arm (27%) compared to the trabectedin arm (5.9%).	('trabectedin', 'Chemical', 'MESH:D000077606', (55, 66))	('doxorubicin', 'Var', (330, 341))	('solid tumors', 'Disease', 'MESH:D009369', (280, 292))	('trabectedin', 'Chemical', 'MESH:D000077606', (368, 379))	('sarcomas', 'Disease', 'MESH:D012509', (115, 123))	('doxorubicin', 'Chemical', 'MESH:D004317', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('patients', 'Species', '9606', (137, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('doxorubicin', 'Chemical', 'MESH:D004317', (330, 341))	('sarcomas', 'Disease', (115, 123))	('higher', 'PosReg', (316, 322))	('solid tumors', 'Disease', (280, 292))
545459	25751255	The Cell Cycle Regulator CCDC6 Is a Key Target of RNA-Binding Protein EWS Genetic translocation of EWSR1 to ETS transcription factor coding region is considered as primary cause for Ewing sarcoma.	('EWSR1', 'Gene', '2130', (99, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('RNA-Binding Protein', 'Gene', (50, 69))	('RNA-Binding Protein', 'Gene', '27303', (50, 69))	('Ewing sarcoma', 'Disease', (182, 195))	('cause', 'Reg', (172, 177))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('CCDC6', 'Gene', (25, 30))	('Genetic translocation', 'Var', (74, 95))	('EWSR1', 'Gene', (99, 104))	('CCDC6', 'Gene', '8030', (25, 30))
545468	25751255	Additionally, EWSR1 fusions to ATF1 cause soft tissue clear cell sarcoma while fusions to CHOP cause myxoid liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('myxoid liposarcoma', 'Disease', (101, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (101, 119))	('CHOP', 'Gene', (90, 94))	('liposarcoma', 'Phenotype', 'HP:0012034', (108, 119))	('ATF1', 'Gene', (31, 35))	('fusions', 'Var', (20, 27))	('ATF1', 'Gene', '466', (31, 35))	('EWSR1', 'Gene', '2130', (14, 19))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))	('sarcoma', 'Disease', (65, 72))	('cause', 'Reg', (36, 41))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('sarcoma', 'Disease', (112, 119))	('CHOP', 'Gene', '1649', (90, 94))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (101, 119))	('fusions', 'Var', (79, 86))	('EWSR1', 'Gene', (14, 19))
545470	25751255	Additionally, the loss of the EWSR1 allele creates haploinsufficiency of EWS protein which affects its RNA-binding activity and also its mRNA targets suggesting that EWS and its targets have important roles in the development of disease.	('EWSR1', 'Gene', '2130', (30, 35))	('haploinsufficiency', 'Disease', (51, 69))	('affects', 'Reg', (91, 98))	('RNA-binding', 'Interaction', (103, 114))	('loss', 'Var', (18, 22))	('EWS', 'Gene', (73, 76))	('mRNA targets', 'MPA', (137, 149))	('protein', 'Protein', (77, 84))	('haploinsufficiency', 'Disease', 'MESH:D058495', (51, 69))	('EWSR1', 'Gene', (30, 35))
545474	25751255	Altered protein expression of these ubiquitously expressed proteins has been shown to cause various human cancers EWS affects cellular growth mechanism like proliferation, migration and invasion by regulating AKT substrate PRAS40 and FAS dependent apoptosis by regulating the exon skipping of FAS/CD90.	('affects', 'Reg', (118, 125))	('regulating', 'Reg', (198, 208))	('protein', 'Protein', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('regulating', 'Reg', (261, 271))	('cancers', 'Disease', (106, 113))	('invasion', 'CPA', (186, 194))	('PRAS40', 'Gene', '84335', (223, 229))	('Altered', 'Var', (0, 7))	('cellular growth mechanism', 'CPA', (126, 151))	('cause', 'Reg', (86, 91))	('CD90', 'Gene', (297, 301))	('AKT', 'Gene', (209, 212))	('migration', 'CPA', (172, 181))	('CD90', 'Gene', '7070', (297, 301))	('exon', 'MPA', (276, 280))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('human', 'Species', '9606', (100, 105))	('AKT', 'Gene', '207', (209, 212))	('EWS', 'Disease', (114, 117))	('FAS dependent apoptosis', 'CPA', (234, 257))	('PRAS40', 'Gene', (223, 229))
545487	25751255	Transfection rates were in the range of 60-70% for MHH-ES-1 and 90% for HEK293T cell lines.	('MHH-ES-1', 'Var', (51, 59))	('HEK293T', 'CellLine', 'CVCL:0063', (72, 79))	('Transfection', 'CPA', (0, 12))
545504	25751255	The regulated genes included tumor-associated genes such as LIN28B (regulates let-7 miRNA processing), PURB (controls both DNA replication and transcription, its deletion has been associated with acute myeloid leukemia), CCDC6 (a potential tumor suppressor), CDCA4 (regulates E2F-dependent transcriptional activation and cell proliferation, mainly through the E2F/retinoblastoma pathway), MDM2 (E3 ubiquitin protein ligase and repressor of transcription factor p53) and FGF9 (roles in tissue repair, tumor growth and invasion).	('cell proliferation', 'CPA', (321, 339))	('FGF9', 'Gene', (470, 474))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('retinoblastoma', 'Phenotype', 'HP:0009919', (364, 378))	('FGF9', 'Gene', '2254', (470, 474))	('tumor', 'Phenotype', 'HP:0002664', (500, 505))	('CDCA4', 'Gene', (259, 264))	('retinoblastoma', 'Disease', (364, 378))	('tumor', 'Disease', (240, 245))	('p53', 'Gene', '7157', (461, 464))	('associated', 'Reg', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('acute myeloid leukemia', 'Disease', (196, 218))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('CCDC6', 'Gene', '8030', (221, 226))	('CCDC6', 'Gene', (221, 226))	('leukemia', 'Phenotype', 'HP:0001909', (210, 218))	('p53', 'Gene', (461, 464))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (202, 218))	('LIN28B', 'Gene', (60, 66))	('PURB', 'Gene', (103, 107))	('PURB', 'Gene', '5814', (103, 107))	('retinoblastoma', 'Disease', 'MESH:D012175', (364, 378))	('tumor', 'Disease', (500, 505))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('MDM2', 'Gene', (389, 393))	('deletion', 'Var', (162, 170))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (196, 218))	('CDCA4', 'Gene', '55038', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (500, 505))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (196, 218))	('tumor', 'Disease', (29, 34))	('MDM2', 'Gene', '4193', (389, 393))	('LIN28B', 'Gene', '389421', (60, 66))
545508	25751255	Another target, FGF9, which was reported to be downregulated and mutated in several carcinomas plays an important role in activating FGFR signaling.	('activating', 'PosReg', (122, 132))	('downregulated', 'NegReg', (47, 60))	('FGFR signaling', 'MPA', (133, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('carcinomas', 'Disease', 'MESH:D002277', (84, 94))	('carcinomas', 'Disease', (84, 94))	('FGF9', 'Gene', (16, 20))	('FGF9', 'Gene', '2254', (16, 20))	('mutated', 'Var', (65, 72))
545511	25751255	Similarly, CBFB is also frequently mutated in AML and is known to play a role in hematopoietic development.	('mutated', 'Var', (35, 42))	('role', 'Reg', (73, 77))	('CBFB', 'Gene', '865', (11, 15))	('AML', 'Disease', (46, 49))	('CBFB', 'Gene', (11, 15))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('play', 'Reg', (66, 70))
545514	25751255	Since ectopic expression of EWS/FLI1 resulted in growth arrest and apoptosis rather than promoting cellular transformation in cells as well as in mice, we next sought to look at the genes regulated by EWS with roles in cellular proliferation, cell cycle and cell death.	('apoptosis', 'CPA', (67, 76))	('growth arrest', 'Phenotype', 'HP:0001510', (49, 62))	('EWS/FLI1', 'Gene', (28, 36))	('mice', 'Species', '10090', (146, 150))	('ectopic expression', 'Var', (6, 24))	('growth arrest', 'Disease', (49, 62))	('growth arrest', 'Disease', 'MESH:D006323', (49, 62))
545522	25751255	It is known to be frequently rearranged with RET protein in papillary thyroid carcinomas and fuses to platelet derived growth factor receptor beta gene causing atypical chronic myeloid leukemia.	('RET', 'Gene', '5979', (45, 48))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (177, 193))	('rearranged', 'Var', (29, 39))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))	('platelet derived growth factor receptor beta', 'Gene', '5159', (102, 146))	('causing', 'Reg', (152, 159))	('RET', 'Gene', (45, 48))	('papillary thyroid carcinomas', 'Disease', (60, 88))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (60, 88))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (169, 193))	('chronic myeloid leukemia', 'Disease', (169, 193))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (169, 193))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (70, 88))	('platelet derived growth factor receptor beta', 'Gene', (102, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (60, 88))
545531	25751255	qRT-PCR results showed downregulation of CCDC6 mRNA levels upon knockdown of EWS.	('downregulation', 'NegReg', (23, 37))	('knockdown', 'Var', (64, 73))	('mRNA levels', 'MPA', (47, 58))	('CCDC6', 'Gene', '8030', (41, 46))	('CCDC6', 'Gene', (41, 46))
545534	25751255	Also, Western blot showed decreased expression of CCDC6 protein upon EWS knockdown in MHH-ES-1 (Fig.	('CCDC6', 'Gene', '8030', (50, 55))	('CCDC6', 'Gene', (50, 55))	('protein', 'Protein', (56, 63))	('MHH-ES-1', 'Gene', (86, 94))	('decreased', 'NegReg', (26, 35))	('expression', 'MPA', (36, 46))	('knockdown', 'Var', (73, 82))
545537	25751255	Since this regulation might further have an impact on several other downstream genes that CCDC6 itself regulates, we tested one of these published targets, namely FBXW7, which is required for DNA damage response, and indeed, qRT-PCR on FBXW7 following knockdown of EWS showed reduced RNA levels (Fig.	('CCDC6', 'Gene', '8030', (90, 95))	('CCDC6', 'Gene', (90, 95))	('RNA levels', 'MPA', (284, 294))	('FBXW7', 'Gene', (236, 241))	('qRT-PCR', 'Var', (225, 232))	('reduced', 'NegReg', (276, 283))	('FBXW7', 'Gene', '55294', (163, 168))	('FBXW7', 'Gene', '55294', (236, 241))	('FBXW7', 'Gene', (163, 168))
545541	25751255	It was previously shown that FET proteins show redundancy and that knockdown of EWS upregulates its two family members FUS and TAF15 in HEK293 cells as well as in liposarcoma cell lines.	('TAF15', 'Gene', '8148', (127, 132))	('redundancy', 'MPA', (47, 57))	('liposarcoma', 'Disease', 'MESH:D008080', (163, 174))	('HEK293', 'CellLine', 'CVCL:0045', (136, 142))	('liposarcoma', 'Phenotype', 'HP:0012034', (163, 174))	('knockdown', 'Var', (67, 76))	('EWS', 'Gene', (80, 83))	('upregulates', 'PosReg', (84, 95))	('FUS', 'Gene', (119, 122))	('TAF15', 'Gene', (127, 132))	('FUS', 'Gene', '2521', (119, 122))	('liposarcoma', 'Disease', (163, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
545545	25751255	Earlier studies reported that CCDC6 silencing increased apoptosis, decreased cell proliferation and affected cell cycle division by controlling the intra S phase and G2/M checkpoints.	('cell cycle division', 'CPA', (109, 128))	('increased', 'PosReg', (46, 55))	('CCDC6', 'Gene', (30, 35))	('intra S phase', 'CPA', (148, 161))	('G2/M checkpoints', 'CPA', (166, 182))	('affected', 'Reg', (100, 108))	('CCDC6', 'Gene', '8030', (30, 35))	('silencing', 'Var', (36, 45))	('apoptosis', 'CPA', (56, 65))	('decreased', 'NegReg', (67, 76))	('controlling', 'Reg', (132, 143))	('cell proliferation', 'CPA', (77, 95))
545547	25751255	To confirm whether downregulation of EWS also affects those processes, we assessed apoptosis using Annexin V FITC and PI double staining of EWS knockdown and control HEK293T cells.	('Annexin V', 'Gene', (99, 108))	('knockdown', 'Var', (144, 153))	('apoptosis', 'CPA', (83, 92))	('EWS', 'Gene', (140, 143))	('downregulation', 'NegReg', (19, 33))	('HEK293T', 'CellLine', 'CVCL:0063', (166, 173))	('Annexin V', 'Gene', '308', (99, 108))
545624	24927770	Site directed mutagenesis (QuickChange II XL, site directed mutagenesis kit, Agilent Technologies, Amsterdam, The Netherlands) was performed to mutate miR-210-3p and miR-485-5p target sites in the 3'UTR of HIF3alpha in psiCHECK2/HIF3alpha-short (Additional file 1: Figure S1).	('HIF3alpha', 'Gene', '64344', (229, 238))	('mutate', 'Var', (144, 150))	('miR-485', 'Gene', '574436', (166, 173))	('miR-485', 'Gene', (166, 173))	('HIF3alpha', 'Gene', (206, 215))	('5p', 'Chemical', '-', (174, 176))	('miR-210', 'Gene', (151, 158))	('miR-210', 'Gene', '406992', (151, 158))	('HIF3alpha', 'Gene', (229, 238))	('HIF3alpha', 'Gene', '64344', (206, 215))
545653	24927770	According to the Ensembl Genome Browser release 72 (http://www.ensembl.org) the HIF3alpha transcript variants 003 and 201 (consistent with HIF3alpha transcription variant 1, 2 and 3 according to GenBank (http://www.ncbi.nlm.nih.gov/genbank)) contain a long 3'UTR of 3811 bp which includes the potential miR-210-3p and miR-485-5p binding sites.	('miR-210', 'Gene', (303, 310))	('HIF3alpha', 'Gene', '64344', (80, 89))	('HIF3alpha', 'Gene', '64344', (139, 148))	('miR-210', 'Gene', '406992', (303, 310))	('variants', 'Var', (101, 109))	('5p', 'Chemical', '-', (326, 328))	('miR-485', 'Gene', '574436', (318, 325))	('HIF3alpha', 'Gene', (80, 89))	('miR-485', 'Gene', (318, 325))	('HIF3alpha', 'Gene', (139, 148))
545668	24927770	Compared to the scrambled negative control (mneg), miR-210-3p overexpression decreased the luciferase activity to 36% and 41% in SW872 (Figure 4C, left panel) and 37% and 43% in SK-UT-1 (Figure 4C, right panel) in the HIF3alpha-short and HIF3alpha-long transfectants respectively.	('miR-210', 'Gene', '406992', (51, 58))	('HIF3alpha', 'Gene', (218, 227))	('HIF3alpha', 'Gene', '64344', (238, 247))	('luciferase', 'Enzyme', (91, 101))	('HIF3alpha', 'Gene', '64344', (218, 227))	('activity', 'MPA', (102, 110))	('miR-210', 'Gene', (51, 58))	('overexpression', 'PosReg', (62, 76))	('SW872', 'CellLine', 'CVCL:1730', (129, 134))	('SW872', 'Var', (129, 134))	('SK-UT-1', 'CellLine', 'CVCL:0533', (178, 185))	('HIF3alpha', 'Gene', (238, 247))	('decreased', 'NegReg', (77, 86))
545672	24927770	To prove whether the regulation of HIF3alpha is due to direct binding of miR-210-3p and miR-485-5p to target sites in the 3'UTR, the predicted binding sites were mutated to prevent miRNA binding (Additional file 1: Figure S1).	('miR', 'Gene', (88, 91))	('HIF3alpha', 'Gene', '64344', (35, 44))	('miR-210', 'Gene', '406992', (73, 80))	('mutated', 'Var', (162, 169))	('prevent', 'Reg', (173, 180))	('miR', 'Gene', '220972', (181, 184))	('miR', 'Gene', (181, 184))	('miR-485', 'Gene', '574436', (88, 95))	('miR-485', 'Gene', (88, 95))	('miR', 'Gene', '220972', (73, 76))	('HIF3alpha', 'Gene', (35, 44))	('miR', 'Gene', (73, 76))	('5p', 'Chemical', '-', (96, 98))	('miR-210', 'Gene', (73, 80))	('miR', 'Gene', '220972', (88, 91))
545674	24927770	The presence of a mutated miR-210-3p binding site significantly increased (SW872) or restored (SK-UT-1) luciferase activity (Figure 4D).	('luciferase', 'Enzyme', (104, 114))	('binding', 'Interaction', (37, 44))	('restored', 'PosReg', (85, 93))	('mutated', 'Var', (18, 25))	('miR-210', 'Gene', (26, 33))	('activity', 'MPA', (115, 123))	('miR-210', 'Gene', '406992', (26, 33))	('SK-UT-1', 'CellLine', 'CVCL:0533', (95, 102))	('increased', 'PosReg', (64, 73))	('SW872', 'CellLine', 'CVCL:1730', (75, 80))
545675	24927770	Mutation of the miR-485-5p target site did not affect luciferase activity in SW872 cells and restored luciferase activity to some extent in the SK-UT-1 cells.	('activity', 'MPA', (65, 73))	('SK-UT-1', 'CellLine', 'CVCL:0533', (144, 151))	('Mutation', 'Var', (0, 8))	('miR-485', 'Gene', '574436', (16, 23))	('luciferase', 'Enzyme', (54, 64))	('luciferase', 'Enzyme', (102, 112))	('miR-485', 'Gene', (16, 23))	('restored', 'PosReg', (93, 101))	('activity', 'MPA', (113, 121))	('SW872', 'CellLine', 'CVCL:1730', (77, 82))	('5p', 'Chemical', '-', (24, 26))
545715	24927770	At least two other HIF3alpha transcripts that contain a smaller 3'UTR (478 bp in variant 006 and 287 bp in variant 007) also contain the miR-210-3p binding site suggesting that the HIF3alpha isoforms they encode may be controlled by miR-210-3p.	('variant', 'Var', (107, 114))	('HIF3alpha', 'Gene', (181, 190))	('HIF3alpha', 'Gene', '64344', (19, 28))	('miR-210', 'Gene', (137, 144))	('miR-210', 'Gene', (233, 240))	('HIF3alpha', 'Gene', '64344', (181, 190))	('miR-210', 'Gene', '406992', (233, 240))	('miR-210', 'Gene', '406992', (137, 144))	('variant 006', 'Var', (81, 92))	('HIF3alpha', 'Gene', (19, 28))
545737	24927770	None of the HIF3alpha variants are likely to act as potent transcription factors, since they lack a C-terminal transactivation domain.	('HIF3alpha', 'Gene', '64344', (12, 21))	('C-terminal transactivation domain', 'MPA', (100, 133))	('lack', 'NegReg', (93, 97))	('HIF3alpha', 'Gene', (12, 21))	('variants', 'Var', (22, 30))
545746	24927770	by therapeutic modulation of levels of miRNAs that are important for the hypoxic response, may inhibit the adaptive potential of the cells, and reduce their resistance against radiation and systemic agents.	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('adaptive potential of the cells', 'CPA', (107, 138))	('inhibit', 'NegReg', (95, 102))	('modulation', 'Var', (15, 25))	('reduce', 'NegReg', (144, 150))
545800	23894357	As the equation shows, the image, which contains only information from the focal plane, ISectioned, is calculated by acquiring three separate images (I1, I2, I3) which differ only in phase shift (phi1 = 0, phi2 = 2pi/3, phi3 = 4pi/3).	('phi1', 'Gene', (196, 200))	('I1, I2, I3', 'Gene', '64652', (150, 160))	('phi2 = 2pi/3', 'Var', (206, 218))	('phi1', 'Gene', '18938', (196, 200))	('rat', 'Species', '10116', (137, 140))	('phi3', 'Var', (220, 224))
545832	23894357	Primary sarcomas were induced by intramuscular injection of mice with conditional mutations in oncogenic K-ras or Braf and p53 with an adenovirus expressing Cre recombinase as previously described.	('p53', 'Gene', '22060', (123, 126))	('Primary sarcomas', 'Disease', 'MESH:D012509', (0, 16))	('induced', 'Reg', (22, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('Braf', 'Gene', (114, 118))	('K-ras', 'Gene', (105, 110))	('K-ras', 'Gene', '16653', (105, 110))	('mutations', 'Var', (82, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('p53', 'Gene', (123, 126))	('Primary sarcomas', 'Disease', (0, 16))	('mice', 'Species', '10090', (60, 64))	('Braf', 'Gene', '109880', (114, 118))
545919	20463876	The results of our algorithm are conceptually similar to the mapping of cellular expansion occurring during hematopoietic malignancies to the differentiation hierarchy of hematopoiesis.	('hematopoiesis', 'Disease', (171, 184))	('cellular expansion', 'Var', (72, 90))	('hematopoiesis', 'Disease', 'MESH:C536227', (171, 184))	('hematopoietic malignancies', 'Disease', (108, 134))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (108, 134))
546011	20463876	We use gene expression data of AML patient samples available within GEO (accession numbers GSE1159, GSE9476, GSE1729, and GSE12417).	('GSE1729', 'Chemical', '-', (109, 116))	('AML', 'Phenotype', 'HP:0004808', (31, 34))	('patient', 'Species', '9606', (35, 42))	('GSE9476', 'Chemical', '-', (100, 107))	('AML', 'Disease', 'MESH:D015470', (31, 34))	('GSE1159', 'Chemical', '-', (91, 98))	('GSE9476', 'Var', (100, 107))	('GSE1729', 'Var', (109, 116))	('AML', 'Disease', (31, 34))
546012	20463876	The breast cancer dataset is also compiled from Microarray data published in GEO with dataset numbers GSE7390, GSE2990, GSE3494, and GSE9574.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('GSE9574', 'Chemical', '-', (133, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('GSE3494', 'Chemical', '-', (120, 127))	('breast cancer', 'Disease', (4, 17))	('GSE2990', 'Var', (111, 118))	('GSE2990', 'Chemical', '-', (111, 118))	('GSE9574', 'Var', (133, 140))	('GSE7390', 'Var', (102, 109))	('GSE7390', 'Chemical', '-', (102, 109))	('GSE3494', 'Var', (120, 127))
546044	30693030	Immunosurveillance for cancer requires the recognition of tumor-specific antigens, including the products of mutated genes, overexpressed normal genes, or genes encoding viral proteins.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutated genes', 'Var', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
546061	30693030	The liposomes encapsulating MTP-PE can deliver the agent selectively to monocytes and macrophages.	('MTP-PE', 'Chemical', '-', (28, 34))	('MTP-PE', 'Var', (28, 34))	('deliver', 'MPA', (39, 46))
546062	30693030	After the delivery of MTP-PE to monocytes and macrophages, these cells become activated and tumoricidal.	('MTP-PE', 'Chemical', '-', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('MTP-PE', 'Var', (22, 28))	('tumor', 'Disease', (92, 97))
546067	30693030	On the other hand, a randomized phase 3 trial showed that five-year event-free survival rates for 91 patients with metastatic osteosarcoma who received L-MTP-PE and those who did not were 42% and 26%, respectively.	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('patients', 'Species', '9606', (101, 109))	('osteosarcoma', 'Disease', (126, 138))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('L-MTP-PE', 'Chemical', '-', (152, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('L-MTP-PE', 'Var', (152, 160))
546090	30693030	In the study, treatment with either the anti-CTLA-4 antibody or tumor lysate-pulsed DCs resulted in an increased number of CD8+ T lymphocytes, inhibition of primary and metastatic lesion growth, prolonged survival, reduced number of regulatory T lymphocytes, and increased levels of serum IFN-gamma, and the combination of these treatments enhanced the systemic immune response.	('anti-CTLA-4', 'Var', (40, 51))	('CD8', 'Gene', (123, 126))	('tumor', 'Disease', (64, 69))	('prolonged', 'PosReg', (195, 204))	('enhanced', 'PosReg', (340, 348))	('anti-CTLA-4', 'Gene', (40, 51))	('increased', 'PosReg', (103, 112))	('IFN-gamma', 'Gene', '3458', (289, 298))	('IFN-gamma', 'Gene', (289, 298))	('increased', 'PosReg', (263, 272))	('CD8', 'Gene', '925', (123, 126))	('reduced', 'NegReg', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('survival', 'CPA', (205, 213))	('inhibition', 'NegReg', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('systemic immune response', 'CPA', (353, 377))
546130	30693030	Blockade of PD-1 by anti-PD-1 nivolumab or anti-PD-L1 BMS-936559 has demonstrated objective responses and improved oncological survival in patients with lung cancer, melanoma, renal cell cancer, and ovarian cancer.	('improved', 'PosReg', (106, 114))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('renal cell cancer', 'Disease', 'MESH:C538614', (176, 193))	('anti-PD-1', 'Var', (20, 29))	('renal cell cancer', 'Disease', (176, 193))	('renal cell cancer', 'Phenotype', 'HP:0005584', (176, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('PD-1', 'Gene', (12, 16))	('anti-PD-L1 BMS-936559', 'Var', (43, 64))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('ovarian cancer', 'Disease', 'MESH:D010051', (199, 213))	('oncological survival', 'CPA', (115, 135))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('patients', 'Species', '9606', (139, 147))	('nivolumab', 'Chemical', 'MESH:D000077594', (30, 39))	('ovarian cancer', 'Disease', (199, 213))	('lung cancer', 'Disease', (153, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (199, 213))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
546133	30693030	In sarcomas with high PD-1 expression, PD-1 inhibitors are considered to be promising, while tumor antigen-specific treatments, such as dendritic cell-based immunotherapy, can be a candidate treatment in sarcomas with a high expression of tumor-specific antigen.	('PD-1', 'Gene', (22, 26))	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('sarcomas', 'Disease', (3, 11))	('high', 'Var', (17, 21))	('tumor', 'Disease', (93, 98))	('sarcomas', 'Disease', 'MESH:D012509', (204, 212))	('expression', 'MPA', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('sarcomas', 'Phenotype', 'HP:0100242', (204, 212))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('tumor', 'Disease', (239, 244))	('sarcomas', 'Disease', (204, 212))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
546142	30693030	Furthermore, combination immunotherapy using anti-CTLA-4 and anti-PD-L1 antibodies improved overall survival in a mouse model of osteosarcoma, whereas no benefit was observed upon treatment with an anti-CTLA-4 antibody alone.	('improved', 'PosReg', (83, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('anti-CTLA-4', 'Var', (45, 56))	('mouse', 'Species', '10090', (114, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (129, 141))	('antibodies', 'Var', (72, 82))	('overall survival', 'CPA', (92, 108))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('osteosarcoma', 'Disease', (129, 141))	('anti-PD-L1 antibodies', 'Var', (61, 82))
546178	30120321	EZH2 expression can be induced by the fusion gene of EWS/FLI1 via binding to its promoter in Ewing sarcoma in vivo.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (93, 106))	('expression', 'MPA', (5, 15))	('EZH2', 'Gene', '2146', (0, 4))	('fusion', 'Var', (38, 44))	('EZH2', 'Gene', (0, 4))	('binding', 'Interaction', (66, 73))	('induced', 'Reg', (23, 30))	('EWS', 'Gene', '2130', (53, 56))	('EWS', 'Gene', (53, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Ewing sarcoma', 'Disease', (93, 106))	('FLI1', 'Gene', (57, 61))	('FLI1', 'Gene', '2313', (57, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (93, 106))
546250	30120321	Further subgroup analysis showed that the sensitivity and specificity of EZH2 in well-differentiated LMS were 91.30% and 100%, respectively, which indicated that high expression of EZH2 is highly sensitive and specific to LMS, especially to well-differentiated LMS.	('EZH2', 'Gene', '2146', (181, 185))	('LMS', 'Phenotype', 'HP:0100243', (261, 264))	('LMS', 'Phenotype', 'HP:0100243', (222, 225))	('EZH2', 'Gene', (181, 185))	('well-differentiated LMS', 'Disease', (241, 264))	('EZH2', 'Gene', '2146', (73, 77))	('LMS', 'Phenotype', 'HP:0100243', (101, 104))	('EZH2', 'Gene', (73, 77))	('LMS', 'Disease', (222, 225))	('high', 'Var', (162, 166))
546259	30120321	RAS/KARS mutation promotes the expression of EZH2 by activating the MEK-ERK-ELK1 and PI3K-AKT signaling pathways of pancreatic cancer and non-small cell lung cancer.	('ELK1', 'Gene', (76, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))	('MEK', 'Gene', '5609', (68, 71))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (138, 164))	('activating', 'PosReg', (53, 63))	('pancreatic cancer', 'Disease', (116, 133))	('ERK', 'Gene', '5594', (72, 75))	('KARS', 'Gene', '3735', (4, 8))	('MEK', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('mutation', 'Var', (9, 17))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (142, 164))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('EZH2', 'Gene', '2146', (45, 49))	('EZH2', 'Gene', (45, 49))	('ELK1', 'Gene', '2002', (76, 80))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (138, 164))	('expression', 'MPA', (31, 41))	('promotes', 'PosReg', (18, 26))	('ERK', 'Gene', (72, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('KARS', 'Gene', (4, 8))	('non-small cell lung cancer', 'Disease', (138, 164))
546267	30120321	Recent studies reported that mutations of SUZ12 and EED had occurred in malignant peripheral nerve sheath tumors as well as head and neck high-grade malignant peripheral nerve sheath tumors had led to the loss of trimethylation at lysine 27 of histone H3 (H3K27me3), a downstream gene of EZH2.	('EZH2', 'Gene', (288, 292))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (72, 112))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('EED', 'Gene', (52, 55))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (72, 112))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (149, 189))	('malignant peripheral nerve sheath tumors', 'Disease', (72, 112))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (72, 111))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (149, 189))	('mutations', 'Var', (29, 38))	('SUZ12', 'Gene', (42, 47))	('trimethylation at lysine 27', 'MPA', (213, 240))	('EED', 'Gene', '8726', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('malignant peripheral nerve sheath tumors', 'Disease', (149, 189))	('SUZ12', 'Gene', '23512', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('H3K27me3', 'Protein', (256, 264))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (149, 188))	('loss', 'NegReg', (205, 209))	('occurred', 'Reg', (60, 68))	('lysine', 'Chemical', 'MESH:D008239', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('EZH2', 'Gene', '2146', (288, 292))
546282	30120321	The sections were blocked with goat serum and incubated with EZH2 antibody (1:200; catalog number: 5246, Cell Signaling Technology, MA, U.S.), SUZ12 antibody (1:100; catalog number: ab12073, Abcam, Cambridge, UK), RbAp46 antibody (1 microg/ml; catalog number: ab3535, Abcam, Cambridge,UK), EED antibody (1:200; catalog number: ab96801, Abcam, Cambridge, UK) and ki-67 antibody (1:400, catalog number: 12202, Cell Signaling Technology, MA, U.S.) at 4  C overnight.	('EED', 'Gene', (290, 293))	('EZH2', 'Gene', (61, 65))	('EZH2', 'Gene', '2146', (61, 65))	('SUZ12', 'Gene', '23512', (143, 148))	('1:200', 'Var', (304, 309))	('SUZ12', 'Gene', (143, 148))	('RbAp46', 'Gene', '5931', (214, 220))	('RbAp46', 'Gene', (214, 220))	('1:400', 'Var', (378, 383))	('goat', 'Species', '9925', (31, 35))	('EED', 'Gene', '8726', (290, 293))
546305	26463439	The distinctions in both clinicopathological and prognostic characteristics between UCS and G3EC suggest that this subtype should be treated separately from high-risk epithelial endometrial carcinoma.	('G3EC', 'Var', (92, 96))	('UCS', 'Chemical', '-', (84, 87))	('UCS', 'Disease', (84, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('epithelial endometrial carcinoma', 'Disease', 'MESH:D016889', (167, 199))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (178, 199))	('epithelial endometrial carcinoma', 'Disease', (167, 199))	('EC', 'Phenotype', 'HP:0012114', (94, 96))	('UCS', 'Phenotype', 'HP:0002891', (84, 87))
546345	26463439	The average diameter of the largest tumors observed in UCS and G3EC patients were 4.6 cm (range, 0.3 to 14.0 cm) and 4.0 cm (range, 0.3 to 11.0 cm), respectively, and these values showed significant statistical differences (p=0.046).	('UCS', 'Phenotype', 'HP:0002891', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('patients', 'Species', '9606', (68, 76))	('G3EC', 'Var', (63, 67))	('UCS', 'Chemical', '-', (55, 58))	('EC', 'Phenotype', 'HP:0012114', (65, 67))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
546361	26463439	G3EC patients with ascites fluid (p=0.003), advanced disease (p<0.001), adnexal involvement (p=0.043), vaginal involvement (p=0.027), LVSI and nerve invasion (p<0.001), and lymph node metastases (p<0.001) were correlated with worse OS (Table 3).	('worse OS', 'Disease', (226, 234))	('patients', 'Species', '9606', (5, 13))	('ascites', 'Phenotype', 'HP:0001541', (19, 26))	('lymph node metastases', 'Disease', 'MESH:D009362', (173, 194))	('ascites fluid', 'Disease', (19, 32))	('lymph node metastases', 'Disease', (173, 194))	('G3EC', 'Var', (0, 4))	('ascites fluid', 'Disease', 'MESH:D001201', (19, 32))	('OS', 'Chemical', '-', (232, 234))	('EC', 'Phenotype', 'HP:0012114', (2, 4))
546371	26463439	A SEER (Surveillance, Epidemiology and End Results) study reported that high-grade EM cases had significantly better OS than UCS cases after adjusting for age, race, lymph node dissection, stage, and postoperative RT.	('OS', 'Chemical', '-', (117, 119))	('high-grade', 'Var', (72, 82))	('UCS', 'Phenotype', 'HP:0002891', (125, 128))	('better', 'PosReg', (110, 116))	('UCS', 'Chemical', '-', (125, 128))
546400	26463439	Several studies have shown favorable outcomes in carcinosarcoma patients treated with carboplatin-paclitaxel and recommended this regimen as a first-line treatment.	('patients', 'Species', '9606', (64, 72))	('carcinosarcoma', 'Disease', 'MESH:D002296', (49, 63))	('carboplatin', 'Chemical', 'MESH:D016190', (86, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('carboplatin-paclitaxel', 'Var', (86, 108))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('carcinosarcoma', 'Disease', (49, 63))
546451	25685343	Lymphadenopathy from myocobacterium avium interacellulare or lymphoma can result in appendicitis or jaundice by obstructing the appendiceal ostium or porta hepatis, respectively.	('Lymphadenopathy', 'Disease', 'MESH:D008206', (0, 15))	('Lymphadenopathy', 'Disease', (0, 15))	('appendiceal', 'Disease', (128, 139))	('lymphoma', 'Disease', 'MESH:D008223', (61, 69))	('obstructing', 'NegReg', (112, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('result in', 'Reg', (74, 83))	('hepatis', 'Disease', (156, 163))	('appendicitis or jaundice', 'Disease', 'MESH:D007565', (84, 108))	('Lymphadenopathy', 'Phenotype', 'HP:0002716', (0, 15))	('jaundice', 'Phenotype', 'HP:0000952', (100, 108))	('appendicitis or jaundice', 'Disease', (84, 108))	('hepatis', 'Disease', 'MESH:D010382', (156, 163))	('myocobacterium', 'Var', (21, 35))	('lymphoma', 'Disease', (61, 69))
546513	25685343	Inappropriate anal instrumentation or 'fisting' injuries can result in the most horrendous sphincter injuries which usually require permanent faecal diversion.	('injuries', 'Var', (48, 56))	('result', 'Reg', (61, 67))	('anal instrumentation', 'Phenotype', 'HP:0012390', (14, 34))	('sphincter injuries', 'Phenotype', 'HP:0002839', (91, 109))	('horrendous sphincter injuries', 'Disease', (80, 109))	('men', 'Species', '9606', (25, 28))
546753	33389928	It should be kept in mind that morcellation significantly increases the risk of these benign sequelae compared to the risk of spreading malignancies.	('malignancies', 'Disease', (136, 148))	('morcellation', 'Var', (31, 43))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))
546755	33389928	Besides, there are publications supporting the idea that morcellation can worsen the stage and negatively affect survival in the presence of malignancy.	('survival', 'CPA', (113, 121))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('worsen', 'PosReg', (74, 80))	('malignancy', 'Disease', (141, 151))	('stage', 'MPA', (85, 90))	('morcellation', 'Var', (57, 69))	('negatively', 'NegReg', (95, 105))	('affect', 'Reg', (106, 112))
546759	33389928	In another case series, the 1-year mortality rate was found to be significantly higher in the morcellation group.	('mortality', 'Disease', (35, 44))	('higher', 'PosReg', (80, 86))	('mortality', 'Disease', 'MESH:D003643', (35, 44))	('morcellation', 'Var', (94, 106))
546781	33389928	In a study using receiver operating characteristic curve analysis for the prediction of sarcoma in the pre-operative period, the optimum cut-off value for LDH was 279.0 U/L.	('279.0 U/L', 'Var', (163, 172))	('LDH', 'Gene', (155, 158))	('sarcoma', 'Disease', 'MESH:D012509', (88, 95))	('sarcoma', 'Disease', (88, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
546796	33389928	The morcellation of sarcomas can result in disease progression and worsen survival outcomes compared to non-morcellation.	('worsen', 'NegReg', (67, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('result in', 'Reg', (33, 42))	('sarcomas', 'Disease', (20, 28))	('disease progression', 'CPA', (43, 62))	('morcellation', 'Var', (4, 16))	('sarcomas', 'Disease', 'MESH:D012509', (20, 28))	('survival outcomes', 'MPA', (74, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
546802	32272784	In Ewing sarcoma, we identified RON among RTKs conferring resistance to insulin-like growth factor-1 receptor (IGF1R) targeting.	('RTK', 'Gene', (42, 45))	('IGF1R', 'Gene', '3480', (111, 116))	('resistance to insulin', 'Phenotype', 'HP:0000855', (58, 79))	('Ewing sarcoma', 'Disease', (3, 16))	('RON', 'Var', (32, 35))	('RTK', 'Gene', '5979', (42, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('insulin-like growth factor-1 receptor', 'Gene', (72, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('IGF1R', 'Gene', (111, 116))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (72, 109))
546816	32272784	Targeted inhibition of RON reversed these features, linking RON to both progression and maintenance of an aggressive invasive-metastatic carcinoma phenotype.	('carcinoma', 'Disease', 'MESH:D009369', (137, 146))	('RON', 'Protein', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('carcinoma', 'Disease', (137, 146))	('inhibition', 'Var', (9, 19))
546846	32272784	Interestingly, RON silencing did not affect monolayer cell proliferation in vitro, neither for the A673 nor TC-32 cells (Figure 2b).	('monolayer cell proliferation', 'CPA', (44, 72))	('silencing', 'Var', (19, 28))	('RON', 'Protein', (15, 18))	('TC-32', 'CellLine', 'CVCL:7151', (108, 113))
546856	32272784	While we did not observe formation of multi-cellular micrometastases by our time point of analysis at 4 dpi, CHT areas showed A673 cells harboring non-silencing shRNA that persisted outside the vasculature (Figure 3c).	('non-silencing', 'Var', (147, 160))	('metastases', 'Disease', (58, 68))	('metastases', 'Disease', 'MESH:D009362', (58, 68))
546857	32272784	Although these dissemination and invasion capacities could not be conclusively quantified, they appeared reduced with RON silencing, suggesting that RON contributes to tumor burden in vivo and to the micrometastatic potential of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (229, 242))	('tumor', 'Disease', (168, 173))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (229, 242))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('micrometastatic potential', 'CPA', (200, 225))	('reduced', 'NegReg', (105, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('invasion capacities', 'CPA', (33, 52))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('silencing', 'Var', (122, 131))	('Ewing sarcoma', 'Disease', (229, 242))	('RON', 'Protein', (118, 121))
546880	32272784	Yet, although our data reveal RON activation through both MSP and IGF1 ligand-mediated mechanisms, IMC-A12 failed to sensitize sarcoma cells to IMC-RON8.	('IGF1', 'Gene', '3479', (66, 70))	('RON', 'Protein', (30, 33))	('IMC-A12', 'Chemical', 'MESH:C557414', (99, 106))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('IGF1', 'Gene', (66, 70))	('activation', 'PosReg', (34, 44))	('IMC-A12', 'Var', (99, 106))	('sarcoma', 'Disease', (127, 134))	('MSP', 'Gene', '4485', (58, 61))	('MSP', 'Gene', (58, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('IMC-RON8', 'Chemical', '-', (144, 152))
546882	32272784	RON isoform variants with ligand-independent activities bear the potential to subvert the effects of IMC-RON8 or other compounds that target ligand-receptor binding.	('effects', 'MPA', (90, 97))	('variants', 'Var', (12, 20))	('subvert', 'NegReg', (78, 85))	('IMC-RON8', 'Chemical', '-', (101, 109))
546883	32272784	In carcinomas, at least eight isoforms have been reported, most due to alternative splicing.	('carcinomas', 'Phenotype', 'HP:0030731', (3, 13))	('carcinomas', 'Disease', (3, 13))	('alternative splicing', 'Var', (71, 91))	('carcinomas', 'Disease', 'MESH:D009369', (3, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (3, 12))
546887	32272784	Alternative splicing with deletion of exons 5-6 (corresponding to the IPT1 domain) results in a 160 kDa precursor chain that is cleaved into the alpha-chain and a constitutively active 125 kDa beta-chain.	('results in', 'Reg', (83, 93))	('alpha-chain', 'Gene', '2217', (145, 156))	('alpha-chain', 'Gene', (145, 156))	('deletion', 'Var', (26, 34))
546888	32272784	HCT-116 cells are characterized by the splicing variant Delta160E2E3 with deletion of exons 2-3 (corresponding to parts of the beta-chain SEMA domain).	('SEMA', 'Gene', '7869', (138, 142))	('HCT-116', 'CellLine', 'CVCL:0291', (0, 7))	('SEMA', 'Gene', (138, 142))	('Delta160E2E3', 'Var', (56, 68))
546890	32272784	In keeping, Western blots of Figure 5a revealed the Delta160E5E6 variant with phospho-specific and both SEMA and IPT3 domain-directed antibodies, whereas the Delta160E2E3 variant was better visualized with an IPT3 epitope-directed antibody.	('SEMA', 'Gene', (104, 108))	('SEMA', 'Gene', '7869', (104, 108))	('Delta160E5E6', 'Var', (52, 64))
546891	32272784	Interestingly, all Ewing sarcoma and RH-41 rhabdomyosarcoma cells expressed a single phosphorylated protein band of similar weight as the 125 kDa Delta160E5E6 beta-chain, while RH-18 and RH-30 showed a second band corresponding in weight to the 150 kDa beta-chain of wild-type RON.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (43, 59))	('RH-30', 'Gene', (187, 192))	('Delta160E5E6', 'Var', (146, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (19, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (43, 59))	('RH-30', 'Gene', '6007', (187, 192))	('rhabdomyosarcoma', 'Disease', (43, 59))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (19, 32))	('RH', 'Chemical', 'MESH:D012238', (37, 39))	('RH', 'Chemical', 'MESH:D012238', (187, 189))	('RH', 'Chemical', 'MESH:D012238', (177, 179))	('Ewing sarcoma', 'Disease', (19, 32))
546892	32272784	Although these preliminary findings require further validation of specific isoforms, they suggest that pediatric sarcomas may express splicing variants of full-length RON (flRON) that evade targeting strategies based on interruption of ligand-receptor binding, such as IMC-RON8.	('sarcomas', 'Disease', (113, 121))	('flRON', 'Gene', (172, 177))	('ligand-receptor', 'Interaction', (236, 251))	('splicing variants', 'Var', (134, 151))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('IMC-RON8', 'Chemical', '-', (269, 277))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('flRON', 'Chemical', '-', (172, 177))
546897	32272784	Sequencing of the double bands revealed sfRON variants with and without splicing of intron 11 (Figure S4), as previously reported in carcinomas.	('carcinomas', 'Disease', (133, 143))	('sfRON', 'Gene', (40, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('variants', 'Var', (46, 54))	('sfRON', 'Chemical', '-', (40, 45))	('carcinomas', 'Disease', 'MESH:D009369', (133, 143))
546900	32272784	In carcinomas and leukemias, differential expression of full-length RON (flRON) and sfRON isoforms has been found governed, at least in part, by methylation patterns of two CpG islands in the proximal RON promoter.	('carcinomas', 'Phenotype', 'HP:0030731', (3, 13))	('flRON', 'Chemical', '-', (73, 78))	('sfRON', 'Chemical', '-', (84, 89))	('leukemia', 'Phenotype', 'HP:0001909', (18, 26))	('RON', 'Gene', (68, 71))	('carcinomas and leukemias', 'Disease', 'MESH:D009369', (3, 27))	('methylation', 'Var', (145, 156))	('leukemias', 'Phenotype', 'HP:0001909', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (3, 12))
546901	32272784	Hypermethylation of island 1 coincided with lack of flRON, whereas hypermethylation of island 2 was associated with sfRON transcription.	('flRON', 'MPA', (52, 57))	('Hypermethylation', 'Var', (0, 16))	('hypermethylation', 'Var', (67, 83))	('flRON', 'Chemical', '-', (52, 57))	('sfRON', 'Chemical', '-', (116, 121))	('lack', 'NegReg', (44, 48))	('sfRON transcription', 'MPA', (116, 135))
546935	32272784	While therefore being less suitable when studying specific RON functions, a broader target spectrum comprising RON among other, more-established RTK targets (including its interacting co-targets MET and IGF1R) may promote the clinical development of tyrosine kinase inhibitors, such as crizotinib (NCT02612194) or ASLAN002 (also known as BMS-777607; NCT01721148).	('IGF1R', 'Gene', '3480', (203, 208))	('RTK', 'Gene', (145, 148))	('promote', 'PosReg', (214, 221))	('MET', 'Chemical', 'MESH:D008715', (195, 198))	('RTK', 'Gene', '5979', (145, 148))	('IGF1R', 'Gene', (203, 208))	('NCT02612194', 'Var', (298, 309))	('ASLAN002', 'Gene', (314, 322))	('tyrosine', 'Chemical', 'MESH:D014443', (250, 258))	('crizotinib', 'Chemical', 'MESH:D000077547', (286, 296))
546950	32272784	Therefore, our data so far provide no more than starting-points for future analyses: To distinguish the exact functional significance of specific isoform variants on the proliferative, migratory or metastatic phenotype of Ewing sarcoma, signaling crosstalk, drug response, selective depletion or overexpression experiments are warranted.	('Ewing sarcoma', 'Disease', (222, 235))	('variants', 'Var', (154, 162))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (222, 235))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (222, 235))	('metastatic', 'CPA', (198, 208))	('migratory', 'CPA', (185, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))
546953	32272784	Modulating RON promoter methylation to shift relative sfRON and flRON expressions towards a more drug-sensitive pattern provides an intriguing strategy.	('Modulating', 'Var', (0, 10))	('flRON', 'Chemical', '-', (64, 69))	('RON', 'Protein', (11, 14))	('sfRON', 'Chemical', '-', (54, 59))
546955	32272784	In most Ewing sarcoma cell lines, DNA methyltransferase inhibition did not prompt a shift between isoforms, but an increase in both sfRON and flRON.	('flRON', 'Chemical', '-', (142, 147))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (8, 21))	('flRON', 'MPA', (142, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (8, 21))	('increase', 'PosReg', (115, 123))	('sfRON', 'MPA', (132, 137))	('sfRON', 'Chemical', '-', (132, 137))	('inhibition', 'Var', (56, 66))	('Ewing sarcoma', 'Disease', (8, 21))
546963	32272784	While flRON acted transactivated by MET and MSP ligand failed to reactivate flRON in the presence of a MET inhibitor, sfRON maintained downstream signaling and conferred resistance.	('conferred', 'Reg', (160, 169))	('resistance', 'MPA', (170, 180))	('flRON', 'Chemical', '-', (76, 81))	('MSP', 'Gene', '4485', (44, 47))	('MSP', 'Gene', (44, 47))	('MET', 'Chemical', 'MESH:D008715', (103, 106))	('sfRON', 'Chemical', '-', (118, 123))	('maintained', 'PosReg', (124, 134))	('downstream signaling', 'MPA', (135, 155))	('MET', 'Chemical', 'MESH:D008715', (36, 39))	('flRON', 'Chemical', '-', (6, 11))	('sfRON', 'Var', (118, 123))
546964	32272784	In myeloid leukemia, sfRON but not flRON physically interacted with the intracellular tyrosine kinase LYN to drive cell proliferation in a PI3K/AKT-independent manner.	('flRON', 'Chemical', '-', (35, 40))	('LYN', 'Gene', '4067', (102, 105))	('sfRON', 'Chemical', '-', (21, 26))	('AKT', 'Gene', (144, 147))	('interacted', 'Interaction', (52, 62))	('myeloid leukemia', 'Disease', 'MESH:D007951', (3, 19))	('tyrosine', 'Chemical', 'MESH:D014443', (86, 94))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (3, 19))	('drive', 'PosReg', (109, 114))	('sfRON', 'Var', (21, 26))	('leukemia', 'Phenotype', 'HP:0001909', (11, 19))	('cell proliferation', 'CPA', (115, 133))	('AKT', 'Gene', '207', (144, 147))	('myeloid leukemia', 'Disease', (3, 19))	('LYN', 'Gene', (102, 105))
546989	32272784	3077) and phospho-IGF1R (Tyr1131/1146) (Cat-No.	('IGF1R', 'Gene', (18, 23))	('Tyr1131/1146', 'Var', (25, 37))	('IGF1R', 'Gene', '3480', (18, 23))	('Tyr1131', 'Chemical', '-', (25, 32))
547042	27466209	Abdominal distention or distortion and pelvic pressure on the ureters (causing hydronephrosis) and pelvic blood vessels (particularly pelvic veins) could also interfere with quality of life (QoL).	('interfere', 'NegReg', (159, 168))	('Abdominal distention', 'Phenotype', 'HP:0003270', (0, 20))	('hydronephrosis', 'Disease', 'MESH:D006869', (79, 93))	('hydronephrosis', 'Disease', (79, 93))	('hydronephrosis', 'Phenotype', 'HP:0000126', (79, 93))	('quality of life', 'CPA', (174, 189))	('distortion', 'Var', (24, 34))
547069	27466209	After resection or ablation of the protruded portion of the myoma during first-step hysteroscopy, the residual intramural component rapidly migrates to the uterine cavity, with a parallel increase in myometrial thickness, allowing complete and safe myoma excision during second-step hysteroscopy.	('myoma', 'Disease', (249, 254))	('myoma', 'Disease', 'MESH:D009214', (60, 65))	('ablation', 'Var', (19, 27))	('myoma', 'Disease', (60, 65))	('myometrial', 'MPA', (200, 210))	('increase', 'PosReg', (188, 196))	('myoma', 'Disease', 'MESH:D009214', (249, 254))
547108	27466209	As stressed by in their review, hyperintensive MRI images are associated with reduced treatment success compared with hypointensive images of fibroids.	('hypointensive', 'Disease', (118, 131))	('treatment success', 'CPA', (86, 103))	('hyperintensive MRI images', 'Var', (32, 57))	('reduced', 'NegReg', (78, 85))	('hypointensive', 'Disease', 'None', (118, 131))
547232	26987019	Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes.	('promotes', 'PosReg', (69, 77))	('Embryonal Rhabdomyosarcoma', 'Disease', (119, 145))	('distinct sarcoma subtypes', 'Disease', 'MESH:D012509', (93, 118))	('sarcoma', 'Disease', 'MESH:D012509', (102, 109))	('Embryonal Rhabdomyosarcoma', 'Disease', 'MESH:D018233', (119, 145))	('distinct sarcoma subtypes', 'Disease', 'MESH:D012509', (204, 229))	('Hepatocyte Growth Factor', 'Gene', '15234', (0, 24))	('sarcoma', 'Disease', (102, 109))	('Pleomorphic Sarcoma (UPS', 'Gene', (174, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('sarcoma', 'Disease', (138, 145))	('Embryonal Rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (119, 145))	('perturbation', 'Var', (56, 68))	('distinct sarcoma subtypes', 'Disease', (93, 118))	('Pleomorphic Sarcoma (UPS)', 'Gene', '15288', (174, 199))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (129, 145))	('Hepatocyte Growth Factor', 'Gene', (0, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('distinct sarcoma subtypes', 'Disease', (204, 229))	('Sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('sarcoma', 'Disease', 'MESH:D012509', (213, 220))	('sarcoma', 'Disease', (213, 220))
547237	26987019	Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation.	('perturbation', 'Var', (48, 60))	('sarcoma initiation', 'Disease', (197, 215))	('Pax7', 'Gene', '18509', (119, 123))	('results in', 'Reg', (77, 87))	('sarcoma initiation', 'Disease', 'MESH:D012509', (197, 215))	('distinct sarcoma subtypes', 'Disease', (88, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('Pax7', 'Gene', (119, 123))	('distinct sarcoma subtypes', 'Disease', 'MESH:D012509', (88, 113))
547259	26987019	While ARMS carry only a few genetic lesions in addition to the pathognomonic ones, the ERMS subtype is highly heterogeneous, with recurrent mutations/copy number variations in genes coding for tyrosine kinase receptors (RTKs) and their downstream effectors (RAS and PIK3CA).	('genetic lesion', 'Disease', (28, 42))	('genetic lesion', 'Disease', 'MESH:D020022', (28, 42))	('mutations/copy', 'Var', (140, 154))	('PIK3CA', 'Gene', '18706', (266, 272))	('ERMS', 'Disease', (87, 91))	('PIK3CA', 'Gene', (266, 272))
547268	26987019	Altogether, our data show that perturbation of the SC niche with HGF can promote distinct sarcoma subtypes in a Pax7 lineage-dependent manner, thus offering a possible explanation of why ERMS and UPS are part of a tumor continuum.	('distinct sarcoma subtypes', 'Disease', 'MESH:D012509', (81, 106))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('Pax7', 'Gene', (112, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('Pax7', 'Gene', '18509', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('UPS', 'Gene', '15288', (196, 199))	('HGF', 'Gene', (65, 68))	('distinct sarcoma subtypes', 'Disease', (81, 106))	('tumor', 'Disease', (214, 219))	('perturbation', 'Var', (31, 43))	('promote', 'PosReg', (73, 80))	('UPS', 'Gene', (196, 199))	('ERMS', 'Disease', (187, 191))
547286	26987019	Homozygous deletions of the CDKN2A locus has been reported in the majority of human tumors including sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('human tumors', 'Disease', (78, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('CDKN2A', 'Gene', (28, 34))	('human tumors', 'Disease', 'MESH:D009369', (78, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('reported', 'Reg', (50, 58))	('sarcomas', 'Disease', (101, 109))	('Homozygous deletions', 'Var', (0, 20))
547288	26987019	The frequent inactivation of the locus has been confirmed by an additional study reporting the deletion in 32% of UPS cases.	('UPS', 'Gene', '15288', (114, 117))	('deletion', 'Var', (95, 103))	('UPS', 'Gene', (114, 117))
547300	26987019	PCR analysis revealed that the majority of the tumors in MHI-het mice had lost the wild type allele (Figure 3:figure supplement 1D).	('lost', 'NegReg', (74, 78))	('tumors', 'Disease', (47, 53))	('MHI-het', 'Var', (57, 64))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('mice', 'Species', '10090', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
547310	26987019	However MHI-null P-null mice showed a drastic reduction in ERMS incidence (Figure 4C).	('ERMS incidence', 'CPA', (59, 73))	('reduction', 'NegReg', (46, 55))	('MHI-null', 'Var', (8, 16))	('mice', 'Species', '10090', (24, 28))
547318	26987019	Altogether our data clearly indicate that perturbation of the SC niche microenvironment can give rise to distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and provide evidence for a fibroblast cell origin of UPS.	('give rise to', 'Reg', (92, 104))	('UPS', 'Gene', (220, 223))	('Pax7', 'Gene', '18509', (136, 140))	('distinct sarcoma subtypes', 'Disease', (105, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('UPS', 'Gene', '15288', (220, 223))	('Pax7', 'Gene', (136, 140))	('perturbation', 'Var', (42, 54))	('distinct sarcoma subtypes', 'Disease', 'MESH:D012509', (105, 130))
547319	26987019	In our model transgenic Hgf comes from differentiated muscle fibers.	('Hgf', 'Gene', '15234', (24, 27))	('transgenic', 'Species', '10090', (13, 23))	('transgenic', 'Var', (13, 23))	('Hgf', 'Gene', (24, 27))
547324	26987019	To identify signaling pathways involved in tumor maintenance, we tested a panel of 18 ERMS lines with receptor tyrosine kinase (RTK) phosphoarrays.	('phosphoarrays', 'Var', (133, 146))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tested', 'Reg', (65, 71))
547329	26987019	Overall murine and human data indicate a considerable variability of Met expression and rare Met amplification.	('Met expression', 'MPA', (69, 83))	('rare', 'Var', (88, 92))	('human', 'Species', '9606', (19, 24))	('murine', 'Species', '10090', (8, 14))
547332	26987019	Accordingly, some ERMS cases of mutated phosphatidylinositol 3 kinase A (PIK3CA) have been reported and 82.5% of RMS tumors have been found to display a strong activation of the pathway.	('RMS tumors', 'Disease', 'MESH:D009369', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('activation', 'PosReg', (160, 170))	('PIK3CA', 'Gene', '18706', (73, 79))	('mutated', 'Var', (32, 39))	('RMS tumors', 'Disease', (113, 123))	('ERMS', 'Disease', (18, 22))	('PIK3CA', 'Gene', (73, 79))
547343	26987019	In L cells Crizotinib caused a strong inhibition of ALK signaling, impairment of anchorage-independent growth and induction of myogenic differentiation (Figure 7E-G), as well as G0/G1 accumulation and induction of apoptosis (Figure 7:figure supplement 1B,C).	('apoptosis', 'CPA', (214, 223))	('anchorage-independent growth', 'CPA', (81, 109))	('myogenic differentiation', 'CPA', (127, 151))	('Crizotinib', 'Chemical', 'MESH:D000077547', (11, 21))	('ALK signaling', 'MPA', (52, 65))	('Crizotinib', 'Var', (11, 21))	('impairment', 'NegReg', (67, 77))	('G0/G1', 'CPA', (178, 183))	('induction', 'Reg', (114, 123))	('inhibition', 'NegReg', (38, 48))	('accumulation', 'PosReg', (184, 196))
547363	26987019	obtained an aggressive form of head and neck ERMS by activating the Sonic Hedgehog pathway in combination with Cdkn2a deletion in adipocyte precursors.	('Cdkn2a', 'Gene', (111, 117))	('Sonic Hedgehog pathway', 'Pathway', (68, 90))	('activating', 'PosReg', (53, 63))	('Cdkn2a', 'Gene', '12578', (111, 117))	('deletion', 'Var', (118, 126))
547364	26987019	According to Rubin et al., 100% of ERMS incidence occurred when p53 was knocked out in late myogenic precursors (Myf6-driven Cre), while its deletion in satellite cells (Pax7-driven Cre) resulted in UPS.	('knocked out', 'Var', (72, 83))	('deletion', 'Var', (141, 149))	('Pax7', 'Gene', (170, 174))	('p53', 'Gene', (64, 67))	('UPS', 'Gene', '15288', (199, 202))	('Myf6', 'Gene', (113, 117))	('p53', 'Gene', '22059', (64, 67))	('Myf6', 'Gene', '17878', (113, 117))	('Pax7', 'Gene', '18509', (170, 174))	('ERMS', 'Disease', (35, 39))	('UPS', 'Gene', (199, 202))
547365	26987019	Notably, activation of Sonic Hedgehog in satellite cells in the same context of p53 deficiency, triggered ERMS formation, while its dysregulation in Myf6-positive-cells, promoted UPS development.	('activation', 'PosReg', (9, 19))	('p53', 'Gene', (80, 83))	('ERMS formation', 'CPA', (106, 120))	('Myf6', 'Gene', '17878', (149, 153))	('UPS', 'Gene', '15288', (179, 182))	('p53', 'Gene', '22059', (80, 83))	('Myf6', 'Gene', (149, 153))	('deficiency', 'Var', (84, 94))	('triggered', 'PosReg', (96, 105))	('UPS', 'Gene', (179, 182))	('promoted', 'PosReg', (170, 178))
547368	26987019	Notwithstanding, the same group showed that MyoD-driven KrasG12D in association with loss of Trp53 principally resulted in UPS rather than ERMS.	('resulted', 'Reg', (111, 119))	('loss', 'Var', (85, 89))	('Kras', 'Gene', '16653', (56, 60))	('Trp53', 'Gene', (93, 98))	('MyoD', 'Gene', (44, 48))	('UPS', 'Gene', '15288', (123, 126))	('MyoD', 'Gene', '17927', (44, 48))	('UPS', 'Gene', (123, 126))	('Trp53', 'Gene', '22059', (93, 98))	('Kras', 'Gene', (56, 60))	('ERMS', 'Disease', (139, 143))
547386	26987019	Our bioinformatic analysis revealed an enriched Met score in both human RMS and UPS.	('human', 'Species', '9606', (66, 71))	('Met score', 'Var', (48, 57))	('UPS', 'Gene', (80, 83))	('UPS', 'Gene', '15288', (80, 83))
547393	26987019	Tumor cells harboring MET amplification display exquisite sensitivity to Met inhibitors, providing a rationale for the use of targeted therapies in patients carrying this lesion.	('patients', 'Species', '9606', (148, 156))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('sensitivity', 'MPA', (58, 69))	('MET amplification', 'Var', (22, 39))
547411	26987019	Ki67 (#NCL-Ki67p) was from Leica Biosystems (UK); MyoD (#M3512) was from Dako (Denmark); Myogenin (DSHB (Iowa City, IA) Hybridoma Product F5D was deposited by Wright, Woodring E.); Pax7 (DSHB Hybridoma Product PAX7 was deposited by Kawakami, Atsushi); eMHC (DSHB Hybridoma Product F1.652 was deposited by Blau, H.M.); P-Met (#3126) and PDGFRalpha (#3164) were from Cell Signaling Technology (Danvers, MA); Met (#18-7366) was from Invitrogen.	('#3164', 'Var', (348, 353))	('MyoD', 'Gene', (50, 54))	('MyoD', 'Gene', '17927', (50, 54))	('Blau', 'Gene', (305, 309))	('Myogenin', 'Gene', (89, 97))	('Blau', 'Gene', '257632', (305, 309))	('Ki67', 'Gene', '17345', (0, 4))	('IA', 'Disease', 'MESH:C536041', (116, 118))	('Ki67', 'Gene', '17345', (11, 15))	('PAX7', 'Gene', (210, 214))	('Pax7', 'Gene', '18509', (181, 185))	('Ki67', 'Gene', (0, 4))	('Myogenin', 'Gene', '17928', (89, 97))	('PAX7', 'Gene', '18509', (210, 214))	('Pax7', 'Gene', (181, 185))	('Ki67', 'Gene', (11, 15))
547414	26987019	Laminin (#L9393) and Desmin (#D1033) were from Sigma-Aldrich; Pax7 (DSHB Hybridoma Product PAX7 was deposited by Kawakami, Atsushi); MyoD (#sc-760) was from Santa Cruz Biotechnology (Dallas, TX); 488, 555 and Cy3-conjugated secondary antibodies were from Invitrogen.	('Desmin', 'Gene', (21, 27))	('#D1033', 'Var', (29, 35))	('L9393', 'CellLine', 'CVCL:0462', (10, 15))	('Pax7', 'Gene', (62, 66))	('MyoD', 'Gene', (133, 137))	('MyoD', 'Gene', '17927', (133, 137))	('PAX7', 'Gene', (91, 95))	('#L9393', 'Var', (9, 15))	('Cy3', 'Chemical', '-', (209, 212))	('PAX7', 'Gene', '18509', (91, 95))	('Desmin', 'Gene', '13346', (21, 27))	('Pax7', 'Gene', '18509', (62, 66))
547429	26987019	MHC (#sc-32732) and Myogenin (#sc-12732) were from Santa Cruz Biotechnology; Met (#18-7366) was from Invitrogen; P-Met (#3126), P-Akt (#9271), GAPDH (#5174), P-TYR (#9411), hALK (#3633), P-hALK (#3341) and PDGFRalpha (#3164) were from Cell Signaling Technology; mALK (#ab16670) was from Abcam (UK); MyoD (#M3512) was from Dako; P-MAPK (# M8159), Tubulin (#T5201), Actin (#A5060) were from Sigma-Aldrich.	('#M3512', 'Var', (305, 311))	('hALK', 'Gene', (189, 193))	('hALK', 'Gene', '238', (189, 193))	('GAPDH', 'Gene', (143, 148))	('P-MAPK', 'Disease', (328, 334))	('MyoD', 'Gene', (299, 303))	('# M8159', 'Var', (336, 343))	('#T5201', 'Var', (355, 361))	('GAPDH', 'Gene', '14433', (143, 148))	('Akt', 'Gene', '11651', (130, 133))	('hALK', 'Gene', (173, 177))	('hALK', 'Gene', '238', (173, 177))	('Myogenin', 'Gene', (20, 28))	('Akt', 'Gene', (130, 133))	('MyoD', 'Gene', '17927', (299, 303))	('Myogenin', 'Gene', '17928', (20, 28))	('#A5060', 'Var', (371, 377))	('P-MAPK', 'Disease', 'MESH:C000656865', (328, 334))
547456	26987019	Muscle datasets GSE3307 and GSE1462 were used in comparison with RMS dataset 'Davicioni', while muscle datasets GSE3526 and GSE2328 were used in comparison with RMS dataset 'Williamson'.	('GSE3526', 'Chemical', '-', (112, 119))	('GSE3307', 'Var', (16, 23))	('GSE1462', 'Var', (28, 35))	('GSE3307', 'Chemical', '-', (16, 23))	('GSE2328', 'Chemical', '-', (124, 131))	('GSE1462', 'Chemical', '-', (28, 35))
547468	26987019	Thank you for submitting your work entitled "HGF-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes" for consideration by eLife.	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('perturbation', 'Var', (80, 92))	('distinct sarcoma subtypes', 'Disease', 'MESH:D012509', (117, 142))	('promotes', 'PosReg', (93, 101))	('distinct sarcoma subtypes', 'Disease', (117, 142))
547479	26987019	4) In a previous study (Sharp et al., 2002) it was shown that HGF/Met signaling was constitutively activated in most of RMS derived from HGF transgenic with Ink4/Arf deficient mice.	('transgenic', 'Var', (141, 151))	('transgenic', 'Species', '10090', (141, 151))	('HGF', 'Gene', (137, 140))	('HGF/Met signaling', 'Gene', (62, 79))	('activated', 'PosReg', (99, 108))	('mice', 'Species', '10090', (176, 180))
547487	26987019	With respect to Met as a driver, Western blot and immunohistochemical analysis of sections of primary tumors (Figure 5A and new Figure 5B) show strong Met expression and activation only in tumors which yielded cell lines subsequently found Met-amplified (Figure 5E, Figure 5:figure supplement 3C) and Met addicted (Figure 6A-D, Figure 6:figure supplement 1A-D).	('tumors', 'Disease', (102, 108))	('activation', 'PosReg', (170, 180))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('Met-amplified', 'Var', (240, 253))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('primary tumors', 'Disease', (94, 108))	('primary tumors', 'Disease', 'MESH:D009369', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('Met expression', 'MPA', (151, 165))
547488	26987019	These findings have been commented in the revised version of the manuscript (paragraph two, subheading "SC niche perturbation results in heterogeneous tumors, with only a subset displaying sensitivity to Met or PI3K pathway inhibition").	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('perturbation', 'Var', (113, 125))	('results in', 'Reg', (126, 136))
547491	26987019	A comment regarding the consistency between murine and human data has been included in the revised version of the manuscript (paragraph three, subheading "SC niche perturbation results in heterogeneous tumors, with only a subset displaying sensitivity to Met or PI3K pathway inhibition").	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('results in', 'Reg', (177, 187))	('Met or PI3K pathway', 'Pathway', (255, 274))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumors', 'Disease', (202, 208))	('human', 'Species', '9606', (55, 60))	('murine', 'Species', '10090', (44, 50))	('perturbation', 'Var', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
547495	26987019	As we reported in the manuscript (subheading subheading "Treatments based on combination therapy can be effective in preventing ERMS recurrence and clonal evolution"), lesions in the ALK gene have been repeatedly found in human ERMS, again strengthening the congruity of our model.	('human', 'Species', '9606', (222, 227))	('found', 'Reg', (213, 218))	('lesions', 'Var', (168, 175))	('ALK', 'Gene', (183, 186))
547500	26987019	We have also included in new Figure 4E a panel showing that murine primary UPS express Met (subheading "SC niche perturbation in a Pax7-deficient background mainly results in UPS development").	('UPS', 'Gene', '15288', (75, 78))	('murine', 'Species', '10090', (60, 66))	('Pax7', 'Gene', (131, 135))	('UPS', 'Gene', '15288', (175, 178))	('UPS', 'Gene', (75, 78))	('perturbation', 'Var', (113, 125))	('results in', 'Reg', (164, 174))	('UPS', 'Gene', (175, 178))	('Pax7', 'Gene', '18509', (131, 135))
547509	26987019	The text has been modified accordingly (subheading "SC niche perturbation in a Pax7-deficient background mainly results in UPS development";paragraph one, Discussion).	('Pax7', 'Gene', (79, 83))	('UPS', 'Gene', '15288', (123, 126))	('results in', 'Reg', (112, 122))	('perturbation', 'Var', (61, 73))	('Pax7', 'Gene', '18509', (79, 83))	('UPS', 'Gene', (123, 126))
547515	26987019	We have described these findings in the Results section (paragraph one, subheading "SC niche perturbation results in heterogeneous tumors, with only a subset displaying sensitivity to Met or PI3K pathway inhibition").	('perturbation', 'Var', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('results in', 'Reg', (106, 116))
547519	26987019	In Met-amplified tumors, where activation is most likely due to overexpression, Met and P-Met were easily detectable (Figure 5A, B and Figure 5:figure supplement 2B).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Met-amplified', 'Var', (3, 16))	('activation', 'PosReg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
547556	26213607	Types and definitions of STS by ICD-O-3 histology codes are as follows: GIST (8935, 8936), leiomyosarcoma (8890-91, 8894-97), malignant fibrous histiocytoma (8830), liposarcoma (8850-8855, 8858), dermatofibrosarcoma (8832, 8833), rhabdomyosarcoma (8900-8902, 8910, 8912, 8920), angiosarcoma (9120, 9130, 9133, 9170), nerve sheath tumor (9540, 9560-62), fibrosarcoma (8810, 8811, 8814, 8815), sarcoma NOS (not otherwise specified) (8800-8805), Ewing Sarcoma/primitive neuroectodermal tumor (9260, 9364, 9365, 9473), extraskeletal osteosarcoma (9180, 9181), extraskeletal chondrosarcoma (9220, 9231, 9240), synovial sarcoma (9040-9043), clear cell sarcoma (9044), myxosarcoma (8840), malignant hemangiopericytoma (9150), malignant giant cell tumor (9251, 9252), malignant granular cell tumor (9580), alveolar soft part sarcoma (9581), and desmoplastic small round cell tumor (8806).	('fibrosarcoma', 'Disease', 'MESH:D005354', (203, 215))	('fibrosarcoma', 'Disease', (353, 365))	('tumor', 'Phenotype', 'HP:0002664', (483, 488))	('fibrosarcoma', 'Disease', (203, 215))	('malignant giant cell tumor', 'Disease', (719, 745))	('liposarcoma', 'Phenotype', 'HP:0012034', (165, 176))	('myxosarcoma', 'Disease', 'MESH:D009236', (662, 673))	('angiosarcoma', 'Disease', 'MESH:D006394', (278, 290))	('leiomyosarcoma', 'Disease', (91, 105))	('chondrosarcoma', 'Disease', 'MESH:D002813', (570, 584))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (443, 456))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (605, 621))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (353, 365))	('malignant hemangiopericytoma', 'Disease', (682, 710))	('nerve sheath tumor', 'Disease', (317, 335))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (203, 215))	('malignant giant cell tumor', 'Disease', 'MESH:D005870', (719, 745))	('9580', 'Var', (791, 795))	('synovial sarcoma', 'Disease', (605, 621))	('dermatofibrosarcoma', 'Disease', (196, 215))	('synovial sarcoma', 'Disease', 'MESH:D013584', (605, 621))	('sarcoma NOS', 'Disease', 'MESH:D012509', (392, 403))	('malignant fibrous histiocytoma', 'Disease', (126, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (283, 290))	('liposarcoma', 'Disease', 'MESH:D008080', (165, 176))	('8840', 'Var', (675, 679))	('chondrosarcoma', 'Disease', (570, 584))	('alveolar soft part sarcoma', 'Disease', (798, 824))	('9044', 'Var', (655, 659))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (467, 488))	('malignant fibrous histiocytoma', 'Disease', 'MESH:D051677', (126, 156))	('clear cell sarcoma', 'Disease', (635, 653))	('STS', 'Phenotype', 'HP:0030448', (25, 28))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (457, 488))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (230, 246))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (837, 872))	('dermatofibrosarcoma', 'Disease', 'MESH:D018223', (196, 215))	('giant cell tumor', 'Phenotype', 'HP:0011847', (729, 745))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (570, 584))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (529, 541))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (798, 824))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (91, 105))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (635, 653))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (807, 824))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('tumor', 'Phenotype', 'HP:0002664', (784, 789))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (798, 824))	('Ewing Sarcoma', 'Disease', (443, 456))	('malignant granular cell tumor', 'Disease', (760, 789))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (443, 456))	('osteosarcoma', 'Phenotype', 'HP:0002669', (529, 541))	('angiosarcoma', 'Phenotype', 'HP:0200058', (278, 290))	('histiocytoma', 'Phenotype', 'HP:0012315', (144, 156))	('myxosarcoma', 'Disease', (662, 673))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (230, 246))	('desmoplastic small round cell tumor', 'Disease', (837, 872))	('tumor', 'Phenotype', 'HP:0002664', (867, 872))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('fibrosarcoma', 'Disease', 'MESH:D005354', (353, 365))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (91, 105))	('nerve sheath tumor', 'Disease', 'MESH:D010524', (317, 335))	('osteosarcoma', 'Disease', (529, 541))	('9040-9043', 'Var', (623, 632))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (467, 488))	('9150', 'Var', (712, 716))	('rhabdomyosarcoma', 'Disease', (230, 246))	('neuroectodermal tumor', 'Disease', (467, 488))	('9251', 'Var', (747, 751))	('sarcoma NOS', 'Disease', (392, 403))	('Sarcoma', 'Phenotype', 'HP:0100242', (449, 456))	('malignant hemangiopericytoma', 'Disease', 'MESH:C562740', (682, 710))	('angiosarcoma', 'Disease', (278, 290))	('9581', 'Var', (826, 830))	('liposarcoma', 'Disease', (165, 176))	('malignant granular cell tumor', 'Disease', 'MESH:D016586', (760, 789))	('tumor', 'Phenotype', 'HP:0002664', (740, 745))
547617	26213607	The major risk factors for VTEs among cancer patients reported in the literature are increased age, female sex, African American race, renal disease, infection, pulmonary disease, obesity, arterial thromboembolism, inherited prothrombotic mutations, prior history of VTE, performance status, advanced stage cancer, major surgery, hospitalization, chemotherapy, hormone therapy, anti-angiogenic agents, erythropoiesis-stimulating agents, transfusions, and central venous catheters.	('arterial thromboembolism', 'Disease', 'MESH:D013923', (189, 213))	('obesity', 'Disease', (180, 187))	('pulmonary disease', 'Disease', 'MESH:D008171', (161, 178))	('mutations', 'Var', (239, 248))	('patients', 'Species', '9606', (45, 53))	('pulmonary disease', 'Disease', (161, 178))	('thromboembolism', 'Phenotype', 'HP:0001907', (198, 213))	('obesity', 'Disease', 'MESH:D009765', (180, 187))	('VTE', 'Disease', 'MESH:D054556', (267, 270))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('VTE', 'Disease', 'MESH:D054556', (27, 30))	('cancer', 'Disease', (38, 44))	('VTE', 'Disease', (267, 270))	('renal disease', 'Phenotype', 'HP:0000112', (135, 148))	('infection', 'Disease', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('infection', 'Disease', 'MESH:D007239', (150, 159))	('arterial thromboembolism', 'Disease', (189, 213))	('VTE', 'Disease', (27, 30))	('obesity', 'Phenotype', 'HP:0001513', (180, 187))	('renal disease', 'Disease', (135, 148))	('cancer', 'Disease', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('renal disease', 'Disease', 'MESH:D007674', (135, 148))
547645	24308011	Direct sequencing of the promoter and nine coding exons of SMARCB1, multiplex ligation-dependent probe amplification, and whole genome single nucleotide polymorphism array were performed on the two adult cases and showed only a heterozygous deletion of chromosome 22 in a minority of cells in one of the cases.	('SMARCB1', 'Gene', (59, 66))	('deletion', 'Var', (241, 249))	('SMARCB1', 'Gene', '6598', (59, 66))
547657	24308011	The molecular events mediating this loss of expression might differ between these two entities, with point mutations more common in MRT and deletions in PES.	('PES', 'Disease', (153, 156))	('MRT', 'Disease', (132, 135))	('deletions', 'Var', (140, 149))	('PES', 'Chemical', '-', (153, 156))	('common', 'Reg', (122, 128))	('point mutations', 'Var', (101, 116))
547682	24308011	IHC staining showed that the neoplastic cells were positive for PANCK, EMA, E-cadherin and B72.3.	('EMA', 'Gene', '4582', (71, 74))	('EMA', 'Gene', (71, 74))	('E-cadherin', 'Gene', (76, 86))	('PANCK', 'Protein', (64, 69))	('B72.3', 'Var', (91, 96))	('E-cadherin', 'Gene', '999', (76, 86))
547707	24308011	Biallelic inactivation of SMARCB1 has been reported in approximately 98% of rhabdoid tumors of the kidney, brain and soft tissues.	('tumors of the kidney', 'Phenotype', 'HP:0009726', (85, 105))	('SMARCB1', 'Gene', '6598', (26, 33))	('Biallelic inactivation', 'Var', (0, 22))	('SMARCB1', 'Gene', (26, 33))	('rhabdoid tumors of the kidney', 'Disease', 'MESH:D018335', (76, 105))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('reported', 'Reg', (43, 51))	('rhabdoid tumors of the kidney', 'Disease', (76, 105))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
547714	24308011	Evaluation of detectable molecular alterations suggests that the spectrum of SMARCB1 alterations may be biased to deletions, some of which arise as a consequence of unbalanced translocations.	('SMARCB1', 'Gene', '6598', (77, 84))	('SMARCB1', 'Gene', (77, 84))	('deletions', 'Var', (114, 123))	('alterations', 'Var', (85, 96))
547715	24308011	Furthermore, there is a heterogeneous distribution of the deletions observed thus far in epithelioid sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('deletions', 'Var', (58, 67))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (89, 109))	('epithelioid sarcomas', 'Disease', (89, 109))
547724	24308011	The distinction of PES from MRT is supported by the observation that the prognosis of patients with MRT is significantly worse than in patients with PES.	('worse', 'Reg', (121, 126))	('patients', 'Species', '9606', (135, 143))	('PES', 'Chemical', '-', (149, 152))	('PES', 'Chemical', '-', (19, 22))	('MRT', 'Var', (100, 103))	('patients', 'Species', '9606', (86, 94))
547725	24308011	There is a strong association of deletions with PES, although that is also the case for other extra-renal, non-CNS rhabdoid tumors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (115, 130))	('PES', 'Chemical', '-', (48, 51))	('association', 'Interaction', (18, 29))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('PES', 'Disease', (48, 51))	('deletions', 'Var', (33, 42))	('rhabdoid tumors', 'Disease', (115, 130))
547728	24308011	Meanwhile, due to the similar morphologic features and loss of SMARCB1 expression in these tumors, PES and MRT can certainly be two different presentation of a specific morphologic spectrum spanning at one end with more epithelioid phenotype to the other with more rhabdoid phenotype of a neoplastic process related to the SMARCB1 alteration regardless of the underlying molecular events leading to its inactivation.	('alteration', 'Var', (331, 341))	('SMARCB1', 'Gene', (323, 330))	('tumors', 'Disease', (91, 97))	('SMARCB1', 'Gene', '6598', (323, 330))	('loss', 'NegReg', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('neoplastic process', 'Phenotype', 'HP:0002664', (289, 307))	('neoplastic process', 'Disease', (289, 307))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('SMARCB1', 'Gene', '6598', (63, 70))	('PES', 'Chemical', '-', (99, 102))	('SMARCB1', 'Gene', (63, 70))
547732	24308011	The lack of known SMARCB1 mutation and deletion in a HN PES warrants further study to investigate alternative mechanisms of inactivation of this gene.	('PES', 'Chemical', '-', (56, 59))	('deletion', 'Var', (39, 47))	('SMARCB1', 'Gene', (18, 25))	('SMARCB1', 'Gene', '6598', (18, 25))
547763	22359254	For example, the category "immunoproliferative disease" includes immunoproliferative diseases, not otherwise specified (NOS; ICD-O3 code 9760), Waldenstrom macroglobulinemia (9761) and heavy chain disease, NOS (9762).	('Waldenstrom macroglobulinemia', 'Phenotype', 'HP:0005508', (144, 173))	('immunoproliferative diseases', 'Disease', (65, 93))	('Waldenstrom macroglobulinemia', 'Disease', (144, 173))	('9761', 'Var', (175, 179))	('heavy chain disease', 'Disease', (185, 204))	('Waldenstrom macroglobulinemia', 'Disease', 'MESH:D008258', (144, 173))
547771	22359254	We estimated SIRs stratified by attained age group (0-14, 15-29, 30-49 and 50+ years old), time relative to AIDS onset (-60 to -25, -24 to -7, -6 to +3, +4 to +27, +28 to +60 and +61 to +120 months), and attained calendar period (1980-1989 [no antiretroviral therapy era], 1990-1995 [some antiretroviral therapy era], 1996-2000 [early highly active antiretroviral therapy (HAART) era], 2001-2007 [late HAART era]).	('to -7', 'Species', '1214577', (136, 141))	('AIDS', 'Disease', 'MESH:D000163', (108, 112))	('-60', 'Var', (120, 123))	('AIDS', 'Disease', (108, 112))
547918	24715928	Histologically, it is composed of relatively monomorphic ovoid or round cells with clear to eosinophilic cytoplasm, arranged in sheets and sometimes papillary or alveolar architectures, often with CD68-positive osteoclast-like giant cells in variable numbers, and is associated with EWSR1-CREB1 gene fusions.	('CREB1', 'Gene', '1385', (289, 294))	('EWSR1', 'Gene', (283, 288))	('CREB1', 'Gene', (289, 294))	('EWSR1', 'Gene', '2130', (283, 288))	('CD68', 'Gene', (197, 201))	('CD68', 'Gene', '968', (197, 201))	('associated', 'Reg', (267, 277))	('fusions', 'Var', (300, 307))
547925	24715928	Because of the nonspecific immunoprofile of focal S100 protein expression and general lack of immunoreactivity to other antibodies, it may be misdiagnosed as a variety of neoplasms, including melanoma, malignant peripheral nerve sheath tumor, or gastrointestinal stromal tumor (GIST).	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('neoplasms', 'Phenotype', 'HP:0002664', (171, 180))	('malignant peripheral nerve sheath tumor', 'Disease', (202, 241))	('S100', 'Gene', (50, 54))	('neoplasm', 'Phenotype', 'HP:0002664', (171, 179))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (202, 241))	('S100', 'Gene', '6271', (50, 54))	('protein', 'Protein', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('neoplasms', 'Disease', 'MESH:D009369', (171, 180))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (246, 276))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (202, 241))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (246, 276))	('neoplasms', 'Disease', (171, 180))	('focal', 'Var', (44, 49))	('gastrointestinal stromal tumor', 'Disease', (246, 276))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('GIST', 'Phenotype', 'HP:0100723', (278, 282))
547926	24715928	We describe a case arising in the small bowel wall and harboring EWSR1-CREB1 gene fusion by reverse transcription polymerase chain reaction, which occurred in a 33-year-old male who had previously had surgery, irradiation, and chemotherapy for childhood hepatoblastoma.	('EWSR1', 'Gene', (65, 70))	('fusion', 'Var', (82, 88))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (254, 268))	('EWSR1', 'Gene', '2130', (65, 70))	('CREB1', 'Gene', '1385', (71, 76))	('childhood hepatoblastoma', 'Disease', (244, 268))	('CREB1', 'Gene', (71, 76))	('childhood hepatoblastoma', 'Disease', 'MESH:D018197', (244, 268))	('occurred', 'Reg', (147, 155))
547944	24715928	Molecular genetic and molecular cytogenetic analyses were performed on formalin fixed, paraffin embedded (FFPE) material for each case, for EWSR1 rearrangements by fluorescence in situ hybridization (FISH), and for specific fusion transcripts by reverse transcription polymerase chain reaction (RT-PCR).	('EWSR1', 'Gene', '2130', (140, 145))	('paraffin', 'Chemical', 'MESH:D010232', (87, 95))	('formalin', 'Chemical', 'MESH:D005557', (71, 79))	('rearrangements', 'Var', (146, 160))	('EWSR1', 'Gene', (140, 145))
547960	24715928	FISH using break-apart probes for EWSR1 at 22q12 showed cells with a split EWSR1 signal, indicating the presence of a translocation involving the EWSR1 gene at 22q12.	('EWSR1', 'Gene', (34, 39))	('EWSR1', 'Gene', '2130', (75, 80))	('EWSR1', 'Gene', (146, 151))	('EWSR1', 'Gene', '2130', (34, 39))	('EWSR1', 'Gene', '2130', (146, 151))	('translocation', 'Var', (118, 131))	('EWSR1', 'Gene', (75, 80))
547973	24715928	Most of the small numbers of CCSLGT reported have shown EWSR1-CREB1 fusions, although some harbor EWSR1-ATF1 fusions that are associated with conventional CCS.	('ATF1', 'Gene', (104, 108))	('EWSR1', 'Gene', '2130', (98, 103))	('EWSR1', 'Gene', (56, 61))	('CREB1', 'Gene', (62, 67))	('ATF1', 'Gene', '466', (104, 108))	('EWSR1', 'Gene', '2130', (56, 61))	('fusions', 'Var', (68, 75))	('EWSR1', 'Gene', (98, 103))	('CREB1', 'Gene', '1385', (62, 67))
547974	24715928	While the latter can also arise in the gastrointestinal tract, most contain EWSR1-ATF1 fusions.	('gastrointestinal tract', 'Disease', (39, 61))	('fusions', 'Var', (87, 94))	('ATF1', 'Gene', '466', (82, 86))	('EWSR1', 'Gene', (76, 81))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (39, 61))	('EWSR1', 'Gene', '2130', (76, 81))	('ATF1', 'Gene', (82, 86))
548095	22729153	Finally, to understand the face of HIV-associated KS in the future, we need additional specific estimates of the incidence of KS in ART-treated patients who have achieved CD4 counts >350 cells/mul as well as an understanding why patients continue to develop KS at this stage of HIV disease.	('patients', 'Species', '9606', (229, 237))	('CD4', 'Gene', '920', (171, 174))	('HIV disease', 'Disease', 'MESH:D015658', (278, 289))	('ART', 'Chemical', '-', (132, 135))	('>350', 'Var', (182, 186))	('patients', 'Species', '9606', (144, 152))	('CD4', 'Gene', (171, 174))	('HIV disease', 'Disease', (278, 289))
548096	22729153	Papers of particular interest, published within the annual period of review, have been highlighted as   of special intrest    of outstanding interest There are abundant data from resource-rich settings indicating the beneficial effect of ART on preventing Kaposi's sarcoma (KS) both among ART users and within the entire HIV-infected population.	('HIV-infected', 'Disease', 'MESH:D015658', (321, 333))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (256, 272))	('ART', 'Chemical', '-', (289, 292))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (256, 272))	('ART', 'Chemical', '-', (238, 241))	("Kaposi's sarcoma", 'Disease', (256, 272))	('HIV-infected', 'Disease', (321, 333))	('ART', 'Var', (238, 241))
548181	31053105	The second stage employed a burden analysis of rare variants within prioritized candidate genes identified from stage one in 560 sarcoma cases and 1144 healthy ageing controls, for which whole genome sequence was available.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('variants', 'Var', (52, 60))	('sarcoma', 'Disease', (129, 136))
548183	31053105	The ABCB5 gene was found to have a higher burden of putative regulatory variants (OR = 4.9, p-value = 0.007, q-value = 0.04) based on allele counts in sarcoma cases compared to controls.	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('variants', 'Var', (72, 80))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('ABCB5', 'Gene', (4, 9))	('sarcoma', 'Disease', (151, 158))	('ABCB5', 'Gene', '340273', (4, 9))
548184	31053105	C16orf96, was found to have a significantly lower burden (OR = 0.58, p-value = 0.0004, q-value = 0.003) of regulatory variants in controls compared to sarcoma cases.	('lower', 'NegReg', (44, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('burden', 'MPA', (50, 56))	('C16orf96', 'Gene', '342346', (0, 8))	('C16orf96', 'Gene', (0, 8))	('variants', 'Var', (118, 126))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('sarcoma', 'Disease', (151, 158))
548188	31053105	Cancers can be caused by mutations that arise in single somatic cells resulting in sporadic tumors, or by heritable germline susceptibility variants.	('mutations', 'Var', (25, 34))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('sporadic tumors', 'Disease', 'MESH:D009369', (83, 98))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('caused', 'Reg', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('sporadic tumors', 'Disease', (83, 98))
548191	31053105	The study of cancer families using contemporary genome-wide DNA sequencing technologies now offers an opportunity to identify novel germline risk variants and potentially novel gene targets that will be of clinical utility for better prediction of cancer risk and improved therapeutic intervention.	('cancer', 'Disease', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('variants', 'Var', (146, 154))	('cancer', 'Disease', 'MESH:D009369', (248, 254))
548195	31053105	Families in which related individuals develop a rare form of cancer, such as sarcoma, are more likely to have a heritable susceptibility variant segregating in a cancer risk gene compared to families affected by more common types of cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (162, 168))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('cancer', 'Disease', (61, 67))	('variant', 'Var', (137, 144))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('sarcoma', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
548214	31053105	The third category were variants within candidate genes that were selected based on a priori knowledge of cancer biology.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('variants', 'Var', (24, 32))
548215	31053105	Variants in 118 known cancer and sarcoma genes, and in genes 25 kb upstream and downstream of each known gene to include any potential regulatory variants captured in off-target reads, were identified from the intersect file (see Additional file 1: Table S1).	('Variants', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('sarcoma', 'Disease', 'MESH:D012509', (33, 40))	('cancer', 'Disease', (22, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcoma', 'Disease', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
548222	31053105	Variant filtering retained loci if they were: stop-gain or stop-loss, predicted to be deleterious or probably damaging in SIFT (Sorting Intolerant from Tolerant) and PolyPhen-2 and had a Genomic Evolutionary Rate Profiling score < 3.	('SIFT', 'Disease', 'None', (122, 126))	('stop-loss', 'Var', (59, 68))	('SIFT', 'Disease', (122, 126))	('Variant', 'Var', (0, 7))	('stop-gain', 'PosReg', (46, 55))
548227	31053105	The variants from each category were tested for association using a variance-component model for quantitative phenotypes (age at onset of cancer and age at onset of sarcoma) and disease status (cancer and sarcoma) in SOLAR.	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (194, 200))	('variants', 'Var', (4, 12))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('sarcoma', 'Disease', (205, 212))	('association', 'Interaction', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('sarcoma', 'Disease', 'MESH:D012509', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('sarcoma', 'Disease', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
548229	31053105	No variants were significantly associated with any of the four cancer outcomes after correcting for multiple testing.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('variants', 'Var', (3, 11))	('associated', 'Reg', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
548231	31053105	Variants in three genes (C16orf96, ABCB5, and PDIA2) were detected in Pedigree 2 after segregation analysis.	('Variants', 'Var', (0, 8))	('C16orf96', 'Gene', '342346', (25, 33))	('C16orf96', 'Gene', (25, 33))	('ABCB5', 'Gene', (35, 40))	('ABCB5', 'Gene', '340273', (35, 40))	('PDIA2', 'Gene', '64714', (46, 51))	('PDIA2', 'Gene', (46, 51))
548232	31053105	Variants in five genes (ARHGAP39, ZFP69B, UVSSA, BEAN1, and KIF2C) were nominally significant and segregated in Pedigree 3.	('ZFP69B', 'Gene', (34, 40))	('Variants', 'Var', (0, 8))	('KIF2C', 'Gene', '11004', (60, 65))	('ARHGAP39', 'Gene', (24, 32))	('BEAN1', 'Gene', (49, 54))	('BEAN1', 'Gene', '146227', (49, 54))	('UVSSA', 'Gene', (42, 47))	('UVSSA', 'Gene', '57654', (42, 47))	('significant', 'Reg', (82, 93))	('ARHGAP39', 'Gene', '80728', (24, 32))	('ZFP69B', 'Gene', '65243', (34, 40))	('KIF2C', 'Gene', (60, 65))
548238	31053105	The ABCB5 gene was found to have a nominally significantly higher burden (OR = 1.79, p-value = 0.02, q-value = 0.16, Table 4) associated with nonsynonymous deleterious variants and significant putative regulatory variants based on allele counts (OR = 4.9, p-value = 0.007, q-value = 0.049, Table 5) in sarcoma cases compared to controls.	('sarcoma', 'Phenotype', 'HP:0100242', (302, 309))	('associated', 'Reg', (126, 136))	('variants', 'Var', (168, 176))	('ABCB5', 'Gene', '340273', (4, 9))	('higher', 'PosReg', (59, 65))	('sarcoma', 'Disease', 'MESH:D012509', (302, 309))	('ABCB5', 'Gene', (4, 9))	('burden', 'MPA', (66, 72))	('sarcoma', 'Disease', (302, 309))
548239	31053105	For deleterious variants within ABCB5, these gene burden association results are driven by higher heterozygosity at two variants (rs2074000, rs58795451) and lower heterozygosity at one variant (rs751879475).	('rs58795451', 'Var', (141, 151))	('rs58795451', 'Mutation', 'rs58795451', (141, 151))	('higher', 'PosReg', (91, 97))	('rs751879475', 'Mutation', 'rs751879475', (194, 205))	('rs751879475', 'Var', (194, 205))	('ABCB5', 'Gene', (32, 37))	('heterozygosity', 'MPA', (163, 177))	('rs2074000', 'Var', (130, 139))	('ABCB5', 'Gene', '340273', (32, 37))	('rs2074000', 'Mutation', 'rs2074000', (130, 139))	('lower', 'NegReg', (157, 162))
548240	31053105	For the regulatory variants in ABCB5, this result is driven by higher heterozygosity at three variants (rs73684574, rs78879263, rs78155891).	('rs78879263', 'Mutation', 'rs78879263', (116, 126))	('rs78879263', 'Var', (116, 126))	('ABCB5', 'Gene', (31, 36))	('ABCB5', 'Gene', '340273', (31, 36))	('rs78155891', 'Var', (128, 138))	('rs73684574', 'Mutation', 'rs73684574', (104, 114))	('rs73684574', 'Var', (104, 114))	('rs78155891', 'Mutation', 'rs78155891', (128, 138))	('higher', 'PosReg', (63, 69))
548241	31053105	All three ABCB5 variants have RegulomeDB scores of 2, suggesting that they have a likely impact on the transcription factor binding of this gene.	('ABCB5', 'Gene', (10, 15))	('ABCB5', 'Gene', '340273', (10, 15))	('impact', 'Reg', (89, 95))	('binding', 'Interaction', (124, 131))	('transcription factor', 'MPA', (103, 123))	('variants', 'Var', (16, 24))
548242	31053105	One other gene, C16orf96, was found to have a significantly lower burden (OR = 0.58, p-value = 0.0004, q-value = 0.003, Table 5) of regulatory variants in controls compared to sarcoma cases.	('sarcoma', 'Disease', (176, 183))	('lower', 'NegReg', (60, 65))	('sarcoma', 'Disease', 'MESH:D012509', (176, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('C16orf96', 'Gene', (16, 24))	('C16orf96', 'Gene', '342346', (16, 24))	('burden', 'MPA', (66, 72))	('variants', 'Var', (143, 151))
548243	31053105	This result was driven by the lower heterozygosity at two variants (rs11862083, rs76048912).	('rs11862083', 'Var', (68, 78))	('rs76048912', 'Mutation', 'rs76048912', (80, 90))	('rs76048912', 'Var', (80, 90))	('rs11862083', 'Mutation', 'rs11862083', (68, 78))
548244	31053105	The variant rs11862083 is a known eQTL with a RegulomeDB score of 1f and is linked to expression of HSCARG (also named NmrA-like family domain containing protein 1).	('NmrA-like family domain containing protein 1', 'Gene', (119, 163))	('rs11862083', 'Var', (12, 22))	('HSCARG', 'Gene', (100, 106))	('linked', 'Reg', (76, 82))	('rs11862083', 'Mutation', 'rs11862083', (12, 22))	('NmrA-like family domain containing protein 1', 'Gene', '57407', (119, 163))	('HSCARG', 'Gene', '57407', (100, 106))
548245	31053105	The second variant, rs76048912, has a RegulomeDB score of 2 suggesting that this variant is likely to affect transcription factor binding.	('rs76048912', 'Mutation', 'rs76048912', (20, 30))	('affect', 'Reg', (102, 108))	('rs76048912', 'Var', (20, 30))	('transcription factor', 'MPA', (109, 129))	('binding', 'Interaction', (130, 137))
548250	31053105	Third, every individual with the phenotype (cancer) will carry the putative disease-causing variant (100% probability of observing a genotype given the phenotype).	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('variant', 'Var', (92, 99))	('disease-causing', 'Reg', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
548251	31053105	Despite these limitations, by treating each cancer pedigree as a separate discovery unit we were able to identify novel rare variants showing nominal evidence of association with cancer risk in these families.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('variants', 'Var', (125, 133))	('association', 'Interaction', (162, 173))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
548252	31053105	Importantly, although not sufficient evidence on their own, these nominal variant associations pointed to candidate risk genes that we could then evaluate extensively in the second stage of our study design, dependent on the availability of large population cohorts of unrelated sarcoma cases and cancer free controls for which there was whole genome sequence; a powerful resource for gene validation.	('sarcoma', 'Disease', (279, 286))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('cancer', 'Disease', (297, 303))	('sarcoma', 'Phenotype', 'HP:0100242', (279, 286))	('variant', 'Var', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('sarcoma', 'Disease', 'MESH:D012509', (279, 286))
548256	31053105	In addition, one of the variants, rs11862083, driving this signal is known to be linked to the expression of the gene, HSCARG, which has been shown to be involved in histone H2A ubiquitination known to be involved in transcriptional repression and DNA damage response.	('rs11862083', 'Var', (34, 44))	('HSCARG', 'Gene', '57407', (119, 125))	('involved', 'Reg', (154, 162))	('rs11862083', 'Mutation', 'rs11862083', (34, 44))	('HSCARG', 'Gene', (119, 125))
548262	31053105	In addition, the clinical utility of these genes and associated variants in risk prediction models for relatives of cancer patients will also require further validation in other large independent studies, for example, the large Genomics England resource, that has a major focus on risk prediction for cancers.	('cancers', 'Phenotype', 'HP:0002664', (301, 308))	('cancers', 'Disease', (301, 308))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('cancers', 'Disease', 'MESH:D009369', (301, 308))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (301, 307))	('patients', 'Species', '9606', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('variants', 'Var', (64, 72))
548267	30909651	Epigenetic Changes at the Birc5 Promoter Induced by YM155 in Synovial Sarcoma YM155 is an anti-cancer therapy that has advanced into 11 different human clinical trials to treat various cancers.	('YM155', 'Chemical', 'MESH:C523798', (78, 83))	('Birc5', 'Gene', '11799', (26, 31))	('Sarcoma', 'Disease', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('cancer', 'Disease', (185, 191))	('Sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('YM155', 'Chemical', 'MESH:C523798', (52, 57))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (61, 77))	('Epigenetic Changes', 'Var', (0, 18))	('Birc5', 'Gene', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('YM155', 'Var', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('human', 'Species', '9606', (146, 151))	('Sarcoma', 'Disease', 'MESH:D012509', (70, 77))
548272	30909651	We discovered that YM155 exhibited nanomolar potency against human synovial sarcoma cell lines and the treated mice with synovial sarcoma demonstrated a 50% reduction in tumor volume compared to control treated mice.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('YM155', 'Var', (19, 24))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (121, 137))	('synovial sarcoma', 'Disease', 'MESH:D013584', (121, 137))	('YM155', 'Chemical', 'MESH:C523798', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (67, 83))	('synovial sarcoma', 'Disease', 'MESH:D013584', (67, 83))	('mice', 'Species', '10090', (111, 115))	('reduction', 'NegReg', (157, 166))	('tumor', 'Disease', (170, 175))	('mice', 'Species', '10090', (211, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('human', 'Species', '9606', (61, 66))	('synovial sarcoma', 'Disease', (121, 137))	('synovial sarcoma', 'Disease', (67, 83))
548273	30909651	We further investigated the mechanism of action of YM155 by looking at the change of lysine modifications of the histone tails that were within 250 base pairs of the Birc5 promoter.	('YM155', 'Chemical', 'MESH:C523798', (51, 56))	('YM155', 'Var', (51, 56))	('lysine', 'Chemical', 'MESH:D008239', (85, 91))	('lysine modifications', 'MPA', (85, 105))
548274	30909651	Using chromatin immunoprecipitation (ChIP)-qPCR, we discovered that the histone epigenetic marks of H3K27 for the Birc5 promoter changed upon YM155 treatment.	('changed', 'Reg', (129, 136))	('YM155', 'Chemical', 'MESH:C523798', (142, 147))	('H3K27', 'Gene', (100, 105))	('YM155 treatment', 'Var', (142, 157))
548275	30909651	H3K27me3 and H3K27ac increased, but the net result was decreased Birc5/survivin expression.	('increased', 'PosReg', (21, 30))	('H3K27me3', 'Protein', (0, 8))	('survivin', 'Gene', '11799', (71, 79))	('decreased', 'NegReg', (55, 64))	('survivin', 'Gene', (71, 79))	('H3K27ac', 'Var', (13, 20))
548287	30909651	In recent years, YM155 (sepantronium bromide) has been increasingly used as an anti-cancer agent due to its inhibitory effect on survivin.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('YM155', 'Var', (17, 22))	('cancer', 'Disease', (84, 90))	('sepantronium bromide', 'Chemical', 'MESH:C523798', (24, 44))	('survivin', 'Gene', '11799', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('YM155', 'Chemical', 'MESH:C523798', (17, 22))	('inhibitory effect', 'NegReg', (108, 125))	('survivin', 'Gene', (129, 137))
548288	30909651	Despite the advancements of this drug in clinical trials, the mechanism whereby YM155 reduces survivin expression is also unknown.	('YM155', 'Chemical', 'MESH:C523798', (80, 85))	('survivin', 'Gene', '11799', (94, 102))	('YM155', 'Var', (80, 85))	('reduces', 'NegReg', (86, 93))	('expression', 'MPA', (103, 113))	('survivin', 'Gene', (94, 102))
548289	30909651	Reports differ on how YM155 might achieve indirect regulation of survivin, by epigenetically silencing Birc5 at the promoter or by altering posttranslational modifications that impact the stability of the survivin protein.	('stability', 'MPA', (188, 197))	('survivin', 'Gene', '11799', (205, 213))	('impact', 'Reg', (177, 183))	('survivin', 'Gene', (65, 73))	('epigenetically', 'Var', (78, 92))	('YM155', 'Chemical', 'MESH:C523798', (22, 27))	('posttranslational modifications', 'MPA', (140, 171))	('Birc5', 'Gene', (103, 108))	('altering', 'Reg', (131, 139))	('survivin', 'Gene', (205, 213))	('survivin', 'Gene', '11799', (65, 73))	('silencing', 'NegReg', (93, 102))
548290	30909651	Our objective was to understand how YM155 induces synovial sarcoma cells to undergo apoptosis.	('YM155', 'Chemical', 'MESH:C523798', (36, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (50, 66))	('YM155', 'Var', (36, 41))	('synovial sarcoma', 'Disease', 'MESH:D013584', (50, 66))	('induces', 'Reg', (42, 49))	('synovial sarcoma', 'Disease', (50, 66))
548291	30909651	In previous studies, YM155 has been found not only to affect the expression of survivin, but also the anti-apoptotic BCL2 family protein MCL1 in several tumor-derived cell lines.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('MCL1', 'Gene', '4170', (137, 141))	('survivin', 'Gene', (79, 87))	('MCL1', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('expression', 'MPA', (65, 75))	('survivin', 'Gene', '11799', (79, 87))	('affect', 'Reg', (54, 60))	('YM155', 'Var', (21, 26))	('anti-apoptotic', 'MPA', (102, 116))	('YM155', 'Chemical', 'MESH:C523798', (21, 26))
548293	30909651	Because YM155 is an effective pro-apoptotic compound, it has been difficult to determine if survivin expression is a direct effect of the drug on epigenetic regulation of the Birc5 promoter or if it is a secondary consequence of activating other pro-apoptotic pathways in synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (272, 288))	('YM155', 'Var', (8, 13))	('YM155', 'Chemical', 'MESH:C523798', (8, 13))	('synovial sarcoma', 'Disease', 'MESH:D013584', (272, 288))	('survivin', 'Gene', '11799', (92, 100))	('survivin', 'Gene', (92, 100))	('pro-apoptotic', 'Pathway', (246, 259))	('synovial sarcoma', 'Disease', (272, 288))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))	('activating', 'PosReg', (229, 239))
548315	30909651	Western blots were probed with the following primary antibodies: anti-Survivin (Cell Signaling Technology, 2808, 1:1000), anti-NFkappaB/p65 (Cell Signaling Technology, 8242, 1:800) anti-GAPDH (Proteintech, 10494-1-AP, 1:1000).	('anti-GAPDH', 'Var', (181, 191))	('NFkappaB', 'Gene', (127, 135))	('p65', 'Gene', (136, 139))	('p65', 'Gene', '19697', (136, 139))	('NFkappaB', 'Gene', '18033', (127, 135))	('Survivin', 'Gene', (70, 78))	('Survivin', 'Gene', '11799', (70, 78))
548327	30909651	Anti-H3K27me3 (Rockland, 600-401-I84), anti-H3K27ac (Rockland, 600-401-K00), anti-H3K4me1 (Rockland, 600-401-I61), and anti-NFkappaB/p65 (Cell Signaling Technology, 8242).	('Anti-H3K27me3', 'Var', (0, 13))	('p65', 'Gene', (133, 136))	('p65', 'Gene', '19697', (133, 136))	('NFkappaB', 'Gene', (124, 132))	('anti-H3K27ac', 'Var', (39, 51))	('NFkappaB', 'Gene', '18033', (124, 132))	('anti-H3K4me1', 'Var', (77, 89))
548332	30909651	For most comparisons between control and YM155 treated synovial sarcomas, Student's t-tests were performed.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (55, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (55, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('YM155', 'Chemical', 'MESH:C523798', (41, 46))	('synovial sarcomas', 'Disease', 'MESH:D013584', (55, 72))	('synovial sarcomas', 'Disease', (55, 72))	('YM155', 'Var', (41, 46))
548334	30909651	405 patients with various forms of cancer were treated with YM155, with the earliest studies ending in 2007 and the most recent ending in 2015 (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('YM155', 'Chemical', 'MESH:C523798', (60, 65))	('YM155', 'Var', (60, 65))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
548335	30909651	While YM155 is associated with adverse events at doses above 4.8 mg/m2/day, proper combination therapies might be able to achieve efficacy and avoid toxicity-related events.	('toxicity', 'Disease', 'MESH:D064420', (149, 157))	('toxicity', 'Disease', (149, 157))	('YM155', 'Var', (6, 11))	('YM155', 'Chemical', 'MESH:C523798', (6, 11))
548349	30909651	This submicromolar potency prompted further investigation of YM155 in our mouse model of synovial sarcoma.	('YM155', 'Chemical', 'MESH:C523798', (61, 66))	('synovial sarcoma', 'Disease', (89, 105))	('YM155', 'Var', (61, 66))	('mouse', 'Species', '10090', (74, 79))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (89, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('synovial sarcoma', 'Disease', 'MESH:D013584', (89, 105))
548355	30909651	The most notable cellular response to YM155 therapy in most settings is characterized by decreased levels of survivin protein.	('levels of', 'MPA', (99, 108))	('survivin', 'Gene', '11799', (109, 117))	('YM155', 'Chemical', 'MESH:C523798', (38, 43))	('YM155', 'Var', (38, 43))	('survivin', 'Gene', (109, 117))	('decreased', 'NegReg', (89, 98))
548356	30909651	We therefore measured survivin levels in our mice that were treated with YM155.	('YM155', 'Var', (73, 78))	('mice', 'Species', '10090', (45, 49))	('survivin', 'Gene', '11799', (22, 30))	('YM155', 'Chemical', 'MESH:C523798', (73, 78))	('survivin', 'Gene', (22, 30))
548358	30909651	A striking decrease of survivin was measured after immunoblotting in the YM155 treated sarcomas.	('YM155', 'Var', (73, 78))	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('survivin', 'Gene', '11799', (23, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcomas', 'Disease', (87, 95))	('decrease', 'NegReg', (11, 19))	('survivin', 'Gene', (23, 31))	('YM155', 'Chemical', 'MESH:C523798', (73, 78))
548359	30909651	Despite the large variation in the control treated samples, the comparison between control and YM155 treated synovial sarcomas was significant (p = 0.034, Student's t-test) (Figure 5a,b).	('synovial sarcomas', 'Phenotype', 'HP:0012570', (109, 126))	('synovial sarcomas', 'Disease', 'MESH:D013584', (109, 126))	('synovial sarcomas', 'Disease', (109, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('YM155', 'Chemical', 'MESH:C523798', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (109, 125))	('YM155', 'Var', (95, 100))
548360	30909651	While it is noteworthy to discover another potential indication for the use of YM155 to treat cancers, we sought to understand better how YM155 exerts its negative effects on Birc5/Survivin expression.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('Survivin', 'Gene', '11799', (181, 189))	('Survivin', 'Gene', (181, 189))	('YM155', 'Chemical', 'MESH:C523798', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('YM155', 'Chemical', 'MESH:C523798', (138, 143))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('YM155', 'Var', (138, 143))	('cancers', 'Disease', (94, 101))
548363	30909651	Congruently, levels of caspase 3/7 and caspase 8 activity increased with higher concentrations of YM155 as detected by Caspase-Glo bioluminescent assays after 24 h incubation with YM155 (Figure 6b).	('activity', 'MPA', (49, 57))	('increased', 'PosReg', (58, 67))	('Glo', 'Gene', (127, 130))	('YM155', 'Chemical', 'MESH:C523798', (98, 103))	('YM155', 'Var', (98, 103))	('caspase 3', 'Gene', (23, 32))	('caspase 8', 'Gene', '12370', (39, 48))	('caspase 8', 'Gene', (39, 48))	('YM155', 'Chemical', 'MESH:C523798', (180, 185))	('caspase 3', 'Gene', '12367', (23, 32))	('Glo', 'Gene', '268756', (127, 130))
548365	30909651	We observed a 39.5% reduction in normalized BIRC5 expression in YM155 treated synovial sarcomas (p = 0.0006) (Figure 6c).	('YM155 treated', 'Var', (64, 77))	('synovial sarcomas', 'Disease', 'MESH:D013584', (78, 95))	('BIRC5', 'Protein', (44, 49))	('synovial sarcomas', 'Disease', (78, 95))	('YM155', 'Chemical', 'MESH:C523798', (64, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('normalized', 'MPA', (33, 43))	('reduction', 'NegReg', (20, 29))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (78, 95))
548370	30909651	The treatment of HS-SY-II cells with YM155 resulted in an increase in enriched DNA in association with both H3K27 trimethylation and acetylation marks (Figure A3).	('acetylation marks', 'MPA', (133, 150))	('increase', 'PosReg', (58, 66))	('YM155', 'Chemical', 'MESH:C523798', (37, 42))	('H3K27', 'Protein', (108, 113))	('YM155', 'Var', (37, 42))	('enriched DNA in', 'MPA', (70, 85))	('trimethylation', 'MPA', (114, 128))	('HS-SY-II', 'CellLine', 'CVCL:8719', (17, 25))
548371	30909651	We similarly performed PCR-chromatin immunoprecipitation on the mouse synovial sarcoma samples that were treated for 11 days with YM155.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (70, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('YM155', 'Chemical', 'MESH:C523798', (130, 135))	('synovial sarcoma', 'Disease', 'MESH:D013584', (70, 86))	('YM155', 'Var', (130, 135))	('synovial sarcoma', 'Disease', (70, 86))	('mouse', 'Species', '10090', (64, 69))
548372	30909651	The concomitant enrichment for H3K27me3 and H3K27ac was also observed in these mouse synovial sarcomas (Figure 7a,b).	('mouse', 'Species', '10090', (79, 84))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (85, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('synovial sarcomas', 'Disease', 'MESH:D013584', (85, 102))	('synovial sarcomas', 'Disease', (85, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('H3K27me3', 'Var', (31, 39))	('H3K27ac', 'Var', (44, 51))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (85, 101))
548374	30909651	We next studied the levels of NFkappaB in response to YM155.	('YM155', 'Chemical', 'MESH:C523798', (54, 59))	('NFkappaB', 'Gene', (30, 38))	('NFkappaB', 'Gene', '18033', (30, 38))	('YM155', 'Var', (54, 59))
548377	30909651	A striking increase of NFkappaB was measured after immunoblotting in the YM155 treated sarcomas (p = 0.015, Student's t-test) (Figure 8a,b).	('NFkappaB', 'Gene', (23, 31))	('sarcomas', 'Disease', 'MESH:D012509', (87, 95))	('increase', 'PosReg', (11, 19))	('NFkappaB', 'Gene', '18033', (23, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcomas', 'Disease', (87, 95))	('YM155 treated', 'Var', (73, 86))	('YM155', 'Chemical', 'MESH:C523798', (73, 78))
548380	30909651	Therefore, despite the increase in survivin expression provided through a feedback loop mechanism, the repression of BIRC5 as evidenced by H3K27me3 ChIP-qPCR and decreased survivin expression results in an apoptotic phenotype (Figure 9).	('expression', 'MPA', (44, 54))	('expression', 'MPA', (181, 191))	('H3K27me3', 'Var', (139, 147))	('survivin', 'Gene', (35, 43))	('survivin', 'Gene', (172, 180))	('decreased', 'NegReg', (162, 171))	('increase', 'PosReg', (23, 31))	('apoptotic phenotype', 'CPA', (206, 225))	('repression', 'NegReg', (103, 113))	('results in', 'Reg', (192, 202))	('survivin', 'Gene', '11799', (35, 43))	('survivin', 'Gene', '11799', (172, 180))	('BIRC5', 'Gene', (117, 122))
548383	30909651	Furthermore, the most studied inhibitor of survivin, YM155, is associated with serious adverse events without demonstrating increases in efficacy.	('survivin', 'Gene', '11799', (43, 51))	('YM155', 'Chemical', 'MESH:C523798', (53, 58))	('survivin', 'Gene', (43, 51))	('YM155', 'Var', (53, 58))
548385	30909651	There is potential in treating synovial sarcoma and other survivin-expressing cancers with YM155 in combination with another targeted therapy.	('YM155', 'Var', (91, 96))	('survivin', 'Gene', (58, 66))	('YM155', 'Chemical', 'MESH:C523798', (91, 96))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('synovial sarcoma', 'Disease', (31, 47))	('cancers', 'Disease', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('survivin', 'Gene', '11799', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (31, 47))	('synovial sarcoma', 'Disease', 'MESH:D013584', (31, 47))
548388	30909651	In this study, we have demonstrated the potential indication utilizing YM155 in synovial sarcomas by applying YM155 to both in vitro and in vivo models of synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (155, 171))	('synovial sarcoma', 'Disease', 'MESH:D013584', (155, 171))	('synovial sarcomas', 'Disease', 'MESH:D013584', (80, 97))	('YM155', 'Var', (110, 115))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (80, 96))	('YM155', 'Var', (71, 76))	('YM155', 'Chemical', 'MESH:C523798', (71, 76))	('synovial sarcoma', 'Disease', (155, 171))	('synovial sarcoma', 'Disease', 'MESH:D013584', (80, 96))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (80, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))	('YM155', 'Chemical', 'MESH:C523798', (110, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('synovial sarcomas', 'Disease', (80, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
548389	30909651	The decrease in Birc5 and survivin expression, the induction of apoptosis, and the decrease in cell viability were clearly detected in synovial sarcoma upon YM155 exposure.	('survivin', 'Gene', (26, 34))	('synovial sarcoma', 'Disease', (135, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('apoptosis', 'CPA', (64, 73))	('YM155', 'Chemical', 'MESH:C523798', (157, 162))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (135, 151))	('expression', 'MPA', (35, 45))	('YM155', 'Var', (157, 162))	('decrease', 'NegReg', (4, 12))	('decrease', 'NegReg', (83, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (135, 151))	('survivin', 'Gene', '11799', (26, 34))	('Birc5', 'Protein', (16, 21))	('cell viability', 'CPA', (95, 109))
548400	30909651	We have demonstrated that NFkappaB is significantly upregulated in response to YM155 and that it loosely associates with the Birc5 promoter.	('NFkappaB', 'Gene', (26, 34))	('associates', 'Interaction', (105, 115))	('YM155', 'Chemical', 'MESH:C523798', (79, 84))	('NFkappaB', 'Gene', '18033', (26, 34))	('YM155', 'Var', (79, 84))	('upregulated', 'PosReg', (52, 63))
548401	30909651	The association of NFkappaB with the Birc5 promoter did not change in the presence of YM155.	('NFkappaB', 'Gene', (19, 27))	('NFkappaB', 'Gene', '18033', (19, 27))	('association', 'Interaction', (4, 15))	('YM155', 'Chemical', 'MESH:C523798', (86, 91))	('YM155', 'Var', (86, 91))
548402	30909651	While YM155 could be interacting with NFkappaB to regulate survivin expression, another study demonstrated indirect effects of YM155 on ILF3/NF110 induced Birc5 expression.	('survivin', 'Gene', (59, 67))	('ILF3', 'Gene', (136, 140))	('NFkappaB', 'Gene', (38, 46))	('YM155', 'Chemical', 'MESH:C523798', (6, 11))	('YM155', 'Chemical', 'MESH:C523798', (127, 132))	('survivin', 'Gene', '11799', (59, 67))	('YM155', 'Var', (127, 132))	('Birc5 expression', 'MPA', (155, 171))	('NFkappaB', 'Gene', '18033', (38, 46))	('ILF3', 'Gene', '16201', (136, 140))
548403	30909651	The direct target of YM155 remains unproven, but the effects on epigenetic changes at the Birc5 promoter are evident in synovial sarcoma.	('epigenetic changes', 'Var', (64, 82))	('synovial sarcoma', 'Disease', (120, 136))	('effects', 'Reg', (53, 60))	('YM155', 'Chemical', 'MESH:C523798', (21, 26))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (120, 136))	('synovial sarcoma', 'Disease', 'MESH:D013584', (120, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
548405	30909651	The synergy of these approaches could overcome the concomitant expression of H3K27ac and H3K27me3 to predominantly favor repression of the Birc5 promoter, resulting in a more sensitive induction of apoptosis in cancer.	('apoptosis', 'CPA', (198, 207))	('repression', 'MPA', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('induction', 'PosReg', (185, 194))	('cancer', 'Disease', (211, 217))	('H3K27me3', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('H3K27ac', 'Var', (77, 84))	('more', 'PosReg', (170, 174))
548407	30909651	However, the most widely used survivin inhibitor, YM155, exhibits adverse effects in patients and indirectly affects survivin/Birc5 levels through an ambiguous mechanism of action.	('affects', 'Reg', (109, 116))	('survivin', 'Gene', (30, 38))	('YM155', 'Chemical', 'MESH:C523798', (50, 55))	('survivin', 'Gene', (117, 125))	('YM155', 'Var', (50, 55))	('patients', 'Species', '9606', (85, 93))	('survivin', 'Gene', '11799', (30, 38))	('survivin', 'Gene', '11799', (117, 125))
548408	30909651	We have demonstrated that histone modifications are altered in synovial sarcoma cells at the Birc5 promoter upon YM155 administration.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (63, 79))	('synovial sarcoma', 'Disease', 'MESH:D013584', (63, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('altered', 'Reg', (52, 59))	('YM155', 'Chemical', 'MESH:C523798', (113, 118))	('YM155', 'Var', (113, 118))	('histone modifications', 'MPA', (26, 47))	('synovial sarcoma', 'Disease', (63, 79))
548409	30909651	Because YM155 exerts its effects through epigenetic regulation of the Birc5 promoter, administering YM155 in combination with histone acetyltransferase and DNA demethylase inhibitors might prove efficacious.	('YM155', 'Chemical', 'MESH:C523798', (8, 13))	('epigenetic regulation', 'MPA', (41, 62))	('Birc5 promoter', 'Gene', (70, 84))	('YM155', 'Chemical', 'MESH:C523798', (100, 105))	('YM155', 'Var', (100, 105))
548415	30237855	Recent work has pointed to epigenetic mechanisms as key players, and potential new therapeutic targets, in Ewing Sarcoma.	('epigenetic mechanisms', 'Var', (27, 48))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (107, 120))	('Sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('Ewing Sarcoma', 'Disease', (107, 120))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (107, 120))
548431	30237855	Epigenetic mechanisms have recently emerged as very important players in Ewing Sarcoma pathogenesis, and a number of studies have identified pathogenic roles for specific chromatin modifiers in the disease.	('Sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (73, 86))	('Epigenetic', 'Var', (0, 10))	('Ewing Sarcoma', 'Disease', (73, 86))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (73, 86))
548476	30237855	However, JIB-04 also leads to increased CDKN1A levels in p53-mutant A673 cells (Figures 3B and 6B), which, notably, do not induce CDKN1A in response to the DNA-damaging agent etoposide.	('CDKN1A', 'Gene', (130, 136))	('JIB-04', 'Chemical', 'MESH:C585278', (9, 15))	('CDKN1A', 'Gene', (40, 46))	('CDKN1A', 'Gene', '1026', (130, 136))	('JIB-04', 'Var', (9, 15))	('CDKN1A', 'Gene', '1026', (40, 46))	('p53', 'Gene', (57, 60))	('increased', 'PosReg', (30, 39))	('etoposide', 'Chemical', 'MESH:D005047', (175, 184))	('p53', 'Gene', '7157', (57, 60))
548481	30237855	Thus, JIB-04 increases DNA damage, which in turn may be one, but not an exclusive, mechanism of CDKN1A induction in Ewing Sarcoma cells.	('increases', 'PosReg', (13, 22))	('JIB-04', 'Var', (6, 12))	('Ewing Sarcoma cells', 'Disease', (116, 135))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('DNA damage', 'MPA', (23, 33))	('CDKN1A', 'Gene', (96, 102))	('CDKN1A', 'Gene', '1026', (96, 102))	('JIB-04', 'Chemical', 'MESH:C585278', (6, 12))	('Sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('Ewing Sarcoma cells', 'Disease', 'MESH:C563168', (116, 135))
548489	30237855	Epigenetic alterations have recently emerged as playing very important roles in cancer.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))
548490	30237855	Epigenetic mechanisms appear to play particularly prominent roles in the pathogenesis of pediatric cancers, which tend to have few genetic lesions.	('pediatric cancers', 'Disease', 'MESH:D009369', (89, 106))	('roles', 'Reg', (60, 65))	('pediatric cancers', 'Disease', (89, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('genetic lesions', 'Disease', 'MESH:D020022', (131, 146))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('genetic lesions', 'Disease', (131, 146))
548500	30237855	In Ewing Sarcoma, we find evidence of activity against multiple histone methyl marks controlled by different JHDM families (eg: H3K27 demethylation/ KDM6 family, H3K4 demethylation/ KDM5 family).	('activity', 'MPA', (38, 46))	('H3K4 demethylation/', 'Var', (162, 181))	('Sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('Ewing Sarcoma', 'Disease', (3, 16))	('H3K27 demethylation/', 'Var', (128, 148))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (3, 16))
548509	30237855	The consistently increased DNA damage observed upon JIB-04 treatment suggests that the drug could have favorable combinatorial activity with other DNA damaging agents (eg: temozolomide) or/and inhibitors of DNA repair (eg: PARP inhibitors), the former observed in glioblastoma.	('increased', 'PosReg', (17, 26))	('inhibitors', 'Var', (193, 203))	('PARP', 'Gene', '142', (223, 227))	('glioblastoma', 'Disease', (264, 276))	('PARP', 'Gene', (223, 227))	('temozolomide', 'Chemical', 'MESH:D000077204', (172, 184))	('glioblastoma', 'Disease', 'MESH:D005909', (264, 276))	('JIB-04', 'Chemical', 'MESH:C585278', (52, 58))	('DNA damage', 'MPA', (27, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (264, 276))
548533	30237855	Primary antibodies used were: H3K4me3 (Cell Signaling Technologies, #9751, 1:1000); H3K9me3 (Cell Signaling Technologies, #13969, 1:1000); H3K27me3 (Cell Signaling Technologies, #9733, 1:1000); phospho-H2AX (Ser139; Cell Signaling Technologies, #9718, 1:1000); H2AX (Cell Signaling Technologies, #2595S, 1:1000); and H3 (Abcam, #1791, 1:1000).	('Ser139', 'Chemical', '-', (208, 214))	('H3K9me3', 'Var', (84, 91))	('H3K27me3', 'Var', (139, 147))	('H2AX', 'Gene', (261, 265))	('H3K4me3', 'Protein', (30, 37))	('H2AX', 'Gene', '3014', (202, 206))	('H2AX', 'Gene', (202, 206))	('H2AX', 'Gene', '3014', (261, 265))
548550	27563810	Cell lines with high levels of MAP17 show a better response to bortezomib in vitro.	('better', 'PosReg', (44, 50))	('MAP17', 'Gene', (31, 36))	('bortezomib', 'Chemical', 'MESH:D000069286', (63, 73))	('high levels', 'Var', (16, 27))	('response', 'MPA', (51, 59))
548557	27563810	Sarcomas are usually grouped into two broad categories according to molecular genetics: sarcomas harboring a diploid or nearly diploid karyotype and simple genetic driver alterations, such as Ewing's sarcoma, or sarcomas with a complex and imbalanced karyotype, such as osteosarcoma.	('sarcomas', 'Disease', (88, 96))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('osteosarcoma', 'Phenotype', 'HP:0002669', (270, 282))	('sarcomas', 'Disease', 'MESH:D012509', (212, 220))	('alterations', 'Var', (171, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (212, 220))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('sarcomas', 'Disease', (212, 220))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (192, 207))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (192, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('osteosarcoma', 'Disease', (270, 282))	('osteosarcoma', 'Disease', 'MESH:D012516', (270, 282))	('Sarcomas', 'Disease', (0, 8))	("Ewing's sarcoma", 'Disease', (192, 207))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))
548569	27563810	MAP17 increases the cellular reactive oxygen species (ROS), which have been shown to enhance the malignant properties of tumor cells.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (29, 52))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('MAP17', 'Var', (0, 5))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('enhance', 'PosReg', (85, 92))	('ROS', 'Chemical', 'MESH:D017382', (54, 57))	('cellular reactive oxygen species', 'MPA', (20, 52))	('increases', 'PosReg', (6, 15))
548598	27563810	Furthermore, the analysis of databases for the expression of MAP17 in other types not sufficiently represented in our cohort, such as osteosarcoma or Ewing's sarcoma with a high MAP17 level, also shows a worse prognosis in either OS or metastasis-free survival (Supplementary Figure S3).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (150, 165))	('metastasis-free survival', 'CPA', (236, 260))	('osteosarcoma', 'Disease', (134, 146))	('osteosarcoma', 'Disease', 'MESH:D012516', (134, 146))	('high', 'Var', (173, 177))	('MAP17', 'Gene', (61, 66))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (150, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	("Ewing's sarcoma", 'Disease', (150, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('osteosarcoma', 'Phenotype', 'HP:0002669', (134, 146))
548602	27563810	Because these patients with high MAP17 showed a worse prognosis, we wondered whether we can find an alternative treatment for these patients.	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))	('MAP17', 'Gene', (33, 38))	('patients', 'Species', '9606', (132, 140))
548607	27563810	We distributed the cell lines into three groups according to the MAP17 mRNA level: those with barely detectable MAP17 mRNA (BP, CE, CD0024, SAOS2, SK-UT-1, HT-1080 and CP0038), those with low but clearly detectable levels of MAP17 mRNA (AA, AW, BG and BD) and those with high levels of expression (BC, AZ, AX, SW872 and 93T449).	('93T449', 'CellLine', 'CVCL:M807', (320, 326))	('SK-UT-1', 'CellLine', 'CVCL:0533', (147, 154))	('SAOS2', 'CellLine', 'CVCL:0548', (140, 145))	('CP0038', 'Var', (168, 174))	('SW872', 'CellLine', 'CVCL:1730', (310, 315))	('MAP17', 'Gene', (112, 117))	('HT-1080', 'CellLine', 'CVCL:0317', (156, 163))
548610	27563810	We found that the ectopic expression of MAP17 increases the sensitivity to bortezomib 2-3 fold (Figure 4C).	('bortezomib', 'Chemical', 'MESH:D000069286', (75, 85))	('ectopic expression', 'Var', (18, 36))	('sensitivity to bortezomib', 'MPA', (60, 85))	('increases', 'PosReg', (46, 55))	('MAP17', 'Gene', (40, 45))
548616	27563810	We found that the PDX with high levels of MAP17 showed a better response to bortezomib (Figure 5C).	('MAP17', 'Gene', (42, 47))	('high levels', 'Var', (27, 38))	('response', 'MPA', (64, 72))	('bortezomib', 'Chemical', 'MESH:D000069286', (76, 86))	('better', 'PosReg', (57, 63))
548619	27563810	However, the models with low or no MAP17 (S14 and S29) did not respond to bortezomib (Figure 5C).	('not', 'NegReg', (59, 62))	('bortezomib', 'Chemical', 'MESH:D000069286', (74, 84))	('respond', 'MPA', (63, 70))	('S29', 'Var', (50, 53))	('S14', 'Var', (42, 45))
548620	27563810	Thus, our data in vivo, in PDX models of sarcoma, support our data in vitro and suggest that bortezomib may be a suitable therapy for sarcoma patients with high MAP17 at diagnosis.	('sarcoma', 'Disease', (41, 48))	('high MAP17', 'Var', (156, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('sarcoma', 'Disease', (134, 141))	('bortezomib', 'Chemical', 'MESH:D000069286', (93, 103))	('patients', 'Species', '9606', (142, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
548630	27563810	We found that multiple myeloma patients with higher MAP17 mRNA levels respond better to bortezomib and exhibit prolonged survival.	('multiple myeloma', 'Phenotype', 'HP:0006775', (14, 30))	('better', 'PosReg', (78, 84))	('respond', 'MPA', (70, 77))	('MAP17', 'Gene', (52, 57))	('multiple myeloma', 'Disease', 'MESH:D009101', (14, 30))	('multiple myeloma', 'Disease', (14, 30))	('higher', 'Var', (45, 51))	('patients', 'Species', '9606', (31, 39))	('bortezomib', 'Chemical', 'MESH:D000069286', (88, 98))
548631	27563810	We also showed that MAP17 determines the bortezomib sensitivity by inhibiting the cytoprotective effects related to bortezomib-induced NFkappaB nuclear translocation and autophagy.	('NFkappaB', 'Gene', '4790', (135, 143))	('cytoprotective effects', 'CPA', (82, 104))	('bortezomib', 'Chemical', 'MESH:D000069286', (116, 126))	('autophagy', 'CPA', (170, 179))	('MAP17', 'Var', (20, 25))	('bortezomib', 'Chemical', 'MESH:D000069286', (41, 51))	('NFkappaB', 'Gene', (135, 143))	('inhibiting', 'NegReg', (67, 77))
548633	27563810	We found that the MAP17-dependent increase in sensitivity in sarcoma was correlated with lower levels of phosphorylated NFkappaB and autophagy measured as p62/LC3II, further supporting the relevance of these two pathways in MAP17 increased sensitivity.	('lower', 'NegReg', (89, 94))	('LC3', 'Gene', '84557', (159, 162))	('autophagy', 'CPA', (133, 142))	('LC3', 'Gene', (159, 162))	('p62', 'Gene', '8878', (155, 158))	('NFkappaB', 'Gene', (120, 128))	('p62', 'Gene', (155, 158))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('NFkappaB', 'Gene', '4790', (120, 128))	('MAP17-dependent', 'Var', (18, 33))	('sensitivity', 'MPA', (46, 57))	('increase', 'PosReg', (34, 42))	('sarcoma', 'Disease', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
548640	27563810	The increased tumorigenic properties caused by the expression of MAP17 are associated with high levels of ROS, and the inhibition of antioxidants decreases their malignant properties.	('increased', 'PosReg', (4, 13))	('malignant properties', 'CPA', (162, 182))	('tumor', 'Disease', (14, 19))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('decreases', 'NegReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('ROS', 'MPA', (106, 109))	('MAP17', 'Gene', (65, 70))	('expression', 'Var', (51, 61))
548645	27563810	Inhibition of these transporters by furosemide impairs the response to bortezomib, thus leading to the recovery of bortezomib resistance in MAP17-overexpressing cells.	('furosemide', 'Chemical', 'MESH:D005665', (36, 46))	('bortezomib resistance', 'MPA', (115, 136))	('impairs', 'NegReg', (47, 54))	('Inhibition', 'Var', (0, 10))	('response to bortezomib', 'MPA', (59, 81))	('bortezomib', 'Chemical', 'MESH:D000069286', (115, 125))	('recovery', 'MPA', (103, 111))	('bortezomib', 'Chemical', 'MESH:D000069286', (71, 81))
548688	26679553	All cases were positive for CD99, and 3 patients with genetic confirmation were positive for EWS-FLI1 fusion or EWSR1 gene rearrangement.	('CD99', 'Gene', '4267', (28, 32))	('EWS', 'Gene', '2130', (93, 96))	('EWS', 'Gene', (93, 96))	('fusion', 'Var', (102, 108))	('patients', 'Species', '9606', (40, 48))	('FLI1', 'Gene', (97, 101))	('EWSR1', 'Gene', '2130', (112, 117))	('FLI1', 'Gene', '2313', (97, 101))	('CD99', 'Gene', (28, 32))	('EWSR1', 'Gene', (112, 117))	('EWS', 'Gene', (112, 115))	('EWS', 'Gene', '2130', (112, 115))	('positive', 'Reg', (80, 88))	('positive', 'Reg', (15, 23))
548721	26679553	Three cases tested were confirmed cytogenetically, with 2 cases showing EWSR1 gene rearrangements by fluorescence in situ hybridization (FISH; Fig 6), and reverse transcriptase polymerase chain reaction (PCR) detected the presence of EWSR1-FLI1 fusion in 1 case.	('FLI1', 'Gene', (240, 244))	('rearrangements', 'Var', (83, 97))	('EWSR1', 'Gene', (72, 77))	('FLI1', 'Gene', '2313', (240, 244))	('EWSR1', 'Gene', '2130', (234, 239))	('EWSR1', 'Gene', '2130', (72, 77))	('fusion', 'Var', (245, 251))	('EWSR1', 'Gene', (234, 239))
548729	26679553	In the present study, the 3 tested cases were positive for EWSR1-FLI1 fusion or EWSR1 gene rearrangement.	('EWSR1', 'Gene', (59, 64))	('FLI1', 'Gene', '2313', (65, 69))	('FLI1', 'Gene', (65, 69))	('EWSR1', 'Gene', (80, 85))	('EWSR1', 'Gene', '2130', (59, 64))	('fusion', 'Var', (70, 76))	('gene rearrangement', 'Var', (86, 104))	('positive', 'Reg', (46, 54))	('EWSR1', 'Gene', '2130', (80, 85))
548737	26679553	Therefore, identification of EWSR1 rearrangement by FISH or PCR is crucial, but also not specific for ES.	('ES', 'Phenotype', 'HP:0012254', (102, 104))	('EWSR1', 'Gene', '2130', (29, 34))	('rearrangement', 'Var', (35, 48))	('EWSR1', 'Gene', (29, 34))
548738	26679553	The t(11;22)(q24;q12) resulting in EWSR1-FLI1 and t(21;22)(q22;q12) resulting in EWSR1-ERG are detected in 85 and 10% of ES cases, respectively.	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (50, 67))	('FLI1', 'Gene', '2313', (41, 45))	('EWSR1', 'Gene', '2130', (81, 86))	('ES', 'Phenotype', 'HP:0012254', (121, 123))	('t(11;22)(q24;q12', 'Var', (4, 20))	('t(21;22)(q22;q12', 'Var', (50, 66))	('EWSR1', 'Gene', (35, 40))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 21))	('EWSR1', 'Gene', '2130', (35, 40))	('EWSR1', 'Gene', (81, 86))	('FLI1', 'Gene', (41, 45))
548740	26679553	EWSR1 gene rearrangement also can be seen in extraskeletal myxoid chondrosarcoma, clear cell sarcoma, hyalinizing clear cell carcinoma, clear cell odontogenic carcinoma, desmoplastic small round cell tumor, and myxoid liposarcoma.	('carcinoma', 'Disease', 'MESH:D002277', (125, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (66, 80))	('myxoid liposarcoma', 'Disease', (211, 229))	('seen', 'Reg', (37, 41))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (82, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('EWSR1', 'Gene', '2130', (0, 5))	('rearrangement', 'Var', (11, 24))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (211, 229))	('carcinoma', 'Disease', (159, 168))	('clear cell odontogenic carcinoma', 'Phenotype', 'HP:0010603', (136, 168))	('odontogenic carcinoma', 'Phenotype', 'HP:0100612', (147, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('clear cell odontogenic carcinoma', 'Disease', 'MESH:C538614', (136, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinoma', 'Disease', (125, 134))	('clear cell odontogenic carcinoma', 'Disease', (136, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('clear cell sarcoma', 'Disease', (82, 100))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (59, 80))	('liposarcoma', 'Phenotype', 'HP:0012034', (218, 229))	('EWSR1', 'Gene', (0, 5))	('carcinoma', 'Disease', 'MESH:D002277', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('myxoid chondrosarcoma', 'Disease', (59, 80))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (170, 205))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (211, 229))	('desmoplastic small round cell tumor', 'Disease', (170, 205))
548749	26824057	Regulated lysosomal exocytosis mediates cancer progression LAMP1 oversialylation results in excessive lysosomal exocytosis, promoting tumor invasion and drug resistance.	('promoting', 'PosReg', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('drug resistance', 'CPA', (153, 168))	('excessive lysosomal exocytosis', 'MPA', (92, 122))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('LAMP1', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('oversialylation', 'Var', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', (134, 139))
548752	26824057	Cleavage of LAMP1 sialic acids by NEU1 limits the extent of lysosomal exocytosis.	('Cleavage', 'Var', (0, 8))	('sialic acids', 'Protein', (18, 30))	('limits', 'NegReg', (39, 45))	('lysosomal exocytosis', 'MPA', (60, 80))	('sialic acids', 'Chemical', 'MESH:D012794', (18, 30))	('NEU1', 'Gene', (34, 38))	('extent', 'MPA', (50, 56))
548753	26824057	We found that by down-regulation of NEU1 and accumulation of oversialylated LAMP1, tumor cells exacerbate lysosomal exocytosis of soluble hydrolases and exosomes.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LAMP1', 'Gene', (76, 81))	('NEU1', 'Gene', (36, 40))	('tumor', 'Disease', (83, 88))	('exacerbate', 'PosReg', (95, 105))	('accumulation', 'PosReg', (45, 57))	('oversialylated', 'Var', (61, 75))	('down-regulation', 'NegReg', (17, 32))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
548756	26824057	In a therapeutic proof of principle, we demonstrate that inhibiting lysosomal exocytosis reversed invasiveness and chemoresistance in aggressive sarcoma cells.	('aggressive sarcoma', 'Disease', 'MESH:D012509', (134, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('aggressive sarcoma', 'Disease', (134, 152))	('chemoresistance', 'CPA', (115, 130))	('inhibiting', 'Var', (57, 67))	('lysosomal exocytosis', 'MPA', (68, 88))	('invasiveness', 'CPA', (98, 110))
548763	26824057	NEU1 limits lysosomal exocytosis by processing LAMP1 sialic acids, thereby shortening its half-life.	('LAMP1', 'Var', (47, 52))	('sialic acids', 'Chemical', 'MESH:D012794', (53, 65))	('lysosomal exocytosis', 'MPA', (12, 32))	('half-life', 'MPA', (90, 99))	('processing LAMP1', 'Var', (36, 52))	('limits', 'NegReg', (5, 11))	('NEU1', 'Gene', (0, 4))	('sialic', 'Protein', (53, 59))	('shortening', 'NegReg', (75, 85))
548771	26824057	Therapeutic regimens for sarcomas currently include inhibitors of tyrosine kinases, vascular endothelial growth factor (VEGF), or mammalian target of rapamycin (mTOR) and monoclonal antibodies, which are frequently combined with chemotherapeutics (for example, doxorubicin).	('vascular endothelial growth factor', 'Gene', '7422', (84, 118))	('VEGF', 'Gene', '7422', (120, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('sarcomas', 'Disease', (25, 33))	('mTOR', 'Gene', '2475', (161, 165))	('mammalian target of rapamycin', 'Gene', '2475', (130, 159))	('mammalian target of rapamycin', 'Gene', (130, 159))	('doxorubicin', 'Chemical', 'MESH:D004317', (261, 272))	('VEGF', 'Gene', (120, 124))	('vascular endothelial growth factor', 'Gene', (84, 118))	('inhibitors', 'Var', (52, 62))	('sarcomas', 'Disease', 'MESH:D012509', (25, 33))	('mTOR', 'Gene', (161, 165))	('sarcomas', 'Phenotype', 'HP:0100242', (25, 33))
548778	26824057	The authors attributed these effects to NEU1-mediated processing of sialic acids on beta4 integrin and consequent attenuation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways.	('attenuation', 'NegReg', (114, 125))	('extracellular signal-regulated kinase 1/2', 'Gene', (129, 170))	('sialic acids', 'Chemical', 'MESH:D012794', (68, 80))	('ERK1/2', 'Gene', '5595;5594', (172, 178))	('beta4 integrin', 'Protein', (84, 98))	('extracellular signal-regulated kinase 1/2', 'Gene', '5595', (129, 170))	('sialic acids', 'Var', (68, 80))	('ERK1/2', 'Gene', (172, 178))
548784	26824057	To investigate the contribution of NEU1-regulated lysosomal exocytosis in cancer, we compared the effects of low-Neu1 expression in tumors in Neu1+/-/Arf-/- mice with those in Neu1+/+/Arf-/- mice.	('mice', 'Species', '10090', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('low-Neu1', 'Var', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('mice', 'Species', '10090', (191, 195))	('tumors', 'Disease', (132, 138))	('Neu1+/-/Arf-/-', 'Var', (142, 156))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
548785	26824057	Even though the range of tumors was similar in the two experimental groups, distinct skewing toward the development of highly aggressive sarcomas occurred almost exclusively in the Neu1+/-/Arf-/- mice (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('aggressive sarcomas', 'Disease', (126, 145))	('highly', 'Disease', (119, 125))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('Neu1+/-/Arf-/-', 'Var', (181, 195))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('aggressive sarcomas', 'Disease', 'MESH:D012509', (126, 145))
548793	26824057	In some Neu1+/-/Arf-/- mice, sarcomas developed concurrently with other malignancies (for example, hematologic tumors and carcinomas).	('Neu1+/-/Arf-/-', 'Var', (8, 22))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('malignancies', 'Disease', (72, 84))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('sarcomas', 'Disease', (29, 37))	('hematologic tumors and carcinomas', 'Disease', 'MESH:D009369', (99, 132))	('mice', 'Species', '10090', (23, 27))
548796	26824057	To test this further, we established primary cells from various types of sarcomas resected from Neu1+/-/Arf-/- mice.	('sarcomas', 'Disease', 'MESH:D012509', (73, 81))	('sarcomas', 'Phenotype', 'HP:0100242', (73, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('mice', 'Species', '10090', (111, 115))	('sarcomas', 'Disease', (73, 81))	('Neu1+/-/Arf-/-', 'Var', (96, 110))
548815	26824057	Moreover, considering the attention given recently to the role of exosomes in cancer progression, we wanted to test whether enhanced lysosomal exocytosis in low-NEU1-expressing cells would promote increased release of exosomes.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('enhanced', 'PosReg', (124, 132))	('lysosomal exocytosis', 'MPA', (133, 153))	('release of exosomes', 'MPA', (207, 226))	('low-NEU1-expressing', 'Var', (157, 176))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
548817	26824057	The involvement of LAMP1 in promoting the movement of lysosomes to the cell periphery and consequently increased lysosomal exocytosis in the RH30 cells was demonstrated by silencing LAMP1 (RH30shLAMP1) (Fig.	('movement of lysosomes to the cell periphery', 'MPA', (42, 85))	('increased', 'PosReg', (103, 112))	('LAMP1', 'Gene', (19, 24))	('RH30shLAMP1', 'Gene', (189, 200))	('RH30shLAMP1', 'Gene', '6007;3916', (189, 200))	('lysosomal exocytosis', 'MPA', (113, 133))	('silencing', 'Var', (172, 181))	('RH30', 'Gene', (189, 193))	('RH30', 'Gene', '6007', (189, 193))	('RH30', 'Gene', (141, 145))	('LAMP1', 'Gene', (182, 187))	('RH30', 'Gene', '6007', (141, 145))	('promoting', 'PosReg', (28, 37))
548819	26824057	Knocking down NEU1 in RH41 (RH41shNEU1) or overexpressing NEU1 in RH30 (RH30NEU1) also inversely modulated the extent of lysosomal exocytosis (fig.	('modulated', 'Reg', (97, 106))	('lysosomal exocytosis', 'MPA', (121, 141))	('Knocking down', 'Var', (0, 13))	('RH30NEU1', 'Gene', (72, 80))	('RH30NEU1', 'Gene', '6007', (72, 80))	('RH41shNEU1', 'Gene', (28, 38))	('RH41shNEU1', 'Gene', '4758', (28, 38))	('RH30', 'Gene', (66, 70))	('RH30', 'Gene', (72, 76))	('RH30', 'Gene', '6007', (66, 70))	('RH30', 'Gene', '6007', (72, 76))
548832	26824057	These findings indicate that in most of the highly malignant human sarcomas, the low-NEU1-high-LAMP1 pattern is associated with high Myosin-11 expression, suggesting that they synergistically promote an invasive/metastatic state.	('Myosin-11', 'Protein', (133, 142))	('expression', 'MPA', (143, 153))	('promote', 'PosReg', (192, 199))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('low-NEU1-high-LAMP1', 'Var', (81, 100))	('human', 'Species', '9606', (61, 66))	('sarcomas', 'Disease', (67, 75))	('invasive/metastatic state', 'CPA', (203, 228))
548841	26824057	Silencing Myh11, Lamp1, or the combination of the two in the same tumor cells lowered lysosomal exocytosis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('lowered', 'NegReg', (78, 85))	('Lamp1', 'Gene', (17, 22))	('Myh11', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Silencing', 'Var', (0, 9))	('lysosomal exocytosis', 'MPA', (86, 106))
548854	26824057	In contrast, RH30PPCA xenografts grew at a rate similar to that of xenografts in Neu1+/+/NSG mice (Fig.	('RH30PPCA', 'Var', (13, 21))	('grew', 'CPA', (33, 37))	('mice', 'Species', '10090', (93, 97))
548855	26824057	Thus, the combined effect of low NEU1 in tumor cells and the microenvironment created the most permissive setting for tumor growth and spread.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('NEU1', 'Protein', (33, 37))	('tumor', 'Disease', (41, 46))	('low', 'Var', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('spread', 'CPA', (135, 141))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
548856	26824057	We found that doxorubicin endogenous fluorescence colocalized, in part, with LysoTracker Green in RH41 and RH30 cells; however, in RH41 cells, doxorubicin-loaded lysosomes were mainly perinuclear, whereas in RH30 cells, they were scattered throughout the cytoplasm (fig.	('RH30', 'Gene', '6007', (208, 212))	('doxorubicin-loaded', 'MPA', (143, 161))	('doxorubicin', 'Chemical', 'MESH:D004317', (143, 154))	('RH41', 'Var', (131, 135))	('LysoTracker Green', 'Chemical', '-', (77, 94))	('RH30', 'Gene', (107, 111))	('doxorubicin', 'Chemical', 'MESH:D004317', (14, 25))	('RH30', 'Gene', (208, 212))	('RH30', 'Gene', '6007', (107, 111))
548869	26824057	We then tested the invasive and drug-resistant characteristics of our primary mouse cells isolated from Neu1+/-/Arf-/- sarcomas that had enhanced lysosomal exocytosis (Fig.	('enhanced', 'PosReg', (137, 145))	('sarcomas', 'Disease', (119, 127))	('tested', 'Reg', (8, 14))	('lysosomal exocytosis', 'MPA', (146, 166))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('mouse', 'Species', '10090', (78, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('Neu1+/-/Arf-/-', 'Var', (104, 118))
548876	26824057	The genetic or epigenetic changes that cancer cells undergo during primary tumorigenesis may predispose them to respond to extrinsic cues that initiate an EMT process, allowing them to acquire a more aggressive phenotype.	('allowing', 'Reg', (168, 176))	('acquire', 'PosReg', (185, 192))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('more', 'PosReg', (195, 199))	('predispose', 'Reg', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('respond', 'MPA', (112, 119))	('epigenetic changes', 'Var', (15, 33))	('tumor', 'Disease', (75, 80))
548878	26824057	We found that impaired sialic acid processing on LAMP1 directly affected lysosomal exocytosis, which we have now linked to the acquisition of an invasive, drug-resistant phenotype.	('lysosomal exocytosis', 'MPA', (73, 93))	('sialic', 'Protein', (23, 29))	('affected', 'Reg', (64, 72))	('sialic acid', 'Chemical', 'MESH:D019158', (23, 34))	('impaired', 'Var', (14, 22))	('LAMP1', 'Gene', (49, 54))
548882	26824057	These combined sialic acid modifications on these NEU1 substrates would affect cell-cell communication and simultaneously exacerbate lysosomal exocytosis of soluble hydrolases and exosomes.	('cell-cell communication', 'CPA', (79, 102))	('affect', 'Reg', (72, 78))	('sialic acid modifications', 'Var', (15, 40))	('NEU1', 'Gene', (50, 54))	('sialic acid', 'Chemical', 'MESH:D019158', (15, 26))	('exacerbate', 'PosReg', (122, 132))
548883	26824057	This scenario would reconcile the early observations made in colon carcinoma cells, that is, that oversialylation of beta4 integrin activates the ERK1/2 signaling pathway, thereby increasing the cells' metastatic potential, with our current findings in sarcoma cells in which oversialylated LAMP1 enhances lysosomal exocytosis, making cancer cells migratory and invasive.	('enhances', 'PosReg', (297, 305))	('sarcoma', 'Disease', 'MESH:D012509', (253, 260))	('cancer', 'Disease', (335, 341))	('ERK1/2', 'Gene', (146, 152))	('sarcoma', 'Disease', (253, 260))	('increasing', 'PosReg', (180, 190))	('ERK1/2', 'Gene', '5595;5594', (146, 152))	('metastatic potential', 'CPA', (202, 222))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('lysosomal exocytosis', 'MPA', (306, 326))	('LAMP1', 'Gene', (291, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('colon carcinoma', 'Disease', (61, 76))	('migratory', 'CPA', (348, 357))	('activates', 'PosReg', (132, 141))	('oversialylated', 'Var', (276, 290))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('oversialylation', 'Var', (98, 113))	('colon carcinoma', 'Disease', 'MESH:D015179', (61, 76))	('invasive', 'CPA', (362, 370))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
548887	26824057	Recent examples are Myosin-X up-regulation in mutant p53-driven breast cancer models and Myosin-Va in colorectal cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('colorectal cancer', 'Disease', (102, 119))	('Myosin-Va', 'Gene', (89, 98))	('Myosin-X', 'Gene', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('up-regulation', 'PosReg', (29, 42))	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('Myosin-Va', 'Gene', '4644', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Myosin-X', 'Gene', '4651', (20, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
548906	26824057	We established primary tumor cell cultures from sarcomas resected from Neu1+/-/Arf-/- mice to verify the occurrence of Neu1-dependent lysosomal exocytosis and chemoresistance.	('Neu1-dependent', 'Var', (119, 133))	('sarcomas', 'Disease', 'MESH:D012509', (48, 56))	('chemoresistance', 'CPA', (159, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('mice', 'Species', '10090', (86, 90))	('sarcomas', 'Disease', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('lysosomal exocytosis', 'MPA', (134, 154))
548908	26824057	The latter was shown to be oversialylated in the low-NEU1 RMS cells compared to the high-NEU1 RMS cells by using sialic acid binding specific lectins (SNA and MAL).	('sialic acid binding', 'Protein', (113, 132))	('MAL', 'Gene', '4118', (159, 162))	('low-NEU1', 'Var', (49, 57))	('sialic acid', 'Chemical', 'MESH:D019158', (113, 124))	('MAL', 'Gene', (159, 162))	('SNA', 'Species', '4202', (151, 154))
548911	26824057	To determine whether Lamp1 and Myosin-11 interact, we coimmunoprecipitated the two proteins in a sarcoma cell line from a Neu1+/-/Arf-/- mouse, and Myosin-11 function in lysosomal exocytosis was further verified by silencing Myo11 and assaying lysosomal exocytosis effect by enzyme activity.	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('mouse', 'Species', '10090', (137, 142))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('Myo11', 'Gene', '4629', (225, 230))	('silencing', 'Var', (215, 224))	('Myo11', 'Gene', (225, 230))
548912	26824057	To show that NEU1-dependent exacerbation of lysosomal exocytosis increased the invasive capacity of tumors, we performed ex vivo invasion assays by seeding RMS cells onto peritonea from Neu1+/+ or Neu1-/- mice and counting the number of cells that invaded the basement membrane.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('increased', 'PosReg', (65, 74))	('tumors', 'Disease', (100, 106))	('exacerbation', 'MPA', (28, 40))	('NEU1-dependent', 'Var', (13, 27))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('lysosomal exocytosis', 'MPA', (44, 64))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mice', 'Species', '10090', (205, 209))
548914	26824057	Finally, to verify that exacerbated lysosomal exocytosis in RMS cells with low-NEU1 expression conferred chemoresistance by the efflux of lysosome-sequestered drugs, we exposed cells to doxorubicin and quantified the release of its native fluorescence into the culture medium.	('efflux of lysosome-sequestered drugs', 'MPA', (128, 164))	('doxorubicin', 'Chemical', 'MESH:D004317', (186, 197))	('low-NEU1 expression', 'Var', (75, 94))	('lysosomal exocytosis', 'MPA', (36, 56))	('chemoresistance', 'CPA', (105, 120))	('conferred', 'Reg', (95, 104))	('exacerbated', 'PosReg', (24, 35))
548917	26824057	Additionally, we used the apoptotic marker cPARP to show that primary cells derived from Neu1+/-/Arf-/- mice with increased lysosomal exocytosis were resistant to doxorubicin exposure.	('lysosomal exocytosis', 'MPA', (124, 144))	('Neu1+/-/Arf-/-', 'Var', (89, 103))	('mice', 'Species', '10090', (104, 108))	('increased', 'PosReg', (114, 123))	('doxorubicin', 'Chemical', 'MESH:D004317', (163, 174))
548918	26824057	Neu1+/- FVB/NJ mice were crossed with NSG or C57Bl6/129sv Arf-/- mice (provided by C. Sherr).	('129sv', 'Species', '10090', (52, 57))	('C57Bl6/129sv', 'Var', (45, 57))	('mice', 'Species', '10090', (65, 69))	('Neu1+/-', 'Var', (0, 7))	('mice', 'Species', '10090', (15, 19))
548919	26824057	For orthotopic xenografts, 2 x 106 RMS cells were engrafted into the flanks of 4- to 6-week-old Neu1+/+/NSG or Neu1+/-/NSG male mice.	('mice', 'Species', '10090', (128, 132))	('Neu1+/+/NSG', 'Var', (96, 107))	('Neu1+/-/NSG', 'Var', (111, 122))
548934	26824057	The primary sarcoma cell line was transduced with five shRNA constructs for mouse Myh11 and mouse Lamp1 genes cloned into the pLKO1 HIV-based lentiviral vector plasmid (TRC-Mn1.0 RMM4534-EG17880, RMM4534-EG16783 Dharmacon RNAi, GE Healthcare).	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('Myh11', 'Gene', (82, 87))	('sarcoma', 'Disease', (12, 19))	('mouse', 'Species', '10090', (76, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('mouse', 'Species', '10090', (92, 97))	('RMM4534-EG16783', 'Var', (196, 211))
548941	26824057	Slides were blocked [0.1% bovine serum albumin (BSA) and 0.5% Tween 20 with 10% normal goat serum] and incubated with the following primary antibodies overnight: anti-NEU1 (1:50), anti-LAMP1 (1:400) (Cell Signaling), and anti-Myosin-11 (1:300) (Millipore and LSBio).	('anti-NEU1', 'Var', (162, 171))	('anti-LAMP1', 'Var', (180, 190))	('Tween 20', 'Chemical', 'MESH:D011136', (62, 70))	('anti-Myosin-11', 'Var', (221, 235))	('goat', 'Species', '9925', (87, 91))	('bovine', 'Species', '9913', (26, 32))
548945	26824057	Immunohistochemical analysis was done using Target Retrieval Solution, pH 9 (DAKO), for 30 min at 98 C. Primary antibodies used were anti-cytokeratin OSCAR (1:100) and anti-vimentin (1:20).	('vimentin', 'Gene', '7431', (173, 181))	('vimentin', 'Gene', (173, 181))	('anti-cytokeratin', 'Var', (133, 149))
548948	26824057	The following primary antibodies were used: anti-cytokeratin OSCAR (SIG-3465, Covance), anti-vimentin (EPR3776, Novus Biologicals), anti-laminin (L9393 Sigma), anti-collagen IV (#2150/1470, AbD Serotec), and anti-TGFbeta (T 0438, Sigma).	('vimentin', 'Gene', '7431', (93, 101))	('vimentin', 'Gene', (93, 101))	('L9393', 'CellLine', 'CVCL:0462', (146, 151))	('TGFbeta', 'Gene', (213, 220))	('#2150/1470', 'Var', (178, 188))	('L9393', 'Var', (146, 151))	('TGFbeta', 'Gene', '7040', (213, 220))
548961	26824057	Nitrocellulose or polyvinylidene difluoride (PVDF) membranes were blocked for 1 hour with 5% nonfat milk and subsequently probed with primary antibodies overnight: anti-LAMP1 (1:2000, Cell Signaling or BD Biosciences), anti-MYH11 (1:1000, LSBio or Proteintech), anti-cPARP, anti-alpha/beta-tubulin (1:1000, Cell Signaling), and anti-NEU1 (1:250).	('MYH11', 'Gene', '4629', (224, 229))	('PVDF', 'Chemical', 'MESH:C024865', (45, 49))	('polyvinylidene difluoride', 'Chemical', 'MESH:C024865', (18, 43))	('anti-NEU1', 'Var', (328, 337))	('MYH11', 'Gene', (224, 229))	('anti-cPARP', 'Var', (262, 272))	('anti-alpha/beta-tubulin', 'Var', (274, 297))
548998	26091466	In addition, the identification of epidermal growth factor receptor (EGFR) mutations and the introduction of EGFR inhibitors to successfully treat EGFR mutated non-small cell lung cancers are breakthroughs for lung cancer treatment.	('lung cancer', 'Disease', 'MESH:D008175', (210, 221))	('EGFR', 'Gene', (147, 151))	('men', 'Species', '9606', (227, 230))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (164, 187))	('EGFR', 'Gene', '1956', (109, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('EGFR', 'Gene', '1956', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (160, 187))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('EGFR', 'Gene', '1956', (147, 151))	('epidermal growth factor receptor', 'Gene', (35, 67))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('lung cancer', 'Disease', (210, 221))	('lung cancers', 'Phenotype', 'HP:0100526', (175, 187))	('epidermal growth factor receptor', 'Gene', '1956', (35, 67))	('EGFR', 'Gene', (109, 113))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('mutated', 'Var', (152, 159))	('EGFR', 'Gene', (69, 73))	('non-small cell lung cancers', 'Disease', (160, 187))	('mutations', 'Var', (75, 84))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (160, 187))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))
549022	26091466	However, the prognosis of lung cancer became different after the introduction of EGFR inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('inhibitors', 'Var', (86, 96))	('lung cancer', 'Disease', (26, 37))	('EGFR', 'Gene', '1956', (81, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('EGFR', 'Gene', (81, 85))
549023	26091466	Lung cancers with EGFR mutations are more likely to be adenocarcinoma and occur more often in women, East Asians, and nonsmokers.	('women', 'Species', '9606', (94, 99))	('EGFR', 'Gene', '1956', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('Lung cancers', 'Disease', 'MESH:D008175', (0, 12))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('EGFR', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('Lung cancers', 'Phenotype', 'HP:0100526', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('adenocarcinoma', 'Disease', (55, 69))	('Lung cancers', 'Disease', (0, 12))	('adenocarcinoma', 'Disease', 'MESH:D000230', (55, 69))
549024	26091466	Lung cancers with EGFR mutations have been associated with a more favorable clinical response to EGFR inhibitors.	('EGFR', 'Gene', '1956', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('EGFR', 'Gene', '1956', (97, 101))	('Lung cancers', 'Disease', 'MESH:D008175', (0, 12))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', (97, 101))	('mutations', 'Var', (23, 32))	('Lung cancers', 'Phenotype', 'HP:0100526', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancers', 'Disease', (0, 12))
549026	26091466	Furthermore, first-line EGFR inhibitors achieved good response and prolonged the survival of advanced lung cancer patients with EGFR mutations.	('EGFR', 'Gene', '1956', (24, 28))	('survival', 'CPA', (81, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EGFR', 'Gene', (24, 28))	('EGFR', 'Gene', '1956', (128, 132))	('lung cancer', 'Disease', (102, 113))	('EGFR', 'Gene', (128, 132))	('mutations', 'Var', (133, 142))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('patients', 'Species', '9606', (114, 122))	('prolonged', 'PosReg', (67, 76))
549029	26091466	The survival of lung cancer patients has been significantly improved by EGFR inhibitors, particularly for Asian patients with lung cancer harboring specific EGFR mutations; however, most data published to date have been hospital-based or clinical trial-based and mostly on NSCLC.	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', '1956', (157, 161))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', 'MESH:D002289', (273, 278))	('survival', 'CPA', (4, 12))	('EGFR', 'Gene', (72, 76))	('NSCLC', 'Disease', (273, 278))	('improved', 'PosReg', (60, 68))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('EGFR', 'Gene', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (162, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (273, 278))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('patients', 'Species', '9606', (112, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('lung cancer', 'Disease', (16, 27))
549039	26091466	For NET, we adopted the M codes used by Hauso et al  and included: 8240 (carcinoid tumor), 8241 (enterochromaffin cell carcinoid), 8242 (enterochromaffin-like cell tumors), 8243 (goblet cell carcinoid), 8244 (composite carcinoid), 8245 (adenocarcinoid), 8246 (neuroendocrine carcinoma), 8249 (atypical carcinoid), 8013 (large cell neuroendocrine carcinoma), and 8574 (adenocarcinoma with neuroendocrine differentiation).	('8013', 'Var', (314, 318))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (331, 355))	('carcinoid', 'Phenotype', 'HP:0100570', (219, 228))	('NET', 'Gene', (4, 7))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (331, 355))	('carcinoid', 'Phenotype', 'HP:0100570', (242, 251))	('8249', 'Var', (287, 291))	('carcinoid', 'Phenotype', 'HP:0100570', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('enterochromaffin cell carcinoid', 'Phenotype', 'HP:0002666', (97, 128))	('neuroendocrine carcinoma', 'Disease', (260, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (373, 382))	('adenocarcinoid', 'Disease', 'MESH:C538230', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('carcinoid tumor', 'Disease', 'MESH:D002276', (73, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('neuroendocrine carcinoma', 'Disease', (331, 355))	('enterochromaffin-like cell tumors', 'Phenotype', 'HP:0002666', (137, 170))	('large cell neuroendocrine carcinoma', 'Phenotype', 'HP:0030360', (320, 355))	('cell tumors', 'Disease', (159, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('NET', 'Gene', '2004', (4, 7))	('adenocarcinoid', 'Disease', (237, 251))	('carcinoid', 'Phenotype', 'HP:0100570', (191, 200))	('cell tumors', 'Disease', 'MESH:D005935', (159, 170))	('adenocarcinoma', 'Disease', (368, 382))	('carcinoid tumor', 'Disease', (73, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('carcinoid', 'Phenotype', 'HP:0100570', (119, 128))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (260, 284))	('8574', 'Var', (362, 366))	('atypical carcinoid', 'Phenotype', 'HP:0030446', (293, 311))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (260, 284))	('adenocarcinoma', 'Disease', 'MESH:D000230', (368, 382))
549169	26091466	This observation was later correlated with EGFR mutations.	('correlated', 'Reg', (27, 37))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
549170	26091466	In a large multinational series of NSCLC, the prevalence of EGFR mutation was 27% and 34% in Taiwanese and Japanese NSCLC patients, respectively, and only 14% and 7% in US and Australian NSCLC patients, respectively.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('patients', 'Species', '9606', (193, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('NSCLC', 'Disease', (35, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('NSCLC', 'Disease', (187, 192))	('patients', 'Species', '9606', (122, 130))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('mutation', 'Var', (65, 73))	('EGFR', 'Gene', '1956', (60, 64))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('NSCLC', 'Disease', (116, 121))	('EGFR', 'Gene', (60, 64))
549171	26091466	A percentage of EGFR mutations as high as 61% was noted in Taiwanese samples from clinical trials.	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
549172	26091466	EGFR inhibitors not only increased the response rate of lung cancers with EGFR mutations but also prolonged the progression-free survival and overall survival.	('prolonged', 'PosReg', (98, 107))	('lung cancers', 'Phenotype', 'HP:0100526', (56, 68))	('EGFR', 'Gene', (0, 4))	('increased', 'PosReg', (25, 34))	('lung cancers', 'Disease', (56, 68))	('response', 'CPA', (39, 47))	('overall survival', 'CPA', (142, 158))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('EGFR', 'Gene', '1956', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('EGFR', 'Gene', '1956', (0, 4))	('lung cancers', 'Disease', 'MESH:D008175', (56, 68))	('progression-free survival', 'CPA', (112, 137))	('EGFR', 'Gene', (74, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('mutations', 'Var', (79, 88))
549174	26091466	Since November of 2007, the BNHI began to reimburse Gefitinib as a second-line treatment for adenocarcinoma and in June of 2011, the BNHI started to reimburse Gefitinib as a first-line treatment for lung adenocarcinoma with EGFR mutations.	('adenocarcinoma', 'Disease', 'MESH:D000230', (204, 218))	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('EGFR', 'Gene', (224, 228))	('mutations', 'Var', (229, 238))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (199, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('men', 'Species', '9606', (84, 87))	('men', 'Species', '9606', (190, 193))	('adenocarcinoma', 'Disease', (204, 218))	('adenocarcinoma', 'Disease', (93, 107))	('Gefitinib', 'Chemical', 'MESH:D000077156', (52, 61))	('Gefitinib', 'Chemical', 'MESH:D000077156', (159, 168))	('lung adenocarcinoma', 'Disease', (199, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (199, 218))	('EGFR', 'Gene', '1956', (224, 228))
549176	26091466	The use of EGFR inhibitors for lung adenocarcinoma since 2004 may explain the improvement in the survival of adenocarcinoma patients from 2000-2004 to 2005-2008, particularly for women, with improvement of the 1-, 3- and 5-year survival from 46.24%, 20.86%, and 15.26% in 1996-1999 to 64.53%, 31.81% and 19.86% in 2005-2008, respectively.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('improvement', 'PosReg', (78, 89))	('patients', 'Species', '9606', (124, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('inhibitors', 'Var', (16, 26))	('adenocarcinoma', 'Disease', (109, 123))	('EGFR', 'Gene', (11, 15))	('adenocarcinoma', 'Disease', (36, 50))	('adenocarcinoma', 'Disease', 'MESH:D000230', (109, 123))	('women', 'Species', '9606', (179, 184))	('men', 'Species', '9606', (85, 88))	('men', 'Species', '9606', (198, 201))	('men', 'Species', '9606', (181, 184))	('lung adenocarcinoma', 'Disease', (31, 50))	('EGFR', 'Gene', '1956', (11, 15))	('adenocarcinoma', 'Disease', 'MESH:D000230', (36, 50))	('improvement', 'PosReg', (191, 202))
549177	26091466	In a large molecular epidemiologic study of lung adenocarcinoma in Asian patients, including patients from Taiwan, women were found to have a significantly higher percentage of EGFR mutations than men (61.1% vs 44%).	('patients', 'Species', '9606', (93, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (44, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('men', 'Species', '9606', (117, 120))	('lung adenocarcinoma', 'Disease', (44, 63))	('men', 'Species', '9606', (197, 200))	('women', 'Species', '9606', (115, 120))	('EGFR', 'Gene', '1956', (177, 181))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (44, 63))	('patients', 'Species', '9606', (73, 81))	('EGFR', 'Gene', (177, 181))	('mutations', 'Var', (182, 191))
549178	26091466	The higher percentage of EGFR mutations among female patients with lung adenocarcinoma compared to men with lung adenocarcinoma may explain the better survival of lung adenocarcinoma in Taiwanese women, particularly after the introduction of EGFR inhibitors.	('lung adenocarcinoma', 'Disease', (108, 127))	('lung adenocarcinoma', 'Disease', (163, 182))	('lung adenocarcinoma', 'Disease', (67, 86))	('EGFR', 'Gene', (242, 246))	('EGFR', 'Gene', (25, 29))	('patients', 'Species', '9606', (53, 61))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (163, 182))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (163, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('EGFR', 'Gene', '1956', (242, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('mutations', 'Var', (30, 39))	('women', 'Species', '9606', (196, 201))	('men', 'Species', '9606', (198, 201))	('EGFR', 'Gene', '1956', (25, 29))	('men', 'Species', '9606', (99, 102))
549225	29850398	One to three million A673 cells are sufficient to generate a tumour mass after subcutaneous implantation into the flank or in the inguinal region of nude mice.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('nude mice', 'Species', '10090', (149, 158))	('tumour', 'Disease', (61, 67))	('A673 cells', 'Var', (21, 31))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
549242	29850398	In a recent study, osteosarcomas were induced using the intratibial injection method using either 1 x 105 human 143B or K7M2L2 osteosarcoma cells resuspended in 10 microL PBS/0.05% EDTA into SCID and BALB/c mice respectively, thus generating highly metastatic pre-clinical models.	('osteosarcomas', 'Disease', 'MESH:D012516', (19, 32))	('human', 'Species', '9606', (106, 111))	('SCID', 'Gene', (191, 195))	('PBS', 'Chemical', 'MESH:D007854', (171, 174))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('osteosarcomas', 'Disease', (19, 32))	('EDTA', 'Chemical', 'MESH:D004492', (181, 185))	('osteosarcoma', 'Phenotype', 'HP:0002669', (127, 139))	('K7M2L2', 'Var', (120, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('osteosarcoma', 'Disease', (19, 31))	('osteosarcoma', 'Disease', 'MESH:D012516', (19, 31))	('osteosarcomas', 'Phenotype', 'HP:0002669', (19, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('mice', 'Species', '10090', (207, 211))	('osteosarcoma', 'Disease', (127, 139))	('SCID', 'Gene', '19090', (191, 195))	('osteosarcoma', 'Disease', 'MESH:D012516', (127, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))
549289	26599335	Furthermore PDGFRA represents an oncogene that is involved in cancer cell survival including pediatric glial tumours as well as resistance to chemotherapy and radiation therapy, and its inhibition may sensitize tumors to DNA damaging agents.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('glial tumours', 'Disease', 'MESH:D009369', (103, 116))	('sensitize', 'Reg', (201, 210))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('glial tumours', 'Disease', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('PDGFRA', 'Gene', (12, 18))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('PDGFRA', 'Gene', '5156', (12, 18))	('inhibition', 'Var', (186, 196))	('tumors', 'Disease', (211, 217))
549359	26599335	We therefore set out to then examine if PDGFRA activation, due to amplification of the PDGFRA gene, an alteration frequently found in pediatric brain tumors (eg.	('PDGFRA', 'Gene', '5156', (40, 46))	('amplification', 'Var', (66, 79))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('PDGFRA', 'Gene', (87, 93))	('activation', 'PosReg', (47, 57))	('PDGFRA', 'Gene', '5156', (87, 93))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (134, 156))	('brain tumors', 'Phenotype', 'HP:0030692', (144, 156))	('brain tumor', 'Phenotype', 'HP:0030692', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PDGFRA', 'Gene', (40, 46))	('pediatric brain tumors', 'Disease', (134, 156))	('rat', 'Species', '10116', (107, 110))
549381	26599335	The amplification of the PDGFRA gene in IGRG93 leads to PDGF receptor A overexpression and its activation, when compared to NEM14 tumors, where the PDGFRA gene is not amplified.	('PDGFRA', 'Gene', (25, 31))	('NEM14 tumors', 'Disease', (124, 136))	('PDGFRA', 'Gene', '5156', (25, 31))	('PDGF', 'Protein', (56, 60))	('activation', 'PosReg', (95, 105))	('PDGFRA', 'Gene', '5156', (148, 154))	('NEM14 tumors', 'Disease', 'MESH:D009369', (124, 136))	('PDGFRA', 'Gene', (148, 154))	('amplification', 'Var', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('overexpression', 'PosReg', (72, 86))
549396	26599335	Importantly, deactivation of PDGFR signaling in models with an amplified PDGFRA gene appeared to be involved in the induction of tumor regressions when regorafenib is given in combination with DNA damaging agents.	('amplified', 'Var', (63, 72))	('PDGFR', 'Gene', (73, 78))	('PDGFR', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('PDGFRA', 'Gene', (73, 79))	('PDGFR', 'Gene', '5159', (73, 78))	('PDGFR', 'Gene', '5159', (29, 34))	('PDGFRA', 'Gene', '5156', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('regorafenib', 'Chemical', 'MESH:C559147', (152, 163))	('tumor', 'Disease', (129, 134))	('deactivation', 'NegReg', (13, 25))
549406	26599335	The extent of response varied among models whereby decelerated tumor progression compared to untreated controls was observed in most cases approaching disease stabilization in EW7 and IGRG93 at a dose of 30 mg/kg/d.	('tumor', 'Disease', (63, 68))	('IGRG93', 'Var', (184, 190))	('rat', 'Species', '10116', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('decelerated', 'NegReg', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
549407	26599335	Partial regressions were observed in IGRM57 tumors, which were previously seen with regorafenib only in preclinical GIST models carrying a mutated KIT oncogene (DZ, manuscript in preparation).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('GIST', 'Phenotype', 'HP:0100723', (116, 120))	('rat', 'Species', '10116', (184, 187))	('mutated', 'Var', (139, 146))	('IGRM57', 'Gene', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('regorafenib', 'Chemical', 'MESH:C559147', (84, 95))
549408	26599335	Mutated KIT is a major driver of tumor growth in GIST cancer and is very potently inhibited by regorafenib.	('KIT', 'Gene', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('GIST cancer', 'Disease', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('GIST cancer', 'Disease', 'MESH:D046152', (49, 60))	('GIST', 'Phenotype', 'HP:0100723', (49, 53))	('tumor', 'Disease', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Mutated', 'Var', (0, 7))	('regorafenib', 'Chemical', 'MESH:C559147', (95, 106))
549409	26599335	The association between inhibitions of oncogenic kinases such as mutated RET and KIT and very potent antitumor activity suggests that regorafenib may also inhibit a tumor cell kinase which is critical for the growth of IGRM57 tumors.	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('RET', 'Gene', '5979', (73, 76))	('inhibitions', 'NegReg', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('KIT', 'Gene', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('RET', 'Gene', (73, 76))	('tumor', 'Disease', (105, 110))	('inhibit', 'NegReg', (155, 162))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('regorafenib', 'Chemical', 'MESH:C559147', (134, 145))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('mutated', 'Var', (65, 72))	('tumor', 'Disease', (165, 170))	('tumors', 'Disease', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (226, 231))
549413	26599335	For this purpose we selected three unique primary patient-derived xenograft models previously established and molecularly characterized at Gustave Roussy, which harbor amplifications of the PDGFRA gene, IGRG93 glioma derived from an adult glioblastoma and IGRM57 from a childhood medulloblastoma, or a normal copy number of the PDGFRA gene, NEM14 pediatric glioma.	('glioma', 'Phenotype', 'HP:0009733', (357, 363))	('amplifications', 'Var', (168, 182))	('glioma', 'Disease', (210, 216))	('IGRG93', 'Gene', (203, 209))	('pediatric glioma', 'Disease', 'MESH:D005910', (347, 363))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('pediatric glioma', 'Disease', (347, 363))	('glioblastoma', 'Disease', 'MESH:D005909', (239, 251))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('medulloblastoma', 'Disease', 'MESH:D008527', (280, 295))	('PDGFRA', 'Gene', (328, 334))	('glioma', 'Disease', (357, 363))	('PDGFRA', 'Gene', '5156', (328, 334))	('glioblastoma', 'Disease', (239, 251))	('medulloblastoma', 'Phenotype', 'HP:0002885', (280, 295))	('glioma', 'Disease', 'MESH:D005910', (357, 363))	('glioblastoma', 'Phenotype', 'HP:0012174', (239, 251))	('medulloblastoma', 'Disease', (280, 295))	('PDGFRA', 'Gene', '5156', (190, 196))	('PDGFRA', 'Gene', (190, 196))	('patient', 'Species', '9606', (50, 57))
549434	26599335	Recently, a case of a patient with colorectal cancer harboring strong PDGFR-beta expression due to a newly described germline PDRFR-beta mutation c.17C>T (NM_002609.3) was reported with substantial clinical response to regorafenib as compared to non-mutated colorectal cancer patients.	('patients', 'Species', '9606', (276, 284))	('colorectal cancer', 'Disease', 'MESH:D015179', (35, 52))	('PDRFR-beta', 'Gene', (126, 136))	('strong', 'PosReg', (63, 69))	('colorectal cancer', 'Disease', (35, 52))	('expression', 'MPA', (81, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (258, 275))	('c.17C>T', 'Var', (146, 153))	('PDGFR-beta', 'Gene', '5159', (70, 80))	('patient', 'Species', '9606', (22, 29))	('patient', 'Species', '9606', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('colorectal cancer', 'Phenotype', 'HP:0003003', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (258, 275))	('regorafenib', 'Chemical', 'MESH:C559147', (219, 230))	('c.17C>T', 'Mutation', 'rs150173975', (146, 153))	('colorectal cancer', 'Disease', (258, 275))	('PDGFR-beta', 'Gene', (70, 80))
549439	26599335	AKT and ERK1/2 pathways) in IGRM57 and may promote the induction of apoptotic cell death as detected by increased PARP-1 cleavage (data not shown) and necrosis.	('AKT', 'Gene', (0, 3))	('promote', 'PosReg', (43, 50))	('increased', 'PosReg', (104, 113))	('PARP-1', 'Gene', (114, 120))	('necrosis', 'Disease', 'MESH:D009336', (151, 159))	('apoptotic cell death', 'CPA', (68, 88))	('PARP-1', 'Gene', '142', (114, 120))	('AKT', 'Gene', '207', (0, 3))	('cleavage', 'MPA', (121, 129))	('necrosis', 'Disease', (151, 159))	('IGRM57', 'Var', (28, 34))
549452	26064078	About 90% of ESFT cases are characterized by the chromosome translocation t(11;22)(q24;q12) which involves the EWS/FLI-1 fusion gene and may share a common neural histogenesis.	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (74, 91))	('FLI-1', 'Gene', '2313', (115, 120))	('t(11', 'Var', (74, 78))	('EWS', 'Gene', (111, 114))	('FLI-1', 'Gene', (115, 120))	('EWS', 'Gene', '2130', (111, 114))	('ES', 'Phenotype', 'HP:0012254', (13, 15))	('ESFT', 'Disease', (13, 17))
549505	26064078	Mood disorders such as anxiety, bipolar disorder, insomnia, and fibromyalgia also involve the HPA axis and GH deficiency is associated with high cholesterolemia, osteoporosis, and short stature.	('short stature', 'Phenotype', 'HP:0004322', (180, 193))	('anxiety', 'Disease', 'MESH:D001008', (23, 30))	('Mood disorders', 'Disease', 'MESH:D019964', (0, 14))	('bipolar disorder', 'Phenotype', 'HP:0007302', (32, 48))	('insomnia', 'Disease', (50, 58))	('fibromyalgia', 'Disease', (64, 76))	('deficiency', 'Var', (110, 120))	('high cholesterolemia', 'Disease', 'MESH:D008228', (140, 160))	('Mood disorders', 'Disease', (0, 14))	('high cholesterolemia', 'Disease', (140, 160))	('involve', 'Reg', (82, 89))	('osteoporosis', 'Disease', (162, 174))	('bipolar disorder', 'Disease', (32, 48))	('anxiety', 'Phenotype', 'HP:0000739', (23, 30))	('fibromyalgia', 'Disease', 'MESH:D005356', (64, 76))	('osteoporosis', 'Phenotype', 'HP:0000939', (162, 174))	('short stature', 'Disease', (180, 193))	('associated', 'Reg', (124, 134))	('insomnia', 'Phenotype', 'HP:0100785', (50, 58))	('bipolar disorder', 'Disease', 'MESH:D001714', (32, 48))	('anxiety', 'Disease', (23, 30))	('insomnia', 'Disease', 'MESH:D007319', (50, 58))	('high cholesterolemia', 'Phenotype', 'HP:0003124', (140, 160))
549616	22326461	It would be interesting to establish human sarcoma cell lines that metastasize to lymph nodes, for example, by transfection with genes including vegfs.	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('human', 'Species', '9606', (37, 42))	('sarcoma', 'Disease', (43, 50))	('vegfs', 'Gene', (145, 150))	('transfection', 'Var', (111, 123))
549654	20459746	Figure 4 shows a flow diagram of the exclusion criteria applied to the articles retrieved by PM2: the initial number returned by PM2 (25) was remarkably smaller than that provided by GS1 (755) and GS2 (437).	('GS2', 'Gene', (197, 200))	('PM2', 'Var', (129, 132))	('GS1', 'Gene', '8226', (183, 186))	('smaller', 'NegReg', (153, 160))	('GS2', 'Gene', '8228', (197, 200))	('GS1', 'Gene', (183, 186))
549679	33524869	Interestingly, high PDGFA expression levels were associated with higher risk of metastasis (P = 0.006), whereas PDGFD levels above average were associated with a reduced risk of metastasis (P = 0.01) in univariate and multivariate analysis.	('high', 'Var', (15, 19))	('PDGFD', 'Gene', (112, 117))	('metastasis', 'CPA', (80, 90))	('PDGFD', 'Gene', '80310', (112, 117))	('PDGFA', 'Gene', (20, 25))	('PDGFA', 'Gene', '5154', (20, 25))	('expression levels', 'MPA', (26, 43))
549701	33524869	Selected probes (maximum interquartile range) were A_23_P113701 (PDGFA), A_24_P339944 (PDGFB), A_24_P163168 (PDGFC), A_24_P124349 (PDGFD), A_23_P332536 (PDGFRA), A_23_P421401 (PDGFRB) and A_23_P60146 (PDGFRL).	('A_23_P113701', 'Var', (51, 63))	('PDGFB', 'Gene', (87, 92))	('PDGFC', 'Gene', '56034', (109, 114))	('PDGFA', 'Gene', (65, 70))	('PDGFC', 'Gene', (109, 114))	('PDGFD', 'Gene', '80310', (131, 136))	('PDGFRB', 'Gene', '5159', (176, 182))	('A_24_P163168', 'Var', (95, 107))	('PDGFRB', 'Gene', (176, 182))	('PDGFRL', 'Gene', '5157', (201, 207))	('PDGFRA', 'Gene', (153, 159))	('PDGFRA', 'Gene', '5156', (153, 159))	('PDGFD', 'Gene', (131, 136))	('A_24_P339944', 'Var', (73, 85))	('A_23_P332536', 'Var', (139, 151))	('A_23_P421401', 'Var', (162, 174))	('PDGFRL', 'Gene', (201, 207))	('PDGFB', 'Gene', '5155', (87, 92))	('PDGFA', 'Gene', '5154', (65, 70))	('A_24_P124349', 'Var', (117, 129))	('A_23_P60146', 'Var', (188, 199))
549732	33524869	In human gastric cancers, high levels of PDGFA correlate with high-grade carcinomas and reduced patient survival.	('PDGFA', 'Gene', '5154', (41, 46))	('gastric cancers', 'Disease', (9, 24))	('gastric cancers', 'Phenotype', 'HP:0012126', (9, 24))	('patient survival', 'CPA', (96, 112))	('carcinomas', 'Disease', 'MESH:D009369', (73, 83))	('human', 'Species', '9606', (3, 8))	('patient', 'Species', '9606', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinomas', 'Disease', (73, 83))	('PDGFA', 'Gene', (41, 46))	('high levels', 'Var', (26, 37))	('reduced', 'NegReg', (88, 95))	('gastric cancers', 'Disease', 'MESH:D013274', (9, 24))
549734	33524869	Copy number variations of the seven genes were observed in <5% of the tumors (with occasional losses or gains, and no amplifications).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('gains', 'PosReg', (104, 109))	('losses', 'NegReg', (94, 100))	('Copy number variations', 'Var', (0, 22))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
549737	33524869	While there was no apparent effect on PFS in patients without PDGFRalpha mutations, PDGFRalpha-mutant GIST patients (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype.	('PDGFRalpha', 'Gene', '5156', (62, 72))	('disease control', 'CPA', (178, 193))	('GIST', 'Phenotype', 'HP:0100723', (102, 106))	('longer', 'PosReg', (171, 177))	('PDGFRalpha', 'Gene', (62, 72))	('olaratumab', 'Chemical', 'MESH:C000589393', (156, 166))	('PDGFRalpha', 'Gene', '5156', (84, 94))	('patients', 'Species', '9606', (45, 53))	('PDGFRalpha', 'Gene', (84, 94))	('D842V', 'Mutation', 'rs121908585', (126, 131))	('D842V mutations', 'Var', (126, 141))	('patients', 'Species', '9606', (107, 115))
549738	33524869	Olaratumab has not yet been tested in DFSP, which bears a translocation involving PDGFA as a nosological hallmark.	('PDGFA', 'Gene', (82, 87))	('translocation', 'Var', (58, 71))	('DFSP', 'Disease', (38, 42))	('Olaratumab', 'Chemical', 'MESH:C000589393', (0, 10))	('PDGFA', 'Gene', '5154', (82, 87))	('DFSP', 'Disease', 'MESH:D018223', (38, 42))
549823	32082530	By transposing the ovaries out of the field of radiation, the ovarian dose is reduced to 5-10% of that of nontransposed ovaries.	('ovaries', 'Disease', (19, 26))	('ovaries', 'Disease', (120, 127))	('ovarian dose', 'CPA', (62, 74))	('transposing', 'Var', (3, 14))	('ovaries', 'Disease', 'MESH:D010051', (19, 26))	('reduced', 'NegReg', (78, 85))	('ovaries', 'Disease', 'MESH:D010051', (120, 127))
549857	32082530	Although the aim is to move the ovaries as far as possible from the field of radiation during the OT/OP procedure, care must be taken to avoid compromising the blood supply of the ovaries by overstretching, torsion or kinking of the infundibulopelvic ligaments.	('ovaries', 'Disease', (180, 187))	('ovaries', 'Disease', 'MESH:D010051', (32, 39))	('ovaries', 'Disease', 'MESH:D010051', (180, 187))	('torsion', 'Var', (207, 214))	('blood supply', 'MPA', (160, 172))	('kinking', 'Var', (218, 225))	('overstretching', 'Var', (191, 205))	('ovaries', 'Disease', (32, 39))
549878	32082530	Uterine radiation has been associated with uterine fibrosis and decreased vascularity leading to implantation failure and pregnancy complications including spontaneous abortions, intrauterine growth retardation and preterm labour.	('intrauterine growth retardation', 'Disease', 'MESH:D005317', (179, 210))	('spontaneous abortions', 'Phenotype', 'HP:0005268', (156, 177))	('abortions', 'Disease', (168, 177))	('preterm labour', 'Phenotype', 'HP:0001622', (215, 229))	('vascularity', 'MPA', (74, 85))	('fibrosis', 'Disease', (51, 59))	('implantation failure', 'Disease', 'MESH:D057873', (97, 117))	('implantation failure', 'Disease', (97, 117))	('Uterine', 'Var', (0, 7))	('fibrosis', 'Disease', 'MESH:D005355', (51, 59))	('abortions', 'Disease', 'MESH:D000031', (168, 177))	('intrauterine growth retardation', 'Disease', (179, 210))	('preterm labour', 'CPA', (215, 229))	('intrauterine growth retardation', 'Phenotype', 'HP:0001511', (179, 210))	('growth retardation', 'Phenotype', 'HP:0001510', (192, 210))	('decreased', 'NegReg', (64, 73))
549987	26598981	Mutations involved TP53, FAT1 and TERT.	('TERT', 'Gene', (34, 38))	('FAT1', 'Gene', '2195', (25, 29))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', '7015', (34, 38))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('FAT1', 'Gene', (25, 29))
549988	26598981	Deletions were seen in PTEN and RB1.	('RB1', 'Gene', (32, 35))	('PTEN', 'Gene', (23, 27))	('PTEN', 'Gene', '5728', (23, 27))	('RB1', 'Gene', '5925', (32, 35))	('Deletions', 'Var', (0, 9))
550009	26598981	These mutations and deletions are commonly found in many forms of cancer and are not intrinsically diagnostic either in isolation or in combination.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('deletions', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (66, 72))
550012	26598981	TP53 mutations have been identified in some, but not all, leiomyosarcomas and pleomorphic liposarcomas.	('TP53', 'Gene', '7157', (0, 4))	('liposarcoma', 'Phenotype', 'HP:0012034', (90, 101))	('TP53', 'Gene', (0, 4))	('identified', 'Reg', (25, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (58, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('pleomorphic liposarcomas', 'Disease', (78, 102))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (58, 73))	('mutations', 'Var', (5, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (58, 72))	('leiomyosarcomas', 'Disease', (58, 73))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (78, 102))	('liposarcomas', 'Phenotype', 'HP:0012034', (90, 102))
550013	26598981	The present case had a TP53 nonsense mutation in exon 5 identical to that in a prior report of conventional soft tissue leiomyosarcoma.	('leiomyosarcoma', 'Disease', (120, 134))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (120, 134))	('nonsense mutation', 'Var', (28, 45))	('TP53', 'Gene', '7157', (23, 27))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (120, 134))	('TP53', 'Gene', (23, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
550014	26598981	It is believed that soft tissue leiomyosarcomas bearing inactivating TP53 mutations are more aggressive and such patients have a poorer prognosis.	('inactivating', 'Var', (56, 68))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (32, 46))	('TP53', 'Gene', '7157', (69, 73))	('leiomyosarcomas', 'Disease', (32, 47))	('TP53', 'Gene', (69, 73))	('patients', 'Species', '9606', (113, 121))	('mutations', 'Var', (74, 83))	('soft tissue leiomyosarcomas', 'Phenotype', 'HP:0030448', (20, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (32, 47))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (32, 47))
550015	26598981	PTEN is a ubiquitous tumor suppressor gene located at 10q23.31 that can be inactivated in several ways including promoter methylation, mutation or deletion, and is commonly altered in numerous forms of cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ubiquitous tumor', 'Disease', 'MESH:D009369', (10, 26))	('altered', 'Reg', (173, 180))	('ubiquitous tumor', 'Disease', (10, 26))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('deletion', 'Var', (147, 155))	('cancer', 'Disease', (202, 208))	('PTEN', 'Gene', (0, 4))	('mutation', 'Var', (135, 143))	('PTEN', 'Gene', '5728', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
550019	26598981	PTEN deletions similar to the one identified in the present case are seen in a subset of leiomyosarcoma, but not pleomorphic liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (113, 136))	('seen', 'Reg', (69, 73))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('leiomyosarcoma', 'Disease', (89, 103))	('PTEN', 'Gene', '5728', (0, 4))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (89, 103))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (89, 103))	('pleomorphic liposarcoma', 'Disease', (113, 136))	('PTEN', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('deletions', 'Var', (5, 14))
550021	26598981	Dysfunctional pRB also plays a critical role in cervical neoplasia via its interactions with the E7 viral oncoprotein produced in high risk types of human papilloma virus.	('cervical neoplasia', 'Phenotype', 'HP:0032241', (48, 66))	('neoplasia', 'Disease', (57, 66))	('pRB', 'Gene', '5925', (14, 17))	('pRB', 'Gene', (14, 17))	('neoplasia', 'Phenotype', 'HP:0002664', (57, 66))	('papilloma', 'Phenotype', 'HP:0012740', (155, 164))	('neoplasia', 'Disease', 'MESH:D009369', (57, 66))	('Dysfunctional', 'Var', (0, 13))	('interactions', 'Interaction', (75, 87))	('human papilloma virus', 'Species', '10566', (149, 170))
550022	26598981	Deletions of RB1 have been recorded in pleomorphic liposarcoma and leiomyosarcoma.	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (39, 62))	('liposarcoma', 'Phenotype', 'HP:0012034', (51, 62))	('RB1', 'Gene', '5925', (13, 16))	('leiomyosarcoma', 'Disease', (67, 81))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (67, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('pleomorphic liposarcoma', 'Disease', (39, 62))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (67, 81))	('RB1', 'Gene', (13, 16))	('recorded', 'Reg', (27, 35))	('Deletions', 'Var', (0, 9))
550024	26598981	Studies have shown that inactivation of FAT1, a cadherin-like protein that mediates cell-cell adhesion interactions, may contribute to invasion and metastasis of neoplasms.	('FAT1', 'Gene', '2195', (40, 44))	('metastasis of neoplasms', 'Disease', 'MESH:D009362', (148, 171))	('inactivation', 'Var', (24, 36))	('FAT1', 'Gene', (40, 44))	('neoplasm', 'Phenotype', 'HP:0002664', (162, 170))	('contribute', 'Reg', (121, 131))	('neoplasms', 'Phenotype', 'HP:0002664', (162, 171))	('metastasis of neoplasms', 'Disease', (148, 171))
550025	26598981	To date, alteration of FAT1 has not been documented in leiomyosarcoma nor pleomorphic liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (86, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (55, 69))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (74, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (55, 69))	('FAT1', 'Gene', '2195', (23, 27))	('FAT1', 'Gene', (23, 27))	('pleomorphic liposarcoma', 'Disease', (74, 97))	('alteration', 'Var', (9, 19))	('leiomyosarcoma', 'Disease', (55, 69))
550026	26598981	The mutation in the present case resulted in an amino acid substitution of valine for isoleucine, both of which are hydrophobic branched chain amino acids with similar structural properties.	('isoleucine', 'MPA', (86, 96))	('isoleucine', 'Chemical', 'MESH:D007532', (86, 96))	('resulted in', 'Reg', (33, 44))	('branched chain amino acids', 'Chemical', 'MESH:D000597', (128, 154))	('valine', 'MPA', (75, 81))	('mutation', 'Var', (4, 12))	('valine', 'Chemical', 'MESH:D014633', (75, 81))
550030	26598981	TERT alterations have not been found in leiomyosarcoma or pleomorphic liposarcoma, but a majority (74%) of myxoid/round cell liposarcomas harbor mutation of the TERT promoter region.	('liposarcomas', 'Disease', (125, 137))	('liposarcoma', 'Phenotype', 'HP:0012034', (70, 81))	('liposarcoma', 'Phenotype', 'HP:0012034', (125, 136))	('TERT', 'Gene', (161, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (40, 54))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (161, 165))	('leiomyosarcoma or pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (40, 81))	('TERT', 'Gene', '7015', (0, 4))	('leiomyosarcoma or pleomorphic liposarcoma', 'Disease', (40, 81))	('liposarcomas', 'Phenotype', 'HP:0012034', (125, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('liposarcomas', 'Disease', 'MESH:D008080', (125, 137))	('mutation', 'Var', (145, 153))
550036	28626837	Chromosomal translocation is a hallmark of Ewing Sarcoma and has long been considered the primary cause in its development.	('Sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('hallmark of Ewing Sarcoma', 'Disease', (31, 56))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('Chromosomal translocation', 'Var', (0, 25))	('hallmark of Ewing Sarcoma', 'Disease', 'MESH:C563168', (31, 56))
550047	28626837	A spectrum of neural crest developmental genes are significantly upregulated by ectopic expression of the EWS-FLI1 chimeric protein in a rhabdomyosarcoma cell line, driving the cells to become less differentiated and develop the observed phenotype of Ewing sarcoma.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (137, 153))	('less', 'NegReg', (193, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('Ewing sarcoma', 'Disease', (251, 264))	('rhabdomyosarcoma', 'Disease', (137, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('EWS-FLI1', 'Gene', (106, 114))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (137, 153))	('upregulated', 'PosReg', (65, 76))	('neural crest developmental genes', 'Gene', (14, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (251, 264))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (251, 264))	('ectopic expression', 'Var', (80, 98))
550051	28626837	Ectopic EWS-FLI1 expression in murine primary bone marrow-derived mesenchymal stem cells leads to cell transformation and engraftment of Ewing sarcoma-like tumors in vivo.	('Ewing sarcoma-like tumors', 'Disease', 'MESH:C563168', (137, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('murine', 'Species', '10090', (31, 37))	('engraftment', 'CPA', (122, 133))	('leads to', 'Reg', (89, 97))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Ectopic', 'Var', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('cell transformation', 'CPA', (98, 117))	('EWS-FLI1', 'Gene', (8, 16))	('Ewing sarcoma-like tumors', 'Disease', (137, 162))
550053	28626837	The knock-down of EWS-FLI1 expression in Ewing Sarcoma results in convergence of the tumor gene expression profiles to that of mesenchymal stem cells.	('tumor', 'Disease', (85, 90))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (41, 54))	('Ewing Sarcoma', 'Disease', (41, 54))	('knock-down', 'Var', (4, 14))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('EWS-FLI1', 'Gene', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
550116	33043529	In this review, we focus on studies reporting familial aggregation of susceptibility to KSHV infection and/or KSHV-associated diseases and particular genetic polymorphisms in candidate susceptibility genes or haplotypes found to be statistically associated with aspects of KSHV pathogenesis.	('KSHV', 'Species', '37296', (110, 114))	('polymorphisms', 'Var', (158, 171))	('familial aggregation', 'Disease', 'MESH:D001791', (46, 66))	('KS', 'Phenotype', 'HP:0100726', (110, 112))	('KSHV infection', 'Disease', (88, 102))	('familial aggregation', 'Disease', (46, 66))	('KSHV', 'Species', '37296', (88, 92))	('KSHV infection', 'Disease', 'MESH:D007239', (88, 102))	('KS', 'Phenotype', 'HP:0100726', (273, 275))	('KSHV', 'Species', '37296', (273, 277))	('KS', 'Phenotype', 'HP:0100726', (88, 90))
550133	33043529	Similarly, African ancestry has been shown to be a significant independent predictor of MCD incidence in HIV patients, suggesting a putative genetic susceptibility.	('MCD', 'Disease', 'MESH:D012514', (88, 91))	('MCD', 'Disease', (88, 91))	('African ancestry', 'Var', (11, 27))	('patients', 'Species', '9606', (109, 117))
550136	33043529	57  Additionally, we identified genetic variants in the KSHV entry receptor Eph receptor A2 (EPHA2) to be significantly associated with KSHV infection and KS development.	('men', 'Species', '9606', (165, 168))	('KSHV infection', 'Disease', 'MESH:D007239', (136, 150))	('KS development', 'CPA', (155, 169))	('KSHV', 'Species', '37296', (136, 140))	('KSHV infection', 'Disease', (136, 150))	('associated with', 'Reg', (120, 135))	('Eph receptor A2', 'Gene', '1969', (76, 91))	('EPHA2', 'Gene', '1969', (93, 98))	('KS', 'Phenotype', 'HP:0100726', (56, 58))	('Eph receptor A2', 'Gene', (76, 91))	('KS', 'Phenotype', 'HP:0100726', (155, 157))	('KSHV', 'Species', '37296', (56, 60))	('EPHA2', 'Gene', (93, 98))	('KS', 'Phenotype', 'HP:0100726', (136, 138))	('variants', 'Var', (40, 48))
550142	33043529	Two triplet infants have been reported with familial hemophagocytic lymphohistiocytosis related to compound heterozygous perforin mutations and KSHV infection; in these cases, a defective perforin-granzyme pathway is suggested to have led to reduced viral clearance ability and therefore to the onset of symptoms related to lytic KSHV infection.	('KSHV infection', 'Disease', 'MESH:D007239', (144, 158))	('KS', 'Phenotype', 'HP:0100726', (330, 332))	('perforin-granzyme pathway', 'Pathway', (188, 213))	('infants', 'Species', '9606', (12, 19))	('reduced', 'NegReg', (242, 249))	('defective', 'NegReg', (178, 187))	('viral clearance', 'CPA', (250, 265))	('mutations', 'Var', (130, 139))	('lytic KSHV infection', 'Disease', (324, 344))	('KSHV infection', 'Disease', 'MESH:D007239', (330, 344))	('familial hemophagocytic lymphohistiocytosis', 'Disease', 'MESH:D051359', (44, 87))	('lytic KSHV infection', 'Disease', 'MESH:D007239', (324, 344))	('familial hemophagocytic lymphohistiocytosis', 'Disease', (44, 87))	('KS', 'Phenotype', 'HP:0100726', (144, 146))	('KSHV infection', 'Disease', (144, 158))
550143	33043529	MBL2 haplotypes (based on combinations of two promoter region genotypes (-550 H/L and -221 Y/X) and a structural region genotype (exon 1 A/O)) associated with intermediate expression of MBL, an innate immune system protein, were found to be associated with lower CD4 count in HIV and KSHV co-infected patients compared to patients with only HIV infection.	('MBL', 'Gene', '4153', (186, 189))	('-550 H/L', 'Var', (73, 81))	('MBL', 'Gene', (186, 189))	('HIV infection', 'Disease', (341, 354))	('lower', 'NegReg', (257, 262))	('HIV and KSHV co-infected', 'Disease', 'MESH:D060085', (276, 300))	('MBL2', 'Gene', '4153', (0, 4))	('patients', 'Species', '9606', (322, 330))	('MBL', 'Gene', '4153', (0, 3))	('patients', 'Species', '9606', (301, 309))	('MBL', 'Gene', (0, 3))	('CD4', 'Gene', (263, 266))	('MBL2', 'Gene', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (284, 286))	('HIV infection', 'Disease', 'MESH:D015658', (341, 354))	('CD4', 'Gene', '920', (263, 266))
550144	33043529	47  Additionally, polymorphisms in the NFkappaB1 promoter (NG_050628.1:g.4670_4673ATTG[1], reference SNP (rs)28 362 491) and the 3' UTR region of the NFkappaB1 inhibitor alpha (NM_020529.3:NFkappaBIA c.*126G>A, rs696) were found to be associated with the presence of antibodies to KSHV lytic antigens.	('antibodies', 'MPA', (267, 277))	('c.*126G>A', 'Var', (200, 209))	('c.*126G>A', 'Mutation', 'rs696', (200, 209))	('NFkappaB', 'Gene', (39, 47))	('NFkappaB', 'Gene', '4790', (39, 47))	('KS', 'Phenotype', 'HP:0100726', (281, 283))	('NFkappaB', 'Gene', (150, 158))	('NFkappaBIA', 'Gene', (189, 199))	('KSHV lytic antigens', 'Gene', (281, 300))	('NFkappaB', 'Gene', '4790', (150, 158))	('rs696', 'Var', (211, 216))	('NFkappaB', 'Gene', (189, 197))	('rs696', 'Mutation', 'rs696', (211, 216))	('polymorphisms', 'Var', (18, 31))	('NFkappaBIA', 'Gene', '4790', (189, 199))	('NFkappaB', 'Gene', '4790', (189, 197))	('KSHV', 'Species', '37296', (281, 285))	('associated', 'Reg', (235, 245))
550151	33043529	Mutation analysis revealed a novel heterozygous transition (NM_004431.5:c.2572C>T) associated with KSHV infection in a cohort of HIV-infected South African patients stratified by KSHV status.	('patients', 'Species', '9606', (156, 164))	('HIV-infected', 'Disease', 'MESH:D015658', (129, 141))	('c.2572C>T', 'Var', (72, 81))	('KS', 'Phenotype', 'HP:0100726', (179, 181))	('associated', 'Reg', (83, 93))	('KSHV infection', 'Disease', (99, 113))	('HIV-infected', 'Disease', (129, 141))	('NM_004431.5:c.2572C>T', 'Mutation', 'rs1372100828', (60, 81))	('KSHV', 'Species', '37296', (179, 183))	('KS', 'Phenotype', 'HP:0100726', (99, 101))	('KSHV', 'Species', '37296', (99, 103))	('KSHV infection', 'Disease', 'MESH:D007239', (99, 113))
550152	33043529	58  The angiogenesis-related VEGF, shown to augment entry of KSHV into target cells, 70  harboured a promoter region SNP (NG_008732.1:g.4822C>A, rs59260042) associated with KSHV viremia in kidney transplant recipients, and a SNP in the 5' untranslated region (UTR, NM_001025366.3:c.-94C>T, rs2010963) was likewise associated with KSHV viremia but in females only.	('viremia', 'Phenotype', 'HP:0020071', (335, 342))	('KS', 'Phenotype', 'HP:0100726', (330, 332))	('VEGF', 'Gene', (29, 33))	('angiogenesis-related', 'Gene', (8, 28))	('NM_001025366.3:c.-94C>T', 'Mutation', 'rs1004873584', (265, 288))	('rs2010963', 'Mutation', 'rs2010963', (290, 299))	('KSHV', 'Species', '37296', (330, 334))	('KSHV', 'Species', '37296', (173, 177))	('KSHV', 'Species', '37296', (61, 65))	('KSHV viremia', 'Disease', 'MESH:D014766', (330, 342))	('KSHV viremia', 'Disease', 'MESH:D014766', (173, 185))	('NG_008732.1:g.4822C>A', 'Mutation', 'rs59260042', (122, 143))	('associated', 'Reg', (314, 324))	('men', 'Species', '9606', (47, 50))	('augment', 'PosReg', (44, 51))	('KSHV viremia', 'Disease', (330, 342))	('viremia', 'Phenotype', 'HP:0020071', (178, 185))	('KSHV viremia', 'Disease', (173, 185))	('associated with', 'Reg', (157, 172))	('rs59260042', 'Mutation', 'rs59260042', (145, 155))	('KS', 'Phenotype', 'HP:0100726', (173, 175))	('VEGF', 'Gene', '7422', (29, 33))	('KS', 'Phenotype', 'HP:0100726', (61, 63))	('g.4822C>A', 'Var', (134, 143))
550158	33043529	There is evidence from several case reports to suggest that genetic primary immunodeficiency predisposes to KS.	('immunodeficiency', 'Phenotype', 'HP:0002721', (76, 92))	('primary immunodeficiency', 'Disease', 'MESH:D000081207', (68, 92))	('KS', 'Phenotype', 'HP:0100726', (108, 110))	('primary immunodeficiency', 'Disease', (68, 92))	('genetic', 'Var', (60, 67))
550160	33043529	73  One of these children, who died from severe disseminated KS at the age of two, harboured a homozygous splice-site stromal interaction molecule 1 (STIM1) mutation resulting in T cell immunodeficiency.	('died', 'Disease', (31, 35))	('died', 'Disease', 'MESH:D003643', (31, 35))	('immunodeficiency', 'Phenotype', 'HP:0002721', (186, 202))	('T cell immunodeficiency', 'Disease', 'MESH:D016399', (179, 202))	('mutation', 'Var', (157, 165))	('T cell immunodeficiency', 'Disease', (179, 202))	('STIM1', 'Gene', (150, 155))	('stromal interaction molecule 1', 'Gene', '6786', (118, 148))	('KS', 'Phenotype', 'HP:0100726', (61, 63))	('stromal interaction molecule 1', 'Gene', (118, 148))	('children', 'Species', '9606', (17, 25))	('STIM1', 'Gene', '6786', (150, 155))
550161	33043529	74  A further case report describes a Turkish boy with inherited IFNgammaR1 deficiency due to homozygous INFGR1 mutation (NP_000407.1:p.Cys77Tyr, rs104893974) who developed and died from classic KS.	('KS', 'Phenotype', 'HP:0100726', (195, 197))	('IFNgammaR1', 'Gene', (65, 75))	('IFNgammaR1', 'Gene', '3459', (65, 75))	('INFGR1', 'Gene', (105, 111))	('rs104893974', 'Var', (146, 157))	('deficiency', 'Disease', (76, 86))	('NP_000407.1', 'Var', (122, 133))	('deficiency', 'Disease', 'MESH:D007153', (76, 86))	('died', 'Disease', (177, 181))	('died', 'Disease', 'MESH:D003643', (177, 181))	('rs104893974', 'Mutation', 'rs104893974', (146, 157))	('NP_000407.1:p.Cys77Tyr', 'Mutation', 'rs104893974', (122, 144))	('boy', 'Species', '9606', (46, 49))
550163	33043529	75  A Tunisian boy with Wiskott-Aldrich syndrome caused by a WAS deletion (NP_000368.1:p.Asp130_Glu131del) provides further evidence of a possible predisposition to classic KS.	('caused by', 'Reg', (49, 58))	('p.Asp130_Glu131del', 'Var', (87, 105))	('WAS', 'Disease', 'None', (61, 64))	('NP_000368.1:p.Asp130_Glu131del', 'Mutation', 'p.130_,131delE', (75, 105))	('WAS', 'Disease', (61, 64))	('boy', 'Species', '9606', (15, 18))	('classic KS', 'Disease', (165, 175))	('KS', 'Phenotype', 'HP:0100726', (173, 175))	('Wiskott-Aldrich syndrome', 'Disease', (24, 48))	('Wiskott-Aldrich syndrome', 'Disease', 'MESH:D014923', (24, 48))
550164	33043529	A SNP in the IL6 promoter (XM_011515390.2:c.-84-153C>G, rs1800795) which is associated with increased levels of IL6 was noted in a familial clustering of classic KS and was further associated with KS in HIV-infected men and renal transplant recipients.	('associated', 'Reg', (181, 191))	('rs1800795', 'Mutation', 'rs1800795', (56, 65))	('rs1800795', 'Var', (56, 65))	('men', 'Species', '9606', (216, 219))	('IL6', 'Gene', (13, 16))	('IL6', 'Gene', '3569', (13, 16))	('IL6', 'Gene', (112, 115))	('HIV-infected', 'Disease', (203, 215))	('KS', 'Phenotype', 'HP:0100726', (197, 199))	('HIV-infected', 'Disease', 'MESH:D015658', (203, 215))	('increased', 'PosReg', (92, 101))	('KS', 'Phenotype', 'HP:0100726', (162, 164))	('XM_011515390.2:c.-84-153C>G', 'Mutation', 'rs1800795', (27, 54))	('c.-84-153C>G', 'Var', (42, 54))	('IL6', 'Gene', '3569', (112, 115))
550166	33043529	76  Additionally, a SNP in the IL13 promoter region (NM_002188.3:c.431A>G, rs20541) was associated with classic KS in patients latently infected with KSHV.	('KSHV', 'Species', '37296', (150, 154))	('KS', 'Phenotype', 'HP:0100726', (112, 114))	('infected', 'Disease', 'MESH:D007239', (136, 144))	('rs20541', 'Var', (75, 82))	('infected', 'Disease', (136, 144))	('IL13', 'Gene', (31, 35))	('IL13', 'Gene', '3596', (31, 35))	('classic KS', 'Disease', (104, 114))	('c.431A>G', 'Var', (65, 73))	('KS', 'Phenotype', 'HP:0100726', (150, 152))	('rs20541', 'Mutation', 'rs20541', (75, 82))	('NM_002188.3:c.431A>G', 'Mutation', 'rs20541', (53, 73))	('patients', 'Species', '9606', (118, 126))	('associated with', 'Reg', (88, 103))
550167	33043529	44  Similarly, an IL8 promoter SNP (NG_029889.1:g.4802A>T, rs4073), linked to below normal IL8 expression, was identified in a cohort of patients with classic KS 44 ; however, it was conversely found to decrease the risk of AIDS-KS in HIV-positive patients.	('g.4802A>T', 'Var', (48, 57))	('IL8', 'Gene', '3576', (18, 21))	('NG_029889.1:g.4802A>T', 'Mutation', 'rs4073', (36, 57))	('KS', 'Phenotype', 'HP:0100726', (229, 231))	('IL8', 'Gene', (91, 94))	('AIDS-KS in HIV-positive', 'Disease', 'MESH:D015658', (224, 247))	('KS', 'Phenotype', 'HP:0100726', (159, 161))	('AIDS-KS in HIV-positive', 'Disease', (224, 247))	('patients', 'Species', '9606', (137, 145))	('IL8', 'Gene', '3576', (91, 94))	('decrease', 'NegReg', (203, 211))	('NG_029889.1', 'Var', (36, 47))	('rs4073', 'Var', (59, 65))	('patients', 'Species', '9606', (248, 256))	('IL8', 'Gene', (18, 21))	('rs4073', 'Mutation', 'rs4073', (59, 65))
550168	33043529	43  An IL8 SNP (NM_000584.4:c.65-204C>T, rs2227306) was reported to decrease risk of classic KS 44  and the combination of two SNPs (NM_001557.4:c.*127T>C, rs1126579 and NM_001557.4:c.*359G>A, rs1126580) in the human homologue to the KSHV-encoded viral G-protein coupled receptor (vGPCR), IL8 receptor beta (IL8RB), were similarly found to be protective against the development of classic KS.	('IL8', 'Gene', (289, 292))	('IL8', 'Gene', '3576', (289, 292))	('rs2227306', 'Var', (41, 50))	('G-protein coupled receptor', 'Gene', (253, 279))	('KS', 'Phenotype', 'HP:0100726', (93, 95))	('rs2227306', 'Mutation', 'rs2227306', (41, 50))	('rs1126580', 'Var', (193, 202))	('KS', 'Phenotype', 'HP:0100726', (234, 236))	('decrease', 'NegReg', (68, 76))	('NM_000584.4', 'Var', (16, 27))	('vGPCR', 'Gene', 'None', (281, 286))	('rs1126579', 'Mutation', 'rs1126579', (156, 165))	('IL8', 'Gene', (7, 10))	('G-protein coupled receptor', 'Gene', '10663', (253, 279))	('vGPCR', 'Gene', (281, 286))	('NM_001557.4:c.*127T>C', 'Var', (133, 154))	('IL8', 'Gene', '3576', (7, 10))	('men', 'Species', '9606', (373, 376))	('KSHV', 'Species', '37296', (234, 238))	('classic KS 44', 'Disease', (85, 98))	('IL8RB', 'Gene', (308, 313))	('NM_000584.4:c.65-204C>T', 'Mutation', 'c.65_204C>T', (16, 39))	('c.65-204C>T', 'Var', (28, 39))	('IL8', 'Gene', (308, 311))	('KS', 'Phenotype', 'HP:0100726', (389, 391))	('rs1126580', 'Mutation', 'rs1126580', (193, 202))	('IL8', 'Gene', '3576', (308, 311))	('classic KS', 'Disease', (381, 391))	('rs1126579', 'Var', (156, 165))	('NM_001557.4:c.*127T>C', 'Mutation', 'rs1126579', (133, 154))	('human', 'Species', '9606', (211, 216))	('NM_001557.4', 'Var', (170, 181))	('IL8RB', 'Gene', '3579', (308, 313))	('NM_001557.4:c.*359G>A', 'Mutation', 'rs1126580', (170, 191))
550170	33043529	A polymorphic form (NM_000569.8:c.526T>C, rs396991) of the IgG binding receptor, FcgammaRIIIA, was associated with AIDS-KS in a cohort of HIV-positive men and was found to enhance IgG affinity in vitro and promote NK cell activation.	('men', 'Species', '9606', (151, 154))	('enhance IgG', 'Phenotype', 'HP:0003237', (172, 183))	('NK cell activation', 'CPA', (214, 232))	('enhance', 'PosReg', (172, 179))	('rs396991', 'Mutation', 'rs396991', (42, 50))	('FcgammaRIIIA', 'Gene', (81, 93))	('FcgammaRIIIA', 'Gene', '2214', (81, 93))	('c.526T>C', 'Var', (32, 40))	('IgG', 'Protein', (180, 183))	('NM_000569.8:c.526T>C', 'Mutation', 'rs396991', (20, 40))	('promote', 'PosReg', (206, 213))	('AIDS-KS', 'Disease', 'MESH:D000163', (115, 122))	('KS', 'Phenotype', 'HP:0100726', (120, 122))	('AIDS-KS', 'Disease', (115, 122))
550183	33043529	62   Several variants identified in a SNP screening of the HLA-DMB gene region were found to increase AIDS-KS risk.	('variants', 'Var', (13, 21))	('AIDS-KS', 'Disease', 'MESH:D000163', (102, 109))	('increase', 'PosReg', (93, 101))	('KS', 'Phenotype', 'HP:0100726', (107, 109))	('HLA-DMB', 'Gene', '3109', (59, 66))	('HLA-DMB', 'Gene', (59, 66))	('AIDS-KS', 'Disease', (102, 109))
550184	33043529	Most significantly, a SNP in the HLA-DMB intronic region (NM_002118.4:c.55+649T>C, rs6902982) was associated with a four-times higher risk of AIDS-KS in HIV-KSHV co-infected men.	('AIDS-KS in HIV-KSHV co-infected', 'Disease', (142, 173))	('associated with', 'Reg', (98, 113))	('NM_002118.4:c.55+649T>C', 'Mutation', 'rs6902982', (58, 81))	('KS', 'Phenotype', 'HP:0100726', (157, 159))	('KS', 'Phenotype', 'HP:0100726', (147, 149))	('rs6902982', 'Mutation', 'rs6902982', (83, 92))	('men', 'Species', '9606', (174, 177))	('rs6902982', 'Var', (83, 92))	('HLA-DMB', 'Gene', '3109', (33, 40))	('HLA-DMB', 'Gene', (33, 40))	('AIDS-KS in HIV-KSHV co-infected', 'Disease', 'MESH:D060085', (142, 173))
550185	33043529	51  Non-synonymous SNPs in tripartite motif-containing protein 31 (TRIM31, NM_007028.3:c.1261G>A, rs1116221) and lymphotoxin alpha (LTA, NM_000595.4:c.-10+90A>G, rs909253) were observed to be protective whereas SNPs within HLA-DMB linked genes, transporter associated with antigen processing 1 (TAP1, NM_000593.5:c.2090A>G, rs1135216; c.1177A>G, rs1057141), TAPSAR1 microRNA (NG_011759.1:g.13891T>C, rs2071541), G-patch domain and ankyrin repeats 1 (GPANK, NM_001199237.1:c.*90T>C, rs7029) and lymphocyte antigen 6 family member G6C (LY6G6C, NM_025261.3:c.243C>T, rs1065356), were associated with increased risk of AIDS-KS.	('TRIM31', 'Gene', '11074', (67, 73))	('TAP1', 'Gene', (295, 299))	('TAP1', 'Gene', '6890', (295, 299))	('rs909253', 'Mutation', 'rs909253', (162, 170))	('NM_025261.3:c.243C>T', 'Mutation', 'rs1065356', (542, 562))	('rs1057141', 'Mutation', 'rs1057141', (346, 355))	('g.13891T>C', 'Var', (388, 398))	('lymphotoxin alpha', 'Gene', '4049', (113, 130))	('NG_011759.1:g.13891T>C', 'Mutation', 'g.13891T>C', (376, 398))	('tripartite motif-containing protein 31', 'Gene', '11074', (27, 65))	('rs2071541', 'Mutation', 'rs2071541', (400, 409))	('NM_000593.5:c.2090A>G', 'Mutation', 'rs1135216', (301, 322))	('HLA-DMB', 'Gene', '3109', (223, 230))	('rs7029', 'Var', (482, 488))	('lymphotoxin alpha', 'Gene', (113, 130))	('rs1065356', 'Mutation', 'rs1065356', (564, 573))	('NM_007028.3:c.1261G>A', 'Mutation', 'rs1116221', (75, 96))	('G6C', 'Mutation', 'c.6G>C', (537, 540))	('G6C', 'Mutation', 'c.6G>C', (529, 532))	('TRIM31', 'Gene', (67, 73))	('rs1135216', 'Mutation', 'rs1135216', (324, 333))	('c.*90T>C', 'Var', (472, 480))	('NM_000595.4:c.-10+90A>G', 'Mutation', 'rs909253', (137, 160))	('TAPSAR1', 'Gene', '100507463', (358, 365))	('KS', 'Phenotype', 'HP:0100726', (620, 622))	('NM_001199237.1:c.*90T>C', 'Mutation', 'rs7029', (457, 480))	('tripartite motif-containing protein 31', 'Gene', (27, 65))	('AIDS-KS', 'Disease', 'MESH:D000163', (615, 622))	('rs7029', 'Mutation', 'rs7029', (482, 488))	('HLA-DMB', 'Gene', (223, 230))	('TAPSAR1', 'Gene', (358, 365))	('c.1177A>G', 'Mutation', 'rs1057141', (335, 344))	('rs1065356', 'Var', (564, 573))	('AIDS-KS', 'Disease', (615, 622))	('rs1116221', 'Mutation', 'rs1116221', (98, 107))
550187	33043529	57  A SNP screening in AIDS-KS patients including several cellular homologues identified SNPs in CCND1, IL6, CCL2 and CFLAR (homologues of KSHV-encoded vCyclin, vIL6, viral FLICE-inhibitory protein (vFLIP) and viral CC chemokine ligand (vCCL), respectively).	('vIL6', 'Gene', (161, 165))	('CCND1', 'Gene', '595', (97, 102))	('IL6', 'Gene', '3569', (104, 107))	('KS', 'Phenotype', 'HP:0100726', (139, 141))	('IL6', 'Gene', (162, 165))	('CCND1', 'Gene', (97, 102))	('CCL2', 'Gene', '6347', (109, 113))	('KS', 'Phenotype', 'HP:0100726', (28, 30))	('IL6', 'Gene', (104, 107))	('vCyclin', 'Gene', '4961471', (152, 159))	('AIDS-KS', 'Disease', 'MESH:D000163', (23, 30))	('AIDS-KS', 'Disease', (23, 30))	('vIL6', 'Gene', '4961449', (161, 165))	('CFLAR', 'Gene', '8837', (118, 123))	('KSHV', 'Species', '37296', (139, 143))	('CFLAR', 'Gene', (118, 123))	('SNPs', 'Var', (89, 93))	('IL6', 'Gene', '3569', (162, 165))	('vCyclin', 'Gene', (152, 159))	('patients', 'Species', '9606', (31, 39))	('CCL2', 'Gene', (109, 113))
550190	33043529	83 ,  84  Indeed, mutation analysis revealed two novel, non-synonymous heterozygous variants (NM_004431.5:c.2099T>C and NM_004431.5:c.2835G>T) in the EPHA2 tyrosine kinase domain to be significantly associated with KS in a cohort of HIV-infected South African patients stratified by KS status.	('c.2835G>T', 'Var', (132, 141))	('EPHA2', 'Gene', (150, 155))	('associated', 'Reg', (199, 209))	('HIV-infected', 'Disease', (233, 245))	('NM_004431.5', 'Var', (94, 105))	('NM_004431.5:c.2099T>C', 'Mutation', 'c.2099T>C', (94, 115))	('NM_004431.5:c.2835G>T', 'Mutation', 'rs757935059', (120, 141))	('tyrosine', 'Chemical', 'MESH:D014443', (156, 164))	('patients', 'Species', '9606', (260, 268))	('HIV-infected', 'Disease', 'MESH:D015658', (233, 245))	('KS', 'Phenotype', 'HP:0100726', (283, 285))	('EPHA2', 'Gene', '1969', (150, 155))	('KS', 'Phenotype', 'HP:0100726', (215, 217))	('c.2099T>C', 'Var', (106, 115))	('NM_004431.5', 'Var', (120, 131))
550194	33043529	86  A toll-like receptor 4 (TLR4) SNP (NM_138554.5:c.896A>G, rs4986790) which results in decreased surface expression of TLR4, an important pattern recognition receptor in activation of the innate immune system, was associated with increased incidence of MCD in KSHV+ HIV-1+ patients compared to non-KSHV cancer controls and patients with KS 63 ; this SNP was further linked to patients with African ancestry.	('NM_138554.5:c.896A>G', 'Mutation', 'rs4986790', (39, 59))	('c.896A>G', 'Var', (51, 59))	('TLR4', 'Gene', '7099', (121, 125))	('KS', 'Phenotype', 'HP:0100726', (339, 341))	('KSHV', 'Species', '37296', (262, 266))	('TLR4', 'Gene', (121, 125))	('patients', 'Species', '9606', (275, 283))	('decreased', 'NegReg', (89, 98))	('rs4986790', 'Mutation', 'rs4986790', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('KSHV', 'Species', '37296', (300, 304))	('rs4986790', 'Var', (61, 70))	('patients', 'Species', '9606', (378, 386))	('surface expression', 'MPA', (99, 117))	('toll-like receptor 4', 'Gene', (6, 26))	('MCD', 'Disease', 'MESH:D012514', (255, 258))	('MCD', 'Disease', (255, 258))	('toll-like receptor 4', 'Gene', '7099', (6, 26))	('TLR4', 'Gene', '7099', (28, 32))	('HIV-1', 'Species', '11676', (268, 273))	('patients', 'Species', '9606', (325, 333))	('cancer', 'Disease', (305, 311))	('KS', 'Phenotype', 'HP:0100726', (300, 302))	('TLR4', 'Gene', (28, 32))	('KS', 'Phenotype', 'HP:0100726', (262, 264))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
550195	33043529	Indeed, few associations reported here have been satisfactorily replicated yet, with the exception of the reported association of an IL6 promoter polymorphism (XM_011515390.2:c.-84-153C>G) with increased risk of AIDS-related KS and iatrogenic KS, 41 ,  42  the HLA-B*1401 allele with increased risk of AIDS-KS 51 ,  52  and the HLA-B*2702/5 haplotype with decreased risk of AIDS-related KS.	('iatrogenic KS', 'Disease', (232, 245))	('AIDS-KS', 'Disease', 'MESH:D000163', (302, 309))	('XM_011515390.2:c.-84-153C>G', 'Mutation', 'rs1800795', (160, 187))	('AIDS', 'Disease', (374, 378))	('AIDS-KS', 'Disease', (302, 309))	('KS', 'Phenotype', 'HP:0100726', (307, 309))	('HLA-B', 'Gene', '3106', (328, 333))	('AIDS', 'Disease', (302, 306))	('KS', 'Phenotype', 'HP:0100726', (243, 245))	('HLA-B', 'Gene', (261, 266))	('AIDS', 'Disease', (212, 216))	('KS', 'Phenotype', 'HP:0100726', (225, 227))	('IL6', 'Gene', '3569', (133, 136))	('AIDS', 'Disease', 'MESH:D000163', (374, 378))	('HLA-B', 'Gene', (328, 333))	('c.-84-153C>G', 'Var', (175, 187))	('AIDS', 'Disease', 'MESH:D000163', (302, 306))	('IL6', 'Gene', (133, 136))	('iatrogenic KS', 'Disease', 'MESH:D007049', (232, 245))	('AIDS', 'Disease', 'MESH:D000163', (212, 216))	('HLA-B', 'Gene', '3106', (261, 266))	('KS', 'Phenotype', 'HP:0100726', (387, 389))
550207	33043529	Further insights into KSHV infection mechanisms provide new potential candidate genes such as the androgen receptor, recently described by Wang et al, 91  to promote KSHV endocytosis and trafficking via EPHA2 serine phosphorylation.	('androgen receptor', 'Gene', '367', (98, 115))	('EPHA2', 'Gene', '1969', (203, 208))	('serine', 'Chemical', 'MESH:D012694', (209, 215))	('promote', 'PosReg', (158, 165))	('trafficking', 'MPA', (187, 198))	('KSHV', 'Species', '37296', (166, 170))	('KSHV endocytosis', 'MPA', (166, 182))	('EPHA2', 'Gene', (203, 208))	('androgen receptor', 'Gene', (98, 115))	('KSHV infection', 'Disease', (22, 36))	('KS', 'Phenotype', 'HP:0100726', (166, 168))	('KS', 'Phenotype', 'HP:0100726', (22, 24))	('KSHV', 'Species', '37296', (22, 26))	('KSHV infection', 'Disease', 'MESH:D007239', (22, 36))	('genes', 'Var', (80, 85))
550208	33043529	While classic p53 mutations have not been implicated in KSHV-associated pathologies, p53-linked genes are under-researched.	('p53', 'Gene', (85, 88))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('KS', 'Phenotype', 'HP:0100726', (56, 58))	('KSHV', 'Species', '37296', (56, 60))	('p53', 'Gene', '7157', (85, 88))	('mutations', 'Var', (18, 27))
550209	33043529	A plausible candidate SNP for future studies is a homozygous variant (309 G/G) of the p53-modulator, MDM2, which has been suggested as a potential risk factor for development of visceral KS, PEL or MCD after the heterozygous form was found to be associated with cutaneous classic KS in Caucasians and the homozygous form identified in a number of PEL cell lines.	('MCD', 'Disease', (198, 201))	('PEL', 'Phenotype', 'HP:0030069', (347, 350))	('visceral KS', 'Disease', (178, 189))	('p53', 'Gene', '7157', (86, 89))	('PEL', 'Phenotype', 'HP:0030069', (191, 194))	('cutaneous classic KS', 'Disease', (262, 282))	('MCD', 'Disease', 'MESH:D012514', (198, 201))	('men', 'Species', '9606', (170, 173))	('309 G/G', 'Var', (70, 77))	('KS', 'Phenotype', 'HP:0100726', (187, 189))	('associated', 'Reg', (246, 256))	('KS', 'Phenotype', 'HP:0100726', (280, 282))	('PEL', 'Disease', (191, 194))	('MDM2', 'Gene', '4193', (101, 105))	('risk factor', 'Reg', (147, 158))	('MDM2', 'Gene', (101, 105))	('p53', 'Gene', (86, 89))
550211	33043529	Although many different genetic variants predisposing individuals to either KSHV infection and/or KSHV-associated diseases appear to exist which makes designing a therapy against all of them rather difficult, there are a few promising candidate genes: familiar KS has been linked to inborn defects in T cell immunity, in particular T cell effector functions and possibly interferon signalling, 71 ,  74  while genetic polymorphism associated with differing sensitivities to cytotoxic drugs have been reported, such as the EPHA2 substitution, NP_004422.2:p.Gly391Arg, which showed increased sensitivity to rapamycin 93 ,  94  and low dose resistance to cisplatin 94  in human lung epithelial cells.	('human', 'Species', '9606', (669, 674))	('p.Gly391Arg', 'Var', (554, 565))	('defects in T cell', 'Phenotype', 'HP:0002843', (290, 307))	('KS', 'Phenotype', 'HP:0100726', (76, 78))	('KSHV infection', 'Disease', 'MESH:D007239', (76, 90))	('EPHA2', 'Gene', (522, 527))	('cisplatin', 'Chemical', 'MESH:D002945', (652, 661))	('rapamycin', 'Chemical', 'MESH:D020123', (605, 614))	('sensitivity', 'MPA', (590, 601))	('inborn defects', 'Disease', (283, 297))	('KS', 'Phenotype', 'HP:0100726', (98, 100))	('EPHA2', 'Gene', '1969', (522, 527))	('KSHV infection', 'Disease', (76, 90))	('KSHV', 'Species', '37296', (76, 80))	('increased', 'PosReg', (580, 589))	('inborn defects', 'Disease', 'MESH:D030342', (283, 297))	('KSHV', 'Species', '37296', (98, 102))	('NP_004422.2:p.Gly391Arg', 'Mutation', 'rs34192549', (542, 565))	('KS', 'Phenotype', 'HP:0100726', (261, 263))	('linked', 'Reg', (273, 279))
550212	33043529	Selected validated genetic variants conferring KSHV and KS susceptibility should therefore be assessed for drug sensitives.	('variants', 'Var', (27, 35))	('KS', 'Phenotype', 'HP:0100726', (56, 58))	('KSHV', 'Gene', (47, 51))	('KSHV', 'Species', '37296', (47, 51))	('KS', 'Phenotype', 'HP:0100726', (47, 49))
550239	33452711	One trial included patients in first recurrent/refractory disease only (NCT00516295), while other two were restricted to patients with lung metastasis only (NCT01590069 and NCT00492141).	('patients', 'Species', '9606', (19, 27))	('NCT00516295', 'Var', (72, 83))	('refractory disease', 'Disease', 'MESH:D000069279', (47, 65))	('NCT01590069', 'Var', (157, 168))	('refractory disease', 'Disease', (47, 65))	('patients', 'Species', '9606', (121, 129))
550271	33452711	For example, 10 separate trials tested anti-IGF1/IGFR inhibitors between 2008 and 2010, based on biological rational and some spectacular early responses.	('IGF1', 'Gene', (44, 48))	('IGFR', 'Gene', (49, 53))	('inhibitors', 'Var', (54, 64))	('IGFR', 'Gene', '3480', (49, 53))	('IGF1', 'Gene', '3479', (44, 48))
550285	32244416	Even low-dose irradiation harbors a significant risk for SMNs with a cumulative incidence of 17% at 20 years.	('low-dose', 'Var', (5, 13))	('SMN', 'Gene', '6606', (57, 60))	('SMN', 'Gene', (57, 60))
550363	25024862	Further testing included fluorescence in situ hybridization (FISH) study which tested positive for the rearrangement involving EWSR1 gene at chromosome 22q12 (Figure 8) and was diagnostic for Ewing sarcoma.	('EWSR1', 'Gene', (127, 132))	('Ewing sarcoma', 'Disease', (192, 205))	('EWSR1', 'Gene', '2130', (127, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))	('rearrangement', 'Var', (103, 116))	('positive', 'Reg', (86, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (192, 205))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (192, 205))
550379	25024862	The genetics of the tumor offers a more definitive diagnosis with chromosomal translocation involving chromosome 22, particularly the t(11; 22) (q24; q12) translocation accounting for approximately 90% of the tumors.	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumor', 'Disease', (209, 214))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('chromosomal translocation', 'Var', (66, 91))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', (20, 25))
550386	24694277	The heterogeneity of study populations in the literature:inclusion of selected subtypes only, high-grade tumors, or patients from centers with major tertiary referral practices and a larger proportion of large, high-grade, recurrent, or otherwise complicated sarcomas:results in possible selection bias and low generalizability.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (116, 124))	('sarcomas', 'Disease', 'MESH:D012509', (259, 267))	('high-grade', 'Var', (211, 221))	('sarcomas', 'Phenotype', 'HP:0100242', (259, 267))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('sarcomas', 'Disease', (259, 267))
550417	24694277	In the confounder-adjusted analyses, age > 55 years (vs. 45 years), duration of symptoms < 3 months (vs. 3 months), tumor size 5-7 cm or > 20 cm (vs. 4 cm), grade 3, and intralesional/marginal excision were adverse prognostic factors, while duration of symptoms > 3 months and < 24 months (vs. 3 months), tumor size < 4 cm (vs. 4 cm), and treatment with radiotherapy were favorable prognostic factors.	('grade 3', 'Var', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (305, 310))	('tumor', 'Disease', (116, 121))
550419	24694277	Adverse prognostic factors were age > 45 years (vs. 45 years), tumor size > 4 cm (vs. 4 cm), trunk and lower extremity location, grade 2-3 or unclassifiable, and intralesional/marginal excision, while duration of symptoms >= 15 and <= 30 months, tumor size < 4 cm (vs. 4 cm), and treatment with radiotherapy were favorable prognostic factors.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('intralesional/marginal', 'Var', (162, 184))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('lower extremity', 'Phenotype', 'HP:0006385', (103, 118))	('tumor', 'Disease', (246, 251))
550560	31795974	Adoptive transfer of NK cells already has been tested in various clinical trials (e.g., NCT00582816, NCT01287104) and has emerged as a safe and potentially efficacious immunotherapy for cancer patients.	('patients', 'Species', '9606', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('NCT01287104', 'Var', (101, 112))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
550594	31795974	The following antibody clones were used for phenotypical NK cell characterization: CD3 (UCHT1), CD16 (3G8), CD25 (2A3), CD56 (HCD56), CD69 (L78), CD94 (HP-3D9), CD158a/b/e (HP-3E4), CD161 (HP-3G10), NKp30 (Z25), NKp44 (Z231), NKp46 (9E2/NKp46), NKG2A (Z199), NKG2C (134591), and NKG2D (BAT221).	('CD', 'Chemical', 'MESH:D002104', (108, 110))	('NKG2D', 'Gene', (279, 284))	('CD16', 'Gene', '2214', (182, 186))	('NKp46', 'Gene', '9437', (226, 231))	('CD', 'Chemical', 'MESH:D002104', (83, 85))	('NKG2D', 'Gene', '22914', (279, 284))	('Z25', 'Gene', '25826', (206, 209))	('CD', 'Chemical', 'MESH:D002104', (146, 148))	('CD25', 'Gene', '3559', (108, 112))	('NKp30', 'Gene', (199, 204))	('NKp44', 'Gene', (212, 217))	('CD161', 'Gene', (182, 187))	('CD', 'Chemical', 'MESH:D002104', (120, 122))	('NKp46', 'Gene', (237, 242))	('CD', 'Chemical', 'MESH:D002104', (96, 98))	('NKp44', 'Gene', '9436', (212, 217))	('CD161', 'Gene', '3820', (182, 187))	('CD', 'Chemical', 'MESH:D002104', (161, 163))	('CD94', 'Gene', (146, 150))	('CD16', 'Gene', (182, 186))	('NKp46', 'Gene', (226, 231))	('Z199', 'Var', (252, 256))	('NKG2A', 'Gene', '3821', (245, 250))	('CD', 'Chemical', 'MESH:D002104', (134, 136))	('NKG2C', 'Gene', '3822', (259, 264))	('CD', 'Chemical', 'MESH:D002104', (127, 129))	('Z25', 'Gene', (206, 209))	('CD94', 'Gene', '3824', (146, 150))	('CD16', 'Gene', '2214', (96, 100))	('CD', 'Chemical', 'MESH:D002104', (182, 184))	('NKp30', 'Gene', '259197', (199, 204))	('CD69', 'Gene', '969', (134, 138))	('CD56', 'Gene', (120, 124))	('CD56', 'Gene', (127, 131))	('CD69', 'Gene', (134, 138))	('CD25', 'Gene', (108, 112))	('NKG2A', 'Gene', (245, 250))	('CD16', 'Gene', (96, 100))	('CD56', 'Gene', '4684', (127, 131))	('NKG2C', 'Gene', (259, 264))	('CD56', 'Gene', '4684', (120, 124))	('NKp46', 'Gene', '9437', (237, 242))
550598	31795974	Cell surface molecules of tumor cells were characterized by flow cytometry using fluorochrome conjugated antibody clones CD112 (TX31), CD155 (SKII4), MICA/B (159207), PD-L1 (29E2A3), ULBP1 (170818), ULBP2/5/6 (165903) or ULBP3 (166510).	('ULBP1', 'Gene', '80329', (183, 188))	('CD112', 'Gene', '5819', (121, 126))	('PD-L1', 'Gene', (167, 172))	('165903', 'Var', (210, 216))	('PD-L1', 'Gene', '29126', (167, 172))	('MICA', 'Gene', (150, 154))	('ULBP3', 'Gene', '79465', (221, 226))	('170818', 'Var', (190, 196))	('CD155', 'Gene', (135, 140))	('159207', 'Var', (158, 164))	('tumor', 'Disease', (26, 31))	('ULBP2', 'Gene', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('ULBP1', 'Gene', (183, 188))	('MICA', 'Gene', '100507436', (150, 154))	('ULBP3', 'Gene', (221, 226))	('CD112', 'Gene', (121, 126))	('ULBP2', 'Gene', '80328', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('CD155', 'Gene', '5817', (135, 140))
550642	31795974	Therefore, NKAES co-cultured with MeV-infected A673 cells exhibited an inconspicuous phenotype resembling overall features of control NK cells or NK cells co-cultured with uninfected A673 cells.	('infected', 'Disease', 'MESH:D007239', (174, 182))	('exhibited', 'Reg', (58, 67))	('infected', 'Disease', 'MESH:D007239', (38, 46))	('infected', 'Disease', (174, 182))	('MeV-infected', 'Disease', (34, 46))	('A673', 'Var', (47, 51))	('infected', 'Disease', (38, 46))	('MeV-infected', 'Disease', 'MESH:D007239', (34, 46))
550651	31795974	Addition of PBMC to MeV-infected A673 cells led to a much higher cytotoxicity when compared to mock-infected cells (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('PBMC', 'Chemical', '-', (12, 16))	('MeV-infected', 'Disease', (20, 32))	('mock-infected', 'Disease', 'MESH:D007239', (95, 108))	('PBMC', 'Var', (12, 16))	('mock-infected', 'Disease', (95, 108))	('MeV-infected', 'Disease', 'MESH:D007239', (20, 32))	('cytotoxicity', 'Disease', (65, 77))	('higher', 'PosReg', (58, 64))
550682	31795974	Currently, there are many clinical trials investigating the immunotherapeutic effect of NK cell restoration for the treatment of cancer; specifically, there are two ongoing clinical trials utilizing NK cells (NCT01807468, NCT02100891) including also pediatric solid tumors such as pediatric sarcomas.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (291, 299))	('sarcomas', 'Disease', (291, 299))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('sarcomas', 'Disease', 'MESH:D012509', (291, 299))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('NCT01807468', 'Var', (209, 220))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('tumors', 'Disease', (266, 272))
550770	26566160	Sequencing of the canine genome has further accelerated the usefulness of the dog model by identifying plausible candidate genes and single-nucleotide polymorphisms (SNPs) potentially useful for mapping breed-specific traits.	('dog', 'Species', '9615', (78, 81))	('single-nucleotide polymorphisms', 'Var', (133, 164))	('accelerated', 'PosReg', (44, 55))	('canine', 'Species', '9615', (18, 24))
550778	26566160	By stimulating anchorage-independent growth and proliferation, it is possible that hyaluronidase mutations could promote a more favorable tumor microenvironment, thereby contributing to tumor progression.	('anchorage-independent growth', 'CPA', (15, 43))	('mutations', 'Var', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (138, 143))	('proliferation', 'CPA', (48, 61))	('promote', 'PosReg', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('stimulating', 'Reg', (3, 14))	('hyaluronidase', 'Gene', (83, 96))	('contributing', 'Reg', (170, 182))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
550779	26566160	The identification of germline risk factors in dogs with MCT may help identify at-risk populations and implicate variant genes and genetic networks important in normal and malignant mast cell biology with applicability to both humans and dogs.	('MCT', 'Disease', (57, 60))	('MCT', 'Chemical', '-', (57, 60))	('MCT', 'Phenotype', 'HP:0100495', (57, 60))	('variant', 'Var', (113, 120))	('humans', 'Species', '9606', (227, 233))	('dogs', 'Species', '9615', (238, 242))	('dogs', 'Species', '9615', (47, 51))
550781	26566160	Canine and human OSA exhibit overlapping transcriptional profiles, shared regions of genomic instability, and gene alterations, supporting the idea that these diseases are similar at the molecular level.	('OSA', 'Phenotype', 'HP:0002669', (17, 20))	('Canine', 'Species', '9615', (0, 6))	('human', 'Species', '9606', (11, 16))	('OSA', 'Disease', (17, 20))	('alterations', 'Var', (115, 126))	('transcriptional', 'MPA', (41, 56))
550792	26566160	Additionally, the six most common CNAs were deletions in chromosomal regions harboring the tumor suppressor genes CDKN2A/B, RB1, and PTEN, with loss of CDKN2A/B seen in 60.7% of Bernese mountain dogs.	('RB1', 'Gene', (124, 127))	('CNAs', 'Disease', (34, 38))	('dogs', 'Species', '9615', (195, 199))	('CDKN2A/B', 'Gene', (114, 122))	('deletions', 'Var', (44, 53))	('CDKN2A/B', 'Gene', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('PTEN', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PTEN', 'Gene', '403832', (133, 137))	('CDKN2A/B', 'Gene', '100271861;481563', (114, 122))	('tumor', 'Disease', (91, 96))	('CDKN2A/B', 'Gene', '100271861;481563', (152, 160))
550796	26566160	These three SNPs overlap the gene MTAP and the tumor suppressor gene CDKN2A/B, providing further support for the notion that CDKN2 dysregulation likely plays a role in the pathogenesis of this disease.	('CDKN2A/B', 'Gene', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('MTAP', 'Gene', '474729', (34, 38))	('MTAP', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CDKN2A/B', 'Gene', '100271861;481563', (69, 77))	('CDKN2', 'Gene', (125, 130))	('dysregulation', 'Var', (131, 144))	('tumor', 'Disease', (47, 52))
550798	26566160	Additional fine-mapping and haplotype analysis resolved this region to the KITLG (KIT ligand/stem cell factor) locus, and it was subsequently determined that although light-colored dogs carry the copy number variation, they have a significantly lower risk of developing SCC.	('SCC', 'Disease', (270, 273))	('dogs', 'Species', '9615', (181, 185))	('copy number variation', 'Var', (196, 217))	('SCC', 'Phenotype', 'HP:0002860', (270, 273))	('lower', 'NegReg', (245, 250))
550807	26566160	Dysregulation of specific candidate genes implicated in the etiopathogenesis of OSA are found in both species, including mutations in the tumor suppressor genes p53, RB1, and PTEN and alterations of the oncogenes MYC and MET, among others.	('mutations', 'Var', (121, 130))	('PTEN', 'Gene', '403832', (175, 179))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('RB1', 'Gene', (166, 169))	('MET', 'Gene', (221, 224))	('OSA', 'Phenotype', 'HP:0002669', (80, 83))	('p53', 'Gene', (161, 164))	('PTEN', 'Gene', (175, 179))	('OSA', 'Disease', (80, 83))	('MYC', 'Gene', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
550811	26566160	Subsequently, expression of these genes was found to be associated with an aggressive clinical course and poor outcome in human OSA.	('human', 'Species', '9606', (122, 127))	('expression', 'Var', (14, 24))	('OSA', 'Phenotype', 'HP:0002669', (128, 131))	('human OSA', 'Disease', (122, 131))	('associated', 'Reg', (56, 66))
550813	26566160	There is strong homology and similar incidence of mutations in the highly conserved coding regions of the p53 gene in dog and human OSA.	('human', 'Species', '9606', (126, 131))	('dog', 'Species', '9615', (118, 121))	('mutations', 'Var', (50, 59))	('OSA', 'Phenotype', 'HP:0002669', (132, 135))	('p53', 'Gene', (106, 109))
550814	26566160	p53 is often overexpressed in canine primary OSA samples, with the frequency of reported mutations ranging from 23% to47%.	('p53', 'Gene', (0, 3))	('overexpressed', 'PosReg', (13, 26))	('OSA', 'Phenotype', 'HP:0002669', (45, 48))	('canine', 'Species', '9615', (30, 36))	('mutations', 'Var', (89, 98))
550815	26566160	Although a similar incidence (15-30%) of p53 mutations is found in human OSA, the nature of mutations differs, with point mutations more common in dogs and large alterations more common in humans.	('mutations', 'Var', (45, 54))	('dogs', 'Species', '9615', (147, 151))	('point mutations', 'Var', (116, 131))	('human', 'Species', '9606', (189, 194))	('OSA', 'Phenotype', 'HP:0002669', (73, 76))	('OSA', 'Disease', (73, 76))	('human', 'Species', '9606', (67, 72))	('p53', 'Gene', (41, 44))	('humans', 'Species', '9606', (189, 195))
550817	26566160	Copy number loss of the RB1 gene was detected in 29% of canine OSA tumor samples, corresponding to reduced or absent Rb protein expression in 8 of 13 (61.5%) samples analyzed.	('canine', 'Species', '9615', (56, 62))	('OSA', 'Phenotype', 'HP:0002669', (63, 66))	('tumor', 'Disease', (67, 72))	('RB1', 'Gene', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Rb protein', 'Protein', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('absent', 'NegReg', (110, 116))	('Rb', 'Chemical', 'MESH:D012413', (117, 119))	('expression', 'MPA', (128, 138))	('reduced', 'NegReg', (99, 106))	('Copy number loss', 'Var', (0, 16))
550842	26566160	Additionally, aCGH was used to identify copy number aberrations in 12 dogs with DLBCL that were associated with outcome.	('associated', 'Reg', (96, 106))	('dogs', 'Species', '9615', (70, 74))	('copy number aberrations', 'Var', (40, 63))
550858	26566160	More recently, inactivating mutations in TRAF3 were first identified in canine DLBCL and then in a small number of human DLBCL samples.	('inactivating mutations', 'Var', (15, 37))	('human', 'Species', '9606', (115, 120))	('DLBCL', 'Disease', (79, 84))	('TRAF3', 'Gene', (41, 46))	('canine', 'Species', '9615', (72, 78))
550859	26566160	The TRAF3 gene encodes a negative regulator of the noncanonical NF-kappaB pathway and was mutated in 44% of the canine samples, resulting in downregulation of gene expression.	('mutated', 'Var', (90, 97))	('NF-kappaB', 'Gene', '4790', (64, 73))	('canine', 'Species', '9615', (112, 118))	('NF-kappaB', 'Gene', (64, 73))	('TRAF3', 'Gene', (4, 9))	('downregulation', 'NegReg', (141, 155))	('gene expression', 'MPA', (159, 174))
550861	26566160	Lymphocytic and myelogenous leukemias are a heterogeneous group of hematopoietic neoplasms distinguished by their individual clinical and biologic features and genetic aberrations, including gene mutations, chromosomal translocations, and altered activity of signaling proteins.	('myelogenous leukemias', 'Disease', 'MESH:D007951', (16, 37))	('leukemias', 'Phenotype', 'HP:0001909', (28, 37))	('hematopoietic neoplasms', 'Disease', (67, 90))	('neoplasms', 'Phenotype', 'HP:0002664', (81, 90))	('hematopoietic neoplasms', 'Disease', 'MESH:D019337', (67, 90))	('chromosomal translocations', 'Var', (207, 233))	('leukemia', 'Phenotype', 'HP:0001909', (28, 36))	('gene mutations', 'Var', (191, 205))	('myelogenous leukemias', 'Disease', (16, 37))	('myelogenous leukemias', 'Phenotype', 'HP:0012324', (16, 37))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (16, 36))	('hematopoietic neoplasms', 'Phenotype', 'HP:0004377', (67, 90))	('altered', 'Reg', (239, 246))	('activity', 'MPA', (247, 255))	('neoplasm', 'Phenotype', 'HP:0002664', (81, 89))
550868	26566160	Deletion or loss of heterozygosity of chromosome 13q14 is present in approximately 68% of human CLL patients, and this region contains the RB1 gene locus.	('CLL', 'Phenotype', 'HP:0005550', (96, 99))	('CLL', 'Disease', (96, 99))	('loss of', 'NegReg', (12, 19))	('human', 'Species', '9606', (90, 95))	('patients', 'Species', '9606', (100, 108))	('RB1', 'Gene', (139, 142))	('Deletion', 'Var', (0, 8))
550870	26566160	As in people, the CFA 22 deletion included the RB1 locus, resulting in reduced or absent Rb protein expression in CLL samples from dogs.	('people', 'Species', '9606', (6, 12))	('Rb protein', 'Protein', (89, 99))	('Rb', 'Chemical', 'MESH:D012413', (89, 91))	('CLL', 'Phenotype', 'HP:0005550', (114, 117))	('deletion', 'Var', (25, 33))	('reduced', 'NegReg', (71, 78))	('dogs', 'Species', '9615', (131, 135))	('CFA 22', 'Gene', (18, 24))	('absent', 'NegReg', (82, 88))
550876	26566160	Subsequently, two case reports have identified BCR-ABL translocations in a dog with chronic myelomonocytic leukemia and acute myeloblastic leukemia (AML).	('AML', 'Disease', (149, 152))	('chronic myelomonocytic leukemia', 'Disease', (84, 115))	('AML', 'Phenotype', 'HP:0004808', (149, 152))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('translocations', 'Var', (55, 69))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (84, 115))	('dog', 'Species', '9615', (75, 78))	('acute myeloblastic leukemia', 'Phenotype', 'HP:0004808', (120, 147))	('myeloblastic leukemia', 'Phenotype', 'HP:0012324', (126, 147))	('BCR-ABL', 'Gene', (47, 54))	('BCR-ABL', 'Gene', '25', (47, 54))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (84, 115))	('acute myeloblastic leukemia', 'Disease', (120, 147))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('acute myeloblastic leukemia', 'Disease', 'MESH:D015470', (120, 147))
550879	26566160	FLT3 juxtamembrane internal tandem duplications (ITDs) or point mutations are more commonly seen in human AML as compared with ALL, representing approximately 25-30% and 1% of cases, respectively.	('human', 'Species', '9606', (100, 105))	('AML', 'Disease', 'MESH:D015470', (106, 109))	('point mutations', 'Var', (58, 73))	('ALL', 'Phenotype', 'HP:0006721', (127, 130))	('FLT3', 'Gene', (0, 4))	('AML', 'Phenotype', 'HP:0004808', (106, 109))	('AML', 'Disease', (106, 109))
550881	26566160	Corroborating these data, the presence of ITD mutations in spontaneous canine ALL was shown to result in activation of downstream JAK/STAT and MAP kinase signaling pathways, providing further evidence to support the notion that ALL and FLT3 biology are conserved between dogs and humans.	('mutations', 'Var', (46, 55))	('STA', 'Gene', (134, 137))	('MAP kinase signaling pathways', 'Pathway', (143, 172))	('dogs', 'Species', '9615', (271, 275))	('canine', 'Species', '9615', (71, 77))	('humans', 'Species', '9606', (280, 286))	('activation', 'PosReg', (105, 115))	('ALL', 'Phenotype', 'HP:0006721', (78, 81))	('STA', 'Gene', '104044', (134, 137))	('ALL', 'Phenotype', 'HP:0006721', (228, 231))
550898	26566160	Interestingly, over 80% of canine invasive TCC tumors carry an activating mutation in BRAF homologous to the activating BRAF(V600E) mutation typically found in human malignant melanoma and a small proportion of thyroid carcinoma and colon carcinoma patients.	('colon carcinoma', 'Disease', 'MESH:D015179', (233, 248))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('TCC', 'Phenotype', 'HP:0006740', (43, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('thyroid carcinoma', 'Disease', (211, 228))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('canine', 'Species', '9615', (27, 33))	('mutation', 'Var', (74, 82))	('V600E', 'Var', (125, 130))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (211, 228))	('malignant melanoma', 'Phenotype', 'HP:0002861', (166, 184))	('activating', 'PosReg', (63, 73))	('malignant melanoma', 'Disease', 'MESH:D008545', (166, 184))	('BRAF', 'Gene', (86, 90))	('human', 'Species', '9606', (160, 165))	('patients', 'Species', '9606', (249, 257))	('V600E', 'SUBSTITUTION', 'None', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('colon carcinoma', 'Disease', (233, 248))	('invasive TCC tumors', 'Disease', 'MESH:C536943', (34, 53))	('invasive TCC tumors', 'Disease', (34, 53))	('malignant melanoma', 'Disease', (166, 184))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (211, 228))
550899	26566160	BRAF mutations are found in approximately 8% of all human cancers but are rare in human urothelial tumors.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('found', 'Reg', (19, 24))	('human', 'Species', '9606', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('mutations', 'Var', (5, 14))	('urothelial tumors', 'Disease', (88, 105))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('BRAF', 'Gene', (0, 4))	('cancers', 'Disease', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('urothelial tumors', 'Disease', 'MESH:D001749', (88, 105))	('human', 'Species', '9606', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
550900	26566160	Despite this, given the high prevalence of mutation in canine TCC, this tumor may represent an interesting model of BRAF dysfunction that can be used to study the activity of novel small molecule inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('canine', 'Species', '9615', (55, 61))	('mutation', 'Var', (43, 51))	('tumor', 'Disease', (72, 77))	('BRAF dysfunction', 'Disease', (116, 132))	('BRAF dysfunction', 'Disease', 'MESH:D006331', (116, 132))	('TCC', 'Gene', (62, 65))	('TCC', 'Phenotype', 'HP:0006740', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
550908	26566160	Abnormalities in chromosomes 11 and 30 were found in primary cell cultures taken from two Labrador retrievers with anaplastic fibrosarcoma.	('anaplastic fibrosarcoma', 'Disease', (115, 138))	('Abnormalities', 'Var', (0, 13))	('anaplastic fibrosarcoma', 'Disease', 'MESH:D005354', (115, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (126, 138))
550910	26566160	Although this study did not provide prognostic information, loss of CDKN2A/CDKN2B in people with STS has been associated with a worse prognosis.	('loss', 'Var', (60, 64))	('STS', 'Phenotype', 'HP:0030448', (97, 100))	('CDKN2A/CDKN2B', 'Gene', (68, 81))	('people', 'Species', '9606', (85, 91))
550911	26566160	Similarly, genetic aberrations in the proto-oncogene KIT have been used to classify molecular subtypes of gastrointestinal stromal tumors (GIST).	('GIST', 'Phenotype', 'HP:0100723', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (106, 137))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (106, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('genetic aberrations', 'Var', (11, 30))	('gastrointestinal stromal tumors', 'Disease', (106, 137))
550912	26566160	In people, GIST are driven primarily by activating mutations in KIT, with approximately 80% of tumors possessing activating mutations in exon 11 of this gene.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('activating mutations', 'Var', (40, 60))	('GIST', 'Phenotype', 'HP:0100723', (11, 15))	('KIT', 'Gene', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('people', 'Species', '9606', (3, 9))	('tumors', 'Disease', (95, 101))
550913	26566160	KIT mutations involving mutations in exon 11 have also been reported in 35.5% of canine GIST.	('mutations', 'Var', (4, 13))	('reported', 'Reg', (60, 68))	('canine', 'Species', '9615', (81, 87))	('GIST', 'Phenotype', 'HP:0100723', (88, 92))
550914	26566160	Although mutations in PDGFRA have been reported in 5-10% of human GIST cases, these have not been identified in canine GIST.	('GIST', 'Phenotype', 'HP:0100723', (119, 123))	('GIST', 'Disease', (66, 70))	('mutations', 'Var', (9, 18))	('canine', 'Species', '9615', (112, 118))	('PDGFRA', 'Gene', (22, 28))	('GIST', 'Phenotype', 'HP:0100723', (66, 70))	('reported', 'Reg', (39, 47))	('human', 'Species', '9606', (60, 65))
550915	26566160	The presence of KIT mutations in human GIST led to the use of the small molecule inhibitor imatinib (GLEEVEC ) for inoperable or metastatic GIST, with objective response rates in affected patients exceeding 60%.	('GIST', 'Phenotype', 'HP:0100723', (39, 43))	('GLEEVEC', 'Chemical', 'MESH:D000068877', (101, 108))	('imatinib', 'Chemical', 'MESH:D000068877', (91, 99))	('KIT', 'Gene', (16, 19))	('patients', 'Species', '9606', (188, 196))	('GIST', 'Phenotype', 'HP:0100723', (140, 144))	('human', 'Species', '9606', (33, 38))	('mutations', 'Var', (20, 29))
550927	26566160	This study demonstrated that germline mutations in BRCA1 and BRCA2 are significantly associated with mammary cancer in that breed.	('associated with', 'Reg', (85, 100))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('BRCA2', 'Gene', (61, 66))	('BRCA1', 'Gene', '403437', (51, 56))	('BRCA2', 'Gene', '474180', (61, 66))	('BRCA1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('germline mutations', 'Var', (29, 47))
550938	26566160	Nearly all cases of cutaneous melanoma in people are malignant, and molecular characterization has shown that an activating mutation in BRAF is the primary driver in at least 60% of affected patients.	('people', 'Species', '9606', (42, 48))	('activating', 'PosReg', (113, 123))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (20, 38))	('patients', 'Species', '9606', (191, 199))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (20, 38))	('BRAF', 'Gene', (136, 140))	('mutation', 'Var', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('cutaneous melanoma', 'Disease', (20, 38))
550943	26566160	Activating mutations in KIT have been identified in human malignant melanoma, with the largest subset of RTT-mutant-positive tumors representing mucosal melanomas (16%).	('mutations', 'Var', (11, 20))	('mucosal melanomas', 'Disease', 'MESH:D008545', (145, 162))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('malignant melanoma', 'Phenotype', 'HP:0002861', (58, 76))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('malignant melanoma', 'Disease', 'MESH:D008545', (58, 76))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('human', 'Species', '9606', (52, 57))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('malignant melanoma', 'Disease', (58, 76))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('RTT-mutant-positive', 'Gene', (105, 124))	('mucosal melanomas', 'Disease', (145, 162))	('KIT', 'Gene', (24, 27))
550945	26566160	Furthermore, the role of wild-type or mutant KIT signaling and its contribution to melanoma tumorigenesis have not been characterized in canine malignant melanoma.	('mutant', 'Var', (38, 44))	('malignant melanoma', 'Phenotype', 'HP:0002861', (144, 162))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('KIT', 'Gene', (45, 48))	('malignant melanoma', 'Disease', (144, 162))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('malignant melanoma', 'Disease', 'MESH:D008545', (144, 162))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('canine', 'Species', '9615', (137, 143))	('tumor', 'Disease', (92, 97))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
550946	26566160	As previously mentioned, approximately 60% of cutaneous melanomas in people contain activating BRAF mutations, with the majority of tumors harboring V600E mutations.In contrast, activating BRAF mutations have not been identified in canine or human mucosal melanomas, although MAPK and PI3K/AKT pathway dysregulation has been found in mucosal melanomas derived from both species.	('V600E', 'Mutation', 'rs113488022', (149, 154))	('melanoma', 'Phenotype', 'HP:0002861', (342, 350))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('canine', 'Species', '9615', (232, 238))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (46, 65))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (46, 65))	('AKT', 'Gene', (290, 293))	('mucosal melanomas', 'Disease', 'MESH:D008545', (248, 265))	('BRAF', 'Gene', (189, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mucosal melanomas', 'Disease', (248, 265))	('tumors', 'Disease', (132, 138))	('cutaneous melanomas', 'Disease', (46, 65))	('mucosal melanomas', 'Disease', 'MESH:D008545', (334, 351))	('people', 'Species', '9606', (69, 75))	('AKT', 'Gene', '207', (290, 293))	('mutations', 'Var', (194, 203))	('melanomas', 'Phenotype', 'HP:0002861', (342, 351))	('melanomas', 'Phenotype', 'HP:0002861', (256, 265))	('mucosal melanomas', 'Disease', (334, 351))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('human', 'Species', '9606', (242, 247))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
550948	26566160	NRAS mutations are typically present in cutaneous sun-induced melanomas in people.	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('mutations', 'Var', (5, 14))	('melanomas', 'Disease', (62, 71))	('cutaneous sun-induced melanomas', 'Phenotype', 'HP:0012056', (40, 71))	('people', 'Species', '9606', (75, 81))	('NRAS', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
550950	26566160	Consistent with this idea, activating NRAS oncogene mutations are rare in canine oral malignant melanoma.	('mutations', 'Var', (52, 61))	('oral malignant melanoma', 'Disease', 'MESH:D008545', (81, 104))	('malignant melanoma', 'Phenotype', 'HP:0002861', (86, 104))	('activating', 'PosReg', (27, 37))	('canine', 'Species', '9615', (74, 80))	('oral malignant melanoma', 'Disease', (81, 104))	('NRAS', 'Gene', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
550960	26566160	The highest response rates were noted in dogs with MCT that harbored activating KIT mutations.	('dogs', 'Species', '9615', (41, 45))	('MCT', 'Chemical', '-', (51, 54))	('KIT', 'Gene', (80, 83))	('activating', 'PosReg', (69, 79))	('mutations', 'Var', (84, 93))	('MCT', 'Phenotype', 'HP:0100495', (51, 54))
550975	26566160	Preclinical murine xenograft models demonstrated that xenogeneic DNA vaccines with genes encoding melanosomal differentiation antigens can induce specific antibody and cytotoxic T-cell responses against syngeneic tumor cells.	('cytotoxic T-cell responses', 'CPA', (168, 194))	('antibody', 'CPA', (155, 163))	('murine', 'Species', '10090', (12, 18))	('syngeneic tumor', 'Disease', (203, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('induce', 'PosReg', (139, 145))	('genes', 'Var', (83, 88))	('syngeneic tumor', 'Disease', 'MESH:D009369', (203, 218))
550983	26566160	Selinexor (KPT-330) and verdinexor (KPT-335) are orally bioavailable small molecule selective inhibitors of nuclear export that reversibly block XPO1 function.	('function', 'MPA', (150, 158))	('verdinexor', 'Chemical', 'MESH:C000593855', (24, 34))	('XPO1', 'Gene', '474609', (145, 149))	('KPT-335', 'Var', (36, 43))	('KPT-335', 'Chemical', 'MESH:C000593855', (36, 43))	('nuclear export', 'MPA', (108, 122))	('Selinexor', 'Chemical', 'MESH:C585161', (0, 9))	('block', 'NegReg', (139, 144))	('KPT-330', 'Chemical', 'MESH:C585161', (11, 18))	('XPO1', 'Gene', (145, 149))
551080	26115508	The phenotypic enumeration of circulating endothelial progenitor cells in that study involved CD146+, CD31+, CD45-, and CD133+ cells.	('CD45', 'Gene', (109, 113))	('CD31', 'Gene', (102, 106))	('CD14', 'Gene', (94, 98))	('CD31', 'Gene', '5175', (102, 106))	('CD14', 'Gene', '929', (94, 98))	('CD133+ cells', 'Var', (120, 132))	('CD45', 'Gene', '5788', (109, 113))
551103	26076995	In the 14 patients with KS, heterozygosity of the HUMARA gene was observed in 12 (85.7%) cases.	('HUMARA', 'Gene', (50, 56))	('observed', 'Reg', (66, 74))	('heterozygosity', 'Var', (28, 42))	('patients', 'Species', '9606', (10, 18))	('HUMARA', 'Gene', '367', (50, 56))
551157	26076995	Among various methods in clonality analysis, X chromosome inactivation analysis is the best for tumor clonality analysis.	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (96, 101))	('X chromosome inactivation analysis', 'Var', (45, 79))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))
551164	26076995	In heterozygous females, the paternal and maternal X-chromosome sequences can be distinguished by the CAG repeat polymorphism, and the active and inactive allele can also be distinguished by the methylation status.	('polymorphism', 'Var', (113, 125))	('CAG repeat polymorphism', 'Var', (102, 125))	('CAG', 'Chemical', '-', (102, 105))
551166	26076995	Random distribution of the PGK-1BstXI polymorphism becomes a detection marker of X-chromosome inactivation.	('PGK-1', 'Gene', '5230', (27, 32))	('PGK-1', 'Gene', (27, 32))	('polymorphism', 'Var', (38, 50))
551210	22615950	GLV-1h68 showed potent anticancer efficacy in many different human tumor xenograft models, including human breast cancer, anaplastic thyroid carcinoma, malignant pleural mesothelioma, pancreatic tumor, hepatocellular carcinoma (HCC), prostate carcinoma, and squamous cell carcinoma.	('pancreatic tumor', 'Disease', (184, 200))	('tumor', 'Disease', (195, 200))	('prostate carcinoma', 'Disease', 'MESH:D011472', (234, 252))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (258, 281))	('pancreatic tumor', 'Disease', 'MESH:D010190', (184, 200))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', (67, 72))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (234, 252))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (202, 226))	('squamous cell carcinoma', 'Disease', (258, 281))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (152, 182))	('anaplastic thyroid carcinoma', 'Disease', (122, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('GLV-1h68', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (202, 226))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('prostate carcinoma', 'Disease', (234, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('GLV-1h68', 'Species', '502057', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('human', 'Species', '9606', (101, 106))	('breast cancer', 'Disease', (107, 120))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (162, 182))	('human', 'Species', '9606', (61, 66))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (184, 200))	('hepatocellular carcinoma', 'Disease', (202, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (122, 150))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (122, 150))	('malignant pleural mesothelioma', 'Disease', (152, 182))	('cancer', 'Disease', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('cancer', 'Disease', (114, 120))
551238	22615950	The sequence analysis of LIVP1.1.1 revealed the presence of different mutations in several genes including that of thymidine kinase (Chen et al manuscript in preparation).	('rat', 'Species', '10116', (163, 166))	('mutations', 'Var', (70, 79))	('thymidine kinase', 'MPA', (115, 131))
551263	22615950	After that, the cells were incubated at 4 C for 10 min in PBS with 2% FCS in the presence of appropriate dilutions of labeled monoclonal antibodies: anti-mouse MHCII-PE (Clone M5, eBioscience, San Diego, CA, USA), anti-CD11b-PerCPCy5.5 (Clone M1/70, eBioscience), anti-CD11c-APC (Clone N418, BioLegend, San Diego, USA), anti-CD49b-APC (Clone DX5, BioLegend), anti-CD19-PerCP-Cy5.5 (Clone 6D5, BioLegend), anti-F4/80-APC (Clone BM8, eBioscience), anti-Ly-6G-PE (Clone 1A8, BD Biosciences) and anti-CD45-PerCP (Clone 30-F11, BD Biosciences).	('mouse', 'Species', '10090', (154, 159))	('anti-F4/80-APC', 'Var', (405, 419))	('San', 'Gene', (303, 306))	('CD11b', 'Gene', '3684', (219, 224))	('San', 'Gene', (193, 196))	('CD11b', 'Gene', (219, 224))	('anti-CD45-PerCP', 'Var', (492, 507))	('Ly-6G', 'Gene', '546644', (451, 456))	('Ly-6G', 'Gene', (451, 456))	('CD11c', 'Gene', '3687', (269, 274))	('PBS', 'Chemical', '-', (58, 61))	('CD11c', 'Gene', (269, 274))	('CD49b', 'Gene', '3673', (325, 330))	('anti-CD19-PerCP-Cy5.5', 'Var', (359, 380))	('San', 'Gene', '72117', (303, 306))	('San', 'Gene', '72117', (193, 196))	('CD49b', 'Gene', (325, 330))
551285	22615950	In addition, we found significant differences from titers of LIVP1.1.1 compared with GLV-1h68 at 24 hpvi (***P<0.001) and 48 hpvi (**P<0.01) as well as at 96 hpvi (*P<0.05).	('LIVP1.1.1', 'Var', (61, 70))	('differences', 'Reg', (34, 45))	('GLV-1h68', 'Species', '502057', (85, 93))
551294	22615950	These data indicated that LIVP1.1.1 had a higher oncolytic potential than GLV-1h68 against canine soft tissue sarcoma xenografts.	('LIVP1.1.1', 'Var', (26, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (98, 117))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (98, 117))	('higher', 'PosReg', (42, 48))	('canine', 'Species', '9615', (91, 97))	('soft tissue sarcoma', 'Disease', (98, 117))	('oncolytic potential', 'CPA', (49, 68))	('GLV-1h68', 'Species', '502057', (74, 82))
551308	22615950	At the same time point, we also found plaque forming units in some organs of mice injected with LIVP1.1.1 but not with GLV-1h68 (Fig.	('GLV-1h68', 'Species', '502057', (119, 127))	('mice', 'Species', '10090', (77, 81))	('LIVP1.1.1', 'Var', (96, 105))	('plaque forming units', 'CPA', (38, 58))
551314	22615950	The numbers of all tested CD11b-, MHCII-, CD19-, CD45-, F4/80-, Ly6G high, CD11c- and CD49b-positive immune cells were higher in cell suspensions derived from virus-infected tumors compared to that from uninfected controls (Table 2; ratios greater than 1).	('CD11c', 'Gene', (75, 80))	('CD11c', 'Gene', '3687', (75, 80))	('CD49b', 'Gene', '3673', (86, 91))	('Ly6G', 'Gene', (64, 68))	('CD49b', 'Gene', (86, 91))	('higher', 'PosReg', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('virus-infected tumors', 'Disease', 'MESH:D014412', (159, 180))	('CD45-', 'Var', (49, 54))	('rat', 'Species', '10116', (233, 236))	('F4/80-', 'Var', (56, 62))	('CD11b', 'Gene', '3684', (26, 31))	('Ly6G', 'Gene', '546644', (64, 68))	('virus-infected tumors', 'Disease', (159, 180))	('CD19-', 'Var', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('CD11b', 'Gene', (26, 31))
551319	22615950	7A there was approximately 6.6-42.1 fold higher accumulation of neutrophils in the LIVP1.1.1-treated tumors compared to GLV-1h68- and PBS-treated tumors (**P = 0.0075; **P = 0.0026), respectively.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('GLV-1h68', 'Species', '502057', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('LIVP1.1.1-treated', 'Var', (83, 100))	('higher accumulation', 'PosReg', (41, 60))	('PBS-treated tumors', 'Disease', 'MESH:D011535', (134, 152))	('PBS-treated tumors', 'Disease', (134, 152))	('tumors', 'Disease', (146, 152))	('tumors', 'Disease', (101, 107))
551329	22615950	In this experimental setting, however, there was no significant difference between the fluorescence intensity of vessel-related pixels of LIPV1.1.1- and GLV-1h68-tumors (P = 0.0351).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('GLV-1h68-tumors', 'Disease', 'MESH:D009369', (153, 168))	('fluorescence', 'MPA', (87, 99))	('GLV-1h68-tumors', 'Disease', (153, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('LIPV1.1.1-', 'Var', (138, 148))
551330	22615950	By immunohistolchemistry we analyzed tissue sections of primary tumors of STSA-1 tumor bearing mice injected with LIVP1.1.1, GLV-1h68 or PBS at 21 dpvi (Fig.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Disease', (64, 69))	('mice', 'Species', '10090', (95, 99))	('primary tumors', 'Disease', (56, 70))	('primary tumors', 'Disease', 'MESH:D009369', (56, 70))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('dpvi', 'Chemical', '-', (147, 151))	('GLV-1h68', 'Species', '502057', (125, 133))	('PBS', 'Chemical', '-', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('LIVP1.1.1', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (81, 86))
551332	22615950	The single injection with LIVP1.1.1 or GLV-1h68 led to similar specific intratumoral infiltration of these host cells in the tumor tissue (Fig.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('rat', 'Species', '10116', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('rat', 'Species', '10116', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('GLV-1h68', 'Var', (39, 47))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumoral infiltration', 'Disease', (77, 97))	('GLV-1h68', 'Species', '502057', (39, 47))	('tumor', 'Disease', (77, 82))	('tumoral infiltration', 'Disease', 'MESH:D017254', (77, 97))
551347	22615950	The current study also demonstrated the suitability of LIVP1.1.1 and GLV-1h68, to achieve a significant inhibition of tumor growth and damage of tumor tissues in the tumor-bearing mice when compared to PBS controls.	('GLV-1h68', 'Var', (69, 77))	('inhibition', 'NegReg', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('GLV-1h68', 'Species', '502057', (69, 77))	('tumor', 'Disease', (166, 171))	('rat', 'Species', '10116', (30, 33))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (118, 123))	('PBS', 'Chemical', '-', (202, 205))	('mice', 'Species', '10090', (180, 184))	('LIVP1.1.1', 'Var', (55, 64))	('damage', 'CPA', (135, 141))
551348	22615950	We also found that LIVP1.1.1 had a higher oncolytic potential than GLV-1h68 in these experimental settings.	('oncolytic potential', 'CPA', (42, 61))	('GLV-1h68', 'Species', '502057', (67, 75))	('higher', 'PosReg', (35, 41))	('LIVP1.1.1', 'Var', (19, 28))
551355	22615950	This fact could be evidence that the LIVP1.1.1 was either less tumor-specific or more virulent in mice compared to GLV-1h68.	('LIVP1.1.1', 'Var', (37, 46))	('tumor', 'Disease', (63, 68))	('more', 'PosReg', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('GLV-1h68', 'Species', '502057', (115, 123))	('mice', 'Species', '10090', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('virulent', 'MPA', (86, 94))	('less', 'NegReg', (58, 62))
551358	22615950	Moreover, we have demonstrated that GLV-1h68 is a highly tumor- and metastases-selective.	('GLV-1h68', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('GLV-1h68', 'Species', '502057', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('rat', 'Species', '10116', (25, 28))	('metastases', 'Disease', (68, 78))	('tumor', 'Disease', (57, 62))	('metastases', 'Disease', 'MESH:D009362', (68, 78))
551362	22615950	Our survival experiment revealed a significantly longer survival (P = 0.0039) of the LIVP1.1.1-treated mice compared to the PBS-treated animals.	('PBS', 'Chemical', '-', (124, 127))	('LIVP1.1.1-treated', 'Var', (85, 102))	('mice', 'Species', '10090', (103, 107))	('longer', 'PosReg', (49, 55))	('survival', 'CPA', (56, 64))
551375	22615950	In addition, the number of neutrophils in LIVP1.1.1 infected tumors was significantly higher than that in GLV-1h68 tumors.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('infected tumors', 'Disease', (52, 67))	('GLV-1h68', 'Species', '502057', (106, 114))	('infected tumors', 'Disease', 'MESH:D009369', (52, 67))	('tumors', 'Disease', (115, 121))	('LIVP1.1.1', 'Var', (42, 51))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('higher', 'PosReg', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
551376	22615950	On the basis of these data, we assume that the stronger anti-tumor effect of LIVP1.1.1 in comparison to GLV-1h68 could be dependent on the increased number of neutrophils in the tumor bed.	('LIVP1.1.1', 'Var', (77, 86))	('tumor', 'Disease', (178, 183))	('stronger', 'PosReg', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('GLV-1h68', 'Species', '502057', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (61, 66))
551388	30559927	Ewing sarcoma resistance to SP-2509 is not mediated through KDM1A/LSD1 mutation Ewing sarcoma is the second most common solid bone malignancy diagnosed in pediatric and young adolescent populations.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('bone malignancy', 'Phenotype', 'HP:0010622', (126, 141))	('LSD1', 'Gene', (66, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('mutation', 'Var', (71, 79))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('KDM1A', 'Gene', '23028', (60, 65))	('LSD1', 'Gene', '23028', (66, 70))	('Ewing sarcoma', 'Disease', (0, 13))	('malignancy', 'Disease', 'MESH:D009369', (131, 141))	('SP-2509', 'Chemical', 'MESH:C000594309', (28, 35))	('malignancy', 'Disease', (131, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('KDM1A', 'Gene', (60, 65))	('Ewing sarcoma', 'Disease', (80, 93))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
551392	30559927	Surprisingly, whole exome sequencing analysis of our generated A673 SP-2509 drug resistant cell line revealed an absence of mutations in KDM1A.	('KDM1A', 'Gene', (137, 142))	('SP-2509', 'Chemical', 'MESH:C000594309', (68, 75))	('mutations', 'Var', (124, 133))	('absence', 'NegReg', (113, 120))	('KDM1A', 'Gene', '23028', (137, 142))
551394	30559927	SP-2509 drug resistant cells also exhibited elevated expression levels of the multi-drug resistance genes ABCB1, ABCC3, and ABBC5 and decreased expression of the transcriptional repressor RCOR1/CoREST.	('decreased', 'NegReg', (134, 143))	('ABCC3', 'Gene', (113, 118))	('elevated', 'PosReg', (44, 52))	('ABCC3', 'Gene', '8714', (113, 118))	('SP-2509', 'Chemical', 'MESH:C000594309', (0, 7))	('expression', 'MPA', (144, 154))	('ABCB1', 'Gene', (106, 111))	('RCOR1', 'Gene', '23186', (188, 193))	('ABCB1', 'Gene', '5243', (106, 111))	('CoREST', 'Gene', '23186', (194, 200))	('RCOR1', 'Gene', (188, 193))	('CoREST', 'Gene', (194, 200))	('ABBC5', 'Gene', (124, 129))	('drug resistance', 'Phenotype', 'HP:0020174', (84, 99))	('expression levels', 'MPA', (53, 70))	('SP-2509', 'Var', (0, 7))
551397	30559927	Together these findings indicate that resistance to SP-2509 is not fully reversible or driven by direct mutation in KDM1A.	('KDM1A', 'Gene', '23028', (116, 121))	('SP-2509', 'Chemical', 'MESH:C000594309', (52, 59))	('mutation', 'Var', (104, 112))	('KDM1A', 'Gene', (116, 121))
551399	30559927	The unifying genetic trait of this highly aggressive cancer is a reciprocal chromosomal translocation that fuses the EWSR1 gene with members of the ETS family of transcription factors, most commonly FLI1 (85% of cases).	('FLI1', 'Gene', (199, 203))	('EWSR1', 'Gene', (117, 122))	('cancer', 'Disease', (53, 59))	('FLI1', 'Gene', '2313', (199, 203))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('EWSR1', 'Gene', '2130', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('fuses', 'Var', (107, 112))
551420	30559927	Indeed, following prolonged continuous treatment for seven months, a 55.0 fold increase in SP-2509 concentration was required to reduce the viability of generated A673 SP-2509 DR cells compared to parental controls (IC50: 0.138 muM versus 7.586 muM) by 50% (Figure 1A).	('reduce', 'NegReg', (129, 135))	('SP-2509', 'Chemical', 'MESH:C000594309', (168, 175))	('A673 SP-2509 DR', 'Var', (163, 178))	('muM', 'Gene', '56925', (228, 231))	('muM', 'Gene', '56925', (245, 248))	('SP-2509', 'Chemical', 'MESH:C000594309', (91, 98))	('muM', 'Gene', (228, 231))	('muM', 'Gene', (245, 248))
551422	30559927	Treatment of A673 parental cells with doses of SP-2509 as low as 0.250 muM significantly reduced their proliferative capacity and induced apoptosis as evidenced through caspase 3/7 induction.	('muM', 'Gene', (71, 74))	('SP-2509', 'Chemical', 'MESH:C000594309', (47, 54))	('induced', 'Reg', (130, 137))	('caspase 3', 'Gene', (169, 178))	('caspase 3', 'Gene', '836', (169, 178))	('SP-2509', 'Var', (47, 54))	('apoptosis', 'CPA', (138, 147))	('reduced', 'NegReg', (89, 96))	('muM', 'Gene', '56925', (71, 74))	('proliferative capacity', 'CPA', (103, 125))
551423	30559927	In contrast, diminished proliferative capacity of SP-2509 DR cells was only observed at SP-2509 concentrations exceeding 4 muM, with apoptotic cytotoxicity only observed at 10 muM (Figure 1D, 1E).	('muM', 'Gene', (123, 126))	('cytotoxicity', 'Disease', (143, 155))	('diminished', 'NegReg', (13, 23))	('muM', 'Gene', '56925', (176, 179))	('proliferative capacity', 'CPA', (24, 46))	('SP-2509', 'Var', (88, 95))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('muM', 'Gene', (176, 179))	('muM', 'Gene', '56925', (123, 126))	('SP-2509', 'Chemical', 'MESH:C000594309', (50, 57))	('SP-2509', 'Chemical', 'MESH:C000594309', (88, 95))
551424	30559927	We previously showed that SP-2509 treatment significantly decreases both KDM1A mRNA and protein levels in Ewing sarcoma cells.	('decreases', 'NegReg', (58, 67))	('SP-2509', 'Var', (26, 33))	('SP-2509', 'Chemical', 'MESH:C000594309', (26, 33))	('Ewing sarcoma cells', 'Disease', 'MESH:C563168', (106, 125))	('KDM1A', 'Gene', (73, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('KDM1A', 'Gene', '23028', (73, 78))	('Ewing sarcoma cells', 'Disease', (106, 125))
551425	30559927	Correspondingly, A673 SP-2509 DR cells showed a 30.9% and 25.9% basal decrease in KDM1A mRNA and protein respectively.	('KDM1A', 'Gene', '23028', (82, 87))	('A673 SP-2509 DR', 'Var', (17, 32))	('KDM1A', 'Gene', (82, 87))	('decrease', 'NegReg', (70, 78))	('SP-2509', 'Chemical', 'MESH:C000594309', (22, 29))
551428	30559927	Following 72 hrs of drug exposure, SP-2509 DR A673 cells exhibited a 2.6 and 3.0 fold decreased sensitivity to doxorubicin (P = 0.005) and vincristine (P = 0.004) respectively, with sensitivity to etoposide maintained (Figure 2).	('sensitivity', 'MPA', (96, 107))	('SP-2509', 'Chemical', 'MESH:C000594309', (35, 42))	('decreased', 'NegReg', (86, 95))	('etoposide', 'Chemical', 'MESH:D005047', (197, 206))	('SP-2509 DR', 'Var', (35, 45))	('doxorubicin', 'Chemical', 'MESH:D004317', (111, 122))	('vincristine', 'Chemical', 'MESH:D014750', (139, 150))
551433	30559927	To address whether resistance to SP-2509 is a direct consequence of acquired mutations in KDM1A, sanger sequencing of all 19 exons of KDM1A was performed.	('KDM1A', 'Gene', (90, 95))	('KDM1A', 'Gene', '23028', (134, 139))	('mutations', 'Var', (77, 86))	('KDM1A', 'Gene', (134, 139))	('SP-2509', 'Chemical', 'MESH:C000594309', (33, 40))	('KDM1A', 'Gene', '23028', (90, 95))
551435	30559927	To establish whether resistance can be attributed to mutation in other key KDM1A interacting partners, A673 SP-2509 DR and parental cells were subjected to 250X whole exome sequencing (WES).	('SP-2509', 'Chemical', 'MESH:C000594309', (108, 115))	('KDM1A', 'Gene', (75, 80))	('mutation', 'Var', (53, 61))	('KDM1A', 'Gene', '23028', (75, 80))
551436	30559927	Twenty-three mutations were identified specifically in the SP-2509 DR population, with no aberrations in KDM1A or its interacting partners (CoREST, NuRD, HDAC) observed (Table 1).	('CoREST', 'Gene', (140, 146))	('KDM1A', 'Gene', '23028', (105, 110))	('SP-2509', 'Chemical', 'MESH:C000594309', (59, 66))	('SP-2509 DR', 'Var', (59, 69))	('KDM1A', 'Gene', (105, 110))	('CoREST', 'Gene', '23186', (140, 146))
551439	30559927	A second stop-gain mutation in MRPS10 (mitochondrial ribosomal protein S10) (Glu146*) which encodes the 28S subunit protein was also observed in 35.6% of the SP-2509 DR cell population.	('Glu146', 'Chemical', '-', (77, 83))	('SP-2509', 'Chemical', 'MESH:C000594309', (158, 165))	('MRPS10', 'Gene', (31, 37))	('ribosomal protein S10', 'Gene', (53, 74))	('MRPS10', 'Gene', '55173', (31, 37))	('Glu146*', 'Var', (77, 84))	('ribosomal protein S10', 'Gene', '6204', (53, 74))
551441	30559927	As resistance to SP-2509 was not mediated through mutation in KDM1A, we next addressed whether SP-2509 drug resistance is attributed to a specific transcriptional signature.	('KDM1A', 'Gene', (62, 67))	('SP-2509', 'Chemical', 'MESH:C000594309', (17, 24))	('SP-2509', 'Var', (95, 102))	('drug resistance', 'Phenotype', 'HP:0020174', (103, 118))	('KDM1A', 'Gene', '23028', (62, 67))	('SP-2509', 'Chemical', 'MESH:C000594309', (95, 102))
551451	30559927	IPA of the cohort of induced genes modulated by SP-2509 in DR cells revealed enrichment for the following five pathways, netrin signaling (P = 3.52 x 105), phenylalanine degradation IV (P = 2.84 x 105), serine biosynthesis (P = 8.81 x 104), AMPK signaling (P = 1.07 x 104) and xenobiotic metabolism signaling (P = 1.44 x 103) (Supplementary Figure 1).	('serine biosynthesis', 'MPA', (203, 222))	('SP-2509', 'Var', (48, 55))	('xenobiotic metabolism', 'Disease', (277, 298))	('serine', 'Chemical', 'MESH:D012694', (203, 209))	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (277, 298))	('phenylalanine', 'Chemical', 'MESH:D010649', (156, 169))	('AMPK signaling', 'MPA', (241, 255))	('SP-2509', 'Chemical', 'MESH:C000594309', (48, 55))	('phenylalanine degradation IV', 'MPA', (156, 184))	('netrin signaling', 'MPA', (121, 137))
551452	30559927	This suggests that SP-2509 is unable to induce cytotoxic effects in DR cells due to the loss of ER stress response engagement.	('SP-2509', 'Chemical', 'MESH:C000594309', (19, 26))	('SP-2509', 'Var', (19, 26))	('ER stress response engagement', 'MPA', (96, 125))	('loss', 'NegReg', (88, 92))
551454	30559927	From our RNA-Seq analysis we next addressed whether SP-2509 drug resistance can be attributed to overexpression of these transporters.	('overexpression', 'PosReg', (97, 111))	('drug resistance', 'Phenotype', 'HP:0020174', (60, 75))	('SP-2509', 'Chemical', 'MESH:C000594309', (52, 59))	('SP-2509', 'Var', (52, 59))
551455	30559927	Basal expression of ABCB1, ABCC3 and ABBC5 was significantly higher in SP-2509 DR cells compared to parental A673 cells (19.2, 15.0 and 14.3 fold increase).	('SP-2509 DR', 'Var', (71, 81))	('ABCC3', 'Gene', (27, 32))	('increase', 'PosReg', (146, 154))	('higher', 'PosReg', (61, 67))	('expression', 'MPA', (6, 16))	('ABCB1', 'Gene', (20, 25))	('ABCB1', 'Gene', '5243', (20, 25))	('ABCC3', 'Gene', '8714', (27, 32))	('SP-2509', 'Chemical', 'MESH:C000594309', (71, 78))	('ABBC5', 'Gene', (37, 42))
551456	30559927	In contrast, expression of ABCC4 which is implicated in the transport of antiviral agents and endogenous molecules was significantly decreased (4.5 fold) in SP-2509 DR cells (Figure 3E).	('SP-2509', 'Chemical', 'MESH:C000594309', (157, 164))	('expression', 'MPA', (13, 23))	('ABCC4', 'Gene', (27, 32))	('SP-2509', 'Var', (157, 164))	('ABCC4', 'Gene', '10257', (27, 32))	('decreased', 'NegReg', (133, 142))
551463	30559927	Furthermore, SP-2509 DR-washout cells were significantly impaired in their ability to form colonies in soft agar, across all time points (Figure 4D).	('SP-2509 DR-washout', 'Var', (13, 31))	('agar', 'Chemical', 'MESH:D000362', (108, 112))	('SP-2509', 'Chemical', 'MESH:C000594309', (13, 20))	('impaired', 'NegReg', (57, 65))
551466	30559927	SP-2509 DR-washout cells were significantly impaired in their ability to close the scratch wound by 75% (24.1 versus 46.1 hrs respectively) (P = 0.002) (Figure 4E).	('SP-2509', 'Chemical', 'MESH:C000594309', (0, 7))	('impaired', 'NegReg', (44, 52))	('SP-2509 DR-washout', 'Var', (0, 18))
551468	30559927	As such, microscopic evaluation of SP-2509 DR cells revealed a distinct morphological change compared to parental A673 cells.	('morphological change', 'CPA', (72, 92))	('SP-2509', 'Chemical', 'MESH:C000594309', (35, 42))	('SP-2509', 'Var', (35, 42))
551470	30559927	Indeed, quantification of cell size revealed a 52.2% increase in cell length upon acquisition of SP-2509 DR (P < 0.0001) (Supplementary Figure 3A).	('SP-2509 DR', 'Var', (97, 107))	('increase', 'PosReg', (53, 61))	('cell length', 'CPA', (65, 76))	('SP-2509', 'Chemical', 'MESH:C000594309', (97, 104))
551472	30559927	Within 4 days of SP-2509 removal a 34.5% decrease in cell length between SP-2509 DR and washout cells was observed.	('SP-2509', 'Chemical', 'MESH:C000594309', (17, 24))	('decrease', 'NegReg', (41, 49))	('SP-2509', 'Chemical', 'MESH:C000594309', (73, 80))	('cell length', 'CPA', (53, 64))	('SP-2509 DR', 'Var', (73, 83))
551474	30559927	To confirm the mesenchymal-like state induced upon SP-2509 DR, 51 markers of EMT were assessed.	('SP-2509', 'Chemical', 'MESH:C000594309', (51, 58))	('EMT', 'Gene', (77, 80))	('mesenchymal-like state', 'CPA', (15, 37))	('EMT', 'Gene', '3702', (77, 80))	('SP-2509 DR', 'Var', (51, 61))
551485	30559927	Of these 43 mutations, 32 (74.4%) resulted in non-synonymous single nucleotide variants (SNP), with an A>T transversion in the extended intronic splice region of EQTN (Equatorin) occurring in 43.3% of the population.	('EQTN', 'Gene', '54586', (162, 166))	('mutations', 'Var', (12, 21))	('>T transversion', 'Var', (104, 119))	('resulted in', 'Reg', (34, 45))	('EQTN', 'Gene', (162, 166))	('Equatorin', 'Gene', (168, 177))	('Equatorin', 'Gene', '54586', (168, 177))
551487	30559927	The second and third highest ranking variants (non-synonymous SNP's) were both detected in EML4 (Echinoderm Microtubule Associated Protein Like 4), Q872R (32.9%), N873D (32.6%).	('N873D', 'Mutation', 'p.N873D', (163, 168))	('EML4', 'Gene', (91, 95))	('Echinoderm Microtubule Associated Protein Like 4', 'Gene', '27436', (97, 145))	('EML4', 'Gene', '27436', (91, 95))	('Echinoderm Microtubule Associated Protein Like 4', 'Gene', (97, 145))	('Q872R', 'Var', (148, 153))	('Q872R', 'Mutation', 'rs1231766466', (148, 153))	('N873D', 'Var', (163, 168))
551489	30559927	These results strengthen our previous WES findings that mutation of KDM1A does not drive resistance to KDM1A blockade.	('KDM1A', 'Gene', (103, 108))	('KDM1A', 'Gene', '23028', (68, 73))	('KDM1A', 'Gene', '23028', (103, 108))	('mutation', 'Var', (56, 64))	('KDM1A', 'Gene', (68, 73))
551498	30559927	In comparison to SP-2509 DR-washout cells (4 and 6 months) 3851 and 4269 genes were significantly induced/repressed respectively in SP-2509 DR cells.	('induced/repressed', 'PosReg', (98, 115))	('SP-2509', 'Chemical', 'MESH:C000594309', (132, 139))	('SP-2509 DR', 'Var', (132, 142))	('SP-2509', 'Chemical', 'MESH:C000594309', (17, 24))
551500	30559927	Together these results highlight that SP-2509 resistance is not mediated through mutation, but through upregulation of multi-drug resistance genes and the generation of a non-reversible transcriptional profile that is maintained even post drug withdrawal.	('upregulation', 'PosReg', (103, 115))	('multi-drug resistance genes', 'MPA', (119, 146))	('drug resistance', 'Phenotype', 'HP:0020174', (125, 140))	('SP-2509', 'Chemical', 'MESH:C000594309', (38, 45))	('non-reversible transcriptional profile', 'MPA', (171, 209))	('SP-2509', 'Var', (38, 45))
551508	30559927	Studies have also shown that decreased catalase expression can be attributed to loss of heterozygosity, deletion of chromosome 11, phosphorylation of Tyr231 and Tyr386 and DNA hypermethylation.	('Tyr386', 'Var', (161, 167))	('loss', 'NegReg', (80, 84))	('Tyr231', 'Var', (150, 156))	('expression', 'MPA', (48, 58))	('Tyr386', 'Chemical', '-', (161, 167))	('decreased', 'NegReg', (29, 38))	('DNA hypermethylation', 'Var', (172, 192))	('phosphorylation', 'MPA', (131, 146))	('catalase', 'Gene', (39, 47))	('decreased catalase expression', 'Phenotype', 'HP:0012517', (29, 58))	('deletion', 'Var', (104, 112))	('Tyr231', 'Chemical', '-', (150, 156))	('catalase', 'Gene', '847', (39, 47))
551512	30559927	Interestingly, when only comparing SP-2509 DR-washout cohorts, a 74.8% (1876 genes) and 74.3% (2025 genes) overlap in up/down-regulated genes was observed, strongly supporting that SP-2509 drug resistance is mediated through acquisition of a fixed non-reversible epigenetic state (Supplementary Figure 4A, 4B).	('SP-2509', 'Chemical', 'MESH:C000594309', (181, 188))	('drug resistance', 'Phenotype', 'HP:0020174', (189, 204))	('SP-2509', 'Chemical', 'MESH:C000594309', (35, 42))	('SP-2509', 'Var', (181, 188))	('drug resistance', 'MPA', (189, 204))
551525	30559927	Together, these results may suggest that SP-2509 drug resistance is mediated through alteration of key EWS/FLI transcriptional co-repressor complexes leading to epigenetic fixation and cellular differentiation away from the traditional Ewing sarcoma cellular phenotype.	('Ewing sarcoma', 'Disease', (236, 249))	('EWS', 'Gene', (103, 106))	('mediated', 'Reg', (68, 76))	('EWS', 'Gene', '2130', (103, 106))	('drug resistance', 'Phenotype', 'HP:0020174', (49, 64))	('cellular differentiation', 'CPA', (185, 209))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (236, 249))	('epigenetic fixation', 'Var', (161, 180))	('SP-2509', 'Chemical', 'MESH:C000594309', (41, 48))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (236, 249))	('FLI', 'Gene', '2314', (107, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('alteration', 'Reg', (85, 95))	('SP-2509', 'Var', (41, 48))	('FLI', 'Gene', (107, 110))
551533	30559927	Several drug resistant features were revealed, most importantly that resistance to SP-2509 is not mutational in nature as aberrations in KDM1A itself were not observed.	('KDM1A', 'Gene', (137, 142))	('SP-2509', 'Chemical', 'MESH:C000594309', (83, 90))	('SP-2509', 'Var', (83, 90))	('KDM1A', 'Gene', '23028', (137, 142))
551535	30559927	Interestingly, KDM1A has been shown to coordinate glycolytic metabolism through direct suppression of mitochondrial metabolism genes via H3K4 demethylation.	('glycolytic metabolism', 'MPA', (50, 71))	('KDM1A', 'Gene', '23028', (15, 20))	('suppression', 'NegReg', (87, 98))	('H3K4', 'Protein', (137, 141))	('KDM1A', 'Gene', (15, 20))	('mitochondrial', 'MPA', (102, 115))	('demethylation', 'Var', (142, 155))
551540	30559927	Following drug washout, high level resistance to SP-2509 (IC50 > 2 muM) was maintained for a minimum of 4 months, with residual low level resistant cells displaying the same transcriptomic profile of both SP-2509 drug resistant and high level resistant washout counterparts.	('SP-2509', 'Var', (205, 212))	('SP-2509', 'Chemical', 'MESH:C000594309', (49, 56))	('muM', 'Gene', '56925', (67, 70))	('muM', 'Gene', (67, 70))	('SP-2509', 'Chemical', 'MESH:C000594309', (205, 212))
551541	30559927	Finally, we show that SP-2509 DR and washout cells significantly down-regulate RCOR1, a key member of the REST complex required for EWS/FLI mediated transcriptional repression.	('FLI', 'Gene', '2314', (136, 139))	('SP-2509 DR', 'Var', (22, 32))	('EWS', 'Gene', (132, 135))	('EWS', 'Gene', '2130', (132, 135))	('RCOR1', 'Gene', '23186', (79, 84))	('FLI', 'Gene', (136, 139))	('RCOR1', 'Gene', (79, 84))	('down-regulate', 'NegReg', (65, 78))	('SP-2509', 'Chemical', 'MESH:C000594309', (22, 29))
551542	30559927	Together, these findings support the intriguing possibility that resistance to epigenetic inhibitors such as SP-2509 is mediated through epigenetic, and not mutational means.	('SP-2509', 'Gene', (109, 116))	('mediated', 'Reg', (120, 128))	('epigenetic', 'Var', (137, 147))	('epigenetic', 'Var', (79, 89))	('SP-2509', 'Chemical', 'MESH:C000594309', (109, 116))	('resistance', 'MPA', (65, 75))
551543	30559927	Several groups have highlighted the emerging role of epigenetic reprogramming in Ewing sarcoma.	('Ewing sarcoma', 'Disease', (81, 94))	('epigenetic', 'Var', (53, 63))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))
551545	30559927	Inhibition of KDM1A either through genetic depletion (shRNA) or small molecule blockade (SP-2509), reverses the EWS/ETS-driven transcriptional signature in Ewing sarcoma.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (156, 169))	('SP-2509', 'Chemical', 'MESH:C000594309', (89, 96))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (156, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('genetic depletion', 'Var', (35, 52))	('EWS', 'Gene', (112, 115))	('reverses', 'NegReg', (99, 107))	('EWS', 'Gene', '2130', (112, 115))	('KDM1A', 'Gene', '23028', (14, 19))	('Ewing sarcoma', 'Disease', (156, 169))	('KDM1A', 'Gene', (14, 19))
551548	30559927	The emergence of epigenetic dysregulation and reprogramming in Ewing sarcoma development is likely linked to the biophysical and biochemical properties of the EWS portion of EWS/FLI itself.	('EWS', 'Gene', '2130', (159, 162))	('EWS', 'Gene', (159, 162))	('FLI', 'Gene', '2314', (178, 181))	('epigenetic dysregulation', 'Var', (17, 41))	('FLI', 'Gene', (178, 181))	('reprogramming', 'CPA', (46, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Ewing sarcoma', 'Disease', (63, 76))	('EWS', 'Gene', '2130', (174, 177))	('EWS', 'Gene', (174, 177))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))
551557	30559927	In this model we hypothesize that KDM1A inhibition serves to disrupt the chromatin landscape within the cell, ultimately leading to epigenetic reprogramming.	('KDM1A', 'Gene', (34, 39))	('chromatin landscape', 'MPA', (73, 92))	('inhibition', 'Var', (40, 50))	('epigenetic reprogramming', 'CPA', (132, 156))	('KDM1A', 'Gene', '23028', (34, 39))	('disrupt', 'Reg', (61, 68))	('leading to', 'Reg', (121, 131))
551565	30559927	Similarly, the transcriptional signature induced by SP-2509 varies considerably.	('transcriptional signature', 'MPA', (15, 40))	('SP-2509', 'Chemical', 'MESH:C000594309', (52, 59))	('SP-2509', 'Var', (52, 59))
551573	30559927	In summary, our SP-2509 drug resistance data and proposed speculative model suggests a broad role for epigenetic inhibitors/modulators as cancer therapeutics.	('cancer', 'Disease', (138, 144))	('drug resistance', 'Phenotype', 'HP:0020174', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('epigenetic inhibitors/modulators', 'Var', (102, 134))	('SP-2509', 'Chemical', 'MESH:C000594309', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
551576	30559927	We would suggest that any cancer that has a high dependence on epigenetic reprogramming such as pediatric cancers associated with fusion oncoproteins, might be uniquely sensitive to disruption of chromatin state via long term epigenetic inhibition.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('pediatric cancers', 'Disease', 'MESH:D009369', (96, 113))	('cancer', 'Disease', (106, 112))	('associated', 'Reg', (114, 124))	('pediatric cancers', 'Disease', (96, 113))	('sensitive', 'Reg', (169, 178))	('epigenetic inhibition', 'Var', (226, 247))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
551592	30559927	Sequence alignment, post alignment processing, variant calling and genotyping were performed with the Churchill pipeline, resulting in SNPs, INDELs and regions of copy number alteration and loss of heterozygosity using reference build GRCh37.	('SNPs', 'Var', (135, 139))	('Churchill', 'Species', '868862', (102, 111))	('INDELs', 'Var', (141, 147))	('copy number alteration', 'Var', (163, 185))	('loss', 'NegReg', (190, 194))
551593	30559927	The results were annotated with gene, transcript, variant effect, and numerous cancer-related databases including frequency in various cancer populations and disease association using SnpEff and custom in-house scripts.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('variant', 'Var', (50, 57))	('numerous cancer', 'Disease', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('numerous cancer', 'Disease', 'MESH:D009369', (70, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
551630	28947977	As a proof-of-concept of ENDOS/ADC activity in vitro, cell cycle analysis of ADC-treated SJSA-1 cells was evaluated and compared to cells treated with PBS.	('ADC-treated', 'Var', (77, 88))	('cell cycle', 'CPA', (54, 64))	('SJSA-1', 'CellLine', 'CVCL:1697', (89, 95))	('PBS', 'Chemical', '-', (151, 154))
551632	28947977	The induced mutation in SJSA-1 endosialin -/- cells was validated by genomic DNA sequencing and the absence of expression of endosialin was confirmed by FACS analysis and western blotting (Figure 2A-2B).	('SJSA-1', 'Gene', (24, 30))	('mutation', 'Var', (12, 20))	('SJSA-1', 'CellLine', 'CVCL:1697', (24, 30))
551675	28947977	Antibody variants were screened for antigen binding affinity by ELISA and FACS and lead candidate was selected and named hMP-E-8.3.	('variants', 'Var', (9, 17))	('hMP', 'Gene', '10989', (121, 124))	('hMP', 'Gene', (121, 124))
551730	28781648	The transcript levels of calcium channels may cause different domino effects on specific cell functions, as well as on cell proliferation, motility or even cell apoptosis.	('cell proliferation', 'CPA', (119, 137))	('transcript levels', 'Var', (4, 21))	('cell apoptosis', 'CPA', (156, 170))	('motility', 'CPA', (139, 147))	('cause', 'Reg', (46, 51))	('calcium', 'Chemical', 'MESH:D002118', (25, 32))
551733	28781648	These variations affect the abnormal activation of oncogenes and/or the inactivation of tumor suppressor genes, resulting in tumor formation and development.	('resulting in', 'Reg', (112, 124))	('oncogenes', 'Protein', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('variations', 'Var', (6, 16))	('activation', 'PosReg', (37, 47))	('tumor suppressor', 'Gene', (88, 104))	('inactivation', 'NegReg', (72, 84))	('tumor', 'Disease', (125, 130))	('tumor suppressor', 'Gene', '7248', (88, 104))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('development', 'CPA', (145, 156))	('affect', 'Reg', (17, 23))	('tumor', 'Disease', (88, 93))
551738	28781648	SIRT3 induced destabilization of hypoxia-inducible factor-1alpha, whereas knockdown of SIRT3 increased cancer cell growth and angiogenesis.	('SIRT3', 'Gene', '23410', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('SIRT3', 'Gene', (87, 92))	('increased', 'PosReg', (93, 102))	('destabilization', 'NegReg', (14, 29))	('knockdown', 'Var', (74, 83))	('angiogenesis', 'CPA', (126, 138))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (33, 64))	('hypoxia-inducible factor-1alpha', 'Gene', (33, 64))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('SIRT3', 'Gene', '23410', (0, 5))	('SIRT3', 'Gene', (0, 5))
551741	28781648	The blockage of T-type calcium channels in HCT116 cells was shown to inhibit cell development and promote apoptosis.	('promote', 'PosReg', (98, 105))	('apoptosis', 'CPA', (106, 115))	('T-type calcium channels', 'Protein', (16, 39))	('cell development', 'CPA', (77, 93))	('calcium', 'Chemical', 'MESH:D002118', (23, 30))	('inhibit', 'NegReg', (69, 76))	('blockage', 'Var', (4, 12))	('HCT116', 'CellLine', 'CVCL:0291', (43, 49))
551765	28781648	A mutation of these anti-oncogenes may affect cell proliferation, cell cycle and apoptosis, which is then likely to trigger the onset of a specific type of cancer.	('mutation', 'Var', (2, 10))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cell cycle', 'CPA', (66, 76))	('apoptosis', 'CPA', (81, 90))	('affect', 'Reg', (39, 45))	('trigger', 'Reg', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cell proliferation', 'CPA', (46, 64))
551766	28781648	In cancer tissues, abnormal cell growth is mainly caused by the inactivation or lack of tumor suppressor genes.	('inactivation', 'Var', (64, 76))	('abnormal cell growth', 'CPA', (19, 39))	('caused by', 'Reg', (50, 59))	('tumor suppressor', 'Gene', (88, 104))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('lack', 'NegReg', (80, 84))	('tumor suppressor', 'Gene', '7248', (88, 104))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
551773	28781648	A high expression of CASZ1 may interrupt the cancer development process of other types of tissue and play a role in their tumorigenesis.	('high expression', 'Var', (2, 17))	('role', 'Reg', (108, 112))	('play', 'Reg', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('CASZ1', 'Gene', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('interrupt', 'NegReg', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Disease', (45, 51))	('tumor', 'Disease', (122, 127))	('CASZ1', 'Gene', '54897', (21, 26))
551806	28781648	Collectively, our data suggested that alterations in CACNA1C expression may have an adverse effect on tissue homeostasis, which may result in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('result in', 'Reg', (132, 141))	('tumor', 'Disease', (142, 147))	('CACNA1C', 'Gene', '775', (53, 60))	('CACNA1C', 'Gene', (53, 60))	('tissue homeostasis', 'MPA', (102, 120))	('alterations', 'Var', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
551867	28781648	Variations in the CACNA1A gene have been well documented to result in certain neurological diseases, including familial hemiplegic migraine type 1, sporadic hemiplegic type 1 and spinocerebellar ataxia type 6.	('neurological diseases', 'Disease', (78, 99))	('ataxia', 'Phenotype', 'HP:0001251', (195, 201))	('spinocerebellar ataxia type', 'Disease', (179, 206))	('migraine', 'Phenotype', 'HP:0002076', (131, 139))	('familial hemiplegic migraine', 'Disease', (111, 139))	('CACNA1A', 'Gene', (18, 25))	('result in', 'Reg', (60, 69))	('Variations', 'Var', (0, 10))	('spinocerebellar ataxia type', 'Disease', 'MESH:D017827', (179, 206))	('sporadic hemiplegic type 1', 'Disease', (148, 174))	('familial hemiplegic migraine', 'Disease', 'MESH:D020325', (111, 139))	('neurological diseases', 'Disease', 'MESH:D019636', (78, 99))	('neurological disease', 'Phenotype', 'HP:0000707', (78, 98))	('CACNA1A', 'Gene', '773', (18, 25))
551894	28781648	Tumor suppressor gene changes result in the onset and progression of cancer.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('changes', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Tumor suppressor', 'Gene', '7248', (0, 16))	('result in', 'Reg', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('Tumor suppressor', 'Gene', (0, 16))	('cancer', 'Disease', (69, 75))
551904	28505004	A Subset of Malignant Mesotheliomas in Young Adults are Associated with Recurrent EWSR1/FUS-ATF1 Fusions Malignant mesothelioma (MM) is a rare, aggressive tumor often associated with asbestos exposure and characterized by complex genetic abnormalities, including deletions of chromosome 22.	('genetic abnormalities', 'Disease', 'MESH:D030342', (230, 251))	('FUS-ATF1', 'Gene', '466;2521', (88, 96))	('genetic abnormalities', 'Disease', (230, 251))	('EWSR1', 'Gene', (82, 87))	('Malignant Mesotheliomas', 'Phenotype', 'HP:0100001', (12, 35))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (105, 127))	('deletions', 'Var', (263, 272))	('Malignant Mesotheliomas', 'Disease', (12, 35))	('FUS-ATF1', 'Gene', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('asbestos', 'Chemical', 'MESH:D001194', (183, 191))	('aggressive tumor', 'Disease', 'MESH:D001523', (144, 160))	('Associated', 'Reg', (56, 66))	('Fusions', 'Var', (97, 104))	('aggressive tumor', 'Disease', (144, 160))	('Malignant Mesotheliomas', 'Disease', 'MESH:C562839', (12, 35))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (105, 127))	('Malignant mesothelioma', 'Disease', (105, 127))	('EWSR1', 'Gene', '2130', (82, 87))
551906	28505004	However, the incidence of EWSR1 rearrangements in MM and the spectrum of its fusion partners remain unknown.	('EWSR1', 'Gene', (26, 31))	('rearrangements', 'Var', (32, 46))	('EWSR1', 'Gene', '2130', (26, 31))
551907	28505004	We recently encountered 2 MM cases with EWSR1-ATF1 fusions and sought to investigate the prevalence and clinicopathologic features associated with this abnormality.	('EWSR1', 'Gene', '2130', (40, 45))	('ATF1', 'Gene', (46, 50))	('EWSR1', 'Gene', (40, 45))	('ATF1', 'Gene', '466', (46, 50))	('fusions', 'Var', (51, 58))
551921	28505004	Germline mutations in BRCA1 associated protein-1 (BAP1) predisposing to MM may account for a small portion of these cases, and have also been implicated in increasing sensitivity to asbestos carcinogenesis.	('Germline mutations', 'Var', (0, 18))	('sensitivity', 'MPA', (167, 178))	('asbestos carcinogenesis', 'Disease', (182, 205))	('implicated', 'Reg', (142, 152))	('BAP1', 'Gene', '8314', (50, 54))	('BRCA1 associated protein-1', 'Gene', '8314', (22, 48))	('asbestos carcinogenesis', 'Disease', 'MESH:D063646', (182, 205))	('BAP1', 'Gene', (50, 54))	('BRCA1 associated protein-1', 'Gene', (22, 48))	('increasing', 'PosReg', (156, 166))
551924	28505004	We recently encountered 2 similar peritoneal MM cases exhibiting EWSR1 rearrangements, but being fused instead to the ATF1 gene, and sought to investigate the prevalence and clinicopathologic features associated with this abnormality.	('EWSR1', 'Gene', (65, 70))	('ATF1', 'Gene', (118, 122))	('EWSR1', 'Gene', '2130', (65, 70))	('ATF1', 'Gene', '466', (118, 122))	('rearrangements', 'Var', (71, 85))
551929	28505004	Thus, FISH analysis revealed an ATF1 gene rearrangement.	('ATF1', 'Gene', '466', (32, 36))	('ATF1', 'Gene', (32, 36))	('rearrangement', 'Var', (42, 55))
551938	28505004	All cases were first tested for EWSR1 gene abnormalities.	('abnormalities', 'Var', (43, 56))	('EWSR1', 'Gene', (32, 37))	('EWSR1', 'Gene', '2130', (32, 37))
551941	28505004	As deletions of 22q have been reported as a common finding in MM, we have also examined abnormalities of this region by FISH using EWSR1, SMARCB1 and a 22q11 reference (RP11-960P211 and RP11-81B3), as previously described.	('EWSR1', 'Gene', (131, 136))	('deletions', 'Var', (3, 12))	('EWSR1', 'Gene', '2130', (131, 136))	('SMARCB1', 'Gene', (138, 145))	('RP11-960P211', 'Var', (169, 181))	('RP11-81B3', 'Var', (186, 195))	('SMARCB1', 'Gene', '6598', (138, 145))
551946	28505004	This hybridization capture-based next-generation sequencing (NGS) assay detects somatic single nucleotide mutations, small indels, copy number alterations and selected structural variants in several cancer-related genes (410 for the version used).	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('small indels', 'Var', (117, 129))	('copy number alterations', 'Var', (131, 154))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('single nucleotide mutations', 'Var', (88, 115))
551959	28505004	This revealed fusion of EWSR1 exons 1-14 (NM_013986) to ATF1 exons 5-7 (NM_005171)(Fig.	('NM_013986', 'Var', (42, 51))	('NM_005171', 'Var', (72, 81))	('EWSR1', 'Gene', (24, 29))	('EWSR1', 'Gene', '2130', (24, 29))	('ATF1', 'Gene', (56, 60))	('ATF1', 'Gene', '466', (56, 60))
551974	28505004	Additionally, among the 21 fusion-negative MM, 5 (24%) cases showed large deletions by FISH of EWSR1 and SMARCB1, with a 1:1 ratio (Fig.	('deletions', 'Var', (74, 83))	('EWSR1', 'Gene', '2130', (95, 100))	('SMARCB1', 'Gene', '6598', (105, 112))	('SMARCB1', 'Gene', (105, 112))	('EWSR1', 'Gene', (95, 100))
551982	28505004	These findings further expand understanding of the pathogenesis of MM, as well as enrich the growing list of pathologic entities harboring fusions of EWSR1 with members of the CREB family of transcription factors.	('CREB', 'Gene', '1385', (176, 180))	('EWSR1', 'Gene', '2130', (150, 155))	('fusions', 'Var', (139, 146))	('EWSR1', 'Gene', (150, 155))	('CREB', 'Gene', (176, 180))
551986	28505004	Particularly complex and heterogeneous is the spectrum of pathologic entities recently described as sharing fusions between EWSR1 and one of the c-AMP dependent transcription factor member of the CREB-ATF1 family.	('CREB', 'Gene', (196, 200))	('EWSR1', 'Gene', (124, 129))	('CREB', 'Gene', '1385', (196, 200))	('ATF1', 'Gene', (201, 205))	('ATF1', 'Gene', '466', (201, 205))	('EWSR1', 'Gene', '2130', (124, 129))	('fusions', 'Var', (108, 115))
551987	28505004	An EWSR1-ATF1 fusion transcript has been described in several tumor types without an unifying cell lineage, morphology or behavior, spanning both benign and malignant tumors of either mesenchymal or epithelial differentiation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('described', 'Reg', (41, 50))	('malignant tumors', 'Disease', (157, 173))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('EWSR1', 'Gene', '2130', (3, 8))	('fusion', 'Var', (14, 20))	('malignant tumors', 'Disease', 'MESH:D018198', (157, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ATF1', 'Gene', (9, 13))	('ATF1', 'Gene', '466', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('EWSR1', 'Gene', (3, 8))
551990	28505004	Two studies involving whole genome sequencing did not reveal rearrangements of EWSR1 or ATF1 in 99 and 22 MM cases, respectively.	('EWSR1', 'Gene', (79, 84))	('rearrangements', 'Var', (61, 75))	('EWSR1', 'Gene', '2130', (79, 84))	('ATF1', 'Gene', (88, 92))	('ATF1', 'Gene', '466', (88, 92))
551992	28505004	Our index case 2 represents the single MM case with alterations in either EWSR1, FUS or ATF1 genes from the MSK-IMPACT cohort, which contains genomic data for 131 patients with MM (data not shown).	('patients', 'Species', '9606', (163, 171))	('alterations', 'Var', (52, 63))	('FUS', 'Gene', (81, 84))	('FUS', 'Gene', '2521', (81, 84))	('EWSR1', 'Gene', (74, 79))	('EWSR1', 'Gene', '2130', (74, 79))	('ATF1', 'Gene', (88, 92))	('ATF1', 'Gene', '466', (88, 92))
551994	28505004	Recently, a biphasic pleural tumor with features of mesothelioma and undifferentiated round cell harboring EWSR1 rearrangement was reported, but the gene partner was not identified.	('rearrangement', 'Var', (113, 126))	('EWSR1', 'Gene', (107, 112))	('biphasic pleural tumor', 'Disease', 'MESH:D010997', (12, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mesothelioma', 'Disease', (52, 64))	('EWSR1', 'Gene', '2130', (107, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('biphasic pleural tumor', 'Disease', (12, 34))
552011	28505004	In contrast, copy number alterations in chromosome 12, where ATF1 is located, appear to be less frequent in MM.	('ATF1', 'Gene', '466', (61, 65))	('ATF1', 'Gene', (61, 65))	('copy number alterations', 'Var', (13, 36))
552013	28505004	Several entities with EWSR1-ATF1 fusions are considered in the differential diagnosis of epithelioid malignancies that could occur in abdomen or thorax of young patients, though given classic morphology and immunoprofile of fusion-positive MM these entities are discussed for general reference.	('epithelioid malignancies', 'Disease', 'MESH:D009369', (89, 113))	('EWSR1', 'Gene', '2130', (22, 27))	('epithelioid malignancies', 'Disease', (89, 113))	('ATF1', 'Gene', (28, 32))	('fusions', 'Var', (33, 40))	('ATF1', 'Gene', '466', (28, 32))	('EWSR1', 'Gene', (22, 27))	('patients', 'Species', '9606', (161, 169))
552024	28505004	The tumor is typically negative for cytokeratins and harbors the related EWSR1-CREB1 fusion; while no example with EWSR1-ATF1 fusion has been yet reported.	('CREB1', 'Gene', (79, 84))	('fusion', 'Var', (85, 91))	('tumor', 'Disease', (4, 9))	('CREB1', 'Gene', '1385', (79, 84))	('EWSR1', 'Gene', (115, 120))	('ATF1', 'Gene', (121, 125))	('harbors', 'Reg', (53, 60))	('EWSR1', 'Gene', (73, 78))	('ATF1', 'Gene', '466', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('EWSR1', 'Gene', '2130', (73, 78))	('EWSR1', 'Gene', '2130', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('negative', 'NegReg', (23, 31))
552025	28505004	Finally, a group of unclassified myxoid mesenchymal neoplasms with predilection for the intracranial compartment and characterized by fusions of EWSR1 with members of the CREB gene family, including ATF1, was recently described.	('ATF1', 'Gene', (199, 203))	('CREB', 'Gene', (171, 175))	('ATF1', 'Gene', '466', (199, 203))	('EWSR1', 'Gene', (145, 150))	('fusions', 'Var', (134, 141))	('CREB', 'Gene', '1385', (171, 175))	('myxoid mesenchymal neoplasms', 'Disease', 'MESH:D045888', (33, 61))	('EWSR1', 'Gene', '2130', (145, 150))	('myxoid mesenchymal neoplasms', 'Disease', (33, 61))	('neoplasms', 'Phenotype', 'HP:0002664', (52, 61))
552030	28505004	Immunohistochemically, serous carcinomas express MOC31, Ber-EP4 as well as PAX8, which is only rarely expressed in MM.	('Ber-EP4', 'Gene', (56, 63))	('PAX8', 'Gene', (75, 79))	('MOC31', 'Var', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('PAX8', 'Gene', '7849', (75, 79))	('serous carcinomas', 'Disease', 'MESH:D018284', (23, 40))	('serous carcinomas', 'Disease', (23, 40))
552037	28505004	This finding expands the spectrum of heterogeneous entities harboring EWSR1/FUS-ATF1 fusions, to include MM, among other mesenchymal and epithelial malignancies.	('FUS-ATF1', 'Gene', '466;2521', (76, 84))	('epithelial malignancies', 'Disease', (137, 160))	('EWSR1', 'Gene', (70, 75))	('epithelial malignancies', 'Disease', 'MESH:D002277', (137, 160))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (137, 160))	('EWSR1', 'Gene', '2130', (70, 75))	('fusions', 'Var', (85, 92))	('FUS-ATF1', 'Gene', (76, 84))
552038	28505004	Taken together, our findings suggest that fusions involving EWSR1 or FUS and ATF1 are rare events in mesothelioma, which appear to be restricted to younger patients without significant exposure to asbestos or BAP1 germline or somatic loss, and indistinguishable from conventional MM.	('patients', 'Species', '9606', (156, 164))	('BAP1', 'Gene', '8314', (209, 213))	('BAP1', 'Gene', (209, 213))	('EWSR1', 'Gene', '2130', (60, 65))	('asbestos', 'Chemical', 'MESH:D001194', (197, 205))	('mesothelioma', 'Disease', (101, 113))	('EWSR1', 'Gene', (60, 65))	('ATF1', 'Gene', (77, 81))	('fusions', 'Var', (42, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))	('FUS', 'Gene', (69, 72))	('FUS', 'Gene', '2521', (69, 72))	('ATF1', 'Gene', '466', (77, 81))
552039	28505004	In keeping with the simple genomic profile of other translocation-associated neoplasms, one of the index cases tested by targeted NGS showed that the EWSR1-ATF1 fusion was the sole genetic abnormality identified, without other mutations or copy number changes.	('EWSR1', 'Gene', '2130', (150, 155))	('neoplasms', 'Phenotype', 'HP:0002664', (77, 86))	('fusion', 'Var', (161, 167))	('ATF1', 'Gene', (156, 160))	('ATF1', 'Gene', '466', (156, 160))	('neoplasms', 'Disease', 'MESH:D009369', (77, 86))	('EWSR1', 'Gene', (150, 155))	('neoplasms', 'Disease', (77, 86))
552040	28505004	Whether the genetic profile of MM occurring in children and young adults is similarly heterogeneous to the older age group will require further study, but our findings suggest that at least a small subset harbors abnormalities such as losses of 22q and BAP1 at chromosomal and immunohistochemical levels, respectively.	('children', 'Species', '9606', (47, 55))	('BAP1', 'Gene', (253, 257))	('losses of 22q', 'Var', (235, 248))	('BAP1', 'Gene', '8314', (253, 257))
552055	26538721	Further, alitretinoin also markedly reduces the number of macrophages and activated dendritic cells, two major sources of TNF-alpha and hence considerably reduces the inflammation.	('TNF-alpha', 'Gene', '7124', (122, 131))	('TNF-alpha', 'Gene', (122, 131))	('activated dendritic cells', 'CPA', (74, 99))	('reduces', 'NegReg', (155, 162))	('alitretinoin', 'Chemical', 'MESH:D000077556', (9, 21))	('inflammation', 'Disease', 'MESH:D007249', (167, 179))	('reduces', 'NegReg', (36, 43))	('inflammation', 'Disease', (167, 179))	('alitretinoin', 'Var', (9, 21))
552056	26538721	Other inflammatory chemokines, whose levels alitretinoin diminishes include IL-4, IL-1beta and IL-12p40.	('IL-4', 'Gene', '3565', (76, 80))	('IL-1beta', 'Gene', (82, 90))	('levels', 'MPA', (37, 43))	('alitretinoin', 'Chemical', 'MESH:D000077556', (44, 56))	('IL-1beta', 'Gene', '3553', (82, 90))	('IL-12p40', 'Var', (95, 103))	('diminishes', 'NegReg', (57, 67))	('IL-4', 'Gene', (76, 80))
552057	26538721	Alitretinoin also inhibits the production of nitric oxide (NO), secondary to stimulation by other cytokines and lipopolysaccharides, further bringing about immunomodulation by downregulating the activity of leucocytes.	('Alitretinoin', 'Chemical', 'MESH:D000077556', (0, 12))	('bringing about', 'Reg', (141, 155))	('production of nitric oxide', 'MPA', (31, 57))	('activity of leucocytes', 'CPA', (195, 217))	('downregulating', 'NegReg', (176, 190))	('inhibits', 'NegReg', (18, 26))	('nitric oxide', 'Chemical', 'MESH:D009569', (45, 57))	('Alitretinoin', 'Var', (0, 12))
552058	26538721	Anti-proliferative and apoptotic effects The anti-proliferative effect of alitretinoin is related to RARs, whereas RXRs mediate the apoptotic activity of alitretinoin.	('alitretinoin', 'Gene', (74, 86))	('anti-proliferative effect', 'MPA', (45, 70))	('alitretinoin', 'Chemical', 'MESH:D000077556', (74, 86))	('RARs', 'Var', (101, 105))	('alitretinoin', 'Chemical', 'MESH:D000077556', (154, 166))
552094	26538721	With its property to abrogate inflammation, alitretinoin brings about a rapid subsidence of the plaques and pustules encountered in palmoplantar psoriasis.	('psoriasis', 'Phenotype', 'HP:0003765', (145, 154))	('palmoplantar psoriasis', 'Disease', 'MESH:D011565', (132, 154))	('palmoplantar psoriasis', 'Disease', (132, 154))	('alitretinoin', 'Chemical', 'MESH:D000077556', (44, 56))	('inflammation', 'Disease', 'MESH:D007249', (30, 42))	('alitretinoin', 'Var', (44, 56))	('pustules', 'Phenotype', 'HP:0200039', (108, 116))	('inflammation', 'Disease', (30, 42))	('palmoplantar psoriasis', 'Phenotype', 'HP:0025524', (132, 154))	('subsidence', 'NegReg', (78, 88))
552099	26538721	Further, alitretinoin reduces the cohesion between the malignant kerationcytes and reduces its propensity for malignant degeneration.	('malignant degeneration', 'Disease', (110, 132))	('propensity', 'MPA', (95, 105))	('alitretinoin', 'Chemical', 'MESH:D000077556', (9, 21))	('cohesion', 'MPA', (34, 42))	('reduces', 'NegReg', (83, 90))	('reduces', 'NegReg', (22, 29))	('alitretinoin', 'Var', (9, 21))	('malignant degeneration', 'Disease', 'MESH:D009369', (110, 132))
552119	26538721	Yet, more randomized controlled trials need to be conducted to verify the therapeutic improvement in cases of LSC with alitretinoin.	('LSC', 'Disease', (110, 113))	('alitretinoin', 'Chemical', 'MESH:D000077556', (119, 131))	('alitretinoin', 'Var', (119, 131))
552161	26538721	On the other hand, the pharmacokinetic profile of alitretinoin was not affected by cyclosporine A or simvastatin, but ketoconazole brought about a significant increase in the plasma concentrations of alitretinoin when both the drugs were administered together.	('plasma concentrations of alitretinoin', 'MPA', (175, 212))	('ketoconazole', 'Chemical', 'MESH:D007654', (118, 130))	('alitretinoin', 'Chemical', 'MESH:D000077556', (200, 212))	('simvastatin', 'Chemical', 'MESH:D019821', (101, 112))	('cyclosporine A', 'Chemical', 'MESH:D016572', (83, 97))	('alitretinoin', 'Chemical', 'MESH:D000077556', (50, 62))	('ketoconazole', 'Var', (118, 130))	('increase', 'PosReg', (159, 167))
552273	33614766	FMEC cells were grown in a 50/50 v/v mixture of DMEM and F12K (Ham's F-12K Nutrient Mixture, Kaighn's Modification with L-glutamine) with 10% FBS, 1% penicillin, and streptomycin, 1% non-essential amino acids (NEAA), and 10 ng/mL endothelial mitogen factor (MP Biomedicals, Fisher Scientific, Rockford, IL).	('NEAA', 'Chemical', '-', (210, 214))	('L-glutamine', 'Chemical', 'MESH:D005973', (120, 131))	('streptomycin', 'Chemical', 'MESH:D013307', (166, 178))	('DMEM', 'Chemical', '-', (48, 52))	('cat', 'Gene', '847', (108, 111))	('penicillin', 'Chemical', 'MESH:D010406', (150, 160))	('cat', 'Gene', (108, 111))	('F12K', 'SUBSTITUTION', 'None', (57, 61))	('F12K', 'Var', (57, 61))	('-essential amino acids', 'Chemical', 'MESH:D000601', (186, 208))
552436	30641971	RCBTB1 Deletion Is Associated with Metastatic Outcome and Contributes to Docetaxel Resistance in Nontranslocation-Related Pleomorphic Sarcomas Half of soft-tissue sarcomas are tumors with complex genomics, which display no specific genetic alterations and respond poorly to treatment.	('Contributes', 'Reg', (58, 69))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (151, 171))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('Sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('Sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('Docetaxel Resistance', 'MPA', (73, 93))	('RCBTB1', 'Gene', '55213', (0, 6))	('Docetaxel', 'Chemical', 'MESH:D000077143', (73, 82))	('sarcomas', 'Disease', 'MESH:D012509', (163, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('Sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (163, 171))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('sarcomas', 'Disease', (163, 171))	('Associated', 'Reg', (19, 29))	('Deletion', 'Var', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Metastatic', 'Disease', (35, 45))	('tumors', 'Disease', (176, 182))	('RCBTB1', 'Gene', (0, 6))	('Sarcomas', 'Disease', (134, 142))
552441	30641971	In vitro and in vivo, RCBTB1 overexpression in leiomyosarcoma cells specifically sensitized to docetaxel-induced apoptosis.	('RCBTB1', 'Gene', (22, 28))	('leiomyosarcoma', 'Disease', (47, 61))	('docetaxel', 'Chemical', 'MESH:D000077143', (95, 104))	('apoptosis', 'CPA', (113, 122))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (47, 61))	('overexpression', 'Var', (29, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (47, 61))	('sensitized', 'Reg', (81, 91))
552442	30641971	By contrast, RCBTB1 inhibition decreased cell proliferation and protected sarcoma cells from apoptosis induced by docetaxel.	('inhibition', 'Var', (20, 30))	('cell proliferation', 'CPA', (41, 59))	('RCBTB1', 'Gene', (13, 19))	('decreased', 'NegReg', (31, 40))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('docetaxel', 'Chemical', 'MESH:D000077143', (114, 123))	('sarcoma', 'Disease', (74, 81))	('apoptosis', 'CPA', (93, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
552445	30641971	Molecular approaches have described three main genetics in these tumors: reciprocal translocations, specific mutations, and complex genomic profiles.	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
552457	30641971	Among them, the most frequent is the 13q14-21 region loss in LMSs and UPSs, leading to RB1 deletion or inactivation.	('UPS', 'Disease', 'MESH:D017118', (70, 73))	('deletion', 'Var', (91, 99))	('inactivation', 'NegReg', (103, 115))	('RB1', 'Gene', (87, 90))	('RB1', 'Gene', '5925', (87, 90))	('loss', 'NegReg', (53, 57))	('LMSs', 'Phenotype', 'HP:0100243', (61, 65))	('UPS', 'Disease', (70, 73))
552463	30641971	To discriminate driver and passenger alterations, we hypothesized that oncogenesis and tumoral progression are driven by recurrent pathway alterations shared by sarcomas with complex genomics.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcomas', 'Disease', (161, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('alterations', 'Var', (139, 150))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('oncogenesis', 'CPA', (71, 82))
552469	30641971	In addition, the most frequently deleted histotype is in LMSs, with 58% RCBTB1 deletion against 36% in the rest of the cohort #1 (UPSs, myxofibrosarcomas, pleomorphic liposarcomas, dedifferentiated liposarcomas, and other sarcomas combined) (Chi-squared test; p = 3.64e-2).	('liposarcomas', 'Phenotype', 'HP:0012034', (198, 210))	('sarcomas', 'Disease', 'MESH:D012509', (222, 230))	('myxofibrosarcomas', 'Disease', 'None', (136, 153))	('liposarcoma', 'Phenotype', 'HP:0012034', (198, 209))	('sarcomas', 'Phenotype', 'HP:0100242', (222, 230))	('deletion', 'Var', (79, 87))	('sarcomas', 'Disease', (222, 230))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('sarcomas', 'Disease', 'MESH:D012509', (202, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (202, 210))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (155, 179))	('sarcomas', 'Disease', (171, 179))	('sarcomas', 'Disease', (202, 210))	('UPS', 'Disease', (130, 133))	('LMSs', 'Disease', (57, 61))	('LMSs', 'Phenotype', 'HP:0100243', (57, 61))	('RCBTB1', 'Gene', (72, 78))	('dedifferentiated liposarcoma', 'Disease', (181, 209))	('UPS', 'Disease', 'MESH:D017118', (130, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('liposarcomas', 'Phenotype', 'HP:0012034', (167, 179))	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (181, 209))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('pleomorphic liposarcomas', 'Disease', (155, 179))	('sarcomas', 'Disease', (145, 153))	('liposarcoma', 'Phenotype', 'HP:0012034', (167, 178))	('myxofibrosarcomas', 'Disease', (136, 153))
552473	30641971	Eleven variants were synonymous and one was a missense variant (NM_018191:p.A24V) already known as a common single nucleotide polymorphism, described in the dbSNP database (rs4942848) and in the 1000 G project (allele frequency: 0.59).	('p.A24V', 'Var', (74, 80))	('rs4942848', 'Var', (173, 182))	('NM_018191:p.A24V', 'Mutation', 'rs4942848', (64, 80))	('rs4942848', 'Mutation', 'rs4942848', (173, 182))
552476	30641971	We note that, among the 162 tumors, 13% and 61% harbor a homozygous and a heterozygous deletion of RCBTB1, respectively (Supplementary Table S2).	('RCBTB1', 'Gene', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('deletion', 'Var', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
552478	30641971	In this cohort, RCBTB1 expression is also significantly reduced in deleted samples compared to non-deleted tumors (Supplementary Figure S1).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('reduced', 'NegReg', (56, 63))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('expression', 'MPA', (23, 33))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('deleted', 'Var', (67, 74))	('RCBTB1', 'Gene', (16, 22))
552481	30641971	To circumvent this lack of information, current drugs for pleomorphic sarcoma treatment (doxorubicin, gemcitabine, and docetaxel) were screened and apoptotic responses of LMS cell lines (the main histotype affected by RCBTB1 deletions) with induced RCBTB1 expression were measured.	('gemcitabine', 'Chemical', 'MESH:C056507', (102, 113))	('docetaxel', 'Chemical', 'MESH:D000077143', (119, 128))	('RCBTB1', 'Gene', (218, 224))	('pleomorphic sarcoma', 'Disease', (58, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('doxorubicin', 'Chemical', 'MESH:D004317', (89, 100))	('RCBTB1', 'Gene', (249, 255))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (58, 77))	('deletions', 'Var', (225, 234))
552483	30641971	Indeed, in IB112-RCBTB1-HA cells, dual Annexin V- fluorescein isothiocyanate/propidium iodide (FITC/PI) staining occurs in 35.8% of cells, whereas control cell line shows 22.6% of cell death after docetaxel treatment (Figure 3B).	('IB112-RCBTB1-HA', 'Var', (11, 26))	('fluorescein isothiocyanate', 'Chemical', 'MESH:D016650', (50, 76))	('FITC', 'Chemical', 'MESH:D016650', (95, 99))	('propidium iodide', 'Chemical', 'MESH:D011419', (77, 93))	('docetaxel', 'Chemical', 'MESH:D000077143', (197, 206))	('Annexin V', 'Gene', '308', (39, 48))	('Annexin V', 'Gene', (39, 48))
552484	30641971	The same experiments were repeated in another LMS cell line (IB136) that bears a heterozygous deletion of RCBTB1 and is more resistant to docetaxel than the IB112 cell line (500 nM of docetaxel was used during 72 h to induce an apoptotic rate comparable to IB112 cells).	('IB136', 'Chemical', '-', (61, 66))	('deletion', 'Var', (94, 102))	('resistant', 'MPA', (125, 134))	('docetaxel', 'Chemical', 'MESH:D000077143', (138, 147))	('docetaxel', 'Chemical', 'MESH:D000077143', (184, 193))	('apoptotic', 'MPA', (228, 237))	('RCBTB1', 'Gene', (106, 112))
552496	30641971	In accordance with in vitro results, mice bearing IB136 RCBTB1-HA tumors harbored a significant reduction of tumor weight after treatments, with on average a 49.3% and a 56.7% reduction after 1 mg/mL and 2 mg/mL of docetaxel, respectively (Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('reduction', 'NegReg', (176, 185))	('IB136', 'Chemical', '-', (50, 55))	('RCBTB1-HA tumors', 'Disease', 'MESH:D009369', (56, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('reduction of tumor', 'Disease', (96, 114))	('RCBTB1-HA tumors', 'Disease', (56, 72))	('docetaxel', 'Chemical', 'MESH:D000077143', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('reduction of tumor', 'Disease', 'MESH:D009369', (96, 114))	('IB136', 'Var', (50, 55))	('mice', 'Species', '10090', (37, 41))
552501	30641971	This was confirmed by weighing tumors at the end of DMSO treatment, with an average of 260 mg and 890 mg for tumors produced by IB136-EV and IB136 RCBTB1-HA cell lines, respectively (Figure 4A).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('IB136 RCBTB1-HA', 'Var', (141, 156))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('IB136', 'Chemical', '-', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IB136-EV', 'Var', (128, 136))	('DMSO', 'Chemical', 'MESH:D004121', (52, 56))	('tumors', 'Disease', (109, 115))	('IB136', 'Chemical', '-', (128, 133))
552510	30641971	In line with this observation, inhibition of RCBTB1 in LPS80 cell line dramatically decreased the number of cells among days: from 5479 to 2893 cells with shRNA#1 and from 4567 to 600 cells with shRNA#2 on average after 7 days (Figure 5C).	('number of cells among days', 'CPA', (98, 124))	('inhibition', 'Var', (31, 41))	('RCBTB1', 'Gene', (45, 51))	('decreased', 'NegReg', (84, 93))	('LPS80', 'Chemical', '-', (55, 60))
552519	30641971	Data reported here evidenced that RCBTB1 expression impacts docetaxel-induced apoptosis in dedifferentiated liposarcoma (LPS80) and LMS (IB112, IB136) cell lines.	('dedifferentiated liposarcoma', 'Disease', 'MESH:D008080', (91, 119))	('apoptosis', 'CPA', (78, 87))	('dedifferentiated liposarcoma', 'Disease', (91, 119))	('liposarcoma', 'Phenotype', 'HP:0012034', (108, 119))	('RCBTB1', 'Gene', (34, 40))	('docetaxel-induced', 'MPA', (60, 77))	('IB136', 'Chemical', '-', (144, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('expression', 'Var', (41, 51))	('docetaxel', 'Chemical', 'MESH:D000077143', (60, 69))	('LPS80', 'Chemical', '-', (121, 126))	('impacts', 'Reg', (52, 59))
552521	30641971	(2013) reported that RCBTB1 inhibition protects in vitro liposarcoma cells from apoptosis induced by nocodazole, another inhibitor of microtubule polymerization.	('nocodazole', 'Chemical', 'MESH:D015739', (101, 111))	('liposarcoma', 'Phenotype', 'HP:0012034', (57, 68))	('liposarcoma', 'Disease', 'MESH:D008080', (57, 68))	('inhibition', 'Var', (28, 38))	('RCBTB1', 'Gene', (21, 27))	('apoptosis', 'CPA', (80, 89))	('liposarcoma', 'Disease', (57, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
552522	30641971	Conversely, in LMS cell lines overexpressing RCBTB1, we observed an enhanced apoptosis after docetaxel treatment.	('enhanced', 'PosReg', (68, 76))	('docetaxel', 'Chemical', 'MESH:D000077143', (93, 102))	('apoptosis', 'CPA', (77, 86))	('overexpressing', 'Var', (30, 44))	('RCBTB1', 'Gene', (45, 51))
552527	30641971	One can hypothesize that GD and G will be equivalent in sarcomas harboring RCBTB1 deletion whereas GD will be more effective than G on sarcomas with preserved RCBTB1 expression.	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('RCBTB1', 'Gene', (75, 81))	('sarcomas', 'Disease', 'MESH:D012509', (135, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('GD', 'Chemical', '-', (99, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('deletion', 'Var', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('sarcomas', 'Disease', (56, 64))	('sarcomas', 'Disease', (135, 143))	('GD', 'Chemical', '-', (25, 27))
552528	30641971	Nevertheless, although we did not observe in vitro any sensitization effect on IB112 cells after gemcitabine or doxorubicin treatment in our experimental conditions, it is not excluded that high RCBTB1 expression could sensitize other sarcoma models to other chemotherapies than docetaxel.	('RCBTB1', 'Gene', (195, 201))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('docetaxel', 'Chemical', 'MESH:D000077143', (279, 288))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('sarcoma', 'Disease', (235, 242))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('sensitize', 'Reg', (219, 228))	('high', 'Var', (190, 194))
552534	30641971	The surprising pro-proliferative effect of RCBTB1 appears to be contradictory with our hypothesis of a tumor suppressor gene, coming out of our clinical data demonstrating that RCBTB1 is frequently deleted and that its downregulation is prognostic for a higher risk for developing metastases.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('metastases', 'Disease', (281, 291))	('downregulation', 'NegReg', (219, 233))	('metastases', 'Disease', 'MESH:D009362', (281, 291))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('RCBTB1', 'Gene', (177, 183))	('deleted', 'Var', (198, 205))
552536	30641971	The fact that RCBTB1 and RB1 have antagonistic roles in cell growth and are frequently co-deleted, as in 50% of our 106 sarcomas, suggests that RCBTB1 may not be just a passenger gene affected by RB1 deletion.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('deletion', 'Var', (200, 208))	('RB1', 'Gene', '5925', (25, 28))	('RB1', 'Gene', '5925', (196, 199))	('sarcomas', 'Disease', (120, 128))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('RCBTB1', 'Gene', (144, 150))	('RB1', 'Gene', (25, 28))	('RB1', 'Gene', (196, 199))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
552537	30641971	Its inactivation in addition to RB1 loss could avoid excessive cell proliferation, which could be deleterious for tumor development in terms of nutrient and energy expenditure for example but also in terms of response to treatment.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('inactivation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('RB1', 'Gene', (32, 35))	('loss', 'NegReg', (36, 40))	('avoid', 'NegReg', (47, 52))	('tumor', 'Disease', (114, 119))	('cell proliferation', 'CPA', (63, 81))	('RB1', 'Gene', '5925', (32, 35))
552538	30641971	Thus, co-deletion of RCBTB1 and RB1 might represent a selective advantage over cells only deleted for RB1.	('co-deletion', 'Var', (6, 17))	('RB1', 'Gene', '5925', (102, 105))	('RB1', 'Gene', (32, 35))	('RCBTB1', 'Gene', (21, 27))	('RB1', 'Gene', '5925', (32, 35))	('RB1', 'Gene', (102, 105))
552540	30641971	The idea that RB1 is not the only target of the frequent deletions in this chromosomal region is reinforced by the fact that in the cohort of 106 sarcomas, 7% of tumors are deleted only for RB1, whereas 13% carry a deletion that only affects RCBTB1.	('RCBTB1', 'Gene', (242, 248))	('RB1', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('RB1', 'Gene', '5925', (14, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('RB1', 'Gene', (190, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('sarcomas', 'Disease', (146, 154))	('deleted', 'Var', (173, 180))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('RB1', 'Gene', '5925', (190, 193))
552543	30641971	Altogether, this rules out the hypothesis that RCBTB1 is only a passenger gene affected by RB1 deletion.	('RB1', 'Gene', (91, 94))	('deletion', 'Var', (95, 103))	('RB1', 'Gene', '5925', (91, 94))
552546	30641971	RCBTB1 deletion could possibly take part in the "Go or Grow" mechanism, which triggers a switch from a proliferative to an invasive phenotype in response to environmental stresses such as hypoxia, as demonstrated in other cancers.	('proliferative', 'MPA', (103, 116))	('hypoxia', 'Disease', (188, 195))	('hypoxia', 'Disease', 'MESH:D000860', (188, 195))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('RCBTB1', 'Gene', (0, 6))	('take', 'Reg', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('deletion', 'Var', (7, 15))
552551	30641971	Understanding these mechanisms will probably shed light on a central role for RCBTB1 deletion in tumor development, as suggested by our bioinformatic analysis and our in vivo experiments.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('RCBTB1', 'Gene', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('deletion', 'Var', (85, 93))
552566	30641971	IB112 and IB136 were infected with a lentiviral vector containing the cDNA sequence of RCBTB1 coupled to the HA-tag under the control of a CMV promoter (EX-Z7772-Lv120, GeneCopoeia, Rockville, MD, USA).	('RCBTB1', 'Gene', (87, 93))	('EX-Z7772-Lv120', 'Var', (153, 167))	('IB136', 'Chemical', '-', (10, 15))
552575	30641971	The assay IDs were as follows: Hs00216991_m1 for RCBTB1 and Hs99999902_m1 for RPLP0.	('Hs00216991_m1', 'Var', (31, 44))	('RPLP0', 'Gene', '6175', (78, 83))	('Hs99999902_m1', 'Var', (60, 73))	('RPLP0', 'Gene', (78, 83))	('RCBTB1', 'Gene', (49, 55))
552577	30641971	Cells were rinsed with ice-cold PBS and lysed for 30 min at 4  C in RIPA lysis and extraction buffer (#R0278, Sigma Aldrich, St.) supplemented with a protease/phosphatase inhibitor cocktail (#11697498001, Roche, Basel, Switzerland).	('#11697498001', 'Var', (191, 203))	('PBS', 'Disease', 'MESH:D011535', (32, 35))	('PBS', 'Disease', (32, 35))	('RIPA lysis', 'Chemical', '-', (68, 78))
552599	30641971	Table S1: List of the 41 biological pathways referenced in Gene Ontology database commonly altered in 100% of sarcomas, Table S2: Description of the repartition of the 162 tumor samples according to histotype and RCBTB1 genomic status, Table S3: Repartition of cases of metastatic disease according to RCBTB1 expression level in tumors (high or low, cut-off = median), Figure S1: Boxplot of RCBTB1 expression (RNA Seq V2 RSEM) in the TCGA cohort of 162 soft tissue sarcomas, according to RCBTB1 genomic status, Figure S2: Apoptotic rate of IB112 cells expressing an empty vector or RCBTB1-HA after 72 h incubation with doxorubicin or gemcitabine, Figure S3: Cell migration of IB112 cell line expressing RCBTB1, Figure S4: Follow-up of tumor volume during treatment.	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (329, 335))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (735, 740))	('sarcomas', 'Disease', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (735, 740))	('Cell migration', 'CPA', (658, 672))	('doxorubicin', 'Chemical', 'MESH:D004317', (619, 630))	('tumor', 'Disease', (329, 334))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('RCBTB1', 'Var', (703, 709))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('sarcomas', 'Disease', 'MESH:D012509', (465, 473))	('sarcomas', 'Phenotype', 'HP:0100242', (465, 473))	('sarcomas', 'Disease', (465, 473))	('tumor', 'Phenotype', 'HP:0002664', (735, 740))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (329, 335))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (453, 473))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('sarcoma', 'Phenotype', 'HP:0100242', (465, 472))	('gemcitabine', 'Chemical', 'MESH:C056507', (634, 645))	('tumors', 'Disease', (329, 335))	('Apoptotic', 'CPA', (522, 531))
552650	23711273	Median survival for patients with peritoneal sarcomatosis treated with CRS-HIPEC is similar with the historical reported survival before introducing chemoperfusion.	('peritoneal sarcomatosis', 'Disease', (34, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('CRS-HIPEC', 'Var', (71, 80))	('CRS-HIPEC', 'Chemical', '-', (71, 80))	('patients', 'Species', '9606', (20, 28))	('peritoneal sarcomatosis', 'Disease', 'MESH:D010534', (34, 57))
552692	23711273	Of all patients who received CRS-HIPEC, four (57%) died from peritoneal recurrence, one (14%) died from unknown causes with recurrence, and two (29%) were alive five years after surgery with no evidence of disease.	('peritoneal recurrence', 'Disease', (61, 82))	('CRS-HIPEC', 'Var', (29, 38))	('CRS-HIPEC', 'Chemical', '-', (29, 38))	('patients', 'Species', '9606', (7, 15))
552758	32839252	SN22 prodrug delivery resulted in sustained intratumoral drug concentrations, dramatically higher than those of SN38 at all time points.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('higher', 'PosReg', (91, 97))	('SN22', 'Var', (0, 4))	('tumor', 'Disease', (49, 54))	('SN38', 'Chemical', 'MESH:D000077146', (112, 116))	('SN22', 'Chemical', 'MESH:C051891', (0, 4))
552760	32839252	PEG-[SN22]4 also markedly extended survival of mice with drug-resistant, orthotopic NB and it caused long-term (6+ month) remissions in 80-100% of NB and sarcoma xenografts.	('PEG-[SN22]4', 'Chemical', '-', (0, 11))	('survival', 'CPA', (35, 43))	('PEG-[SN22]4', 'Var', (0, 11))	('extended', 'PosReg', (26, 34))	('NB', 'Gene', '230972', (147, 149))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('mice', 'Species', '10090', (47, 51))	('NB', 'Gene', '230972', (84, 86))
552776	32839252	The results of our studies show that PEG-[SN22]4 is a cancer therapeutic that is highly effective in treating at least three different types of high-risk pediatric solid tumors with intrinsic or acquired drug resistance, and warrants further development for clinical trials.	('PEG-[SN22]4', 'Var', (37, 48))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('solid tumors', 'Disease', (164, 176))	('cancer', 'Disease', (54, 60))	('drug resistance', 'Phenotype', 'HP:0020174', (204, 219))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('PEG-[SN22]4', 'Chemical', '-', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('solid tumors', 'Disease', 'MESH:D009369', (164, 176))
552797	32839252	Mice were treated according to the following groups: a) vehicle (saline) (n=8), b) free CPT-11 (n=7; 15 mg/kg), c) liposomal CPT-11 (n=6; 15 mg/kg), d) PEG-[SN38]4 (n=6; 10 mg/kg), or e) PEG-[SN22]4 (n=6; 10 mg/kg).	('liposomal', 'Var', (115, 124))	('CPT-11', 'Chemical', 'MESH:D000077146', (88, 94))	('PEG-[SN38]4', 'Var', (152, 163))	('PEG-[SN22]4', 'Chemical', '-', (187, 198))	('PEG-[SN38]4', 'Chemical', '-', (152, 163))	('Mice', 'Species', '10090', (0, 4))	('CPT-11', 'Chemical', 'MESH:D000077146', (125, 131))
552812	32839252	This line was derived from a relapse tumor that had both MYCN amplification and TP53 mutation, so it represented a very high-risk tumor.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
552818	32839252	Mice with TC-71 or Rh30 xenografts (n=10/arm) received vehicle (saline), free CPT-11 (15 mg/kg), or PEG-[SN22]4 (10 mg/kg) 1x/week for 4 weeks.	('PEG-[SN22]', 'Var', (100, 110))	('Rh30', 'Gene', '6007', (19, 23))	('PEG-[SN22]4', 'Chemical', '-', (100, 111))	('CPT-11', 'Chemical', 'MESH:D000077146', (78, 84))	('Mice', 'Species', '10090', (0, 4))	('Rh30', 'Gene', (19, 23))	('TC-71', 'Chemical', '-', (10, 15))
552820	32839252	Homozygous TH-MYCN mice with easily palpable tumors (n=4/arm, each time point) were given a single dose by tail vein of either PEG-[SN22]4 (10 mg/kg), free CPT-11 (15 mg/kg), liposomal CPT-11 (15 mg/kg), or PEG-[SN38]4 (10 mg/kg) as controls.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CPT-11', 'Chemical', 'MESH:D000077146', (156, 162))	('PEG-', 'Var', (127, 131))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('PEG-[SN38]4', 'Chemical', '-', (207, 218))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('PEG-[SN22]4', 'Chemical', '-', (127, 138))	('CPT-11', 'Chemical', 'MESH:D000077146', (185, 191))	('mice', 'Species', '10090', (19, 23))
552832	32839252	NB cells derived from a spontaneous tumor in the TH-MYCN mouse (TH-MYCN-G1) were exposed in vitro to different concentrations of SN38 or SN22.	('SN22', 'Var', (137, 141))	('NB', 'Gene', '230972', (0, 2))	('SN38', 'Chemical', 'MESH:D000077146', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SN22', 'Chemical', 'MESH:C051891', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('SN38', 'Var', (129, 133))	('mouse', 'Species', '10090', (57, 62))	('tumor', 'Disease', (36, 41))
552833	32839252	The IC50 at 48 hr for SN38 (80 nM) was about 11 times higher than the IC50 at 48 hr for SN22 (7 nm).	('IC50', 'MPA', (4, 8))	('higher', 'PosReg', (54, 60))	('SN22', 'Chemical', 'MESH:C051891', (88, 92))	('SN38', 'Chemical', 'MESH:D000077146', (22, 26))	('SN38', 'Var', (22, 26))
552839	32839252	Mice were divided into 5 groups once tumors became palpable (4-5 weeks): vehicle (saline), free CPT-11, liposomal CPT-11, PEG-[SN38]4, or PEG-[SN22]4 at comparable doses, and treated 1x/week for 4 weeks.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('PEG-[SN22]4', 'Var', (138, 149))	('PEG-[SN22]4', 'Chemical', '-', (138, 149))	('CPT-11', 'Chemical', 'MESH:D000077146', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('PEG-[SN38]4', 'Var', (122, 133))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Disease', (37, 43))	('CPT-11', 'Chemical', 'MESH:D000077146', (96, 102))	('CPT-11', 'Gene', (114, 120))	('PEG-[SN38]4', 'Chemical', '-', (122, 133))
552842	32839252	Interestingly, some mice with growing tumors treated with liposomal CPT-11 developed a progressive neurological syndrome that included ataxia and rolling behavior, and they were removed from the study.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('developed', 'Reg', (75, 84))	('tumors', 'Disease', (38, 44))	('rolling behavior', 'CPA', (146, 162))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('mice', 'Species', '10090', (20, 24))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('CPT-11', 'Gene', (68, 74))	('ataxia', 'Phenotype', 'HP:0001251', (135, 141))	('CPT-11', 'Chemical', 'MESH:D000077146', (68, 74))	('ataxia', 'Disease', 'MESH:D001259', (135, 141))	('neurological syndrome', 'Disease', 'MESH:D009422', (99, 120))	('liposomal', 'Var', (58, 67))	('ataxia', 'Disease', (135, 141))	('neurological syndrome', 'Disease', (99, 120))	('progressive neurological syndrome', 'Phenotype', 'HP:0002344', (87, 120))	('neurological syndrome', 'Phenotype', 'HP:0000707', (99, 120))
552846	32839252	These results suggest that PEG-[SN22]4 is extremely effective against intrinsically resistant, ABCG2-overexpressing tumors arising in immunocompetent mice, as evidenced by long-term remissions and cures in all the animals treated with only 4 weekly doses of the prodrug.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('mice', 'Species', '10090', (150, 154))	('ABCG2-overexpressing', 'Gene', (95, 115))	('PEG-[SN22]4', 'Var', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('PEG-[SN22]4', 'Chemical', '-', (27, 38))
552850	32839252	In contrast, the drug delivered as free or liposomal CPT-11 was fully eliminated from blood by 24 and 72 hr, respectively.	('liposomal', 'Var', (43, 52))	('CPT-11', 'Chemical', 'MESH:D000077146', (53, 59))	('CPT-11', 'Gene', (53, 59))
552853	32839252	With PEG-[SN22]4, slightly higher drug levels were seen in the liver, spleen, and intestine, but the tumor/liver ratio of all agents still strongly favored PEG-[SN22]4.	('PEG-[SN22]4', 'Var', (156, 167))	('PEG-[SN22]4', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PEG-[SN22]4', 'Chemical', '-', (156, 167))	('PEG-[SN22]4', 'Chemical', '-', (5, 16))	('higher', 'PosReg', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('drug levels', 'MPA', (34, 45))
552854	32839252	Next, we compared PEG-[SN22]4 to free CPT-11 and to PEG-[SN38]4 in an orthotopic xenograft mouse model of NB using the chemoresistant NB line SK-N-BE(2)C with mutated TP53.	('SK-N-BE(2)C', 'Disease', 'MESH:D020216', (142, 153))	('mutated', 'Var', (159, 166))	('NB', 'Gene', '230972', (134, 136))	('NB', 'Gene', '230972', (106, 108))	('PEG-[SN38]4', 'Chemical', '-', (52, 63))	('PEG-[SN22]4', 'Chemical', '-', (18, 29))	('CPT-11', 'Gene', (38, 44))	('CPT-11', 'Chemical', 'MESH:D000077146', (38, 44))	('mouse', 'Species', '10090', (91, 96))	('TP53', 'Gene', (167, 171))
552856	32839252	In this model of acquired chemoresistance, CPT-11 had no effect, whereas both PEG-[SN22]4 and PEG-[SN38]4 were initially effective at shrinking the tumor (Fig.	('CPT-11', 'Gene', (43, 49))	('PEG-[SN38]4', 'Var', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('PEG-[SN38]4', 'Chemical', '-', (94, 105))	('PEG-[SN22]4', 'Var', (78, 89))	('CPT-11', 'Chemical', 'MESH:D000077146', (43, 49))	('tumor', 'Disease', (148, 153))	('PEG-[SN22]4', 'Chemical', '-', (78, 89))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('shrinking', 'NegReg', (134, 143))
552857	32839252	However, tumors rapidly regrew right after treatment cessation in the PEG-[SN38]4 treated mice, but PEG-[SN22]4 treatment resulted in complete disappearance of the tumor-associated signal and lasting inhibition of tumor growth for a number of weeks beyond the treatment period.	('tumor', 'Disease', (164, 169))	('inhibition', 'NegReg', (200, 210))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('PEG-[SN22]4', 'Chemical', '-', (100, 111))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('PEG-[SN38]4', 'Chemical', '-', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('disappearance', 'NegReg', (143, 156))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (9, 14))	('PEG-[SN22]4', 'Var', (100, 111))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (214, 219))	('tumors', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
552864	32839252	Tumors in mice treated with liposomal CPT-11 showed regression but began progressing within weeks after stopping treatment, and all had progressed and had to be sacrificed by 3 mo.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (10, 14))	('CPT-11', 'Gene', (38, 44))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CPT-11', 'Chemical', 'MESH:D000077146', (38, 44))	('liposomal', 'Var', (28, 37))
552865	32839252	However, all the tumors in mice treated with PEG-[SN22]4 regressed completely, and no recurrence was observed up to 6+ months (Fig.	('PEG-[SN22]4', 'Chemical', '-', (45, 56))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mice', 'Species', '10090', (27, 31))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('PEG-[SN22]4', 'Var', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
552866	32839252	To demonstrate the efficacy of PEG-[SN22]4 to treat other high-risk childhood solid tumors, we treated two representative high-risk sarcomas growing as orthotopic/flank xenografts in mice inoculated either with TC-71, a chemoresistant EWS with nonfunctional p53, or an alveolar (fusion-positive) RMS line Rh30 with mutated TP53.	('solid tumors', 'Disease', (78, 90))	('Rh30', 'Gene', (305, 309))	('PEG-[SN22]4', 'Chemical', '-', (31, 42))	('sarcomas', 'Disease', 'MESH:D012509', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Rh30', 'Gene', '6007', (305, 309))	('mice', 'Species', '10090', (183, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('TP53', 'Gene', (323, 327))	('sarcomas', 'Disease', (132, 140))	('TC-71', 'Chemical', '-', (211, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mutated', 'Var', (315, 322))
552867	32839252	After 180 days, all EWS mice treated with PEG-[SN22]4 had complete tumor regression with no palpable tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('mice', 'Species', '10090', (24, 28))	('PEG-[SN22]4', 'Chemical', '-', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PEG-[SN22]4', 'Var', (42, 53))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumors', 'Disease', (101, 107))
552868	32839252	Complete regression was also achieved with the RMS xenografts treated with PEG-[SN22]4, but slow tumor regrowth occurred in two out of ten mice at around 150 days (Fig.	('PEG-[SN22]4', 'Var', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('PEG-[SN22]4', 'Chemical', '-', (75, 86))	('mice', 'Species', '10090', (139, 143))
552871	32839252	In addition to pharmacokinetics and biodistribution, we monitored mouse weight and behavior, as well as complete blood counts (CBCs) and liver function tests (LFTs) after a single injection of free or liposomal CPT-11, as well as PEG-[SN38]4 and PEG-[SN22]4 in 129SvJ mice without tumors.	('tumors', 'Disease', (281, 287))	('CPT-11', 'Gene', (211, 217))	('PEG-[SN38]4', 'Chemical', '-', (230, 241))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('mouse', 'Species', '10090', (66, 71))	('CPT-11', 'Chemical', 'MESH:D000077146', (211, 217))	('mice', 'Species', '10090', (268, 272))	('liver function tests', 'MPA', (137, 157))	('PEG-[SN22]4', 'Chemical', '-', (246, 257))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('PEG-[SN38]4', 'Var', (230, 241))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))
552874	32839252	Thus, there were no significant hepatic or hematological toxicities with PEG-[SN22]4 compared to other related treatments.	('PEG-[SN22]4', 'Chemical', '-', (73, 84))	('hepatic or hematological toxicities', 'Disease', (32, 67))	('PEG-[SN22]4', 'Var', (73, 84))	('hepatic or hematological toxicities', 'Disease', 'MESH:D056486', (32, 67))
552875	32839252	The only significant untoward effect observed in these studies was the development of ataxia and a rolling behavior in four of the six TH-MYCN (129SvJ) mice treated with liposomal CPT-11.	('liposomal', 'Var', (170, 179))	('rolling behavior', 'CPA', (99, 115))	('ataxia', 'Phenotype', 'HP:0001251', (86, 92))	('ataxia', 'Disease', 'MESH:D001259', (86, 92))	('mice', 'Species', '10090', (152, 156))	('ataxia', 'Disease', (86, 92))	('CPT-11', 'Gene', (180, 186))	('CPT-11', 'Chemical', 'MESH:D000077146', (180, 186))
552892	32839252	Furthermore, SN22 delivery as a macromolecular prodrug prevents widespread systemic tissue and organ exposure, as well as rapid renal clearance of the active compound, which are key to its greater accumulation in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('SN22', 'Var', (13, 17))	('renal', 'MPA', (128, 133))	('SN22', 'Chemical', 'MESH:C051891', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('prevents', 'NegReg', (55, 63))
552896	32839252	Consistent with this mechanism driving primary drug resistance in high-risk tumors, therapeutics delivering SN38 had limited efficacy, whereas four weekly doses of PEG-[SN22]4 fully eradicated established tumors and led to complete remission for at least 6 months (Fig.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('SN38', 'Chemical', 'MESH:D000077146', (108, 112))	('eradicated', 'NegReg', (182, 192))	('drug resistance', 'Phenotype', 'HP:0020174', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('SN38', 'Var', (108, 112))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))	('PEG-[SN22]4', 'Chemical', '-', (164, 175))
552898	32839252	Mutant TP53 usually represent an acquired drug resistance mechanism in recurrent NBs.	('drug resistance', 'Phenotype', 'HP:0020174', (42, 57))	('TP53', 'Gene', (7, 11))	('NBs', 'Disease', (81, 84))	('NBs', 'Chemical', 'MESH:D009556', (81, 84))	('Mutant', 'Var', (0, 6))
552900	32839252	Although free CPT-11 had no effect in these two models, PEG-[SN22]4 caused rapid tumor shrinkage and produced durable remissions (Figs.	('PEG-[', 'Var', (56, 61))	('PEG-[SN22]4', 'Chemical', '-', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('CPT-11', 'Chemical', 'MESH:D000077146', (14, 20))
552902	32839252	Remarkably, these preliminary results demonstrate that the superior efficacy of PEG-[SN22]4 extends to other chemoresistance mechanisms, including those present in recurrent tumors, and is not restricted to de novo drug-resistant tumors characterized by ABC transporter overexpression.	('PEG-[SN22', 'Var', (80, 89))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('PEG-[SN22]4', 'Chemical', '-', (80, 91))	('chemoresistance', 'CPA', (109, 124))	('drug-resistant tumors', 'Disease', 'MESH:D000069279', (215, 236))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('drug-resistant tumors', 'Disease', (215, 236))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
552904	32839252	TC71 is a drug-resistant EWS line with mutated, nonfunctional p53, and although free CPT-11 had no effect, PEG-[SN22]4 again achieved complete remissions and "cures" in all 10 mice, as demonstrated by 6 months without recurrence and confirmed by necropsy (Fig.	('PEG-[SN22]4', 'Chemical', '-', (107, 118))	('CPT-11', 'Chemical', 'MESH:D000077146', (85, 91))	('mutated', 'Var', (39, 46))	('mice', 'Species', '10090', (176, 180))	('PEG-', 'Var', (107, 111))	('p53', 'Gene', (62, 65))
552905	32839252	CPT-11 had a modest and transient effect against xenografts established with Rh30, a fusion-positive, alveolar RMS line, but PEG-[SN22]4 produced complete and durable remissions after four weekly doses, with only 2 of 10 late recurrences after 6 months (Fig.	('Rh30', 'Gene', '6007', (77, 81))	('PEG-[SN22]4', 'Chemical', '-', (125, 136))	('CPT-11', 'Chemical', 'MESH:D000077146', (0, 6))	('PEG-[SN22]4', 'Var', (125, 136))	('Rh30', 'Gene', (77, 81))
552906	32839252	Thus, PEG-[SN22]4 provides a highly promising approach for treating both NBs exhibiting intrinsic and acquired resistance, as well as high-risk EWS and RMS based on the results of our preclinical model studies.	('NBs', 'Disease', (73, 76))	('PEG-[SN22]4', 'Chemical', '-', (6, 17))	('NBs', 'Chemical', 'MESH:D009556', (73, 76))	('RMS', 'Disease', (152, 155))	('PEG-[SN22]4', 'Var', (6, 17))
552907	32839252	Although much of the efficacy of PEG-[SN22]4 can be attributed to the unique chemical properties of SN22, the long-circulating aspect of the multivalent macromolecule resulted in sustained dwell time and significantly more accumulation in the tumor than was achieved with CPT-11 (free or liposomal) or an analogously made SN38 prodrug construct.	('more', 'PosReg', (218, 222))	('SN22', 'Var', (100, 104))	('SN38', 'Chemical', 'MESH:D000077146', (322, 326))	('accumulation', 'MPA', (223, 235))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('PEG-[SN22]4', 'Chemical', '-', (33, 44))	('CPT-11', 'Chemical', 'MESH:D000077146', (272, 278))	('SN22', 'Chemical', 'MESH:C051891', (38, 42))	('SN22', 'Chemical', 'MESH:C051891', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
552908	32839252	Dramatically higher blood and tumor drug concentrations of SN22 were consistently achieved with PEG-[SN22]4 at all examined time points (Table 1, Supplemental Table 1).	('PEG-[SN22', 'Var', (96, 105))	('PEG-[SN22]4', 'Chemical', '-', (96, 107))	('SN22', 'Chemical', 'MESH:C051891', (101, 105))	('higher', 'PosReg', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('SN22', 'Chemical', 'MESH:C051891', (59, 63))	('blood and', 'MPA', (20, 29))	('tumor', 'Disease', (30, 35))
552914	32839252	Most mechanisms of drug resistance, including mutated TP53, can be overcome by dramatically increasing the drug concentration and duration of drug exposure in the tumor, and this is an important advantage of our formulation employing SN22, due in large part to its resistance to glucuronidation.	('drug concentration', 'MPA', (107, 125))	('increasing', 'PosReg', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mutated', 'Var', (46, 53))	('tumor', 'Disease', (163, 168))	('TP53', 'Gene', (54, 58))	('SN22', 'Chemical', 'MESH:C051891', (234, 238))	('drug resistance', 'Phenotype', 'HP:0020174', (19, 34))
552916	32839252	The neurological syndrome that developed in four of the six TH-MYCN (129SvJ) mice treated with liposomal CPT-11 was unanticipated and is noteworthy.	('mice', 'Species', '10090', (77, 81))	('neurological syndrome', 'Disease', (4, 25))	('CPT-11', 'Gene', (105, 111))	('CPT-11', 'Chemical', 'MESH:D000077146', (105, 111))	('liposomal', 'Var', (95, 104))	('neurological syndrome', 'Disease', 'MESH:D009422', (4, 25))	('neurological syndrome', 'Phenotype', 'HP:0000707', (4, 25))
552921	32839252	The profound antitumor efficacy of PEG-[SN22]4 in models of NB and other solid tumors was not accompanied by any significant toxicity.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (17, 22))	('PEG-[SN22]4', 'Chemical', '-', (35, 46))	('tumor', 'Disease', (79, 84))	('NB', 'Gene', '230972', (60, 62))	('solid tumors', 'Disease', (73, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('toxicity', 'Disease', 'MESH:D064420', (125, 133))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('toxicity', 'Disease', (125, 133))	('PEG-[SN22]4', 'Var', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('solid tumors', 'Disease', 'MESH:D009369', (73, 85))
552922	32839252	CPT-11 treatment caused transient elevations of transaminases ALT and AST, and a modest effect on blood counts, whereas PEG-[SN22]4 did not.	('elevations of transaminases', 'Phenotype', 'HP:0002910', (34, 61))	('elevations', 'PosReg', (34, 44))	('blood counts', 'MPA', (98, 110))	('ALT', 'Gene', (62, 65))	('AST', 'Gene', '235504', (70, 73))	('AST', 'Gene', (70, 73))	('CPT-11', 'Gene', (0, 6))	('treatment', 'Var', (7, 16))	('CPT-11', 'Chemical', 'MESH:D000077146', (0, 6))	('ALT', 'Gene', '76282', (62, 65))	('PEG-[SN22]4', 'Chemical', '-', (120, 131))
552926	32839252	Furthermore, the glucuronidated form of SN38 in the GI tract also contributes to the GI toxicity, whereas the likelihood of intractable diarrhea is markedly reduced with SN22, which is not susceptible to glucuronidation and does not release a dipiperidino moiety upon activation.	('diarrhea', 'Phenotype', 'HP:0002014', (136, 144))	('diarrhea', 'Disease', (136, 144))	('diarrhea', 'Disease', 'MESH:D003967', (136, 144))	('SN22', 'Chemical', 'MESH:C051891', (170, 174))	('SN38', 'Chemical', 'MESH:D000077146', (40, 44))	('SN38', 'Gene', (40, 44))	('intractable diarrhea', 'Phenotype', 'HP:0002041', (124, 144))	('dipiperidino', 'Chemical', '-', (243, 255))	('toxicity', 'Disease', 'MESH:D064420', (88, 96))	('SN22', 'Var', (170, 174))	('toxicity', 'Disease', (88, 96))	('reduced', 'NegReg', (157, 164))
552928	32839252	Taken together, the superior efficacy and improved biocompatibility of PEG-[SN22]4 demonstrated in clinically relevant models of high-risk solid tumors make it a highly promising new therapeutic capable of addressing the considerable limitations of clinically used camptothecins.	('improved', 'PosReg', (42, 50))	('solid tumors', 'Disease', 'MESH:D009369', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('PEG-[SN22]4', 'Chemical', '-', (71, 82))	('camptothecins', 'Chemical', 'MESH:D002166', (265, 278))	('biocompatibility', 'MPA', (51, 67))	('solid tumors', 'Disease', (139, 151))	('PEG-[', 'Var', (71, 76))
552933	31562358	The signatures substantially recover the leiomyosarcoma, dedifferentiated liposarcoma (DDLPS), and synovial sarcoma histological subtype diagnoses, and they also include a new signature defined by activation and inactivation of about a dozen genes, including activation of serine endopeptidase inhibitor SERPINE1 and inactivation of TP53-family tumor suppressor gene TP73.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (99, 115))	('tumor', 'Disease', (345, 350))	('P53', 'Gene', '7157', (334, 337))	('P73', 'Gene', (368, 371))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('liposarcoma', 'Disease', (74, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (41, 55))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('liposarcoma', 'Phenotype', 'HP:0012034', (74, 85))	('synovial sarcoma', 'Disease', (99, 115))	('serine', 'Chemical', 'MESH:C047902', (273, 279))	('inactivation', 'NegReg', (212, 224))	('activation', 'PosReg', (259, 269))	('inactivation', 'Var', (317, 329))	('activation', 'PosReg', (197, 207))	('P73', 'Gene', '7161', (368, 371))	('liposarcoma', 'Disease', 'MESH:D008080', (74, 85))	('synovial sarcoma', 'Disease', 'MESH:D013584', (99, 115))	('leiomyosarcoma', 'Disease', (41, 55))	('P53', 'Gene', (334, 337))
552945	31562358	As expected, high levels of CCNG1 (cyclin G), PPM1D (Wip1), and TP73 (P73), as well as MDM2 are all negatively regulating TP53, which is not substantially activated.	('negatively', 'NegReg', (100, 110))	('P73', 'Gene', (70, 73))	('P53', 'Gene', (123, 126))	('Wip1', 'Gene', (53, 57))	('PPM1D', 'Var', (46, 51))	('P73', 'Gene', '7161', (65, 68))	('P73', 'Gene', '7161', (70, 73))	('P53', 'Gene', '7157', (123, 126))	('cyclin G', 'Gene', '900', (35, 43))	('MDM2', 'Gene', '4193', (87, 91))	('(Wip1', 'Gene', '8493', (52, 57))	('MDM2', 'Gene', (87, 91))	('regulating', 'Reg', (111, 121))	('P73', 'Gene', (65, 68))	('cyclin G', 'Gene', (35, 43))
552956	31562358	On the other hand, synovial sarcoma is known to be well-characterized by a specific translocation resulting in gene fusion of SYT with either SSX1, SSX2, or SSX4.	('SSX', 'Gene', (148, 151))	('synovial sarcoma', 'Disease', (19, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (19, 35))	('SSX', 'Gene', (157, 160))	('synovial sarcoma', 'Disease', 'MESH:D013584', (19, 35))	('SSX', 'Gene', '6757', (157, 160))	('SSX2', 'Gene', '6757', (148, 152))	('gene fusion', 'Var', (111, 122))	('SYT', 'Gene', (126, 129))	('SSX', 'Gene', (142, 145))	('SSX', 'Gene', '6757', (142, 145))	('SSX', 'Gene', '6757', (148, 151))	('SSX2', 'Gene', (148, 152))
552965	31562358	Damage to SERPINB3 on chromosome 18q disrupts serine/cysteine-type endopeptidase inhibitor activity, which is then restored by SERPINE1 upregulation by some intermediate process.	('SERPINB3', 'Gene', (10, 18))	('SERPINB3', 'Gene', '6317', (10, 18))	('Damage', 'Var', (0, 6))	('cysteine', 'Chemical', 'MESH:D003545', (53, 61))	('disrupts', 'NegReg', (37, 45))	('serine', 'Chemical', 'MESH:C047902', (46, 52))
552977	29093183	In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis.	('AZD6738', 'Chemical', 'MESH:C000611951', (71, 78))	('PGBD5-dependent', 'Gene', (107, 122))	('AZD6738', 'Var', (71, 78))
552981	29093183	Accordingly, AZD6738 exhibited nanomolar potency against the majority of neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdoid tumor cells tested, while sparing non-transformed human and mouse embryonic fibroblasts in vitro.	('AZD6738', 'Chemical', 'MESH:C000611951', (13, 20))	('medulloblastoma', 'Phenotype', 'HP:0002885', (88, 103))	('mouse', 'Species', '10090', (192, 197))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('neuroblastoma', 'Phenotype', 'HP:0003006', (73, 86))	('human', 'Species', '9606', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('medulloblastoma', 'Disease', (88, 103))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (123, 137))	('rhabdoid tumor', 'Disease', (123, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('neuroblastoma', 'Disease', 'MESH:D009447', (73, 86))	('medulloblastoma', 'Disease', 'MESH:D008527', (88, 103))	('Ewing sarcoma', 'Disease', (105, 118))	('AZD6738', 'Var', (13, 20))	('neuroblastoma', 'Disease', (73, 86))
552982	29093183	Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo.	('AZD6738', 'Var', (24, 31))	('human', 'Species', '9606', (68, 73))	('apoptosis', 'CPA', (40, 49))	('neuroblastoma', 'Disease', 'MESH:D009447', (74, 87))	('mice', 'Species', '10090', (144, 148))	('AZD6738', 'Chemical', 'MESH:C000611951', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('medulloblastoma', 'Phenotype', 'HP:0002885', (92, 107))	('medulloblastoma tumors', 'Disease', 'MESH:D008527', (92, 114))	('neuroblastoma', 'Disease', (74, 87))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('neuroblastoma', 'Phenotype', 'HP:0003006', (74, 87))	('regression', 'CPA', (54, 64))	('medulloblastoma tumors', 'Disease', (92, 114))
552986	29093183	For example, neuroblastomas and medulloblastomas characterized by amplifications of the MYCN and MYC oncogenes, respectively, remain mostly fatal.	('medulloblastoma', 'Phenotype', 'HP:0002885', (32, 47))	('neuroblastoma', 'Phenotype', 'HP:0003006', (13, 26))	('MYC', 'Gene', '4609', (88, 91))	('neuroblastomas and medulloblastomas', 'Disease', 'MESH:D008527', (13, 48))	('MYC', 'Gene', (97, 100))	('amplifications', 'Var', (66, 80))	('neuroblastomas', 'Phenotype', 'HP:0003006', (13, 27))	('MYC', 'Gene', (88, 91))	('MYC', 'Gene', '4609', (97, 100))
552987	29093183	Likewise, cancers defined by mutations of the genes encoding the SWI/SNF chromatin remodeling complex, such as rhabdoid tumors, are almost uniformly incurable.	('rhabdoid tumors', 'Disease', (111, 126))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (111, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('mutations', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancers', 'Disease', (10, 17))
552989	29093183	The majority of refractory childhood solid tumors are characterized by mutations of factors that regulate gene expression or complex genomic rearrangements, both of which are not generally amenable to current pharmacologic strategies.	('solid tumors', 'Disease', 'MESH:D009369', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('solid tumors', 'Disease', (37, 49))	('characterized by', 'Reg', (54, 70))
552992	29093183	For example, tumors with inefficient homologous recombination DNA repair due to mutations of BRCA1/2 exhibit synthetic lethality with inhibitors of poly ADP-ribose polymerases (PARPs), enabling significant improvements in the treatment of patients as a result of clinical PARP inhibitors.	('PARP', 'Gene', '142', (272, 276))	('synthetic', 'Species', '32630', (109, 118))	('BRCA1/2', 'Gene', (93, 100))	('tumors', 'Disease', (13, 19))	('mutations', 'Var', (80, 89))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('PARP', 'Gene', '142', (177, 181))	('patients', 'Species', '9606', (239, 247))	('PARPs', 'Gene', (177, 182))	('treatment', 'CPA', (226, 235))	('PARP', 'Gene', (272, 276))	('improvements', 'PosReg', (206, 218))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PARPs', 'Gene', '142', (177, 182))	('PARP', 'Gene', (177, 181))
552994	29093183	In particular, intrinsic DNA damage due to oncogene or replication stress such as MYC, and tumorigenic deficiencies in the DNA damage response due to mutations of TP53, ATM or ATR have been found to confer susceptibility to specific inhibitors of DNA damage repair signaling.	('susceptibility', 'MPA', (206, 220))	('tumorigenic deficiencies', 'Disease', 'MESH:D002471', (91, 115))	('ATM', 'Gene', '472', (169, 172))	('TP53', 'Gene', '7157', (163, 167))	('MYC', 'Gene', '4609', (82, 85))	('ATR', 'Gene', '545', (176, 179))	('DNA damage', 'MPA', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TP53', 'Gene', (163, 167))	('mutations', 'Var', (150, 159))	('ATM', 'Gene', (169, 172))	('ATR', 'Gene', (176, 179))	('MYC', 'Gene', (82, 85))	('tumorigenic deficiencies', 'Disease', (91, 115))
552995	29093183	However, these mutations are generally rare in pediatric cancers, and little is known about therapeutically targetable synthetic dependencies in childhood solid tumors.	('pediatric cancers', 'Disease', (47, 64))	('synthetic', 'Species', '32630', (119, 128))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('pediatric cancers', 'Disease', 'MESH:D009369', (47, 64))	('solid tumors', 'Disease', (155, 167))	('mutations', 'Var', (15, 24))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('solid tumors', 'Disease', 'MESH:D009369', (155, 167))
552998	29093183	In particular, PGBD5 was found to be expressed in the majority of childhood solid tumors, including refractory rhabdoid tumors, where it promotes site-specific genomic rearrangements and mutations of tumor suppressor genes at least in part due to the aberrant targeting of its DNA nuclease activity.	('rhabdoid tumors', 'Disease', (111, 126))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (111, 126))	('genomic rearrangements', 'CPA', (160, 182))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (200, 205))	('solid tumors', 'Disease', (76, 88))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('promotes', 'PosReg', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mutations', 'Var', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('PGBD5', 'Gene', (15, 20))
553007	29093183	To test the cellular DNA repair requirements of PGBD5, we used mouse embryonic fibroblasts (MEFs) from mice deficient for Ku80-/-, Atm-/-, and hypomorphic Seckel syndrome allele of AtrS/S, and immortalized with the SV40 large T antigen (Fig.	('hypomorphic Seckel syndrome', 'Disease', 'MESH:C537533', (143, 170))	('Atr', 'Gene', (181, 184))	('mouse', 'Species', '10090', (63, 68))	('mice', 'Species', '10090', (103, 107))	('Atr', 'Gene', '545', (181, 184))	('Ku80-/-', 'Var', (122, 129))	('hypomorphic Seckel syndrome', 'Disease', (143, 170))	('MEFs', 'CellLine', 'CVCL:9115', (92, 96))
553011	29093183	In contrast, Atm-/-, AtrS/S, and Ku80-/- MEFs underwent cell death, as detected by the significant accumulation of cleaved caspase 3 (p = 1.0e-2, 8.0e-3, and 1.0e-3, respectively, Figs.	('Ku80-/-', 'Var', (33, 40))	('caspase 3', 'Gene', '836', (123, 132))	('MEFs', 'CellLine', 'CVCL:9115', (41, 45))	('Atr', 'Gene', '545', (21, 24))	('cell death', 'CPA', (56, 66))	('accumulation', 'PosReg', (99, 111))	('caspase 3', 'Gene', (123, 132))	('Atr', 'Gene', (21, 24))
553013	29093183	Deficiency of Ku80 that functions in direct DSB binding during NHEJ DNA repair exhibited similar levels of cell death as the respective deficiencies of Atm and Atr that contribute to the activation and propagation of DNA damage signaling (Fig.	('Ku80', 'Gene', (14, 18))	('deficiencies of Atm', 'Disease', 'MESH:D001260', (136, 155))	('Atr', 'Gene', '545', (160, 163))	('Atr', 'Gene', (160, 163))	('DNA damage signaling', 'MPA', (217, 237))	('deficiencies of Atm', 'Disease', (136, 155))	('Deficiency', 'Var', (0, 10))
553015	29093183	We reasoned that specific PGBD5-dependent DNA damage response requirements may be identified by comparative analysis of growth and survival of RPE cells expressing GFP-PGBD5, as compared to GFP control and its catalytically inactive GFP-PGBD5 D168A/D194A/D386A mutant.	('D168A', 'SUBSTITUTION', 'None', (243, 248))	('RPE', 'CellLine', 'CVCL:4388', (143, 146))	('D386A', 'Mutation', 'p.D386A', (255, 260))	('D194A', 'Mutation', 'p.D194A', (249, 254))	('GFP-PGBD5', 'Var', (164, 173))	('D168A', 'Var', (243, 248))
553017	29093183	In particular, we observed that the ATR- and ATM-selective kinase inhibitors AZD6738 and KU60019 exhibited more than 20-fold and 5-fold enhanced activity, respectively, against RPE cells expressing GFP-PGBD5 as compared GFP control (Fig.	('ATR', 'Gene', '545', (36, 39))	('ATR', 'Gene', (36, 39))	('KU60019', 'Chemical', 'MESH:C546193', (89, 96))	('enhanced', 'PosReg', (136, 144))	('ATM', 'Gene', '472', (45, 48))	('activity', 'MPA', (145, 153))	('AZD6738', 'Chemical', 'MESH:C000611951', (77, 84))	('RPE', 'CellLine', 'CVCL:4388', (177, 180))	('AZD6738', 'Var', (77, 84))	('ATM', 'Gene', (45, 48))	('GFP-PGBD5', 'Var', (198, 207))	('KU60019', 'Var', (89, 96))
553018	29093183	Consistent with the notion that tolerance of PGBD5 DNA nuclease activity requires active DNA repair in cells, mutation of the aspartate catalytic triad (D168A, D194A, D386A) thought to catalyze phosphodiester bond hydrolysis during transposase-induced DNA rearrangements, completely abrogated the enhanced susceptibility of RPE cells upon PGBD5 expression (Fig.	('D386A', 'Var', (167, 172))	('D386A', 'Mutation', 'p.D386A', (167, 172))	('D168A', 'Var', (153, 158))	('susceptibility', 'MPA', (306, 320))	('aspartate', 'Chemical', 'MESH:D001224', (126, 135))	('abrogated', 'NegReg', (283, 292))	('D194A', 'Mutation', 'p.D194A', (160, 165))	('mutation', 'Var', (110, 118))	('D168A', 'Mutation', 'p.D168A', (153, 158))	('RPE', 'CellLine', 'CVCL:4388', (324, 327))	('enhanced', 'PosReg', (297, 305))	('D194A', 'Var', (160, 165))
553019	29093183	We confirmed that the activity of AZD6738 is at least in part due to its selective inhibition of ATR as compared to ATM, insofar as Atm-/- and AtrS/S MEFs exhibited respectively increased and diminished susceptibilities to AZD6738, in agreement with the known relationship between ATM and ATR kinase signaling (IC50 = 0.023 and 2.0 muM, respectively, as compared to 0.36 muM for wild-type control; Fig.	('AZD6738', 'Chemical', 'MESH:C000611951', (34, 41))	('ATM', 'Gene', (281, 284))	('ATR', 'Gene', '545', (289, 292))	('susceptibilities', 'MPA', (203, 219))	('AZD6738', 'Chemical', 'MESH:C000611951', (223, 230))	('Atr', 'Gene', '545', (143, 146))	('MEFs', 'CellLine', 'CVCL:9115', (150, 154))	('diminished', 'NegReg', (192, 202))	('ATR', 'Gene', '545', (97, 100))	('ATM', 'Gene', '472', (116, 119))	('Atr', 'Gene', (143, 146))	('ATM', 'Gene', '472', (281, 284))	('activity', 'MPA', (22, 30))	('muM', 'Gene', '56925', (332, 335))	('ATR', 'Gene', (289, 292))	('muM', 'Gene', '56925', (371, 374))	('inhibition', 'NegReg', (83, 93))	('muM', 'Gene', (332, 335))	('muM', 'Gene', (371, 374))	('AZD6738', 'Var', (34, 41))	('ATM', 'Gene', (116, 119))	('ATR', 'Gene', (97, 100))
553020	29093183	Thus, PGBD5-dependent effects may be explained by the selective inhibition of DNA damage signaling by ATR- and ATM-selective AZD6738 and KU60019, respectively.	('DNA damage signaling', 'MPA', (78, 98))	('ATM', 'Gene', (111, 114))	('KU60019', 'Chemical', 'MESH:C546193', (137, 144))	('ATM', 'Gene', '472', (111, 114))	('ATR', 'Gene', '545', (102, 105))	('ATR', 'Gene', (102, 105))	('AZD6738', 'Chemical', 'MESH:C000611951', (125, 132))	('inhibition', 'NegReg', (64, 74))	('AZD6738', 'Var', (125, 132))	('KU60019', 'Var', (137, 144))
553023	29093183	1), we found that active DNA damage signaling blocked by AZD6738 is also required for the growth and survival of PGBD5-expressing human RPE cells (Figs.	('RPE', 'CellLine', 'CVCL:4388', (136, 139))	('PGBD5-expressing', 'Gene', (113, 129))	('AZD6738', 'Chemical', 'MESH:C000611951', (57, 64))	('AZD6738', 'Var', (57, 64))	('human', 'Species', '9606', (130, 135))
553024	29093183	Specifically, we found that RPE cells expressing GFP-PGBD5, but not those expressing GFP or inactive mutant GFP-PGBD5, exhibited significantly increased DNA damage upon treatment with AZD6738, as measured gammaH2AX staining analysis (p = 0.040, Fig.	('increased', 'PosReg', (143, 152))	('DNA damage', 'MPA', (153, 163))	('gammaH2AX', 'Gene', '15270', (205, 214))	('AZD6738', 'Chemical', 'MESH:C000611951', (184, 191))	('gammaH2AX', 'Gene', (205, 214))	('RPE', 'CellLine', 'CVCL:4388', (28, 31))	('GFP-PGBD5', 'Var', (49, 58))
553025	29093183	Similarly, we observed significantly increased TUNEL labeling in RPE cells expressing GFP-PGBD5 upon treatment with AZD6738, whereas cells expressing control GFP or the catalytically inactive GFP-PGBD5 mutant exhibited unperturbed steady-state background TUNEL levels (p = 5.6 x 10-6, Fig.	('AZD6738', 'Chemical', 'MESH:C000611951', (116, 123))	('RPE', 'CellLine', 'CVCL:4388', (65, 68))	('TUNEL labeling', 'MPA', (47, 61))	('increased', 'PosReg', (37, 46))	('GFP-PGBD5', 'Var', (86, 95))
553026	29093183	Consistent with the notion that wild-type PGBD5 is actively inducing DSBs in cells, we observed significantly increased TUNEL levels even in the absence of AZD6738 treatment, an effect that was completely abolished by the mutation of its putative nuclease catalytic triad (Figs.	('mutation', 'Var', (222, 230))	('increased', 'PosReg', (110, 119))	('AZD6738', 'Chemical', 'MESH:C000611951', (156, 163))	('DSBs', 'Chemical', '-', (69, 73))	('TUNEL levels', 'MPA', (120, 132))
553027	29093183	Likewise, TUNEL accumulation upon PGBD5 expression and AZD6738 treatment was predominantly observed in G1 phase of the cell cycle (Fig.	('PGBD5', 'Gene', (34, 39))	('AZD6738', 'Chemical', 'MESH:C000611951', (55, 62))	('expression', 'Var', (40, 50))	('AZD6738', 'Var', (55, 62))	('TUNEL', 'MPA', (10, 15))	('accumulation', 'PosReg', (16, 28))
553028	29093183	In accordance with the accumulation of unrepaired DNA damage upon AZD6738 treatment in PGBD5-expressing cells, we observed significantly increased levels of apoptosis, as measured by caspase 3 cleavage, in cells expressing GFP-PGBD5, as compared to those expressing its inactive mutant or GFP control (p = 3.0e-4, Fig.	('AZD6738', 'Chemical', 'MESH:C000611951', (66, 73))	('apoptosis', 'MPA', (157, 166))	('caspase 3', 'Gene', (183, 192))	('caspase 3', 'Gene', '836', (183, 192))	('GFP-PGBD5', 'Var', (223, 232))	('increased', 'PosReg', (137, 146))
553030	29093183	2E), we confirmed that the PGBD5-specific susceptibility to AZD6738 was not immediately associated with DNA replication stress, as assessed by Western immunoblotting of phosphorylated RPA32 T21 and S4/8, as compared to the DNA topoisomerase I inhibitor camptothecin that predominantly induces DSBs during DNA replication in S phase (Fig.	('RPA32', 'Gene', '6118', (184, 189))	('DSBs', 'Chemical', '-', (293, 297))	('PGBD5-specific', 'Gene', (27, 41))	('RPA32', 'Gene', (184, 189))	('AZD6738', 'Chemical', 'MESH:C000611951', (60, 67))	('AZD6738', 'Var', (60, 67))	('camptothecin', 'Chemical', 'MESH:D002166', (253, 265))
553031	29093183	In agreement with this, RPE cells expressing GFP-PGBD5 did not show increased cell cycling as compared to cells expressing GFP control, as measured by 5-ethynyl-2'-deoxyuridine (EdU) incorporation (Fig.	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (151, 176))	('EdU', 'Chemical', 'MESH:C031086', (178, 181))	('cell cycling', 'CPA', (78, 90))	('RPE', 'CellLine', 'CVCL:4388', (24, 27))	('GFP-PGBD5', 'Var', (45, 54))
553036	29093183	We have now found that expression of PGBD5 in non-transformed mouse embryonic fibroblasts and human RPE cells is sufficient to induce DNA damage as measured by TUNEL incorporation in cells, which can be potentiated by DNA damage signaling inhibitor AZD6738.	('induce', 'Reg', (127, 133))	('mouse', 'Species', '10090', (62, 67))	('AZD6738', 'Chemical', 'MESH:C000611951', (249, 256))	('RPE', 'CellLine', 'CVCL:4388', (100, 103))	('TUNEL incorporation', 'MPA', (160, 179))	('expression', 'Var', (23, 33))	('DNA damage', 'MPA', (134, 144))	('human', 'Species', '9606', (94, 99))	('PGBD5', 'Gene', (37, 42))
553037	29093183	Thus, we reasoned that AZD6738 may exhibit anti-tumor activity against childhood solid tumor cells expressing PGBD5.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (87, 92))	('PGBD5', 'Gene', (110, 115))	('AZD6738', 'Var', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('AZD6738', 'Chemical', 'MESH:C000611951', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
553039	29093183	We observed that 19 childhood tumor cell lines tested exhibited enhanced sensitivity to AZD6738, with 50% inhibitory concentrations (IC50) largely in the nanomolar range (Fig.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('sensitivity', 'MPA', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('AZD6738', 'Var', (88, 95))	('AZD6738', 'Chemical', 'MESH:C000611951', (88, 95))	('tumor', 'Disease', (30, 35))	('enhanced', 'PosReg', (64, 72))
553040	29093183	In contrast, non-transformed RPE and BJ cells were relatively resistant to AZD6738, with IC50 values in the high micromolar range (Fig.	('BJ', 'CellLine', 'CVCL:6573', (37, 39))	('RPE', 'CellLine', 'CVCL:4388', (29, 32))	('AZD6738', 'Var', (75, 82))	('AZD6738', 'Chemical', 'MESH:C000611951', (75, 82))	('IC50', 'MPA', (89, 93))
553041	29093183	Indeed, the susceptibility to AZD6738, as measured by its IC50 values in vitro, exhibited a significant correlation with the level of PGBD5 protein expression, as assessed by quantitative fluorescent Western immunoblotting (p = 4.4e-3, Fig.	('susceptibility', 'MPA', (12, 26))	('AZD6738', 'Chemical', 'MESH:C000611951', (30, 37))	('AZD6738', 'Var', (30, 37))
553043	29093183	4B), or the presence of mutations in genes known to affect DNA damage signaling, such as TP53, ATM, ATR, MYC, MYCN, XRCC3, XRCC5, CHK1, BRCA2, RAS, and ATRX (Fig.	('ATR', 'Gene', (152, 155))	('CHK1', 'Gene', (130, 134))	('XRCC3', 'Gene', '7517', (116, 121))	('DNA damage signaling', 'MPA', (59, 79))	('MYC', 'Gene', (105, 108))	('BRCA2', 'Gene', (136, 141))	('mutations', 'Var', (24, 33))	('affect', 'Reg', (52, 58))	('TP53', 'Gene', '7157', (89, 93))	('ATM', 'Gene', (95, 98))	('CHK1', 'Gene', '1111', (130, 134))	('ATR', 'Gene', (100, 103))	('XRCC5', 'Gene', (123, 128))	('BRCA2', 'Gene', '675', (136, 141))	('XRCC5', 'Gene', '7520', (123, 128))	('ATR', 'Gene', '545', (152, 155))	('MYC', 'Gene', '4609', (105, 108))	('MYC', 'Gene', (110, 113))	('XRCC3', 'Gene', (116, 121))	('ATRX', 'Gene', (152, 156))	('ATRX', 'Gene', '546', (152, 156))	('TP53', 'Gene', (89, 93))	('ATM', 'Gene', '472', (95, 98))	('ATR', 'Gene', '545', (100, 103))	('MYC', 'Gene', '4609', (110, 113))
553044	29093183	In addition, since ATM deficiency can confer increased sensitivity to AZD6738, we confirmed that PGBD5 expression did not affect the expression of ATM itself in RPE cells, and that human tumor cells exhibiting enhanced susceptibility to AZD6738 lacked ATM mutations and retained ATM protein expression (Fig.	('ATM', 'Gene', (252, 255))	('lacked', 'NegReg', (245, 251))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('AZD6738', 'Chemical', 'MESH:C000611951', (70, 77))	('human', 'Species', '9606', (181, 186))	('ATM', 'Gene', '472', (279, 282))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('ATM', 'Gene', (19, 22))	('RPE', 'CellLine', 'CVCL:4388', (161, 164))	('ATM', 'Gene', '472', (252, 255))	('PGBD5', 'Gene', (97, 102))	('tumor', 'Disease', (187, 192))	('ATM', 'Gene', (147, 150))	('mutations', 'Var', (256, 265))	('ATM', 'Gene', '472', (19, 22))	('ATM', 'Gene', (279, 282))	('AZD6738', 'Chemical', 'MESH:C000611951', (237, 244))	('ATM', 'Gene', '472', (147, 150))
553045	29093183	In agreement with observations of MEFs and RPE cells expressing PGBD5, human tumor cell lines expressing endogenous PGBD5 and treated with AZD6738 underwent apoptosis and accumulated unrepaired DNA damage, as measured by caspase 3 cleavage and TUNEL staining (Figs.	('underwent', 'Reg', (147, 156))	('PGBD5', 'Gene', (116, 121))	('RPE', 'CellLine', 'CVCL:4388', (43, 46))	('apoptosis', 'CPA', (157, 166))	('caspase 3', 'Gene', (221, 230))	('caspase 3', 'Gene', '836', (221, 230))	('MEFs', 'CellLine', 'CVCL:9115', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('unrepaired', 'MPA', (183, 193))	('AZD6738', 'Var', (139, 146))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('AZD6738', 'Chemical', 'MESH:C000611951', (139, 146))	('accumulated', 'PosReg', (171, 182))	('tumor', 'Disease', (77, 82))	('human', 'Species', '9606', (71, 76))
553046	29093183	Most of the TUNEL incorporation induced by AZD6738 in PGBD5-expressing tumor cells was observed in G1 cells (Figs.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TUNEL incorporation', 'MPA', (12, 31))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('AZD6738', 'Chemical', 'MESH:C000611951', (43, 50))	('tumor', 'Disease', (71, 76))	('AZD6738', 'Var', (43, 50))
553047	29093183	Thus, AZD6738 exhibits anti-tumor efficacy against PGBD5-expressing childhood solid tumors in vitro.	('solid tumors', 'Disease', (78, 90))	('AZD6738', 'Var', (6, 13))	('PGBD5-expressing', 'Gene', (51, 67))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (28, 33))	('AZD6738', 'Chemical', 'MESH:C000611951', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
553048	29093183	Since ectopic PGBD5 expression may induce DNA damage and signaling dependencies not present in human tumors with endogenous PGBD5, we sought to determine if endogenous PGBD5 expression is required for the enhanced susceptibility to inhibitors of DNA damage signaling.	('human', 'Species', '9606', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('induce', 'Reg', (35, 41))	('PGBD5', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('expression', 'Var', (20, 30))	('signaling dependencies', 'MPA', (57, 79))	('ectopic', 'Var', (6, 13))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('DNA damage', 'MPA', (42, 52))	('tumors', 'Disease', (101, 107))
553055	29093183	Compelled by the finding that AZD6738 induced PGBD5-dependent DNA damage and apoptosis in pediatric solid tumor cell lines in vitro, we set out to test whether single-agent AZD6738 treatment has anti-tumor activity in preclinical models of pediatric solid tumors in vivo.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('pediatric solid tumors', 'Disease', (240, 262))	('PGBD5-dependent', 'Gene', (46, 61))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('apoptosis', 'CPA', (77, 86))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (240, 262))	('AZD6738', 'Chemical', 'MESH:C000611951', (173, 180))	('AZD6738', 'Var', (173, 180))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('AZD6738', 'Chemical', 'MESH:C000611951', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('AZD6738', 'Var', (30, 37))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', (106, 111))
553058	29093183	We found that AZD6738 significantly impaired the growth of both neuroblastoma IMR5 and medulloblastoma HD-MB03 tumors, as compared to vehicle control treated mice in vivo (p = 4.9e-3 and 5.5e-6 at day 28 respectively, Fig.	('AZD6738', 'Chemical', 'MESH:C000611951', (14, 21))	('impaired', 'NegReg', (36, 44))	('neuroblastoma', 'Disease', 'MESH:D009447', (64, 77))	('AZD6738', 'Var', (14, 21))	('mice', 'Species', '10090', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('neuroblastoma', 'Disease', (64, 77))	('medulloblastoma HD-MB03 tumors', 'Disease', 'MESH:D006816', (87, 117))	('medulloblastoma HD-MB03 tumors', 'Disease', (87, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('neuroblastoma', 'Phenotype', 'HP:0003006', (64, 77))	('growth', 'MPA', (49, 55))	('medulloblastoma', 'Phenotype', 'HP:0002885', (87, 102))
553062	29093183	Residual tumor cells isolated from mice upon the completion of 20 days of AZD6738 treatment exhibited significantly reduced proliferation, as measured by Ki67 staining (p = 3.1e-5 and 1.0e-3 for IMR5 and HD-MB03 respectively, Fig.	('HD-MB03', 'CellLine', 'CVCL:S506', (204, 211))	('Ki67', 'Gene', '17345', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('proliferation', 'CPA', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('Ki67', 'Gene', (154, 158))	('mice', 'Species', '10090', (35, 39))	('AZD6738', 'Var', (74, 81))	('reduced', 'NegReg', (116, 123))	('AZD6738', 'Chemical', 'MESH:C000611951', (74, 81))
553072	29093183	Subsequently, we transplanted these tumor specimens subcutaneously into NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac (NOG) immunodeficient mice, and upon tumor engraftment as evidenced by tumor volumetric measurements, randomized recipient mice to be treated with single-agent AZD6738 (50 mg/kg daily PO for 14 days), single-agent cisplatin (2 mg/kg IP every 7 days), combination of AZD6738 and cisplatin, or vehicle control (Fig.	('mice', 'Species', '10090', (130, 134))	('AZD6738', 'Var', (374, 381))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('AZD6738', 'Chemical', 'MESH:C000611951', (374, 381))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (386, 395))	('AZD6738', 'Chemical', 'MESH:C000611951', (268, 275))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (322, 331))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mice', 'Species', '10090', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (179, 184))
553074	29093183	7B), we found that single-agent treatment with AZD6738 or cisplatin had limited effects, whereas combination of AZD6738 with cisplatin exhibited significant reduction in tumor growth, as compared to single-agent or vehicle control treatments (p = 1.9e-3, Fig.	('combination', 'Interaction', (97, 108))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('reduction', 'NegReg', (157, 166))	('tumor', 'Disease', (170, 175))	('AZD6738', 'Chemical', 'MESH:C000611951', (112, 119))	('AZD6738', 'Var', (112, 119))	('AZD6738', 'Chemical', 'MESH:C000611951', (47, 54))
553075	29093183	7B), we observed significant reduction in tumor growth upon single-agent AZD6738 and cisplatin treatment, as compared to vehicle control (p = 0.032 and 0.079, respectively, Fig.	('tumor', 'Disease', (42, 47))	('reduction', 'NegReg', (29, 38))	('AZD6738', 'Chemical', 'MESH:C000611951', (73, 80))	('AZD6738', 'Var', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
553076	29093183	Altogether, these results indicate that AZD6738 exhibits significant single-agent and cisplatin-combination efficacy against PGBD5-expressing solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('PGBD5-expressing', 'Gene', (125, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('AZD6738', 'Chemical', 'MESH:C000611951', (40, 47))	('cisplatin-combination', 'MPA', (86, 107))	('solid tumors', 'Disease', (142, 154))	('AZD6738', 'Var', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
553078	29093183	Consistent with the genomic rearrangements promoted by PGBD5 in rhabdoid tumors, expression of PGBD5 induces DNA damage, which requires both DNA damage repair and DNA damage signaling, resulting in apoptosis if impaired by their selective inhibitors (Fig.	('apoptosis', 'CPA', (198, 207))	('rhabdoid tumors', 'Disease', (64, 79))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (64, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('expression', 'Var', (81, 91))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('DNA damage', 'MPA', (109, 119))	('induces', 'Reg', (101, 108))	('PGBD5', 'Gene', (95, 100))
553086	29093183	However, chemical DNA damage signaling kinase inhibitors exhibited a specific profile with the ATR- and ATM-selective AZD6738 and KU60019 inhibitors exhibiting enhanced PGBD5-dependent activity.	('ATR', 'Gene', '545', (95, 98))	('ATR', 'Gene', (95, 98))	('KU60019', 'Chemical', 'MESH:C546193', (130, 137))	('ATM', 'Gene', '472', (104, 107))	('AZD6738', 'Chemical', 'MESH:C000611951', (118, 125))	('enhanced', 'PosReg', (160, 168))	('PGBD5-dependent', 'Enzyme', (169, 184))	('ATM', 'Gene', (104, 107))	('KU60019', 'Var', (130, 137))	('AZD6738', 'Gene', (118, 125))
553090	29093183	Lastly, the susceptibility of PGBD5-expressing tumors to selective inhibitors of DNA damage signaling is expected to cooperate with other sources of DNA damage in tumors, such as oncogene or replication stress.	('inhibitors', 'Var', (67, 77))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('PGBD5-expressing', 'Gene', (30, 46))
553095	29093183	Inhibitors of DNA damage signaling are currently being investigated in clinical trials, including AZD6738 (NCT02264678, NCT02223923, NCT02630199).	('NCT02264678', 'Var', (107, 118))	('NCT02223923', 'Var', (120, 131))	('AZD6738', 'Chemical', 'MESH:C000611951', (98, 105))
553099	29093183	All small molecule inhibitors used were dissolved in dimethyl sulfoxide at 10 mM (Fisher Scientific, Watham, MA, USA) and stored at -20  C until further use: AZD6738 (Astra Zeneca, London, UK), KU60019 (Selleck Chemicals LLC, Munich, Germany), AZ20 (Tocris, Bristol, UK), VE822 (Selleck Chemicals LLC), AZD7762 (Selleck Chemicals LLC).	('KU60019', 'Chemical', 'MESH:C546193', (194, 201))	('AZD7762', 'Var', (303, 310))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (53, 71))	('AZD6738', 'Chemical', 'MESH:C000611951', (158, 165))	('KU60019', 'Var', (194, 201))	('VE822', 'Var', (272, 277))	('AZD6738', 'Var', (158, 165))
553100	29093183	Human PGBD5 cDNA (Refseq ID: NM_001258311.1) was cloned into the lentiviral vector in frame with N-terminal GFP to generate pRecLV103-GFP-PGBD5 (GeneCopoeia, Rockville, MD, USA).	('Human', 'Species', '9606', (0, 5))	('PGBD5', 'Gene', (6, 11))	('pRecLV103-GFP-PGBD5', 'Var', (124, 143))
553106	29093183	Ku80-/-, AtrS/S, and Atm-/- mouse embryonic fibroblasts were generated by transduction with SV40 large T antigen.	('mouse', 'Species', '10090', (28, 33))	('SV40', 'Var', (92, 96))	('Atr', 'Gene', '545', (9, 12))	('Atr', 'Gene', (9, 12))
553250	26622492	Development of squamous cell carcinoma in burn scar ulcers was reported to be associated with local Fas gene mutation and deletion.	('ulcers', 'Disease', (52, 58))	('local Fas gene', 'Gene', (94, 108))	('associated', 'Reg', (78, 88))	('ulcers', 'Disease', 'MESH:D014456', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('deletion', 'Var', (122, 130))	('squamous cell carcinoma', 'Disease', (15, 38))	('scar', 'Phenotype', 'HP:0100699', (47, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (15, 38))	('burn scar ulcer', 'Phenotype', 'HP:0200042', (42, 57))	('mutation', 'Var', (109, 117))
553265	26622492	Radiotherapy may also induce further carcinomatous change.	('Radiotherapy', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomatous change', 'Disease', (37, 57))	('induce', 'Reg', (22, 28))	('carcinomatous change', 'Disease', 'MESH:D055756', (37, 57))
553276	22976541	Over 90 % of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of oncogenic SS18-SSX1 or SS18-SSX2 fusions.	('t(X;18)(', 'Var', (47, 55))	('SS', 'Phenotype', 'HP:0012570', (152, 154))	('SS18', 'Gene', '6760', (147, 151))	('SS18', 'Gene', '6760', (134, 138))	('SSX1', 'Gene', (139, 143))	('SS', 'Phenotype', 'HP:0012570', (134, 136))	('SSX2', 'Gene', (152, 156))	('SS', 'Phenotype', 'HP:0012570', (13, 15))	('SSX2', 'Gene', '6757', (152, 156))	('SS18', 'Gene', (134, 138))	('SS', 'Phenotype', 'HP:0012570', (147, 149))	('SS18', 'Gene', (147, 151))	('SSX1', 'Gene', '6756', (139, 143))	('SS', 'Phenotype', 'HP:0012570', (139, 141))	('results', 'Reg', (89, 96))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (47, 67))
553280	22976541	Among the cases under study, two tumors carried novel SS18-SSX1 and SS18-SSX2 variant translocations that were allegedly created by an alternative splicing, and in additional case, an unusual translocation variant previously described by other group was found.	('SSX2', 'Gene', (73, 77))	('SS18', 'Gene', '6760', (68, 72))	('SS', 'Phenotype', 'HP:0012570', (54, 56))	('SSX1', 'Gene', '6756', (59, 63))	('SS', 'Phenotype', 'HP:0012570', (68, 70))	('SS18', 'Gene', (68, 72))	('SS18', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('SSX1', 'Gene', (59, 63))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('variant translocations', 'Var', (78, 100))	('SSX2', 'Gene', '6757', (73, 77))	('SS', 'Phenotype', 'HP:0012570', (59, 61))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('SS18', 'Gene', '6760', (54, 58))	('tumors', 'Disease', (33, 39))	('SS', 'Phenotype', 'HP:0012570', (73, 75))
553288	22976541	Moreover, rare cases of SS18-SSX4 chimeric variants in SS have been described.	('SSX4', 'Gene', (29, 33))	('SS18', 'Gene', '6760', (24, 28))	('SS', 'Phenotype', 'HP:0012570', (24, 26))	('chimeric variants', 'Var', (34, 51))	('SS18', 'Gene', (24, 28))	('SS', 'Phenotype', 'HP:0012570', (55, 57))	('SS', 'Phenotype', 'HP:0012570', (29, 31))	('SSX4', 'Gene', '6759', (29, 33))
553289	22976541	However, SS18-SSX4 fusions have been characterized by high breakpoint variability, resulting in functional unpredictability.	('SS', 'Phenotype', 'HP:0012570', (9, 11))	('SS18', 'Gene', (9, 13))	('fusions', 'Var', (19, 26))	('SSX4', 'Gene', '6759', (14, 18))	('SSX4', 'Gene', (14, 18))	('SS', 'Phenotype', 'HP:0012570', (14, 16))	('SS18', 'Gene', '6760', (9, 13))
553291	22976541	Several studies reported a more favorable outcome in patients carrying SS18-SSX2 fusions, and others failed to find any significant correlation between fusion type and clinical outcome.	('SS18', 'Gene', '6760', (71, 75))	('SS', 'Phenotype', 'HP:0012570', (71, 73))	('patients', 'Species', '9606', (53, 61))	('SSX2', 'Gene', (76, 80))	('SS18', 'Gene', (71, 75))	('fusions', 'Var', (81, 88))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('SSX2', 'Gene', '6757', (76, 80))
553293	22976541	We report two novel SS18-SSX1 and SS18-SSX2 variant translocations, and in one patient we detected unusual SS18-SSX1 translocation variant previously described by other group.	('SS18', 'Gene', (107, 111))	('SSX2', 'Gene', (39, 43))	('SS', 'Phenotype', 'HP:0012570', (25, 27))	('SS18', 'Gene', (34, 38))	('SSX2', 'Gene', '6757', (39, 43))	('SS', 'Phenotype', 'HP:0012570', (39, 41))	('SS18', 'Gene', '6760', (20, 24))	('patient', 'Species', '9606', (79, 86))	('SS18', 'Gene', '6760', (107, 111))	('SSX1', 'Gene', '6756', (25, 29))	('SS18', 'Gene', '6760', (34, 38))	('SS', 'Phenotype', 'HP:0012570', (20, 22))	('SSX1', 'Gene', (25, 29))	('SS', 'Phenotype', 'HP:0012570', (107, 109))	('SSX1', 'Gene', '6756', (112, 116))	('variant', 'Var', (44, 51))	('SSX1', 'Gene', (112, 116))	('SS', 'Phenotype', 'HP:0012570', (34, 36))	('SS18', 'Gene', (20, 24))
553307	22976541	Two patients carried novel SS18-SSX variant translocations, and in one patient we detected atypical variant that was previously described by Amary et al.	('SSX', 'Gene', '6757', (32, 35))	('SS', 'Phenotype', 'HP:0012570', (32, 34))	('SSX', 'Gene', (32, 35))	('SS18', 'Gene', '6760', (27, 31))	('patient', 'Species', '9606', (4, 11))	('SS', 'Phenotype', 'HP:0012570', (27, 29))	('variant translocations', 'Var', (36, 58))	('patients', 'Species', '9606', (4, 12))	('SS18', 'Gene', (27, 31))	('patient', 'Species', '9606', (71, 78))
553309	22976541	Direct sequencing indicated the identical SS18-SSX1 variant transcript that was previously described by Amary and coworkers.	('variant', 'Var', (52, 59))	('SS18', 'Gene', '6760', (42, 46))	('SSX1', 'Gene', (47, 51))	('SS', 'Phenotype', 'HP:0012570', (42, 44))	('SS', 'Phenotype', 'HP:0012570', (47, 49))	('SSX1', 'Gene', '6756', (47, 51))	('SS18', 'Gene', (42, 46))
553310	22976541	This variant includes additional 12 codons derived from exon 5 of SSX1, which results in the fusion of codon 410 of SS18 to codon 99 of SSX1 without reading frame shift.	('codon 410', 'Var', (103, 112))	('SS18', 'Gene', '6760', (116, 120))	('SSX1', 'Gene', '6756', (136, 140))	('SS', 'Phenotype', 'HP:0012570', (136, 138))	('SS', 'Phenotype', 'HP:0012570', (116, 118))	('SSX1', 'Gene', (136, 140))	('SS18', 'Gene', (116, 120))	('SSX1', 'Gene', '6756', (66, 70))	('SS', 'Phenotype', 'HP:0012570', (66, 68))	('SSX1', 'Gene', (66, 70))
553330	22976541	Novel SS18-SSX transcript variants are frequently created not only by the unusual junction of SS18 and one of SSX genes but also by the mutations within SS18 or SSX genes which occur apart from the fusion site, e.g., deletion or truncation of SSX1 or insertion in SS18 sequence.	('SSX', 'Gene', '6757', (243, 246))	('SS18', 'Gene', '6760', (6, 10))	('SSX', 'Gene', '6757', (11, 14))	('mutations', 'Var', (136, 145))	('SS18', 'Gene', '6760', (94, 98))	('SS18', 'Gene', (264, 268))	('SSX1', 'Gene', '6756', (243, 247))	('SS18', 'Gene', (153, 157))	('SSX1', 'Gene', (243, 247))	('SSX', 'Gene', (243, 246))	('truncation', 'Var', (229, 239))	('SSX', 'Gene', '6757', (161, 164))	('SSX', 'Gene', (11, 14))	('SS', 'Phenotype', 'HP:0012570', (110, 112))	('SS', 'Phenotype', 'HP:0012570', (94, 96))	('variants', 'Var', (26, 34))	('SS18', 'Gene', '6760', (264, 268))	('insertion', 'Var', (251, 260))	('SSX', 'Gene', (161, 164))	('SS', 'Phenotype', 'HP:0012570', (6, 8))	('SS18', 'Gene', '6760', (153, 157))	('SS18', 'Gene', (6, 10))	('SSX', 'Gene', '6757', (110, 113))	('created', 'Reg', (50, 57))	('SS18', 'Gene', (94, 98))	('SS', 'Phenotype', 'HP:0012570', (11, 13))	('deletion', 'Var', (217, 225))	('SS', 'Phenotype', 'HP:0012570', (153, 155))	('SSX', 'Gene', (110, 113))
553331	22976541	Figure 4 presents previously reported fusion variants characterized by different SS18-SSX junction sites.	('SS18', 'Gene', '6760', (81, 85))	('SS', 'Phenotype', 'HP:0012570', (81, 83))	('variants', 'Var', (45, 53))	('SS18', 'Gene', (81, 85))	('SS', 'Phenotype', 'HP:0012570', (86, 88))	('SSX', 'Gene', '6757', (86, 89))	('SSX', 'Gene', (86, 89))
553333	22976541	The first unusual SS18-SSX1 transcript variant detected in our study was earlier described by Amary et al.. Our detection of the identical fusion transcript variant confirms that the rare variants can be recurrent in SS patients and they are probably not caused by unique nor random events.	('SSX1', 'Gene', '6756', (23, 27))	('SSX1', 'Gene', (23, 27))	('SS', 'Phenotype', 'HP:0012570', (23, 25))	('SS', 'Phenotype', 'HP:0012570', (217, 219))	('SS18', 'Gene', '6760', (18, 22))	('variant', 'Var', (157, 164))	('patients', 'Species', '9606', (220, 228))	('SS', 'Phenotype', 'HP:0012570', (18, 20))	('SS18', 'Gene', (18, 22))
553337	22976541	The fusion site of REPS2 and SSX1 involves amino acids encoded across a splice junction:codon 303 for glycine on the border of exons 6 and 7 of REPS2 and codon 94 for valine at the junction of exons 4 and 5 of SSX1.	('codon 303 for glycine', 'Var', (88, 109))	('SSX1', 'Gene', (29, 33))	('glycine', 'Chemical', 'MESH:D005998', (102, 109))	('codon 94 for', 'Var', (154, 166))	('REPS2', 'Gene', (144, 149))	('SSX1', 'Gene', '6756', (210, 214))	('REPS2', 'Gene', '9185', (144, 149))	('valine', 'Chemical', 'MESH:D014633', (167, 173))	('REPS2', 'Gene', '9185', (19, 24))	('SSX1', 'Gene', (210, 214))	('SS', 'Phenotype', 'HP:0012570', (210, 212))	('REPS2', 'Gene', (19, 24))	('SSX1', 'Gene', '6756', (29, 33))	('SS', 'Phenotype', 'HP:0012570', (29, 31))
553340	22976541	REPS2 exon 6, which is involved in this unusual fusion, encodes a portion of the Eps15 homology domain (residues 282-373).	('REPS2', 'Gene', (0, 5))	('Eps15', 'Gene', (81, 86))	('REPS2', 'Gene', '9185', (0, 5))	('Eps15', 'Gene', '2060', (81, 86))	('residues 282-373', 'Var', (104, 120))
553344	22976541	Apparently, this variant preserved the transforming function of the usual SS18-SSX1 fusion oncogene, which indicates that the mechanism of tumorigenesis in this case might have been similar as in other synovial sarcoma cases.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('SS', 'Phenotype', 'HP:0012570', (74, 76))	('transforming function', 'MPA', (39, 60))	('SSX1', 'Gene', '6756', (79, 83))	('synovial sarcoma', 'Disease', (202, 218))	('tumor', 'Disease', (139, 144))	('SS18', 'Gene', (74, 78))	('synovial sarcoma', 'Disease', 'MESH:D013584', (202, 218))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('SSX1', 'Gene', (79, 83))	('variant', 'Var', (17, 24))	('SS', 'Phenotype', 'HP:0012570', (79, 81))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (202, 218))	('SS18', 'Gene', '6760', (74, 78))
553362	24797726	R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (108, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))	('patients', 'Species', '9606', (61, 69))	('soft tissue sarcomas', 'Disease', (108, 128))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (108, 128))	('R1507', 'Var', (0, 5))
553372	24797726	Antibodies against IGF-1R are safe and exhibit clinical activity in patients with recurrent ES and neuroendocrine tumors.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (99, 120))	('Antibodies', 'Var', (0, 10))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (99, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('IGF-1R', 'Gene', (19, 25))	('neuroendocrine tumors', 'Disease', (99, 120))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('ES', 'Phenotype', 'HP:0012254', (92, 94))	('ES', 'Disease', 'MESH:D012512', (92, 94))
553373	24797726	R1507 (F. Hoffman-LaRoche, Basel, Switzerland) is a fully human immunoglobulin G1 (IgG1)-type monoclonal antibody directed against the human IGF-1R, and the Sarcoma Alliance for Research through Collaboration (SARC) conducted a phase 2, multiarm study with this agent in multiple sarcoma subtypes.	('sarcoma', 'Disease', 'MESH:D012509', (280, 287))	('human', 'Species', '9606', (58, 63))	('Sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('Sarcoma', 'Disease', (157, 164))	('human', 'Species', '9606', (135, 140))	('sarcoma', 'Disease', (280, 287))	('sarcoma', 'Phenotype', 'HP:0100242', (280, 287))	('Sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('R1507', 'Var', (0, 5))
553383	24797726	Off-study criteria included progressive disease, illness that prevented further administration of therapy, unacceptable adverse events, patient withdrawal from the study, a lapse >2 weeks since R1507 administration or missing >=2 consecutive doses, death, loss to follow-up, or an unacceptable condition that, in the opinion of the investigator, would prevent the patient from receiving further therapy.	('illness', 'Disease', 'MESH:D002908', (49, 56))	('patient', 'Species', '9606', (136, 143))	('illness', 'Disease', (49, 56))	('progressive disease', 'Disease', (28, 47))	('patient', 'Species', '9606', (364, 371))	('R1507', 'Var', (194, 199))	('prevent', 'NegReg', (352, 359))	('death', 'Disease', 'MESH:D003643', (249, 254))	('death', 'Disease', (249, 254))
553412	24797726	Multivariate Cox regression analysis identified that an IGF-1 level >110 ng/mL, a Karnofsky performance status >90%, older age at diagnosis, and a diagnosis of OS were associated with longer survival (Table 3, Fig.	('>110', 'Var', (68, 72))	('OS', 'Phenotype', 'HP:0002669', (160, 162))	('longer', 'PosReg', (184, 190))	('IGF-1', 'Gene', '3479', (56, 61))	('IGF-1', 'Gene', (56, 61))
553415	24797726	The most common R1507-related adverse events included fatigue (n = 33), nausea (n = 23), hyperglycemia (n = 15), and muscle spasms (n = 14).	('R1507-related', 'Var', (16, 29))	('muscle spasms', 'Phenotype', 'HP:0003394', (117, 130))	('hyperglycemia', 'Phenotype', 'HP:0003074', (89, 102))	('muscle spasms', 'Disease', 'MESH:D013035', (117, 130))	('fatigue', 'Phenotype', 'HP:0012378', (54, 61))	('nausea', 'Disease', (72, 78))	('hyperglycemia', 'Disease', 'MESH:D006943', (89, 102))	('fatigue', 'Disease', 'MESH:D005221', (54, 61))	('nausea', 'Phenotype', 'HP:0002018', (72, 78))	('fatigue', 'Disease', (54, 61))	('nausea', 'Disease', 'MESH:D009325', (72, 78))	('hyperglycemia', 'Disease', (89, 102))	('muscle spasms', 'Disease', (117, 130))
553418	24797726	Our study demonstrates that R1507 has limited activity in selected bone and soft tissue sarcomas and has a very favorable toxicity profile.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (76, 96))	('R1507', 'Var', (28, 33))	('toxicity', 'Disease', 'MESH:D064420', (122, 130))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (76, 96))	('toxicity', 'Disease', (122, 130))	('activity', 'MPA', (46, 54))	('soft tissue sarcomas', 'Disease', (76, 96))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
553423	24797726	The first group, which accounted for about 66% of patients, failed to exhibit a clinical response and progressed after a median of 2 cycles of R1507.	('R1507', 'Var', (143, 148))	('patients', 'Species', '9606', (50, 58))	('progressed', 'PosReg', (102, 112))
553434	24797726	Finally, the low response rates observed in our trial could have been related to inadequate drug dosing, because R1507 tumor biodistribution reportedly was correlated with tumor response in a panel of sarcoma xenografts using immuno-single-photon emission computed tomography imaging.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (119, 124))	('sarcoma', 'Disease', 'MESH:D012509', (201, 208))	('tumor', 'Disease', (172, 177))	('correlated', 'Reg', (156, 166))	('sarcoma', 'Disease', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('R1507', 'Var', (113, 118))
553438	24797726	Although the company has halted development of this drug, we believe that IGF-1R inhibitors may play a role in the treatment of selected sarcomas, particularly ES and RMS.	('RMS', 'Disease', (167, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('RMS', 'Phenotype', 'HP:0002859', (167, 170))	('sarcomas', 'Disease', (137, 145))	('inhibitors', 'Var', (81, 91))	('ES', 'Phenotype', 'HP:0012254', (160, 162))	('IGF-1R', 'Gene', (74, 80))	('ES', 'Disease', 'MESH:D012512', (160, 162))	('sarcomas', 'Disease', 'MESH:D012509', (137, 145))	('RMS', 'Disease', 'MESH:D012208', (167, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))
553464	30921232	Immunohistochemical examination showed: Ki-67 (+40%), SMA(-), ER(-), Desmin(-), H-caldesmon(-), PR(-), CD10(-), WT-1(+), Cyclin D1(+).	('CD10', 'Gene', (103, 107))	('Cyclin D1', 'Gene', (121, 130))	('Desmin', 'Gene', (69, 75))	('CD10', 'Gene', '4311', (103, 107))	('Desmin', 'Gene', '1674', (69, 75))	('SMA', 'Gene', '6606', (54, 57))	('SMA', 'Gene', (54, 57))	('Cyclin D1', 'Gene', '595', (121, 130))	('Ki-67', 'Var', (40, 45))
553505	28691904	Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (141, 150))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('STAG1', 'Gene', (49, 54))	('STAG2', 'Gene', '10735', (59, 64))	('cancer', 'Disease', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('STAG2', 'Gene', (59, 64))	('human', 'Species', '9606', (193, 198))	('STAG1', 'Gene', '10274', (49, 54))
553506	28691904	Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1.	('STAG2', 'Gene', '10735', (85, 90))	('STAG1', 'Gene', '10274', (156, 161))	('synthetic lethal', 'CPA', (110, 126))	('STAG2', 'Gene', (85, 90))	('STAG1', 'Gene', (156, 161))	('mutated', 'Var', (45, 52))
553507	28691904	Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis.	('mutated', 'Var', (73, 80))	('sister chromatid cohesion', 'MPA', (38, 63))	('STAG1', 'Gene', (17, 22))	('mitotic catastrophe', 'CPA', (119, 138))	('defective', 'NegReg', (140, 149))	('loss abrogates', 'NegReg', (23, 37))	('apoptosis', 'CPA', (168, 177))	('STAG2', 'Gene', (67, 72))	('STAG2', 'Gene', '10735', (67, 72))	('STAG1', 'Gene', '10274', (17, 22))
553508	28691904	STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (100, 113))	('STAG1', 'Gene', (0, 5))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (100, 113))	('STAG2', 'Gene', (49, 54))	('STAG2', 'Gene', '10735', (49, 54))	('mutated', 'Var', (55, 62))	('Ewing sarcoma', 'Disease', (100, 113))	('inactivation inhibits', 'NegReg', (6, 27))	('bladder cancer', 'Disease', (81, 95))	('STAG1', 'Gene', '10274', (0, 5))	('bladder cancer', 'Disease', 'MESH:D001749', (81, 95))	('proliferation', 'CPA', (32, 45))	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
553511	28691904	STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts.	('STAG1', 'Gene', (0, 5))	('mutations', 'Var', (58, 67))	('STAG2', 'Gene', (107, 112))	('STAG2', 'Gene', '10735', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Disease', (36, 42))	('STAG1', 'Gene', '10274', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
553512	28691904	Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g.	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cohesin', 'Protein', (61, 68))
553515	28691904	About half a million cancer patients worldwide have tumors that feature mutations to the gene that produces a protein called STAG2, a component of a large protein ring called cohesin.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('STAG2', 'Gene', (125, 130))	('STAG2', 'Gene', '10735', (125, 130))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('patients', 'Species', '9606', (28, 36))
553516	28691904	These mutations are particularly common in bladder cancers and Ewing sarcoma, a childhood bone cancer.	('bladder cancers', 'Disease', 'MESH:D001749', (43, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (43, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('common', 'Reg', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('bladder cancers', 'Disease', (43, 58))	('Ewing sarcoma', 'Disease', (63, 76))	('bone cancer', 'Disease', 'MESH:D001859', (90, 101))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bladder cancers', 'Phenotype', 'HP:0009725', (43, 58))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('mutations', 'Var', (6, 15))	('bone cancer', 'Disease', (90, 101))
553517	28691904	It is not clear exactly how mutations that affect STAG2 make cancer more likely to develop.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('STAG2', 'Gene', '10735', (50, 55))	('STAG2', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (28, 37))
553518	28691904	However, it is possible that these cancer-specific mutations make cancer cells vulnerable in ways that healthy cells are not.	('mutations', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (66, 72))
553520	28691904	searched for genes whose inactivation would harm only those cells that have mutant STAG2 proteins.	('STAG2', 'Gene', (83, 88))	('STAG2', 'Gene', '10735', (83, 88))	('mutant', 'Var', (76, 82))	('proteins', 'Protein', (89, 97))
553522	28691904	Reducing the amount of STAG1 protein in cells with mutant forms for STAG2 caused these cells to start dying, whereas healthy cells were unaffected.	('STAG1', 'Gene', '10274', (23, 28))	('mutant', 'Var', (51, 57))	('STAG2', 'Gene', '10735', (68, 73))	('STAG1', 'Gene', (23, 28))	('protein', 'Protein', (29, 36))	('STAG2', 'Gene', (68, 73))
553526	28691904	This knowledge could ultimately be used to develop drugs that would kill off only those cancer cells that have mutations that affect STAG2.	('mutations', 'Var', (111, 120))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('STAG2', 'Gene', '10735', (133, 138))	('STAG2', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
553530	28691904	Recent cancer genome studies identified recurrent mutations in cohesin subunits and regulators in approximately 7.3% of all human cancers.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('mutations', 'Var', (50, 59))	('cancers', 'Disease', (130, 137))	('cancer', 'Disease', (130, 136))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('human', 'Species', '9606', (124, 129))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cohesin subunits', 'Protein', (63, 79))
553532	28691904	STAG2 mutations have been reported in ~6% of acute myeloid leukemias and myelodysplastic syndromes, 15-22% of Ewing's sarcomas, and in up to 26% of bladder cancers of various stages and grades.	('acute myeloid leukemias', 'Disease', (45, 68))	("Ewing's sarcomas", 'Disease', (110, 126))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (45, 68))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('bladder cancers', 'Disease', 'MESH:D001749', (148, 163))	('STAG2', 'Gene', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))	('bladder cancers', 'Disease', (148, 163))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (51, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('leukemias', 'Phenotype', 'HP:0001909', (59, 68))	('mutations', 'Var', (6, 15))	('reported', 'Reg', (26, 34))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (110, 126))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (73, 98))	('myelodysplastic syndromes', 'Disease', (73, 98))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (110, 126))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('bladder cancers', 'Phenotype', 'HP:0009725', (148, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (45, 68))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (73, 98))	('STAG2', 'Gene', '10735', (0, 5))
553533	28691904	The deleterious nature of most STAG2 mutations strongly suggests that the gene represents a new tumor suppressor.	('STAG2', 'Gene', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('STAG2', 'Gene', '10735', (31, 36))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
553534	28691904	STAG2 mutations were initially thought to promote tumorigenesis due to defects in sister chromatid cohesin leading to genome instability.	('STAG2', 'Gene', '10735', (0, 5))	('sister chromatid cohesin', 'Protein', (82, 106))	('defects', 'NegReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('promote', 'PosReg', (42, 49))	('genome instability', 'MPA', (118, 136))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('STAG2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
553535	28691904	However, the vast majority of cohesin-mutated cancers are euploid, indicating that cohesin mutations may promote tumorigenesis through altering different cohesin functions such as genome organization and transcriptional regulation.	('tumor', 'Disease', (113, 118))	('promote', 'PosReg', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cohesin', 'Gene', (83, 90))	('cancers', 'Disease', (46, 53))	('cohesin', 'Protein', (154, 161))	('altering', 'Reg', (135, 143))	('mutations', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
553536	28691904	Regardless of the mechanisms driving cohesin mutant tumors, the recent success of poly(ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated ovarian and prostate cancer demonstrates that exploiting tumor suppressor loss by applying the concept of synthetic lethality in defined patient populations can impact clinical cancer care.	('tumor', 'Disease', (52, 57))	('BRCA', 'Gene', '672', (141, 145))	('cancer', 'Disease', (175, 181))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('BRCA', 'Gene', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ovarian and prostate cancer', 'Disease', 'MESH:D010051', (154, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Disease', (52, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (166, 181))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mutant', 'Var', (45, 51))	('cancer', 'Disease', (331, 337))	('impact', 'Reg', (315, 321))	('patient', 'Species', '9606', (291, 298))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
553538	28691904	We hypothesized that STAG2 loss could alter the properties and function of the cohesin complex leading to unique vulnerabilities of STAG2 mutated cells.	('vulnerabilities', 'MPA', (113, 128))	('mutated', 'Var', (138, 145))	('STAG2', 'Gene', (132, 137))	('function', 'MPA', (63, 71))	('STAG2', 'Gene', '10735', (132, 137))	('alter', 'Reg', (38, 43))	('STAG2', 'Gene', '10735', (21, 26))	('properties', 'MPA', (48, 58))	('loss', 'NegReg', (27, 31))	('STAG2', 'Gene', (21, 26))
553540	28691904	Two clones, STAG2- 505c1 and 502c4, harboring deleterious mutations in STAG2 and lacking detectable STAG2 protein expression were selected for analyses (Figure 1:figure supplement 1 and Supplementary file 1).	('STAG2', 'Gene', (100, 105))	('mutations', 'Var', (58, 67))	('STAG2', 'Gene', '10735', (100, 105))	('STAG2', 'Gene', (12, 17))	('STAG2', 'Gene', '10735', (71, 76))	('STAG2', 'Gene', (71, 76))	('STAG2', 'Gene', '10735', (12, 17))
553545	28691904	The pronounced selective effect of STAG1 depletion on STAG2- cells was confirmed in individual transfection experiments and colony formation assays (Figure 1C,D,E).	('STAG2', 'Gene', (54, 59))	('STAG1', 'Gene', (35, 40))	('depletion', 'Var', (41, 50))	('STAG2', 'Gene', '10735', (54, 59))	('STAG1', 'Gene', '10274', (35, 40))
553546	28691904	Expression of an siRNA-resistant STAG1 transgene alleviated the anti-proliferative effect of STAG1 but not of SGOL1 siRNA duplexes in STAG2- HCT 116 cells demonstrating the specificity of the siRNA treatment (Figure 1:figure supplement 2).	('alleviated', 'NegReg', (49, 59))	('transgene', 'Var', (39, 48))	('STAG1', 'Gene', '10274', (33, 38))	('STAG1', 'Gene', (93, 98))	('anti-proliferative', 'CPA', (64, 82))	('STAG2', 'Gene', (134, 139))	('STAG2', 'Gene', '10735', (134, 139))	('HCT 116', 'CellLine', 'CVCL:0291', (141, 148))	('STAG1', 'Gene', (33, 38))	('STAG1', 'Gene', '10274', (93, 98))
553553	28691904	In striking contrast, transduction with sgRNAs targeting STAG1 caused the depletion of STAG2- HCT 116 and KBM-7 cells but not of their parental STAG2 proficient counterparts (Figure 1F).	('STAG2', 'Gene', '10735', (144, 149))	('STAG2', 'Gene', (87, 92))	('transduction', 'Var', (22, 34))	('STAG2', 'Gene', '10735', (87, 92))	('STAG1', 'Gene', '10274', (57, 62))	('KBM-7', 'CellLine', 'CVCL:A426', (106, 111))	('HCT 116', 'CellLine', 'CVCL:0291', (94, 101))	('STAG2', 'Gene', (144, 149))	('STAG1', 'Gene', (57, 62))
553554	28691904	Collectively, these experiments identify STAG1 as a vulnerability of STAG2 mutated cells in engineered solid cancer and leukemia models.	('STAG2', 'Gene', (69, 74))	('STAG2', 'Gene', '10735', (69, 74))	('leukemia', 'Disease', (120, 128))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('leukemia', 'Disease', 'MESH:D007938', (120, 128))	('STAG1', 'Gene', (41, 46))	('mutated', 'Var', (75, 82))	('engineered solid cancer', 'Disease', (92, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('engineered solid cancer', 'Disease', 'MESH:D009369', (92, 115))	('STAG1', 'Gene', '10274', (41, 46))
553555	28691904	STAG1 inactivation has little if any impact on the viability and proliferation of STAG2 wild-type cancer cells and non-transformed cells, but is essential for survival in the absence of STAG2.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('STAG1', 'Gene', (0, 5))	('inactivation', 'Var', (6, 18))	('STAG2', 'Gene', (186, 191))	('STAG2', 'Gene', '10735', (186, 191))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('STAG2', 'Gene', (82, 87))	('STAG2', 'Gene', '10735', (82, 87))	('cancer', 'Disease', (98, 104))	('STAG1', 'Gene', '10274', (0, 5))
553556	28691904	To elucidate the mechanistic basis for this synthetic lethal interaction, we hypothesized that the combined loss of STAG1 and STAG2, in contrast to loss of either component alone, could severely impair cell division.	('impair', 'NegReg', (195, 201))	('loss', 'Var', (108, 112))	('STAG1', 'Gene', '10274', (116, 121))	('STAG2', 'Gene', (126, 131))	('STAG2', 'Gene', '10735', (126, 131))	('cell division', 'CPA', (202, 215))	('STAG1', 'Gene', (116, 121))
553560	28691904	In mitotic chromosome spread analysis STAG2 inactivation caused a partial loss of centromeric cohesion in HCT 116 cells as previously reported (Figure 2C).	('partial loss of centromeric cohesion', 'Phenotype', 'HP:0003616', (66, 102))	('HCT 116', 'CellLine', 'CVCL:0291', (106, 113))	('loss', 'NegReg', (74, 78))	('centromeric cohesion', 'MPA', (82, 102))	('STAG2', 'Gene', '10735', (38, 43))	('inactivation', 'Var', (44, 56))	('STAG2', 'Gene', (38, 43))
553562	28691904	In striking contrast, STAG1 depletion selectively abrogated sister chromatid cohesion in STAG2- but not parental cells (Figure 2C, single chromatids).	('abrogated', 'NegReg', (50, 59))	('STAG1', 'Gene', '10274', (22, 27))	('STAG2', 'Gene', '10735', (89, 94))	('depletion', 'Var', (28, 37))	('sister chromatid cohesion', 'CPA', (60, 85))	('STAG1', 'Gene', (22, 27))	('STAG2', 'Gene', (89, 94))
553563	28691904	The severe mitotic defects observed upon loss of STAG1 in STAG2- cells were accompanied by the emergence of aberrantly sized and shaped interphase nuclei (Figure 2:figure supplement 2) and by a progressive increase in apoptosis (Figure 2D).	('STAG2', 'Gene', (58, 63))	('loss', 'Var', (41, 45))	('STAG2', 'Gene', '10735', (58, 63))	('apoptosis', 'CPA', (218, 227))	('STAG1', 'Gene', '10274', (49, 54))	('mitotic defects', 'Disease', (11, 26))	('STAG1', 'Gene', (49, 54))	('mitotic defects', 'Disease', 'MESH:C536987', (11, 26))	('increase', 'PosReg', (206, 214))
553565	28691904	STAG1 inactivation abrogates sister chromatid cohesion exclusively in STAG2- cells resulting in catastrophic mitotic failure, abnormal cell division and apoptosis.	('STAG1', 'Gene', (0, 5))	('abnormal cell division', 'CPA', (126, 148))	('STAG2', 'Gene', (70, 75))	('STAG2', 'Gene', '10735', (70, 75))	('abrogates', 'NegReg', (19, 28))	('inactivation', 'Var', (6, 18))	('catastrophic mitotic failure', 'Disease', (96, 124))	('catastrophic mitotic failure', 'Disease', 'MESH:D002388', (96, 124))	('STAG1', 'Gene', '10274', (0, 5))	('sister chromatid', 'Protein', (29, 45))	('apoptosis', 'CPA', (153, 162))
553566	28691904	To hold sister chromatids together, cohesin can tolerate the loss of either STAG1 or STAG2 alone but not the loss of both.	('STAG1', 'Gene', '10274', (76, 81))	('cohesin', 'Protein', (36, 43))	('STAG1', 'Gene', (76, 81))	('STAG2', 'Gene', (85, 90))	('STAG2', 'Gene', '10735', (85, 90))	('loss', 'Var', (61, 65))
553567	28691904	We next expanded our analysis to patient-derived STAG2 mutations and STAG2-mutant cancer cell lines in order to investigate the disease relevance of the observed synthetic lethality (Figure 3).	('STAG2', 'Gene', (69, 74))	('STAG2', 'Gene', '10735', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('patient', 'Species', '9606', (33, 40))	('STAG2', 'Gene', '10735', (49, 54))	('STAG2', 'Gene', (49, 54))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
553568	28691904	STAG1 depletion by siRNA abrogated both cell viability and sister chromatid cohesion in HCT 116 cell clones, in which three patient-derived deleterious mutations had been engineered into the STAG2 locus, but not in parental HCT 116 cells (Figure 3:figure supplement 1).	('STAG1', 'Gene', (0, 5))	('abrogated', 'NegReg', (25, 34))	('mutations', 'Var', (152, 161))	('sister chromatid cohesion', 'CPA', (59, 84))	('HCT 116', 'CellLine', 'CVCL:0291', (88, 95))	('depletion', 'NegReg', (6, 15))	('STAG2', 'Gene', (191, 196))	('STAG2', 'Gene', '10735', (191, 196))	('STAG1', 'Gene', '10274', (0, 5))	('patient', 'Species', '9606', (124, 131))	('HCT 116', 'CellLine', 'CVCL:0291', (224, 231))	('cell viability', 'CPA', (40, 54))
553569	28691904	Among solid human cancers, STAG2 mutational inactivation is most prevalent in urothelial bladder cancer and Ewing sarcoma.	('mutational inactivation', 'Var', (33, 56))	('urothelial bladder cancer', 'Disease', (78, 103))	('cancers', 'Disease', (18, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (78, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('STAG2', 'Gene', '10735', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (12, 17))	('Ewing sarcoma', 'Disease', (108, 121))	('prevalent', 'Reg', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('STAG2', 'Gene', (27, 32))
553570	28691904	Therefore, we assembled a panel of 16 bladder cancer cell lines: 11 STAG2-positive, three with deleterious STAG2 mutations (UM-UC-3, UM-UC-6 and VM-CUB-3), one in which STAG2 was inactivated by CRISPR/Cas9 (UM-UC-5 STAG2- 505c6) (Figure 3:figure supplement 2), and two with no detectable STAG2 expression (LGWO1 and MGH-U3) (Supplementary file 2).	('STAG2', 'Gene', (107, 112))	('UC-5', 'Species', '947040', (210, 214))	('STAG2', 'Gene', '10735', (107, 112))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('STAG2', 'Gene', '10735', (288, 293))	('STAG2', 'Gene', (169, 174))	('UM-UC-3', 'CellLine', 'CVCL:1783', (124, 131))	('STAG2', 'Gene', '10735', (169, 174))	('STAG2', 'Gene', (215, 220))	('mutations', 'Var', (113, 122))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('bladder cancer', 'Disease', (38, 52))	('STAG2', 'Gene', '10735', (215, 220))	('STAG2', 'Gene', (288, 293))	('STAG2', 'Gene', '10735', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('STAG2', 'Gene', (68, 73))
553574	28691904	STAG1 depletion prevented colony formation and abolished sister chromatid cohesion selectively in STAG2 mutated UM-UC-3 (F983fs) but not in STAG2 wild-type UM-UC-5 bladder cancer cells (Figure 3C,D).	('abolished', 'NegReg', (47, 56))	('STAG1', 'Gene', (0, 5))	('F983fs', 'Mutation', 'p.F983fsX', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('mutated', 'Var', (104, 111))	('colony formation', 'CPA', (26, 42))	('UC-5', 'Species', '947040', (159, 163))	('STAG2', 'Gene', (98, 103))	('sister chromatid', 'CPA', (57, 73))	('STAG1', 'Gene', '10274', (0, 5))	('STAG2', 'Gene', (140, 145))	('bladder cancer', 'Disease', (164, 178))	('STAG2', 'Gene', '10735', (98, 103))	('STAG2', 'Gene', '10735', (140, 145))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('UM-UC-3', 'CellLine', 'CVCL:1783', (112, 119))	('prevented', 'NegReg', (16, 25))
553576	28691904	Lentiviral transduction of a FLAG-STAG2 transgene into STAG2 mutated UM-UC-3 bladder cancer cells resulted in the restoration of STAG2 expression, nuclear localization of the transgenic protein and its incorporation into the cohesin complex (Figure 3:figure supplement 3).	('incorporation', 'MPA', (202, 215))	('STAG2', 'Gene', (55, 60))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('STAG2', 'Gene', '10735', (55, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('STAG2', 'Gene', '10735', (34, 39))	('restoration', 'PosReg', (114, 125))	('bladder cancer', 'Disease', (77, 91))	('STAG2', 'Gene', (129, 134))	('UM-UC-3', 'CellLine', 'CVCL:1783', (69, 76))	('STAG2', 'Gene', '10735', (129, 134))	('expression', 'MPA', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutated', 'Var', (61, 68))	('nuclear localization', 'MPA', (147, 167))	('STAG2', 'Gene', (34, 39))
553577	28691904	Crucially, restoration of STAG2 expression alleviated the STAG1 dependency of UM-UC-3 cells providing a causal link between STAG2 loss and STAG1 dependency (Figure 3G).	('restoration', 'Var', (11, 22))	('UM-UC-3', 'CellLine', 'CVCL:1783', (78, 85))	('STAG1', 'Gene', (58, 63))	('STAG1', 'Gene', '10274', (139, 144))	('STAG2', 'Gene', (124, 129))	('alleviated', 'NegReg', (43, 53))	('STAG2', 'Gene', '10735', (124, 129))	('STAG2', 'Gene', '10735', (26, 31))	('STAG1', 'Gene', (139, 144))	('loss', 'NegReg', (130, 134))	('STAG2', 'Gene', (26, 31))	('STAG1', 'Gene', '10274', (58, 63))
553583	28691904	Importantly, the finding that cancer cells harboring deleterious STAG2 mutations remain exquisitely dependent on STAG1 demonstrates that this genetic vulnerability is maintained throughout the process of carcinogenesis and not bypassed by adaptive processes, such as the transcriptional activation of the germline-specific paralog STAG3.	('carcinogenesis', 'Disease', (204, 218))	('STAG3', 'Gene', '10734', (331, 336))	('STAG1', 'Gene', (113, 118))	('cancer', 'Disease', (30, 36))	('STAG2', 'Gene', '10735', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('STAG3', 'Gene', (331, 336))	('STAG1', 'Gene', '10274', (113, 118))	('mutations', 'Var', (71, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (204, 218))	('STAG2', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
553588	28691904	Since STAG1 inactivation has little or no effect on the proliferation of STAG2 proficient cells, selective targeting of STAG1 could offer a large therapeutic window.	('STAG1', 'Gene', (120, 125))	('STAG1', 'Gene', (6, 11))	('STAG2', 'Gene', (73, 78))	('STAG2', 'Gene', '10735', (73, 78))	('STAG1', 'Gene', '10274', (120, 125))	('STAG1', 'Gene', '10274', (6, 11))	('inactivation', 'Var', (12, 24))
553592	28691904	The mechanisms by which mutations in STAG2 and other cohesin subunits drive tumorigenesis in solid and hematological tissues are not yet firmly established.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('drive', 'Reg', (70, 75))	('STAG2', 'Gene', (37, 42))	('STAG2', 'Gene', '10735', (37, 42))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
553593	28691904	Both deleterious STAG2 mutations and the loss of STAG2 expression are strong predictive biomarkers for STAG1 dependence in cell models and could be utilized for patient stratification in the future.	('STAG2', 'Gene', (17, 22))	('STAG2', 'Gene', '10735', (17, 22))	('STAG2', 'Gene', (49, 54))	('STAG2', 'Gene', '10735', (49, 54))	('patient', 'Species', '9606', (161, 168))	('STAG1', 'Gene', (103, 108))	('expression', 'MPA', (55, 65))	('mutations', 'Var', (23, 32))	('STAG1', 'Gene', '10274', (103, 108))	('loss', 'NegReg', (41, 45))
553594	28691904	Our work demonstrates that unique genetic dependencies of cohesin mutated cancer cells exist.	('mutated', 'Var', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cohesin', 'Protein', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
553596	28691904	pAb goat anti-STAG2 (Bethyl, Montgomery, TX, US; A300-158A and A300-159A), N-term.	('STAG2', 'Gene', (14, 19))	('STAG2', 'Gene', '10735', (14, 19))	('A300-158A', 'Var', (49, 58))	('A300-159A', 'Var', (63, 72))	('goat', 'Species', '9925', (4, 8))
553597	28691904	mAb rabbit anti-STAG2 (Cell Signaling, Danvers, MA, US; 5882), full length pAb rabbit anti-STAG2 (Cell Signaling, Danvers, MA, US; 4239), mouse anti-GAPDH (Abcam, UK; ab8245), rabbit anti-STAG1 (GeneTex, Irvine, CA, US; GTX129912), mouse anti-FLAG (Sigma-Aldrich, St. Louis, MO, US; F3165 and F1804), mouse anti-p53 (Calbiochem, San Diego, CA, US; OP43), rabbit anti-H3pS10 (Merck Millipore, Billerica, MA, US; 06570), FITC Conjugated mouse anti-Tubulin (Sigma-Aldrich, St. Louis, MO, US; F2168), rabbit anti-SGOL1 (Peters laboratory ID A975M), SMC3 (Peters laboratory ID 845), mouse anti-RAD21 (Merck Millipore, Billerica, MA, US; 05-908), rabbit anti-SMC1 (Bethyl, Montgomery, TX, US; A300-055A), and secondary rabbit (P0448), mouse (P0161) and goat (P0160) anti-IgG-HRP (all Dako, Denmark).	('A975M', 'Mutation', 'p.A975M', (537, 542))	('STAG2', 'Gene', '10735', (16, 21))	('mouse', 'Species', '10090', (232, 237))	('mouse', 'Species', '10090', (301, 306))	('p53', 'Gene', (312, 315))	('SMC1', 'Gene', '8243', (653, 657))	('rabbit', 'Species', '9986', (4, 10))	('rabbit', 'Species', '9986', (176, 182))	('SMC1', 'Gene', (653, 657))	('goat', 'Species', '9925', (747, 751))	('mouse', 'Species', '10090', (729, 734))	('STAG2', 'Gene', (16, 21))	('mouse', 'Species', '10090', (578, 583))	('FITC', 'Chemical', 'MESH:D016650', (419, 423))	('mouse', 'Species', '10090', (435, 440))	('STAG1', 'Gene', (188, 193))	('mouse', 'Species', '10090', (138, 143))	('GAPDH', 'Gene', '2597', (149, 154))	('P0161', 'Var', (736, 741))	('STAG2', 'Gene', '10735', (91, 96))	('STAG1', 'Gene', '10274', (188, 193))	('rabbit', 'Species', '9986', (79, 85))	('rabbit', 'Species', '9986', (355, 361))	('P0448', 'Var', (721, 726))	('P0160', 'Var', (753, 758))	('rabbit', 'Species', '9986', (497, 503))	('rabbit', 'Species', '9986', (641, 647))	('STAG2', 'Gene', (91, 96))	('rabbit', 'Species', '9986', (713, 719))	('GAPDH', 'Gene', (149, 154))	('p53', 'Gene', '7157', (312, 315))
553598	28691904	The following lentiviral vectors were used to introduce mutations in STAG2 in HCT 116 and UM-UC-5 cells: CRISPR STAG2 Hs0000077505_U6gRNA-Cas9-2A-GFP and CRISPR STAG2 Hs0000077502_U6gRNA-Cas9-2A-GFP (Sigma-Aldrich, St. Louis, MO, US).	('STAG2', 'Gene', (69, 74))	('STAG2', 'Gene', '10735', (69, 74))	('mutations', 'Var', (56, 65))	('UC-5', 'Species', '947040', (93, 97))	('HCT 116', 'CellLine', 'CVCL:0291', (78, 85))	('STAG2', 'Gene', (112, 117))	('STAG2', 'Gene', (161, 166))	('STAG2', 'Gene', '10735', (112, 117))	('STAG2', 'Gene', '10735', (161, 166))
553599	28691904	CRISPR sgRNA STAG2_16 and sgRNA STAG2_19 were co-expressed from U6gRNA 16-U6gRNA 19-EF1alphas-Thy1.1-P2A-neo to introduce mutations in STAG2 in KBM-7 cells.	('STAG2', 'Gene', '10735', (13, 18))	('introduce', 'Reg', (112, 121))	('STAG2', 'Gene', (135, 140))	('STAG2', 'Gene', '10735', (135, 140))	('KBM-7', 'CellLine', 'CVCL:A426', (144, 149))	('STAG2', 'Gene', (32, 37))	('STAG2', 'Gene', '10735', (32, 37))	('mutations', 'Var', (122, 131))	('STAG2', 'Gene', (13, 18))
553603	28691904	Silent nucleotide changes were introduced into the STAG1 and STAG2 coding sequences within the siRNA target sequences to render the transgenes siRNA-resistant.	('STAG1', 'Gene', (51, 56))	('Silent nucleotide changes', 'Var', (0, 25))	('STAG2', 'Gene', '10735', (61, 66))	('STAG2', 'Gene', (61, 66))	('STAG1', 'Gene', '10274', (51, 56))
553634	28691904	Samples were labeled as STAG2 mutated if they carried an alteration resulting in an amino acid change in STAG2 (i.e.	('alteration', 'Var', (57, 67))	('STAG2', 'Gene', (105, 110))	('STAG2', 'Gene', '10735', (105, 110))	('amino acid change', 'MPA', (84, 101))	('STAG2', 'Gene', '10735', (24, 29))	('STAG2', 'Gene', (24, 29))
553638	28691904	siRNA-meditated depletion of STAG1 leads to cohesion defects and subsequent cell death in STAG2 knockout cells but hardly if at all in wild type cells.	('STAG1', 'Gene', '10274', (29, 34))	('depletion', 'Var', (16, 25))	('cohesion defects', 'CPA', (44, 60))	('STAG2', 'Gene', (90, 95))	('STAG2', 'Gene', '10735', (90, 95))	('cell death', 'CPA', (76, 86))	('STAG1', 'Gene', (29, 34))	('knockout', 'Var', (96, 104))
553648	28691904	4) Reviewer 2 also asks if it would be possible for the authors to compare the gene expression profiles upon loss of STAG1 and loss of other cohesion subunits in isogenic STAG2-/- lines (i.e.	('STAG2', 'Gene', (171, 176))	('STAG1', 'Gene', (117, 122))	('loss', 'Var', (109, 113))	('loss', 'NegReg', (127, 131))	('STAG2', 'Gene', '10735', (171, 176))	('STAG1', 'Gene', '10274', (117, 122))
553656	28691904	Stratification of samples by STAG2 mutational status reveals that also in patient tumors STAG1 mRNA expression is not elevated in STAG2 mutated versus STAG2 wild-type tumors (new Figure 4:figure supplement 1A).	('STAG1', 'Gene', (89, 94))	('patient', 'Species', '9606', (74, 81))	('tumors', 'Disease', (82, 88))	('STAG1', 'Gene', '10274', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('STAG2', 'Gene', '10735', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('STAG2', 'Gene', '10735', (29, 34))	('STAG2', 'Gene', (151, 156))	('STAG2', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutated', 'Var', (136, 143))	('STAG2', 'Gene', '10735', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('elevated', 'PosReg', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('STAG2', 'Gene', (130, 135))	('tumors', 'Disease', (167, 173))
553660	28691904	The fact that STAG2 is expressed in all normal human tissues analyzed supports our conclusion that STAG1 inhibition has the potential to yield a large therapeutic window by sparing normal tissues and selectively affecting STAG2 mutated cancer cells (discussed in the eighth paragraph of the main text).	('STAG2', 'Gene', (14, 19))	('STAG2', 'Gene', '10735', (14, 19))	('affecting', 'Reg', (212, 221))	('STAG1', 'Gene', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('inhibition', 'NegReg', (105, 115))	('mutated', 'Var', (228, 235))	('cancer', 'Disease', (236, 242))	('STAG1', 'Gene', '10274', (99, 104))	('sparing', 'NegReg', (173, 180))	('STAG2', 'Gene', (222, 227))	('STAG2', 'Gene', '10735', (222, 227))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('human', 'Species', '9606', (47, 52))
553661	28691904	The effect of cohesin mutations in cancer on transcriptional programs is a very interesting area that could lie at the heart of the tumor-promoting role of these alterations.	('cohesin', 'Gene', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
553662	28691904	Published data reveal that the genetic inactivation of STAG2 in isogenic HCT 116 models causes only very minor changes in gene expression (Solomon et al., Science 2011; PMID: 21852505).	('STAG2', 'Gene', '10735', (55, 60))	('STAG2', 'Gene', (55, 60))	('genetic inactivation', 'Var', (31, 51))	('gene expression', 'MPA', (122, 137))	('HCT 116', 'CellLine', 'CVCL:0291', (73, 80))
553663	28691904	As shown in this work, removing STAG1 in addition will result in mitotic arrest and cell death.	('result in', 'Reg', (55, 64))	('STAG1', 'Gene', '10274', (32, 37))	('mitotic arrest', 'Disease', (65, 79))	('mitotic arrest', 'Disease', 'MESH:D006323', (65, 79))	('removing', 'Var', (23, 31))	('STAG1', 'Gene', (32, 37))	('cell death', 'CPA', (84, 94))
553665	28691904	In the future, the effects of cancer-linked cohesin alterations on gene expression and chromatin organization should be analyzed e.g.	('alterations', 'Var', (52, 63))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cohesin', 'Protein', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
553667	28691904	Defining the transcriptional deregulation that might underlie the tumor promoting function of cohesin mutations is a key area of future 3 research but in our opinion beyond the scope of this Short Report.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cohesin', 'Gene', (94, 101))	('tumor', 'Disease', (66, 71))	('mutations', 'Var', (102, 111))	('transcriptional', 'MPA', (13, 28))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
553800	25405526	LCH variant as a focal "eosinophilic granuloma" presentation has been described as a self-limiting disorder in the lungs of smokers, in which lesions may regress with the cessation of smoking.	('LCH', 'Gene', (0, 3))	('eosinophilic granuloma', 'Disease', (24, 46))	('granuloma', 'Phenotype', 'HP:0032252', (37, 46))	('eosinophilic granuloma', 'Disease', 'MESH:D004802', (24, 46))	('variant', 'Var', (4, 11))	('eosinophilic granuloma', 'Phenotype', 'HP:0032253', (24, 46))
553817	25405526	In patients who require systemic therapy, agents such as methotrexate, cyclophosphamide, cyclosporine, 6-mercaptopurine, and vinblastine have been reported to have efficacy in LCH.	('6-mercaptopurine', 'Chemical', 'MESH:D015122', (103, 119))	('LCH', 'Disease', (176, 179))	('vinblastine', 'Chemical', 'MESH:D014747', (125, 136))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (71, 87))	('patients', 'Species', '9606', (3, 11))	('methotrexate', 'Chemical', 'MESH:D008727', (57, 69))	('cyclosporine', 'Var', (89, 101))	('cyclosporine', 'Chemical', 'MESH:D016572', (89, 101))
553898	21197468	Numerous investigations on tumor development have shown that an alteration in the blood supply can noticeably influence the tumor growth and its metastasis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('metastasis', 'CPA', (145, 155))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (124, 129))	('alteration', 'Var', (64, 74))	('influence', 'Reg', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
553902	21197468	However, in the early 1900s it was recognized that "vessels showed changes, such as defective coatings, dilation, obliteration, and thrombosis" (cited in).	('dilation', 'CPA', (104, 112))	('thrombosis', 'Disease', (132, 142))	('obliteration', 'CPA', (114, 126))	('defective', 'Var', (84, 93))	('thrombosis', 'Disease', 'MESH:D013927', (132, 142))
553914	21197468	Inhibitors of angiogenesis have demonstrated antitumor activity in animal models of childhood sarcomas, and clinical trials are in the early stages, although promising results are already being seen.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('angiogenesis', 'Protein', (14, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('childhood sarcomas', 'Disease', (84, 102))	('tumor', 'Disease', (49, 54))	('Inhibitors', 'Var', (0, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('childhood sarcomas', 'Disease', 'MESH:D012509', (84, 102))
553976	21197468	Tumor growth and tumor vascularity were decreased in the presence of IGFBP-5 expression in a xenograft model of human ovarian cancer.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ovarian cancer', 'Disease', (118, 132))	('tumor', 'Disease', (17, 22))	('IGFBP-5', 'Gene', (69, 76))	('IGFBP-5', 'Gene', '3488', (69, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (118, 132))	('presence', 'Var', (57, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('decreased', 'NegReg', (40, 49))	('human', 'Species', '9606', (112, 117))	('Tumor growth', 'CPA', (0, 12))
553995	21197468	This epidemiological correlation has led to the hypothesis that high levels of IGF-1 play an important role in the pathogenesis of osteosarcoma.	('high', 'Var', (64, 68))	('osteosarcoma', 'Phenotype', 'HP:0002669', (131, 143))	('osteosarcoma', 'Disease', (131, 143))	('osteosarcoma', 'Disease', 'MESH:D012516', (131, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('IGF-1', 'Gene', (79, 84))
553996	21197468	This hypothesis is supported by a host of preclinical data: (a) osteosarcoma cells express functional IGF-1R on the cell surface, (b) exogenous IGF-1 stimulates osteosarcoma cells to proliferate, (c) IGF-1-dependent growth can be inhibited using monoclonal antibodies or antisense oligonucleotides against IGF-1R, (d) the treatment of mice with a humanized anti-IGF-1R antibody resulted in tumor regression in two osteosarcoma xenograft models, and (e) the majority of osteosarcoma patient samples express IGF ligands, and 45% express IGF-1R.	('osteosarcoma', 'Phenotype', 'HP:0002669', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (390, 395))	('osteosarcoma', 'Phenotype', 'HP:0002669', (414, 426))	('osteosarcoma', 'Phenotype', 'HP:0002669', (469, 481))	('osteosarcoma', 'Phenotype', 'HP:0002669', (64, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('patient', 'Species', '9606', (482, 489))	('osteosarcoma', 'Disease', (161, 173))	('IGF ligands', 'Protein', (506, 517))	('sarcoma', 'Phenotype', 'HP:0100242', (474, 481))	('osteosarcoma', 'Disease', 'MESH:D012516', (161, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (419, 426))	('human', 'Species', '9606', (347, 352))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('osteosarcoma', 'Disease', (414, 426))	('osteosarcoma', 'Disease', (469, 481))	('tumor', 'Disease', (390, 395))	('anti-IGF-1R', 'Var', (357, 368))	('osteosarcoma', 'Disease', 'MESH:D012516', (414, 426))	('osteosarcoma', 'Disease', (64, 76))	('osteosarcoma', 'Disease', 'MESH:D012516', (469, 481))	('osteosarcoma', 'Disease', 'MESH:D012516', (64, 76))	('mice', 'Species', '10090', (335, 339))	('tumor', 'Disease', 'MESH:D009369', (390, 395))
554003	21197468	SCH717454 significantly inhibits growth of RMS xenografts and induces regressions in several sarcoma histotypes, notably osteosarcoma and Ewing sarcoma.	('sarcoma', 'Disease', (144, 151))	('inhibits', 'NegReg', (24, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (121, 133))	('Ewing sarcoma', 'Disease', (138, 151))	('SCH717454', 'Chemical', 'MESH:C573312', (0, 9))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('growth', 'CPA', (33, 39))	('sarcoma', 'Disease', (126, 133))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('sarcoma', 'Disease', (93, 100))	('SCH717454', 'Var', (0, 9))	('RMS', 'Phenotype', 'HP:0002859', (43, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('osteosarcoma', 'Disease', (121, 133))	('osteosarcoma', 'Disease', 'MESH:D012516', (121, 133))	('regressions', 'NegReg', (70, 81))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (138, 151))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (138, 151))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))
554004	21197468	R1507 was found to inhibit growth of osteosarcoma xenografts.	('osteosarcoma xenografts', 'Disease', (37, 60))	('growth', 'CPA', (27, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('osteosarcoma xenografts', 'Disease', 'MESH:D012516', (37, 60))	('inhibit', 'NegReg', (19, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (37, 49))	('R1507', 'Var', (0, 5))
554005	21197468	In some in vivo models of Ewing sarcoma and osteosarcoma targeting IGF-1R with CP751871 dramatically suppressed VEGF transcription and reduced tumor-associated VEGF within 24 hours of antibody administration.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('osteosarcoma', 'Disease', (44, 56))	('osteosarcoma', 'Disease', 'MESH:D012516', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('VEGF', 'Gene', '7422', (160, 164))	('Ewing sarcoma', 'Disease', (26, 39))	('CP751871', 'Chemical', 'MESH:C525021', (79, 87))	('VEGF', 'Gene', '7422', (112, 116))	('CP751871', 'Var', (79, 87))	('VEGF', 'Gene', (160, 164))	('VEGF', 'Gene', (112, 116))	('reduced', 'NegReg', (135, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (44, 56))	('suppressed', 'NegReg', (101, 111))	('tumor', 'Disease', (143, 148))	('IGF-1R', 'Gene', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
554006	21197468	Furthermore, SCH717454 treatment markedly reduced blood vessel formation in tumor xenografts, showing that the in vivo activity is derived not only from its inhibition of tumor cell proliferation, but also from its angiogenesis activity.	('reduced', 'NegReg', (42, 49))	('angiogenesis activity', 'CPA', (215, 236))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('SCH717454', 'Chemical', 'MESH:C573312', (13, 22))	('inhibition', 'NegReg', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('SCH717454', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
554009	21197468	In these models with intermediate sensitivity, such as RMS, combinations of signaling inhibitors would be a potentially more effective antitumor therapy.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('RMS', 'Phenotype', 'HP:0002859', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('combinations', 'Var', (60, 72))
554011	21197468	The basis for this combination is that inhibition of mTOR upregulates IGF-1R signaling through stabilization of IRS-1 and IGF-1R signaling blocks rapamycin-induced apoptosis.	('inhibition', 'Var', (39, 49))	('IGF-1R', 'MPA', (122, 128))	('stabilization', 'MPA', (95, 108))	('IRS-1', 'Gene', '3667', (112, 117))	('rapamycin', 'Chemical', 'MESH:D020123', (146, 155))	('mTOR', 'Gene', (53, 57))	('IRS-1', 'Gene', (112, 117))	('mTOR', 'Gene', '2475', (53, 57))	('rapamycin-induced apoptosis', 'CPA', (146, 173))	('upregulates', 'PosReg', (58, 69))	('blocks', 'NegReg', (139, 145))	('IGF-1R', 'Gene', (70, 76))
554012	21197468	One IGF-1R inhibitor, CP751871, caused complete IGF-1R downregulation, suppressed AKT phosphorylation, and dramatically suppressed tumor-derived vascular endothelial growth factor (VEGF) in some sarcoma xenografts.	('sarcoma', 'Disease', (195, 202))	('suppressed', 'NegReg', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('downregulation', 'NegReg', (55, 69))	('vascular endothelial growth factor', 'Gene', (145, 179))	('AKT', 'Gene', (82, 85))	('VEGF', 'Gene', '7422', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('tumor', 'Disease', (131, 136))	('CP751871', 'Chemical', 'MESH:C525021', (22, 30))	('AKT', 'Gene', '207', (82, 85))	('VEGF', 'Gene', (181, 185))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('CP751871', 'Var', (22, 30))	('vascular endothelial growth factor', 'Gene', '7422', (145, 179))	('IGF-1R', 'Gene', (48, 54))	('suppressed', 'NegReg', (71, 81))
554013	21197468	Treatment with rapamycin alone did not markedly suppress VEGF in tumors and synergized only in those tumor lines where VEGF was inhibited by CP751871.	('suppress', 'NegReg', (48, 56))	('VEGF', 'Gene', '7422', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('rapamycin', 'Chemical', 'MESH:D020123', (15, 24))	('CP751871', 'Chemical', 'MESH:C525021', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('CP751871', 'Var', (141, 149))	('tumors', 'Disease', (65, 71))	('VEGF', 'Gene', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('VEGF', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('VEGF', 'Gene', '7422', (57, 61))
554014	21197468	This data suggests a model in which the blockade of IGF-1R suppresses tumor-derived VEGF to a level where rapamycin can effectively suppress the response in vascular endothelial cells.	('blockade', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('suppress', 'NegReg', (132, 140))	('tumor', 'Disease', (70, 75))	('rapamycin', 'Chemical', 'MESH:D020123', (106, 115))	('VEGF', 'Gene', (84, 88))	('suppresses', 'NegReg', (59, 69))	('IGF-1R', 'Gene', (52, 58))	('response in vascular endothelial cells', 'MPA', (145, 183))	('VEGF', 'Gene', '7422', (84, 88))
554016	21197468	However, recent studies show that SCH717454 potently inhibits VEGF-induced proliferation of HUVECs, indicating that IGF-1R-mediated signaling is essential for vascular endothelial cell proliferation (H. K. Bid, PJH, unpublished data).	('Bid', 'Gene', (206, 209))	('VEGF', 'Gene', '7422', (62, 66))	('Bid', 'Gene', '637', (206, 209))	('HUVEC', 'CellLine', 'CVCL:2959', (92, 97))	('SCH717454', 'Chemical', 'MESH:C573312', (34, 43))	('inhibits', 'NegReg', (53, 61))	('SCH717454', 'Var', (34, 43))	('VEGF', 'Gene', (62, 66))
554033	21197468	Disruption of the SDF-1/CXCR4 axis was found to inhibit tumor growth, microvessel density, and intratumoral blood flow without affecting VEGF levels.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('microvessel density', 'CPA', (70, 89))	('VEGF', 'Gene', '7422', (137, 141))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (56, 61))	('Disruption', 'Var', (0, 10))	('SDF-1', 'Gene', (18, 23))	('CXCR4', 'Gene', '7852', (24, 29))	('SDF-1', 'Gene', '6387', (18, 23))	('VEGF', 'Gene', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('CXCR4', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('inhibit', 'NegReg', (48, 55))
554066	24368892	The risk factors for GS include specific chromosomal abnormalities, such as translocations between chromosomes 8 and 21 (t[8;21]) and inversion of chromosome 16 (inv[16]), the expression of cell-surface markers (cluster of differentiation [CD]56, CD2, CD4, and CD7), and the French-American-British (FAB) classification M2, M4, and M5 leukemia subtypes.	('CD2', 'Gene', (247, 250))	('inversion', 'Var', (134, 143))	('translocations', 'Var', (76, 90))	('chromosomal abnormalities', 'Disease', (41, 66))	('CD7', 'Gene', (261, 264))	('leukemia subtypes', 'Disease', (335, 352))	('CD2', 'Gene', '914', (247, 250))	('leukemia subtypes', 'Disease', 'MESH:C535673', (335, 352))	('CD7', 'Gene', '924', (261, 264))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (41, 66))	('CD4', 'Gene', (252, 255))	('leukemia', 'Phenotype', 'HP:0001909', (335, 343))	('cluster', 'Gene', (212, 219))	('GS', 'Disease', 'MESH:D011125', (21, 23))	('CD4', 'Gene', '920', (252, 255))
554076	24368892	A flow cytometry study of the circulating white cells was also unremarkable, as were the polymerase chain reaction (PCR) studies of peripheral blood for the breakpoint cluster region (BCR)-Abelson (ABL) gene rearrangements and Janus kinase 2 (JAK-2) mutations.	('Janus kinase 2', 'Gene', (227, 241))	('men', 'Species', '9606', (217, 220))	('JAK-2', 'Gene', (243, 248))	('Janus kinase 2', 'Gene', '3717', (227, 241))	('ABL', 'Gene', '25', (198, 201))	('ABL', 'Gene', (198, 201))	('mutations', 'Var', (250, 259))	('rearrangements', 'Var', (208, 222))	('JAK-2', 'Gene', '3717', (243, 248))
554103	24368892	Cytogenetic abnormalities are seen in roughly 50% of cases and include monosomy 7, trisomy 8, inv(16), t(9;11), deletion (del)(16q), t(8;16), and t(1;11).Nucleophosmin (NPM1) mutations have been reported in 15% and FMS-related tyrosine kinase 3 (FLT 3) gene mutations in 20%-30% of GS cases; however, the clinical significance of NPM1 and FLT3 mutation in this clinical context remains uncertain.	('mutations', 'Var', (258, 267))	('FLT3', 'Gene', (339, 343))	('FLT 3', 'Gene', (246, 251))	('FMS-related tyrosine kinase 3', 'Gene', '2322', (215, 244))	('NPM1', 'Gene', '4869', (169, 173))	('FLT 3', 'Gene', '2322', (246, 251))	('Nucleophosmin', 'Gene', (154, 167))	('NPM1', 'Gene', (330, 334))	('mutations', 'Var', (175, 184))	('FLT3', 'Gene', '2322', (339, 343))	('FMS-related tyrosine kinase 3', 'Gene', (215, 244))	('Nucleophosmin', 'Gene', '4869', (154, 167))	('GS', 'Disease', 'MESH:D011125', (282, 284))	('NPM1', 'Gene', '4869', (330, 334))	('NPM1', 'Gene', (169, 173))
554121	23800680	Germline PTPRD Mutations in Ewing Sarcoma: Biologic and Clinical Implications Ewing sarcoma occurs in children, adolescents and young adults.	('Sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('Mutations', 'Var', (15, 24))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (28, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('PTPRD', 'Gene', '5789', (9, 14))	('PTPRD', 'Gene', (9, 14))	('children', 'Species', '9606', (102, 110))	('Ewing Sarcoma', 'Disease', (28, 41))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (28, 41))	('Ewing sarcoma', 'Disease', (78, 91))
554122	23800680	High STAT3 levels have been reported in approximately 50% of patients with Ewing sarcoma, and may be important in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Ewing sarcoma', 'Disease', (75, 88))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('STAT3', 'Gene', '6774', (5, 10))	('patients', 'Species', '9606', (61, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('tumor', 'Disease', (114, 119))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('STAT3', 'Gene', (5, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
554124	23800680	To date, while somatic mutations in PTPRD have been reported in diverse tumors, germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers.	('PTPRD', 'Gene', (36, 41))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PTPRD', 'Gene', '5789', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PTPRD', 'Gene', (102, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('tumors', 'Disease', (72, 78))	('reported', 'Reg', (52, 60))	('Ewing sarcoma', 'Disease', (138, 151))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Disease', (161, 168))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (138, 151))	('PTPRD', 'Gene', '5789', (36, 41))
554125	23800680	We identified a novel germline mutation in the PTPRD gene in three of eight patients (37.5%) with metastatic Ewing sarcoma.	('PTPRD', 'Gene', (47, 52))	('patients', 'Species', '9606', (76, 84))	('Ewing sarcoma', 'Disease', (109, 122))	('germline mutation', 'Var', (22, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('PTPRD', 'Gene', '5789', (47, 52))
554126	23800680	Although the functional impact in two of the patients is unclear, in one of them the aberration was annotated as a W775stop germline mutation, and would be expected to lead to gene truncation and, hence, loss of the STAT3 dephosphorylation function of PTPRD.	('PTPRD', 'Gene', '5789', (252, 257))	('PTPRD', 'Gene', (252, 257))	('gene', 'MPA', (176, 180))	('loss', 'NegReg', (204, 208))	('W775stop', 'Var', (115, 123))	('STAT3', 'Gene', '6774', (216, 221))	('lead to', 'Reg', (168, 175))	('patients', 'Species', '9606', (45, 53))	('W775stop', 'Mutation', 'rs747543296', (115, 123))	('STAT3', 'Gene', (216, 221))
554127	23800680	Since STAT3 is phosphorylated after being recruited to the insulin growth factor receptor (IGF-1R), suppression of IGF-1R could attenuate the enhanced STAT3 activation expected in the presence of PTPRD mutations.	('STAT3', 'Gene', (151, 156))	('IGF-1R', 'Gene', (115, 121))	('suppression', 'NegReg', (100, 111))	('PTPRD', 'Gene', '5789', (196, 201))	('PTPRD', 'Gene', (196, 201))	('IGF-1R', 'Gene', (91, 97))	('IGF-1R', 'Gene', '3480', (91, 97))	('enhanced', 'PosReg', (142, 150))	('STAT3', 'Gene', '6774', (6, 11))	('attenuate', 'NegReg', (128, 137))	('IGF-1R', 'Gene', '3480', (115, 121))	('STAT3', 'Gene', '6774', (151, 156))	('STAT3', 'Gene', (6, 11))	('mutations', 'Var', (202, 211))
554128	23800680	Of interest, two of three patients with germline PTPRD mutations achieved durable complete responses following treatment with IGF-1R monoclonal antibody-based therapies.	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (26, 34))	('IGF-1R', 'Gene', (126, 132))	('PTPRD', 'Gene', '5789', (49, 54))	('PTPRD', 'Gene', (49, 54))	('IGF-1R', 'Gene', '3480', (126, 132))
554129	23800680	Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma, a disease of young people, and their presence may have implications for therapy.	('Ewing sarcoma', 'Disease', (91, 104))	('people', 'Species', '9606', (125, 131))	('play', 'Reg', (57, 61))	('PTPRD', 'Gene', '5789', (28, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('PTPRD', 'Gene', (28, 33))	('germline mutations', 'Var', (34, 52))	('role', 'Reg', (64, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('implications', 'Reg', (161, 173))
554130	23800680	Germline mutations occur in several cancer-related genes including, but not limited to, BRCA1, BRCA2, RB1 and TP53.	('Germline mutations', 'Var', (0, 18))	('BRCA1', 'Gene', (88, 93))	('BRCA2', 'Gene', '675', (95, 100))	('RB1', 'Gene', '5925', (102, 105))	('TP53', 'Gene', '7157', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('TP53', 'Gene', (110, 114))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('BRCA2', 'Gene', (95, 100))	('BRCA1', 'Gene', '672', (88, 93))	('RB1', 'Gene', (102, 105))	('occur', 'Reg', (19, 24))
554131	23800680	Patients with these mutations often develop tumors at a young age.	('develop', 'Reg', (36, 43))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutations', 'Var', (20, 29))
554137	23800680	Genetic aberrations of PTPRD are associated with a poor prognosis in malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('associated', 'Reg', (33, 43))	('malignant tumors', 'Disease', (69, 85))	('Genetic aberrations', 'Var', (0, 19))	('malignant tumors', 'Disease', 'MESH:D018198', (69, 85))	('PTPRD', 'Gene', '5789', (23, 28))	('PTPRD', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
554138	23800680	Mutations in PTPRD have been reported in approximately 13% of head and neck squamous cell carcinoma, 12% of melanoma, and in a small subset of various other malignancies.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('malignancies', 'Disease', 'MESH:D009369', (157, 169))	('PTPRD', 'Gene', '5789', (13, 18))	('PTPRD', 'Gene', (13, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (71, 99))	('malignancies', 'Disease', (157, 169))	('Mutations', 'Var', (0, 9))	('neck squamous cell carcinoma', 'Disease', (71, 99))	('reported', 'Reg', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (62, 99))	('melanoma', 'Disease', (108, 116))
554140	23800680	Here we report three of eight patients (37.5%) with metastatic Ewing sarcoma who harbored germline mutations in the PTPRD gene.	('PTPRD', 'Gene', '5789', (116, 121))	('PTPRD', 'Gene', (116, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Ewing sarcoma', 'Disease', (63, 76))	('patients', 'Species', '9606', (30, 38))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (63, 76))	('germline mutations', 'Var', (90, 108))
554143	23800680	Because phosphorylated STAT3 is frequently upregulated in Ewing sarcoma and PTPRD dephosphorylates STAT3, the role of germline and somatic PTPRD mutations in Ewing sarcoma as well as the implications for IGF-1R targeted therapy warrant exploration.	('mutations', 'Var', (145, 154))	('PTPRD', 'Gene', '5789', (139, 144))	('STAT3', 'Gene', (23, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('STAT3', 'Gene', '6774', (23, 28))	('Ewing sarcoma', 'Disease', (58, 71))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (158, 171))	('phosphorylated', 'MPA', (8, 22))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (158, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('IGF-1R', 'Gene', (204, 210))	('upregulated', 'PosReg', (43, 54))	('IGF-1R', 'Gene', '3480', (204, 210))	('STAT3', 'Gene', (99, 104))	('PTPRD', 'Gene', (76, 81))	('PTPRD', 'Gene', (139, 144))	('Ewing sarcoma', 'Disease', (158, 171))	('STAT3', 'Gene', '6774', (99, 104))	('PTPRD', 'Gene', '5789', (76, 81))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (58, 71))
554147	23800680	Patient 1 (Table 1; age 24 at diagnosis) had mutational analysis of 182 cancer-related genomic alterations in formalin-fixed paraffin-embedded tumor tissue performed using a Clinical Laboratory Improvement Amendment approved Foundation One platform.	('mutational', 'Var', (45, 55))	('tumor', 'Disease', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('paraffin', 'Chemical', 'MESH:D010232', (125, 133))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('formalin', 'Chemical', 'MESH:D005557', (110, 118))	('Patient', 'Species', '9606', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cancer', 'Disease', (72, 78))
554149	23800680	A PTPRD mutation annotated as a W775stop germline mutation was found in both the patient's tumor and PBMCs (Figure 1).	('PTPRD', 'Gene', (2, 7))	('patient', 'Species', '9606', (81, 88))	('W775stop', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('W775stop', 'Mutation', 'rs747543296', (32, 40))	('PTPRD', 'Gene', '5789', (2, 7))
554150	23800680	The PTPRD mutation was confirmed by polymerase chain reaction (PCR)-based Sanger sequencing in genomic DNA derived from tumor and PBMCs.	('PTPRD', 'Gene', '5789', (4, 9))	('PTPRD', 'Gene', (4, 9))	('mutation', 'Var', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
554152	23800680	The mutation of tryptophan to a stop codon results in the truncation of all transmembrane and intracellular domains, which leads to partial loss of the dephosphorylation function of PTPRD.	('dephosphorylation function', 'MPA', (152, 178))	('mutation', 'Var', (4, 12))	('PTPRD', 'Gene', '5789', (182, 187))	('truncation', 'MPA', (58, 68))	('PTPRD', 'Gene', (182, 187))	('tryptophan', 'Chemical', 'MESH:D014364', (16, 26))	('loss', 'NegReg', (140, 144))
554154	23800680	In addition, NGS revealed a V253I germline mutation located in the third immunoglobulin (Ig)-like domain of the receptor protein tyrosine phosphatase (RPTP)-F region, also known as LAR, within the extracellular domain (Figure 1).	('V253I', 'Var', (28, 33))	('V253I', 'Mutation', 'rs760428875', (28, 33))	('LAR', 'Gene', '5792', (181, 184))	('LAR', 'Gene', (181, 184))
554156	23800680	PBMCs from an additional seven patients (2 to 8, Table 1) with advanced Ewing sarcoma were analyzed for PTPRD germline mutations in all 35 exons (exons 11-45, ENST00000381196) using Sanger sequencing, as previously described.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 85))	('mutations in', 'Var', (119, 131))	('Ewing sarcoma', 'Disease', (72, 85))	('patients', 'Species', '9606', (31, 39))	('PTPRD', 'Gene', '5789', (104, 109))	('PTPRD', 'Gene', (104, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))
554157	23800680	Among these seven patients, five had wild-type PTPRD and two had PTPRD germline mutations: T781A and R995C.	('PTPRD', 'Gene', (47, 52))	('PTPRD', 'Gene', '5789', (65, 70))	('PTPRD', 'Gene', (65, 70))	('T781A', 'Var', (91, 96))	('patients', 'Species', '9606', (18, 26))	('R995C', 'Mutation', 'rs35929428', (101, 106))	('T781A', 'Mutation', 'rs72694737', (91, 96))	('R995C', 'Var', (101, 106))	('PTPRD', 'Gene', '5789', (47, 52))
554159	23800680	A second patient with a PTPRD mutation (Patient 5, Table 1) also attained a CR on IGF-1R inhibitor-based therapy.	('patient', 'Species', '9606', (9, 16))	('mutation', 'Var', (30, 38))	('PTPRD', 'Gene', '5789', (24, 29))	('Patient', 'Species', '9606', (40, 47))	('PTPRD', 'Gene', (24, 29))	('IGF-1R', 'Gene', '3480', (82, 88))	('IGF-1R', 'Gene', (82, 88))
554160	23800680	We identified germline PTPRD mutations in three (37.5%) of eight patients with advanced/metastatic Ewing sarcoma.	('Ewing sarcoma', 'Disease', (99, 112))	('mutations', 'Var', (29, 38))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (99, 112))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (99, 112))	('patients', 'Species', '9606', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('PTPRD', 'Gene', '5789', (23, 28))	('PTPRD', 'Gene', (23, 28))
554162	23800680	The PTPRD W775stop germline mutation is expected to express truncated PTPRD protein, leading to loss of function; however, it has not previously been reported in the Exome Sequencing Project (ESP) and Catalogue of Somatic Mutations in Cancer (COSMIC) databases in the general population or in cancer patients (Figure 1).	('cancer', 'Disease', (293, 299))	('PTPRD', 'Gene', '5789', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('PTPRD', 'Gene', (4, 9))	('Cancer', 'Phenotype', 'HP:0002664', (235, 241))	('PTPRD', 'Gene', '5789', (70, 75))	('PTPRD', 'Gene', (70, 75))	('W775stop', 'Mutation', 'rs747543296', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('loss', 'NegReg', (96, 100))	('W775stop', 'Var', (10, 18))	('patients', 'Species', '9606', (300, 308))
554163	23800680	The W775stop germline mutation can lead to the truncation of all transmembrane and intracellular domains, which can putatively result in partial loss of the dephosphorylation function of PTPRD.	('loss', 'NegReg', (145, 149))	('dephosphorylation function', 'MPA', (157, 183))	('W775stop', 'Mutation', 'rs747543296', (4, 12))	('lead to', 'Reg', (35, 42))	('W775stop', 'Var', (4, 12))	('PTPRD', 'Gene', (187, 192))	('PTPRD', 'Gene', '5789', (187, 192))
554165	23800680	Patient 1 also had a PTPRD V253I germline mutation located within the extracellular domain coding region; its functional consequences are unclear (Figure 1).	('PTPRD', 'Gene', '5789', (21, 26))	('PTPRD', 'Gene', (21, 26))	('V253I', 'Var', (27, 32))	('V253I', 'Mutation', 'rs760428875', (27, 32))	('Patient', 'Species', '9606', (0, 7))
554166	23800680	[10] In another two patients, we identified germline mutations T781A and R995C, which are single nucleotide polymorphisms of the PTPRD suppressor that have been reported in a small subset (2.2% and 7.4%, respectively) of the general population [21], but whose functional impact is unclear.	('T781A', 'Var', (63, 68))	('R995C', 'Var', (73, 78))	('T781A', 'Mutation', 'rs72694737', (63, 68))	('patients', 'Species', '9606', (20, 28))	('PTPRD', 'Gene', '5789', (129, 134))	('PTPRD', 'Gene', (129, 134))	('R995C', 'Mutation', 'rs35929428', (73, 78))
554167	23800680	Two of three patients with germline PTPRD mutations attained a CR in response to therapies with a IGF-1R monoclonal antibody and or a combination of an IGF-1R monoclonal antibody and the mTOR inhibitor temsirolimus.	('PTPRD', 'Gene', (36, 41))	('temsirolimus', 'Chemical', 'MESH:C401859', (202, 214))	('IGF-1R', 'Gene', '3480', (152, 158))	('mTOR', 'Gene', '2475', (187, 191))	('patients', 'Species', '9606', (13, 21))	('mTOR', 'Gene', (187, 191))	('IGF-1R', 'Gene', (152, 158))	('IGF-1R', 'Gene', '3480', (98, 104))	('IGF-1R', 'Gene', (98, 104))	('mutations', 'Var', (42, 51))	('PTPRD', 'Gene', '5789', (36, 41))
554171	23800680	In the presence of truncated PTPRD, STAT3 would remain phosphorylated.	('STAT3', 'Gene', '6774', (36, 41))	('STAT3', 'Gene', (36, 41))	('truncated', 'Var', (19, 28))	('PTPRD', 'Gene', '5789', (29, 34))	('PTPRD', 'Gene', (29, 34))
554173	23800680	Somatic PTPRD mutations have been identified in a small subset of patients with cancer types such as glioblastoma multiforme, melanoma, squamous cell carcinoma of the head and neck, and others.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('PTPRD', 'Gene', (8, 13))	('cancer', 'Disease', (80, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('squamous cell carcinoma', 'Disease', (136, 159))	('PTPRD', 'Gene', '5789', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('mutations', 'Var', (14, 23))	('glioblastoma multiforme', 'Disease', (101, 124))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (101, 124))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (150, 180))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('patients', 'Species', '9606', (66, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('identified', 'Reg', (34, 44))
554175	23800680	However, the role of germline PTPRD mutations in predisposition to Ewing sarcoma, a disease of children, adolescents, and young adults, and the implications of these mutations for therapy with IGF-1R and STAT3 inhibitors warrants further investigation.	('PTPRD', 'Gene', (30, 35))	('IGF-1R', 'Gene', '3480', (193, 199))	('STAT3', 'Gene', '6774', (204, 209))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('IGF-1R', 'Gene', (193, 199))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('mutations', 'Var', (36, 45))	('STAT3', 'Gene', (204, 209))	('children', 'Species', '9606', (95, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('PTPRD', 'Gene', '5789', (30, 35))	('Ewing sarcoma', 'Disease', (67, 80))
554181	23800680	This level of data throughput enables 30X coverage of the human genome with high accuracy and depth, facilitating detection of rare somatic mutations, insertions and deletions in patient samples.	('human', 'Species', '9606', (58, 63))	('patient', 'Species', '9606', (179, 186))	('insertions', 'Var', (151, 161))	('mutations', 'Var', (140, 149))	('deletions', 'Var', (166, 175))
554182	23800680	Sanger sequencing of tumor tissue and PBMCs used to identify PTPRD mutations in all 35 exon (exons 11-45, ENST00000381196) was done as previously described.	('PTPRD', 'Gene', (61, 66))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('PTPRD', 'Gene', '5789', (61, 66))
554369	29072181	Fluorescence in situ hybridization showed a rearrangement of the EWSR1 gene on chromosome 22q12, which led to a diagnosis of primary clear cell sarcoma in the skin.	('EWSR1', 'Gene', (65, 70))	('primary clear cell sarcoma in the skin', 'Phenotype', 'HP:0030447', (125, 163))	('led to', 'Reg', (103, 109))	('rearrangement', 'Var', (44, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('clear cell sarcoma', 'Disease', (133, 151))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (133, 151))
554400	29072181	Another translocation of EWSR to CREB1, a gene at 2q13, has also been described in a subset of clear cell sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('clear cell sarcomas', 'Disease', 'MESH:D018227', (95, 114))	('clear cell sarcomas', 'Disease', (95, 114))	('described', 'Reg', (70, 79))	('CREB1', 'Gene', (33, 38))	('translocation', 'Var', (8, 21))	('EWSR', 'Gene', (25, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))
554455	28469480	The characteristic t(X;18)(p11.2;q11.2) translocation is a cytogenetic hallmark of SS, which presents in nearly all SS and does not occur in other forms of sarcomas.	('SS', 'Phenotype', 'HP:0012570', (116, 118))	('SS', 'Phenotype', 'HP:0012570', (83, 85))	('sarcomas', 'Disease', 'MESH:D012509', (156, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('sarcomas', 'Disease', (156, 164))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (19, 39))	('presents', 'Reg', (93, 101))	('translocation', 'Var', (40, 53))
554507	24664352	While the conclusion is that oral transmucosal fentanyl citrate can be effective for the management of breakthrough cancer pain, clinicians should remember that genetic variation in the catechol-O-methyltransferase gene affects cancer patients' response to morphine, which might explain the non-responding patient.	('catechol-O-methyltransferase', 'Gene', '1312', (186, 214))	('catechol-O-methyltransferase', 'Gene', (186, 214))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('affects', 'Reg', (220, 227))	('response to morphine', 'MPA', (245, 265))	('patients', 'Species', '9606', (235, 243))	('breakthrough cancer pain', 'Disease', 'MESH:D059390', (103, 127))	('breakthrough cancer pain', 'Disease', (103, 127))	('fentanyl citrate', 'Chemical', 'MESH:D005283', (47, 63))	('morphine', 'Chemical', 'MESH:D009020', (257, 265))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', (116, 122))	('breakthrough cancer pain', 'Phenotype', 'HP:0032149', (103, 127))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patient', 'Species', '9606', (235, 242))	('pain', 'Phenotype', 'HP:0012531', (123, 127))	('genetic variation', 'Var', (161, 178))	('patient', 'Species', '9606', (306, 313))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
554584	24664352	AEA and FAAH inhibition affects calcium ion transduction, which the investigators measured in DRG neurons co-cultured with fibrosarcoma cells.	('coma', 'Phenotype', 'HP:0001259', (131, 135))	('AEA', 'Chemical', 'MESH:C078814', (0, 3))	('fibrosarcoma', 'Disease', (123, 135))	('inhibition', 'Var', (13, 23))	('FAAH', 'Gene', (8, 12))	('calcium', 'Chemical', 'MESH:D002118', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (123, 135))	('calcium ion transduction', 'MPA', (32, 56))	('FAAH', 'Gene', '14073', (8, 12))	('fibrosarcoma', 'Disease', 'MESH:D005354', (123, 135))
554619	24664352	A317491, an antagonist of the P2X3 receptor, attenuates bone cancer pain when injected locally or intrathecally.	('bone cancer pain', 'Disease', (56, 72))	('rat', 'Species', '10116', (101, 104))	('bone cancer pain', 'Phenotype', 'HP:0002653', (56, 72))	('A317491', 'Chemical', 'MESH:C470346', (0, 7))	('attenuates', 'NegReg', (45, 55))	('pain', 'Phenotype', 'HP:0012531', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('A317491', 'Var', (0, 7))	('bone cancer pain', 'Disease', 'MESH:D001859', (56, 72))
554654	24664352	Interestingly disruption of the signaling leads to a decrease in cancer growth.	('decrease', 'NegReg', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('disruption', 'Var', (14, 24))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
554672	24664352	In a bone cancer model inoculated with human cancer cells that express mutated alpha6 integrin, the mice show a decrease in bone fractures, a decrease in tumor cell migration within the bone and a decrease in cancer pain behavior.	('cancer pain behavior', 'Disease', 'MESH:D000072716', (209, 229))	('bone cancer', 'Disease', 'MESH:D001859', (5, 16))	('mice', 'Species', '10090', (100, 104))	('bone cancer', 'Disease', (5, 16))	('bone fractures', 'Disease', 'MESH:D050723', (124, 138))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('pain', 'Phenotype', 'HP:0012531', (216, 220))	('cancer', 'Disease', (10, 16))	('tumor', 'Disease', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer pain behavior', 'Disease', (209, 229))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('human', 'Species', '9606', (39, 44))	('bone fractures', 'Disease', (124, 138))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('decrease', 'NegReg', (112, 120))	('mutated', 'Var', (71, 78))	('alpha6 integrin', 'Protein', (79, 94))	('decrease', 'NegReg', (142, 150))	('cancer', 'Disease', (209, 215))	('rat', 'Species', '10116', (168, 171))	('bone fractures', 'Phenotype', 'HP:0020110', (124, 138))	('decrease', 'NegReg', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
554695	24664352	Administration of H89, a PKA inhibitor, attenuates bone cancer pain in this model.	('H89', 'Var', (18, 21))	('rat', 'Species', '10116', (8, 11))	('pain', 'Phenotype', 'HP:0012531', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bone cancer pain', 'Disease', 'MESH:D001859', (51, 67))	('H89', 'Chemical', 'MESH:C063509', (18, 21))	('bone cancer pain', 'Disease', (51, 67))	('bone cancer pain', 'Phenotype', 'HP:0002653', (51, 67))	('attenuates', 'NegReg', (40, 50))
554704	24664352	Spinal inhibition of the EphB1 receptor relieves bone cancer pain and restores morphine induced analgesia in this model; spinal cord neurochemical changes are also reversed.	('restores', 'PosReg', (70, 78))	('bone cancer pain', 'Disease', (49, 65))	('neurochemical changes', 'Phenotype', 'HP:0000707', (133, 154))	('EphB1', 'Gene', '270190', (25, 30))	('morphine', 'Chemical', 'MESH:D009020', (79, 87))	('analgesia', 'Disease', (96, 105))	('analgesia', 'Disease', 'MESH:D000699', (96, 105))	('inhibition', 'Var', (7, 17))	('relieves', 'NegReg', (40, 48))	('EphB1', 'Gene', (25, 30))	('bone cancer pain', 'Disease', 'MESH:D001859', (49, 65))	('pain', 'Phenotype', 'HP:0012531', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('bone cancer pain', 'Phenotype', 'HP:0002653', (49, 65))
554705	24664352	Descending modulation of serotonin-dependent spinal processing contributes to cancer-induced bone pain.	('modulation', 'Var', (11, 21))	('bone pain', 'Disease', 'MESH:D010146', (93, 102))	('serotonin-dependent spinal processing', 'MPA', (25, 62))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('bone pain', 'Disease', (93, 102))	('pain', 'Phenotype', 'HP:0012531', (98, 102))	('bone pain', 'Phenotype', 'HP:0002653', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('serotonin', 'Chemical', 'MESH:D012701', (25, 34))
554710	24664352	Blockade of WNT signaling in the spinal cord reduces neurochemical alterations consistent with mouse bone cancer pain.	('bone cancer pain', 'Disease', 'MESH:D001859', (101, 117))	('neurochemical alterations', 'Phenotype', 'HP:0000707', (53, 78))	('bone cancer pain', 'Disease', (101, 117))	('rat', 'Species', '10116', (71, 74))	('bone cancer pain', 'Phenotype', 'HP:0002653', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Blockade', 'Var', (0, 8))	('reduces', 'NegReg', (45, 52))	('pain', 'Phenotype', 'HP:0012531', (113, 117))	('neurochemical alterations', 'MPA', (53, 78))	('mouse', 'Species', '10090', (95, 100))
554712	24664352	The cancer-induced molecular changes within the spinal cord result in electrophysiologic changes which are distinct relative to the changes induced by neuropathic or inflammatory pain (Figure 6).	('electrophysiologic changes', 'Phenotype', 'HP:0001311', (70, 96))	('electrophysiologic changes', 'MPA', (70, 96))	('neuropathic', 'Disease', (151, 162))	('changes', 'Var', (29, 36))	('molecular', 'MPA', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('neuropathic', 'Disease', 'MESH:D012678', (151, 162))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('inflammatory pain', 'Disease', (166, 183))	('pain', 'Phenotype', 'HP:0012531', (179, 183))	('cancer', 'Disease', (4, 10))	('inflammatory pain', 'Disease', 'MESH:D010146', (166, 183))
554732	24664352	Subcutaneous injection of CBIO reduces the production of hydrogen peroxide in the spinal cord and reduces GFAP expression in the spinal cord; moreover, CBIO prevents morphine tolerance when the two drugs are used together.	('CBIO', 'Var', (152, 156))	('GFAP', 'Protein', (106, 110))	('CBIO', 'Chemical', '-', (152, 156))	('reduces', 'NegReg', (31, 38))	('morphine tolerance', 'CPA', (166, 184))	('prevents', 'NegReg', (157, 165))	('CBIO', 'Chemical', '-', (26, 30))	('morphine', 'Chemical', 'MESH:D009020', (166, 174))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (57, 74))	('production of hydrogen peroxide', 'MPA', (43, 74))	('reduces', 'NegReg', (98, 105))
554737	24664352	Intrathecal PPF relieves cancer-induced pain and inhibits activation of spinal glial cells and the expression of glia-associated pro-inflammatory cytokines, including IL-1beta, IL-6, and TNFalpha.	('expression', 'MPA', (99, 109))	('TNFalpha', 'Gene', '21926', (187, 195))	('PPF', 'Chemical', 'MESH:C032114', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('pain', 'Phenotype', 'HP:0012531', (40, 44))	('IL-6', 'Gene', (177, 181))	('inhibits', 'NegReg', (49, 57))	('IL-6', 'Gene', '16193', (177, 181))	('PPF', 'Var', (12, 15))	('TNFalpha', 'Gene', (187, 195))	('relieves', 'NegReg', (16, 24))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('pain', 'Disease', (40, 44))	('pain', 'Disease', 'MESH:D010146', (40, 44))	('rat', 'Species', '10116', (3, 6))	('cancer', 'Disease', (25, 31))	('activation', 'CPA', (58, 68))
554748	24664352	Systemic injections of inhibitors of JNK reduce cancer-related mechanical allodynia, heat hyperalgesia, and tumor growth both in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('heat hyperalgesia', 'Disease', 'MESH:D006930', (85, 102))	('hyperalgesia', 'Phenotype', 'HP:0031005', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('inhibitors', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('JNK', 'Gene', (37, 40))	('tumor', 'Disease', (108, 113))	('heat hyperalgesia', 'Disease', (85, 102))	('reduce', 'NegReg', (41, 47))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mechanical allodynia', 'Disease', 'MESH:D006930', (63, 83))	('mechanical allodynia', 'Disease', (63, 83))	('allodynia', 'Phenotype', 'HP:0012533', (74, 83))
554826	30282812	We recently identified that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), the rate limiting enzyme in the synthesis of deoxyribonucleotides.	('Ewing sarcoma cells', 'Disease', (28, 47))	('inhibitors', 'Var', (75, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('ribonucleotide', 'Chemical', 'MESH:D012265', (171, 185))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))	('ribonucleotide', 'Chemical', 'MESH:D012265', (89, 103))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (28, 47))	('RNR', 'Gene', (115, 118))	('deoxyribonucleotides', 'Chemical', 'MESH:D003854', (166, 186))
554827	30282812	We subsequently found that the inhibition of checkpoint kinase 1 (CHK1) increases the sensitivity of Ewing sarcoma cells to inhibitors of RNR, such as gemcitabine.	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (101, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('gemcitabine', 'Chemical', 'MESH:C056507', (151, 162))	('increases', 'PosReg', (72, 81))	('Ewing sarcoma cells', 'Disease', (101, 120))	('sensitivity', 'MPA', (86, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('CHK1', 'Gene', (66, 70))	('inhibition', 'Var', (31, 41))	('checkpoint kinase 1', 'Gene', (45, 64))	('checkpoint kinase 1', 'Gene', '1111', (45, 64))	('CHK1', 'Gene', '1111', (66, 70))
554831	30282812	However, inhibition of mTORC1/2 activates the translational repressor 4E-BP1, reduces protein synthesis, and decreases levels of the CHK1 protein in Ewing sarcoma cells.	('protein synthesis', 'MPA', (86, 103))	('4E-BP1', 'Gene', (70, 76))	('mTORC1/2', 'Gene', (23, 31))	('CHK1', 'Gene', (133, 137))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('Ewing sarcoma cells', 'Disease', (149, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('levels of', 'MPA', (119, 128))	('CHK1', 'Gene', '1111', (133, 137))	('activates', 'PosReg', (32, 41))	('4E-BP1', 'Gene', '1978', (70, 76))	('mTORC1/2', 'Gene', '74343;382056', (23, 31))	('reduces', 'NegReg', (78, 85))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (149, 168))	('inhibition', 'Var', (9, 19))	('decreases', 'NegReg', (109, 118))
554838	30282812	More recently, we found that the inhibition of checkpoint kinase 1 (CHK1), a downstream effector of Ataxia Telangiectasia and Rad3-Related Protein (ATR) and a critical mediator of the response to DNA replication stress, increases the sensitivity of Ewing sarcoma cells to RNR inhibitors in vitro and in vivo .	('inhibition', 'Var', (33, 43))	('CHK1', 'Gene', (68, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('sensitivity', 'MPA', (234, 245))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (249, 268))	('Ataxia', 'Phenotype', 'HP:0001251', (100, 106))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (249, 262))	('CHK1', 'Gene', '1111', (68, 72))	('checkpoint kinase 1', 'Gene', (47, 66))	('checkpoint kinase 1', 'Gene', '1111', (47, 66))	('Ewing sarcoma cells', 'Disease', (249, 268))	('Telangiectasia', 'Phenotype', 'HP:0001009', (107, 121))	('Ataxia Telangiectasia and Rad3-Related Protein', 'Gene', '545', (100, 146))	('ATR', 'Gene', '545', (148, 151))	('ATR', 'Gene', (148, 151))	('increases', 'PosReg', (220, 229))
554844	30282812	The mTOR pathway is also known to have a critical role in Ewing sarcoma tumors and mTOR inhibitors reduce the growth of Ewing sarcoma cells in vitro and in xenograft experiments.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('mTOR', 'Gene', (83, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('reduce', 'NegReg', (99, 105))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (120, 139))	('Ewing sarcoma tumors', 'Disease', (58, 78))	('Ewing sarcoma tumors', 'Disease', 'MESH:D012512', (58, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (120, 133))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (58, 71))	('mTOR', 'Gene', (4, 8))	('growth', 'MPA', (110, 116))	('mTOR', 'Gene', '2475', (4, 8))	('inhibitors', 'Var', (88, 98))	('Ewing sarcoma cells', 'Disease', (120, 139))	('mTOR', 'Gene', '2475', (83, 87))
554847	30282812	We identified that the inhibition of mTORC1/2, but not mTORC1, activates the protein translation repressor 4E-BP1, reduces protein synthesis, and decreases levels of the CHK1 protein in Ewing sarcoma cells.	('mTORC1/2', 'Gene', (37, 45))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (186, 205))	('reduces', 'NegReg', (115, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('CHK1', 'Gene', '1111', (170, 174))	('decreases', 'NegReg', (146, 155))	('4E-BP1', 'Gene', '1978', (107, 113))	('levels', 'MPA', (156, 162))	('mTORC1/2', 'Gene', '74343;382056', (37, 45))	('protein synthesis', 'MPA', (123, 140))	('mTORC1', 'Gene', (55, 61))	('4E-BP1', 'Gene', (107, 113))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (186, 199))	('mTORC1', 'Gene', (37, 43))	('inhibition', 'Var', (23, 33))	('mTORC1', 'Gene', '382056', (55, 61))	('Ewing sarcoma cells', 'Disease', (186, 205))	('mTORC1', 'Gene', '382056', (37, 43))	('CHK1', 'Gene', (170, 174))	('activates', 'PosReg', (63, 72))
554863	30282812	A shERWOOD UltramiR Lentiviral Inducible shRNA plasmid targeting CHK1 (ULTRA342152) was obtained from Transomic Technologies (Huntsville, AL).	('CHK1', 'Gene', '1111', (65, 69))	('ULTRA342152', 'Var', (71, 82))	('ULTRA342152', 'Chemical', 'MESH:C489164', (71, 82))	('CHK1', 'Gene', (65, 69))
554871	30282812	Antibodies to the following proteins were used in the immunoblots: phospho-Histone-139 H2A.X (Cell Signaling, #9718, 1:1000), phospho-Chk1-345 ( Cell Signaling, #2348, 1:1000), phospho-Chk1-296 (Cell Signaling, #12302, 1:1000), Chk1 (Cell Signaling, #2360, 1:1000), c-MYC (Cell Signaling, #5605, 1:1000), puromycin (Millipore, #AF488, 1:2000), 4E-BP1 (Cell Signaling, #9644, 1:1000), PARP (Cell Signaling, #9532, 1:1000), cleaved caspase-3 (Cell Signaling, #9664, 1:1000), p-4E-BP1-37/46 (Cell Signaling, #2855, 1:1000), RRM1 (Cell Signaling, #8637, 1:1000), RRM2 (Santa Cruz, #398294, 1:500), CHK2 (Cell Signaling, #6334, 1:1000), S6 (Abcam, #40820, 1:1000), P-S6-235/236 (Cell Signaling, #4858, 1:1000) and tubulin (Proteintech, 66031-1, 1:2000).	('c-MYC', 'Gene', '4609', (266, 271))	('RRM2', 'Gene', (559, 563))	('Chk1', 'Gene', (134, 138))	('4E-BP1', 'Gene', (344, 350))	('H2A.X', 'Gene', (87, 92))	('caspase-3', 'Gene', '836', (430, 439))	('4E-BP1', 'Gene', '1978', (475, 481))	('P-S6-235/236', 'Var', (660, 672))	('c-MYC', 'Gene', (266, 271))	('Chk1', 'Gene', '1111', (134, 138))	('caspase-3', 'Gene', (430, 439))	('puromycin', 'Chemical', 'MESH:D011691', (305, 314))	('Chk1', 'Gene', (228, 232))	('Chk1', 'Gene', '1111', (228, 232))	('phospho', 'Chemical', 'MESH:C033601', (126, 133))	('PARP', 'Gene', '142', (384, 388))	('4E-BP1', 'Gene', (475, 481))	('RRM1', 'Gene', (521, 525))	('phospho', 'Chemical', 'MESH:C033601', (67, 74))	('PARP', 'Gene', (384, 388))	('Chk1', 'Gene', (185, 189))	('CHK2', 'Gene', (594, 598))	('H2A.X', 'Gene', '3014', (87, 92))	('4E-BP1', 'Gene', '1978', (344, 350))	('Chk1', 'Gene', '1111', (185, 189))	('P-S6-235', 'Chemical', 'MESH:C056056', (660, 668))	('RRM2', 'Gene', '6241', (559, 563))	('phospho', 'Chemical', 'MESH:C033601', (177, 184))	('tubulin', 'Protein', (709, 716))	('CHK2', 'Gene', '11200', (594, 598))	('RRM1', 'Gene', '6240', (521, 525))
554883	30282812	We used multiple siRNAs to knockdown CHK1 in Ewing sarcoma cells (Figures 1A and Supplementary Figure 1).	('CHK1', 'Gene', (37, 41))	('knockdown', 'Var', (27, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('CHK1', 'Gene', '1111', (37, 41))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (45, 64))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (45, 58))	('Ewing sarcoma cells', 'Disease', (45, 64))
554887	30282812	Next, we used immunoblotting for the CHK1 auto-phosphorylation site Ser-296 to test the ability of three CHK1 inhibitors, LY2603618, MK-8776, and prexasertib, to inhibit CHK1 function.	('MK-8776', 'Var', (133, 140))	('CHK1', 'Gene', (37, 41))	('function', 'MPA', (175, 183))	('CHK1', 'Gene', '1111', (170, 174))	('inhibit', 'NegReg', (162, 169))	('LY2603618', 'Chemical', 'MESH:C582547', (122, 131))	('CHK1', 'Gene', '1111', (105, 109))	('CHK1', 'Gene', '1111', (37, 41))	('LY2603618', 'Var', (122, 131))	('phospho', 'Chemical', 'MESH:C033601', (47, 54))	('MK-8776', 'Chemical', 'MESH:C559815', (133, 140))	('CHK1', 'Gene', (170, 174))	('CHK1', 'Gene', (105, 109))	('Ser', 'Chemical', 'MESH:C530429', (68, 71))
554890	30282812	Inhibition of CHK1, in addition to impairing the response to DNA replication stress, also causes DNA replication stress by altering origin licensing, which results in the phosphorylation of CHK1 itself at Ser-345 via ATR.	('CHK1', 'Gene', '1111', (190, 194))	('impairing', 'NegReg', (35, 44))	('results in', 'Reg', (156, 166))	('phosphorylation', 'MPA', (171, 186))	('CHK1', 'Gene', (14, 18))	('Ser-345', 'Var', (205, 212))	('phospho', 'Chemical', 'MESH:C033601', (171, 178))	('ATR', 'Gene', '545', (217, 220))	('Inhibition', 'Var', (0, 10))	('ATR', 'Gene', (217, 220))	('response', 'MPA', (49, 57))	('causes', 'Reg', (90, 96))	('Ser', 'Chemical', 'MESH:C530429', (205, 208))	('CHK1', 'Gene', (190, 194))	('CHK1', 'Gene', '1111', (14, 18))	('origin licensing', 'MPA', (132, 148))	('altering', 'Reg', (123, 131))
554900	30282812	Based on reports in the literature, as well as the sensitivity of Ewing sarcoma cells to inhibitors of RNR, we also tested whether inhibition of the mTOR pathway reduces levels of RRM1 and RRM2.	('Ewing sarcoma cells', 'Disease', (66, 85))	('RRM2', 'Gene', '6241', (189, 193))	('RRM2', 'Gene', (189, 193))	('tested', 'Reg', (116, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('mTOR', 'Gene', '2475', (149, 153))	('RRM1', 'Gene', '6240', (180, 184))	('mTOR', 'Gene', (149, 153))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (66, 85))	('reduces', 'NegReg', (162, 169))	('RRM1', 'Gene', (180, 184))	('inhibition', 'Var', (131, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (66, 79))
554901	30282812	Figure 2B shows that inhibition of mTOR reduced levels of both RRM1 and RRM2, although the effect was larger for RRM2 than RRM1.	('RRM1', 'Gene', (123, 127))	('levels', 'MPA', (48, 54))	('RRM1', 'Gene', '6240', (63, 67))	('mTOR', 'Gene', (35, 39))	('RRM1', 'Gene', (63, 67))	('mTOR', 'Gene', '2475', (35, 39))	('RRM2', 'Gene', '6241', (72, 76))	('inhibition', 'Var', (21, 31))	('reduced', 'NegReg', (40, 47))	('RRM2', 'Gene', (72, 76))	('RRM2', 'Gene', '6241', (113, 117))	('RRM2', 'Gene', (113, 117))	('RRM1', 'Gene', '6240', (123, 127))
554902	30282812	TAK-228 also reduced CHK1 levels in three non-Ewing sarcoma cell lines, HT1080, RD, and U2OS, but did not alter CHK1 levels in HEK-293T cells (Figure 2C).	('TAK-228', 'Var', (0, 7))	('CHK1', 'Gene', (112, 116))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (46, 59))	('CHK1', 'Gene', (21, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('CHK1', 'Gene', '1111', (112, 116))	('CHK1', 'Gene', '1111', (21, 25))	('HEK-293T', 'CellLine', 'CVCL:0063', (127, 135))	('Ewing sarcoma', 'Disease', (46, 59))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (46, 59))	('HT1080', 'CellLine', 'CVCL:0317', (72, 78))	('U2OS', 'CellLine', 'CVCL:0042', (88, 92))	('reduced', 'NegReg', (13, 20))
554905	30282812	Figure 2D shows that TAK-228 reduced protein synthesis in four Ewing sarcoma cell lines, similar to results obtained with the protein translation inhibitor cycloheximide (Supplementary Figure 2).	('cycloheximide', 'Chemical', 'MESH:D003513', (156, 169))	('protein synthesis', 'MPA', (37, 54))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (63, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Ewing sarcoma', 'Disease', (63, 76))	('reduced', 'NegReg', (29, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))	('TAK-228', 'Var', (21, 28))
554906	30282812	TAK-228 also reduced protein synthesis in several non-Ewing sarcoma cell lines with the exception of HEK-293T cells, similar to the results for CHK1 protein levels (Figure 2E).	('TAK-228', 'Var', (0, 7))	('HEK-293T', 'CellLine', 'CVCL:0063', (101, 109))	('CHK1', 'Gene', (144, 148))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (54, 67))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (54, 67))	('CHK1', 'Gene', '1111', (144, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('reduced', 'NegReg', (13, 20))	('Ewing sarcoma', 'Disease', (54, 67))	('protein synthesis', 'MPA', (21, 38))
554913	30282812	These findings are consistent with work that has shown that the ATP-competitive mTORC1/2 inhibitors suppress cap-dependent protein translation through 4E-BP1 protein dephosphorylation, while the effects of temsirolimus on this pathway are more variable.	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('4E-BP1', 'Gene', '1978', (151, 157))	('mTORC1/2', 'Gene', '74343;382056', (80, 88))	('inhibitors', 'Var', (89, 99))	('phospho', 'Chemical', 'MESH:C033601', (168, 175))	('suppress', 'NegReg', (100, 108))	('4E-BP1', 'Gene', (151, 157))	('cap-dependent protein translation', 'MPA', (109, 142))	('temsirolimus', 'Chemical', 'MESH:C401859', (206, 218))	('mTORC1/2', 'Gene', (80, 88))
554917	30282812	Figure 2H shows that 4EGI-1 reduced total protein synthesis, as assessed using puromycin labeling, and specifically reduced levels of CHK1 in Ewing sarcoma and osteosarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('reduced', 'NegReg', (28, 35))	('CHK1', 'Gene', (134, 138))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (142, 155))	('levels', 'MPA', (124, 130))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (142, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('CHK1', 'Gene', '1111', (134, 138))	('Ewing sarcoma', 'Disease', (142, 155))	('total protein synthesis', 'MPA', (36, 59))	('4EGI-1', 'Var', (21, 27))	('osteosarcoma', 'Phenotype', 'HP:0002669', (160, 172))	('osteosarcoma', 'Disease', (160, 172))	('osteosarcoma', 'Disease', 'MESH:D012516', (160, 172))	('reduced', 'NegReg', (116, 123))	('puromycin', 'Chemical', 'MESH:D011691', (79, 88))
554918	30282812	4E-BP1 is known to regulate the translation of c-Myc, which has a well-described role in Ewing sarcoma tumorigenesis, and Figure 2I shows that TAK-228 caused a dose-dependent reduction in the c-Myc protein.	('4E-BP1', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('c-Myc', 'Gene', (192, 197))	('Ewing sarcoma tumorigenesis', 'Disease', (89, 116))	('4E-BP1', 'Gene', '1978', (0, 6))	('c-Myc', 'Gene', '4609', (47, 52))	('reduction', 'NegReg', (175, 184))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('Ewing sarcoma tumorigenesis', 'Disease', 'MESH:D012512', (89, 116))	('c-Myc', 'Gene', '4609', (192, 197))	('c-Myc', 'Gene', (47, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('TAK-228', 'Var', (143, 150))
554920	30282812	Figure 2J demonstrates that TAK-228 caused a small, ~20% reduction in CHEK1 mRNA in both EW8 and TC71 cells, suggesting that inhibition of protein synthesis is the primary mechanism regulating CHK1 levels.	('CHK1', 'Gene', '1111', (193, 197))	('TC71', 'CellLine', 'CVCL:2213', (97, 101))	('mRNA', 'MPA', (76, 80))	('TAK-228', 'Var', (28, 35))	('reduction', 'NegReg', (57, 66))	('CHEK1', 'Gene', '1111', (70, 75))	('CHEK1', 'Gene', (70, 75))	('CHK1', 'Gene', (193, 197))
554959	30282812	Figure 5H shows that gemcitabine (10 nM) and prexasertib (1 nM or 2 nM) also suppressed protein synthesis, in contrast to either drug as a single agent (at the specified doses) (Figure 3B and Figure 5C).	('suppressed', 'NegReg', (77, 87))	('protein synthesis', 'MPA', (88, 105))	('gemcitabine', 'Chemical', 'MESH:C056507', (21, 32))	('10', 'Var', (34, 36))
554967	30282812	In addition, the knockdown of EWS-FLI1 in A673 cells reversed the effect of gemcitabine on 4E-BP1 phosphorylation (Figure 6E).	('FLI1', 'Gene', (34, 38))	('4E-BP1', 'Gene', '1978', (91, 97))	('FLI1', 'Gene', '2313', (34, 38))	('gemcitabine', 'Chemical', 'MESH:C056507', (76, 87))	('phospho', 'Chemical', 'MESH:C033601', (98, 105))	('EWS', 'Gene', '2130', (30, 33))	('EWS', 'Gene', (30, 33))	('4E-BP1', 'Gene', (91, 97))	('knockdown', 'Var', (17, 26))	('effect', 'MPA', (66, 72))
554968	30282812	Knockdown of EWS-FLI1 also caused a reduction in total 4E-BP1 levels, which may provide an explanation for the high levels of 4E-BP1 in Ewing sarcoma cells (Supplementary Figure 3).	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (136, 155))	('4E-BP1', 'Gene', (55, 61))	('Knockdown', 'Var', (0, 9))	('4E-BP1', 'Gene', '1978', (126, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('reduction', 'NegReg', (36, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('4E-BP1', 'Gene', (126, 132))	('Ewing sarcoma cells', 'Disease', (136, 155))	('EWS', 'Gene', (13, 16))	('4E-BP1', 'Gene', '1978', (55, 61))	('EWS', 'Gene', '2130', (13, 16))	('FLI1', 'Gene', (17, 21))	('FLI1', 'Gene', '2313', (17, 21))
554969	30282812	In an approach complementary to gemcitabine treatment, we also used siRNA (siRRM2) to knockdown RRM2 in two Ewing sarcoma cell lines and identified a reduction in protein synthesis (Figure 6F), as well as a loss of CHK1 (Figure 6G) and c-Myc (Figure 6H) proteins.	('RRM2', 'Gene', (96, 100))	('knockdown', 'Var', (86, 95))	('protein synthesis', 'MPA', (163, 180))	('CHK1', 'Gene', '1111', (215, 219))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('loss', 'NegReg', (207, 211))	('RRM2', 'Gene', '6241', (96, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('c-Myc', 'Gene', '4609', (236, 241))	('reduction', 'NegReg', (150, 159))	('Ewing sarcoma', 'Disease', (108, 121))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (108, 121))	('gemcitabine', 'Chemical', 'MESH:C056507', (32, 43))	('CHK1', 'Gene', (215, 219))	('RRM2', 'Gene', '6241', (77, 81))	('RRM2', 'Gene', (77, 81))	('c-Myc', 'Gene', (236, 241))
554975	30282812	However, from a mechanistic standpoint, we discovered that inhibition of mTORC1/2 decreases levels of CHK1 protein via a reduction in protein synthesis.	('CHK1', 'Gene', (102, 106))	('mTORC1/2', 'Gene', '74343;382056', (73, 81))	('CHK1', 'Gene', '1111', (102, 106))	('protein synthesis', 'MPA', (134, 151))	('inhibition', 'Var', (59, 69))	('mTORC1/2', 'Gene', (73, 81))	('decreases', 'NegReg', (82, 91))	('reduction', 'NegReg', (121, 130))
554976	30282812	Inhibition of mTORC1/2 also reduced levels of the subunits of RNR, RRM1 and RRM2, in Ewing sarcoma cells.	('RRM1', 'Gene', (67, 71))	('mTORC1/2', 'Gene', '74343;382056', (14, 22))	('levels of', 'MPA', (36, 45))	('reduced', 'NegReg', (28, 35))	('RNR', 'Gene', (62, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (85, 104))	('subunits', 'MPA', (50, 58))	('RRM2', 'Gene', '6241', (76, 80))	('RRM2', 'Gene', (76, 80))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('mTORC1/2', 'Gene', (14, 22))	('Inhibition', 'Var', (0, 10))	('Ewing sarcoma cells', 'Disease', (85, 104))	('RRM1', 'Gene', '6240', (67, 71))
554977	30282812	This reduction of RRM1, RRM2, and CHK1 levels by inhibition of mTORC1/2 may provide an explanation, in part, for the toxicity of mTOR inhibitors toward Ewing sarcoma cells, although other targets and mechanisms likely contribute as well.	('RRM2', 'Gene', '6241', (24, 28))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (152, 165))	('CHK1', 'Gene', (34, 38))	('reduction', 'NegReg', (5, 14))	('Ewing sarcoma cells', 'Disease', (152, 171))	('mTOR', 'Gene', (129, 133))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (152, 171))	('mTORC1/2', 'Gene', '74343;382056', (63, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('RRM2', 'Gene', (24, 28))	('RRM1', 'Gene', '6240', (18, 22))	('mTOR', 'Gene', '2475', (129, 133))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('CHK1', 'Gene', '1111', (34, 38))	('inhibition', 'Var', (49, 59))	('mTOR', 'Gene', (63, 67))	('mTORC1/2', 'Gene', (63, 71))	('toxicity', 'Disease', (117, 125))	('mTOR', 'Gene', '2475', (63, 67))	('RRM1', 'Gene', (18, 22))
554991	30282812	However, the finding that gemcitabine and/or knockdown of RRM2 activated 4E-BP1 and inhibited protein synthesis in Ewing sarcoma cells was unexpected.	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (115, 134))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (115, 128))	('protein synthesis', 'MPA', (94, 111))	('4E-BP1', 'Gene', (73, 79))	('RRM2', 'Gene', '6241', (58, 62))	('4E-BP1', 'Gene', '1978', (73, 79))	('RRM2', 'Gene', (58, 62))	('Ewing sarcoma cells', 'Disease', (115, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('activated', 'PosReg', (63, 72))	('gemcitabine', 'Chemical', 'MESH:C056507', (26, 37))	('knockdown', 'Var', (45, 54))	('inhibited', 'NegReg', (84, 93))
554998	30282812	recently showed that ciclopirox, which inhibits RNR and the growth of Ewing sarcoma cells in vitro and in vivo, inhibits mTOR signaling by activation of AMP-activated protein kinase (AMPK).	('mTOR', 'Gene', '2475', (121, 125))	('ciclopirox', 'Var', (21, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('RNR', 'MPA', (48, 51))	('AMPK', 'Gene', '5562', (183, 187))	('mTOR', 'Gene', (121, 125))	('AMP-activated protein kinase', 'Gene', '5562', (153, 181))	('AMP-activated protein kinase', 'Gene', (153, 181))	('Ewing sarcoma cells', 'Disease', 'MESH:D012512', (70, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('ciclopirox', 'Chemical', 'MESH:C011585', (21, 31))	('growth', 'CPA', (60, 66))	('inhibits', 'NegReg', (39, 47))	('inhibits', 'NegReg', (112, 120))	('AMPK', 'Gene', (183, 187))	('Ewing sarcoma cells', 'Disease', (70, 89))
555068	26505995	PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR).	('PARP', 'Gene', '142', (0, 4))	('deficiency', 'NegReg', (77, 87))	('PARP', 'Gene', (0, 4))	('BRCA1/2', 'Gene', '672;675', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (53, 62))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('BRCA1/2', 'Gene', (45, 52))
555070	26505995	PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA.	('inhibiting', 'NegReg', (43, 53))	('blocking', 'NegReg', (79, 87))	('PARP', 'Gene', (0, 4))	('PARP1/2', 'Gene', '64761;142;10038', (54, 61))	('PARP1/2', 'Gene', '64761;142;10038', (88, 95))	('PARP', 'Gene', '142', (54, 58))	('inhibitors', 'Var', (5, 15))	('PARP', 'Gene', '142', (88, 92))	('release from substrate DNA', 'MPA', (96, 122))	('PARP1/2', 'Gene', (54, 61))	('auto-PARylation', 'MPA', (62, 77))	('PARP1/2', 'Gene', (88, 95))	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', (54, 58))	('PARP', 'Gene', (88, 92))
555075	26505995	Ewing's sarcoma is a malignant bone tumour in which 85% of patients harbour a gene translocation involving the Ewing's sarcoma breakpoint region 1 (EWS) gene fused to the Friend leukaemia virus integration site 1 (FLI1) gene: EWS-FLI1 t(11;22).	("Ewing's sarcoma", 'Disease', (0, 15))	('FLI1', 'Gene', (230, 234))	('bone tumour', 'Phenotype', 'HP:0010622', (31, 42))	('FLI1', 'Gene', (214, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	("Ewing's sarcoma", 'Disease', (111, 126))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('FLI1', 'Gene', '2313', (230, 234))	('bone tumour', 'Disease', 'MESH:D001859', (31, 42))	('EWS', 'Gene', '2130', (148, 151))	('EWS-FLI1', 'Gene', (226, 234))	('patients', 'Species', '9606', (59, 67))	('FLI1', 'Gene', '2313', (214, 218))	('EWS', 'Gene', '2130', (226, 229))	('Friend leukaemia virus integration site 1', 'Gene', '2313', (171, 212))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('gene translocation', 'Var', (78, 96))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (111, 126))	('bone tumour', 'Disease', (31, 42))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('EWS-FLI1', 'Gene', '2130;2313', (226, 234))	('EWS', 'Gene', (148, 151))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (111, 126))	('Friend leukaemia virus integration site 1', 'Gene', (171, 212))	('EWS', 'Gene', (226, 229))
555086	26505995	Olaparib, a potent PARPi, exhibits synthetic lethality in cells with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair mediated by homologous recombination (HR).	('BRCA1/2', 'Gene', (69, 76))	('deficiency', 'NegReg', (101, 111))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('PARP', 'Gene', '142', (19, 23))	('BRCA1/2', 'Gene', '672;675', (69, 76))	('mutations', 'Var', (77, 86))	('PARP', 'Gene', (19, 23))	('homologous recombination', 'MPA', (164, 188))
555089	26505995	Additional genetic modulators of PARPi sensitivity have been identified, such as mutations in the genes encoding ATM, ATR or PTEN, and elevated PARP1 expression is emerging as a measure of PARPi sensitivity.	('PARP', 'Gene', '142', (144, 148))	('expression', 'MPA', (150, 160))	('elevated', 'PosReg', (135, 143))	('PTEN', 'Gene', (125, 129))	('ATM', 'Gene', (113, 116))	('PTEN', 'Gene', '5728', (125, 129))	('PARP', 'Gene', (144, 148))	('PARP', 'Gene', (189, 193))	('PARP', 'Gene', '142', (33, 37))	('ATM', 'Gene', '472', (113, 116))	('mutations', 'Var', (81, 90))	('PARP', 'Gene', (33, 37))	('PARP', 'Gene', '142', (189, 193))	('ATR', 'Gene', '545', (118, 121))	('ATR', 'Gene', (118, 121))
555118	26505995	To validate EWS-FLI1 as a marker of sensitivity, we confirmed disruption of the EWS gene in all the EWSCs in our cell panel (S1A Fig).	('EWS', 'Gene', (80, 83))	('EWS-FLI1', 'Gene', '2130;2313', (12, 20))	('EWS', 'Gene', '2130', (12, 15))	('EWS', 'Gene', (12, 15))	('EWS', 'Gene', '2130', (80, 83))	('disruption', 'Var', (62, 72))	('EWS', 'Gene', '2130', (100, 103))	('EWS', 'Gene', (100, 103))	('EWS-FLI1', 'Gene', (12, 20))
555128	26505995	Whole-exome sequencing of EWSCs did not identify mutations in DNA repair genes as a possible reason for the observed sensitivity (sequencing data available on COSMIC).	('DNA repair', 'Gene', (62, 72))	('mutations', 'Var', (49, 58))	('EWS', 'Gene', (26, 29))	('EWS', 'Gene', '2130', (26, 29))
555135	26505995	ATM is typically activated in response to DSBs, promotes DSB exonuclease processing, and activates an S-phase checkpoint.	('DSB exonuclease processing', 'MPA', (57, 83))	('DSBs', 'Chemical', 'MESH:C007563', (42, 46))	('ATM', 'Gene', (0, 3))	('DSBs', 'Var', (42, 46))	('promotes', 'PosReg', (48, 56))	('activates', 'PosReg', (89, 98))	('S-phase checkpoint', 'MPA', (102, 120))	('ATM', 'Gene', '472', (0, 3))
555139	26505995	KAP1 Ser-473 is phosphorylated by CHK1, and was also induced.	('CHK1', 'Gene', (34, 38))	('Ser-473', 'Var', (5, 12))	('KAP1', 'Gene', '1033', (0, 4))	('CHK1', 'Gene', '1111', (34, 38))	('KAP1', 'Gene', (0, 4))	('Ser', 'Chemical', 'MESH:D012694', (5, 8))
555142	26505995	A key step in HR is recruitment of RAD51 to sites of DNA damage, facilitating homology search and recombination, an event notably impaired in cancer cells that harbor deficiencies in HR.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('homology', 'Var', (78, 86))	('RAD51', 'Gene', (35, 40))	('harbor deficiencies in HR', 'Disease', 'MESH:C537062', (160, 185))	('RAD51', 'Gene', '5888', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('harbor deficiencies in HR', 'Disease', (160, 185))	('cancer', 'Disease', (142, 148))
555147	26505995	Notably, further support for functional repair pathways in EWSCs comes from the exceptionally low burden of mutations and structural variation observed in the tumours of Ewing's sarcoma patients compared to other malignancies.	('EWS', 'Gene', (59, 62))	("tumours of Ewing's sarcoma", 'Disease', 'MESH:C563168', (159, 185))	('structural variation', 'Var', (122, 142))	("tumours of Ewing's sarcoma", 'Disease', (159, 185))	('malignancies', 'Disease', 'MESH:D009369', (213, 225))	('malignancies', 'Disease', (213, 225))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (170, 185))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('patients', 'Species', '9606', (186, 194))	('EWS', 'Gene', '2130', (59, 62))
555149	26505995	Notably, however, PARP1 depletion reversed the sensitivity of ES8 cells towards olaparib and also the structurally and chemically distinct PARPi rucaparib (Fig 4A white columns and S4C Fig), and by using a titration of PARP1 siRNA we observed that the extent of the reversal correlated with PARP1 expression levels (Fig 4B).	('sensitivity', 'MPA', (47, 58))	('PARP', 'Gene', '142', (219, 223))	('PARP', 'Gene', (291, 295))	('PARP', 'Gene', '142', (139, 143))	('PARP', 'Gene', (219, 223))	('depletion', 'Var', (24, 33))	('expression', 'MPA', (297, 307))	('PARP', 'Gene', (18, 22))	('PARP', 'Gene', '142', (291, 295))	('olaparib', 'Chemical', 'MESH:C531550', (80, 88))	('PARP', 'Gene', (139, 143))	('rucaparib', 'Chemical', 'MESH:C531549', (145, 154))	('PARP', 'Gene', '142', (18, 22))
555150	26505995	Similar effects were observed in ES7 and MHH-ES-1 cells, and when using two different siRNA targeting PARP (S4B, S4D and S4E Fig).	('S4D', 'Var', (113, 116))	('S4E', 'Var', (121, 124))	('PARP', 'Gene', (102, 106))	('PARP', 'Gene', '142', (102, 106))
555161	26505995	Importantly, temozolomide more substantially enhanced sensitivity to PARPi in all EWSCs tested, doing so to a degree comparable with MMS (Fig 5A and S5 Fig).	('PARP', 'Gene', '142', (69, 73))	('temozolomide', 'Chemical', 'MESH:D000077204', (13, 25))	('temozolomide', 'Var', (13, 25))	('enhanced', 'PosReg', (45, 53))	('PARP', 'Gene', (69, 73))	('EWS', 'Gene', (82, 85))	('EWS', 'Gene', '2130', (82, 85))	('MMS', 'Chemical', 'MESH:D008741', (133, 136))	('sensitivity', 'MPA', (54, 65))
555171	26505995	The lack of sensitivity of the trapping assay is demonstrated by the fact that MMS strongly potentiated the effects of olaparib on cell viability at concentrations of 0.0001% and 0.5muM respectively (S6D Fig), whereas PARP1-DNA complexes were only detected at 10-100 fold higher concentrations (0.01% MMS and 5muM olaparib; Fig 5D and S6E Fig).	('MMS', 'Chemical', 'MESH:D008741', (79, 82))	('muM', 'Gene', (182, 185))	('olaparib', 'Chemical', 'MESH:C531550', (314, 322))	('potentiated', 'PosReg', (92, 103))	('cell viability', 'CPA', (131, 145))	('effects', 'MPA', (108, 115))	('MMS', 'Var', (79, 82))	('muM', 'Gene', '56925', (310, 313))	('MMS', 'Chemical', 'MESH:D008741', (301, 304))	('muM', 'Gene', (310, 313))	('muM', 'Gene', '56925', (182, 185))	('olaparib', 'Chemical', 'MESH:C531550', (119, 127))
555180	26505995	PARP inhibition elicits anti-tumour activity in BRCA-mutant HR-deficient cancers, due to the dependency of these cancers on PARP1 activity in SSB repair to avoid replication-dependent accumulation of DSBs.	('tumour', 'Disease', (29, 35))	('inhibition', 'Var', (5, 15))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('BRCA', 'Gene', (48, 52))	('cancers', 'Disease', (113, 120))	('PARP', 'Gene', (124, 128))	('HR-deficient cancers', 'Disease', 'MESH:D009369', (60, 80))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('HR-deficient cancers', 'Disease', (60, 80))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('DSBs', 'Chemical', 'MESH:C007563', (200, 204))	('PARP', 'Gene', '142', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('BRCA', 'Gene', '672', (48, 52))	('PARP', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('PARP', 'Gene', '142', (124, 128))
555184	26505995	This is consistent with an exceptionally low burden of mutations and structural variation in Ewing's sarcoma patient tumours, which is in contrast to tumors deficient in key DNA repair processes.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumours', 'Disease', (117, 124))	('patient', 'Species', '9606', (109, 116))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (93, 108))	('tumors deficient', 'Disease', 'MESH:D009369', (150, 166))	('structural variation', 'Var', (69, 89))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (93, 108))	("Ewing's sarcoma", 'Disease', (93, 108))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('tumours', 'Disease', 'MESH:D009369', (117, 124))	('tumors deficient', 'Disease', (150, 166))
555185	26505995	An alternative mechanism of toxicity for PARPi has been described, where inhibition of PARP blocks auto-PARylation and prevents PARP release from DNA.	('PARP', 'Gene', '142', (128, 132))	('prevents', 'NegReg', (119, 127))	('PARP', 'Gene', (41, 45))	('auto-PARylation', 'MPA', (99, 114))	('PARP', 'Gene', (87, 91))	('toxicity', 'Disease', 'MESH:D064420', (28, 36))	('toxicity', 'Disease', (28, 36))	('PARP', 'Gene', (128, 132))	('PARP', 'Gene', '142', (41, 45))	('inhibition', 'Var', (73, 83))	('PARP', 'Gene', '142', (87, 91))	('blocks', 'NegReg', (92, 98))
555187	26505995	We demonstrated that an EWSC line with acquired resistance to olaparib had downregulated PARP1 protein, and siRNA-mediated depletion of PARP1 rescued EWSCs from PARPi hypersensitivity, indicating that PARP1 protein is required for drug toxicity.	('EWS', 'Gene', '2130', (24, 27))	('drug toxicity', 'Disease', 'MESH:D064420', (231, 244))	('downregulated', 'NegReg', (75, 88))	('protein', 'Protein', (95, 102))	('PARP', 'Gene', '142', (201, 205))	('hypersensitivity,', 'Disease', 'MESH:D004342', (167, 184))	('EWS', 'Gene', (150, 153))	('depletion', 'Var', (123, 132))	('PARP', 'Gene', '142', (161, 165))	('PARP', 'Gene', (201, 205))	('EWS', 'Gene', (24, 27))	('PARP', 'Gene', (161, 165))	('olaparib', 'Chemical', 'MESH:C531550', (62, 70))	('PARP', 'Gene', '142', (136, 140))	('PARP', 'Gene', '142', (89, 93))	('drug toxicity', 'Disease', (231, 244))	('PARP', 'Gene', (136, 140))	('PARP', 'Gene', (89, 93))	('EWS', 'Gene', '2130', (150, 153))
555211	26505995	If so, combining etoposide with alkylating agents and PARP1 inhibition would potentially suppress resistance mediated through down-regulation of PARP1, which we have shown can provide a possible route of resistance to this type of combination therapy.	('inhibition', 'Var', (60, 70))	('down-regulation', 'MPA', (126, 141))	('PARP1', 'Gene', (145, 150))	('resistance', 'MPA', (98, 108))	('PARP1', 'Gene', (54, 59))	('suppress', 'NegReg', (89, 97))	('etoposide', 'Chemical', 'MESH:D005047', (17, 26))
555215	25834713	Oncogenicity refers to viruses that may cause cancers, more importantly in immunocompromised subjects such as transplant and hemodialysis patients.	('cause', 'Reg', (40, 45))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('patients', 'Species', '9606', (138, 146))	('viruses', 'Var', (23, 30))
555476	29850352	Factors predicting a worse prognosis for patients with synovial sarcomas include tumour size (>5 cm), male gender, older age (>20 years), extensive tumour necrosis, high grade, large number of mitotic figures (>10 per 10 hpf), neurovascular invasion, and, recently, the SYT-SSX1 variant.	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('variant', 'Var', (279, 286))	('tumour', 'Disease', (148, 154))	('high', 'Var', (165, 169))	('SYT-SSX1', 'Gene', (270, 278))	('tumour necrosis', 'Disease', 'MESH:D009336', (148, 163))	('tumour necrosis', 'Disease', (148, 163))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Disease', (81, 87))	('neurovascular invasion', 'CPA', (227, 249))	('patients', 'Species', '9606', (41, 49))	('SYT-SSX1', 'Gene', '6760;6756', (270, 278))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (55, 72))	('synovial sarcomas', 'Disease', (55, 72))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (55, 71))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('synovial sarcomas', 'Disease', 'MESH:D013584', (55, 72))
555508	27114889	For the first time, we identify high BMP2 expression within the context of high BMPR1A expression as a biomarker of disease relapse in dedifferentiated liposarcomas.	('high', 'Var', (32, 36))	('liposarcomas', 'Disease', (152, 164))	('BMP2', 'Gene', (37, 41))	('high', 'Var', (75, 79))	('liposarcoma', 'Phenotype', 'HP:0012034', (152, 163))	('BMPR1A', 'Gene', (80, 86))	('expression', 'MPA', (87, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('liposarcomas', 'Disease', 'MESH:D008080', (152, 164))	('liposarcomas', 'Phenotype', 'HP:0012034', (152, 164))
555541	27114889	Although most patients expressed relatively similar levels of the two type I receptors there were clear groups who favoured either BMPR1A (red) or BMPR1B (blue) but who did not show differential expression of BMP2 (Fig.	('favoured', 'PosReg', (115, 123))	('BMPR1B', 'Var', (147, 153))	('patients', 'Species', '9606', (14, 22))	('BMPR1A', 'Gene', (131, 137))
555552	27114889	Thus, in addition to ECM remodelling and reduced bone formation, soft tissue sarcoma patients with BMPR1A-biased BMP2 expression are more likely to show tumour progression in the presence of high levels of endogenous BMP2.	('tumour', 'Disease', (153, 159))	('expression', 'Var', (118, 128))	('BMPR1A-biased BMP2', 'Gene', (99, 117))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('BMP2', 'Gene', (113, 117))	('patients', 'Species', '9606', (85, 93))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('sarcoma', 'Disease', (77, 84))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (65, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('tumour', 'Disease', 'MESH:D009369', (153, 159))
555563	27114889	4A), though high expression and R1A-biased BMP2 was highly detrimental in patients with DLS (Fig.	('patients', 'Species', '9606', (74, 82))	('BMP2', 'Gene', (43, 47))	('detrimental', 'NegReg', (59, 70))	('R1A-biased', 'Var', (32, 42))	('high expression', 'Var', (12, 27))	('DLS', 'Disease', (88, 91))
555564	27114889	To investigate the mechanism for this effect, we compared global gene expression in DLS patients with BMPR1A-biased signalling versus those with BMPR1B-biased signalling.	('global gene expression', 'MPA', (58, 80))	('compared', 'Reg', (49, 57))	('BMPR1A-biased signalling', 'Var', (102, 126))	('patients', 'Species', '9606', (88, 96))
555572	27114889	Several large studies performed by The Cancer Genome Atlas (TCGA) show copy number changes and mutational events in BMP2 interacting partners as defining features of that malignancy (Fig.	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Cancer Genome Atlas', 'Disease', (39, 58))	('copy number changes', 'Var', (71, 90))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (39, 58))	('BMP2', 'Gene', (116, 120))	('mutational events', 'Var', (95, 112))	('malignancy', 'Disease', 'MESH:D009369', (171, 181))	('malignancy', 'Disease', (171, 181))
555573	27114889	For example, two separate studies in Ovarian cancer show copy number gains as frequent events, which we later determined to be due to amplifications in the BMP2 and BMP7 loci (Fig.	('BMP7', 'Gene', (165, 169))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (37, 51))	('BMP2', 'Gene', (156, 160))	('amplifications', 'Var', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('copy number', 'MPA', (57, 68))	('BMP7', 'Gene', '655', (165, 169))	('Ovarian cancer', 'Disease', (37, 51))	('Ovarian cancer', 'Disease', 'MESH:D010051', (37, 51))	('gains', 'PosReg', (69, 74))
555575	27114889	Deep deletion of BMPR1A was a frequent event in prostate cancers, this has previously been shown to be related to the loss of the PTEN locus, which is associated with invasive forms of prostate cancer.	('BMPR1A', 'Gene', (17, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (48, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('prostate cancers', 'Disease', 'MESH:D011471', (48, 64))	('loss', 'NegReg', (118, 122))	('frequent', 'Reg', (30, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('prostate cancer', 'Disease', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('PTEN', 'Gene', (130, 134))	('prostate cancers', 'Phenotype', 'HP:0012125', (48, 64))	('PTEN', 'Gene', '5728', (130, 134))	('Deep deletion', 'Var', (0, 13))	('prostate cancers', 'Disease', (48, 64))
555578	27114889	Sahni and colleagues found that BMPR1A, but not BMPR1B, knockout mice exhibited defective astrocytic hypertrophy and increased inflammatory infiltrate after spinal chord injury.	('chord injury', 'Disease', (164, 176))	('increased', 'PosReg', (117, 126))	('defective astrocytic hypertrophy', 'Disease', 'MESH:D006984', (80, 112))	('mice', 'Species', '10090', (65, 69))	('chord injury', 'Disease', 'MESH:D058186', (164, 176))	('defective astrocytic hypertrophy', 'Disease', (80, 112))	('BMPR1A', 'Var', (32, 38))	('inflammatory infiltrate', 'CPA', (127, 150))
555581	27114889	Loss of BMPR1A has previously been associated with the formation of juvenile polyposis, a predisposing factor for gastrointestinal and colorectal cancers.	('gastrointestinal and colorectal cancers', 'Disease', 'MESH:D015179', (114, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('associated', 'Reg', (35, 45))	('BMPR1A', 'Gene', (8, 14))	('juvenile polyposis', 'Disease', 'MESH:C537702', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('juvenile polyposis', 'Phenotype', 'HP:0004784', (68, 86))	('Loss', 'Var', (0, 4))	('juvenile polyposis', 'Disease', (68, 86))
555583	27114889	Exemplifying the dichotomy of this signalling pathway in cancer, BMPR1A antagonists reduce growth and induce cell death in lung cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('reduce', 'NegReg', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('death in lung cancer', 'Disease', (114, 134))	('antagonists', 'Var', (72, 83))	('cancer', 'Disease', (57, 63))	('BMPR1A', 'Gene', (65, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('death in lung cancer', 'Disease', 'MESH:D008175', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('reduce growth', 'Phenotype', 'HP:0001510', (84, 97))	('growth', 'CPA', (91, 97))	('cancer', 'Disease', (128, 134))
555588	27114889	Further to linking BMPR1A-biased BMP2 expression to reduced disease free survival, we report a detailed differential expression analysis in both the sarcoma dataset as a whole and dedifferentiated liposarcomas.	('sarcoma', 'Disease', 'MESH:D012509', (149, 156))	('sarcoma', 'Disease', 'MESH:D012509', (201, 208))	('liposarcomas', 'Disease', 'MESH:D008080', (197, 209))	('reduced', 'NegReg', (52, 59))	('liposarcomas', 'Disease', (197, 209))	('BMP2', 'Gene', (33, 37))	('sarcoma', 'Disease', (149, 156))	('liposarcoma', 'Phenotype', 'HP:0012034', (197, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (201, 209))	('sarcoma', 'Disease', (201, 208))	('disease free survival', 'CPA', (60, 81))	('expression', 'Var', (38, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('liposarcomas', 'Phenotype', 'HP:0012034', (197, 209))
555592	27114889	Indeed we find that patients with BMPR1A-biased BMP2 expression also exhibit increased expression of genes typically linked with the matrisome and ECM remodelling.	('BMPR1A-biased', 'Var', (34, 47))	('expression of genes', 'MPA', (87, 106))	('patients', 'Species', '9606', (20, 28))	('increased', 'PosReg', (77, 86))	('BMP2', 'Gene', (48, 52))
555595	27114889	In summary, we present here evidence that high expression of BMP2 leads to extracellular matrix remodelling and tumour progression in dedifferentiated liposarcomas, only within the context of high BMPR1B expression.	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('BMP2', 'Gene', (61, 65))	('high expression', 'Var', (42, 57))	('liposarcomas', 'Phenotype', 'HP:0012034', (151, 163))	('leads to', 'Reg', (66, 74))	('liposarcomas', 'Disease', 'MESH:D008080', (151, 163))	('liposarcomas', 'Disease', (151, 163))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('liposarcoma', 'Phenotype', 'HP:0012034', (151, 162))	('extracellular matrix remodelling', 'CPA', (75, 107))
555615	31409302	In a placebo-controlled, randomized, phase 3 trial in patients with advanced STS (aSTS; excluding liposarcomas and gastrointestinal stromal tumor [GIST]), pazopanib administration led to significantly improved progression-free survival (PFS) compared with placebo.	('liposarcomas and gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (98, 145))	('liposarcomas', 'Phenotype', 'HP:0012034', (98, 110))	('progression-free survival', 'CPA', (210, 235))	('patients', 'Species', '9606', (54, 62))	('STS', 'Phenotype', 'HP:0030448', (77, 80))	('improved', 'PosReg', (201, 209))	('pazopanib', 'Chemical', 'MESH:C516667', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (115, 145))	('pazopanib', 'Var', (155, 164))	('STS', 'Phenotype', 'HP:0030448', (83, 86))
555635	31409302	Subgroups of interest in our current post hoc analyses were based on the following metrics: prior lines of therapy (only 1 prior line of therapy vs 2+ prior lines of therapy), age (< 65 years vs >=65 years) dose intensity (dose < 400 mg, >=400 mg to < 600 mg, and >= 600 mg to <=800 mg), and dose modifications (no dose reduction vs dose reductions; no dose interruption vs dose interruptions) among patients randomized to receive pazopanib in the PALETTE trial.	('patients', 'Species', '9606', (400, 408))	('dose < 400 mg', 'Var', (223, 236))	('pazopanib', 'Chemical', 'MESH:C516667', (431, 440))	('>= 600 mg to <=800 mg', 'Var', (264, 285))
555674	31409302	Mutagenesis driven by cytotoxic therapies or by acquired chromosomal instability could drive clonal selection, leading to greater intratumoral heterogeneity and thereby increasing the likelihood of resistance to subsequent treatment.	('greater', 'PosReg', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Mutagenesis', 'Var', (0, 11))	('resistance', 'MPA', (198, 208))	('tumor', 'Disease', (135, 140))	('increasing', 'PosReg', (169, 179))	('chromosomal instability', 'Phenotype', 'HP:0040012', (57, 80))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
555679	31409302	Intriguingly, patients receiving pazopanib with 1 or more dose reductions or dose interruptions because of drug toxicity had improved mPFS compared with patients in whom dose modifications were not required.	('pazopanib', 'Var', (33, 42))	('mPFS', 'MPA', (134, 138))	('toxicity', 'Disease', (112, 120))	('patients', 'Species', '9606', (153, 161))	('improved', 'PosReg', (125, 133))	('pazopanib', 'Chemical', 'MESH:C516667', (33, 42))	('patients', 'Species', '9606', (14, 22))	('reductions', 'NegReg', (63, 73))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))	('dose', 'MPA', (58, 62))
555685	31409302	In conclusion, longer mPFS was observed in patients receiving pazopanib as a second-line therapy for aSTS, rather than in later lines of treatment.	('patients', 'Species', '9606', (43, 51))	('pazopanib', 'Chemical', 'MESH:C516667', (62, 71))	('STS', 'Phenotype', 'HP:0030448', (102, 105))	('aSTS', 'Disease', (101, 105))	('pazopanib', 'Var', (62, 71))
555705	32477556	Granulocytic/myeloid sarcoma with trisomy 21 presented as an epididymal tumor: A case report and review of the literature Myeloid sarcoma is an extramedullary tumor composed of immature myeloid cells and occurs in various extramedullary sites.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (13, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('tumor', 'Disease', (72, 77))	('myeloid sarcoma', 'Disease', (13, 28))	('Myeloid sarcoma', 'Disease', 'MESH:D023981', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Myeloid sarcoma', 'Disease', (122, 137))	('epididymal tumor', 'Disease', 'MESH:D004823', (61, 77))	('tumor', 'Disease', (159, 164))	('epididymal tumor', 'Phenotype', 'HP:0030421', (61, 77))	('epididymal tumor', 'Disease', (61, 77))	('trisomy 21', 'Var', (34, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
555732	32477556	However, cytogenetic analysis showed abnormal karyotype, 47XY, add(2)(p13), del(6)(q21q25), add(8)(p11.2), +21, in 13 of 20 metaphases examined (Supplemental Figure 1).	('p11', 'Gene', (99, 102))	('del(6)(q21q25', 'Var', (76, 89))	('47XY', 'Var', (57, 61))	('p13', 'Gene', (70, 73))	('p11', 'Gene', '6281', (99, 102))	('p13', 'Gene', '440926', (70, 73))
555745	32477556	A previous report found several chromosomal aberrations, such as monosomy 7, trisomy 8, trisomy 4, trisomy 11, and monosomy 16, in 54% of patients.	('trisomy 8', 'Disease', (77, 86))	('monosomy 7', 'Disease', (65, 75))	('monosomy 16', 'Var', (115, 126))	('trisomy 11', 'Var', (99, 109))	('trisomy 4', 'Var', (88, 97))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (32, 55))	('patients', 'Species', '9606', (138, 146))
555746	32477556	Furthermore, cytogenetic abnormalities t(8;21) or inv(16) were often detected.	('inv', 'Var', (50, 53))	('cytogenetic abnormalities', 'Disease', 'MESH:D002869', (13, 38))	('cytogenetic abnormalities', 'Disease', (13, 38))
555774	31408723	We and others have recently proposed a model of cancer/leukemia evolution where the earliest stages of carcinogenesis are defined by expression of somatic mutations in small-sized clones containing pre-leukemic NSC (pre-L-NSC).	('mutations', 'Var', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('age', 'Gene', '5973', (95, 98))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('leukemia', 'Disease', 'MESH:D007938', (55, 63))	('leukemia', 'Disease', (55, 63))	('leukemic NSC', 'Disease', (202, 214))	('cancer', 'Disease', (48, 54))	('leukemic NSC', 'Disease', 'OMIM:617394', (202, 214))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('carcinogenesis', 'Disease', (103, 117))	('age', 'Gene', (95, 98))
555824	31408723	These enzymes, in turn, cleave vascular cell adhesion molecule 1 (VCAM-1) and disrupt the interaction between SDF-1 and CXCR4 on BM stem cells.	('interaction', 'MPA', (90, 101))	('vascular cell adhesion molecule 1', 'Gene', '7412', (31, 64))	('VCAM-1', 'Gene', (66, 72))	('cleave', 'Var', (24, 30))	('vascular cell adhesion molecule 1', 'Gene', (31, 64))	('CXCR4', 'Gene', '7852', (120, 125))	('VCAM-1', 'Gene', '7412', (66, 72))	('CXCR4', 'Gene', (120, 125))	('SDF-1', 'Gene', '6387', (110, 115))	('SDF-1', 'Gene', (110, 115))	('disrupt', 'NegReg', (78, 85))
555851	31408723	Especially in CML and MPN, but also in certain AML variants and MCL, neoplastic cells produce large amounts of VEGF (immature myeloid cells, megakaryocytes, basophils, mast cells), hepatocyte growth factor (HGF) (basophils) and/or histamine (basophils, mast cells).	('MPN', 'Phenotype', 'HP:0005547', (22, 25))	('VEGF', 'Gene', (111, 115))	('HGF', 'Gene', '3082', (207, 210))	('MCL', 'Disease', 'MESH:C535516', (64, 67))	('hepatocyte growth factor', 'Gene', (181, 205))	('variants', 'Var', (51, 59))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('CML', 'Disease', 'MESH:D015464', (14, 17))	('hepatocyte growth factor', 'Gene', '3082', (181, 205))	('MCL', 'Disease', (64, 67))	('CML', 'Phenotype', 'HP:0005506', (14, 17))	('VEGF', 'Gene', '7422', (111, 115))	('histamine', 'Chemical', 'MESH:D006632', (231, 240))	('AML', 'Disease', (47, 50))	('CML', 'Disease', (14, 17))	('HGF', 'Gene', (207, 210))
555909	31408723	For example, the safety and efficacy of RG7356, an anti-CD44 humanized antibody was tested in a Phase I study in patients with refractory or relapsed AML.	('CD44', 'Gene', (56, 60))	('RG7356', 'Var', (40, 46))	('AML', 'Disease', 'MESH:D015470', (150, 153))	('patients', 'Species', '9606', (113, 121))	('AML', 'Disease', (150, 153))	('CD44', 'Gene', '960', (56, 60))	('RG7356', 'Chemical', 'MESH:C576196', (40, 46))
555930	31417021	Skeletal/extraskeletal Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumors together form the Ewing sarcoma family of tumors with a characteristic karyotype abnormality involving translocation between chromosome 11 and 22 in common.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Disease', (81, 87))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (48, 69))	('Askin tumors', 'Disease', (75, 87))	('neuroectodermal tumor', 'Disease', (48, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('Askin tumors', 'Disease', 'MESH:C563168', (75, 87))	('Ewing sarcoma', 'Disease', (106, 119))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (23, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (23, 36))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (48, 69))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (38, 69))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumors', 'Disease', (130, 136))	('Ewing sarcoma', 'Disease', (23, 36))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('translocation', 'Var', (191, 204))
556022	30133055	Patients with high expression of HLA class I showed a trend toward a higher number of infiltrated CD8+ lymphocytes compared with low or negative expression of HLA class I, but this was not statistically significant (data not shown).	('CD8', 'Gene', (98, 101))	('CD8', 'Gene', '925', (98, 101))	('HLA', 'Protein', (33, 36))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('higher', 'PosReg', (69, 75))
556144	24633303	No TP53 mutations were identified in the peripheral blood of 2 patients (one who developed Ewing sarcoma and one who developed rhabdomyosarcoma), although several known polymorphic variants were detected.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (127, 143))	('TP53', 'Gene', '7157', (3, 7))	('Ewing sarcoma', 'Disease', (91, 104))	('TP53', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))	('rhabdomyosarcoma', 'Disease', (127, 143))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (127, 143))	('patients', 'Species', '9606', (63, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))
556249	22190861	Functional status, as per the Toronto Extremity Salvage Score, was found to be identical in both groups but, at a minimum 2-year followup, patients treated with higher dose postoperative radiotherapy tended to have significant fibrosis, joint stiffness, and edema, all of which correlated with worse functional outcomes.	('radiotherapy', 'Var', (187, 199))	('edema', 'Phenotype', 'HP:0000969', (258, 263))	('fibrosis', 'CPA', (227, 235))	('joint stiffness', 'Phenotype', 'HP:0001387', (237, 252))	('edema', 'CPA', (258, 263))	('joint stiffness', 'Disease', 'MESH:C535724', (237, 252))	('joint stiffness', 'Disease', (237, 252))
556256	32161142	MFS and UPS have recently been shown to commonly harbor copy number alterations or mutations in the tumor suppressor genes RB1 and TP53.	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('copy number alterations', 'Var', (56, 79))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('TP53', 'Gene', (131, 135))	('MFS', 'Disease', 'MESH:D008382', (0, 3))	('RB1', 'Gene', (123, 126))	('MFS', 'Disease', (0, 3))
556257	32161142	As these alterations have been shown to engender dependence on the oncogenic protein Skp2 for survival of transformed cells in mouse models, we sought to examine its function and potential as a therapeutic target in MFS/UPS.	('Skp2', 'Gene', (85, 89))	('mouse', 'Species', '10090', (127, 132))	('engender dependence', 'Reg', (40, 59))	('alterations', 'Var', (9, 20))	('MFS', 'Disease', 'MESH:D008382', (216, 219))	('MFS', 'Disease', (216, 219))
556258	32161142	Comparative genomic hybridization (CGH) and next-generation sequencing (NGS) confirmed that a significant fraction of MFS and UPS patient samples (n=94) harbor chromosomal deletions and/or loss-of-function mutations in RB1 and TP53 (88% carry alterations in at least one gene; 60% carry alterations in both).	('MFS', 'Disease', 'MESH:D008382', (118, 121))	('mutations', 'Var', (206, 215))	('patient', 'Species', '9606', (130, 137))	('MFS', 'Disease', (118, 121))	('loss-of-function', 'NegReg', (189, 205))	('TP53', 'Gene', (227, 231))	('RB1', 'Gene', (219, 222))
556260	32161142	Downregulation of Skp2 or treatment with the Skp2-specific inhibitor C1 revealed that Skp2 drives proliferation of patient-derived MFS/UPS cell lines deficient in both Rb and p53 by degrading p21 and p27.	('p27', 'MPA', (200, 203))	('deficient', 'Var', (150, 159))	('p21', 'MPA', (192, 195))	('MFS', 'Disease', (131, 134))	('Skp2', 'Gene', (86, 90))	('patient', 'Species', '9606', (115, 122))	('degrading', 'NegReg', (182, 191))	('Rb', 'Gene', '19645', (168, 170))	('MFS', 'Disease', 'MESH:D008382', (131, 134))
556262	32161142	These results demonstrate that loss of both Rb and p53 renders MFS and UPS dependent on Skp2, which can be therapeutically exploited and could provide the basis for promising novel systemic therapies for MFS and UPS.	('p53', 'Gene', (51, 54))	('MFS', 'Disease', 'MESH:D008382', (204, 207))	('MFS', 'Disease', (204, 207))	('loss', 'Var', (31, 35))	('MFS', 'Disease', 'MESH:D008382', (63, 66))	('UPS', 'Disease', (71, 74))	('Rb', 'Gene', '19645', (44, 46))	('MFS', 'Disease', (63, 66))
556270	32161142	Developing targeted therapies for MFS/UPS has been challenging because these tumors characteristically harbor vast numbers of copy number alterations and do not contain a defining fusion product or gene mutation.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('copy number alterations', 'Var', (126, 149))	('MFS', 'Disease', 'MESH:D008382', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MFS', 'Disease', (34, 37))	('harbor', 'Reg', (103, 109))
556271	32161142	However, a recent analysis by The Cancer Genome Atlas (TCGA) found that the most common copy number alterations in MFS/UPS involve RB1 and TP53, which encode the Rb and p53 tumor suppressors, respectively.	('MFS', 'Disease', 'MESH:D008382', (115, 118))	('copy number alterations', 'Var', (88, 111))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('Rb', 'Gene', '19645', (162, 164))	('MFS', 'Disease', (115, 118))	('Cancer', 'Disease', (34, 40))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('RB1', 'Gene', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('TP53', 'Gene', (139, 143))	('alterations', 'Var', (100, 111))
556276	32161142	In an Rb+/- loss-of-heterozygosity mouse model of retinoblastoma, the prototypical Rb-deficient cancer, Skp2 germline deletion was protective against tumor formation.	('germline', 'Var', (109, 117))	('Rb', 'Gene', '19645', (6, 8))	('retinoblastoma', 'Phenotype', 'HP:0009919', (50, 64))	('Skp2', 'Gene', (104, 108))	('Rb', 'Gene', '19645', (83, 85))	('Rb-deficient cancer', 'Disease', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mouse', 'Species', '10090', (35, 40))	('loss-of-heterozygosity', 'NegReg', (12, 34))	('retinoblastoma', 'Disease', 'MESH:D012175', (50, 64))	('retinoblastoma', 'Disease', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('Rb-deficient cancer', 'Disease', 'MESH:D009369', (83, 102))
556277	32161142	Targeting Skp2 also suppresses tumorigenesis in p53/PTEN-deficient cells by inducing senescence via Atf4, p27, and p21.	('senescence', 'MPA', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PTEN', 'Gene', (52, 56))	('p21', 'Var', (115, 118))	('Skp2', 'Gene', (10, 14))	('Atf4', 'Gene', (100, 104))	('p27', 'Var', (106, 109))	('PTEN', 'Gene', '5728', (52, 56))	('tumor', 'Disease', (31, 36))	('Atf4', 'Gene', '468', (100, 104))	('suppresses', 'NegReg', (20, 30))	('inducing', 'Reg', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
556278	32161142	Skp2 deletion also blocks prostate cancer and pituitary tumorigenesis in Rb/p53 doubly deficient mouse models.	('Skp2', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('blocks', 'NegReg', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('prostate cancer', 'Disease', (26, 41))	('Rb', 'Gene', '19645', (73, 75))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (56, 61))	('mouse', 'Species', '10090', (97, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))
556279	32161142	The underlying mechanism involves accumulation of p27, which is normally degraded by Skp2 and two other p27 ubiquitin ligases that are also p53 target genes; in the absence of Rb and p53, p27 accumulation blocks cell division.	('Rb', 'Gene', '19645', (176, 178))	('p27', 'Var', (188, 191))	('cell division', 'CPA', (212, 225))	('blocks', 'NegReg', (205, 211))	('accumulation', 'PosReg', (192, 204))
556281	32161142	Skp2 inhibition decreased transwell invasion of MFS cells in vitro, and pharmacological inhibition via the proteasome inhibitor bortezomib inhibited MFS xenograft growth in vivo.	('MFS', 'Disease', (48, 51))	('Skp2', 'Gene', (0, 4))	('decreased', 'NegReg', (16, 25))	('inhibition', 'Var', (5, 15))	('transwell invasion', 'CPA', (26, 44))	('MFS', 'Disease', (149, 152))	('bortezomib', 'Chemical', 'MESH:D000069286', (128, 138))	('MFS', 'Disease', 'MESH:D008382', (48, 51))	('MFS', 'Disease', 'MESH:D008382', (149, 152))	('inhibited', 'NegReg', (139, 148))
556284	32161142	To test our hypothesis, we assessed Rb, p53, and Skp2 expression in a panel of MFS/UPS patient tissue samples, examined the effects of SKP2 knockdown on proliferation and cell cycle regulation in MFS/UPS patient-derived cell lines, and tested the in vitro and in vivo efficacy of pharmacologic Skp2 inhibition.	('tested', 'Reg', (236, 242))	('Skp2', 'Gene', (49, 53))	('SKP2', 'Gene', (135, 139))	('p53', 'Gene', (40, 43))	('patient', 'Species', '9606', (87, 94))	('Rb', 'Gene', '19645', (36, 38))	('MFS', 'Disease', 'MESH:D008382', (196, 199))	('SKP2', 'Gene', '6502', (135, 139))	('MFS', 'Disease', 'MESH:D008382', (79, 82))	('MFS', 'Disease', (196, 199))	('examined', 'Reg', (111, 119))	('knockdown', 'Var', (140, 149))	('cell cycle', 'CPA', (171, 181))	('MFS', 'Disease', (79, 82))	('patient', 'Species', '9606', (204, 211))
556288	32161142	Inclusion criteria included a diagnosis of UPS or high-grade MFS, no prior treatment with chemotherapy or radiation, and documentation of consent for tissue banking.	('MFS', 'Disease', 'MESH:D008382', (61, 64))	('high-grade', 'Var', (50, 60))	('MFS', 'Disease', (61, 64))	('UPS', 'Disease', (43, 46))
556295	32161142	The 7 MFS and UPS cell lines were also analyzed using MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets), a next generation targeted sequencing assay that identifies mutations, copy number alterations and structural rearrangements in a panel of 468 genes.	('Cancer', 'Disease', 'MESH:D009369', (135, 141))	('copy number alterations', 'Var', (223, 246))	('MFS', 'Disease', 'MESH:D008382', (6, 9))	('mutations', 'Var', (212, 221))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (135, 141))	('MFS', 'Disease', (6, 9))	('structural rearrangements', 'Var', (251, 276))
556300	32161142	After obtaining IRB approval, 7 primary high-grade MFS and UPS cell lines (8000S, 91002B, 8500, 4746, 9172, 2734, and 3672-3) were derived from fresh human tumor samples.	('human', 'Species', '9606', (150, 155))	('8000S', 'Var', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('91002B', 'Var', (82, 88))	('tumor', 'Disease', (156, 161))	('MFS', 'Disease', 'MESH:D008382', (51, 54))	('MFS', 'Disease', (51, 54))	('9172', 'Var', (102, 106))
556326	32161142	To confirm the relevance of Skp2 as a potential therapeutic target to MFS/UPS, we first examined the prevalence of RB1 and TP53 deletions and mutations in a panel of 94 untreated primary tumor tissue samples, of which 64 were high-grade MFS and 30 were UPS.	('mutations', 'Var', (142, 151))	('MFS', 'Disease', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('RB1', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('MFS', 'Disease', 'MESH:D008382', (237, 240))	('MFS', 'Disease', (237, 240))	('MFS', 'Disease', 'MESH:D008382', (70, 73))	('deletions', 'Var', (128, 137))	('TP53', 'Gene', (123, 127))
556330	32161142	Of the 80 samples with sufficient quality and quantity of paired normal and tumor DNA for NGS, loss-of-function mutations were identified in RB1 in 9 samples (11%) and in the TP53 gene in 27 samples (33%) (Figure 1A).	('loss-of-function', 'NegReg', (95, 111))	('TP53', 'Gene', (175, 179))	('RB1', 'Gene', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutations', 'Var', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
556331	32161142	We compared results from our cohort to MFS/UPS samples in three other datasets: the MSK-IMPACT dataset from MSKCC, the GENIE dataset from the Dana Farber Cancer Institute (DFCI), and the sarcoma TCGA (which shares 20 patients with our cohort), and found similarly high rates of RB1 and TP53 copy number alterations and/or mutations in all datasets (Supplementary Figure 1A, B).	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('Cancer', 'Disease', (154, 160))	('RB1', 'Gene', (278, 281))	('MFS', 'Disease', 'MESH:D008382', (39, 42))	('mutations', 'Var', (322, 331))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('MFS', 'Disease', (39, 42))	('TP53', 'Gene', (286, 290))	('sarcoma', 'Disease', (187, 194))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('patients', 'Species', '9606', (217, 225))	('copy number alterations', 'Var', (291, 314))
556336	32161142	Towards examining the function of Skp2 in Rb/p53-deficient MFS/UPS patient-derived cell lines, we first characterized 7 cell lines (5 MFS and 2 UPS) in terms of copy number variations, mRNA expression, and protein levels of Rb, p53, and Skp2.	('protein levels', 'MPA', (206, 220))	('Rb', 'Gene', '19645', (42, 44))	('Rb', 'Gene', '19645', (224, 226))	('MFS', 'Disease', 'MESH:D008382', (134, 137))	('mRNA expression', 'MPA', (185, 200))	('copy number variations', 'Var', (161, 183))	('MFS', 'Disease', (134, 137))	('MFS', 'Disease', 'MESH:D008382', (59, 62))	('MFS', 'Disease', (59, 62))	('patient', 'Species', '9606', (67, 74))
556338	32161142	One MFS cell line (9172) had both a missense mutation and a shallow copy deletion in RB1.	('shallow copy deletion', 'Var', (60, 81))	('RB1', 'Gene', (85, 88))	('MFS', 'Disease', 'MESH:D008382', (4, 7))	('MFS', 'Disease', (4, 7))	('missense mutation', 'Var', (36, 53))
556344	32161142	To test the hypothesis that Rb/p53-deficient cells require Skp2 for survival, we used two siRNAs to knock down Skp2 in both Rb/p53-deficient and Rb-WT/p53-deficient cells.	('Rb', 'Gene', '19645', (28, 30))	('Rb', 'Gene', '19645', (124, 126))	('Rb', 'Gene', '19645', (145, 147))	('Skp2', 'Gene', (111, 115))	('knock down', 'Var', (100, 110))
556345	32161142	Skp2 knockdown in the Rb/p53-deficient 9100 2B and 8000S cell lines significantly decreased proliferation (by ~35% and ~50%, respectively; Figure 3A) and increased apoptosis (Figure 3B-C).	('Skp2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('apoptosis', 'CPA', (164, 173))	('Rb', 'Gene', '19645', (22, 24))	('proliferation', 'CPA', (92, 105))	('increased', 'PosReg', (154, 163))	('decreased', 'NegReg', (82, 91))
556346	32161142	By comparison, Skp2 knockdown in the Rb-WT/p53-deficient 2734 and 3672-3 had much smaller effects on proliferation (Figure 3A) and apoptosis (Figure 3B-C).	('3672-3', 'Var', (66, 72))	('Rb', 'Gene', '19645', (37, 39))	('apoptosis', 'CPA', (131, 140))	('knockdown', 'Var', (20, 29))	('Skp2', 'Gene', (15, 19))
556347	32161142	As expected, Skp2 knockdown increased protein levels of both of its degradation targets, p21 and p27, in Rb/p53-deficient cells (Figure 3C).	('increased', 'PosReg', (28, 37))	('Skp2', 'Gene', (13, 17))	('knockdown', 'Var', (18, 27))	('p21', 'MPA', (89, 92))	('Rb', 'Gene', '19645', (105, 107))	('protein levels', 'MPA', (38, 52))	('p27', 'MPA', (97, 100))
556348	32161142	Interestingly, Skp2 knockdown increased levels of p27, but not p21, in Rb-WT/p53-deficient cells.	('p27', 'MPA', (50, 53))	('Rb', 'Gene', '19645', (71, 73))	('increased', 'PosReg', (30, 39))	('levels', 'MPA', (40, 46))	('knockdown', 'Var', (20, 29))	('Skp2', 'Gene', (15, 19))
556349	32161142	Three anti-Skp2 shRNAs decreased proliferation and increased apoptosis to a greater degree in Rb/p53-deficient 8000S cells than in the Rb-WT/p53-deficient 2734 cells or normal ASCs (Supplementary Figure 3D-F).	('apoptosis', 'CPA', (61, 70))	('Rb', 'Gene', '19645', (94, 96))	('increased', 'PosReg', (51, 60))	('anti-Skp2', 'Var', (6, 15))	('Rb', 'Gene', '19645', (135, 137))	('proliferation', 'CPA', (33, 46))	('decreased', 'NegReg', (23, 32))
556350	32161142	Silencing of Skp2 using siRNA also induced cell cycle arrest, as indicated by a significant decrease in BrdU incorporation at day 3 and phosphorylation of histone H3 compared control (scramble or non-transfected) cells at days 3 and 5 (Supplementary Figure 4A-B).	('Skp2', 'Gene', (13, 17))	('phosphorylation', 'MPA', (136, 151))	('decrease', 'NegReg', (92, 100))	('BrdU incorporation at day 3', 'MPA', (104, 131))	('BrdU', 'Chemical', 'MESH:D001973', (104, 108))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('histone H3', 'Protein', (155, 165))	('Silencing', 'Var', (0, 9))	('arrest', 'Disease', (54, 60))
556351	32161142	In addition, consistent with a previous report demonstrating the requirement for Skp2 to activate Akt and enhance glycolysis, we also found that Skp2 knockdown led to reduced phospho-Akt at day 5 (Supplementary Figure 4B).	('glycolysis', 'MPA', (114, 124))	('enhance', 'PosReg', (106, 113))	('activate', 'PosReg', (89, 97))	('Akt', 'Gene', (183, 186))	('Akt', 'Gene', '207', (98, 101))	('Akt', 'Gene', '207', (183, 186))	('knockdown', 'Var', (150, 159))	('Skp2', 'Gene', (145, 149))	('Akt', 'Gene', (98, 101))	('reduced', 'NegReg', (167, 174))
556354	32161142	Although this may be a result of the knockdown potency of the p21 siRNA being much higher than that of the p27 siRNA, these results suggest that the reduction of p21 and p27 mediate Skp2's promotion of proliferation in Rb/p53-deficient MFS/UPS, and that p21 may be the major checkpoint inhibitor to overcome in Rb/p53-deficient MFS/UPS tumorigenesis.	('promotion', 'PosReg', (189, 198))	('proliferation', 'CPA', (202, 215))	('Skp2', 'Gene', (182, 186))	('MFS', 'Disease', (236, 239))	('reduction', 'NegReg', (149, 158))	('MFS', 'Disease', 'MESH:D008382', (236, 239))	('MFS', 'Disease', 'MESH:D008382', (328, 331))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('p21', 'Protein', (162, 165))	('MFS', 'Disease', (328, 331))	('Rb', 'Gene', '19645', (311, 313))	('deficient MFS/UPS tumorigenesis', 'Disease', (318, 349))	('p27', 'Var', (170, 173))	('Rb', 'Gene', '19645', (219, 221))	('deficient MFS/UPS tumorigenesis', 'Disease', 'MESH:D008382', (318, 349))
556355	32161142	Given the anti-proliferative and pro-apoptotic effects of Skp2 knockdown in Rb/p53-deficient MFS/UPS cell lines, we next investigated whether pharmacologic inhibition of the Skp2 interaction with cullin1 could promote the self-degradation of Skp2 and produce similar effects.	('inhibition', 'Var', (156, 166))	('Rb', 'Gene', '19645', (76, 78))	('interaction', 'Interaction', (179, 190))	('MFS', 'Disease', (93, 96))	('Skp2', 'Gene', (58, 62))	('self-degradation', 'MPA', (222, 238))	('cullin1', 'Gene', '8454', (196, 203))	('cullin1', 'Gene', (196, 203))	('promote', 'PosReg', (210, 217))	('MFS', 'Disease', 'MESH:D008382', (93, 96))	('knockdown', 'Var', (63, 72))
556356	32161142	Pevonedistat (MLN4924), a neddylation-activating enzyme (NAE) inhibitor, which blocks formation of the Skp2 complex by inhibiting the addition of NEDD8 to cullin-1 was used to promote the self-degradation of Skp2.	('self-degradation', 'MPA', (188, 204))	('MLN4924', 'Var', (14, 21))	('inhibiting', 'NegReg', (119, 129))	('Pevonedistat', 'Chemical', 'MESH:C539933', (0, 12))	('addition', 'MPA', (134, 142))	('NEDD8', 'Gene', '4738', (146, 151))	('NEDD8', 'Gene', (146, 151))	('promote', 'PosReg', (176, 183))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))
556360	32161142	Pevonedistat also increased apoptosis in a dose-dependent manner and increased p21 and p27 protein levels in the Rb/p53-deficient 8000S and 91002B cell lines (Figure 5B-C).	('increased', 'PosReg', (18, 27))	('increased', 'PosReg', (69, 78))	('Pevonedistat', 'Chemical', 'MESH:C539933', (0, 12))	('apoptosis', 'CPA', (28, 37))	('Rb', 'Gene', '19645', (113, 115))	('Pevonedistat', 'Var', (0, 12))
556363	32161142	Similar to pevonedistat and genetic silencing of Skp2, C1 inhibited proliferation, induced apoptosis, and increased expression of p21 and p27 in 8000S cells (Supplementary Figure 5A-C).	('expression', 'MPA', (116, 126))	('proliferation', 'CPA', (68, 81))	('apoptosis', 'CPA', (91, 100))	('genetic silencing', 'Var', (28, 45))	('p27', 'Var', (138, 141))	('pevonedistat', 'Chemical', 'MESH:C539933', (11, 23))	('inhibited', 'NegReg', (58, 67))	('increased', 'PosReg', (106, 115))	('induced', 'Reg', (83, 90))	('p21', 'Protein', (130, 133))
556366	32161142	In both xenograft models, pevonedistat treatment significantly inhibited tumor growth relative to vehicle control; tumor size remained relatively stable over the treatment period in mice treated with pevonedistat, compared with the growth in mice treated with vehicle control (Figure 6A).	('pevonedistat', 'Chemical', 'MESH:C539933', (200, 212))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pevonedistat', 'Var', (200, 212))	('pevonedistat', 'Chemical', 'MESH:C539933', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (115, 120))	('mice', 'Species', '10090', (182, 186))	('tumor', 'Disease', (73, 78))	('inhibited', 'NegReg', (63, 72))	('mice', 'Species', '10090', (242, 246))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
556368	32161142	Greater p21 and p27 expression after pevonedistat treatment was also evident by IHC staining; p21 appeared exclusively on tumor cells, while p27 was mostly expressed on the stromal component and a minor population of positive tumor cells (Figure 6C, Supplementary Figure 6A).	('pevonedistat', 'Chemical', 'MESH:C539933', (37, 49))	('p21', 'Var', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (226, 231))
556369	32161142	The inhibitor also increased levels of cleaved caspase-3 compared with vehicle-treated xenografts, as seen on both Western blot and IHC staining (Figure 6B-C, Supplementary Figure 6A).	('inhibitor', 'Var', (4, 13))	('levels', 'MPA', (29, 35))	('cleaved', 'MPA', (39, 46))	('caspase-3', 'Gene', (47, 56))	('increased', 'PosReg', (19, 28))	('caspase-3', 'Gene', '836', (47, 56))
556370	32161142	Pevonedistat caused no weight loss in the first 14 days of treatment, though it led to a statistically significant but small amount of weight loss at later time points in mice bearing 8000S xenografts (11%, Supplementary Figure S6B); no other significant toxicities were observed.	('weight loss', 'Disease', (23, 34))	('toxicities', 'Disease', (255, 265))	('weight loss', 'Phenotype', 'HP:0001824', (23, 34))	('mice', 'Species', '10090', (171, 175))	('Pevonedistat', 'Chemical', 'MESH:C539933', (0, 12))	('weight loss', 'Disease', 'MESH:D015431', (135, 146))	('toxicities', 'Disease', 'MESH:D064420', (255, 265))	('weight loss', 'Disease', 'MESH:D015431', (23, 34))	('weight loss', 'Disease', (135, 146))	('Pevonedistat', 'Var', (0, 12))	('weight loss', 'Phenotype', 'HP:0001824', (135, 146))
556372	32161142	Though MFS and UPS are genetically complex and lack a defining chromosomal alteration or gene mutation, we found that loss of Rb and p53 due to chromosomal deletions or loss-of-function mutations in the RB1 and TP53 genes are common in MFS and UPS.	('RB1', 'Gene', (203, 206))	('MFS', 'Disease', 'MESH:D008382', (236, 239))	('MFS', 'Disease', (236, 239))	('mutations', 'Var', (186, 195))	('loss', 'NegReg', (118, 122))	('MFS', 'Disease', (7, 10))	('loss-of-function', 'NegReg', (169, 185))	('MFS', 'Disease', 'MESH:D008382', (7, 10))	('Rb', 'Gene', '19645', (126, 128))	('TP53', 'Gene', (211, 215))	('p53', 'Gene', (133, 136))
556373	32161142	Together, our results show that loss of Rb and p53 renders MFS/UPS cells reliant on Skp2, representing, to our knowledge, the first demonstration of this conditional dependence in Rb and p53-deficient human cancer.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('Rb', 'Gene', '19645', (180, 182))	('cancer', 'Disease', (207, 213))	('Rb', 'Gene', '19645', (40, 42))	('MFS', 'Disease', 'MESH:D008382', (59, 62))	('loss', 'Var', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human', 'Species', '9606', (201, 206))	('p53', 'Gene', (47, 50))	('MFS', 'Disease', (59, 62))
556380	32161142	p21 is a well-described target of Skp2, and inactivation of the p21 gene accelerates tumor development in Rb+/- mice.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('accelerates', 'PosReg', (73, 84))	('mice', 'Species', '10090', (112, 116))	('inactivation', 'Var', (44, 56))	('Rb', 'Gene', '19645', (106, 108))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p21', 'Gene', (64, 67))
556400	32161142	In addition, MSK-IMPACT could be used to identify MFS/UPS with RB1 and TP53 mutations or deletions that are likely to respond to anti-Skp2 therapy.	('mutations', 'Var', (76, 85))	('MFS', 'Disease', 'MESH:D008382', (50, 53))	('deletions', 'Var', (89, 98))	('MFS', 'Disease', (50, 53))	('TP53', 'Gene', (71, 75))	('RB1', 'Gene', (63, 66))
556402	32161142	Significance: Loss of both Rb and p53 renders myxofibrosarcoma and undifferentiated pleomorphic sarcoma dependent on Skp2, which could provide the basis for promising novel systemic therapies.	('p53', 'Gene', (34, 37))	('myxofibrosarcoma and undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (46, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('Loss', 'Var', (14, 18))	('Rb', 'Gene', '19645', (27, 29))
556502	23456376	This same study also reported a 4% development of deep venous thrombosis (DVT) with ILI vs. 11% with ILP.	('deep venous thrombosis', 'Disease', (50, 72))	('ILI', 'Var', (84, 87))	('deep venous thrombosis', 'Disease', 'MESH:D020246', (50, 72))	('venous thrombosis', 'Phenotype', 'HP:0004936', (55, 72))	('DVT', 'Phenotype', 'HP:0002625', (74, 77))	('deep venous thrombosis', 'Phenotype', 'HP:0002625', (50, 72))
556509	23456376	Even in the modern era of melanoma treatment, HILP appears to improve overall survival (OS) in only a small subset of patients, with a 34% 10 year actuarial survival <>.	('overall survival', 'MPA', (70, 86))	('HILP', 'Var', (46, 50))	('improve', 'PosReg', (62, 69))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('patients', 'Species', '9606', (118, 126))
556615	24756371	In this article we outline some of the promising therapies that have the potential to change the Ewings Sarcoma therapeutic paradigm in the not too distant future: insulin growth factor receptor inhibitors, targeting of the fusion protein, epigenetic manipulation, poly-ADP-ribose polymerase inhibitors and immunotherapy.	('poly-ADP-ribose polymerase', 'Gene', (265, 291))	('fusion protein', 'Protein', (224, 238))	('targeting', 'Var', (207, 216))	('insulin growth', 'Protein', (164, 178))	('Ewings Sarcoma', 'Phenotype', 'HP:0012254', (97, 111))	('Sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('Ewings Sarcoma', 'Disease', (97, 111))	('poly-ADP-ribose polymerase', 'Gene', '142', (265, 291))	('epigenetic manipulation', 'Var', (240, 263))	('Ewings Sarcoma', 'Disease', 'MESH:C563168', (97, 111))
556626	24756371	In these models, RNA interference (RNAi) knock-down was associated with decreased expression of the EF fusion protein and downregulation of EF transcriptional targets such as c-Myc.	('expression', 'MPA', (82, 92))	('downregulation', 'NegReg', (122, 136))	('knock-down', 'Var', (41, 51))	('decreased', 'NegReg', (72, 81))	('Myc', 'Gene', '4609', (177, 180))	('Myc', 'Gene', (177, 180))	('EF fusion protein', 'Protein', (100, 117))
556627	24756371	Inhibition or knock down of EWS-Fli1 in vitro leads to decreased cell viability in vitro.	('EWS', 'Gene', '2130', (28, 31))	('knock down', 'Var', (14, 24))	('Fli1', 'Gene', (32, 36))	('decreased', 'NegReg', (55, 64))	('Fli1', 'Gene', '2313', (32, 36))	('cell viability in vitro', 'CPA', (65, 88))	('EWS', 'Gene', (28, 31))
556628	24756371	Concurrent administration of rapamycin and antisense oligonucleotides showed delayed tumor growth in murine xenografts.	('tumor', 'Disease', (85, 90))	('rapamycin', 'Chemical', 'MESH:D020123', (29, 38))	('oligonucleotides', 'Chemical', 'MESH:D009841', (53, 69))	('murine', 'Species', '10090', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('antisense oligonucleotides', 'Var', (43, 69))	('delayed', 'NegReg', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
556649	24756371	A Phase II trial of R1507, a fully human IGF1R blocking antibody, showed an overall complete response/partial response rate of ten percent.	('R1507', 'Var', (20, 25))	('IGF1R', 'Gene', (41, 46))	('human', 'Species', '9606', (35, 40))	('IGF1R', 'Gene', '3480', (41, 46))
556670	24756371	These findings suggest a rationale for the exploration of the use of the new EZH2 inhibitors in this tumor.	('EZH2', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('inhibitors', 'Var', (82, 92))	('EZH2', 'Gene', '2146', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
556696	24756371	Inhibition of the aberrant fusion protein, PARP inhibition, epigenetic manipulation, insulin growth factor receptor blockade and immune therapies all hold the promise of achieving improved outcomes in patients with Ewings sarcoma.	('patients', 'Species', '9606', (201, 209))	('PARP', 'Gene', (43, 47))	('epigenetic manipulation', 'Var', (60, 83))	('Ewings sarcoma', 'Disease', 'MESH:C563168', (215, 229))	('Ewings sarcoma', 'Phenotype', 'HP:0012254', (215, 229))	('PARP', 'Gene', '142', (43, 47))	('insulin', 'Protein', (85, 92))	('Inhibition', 'Var', (0, 10))	('aberrant fusion protein', 'Protein', (18, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('Ewings sarcoma', 'Disease', (215, 229))
556701	24756371	Unfortunately, no such activating kinase mutations have been found in Ewings sarcomas, further making the point that better predictors for clinical activity are necessary for this tumor.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Ewings sarcomas', 'Phenotype', 'HP:0012254', (70, 85))	('tumor', 'Disease', (180, 185))	('Ewings sarcomas', 'Disease', (70, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('Ewings sarcoma', 'Phenotype', 'HP:0012254', (70, 84))	('Ewings sarcomas', 'Disease', 'MESH:C563168', (70, 85))
556940	32313720	Overall, we were able to define the landscape of transcriptomic states of endogenous CD8 TILs in B16 melanoma tumors and recapitulate the naive, memory-like and exhausted CD8 TIL subsets through an unbiased analysis of single-cell heterogeneity.	('a', 'Gene', '14961', (4, 5))	('a', 'Gene', '14961', (164, 165))	('a', 'Gene', '14961', (195, 196))	('CD8', 'Gene', (171, 174))	('a', 'Gene', '14961', (124, 125))	('a', 'Gene', '14961', (108, 109))	('a', 'Gene', '14961', (139, 140))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('a', 'Gene', '14961', (130, 131))	('a', 'Gene', '14961', (209, 210))	('a', 'Gene', '14961', (42, 43))	('a', 'Gene', '14961', (202, 203))	('CD8', 'Gene', '925', (85, 88))	('a', 'Gene', '14961', (66, 67))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('a', 'Gene', '14961', (51, 52))	('a', 'Gene', '14961', (17, 18))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('a', 'Gene', '14961', (104, 105))	('CD8', 'Gene', '925', (171, 174))	('melanoma tumors', 'Disease', 'MESH:D008545', (101, 116))	('a', 'Gene', '14961', (207, 208))	('a', 'Gene', '14961', (157, 158))	('TILs', 'Var', (89, 93))	('CD8', 'Gene', (85, 88))	('a', 'Gene', '14961', (117, 118))	('melanoma tumors', 'Disease', (101, 116))	('a', 'Gene', '14961', (37, 38))
556946	32313720	Next, CD44high CD8 TILs were classified into four compartments according to Tcf1 and PD-1 expression: Tcf1low PD-1high (~9% on average), Tcf1high PD-1high (~31%) and Tcf1high cells with low (~21%) or intermediate (~30%) PD-1 levels (Figure 2(a,b)).	('CD8', 'Gene', '925', (15, 18))	('a', 'Gene', '14961', (63, 64))	('Tcf1high', 'Var', (137, 145))	('a', 'Gene', '14961', (209, 210))	('a', 'Gene', '14961', (127, 128))	('a', 'Gene', '14961', (31, 32))	('a', 'Gene', '14961', (162, 163))	('Tcf1low', 'Gene', (102, 109))	('a', 'Gene', '14961', (131, 132))	('a', 'Gene', '14961', (242, 243))	('PD-1', 'MPA', (220, 224))	('a', 'Gene', '14961', (54, 55))	('CD8', 'Gene', (15, 18))	('a', 'Gene', '14961', (81, 82))
556982	32313720	TILPRED classification of CD8 TILs from MC38 colon adenocarcinoma and sarcoma showed an increase in the proportion of EM-like TILs upon ICB at the single-cell level (Figure 4(d), Supplemental Figure 4), consistent with the enrichment of the EM-like signature in the bulk transcriptomics data.	('a', 'Gene', '14961', (140, 141))	('a', 'Gene', '14961', (76, 77))	('a', 'Gene', '14961', (273, 274))	('CD8', 'Gene', (26, 29))	('a', 'Gene', '14961', (290, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('a', 'Gene', '14961', (10, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('a', 'Gene', '14961', (66, 67))	('a', 'Gene', '14961', (51, 52))	('a', 'Gene', '14961', (57, 58))	('a', 'Gene', '14961', (288, 289))	('a', 'Gene', '14961', (17, 18))	('a', 'Gene', '14961', (253, 254))	('a', 'Gene', '14961', (71, 72))	('a', 'Gene', '14961', (64, 65))	('a', 'Gene', '14961', (189, 190))	('MC38', 'Var', (40, 44))	('colon adenocarcinoma and sarcoma', 'Disease', 'MESH:D003110', (45, 77))	('CD8', 'Gene', '925', (26, 29))	('a', 'Gene', '14961', (93, 94))	('a', 'Gene', '14961', (85, 86))
557042	32313720	Single-cell datasets re-analyzed in this study are available in NCBI GEO under accession numbers GSE86042 (CD8 TILs from B16 melanoma), GSE122969 (PD-1- CD8 TILs from MC38), GSE119352 (whole-tumor sarcoma), GSE120575 (CD8 TILs of melanoma patients); and in EBI Array Express E-MTAB-7919 (T cells from MC38 tumors).	('a', 'Gene', '14961', (13, 14))	('GSE122969', 'Var', (136, 145))	('a', 'Gene', '14961', (203, 204))	('CD8', 'Gene', '925', (153, 156))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('tumor sarcoma', 'Disease', 'MESH:D012509', (191, 204))	('GSE119352', 'Var', (174, 183))	('a', 'Gene', '14961', (132, 133))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanoma', 'Disease', (230, 238))	('a', 'Gene', '14961', (250, 251))	('CD8', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('A', 'Gene', '14961', (279, 280))	('a', 'Gene', '14961', (233, 234))	('CD8', 'Gene', (218, 221))	('a', 'Gene', '14961', (240, 241))	('a', 'Gene', '14961', (264, 265))	('a', 'Gene', '14961', (51, 52))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('a', 'Gene', '14961', (26, 27))	('A', 'Gene', '14961', (261, 262))	('CD8', 'Gene', (153, 156))	('a', 'Gene', '14961', (24, 25))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('a', 'Gene', '14961', (79, 80))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('a', 'Gene', '14961', (56, 57))	('tumors', 'Disease', (306, 312))	('a', 'Gene', '14961', (128, 129))	('a', 'Gene', '14961', (198, 199))	('a', 'Gene', '14961', (15, 16))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('CD8', 'Gene', '925', (107, 110))	('a', 'Gene', '14961', (47, 48))	('a', 'Gene', '14961', (237, 238))	('CD8', 'Gene', '925', (218, 221))	('patients', 'Species', '9606', (239, 247))	('tumor sarcoma', 'Disease', (191, 204))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('a', 'Gene', '14961', (53, 54))
557127	25918659	He had been diagnosed with T3bN0M0 Gleason score 4 + 5 prostatic adenocarcinoma 6 months prior to this, for which he had elected for systemic treatment.	('prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (55, 79))	('T3bN0M0', 'Var', (27, 34))	('prostatic adenocarcinoma', 'Disease', (55, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('men', 'Species', '9606', (147, 150))
557136	25918659	He had a history of T3bN0Mx Gleason score 3 + 4 prostatic adenocarcinoma, had been previously treated with prostate radiotherapy, and was currently being treated with neoadjuvant and adjuvant hormone therapy including leuprorelin acetate.	('T3bN0Mx', 'Var', (20, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('prostatic adenocarcinoma', 'Disease', 'MESH:D011471', (48, 72))	('prostatic adenocarcinoma', 'Disease', (48, 72))
557198	23178314	Genetic studies identified multiple chromosomal aberrations in ESS (reviewed in), the most common characteristic of which is t(7;17)(p15;q21) leading to fusion of the JAZF1/JJAZ1 zinc finger genes.	('t(7;17)(p15;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (125, 141))	('JAZF1', 'Gene', (167, 172))	('JJAZ1', 'Gene', '23512', (173, 178))	('JJAZ1', 'Gene', (173, 178))	('JAZF1', 'Gene', '221895', (167, 172))	('fusion', 'Var', (153, 159))	('t(7;17)(p15;q21', 'Var', (125, 140))	('ESS', 'Disease', (63, 66))	('multiple chromosomal aberrations', 'Phenotype', 'HP:0040012', (27, 59))
557199	23178314	More recently described molecular changes in ESS include fusion of the PHD finger protein-1 gene PHF1 at 6p21 with JAZF1 and the enhancer of polycomb gene EPC1, as well as with MYST/Esa1-associated factor 6 (MEAF6), and fusion of the 14-3-3epsilon gene YWHAE with FAM22, involving t(10;17)(q22;p13), the latter characterizing an ESS sub-type with more aggressive clinical behavior.	('JAZF1', 'Gene', '221895', (115, 120))	('MYST/Esa1-associated factor 6', 'Gene', '64769', (177, 206))	('p21', 'Gene', '644914', (106, 109))	('fusion', 'Var', (220, 226))	('MYST/Esa1-associated factor 6', 'Gene', (177, 206))	('PHD finger protein-1', 'Gene', (71, 91))	('14-3-3epsilon', 'Gene', (234, 247))	('JAZF1', 'Gene', (115, 120))	('YWHAE', 'Gene', (253, 258))	('YWHAE', 'Gene', '7531', (253, 258))	('MEAF6', 'Gene', (208, 213))	('ESS', 'Disease', (45, 48))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (352, 380))	('MEAF6', 'Gene', '64769', (208, 213))	('PHD finger protein-1', 'Gene', '5252', (71, 91))	('PHF1', 'Gene', (97, 101))	('FAM22', 'Gene', (264, 269))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (281, 298))	('PHF1', 'Gene', '5252', (97, 101))	('EPC1', 'Gene', (155, 159))	('14-3-3epsilon', 'Gene', '7531', (234, 247))	('EPC1', 'Gene', '80314', (155, 159))	('p21', 'Gene', (106, 109))
557241	23178314	High ECEL1 expression was associated with clinical and biological parameters of a less aggressive disease and with a favorable outcome in neuroblastoma, and the ECEL1 gene was recently reported to be frequently hypermethylated in bladder cancer.	('neuroblastoma', 'Disease', (138, 151))	('bladder cancer', 'Phenotype', 'HP:0009725', (230, 244))	('less', 'Disease', (82, 86))	('High', 'Var', (0, 4))	('ECEL1', 'Gene', '9427', (161, 166))	('expression', 'MPA', (11, 21))	('neuroblastoma', 'Phenotype', 'HP:0003006', (138, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (230, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('aggressive disease', 'Disease', 'MESH:D001523', (87, 105))	('bladder cancer', 'Disease', (230, 244))	('ECEL1', 'Gene', (5, 10))	('ECEL1', 'Gene', '9427', (5, 10))	('neuroblastoma', 'Disease', 'MESH:D009447', (138, 151))	('aggressive disease', 'Disease', (87, 105))	('associated', 'Reg', (26, 36))	('ECEL1', 'Gene', (161, 166))
557243	23178314	ITM2A, coding for integral membrane protein 2A, is regulated by PAX3, a transcription factor involved in neural, muscle and facial development during embryogenesis that is mutated in alveolar rhabdomyosarcoma, and its fusion product PAX3-FKHR in the latter tumor.	('PAX3', 'Gene', '5077', (64, 68))	('FKHR', 'Gene', '2308', (238, 242))	('mutated', 'Var', (172, 179))	('alveolar rhabdomyosarcoma', 'Disease', (183, 208))	('tumor', 'Disease', (257, 262))	('integral membrane protein 2A', 'Gene', '9452', (18, 46))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('ITM2A', 'Gene', (0, 5))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (192, 208))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (183, 208))	('PAX3', 'Gene', (233, 237))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (183, 208))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('PAX3', 'Gene', (64, 68))	('FKHR', 'Gene', (238, 242))	('PAX3', 'Gene', '5077', (233, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('integral membrane protein 2A', 'Gene', (18, 46))	('ITM2A', 'Gene', '9452', (0, 5))
557250	23178314	JPH2 regulates calcium release in the heart by keeping the plasma membrane and sarcoplasmic reticulum at a fixed distance during the excitation-contraction process and mutations in the JPH2 gene result in hypertrophic cardiomyopathy.	('JPH2', 'Gene', '57158', (0, 4))	('JPH2', 'Gene', '57158', (185, 189))	('calcium', 'Chemical', 'MESH:D002118', (15, 22))	('hypertrophic cardiomyopathy', 'Disease', 'MESH:D002312', (205, 232))	('JPH2', 'Gene', (0, 4))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (218, 232))	('JPH2', 'Gene', (185, 189))	('hypertrophic cardiomyopathy', 'Phenotype', 'HP:0001639', (205, 232))	('result in', 'Reg', (195, 204))	('hypertrophic cardiomyopathy', 'Disease', (205, 232))	('mutations', 'Var', (168, 177))
557255	23178314	FBXO32 was more recently reported to be a target gene of transforming growth factor-beta (TGFbeta)/SMAD4 that undergoes promoter hypermethylation in ovarian carcinoma, and FBXO32 methylation was associated with poor progression-free survival.	('SMAD4', 'Gene', '4089', (99, 104))	('associated', 'Reg', (195, 205))	('TGFbeta', 'Gene', '7040', (90, 97))	('transforming growth factor-beta', 'Gene', '7040', (57, 88))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (149, 166))	('ovarian carcinoma', 'Disease', (149, 166))	('methylation', 'Var', (179, 190))	('FBXO32', 'Gene', '114907', (172, 178))	('FBXO32', 'Gene', '114907', (0, 6))	('SMAD4', 'Gene', (99, 104))	('FBXO32', 'Gene', (172, 178))	('FBXO32', 'Gene', (0, 6))	('transforming growth factor-beta', 'Gene', (57, 88))	('TGFbeta', 'Gene', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (149, 166))
557259	23178314	However, a more recent study showed association between transgelin expression and lymph node metastasis in colon carcinoma, as well as promotion of invasion, resistance to anoikis and survival in vitro in colon carcinoma cell lines.	('resistance', 'CPA', (158, 168))	('transgelin', 'Gene', '6876', (56, 66))	('colon carcinoma', 'Disease', 'MESH:D015179', (205, 220))	('expression', 'Var', (67, 77))	('promotion', 'PosReg', (135, 144))	('survival', 'CPA', (184, 192))	('transgelin', 'Gene', (56, 66))	('lymph node metastasis', 'CPA', (82, 103))	('colon carcinoma', 'Disease', 'MESH:D015179', (107, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('colon carcinoma', 'Disease', (107, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('association', 'Interaction', (36, 47))	('colon carcinoma', 'Disease', (205, 220))	('invasion', 'CPA', (148, 156))
557366	33672857	We found a statistically significant association between the GMI > 1.33 and median OS and TTP (p < 0.001; Table 3).	('OS', 'Gene', '17451', (83, 85))	('TTP', 'Gene', (90, 93))	('TTP', 'Gene', '22695', (90, 93))	('GMI > 1.33', 'Var', (61, 71))	('significant association', 'Reg', (25, 48))	('et', 'Gene', '79157', (50, 52))	('GMI', 'Chemical', '-', (61, 64))
557443	32349235	As a mutant of FeLV, the feline sarcomavirus can cause sarcomas in cats, but literature about feline pancreatic sarcomas is scant.	('FeLV', 'Species', '11768', (15, 19))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('sarcomas', 'Disease', (112, 120))	('cats', 'Species', '9685', (67, 71))	('FeLV', 'Gene', (15, 19))	('sarcomavirus', 'Disease', (32, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcomavirus', 'Disease', 'None', (32, 44))	('sarcomas', 'Disease', (55, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('mutant', 'Var', (5, 11))	('sarcomas', 'Disease', 'MESH:D012509', (112, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('cause', 'Reg', (49, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('pancreatic sarcomas', 'Disease', 'MESH:D010195', (101, 120))	('pancreatic sarcomas', 'Disease', (101, 120))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))
557464	32349235	Dako EnVision+ System-HPR for mouse or rabbit primary antibodies (Dako, Glostrup, Denmark, K4006 or K4010) with 3,3'-diaminobenzine (DAB) was used for immunohistochemical staining.	("3,3'-diaminobenzine", 'Chemical', '-', (112, 131))	('DAB', 'Chemical', '-', (133, 136))	('K4006', 'Var', (91, 96))	('K4010', 'Var', (100, 105))	('mouse', 'Species', '10090', (30, 35))
557592	31881905	Patients often present a germ-line mutation of RB1 tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('RB1', 'Gene', '5925', (47, 50))	('tumor', 'Disease', (51, 56))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (35, 43))	('RB1', 'Gene', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
557594	31881905	Furthermore, although RB is a radiosensitive tumor, the use of RT could increase the risks of radiation-induced SMNs, which is greater in children with hereditary RB gene mutation.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('children', 'Species', '9606', (138, 146))	('mutation', 'Var', (171, 179))	('RB', 'Disease', 'MESH:D012175', (163, 165))	('tumor', 'Disease', (45, 50))	('RB', 'Disease', 'MESH:D012175', (22, 24))	('radiation-induced SMNs', 'Disease', (94, 116))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
557596	31881905	Krengli et al., in their study on the optimization of proton-beam arrangements for various intra-ocular tumor locations, concluded that PBT could reduce the risk of radiation-induced SMNs and cosmetic and functional side-effects due to its dosimetric benefits (Table 1).	('intra-ocular tumor', 'Disease', 'MESH:D005134', (91, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('radiation-induced', 'CPA', (165, 182))	('ocular tumor', 'Phenotype', 'HP:0100012', (97, 109))	('intra-ocular tumor', 'Disease', (91, 109))	('PBT', 'Var', (136, 139))	('reduce', 'NegReg', (146, 152))
557597	31881905	In the treatment planning study presented by Lee et al., (Table 1), PBT achieved the best target-coverage (which clinically might translate into a reduced risk of tumor recurrence) and orbital bone dose-sparing compared to photon-RT techniques.	('target-coverage', 'CPA', (90, 105))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('orbital bone dose-sparing', 'CPA', (185, 210))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('PBT', 'Var', (68, 71))
557613	31881905	They observed that PBT provided the lowest mean dose to heart, lungs and breasts for all patients (Table 1), with an improvement in dose-sparing also for esophagus and thyroid.	('patients', 'Species', '9606', (89, 97))	('esophagus', 'Disease', (154, 163))	('PBT', 'Var', (19, 22))	('lowest', 'NegReg', (36, 42))
557628	31881905	evaluated patients with extra-cranial CH (Table 2) treated with postoperative spot-scanning PBT1 (performed after a function-preserving surgery) and observed high OS and PFS rates with acceptable treatment tolerance.	('treated', 'Reg', (51, 58))	('spot-scanning', 'Var', (78, 91))	('extra-cranial CH', 'Disease', 'MESH:D010236', (24, 40))	('high', 'PosReg', (158, 162))	('extra-cranial CH', 'Disease', (24, 40))	('patients', 'Species', '9606', (10, 18))	('PBT1', 'Gene', (92, 96))	('PFS', 'CPA', (170, 173))
557643	31881905	A potential reduction of radiation-induced SMNs using PBT was suggested by a model-based secondary cancer risk assessment performed by Miralbell et al.. PBT has also provided dosimetric and clinical advantages, as highlighted in the following summarized studies (Tables 1 and 2).	('dosimetric', 'CPA', (175, 185))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('PBT', 'Var', (153, 156))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
557650	31881905	reported comparable target dosimetry between PBT and IMRT in this setting, but PBT led to a significant decrease in mean dose to the considered OARs (bladder, testes, femoral heads, growth plates and pelvic bones), suggesting for a reduced risk of late toxicity.	('mean dose', 'MPA', (116, 125))	('decrease', 'NegReg', (104, 112))	('toxicity', 'Disease', (253, 261))	('toxicity', 'Disease', 'MESH:D064420', (253, 261))	('PBT', 'Var', (79, 82))
557651	31881905	compared dose-distributions and dose-volume histograms (DVHs) of 3D-CRT, electron-RT, IMRT and PBT plans for three pediatric disease sites, including pelvic sarcomas: PBT was superior in eliminating any dose to the ovaries and reducing doses to the pelvic bones and vertebrae.	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('ovaries', 'Disease', (215, 222))	('eliminating', 'NegReg', (187, 198))	('pelvic sarcomas', 'Disease', 'MESH:D012509', (150, 165))	('reducing', 'NegReg', (227, 235))	('PBT', 'Var', (167, 170))	('ovaries', 'Disease', 'MESH:D010051', (215, 222))	('pelvic sarcomas', 'Disease', (150, 165))	('doses', 'MPA', (236, 241))
557652	31881905	Due to these advantages, PBT in pelvic sarcoma could have the potential clinical benefit of preserving reproductive and hormonal functions, as well as body growth.	('pelvic sarcoma', 'Disease', (32, 46))	('PBT', 'Var', (25, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('body growth', 'CPA', (151, 162))	('pelvic sarcoma', 'Disease', 'MESH:D012509', (32, 46))
557670	31881905	In 2018 one of the first treatment planning comparison between IMPT and highly sophisticated deep-inspiration breath hold Volumetric Modulated Arc Therapy (VMAT) in adults has been published: even if VMAT was planned in a very experienced center, IMPT provided higher target coverage and reduced mean doses to the considered OARs.	('deep-inspiration breath', 'Disease', (93, 116))	('mean doses', 'MPA', (296, 306))	('target coverage', 'CPA', (268, 283))	('deep-inspiration breath', 'Disease', 'MESH:D004417', (93, 116))	('breath hold', 'Phenotype', 'HP:0002098', (110, 121))	('higher', 'PosReg', (261, 267))	('reduced', 'NegReg', (288, 295))	('IMPT', 'Var', (247, 251))
557876	23075171	It was suggested that vascular permeation could induce multiple foci of peripheral anemic infarction associated with hemorrhage.	('hemorrhage', 'Disease', (117, 127))	('induce', 'Reg', (48, 54))	('peripheral anemic infarction', 'Phenotype', 'HP:0004950', (72, 100))	('hemorrhage', 'Disease', 'MESH:D006470', (117, 127))	('peripheral anemic infarction', 'Disease', (72, 100))	('vascular', 'Var', (22, 30))	('peripheral anemic infarction', 'Disease', 'MESH:D007238', (72, 100))
557973	33115972	The extent of tumor involvement, as assessed using the scoring system, was also greater in R0 resections than in R2 resections, but the difference was not significantly different (p=0.184) (Table 4).	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('men', 'Species', '9606', (27, 30))	('R0 resections', 'Var', (91, 104))
558003	33115972	In this respect, we could expect that patients with R2 resections had more invasive tumor characteristics before surgery than patients with R0 or R1 resections.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('invasive tumor', 'Disease', 'MESH:D009361', (75, 89))	('R2 resections', 'Var', (52, 65))	('patients', 'Species', '9606', (126, 134))	('invasive tumor', 'Disease', (75, 89))	('patients', 'Species', '9606', (38, 46))
558041	32627015	TYMS knockdown had the most notable effect on the proliferative capacity of RLPS cells according to the HCS results.	('TYMS', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('proliferative capacity', 'CPA', (50, 72))	('effect', 'Reg', (36, 42))	('TYMS', 'Gene', '7298', (0, 4))
558044	32627015	The patients with positive TYMS expression had a worse overall survival (OS) and disease-free survival (DFS) compared with the patients with negative TYMS expression (OS, P=0.024; DFS, P=0.030).	('TYMS', 'Gene', (27, 31))	('TYMS', 'Gene', (150, 154))	('overall survival', 'CPA', (55, 71))	('disease-free survival', 'CPA', (81, 102))	('positive', 'Var', (18, 26))	('patients', 'Species', '9606', (127, 135))	('TYMS', 'Gene', '7298', (27, 31))	('TYMS', 'Gene', '7298', (150, 154))	('patients', 'Species', '9606', (4, 12))
558046	32627015	Protein microarray analysis and western blotting showed that the Janus Kinase/Signal transducers and activators of transcription pathway was downregulated following TYMS knockdown.	('knockdown', 'Var', (170, 179))	('activators of transcription pathway', 'Pathway', (101, 136))	('TYMS', 'Gene', '7298', (165, 169))	('downregulated', 'NegReg', (141, 154))	('TYMS', 'Gene', (165, 169))
558092	32627015	354480; Corning, Inc.) were hydrated in serum-free RPMI-1640 medium (Gibco; Thermo Fisher Scientific, Inc.) for at least 2 h at 37 C. A total of 1x105 93T449 cells, 3x104 94T778 cells or 3x104 SW872 cells were mixed in serum-free medium with a total volume of 200 microl for migration or 500 microl for invasion.	('migration', 'CPA', (275, 284))	('354480', 'Var', (0, 6))	('93T449', 'Var', (151, 157))	('SW872', 'CellLine', 'CVCL:1730', (193, 198))	('RPMI-1640 medium', 'Chemical', '-', (51, 67))	('invasion', 'CPA', (303, 311))	('93T449', 'CellLine', 'CVCL:M807', (151, 157))
558098	32627015	Based on the results of HCS, knockdown of the TYMS gene had the most notable effect on the proliferative capacity of RLPS cells, and thus was selected to further explore its effect on the biological behaviors and the potential mechanisms involved in RLPS cells.	('TYMS', 'Gene', '7298', (46, 50))	('knockdown', 'Var', (29, 38))	('proliferative capacity', 'CPA', (91, 113))	('TYMS', 'Gene', (46, 50))	('effect', 'Reg', (77, 83))
558109	32627015	The aforementioned results showed that high TYMS expression was associated with progression of RLPS or sarcoma.	('associated', 'Reg', (64, 74))	('high', 'Var', (39, 43))	('TYMS', 'Gene', '7298', (44, 48))	('sarcoma', 'Disease', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('expression', 'MPA', (49, 59))	('RLPS', 'Disease', (95, 99))	('TYMS', 'Gene', (44, 48))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))
558118	32627015	Flow cytometry analysis demonstrated that TYMS knockdown promoted progression of the cell cycle from G1 to S phase.	('promoted', 'PosReg', (57, 65))	('TYMS', 'Gene', (42, 46))	('knockdown', 'Var', (47, 56))	('progression', 'CPA', (66, 77))	('TYMS', 'Gene', '7298', (42, 46))
558125	32627015	The results showed that TYMS knockdown significantly decreased both the migration and invasive capacities of RLPS cells, thereby indicating that TYMS downregulation may inhibit RLPS progression.	('TYMS', 'Gene', '7298', (145, 149))	('inhibit', 'NegReg', (169, 176))	('invasive capacities of RLPS cells', 'CPA', (86, 119))	('migration', 'CPA', (72, 81))	('knockdown', 'Var', (29, 38))	('TYMS', 'Gene', (24, 28))	('downregulation', 'NegReg', (150, 164))	('RLPS', 'Disease', (177, 181))	('TYMS', 'Gene', (145, 149))	('TYMS', 'Gene', '7298', (24, 28))	('decreased', 'NegReg', (53, 62))
558128	32627015	The results showed that phospho-STAT3 (Ser727), phospho-STAT5 (Y694) and phospho-STAT6 (Y641) were downregulated in Lenti-shTYMS transfected 94T778 and SW872 cells (Fig.	('STAT6', 'Gene', '6778', (81, 86))	('STAT5', 'Gene', (56, 61))	('STAT3', 'Gene', '6774', (32, 37))	('downregulated', 'NegReg', (99, 112))	('SW872', 'CellLine', 'CVCL:1730', (152, 157))	('TYMS', 'Gene', (124, 128))	('STAT3', 'Gene', (32, 37))	('TYMS', 'Gene', '7298', (124, 128))	('STAT6', 'Gene', (81, 86))	('Ser727', 'Var', (39, 45))	('Ser727', 'Chemical', '-', (39, 45))	('Y641', 'Var', (88, 92))	('STAT5', 'Gene', '6776', (56, 61))
558129	32627015	Therefore, it was hypothesized that TYMS knockdown may have resulted in decreased activity of the JAK/STAT signaling pathway.	('TYMS', 'Gene', '7298', (36, 40))	('decreased', 'NegReg', (72, 81))	('JAK/STAT signaling pathway', 'Pathway', (98, 124))	('activity', 'MPA', (82, 90))	('TYMS', 'Gene', (36, 40))	('knockdown', 'Var', (41, 50))
558131	32627015	The results showed that TYMS knockdown resulted in downregulation of the expression of phosphorylated Tyk2 in Lenti-shTYMS cells compared with the control cells, and the expression of phosphorylated Jak1, total Jak2, phosphorylated Jak2, total Jak3 and phosphorylated Jak3 were not detected.	('Tyk2', 'Gene', '7297', (102, 106))	('Jak1', 'Gene', (199, 203))	('knockdown', 'Var', (29, 38))	('Jak3', 'Gene', (244, 248))	('Tyk2', 'Gene', (102, 106))	('Jak3', 'Gene', (268, 272))	('TYMS', 'Gene', '7298', (24, 28))	('Jak2', 'Gene', (211, 215))	('Jak2', 'Gene', '3717', (211, 215))	('expression', 'MPA', (73, 83))	('Jak3', 'Gene', '3718', (244, 248))	('TYMS', 'Gene', '7298', (118, 122))	('Jak3', 'Gene', '3718', (268, 272))	('TYMS', 'Gene', (24, 28))	('Jak1', 'Gene', '3716', (199, 203))	('downregulation', 'NegReg', (51, 65))	('Jak2', 'Gene', (232, 236))	('Jak2', 'Gene', '3717', (232, 236))	('TYMS', 'Gene', (118, 122))
558132	32627015	Meanwhile, phosphorylated STAT1 (Tyr701), phosphorylated STAT3 (Ser727), phosphorylated STAT5 (Y694) and phosphorylated STAT6 (Y641) in the STAT family were significantly downregulated in Lenti-shTYMS cells, consistent with the results of protein microarray analysis (Fig.	('STAT6', 'Gene', '6778', (120, 125))	('STAT1', 'Gene', '6772', (26, 31))	('Ser727', 'Chemical', '-', (64, 70))	('downregulated', 'NegReg', (171, 184))	('Y694', 'Var', (95, 99))	('Y641', 'Var', (127, 131))	('STAT5', 'Gene', '6776', (88, 93))	('STAT3', 'Gene', '6774', (57, 62))	('STAT5', 'Gene', (88, 93))	('TYMS', 'Gene', '7298', (196, 200))	('Tyr701', 'Chemical', '-', (33, 39))	('STAT3', 'Gene', (57, 62))	('STAT6', 'Gene', (120, 125))	('Tyr701', 'Var', (33, 39))	('STAT1', 'Gene', (26, 31))	('Ser727', 'Var', (64, 70))	('TYMS', 'Gene', (196, 200))
558133	32627015	These results suggest that TYMS knockdown may downregulate the activity of the JAK/STAT signaling pathway in RLPS cells, thereby inhibiting the progression of RLPS.	('downregulate', 'NegReg', (46, 58))	('TYMS', 'Gene', (27, 31))	('activity', 'MPA', (63, 71))	('inhibiting', 'NegReg', (129, 139))	('RLPS', 'Disease', (159, 163))	('progression', 'CPA', (144, 155))	('knockdown', 'Var', (32, 41))	('JAK/STAT signaling pathway', 'Pathway', (79, 105))	('TYMS', 'Gene', '7298', (27, 31))
558150	32627015	Ligabue et al, showed that inhibition of TYMS significantly interfered with cell cycle progression in ovarian cystadenocarcinoma cells, resulting in the accumulation of cells in the S phase and a substantial decrease in cells in the G0-G1 phase and G2-M phases.	('TYMS', 'Gene', (41, 45))	('cell cycle progression', 'CPA', (76, 98))	('G2-M phases', 'CPA', (249, 260))	('ovarian cystadenocarcinoma', 'Disease', (102, 128))	('ovarian cystadenocarcinoma', 'Phenotype', 'HP:0012887', (102, 128))	('cells in the S phase', 'CPA', (169, 189))	('inhibition', 'Var', (27, 37))	('TYMS', 'Gene', '7298', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cells in the G0-G1 phase', 'CPA', (220, 244))	('accumulation', 'PosReg', (153, 165))	('ovarian cystadenocarcinoma', 'Disease', 'MESH:D003536', (102, 128))	('interfered', 'NegReg', (60, 70))	('decrease', 'NegReg', (208, 216))
558152	32627015	Furthermore, migration and invasion of cells with TYMS expression knocked down was decreased compared with the control cells.	('TYMS', 'Gene', '7298', (50, 54))	('decreased', 'NegReg', (83, 92))	('knocked down', 'Var', (66, 78))	('TYMS', 'Gene', (50, 54))
558154	32627015	Following TYMS knockdown, protein microarray analysis was performed.	('TYMS', 'Gene', '7298', (10, 14))	('knockdown', 'Var', (15, 24))	('TYMS', 'Gene', (10, 14))
558157	32627015	Multiple hematological malignancies exhibit inappropriate activation of the JAK signaling pathway, as a result of a variety of mechanisms, including the downregulation of negative regulators, activating mutations and fusions.	('negative', 'Protein', (171, 179))	('hematological malignancies', 'Phenotype', 'HP:0004377', (9, 35))	('malignancies', 'Disease', (23, 35))	('activating mutations', 'Var', (192, 212))	('fusions', 'Var', (217, 224))	('activation', 'PosReg', (58, 68))	('mutations', 'Var', (203, 212))	('malignancies', 'Disease', 'MESH:D009369', (23, 35))	('JAK signaling pathway', 'Pathway', (76, 97))	('downregulation', 'NegReg', (153, 167))
558160	32627015	In agreement with this, it was previously reported that inhibition of the JAK/STAT pathway reduced cell proliferation and induced apoptosis in cutaneous T-cell lymphomas.	('cell proliferation', 'CPA', (99, 117))	('cutaneous T-cell lymphomas', 'Disease', (143, 169))	('apoptosis', 'CPA', (130, 139))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (153, 169))	('induced', 'Reg', (122, 129))	('cutaneous T-cell lymphomas', 'Phenotype', 'HP:0012192', (143, 169))	('JAK/STAT pathway', 'Pathway', (74, 90))	('lymphomas', 'Phenotype', 'HP:0002665', (160, 169))	('reduced', 'NegReg', (91, 98))	('inhibition', 'Var', (56, 66))	('cutaneous T-cell lymphomas', 'Disease', 'MESH:D016410', (143, 169))
558162	32627015	The results of the protein microarray analysis showed increased expression of phosphorylated P53 following TYMS knockdown.	('expression', 'MPA', (64, 74))	('TYMS', 'Gene', (107, 111))	('increased', 'PosReg', (54, 63))	('knockdown', 'Var', (112, 121))	('P53', 'Gene', (93, 96))	('TYMS', 'Gene', '7298', (107, 111))	('P53', 'Gene', '7157', (93, 96))
558163	32627015	Two previous studies demonstrated that the p53-dependent response limited the viability of mammalian haploid cells, likely by increasing cell apoptosis, and p53 deletion increased the viability and proliferation of the haploid cells.	('p53', 'Gene', '7157', (157, 160))	('limited', 'NegReg', (66, 73))	('increasing', 'PosReg', (126, 136))	('cell apoptosis', 'CPA', (137, 151))	('increased', 'PosReg', (170, 179))	('viability', 'CPA', (184, 193))	('deletion', 'Var', (161, 169))	('proliferation', 'CPA', (198, 211))	('p53', 'Gene', (43, 46))	('mammalian', 'Species', '9606', (91, 100))	('p53', 'Gene', '7157', (43, 46))	('p53', 'Gene', (157, 160))	('viability', 'CPA', (78, 87))
558164	32627015	This suggests that decreased RLPS cell viability and increased apoptosis, following TYMS knockdown may be associated with an increase in P53.	('decreased RLPS', 'Disease', 'MESH:D002303', (19, 33))	('decreased RLPS', 'Disease', (19, 33))	('TYMS', 'Gene', '7298', (84, 88))	('increase', 'PosReg', (125, 133))	('P53', 'Gene', (137, 140))	('P53', 'Gene', '7157', (137, 140))	('knockdown', 'Var', (89, 98))	('apoptosis', 'CPA', (63, 72))	('TYMS', 'Gene', (84, 88))
558167	32627015	Knocking out target genes in haploid embryonic stem cells not only results in complete silencing at the mRNA level, but also guarantees that mutations, which only affected one set of chromosomes carried by haploid cells, are represented in the corresponding phenotypes.	('haploid embryonic', 'Disease', 'MESH:D020964', (29, 46))	('haploid embryonic', 'Disease', (29, 46))	('silencing', 'NegReg', (87, 96))	('Knocking', 'Var', (0, 8))
558231	23351137	Cytogenetic examination revealed translocation of the EWSR1 gene.	('EWSR1', 'Gene', '2130', (54, 59))	('translocation', 'Var', (33, 46))	('EWSR1', 'Gene', (54, 59))	('revealed', 'Reg', (24, 32))
558264	23351137	However, the majority of cases of CCS of the soft parts are characterized by expression of melanocytic markers (HMB45, A103, MITF and so on) more often than gastrointestinal CCS, where most tumors are negative for these markers .	('HMB45', 'Gene', (112, 117))	('gastrointestinal CCS', 'Disease', (157, 177))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('A103', 'Var', (119, 123))	('CCS', 'Disease', (34, 37))	('gastrointestinal CCS', 'Disease', 'MESH:D005767', (157, 177))	('tumors', 'Disease', (190, 196))	('MITF', 'Gene', '4286', (125, 129))	('MITF', 'Gene', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
558337	23189178	Unexpected diagnoses of leiomyoma variants or atypical and malignant smooth muscle tumors occurred in 1.2% of cases using power morcellation for uterine masses clinically presumed to be "fibroids" over this period, including one endometrial stromal sarcoma (ESS), one cellular leiomyoma (CL), six atypical leiomyomas (AL), three smooth muscle tumor of uncertain malignant potential (STUMPs), and one leiomyosarcoma (LMS).	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (400, 414))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (400, 414))	('muscle tumors', 'Disease', (76, 89))	('leiomyoma', 'Disease', (277, 286))	('leiomyoma', 'Disease', 'MESH:D007889', (306, 315))	('muscle tumor', 'Disease', 'MESH:D009217', (76, 88))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (229, 256))	('variants', 'Var', (34, 42))	('LMS', 'Phenotype', 'HP:0100243', (416, 419))	('leiomyomas', 'Disease', (306, 316))	('uterine masses', 'Phenotype', 'HP:0010784', (145, 159))	('atypical leiomyoma', 'Disease', (297, 315))	('muscle tumor', 'Disease', 'MESH:D009217', (336, 348))	('muscle tumor', 'Disease', (336, 348))	('leiomyosarcoma', 'Disease', (400, 414))	('leiomyomas', 'Disease', 'MESH:D007889', (306, 316))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('leiomyoma', 'Disease', 'MESH:D007889', (24, 33))	('leiomyoma', 'Disease', (306, 315))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('endometrial stromal sarcoma', 'Disease', (229, 256))	('leiomyoma', 'Disease', 'MESH:D007889', (277, 286))	('AL', 'Chemical', '-', (318, 320))	('muscle tumors', 'Disease', 'MESH:D009217', (76, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (407, 414))	('sarcoma', 'Phenotype', 'HP:0100242', (249, 256))	('atypical leiomyoma', 'Disease', 'MESH:D007889', (297, 315))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('leiomyoma', 'Disease', (24, 33))
558341	23189178	While additional study is warranted, these data suggest uterine morcellation carries a risk of disseminating unexpected malignancy with apparent associated increase in mortality much higher than appreciated currently.	('malignancy', 'Disease', (120, 130))	('increase', 'PosReg', (156, 164))	('uterine morcellation', 'Var', (56, 76))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))	('mortality', 'MPA', (168, 177))
558356	23189178	Of the 1091 morcellated surgical resections for clinically presumed leiomyoma, thirteen cases were diagnosed as clinically relevant leiomyoma variants, atypical lesions, or malignancy upon histopathologic examination (summarized in Figure 2 and Table 1); all of these cases were found to have been morcellated using a laparoscopic power morcellator.	('leiomyoma', 'Disease', 'MESH:D007889', (68, 77))	('variants', 'Var', (142, 150))	('leiomyoma', 'Disease', (132, 141))	('malignancy', 'Disease', 'MESH:D009369', (173, 183))	('malignancy', 'Disease', (173, 183))	('leiomyoma', 'Disease', 'MESH:D007889', (132, 141))	('leiomyoma', 'Disease', (68, 77))
558464	20860481	Specifically, the type I IFNs, IFN-alpha/beta, represent a powerful and universal intracellular defense system against viruses of all sorts, which is best demonstrated in knockout mice that are unresponsive to IFN-alpha/beta due to targeted deletions in their type I IFN receptor.	('IFN', 'Gene', '3439', (25, 28))	('IFN', 'Gene', '3439', (31, 34))	('IFN', 'Gene', (267, 270))	('IFN', 'Gene', '3439', (210, 213))	('IFN', 'Gene', (25, 28))	('mice', 'Species', '10090', (180, 184))	('IFN', 'Gene', (210, 213))	('deletions', 'Var', (241, 250))	('IFN', 'Gene', (31, 34))	('IFN', 'Gene', '3439', (267, 270))
558481	20860481	Indeed, full-length vIRF2 (which is translated from exons K11.1 and K11) inhibits the expression of IFN-inducible genes driven by IRF1, IRF3 and IFN-stimulating gene factor-3 (ISGF3), but not IRF7.	('IRF1', 'Gene', (130, 134))	('IRF', 'Gene', '4961464', (136, 139))	('IFN', 'Gene', (145, 148))	('IRF', 'Gene', (136, 139))	('IRF1', 'Gene', '3659', (130, 134))	('IRF', 'Gene', '4961464', (21, 24))	('K11', 'Var', (68, 71))	('IRF', 'Gene', (21, 24))	('IRF3', 'Gene', (136, 140))	('IRF7', 'Gene', '3665', (192, 196))	('ISGF3', 'Gene', '6772', (176, 181))	('IFN', 'Gene', '3439', (100, 103))	('expression', 'MPA', (86, 96))	('IRF7', 'Gene', (192, 196))	('ISGF3', 'Gene', (176, 181))	('IFN-stimulating gene factor-3', 'Gene', '6772', (145, 174))	('IRF3', 'Gene', '3661', (136, 140))	('IRF', 'Gene', '4961464', (130, 133))	('IRF', 'Gene', '4961464', (192, 195))	('IFN-stimulating gene factor-3', 'Gene', (145, 174))	('inhibits', 'NegReg', (73, 81))	('IFN', 'Gene', '3439', (145, 148))	('IRF', 'Gene', (192, 195))	('IFN', 'Gene', (100, 103))	('IRF', 'Gene', (130, 133))
558497	20860481	The manipulation of the stability, function and modification of host IRF3 and IRF7 by many KSHV gene products provides a number of novel regulatory strategies for circumventing the innate immune defense system whilst enabling them to act at different stages of the viral cycle, with some proteins playing a role during the lytic replication cycle and others during latency.	('enabling', 'PosReg', (217, 225))	('IRF3', 'Gene', (69, 73))	('KSHV', 'Gene', (91, 95))	('IRF3', 'Gene', '3661', (69, 73))	('IRF7', 'Gene', (78, 82))	('manipulation', 'Var', (4, 16))	('circumventing', 'NegReg', (163, 176))	('IRF7', 'Gene', '3665', (78, 82))	('modification', 'Var', (48, 60))	('KS', 'Phenotype', 'HP:0100726', (91, 93))	('KSHV', 'Species', '37296', (91, 95))
558506	20860481	Meanwhile, vCCL2 can also antagonize Th1 cells by inhibiting signaling mediated by many other classes of chemokine receptors with which it has a high affinity, including CCR1, CCR2, CCR5, CX3C-chemokine receptor-1 (CXCR1) and CXCR4.	('CCR1', 'Gene', '1230', (170, 174))	('inhibiting', 'NegReg', (50, 60))	('CCR5', 'Gene', '1234', (182, 186))	('vCCL2', 'Chemical', '-', (11, 16))	('vCCL2', 'Var', (11, 16))	('Th1', 'Gene', '51497', (37, 40))	('CCR5', 'Gene', (182, 186))	('CXCR4', 'Gene', '7852', (226, 231))	('CX3C-chemokine receptor-1', 'Gene', '1524', (188, 213))	('CX3C-chemokine receptor-1', 'Gene', (188, 213))	('CXCR4', 'Gene', (226, 231))	('signaling mediated', 'MPA', (61, 79))	('CXCR1', 'Gene', (215, 220))	('CCR2', 'Gene', '729230', (176, 180))	('CXCR1', 'Gene', '1524', (215, 220))	('CCR1', 'Gene', (170, 174))	('Th1', 'Gene', (37, 40))	('CCR2', 'Gene', (176, 180))
558545	20860481	Furthermore, vFLIP likely contributes to the proinflammatory micro-environment because its expression was found to induce NF-kappaB-regulated cytokine expression and secretion.	('NF-kappaB-regulated cytokine expression', 'MPA', (122, 161))	('vFLIP', 'Gene', '4961494', (13, 18))	('expression', 'Var', (91, 101))	('vFLIP', 'Gene', (13, 18))	('induce', 'PosReg', (115, 121))	('secretion', 'MPA', (166, 175))
558557	20860481	In fact, MHV68 vBcl-2 exhibits an even higher binding affinity to Beclin1 and thus a more robust and persistent inhibition of Beclin1-mediated autophagy upon environmental stress, compared with its cellular counterpart.	('higher', 'PosReg', (39, 45))	('binding affinity', 'Interaction', (46, 62))	('MHV68', 'Var', (9, 14))	('Beclin1-mediated', 'Protein', (126, 142))	('inhibition', 'NegReg', (112, 122))	('Beclin1', 'Protein', (66, 73))	('MHV68', 'Species', '1440122', (9, 14))
558568	20860481	It was found that stimulation of TLR7 and TLR8 with a TLR8 ligand, single-stranded polyuridine (a synthetic single-stranded RNA homolog), strongly reactivated KSHV.	('TLR7', 'Gene', (33, 37))	('TLR8', 'Gene', '51311', (54, 58))	('single-stranded polyuridine', 'Var', (67, 94))	('TLR7', 'Gene', '51284', (33, 37))	('reactivated', 'MPA', (147, 158))	('TLR8', 'Gene', (42, 46))	('KSHV', 'Species', '37296', (159, 163))	('KS', 'Phenotype', 'HP:0100726', (159, 161))	('TLR8', 'Gene', '51311', (42, 46))	('stimulation', 'PosReg', (18, 29))	('KSHV', 'Gene', (159, 163))	('TLR8', 'Gene', (54, 58))	('polyuridine', 'Chemical', '-', (83, 94))
558576	20860481	Other indirect effects caused by antibodies include the recruitment or activation of the innate immune effector system, such as antibody-dependent cell cytotoxicity, engulfment of antibody-coated (opsonized) viruses by phagocytes and complement activation.	('engulfment', 'CPA', (166, 176))	('antibody-dependent', 'CPA', (128, 146))	('activation', 'PosReg', (71, 81))	('cytotoxicity', 'Disease', 'MESH:D064420', (152, 164))	('cytotoxicity', 'Disease', (152, 164))	('innate immune effector system', 'CPA', (89, 118))	('antibodies', 'Var', (33, 43))
558577	20860481	B cells are the likely cellular reservoir of KSHV infection; therefore, KSHV seems to influence several aspects of B-cell biology through the modulation of the humoral immune response.	('KSHV', 'Species', '37296', (45, 49))	('modulation', 'Reg', (142, 152))	('KS', 'Phenotype', 'HP:0100726', (45, 47))	('KSHV infection', 'Disease', (45, 59))	('KS', 'Phenotype', 'HP:0100726', (72, 74))	('KSHV', 'Species', '37296', (72, 76))	('KSHV', 'Var', (72, 76))	('KSHV infection', 'Disease', 'MESH:C537372', (45, 59))	('influence', 'Reg', (86, 95))
558595	20860481	Thus, KSHV can also inhibit MHC class I transcription as another way of down-regulating MHC class I molecules on the cell surface of infected cells.	('KSHV', 'Species', '37296', (6, 10))	('KSHV', 'Var', (6, 10))	('MHC', 'Gene', (28, 31))	('KS', 'Phenotype', 'HP:0100726', (6, 8))	('MHC', 'Gene', '3107', (28, 31))	('MHC', 'Gene', (88, 91))	('inhibit', 'NegReg', (20, 27))	('MHC', 'Gene', '3107', (88, 91))	('down-regulating', 'NegReg', (72, 87))
558597	20860481	Furthermore, they can rapidly produce large amounts of IFN-gamma, which induce diverse antiviral immune consequences upon receptor ligation, including the augmentation of antigen presentation and activation/polarization of CD4+ T cells and macrophage.	('antiviral immune', 'MPA', (87, 103))	('ligation', 'Var', (131, 139))	('CD4', 'Gene', (223, 226))	('antigen presentation', 'MPA', (171, 191))	('induce', 'Reg', (72, 78))	('augmentation', 'PosReg', (155, 167))	('IFN-gamma', 'Gene', (55, 64))	('IFN-gamma', 'Gene', '3458', (55, 64))	('CD4', 'Gene', '920', (223, 226))
558628	22592145	One case showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy.	('polysomy', 'Var', (130, 138))	('EWSR1', 'Gene', '2130', (102, 107))	('EWSR1', 'Gene', (102, 107))	('extra copies', 'Var', (82, 94))
558630	22592145	Six cases demonstrated rearrangement of the partner fusion gene ATF1 (46%), and 3 showed rearrangement of CREB1 (23%); 2 cases lacked rearrangement of either partner gene.	('men', 'Species', '9606', (98, 101))	('men', 'Species', '9606', (32, 35))	('CREB1', 'Gene', '1385', (106, 111))	('ATF1', 'Gene', '466', (64, 68))	('rearrangement', 'Var', (23, 36))	('men', 'Species', '9606', (143, 146))	('ATF1', 'Gene', (64, 68))	('CREB1', 'Gene', (106, 111))
558668	22592145	Only cell nuclei with one or more yellow (fusion) and, in addition, separate green and red signals detected simultaneously were considered positive for EWSR1 rearrangement.	('EWSR1', 'Gene', (152, 157))	('rearrangement', 'Var', (158, 171))	('EWSR1', 'Gene', '2130', (152, 157))	('men', 'Species', '9606', (167, 170))
558670	22592145	Probe specificity was confirmed by mapping back to banded metaphase nuclei and by hybridization to previously identified cases with rearrangements involving 22q12 (EWSR1) on conventional cytogenetic and FISH analyses.	('men', 'Species', '9606', (141, 144))	('rearrangements', 'Var', (132, 146))	('EWSR1', 'Gene', (164, 169))	('EWSR1', 'Gene', '2130', (164, 169))
558714	22592145	One case (case 5) showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy.	('extra copies', 'Var', (91, 103))	('EWSR1', 'Gene', (111, 116))	('EWSR1', 'Gene', '2130', (111, 116))	('polysomy', 'Var', (139, 147))	('chromosome', 'Var', (125, 135))
558716	22592145	Of the 12 cases positive for a split EWSR1 signal, 6 showed rearrangement of ATF1 (50%) (Fig.	('men', 'Species', '9606', (69, 72))	('EWSR1', 'Gene', (37, 42))	('ATF1', 'Gene', (77, 81))	('rearrangement', 'Var', (60, 73))	('EWSR1', 'Gene', '2130', (37, 42))	('ATF1', 'Gene', '466', (77, 81))
558717	22592145	7B), 3 showed rearrangement of CREB1 (25%), 2 showed no rearrangements of either ATF1 or CREB1 genes, and in 1 case ATF1 and CREB1 were not evaluated (case 16).	('CREB1', 'Gene', '1385', (125, 130))	('ATF1', 'Gene', '466', (81, 85))	('ATF1', 'Gene', '466', (116, 120))	('men', 'Species', '9606', (65, 68))	('CREB1', 'Gene', (125, 130))	('rearrangement', 'Var', (14, 27))	('CREB1', 'Gene', (31, 36))	('men', 'Species', '9606', (23, 26))	('CREB1', 'Gene', '1385', (89, 94))	('ATF1', 'Gene', (81, 85))	('CREB1', 'Gene', '1385', (31, 36))	('CREB1', 'Gene', (89, 94))	('ATF1', 'Gene', (116, 120))
558728	22592145	Genetically, they were characterized by EWSR1 gene rearrangements, including EWSR1-ATF1 or EWSR1-CREB1 fusions.	('fusions', 'Var', (103, 110))	('CREB1', 'Gene', '1385', (97, 102))	('EWSR1', 'Gene', '2130', (40, 45))	('ATF1', 'Gene', (83, 87))	('CREB1', 'Gene', (97, 102))	('ATF1', 'Gene', '466', (83, 87))	('EWSR1', 'Gene', '2130', (91, 96))	('EWSR1', 'Gene', (40, 45))	('men', 'Species', '9606', (60, 63))	('EWSR1', 'Gene', (77, 82))	('EWSR1', 'Gene', (91, 96))	('EWSR1', 'Gene', '2130', (77, 82))
558739	22592145	The molecular genetic study in 13 of our cases showed EWSR1 gene rearrangements, usually fused with ATF1 or CREB1, a finding that is shared with several other types of tumors of uncertain or disputed histogenesis.	('CREB1', 'Gene', '1385', (108, 113))	('EWSR1', 'Gene', '2130', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('ATF1', 'Gene', (100, 104))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('rearrangements', 'Var', (65, 79))	('ATF1', 'Gene', '466', (100, 104))	('CREB1', 'Gene', (108, 113))	('EWSR1', 'Gene', (54, 59))	('men', 'Species', '9606', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
558741	22592145	Rearrangements of this gene occur in Ewing sarcoma, hyalinizing clear cell carcinoma of salivary gland, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, myxoid liposarcoma, angiomatoid fibrous histiocytoma, and desmoplastic small round cell tumors.	('Ewing sarcoma', 'Disease', (37, 50))	('liposarcoma', 'Phenotype', 'HP:0012034', (173, 184))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (143, 164))	('myoepithelial carcinoma', 'Disease', (104, 127))	('myxoid chondrosarcoma', 'Disease', (143, 164))	('carcinoma of salivary', 'Phenotype', 'HP:0100684', (75, 96))	('men', 'Species', '9606', (9, 12))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (166, 184))	('desmoplastic small round cell tumors', 'Disease', 'MESH:D058405', (224, 260))	('clear cell carcinoma', 'Disease', (64, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('Rearrangements', 'Var', (0, 14))	('myxoid liposarcoma', 'Disease', (166, 184))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (150, 164))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (37, 50))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (37, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('desmoplastic small round cell tumors', 'Disease', (224, 260))	('histiocytoma', 'Phenotype', 'HP:0012315', (206, 218))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (166, 184))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (64, 84))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (186, 218))	('occur', 'Reg', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (104, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('angiomatoid fibrous histiocytoma', 'Disease', (186, 218))
558787	26215971	In other malignant diseases, such as Hodgkin's lymphoma or neuroblastoma, high IL6 blood serum expression is associated with poor prognosis.	('neuroblastoma', 'Phenotype', 'HP:0003006', (59, 72))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (37, 55))	("Hodgkin's lymphoma", 'Disease', (37, 55))	('malignant diseases', 'Disease', (9, 27))	('high', 'Var', (74, 78))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('IL6', 'Gene', '3569', (79, 82))	('IL6', 'Gene', (79, 82))	('neuroblastoma', 'Disease', 'MESH:D009447', (59, 72))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (37, 55))	('neuroblastoma', 'Disease', (59, 72))	('malignant diseases', 'Disease', 'MESH:D009369', (9, 27))
558840	26215971	Mean (+- SEM) zone 1-3 coverage values of n = 3 independent experiments were computed for all three images per tumor as a measure of cell motility in response to PBS, 250 ng and 500 ng IL6.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('250 ng', 'Var', (167, 173))	('IL6', 'Gene', '3569', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('IL6', 'Gene', (185, 188))	('PBS', 'Chemical', 'MESH:D007854', (162, 165))
558846	26215971	Interestingly, a group of four patients with IL6 levels >= 20 pg/ml had a different clinical course than the other eight patients with lower levels (Table 1).	('IL6', 'Gene', '3569', (45, 48))	('IL6', 'Gene', (45, 48))	('patients', 'Species', '9606', (31, 39))	('>= 20 pg/ml', 'Var', (56, 67))	('patients', 'Species', '9606', (121, 129))
558921	26215971	We found that 2 out of 4 patients with IL6 levels >= 20 pg/ml had fever and 3 out of 4 metastases at diagnosis, whereas only two out eight patients with IL6 levels below 20 pg/ml presented with fever and metastases at diagnosis.	('IL6', 'Gene', '3569', (153, 156))	('IL6', 'Gene', (153, 156))	('IL6', 'Gene', (39, 42))	('metastases', 'Disease', (87, 97))	('metastases', 'Disease', (204, 214))	('fever', 'Disease', (194, 199))	('patients', 'Species', '9606', (139, 147))	('IL6', 'Gene', '3569', (39, 42))	('fever', 'Phenotype', 'HP:0001945', (194, 199))	('metastases', 'Disease', 'MESH:D009362', (204, 214))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('patients', 'Species', '9606', (25, 33))	('levels >= 20 pg/ml', 'Var', (43, 61))	('fever', 'Disease', 'MESH:D005334', (66, 71))	('fever', 'Disease', (66, 71))	('fever', 'Disease', 'MESH:D005334', (194, 199))	('fever', 'Phenotype', 'HP:0001945', (66, 71))
558972	21904536	Transfection of ORF50 to KSHV-infected cells resulted in the activation of lytic gene expression (Lukac et al.,).	('KS', 'Phenotype', 'HP:0100726', (25, 27))	('lytic gene expression', 'Gene', (75, 96))	('activation', 'PosReg', (61, 71))	('Transfection', 'Var', (0, 12))	('ORF50', 'Gene', (16, 21))	('KSHV-infected', 'Disease', (25, 38))	('KSHV-infected', 'Disease', 'MESH:C537372', (25, 38))
558974	21904536	ORF50 protein also induces expression of K8 (K-bZIP, a positional homolog of EBV BZLF1) protein, an early protein.	('ORF50 protein', 'Var', (0, 13))	('BZLF1', 'Gene', '3783744', (81, 86))	('protein', 'Var', (6, 13))	('EBV', 'Species', '10376', (77, 80))	('expression', 'MPA', (27, 37))	('induces', 'Reg', (19, 26))	('BZLF1', 'Gene', (81, 86))
558983	21904536	KSHV efficiently infects primary cultures of human endothelial cells in vitro (Sakurada et al.,; Gao et al.,).	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('human', 'Species', '9606', (45, 50))	('infects', 'Reg', (17, 24))
558992	21904536	Probably the most important role of LANA-1 is to establish and maintain the latency in KSHV-infected cells by tethering KSHV DNA to host chromosomes (Ballestas et al.,).	('LANA', 'Gene', (36, 40))	('tethering', 'Var', (110, 119))	('LANA', 'Gene', '4961527', (36, 40))	('KSHV', 'Species', '37296', (87, 91))	('KS', 'Phenotype', 'HP:0100726', (87, 89))	('latency', 'MPA', (76, 83))	('KSHV-infected', 'Disease', 'MESH:C537372', (87, 100))	('KS', 'Phenotype', 'HP:0100726', (120, 122))	('KSHV', 'Species', '37296', (120, 124))	('KSHV-infected', 'Disease', (87, 100))
559022	21904536	Although the transmission modes of KSHV have not yet been clarified, transmission though saliva is likely (Pauk et al.,), because high KSHV copy numbers are detected in saliva of seropositives.	('KS', 'Phenotype', 'HP:0100726', (35, 37))	('KSHV', 'Species', '37296', (35, 39))	('copy numbers', 'Var', (140, 152))	('KS', 'Phenotype', 'HP:0100726', (135, 137))	('KSHV', 'Species', '37296', (135, 139))	('KSHV', 'Gene', (135, 139))
559063	21904536	Infection by KSHV induces a dynamic alteration of gene expression in endothelial cells (Hong et al.,; Wang et al.,).	('gene expression', 'MPA', (50, 65))	('KS', 'Phenotype', 'HP:0100726', (13, 15))	('KSHV', 'Gene', (13, 17))	('alteration', 'Reg', (36, 46))	('induces', 'Reg', (18, 25))	('Infection', 'Var', (0, 9))	('KSHV', 'Species', '37296', (13, 17))
559065	21904536	Thus, KSHV can affect the expression level of cellular proteins in endothelial cells.	('KSHV', 'Species', '37296', (6, 10))	('KSHV', 'Var', (6, 10))	('KS', 'Phenotype', 'HP:0100726', (6, 8))	('affect', 'Reg', (15, 21))	('expression level of cellular proteins', 'MPA', (26, 63))
559174	30131449	USP6 Confers Sensitivity to IFN-Mediated Apoptosis through Modulation of TRAIL Signaling in Ewing Sarcoma Ewing sarcoma is the second most common sarcoma of the bone, afflicting predominantly the pediatric population.	('sarcoma of the bone', 'Phenotype', 'HP:0010622', (146, 165))	('Ewing Sarcoma', 'Disease', 'MESH:D012512', (92, 105))	('IFN', 'Gene', (28, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (106, 119))	('Ewing sarcoma', 'Disease', (106, 119))	('TRAIL', 'Gene', '8743', (73, 78))	('sarcoma', 'Disease', 'MESH:D012509', (146, 153))	('Modulation', 'Var', (59, 69))	('USP6', 'Gene', (0, 4))	('Ewing Sarcoma', 'Disease', (92, 105))	('sarcoma', 'Disease', (146, 153))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('TRAIL', 'Gene', (73, 78))	('USP6', 'Gene', '9098', (0, 4))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('IFN', 'Gene', '3439', (28, 31))	('sarcoma', 'Disease', (112, 119))	('Sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
559187	30131449	The key etiologic agent in ES is a translocation product that fuses the EWS RNA-binding protein with an Ets family transcription factor, most commonly FLI1.	('FLI1', 'Gene', (151, 155))	('ES', 'Phenotype', 'HP:0012254', (27, 29))	('ES', 'Disease', 'MESH:D012512', (27, 29))	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', (72, 75))	('fuses', 'Var', (62, 67))	('FLI1', 'Gene', '2313', (151, 155))
559193	30131449	USP6 translocations were also identified in fibroma of tendon sheath and giant-cell rich granuloma .	('USP6', 'Gene', (0, 4))	('fibroma of tendon sheath', 'Disease', (44, 68))	('USP6', 'Gene', '9098', (0, 4))	('giant-cell rich granuloma', 'Disease', (73, 98))	('translocations', 'Var', (5, 19))	('granuloma', 'Phenotype', 'HP:0032252', (89, 98))	('fibroma of tendon sheath', 'Disease', 'MESH:D015835', (44, 68))	('fibroma', 'Phenotype', 'HP:0010614', (44, 51))	('identified', 'Reg', (30, 40))	('giant-cell rich granuloma', 'Disease', 'MESH:D006101', (73, 98))
559194	30131449	In all cases, translocation resulted in promoter swapping and high level expression of wild type USP6.	('translocation', 'Var', (14, 27))	('USP6', 'Gene', (97, 101))	('USP6', 'Gene', '9098', (97, 101))	('high level expression', 'MPA', (62, 83))	('resulted in', 'Reg', (28, 39))	('promoter swapping', 'MPA', (40, 57))
559202	30131449	While translocation-driven overexpression of USP6 plays a key role in benign neoplasms, its role in malignant entities where it is not the oncogenic driver remains unexplored.	('translocation-driven', 'Var', (6, 26))	('USP6', 'Gene', (45, 49))	('USP6', 'Gene', '9098', (45, 49))	('neoplasms', 'Phenotype', 'HP:0002664', (77, 86))	('benign neoplasms', 'Disease', (70, 86))	('overexpression', 'PosReg', (27, 41))	('benign neoplasms', 'Disease', 'MESH:D009369', (70, 86))
559219	30131449	Jak Inhibitor I (CAS 457081-03-7; #420099) and PS-1145 (P6624) were from Sigma.	('P6624', 'Var', (56, 61))	('CAS 457081-03-7', 'Chemical', 'MESH:C073303', (17, 32))	('PS-1145', 'Chemical', 'MESH:C456319', (47, 54))	('CAS 457081-03-7; #420099', 'Var', (17, 41))	('P6624', 'Chemical', 'MESH:D010695', (56, 61))
559220	30131449	Interferon alpha, beta, and gamma were obtained PBL Assay Science (#11410-2 and #11200-1) and PeproTech (#300-02) respectively.	('#11410-2', 'Var', (67, 75))	('#11200-1', 'Var', (80, 88))	('Interferon', 'Gene', (0, 10))	('Interferon', 'Gene', '3439', (0, 10))
559221	30131449	Caspase-3/7 (#G8090) and Caspase-9 (#G8210) activation kits were purchased from Promega, and assays were performed on Molecular Devices SpectroMax.	('Caspase-3', 'Gene', (0, 9))	('Caspase-9', 'Gene', '842', (25, 34))	('#G8090', 'Var', (13, 19))	('Caspase-9', 'Gene', (25, 34))	('Caspase-3', 'Gene', '836', (0, 9))
559223	30131449	Jak1 (cs-3332), pSTAT1 (cs-9167), pSTAT3 (cs-9145), TRAIL (cs-3219), PARP (cs-9542), Caspase-8 (cs-9746), and Bid (cs-2002) were from Cell Signaling.	('Jak1', 'Gene', (0, 4))	('STAT3', 'Gene', (35, 40))	('STAT3', 'Gene', '6774', (35, 40))	('STAT1', 'Gene', (17, 22))	('STAT1', 'Gene', '6772', (17, 22))	('PARP', 'Gene', '1302', (69, 73))	('cs-9746', 'Var', (96, 103))	('cs-9167', 'Var', (24, 31))	('cs-9145', 'Var', (42, 49))	('Jak1', 'Gene', '3716', (0, 4))	('Caspase-8', 'Gene', '841', (85, 94))	('cs-3219', 'Var', (59, 66))	('PARP', 'Gene', (69, 73))	('cs-9542', 'Var', (75, 82))	('Bid', 'Gene', (110, 113))	('cs-3332', 'Var', (6, 13))	('Caspase-8', 'Gene', (85, 94))	('Bid', 'Gene', '637', (110, 113))
559229	30131449	The CDF files for the Affymetrix U133A and U133 Plus 2.0 arrays were edited to remove probes from the USP6 probe set (206405_x_at) that cross-reacted with USP32 or other genes.	('USP32', 'Gene', (155, 160))	('206405_x_at', 'Var', (118, 129))	('USP32', 'Gene', '84669', (155, 160))	('USP6', 'Gene', '9098', (102, 106))	('USP6', 'Gene', (102, 106))
559231	30131449	Publicly available Ewing sarcoma datasets (GSE7007 and GSE37371 U133A) were sorted by USP6 expression.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('USP6', 'Gene', (86, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (19, 32))	('GSE7007', 'Var', (43, 50))	('GSE37371 U133A', 'Var', (55, 69))	('USP6', 'Gene', '9098', (86, 90))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (19, 32))	('Ewing sarcoma', 'Disease', (19, 32))
559239	30131449	However, most probes in the USP6 probeset (206405_x_at) cross-reacted with USP32 or other genes.	('USP32', 'Gene', '84669', (75, 80))	('206405_x_at', 'Var', (43, 54))	('USP32', 'Gene', (75, 80))	('USP6', 'Gene', (28, 32))	('USP6', 'Gene', '9098', (28, 32))	('cross-reacted', 'Reg', (56, 69))
559241	30131449	From two independent patient datasets, IFNalpha (Type I) and IFNgamma (Type II) responses emerged among the top signatures associated with high USP6 expression (Figure 1A; see Supplemental Table 1 for expanded GSEA results).	('IFNalpha', 'Gene', (39, 47))	('USP6', 'Gene', '9098', (144, 148))	('USP6', 'Gene', (144, 148))	('patient', 'Species', '9606', (21, 28))	('IFNalpha', 'Gene', '3439', (39, 47))	('IFNgamma', 'Gene', '3458', (61, 69))	('IFNgamma', 'Gene', (61, 69))	('high', 'Var', (139, 143))
559244	30131449	We found extensive CpG methylation across the USP6 promoter in all immortalized ES cell lines examined, while comparatively low methylation was observed in primary ES tumors (Supplemental Figure 1A).	('ES', 'Disease', 'MESH:D012512', (164, 166))	('ES', 'Phenotype', 'HP:0012254', (80, 82))	('methylation', 'Var', (23, 34))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('ES', 'Disease', 'MESH:D012512', (80, 82))	('USP6', 'Gene', (46, 50))	('USP6', 'Gene', '9098', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ES', 'Phenotype', 'HP:0012254', (164, 166))	('tumors', 'Disease', (167, 173))	('CpG methylation', 'Var', (19, 34))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
559256	30131449	In addition, USP6 expression was associated with an IFN response in germ cell tumors.	('germ', 'Disease', (68, 72))	('USP6', 'Gene', (13, 17))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('germ cell tumor', 'Phenotype', 'HP:0100728', (68, 83))	('germ cell tumors', 'Phenotype', 'HP:0100728', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IFN', 'Gene', '3439', (52, 55))	('IFN', 'Gene', (52, 55))	('USP6', 'Gene', '9098', (13, 17))	('expression', 'Var', (18, 28))	('associated with', 'Reg', (33, 48))
559290	30131449	To confirm the requirement of the Jak1-STAT pathway, CRISPR-mediated knockouts of Jak1, STAT1, and STAT3 were generated in USP6/RD-ES cells (Figure 4F and Supplemental Figure 5C).	('USP6', 'Gene', '9098', (123, 127))	('Jak1', 'Gene', (34, 38))	('ES', 'Phenotype', 'HP:0012254', (131, 133))	('ES', 'Disease', 'MESH:D012512', (131, 133))	('Jak1', 'Gene', '3716', (82, 86))	('STAT3', 'Gene', '6774', (99, 104))	('Jak1', 'Gene', '3716', (34, 38))	('Jak1', 'Gene', (82, 86))	('STAT3', 'Gene', (99, 104))	('STAT1', 'Gene', (88, 93))	('knockouts', 'Var', (69, 78))	('USP6', 'Gene', (123, 127))	('STAT1', 'Gene', '6772', (88, 93))
559292	30131449	Deletion of both STAT1 and STAT3 was required to obtain robust inhibition of death, indicating that they play distinct roles in the apoptotic response, consistent with their ability to function as homo- and hetero-dimers in response to IFN.	('STAT3', 'Gene', (27, 32))	('IFN', 'Gene', (236, 239))	('STAT1', 'Gene', (17, 22))	('STAT1', 'Gene', '6772', (17, 22))	('apoptotic response', 'CPA', (132, 150))	('IFN', 'Gene', '3439', (236, 239))	('STAT3', 'Gene', '6774', (27, 32))	('Deletion', 'Var', (0, 8))
559305	30131449	Furthermore, CRISPR-mediated deletion of TRAIL completely abrogated death of USP6/RD-ES by IFNbeta (Figure 5F).	('abrogated', 'NegReg', (58, 67))	('deletion', 'Var', (29, 37))	('TRAIL', 'Gene', (41, 46))	('IFNbeta', 'Gene', (91, 98))	('ES', 'Phenotype', 'HP:0012254', (85, 87))	('USP6', 'Gene', (77, 81))	('IFNbeta', 'Gene', '3456', (91, 98))	('ES', 'Disease', 'MESH:D012512', (85, 87))	('USP6', 'Gene', '9098', (77, 81))	('death', 'CPA', (68, 73))
559411	24583616	PLWHA were defined as patients diagnosed with ICD-9-CM codes 042-044, 7958, or V08 who were tested for viral load or CD4 count (order codes: 26017A1, 14074B, 12071A, 12071B, 12073A, 12073B, 12074A, 12074B).	('12074A', 'Var', (190, 196))	('14074B', 'Var', (150, 156))	('CD4', 'Gene', (117, 120))	('CD4', 'Gene', '920', (117, 120))	('12073A', 'Var', (174, 180))	('patients', 'Species', '9606', (22, 30))	('12071A', 'Var', (158, 164))	('12073B', 'Var', (182, 188))	('12071B', 'Var', (166, 172))
559479	24583616	However, it is hard to determine whether HIV plays a direct role, or if people who are more likely to contract HIV through risky sexual behavior or injection drug use, are more likely to contract other risk factors for the cancers such as HCV and HPV infection.	('cancers', 'Disease', (223, 230))	('risky sexual behavior', 'Phenotype', 'HP:0008768', (123, 144))	('HIV', 'Disease', (111, 114))	('sexual behavior', 'Disease', 'MESH:D012735', (129, 144))	('people', 'Species', '9606', (72, 78))	('injection drug', 'Var', (148, 162))	('HCV', 'Disease', (239, 242))	('HCV', 'Disease', 'MESH:D006526', (239, 242))	('HPV infection', 'Disease', 'MESH:D030361', (247, 260))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('HIV', 'Disease', 'MESH:D015658', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('HPV infection', 'Disease', (247, 260))	('sexual behavior', 'Phenotype', 'HP:0030214', (129, 144))	('HIV', 'Disease', 'MESH:D015658', (41, 44))	('HIV', 'Disease', (41, 44))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('sexual behavior', 'Disease', (129, 144))
559552	31882696	The nonsynonymous mutation for KMT2B p.Ile2602Val identified in the formalin-fixed paraffin-embedded tumor sample was also confirmed in the CSC.	('KMT2B', 'Gene', (31, 36))	('p.Ile2602Val', 'Mutation', 'p.I2602V', (37, 49))	('p.Ile2602Val', 'Var', (37, 49))	('paraffin', 'Chemical', 'MESH:D010232', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('formalin', 'Chemical', 'MESH:D005557', (68, 76))	('KMT2B', 'Gene', '9757', (31, 36))	('CSC', 'Disease', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
559568	31882696	The Todai OncoPanel (TOP), a multi-gene panel test that examines 464 genes, was used to confirm that CSCs harbored somatic mutations that were identical to the original tumor.	('CSCs', 'Disease', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('mutations', 'Var', (123, 132))
559576	31882696	The sample was then fixed and stained with anti-CD45 mouse monoclonal antibody (mAb) conjugated to allophycocyanin (APC), anti-CD14 mouse mAb conjugated to APC, 4',6-Diamidino-2-phenylindole dihydrochloride (DAPI), and anti-vimentin Alexa Flour 488-conjugated rabbit mAb.	('APC', 'Disease', (156, 159))	("4',6-Diamidino-2-phenylindole dihydrochloride", 'Chemical', '-', (161, 206))	('anti-CD14', 'Var', (122, 131))	('APC', 'Disease', 'MESH:D011125', (116, 119))	('DAPI', 'Chemical', '-', (208, 212))	('anti-CD45', 'Var', (43, 52))	('APC', 'Disease', (116, 119))	('mouse', 'Species', '10090', (132, 137))	('APC', 'Disease', 'MESH:D011125', (156, 159))	('mouse', 'Species', '10090', (53, 58))	('Alexa Flour 488', 'Chemical', '-', (233, 248))
559578	31882696	To completely remove macrophages and monocytes, we utilized an APC-conjugated anti-CD45 Ab combined with an anti-CD14 Ab.	('anti-CD45', 'Var', (78, 87))	('APC', 'Disease', 'MESH:D011125', (63, 66))	('APC', 'Disease', (63, 66))
559585	31882696	Sanger sequencing was performed to confirm the TP53 c.817C > T DNA mutation (protein mutation: p.Arg273 Cys) in the amplified DNA, which is known to be present in the RH30 genome.	('p.Arg273 Cys', 'Var', (95, 107))	('p.Arg273 Cys', 'Mutation', 'rs121913343', (95, 107))	('RH30', 'Gene', (167, 171))	('RH30', 'Gene', '6007', (167, 171))	('c.817C > T', 'Mutation', 'rs121913343', (52, 62))	('DNA', 'Gene', (63, 66))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
559587	31882696	Thus, depleting WBCs before loading the sample onto On-chip Sort improved the separation accuracy for sorting spiked sarcoma cells from whole blood samples.	('sarcoma', 'Disease', (117, 124))	('depleting', 'Var', (6, 15))	('improved', 'PosReg', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('separation accuracy', 'MPA', (78, 97))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))
559596	31882696	A subsequent bioinformatics analysis revealed cancer-associated somatic mutations, including KMT2B c.7804A > G DNA (protein: p.Ile2602Val) and MGA c.3628C > G DNA (protein: p.Arg1210Gly) with allele frequencies of 13.06% and 6.12%, respectively (Table 1).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('p.Arg1210Gly', 'Mutation', 'p.R1210G', (173, 185))	('c.7804A > G DNA', 'Var', (99, 114))	('cancer', 'Disease', (46, 52))	('KMT2B', 'Gene', '9757', (93, 98))	('MGA c.3628C > G', 'Var', (143, 158))	('c.7804A > G', 'Mutation', 'c.7804A>G', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('KMT2B', 'Gene', (93, 98))	('p.Ile2602Val', 'Mutation', 'p.I2602V', (125, 137))	('c.3628C > G', 'Mutation', 'c.3628C>G', (147, 158))
559598	31882696	Importantly, the KMT2B c.7804A > G mutation was confirmed to be present in the CSC [variant allele frequency (VAF) of 34.9%], whereas KMT2B c.7804A > G, c.7804A > C, and c.7804A > T were also observed in the cfDNA at 0.18%, 0.011%, and 0.015%, respectively (Table 1).	('c.7804A > T', 'Var', (170, 181))	('KMT2B', 'Gene', '9757', (134, 139))	('c.7804A > G', 'Var', (23, 34))	('c.7804A > G', 'Var', (140, 151))	('c.7804A > C', 'Var', (153, 164))	('c.7804A > C', 'Mutation', 'c.7804A>C', (153, 164))	('KMT2B', 'Gene', '9757', (17, 22))	('c.7804A > G', 'Mutation', 'c.7804A>G', (140, 151))	('c.7804A > G', 'Mutation', 'c.7804A>G', (23, 34))	('KMT2B', 'Gene', (134, 139))	('KMT2B', 'Gene', (17, 22))	('c.7804A > T', 'Mutation', 'c.7804A>T', (170, 181))
559599	31882696	To verify that the KMT2B mutations observed in cfDNA at low VAFs were true positive mutations, targeted deep sequencing was performed in two giant cell tumor of bone (GCTB) specimens that did not have KMT2B c.7804A > G in the original tumors.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('KMT2B', 'Gene', (19, 24))	('c.7804A > G', 'Var', (207, 218))	('low VAFs', 'Disease', (56, 64))	('mutations', 'Var', (25, 34))	('KMT2B', 'Gene', (201, 206))	('GCTB', 'Phenotype', 'HP:0011847', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('low VAFs', 'Disease', 'MESH:D009800', (56, 64))	('KMT2B', 'Gene', '9757', (19, 24))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (141, 165))	('tumors', 'Disease', (235, 241))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('c.7804A > G', 'Mutation', 'c.7804A>G', (207, 218))	('tumor', 'Disease', (235, 240))	('KMT2B', 'Gene', '9757', (201, 206))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
559600	31882696	The KMT2B c.7804A > G mutation was also found in the GCTB tumors at VAFs of 0.19% and 0.20% (Table 1).	('GCTB', 'Phenotype', 'HP:0011847', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('KMT2B', 'Gene', '9757', (4, 9))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('GCTB', 'Gene', (53, 57))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('c.7804A > G', 'Var', (10, 21))	('KMT2B', 'Gene', (4, 9))	('c.7804A > G', 'Mutation', 'c.7804A>G', (10, 21))
559601	31882696	Therefore, the KMT2B mutations found at low VAFs were likely to be sequence errors.	('low VAFs', 'Disease', 'MESH:D009800', (40, 48))	('low VAFs', 'Disease', (40, 48))	('KMT2B', 'Gene', (15, 20))	('KMT2B', 'Gene', '9757', (15, 20))	('mutations', 'Var', (21, 30))
559604	31882696	Although fusion genes are found in about one-third of sarcomas, no specific genetic abnormalities can be identified in the remaining two-thirds of sarcomas, including myxofibrosarcoma.	('myxofibrosarcoma', 'Disease', (167, 183))	('myxofibrosarcoma', 'Disease', 'None', (167, 183))	('sarcomas', 'Disease', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('found', 'Reg', (26, 31))	('genetic abnormalities', 'Disease', 'MESH:D030342', (76, 97))	('fusion genes', 'Var', (9, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcomas', 'Disease', 'MESH:D012509', (147, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('genetic abnormalities', 'Disease', (76, 97))	('sarcomas', 'Disease', (54, 62))
559606	31882696	The current study showed that, in contrast to the CSC analysis, cfDNA was unable to detect the somatic KMT2B mutation found in the sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('mutation', 'Var', (109, 117))	('KMT2B', 'Gene', '9757', (103, 108))	('sarcoma', 'Disease', (131, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('KMT2B', 'Gene', (103, 108))
559632	31882696	For capillary sequencing with a 3130xl Genetic Analyzer (Thermo Fisher Scientific), 10 ng of template DNA is used to amplify the STR locus of the D5S818 and TP53 gene mutation (p.Arg 273 Cys) with GoTaq G2 Hot Start Green Master Mix (Promega, Madison, WI, USA) according to the manufacturer's instructions.	('TP53', 'Gene', (157, 161))	('D5S818', 'Gene', (146, 152))	('Hot Start', 'Phenotype', 'HP:0031217', (206, 215))	('p.Arg 273 Cys', 'Var', (177, 190))	('p.Arg 273 Cys', 'Mutation', 'rs121913343', (177, 190))	('TP53', 'Gene', '7157', (157, 161))
559633	31882696	The following primer sets were used: the STR locus of D5S818, 5'-GGGTGATTTTCCTCTTTGGT-3' (sense) and 5'-TGATTCCAATCATAGCCACA-3' (antisense), and TP53 gene mutation (p.Arg 273 Cys), 5'-GGGACAGGTAGGACCTGATTTCC-3' (sense) and 5'-GTGGTGAGGCTCCCCTTTCTTG-3' (antisense).	("5'-GTGGTGAGGCTCCCCTTTCTTG-3", 'Chemical', '-', (223, 250))	("5'-GGGACAGGTAGGACCTGATTTCC-3", 'Chemical', '-', (181, 209))	('p.Arg 273 Cys', 'Var', (165, 178))	('TP53', 'Gene', (145, 149))	('TP53', 'Gene', '7157', (145, 149))	('p.Arg 273 Cys', 'Mutation', 'rs121913343', (165, 178))
559636	31882696	WGA DNA of CSCs (100 ng) or cfDNA (100 ng) was subjected to PCR with the following primers for the KMT2B mutation (p.Ile2602Val): 5'-CCTGTTCTGTAAGCGCAACATCG -3' (sense) and 5'-CTTGTCAGTCAACACCGAGCG-3' (antisense).	('mutation', 'Var', (105, 113))	('KMT2B', 'Gene', '9757', (99, 104))	('p.Ile2602Val', 'Mutation', 'p.I2602V', (115, 127))	('KMT2B', 'Gene', (99, 104))
559758	27195266	The resultant chimeric gene has been shown to produce a transcription-activating protein SYT-SSX, which plays a major role in the oncogenesis of SS.	('SSX', 'Gene', '6757', (93, 96))	('SYT', 'Gene', '6760', (89, 92))	('chimeric gene', 'Var', (14, 27))	('SYT', 'Gene', (89, 92))	('SS', 'Phenotype', 'HP:0100242', (145, 147))	('SS', 'Phenotype', 'HP:0100242', (93, 95))	('SSX', 'Gene', (93, 96))
559856	25699089	However, in epithelial cells, expression of high-levels of LMP-1 induces apoptosis, as there is no Bcl-2 expression to mediate the signal.	('LMP-1', 'Gene', '9260', (59, 64))	('expression', 'Var', (30, 40))	('induces', 'Reg', (65, 72))	('apoptosis', 'CPA', (73, 82))	('Bcl-2', 'Gene', (99, 104))	('Bcl-2', 'Gene', '596', (99, 104))	('high-levels', 'Var', (44, 55))	('LMP-1', 'Gene', (59, 64))
559858	25699089	Moreover, co-expression of LMP-1 and Bcl-2 allows epithelial cells to grow under low-serum conditions.	('LMP-1', 'Gene', (27, 32))	('co-expression', 'Var', (10, 23))	('Bcl-2', 'Gene', (37, 42))	('Bcl-2', 'Gene', '596', (37, 42))	('LMP-1', 'Gene', '9260', (27, 32))
559883	25699089	Experimental deletion of such genes from HCMV results in apoptosis.	('deletion', 'Var', (13, 21))	('HCMV', 'Species', '10359', (41, 45))	('apoptosis', 'CPA', (57, 66))
559884	25699089	Fibroblasts at the G0-phase, when infected with high levels of HCMV, undergo less cell death and exhibit a 10-fold increase in Bcl-2 expression.	('expression', 'MPA', (133, 143))	('HCMV', 'Species', '10359', (63, 67))	('cell death', 'CPA', (82, 92))	('HCMV', 'Var', (63, 67))	('increase', 'PosReg', (115, 123))	('Bcl-2', 'Gene', (127, 132))	('Bcl-2', 'Gene', '596', (127, 132))
559885	25699089	When HCMV proteins IE72, pp65, and gB are expressed, markers of mitochondrial apoptosis (cytochrome c and caspase 3) accumulate in cells, indicating dysfunction of programmed cell death.	('cytochrome c', 'Gene', '54205', (89, 101))	('dysfunction', 'Disease', 'MESH:D006331', (149, 160))	('accumulate', 'PosReg', (117, 127))	('dysfunction', 'Disease', (149, 160))	('mitochondrial', 'MPA', (64, 77))	('caspase', 'Gene', (106, 113))	('HCMV', 'Species', '10359', (5, 9))	('cytochrome c', 'Gene', (89, 101))	('caspase', 'Gene', '841', (106, 113))	('pp65', 'Var', (25, 29))	('IE72', 'Var', (19, 23))
559888	25699089	Furthermore, expression of US27 causes upregulation of the pro-survival factor Bcl-x, AP-1 transcription factor components jun and fos, and the IL-6 family cytokine oncostatin M (Figure 1).	('Bcl-x', 'Gene', '598', (79, 84))	('jun', 'MPA', (123, 126))	('upregulation', 'PosReg', (39, 51))	('expression', 'Var', (13, 23))	('Bcl-x', 'Gene', (79, 84))	('US27', 'Gene', (27, 31))	('IL-6', 'Gene', (144, 148))	('fos', 'Gene', '2353', (131, 134))	('fos', 'Gene', (131, 134))	('IL-6', 'Gene', '3569', (144, 148))	('US27', 'Gene', '3077557', (27, 31))
559908	25699089	The exact mechanism by which KSHV Bcl-2 prolongs cell survival is still unclear.	('cell survival', 'CPA', (49, 62))	('prolongs', 'PosReg', (40, 48))	('KSHV', 'Species', '37296', (29, 33))	('KSHV', 'Var', (29, 33))	('Bcl-2', 'Gene', (34, 39))	('Bcl-2', 'Gene', '596', (34, 39))
559913	25699089	Introduction into yeast and human cells demonstrates that KSHV vBcl-2 suppresses Bax toxicity, and it heterodimerizes with human Bcl-2 (huBcl-2) in a yeast two-hybrid system.	('Bcl-2', 'Gene', (138, 143))	('Bcl-2', 'Gene', '596', (138, 143))	('Bax', 'Gene', (81, 84))	('KSHV', 'Var', (58, 62))	('toxicity', 'Disease', (85, 93))	('human', 'Species', '9606', (123, 128))	('toxicity', 'Disease', 'MESH:D064420', (85, 93))	('Bax', 'Gene', '581', (81, 84))	('human', 'Species', '9606', (28, 33))	('heterodimerizes', 'MPA', (102, 117))	('Bcl-2', 'Gene', (129, 134))	('KSHV', 'Species', '37296', (58, 62))	('Bcl-2', 'Gene', '596', (129, 134))	('yeast', 'Species', '4932', (18, 23))	('yeast', 'Species', '4932', (150, 155))	('suppresses', 'NegReg', (70, 80))	('Bcl-2', 'Gene', (64, 69))	('Bcl-2', 'Gene', '596', (64, 69))
559925	25699089	HPV 16/18, a member of supergroup A that has a genome of about 8000 base pairs, is considered a high-risk type of HPV that can cause cervical cancer.	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Var', (0, 3))	('cervical cancer', 'Disease', 'MESH:D002583', (133, 148))	('HPV', 'Species', '10566', (114, 117))	('cause', 'Reg', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cervical cancer', 'Disease', (133, 148))	('HPV 16', 'Species', '333760', (0, 6))
559932	25699089	Since p53 blocks expression of the anti-apoptotic Bcl-2 protein, E6 promotes increased Bcl-2 expression.	('Bcl-2', 'Gene', (87, 92))	('Bcl-2', 'Gene', '596', (87, 92))	('expression', 'MPA', (17, 27))	('Bcl-2', 'Gene', (50, 55))	('expression', 'MPA', (93, 103))	('p53', 'Var', (6, 9))	('Bcl-2', 'Gene', '596', (50, 55))	('increased', 'PosReg', (77, 86))
559940	25699089	Further reports portray E5 as an additional helper to aid the E6/E7 triggered cancer development process.	('aid', 'Gene', (54, 57))	('E6/E7', 'Var', (62, 67))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('aid', 'Gene', '57379', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
559958	25699089	Together with its anti-apoptotic effect, Tax causes genome instability and mutations, deregulates cellular energy exchange, and is able to induce regulatory factors that activate the replication of T-cells, resulting in its uncontrolled replication.	('activate', 'PosReg', (170, 178))	('genome instability', 'MPA', (52, 70))	('uncontrolled replication', 'MPA', (224, 248))	('Tax', 'Chemical', '-', (41, 44))	('causes', 'Reg', (45, 51))	('mutations', 'Var', (75, 84))	('replication', 'MPA', (183, 194))	('deregulates', 'Reg', (86, 97))	('cellular energy exchange', 'MPA', (98, 122))
559986	25699089	Hepatocarcinogenesis results from dysregulation of the balance between cell death and proliferation.	('dysregulation', 'Var', (34, 47))	('Hepatocarcinogenesis', 'Disease', 'MESH:D063646', (0, 20))	('Hepatocarcinogenesis', 'Disease', (0, 20))
560006	25699089	Recent studies have shown that over-expression of SMAD3, a major TGF-beta signalling transducer, reduces susceptibility to HCC by sensitising hepatocytes to apoptosis via Bcl-2 downregulation.	('SMAD3', 'Gene', (50, 55))	('TGF-beta', 'Gene', (65, 73))	('downregulation', 'NegReg', (177, 191))	('HCC', 'Gene', (123, 126))	('sensitising', 'Reg', (130, 141))	('SMAD3', 'Gene', '4088', (50, 55))	('HCC', 'Gene', '619501', (123, 126))	('Bcl-2', 'Gene', '596', (171, 176))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('reduces', 'NegReg', (97, 104))	('over-expression', 'Var', (31, 46))	('Bcl-2', 'Gene', (171, 176))	('susceptibility', 'MPA', (105, 119))	('hepatocytes', 'MPA', (142, 153))	('TGF-beta', 'Gene', '7040', (65, 73))
560013	25699089	When targeting LMP-1 with antisense oligodeoxynucleotides in EBV lymphoblastoid cells, the oligodeoxynucleotides targets codons one to five of the LMP-1 open-reading frames and suppresses the levels of LMP-1 in EBV-positive lymphoblastoid cell lines, inhibiting its function.	('LMP-1', 'Gene', (202, 207))	('LMP-1', 'Gene', '9260', (15, 20))	('LMP-1', 'Gene', (147, 152))	('suppresses', 'NegReg', (177, 187))	('LMP-1', 'Gene', (15, 20))	('EBV', 'Species', '10376', (211, 214))	('oligodeoxynucleotides', 'Var', (91, 112))	('EBV', 'Species', '10376', (61, 64))	('codons', 'Var', (121, 127))	('LMP-1', 'Gene', '9260', (147, 152))	('levels', 'MPA', (192, 198))	('LMP-1', 'Gene', '9260', (202, 207))	('function', 'MPA', (266, 274))
560018	25699089	For instance, HCMV induces expression of Bcl-2 in neuroblastoma cells, resulting in apoptosis inhibition and chemoresistance.	('neuroblastoma cells', 'Disease', (50, 69))	('Bcl-2', 'Gene', (41, 46))	('HCMV', 'Var', (14, 18))	('HCMV', 'Species', '10359', (14, 18))	('Bcl-2', 'Gene', '596', (41, 46))	('neuroblastoma cells', 'Disease', 'MESH:D009447', (50, 69))	('apoptosis inhibition', 'CPA', (84, 104))	('chemoresistance', 'CPA', (109, 124))	('neuroblastoma', 'Phenotype', 'HP:0003006', (50, 63))	('expression', 'MPA', (27, 37))
560046	25699089	An extensive review of various targeted treatment regimens suggest a combination of arsenic, IFN and Zidovudine might be successful in ATLL treatment, as HTLV-1 load is decreased by Zidovudine, and Tax is degraded by arsenic/IFN.	('Tax', 'Chemical', '-', (198, 201))	('arsenic', 'Chemical', 'MESH:D001151', (217, 224))	('HTLV-1', 'Gene', (154, 160))	('Zidovudine', 'Chemical', 'MESH:D015215', (182, 192))	('Tax', 'MPA', (198, 201))	('load', 'MPA', (161, 165))	('HTLV-1', 'Species', '11908', (154, 160))	('degraded', 'NegReg', (205, 213))	('arsenic', 'Chemical', 'MESH:D001151', (84, 91))	('Zidovudine', 'Chemical', 'MESH:D015215', (101, 111))	('decreased', 'NegReg', (169, 178))	('Zidovudine', 'Var', (182, 192))
560053	25699089	For instance, EAPB0203, derived from imidazo [1,2a] quinoxaline, inhibitscIAP1 and Bcl-xL in malignant T-cells with and without the virus present, and does not have the proinflammatory effect of imiquimod.	('EAPB0203', 'Var', (14, 22))	('Bcl-xL', 'Gene', '598', (83, 89))	('Bcl-xL', 'Gene', (83, 89))	('imidazo [1,2a] quinoxaline', 'Chemical', '-', (37, 63))	('inhibitscIAP1', 'NegReg', (65, 78))
560055	25699089	The effect of EAPB0203 is reversed by treatment with caspase inhibitors.	('caspase', 'Gene', '841', (53, 60))	('caspase', 'Gene', (53, 60))	('EAPB0203', 'Var', (14, 22))
560057	25699089	This promising drug for the treatment of ATLL interacts with the BH3 binding groove of Bcl-2, Bcl-xL, and Bcl-w. ABT737 induces apoptosis in the ATLL cells of mice, both in vitro and in vivo.	('Bcl-2', 'Gene', (87, 92))	('Bcl-2', 'Gene', '596', (87, 92))	('Bcl-xL', 'Gene', (94, 100))	('induces', 'Reg', (120, 127))	('Bcl-w', 'Gene', '599', (106, 111))	('Bcl-xL', 'Gene', '598', (94, 100))	('BH3', 'Chemical', 'MESH:C006008', (65, 68))	('Bcl-w', 'Gene', (106, 111))	('mice', 'Species', '10090', (159, 163))	('ABT737', 'Chemical', 'MESH:C501332', (113, 119))	('ABT737', 'Var', (113, 119))	('apoptosis', 'CPA', (128, 137))
560067	25699089	Treating with a combination of the HCV protease inhibitor VX -950 and pegylated interferon-alpha displays an antiviral effect; however, results remain inconsistent.	('pegylated', 'Var', (70, 79))	('antiviral effect', 'MPA', (109, 125))	('HCV', 'Species', '11103', (35, 38))
560182	23288701	Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein Oncogenic rearrangements of the TFE3 transcription factor gene are found in two distinct human cancers.	('ASPSCR1', 'Gene', (136, 143))	('cancer', 'Disease', (263, 269))	('human', 'Species', '9606', (257, 262))	('cancer', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('TFE3', 'Gene', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ASPS', 'Gene', '79058', (136, 140))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('ASPS', 'Phenotype', 'HP:0012218', (136, 140))	('TFE3', 'Gene', '7030', (200, 204))	('cancers', 'Disease', (263, 270))	('TFE3', 'Gene', (144, 148))	('TFE3', 'Gene', '7030', (144, 148))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ASPSCR1', 'Gene', '79058', (136, 143))	('rearrangements', 'Var', (178, 192))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('ASPS', 'Gene', (136, 140))
560183	23288701	These include ASPSCR1-TFE3 in all cases of alveolar soft part sarcoma (ASPS) and ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3 and others in a subset of paediatric and adult RCCs.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('PRCC', 'Gene', (95, 99))	('RCC', 'Disease', (163, 166))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (52, 69))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (43, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('ASPSCR1-TFE3', 'Var', (14, 26))	('ASPS', 'Phenotype', 'HP:0012218', (81, 85))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (43, 69))	('PRCC', 'Gene', '5546', (95, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', (96, 99))	('ASPS', 'Phenotype', 'HP:0012218', (71, 75))	('alveolar soft part sarcoma', 'Disease', (43, 69))	('ASPS', 'Phenotype', 'HP:0012218', (14, 18))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('SFPQ', 'Gene', '6421', (106, 110))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('SFPQ', 'Gene', (106, 110))	('ASPSCR1-TFE3', 'Var', (81, 93))	('sarcoma', 'Disease', (62, 69))
560190	23288701	Notably, the only generally available human cancer cell line endogenously expressing ASPSCR1-TFE3 is derived from such a kidney tumour (FU-UR-1).	('kidney tumour', 'Disease', 'MESH:D007680', (121, 134))	('kidney tumour', 'Disease', (121, 134))	('kidney tumour', 'Phenotype', 'HP:0009726', (121, 134))	('ASPS', 'Phenotype', 'HP:0012218', (85, 89))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('ASPSCR1-TFE3', 'Var', (85, 97))
560202	23288701	ASPSCR1-TFE3 was a stronger activator of the uE3 reporter compared to TFE3 in the 293 T, COS7 and MCF7 cell lines (Figure 1B).	('stronger', 'PosReg', (19, 27))	('ASPSCR1-TFE3', 'Var', (0, 12))	('activator', 'MPA', (28, 37))	('uE3 reporter', 'Gene', (45, 57))	('ASPS', 'Phenotype', 'HP:0012218', (0, 4))	('MCF7', 'CellLine', 'CVCL:0031', (98, 102))
560210	23288701	We confirmed a decrease in cell proliferation when the following genes were knocked down: ANGPTL2 , LGALS3BP, NAMPT, PCGF1 , PRICKLE3 , PTPRF, SLC29A1 , SOCS3 , SV2B, TYRO3 and UPP1 (Table 2, Figure 7).	('SOCS3', 'Gene', (153, 158))	('decrease', 'NegReg', (15, 23))	('NAMPT', 'Gene', '10135', (110, 115))	('PTPRF', 'Gene', (136, 141))	('cell proliferation', 'CPA', (27, 45))	('SV2B', 'Gene', (161, 165))	('SOCS3', 'Gene', '9021', (153, 158))	('SLC29A1', 'Gene', '2030', (143, 150))	('knocked down', 'Var', (76, 88))	('PCGF1', 'Gene', '84759', (117, 122))	('ANGPTL2', 'Gene', (90, 97))	('NAMPT', 'Gene', (110, 115))	('PCGF1', 'Gene', (117, 122))	('PTPRF', 'Gene', '5792', (136, 141))	('TYRO3', 'Gene', (167, 172))	('PRICKLE3', 'Gene', (125, 133))	('PRICKLE3', 'Gene', '4007', (125, 133))	('LGALS3BP', 'Gene', (100, 108))	('SV2B', 'Gene', '9899', (161, 165))	('ANGPTL2', 'Gene', '23452', (90, 97))	('LGALS3BP', 'Gene', '3959', (100, 108))	('TYRO3', 'Gene', '7301', (167, 172))	('SLC29A1', 'Gene', (143, 150))
560282	21740480	Two KSHV seronegatives had Elispot responses to both K8.1 and LANA (Table 1, Figure 1); the other 13 KSHV seronegatives had no responses to the KSHV peptide pools.	('KSHV', 'Species', '37296', (4, 8))	('KSHV', 'Species', '37296', (101, 105))	('KS', 'Phenotype', 'HP:0100726', (4, 6))	('Elispot responses', 'MPA', (27, 44))	('KS', 'Phenotype', 'HP:0100726', (101, 103))	('LANA', 'Gene', (62, 66))	('LANA', 'Gene', '4961527', (62, 66))	('K8.1', 'Var', (53, 57))	('KS', 'Phenotype', 'HP:0100726', (144, 146))	('KSHV', 'Species', '37296', (144, 148))
560287	21740480	As noted previously, the KSHV seronegatives tended to have stronger DTH responses, particularly in the thigh, compared to the cKS cases and KSHV+/cKS- controls.	('KSHV', 'Species', '37296', (25, 29))	('KSHV', 'Var', (25, 29))	('KSHV', 'Species', '37296', (140, 144))	('DTH', 'Phenotype', 'HP:0002972', (68, 71))	('cKS', 'Chemical', '-', (126, 129))	('KS', 'Phenotype', 'HP:0100726', (147, 149))	('KS', 'Phenotype', 'HP:0100726', (140, 142))	('KS', 'Phenotype', 'HP:0100726', (127, 129))	('KS', 'Phenotype', 'HP:0100726', (25, 27))	('stronger', 'PosReg', (59, 67))	('DTH responses', 'MPA', (68, 81))	('cKS', 'Chemical', '-', (146, 149))
560288	21740480	As shown in Table 2, compared to the KSHV seronegatives, cKS was associated with weaker DTH response in the thigh (OR 0.71, 95% CI 0.55-0.94, P=0.01), with stronger DTH in the forearm (OR 1.35, 95% CI 1.02-1.80, P=0.04), and with the number of KSHV Elispot responses to K8.1, LANA or both (OR 5.13, 95% CI 0.86-30.77, P=0.07).	('cKS', 'Chemical', '-', (57, 60))	('DTH response', 'MPA', (88, 100))	('LANA', 'Gene', (276, 280))	('DTH', 'MPA', (165, 168))	('KSHV', 'Species', '37296', (244, 248))	('weaker', 'NegReg', (81, 87))	('LANA', 'Gene', '4961527', (276, 280))	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('KS', 'Phenotype', 'HP:0100726', (244, 246))	('DTH', 'Phenotype', 'HP:0002972', (165, 168))	('KS', 'Phenotype', 'HP:0100726', (37, 39))	('KSHV', 'Species', '37296', (37, 41))	('cKS', 'Var', (57, 60))	('stronger', 'PosReg', (156, 164))	('DTH', 'Phenotype', 'HP:0002972', (88, 91))
560290	21740480	The odds of Elispot responses to KSHV peptides were 3.7-fold higher in KSHV+/cKS- controls (OR 18.77) than in cKS cases (OR 5.13), but this difference was not statistically significant given the small sample size and very wide confidence intervals (Table 1).	('KS', 'Phenotype', 'HP:0100726', (78, 80))	('higher', 'PosReg', (61, 67))	('cKS', 'Chemical', '-', (110, 113))	('KS', 'Phenotype', 'HP:0100726', (33, 35))	('KSHV', 'Species', '37296', (33, 37))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('KSHV+/cKS-', 'Var', (71, 81))	('KS', 'Phenotype', 'HP:0100726', (71, 73))	('KSHV', 'Species', '37296', (71, 75))	('cKS', 'Chemical', '-', (77, 80))	('Elispot responses', 'MPA', (12, 29))
560291	21740480	In a model (not shown) that considered K8.1 and LANA Elispot responses separately, the odds of cKS were higher with K8.1 than LANA (OR 12.74 and 2.82, respectively), as were the odds of KSHV+/cKS- (OR 45.46 and 10.51 with K8.1 and LANA, respectively); the associations with forearm and thigh DTH in both cKS cases and KSHV+/cKS- controls in this model were almost identical to those presented in Table 1.	('cKS', 'Chemical', '-', (324, 327))	('KS', 'Phenotype', 'HP:0100726', (186, 188))	('KS', 'Phenotype', 'HP:0100726', (305, 307))	('K8.1', 'Var', (116, 120))	('DTH', 'Phenotype', 'HP:0002972', (292, 295))	('KS', 'Phenotype', 'HP:0100726', (193, 195))	('LANA', 'Gene', (231, 235))	('LANA', 'Gene', '4961527', (231, 235))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('KSHV', 'Species', '37296', (186, 190))	('LANA', 'Gene', (48, 52))	('cKS', 'Chemical', '-', (304, 307))	('KS', 'Phenotype', 'HP:0100726', (318, 320))	('LANA', 'Gene', '4961527', (48, 52))	('cKS', 'Chemical', '-', (192, 195))	('cKS', 'Disease', (304, 307))	('LANA', 'Gene', (126, 130))	('LANA', 'Gene', '4961527', (126, 130))	('KSHV', 'Species', '37296', (318, 322))	('cKS', 'Chemical', '-', (95, 98))
560312	21740480	In addition, KSHV may suppress the generation of hematopoietic progenitor cells.	('KSHV', 'Var', (13, 17))	('suppress', 'NegReg', (22, 30))	('KS', 'Phenotype', 'HP:0100726', (13, 15))	('KSHV', 'Species', '37296', (13, 17))
560315	21740480	KSHV-LANA and KSHV-K8.1 Elispot responses were highly concordant in the KSHV+/cKS- and seronegative control groups.	('LANA', 'Gene', (5, 9))	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Species', '37296', (14, 18))	('KSHV+/cKS-', 'Var', (72, 82))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('Elispot responses', 'CPA', (24, 41))	('LANA', 'Gene', '4961527', (5, 9))	('KSHV', 'Species', '37296', (72, 76))	('KS', 'Phenotype', 'HP:0100726', (72, 74))	('KS', 'Phenotype', 'HP:0100726', (79, 81))	('KS', 'Phenotype', 'HP:0100726', (14, 16))	('cKS', 'Chemical', '-', (78, 81))
560395	21826194	Sarcomas with specific translocations, with point mutations (deletion, insertion, duplication) or with gene amplifications represented respectively 35%, 38% and 27% of all cases with known molecular alterations.	('point mutations', 'Var', (44, 59))	('insertion', 'Var', (71, 80))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('translocations', 'Var', (23, 37))	('duplication', 'Var', (82, 93))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
560447	21826194	Molecular characterization already has clinical implications for some subtypes of sarcoma, either for prognosis (e.g., poor prognosis for patients with KIT exon 11 deletion in GIST, FKHR-PAX3 expression in metastatic rhabdomyosarcoma and SYT-SSX1 fusion type in synovial sarcoma), treatment (adjuvant radiotherapy), or response to treatment (e.g.	('FKHR', 'Gene', (182, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('metastatic rhabdomyosarcoma', 'Phenotype', 'HP:0200059', (206, 233))	('rhabdomyosarcoma', 'Disease', (217, 233))	('men', 'Species', '9606', (336, 339))	('PAX3', 'Gene', (187, 191))	('SYT', 'Gene', (238, 241))	('FKHR', 'Gene', '2308', (182, 186))	('sarcoma', 'Disease', 'MESH:D012509', (226, 233))	('KIT exon 11', 'Gene', (152, 163))	('synovial sarcoma', 'Disease', (262, 278))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (217, 233))	('sarcoma', 'Disease', (226, 233))	('patients', 'Species', '9606', (138, 146))	('SSX1', 'Gene', '6756', (242, 246))	('PAX3', 'Gene', '5077', (187, 191))	('SSX1', 'Gene', (242, 246))	('synovial sarcoma', 'Disease', 'MESH:D013584', (262, 278))	('men', 'Species', '9606', (286, 289))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (217, 233))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('SYT', 'Gene', '6760', (238, 241))	('deletion', 'Var', (164, 172))	('sarcoma', 'Disease', (82, 89))	('sarcoma', 'Disease', 'MESH:D012509', (271, 278))	('GIST', 'Phenotype', 'HP:0100723', (176, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('sarcoma', 'Disease', (271, 278))	('GIST', 'Gene', (176, 180))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (262, 278))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
560448	21826194	better response to imatinib for GIST with exon 11 mutation than with exon 9 mutation).	('GIST', 'Phenotype', 'HP:0100723', (32, 36))	('imatinib', 'Chemical', 'MESH:D000068877', (19, 27))	('exon 11 mutation', 'Var', (42, 58))	('response to imatinib', 'MPA', (7, 27))
560449	21826194	In our population-based study, the incidence of PDGFRA mutated GIST was higher than previously reported in patients with advanced disease indicating that tumors bearing mutant PDGFRA have a more indolent behaviour.	('tumors', 'Disease', (154, 160))	('PDGFRA', 'Gene', '5156', (48, 54))	('PDGFRA', 'Gene', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('mutated', 'Var', (55, 62))	('PDGFRA', 'Gene', '5156', (176, 182))	('PDGFRA', 'Gene', (176, 182))	('indolent behaviour', 'MPA', (195, 213))	('GIST', 'Phenotype', 'HP:0100723', (63, 67))	('mutant', 'Var', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('patients', 'Species', '9606', (107, 115))
560450	21826194	demonstrated that rather than histology, the key factor in terms of biology and clinical progression of rhabdomyosarcoma was the presence or absence of a fusion gene.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (104, 120))	('fusion gene', 'Var', (154, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (104, 120))	('rhabdomyosarcoma', 'Disease', (104, 120))
560456	21826194	initiating role of mutation of KIT or PDGFRA receptors).	('PDGFRA', 'Gene', (38, 44))	('mutation', 'Var', (19, 27))	('KIT', 'Protein', (31, 34))	('PDGFRA', 'Gene', '5156', (38, 44))
560462	21826194	Specific molecular events defined sarcoma histological types: most pediatric-type sarcoma are associated with translocation due to the high incidence of genetic factors unlike adult-type sarcoma, with more complexe karyotypes, for which environmental factors will tend to influence more often.	('men', 'Species', '9606', (244, 247))	('sarcoma', 'Disease', (34, 41))	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('translocation', 'Var', (110, 123))	('sarcoma', 'Disease', (187, 194))	('associated', 'Reg', (94, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('sarcoma', 'Disease', (82, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
560473	33030103	In vitro, SENP3 knockdown in OS cancer cells inhibited cell proliferation, migration, and invasion and induced apoptosis.	('OS', 'Phenotype', 'HP:0002669', (29, 31))	('inhibited', 'NegReg', (45, 54))	('SENP3', 'Gene', '26168', (10, 15))	('knockdown', 'Var', (16, 25))	('OS cancer', 'Disease', (29, 38))	('cell proliferation', 'CPA', (55, 73))	('SENP3', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('migration', 'CPA', (75, 84))	('induced', 'Reg', (103, 110))	('apoptosis', 'CPA', (111, 120))	('invasion', 'CPA', (90, 98))	('OS cancer', 'Disease', 'MESH:C567932', (29, 38))
560476	33030103	Finally, E-Cad expression was increased in the OS cell line MG63 following methylation, and the cell proliferation, migration, and invasion capacity were decreased.	('decreased', 'NegReg', (154, 163))	('E-Cad', 'Gene', '999', (9, 14))	('methylation', 'Var', (75, 86))	('cell proliferation', 'CPA', (96, 114))	('E-Cad', 'Gene', (9, 14))	('expression', 'MPA', (15, 25))	('invasion capacity', 'CPA', (131, 148))	('OS', 'Phenotype', 'HP:0002669', (47, 49))	('migration', 'CPA', (116, 125))	('increased', 'PosReg', (30, 39))
560490	33030103	In addition, the dysregulated expression of the non-coding RNAs involved in regulating EMT progression plays a crucial role in human EMT-induced carcinogenesis.	('expression', 'MPA', (30, 40))	('RNAs', 'Gene', (59, 63))	('human', 'Species', '9606', (127, 132))	('carcinogenesis', 'Disease', 'MESH:D063646', (145, 159))	('dysregulated', 'Var', (17, 29))	('carcinogenesis', 'Disease', (145, 159))
560517	33030103	Based on the TCGA data, the high expression of SENP3 in sarcoma patients indicated a shorter disease-free survival (Figure 1D) and overall survival (Figure 1E).	('shorter', 'NegReg', (85, 92))	('patients', 'Species', '9606', (64, 72))	('SENP3', 'Gene', (47, 52))	('sarcoma', 'Disease', (56, 63))	('overall survival', 'CPA', (131, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('disease-free survival', 'CPA', (93, 114))	('high', 'Var', (28, 32))	('SENP3', 'Gene', '26168', (47, 52))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))
560527	33030103	Western blotting analysis showed that SENP3 overexpression in MG63 cells decreased the protein expression of E-Cad, and silencing SENP3 expression in MG63 cells increased the protein expression of E-Cad (Figure 2F).	('SENP3', 'Gene', '26168', (130, 135))	('SENP3', 'Gene', (130, 135))	('decreased', 'NegReg', (73, 82))	('SENP3', 'Gene', '26168', (38, 43))	('E-Cad', 'Gene', '999', (197, 202))	('SENP3', 'Gene', (38, 43))	('protein expression', 'MPA', (87, 105))	('E-Cad', 'Gene', '999', (109, 114))	('E-Cad', 'Gene', (197, 202))	('silencing', 'Var', (120, 129))	('increased', 'PosReg', (161, 170))	('E-Cad', 'Gene', (109, 114))	('protein expression', 'MPA', (175, 193))
560531	33030103	The effects of silencing or overexpression of SENP3 on cell invasion and migration were examined by Transwell and wound-healing assays, respectively.	('silencing', 'Var', (15, 24))	('SENP3', 'Gene', (46, 51))	('SENP3', 'Gene', '26168', (46, 51))	('overexpression', 'PosReg', (28, 42))
560532	33030103	Silencing SENP3 expression decreased cell invasion and migration, whereas overexpressing SENP3 expression increased cell migration (Figure 3A and B).	('SENP3', 'Gene', '26168', (89, 94))	('SENP3', 'Gene', '26168', (10, 15))	('SENP3', 'Gene', (89, 94))	('decreased', 'NegReg', (27, 36))	('Silencing', 'Var', (0, 9))	('increased', 'PosReg', (106, 115))	('SENP3', 'Gene', (10, 15))	('cell invasion', 'CPA', (37, 50))	('cell migration', 'CPA', (116, 130))
560549	33030103	There is growing evidence that transcription factors participate in the biological processes of EMT and that abnormal expression of some transcription factors can promote malignant tumor occurrence and development by inducing EMT progression, including ZEB1, STAT3, TWIST1, and FOXQ1.	('FOXQ1', 'Gene', (278, 283))	('STAT3', 'Gene', '6774', (259, 264))	('malignant tumor', 'Disease', 'MESH:D009369', (171, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('inducing', 'Reg', (217, 225))	('ZEB1', 'Gene', '6935', (253, 257))	('STAT3', 'Gene', (259, 264))	('FOXQ1', 'Gene', '94234', (278, 283))	('ZEB1', 'Gene', (253, 257))	('EMT progression', 'CPA', (226, 241))	('TWIST1', 'Gene', (266, 272))	('abnormal', 'Var', (109, 117))	('expression', 'MPA', (118, 128))	('TWIST1', 'Gene', '7291', (266, 272))	('promote', 'PosReg', (163, 170))	('malignant tumor', 'Disease', (171, 186))
560553	33030103	Downregulation of E-Cad promotes tumor invasion and migration, and post-translational modification is the main manner by which E-cad transcriptional activity is regulated, including acetylation, methylation, and poly- and mono-ubiquitination.	('methylation', 'MPA', (195, 206))	('migration', 'CPA', (52, 61))	('E-Cad', 'Gene', (18, 23))	('E-cad', 'Gene', '999', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Downregulation', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('acetylation', 'MPA', (182, 193))	('E-cad', 'Gene', (127, 132))	('promotes', 'PosReg', (24, 32))	('tumor', 'Disease', (33, 38))	('E-Cad', 'Gene', '999', (18, 23))
560567	30486883	The hallmark of DSRCT is the specific t(1;22)(p13;q12) translocation that leads to the fusion of the Ewing sarcoma RNA binding protein 1 (EWSR1) and Wilm's tumor suppressor (WT1) genes.	("Wilm's tumor", 'Disease', 'MESH:D009396', (149, 161))	('EWSR1', 'Gene', (138, 143))	('WT1', 'Gene', '7490', (174, 177))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('WT1', 'Gene', (174, 177))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('EWSR1', 'Gene', '2130', (138, 143))	('t(1;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (149, 161))	('leads to', 'Reg', (74, 82))	('fusion', 'Var', (87, 93))	('Ewing sarcoma', 'Disease', (101, 114))	("Wilm's tumor", 'Disease', (149, 161))	('DSRCT', 'Disease', (16, 21))
560568	30486883	The MET proto-oncogene, receptor tyrosine kinase (c-MET) N375S mutation (the most frequently encountered in lung carcinoma) and two mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3KCA) have been described in 2 of 10 pre-treated DSRCTs interrogated using a single-gene polymerase chain reaction (PCR)-based assay.	('PI3KCA', 'Gene', (217, 223))	('c-MET', 'Gene', '4233', (50, 55))	('lung carcinoma', 'Disease', (108, 122))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (145, 215))	('c-MET', 'Gene', (50, 55))	('N375S', 'Var', (57, 62))	('MET proto-oncogene, receptor tyrosine kinase', 'Gene', '4233', (4, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('lung carcinoma', 'Disease', 'MESH:D008175', (108, 122))	('N375S', 'SUBSTITUTION', 'None', (57, 62))
560569	30486883	Evidence indicating the involvement of epigenetic regulators has been reported in two cases: the first, investigated using immunohistochemistry (IHC), showed the complete loss of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1/INI) protein, and the other, investigated using targeted next-generation sequencing (NGS), showed a mutation in AT-rich interaction domain 1A (ARID1A) gene corresponding to a variant of unknown significance.	('SMARCB1', 'Gene', '6598', (278, 285))	('ARID1A', 'Gene', '8289', (429, 435))	('SMARCB1', 'Gene', (278, 285))	('INI', 'Gene', '84844', (286, 289))	('ARID1A', 'Gene', (429, 435))	('loss', 'NegReg', (171, 175))	('SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1', 'Gene', '6598', (179, 276))	('INI', 'Gene', (286, 289))	('mutation', 'Var', (386, 394))
560570	30486883	More recently, whole-exome sequencing (WES) analysis of a thoroughly investigated, pre-treated case revealed the presence of 15 acquired somatic mutations, 7 of which were regulated by the same lymphoid enhancer binding factor 1 (LEF1) transcription factor which, in addition to being involved in the Wnt/beta-catenin signalling pathway, is a facilitator of the epithelial-mesenchymal transition (EMT).	('transcription factor', 'Gene', '2114', (236, 256))	('mutations', 'Var', (145, 154))	('LEF1', 'Gene', '51176', (230, 234))	('lymphoid enhancer binding factor 1', 'Gene', (194, 228))	('transcription factor', 'Gene', (236, 256))	('epithelial-mesenchymal transition', 'CPA', (362, 395))	('lymphoid enhancer binding factor 1', 'Gene', '51176', (194, 228))	('LEF1', 'Gene', (230, 234))	('beta-catenin', 'Gene', (305, 317))	('beta-catenin', 'Gene', '1499', (305, 317))
560571	30486883	Finally, amplification of aurora kinase B (AURKB) and MCL1, BCL2 family apoptosis regulator 1 (MCL1) has been reported in one case of DSRCT interrogated using targeted NGS, and gains in chromosome 5 and 18 and loss at 13q have been detected in one case interrogated using WES and comparative genomic hybridization.	('AURKB', 'Gene', (43, 48))	('MCL1', 'Gene', '4170', (54, 58))	('MCL1', 'Gene', '4170', (95, 99))	('amplification', 'Var', (9, 22))	('MCL1', 'Gene', (54, 58))	('MCL1', 'Gene', (95, 99))	('aurora kinase B', 'Gene', '9212', (26, 41))	('gains', 'PosReg', (177, 182))	('aurora kinase B', 'Gene', (26, 41))	('BCL2', 'Gene', '596', (60, 64))	('AURKB', 'Gene', '9212', (43, 48))	('loss', 'NegReg', (210, 214))	('BCL2', 'Gene', (60, 64))
560579	30486883	Concordance and cross sample contamination was assessed using the computational method Conpair which detects cross sample contamination among tumor-normal pairs at levels as low as 0.1%, even in presence of copy number changes.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('presence', 'Reg', (195, 203))	('copy number changes', 'Var', (207, 226))	('cross sample contamination', 'MPA', (109, 135))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
560583	30486883	Mutations were analyzed for presence in COSMIC and in the Cancer Census collection of genes which contain mutations that have been causally implicated in cancer (downloaded on 18 February 2018 from http://cancer.sanger.ac.uk/census).	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cancer Census', 'Disease', 'MESH:D009369', (58, 71))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('Cancer Census', 'Disease', (58, 71))
560596	30486883	A damaging missense mutation in ATR serine/threonine kinase (ATR), one of the two core genes of DDR (the other is serine/threonine kinase, ATM), was found in DSRCT4 of the MErT group.	('ATM', 'Gene', (139, 142))	('missense mutation', 'Var', (11, 28))	('ATR', 'Gene', '545', (61, 64))	('ATR', 'Gene', (61, 64))	('ATM', 'Gene', '472', (139, 142))	('ATR', 'Gene', '545', (32, 35))	('ATR', 'Gene', (32, 35))
560601	30486883	4b), being mutations in BCL2-associated transcription factor 1 (BCLAF1) and cleavage and polyadenylation factor subunit (PCF11) genes predicted to be damaging.	('mutations', 'Var', (11, 20))	('PCF11', 'Gene', (121, 126))	('BCLAF1', 'Gene', '9774', (64, 70))	('PCF11', 'Gene', '51585', (121, 126))	('BCL2-associated transcription factor 1', 'Gene', '9774', (24, 62))	('BCLAF1', 'Gene', (64, 70))	('BCL2-associated transcription factor 1', 'Gene', (24, 62))
560603	30486883	In particular, ADAD1 function has not yet been deciphered but, on the basis of the hypothesis that the adenosine deaminase acting on RNA (ADAR) enzyme family controls RNA editing, an alteration in one of its members may affect a wide range of RNA processing activities.	('ADAR', 'Gene', '103', (138, 142))	('RNA processing activities', 'MPA', (243, 268))	('ADAD1', 'Gene', '132612', (15, 20))	('adenosine deaminase acting on RNA', 'Gene', '103', (103, 136))	('ADAD1', 'Gene', (15, 20))	('ADAR', 'Gene', (138, 142))	('RNA editing', 'MPA', (167, 178))	('adenosine deaminase acting on RNA', 'Gene', (103, 136))	('alteration', 'Var', (183, 193))	('affect', 'Reg', (220, 226))
560604	30486883	The function of HIV-1 Tat specific factor 1 (HTATSF) gene is also largely unknown, but its mutation has been reported to parallel the decreased expression of many genes.	('decreased', 'NegReg', (134, 143))	('mutation', 'Var', (91, 99))	('expression', 'MPA', (144, 154))	('HIV-1', 'Species', '11676', (16, 21))	('HTATSF', 'Gene', (45, 51))
560606	30486883	Three out of ZNF mutated genes (ZNF254, ZNF600, and ZNF225) were annotated among the RBP subset because they belong to the class of Cys2-His2 (C2H2) ZNFs and thus are expected to act consistently.	('Cys2-His2', 'Gene', (132, 141))	('RBP', 'Gene', (85, 88))	('ZNF254', 'Gene', (32, 38))	('Cys2-His2', 'Gene', '3347', (132, 141))	('RBP', 'Gene', '57794', (85, 88))	('ZNF600', 'Gene', '162966', (40, 46))	('ZNF600', 'Gene', (40, 46))	('ZNF', 'Gene', (13, 16))	('ZNF225', 'Gene', (52, 58))	('ZNFs', 'Chemical', '-', (149, 153))	('ZNF225', 'Gene', '7768', (52, 58))	('ZNF254', 'Gene', '9534', (32, 38))	('mutated', 'Var', (17, 24))
560607	30486883	Finally, two additional genes, U2 small nuclear RNA auxiliary factor (U2AF1) and RNA binding motif protein 45 (RBM45), were found mutated at an intron site, and such mutations might have a negative impact on translational efficiency, as reported.	('U2AF1', 'Gene', (70, 75))	('mutations', 'Var', (166, 175))	('negative impact', 'NegReg', (189, 204))	('RBM45', 'Gene', (111, 116))	('U2AF1', 'Gene', '7307', (70, 75))	('RNA binding motif protein 45', 'Gene', '129831', (81, 109))	('RBM45', 'Gene', '129831', (111, 116))	('mutated', 'Var', (130, 137))	('translational efficiency', 'MPA', (208, 232))	('RNA binding motif protein 45', 'Gene', (81, 109))
560608	30486883	The genes affected by a damaging mutation were ribonucleotide reductase regulatory subunit M2 (RRM2), whose deregulation was reported to impair a key step in DNA synthesis; ARID1A, whose wild type-encoded protein acts as an epigenetic regulator; eukaryotic translation initiation factor 4 gamma 1 (EIF4G1), whose deregulation could negatively affect the correct mRNA circularization and/or translation activity downstream of serine/threonine-protein kinase mTOR; ZNF708, that, like RBPs, is reported to act as interaction module with DNA, RNA, proteins, and other molecules and whose deregulation could affect gene transcription, translation, and mRNA trafficking.	('ribonucleotide reductase regulatory subunit M2', 'Gene', (47, 93))	('mTOR', 'Gene', (457, 461))	('EIF4G1', 'Gene', '1981', (298, 304))	('mRNA circularization', 'MPA', (362, 382))	('gene transcription', 'MPA', (610, 628))	('RRM2', 'Gene', '6241', (95, 99))	('ZNF708', 'Gene', (463, 469))	('translation', 'MPA', (630, 641))	('eukaryotic translation initiation factor 4 gamma 1', 'Gene', '1981', (246, 296))	('mTOR', 'Gene', '2475', (457, 461))	('RBP', 'Gene', '57794', (482, 485))	('RRM2', 'Gene', (95, 99))	('deregulation', 'Var', (584, 596))	('mutation', 'Var', (33, 41))	('ZNF708', 'Gene', '7562', (463, 469))	('EIF4G1', 'Gene', (298, 304))	('translation activity', 'MPA', (390, 410))	('interaction', 'Interaction', (510, 521))	('ARID1A', 'Gene', (173, 179))	('affect', 'Reg', (603, 609))	('ribonucleotide reductase regulatory subunit M2', 'Gene', '6241', (47, 93))	('ARID1A', 'Gene', '8289', (173, 179))	('eukaryotic translation initiation factor 4 gamma 1', 'Gene', (246, 296))	('RBP', 'Gene', (482, 485))	('mRNA trafficking', 'MPA', (647, 663))
560610	30486883	Four genes [transgelin (TAGLN1), ubiquitin specific peptidase 9, X chromosome (USP9X), WW and C2 domain containing 1 (WWC1), and transducing beta like 1 X-linked receptor 1 (TBL1XR1)], harbouring missense damaging mutations, were found in the MErT group, strongly supporting the hypothesis that such mutations induced changes consistent with an epithelial-like phenotype.	('mutations', 'Var', (300, 309))	('transgelin', 'Gene', '6876', (12, 22))	('USP9X', 'Gene', (79, 84))	('TAGLN1', 'Gene', (24, 30))	('TBL1XR1', 'Gene', (174, 181))	('WWC1', 'Gene', '23286', (118, 122))	('TAGLN1', 'Gene', '6876', (24, 30))	('WWC1', 'Gene', (118, 122))	('USP9X', 'Gene', '8239', (79, 84))	('TBL1XR1', 'Gene', '79718', (174, 181))	('transgelin', 'Gene', (12, 22))
560613	30486883	Interestingly, aberrant expression of ACTL8, a cancer/testis antigen gene, is reported to associate with stem cell-like enrichment and an EMT signature, both of which are characteristics of DSRCT.	('stem cell-like enrichment', 'CPA', (105, 130))	('aberrant expression', 'Var', (15, 34))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('ACTL8', 'Gene', (38, 43))	('ACTL8', 'Gene', '81569', (38, 43))	('cancer', 'Disease', (47, 53))	('EMT signature', 'CPA', (138, 151))	('associate', 'Interaction', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
560614	30486883	As GRM7, it has been proposed that its silencing may provide a further mechanism that regulates MErT/EMT by inhibiting TGFbeta/SNAIL via AMPK activation.	('MErT/EMT', 'CPA', (96, 104))	('GRM7', 'Gene', '2917', (3, 7))	('GRM7', 'Gene', (3, 7))	('silencing', 'Var', (39, 48))	('AMPK', 'MPA', (137, 141))	('inhibiting', 'NegReg', (108, 118))	('SNAIL', 'Gene', (127, 132))	('SNAIL', 'Gene', '6615', (127, 132))	('regulates', 'MPA', (86, 95))
560615	30486883	A non-damaging missense mutation was detected in dehydrodolichyl diphosphate synthase subunit (NUS1) gene in a case belonging to the EMT group.	('NUS1', 'Gene', '116150', (95, 99))	('missense mutation', 'Var', (15, 32))	('NUS1', 'Gene', (95, 99))
560616	30486883	Furthermore, missense non-damaging mutations were observed in two genes, deasmoglein2 (DSG2) and calcium-responsive transcription factor (CARF), whose involvement in MErT is indirectly suggested: for DSG2, by its belonging to a cadherin cell adhesion molecule superfamily; for CARF, by its contribution to WNT signalling activation.	('missense', 'Var', (13, 21))	('CARF', 'Gene', (138, 142))	('calcium-responsive transcription factor', 'Gene', '79800', (97, 136))	('calcium-responsive transcription factor', 'Gene', (97, 136))	('CARF', 'Gene', '79800', (277, 281))	('DSG2', 'Gene', (200, 204))	('CARF', 'Gene', (277, 281))	('CARF', 'Gene', '79800', (138, 142))	('mutations', 'Var', (35, 44))
560617	30486883	Regarding the non-damaging splice-site mutation in TYRO3 protein tyrosine kinase (TYRO3), the aberrant SNAIL-mediated expression of TYRO3 is reported to be associated with EMT.	('TYRO3', 'Gene', '7301', (82, 87))	('TYRO3', 'Gene', (51, 56))	('EMT', 'Disease', (172, 175))	('associated', 'Reg', (156, 166))	('TYRO3', 'Gene', '7301', (51, 56))	('TYRO3', 'Gene', (132, 137))	('TYRO3', 'Gene', (82, 87))	('aberrant', 'Var', (94, 102))	('TYRO3', 'Gene', '7301', (132, 137))	('SNAIL', 'Gene', '6615', (103, 108))	('SNAIL', 'Gene', (103, 108))
560620	30486883	A homozygous deletion of ataxin 2 (ATXN2), codifying for a RBP, was observed; it has been reported that silencing of ATXN2 gene, which is known to affect neurodegenerative diseases, led to disturbance in RNA transcription.	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (154, 180))	('ATXN2', 'Gene', '6311', (35, 40))	('ataxin 2', 'Gene', '6311', (25, 33))	('silencing', 'Var', (104, 113))	('disturbance', 'Reg', (189, 200))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (154, 180))	('RNA transcription', 'MPA', (204, 221))	('RBP', 'Gene', (59, 62))	('RBP', 'Gene', '57794', (59, 62))	('ataxin 2', 'Gene', (25, 33))	('ATXN2', 'Gene', (117, 122))	('neurodegenerative diseases', 'Disease', (154, 180))	('ATXN2', 'Gene', (35, 40))	('affect', 'Reg', (147, 153))	('ATXN2', 'Gene', '6311', (117, 122))
560624	30486883	FOXQ1 and FOXF2 genes on chromosome 6 were present in homozygous deletion in DSRTC5 of the hybrid EMT group and in heterozygous deletion in DSRTC2, 3, and 7.	('FOXQ1', 'Gene', '94234', (0, 5))	('FOXF2', 'Gene', (10, 15))	('FOXF2', 'Gene', '2295', (10, 15))	('FOXQ1', 'Gene', (0, 5))	('DSRTC5', 'Gene', (77, 83))	('deletion', 'Var', (65, 73))
560631	30486883	Molecular classification of sarcomas splits these tumors into two broad categories: simple sarcomas with near diploid karyotype and simple genetic alterations including translocation or specific activating mutations; complex sarcomas with complex/unbalanced karyotypes.	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('sarcomas', 'Disease', (225, 233))	('activating', 'PosReg', (195, 205))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('sarcomas', 'Disease', 'MESH:D012509', (225, 233))	('sarcomas', 'Disease', (28, 36))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (225, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (225, 232))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('translocation', 'Var', (169, 182))	('sarcomas', 'Disease', (91, 99))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
560637	30486883	Of note, Signature 1 is the result of an endogenous mutational process and is a common signature in most human cancer types, whereas Signature 3 indicates defective homology-directed double-strand DNA break repair and is associated with germline and somatic BRCA1 and BRCA2 mutations in breast, pancreatic, and ovarian cancers.	('BRCA1', 'Gene', '672', (258, 263))	('cancers', 'Phenotype', 'HP:0002664', (319, 326))	('BRCA1', 'Gene', (258, 263))	('cancer', 'Disease', (319, 325))	('human', 'Species', '9606', (105, 110))	('cancer', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('ovarian cancers', 'Phenotype', 'HP:0100615', (311, 326))	('pancreatic', 'Disease', 'MESH:D010195', (295, 305))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('homology-directed double-strand DNA break repair', 'MPA', (165, 213))	('associated', 'Reg', (221, 231))	('BRCA2', 'Gene', (268, 273))	('pancreatic', 'Disease', (295, 305))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('breast', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('ovarian cancers', 'Disease', (311, 326))	('BRCA2', 'Gene', '675', (268, 273))	('ovarian cancers', 'Disease', 'MESH:D010051', (311, 326))	('mutations', 'Var', (274, 283))	('defective', 'NegReg', (155, 164))
560640	30486883	Overall, considering our WES and CNAs data, we focused our analyses on the DDR network and MErT/EMT pathways, hypothesizing that the co-occurrence of a tumor with refractory characteristics and deregulation of these specific network/pathways may contribute to the distinctive traits of DSRCT.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('contribute', 'Reg', (246, 256))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('DSRCT', 'Disease', (286, 291))	('deregulation', 'Var', (194, 206))
560641	30486883	Given the biological relevance of genes belonging to the DDR network or associated with DDR, including RBPs, it has been suggested that their mutations should be added to the list of cancer hallmarks as the eleventh item under the name of "epigenetic and RNA deregulation".	('mutations', 'Var', (142, 151))	('cancer', 'Disease', (183, 189))	('DDR', 'Disease', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('RBP', 'Gene', (103, 106))	('RBP', 'Gene', '57794', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
560643	30486883	As a result of this interplay, RBP alterations are drivers in oncogenesis and lead to a wide range of cellular dysfunctions despite of their low expression levels.	('alterations', 'Var', (35, 46))	('cellular dysfunctions', 'MPA', (102, 123))	('lead to', 'Reg', (78, 85))	('RBP', 'Gene', (31, 34))	('RBP', 'Gene', '57794', (31, 34))	('expression levels', 'MPA', (145, 162))
560645	30486883	In fact, we previously suggested that ZEB1 and miRNA34 (in the form of a miRNA/protein chimera) may drive the shift either towards EMT or MErT according to the prevalence of expression of ZEB1 over that of miRNA34 or the reverse, respectively.	('miRNA34', 'Var', (47, 54))	('ZEB1', 'Gene', (188, 192))	('ZEB1', 'Gene', '6935', (188, 192))	('shift', 'CPA', (110, 115))	('ZEB1', 'Gene', '6935', (38, 42))	('ZEB1', 'Gene', (38, 42))
560654	30486883	CNA copy number alteration CTA cancer-testis antigen DDR DNA damage-response DRBP DNA/RNA binding protein DDRBPs DNA damage response RNA binding proteins DSRCT desmoplastic small round cell tumor EMT epithelial mesenchymal transition FFPE formalin-fixed, paraffin-embedded GATK Genome Analysis Toolkit HLA human leukocyte antigen IHC immunohistochemistry IPA Ingenuity Pathway Analysis ISH in situ hybridisation MErT mesenchymal epithelial reverse transition NGS next-generation sequencing PCR polymerase chain reaction RBP RNA binding protein WES whole-exome sequencing	('paraffin', 'Chemical', 'MESH:D010232', (255, 263))	('RBP', 'Gene', '57794', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('formalin', 'Chemical', 'MESH:D005557', (239, 247))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('DRBP', 'Chemical', '-', (107, 111))	('RBP', 'Gene', (108, 111))	('cancer-testis', 'Disease', (31, 44))	('RBP', 'Gene', (78, 81))	('human', 'Species', '9606', (306, 311))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (160, 195))	('RBP', 'Gene', '57794', (108, 111))	('RBP', 'Gene', (520, 523))	('desmoplastic small round cell tumor', 'Disease', (160, 195))	('RBP', 'Gene', '57794', (520, 523))	('cancer-testis', 'Disease', 'MESH:D013736', (31, 44))	('DRBP', 'Chemical', '-', (77, 81))	('alteration', 'Var', (16, 26))
560775	27721667	Investigators reported a 3-month increase in progression-free survival for patients who received pazopanib.	('increase', 'PosReg', (33, 41))	('pazopanib', 'Chemical', 'MESH:C516667', (97, 106))	('patients', 'Species', '9606', (75, 83))	('pazopanib', 'Var', (97, 106))
560809	27721667	In a number of cancers, promoter hypermethylation has been shown to result in decreased expression of MGMT and gene as well as diminished DNA repair activity, rendering cells more susceptible to alkylating agents.	('MGMT', 'Gene', '4255', (102, 106))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('diminished', 'NegReg', (127, 137))	('cancers', 'Disease', (15, 22))	('MGMT', 'Gene', (102, 106))	('decreased', 'NegReg', (78, 87))	('DNA repair activity', 'MPA', (138, 157))	('expression', 'MPA', (88, 98))	('promoter hypermethylation', 'Var', (24, 49))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
560810	27721667	Hypermethylation of the MGMT gene promoter has also been observed in uterine sarcomas and thus could serve as a potential marker to identify patients who would benefit from temozolomide use.	('MGMT', 'Gene', '4255', (24, 28))	('sarcomas', 'Disease', (77, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('Hypermethylation', 'Var', (0, 16))	('patients', 'Species', '9606', (141, 149))	('observed', 'Reg', (57, 65))	('sarcomas', 'Disease', 'MESH:D012509', (77, 85))	('temozolomide', 'Chemical', 'MESH:D000077204', (173, 185))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('MGMT', 'Gene', (24, 28))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (69, 84))
560819	27721667	In transgenic mice, inactivation or loss of PTEN leads to the development of uLMS.	('uLMS', 'Phenotype', 'HP:0002891', (77, 81))	('inactivation', 'Var', (20, 32))	('leads to', 'Reg', (49, 57))	('loss', 'Var', (36, 40))	('PTEN', 'Gene', (44, 48))	('uLMS', 'Disease', (77, 81))	('transgenic mice', 'Species', '10090', (3, 18))
560827	27721667	Additional therapeutic benefit was observed when MLN82237 was combined with mTOR inhibition, consistent with AurkA's ability to cross-regulate mTOR pathway activity.	('mTOR', 'MPA', (76, 80))	('MLN82237', 'Var', (49, 57))	('AurkA', 'Gene', '6790', (109, 114))	('AurkA', 'Gene', (109, 114))
560833	27721667	Data has also shown that HDAC inhibitors can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models.	('HDAC', 'Gene', '9734', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('chemotherapy-induced apoptosis', 'CPA', (53, 83))	('enhance', 'PosReg', (45, 52))	('inhibitors', 'Var', (30, 40))	('sarcoma tumor', 'Disease', 'MESH:D012509', (95, 108))	('sarcoma tumor', 'Disease', (95, 108))	('HDAC', 'Gene', (25, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('reduce', 'NegReg', (88, 94))
560930	20939920	Only 5 cases and 6 seropositive controls had low-EBNA-1/high-VCA, which was associated with a non-significantly lower risk of cKS (Table 2, upper panel).	('KS', 'Phenotype', 'HP:0100726', (127, 129))	('cKS', 'Chemical', '-', (126, 129))	('low-EBNA-1/high-VCA', 'Var', (45, 64))	('cKS', 'Disease', (126, 129))	('EBNA', 'Chemical', '-', (49, 53))	('lower', 'NegReg', (112, 117))
560931	20939920	Comparing KSHV-seropositive versus -seronegative controls, adjusted for age and sex, mean differences were 0.34 (95% CI: -0.11, 0.80) for both anti-EBNA-1 and anti-VCA.	('anti-EBNA-1', 'Var', (143, 154))	('anti-VCA', 'Var', (159, 167))	('KSHV', 'Species', '37296', (10, 14))	('KS', 'Phenotype', 'HP:0100726', (10, 12))	('EBNA', 'Chemical', '-', (148, 152))
560961	20939920	As done previously, cKS risk was postulated to be highest with low-EBNA-1/high-VCA, defined using tertiles among controls.	('KS', 'Phenotype', 'HP:0100726', (21, 23))	('cKS', 'Chemical', '-', (20, 23))	('EBNA', 'Chemical', '-', (67, 71))	('low-EBNA-1/high-VCA', 'Var', (63, 82))	('cKS', 'Disease', (20, 23))
561012	30736802	Recently, CCSK has also been shown to consistently demonstrate BCOR gene abnormalities including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion which distinguish it from other pediatric renal tumors.	('BCOR', 'Gene', (138, 142))	('BCOR', 'Gene', (63, 67))	('pediatric renal tumors', 'Disease', (193, 215))	('abnormalities', 'Var', (73, 86))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('BCOR', 'Gene', '54880', (63, 67))	('renal tumor', 'Phenotype', 'HP:0009726', (203, 214))	('CCSK', 'Chemical', '-', (10, 14))	('renal tumors', 'Phenotype', 'HP:0009726', (203, 215))	('BCOR', 'Gene', '54880', (138, 142))	('pediatric renal tumors', 'Disease', 'MESH:D007674', (193, 215))	('CCNB3', 'Gene', '85417', (143, 148))	('internal tandem duplications', 'Var', (105, 133))	('CCSK', 'Phenotype', 'HP:0006770', (10, 14))	('exon', 'Var', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('CCNB3', 'Gene', (143, 148))
561015	30736802	Failure to do so can prevent a child from getting optimal chemotherapy.	('Failure', 'Var', (0, 7))	('prevent', 'Reg', (21, 28))	('child', 'Species', '9606', (31, 36))
561022	30736802	More importantly, recent studies suggest that BCOR immunohistochemistry appear to be highly sensitive and specific for the diagnosis of CCSK based on the recently identified BCOR gene abnormalities.	('BCOR', 'Gene', '54880', (174, 178))	('BCOR', 'Gene', (46, 50))	('CCSK', 'Chemical', '-', (136, 140))	('abnormalities', 'Var', (184, 197))	('CCSK', 'Phenotype', 'HP:0006770', (136, 140))	('BCOR', 'Gene', '54880', (46, 50))	('BCOR', 'Gene', (174, 178))	('CCSK', 'Disease', (136, 140))
561078	30736802	All 19 cases of CCSK in our study demonstrated positivity for Cyclin D1 which was very intense (3+) in over 68% of cases and moderately intense (2+) in 21%.	('Cyclin D1', 'Gene', (62, 71))	('CCSK', 'Phenotype', 'HP:0006770', (16, 20))	('CCSK', 'Disease', (16, 20))	('Cyclin D1', 'Gene', '595', (62, 71))	('positivity', 'Var', (47, 57))	('CCSK', 'Chemical', '-', (16, 20))
561111	29854399	Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of the glycolytic enzyme pyruvate kinase.	('PKM', 'Gene', (161, 164))	('PKM', 'Gene', '18746', (161, 164))	('Pkm', 'Gene', (130, 133))	('sarcoma', 'Disease', (94, 101))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (82, 101))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('PKM2', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Pkm', 'Gene', '18746', (130, 133))	('PKM2', 'Gene', '18746', (29, 33))	('PKM2', 'Gene', (170, 174))	('mouse', 'Species', '10090', (67, 72))	('PKM', 'Gene', (29, 32))	('PKM', 'Gene', '18746', (29, 32))	('PKM2', 'Gene', '18746', (170, 174))	('constrains', 'Reg', (34, 44))	('deletion', 'Var', (17, 25))	('PKM', 'Gene', (170, 173))	('PKM', 'Gene', '18746', (170, 173))	('sarcoma', 'Disease', 'MESH:D012509', (94, 101))	('Alternative', 'Var', (102, 113))
561115	29854399	PKM2 deletion slowed tumor onset but did not abrogate eventual tumor outgrowth.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('deletion', 'Var', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('PKM2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('slowed', 'NegReg', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
561118	29854399	While PKM2 is not required for soft tissue sarcoma growth, PKM2 expression may facilitate initiation of this tumor type.	('PKM2 expression', 'Var', (59, 74))	('sarcoma growth', 'Disease', 'MESH:D006130', (43, 57))	('soft tissue sarcoma', 'Disease', (31, 50))	('sarcoma growth', 'Disease', (43, 57))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (31, 50))	('initiation', 'CPA', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (31, 50))	('tumor', 'Disease', (109, 114))	('facilitate', 'PosReg', (79, 89))
561124	29854399	Expression of the PKM2 isoform is widespread in adult epithelial tissues and has been associated with embryogenesis, tissue regeneration, and cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('PKM2', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated', 'Reg', (86, 96))	('cancer', 'Disease', (142, 148))
561125	29854399	Importantly, expression of PKM2 impacts the fate of glucose, in part through regulated enzymatic activity.	('impacts', 'Reg', (32, 39))	('PKM2', 'Gene', (27, 31))	('glucose', 'Chemical', 'MESH:D005947', (52, 59))	('expression', 'Var', (13, 23))	('regulated enzymatic activity', 'MPA', (77, 105))	('fate of glucose', 'MPA', (44, 59))
561128	29854399	PKM2 is highly expressed in many tumor types, and a number of metabolic and non-metabolic functions in cancer have been attributed to PKM2.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('metabolic', 'MPA', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('attributed', 'Reg', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('PKM2', 'Var', (134, 138))
561131	29854399	For example, loss of PKM2 in a leukemia and breast cancer model led to contrasting results: while PKM2 loss limited progression in one case, it led to accelerated tumor growth in the other.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('leukemia', 'Disease', (31, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('leukemia', 'Disease', 'MESH:D007938', (31, 39))	('breast cancer', 'Disease', (44, 57))	('progression', 'CPA', (116, 127))	('limited', 'NegReg', (108, 115))	('leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('PKM2 loss', 'Disease', (98, 107))	('accelerated', 'PosReg', (151, 162))	('tumor', 'Disease', (163, 168))	('PKM2 loss', 'Disease', 'MESH:D015431', (98, 107))	('loss', 'Var', (13, 17))
561132	29854399	PKM2 deletion also accelerated tumor growth in a mouse medulloblastoma model.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('deletion', 'Var', (5, 13))	('PKM2', 'Gene', (0, 4))	('accelerated', 'PosReg', (19, 30))	('tumor', 'Disease', (31, 36))	('mouse', 'Species', '10090', (49, 54))	('medulloblastoma', 'Disease', 'MESH:D008527', (55, 70))	('medulloblastoma', 'Phenotype', 'HP:0002885', (55, 70))	('medulloblastoma', 'Disease', (55, 70))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
561133	29854399	Loss of PKM2 in a colon cancer model driven by APC loss did not alter tumor initiation, growth, or progression.	('colon cancer', 'Disease', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor initiation', 'Disease', 'MESH:D009369', (70, 86))	('APC loss', 'Disease', 'MESH:D011125', (47, 55))	('APC loss', 'Disease', (47, 55))	('growth', 'CPA', (88, 94))	('tumor initiation', 'Disease', (70, 86))	('colon cancer', 'Phenotype', 'HP:0003003', (18, 30))	('colon cancer', 'Disease', 'MESH:D015179', (18, 30))	('Loss', 'Var', (0, 4))	('PKM2', 'Gene', (8, 12))
561134	29854399	Finally, germline loss of PKM2 led to late onset of hepatocellular carcinoma, at least in part through non-cell autonomous means.	('loss', 'Var', (18, 22))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (52, 76))	('hepatocellular carcinoma', 'Disease', (52, 76))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (52, 76))	('PKM2', 'Enzyme', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
561137	29854399	In this model, Cre-mediated activation of oncogenic Kras and loss of p53 (KP) in the hind limb of mice leads to the formation of soft tissue sarcomas within 3 months.	('p53', 'Gene', (69, 72))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (129, 149))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (129, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('p53', 'Gene', '22060', (69, 72))	('activation', 'PosReg', (28, 38))	('Kras', 'Gene', (52, 56))	('soft tissue sarcomas', 'Disease', (129, 149))	('Kras', 'Gene', '16653', (52, 56))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (129, 149))	('loss', 'Var', (61, 65))	('mice', 'Species', '10090', (98, 102))
561138	29854399	Loss of PKM2 in this context led to delayed tumor initiation and decreased tumor penetrance.	('decreased tumor', 'Disease', (65, 80))	('decreased tumor', 'Disease', 'MESH:D009369', (65, 80))	('tumor initiation', 'Disease', 'MESH:D009369', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Loss', 'Var', (0, 4))	('delayed', 'NegReg', (36, 43))	('PKM2', 'Gene', (8, 12))	('tumor initiation', 'Disease', (44, 60))
561140	29854399	Metabolite analysis of KP M2-/- sarcoma tissue showed changes in the pool sizes of several metabolites, arguing that metabolism in these tumors changes as a result of PKM2 deletion and consequent PKM1 expression.	('metabolism', 'MPA', (117, 127))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('changes', 'Reg', (54, 61))	('PKM', 'Gene', (196, 199))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('PKM', 'Gene', '18746', (167, 170))	('PKM', 'Gene', '18746', (196, 199))	('sarcoma', 'Disease', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('changes', 'Reg', (144, 151))	('deletion', 'Var', (172, 180))	('expression', 'MPA', (201, 211))	('pool sizes of several metabolites', 'MPA', (69, 102))	('PKM', 'Gene', (167, 170))
561178	29854399	Furthermore, Cox regression analysis using this TCGA sarcoma patient cohort showed that a high PKM2/PKM1 ratio was independently prognostic of shorter survival when controlling for age and gender (Fig.	('patient', 'Species', '9606', (61, 68))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('shorter', 'NegReg', (143, 150))	('PKM', 'Gene', (100, 103))	('PKM', 'Gene', '18746', (100, 103))	('sarcoma', 'Disease', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('PKM', 'Gene', (95, 98))	('high', 'Var', (90, 94))	('PKM', 'Gene', '18746', (95, 98))
561182	29854399	This, in addition to the prognostic value of PKM2/PKM1 revealed by our analysis of the TCGA sarcoma cohort, led us to postulate that expression of PKM2 may play a role in malignant transformation of skeletal muscle tissue to form STS.	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('play', 'Reg', (156, 160))	('sarcoma cohort', 'Disease', (92, 106))	('PKM', 'Gene', (147, 150))	('PKM', 'Gene', (45, 48))	('PKM', 'Gene', '18746', (147, 150))	('role', 'Reg', (163, 167))	('PKM', 'Gene', '18746', (45, 48))	('expression', 'Var', (133, 143))	('sarcoma cohort', 'Disease', 'MESH:D012509', (92, 106))	('STS', 'Phenotype', 'HP:0030448', (230, 233))	('PKM', 'Gene', (50, 53))	('PKM', 'Gene', '18746', (50, 53))	('malignant transformation', 'CPA', (171, 195))
561184	29854399	Conditional activation of oncogenic Kras and inactivation of p53 in a KrasLSL-G12D/+; p53fl/fl (KP) mouse model by viral delivery of Cre recombinase to skeletal muscle tissue initiates the development of high-grade sarcomas with myofibroblastic differentiation.	('p53', 'Gene', (61, 64))	('Kras', 'Gene', '16653', (36, 40))	('p53', 'Gene', '22060', (61, 64))	('inactivation', 'Var', (45, 57))	('mouse', 'Species', '10090', (100, 105))	('Kras', 'Gene', '16653', (70, 74))	('p53', 'Gene', '22060', (86, 89))	('sarcomas', 'Disease', 'MESH:D012509', (215, 223))	('G12D', 'Mutation', 'rs121913529', (78, 82))	('sarcomas', 'Phenotype', 'HP:0100242', (215, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('sarcomas', 'Disease', (215, 223))	('Kras', 'Gene', (70, 74))	('Kras', 'Gene', (36, 40))	('p53', 'Gene', (86, 89))
561188	29854399	In contrast to similar experiments performed in other autochthonous mouse cancer models, we found that deletion of PKM2 concomitant with sarcoma initiation delayed tumor onset and decreased penetrance of the model (Fig.	('mouse', 'Species', '10090', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('PKM2', 'Gene', (115, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('sarcoma initiation delayed tumor', 'Disease', 'MESH:D012509', (137, 169))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('decreased', 'NegReg', (180, 189))	('penetrance of the model', 'CPA', (190, 213))	('sarcoma initiation delayed tumor', 'Disease', (137, 169))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('deletion', 'Var', (103, 111))
561189	29854399	Deletion of PKM2 delayed the date of tumor onset by approximately 8 days (56.45 days for KP M2+/+ versus 64.05 days for KP M2flfl) (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('delayed', 'NegReg', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('PKM2', 'Gene', (12, 16))	('Deletion', 'Var', (0, 8))
561190	29854399	To characterize the PKM expression patterns of sarcomas arising in KP M2+/+ and KP M2fl/fl mice, we performed Western blot analysis of PKM1 and PKM2 expression in primary tumors.	('primary tumor', 'Disease', (163, 176))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('sarcomas', 'Disease', (47, 55))	('PKM', 'Gene', (144, 147))	('PKM', 'Gene', '18746', (144, 147))	('PKM', 'Gene', (135, 138))	('PKM', 'Gene', '18746', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('mice', 'Species', '10090', (91, 95))	('KP M2fl/fl', 'Var', (80, 90))	('PKM', 'Gene', (20, 23))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('PKM', 'Gene', '18746', (20, 23))	('primary tumor', 'Disease', 'MESH:D009369', (163, 176))	('KP M2+/+', 'Var', (67, 75))
561192	29854399	Consistent with our protein analysis, qRT-PCR analysis of the same tumors showed very low transcript levels for Pkm2 accompanied by a dramatic increase in the transcript levels for Pkm1 in KP M2-/- tumors relative to KP M2+/+ tumors (Fig.	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('Pkm2', 'Gene', (112, 116))	('Pkm', 'Gene', '18746', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('Pkm', 'Gene', (112, 115))	('Pkm2', 'Gene', '18746', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('low', 'NegReg', (86, 89))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('transcript levels', 'MPA', (90, 107))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Pkm', 'Gene', (181, 184))	('tumors', 'Disease', (67, 73))	('Pkm', 'Gene', '18746', (112, 115))	('transcript levels', 'MPA', (159, 176))	('tumors', 'Disease', (226, 232))	('KP M2-/-', 'Var', (189, 197))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('increase', 'PosReg', (143, 151))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
561193	29854399	Of note, the levels of Pkm1 in KP M2-/- tumors were lower than the levels of Pkm1 in wild-type untransformed skeletal muscle tissue.	('Pkm', 'Gene', (77, 80))	('Pkm', 'Gene', '18746', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('KP M2-/-', 'Var', (31, 39))	('lower', 'NegReg', (52, 57))	('levels', 'MPA', (13, 19))	('Pkm', 'Gene', (23, 26))	('tumors', 'Disease', (40, 46))	('Pkm', 'Gene', '18746', (77, 80))
561194	29854399	This quantitative assessment of mRNA abundance also revealed that the levels of total Pkm transcripts were reduced in KP M2-/- tumors compared to KP M2+/+ tumors.	('levels', 'MPA', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('reduced', 'NegReg', (107, 114))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('Pkm', 'Gene', '18746', (86, 89))	('Pkm', 'Gene', (86, 89))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (155, 161))	('KP M2-/-', 'Var', (118, 126))	('tumors', 'Disease', 'MESH:D009369', (155, 161))
561195	29854399	The observed decrease in total Pkm transcripts in KP M2-/- tumors was accompanied by a reduction in the maximum rate of reaction (Vmax) when pyruvate kinase enzyme activity was assessed in KP M2-/- tumor lysates compared to KP M2+/+ tumor lysates (Fig.	('tumor', 'Disease', (59, 64))	('decrease', 'NegReg', (13, 21))	('maximum rate of reaction', 'MPA', (104, 128))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('KP M2-/-', 'Var', (50, 58))	('tumor', 'Disease', (233, 238))	('Pkm', 'Gene', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', (198, 203))	('reduction', 'NegReg', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('activity', 'MPA', (164, 172))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('Pkm', 'Gene', '18746', (31, 34))	('tumors', 'Disease', (59, 65))	('KP M2-/-', 'Var', (189, 197))
561198	29854399	To further characterize the PKM expression patterns of sarcomas from KP; M2+/+ and KP; M2fl/fl mice at the cell and tissue level, we performed IHC for PKM1 and PKM2 (Fig.	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('mice', 'Species', '10090', (95, 99))	('PKM', 'Gene', (151, 154))	('PKM', 'Gene', '18746', (151, 154))	('KP; M2+/+', 'Var', (69, 78))	('PKM', 'Gene', (28, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('PKM', 'Gene', '18746', (28, 31))	('sarcomas', 'Disease', (55, 63))	('PKM', 'Gene', (160, 163))	('KP; M2fl/fl', 'Var', (83, 94))	('PKM', 'Gene', '18746', (160, 163))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))
561199	29854399	Consistent with Western blot analysis, KP M2+/+ tumors primarily and uniformly expressed PKM2.	('PKM2', 'Gene', (89, 93))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('KP M2+/+', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
561200	29854399	In contrast, KP M2-/- tumors consisted primarily of PKM1-expressing cells and also contained a number of cells that had high expression of PKM2.	('PKM', 'Gene', '18746', (139, 142))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('KP M2-/-', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PKM', 'Gene', (52, 55))	('PKM', 'Gene', '18746', (52, 55))	('PKM', 'Gene', (139, 142))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
561203	29854399	Consistent with efficient deletion of PKM2 and consequent expression of PKM1 in tumor cells, we found that PKM2 was expressed exclusively in the tdTomato-negative stromal cells.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PKM', 'Gene', (38, 41))	('PKM', 'Gene', '18746', (38, 41))	('PKM', 'Gene', (107, 110))	('deletion', 'Var', (26, 34))	('tumor', 'Disease', (80, 85))	('PKM', 'Gene', (72, 75))	('PKM', 'Gene', '18746', (72, 75))	('PKM', 'Gene', '18746', (107, 110))
561204	29854399	Collectively, these data argue that while loss of PKM2 concomitant with KP sarcoma initiation delays tumor onset, it does not fully abrogate the eventual outgrowth of tumors in most cases.	('PKM2', 'Enzyme', (50, 54))	('loss', 'Var', (42, 46))	('abrogate', 'NegReg', (132, 140))	('eventual outgrowth', 'Phenotype', 'HP:0001548', (145, 163))	('KP sarcoma initiation delays tumor', 'Disease', (72, 106))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('KP sarcoma initiation delays tumor', 'Disease', 'MESH:D012509', (72, 106))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
561206	29854399	Furthermore, in breast cancers with PKM2 deletion, PKM1 expression was only observed in the non-proliferating population of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PKM', 'Gene', (51, 54))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('tumor', 'Disease', (124, 129))	('PKM', 'Gene', '18746', (51, 54))	('deletion', 'Var', (41, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (16, 30))	('PKM', 'Gene', (36, 39))	('PKM', 'Gene', '18746', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancers', 'Disease', 'MESH:D001943', (16, 30))	('breast cancers', 'Disease', (16, 30))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
561208	29854399	Contrary to the conclusions from breast cancer, we found that a large portion of PKM1-expressing tumor cells in KP M2-/- sarcomas also expressed pHH3.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('sarcomas', 'Disease', 'MESH:D012509', (121, 129))	('pHH3', 'Chemical', '-', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('pHH3', 'Var', (145, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('tumor', 'Disease', (97, 102))	('sarcomas', 'Disease', (121, 129))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('PKM', 'Gene', (81, 84))	('PKM', 'Gene', '18746', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
561211	29854399	5b), as was an analysis of proliferating cells in cell lines derived from primary tumors in KP M2+/+ and KP M2fl/fl mice (Additional file 3: Figure S3A).	('mice', 'Species', '10090', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('KP M2fl/fl', 'Var', (105, 115))	('primary tumor', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('primary tumor', 'Disease', 'MESH:D009369', (74, 87))	('KP M2+/+', 'Var', (92, 100))
561213	29854399	Despite the longer time to palpable tumor formation and the decreased tumor penetrance in KP M2fl/fl mice, there was no significant difference in the tumor weight at time of death of KP M2fl/fl mice relative to KP M2+/+ mice (Additional file 3: Figure S3C).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('KP M2fl/fl', 'Var', (90, 100))	('KP M2fl/fl', 'Var', (183, 193))	('mice', 'Species', '10090', (220, 224))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('decreased tumor', 'Disease', 'MESH:D009369', (60, 75))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('decreased tumor', 'Disease', (60, 75))	('mice', 'Species', '10090', (194, 198))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (36, 41))
561217	29854399	The fact that deletion of PKM2 in our KP model of soft tissue sarcoma led to delayed tumor onset and decreased penetrance but did not appear to limit proliferation or progression of late-stage tumors raised the possibility that KP M2-/- tumors had arisen through an adaptive process that might modulate the effects of PKM2 loss and consequent expression of PKM1.	('tumor', 'Disease', (85, 90))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (50, 69))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('soft tissue sarcoma', 'Disease', (50, 69))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('PKM', 'Gene', (318, 321))	('PKM', 'Gene', (357, 360))	('PKM', 'Gene', '18746', (318, 321))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('PKM', 'Gene', '18746', (357, 360))	('tumors', 'Disease', (237, 243))	('tumor', 'Disease', (193, 198))	('deletion', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('late-stage tumors', 'Disease', 'MESH:D062706', (182, 199))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('decreased', 'NegReg', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('late-stage tumors', 'Disease', (182, 199))	('tumor', 'Disease', (237, 242))	('PKM2 loss', 'Disease', (318, 327))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('PKM2 loss', 'Disease', 'MESH:D015431', (318, 327))	('penetrance', 'MPA', (111, 121))	('tumors', 'Disease', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('PKM', 'Gene', (26, 29))	('PKM', 'Gene', '18746', (26, 29))
561218	29854399	Therefore, we hypothesized that the adaptive process that had allowed for KP M2-/- tumor outgrowth might involve changes in glucose metabolism that could be apparent as changes in metabolite pool sizes.	('KP M2-/-', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('changes', 'Reg', (113, 120))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('glucose metabolism', 'Disease', 'MESH:D044882', (124, 142))	('changes', 'Reg', (169, 176))	('metabolite pool sizes', 'MPA', (180, 201))	('glucose metabolism', 'Disease', (124, 142))
561219	29854399	Therefore, we conducted targeted metabolomics analysis of primary tumors derived from KP M2+/+ and KP M2fl/fl mice.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('primary tumor', 'Disease', (58, 71))	('tumors', 'Disease', (66, 72))	('primary tumor', 'Disease', 'MESH:D009369', (58, 71))	('KP M2+/+', 'Var', (86, 94))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('mice', 'Species', '10090', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('KP M2fl/fl', 'Var', (99, 109))
561223	29854399	The delay in tumor initiation that we observe upon loss of PKM2 suggests that tumor initiation in this model is partially dependent on the activation of PKM2 expression in tumor-initiating cells.	('tumor', 'Disease', (13, 18))	('tumor initiation', 'Disease', (13, 29))	('PKM2', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('loss', 'Var', (51, 55))	('activation', 'PosReg', (139, 149))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor initiation', 'Disease', 'MESH:D009369', (13, 29))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor initiation', 'Disease', 'MESH:D009369', (78, 94))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('PKM2', 'Gene', (153, 157))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor initiation', 'Disease', (78, 94))
561228	29854399	Moreover, the metabolic changes that we observe in KP M2-/- tumors might be indicative of a compensatory change in the metabolic program of these cells compared to KP M2+/+ tumor cells.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('metabolic', 'MPA', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('KP M2-/-', 'Var', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (60, 65))	('tumors', 'Disease', (60, 66))
561236	29854399	Our study found that PKM2 loss at the time of tumor initiation in a mouse model of STS driven by activation of oncogenic Kras and loss of p53 leads to delayed tumor onset and decreased tumor penetrance.	('decreased tumor', 'Disease', (175, 190))	('p53', 'Gene', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('p53', 'Gene', '22060', (138, 141))	('Kras', 'Gene', (121, 125))	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Kras', 'Gene', '16653', (121, 125))	('STS', 'Phenotype', 'HP:0030448', (83, 86))	('PKM2 loss', 'Disease', (21, 30))	('PKM2 loss', 'Disease', 'MESH:D015431', (21, 30))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (159, 164))	('decreased tumor', 'Disease', 'MESH:D009369', (175, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('loss', 'Var', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('mouse', 'Species', '10090', (68, 73))	('tumor initiation', 'Disease', 'MESH:D009369', (46, 62))	('tumor initiation', 'Disease', (46, 62))
561240	29854399	We show that KP M2-/- tumors have an altered metabolite profile, suggesting metabolic changes accompany loss of PKM2 expression in these tumors.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('loss', 'NegReg', (104, 108))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('KP M2-/-', 'Var', (13, 21))	('metabolic changes', 'MPA', (76, 93))	('expression', 'MPA', (117, 127))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('metabolite profile', 'MPA', (45, 63))	('tumors', 'Disease', (22, 28))	('altered', 'Reg', (37, 44))	('PKM2', 'Gene', (112, 116))
561244	29089486	Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors Homozygous deletions are rare in cancers and often target tumour suppressor genes.	('tumour', 'Disease', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('tumour', 'Disease', (77, 83))	('cancers', 'Disease', (129, 136))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('tumour', 'Disease', (154, 160))	('primary tumours uncovers rare tumour', 'Disease', (47, 83))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('target', 'Reg', (147, 153))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('Homozygous', 'Var', (96, 106))	('Pan-cancer', 'Disease', (0, 10))	('primary tumours uncovers rare tumour', 'Disease', 'MESH:D009369', (47, 83))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
561246	29089486	These recurrent homozygous deletions occur either over tumour suppressors or over fragile sites, regions of increased genomic instability.	('tumour', 'Disease', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('deletions', 'Var', (27, 36))	('occur', 'Reg', (37, 42))
561247	29089486	We construct a statistical model that separates fragile sites from regions showing signatures of positive selection for homozygous deletions and identify candidate tumour suppressors within those regions.	('deletions', 'Var', (131, 140))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumour', 'Disease', (164, 170))	('tumour', 'Disease', 'MESH:D009369', (164, 170))
561252	29089486	Homozygous deletions are rare in cancers and often target tumour suppressor genes.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', (58, 64))	('target', 'Reg', (51, 57))	('Homozygous deletions', 'Var', (0, 20))
561254	29089486	The genomes of cancer cells are shaped by somatic mutations, including base substitutions, small insertions and deletions, genomic rearrangements, and copy number changes.	('deletions', 'Var', (112, 121))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('base substitutions', 'Var', (71, 89))	('copy number changes', 'Var', (151, 170))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
561255	29089486	Many of these somatic changes are neutral passenger events, yet some confer a clonal selective advantage on cancer cells and drive oncogenesis.	('oncogenesis', 'CPA', (131, 142))	('changes', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('drive', 'Reg', (125, 130))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
561256	29089486	The genes involved can be oncogenes, which are frequently hit by activating point mutations or amplifications and behave in a dominant fashion, or tumour suppressor genes, which are recurrently targeted by inactivating mutations such as truncating point mutations or deletions and display a recessive pattern.	('deletions', 'Var', (267, 276))	('truncating point mutations', 'Var', (237, 263))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Disease', (147, 153))
561257	29089486	The most frequently used approach to identify cancer genes is assessing recurrence of non-synonymous somatic point mutations above background level.	('cancer', 'Disease', (46, 52))	('non-synonymous', 'Var', (86, 100))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
561258	29089486	The power to detect cancer genes varies based on sample size and background mutation frequency: for most tumour types, current sample sizes are inadequate to reliably detect rare cancer genes mutated at <= 5% above background.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumour type', 'Disease', (105, 116))	('tumour type', 'Disease', 'MESH:D009369', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('mutated', 'Var', (192, 199))	('cancer', 'Disease', (179, 185))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
561260	29089486	We reasoned that a systematic screen for homozygous deletions in a large series of cancer samples would be a powerful orthogonal way to specifically identify tumour suppressors, hypothesising that some tumour suppressors may be more prone to inactivation by homozygous deletions than by truncating point mutations.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('inactivation', 'NegReg', (242, 254))	('tumour', 'Disease', (158, 164))	('tumour', 'Disease', (202, 208))	('deletions', 'Var', (269, 278))	('cancer', 'Disease', (83, 89))
561262	29089486	Tumour samples contain both tumour cells and admixed normal cells in unknown proportions, complicating the distinction between homozygous and hemizygous deletions and hampering the discovery of tumour suppressors.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour', 'Disease', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Disease', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('deletions', 'Var', (153, 162))
561263	29089486	Cancer cell lines represent a simplified model system that does not show this normal cell admixture and a comprehensive catalogue of homozygous deletions in cancer cell lines has been constructed.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('deletions', 'Var', (144, 153))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (157, 163))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
561264	29089486	However, this model system has important limitations: cancer cell lines are biased towards late stage cancers and metastases, they have accumulated mutations to adapt to growth in culture, their numbers are limited, and some cancer types do not lend themselves to growth in culture.	('metastases', 'Disease', (114, 124))	('mutations', 'Var', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (225, 231))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('late stage cancers', 'Disease', (91, 109))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('late stage cancers', 'Disease', 'MESH:D009369', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
561267	29089486	These methods are able to reliably separate homozygous from hemizygous deletions, and have been able to pinpoint driver homozygous deletions in known and newly identified tumour suppressors.	('deletions', 'Var', (131, 140))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('tumour', 'Disease', (171, 177))	('tumour', 'Disease', 'MESH:D009369', (171, 177))
561268	29089486	Here, we perform a systematic screen for homozygous deletions over a compendium of 2218 SNP arrays across 12 cancer types, aiming to identify rare tumour suppressors.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('deletions', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumour', 'Disease', (147, 153))
561269	29089486	We find 96 genomic regions recurrently targeted by homozygous deletions, overlapping 16 established tumour suppressors.	('tumour', 'Disease', (100, 106))	('deletions', 'Var', (62, 71))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))
561278	29089486	All tumour types showed a substantial fraction of diploid or near-diploid cases, though with a much tighter distribution around the diploid state in some cancer types (notably leukaemias and lymphomas) than in others.	('lymphoma', 'Phenotype', 'HP:0002665', (191, 199))	('tighter', 'PosReg', (100, 107))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('near-diploid', 'Var', (61, 73))	('diploid', 'Var', (50, 57))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumour type', 'Disease', (4, 15))	('tumour type', 'Disease', 'MESH:D009369', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('leukaemias and lymphomas', 'Disease', 'MESH:D007938', (176, 200))
561279	29089486	Aneuploid cases are present in varying degree and with varying distribution across the 12 cancer types, with leukaemias displaying the lowest and oesophageal carcinomas the highest proportion of aneuploid cases (Fig.	('oesophageal carcinomas', 'Disease', 'MESH:D005764', (146, 168))	('oesophageal carcinomas', 'Disease', (146, 168))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('leukaemias', 'Disease', 'MESH:D007938', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('leukaemias', 'Disease', (109, 119))	('aneuploid', 'Var', (195, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))
561284	29089486	We identified 1865 homozygous deletions in total (median length: 315 kb), involving 826 tumours, each having on average 2.0 Mb (median 524 kb) homozygously deleted (Table 1, Supplementary Data 2).	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('deletions', 'Var', (30, 39))	('tumours', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))
561287	29089486	Homozygous deletions were rarely found in renal cancer and more commonly in oesophageal cancer, lung cancer, and sarcoma (Table 1).	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('renal cancer', 'Disease', (42, 54))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('renal cancer', 'Disease', 'MESH:D007680', (42, 54))	('renal cancer', 'Phenotype', 'HP:0009726', (42, 54))	('lung cancer', 'Disease', (96, 107))	('sarcoma', 'Disease', (113, 120))	('oesophageal cancer', 'Disease', (76, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('oesophageal cancer', 'Disease', 'MESH:D009369', (76, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('Homozygous deletions', 'Var', (0, 20))
561288	29089486	Diploid tumours tended to carry a higher number of homozygous deletions than tetraploid ones (ploidy > 2.7), while the size distribution of the deletions is the same for both (Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('deletions', 'Var', (62, 71))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('Diploid tumours', 'Disease', (0, 15))	('Diploid tumours', 'Disease', 'MESH:C548012', (0, 15))
561290	29089486	A positive correlation between Rb inactivation and polyploidy has previously been observed and its role in the cell cycle G1/S checkpoint further supports a role in tetraploidisation during tumorigenesis.	('inactivation', 'Var', (34, 46))	('polyploidy', 'Disease', (51, 61))	('Rb', 'Chemical', 'MESH:D012413', (31, 33))	('polyploidy', 'Disease', 'MESH:D011123', (51, 61))
561294	29089486	Virtually all of these homozygous deletions inactivate the adjacent "backup" tumour suppressor CDKN2B as well, rationalising the frequent loss of the combined locus.	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('inactivate', 'NegReg', (44, 54))	('deletions', 'Var', (34, 43))	('CDKN2B', 'Gene', (95, 101))	('CDKN2B', 'Gene', '1030', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
561296	29089486	All BIRC3 deletions include its adjacent homologue BIRC2, consistent with previous observations that only loss of both was shown to induce alternative NF-kappaB activation in B-cells.	('alternative NF-kappaB activation', 'MPA', (139, 171))	('deletions', 'Var', (10, 19))	('BIRC2', 'Gene', '329', (51, 56))	('BIRC3', 'Gene', (4, 9))	('BIRC3', 'Gene', '330', (4, 9))	('BIRC2', 'Gene', (51, 56))
561297	29089486	Similarly, we observed six homozygous deletions over VHL, five of which take out the nearby tumour suppressor FANCD2 as well.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('FANCD2', 'Gene', '2177', (110, 116))	('tumour', 'Disease', (92, 98))	('VHL', 'Gene', (53, 56))	('FANCD2', 'Gene', (110, 116))	('deletions', 'Var', (38, 47))	('VHL', 'Gene', '7428', (53, 56))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
561298	29089486	We detected 16 homozygous deletions over PTEN in multiple cancer types and 5 homozygous deletions over NF1.	('NF1', 'Gene', '4763', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('deletions', 'Var', (26, 35))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))	('NF1', 'Gene', (103, 106))
561299	29089486	Homozygous deletions of RB1 were most frequently found in tetraploid sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('RB1', 'Gene', (24, 27))	('RB1', 'Gene', '5925', (24, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Homozygous', 'Var', (0, 10))	('tetraploid sarcomas', 'Disease', 'MESH:D057891', (58, 77))	('tetraploid sarcomas', 'Disease', (58, 77))	('found', 'Reg', (49, 54))
561300	29089486	We further observed four homozygous deletions each over TP53 (three sarcomas), CDKN2C, and FAT1, and six homozygous deletions each over MAP2K4 (three breast carcinomas) and CDH1 (five lung cancers).	('CDH1', 'Gene', '999', (173, 177))	('lung cancers', 'Disease', 'MESH:D008175', (184, 196))	('deletions', 'Var', (36, 45))	('TP53', 'Gene', '7157', (56, 60))	('lung cancers', 'Disease', (184, 196))	('CDH1', 'Gene', (173, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('FAT1', 'Gene', (91, 95))	('sarcomas', 'Disease', 'MESH:D012509', (68, 76))	('CDKN2C', 'Gene', (79, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('lung cancers', 'Phenotype', 'HP:0100526', (184, 196))	('breast carcinomas', 'Disease', 'MESH:D001943', (150, 167))	('breast carcinomas', 'Disease', (150, 167))	('sarcomas', 'Disease', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('CDKN2C', 'Gene', '1031', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast carcinomas', 'Phenotype', 'HP:0003002', (150, 167))	('FAT1', 'Gene', '2195', (91, 95))	('TP53', 'Gene', (56, 60))	('MAP2K4', 'Gene', '6416', (136, 142))	('MAP2K4', 'Gene', (136, 142))
561302	29089486	Interestingly, the four homozygous deletions over BRCA2 included two sarcomas, a cancer type not previously linked to BRCA2 mutations.	('included', 'Reg', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BRCA2', 'Gene', (118, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('cancer', 'Disease', (81, 87))	('sarcomas', 'Disease', (69, 77))	('BRCA2', 'Gene', (50, 55))	('deletions', 'Var', (35, 44))	('BRCA2', 'Gene', '675', (118, 123))	('BRCA2', 'Gene', '675', (50, 55))	('sarcomas', 'Disease', 'MESH:D012509', (69, 77))
561303	29089486	The 96 regions showing frequent homozygous deletions also include the T-cell receptor alpha locus, as well as both the immunoglobulin heavy and light chain loci (Fig.	('deletions', 'Var', (43, 52))	('T-cell receptor alpha locus', 'Gene', '6955', (70, 97))	('T-cell receptor alpha locus', 'Gene', (70, 97))
561306	29089486	Consequently, the structural signature of deletions is distinct in fragile sites, compared to regions harbouring tumour suppressors.	('tumour', 'Disease', (113, 119))	('deletions', 'Var', (42, 51))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))
561314	29089486	Therefore, we can use differences in tumour-type specificity between homozygous and small hemizygous deletions as an indication that tissue-specificity of homozygous deletions is driven by selection (Fig.	('deletions', 'Var', (101, 110))	('tumour-type', 'Disease', 'MESH:D009369', (37, 48))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour-type', 'Disease', (37, 48))
561315	29089486	Only when the signature of deletions over a peak is unlikely to be explained by local fragility (q <= 0.05), do we reject the null model and consider the presence of a tumour suppressor.	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('deletions', 'Var', (27, 36))	('tumour', 'Disease', (168, 174))
561317	29089486	Notably, VHL shows frequent biallelic inactivation by a hemizygous deletion combined with a point mutation, while homozygous deletions are rare.	('biallelic', 'MPA', (28, 37))	('deletion', 'Var', (67, 75))	('VHL', 'Gene', '7428', (9, 12))	('VHL', 'Gene', (9, 12))
561321	29089486	The resulting dicentric chromosome is mitotically unstable and sparks a number of breakage-fusion-bridge cycles in the subsequent cell divisions or catastrophic events such as chromothripsis and kataegis, creating increasing numbers of subclones.	('chromothripsis', 'Disease', 'MESH:D000072837', (176, 190))	('chromothripsis', 'Disease', (176, 190))	('dicentric chromosome', 'Var', (14, 34))	('sparks', 'Reg', (63, 69))
561330	29089486	Another peak of homozygous deletions targeted the ubiquitin-specific protease USP44, specifically in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('ubiquitin-specific protease USP44', 'Enzyme', (50, 83))	('deletions', 'Var', (27, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('targeted', 'Reg', (37, 45))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
561331	29089486	Interestingly, USP44 was recently found to regulate the mitotic cell cycle checkpoint and Usp44 knockout mice spontaneously formed tumours, particularly in the lungs.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('formed', 'Reg', (124, 130))	('tumours', 'Disease', (131, 138))	('Usp44', 'Gene', '327799', (90, 95))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('knockout', 'Var', (96, 104))	('Usp44', 'Gene', (90, 95))	('mice', 'Species', '10090', (105, 109))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))
561332	29089486	Homozygous deletions over or near SOX21 were found in three cases of multiple myeloma, one lymphoma and one breast cancer.	('lymphoma', 'Disease', 'MESH:D008223', (91, 99))	('SOX21', 'Gene', '11166', (34, 39))	('multiple myeloma', 'Disease', 'MESH:D009101', (69, 85))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('multiple myeloma', 'Phenotype', 'HP:0006775', (69, 85))	('multiple myeloma', 'Disease', (69, 85))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('one breast', 'Phenotype', 'HP:0012813', (104, 114))	('SOX21', 'Gene', (34, 39))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('lymphoma', 'Disease', (91, 99))	('Homozygous deletions over', 'Var', (0, 25))	('found', 'Reg', (45, 50))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
561335	29089486	In addition, we found homozygous deletions targeting the histone H3K23 acetyltransferase KAT6B that, combined with a series of truncating mutations, implicate this gene as a tumour suppressor.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('KAT6B', 'Gene', (89, 94))	('tumour', 'Disease', (174, 180))	('KAT6B', 'Gene', '23522', (89, 94))	('deletions', 'Var', (33, 42))
561338	29089486	Likewise, we identified homozygous deletions within GPC5, encoding the heparin sulphate proteoglycan Glypican-5.	('GPC5', 'Gene', '2262', (52, 56))	('GPC5', 'Gene', (52, 56))	('deletions', 'Var', (35, 44))
561340	29089486	Interestingly, we observe homozygous deletions not only in lung cancer, but also in ovarian and liver cancer, supporting a tumour suppressive role in a wider range of cancer types.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('liver cancer', 'Phenotype', 'HP:0002896', (96, 108))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('homozygous deletions', 'Var', (26, 46))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', (167, 173))	('lung cancer', 'Disease', (59, 70))	('tumour', 'Disease', (123, 129))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('ovarian and liver cancer', 'Disease', 'MESH:D008113', (84, 108))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
561342	29089486	It is frequently mutated in gynaecological carcinosarcoma and to a lesser extent in ovarian cancer.	('ovarian cancer', 'Disease', (84, 98))	('carcinosarcoma', 'Disease', (43, 57))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('carcinosarcoma', 'Disease', 'MESH:D002296', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('mutated', 'Var', (17, 24))
561343	29089486	While copy number losses of BAZ1A are known to occur in renal papillary carcinoma, we observe homozygous deletions in lung cancer and sarcoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('renal papillary carcinoma', 'Disease', (56, 81))	('copy number losses', 'Var', (6, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('renal papillary carcinoma', 'Disease', 'MESH:D007681', (56, 81))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('renal papillary carcinoma', 'Phenotype', 'HP:0006766', (56, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('BAZ1A', 'Gene', '11177', (28, 33))	('sarcoma', 'Disease', (134, 141))	('lung cancer', 'Disease', (118, 129))	('BAZ1A', 'Gene', (28, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
561344	29089486	Another peak of homozygous deletions targets CPEB3, mostly in lung cancer.	('CPEB3', 'Gene', (45, 50))	('CPEB3', 'Gene', '22849', (45, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('deletions', 'Var', (27, 36))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))
561346	29089486	Therefore, our results suggest that, in addition to amplification of EGFR, lung cancers can also adopt homozygous deletions of CPEB3 as an alternative mechanism to overexpress EGFR.	('EGFR', 'Gene', '1956', (69, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('overexpress', 'PosReg', (164, 175))	('EGFR', 'Gene', (69, 73))	('lung cancers', 'Disease', 'MESH:D008175', (75, 87))	('EGFR', 'Gene', '1956', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancers', 'Phenotype', 'HP:0100526', (75, 87))	('EGFR', 'Gene', (176, 180))	('CPEB3', 'Gene', (127, 132))	('lung cancers', 'Disease', (75, 87))	('deletions', 'Var', (114, 123))	('CPEB3', 'Gene', '22849', (127, 132))
561347	29089486	This raises the possibility that EGFR-targeted therapy may also be effective in patients with homozygous deletions of CPEB3.	('patients', 'Species', '9606', (80, 88))	('CPEB3', 'Gene', (118, 123))	('CPEB3', 'Gene', '22849', (118, 123))	('deletions', 'Var', (105, 114))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))
561354	29089486	RFWD3 encodes a ubiquitin ligase that acts as a positive regulator of TP53 stability in response to DNA damage and loss of RFWD3 results in persistent DNA damage.	('response to DNA damage', 'MPA', (88, 110))	('DNA damage', 'MPA', (151, 161))	('TP53', 'Gene', '7157', (70, 74))	('RFWD3', 'Gene', (0, 5))	('TP53', 'Gene', (70, 74))	('RFWD3', 'Gene', (123, 128))	('loss', 'Var', (115, 119))	('RFWD3', 'Gene', '55159', (0, 5))	('RFWD3', 'Gene', '55159', (123, 128))
561356	29089486	Interestingly, the same peak region of homozygous deletions also contains FAM175A (also called ABRAXAS), a suggested tumour suppressor gene that encodes a protein component of the BRCA1-A complex that leads the BRCA1-BARD1 heterodimer to sites of DNA double-strand breaks, targeting these for homologous recombination.	('FAM175A', 'Gene', (74, 81))	('BRCA1', 'Gene', (211, 216))	('BRCA1', 'Gene', '672', (180, 185))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('BARD1', 'Gene', '580', (217, 222))	('BRCA1', 'Gene', '672', (211, 216))	('BRCA1', 'Gene', (180, 185))	('BARD1', 'Gene', (217, 222))	('FAM175A', 'Gene', '84142', (74, 81))	('tumour', 'Disease', (117, 123))	('deletions', 'Var', (50, 59))
561357	29089486	We therefore hypothesise that homozygous deletions of this region on chromosome 4 coordinately inactivate two tumour suppressor genes, involved in different DNA damage repair pathways.	('inactivate', 'NegReg', (95, 105))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('deletions', 'Var', (41, 50))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
561362	29089486	It is therefore likely that perturbation of any of these three caspase genes may abrogate apoptosis.	('caspase', 'Gene', '841;842', (63, 70))	('abrogate', 'NegReg', (81, 89))	('apoptosis', 'CPA', (90, 99))	('caspase', 'Gene', (63, 70))	('perturbation', 'Var', (28, 40))
561364	29089486	SETD1B specifically methylates H3K4, thereby playing a role in epigenetic control of transcription.	('methylates', 'Var', (20, 30))	('SETD1B', 'Gene', (0, 6))	('playing', 'Reg', (45, 52))	('H3K4', 'Protein', (31, 35))	('SETD1B', 'Gene', '23067', (0, 6))
561365	29089486	We identified several large and smaller homozygous deletions targeting ARHGEF10, a Rho guanine nucleotide exchange factor regulating mitotic spindle formation that has been proposed as a tumour suppressor.	('tumour', 'Disease', (187, 193))	('ARHGEF10', 'Gene', '9639', (71, 79))	('ARHGEF10', 'Gene', (71, 79))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('deletions', 'Var', (51, 60))	('tumour', 'Disease', 'MESH:D009369', (187, 193))
561366	29089486	Interestingly, we also observed homozygous deletions affecting its closest paralog ARHGEF10L, suggesting that both genes may be tumour suppressors.	('tumour', 'Disease', (128, 134))	('ARHGEF10L', 'Gene', (83, 92))	('homozygous', 'Var', (32, 42))	('ARHGEF10L', 'Gene', '55160', (83, 92))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
561367	29089486	Some homozygous deletions may drive oncogenesis through other mechanisms than inactivation of a tumour suppressor gene.	('drive', 'Reg', (30, 35))	('oncogenesis', 'CPA', (36, 47))	('deletions', 'Var', (16, 25))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (96, 102))
561368	29089486	We observed intragenic deletions of PDE4D, encoding phosphodiesterase 4D.	('deletions', 'Var', (23, 32))	('phosphodiesterase 4D', 'Gene', (52, 72))	('PDE4D', 'Gene', (36, 41))	('phosphodiesterase 4D', 'Gene', '5144', (52, 72))	('PDE4D', 'Gene', '5144', (36, 41))
561370	29089486	Several peaks of homozygous deletions point to genes not previously implicated as tumour suppressors, e.g., LEPROTL1, KIAA1551, MIDEAS, MAFTRR, and IGF2BP2.	('KIAA1551', 'Gene', (118, 126))	('KIAA1551', 'Gene', '55196', (118, 126))	('IGF2BP2', 'Gene', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('MIDEAS', 'Gene', (128, 134))	('MAFTRR', 'Gene', '102467146', (136, 142))	('deletions', 'Var', (28, 37))	('MAFTRR', 'Gene', (136, 142))	('LEPROTL1', 'Gene', '23484', (108, 116))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('MIDEAS', 'Gene', '91748', (128, 134))	('IGF2BP2', 'Gene', '10644', (148, 155))	('LEPROTL1', 'Gene', (108, 116))
561373	29089486	Four homozygous deletions in lung cancer suggest a role for LEPROTL1 in keeping this feedback loop in check in normal lung cells.	('role', 'Reg', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('deletions', 'Var', (16, 25))	('LEPROTL1', 'Gene', (60, 68))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('LEPROTL1', 'Gene', '23484', (60, 68))
561377	29089486	Two homozygous deletions each in myeloma and sarcoma targeted MAFTRR (MAF transcriptional regulator RNA), a long intergenic noncoding RNA gene.	('MAFTRR', 'Gene', (62, 68))	('MAF transcriptional regulator RNA', 'Gene', '102467146', (70, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('MAF transcriptional regulator RNA', 'Gene', (70, 103))	('MAFTRR', 'Gene', '102467146', (62, 68))	('targeted', 'Reg', (53, 61))	('deletions', 'Var', (15, 24))	('myeloma and sarcoma', 'Disease', 'MESH:D009101', (33, 52))
561380	29089486	Note that one homozygous deletion in sarcoma abolishes both MAF and MAFTRR, suggesting MAFTRR may still have other functions.	('MAF', 'Gene', '4094', (68, 71))	('MAF', 'Gene', '4094', (60, 63))	('MAF', 'Gene', (60, 63))	('MAF', 'Gene', (68, 71))	('MAFTRR', 'Gene', '102467146', (68, 74))	('sarcoma', 'Disease', 'MESH:D012509', (37, 44))	('MAFTRR', 'Gene', (87, 93))	('deletion', 'Var', (25, 33))	('MAF', 'Gene', '4094', (87, 90))	('sarcoma', 'Disease', (37, 44))	('MAFTRR', 'Gene', '102467146', (87, 93))	('MAF', 'Gene', (87, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('MAFTRR', 'Gene', (68, 74))	('abolishes', 'NegReg', (45, 54))
561385	29089486	Our observation of a peak of homozygous deletions suggests it could act as a rare tumour suppressor, controlling a switch in cancer nutrient and energy metabolism.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('deletions', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
561386	29089486	In this study, we aimed to identify rare tumour suppressors through a systematic pan-cancer analysis of homozygous deletions in primary tumours.	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (136, 142))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', (85, 91))	('primary tumours', 'Disease', (128, 143))	('primary tumours', 'Disease', 'MESH:D009369', (128, 143))	('tumour', 'Disease', (41, 47))	('deletions', 'Var', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
561387	29089486	Our screen detected 16 established tumour suppressors, 3 immune regions, 15 known (named) fragile sites, 24 additional intrachromosomal fragile sites, 9 regions of telomeric instability, and 32 regions showing signatures of positive selection for homozygous deletions (Fig.	('deletions', 'Var', (258, 267))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('intrachromosomal fragile sites', 'Phenotype', 'HP:0040012', (119, 149))	('tumour', 'Disease', (35, 41))
561391	29089486	VHL is only rarely targeted by homozygous deletions and is typically biallically inactivated by a point mutation combined with loss-of-heterozygosity of the other allele.	('loss-of-heterozygosity', 'NegReg', (127, 149))	('VHL', 'Gene', (0, 3))	('deletions', 'Var', (42, 51))	('point mutation', 'Var', (98, 112))	('VHL', 'Gene', '7428', (0, 3))	('inactivated', 'NegReg', (81, 92))
561397	29089486	Out of eight homozygous deletions affecting DMD (encoding dystrophin), we observe seven in sarcomas.	('DMD', 'Disease', (44, 47))	('deletions', 'Var', (24, 33))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcomas', 'Disease', (91, 99))	('DMD', 'Disease', 'MESH:D020388', (44, 47))
561398	29089486	Although DMD is the largest gene in the human genome and is part of known fragile site FRAXC, this suggests homozygous deletions of DMD may play a role in sarcoma.	('sarcoma', 'Disease', (155, 162))	('deletions', 'Var', (119, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('DMD', 'Disease', 'MESH:D020388', (132, 135))	('play', 'Reg', (140, 144))	('DMD', 'Disease', (132, 135))	('role', 'Reg', (147, 151))	('DMD', 'Disease', 'MESH:D020388', (9, 12))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('DMD', 'Disease', (9, 12))	('human', 'Species', '9606', (40, 45))
561403	29089486	Due to our strict focus on homozygous deletions rather than focal losses in general, we aim to identify tumour suppressors recurrently targeted by two independent copy number changes.	('copy', 'Var', (163, 167))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('deletions', 'Var', (38, 47))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour', 'Disease', (104, 110))
561404	29089486	This approach is not well suited to identify haploinsufficient tumour suppressors or tumour suppressors showing mainly recurrent point mutations combined with copy number losses of the other allele, as discussed above for VHL.	('point mutations', 'Var', (129, 144))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('VHL', 'Gene', (222, 225))	('tumour', 'Disease', (85, 91))	('haploinsufficient tumour', 'Disease', 'MESH:D058495', (45, 69))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('VHL', 'Gene', '7428', (222, 225))	('haploinsufficient tumour', 'Disease', (45, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('tumour', 'Disease', (63, 69))
561407	29089486	Our results provide a view on the landscape of tumour suppressors that is complementary to sequencing screens for recurrent single-nucleotide substitutions and small insertions and deletions.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('deletions', 'Var', (181, 190))	('tumour', 'Disease', (47, 53))	('single-nucleotide substitutions', 'Var', (124, 155))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
561408	29089486	Many genes frequently targeted by inactivating mutations in cancers do not seem to be frequently targeted by homozygous deletions.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('inactivating mutations', 'Var', (34, 56))
561409	29089486	This is exemplified by TP53, found mutated in a very high proportion of cases across cancer types, but homozygously deleted in less than 0.2% of cancers in this study.	('cancers', 'Disease', (145, 152))	('mutated', 'Var', (35, 42))	('cancer', 'Disease', (145, 151))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (85, 91))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
561410	29089486	Other known tumour suppressors, such as RB1 and PTEN, can readily be inactivated by both homozygous deletions and inactivating point mutations (often in combination with loss-of-heterozygosity of the other allele).	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('tumour', 'Disease', (12, 18))	('inactivated', 'NegReg', (69, 80))	('RB1', 'Gene', (40, 43))	('deletions', 'Var', (100, 109))	('inactivating point mutations', 'Var', (114, 142))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('RB1', 'Gene', '5925', (40, 43))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
561411	29089486	Adjacent tumour suppressor pairs (e.g., CDKN2A/CDKN2B, BIRC2/BIRC3, HELQ/FAM175A, ...) may be especially rewarding targets for homozygous deletion in some cases, as two mutation events can abolish all tumour suppressor activity.	('CDKN2B', 'Gene', (47, 53))	('HELQ', 'Gene', (68, 72))	('abolish', 'NegReg', (189, 196))	('CDKN2B', 'Gene', '1030', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('BIRC3', 'Gene', '330', (61, 66))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('tumour', 'Disease', (201, 207))	('tumour', 'Disease', (9, 15))	('FAM175A', 'Gene', '84142', (73, 80))	('CDKN2A', 'Gene', (40, 46))	('FAM175A', 'Gene', (73, 80))	('HELQ', 'Gene', '113510', (68, 72))	('deletion', 'Var', (138, 146))	('BIRC2', 'Gene', '329', (55, 60))	('BIRC3', 'Gene', (61, 66))	('CDKN2A', 'Gene', '1029', (40, 46))	('BIRC2', 'Gene', (55, 60))
561412	29089486	We conjecture that this study identifies a class of predominantly rare tumour suppressors, such as CPEB3 and MGMT, that are more prone to be inactivated by homozygous deletions than point mutations, a proportion of which therefore may not be readily identifiable through mutation analysis given current sample sizes.	('tumour', 'Disease', (71, 77))	('deletions', 'Var', (167, 176))	('MGMT', 'Gene', (109, 113))	('MGMT', 'Gene', '4255', (109, 113))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('CPEB3', 'Gene', (99, 104))	('CPEB3', 'Gene', '22849', (99, 104))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
561421	29089486	Step 1: Identification of hotspots of homozygous deletions: After ASCAT analysis, homozygous deletions were straightforwardly identified as regions having zero copies of both alleles in the tumour cells, each region extending from the position of the first probe being homozygously deleted to the last probe being homozygously deleted.	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', (190, 196))	('deleted', 'Var', (282, 289))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
561423	29089486	This indicates that in most regions of the genome of tumour (and normal) cells, there is strong negative selection against homozygous deletions: for many genes, removal of both copies results in a selective disadvantage of the cell in which this occurs.	('removal', 'Var', (161, 168))	('tumour', 'Disease', (53, 59))	('disadvantage', 'NegReg', (207, 219))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
561424	29089486	In each permutation, the homozygous deletions in every sample were randomly assigned to a new position in the genome (treating all chromosomes as one unit, but ensuring that each homozygous deletion fits within the borders of one chromosome).	('fits', 'Disease', 'MESH:D012640', (199, 203))	('fits', 'Disease', (199, 203))	('deletion', 'Var', (190, 198))
561427	29089486	To assess whether the list of genes affected by recurrent homozygous deletions is enriched for known tumour suppressors, we performed the following hypergeometric test.	('deletions', 'Var', (69, 78))	('tumour', 'Disease', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
561429	29089486	Step 2: Identifying peaks containing tumour suppressors: A statistical model was constructed quantifying the probability that the observed signature of deletions in a given peak (i.e., the peak in a significant homozygous deletion region from step 1) can be ascribed to local fragility alone (Fig.	('local fragility', 'Disease', (270, 285))	('tumour', 'Disease', (37, 43))	('deletions', 'Var', (152, 161))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
561431	29089486	As a third metric, we leveraged tumour-type specificity of homozygous deletions vs. small hemizygous deletions (Fig.	('deletions', 'Var', (70, 79))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour-type', 'Disease', 'MESH:D009369', (32, 43))	('tumour-type', 'Disease', (32, 43))
561432	29089486	A one-sided Fisher-Boschloo exact unconditional test for association is performed on a 2 x 2 table of the number of homozygous against hemizygous deletions and the tumour type showing the highest number of deletions (at least one homozygous) against the other tumour types combined.	('tumour', 'Phenotype', 'HP:0002664', (260, 266))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumour type', 'Disease', (260, 271))	('tumour type', 'Disease', (164, 175))	('tumour type', 'Disease', 'MESH:D009369', (260, 271))	('tumour type', 'Disease', 'MESH:D009369', (164, 175))	('deletions', 'Var', (146, 155))
561433	29089486	Only when the signature of deletions in a peak is unlikely to be explained by local fragility (q <= 0.05) do we consider the presence of a tumour suppressor in the region.	('tumour', 'Disease', (139, 145))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('deletions', 'Var', (27, 36))
561599	27610254	Molecular studies showed the EWSR1 rearrangement, confirming the diagnosis of Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (78, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('EWSR1', 'Gene', (29, 34))	('rearrangement', 'Var', (35, 48))	("Ewing's sarcoma", 'Disease', (78, 93))	('EWSR1', 'Gene', '2130', (29, 34))
561609	27610254	The t(11;22)(q24;q12) translocation results in the formation of a chimeric gene (EWSR1-FLI1), which has been found to act as an oncogenic transcription factor in ES and pPNET.	('FLI1', 'Gene', '2313', (87, 91))	('t(11;22)(q24;q12', 'Var', (4, 20))	('FLI1', 'Gene', (87, 91))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 21))	('results in', 'Reg', (36, 46))	('ES', 'Phenotype', 'HP:0012254', (162, 164))
561627	20687936	Premature termination codons within the open reading frame of gag result in a decrease in unspliced viral RNA levels.	('unspliced viral RNA levels', 'MPA', (90, 116))	('decrease', 'NegReg', (78, 86))	('Premature', 'Var', (0, 9))	('gag', 'Gene', '1491923', (62, 65))	('gag', 'Gene', (62, 65))
561636	20687936	During initial efforts to characterize the decay of unspliced RSV RNA, it was noted that deletions downstream of gag decreased unspliced viral RNA levels.	('deletions', 'Var', (89, 98))	('decreased', 'NegReg', (117, 126))	('gag', 'Gene', '1491923', (113, 116))	('gag', 'Gene', (113, 116))	('RSV', 'Species', '11886', (62, 65))	('unspliced viral RNA levels', 'MPA', (127, 153))
561637	20687936	When 400 nucleotides downstream of gag are deleted or inverted, unspliced viral RNA levels are reduced to quantities comparable to viral constructs containing a premature termination codon within gag .	('gag', 'Gene', '1491923', (35, 38))	('deleted', 'Var', (43, 50))	('gag', 'Gene', (35, 38))	('reduced', 'NegReg', (95, 102))	('gag', 'Gene', '1491923', (196, 199))	('gag', 'Gene', (196, 199))
561659	20687936	We hypothesize that this is likely due to a disruption of the RSE RNA secondary structure in this region, including a previously described strong stem loop (nts 2755-2809).	('RSE RNA', 'Gene', (62, 69))	('nts', 'Chemical', 'MESH:D009711', (157, 160))	('disruption', 'NegReg', (44, 54))	('nts 2755-2809', 'Var', (157, 170))	('RSE', 'Chemical', '-', (62, 65))
561664	20687936	To confirm that the minimal RSE was still capable of insulating the gag termination codon from NMD recognition, we transiently co-transfected CEFs with either a wildtype or dominant negative form of Upf1 with each of the viral constructs (wildtype, DeltaRSE, 2577-2732 and 2588-2732).	('RSE', 'Chemical', '-', (28, 31))	('Upf1', 'Gene', '5976', (199, 203))	('2577-2732', 'Var', (259, 268))	('gag', 'Gene', '1491923', (68, 71))	('gag', 'Gene', (68, 71))	('Upf1', 'Gene', (199, 203))	('2588-2732', 'Var', (273, 282))	('RSE', 'Chemical', '-', (254, 257))
561665	20687936	As shown previously, the wildtype virus showed no significant change in the levels of unspliced RNA, while viral RNA lacking the RSE exhibited a 1.5 fold increase in the observed steady state RNA levels in the presence of mutant Upf1 (Figure 2).	('Upf1', 'Gene', (229, 233))	('RNA levels', 'MPA', (192, 202))	('lacking', 'NegReg', (117, 124))	('Upf1', 'Gene', '5976', (229, 233))	('RSE', 'Chemical', '-', (129, 132))	('mutant', 'Var', (222, 228))	('increase', 'PosReg', (154, 162))
561667	20687936	Furthermore, an RSE fragment slightly smaller than the minimal RSE (2588-2732) exhibited nearly a 3 fold increase in the level of unspliced RNA in the presence of mutant Upf1.	('Upf1', 'Gene', (170, 174))	('RSE', 'Chemical', '-', (16, 19))	('mutant', 'Var', (163, 169))	('increase', 'PosReg', (105, 113))	('Upf1', 'Gene', '5976', (170, 174))	('level of unspliced RNA', 'MPA', (121, 143))	('RSE', 'Chemical', '-', (63, 66))
561672	20687936	A disruption of an essential RSE sub-element by these mutations would result in a loss of stability in the full-length viral RNA.	('RSE', 'Chemical', '-', (29, 32))	('mutations', 'Var', (54, 63))	('loss', 'NegReg', (82, 86))	('stability', 'MPA', (90, 99))
561676	20687936	To ensure that the internal deletions do not alter the spacing of individual RNA sub-elements within the RSE or RNA features flanking the RSE, we added back scrambled sequence at the deletion site (Figure 3D, Mix).	('RSE', 'Chemical', '-', (138, 141))	('deletions', 'Var', (28, 37))	('nts', 'Chemical', 'MESH:D009711', (90, 93))	('RSE', 'Chemical', '-', (105, 108))	('Mix', 'Gene', (209, 212))	('Mix', 'Gene', '83881', (209, 212))
561679	20687936	As a means of understanding whether the spacing to an element upstream or downstream of the minimal RSE causes the reduction in RNA levels observed from the deletion constructs, 10 nts of viral sequence were added back to either the 5' or 3' end of the minimal RSE with the deletion (see diagram in Figure 3D).	('reduction', 'NegReg', (115, 124))	('deletion', 'Var', (274, 282))	('nts', 'Chemical', 'MESH:D009711', (181, 184))	('deletion', 'Var', (157, 165))	('RNA levels', 'MPA', (128, 138))	('RSE', 'Chemical', '-', (261, 264))	('RSE', 'Chemical', '-', (100, 103))
561681	20687936	It is possible that the spacing of an RSE sub-element 3' to the deletion site is altered relative to an RNA feature 5' of the RSE.	('RSE', 'Chemical', '-', (38, 41))	('deletion', 'Var', (64, 72))	('spacing', 'MPA', (24, 31))	('RSE', 'Chemical', '-', (126, 129))	('altered', 'Reg', (81, 88))
561684	20687936	These different sub-elements seem to be dependent upon each other such that changes to any of these features result in a partial loss of RSE function.	('nts', 'Chemical', 'MESH:D009711', (25, 28))	('changes', 'Var', (76, 83))	('loss', 'NegReg', (129, 133))	('RSE function', 'MPA', (137, 149))	('RSE', 'Chemical', '-', (137, 140))
561685	20687936	Deletion of sequences within the minimal RSE suggests that the spacing of sub-elements within and flanking the RSE are important for maintaining function.	('RSE', 'Chemical', '-', (111, 114))	('nts', 'Chemical', 'MESH:D009711', (83, 86))	('function', 'MPA', (145, 153))	('RSE', 'Chemical', '-', (41, 44))	('Deletion', 'Var', (0, 8))
561691	20687936	Five stop codons were inserted into the RSE at nucleotide positions 2535, 2586, 2631, 2685 and 2736; numbered 1-5, respectively (Figure 4A).	('2685', 'Var', (86, 90))	('2631', 'Var', (80, 84))	('RSE', 'Chemical', '-', (40, 43))
561693	20687936	When a single nucleotide insertion immediately 5' of the stop codon constitutively forced the ribosome past the gag stop codon and into the pol open reading frame, the termination codon at position 2685 resulted in a reduction in the steady state levels of unspliced viral RNA (Figure 4B, Readthrough gag stop 4).	('single nucleotide insertion', 'Var', (7, 34))	('gag', 'Gene', (301, 304))	('steady', 'MPA', (234, 240))	('unspliced viral RNA', 'MPA', (257, 276))	('gag', 'Gene', '1491923', (301, 304))	('gag', 'Gene', '1491923', (112, 115))	('gag', 'Gene', (112, 115))	('reduction', 'NegReg', (217, 226))	('forced', 'Reg', (83, 89))
561694	20687936	The 5' boundary of the functional RSE as determined by truncations is 2577; however, a termination codon at position 2631 was still protected from NMD recognition (Figure 4B, Readthrough gag stop 3).	('gag', 'Gene', (187, 190))	('gag', 'Gene', '1491923', (187, 190))	('RSE', 'Chemical', '-', (34, 37))	('2577', 'Var', (70, 74))	('truncations', 'Var', (55, 66))
561700	20687936	The 100 nucleotide core fragment encompasses the structural features of the minimal RSE that we have herein named stem 2, single-stranded region 2 and stem 3; although, sequence flanking this region may enhance RSE function when present in the full-length viral RNA.	('RSE function', 'MPA', (211, 223))	('RSE', 'Chemical', '-', (211, 214))	('RSE', 'Chemical', '-', (84, 87))	('sequence', 'Var', (169, 177))	('enhance', 'PosReg', (203, 210))
561709	20687936	While Env and Src are expressed from two separate spliced transcripts, Pol is generated by a programmed -1 frameshift that repositions the ribosome out of the gag reading frame and into the pol reading frame.	('gag', 'Gene', '1491923', (159, 162))	('gag', 'Gene', (159, 162))	('repositions', 'Reg', (123, 134))	('Env', 'Gene', (6, 9))	('Env', 'Gene', '100616444', (6, 9))	('Src', 'Gene', (14, 17))	('Src', 'Gene', '6714', (14, 17))	('frameshift', 'Var', (107, 117))
561730	20687936	Furthermore, when as little as 10 nucleotides of additional RSE sequence were added to the 5' end of the minimal RSE (2577-2732), a modest but reproducible increase in the level of RNA was observed.	('increase', 'PosReg', (156, 164))	('2577-2732', 'Var', (118, 127))	('RSE', 'Chemical', '-', (60, 63))	('RSE', 'Chemical', '-', (113, 116))	('RNA', 'MPA', (181, 184))
561732	20687936	This enhancement was absent when the same truncated RSE fragments were tested after the natural gag termination codon (Figure 1, compare 2577-2732 and 2567-2732).	('gag', 'Gene', '1491923', (96, 99))	('gag', 'Gene', (96, 99))	('RSE', 'Chemical', '-', (52, 55))	('nts', 'Chemical', 'MESH:D009711', (62, 65))	('2567-2732', 'Var', (151, 160))
561735	20687936	All of the mutations tested resulted in a partial reduction in RSE function, which suggests that the sequence and structure of multiple sub-elements within the RSE may work together to generate a signal or recruit a protein that identifies the correct stop codon.	('recruit', 'PosReg', (206, 213))	('mutations', 'Var', (11, 20))	('reduction', 'NegReg', (50, 59))	('nts', 'Chemical', 'MESH:D009711', (145, 148))	('RSE', 'Chemical', '-', (160, 163))	('RSE', 'Chemical', '-', (63, 66))	('RSE function', 'MPA', (63, 75))
561737	20687936	Additional deletions that reduce the size of the RSE below this critical limit would be unstable because the gag termination codon would be moved closer to a yet uncharacterized destabilizing element further downstream from the RSE.	('RSE', 'Chemical', '-', (49, 52))	('RSE', 'Chemical', '-', (228, 231))	('deletions', 'Var', (11, 20))	('gag', 'Gene', (109, 112))	('gag', 'Gene', '1491923', (109, 112))
561744	20687936	The deletions within the minimal RSE suggest that there may be sequences upstream of the gag stop codon that contribute to RSE function.	('contribute', 'Reg', (109, 119))	('deletions', 'Var', (4, 13))	('RSE', 'Chemical', '-', (33, 36))	('RSE', 'Chemical', '-', (123, 126))	('gag', 'Gene', '1491923', (89, 92))	('gag', 'Gene', (89, 92))
561749	20687936	First, a study by Simpson and Stoltzfus showed that the src mRNA, but not the env mRNA, undergoes decay when premature termination codons are generated by deletions that cause frameshifts.	('decay', 'MPA', (98, 103))	('env', 'Gene', (78, 81))	('frameshifts', 'Var', (176, 187))	('env', 'Gene', '100616444', (78, 81))	('deletions', 'Var', (155, 164))	('src mRNA', 'MPA', (56, 64))
561760	20687936	It seems unlikely that the viral NMD evasion is due to a fold-back mechanism since multiple insertions and deletions as small as 10 nts are capable of significantly reducing RSE function.	('reducing', 'NegReg', (165, 173))	('NMD', 'MPA', (33, 36))	('RSE function', 'MPA', (174, 186))	('deletions', 'Var', (107, 116))	('RSE', 'Chemical', '-', (174, 177))	('nts', 'Chemical', 'MESH:D009711', (132, 135))	('insertions', 'Var', (92, 102))
561771	20687936	We have also described in this study a size dependence of the RSE, such that shortening the RSE below 150 nucleotides results in a loss of function.	('loss', 'NegReg', (131, 135))	('RSE', 'Gene', (92, 95))	('RSE', 'Chemical', '-', (92, 95))	('shortening', 'Var', (77, 87))	('RSE', 'Chemical', '-', (62, 65))	('function', 'MPA', (139, 147))
561789	20687936	The 10.8 viral plasmid used to generate each of the constructs contains a deletion in the nucleocapsid region of the gag gene.	('deletion in', 'Var', (74, 85))	('gag', 'Gene', '1491923', (117, 120))	('gag', 'Gene', (117, 120))
561793	20687936	To generate each of the truncations or viral UTR insertions after the gag stop codon, PCR primers were designed that possessed an EagI recognition site in the forward primer and an SpeI recognition site in the reverse primer.	('gag', 'Gene', '1491923', (70, 73))	('gag', 'Gene', (70, 73))	('insertions', 'Var', (49, 59))
561812	20360265	The biology of tumors is further modified by factors such as epigenetic regulators of chromatin structure, and pathways that regulate protein stability such as molecular chaperones and ubiquitin-proteasome pathways.	('tumors', 'Disease', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('epigenetic', 'Var', (61, 71))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
561826	20360265	Dysregulation of HGF/c-Met signaling in tumors can occur via multiple mechanisms including mutations to the proto-oncogene MET that increase c-MET expression, and gene amplification of both ligand and receptor.	('MET', 'Gene', (123, 126))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('increase', 'PosReg', (132, 140))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('HGF', 'Gene', (17, 20))	('gene amplification', 'Var', (163, 181))	('HGF', 'Gene', '3082', (17, 20))	('occur', 'Reg', (51, 56))	('mutations', 'Var', (91, 100))	('c-MET expression', 'MPA', (141, 157))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
561829	20360265	In the adult heart HGF/c-Met interactions also regulate cardiac hypertrophy and remodeling, in part due to activation of the local renin-angiotensin system.	('HGF', 'Gene', (19, 22))	('HGF', 'Gene', '3082', (19, 22))	('regulate', 'Reg', (47, 55))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (56, 75))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (56, 75))	('local renin-angiotensin system', 'MPA', (125, 155))	('interactions', 'Var', (29, 41))	('activation', 'PosReg', (107, 117))	('remodeling', 'CPA', (80, 90))	('cardiac hypertrophy', 'Disease', (56, 75))
561846	20360265	Mutations in Notch signaling elements cause cardiac abnormalities in mice and humans, demonstrating an essential role for Notch during cardiac morphogenesis.	('cause', 'Reg', (38, 43))	('humans', 'Species', '9606', (78, 84))	('mice', 'Species', '10090', (69, 73))	('Mutations', 'Var', (0, 9))	('cardiac abnormalities', 'Disease', 'MESH:D006331', (44, 65))	('cardiac abnormalities', 'Phenotype', 'HP:0001627', (44, 65))	('cardiac abnormalities', 'Disease', (44, 65))	('rat', 'Species', '10116', (93, 96))
561858	20360265	The IGF-1R has been implicated in the development and maintenance of malignant phenotypes, and disruption of IGF-1R signaling does inhibit cancer cell growth and motility both in vitro and in vivo.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('inhibit', 'NegReg', (131, 138))	('disruption', 'Var', (95, 105))	('IGF-1R', 'Gene', '3480', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('IGF-1R', 'Gene', (109, 115))	('IGF-1R', 'Gene', '3480', (4, 10))	('IGF-1R', 'Gene', (4, 10))	('cancer', 'Disease', (139, 145))
561859	20360265	Increasing levels of circulating IGF are associated with higher risk for colon and breast cancer, and aberrant activation of IGF-1R was also associated with worse prognosis in many neoplasms, including multiple myeloma, prostate cancer, non-small cell lung cancer, and renal cell cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (237, 263))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('neoplasms', 'Disease', 'MESH:D009369', (181, 190))	('multiple myeloma', 'Phenotype', 'HP:0006775', (202, 218))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (241, 263))	('IGF', 'Protein', (33, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (237, 263))	('multiple myeloma', 'Disease', 'MESH:D009101', (202, 218))	('IGF-1R', 'Gene', '3480', (125, 131))	('colon and breast cancer', 'Disease', 'MESH:D001943', (73, 96))	('aberrant', 'Var', (102, 110))	('activation', 'PosReg', (111, 121))	('IGF-1R', 'Gene', (125, 131))	('neoplasms', 'Disease', (181, 190))	('renal cell cancer', 'Disease', (269, 286))	('renal cell cancer', 'Disease', 'MESH:C538614', (269, 286))	('renal cell cancer', 'Phenotype', 'HP:0005584', (269, 286))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('non-small cell lung cancer', 'Disease', (237, 263))	('lung cancer', 'Phenotype', 'HP:0100526', (252, 263))	('multiple myeloma', 'Disease', (202, 218))	('prostate cancer', 'Disease', 'MESH:D011471', (220, 235))	('prostate cancer', 'Phenotype', 'HP:0012125', (220, 235))	('neoplasms', 'Phenotype', 'HP:0002664', (181, 190))	('prostate cancer', 'Disease', (220, 235))
561860	20360265	Aside from the IGF-1R, abnormally activated IR by insulin or IGF-II stimulation enhances mitogenesis in cancer cells.	('enhances', 'PosReg', (80, 88))	('insulin', 'Gene', (50, 57))	('mitogenesis', 'MPA', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IGF-1R', 'Gene', (15, 21))	('insulin', 'Gene', '3630', (50, 57))	('IGF-1R', 'Gene', '3480', (15, 21))	('abnormally', 'Var', (23, 33))	('IGF-II', 'Gene', (61, 67))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('IGF-II', 'Gene', '3481', (61, 67))
561864	20360265	Heterozygote cardiac specific knock out of IGF-1R does not alter baseline function but is critical for heart recovery after myocardial infarction.	('IGF-1R', 'Gene', '3480', (43, 49))	('myocardial infarction', 'Disease', (124, 145))	('knock out', 'Var', (30, 39))	('myocardial infarction', 'Disease', 'MESH:D009203', (124, 145))	('IGF-1R', 'Gene', (43, 49))	('myocardial infarction', 'Phenotype', 'HP:0001658', (124, 145))
561872	20360265	Inhibition of intracellular signaling can suppress cell proliferation, differentiation or angiogenesis induced by diverse extracellular stimuli.	('suppress', 'NegReg', (42, 50))	('angiogenesis', 'CPA', (90, 102))	('differentiation', 'CPA', (71, 86))	('Inhibition', 'Var', (0, 10))	('cell proliferation', 'CPA', (51, 69))	('rat', 'Species', '10116', (63, 66))
561880	20360265	Vinaxanthone, Q12713, hispidospermidine, caloporoside, CRM-51005, CRM-51006 have shown anti-cancer activity.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('caloporoside', 'Chemical', 'MESH:C091111', (41, 53))	('Q12713', 'Chemical', '-', (14, 20))	('CRM-51006', 'Var', (66, 75))	('Q12713', 'Var', (14, 20))	('Vinaxanthone', 'Chemical', 'MESH:C086647', (0, 12))	('CRM-51005', 'Var', (55, 64))	('hispidospermidine', 'Chemical', '-', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
561886	20360265	In cancers, epigenetic modifications are known to regulate tumor-suppressor genes or oncogenes, leading to dysregulated cellular proliferation and apoptosis.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('dysregulated cellular proliferation', 'CPA', (107, 142))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('apoptosis', 'CPA', (147, 156))	('rat', 'Species', '10116', (136, 139))	('epigenetic modifications', 'Var', (12, 36))	('leading to', 'Reg', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
561887	20360265	Epigenetic regulation of cellular phenotype and proliferation is also recognized to play a role in malignant transformation and tumorigenesis, with DNA methylation and histone modifications being the most developed targets for anticancer therapy DNA methylation occurs at specific DNA sequences, termed CpG islands, and are most often located near promoters.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('rat', 'Species', '10116', (55, 58))	('methylation', 'Var', (250, 261))
561889	20360265	For example, hypermethylation of CpG island near the promoter of the estrogen gene and methylation of the APC and APC2 gene in colon and rectal cancer tissue has been reported in over 50% of patients.	('patients', 'Species', '9606', (191, 199))	('APC2', 'Gene', '10297', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('APC', 'Gene', (106, 109))	('hypermethylation', 'Var', (13, 29))	('APC', 'Gene', '324', (106, 109))	('colon and rectal cancer', 'Disease', 'MESH:D012004', (127, 150))	('rectal cancer', 'Phenotype', 'HP:0100743', (137, 150))	('APC', 'Gene', (114, 117))	('APC', 'Gene', '324', (114, 117))	('methylation', 'Var', (87, 98))	('APC2', 'Gene', (114, 118))	('reported', 'Reg', (167, 175))
561894	20360265	Genes that regulate tumor response to cytotoxic therapy are also regulated by epigenetic mechanisms.	('epigenetic', 'Var', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (20, 25))
561897	20360265	It is becoming clear that epigenetic modifications occur in and contribute to the pathogenesis of cardiovascular conditions including cardiac hypertrophy and heart failure.	('epigenetic modifications', 'Var', (26, 50))	('heart failure', 'Disease', (158, 171))	('contribute', 'Reg', (64, 74))	('cardiac hypertrophy', 'Disease', (134, 153))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (134, 153))	('heart failure', 'Phenotype', 'HP:0001635', (158, 171))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (134, 153))	('heart failure', 'Disease', 'MESH:D006333', (158, 171))
561899	20360265	HDAC5 or HDAC9 deletion leads to cardiac hypertrophy.	('HDAC9', 'Gene', '9734', (9, 14))	('HDAC9', 'Gene', (9, 14))	('HDAC5', 'Gene', '10014', (0, 5))	('HDAC5', 'Gene', (0, 5))	('deletion', 'Var', (15, 23))	('cardiac hypertrophy', 'Disease', (33, 52))	('leads to', 'Reg', (24, 32))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (33, 52))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (33, 52))
561901	20360265	Differential chromatin scanning methods applied to myocardium from humans with dilated cardiomyopathy reveals global epigenetic changes involving many canonical signaling pathways implicated in the regulation of myocardial function.	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (79, 101))	('humans', 'Species', '9606', (67, 73))	('canonical signaling pathways', 'Pathway', (151, 179))	('dilated cardiomyopathy', 'Disease', (79, 101))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (79, 101))	('epigenetic changes', 'Var', (117, 135))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (87, 101))
561914	20360265	RTA 402 is a dual inhibitor for NF-kappaB and I-kappa-b kinase (IKK)/STAT, and it induces nuclear erythroid 2 p45 related factor (Nrf)-2-mediated transcription of antioxidant proteins which helps suppress tumor proliferation.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('AT', 'Disease', 'None', (71, 73))	('NF-kappaB', 'Gene', (32, 41))	('p45', 'Gene', '4778', (110, 113))	('nuclear', 'MPA', (90, 97))	('p45', 'Gene', (110, 113))	('RTA', 'Var', (0, 3))	('rat', 'Species', '10116', (218, 221))	('tumor', 'Disease', (205, 210))	('suppress', 'NegReg', (196, 204))	('Nrf', 'Gene', (130, 133))	('Nrf', 'Gene', '55922', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('NF-kappaB', 'Gene', '4790', (32, 41))	('induces', 'PosReg', (82, 89))
561923	20360265	Cardiac-specific inhibition of NF-kappaB attenuates Angiotensin II (AngII) induced left ventricular (LV) hypertrophy in vivo.	('Angiotensin II', 'Gene', (52, 66))	('attenuates', 'NegReg', (41, 51))	('Angiotensin II', 'Gene', '183', (52, 66))	('left ventricular (LV) hypertrophy', 'Disease', 'MESH:D017379', (83, 116))	('inhibition', 'Var', (17, 27))	('NF-kappaB', 'Gene', '4790', (31, 40))	('AngII', 'Gene', (68, 73))	('AngII', 'Gene', '183', (68, 73))	('NF-kappaB', 'Gene', (31, 40))
561933	20360265	Studies in cell systems and mice indicate the miRNAs may play a pivotal role in altering global signaling networks during progression of cardiac pathology, and dysregulation of miRNAs could promote cardiac dysfunction.	('promote', 'PosReg', (190, 197))	('miRNAs', 'Gene', (177, 183))	('global', 'MPA', (89, 95))	('mice', 'Species', '10090', (28, 32))	('altering', 'Reg', (80, 88))	('cardiac dysfunction', 'Disease', (198, 217))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (198, 217))	('dysregulation', 'Var', (160, 173))
561942	20360265	Dysfunction in the regulation of anti- or pro-apoptotic genes confers enhanced survival and chemotherapy resistance to cancer cells.	('anti- or pro-apoptotic genes', 'Gene', (33, 61))	('Dysfunction', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('survival', 'CPA', (79, 87))	('regulation', 'MPA', (19, 29))	('enhanced', 'PosReg', (70, 78))	('chemotherapy resistance', 'CPA', (92, 115))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
561946	20360265	LY2181308 is an antisense molecule targeting survivin currently in phase I testing.	('survivin', 'Gene', '11799', (45, 53))	('LY2181308', 'Var', (0, 9))	('survivin', 'Gene', (45, 53))	('LY2181308', 'Chemical', 'MESH:C529350', (0, 9))
561948	20360265	YM155 sensitizes NSCLC cells to radiation both in vitro and in vivo, and this effect is likely attributable, at least in part, to the inhibition of DNA repair and enhancement of apoptosis that result from the down-regulation of survivin expression.	('enhancement', 'PosReg', (163, 174))	('survivin', 'Gene', '11799', (228, 236))	('DNA', 'Protein', (148, 151))	('apoptosis', 'CPA', (178, 187))	('YM155', 'Var', (0, 5))	('inhibition', 'NegReg', (134, 144))	('down-regulation', 'NegReg', (209, 224))	('survivin', 'Gene', (228, 236))	('sensitizes', 'Reg', (6, 16))
561958	20360265	TRAIL is also required for serum-inducible IGF-1R expression, and antisense IGF-1R inhibits TRAIL-induced VSMC proliferation.	('TRAIL', 'Gene', (92, 97))	('IGF-1R', 'Gene', '3480', (43, 49))	('rat', 'Species', '10116', (118, 121))	('TRAIL', 'Gene', (0, 5))	('IGF-1R', 'Gene', (43, 49))	('inhibits', 'NegReg', (83, 91))	('VSMC', 'Chemical', '-', (106, 110))	('TRAIL', 'Gene', '8743', (92, 97))	('antisense', 'Var', (66, 75))	('IGF-1R', 'Gene', (76, 82))	('TRAIL', 'Gene', '8743', (0, 5))	('IGF-1R', 'Gene', '3480', (76, 82))
561963	20360265	Inhibitors of PARP-1, including Olaparib and AG-014699 are currently in phase I and II of clinical trials as novel cancer therapeutics and thus far no adverse effects on the heart have been reported.	('cancer', 'Disease', (115, 121))	('PARP-1', 'Gene', (14, 20))	('PARP-1', 'Gene', '142', (14, 20))	('AG-014699', 'Var', (45, 54))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('Olaparib', 'Chemical', 'MESH:C531550', (32, 40))	('AG-014699', 'Chemical', 'MESH:C531549', (45, 54))
561965	20360265	Several studies demonstrate that inhibition of PARP enzyme can efficiently reduce oxidative myocardial damage.	('inhibition', 'Var', (33, 43))	('PARP', 'Gene', (47, 51))	('reduce', 'NegReg', (75, 81))	('rat', 'Species', '10116', (23, 26))	('PARP', 'Gene', '142', (47, 51))	('myocardial damage', 'Disease', 'MESH:D009202', (92, 109))	('myocardial damage', 'Disease', (92, 109))
561970	20360265	Moreover, for those patients with specific DNA-repair defects, including those arising in carriers of breast-ovarian cancer (BRCA) 1 or BRCA2 mutations, the additional inhibition of PARP mediated DNA repair pathways would likely lead to less effective repair of DNA damage in cardiac tissue as well as in cancer cells.	('less', 'NegReg', (237, 241))	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('breast-ovarian cancer (BRCA) 1', 'Gene', (102, 132))	('breast-ovarian cancer (BRCA) 1', 'Gene', '672', (102, 132))	('cancer', 'Disease', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('repair', 'MPA', (252, 258))	('PARP', 'Gene', (182, 186))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('BRCA2', 'Gene', (136, 141))	('inhibition', 'NegReg', (168, 178))	('patients', 'Species', '9606', (20, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('PARP', 'Gene', '142', (182, 186))	('BRCA2', 'Gene', '675', (136, 141))
561977	20360265	Inhibition of Hsp90 in cancer cells leads to ubiquitin-proteasome degradation of a large population of oncogenic client proteins, with alterations in multiple steps of carcinogenesis and cancer progression.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('Hsp90', 'Gene', (14, 19))	('cancer', 'Disease', (187, 193))	('rat', 'Species', '10116', (139, 142))	('alterations', 'Reg', (135, 146))	('Hsp90', 'Gene', '3320', (14, 19))	('cancer', 'Disease', (23, 29))	('carcinogenesis', 'Disease', 'MESH:D063646', (168, 182))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('Inhibition', 'Var', (0, 10))	('carcinogenesis', 'Disease', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
561988	20360265	Thus further work will be necessary to fully understand the cardiac effects of targeting Hsp90 activity on cardiac function and response to stress.	('targeting', 'Var', (79, 88))	('activity', 'MPA', (95, 103))	('Hsp90', 'Gene', '3320', (89, 94))	('Hsp90', 'Gene', (89, 94))
561998	20360265	A few reports of cardiac failure occurring in patients during treatment with bortezomib suggest that under some circumstances inactivation of the cardiac proteasome can result in adverse effects on the heart.	('cardiac failure', 'Disease', 'MESH:D006333', (17, 32))	('bortezomib', 'Chemical', 'MESH:D000069286', (77, 87))	('inactivation', 'Var', (126, 138))	('heart', 'MPA', (202, 207))	('patients', 'Species', '9606', (46, 54))	('cardiac proteasome', 'Protein', (146, 164))	('cardiac failure', 'Disease', (17, 32))	('cardiac failure', 'Phenotype', 'HP:0001635', (17, 32))	('result', 'Reg', (169, 175))
562006	20360265	Restricted deletion of beta1 integrin in myocytes leads to myocardial fibrosis and development of spontaneous dilated cardiomyopathy in 6 month old mice, as well as an explained response to pressure overload without evidence of cell death.	('beta1 integrin', 'Gene', '3688', (23, 37))	('myocardial fibrosis', 'Disease', (59, 78))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (110, 132))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (118, 132))	('response to pressure overload', 'MPA', (178, 207))	('mice', 'Species', '10090', (148, 152))	('myocardial fibrosis', 'Disease', 'MESH:D005355', (59, 78))	('dilated cardiomyopathy', 'Disease', (110, 132))	('beta1 integrin', 'Gene', (23, 37))	('deletion', 'Var', (11, 19))	('myocardial fibrosis', 'Phenotype', 'HP:0001685', (59, 78))	('leads to', 'Reg', (50, 58))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (110, 132))
562009	20360265	Mice with gain-of-function mutation in alpha5 integrin develop fibrotic changes, with decreased expression of connectin-43, loss of functional gap junctions, and abnormal intercalated disks.	('loss', 'NegReg', (124, 128))	('fibrotic changes', 'CPA', (63, 79))	('connectin-43', 'Protein', (110, 122))	('intercalated disks', 'CPA', (171, 189))	('alpha5 integrin', 'Protein', (39, 54))	('expression', 'MPA', (96, 106))	('mutation', 'Var', (27, 35))	('gain-of-function', 'PosReg', (10, 26))	('decreased', 'NegReg', (86, 95))	('Mice', 'Species', '10090', (0, 4))
562011	20360265	Alterations in Src/FAK signalling has been associate with several tumors, including breast, colon, pancreatic, ovarian, cervical, kidney, lung, and melanoma.	('colon', 'Disease', (92, 97))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('Alterations', 'Var', (0, 11))	('pancreatic', 'Disease', 'MESH:D010195', (99, 109))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('Src', 'Phenotype', 'HP:0100242', (15, 18))	('breast', 'Disease', (84, 90))	('pancreatic', 'Disease', (99, 109))	('cervical', 'Disease', (120, 128))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('associate', 'Reg', (43, 52))	('rat', 'Species', '10116', (4, 7))	('kidney', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Src/FAK signalling', 'MPA', (15, 33))	('tumors', 'Disease', (66, 72))	('lung', 'Disease', (138, 142))	('ovarian', 'Disease', (111, 118))	('ovarian', 'Disease', 'MESH:D010051', (111, 118))
562014	20360265	In the heart, FAK is activated in response to pressure overload, mechanical stretch and deformation of adhesion plaques, atrial natriuretic factor (ANF), angiotensin II, and endothelin-I.	('ANF', 'Gene', (148, 151))	('ANF', 'Gene', '4878', (148, 151))	('deformation', 'Var', (88, 99))	('angiotensin II', 'Gene', '183', (154, 168))	('atrial natriuretic factor', 'Gene', (121, 146))	('angiotensin II', 'Gene', (154, 168))	('atrial natriuretic factor', 'Gene', '4878', (121, 146))
562016	20360265	Mice with cardiac deletion of FAK are viable, but under pressure overload develop a dilated cardiomyopathyThese observations suggest that inhibition of Src and FAK would lead to cardiac effects via alterations of cell-cell and cell-matrix interactions.	('rat', 'Species', '10116', (202, 205))	('inhibition', 'NegReg', (138, 148))	('lead to', 'Reg', (170, 177))	('cell-cell', 'CellLine', 'CVCL:0320', (213, 222))	('FAK', 'Gene', (160, 163))	('FAK', 'Gene', (30, 33))	('alterations', 'Reg', (198, 209))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (84, 106))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (92, 106))	('Src', 'Phenotype', 'HP:0100242', (152, 155))	('cardiac effects', 'MPA', (178, 193))	('Mice', 'Species', '10090', (0, 4))	('Src', 'Gene', (152, 155))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (84, 106))	('dilated cardiomyopathy', 'Disease', (84, 106))	('deletion', 'Var', (18, 26))
562034	31133068	Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed.	('clinical', 'Species', '191496', (112, 120))	('fusions', 'Var', (63, 70))	('copy number variations', 'Var', (35, 57))
562050	31133068	However, these have typically been developed to detect the spectrum of mutations present in adult cancer, and often, genes important in pediatric cancer are not interrogated.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('pediatric cancer', 'Disease', (136, 152))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (71, 80))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('pediatric cancer', 'Disease', 'MESH:D009369', (136, 152))
562051	31133068	Our laboratory has designed, validated, and implemented comprehensive-targeted sequencing panels that cover single nucleotide variants (SNV), small insertions/deletions (indel), copy number alterations (CNV), and fusion genes that are recurrent in pediatric (and often adult) cancers.	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('small insertions/deletions', 'Var', (142, 168))	('copy number alterations', 'Var', (178, 201))	('single nucleotide variants', 'Var', (108, 134))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('cancers', 'Disease', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('indel', 'Chemical', '-', (170, 175))
562053	31133068	Other studies have evaluated the use of whole-exome/transcriptome sequencing in the pediatric oncology population to identify clinically actionable variants in both the upfront and relapsed settings, as well as the feasibility of real-time molecular diagnosis from tumor specimens.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', (265, 270))	('variants', 'Var', (148, 156))	('oncology', 'Phenotype', 'HP:0002664', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('clinical', 'Species', '191496', (126, 134))
562056	31133068	The panels also contain probes covering at least a 300-bp TERT promoter region as well as four single nucleotide polymorphisms (SNPs) in TPMT (rs1142345, rs1800462 and rs1800460) and NUDT15 (rs116855232) genes associated with increased risk of thiopurine-related toxicities.	('rs1800462', 'Var', (154, 163))	('rs116855232', 'Var', (191, 202))	('rs1800460', 'Var', (168, 177))	('rs1800462', 'Mutation', 'rs1800462', (154, 163))	('rs116855232', 'Mutation', 'rs116855232', (191, 202))	('TPMT', 'Gene', '7172', (137, 141))	('toxicities', 'Disease', (263, 273))	('NUDT15', 'Gene', '55270', (183, 189))	('rs1142345', 'Mutation', 'rs1142345', (143, 152))	('TERT', 'Gene', (58, 62))	('TERT', 'Gene', '7015', (58, 62))	('thiopurine', 'Chemical', '-', (244, 254))	('rs1142345', 'Var', (143, 152))	('NUDT15', 'Gene', (183, 189))	('rs1800460', 'Mutation', 'rs1800460', (168, 177))	('toxicities', 'Disease', 'MESH:D064420', (263, 273))	('TPMT', 'Gene', (137, 141))
562058	31133068	For targeted RNA sequencing, custom DNA primers were designed using ArcherDX Assay Designer (ArcherDX, Boulder, CO) to cover 586 known fusion transcripts and potential novel fusions associated with 106 cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('associated', 'Reg', (182, 192))	('fusions', 'Var', (174, 181))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))
562082	31133068	Clinical impact was determined based on effect on diagnosis, prognosis, and potential treatment decision-making according to currently available evidence including professional guidelines outlined by the Children's Oncology Group (COG) and the National Comprehensive Cancer Network (NCCN) among others: (1) variants qualify the patients for a FDA-approved therapy or to be enrolled in a clinical trial; (2) variants define or contribute to the diagnosis of a tumor or a subtype of tumor; (3) variants that define or contribute to patient risk stratification.	('patient', 'Species', '9606', (328, 335))	('Oncology', 'Phenotype', 'HP:0002664', (215, 223))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('tumor', 'Disease', (481, 486))	('contribute', 'Reg', (426, 436))	('tumor', 'Disease', 'MESH:D009369', (481, 486))	('Cancer', 'Disease', 'MESH:D009369', (267, 273))	('define', 'Reg', (416, 422))	('patient', 'Species', '9606', (530, 537))	('clinical', 'Species', '191496', (387, 395))	('variants', 'Var', (407, 415))	('Clinical', 'Species', '191496', (0, 8))	('variants', 'Var', (492, 500))	('tumor', 'Phenotype', 'HP:0002664', (481, 486))	('patients', 'Species', '9606', (328, 336))	('tumor', 'Disease', (459, 464))	('contribute', 'Reg', (516, 526))	('Cancer', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('variants', 'Var', (307, 315))	('Children', 'Species', '9606', (204, 212))	('Cancer', 'Disease', (267, 273))
562087	31133068	Somatic findings were considered potentially germline if they met several specific criteria: (1) pathogenic/likely pathogenic variants in genes known to be associated with cancer predisposition with variant allele frequency (VAF) between 40 and 100%; (2) large indels or exonic deletions/duplications in genes known to be associated with cancer predisposition regardless of VAF; and/or (3) suspected germline pathogenic variants regardless of VAF if the variant is a known founder mutation or if clinical features (such as tumor type) suggest that germline predisposition related to the involved variant is more likely.	('tumor', 'Disease', 'MESH:D009369', (523, 528))	('VAF', 'Chemical', '-', (443, 446))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('VAF', 'Chemical', '-', (374, 377))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('variant', 'Var', (454, 461))	('tumor', 'Phenotype', 'HP:0002664', (523, 528))	('exonic deletions/duplications', 'Var', (271, 300))	('clinical', 'Species', '191496', (496, 504))	('indel', 'Chemical', '-', (261, 266))	('variants', 'Var', (420, 428))	('cancer', 'Disease', (172, 178))	('VAF', 'Chemical', '-', (225, 228))	('cancer', 'Disease', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('variants', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('tumor', 'Disease', (523, 528))	('large indels', 'Var', (255, 267))
562088	31133068	In the CNS and non-CNS solid cases, TPMT and NUDT15 pharmacogenomic variants along with MPL p.Lys29Asn (MPL Baltimore) were filtered out pre-analysis.	('TPMT', 'Gene', '7172', (36, 40))	('MPL', 'Gene', (88, 91))	('NUDT15', 'Gene', '55270', (45, 51))	('MPL', 'Gene', '4352', (104, 107))	('p.Lys29Asn', 'Mutation', 'p.K29N', (92, 102))	('NUDT15', 'Gene', (45, 51))	('MPL', 'Gene', '4352', (88, 91))	('p.Lys29Asn', 'Var', (92, 102))	('TPMT', 'Gene', (36, 40))	('MPL', 'Gene', (104, 107))
562089	31133068	TPMT and NUDT15 significant variants were included in analysis of therapeutic impact in liquid tumor cases.	('TPMT', 'Gene', (0, 4))	('variants', 'Var', (28, 36))	('NUDT15', 'Gene', '55270', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('TPMT', 'Gene', '7172', (0, 4))	('NUDT15', 'Gene', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
562092	31133068	The sensitivity and specificity for both panels were > 99.99% for SNVs and indels with average positive predictive values of 81.23% and 88.79% for CHMP and CSTP, respectively, for the HapMap sample (Additional file 1: Table S3).	('indel', 'Chemical', '-', (75, 80))	('indels', 'Var', (75, 81))	('CSTP', 'Chemical', '-', (156, 160))	('SNVs', 'Var', (66, 70))
562094	31133068	The detection limit was set at 5% VAF for SNVs and indels in the Concord pipeline, and all variants at or above 5% were correctly identified.	('SNVs', 'Var', (42, 46))	('indels', 'Var', (51, 57))	('VAF', 'Chemical', '-', (34, 37))	('indel', 'Chemical', '-', (51, 56))
562099	31133068	Overall, 2254 clinically significant Tier 1 or 2 variants of any type were detected across all panels, including 397 SNVs/indels in 101 different genes (Additional file 2: Figure S4), 1751 CNVs (Fig.	('clinical', 'Species', '191496', (14, 22))	('indel', 'Chemical', '-', (122, 127))	('variants', 'Var', (49, 57))	('SNVs/indels', 'Var', (117, 128))	('detected', 'Reg', (75, 83))
562105	31133068	An overall summary of Tier 1 and 2 sequence and fusion variants identified in > 1 solid tumor sample by frequency, age, and tumor type is displayed in (Fig.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('variants', 'Var', (55, 63))	('tumor', 'Disease', (124, 129))	('solid tumor', 'Disease', (82, 93))	('solid tumor', 'Disease', 'MESH:D009369', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
562108	31133068	Fusions were most often associated with sarcoma or carcinoma diagnosis, consisting of classic/canonical fusions as well as eight novel/rare fusions (Fig.	('Fusions', 'Var', (0, 7))	('associated', 'Reg', (24, 34))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('carcinoma', 'Disease', (51, 60))	('sarcoma', 'Disease', (40, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('carcinoma', 'Disease', 'MESH:D002277', (51, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
562115	31133068	Low-grade astrocytomas, including pilocytic astrocytoma, were the most commonly tested tumor type, and as a result, the most common alteration was a BRAF fusion or variant (V600E or T599dup), present in 30.7% (n = 31/101) of cases (Fig.	('astrocytoma', 'Phenotype', 'HP:0009592', (44, 55))	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('T599dup', 'Mutation', 'c.599dupT', (182, 189))	('T599dup', 'Var', (182, 189))	('V600E', 'Mutation', 'rs113488022', (173, 178))	('astrocytomas', 'Disease', 'MESH:D001254', (10, 22))	('tumor', 'Disease', (87, 92))	('astrocytoma', 'Phenotype', 'HP:0009592', (10, 21))	('pilocytic astrocytoma', 'Disease', (34, 55))	('V600E', 'Var', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('astrocytomas', 'Disease', (10, 22))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (34, 55))
562116	31133068	After BRAF alterations, the most common Tier 1 or 2 sequence variants were TP53 and H3F3A K27 M. Most cases contained only one Tier 1 or 2 SNV/indel or fusion, with 8% (n = 8) tumors containing >= 3 sequence alterations (Fig.	('alterations', 'Var', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('indel', 'Chemical', '-', (143, 148))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('H3F3A', 'Gene', '3020', (84, 89))	('BRAF', 'Gene', '673', (6, 10))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('TP53', 'Gene', (75, 79))	('K27 M', 'Mutation', 'p.K27M', (90, 95))	('BRAF', 'Gene', (6, 10))	('TP53', 'Gene', '7157', (75, 79))	('H3F3A', 'Gene', (84, 89))
562120	31133068	Of those Tier 1 or 2 variants, CNVs were the most common alteration identified in 70.9% (95/134) of panels followed by SNVs/indels (62.7%, 84/134) and fusions (23.9%, 32/134).	('CNVs', 'Var', (31, 35))	('SNVs/indels', 'Var', (119, 130))	('variants', 'Var', (21, 29))	('indel', 'Chemical', '-', (124, 129))
562122	31133068	Clinically significant CNVs were more common in ALL, the most common of which was -9p or loss of heterozygosity (LOH) of 9p including CDKN2A, CDKN2B, and PAX5.	('CDKN2B', 'Gene', (142, 148))	('loss', 'Var', (89, 93))	('Clinical', 'Species', '191496', (0, 8))	('CNVs', 'Disease', (23, 27))	('PAX5', 'Gene', '5079', (154, 158))	('-9p', 'Var', (82, 85))	('CDKN2A', 'Gene', (134, 140))	('CDKN2B', 'Gene', '1030', (142, 148))	('PAX5', 'Gene', (154, 158))	('CDKN2A', 'Gene', '1029', (134, 140))	('ALL', 'Phenotype', 'HP:0006721', (48, 51))
562124	31133068	The most commonly identified variants in leukemia/lymphoma specimens were in NRAS (12.7%, 17/134), including patients with B-ALL, acute myelogenous leukemia (AML), JMML, T-ALL, and T-myeloid leukemia (Fig.	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (136, 156))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (130, 156))	('patients', 'Species', '9606', (109, 117))	('acute myelogenous leukemia', 'Disease', (130, 156))	('AML', 'Disease', 'MESH:D015470', (158, 161))	('JMML', 'Disease', (164, 168))	('NRAS', 'Gene', '4893', (77, 81))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('AML', 'Disease', (158, 161))	('leukemia/lymphoma', 'Disease', (41, 58))	('AML', 'Phenotype', 'HP:0004808', (158, 161))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (130, 156))	('T-myeloid leukemia', 'Disease', (181, 199))	('T-ALL', 'Disease', (170, 175))	('ALL', 'Phenotype', 'HP:0006721', (172, 175))	('T-myeloid leukemia', 'Disease', 'MESH:D007951', (181, 199))	('ALL', 'Phenotype', 'HP:0006721', (125, 128))	('leukemia', 'Phenotype', 'HP:0001909', (41, 49))	('leukemia/lymphoma', 'Disease', 'MESH:D007938', (41, 58))	('NRAS', 'Gene', (77, 81))	('variants', 'Var', (29, 37))	('leukemia', 'Phenotype', 'HP:0001909', (191, 199))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (183, 199))	('JMML', 'Disease', 'MESH:D054429', (164, 168))
562125	31133068	The majority of these patients also had variants and/or fusions identified in other genes tested.	('fusions', 'Var', (56, 63))	('patients', 'Species', '9606', (22, 30))	('variants', 'Var', (40, 48))
562126	31133068	KRAS hotspot variants in codons 12, 13, and 61 were the second most common finding, present exclusively in patients with B-ALL, followed by variants in PTPN11, TP53, and NOTCH1 (Fig.	('variants', 'Var', (13, 21))	('NOTCH1', 'Gene', '4851', (170, 176))	('NOTCH1', 'Gene', (170, 176))	('variants', 'Var', (140, 148))	('ALL', 'Phenotype', 'HP:0006721', (123, 126))	('TP53', 'Gene', '7157', (160, 164))	('TP53', 'Gene', (160, 164))	('PTPN11', 'Gene', '5781', (152, 158))	('KRAS', 'Gene', (0, 4))	('patients', 'Species', '9606', (107, 115))	('PTPN11', 'Gene', (152, 158))	('KRAS', 'Gene', '3845', (0, 4))
562127	31133068	When classified by tumor type, the majority of variants in B-ALL were in KRAS, NOTCH1, PAX5, CREBBP, PTPN11, and JAK2.	('CREBBP', 'Gene', (93, 99))	('KRAS', 'Gene', (73, 77))	('variants', 'Var', (47, 55))	('B-ALL', 'Gene', (59, 64))	('KRAS', 'Gene', '3845', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('ALL', 'Phenotype', 'HP:0006721', (61, 64))	('JAK2', 'Gene', (113, 117))	('CREBBP', 'Gene', '1387', (93, 99))	('PAX5', 'Gene', '5079', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PTPN11', 'Gene', '5781', (101, 107))	('tumor', 'Disease', (19, 24))	('PAX5', 'Gene', (87, 91))	('NOTCH1', 'Gene', '4851', (79, 85))	('NOTCH1', 'Gene', (79, 85))	('JAK2', 'Gene', '3717', (113, 117))	('PTPN11', 'Gene', (101, 107))
562128	31133068	In AML, the most common mutations identified were in NRAS, RUNX1, and FLT3.	('FLT3', 'Gene', (70, 74))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('NRAS', 'Gene', (53, 57))	('RUNX1', 'Gene', '861', (59, 64))	('RUNX1', 'Gene', (59, 64))	('NRAS', 'Gene', '4893', (53, 57))	('mutations', 'Var', (24, 33))	('common', 'Reg', (17, 23))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('FLT3', 'Gene', '2322', (70, 74))	('AML', 'Disease', (3, 6))
562130	31133068	Finally, 15 patients (12.1%) had clinically significant pharmacogenomic variants detected in TPMT and NUDT15, including 1 ALL case with homozygous pharmacogenetic variants in NUDT15 that prompted alterations in thiopurine dosing.	('NUDT15', 'Gene', (175, 181))	('patients', 'Species', '9606', (12, 20))	('NUDT15', 'Gene', (102, 108))	('thiopurine', 'MPA', (211, 221))	('TPMT', 'Gene', (93, 97))	('ALL', 'Phenotype', 'HP:0006721', (122, 125))	('variants', 'Var', (72, 80))	('clinical', 'Species', '191496', (33, 41))	('alterations', 'Reg', (196, 207))	('NUDT15', 'Gene', '55270', (175, 181))	('NUDT15', 'Gene', '55270', (102, 108))	('TPMT', 'Gene', '7172', (93, 97))	('thiopurine', 'Chemical', '-', (211, 221))
562138	31133068	A small but important finding is that genomic testing resulted in a diagnosis change across all tumor types in 12 patients (3.3%, Additional file 3: Table S9).	('change', 'Reg', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('resulted in', 'Reg', (54, 65))	('diagnosis', 'Disease', (68, 77))	('tumor', 'Disease', (96, 101))	('genomic testing', 'Var', (38, 53))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('patients', 'Species', '9606', (114, 122))
562142	31133068	The number of clinically significant (Tier 1 or 2) sequence alterations per case is relatively low, especially in CNS and non-CNS solid tumors (Figs.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('clinical', 'Species', '191496', (14, 22))	('solid tumors', 'Disease', (130, 142))	('CNS', 'Disease', (114, 117))	('solid tumors', 'Disease', 'MESH:D009369', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('alterations', 'Var', (60, 71))
562144	31133068	The general landscape of mutations observed from our cohort in large part matches data observed from recent large-scale pan-pediatric cancer studies.	('pediatric cancer', 'Disease', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (25, 34))	('pediatric cancer', 'Disease', 'MESH:D009369', (124, 140))
562147	31133068	The rate of actionable alterations, including the rate of potentially germline alterations, is similar to that detected in other published clinical sequencing studies in pediatric oncology which show an approximate 30-60% rate of potentially targetable mutations, ~ 10% rate of germline mutations with tumor/normal paired testing, and significant changes to diagnosis.	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', (302, 307))	('mutations', 'Var', (253, 262))	('clinical', 'Species', '191496', (139, 147))	('germline mutations', 'Var', (278, 296))	('oncology', 'Phenotype', 'HP:0002664', (180, 188))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
562153	31133068	As such, panel testing in our cohort of leukemia/lymphoma patients had impact on diagnosis in 83.9% of cases, particularly in ALL and AML, and impacted prognosis in 52.4% of cases (Fig.	('impact', 'Reg', (71, 77))	('patients', 'Species', '9606', (58, 66))	('leukemia/lymphoma', 'Disease', 'MESH:D007938', (40, 57))	('AML', 'Disease', (134, 137))	('prognosis', 'MPA', (152, 161))	('AML', 'Disease', 'MESH:D015470', (134, 137))	('ALL', 'Phenotype', 'HP:0006721', (126, 129))	('diagnosis', 'MPA', (81, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))	('AML', 'Phenotype', 'HP:0004808', (134, 137))	('leukemia/lymphoma', 'Disease', (40, 57))	('panel testing', 'Var', (9, 22))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))	('impacted', 'Reg', (143, 151))
562154	31133068	In non-CNS solid tumors, 49.7% of somatic panels had diagnostic relevance, particularly in neuroblastoma, Ewing sarcoma, and fusion-positive rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (141, 157))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('rhabdomyosarcoma', 'Disease', (141, 157))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('Ewing sarcoma', 'Disease', (106, 119))	('neuroblastoma', 'Disease', 'MESH:D009447', (91, 104))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('solid tumors', 'Disease', (11, 23))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (141, 157))	('neuroblastoma', 'Disease', (91, 104))	('neuroblastoma', 'Phenotype', 'HP:0003006', (91, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('solid tumors', 'Disease', 'MESH:D009369', (11, 23))	('fusion-positive', 'Var', (125, 140))
562156	31133068	Nonetheless, all neuroblastomas in our cohort showed prognostic impact from testing because the comprehensive nature of the panel allowed detection of MYCN amplification, segmental chromosomal gains/losses, and ploidy estimates from copy number analysis, all of which are important for risk stratification based on current guidelines.	('neuroblastomas', 'Disease', (17, 31))	('neuroblastoma', 'Phenotype', 'HP:0003006', (17, 30))	('MYCN', 'Gene', (151, 155))	('amplification', 'Var', (156, 169))	('MYCN', 'Gene', '4613', (151, 155))	('neuroblastomas', 'Phenotype', 'HP:0003006', (17, 31))	('neuroblastomas', 'Disease', 'MESH:D009447', (17, 31))	('ploidy', 'Var', (211, 217))
562159	31133068	One case is particularly notable because the diagnosis of atypical Ewing sarcoma was made prior to the implementation of the comprehensive solid tumor panel and was supported by EWSR1 rearrangement by break apart FISH.	('solid tumor', 'Disease', (139, 150))	('solid tumor', 'Disease', 'MESH:D009369', (139, 150))	('EWSR1', 'Gene', '2130', (178, 183))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('rearrangement', 'Var', (184, 197))	('break apart', 'Phenotype', 'HP:0001061', (201, 212))	('EWSR1', 'Gene', (178, 183))	('Ewing sarcoma', 'Disease', (67, 80))
562164	31133068	The number of targetable variants was highest in the non-CNS solid tumor cohort (21.8%), including ALK variants in neuroblastoma, NTRK fusions in several different tumor types (including papillary thyroid cancer, mammary analogue secretory carcinoma, and myofibroblastic sarcoma), for whom targeted therapy with crizotinib or TRK inhibition (larotrectinib, entrectinib) was either recommended or available in the relapse setting.	('tumor', 'Disease', (164, 169))	('carcinoma', 'Disease', (240, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('myofibroblastic sarcoma', 'Disease', 'MESH:D012509', (255, 278))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('ALK', 'Gene', '238', (99, 102))	('tumor', 'Disease', (67, 72))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (187, 211))	('variants', 'Var', (25, 33))	('TRK', 'Gene', (131, 134))	('ALK', 'Gene', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('thyroid cancer', 'Phenotype', 'HP:0002890', (197, 211))	('carcinoma', 'Disease', 'MESH:D002277', (240, 249))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('solid tumor', 'Disease', (61, 72))	('TRK', 'Gene', '4914', (131, 134))	('TRK', 'Gene', (326, 329))	('crizotinib', 'Chemical', 'MESH:D000077547', (312, 322))	('variants', 'Var', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('entrectinib', 'Chemical', 'MESH:C000607349', (357, 368))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('papillary thyroid cancer', 'Disease', (187, 211))	('larotrectinib', 'Chemical', 'MESH:C000609083', (342, 355))	('neuroblastoma', 'Disease', (115, 128))	('TRK', 'Gene', '4914', (326, 329))	('solid tumor', 'Disease', 'MESH:D009369', (61, 72))	('neuroblastoma', 'Phenotype', 'HP:0003006', (115, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('myofibroblastic sarcoma', 'Disease', (255, 278))	('neuroblastoma', 'Disease', 'MESH:D009447', (115, 128))
562165	31133068	There were also several KRAS and BRAF fusions and variants in non-CNS solid tumor cases for which targeted therapy could be significant in the relapsed setting.	('BRAF', 'Gene', '673', (33, 37))	('KRAS', 'Gene', '3845', (24, 28))	('BRAF', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('variants', 'Var', (50, 58))	('solid tumor', 'Disease', (70, 81))	('solid tumor', 'Disease', 'MESH:D009369', (70, 81))	('fusions', 'Var', (38, 45))	('KRAS', 'Gene', (24, 28))
562167	31133068	FLT3 internal tandem duplication (ITD) was identified in one patient with AML which led to up-staging and change in treatment (addition of gilteritinib).	('gilteritinib', 'Chemical', 'MESH:C000609080', (139, 151))	('patient', 'Species', '9606', (61, 68))	('AML', 'Disease', 'MESH:D015470', (74, 77))	('AML', 'Phenotype', 'HP:0004808', (74, 77))	('AML', 'Disease', (74, 77))	('up-staging', 'PosReg', (91, 101))	('FLT3', 'Gene', '2322', (0, 4))	('internal tandem duplication', 'Var', (5, 32))	('FLT3', 'Gene', (0, 4))
562170	31133068	Finally, variant testing in TPMT and NUDT15 was included in leukemia/lymphoma cases, given that certain polymorphisms in these genes lead to altered metabolism of the therapeutic agents, thioguanine and mercaptopurine.	('thioguanine', 'MPA', (187, 198))	('thioguanine', 'Chemical', 'MESH:D013866', (187, 198))	('variant', 'Var', (9, 16))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('NUDT15', 'Gene', (37, 43))	('TPMT', 'Gene', (28, 32))	('leukemia/lymphoma', 'Disease', (60, 77))	('lead to altered', 'Reg', (133, 148))	('NUDT15', 'Gene', '55270', (37, 43))	('mercaptopurine', 'Chemical', 'MESH:D015122', (203, 217))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('TPMT', 'Gene', '7172', (28, 32))	('polymorphisms', 'Var', (104, 117))	('metabolism of the therapeutic agents', 'MPA', (149, 185))	('leukemia/lymphoma', 'Disease', 'MESH:D007938', (60, 77))
562171	31133068	Knowing the relevant TPMT and NUDT15 polymorphisms early in therapy allows appropriate chemotherapeutic dosing, prior to onset of toxicity, which were identified in 12% of leukemia cases in this cohort.	('polymorphisms', 'Var', (37, 50))	('NUDT15', 'Gene', (30, 36))	('TPMT', 'Gene', (21, 25))	('toxicity', 'Disease', 'MESH:D064420', (130, 138))	('toxicity', 'Disease', (130, 138))	('leukemia', 'Disease', (172, 180))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('leukemia', 'Disease', 'MESH:D007938', (172, 180))	('TPMT', 'Gene', '7172', (21, 25))	('NUDT15', 'Gene', '55270', (30, 36))
562172	31133068	Somatic sequencing can also identify potential underlying germline variants and subsequent cancer predisposition syndromes.	('germline variants', 'Var', (58, 75))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
562177	31133068	While some of these alterations are somatic changes only and tumor testing alone is not sufficient to diagnose germline conditions, the panel results allow for timely identification of patients to refer for genetic counseling and potential germline testing for a variety of cancer predisposition syndromes that may have important clinical implications for the patient and/or family members.	('clinical', 'Species', '191496', (330, 338))	('alterations', 'Var', (20, 31))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('patient', 'Species', '9606', (360, 367))	('patient', 'Species', '9606', (185, 192))	('cancer', 'Disease', (274, 280))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('refer', 'Reg', (197, 202))	('patients', 'Species', '9606', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('tumor', 'Disease', (61, 66))
562178	31133068	Of particular interest are the high frequency of BRCA2 variants identified in our cohort, which are emerging therapeutic targets in some tumors other than breast and ovarian cancer.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('variants', 'Var', (55, 63))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (155, 180))	('BRCA2', 'Gene', '675', (49, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('BRCA2', 'Gene', (49, 54))
562179	31133068	Studies have suggested that germline confirmation of somatic BRCA2 variants are relevant to evaluation and care of pediatric patients and their families.	('BRCA2', 'Gene', '675', (61, 66))	('variants', 'Var', (67, 75))	('BRCA2', 'Gene', (61, 66))	('patients', 'Species', '9606', (125, 133))
562180	31133068	In the future, pairing somatic cancer gene panel sequencing with a matched normal tissue (blood or fibroblast) would both improve precision and variant calling and definitively identify pathogenic germline variants.	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('improve', 'PosReg', (122, 129))	('precision', 'MPA', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('variant', 'Var', (144, 151))
562183	31133068	For example, a novel MTP-BRAF fusion was consistent with the histologic diagnosis of Langerhan cell sarcoma, and TFG-ROS1 was consistent with an abdominal inflammatory myofibroblastic tumor.	('fusion', 'Var', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (168, 189))	('TP', 'Chemical', '-', (22, 24))	('tumor', 'Disease', (184, 189))	('Langerhan cell sarcoma', 'Disease', 'MESH:D054752', (85, 107))	('BRAF', 'Gene', '673', (25, 29))	('ROS1', 'Gene', (117, 121))	('Langerhan cell sarcoma', 'Disease', (85, 107))	('TFG', 'Gene', '10342', (113, 116))	('BRAF', 'Gene', (25, 29))	('ROS1', 'Gene', '6098', (117, 121))	('TFG', 'Gene', (113, 116))
562185	31133068	Copy number alterations were the most commonly detected variant in our cohort and have important prognostic significance in tumors such as neuroblastoma and B-ALL, mirroring findings from other studies.	('neuroblastoma', 'Disease', 'MESH:D009447', (139, 152))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('neuroblastoma', 'Disease', (139, 152))	('neuroblastoma', 'Phenotype', 'HP:0003006', (139, 152))	('B-ALL', 'Disease', (157, 162))	('Copy number alterations', 'Var', (0, 23))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('ALL', 'Phenotype', 'HP:0006721', (159, 162))	('detected', 'Reg', (47, 55))
562189	31133068	Our laboratory interpreted and reported sequence, fusion, and copy number variants in a single report using the published guidelines for sequence variant interpretation in cancer.	('cancer', 'Disease', (172, 178))	('variants', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))
562192	31133068	While few pediatric tumors have FDA-approved targeted therapy, many genomic variants have Tier 1 diagnostic and/or prognostic significance.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('variants', 'Var', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('pediatric tumors', 'Disease', 'MESH:D063766', (10, 26))	('pediatric tumors', 'Disease', (10, 26))
562195	31133068	Somatic NGS testing was efficiently incorporated into clinical care, providing comprehensive SNV/indel, copy number, and fusion information within a single report.	('indel', 'Chemical', '-', (97, 102))	('copy number', 'Var', (104, 115))	('SNV/indel', 'Var', (93, 102))	('clinical', 'Species', '191496', (54, 62))
562204	33535525	The mean and median values of MVD/CD105 in RMS were lower than MVD/CD31 and MVD/CD34.	('CD34', 'Gene', (80, 84))	('CD34', 'Gene', '947', (80, 84))	('CD31', 'Gene', (67, 71))	('lower', 'NegReg', (52, 57))	('CD31', 'Gene', '5175', (67, 71))	('MVD/CD105', 'Var', (30, 39))	('RMS', 'Phenotype', 'HP:0002859', (43, 46))
562206	33535525	Patients with higher levels of MVD/CD105 had a higher risk of death (HR = 1.009).	('Patients', 'Species', '9606', (0, 8))	('MVD/CD105', 'Var', (31, 40))	('death', 'Disease', 'MESH:D003643', (62, 67))	('death', 'Disease', (62, 67))
562207	33535525	(4) Conclusion: CD105 is a relevant angiogenesis marker in pediatric RMS, and MVD/CD105 is an independent risk factor of short overall survival in children with RMS.	('RMS', 'Disease', (69, 72))	('MVD/CD105', 'Var', (78, 87))	('RMS', 'Phenotype', 'HP:0002859', (161, 164))	('RMS', 'Phenotype', 'HP:0002859', (69, 72))	('children', 'Species', '9606', (147, 155))	('CD105', 'Gene', (16, 21))
562212	33535525	Various epigenetic changes are found in ERMS tumors, including loss of heterozygosity in the 11p15 locus (insulin-like growth factor IGF-2) as well as trisomy of chromosome 8, mutations of the TP53 gene, and deregulations of the p38, JKN, ERK, cyclin, and cyclin-dependent kinases activity.	('mutations', 'Var', (176, 185))	('cyclin', 'Gene', (256, 262))	('deregulations', 'Reg', (208, 221))	('p38', 'Gene', '1432', (229, 232))	('trisomy', 'Var', (151, 158))	('ERK', 'Gene', '5594', (239, 242))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('TP53', 'Gene', (193, 197))	('cyclin', 'Gene', '5111', (244, 250))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ERMS tumors', 'Disease', (40, 51))	('RMS', 'Phenotype', 'HP:0002859', (41, 44))	('ERMS tumors', 'Disease', 'MESH:D009369', (40, 51))	('ERK', 'Gene', (239, 242))	('loss', 'NegReg', (63, 67))	('cyclin', 'Gene', (244, 250))	('cyclin', 'Gene', '5111', (256, 262))	('TP53', 'Gene', '7157', (193, 197))	('p38', 'Gene', (229, 232))	('activity', 'MPA', (281, 289))	('JKN', 'Enzyme', (234, 237))
562213	33535525	The most common translocation, t(2;3) (q35;q14), gives rise to the chimeric protein PAX3-FKHR, which affects the growth, mobility, differentiation, and apoptosis of tumor cells, intensifying carcinogenesis.	('tumor', 'Disease', (165, 170))	('PAX3', 'Gene', '5077', (84, 88))	('carcinogenesis', 'Disease', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('PAX3', 'Gene', (84, 88))	('differentiation', 'CPA', (131, 146))	('FKHR', 'Gene', '2308', (89, 93))	('t(2;3) (q35;q14', 'Var', (31, 46))	('mobility', 'CPA', (121, 129))	('gives rise', 'Reg', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('intensifying', 'PosReg', (178, 190))	('FKHR', 'Gene', (89, 93))	('apoptosis', 'CPA', (152, 161))	('carcinogenesis', 'Disease', 'MESH:D063646', (191, 205))	('growth', 'CPA', (113, 119))	('affects', 'Reg', (101, 108))
562214	33535525	Favorable prognostic factors are: the embryonal histological subtype; fusion gene-negative status; primary localization in the orbit or other areas of the head and neck (except for the parameningeal region) as well as the genitourinary tract (except for the bladder and prostate); lack of distant metastases at the time of diagnosis; R0 tumor excision; tumor size <=5 cm; age <12 years; and long time to relapse.	('tumor', 'Disease', (353, 358))	('fusion gene-negative status', 'Var', (70, 97))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumor', 'Disease', (337, 342))	('metastases', 'Disease', (297, 307))	('metastases', 'Disease', 'MESH:D009362', (297, 307))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('tumor', 'Disease', 'MESH:D009369', (337, 342))
562225	33535525	It is expected that combining anti-CD105 antibodies with VEGF inhibitors may improve the effectiveness of antiangiogenic therapy.	('improve', 'PosReg', (77, 84))	('antiangiogenic therapy', 'CPA', (106, 128))	('anti-CD105', 'Var', (30, 40))	('VEGF', 'Gene', (57, 61))	('anti-CD105', 'Gene', (30, 40))	('VEGF', 'Gene', '7422', (57, 61))
562244	33535525	The following primary antibodies were used: anti-CD31 (clone JC70A, Ready-to-Use, DAKO IR610), anti-CD34 (clone QBEnd 10, Ready-to-Use, DAKO IR632), and anti-CD105 (clone SN6h, 1:20, DAKO M3527).	('CD31', 'Gene', '5175', (49, 53))	('anti-CD105', 'Var', (153, 163))	('CD34', 'Gene', '947', (100, 104))	('CD31', 'Gene', (49, 53))	('CD34', 'Gene', (100, 104))
562249	33535525	MVD was assessed based on immunohistochemical staining of CD31 (MVD/CD31), CD34 (MVD/CD34), and CD105 (MVD/CD105), consistent with the method developed by Weidner.	('CD31', 'Gene', '5175', (58, 62))	('CD105', 'Var', (96, 101))	('CD31', 'Gene', (68, 72))	('CD34', 'Gene', '947', (85, 89))	('CD34', 'Gene', (75, 79))	('CD34', 'Gene', '947', (75, 79))	('CD34', 'Gene', (85, 89))	('CD31', 'Gene', '5175', (68, 72))	('CD31', 'Gene', (58, 62))
562265	33535525	Higher mortality risk was observed in RMS patients with metastasis to regional lymph nodes at the time of diagnosis (hazard ratio = 11.51) and in patients under one year of age and over ten years of age at the time of diagnosis (the hazard ratios were 7.97 and 6.22, respectively).	('RMS', 'Disease', (38, 41))	('patients', 'Species', '9606', (146, 154))	('mortality', 'Disease', 'MESH:D003643', (7, 16))	('RMS', 'Phenotype', 'HP:0002859', (38, 41))	('metastasis', 'Var', (56, 66))	('patients', 'Species', '9606', (42, 50))	('mortality', 'Disease', (7, 16))
562267	33535525	In histopathology analysis, increased mortality risk was observed in participants with higher MVD/CD105 (HR = 1.009).	('mortality', 'Disease', 'MESH:D003643', (38, 47))	('MVD/CD105', 'Gene', (94, 103))	('mortality', 'Disease', (38, 47))	('participants', 'Species', '9606', (69, 81))	('higher', 'Var', (87, 93))
562292	33535525	Moreover, we confirmed the prognostic significance of MVD/CD105 (HR = 1.009) and the statistically significant relationship between higher values of MVD/CD31, MVD/CD34, and MVD/CD105, as well as the presence of distant metastases at diagnosis.	('higher', 'PosReg', (132, 138))	('MVD/CD105', 'Var', (54, 63))	('CD31', 'Gene', (153, 157))	('CD34', 'Gene', (163, 167))	('MVD/CD105', 'Var', (173, 182))	('CD31', 'Gene', '5175', (153, 157))	('metastases', 'Disease', (219, 229))	('metastases', 'Disease', 'MESH:D009362', (219, 229))	('CD34', 'Gene', '947', (163, 167))
562304	33535525	TRC105 competitively inhibits the binding of downstream target BMP9, thus preventing the activation of the pathway involving Smad1/5/8 proteins.	('pathway', 'Pathway', (107, 114))	('TRC105', 'Chemical', 'MESH:C579557', (0, 6))	('inhibits', 'NegReg', (21, 29))	('binding', 'Interaction', (34, 41))	('Smad1/5/8', 'Gene', '4086;4090;4093', (125, 134))	('preventing', 'NegReg', (74, 84))	('BMP9', 'Gene', '2658', (63, 67))	('TRC105', 'Var', (0, 6))	('BMP9', 'Gene', (63, 67))	('Smad1/5/8', 'Gene', (125, 134))
562305	33535525	Furthermore, TRC105 downregulates the expression of VEGF and PDGF.	('VEGF', 'Gene', (52, 56))	('TRC105', 'Chemical', 'MESH:C579557', (13, 19))	('expression', 'MPA', (38, 48))	('TRC105', 'Var', (13, 19))	('VEGF', 'Gene', '7422', (52, 56))	('downregulates', 'NegReg', (20, 33))	('PDGF', 'Gene', (61, 65))
562306	33535525	Phase 1 research using a combination of bevacizumab and TRC105 in patients with advanced solid tumors has shown good tolerance and clinical activity of TRC105 in a group of patients resistant to therapy with VEGF inhibitors.	('TRC105', 'Var', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (173, 181))	('TRC105', 'Chemical', 'MESH:C579557', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('bevacizumab', 'Chemical', 'MESH:D000068258', (40, 51))	('VEGF', 'Gene', (208, 212))	('TRC105', 'Chemical', 'MESH:C579557', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('VEGF', 'Gene', '7422', (208, 212))	('tumors', 'Disease', (95, 101))	('patients', 'Species', '9606', (66, 74))
562315	33535525	Estimation of MVD makes use of specific markers on the surface of endothelial cells, such as CD31, CD34, factor VIII, or CD105, which allow visualization of the vessel structure in a microscope image.	('CD31', 'Gene', (93, 97))	('CD31', 'Gene', '5175', (93, 97))	('CD105', 'Var', (121, 126))	('CD34', 'Gene', '947', (99, 103))	('CD34', 'Gene', (99, 103))
562320	33535525	MVD/CD105 is correlated with unfavorable prognostic factors of RMS survival, such as the alveolar histopathological subtype or the presence of distant metastases at diagnosis.	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('RMS', 'Phenotype', 'HP:0002859', (63, 66))	('metastases', 'Disease', (151, 161))	('MVD/CD105', 'Var', (0, 9))	('alveolar', 'Disease', (89, 97))	('RMS survival', 'Disease', (63, 75))
562380	32532153	Noteworthy, dermatofibrosarcoma protuberans (DFSP), a rare STS subtype with a local infiltrative growth pattern, carries a COL1A1/PDGFB fusion-gene that is responsible for PDGFRbeta autocrine activation and subsequent tumorigenesis.	('DFSP', 'Disease', (45, 49))	('COL1A1', 'Gene', '1277', (123, 129))	('dermatofibrosarcoma protuberans', 'Disease', (12, 43))	('STS', 'Phenotype', 'HP:0030448', (59, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('PDGFB', 'Gene', '5155', (130, 135))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (19, 31))	('PDGFRbeta', 'Gene', '5156', (172, 181))	('DFSP', 'Disease', 'MESH:D018223', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (12, 43))	('fusion-gene', 'Var', (136, 147))	('PDGFB', 'Gene', (130, 135))	('tumor', 'Disease', (218, 223))	('PDGFRbeta', 'Gene', (172, 181))	('COL1A1', 'Gene', (123, 129))
562399	32532153	Epigenetic and genetic changes involved in the sarcomagenesis have a deep impact on the biology of sarcoma stem cells.	('sarcomagenesis', 'Disease', (47, 61))	('impact', 'Reg', (74, 80))	('sarcomagenesis', 'Disease', 'None', (47, 61))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('sarcoma', 'Disease', 'MESH:D012509', (47, 54))	('Epigenetic', 'Var', (0, 10))	('genetic changes', 'Var', (15, 30))	('sarcoma', 'Disease', (99, 106))	('sarcoma', 'Disease', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
562400	32532153	Certain subtypes of sarcoma are characterized by stable karyotypes and reciprocal translocations, leading to activated fusion-oncogenes that can be crucial in conferring stemness, as they have the ability to modify the transcriptome and to interfere with normal epigenetic processes, as shown for EWS and SS.	('sarcoma', 'Disease', (20, 27))	('modify', 'Reg', (208, 214))	('fusion-oncogenes', 'Gene', (119, 135))	('SS', 'Phenotype', 'HP:0012570', (305, 307))	('EWS', 'Phenotype', 'HP:0012254', (297, 300))	('EWS', 'Gene', '2130', (297, 300))	('EWS', 'Gene', (297, 300))	('transcriptome', 'MPA', (219, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('epigenetic processes', 'MPA', (262, 282))	('interfere', 'NegReg', (240, 249))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('fusion-oncogenes', 'Var', (119, 135))
562403	32532153	Notwithstanding this heterogeneity, diverse sarcoma types share similar molecular mechanisms of stemness, such as the abrogation of classical tumor suppressors p53 and Rb, Sox2 activation, or inhibition of canonical Wnt/beta-catenin signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('Sox2', 'Enzyme', (172, 176))	('abrogation', 'Var', (118, 128))	('beta-catenin', 'Gene', '1499', (220, 232))	('tumor', 'Disease', (142, 147))	('activation', 'PosReg', (177, 187))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('sarcoma', 'Disease', (44, 51))	('inhibition', 'NegReg', (192, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('beta-catenin', 'Gene', (220, 232))
562415	32532153	LIN28 silencing changed the metabolism of cells and induced the loss of CSC traits.	('LIN28', 'Gene', (0, 5))	('LIN28', 'Gene', '79727', (0, 5))	('CSC traits', 'CPA', (72, 82))	('changed', 'Reg', (16, 23))	('loss', 'NegReg', (64, 68))	('metabolism', 'MPA', (28, 38))	('silencing', 'Var', (6, 15))
562420	32532153	Epigenetic processes can change gene expression without causing any modification in cellular DNA and they can affect the balance of self-renewal and pluripotency versus differentiation.	('gene expression', 'MPA', (32, 47))	('affect', 'Reg', (110, 116))	('Epigenetic processes', 'Var', (0, 20))	('change', 'Reg', (25, 31))	('pluripotency versus differentiation', 'Disease', (149, 184))	('pluripotency versus differentiation', 'Disease', 'MESH:D006086', (149, 184))	('balance', 'MPA', (121, 128))
562421	32532153	In line with this, it has been reported that DNA methylation might promote a CSC phenotype, and that hyperactivation of DNA methyltransferases (DNMT) is required for CSC maintenance.	('DNA methylation', 'Var', (45, 60))	('DNA methyltransferases', 'Gene', '1786', (120, 142))	('DNA methyltransferases', 'Gene', (120, 142))	('CSC', 'Disease', (77, 80))	('methylation', 'Var', (49, 60))	('DNMT', 'Gene', '1786', (144, 148))	('DNMT', 'Gene', (144, 148))	('promote', 'PosReg', (67, 74))
562422	32532153	In fact, it has been reported that both a CSC phonotype and the oncogenic transformation of precancerous cells are induced by local DNA hypermethylation at tumor-suppressor genes or genes associated with differentiation.	('CSC', 'Disease', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Disease', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('local DNA', 'Var', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('induced by', 'Reg', (115, 125))
562430	32532153	Aberrant epigenetic regulation and EZH2 overexpression have been also described in clear cell sarcoma of the kidney.	('sarcoma of the kidney', 'Disease', (94, 115))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (83, 115))	('overexpression', 'PosReg', (40, 54))	('described', 'Reg', (70, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcoma of the kidney', 'Disease', 'MESH:D012509', (94, 115))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (94, 115))	('EZH2', 'Gene', (35, 39))	('EZH2', 'Gene', '2146', (35, 39))	('Aberrant epigenetic regulation', 'Var', (0, 30))
562441	32532153	Of note, MRP-1 was shown to be a strong prognostic factor in patients with localized high-risk STS treated with anthracyclines-based regimens, suggesting that inhibiting the activity of this efflux pump could improve the efficacy of chemotherapy.	('improve', 'PosReg', (209, 216))	('anthracyclines', 'Chemical', 'MESH:D018943', (112, 126))	('inhibiting', 'Var', (159, 169))	('MRP-1', 'Gene', (9, 14))	('MRP-1', 'Gene', '4363', (9, 14))	('patients', 'Species', '9606', (61, 69))	('STS', 'Phenotype', 'HP:0030448', (95, 98))	('activity', 'MPA', (174, 182))	('efficacy of chemotherapy', 'CPA', (221, 245))
562446	32532153	For example, it was reported that the TKI dasatinib, but not EGFR-directed inhibition, decreased cell viability of sarcoma initiating cells in combination with doxorubicin.	('sarcoma', 'Disease', 'MESH:D012509', (115, 122))	('decreased', 'NegReg', (87, 96))	('sarcoma', 'Disease', (115, 122))	('dasatinib', 'Chemical', 'MESH:D000069439', (42, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('TKI', 'Var', (38, 41))	('cell viability', 'CPA', (97, 111))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('doxorubicin', 'Chemical', 'MESH:D004317', (160, 171))
562447	32532153	Moreover, total topotecan exposure was 1.7-fold higher in solid tumors patients treated with topotecan in combination with pazopanib, compared with patients treated with topotecan alone, primarily due to the fact that pazopanib inhibits ABCG2, thus increasing the absorption of orally administered topotecan.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('patients', 'Species', '9606', (71, 79))	('topotecan', 'Chemical', 'MESH:D019772', (170, 179))	('pazopanib', 'Chemical', 'MESH:C516667', (218, 227))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('topotecan', 'Chemical', 'MESH:D019772', (298, 307))	('tumors', 'Disease', (64, 70))	('patients', 'Species', '9606', (148, 156))	('pazopanib', 'Chemical', 'MESH:C516667', (123, 132))	('inhibits', 'NegReg', (228, 236))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('topotecan', 'Chemical', 'MESH:D019772', (16, 25))	('ABCG2', 'Gene', (237, 242))	('increasing', 'PosReg', (249, 259))	('pazopanib', 'Var', (218, 227))	('ABCG2', 'Gene', '9429', (237, 242))	('topotecan', 'Chemical', 'MESH:D019772', (93, 102))	('higher', 'PosReg', (48, 54))	('absorption', 'MPA', (264, 274))
562461	32532153	In line with this, a Phase I/II clinical trial was conducted with the combination of liposomal doxorubicin and temsirolimus, based on pre-clinical evidences in which it was demonstrated that inhibition of mTOR increases the sensitivity of CSCs to doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (95, 106))	('inhibition', 'Var', (191, 201))	('increases', 'PosReg', (210, 219))	('mTOR', 'Gene', (205, 209))	('temsirolimus', 'Chemical', 'MESH:C401859', (111, 123))	('mTOR', 'Gene', '2475', (205, 209))	('doxorubicin', 'Chemical', 'MESH:D004317', (247, 258))	('sensitivity of CSCs to doxorubicin', 'MPA', (224, 258))
562462	32532153	In this trial, the combination of liposomal doxorubicin and temsirolimus has led to a PFS three times longer, compared to the results obtained with a mTOR inhibitor in monotherapy, and at least two times longer compared with liposomal doxorubicin alone or in combination with other conventional chemotherapy agents.	('doxorubicin', 'Chemical', 'MESH:D004317', (235, 246))	('longer', 'PosReg', (102, 108))	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('PFS', 'MPA', (86, 89))	('liposomal', 'Var', (34, 43))	('temsirolimus', 'Chemical', 'MESH:C401859', (60, 72))	('mTOR', 'Gene', '2475', (150, 154))	('mTOR', 'Gene', (150, 154))
562464	32532153	Hence, mTOR inhibitors cause an increase in the efficacy of chemotherapy, probably by sensitizing chemoresistant CSCs.	('mTOR', 'Gene', (7, 11))	('inhibitors', 'Var', (12, 22))	('increase', 'PosReg', (32, 40))	('chemotherapy', 'CPA', (60, 72))	('efficacy', 'CPA', (48, 56))	('chemoresistant CSCs', 'Disease', (98, 117))	('mTOR', 'Gene', '2475', (7, 11))
562471	32532153	Tumors carrying inactivating RNF43 mutations depend on paracrine Wnt signaling to activate the stem cell program.	('activate', 'PosReg', (82, 90))	('RNF43', 'Gene', (29, 34))	('inactivating', 'Var', (16, 28))	('RNF43', 'Gene', '54894', (29, 34))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('stem cell program', 'CPA', (95, 112))	('mutations', 'Var', (35, 44))
562478	32532153	ALK inhibitors suppressed stem cell marker expression levels both in vitro and in vivo, therefore probably induced a downregulation of their downstream signaling pathways, and suppressed CSC-like properties.	('downstream signaling pathways', 'Pathway', (141, 170))	('stem cell', 'CPA', (26, 35))	('ALK', 'Gene', '238', (0, 3))	('suppressed', 'NegReg', (176, 186))	('downregulation', 'NegReg', (117, 131))	('ALK', 'Gene', (0, 3))	('inhibitors', 'Var', (4, 14))	('suppressed', 'NegReg', (15, 25))	('CSC-like properties', 'CPA', (187, 206))
562481	32532153	Of note, ALK inhibitors caused a decrease in stem cell markers expression levels both in vitro and in vivo, that subsequently suppressed the oncogenic functions of ALKATI and attenuated ALKATI-induced CSC-like traits.	('ALK', 'Gene', (9, 12))	('stem cell markers', 'CPA', (45, 62))	('ALK', 'Gene', '238', (164, 167))	('suppressed', 'NegReg', (126, 136))	('decrease', 'NegReg', (33, 41))	('ALK', 'Gene', (186, 189))	('inhibitors', 'Var', (13, 23))	('ALK', 'Gene', (164, 167))	('ALK', 'Gene', '238', (9, 12))	('ALK', 'Gene', '238', (186, 189))	('oncogenic functions', 'CPA', (141, 160))	('attenuated', 'NegReg', (175, 185))
562484	32532153	High CD44 expression was associated with worse outcome in STS.	('High', 'Var', (0, 4))	('CD44', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('STS', 'Phenotype', 'HP:0030448', (58, 61))	('CD44', 'Gene', '960', (5, 9))
562494	32532153	In cancer cells the EMT induces epigenetic modifications that result in heritable phenotypic changes without causing new genetic alterations.	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('induces', 'Reg', (24, 31))	('cancer', 'Disease', (3, 9))	('epigenetic modifications', 'Var', (32, 56))	('result in', 'Reg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
562497	32532153	A MET transcription profile was correlated with enhanced survival in sarcoma patients.	('MET transcription', 'Var', (2, 19))	('sarcoma', 'Disease', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('enhanced', 'PosReg', (48, 56))	('survival', 'MPA', (57, 65))	('patients', 'Species', '9606', (77, 85))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))
562516	32532153	As an example, high expression of LIN28B has been associated with doxorubicin resistance and worse survival, pointing that this protein may be a relevant therapeutic target in STS.	('high', 'Var', (15, 19))	('LIN28B', 'Gene', '389421', (34, 40))	('doxorubicin resistance', 'MPA', (66, 88))	('LIN28B', 'Gene', (34, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('associated', 'Reg', (50, 60))	('STS', 'Phenotype', 'HP:0030448', (176, 179))
562525	32532153	EZH2 mediates H3K27me3 silencing of tumor suppressor genes, enabling CSC expansion.	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('H3K27me3 silencing', 'Var', (14, 32))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('enabling', 'PosReg', (60, 68))	('tumor', 'Disease', (36, 41))	('CSC expansion', 'CPA', (69, 82))
562527	32532153	In addition, it has been shown that EZH2 inhibition is able to suppress leiomyosarcoma CSCs proprieties and retrieve the anti-tumor effect of PI3K/mTOR inhibition, supporting the therapeutic value of this combination.	('leiomyosarcoma CSCs', 'Disease', 'MESH:D007890', (72, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('tumor', 'Disease', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('inhibition', 'Var', (41, 51))	('leiomyosarcoma CSCs', 'Disease', (72, 91))	('EZH2', 'Gene', '2146', (36, 40))	('mTOR', 'Gene', '2475', (147, 151))	('mTOR', 'Gene', (147, 151))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (72, 86))	('EZH2', 'Gene', (36, 40))	('suppress', 'NegReg', (63, 71))
562535	32532153	Plasticity is a feature of the TME, which leads to tumor aggressive behavior and to the development of phenotypically unstable heterogeneous cell populations within the same tumor or between tumors from different patients.	('tumor', 'Disease', (174, 179))	('Plasticity', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor aggressive behavior', 'Disease', (51, 76))	('leads to', 'Reg', (42, 50))	('aggressive behavior', 'Phenotype', 'HP:0000718', (57, 76))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('patients', 'Species', '9606', (213, 221))	('tumor aggressive behavior', 'Disease', 'MESH:D001523', (51, 76))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Disease', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
562676	26854812	While increased exposure to non-nelfinavir, PI-ART was associated with a higher risk of anal cancer (aRR 1.40 per additional five years, 95%CI 1.16-1.71, p<0.01), no such association was found for nelfinavir-based ART.	('PI-ART', 'Var', (44, 50))	('aRR 1', 'Gene', '408', (101, 106))	('anal cancer', 'Disease', 'MESH:D001005', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PI-ART', 'Chemical', '-', (44, 50))	('nelfinavir', 'Chemical', 'MESH:D019888', (32, 42))	('anal cancer', 'Phenotype', 'HP:0032186', (88, 99))	('nelfinavir', 'Chemical', 'MESH:D019888', (197, 207))	('ART', 'Chemical', '-', (214, 217))	('aRR 1', 'Gene', (101, 106))	('anal cancer', 'Disease', (88, 99))	('ART', 'Chemical', '-', (47, 50))
562680	26854812	Rates of cancer were non-significantly different between individuals receiving nelfinavir-based treatment and other PI-based ART.	('nelfinavir', 'Chemical', 'MESH:D019888', (79, 89))	('nelfinavir-based', 'Var', (79, 95))	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('ART', 'Chemical', '-', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
562682	26854812	However, rates of all cancer, AIDS-defining cancer, non-AIDS-defining cancer, non-Hodgkin's lymphoma, Kaposi's sarcoma, and anal cancer were lower in individuals using NNRTI-based ART compared with those using non-nelfinavir, PI-ART (see Table 3).	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('AIDS-defining cancer', 'Disease', 'MESH:D000163', (30, 50))	('cancer', 'Disease', (129, 135))	('PI-ART', 'Chemical', '-', (226, 232))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (102, 118))	('non-AIDS-defining cancer', 'Disease', (52, 76))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (78, 100))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('anal cancer', 'Disease', (124, 135))	('anal cancer', 'Disease', 'MESH:D001005', (124, 135))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (102, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	("Kaposi's sarcoma", 'Disease', (102, 118))	('cancer', 'Disease', (70, 76))	('non-AIDS-defining cancer', 'Disease', 'MESH:D000163', (52, 76))	('AIDS-defining cancer', 'Disease', (30, 50))	("non-Hodgkin's lymphoma", 'Disease', (78, 100))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('anal cancer', 'Phenotype', 'HP:0032186', (124, 135))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('ART', 'Chemical', '-', (229, 232))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (44, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('NNRTI-based ART', 'Var', (168, 183))	('ART', 'Chemical', '-', (180, 183))	('lower', 'NegReg', (141, 146))	('nelfinavir', 'Chemical', 'MESH:D019888', (214, 224))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('AIDS-defining cancer', 'Disease', 'MESH:D000163', (56, 76))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
562707	26854812	The effect size of these associations were similar to those seen with NNRTI-based ART which suggests the increased risk of non-AIDS-defining cancer with PI-based ART compared to NNRTI-based ART may be related to an increased rate of cancer with PI exposure rather than a lower rate of cancer with NNRTI use.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ART', 'Chemical', '-', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('ART', 'Chemical', '-', (82, 85))	('ART', 'Chemical', '-', (190, 193))	('PI-based ART', 'Var', (153, 165))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('non-AIDS-defining cancer', 'Disease', (123, 147))	('non-AIDS-defining cancer', 'Disease', 'MESH:D000163', (123, 147))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('cancer', 'Disease', (141, 147))
562722	21776194	FISH showed rearrangement of chromosomes 22q12 (EWSR1).	('EWSR1', 'Gene', (48, 53))	('rearrangement', 'Var', (12, 25))	('EWSR1', 'Gene', '2130', (48, 53))
562744	32256354	Four Epimedii Herba-derived flavonoid compounds, namely, limonianin, epimedokoreanin B, icaritin, and desmethylicaritin, inhibited CD163 expression and interleukin (IL)-10 production, which are known M2 markers, suggesting that these compounds inhibit M2 polarization.	('icaritin', 'Chemical', 'MESH:C499403', (88, 96))	('icaritin', 'Chemical', 'MESH:C499403', (111, 119))	('desmethylicaritin', 'Var', (102, 119))	('interleukin (IL)-10', 'Gene', (152, 171))	('CD163 expression', 'MPA', (131, 147))	('limonianin', 'Chemical', '-', (57, 67))	('M2 polarization', 'CPA', (252, 267))	('epimedokoreanin B', 'Chemical', '-', (69, 86))	('epimedokoreanin B', 'Var', (69, 86))	('flavonoid', 'Chemical', 'MESH:D005419', (28, 37))	('inhibited', 'NegReg', (121, 130))	('desmethylicaritin', 'Chemical', 'MESH:C499404', (102, 119))	('inhibit', 'NegReg', (244, 251))	('interleukin (IL)-10', 'Gene', '16153', (152, 171))
562745	32256354	Among these compounds, epimedokoreanin B and limonianin suppressed STAT3 activation in HMDMs.	('epimedokoreanin', 'Var', (23, 38))	('epimedokoreanin B', 'Chemical', '-', (23, 40))	('limonianin', 'Chemical', '-', (45, 55))	('STAT3 activation', 'MPA', (67, 83))	('suppressed', 'NegReg', (56, 66))
562746	32256354	Notably, epimedokoreanin B also suppressed cell proliferation by blocking STAT3 activation in Saos-2 human sarcoma and LM8 mouse sarcoma cell lines.	('blocking', 'NegReg', (65, 73))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('LM8', 'CellLine', 'CVCL:6669', (119, 122))	('mouse', 'Species', '10090', (123, 128))	('sarcoma', 'Disease', (107, 114))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('STAT3 activation', 'MPA', (74, 90))	('human', 'Species', '9606', (101, 106))	('sarcoma', 'Disease', (129, 136))	('epimedokoreanin', 'Var', (9, 24))	('cell proliferation', 'CPA', (43, 61))	('epimedokoreanin B', 'Chemical', '-', (9, 26))	('suppressed', 'NegReg', (32, 42))
562747	32256354	Furthermore, oral administration of epimedokoreanin B inhibited tumor growth in an LM8 tumor-bearing murine model.	('epimedokoreanin', 'Var', (36, 51))	('inhibited', 'NegReg', (54, 63))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('epimedokoreanin B', 'Chemical', '-', (36, 53))	('murine', 'Species', '10090', (101, 107))	('tumor', 'Disease', (87, 92))	('LM8', 'CellLine', 'CVCL:6669', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
562819	32256354	We found that limonianin, epimedokoreanin B, icaritin, and desmethylicaritin inhibited IL-10-induced CD163 expression (Figure 4A), while they had no cytotoxic effect on the macrophages (Figure 4B), suggesting that aglycons are the active compounds in this study.	('desmethylicaritin', 'Chemical', 'MESH:C499404', (59, 76))	('inhibited', 'NegReg', (77, 86))	('icaritin', 'Chemical', 'MESH:C499403', (68, 76))	('epimedokoreanin B', 'Chemical', '-', (26, 43))	('limonianin', 'Chemical', '-', (14, 24))	('expression', 'MPA', (107, 117))	('epimedokoreanin B', 'Var', (26, 43))	('IL-10', 'Gene', '16153', (87, 92))	('icaritin', 'Chemical', 'MESH:C499403', (45, 53))	('IL-10', 'Gene', (87, 92))	('aglycons', 'Chemical', '-', (214, 222))	('CD163', 'Gene', (101, 106))
562824	32256354	In addition, epimedokoreanin B also enhanced TNF-alpha and IL-1beta secretion reduced by TCS stimulation (Figure 4C).	('epimedokoreanin', 'Var', (13, 28))	('TCS', 'Chemical', '-', (89, 92))	('IL-1beta', 'Gene', '16175', (59, 67))	('TNF-alpha', 'Gene', (45, 54))	('epimedokoreanin B', 'Chemical', '-', (13, 30))	('IL-1beta', 'Gene', (59, 67))	('reduced', 'NegReg', (78, 85))	('enhanced', 'PosReg', (36, 44))	('TNF-alpha', 'Gene', '21926', (45, 54))
562825	32256354	Furthermore, epimedokoreanin B also inhibited IL-4-induced CD206 expression, another M2 phenotype marker (Figure 4D).	('CD206', 'Gene', (59, 64))	('epimedokoreanin', 'Var', (13, 28))	('inhibited', 'NegReg', (36, 45))	('IL-4', 'Gene', '16189', (46, 50))	('expression', 'MPA', (65, 75))	('epimedokoreanin B', 'Chemical', '-', (13, 30))	('IL-4', 'Gene', (46, 50))
562826	32256354	These data indicate that epimedokoreanin B has a potentially inhibitory effect on M2 polarization of HMDMs.	('epimedokoreanin B', 'Chemical', '-', (25, 42))	('M2 polarization', 'MPA', (82, 97))	('epimedokoreanin', 'Var', (25, 40))	('inhibitory effect', 'NegReg', (61, 78))
562829	32256354	Under the assay conditions employed, epimedokoreanin B significantly suppressed IL-10-induced JAK1/STAT3 activation.	('JAK1', 'Gene', (94, 98))	('IL-10', 'Gene', (80, 85))	('epimedokoreanin', 'Var', (37, 52))	('epimedokoreanin B', 'Chemical', '-', (37, 54))	('JAK1', 'Gene', '16451', (94, 98))	('suppressed', 'NegReg', (69, 79))	('IL-10', 'Gene', '16153', (80, 85))
562830	32256354	These results suggest that epimedokoreanin B regulates conversion of M2 into M1 phenotype in HMDMs by inhibiting STAT3 activation.	('conversion', 'MPA', (55, 65))	('inhibiting', 'NegReg', (102, 112))	('epimedokoreanin', 'Var', (27, 42))	('STAT3 activation', 'MPA', (113, 129))	('epimedokoreanin B', 'Chemical', '-', (27, 44))
562833	32256354	As shown in Figure 5A, epimedokoreanin B, icaritin, and desmethylicaritin significantly inhibited the proliferation of Saos-2 cells.	('inhibited', 'NegReg', (88, 97))	('epimedokoreanin B', 'Chemical', '-', (23, 40))	('epimedokoreanin B', 'Var', (23, 40))	('desmethylicaritin', 'Chemical', 'MESH:C499404', (56, 73))	('icaritin', 'Chemical', 'MESH:C499403', (42, 50))	('icaritin', 'Chemical', 'MESH:C499403', (65, 73))	('proliferation', 'CPA', (102, 115))	('desmethylicaritin', 'Var', (56, 73))
562834	32256354	Among these compounds, epimedokoreanin B had a strong inhibitory effect on Saos-2 cell proliferation.	('epimedokoreanin', 'Var', (23, 38))	('epimedokoreanin B', 'Chemical', '-', (23, 40))	('Saos-2 cell proliferation', 'CPA', (75, 100))	('inhibitory effect', 'NegReg', (54, 71))
562835	32256354	Epimedokoreanin B also significantly inhibited the proliferation of LM8 cells (Figure 5B).	('LM8', 'CellLine', 'CVCL:6669', (68, 71))	('Epimedokoreanin', 'Var', (0, 15))	('inhibited', 'NegReg', (37, 46))	('Epimedokoreanin B', 'Chemical', '-', (0, 17))	('proliferation', 'CPA', (51, 64))
562836	32256354	Furthermore, epimedokoreanin B also inhibited colony formation in both Saos-2 and LM-8 cells (Figure 5C).	('epimedokoreanin', 'Var', (13, 28))	('inhibited', 'NegReg', (36, 45))	('colony formation', 'CPA', (46, 62))	('epimedokoreanin B', 'Chemical', '-', (13, 30))	('LM-8', 'CellLine', 'CVCL:6669', (82, 86))
562837	32256354	Under the assay conditions used, epimedokoreanin B also suppressed STAT3 activation in both Saos-2 cells and LM8 cells (Figures 5D,E).	('LM8', 'CellLine', 'CVCL:6669', (109, 112))	('epimedokoreanin B', 'Var', (33, 50))	('epimedokoreanin B', 'Chemical', '-', (33, 50))	('STAT3 activation', 'MPA', (67, 83))	('suppressed', 'NegReg', (56, 66))
562838	32256354	These data suggest that inhibition of STAT3-related signal pathway by epimedokoreanin B suppresses tumor cell proliferation.	('suppresses', 'NegReg', (88, 98))	('tumor', 'Disease', (99, 104))	('epimedokoreanin', 'Var', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('inhibition', 'NegReg', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('STAT3-related signal pathway', 'Pathway', (38, 66))	('epimedokoreanin B', 'Chemical', '-', (70, 87))
562841	32256354	These data suggest that epimedokoreanin B regulates macrophage activation in both human and mouse macrophages.	('epimedokoreanin', 'Var', (24, 39))	('epimedokoreanin B', 'Chemical', '-', (24, 41))	('mouse', 'Species', '10090', (92, 97))	('macrophage activation', 'CPA', (52, 73))	('human', 'Species', '9606', (82, 87))
562845	32256354	This enhanced effect was reduced by co-culture with epimedokoreanin B-treated macrophages (Figure 6B), indicating that epimedokoreanin B suppresses tumor proliferation by regulating macrophage activation.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('epimedokoreanin', 'Var', (119, 134))	('epimedokoreanin B', 'Chemical', '-', (52, 69))	('tumor', 'Disease', (148, 153))	('epimedokoreanin B', 'Chemical', '-', (119, 136))	('suppresses', 'NegReg', (137, 147))	('macrophage activation', 'CPA', (182, 203))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
562849	32256354	On the other hand, epimedokoreanin B significantly inhibited subcutaneous tumor development (Figure 7B).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('epimedokoreanin', 'Var', (19, 34))	('epimedokoreanin B', 'Chemical', '-', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (61, 79))	('tumor', 'Disease', (74, 79))	('inhibited', 'NegReg', (51, 60))
562853	32256354	STAT3 activation in the subcutaneous tumor tissue was also reduced following epimedokoreanin B administration (Figure 7C).	('reduced', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('epimedokoreanin B', 'Chemical', '-', (77, 94))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (24, 42))	('STAT3 activation', 'MPA', (0, 16))	('epimedokoreanin', 'Var', (77, 92))
562856	32256354	These data indicate that epimedokoreanin B also inhibits tumor development in a mouse model by suppressing STAT3 activation.	('suppressing', 'NegReg', (95, 106))	('inhibits', 'NegReg', (48, 56))	('STAT3 activation', 'MPA', (107, 123))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('epimedokoreanin', 'Var', (25, 40))	('mouse', 'Species', '10090', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('epimedokoreanin B', 'Chemical', '-', (25, 42))	('tumor', 'Disease', (57, 62))
562858	32256354	Desmethylicaritin has an inhibitory effect on LPS-induced NO production in murine macrophages by suppressing iNOS activity and an inhibitory effect on tumor proliferation in U87MG human glioblastoma cells.	('inhibitory', 'NegReg', (130, 140))	('Desmethylicaritin', 'Var', (0, 17))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('human', 'Species', '9606', (180, 185))	('tumor', 'Disease', (151, 156))	('murine', 'Species', '10090', (75, 81))	('U87MG', 'CellLine', 'CVCL:0022', (174, 179))	('Desmethylicaritin', 'Chemical', 'MESH:C499404', (0, 17))	('iNOS', 'Gene', '18126', (109, 113))	('suppressing', 'NegReg', (97, 108))	('iNOS', 'Gene', (109, 113))	('glioblastoma', 'Disease', (186, 198))	('LPS', 'Chemical', 'MESH:D008070', (46, 49))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
562859	32256354	In the present study, desmethylicaritin inhibited the proliferation of Saos-2 cells (Figure 5A).	('desmethylicaritin', 'Chemical', 'MESH:C499404', (22, 39))	('desmethylicaritin', 'Var', (22, 39))	('proliferation', 'CPA', (54, 67))	('inhibited', 'NegReg', (40, 49))
562865	32256354	It binds the hemoglobin-haptoglobin (Hb-Hp) complex and subsequently induces IL-10 secretion and HO-1 expression, which suggests that CD163 contributes to immunosuppression.	('CD163', 'Var', (134, 139))	('binds', 'Interaction', (3, 8))	('IL-10', 'Gene', '16153', (77, 82))	('HO-1', 'Gene', '15368', (97, 101))	('expression', 'MPA', (102, 112))	('HO-1', 'Gene', (97, 101))	('Hb-Hp', 'Gene', (37, 42))	('IL-10', 'Gene', (77, 82))	('induces', 'Reg', (69, 76))
562866	32256354	Therefore, inhibition of TAM polarization to a CD163-positive M2 phenotype is a probable therapeutic strategy for cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('inhibition', 'Var', (11, 21))	('TAM', 'Chemical', '-', (25, 28))	('cancer', 'Disease', (114, 120))
562873	32256354	It was recently reported that CD163-positive macrophages are also associated with both proliferation in Saos-2 cells and tumor progression in a sarcoma-bearing mouse model by IL-6-induced STAT3 activation.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('proliferation', 'CPA', (87, 100))	('associated', 'Reg', (66, 76))	('tumor', 'Disease', (121, 126))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('CD163-positive', 'Var', (30, 44))	('mouse', 'Species', '10090', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
562874	32256354	Epimedokoreanin B showed an inhibitory effect on STAT3 activation in both macrophages and tumor cells (Figures 4D, 5C,D), and epimedokoreanin B suppressed tumor progression in the LM8 tumor-bearing mouse model in the present study (Figure 7B).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('STAT3 activation', 'MPA', (49, 65))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Epimedokoreanin B', 'Chemical', '-', (0, 17))	('suppressed', 'NegReg', (144, 154))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (184, 189))	('epimedokoreanin B', 'Chemical', '-', (126, 143))	('epimedokoreanin B', 'Var', (126, 143))	('LM8', 'CellLine', 'CVCL:6669', (180, 183))	('mouse', 'Species', '10090', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
562875	32256354	Furthermore, administration of epimedokoreanin B significantly decreased both pSTAT3-positive area and PCNA-positive cells in subcutaneous tumor tissues (Figure 7C), thus indicating that epimedokoreanin B suppresses tumor development in a mouse model by inhibiting STAT3 activation in both macrophages and tumor cells.	('epimedokoreanin B', 'Chemical', '-', (187, 204))	('PCNA', 'Gene', '18538', (103, 107))	('pSTAT3-positive', 'MPA', (78, 93))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (306, 311))	('STAT3 activation', 'MPA', (265, 281))	('tumor', 'Disease', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('epimedokoreanin B', 'Var', (187, 204))	('decreased', 'NegReg', (63, 72))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (126, 144))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('PCNA', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('inhibiting', 'NegReg', (254, 264))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('epimedokoreanin B', 'Chemical', '-', (31, 48))	('suppresses', 'NegReg', (205, 215))	('mouse', 'Species', '10090', (239, 244))
562876	32256354	As shown in Figure 8, epimedokoreanin B reduced the ratio of CD204+ M2 macrophages to Iba-1+ total macrophages in the subcutaneous tumor tissues.	('epimedokoreanin', 'Var', (22, 37))	('Iba-1', 'Gene', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (118, 136))	('epimedokoreanin B', 'Chemical', '-', (22, 39))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('CD204+ M2 macrophages', 'MPA', (61, 82))	('ratio', 'MPA', (52, 57))	('tumor', 'Disease', (131, 136))	('reduced', 'NegReg', (40, 47))	('Iba-1', 'Gene', '114737', (86, 91))
562890	32256354	In the present study, we revealed that epimedokoreanin B significantly inhibited STAT3 activation in human macrophages and tumor cells and suppressed macrophage polarization to the M2 phenotype.	('tumor', 'Disease', (123, 128))	('epimedokoreanin', 'Var', (39, 54))	('inhibited', 'NegReg', (71, 80))	('epimedokoreanin B', 'Chemical', '-', (39, 56))	('human', 'Species', '9606', (101, 106))	('macrophage polarization', 'CPA', (150, 173))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('STAT3 activation', 'MPA', (81, 97))	('suppressed', 'NegReg', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
562891	32256354	In addition, the oral administration of epimedokoreanin B significantly suppressed tumor development in tumor-bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('epimedokoreanin', 'Var', (40, 55))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (83, 88))	('epimedokoreanin B', 'Chemical', '-', (40, 57))	('tumor', 'Disease', (104, 109))	('suppressed', 'NegReg', (72, 82))	('mice', 'Species', '10090', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
562893	32256354	Epimedokoreanin B may also directly suppress tumor proliferation and enhance tumor sensitivity to radiotherapy and chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Epimedokoreanin', 'Var', (0, 15))	('tumor', 'Disease', (45, 50))	('suppress', 'NegReg', (36, 44))	('enhance', 'PosReg', (69, 76))	('Epimedokoreanin B', 'Chemical', '-', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('enhance tumor sensitivity to radiotherapy', 'Phenotype', 'HP:0011133', (69, 110))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
562917	31827370	The resultant nanosomal particles (<100 nm) may allow the docetaxel infiltration and entrapment in the weakened tumor vasculature and necrotic tumor tissue collagen material, thus causing increased retention (enhanced permeability retention (EPR) effect), leading to a greater systemic availability of docetaxel, and ultimately improved outcome, which may have potential in the treatment of difficult to treat cancers such as sarcomas.	('retention', 'MPA', (198, 207))	('greater', 'PosReg', (269, 276))	('<100', 'Var', (35, 39))	('increased', 'PosReg', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (426, 434))	('entrapment', 'CPA', (85, 95))	('sarcomas', 'Disease', (426, 434))	('necrotic tumor', 'Disease', 'MESH:D009369', (134, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (426, 433))	('systemic availability', 'MPA', (277, 298))	('tumor vasculature', 'Disease', (112, 129))	('outcome', 'MPA', (337, 344))	('cancers', 'Phenotype', 'HP:0002664', (410, 417))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('necrotic tumor', 'Disease', (134, 148))	('tumor vasculature', 'Disease', 'MESH:C565633', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('improved', 'PosReg', (328, 336))
562927	31686913	We hypothesized that phenotypic changes driven by differential gene expression in a finite subpopulation of tumor cells render those cells capable of metastasis and sought to identify key pathways through analysis of gene expression in primary and metastatic lesions from the same patients.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('differential gene expression', 'Var', (50, 78))	('patients', 'Species', '9606', (281, 289))	('tumor', 'Disease', (108, 113))	('metastasis', 'CPA', (150, 160))
562930	31686913	Silencing of KRT7 and MUC1 via targeted siRNAs suppressed sarcoma cell migration in vitro, and a significant correlation (two-sided) was observed between both KRT7 and MUC1 expression in metastases and overall patient survival.	('KRT7', 'Gene', '3855', (13, 17))	('suppressed', 'NegReg', (47, 57))	('KRT7', 'Gene', (13, 17))	('siRNAs', 'Gene', (40, 46))	('metastases', 'Disease', (187, 197))	('Silencing', 'Var', (0, 9))	('metastases', 'Disease', 'MESH:D009362', (187, 197))	('MUC1', 'Gene', (22, 26))	('MUC1', 'Gene', '4582', (22, 26))	('KRT7', 'Gene', '3855', (159, 163))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('patient', 'Species', '9606', (210, 217))	('MUC1', 'Gene', (168, 172))	('sarcoma', 'Disease', (58, 65))	('MUC1', 'Gene', '4582', (168, 172))	('KRT7', 'Gene', (159, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
562953	31686913	Sarcoma cell lines U2OS (osteosarcoma), MES-SA (uterine sarcoma), and SKUT1 (leiomyosarcoma) were obtained from ATCC (Manassas, VA), as was rhabdoid tumor cell line A204 (rhabdoid tumors bear a SMARCB1 mutation and are mostly found in small children).	('osteosarcoma', 'Phenotype', 'HP:0002669', (25, 37))	('SKUT1', 'CellLine', 'CVCL:0533', (70, 75))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('sarcoma', 'Disease', (56, 63))	('Sarcoma', 'Disease', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mutation', 'Var', (202, 210))	('sarcoma', 'Disease', (30, 37))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (171, 185))	('leiomyosarcoma', 'Disease', (77, 91))	('children', 'Species', '9606', (241, 249))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (140, 154))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('rhabdoid tumors', 'Disease', (171, 186))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('SMARCB1', 'Gene', '6598', (194, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('sarcoma', 'Disease', (84, 91))	('SMARCB1', 'Gene', (194, 201))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (171, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('osteosarcoma', 'Disease', (25, 37))	('osteosarcoma', 'Disease', 'MESH:D012516', (25, 37))	('rhabdoid tumor', 'Disease', (140, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('A204', 'CellLine', 'CVCL:1N55', (165, 169))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (48, 63))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (77, 91))	('Sarcoma', 'Disease', 'MESH:D012509', (0, 7))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (77, 91))	('U2OS', 'CellLine', 'CVCL:0042', (19, 23))	('sarcoma', 'Disease', 'MESH:D012509', (56, 63))
562980	31686913	We focused on gene sets known to be regulated in response to adhesion modules specifically because aberration in cell-cell adhesion may be a critical factor contributing to tumor transformation, invasion, and metastasis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('cell-cell adhesion', 'CPA', (113, 131))	('aberration', 'Var', (99, 109))	('invasion', 'CPA', (195, 203))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('metastasis', 'CPA', (209, 219))	('contributing', 'Reg', (157, 169))
562993	31686913	In the event that sarcoma metastases are supported by the contributions of upregulated KRT7 and MUC1 expression, then silencing KRT7 and MUC1 by siRNAs would be expected to result in reduced EMT and therefore reduced wound healing.	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcoma metastases', 'Disease', (18, 36))	('KRT7', 'Gene', '3855', (87, 91))	('reduced wound healing', 'Phenotype', 'HP:0001058', (209, 230))	('upregulated', 'PosReg', (75, 86))	('reduced', 'NegReg', (183, 190))	('silencing', 'Var', (118, 127))	('sarcoma metastases', 'Disease', 'MESH:D009362', (18, 36))	('MUC1', 'Gene', (137, 141))	('MUC1', 'Gene', '4582', (137, 141))	('KRT7', 'Gene', (128, 132))	('MUC1', 'Gene', (96, 100))	('MUC1', 'Gene', '4582', (96, 100))	('wound healing', 'CPA', (217, 230))	('KRT7', 'Gene', '3855', (128, 132))	('EMT', 'CPA', (191, 194))	('KRT7', 'Gene', (87, 91))	('reduced', 'NegReg', (209, 216))	('reduced EMT', 'Phenotype', 'HP:0032198', (183, 194))
562996	31686913	Importantly, these knockdowns of either KRT7 or MUC1 in U2OS osteosarcoma cells also resulted in a reduction in wound healing in an in vitro assay (Figure 4B).	('MUC1', 'Gene', (48, 52))	('osteosarcoma', 'Disease', (61, 73))	('MUC1', 'Gene', '4582', (48, 52))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('wound healing in an in vitro assay', 'CPA', (112, 146))	('knockdowns', 'Var', (19, 29))	('U2OS', 'CellLine', 'CVCL:0042', (56, 60))	('reduction', 'NegReg', (99, 108))	('KRT7', 'Gene', '3855', (40, 44))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))	('KRT7', 'Gene', (40, 44))
563013	31686913	Finally, we found that suppression of KRT7 and MUC1 reduces cell migration in an in vitro wound healing/EMT assay, suggesting that changes in these proteins that are related to cell adhesive properties and cytoskeletal function may contribute to sarcoma cell mobility, migration, and metastases.	('contribute', 'Reg', (232, 242))	('changes', 'Var', (131, 138))	('sarcoma', 'Disease', 'MESH:D012509', (246, 253))	('KRT7', 'Gene', '3855', (38, 42))	('migration', 'CPA', (269, 278))	('reduces', 'NegReg', (52, 59))	('KRT7', 'Gene', (38, 42))	('metastases', 'Disease', (284, 294))	('MUC1', 'Gene', (47, 51))	('sarcoma', 'Disease', (246, 253))	('MUC1', 'Gene', '4582', (47, 51))	('suppression', 'NegReg', (23, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('metastases', 'Disease', 'MESH:D009362', (284, 294))
563175	27116656	The Caspase-Glo 3/7 Assay (Promega) was used to determine the relative levels of Caspase 3/7 activation 48 hr postinfection with GLV-1h68 (MOI 0.1), +/- melphalan 250 nM, +/- radiation (2 or 4 Gy) according to the manufacturer's instructions.	('melphalan', 'Chemical', 'MESH:D008558', (153, 162))	('activation', 'PosReg', (93, 103))	('+/- radiation', 'Var', (171, 184))	('+/- melphalan', 'Var', (149, 162))	('Caspase 3/7', 'Enzyme', (81, 92))	('GLV-1h68', 'Species', '502057', (129, 137))
563205	27116656	However, the combinations of melphalan and GLV-1h68, GLV-1h68 and EBRT or melphalan and EBRT resulted in greater cleavage of caspase-3.	('combinations', 'Interaction', (13, 25))	('caspase-3', 'Protein', (125, 134))	('cleavage', 'MPA', (113, 121))	('EBRT', 'Chemical', '-', (88, 92))	('melphalan', 'Chemical', 'MESH:D008558', (74, 83))	('GLV-1h68', 'Var', (53, 61))	('GLV-1h68', 'Var', (43, 51))	('EBRT', 'Chemical', '-', (66, 70))	('GLV-1h68', 'Species', '502057', (53, 61))	('greater', 'PosReg', (105, 112))	('GLV-1h68', 'Species', '502057', (43, 51))	('melphalan', 'Chemical', 'MESH:D008558', (29, 38))
563206	27116656	This was markedly increased with triple combination therapy (GLV-1h68, melphalan and EBRT) compared to double therapy at both 2 and 4 Gy (Fig.	('GLV-1h68', 'Species', '502057', (61, 69))	('increased', 'PosReg', (18, 27))	('melphalan', 'Chemical', 'MESH:D008558', (71, 80))	('EBRT', 'Chemical', '-', (85, 89))	('GLV-1h68', 'Var', (61, 69))
563207	27116656	The combination of GLV-1h68 and melphalan caused a significant increase in cleaved caspase 3/7 activity compared to controls at all doses of radiation (zero, 2 and 4 Gy; p < 0.01) and was superior to GLV-1h68 alone and GLV-1h68 with 2 Gy (two-way ANOVA with Bonferroni post-test; p < 0.05).	('GLV-1h68', 'Species', '502057', (19, 27))	('increase', 'PosReg', (63, 71))	('melphalan', 'Chemical', 'MESH:D008558', (32, 41))	('cleaved', 'MPA', (75, 82))	('GLV-1h68', 'Species', '502057', (219, 227))	('GLV-1h68', 'Var', (19, 27))	('melphalan', 'Var', (32, 41))	('activity', 'MPA', (95, 103))	('GLV-1h68', 'Species', '502057', (200, 208))
563251	27116656	If their potential were realised, these combinations may provide a means of engendering a tumour-specific immune response prior to the resection of a tumour to safeguard against both local and distant recurrence.	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('tumour', 'Disease', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('engendering', 'Reg', (76, 87))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))	('combinations', 'Var', (40, 52))
563255	26885691	For instance, silencing of RHA and/or disruption of its interaction with the oncoprotein EWS-FLI1 rendered Ewing sarcoma cells more sensitive to genotoxic stresses and affected tumor growth and maintenance, suggesting possible therapeutic implications.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (107, 120))	('silencing', 'Var', (14, 23))	('sensitive', 'MPA', (132, 141))	('EWS-FLI1', 'Gene', '2130;2313', (89, 97))	('RHA', 'Gene', (27, 30))	('maintenance', 'CPA', (194, 205))	('more', 'PosReg', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('EWS-FLI1', 'Gene', (89, 97))	('interaction', 'Interaction', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('affected', 'Reg', (168, 176))	('Ewing sarcoma', 'Disease', (107, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('tumor', 'Disease', (177, 182))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (107, 120))
563265	26885691	Rha-1 mutations in worms produce transcriptional de-silencing at restrictive temperature causing defects in germ cell proliferation.	('defects', 'NegReg', (97, 104))	('Rha-1', 'Gene', '174417', (0, 5))	('defects in germ cell', 'Phenotype', 'HP:0012862', (97, 117))	('germ cell proliferation', 'CPA', (108, 131))	('de-silencing', 'NegReg', (49, 61))	('Rha-1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
563266	26885691	Homozygous rha mutation in mice determines apoptosis of embryonic ectodermal cells during gastrulation and early embryonic lethality in both sexes.	('mutation', 'Var', (15, 23))	('embryonic lethality', 'Disease', 'MESH:D020964', (113, 132))	('embryonic lethality', 'Disease', (113, 132))	('rha', 'Gene', (11, 14))	('apoptosis', 'CPA', (43, 52))	('mice', 'Species', '10090', (27, 31))	('rha', 'Gene', '13211', (11, 14))
563267	26885691	Mice carrying rha mutations on one allele are viable, albeit they express lower protein level than wild type.	('rha', 'Gene', '13211', (14, 17))	('protein level', 'MPA', (80, 93))	('rha', 'Gene', (14, 17))	('Mice', 'Species', '10090', (0, 4))	('lower', 'NegReg', (74, 79))	('mutations', 'Var', (18, 27))
563268	26885691	In humans, mutations in RHA and alteration in RHA expression are found in a wide range of cancers, suggesting that non-functional RHA protein is involved in malignant transformation.	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (11, 20))	('alteration', 'Var', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RHA', 'Gene', (24, 27))	('RHA', 'Gene', (46, 49))	('humans', 'Species', '9606', (3, 9))	('involved', 'Reg', (145, 153))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('found', 'Reg', (65, 70))	('expression', 'MPA', (50, 60))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
563269	26885691	For instance, the gene encoding RHA was identified as one of ten genes displaying recurrent mutations that were highly correlated with pathway deregulation and patient survival in lung adenocarcinoma.	('pathway', 'MPA', (135, 142))	('lung adenocarcinoma', 'Disease', (180, 199))	('mutations', 'Var', (92, 101))	('RHA', 'Gene', (32, 35))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (180, 199))	('correlated', 'Reg', (119, 129))	('patient', 'Species', '9606', (160, 167))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (180, 199))
563281	26885691	Importantly, proteolytic deletion studies documented that neither disruption of the RGG-box nor of the two dsRBDs abolished the unwinding activity, although their proteolytic removal diminished the nucleic acid-stimulated ATPase activity of RHA.	('diminished', 'NegReg', (183, 193))	('ATP', 'Chemical', 'MESH:D000255', (222, 225))	('nucleic acid-stimulated ATPase activity', 'MPA', (198, 237))	('abolished', 'NegReg', (114, 123))	('disruption', 'Var', (66, 76))	('unwinding activity', 'MPA', (128, 146))
563282	26885691	Thus, single-stranded/double-stranded nucleic acid contacts with the RGG domain and the dsRBDs might trigger the activation of the ATPase/helicase activity, and cooperation between the RGG domain and the dsRBDs might represent the first step in the enzymatic activity of RHA.	('helicase', 'Gene', (138, 146))	('single-stranded/double-stranded', 'Var', (6, 37))	('activation', 'PosReg', (113, 123))	('ATP', 'Chemical', 'MESH:D000255', (131, 134))	('helicase', 'Gene', '164045', (138, 146))	('activity', 'MPA', (147, 155))
563290	26885691	Remarkably, mutations in the CBP-binding region of RHA occur in several human tumors and were reported to strongly affect regulation of gene expression.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('affect', 'Reg', (115, 121))	('RHA', 'Gene', (51, 54))	('mutations', 'Var', (12, 21))	('human', 'Species', '9606', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('regulation of gene expression', 'MPA', (122, 151))	('CBP', 'Gene', (29, 32))	('CBP', 'Gene', '1387', (29, 32))
563294	26885691	BRCA1 inherited mutations in BRCA1 or BRCA2 predispose to breast, ovarian, and other cancers.	('breast', 'Disease', (58, 64))	('BRCA1', 'Gene', (0, 5))	('ovarian', 'Disease', (66, 73))	('BRCA2', 'Gene', '675', (38, 43))	('BRCA1', 'Gene', '672', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('mutations', 'Var', (16, 25))	('BRCA1', 'Gene', '672', (29, 34))	('cancers', 'Disease', (85, 92))	('predispose', 'Reg', (44, 54))	('BRCA1', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('BRCA2', 'Gene', (38, 43))
563295	26885691	It is possible that mutations in the CBP-binding region of RHA affect CBP/p300 co-factor transcriptional activity, thus impairing the transcription of BRCA-1.	('affect', 'Reg', (63, 69))	('transcription', 'MPA', (134, 147))	('RHA', 'Gene', (59, 62))	('CBP', 'Gene', (70, 73))	('CBP/p300', 'Gene', (70, 78))	('CBP', 'Gene', '1387', (37, 40))	('CBP', 'Gene', '1387', (70, 73))	('impairing', 'NegReg', (120, 129))	('CBP/p300', 'Gene', '1387;2033', (70, 78))	('CBP', 'Gene', (37, 40))	('BRCA-1', 'Gene', (151, 157))	('mutations', 'Var', (20, 29))	('BRCA-1', 'Gene', '672', (151, 157))
563297	26885691	Breast cancer-related BRCA1 mutants display low ability to bind RHA thus reducing BRCA1 tumor suppressor activity and promoting cancer growth.	('BRCA1', 'Gene', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutants', 'Var', (28, 35))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('BRCA1 tumor', 'Disease', (82, 93))	('promoting', 'PosReg', (118, 127))	('reducing', 'NegReg', (73, 81))	('BRCA1', 'Gene', '672', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('BRCA1', 'Gene', '672', (82, 87))	('BRCA1 tumor', 'Disease', 'MESH:D009369', (82, 93))	('BRCA1', 'Gene', (22, 27))	('cancer', 'Disease', (128, 134))
563300	26885691	Importantly, the expression of several miRNAs is dysregulated in BRCA1/2 mutated cells.	('BRCA1', 'Gene', '672', (65, 70))	('mutated', 'Var', (73, 80))	('expression', 'MPA', (17, 27))	('BRCA1', 'Gene', (65, 70))	('dysregulated', 'Reg', (49, 61))
563302	26885691	Accordingly, RNA immunoprecipitation (RIP) experiments showed that both BRCA1 and RHA associate with pri-let-7a-1, miR-16-1, miR-145, and miR-34a, while RHA knockdown suppressed the processing of the pri-miRNAs let-7a-1, miR-16-1, miR-145, and miR-34a.	('suppressed', 'NegReg', (167, 177))	('miR-16-1', 'Gene', (221, 229))	('miR-34a', 'Gene', (244, 251))	('miR-145', 'Gene', (231, 238))	('let-7a-1', 'Gene', '406881', (211, 219))	('associate', 'Interaction', (86, 95))	('let-7a-1', 'Gene', (105, 113))	('miR-34a', 'Gene', '407040', (244, 251))	('miR-34a', 'Gene', (138, 145))	('miR-145', 'Gene', '406937', (125, 132))	('miR-16-1', 'Gene', '406950', (115, 123))	('let-7a-1', 'Gene', '406881', (105, 113))	('miR-34a', 'Gene', '407040', (138, 145))	('miR-145', 'Gene', (125, 132))	('miR-16-1', 'Gene', (115, 123))	('BRCA1', 'Gene', '672', (72, 77))	('BRCA1', 'Gene', (72, 77))	('processing', 'MPA', (182, 192))	('miR-145', 'Gene', '406937', (231, 238))	('miR-16-1', 'Gene', '406950', (221, 229))	('knockdown', 'Var', (157, 166))	('let-7a-1', 'Gene', (211, 219))
563303	26885691	These findings open the possibility that RHA participates in miRNA processing in complex with BRCA1 and that aberrant regulation of miRNA processing by mutations in BRCA1 and/or RHA contribute to oncogenic transformation.	('RHA', 'Gene', (178, 181))	('BRCA1', 'Gene', (165, 170))	('mutations', 'Var', (152, 161))	('miRNA processing', 'MPA', (132, 148))	('oncogenic transformation', 'CPA', (196, 220))	('BRCA1', 'Gene', '672', (94, 99))	('contribute', 'Reg', (182, 192))	('BRCA1', 'Gene', (94, 99))	('BRCA1', 'Gene', '672', (165, 170))	('miRNA', 'MPA', (61, 66))
563310	26885691	This NF-kappaB-dependent gene expression program is inhibited by both RHA knockdown or dominant negative mutants of RHA (lacking the ATP-binding and helicase activity) while it is increased by RHA overexpression.	('ATP', 'Chemical', 'MESH:D000255', (133, 136))	('helicase', 'Gene', (149, 157))	('negative', 'NegReg', (96, 104))	('RHA', 'Gene', (70, 73))	('knockdown', 'Var', (74, 83))	('lacking', 'NegReg', (121, 128))	('NF-kappaB-dependent gene', 'Gene', (5, 29))	('mutants', 'Var', (105, 112))	('inhibited', 'NegReg', (52, 61))	('RHA', 'Gene', (116, 119))	('helicase', 'Gene', '164045', (149, 157))
563322	26885691	Importantly, mutations in the PCE stem-loop inhibit translation and do not allow RHA binding.	('PCE', 'Chemical', '-', (30, 33))	('inhibit', 'NegReg', (44, 51))	('translation', 'MPA', (52, 63))	('mutations', 'Var', (13, 22))	('binding', 'Interaction', (85, 92))	('PCE', 'Gene', (30, 33))
563323	26885691	On the other side, mutations in the conserved lysine residues of dsRBD I or II of RHA reduce, but do not abolish, RHA affinity for PCE structures.	('PCE', 'Chemical', '-', (131, 134))	('dsRBD I', 'Gene', (65, 72))	('mutations', 'Var', (19, 28))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('reduce', 'NegReg', (86, 92))	('RHA', 'Gene', (82, 85))	('affinity', 'MPA', (118, 126))
563324	26885691	Mutations affecting both the dsRBD domains of RHA completely abolish RHA translational activity of retroviral PCE-containing RNAs.	('RHA', 'Gene', (46, 49))	('Mutations', 'Var', (0, 9))	('PCE', 'Chemical', '-', (110, 113))	('RHA translational activity', 'MPA', (69, 95))	('abolish', 'NegReg', (61, 68))
563334	26885691	Importantly, a mutant Lin28 that still binds RNA but is unable to interact with RHA, acts as a dominant-negative inhibitor of Lin28-dependent stimulation of translation.	('RNA', 'Protein', (45, 48))	('Lin28', 'Gene', (22, 27))	('Lin28', 'Gene', '79727', (22, 27))	('binds', 'Interaction', (39, 44))	('inhibitor', 'NegReg', (113, 122))	('mutant', 'Var', (15, 21))	('Lin28', 'Gene', (126, 131))	('Lin28', 'Gene', '79727', (126, 131))
563335	26885691	Similarly, knockdown of RHA in human lung fibroblasts prevents formation of polysomes on collagen mRNAs and dramatically reduces synthesis of collagen protein, without affecting the level of the mRNAs.	('prevents', 'NegReg', (54, 62))	('RHA', 'Gene', (24, 27))	('human', 'Species', '9606', (31, 36))	('synthesis of collagen protein', 'MPA', (129, 158))	('reduces', 'NegReg', (121, 128))	('formation of polysomes on collagen mRNAs', 'MPA', (63, 103))	('reduces synthesis of collagen protein', 'Phenotype', 'HP:0030095', (121, 158))	('knockdown', 'Var', (11, 20))
563336	26885691	Thus these non-B DNA-structures (like repetitive DNA motifs, short tandem repeats, inverted repeats, alternating purine-pyrimidine tracts, and G-rich sequences) induce genetic instabilities in the form of deletions, translocations and single-base substitutions.	('deletions', 'Var', (205, 214))	('genetic instabilities', 'Disease', 'MESH:D030342', (168, 189))	('induce', 'Reg', (161, 167))	('pyrimidine', 'Chemical', 'MESH:C030986', (120, 130))	('translocations', 'CPA', (216, 230))	('purine', 'Chemical', 'MESH:C030985', (113, 119))	('single-base substitutions', 'Var', (235, 260))	('genetic instabilities', 'Disease', (168, 189))
563347	26885691	Importantly, defective WRN DNA helicase causes the Werner syndrome, a rare autosomal recessive genetic disorder manifested by the symptoms of premature aging, such as atherosclerosis, osteoporosis, diabetes mellitus type II, cataracts, and genomic instability with an increased incidence of tumor formation.	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('cataracts', 'Disease', 'MESH:D002386', (225, 234))	('autosomal recessive genetic disorder', 'Disease', 'MESH:D030342', (75, 111))	('WRN', 'Gene', (23, 26))	('WRN', 'Gene', '7486', (23, 26))	('Werner syndrome', 'Disease', 'MESH:D014898', (51, 66))	('diabetes mellitus type II', 'Disease', 'MESH:D003924', (198, 223))	('diabetes mellitus type II', 'Disease', (198, 223))	('causes', 'Reg', (40, 46))	('defective', 'Var', (13, 22))	('genomic instability', 'Disease', (240, 259))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('helicase', 'Gene', (31, 39))	('cataracts', 'Disease', (225, 234))	('atherosclerosis', 'Disease', 'MESH:D050197', (167, 182))	('autosomal recessive genetic disorder', 'Disease', (75, 111))	('osteoporosis', 'Disease', (184, 196))	('atherosclerosis', 'Disease', (167, 182))	('diabetes mellitus type II', 'Phenotype', 'HP:0005978', (198, 223))	('osteoporosis', 'Phenotype', 'HP:0000939', (184, 196))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (198, 215))	('atherosclerosis', 'Phenotype', 'HP:0002621', (167, 182))	('helicase', 'Gene', '164045', (31, 39))	('cataracts', 'Phenotype', 'HP:0000518', (225, 234))	('osteoporosis', 'Disease', 'MESH:D010024', (184, 196))	('Werner syndrome', 'Disease', (51, 66))	('tumor', 'Disease', (291, 296))
563349	26885691	Importantly, centrosome amplification occurs frequently in almost all types of cancer, and is considered as the major contributing factor for chromosome instability in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('chromosome instability', 'Phenotype', 'HP:0040012', (142, 164))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('centrosome amplification', 'Var', (13, 37))
563351	26885691	Deregulation of the mechanisms guiding programmed cell death plays an important role in the pathogenesis and progression of cancer, as well as in tumor response to therapeutic intervention.	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Deregulation', 'Var', (0, 12))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
563352	26885691	Evading apoptosis through genetic mutation is considered a hallmark of cancer malignancy.	('apoptosis', 'CPA', (8, 17))	('genetic mutation', 'Var', (26, 42))	('hallmark of cancer malignancy', 'Disease', (59, 88))	('hallmark of cancer malignancy', 'Disease', 'MESH:D009369', (59, 88))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
563353	26885691	Notably, defective apoptosis not only allows tumorigenesis but can also lead to resistance to chemotherapy.	('apoptosis', 'CPA', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('allows', 'PosReg', (38, 44))	('tumor', 'Disease', (45, 50))	('defective', 'Var', (9, 18))	('lead to', 'Reg', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('resistance to chemotherapy', 'CPA', (80, 106))
563354	26885691	As mentioned above, mutations in the gene encoding RHA and alterations in RHA expression are found in a wide range of cancers.	('alterations', 'Var', (59, 70))	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('expression', 'MPA', (78, 88))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('RHA', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('RHA', 'Gene', (74, 77))	('mutations', 'Var', (20, 29))	('found', 'Reg', (93, 98))
563357	26885691	Loss of RHA improved ABT-737 sensitivity by intensifying MYC oncogene-induced replicative stress and triggering induction of the p53 apoptotic program.	('triggering induction', 'Reg', (101, 121))	('intensifying', 'PosReg', (44, 56))	('RHA', 'Gene', (8, 11))	('MYC', 'Gene', '4609', (57, 60))	('improved', 'PosReg', (12, 20))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('replicative stress', 'MPA', (78, 96))	('ABT-737', 'Gene', (21, 28))	('ABT', 'Chemical', 'MESH:C002502', (21, 24))	('Loss', 'Var', (0, 4))	('MYC', 'Gene', (57, 60))
563359	26885691	In neuronal cells, RHA interacts with the tumor suppressor KIF1Bbeta and it is necessary for KIF1Bbeta-mediated apoptosis in NGF-limiting conditions.	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('KIF1Bbeta-mediated', 'Var', (93, 111))
563360	26885691	Abnormal NGF signaling has been linked to nervous system tumors such as neuroblastoma, medulloblastoma, and pheochromocytoma.	('neuroblastoma', 'Disease', (72, 85))	('nervous system tumors', 'Disease', (42, 63))	('pheochromocytoma', 'Disease', 'MESH:D010673', (108, 124))	('nervous system tumors', 'Phenotype', 'HP:0004375', (42, 63))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (108, 124))	('neuroblastoma', 'Phenotype', 'HP:0003006', (72, 85))	('NGF signaling', 'MPA', (9, 22))	('nervous system tumors', 'Disease', 'MESH:D009423', (42, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('linked', 'Reg', (32, 38))	('Abnormal', 'Var', (0, 8))	('medulloblastoma', 'Disease', 'MESH:D008527', (87, 102))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('medulloblastoma', 'Phenotype', 'HP:0002885', (87, 102))	('pheochromocytoma', 'Disease', (108, 124))	('neuroblastoma', 'Disease', 'MESH:D009447', (72, 85))	('medulloblastoma', 'Disease', (87, 102))
563361	26885691	Low expression of KIF1Bbeta correlated with poor prognosis and reduced survival of patients with neuroblastoma, providing evidence that KIF1Bbeta is a neuroblastoma tumor suppressor.	('neuroblastoma', 'Disease', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('neuroblastoma tumor', 'Disease', (151, 170))	('reduced', 'NegReg', (63, 70))	('neuroblastoma', 'Phenotype', 'HP:0003006', (151, 164))	('KIF1Bbeta', 'Var', (136, 145))	('neuroblastoma', 'Phenotype', 'HP:0003006', (97, 110))	('expression', 'MPA', (4, 14))	('neuroblastoma', 'Disease', 'MESH:D009447', (151, 164))	('KIF1Bbeta', 'Gene', (18, 27))	('survival', 'MPA', (71, 79))	('patients', 'Species', '9606', (83, 91))	('neuroblastoma tumor', 'Disease', 'MESH:D009447', (151, 170))	('Low', 'NegReg', (0, 3))	('neuroblastoma', 'Disease', 'MESH:D009447', (97, 110))	('neuroblastoma', 'Disease', (151, 164))
563363	26885691	This suggests that loss of KIF1Bbeta may impair NGF-deprived apoptosis due to mislocalization of RHA and predispose to neuroblastoma formation.	('RHA', 'Protein', (97, 100))	('NGF-deprived', 'MPA', (48, 60))	('mislocalization', 'MPA', (78, 93))	('impair', 'NegReg', (41, 47))	('neuroblastoma', 'Disease', 'MESH:D009447', (119, 132))	('loss', 'Var', (19, 23))	('KIF1Bbeta', 'Gene', (27, 36))	('predispose', 'Reg', (105, 115))	('neuroblastoma', 'Disease', (119, 132))	('neuroblastoma', 'Phenotype', 'HP:0003006', (119, 132))
563367	26885691	It results from the fusion between the Ewing sarcoma breakpoint region 1 gene (EWSR1) on chromosome 22 and the Friend leukemia virus integration site 1 gene (FLI1) on chromosome 11.	('EWSR1', 'Gene', (79, 84))	('Ewing sarcoma breakpoint region 1', 'Gene', (39, 72))	('fusion', 'Var', (20, 26))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (39, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('EWSR1', 'Gene', '2130', (79, 84))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('Friend leukemia', 'Disease', (111, 126))	('Friend leukemia', 'Disease', 'MESH:D007938', (111, 126))	('results from', 'Reg', (3, 15))	('FLI1', 'Gene', (158, 162))
563374	26885691	In line with the findings illustrated above, knockdown of RHA expression critically reduced Ewing sarcoma cell viability, while no decrease in cell viability was detected in pancreatic (PANC1) and cervical (HeLa) tumor cell lines that do not express the EWS-FLI1 oncogene.	('tumor', 'Disease', (213, 218))	('HeLa', 'CellLine', 'CVCL:0030', (207, 211))	('Ewing sarcoma', 'Disease', (92, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (92, 105))	('reduced', 'NegReg', (84, 91))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('pancreatic', 'Disease', 'MESH:D010195', (174, 184))	('PANC1', 'CellLine', 'CVCL:0480', (186, 191))	('EWS-FLI1', 'Gene', (254, 262))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('pancreatic', 'Disease', (174, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('EWS-FLI1', 'Gene', '2130;2313', (254, 262))	('knockdown', 'Var', (45, 54))	('RHA', 'Gene', (58, 61))
563381	26885691	The screen selected NSC635437 as lead compound for the binding to EWS-FLI1 and for its ability to reduce the binding between GST-RHA(647-1075) and EWS-FLI1.	('EWS-FLI1', 'Gene', '2130;2313', (66, 74))	('binding', 'Interaction', (109, 116))	('NSC635437', 'Var', (20, 29))	('EWS-FLI1', 'Gene', (147, 155))	('reduce', 'NegReg', (98, 104))	('binding', 'Interaction', (55, 62))	('EWS-FLI1', 'Gene', '2130;2313', (147, 155))	('EWS-FLI1', 'Gene', (66, 74))
563385	26885691	To evaluate the specific effects of the two enantiomers, they were separated and tested individually or in racemic form, demonstrating that both YK-4-279 and (S)-YK-4-279 were able to prevent EWS-FLI1 mediated transcriptional activity, while the (R) enantiomer did not show any significant effect.	('EWS-FLI1', 'Gene', (192, 200))	('EWS-FLI1', 'Gene', '2130;2313', (192, 200))	('S)-YK-4-279', 'Var', (159, 170))	('YK-4-279', 'Var', (145, 153))	('prevent', 'NegReg', (184, 191))
563386	26885691	Recently, it has been demonstrated that EWS-FLI1 inhibits the helicase activity of RHA in vitro while YK-4-279 reverted EWS-FLI1 inhibitory effect thus restoring RHA helicase activity.	('helicase', 'Gene', '164045', (166, 174))	('helicase', 'Gene', (62, 70))	('restoring', 'PosReg', (152, 161))	('RHA', 'Protein', (83, 86))	('YK-4-279', 'Var', (102, 110))	('EWS-FLI1', 'Gene', (40, 48))	('inhibits', 'NegReg', (49, 57))	('helicase', 'Gene', (166, 174))	('EWS-FLI1', 'Gene', (120, 128))	('inhibitory effect', 'MPA', (129, 146))	('EWS-FLI1', 'Gene', '2130;2313', (40, 48))	('EWS-FLI1', 'Gene', '2130;2313', (120, 128))	('helicase', 'Gene', '164045', (62, 70))	('RHA', 'MPA', (162, 165))	('activity', 'MPA', (175, 183))
563388	26885691	For example, the activity of p68 (DDX5), a RNA helicase that directly binds to EWS-FLI1, is affected by YK-4-279 treatment.	('RNA helicase', 'Gene', '9879', (43, 55))	('affected', 'Reg', (92, 100))	('YK-4-279 treatment', 'Var', (104, 122))	('RNA helicase', 'Gene', (43, 55))	('p68', 'Gene', (29, 32))	('p68', 'Gene', '1655', (29, 32))	('EWS-FLI1', 'Gene', (79, 87))	('activity', 'MPA', (17, 25))	('DDX5', 'Gene', (34, 38))	('EWS-FLI1', 'Gene', '2130;2313', (79, 87))	('DDX5', 'Gene', '1655', (34, 38))
563395	26885691	Thus, modulation of RHA splicing could be exploited as a new potential tool to enhance Ewing sarcoma cell sensitivity to genotoxic stresses.	('modulation', 'Var', (6, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('enhance', 'PosReg', (79, 86))	('Ewing sarcoma', 'Disease', (87, 100))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (87, 100))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (87, 100))
563398	26885691	Indeed, CBP transcriptional activity is reduced both by deletion of the MTAD domain from RHA and by mutations that alter its ATPase activity (without modifying RNAPII binding) while the double mutant produces more severe effects.	('deletion', 'Var', (56, 64))	('mutations', 'Var', (100, 109))	('ATPase', 'Protein', (125, 131))	('CBP', 'Gene', (8, 11))	('activity', 'MPA', (132, 140))	('MTAD domain', 'Gene', (72, 83))	('CBP', 'Gene', '1387', (8, 11))	('transcriptional activity', 'MPA', (12, 36))	('reduced', 'NegReg', (40, 47))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('RHA', 'Gene', (89, 92))
563406	26885691	The alterations of RHA (mutations or overexpression) observed in various tumors highlighted the involvement of this protein in cancer transformation and in sustaining genomic stability.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('overexpression', 'PosReg', (37, 51))	('alterations', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Disease', (73, 79))	('cancer', 'Disease', (127, 133))	('RHA', 'Gene', (19, 22))	('involvement', 'Reg', (96, 107))	('genomic stability', 'CPA', (167, 184))
563414	26885691	Moreover, modulation of RHA expression levels by inducing a genotoxic stress-regulated NMD-targeted isoform could be a valuable additional tool to lower the expression levels of RHA, thus rendering Ewing sarcoma cells more sensitive to chemotherapeutic treatment.	('expression levels', 'MPA', (157, 174))	('modulation', 'Var', (10, 20))	('inducing', 'Reg', (49, 57))	('lower', 'NegReg', (147, 152))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (198, 211))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (198, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('Ewing sarcoma', 'Disease', (198, 211))	('RHA', 'Protein', (178, 181))
563415	26885691	In this scenario, the development of antisense oligonucleotides (ASOs) recruiting the spliceosomal complex to the alternative exon 6A in RHA could be instrumental to drive RHA downregulation in live cells and might provide a valuable additional therapy for the treatment of Ewing sarcoma.	('ASOs', 'Chemical', 'MESH:D016376', (65, 69))	('Ewing sarcoma', 'Disease', (274, 287))	('antisense', 'Var', (37, 46))	('oligonucleotides', 'Chemical', 'MESH:D009841', (47, 63))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (274, 287))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (274, 287))	('sarcoma', 'Phenotype', 'HP:0100242', (280, 287))	('downregulation', 'NegReg', (176, 190))
563483	25195862	The Hippo tumor-suppressor pathway is fundamental in regulating organ size, and its dysregulation promotes tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('dysregulation', 'Var', (84, 97))	('promotes', 'PosReg', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
563487	25195862	For example, transgenic YAP expression in mice induces tissue overgrowth and tumorigenesis, and deletion of Lats1 results in development of different tumors including sarcoma.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('YAP', 'Gene', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('overgrowth', 'Phenotype', 'HP:0001548', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('tumors', 'Disease', (150, 156))	('results in', 'Reg', (114, 124))	('induces', 'Reg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('sarcoma', 'Disease', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('mice', 'Species', '10090', (42, 46))	('Lats1', 'Gene', (108, 113))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('tissue overgrowth', 'CPA', (55, 72))	('deletion', 'Var', (96, 104))	('transgenic', 'Species', '10090', (13, 23))	('tumor', 'Disease', (77, 82))
563505	25195862	Phosphorylation of serine 127 (S127) and additional sites of YAP by Lats1/2 results in YAP cytoplasmic retention, ubiquitination, and degradation.	('YAP', 'MPA', (87, 90))	('Phosphorylation', 'MPA', (0, 15))	('ubiquitination', 'MPA', (114, 128))	('degradation', 'MPA', (134, 145))	('S127', 'Var', (31, 35))	('serine', 'Chemical', 'MESH:D012694', (19, 25))
563519	25195862	Moreover, we observed a significant decrease of Lats1 phosphorylation in its hydrophobic motif (threonine 1079, T1079), which positively correlates with Lats activity, upon induction of lytic KSHV gene expression (Figure 2c), suggesting that Lats1 is inactivated by KSHV.	('Lats1', 'Gene', (48, 53))	('T1079', 'Var', (112, 117))	('threonine', 'Chemical', 'MESH:D013912', (96, 105))	('KS', 'Phenotype', 'HP:0100726', (192, 194))	('KSHV', 'Gene', (192, 196))	('phosphorylation in', 'MPA', (54, 72))	('KSHV', 'Species', '37296', (266, 270))	('induction', 'Reg', (173, 182))	('KS', 'Phenotype', 'HP:0100726', (266, 268))	('KSHV', 'Species', '37296', (192, 196))	('decrease', 'NegReg', (36, 44))
563524	25195862	We established a SV40-immortalized murine endothelial cell line (SVEC) stably expressing HA-tagged vGPCR.	('vGPCR', 'Gene', '4961465', (99, 104))	('HA-tagged', 'Var', (89, 98))	('SVEC', 'CellLine', 'CVCL:4393', (65, 69))	('murine', 'Species', '10090', (35, 41))	('vGPCR', 'Gene', (99, 104))
563527	25195862	vGPCR overexpression also increased TAZ protein levels.	('TAZ protein levels', 'MPA', (36, 54))	('overexpression', 'Var', (6, 20))	('vGPCR', 'Gene', '4961465', (0, 5))	('increased', 'PosReg', (26, 35))	('vGPCR', 'Gene', (0, 5))
563544	25195862	Gq/11 or G12/13 are pairs of closely related G alpha proteins with similar functions, their expression was knocked down by shRNAs.	('knocked down', 'NegReg', (107, 119))	('G12/13', 'Gene', '10672', (9, 15))	('G alpha proteins', 'Protein', (45, 61))	('Gq/11', 'Var', (0, 5))	('G12/13', 'Gene', (9, 15))	('expression', 'MPA', (92, 102))
563546	25195862	Consistently, expression of the YAP/TAZ target gene CTGF was also blocked by knockdown of Gq/11 or G12/13.	('CTGF', 'Gene', '1490', (52, 56))	('CTGF', 'Gene', (52, 56))	('G12/13', 'Gene', (99, 105))	('knockdown', 'Var', (77, 86))	('Gq/11', 'Gene', (90, 95))	('expression', 'MPA', (14, 24))	('G12/13', 'Gene', '10672', (99, 105))	('blocked', 'NegReg', (66, 73))
563547	25195862	It is worth noting that knockdown of Gq/11 or G12/13 only partially suppressed YAP/TAZ activation by vGPCR.	('G12/13', 'Gene', (46, 52))	('YAP/TAZ activation', 'MPA', (79, 97))	('vGPCR', 'Gene', (101, 106))	('G12/13', 'Gene', '10672', (46, 52))	('suppressed', 'NegReg', (68, 78))	('Gq/11', 'Gene', (37, 42))	('vGPCR', 'Gene', '4961465', (101, 106))	('knockdown', 'Var', (24, 33))
563558	25195862	In vGPCR overexpressing cells, Lats1 phosphorylation was decreased at both T1079 and S909 sites.	('S909 sites', 'Var', (85, 95))	('vGPCR', 'Gene', (3, 8))	('T1079', 'Var', (75, 80))	('Lats1', 'Protein', (31, 36))	('phosphorylation', 'MPA', (37, 52))	('vGPCR', 'Gene', '4961465', (3, 8))	('decreased', 'NegReg', (57, 66))
563559	25195862	Furthermore, in an in vitro kinase assay using bacterially expressed GST-tagged YAP as a substrate, endogenous Lats1 or over-expressed Lats2 immunoprecipitated from vGPCR expressing cells exhibited a weaker kinase activity than Lats1/2 from control cells (Figures 4f, Figure S4a).	('Lats2', 'Gene', '26524', (135, 140))	('vGPCR', 'Gene', (165, 170))	('vGPCR', 'Gene', '4961465', (165, 170))	('kinase activity', 'MPA', (207, 222))	('Lats2', 'Gene', (135, 140))	('weaker', 'NegReg', (200, 206))	('expressing', 'Var', (171, 181))
563570	25195862	As expected, expression of vGPCR promoted SVEC cell proliferation (Figure 5b).	('promoted', 'PosReg', (33, 41))	('vGPCR', 'Gene', (27, 32))	('SVEC cell proliferation', 'CPA', (42, 65))	('vGPCR', 'Gene', '4961465', (27, 32))	('expression', 'Var', (13, 23))	('SVEC', 'CellLine', 'CVCL:4393', (42, 46))
563574	25195862	In the wound healing assay, expression of vGPCR induced a rapid closure of the wound, whereas when YAP and/or TAZ were depleted, the effect of vGPCR cell migration was largely blocked (Figure 5c).	('rapid closure of the wound', 'Phenotype', 'HP:0005458', (58, 84))	('vGPCR', 'Gene', (42, 47))	('vGPCR', 'Gene', (143, 148))	('vGPCR', 'Gene', '4961465', (143, 148))	('vGPCR', 'Gene', '4961465', (42, 47))	('expression', 'Var', (28, 38))
563588	25195862	Importantly, knockdown of YAP/TAZ individually or combinatory impaired the ability of vGPCR to induce tumor formation (Figures 6c, Figure 6d, Figure S6).	('impaired', 'NegReg', (62, 70))	('ability', 'MPA', (75, 82))	('tumor', 'Disease', (102, 107))	('vGPCR', 'Gene', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('vGPCR', 'Gene', '4961465', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('knockdown', 'Var', (13, 22))	('induce', 'PosReg', (95, 101))
563591	25195862	We have recently shown that tumorigenesis of active BRAF mutant (V600E) in uveal melanomas is YAP-independent.	('V600E', 'Var', (65, 70))	('uveal melanomas', 'Disease', (75, 90))	('uveal melanomas', 'Phenotype', 'HP:0007716', (75, 90))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('uveal melanomas', 'Disease', 'MESH:C536494', (75, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('BRAF', 'Gene', '673', (52, 56))	('V600E', 'Mutation', 'rs113488022', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('BRAF', 'Gene', (52, 56))
563593	25195862	Although expression of either vGPCR or BRAFV600E induced ERK phosphorylation, BRAFV600E failed to induce YAP dephosphorylation and TAZ accumulation (Figure 7a).	('vGPCR', 'Gene', '4961465', (30, 35))	('BRAFV600E', 'Var', (78, 87))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('induced', 'Reg', (49, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (78, 87))	('ERK phosphorylation', 'MPA', (57, 76))	('TAZ accumulation', 'MPA', (131, 147))	('BRAFV600E', 'Var', (39, 48))	('YAP dephosphorylation', 'MPA', (105, 126))	('vGPCR', 'Gene', (30, 35))
563603	25195862	Besides KS, KSHV can also cause other types of cancers such as multi centric Castleman's disease and primary effusion lymphoma.	('cause', 'Reg', (26, 31))	("multi centric Castleman's disease", 'Disease', (63, 96))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (101, 126))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('KS', 'Phenotype', 'HP:0100726', (8, 10))	('primary effusion lymphoma', 'Disease', (101, 126))	('KSHV', 'Species', '37296', (12, 16))	('KSHV', 'Var', (12, 16))	('KS', 'Phenotype', 'HP:0100726', (12, 14))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	("multi centric Castleman's disease", 'Disease', 'MESH:C537372', (63, 96))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (101, 126))
563609	25195862	In support, it has been recently shown that activation of YAP by GNAQ or GNA11 mutation is indispensible for the development of uveal melanoma, the most common malignancy in adult eyes.	('GNA11', 'Gene', (73, 78))	('malignancy', 'Disease', (160, 170))	('GNA11', 'Gene', '2767', (73, 78))	('GNAQ', 'Gene', '2776', (65, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('activation', 'PosReg', (44, 54))	('uveal melanoma', 'Disease', (128, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('mutation', 'Var', (79, 87))	('GNAQ', 'Gene', (65, 69))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))
563641	25195862	Antibodies for YAP, TAZ (V386), YAP/TAZ, MST1, Lats1, phospho-Lats1/2 (S909/872), and phospho-Lats1/2 (T1079/999) are from Cell Signaling Technology.	('MST1', 'Gene', (41, 45))	('MST1', 'Gene', '4485', (41, 45))	('V386', 'Var', (25, 29))	('S909/872', 'Var', (71, 79))
563642	25195862	CTGF, Gq, G11, G12, G13, Myc-HRP, and GFP antibodies are from Santa Cruz Biotechnology.	('CTGF', 'Gene', (0, 4))	('G11', 'Gene', (10, 13))	('G12', 'Var', (15, 18))	('Myc', 'Gene', '4609', (25, 28))	('Myc', 'Gene', (25, 28))	('G13', 'Gene', '10672', (20, 23))	('G11', 'Gene', '8859', (10, 13))	('G13', 'Gene', (20, 23))	('CTGF', 'Gene', '1490', (0, 4))
563655	26097728	Unbalanced karyotypic defects are the only shared features observed across different leiomyosarcoma subtypes.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (85, 99))	('leiomyosarcoma subtypes', 'Disease', (85, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('leiomyosarcoma subtypes', 'Disease', 'MESH:D007890', (85, 108))	('Unbalanced karyotypic defects', 'Var', (0, 29))
563675	26097728	The familial syndrome hereditary leiomyomatosis with renal cell carcinoma (HLRCC), in which there are germline mutations in fumarate hydratase, has also been associated with an increased risk of uterine leiomyosarcomas.	('uterine leiomyosarcomas', 'Phenotype', 'HP:0002891', (195, 218))	('mutations', 'Var', (111, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (210, 218))	('associated', 'Reg', (158, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('familial syndrome hereditary leiomyomatosis', 'Disease', (4, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('renal cell carcinoma', 'Disease', (53, 73))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (203, 218))	('familial syndrome hereditary leiomyomatosis', 'Disease', 'MESH:C535516', (4, 47))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (203, 218))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (195, 217))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (203, 217))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (53, 73))	('fumarate hydratase', 'Gene', '2271', (124, 142))	('fumarate hydratase', 'Gene', (124, 142))	('leiomyosarcomas', 'Disease', (203, 218))
563684	26097728	Karyotypes of soft tissue leiomyosarcomas are usually highly complex with genomic instability, and often associated with defects in TP53 or sometimes FANCA and ATM.	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (26, 41))	('soft tissue leiomyosarcomas', 'Phenotype', 'HP:0030448', (14, 41))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (26, 41))	('ATM', 'Gene', (160, 163))	('defects', 'Var', (121, 128))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('leiomyosarcomas', 'Disease', (26, 41))	('ATM', 'Gene', '472', (160, 163))	('FANCA', 'Gene', '2175', (150, 155))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (26, 40))	('FANCA', 'Gene', (150, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (33, 41))	('associated', 'Reg', (105, 115))
563688	26097728	There is frequent involvement of the retinoblastoma-cyclin D pathway with genomic loss at 13q14 centred on the RB1 gene.	('retinoblastoma', 'Phenotype', 'HP:0009919', (37, 51))	('RB1', 'Gene', (111, 114))	('genomic loss at', 'Var', (74, 89))	('RB1', 'Gene', '5925', (111, 114))	('retinoblastoma', 'Gene', '5925', (37, 51))	('involvement', 'Reg', (18, 29))	('retinoblastoma', 'Gene', (37, 51))
563784	24267748	The arterial blood supply to the sequestered lung by aberrant elastic arteries mostly originates from the thoracic or abdominal aorta in most cases with EPS.	('aberrant', 'Var', (53, 61))	('EPS', 'Disease', (153, 156))	('EPS', 'Chemical', 'MESH:C100219', (153, 156))
30859	23900236	Binding to plasminogen active sites, lysine blocks plasminogen activation into plasmin by tissue plasminogen activator (t-PA).	('tissue plasminogen activator (t-PA', 'Gene', '5327', (90, 124))	('blocks', 'NegReg', (44, 50))	('t-PA', 'Gene', '5327', (120, 124))	('t-PA', 'Gene', (120, 124))	('lysine', 'Var', (37, 43))	('plasminogen activation into plasmin', 'MPA', (51, 86))
563835	23900236	For example, increased expression of MMP-9 has been found to correlate with osteosarcoma metastasis in patients and inhibitors of MMPs, such as TIMP-1 have been shown to inhibit invasiveness of osteosarcoma tumor cells   in vitro   .	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('inhibit', 'NegReg', (170, 177))	('osteosarcoma metastasis', 'Disease', (76, 99))	('MMPs', 'Gene', (130, 134))	('osteosarcoma metastasis', 'Disease', 'MESH:D009362', (76, 99))	('inhibitors', 'Var', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('invasiveness of osteosarcoma tumor', 'Disease', (178, 212))	('MMP-9', 'Gene', (37, 42))	('invasiveness of osteosarcoma tumor', 'Disease', 'MESH:D012516', (178, 212))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (194, 206))	('TIMP-1', 'Gene', (144, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('TIMP-1', 'Gene', '7076', (144, 150))	('increased', 'PosReg', (13, 22))	('expression', 'MPA', (23, 33))
563910	20354522	Acetate megestrol had been associated with compulsive eating and hypertriglyceridemia as a consequence of its orexigen effect.	('hypertriglyceridemia', 'Phenotype', 'HP:0002155', (65, 85))	('Acetate megestrol', 'Chemical', 'MESH:D019290', (0, 17))	('associated', 'Reg', (27, 37))	('compulsive eating and hypertriglyceridemia', 'Disease', 'MESH:D000073932', (43, 85))	('Acetate', 'Var', (0, 7))
564003	26900951	For example, the identification of c-Kit and PDGFRalpha mutations in gastrointestinal stromal tumours has led to the successful treatment of these cancers by the tyrosine kinase inhibitor, imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (189, 197))	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('PDGFRalpha', 'Gene', '5156', (45, 55))	('PDGFRalpha', 'Gene', (45, 55))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (69, 101))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('gastrointestinal stromal tumours', 'Disease', (69, 101))	('c-Kit', 'Gene', (35, 40))	('c-Kit', 'Gene', '3815', (35, 40))	('cancers', 'Disease', (147, 154))	('led to', 'Reg', (106, 112))
564006	26900951	In addition, the mechanistic target of rapamycin inhibitor, AP23573, has shown promising clinical efficacy in patients with advanced soft tissue sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('AP23573', 'Var', (60, 67))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (133, 152))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('sarcomas', 'Disease', (145, 153))	('AP23573', 'Chemical', 'MESH:C515074', (60, 67))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (133, 153))	('patients', 'Species', '9606', (110, 118))
564010	26900951	TBX3 negatively regulates apoptosis in rat bladder and liver carcinoma, can bypass senescence and promote proliferation by repressing the key cell cycle regulators p14/p19ARF, p21WAFI/CIPI/SDII (referred to as p21) and the tumour suppressor phosphatase and tensin homologue (PTEN).	('liver carcinoma', 'Phenotype', 'HP:0001402', (55, 70))	('liver carcinoma', 'Disease', 'MESH:D006528', (55, 70))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('regulates', 'Reg', (16, 25))	('apoptosis', 'CPA', (26, 35))	('promote', 'PosReg', (98, 105))	('liver carcinoma', 'Disease', (55, 70))	('TBX3', 'Gene', (0, 4))	('p14/p19ARF', 'Var', (164, 174))	('CIPI', 'Disease', 'None', (184, 188))	('rat', 'Species', '10116', (113, 116))	('rat', 'Species', '10116', (39, 42))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('CIPI', 'Disease', (184, 188))	('tumour', 'Disease', (223, 229))	('negatively', 'NegReg', (5, 15))	('proliferation', 'CPA', (106, 119))
564015	26900951	We further explore this possibility by establishing and characterizing cell culture models in which TBX3 is either knocked down or overexpressed in chondrosarcoma and fibrosarcoma cell lines.	('knocked', 'Var', (115, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('fibrosarcoma', 'Disease', (167, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('chondrosarcoma', 'Disease', 'MESH:D002813', (148, 162))	('chondrosarcoma', 'Disease', (148, 162))	('overexpressed', 'PosReg', (131, 144))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (167, 179))	('fibrosarcoma', 'Disease', 'MESH:D005354', (167, 179))	('TBX3', 'Gene', (100, 104))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (148, 162))
564028	26900951	While TBX3 depletion had no effect on the migratory ability of synovial sarcoma (SW982) cells (Figure 2a), it led to a significant reduction in the migration of chondrosarcoma (SW1353) (Figure 2b), rhabdomyosarcoma (RD) (Figure 2c) and liposarcoma (SW872) (Figure 2d) cells.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('chondrosarcoma', 'Disease', (161, 175))	('chondrosarcoma', 'Disease', 'MESH:D002813', (161, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (240, 247))	('SW982', 'CellLine', 'CVCL:1734', (81, 86))	('liposarcoma', 'Phenotype', 'HP:0012034', (236, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('SW872', 'CellLine', 'CVCL:1730', (249, 254))	('rat', 'Species', '10116', (151, 154))	('RD', 'Phenotype', 'HP:0002859', (216, 218))	('reduction', 'NegReg', (131, 140))	('migration', 'CPA', (148, 157))	('liposarcoma', 'Disease', 'MESH:D008080', (236, 247))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (161, 175))	('synovial sarcoma', 'Disease', (63, 79))	('depletion', 'Var', (11, 20))	('rat', 'Species', '10116', (45, 48))	('synovial sarcoma', 'Disease', 'MESH:D013584', (63, 79))	('rhabdomyosarcoma', 'Disease', (198, 214))	('SW1353', 'CellLine', 'CVCL:0543', (177, 183))	('liposarcoma', 'Disease', (236, 247))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (63, 79))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (198, 214))	('migratory ability', 'CPA', (42, 59))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (198, 214))	('TBX3', 'Gene', (6, 10))
564029	26900951	Quite unexpectedly, knocking down TBX3 resulted in increased migration of fibrosarcoma (HT1080) cells (Figure 2e).	('fibrosarcoma', 'Disease', (74, 86))	('increased', 'PosReg', (51, 60))	('HT1080', 'Gene', (88, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (74, 86))	('HT1080', 'Gene', '8872', (88, 94))	('rat', 'Species', '10116', (64, 67))	('migration', 'CPA', (61, 70))	('fibrosarcoma', 'Disease', 'MESH:D005354', (74, 86))	('TBX3', 'Gene', (34, 38))	('knocking down', 'Var', (20, 33))
564030	26900951	The above data gave an initial indication that TBX3 may have different oncogenic roles in sarcomas and we therefore further investigated this in fibrosarcoma and chondrosarcoma cell lines in which TBX3 was either knocked down or overexpressed.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (145, 157))	('chondrosarcoma', 'Disease', 'MESH:D002813', (162, 176))	('TBX3', 'Gene', (197, 201))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('fibrosarcoma', 'Disease', 'MESH:D005354', (145, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('chondrosarcoma', 'Disease', (162, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('TBX3', 'Gene', (47, 51))	('sarcomas', 'Disease', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('knocked', 'Var', (213, 220))	('overexpressed', 'PosReg', (229, 242))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (162, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('fibrosarcoma', 'Disease', (145, 157))
564034	26900951	Consistent with this finding, levels of the previously identified TBX3 targets, p14/p19ARF and p21, increased in both shTBX3 chondrosarcoma cell lines (Figure 3e), which suggest that TBX3 promotes proliferation of chondrosarcoma cells by, in part, repressing key cell cycle regulators.	('repressing', 'NegReg', (248, 258))	('chondrosarcoma', 'Disease', 'MESH:D002813', (125, 139))	('promotes', 'PosReg', (188, 196))	('chondrosarcoma', 'Disease', (125, 139))	('rat', 'Species', '10116', (204, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('chondrosarcoma', 'Disease', (214, 228))	('chondrosarcoma', 'Disease', 'MESH:D002813', (214, 228))	('cell cycle', 'CPA', (263, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('p14/p19ARF', 'Var', (80, 90))	('proliferation', 'CPA', (197, 210))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (125, 139))	('TBX3', 'Gene', (183, 187))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (214, 228))
564035	26900951	It is worth noting that knockdown of TBX3 in the SW1353, but not the ATDC5 (data not shown), cells also resulted in increased p53 protein levels, which suggest that the proproliferative ability of TBX3 in chondrosarcoma cells may be both p53 dependent and independent.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('SW1353', 'CellLine', 'CVCL:0543', (49, 55))	('TBX3', 'Gene', (37, 41))	('chondrosarcoma', 'Disease', 'MESH:D002813', (205, 219))	('chondrosarcoma', 'Disease', (205, 219))	('increased', 'PosReg', (116, 125))	('rat', 'Species', '10116', (179, 182))	('knockdown', 'Var', (24, 33))	('p53 protein levels', 'MPA', (126, 144))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (205, 219))
564040	26900951	Consistent with this ability of TBX3 to promote anchorage-independent growth in vitro, when NOD scid gamma (NSG) mice were injected subcutaneously with SW1353 FLAG-Tbx3 cells or FLAG-Empty cells, the tumour volume and weight for cells overexpressing TBX3 were significantly greater (Figure 4c) Results shown in Figure 2 suggested that TBX3 promotes migration in chondrosarcoma cells.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (362, 376))	('rat', 'Species', '10116', (352, 355))	('SW1353', 'CellLine', 'CVCL:0543', (152, 158))	('promotes', 'PosReg', (340, 348))	('chondrosarcoma', 'Disease', 'MESH:D002813', (362, 376))	('tumour volume', 'Disease', 'MESH:D009369', (200, 213))	('SW1353', 'Var', (152, 158))	('FLAG-Tbx3', 'Gene', (159, 168))	('chondrosarcoma', 'Disease', (362, 376))	('tumour volume', 'Disease', (200, 213))	('TBX3', 'Gene', (250, 254))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (369, 376))	('FLAG-Tbx3', 'Gene', '6926', (159, 168))	('TBX3', 'Gene', (335, 339))	('mice', 'Species', '10090', (113, 117))	('greater', 'PosReg', (274, 281))
564041	26900951	To confirm this in our chondrosarcoma cell lines in which TBX3 was either stably knocked down or overexpressed, we performed scratch and transwell motility assays.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (23, 37))	('knocked', 'Var', (81, 88))	('chondrosarcoma', 'Disease', 'MESH:D002813', (23, 37))	('chondrosarcoma', 'Disease', (23, 37))	('rat', 'Species', '10116', (127, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('TBX3', 'Gene', (58, 62))
564042	26900951	As expected, whereas depleting TBX3 inhibited the migration of chondrosarcoma cells (Figure 5a), ectopic overexpression of TBX3 promoted their migration (Figure 5b).	('chondrosarcoma', 'Phenotype', 'HP:0006765', (63, 77))	('inhibited', 'NegReg', (36, 45))	('depleting', 'Var', (21, 30))	('rat', 'Species', '10116', (146, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('chondrosarcoma', 'Disease', 'MESH:D002813', (63, 77))	('TBX3', 'Gene', (123, 127))	('chondrosarcoma', 'Disease', (63, 77))	('rat', 'Species', '10116', (53, 56))	('promoted', 'PosReg', (128, 136))	('migration', 'CPA', (143, 152))	('TBX3', 'Gene', (31, 35))
564044	26900951	To further explore the putative tumour suppressor activity of TBX3 in fibrosarcomas, we characterized the impact of stably knocking down TBX3 in CT-1 and HT1080 fibroblasts (Figure 6a) or overexpressing the Tbx3 and Tbx3+2a isoforms in the HT1080 cells (Figure 6b) on key features of the cancer phenotype.	('cancer', 'Disease', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('CT-1', 'Gene', '1489', (145, 149))	('TBX3', 'Gene', (137, 141))	('overexpressing', 'PosReg', (188, 202))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (70, 82))	('fibrosarcomas', 'Disease', 'MESH:D005354', (70, 83))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('HT1080', 'Gene', (154, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('HT1080', 'Gene', '8872', (154, 160))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))	('tumour', 'Disease', 'MESH:D009369', (32, 38))	('CT-1', 'Gene', (145, 149))	('fibrosarcomas', 'Disease', (70, 83))	('tumour', 'Disease', (32, 38))	('HT1080', 'Gene', (240, 246))	('knocking', 'Var', (123, 131))	('HT1080', 'Gene', '8872', (240, 246))
564049	26900951	Consistent with it having antitumour activity in fibroblasts, depleting TBX3 led to an increase in their anchorage-independent cell proliferation in soft agar assays (Figure 7a) while overexpressing either TBX3 isoform had the opposite effect (Figure 7b).	('TBX3', 'Gene', (72, 76))	('increase', 'PosReg', (87, 95))	('agar', 'Chemical', 'MESH:D000362', (154, 158))	('depleting', 'Var', (62, 71))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('rat', 'Species', '10116', (139, 142))	('tumour', 'Disease', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
564050	26900951	Similarly, while knocking down TBX3 enhanced the migratory ability of both CT-1 and HT1080 cells in motility assays (Figure 7c), overexpressing either isoform reduced this ability (Figure 7d).	('rat', 'Species', '10116', (52, 55))	('HT1080', 'Gene', (84, 90))	('HT1080', 'Gene', '8872', (84, 90))	('migratory ability', 'CPA', (49, 66))	('CT-1', 'Gene', '1489', (75, 79))	('CT-1', 'Gene', (75, 79))	('enhanced', 'PosReg', (36, 44))	('TBX3', 'Gene', (31, 35))	('knocking down', 'Var', (17, 30))
564051	26900951	Together these results confirm that TBX3 and TBX3+2a have tumour suppressor activity in fibroblasts in vitro.	('TBX3', 'Gene', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('TBX3+2a', 'Var', (45, 52))
564054	26900951	Furthermore, the overexpression of Tbx3+2a was able to significantly reduce the tumour volume and weight (Figure 8b).	('tumour volume', 'Disease', (80, 93))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('overexpression', 'PosReg', (17, 31))	('reduce', 'NegReg', (69, 75))	('tumour volume', 'Disease', 'MESH:D009369', (80, 93))	('Tbx3+2a', 'Var', (35, 42))
564069	26900951	Furthermore, our data showing that depleting TBX3 inhibits the cancer phenotype of several sarcoma subtypes suggests that it may also represent a common target to treat diverse sarcomas.	('sarcomas', 'Disease', (177, 185))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (91, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('depleting', 'Var', (35, 44))	('sarcoma subtypes', 'Disease', (91, 107))	('sarcomas', 'Disease', 'MESH:D012509', (177, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (177, 185))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('TBX3', 'Gene', (45, 49))	('inhibits', 'NegReg', (50, 58))	('cancer', 'Disease', (63, 69))
564076	26900951	Furthermore, constitutive activation of AKT, in part due to the repression of PTEN, is observed in 55% of soft tissue sarcoma cases and targeting AKT was shown to reduce pulmonary metastasis in osteosarcoma bearing mice.	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('AKT', 'Pathway', (40, 43))	('targeting', 'Var', (136, 145))	('pulmonary metastasis in osteosarcoma', 'Disease', (170, 206))	('sarcoma', 'Disease', (118, 125))	('PTEN', 'Gene', (78, 82))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (106, 125))	('repression', 'NegReg', (64, 74))	('activation', 'PosReg', (26, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('pulmonary metastasis in osteosarcoma', 'Disease', 'MESH:D009362', (170, 206))	('osteosarcoma', 'Phenotype', 'HP:0002669', (194, 206))	('mice', 'Species', '10090', (215, 219))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('reduce', 'NegReg', (163, 169))	('sarcoma', 'Disease', (199, 206))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
564080	26900951	Indeed, whereas knocking down TBX3 in transformed fibroblasts resulted in a more aggressive cancer phenotype, ectopic overexpression of Tbx3, or its splice variant Tbx3+2a, was sufficient to inhibit key features of the cancer phenotype in the aggressive HT1080 cell line.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('Tbx3', 'Gene', (136, 140))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('inhibit', 'NegReg', (191, 198))	('TBX3', 'Gene', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('HT1080', 'Gene', (254, 260))	('aggressive cancer', 'Disease', 'MESH:D009369', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('knocking down', 'Var', (16, 29))	('cancer', 'Disease', (219, 225))	('HT1080', 'Gene', '8872', (254, 260))	('more', 'PosReg', (76, 80))	('aggressive cancer', 'Disease', (81, 98))
564083	26900951	In addition, the silencing of TBX3 by methylation has been associated with progression to muscle-invasive bladder tumours and with more aggressive prostate tumours and this correlated with significantly lowered survival rate.	('aggressive prostate tumours', 'Disease', 'MESH:D011471', (136, 163))	('invasive bladder', 'Phenotype', 'HP:0100645', (97, 113))	('methylation', 'Var', (38, 49))	('muscle-invasive bladder tumours', 'Disease', 'MESH:D001749', (90, 121))	('aggressive prostate tumours', 'Disease', (136, 163))	('muscle-invasive bladder tumours', 'Disease', (90, 121))	('TBX3', 'Gene', (30, 34))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('lowered', 'NegReg', (203, 210))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('silencing', 'NegReg', (17, 26))	('rat', 'Species', '10116', (220, 223))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('survival', 'CPA', (211, 219))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))
564085	26900951	For example, while the overexpression of Brachyury contributes to a number of tumour types through its ability to promote epithelial-mesenchymal transition, a high-throughput study has revealed that Brachyury is epigenetically silenced in lung cancer and may be a tumour suppressor.	('tumour', 'Disease', (264, 270))	('Brachyury', 'Gene', (199, 208))	('overexpression', 'PosReg', (23, 37))	('epithelial-mesenchymal transition', 'CPA', (122, 155))	('lung cancer', 'Disease', (239, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('Brachyury', 'Gene', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('Brachyury', 'Gene', '6899', (41, 50))	('tumour', 'Disease', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('Brachyury', 'Gene', '6899', (199, 208))	('epigenetically silenced', 'Var', (212, 235))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('promote', 'PosReg', (114, 121))
564096	26900951	Secondary antibody (K400211; Dako) and DAB chromogen (K346711; Dako) were applied according to the manufacturer's instructions.	('DAB', 'Chemical', 'MESH:C000469', (39, 42))	('K400211', 'Var', (20, 27))	('K346711', 'Var', (54, 61))
564099	26900951	Stable transfectants were selected in growth medium containing 400 mug/ml G418 (Promega, Madison, WI, USA) (ATDC5 and CT-1 cells) or 800 mug/ml G418 (HT1080 and SW1353 cells).	('CT-1', 'Gene', '1489', (118, 122))	('CT-1', 'Gene', (118, 122))	('G418', 'Var', (74, 78))	('G418', 'Chemical', 'MESH:C010680', (144, 148))	('HT1080', 'Gene', (150, 156))	('SW1353', 'CellLine', 'CVCL:0543', (161, 167))	('G418', 'Var', (144, 148))	('HT1080', 'Gene', '8872', (150, 156))	('G418', 'Chemical', 'MESH:C010680', (74, 78))
564135	27004955	reported that RIS had a worse DSS than sporadic STS with a hazard ratio of 1.7.	('RIS', 'Var', (14, 17))	('RIS', 'Chemical', '-', (14, 17))	('STS', 'Phenotype', 'HP:0030448', (48, 51))	('DSS', 'Chemical', '-', (30, 33))	('DSS', 'MPA', (30, 33))
564204	27004955	On the other hand, the study by Kadouri et al., investigating the role of p53 and BRCA mutation in RIS development, found a higher frequency of BRCA mutation in RIS patients, but was insignificant, thus they concluded that BRCA mutation should not be considered when making the treatment decision.	('RIS', 'Chemical', '-', (99, 102))	('RIS', 'Chemical', '-', (161, 164))	('BRCA', 'Gene', (82, 86))	('BRCA', 'Gene', (144, 148))	('BRCA', 'Gene', '672', (223, 227))	('BRCA', 'Gene', (223, 227))	('p53', 'Gene', (74, 77))	('patients', 'Species', '9606', (165, 173))	('p53', 'Gene', '7157', (74, 77))	('mutation', 'Var', (149, 157))	('BRCA', 'Gene', '672', (82, 86))	('BRCA', 'Gene', '672', (144, 148))
564247	25232328	Notably, nontumor prostate cells had enlarged as well as atypical nuclei due to RTx.	('RTx', 'Chemical', 'MESH:C024353', (80, 83))	('RTx', 'Var', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
564273	25232328	demonstrated that the rate of p53 mutation in RISs (58%) was significantly higher than that in sporadic sarcomas (16.8%).	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('mutation', 'Var', (34, 42))	('sporadic sarcomas', 'Disease', (95, 112))	('higher', 'Reg', (75, 81))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('sporadic sarcomas', 'Disease', 'MESH:D012509', (95, 112))
564276	25232328	This suggested that p53 inactivation might be associated with the onset of this radiation-induced leiomyosarcoma.	('p53', 'Gene', '7157', (20, 23))	('p53', 'Gene', (20, 23))	('leiomyosarcoma', 'Disease', (98, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('inactivation', 'Var', (24, 36))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (98, 112))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (98, 112))	('associated', 'Reg', (46, 56))
564288	23497372	Age was the only variable to predict for OS, DFS and DMFS on UVA.	('DMFS', 'Chemical', '-', (53, 57))	('DMFS', 'Var', (53, 57))	('DFS', 'Disease', (45, 48))
564297	23497372	For instance, neoadjuvant chemotherapy (MAID regimen) interdigitated with neoadjuvant radiotherapy (44 Gy in 22 fractions) has been shown to decrease the rate of distant metastasis (DM) and to increase disease free survival (DFS) and overall survival (OS) in patients with STS of the extremity and trunk with >= 8 cm tumors compared with historical control.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('patients', 'Species', '9606', (259, 267))	('DM', 'Disease', 'MESH:D009223', (182, 184))	('STS', 'Phenotype', 'HP:0030448', (273, 276))	('al', 'Chemical', 'MESH:D000535', (248, 250))	('al', 'Chemical', 'MESH:D000535', (238, 240))	('decrease', 'NegReg', (141, 149))	('tumors', 'Disease', (317, 323))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('al', 'Chemical', 'MESH:D000535', (221, 223))	('increase disease', 'Disease', 'MESH:D019586', (193, 209))	('neoadjuvant', 'Var', (14, 25))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('distant metastasis', 'CPA', (162, 180))	('al', 'Chemical', 'MESH:D000535', (346, 348))	('increase disease', 'Disease', (193, 209))	('overall survival', 'CPA', (234, 250))
564353	23497372	Stage also predicted for DMFS on UVA (p=0.017).	('predicted', 'Reg', (11, 20))	('DMFS', 'Var', (25, 29))	('DMFS', 'Chemical', '-', (25, 29))	('al', 'Chemical', 'MESH:D000535', (6, 8))
564407	23497372	Finally, different from many other types of human malignancy, high grade and large size are often associated with a significant increase in STS necrosis at initial diagnosis.	('al', 'Chemical', 'MESH:D000535', (3, 5))	('human', 'Species', '9606', (44, 49))	('increase', 'PosReg', (128, 136))	('large size', 'Var', (77, 87))	('al', 'Chemical', 'MESH:D000535', (161, 163))	('al', 'Chemical', 'MESH:D000535', (51, 53))	('necrosis', 'Disease', 'MESH:D009336', (144, 152))	('high grade', 'Var', (62, 72))	('STS', 'Phenotype', 'HP:0030448', (140, 143))	('malignancy', 'Disease', 'MESH:D009369', (50, 60))	('malignancy', 'Disease', (50, 60))	('necrosis', 'Disease', (144, 152))
564420	33194750	In this review, we provide an overview of genetic variations predisposing to solid pediatric tumors (medulloblastoma, ependymoma, astrocytoma, neuroblastoma, retinoblastoma, Wilms tumor, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma) and outline the biological processes affected by the involved mutated genes.	('retinoblastoma', 'Phenotype', 'HP:0009919', (158, 172))	('ependymoma', 'Disease', (118, 128))	('osteosarcoma', 'Disease', (187, 199))	('neuroblastoma', 'Disease', (143, 156))	('osteosarcoma', 'Disease', 'MESH:D012516', (187, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('retinoblastoma', 'Disease', (158, 172))	('variations', 'Var', (50, 60))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (223, 236))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('ependymoma', 'Phenotype', 'HP:0002888', (118, 128))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (201, 217))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('Wilms tumor', 'Disease', 'MESH:D009396', (174, 185))	('astrocytoma', 'Disease', 'MESH:D001254', (130, 141))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (201, 217))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('astrocytoma', 'Disease', (130, 141))	('medulloblastoma', 'Disease', 'MESH:D008527', (101, 116))	('medulloblastoma', 'Phenotype', 'HP:0002885', (101, 116))	('medulloblastoma', 'Disease', (101, 116))	('ependymoma', 'Disease', 'MESH:D004806', (118, 128))	('osteosarcoma', 'Phenotype', 'HP:0002669', (187, 199))	('Wilms tumor', 'Phenotype', 'HP:0002667', (174, 185))	('Ewing sarcoma', 'Gene', (223, 236))	('retinoblastoma', 'Disease', 'MESH:D012175', (158, 172))	('tumors', 'Disease', (93, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('Wilms tumor', 'Disease', (174, 185))	('astrocytoma', 'Phenotype', 'HP:0009592', (130, 141))	('Ewing sarcoma', 'Gene', '2130', (223, 236))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('rhabdomyosarcoma', 'Disease', (201, 217))
564425	33194750	On the other hand, WGS can capture nearly all known genetic variations, including those falling in regulatory elements, with much more uniform coverage of the genome, but it does not allow to detect mosaic variants with low clonality or variations causing DNA repetitions.	('falling', 'Disease', (88, 95))	('falling', 'Disease', 'MESH:D002303', (88, 95))	('falling', 'Phenotype', 'HP:0002527', (88, 95))	('variations', 'Var', (60, 70))
564426	33194750	Finally, besides SNP array, copy-number variations (CNV) can be identified also through CGH array.	('CGH', 'Gene', (88, 91))	('CGH', 'Gene', '3342', (88, 91))	('copy-number variations', 'Var', (28, 50))
564427	33194750	Recently, in addition to germline pathogenic and/or likely pathogenic variants in known cancer-predisposing genes, it has been estimated that a high percentage (61%) of children, adolescent and young adult patients with solid tumors carry germline pathogenic and likely pathogenic variants in new candidate genes, including PRKN, SMACAL1, SMAD7, and TMPRSS3.	('cancer', 'Disease', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('SMAD7', 'Gene', (339, 344))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PRKN', 'Gene', '5071', (324, 328))	('variants', 'Var', (281, 289))	('TMPRSS3', 'Gene', (350, 357))	('children', 'Species', '9606', (169, 177))	('SMAD7', 'Gene', '4092', (339, 344))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('PRKN', 'Gene', (324, 328))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('SMACAL1', 'Gene', (330, 337))	('pathogenic', 'Reg', (248, 258))	('tumors', 'Disease', (226, 232))	('TMPRSS3', 'Gene', '64699', (350, 357))	('patients', 'Species', '9606', (206, 214))	('pathogenic', 'CPA', (270, 280))
564434	33194750	In sporadic cancers, genetic factors can be categorized into two types: uncommon, moderate-penetrance genetic variants, which for the studies considered in this review show a frequency lower than 1-0.001% in the general population and are not so rare as those associated with familial cancer, and common, low-penetrance genetic variants.	('familial cancer', 'Disease', 'MESH:D009369', (276, 291))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('variants', 'Var', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('familial cancer', 'Disease', (276, 291))
564439	33194750	Therefore, alterations in these genes compromise the normal control of cell growth and lead to a substantial increase in the risk of developing cancer.	('alterations', 'Var', (11, 22))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('compromise', 'NegReg', (38, 48))	('increase', 'Reg', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('control', 'MPA', (60, 67))
564446	33194750	Damaging germline mutations in known cancer-predisposing genes play an important role in two main subgroups, MBWNT and MBSHH, in which genetic testing is highly recommended.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('MB', 'Phenotype', 'HP:0002885', (119, 121))	('cancer', 'Disease', (37, 43))	('SHH', 'Gene', (121, 124))	('MBWNT', 'Disease', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('SHH', 'Gene', '6469', (121, 124))	('MB', 'Phenotype', 'HP:0002885', (109, 111))	('germline mutations', 'Var', (9, 27))
564447	33194750	MBWNT is characterized at somatic level by activating mutations in exon 3 of beta-catenin (CTNNB1) and monosomy of chromosome 6, while MBSHH by amplification of GLI2 and MYCN, as well as loss of 17p.	('CTNNB1', 'Gene', (91, 97))	('MB', 'Phenotype', 'HP:0002885', (0, 2))	('GLI2', 'Gene', (161, 165))	('loss', 'Var', (187, 191))	('17p', 'Protein', (195, 198))	('mutations in', 'Var', (54, 66))	('CTNNB1', 'Gene', '1499', (91, 97))	('SHH', 'Gene', '6469', (137, 140))	('beta-catenin', 'Gene', '1499', (77, 89))	('MB', 'Phenotype', 'HP:0002885', (135, 137))	('MYCN', 'Gene', (170, 174))	('amplification', 'Var', (144, 157))	('MYCN', 'Gene', '4613', (170, 174))	('NB', 'Phenotype', 'HP:0003006', (94, 96))	('beta-catenin', 'Gene', (77, 89))	('GLI2', 'Gene', '2736', (161, 165))	('activating', 'PosReg', (43, 53))	('SHH', 'Gene', (137, 140))
564450	33194750	Germline mutations of PTCH1 and SUFU, by causing activation of the SHH signaling pathway, predispose to MBSHH in Gorlin syndrome, an autosomal dominant disease caused by mutations in PTCH1.	('PTCH1', 'Gene', (22, 27))	('PTCH1', 'Gene', (183, 188))	('SHH', 'Gene', (106, 109))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (133, 159))	('predispose', 'Reg', (90, 100))	('caused by', 'Reg', (160, 169))	('PTCH1', 'Gene', '5727', (183, 188))	('mutations', 'Var', (170, 179))	('Gorlin syndrome', 'Disease', (113, 128))	('PTCH1', 'Gene', '5727', (22, 27))	('SHH', 'Gene', (67, 70))	('SHH', 'Gene', '6469', (106, 109))	('MB', 'Phenotype', 'HP:0002885', (104, 106))	('SUFU', 'Gene', (32, 36))	('autosomal dominant disease', 'Disease', (133, 159))	('SUFU', 'Gene', '51684', (32, 36))	('SHH', 'Gene', '6469', (67, 70))	('activation', 'PosReg', (49, 59))
564452	33194750	In MBWNT, activation of the WNT pathway is due to somatic mutations of CTNNB1 in most of tumors but it is also observed in patients with only germline mutations of APC, stressing the importance of genetic predisposition in high-risk patients.	('mutations', 'Var', (58, 67))	('CTNNB1', 'Gene', (71, 77))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('NB', 'Phenotype', 'HP:0003006', (74, 76))	('MB', 'Phenotype', 'HP:0002885', (3, 5))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('APC', 'Disease', 'MESH:D011125', (164, 167))	('WNT pathway', 'Pathway', (28, 39))	('APC', 'Disease', (164, 167))	('patients', 'Species', '9606', (123, 131))	('CTNNB1', 'Gene', '1499', (71, 77))	('patients', 'Species', '9606', (233, 241))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('activation', 'PosReg', (10, 20))
564453	33194750	Germline mutations in BRCA2 and PALB2, associated or not associated with Fanconi anemia, have been found in MBSHH and are often observed in association with somatic homologous recombination repair defects.	('Germline mutations', 'Var', (0, 18))	('Fanconi anemia', 'Disease', (73, 87))	('PALB2', 'Gene', '79728', (32, 37))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (73, 87))	('PALB2', 'Gene', (32, 37))	('SHH', 'Gene', (110, 113))	('MB', 'Phenotype', 'HP:0002885', (108, 110))	('Fanconi anemia', 'Disease', 'MESH:D005199', (73, 87))	('BRCA2', 'Gene', (22, 27))	('associated', 'Reg', (39, 49))	('anemia', 'Phenotype', 'HP:0001903', (81, 87))	('BRCA2', 'Gene', '675', (22, 27))	('SHH', 'Gene', '6469', (110, 113))
564454	33194750	The role of germline mutations in TP53 in MB is still widely debated today.	('MB', 'Phenotype', 'HP:0002885', (42, 44))	('germline mutations', 'Var', (12, 30))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', '7157', (34, 38))
564455	33194750	TP53 germline mutations affect MB prognosis differently according to the different subgroups: germline mutations in MBSHH are associated with poor prognosis, while both germline and somatic mutations in MBWNT are associated with better prognosis.	('SHH', 'Gene', '6469', (118, 121))	('mutations', 'Var', (103, 112))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('MB', 'Phenotype', 'HP:0002885', (203, 205))	('SHH', 'Gene', (118, 121))	('MB', 'Phenotype', 'HP:0002885', (31, 33))	('MBWNT', 'Gene', (203, 208))	('affect', 'Reg', (24, 30))	('MB', 'Phenotype', 'HP:0002885', (116, 118))
564456	33194750	Patients with germline TP53 mutations can have tumors characterized by catastrophic DNA chromothripsis and are often associated with Li-Fraumeni syndrome (LFS), a cancer predisposition disorder caused by germline mutations of the tumor-suppressor p53.	('chromothripsis', 'Disease', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Li-Fraumeni syndrome', 'Disease', (133, 153))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('p53', 'Gene', (247, 250))	('tumors', 'Disease', (47, 53))	('associated', 'Reg', (117, 127))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (133, 153))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', '7157', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (230, 235))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('LFS', 'Disease', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('LFS', 'Disease', 'MESH:D016864', (155, 158))	('cancer', 'Disease', (163, 169))	('tumor', 'Disease', (47, 52))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('chromothripsis', 'Disease', 'MESH:D000072837', (88, 102))	('TP53', 'Gene', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('p53', 'Gene', '7157', (247, 250))
564459	33194750	In a study on 1,022 MB patients, novel partial or total APC deletions were found.	('MB', 'Phenotype', 'HP:0002885', (20, 22))	('patients', 'Species', '9606', (23, 31))	('APC', 'Disease', 'MESH:D011125', (56, 59))	('APC', 'Disease', (56, 59))	('partial', 'Var', (39, 46))
564460	33194750	These mutations were not associated with any familial syndrome and predisposed to MBWNT.	('familial syndrome', 'Disease', (45, 62))	('MB', 'Phenotype', 'HP:0002885', (82, 84))	('associated', 'Reg', (25, 35))	('MBWNT', 'Disease', (82, 87))	('familial syndrome', 'Disease', 'MESH:D061325', (45, 62))	('mutations', 'Var', (6, 15))
564461	33194750	In the same study, 1% of patients (classified as MBSHH) had TP53 mutations but only 5/11 patients showed family history of cancer, emphasizing the role of TP53 germline mutations in predisposing to sporadic MB.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('TP53', 'Gene', '7157', (155, 159))	('SHH', 'Gene', (51, 54))	('TP53', 'Gene', (155, 159))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TP53', 'Gene', '7157', (60, 64))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Disease', (123, 129))	('patients', 'Species', '9606', (89, 97))	('MB', 'Phenotype', 'HP:0002885', (207, 209))	('MB', 'Phenotype', 'HP:0002885', (49, 51))	('SHH', 'Gene', '6469', (51, 54))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
564462	33194750	Notably, germline missense, frameshift, or non-sense mutations in the DNA-binding domain of TP53 were found to be associated with a series of events at the somatic level such as rearrangements, chromothripsis, and loss of heterozygosity in MBSHH patients, whereas germline mutations in SUFU and PTCH1 co-occurred with somatic loss of heterozygosity (Table 4).	('non-sense mutations', 'Var', (43, 62))	('SHH', 'Gene', '6469', (242, 245))	('PTCH1', 'Gene', (295, 300))	('patients', 'Species', '9606', (246, 254))	('missense', 'Var', (18, 26))	('chromothripsis', 'Disease', (194, 208))	('rearrangements', 'MPA', (178, 192))	('SUFU', 'Gene', (286, 290))	('TP53', 'Gene', (92, 96))	('SHH', 'Gene', (242, 245))	('MB', 'Phenotype', 'HP:0002885', (240, 242))	('associated', 'Reg', (114, 124))	('SUFU', 'Gene', '51684', (286, 290))	('TP53', 'Gene', '7157', (92, 96))	('loss of', 'NegReg', (214, 221))	('chromothripsis', 'Disease', 'MESH:D000072837', (194, 208))	('PTCH1', 'Gene', '5727', (295, 300))	('frameshift', 'Var', (28, 38))
564464	33194750	MB can also arise in patients with germline mutations in other known cancer genes such as ATM, FANCA, FANCC, NBN, WRN, BLM, and BRIP1 and in candidate genes like CHEK2, CREBBP, RAD51, ERCC2, and ERCC4.	('NB', 'Phenotype', 'HP:0003006', (109, 111))	('FANCC', 'Gene', '2176', (102, 107))	('CHEK2', 'Gene', (162, 167))	('patients', 'Species', '9606', (21, 29))	('BRIP1', 'Gene', '83990', (128, 133))	('ERCC2', 'Gene', (184, 189))	('RAD51', 'Gene', (177, 182))	('NBN', 'Gene', '4683', (109, 112))	('RAD51', 'Gene', '5888', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('arise', 'Reg', (12, 17))	('CREBBP', 'Gene', (169, 175))	('CHEK2', 'Gene', '11200', (162, 167))	('ERCC2', 'Gene', '2068', (184, 189))	('ERCC4', 'Gene', '2072', (195, 200))	('ERCC4', 'Gene', (195, 200))	('FANCC', 'Gene', (102, 107))	('FANCA', 'Gene', '2175', (95, 100))	('NBN', 'Gene', (109, 112))	('BLM', 'Gene', (119, 122))	('WRN', 'Gene', (114, 117))	('WRN', 'Gene', '7486', (114, 117))	('ATM', 'Gene', '472', (90, 93))	('BLM', 'Gene', '641', (119, 122))	('BRIP1', 'Gene', (128, 133))	('CREBBP', 'Gene', '1387', (169, 175))	('FANCA', 'Gene', (95, 100))	('germline mutations', 'Var', (35, 53))	('cancer', 'Disease', (69, 75))	('MB', 'Phenotype', 'HP:0002885', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ATM', 'Gene', (90, 93))
564465	33194750	Frameshift, protein-truncating, and missense mutations occurring in GPR161, a gene never previously associated with MB, were found in 6 MBSHH cases that, at the somatic level, showed loss of heterozygosity with retention of the mutated allele, confirming its role as driver gene in MBSHH.	('MB', 'Phenotype', 'HP:0002885', (136, 138))	('found', 'Reg', (125, 130))	('SHH', 'Gene', '6469', (284, 287))	('protein-truncating', 'MPA', (12, 30))	('missense mutations', 'Var', (36, 54))	('SHH', 'Gene', (138, 141))	('MB', 'Phenotype', 'HP:0002885', (282, 284))	('GPR161', 'Gene', (68, 74))	('Frameshift', 'Var', (0, 10))	('SHH', 'Gene', (284, 287))	('GPR161', 'Gene', '23432', (68, 74))	('SHH', 'Gene', '6469', (138, 141))	('MB', 'Phenotype', 'HP:0002885', (116, 118))
564467	33194750	Germline mutations in ELP1 have been very recently found to predispose to MBSHH and to be associated with two consecutive somatic events: loss of the 9q arm, with consequent loss of the wild-type copy of PTCH1 and ELP1, and a second independent mutation event in PTCH1 (Table 4).	('Germline mutations', 'Var', (0, 18))	('loss', 'NegReg', (138, 142))	('ELP1', 'Gene', '8518', (214, 218))	('ELP1', 'Gene', '8518', (22, 26))	('PTCH1', 'Gene', '5727', (204, 209))	('SHH', 'Gene', (76, 79))	('PTCH1', 'Gene', '5727', (263, 268))	('ELP1', 'Gene', (214, 218))	('associated', 'Reg', (90, 100))	('predispose', 'Reg', (60, 70))	('PTCH1', 'Gene', (204, 209))	('ELP1', 'Gene', (22, 26))	('loss', 'NegReg', (174, 178))	('9q arm', 'Protein', (150, 156))	('PTCH1', 'Gene', (263, 268))	('MB', 'Phenotype', 'HP:0002885', (74, 76))	('SHH', 'Gene', '6469', (76, 79))
564468	33194750	This study, importantly, showed that 40% of MBSHH patients carry disease-predisposing mutations and that genetic predisposition to proteome instability may be a determinant in the pathogenesis of pediatric brain cancers (Table 1).	('SHH', 'Gene', '6469', (46, 49))	('mutations', 'Var', (86, 95))	('MB', 'Phenotype', 'HP:0002885', (44, 46))	('disease-predisposing', 'Reg', (65, 85))	('brain cancers', 'Disease', 'MESH:D001932', (206, 219))	('patients', 'Species', '9606', (50, 58))	('brain cancers', 'Disease', (206, 219))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('SHH', 'Gene', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
564472	33194750	Microsatellites are tandem repeats of 1-6 base pairs, and their variability is associated with numerous tumors, including MB.	('MB', 'Phenotype', 'HP:0002885', (122, 124))	('associated', 'Reg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('numerous tumors', 'Disease', (95, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('variability', 'MPA', (64, 75))	('numerous tumors', 'Disease', 'MESH:D009369', (95, 110))	('Microsatellites', 'Var', (0, 15))
564473	33194750	Interestingly, in silico analyses revealed that genes harboring these microsatellite loci had cellular functions important for tumorigenesis.	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('microsatellite loci', 'Var', (70, 89))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))
564475	33194750	EP is diagnosed in ~33-53% of patients with type 2 neurofibromatosis, with high occurrence of truncating mutations in NF2.	('neurofibromatosis', 'Disease', 'MESH:C537392', (51, 68))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (51, 68))	('EP', 'Phenotype', 'HP:0002888', (0, 2))	('NF2', 'Gene', (118, 121))	('patients', 'Species', '9606', (30, 38))	('truncating mutations', 'Var', (94, 114))	('EP', 'Gene', '2069', (0, 2))	('neurofibromatosis', 'Disease', (51, 68))	('NF2', 'Gene', '4771', (118, 121))
564476	33194750	EP has recently been associated with Kabuki syndrome, with mutations in KMT2D and rarely occurs in Turcot and MEN1 syndromes with mutations in MSH2 and MEN1, respectively (Table 2).	('MEN1', 'Gene', (110, 114))	('MSH2', 'Gene', (143, 147))	('MEN1', 'Gene', '4221', (110, 114))	('Kabuki syndrome', 'Disease', 'MESH:C537705', (37, 52))	('MSH2', 'Gene', '4436', (143, 147))	('associated', 'Reg', (21, 31))	('Kabuki syndrome', 'Disease', (37, 52))	('KMT2D', 'Gene', '8085', (72, 77))	('MEN1', 'Gene', (152, 156))	('mutations', 'Var', (130, 139))	('MEN1', 'Gene', '4221', (152, 156))	('mutations', 'Var', (59, 68))	('EP', 'Phenotype', 'HP:0002888', (0, 2))	('EP', 'Gene', '2069', (0, 2))	('KMT2D', 'Gene', (72, 77))
564479	33194750	Regarding the genetic predisposition, one large study reported germline splicing mutations in the tumor-suppressor genes MUTYH and ERCC2 and point mutations in TP53 and PMS2 (Table 1).	('ERCC2', 'Gene', '2068', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('TP53', 'Gene', '7157', (160, 164))	('ERCC2', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MUTYH', 'Gene', (121, 126))	('PMS2', 'Gene', (169, 173))	('TP53', 'Gene', (160, 164))	('point mutations', 'Var', (141, 156))	('MUTYH', 'Gene', '4595', (121, 126))	('tumor', 'Disease', (98, 103))	('PMS2', 'Gene', '5395', (169, 173))	('germline splicing mutations', 'Var', (63, 90))
564480	33194750	Pathogenic mutations in NF1, BRCA2, FANCA, and GJB2 have been also identified in a recent study involving 280 patients with different forms of AS.	('GJB2', 'Gene', (47, 51))	('mutations', 'Var', (11, 20))	('FANCA', 'Gene', '2175', (36, 41))	('Pathogenic', 'Reg', (0, 10))	('BRCA2', 'Gene', (29, 34))	('AS', 'Phenotype', 'HP:0009592', (143, 145))	('GJB2', 'Gene', '2706', (47, 51))	('FANCA', 'Gene', (36, 41))	('BRCA2', 'Gene', '675', (29, 34))	('NF1', 'Gene', (24, 27))	('patients', 'Species', '9606', (110, 118))	('NF1', 'Gene', '4763', (24, 27))
564483	33194750	NB tumors, as well as other pediatric cancers, present few recurrent somatic mutations but frequent chromosomic aberrations such MYCN amplification, 17q gain, 1p deletion, and 11q deletion.	('11q deletion', 'Var', (176, 188))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('NB tumors', 'Disease', (0, 9))	('1p deletion', 'Var', (159, 170))	('NB', 'Phenotype', 'HP:0003006', (0, 2))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('gain', 'PosReg', (153, 157))	('17q', 'CPA', (149, 152))	('NB tumors', 'Disease', 'MESH:D009369', (0, 9))	('MYCN', 'Gene', (129, 133))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('cancers', 'Disease', (38, 45))	('MYCN', 'Gene', '4613', (129, 133))
564489	33194750	Mutations in KIF1Bbeta and GALNT14 and in 16p12-13, 4p16, and 1p loci (Table 1) have been reported in related patients, but further validations are needed.	('reported', 'Reg', (90, 98))	('KIF1Bbeta', 'Gene', (13, 22))	('Mutations', 'Var', (0, 9))	('GALNT14', 'Gene', (27, 34))	('patients', 'Species', '9606', (110, 118))	('GALNT14', 'Gene', '79623', (27, 34))
564491	33194750	In different studies, pathogenic and likely pathogenic variants were identified in predisposition genes such as ALK, CHEK2, BRCA2, SMARCA4, and TP53 (Table 1) but also in candidate genes like AXIN2, PALB2, BARD1, PINK1, APC, BRCA1, SDHB, and LZTR1 Specifically, TP53 variants are strongly associated with NB susceptibility.	('AXIN2', 'Gene', (192, 197))	('PINK1', 'Gene', (213, 218))	('CHEK2', 'Gene', '11200', (117, 122))	('BRCA1', 'Gene', '672', (225, 230))	('PALB2', 'Gene', '79728', (199, 204))	('BRCA2', 'Gene', '675', (124, 129))	('LZTR1', 'Gene', '8216', (242, 247))	('SDHB', 'Gene', (232, 236))	('associated with', 'Reg', (289, 304))	('BRCA1', 'Gene', (225, 230))	('TP53', 'Gene', '7157', (144, 148))	('NB', 'Phenotype', 'HP:0003006', (305, 307))	('TP53', 'Gene', '7157', (262, 266))	('APC', 'Disease', 'MESH:D011125', (220, 223))	('APC', 'Disease', (220, 223))	('BARD1', 'Gene', '580', (206, 211))	('SMARCA4', 'Gene', '6597', (131, 138))	('BARD1', 'Gene', (206, 211))	('PINK1', 'Gene', '65018', (213, 218))	('AXIN2', 'Gene', '8313', (192, 197))	('variants', 'Var', (55, 63))	('ALK', 'Gene', '238', (112, 115))	('TP53', 'Gene', (144, 148))	('BRCA2', 'Gene', (124, 129))	('ALK', 'Gene', (112, 115))	('SDHB', 'Gene', '6390', (232, 236))	('TP53', 'Gene', (262, 266))	('CHEK2', 'Gene', (117, 122))	('LZTR1', 'Gene', (242, 247))	('PALB2', 'Gene', (199, 204))	('SMARCA4', 'Gene', (131, 138))	('variants', 'Var', (267, 275))
564494	33194750	A SNP in the long non-coding RNA (lcnRNA) CASC15 produces a truncated isoform, whose lower expression correlates with advanced disease.	('AS', 'Phenotype', 'HP:0009592', (43, 45))	('SNP', 'Var', (2, 5))	('advanced disease', 'Disease', (118, 134))	('CASC15', 'Gene', (42, 48))	('CASC15', 'Gene', '401237', (42, 48))	('truncated isoform', 'MPA', (60, 77))
564495	33194750	Loss of another lncRNA, NBAT-1, at the same locus, contributes to aggressive NB by increasing proliferation and impairing differentiation of neuronal precursors.	('NB', 'Phenotype', 'HP:0003006', (77, 79))	('aggressive NB', 'Disease', 'MESH:D001523', (66, 79))	('aggressive NB', 'Disease', (66, 79))	('NBAT-1', 'Gene', '729177', (24, 30))	('NB', 'Phenotype', 'HP:0003006', (24, 26))	('proliferation', 'CPA', (94, 107))	('NBAT-1', 'Gene', (24, 30))	('impairing', 'NegReg', (112, 121))	('differentiation of neuronal precursors', 'CPA', (122, 160))	('Loss', 'Var', (0, 4))	('increasing', 'PosReg', (83, 93))
564496	33194750	Diverse functional studies have elucidated the role of BARD1 and its variants in NB development.	('variants', 'Var', (69, 77))	('BARD1', 'Gene', (55, 60))	('BARD1', 'Gene', '580', (55, 60))	('NB', 'Phenotype', 'HP:0003006', (81, 83))
564497	33194750	Variants in the BARD1 promoter decrease the expression of the tumor-suppressor form which protects NB cells from DNA damage, whereas variants in introns increase the expression of an oncogenic isoform, BARD1beta, which stabilizes the Aurora kinases.	('NB', 'Phenotype', 'HP:0003006', (99, 101))	('BARD1', 'Gene', '580', (16, 21))	('Variants', 'Var', (0, 8))	('expression', 'MPA', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BARD1', 'Gene', (202, 207))	('BARD1', 'Gene', (16, 21))	('tumor', 'Disease', (62, 67))	('decrease', 'NegReg', (31, 39))	('increase', 'PosReg', (153, 161))	('BARD1', 'Gene', '580', (202, 207))	('variants', 'Var', (133, 141))	('expression', 'MPA', (166, 176))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
564498	33194750	LMO1 decreased expression, caused by a variant in a super-enhancer which disrupts GATA binding, reduces NB cell proliferation.	('LMO1', 'Gene', '4004', (0, 4))	('reduces', 'NegReg', (96, 103))	('NB cell proliferation', 'CPA', (104, 125))	('variant', 'Var', (39, 46))	('GATA', 'Gene', (82, 86))	('reduces NB cell proliferation', 'Phenotype', 'HP:0040218', (96, 125))	('expression', 'MPA', (15, 25))	('GATA', 'Gene', '55278', (82, 86))	('NB', 'Phenotype', 'HP:0003006', (104, 106))	('disrupts', 'NegReg', (73, 81))	('decreased', 'NegReg', (5, 14))	('LMO1', 'Gene', (0, 4))
564501	33194750	Indeed, SNPs in MMP20 and KIF15 increase NB susceptibility in the presence of 11q deletion and MYCN amplification, respectively, whereas another study shows that specific mtDNA haplogroups can influence the risk of NB.	('SNPs', 'Var', (8, 12))	('MYCN', 'Gene', (95, 99))	('MYCN', 'Gene', '4613', (95, 99))	('influence', 'Reg', (193, 202))	('increase', 'PosReg', (32, 40))	('MMP20', 'Gene', (16, 21))	('KIF15', 'Gene', '56992', (26, 31))	('KIF15', 'Gene', (26, 31))	('NB', 'Phenotype', 'HP:0003006', (41, 43))	('MMP20', 'Gene', '9313', (16, 21))	('NB', 'Phenotype', 'HP:0003006', (215, 217))
564502	33194750	We have provided evidence that SNPs in PARP1 and IL6 might be predictive biomarkers of response to chemotherapy and prognosis.	('IL6', 'Gene', '3569', (49, 52))	('PARP1', 'Gene', (39, 44))	('PARP1', 'Gene', '142', (39, 44))	('IL6', 'Gene', (49, 52))	('SNPs', 'Var', (31, 35))
564504	33194750	Indeed, SNPs in 2q35, 3q25.32, and 4p16.2 are cross-associated with congenital heart disease (CHD) and NB, while 1p13.2 showed cross-association with NB and melanoma.	('SNPs', 'Var', (8, 12))	('NB', 'Phenotype', 'HP:0003006', (150, 152))	('congenital heart disease', 'Disease', 'MESH:D006331', (68, 92))	('CHD', 'Phenotype', 'HP:0001627', (94, 97))	('NB', 'Phenotype', 'HP:0003006', (103, 105))	('CHD', 'Disease', (94, 97))	('CHD', 'Disease', 'None', (94, 97))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('congenital heart disease', 'Disease', (68, 92))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('congenital heart disease', 'Phenotype', 'HP:0001627', (68, 92))
564505	33194750	Very recently, a cross-match investigation between germline alterations in pediatric patients with different solid tumors and CHD-related genes has identified that NB is among the tumors with the highest enrichment of germline pathogenic and likely pathogenic variants in these genes.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CHD', 'Disease', (126, 129))	('CHD', 'Phenotype', 'HP:0001627', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('CHD', 'Disease', 'None', (126, 129))	('NB', 'Phenotype', 'HP:0003006', (164, 166))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('patients', 'Species', '9606', (85, 93))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('variants', 'Var', (260, 268))
564506	33194750	Highly associated with NB are hemizygous deletion in 1q21.1, disruption in NBPF23, and microdeletion in 16p11.2, containing SEZ6L2 and PRRT2.	('NBPF23', 'Gene', '401967', (75, 81))	('NB', 'Phenotype', 'HP:0003006', (23, 25))	('disruption', 'Var', (61, 71))	('SEZ6L2', 'Gene', (124, 130))	('associated', 'Reg', (7, 17))	('NBPF23', 'Gene', (75, 81))	('PRRT2', 'Gene', (135, 140))	('microdeletion', 'Var', (87, 100))	('SEZ6L2', 'Gene', '26470', (124, 130))	('NB', 'Phenotype', 'HP:0003006', (75, 77))	('PRRT2', 'Gene', '112476', (135, 140))
564507	33194750	Deletion including SLFN11, duplication of SOX4, and partial deletion of PARK2 have been identified in three different patients, respectively.	('SOX4', 'Gene', '6659', (42, 46))	('PARK2', 'Gene', '5071', (72, 77))	('patients', 'Species', '9606', (118, 126))	('SLFN11', 'Gene', (19, 25))	('partial deletion', 'Var', (52, 68))	('PARK2', 'Gene', (72, 77))	('duplication', 'Var', (27, 38))	('SLFN11', 'Gene', '91607', (19, 25))	('SOX4', 'Gene', (42, 46))	('Deletion', 'Var', (0, 8))
564508	33194750	Retinoblastoma (RB) is a pediatric malignancy of the neural retina, commonly initiated by biallelic inactivation of RB1 and affecting one (unilateral) or both eyes (bilateral).	('RB', 'Phenotype', 'HP:0009919', (116, 118))	('malignancy of the neural retina', 'Disease', 'MESH:D019572', (35, 66))	('RB1', 'Gene', '5925', (116, 119))	('RB', 'Phenotype', 'HP:0009919', (16, 18))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('biallelic inactivation', 'Var', (90, 112))	('malignancy of the neural retina', 'Disease', (35, 66))	('RB', 'Gene', '5925', (16, 18))	('Retinoblastoma', 'Disease', 'MESH:D012175', (0, 14))	('RB1', 'Gene', (116, 119))	('affecting', 'Reg', (124, 133))	('Retinoblastoma', 'Disease', (0, 14))	('RB', 'Gene', '5925', (116, 118))	('initiated by', 'Reg', (77, 89))
564514	33194750	Germline mutations in RB1 are inherited in 25% of cases in an autosomal-dominant manner.	('Germline mutations', 'Var', (0, 18))	('RB1', 'Gene', '5925', (22, 25))	('RB', 'Phenotype', 'HP:0009919', (22, 24))	('RB1', 'Gene', (22, 25))
564515	33194750	A broad spectrum of inactivating RB1 germline mutations have been described, mainly nonsense and frameshifts affecting the coding region, few large deletions, and <5% silencing gene promoter.	('nonsense', 'Var', (84, 92))	('frameshifts', 'Var', (97, 108))	('RB1', 'Gene', (33, 36))	('inactivating', 'Reg', (20, 32))	('RB', 'Phenotype', 'HP:0009919', (33, 35))	('RB1', 'Gene', '5925', (33, 36))
564517	33194750	Influence of genetic modifiers such as MDM2, MDM4, or MED4 and polymorphisms in p53, CDKN1A, and CDKN2A could also influence RB development.	('MDM4', 'Gene', '4194', (45, 49))	('CDKN2A', 'Gene', (97, 103))	('MDM2', 'Gene', '4193', (39, 43))	('RB', 'Phenotype', 'HP:0009919', (125, 127))	('MDM2', 'Gene', (39, 43))	('MDM4', 'Gene', (45, 49))	('CDKN1A', 'Gene', (85, 91))	('p53', 'Gene', (80, 83))	('CDKN2A', 'Gene', '1029', (97, 103))	('RB', 'Gene', '5925', (125, 127))	('CDKN1A', 'Gene', '1026', (85, 91))	('polymorphisms', 'Var', (63, 76))	('p53', 'Gene', '7157', (80, 83))	('MED4', 'Gene', '29079', (54, 58))	('MED4', 'Gene', (54, 58))	('influence', 'Reg', (115, 124))
564518	33194750	Reduced MDM2 and MDM4 expression may increase the RB1 haploinsufficiency, whereas variants affecting the activity of p53 pathway effectors impact cell-cycle arrest.	('impact', 'Reg', (139, 145))	('variants', 'Var', (82, 90))	('MDM4', 'Gene', (17, 21))	('haploinsufficiency', 'Disease', 'MESH:D058495', (54, 72))	('MDM2', 'Gene', '4193', (8, 12))	('RB', 'Phenotype', 'HP:0009919', (50, 52))	('p53', 'Gene', (117, 120))	('MDM2', 'Gene', (8, 12))	('p53', 'Gene', '7157', (117, 120))	('arrest', 'Disease', (157, 163))	('Reduced', 'NegReg', (0, 7))	('MDM4', 'Gene', '4194', (17, 21))	('activity', 'MPA', (105, 113))	('increase', 'PosReg', (37, 45))	('RB1', 'Gene', (50, 53))	('haploinsufficiency', 'Disease', (54, 72))	('RB1', 'Gene', '5925', (50, 53))	('arrest', 'Disease', 'MESH:D006323', (157, 163))
564520	33194750	A small subset of hereditary RB patients is not carrier of RB1 mutations.	('mutations', 'Var', (63, 72))	('RB1', 'Gene', (59, 62))	('patients', 'Species', '9606', (32, 40))	('RB', 'Gene', '5925', (59, 61))	('RB1', 'Gene', '5925', (59, 62))	('RB', 'Gene', '5925', (29, 31))	('RB', 'Phenotype', 'HP:0009919', (59, 61))	('RB', 'Phenotype', 'HP:0009919', (29, 31))
564522	33194750	RB is generally described as retinoblastoma predisposition syndrome since germline RB1 mutations lead to a high risk of second primary malignancies.	('RB', 'Gene', '5925', (0, 2))	('RB1', 'Gene', (83, 86))	('lead to', 'Reg', (97, 104))	('retinoblastoma predisposition syndrome', 'Disease', 'MESH:D012175', (29, 67))	('RB', 'Gene', '5925', (83, 85))	('RB', 'Phenotype', 'HP:0009919', (83, 85))	('retinoblastoma predisposition syndrome', 'Disease', (29, 67))	('RB1', 'Gene', '5925', (83, 86))	('RB', 'Phenotype', 'HP:0009919', (0, 2))	('malignancies', 'Disease', 'MESH:D009369', (135, 147))	('retinoblastoma', 'Phenotype', 'HP:0009919', (29, 43))	('malignancies', 'Disease', (135, 147))	('mutations', 'Var', (87, 96))
564523	33194750	Interestingly, RB onset is reported in 13q deletion syndrome, caused by deletion of part of the long arm of chromosome 13, where RB1 is located (Table 2).	('RB1', 'Gene', '5925', (129, 132))	('RB', 'Phenotype', 'HP:0009919', (129, 131))	('RB', 'Phenotype', 'HP:0009919', (15, 17))	('13q deletion syndrome', 'Disease', (39, 60))	('RB1', 'Gene', (129, 132))	('RB', 'Gene', '5925', (129, 131))	('RB', 'Gene', '5925', (15, 17))	('deletion', 'Var', (72, 80))
564527	33194750	A significant proportion of sporadic RB exhibits somatic mosaicism for RB1 mutations.	('RB', 'Phenotype', 'HP:0009919', (37, 39))	('RB', 'Phenotype', 'HP:0009919', (71, 73))	('RB1', 'Gene', (71, 74))	('RB', 'Gene', '5925', (37, 39))	('RB', 'Gene', '5925', (71, 73))	('mutations', 'Var', (75, 84))	('RB1', 'Gene', '5925', (71, 74))
564529	33194750	However, given the role of the p53 pathway in RB development, polymorphisms in genes such as MDM2, MDM4, and CDKN1A could also influence the development of the sporadic form (Table 3).	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('RB', 'Phenotype', 'HP:0009919', (46, 48))	('CDKN1A', 'Gene', (109, 115))	('MDM4', 'Gene', (99, 103))	('CDKN1A', 'Gene', '1026', (109, 115))	('development of the sporadic form', 'CPA', (141, 173))	('polymorphisms', 'Var', (62, 75))	('influence', 'Reg', (127, 136))	('RB', 'Gene', '5925', (46, 48))	('MDM2', 'Gene', '4193', (93, 97))	('MDM4', 'Gene', '4194', (99, 103))	('MDM2', 'Gene', (93, 97))
564531	33194750	Indeed, high-throughput analysis revealed that several low-frequency RB1 variants are present in the human population, including rare alleles disrupting splicing.	('splicing', 'MPA', (153, 161))	('variants', 'Var', (73, 81))	('RB1', 'Gene', '5925', (69, 72))	('human', 'Species', '9606', (101, 106))	('RB', 'Phenotype', 'HP:0009919', (69, 71))	('disrupting', 'NegReg', (142, 152))	('RB1', 'Gene', (69, 72))
564532	33194750	Mosaic and non-mosaic chromosomal deletions of 13q14 region are causative of RB.	('Mosaic', 'Var', (0, 6))	('13q14', 'Gene', (47, 52))	('RB', 'Phenotype', 'HP:0009919', (77, 79))	('RB', 'Gene', '5925', (77, 79))
564533	33194750	Additionally, duplication of 1q21.1, containing the oncogene BCL9, has been reported in a patient with bilateral RB.	('BCL9', 'Gene', '607', (61, 65))	('RB', 'Phenotype', 'HP:0009919', (113, 115))	('reported', 'Reg', (76, 84))	('patient', 'Species', '9606', (90, 97))	('duplication', 'Var', (14, 25))	('RB', 'Gene', '5925', (113, 115))	('BCL9', 'Gene', (61, 65))
564536	33194750	The landscape of somatic genetic alterations in WT is quite broad, with classical genetic changes involving WT1, the IGF2 locus, the WNT pathway, MYCN and TP53 but also driver mutations in several additional cancer genes including epigenetic remodelers, miRNA processing genes and transcription factors essential for nephrogenesis.	('mutations', 'Var', (176, 185))	('cancer', 'Disease', (208, 214))	('TP53', 'Gene', '7157', (155, 159))	('IGF2', 'Gene', (117, 121))	('MYCN', 'Gene', (146, 150))	('TP53', 'Gene', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('WT1', 'Gene', '7490', (108, 111))	('MYCN', 'Gene', '4613', (146, 150))	('WT1', 'Gene', (108, 111))	('WT', 'Phenotype', 'HP:0002667', (48, 50))	('IGF2', 'Gene', '3481', (117, 121))	('WT', 'Phenotype', 'HP:0002667', (108, 110))	('miRNA processing genes', 'Gene', (254, 276))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
564538	33194750	Some of the most known and characterized syndromes are associated with constitutional alterations in WT1 at 11p13.	('WT', 'Phenotype', 'HP:0002667', (101, 103))	('associated', 'Reg', (55, 65))	('WT1', 'Gene', '7490', (101, 104))	('constitutional alterations', 'Var', (71, 97))	('WT1', 'Gene', (101, 104))
564540	33194750	A syndrome frequently associated with high risk of developing WT (around 50%) is the Wilms tumor-aniridia syndrome (WAGR), caused by microdeletions of 11p13 including WT1 and PAX6.	('WAGR', 'Disease', 'MESH:D017624', (116, 120))	('Wilms tumor-aniridia syndrome', 'Disease', 'MESH:D017624', (85, 114))	('Wilms tumor-aniridia syndrome', 'Disease', (85, 114))	('WT1', 'Gene', '7490', (167, 170))	('Wilms tumor', 'Phenotype', 'HP:0002667', (85, 96))	('PAX6', 'Gene', (175, 179))	('WT1', 'Gene', (167, 170))	('WT', 'Phenotype', 'HP:0002667', (167, 169))	('11p13', 'Gene', (151, 156))	('PAX6', 'Gene', '5080', (175, 179))	('aniridia', 'Phenotype', 'HP:0000526', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('WT', 'Phenotype', 'HP:0002667', (62, 64))	('caused by', 'Reg', (123, 132))	('WAGR', 'Disease', (116, 120))	('microdeletions', 'Var', (133, 147))
564541	33194750	The second WT1-related disorder is Denys-Drash syndrome (DDS), due to missense variants in WT1 exons 8 or 9, which affect critical residues in the zinc finger domains.	('WT1', 'Gene', (91, 94))	('Denys-Drash syndrome', 'Disease', 'MESH:D030321', (35, 55))	('WT1', 'Gene', '7490', (11, 14))	('WT', 'Phenotype', 'HP:0002667', (91, 93))	('affect', 'Reg', (115, 121))	('Denys-Drash syndrome', 'Disease', (35, 55))	('WT1', 'Gene', (11, 14))	('WT', 'Phenotype', 'HP:0002667', (11, 13))	('WT1', 'Gene', '7490', (91, 94))	('missense variants', 'Var', (70, 87))	('DDS', 'Disease', 'MESH:D030321', (57, 60))	('DDS', 'Disease', (57, 60))
564543	33194750	Another syndrome, phenotypically similar to DDS but with a lower risk of WT development, is Frasier syndrome (FS), caused by splicing variants that result in an imbalance of WT1 isoforms.	('WT1', 'Gene', '7490', (174, 177))	('WT1', 'Gene', (174, 177))	('FS', 'Disease', 'MESH:D018223', (110, 112))	('WT', 'Phenotype', 'HP:0002667', (174, 176))	('Frasier syndrome', 'Disease', 'MESH:D052159', (92, 108))	('splicing variants', 'Var', (125, 142))	('Frasier syndrome', 'Disease', (92, 108))	('imbalance', 'Phenotype', 'HP:0002172', (161, 170))	('DDS', 'Disease', 'MESH:D030321', (44, 47))	('DDS', 'Disease', (44, 47))	('WT', 'Phenotype', 'HP:0002667', (73, 75))	('caused by', 'Reg', (115, 124))
564545	33194750	High WT risk is specifically associated with uniparental paternal disomy at 11p15 and to isolated H19 hyper-methylation that results in biallelic expression of IGF2 and over-activation of the IGF signaling pathway.	('biallelic', 'MPA', (136, 145))	('IGF2', 'Gene', '3481', (160, 164))	('IGF signaling pathway', 'Pathway', (192, 213))	('WT', 'Phenotype', 'HP:0002667', (5, 7))	('uniparental paternal disomy', 'Disease', (45, 72))	('IGF2', 'Gene', (160, 164))	('hyper-methylation', 'Var', (102, 119))	('H19', 'Gene', '283120', (98, 101))	('uniparental paternal disomy', 'Disease', 'MESH:C536471', (45, 72))	('over-activation', 'PosReg', (169, 184))	('results in', 'Reg', (125, 135))	('H19', 'Gene', (98, 101))
564546	33194750	A small proportion of familial cases are due to germline WT1 variants and mutations in the H19 region of 11p15.	('WT1', 'Gene', '7490', (57, 60))	('WT', 'Phenotype', 'HP:0002667', (57, 59))	('WT1', 'Gene', (57, 60))	('mutations', 'Var', (74, 83))	('familial cases', 'Disease', (22, 36))	('H19', 'Gene', (91, 94))	('due', 'Reg', (41, 44))	('H19', 'Gene', '283120', (91, 94))	('variants', 'Var', (61, 69))
564548	33194750	Another cause of familial WT is the presence of inactivating mutations in the DICER1 miRNA processing gene, also causative of cancer susceptibility in DICER1 syndrome.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('WT', 'Phenotype', 'HP:0002667', (26, 28))	('inactivating mutations', 'Var', (48, 70))	('familial WT', 'Disease', (17, 28))	('DICER1', 'Gene', (151, 157))	('DICER1', 'Gene', '23405', (151, 157))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('DICER1', 'Gene', (78, 84))	('DICER1', 'Gene', '23405', (78, 84))
564551	33194750	Rare biallelic TRIP13 mutations have been found in a WES study on familial WT pedigrees.	('WT', 'Phenotype', 'HP:0002667', (75, 77))	('TRIP13', 'Gene', (15, 21))	('mutations', 'Var', (22, 31))	('found', 'Reg', (42, 47))	('TRIP13', 'Gene', '9319', (15, 21))
564552	33194750	TRIP13 encodes a member of the spindle assembly checkpoint complex, whose inactivation leads to chromosome segregation dysfunction and aneuploidy.	('chromosome segregation dysfunction', 'CPA', (96, 130))	('aneuploidy', 'Disease', (135, 145))	('TRIP13', 'Gene', '9319', (0, 6))	('TRIP13', 'Gene', (0, 6))	('leads to', 'Reg', (87, 95))	('aneuploidy', 'Disease', 'MESH:D000782', (135, 145))	('inactivation', 'Var', (74, 86))
564553	33194750	Pathogenic inactivating mutations of TRIM28 have been found in about 8% of familial WT in a sequencing study on 890 patients.	('inactivating mutations', 'Var', (11, 33))	('WT', 'Phenotype', 'HP:0002667', (84, 86))	('Pathogenic', 'Reg', (0, 10))	('patients', 'Species', '9606', (116, 124))	('found', 'Reg', (54, 59))	('TRIM28', 'Gene', (37, 43))	('TRIM28', 'Gene', '10155', (37, 43))	('familial WT', 'Disease', (75, 86))
564554	33194750	The same study reports constitutional mutations in FBXW7, NYNRIN, and CDC73 as contributors to a small number of familial cases, and pathogenic mutations in TRIM28, FBXW7, and KDM3B as de novo events in children with sporadic tumors.	('children', 'Species', '9606', (203, 211))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('NYNRIN', 'Gene', '57523', (58, 64))	('mutations', 'Var', (144, 153))	('KDM3B', 'Gene', (176, 181))	('CDC73', 'Gene', (70, 75))	('CDC73', 'Gene', '79577', (70, 75))	('FBXW7', 'Gene', (165, 170))	('FBXW7', 'Gene', '55294', (51, 56))	('NYNRIN', 'Gene', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('mutations', 'Var', (38, 47))	('TRIM28', 'Gene', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('FBXW7', 'Gene', '55294', (165, 170))	('TRIM28', 'Gene', '10155', (157, 163))	('tumors', 'Disease', (226, 232))	('KDM3B', 'Gene', '51780', (176, 181))	('FBXW7', 'Gene', (51, 56))
564556	33194750	Two recent WGS and WES studies have identified new pathogenic germline variants in CHEK2 and PALB2 in children with sporadic WT.	('pathogenic', 'Reg', (51, 61))	('CHEK2', 'Gene', '11200', (83, 88))	('CHEK2', 'Gene', (83, 88))	('germline', 'Var', (62, 70))	('WT', 'Phenotype', 'HP:0002667', (125, 127))	('PALB2', 'Gene', '79728', (93, 98))	('children', 'Species', '9606', (102, 110))	('PALB2', 'Gene', (93, 98))
564558	33194750	Germline mutations in REST and TRIM28, in addition to their role of familial WT predisposition genes, are also responsible for uncommon sporadic cases.	('Germline mutations', 'Var', (0, 18))	('responsible', 'Reg', (111, 122))	('TRIM28', 'Gene', (31, 37))	('WT', 'Phenotype', 'HP:0002667', (77, 79))	('REST', 'Gene', (22, 26))	('TRIM28', 'Gene', '10155', (31, 37))
564559	33194750	Additional pathogenic and likely pathogenic variants were identified in predisposition genes such as TP53, DIS3L2, and MLLT1, but also in candidate genes like EP300, HDAC4, HACE1, ARID1A, NF1, MYCN, and GLI3, that need to be validated in independent cohorts.	('HACE1', 'Gene', (173, 178))	('HDAC4', 'Gene', '9759', (166, 171))	('NF1', 'Gene', '4763', (188, 191))	('TP53', 'Gene', (101, 105))	('DIS3L2', 'Gene', '129563', (107, 113))	('DIS3L2', 'Gene', (107, 113))	('HDAC4', 'Gene', (166, 171))	('EP', 'Phenotype', 'HP:0002888', (159, 161))	('MLLT1', 'Gene', (119, 124))	('NF1', 'Gene', (188, 191))	('MYCN', 'Gene', (193, 197))	('pathogenic', 'Reg', (11, 21))	('TP53', 'Gene', '7157', (101, 105))	('pathogenic', 'CPA', (33, 43))	('EP300', 'Gene', '2033', (159, 164))	('ARID1A', 'Gene', (180, 186))	('GLI3', 'Gene', '2737', (203, 207))	('MLLT1', 'Gene', '4298', (119, 124))	('GLI3', 'Gene', (203, 207))	('HACE1', 'Gene', '57531', (173, 178))	('ARID1A', 'Gene', '8289', (180, 186))	('EP300', 'Gene', (159, 164))	('MYCN', 'Gene', '4613', (193, 197))	('variants', 'Var', (44, 52))
564560	33194750	Finally, exome and transcriptome sequencing studies have revealed constitutional mutations in the miRNA processing genes DROSHA, DGCR8, DICER1, and XPO5, some of which associated with the blastemal subtype of WT.	('XPO5', 'Gene', (148, 152))	('XPO5', 'Gene', '57510', (148, 152))	('DGCR8', 'Gene', (129, 134))	('WT', 'Phenotype', 'HP:0002667', (209, 211))	('associated with', 'Reg', (168, 183))	('DROSHA', 'Gene', '29102', (121, 127))	('DROSHA', 'Gene', (121, 127))	('mutations', 'Var', (81, 90))	('DGCR8', 'Gene', '54487', (129, 134))	('OS', 'Phenotype', 'HP:0002669', (123, 125))	('DICER1', 'Gene', (136, 142))	('blastemal subtype', 'Disease', (188, 205))	('DICER1', 'Gene', '23405', (136, 142))
564561	33194750	They identified two significant SNPs at 2p24 (rs807624 and rs3755132), in the promoter of DDX1, and one SNP at 11q14 (rs790356) located near DLG2.	('rs790356', 'Mutation', 'rs790356', (118, 126))	('rs807624', 'Mutation', 'rs807624', (46, 54))	('p24', 'Gene', (41, 44))	('rs807624', 'Var', (46, 54))	('rs3755132', 'Mutation', 'rs3755132', (59, 68))	('DLG2', 'Gene', (141, 145))	('p24', 'Gene', '140767', (41, 44))	('rs790356', 'Var', (118, 126))	('DDX1', 'Gene', '1653', (90, 94))	('DDX1', 'Gene', (90, 94))	('rs3755132', 'Var', (59, 68))	('DLG2', 'Gene', '1740', (141, 145))
564563	33194750	More recently, the group of Fu and colleagues performed two candidate gene studies on Southern Chinese populations and found a significant association between WT risk and BARD1 and KRAS polymorphisms, respectively.	('BARD1', 'Gene', '580', (171, 176))	('AS', 'Phenotype', 'HP:0009592', (183, 185))	('BARD1', 'Gene', (171, 176))	('polymorphisms', 'Var', (186, 199))	('KRAS', 'Gene', (181, 185))	('WT', 'Phenotype', 'HP:0002667', (159, 161))	('KRAS', 'Gene', '3845', (181, 185))
564564	33194750	In addition to karyotypic abnormalities affecting 11p13 and 11p15, a very small number of WT patients with gain of entire chromosomes have been reported, specifically with trisomy 18 and trisomy 13.	('trisomy 18', 'Var', (172, 182))	('trisomy 13', 'Var', (187, 197))	('patients', 'Species', '9606', (93, 101))	('WT', 'Phenotype', 'HP:0002667', (90, 92))
564577	33194750	Targeted gene sequencing and WGS and WES studies have identified uncommon variants in tumor-suppressor and cancer predisposition genes (Table 1), while candidate gene, pathway studies, and GWAS have discovered common variants in genes involved in several key pathways for OS development (Table 3).	('AS', 'Phenotype', 'HP:0009592', (191, 193))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (86, 91))	('variants', 'Var', (217, 225))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('OS', 'Phenotype', 'HP:0002669', (272, 274))	('variants', 'Var', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cancer', 'Disease', (107, 113))
564578	33194750	In 2015, a sequencing study on 765 germline DNA samples showed the presence of uncommon TP53 germline variants that could contribute to OS development; 3.8% of these variants were associated with LFS, and 5.7% were uncommon exonic variants of uncertain clinical significance.	('variants', 'Var', (102, 110))	('LFS', 'Disease', (196, 199))	('contribute', 'Reg', (122, 132))	('associated', 'Reg', (180, 190))	('OS', 'Phenotype', 'HP:0002669', (136, 138))	('OS development', 'CPA', (136, 150))	('LFS', 'Disease', 'MESH:D016864', (196, 199))	('TP53', 'Gene', '7157', (88, 92))	('variants', 'Var', (166, 174))	('TP53', 'Gene', (88, 92))
564579	33194750	Another sequencing study on 1120 cases found 7/39 OS patients carrying pathogenic and likely pathogenic variants in TP53, RB1, APC, MSH2, and PALB2.	('TP53', 'Gene', (116, 120))	('RB', 'Phenotype', 'HP:0009919', (122, 124))	('RB1', 'Gene', '5925', (122, 125))	('patients', 'Species', '9606', (53, 61))	('OS', 'Phenotype', 'HP:0002669', (50, 52))	('APC', 'Disease', 'MESH:D011125', (127, 130))	('variants', 'Var', (104, 112))	('pathogenic', 'Reg', (71, 81))	('APC', 'Disease', (127, 130))	('MSH2', 'Gene', (132, 136))	('TP53', 'Gene', '7157', (116, 120))	('PALB2', 'Gene', '79728', (142, 147))	('RB1', 'Gene', (122, 125))	('MSH2', 'Gene', '4436', (132, 136))	('PALB2', 'Gene', (142, 147))
564580	33194750	In 2016, a targeted exon sequencing on 1162 patients with sarcoma found that >50% of all patients carried pathogenic variants in TP53, BRCA2, ATM, ATR, and in ERCC2.	('ERCC2', 'Gene', '2068', (159, 164))	('ATM', 'Gene', '472', (142, 145))	('BRCA2', 'Gene', (135, 140))	('patients', 'Species', '9606', (44, 52))	('ERCC2', 'Gene', (159, 164))	('ATR', 'Gene', '545', (147, 150))	('ATR', 'Gene', (147, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('variants', 'Var', (117, 125))	('BRCA2', 'Gene', '675', (135, 140))	('TP53', 'Gene', '7157', (129, 133))	('patients', 'Species', '9606', (89, 97))	('pathogenic', 'Reg', (106, 116))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('TP53', 'Gene', (129, 133))	('sarcoma', 'Disease', (58, 65))	('ATM', 'Gene', (142, 145))
564581	33194750	Among 11% of patients with OS, one patient showed a probable pathogenic variant in ERCC2.	('patient', 'Species', '9606', (13, 20))	('patients', 'Species', '9606', (13, 21))	('ERCC2', 'Gene', (83, 88))	('pathogenic', 'Reg', (61, 71))	('patient', 'Species', '9606', (35, 42))	('OS', 'Phenotype', 'HP:0002669', (27, 29))	('variant', 'Var', (72, 79))	('ERCC2', 'Gene', '2068', (83, 88))
564582	33194750	In the same work, an excess of functionally pathogenic variants in ERCC2 was found to enhance cell sensitivity to cisplatin, commonly used in the treatment of OS.	('OS', 'Phenotype', 'HP:0002669', (159, 161))	('enhance', 'PosReg', (86, 93))	('variants', 'Var', (55, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('ERCC2', 'Gene', '2068', (67, 72))	('ERCC2', 'Gene', (67, 72))	('cell sensitivity to cisplatin', 'MPA', (94, 123))
564583	33194750	Recently, a sequencing study of 1244 OS patients showed that 28% of patients carried pathogenic and likely pathogenic variants in OS susceptibility genes, identifying new candidates (CDKN2A, MEN1, VHL, POT1, and ATRX) that require further confirmation in independent cohorts.	('CDKN2A', 'Gene', (183, 189))	('OS', 'Phenotype', 'HP:0002669', (37, 39))	('VHL', 'Gene', (197, 200))	('ATRX', 'Gene', (212, 216))	('pathogenic', 'CPA', (107, 117))	('CDKN2A', 'Gene', '1029', (183, 189))	('VHL', 'Gene', '7428', (197, 200))	('variants', 'Var', (118, 126))	('MEN1', 'Gene', '4221', (191, 195))	('POT1', 'Gene', '25913', (202, 206))	('patients', 'Species', '9606', (40, 48))	('MEN1', 'Gene', (191, 195))	('ATRX', 'Gene', '546', (212, 216))	('patients', 'Species', '9606', (68, 76))	('OS', 'Phenotype', 'HP:0002669', (130, 132))	('POT1', 'Gene', (202, 206))	('pathogenic', 'Reg', (85, 95))
564584	33194750	In 2013, the first GWAS study on 941 cases and 3291 controls of European ancestry, identified two risk loci, one at 6p21.3 (rs1906953) mapping in intron 7 of GRM4, and the other at 2p25.2 (rs7591996) in an intergenic region.	('GRM4', 'Gene', '2914', (158, 162))	('rs1906953', 'Mutation', 'rs1906953', (124, 133))	('AS', 'Phenotype', 'HP:0009592', (21, 23))	('rs1906953', 'Var', (124, 133))	('rs7591996', 'Mutation', 'rs7591996', (189, 198))	('rs7591996', 'Var', (189, 198))	('GRM4', 'Gene', (158, 162))
564585	33194750	Subsequently, a GWAS study on OS metastasis at diagnosis identified rs7034162 at 9p24.1 (in NFIB) associated with metastasis.	('p24', 'Gene', (82, 85))	('rs7034162', 'Var', (68, 77))	('p24', 'Gene', '140767', (82, 85))	('metastasis', 'Disease', (114, 124))	('OS', 'Phenotype', 'HP:0002669', (30, 32))	('NFIB', 'Gene', (92, 96))	('rs7034162', 'Mutation', 'rs7034162', (68, 77))	('NFIB', 'Gene', '4781', (92, 96))	('AS', 'Phenotype', 'HP:0009592', (18, 20))	('associated', 'Reg', (98, 108))
564586	33194750	Functional investigations showed that reduced NFIB expression, due to the risk allele of the rs7034162 SNP, promoted an increase of OS cell migration, proliferation, and colony formation.	('OS', 'Phenotype', 'HP:0002669', (132, 134))	('colony formation', 'CPA', (170, 186))	('reduced', 'NegReg', (38, 45))	('proliferation', 'CPA', (151, 164))	('NFIB', 'Gene', (46, 50))	('OS cell migration', 'CPA', (132, 149))	('NFIB', 'Gene', '4781', (46, 50))	('rs7034162', 'Var', (93, 102))	('expression', 'MPA', (51, 61))	('increase', 'PosReg', (120, 128))	('rs7034162', 'Mutation', 'rs7034162', (93, 102))
564587	33194750	In 2016, a case-control study identified that, for SNPs in genes associated with inter-individual variation in leukocyte telomere length (LTL) (ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, and RTEL1), the allele associated with longer LTL increased OS risk, mainly rs9420907 in OBFC1.	('ACYP2', 'Gene', '98', (144, 149))	('TERC', 'Gene', (151, 155))	('CTC1', 'Gene', (176, 180))	('OS', 'Phenotype', 'HP:0002669', (242, 244))	('NAF1', 'Gene', '92345', (157, 161))	('rs9420907', 'Var', (258, 267))	('TERT', 'Gene', (163, 167))	('TERT', 'Gene', '7015', (163, 167))	('RTEL1', 'Gene', (186, 191))	('NAF1', 'Gene', (157, 161))	('OBFC1', 'Gene', (169, 174))	('CTC1', 'Gene', '80169', (176, 180))	('rs9420907', 'Mutation', 'rs9420907', (258, 267))	('OBFC1', 'Gene', '79991', (169, 174))	('increased', 'PosReg', (232, 241))	('OBFC1', 'Gene', (271, 276))	('OBFC1', 'Gene', '79991', (271, 276))	('TERC', 'Gene', '7012', (151, 155))	('ACYP2', 'Gene', (144, 149))	('RTEL1', 'Gene', '51750', (186, 191))
564589	33194750	Next to the heterogeneous somatic CNV scenario present in OS, in a study conducted on 54 patients with childhood tumor, two large germinal CNVs were identified in 2 OS patients: dup4q13.33 of 476 kb containing STATH, CSN1S2B, CABS1, CSN1S1, CSN2, HTN3, HTN1, CSN1S2A, C4orf40, ODAM, FDCSP, and CSN3; and dup18q21.33 of 600 kb containing RNF152, CDH20, and PIGN.	('CSN1S2A', 'Gene', (259, 266))	('PIGN', 'Gene', '23556', (356, 360))	('CSN1S1', 'Gene', '1446', (233, 239))	('CABS1', 'Gene', '85438', (226, 231))	('OS', 'Phenotype', 'HP:0002669', (165, 167))	('STATH', 'Gene', (210, 215))	('child', 'Species', '9606', (103, 108))	('CDH20', 'Gene', '28316', (345, 350))	('RNF152', 'Gene', '220441', (337, 343))	('HTN1', 'Gene', (253, 257))	('CSN1S2B', 'Gene', (217, 224))	('CSN3', 'Gene', '1448', (294, 298))	('CSN1S2A', 'Gene', '286828', (259, 266))	('CDH20', 'Gene', (345, 350))	('CSN1S1', 'Gene', (233, 239))	('HTN3', 'Gene', (247, 251))	('CSN2', 'Gene', '1447', (241, 245))	('C4orf40', 'Gene', (268, 275))	('STATH', 'Gene', '6779', (210, 215))	('OS', 'Phenotype', 'HP:0002669', (58, 60))	('RNF152', 'Gene', (337, 343))	('tumor', 'Disease', (113, 118))	('CSN3', 'Gene', (294, 298))	('HTN3', 'Gene', '3347', (247, 251))	('CSN1S2B', 'Gene', '100337616', (217, 224))	('PIGN', 'Gene', (356, 360))	('CSN2', 'Gene', (241, 245))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('FDCSP', 'Gene', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('ODAM', 'Gene', (277, 281))	('dup4q13.33 of 476 kb', 'Var', (178, 198))	('FDCSP', 'Gene', '260436', (283, 288))	('dup18q21.33 of 600 kb', 'Var', (304, 325))	('ODAM', 'Gene', '54959', (277, 281))	('HTN1', 'Gene', '3346', (253, 257))	('patients', 'Species', '9606', (89, 97))	('C4orf40', 'Gene', '401137', (268, 275))	('patients', 'Species', '9606', (168, 176))	('CABS1', 'Gene', (226, 231))
564590	33194750	In 2020, a duplication of DDX10 in an OS patient with a germline variant in GJB2 has been reported.	('variant', 'Var', (65, 72))	('GJB2', 'Gene', '2706', (76, 80))	('patient', 'Species', '9606', (41, 48))	('duplication', 'Var', (11, 22))	('OS', 'Phenotype', 'HP:0002669', (38, 40))	('GJB2', 'Gene', (76, 80))	('DDX10', 'Gene', (26, 31))	('DDX10', 'Gene', '1662', (26, 31))
564593	33194750	At somatic level, ARMS is often associated with fusion of FOXO and PAX3 or PAX7, while ERMS does not show such translocations, but it is characterized by loss of heterozygosity at 11p15.5 as well as mutations in TP53, NRAS, KRAS, HRAS, PIK3CA, CTNNB1, and FGFR4.	('ARMS', 'Disease', (18, 22))	('PIK3CA', 'Gene', (236, 242))	('NRAS', 'Gene', (218, 222))	('AS', 'Phenotype', 'HP:0009592', (226, 228))	('FGFR4', 'Gene', '2264', (256, 261))	('associated', 'Reg', (32, 42))	('CTNNB1', 'Gene', (244, 250))	('mutations', 'Var', (199, 208))	('AS', 'Phenotype', 'HP:0009592', (232, 234))	('KRAS', 'Gene', '3845', (224, 228))	('PAX7', 'Gene', '5081', (75, 79))	('FGFR4', 'Gene', (256, 261))	('RMS', 'Phenotype', 'HP:0002859', (19, 22))	('TP53', 'Gene', '7157', (212, 216))	('KRAS', 'Gene', (224, 228))	('PAX7', 'Gene', (75, 79))	('PIK3CA', 'Gene', '5290', (236, 242))	('NB', 'Phenotype', 'HP:0003006', (247, 249))	('PAX3', 'Gene', (67, 71))	('NRAS', 'Gene', '4893', (218, 222))	('RMS', 'Phenotype', 'HP:0002859', (88, 91))	('HRAS', 'Gene', '3265', (230, 234))	('CTNNB1', 'Gene', '1499', (244, 250))	('HRAS', 'Gene', (230, 234))	('PAX3', 'Gene', '5077', (67, 71))	('AS', 'Phenotype', 'HP:0009592', (220, 222))	('TP53', 'Gene', (212, 216))
564596	33194750	Among syndromes commonly associated with RMS and reported in Table 2, a high RMS risk is associated with RASopathies-like type I neurofibromatosis (NF1) (deletions in NF1), Costello syndrome (HRAS mutations), and Noonan syndrome (germline variants activating RAS-MAPK pathway), highlighting the tight dependence of RMS on the RAS pathway, which results to be activated in 40% of sporadic ERMS.	('Costello syndrome', 'Disease', (173, 190))	('NF1', 'Gene', (167, 170))	('Noonan syndrome', 'Disease', (213, 228))	('AS', 'Phenotype', 'HP:0009592', (194, 196))	('NF1', 'Gene', '4763', (148, 151))	('deletions', 'Var', (154, 163))	('RMS', 'Disease', (77, 80))	('AS', 'Phenotype', 'HP:0009592', (106, 108))	('HRAS', 'Gene', '3265', (192, 196))	('AS', 'Phenotype', 'HP:0009592', (327, 329))	('RASopathies-like type I neurofibromatosis (NF1)', 'Gene', '4763', (105, 152))	('HRAS', 'Gene', (192, 196))	('NF1', 'Gene', (148, 151))	('RMS', 'Phenotype', 'HP:0002859', (41, 44))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (129, 146))	('RMS', 'Phenotype', 'HP:0002859', (389, 392))	('Noonan syndrome', 'Disease', 'MESH:D009634', (213, 228))	('Costello syndrome', 'Disease', 'MESH:D056685', (173, 190))	('AS', 'Phenotype', 'HP:0009592', (260, 262))	('NF1', 'Gene', '4763', (167, 170))	('RMS', 'Phenotype', 'HP:0002859', (77, 80))	('RASopathies-like type I neurofibromatosis (NF1', 'Gene', (105, 151))	('RMS', 'Phenotype', 'HP:0002859', (315, 318))
564599	33194750	Unlike OS and Ewing sarcoma, GWAS studies for RMS have not been published and few studies identified uncommon germline variants associated with tumor susceptibility (Table 1).	('tumor', 'Disease', (144, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('Ewing sarcoma', 'Gene', '2130', (14, 27))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (14, 27))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('associated', 'Reg', (128, 138))	('Ewing sarcoma', 'Gene', (14, 27))	('OS', 'Phenotype', 'HP:0002669', (7, 9))	('AS', 'Phenotype', 'HP:0009592', (31, 33))	('RMS', 'Phenotype', 'HP:0002859', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('variants', 'Var', (119, 127))
564600	33194750	Many studies have found the presence of DICER1 germline mutations in sporadic RMS patients for whom DICER syndrome has been ruled out.	('RMS', 'Phenotype', 'HP:0002859', (78, 81))	('DICER', 'Gene', (100, 105))	('germline mutations', 'Var', (47, 65))	('patients', 'Species', '9606', (82, 90))	('DICER', 'Gene', '23405', (40, 45))	('DICER1', 'Gene', '23405', (40, 46))	('DICER', 'Gene', (40, 45))	('DICER1', 'Gene', (40, 46))	('RMS', 'Disease', (78, 81))	('DICER', 'Gene', '23405', (100, 105))
564601	33194750	WES and WGS on 1,120 patients with pediatric cancers identified germline pathogenic variants in 3/43 RMS patients in TP53 and BRCA2.	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('pathogenic', 'Reg', (73, 83))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('RMS', 'Disease', (101, 104))	('BRCA2', 'Gene', (126, 131))	('patients', 'Species', '9606', (21, 29))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('variants', 'Var', (84, 92))	('RMS', 'Phenotype', 'HP:0002859', (101, 104))	('cancers', 'Disease', (45, 52))	('BRCA2', 'Gene', '675', (126, 131))
564602	33194750	In a cohort of 66 patients with sarcoma, one patient with ARMS showed a protein-truncating variant (in ERCC4) co-occurring with predicted pathogenic mutations (in ATM, FANCI, and MSH6), suggesting a possible collective impact of these genetic variants on DNA repair and genomic instability, therefore conferring susceptibility to tumorigenesis.	('tumor', 'Disease', (330, 335))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('patient', 'Species', '9606', (18, 25))	('FANCI', 'Gene', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('ATM', 'Gene', '472', (163, 166))	('RMS', 'Phenotype', 'HP:0002859', (59, 62))	('FANCI', 'Gene', '55215', (168, 173))	('MSH6', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('susceptibility', 'Reg', (312, 326))	('MSH6', 'Gene', '2956', (179, 183))	('patient', 'Species', '9606', (45, 52))	('patients', 'Species', '9606', (18, 26))	('ATM', 'Gene', (163, 166))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('sarcoma', 'Disease', (32, 39))	('ERCC4', 'Gene', '2072', (103, 108))	('impact', 'Reg', (219, 225))	('ERCC4', 'Gene', (103, 108))	('variants', 'Var', (243, 251))
564606	33194750	EWS is characterized by low somatic mutation rate, mainly including fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, that play a key role in its pathogenesis.	('EWSR1', 'Gene', '2130', (84, 89))	('FLI1', 'Gene', (140, 144))	('EWSR1', 'Gene', '2130', (134, 139))	('EWS', 'Phenotype', 'HP:0012254', (84, 87))	('EWSR1', 'Gene', (84, 89))	('fusions', 'Var', (68, 75))	('EWS', 'Gene', '2130', (84, 87))	('EWS', 'Gene', (84, 87))	('EWS', 'Phenotype', 'HP:0012254', (134, 137))	('FLI1', 'Gene', '2313', (140, 144))	('EWS', 'Phenotype', 'HP:0012254', (0, 3))	('EWS', 'Gene', '2130', (134, 137))	('EWSR1', 'Gene', (134, 139))	('EWS', 'Gene', (134, 137))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
564611	33194750	WES, WGS, and GWAS studies have led to the identification of uncommon (Table 1) and common (Table 3) germline variants associated with the risk of developing EWS.	('AS', 'Phenotype', 'HP:0009592', (16, 18))	('variants', 'Var', (110, 118))	('EWS', 'Phenotype', 'HP:0012254', (158, 161))	('EWS', 'Gene', '2130', (158, 161))	('EWS', 'Gene', (158, 161))	('associated', 'Reg', (119, 129))
564613	33194750	Two WGS and WES studies on EWS revealed an over-representation of uncommon pathogenic and likely pathogenic variants in DNA repair and cancer-predisposing syndrome genes.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('pathogenic', 'Reg', (75, 85))	('EWS', 'Gene', (27, 30))	('variants', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('EWS', 'Phenotype', 'HP:0012254', (27, 30))	('EWS', 'Gene', '2130', (27, 30))	('DNA repair', 'Gene', (120, 130))
564615	33194750	In 2012, the first GWAS on EWS found 3 susceptibility loci at 1p36.22, 10q21, and 15q15, identifying a strong association of EWS risk with rs9430161 (25 kb upstream of TARDBP) and rs224278 (5 kb upstream of EGR2), and a modest association with rs4924410 (at 15q15).	('EWS', 'Phenotype', 'HP:0012254', (125, 128))	('rs9430161', 'Mutation', 'rs9430161', (139, 148))	('rs4924410', 'Mutation', 'rs4924410', (244, 253))	('EWS', 'Gene', (125, 128))	('EWS', 'Gene', '2130', (125, 128))	('AS', 'Phenotype', 'HP:0009592', (21, 23))	('EGR2', 'Gene', '1959', (207, 211))	('EGR2', 'Gene', (207, 211))	('TARDBP', 'Gene', '23435', (168, 174))	('rs224278', 'Mutation', 'rs224278', (180, 188))	('rs4924410', 'Var', (244, 253))	('EWS', 'Phenotype', 'HP:0012254', (27, 30))	('rs9430161', 'Var', (139, 148))	('TARDBP', 'Gene', (168, 174))	('EWS', 'Gene', '2130', (27, 30))	('EWS', 'Gene', (27, 30))	('rs224278', 'Var', (180, 188))
564616	33194750	The second GWAS detected a tagging variant strongly associated with EWS at 15q.15.1 (rs2412476 near BMF) and new risk loci at 6p25.1, 20p11.22, and 20p11.23.	('rs2412476', 'Mutation', 'rs2412476', (85, 94))	('associated', 'Reg', (52, 62))	('AS', 'Phenotype', 'HP:0009592', (13, 15))	('rs2412476 near', 'Var', (85, 99))	('EWS', 'Phenotype', 'HP:0012254', (68, 71))	('EWS', 'Gene', '2130', (68, 71))	('EWS', 'Gene', (68, 71))
564618	33194750	Independent studies showed that a different number of germline GGAA repeats in polymorphic enhancer-like GGAA microsatellites impacts the binding between these regulatory elements and EWS cancer driver mutations (EWSR1-FLI1), affecting downstream genes expression.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('expression', 'MPA', (253, 263))	('FLI1', 'Gene', (219, 223))	('affecting', 'Reg', (226, 235))	('repeats', 'Var', (68, 75))	('FLI1', 'Gene', '2313', (219, 223))	('EWS', 'Phenotype', 'HP:0012254', (184, 187))	('EWSR1', 'Gene', '2130', (213, 218))	('EWS', 'Gene', (184, 187))	('EWS', 'Gene', '2130', (184, 187))	('binding', 'Interaction', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('impacts', 'Reg', (126, 133))	('EWS', 'Gene', '2130', (213, 216))	('EWS', 'Gene', (213, 216))	('cancer', 'Disease', (188, 194))	('EWS', 'Phenotype', 'HP:0012254', (213, 216))	('EWSR1', 'Gene', (213, 218))
564620	33194750	Only one study reports the presence of germline CNV associated with EWS, describing a 14-year-old male with EWS carrying an intragenic deletion in PTPRD.	('deletion', 'Var', (135, 143))	('EWS', 'Gene', '2130', (108, 111))	('EWS', 'Gene', (108, 111))	('EWS', 'Phenotype', 'HP:0012254', (108, 111))	('PTPRD', 'Gene', '5789', (147, 152))	('PTPRD', 'Gene', (147, 152))	('EWS', 'Phenotype', 'HP:0012254', (68, 71))	('EWS', 'Gene', '2130', (68, 71))	('EWS', 'Gene', (68, 71))
564621	33194750	Notably, germline and somatic variants in PTPRD have been already identified in a limited number of EWS patients.	('EWS', 'Phenotype', 'HP:0012254', (100, 103))	('variants', 'Var', (30, 38))	('identified', 'Reg', (66, 76))	('PTPRD', 'Gene', '5789', (42, 47))	('PTPRD', 'Gene', (42, 47))	('patients', 'Species', '9606', (104, 112))	('EWS', 'Gene', '2130', (100, 103))	('EWS', 'Gene', (100, 103))
564623	33194750	However, to date, WGS, WES, and GWAS studies performed on pediatric cancers have made it possible to highlight a strong contribution of germline variants to tumorigenesis, helping us to better understand the etiology underlying pediatric tumors.	('tumor', 'Disease', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('AS', 'Phenotype', 'HP:0009592', (34, 36))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('cancers', 'Disease', (68, 75))	('variants', 'Var', (145, 153))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Disease', (238, 243))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Disease', (238, 244))
564624	33194750	Indeed, an important body of work allows us to highlight that the prevalence of hereditable risk variants in pediatric solid cancers ranges between 6% and 18% (Figure 3).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('variants', 'Var', (97, 105))
564625	33194750	These variants generally affect the functions of genes belonging to biological processes linked to tumorigenesis, such as cell-cycle control, apoptosis, DNA repair, and transcriptional regulatory programs.	('tumor', 'Disease', (99, 104))	('variants', 'Var', (6, 14))	('apoptosis', 'CPA', (142, 151))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cell-cycle control', 'CPA', (122, 140))	('genes', 'Gene', (49, 54))	('transcriptional', 'CPA', (169, 184))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('functions', 'MPA', (36, 45))	('affect', 'Reg', (25, 31))
564629	33194750	It should be emphasized that the presence of germline variants in target therapeutic genes could improve current approaches of personalized therapy, making them more efficient and less toxic to patients.	('more', 'PosReg', (161, 165))	('improve', 'PosReg', (97, 104))	('germline variants', 'Var', (45, 62))	('patients', 'Species', '9606', (194, 202))
564631	33194750	Our literature review reveals that the presence of specific germline mutations is often associated with increased frequency of somatically acquired cancer-specific abnormalities (such as aberrations, rearrangements).	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('germline mutations', 'Var', (60, 78))
564634	33194750	A similar germline-somatic interaction has been proposed for MB; indeed, germline TP53 mutations are often found in combination with tumors characterized by catastrophic DNA chromothripsis.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('TP53', 'Gene', (82, 86))	('chromothripsis', 'Disease', 'MESH:D000072837', (174, 188))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('TP53', 'Gene', '7157', (82, 86))	('MB', 'Phenotype', 'HP:0002885', (61, 63))	('mutations', 'Var', (87, 96))	('found', 'Reg', (107, 112))	('chromothripsis', 'Disease', (174, 188))
564640	33194750	Confirming a germline contribution to the clinical heterogeneity, some studies have highlighted that specific pathogenic variants are much more common in specific tumor histotypes and these associations could be used for the management and stratification of patients.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('variants', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('patients', 'Species', '9606', (258, 266))
564645	33194750	A clinical management that includes a cancer genetic test not only is useful to indicate a modification of the surveillance that also integrates periodic and cancer specific diagnostic tests, but over time it will increase our knowledge of genetic risk variants and thus will give a clearer picture of cancer risk in children affected by genetic syndrome.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('children', 'Species', '9606', (317, 325))	('genetic syndrome', 'Disease', 'MESH:D030342', (338, 354))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('increase', 'PosReg', (214, 222))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('cancer', 'Disease', (38, 44))	('variants', 'Var', (253, 261))	('cancer', 'Disease', (302, 308))	('genetic syndrome', 'Disease', (338, 354))
564704	32712619	According to one report, staining for Ki-67 with MIB--1 was seen in 10% of patients and over 72% of all subtypes of angiosarcomas studied, indicating that these malignancies have a highly proliferative nature.	('angiosarcomas', 'Disease', (116, 129))	('Ki-67', 'Var', (38, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('angiosarcomas', 'Disease', 'MESH:D006394', (116, 129))	('malignancies', 'Disease', (161, 173))	('patients', 'Species', '9606', (75, 83))	('MIB--1', 'Gene', (49, 55))	('Ki-67', 'Chemical', '-', (38, 43))	('angiosarcomas', 'Phenotype', 'HP:0200058', (116, 129))	('died', 'Disease', (133, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('MIB--1', 'Gene', '57534', (49, 55))	('died', 'Disease', 'MESH:D003643', (133, 137))	('angiosarcoma', 'Phenotype', 'HP:0200058', (116, 128))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
564849	29263959	S-STS are frequently smaller than deep tumors, and as a result are associated with lower rates of distant metastasis and higher rates of disease-free survival (DFS).	('disease-free survival', 'CPA', (137, 158))	('deep tumors', 'Disease', 'MESH:D057887', (34, 45))	('S-STS', 'Var', (0, 5))	('distant metastasis', 'CPA', (98, 116))	('lower', 'NegReg', (83, 88))	('deep tumors', 'Disease', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('higher', 'PosReg', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
564990	22984684	The incidence of complications was significantly higher among the patients receiving chemotherapy compared with those not receiving chemotherapy (42.9%, 8.3%, respectively; p = 0.02).	('chemotherapy', 'Var', (85, 97))	('higher', 'PosReg', (49, 55))	('patients', 'Species', '9606', (66, 74))
565013	22984684	Our multivariate analysis also demonstrated higher OS and DSS rate for low grade tumor.	('OS', 'Chemical', '-', (51, 53))	('higher', 'PosReg', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('DSS', 'Gene', (58, 61))	('DSS', 'Gene', '5376', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('low grade', 'Var', (71, 80))	('tumor', 'Disease', (81, 86))
565114	31739284	LPP-AS2 (P = 0.039), MUC1 (P = 0.003), GAB2 (P =0.049), hsa-let-7i-5p (P < 0.001), hsa-let-7f-5p (P = 0.025), hsa-miR-101-3p (P = 0.028) and hsa-miR-1226-3p (P = 0.001) were significantly associated with survival in Kaplan-Meier analysis (Figure 3B-3G).	('LPP-AS2', 'Gene', (0, 7))	('associated with', 'Reg', (188, 203))	('hsa-let-7i', 'Gene', '406891', (56, 66))	('GAB2', 'Gene', '9846', (39, 43))	('hsa-let-7i', 'Gene', (56, 66))	('hsa-miR-1226', 'Gene', (141, 153))	('LPP-AS2', 'Gene', '339929', (0, 7))	('hsa-miR-1226', 'Gene', '100302232', (141, 153))	('hsa-miR-101-3p', 'Var', (110, 124))	('MUC1', 'Gene', (21, 25))	('MUC1', 'Gene', '4582', (21, 25))	('GAB2', 'Gene', (39, 43))
565148	31739284	In this study, hypergeometric testing and correlation analysis results of the ceRNAs network revealed that hsa-miR-1226-3p (miRNA), MUC1 (protein-coding RNA) and AL441992.1 (lncRNA) were significantly correlated.	('MUC1', 'Gene', (132, 136))	('AL441992.1', 'Var', (162, 172))	('MUC1', 'Gene', '4582', (132, 136))	('hsa-miR-1226', 'Gene', (107, 119))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('hsa-miR-1226', 'Gene', '100302232', (107, 119))	('correlated', 'Interaction', (201, 211))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('N', 'Chemical', 'MESH:D009584', (127, 128))	('N', 'Chemical', 'MESH:D009584', (178, 179))
565154	31739284	Aberrantly glycosylated MUC1 is often overexpressed in most human epithelial cancers, but not reported in mesenchymal cell originated STS.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('overexpressed', 'PosReg', (38, 51))	('cancers', 'Disease', (77, 84))	('STS', 'Phenotype', 'HP:0030448', (134, 137))	('Aberrantly glycosylated', 'Var', (0, 23))	('MUC1', 'Gene', (24, 28))	('MUC1', 'Gene', '4582', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (60, 65))
565199	31739284	Sections were incubated overnight in a humidified container at 4 C with the primary antibodies of MUC1 (1:100, ab109185; Abcam) and CD11c (1:100, ab52632, Abcam).	('1:100', 'Var', (139, 144))	('MUC1', 'Gene', (98, 102))	('MUC1', 'Gene', '4582', (98, 102))	('CD11c', 'Gene', '3687', (132, 137))	('CD11c', 'Gene', (132, 137))	('1:100', 'Var', (104, 109))
565203	31739284	To minimize bias, multiple databases including the Gene Expression Omnibus (GEO) (ID: GSE21050, GSE21122, GSE6481.	('GSE6481', 'Var', (106, 113))	('GSE21122', 'Var', (96, 104))	('GSE6481', 'Chemical', '-', (106, 113))
565384	27587965	reported that a disturbance in portal blood flow possibly results in segmental hepatic iron deposition.	('iron', 'Chemical', 'MESH:D007501', (87, 91))	('results in', 'Reg', (58, 68))	('portal blood flow', 'MPA', (31, 48))	('hepatic iron deposition', 'Phenotype', 'HP:0012465', (79, 102))	('disturbance', 'Var', (16, 27))
565477	22953099	No difference was noted between the patients treated with megavoltage radiation and with orthovoltage radiation in the type of sarcoma, location, or survival.	('patients', 'Species', '9606', (36, 44))	('megavoltage radiation', 'Var', (58, 79))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('sarcoma', 'Disease', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
565757	30194005	In addition to TP53, other recurrently mutated genes harboring putative driver or loss-offunction mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS.	('CTNNB1', 'Gene', (154, 160))	('FBXW7', 'Gene', '55294', (123, 128))	('UCS', 'Phenotype', 'HP:0002891', (192, 195))	('PTEN', 'Gene', (117, 121))	('loss-offunction', 'NegReg', (82, 97))	('PTEN', 'Gene', '5728', (117, 121))	('PIK3CA', 'Gene', (143, 149))	('FBXW7', 'Gene', (123, 128))	('mutations', 'Var', (98, 107))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('CTNNB1', 'Gene', '1499', (154, 160))	('KRAS', 'Gene', (137, 141))	('FGFR2', 'Gene', (130, 135))	('PIK3CA', 'Gene', '5290', (143, 149))	('FGFR2', 'Gene', '2263', (130, 135))	('KRAS', 'Gene', '3845', (137, 141))
565775	30194005	Other studies have shown consistent patterns of deletions, preserved across carcinoma and sarcoma components, also suggesting monoclonal origin.	('sarcoma', 'Disease', (90, 97))	('carcinoma', 'Disease', 'MESH:D002277', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('carcinoma', 'Disease', (76, 85))	('deletions', 'Var', (48, 57))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))
565785	30194005	Separately in both tissue types in each patient, using paired adjacent normal tissue as a contrast, we performed genome-wide SCA and targeted point mutation profiling, using SNP DNA microarrays and deep next-generation sequencing (NGS).	('patient', 'Species', '9606', (40, 47))	('SCA', 'Disease', (125, 128))	('point mutation', 'Var', (142, 156))
565799	30194005	To profile SCAs, we applied a haplotype-aware hidden Markov model (HMM), hapLOH, designed to detect acquired allelic imbalance, including those at low mutant cell fractions or exhibited in tumor samples of low cellularity.	('tumor', 'Disease', (189, 194))	('mutant', 'Var', (151, 157))	('imbalance', 'Phenotype', 'HP:0002172', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
565814	30194005	Mutations in TP53 were the most prevalent, detected in 12 of 18 (67%) samples from 6 of 9 patients (Figure 3).	('TP53', 'Gene', (13, 17))	('prevalent', 'Reg', (32, 41))	('Mutations', 'Var', (0, 9))	('detected', 'Reg', (43, 51))	('TP53', 'Gene', '7157', (13, 17))	('patients', 'Species', '9606', (90, 98))
565816	30194005	Mutations identified in the sarcomas were identical to those identified in their carcinoma counterparts with the exception of one mutation identified (18 of 19).	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('carcinoma', 'Disease', (81, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('sarcomas', 'Disease', (28, 36))	('carcinoma', 'Disease', 'MESH:D002277', (81, 90))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))
565817	30194005	A highly recurrent COSMIC PIK3CA E542K mutation was unique to subject 0609's sarcoma component.	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('E542K', 'Var', (33, 38))	('PIK3CA', 'Gene', '5290', (26, 32))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('E542K', 'Mutation', 'p.E542K', (33, 38))	('PIK3CA', 'Gene', (26, 32))
565818	30194005	Other highly recurrent COSMIC and putative driver mutations were identified in PIK3CA (E545K), KRAS (G12A and G12S), CTNBB1 (D32A) and TP53 (R175H and R273C), identified in both UCS component samples of 5 subjects.	('KRAS', 'Gene', '3845', (95, 99))	('CTNBB1', 'Gene', (117, 123))	('E545K', 'Mutation', 'p.E545K', (87, 92))	('R273C', 'SUBSTITUTION', 'None', (151, 156))	('D32A', 'Mutation', 'p.D32A', (125, 129))	('TP53', 'Gene', '7157', (135, 139))	('R175H', 'Var', (141, 146))	('G12A', 'Mutation', 'c.12G>A', (101, 105))	('E545K', 'Var', (87, 92))	('PIK3CA', 'Gene', (79, 85))	('D32A', 'Var', (125, 129))	('TP53', 'Gene', (135, 139))	('KRAS', 'Gene', (95, 99))	('G12S', 'Mutation', 'p.G12S', (110, 114))	('UCS', 'Phenotype', 'HP:0002891', (178, 181))	('PIK3CA', 'Gene', '5290', (79, 85))	('R273C', 'Var', (151, 156))	('R175H', 'Mutation', 'p.R175H', (141, 146))
565823	30194005	Where a mutation difference existed within components of a single patient, the sarcoma component harbored the additional mutation (a highly recurrent PIK3CA E542K mutation), hinting that in this case, the sarcoma may have evolved from the carcinoma.	('E542K mutation', 'Var', (157, 171))	('PIK3CA', 'Gene', (150, 156))	('sarcoma', 'Disease', (79, 86))	('sarcoma component harbored', 'Disease', 'MESH:C537062', (79, 105))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('carcinoma', 'Disease', 'MESH:D002277', (239, 248))	('E542K', 'Mutation', 'p.E542K', (157, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcoma', 'Disease', (205, 212))	('PIK3CA', 'Gene', '5290', (150, 156))	('sarcoma component harbored', 'Disease', (79, 105))	('patient', 'Species', '9606', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('carcinoma', 'Disease', (239, 248))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
565928	29215551	Mutations in CMG2 are linked to hyaline fibromatosis syndrome characterized, besides others, by the accumulation of hyaline material in connective tissues.	('CMG2', 'Gene', (13, 17))	('hyaline fibromatosis syndrome', 'Disease', (32, 61))	('hyaline material', 'Chemical', '-', (116, 132))	('Mutations', 'Var', (0, 9))	('hyaline fibromatosis syndrome', 'Disease', 'MESH:D057770', (32, 61))	('linked', 'Reg', (22, 28))
565929	29215551	Concordantly, a low CMG2 mRNA expression was shown to be an independent negative prognostic marker in breast carcinoma patients, and a knockdown of CMG2 significantly increased the invasiveness of prostate carcinoma cell lines.	('low', 'NegReg', (16, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('breast carcinoma', 'Disease', (102, 118))	('knockdown', 'Var', (135, 144))	('CMG2', 'Gene', (20, 24))	('patients', 'Species', '9606', (119, 127))	('breast carcinoma', 'Disease', 'MESH:D001943', (102, 118))	('invasiveness of prostate carcinoma', 'Disease', (181, 215))	('CMG2', 'Gene', (148, 152))	('mRNA expression', 'MPA', (25, 40))	('increased', 'PosReg', (167, 176))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (197, 215))	('breast carcinoma', 'Phenotype', 'HP:0003002', (102, 118))	('negative', 'NegReg', (72, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('invasiveness of prostate carcinoma', 'Disease', 'MESH:D011472', (181, 215))
565937	29215551	In a separate analysis of the different histological subtypes, the median expressions of the CMG2 mRNA in liposarcoma, fibrosarcoma, rhabdomyosarcoma, synovial sarcoma, and neuronal sarcoma were relatively similar (0.01-0.015 fg/fg HPRT), while the median CMG2 mRNA expression in leiomyosarcoma and NOS (not other specified) was slightly, but not significantly, increased (0.032 fg/fg HPRT and 0.026 fg/fg HPRT, respectively, see Figure 1a).	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (133, 149))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (119, 131))	('neuronal sarcoma', 'Disease', 'MESH:D012509', (173, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('0.01-0.015', 'Var', (215, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('HPRT', 'Gene', (406, 410))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (280, 294))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('synovial sarcoma', 'Disease', (151, 167))	('liposarcoma', 'Disease', (106, 117))	('HPRT', 'Gene', '3251', (385, 389))	('HPRT', 'Gene', (232, 236))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (280, 294))	('fibrosarcoma', 'Disease', 'MESH:D005354', (119, 131))	('fibrosarcoma', 'Disease', (119, 131))	('synovial sarcoma', 'Disease', 'MESH:D013584', (151, 167))	('rhabdomyosarcoma', 'Disease', (133, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('CMG2', 'Gene', (93, 97))	('HPRT', 'Gene', '3251', (406, 410))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (151, 167))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))	('HPRT', 'Gene', '3251', (232, 236))	('neuronal sarcoma', 'Disease', (173, 189))	('leiomyosarcoma', 'Disease', (280, 294))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (133, 149))	('liposarcoma', 'Disease', 'MESH:D008080', (106, 117))	('HPRT', 'Gene', (385, 389))
565947	29215551	A multivariate Cox's regression analysis adjusted to tumor localization, tumor stage, tumor entity, and resection mode revealed a 2.12-fold increased risk of cancer-related death for patients with a low CMG2 mRNA expression (p = 0.019; see Figure 3b).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('low', 'Var', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CMG2', 'Gene', (203, 207))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cancer', 'Disease', (158, 164))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Cox', 'Gene', '1351', (15, 18))	('tumor', 'Disease', (53, 58))	('mRNA expression', 'MPA', (208, 223))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('patients', 'Species', '9606', (183, 191))	('Cox', 'Gene', (15, 18))
565948	29215551	CMG2 protein expression was not significantly associated with soft tissue sarcoma patient survival (p = 0.07; log-rank test; see Figure 3c); however, the patient group with a low CMG2 protein expression also exhibited a decreased median survival time of 20 months in comparison to 86 months for patients with a high CMG2 protein expression.	('soft tissue sarcoma', 'Disease', (62, 81))	('CMG2', 'Gene', (179, 183))	('decreased', 'NegReg', (220, 229))	('patient', 'Species', '9606', (154, 161))	('patient', 'Species', '9606', (82, 89))	('patient', 'Species', '9606', (295, 302))	('patients', 'Species', '9606', (295, 303))	('low', 'Var', (175, 178))	('protein', 'Protein', (184, 191))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (62, 81))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (62, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
565954	29215551	Univariate Cox's regression analyses in these tumor entities showed a 1.4-fold increased relative risk for patients with a low CMG2 mRNA expression.	('mRNA expression', 'MPA', (132, 147))	('CMG2', 'Gene', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('tumor', 'Disease', (46, 51))	('low', 'Var', (123, 126))	('patients', 'Species', '9606', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
565964	29215551	Furthermore, as it was shown in the actual soft tissue sarcoma patient cohort, the elevated expression of combinations of uPA, uPAR, or PAI protein in the tumor tissue as well as in the serum of patients was significantly associated with a worsened survival.	('uPAR', 'Gene', (127, 131))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (43, 62))	('uPA', 'Gene', (127, 130))	('tumor', 'Disease', (155, 160))	('uPA', 'Gene', '5328', (127, 130))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (43, 62))	('elevated', 'PosReg', (83, 91))	('soft tissue sarcoma', 'Disease', (43, 62))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('patients', 'Species', '9606', (195, 203))	('patient', 'Species', '9606', (63, 70))	('uPAR', 'Gene', '5329', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('combinations', 'Var', (106, 118))	('worsened', 'NegReg', (240, 248))	('PAI', 'Gene', (136, 139))	('PAI', 'Gene', '5054', (136, 139))	('expression', 'MPA', (92, 102))	('survival', 'CPA', (249, 257))	('patient', 'Species', '9606', (195, 202))	('uPA', 'Gene', (122, 125))	('uPA', 'Gene', '5328', (122, 125))
565968	29215551	However, an in silico analysis (Available online: ) exhibited no direct regulation of CMG2 by miR-199a-5p or -3p or its cluster mate miR-214.	('miR-199a-5p', 'Var', (94, 105))	('miR-214', 'Gene', '406996', (133, 140))	('miR-214', 'Gene', (133, 140))	('CMG2', 'Gene', (86, 90))
565970	29215551	Furthermore, miR-199a was demonstrated to downregulate Smad4 expression and subsequently negatively regulate the TGF-beta signaling pathway.	('TGF-beta signaling pathway', 'Pathway', (113, 139))	('miR-199a', 'Var', (13, 21))	('Smad4', 'Gene', (55, 60))	('Smad4', 'Gene', '4089', (55, 60))	('downregulate', 'NegReg', (42, 54))	('expression', 'MPA', (61, 71))	('negatively regulate', 'NegReg', (89, 108))
565972	29215551	While miR-199a overexpression is detected in progressed gastric cancer and highly invasive melanoma, in renal cancer or testicular cancer miR-199a is considered a tumor suppressor gene.	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('testicular cancer', 'Disease', 'MESH:D013736', (120, 137))	('tumor', 'Disease', (163, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('miR-199a', 'Gene', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('miR-199a', 'Var', (138, 146))	('testicular cancer', 'Disease', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('renal cancer', 'Disease', (104, 116))	('testicular cancer', 'Phenotype', 'HP:0010788', (120, 137))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('overexpression', 'PosReg', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('renal cancer', 'Disease', 'MESH:D007680', (104, 116))	('gastric cancer', 'Disease', (56, 70))
565980	29215551	In breast cancer cell lines, a CMG2 knockdown results in a decreased proliferation and increased adherence of the cells.	('increased', 'PosReg', (87, 96))	('proliferation', 'CPA', (69, 82))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('decreased', 'NegReg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('knockdown', 'Var', (36, 45))	('CMG2', 'Gene', (31, 35))	('adherence of the cells', 'CPA', (97, 119))
565981	29215551	In contrary, a decreased adherence and no effects on proliferation due to a CMG2 knockdown was observed in prostate carcinoma cells.	('prostate carcinoma', 'Phenotype', 'HP:0012125', (107, 125))	('prostate carcinoma', 'Disease', (107, 125))	('prostate carcinoma', 'Disease', 'MESH:D011472', (107, 125))	('knockdown', 'Var', (81, 90))	('decreased', 'NegReg', (15, 24))	('adherence', 'CPA', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('CMG2', 'Gene', (76, 80))
565982	29215551	CMG2 mutations revealed that CMG2 protein is essential in mouse parturition by regulating the uterine collagen homeostasis, a function facilitated by CMG2 for instance by the mediation of collagen VI uptake.	('mouse', 'Species', '10090', (58, 63))	('uterine collagen homeostasis', 'MPA', (94, 122))	('CMG2', 'Gene', (150, 154))	('CMG2', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('regulating', 'Reg', (79, 89))	('CMG2', 'Gene', (29, 33))
565989	29215551	On the other hand, a CMG2-knockdown resulted in a decreased matrix adhesion in prostate carcinoma cells.	('matrix adhesion', 'CPA', (60, 75))	('prostate carcinoma', 'Disease', (79, 97))	('prostate carcinoma', 'Disease', 'MESH:D011472', (79, 97))	('CMG2-knockdown', 'Var', (21, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('decreased', 'NegReg', (50, 59))	('CMG2-knockdown', 'Gene', (21, 35))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (79, 97))
566007	28498454	Identification of SETD2-NF1 fusion gene in a pediatric spindle cell tumor with the chromosomal translocation t(3;17)(p21;q12) Spindle cell tumors are clinically heterogeneous but morphologically similar neoplasms.	('fusion', 'Var', (28, 34))	('tumor', 'Disease', (139, 144))	('SETD2', 'Gene', (18, 23))	('neoplasms', 'Phenotype', 'HP:0002664', (203, 212))	('NF1', 'Gene', (24, 27))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('neoplasm', 'Phenotype', 'HP:0002664', (203, 211))	('SETD2', 'Gene', '29072', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('neoplasms', 'Disease', 'MESH:D009369', (203, 212))	('t(3;17)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (109, 125))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('neoplasms', 'Disease', (203, 212))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('NF1', 'Gene', '4763', (24, 27))
566009	28498454	Distinct subgroups of spindle cell tumors are characterized by chromosomal translocations and also fusion genes.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('spindle cell tumors', 'Disease', 'MESH:D002277', (22, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('spindle cell tumors', 'Disease', (22, 41))	('fusion genes', 'Var', (99, 111))
566013	28498454	Karyotyping showed the tumor cells to carry a t(3;17)(p21;q12) chromosomal translocation whereas RNA sequencing identified a SETD2-NF1 fusion gene caused by the translocation.	('NF1', 'Gene', (131, 134))	('NF1', 'Gene', '4763', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('t(3;17)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SETD2', 'Gene', '29072', (125, 130))	('tumor', 'Disease', (23, 28))	('t(3;17)(p21;q12', 'Var', (46, 61))	('SETD2', 'Gene', (125, 130))
566015	28498454	The result would be similar to that seen with truncating SETD2 mutations in leukemias.	('mutations', 'Var', (63, 72))	('SETD2', 'Gene', '29072', (57, 62))	('leukemias', 'Phenotype', 'HP:0001909', (76, 85))	('leukemias', 'Disease', (76, 85))	('SETD2', 'Gene', (57, 62))	('leukemias', 'Disease', 'MESH:D007938', (76, 85))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))
566017	28498454	Alternatively, loss of one of two functional SETD2 alleles might be the crucial tumorigenic factor.	('SETD2', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('loss', 'Var', (15, 19))	('SETD2', 'Gene', '29072', (45, 50))
566022	28498454	Cytogenetic and molecular genetic analyses of spindle cell tumors have led to the recognition of several distinct karyotypic entities, presumably corresponding to equally distinct pathogenetic subgroups, characterized by chromosomal translocations and also fusion genes that identify specific tumor types.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('tumor', 'Disease', (59, 64))	('spindle cell tumors', 'Disease', 'MESH:D002277', (46, 65))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('fusion', 'Var', (257, 263))	('spindle cell tumors', 'Disease', (46, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', (293, 298))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
566024	28498454	Dermatofibrosarcoma protuberans, another subtype of spindle cell sarcoma, is characterized cytogenetically by supernumerary ring chromosomes or the translocation t(17;22)(q22;q13).	('Dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (0, 31))	('sarcoma', 'Disease', (65, 72))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('Dermatofibrosarcoma protuberans', 'Disease', (0, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('sarcoma', 'Disease', (12, 19))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (162, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('t(17;22)(q22;q13', 'Var', (162, 178))	('sarcoma', 'Disease', 'MESH:D012509', (65, 72))
566027	28498454	These rearrangements target the ALK gene which may serve as the 3'-partner in fusions with various translocation partners bringing about ALK tyrosine kinase activation.	('ALK', 'Gene', (32, 35))	('rearrangements', 'Var', (6, 20))	('ALK', 'Gene', (137, 140))	('ALK', 'Gene', '238', (32, 35))	('activation', 'PosReg', (157, 167))	('ALK', 'Gene', '238', (137, 140))
566028	28498454	Solitary fibrous tumor, another rare spindle cell tumor, is now defined genetically as carrying a submicroscopic inversion of the long arm of chromosome 12 (12q13) resulting in fusion of the two neighboring genes NAB2 and STAT6.	('fibrous tumor', 'Disease', (9, 22))	('tumor', 'Disease', (17, 22))	('fibrous tumor', 'Disease', 'MESH:D054364', (9, 22))	('NAB2', 'Gene', '4665', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('STAT6', 'Gene', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('STAT6', 'Gene', '6778', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('fusion', 'Var', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (50, 55))	('NAB2', 'Gene', (213, 217))
566034	28498454	In a previous study of ours, we described a spindle cell sarcoma that could not be further sub-classified, but which carried a ring chromosome composed of chromosome 12 material, several fusion genes mapping to 12q, and amplification of MDM2.	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('MDM2', 'Gene', '4193', (237, 241))	('amplification', 'Var', (220, 233))	('sarcoma', 'Disease', (57, 64))	('MDM2', 'Gene', (237, 241))
566035	28498454	Nord et al reported a spindle cell sarcoma of the heart with a ring chromosome, amplification of the MDM2 gene, and homozygous deletion of CDKN2A.	('amplification', 'Var', (80, 93))	('CDKN2A', 'Gene', '1029', (139, 145))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('sarcoma', 'Disease', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('CDKN2A', 'Gene', (139, 145))	('MDM2', 'Gene', '4193', (101, 105))	('MDM2', 'Gene', (101, 105))
566036	28498454	Finally, Lestou et al reported a case of spindle cell sarcoma in the lower abdominal wall with a complex karyotype, ring chromosomes, amplification of chromosome 18, and co-amplification of 12p11 and 12q13-q22 in the ring chromosomes.	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('sarcoma', 'Disease', (54, 61))	('amplification', 'Var', (134, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('co-amplification', 'Var', (170, 186))
566057	28498454	The clones were RP11-565B06 (chr3:46962826-47104129) and RP11-380M12 (chr3:47033474-47226748) mapping to chromosome subband 3p21.31 which contains the SETD2 gene (red signal), and RP11-518B17 (chr17:26576215-26749754) and RP11-592F3 (chr17:26705272-26874157) mapping to chromosome subband 17q11.2 which contains the NF1 gene (green signal).	('RP11', 'Gene', (180, 184))	('chr3:47033474-47226748', 'STRUCTURAL_ABNORMALITY', 'None', (70, 92))	('RP11', 'Gene', '26121', (57, 61))	('NF1', 'Gene', (316, 319))	('chr17:26576215-26749754', 'STRUCTURAL_ABNORMALITY', 'None', (193, 216))	('chr3:46962826-47104129', 'STRUCTURAL_ABNORMALITY', 'None', (29, 51))	('RP11', 'Gene', '26121', (222, 226))	('RP11', 'Gene', '26121', (16, 20))	('p21', 'Gene', (125, 128))	('RP11', 'Gene', (57, 61))	('RP11', 'Gene', '26121', (180, 184))	('p21', 'Gene', '644914', (125, 128))	('SETD2', 'Gene', (151, 156))	('chr17:26705272-26874157', 'Var', (234, 257))	('SETD2', 'Gene', '29072', (151, 156))	('RP11', 'Gene', (222, 226))	('RP11', 'Gene', (16, 20))	('chr17:26705272-26874157', 'STRUCTURAL_ABNORMALITY', 'None', (234, 257))	('NF1', 'Gene', '4763', (316, 319))
566058	28498454	The G-banding analysis of short-term cultured cells from both the core needle biopsy and surgical specimen yielded the karyotype 46,XY,t(3;17)(p21;q12),del(10)(q24)[11] (Fig.	('del(10)(q24)[11]', 'Var', (152, 168))	('t(3;17)(p21;q12', 'Var', (135, 150))	('46,XY,t(3;17)(p21;q12),del(10)(q24)', 'STRUCTURAL_ABNORMALITY', 'None', (129, 164))
566068	28498454	Fusion transcripts of both NF1 and SETD2 with various partners have been described in hematologic malignancies as well as solid tumors.	('hematologic malignancies', 'Disease', (86, 110))	('solid tumors', 'Disease', (122, 134))	('described', 'Reg', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Fusion transcripts', 'Var', (0, 18))	('NF1', 'Gene', (27, 30))	('SETD2', 'Gene', '29072', (35, 40))	('solid tumors', 'Disease', 'MESH:D009369', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('hematologic malignancies', 'Disease', 'MESH:D019337', (86, 110))	('SETD2', 'Gene', (35, 40))	('NF1', 'Gene', '4763', (27, 30))
566075	28498454	Deletion of the SRI domain in yeast Set2 abolishes H3K36 methylation, which in turn prevents elongation by RNA polymerase II.	('prevents', 'NegReg', (84, 92))	('yeast', 'Species', '4932', (30, 35))	('methylation', 'MPA', (57, 68))	('elongation', 'MPA', (93, 103))	('H3', 'Chemical', 'MESH:C012616', (51, 53))	('abolishes', 'NegReg', (41, 50))	('H3K36', 'Protein', (51, 56))	('Deletion', 'Var', (0, 8))
566078	28498454	Inactivation of SETD is common in clear cell renal carcinoma with loss or decrease of H3K36me3 mark, when it is associated with worse prognosis and development of recurrent and/or metastatic disease.	('H3', 'Chemical', 'MESH:C012616', (86, 88))	('SETD', 'Gene', (16, 20))	('clear cell renal carcinoma with loss', 'Disease', (34, 70))	('decrease', 'NegReg', (74, 82))	('clear cell renal carcinoma with loss', 'Disease', 'MESH:C538614', (34, 70))	('H3K36me3 mark', 'Protein', (86, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('Inactivation', 'Var', (0, 12))	('renal carcinoma', 'Phenotype', 'HP:0005584', (45, 60))
566081	28498454	SETD2 mutations were also described in high-grade gliomas and in leukemias.	('leukemia', 'Phenotype', 'HP:0001909', (65, 73))	('gliomas', 'Disease', (50, 57))	('leukemias', 'Disease', 'MESH:D007938', (65, 74))	('SETD2', 'Gene', '29072', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('SETD2', 'Gene', (0, 5))	('described', 'Reg', (26, 35))	('leukemias', 'Phenotype', 'HP:0001909', (65, 74))	('mutations', 'Var', (6, 15))	('leukemias', 'Disease', (65, 74))
566082	28498454	The mutations are either nonsense or frameshift mutations that truncate a portion of the C terminus domain of SETD2.	('SETD2', 'Gene', '29072', (110, 115))	('SETD2', 'Gene', (110, 115))	('frameshift', 'Var', (37, 47))	('truncate', 'NegReg', (63, 71))
566083	28498454	Truncating mutations result in loss of the C terminus SRI domain which is responsible for the recruitment of SETD2 to its target gene locus through binding to the phosphor-C-terminal repeat domain (PCTD) of elongating RNA polymerase II.	('recruitment', 'MPA', (94, 105))	('SETD2', 'Gene', '29072', (109, 114))	('loss', 'NegReg', (31, 35))	('SETD2', 'Gene', (109, 114))	('binding', 'Interaction', (148, 155))	('Truncating', 'Var', (0, 10))	('C terminus', 'MPA', (43, 53))
566084	28498454	Recently, genomic disruption of SETD2 was reported in chronic lymphocytic leukemia and the data suggested that SETD2 aberrations may be clinically relevant.	('SETD2', 'Gene', '29072', (32, 37))	('genomic disruption', 'Var', (10, 28))	('lymphocytic leukemia', 'Disease', (62, 82))	('SETD2', 'Gene', (32, 37))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (62, 82))	('reported', 'Reg', (42, 50))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (54, 82))	('SETD2', 'Gene', '29072', (111, 116))	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('SETD2', 'Gene', (111, 116))
566085	28498454	Patients with SETD2 abnormalities and wild-type TP53 and ATM had significantly shorter progression-free and overall survival compared with cases with wild-type for all three genes.	('TP53', 'Gene', '7157', (48, 52))	('overall survival', 'CPA', (108, 124))	('shorter', 'NegReg', (79, 86))	('TP53', 'Gene', (48, 52))	('ATM', 'Gene', (57, 60))	('Patients', 'Species', '9606', (0, 8))	('SETD2', 'Gene', '29072', (14, 19))	('SETD2', 'Gene', (14, 19))	('ATM', 'Gene', '472', (57, 60))	('abnormalities', 'Var', (20, 33))
566086	28498454	In malignant mesotheliomas, a combination of the methods array comparative genomic hybridization and targeted next-generation sequencing revealed biallelic SETD2 inactivation in 9 out of 33 examined tumors.	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (3, 26))	('tumors', 'Disease', (199, 205))	('SETD2', 'Gene', '29072', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('malignant mesotheliomas', 'Disease', (3, 26))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (3, 26))	('SETD2', 'Gene', (156, 161))	('inactivation', 'Var', (162, 174))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('biallelic', 'Var', (146, 155))
566087	28498454	Gene fusions and splice alterations were also reported to be frequent mechanisms for SETD2 inactivation.	('SETD2', 'Gene', '29072', (85, 90))	('Gene fusions', 'Var', (0, 12))	('SETD2', 'Gene', (85, 90))	('inactivation', 'NegReg', (91, 103))	('splice alterations', 'Var', (17, 35))
566092	28498454	The NF1 gene is a classical tumor suppressor gene whose inactivation is responsible for the neurofibromatosis type 1 (NF1) tumor predisposition syndrome .	('NF1', 'Gene', '4763', (4, 7))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', (123, 128))	('NF1', 'Gene', '4763', (118, 121))	('inactivation', 'Var', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (92, 109))	('NF1', 'Gene', (4, 7))	('neurofibromatosis type 1 (NF1) tumor', 'Disease', 'MESH:C537392', (92, 128))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('responsible', 'Reg', (72, 83))	('NF1', 'Gene', (118, 121))
566093	28498454	Mutations of NF1 are also linked to juvenile myelomonocytic leukemia  and Watson syndrome .	('juvenile myelomonocytic leukemia', 'Disease', (36, 68))	('Watson syndrome', 'Disease', 'OMIM:193520', (74, 89))	('Watson syndrome', 'Disease', (74, 89))	('NF1', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('linked', 'Reg', (26, 32))	('NF1', 'Gene', '4763', (13, 16))	('juvenile myelomonocytic leukemia', 'Phenotype', 'HP:0012209', (36, 68))	('juvenile myelomonocytic leukemia', 'Disease', 'MESH:D054429', (36, 68))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))
566097	28498454	Mutations in the NF1 gene may also result in cardiovascular, musculoskeletal, and nervous system anomalies.	('result in', 'Reg', (35, 44))	('cardiovascular', 'Disease', (45, 59))	('NF1', 'Gene', (17, 20))	('nervous system anomalies', 'Phenotype', 'HP:0000707', (82, 106))	('Mutations', 'Var', (0, 9))	('musculoskeletal', 'Disease', (61, 76))	('NF1', 'Gene', '4763', (17, 20))	('musculoskeletal', 'Disease', 'MESH:D009140', (61, 76))	('nervous system anomalies', 'Disease', 'MESH:D009421', (82, 106))	('nervous system anomalies', 'Disease', (82, 106))
566099	28498454	The transcript NF1-020 (ENST00000422121) has three exons and is thought to undergo nonsense mediated decay, a process which detects nonsense mutations and prevents the expression of truncated or erroneous proteins.	('NF1', 'Gene', (15, 18))	('expression', 'MPA', (168, 178))	('NF1', 'Gene', '4763', (15, 18))	('nonsense mutations', 'Var', (132, 150))	('truncated', 'MPA', (182, 191))	('prevents', 'NegReg', (155, 163))	('erroneous proteins', 'MPA', (195, 213))
566103	28498454	The result would be similar to that seen with the truncating SETD2 mutations found in leukemias.	('leukemias', 'Disease', (86, 95))	('SETD2', 'Gene', '29072', (61, 66))	('SETD2', 'Gene', (61, 66))	('leukemias', 'Disease', 'MESH:D007938', (86, 95))	('mutations', 'Var', (67, 76))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('leukemias', 'Phenotype', 'HP:0001909', (86, 95))
566105	28498454	Whether aberrations of SETD2 are recurrent and define a specific subgroup of spindle cell tumors, remains to be seen.	('SETD2', 'Gene', '29072', (23, 28))	('spindle cell tumors', 'Disease', 'MESH:D002277', (77, 96))	('SETD2', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('aberrations', 'Var', (8, 19))	('spindle cell tumors', 'Disease', (77, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))
566113	23923114	More importantly, for the first time, BRAF V600E mutation was detected in LCS.	('detected', 'Reg', (62, 70))	('LCS', 'Disease', (74, 77))	('V600E', 'Mutation', 'rs113488022', (43, 48))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (38, 42))	('V600E', 'Var', (43, 48))
566119	23923114	The BRAF V600E mutation (T1799A) has been shown to be a molecular change underlying the pathogenesis of many malignancies, the most notable one being melanoma.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('T1799A', 'Mutation', 'rs113488022', (25, 31))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', (4, 8))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('BRAF', 'Gene', '673', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))
566121	23923114	Considering the effectiveness of this drug in melanoma treatment, it would be interesting to look into its potential effect on other cancers bearing the same mutation.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('mutation', 'Var', (158, 166))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))
566135	23923114	The positivity for langerin [Figure 1i] convincingly supported the LCS diagnosis.	('positivity', 'Var', (4, 14))	('langerin', 'Gene', (19, 27))	('langerin', 'Gene', '50489', (19, 27))	('LCS', 'Disease', (67, 70))
566139	23923114	To address this question, we performed a fluorescence in situ hybridization (FISH) analysis using a CLL panel probes (centromere6, 6q23, 11q23, 13q14, 13q34, centromere12, IGH, and 17p13; Vysis CLL FISH probe kit, Abbott Laboratories.	('IGH', 'Gene', '3492', (172, 175))	('IGH', 'Gene', (172, 175))	('centromere12', 'Var', (158, 170))	('centromere6', 'Var', (118, 129))
566141	23923114	To further understand the genetic changes in LCS cells, we investigated whether the LCS cells carry a BRAF V600E mutation.	('BRAF', 'Gene', '673', (102, 106))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('BRAF', 'Gene', (102, 106))	('V600E', 'Var', (107, 112))
566158	23923114	For example, in vitro deletion of PAX-5, an important regulator for B-cell development, can lead to de-differentiation of mature B-cells into progenitor cells, which subsequently differentiate to T-cells.	('de-differentiation', 'MPA', (100, 118))	('lead to', 'Reg', (92, 99))	('deletion', 'Var', (22, 30))	('PAX-5', 'Gene', (34, 39))	('PAX-5', 'Gene', '5079', (34, 39))
566161	23923114	Although the role of BRAF mutation in LCS oncogenesis has never been studied, it is well known that BRAF mutation is associated with activation of the mitogen-activated protein kinase (MAPK) pathway in melanoma.	('mutation', 'Var', (105, 113))	('mutation', 'Var', (26, 34))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', '673', (100, 104))	('activation', 'PosReg', (133, 143))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('BRAF', 'Gene', (21, 25))	('melanoma', 'Disease', (202, 210))	('BRAF', 'Gene', (100, 104))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))
566165	23923114	Whether similar mechanism is responsible for the potential role of BRAF mutation in the transformation of CLL/SLL to LCS needs to be addressed by further investigation.	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (67, 71))	('mutation', 'Var', (72, 80))	('CLL/SLL', 'Gene', (106, 113))	('CLL/SLL', 'Gene', '347734', (106, 113))
566175	23923114	In this case, 6q23 deletion, but not 17p abnormalities, was detected in both the CLL/SLL and the LCS components.	('6q23 deletion', 'Var', (14, 27))	('CLL/SLL', 'Gene', (81, 88))	('17p abnormalities', 'Disease', (37, 54))	('17p abnormalities', 'Disease', 'MESH:C538045', (37, 54))	('CLL/SLL', 'Gene', '347734', (81, 88))
566180	23923114	BRAF V600E mutation has been shown in many types of malignancy and the best known ones are melanoma and papillary thyroid carcinoma.	('papillary thyroid carcinoma', 'Disease', (104, 131))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (114, 131))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('melanoma', 'Disease', (91, 99))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (104, 131))	('malignancy', 'Disease', (52, 62))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('V600E', 'Var', (5, 10))	('shown', 'Reg', (29, 34))	('BRAF', 'Gene', '673', (0, 4))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (104, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('BRAF', 'Gene', (0, 4))
566182	23923114	Our result demonstrates, for the first time, that LCS can bear the BRAF V600E mutation.	('V600E', 'Var', (72, 77))	('BRAF', 'Gene', (67, 71))	('BRAF', 'Gene', '673', (67, 71))	('V600E', 'Mutation', 'rs113488022', (72, 77))
566191	23482293	Immunohistochemical studies revealed that tumor cells expressed positivity against CD99 (MIC2), CD57, neuron-specific enolase, and vimentin.	('neuron-specific enolase', 'Gene', (102, 125))	('positivity', 'Var', (64, 74))	('tumor', 'Disease', (42, 47))	('CD99', 'Gene', '4267', (83, 87))	('vimentin', 'Gene', '7431', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('MIC2', 'Gene', '4267', (89, 93))	('CD57', 'Gene', (96, 100))	('vimentin', 'Gene', (131, 139))	('CD99', 'Gene', (83, 87))	('CD57', 'Gene', '27087', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('neuron-specific enolase', 'Gene', '2026', (102, 125))	('MIC2', 'Gene', (89, 93))
566192	23482293	Fluorescence in situ hybridization study revealed Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement on chromosome 22q12.	('Ewing sarcoma breakpoint region 1', 'Gene', (50, 83))	('EWSR1', 'Gene', '2130', (85, 90))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (50, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (50, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('rearrangement', 'Var', (97, 110))	('EWSR1', 'Gene', (85, 90))
566225	23482293	FISH showed a split signal pattern (one green and one orange) in interphase nuclei which was indicative of a EWSR1 gene rearrangement (Fig.	('EWSR1', 'Gene', (109, 114))	('EWSR1', 'Gene', '2130', (109, 114))	('rearrangement', 'Var', (120, 133))
566241	23482293	The detection of EWS/FLI-1 chimeric mRNA originating from the t(11;22)(q24;q12) translocation of the pPNET-Ewing's sarcoma family, facilitated by reverse transcription-polymerase chain reactions, have been reported in recent studies.	('FLI-1', 'Gene', (21, 26))	('pPNET', 'Phenotype', 'HP:0030067', (101, 106))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (107, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (107, 122))	("Ewing's sarcoma", 'Disease', (107, 122))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (62, 79))	('chimeric', 'Var', (27, 35))	('EWS', 'Gene', '2130', (17, 20))	('EWS', 'Gene', (17, 20))	('FLI-1', 'Gene', '2313', (21, 26))
566244	23482293	In addition, chromosomal rearrangements involving the EWSR1 gene on chromosome 22q12 was detected by FISH, which was a strong supportive finding for pPNET.	('EWSR1', 'Gene', '2130', (54, 59))	('pPNET', 'Phenotype', 'HP:0030067', (149, 154))	('chromosomal rearrangements', 'Var', (13, 39))	('EWSR1', 'Gene', (54, 59))
566255	21179485	In the multivariate analysis, high expression of VEGFR-3 (P = 0.042, HR = 1.907, 95% CI 1.024-3.549) was an independent significant negative prognostic marker for DSS among patients with wide resection margins.	('DSS', 'Gene', '5376', (163, 166))	('VEGFR-3', 'Gene', '2324', (49, 56))	('patients', 'Species', '9606', (173, 181))	('high expression', 'Var', (30, 45))	('VEGFR-3', 'Gene', (49, 56))	('negative', 'NegReg', (132, 140))	('DSS', 'Gene', (163, 166))
566272	21179485	High levels of VEGF-A in tumors and blood samples from STS patients have previously been associated with higher tumor grade, increased tendency to metastasis, reduced response to treatment, lower overall survival (OS) and increased risk of recurrence.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('response to treatment', 'MPA', (167, 188))	('tumors', 'Disease', (25, 31))	('High levels', 'Var', (0, 11))	('VEGF-A', 'Gene', '7422', (15, 21))	('reduced', 'NegReg', (159, 166))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('lower', 'NegReg', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('overall', 'MPA', (196, 203))	('metastasis', 'CPA', (147, 157))	('VEGF-A', 'Gene', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('STS', 'Phenotype', 'HP:0030448', (55, 58))
566273	21179485	In angiosarcomas, however, high expression of VEGFR-2 has been associated with longer OS.	('VEGFR-2', 'Gene', (46, 53))	('angiosarcoma', 'Phenotype', 'HP:0200058', (3, 15))	('angiosarcomas', 'Disease', (3, 16))	('associated', 'Reg', (63, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('angiosarcomas', 'Disease', 'MESH:D006394', (3, 16))	('high expression', 'Var', (27, 42))	('VEGFR-2', 'Gene', '3791', (46, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('angiosarcomas', 'Phenotype', 'HP:0200058', (3, 16))	('longer OS', 'Disease', (79, 88))
566312	21179485	In the wide resection margins group, Russian nationality (P = 0.013), high malignancy grade (P = 0.009), metastasis at diagnosis (P = 0.007) and high VEGFR-3 expression (P = 0.042, HR = 1.907, 95% CI 1.024-3.549) were significant independent prognostic indicators for reduced DSS (Table 4).	('DSS', 'Gene', (276, 279))	('DSS', 'Gene', '5376', (276, 279))	('expression', 'MPA', (158, 168))	('metastasis', 'CPA', (105, 115))	('high malignancy', 'Disease', (70, 85))	('VEGFR-3', 'Gene', '2324', (150, 157))	('high malignancy', 'Disease', 'MESH:D009369', (70, 85))	('VEGFR-3', 'Gene', (150, 157))	('high', 'Var', (145, 149))
566314	21179485	In this study we observed that high expression of VEGFR-3 was a significant independent negative prognostic indicator of DSS in non-GIST STS patients with wide resection margins.	('negative', 'NegReg', (88, 96))	('DSS', 'Gene', '5376', (121, 124))	('VEGFR-3', 'Gene', '2324', (50, 57))	('STS', 'Phenotype', 'HP:0030448', (137, 140))	('high', 'Var', (31, 35))	('DSS', 'Gene', (121, 124))	('patients', 'Species', '9606', (141, 149))	('VEGFR-3', 'Gene', (50, 57))
566333	21179485	concluded surprisingly that high expression of VEGF-C mRNA led to a longer overall survival.	('VEGF-C', 'Gene', '7424', (47, 53))	('longer', 'PosReg', (68, 74))	('VEGF-C', 'Gene', (47, 53))	('overall survival', 'MPA', (75, 91))	('high', 'Var', (28, 32))
566360	32599807	Although EwSs of the central nervous system may histologically appear quite similar to primitive neuroectodermal tumors of the central nervous system, EwSs show the characteristic chromosomal translocation t(11;22)(q24;12) in 85-90% of patients.	('neuroectodermal tumors of the central nervous system', 'Disease', 'MESH:D016543', (97, 149))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (87, 119))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (87, 118))	('EwS', 'Gene', (151, 154))	('patients', 'Species', '9606', (236, 244))	('EwS', 'Gene', '2130', (9, 12))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (97, 119))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (97, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('EwS', 'Gene', '2130', (151, 154))	('EwS', 'Gene', (9, 12))	('t(11;22)(q24;12', 'Var', (206, 221))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (113, 149))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
566361	32599807	This translocation results in fusion of the gene EWSR1 with the ETS family gene FLI1 (alias EWSR2).	('fusion', 'Var', (30, 36))	('EWSR2', 'Gene', '2313', (92, 97))	('EWSR1', 'Gene', (49, 54))	('FLI1', 'Gene', (80, 84))	('results in', 'Reg', (19, 29))	('FLI1', 'Gene', '2313', (80, 84))	('EWSR2', 'Gene', (92, 97))	('EWSR1', 'Gene', '2130', (49, 54))
566362	32599807	Less frequently, in about 10% of patients, EwSR1 fusions with other members of the ETS family occur, most commonly ERG.	('ERG', 'Var', (115, 118))	('EwSR1', 'Gene', '2130', (43, 48))	('patients', 'Species', '9606', (33, 41))	('EwSR1', 'Gene', (43, 48))
566547	28708250	Relative to classic cases of cutaneous myoepithelioma, the incidence of keratin positivity is much lower in cases of CSM, with staining in only 14% of cases in a focal and weak pattern in the largest series of 38 cases.	('lower', 'NegReg', (99, 104))	('cutaneous myoepithelioma', 'Disease', 'MESH:D009208', (29, 53))	('cutaneous myoepithelioma', 'Disease', (29, 53))	('positivity', 'Var', (80, 90))	('keratin', 'Protein', (72, 79))	('CSM', 'Disease', (117, 120))
566551	28708250	Cases with significant mitotic activity and cellular pleomorphism have been designated as myoepithelial carcinomas, although definitive diagnostic criteria have not been elucidated for cutaneous lesions, in contrast to their soft tissue counterparts.	('mitotic activity', 'CPA', (23, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cellular pleomorphism', 'Var', (44, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('myoepithelial carcinomas', 'Disease', (90, 114))	('myoepithelial carcinomas', 'Disease', 'MESH:D009208', (90, 114))
566559	28556483	Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity, and apoptosis.	('BI2536', 'Chemical', 'MESH:C518477', (71, 77))	('PLK1', 'Gene', '5347', (38, 42))	('cytotoxicity', 'Disease', 'MESH:D064420', (180, 192))	('Polo-like kinase 1', 'Gene', '5347', (18, 36))	('gemcitabine', 'Chemical', 'MESH:C056507', (104, 115))	('Polo-like kinase 1', 'Gene', (18, 36))	('BI2536', 'Var', (71, 77))	('PLK1', 'Gene', (38, 42))	('fluoronucleoside', 'Chemical', '-', (87, 103))	('cytotoxicity', 'Disease', (180, 192))	('volasertib', 'Chemical', 'MESH:C541363', (56, 66))
566577	28556483	Inactivating mutations in the NF1 tumor suppressor gene are found in both NF1-associated and sporadic MPNST (Bottillo et al., 2009; Upadhyaya et al., 2008).	('tumor', 'Disease', (34, 39))	('NF1', 'Gene', (74, 77))	('NF1', 'Gene', (30, 33))	('sporadic MPNST', 'Disease', (93, 107))	('NF1', 'Gene', '4763', (74, 77))	('MPNST', 'Phenotype', 'HP:0100697', (102, 107))	('NF1', 'Gene', '4763', (30, 33))	('Inactivating mutations', 'Var', (0, 22))	('found', 'Reg', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
566629	28556483	Only three, docetaxel, vincristine, and BI2536, showed selectively higher response in MPNST cells as compared to HSC (Fig.	('vincristine', 'Chemical', 'MESH:D014750', (23, 34))	('HSC', 'Gene', (113, 116))	('higher', 'PosReg', (67, 73))	('BI2536', 'Chemical', 'MESH:C518477', (40, 46))	('response', 'MPA', (74, 82))	('HSC', 'Gene', '2523', (113, 116))	('docetaxel', 'Chemical', 'MESH:D000077143', (12, 21))	('MPNST', 'Phenotype', 'HP:0100697', (86, 91))	('BI2536', 'Var', (40, 46))
566634	28556483	These included the polo-like kinase 1 (PLK1) inhibitor BI2536, three tubulin/kinesin inhibitors (vinorelbine, vincristine, and SB 743921), two nucleoside analogs (floxuridine and thioguanine), two folate analogs (methotrexate and pemetrexed), as well as one proteasome-ubiquitin inhibitor [NEDD8-activating enzyme (NAE) inhibitor pevonedistat].	('polo-like kinase 1', 'Gene', (19, 37))	('BI2536', 'Var', (55, 61))	('thioguanine', 'Chemical', 'MESH:D013866', (179, 190))	('vincristine', 'Chemical', 'MESH:D014750', (110, 121))	('floxuridine', 'Chemical', 'MESH:D005467', (163, 174))	('methotrexate', 'Chemical', 'MESH:D008727', (213, 225))	('pevonedistat', 'Chemical', 'MESH:C539933', (330, 342))	('BI2536', 'Chemical', 'MESH:C518477', (55, 61))	('polo-like kinase 1', 'Gene', '5347', (19, 37))	('NEDD8', 'Gene', '4738', (290, 295))	('nucleoside', 'Chemical', 'MESH:D009705', (143, 153))	('PLK1', 'Gene', (39, 43))	('SB 743921', 'Chemical', 'MESH:C557279', (127, 136))	('NEDD8', 'Gene', (290, 295))	('NAE', 'Chemical', '-', (315, 318))	('inhibitor BI2536', 'Var', (45, 61))	('vinorelbine', 'Chemical', 'MESH:D000077235', (97, 108))	('pemetrexed', 'Chemical', 'MESH:D000068437', (230, 240))	('PLK1', 'Gene', '5347', (39, 43))	('folate', 'Chemical', 'MESH:D005492', (197, 203))
566635	28556483	Four of these nine compounds were selected for validation: BI2536 was selected as a targeted kinase inhibitor, floxuridine was selected due to its association with thymidine kinase 1 (TK1), previously identified as a prognostic biomarker (Kolberg et al., 2015), while methotrexate and pemetrexed were selected for their differential response in MPNST cell lines.	('MPNST', 'Phenotype', 'HP:0100697', (345, 350))	('association', 'Interaction', (147, 158))	('floxuridine', 'Chemical', 'MESH:D005467', (111, 122))	('methotrexate', 'Chemical', 'MESH:D008727', (268, 280))	('thymidine kinase 1', 'Gene', (164, 182))	('BI2536', 'Var', (59, 65))	('thymidine kinase 1', 'Gene', '7083', (164, 182))	('BI2536', 'Chemical', 'MESH:C518477', (59, 65))	('pemetrexed', 'Chemical', 'MESH:D000068437', (285, 295))	('TK1', 'Gene', (184, 187))	('TK1', 'Gene', '7083', (184, 187))
566637	28556483	Three of these six compounds, BI2536, volasertib, and gemcitabine, also showed a strong cytotoxic effect (DSSCTX > 10) in the MPNST cells, while methotrexate, pemetrexed, and floxuridine showed limited or no cytotoxicity in the CTX assay (Table S6).	('cytotoxicity', 'Disease', (208, 220))	('CTX', 'Disease', 'MESH:D019294', (109, 112))	('BI2536', 'Chemical', 'MESH:C518477', (30, 36))	('pemetrexed', 'Chemical', 'MESH:D000068437', (159, 169))	('methotrexate', 'Chemical', 'MESH:D008727', (145, 157))	('MPNST', 'Phenotype', 'HP:0100697', (126, 131))	('CTX', 'Disease', 'MESH:D019294', (228, 231))	('floxuridine', 'Chemical', 'MESH:D005467', (175, 186))	('cytotoxicity', 'Disease', 'MESH:D064420', (208, 220))	('volasertib', 'Chemical', 'MESH:C541363', (38, 48))	('CTX', 'Disease', (228, 231))	('gemcitabine', 'Chemical', 'MESH:C056507', (54, 65))	('DSSCTX', 'Chemical', '-', (106, 112))	('cytotoxic effect', 'CPA', (88, 104))	('CTX', 'Disease', (109, 112))	('BI2536', 'Var', (30, 36))
566639	28556483	A good correlation between the initial screen and the validations was observed for the two PLK1 inhibitors, BI2536 and volasertib, as well as for gemcitabine (Fig.	('volasertib', 'Chemical', 'MESH:C541363', (119, 129))	('BI2536', 'Var', (108, 114))	('gemcitabine', 'Chemical', 'MESH:C056507', (146, 157))	('PLK1', 'Gene', (91, 95))	('BI2536', 'Chemical', 'MESH:C518477', (108, 114))	('PLK1', 'Gene', '5347', (91, 95))
566641	28556483	Interestingly, the DSSCTG values of BI2536 and volasertib appear to be slightly higher for the seven MPNST cell lines as compared to the DSSCTG values of a panel of 94 cell lines from colon and ovarian cancer and leukemia (Fig.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('volasertib', 'Gene', (47, 57))	('BI2536', 'Chemical', 'MESH:C518477', (36, 42))	('volasertib', 'Chemical', 'MESH:C541363', (47, 57))	('leukemia', 'Disease', (213, 221))	('leukemia', 'Phenotype', 'HP:0001909', (213, 221))	('leukemia', 'Disease', 'MESH:D007938', (213, 221))	('colon and ovarian cancer', 'Disease', 'MESH:D010051', (184, 208))	('DSSCTG', 'MPA', (19, 25))	('ovarian cancer', 'Phenotype', 'HP:0100615', (194, 208))	('BI2536', 'Var', (36, 42))	('MPNST', 'Phenotype', 'HP:0100697', (101, 106))	('higher', 'PosReg', (80, 86))
566646	28556483	We found that both PLK1 inhibitors, BI2536 and volasertib, induced apoptosis in the TP53-mutant cell lines S1507-2 and S462, as well as in the TP53 wild-type cells ST8814, while the STS26T cell line, which harbors a homozygous 10-bp deletion in exon 4 of TP53, had the lowest level of apoptosis induced by PLK1 inhibition (Fig.	('TP53', 'Gene', (143, 147))	('TP53', 'Gene', (255, 259))	('STS26T', 'CellLine', 'CVCL:8917', (182, 188))	('PLK1', 'Gene', (306, 310))	('apoptosis', 'CPA', (67, 76))	('BI2536', 'Chemical', 'MESH:C518477', (36, 42))	('volasertib', 'Chemical', 'MESH:C541363', (47, 57))	('PLK1', 'Gene', (19, 23))	('TP53', 'Gene', '7157', (143, 147))	('PLK1', 'Gene', '5347', (306, 310))	('TP53', 'Gene', '7157', (84, 88))	('inhibition', 'NegReg', (311, 321))	('PLK1', 'Gene', '5347', (19, 23))	('induced', 'Reg', (59, 66))	('TP53', 'Gene', (84, 88))	('BI2536', 'Var', (36, 42))	('TP53', 'Gene', '7157', (255, 259))
566648	28556483	One of the MPNST cell lines, STS26T, had an oncogenic V600E mutation in BRAF (Fig.	('BRAF', 'Gene', (72, 76))	('STS26T', 'CellLine', 'CVCL:8917', (29, 35))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('MPNST', 'Phenotype', 'HP:0100697', (11, 16))	('V600E', 'Var', (54, 59))	('BRAF', 'Gene', '673', (72, 76))
566657	28556483	Actually, two of the cell lines, S1507-2 and ST8814, had genomic losses from a chromosomal region covering PLK1 (16p12.2), and for ST8814, this may partly explain the relatively low PLK1 protein level as compared to the other MPNST cell lines (Fig.	('PLK1', 'Gene', (107, 111))	('ST8814', 'Var', (131, 137))	('genomic', 'CPA', (57, 64))	('PLK1', 'Gene', '5347', (182, 186))	('losses', 'NegReg', (65, 71))	('S1507-2', 'Var', (33, 40))	('PLK1', 'Gene', '5347', (107, 111))	('low', 'NegReg', (178, 181))	('MPNST', 'Phenotype', 'HP:0100697', (226, 231))	('PLK1', 'Gene', (182, 186))
566672	28556483	The most promising drug candidates identified here include the PLK1 inhibitors volasertib and BI2536, and the fluoronucleoside gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (127, 138))	('PLK1', 'Gene', '5347', (63, 67))	('volasertib', 'Chemical', 'MESH:C541363', (79, 89))	('BI2536', 'Var', (94, 100))	('PLK1', 'Gene', (63, 67))	('BI2536', 'Chemical', 'MESH:C518477', (94, 100))	('fluoronucleoside', 'Chemical', '-', (110, 126))
566681	28556483	BI2536 was among the first PLK1 inhibitors to be tested in the clinic, but the efficacy was limited, partly due to the short terminal half-life.	('BI2536', 'Chemical', 'MESH:C518477', (0, 6))	('BI2536', 'Var', (0, 6))	('PLK1', 'Gene', (27, 31))	('PLK1', 'Gene', '5347', (27, 31))
566685	28556483	The authors also found that inhibition of PLK1 in the TP53-mutant MPNST cell lines, both by small compound inhibition and by siRNA-mediated gene knockdown, led to the induction of polyploidy, which was in contrast to TP53 wild-type or TP53 -/- sarcoma cell lines where PLK1 inhibition led to G2 arrest and apoptosis (Nair and Schwartz, 2015).	('TP53', 'Gene', '7157', (217, 221))	('PLK1', 'Gene', '5347', (269, 273))	('arrest', 'Disease', 'MESH:D006323', (295, 301))	('TP53', 'Gene', (235, 239))	('induction', 'Reg', (167, 176))	('sarcoma', 'Disease', 'MESH:D012509', (244, 251))	('PLK1', 'Gene', (42, 46))	('sarcoma', 'Disease', (244, 251))	('polyploidy', 'MPA', (180, 190))	('TP53', 'Gene', '7157', (54, 58))	('inhibition', 'NegReg', (107, 117))	('apoptosis', 'CPA', (306, 315))	('PLK1', 'Gene', '5347', (42, 46))	('TP53', 'Gene', (217, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('TP53', 'Gene', '7157', (235, 239))	('arrest', 'Disease', (295, 301))	('PLK1', 'Gene', (269, 273))	('inhibition', 'Var', (28, 38))	('MPNST', 'Phenotype', 'HP:0100697', (66, 71))	('TP53', 'Gene', (54, 58))
566686	28556483	In our study, however, we also observed apoptosis in the two TP53-mutant cell lines S1507-2 and S462, which carry point mutations P152L and R110P, respectively (Fig.	('TP53', 'Gene', '7157', (61, 65))	('R110P', 'Var', (140, 145))	('P152L', 'Var', (130, 135))	('P152L', 'Mutation', 'rs587782705', (130, 135))	('R110P', 'Mutation', 'rs11540654', (140, 145))	('TP53', 'Gene', (61, 65))
566700	28556483	In a clinical setting, PLK1 and RRM2 expression may have both prognostic and predictive values, as patients with high expression of these genes are most likely to experience disease progression, and at the same time, those with the highest levels are most likely to respond to PLK1 inhibitors and gemcitabine treatment.	('high expression', 'Var', (113, 128))	('experience', 'PosReg', (163, 173))	('PLK1', 'Gene', (23, 27))	('PLK1', 'Gene', (277, 281))	('RRM2', 'Gene', (32, 36))	('patients', 'Species', '9606', (99, 107))	('respond', 'MPA', (266, 273))	('RRM2', 'Gene', '6241', (32, 36))	('gemcitabine', 'Chemical', 'MESH:C056507', (297, 308))	('PLK1', 'Gene', '5347', (23, 27))	('PLK1', 'Gene', '5347', (277, 281))	('disease progression', 'CPA', (174, 193))
566705	28556483	However, in the available raw data, which were recorded after 96-h drug exposure, both PLK1 inhibitors BI2536 and volasertib, as well as gemcitabine, were among the top-ranked drugs with respect to low IC 50 values, which are in agreement with our own data (Fig.	('volasertib', 'Chemical', 'MESH:C541363', (114, 124))	('gemcitabine', 'Chemical', 'MESH:C056507', (137, 148))	('PLK1', 'Gene', '5347', (87, 91))	('BI2536', 'Var', (103, 109))	('BI2536', 'Chemical', 'MESH:C518477', (103, 109))	('inhibitors BI2536', 'Var', (92, 109))	('IC 50 values', 'MPA', (202, 214))	('PLK1', 'Gene', (87, 91))
566706	28556483	In conclusion, we have identified two PLK1 inhibitors, BI2536 and volasertib, and the DNA synthesis inhibitor gemcitabine as highly effective against MPNST cells, while being tolerable to normal HSC cells and bone marrow cells, and we propose these drugs as good candidates for future clinical testing, alone or in combination.	('PLK1', 'Gene', '5347', (38, 42))	('effective', 'MPA', (132, 141))	('MPNST', 'Phenotype', 'HP:0100697', (150, 155))	('gemcitabine', 'Chemical', 'MESH:C056507', (110, 121))	('DNA synthesis inhibitor', 'Gene', '1026', (86, 109))	('DNA synthesis inhibitor', 'Gene', (86, 109))	('BI2536', 'Var', (55, 61))	('HSC', 'Gene', (195, 198))	('HSC', 'Gene', '2523', (195, 198))	('volasertib', 'Chemical', 'MESH:C541363', (66, 76))	('PLK1', 'Gene', (38, 42))	('BI2536', 'Chemical', 'MESH:C518477', (55, 61))
566730	28056055	When this association is disrupted by specific knockdown of TLE1, ATF2 or SS18-SSX, synovial sarcoma cell lines undergo apoptosis, indicating this complex association is important for tumor cell survival.	('SSX', 'Gene', '727837', (79, 82))	('ATF2', 'Gene', (66, 70))	('undergo', 'Reg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('synovial sarcoma', 'Disease', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('apoptosis', 'CPA', (120, 129))	('SS18', 'Gene', (74, 78))	('knockdown', 'Var', (47, 56))	('tumor', 'Disease', (184, 189))	('TLE1', 'Gene', (60, 64))	('synovial sarcoma', 'Disease', 'MESH:D013584', (84, 100))	('ATF2', 'Gene', '11909', (66, 70))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (84, 100))	('SSX', 'Gene', (79, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('TLE1', 'Gene', '21885', (60, 64))	('SS18', 'Gene', '268996', (74, 78))
566733	28056055	HDAC inhibitors have been shown to disrupt the SS18-SSX/TLE1/ATF2 protein complex, providing an explanation for the sensitivity of synovial sarcoma cells to HDAC inhibition.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (157, 161))	('SS18', 'Gene', '268996', (47, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('disrupt', 'NegReg', (35, 42))	('SSX', 'Gene', '727837', (52, 55))	('HDAC', 'Gene', '9734', (0, 4))	('synovial sarcoma', 'Disease', (131, 147))	('TLE1', 'Gene', (56, 60))	('synovial sarcoma', 'Disease', 'MESH:D013584', (131, 147))	('inhibitors', 'Var', (5, 15))	('ATF2', 'Gene', '11909', (61, 65))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (131, 147))	('SS18', 'Gene', (47, 51))	('TLE1', 'Gene', '21885', (56, 60))	('ATF2', 'Gene', (61, 65))	('HDAC', 'Gene', (157, 161))	('SSX', 'Gene', (52, 55))
566750	28056055	Blots were incubated with indicated antibodies; Santa-Cruz Biotechnology (Dallas, TX, USA): SS18 sc-28698 1:200, GAPDH sc-25778 1:1500, BIK (NBK) sc-305625 1:500, BIM sc-374358 1:500, BCL-2 sc-492 1:250, p-BCL-2 sc-101762 1:250, HDAC6 sc-11420 1:250, vinculin sc-5573 1:5000, alpha-tubulin sc-8035 1:200; Cell Signaling (Danvers, MA, USA): EGR1 4153S 1:1000, Ac-alpha-tubulin 5335 1:1000, HDAC1 5356 1:1000, LC3B 2775 1:1000, p-PERK 3179S 1:1000, ER stress antibody kit 9956 (PERK, IRE1alpha, BiP, CHOP) 1:1000; Abcam (Cambridge, MA, USA): p16INK4a ab108349 1:500, p14ARF ab124282 1:500.	('BiP', 'Gene', (493, 496))	('vinculin', 'Gene', '22330', (251, 259))	('LC3B', 'Gene', '67443', (408, 412))	('CHOP', 'Gene', '13198', (498, 502))	('BIM', 'Gene', '12125', (163, 166))	('HDAC1', 'Gene', '433759', (389, 394))	('BCL-2', 'Gene', '12043', (184, 189))	('HDAC6', 'Gene', (229, 234))	('BCL-2', 'Gene', (184, 189))	('EGR1', 'Gene', (340, 344))	('LC3B', 'Gene', (408, 412))	('vinculin', 'Gene', (251, 259))	('HDAC6', 'Gene', '15185', (229, 234))	('BiP', 'Gene', '14828', (493, 496))	('SS18', 'Gene', '268996', (92, 96))	('GAPDH', 'Gene', (113, 118))	('EGR1', 'Gene', '13653', (340, 344))	('BCL-2', 'Gene', '12043', (206, 211))	('BCL-2', 'Gene', (206, 211))	('GAPDH', 'Gene', '14433', (113, 118))	('BIK', 'Gene', '12124', (136, 139))	('BIK', 'Gene', (136, 139))	('IRE1alpha', 'Gene', '78943', (482, 491))	('NBK', 'Gene', '12124', (141, 144))	('IRE1alpha', 'Gene', (482, 491))	('CHOP', 'Gene', (498, 502))	('PERK', 'Gene', '13666', (428, 432))	('PERK', 'Gene', '13666', (476, 480))	('BIM', 'Gene', (163, 166))	('SS18', 'Gene', (92, 96))	('p16INK4a', 'Gene', '12578', (540, 548))	('NBK', 'Gene', (141, 144))	('PERK', 'Gene', (428, 432))	('PERK', 'Gene', (476, 480))	('HDAC1', 'Gene', (389, 394))	('p16INK4a', 'Gene', (540, 548))	('p14ARF ab124282', 'Var', (565, 580))
566793	28056055	Similar studies were also undertaken with HDAC and PI3K inhibitor combinations, but with this combination no synergy was observed in the synovial sarcoma cell lines at the studied doses.	('HDAC', 'Gene', (42, 46))	('HDAC', 'Gene', '9734', (42, 46))	('PI3K', 'Var', (51, 55))	('synovial sarcoma', 'Disease', (137, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (137, 153))	('synovial sarcoma', 'Disease', 'MESH:D013584', (137, 153))
566800	28056055	Silencing of HDAC6 by siRNA brings about a decrease in LC3B protein levels, a marker of aggresome formation (Fig 5A).	('decrease', 'NegReg', (43, 51))	('HDAC6', 'Gene', '15185', (13, 18))	('HDAC6', 'Gene', (13, 18))	('LC3B', 'Gene', (55, 59))	('Silencing', 'Var', (0, 9))	('LC3B', 'Gene', '67443', (55, 59))
566804	28056055	HDAC inhibition by quisinostat is consistently found to inhibit the aggresome response.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('inhibition', 'Var', (5, 15))	('quisinostat', 'Chemical', 'MESH:C541788', (19, 30))	('aggresome response', 'CPA', (68, 86))	('inhibit', 'NegReg', (56, 63))
566828	28056055	In addition, regulation by p16INK4a and p14ARF is important for cell cycle arrest via inhibition of CDK4/6, as well as for apoptosis induction via upregulation of BIK and p53-dependent signaling.	('BIK', 'Gene', '12124', (163, 166))	('BIK', 'Gene', (163, 166))	('CDK4/6', 'Gene', '12567;12571', (100, 106))	('p53', 'Gene', '22060', (171, 174))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('p16INK4a', 'Gene', (27, 35))	('p14ARF', 'Var', (40, 46))	('apoptosis', 'CPA', (123, 132))	('upregulation', 'PosReg', (147, 159))	('CDK4/6', 'Gene', (100, 106))	('inhibition', 'NegReg', (86, 96))	('p53', 'Gene', (171, 174))	('p16INK4a', 'Gene', '12578', (27, 35))	('cell cycle arrest', 'CPA', (64, 81))
566829	28056055	HDAC inhibition may therefore impede SS18-SSX-mediated deregulation at these loci, allowing for reactivation of normal cell cycle regulation and apoptotic pathways.	('reactivation', 'PosReg', (96, 108))	('HDAC', 'Gene', (0, 4))	('SSX', 'Gene', '727837', (42, 45))	('SS18', 'Gene', '268996', (37, 41))	('HDAC', 'Gene', '9734', (0, 4))	('inhibition', 'Var', (5, 15))	('SS18', 'Gene', (37, 41))	('impede', 'NegReg', (30, 36))	('apoptotic pathways', 'Pathway', (145, 163))	('SSX', 'Gene', (42, 45))	('cell cycle', 'CPA', (119, 129))	('deregulation', 'MPA', (55, 67))
566837	28056055	These studies suggest RAD23B is regulated by HDAC activity, and upon HDAC inhibition the shuttling function is over-activated and may sensitize cells to proteasome inhibition, providing further support for a combinatorial treatment strategy combining these drug classes.	('over-activated', 'PosReg', (111, 125))	('inhibition', 'Var', (74, 84))	('HDAC', 'Gene', (69, 73))	('RAD23B', 'Gene', (22, 28))	('HDAC', 'Gene', '9734', (69, 73))	('RAD23B', 'Gene', '19359', (22, 28))	('sensitize', 'Reg', (134, 143))	('shuttling function', 'MPA', (89, 107))	('HDAC', 'Gene', (45, 49))	('HDAC', 'Gene', '9734', (45, 49))
566864	27413360	The chimaeric fusion transcript EWS-FLI1 is the result of fusion of the EWS gene on 22q12 with the FLI1 gene on 11q24.	('FLI1', 'Gene', '2313', (99, 103))	('fusion', 'Var', (58, 64))	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', (72, 75))	('EWS', 'Gene', '2130', (32, 35))	('EWS', 'Gene', (32, 35))	('FLI1', 'Gene', '2313', (36, 40))	('FLI1', 'Gene', (36, 40))	('FLI1', 'Gene', (99, 103))
566865	27413360	Substitution of the EWS domain with a portion of the FLI1 transcriptional domain results in an EWS-FLI1 fusion transcript with increased transcriptional activity.	('EWS', 'Gene', (20, 23))	('Substitution', 'Var', (0, 12))	('FLI1', 'Gene', '2313', (99, 103))	('transcriptional activity', 'MPA', (137, 161))	('FLI1', 'Gene', (99, 103))	('results in', 'Reg', (81, 91))	('EWS', 'Gene', '2130', (95, 98))	('EWS', 'Gene', (95, 98))	('FLI1', 'Gene', '2313', (53, 57))	('FLI1', 'Gene', (53, 57))	('increased', 'PosReg', (127, 136))	('EWS', 'Gene', '2130', (20, 23))
566867	27413360	In the remaining 15% of tumors, other EWS-ETS gene family rearrangements have been identified, the second most common being the t(21;22)(q22;q12) translocation resulting in fusion of EWS with the ERG gene on 21q22.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('EWS', 'Gene', '2130', (38, 41))	('EWS', 'Gene', (38, 41))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('ERG', 'Gene', (196, 199))	('EWS', 'Gene', (183, 186))	('men', 'Species', '9606', (67, 70))	('EWS', 'Gene', '2130', (183, 186))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (128, 145))	('fusion', 'Var', (173, 179))	('ERG', 'Gene', '2078', (196, 199))
566869	27413360	The oncogenic effect of EWS-ETS fusion transcripts, may be partly mediated by upregulation of LAMB3 expression, a gene encoding the beta3 chain of laminin-5.	('fusion transcripts', 'Var', (32, 50))	('EWS', 'Gene', (24, 27))	('EWS', 'Gene', '2130', (24, 27))	('expression', 'MPA', (100, 110))	('upregulation', 'PosReg', (78, 90))	('LAMB3', 'Gene', (94, 99))	('oncogenic effect', 'CPA', (4, 20))	('LAMB3', 'Gene', '3914', (94, 99))
566923	27413360	MRI of Ewing's sarcoma typically shows the lesion as hypointense to isointense on T1W1 and hypointense to hyperintense on T2W1.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (7, 22))	("Ewing's sarcoma", 'Disease', (7, 22))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (7, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('hypointense', 'Var', (91, 102))
566942	27413360	Radiotherapy in this region may also lead to serious adverse effects, such as mucositis and stomatitis, with consecutive loss of taste and appetite, as well as severe pain.	('stomatitis', 'Phenotype', 'HP:0010280', (92, 102))	('loss', 'NegReg', (121, 125))	('Radiotherapy', 'Var', (0, 12))	('lead to', 'Reg', (37, 44))	('mucositis', 'Disease', (78, 87))	('pain', 'Phenotype', 'HP:0012531', (167, 171))	('stomatitis', 'Disease', 'MESH:D013280', (92, 102))	('pain', 'Disease', 'MESH:D010146', (167, 171))	('mucositis', 'Disease', 'MESH:D052016', (78, 87))	('pain', 'Disease', (167, 171))	('loss of taste', 'Phenotype', 'HP:0000224', (121, 134))	('stomatitis', 'Disease', (92, 102))
566943	27413360	Radiotherapy may harm the function of salivary and nasal glands, be detrimental to dental health status, and compromise nasal inspiration by injuring mucous membranes as well as causing a multitude of ocular disorders, like irritations and dryness, conjunctivitis, lens opacification, or even total blindness.	('conjunctivitis', 'Phenotype', 'HP:0000509', (249, 263))	('lens opacification', 'Disease', (265, 283))	('mucous', 'MPA', (150, 156))	('men', 'Species', '9606', (73, 76))	('function', 'MPA', (26, 34))	('injuring', 'Reg', (141, 149))	('conjunctivitis', 'Disease', (249, 263))	('causing', 'Reg', (178, 185))	('ocular disorders', 'Disease', 'MESH:D005128', (201, 217))	('harm', 'NegReg', (17, 21))	('nasal inspiration', 'MPA', (120, 137))	('blindness', 'Disease', 'MESH:D001766', (299, 308))	('compromise', 'NegReg', (109, 119))	('Radiotherapy', 'Var', (0, 12))	('blindness', 'Phenotype', 'HP:0000618', (299, 308))	('detrimental to dental health', 'Phenotype', 'HP:0000670', (68, 96))	('conjunctivitis', 'Disease', 'MESH:D003231', (249, 263))	('ocular disorders', 'Disease', (201, 217))	('lens opacification', 'Phenotype', 'HP:0000518', (265, 283))	('ocular disorders', 'Phenotype', 'HP:0000478', (201, 217))	('blindness', 'Disease', (299, 308))	('irritations and dryness', 'Disease', 'MESH:D014987', (224, 247))
566950	27413360	When radiotherapy has been administered as the primary local treatment modality (e.g., neoadjuvantly), subsequent surgery can lead to common complications, including wound infections, fistula formation, and the need for surgical revision, whereas flap survival does not seem to be negatively impacted by prior radiation.	('men', 'Species', '9606', (66, 69))	('surgery', 'Var', (114, 121))	('fistula', 'Disease', 'MESH:D005402', (184, 191))	('lead to', 'Reg', (126, 133))	('fistula', 'Disease', (184, 191))	('infections', 'Disease', 'MESH:D007239', (172, 182))	('wound infections', 'Phenotype', 'HP:0001581', (166, 182))	('infections', 'Disease', (172, 182))
566968	27413360	For example, anthracyclines, including doxorubicin, may induce a dose-related cardiomyopathy leading to congestive heart failure.	('dose-related', 'Disease', (65, 77))	('cardiomyopathy', 'Disease', (78, 92))	('doxorubicin', 'Chemical', 'MESH:D004317', (39, 50))	('anthracyclines', 'Var', (13, 27))	('induce', 'Reg', (56, 62))	('cardiomyopathy', 'Disease', 'MESH:D009202', (78, 92))	('anthracyclines', 'Chemical', 'MESH:D018943', (13, 27))	('congestive heart failure', 'Disease', 'MESH:D006333', (104, 128))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (78, 92))	('congestive heart failure', 'Phenotype', 'HP:0001635', (104, 128))	('congestive heart failure', 'Disease', (104, 128))
567074	21190557	Patients with lumbar spine Z-scores below -1 had equal BMI values compared to patients with BMD values greater than -1, but Z-scores for weight and BMI were significantly lower.	('below -1', 'Var', (36, 44))	('patients', 'Species', '9606', (78, 86))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (171, 176))	('BMI', 'MPA', (55, 58))
567099	21190557	Low BMD was correlated with younger age at diagnosis and treatment with cyclophosphamide in rhabdomyosarcoma patients.	('Low BMD', 'Var', (0, 7))	('patients', 'Species', '9606', (109, 117))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (72, 88))	('rhabdomyosarcoma', 'Disease', (92, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (92, 108))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (92, 108))
567164	32365979	In fact, after DNA damage, DDBs proteins form a complex that targets histones towards their ubiquitination and degradation during NER.	('degradation', 'MPA', (111, 122))	('DDBs', 'Var', (27, 31))	('targets', 'Reg', (61, 68))	('DDBs', 'Chemical', 'MESH:C010098', (27, 31))	('ubiquitination', 'MPA', (92, 106))	('histones', 'Protein', (69, 77))
567189	32365979	Amongst the transcripts analyzed, high expression of ERCC1 was the most significantly associated with longer PFS on trabectedin plus doxorubicin arm (8.10 months (95% CI: 4.77-11.43) vs 2.63 months (95% CI: 0.41-4.86) p = 0.006).	('high expression', 'Var', (34, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (133, 144))	('ERCC1', 'Gene', (53, 58))	('trabectedin', 'Chemical', 'MESH:D000077606', (116, 127))	('ERCC1', 'Gene', '2067', (53, 58))
567206	32365979	Noteworthy, high expression of ERCC1 was significantly correlated with lower trabectedin IC50 values (rho = -0.964; p < 0.001).	('trabectedin IC50 values', 'MPA', (77, 100))	('ERCC1', 'Gene', '2067', (31, 36))	('ERCC1', 'Gene', (31, 36))	('trabectedin', 'Chemical', 'MESH:D000077606', (77, 88))	('high expression', 'Var', (12, 27))	('lower', 'NegReg', (71, 76))
567216	32365979	Moreover, the ectopic expression of ERCC1 in NER-deficient cells sensitized them to trabectedin.	('ERCC1', 'Gene', '2067', (36, 41))	('sensitized', 'Reg', (65, 75))	('trabectedin', 'Chemical', 'MESH:D000077606', (84, 95))	('ERCC1', 'Gene', (36, 41))	('ectopic expression', 'Var', (14, 32))
567218	32365979	Yet, another study reported that low levels of BRCA1 expression correlated with statistically significant better response to trabectedin.	('BRCA1', 'Gene', (47, 52))	('response', 'CPA', (113, 121))	('better', 'PosReg', (106, 112))	('trabectedin', 'Chemical', 'MESH:D000077606', (125, 136))	('expression', 'MPA', (53, 63))	('BRCA1', 'Gene', '672', (47, 52))	('low levels', 'Var', (33, 43))
567221	32365979	The high expression of CUL4A was also significantly associated with better outcome in patients treated with trabectedin.	('trabectedin', 'Chemical', 'MESH:D000077606', (108, 119))	('CUL4A', 'Gene', (23, 28))	('high', 'Var', (4, 8))	('CUL4A', 'Gene', '8451', (23, 28))	('patients', 'Species', '9606', (86, 94))
567223	32365979	Accordingly, and taking into account that trabectedin activity seems to rely at least partially on NER-efficiency, our results support that high expression of CUL4A should be associated with improved trabectedin activity.	('trabectedin activity', 'CPA', (200, 220))	('trabectedin', 'Chemical', 'MESH:D000077606', (200, 211))	('trabectedin', 'Chemical', 'MESH:D000077606', (42, 53))	('high expression', 'Var', (140, 155))	('CUL4A', 'Gene', (159, 164))	('improved', 'PosReg', (191, 199))	('CUL4A', 'Gene', '8451', (159, 164))
567224	32365979	The potential predictive value of CUL4A has previously been reported in a panel of 10 breast cancer cell lines, where the expression of CUL4A was associated with higher trabectedin sensitivity.	('CUL4A', 'Gene', '8451', (136, 141))	('trabectedin', 'Chemical', 'MESH:D000077606', (169, 180))	('higher', 'PosReg', (162, 168))	('CUL4A', 'Gene', '8451', (34, 39))	('expression', 'Var', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('CUL4A', 'Gene', (136, 141))	('breast cancer', 'Disease', (86, 99))	('CUL4A', 'Gene', (34, 39))
567252	32365979	Gene expression was measured by qRT-PCR using the following TaqMan assays on demand (Applied Biosystems, Foster City, CA, USA): BRCA1 (Hs01556190_m1), CUL4A (Hs00757716_m1), ERCC1 (Hs01012159_m1), ERCC5 (Hs01012159_m1) in a 7500 Fast thermocycler (Applied Biosystems).	('ERCC1', 'Gene', '2067', (174, 179))	('ERCC1', 'Gene', (174, 179))	('Hs00757716_m1', 'Var', (158, 171))	('CUL4A', 'Gene', (151, 156))	('CUL4A', 'Gene', '8451', (151, 156))	('ERCC5', 'Gene', (197, 202))	('Hs01012159_m1', 'Var', (204, 217))	('BRCA1', 'Gene', '672', (128, 133))	('ERCC5', 'Gene', '2073', (197, 202))	('Hs01556190_m1', 'Var', (135, 148))	('Hs01012159_m1', 'Var', (181, 194))	('BRCA1', 'Gene', (128, 133))
567253	32365979	Furthermore, beta-2-microglobulin (Hs99999907_m1) and GAPDH (Hs00266705_m1) were used as housekeeping genes.	('beta-2-microglobulin', 'Gene', '567', (13, 33))	('beta-2-microglobulin', 'Gene', (13, 33))	('Hs00266705_m1', 'Var', (61, 74))	('GAPDH', 'Gene', '2597', (54, 59))	('GAPDH', 'Gene', (54, 59))	('Hs99999907_m1', 'Var', (35, 48))
567282	31810195	Under s-microg, the tumor marker EWS/FLI1 is intensified, while targeting CXCR4, which influences adhesion proteins, did not affect spheroid formation.	('intensified', 'PosReg', (45, 56))	('adhesion proteins', 'MPA', (98, 115))	('EWS', 'Gene', '2130', (33, 36))	('EWS', 'Gene', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('s-microg', 'Chemical', '-', (6, 14))	('s-microg', 'Var', (6, 14))	('tumor', 'Disease', (20, 25))
567319	31810195	VEGF-A expression remained constant in the control group as well as in spheroids, but significantly decreased in adherent cells under s-microg (0.7x; p < 0.05) (Figure 3d, Table 1).	('VEGF-A', 'Gene', '7422', (0, 6))	('VEGF-A', 'Gene', (0, 6))	('spheroids', 'Chemical', '-', (71, 80))	('expression', 'MPA', (7, 17))	('s-microg', 'Chemical', '-', (134, 142))	('decreased', 'NegReg', (100, 109))	('s-microg', 'Var', (134, 142))
567322	31810195	Additionally, 24 h of s-microg lead to a insignificantly decreased gene expression in spheroids and adherent cells for IGFR1 (both 0.8x; Supplementary Figure S2a; Table 1), LOX (both 0.6x; Supplementary Figure S2c; Table 1), ERBB4 (0.8x, 0.9x; Supplementary Figure S2f; Table 1) and MMP9 (0.9x, 1.0x; Supplementary Figure S2b; Table 1).	('spheroids', 'Chemical', '-', (86, 95))	('MMP9', 'Gene', '4318', (283, 287))	('s-microg', 'Chemical', '-', (22, 30))	('LOX', 'Gene', '4015', (173, 176))	('s-microg', 'Var', (22, 30))	('LOX', 'Gene', (173, 176))	('ERBB4', 'Gene', '2066', (225, 230))	('IGFR1', 'Gene', (119, 124))	('MMP9', 'Gene', (283, 287))	('decreased', 'NegReg', (57, 66))	('gene expression', 'MPA', (67, 82))	('IGFR1', 'Gene', '100132417', (119, 124))	('ERBB4', 'Gene', (225, 230))
567326	31810195	The relative protein accumulation of EWS/FLI1 was significantly increased in adherent cells under s-microg compared to the control group (1.6x, p < 0.05).	('relative protein accumulation', 'MPA', (4, 33))	('s-microg', 'Chemical', '-', (98, 106))	('s-microg', 'Var', (98, 106))	('EWS', 'Gene', '2130', (37, 40))	('EWS', 'Gene', (37, 40))	('increased', 'PosReg', (64, 73))
567329	31810195	CXCR4 protein accumulation was not significantly altered after 24 h of s-microg (Figure 4c).	('s-microg', 'Var', (71, 79))	('s-microg', 'Chemical', '-', (71, 79))	('CXCR4 protein accumulation', 'MPA', (0, 26))
567337	31810195	The following gene were integrated into the STRING Network with their UniProtKB identifiers: EWSR1 Q01844), FLI1 (Q01543), CAV1 (Q03135), CXCR4 (P61073), DKK2 (Q9UBU2), VEGFA (P15692), CD44 (P16070), IGFLR1 (Q9H665), MMP9 (P14780), LOXL1 (Q08397), NKX2.2 (O95096), ZEB2 (O60315), ERBB4 (Q15303), ACKR3 (P25106), CD99 (P14209), CDH1 (P12830).	('P16070', 'Var', (191, 197))	('CD99', 'Gene', (312, 316))	('EWSR1', 'Gene', (93, 98))	('NKX2.2', 'Gene', '4821', (248, 254))	('ERBB4', 'Gene', (280, 285))	('VEGFA', 'Gene', (169, 174))	('CAV1', 'Gene', '857', (123, 127))	('CD99', 'Gene', '4267', (312, 316))	('Q15303', 'Var', (287, 293))	('O95096', 'Var', (256, 262))	('LOXL1', 'Gene', (232, 237))	('ACKR3', 'Gene', '57007', (296, 301))	('Q9H665', 'Var', (208, 214))	('P25106', 'Var', (303, 309))	('P14209', 'Var', (318, 324))	('VEGFA', 'Gene', '7422', (169, 174))	('CAV1', 'Gene', (123, 127))	('DKK2', 'Gene', (154, 158))	('DKK2', 'Gene', '27123', (154, 158))	('IGFLR1', 'Gene', (200, 206))	('P15692', 'Var', (176, 182))	('EWSR1', 'Gene', '2130', (93, 98))	('CDH1', 'Gene', '999', (327, 331))	('IGFLR1', 'Gene', '79713', (200, 206))	('MMP9', 'Gene', (217, 221))	('ACKR3', 'Gene', (296, 301))	('ZEB2', 'Gene', (265, 269))	('LOXL1', 'Gene', '4016', (232, 237))	('MMP9', 'Gene', '4318', (217, 221))	('CDH1', 'Gene', (327, 331))	('Q08397', 'Var', (239, 245))	('NKX2.2', 'Gene', (248, 254))	('O60315', 'Var', (271, 277))	('ZEB2', 'Gene', '9839', (265, 269))	('P14780', 'Var', (223, 229))	('ERBB4', 'Gene', '2066', (280, 285))
567348	31810195	Initially, we observed that s-microg reliably induces spheroid formation in human ES cells.	('human', 'Species', '9606', (76, 81))	('s-microg', 'Chemical', '-', (28, 36))	('spheroid formation', 'CPA', (54, 72))	('induces', 'Reg', (46, 53))	('s-microg', 'Var', (28, 36))
567351	31810195	By applying s-microg, we achieved an opposite effect, with a transformation from a longitudinal to a spherical actin orientation.	('s-microg', 'Chemical', '-', (12, 20))	('s-microg', 'Var', (12, 20))	('transformation', 'Reg', (61, 75))
567354	31810195	Sustained expression of EWS/FLI1 is necessary to maintain the phenotype of this tumor, and EWS/FLI1 inhibition has been shown to reduce oncogenic transformation.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('EWS', 'Gene', '2130', (24, 27))	('EWS', 'Gene', (24, 27))	('oncogenic transformation', 'CPA', (136, 160))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('reduce', 'NegReg', (129, 135))	('tumor', 'Disease', (80, 85))	('EWS', 'Gene', (91, 94))	('EWS', 'Gene', '2130', (91, 94))	('inhibition', 'Var', (100, 110))
567355	31810195	EWS/FLI1 knockdown by RNA interference has been shown to have tremendous effects on Ewing s sarcoma cell motility and adhesion.	('knockdown', 'Var', (9, 18))	('effects', 'Reg', (73, 80))	('RNA interference', 'MPA', (22, 38))	('Ewing s sarcoma', 'Disease', (84, 99))	('adhesion', 'CPA', (118, 126))	('Ewing s sarcoma', 'Disease', 'MESH:C563168', (84, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('Ewing s sarcoma', 'Phenotype', 'HP:0012254', (84, 99))	('EWS', 'Gene', '2130', (0, 3))	('EWS', 'Gene', (0, 3))
567365	31810195	Overexpression of CD44 is supposed to be related to higher aggressiveness of the tumor.	('aggressiveness of the tumor', 'Disease', 'MESH:D001523', (59, 86))	('aggressiveness of the tumor', 'Disease', (59, 86))	('higher', 'PosReg', (52, 58))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CD44', 'Protein', (18, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (59, 73))
567379	31810195	Furthermore, it is possible that the set in of microgravity, which is a known stressor to mammalian cells, caused a stress reaction in tumor cells, protein synthesis stalled and has not yet caught up with an already reconstituting gene expression.	('stress', 'Disease', (78, 84))	('protein synthesis', 'MPA', (148, 165))	('stress', 'Disease', 'MESH:D000079225', (116, 122))	('caused', 'Reg', (107, 113))	('microgravity', 'Var', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('mammalian', 'Species', '9606', (90, 99))	('tumor', 'Disease', (135, 140))	('stress', 'Disease', (116, 122))	('stress', 'Disease', 'MESH:D000079225', (78, 84))	('stalled', 'NegReg', (166, 173))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
567408	31810195	Yet, despite reciprocal upregulation (reciprocal green arrow in Figure 6b) between the two, s-microg only significantly increases CXCR4 expression whereas CXCR7 expression remains unaffected.	('s-microg', 'Chemical', '-', (92, 100))	('CXCR7', 'Gene', '57007', (155, 160))	('upregulation', 'PosReg', (24, 36))	('s-microg', 'Var', (92, 100))	('increases', 'PosReg', (120, 129))	('CXCR7', 'Gene', (155, 160))	('CXCR4 expression', 'MPA', (130, 146))
567552	31610788	After exclusion of the patients with alveolar histology from the analysis, the patients with botryoid RME still had better survival rates compared to those with non-botryoid RME (OS: 100% vs 47%, 28-66, p = 0.084; EFS: 83%, 68-98 vs 38%, 21-55, p = 0.25).	('better', 'PosReg', (116, 122))	('patients', 'Species', '9606', (23, 31))	('botryoid RME', 'Var', (93, 105))	('patients', 'Species', '9606', (79, 87))	('survival rates', 'CPA', (123, 137))
567579	31610788	(2013) reported that liver irradiation was significantly associated with hepatic adverse effects in a large cohort of childhood cancer survivors (n = 1404, follow-up 12 years).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('child', 'Species', '9606', (118, 123))	('hepatic adverse effects', 'MPA', (73, 96))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('liver irradiation', 'Var', (21, 38))	('associated', 'Reg', (57, 67))	('cancer', 'Disease', (128, 134))
567691	26154614	Conversely, the median rIC50 for neuroblastoma lines (0.87 nM) is significantly greater than that of non-neuroblastoma cell lines (0.43 nM) (p=0.02).	('neuroblastoma lines', 'Disease', (33, 52))	('neuroblastoma', 'Phenotype', 'HP:0003006', (105, 118))	('rIC50', 'MPA', (23, 28))	('neuroblastoma', 'Phenotype', 'HP:0003006', (33, 46))	('greater', 'PosReg', (80, 87))	('non-neuroblastoma', 'Disease', 'MESH:D009447', (101, 118))	('0.87', 'Var', (54, 58))	('neuroblastoma lines', 'Disease', 'MESH:D009447', (33, 52))	('non-neuroblastoma', 'Disease', (101, 118))
567715	26154614	For cabazitaxel, Rh18, NB-1643, and NB-1691 (7.5 mg/kg group) met criteria for low EFS T/C activity, while for docetaxel 4 models (Rh18, KT-10, NB-1643, and NB-1691) met criteria for low activity.	('cabazitaxel', 'Chemical', 'MESH:C552428', (4, 15))	('NB-1643', 'Var', (23, 30))	('docetaxel', 'Chemical', 'MESH:D000077143', (111, 120))	('low EFS T', 'Disease', (79, 88))	('Rh18', 'Var', (17, 21))	('low EFS T', 'Disease', 'MESH:D009800', (79, 88))
567728	26154614	Although cabazitaxel is a substrate for p-glycoprotein, the level of resistance induced by p-glycoprotein is less for cabazitaxel than it is for docetaxel.	('level', 'MPA', (60, 65))	('p-glycoprotein', 'Gene', (40, 54))	('less', 'NegReg', (109, 113))	('p-glycoprotein', 'Gene', (91, 105))	('docetaxel', 'Chemical', 'MESH:D000077143', (145, 154))	('cabazitaxel', 'Chemical', 'MESH:C552428', (118, 129))	('cabazitaxel', 'Chemical', 'MESH:C552428', (9, 20))	('p-glycoprotein', 'Gene', '5243', (91, 105))	('p-glycoprotein', 'Gene', '5243', (40, 54))	('cabazitaxel', 'Var', (118, 129))
567734	26154614	It was reported that prostate cancer resistant to androgen therapy by virtue of RB1 mutations was more sensitive to cabazitaxel.	('prostate cancer', 'Disease', 'MESH:D011471', (21, 36))	('prostate cancer', 'Phenotype', 'HP:0012125', (21, 36))	('RB1', 'Gene', (80, 83))	('mutations', 'Var', (84, 93))	('prostate cancer', 'Disease', (21, 36))	('sensitive to cabazitaxel', 'MPA', (103, 127))	('RB1', 'Gene', '5925', (80, 83))	('cabazitaxel', 'Chemical', 'MESH:C552428', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
567735	26154614	In vitro, knockdown of RB1 using siRNA marginally sensitized LNCaP cells.	('LNCaP', 'CellLine', 'CVCL:0395', (61, 66))	('RB1', 'Gene', (23, 26))	('LNCaP cells', 'CPA', (61, 72))	('knockdown', 'Var', (10, 19))	('sensitized', 'Reg', (50, 60))	('RB1', 'Gene', '5925', (23, 26))
567737	26154614	None of the xenograft models used in the current testing have RB1 mutations.	('mutations', 'Var', (66, 75))	('RB1', 'Gene', (62, 65))	('RB1', 'Gene', '5925', (62, 65))
567756	25176350	Several fusion genes identified by whole transcriptome sequencing in a spindle cell sarcoma with rearrangements of chromosome arm 12q and MDM2 amplification Spindle cell tumors are clinically heterogeneous but morphologically similar neoplasms that can occur anywhere, mostly in adult patients.	('neoplasms', 'Disease', (234, 243))	('neoplasm', 'Phenotype', 'HP:0002664', (234, 242))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Disease', (84, 91))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('neoplasms', 'Phenotype', 'HP:0002664', (234, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('patients', 'Species', '9606', (285, 293))	('MDM2', 'Gene', '4193', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('MDM2', 'Gene', (138, 142))	('rearrangements', 'Var', (97, 111))	('tumors', 'Disease', (170, 176))	('neoplasms', 'Disease', 'MESH:D009369', (234, 243))
567758	25176350	Some of the tumor subtypes are characterized by the presence of distinct chromosomal translocations and fusion genes.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('fusion genes', 'Var', (104, 116))
567774	25176350	Cytogenetic and molecular genetic analyses of spindle cell sarcomas have led to the recognition of several distinct chromosomal translocations and fusion genes that characterize specific tumor types.	('cell sarcoma', 'Disease', (54, 66))	('sarcomas', 'Disease', 'MESH:D012509', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('fusion genes', 'Var', (147, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('sarcomas', 'Disease', (59, 67))	('tumor', 'Disease', (187, 192))	('cell sarcoma', 'Disease', 'MESH:D012509', (54, 66))
567775	25176350	For example, synovial sarcomas carry the translocation t(X;18)(p11;q11) in more than 95% of the cases.	('synovial sarcomas', 'Phenotype', 'HP:0012570', (13, 30))	('synovial sarcomas', 'Disease', (13, 30))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (55, 71))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (13, 29))	('synovial sarcomas', 'Disease', 'MESH:D013584', (13, 30))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('t(X;18)(p11;q11', 'Var', (55, 70))
567776	25176350	It results in rearrangement of the SS18 gene in 18q11 with one of the SSX1, SSX2 or SSX4 genes in Xp11 creating an SS18-SSX1, SS18-SSX2 or SS18-SSX4 chimeric gene.	('SS18', 'Gene', (139, 143))	('SS18', 'Gene', '6760', (126, 130))	('SS18', 'Gene', (115, 119))	('SSX4', 'Gene', '6759', (144, 148))	('SSX1', 'Gene', '6756', (70, 74))	('results in', 'Reg', (3, 13))	('SSX1', 'Gene', (70, 74))	('SS18', 'Gene', (35, 39))	('SSX4', 'Gene', (84, 88))	('SS18', 'Gene', '6760', (139, 143))	('SS18', 'Gene', '6760', (115, 119))	('SSX4', 'Gene', '6759', (84, 88))	('SSX2', 'Gene', (131, 135))	('SSX2', 'Gene', (76, 80))	('SS18', 'Gene', (126, 130))	('SS18', 'Gene', '6760', (35, 39))	('SSX2', 'Gene', '6757', (131, 135))	('SSX2', 'Gene', '6757', (76, 80))	('SSX1', 'Gene', '6756', (120, 124))	('rearrangement', 'Var', (14, 27))	('SSX1', 'Gene', (120, 124))	('SSX4', 'Gene', (144, 148))
567779	25176350	Dermatofibrosarcoma protuberans, another subtype of spindle cell sarcoma, is characterized cytogenetically either by supernumerary ring chromosomes (60% of all examined tumors) or by the translocation t(17;22)(q22;q13) (http://cgap.nci.nih.gov/Chromosomes/Mitelman).	('cell sarcoma', 'Disease', (60, 72))	('Dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (0, 31))	('Dermatofibrosarcoma protuberans', 'Disease', (0, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (7, 19))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (201, 218))	('cell sarcoma', 'Disease', 'MESH:D012509', (60, 72))	('tumors', 'Disease', (169, 175))	('t(17', 'Var', (201, 205))	('translocation t(17', 'Var', (187, 205))
567781	25176350	Solitary fibrous tumors are distinguished by their hemangiopericytoma-like branching vascular pattern, positivity for CD34 by immunohistochemistry and NAB2-STAT6 fusion.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('CD34', 'Gene', (118, 122))	('CD34', 'Gene', '947', (118, 122))	('hemangiopericytoma-like', 'Disease', (51, 74))	('positivity', 'Var', (103, 113))	('NAB2', 'Gene', '4665', (151, 155))	('fibrous tumors', 'Disease', (9, 23))	('STAT6', 'Gene', (156, 161))	('NAB2', 'Gene', (151, 155))	('STAT6', 'Gene', '6778', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('fibrous tumors', 'Disease', 'MESH:D054364', (9, 23))
567785	25176350	Alaggio et al described two spindle cell tumors with EWSR1-WT1 fusion gene and favorable prognosis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('WT1', 'Gene', '7490', (59, 62))	('WT1', 'Gene', (59, 62))	('EWSR1', 'Gene', (53, 58))	('EWSR1', 'Gene', '2130', (53, 58))	('fusion gene', 'Var', (63, 74))
567788	25176350	Recently, Nord et al reported a spindle cell sarcoma of the heart with ring chromosome, amplification of the MDM2 gene and homozygous deletion of CDKN2A.	('cell sarcoma', 'Disease', (40, 52))	('CDKN2A', 'Gene', (146, 152))	('MDM2', 'Gene', (109, 113))	('amplification', 'Var', (88, 101))	('CDKN2A', 'Gene', '1029', (146, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('cell sarcoma', 'Disease', 'MESH:D012509', (40, 52))	('MDM2', 'Gene', '4193', (109, 113))
567789	25176350	In the present study, we describe a spindle cell sarcoma with ring chromosome composed of chromosome 12 material, several fusion genes mapping to 12q, and amplification of MDM2.	('amplification', 'Var', (155, 168))	('cell sarcoma', 'Disease', (44, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('MDM2', 'Gene', '4193', (172, 176))	('MDM2', 'Gene', (172, 176))	('cell sarcoma', 'Disease', 'MESH:D012509', (44, 56))
567844	25176350	The multiple copies of MDM2 are not only correlated with the occurrence of ring chromosomes but are located on the rings.	('MDM2', 'Gene', '4193', (23, 27))	('multiple copies', 'Var', (4, 19))	('MDM2', 'Gene', (23, 27))	('correlated', 'Reg', (41, 51))	('ring chromosomes', 'CPA', (75, 91))
567857	25176350	Bicistronic transcripts encoding two independent proteins have been reported in humans, and a bicistronic CCND1-TROP2 mRNA chimera was even shown to have an oncogenic role in human cancer.	('human', 'Species', '9606', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('TROP2', 'Gene', '4070', (112, 117))	('TROP2', 'Gene', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('human', 'Species', '9606', (80, 85))	('oncogenic', 'CPA', (157, 166))	('CCND1', 'Gene', (106, 111))	('cancer', 'Disease', (181, 187))	('bicistronic', 'Var', (94, 105))	('humans', 'Species', '9606', (80, 86))	('CCND1', 'Gene', '595', (106, 111))
567869	25176350	In a recent study, Nord et al divided ring chromosomes in neoplastic cells into those with MDM2 amplification and those without MDM2 amplification.	('amplification', 'Var', (96, 109))	('MDM2', 'Gene', '4193', (91, 95))	('MDM2', 'Gene', (91, 95))	('MDM2', 'Gene', '4193', (128, 132))	('MDM2', 'Gene', (128, 132))
567870	25176350	The amplification of MDM2 is associated with co-amplification of a variety of potential driver oncogenes.	('MDM2', 'Gene', '4193', (21, 25))	('MDM2', 'Gene', (21, 25))	('amplification', 'Var', (4, 17))	('associated', 'Reg', (29, 39))	('co-amplification', 'MPA', (45, 61))
567871	25176350	Here we show that MDM2 amplification may be associated with a variety of fusion genes.	('associated', 'Reg', (44, 54))	('amplification', 'Var', (23, 36))	('MDM2', 'Gene', '4193', (18, 22))	('MDM2', 'Gene', (18, 22))	('fusion genes', 'Disease', (73, 85))
567879	24963049	HCI2509 caused a dramatic reversal of both the up- and down-regulated transcriptional profiles of EWS/FLI and EWS/ERG accompanied by the induction of apoptosis, and disruption of morphological and oncogenic phenotypes modulated by EWS/FLI.	('FLI', 'Gene', '2314', (102, 105))	('up-', 'PosReg', (47, 50))	('FLI', 'Gene', (235, 238))	('apoptosis', 'CPA', (150, 159))	('FLI', 'Gene', (102, 105))	('HCI2509', 'Var', (0, 7))	('HCI2509', 'Chemical', '-', (0, 7))	('down-regulated', 'NegReg', (55, 69))	('oncogenic phenotypes', 'CPA', (197, 217))	('transcriptional profiles', 'MPA', (70, 94))	('FLI', 'Gene', '2314', (235, 238))	('disruption', 'Reg', (165, 175))
567881	24963049	These data support epigenetic modulation with HCI2509 as a therapeutic strategy for Ewing sarcoma, and highlight a critical dual role for LSD1 in the oncogenic transcriptional activity of EWS/ETS proteins.	('Ewing sarcoma', 'Disease', (84, 97))	('HCI2509', 'Chemical', '-', (46, 53))	('HCI2509', 'Gene', (46, 53))	('LSD1', 'Gene', (138, 142))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (84, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('LSD1', 'Gene', '23028', (138, 142))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (84, 97))	('epigenetic modulation', 'Var', (19, 40))
567882	24963049	Indeed, enzymes which mediate epigenetic modifications are now emerging as therapeutic targets in cancer.	('epigenetic', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
567888	24963049	Recently, high LSD1 expression was reported in certain mesenchymal tumors, including Ewing sarcoma.	('Ewing sarcoma', 'Disease', (85, 98))	('expression', 'MPA', (20, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('reported', 'Reg', (35, 43))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (55, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('LSD1', 'Gene', (15, 19))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('mesenchymal tumors', 'Disease', (55, 73))	('high', 'Var', (10, 14))	('LSD1', 'Gene', '23028', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))
567921	24963049	Briefly, cells were immunostained with paxillin antibody (1:100) or LSD1 antibody (1:400), then with secondary antibody (1:100) and DAPI (0.3 muM).	('paxillin', 'Gene', '5829', (39, 47))	('LSD1', 'Gene', (68, 72))	('DAPI', 'Chemical', 'MESH:C007293', (132, 136))	('paxillin', 'Gene', (39, 47))	('LSD1', 'Gene', '23028', (68, 72))	('1:400', 'Var', (83, 88))
567926	24963049	Raw sequence reads can be found in the NCBI SRA under numbers SRA096343, SRA096347, SRA096354.	('SRA096354', 'Chemical', '-', (84, 93))	('SRA096343', 'Chemical', '-', (62, 71))	('SRA096354', 'Var', (84, 93))	('SRA096347', 'Chemical', '-', (73, 82))	('SRA096343', 'Var', (62, 71))	('SRA096347', 'Var', (73, 82))
567927	24963049	HCI2509 is a specific and reversible noncompetitive inhibitor of LSD1 previously shown to derepress the critical EWS/FLI target genes LOX and TGFBR2, and to kill multiple Ewing sarcoma cell lines in vitro.	('LSD1', 'Gene', (65, 69))	('kill', 'Reg', (157, 161))	('derepress', 'PosReg', (90, 99))	('LOX', 'Gene', (134, 137))	('Ewing sarcoma', 'Disease', (171, 184))	('LSD1', 'Gene', '23028', (65, 69))	('HCI2509', 'Var', (0, 7))	('TGFBR2', 'Gene', (142, 148))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (171, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('HCI2509', 'Chemical', '-', (0, 7))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (171, 184))	('FLI', 'Gene', '2314', (117, 120))	('FLI', 'Gene', (117, 120))	('TGFBR2', 'Gene', '7048', (142, 148))	('LOX', 'Gene', '4015', (134, 137))
567929	24963049	To determine whether the Ewing sarcoma cell death observed with HCI2509 treatment was also dependent on EWS/FLI, we knocked down the fusion protein using retroviral-mediated shRNA, and assessed viability after treatment with HCI2509.	('HCI2509', 'Chemical', '-', (225, 232))	('Ewing sarcoma cell death', 'Disease', 'MESH:C563168', (25, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Ewing sarcoma cell death', 'Disease', (25, 49))	('HCI2509', 'Chemical', '-', (64, 71))	('FLI', 'Gene', '2314', (108, 111))	('knocked', 'Var', (116, 123))	('FLI', 'Gene', (108, 111))	('fusion protein', 'Protein', (133, 147))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (25, 38))
567933	24963049	Like A673 cells, TTC-466 cells with EWS/ERG knockdown showed decreased sensitivity to HCI2509.	('TTC-466', 'CellLine', 'CVCL:A444', (17, 24))	('EWS/ERG', 'Gene', (36, 43))	('HCI2509', 'Chemical', '-', (86, 93))	('knockdown', 'Var', (44, 53))	('decreased', 'NegReg', (61, 70))	('sensitivity to HCI2509', 'MPA', (71, 93))
567940	24963049	The comparison of the HCI2509 signature with both fusion proteins showed treatment with HCI2509 comprehensively reversed the transcriptional profiles driven by both EWS/FLI (Figure 1B) and EWS/ERG (Figure 1C).	('transcriptional profiles', 'MPA', (125, 149))	('HCI2509', 'Gene', (88, 95))	('HCI2509', 'Chemical', '-', (22, 29))	('reversed', 'NegReg', (112, 120))	('HCI2509', 'Chemical', '-', (88, 95))	('EWS/ERG', 'Var', (189, 196))	('FLI', 'Gene', '2314', (169, 172))	('FLI', 'Gene', (169, 172))
567955	24963049	Together, these data illustrate that LSD1 inhibition has a unique dual effect in both transcriptional activation and repression mediated by EWS/FLI, while targeted inhibition of HDACs only blocks EWS/FLI mediated transcriptional repression.	('repression', 'MPA', (117, 127))	('FLI', 'Gene', (200, 203))	('FLI', 'Gene', '2314', (144, 147))	('inhibition', 'Var', (42, 52))	('LSD1', 'Gene', (37, 41))	('LSD1', 'Gene', '23028', (37, 41))	('FLI', 'Gene', (144, 147))	('FLI', 'Gene', '2314', (200, 203))	('transcriptional activation', 'MPA', (86, 112))
567957	24963049	The most significant classes of genes downregulated by HCI2509 are related to DNA replication and cell cycle while the classes of genes upregulated by HCI2509 are related to regulation of cell death and extracellular matrix (Figure S1I, S1J).	('upregulated', 'PosReg', (136, 147))	('DNA replication', 'CPA', (78, 93))	('HCI2509', 'Chemical', '-', (55, 62))	('cell death', 'CPA', (188, 198))	('HCI2509', 'Gene', (151, 158))	('downregulated', 'NegReg', (38, 51))	('HCI2509', 'Chemical', '-', (151, 158))	('extracellular matrix', 'CPA', (203, 223))	('HCI2509', 'Var', (55, 62))	('cell cycle', 'CPA', (98, 108))
567965	24963049	To test this, we first asked whether HCI2509 mimics the morphological phenotypes associated with EWS/ETS knockdown.	('EWS/ETS', 'Gene', (97, 104))	('knockdown', 'Var', (105, 114))	('HCI2509', 'Chemical', '-', (37, 44))
567968	24963049	EWS/FLI knockdown induces a robust actin cytoarchitecture with striking actin stress fibers anchored to integrin-based focal adhesions, increased cell adhesion, and spreading, that correlated with increased migration.	('knockdown', 'Var', (8, 17))	('spreading', 'CPA', (165, 174))	('FLI', 'Gene', '2314', (4, 7))	('cell adhesion', 'CPA', (146, 159))	('migration', 'CPA', (207, 216))	('increased', 'PosReg', (197, 206))	('FLI', 'Gene', (4, 7))	('increased', 'PosReg', (136, 145))	('actin stress', 'Protein', (72, 84))
567976	24963049	We next tested whether HCI2509 would impair EWS-ETS-driven oncogenic transformation using colony formation assays as a measure of anchorage-independent growth (Figure 3A-B, S3A-C).	('HCI2509', 'Var', (23, 30))	('impair', 'NegReg', (37, 43))	('EWS-ETS-driven oncogenic transformation', 'CPA', (44, 83))	('HCI2509', 'Chemical', '-', (23, 30))
567977	24963049	Interestingly, both the A673 and TTC-466 showed a shift in sensitivity (Figure 3A-B) to the low nanomolar range in 3D cultures.	('A673', 'Var', (24, 28))	('shift', 'Reg', (50, 55))	('sensitivity', 'MPA', (59, 70))	('TTC-466', 'Gene', (33, 40))	('TTC-466', 'CellLine', 'CVCL:A444', (33, 40))
567983	24963049	Thus, HCI2509 likely reduces Ewing sarcoma cell viability through induction of apoptosis.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (29, 42))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (29, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('HCI2509', 'Chemical', '-', (6, 13))	('apoptosis', 'CPA', (79, 88))	('HCI2509', 'Var', (6, 13))	('Ewing sarcoma', 'Disease', (29, 42))	('reduces', 'NegReg', (21, 28))
567985	24963049	TUNEL-stained cells treated with HCI2509 for 48 hours showed increased staining as compared to vehicle (Figure 3D).	('HCI2509', 'Chemical', '-', (33, 40))	('increased', 'PosReg', (61, 70))	('staining', 'MPA', (71, 79))	('HCI2509', 'Var', (33, 40))
567986	24963049	Similarly, treatment with HCI2509 showed increased activation of caspase 3/7 over 48 hours, which corresponded with decreased viability in multiple Ewing sarcoma cell lines (Figure 3E-F, S3D-F).	('caspase 3/7 over 48', 'Gene', '836', (65, 84))	('HCI2509', 'Var', (26, 33))	('HCI2509', 'Chemical', '-', (26, 33))	('Ewing sarcoma', 'Disease', (148, 161))	('caspase 3/7 over 48', 'Gene', (65, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('viability', 'MPA', (126, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (148, 161))	('activation', 'PosReg', (51, 61))	('decreased', 'NegReg', (116, 125))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (148, 161))
567987	24963049	Collectively, these data show HCI2509 not only reversed EWS/FLI-associated oncogenic phenotypes, but also altered H3K9 methylation status and induced apoptosis.	('H3K9', 'Protein', (114, 118))	('altered', 'Reg', (106, 113))	('HCI2509', 'Chemical', '-', (30, 37))	('HCI2509', 'Var', (30, 37))	('FLI', 'Gene', (60, 63))	('apoptosis', 'CPA', (150, 159))	('induced', 'PosReg', (142, 149))	('FLI', 'Gene', '2314', (60, 63))	('methylation status', 'MPA', (119, 137))
567990	24963049	HMOX1 was significantly upregulated by HCI2509 in both EWS/ETS transcriptional profiles.	('HCI2509', 'Chemical', '-', (39, 46))	('HCI2509', 'Var', (39, 46))	('HMOX1', 'Gene', (0, 5))	('upregulated', 'PosReg', (24, 35))	('HMOX1', 'Gene', '3162', (0, 5))
567994	24963049	We found HMOX1 protein levels elevated with EWS/FLI knockdown, returned to baseline levels with EWS/FLI reexpression (Figure 4C), and likewise increased in response to HCI2509 (Figure 4D).	('increased', 'PosReg', (143, 152))	('HMOX1', 'Gene', '3162', (9, 14))	('FLI', 'Gene', '2314', (100, 103))	('HCI2509', 'Chemical', '-', (168, 175))	('FLI', 'Gene', '2314', (48, 51))	('FLI', 'Gene', (100, 103))	('elevated', 'PosReg', (30, 38))	('FLI', 'Gene', (48, 51))	('knockdown', 'Var', (52, 61))	('HMOX1', 'Gene', (9, 14))
567997	24963049	Both siRNA-mediated knockdown of LSD1 and LSD1 inhibition with HCI2509 derepressed HMOX1 in a dose-dependent manner (Figure 4F-G).	('LSD1', 'Gene', (42, 46))	('derepressed', 'NegReg', (71, 82))	('LSD1', 'Gene', '23028', (42, 46))	('inhibition', 'NegReg', (47, 57))	('LSD1', 'Gene', (33, 37))	('LSD1', 'Gene', '23028', (33, 37))	('HCI2509', 'Chemical', '-', (63, 70))	('knockdown', 'Var', (20, 29))	('HMOX1', 'Gene', (83, 88))	('HMOX1', 'Gene', '3162', (83, 88))
567998	24963049	EWS/FLI knockdown resulted in similar HMOX1 induction as 100 nM LSD1 siRNA (Figure 4I).	('knockdown', 'Var', (8, 17))	('FLI', 'Gene', '2314', (4, 7))	('HMOX1', 'Gene', (38, 43))	('FLI', 'Gene', (4, 7))	('LSD1', 'Gene', (64, 68))	('LSD1', 'Gene', '23028', (64, 68))	('HMOX1', 'Gene', '3162', (38, 43))
567999	24963049	HMOX1 repression was restored with full-length EWS/FLI rescue; however rescue with either the Delta22 mutant lacking most of the EWS domain or the DNA-binding mutant R2L2 failed to repress HMOX1 (Figure 4I, S4B).	('mutant', 'Var', (102, 108))	('HMOX1', 'Gene', (0, 5))	('FLI', 'Gene', '2314', (51, 54))	('FLI', 'Gene', (51, 54))	('HMOX1', 'Gene', (189, 194))	('HMOX1', 'Gene', '3162', (0, 5))	('HMOX1', 'Gene', '3162', (189, 194))	('lacking', 'NegReg', (109, 116))	('Delta22', 'Mutation', 'c.del22', (94, 101))
568005	24963049	Only REST knockdown showed a significant, though lower magnitude, increase in HMOX1 mRNA (Figure S4C).	('HMOX1', 'Gene', (78, 83))	('increase', 'PosReg', (66, 74))	('knockdown', 'Var', (10, 19))	('HMOX1', 'Gene', '3162', (78, 83))
568007	24963049	Because HMOX1 protein was strongly induced in cells treated with HCI2509 in addition to those with EWS/FLI knockdown, we investigated whether HMOX1 affects cellular transformation.	('HMOX1', 'Gene', '3162', (142, 147))	('induced', 'PosReg', (35, 42))	('HMOX1', 'Gene', (8, 13))	('protein', 'Protein', (14, 21))	('HMOX1', 'Gene', '3162', (8, 13))	('HCI2509', 'Chemical', '-', (65, 72))	('HCI2509', 'Var', (65, 72))	('FLI', 'Gene', '2314', (103, 106))	('FLI', 'Gene', (103, 106))	('HMOX1', 'Gene', (142, 147))
568012	24963049	Having observed HCI2509-mediated disruption of global EWS/ETS transcriptional function, reversal of EWS/ETS-associated morphological and oncogenic phenotypes, and induction of apoptosis, we next investigated whether HCI2509 would impair tumorigenesis in vivo.	('tumor', 'Disease', (237, 242))	('impair', 'NegReg', (230, 236))	('disruption', 'NegReg', (33, 43))	('HCI2509-mediated', 'Gene', (16, 32))	('HCI2509', 'Chemical', '-', (216, 223))	('HCI2509', 'Var', (216, 223))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('EWS/ETS', 'Gene', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('HCI2509', 'Chemical', '-', (16, 23))
568015	24963049	Blood counts were also examined due to hematopoietic toxicity associated with LSD1 knockdown.	('knockdown', 'Var', (83, 92))	('LSD1', 'Gene', (78, 82))	('LSD1', 'Gene', '23028', (78, 82))	('toxicity', 'Disease', 'MESH:D064420', (53, 61))	('toxicity', 'Disease', (53, 61))
568016	24963049	Importantly, Animals treated with HCI2509 showed improved survival over 60 days (Figure 5C-D) as compared to vehicle in both A673 and SK-N-MC xenograft models.	('improved', 'PosReg', (49, 57))	('survival', 'CPA', (58, 66))	('HCI2509', 'Chemical', '-', (34, 41))	('HCI2509', 'Var', (34, 41))	('SK-N-MC', 'CellLine', 'CVCL:0530', (134, 141))
568022	24963049	Our findings reveal a novel dual role for LSD1 in mediating both the transcriptional activating and repressive function of EWS/ETS fusions in Ewing sarcoma and modulating the oncogenic phenotypes resulting from the presence of EWS/ETS fusions proteins.	('LSD1', 'Gene', (42, 46))	('fusions', 'Var', (131, 138))	('LSD1', 'Gene', '23028', (42, 46))	('transcriptional activating', 'MPA', (69, 95))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (142, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Ewing sarcoma', 'Disease', (142, 155))	('repressive function', 'MPA', (100, 119))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (142, 155))	('modulating', 'Reg', (160, 170))	('EWS/ETS', 'Gene', (123, 130))
568023	24963049	Small molecule blockade of LSD1 with the potent and reversible inhibitor, HCI2509, comprehensively disrupted the transcriptional signature of EWS/FLI and EWS/ERG as well as the subsequent downstream malignant characteristics of Ewing sarcoma cells as depicted in Figure 6.	('blockade', 'Var', (15, 23))	('LSD1', 'Gene', (27, 31))	('LSD1', 'Gene', '23028', (27, 31))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (228, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('transcriptional signature', 'MPA', (113, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (228, 241))	('HCI2509', 'Chemical', '-', (74, 81))	('disrupted', 'NegReg', (99, 108))	('malignant characteristics', 'CPA', (199, 224))	('FLI', 'Gene', '2314', (146, 149))	('FLI', 'Gene', (146, 149))	('Ewing sarcoma', 'Disease', (228, 241))
568035	24963049	LSD1-mediated demethylation of p53 disrupts association of its cofactor 53BP1 and prevents induction of apoptosis.	('LSD1', 'Gene', '23028', (0, 4))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('induction of apoptosis', 'CPA', (91, 113))	('53BP1', 'Protein', (72, 77))	('disrupts', 'NegReg', (35, 43))	('prevents', 'NegReg', (82, 90))	('demethylation', 'Var', (14, 27))	('LSD1', 'Gene', (0, 4))	('association', 'Interaction', (44, 55))
568042	24963049	Methylation at H3K9 is typically associated with gene repression so this may be linked to the apparent role of LSD1 in EWS/ETS-mediated gene activation.	('H3K9', 'Protein', (15, 19))	('LSD1', 'Gene', (111, 115))	('Methylation', 'Var', (0, 11))	('LSD1', 'Gene', '23028', (111, 115))	('gene', 'MPA', (49, 53))
568043	24963049	LSD1-mediated demethylation of MTA1 causes a switch in the associated complex from the repressive NuRD complex to the activated NURF complex.	('LSD1', 'Gene', '23028', (0, 4))	('switch', 'MPA', (45, 51))	('MTA1', 'Gene', '9112', (31, 35))	('demethylation', 'Var', (14, 27))	('MTA1', 'Gene', (31, 35))	('LSD1', 'Gene', (0, 4))	('associated complex', 'MPA', (59, 77))
568047	24963049	Inhibition of LSD1 in this model impaired the cellular migration and chemoresistance resulting from EMT.	('chemoresistance', 'CPA', (69, 84))	('LSD1', 'Gene', (14, 18))	('LSD1', 'Gene', '23028', (14, 18))	('impaired', 'NegReg', (33, 41))	('cellular migration', 'CPA', (46, 64))	('Inhibition', 'Var', (0, 10))
568055	24963049	While the presence of an EWS/ETS fusion may predict a favorable response to an LSD1 inhibitor, these results underscore the difficulty in identifying of appropriate treatment response biomarkers in Ewing sarcoma.	('LSD1', 'Gene', (79, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (198, 211))	('EWS/ETS', 'Gene', (25, 32))	('LSD1', 'Gene', '23028', (79, 83))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (198, 211))	('response to', 'MPA', (64, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('Ewing sarcoma', 'Disease', (198, 211))	('presence', 'Var', (10, 18))
568063	24963049	With several targeted LSD1 inhibitors in pre-clinical development, these results highlight a new therapeutic strategy for this disease.	('inhibitors', 'Var', (27, 37))	('LSD1', 'Gene', (22, 26))	('LSD1', 'Gene', '23028', (22, 26))
568213	32210617	The positive rates of phosphorylated (p)Akt, pmTOR, p4E-BP1, and CyclinD1 were 62.7%, 55.6%, 47.1%, and 52.6%, respectively.	('phosphorylated', 'Var', (22, 36))	('Akt', 'Gene', '207', (40, 43))	('pmTOR', 'Chemical', '-', (45, 50))	('4E-BP1', 'Gene', (53, 59))	('Akt', 'Gene', (40, 43))	('4E-BP1', 'Gene', '1978', (53, 59))	('CyclinD1', 'Var', (65, 73))	('pmTOR', 'Gene', (45, 50))
568277	32210617	The Akt/mTOR pathway regulates all critical phases of cell growth, including proliferation, differentiation, and apoptosis, and deregulation of this pathway has been reported in several types of tumours.	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('apoptosis', 'CPA', (113, 122))	('deregulation', 'Var', (128, 140))	('Akt', 'Gene', '207', (4, 7))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('regulates', 'Reg', (21, 30))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('differentiation', 'CPA', (92, 107))	('tumours', 'Disease', (195, 202))	('Akt', 'Gene', (4, 7))
568278	32210617	The oncogenic role of aberrant Akt/mTOR signalling pathway activation has been investigated in sarcoma.	('aberrant', 'Var', (22, 30))	('Akt', 'Gene', (31, 34))	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('Akt', 'Gene', '207', (31, 34))	('sarcoma', 'Disease', (95, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('activation', 'PosReg', (59, 69))
568315	32210617	As a downstream target of phosphorylated Akt, inhibition of mTOR would also be a potential therapeutic approach to reduce the effects of constitutively activated Akt in sarcomas.	('inhibition', 'Var', (46, 56))	('Akt', 'Gene', (162, 165))	('Akt', 'Gene', '207', (41, 44))	('sarcomas', 'Disease', 'MESH:D012509', (169, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('mTOR', 'Gene', (60, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('Akt', 'Gene', (41, 44))	('sarcomas', 'Disease', (169, 177))	('reduce', 'NegReg', (115, 121))	('Akt', 'Gene', '207', (162, 165))
568316	32210617	Previous studies have demonstrated that mTOR inhibition could decrease the proliferation, migration and invasion of multiple synovial sarcoma cell lines in vitro.	('mTOR', 'Protein', (40, 44))	('migration', 'CPA', (90, 99))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (125, 141))	('invasion of multiple', 'CPA', (104, 124))	('synovial sarcoma', 'Disease', 'MESH:D013584', (125, 141))	('decrease', 'NegReg', (62, 70))	('inhibition', 'Var', (45, 55))	('synovial sarcoma', 'Disease', (125, 141))	('proliferation', 'CPA', (75, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))
568365	28748443	Histomorphological codes M8800-M8806 were considered sarcoma lacking specific subtyping, and the availability of grade was assessed separately in the subgroup of liposarcoma (excluding well-differentiated tumors), fibrosarcoma, and leiomyosarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('sarcoma', 'Disease', (166, 173))	('sarcoma', 'Disease', (53, 60))	('sarcoma', 'Disease', 'MESH:D012509', (219, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('liposarcoma', 'Disease', (162, 173))	('sarcoma', 'Disease', (219, 226))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (232, 246))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (214, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (232, 246))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('tumors', 'Disease', (205, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('liposarcoma', 'Phenotype', 'HP:0012034', (162, 173))	('fibrosarcoma', 'Disease', 'MESH:D005354', (214, 226))	('M8800-M8806', 'Var', (25, 36))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('leiomyosarcoma', 'Disease', (232, 246))	('fibrosarcoma', 'Disease', (214, 226))	('liposarcoma', 'Disease', 'MESH:D008080', (162, 173))	('sarcoma', 'Disease', 'MESH:D012509', (239, 246))	('sarcoma', 'Disease', (239, 246))
568369	28748443	In particular, the prevalent guidelines recommend provision of adjuvant radiotherapy to patients with R1 resections, irrespective of their tumors' grade.	('men', 'Species', '9606', (45, 48))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('R1 resections', 'Var', (102, 115))
568431	21264837	We analyzed the characteristics, treatment administered, outcomes, and patterns of failure for infants < 1 year of age with non-metastatic RMS who were treated with multimodal therapy on Intergroup Rhabdomyosarcoma Study (IRS) protocols IRS-IV, D9602, and D9803.	('infants', 'Species', '9606', (95, 102))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (198, 214))	('D9602', 'Var', (245, 250))	('Rhabdomyosarcoma', 'Disease', (198, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('D9803', 'Var', (256, 261))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (198, 214))	('RMS', 'Phenotype', 'HP:0002859', (139, 142))
568452	21264837	The study population consists of infants with non-metastatic RMS who were treated on intergroup RMS studies, IRS-IV and IRS-V. IRS-V was conducted through the Children's Oncology Group (COG) as studies D9803 for "intermediate risk" RMS and D9602 for "low risk" RMS.	('D9803', 'Var', (202, 207))	('RMS', 'Phenotype', 'HP:0002859', (61, 64))	('non-metastatic RMS', 'Disease', (46, 64))	('Children', 'Species', '9606', (159, 167))	('RMS', 'Phenotype', 'HP:0002859', (96, 99))	('RMS', 'Phenotype', 'HP:0002859', (261, 264))	('RMS', 'Phenotype', 'HP:0002859', (232, 235))	('D9602', 'Var', (240, 245))	('Oncology', 'Phenotype', 'HP:0002664', (170, 178))	('infants', 'Species', '9606', (33, 40))
568483	21264837	Among the 1843 patients with non-metastatic RMS enrolled on IRS-IV, D9602, and D9803, 76 (4%) were < 1 year of age at the time of diagnosis (IRS-IV:n=41; D9602:n=20; D9803:n=15).	('patients', 'Species', '9606', (15, 23))	('D9803', 'Var', (166, 171))	('D9602', 'Var', (154, 159))	('D9602', 'Var', (68, 73))	('D9803', 'Var', (79, 84))	('RMS', 'Phenotype', 'HP:0002859', (44, 47))
568496	21264837	Outcome for patients with non-metastatic RMS treated on IRS-IV, D9602, and D9803 differed by age at diagnosis (Figure 1).	('patients', 'Species', '9606', (12, 20))	('non-metastatic RMS', 'Disease', (26, 44))	('RMS', 'Phenotype', 'HP:0002859', (41, 44))	('D9803', 'Var', (75, 80))	('D9602', 'Var', (64, 69))
568506	21264837	Thirty-four of 58 infants (59%) with Group II or Group III tumors underwent second look operations (SLO) after the initiation of protocol therapy: re-biopsy in 11 patients, incomplete excision in 9 patients, and complete excision (defined as resection with negative margins) in 14 patients.	('patients', 'Species', '9606', (163, 171))	('III tumors', 'Disease', 'MESH:D009369', (55, 65))	('incomplete', 'Var', (173, 183))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (281, 289))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('infants', 'Species', '9606', (18, 25))	('III tumors', 'Disease', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
568530	21264837	The overall incidence of local failure (defined as any local failure with or without failure at other sites) in this infant cohort was 30% compared to 13% for all patients treated on IRS-IV, D9602, and D9803.	('D9803', 'Var', (202, 207))	('local failure', 'Disease', 'MESH:D012594', (25, 38))	('patients', 'Species', '9606', (163, 171))	('local failure', 'Disease', 'MESH:D012594', (55, 68))	('infant', 'Species', '9606', (117, 123))	('D9602', 'Var', (191, 196))	('local failure', 'Disease', (25, 38))	('local failure', 'Disease', (55, 68))
568532	21264837	The rate of local failure for infants with Group III tumors was 42% compared to 17% for all Group III patients on IRS-IV, D9602, and D9803.	('III tumors', 'Disease', 'MESH:D009369', (49, 59))	('local failure', 'Disease', (12, 25))	('patients', 'Species', '9606', (102, 110))	('D9803', 'Var', (133, 138))	('D9602', 'Var', (122, 127))	('local failure', 'Disease', 'MESH:D012594', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('III tumors', 'Disease', (49, 59))	('infants', 'Species', '9606', (30, 37))
568536	21264837	While there has been a significant improvement in FFS for children with RMS over sequential IRS studies, the same improvement in outcome has not been seen for infants.	('improvement', 'PosReg', (35, 46))	('infants', 'Species', '9606', (159, 166))	('RMS', 'Phenotype', 'HP:0002859', (72, 75))	('RMS', 'Var', (72, 75))	('FFS', 'MPA', (50, 53))	('children', 'Species', '9606', (58, 66))
568598	31976102	Immunoperoxidase staining of paraffin tissue sections showed that these mononuclear cells expressed HLA-DR, CD33, CD56, KP1 (CD68), CD123, and dim focal MPO but were negative for CD34 and CD117, an immunophenotypic profile identical to that of the patient's previously diagnosed AML (Figures 2(a)-2(f)).	('HLA-DR', 'Var', (100, 106))	('AML', 'Disease', 'MESH:D015470', (279, 282))	('patient', 'Species', '9606', (248, 255))	('CD123', 'Gene', (132, 137))	('AML', 'Disease', (279, 282))	('AML', 'Phenotype', 'HP:0004808', (279, 282))	('CD68', 'Gene', '968', (125, 129))	('CD34', 'Gene', '947', (179, 183))	('CD117', 'Gene', '3815', (188, 193))	('MPO', 'Gene', '4353', (153, 156))	('CD33', 'Gene', '945', (108, 112))	('CD123', 'Gene', '3563', (132, 137))	('CD68', 'Gene', (125, 129))	('CD33', 'Gene', (108, 112))	('MPO', 'Gene', (153, 156))	('CD56', 'Gene', (114, 118))	('CD117', 'Gene', (188, 193))	('CD56', 'Gene', '4684', (114, 118))	('CD34', 'Gene', (179, 183))
568773	31703609	Melanocytes express highly immunogenic gangliosides that are also expressed on Schwann cells in the peripheral nervous system; thus, antibody formation against melanoma cells may also lead to immune-mediated neurotoxicities, including GBS/AIDP.	('neurotoxicities', 'Disease', 'MESH:D020258', (208, 223))	('ganglioside', 'Chemical', 'MESH:D005732', (39, 50))	('AIDP', 'Disease', (239, 243))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('neurotoxicities', 'Disease', (208, 223))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('AIDP', 'Disease', 'MESH:D020275', (239, 243))	('antibody', 'Var', (133, 141))	('AIDP', 'Phenotype', 'HP:0007131', (239, 243))	('lead to', 'Reg', (184, 191))
568814	31321082	Recently, the combination of doxorubicin with olaratumab in metastatic or unresectable doxorubicin-naive patients with sarcoma studied in a phase Ib-II clinical trial showed an improvement in the median overall survival (OS) of 11.8 months, compared with those patients who received doxorubicin monotherapy.	('doxorubicin', 'Chemical', 'MESH:D004317', (283, 294))	('patients', 'Species', '9606', (105, 113))	('doxorubicin', 'Chemical', 'MESH:D004317', (29, 40))	('combination', 'Var', (14, 25))	('olaratumab', 'Chemical', 'MESH:C000589393', (46, 56))	('improvement', 'PosReg', (177, 188))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('patients', 'Species', '9606', (261, 269))	('overall survival', 'MPA', (203, 219))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))
568866	26858920	Molecular testing revealed a BRAF V600E mutation in the primary tumor.	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('primary tumor', 'Disease', (56, 69))	('primary tumor', 'Disease', 'MESH:D009369', (56, 69))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('revealed', 'Reg', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('V600E', 'Var', (34, 39))
568891	26858920	Given his disease progression on prior chemotherapy and limited next therapeutic options, dual next-generation sequencing was performed and showed a BRAF V600E mutation.	('V600E', 'Var', (154, 159))	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('V600E', 'Mutation', 'rs113488022', (154, 159))
568893	26858920	This combination regimen was chosen over vemurafenib monotherapy because dabrafenib, plus trametinib, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.	('BRAF', 'Gene', (205, 209))	('overall survival', 'MPA', (125, 141))	('dabrafenib', 'Chemical', 'MESH:C561627', (73, 83))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('vemurafenib', 'Chemical', 'MESH:D000077484', (41, 52))	('melanoma', 'Disease', (191, 199))	('V600K', 'Mutation', 'rs121913227', (219, 224))	('toxicity', 'Disease', 'MESH:D064420', (262, 270))	('toxicity', 'Disease', (262, 270))	('trametinib', 'Chemical', 'MESH:C560077', (90, 100))	('V600K', 'Var', (219, 224))	('BRAF', 'Gene', '673', (205, 209))	('V600E', 'Mutation', 'rs113488022', (210, 215))	('patients', 'Species', '9606', (166, 174))	('improved', 'PosReg', (116, 124))
569057	33718180	In the early phase, ionization leads to inflammatory changes with extravasations, edema, and thrombotic state.	('edema', 'Disease', (82, 87))	('ionization', 'Var', (20, 30))	('leads to', 'Reg', (31, 39))	('extravasations', 'MPA', (66, 80))	('edema', 'Disease', 'MESH:D004487', (82, 87))	('thrombotic', 'Disease', 'MESH:D013927', (93, 103))	('edema', 'Phenotype', 'HP:0000969', (82, 87))	('inflammatory changes', 'CPA', (40, 60))	('thrombotic', 'Disease', (93, 103))
569062	33718180	The classic QUANTEC analysis established dose constraints for breast cancer patients with V25 Gy of <10% (dose per fraction = 2 Gy), corresponding to the risk of cardiac mortality of <1%, assessed 15 years post-RTH.	('patients', 'Species', '9606', (76, 84))	('mortality', 'Disease', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('mortality', 'Disease', 'MESH:D003643', (170, 179))	('V25 Gy', 'Var', (90, 96))
569063	33718180	The authors also reported the mean pericardium dose of >26 Gy and V30 >46% as risk factors for pericarditis.	('pericarditis', 'Disease', 'MESH:D010493', (95, 107))	('pericarditis', 'Phenotype', 'HP:0001701', (95, 107))	('V30', 'Var', (66, 69))	('pericarditis', 'Disease', (95, 107))
569140	30197062	In endometrioid endometrial cancer, OS was significantly worse in metachronous cases compared to non-metachronous cases (HR 6.17, P < 0.001).	('endometrioid endometrial cancer', 'Disease', (3, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('metachronous', 'Var', (66, 78))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (3, 34))	('endometrial cancer', 'Phenotype', 'HP:0012114', (16, 34))	('worse', 'NegReg', (57, 62))
569144	30197062	Similarly, in early-stage endometrial cancer, metachronous cases were significantly associated with decreased OS compared to non-metachronous cases (HR for stage I-II: 5.29, P < 0.001).	('endometrial cancer', 'Disease', 'MESH:D016889', (26, 44))	('metachronous cases', 'Var', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('decreased', 'NegReg', (100, 109))	('endometrial cancer', 'Disease', (26, 44))	('endometrial cancer', 'Phenotype', 'HP:0012114', (26, 44))
569151	30197062	Due to lack of prior studies examining the tumor factor-specific significance of metachronous uterine malignancy, it remains unknown as to why metachronicity impacts survival more in tumors that are low-grade, early-stage, and of endometrioid histology compared to tumors that are high-grade, advanced-stage, and of non-endometrioid histology.	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumor', 'Disease', (43, 48))	('tumors', 'Disease', (183, 189))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('uterine malignancy', 'Phenotype', 'HP:0010784', (94, 112))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('survival', 'MPA', (166, 174))	('low-grade', 'Var', (199, 208))	('metachronous uterine malignancy', 'Disease', 'MESH:D016609', (81, 112))	('impacts', 'Reg', (158, 165))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (183, 188))	('endometrioid', 'Disease', (230, 242))	('metachronous uterine malignancy', 'Disease', (81, 112))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumors', 'Disease', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
569161	30197062	Radiotherapy is generally known, however, to induce enhanced short-term immune function via various mechanisms such as increased immunogenic cell death but the long-term effects are not known.	('enhanced', 'PosReg', (52, 60))	('Radiotherapy', 'Var', (0, 12))	('death', 'Disease', 'MESH:D003643', (146, 151))	('death', 'Disease', (146, 151))
569164	30197062	This observation is likely due to the fact that women with lower grade cervical cancers have more favorable survival and are more likely to be cured of their disease and become cancer survivors, with the potential to develop metachronous uterine malignancy several years remote from their cervical cancer diagnosis.	('lower grade', 'Var', (59, 70))	('cancer', 'Disease', (177, 183))	('cervical cancer', 'Disease', 'MESH:D002583', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('women', 'Species', '9606', (48, 53))	('uterine malignancy', 'Phenotype', 'HP:0010784', (238, 256))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('metachronous uterine malignancy', 'Disease', 'MESH:D016609', (225, 256))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cervical cancers', 'Disease', (71, 87))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cervical cancers', 'Disease', 'MESH:D002583', (71, 87))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('more', 'PosReg', (93, 97))	('cervical cancer', 'Disease', (289, 304))	('cervical cancer', 'Disease', 'MESH:D002583', (289, 304))	('metachronous uterine malignancy', 'Disease', (225, 256))	('develop', 'PosReg', (217, 224))	('cancer', 'Disease', (298, 304))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
569223	32083956	Collected data fields include the following: demographic information (age, sex, country of residence); tumor diagnostic information (date of diagnosis, primary site, tumor histologic type, genetic testing); treatment information (surgeries and biopsies, radiation therapies, drug therapy received, including drug access:such as participation in clinical trials, and adverse effects experienced); risk factors for the development of tumors (family history of cancer, germline mutation testing, history of an inherited familial cancer syndrome, smoking and alcohol consumption); and comorbidities.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (458, 464))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('alcohol', 'Chemical', 'MESH:D000438', (555, 562))	('cancer', 'Phenotype', 'HP:0002664', (526, 532))	('inherited familial cancer syndrome', 'Disease', 'MESH:D009386', (507, 541))	('tumors', 'Disease', 'MESH:D009369', (432, 438))	('men', 'Species', '9606', (424, 427))	('tumor', 'Disease', (432, 437))	('germline mutation testing', 'Var', (466, 491))	('cancer', 'Disease', 'MESH:D009369', (526, 532))	('tumor', 'Disease', 'MESH:D009369', (432, 437))	('inherited familial cancer syndrome', 'Disease', (507, 541))	('cancer', 'Disease', (458, 464))	('tumor', 'Disease', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (432, 438))	('tumor', 'Disease', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (458, 464))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('men', 'Species', '9606', (212, 215))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (432, 437))	('tumors', 'Disease', (432, 438))	('cancer', 'Disease', (526, 532))
569285	32083956	One of the hallmarks of an unrecognized germline mutation is a family history that includes rare tumors occurring in more than one individual or multiple primary tumors occurring within an individual, so CART-WHEEL.org can provide a fertile platform for discovery of novel cancer predisposition genes.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('CART', 'Gene', '9607', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CART', 'Gene', (204, 208))	('mutation', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
569364	28848704	Angio-computed tomography: Filling defect in the pulmonary artery trunk, extending from the subvalvular area to the origin of the right pulmonary artery.	('pulmonary artery trunk', 'Disease', (49, 71))	('pulmonary artery trunk', 'Disease', 'MESH:D000071079', (49, 71))	('Filling defect', 'Var', (27, 41))
569478	26909615	In addition, biodistribution studies demonstrated high uptake of iodinated Ontuxizumab in tumors compared to normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('iodinated', 'Var', (65, 74))	('rat', 'Species', '10116', (44, 47))	('Ontuxizumab', 'Gene', (75, 86))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('uptake', 'MPA', (55, 61))	('Ontuxizumab', 'Chemical', '-', (75, 86))
569479	26909615	First, to develop a 89Zr-PET imaging agent for imaging of TEM-1 expression as 89Zr is known to be a residualizing radionuclide (trapped inside cells after metabolism) and thus has the potential of generating higher quality images.	('TEM-1', 'Gene', (58, 63))	('89Zr', 'Var', (78, 82))	('rat', 'Species', '10116', (201, 204))	('radionuclide', 'Chemical', 'MESH:D011868', (114, 126))	('89Zr', 'Chemical', 'MESH:C000615502', (78, 82))	('89Zr', 'Chemical', 'MESH:C000615502', (20, 24))
569511	26909615	The in vivo utility of 89Zr-Ontuxizumab was demonstrated in RD-ES and LUPI xenografts with RD-ES xenografts displaying significantly higher SUVs at post-injection PET imaging at both 3 and 7 days when compared to LUPI xenografts.	('RD-ES', 'Var', (91, 96))	('SUVs', 'MPA', (140, 144))	('higher', 'PosReg', (133, 139))	('RD', 'Phenotype', 'HP:0002859', (91, 93))	('Ontuxizumab', 'Chemical', '-', (28, 39))	('RD', 'Phenotype', 'HP:0002859', (60, 62))	('89Zr', 'Chemical', 'MESH:C000615502', (23, 27))	('rat', 'Species', '10116', (51, 54))
569513	26909615	Biodistribution studies performed 7 days post-injection of the 89Zr-Ontuxizumab showed accumulation of the antibody within the target tumor, while non-target tissues and organs of interest showed very little uptake of the antibody.	('Ontuxizumab', 'Chemical', '-', (68, 79))	('accumulation', 'PosReg', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('89Zr-Ontuxizumab', 'Var', (63, 79))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('89Zr', 'Chemical', 'MESH:C000615502', (63, 67))
569664	25299066	Studies have linked the expression of KSHV latency genes ORF71 (v-FLIP), -72 (v-Cyclin), -73 (LANA-1) and K12 (Kaposin A) to the oncogenic activity of latently infected cells.	('KS', 'Phenotype', 'HP:0100726', (38, 40))	('KSHV', 'Species', '37296', (38, 42))	('ORF71', 'Gene', (57, 62))	('Kaposin A', 'Gene', (111, 120))	('ORF71', 'Gene', '4961494', (57, 62))	('KSHV', 'Gene', (38, 42))	('K12', 'Var', (106, 109))	('Kaposin A', 'Gene', '4961446', (111, 120))	('oncogenic activity', 'CPA', (129, 147))
569665	25299066	These genes induce the oncogenic potential of KSHV by increasing proliferative potential, growth and chromosome instability as well as by preventing apoptosis of the infected cells.	('oncogenic potential', 'CPA', (23, 42))	('apoptosis', 'CPA', (149, 158))	('preventing', 'NegReg', (138, 148))	('increasing', 'PosReg', (54, 64))	('growth', 'CPA', (90, 96))	('chromosome instability', 'CPA', (101, 123))	('genes', 'Var', (6, 11))	('KSHV', 'Species', '37296', (46, 50))	('KS', 'Phenotype', 'HP:0100726', (46, 48))	('induce', 'PosReg', (12, 18))	('chromosome instability', 'Phenotype', 'HP:0040012', (101, 123))	('proliferative potential', 'CPA', (65, 88))	('KSHV', 'Gene', (46, 50))
569691	25299066	Similar to de novo KSHV infection, higher levels of glutamate release were observed in KSHV(+) TIVE-LTC cells than in KSHV(-) TIVE cells (Figure 1B).	('levels of glutamate release', 'MPA', (42, 69))	('KSHV infection', 'Disease', 'MESH:C537372', (19, 33))	('KSHV', 'Species', '37296', (87, 91))	('glutamate', 'Chemical', 'MESH:D018698', (52, 61))	('KSHV infection', 'Disease', (19, 33))	('KSHV(+) TIVE-LTC', 'Var', (87, 103))	('KS', 'Phenotype', 'HP:0100726', (87, 89))	('KSHV', 'Species', '37296', (118, 122))	('KS', 'Phenotype', 'HP:0100726', (118, 120))	('KSHV', 'Species', '37296', (19, 23))	('KS', 'Phenotype', 'HP:0100726', (19, 21))	('higher', 'PosReg', (35, 41))
569692	25299066	When the association of glutamate to PEL was assessed, high levels of glutamate release were observed in KSHV (+) BCBL-1 and BJAB-KSHV cells compared to the KSHV (-) B-cell line BJAB (Figure 1C).	('high levels of glutamate', 'Phenotype', 'HP:0500149', (55, 79))	('KS', 'Phenotype', 'HP:0100726', (157, 159))	('KSHV (+', 'Var', (105, 112))	('glutamate', 'Chemical', 'MESH:D018698', (24, 33))	('PEL', 'Phenotype', 'HP:0030069', (37, 40))	('BJAB', 'CellLine', 'CVCL:5711', (178, 182))	('KSHV', 'Species', '37296', (105, 109))	('BCBL-1', 'CellLine', 'CVCL:0165', (114, 120))	('glutamate release', 'MPA', (70, 87))	('glutamate', 'Chemical', 'MESH:D018698', (70, 79))	('KS', 'Phenotype', 'HP:0100726', (130, 132))	('BJAB', 'CellLine', 'CVCL:5711', (125, 129))	('KSHV', 'Species', '37296', (130, 134))	('KSHV', 'Species', '37296', (157, 161))	('KS', 'Phenotype', 'HP:0100726', (105, 107))	('BJAB-KSHV', 'CellLine', 'CVCL:5711', (125, 134))
569698	25299066	To further investigate the role of glutaminase in glutamate secretion, we used a glutaminase specific inhibitor, L-DON (6-diazo-5-oxo-norleucine).	('L-DON', 'Var', (113, 118))	('glutaminase', 'Gene', (81, 92))	('glutaminase', 'Gene', '2744', (35, 46))	('6-diazo-5-oxo-norleucine', 'Chemical', 'MESH:C000590535', (120, 144))	('glutaminase', 'Gene', '2744', (81, 92))	('L-DON', 'Chemical', '-', (113, 118))	('glutamate', 'Chemical', 'MESH:D018698', (50, 59))	('glutaminase', 'Gene', (35, 46))
569700	25299066	We found that 500 microM of L-DON inhibited glutamate secretion by >50% and 1 mM of L-DON by >65%.	('L-DON', 'Chemical', '-', (28, 33))	('L-DON', 'Var', (28, 33))	('glutamate', 'Chemical', 'MESH:D018698', (44, 53))	('inhibited', 'NegReg', (34, 43))	('L-DON', 'Chemical', '-', (84, 89))	('glutamate secretion', 'MPA', (44, 63))
569705	25299066	To test this hypothesis, when BJAB cells were transduced with lentivirus constructs of LANA-1, we observed increased secretion of glutamate in LANA-1 transduced cells compared to vector alone (Figure 2A).	('LANA-1', 'Gene', (87, 93))	('transduced', 'Var', (150, 160))	('increased', 'PosReg', (107, 116))	('BJAB', 'CellLine', 'CVCL:5711', (30, 34))	('LANA-1', 'Gene', (143, 149))	('secretion of glutamate', 'MPA', (117, 139))	('glutamate', 'Chemical', 'MESH:D018698', (130, 139))
569706	25299066	We also observed ~2-fold increase in c-Myc and glutaminase protein expression in LANA-1 transduced cells (Figure 2B).	('increase', 'PosReg', (25, 33))	('glutaminase', 'Gene', (47, 58))	('LANA-1', 'Gene', (81, 87))	('c-Myc', 'Gene', '4609', (37, 42))	('c-Myc', 'Gene', (37, 42))	('transduced', 'Var', (88, 98))	('glutaminase', 'Gene', '2744', (47, 58))
569707	25299066	To support our finding that LANA-1 mediated c-Myc activation is directly involved in glutaminase expression and glutamate secretion, we used lentiviruses encoding shRNAs to knock down c-Myc in BJAB cells over expressing LANA-1.	('glutamate', 'Chemical', 'MESH:D018698', (112, 121))	('knock', 'Var', (173, 178))	('c-Myc', 'Gene', '4609', (184, 189))	('glutaminase', 'Gene', (85, 96))	('c-Myc', 'Gene', '4609', (44, 49))	('c-Myc', 'Gene', (184, 189))	('LANA-1', 'Gene', (220, 226))	('glutaminase', 'Gene', '2744', (85, 96))	('BJAB', 'CellLine', 'CVCL:5711', (193, 197))	('c-Myc', 'Gene', (44, 49))
569711	25299066	A significant reduction in glutaminase expression was observed in c-Myc knockdown TIVE-LTC cells (61%) and BCBL-1 cells (67%) compared to control shRNA transduced cells (Figures 2C and D).	('glutaminase', 'Gene', '2744', (27, 38))	('c-Myc', 'Gene', '4609', (66, 71))	('BCBL-1', 'CellLine', 'CVCL:0165', (107, 113))	('c-Myc', 'Gene', (66, 71))	('glutaminase', 'Gene', (27, 38))	('reduction', 'NegReg', (14, 23))	('knockdown', 'Var', (72, 81))
569744	25299066	As shown in figure 6D, compared to the untreated cells (lanes 3, 5, and 7), MG132 treatment increased the protein level of REST in the infected BJAB-KSHV, BCBL-1, and TIVE-LTC cells (lanes 4, 6, and 8).	('MG132', 'Gene', (76, 81))	('treatment', 'Var', (82, 91))	('BCBL-1', 'CellLine', 'CVCL:0165', (155, 161))	('KS', 'Phenotype', 'HP:0100726', (149, 151))	('BJAB-KSHV', 'CellLine', 'CVCL:5711', (144, 153))	('increased', 'PosReg', (92, 101))	('MG132', 'Chemical', 'MESH:C072553', (76, 81))	('protein level of REST', 'MPA', (106, 127))
569745	25299066	However, MG132 treatment had no significant effect on the REST protein level in uninfected BJAB cells (lanes 1 and 2).	('BJAB', 'CellLine', 'CVCL:5711', (91, 95))	('REST protein level', 'MPA', (58, 76))	('MG132', 'Chemical', 'MESH:C072553', (9, 14))	('MG132', 'Var', (9, 14))
569748	25299066	ORF K12 or Kaposin A transduction led to a robust increase in mGluR1 expression in BJAB cells, indicating the involvement of Kaposin A in the regulation of mGluR1 expression, whereas the other latent genes did not significantly induce the expression of mGluR1 (Figure 7A).	('transduction', 'Var', (21, 33))	('Kaposin A', 'Gene', (125, 134))	('mGluR1', 'Gene', (62, 68))	('Kaposin A', 'Gene', (11, 20))	('Kaposin A', 'Gene', '4961446', (11, 20))	('ORF K12', 'Var', (0, 7))	('expression', 'MPA', (69, 79))	('increase', 'PosReg', (50, 58))	('BJAB', 'CellLine', 'CVCL:5711', (83, 87))	('Kaposin A', 'Gene', '4961446', (125, 134))	('mGluR1', 'Gene', (156, 162))	('involvement', 'Reg', (110, 121))
569768	25299066	In contrast, the serine phosphorylation of REST was severely impaired in Kaposin A and FLAG-REST triple mutant transduced cells suggesting that Kaposin A mediates REST phosphorylation in its phosphodegron sites.	('Kaposin A', 'Gene', (144, 153))	('FLAG-REST', 'Gene', (87, 96))	('Kaposin A', 'Gene', (73, 82))	('Kaposin A', 'Gene', '4961446', (144, 153))	('serine', 'Chemical', 'MESH:D012694', (17, 23))	('serine phosphorylation', 'MPA', (17, 39))	('Kaposin A', 'Gene', '4961446', (73, 82))	('impaired', 'NegReg', (61, 69))	('triple mutant', 'Var', (97, 110))
569772	25299066	To further investigate which specific degron site is phosphorylated by Kaposin A, we transiently transduced 293T cells with lentiviral Kaposin A and 48 h after transduction, the cells were transfected with pCMV-FLAG-REST WT plasmid or pCMV-FLAG-REST individually mutated at serine 1024, (pCMV-FLAG-REST-S1024A), 1027 (pCMV-FLAG-REST-S1027A), or 1030 (pCMV-FLAG-REST-S1030A).	('serine', 'Chemical', 'MESH:D012694', (274, 280))	('pCMV-FLAG-REST-S1024A', 'Var', (288, 309))	('293T', 'CellLine', 'CVCL:0063', (108, 112))	('Kaposin A', 'Gene', (135, 144))	('S1027A', 'Mutation', 'p.S1027A', (333, 339))	('S1024A', 'Mutation', 'p.S1024A', (303, 309))	('Kaposin A', 'Gene', (71, 80))	('mutated', 'Var', (263, 270))	('S1030A', 'Mutation', 'p.S1030A', (366, 372))	('Kaposin A', 'Gene', '4961446', (135, 144))	('serine 1024', 'Var', (274, 285))	('Kaposin A', 'Gene', '4961446', (71, 80))
569774	25299066	As shown in Figure 10B, the serine 1027 mutant completely abolished the capacity for phosphorylation (Figure 10B, lane 5, first and second panel).	('capacity for phosphorylation', 'MPA', (72, 100))	('abolished', 'NegReg', (58, 67))	('serine 1027', 'Var', (28, 39))	('serine', 'Chemical', 'MESH:D012694', (28, 34))
569775	25299066	However, the serine 1024 and 1030 mutants had no effect on phosphorylation compared to wild type REST (Figure 10B, lane 4 and 6, first and second panel), indicating that the phosphorylation of these two sites are not directly mediated by Kaposin A.	('serine', 'Chemical', 'MESH:D012694', (13, 19))	('phosphorylation', 'MPA', (59, 74))	('Kaposin A', 'Gene', (238, 247))	('Kaposin A', 'Gene', '4961446', (238, 247))	('serine 1024', 'Var', (13, 24))
569776	25299066	The defect in REST phosphorylation in mutant serine 1027 suggested that Kaposin A initially phosphorylates REST on serine 1027.	('mutant', 'Var', (38, 44))	('Kaposin A', 'Gene', (72, 81))	('Kaposin A', 'Gene', '4961446', (72, 81))	('REST phosphorylation', 'MPA', (14, 34))	('serine', 'Chemical', 'MESH:D012694', (45, 51))	('serine', 'Chemical', 'MESH:D012694', (115, 121))
569777	25299066	In order to determine whether the serine 1027 induced phosphorylation is responsible for REST ubiquitination, the cell lysates immunoprecipitated with anti-FLAG antibody were analyzed by Western blotting with an anti-polyubiquitin antibody.	('serine', 'Chemical', 'MESH:D012694', (34, 40))	('REST ubiquitination', 'Disease', (89, 108))	('REST ubiquitination', 'Disease', 'MESH:C563003', (89, 108))	('serine', 'Var', (34, 40))	('phosphorylation', 'MPA', (54, 69))
569783	25299066	To further verify the role of Kaposin A in REST phosphorylation, 293T cells transduced with vector alone or Kaposin A were transfected with FLAG-REST S1027 or FLAG-REST WT first and then transfected with control or Kaposin A specific siRNA.	('Kaposin A', 'Gene', '4961446', (215, 224))	('293T', 'CellLine', 'CVCL:0063', (65, 69))	('Kaposin A', 'Gene', '4961446', (30, 39))	('Kaposin A', 'Gene', (108, 117))	('Kaposin A', 'Gene', '4961446', (108, 117))	('S1027', 'Var', (150, 155))	('Kaposin A', 'Gene', (215, 224))	('Kaposin A', 'Gene', (30, 39))
569792	25299066	This increased proliferation of HMVEC-d cells was significantly reduced by exposure to riluzole, A841720 and Bay 36-7620 (Figure 11A).	('Bay 36-7620', 'Var', (109, 120))	('Bay 36', 'Chemical', '-', (109, 115))	('HMVEC-d', 'CellLine', 'CVCL:6870', (32, 39))	('proliferation', 'CPA', (15, 28))	('increased', 'PosReg', (5, 14))	('A841720', 'Var', (97, 104))	('reduced', 'NegReg', (64, 71))	('riluzole', 'Chemical', 'MESH:D019782', (87, 95))
569794	25299066	We further tested the involvement of riluzole, A841720, and Bay 36-7620 in TIVE and TIVE-LTC, BJAB and BCBL-1 cell proliferation by BrdU cell proliferation ELISA.	('A841720', 'Var', (47, 54))	('BCBL-1', 'CellLine', 'CVCL:0165', (103, 109))	('riluzole', 'Chemical', 'MESH:D019782', (37, 45))	('Bay 36', 'Chemical', '-', (60, 66))	('tested', 'Reg', (11, 17))	('BrdU', 'Chemical', 'MESH:D001973', (132, 136))	('BJAB', 'CellLine', 'CVCL:5711', (94, 98))
569795	25299066	As shown in Figure 11B, treatment with riluzole, A841720 and Bay 36-7620 showed a concentration dependent decrease in the proliferation of both TIVE-LTC and BCBL-1 cells (Figures 11B and C).	('BCBL-1', 'CellLine', 'CVCL:0165', (157, 163))	('Bay 36', 'Chemical', '-', (61, 67))	('A841720', 'Var', (49, 56))	('decrease', 'NegReg', (106, 114))	('riluzole', 'Chemical', 'MESH:D019782', (39, 47))	('proliferation', 'CPA', (122, 135))
569798	25299066	Riluzole, A841720, and Bay 36-7620 caused a 60-70% decrease in cell growth compared to the untreated control (Fig.	('Bay 36', 'Chemical', '-', (23, 29))	('A841720', 'Var', (10, 17))	('decrease', 'NegReg', (51, 59))	('Riluzole', 'Chemical', 'MESH:D019782', (0, 8))	('cell growth', 'CPA', (63, 74))
569831	25299066	These modifications would create a favorable molecular environment for the cross talk between REST and beta-TRCP.	('beta-TRCP', 'Gene', (103, 112))	('modifications', 'Var', (6, 19))	('cross talk', 'MPA', (75, 85))	('beta-TRCP', 'Gene', '8945', (103, 112))
569852	25299066	Mouse anti-c-Myc (9E10) and REST antibodies were from Santa Cruz, Santa Cruz, CA.	('Mouse', 'Species', '10090', (0, 5))	('9E10', 'Var', (18, 22))	('c-Myc', 'Gene', (11, 16))	('c-Myc', 'Gene', '4609', (11, 16))
569859	25299066	Riluzole, A841720 and Bay 36-7620 were from Tocris Bioscience, Minneapolis, MN.	('Tocris Bioscience', 'Disease', 'None', (44, 61))	('Tocris Bioscience', 'Disease', (44, 61))	('Bay 36', 'Chemical', '-', (22, 28))	('MN', 'CellLine', 'CVCL:U508', (76, 78))	('A841720', 'Var', (10, 17))	('Riluzole', 'Chemical', 'MESH:D019782', (0, 8))
569860	25299066	Plasmids encoding FLAG-tagged human REST wild-type and site-specific REST mutant plasmids (pCMV-FLAG-REST-S1024A, pCMV-FLAG-REST-S1027A, pCMV-FLAG-REST-S1030A), wild type FLAG-REST and triple mutant FLAG-REST-S1024/1027/1030A cloned into retroviral vector pQCXIN were provided by Dr. Stephen Elledge (Harvard Medical School).	('S1024A', 'Mutation', 'p.S1024A', (106, 112))	('human', 'Species', '9606', (30, 35))	('pCMV-FLAG-REST-S1024A', 'Var', (91, 112))	('S1030A', 'Mutation', 'p.S1030A', (152, 158))	('S1027A', 'Mutation', 'p.S1027A', (129, 135))	('pCMV-FLAG-REST-S1027A', 'Var', (114, 135))	('S1024', 'Chemical', '-', (209, 214))	('S1024', 'Chemical', '-', (106, 111))
569873	25299066	A pool of two siRNAs synthesized by Integrated DNA technologies (IDT) were used to knockdown Kaposin A. siRNA sequences were as follows: siRNA1- 5'-r(UUGCAACUCGUGUCCUGAAUGCUACGG)-3', siRNA2-5'- r(CCACAAACACCGUUAAGCCUCUAUCCA)-3'.	("siRNA1- 5'-r", 'Var', (137, 149))	('Kaposin A', 'Gene', '4961446', (93, 102))	('Kaposin A', 'Gene', (93, 102))
569901	31324031	Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the TP53 mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as CCNE1 and c-MYC.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (74, 95))	('c-MYC', 'Gene', '4609', (284, 289))	('mutation', 'Var', (123, 131))	('CCNE1', 'Gene', '898', (274, 279))	('CCNE1', 'Gene', (274, 279))	('amplification', 'Var', (228, 241))	('TP53', 'Gene', '7157', (118, 122))	('ECS', 'Chemical', '-', (5, 8))	('TP53', 'Gene', (118, 122))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (74, 95))	('c-MYC', 'Gene', (284, 289))	('endometrial carcinoma', 'Disease', (74, 95))	('accompanied', 'Reg', (151, 162))
569902	31324031	However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as PTEN, PI3KCA, or ARID1A), after the acquisition of the TP53 mutations.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('TP53', 'Gene', '7157', (261, 265))	('ARID1A', 'Gene', '8289', (223, 229))	('ARID1A', 'Gene', (223, 229))	('PI3', 'Gene', '5266', (212, 215))	('TP53', 'Gene', (261, 265))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('PI3', 'Gene', (212, 215))	('mutations', 'Var', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PTEN', 'Gene', (206, 210))	('tumors', 'Disease', (75, 81))	('PTEN', 'Gene', '5728', (206, 210))
569945	31324031	Four molecular groups have been defined for ECs: the hypermutated (mismatch repair deficiency), the ultramutated (POLE mutated), the copy-number low, and the copy-number high groups.	('deficiency', 'Disease', 'MESH:D007153', (83, 93))	('deficiency', 'Disease', (83, 93))	('copy-number', 'Var', (133, 144))
569948	31324031	Thus, in the study by McConechy et al., most tumors had a molecular profile similar to endometrial serous carcinoma (characterized by the presence of TP53, FBXW7, and PPP2R1A mutations and the absence of ARID1A, CTNNB1, KRAS, or PTEN mutations), while part of the tumors displayed an endometrioid carcinoma-like mutation profile characterized by the presence of ARID1A, CTNNB1, KRAS, and PTEN mutations.	('carcinoma', 'Disease', (106, 115))	('TP53', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (378, 382))	('CTNNB1', 'Gene', (370, 376))	('CTNNB1', 'Gene', (212, 218))	('PTEN', 'Gene', '5728', (229, 233))	('mutations', 'Var', (175, 184))	('tumors', 'Disease', (264, 270))	('ARID1A', 'Gene', '8289', (362, 368))	('FBXW7', 'Gene', '55294', (156, 161))	('PTEN', 'Gene', '5728', (388, 392))	('KRAS', 'Gene', (378, 382))	('PPP2R1A', 'Gene', '5518', (167, 174))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Disease', 'MESH:D002277', (297, 306))	('carcinoma', 'Disease', 'MESH:D002277', (106, 115))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('TP53', 'Gene', '7157', (150, 154))	('PPP2R1A', 'Gene', (167, 174))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (284, 306))	('endometrial serous carcinoma', 'Disease', (87, 115))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('CTNNB1', 'Gene', '1499', (370, 376))	('ARID1A', 'Gene', (204, 210))	('CTNNB1', 'Gene', '1499', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('KRAS', 'Gene', '3845', (220, 224))	('FBXW7', 'Gene', (156, 161))	('mutations', 'Var', (393, 402))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('PTEN', 'Gene', (229, 233))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('carcinoma', 'Disease', (297, 306))	('ARID1A', 'Gene', '8289', (204, 210))	('ARID1A', 'Gene', (362, 368))	('KRAS', 'Gene', (220, 224))	('PTEN', 'Gene', (388, 392))
569953	31324031	Most of the endometrioid-like ECSs also showed TP53 mutations, implying that TP53 could be involved in the progression of part of the copy-number low endometrioid-like carcinomas to ECSs, as we have previously reported in undifferentiated endometrial carcinoma.	('mutations', 'Var', (52, 61))	('involved', 'Reg', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('carcinomas', 'Disease', (168, 178))	('undifferentiated endometrial carcinoma', 'Disease', 'MESH:D002277', (222, 260))	('ECS', 'Chemical', '-', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('TP53', 'Gene', '7157', (47, 51))	('undifferentiated endometrial carcinoma', 'Disease', (222, 260))	('ECS', 'Chemical', '-', (182, 185))	('copy-number low', 'Var', (134, 149))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', (47, 51))	('carcinomas', 'Disease', 'MESH:D002277', (168, 178))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (239, 260))
569956	31324031	Previous studies combining aberrant expression of p53 and mutational analysis estimated a TP53 mutation prevalence of 50-60%.	('TP53', 'Gene', '7157', (90, 94))	('p53', 'Gene', '7157', (50, 53))	('TP53', 'Gene', (90, 94))	('p53', 'Gene', (50, 53))	('mutation', 'Var', (95, 103))
569957	31324031	However, subsequent studies using Next Generation Sequencing (NGS) techniques have shown that the true frequency of TP53 mutation in ECS is very high, between 64% and 91%.	('TP53', 'Gene', '7157', (116, 120))	('TP53', 'Gene', (116, 120))	('mutation', 'Var', (121, 129))	('ECS', 'Chemical', '-', (133, 136))
569958	31324031	In effect, TP53 mutations are the most frequent molecular alterations in ECS (Table 1).	('ECS', 'Chemical', '-', (73, 76))	('ECS', 'Disease', (73, 76))	('frequent', 'Reg', (39, 47))	('TP53', 'Gene', (11, 15))	('TP53', 'Gene', '7157', (11, 15))	('mutations', 'Var', (16, 25))
569959	31324031	The lack of nuclear p53 expression is most commonly detected with indel or nonsense mutations, while missense mutations usually lead to diffuse nuclear p53 immunostaining.	('missense mutations', 'Var', (101, 119))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('lack', 'NegReg', (4, 8))	('expression', 'MPA', (24, 34))	('p53', 'Gene', (152, 155))	('indel', 'Var', (66, 71))	('p53', 'Gene', '7157', (152, 155))	('nonsense mutations', 'Var', (75, 93))	('nuclear', 'MPA', (12, 19))	('lead to', 'Reg', (128, 135))
569960	31324031	In the DNA binding domain, 32% of mutations are located on known hotspot residues, and the most frequent are the R248Q and R273C/H (12% and 7%, respectively) followed by H179R/D, H193R/Y, and S241Y (5% each), .	('R248Q', 'Var', (113, 118))	('H179R', 'Var', (170, 175))	('H193R', 'SUBSTITUTION', 'None', (179, 184))	('S241Y', 'Var', (192, 197))	('H193R', 'Var', (179, 184))	('R248Q', 'Mutation', 'rs11540652', (113, 118))	('S241Y', 'Mutation', 'rs28934573', (192, 197))	('H179R', 'SUBSTITUTION', 'None', (170, 175))	('R273C', 'Var', (123, 128))	('R273C', 'SUBSTITUTION', 'None', (123, 128))
569961	31324031	The carcinomatous and sarcomatous components show a concordance of 85% for the p53 protein overexpression and 96% for the TP53 gene mutation, which points to a monoclonal origin of both components (Figure 1).	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('p53', 'Gene', (79, 82))	('TP53', 'Gene', (122, 126))	('p53', 'Gene', '7157', (79, 82))	('overexpression', 'PosReg', (91, 105))	('carcinomatous', 'Disease', 'MESH:D055756', (4, 17))	('carcinomatous', 'Disease', (4, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (4, 13))	('sarcomatous component', 'Disease', 'MESH:D018316', (22, 43))	('TP53', 'Gene', '7157', (122, 126))	('mutation', 'Var', (132, 140))	('sarcomatous component', 'Disease', (22, 43))
569962	31324031	p16 overexpression (in-block diffuse expression) occurs in about 60% of ECS simultaneously with TP53 mutations.	('ECS', 'Disease', (72, 75))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))	('p16', 'Gene', (0, 3))	('ECS', 'Chemical', '-', (72, 75))	('overexpression', 'PosReg', (4, 18))	('p16', 'Gene', '1029', (0, 3))	('TP53', 'Gene', '7157', (96, 100))
569964	31324031	In addition to TP53, ECSs show mutations in other genes that are also more frequently affected in endometrial serous carcinoma (ESC) than in endometrial endometrioid carcinoma (EEC).	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (98, 126))	('mutations', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (141, 175))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('endometrial serous carcinoma', 'Disease', (98, 126))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (153, 175))	('affected', 'Reg', (86, 94))	('endometrial endometrioid carcinoma', 'Disease', (141, 175))	('ECS', 'Chemical', '-', (21, 24))
569965	31324031	Accordingly, mutations of FBXW7 and PPP2R1A have been reported in 19% to 39% and 1% to 38%, respectively, in different series.	('PPP2R1A', 'Gene', '5518', (36, 43))	('FBXW7', 'Gene', (26, 31))	('PPP2R1A', 'Gene', (36, 43))	('mutations', 'Var', (13, 22))	('reported', 'Reg', (54, 62))	('FBXW7', 'Gene', '55294', (26, 31))
569966	31324031	Regarding the BRCA1 and BRCA2 genes, the frequency of ECS in patients carrying germinal BRCA1/2 mutations has been analyzed in different studies.	('BRCA1', 'Gene', '672', (14, 19))	('BRCA1', 'Gene', (88, 93))	('BRCA2', 'Gene', '675', (24, 29))	('BRCA1', 'Gene', (14, 19))	('patients', 'Species', '9606', (61, 69))	('ECS', 'Chemical', '-', (54, 57))	('BRCA1/2', 'Gene', (88, 95))	('BRCA1', 'Gene', '672', (88, 93))	('BRCA2', 'Gene', (24, 29))	('BRCA1/2', 'Gene', '672;675', (88, 95))	('mutations', 'Var', (96, 105))
569967	31324031	The estimated relative risk for mutation carriers is approximately 2% per year, most importantly among serous carcinoma.	('mutation', 'Var', (32, 40))	('serous carcinoma', 'Disease', (103, 119))	('serous carcinoma', 'Disease', 'MESH:D018284', (103, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))
569968	31324031	A recent series has reported that BRCA1/2 were found mutated in 18% and 27%, respectively of ECS, although in the TCGA (The Cancer Genome Atlas Program) series, only BRCA2 mutations were detected and at a lower frequency (5%).	('ECS', 'Disease', (93, 96))	('ECS', 'Chemical', '-', (93, 96))	('BRCA2', 'Gene', '675', (166, 171))	('BRCA1/2', 'Gene', '672;675', (34, 41))	('mutated', 'Var', (53, 60))	('Cancer Genome Atlas', 'Disease', (124, 143))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (124, 143))	('BRCA1/2', 'Gene', (34, 41))	('BRCA2', 'Gene', (166, 171))
569970	31324031	found an excess of mutations in genes encoding histone H2A and H2B, as well as a significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes.	('H2B', 'Gene', '8349', (63, 66))	('mutations', 'Var', (19, 28))	('H2B', 'Gene', (63, 66))	('histone H2A', 'Protein', (47, 58))
569971	31324031	Thus, mutations in histone H2A/H2B genes were significantly enriched in carcinosarcomas (CSs) compared with carcinomas (mutations in 21.2% of CSs and 5.2% of uterine and ovarian epithelial tumor).	('ovarian epithelial tumor', 'Disease', 'MESH:D000077216', (170, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ovarian epithelial tumor', 'Disease', (170, 194))	('ovarian epithelial tumor', 'Phenotype', 'HP:0025318', (170, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('H2B', 'Gene', (31, 34))	('CSs', 'Disease', (142, 145))	('epithelial tumor', 'Phenotype', 'HP:0031492', (178, 194))	('carcinomas', 'Disease', (108, 118))	('carcinomas', 'Disease', 'MESH:D002277', (108, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('H2B', 'Gene', '8349', (31, 34))	('carcinosarcomas', 'Disease', 'MESH:D002296', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mutations', 'Var', (6, 15))	('carcinosarcomas', 'Disease', (72, 87))
569972	31324031	These findings implicate mutations in histone H2A/H2B genes in ECS.	('mutations', 'Var', (25, 34))	('H2B', 'Gene', '8349', (50, 53))	('ECS', 'Chemical', '-', (63, 66))	('ECS', 'Disease', (63, 66))	('implicate', 'Reg', (15, 24))	('H2B', 'Gene', (50, 53))
569973	31324031	have reported forkhead box A2 (FOXA2) mutations in 15.1% of ECS.	('forkhead box A2', 'Gene', (14, 29))	('FOXA2', 'Gene', '3170', (31, 36))	('FOXA2', 'Gene', (31, 36))	('ECS', 'Chemical', '-', (60, 63))	('ECS', 'Disease', (60, 63))	('forkhead box A2', 'Gene', '3170', (14, 29))	('mutations', 'Var', (38, 47))
569974	31324031	FOXA2 had not previously been implicated in ECSs and was predominated by frameshift and nonsense mutations.	('frameshift', 'Var', (73, 83))	('ECS', 'Chemical', '-', (44, 47))	('nonsense mutations', 'Var', (88, 106))	('FOXA2', 'Gene', '3170', (0, 5))	('FOXA2', 'Gene', (0, 5))
569975	31324031	Sequencing of FOXA2 in 160 primary endometrial carcinomas revealed somatic mutations in 5.7% of serous, 22.7% of clear cell, 9% of endometrioid, and 11.1% of mixed endometrial carcinomas, the majority of which were frameshift mutations.	('FOXA2', 'Gene', (14, 19))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (35, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('endometrial carcinomas', 'Disease', (164, 186))	('serous', 'Disease', (96, 102))	('FOXA2', 'Gene', '3170', (14, 19))	('endometrioid', 'Disease', (131, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (164, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('endometrial carcinomas', 'Disease', (35, 57))	('clear cell', 'Disease', (113, 123))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (164, 186))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (35, 56))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (164, 186))	('frameshift mutations', 'Var', (215, 235))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (35, 57))	('mutations', 'Var', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
569977	31324031	Similarly to ESC, ECS is characterized by aneuploidy and a high frequency of copy number variations (CNVs).	('aneuploidy', 'Disease', (42, 52))	('ECS', 'Disease', (18, 21))	('ECS', 'Chemical', '-', (18, 21))	('aneuploidy', 'Disease', 'MESH:D000782', (42, 52))	('copy number variations', 'Var', (77, 99))
569982	31324031	In other tumors, for example, ovarian high-grade serous carcinoma, amplification of CCNE1 is associated with a worse prognosss and resistance to chemotherapy.	('serous carcinoma', 'Disease', (49, 65))	('CCNE1', 'Gene', (84, 89))	('serous carcinoma', 'Disease', 'MESH:D018284', (49, 65))	('amplification', 'Var', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('ovarian high', 'Phenotype', 'HP:0008209', (30, 42))	('associated', 'Reg', (93, 103))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('CCNE1', 'Gene', '898', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
569987	31324031	Thus, ECS patients with ERBB2 amplification could benefit from anti-HER2 (human epidermal growth factor receptor 2) therapies, such as Trastuzumab.	('Trastuzumab', 'Chemical', 'MESH:D000068878', (135, 146))	('ECS', 'Chemical', '-', (6, 9))	('HER2', 'Gene', (68, 72))	('amplification', 'Var', (30, 43))	('ERBB2', 'Gene', (24, 29))	('epidermal growth factor receptor 2', 'Gene', (80, 114))	('ERBB2', 'Gene', '2064', (24, 29))	('benefit', 'PosReg', (50, 57))	('epidermal growth factor receptor 2', 'Gene', '2064', (80, 114))	('HER2', 'Gene', '2064', (68, 72))	('patients', 'Species', '9606', (10, 18))	('human', 'Species', '9606', (74, 79))	('ECS', 'Disease', (6, 9))
569990	31324031	detected ZNF217 amplification in 87% of gynecological CS.	('gynecological CS', 'Disease', (40, 56))	('ZNF217', 'Gene', '7764', (9, 15))	('ZNF217', 'Gene', (9, 15))	('amplification', 'Var', (16, 29))
569993	31324031	reported EGFR amplification by FISH in 19% of tumors, while in studies with smaller sample size, EGFR (epidermal growth factor receptor) protein overexpression has been reported in 45% to 82% of ECS, where a higher level of expression was seen in the sarcomatous component.	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('ECS', 'Chemical', '-', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sarcomatous component', 'Disease', 'MESH:D018316', (251, 272))	('EGFR', 'Gene', '1956', (97, 101))	('sarcomatous component', 'Disease', (251, 272))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('tumors', 'Disease', (46, 52))	('amplification', 'Var', (14, 27))	('ECS', 'Disease', (195, 198))
569995	31324031	URI1 amplification was also associated with poor survival and reduced response to adjuvant treatment.	('amplification', 'Var', (5, 18))	('URI1', 'Gene', (0, 4))	('URI1', 'Gene', '8725', (0, 4))	('poor', 'NegReg', (44, 48))	('response to adjuvant treatment', 'MPA', (70, 100))	('reduced', 'NegReg', (62, 69))
569996	31324031	Likewise, in a cultured cell model, overexpression of URI1 induced ATM (ATM Serine/Threonine Kinase) expression and resistance to cisplatin.	('URI1', 'Gene', (54, 58))	('resistance', 'CPA', (116, 126))	('ATM', 'Gene', '472', (72, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('ATM', 'Gene', '472', (67, 70))	('ATM Serine/Threonine Kinase', 'Gene', (72, 99))	('ATM Serine/Threonine Kinase', 'Gene', '472', (72, 99))	('induced', 'Reg', (59, 66))	('URI1', 'Gene', '8725', (54, 58))	('expression', 'MPA', (101, 111))	('overexpression', 'Var', (36, 50))	('ATM', 'Gene', (72, 75))	('ATM', 'Gene', (67, 70))
569998	31324031	Mutations in genes encoding for the kinase or regulatory proteins of the PI3K/AKT (phosphatidylinositol 3-kinase/(Protein Kinase B) pathway have been detected in up to 67% of ECS.	('ECS', 'Chemical', '-', (175, 178))	('PI3', 'Gene', (73, 76))	('AKT', 'Gene', '207', (78, 81))	('Protein Kinase B', 'Gene', (114, 130))	('Protein Kinase B', 'Gene', '2185', (114, 130))	('Mutations', 'Var', (0, 9))	('PI3', 'Gene', '5266', (73, 76))	('ECS', 'Disease', (175, 178))	('AKT', 'Gene', (78, 81))	('detected', 'Reg', (150, 158))
569999	31324031	Moreover, multiple PI3K/AKT pathway proteins have been found mutated in one tumor.	('AKT', 'Gene', (24, 27))	('PI3', 'Gene', '5266', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PI3', 'Gene', (19, 22))	('mutated', 'Var', (61, 68))	('AKT', 'Gene', '207', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
570000	31324031	PIK3CA mutations have been found in 11% to 40% of the tumors.	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumors', 'Disease', (54, 60))	('found', 'Reg', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (7, 16))
570001	31324031	Unlike for TP53, with mutations concentrated on HotSpot regions, the mutations in PIK3CA are found scattered in the different functional domains.	('mutations', 'Var', (69, 78))	('PIK3CA', 'Gene', (82, 88))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('PIK3CA', 'Gene', '5290', (82, 88))
570002	31324031	In addition to the traditional PIK3CA hotspots in exons 9 and 20, a smaller portion of ECS has mutations in exon 1, in the adaptor binding domain, helical domain, and C2 domain which increase kinase enzymatic activity.	('exon 1', 'Gene', (108, 114))	('ECS', 'Chemical', '-', (87, 90))	('increase', 'PosReg', (183, 191))	('PIK3CA', 'Gene', (31, 37))	('kinase enzymatic activity', 'MPA', (192, 217))	('PIK3CA', 'Gene', '5290', (31, 37))	('mutations', 'Var', (95, 104))
570003	31324031	The importance of mutations in this pathway comes from the fact that PI3KCA mutations have been detected in both the carcinoma and sarcoma components of the primary tumor and also in the metastatic tumor.	('PI3', 'Gene', (69, 72))	('detected', 'Reg', (96, 104))	('mutations', 'Var', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('sarcoma component', 'Disease', 'MESH:D012509', (131, 148))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('PI3', 'Gene', '5266', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (117, 138))	('sarcoma component', 'Disease', (131, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (165, 170))
570006	31324031	Phosphatase And Tensin Homolog (PTEN) mutations are not as frequent as PIK3CA, but they are present in approximately 20% of ECS: 17% and 19% in the series reported by McConechy et al.	('ECS', 'Disease', (124, 127))	('ECS', 'Chemical', '-', (124, 127))	('PIK3CA', 'Gene', '5290', (71, 77))	('PTEN', 'Gene', (32, 36))	('Phosphatase And Tensin Homolog', 'Gene', (0, 30))	('PTEN', 'Gene', '5728', (32, 36))	('mutations', 'Var', (38, 47))	('Phosphatase And Tensin Homolog', 'Gene', '5728', (0, 30))	('PIK3CA', 'Gene', (71, 77))
570007	31324031	reported that 47% of ECS carried PTEN mutation, but their series included only 17 cases.	('PTEN', 'Gene', (33, 37))	('ECS', 'Chemical', '-', (21, 24))	('mutation', 'Var', (38, 46))	('PTEN', 'Gene', '5728', (33, 37))
570008	31324031	PTEN and PIK3CA mutations frequently coexist in the same ECS.	('mutations', 'Var', (16, 25))	('ECS', 'Chemical', '-', (57, 60))	('PIK3CA', 'Gene', (9, 15))	('PTEN', 'Gene', (0, 4))	('PIK3CA', 'Gene', '5290', (9, 15))	('PTEN', 'Gene', '5728', (0, 4))
570009	31324031	Other genes with less frequency of mutations in the PI3K/AKT pathway in ECSs include Phosphatidylinositol 3-Kinase Regulatory Subunit 1 (PIK3R1) (10-17%), PIK3R2, AKT1, AKT2, and AKT3 (less than 5% for each gene).	('mutations', 'Var', (35, 44))	('AKT3', 'Gene', '10000', (179, 183))	('PI3', 'Gene', (52, 55))	('AKT', 'Gene', (163, 166))	('ECS', 'Chemical', '-', (72, 75))	('AKT2', 'Gene', '208', (169, 173))	('AKT', 'Gene', '207', (57, 60))	('AKT1', 'Gene', '207', (163, 167))	('AKT3', 'Gene', (179, 183))	('PIK3R1', 'Gene', (137, 143))	('AKT', 'Gene', (179, 182))	('PIK3R2', 'Gene', (155, 161))	('AKT2', 'Gene', (169, 173))	('AKT', 'Gene', (169, 172))	('AKT1', 'Gene', (163, 167))	('AKT', 'Gene', '207', (163, 166))	('AKT', 'Gene', (57, 60))	('PIK3R2', 'Gene', '5296', (155, 161))	('AKT', 'Gene', '207', (179, 182))	('PI3', 'Gene', '5266', (52, 55))	('PIK3R1', 'Gene', '5295', (137, 143))	('AKT', 'Gene', '207', (169, 172))
570010	31324031	AT-Rich Interaction Domain 1A (ARID1A) and Catenin Beta 1 (CTNNB1) are commonly mutated in EEC, and ARID1A mutations occur also in 10% to 15% of ECS, leading usually to loss of of protein expression, while mutations in CTNNB1 are infrequent in ECS.	('CTNNB1', 'Gene', '1499', (59, 65))	('AT-Rich Interaction Domain 1A', 'Gene', (0, 29))	('ECS', 'Chemical', '-', (244, 247))	('mutations', 'Var', (107, 116))	('ECS', 'Chemical', '-', (145, 148))	('loss', 'NegReg', (169, 173))	('ARID1A', 'Gene', '8289', (31, 37))	('CTNNB1', 'Gene', (219, 225))	('ARID1A', 'Gene', (31, 37))	('of of protein expression', 'MPA', (174, 198))	('ARID1A', 'Gene', '8289', (100, 106))	('Catenin Beta 1', 'Gene', (43, 57))	('ARID1A', 'Gene', (100, 106))	('AT-Rich Interaction Domain 1A', 'Gene', '8289', (0, 29))	('Catenin Beta 1', 'Gene', '1499', (43, 57))	('CTNNB1', 'Gene', (59, 65))	('CTNNB1', 'Gene', '1499', (219, 225))
570011	31324031	KRAS mutations were found in 12% and Cadherin 4 (CDH4) mutations in 18%.	('CDH4', 'Gene', (49, 53))	('mutations', 'Var', (55, 64))	('mutations', 'Var', (5, 14))	('Cadherin 4', 'Gene', '1002', (37, 47))	('CDH4', 'Gene', '1002', (49, 53))	('found', 'Reg', (20, 25))	('KRAS', 'Gene', (0, 4))	('Cadherin 4', 'Gene', (37, 47))	('KRAS', 'Gene', '3845', (0, 4))
570014	31324031	In sporadic EC, MMR-def is detected in 15-30% of cases, although a higher frequency has been detected among high-grade endometrioid carcinomas (45-63%), most frequently due to MLH1 promotor methylation.	('methylation', 'Var', (190, 201))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (119, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (119, 142))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (119, 142))	('MMR-def', 'Disease', (16, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('MLH1', 'Gene', (176, 180))	('MLH1', 'Gene', '4292', (176, 180))	('endometrioid carcinomas', 'Disease', (119, 142))
570015	31324031	In addition, between 2-6% of endometrial carcinoma occurs in the context of Lynch syndrome due to germline mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('Lynch syndrome', 'Disease', (76, 90))	('due', 'Reg', (91, 94))	('Lynch syndrome', 'Disease', 'MESH:D003123', (76, 90))	('germline mutations', 'Var', (98, 116))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (29, 50))	('occurs', 'Reg', (51, 57))	('endometrial carcinoma', 'Disease', (29, 50))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (29, 50))
570017	31324031	MLH1 promoter methylation is probably the major cause for MMR-def in most tumors, and accordingly, MLH1 was epigenetically silenced in the two samples with MMR-def in the TCGA series.	('MLH1', 'Gene', '4292', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('MLH1', 'Gene', (99, 103))	('MLH1', 'Gene', '4292', (0, 4))	('cause', 'Reg', (48, 53))	('MLH1', 'Gene', (0, 4))	('silenced', 'NegReg', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('epigenetically', 'Var', (108, 122))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('MMR-def', 'Disease', (58, 65))	('tumors', 'Disease', (74, 80))
570018	31324031	Mutations in DNA Polymerase Epsilon, Catalytic Subunit (POLE) are present in some ECS, both of the most common HotSpot-mutations (P286R and V114L) have been identified in individual cases of ECS.	('P286R', 'Var', (130, 135))	('present', 'Reg', (66, 73))	('V114L', 'Var', (140, 145))	('ECS', 'Disease', (191, 194))	('P286R', 'Mutation', 'rs1476441129', (130, 135))	('V114L', 'Mutation', 'rs750420143', (140, 145))	('ECS', 'Chemical', '-', (191, 194))	('ECS', 'Disease', (82, 85))	('ECS', 'Chemical', '-', (82, 85))
570035	31324031	Finally, lower cancer-specific survival has been associated with upregulation of miR-184 and downregulation of let-7b-5p and miR-124.	('cancer', 'Disease', (15, 21))	('miR-184', 'Gene', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('let-7b', 'Gene', '406884', (111, 117))	('miR-184', 'Gene', '406960', (81, 88))	('let-7b', 'Gene', (111, 117))	('lower', 'NegReg', (9, 14))	('upregulation', 'PosReg', (65, 77))	('downregulation', 'NegReg', (93, 107))	('miR-124', 'Var', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
570036	31324031	Similarly to other types of cancers, ECS displays abnormal DNA methylation patterns including genome-wide hypomethylation and site-specific hypermethylation, associated with increased expression of DNA methyltransferases (DNMT1, DNMT3a), when compared to the normal endometrium.	('cancers', 'Disease', (28, 35))	('hypomethylation', 'Var', (106, 121))	('DNMT3a', 'Gene', '1788', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('DNMT3a', 'Gene', (229, 235))	('DNMT1', 'Gene', (222, 227))	('ECS', 'Chemical', '-', (37, 40))	('DNMT1', 'Gene', '1786', (222, 227))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('expression', 'MPA', (184, 194))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('increased', 'PosReg', (174, 183))	('hypermethylation', 'Var', (140, 156))
570043	31324031	Accordingly, the frequency of PTEN mutations was higher in the first group.	('PTEN', 'Gene', (30, 34))	('PTEN', 'Gene', '5728', (30, 34))	('mutations', 'Var', (35, 44))
570044	31324031	A constant characteristic of ECS is the aberrant DNA methylation of miR-200 genes (see discussion in Section 7.	('aberrant', 'Var', (40, 48))	('ECS', 'Chemical', '-', (29, 32))	('DNA', 'MPA', (49, 52))	('miR-200', 'Gene', (68, 75))	('miR-200', 'Chemical', '-', (68, 75))
570058	31324031	A role of the WNT pathway in the transition from an epithelial to a mesenchymal status is demonstrated by the fact that up to 23% of ECS showed nuclear beta-catenin, not associated with CTNNB1 mutation, in the sarcomatous but not in the carcinomatous component.	('sarcomatous', 'Disease', (210, 221))	('CTNNB1', 'Gene', '1499', (186, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('beta-catenin', 'Gene', (152, 164))	('beta-catenin', 'Gene', '1499', (152, 164))	('CTNNB1', 'Gene', (186, 192))	('ECS', 'Chemical', '-', (133, 136))	('carcinomatous component', 'Disease', 'MESH:D055756', (237, 260))	('sarcomatous', 'Disease', 'MESH:D018316', (210, 221))	('mutation', 'Var', (193, 201))	('carcinomatous component', 'Disease', (237, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
570067	31324031	In this sense, experimental studies have demonstrated a major role of ZEB1 in transcriptional repression and of SNAI1 and, to a lesser extent, SNAI2 in the epigenetic silencing through DNA hypermethylation of miR-200 genes.	('miR-200', 'Gene', (209, 216))	('miR-200', 'Chemical', '-', (209, 216))	('ZEB1', 'Gene', (70, 74))	('transcriptional repression', 'MPA', (78, 104))	('SNAI1', 'Gene', '6615', (112, 117))	('SNAI2', 'Gene', '6591', (143, 148))	('SNAI2', 'Gene', (143, 148))	('DNA hypermethylation', 'Var', (185, 205))	('SNAI1', 'Gene', (112, 117))	('epigenetic', 'MPA', (156, 166))	('ZEB1', 'Gene', '6935', (70, 74))
570098	31324031	Molecular observations suggest that, although infrequent, endometrioid carcinomas associated with mutations in PTEN or PIK3CA are more prone to acquire TP53 mutations than those associated with MMR-def, POLE, or CTNNB1 mutations.	('endometrioid carcinomas', 'Disease', (58, 81))	('PTEN', 'Gene', (111, 115))	('PIK3CA', 'Gene', (119, 125))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (58, 80))	('PTEN', 'Gene', '5728', (111, 115))	('PIK3CA', 'Gene', '5290', (119, 125))	('TP53', 'Gene', '7157', (152, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (58, 81))	('CTNNB1', 'Gene', (212, 218))	('mutations', 'Var', (98, 107))	('mutations', 'Var', (157, 166))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (58, 81))	('TP53', 'Gene', (152, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('acquire', 'PosReg', (144, 151))	('CTNNB1', 'Gene', '1499', (212, 218))
570099	31324031	Mutations in TP53 seem to be essential, but not sufficient, to ECS development, since they are as frequent in ECS as in endometrial serous carcinoma.	('TP53', 'Gene', (13, 17))	('ECS', 'Disease', (110, 113))	('ECS', 'Chemical', '-', (110, 113))	('ECS', 'Chemical', '-', (63, 66))	('frequent', 'Reg', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('Mutations', 'Var', (0, 9))	('endometrial serous carcinoma', 'Disease', (120, 148))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (120, 148))	('TP53', 'Gene', '7157', (13, 17))	('ECS', 'Disease', (63, 66))
570100	31324031	Although it is not clear what triggers EMT in tumors with TP53 mutation, a common characteristic of all ECS is the switching of cadherins, the overexpression EMT-TF, and the down-regulation of miR-200 genes.	('ECS', 'Chemical', '-', (104, 107))	('cadherin', 'Gene', '999;1009;1000;1002', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mutation', 'Var', (63, 71))	('miR-200 genes', 'Gene', (193, 206))	('down-regulation', 'NegReg', (174, 189))	('miR-200', 'Chemical', '-', (193, 200))	('tumors', 'Disease', (46, 52))	('cadherin', 'Gene', (128, 136))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
570101	31324031	Probably, the crosstalk of different EMT-TF and the differential regulation of miR-200 genes by transcriptional repression or by epigenetic silencing through DNA hypermethylation play a major role in fixing the mesenchymal phenotype.	('hypermethylation', 'Var', (162, 178))	('miR-200', 'Gene', (79, 86))	('miR-200', 'Chemical', '-', (79, 86))	('mesenchymal phenotype', 'CPA', (211, 232))	('epigenetic silencing', 'Var', (129, 149))
570106	31324031	Although the relatively low-frequency of ECS hinders efforts to design specific clinical trials, there are promising areas of research, such as the use of immunotherapy in tumors with POLE mutations, MMR-def, and high TMB, and also the use of Poly (ADP-ribose) polymerase (PARP) inhibitors in tumors with homologous recombination deficiency, especially due to germline or somatic BRCA mutations.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('BRCA', 'Gene', (380, 384))	('deficiency', 'Disease', (330, 340))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('germline', 'Var', (360, 368))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('TMB', 'Chemical', '-', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('ECS', 'Chemical', '-', (41, 44))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('clinical', 'Species', '191496', (80, 88))	('deficiency', 'Disease', 'MESH:D007153', (330, 340))	('tumors', 'Disease', (293, 299))	('BRCA', 'Gene', '672', (380, 384))	('mutations', 'Var', (385, 394))
570160	29333163	A 41-year-old G2P1001 parous female whose past medical history is pertinent for remote migraines presented to our facility from an outside hospital (OSH) with complaints of sudden onset of left-sided hemiplegia, facial paralysis, and dysarthria.	('dysarthria', 'Disease', (234, 244))	('facial paralysis', 'Phenotype', 'HP:0007209', (212, 228))	('migraines', 'Phenotype', 'HP:0002076', (87, 96))	('hemiplegia', 'Phenotype', 'HP:0002301', (200, 210))	('hemiplegia', 'Disease', (200, 210))	('facial paralysis', 'Disease', (212, 228))	('dysarthria', 'Phenotype', 'HP:0001260', (234, 244))	('facial paralysis', 'Disease', 'MESH:D010243', (212, 228))	('left-sided hemiplegia', 'Phenotype', 'HP:0040292', (189, 210))	('migraines', 'Disease', (87, 96))	('G2P1001', 'Var', (14, 21))	('migraines', 'Disease', 'MESH:D008881', (87, 96))	('paralysis', 'Phenotype', 'HP:0003470', (219, 228))	('dysarthria', 'Disease', 'MESH:D004401', (234, 244))	('hemiplegia', 'Disease', 'MESH:D006429', (200, 210))
570192	29333163	Several studies have shown that knockdown of the SYT-SSX oncogene results in decreased cell viability secondary to an increase in apoptosis.	('SS', 'Phenotype', 'HP:0012570', (53, 55))	('SYT', 'Gene', (49, 52))	('cell viability', 'CPA', (87, 101))	('increase', 'PosReg', (118, 126))	('apoptosis', 'CPA', (130, 139))	('SSX', 'Gene', (53, 56))	('SSX', 'Gene', '6757', (53, 56))	('SYT', 'Gene', '6760', (49, 52))	('knockdown', 'Var', (32, 41))	('decreased', 'NegReg', (77, 86))
570196	29097609	The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib) and tubulin (taxanes, vinca alkaloids), are presented.	('vinca alkaloids', 'Chemical', 'MESH:D014748', (275, 290))	('MLN8237', 'Var', (204, 211))	('MLN8237', 'Chemical', 'MESH:C550258', (204, 211))	('palbociclib', 'Chemical', 'MESH:C500026', (138, 149))	('CDK4', 'Gene', (127, 131))	('AT9283', 'Chemical', 'MESH:C535237', (193, 199))	('taxanes', 'Chemical', 'MESH:D043823', (266, 273))	('patients', 'Species', '9606', (85, 93))	('Wee1', 'Gene', (214, 218))	('AT9283', 'Var', (193, 199))	('CDK4', 'Gene', '1019', (127, 131))	('ispinesib', 'Chemical', 'MESH:C508757', (242, 251))	('CDK6', 'Gene', (132, 136))	('Wee1', 'Gene', '7465', (214, 218))	('CDK6', 'Gene', '1021', (132, 136))	('KSP', 'Chemical', '-', (237, 240))	('MK-1775', 'Chemical', 'MESH:C549567', (227, 234))
570208	29097609	Pharmacological inhibition of CDKs typically results in cell cycle arrest, apoptosis, and transcriptional repression to provide the rationale for therapeutically targeting CDKs in cancer.	('cancer', 'Disease', (180, 186))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('CDKs', 'Gene', '983;1017;1019;12567;1021;12571;1022;1025', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('apoptosis', 'CPA', (75, 84))	('CDKs', 'Gene', (30, 34))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('CDKs', 'Gene', '983;1017;1019;12567;1021;12571;1022;1025', (172, 176))	('transcriptional repression', 'CPA', (90, 116))	('CDKs', 'Gene', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('arrest', 'Disease', (67, 73))	('results in', 'Reg', (45, 55))	('inhibition', 'Var', (16, 26))
570210	29097609	CDK4/6 inhibitors have emerged as promising cell-cycle therapeutics.	('inhibitors', 'Var', (7, 17))	('CDK4/6', 'Gene', (0, 6))	('CDK4/6', 'Gene', '1019;1021', (0, 6))
570217	29097609	High expression of D-type cyclins, genetic mutations or amplification of the CDK4 and CDK6 loci, or loss of the p16Ink4A inhibitory protein that regulates cyclin D/CDK4/6 complexes, are associated with unrestricted cancer cell growth.	('p16Ink4A', 'Gene', '1029', (112, 120))	('expression', 'MPA', (5, 15))	('cyclin', 'Gene', (26, 32))	('CDK4', 'Gene', (77, 81))	('CDK4', 'Gene', (164, 168))	('loss', 'Var', (100, 104))	('unrestricted cancer', 'Disease', 'MESH:D009369', (202, 221))	('CDK4', 'Gene', '1019', (77, 81))	('CDK4/6', 'Gene', (164, 170))	('CDK4', 'Gene', '1019', (164, 168))	('genetic mutations', 'Var', (35, 52))	('CDK6', 'Gene', '1021', (86, 90))	('cyclin', 'Gene', '5111', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('p16Ink4A', 'Gene', (112, 120))	('unrestricted cancer', 'Disease', (202, 221))	('associated', 'Reg', (186, 196))	('CDK6', 'Gene', (86, 90))	('cyclin', 'Gene', (155, 161))	('amplification', 'Var', (56, 69))	('cyclin', 'Gene', '5111', (26, 32))	('CDK4/6', 'Gene', '1019;1021', (164, 170))
570218	29097609	In addition, deletion of RB1 occurs in many tumors and accelerates proliferation independently of cyclin D-CDK4/6 activity.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('RB1', 'Gene', '5925', (25, 28))	('cyclin', 'Gene', '5111', (98, 104))	('deletion', 'Var', (13, 21))	('CDK4/6', 'Gene', '1019;1021', (107, 113))	('proliferation', 'CPA', (67, 80))	('cyclin', 'Gene', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('accelerates', 'PosReg', (55, 66))	('RB1', 'Gene', (25, 28))	('CDK4/6', 'Gene', (107, 113))
570220	29097609	Currently, three selective CDK4/6 inhibitors are approved: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219).	('LY2835219', 'Var', (123, 132))	('PD-0332991', 'Var', (72, 82))	('palbociclib', 'Chemical', 'MESH:C500026', (59, 70))	('LY2835219', 'Chemical', 'MESH:C000590451', (123, 132))	('LEE011', 'Var', (97, 103))	('CDK4/6', 'Gene', '1019;1021', (27, 33))	('PD-0332991', 'Chemical', 'MESH:C500026', (72, 82))	('CDK4/6', 'Gene', (27, 33))
570226	29097609	In another investigation, palbociclib plus PLX4720, an inhibitor against v-raf murine sarcoma viral oncogene homolog B1 (BRAF) extended survival in pediatric malignant astrocytoma, relative to either monotherapy.	('astrocytoma', 'Disease', (168, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (73, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (168, 179))	('extended', 'PosReg', (127, 135))	('PLX4720', 'Var', (43, 50))	('palbociclib', 'Chemical', 'MESH:C500026', (26, 37))	('PLX4720', 'Chemical', 'MESH:C528407', (43, 50))	('survival', 'MPA', (136, 144))	('astrocytoma', 'Disease', 'MESH:D001254', (168, 179))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (73, 119))
570227	29097609	Response was specific for a subset of pediatric astrocytomas with BRAF (V600E) mutation and CDKN2A (encoding cyclin-dependent kinase inhibitor 2A) deficiency.	('CDKN2A', 'Gene', (92, 98))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (109, 145))	('pediatric astrocytomas', 'Phenotype', 'HP:0009592', (38, 60))	('deficiency', 'Var', (147, 157))	('CDKN2A', 'Gene', '1029', (92, 98))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (109, 145))	('astrocytoma', 'Phenotype', 'HP:0009592', (48, 59))	('pediatric astrocytomas', 'Disease', 'MESH:D001254', (38, 60))	('pediatric astrocytomas', 'Disease', (38, 60))	('BRAF', 'Gene', (66, 70))	('V600E', 'Mutation', 'rs113488022', (72, 77))
570239	29097609	Ribociclib was active in vitro in leukemia cells and in vivo in mutant NOTCH1-driven T-ALL mouse models in combination therapy with corticosteroids and mTOR inhibitors.	('leukemia', 'Disease', (34, 42))	('mTOR', 'Gene', (152, 156))	('NOTCH1', 'Gene', (71, 77))	('leukemia', 'Disease', 'MESH:D007938', (34, 42))	('leukemia', 'Phenotype', 'HP:0001909', (34, 42))	('mTOR', 'Gene', '56717', (152, 156))	('mutant', 'Var', (64, 70))	('mouse', 'Species', '10090', (91, 96))	('NOTCH1', 'Gene', '18128', (71, 77))
570260	29097609	Preclinical evaluation of SCH 727965 by the Pediatric Preclinical Testing Program (PTPP) against a panel of human cell lines and pediatric-derived xenografts and ALL, induced significant delays in event free survival distribution compared to control in 64% of solid tumor xenografts and in 43% of ALL xenografts.	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('human', 'Species', '9606', (108, 113))	('delays', 'NegReg', (187, 193))	('SCH 727965', 'Chemical', 'MESH:C553669', (26, 36))	('SCH 727965', 'Var', (26, 36))	('tumor', 'Disease', (266, 271))	('event', 'MPA', (197, 202))
570278	29097609	AT9283 is a multikinase inhibitor with high potency against Aurora A and Aurora B kinase activity.	('Aurora A', 'Gene', (60, 68))	('AT9283', 'Var', (0, 6))	('Aurora B', 'Gene', (73, 81))	('Aurora B', 'Gene', '9212', (73, 81))	('Aurora A', 'Gene', '6790', (60, 68))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
570279	29097609	AT9283 also inhibits Janus kinase 2 (JAK2) and JAK3, FMS-like tyrosine kinase 3 (FLT3), and Abelson tyrosine kinase (ABLT315I) with lower efficacy.	('tyrosine', 'Chemical', 'MESH:D014443', (62, 70))	('Janus kinase 2', 'Gene', '3717', (21, 35))	('FMS-like tyrosine kinase 3', 'Gene', '2322', (53, 79))	('JAK2', 'Gene', (37, 41))	('ABLT315I', 'Mutation', 'rs121913459', (117, 125))	('AT9283', 'Var', (0, 6))	('JAK3', 'Gene', (47, 51))	('FLT3', 'Gene', '2322', (81, 85))	('JAK3', 'Gene', '3718', (47, 51))	('inhibits', 'NegReg', (12, 20))	('FMS-like tyrosine kinase 3', 'Gene', (53, 79))	('JAK2', 'Gene', '3717', (37, 41))	('Janus kinase 2', 'Gene', (21, 35))	('FLT3', 'Gene', (81, 85))	('tyrosine', 'Chemical', 'MESH:D014443', (100, 108))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
570280	29097609	Selective inhibition of Aurora-A blocks Thr228 phosphorylation, promotes formation of monopolar spindles, cell cycle arrest at G2/M-phase and apoptosis.	('promotes', 'PosReg', (64, 72))	('phosphorylation', 'MPA', (47, 62))	('Thr228', 'Protein', (40, 46))	('arrest', 'Disease', (117, 123))	('formation', 'MPA', (73, 82))	('Aurora-A', 'Gene', (24, 32))	('Aurora-A', 'Gene', '6790', (24, 32))	('Thr228', 'Chemical', '-', (40, 46))	('arrest', 'Disease', 'MESH:D006323', (117, 123))	('apoptosis', 'CPA', (142, 151))	('inhibition', 'Var', (10, 20))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (106, 123))	('blocks', 'NegReg', (33, 39))
570281	29097609	Preclinical evidence of activity of AT9283 was demonstrated by growth suppression in imatinib-resistant BCR-ABL-positive leukemic cells and in mice engrafted with BaF3/BCR-ABL, human BCR-ABL(+) cell lines, or primary patient samples expressing BCR-ABL/T315I or glutamic acid 255 to lysine imatinib-resistant mutation.	('BCR-ABL', 'Gene', '25', (183, 190))	('AT9283', 'Chemical', 'MESH:C535237', (36, 42))	('human', 'Species', '9606', (177, 182))	('glutamic acid 255 to lysine', 'Var', (261, 288))	('suppression', 'NegReg', (70, 81))	('activity', 'MPA', (24, 32))	('BCR-ABL', 'Gene', (168, 175))	('BCR-ABL', 'Gene', (104, 111))	('BCR-ABL', 'Gene', '25', (244, 251))	('BCR-ABL', 'Gene', (183, 190))	('imatinib', 'Chemical', 'MESH:D000068877', (85, 93))	('imatinib', 'Chemical', 'MESH:D000068877', (289, 297))	('T315I', 'Mutation', 'rs121913459', (252, 257))	('AT9283', 'Var', (36, 42))	('mice', 'Species', '10090', (143, 147))	('patient', 'Species', '9606', (217, 224))	('leukemic', 'Disease', 'MESH:D007938', (121, 129))	('BCR-ABL', 'Gene', '25', (168, 175))	('growth', 'MPA', (63, 69))	('BCR-ABL', 'Gene', '25', (104, 111))	('BCR-ABL', 'Gene', (244, 251))	('leukemic', 'Disease', (121, 129))	('glutamic acid 255 to lysine', 'SUBSTITUTION', 'None', (261, 288))
570282	29097609	Preclinical reports also indicate that AT9283 synergizes with dasatinib and enhances the repression of medulloblastoma survival and migration.	('medulloblastoma', 'Disease', (103, 118))	('AT9283', 'Chemical', 'MESH:C535237', (39, 45))	('dasatinib', 'Chemical', 'MESH:D000069439', (62, 71))	('medulloblastoma', 'Disease', 'MESH:D008527', (103, 118))	('medulloblastoma', 'Phenotype', 'HP:0002885', (103, 118))	('AT9283', 'Var', (39, 45))	('repression', 'MPA', (89, 99))	('enhances', 'PosReg', (76, 84))
570283	29097609	The first phase I/II trial with AT9283 in thirty-three pediatric patients with solid tumors (NCT00985868) led to a partial response in one patient diagnosed with central nervous system (CNS)-primitive neuroectodermal tumour (PNET) and disease stabilization in 38% of patients, with manageable hematological toxicity.	('patient', 'Species', '9606', (267, 274))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('patients', 'Species', '9606', (267, 275))	('hematological toxicity', 'Disease', 'MESH:D006402', (293, 315))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('hematological toxicity', 'Disease', (293, 315))	('primitive neuroectodermal tumour', 'Phenotype', 'HP:0030065', (191, 223))	('solid tumors', 'Disease', (79, 91))	('neuroectodermal tumour', 'Disease', 'MESH:D017599', (201, 223))	('AT9283', 'Chemical', 'MESH:C535237', (32, 38))	('patient', 'Species', '9606', (65, 72))	('patients', 'Species', '9606', (65, 73))	('solid tumors', 'Disease', 'MESH:D009369', (79, 91))	('neuroectodermal tumour', 'Disease', (201, 223))	('AT9283', 'Var', (32, 38))	('neuroectodermal tumour', 'Phenotype', 'HP:0030061', (201, 223))	('patient', 'Species', '9606', (139, 146))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
570288	29097609	It is likely that the evaluation of this agent in a cohort of pediatric patients with leukemia harboring the JAK, ABL, or FLT3 mutations might increase the potential of clinical responses.	('ABL', 'Gene', (114, 117))	('FLT3', 'Gene', '2322', (122, 126))	('leukemia', 'Disease', (86, 94))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('leukemia', 'Disease', 'MESH:D007938', (86, 94))	('clinical responses', 'CPA', (169, 187))	('mutations', 'Var', (127, 136))	('increase', 'PosReg', (143, 151))	('FLT3', 'Gene', (122, 126))	('patients', 'Species', '9606', (72, 80))
570289	29097609	Alisertib (MLN8237) inhibits Aurora-A and Aurora-B kinase with an IC50 of 1.2 nM and 396.5 nM, respectively.	('Aurora-B', 'Gene', '9212', (42, 50))	('inhibits', 'NegReg', (20, 28))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))	('MLN8237', 'Chemical', 'MESH:C550258', (11, 18))	('MLN8237', 'Var', (11, 18))	('Aurora-B', 'Gene', (42, 50))	('Aurora-A', 'Gene', (29, 37))	('Aurora-A', 'Gene', '6790', (29, 37))
570291	29097609	In the PPTP in vitro and in vivo models of childhood cancer, MLN8237 treatment led to growth repression in neuroblastoma and Ewing sarcoma cell lines as well as maintained complete responses and complete responses in neuroblastoma and ALL xenografts, respectively.	('neuroblastoma', 'Disease', (107, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('MLN8237', 'Chemical', 'MESH:C550258', (61, 68))	('neuroblastoma', 'Phenotype', 'HP:0003006', (107, 120))	('neuroblastoma', 'Phenotype', 'HP:0003006', (217, 230))	('PPTP', 'Chemical', '-', (7, 11))	('growth repression', 'MPA', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('neuroblastoma', 'Disease', 'MESH:D009447', (217, 230))	('Ewing sarcoma', 'Disease', (125, 138))	('neuroblastoma', 'Disease', 'MESH:D009447', (107, 120))	('neuroblastoma', 'Disease', (217, 230))	('MLN8237 treatment', 'Var', (61, 78))
570292	29097609	Preclinical studies established a correlation between alisertib sensitivity and decreased AURKA copy number, in addition to a steep dose-response relationship (1muM).	('AURKA', 'Gene', '6790', (90, 95))	('alisertib', 'Chemical', 'MESH:C550258', (54, 63))	('AURKA', 'Gene', (90, 95))	('decreased', 'NegReg', (80, 89))	('alisertib sensitivity', 'Var', (54, 75))
570303	29097609	In comparison to normal cells that repair DNA damage during G1 arrest, deficiencies in the G1 checkpoint in cancer cells result in DNA repair at the G2/M checkpoint.	('deficiencies', 'Var', (71, 83))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('arrest', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('G1 checkpoint', 'Gene', (91, 104))	('DNA repair', 'MPA', (131, 141))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
570304	29097609	Ataxia-telangiectasia mutated (ATM) kinase and/or ataxia-telangiectasia-related (ATR) kinase mediate the repair of DNA double-strand breaks and DNA single-strand breaks, respectively.	('ATR', 'Gene', '545', (81, 84))	('ATR', 'Gene', (81, 84))	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (50, 71))	('Ataxia-telangiectasia', 'Disease', 'MESH:D001260', (0, 21))	('ATM', 'Gene', '472', (31, 34))	('DNA', 'Var', (115, 118))	('telangiectasia', 'Phenotype', 'HP:0001009', (57, 71))	('ataxia-telangiectasia', 'Disease', (50, 71))	('telangiectasia', 'Phenotype', 'HP:0001009', (7, 21))	('Ataxia', 'Phenotype', 'HP:0001251', (0, 6))	('ATM', 'Gene', (31, 34))	('Ataxia-telangiectasia', 'Disease', (0, 21))	('ataxia', 'Phenotype', 'HP:0001251', (50, 56))
570306	29097609	Phosphorylation of tyrosine 15 on CDK1 by Wee1 inhibits CDK1/cyclin B function, resulting in cell cycle arrest at G2, entry into mitosis and DNA-damage repair.	('arrest', 'Disease', 'MESH:D006323', (104, 110))	('cyclin', 'Gene', '5111', (61, 67))	('Wee1', 'Gene', (42, 46))	('Phosphorylation', 'Var', (0, 15))	('cyclin', 'Gene', (61, 67))	('DNA-damage repair', 'CPA', (141, 158))	('mitosis', 'Disease', (129, 136))	('arrest', 'Disease', (104, 110))	('Wee1', 'Gene', '7465', (42, 46))	('CDK1', 'Gene', (34, 38))	('function', 'MPA', (70, 78))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))	('CDK1', 'Gene', '983', (34, 38))	('mitosis', 'Disease', 'None', (129, 136))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))	('CDK1', 'Gene', '983', (56, 60))	('CDK1', 'Gene', (56, 60))	('inhibits', 'NegReg', (47, 55))
570308	29097609	Since Wee1 functionally interacts with critical regulators of mitosis, inhibition interrupts the DNA repair machinery leading to mitotic catastrophe and apoptotic cell death.	('Wee1', 'Gene', (6, 10))	('apoptotic cell death', 'CPA', (153, 173))	('inhibition', 'Var', (71, 81))	('mitotic catastrophe', 'CPA', (129, 148))	('Wee1', 'Gene', '7465', (6, 10))	('interrupts', 'NegReg', (82, 92))	('DNA', 'Protein', (97, 100))	('interacts', 'Reg', (24, 33))	('mitosis', 'Disease', (62, 69))	('mitosis', 'Disease', 'None', (62, 69))
570310	29097609	Inhibition of Wee1 could sensitize cancer cells to radiation therapy and chemotherapy, by disruption of the G2/M checkpoint.	('Wee1', 'Gene', (14, 18))	('disruption', 'NegReg', (90, 100))	('Wee1', 'Gene', '7465', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('sensitize', 'Reg', (25, 34))	('cancer', 'Disease', (35, 41))	('G2/M checkpoint', 'CPA', (108, 123))
570311	29097609	AZD1775 is the most frequently tested Wee1 inhibitor in preclinical and clinical studies.	('Wee1', 'Gene', '7465', (38, 42))	('Wee1', 'Gene', (38, 42))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))
570312	29097609	Combining gamma radiation and AZD1775 in HGG cell lines and orthotopic HGG and DIPG xenograft tumors led to enhanced sensitivity than achieved by radiation treatment alone.	('sensitivity', 'MPA', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('DIPG xenograft tumors', 'Disease', (79, 100))	('enhanced', 'PosReg', (108, 116))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('AZD1775', 'Var', (30, 37))	('DIPG xenograft tumors', 'Disease', 'MESH:D000080443', (79, 100))	('AZD1775', 'Chemical', 'MESH:C549567', (30, 37))
570314	29097609	In addition, AZD1775 caused activation of cell division cycle protein 2 (CDC2; also known as CDK1) in an osteosarcoma xenograft and reduced tumor growth by 50% as monotherapy, and by approximately 70% when combined with gemcitabine.	('CDK1', 'Gene', '983', (93, 97))	('AZD1775', 'Chemical', 'MESH:C549567', (13, 20))	('gemcitabine', 'Chemical', 'MESH:C056507', (220, 231))	('CDC2', 'Gene', (73, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('reduced', 'NegReg', (132, 139))	('osteosarcoma xenograft', 'Disease', 'MESH:D012516', (105, 127))	('CDC2', 'Gene', '983', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('activation', 'PosReg', (28, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CDK1', 'Gene', (93, 97))	('osteosarcoma xenograft', 'Disease', (105, 127))	('AZD1775', 'Var', (13, 20))	('tumor', 'Disease', (140, 145))
570315	29097609	In hematological malignancies, AZD1775 plus panobinostat demonstrated synergistic antitumor effects in preclinical models of AML and when combined with CDK inhibitor (roscovitine), and cytarabine.	('AML', 'Disease', 'MESH:D015470', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('AZD1775', 'Var', (31, 38))	('cytarabine', 'Chemical', 'MESH:D003561', (185, 195))	('tumor', 'Disease', (86, 91))	('AML', 'Disease', (125, 128))	('hematological malignancies', 'Phenotype', 'HP:0004377', (3, 29))	('panobinostat', 'Gene', (44, 56))	('hematological malignancies', 'Disease', (3, 29))	('AZD1775', 'Chemical', 'MESH:C549567', (31, 38))	('hematological malignancies', 'Disease', 'MESH:D019337', (3, 29))	('panobinostat', 'Chemical', 'MESH:D000077767', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('roscovitine', 'Chemical', 'MESH:D000077546', (167, 178))
570316	29097609	In the latter study, AZD1775 inhibited cytabarine-mediated S-phase arrest and prevented DNA repair.	('prevented', 'NegReg', (78, 87))	('inhibited', 'NegReg', (29, 38))	('AZD1775', 'Var', (21, 28))	('AZD1775', 'Chemical', 'MESH:C549567', (21, 28))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('cytabarine', 'Chemical', '-', (39, 49))	('arrest', 'Disease', (67, 73))	('DNA repair', 'CPA', (88, 98))	('cytabarine-mediated', 'MPA', (39, 58))
570317	29097609	Further, MYC-driven tumors or CDKN2A mutation combined with TP53 mutation could show aberrations in the G1 checkpoint and become more reliant on the S- and G2- phase checkpoints.	('tumors', 'Disease', (20, 26))	('MYC', 'Gene', '4609', (9, 12))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutation', 'Var', (37, 45))	('CDKN2A', 'Gene', (30, 36))	('MYC', 'Gene', (9, 12))	('CDKN2A', 'Gene', '1029', (30, 36))	('G1 checkpoint', 'CPA', (104, 117))	('TP53', 'Gene', '7157', (60, 64))	('mutation', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', (60, 64))
570318	29097609	S- and G2- checkpoint abrogation caused by inhibition of Wee1 may selectively sensitize p53-deficient tumors.	('deficient tumors', 'Disease', 'MESH:D009369', (92, 108))	('inhibition', 'Var', (43, 53))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('G2- checkpoint abrogation', 'CPA', (7, 32))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('Wee1', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Wee1', 'Gene', '7465', (57, 61))	('deficient tumors', 'Disease', (92, 108))
570319	29097609	Other studies also show that AZD1775 sensitizes AML cells to cytarabine and HGG cells to radiation irrespective of p53 mutation status.	('cytarabine', 'Chemical', 'MESH:D003561', (61, 71))	('AML', 'Disease', (48, 51))	('sensitizes', 'Reg', (37, 47))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('AZD1775', 'Var', (29, 36))	('AML', 'Disease', 'MESH:D015470', (48, 51))	('AZD1775', 'Chemical', 'MESH:C549567', (29, 36))
570320	29097609	These observations suggest that the requirement of p53 mutations for sensitivity with combination therapies using AZD1775 is context-dependent and may not be a critical consideration during development of novel therapies.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('mutations', 'Var', (55, 64))	('AZD1775', 'Gene', (114, 121))	('AZD1775', 'Chemical', 'MESH:C549567', (114, 121))
570322	29097609	Patient recruitment for two pediatric phase 1 trials to study side effects and best dose of Wee1 kinase inhibitor AZD1775 when given together with local radiation therapy in treating newly diagnosed DIPG (NCT01922076); and with irinotecan hydrochloride in treating advanced solid tumors (NCT02095132) is ongoing.	('DIPG', 'Disease', (199, 203))	('DIPG', 'Chemical', '-', (199, 203))	('AZD1775', 'Gene', (114, 121))	('irinotecan hydrochloride', 'Chemical', 'MESH:D000077146', (228, 252))	('solid tumors', 'Disease', 'MESH:D009369', (274, 286))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('Wee1', 'Gene', (92, 96))	('AZD1775', 'Chemical', 'MESH:C549567', (114, 121))	('NCT01922076);', 'Var', (205, 218))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('Wee1', 'Gene', '7465', (92, 96))	('solid tumors', 'Disease', (274, 286))	('Patient', 'Species', '9606', (0, 7))
570325	29097609	Inhibition of KSP leads to cell cycle arrest in mitosis with the formation of characteristic monoaster spindles.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (27, 44))	('KSP', 'Chemical', '-', (14, 17))	('arrest in mitosis', 'Disease', (38, 55))	('Inhibition', 'Var', (0, 10))	('KSP', 'Gene', (14, 17))	('arrest in mitosis', 'Disease', 'MESH:D006323', (38, 55))
570339	29097609	Stabilizing factors include microtubule-associated proteins, MAPs (MAP4, XMAP215, XMAP230/XMAP4 and XMAP310) and destabilizing factors include (Stathmin1 and XKCM1).	('MAP4', 'Gene', '4134', (67, 71))	('MAP4', 'Gene', (91, 95))	('MAP4', 'Gene', '4134', (91, 95))	('microtubule-associated proteins', 'Protein', (28, 59))	('XMAP310', 'Var', (100, 107))	('Stathmin1', 'Gene', '3925', (144, 153))	('Stathmin1', 'Gene', (144, 153))	('MAP4', 'Gene', (67, 71))
570340	29097609	Consistent with the disruption of microtubules and the mitotic spindle, MTAs can arrest cell cycle progression in mitosis, resulting in cell death.	('mitosis', 'Disease', (114, 121))	('mitosis', 'Disease', 'None', (114, 121))	('MTAs', 'Var', (72, 76))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('arrest', 'Disease', (81, 87))
570368	29097609	Ongoing trials for the same patient population are evaluating effects of combining brentuximab vedotin with doxorubicin (NCT01920932), dacarbazine (NCT02979522), and gemcitabine (NCT01780662).	('dacarbazine', 'Chemical', 'MESH:D003606', (135, 146))	('patient', 'Species', '9606', (28, 35))	('gemcitabine', 'Chemical', 'MESH:C056507', (166, 177))	('NCT02979522', 'Var', (148, 159))	('doxorubicin', 'Chemical', 'MESH:D004317', (108, 119))	('NCT01920932', 'Var', (121, 132))
570378	29097609	For example, investigations of antitumor activity for inhibitors against ATM (KU-55933, KU-59403; KuDOS Pharmaceuticals, AstraZeneca) and ATR (Schisandrin B, AZD6738) have advanced to early phase trials in adult patients with cancer.	('ATM', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('ATM', 'Gene', '472', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('KU-55933', 'Var', (78, 86))	('patients', 'Species', '9606', (212, 220))	('tumor', 'Disease', (35, 40))	('cancer', 'Disease', (226, 232))	('Schisandrin B', 'Chemical', 'MESH:C015499', (143, 156))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('ATR', 'Gene', '545', (138, 141))	('ATR', 'Gene', (138, 141))	('AZD6738', 'Chemical', 'MESH:C000611951', (158, 165))	('KU-59403', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
570387	29097609	This was seen when MLN8237 (alisertib) failed to reach its primary endpoint for adult lymphomas and lung cancers during early phase studies in pediatric patients.	('lung cancers', 'Disease', (100, 112))	('MLN8237', 'Chemical', 'MESH:C550258', (19, 26))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('patients', 'Species', '9606', (153, 161))	('lymphomas', 'Disease', (86, 95))	('lymphomas', 'Disease', 'MESH:D008223', (86, 95))	('MLN8237', 'Var', (19, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lymphomas', 'Phenotype', 'HP:0002665', (86, 95))	('lung cancers', 'Disease', 'MESH:D008175', (100, 112))	('lung cancers', 'Phenotype', 'HP:0100526', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('alisertib', 'Chemical', 'MESH:C550258', (28, 37))	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))
570439	28741123	Similar to prior studies, we also observed that R0 resection was associated with superior OS.	('R0 resection', 'Var', (48, 60))	('superior OS', 'Disease', (81, 92))	('OS', 'Chemical', '-', (90, 92))
570547	25603314	Dysregulation of receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in Ewing Sarcoma pathogenesis.	('receptor tyrosine kinase signaling', 'MPA', (17, 51))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('Ewing Sarcoma', 'Disease', (116, 129))	('Dysregulation', 'Var', (0, 13))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('IGF-1R', 'Gene', (76, 82))	('Sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('IGF-1R', 'Gene', '3480', (76, 82))
570556	25603314	Ewing Sarcoma is driven by recurrent EWS/Ets oncogenic fusions, which, through gain-of-function transcriptional activity, and possibly other mechanisms, result in dysregulation of expression of many genes, as well as non-coding RNAs.	('dysregulation', 'MPA', (163, 176))	('Sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('expression', 'MPA', (180, 190))	('Ewing Sarcoma', 'Disease', (0, 13))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('EWS', 'Gene', '2130', (37, 40))	('EWS', 'Gene', (37, 40))	('gain-of-function', 'PosReg', (79, 95))	('fusions', 'Var', (55, 62))
570557	25603314	As in all cancers, the ultimate outcome of oncogene-driven dysregulation of gene expression is promotion of the malignant phenotype.	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('dysregulation', 'Var', (59, 72))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', (10, 17))	('promotion', 'PosReg', (95, 104))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('malignant phenotype', 'CPA', (112, 131))
570558	25603314	However, as also true in all cancers, the precise mechanistic connections between oncogene-driven gene expression changes and phenotypic output, as well as the identity of key gene expression changes essential to specific malignant phenotypes, are less well understood.	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))	('changes', 'Var', (114, 121))
570578	25603314	Primary antibodies used were: PIK3R3 (1:1000, Cell Signaling, #11889), PTEN (1:1000, Cell Signaling, #9552), pAkt (Ser473, 1:500, Cell Signaling, #4060L), Akt (1:1000, Cell Signaling, #9272), and tubulin (1:20000, Sigma, T5168).	('Ser473', 'Var', (115, 121))	('Ser473', 'Chemical', '-', (115, 121))	('Akt', 'Gene', (110, 113))	('PIK3R3', 'Gene', (30, 36))	('PIK3R3', 'Gene', '8503', (30, 36))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (71, 75))	('Akt', 'Gene', '207', (155, 158))	('Akt', 'Gene', '207', (110, 113))	('Akt', 'Gene', (155, 158))
570580	25603314	ShRNAs 1 and 2 for PIK3R3 correspond to TRCN0000195144 and TRCN0000197032 (Sigma Mission shRNA, distributed via the University of Colorado Cancer Center Functional Genomics Core Facility).	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('TRCN0000197032', 'Var', (59, 73))	('PIK3R3', 'Gene', (19, 25))	('Cancer', 'Disease', (139, 145))	('TRCN0000195144', 'Var', (40, 54))	('Cancer', 'Disease', 'MESH:D009369', (139, 145))	('PIK3R3', 'Gene', '8503', (19, 25))
570602	25603314	PIK3R3 depletion resulted in inhibition of growth in both a clonogenic assay (Fig.	('growth in both a clonogenic assay', 'CPA', (43, 76))	('inhibition', 'NegReg', (29, 39))	('PIK3R3', 'Gene', '8503', (0, 6))	('depletion', 'Var', (7, 16))	('PIK3R3', 'Gene', (0, 6))
570603	25603314	2B, bottom panels), in a manner that was proportional to the degree of PIK3R3 mRNA and protein knock-down (Fig.	('knock-down', 'Var', (95, 105))	('PIK3R3', 'Gene', (71, 77))	('mRNA and', 'MPA', (78, 86))	('protein', 'Protein', (87, 94))	('PIK3R3', 'Gene', '8503', (71, 77))
570626	25603314	In fact, partial PTEN re-expression resulted in a modest (~50%), but statistically significant, augmentation of anchorage-independent growth in soft agar (Fig.	('augmentation', 'PosReg', (96, 108))	('re-expression', 'Var', (22, 35))	('PTEN', 'Gene', (17, 21))	('PTEN', 'Gene', '5728', (17, 21))	('partial', 'Var', (9, 16))	('anchorage-independent growth in soft agar', 'CPA', (112, 153))
570628	25603314	Re-expression of PTEN in PTEN-negative cells would be predicted to sensitize to inhibition of receptor tyrosine kinase action, by re-instating, at least partially, negative regulation of downstream signaling.	('inhibition', 'NegReg', (80, 90))	('receptor tyrosine kinase action', 'MPA', (94, 125))	('sensitize', 'Reg', (67, 76))	('Re-expression', 'Var', (0, 13))	('PTEN', 'Gene', (17, 21))	('PTEN', 'Gene', '5728', (17, 21))	('PTEN', 'Gene', (25, 29))	('PTEN', 'Gene', '5728', (25, 29))
570638	25603314	Dysregulation of growth factor signaling pathways makes an important contribution to Ewing Sarcoma pathogenesis, as true in many other cancers.	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (85, 98))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('Ewing Sarcoma', 'Disease', (85, 98))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (85, 98))	('growth factor signaling pathways', 'Pathway', (17, 49))	('Sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
570651	25603314	Namely, cell lines lacking PTEN show markedly higher baseline Akt phosphorylation, and reintroduction of PTEN, even at reduced levels compared to PTEN-positive cells, enforces robust downregulation of Akt phosphorylation.	('PTEN', 'Gene', (146, 150))	('PTEN', 'Gene', '5728', (146, 150))	('higher', 'PosReg', (46, 52))	('Akt', 'Gene', (201, 204))	('PTEN', 'Gene', (105, 109))	('Akt', 'Gene', '207', (62, 65))	('PTEN', 'Gene', '5728', (105, 109))	('PTEN', 'Gene', (27, 31))	('baseline', 'MPA', (53, 61))	('reintroduction', 'Var', (87, 101))	('PTEN', 'Gene', '5728', (27, 31))	('downregulation', 'NegReg', (183, 197))	('Akt', 'Gene', (62, 65))	('Akt', 'Gene', '207', (201, 204))
570658	25603314	A surprising observation in our studies was that reintroduction of PTEN into PTEN-negative Ewing Sarcoma cells resulted in modest augmentation of anchorage-independent growth, all in context of downregulation of Akt phosphorylation.	('reintroduction', 'Var', (49, 63))	('downregulation', 'NegReg', (194, 208))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (91, 104))	('Ewing Sarcoma', 'Disease', (91, 104))	('Sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('phosphorylation', 'MPA', (216, 231))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('PTEN', 'Gene', (77, 81))	('Akt', 'Gene', '207', (212, 215))	('PTEN', 'Gene', (67, 71))	('PTEN', 'Gene', '5728', (77, 81))	('PTEN', 'Gene', '5728', (67, 71))	('anchorage-independent growth', 'CPA', (146, 174))	('Akt', 'Gene', (212, 215))	('augmentation', 'NegReg', (130, 142))
570660	25603314	Indeed, the cell state induced by partial PTEN restoration in our studies may be similar to PTEN haploinsufficiency, a state known to be able to support many oncogenic phenotypes, including increased cell proliferation.	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('PTEN haploinsufficiency', 'Disease', (92, 115))	('partial', 'Var', (34, 41))	('increased', 'PosReg', (190, 199))	('PTEN', 'Gene', (92, 96))	('PTEN', 'Gene', '5728', (92, 96))	('cell proliferation', 'CPA', (200, 218))	('PTEN haploinsufficiency', 'Disease', 'MESH:D006223', (92, 115))
570664	25603314	observed inhibition of growth upon PTEN re-expression in Ewing Sarcoma EWS502 cells.	('inhibition', 'NegReg', (9, 19))	('Sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('Ewing Sarcoma', 'Disease', (57, 70))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (57, 70))	('PTEN', 'Gene', (35, 39))	('growth', 'MPA', (23, 29))	('PTEN', 'Gene', '5728', (35, 39))	('re-expression', 'Var', (40, 53))	('EWS502', 'Chemical', '-', (71, 77))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (57, 70))
570671	25603314	In summary, our studies identify a growth-promotional role for PIK3R3 in Ewing Sarcoma, and provide evidence that loss of PTEN expression may diminish responsiveness to vincristine and IGF-1R blockade.	('diminish', 'NegReg', (142, 150))	('Sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('Ewing Sarcoma', 'Disease', (73, 86))	('responsiveness to vincristine', 'MPA', (151, 180))	('IGF-1R', 'Gene', '3480', (185, 191))	('loss', 'Var', (114, 118))	('growth-promotional', 'PosReg', (35, 53))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (73, 86))	('PIK3R3', 'Gene', '8503', (63, 69))	('vincristine', 'Chemical', 'MESH:D014750', (169, 180))	('PIK3R3', 'Gene', (63, 69))	('PTEN', 'Gene', (122, 126))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (73, 86))	('PTEN', 'Gene', '5728', (122, 126))	('IGF-1R', 'Gene', (185, 191))
570685	22550419	MicroRNAs (miRNAs) are noncoding small RNAs, usually 18-25 nucleotides in length, which repress translation and cleave mRNA by base-pairing to the 3' untranslated region of the target genes (Figure 1).	('base-pairing', 'Var', (127, 139))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('mRNA', 'MPA', (119, 123))	('translation', 'MPA', (96, 107))	('repress', 'NegReg', (88, 95))	('cleave', 'Var', (112, 118))
570699	22550419	reported that miR-1 and miR-206 promoted myogenic differentiation to regulate skeletal muscle development, and blocked rhabdomyosarcoma tumor growth in mice xenografts.	('promoted', 'PosReg', (32, 40))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (119, 135))	('blocked', 'NegReg', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('myogenic differentiation', 'CPA', (41, 65))	('rhabdomyosarcoma tumor', 'Disease', (119, 141))	('miR-206', 'Var', (24, 31))	('miR-1', 'Gene', '79187', (14, 19))	('mice', 'Species', '10090', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('rhabdomyosarcoma tumor', 'Disease', 'MESH:D012208', (119, 141))	('miR-1', 'Gene', (14, 19))
570710	22550419	Since a broad range of genetic and epigenetic alterations can be associated with the osteoblast differentiation pathway, osteoblasts have been considered as the origin of OS.	('osteoblast differentiation', 'CPA', (85, 111))	('rat', 'Species', '10116', (50, 53))	('OS', 'Phenotype', 'HP:0002669', (171, 173))	('associated', 'Reg', (65, 75))	('epigenetic alterations', 'Var', (35, 57))
570724	22550419	The TP53 gene is mutated in more than 20% of OS, and its mutations have been demonstrated to be involved in the tumorigenesis of OS.	('TP53', 'Gene', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('involved', 'Reg', (96, 104))	('rat', 'Species', '10116', (84, 87))	('OS', 'Phenotype', 'HP:0002669', (129, 131))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', (112, 117))	('OS', 'Phenotype', 'HP:0002669', (45, 47))	('TP53', 'Gene', '7157', (4, 8))
570725	22550419	In addition, Li-Fraumeni syndrome, which is characterized by an autosomal dominant mutation of TP53, leads to the development of multiple malignancies, including OS.	('OS', 'Phenotype', 'HP:0002669', (162, 164))	('Li-Fraumeni syndrome', 'Disease', (13, 33))	('multiple malignancies', 'Disease', 'MESH:D009369', (129, 150))	('multiple malignancies', 'Disease', (129, 150))	('mutation', 'Var', (83, 91))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (13, 33))	('leads to', 'Reg', (101, 109))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
570730	22550419	According to an examination of the expression of genetic and epigenetic alterations of miR-34 in 117 primary OS samples, the expression of miR-34 was decreased in OS, and miR-34 inhibited the p53-mediated cell cycle arrest and apoptosis in OS cells.	('epigenetic alterations', 'Var', (61, 83))	('miR-34', 'Gene', '407040', (87, 93))	('OS', 'Phenotype', 'HP:0002669', (109, 111))	('p53', 'Gene', (192, 195))	('miR-34', 'Gene', '407040', (171, 177))	('OS', 'Phenotype', 'HP:0002669', (163, 165))	('arrest', 'Disease', 'MESH:D006323', (216, 222))	('miR-34', 'Gene', '407040', (139, 145))	('inhibited', 'NegReg', (178, 187))	('apoptosis', 'CPA', (227, 236))	('decreased', 'NegReg', (150, 159))	('miR-34', 'Gene', (87, 93))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (205, 222))	('expression', 'MPA', (125, 135))	('miR-34', 'Gene', (171, 177))	('OS', 'Phenotype', 'HP:0002669', (240, 242))	('miR-34', 'Gene', (139, 145))	('rat', 'Species', '10116', (76, 79))	('arrest', 'Disease', (216, 222))	('p53', 'Gene', '7157', (192, 195))
570734	22550419	demonstrated that miR-31 was able to inhibit multiple steps in the metastatic development of breast cancer.	('miR-31', 'Var', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('inhibit', 'NegReg', (37, 44))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('rat', 'Species', '10116', (7, 10))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('metastatic development', 'CPA', (67, 89))
570735	22550419	The silencing of the mRNA targets of miR-31, integrin-alpha5 (ITGA5), radixin (RDX), and RhoA, reduced local invasion and motility in vitro and decreased the development of metastases in a xenograft mouse model of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('mouse', 'Species', '10090', (199, 204))	('RhoA', 'Gene', '11848', (89, 93))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('breast cancer', 'Disease', (214, 227))	('ITGA5', 'Gene', (62, 67))	('decreased', 'NegReg', (144, 153))	('RDX', 'Gene', '19684', (79, 82))	('miR-31', 'Gene', (37, 43))	('RDX', 'Gene', (79, 82))	('reduced', 'NegReg', (95, 102))	('integrin-alpha5', 'Gene', (45, 60))	('silencing', 'Var', (4, 13))	('ITGA5', 'Gene', '16402', (62, 67))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('integrin-alpha5', 'Gene', '16402', (45, 60))	('metastases', 'Disease', (173, 183))	('local invasion', 'CPA', (103, 117))	('radixin', 'Gene', '19684', (70, 77))	('radixin', 'Gene', (70, 77))	('RhoA', 'Gene', (89, 93))
570758	22550419	These data are consistent with that from a previous report which demonstrated that the restoration of miR-143 reduced cell viability and induced apoptosis in OS cell lines via an antiapoptotic molecule, BCL-2.	('rat', 'Species', '10116', (72, 75))	('reduced', 'NegReg', (110, 117))	('restoration', 'Var', (87, 98))	('BCL-2', 'Gene', '596', (203, 208))	('BCL-2', 'Gene', (203, 208))	('miR-143', 'Gene', (102, 109))	('rat', 'Species', '10116', (92, 95))	('induced', 'Reg', (137, 144))	('OS', 'Phenotype', 'HP:0002669', (158, 160))	('cell viability', 'CPA', (118, 132))	('apoptosis', 'CPA', (145, 154))
570785	22550419	Antisense oligonucleotides are single-stranded molecules that form direct bonds by complementary pairing and work as competitive inhibitors of miRNAs.	('Antisense oligonucleotides', 'Var', (0, 26))	('bonds', 'Interaction', (74, 79))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', (143, 146))	('form', 'Reg', (62, 66))	('oligonucleotides', 'Chemical', 'MESH:D009841', (10, 26))
570818	31838786	Low-income patients were more likely to be racial/ethnic minorities and to present with metastatic disease (OR 1.96, 95% CI 1.35-2.86).	('Low-income', 'Var', (0, 10))	('patients', 'Species', '9606', (11, 19))	('metastatic disease', 'CPA', (88, 106))
570853	31838786	There was a higher proportion of bone tumors in the low-income public insurance group compared to the private insurance group (P = .011).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('low-income', 'Var', (52, 62))	('bone tumors', 'Disease', 'MESH:D001859', (33, 44))	('bone tumors', 'Disease', (33, 44))	('bone tumors', 'Phenotype', 'HP:0010622', (33, 44))
570855	31838786	There was a statistically significant difference in OS by insurance status (HR 1.26, 95% CI 1.21-1.78, P = .0001, Figure 1); patients with low-income public insurance had significantly worse 5- and 10-year OS compared to those with private insurance (61% vs 71%, 49% vs 63%, respectively, P = .0001).	('low-income', 'Var', (139, 149))	('worse', 'NegReg', (185, 190))	('patients', 'Species', '9606', (125, 133))
570858	31838786	Patients with low-income public insurance were more likely than those with private insurance to present with metastatic disease (OR 1.96, 95% CI 1.35-2.86, P < .001) after accounting for sex, age at diagnosis, and race/ethnicity.	('Patients', 'Species', '9606', (0, 8))	('metastatic disease', 'Disease', (109, 127))	('low-income', 'Var', (14, 24))
570860	31838786	While patients with public insurance were more likely to present with metastatic disease at diagnosis, public insurance was independently associated with diminished survival, even when controlling for sex, race/ethnicity, age, and stage of disease, as well as when stratified by stage of disease.	('public insurance', 'Var', (103, 119))	('diminished', 'NegReg', (154, 164))	('survival', 'CPA', (165, 173))	('patients', 'Species', '9606', (6, 14))	('metastatic disease', 'Disease', (70, 88))
570934	29948928	Cancer cells release pathogen-associated molecular signals (PAMPs), damage-associated molecular signals (DAMPs), and 'foreign' antigens typically resulting from mutations in protein-coding genes, termed neoantigens.	('pathogen-associated molecular signals', 'MPA', (21, 58))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (161, 170))	('damage-associated molecular signals', 'MPA', (68, 103))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
570943	29948928	The mechanisms behind the tumor cells evading the immune system are numerous and include loss of expression of tumor antigens and down-regulation of human leukocyte antigens (HLA) from tumor surfaces (so-called 'edited' tumor), recruitment of immunosuppressive regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), or tumor-associated M2-like macrophages, upregulation of inhibitory receptors (i.e., cytotoxic T lymphocyte associated protein 4 [CTLA-4], Programmed death receptor 1 [PD-1]) on T cells, or upregulation of inhibitory ligands (PD-L1) on tumor and/or stromal cells (Fig.	('loss', 'Var', (89, 93))	('PD-L1', 'Gene', (556, 561))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (220, 225))	('cytotoxic T lymphocyte associated protein 4', 'Gene', '397286', (415, 458))	('HL', 'CellLine', 'CVCL:2492', (175, 177))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (566, 571))	('tumor', 'Disease', (185, 190))	('cytotoxic T lymphocyte associated protein 4', 'Gene', (415, 458))	('tumor', 'Disease', 'MESH:D009369', (566, 571))	('upregulation', 'PosReg', (371, 383))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('HL', 'Phenotype', 'HP:0012189', (175, 177))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (111, 116))	('down-regulation', 'NegReg', (130, 145))	('human', 'Species', '9606', (149, 154))	('Programmed', 'Gene', (469, 479))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (333, 338))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('upregulation', 'PosReg', (520, 532))	('PD-1', 'Gene', (498, 502))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('PD-1', 'Gene', '5133', (498, 502))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
570947	29948928	Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) detects L-MTP-PE, activating NF-kappabeta to stimulate the production of interleukin (IL)-1beta, IL-6, and tissue necrosis factor (TNF)-alpha, which stimulate macrophages and monocytes.	('tissue necrosis', 'Phenotype', 'HP:0010885', (177, 192))	('production', 'MPA', (129, 139))	('NF-kappabeta', 'Protein', (99, 111))	('interleukin (IL)-1beta', 'Gene', '3553', (143, 165))	('L-MTP-PE', 'Var', (78, 86))	('IL-6', 'Gene', (167, 171))	('NOD2', 'Gene', '64127', (64, 68))	('activating', 'PosReg', (88, 98))	('IL-6', 'Gene', '3569', (167, 171))	('L-MTP-PE', 'Chemical', '-', (78, 86))	('Nucleotide-binding oligomerization domain-containing protein 2', 'Gene', '64127', (0, 62))	('interleukin (IL)-1beta', 'Gene', (143, 165))	('NOD2', 'Gene', (64, 68))	('tissue necrosis factor (TNF)-alpha', 'Gene', '7124', (177, 211))	('stimulate', 'PosReg', (115, 124))
570948	29948928	Initially L-MTP-PE was studied in canine bone and soft tissue sarcomas and demonstrated a median overall survival (OS) of 222 days in the L-MTP-PE-treated group compared with 77 days in the control group.	('L-MTP-PE', 'Chemical', '-', (10, 18))	('sarcomas', 'Disease', 'MESH:D012509', (62, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('L-MTP-PE', 'Chemical', '-', (138, 146))	('L-MTP-PE-treated', 'Var', (138, 154))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (50, 70))	('sarcomas', 'Disease', (62, 70))	('canine', 'Species', '9615', (34, 40))
570949	29948928	In 1993, a cooperative group clinical trial INT0133 (http://www.clinicaltrials.gov, NCT00631631) analyzed whether, in addition to chemotherapy with methotrexate, doxorubicin, cisplatin, L-MTP-PE and/or ifosfamide would improve outcomes.	('ifosfamide', 'Chemical', 'MESH:D007069', (202, 212))	('improve', 'PosReg', (219, 226))	('methotrexate', 'Chemical', 'MESH:D008727', (148, 160))	('L-MTP-PE', 'Chemical', '-', (186, 194))	('outcomes', 'MPA', (227, 235))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('L-MTP-PE', 'Var', (186, 194))	('doxorubicin', 'Chemical', 'MESH:D004317', (162, 173))
570950	29948928	The study enrolled 662 patients and found improvement of the 6-year OS from 70 to 78% (p = 0.03) with addition of L-MTP-PE; the hazard ratio was 0.71 (95% CI 0.52-0.96).	('patients', 'Species', '9606', (23, 31))	('L-MTP-PE', 'Chemical', '-', (114, 122))	('improvement', 'PosReg', (42, 53))	('L-MTP-PE', 'Var', (114, 122))
570973	29948928	One of the advantages of monoclonal antibody therapy is they are tumor-specific instead of patient-specific, thus can be easily stored in clinics and hospitals without the need for local manufacturing expertise.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('monoclonal antibody', 'Var', (25, 44))	('patient', 'Species', '9606', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
570999	29948928	Because GD2 is also expressed in other cancers besides neuroblastoma, there are numerous trials investigating anti-GD2 mAbs alone or in combination with other immunotherapies in solid tumors expressing GD2 (NCT02100930, NCT01857934, NCT01419834, NCT02502786, NCT01662804).	('neuroblastoma', 'Disease', (55, 68))	('solid tumors', 'Disease', (178, 190))	('NCT02502786', 'Var', (246, 257))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('NCT01419834', 'Var', (233, 244))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('neuroblastoma', 'Phenotype', 'HP:0003006', (55, 68))	('cancers', 'Disease', (39, 46))	('NCT01857934', 'Var', (220, 231))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('solid tumors', 'Disease', 'MESH:D009369', (178, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('NCT02100930', 'Var', (207, 218))	('NCT01662804', 'Var', (259, 270))	('neuroblastoma', 'Disease', 'MESH:D009447', (55, 68))
571000	29948928	BiTEs for pediatric solid tumors are only beginning to be explored, an example of which is a phase I study utilizing anti-GD2 BiTE in neuroblastoma and osteosarcoma (NCT02173093).	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (10, 32))	('anti-GD2', 'Var', (117, 125))	('osteosarcoma', 'Phenotype', 'HP:0002669', (152, 164))	('neuroblastoma and osteosarcoma', 'Disease', 'MESH:D012516', (134, 164))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('neuroblastoma', 'Phenotype', 'HP:0003006', (134, 147))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('pediatric solid tumors', 'Disease', (10, 32))
571024	29948928	AML patients have experienced the most success, with these studies confirming that haploidentical NK cells could be expanded in vivo and induce remissions.	('induce', 'Reg', (137, 143))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('haploidentical', 'Var', (83, 97))	('patients', 'Species', '9606', (4, 12))	('remissions', 'MPA', (144, 154))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('AML', 'Disease', (0, 3))
571025	29948928	A pilot study of ten children with AML utilized haploidentical donor NK cells combined with IL-2 and showed remission in all patients 2 years after the treatment.There are a few clinical trials ongoing utilizing NK cell therapy for pediatric hematologic malignancies (NCT02763475, NCT03068819).	('AML', 'Disease', (35, 38))	('IL-2', 'Gene', '3558', (92, 96))	('pediatric hematologic malignancies', 'Disease', 'MESH:D019337', (232, 266))	('NCT02763475', 'Var', (268, 279))	('AML', 'Disease', 'MESH:D015470', (35, 38))	('AML', 'Phenotype', 'HP:0004808', (35, 38))	('children', 'Species', '9606', (21, 29))	('NCT03068819', 'Var', (281, 292))	('donor', 'Species', '9606', (63, 68))	('pediatric hematologic malignancies', 'Disease', (232, 266))	('IL-2', 'Gene', (92, 96))	('patients', 'Species', '9606', (125, 133))
571029	29948928	There are also numerous ongoing clinical trials for pediatric solid tumors utilizing NK cell therapy (NCT01807468, NCT03420963, NCT02573896, NCT02650648, NCT02100891).	('NCT02650648', 'Var', (141, 152))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('pediatric solid tumors', 'Disease', (52, 74))	('NCT02573896', 'Var', (128, 139))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (52, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('NCT03420963', 'Var', (115, 126))	('NCT01807468', 'Var', (102, 113))
571039	29948928	Currently, there are three ongoing studies of oncolytic viruses in pediatric brain tumor patients using attenuated versions of herpes simplex type 1 (NCT02457845), polio virus (NCT03043391), and measles virus (NCT02962167).	('measles virus', 'Species', '11234', (195, 208))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('brain tumor', 'Disease', (77, 88))	('brain tumor', 'Disease', 'MESH:D001932', (77, 88))	('NCT02962167', 'Var', (210, 221))	('NCT03043391', 'Var', (177, 188))	('brain tumor', 'Phenotype', 'HP:0030692', (77, 88))	('patients', 'Species', '9606', (89, 97))	('NCT02457845', 'Var', (150, 161))	('herpes simplex', 'Phenotype', 'HP:0012302', (127, 141))
571048	29948928	Blockade of CTLA-4 signaling is FDA approved for adult and pediatric melanoma, but preclinical data also suggest other solid tumors have high expression of CTLA-4 as well.	('solid tumors', 'Disease', (119, 131))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Blockade', 'Var', (0, 8))	('solid tumors', 'Disease', 'MESH:D009369', (119, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('CTLA-4', 'Gene', (156, 162))	('expression', 'MPA', (142, 152))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
571049	29948928	A recent phase I study (NCT01445379) of pediatric patients with melanoma and other solid tumors treated with CTLA-4 blockade revealed increased cytotoxic T lymphocyte activation without increased infiltration of Tregs; however, there were no observable antitumor responses.	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('patients', 'Species', '9606', (50, 58))	('blockade', 'Var', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('CTLA-4', 'Gene', (109, 115))	('solid tumors', 'Disease', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('increased', 'PosReg', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
571067	29948928	One of the hypotheses to explain the differences in response rates between certain adult cancers compared with pediatric cancers is the mutational load or lack thereof.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pediatric cancers', 'Disease', (111, 128))	('pediatric cancers', 'Disease', 'MESH:D009369', (111, 128))	('adult cancers', 'Disease', 'MESH:C535836', (83, 96))	('adult cancers', 'Disease', (83, 96))	('mutational load', 'Var', (136, 151))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
571069	29948928	A high mutational load in the tumor leads to more neoantigens and a more immunogenic tumor.	('tumor', 'Disease', (85, 90))	('immunogenic tumor', 'Disease', 'MESH:D009369', (73, 90))	('more', 'PosReg', (68, 72))	('high mutational load', 'Var', (2, 22))	('neoantigens', 'MPA', (50, 61))	('more', 'PosReg', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('immunogenic tumor', 'Disease', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (30, 35))
571070	29948928	The success of checkpoint inhibitors in the treatment of melanoma and NSCLC appears to be due to the high mutational load of both of these cancer types.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutational load', 'Var', (106, 121))	('NSCLC', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('cancer', 'Disease', (139, 145))
571072	29948928	The one exception involves pediatric patients with biallelic mismatch repair deficiency (bMMRD).	('biallelic mismatch', 'Var', (51, 69))	('MMRD', 'Disease', 'None', (90, 94))	('patients', 'Species', '9606', (37, 45))	('MMRD', 'Disease', (90, 94))
571094	29948928	PD-1 expression can be increased by Treg infiltration, immunosuppressive cytokine signaling, loss of neoantigen expression, and genomic instability; ultimately this results in T-cell therapy exhaustion and tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('expression', 'MPA', (5, 15))	('immunosuppressive', 'MPA', (55, 72))	('PD-1', 'Gene', (0, 4))	('loss', 'NegReg', (93, 97))	('neoantigen expression', 'MPA', (101, 122))	('tumor', 'Disease', (206, 211))	('PD-1', 'Gene', '5133', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('increased', 'PosReg', (23, 32))	('results in', 'Reg', (165, 175))	('genomic', 'Var', (128, 135))	('T-cell therapy exhaustion', 'CPA', (176, 201))
571095	29948928	Preclinical studies on hepatocellular and prostate cancers found that PD-1 blockade could lead to increased anti-tumor responses and T-cell proliferation.	('tumor', 'Disease', (113, 118))	('blockade', 'Var', (75, 83))	('prostate cancers', 'Disease', 'MESH:D011471', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('increased', 'PosReg', (98, 107))	('PD-1', 'Gene', (70, 74))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('hepatocellular', 'Disease', (23, 37))	('PD-1', 'Gene', '5133', (70, 74))	('prostate cancers', 'Phenotype', 'HP:0012125', (42, 58))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('prostate cancers', 'Disease', (42, 58))	('T-cell proliferation', 'CPA', (133, 153))
571096	29948928	There are ongoing clinical trials combining immune checkpoint inhibition, cancer vaccine, and T-cell therapy (NCT02070406 and NCT02775292).	('NCT02775292', 'Var', (126, 137))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('NCT02070406', 'Var', (110, 121))
571099	29948928	In melanoma and NSCLC, there has been an association with high PD-L1 expression and poor prognosis.	('expression', 'MPA', (69, 79))	('NSCLC', 'Disease', (16, 21))	('PD-L1', 'Gene', (63, 68))	('high', 'Var', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
571108	29948928	One study found that patients with tumors of mismatch repair deficiency (MMRD) showed a response rate of 40% with the PD-L1 inhibitor pembrolizumab compared with a response rate of 0% in those tumors without MMRD.	('MMRD', 'Disease', 'None', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('MMRD', 'Disease', (208, 212))	('mismatch', 'Var', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('MMRD', 'Disease', 'None', (73, 77))	('pembrolizumab', 'Chemical', 'MESH:C582435', (134, 147))	('MMRD', 'Disease', (73, 77))
571109	29948928	In the pediatric population, bMMRDs have been found to have mutations of > 250 per megabase and show response to checkpoint inhibition.	('mutations', 'Var', (60, 69))	('MMRD', 'Disease', 'None', (30, 34))	('MMRD', 'Disease', (30, 34))
571110	29948928	A high frequency of nonsynonymous mutational burden, tumor antigens, and mutations in DNA repair pathways were strongly associated with therapeutic benefit after CLTA-4 and PD-1 blockade.	('associated', 'Reg', (120, 130))	('DNA repair pathways', 'Pathway', (86, 105))	('nonsynonymous mutational burden', 'Var', (20, 51))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('CLTA-4', 'Chemical', '-', (162, 168))	('therapeutic benefit', 'CPA', (136, 155))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('PD-1', 'Gene', (173, 177))	('mutations', 'Var', (73, 82))	('PD-1', 'Gene', '5133', (173, 177))
571118	29948928	For L-MTP-PE, the reaction to the medicine will decrease in intensity with subsequent doses.	('L-MTP-PE', 'Var', (4, 12))	('reaction', 'MPA', (18, 26))	('L-MTP-PE', 'Chemical', '-', (4, 12))	('decrease', 'NegReg', (48, 56))
571120	29948928	For example, rituximab will cause B-cell depletion and humoral immunosuppression.	('humoral immunosuppression', 'Phenotype', 'HP:0005363', (55, 80))	('B-cell depletion', 'MPA', (34, 50))	('rituximab', 'Chemical', 'MESH:D000069283', (13, 22))	('humoral immunosuppression', 'CPA', (55, 80))	('rituximab', 'Var', (13, 22))
571130	29948928	Interestingly, ADEs were associated with tumor responses and favorable outcomes, likely due to the fact that these patients have a more active immune system.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('patients', 'Species', '9606', (115, 123))	('ADEs', 'Phenotype', 'HP:0020172', (15, 19))	('tumor', 'Disease', (41, 46))	('ADEs', 'Var', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
571141	33648512	The resected specimen confirmed margin-free excision of a monophasic spindle cell neoplasm invading the submucosa and presenting the rearrangement of SS18 gene at fluorescence in situ hybridization (FISH).	('neoplasm', 'Disease', 'MESH:D009369', (82, 90))	('SS18', 'Gene', '6760', (150, 154))	('SS', 'Phenotype', 'HP:0012570', (150, 152))	('neoplasm', 'Disease', (82, 90))	('neoplasm', 'Phenotype', 'HP:0002664', (82, 90))	('rearrangement', 'Var', (133, 146))	('SS18', 'Gene', (150, 154))
571154	33648512	Multiple biopsies with immunohistochemical analysis and fluorescence in situ hybridization showed a rearrangement of SS18 gene, indicative for synovial sarcoma.	('synovial sarcoma', 'Disease', (143, 159))	('SS', 'Phenotype', 'HP:0012570', (117, 119))	('rearrangement', 'Var', (100, 113))	('SS18', 'Gene', '6760', (117, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (143, 159))	('synovial sarcoma', 'Disease', 'MESH:D013584', (143, 159))	('SS18', 'Gene', (117, 121))
571165	33648512	Fluorescence in situ hybridization established the rearrangement of SS18 gene confirming the diagnosis of SS (Fig.	('SS18', 'Gene', '6760', (68, 72))	('SS', 'Phenotype', 'HP:0012570', (68, 70))	('SS', 'Phenotype', 'HP:0012570', (106, 108))	('SS18', 'Gene', (68, 72))	('rearrangement', 'Var', (51, 64))
571257	32587785	One patient's symptoms were relieved after 1 cycle of dose-reduced apatinib (250 mg/day) because of grade 3 proteinuria, and one patient stopped the trial because of grade 3 dysgeusia.	('dysgeusia', 'Disease', 'MESH:D004408', (174, 183))	('dose-reduced', 'Var', (54, 66))	('proteinuria', 'Disease', (108, 119))	('apatinib', 'Chemical', 'MESH:C553458', (67, 75))	('patient', 'Species', '9606', (4, 11))	('proteinuria', 'Phenotype', 'HP:0000093', (108, 119))	('apatinib', 'Gene', (67, 75))	('dysgeusia', 'Phenotype', 'HP:0031249', (174, 183))	('proteinuria', 'Disease', 'MESH:D011507', (108, 119))	('dysgeusia', 'Disease', (174, 183))	('patient', 'Species', '9606', (129, 136))
571269	32587785	Overexpression of the VEGFR family, especially VEGFR-2, is significantly associated with a poor survival rate in patients with sarcoma.	('VEGFR', 'Gene', '3791', (47, 52))	('VEGFR-2', 'Gene', (47, 54))	('VEGFR', 'Gene', (22, 27))	('VEGFR', 'Gene', (47, 52))	('patients', 'Species', '9606', (113, 121))	('poor', 'NegReg', (91, 95))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('Overexpression', 'Var', (0, 14))	('sarcoma', 'Disease', (127, 134))	('VEGFR', 'Gene', '3791', (22, 27))	('VEGFR-2', 'Gene', '3791', (47, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
571271	32587785	A study has shown that apatinib inhibits the growth of osteosarcoma in vivo and in vitro, and induces the autophagy and apoptosis of osteosarcoma cells by directly inhibiting the expression of the anti-apoptotic protein Bcl-2 and inactivating signal transduction and activator of transcription 3 (STAT3).	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('inhibiting', 'NegReg', (164, 174))	('signal transduction and activator of transcription 3', 'Gene', '6774', (243, 295))	('inactivating', 'NegReg', (230, 242))	('Bcl-2', 'Gene', (220, 225))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('induces', 'PosReg', (94, 101))	('apatinib', 'Var', (23, 31))	('apatinib', 'Chemical', 'MESH:C553458', (23, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))	('Bcl-2', 'Gene', '596', (220, 225))	('STAT3', 'Gene', (297, 302))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('autophagy', 'CPA', (106, 115))	('expression', 'MPA', (179, 189))	('growth', 'CPA', (45, 51))	('STAT3', 'Gene', '6774', (297, 302))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('apoptosis', 'CPA', (120, 129))	('osteosarcoma', 'Disease', (55, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('inhibits', 'NegReg', (32, 40))	('osteosarcoma', 'Disease', (133, 145))
571294	32587785	Therefore, we changed the apatinib monotherapy to combined therapy and performed new clinical trials featuring apatinib in combination with chemotherapy and apatinib in combination with immunotherapy for advanced sarcomas (NCT04126993 and NCT04126811, respectively).	('NCT04126811', 'Var', (239, 250))	('sarcomas', 'Phenotype', 'HP:0100242', (213, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('apatinib', 'Chemical', 'MESH:C553458', (111, 119))	('sarcomas', 'Disease', (213, 221))	('apatinib', 'Chemical', 'MESH:C553458', (157, 165))	('apatinib', 'Chemical', 'MESH:C553458', (26, 34))	('NCT04126993', 'Var', (223, 234))	('sarcomas', 'Disease', 'MESH:D012509', (213, 221))
571303	28472972	Ewing's sarcoma (ES)/primitive neuroectodermal tumor (PNET) is a small round cell tumor with simple sarcoma-specific genetic alterations resulting in TET/FET family member and ETS family member fusion proteins.	("Ewing's sarcoma", 'Disease', (0, 15))	('ETS family member fusion proteins', 'Protein', (176, 209))	('alterations', 'Var', (125, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ES', 'Phenotype', 'HP:0012254', (17, 19))	('tumor', 'Disease', (82, 87))	('sarcoma', 'Disease', 'MESH:D012509', (100, 107))	('sarcoma', 'Disease', (100, 107))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (31, 52))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('TET/FET family member', 'Protein', (150, 171))	('neuroectodermal tumor', 'Disease', (31, 52))	('PNET', 'Phenotype', 'HP:0030065', (54, 58))	('TET', 'Chemical', 'MESH:C010349', (150, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (31, 52))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (21, 52))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('tumor', 'Disease', (47, 52))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('sarcoma', 'Disease', (8, 15))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
571339	28472972	Such expression results in cell transformation, with the subsequent emergence of tumors bearing the morphological and gene expression hallmarks of Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (147, 162))	('cell transformation', 'CPA', (27, 46))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (147, 162))	('results in', 'Reg', (16, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('expression', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (147, 162))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
571354	28472972	Malignant GIST usually expresses CD117, Dog-1 and CD34, which were all negative in this case.	('CD34', 'Gene', '415130', (50, 54))	('CD34', 'Gene', (50, 54))	('CD', 'Chemical', 'MESH:D002104', (50, 52))	('CD', 'Chemical', 'MESH:D002104', (33, 35))	('CD117', 'Var', (33, 38))	('Dog', 'Species', '9615', (40, 43))	('Dog-1', 'Gene', (40, 45))
571369	24292119	Tumor staging for melanoma was pT1aN3, pTisNx, pTxNxM1b, and pT3bN0.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('pT1', 'Gene', (31, 34))	('pT3bN0', 'Var', (61, 67))	('pT1', 'Gene', '58492', (31, 34))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
571443	24292119	showed similar 5-year survival for T3a versus T2b penile melanoma (79 vs 82 %) and T4a versus T3b (71 vs 68 %).	('penile melanoma', 'Disease', 'MESH:D004414', (50, 65))	('penile melanoma', 'Disease', (50, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('T4a', 'Var', (83, 86))	('T3a', 'Var', (35, 38))
571452	24292119	The optimal approach to clinically positive lymph nodes in penile melanoma is not known; however, node positivity confers a poor prognosis.	('penile melanoma', 'Disease', 'MESH:D004414', (59, 74))	('node positivity', 'Var', (98, 113))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('penile melanoma', 'Disease', (59, 74))
571484	24292119	In addition, they demonstrated that surgical resection was associated with a significantly improved outcome when compared with patients who received radiation alone or in combination with surgery.	('improved', 'PosReg', (91, 99))	('patients', 'Species', '9606', (127, 135))	('surgical resection', 'Var', (36, 54))
571510	24753938	Laboratory investigation showed signs of infection (CRP 44, white blood count 11300 cells/microL, neutrophilia 8803 cells/microL).	('neutrophilia', 'Disease', 'MESH:C563010', (98, 110))	('infection', 'Disease', (41, 50))	('infection', 'Disease', 'MESH:D007239', (41, 50))	('CRP', 'Var', (52, 55))	('neutrophilia', 'Phenotype', 'HP:0011897', (98, 110))	('neutrophilia', 'Disease', (98, 110))
571520	24753938	Additional FISH analysis revealed rearrangement of the EWS gene, and not of the WT1 gene, indicating the diagnosis of Ewing sarcoma (Figure 4).	('EWS', 'Gene', '2130', (55, 58))	('EWS', 'Gene', (55, 58))	('rearrangement', 'Var', (34, 47))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (118, 131))	('Ewing sarcoma', 'Disease', (118, 131))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (118, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('WT1', 'Gene', '7490', (80, 83))	('WT1', 'Gene', (80, 83))
571532	24753938	However it is the characteristic t (11;22) chromosomal translocation and resulting EWS-FLI1 gene fusion that gives a 90% certainty of the diagnosis of Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('EWS', 'Gene', '2130', (83, 86))	('EWS', 'Gene', (83, 86))	('FLI1', 'Gene', '2313', (87, 91))	('FLI1', 'Gene', (87, 91))	('Ewing sarcoma', 'Disease', (151, 164))	('fusion', 'Var', (97, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (151, 164))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (151, 164))
571647	31043968	The stage of disease according to the 3rd edition of the STS classification was IA-III, and according to the 7th edition of TNM lung tumor classification was T1N0-T4N0.	('lung tumor', 'Phenotype', 'HP:0100526', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('STS', 'Phenotype', 'HP:0030448', (57, 60))	('TNM lung tumor', 'Disease', (124, 138))	('TNM lung tumor', 'Disease', 'MESH:D008175', (124, 138))	('T1N0-T4N0', 'Var', (158, 167))	('IA-III', 'Disease', (80, 86))
571657	31043968	All of them were men, with tumor size > 5 cm (7-22, 10.5 cm), stage of disease III according to the STS classification, degree of malignancy G2-3 (75% of patients with G3 degree).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('malignancy', 'Disease', (130, 140))	('tumor', 'Disease', (27, 32))	('G2-3', 'Var', (141, 145))	('patients', 'Species', '9606', (154, 162))	('G3 degree', 'Var', (168, 177))	('malignancy', 'Disease', 'MESH:D009369', (130, 140))	('STS', 'Phenotype', 'HP:0030448', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('men', 'Species', '9606', (17, 20))
571763	27860224	The anti-angiogenic effect of infection was verified by immunohistochemistry, which revealed a lower blood vessel density in an in vivo mouse model, xenotransplanted with DH82-Ond-pi, compared to mice transplanted with non-infected DH82 cells.	('DH82', 'Chemical', '-', (232, 236))	('DH82', 'Chemical', '-', (171, 175))	('lower', 'NegReg', (95, 100))	('blood vessel density', 'CPA', (101, 121))	('mice', 'Species', '10090', (196, 200))	('DH82-Ond-pi', 'Chemical', '-', (171, 182))	('DH82-Ond-pi', 'Var', (171, 182))	('mouse', 'Species', '10090', (136, 141))
571776	27860224	CDV has previously been shown to be capable of influencing the polarization state of canine macrophages 19, and thus, the question arises whether CDV might also polarize neoplastic DH82 cells into a specific phenotype, thereby potentially exerting oncolytic properties.	('polarization state', 'MPA', (63, 81))	('CDV', 'Species', '11232', (0, 3))	('DH82', 'Chemical', '-', (181, 185))	('CDV', 'Var', (146, 149))	('canine', 'Species', '9615', (85, 91))	('CDV', 'Species', '11232', (146, 149))	('exerting', 'Reg', (239, 247))	('polarize', 'Reg', (161, 169))	('influencing', 'Reg', (47, 58))
571780	27860224	DH82-Ond-pi may thus be regarded as a more suitable model to study CDV-induced differences compared to acute infection, although the latter might clinically be more applicable.	('acute infection', 'Disease', 'MESH:D059787', (103, 118))	('DH82-Ond-pi', 'Chemical', '-', (0, 11))	('acute infection', 'Disease', (103, 118))	('CDV', 'Species', '11232', (67, 70))	('DH82-Ond-pi', 'Var', (0, 11))
571832	27860224	The ten top hits of down-regulated DEGs (Table 2) comprised genes such as SERPINB2 (serpin peptidase inhibitor, clade B (ovalbumin), member 2), TPM2 (tropomyosin 2 (beta)), VEGFB (vascular endothelial growth factor B), THBS2 (thrombospondin 2), SCIN (adseverin-like), S100P (S100 calcium-binding protein P) LOC608476 (fatty acid-binding protein, adipocyte-like), GSTA3 (glutathione S-transferase alpha-3), TCEAL1 (transcription elongation factor A (SII)-like 1) and COL4A1 (collagen, type IV, alpha-1) with FCs ranging from -1663.8 to -208.9.	('vascular endothelial growth factor B', 'Gene', (180, 216))	('LOC608476', 'Var', (307, 316))	('tropomyosin 2 (beta', 'Gene', (150, 169))	('SCIN', 'Gene', (245, 249))	('GSTA3', 'Gene', '2940', (363, 368))	('S100P', 'Gene', '6286', (268, 273))	('S100 calcium-binding protein P', 'Gene', (275, 305))	('TCEAL1', 'Gene', '9338', (406, 412))	('GSTA3', 'Gene', (363, 368))	('VEGFB', 'Gene', (173, 178))	('S100P', 'Gene', (268, 273))	('TPM2', 'Gene', (144, 148))	('TCEAL1', 'Gene', (406, 412))	('TPM2', 'Gene', '7169', (144, 148))	('S100 calcium-binding protein P', 'Gene', '6286', (275, 305))	('THBS2', 'Gene', '7058', (219, 224))	('thrombospondin 2', 'Gene', '7058', (226, 242))	('VEGFB', 'Gene', '7423', (173, 178))	('glutathione S-transferase alpha-3', 'Gene', '2940', (370, 403))	('glutathione S-transferase alpha-3', 'Gene', (370, 403))	('serpin peptidase inhibitor, clade B (ovalbumin), member 2', 'Gene', '5055', (84, 141))	('down-regulated', 'NegReg', (20, 34))	('THBS2', 'Gene', (219, 224))	('COL4A1 (collagen, type IV, alpha-1', 'Gene', '146', (466, 500))	('thrombospondin 2', 'Gene', (226, 242))	('tropomyosin 2 (beta)', 'Gene', '7169', (150, 170))	('SERPINB2', 'Gene', (74, 82))	('SCIN', 'Gene', '85477', (245, 249))	('SERPINB2', 'Gene', '5055', (74, 82))	('transcription elongation factor A (SII)-like 1', 'Gene', '9338', (414, 460))	('vascular endothelial growth factor B', 'Gene', '7423', (180, 216))
571850	27860224	Overall, DH82-Ond-pi tumours displayed significantly and markedly larger areas of necrosis than non-infected controls at all histologically investigated time points (day 7, 14 and 21; Fig.	('larger', 'PosReg', (66, 72))	('DH82-Ond-pi', 'Var', (9, 20))	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('necrosis', 'Disease', (82, 90))	('DH82-Ond-pi', 'Chemical', '-', (9, 20))	('tumours', 'Disease', (21, 28))
571854	27860224	Corresponding to the results of Ki67 immunostaining, at 21 days after transplantation, 0-1 mitotic figure per high power field was found in DH82-Ond-pi tumours, whereas non-infected DH82 neoplasms showed up to 20 mitoses per high power field.	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('neoplasms', 'Phenotype', 'HP:0002664', (187, 196))	('tumours', 'Disease', (152, 159))	('DH82-Ond-pi', 'Var', (140, 151))	('non-infected DH82 neoplasms', 'Disease', 'MESH:C580335', (169, 196))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('non-infected DH82 neoplasms', 'Disease', (169, 196))	('mitotic figure', 'CPA', (91, 105))	('DH82-Ond-pi', 'Chemical', '-', (140, 151))
571860	27860224	Functional annotation of the up-regulated genes in DH82-Ond-pi predominantly yielded GO terms related to activation of immune processes.	('DH82-Ond-pi', 'Var', (51, 62))	('up-regulated', 'PosReg', (29, 41))	('DH82-Ond-pi', 'Chemical', '-', (51, 62))
571864	27860224	Previous studies on non-infected cells have, however, shown that DH82 cells may show diminished expression of immune-related surface molecules such as CD11c-, CD14-, CD18-, CD45- and CD80 during long-term passaging 13.	('CD18-', 'Var', (166, 171))	('CD45', 'Gene', '490255', (173, 177))	('CD14', 'Gene', '607076', (159, 163))	('CD45', 'Gene', (173, 177))	('diminished', 'NegReg', (85, 95))	('CD80', 'Gene', (183, 187))	('CD11c-', 'Var', (151, 157))	('expression', 'MPA', (96, 106))	('DH82', 'Chemical', '-', (65, 69))	('CD14', 'Gene', (159, 163))	('CD80', 'Gene', '403765', (183, 187))
572055	26475741	Desmoplastic small round cell tumours of the pleura typically express epithelial, mesenchymal and neural cell markers, and above all a specific translocation t(11;22)(p13;q12).	('t(11;22)(p13;q12', 'Var', (158, 174))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('epithelial', 'CPA', (70, 80))	('Desmoplastic small round cell tumours of the pleura', 'Disease', 'MESH:D058405', (0, 51))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (158, 175))
572083	24249672	Phosphorylation of 4E-BP1 through mTORC1 results in the release of 4EBP1from the eukaryotic translation initiation factor (eIF4E), permitting initiation of translation.	('4E-BP1', 'Gene', '1978', (19, 25))	('mTORC1', 'Gene', '382056', (34, 40))	('translation', 'MPA', (156, 167))	('initiation', 'MPA', (142, 152))	('Phosphorylation', 'Var', (0, 15))	('eIF4E', 'Gene', '1977', (123, 128))	('4EBP1', 'Gene', '1978', (67, 72))	('4E-BP1', 'Gene', (19, 25))	('mTORC1', 'Gene', (34, 40))	('4EBP1', 'Gene', (67, 72))	('eIF4E', 'Gene', (123, 128))	('release', 'MPA', (56, 63))
572084	24249672	Inhibition of mTORC1 therefore alters protein synthesis and results in changes in levels of regulatory proteins including HIF1alpha, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), MYC, cyclin D1, and ornithine decarboxylase (ODC).	('changes', 'Reg', (71, 78))	('mTORC1', 'Gene', (14, 20))	('HIF1alpha', 'Gene', '3091', (122, 131))	('levels of regulatory proteins', 'MPA', (82, 111))	('vascular endothelial growth factor', 'Gene', '7422', (165, 199))	('mTORC1', 'Gene', '382056', (14, 20))	('VEGF', 'Gene', '7422', (201, 205))	('protein synthesis', 'MPA', (38, 55))	('VEGF', 'Gene', (201, 205))	('vascular endothelial growth factor', 'Gene', (165, 199))	('HIF1alpha', 'Gene', (122, 131))	('MYC', 'Gene', (208, 211))	('fibroblast growth factor', 'MPA', (133, 157))	('cyclin D1', 'Gene', (213, 222))	('ornithine decarboxylase', 'Gene', '4953', (228, 251))	('Inhibition', 'Var', (0, 10))	('cyclin D1', 'Gene', '595', (213, 222))	('ODC', 'Gene', '4953', (253, 256))	('MYC', 'Gene', '4609', (208, 211))	('ornithine decarboxylase', 'Gene', (228, 251))	('ODC', 'Gene', (253, 256))	('alters', 'Reg', (31, 37))
572116	24249672	No DLTs were observed among evaluable patients treated on the first two dose levels, however following treatment with irinotecan (50 mg/m2/dose), temozolomide (100 mg/m2/dose) and temsirolimus at a dose of 25 mg/m2 on Days 1 and 8, two of four evaluable patients developed asymptomatic >=Grade 3 hypercholesterolemia that met protocol-defined criteria for DLT.	('irinotecan', 'Chemical', 'MESH:D000077146', (118, 128))	('100 mg/m2/dose', 'Var', (160, 174))	('hypercholesterolemia', 'Disease', (296, 316))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (296, 316))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (296, 316))	('temsirolimus', 'Chemical', 'MESH:C401859', (180, 192))	('temozolomide', 'Chemical', 'MESH:D000077204', (146, 158))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (254, 262))
572190	24249672	A recent retrospective report suggests that temsirolimus-induced elevations in cholesterol (but not glucose or triglycerides) were associated with longer survival among adults with renal cell carcinoma.	('elevations in cholesterol', 'Phenotype', 'HP:0003124', (65, 90))	('glucose', 'Chemical', 'MESH:D005947', (100, 107))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (181, 201))	('triglycerides', 'Chemical', 'MESH:D014280', (111, 124))	('cholesterol', 'MPA', (79, 90))	('longer', 'PosReg', (147, 153))	('temsirolimus', 'Chemical', 'MESH:C401859', (44, 56))	('renal cell carcinoma', 'Disease', (181, 201))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))	('cholesterol', 'Chemical', 'MESH:D002784', (79, 90))	('elevations', 'PosReg', (65, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('temsirolimus-induced', 'Var', (44, 64))
572288	23799090	Our previous study has shown that dehydrocostus lactone inhibited cell proliferation and caused an enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP, indicating apoptosis induction in human sarcoma cell lines, and led to a G2/M phase arrest.	('cleaved', 'MPA', (153, 160))	('PARP', 'Gene', '1302', (161, 165))	('sarcoma', 'Disease', 'MESH:D012509', (207, 214))	('dehydrocostus lactone', 'Var', (34, 55))	('PARP', 'Gene', (161, 165))	('enhanced', 'PosReg', (99, 107))	('cell proliferation', 'CPA', (66, 84))	('caspase 3/7 activity, cleaved caspase-3', 'Gene', '836', (108, 147))	('G2/M phase arrest', 'CPA', (240, 257))	('led to', 'Reg', (231, 237))	('sarcoma', 'Disease', (207, 214))	('human', 'Species', '9606', (201, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('inhibited', 'NegReg', (56, 65))	('dehydrocostus lactone', 'Chemical', 'MESH:C083030', (34, 55))
572353	23799090	We observed in the cell cycle analysis that dehydrocostus lactone-treatment resulted in a significant decrease in the number of cells in G1 phase after 24 h which was accompanied by an increase of the number of S and G2/M phase cells, via the down-regulation of cdc2 (CDK1) together with cyclin B1.	('increase', 'PosReg', (185, 193))	('dehydrocostus lactone-treatment', 'Var', (44, 75))	('S and G2', 'Gene', '7916', (211, 219))	('decrease', 'NegReg', (102, 110))	('CDK1', 'Gene', '983', (268, 272))	('cyclin B1', 'Gene', '891', (288, 297))	('down-regulation', 'NegReg', (243, 258))	('cdc2', 'Gene', (262, 266))	('CDK1', 'Gene', (268, 272))	('dehydrocostus lactone', 'Chemical', 'MESH:C083030', (44, 65))	('cdc2', 'Gene', '983', (262, 266))	('cyclin B1', 'Gene', (288, 297))
572496	33191406	Furthermore, inhibition of mTORC1/2, but not mTORC1, activates 4E-BP1, inhibits protein synthesis, and reduces the level of the RRM2 protein in multiple sarcoma cell lines.	('protein synthesis', 'MPA', (80, 97))	('mTORC1', 'Gene', '382056', (45, 51))	('mTORC1/2', 'Gene', (27, 35))	('level of', 'MPA', (115, 123))	('RRM2', 'Gene', (128, 132))	('4E-BP1', 'Gene', '1978', (63, 69))	('mTORC1', 'Gene', (27, 33))	('inhibits', 'NegReg', (71, 79))	('mTORC1', 'Gene', '382056', (27, 33))	('activates', 'PosReg', (53, 62))	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('4E-BP1', 'Gene', (63, 69))	('sarcoma', 'Disease', (153, 160))	('reduces', 'NegReg', (103, 110))	('mTORC1/2', 'Gene', '74343;382056', (27, 35))	('RRM2', 'Gene', '6241', (128, 132))	('inhibition', 'Var', (13, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('mTORC1', 'Gene', (45, 51))
572497	33191406	This effect of mTORC1/2 inhibitors on protein synthesis and RRM2 levels was rescued in cell lines with the CRISPR/Cas9-mediated knockout of 4E-BP1.	('RRM2', 'Gene', '6241', (60, 64))	('4E-BP1', 'Gene', '1978', (140, 146))	('mTORC1/2', 'Gene', '74343;382056', (15, 23))	('4E-BP1', 'Gene', (140, 146))	('RRM2', 'Gene', (60, 64))	('protein synthesis', 'MPA', (38, 55))	('knockout', 'Var', (128, 136))	('mTORC1/2', 'Gene', (15, 23))
572498	33191406	In addition, the inducible expression of a mutant 4E-BP1 protein that cannot be phosphorylated by mTOR blocked protein synthesis and inhibited the growth of Ewing sarcoma cells in vitro and in vivo in a xenograft.	('protein synthesis', 'MPA', (111, 128))	('Ewing sarcoma', 'Disease', (157, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('inhibited', 'NegReg', (133, 142))	('4E-BP1', 'Gene', (50, 56))	('growth', 'MPA', (147, 153))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('mutant', 'Var', (43, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (157, 170))	('mTOR', 'Gene', '2475', (98, 102))	('mTOR', 'Gene', (98, 102))	('4E-BP1', 'Gene', '1978', (50, 56))	('blocked', 'NegReg', (103, 110))	('protein', 'Protein', (57, 64))
572503	33191406	Notably, in previous work, we showed that Ewing sarcoma tumors are sensitive to inhibitors of RNR, or knockdown of RRM1 or RRM2.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (42, 55))	('knockdown', 'Var', (102, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('Ewing sarcoma tumors', 'Disease', (42, 62))	('RRM1', 'Gene', '6240', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('RRM1', 'Gene', (115, 119))	('RNR', 'Protein', (94, 97))	('RRM2', 'Gene', (123, 127))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (42, 62))	('RRM2', 'Gene', '6241', (123, 127))	('sensitive', 'Reg', (67, 76))
572508	33191406	Inhibition of RNR, or a reduction in the level of the RRM2 protein, depletes nucleoside pools, causes DNA replication stress, and activates the Ataxia Telangiectasia and Rad3-Related Protein (ATR) and Checkpoint Kinase 1 (CHK1) pathway.	('stress', 'Disease', (118, 124))	('Checkpoint Kinase 1', 'Gene', '1111', (201, 220))	('Ataxia', 'Phenotype', 'HP:0001251', (144, 150))	('Ataxia Telangiectasia and Rad3-Related Protein', 'Gene', '545', (144, 190))	('RRM2', 'Gene', '6241', (54, 58))	('RNR', 'Protein', (14, 17))	('causes', 'Reg', (95, 101))	('ATR', 'Gene', '545', (192, 195))	('depletes nucleoside pools', 'MPA', (68, 93))	('RRM2', 'Gene', (54, 58))	('Checkpoint Kinase 1', 'Gene', (201, 220))	('CHK1', 'Gene', (222, 226))	('level', 'MPA', (41, 46))	('activates', 'PosReg', (130, 139))	('Inhibition', 'Var', (0, 10))	('Telangiectasia', 'Phenotype', 'HP:0001009', (151, 165))	('reduction', 'NegReg', (24, 33))	('nucleoside', 'Chemical', 'MESH:D009705', (77, 87))	('CHK1', 'Gene', '1111', (222, 226))	('ATR', 'Gene', (192, 195))	('stress', 'Disease', 'MESH:D000079225', (118, 124))
572511	33191406	For example, inhibition of the ATR-CHK1 pathway increases the toxicity of nucleoside analogues in a variety of cancers, including pancreatic, lung, and ovarian tumors.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('ovarian tumors', 'Phenotype', 'HP:0100615', (152, 166))	('pancreatic', 'Disease', 'MESH:D010195', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('CHK1', 'Gene', (35, 39))	('ATR', 'Gene', (31, 34))	('nucleoside', 'Chemical', 'MESH:D009705', (74, 84))	('lung', 'Disease', (142, 146))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('pancreatic', 'Disease', (130, 140))	('CHK1', 'Gene', '1111', (35, 39))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('increases', 'PosReg', (48, 57))	('ovarian tumors', 'Disease', (152, 166))	('ovarian tumors', 'Disease', 'MESH:D010051', (152, 166))	('toxicity', 'Disease', (62, 70))	('ATR', 'Gene', '545', (31, 34))	('inhibition', 'Var', (13, 23))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
572517	33191406	This effect of mTORC1/2 inhibitors on protein synthesis and RRM2 levels in Ewing sarcoma cells was rescued in cell lines with the CRISPR/Cas9-mediated knockout of 4E-BP1.	('4E-BP1', 'Gene', (163, 169))	('Ewing sarcoma', 'Disease', (75, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('knockout', 'Var', (151, 159))	('mTORC1/2', 'Gene', '74343;382056', (15, 23))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('4E-BP1', 'Gene', '1978', (163, 169))	('RRM2', 'Gene', (60, 64))	('protein synthesis', 'MPA', (38, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('RRM2', 'Gene', '6241', (60, 64))	('mTORC1/2', 'Gene', (15, 23))
572543	33191406	The full-length 4E-BP1 cDNA, with alanine substitutions at Thr37/46, Ser65, and Thr70 and a FLAG-tag, was obtained as a gene block (IDT; Coralville, IA) and inserted into the Lenti-X-Tet-One vector (Clontech).	('Ser65', 'Var', (69, 74))	('Ser65', 'Chemical', '-', (69, 74))	('Thr70', 'Var', (80, 85))	('Thr70', 'Chemical', '-', (80, 85))	('4E-BP1', 'Gene', (16, 22))	('alanine substitutions at Thr37', 'Mutation', 'p.T37A', (34, 64))	('Thr37/46', 'Var', (59, 67))	('4E-BP1', 'Gene', '1978', (16, 22))
572552	33191406	Next, based on the known synergy between RNR and CHK1 inhibitors, as well as the activation of CHK1 by partial knockdown of RRM2, we tested whether RRM2 knockdown sensitizes the cells to inhibition of the CHK1 pathway.	('CHK1', 'Gene', '1111', (205, 209))	('knockdown', 'Var', (153, 162))	('knockdown', 'Var', (111, 120))	('sensitizes', 'Reg', (163, 173))	('CHK1', 'Gene', (95, 99))	('RRM2', 'Gene', (124, 128))	('RRM2', 'Gene', '6241', (148, 152))	('tested', 'Reg', (133, 139))	('RRM2', 'Gene', (148, 152))	('activation', 'PosReg', (81, 91))	('RRM2', 'Gene', '6241', (124, 128))	('CHK1', 'Gene', (49, 53))	('CHK1', 'Gene', '1111', (95, 99))	('CHK1', 'Gene', (205, 209))	('CHK1', 'Gene', '1111', (49, 53))
572565	33191406	To validate the results of the screen we performed dose titration experiments with HHT in the presence and absence of doxycycline, or RRM2 knockdown.	('RRM2', 'Gene', (134, 138))	('HHT', 'Chemical', 'MESH:D000077863', (83, 86))	('doxycycline', 'Chemical', 'MESH:D004318', (118, 129))	('knockdown', 'Var', (139, 148))	('RRM2', 'Gene', '6241', (134, 138))	('HHT', 'Gene', (83, 86))
572566	33191406	Figure 1F shows that the RRM2 knockdown cells are 2-3-fold more sensitive to HHT than the parental cells.	('RRM2', 'Gene', '6241', (25, 29))	('more', 'PosReg', (59, 63))	('sensitive', 'MPA', (64, 73))	('HHT', 'Chemical', 'MESH:D000077863', (77, 80))	('knockdown', 'Var', (30, 39))	('RRM2', 'Gene', (25, 29))
572568	33191406	Similar results regarding enhanced sensitivity to HHT were obtained with two additional Ewing sarcoma cell lines, TC71 and AGPN, with doxycycline-inducible knockdown of RRM2 (Supplementary Figure 3).	('enhanced', 'PosReg', (26, 34))	('knockdown', 'Var', (156, 165))	('sensitivity', 'MPA', (35, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('TC71', 'CellLine', 'CVCL:2213', (114, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('RRM2', 'Gene', (169, 173))	('doxycycline', 'Chemical', 'MESH:D004318', (134, 145))	('HHT', 'Chemical', 'MESH:D000077863', (50, 53))	('RRM2', 'Gene', '6241', (169, 173))	('Ewing sarcoma', 'Disease', (88, 101))
572571	33191406	Figures 1I-J show that HHT reduces protein synthesis in Ewing sarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('protein synthesis', 'MPA', (35, 52))	('reduces', 'NegReg', (27, 34))	('HHT', 'Var', (23, 26))	('Ewing sarcoma', 'Disease', (56, 69))	('HHT', 'Chemical', 'MESH:D000077863', (23, 26))
572576	33191406	In previous work, we showed that the knockdown of RRM2 using siRNA, which is more potent than the shRNA used in the current study, caused DNA replication stress, apoptosis, and cell death as a single agent in Ewing sarcoma cells.	('caused', 'Reg', (131, 137))	('stress', 'Disease', 'MESH:D000079225', (154, 160))	('knockdown', 'Var', (37, 46))	('Ewing sarcoma', 'Disease', (209, 222))	('death', 'Disease', 'MESH:D003643', (182, 187))	('RRM2', 'Gene', '6241', (50, 54))	('death', 'Disease', (182, 187))	('RRM2', 'Gene', (50, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (209, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (209, 222))	('apoptosis', 'CPA', (162, 171))	('stress', 'Disease', (154, 160))
572577	33191406	Consequently, to determine whether the combination of HHT and shRRM2 caused toxicity by reducing the amount of RRM2 below a threshold level, we treated the shRRM2 knockdown cells with HHT (10 nM) and quantified RRM2 levels using immunoblotting.	('RRM2', 'Gene', '6241', (158, 162))	('RRM2', 'Gene', (158, 162))	('RRM2', 'Gene', (111, 115))	('HHT', 'Chemical', 'MESH:D000077863', (184, 187))	('RRM2', 'Gene', '6241', (111, 115))	('RRM2', 'Gene', (211, 215))	('toxicity', 'Disease', 'MESH:D064420', (76, 84))	('toxicity', 'Disease', (76, 84))	('RRM2', 'Gene', '6241', (211, 215))	('RRM2', 'Gene', '6241', (64, 68))	('HHT', 'Chemical', 'MESH:D000077863', (54, 57))	('RRM2', 'Gene', (64, 68))	('combination', 'Var', (39, 50))	('reducing', 'NegReg', (88, 96))
572580	33191406	In addition, as predicted for a drug that reduces RRM2 levels, Figure 2F shows that HHT also decreased DNA replication.	('DNA replication', 'CPA', (103, 118))	('decreased', 'NegReg', (93, 102))	('HHT', 'Var', (84, 87))	('RRM2', 'Gene', '6241', (50, 54))	('RRM2', 'Gene', (50, 54))	('HHT', 'Chemical', 'MESH:D000077863', (84, 87))
572589	33191406	In previous work, while studying the regulation of CHK1, we incidentally noted that the inhibition of mTORC1/2 reduces the level of RRM2 in Ewing sarcoma cell lines.	('mTORC1/2', 'Gene', (102, 110))	('CHK1', 'Gene', (51, 55))	('Ewing sarcoma', 'Disease', (140, 153))	('RRM2', 'Gene', '6241', (132, 136))	('RRM2', 'Gene', (132, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (140, 153))	('reduces', 'NegReg', (111, 118))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (140, 153))	('mTORC1/2', 'Gene', '74343;382056', (102, 110))	('CHK1', 'Gene', '1111', (51, 55))	('inhibition', 'Var', (88, 98))
572590	33191406	using polysome profiling showed that the mTORC1/2 inhibitor PP242 regulates the translation of RRM2 mRNA in pancreatic adenocarcinoma cells.	('RRM2', 'Gene', (95, 99))	('mTORC1/2', 'Gene', (41, 49))	('PP242', 'Var', (60, 65))	('RRM2', 'Gene', '6241', (95, 99))	('regulates', 'Reg', (66, 75))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (108, 133))	('pancreatic adenocarcinoma', 'Disease', (108, 133))	('PP242', 'Chemical', 'MESH:C572919', (60, 65))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (108, 133))	('translation', 'MPA', (80, 91))	('mTORC1/2', 'Gene', '74343;382056', (41, 49))
572595	33191406	Figure 3B shows that TAK-228 reduced the phosphorylation of 4E-BP1 at Thr37/46, Ser65, and Thr70.	('4E-BP1', 'Gene', '1978', (60, 66))	('Thr37', 'Chemical', '-', (70, 75))	('TAK-228', 'Chemical', 'MESH:C572449', (21, 28))	('Ser65', 'Var', (80, 85))	('Ser65', 'Chemical', '-', (80, 85))	('phosphorylation', 'MPA', (41, 56))	('4E-BP1', 'Gene', (60, 66))	('reduced', 'NegReg', (29, 36))	('Thr70', 'Var', (91, 96))	('Thr37/46', 'Var', (70, 78))	('Thr70', 'Chemical', '-', (91, 96))	('TAK-228', 'Var', (21, 28))
572598	33191406	Next, we treated additional sarcoma cell lines, osteosarcoma (U2OS), rhabdomyosarcoma (RH30), and fibrosarcoma (HT1080), with TAK-228 and observed a decrease in protein synthesis and RRM2 protein levels, although the effect was reduced for HT1080 compared to the other cell lines.	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('sarcoma', 'Disease', (103, 110))	('RRM2', 'Gene', (183, 187))	('sarcoma', 'Disease', (53, 60))	('fibrosarcoma', 'Disease', 'MESH:D005354', (98, 110))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (69, 85))	('sarcoma', 'Disease', (78, 85))	('decrease', 'NegReg', (149, 157))	('fibrosarcoma', 'Disease', (98, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('RH30', 'Gene', (87, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))	('sarcoma', 'Disease', (28, 35))	('U2OS', 'CellLine', 'CVCL:0042', (62, 66))	('protein synthesis', 'MPA', (161, 178))	('RH30', 'Gene', '6007', (87, 91))	('rhabdomyosarcoma', 'Disease', (69, 85))	('HT1080', 'CellLine', 'CVCL:0317', (112, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('RRM2', 'Gene', '6241', (183, 187))	('TAK-228', 'Chemical', 'MESH:C572449', (126, 133))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (98, 110))	('osteosarcoma', 'Disease', (48, 60))	('osteosarcoma', 'Disease', 'MESH:D012516', (48, 60))	('HT1080', 'Var', (240, 246))	('HT1080', 'CellLine', 'CVCL:0317', (240, 246))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (69, 85))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))
572604	33191406	Figures 3H-I and Supplementary Figure 6 show that the combination of TAK-228 and AZD1775 or TAK-228 and prexasertib was synergistic with multiple Ewing sarcoma cell lines, as shown in the Loewe synergy matrix plots.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (146, 159))	('TAK-228', 'Chemical', 'MESH:C572449', (92, 99))	('AZD1775', 'Chemical', 'MESH:C549567', (81, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (146, 159))	('TAK-228', 'Var', (69, 76))	('prexasertib', 'Chemical', 'MESH:C000608121', (104, 115))	('combination', 'Interaction', (54, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('TAK-228', 'Chemical', 'MESH:C572449', (69, 76))	('Ewing sarcoma', 'Disease', (146, 159))	('AZD1775', 'Var', (81, 88))	('TAK-228', 'Var', (92, 99))
572606	33191406	Consequently, to determine whether 4E-BP1 regulates protein synthesis downstream of mTORC1/2, we used CRISPR/Cas9 to knockout 4E-BP1 in Ewing sarcoma cell lines (Figure 4A).	('mTORC1/2', 'Gene', (84, 92))	('Ewing sarcoma', 'Disease', (136, 149))	('4E-BP1', 'Gene', (35, 41))	('4E-BP1', 'Gene', '1978', (126, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('mTORC1/2', 'Gene', '74343;382056', (84, 92))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('4E-BP1', 'Gene', '1978', (35, 41))	('4E-BP1', 'Gene', (126, 132))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (136, 149))	('knockout', 'Var', (117, 125))	('protein synthesis', 'MPA', (52, 69))
572607	33191406	We obtained efficient knockout of 4E-BP1, even prior to single cell cloning, so we used both the bulk cell population (prior to single cell cloning) (Figures 4) and single cell-derived clones (Supplementary Figure 7) in the subsequent experiments.	('4E-BP1', 'Gene', (34, 40))	('knockout', 'Var', (22, 30))	('4E-BP1', 'Gene', '1978', (34, 40))
572610	33191406	Similarly, the knockout of 4E-BP1 partially rescued the effect of TAK-228 on the level of the RRM2 protein during a 6-hour drug treatment (Figure 4C).	('knockout', 'Var', (15, 23))	('effect', 'MPA', (56, 62))	('TAK-228', 'Chemical', 'MESH:C572449', (66, 73))	('4E-BP1', 'Gene', '1978', (27, 33))	('RRM2', 'Gene', '6241', (94, 98))	('RRM2', 'Gene', (94, 98))	('TAK-228', 'Gene', (66, 73))	('4E-BP1', 'Gene', (27, 33))
572619	33191406	Consequently, in order to investigate the specific role of 4E-BP1 in mediating toxicity in sarcoma cells, we generated a doxycycline-inducible, constitutively-active 4E-BP1 protein with alanine substitutions at the phosphorylation sites Thr37, Thr46, Ser65, and Thr70 (4E-BP1-Ala).	('4E-BP1', 'Gene', (59, 65))	('Thr70', 'Chemical', '-', (262, 267))	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('alanine', 'Chemical', 'MESH:D000409', (186, 193))	('4E-BP1', 'Gene', '1978', (269, 275))	('4E-BP1', 'Gene', '1978', (166, 172))	('doxycycline', 'Chemical', 'MESH:D004318', (121, 132))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('toxicity', 'Disease', (79, 87))	('alanine substitutions', 'Var', (186, 207))	('sarcoma', 'Disease', (91, 98))	('4E-BP1', 'Gene', (269, 275))	('Thr46', 'Chemical', '-', (244, 249))	('4E-BP1', 'Gene', (166, 172))	('4E-BP1', 'Gene', '1978', (59, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('Ser65', 'Chemical', '-', (251, 256))	('Ala', 'Chemical', 'MESH:D000409', (276, 279))	('Thr37', 'Chemical', '-', (237, 242))
572623	33191406	In addition, expression of 4E-BP1-Ala significantly decreased the growth of the cells (Figure 5D).	('decreased', 'NegReg', (52, 61))	('4E-BP1', 'Gene', '1978', (27, 33))	('expression', 'Var', (13, 23))	('Ala', 'Chemical', 'MESH:D000409', (34, 37))	('growth of the cells', 'CPA', (66, 85))	('4E-BP1', 'Gene', (27, 33))
572630	33191406	In addition, tumor suppressors, such as TP53, are frequently lost in sarcomas due to deletions, nonsense mutations, frame-shift mutations, insertions, or missense mutations.	('tumor', 'Disease', (13, 18))	('lost', 'NegReg', (61, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('nonsense mutations', 'Var', (96, 114))	('missense mutations', 'Var', (154, 172))	('deletions', 'Var', (85, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcomas', 'Disease', (69, 77))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('insertions', 'Var', (139, 149))	('frame-shift mutations', 'Var', (116, 137))	('sarcomas', 'Disease', 'MESH:D012509', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
572633	33191406	Notably, in previous work, we showed that the inhibition or knockdown of RRM2 in Ewing sarcoma cells inhibits cell growth and induces apoptosis in vitro and in vivo.	('Ewing sarcoma', 'Disease', (81, 94))	('RRM2', 'Gene', (73, 77))	('inhibition', 'NegReg', (46, 56))	('induces', 'Reg', (126, 133))	('apoptosis', 'CPA', (134, 143))	('RRM2', 'Gene', '6241', (73, 77))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('knockdown', 'Var', (60, 69))	('inhibits', 'NegReg', (101, 109))	('cell growth', 'CPA', (110, 121))
572634	33191406	The sensitivity of Ewing sarcoma cells to knockdown of RRM2 is due, in part, to the overexpression of the DNA restriction factor SLFN11, which is a direct transcriptional target of EWS-FLI1.	('overexpression', 'PosReg', (84, 98))	('FLI1', 'Gene', (185, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('FLI1', 'Gene', '2313', (185, 189))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (19, 32))	('EWS', 'Gene', '2130', (181, 184))	('Ewing sarcoma', 'Disease', (19, 32))	('RRM2', 'Gene', (55, 59))	('RRM2', 'Gene', '6241', (55, 59))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (19, 32))	('SLFN11', 'Gene', '91607', (129, 135))	('SLFN11', 'Gene', (129, 135))	('knockdown', 'Var', (42, 51))	('EWS', 'Gene', (181, 184))
572635	33191406	Consequently, we propose that 4E-BP1 regulates RRM2 levels in multiple cell types, but that the downstream effects of the loss of the RRM2 protein on cell viability and apoptosis may be more specific to Ewing sarcoma cells.	('RRM2', 'Gene', (134, 138))	('4E-BP1', 'Gene', '1978', (30, 36))	('RRM2', 'Gene', '6241', (47, 51))	('Ewing sarcoma', 'Disease', (203, 216))	('4E-BP1', 'Gene', (30, 36))	('protein', 'Protein', (139, 146))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (203, 216))	('RRM2', 'Gene', (47, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (203, 216))	('loss', 'Var', (122, 126))	('cell viability', 'CPA', (150, 164))	('RRM2', 'Gene', '6241', (134, 138))
572636	33191406	However, other types of cancer are also sensitive to RNR inhibitors, or knockdown of RRM2, and we expect that the results obtained with Ewing sarcoma cells may also apply to additional tumor types.	('tumor', 'Disease', (185, 190))	('sensitive', 'Reg', (40, 49))	('RRM2', 'Gene', '6241', (85, 89))	('knockdown', 'Var', (72, 81))	('Ewing sarcoma', 'Disease', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (136, 149))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('RRM2', 'Gene', (85, 89))
572640	33191406	Consequently, we propose a model whereby the inhibition of CHK1-WEE1 signaling enhances the CDK-mediated degradation of RRM2 while the inhibition of mTORC1/2 blocks the synthesis of the RRM2 protein via the activation of 4E-BP1 (Figure 6).	('RRM2', 'Gene', (120, 124))	('CHK1', 'Gene', (59, 63))	('4E-BP1', 'Gene', (221, 227))	('blocks', 'NegReg', (158, 164))	('mTORC1/2', 'Gene', '74343;382056', (149, 157))	('CDK', 'Gene', (92, 95))	('RRM2', 'Gene', '6241', (186, 190))	('WEE1', 'Gene', (64, 68))	('RRM2', 'Gene', (186, 190))	('CDK', 'Gene', '983;1017;51755', (92, 95))	('WEE1', 'Gene', '7465', (64, 68))	('synthesis', 'MPA', (169, 178))	('inhibition', 'Var', (45, 55))	('CHK1', 'Gene', '1111', (59, 63))	('4E-BP1', 'Gene', '1978', (221, 227))	('enhances', 'PosReg', (79, 87))	('mTORC1/2', 'Gene', (149, 157))	('RRM2', 'Gene', '6241', (120, 124))
572645	33191406	Notably, DNA replication stress is a shared feature of many cancers because it is caused by both chemotherapy drugs, including inhibitors of RNR, and active oncogenes, such as c-Myc and Ras.	('Myc', 'Gene', '4609', (178, 181))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('stress', 'Disease', (25, 31))	('stress', 'Disease', 'MESH:D000079225', (25, 31))	('Myc', 'Gene', (178, 181))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('inhibitors', 'Var', (127, 137))	('RNR', 'Protein', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('caused', 'Reg', (82, 88))
572649	33191406	Notably, TAK-228 and AZD2014, as well as eIF4A inhibitors, have been shown to inhibit the growth of multiple sarcoma subtypes in vitro and in vivo in xenograft experiments.	('AZD2014', 'Var', (21, 28))	('AZD2014', 'Chemical', 'MESH:C585537', (21, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('eIF4A', 'Gene', '1973', (41, 46))	('eIF4A', 'Gene', (41, 46))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('TAK-228', 'Var', (9, 16))	('inhibit', 'NegReg', (78, 85))	('TAK-228', 'Chemical', 'MESH:C572449', (9, 16))	('sarcoma', 'Disease', (109, 116))	('growth', 'MPA', (90, 96))
572652	33191406	We found that constitutively-active 4E-BP1, with alanine mutations at Thr37/46, Ser65, and Thr70, functions as a tumor suppressor in vitro and in vivo.	('tumor', 'Disease', (113, 118))	('Ser65', 'Var', (80, 85))	('Ser65', 'Chemical', '-', (80, 85))	('4E-BP1', 'Gene', (36, 42))	('alanine mutations at Thr37', 'Mutation', 'p.A37T', (49, 75))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Thr70', 'Var', (91, 96))	('Thr37/46', 'Var', (70, 78))	('Thr70', 'Chemical', '-', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('alanine mutations', 'Var', (49, 66))	('4E-BP1', 'Gene', '1978', (36, 42))
572654	33191406	For example, one model proposes that the phosphorylation of 4E-BP1 at Thr37/46 primes the protein for subsequent phosphorylation at Ser65 and Thr70, which then renders the hyperphosphorylated 4E-BP1 unable to bind eIF4E.	('4E-BP1', 'Gene', '1978', (60, 66))	('eIF4E', 'Gene', '1977', (214, 219))	('Thr70', 'Chemical', '-', (142, 147))	('Thr37', 'Chemical', '-', (70, 75))	('phosphorylation', 'MPA', (113, 128))	('4E-BP1', 'Gene', '1978', (192, 198))	('Thr70', 'Var', (142, 147))	('Ser65', 'Var', (132, 137))	('phosphorylation', 'MPA', (41, 56))	('primes', 'PosReg', (79, 85))	('4E-BP1', 'Gene', (60, 66))	('eIF4E', 'Gene', (214, 219))	('Ser65', 'Chemical', '-', (132, 137))	('bind', 'Interaction', (209, 213))	('4E-BP1', 'Gene', (192, 198))
572656	33191406	For example, a recent publication reported that the mTORC1-mediated phosphorylation of 4E-BP1 at Thr37/46 facilitates the subsequent phosphorylation of 4E-BP1 at Ser65 and Thr70 by CDK12, which was recently identified as a therapeutic target in Ewing sarcoma tumors.	('mTORC1', 'Gene', '382056', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('CDK12', 'Gene', (181, 186))	('4E-BP1', 'Gene', '1978', (87, 93))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (245, 265))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (245, 258))	('4E-BP1', 'Gene', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('Thr70', 'Chemical', '-', (172, 177))	('facilitates', 'PosReg', (106, 117))	('CDK12', 'Gene', '51755', (181, 186))	('phosphorylation', 'MPA', (133, 148))	('4E-BP1', 'Gene', (87, 93))	('Thr37', 'Chemical', '-', (97, 102))	('Thr37/46', 'Var', (97, 105))	('Ewing sarcoma tumors', 'Disease', (245, 265))	('phosphorylation', 'MPA', (68, 83))	('Ser65', 'Chemical', '-', (162, 167))	('mTORC1', 'Gene', (52, 58))	('4E-BP1', 'Gene', '1978', (152, 158))
572658	33191406	However, ongoing work in our laboratory is investigating whether inhibition of CDK12 enhances the effects of mTORC1/2 inhibitors on 4E-BP1 activation in sarcomas.	('mTORC1/2', 'Gene', (109, 117))	('effects', 'MPA', (98, 105))	('CDK12', 'Gene', '51755', (79, 84))	('4E-BP1', 'Gene', (132, 138))	('sarcomas', 'Disease', 'MESH:D012509', (153, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('mTORC1/2', 'Gene', '74343;382056', (109, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (153, 161))	('enhances', 'PosReg', (85, 93))	('inhibition', 'Var', (65, 75))	('CDK12', 'Gene', (79, 84))	('4E-BP1', 'Gene', '1978', (132, 138))	('sarcomas', 'Disease', (153, 161))
572662	33191406	In addition, we also propose a model whereby the inhibition of CHK1-WEE1 signaling enhances the CDK-mediated degradation of RRM2 while the inhibition of mTORC1/2 blocks the synthesis of the RRM2 protein via the activation of 4E-BP1.	('mTORC1/2', 'Gene', (153, 161))	('RRM2', 'Gene', (124, 128))	('CDK', 'Gene', '983;1017;51755', (96, 99))	('4E-BP1', 'Gene', (225, 231))	('WEE1', 'Gene', '7465', (68, 72))	('RRM2', 'Gene', '6241', (124, 128))	('CHK1', 'Gene', (63, 67))	('RRM2', 'Gene', '6241', (190, 194))	('WEE1', 'Gene', (68, 72))	('RRM2', 'Gene', (190, 194))	('enhances', 'PosReg', (83, 91))	('mTORC1/2', 'Gene', '74343;382056', (153, 161))	('CDK', 'Gene', (96, 99))	('inhibition', 'Var', (49, 59))	('blocks', 'NegReg', (162, 168))	('CHK1', 'Gene', '1111', (63, 67))	('4E-BP1', 'Gene', '1978', (225, 231))	('synthesis', 'MPA', (173, 182))
572673	31649778	A 20-year-old male patient with body mass index of 21.3 presented to us with a recent history of two episodes of seizures and Glasgow Coma Scale of E3V3M6 (12/15).	('patient', 'Species', '9606', (19, 26))	('Coma', 'Disease', 'MESH:D003128', (134, 138))	('seizures', 'Disease', (113, 121))	('seizures', 'Phenotype', 'HP:0001250', (113, 121))	('E3V3M6', 'Var', (148, 154))	('Coma', 'Disease', (134, 138))	('Coma', 'Phenotype', 'HP:0001259', (134, 138))	('seizures', 'Disease', 'MESH:D012640', (113, 121))
572772	31069009	Patient, tumor and treatment factors varied between those with unknown grade and those with a known grade (Table 3); the patients with unknown grade were more likely to be older (62 vs. 59, p<0.001), Black (11.7% vs. 10.9%, p=0.013), and not undergo surgery (31.0% vs. 13.2%, p<0.001).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('unknown grade', 'Var', (135, 148))	('tumor', 'Disease', (9, 14))	('patients', 'Species', '9606', (121, 129))	('Patient', 'Species', '9606', (0, 7))
572829	28985030	CIC loss-of-function mutations are frequently observed in several human neoplasms such as oligodendroglioma, and lung and gastric carcinoma.	('gastric carcinoma', 'Disease', 'MESH:D013274', (122, 139))	('loss-of-function', 'NegReg', (4, 20))	('neoplasms', 'Disease', 'MESH:D009369', (72, 81))	('human', 'Species', '9606', (66, 71))	('oligodendroglioma', 'Disease', (90, 107))	('gastric carcinoma', 'Disease', (122, 139))	('neoplasms', 'Disease', (72, 81))	('oligodendroglioma', 'Disease', 'MESH:D009837', (90, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('lung', 'Disease', (113, 117))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (122, 139))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))	('mutations', 'Var', (21, 30))
572831	28985030	In these mutations, PEA3 family genes and other important target genes are upregulated, inducing malignant phenotypes.	('PEA3', 'Gene', '2118', (20, 24))	('upregulated', 'PosReg', (75, 86))	('malignant phenotypes', 'CPA', (97, 117))	('mutations', 'Var', (9, 18))	('PEA3', 'Gene', (20, 24))	('inducing', 'PosReg', (88, 96))
572835	28985030	A number of mutations in the pathway have been identified in the broad spectrum of cancer.1 In most of the mutations, enhancement and/or prolongation of phosphorylation was found in proteins of signal mediators in the pathway.	('mutations', 'Var', (107, 116))	('enhancement', 'PosReg', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prolongation', 'PosReg', (137, 149))	('phosphorylation', 'MPA', (153, 168))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
572838	28985030	These aberrations include both loss-of-function and gain-of-function mutations, indicating the pleiotropic characteristics of CIC in cancer.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('loss-of-function', 'NegReg', (31, 47))	('cancer', 'Disease', (133, 139))	('gain-of-function', 'PosReg', (52, 68))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
572845	28985030	Capicua also represses mirror expression that determines the ovarian follicle cell fate.19 Moreover, ATXN1 that is mutated in human SCA1 modulates the repressional activity of capicua, interacting with the N-terminal region of capicua.20, 21 Conversely, haploinsufficiency of Cic improved SCA1 disease phenotypes in Atxn1 mutant mice.22  The homozygous knockout mouse for Cic-L shows the defect of alveolar organization of the lung, and the phenotype is similar with that of the compound Atxn1 and Atxn1l knockout mouse, indicating the importance of CIC/ATXN1 interaction in tissue homeostasis.23 In mutants, Etv4 repression by CIC is cancelled, resulting in upregulation of Mmp9 and aberration of ECM remodeling.23 The conditional Cic mutation lacking exons 2-6 also induced abnormal lung alveolarization with reduced alveolar surfactant protein expression.24 Moreover, hematopoietic lineage cell-specific knockout of Cic induced remarkable autoimmune responses with increased follicular helper T cells, which was mediated by derepression of Etv5.25  Interaction between CIC and ATXN1 protein family is also important for brain development.	('abnormal lung', 'Disease', (776, 789))	('abnormal lung', 'Disease', 'MESH:D008171', (776, 789))	('Atxn1l', 'Gene', '52335', (498, 504))	('derepression', 'PosReg', (1027, 1039))	('SCA1', 'Gene', (289, 293))	('Etv4', 'Gene', '18612', (609, 613))	('Capicua', 'Gene', (0, 7))	('alveolar', 'Disease', 'MESH:D002282', (398, 406))	('SCA1', 'Gene', '6310', (289, 293))	('Capicua', 'Gene', '23152', (0, 7))	('Etv5', 'Gene', (1043, 1047))	('reduced alveolar', 'Phenotype', 'HP:0006329', (811, 827))	('ECM', 'Gene', '22915', (698, 701))	('SCA1 disease', 'Disease', (289, 301))	('alveolar', 'Disease', (790, 798))	('haploinsufficiency of Cic', 'Disease', 'MESH:D058495', (254, 279))	('Atxn1l', 'Gene', (498, 504))	('mouse', 'Species', '10090', (514, 519))	('knockout', 'Var', (907, 915))	('Etv4', 'Gene', (609, 613))	('SCA1 disease', 'Disease', 'MESH:D020754', (289, 301))	('human', 'Species', '9606', (126, 131))	('mice', 'Species', '10090', (329, 333))	('alveolar', 'Disease', (819, 827))	('mouse', 'Species', '10090', (362, 367))	('defect of alveolar', 'Phenotype', 'HP:0006477', (388, 406))	('Mmp9', 'Gene', '17395', (675, 679))	('follicular helper T cells', 'CPA', (978, 1003))	('alveolar', 'Disease', 'MESH:D002282', (790, 798))	('Cic', 'Gene', (919, 922))	('alveolar', 'Disease', (398, 406))	('haploinsufficiency of Cic', 'Disease', (254, 279))	('Etv5', 'Gene', '104156', (1043, 1047))	('ECM', 'Gene', (698, 701))	('increased', 'PosReg', (968, 977))	('SCA1', 'Gene', (132, 136))	('alveolar', 'Disease', 'MESH:D002282', (819, 827))	('Mmp9', 'Gene', (675, 679))	('SCA1', 'Gene', '6310', (132, 136))	('abnormal lung', 'Phenotype', 'HP:0002088', (776, 789))
572853	28985030	Indeed, CIC was found mutated in the majority of human oligodendroglioma, in which biallelic mutations and/or loss of CIC were frequently observed (Fig.	('loss', 'NegReg', (110, 114))	('oligodendroglioma', 'Disease', (55, 72))	('human', 'Species', '9606', (49, 54))	('CIC', 'Gene', (118, 121))	('oligodendroglioma', 'Disease', 'MESH:D009837', (55, 72))	('biallelic mutations', 'Var', (83, 102))
572854	28985030	2a, Table 1).37, 38 In brain tumors, CIC mutations are rather specific to oligodendroglioma and are rarely observed in astrocytic tumors.39 CIC mutations in oligodendroglioma are frequently associated with IDH1 and FUBP1 mutations, suggesting a cooperative role among these three genes in tumorigenesis.39, 40, 41 Cooperative increase of intracellular 2HG, reduced clonogenicity, and slower proliferation in cell lines introduced with IDH1 and CIC double mutations was reported, however, the significance of 2HG increase in oligodendroglioma development and survival remains unclear.11  Subsequently, frequent and recurrent loss-of-function mutations and/or reduced expression of CIC have been reported in lung, stomach, and prostate cancer (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('prostate cancer', 'Disease', 'MESH:D011471', (725, 740))	('stomach', 'Disease', (712, 719))	('prostate cancer', 'Phenotype', 'HP:0012125', (725, 740))	('loss-of-function', 'NegReg', (624, 640))	('oligodendroglioma', 'Disease', (74, 91))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('IDH1', 'Gene', (206, 210))	('prostate cancer', 'Disease', (725, 740))	('tumor', 'Disease', (130, 135))	('CIC', 'Gene', (680, 683))	('oligodendroglioma development', 'Disease', (524, 553))	('oligodendroglioma', 'Disease', 'MESH:D009837', (524, 541))	('IDH1', 'Gene', '3417', (435, 439))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', (289, 294))	('oligodendroglioma', 'Disease', (524, 541))	('astrocytic tumors', 'Disease', (119, 136))	('lung', 'Disease', (706, 710))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('oligodendroglioma', 'Disease', 'MESH:D009837', (157, 174))	('IDH1', 'Gene', '3417', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('FUBP1', 'Gene', (215, 220))	('astrocytic tumors', 'Disease', 'MESH:D001254', (119, 136))	('brain tumors', 'Disease', 'MESH:D001932', (23, 35))	('brain tumors', 'Phenotype', 'HP:0030692', (23, 35))	('expression', 'MPA', (666, 676))	('mutations', 'Var', (641, 650))	('IDH1', 'Gene', (435, 439))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('reduced', 'NegReg', (658, 665))	('oligodendroglioma', 'Disease', (157, 174))	('oligodendroglioma development', 'Disease', 'MESH:D009837', (524, 553))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('brain tumors', 'Disease', (23, 35))	('tumor', 'Disease', (29, 34))	('FUBP1', 'Gene', '8880', (215, 220))	('oligodendroglioma', 'Disease', 'MESH:D009837', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (734, 740))
572855	28985030	2a).7, 13, 28, 38, 42 The mutations were mostly detected around the HMG-box and the C1 domain in oligodendroglioma (Fig.	('mutations', 'Var', (26, 35))	('oligodendroglioma', 'Disease', (97, 114))	('oligodendroglioma', 'Disease', 'MESH:D009837', (97, 114))
572857	28985030	As a result of CIC loss-of-function mutations, repression of PEA3 family genes are cancelled, promoting cellular proliferation and migration (Fig.	('PEA3', 'Gene', (61, 65))	('cellular proliferation', 'CPA', (104, 126))	('migration', 'CPA', (131, 140))	('promoting', 'PosReg', (94, 103))	('mutations', 'Var', (36, 45))	('PEA3', 'Gene', '2118', (61, 65))	('loss-of-function', 'NegReg', (19, 35))
572858	28985030	Interestingly, frequent mutations at the HMG-box and C1 motif observed in oligodendroglioma were not found in lung or gastric cancer (Fig.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung or gastric cancer', 'Disease', (110, 132))	('HMG-box', 'Protein', (41, 48))	('oligodendroglioma', 'Disease', (74, 91))	('C1 motif', 'Gene', (53, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('lung or gastric cancer', 'Disease', 'MESH:D013274', (110, 132))	('mutations', 'Var', (24, 33))	('oligodendroglioma', 'Disease', 'MESH:D009837', (74, 91))
572859	28985030	CIC mutations might occur at the early stage of oligodendroglioma development, whereas mutations were acquired at the advanced stages in lung and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (146, 160))	('gastric cancer', 'Disease', (146, 160))	('oligodendroglioma development', 'Disease', (48, 77))	('oligodendroglioma development', 'Disease', 'MESH:D009837', (48, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (146, 160))	('mutations', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('CIC', 'Gene', (0, 3))
572861	28985030	Interestingly, a glial fibrillary acidic protein-Cre-induced Cic mutation in mouse failed to induce oligodendroglioma.24 Instead, when the same mutation was ubiquitously induced in adult mice, T-cell lymphoblastic leukemia developed at high penetrance.	('oligodendroglioma', 'Disease', (100, 117))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (200, 222))	('T-cell lymphoblastic leukemia', 'Disease', 'MESH:D054218', (193, 222))	('oligodendroglioma', 'Disease', 'MESH:D009837', (100, 117))	('mutation', 'Var', (144, 152))	('mice', 'Species', '10090', (187, 191))	('T-cell lymphoblastic leukemia', 'Disease', (193, 222))	('leukemia', 'Phenotype', 'HP:0001909', (214, 222))	('mouse', 'Species', '10090', (77, 82))
572865	28985030	3a).12 DUX4 encodes a double homeodomain protein and is located in the D4Z4 repeat that is distributed in the subtelomeric regions of the mammalian genome with predominant distribution in 4q and 10q.45, 46 Aberrant expression of DUX4 is associated with facioscapulohumeral muscular dystrophy.47, 48, 49, 50 The mechanisms of transcriptional activation of DUX4, by recruiting p300/CBP using its C-terminal domain that is included in the CIC-DUX4 fusion, was proposed.51 As a result of DUX4 fusion, CIC acquires transcriptional activation, perhaps through recruitment of p300/CBP, and the fusion converts transrepressional activity of CIC to upregulate its target genes, thereby shows strong oncogenic activity.	('muscular dystrophy', 'Disease', (273, 291))	('muscular dystrophy', 'Disease', 'MESH:D009136', (273, 291))	('DUX4', 'Gene', (484, 488))	('CBP', 'Gene', '1387', (574, 577))	('p300', 'Gene', (375, 379))	('DUX4', 'Gene', (229, 233))	('activation', 'PosReg', (526, 536))	('p300', 'Gene', '2033', (375, 379))	('DUX4', 'Gene', (7, 11))	('DUX4', 'Gene', '100288687', (484, 488))	('CBP', 'Gene', (574, 577))	('DUX4', 'Gene', (355, 359))	('CBP', 'Gene', '1387', (380, 383))	('DUX4', 'Gene', '100288687', (229, 233))	('transrepressional activity', 'MPA', (603, 629))	('mammalian', 'Species', '9606', (138, 147))	('upregulate', 'PosReg', (640, 650))	('oncogenic activity', 'CPA', (690, 708))	('DUX4', 'Gene', (440, 444))	('DUX4', 'Gene', '100288687', (7, 11))	('DUX4', 'Gene', '100288687', (355, 359))	('CBP', 'Gene', (380, 383))	('p300', 'Gene', (569, 573))	('DUX4', 'Gene', '100288687', (440, 444))	('transcriptional', 'MPA', (510, 525))	('p300', 'Gene', '2033', (569, 573))	('fusion', 'Var', (489, 495))
572870	28985030	The unique mutations of CIC in human cancer are characterized as a mixture of loss-of-function and gain-of-function mutations, both of which upregulate downstream target genes such as ETV4 (Fig.	('CIC', 'Gene', (24, 27))	('mutations', 'Var', (11, 20))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('gain-of-function', 'PosReg', (99, 115))	('cancer', 'Disease', (37, 43))	('human', 'Species', '9606', (31, 36))	('ETV4', 'Gene', (184, 188))	('mutations', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('upregulate', 'PosReg', (141, 151))	('loss-of-function', 'NegReg', (78, 94))
572875	28985030	The exact mechanism to explain how ATXN1L is downmodulated to reduce CIC protein and sensitivity to trametinib remains to be investigated, however, the result suggests importance of the ATXN1L-CIC axis for targeted therapy against the genetic mutations in the RTK/RAS/MAPK pathway (Fig.	('CIC protein', 'Protein', (69, 80))	('trametinib', 'Chemical', 'MESH:C560077', (100, 110))	('MAPK', 'Gene', (268, 272))	('mutations', 'Var', (243, 252))	('CIC axis', 'Disease', (193, 201))	('ATXN1L', 'Gene', '342371', (35, 41))	('ATXN1L', 'Gene', '342371', (186, 192))	('MAPK', 'Gene', '3354888', (268, 272))	('CIC axis', 'Disease', 'MESH:C566610', (193, 201))	('ATXN1L', 'Gene', (35, 41))	('ATXN1L', 'Gene', (186, 192))
572878	28985030	The COP9 signalosome subunit 1b is another guardian of CIC that acts in an MAPK-independent manner.31 Targeting CIC mutations in carcinoma and sarcoma is more challenging, however, epigenetic therapies that modulate transcription of CIC target genes should be considered.	('MAPK', 'Gene', (75, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('COP9', 'Gene', '10920', (4, 8))	('MAPK', 'Gene', '3354888', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('mutations', 'Var', (116, 125))	('COP9', 'Gene', (4, 8))	('CIC', 'Gene', (112, 115))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (129, 150))
572881	28985030	The Cic-L homozygous KO mice showed abnormal remodeling of ECM in the lung.23 This phenotype is closely recapitulated as upregulation of the ECM gene set in the CDS mouse model.55 In malignancies, mutant CIC could orchestrate biological activities of cancer cells in both cell autonomous and non-autonomous manners.	('mouse', 'Species', '10090', (165, 170))	('ECM', 'Gene', '22915', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('ECM', 'Gene', '22915', (141, 144))	('mice', 'Species', '10090', (24, 28))	('ECM', 'Gene', (59, 62))	('CIC', 'Gene', (204, 207))	('ECM', 'Gene', (141, 144))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('mutant', 'Var', (197, 203))	('CDS', 'Gene', '1040', (161, 164))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (251, 257))	('CDS', 'Gene', (161, 164))	('malignancies', 'Disease', (183, 195))
572882	28985030	In conclusion, CIC acts as a modulator in the pathway and both loss-of-function and gain-of-function mutations of CIC dysregulate the targets, such as the PEA3 family transcription factors, CCND1/D2, and MMPs, resulting in abnormal cellular growth, invasion, and metastasis.	('abnormal cellular growth', 'Phenotype', 'HP:0031377', (223, 247))	('cellular growth', 'CPA', (232, 247))	('CCND1', 'Gene', (190, 195))	('mutations', 'Var', (101, 110))	('invasion', 'CPA', (249, 257))	('metastasis', 'CPA', (263, 273))	('CIC', 'Gene', (114, 117))	('gain-of-function', 'PosReg', (84, 100))	('PEA3', 'Gene', '2118', (155, 159))	('loss-of-function', 'NegReg', (63, 79))	('MMPs', 'Gene', '17395', (204, 208))	('PEA3', 'Gene', (155, 159))	('CCND1', 'Gene', '595', (190, 195))	('MMPs', 'Gene', (204, 208))
572895	27748430	For the sake of simplicity, sarcomas can be grouped into two major categories either by location (e.g., bone vs. soft tissue sarcoma) or by presence or absence of genomic translocations that characterize one-third of sarcoma subtypes.	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (113, 132))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (113, 132))	('sarcomas', 'Disease', (28, 36))	('bone vs.', 'Disease', (104, 112))	('genomic translocations', 'Var', (163, 185))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (217, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('soft tissue sarcoma', 'Disease', (113, 132))	('sarcoma subtypes', 'Disease', (217, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))
572897	27748430	Successful targeting of activating mutations in the KIT receptor tyrosine kinase with imatinib mesylate for gastrointestinal stromal tumor (GIST) illustrates how this approach can potentially change outcomes even for notoriously chemotherapy-resistant sarcoma subtypes.	('sarcoma subtypes', 'Disease', 'MESH:D012509', (252, 268))	('imatinib', 'Chemical', 'MESH:D000068877', (86, 94))	('change', 'Reg', (192, 198))	('gastrointestinal stromal tumor', 'Disease', (108, 138))	('activating', 'PosReg', (24, 34))	('sarcoma subtypes', 'Disease', (252, 268))	('receptor tyrosine kinase', 'Gene', (56, 80))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (108, 138))	('receptor tyrosine kinase', 'Gene', '5979', (56, 80))	('GIST', 'Phenotype', 'HP:0100723', (140, 144))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (108, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('mutations', 'Var', (35, 44))
572898	27748430	Sarcomas, especially those associated with a known translocation or those expressing a specific receptor, may be amenable to this approach with potentially exciting results.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('translocation', 'Var', (51, 64))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('Sarcomas', 'Disease', (0, 8))	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))
572911	27748430	For some patients, mutational analysis was performed during the latter course of phase I trials (from 2008 onwards) if additional samples were available; mutations of interest included those in KRAS, BRAF, C-KIT, EGFR, and P13KCA genes.	('KRAS', 'Gene', '3845', (194, 198))	('patients', 'Species', '9606', (9, 17))	('BRAF', 'Gene', (200, 204))	('EGFR', 'Gene', (213, 217))	('KRAS', 'Gene', (194, 198))	('C-KIT', 'Gene', '3815', (206, 211))	('P13KCA', 'Gene', (223, 229))	('mutations', 'Var', (154, 163))	('C-KIT', 'Gene', (206, 211))	('BRAF', 'Gene', '673', (200, 204))	('EGFR', 'Gene', '1956', (213, 217))
572933	27748430	Other molecular abnormalities included MET mutation (7 of 50 patients), HER2 amplification by fluorescence in situ hybridization (1 of 26 patients), K-RAS G12A mutation (1 of 67 patients), N-RAS Q61K mutation (1 of 45 patients), EGFR G719D mutation (1 of 55 patients), P53 mutation (7 of 36 patients), and C-KIT mutation (1 of 56 patients).	('EGFR', 'Gene', '1956', (229, 233))	('G719D', 'Mutation', 'rs121913428', (234, 239))	('Q61K', 'Mutation', 'rs121913254', (195, 199))	('P53', 'Gene', (269, 272))	('patients', 'Species', '9606', (330, 338))	('MET mutation', 'Var', (39, 51))	('HER2', 'Gene', '2064', (72, 76))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (291, 299))	('patients', 'Species', '9606', (258, 266))	('N-RAS', 'Gene', (189, 194))	('P53', 'Gene', '7157', (269, 272))	('patients', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (218, 226))	('G12A', 'Mutation', 'rs121913529', (155, 159))	('EGFR', 'Gene', (229, 233))	('C-KIT', 'Gene', '3815', (306, 311))	('K-RAS', 'Gene', (149, 154))	('C-KIT', 'Gene', (306, 311))	('HER2', 'Gene', (72, 76))	('K-RAS', 'Gene', '3845', (149, 154))	('N-RAS', 'Gene', '4893', (189, 194))
572940	27748430	The four patients with partial responses included one patient with alveolar soft part sarcoma treated with an anti-VEGF agent, one with malignant fibrous histiocytoma treated with a combination of inhibitors of VEGF and histone deacetylase (HDAC), one with chondrosarcoma treated with a TRAIL (TNF-related apoptosis-inducing ligand) agent, and one patient with lymphangiomyomatosis treated with a combination of VEGF and mTOR inhibitors.	('malignant fibrous histiocytoma', 'Disease', (136, 166))	('HDAC', 'Gene', '9734', (241, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('VEGF', 'Gene', (211, 215))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (257, 271))	('VEGF', 'Gene', '7422', (115, 119))	('patient', 'Species', '9606', (9, 16))	('TRAIL', 'Gene', '8743', (287, 292))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (67, 93))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (76, 93))	('HDAC', 'Gene', (241, 245))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('TNF-related apoptosis-inducing ligand', 'Gene', (294, 331))	('VEGF', 'Gene', (115, 119))	('mTOR', 'Gene', (421, 425))	('histone deacetylase', 'Gene', '9734', (220, 239))	('malignant fibrous histiocytoma', 'Disease', 'MESH:D051677', (136, 166))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (67, 93))	('patient', 'Species', '9606', (348, 355))	('histiocytoma', 'Phenotype', 'HP:0012315', (154, 166))	('patient', 'Species', '9606', (54, 61))	('TRAIL', 'Gene', (287, 292))	('inhibitors', 'Var', (197, 207))	('lymphangiomyomatosis', 'Disease', 'MESH:D018192', (361, 381))	('mTOR', 'Gene', '2475', (421, 425))	('alveolar soft part sarcoma', 'Disease', (67, 93))	('histone deacetylase', 'Gene', (220, 239))	('VEGF', 'Gene', '7422', (211, 215))	('patients', 'Species', '9606', (9, 17))	('chondrosarcoma', 'Disease', (257, 271))	('chondrosarcoma', 'Disease', 'MESH:D002813', (257, 271))	('VEGF', 'Gene', '7422', (412, 416))	('VEGF', 'Gene', (412, 416))	('lymphangiomyomatosis', 'Disease', (361, 381))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (294, 331))
572956	27748430	However, early phase clinical trials of IGF1R inhibitors demonstrated response rates of 10-15% and highlighted the need for markers to identify patients most likely to respond.	('IGF1R', 'Gene', '3480', (40, 45))	('patients', 'Species', '9606', (144, 152))	('inhibitors', 'Var', (46, 56))	('IGF1R', 'Gene', (40, 45))
572960	27748430	Neither demographic features, translocation status, nor mutations in TP53 or MET genes predicted outcome.	('TP53', 'Gene', (69, 73))	('mutations', 'Var', (56, 65))	('MET genes', 'Gene', (77, 86))	('TP53', 'Gene', '7157', (69, 73))
572971	27748430	Third, treatment involved inhibitors of VEGF and/or mTOR in more than three-quarters of the patients and no patients were enrolled on immunotherapy trials.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('inhibitors', 'Var', (26, 36))	('VEGF', 'Gene', (40, 44))	('patients', 'Species', '9606', (92, 100))	('VEGF', 'Gene', '7422', (40, 44))	('patients', 'Species', '9606', (108, 116))
572977	27748430	In conclusion, this retrospective analysis of 100 sarcoma patients treated on phase I trials predominantly involving inhibitors of VEGF and/or mTOR demonstrated a clinical benefit rate of 36%.	('VEGF', 'Gene', (131, 135))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('inhibitors', 'Var', (117, 127))	('mTOR', 'Gene', '2475', (143, 147))	('VEGF', 'Gene', '7422', (131, 135))	('patients', 'Species', '9606', (58, 66))	('mTOR', 'Gene', (143, 147))
573002	27255678	Vascular normalization may then lead to decreased tumor hypoxia and consequently to increased RT efficacy.	('decreased tumor hypoxia', 'Disease', 'MESH:D000860', (40, 63))	('RT efficacy', 'CPA', (94, 105))	('decreased tumor hypoxia', 'Disease', (40, 63))	('increased', 'PosReg', (84, 93))	('Vascular normalization', 'Var', (0, 22))	('increased RT', 'Phenotype', 'HP:0008151', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))
573080	27255678	hepatotoxicity in case of pazopanib or hematotoxicity in case of sunitinib) meaning that the combination of the anti-angiogenic drug with radiation therapy did not lead to unexpected adverse events.	('pazopanib', 'Chemical', 'MESH:C516667', (26, 35))	('sunitinib', 'Chemical', 'MESH:D000077210', (65, 74))	('hepatotoxicity', 'Disease', 'MESH:D056486', (0, 14))	('hematotoxicity', 'Disease', 'MESH:D006402', (39, 53))	('pazopanib', 'Var', (26, 35))	('hematotoxicity', 'Disease', (39, 53))	('hepatotoxicity', 'Disease', (0, 14))
573082	27255678	hepatotoxicity in case of pazopanib or hematotoxicity in case of sunitinib).	('pazopanib', 'Chemical', 'MESH:C516667', (26, 35))	('sunitinib', 'Chemical', 'MESH:D000077210', (65, 74))	('hepatotoxicity', 'Disease', 'MESH:D056486', (0, 14))	('hematotoxicity', 'Disease', 'MESH:D006402', (39, 53))	('pazopanib', 'Var', (26, 35))	('hematotoxicity', 'Disease', (39, 53))	('hepatotoxicity', 'Disease', (0, 14))
573176	23115511	Despite the therapeutic potential and the clinical importance of P. serotinus, no studies on its antitumor and immunomodulating activities have been reported.	('P. serotinus', 'Var', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('P. serotinus', 'Species', '40488', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
573252	23115511	The results suggested that beta-glucan of P. serotinus can improve the immune response of the host by stimulating proliferation of immune-organ, murine spleen cells.	('murine', 'Species', '10090', (145, 151))	('immune response', 'CPA', (71, 86))	('beta-glucan', 'Protein', (27, 38))	('stimulating', 'PosReg', (102, 113))	('improve', 'PosReg', (59, 66))	('beta-glucan', 'Chemical', 'MESH:D047071', (27, 38))	('proliferation', 'CPA', (114, 127))	('P. serotinus', 'Species', '40488', (42, 54))	('P. serotinus', 'Var', (42, 54))
573260	23115511	The results demonstrated that stimulation with beta-glucan of P. serotinus can result in an increase in production of NO and improvement of the immune response in ICR mice.	('P. serotinus', 'Var', (62, 74))	('improvement', 'PosReg', (125, 136))	('immune response', 'CPA', (144, 159))	('beta-glucan', 'Chemical', 'MESH:D047071', (47, 58))	('increase', 'PosReg', (92, 100))	('production of NO', 'MPA', (104, 120))	('P. serotinus', 'Species', '40488', (62, 74))	('mice', 'Species', '10090', (167, 171))	('beta-glucan', 'Protein', (47, 58))
573326	22606585	However, the latter also shows positivity for CD34 which is not seen in synovial sarcoma.	('CD34', 'Gene', (46, 50))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (72, 88))	('synovial sarcoma', 'Disease', 'MESH:D013584', (72, 88))	('positivity', 'Var', (31, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('synovial sarcoma', 'Disease', (72, 88))	('CD34', 'Gene', '947', (46, 50))
573408	30473898	Most of the patients received adjuvant therapy, and these authors reported that those who received adjuvant CT in addition to RT had a longer disease free interval (37.6 months) than those who did not receive adjuvant CT (4.6 months).	('longer disease free interval', 'Disease', (135, 163))	('patients', 'Species', '9606', (12, 20))	('longer disease free interval', 'Disease', 'MESH:D015673', (135, 163))	('adjuvant', 'Var', (99, 107))
573451	29361819	In one analysis, expression of PD-L1 was significantly associated with a poor outcome, especially in soft tissue sarcoma rather than bone sarcoma.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (101, 120))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (101, 120))	('bone sarcoma', 'Disease', 'MESH:D001847', (133, 145))	('bone sarcoma', 'Phenotype', 'HP:0002669', (133, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('associated', 'Reg', (55, 65))	('soft tissue sarcoma', 'Disease', (101, 120))	('expression', 'Var', (17, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('bone sarcoma', 'Disease', (133, 145))	('PD-L1', 'Gene', (31, 36))
573498	26402907	Finally, deletion of miR-K3 from the KSHV genome abrogated its effect on the GRK2/CXCR2/AKT pathway and KSHV-induced migration and invasion.	('KSHV', 'Species', '37296', (104, 108))	('abrogated', 'NegReg', (49, 58))	('deletion', 'Var', (9, 17))	('miR', 'Gene', '220972', (21, 24))	('AKT', 'Gene', '207', (88, 91))	('miR', 'Gene', (21, 24))	('rat', 'Species', '10116', (120, 123))	('KSHV', 'Species', '37296', (37, 41))	('AKT', 'Gene', (88, 91))
573534	26402907	Under this condition, over 95% cells were RFP-positive at day 3 or 4 post-transduction, indicating the successful lentivirus transduction (Fig 1B and 1C).	('lentivirus', 'Var', (114, 124))	('RFP', 'Gene', '5987', (42, 45))	('RFP', 'Gene', (42, 45))
573550	26402907	Mutation of this seed sequence abolished the inhibitory effect of miR-K3 on GRK2 3'UTR (Fig 3D).	('GRK2', 'Gene', (76, 80))	('abolished', 'NegReg', (31, 40))	('Mutation', 'Var', (0, 8))	('miR', 'Gene', (66, 69))	('miR', 'Gene', '220972', (66, 69))	('inhibitory effect', 'MPA', (45, 62))
573565	26402907	In the luciferase reporter assay, transduction of the sponge abolished the inhibitory effect of miR-K3 mimic on its sensor reporter in a dose-dependent manner in HEK 293T cells, indicating that the miR-K3 sponge was functional (Fig 5B).	('miR', 'Gene', '220972', (198, 201))	('miR', 'Gene', (198, 201))	('transduction', 'Var', (34, 46))	('HEK 293T', 'CellLine', 'CVCL:0063', (162, 170))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('inhibitory effect', 'MPA', (75, 92))	('abolished', 'NegReg', (61, 70))
573567	26402907	As expected, knock-down of GRK2 by lentivirus-mediated a mixture of short hairpair RNAs in normal HUVEC alone was sufficient to increase cell migration and invasion (Fig 5E and 5F, S3 Fig).	('knock-down', 'Var', (13, 23))	('increase', 'PosReg', (128, 136))	('cell migration', 'CPA', (137, 151))	('GRK2', 'Gene', (27, 31))	('invasion', 'CPA', (156, 164))	('rat', 'Species', '10116', (145, 148))
573587	26402907	As expected, knockdown of GRK2 with shRNAs was sufficient to increase the phosphorylated AKT level in normal HUVEC (Fig 7E).	('shRNAs', 'Gene', (36, 42))	('GRK2', 'Gene', (26, 30))	('AKT', 'Gene', '207', (89, 92))	('increase', 'PosReg', (61, 69))	('AKT', 'Gene', (89, 92))	('knockdown', 'Var', (13, 22))
573589	26402907	Knock-down of CXCR2 decreased the level of phosphorylated AKT in either miR-K3-expressing or KSHV-infected HUVEC (Fig 7F and 7G).	('decreased', 'NegReg', (20, 29))	('Knock-down', 'Var', (0, 10))	('KSHV-infected', 'Disease', 'MESH:C537372', (93, 106))	('AKT', 'Gene', '207', (58, 61))	('level of phosphorylated', 'MPA', (34, 57))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (72, 75))	('KSHV-infected', 'Disease', (93, 106))	('AKT', 'Gene', (58, 61))
573600	26402907	Similar inhibition of cell migration and invasion was also observed in KSHV-infected HUVEC following knock down of AKT (Fig 8C and 8D, S6 Fig).	('AKT', 'Gene', '207', (115, 118))	('inhibition', 'NegReg', (8, 18))	('KSHV-infected', 'Disease', (71, 84))	('KSHV-infected', 'Disease', 'MESH:C537372', (71, 84))	('invasion', 'CPA', (41, 49))	('knock down', 'Var', (101, 111))	('AKT', 'Gene', (115, 118))	('rat', 'Species', '10116', (30, 33))	('cell migration', 'CPA', (22, 36))
573602	26402907	Consistently, treatment of MK-2206 not only inhibited cell migration and invasion (S7A and S7C Fig), but also decreased the level of phosphorylated AKT (S7B and S7D Fig).	('MK-2206', 'Chemical', 'MESH:C548887', (27, 34))	('AKT', 'Gene', '207', (148, 151))	('MK-2206', 'Var', (27, 34))	('level of phosphorylated', 'MPA', (124, 147))	('inhibited', 'NegReg', (44, 53))	('AKT', 'Gene', (148, 151))	('decreased', 'NegReg', (110, 119))	('rat', 'Species', '10116', (62, 65))	('cell migration', 'CPA', (54, 68))
573603	26402907	Importantly, inhibition of AKT with MK-2206 also blocked the induction of MMP1, 9 and 10, and IL-6, IL-8 by miR-K3 transduction or KSHV infection in HUVEC (Fig 8E and 8F).	('IL-6', 'Gene', (94, 98))	('AKT', 'Gene', (27, 30))	('KSHV infection', 'Disease', (131, 145))	('MMP1', 'Gene', (74, 78))	('IL-6', 'Gene', '3569', (94, 98))	('IL-8', 'Gene', '3576', (100, 104))	('MK-2206', 'Var', (36, 43))	('miR', 'Gene', '220972', (108, 111))	('IL-8', 'Gene', (100, 104))	('miR', 'Gene', (108, 111))	('AKT', 'Gene', '207', (27, 30))	('MK-2206', 'Chemical', 'MESH:C548887', (36, 43))	('MMP1', 'Gene', '4312', (74, 78))	('blocked', 'NegReg', (49, 56))	('KSHV infection', 'Disease', 'MESH:C537372', (131, 145))
573605	26402907	Since inhibition of miR-K3 function with a specific sponge in KSHV infected HUVEC decreased cell migration and invasion (Fig 5D), we wished to further confirm these results by genetic knock out of miR-K3 from the KSHV genome.	('miR', 'Gene', '220972', (197, 200))	('miR', 'Gene', (197, 200))	('KSHV', 'Species', '37296', (213, 217))	('KSHV', 'Species', '37296', (62, 66))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('inhibition', 'NegReg', (6, 16))	('decreased', 'NegReg', (82, 91))	('knock out', 'Var', (184, 193))	('rat', 'Species', '10116', (100, 103))
573607	26402907	We ensured that the expression of miR-K3 was abrogated in miR-K3_mut virus and the deletion of miR-K3 from the KSHV genome didn't affect the expression of other miRNAs by qPCR analysis (S8 Fig).	('miR', 'Gene', '220972', (95, 98))	('abrogated', 'NegReg', (45, 54))	('miR', 'Gene', (95, 98))	('expression', 'MPA', (20, 30))	('miR', 'Gene', '220972', (161, 164))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('miR', 'Gene', (161, 164))	('miR', 'Gene', (34, 37))	('miR', 'Gene', '220972', (34, 37))	('KSHV', 'Species', '37296', (111, 115))	('expression', 'MPA', (141, 151))	('deletion', 'Var', (83, 91))
573608	26402907	As shown in Fig 9A and 9B, the levels of cell migration and invasion in HUVEC infected by the mutant virus were significantly lower than those infected by the wild type virus.	('lower', 'NegReg', (126, 131))	('invasion', 'CPA', (60, 68))	('cell migration', 'CPA', (41, 55))	('mutant', 'Var', (94, 100))	('rat', 'Species', '10116', (49, 52))
573609	26402907	Consistent with these observations, cells infected by the mutant virus had decreased levels of MMP1, 9, and 10 and IL-6 and IL-8 mRNAs transcripts than those infected by the wild type virus (Fig 9C).	('IL-6', 'Gene', (115, 119))	('mutant', 'Var', (58, 64))	('MMP1', 'Gene', '4312', (95, 99))	('IL-8', 'Gene', (124, 128))	('IL-6', 'Gene', '3569', (115, 119))	('MMP1', 'Gene', (95, 99))	('IL-8', 'Gene', '3576', (124, 128))	('levels', 'MPA', (85, 91))	('decreased', 'NegReg', (75, 84))
573610	26402907	Importantly, mutant cells had a higher level of GRK2, and lower levels of CXCR2 and activated AKT than those of wild type cells (Fig 9D), while RTA was dramatically elevated in mutant cells (Fig 9D), which was consistent with previous reports.	('mutant', 'Var', (13, 19))	('AKT', 'Gene', '207', (94, 97))	('levels of CXCR2', 'MPA', (64, 79))	('GRK2', 'MPA', (48, 52))	('higher', 'PosReg', (32, 38))	('activated', 'PosReg', (84, 93))	('lower', 'NegReg', (58, 63))	('AKT', 'Gene', (94, 97))	('mutant', 'Var', (177, 183))	('elevated', 'PosReg', (165, 173))	('RTA', 'MPA', (144, 147))
573611	26402907	To further confirm the role of AKT in miR-K3 regulation of mRNAs transcripts of MMPs and inflammatory cytokines, we transfected AKT cDNA into HUVEC infected by the mutant virus.	('mutant', 'Var', (164, 170))	('AKT', 'Gene', '207', (31, 34))	('MMPs', 'Gene', '4312;4318;4319', (80, 84))	('AKT', 'Gene', (31, 34))	('AKT', 'Gene', (128, 131))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('AKT', 'Gene', '207', (128, 131))	('MMPs', 'Gene', (80, 84))
573612	26402907	As expected, transfection of AKT cDNA in miR-K3_mut-infected HUVEC increased the levels of MMP1, 9, and 10 and IL-6 and IL-8 transcripts compared to cells transfected with control vector (S9 Fig).	('MMP1', 'Gene', '4312', (91, 95))	('IL-6', 'Gene', '3569', (111, 115))	('transfection', 'Var', (13, 25))	('IL-8', 'Gene', '3576', (120, 124))	('AKT', 'Gene', '207', (29, 32))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('IL-8', 'Gene', (120, 124))	('MMP1', 'Gene', (91, 95))	('increased', 'PosReg', (67, 76))	('levels', 'MPA', (81, 87))	('AKT', 'Gene', (29, 32))	('IL-6', 'Gene', (111, 115))
573624	26402907	Importantly, either suppression of miR-K3 function with a sponge or deletion of miR-K3 from the KSHV genome inhibited KSHV-induced cell migration and invasions in endothelial cells.	('miR', 'Gene', '220972', (80, 83))	('suppression', 'NegReg', (20, 31))	('miR', 'Gene', (80, 83))	('KSHV', 'Species', '37296', (96, 100))	('rat', 'Species', '10116', (139, 142))	('function', 'MPA', (42, 50))	('deletion', 'Var', (68, 76))	('KSHV', 'Species', '37296', (118, 122))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('inhibited', 'NegReg', (108, 117))
573639	26402907	Consistently, deletion of K3 from the KSHV genome not only restored the expression of GRK2 but also reduced the expression of CXCR2, resulting in a lower activated AKT level and attenuated cell migration and invasion of KSHV infected endothelial cells.	('AKT', 'Gene', (164, 167))	('KSHV', 'Species', '37296', (220, 224))	('cell migration', 'CPA', (189, 203))	('attenuated', 'NegReg', (178, 188))	('KSHV', 'Species', '37296', (38, 42))	('rat', 'Species', '10116', (197, 200))	('reduced', 'NegReg', (100, 107))	('restored', 'PosReg', (59, 67))	('activated', 'PosReg', (154, 163))	('expression', 'MPA', (72, 82))	('lower', 'NegReg', (148, 153))	('AKT', 'Gene', '207', (164, 167))	('expression of CXCR2', 'MPA', (112, 131))	('deletion', 'Var', (14, 22))	('invasion of', 'CPA', (208, 219))	('GRK2', 'Gene', (86, 90))
573645	26402907	In this study, we found that overexpression of KSHV miR-K3 alone led to elevated AKT signaling in HUVEC, while suppression of the activity of miR-K3 with the sponge construct or deletion of miR-K3 from the KSHV genome significantly decreased the phosphorylation level of AKT in KSHV-infected endothelial cells, indicating the contribution of miR-K3 to aberrant AKT signaling during KSHV infection.	('KSHV', 'Species', '37296', (206, 210))	('AKT', 'Gene', '207', (361, 364))	('KSHV', 'Species', '37296', (278, 282))	('AKT', 'Gene', '207', (81, 84))	('KSHV infection', 'Disease', (382, 396))	('AKT', 'Gene', '207', (271, 274))	('miR', 'Gene', '220972', (52, 55))	('KSHV', 'Species', '37296', (47, 51))	('decreased', 'NegReg', (232, 241))	('KSHV-infected', 'Disease', 'MESH:C537372', (278, 291))	('KSHV infection', 'Disease', 'MESH:C537372', (382, 396))	('miR', 'Gene', (52, 55))	('miR', 'Gene', '220972', (342, 345))	('AKT', 'Gene', (361, 364))	('deletion', 'Var', (178, 186))	('AKT', 'Gene', (81, 84))	('miR', 'Gene', '220972', (142, 145))	('KSHV-infected', 'Disease', (278, 291))	('miR', 'Gene', '220972', (190, 193))	('elevated', 'PosReg', (72, 80))	('AKT', 'Gene', (271, 274))	('miR', 'Gene', (342, 345))	('phosphorylation level', 'MPA', (246, 267))	('KSHV', 'Species', '37296', (382, 386))	('miR', 'Gene', (142, 145))	('miR', 'Gene', (190, 193))
573647	26402907	In agreement with these reports, we showed that knock-down of CXCR2 dramatically inhibited AKT activation, leading to attenuation of miR-K3 induction of cell migration and invasion.	('activation', 'MPA', (95, 105))	('AKT', 'Gene', '207', (91, 94))	('miR', 'Gene', '220972', (133, 136))	('knock-down', 'Var', (48, 58))	('miR', 'Gene', (133, 136))	('inhibited', 'NegReg', (81, 90))	('cell migration', 'CPA', (153, 167))	('AKT', 'Gene', (91, 94))	('rat', 'Species', '10116', (161, 164))	('attenuation', 'NegReg', (118, 129))
573659	26402907	The wild type GRK2 3'UTR reporter construct (GRK2 3'UTR WT) and its mutant (GRK2 3'UTR mut) were made by cloning the full length of the GRK2 3'UTR sequence and the same sequence but with a mutation in the miR-K3 targeting seed sequence into the downstream of the luciferase sequence in the pGL3-Control plasmid (Promega, Shanghai, China), respectively.	('miR', 'Gene', (205, 208))	('mutation', 'Var', (189, 197))	('pGL3', 'Gene', (290, 294))	('pGL3', 'Gene', '6391', (290, 294))	('miR', 'Gene', '220972', (205, 208))
573766	26849003	Although Ph-like ALL lacks the classic Ph translocation (t[9;22] or BCR-ABL1), it contains 1 or more of a complex array of novel genomic mutations in genes that encode tyrosine kinase signaling pathways.	('BC', 'Phenotype', 'HP:0003002', (68, 70))	('ABL1', 'Gene', '25', (72, 76))	('ABL1', 'Gene', (72, 76))	('mutations', 'Var', (137, 146))	('ALL', 'Phenotype', 'HP:0006721', (17, 20))
573768	26849003	The outcomes of patients with BCR-ABL1 and Ph-like ALL were markedly inferior to those with other ALL subtypes.	('ABL1', 'Gene', (34, 38))	('BC', 'Phenotype', 'HP:0003002', (30, 32))	('Ph-like', 'Var', (43, 50))	('ALL', 'Phenotype', 'HP:0006721', (98, 101))	('patients', 'Species', '9606', (16, 24))	('inferior', 'NegReg', (69, 77))	('ALL', 'Phenotype', 'HP:0006721', (51, 54))	('ABL1', 'Gene', '25', (34, 38))
573769	26849003	IKAROS family zinc finger 1 (IKZF1) alterations, which are markers of a poor outcome in childhood ALL, were enriched in patients who had BCR-ABL1 and Ph-like ALL (70% and 77%, respectively) compared with those who had non-Ph-like ALL (26%) and were correlated with inferior 5-year event-free survival in AYAs.	('IKZF1', 'Gene', (29, 34))	('ABL1', 'Gene', '25', (141, 145))	('IKAROS family zinc finger 1', 'Gene', (0, 27))	('ALL', 'Phenotype', 'HP:0006721', (158, 161))	('ABL1', 'Gene', (141, 145))	('ALL', 'Phenotype', 'HP:0006721', (98, 101))	('alterations', 'Var', (36, 47))	('ALL', 'Phenotype', 'HP:0006721', (230, 233))	('BC', 'Phenotype', 'HP:0003002', (137, 139))	('patients', 'Species', '9606', (120, 128))	('IKZF1', 'Gene', '10320', (29, 34))	('IKAROS family zinc finger 1', 'Gene', '10320', (0, 27))
573770	26849003	Different genetic abnormalities were observed in children versus AYAs with Ph-like ALL, and there was a higher frequency of fusions involving ABL class genes (ABL1, ABL2, colonystimulating factor 1 [CSF1R], and platelet-derived growth factor receptor, beta polypeptide [PDGFRB]) in children and a higher frequency of Janus kinase 2 (JAK2) translocations in AYA patients.	('ABL', 'Gene', '25', (142, 145))	('colon', 'Disease', (171, 176))	('ABL', 'Gene', (159, 162))	('platelet-derived growth factor receptor, beta polypeptide', 'Gene', '5159', (211, 268))	('children', 'Species', '9606', (282, 290))	('colon', 'Disease', 'MESH:D003110', (171, 176))	('fusions', 'Var', (124, 131))	('children', 'Species', '9606', (49, 57))	('ABL', 'Gene', '25', (165, 168))	('ABL', 'Gene', (142, 145))	('JAK2', 'Gene', '3717', (333, 337))	('ABL1', 'Gene', (159, 163))	('Janus kinase 2', 'Gene', (317, 331))	('[PDGFRB]', 'Gene', (269, 277))	('ABL', 'Gene', (165, 168))	('patients', 'Species', '9606', (361, 369))	('CSF1R', 'Gene', '1436', (199, 204))	('ABL1', 'Gene', '25', (159, 163))	('CSF1R', 'Gene', (199, 204))	('JAK2', 'Gene', (333, 337))	('ABL2', 'Gene', '27', (165, 169))	('ABL2', 'Gene', (165, 169))	('translocations', 'Var', (339, 353))	('ABL', 'Gene', '25', (159, 162))	('Janus kinase 2', 'Gene', '3717', (317, 331))	('genetic abnormalities', 'Disease', 'MESH:D030342', (10, 31))	('genetic abnormalities', 'Disease', (10, 31))	('ALL', 'Phenotype', 'HP:0006721', (83, 86))
573784	26849003	Melanoma development has been linked to germline mutations in genes encoding cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 4 (CDK4), and melanocortin 1 receptor (MCIR) and has been implicated in somatic mutations in proto-oncogenes v-Raf murine sarcoma viral oncogene homolog B (BRAF), (NRAS), and v-kit Hardy-Zuckerman 4 feline sarcoma homolog (KIT) and tumor-suppressor genes CDKN2A, p53, and phosphatase and tensin homolog (PTEN).	('CDKN2A', 'Gene', (115, 121))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (257, 302))	('NRAS', 'Gene', (312, 316))	('NRAS', 'Gene', '18176', (312, 316))	('melanocortin 1 receptor', 'Gene', (162, 185))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('sarcoma', 'Phenotype', 'HP:0100242', (270, 277))	('sarcoma', 'Disease', 'MESH:D012509', (354, 361))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '12578', (77, 113))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (257, 302))	('mutations', 'Var', (49, 58))	('cyclin-dependent kinase 4', 'Gene', (124, 149))	('sarcoma', 'Disease', (354, 361))	('Melanoma', 'Disease', (0, 8))	('PTEN', 'Gene', '19211', (452, 456))	('kit', 'Gene', '16590', (325, 328))	('cyclin-dependent kinase 4', 'Gene', '12567', (124, 149))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('phosphatase and tensin homolog', 'Gene', '19211', (420, 450))	('mutations', 'Var', (228, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (354, 361))	('MCIR', 'Gene', (187, 191))	('melanocortin 1 receptor', 'Gene', '17199', (162, 185))	('linked', 'Reg', (30, 36))	('CDK4', 'Gene', (151, 155))	('implicated', 'Reg', (206, 216))	('p53', 'Gene', (411, 414))	('CDKN2A', 'Gene', '12578', (403, 409))	('tumor', 'Disease', (380, 385))	('CDKN2A', 'Gene', (403, 409))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (77, 113))	('sarcoma', 'Disease', 'MESH:D012509', (270, 277))	('tumor', 'Disease', 'MESH:D009369', (380, 385))	('sarcoma', 'Disease', (270, 277))	('kit', 'Gene', (325, 328))	('PTEN', 'Gene', (452, 456))	('KIT', 'Gene', (371, 374))	('CDK4', 'Gene', '12567', (151, 155))	('CDKN2A', 'Gene', '12578', (115, 121))	('MCIR', 'Gene', '17199', (187, 191))	('KIT', 'Gene', '16590', (371, 374))
573785	26849003	BRAF gene mutations are the most frequently detected mutations (identified in 60%-80% of patients).	('BRAF gene', 'Gene', (0, 9))	('mutations', 'Var', (10, 19))	('patients', 'Species', '9606', (89, 97))
573786	26849003	Among patients with melanoma ages 18 to 30 years, the BRAF valine to glutamic acid mutation at position 600 was identified in 38.7% of tumors and was associated with vertical growth phase and mild inflammatory infiltrate.	('valine to glutamic acid mutation at position 600', 'SUBSTITUTION', 'None', (59, 107))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('patients', 'Species', '9606', (6, 14))	('vertical growth phase', 'CPA', (166, 187))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('valine to glutamic acid mutation at position 600', 'Var', (59, 107))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))	('associated with', 'Reg', (150, 165))
573794	26849003	In most studies to date, survival of the tumors appears to depend on fusion genes (Supporting Table 1; see online supporting information).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('fusion genes', 'Var', (69, 81))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('depend', 'Reg', (59, 65))
573817	26849003	Having met its target accrual of 300 patients ages 16 to 39 years, C10403 represents a landmark effort in scientific collaboration among the participating NCI cooperative oncology groups and a significant step in increasing access to optimal ALL therapy for the full breadth of the AYA population.	('C10403', 'Var', (67, 73))	('ALL', 'Phenotype', 'HP:0006721', (242, 245))	('oncology', 'Phenotype', 'HP:0002664', (171, 179))	('met', 'Gene', (7, 10))	('patients', 'Species', '9606', (37, 45))	('met', 'Gene', '79811', (7, 10))
573885	26849003	Examples of diseases to target are ALL (to build on the C10403 experience and distinctive biology and therapeutic implications in AYA patients), soft tissue sarcomas, germ cell tumors, translocation-positive renal cell carcinoma, and Hodgkin lymphoma.	('patients', 'Species', '9606', (134, 142))	('sarcomas', 'Disease', 'MESH:D012509', (157, 165))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (208, 228))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('germ cell tumors', 'Phenotype', 'HP:0100728', (167, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcomas', 'Disease', (157, 165))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (145, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('Hodgkin lymphoma', 'Disease', (234, 250))	('translocation-positive', 'Var', (185, 207))	('renal cell carcinoma', 'Disease', (208, 228))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (208, 228))	('C10403', 'Var', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('lymphoma', 'Phenotype', 'HP:0002665', (242, 250))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (234, 250))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (234, 250))	('ALL', 'Phenotype', 'HP:0006721', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))
574028	30349510	Interestingly, KSHV lytic replication, virion production, and expression of late genes were downregulated in BC3-PMLKO cells and upregulated in BC3PML cells, compared to those in control or wild-type BC3 cells.	('KSHV lytic replication', 'CPA', (15, 37))	('upregulated', 'PosReg', (129, 140))	('expression', 'MPA', (62, 72))	('KSHV', 'Species', '37296', (15, 19))	('BC3-PMLKO', 'Var', (109, 118))	('virion production', 'CPA', (39, 56))	('KS', 'Phenotype', 'HP:0100726', (15, 17))	('downregulated', 'NegReg', (92, 105))
574058	30349510	In contrast, KSHV lytic DNA replication, extracellular virion production, and late gene expression were downregulated by PML knockout, but upregulated by exogenous PML.	('late gene', 'CPA', (78, 87))	('knockout', 'Var', (125, 133))	('upregulated', 'PosReg', (139, 150))	('KS', 'Phenotype', 'HP:0100726', (13, 15))	('PML', 'Gene', (121, 124))	('extracellular virion production', 'CPA', (41, 72))	('downregulated', 'NegReg', (104, 117))	('KSHV', 'Species', '37296', (13, 17))	('KSHV lytic DNA replication', 'CPA', (13, 39))
574067	30349510	Rabbit polyclonal anti-hDAXX (HPA008736) and anti-SP100 (HPA016707) Abs were purchased from Sigma-Aldrich.	('HPA016707', 'Var', (57, 66))	('HPA008736', 'Var', (30, 39))	('Rabbit', 'Species', '9986', (0, 6))
574070	30349510	An anti-Halo Tag  mouse monoclonal Ab (Cat# G9211, Promega, United States) was used to detect exogenous Halo-tagged PML.	('mouse', 'Species', '10090', (18, 23))	('Halo-tagged', 'Var', (104, 115))	('PML', 'Gene', (116, 119))
574113	30349510	By IFA, some cells still showed DAXX and SP100 dots in the nucleus (Supplementary Figures S1A,B), despite the previous finding showed that Daxx and SP100 failed to accumulate in the NBs in the absence of PML.	('Daxx', 'Gene', (139, 143))	('NBs', 'Chemical', 'MESH:D009556', (182, 185))	('Daxx', 'Gene', '1616', (139, 143))	('SP100', 'Var', (41, 46))
574120	30349510	These results revealed that the absence of PML in KSHV-infected BC3 cells also did not interfere with the latency, episome copy numbers or expression of LANA.	('KSHV-infected', 'Disease', (50, 63))	('LANA', 'Gene', (153, 157))	('episome copy numbers', 'CPA', (115, 135))	('absence', 'Var', (32, 39))	('LANA', 'Gene', '4961527', (153, 157))	('KSHV-infected', 'Disease', 'MESH:C537372', (50, 63))	('interfere', 'Reg', (87, 96))	('PML', 'Gene', (43, 46))	('latency', 'CPA', (106, 113))	('expression', 'MPA', (139, 149))	('KS', 'Phenotype', 'HP:0100726', (50, 52))
574131	30349510	In terms of lytic replication, PML knockout downregulated KSHV intracellular DNA replication by a factor of one-third compared to wild-type cells or control cells (Figure 5A).	('downregulated', 'NegReg', (44, 57))	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('KSHV', 'Species', '37296', (58, 62))	('lytic replication', 'MPA', (12, 29))	('knockout', 'Var', (35, 43))	('KSHV', 'Gene', (58, 62))	('intracellular DNA replication', 'MPA', (63, 92))	('PML', 'Gene', (31, 34))
574180	30349510	On the other hand, PML-NBs act as an effector of DNA damage, and the number of PML-NBs and expression level of PML increase in response to double-stranded DNA breaks.	('expression', 'MPA', (91, 101))	('double-stranded', 'Var', (139, 154))	('NBs', 'Chemical', 'MESH:D009556', (83, 86))	('increase', 'PosReg', (115, 123))	('response', 'MPA', (127, 135))	('NBs', 'Chemical', 'MESH:D009556', (23, 26))
574187	28488400	Kaposi sarcoma, oral malformations, mitral dysplasia, and scoliosis associated with 7q34-q36.3 heterozygous terminal deletion Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays.	('scoliosis', 'Phenotype', 'HP:0002650', (58, 67))	('developmental delay', 'Phenotype', 'HP:0001263', (222, 241))	('oral malformations', 'Disease', (16, 34))	('oral malformations', 'Disease', 'MESH:C557818', (16, 34))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (0, 14))	('scoliosis', 'Disease', 'MESH:D012600', (58, 67))	('developmental delays', 'Phenotype', 'HP:0001263', (222, 242))	('developmental delays', 'Disease', (222, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('Kaposi sarcoma', 'Disease', (0, 14))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (0, 14))	('congenital malformations', 'Disease', (193, 217))	('scoliosis', 'Disease', (58, 67))	('men', 'Species', '9606', (229, 232))	('associated', 'Reg', (68, 78))	('implicated', 'Reg', (173, 183))	('congenital malformations', 'Disease', 'MESH:D000013', (193, 217))	('mitral dysplasia', 'Disease', 'MESH:D008944', (36, 52))	('human', 'Species', '9606', (187, 192))	('7q34-q36.3', 'Var', (84, 94))	('mitral dysplasia', 'Disease', (36, 52))
574193	28488400	The meiotic pathway is conserved in humans and chromosomal crossover errors during meiosis can cause chromosomal deletions.	('chromosomal crossover errors', 'Var', (47, 75))	('cause', 'Reg', (95, 100))	('humans', 'Species', '9606', (36, 42))	('chromosomal deletions', 'Disease', (101, 122))
574194	28488400	Chromosomal macrodeletions and microdeletions leading to human phenotypes have been described affecting a wide range of syndromes including developmental anomalies and cancer predisposition.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('microdeletions', 'Var', (31, 45))	('developmental anomalies', 'Disease', (140, 163))	('developmental anomalies', 'Disease', 'MESH:D000014', (140, 163))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('affecting', 'Reg', (94, 103))	('cancer', 'Disease', (168, 174))	('human', 'Species', '9606', (57, 62))
574221	28488400	Comparative genomic hybridization (CGH) array of DNA extracted from lymphocytes in the patient performed on an Agilent 60K oligonucleotide microarray platform was significant for 7q34-q36.3 macrodeletion of 16 megabase pairs (Mbp).	('patient', 'Species', '9606', (87, 94))	('7q34-q36.3 macrodeletion', 'Var', (179, 203))	('oligonucleotide', 'Chemical', 'MESH:D009841', (123, 138))	('macrodeletion', 'Var', (190, 203))
574241	28488400	Recent studies have shown that classic KS of childhood can result from rare single-gene lesions, with mutations in WAS, IFNGR1, STIM1, and TNFRSF4.	('TNFRSF4', 'Gene', (139, 146))	('STIM1', 'Gene', (128, 133))	('IFNGR1', 'Gene', '3459', (120, 126))	('KS of childhood', 'Disease', (39, 54))	('WAS', 'Gene', (115, 118))	('TNFRSF4', 'Gene', '7293', (139, 146))	('IFNGR1', 'Gene', (120, 126))	('result from', 'Reg', (59, 70))	('mutations', 'Var', (102, 111))	('STIM1', 'Gene', '6786', (128, 133))	('child', 'Species', '9606', (45, 50))
574251	28488400	Microcephaly and developmental delay (intellectual, growth, or psychomotor) are the predominant phenotypes in terminal 7q deletion, reported to affect 17 out of the 24 patients.	('men', 'Species', '9606', (24, 27))	('Microcephaly', 'Disease', (0, 12))	('psychomotor', 'Disease', (63, 74))	('Microcephaly', 'Disease', 'MESH:D008831', (0, 12))	('developmental delay', 'Phenotype', 'HP:0001263', (17, 36))	('developmental delay', 'Disease', (17, 36))	('patients', 'Species', '9606', (168, 176))	('psychomotor', 'Disease', 'MESH:D011596', (63, 74))	('Microcephaly', 'Phenotype', 'HP:0000252', (0, 12))	('terminal 7q deletion', 'Var', (110, 130))
574254	28488400	Heterozygous mutation in HLXB9 homeobox gene located on 7q36.3 has been associated with sacral agenesis.	('associated', 'Reg', (72, 82))	('sacral agenesis', 'Phenotype', 'HP:0010305', (88, 103))	('sacral agenesis', 'Disease', (88, 103))	('Heterozygous mutation', 'Var', (0, 21))	('HLXB9', 'Gene', (25, 30))	('HLXB9', 'Gene', '3110', (25, 30))
574255	28488400	Currarino syndrome (OMIM #176450), a triad of sacral agenesis, presacral mass, and anorectal malformation, is an autosomal dominant condition caused by mutations in HLXB9, and displays reduced penetrance and variable expressivity even in the same kindred.	('Currarino syndrome', 'Disease', 'MESH:C536221', (0, 18))	('mutations', 'Var', (152, 161))	('anorectal malformation', 'Phenotype', 'HP:0012732', (83, 105))	('anorectal malformation', 'Disease', (83, 105))	('autosomal dominant condition', 'Disease', (113, 141))	('autosomal dominant condition', 'Disease', 'MESH:D017827', (113, 141))	('anorectal malformation', 'Disease', 'MESH:D000014', (83, 105))	('HLXB9', 'Gene', '3110', (165, 170))	('sacral agenesis', 'Phenotype', 'HP:0010305', (46, 61))	('HLXB9', 'Gene', (165, 170))	('caused by', 'Reg', (142, 151))	('Currarino syndrome', 'Disease', (0, 18))
574259	28488400	Cranial-facial anomalies and axial skeletal malformations are commonly described in patients with deleted 7q36-qter, and our patient's furrowed tongue and scoliosis, although not previously reported, may extend the phenotype spectrum of these organ systems due to variable expressivity.	('scoliosis', 'Phenotype', 'HP:0002650', (155, 164))	('patients', 'Species', '9606', (84, 92))	('axial skeletal malformations', 'Phenotype', 'HP:0009121', (29, 57))	('scoliosis', 'Disease', 'MESH:D012600', (155, 164))	('Cranial-facial anomalies and axial skeletal malformations', 'Disease', 'MESH:D000014', (0, 57))	('furrowed tongue', 'Phenotype', 'HP:0000221', (135, 150))	('scoliosis', 'Disease', (155, 164))	('skeletal malformations', 'Phenotype', 'HP:0000924', (35, 57))	('described', 'Reg', (71, 80))	('facial anomalies', 'Phenotype', 'HP:0000271', (8, 24))	('furrowed tongue', 'Disease', (135, 150))	('patient', 'Species', '9606', (125, 132))	('7q36-qter', 'Gene', (106, 115))	('patient', 'Species', '9606', (84, 91))	('deleted', 'Var', (98, 105))
574282	28549419	Expression studies at RNA and protein level revealed that high CXCR4 expression levels were associated with a decreased survival in EWS patients.	('EWS', 'Phenotype', 'HP:0012254', (132, 135))	('CXCR4', 'Gene', (63, 68))	('EWS', 'Gene', (132, 135))	('EWS', 'Gene', '2130', (132, 135))	('CXCR4', 'Gene', '7852', (63, 68))	('decreased', 'NegReg', (110, 119))	('patients', 'Species', '9606', (136, 144))	('high', 'Var', (58, 62))	('survival', 'MPA', (120, 128))
574318	28549419	CXCR4 cell membrane expression levels detected by MSAP-Ac-TZ14011 of five EWS cell lines with varying CXCR4 RNA expression levels (IARC-EW7, A673, L1062, 6647 and TC32) were quantified by flow cytometry.	('MSAP', 'Gene', (50, 54))	('MSAP', 'Gene', '10330', (50, 54))	('Ac-TZ14011', 'Chemical', '-', (55, 65))	('A673', 'Var', (141, 145))	('CXCR4', 'Gene', '7852', (102, 107))	('CXCR4', 'Gene', '7852', (0, 5))	('EWS', 'Phenotype', 'HP:0012254', (74, 77))	('EWS', 'Gene', '2130', (74, 77))	('EWS', 'Gene', (74, 77))	('TC32', 'CellLine', 'CVCL:7151', (163, 167))	('CXCR4', 'Gene', (102, 107))	('CXCR4', 'Gene', (0, 5))	('L1062', 'Var', (147, 152))
574319	28549419	Within the previously tested panel of 20 EWS cell lines, A673 and IARC-EW7 demonstrated very low CXCR4 RNA expression levels, L1062 demonstrated a moderate CXCR4 RNA expression level, and 6647 and TC32 demonstrated high CXCR4 RNA expression levels.	('CXCR4', 'Gene', (97, 102))	('CXCR4', 'Gene', '7852', (156, 161))	('CXCR4', 'Gene', (220, 225))	('CXCR4', 'Gene', '7852', (220, 225))	('CXCR4', 'Gene', (156, 161))	('6647', 'Var', (188, 192))	('TC32', 'CellLine', 'CVCL:7151', (197, 201))	('EWS', 'Phenotype', 'HP:0012254', (41, 44))	('CXCR4', 'Gene', '7852', (97, 102))	('low', 'NegReg', (93, 96))	('L1062', 'Var', (126, 131))	('EWS', 'Gene', (41, 44))	('EWS', 'Gene', '2130', (41, 44))
574325	28549419	In addition, in the MDA-MB-231 X4 cells a lower CXCR4 signal was detected when using ab2074 compared to MSAP-Ac-TZ14011 (Fig.	('lower', 'NegReg', (42, 47))	('MDA-MB-231 X4', 'CellLine', 'CVCL:0062', (20, 33))	('CXCR4', 'Gene', '7852', (48, 53))	('MSAP', 'Gene', (104, 108))	('CXCR4', 'Gene', (48, 53))	('MSAP', 'Gene', '10330', (104, 108))	('Ac-TZ14011', 'Chemical', '-', (109, 119))	('ab2074', 'Var', (85, 91))
574349	28549419	Both the N- and C-terminal ends of CXCR4 contain many potential post-translational modification sites and changes at these sites may influence antibody recognition, potentially explaining the various staining patterns observed in earlier studies.	('CXCR4', 'Gene', (35, 40))	('influence', 'Reg', (133, 142))	('changes', 'Var', (106, 113))	('post-translational modification', 'MPA', (64, 95))	('CXCR4', 'Gene', '7852', (35, 40))	('antibody recognition', 'Interaction', (143, 163))
574360	28549419	In the preclinical setting the in vivo biodistribution of Ac-TZ14011 analogues was shown to be identical to the distribution in immune-deficient nude mice bearing low CXCR expressing control tumors, with exemption of the uptake levels in the tumor.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('nude mice', 'Species', '10090', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('Ac-TZ14011', 'Gene', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', (242, 247))	('tumors', 'Disease', (191, 197))	('analogues', 'Var', (69, 78))	('Ac-TZ14011', 'Chemical', '-', (58, 68))
574404	33969719	Unlike PE, PPAS more commonly occupy the entire vascular lumen, expand the pulmonary artery, and extend into the extraluminal space.	('PPAS', 'Chemical', '-', (11, 15))	('expand', 'PosReg', (64, 70))	('PPAS', 'Var', (11, 15))	('pulmonary artery', 'CPA', (75, 91))	('PE', 'Phenotype', 'HP:0002204', (7, 9))
574425	33331996	This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('toxicity', 'Disease', 'MESH:D064420', (75, 83))	('toxicity', 'Disease', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', (219, 224))	('solid tumors', 'Disease', (213, 225))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('patients', 'Species', '9606', (199, 207))	('ASP3026', 'Chemical', 'MESH:C000595153', (143, 150))	('ASP3026', 'Var', (143, 150))	('solid tumors', 'Disease', 'MESH:D009369', (213, 225))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
574431	33331996	ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile.	('patients', 'Species', '9606', (61, 69))	('solid tumors', 'Disease', 'MESH:D009369', (75, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('therapeutic', 'MPA', (37, 48))	('ASP3026', 'Chemical', 'MESH:C000595153', (0, 7))	('ASP3026', 'Var', (0, 7))	('solid tumors', 'Disease', (75, 87))
574434	33331996	'ALKoma' is the collective term proposed for tumors carrying abnormal ALK as the essential growth driver.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('ALKoma', 'Disease', (1, 7))	('ALKoma', 'Disease', 'None', (1, 7))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('ALK', 'Gene', (70, 73))	('abnormal', 'Var', (61, 69))
574435	33331996	Fusion of the echinoderm microtubule-associated protein-like (EML4) and ALK genes results in the expression of EML4-ALK, which promotes cell malignancy.	('Fusion', 'Var', (0, 6))	('EML4-ALK', 'Gene', (111, 119))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('promotes', 'PosReg', (127, 135))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('malignancy', 'Disease', (141, 151))	('EML4', 'Gene', (62, 66))	('expression', 'MPA', (97, 107))	('ALK', 'Gene', (72, 75))
574443	33331996	ASP3026 is a novel, selective, orally available and ATP-competitive second-generation ALK TKI, with expected antitumor activity against various solid tumors including NSCLC, based on preclinical data of xenograft tumor-bearing mouse models expressing EML4-ALK.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('solid tumors', 'Disease', 'MESH:D009369', (144, 156))	('ATP', 'Chemical', 'MESH:D000255', (52, 55))	('ASP3026', 'Chemical', 'MESH:C000595153', (0, 7))	('ASP3026', 'Var', (0, 7))	('tumor', 'Disease', (113, 118))	('mouse', 'Species', '10090', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (213, 218))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('solid tumors', 'Disease', (144, 156))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('NSCLC', 'Disease', (167, 172))
574444	33331996	ASP3026 has inhibitory effects on multiple kinases (ALK, ROS proto-oncogene 1, receptor tyrosine kinase, tyrosine kinase non-receptor 1, tyrosine kinase non-receptor 2, receptor tyrosine kinase family, Src family tyrosine kinases, discoidin domain receptor tyrosine kinase 1, and fyn-related Src family tyrosine kinase), which differs from the kinase inhibition profile of crizotinib.	('ROS', 'Enzyme', (57, 60))	('fyn', 'Gene', '2534', (280, 283))	('inhibitory effects', 'MPA', (12, 30))	('Src', 'Gene', (292, 295))	('Src', 'Gene', '2534', (202, 205))	('discoidin domain receptor tyrosine kinase 1', 'Enzyme', (231, 274))	('tyrosine kinase non-receptor 2', 'Gene', '10188', (137, 167))	('ASP3026', 'Chemical', 'MESH:C000595153', (0, 7))	('ASP3026', 'Var', (0, 7))	('receptor tyrosine kinase', 'Enzyme', (79, 103))	('Src', 'Gene', (202, 205))	('Src', 'Gene', '2534', (292, 295))	('tyrosine kinase non-receptor 2', 'Gene', (137, 167))	('fyn', 'Gene', (280, 283))	('tyrosine kinase non-receptor 1', 'Gene', '8711', (105, 135))	('tyrosine kinase non-receptor 1', 'Gene', (105, 135))	('crizotinib', 'Chemical', 'MESH:D000077547', (373, 383))	('ROS', 'Chemical', '-', (57, 60))	('receptor tyrosine kinase family', 'Enzyme', (169, 200))
574445	33331996	ASP3026 can also inhibit cell division and survival in cancer-derived cell lines (EML4-ALK transfected 3T3 cells, NSCLC cell lines expressing EML4-ALK or solute carrier family 34 member 2-ROS and others) and has antitumor activity, including inhibition of growth and tumor regression, against cells expressing EML4-ALK with the L1196M mutation.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('L1196M', 'Mutation', 'rs1057519784', (328, 334))	('growth', 'CPA', (256, 262))	('ROS', 'Chemical', '-', (188, 191))	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('solute carrier family 34 member 2', 'Gene', (154, 187))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('ASP3026', 'Chemical', 'MESH:C000595153', (0, 7))	('cell division', 'CPA', (25, 38))	('ASP3026', 'Var', (0, 7))	('cancer', 'Disease', (55, 61))	('3T3', 'CellLine', 'CVCL:0594', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inhibition', 'NegReg', (242, 252))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('solute carrier family 34 member 2', 'Gene', '20531', (154, 187))	('L1196M', 'Var', (328, 334))	('NSCLC', 'Disease', (114, 119))	('inhibit', 'NegReg', (17, 24))	('tumor', 'Disease', (267, 272))	('cancer', 'Disease', 'MESH:D009369', (55, 61))
574446	33331996	These preclinical results suggested that patients with NSCLC, other solid tumors, and hematological malignancies expressing ALK and/or ROS fusion kinases, including EML4-ALK, could benefit from treatment with ASP3026, and provided the rationale for the clinical development of ASP3026.	('hematological malignancies', 'Phenotype', 'HP:0004377', (86, 112))	('men', 'Species', '9606', (199, 202))	('men', 'Species', '9606', (269, 272))	('solid tumors', 'Disease', (68, 80))	('malignancies', 'Disease', 'MESH:D009369', (100, 112))	('NSCLC', 'Disease', (55, 60))	('benefit', 'PosReg', (181, 188))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('patients', 'Species', '9606', (41, 49))	('malignancies', 'Disease', (100, 112))	('solid tumors', 'Disease', 'MESH:D009369', (68, 80))	('ROS', 'Chemical', '-', (135, 138))	('ASP3026', 'Chemical', 'MESH:C000595153', (209, 216))	('ASP3026', 'Var', (209, 216))	('ASP3026', 'Chemical', 'MESH:C000595153', (277, 284))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
574462	33331996	The pharmacokinetic parameters for ASP3026 were assessed based on the maximum plasma concentration (Cmax), area under the plasma concentration-time curve from the time of dosing to 24 h (AUC24h), time to maximal plasma concentration (tmax), apparent total clearance (CL/F), and urinary excretion.	('ASP3026', 'Var', (35, 42))	('met', 'Gene', '79811', (24, 27))	('F', 'Chemical', 'MESH:D005461', (270, 271))	('apparent total clearance', 'MPA', (241, 265))	('urinary', 'MPA', (278, 285))	('met', 'Gene', (24, 27))	('ASP3026', 'Chemical', 'MESH:C000595153', (35, 42))
574465	33331996	Antitumor activity of ASP3026 was measured by the overall response rate at each time point and the best overall response rate by Response Evaluation Criteria in Solid Tumors v1.1 based on the results of imaging examinations such as radiography, computed tomography, or magnetic resonance imaging performed on baseline, Day 28 of Cycles 1-4 and then every two cycles thereafter.	('tumor', 'Disease', (4, 9))	('Tumors', 'Disease', 'MESH:D009369', (167, 173))	('ASP3026', 'Chemical', 'MESH:C000595153', (22, 29))	('ASP3026', 'Var', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Tumors', 'Disease', (167, 173))	('Tumors', 'Phenotype', 'HP:0002664', (167, 173))
574471	33331996	If patients met the criteria to enter the next cycle, treatment with ASP3026 was continued for subsequent cycles.	('ASP3026', 'Chemical', 'MESH:C000595153', (69, 76))	('ASP3026', 'Var', (69, 76))	('met', 'Gene', '79811', (12, 15))	('patients', 'Species', '9606', (3, 11))	('met', 'Gene', (12, 15))	('men', 'Species', '9606', (59, 62))
574473	33331996	The RP2D of ASP3026 was employed as a daily dose in the expansion cohort of the study, and safety and tolerability were evaluated.	('RP2', 'Gene', '6102', (4, 7))	('ASP3026', 'Chemical', 'MESH:C000595153', (12, 19))	('ASP3026', 'Var', (12, 19))	('RP2', 'Gene', (4, 7))
574484	33331996	Twenty-nine patients were registered and assigned to the different daily dose levels of ASP3026 in the escalation cohorts (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and the expansion cohort (200 mg, n = 6) (Fig.	('ASP3026', 'Gene', (88, 95))	('patients', 'Species', '9606', (12, 20))	('25', 'Var', (123, 125))	('F', 'Chemical', 'MESH:D005461', (255, 256))	('ASP3026', 'Chemical', 'MESH:C000595153', (88, 95))
574492	33331996	In the expansion cohort, all six patients had been previously treated using an ALK inhibitor, including crizotinib (n = 3), crizotinib and ceritinib (n = 1), ceritinib and alectinib (n = 1), and alectinib (n = 1).	('alectinib', 'Chemical', 'MESH:C582670', (172, 181))	('patients', 'Species', '9606', (33, 41))	('ceritinib', 'Chemical', 'MESH:C586847', (158, 167))	('crizotinib', 'Var', (124, 134))	('ceritinib', 'Chemical', 'MESH:C586847', (139, 148))	('alectinib', 'Chemical', 'MESH:C582670', (195, 204))	('ALK', 'Enzyme', (79, 82))	('crizotinib', 'Chemical', 'MESH:D000077547', (104, 114))	('crizotinib', 'Chemical', 'MESH:D000077547', (124, 134))
574498	33331996	Finally, EGFR gene analysis of all 29 patients showed that 11 patients were characterized as wild type while four patients were positive for an EGFR mutation and the remaining 14 patients were of unknown status.	('EGFR', 'Gene', (144, 148))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('F', 'Chemical', 'MESH:D005461', (11, 12))	('patients', 'Species', '9606', (62, 70))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('patients', 'Species', '9606', (179, 187))	('F', 'Chemical', 'MESH:D005461', (146, 147))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (114, 122))	('EGFR', 'Gene', '1956', (144, 148))	('mutation', 'Var', (149, 157))
574499	33331996	Two of the four patients with EGFR mutations had been treated with an EGFR-TKI, and in both cases, EGFR-TKI treatment was followed by other treatments.	('EGFR', 'Gene', (99, 103))	('EGFR', 'Gene', (30, 34))	('men', 'Species', '9606', (145, 148))	('EGFR', 'Gene', '1956', (70, 74))	('patients', 'Species', '9606', (16, 24))	('EGFR', 'Gene', (70, 74))	('men', 'Species', '9606', (113, 116))	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', '1956', (30, 34))	('mutations', 'Var', (35, 44))
574511	33331996	After conducting the dose escalation assessments (25-325 mg) and based on the DLTs found, the MTD and RP2D of ASP3026 for Japanese patients was set at 200 mg.	('patients', 'Species', '9606', (131, 139))	('ASP3026', 'Chemical', 'MESH:C000595153', (110, 117))	('ASP3026', 'Var', (110, 117))	('RP2', 'Gene', (102, 105))	('RP2', 'Gene', '6102', (102, 105))	('men', 'Species', '9606', (43, 46))
574522	33331996	Of note, two patients who were confirmed to have EGFR mutations had previously been treated with EGFR-TKIs, but neither of them presented hepatic function abnormalities/hepatic dysfunction during treatment with ASP3026.	('EGFR', 'Gene', '1956', (49, 53))	('hepatic function abnormal', 'Phenotype', 'HP:0002910', (138, 163))	('hepatic function abnormalities/hepatic dysfunction', 'Disease', 'MESH:D008107', (138, 188))	('EGFR', 'Gene', '1956', (97, 101))	('hepatic function abnormalities/hepatic dysfunction', 'Disease', (138, 188))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (54, 63))	('EGFR', 'Gene', (49, 53))	('ASP3026', 'Chemical', 'MESH:C000595153', (211, 218))	('men', 'Species', '9606', (201, 204))	('hepatic dysfunction', 'Phenotype', 'HP:0001410', (169, 188))	('EGFR', 'Gene', (97, 101))	('hepatic function abnormalities', 'Phenotype', 'HP:0002910', (138, 168))
574527	33331996	The urinary excretion was low for ASP3026 at all dose levels.	('ASP3026', 'Chemical', 'MESH:C000595153', (34, 41))	('ASP3026', 'Var', (34, 41))	('low', 'NegReg', (26, 29))	('urinary excretion', 'MPA', (4, 21))
574532	33331996	At the RP2D of 200-mg daily dose of ASP3026, none of the patients in either the dose escalation cohort (n = 3) or the expansion cohort (n = 6) consisting of patients with confirmed ALKr and who had PD after previous treatment with an ALK inhibitor (these included crizotinib, ceritinib, and alectinib, and one patient had received two ALK inhibitors previously) achieved PR in Cycle 1.	('PD', 'Disease', 'MESH:D010300', (198, 200))	('patient', 'Species', '9606', (157, 164))	('patient', 'Species', '9606', (57, 64))	('patients', 'Species', '9606', (57, 65))	('ceritinib', 'Chemical', 'MESH:C586847', (276, 285))	('men', 'Species', '9606', (221, 224))	('ASP3026', 'Chemical', 'MESH:C000595153', (36, 43))	('patients', 'Species', '9606', (157, 165))	('ASP3026', 'Var', (36, 43))	('crizotinib', 'Chemical', 'MESH:D000077547', (264, 274))	('RP2', 'Gene', (7, 10))	('alectinib', 'Chemical', 'MESH:C582670', (291, 300))	('patient', 'Species', '9606', (310, 317))	('RP2', 'Gene', '6102', (7, 10))
574536	33331996	In comparison, the MTD and RP2D of ASP3026 in the study in the US was found to be 525 mg daily.	('ASP3026', 'Var', (35, 42))	('RP2', 'Gene', '6102', (27, 30))	('ASP3026', 'Chemical', 'MESH:C000595153', (35, 42))	('RP2', 'Gene', (27, 30))
574546	33331996	In terms of antitumor activity, one patient with Ewing sarcoma receiving ASP3026 75 mg and one with inflammatory myofibroblastic tumor with ALKr receiving 125 mg in the dose escalation cohorts achieved best overall PR across all treatment cycles.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (49, 62))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (113, 134))	('ASP3026 75 mg', 'Var', (73, 86))	('ASP3026', 'Chemical', 'MESH:C000595153', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (100, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (16, 21))	('inflammatory myofibroblastic tumor', 'Disease', (100, 134))	('Ewing sarcoma', 'Disease', (49, 62))	('tumor', 'Disease', (129, 134))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (49, 62))	('patient', 'Species', '9606', (36, 43))	('men', 'Species', '9606', (234, 237))
574549	33331996	In that case, the antitumor activity of ASP3026 is attributed to its effect on the RANBP2-ALKr protein product.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('RANBP2', 'Gene', (83, 89))	('ASP3026', 'Chemical', 'MESH:C000595153', (40, 47))	('ASP3026', 'Var', (40, 47))	('RANBP2', 'Gene', '5903', (83, 89))	('tumor', 'Disease', (22, 27))
574559	33331996	Our study is the first to investigate the safety, PK, and antitumor activity of ASP3026 in Japanese patients with advanced solid tumors, and we have established the MTD of ASP3026 in Japanese patients with advanced solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('patients', 'Species', '9606', (100, 108))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('solid tumors', 'Disease', (123, 135))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('ASP3026', 'Gene', (80, 87))	('tumor', 'Disease', (221, 226))	('ASP3026', 'Chemical', 'MESH:C000595153', (80, 87))	('patients', 'Species', '9606', (192, 200))	('solid tumors', 'Disease', 'MESH:D009369', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ASP3026', 'Chemical', 'MESH:C000595153', (172, 179))	('solid tumors', 'Disease', (215, 227))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('ASP3026', 'Var', (172, 179))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
574560	33331996	Based on the present results, ASP3026 may be clinically active in patients with Ewing sarcoma and IMT with ALKr, in addition to NSCLC, as shown in the US study.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('NSCLC', 'Disease', (128, 133))	('ASP3026', 'Chemical', 'MESH:C000595153', (30, 37))	('ASP3026', 'Var', (30, 37))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('Ewing sarcoma', 'Disease', (80, 93))	('patients', 'Species', '9606', (66, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
574561	33331996	In conclusion, ASP3026 at a dose of 200 mg has a potential for therapeutic benefit for Japanese patients with solid tumors, with a tolerable safety profile.	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('solid tumors', 'Disease', (110, 122))	('ASP3026', 'Chemical', 'MESH:C000595153', (15, 22))	('ASP3026', 'Var', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('patients', 'Species', '9606', (96, 104))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
574583	31777359	The storiform areas showed positive for CD35, S-100, vemitin, weakly positive to CD21 and CD68.	('CD68', 'Gene', (90, 94))	('CD68', 'Gene', '968', (90, 94))	('CD35', 'Gene', '1378', (40, 44))	('S-100', 'Var', (46, 51))	('CD35', 'Gene', (40, 44))
574678	25884155	Statistical assumptions for the 3 most frequent histological subtypes (liposarcoma, leiomyosarcoma and other sarcomas) are: PFS0 = 1.6, PFS1 = 4.6, alpha = 0.1 (one-sided) and power (1-beta) = 0.95, the sample size is 50 patients per stratum (30 expected events).	('leiomyosarcoma', 'Disease', (84, 98))	('patients', 'Species', '9606', (221, 229))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (84, 98))	('liposarcoma', 'Phenotype', 'HP:0012034', (71, 82))	('liposarcoma', 'Disease', (71, 82))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (84, 98))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('liposarcoma', 'Disease', 'MESH:D008080', (71, 82))	('PFS1', 'Var', (136, 140))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcomas', 'Disease', (109, 117))	('PFS0', 'Var', (124, 128))
574750	24876317	Other recognized factors are chronic lymphoedema, exposure to vinyl chloride and artificial implants as well as Li-Fraumeni syndrome through a p53 mutation.	('p53', 'Gene', '7157', (143, 146))	('vinyl chloride', 'Chemical', 'MESH:D014752', (62, 76))	('mutation', 'Var', (147, 155))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (112, 132))	('chronic lymphoedema', 'Disease', 'MESH:D006505', (29, 48))	('Li-Fraumeni syndrome', 'Disease', (112, 132))	('p53', 'Gene', (143, 146))	('lymphoedema', 'Phenotype', 'HP:0001004', (37, 48))	('chronic lymphoedema', 'Disease', (29, 48))
574884	23983648	These tumors also have known chromosomal translocations, which offer potential for specific targeted therapeutic regimens.	('chromosomal translocations', 'Var', (29, 55))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
574943	23983648	Despite no apparent impact on overall patient survival, the presence of residual microscopic disease is a risk factor for local recurrence, and risk of recurrence is higher than in patients managed by primary wide excision.	('microscopic disease', 'Var', (81, 100))	('local recurrence', 'CPA', (122, 138))	('patient', 'Species', '9606', (181, 188))	('patient', 'Species', '9606', (38, 45))	('patients', 'Species', '9606', (181, 189))
574967	23171444	The results of these studies show that IL-12 based gene therapy elicits a good antitumor effect on spontaneously occurring tumors in large animals, while being safe and well tolerated by the animals.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('gene therapy', 'Var', (51, 63))	('tumor', 'Disease', (83, 88))	('IL-12', 'Gene', (39, 44))	('IL-12', 'Gene', '64546', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
574970	23171444	In the case of genetic disease caused by mutation in a specific gene, the therapeutic effect of gene therapy is usually achieved by the delivery of a functional gene into target cells or tissue.	('mutation', 'Var', (41, 49))	('genetic disease', 'Disease', 'MESH:D030342', (15, 30))	('genetic disease', 'Disease', (15, 30))	('caused by', 'Reg', (31, 40))
575029	23171444	Local response to the therapy was also confirmed with histological evaluation of the treated tumors, which revealed significant peritumoral infiltration with both CD4+ and CD8+ lymphocytes, which was not observed in untreated tumors.	('CD8+', 'Var', (172, 176))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (132, 137))	('CD4+', 'Var', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Disease', (93, 99))	('tumor', 'Disease', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
575039	23171444	IL-12 gene therapy elicited regression in tumor size, with the mean volume of treated tumors decreasing to approximately 80% of the baseline value.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('IL-12', 'Gene', '64546', (0, 5))	('tumor', 'Disease', (42, 47))	('gene therapy', 'Var', (6, 18))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('decreasing', 'NegReg', (93, 103))	('IL-12', 'Gene', (0, 5))
575048	23171444	Another palliative approach to tumor-bearing dogs employed gene therapy with gene encoding growth hormone releasing hormone in order to ameliorate tumor cachexia and improve the general clinical status of patients.	('growth hormone releasing hormone', 'Gene', '485863', (91, 123))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('patients', 'Species', '9606', (205, 213))	('tumor cachexia', 'Disease', 'MESH:D002100', (147, 161))	('growth hormone releasing hormone', 'Gene', (91, 123))	('tumor cachexia', 'Disease', (147, 161))	('ameliorate', 'PosReg', (136, 146))	('gene therapy', 'Var', (59, 71))	('gene', 'Var', (77, 81))	('tumor', 'Disease', (31, 36))	('dogs', 'Species', '9615', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('improve', 'PosReg', (166, 173))	('general clinical status', 'CPA', (178, 201))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cachexia', 'Phenotype', 'HP:0004326', (153, 161))
575066	23171444	IL-12 EGT also had a pronounced systemic effect on distant untreated tumors and induced long-term resistance to tumor regrowth after re-challenge with subcutaneous injection of the same tumor cells.	('induced', 'Reg', (80, 87))	('IL-12', 'Gene', '64546', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('systemic', 'MPA', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (112, 117))	('EGT', 'Chemical', '-', (6, 9))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('EGT', 'Var', (6, 9))	('IL-12', 'Gene', (0, 5))
575073	23171444	The pivotal role of lymphocytic infiltration after intratumoral IL-12 EGT has been demonstrated in preclinical studies, in which no antitumor effect of such therapy was achieved in athymic mice deficient in T cells, compared to immunocompetent mice.	('IL-12', 'Gene', '64546', (64, 69))	('EGT', 'Chemical', '-', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mice', 'Species', '10090', (244, 248))	('mice', 'Species', '10090', (189, 193))	('EGT', 'Var', (70, 73))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('lymphocytic', 'CPA', (20, 31))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('IL-12', 'Gene', (64, 69))
575090	23171444	Such intratumoral cytokine production is not only important for a direct local antitumor effect of EGT, but more and more data is presented that sufficient intratumoral production of transgene can also result in systemic shedding of encoded product, thus expanding local therapy to the systemic level.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('transgene', 'Var', (183, 192))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('EGT', 'Chemical', '-', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('systemic shedding', 'MPA', (212, 229))	('result in', 'Reg', (202, 211))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (161, 166))
575095	23171444	EGT in both of these studies resulted in systemic release of IL-12 and induction of an IFN-gamma response, since both cytokines were detected in blood samples of the treated dogs.	('resulted in', 'Reg', (29, 40))	('IFN-gamma response', 'MPA', (87, 105))	('dogs', 'Species', '9615', (174, 178))	('EGT', 'Chemical', '-', (0, 3))	('IL-12', 'Gene', (61, 66))	('induction', 'Reg', (71, 80))	('IL-12', 'Gene', '64546', (61, 66))	('EGT', 'Var', (0, 3))	('systemic release', 'MPA', (41, 57))
575118	23171444	The results of the melanoma study showed that intratumoral EGT did not cause any clinically detectable adverse effects and did not affect laboratory parameters in the treated animals.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('EGT', 'Var', (59, 62))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('tumor', 'Disease', (51, 56))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('EGT', 'Chemical', '-', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
575145	20165867	Recent studies in model systems as well as on human tumors have provided some answers to these questions and undoubtedly, in the years to come, much of the secrets of mesenchymal stem cells, how they differentiate and how dysregulation of proliferation and differentiation in this system leads to which type of sarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('differentiation', 'CPA', (257, 272))	('dysregulation', 'Var', (222, 235))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (311, 318))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('sarcoma', 'Disease', 'MESH:D012509', (311, 318))	('human', 'Species', '9606', (46, 51))	('sarcoma', 'Disease', (311, 318))	('leads to', 'Reg', (288, 296))
575148	20165867	Some others are characterized by specific somatic mutations (e.g., KIT and platelet-derived growth factor receptor alpha in gastrointestinal stromal tumor (GIST)) or specific amplifications (e.g., MDM2 and CDK4 amplification in the well-differentiated/dedifferentiated liposarcoma category).	('MDM2', 'Gene', '4193', (197, 201))	('liposarcoma', 'Phenotype', 'HP:0012034', (269, 280))	('MDM2', 'Gene', (197, 201))	('gastrointestinal stromal tumor', 'Disease', (124, 154))	('KIT', 'Gene', (67, 70))	('amplification', 'Var', (211, 224))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (75, 120))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (124, 154))	('platelet-derived growth factor receptor alpha', 'Gene', (75, 120))	('CDK4', 'Gene', (206, 210))	('liposarcoma', 'Disease', (269, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (273, 280))	('CDK4', 'Gene', '1019', (206, 210))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (124, 154))	('liposarcoma', 'Disease', 'MESH:D008080', (269, 280))
575391	23666473	In adult GIST patients, 90% of tumors carry mutations in KIT or PDGFR, and a small fraction possesses B-RAF mutations.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('B-RAF', 'Gene', '673', (102, 107))	('tumors', 'Disease', (31, 37))	('B-RAF', 'Gene', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('PDGFR', 'Gene', (64, 69))	('mutations', 'Var', (44, 53))	('PDGFR', 'Gene', '5159', (64, 69))	('KIT', 'Gene', (57, 60))	('patients', 'Species', '9606', (14, 22))	('GIST', 'Phenotype', 'HP:0100723', (9, 13))
575437	23666473	Phase II trials are ongoing in several neglected histologic sarcoma subtypes including imatinib/sunitinib refractory GIST (NCT01524848), well differentiated/dedifferentiated and myxoid/round cell liposarcomas (NCT01692496, NCT01506596), uterine sarcomas (NCT01247571), angiosarcomas (NCT01462630), DFSP (NCT01059656), and bone sarcomas (NCT0179303, NCT01330966).	('imatinib', 'Chemical', 'MESH:D000068877', (87, 95))	('NCT01506596', 'Var', (223, 234))	('NCT01462630', 'Var', (284, 295))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (60, 76))	('sarcoma subtypes', 'Disease', (60, 76))	('sarcomas', 'Disease', 'MESH:D012509', (245, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (327, 334))	('liposarcomas', 'Phenotype', 'HP:0012034', (196, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (245, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('GIST', 'Phenotype', 'HP:0100723', (117, 121))	('sarcomas', 'Disease', (245, 253))	('sarcomas', 'Disease', 'MESH:D012509', (274, 282))	('sarcomas', 'Phenotype', 'HP:0100242', (274, 282))	('liposarcomas', 'Disease', (196, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))	('angiosarcomas', 'Disease', 'MESH:D006394', (269, 282))	('sarcomas', 'Disease', (274, 282))	('NCT01692496', 'Var', (210, 221))	('DFSP', 'Disease', 'MESH:D018223', (298, 302))	('angiosarcoma', 'Phenotype', 'HP:0200058', (269, 281))	('NCT01247571', 'Var', (255, 266))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (274, 281))	('DFSP', 'Disease', (298, 302))	('NCT0179303', 'Var', (337, 347))	('angiosarcomas', 'Phenotype', 'HP:0200058', (269, 282))	('bone sarcomas', 'Disease', 'MESH:D001847', (322, 335))	('bone sarcomas', 'Disease', (322, 335))	('sarcomas', 'Disease', 'MESH:D012509', (327, 335))	('NCT01524848', 'Var', (123, 134))	('NCT01059656', 'Var', (304, 315))	('sarcomas', 'Disease', 'MESH:D012509', (200, 208))	('liposarcomas', 'Disease', 'MESH:D008080', (196, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (327, 335))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('sarcomas', 'Disease', (327, 335))	('angiosarcomas', 'Disease', (269, 282))	('bone sarcomas', 'Phenotype', 'HP:0002669', (322, 335))	('sarcomas', 'Disease', (200, 208))
575439	23666473	Several sarcoma-specific trials are incorporating pazopanib in the neoadjuvant and metastatic setting either alone or in combination with chemotherapy such as gemcitabine, docetaxel, and ixabepilone (NCT01446809, NCT01418001, NCT01543802, NCT01719302, NCT01012362).	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('ixabepilone', 'Chemical', 'MESH:C430592', (187, 198))	('docetaxel', 'Chemical', 'MESH:D000077143', (172, 181))	('sarcoma', 'Disease', (8, 15))	('gemcitabine', 'Chemical', 'MESH:C056507', (159, 170))	('NCT01719302', 'Var', (239, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('NCT01418001', 'Var', (213, 224))	('NCT01543802', 'Var', (226, 237))	('pazopanib', 'Chemical', 'MESH:C516667', (50, 59))	('NCT01446809', 'Var', (200, 211))	('NCT01012362', 'Var', (252, 263))
575440	23666473	Other interesting options for refractory sarcoma patients include ongoing phase I studies combining pazopanib with other targeted therapies inhibiting mammalian target of rapamycin (NCT01072890), MEK (NCT0148554), and c-MET (NCT01468922).	('sarcoma', 'Disease', (41, 48))	('c-MET', 'Gene', '4233', (218, 223))	('NCT01468922', 'Var', (225, 236))	('inhibiting', 'NegReg', (140, 150))	('MEK', 'Gene', (196, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('NCT01072890', 'Var', (182, 193))	('MEK', 'Gene', '5609', (196, 199))	('c-MET', 'Gene', (218, 223))	('mammalian target of rapamycin', 'Gene', '2475', (151, 180))	('mammalian target of rapamycin', 'Gene', (151, 180))	('pazopanib', 'Chemical', 'MESH:C516667', (100, 109))	('NCT0148554', 'Var', (201, 211))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('patients', 'Species', '9606', (49, 57))
575447	23666473	Aberrations in expression of key pazopanib targets, such as VEGFR and PDGFR, are frequently encountered in preclinical studies of sarcomas.	('PDGFR', 'Gene', (70, 75))	('PDGFR', 'Gene', '5159', (70, 75))	('sarcomas', 'Disease', (130, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('VEGFR', 'Gene', (60, 65))	('pazopanib', 'Chemical', 'MESH:C516667', (33, 42))	('expression', 'MPA', (15, 25))	('sarcomas', 'Disease', 'MESH:D012509', (130, 138))	('Aberrations', 'Var', (0, 11))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('VEGFR', 'Gene', '3791', (60, 65))
575455	24715974	Fluorescent in-situ hybridization (FISH) was positive for SS18 (SYT) gene rearrangement on chromosome 18q11, substantiating the diagnosis.	('SYT', 'Gene', '6760', (64, 67))	('positive', 'Reg', (45, 53))	('SS18', 'Gene', '6760', (58, 62))	('SYT', 'Gene', (64, 67))	('rearrangement', 'Var', (74, 87))	('SS18', 'Gene', (58, 62))
575531	26780857	Throughout this document, statements may be followed by a qualifier [EB1], [EB2], [EB3] or [EB4] reflecting an 'evidence base' of category 1, 2, 3 or 4, respectively.	('EB3', 'Gene', (83, 86))	('EB3', 'Gene', '22924', (83, 86))	('EB2', 'Gene', (76, 79))	('EB2', 'Gene', '10982', (76, 79))	('[EB4]', 'Var', (91, 96))
575630	26780857	Initial studies showed that the median survival time of dogs with grade II-IV melanoma increased to 389 days (from an expected survival of 90 days) (Bergman et al.	('increased', 'PosReg', (87, 96))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('grade II-IV', 'Var', (66, 77))	('melanoma', 'Disease', (78, 86))	('dogs', 'Species', '9615', (56, 60))
575663	26780857	The VGG is aware that in some parts of the world, there remains a significant prevalence of FIV seropositivity and/or infection (Bennett et al.	('FIV', 'Species', '11673', (92, 95))	('seropositivity', 'Var', (96, 110))	('FIV', 'Disease', (92, 95))	('infection', 'Disease', (118, 127))	('infection', 'Disease', 'MESH:D007239', (118, 127))
575823	26780857	While most cases of feline panleukopenia are caused by infection with FPV, variants of canine parvovirus (CPV-2a, CPV-2b and CPV-2c) have emerged that infect cats and may cause disease (Decaro & Buonavoglia 2012).	('panleukopenia', 'Disease', 'MESH:D005254', (27, 40))	('cause', 'Reg', (171, 176))	('FPV', 'Species', '10785', (70, 73))	('feline', 'Disease', (20, 26))	('disease', 'Disease', (177, 184))	('cats', 'Species', '9685', (158, 162))	('panleukopenia', 'Disease', (27, 40))	('CPV-2', 'Species', '246878', (125, 130))	('infect', 'Reg', (151, 157))	('canine parvovirus', 'Species', '10788', (87, 104))	('CPV-2c', 'Gene', (125, 131))	('infection', 'Disease', (55, 64))	('CPV-2', 'Species', '246878', (114, 119))	('infection', 'Disease', 'MESH:D007239', (55, 64))	('CPV-2a', 'Gene', (106, 112))	('variants', 'Var', (75, 83))	('caused by', 'Reg', (45, 54))	('CPV-2', 'Species', '246878', (106, 111))
575834	26780857	MLV FPV vaccines should not be used in severely immunosuppressed individuals - although the risk appears small, with severe immunosuppression (for example with clinical FIV or FeLV infection or with the use of highly immunosuppressive drugs) failure to control viral replication could potentially lead to clinical signs after vaccination.	('lead to', 'Reg', (297, 304))	('severe immunosuppression', 'Phenotype', 'HP:0004430', (117, 141))	('FIV', 'Species', '11673', (169, 172))	('FeLV infection', 'Disease', (176, 190))	('MLV', 'Chemical', '-', (0, 3))	('FPV', 'Species', '10785', (4, 7))	('clinical', 'Disease', (305, 313))	('failure', 'Var', (242, 249))	('FeLV infection', 'Disease', 'MESH:D007239', (176, 190))
575841	26780857	Modified Live Virus (MLV) Vaccines: These preparations contain attenuated FHV-1 (feline rhinotracheitis virus, occurring as a single serotype) at various titres, without adjuvant.	('rhinotracheitis virus', 'Disease', 'MESH:D007241', (88, 109))	('attenuated', 'Var', (63, 73))	('FHV-1', 'Gene', (74, 79))	('MLV', 'Chemical', '-', (21, 24))	('FHV-1', 'Species', '10334', (74, 79))	('rhinotracheitis virus', 'Disease', (88, 109))
575957	26780857	Do the current CPV-2 vaccines provide protection from disease caused by the new variant CPV-2c?	('CPV-2c', 'Gene', (88, 94))	('CPV-2', 'Species', '246878', (15, 20))	('CPV-2', 'Species', '246878', (88, 93))	('variant', 'Var', (80, 87))
575959	26780857	antibody response), that provides long term (4 or more years) protection from all current CPV-2 variants (2a, 2b, and 2c) when the dogs are challenged.	('CPV-2', 'Gene', (90, 95))	('dogs', 'Species', '9615', (131, 135))	('variants', 'Var', (96, 104))	('CPV-2 variant', 'Species', '246878', (90, 103))
575993	26780857	Variant strains of this virus have been reported to cause severe systemic disease in adult dogs and puppies in various parts of the world, but it is unclear whether the available vaccines would protect against these variants.	('dogs', 'Species', '9615', (91, 95))	('systemic disease', 'Disease', 'MESH:D034721', (65, 81))	('cause', 'Reg', (52, 57))	('systemic disease', 'Disease', (65, 81))	('Variant', 'Var', (0, 7))
576055	26780857	The vaccine can cause a severe local reaction and may even kill the pet by causing systemic disease (e.g.	('local reaction', 'CPA', (31, 45))	('vaccine', 'Var', (4, 11))	('systemic disease', 'Disease', 'MESH:D034721', (83, 99))	('causing', 'Reg', (75, 82))	('systemic disease', 'Disease', (83, 99))	('cause', 'Reg', (16, 21))
576258	32071657	All things considered, attained evidences suggest: high mean corpuscular volume, high lactate dehydrogenase was significant in the laboratory review of this study with no drop in hematocrit.	('drop in hematocrit', 'Phenotype', 'HP:0031851', (171, 189))	('high', 'Var', (81, 85))	('mean corpuscular volume', 'MPA', (56, 79))	('lactate', 'Chemical', 'MESH:D019344', (86, 93))	('high lactate dehydrogenase', 'Phenotype', 'HP:0025435', (81, 107))
576439	21717526	Consistent t(1;10) with Rearrangements of TGFBR3 and MGEA5 in both Myxoinflammatory Fibroblastic Sarcoma and Hemosiderotic Fibrolipomatous Tumor Despite their shared predilection for superficial soft tissue of distal extremities and frequent local recurrences, myxoinflammatory fibroblastic sarcoma (MIFS) and hemosiderotic fibrolipomatous tumor (HFLT) have distinct morphologic appearances.	('Rearrangements', 'Var', (24, 38))	('TGFBR3', 'Gene', (42, 48))	('myxoinflammatory fibroblastic sarcoma', 'Disease', (261, 298))	('hemosiderotic fibrolipomatous tumor', 'Disease', 'MESH:C565226', (310, 345))	('Sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('myxoinflammatory fibroblastic sarcoma', 'Disease', 'MESH:D012509', (261, 298))	('Tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('lipomatous tumor', 'Phenotype', 'HP:0012031', (329, 345))	('hemosiderotic fibrolipomatous tumor', 'Disease', (310, 345))	('sarcoma', 'Phenotype', 'HP:0100242', (291, 298))	('Myxoinflammatory Fibroblastic Sarcoma and Hemosiderotic Fibrolipomatous Tumor', 'Disease', 'MESH:D012509', (67, 144))
576440	21717526	Recent studies have identified an identical t(1;10)(p22;q24) in 5 cases of MIFS and 2 of HFLT, as well as common amplifications on 3p11-12.	('t(1;10)(p22;q24', 'Var', (44, 59))	('t(1;10)(p22;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (44, 60))	('MIFS', 'Disease', (75, 79))
576441	21717526	FISH analysis for rearrangements of TGFBR3 on 1p22 and of MGEA5 on 10q24 was performed in all cases, while the status of VGLL3 gene amplification on 3p12.1 was investigated in 12 cases.	('VGLL3', 'Gene', (121, 126))	('rearrangements', 'Var', (18, 32))	('VGLL3', 'Gene', '389136', (121, 126))	('TGFBR3', 'Gene', (36, 42))	('MGEA5', 'Chemical', '-', (58, 63))
576442	21717526	Overall 83% of cases showed rearrangements in both TGFBR3 and MGEA5.	('TGFBR3', 'Gene', (51, 57))	('MGEA5', 'Gene', (62, 67))	('MGEA5', 'Chemical', '-', (62, 67))	('rearrangements', 'Var', (28, 42))
576446	21717526	FISH analysis for TGFBR3 and MGEA5 rearrangements can be applied as a reliable diagnostic molecular test when confronted with limited material or a challenging diagnosis.	('TGFBR3', 'Gene', (18, 24))	('MGEA5', 'Chemical', '-', (29, 34))	('rearrangements', 'Var', (35, 49))
576454	21717526	A recurrent t(1;10)(p22;q24) has been identified in 5 cases of MIFS and 2 cases of HFLT.	('t(1;10)(p22;q24', 'Var', (12, 27))	('MIFS', 'Disease', (63, 67))	('t(1;10)(p22;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (12, 28))
576457	21717526	Despite that both of these tumors have the same translocation, non-random chromosome 3 abnormalities or amplifications of chromosome 3p11-12 material, in the form of ring and markers chromosomes, have been reported as a common event in MIFS, but not in HFLT.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('amplifications', 'Var', (104, 118))	('MIFS', 'Disease', (236, 240))
576461	21717526	Accordingly, we also tested 3 PHAT cases for TGFBR3 and MGEA5 gene rearrangements, as well as for VGLL3 amplifications by FISH.	('MGEA5', 'Gene', (56, 61))	('MGEA5', 'Chemical', '-', (56, 61))	('TGFBR3', 'Gene', (45, 51))	('VGLL3', 'Gene', (98, 103))	('tested', 'Reg', (21, 27))	('rearrangements', 'Var', (67, 81))	('VGLL3', 'Gene', '389136', (98, 103))
576483	21717526	The karyotype from the second tumor with mixed morphology showed several aberrations, including an unbalanced translocation involving chromosomes 1 and 3, der(1)t(1;3)(p11;q11), a balanced t(6;15)(p21;q26), an unbalanced translocation involving chromosomes 1 and 10, der(10)t(1;10)(p22;q24), and a few copies of an apparently similar ring chromosome of unknown origin, as previously published.	('der(10)t(1;10)(p22;q24', 'Var', (267, 289))	('der(1)t(1;3)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (155, 176))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('der(10)t(1;10)(p22;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (267, 290))	('der(1)t(1;3)(p11;q11', 'Var', (155, 175))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('t(6;15)(p21;q26)', 'STRUCTURAL_ABNORMALITY', 'None', (189, 205))
576484	21717526	In the MIFS group, 5 of the 7 cases tested by FISH showed the presence of rearrangements in both TGFBR3 and MGEA5 (Fig.	('MGEA5', 'Chemical', '-', (108, 113))	('TGFBR3', 'Gene', (97, 103))	('rearrangements', 'Var', (74, 88))	('presence', 'Reg', (62, 70))
576485	21717526	In all cases, however, the rearrangement pattern observed was unbalanced, with loss of the centromeric part of TGFBR3 and deletion of the telomeric part of MGEA5 (Figs.	('loss', 'NegReg', (79, 83))	('TGFBR3', 'Gene', (111, 117))	('MGEA5', 'Chemical', '-', (156, 161))	('deletion', 'Var', (122, 130))	('centromeric', 'MPA', (91, 102))
576486	21717526	In the HFLT group, 12 of the 14 cases were positive for TGFBR3 and MGEA5 gene rearrangements with a similar unbalanced pattern, as described above and illustrated in Figs.	('TGFBR3', 'Gene', (56, 62))	('MGEA5', 'Gene', (67, 72))	('MGEA5', 'Chemical', '-', (67, 72))	('positive', 'Reg', (43, 51))	('rearrangements', 'Var', (78, 92))
576488	21717526	In all three cases with mixed morphology, the FISH studies showed similar TGFBR3 rearrangements with deletion of the centromeric part and MGEA5 rearrangement with deletion of the telomeric part (Fig.	('deletion', 'Var', (101, 109))	('deletion', 'Var', (163, 171))	('MGEA5', 'Chemical', '-', (138, 143))	('TGFBR3', 'Gene', (74, 80))
576490	21717526	In 12 cases adequate material was available to investigate the copy number alterations at the VGLL3 locus on 3p.12.1 by FISH.	('VGLL3', 'Gene', '389136', (94, 99))	('VGLL3', 'Gene', (94, 99))	('copy number alterations', 'Var', (63, 86))
576495	21717526	Our findings, demonstrating the absence of TGFBR3 or MGEA5 gene rearrangements in the three PHAT tumors tested (including one example containing the previously described 'early' PHAT pattern), suggest a different pathogenesis and do not provide support for a morphologic continuum between the precursor PHAT lesion and HFLT.	('PHAT tumors', 'Disease', (92, 103))	('absence', 'NegReg', (32, 39))	('PHAT tumors', 'Disease', 'MESH:D009369', (92, 103))	('PHAT lesion', 'Disease', 'MESH:D051437', (303, 314))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('PHAT lesion', 'Disease', (303, 314))	('MGEA5', 'Gene', (53, 58))	('MGEA5', 'Chemical', '-', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('TGFBR3', 'Gene', (43, 49))	('rearrangements', 'Var', (64, 78))
576496	21717526	Although most translocations in sarcomas result in functional gene fusions, our data support previous results suggesting that both TGFBR3 and MGEA5 candidates for the gene fusion are transcribed in opposite directions and thus unable to form a fusion transcript.	('unable', 'NegReg', (227, 233))	('MGEA5', 'Chemical', '-', (142, 147))	('translocations', 'Var', (14, 28))	('sarcomas', 'Disease', 'MESH:D012509', (32, 40))	('TGFBR3', 'Gene', (131, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('sarcomas', 'Disease', (32, 40))	('result in', 'Reg', (41, 50))
576499	21717526	Reactivation of FGF8 has been found in a variety of epithelial malignancies as well as in synovial sarcoma.	('synovial sarcoma', 'Disease', 'MESH:D013584', (90, 106))	('found', 'Reg', (30, 35))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (52, 75))	('epithelial malignancies', 'Disease', (52, 75))	('Reactivation', 'Var', (0, 12))	('synovial sarcoma', 'Disease', (90, 106))	('epithelial malignancies', 'Disease', 'MESH:D002277', (52, 75))	('FGF8', 'Gene', (16, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (90, 106))
576500	21717526	Similar ectopic expression of proto-oncogenes secondary to position effects has been reported in other translocation-associated malignancies, such as myeloid leukemia with either t(4;12) or t(5;12) with up regulation of ETV6.	('ETV6', 'Gene', (220, 224))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (150, 166))	('myeloid leukemia', 'Disease', 'MESH:D007951', (150, 166))	('t(4;12', 'Var', (179, 185))	('t(5;12', 'Var', (190, 196))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('malignancies', 'Disease', 'MESH:D009369', (128, 140))	('myeloid leukemia', 'Disease', (150, 166))	('malignancies', 'Disease', (128, 140))	('ectopic expression', 'MPA', (8, 26))	('up regulation', 'PosReg', (203, 216))
576501	21717526	Ring and marker chromosomes have been described in other low grade sarcomas, either due to amplified 12q13-15 material (well-differentiated liposarcoma, parosteal osteosarcoma) or secondary to tandem repeats of the t(17;22) breakpoint region in dermatofibrosarcoma protuberans.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('12q13-15', 'Gene', (101, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('liposarcoma', 'Disease', (140, 151))	('liposarcoma', 'Disease', 'MESH:D008080', (140, 151))	('dermatofibrosarcoma protuberans', 'Disease', (245, 276))	('parosteal osteosarcoma', 'Disease', (153, 175))	('osteosarcoma', 'Phenotype', 'HP:0002669', (163, 175))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('tandem repeats', 'Var', (193, 207))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (245, 276))	('liposarcoma', 'Phenotype', 'HP:0012034', (140, 151))	('t(17;22', 'Gene', (215, 222))	('parosteal osteosarcoma', 'Disease', 'MESH:D012516', (153, 175))	('sarcomas', 'Disease', (67, 75))
576506	21717526	By Genome-Wide Human SNP Array 6.0 on a different series of sarcomas, 6 of 132 tumors had amplification of 3p, with only VGLL3 in common.	('sarcomas', 'Disease', (60, 68))	('VGLL3', 'Gene', (121, 126))	('sarcomas', 'Disease', 'MESH:D012509', (60, 68))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('VGLL3', 'Gene', '389136', (121, 126))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('Human', 'Species', '9606', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('amplification', 'Var', (90, 103))
576508	21717526	Our findings confirm the presence of high level VGLL3 amplification by FISH in MIFS, as well as in HFLT and cases with mixed morphology, suggesting a potential pathogenetic role in this tumor type.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('amplification', 'Var', (54, 67))	('MIFS', 'Disease', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('HFLT', 'Disease', (99, 103))	('VGLL3', 'Gene', '389136', (48, 53))	('tumor', 'Disease', (186, 191))	('VGLL3', 'Gene', (48, 53))
576511	21717526	FISH analysis for TGFBR3 and MGEA5 rearrangements can be applied as a reliable molecular test when confronted with limited biopsy material or a challenging diagnosis.	('TGFBR3', 'Gene', (18, 24))	('MGEA5', 'Chemical', '-', (29, 34))	('rearrangements', 'Var', (35, 49))
576538	22007228	Risk factors for the development of carcinosarcoma are similar to those of endometrial carcinoma and include nulliparity, advanced age, obesity, exposure to exogenous estrogens, and long-term use of tamoxifen.	('obesity', 'Disease', 'MESH:D009765', (136, 143))	('obesity', 'Phenotype', 'HP:0001513', (136, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (75, 96))	('carcinosarcoma', 'Disease', (36, 50))	('obesity', 'Disease', (136, 143))	('tamoxifen', 'Chemical', 'MESH:D013629', (199, 208))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (75, 96))	('carcinosarcoma', 'Disease', 'MESH:D002296', (36, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('endometrial carcinoma', 'Disease', (75, 96))	('nulliparity', 'Var', (109, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
576601	22007228	T2-weighted images found hyperintensity of uterine carcinosarcomas to the myometrium (92%) and hypointensity (55%) or isointensity (41%) to the endometrium, a finding that is highly comparable to endometrial carcinoma (97% hyperintense to myometrium, 23% isointense, and 68% hypointense to endometrium).	('endometrial carcinoma', 'Disease', (196, 217))	('carcinosarcomas', 'Disease', (51, 66))	('carcinosarcomas', 'Disease', 'MESH:D002296', (51, 66))	('abl', 'Gene', (188, 191))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (196, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (43, 65))	('isointensity', 'Var', (118, 130))	('abl', 'Gene', '25', (188, 191))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (196, 217))
576641	22007228	Lymphadenectomy offers a survival advantage only for node-negative patients, as removal of positive nodes upstages the disease and worsens the prognosis.	('prognosis', 'MPA', (143, 152))	('patients', 'Species', '9606', (67, 75))	('nodes upstages the disease', 'Disease', (100, 126))	('nodes upstages the disease', 'Disease', 'MESH:D012804', (100, 126))	('removal', 'Var', (80, 87))	('worsens', 'NegReg', (131, 138))
576673	22007228	Sorafenib acts by inhibiting wild-type Raf-1, mutant B-Raf and several receptor tyrosine kinases such as vascular endothelial growth factor receptors (VEGFR).	('vascular endothelial growth factor receptors', 'Gene', '3791', (105, 149))	('B-Raf', 'Gene', '673', (53, 58))	('Raf-1', 'Gene', (39, 44))	('B-Raf', 'Gene', (53, 58))	('VEGFR', 'Gene', '3791', (151, 156))	('mutant', 'Var', (46, 52))	('inhibiting', 'NegReg', (18, 28))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('Raf-1', 'Gene', '5894', (39, 44))	('VEGFR', 'Gene', (151, 156))	('vascular endothelial growth factor receptors', 'Gene', (105, 149))
576760	22007228	Tumour characteristics of molecular markers such as expression of p53 in older women are associated with a shorter mean survival, while p53 negative tumours occurring in younger women have a longer survival.	('p53', 'Gene', '7157', (66, 69))	('tumours', 'Disease', (149, 156))	('p53', 'Gene', '7157', (136, 139))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('mean survival', 'MPA', (115, 128))	('shorter', 'NegReg', (107, 114))	('women', 'Species', '9606', (178, 183))	('women', 'Species', '9606', (79, 84))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'Var', (52, 62))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('tumours', 'Disease', 'MESH:D009369', (149, 156))	('p53', 'Gene', (66, 69))	('p53', 'Gene', (136, 139))
576868	29668499	These syndromes include Li-Fraumeni Syndrome (TP53), Retinoblastoma (RB1), Rothmund-Thompson Syndrome (RECQL4), Bloom (BLM) and Werner Syndromes (WRN) with individuals inheriting germline inactivating mutations of the respective genes.	('Werner Syndromes', 'Disease', (128, 144))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (24, 44))	('Retinoblastoma', 'Gene', (53, 67))	('RECQL4', 'Gene', '9401', (103, 109))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (53, 67))	('RB1', 'Gene', (69, 72))	('RECQL4', 'Gene', (103, 109))	('TP53', 'Gene', '7157', (46, 50))	('Rothmund-Thompson Syndrome', 'Disease', (75, 101))	('BLM', 'Gene', (119, 122))	('Retinoblastoma', 'Gene', '5925', (53, 67))	('WRN', 'Gene', (146, 149))	('WRN', 'Gene', '7486', (146, 149))	('BLM', 'Gene', '641', (119, 122))	('RB1', 'Gene', '5925', (69, 72))	('Bloom', 'Disease', (112, 117))	('germline inactivating mutations', 'Var', (179, 210))	('Li-Fraumeni Syndrome', 'Disease', (24, 44))	('TP53', 'Gene', (46, 50))
576869	29668499	Hereditary retinoblastoma (OMIM# 180200) is a rare autosomal dominant disorder of infancy caused by biallelic mutation of the RB1 gene in developing retinal tissue.	('autosomal dominant disorder of infancy', 'Disease', 'MESH:D030342', (51, 89))	('Hereditary retinoblastoma', 'Disease', 'MESH:D012175', (0, 25))	('RB1', 'Gene', '5925', (126, 129))	('retinoblastoma', 'Phenotype', 'HP:0009919', (11, 25))	('autosomal dominant disorder of infancy', 'Disease', (51, 89))	('Hereditary retinoblastoma', 'Disease', (0, 25))	('RB1', 'Gene', (126, 129))	('biallelic mutation', 'Var', (100, 118))	('caused by', 'Reg', (90, 99))
576870	29668499	Inherited mutation of RB1 in one allele is a predisposing factor for the development of retinoblastoma following the mutation of the second allele.	('RB1', 'Gene', (22, 25))	('mutation', 'Var', (10, 18))	('retinoblastoma', 'Disease', 'MESH:D012175', (88, 102))	('retinoblastoma', 'Disease', (88, 102))	('RB1', 'Gene', '5925', (22, 25))	('retinoblastoma', 'Phenotype', 'HP:0009919', (88, 102))
576877	29668499	In a study by Dommering et al, in a comprehensive cohort of 500 Dutch Rb patients from the Dutch Retinoblastoma Register, more than 180 Rb mutations were found including 33 novel mutations.	('Retinoblastoma', 'Gene', (97, 111))	('mutations', 'Var', (139, 148))	('Retinoblastoma', 'Gene', '5925', (97, 111))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (97, 111))	('patients', 'Species', '9606', (73, 81))
576878	29668499	In the searchable database (RBGMdb) which is based on 932 publications deletions and nonsense mutations were found to be the main inactivating events and nearly 40% of the mutations were recurrent and localize to 16 hot spots with predominance of C to T conversions and the reminder of mutations were scattered along the gene.	('mutations', 'Var', (172, 181))	('RB', 'Gene', '5925', (28, 30))	('deletions', 'Var', (71, 80))	('C to T conversions', 'Var', (247, 265))
576880	29668499	Some patients with sporadic retinoblastoma cases may carry a mosaic RB1 mutation, and detecting these low-level variants is important for screening and for family planning purposes.	('RB1', 'Gene', '5925', (68, 71))	('patients', 'Species', '9606', (5, 13))	('mosaic', 'Var', (61, 67))	('RB1', 'Gene', (68, 71))	('retinoblastoma', 'Phenotype', 'HP:0009919', (28, 42))	('sporadic retinoblastoma', 'Disease', (19, 42))	('sporadic retinoblastoma', 'Disease', 'MESH:D012175', (19, 42))	('mutation', 'Var', (72, 80))
576881	29668499	Additionally, individuals who present with retinoblastoma and a detected pathogenic RB1 germline variant may either be a "de novo" case, or one parent may be a germline mosaic for the variant.	('variant', 'Var', (97, 104))	('retinoblastoma', 'Phenotype', 'HP:0009919', (43, 57))	('pathogenic', 'Reg', (73, 83))	('RB1', 'Gene', (84, 87))	('retinoblastoma', 'Disease', 'MESH:D012175', (43, 57))	('retinoblastoma', 'Disease', (43, 57))	('RB1', 'Gene', '5925', (84, 87))
576888	29668499	The incidence of somatic RB1 mutation in sporadic osteosarcoma ranges between 30-75% .	('mutation', 'Var', (29, 37))	('sporadic osteosarcoma', 'Disease', (41, 62))	('RB1', 'Gene', '5925', (25, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sporadic osteosarcoma', 'Disease', 'MESH:D012516', (41, 62))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('RB1', 'Gene', (25, 28))
576898	29668499	While nonsense, frameshift and splicing variants can span the gene sequence, many of the pathogenic missense variants in TP53 occur within the DNA binding domain (DBD) LFS has been detected in approximately 5% of osteosarcoma cases under the age of 30, and osteosarcoma is the most common sarcoma found in individuals with LFS .	('LFS', 'Disease', (168, 171))	('osteosarcoma', 'Disease', (213, 225))	('sarcoma', 'Disease', (262, 269))	('TP53', 'Gene', '7157', (121, 125))	('osteosarcoma', 'Disease', 'MESH:D012516', (213, 225))	('LFS', 'Disease', 'MESH:D016864', (168, 171))	('osteosarcoma', 'Disease', (257, 269))	('osteosarcoma', 'Disease', 'MESH:D012516', (257, 269))	('sarcoma', 'Phenotype', 'HP:0100242', (262, 269))	('sarcoma', 'Disease', 'MESH:D012509', (289, 296))	('missense variants', 'Var', (100, 117))	('sarcoma', 'Disease', (289, 296))	('osteosarcoma', 'Phenotype', 'HP:0002669', (213, 225))	('sarcoma', 'Disease', 'MESH:D012509', (218, 225))	('TP53', 'Gene', (121, 125))	('LFS', 'Disease', (323, 326))	('sarcoma', 'Disease', (218, 225))	('osteosarcoma', 'Phenotype', 'HP:0002669', (257, 269))	('LFS', 'Disease', 'MESH:D016864', (323, 326))	('sarcoma', 'Phenotype', 'HP:0100242', (289, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))	('sarcoma', 'Disease', 'MESH:D012509', (262, 269))
576906	29668499	The most common TP53 mutations in sarcoma patients of LFS are missense mutations (72.8%) and involve codons 273,248,282,175 and 220 in the DNA binding domain (DBD).	('sarcoma', 'Disease', (34, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('LFS', 'Disease', 'MESH:D016864', (54, 57))	('LFS', 'Disease', (54, 57))	('missense mutations', 'Var', (62, 80))	('TP53', 'Gene', '7157', (16, 20))	('sarcoma', 'Disease', 'MESH:D012509', (34, 41))	('patients', 'Species', '9606', (42, 50))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
576907	29668499	High prevalence of codon 245 and 282 were seen in osteosarcoma whereas more than 20% of all mutations are seen at codon 273 in patients with rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (141, 157))	('rhabdomyosarcoma', 'Disease', (141, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('282', 'Var', (33, 36))	('patients', 'Species', '9606', (127, 135))	('osteosarcoma', 'Disease', (50, 62))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (141, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('osteosarcoma', 'Disease', 'MESH:D012516', (50, 62))	('codon 245', 'Var', (19, 28))
576908	29668499	Mutations outside the DBD (codons 337 or 344) are associated with leiomyosarcoma and unlike osteosarcoma and rhabdomyosarcoma, frameshift, splice -site and nonsense mutation are more frequent.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (66, 80))	('osteosarcoma and rhabdomyosarcoma', 'Disease', 'MESH:D012516', (92, 125))	('splice -site', 'Var', (139, 151))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (66, 80))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (109, 125))	('osteosarcoma', 'Phenotype', 'HP:0002669', (92, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leiomyosarcoma', 'Disease', (66, 80))	('frameshift', 'Var', (127, 137))	('associated', 'Reg', (50, 60))	('nonsense mutation', 'Var', (156, 173))	('codons 337', 'Var', (27, 37))
576909	29668499	It is postulated that mutations predicting absence of wild type protein lead to late-onset type sarcoma and missense DBD mutations accumulating mutant proteins give rise to early onset types of sarcoma such as osteosarcoma and rhabdomyosarcoma.For those with a known germline mutation in TP53, recommended screening includes whole body MRI to screen for sarcomas and other cancers .	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('sarcoma', 'Disease', 'MESH:D012509', (236, 243))	('type sarcoma', 'Disease', 'MESH:D012509', (91, 103))	('sarcoma', 'Disease', (236, 243))	('osteosarcoma and rhabdomyosarcoma', 'Disease', 'MESH:D012516', (210, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('sarcoma', 'Disease', 'MESH:D012509', (354, 361))	('sarcomas', 'Disease', 'MESH:D012509', (354, 362))	('sarcomas', 'Phenotype', 'HP:0100242', (354, 362))	('sarcoma', 'Disease', (354, 361))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (227, 243))	('cancers', 'Phenotype', 'HP:0002664', (373, 380))	('sarcomas', 'Disease', (354, 362))	('cancers', 'Disease', (373, 380))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('TP53', 'Gene', (288, 292))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('germline mutation', 'Var', (267, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (354, 361))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('sarcoma', 'Disease', (194, 201))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('sarcoma', 'Disease', (96, 103))	('osteosarcoma', 'Phenotype', 'HP:0002669', (210, 222))	('sarcoma', 'Disease', 'MESH:D012509', (215, 222))	('sarcoma', 'Disease', (215, 222))	('TP53', 'Gene', '7157', (288, 292))	('cancers', 'Disease', 'MESH:D009369', (373, 380))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('type sarcoma', 'Disease', (91, 103))
576911	29668499	Werner Syndrome is caused by mutations of the WRN gene, which is a RecQ helicase, located on chromosome 8p11.1 .	('Werner Syndrome', 'Disease', (0, 15))	('WRN', 'Gene', '7486', (46, 49))	('caused by', 'Reg', (19, 28))	('mutations', 'Var', (29, 38))	('WRN', 'Gene', (46, 49))
576914	29668499	More than 90 mutations have been identified and they are all inactivating and include base substitutions, insertions, deletions and complex mutations, which disrupt the WRN, open reading frame .	('base substitutions', 'Var', (86, 104))	('WRN', 'Gene', '7486', (169, 172))	('WRN', 'Gene', (169, 172))	('insertions', 'Var', (106, 116))	('deletions', 'Var', (118, 127))	('disrupt', 'NegReg', (157, 164))	('open reading frame', 'MPA', (174, 192))
576918	29668499	Rothmund-Thompson syndrome (OMIM #268400) is an autosomal recessive disorder caused by biallelic germline mutations in RECQL4, and is strongly associated with osteosarcoma predisposition.	('associated', 'Reg', (143, 153))	('biallelic germline mutations', 'Var', (87, 115))	('osteosarcoma', 'Disease', (159, 171))	('Rothmund-Thompson syndrome', 'Disease', (0, 26))	('RECQL4', 'Gene', '9401', (119, 125))	('RECQL4', 'Gene', (119, 125))	('caused by', 'Reg', (77, 86))	('osteosarcoma', 'Phenotype', 'HP:0002669', (159, 171))	('osteosarcoma', 'Disease', 'MESH:D012516', (159, 171))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (48, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('autosomal recessive disorder', 'Disease', (48, 76))
576920	29668499	Pathogenic mutations in RECQL4 are loss of function mutations and include nonsense, frameshift, splice site and intronic deletions.	('RECQL4', 'Gene', (24, 30))	('splice site', 'Var', (96, 107))	('loss of function', 'NegReg', (35, 51))	('frameshift', 'Var', (84, 94))	('nonsense', 'Var', (74, 82))	('RECQL4', 'Gene', '9401', (24, 30))	('intronic deletions', 'Var', (112, 130))
576921	29668499	Unlike other TP53 and RB mutated syndromes, RECQL4 mutations are not seen in sporadic OS, and present in the context of Rothmund-Thompson syndrome.	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (51, 60))	('RECQL4', 'Gene', '9401', (44, 50))	('TP53', 'Gene', '7157', (13, 17))	('present', 'Reg', (94, 101))	('RB', 'Gene', '5925', (22, 24))	('Rothmund-Thompson syndrome', 'Disease', (120, 146))	('RECQL4', 'Gene', (44, 50))
576925	29668499	A second syndrome caused by RECQL4 mutations and predisposition to OS is RAPADILINO syndrome.	('RECQL4', 'Gene', (28, 34))	('caused', 'Reg', (18, 24))	('RECQL4', 'Gene', '9401', (28, 34))	('RAPADILINO syndrome', 'Disease', 'MESH:C535288', (73, 92))	('RAPADILINO syndrome', 'Disease', (73, 92))	('mutations', 'Var', (35, 44))
576927	29668499	Most individuals with RAPADILINO syndrome carry a specific founder mutation, RECQL4 c.1390+2delT, and also have an increased risk of osteosarcomas and lymphomas.	('RAPADILINO syndrome', 'Disease', 'MESH:C535288', (22, 41))	('RECQL4', 'Gene', '9401', (77, 83))	('RAPADILINO syndrome', 'Disease', (22, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('lymphomas', 'Phenotype', 'HP:0002665', (151, 160))	('c.1390+2delT', 'Var', (84, 96))	('osteosarcomas and lymphomas', 'Disease', 'MESH:D012516', (133, 160))	('RECQL4', 'Gene', (77, 83))	('c.1390+2delT', 'Mutation', 'rs386833843', (84, 96))	('osteosarcomas', 'Phenotype', 'HP:0002669', (133, 146))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))
576928	29668499	Bloom Syndrome (OMIM#210900) is an autosomal recessive disease characterized by short stature, sun sensitive rash and sparse subcutaneous fat and is caused by mutations in BLM gene, which is a RecQ helicase.	('rash', 'Disease', 'MESH:D005076', (109, 113))	('rash', 'Disease', (109, 113))	('short stature', 'Phenotype', 'HP:0004322', (80, 93))	('caused by', 'Reg', (149, 158))	('rash', 'Phenotype', 'HP:0000988', (109, 113))	('mutations', 'Var', (159, 168))	('sparse subcutaneous fat', 'Phenotype', 'HP:0003758', (118, 141))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (35, 62))	('BLM', 'Gene', '641', (172, 175))	('sun sensitive', 'Phenotype', 'HP:0000992', (95, 108))	('autosomal recessive disease', 'Disease', (35, 62))	('Bloom Syndrome', 'Disease', (0, 14))	('BLM', 'Gene', (172, 175))
576933	29668499	In a recent study of 1040 patients with advanced cancers, germline sequencing of a broad panel of cancer related genes showed 17.5% of the individuals had clinically actionable heritable mutations, and over half of these mutations would not have been detected using clinical guidelines alone.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('patients', 'Species', '9606', (26, 34))	('mutations', 'Var', (187, 196))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('cancer', 'Disease', (49, 55))
576971	30723142	10 mug solubilized chromatin was immunoprecipitated with 1 mug mouse IgG (Abcam #18394), or H3K27me3 (Abcam #6002), 1 mug rabbit IgG (Cell Signaling #2729S) or 1 mug H3K9me3 (Abcam #8898), 2 mug rabbit IgG or 1 mug SMARCC1/BAF155 (Cell Signaling #11956S).	('mouse', 'Species', '10090', (63, 68))	('H3K9me3', 'Var', (166, 173))	('H3K27me3', 'Var', (92, 100))
577001	30723142	CRISPR/Cas9 elimination of this microsatellite eliminates NR0B1 expression and while both FLI1 and EWS-FLI1 can bind this region, only EWS-FLI1 can activate NR0B1 expression.	('eliminates', 'NegReg', (47, 57))	('expression', 'MPA', (64, 74))	('NR0B1', 'Gene', (58, 63))	('NR0B1', 'Gene', '190', (157, 162))	('NR0B1', 'Gene', '190', (58, 63))	('elimination', 'Var', (12, 23))	('bind', 'Interaction', (112, 116))	('NR0B1', 'Gene', (157, 162))
577004	30723142	These effects extended to the protein level where again only the Cmax exposure, but not the AUC exposure, led to a loss of expression of NR0B1, EZH2, and WRN in two different Ewing sarcoma cell lines (Fig.	('NR0B1', 'Gene', (137, 142))	('Cmax', 'Var', (65, 69))	('Ewing sarcoma', 'Disease', (175, 188))	('expression', 'MPA', (123, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('loss', 'NegReg', (115, 119))	('EZH2', 'Gene', (144, 148))	('EZH2', 'Gene', '2146', (144, 148))	('NR0B1', 'Gene', '190', (137, 142))	('WRN', 'Gene', (154, 157))	('WRN', 'Gene', '7486', (154, 157))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (175, 188))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (175, 188))
577016	30723142	We treated cells with trabectedin (Cmax exposure), washed out the drug, and then performed chromatin immunoprecipitation of H3K9me3 and H3K27me3 at 1- and 9-hours following drug removal.	('trabectedin', 'Chemical', 'MESH:D000077606', (22, 33))	('H3K27me3', 'Var', (136, 144))	('H3K9me3', 'Protein', (124, 131))
577017	30723142	We found that high dose trabectedin led to the marked accumulation of both H3K27me3 and H3K9me3 epigenetic marks throughout the genome (Fig.	('H3K9me3', 'Var', (88, 95))	('accumulation', 'PosReg', (54, 66))	('trabectedin', 'Chemical', 'MESH:D000077606', (24, 35))	('H3K27me3', 'Protein', (75, 83))
577019	30723142	There are approximately 26,000 GGAA microsatellites in the genome, almost 70% of these or 18,272 are marked with H3K27me3, H3K9me3 or both within 50 KB of a TSS after high dose exposure to trabectedin (Fig.	('H3K27me3', 'Var', (113, 121))	('H3K9me3', 'Var', (123, 130))	('marked', 'Reg', (101, 107))	('trabectedin', 'Chemical', 'MESH:D000077606', (189, 200))
577020	30723142	Of this list of 83 targets, 76 of the 83 or 92% were marked with H3K27me3, H3K9me3 or both following trabectedin treatment (Fig.	('H3K9me3', 'Var', (75, 82))	('trabectedin', 'Chemical', 'MESH:D000077606', (101, 112))	('H3K27me3', 'Protein', (65, 73))
577023	30723142	Similar enrichment of both H3K27me3 and H3K9me3 epigenetic silencing marks was observed at a number of additional well-established EWS-FLI1 target genes including RCOR1, PPP1R1A, MEIS1, WRN, EZH2, BCL11B, LOX, and PRKCB (Supplemental Fig.	('EZH2', 'Gene', (191, 195))	('PPP1R1A', 'Gene', (170, 177))	('EZH2', 'Gene', '2146', (191, 195))	('PRKCB', 'Gene', '5579', (214, 219))	('LOX', 'Gene', '4015', (205, 208))	('BCL11B', 'Gene', '64919', (197, 203))	('epigenetic', 'Var', (48, 58))	('BCL11B', 'Gene', (197, 203))	('RCOR1', 'Gene', (163, 168))	('H3K9me3 epigenetic', 'Var', (40, 58))	('WRN', 'Gene', '7486', (186, 189))	('WRN', 'Gene', (186, 189))	('H3K27me3', 'Var', (27, 35))	('LOX', 'Gene', (205, 208))	('RCOR1', 'Gene', '23186', (163, 168))	('MEIS1', 'Gene', '4211', (179, 184))	('MEIS1', 'Gene', (179, 184))	('PRKCB', 'Gene', (214, 219))	('PPP1R1A', 'Gene', '5502', (170, 177))
577024	30723142	In addition, high dose trabectedin treatment also caused the enrichment of H3K9me3 and H3K27me3 at genomic sites previously associated with SWI/SNF at MYT1, CCND1, and SOX2 (Supplemental Fig.	('SOX2', 'Gene', '6657', (168, 172))	('SOX2', 'Gene', (168, 172))	('MYT1', 'Gene', (151, 155))	('CCND1', 'Gene', (157, 162))	('associated', 'Reg', (124, 134))	('trabectedin', 'Chemical', 'MESH:D000077606', (23, 34))	('CCND1', 'Gene', '595', (157, 162))	('SWI/SNF', 'Disease', (140, 147))	('H3K27me3', 'Var', (87, 95))	('H3K9me3', 'Protein', (75, 82))	('MYT1', 'Gene', '4661', (151, 155))
577025	30723142	Importantly, silencing of SMARCC1 reduces cell viability in Ewing sarcoma cells and further potentiates the activity of the drug in an analogous fashion to silencing of EWS-FLI1 (Supplemental Fig.	('SMARCC1', 'Gene', (26, 33))	('activity', 'MPA', (108, 116))	('cell viability', 'CPA', (42, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('reduces', 'NegReg', (34, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (60, 73))	('potentiates', 'PosReg', (92, 103))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (60, 73))	('Ewing sarcoma', 'Disease', (60, 73))	('silencing', 'Var', (13, 22))
577056	30723142	It is likely that this mechanism contributes to the broad cytotoxicity profile of this compound as SWI/SNF is mutated in up to 25% of human cancer and commonly altered either functionally or through mutation in sarcoma.	('human', 'Species', '9606', (134, 139))	('mutated', 'Var', (110, 117))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('sarcoma', 'Disease', (211, 218))	('cancer', 'Disease', (140, 146))	('mutation', 'Var', (199, 207))	('altered', 'Reg', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('toxicity', 'Disease', (62, 70))	('SWI/SNF', 'Gene', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
577068	30723142	In addition, we establish a novel mechanism of trabectedin as an inhibitor of the SWI/SNF chromatin remodeling complex which is mutated in approximately 25% of all human cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('human', 'Species', '9606', (164, 169))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('mutated', 'Var', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('trabectedin', 'Chemical', 'MESH:D000077606', (47, 58))
577075	30700749	Further, stable shUSP19 depletion resulted in decreased cell growth and diminished colony forming capacity in vitro, and significantly delayed tumor growth in vivo.	('shUSP19', 'Gene', (16, 23))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cell growth', 'CPA', (56, 67))	('depletion', 'Var', (24, 33))	('diminished', 'NegReg', (72, 82))	('decreased', 'NegReg', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('colony forming capacity', 'CPA', (83, 106))	('delayed', 'NegReg', (135, 142))
577076	30700749	Our findings not only provide novel insights into the importance of the N-terminal EWSR1 domain for regulation of fusion protein stability, but also indicate that inhibition of deubiquitinating enzyme(s) might constitute a novel therapeutic strategy in treatment of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (266, 279))	('EWSR1', 'Gene', (83, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (266, 279))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('EWSR1', 'Gene', '2130', (83, 88))	('fusion protein', 'Protein', (114, 128))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (266, 279))	('inhibition', 'Var', (163, 173))
577081	30700749	In contrast to adult cancers harboring an accumulation of multiple driver mutations, pediatric lesions display a high frequency of chromosomal rearrangements and a comparably low mutational burden.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('adult cancers', 'Disease', 'MESH:C535836', (15, 28))	('chromosomal rearrangements', 'Var', (131, 157))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('adult cancers', 'Disease', (15, 28))
577083	30700749	The main genetic event therefore is the balanced translocation between chromosomes 11 and 22 leading to expression of the chimeric transcription factor EWS-FLI1, in the majority of the cases.	('EWS-FLI1', 'Gene', (152, 160))	('expression', 'MPA', (104, 114))	('balanced translocation', 'Var', (40, 62))	('EWS-FLI1', 'Gene', '2130;2313', (152, 160))
577090	30700749	There, USP19 depletion inhibited proliferation of prostate cancer and breast epithelial cell lines suggesting it to have oncogenic properties.	('inhibited', 'NegReg', (23, 32))	('prostate cancer', 'Disease', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('depletion', 'Var', (13, 22))	('proliferation', 'CPA', (33, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))	('USP19', 'Gene', (7, 12))
577105	30700749	Using three different siRNAs for each of the 21 candidates, we identified USP19 as the main and USP46 as a second DUB as potential modulator of EWS-FLI1 protein levels.	('USP46', 'Gene', '64854', (96, 101))	('USP19', 'Var', (74, 79))	('protein levels', 'MPA', (153, 167))	('EWS-FLI1', 'Gene', (144, 152))	('modulator', 'Reg', (131, 140))	('EWS-FLI1', 'Gene', '2130;2313', (144, 152))	('USP46', 'Gene', (96, 101))
577113	30700749	Transient USP19 knockdown also modulated some, but not all of the tested activated and repressed EWS-FLI1 target genes in SKNMC cells.	('modulated', 'Reg', (31, 40))	('EWS-FLI1', 'Gene', '2130;2313', (97, 105))	('knockdown', 'Var', (16, 25))	('EWS-FLI1', 'Gene', (97, 105))	('USP19', 'Gene', (10, 15))
577115	30700749	As further validation, we transiently co-expressed flag-tagged EWS-FLI1 with two increasing concentrations of 3xmyc-tagged USP19 in HEK293T cells.	('myc', 'Gene', '24577', (112, 115))	('flag-tagged', 'Var', (51, 62))	('EWS-FLI1', 'Gene', (63, 71))	('myc', 'Gene', (112, 115))	('HEK293T', 'CellLine', 'CVCL:0063', (132, 139))	('EWS-FLI1', 'Gene', '2130;2313', (63, 71))
577116	30700749	EWS-FLI1 levels were stabilized more than 2-fold in a dose-dependent manner by active USP19, but to a lesser extent with the catalytically inactive C506A mutant, indicating that indeed the deubiquitinating activity of USP19 is involved in modulation of fusion protein levels (Fig.	('USP19', 'Gene', (86, 91))	('fusion protein levels', 'MPA', (253, 274))	('C506A', 'Mutation', 'rs374515105', (148, 153))	('EWS-FLI1', 'Gene', (0, 8))	('involved', 'Reg', (227, 235))	('deubiquitinating activity', 'MPA', (189, 214))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('C506A', 'Var', (148, 153))
577117	30700749	Interestingly, stabilization of EWS-FLI1 by USP19 was specific for the fusion protein as the protein levels of full length wild type EWSR1 or FLI1 remained constant upon co-expression with 3xmyc-USP19 (Fig.	('EWSR1', 'Gene', '2130', (133, 138))	('protein levels', 'MPA', (93, 107))	('EWS-FLI1', 'Gene', '2130;2313', (32, 40))	('USP19', 'Var', (44, 49))	('EWSR1', 'Gene', (133, 138))	('myc', 'Gene', (191, 194))	('myc', 'Gene', '24577', (191, 194))	('EWS-FLI1', 'Gene', (32, 40))
577124	30700749	To further underscore this notion, we co-expressed 3xflag-EWS-FLI1 and HA-ubiquitin together with either active or mutant C506S 3xmyc-USP19 in A673 cells.	('EWS-FLI1', 'Gene', '2130;2313', (58, 66))	('myc', 'Gene', (130, 133))	('mutant C506S', 'Var', (115, 127))	('myc', 'Gene', '24577', (130, 133))	('C506S', 'Var', (122, 127))	('EWS-FLI1', 'Gene', (58, 66))	('C506S', 'Mutation', 'p.C506S', (122, 127))
577128	30700749	2e), we were still interested if USP19 possibly alters EWSR1 monoubiquitination levels.	('EWSR1', 'Gene', (55, 60))	('EWSR1', 'Gene', '2130', (55, 60))	('alters', 'Reg', (48, 54))	('USP19', 'Var', (33, 38))
577130	30700749	As the main ubiquitin acceptor site for EWS-FLI1 degradation is located in the FLI1 terminus, we were next interested in identifying whether USP19 still interacts with EWS-FLI1 ubiquitin acceptor site mutants.	('EWS-FLI1', 'Gene', (40, 48))	('mutants', 'Var', (201, 208))	('EWS-FLI1', 'Gene', '2130;2313', (40, 48))	('EWS-FLI1', 'Gene', (168, 176))	('EWS-FLI1', 'Gene', '2130;2313', (168, 176))
577131	30700749	For this, we co-expressed myc-USP19 with 3xflag-EWS-FLI1 wild-type or mutants (K298R or K380R) and observed binding of USP19 to both EWS-FLI1 mutants, indicating that the interaction itself is independent of the presence of an ubiquitin chain (Fig.	('EWS-FLI1', 'Gene', '2130;2313', (48, 56))	('K298R', 'Mutation', 'p.K298R', (79, 84))	('EWS-FLI1', 'Gene', (133, 141))	('binding', 'Interaction', (108, 115))	('K380R', 'Mutation', 'p.K380R', (88, 93))	('K298R', 'Var', (79, 84))	('EWS-FLI1', 'Gene', '2130;2313', (133, 141))	('EWS-FLI1', 'Gene', (48, 56))	('K380R', 'Var', (88, 93))	('myc', 'Gene', (26, 29))	('myc', 'Gene', '24577', (26, 29))
577132	30700749	We further established stable reporter cell lines expressing a DsRed-IRES-EGFP-EWS-FLI1 wild-type or K380R construct (described previously).	('EWS-FLI1', 'Gene', (79, 87))	('K380R', 'Var', (101, 106))	('K380R', 'Mutation', 'p.K380R', (101, 106))	('EWS-FLI1', 'Gene', '2130;2313', (79, 87))
577133	30700749	Then, we depleted USP19 by siUSP19s and investigated the levels of endogenous as well as exogenous wild type or mutant EWS-FLI1 by western blotting.	('EWS-FLI1', 'Gene', (119, 127))	('EWS-FLI1', 'Gene', '2130;2313', (119, 127))	('mutant', 'Var', (112, 118))	('depleted', 'NegReg', (9, 17))	('USP19', 'Gene', (18, 23))
577134	30700749	Most interestingly, the levels of endogenous-EWS-FLI1 and exogenous wild-type fusion protein decreased by USP19 depletion to a similar extend as observed before while the exogenous mutant form remained stable, indicating that USP19 indeed acts via the C-terminal degradation signal of the fusion protein (Supplementary Fig.	('depletion', 'Var', (112, 121))	('USP19', 'Gene', (106, 111))	('levels', 'MPA', (24, 30))	('EWS-FLI1', 'Gene', (45, 53))	('EWS-FLI1', 'Gene', '2130;2313', (45, 53))
577144	30700749	Interestingly, USP19 depletion in non-tumorigenic cells such as MRC5 fibroblasts or HEK293T cells did not or only slightly affect cell viability (Figs 4h,I and S3i,j).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('HEK293T', 'CellLine', 'CVCL:0063', (84, 91))	('USP19', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('depletion', 'Var', (21, 30))	('affect', 'Reg', (123, 129))	('cell viability', 'CPA', (130, 144))	('MRC5', 'CellLine', 'CVCL:0440', (64, 68))
577145	30700749	Similar growth rates of USP19-/- HEK293T cells have been described previously, suggesting that USP19 supports oncogenic tumor cell growth specifically of tumor cells, despite a slight off-target effect observed for shUSP19#2.	('HEK293T', 'CellLine', 'CVCL:0063', (33, 40))	('USP19', 'Var', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('supports', 'PosReg', (101, 109))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', (154, 159))
577147	30700749	Finally, we investigated whether USP19 depletion would affect tumor growth in mouse xenografts.	('affect', 'Reg', (55, 61))	('depletion', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('USP19', 'Gene', (33, 38))	('mouse', 'Species', '10090', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
577149	30700749	Then, mice were intraperitoneally injected with either doxycycline or PBS for the first two days and subsequently fed with control or doxycycline supplemented food to induce and maintain USP19 knockdown.	('PBS', 'Disease', 'MESH:D011535', (70, 73))	('PBS', 'Disease', (70, 73))	('doxycycline', 'Chemical', 'MESH:D004318', (55, 66))	('mice', 'Species', '10090', (6, 10))	('knockdown', 'Var', (193, 202))	('USP19', 'Gene', (187, 192))	('doxycycline', 'Chemical', 'MESH:D004318', (134, 145))
577154	30700749	Taken together, we could show that USP19 depletion significantly delays tumor cell growth also in vivo confirming our in vitro findings.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('USP19', 'Gene', (35, 40))	('tumor', 'Disease', (72, 77))	('delays', 'NegReg', (65, 71))	('depletion', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
577158	30700749	The decreased EWS-FLI1 protein level upon USP19 depletion abrogated long term cell growth and delayed tumor growth in mouse xenograft experiments.	('abrogated', 'NegReg', (58, 67))	('long term cell growth', 'CPA', (68, 89))	('decreased', 'NegReg', (4, 13))	('EWS-FLI1', 'Gene', '2130;2313', (14, 22))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('protein level', 'MPA', (23, 36))	('delayed', 'NegReg', (94, 101))	('mouse', 'Species', '10090', (118, 123))	('EWS-FLI1', 'Gene', (14, 22))	('depletion', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('USP19', 'Gene', (42, 47))
577168	30700749	In our screening approach, USP9X knockdown resulted in a decrease of EWS-FLI1 stability with only one siRNA which did not reach the defined threshold.	('EWS-FLI1', 'Gene', '2130;2313', (69, 77))	('decrease', 'NegReg', (57, 65))	('knockdown', 'Var', (33, 42))	('USP9X', 'Gene', (27, 32))	('EWS-FLI1', 'Gene', (69, 77))	('USP9X', 'Gene', '8239', (27, 32))	('stability', 'MPA', (78, 87))
577170	30700749	We confirmed USP19 as a stabilizer of endogenous EWS-FLI1 by analyzing steady-state fusion protein levels upon USP19 knockdown.	('fusion protein levels', 'MPA', (84, 105))	('EWS-FLI1', 'Gene', (49, 57))	('USP19', 'Var', (111, 116))	('knockdown', 'Var', (117, 126))	('EWS-FLI1', 'Gene', '2130;2313', (49, 57))
577172	30700749	Most interestingly, co-expression of active USP19 with EWS-FLI1 stabilized the fusion protein whereas full length EWSR1 and FLI1 protein levels remained unchanged even though binding of USP19 to both EWS-FLI1 and full length EWSR1 was observed in immunoprecipitation experiments.	('EWS-FLI1', 'Gene', '2130;2313', (55, 63))	('EWS-FLI1', 'Gene', (200, 208))	('stabilized', 'MPA', (64, 74))	('co-expression', 'Var', (20, 33))	('EWSR1', 'Gene', (225, 230))	('EWSR1', 'Gene', (114, 119))	('fusion protein', 'MPA', (79, 93))	('EWS-FLI1', 'Gene', '2130;2313', (200, 208))	('USP19', 'Gene', (44, 49))	('EWSR1', 'Gene', '2130', (114, 119))	('EWSR1', 'Gene', '2130', (225, 230))	('EWS-FLI1', 'Gene', (55, 63))
577173	30700749	USP19 binds to the EWSR1 domain of the fusion protein, as demonstrated by co-immunoprecipitation experiments, and reduces ubiquitination at an acceptor lysine site (the K380 residue) in the FLI1 domain.	('lysine', 'Chemical', 'MESH:D008239', (152, 158))	('reduces', 'NegReg', (114, 121))	('EWSR1', 'Gene', (19, 24))	('K380', 'Chemical', '-', (169, 173))	('EWSR1', 'Gene', '2130', (19, 24))	('USP19', 'Gene', (0, 5))	('the K380 residue', 'Var', (165, 181))	('ubiquitination', 'MPA', (122, 136))
577175	30700749	Most likely, USP19, and other DUBs, modulate fusion protein levels to maintain Ewing sarcoma cell viability.	('modulate', 'Reg', (36, 44))	('Ewing sarcoma', 'Disease', (79, 92))	('fusion protein levels', 'MPA', (45, 66))	('USP19', 'Var', (13, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (79, 92))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (79, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
577176	30700749	However, the process by which USP19 is directed to remove EWSR1 monoubiquitination, or potential polyubiquitin chains, remains to be investigated as does the questions whether this is a general feature for other RNA-binding proteins.	('USP19', 'Var', (30, 35))	('EWSR1', 'Gene', '2130', (58, 63))	('monoubiquitination', 'MPA', (64, 82))	('remove', 'NegReg', (51, 57))	('polyubiquitin chains', 'MPA', (97, 117))	('EWSR1', 'Gene', (58, 63))
577178	30700749	Finally, we investigated the physiological consequences of USP19 depletion on Ewing sarcoma cell growth.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('depletion', 'Var', (65, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('USP19', 'Gene', (59, 64))	('Ewing sarcoma', 'Disease', (78, 91))
577180	30700749	We observed selectively diminished cell growth, proliferation and colony formation in two Ewing sarcoma cell lines upon specific USP19 depletion.	('depletion', 'Var', (135, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('proliferation', 'CPA', (48, 61))	('diminished', 'NegReg', (24, 34))	('USP19', 'Gene', (129, 134))	('Ewing sarcoma', 'Disease', (90, 103))	('colony formation', 'CPA', (66, 82))	('cell growth', 'CPA', (35, 46))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (90, 103))
577183	30700749	Most importantly, we also observed a significant tumor growth delay upon USP19 knockdown in an in vivo xenograft model.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('USP19', 'Gene', (73, 78))	('tumor', 'Disease', (49, 54))	('delay', 'NegReg', (62, 67))	('growth delay', 'Phenotype', 'HP:0001510', (55, 67))	('knockdown', 'Var', (79, 88))
577184	30700749	Combining USP19 inhibition with other treatment strategies such as classical chemotherapeutics, PARP inhibitors, DNA-damaging agents, inhibition of signaling pathways such as the PI3K pathway, or antagonists of the Wnt pathway might further enhance its growth inhibitory properties.	('growth inhibitory properties', 'CPA', (253, 281))	('PARP', 'Gene', (96, 100))	('enhance', 'PosReg', (241, 248))	('PARP', 'Gene', '142', (96, 100))	('inhibition', 'Var', (16, 26))	('PI3K pathway', 'Pathway', (179, 191))	('Wnt', 'Pathway', (215, 218))	('signaling pathways', 'Pathway', (148, 166))	('USP19', 'Gene', (10, 15))
577186	30700749	Although cells displaying low fusion protein levels show higher invasive potential, re-establishment of higher EWS-FLI1 levels are necessary for active cell proliferation.	('higher', 'PosReg', (57, 63))	('EWS-FLI1', 'Gene', '2130;2313', (111, 119))	('low', 'Var', (26, 29))	('fusion protein', 'Protein', (30, 44))	('EWS-FLI1', 'Gene', (111, 119))	('invasive potential', 'CPA', (64, 82))
577196	30700749	The following commercial antibodies were used: anti-Flag (dilution 1:1000, clone M2, Sigma Aldrich), anti-FLI1 (1:1000, MBS300723 MyBioSource LLC, San Diego, CA, USA), anti-GAPDH (1:1000, D16H11 Cell Signaling Technology, Beverly, MA, USA), anti-HA (both 1:1000, clone 6E2 Cell Signaling Technology and 05-904 Millipore), anti-Myc (1:1000, clone 9B11 Cell Signaling Technology), anti-p27 (1:200, clone DCS-72.F6 ThermoFisher Scientific AG), anti-Tubulin (1:1000, clone DM1A Sigma Aldrich), and anti-USP19 (1:1000 (WB) A301-587A Bethyl Laboratories, Montgomery, TX, USA and 1:200 (IHC) or 1:1000 (WB) ab93159 Abcam, Cambridge, UK).	('Myc', 'Gene', (327, 330))	('Myc', 'Gene', '24577', (327, 330))	('D16H11', 'CellLine', 'CVCL:J162', (188, 194))	('ab93159', 'Var', (600, 607))
577198	30700749	USP19 C506A was mutated by site-directed mutagenesis using the forward primer 5'-CAATTAGGCAACACCGCCTTCATGAACAGCGTC-3' and reverse primer 5'-GACGCTGTTCATGAAGGCGGTGTTGCCTAAATTG-3'.	('USP19', 'Gene', (0, 5))	('C506A', 'Mutation', 'rs374515105', (6, 11))	('C506A', 'Var', (6, 11))
577208	30700749	For co-immunoprecipitation, HEK293T cells were lysed in interactor lysis buffer 1 (50 mM Tris/HCl, 150 mM NaCl, 1 mM EDTA, 0.5% Triton X-100 with protease inhibitor cocktail) and HEK293 cells in interactor lysis buffer 2 (50 mM Tris/HCl, 50 mM NaCl, 1.5 mM MgCl2, 25 mM NaF, 10 mM beta-glycerolphosphate, 5 mM Na4P2O7, 2 mM Na3VO4, 10% glycerol 0.3% NP40 with protease inhibitor cocktail).	('NaF', 'Gene', (270, 273))	('Na4P2O7', 'Var', (310, 317))	('Na3VO4', 'Chemical', '-', (324, 330))	('Tris/HCl', 'Chemical', '-', (228, 236))	('EDTA', 'Chemical', 'MESH:D004492', (117, 121))	('Na4P2O7', 'Chemical', 'MESH:C107241', (310, 317))	('NaCl', 'Chemical', 'MESH:D012965', (106, 110))	('Tris/HCl', 'Chemical', '-', (89, 97))	('HEK293', 'CellLine', 'CVCL:0045', (28, 34))	('Triton X-100', 'Chemical', 'MESH:D017830', (128, 140))	('NaCl', 'Chemical', 'MESH:D012965', (244, 248))	('HEK293', 'CellLine', 'CVCL:0045', (179, 185))	('HEK293T', 'CellLine', 'CVCL:0063', (28, 35))	('NaF', 'Gene', '3576', (270, 273))
577211	30700749	Quantitative RT-PCR was performed using TaqMan gene expression master mix (ThermoFisher Scientific AG) and assays on demand (Applied Biosystems) with the following numbers: USP19 (Hs00324123_m1, Hs01103464_g1), EWS-FLI1 (Hs03024807_ft), GAPDH (Hs04420697_g1), HMBS (Hs00609296_g1), ITGA11 (Hs00201927_m1), LEMD1 (Hs01077215_m1), LOX (Hs00942481_m1), MAP2K6 (Hs00992389_m1), NGFR (Hs00609976_m1), NKX2.2 (Hs00159616_m1), NR0B1 (Hs00230864_m1), PHLDA1 (Hs00378285_g1).	('Hs00230864_m1', 'Var', (427, 440))	('ITGA11', 'Gene', '22801', (282, 288))	('PHLDA1', 'Gene', (443, 449))	('MAP2K6', 'Gene', (350, 356))	('NKX2.2', 'Gene', (396, 402))	('NR0B1', 'Gene', '190', (420, 425))	('Hs00609296_g1', 'Var', (266, 279))	('EWS-FLI1', 'Gene', (211, 219))	('Hs00609976_m1', 'Var', (380, 393))	('Hs00201927_m1', 'Var', (290, 303))	('NKX2.2', 'Gene', '4821', (396, 402))	('NGFR', 'Gene', '4804', (374, 378))	('Hs03024807_ft', 'Var', (221, 234))	('Hs01077215_m1', 'Var', (313, 326))	('Hs00378285_g1', 'Var', (451, 464))	('MAP2K6', 'Gene', '5608', (350, 356))	('NR0B1', 'Gene', (420, 425))	('EWS-FLI1', 'Gene', '2130;2313', (211, 219))	('PHLDA1', 'Gene', '22822', (443, 449))	('LEMD1', 'Gene', '93273', (306, 311))	('ITGA11', 'Gene', (282, 288))	('LOX', 'Gene', '4015', (329, 332))	('Hs04420697_g1', 'Var', (244, 257))	('Hs00942481_m1', 'Var', (334, 347))	('NGFR', 'Gene', (374, 378))	('HMBS', 'Gene', (260, 264))	('Hs00324123_m1', 'Var', (180, 193))	('Hs00992389_m1', 'Var', (358, 371))	('Hs00159616_m1', 'Var', (404, 417))	('LEMD1', 'Gene', (306, 311))	('HMBS', 'Gene', '3145', (260, 264))	('LOX', 'Gene', (329, 332))
577233	30647860	In 2018, a phase I study opened testing the clinical analogue (Seclidemstat) of the lysine demethylase 1A (KDM1A/LSD1) inhibitor SP-2509 (Salarius Pharmaceuticals) in Ewing sarcoma.	('KDM1A', 'Gene', (107, 112))	('lysine demethylase 1A', 'Gene', (84, 105))	('lysine demethylase 1A', 'Gene', '23028', (84, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (167, 180))	('SP-2509', 'Var', (129, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (167, 180))	('LSD1', 'Gene', (113, 117))	('KDM1A', 'Gene', '23028', (107, 112))	('LSD1', 'Gene', '23028', (113, 117))	('SP-2509', 'Chemical', 'MESH:C000594309', (129, 136))	('Ewing sarcoma', 'Disease', (167, 180))
577235	30647860	Despite SP-2509 showing excellent preclinical single agent efficiency, Pishas and Lessnick recognized the concern for the development of resistance to KDM1A inhibition.	('KDM1A', 'Gene', (151, 156))	('SP-2509', 'Chemical', 'MESH:C000594309', (8, 15))	('SP-2509', 'Var', (8, 15))	('KDM1A', 'Gene', '23028', (151, 156))
577237	30647860	Pishas et al determined that de novo KDM1A mutations are not present and do not explain A673 cell resistance to SP-2509.	('mutations', 'Var', (43, 52))	('SP-2509', 'Chemical', 'MESH:C000594309', (112, 119))	('KDM1A', 'Gene', (37, 42))	('KDM1A', 'Gene', '23028', (37, 42))
577239	30647860	This observation highlights the very significant heterogeneity in the response of Ewing tumors and commonly used Ewing cell lines to manipulation of EWS/FLI1 expression and function.	('EWS', 'Gene', '2130', (149, 152))	('EWS', 'Gene', (149, 152))	('Ewing tumors', 'Disease', 'MESH:C563168', (82, 94))	('manipulation', 'Var', (133, 145))	('FLI1', 'Gene', '2313', (153, 157))	('Ewing tumors', 'Phenotype', 'HP:0012254', (82, 94))	('FLI1', 'Gene', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Ewing tumors', 'Disease', (82, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('Ewing tumor', 'Phenotype', 'HP:0012254', (82, 93))
577240	30647860	SP-2509 treatment results in enhanced expression of proteins such as zyxin, a regulator of the actin cytoskeleton that is usually repressed by EWS/FLI1, and cell morphologic changes observed in A673 SP-2509 DR cells are able to be reversed within a week of drug removal.	('enhanced', 'PosReg', (29, 37))	('FLI1', 'Gene', '2313', (147, 151))	('A673 SP-2509', 'Var', (194, 206))	('expression', 'MPA', (38, 48))	('proteins', 'Protein', (52, 60))	('SP-2509', 'Chemical', 'MESH:C000594309', (0, 7))	('SP-2509', 'Chemical', 'MESH:C000594309', (199, 206))	('zyxin', 'Protein', (69, 74))	('EWS', 'Gene', '2130', (143, 146))	('EWS', 'Gene', (143, 146))	('FLI1', 'Gene', (147, 151))
577241	30647860	In stark contrast to the rapidly reversible morphologic change induced by SP-2509, the altered transcriptomic profiles induced by SP-2509 largely persist even following long-term drug washout.	('SP-2509', 'Chemical', 'MESH:C000594309', (130, 137))	('SP-2509', 'Var', (130, 137))	('transcriptomic profiles', 'MPA', (95, 118))	('SP-2509', 'Chemical', 'MESH:C000594309', (74, 81))
577246	30647860	In contrast, A673 SP-2509 DR washout cells were not sensitive to HDAC inhibitors but did regain sensitivity to cytotoxic chemotherapy such as vincristine.	('A673 SP-2509 DR', 'Var', (13, 28))	('regain', 'PosReg', (89, 95))	('sensitivity to cytotoxic chemotherapy', 'MPA', (96, 133))	('SP-2509', 'Chemical', 'MESH:C000594309', (18, 25))	('vincristine', 'Chemical', 'MESH:D014750', (142, 153))
577279	29491605	To confirm this, subsequent cytogenetic studies were performed which demonstrated that all these tumors contained a common karyotypic change, i.e., t (11;22) (q24;q12).	('t (11;22) (q24;q12', 'Var', (148, 166))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('contained', 'Reg', (104, 113))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
577466	32706839	KSHV is known to cause KS, but there are no preventive or curative vaccines.	('KSHV', 'Species', '37296', (0, 4))	('KSHV', 'Var', (0, 4))	('KS', 'Phenotype', 'HP:0100726', (23, 25))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('cause', 'Reg', (17, 22))
577493	32706839	Apart from inducing anti-inflammatory cytokines, KSHV is known to induce metabolic changes in infected cells.	('KSHV', 'Species', '37296', (49, 53))	('anti-inflammatory cytokines', 'MPA', (20, 47))	('KSHV', 'Var', (49, 53))	('inducing', 'Reg', (11, 19))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('induce', 'Reg', (66, 72))	('metabolic changes', 'CPA', (73, 90))	('infected', 'Disease', 'MESH:D007239', (94, 102))	('infected', 'Disease', (94, 102))
577504	32706839	This is to determine whether KSHV has a systematic effect on gene expression profiles, even in non-disease sites, and to ensure that uninvolved control skin in KS patients is indeed 'normal'.	('patients', 'Species', '9606', (163, 171))	('effect', 'Reg', (51, 57))	('gene expression profiles', 'MPA', (61, 85))	('KS', 'Phenotype', 'HP:0100726', (29, 31))	('KSHV', 'Species', '37296', (29, 33))	('KS', 'Phenotype', 'HP:0100726', (160, 162))	('KSHV', 'Var', (29, 33))
577522	32706839	KSHV vDNA was then detected by nested PCR of the KSHV ORF26 gene using the following primers, forward [5'-AGCCGAAAGATTCCACCAT-3'] and reverse [5'-TCCGTGTTGTCTACGTCCAG-3'] in the first round, and forward [5'-CGAATCCAACGGATTTGACCTC-3'] and reverse [5'-CCCATAAATGACACATTGGTGGTA-3'] in the second round reaction.	('KSHV', 'Species', '37296', (0, 4))	("forward [5'-CGAATCCAACGGATTTGACCTC-3", 'Var', (195, 231))	('KSHV', 'Species', '37296', (49, 53))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	("forward [5'-AGCCGAAAGATTCCACCAT-3", 'Var', (94, 127))	('ORF26', 'Gene', (54, 59))	("reverse [5'-CCCATAAATGACACATTGGTGGTA-3", 'Var', (238, 276))	('ORF26', 'Gene', '440829', (54, 59))	("reverse [5'-TCCGTGTTGTCTACGTCCAG-3", 'Var', (134, 168))
577544	32706839	Unlike other reports from SSA, A*02 (13/24, 54%) and B*07 (17/24, 71%) were the major supertypes observed in KS patients (S1 Table).	('A*02', 'Var', (31, 35))	('KS', 'Phenotype', 'HP:0100726', (109, 111))	('patients', 'Species', '9606', (112, 120))	('B*07', 'Var', (53, 57))
577632	32706839	It is possible that KSHV manipulation of IFIH1, an innate immune sensor of viral nucleic acids associated with type-1 interferon antiviral responses, could be important in immune evasion.	('IFIH1', 'Gene', (41, 46))	('KS', 'Phenotype', 'HP:0100726', (20, 22))	('KSHV', 'Species', '37296', (20, 24))	('important', 'Reg', (159, 168))	('immune evasion', 'MPA', (172, 186))	('manipulation', 'Var', (25, 37))	('IFIH1', 'Gene', '64135', (41, 46))
577636	32706839	In other words, it takes a greater extent of cellular reprogramming for KSHV to induce cancer on its own than when in the presence of HIV-1 co-infection.	('HIV-1 co-infection', 'Disease', (134, 152))	('cancer', 'Disease', (87, 93))	('induce', 'Reg', (80, 86))	('KS', 'Phenotype', 'HP:0100726', (72, 74))	('KSHV', 'Species', '37296', (72, 76))	('KSHV', 'Var', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('HIV-1 co-infection', 'Disease', 'MESH:D060085', (134, 152))
577659	32706839	A*02 and B*07 supertypes were the most common supertypes in our KS patients as compared to B*27 and B*44 in Cameroon.	('KS', 'Phenotype', 'HP:0100726', (64, 66))	('patients', 'Species', '9606', (67, 75))	('B*07', 'Var', (9, 13))	('A*02', 'Var', (0, 4))	('common', 'Reg', (39, 45))
577680	32922892	The chromosomal translocation t(11;22) (q24;q12) is pathognomonic for Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (70, 85))	('t(11;22) (q24;q12', 'Var', (30, 47))	("Ewing's sarcoma", 'Disease', (70, 85))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (70, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))
577716	32922892	Isochromosome 17q and c-MYC amplification are the common abnormalities in cPNET.	('cPNET', 'Phenotype', 'HP:0030070', (74, 79))	('c-MYC', 'Gene', '4609', (22, 27))	('cPNET', 'Disease', (74, 79))	('c-MYC', 'Gene', (22, 27))	('Isochromosome 17q', 'Var', (0, 17))	('PNET', 'Phenotype', 'HP:0030065', (75, 79))
577723	32922892	Other factors that have been suggested to result in poor prognosis are large tumor volume (> 200 ml), atypical histology, metastatic lesions, loss of p16 expression, and gains of 1q and12.	('p16', 'Gene', (150, 153))	('loss', 'NegReg', (142, 146))	('metastatic lesions', 'CPA', (122, 140))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('p16', 'Gene', '1029', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('gains', 'Var', (170, 175))	('tumor', 'Disease', (77, 82))	('expression', 'MPA', (154, 164))
577827	25310215	A definitive diagnosis is based of the histopathological finding of at least 1 of the following: langerin (CD207) positivity, CD1a positivity, or the presence of Birbeck granules on electron microscopy.	('CD207', 'Gene', '50489', (107, 112))	('CD1a', 'Gene', '909', (126, 130))	('CD207', 'Gene', (107, 112))	('positivity', 'Var', (114, 124))	('positivity', 'Var', (131, 141))	('langerin', 'Gene', (97, 105))	('langerin', 'Gene', '50489', (97, 105))	('CD1a', 'Gene', (126, 130))
577874	25310215	Patients with the plasma cell variant were more likely to have multicentric disease, and these patients were more likely to be older, have B symptoms, palpable disease, peripheral neuropathy, extravascular volume overload, coexisting polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormality (POEMS) syndrome, bony sclerosis, anemia, leukocytosis, thrombocytosis, a high sedimentation rate, hypergammaglobulinemia, a low albumin rate, and an elevated creatinine level.	('sedimentation rate', 'MPA', (403, 421))	('plasma cell variant', 'Var', (18, 37))	('men', 'Species', '9606', (407, 410))	('anemia', 'Phenotype', 'HP:0001903', (358, 364))	('palpable', 'Disease', (151, 159))	('polyneuropathy', 'Disease', (234, 248))	('leukocytosis', 'Disease', 'MESH:D007964', (366, 378))	('leukocytosis', 'Phenotype', 'HP:0001974', (366, 378))	('multicentric disease', 'Disease', 'MESH:C537372', (63, 83))	('thrombocytosis', 'Disease', (380, 394))	('hypergammaglobulinemia', 'Phenotype', 'HP:0010702', (423, 445))	('multicentric disease', 'Disease', (63, 83))	('leukocytosis', 'Disease', (366, 378))	('hypergammaglobulinemia', 'Disease', 'MESH:D006942', (423, 445))	('endocrinopathy', 'Disease', (264, 278))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (169, 190))	('anemia', 'Disease', (358, 364))	('thrombocytosis', 'Phenotype', 'HP:0001894', (380, 394))	('elevated creatinine', 'Phenotype', 'HP:0003259', (474, 493))	('volume overload', 'Phenotype', 'HP:0011105', (206, 221))	('bony sclerosis', 'Disease', (342, 356))	('B symptoms', 'Disease', (139, 149))	('monoclonal gammopathy', 'Disease', 'MESH:D010265', (280, 301))	('hypergammaglobulinemia', 'Disease', (423, 445))	('Patients', 'Species', '9606', (0, 8))	('bony sclerosis', 'Disease', 'MESH:D012516', (342, 356))	('high sedimentation rate', 'Phenotype', 'HP:0003565', (398, 421))	('skin abnormality (POEMS) syndrome', 'Disease', 'MESH:D016878', (307, 340))	('creatinine level', 'MPA', (483, 499))	('organomegaly', 'Disease', (250, 262))	('variant', 'Var', (30, 37))	('low albumin', 'Phenotype', 'HP:0003073', (449, 460))	('anemia', 'Disease', 'MESH:D000740', (358, 364))	('extravascular volume overload', 'Disease', (192, 221))	('monoclonal gammopathy', 'Disease', (280, 301))	('albumin rate', 'MPA', (453, 465))	('low', 'NegReg', (449, 452))	('patients', 'Species', '9606', (95, 103))	('skin abnormality', 'Phenotype', 'HP:0000951', (307, 323))	('thrombocytosis', 'Disease', 'MESH:D013922', (380, 394))	('polyneuropathy', 'Disease', 'MESH:D011115', (234, 248))	('polyneuropathy', 'Phenotype', 'HP:0001271', (234, 248))	('organomegaly', 'Disease', 'MESH:D016878', (250, 262))	('endocrinopathy', 'Disease', 'MESH:C567425', (264, 278))	('elevated', 'PosReg', (474, 482))	('peripheral neuropathy', 'Disease', (169, 190))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (169, 190))
577917	25873501	Recently, the first definitively oncogenic alteration of STAT6 was identified as a specific driver of tumorigenesis in solitary fibrous tumors.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('alteration', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('solitary fibrous tumors', 'Disease', (119, 142))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('STAT6', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('STAT6', 'Gene', '6778', (57, 62))	('solitary fibrous tumors', 'Disease', 'MESH:D054364', (119, 142))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (136, 141))
577923	25873501	The fusion of NAB2 and STAT6 most commonly results in the replacement of the NAB2 repressor domain by either a full-length STAT6 protein (exon 4 to exon 2/3) or the fusion of a near complete NAB2 protein and the transactivation domain of STAT6 (exon 6 to exon 16/17).	('replacement', 'Var', (58, 69))	('protein', 'Protein', (196, 203))	('results in', 'Reg', (43, 53))	('NAB2', 'Gene', (191, 195))	('NAB2', 'Gene', '4665', (77, 81))	('STAT6', 'Gene', '6778', (123, 128))	('fusion', 'Var', (165, 171))	('fusion', 'Var', (4, 10))	('STAT6', 'Gene', (238, 243))	('NAB2', 'Gene', '4665', (14, 18))	('STAT6', 'Gene', (23, 28))	('NAB2', 'Gene', (77, 81))	('STAT6', 'Gene', '6778', (238, 243))	('NAB2', 'Gene', '4665', (191, 195))	('STAT6', 'Gene', '6778', (23, 28))	('NAB2', 'Gene', (14, 18))	('STAT6', 'Gene', (123, 128))
577924	25873501	While normal cells typically express low levels of cytoplasmic and nuclear STAT6, the chimeric NAB2-STAT6 protein is detected at high levels in the nucleus of the neoplastic cells of solitary fibrous tumor.	('solitary fibrous tumor', 'Disease', (183, 205))	('STAT6', 'Gene', (100, 105))	('chimeric', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('NAB2', 'Gene', '4665', (95, 99))	('solitary fibrous tumor', 'Disease', 'MESH:D054364', (183, 205))	('STAT6', 'Gene', '6778', (100, 105))	('STAT6', 'Gene', (75, 80))	('NAB2', 'Gene', (95, 99))	('STAT6', 'Gene', '6778', (75, 80))
577969	25873501	Nonreactivity for STAT6 was most common in alveolar soft part sarcoma (18/25, 72%), pleomorphic liposarcoma (33/55, 60%), dermatofibrosarcoma protuberans (3/6, 50%) and myxoid liposarcoma (52/108, 48%).	('Nonreactivity', 'Var', (0, 13))	('STAT6', 'Gene', '6778', (18, 23))	('dermatofibrosarcoma protuberans', 'Disease', (122, 153))	('pleomorphic liposarcoma', 'Disease', (84, 107))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (169, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (52, 69))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (43, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('myxoid liposarcoma', 'Disease', (169, 187))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (43, 69))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (122, 153))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (169, 187))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (84, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('common', 'Reg', (33, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('alveolar soft part sarcoma', 'Disease', (43, 69))	('STAT6', 'Gene', (18, 23))	('liposarcoma', 'Phenotype', 'HP:0012034', (96, 107))	('liposarcoma', 'Phenotype', 'HP:0012034', (176, 187))
577985	25873501	In the event of STAT6 expression in such cases, both may be distinguished from solitary fibrous tumor by the pattern of elevated cytoplasmic and nuclear STAT6, as well as by the co-expression of MDM2, demonstrable by immunohistochemistry or molecular evidence of gene amplification.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('expression', 'Var', (22, 32))	('MDM2', 'Gene', '4193', (195, 199))	('STAT6', 'Gene', (16, 21))	('MDM2', 'Gene', (195, 199))	('STAT6', 'Gene', (153, 158))	('solitary fibrous tumor', 'Disease', (79, 101))	('STAT6', 'Gene', '6778', (153, 158))	('elevated', 'PosReg', (120, 128))	('STAT6', 'Gene', '6778', (16, 21))	('solitary fibrous tumor', 'Disease', 'MESH:D054364', (79, 101))
577990	25873501	Thus, positivity for STAT6 in these 2 cases was able to resolve the diagnostic dilemma and confirm a suspected diagnosis of solitary fibrous tumor.	('STAT6', 'Gene', (21, 26))	('solitary fibrous tumor', 'Disease', (124, 146))	('solitary fibrous tumor', 'Disease', 'MESH:D054364', (124, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('STAT6', 'Gene', '6778', (21, 26))	('positivity', 'Var', (6, 16))
577996	25873501	In desmoid tumors however, the role of Il-4/IL-13 signaling is not well studied, and it is possible that alterations in STAT6-mediated signaling may play a role in mediating the distinctive histologic features of this scar-like neoplasm.	('STAT6', 'Gene', '6778', (120, 125))	('IL-13', 'Gene', '3596', (44, 49))	('Il-4', 'Gene', '3565', (39, 43))	('desmoid tumors', 'Phenotype', 'HP:0100245', (3, 17))	('play', 'Reg', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('desmoid tumors', 'Disease', 'MESH:C535944', (3, 17))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('alterations', 'Var', (105, 116))	('neoplasm', 'Disease', (228, 236))	('desmoid tumors', 'Disease', (3, 17))	('Il-4', 'Gene', (39, 43))	('neoplasm', 'Phenotype', 'HP:0002664', (228, 236))	('STAT6', 'Gene', (120, 125))	('scar', 'Phenotype', 'HP:0100699', (218, 222))	('IL-13', 'Gene', (44, 49))	('neoplasm', 'Disease', 'MESH:D009369', (228, 236))
578005	23110891	Methylation specific PCR detected methylated MGMT promoter in 10/75 cases.	('MGMT', 'Gene', (45, 49))	('MGMT', 'Gene', '4255', (45, 49))	('methylated', 'Var', (34, 44))
578009	23110891	MGMT gene silencing is a rare event in soft tissue sarcoma and cannot be recommended as a selection criterion for the therapy of STS patients with alkylating agents such as temozolomide.	('MGMT', 'Gene', (0, 4))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (39, 58))	('gene silencing', 'Var', (5, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('patients', 'Species', '9606', (133, 141))	('STS', 'Phenotype', 'HP:0030448', (129, 132))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (39, 58))	('soft tissue sarcoma', 'Disease', (39, 58))	('temozolomide', 'Chemical', 'MESH:D000077204', (173, 185))	('MGMT', 'Gene', '4255', (0, 4))
578015	23110891	The activity of temozolomide in glioblastoma patients relies on gene silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA repair gene, though .	('glioblastoma', 'Phenotype', 'HP:0012174', (32, 44))	('MGMT', 'Gene', (86, 90))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (92, 130))	('MGMT', 'Gene', '4255', (86, 90))	('glioblastoma', 'Disease', 'MESH:D005909', (32, 44))	('activity', 'MPA', (4, 12))	('O6-methylguanine-DNA methyltransferase', 'Gene', (92, 130))	('patients', 'Species', '9606', (45, 53))	('temozolomide', 'Chemical', 'MESH:D000077204', (16, 28))	('glioblastoma', 'Disease', (32, 44))	('silencing', 'NegReg', (69, 78))	('gene', 'Var', (64, 68))
578022	23110891	These tumor blocks were analysed by methylation specific polymerase chain reaction (PCR) and immunohistochemistry to detect MGMT gene silencing.	('MGMT', 'Gene', (124, 128))	('MGMT', 'Gene', '4255', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('gene', 'Var', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
578056	23110891	Although MGMT gene silencing may increase the effect of alkylating agents given in combination with irradiation, we believe that the frequency of MGMT gene silencing is too low to use it as a selection or stratification criterion in a phase II trial of concomitant irradiation and alkylating agent therapy.	('effect', 'MPA', (46, 52))	('MGMT', 'Gene', '4255', (146, 150))	('MGMT', 'Gene', (146, 150))	('MGMT', 'Gene', '4255', (9, 13))	('MGMT', 'Gene', (9, 13))	('increase', 'PosReg', (33, 41))	('gene silencing', 'Var', (14, 28))
578259	31624749	Unlike other groups of sarcomas with peculiar genetic alterations and simple karyotypes, such as specific KIT mutations in GIST, myxofibrosarcomas seem to be complex and very heterogeneous, lacking specific or recurrent genetic patterns.	('peculiar genetic alterations', 'Disease', (37, 65))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('mutations', 'Var', (110, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('myxofibrosarcomas', 'Disease', 'None', (129, 146))	('peculiar genetic alterations', 'Disease', 'MESH:D030342', (37, 65))	('sarcomas', 'Disease', (138, 146))	('myxofibrosarcomas', 'Disease', (129, 146))	('KIT', 'Gene', '3815', (106, 109))	('sarcomas', 'Disease', 'MESH:D012509', (23, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('GIST', 'Disease', 'MESH:D046152', (123, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('KIT', 'Gene', (106, 109))	('sarcomas', 'Disease', (23, 31))	('GIST', 'Disease', (123, 127))
578261	31624749	Mutations, novel amplifications and copy number alterations have been particularly observed in high grade, metastatic or recurrent myxofibrosarcomas compared with low-grade forms, even if the small case series does not allow for conclusive evaluations.	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('myxofibrosarcomas', 'Disease', 'None', (131, 148))	('amplifications', 'Var', (17, 31))	('myxofibrosarcomas', 'Disease', (131, 148))	('high grade', 'Disease', (95, 105))	('Mutations', 'Var', (0, 9))	('copy number alterations', 'Var', (36, 59))	('metastatic', 'Disease', (107, 117))	('observed', 'Reg', (83, 91))
578368	21750201	Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism.	('Temsirolimus', 'Chemical', 'MESH:C401859', (43, 55))	('IGF-1R', 'Gene', '3480', (214, 220))	('insulin', 'Gene', (177, 184))	('Cixutumumab', 'Chemical', 'MESH:C557414', (17, 28))	('AKT', 'Gene', (145, 148))	('inhibitors', 'Var', (126, 136))	('IGF-1R', 'Gene', (214, 220))	('insulin', 'Gene', '3630', (177, 184))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('Mammalian target of rapamycin', 'Gene', '2475', (89, 118))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Mammalian target of rapamycin', 'Gene', (89, 118))	('mTOR', 'Gene', (120, 124))	('Patients', 'Species', '9606', (59, 67))	('mTOR', 'Gene', '2475', (120, 124))	('AKT', 'Gene', '207', (145, 148))	('activation', 'PosReg', (149, 159))
578369	21750201	Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human IgG1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition.	('mTOR', 'Gene', '2475', (14, 18))	('mTOR', 'Gene', (210, 214))	('modulating', 'Reg', (185, 195))	('enhance', 'PosReg', (140, 147))	('cancer', 'Disease', (166, 172))	('mTOR', 'Gene', (148, 152))	('human', 'Species', '9606', (68, 73))	('IGF-1R', 'Gene', '3480', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('mTOR', 'Gene', '2475', (148, 152))	('cixutumumab', 'Var', (47, 58))	('IGF-1R', 'Gene', (116, 122))	('cixutumumab', 'Chemical', 'MESH:C557414', (47, 58))	('temsirolimus', 'Chemical', 'MESH:C401859', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mTOR', 'Gene', '2475', (210, 214))	('mTOR', 'Gene', (14, 18))
578378	21750201	PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGFBP3.	('increased', 'PosReg', (69, 78))	('IGFBP3', 'Gene', (96, 102))	('temsirolimus', 'Chemical', 'MESH:C401859', (56, 68))	('PD', 'Disease', 'MESH:D010300', (0, 2))	('cixutumumab', 'Var', (21, 32))	('increased plasma IGF-1', 'Phenotype', 'HP:0030269', (69, 91))	('IGFBP3', 'Gene', '3486', (96, 102))	('cixutumumab', 'Chemical', 'MESH:C557414', (21, 32))	('IGF-1', 'Gene', '3479', (86, 91))	('IGF-1', 'Gene', (86, 91))
578382	21750201	Recent studies in in vitro and in vivo models as well as using tumor biopsies from patients have demonstrated that treatment with mTOR inhibitors leads to upregulation of AKT phosphorylation in tumors, which may antagonize the antiproliferative effects of mTOR inhibition.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('AKT', 'Gene', '207', (171, 174))	('mTOR', 'Gene', '2475', (256, 260))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mTOR', 'Gene', (130, 134))	('tumor', 'Disease', (194, 199))	('mTOR', 'Gene', (256, 260))	('mTOR', 'Gene', '2475', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Disease', (194, 200))	('upregulation', 'PosReg', (155, 167))	('AKT', 'Gene', (171, 174))	('inhibitors', 'Var', (135, 145))
578383	21750201	Several studies have shown that mTOR inhibitors mediate AKT activation through an IGF-1R-dependent mechanism and that IGF-1R inhibitors may abrogate or reduce AKT phosphorylation induced by mTOR inhibitors.	('AKT', 'Gene', '207', (56, 59))	('IGF-1R', 'Gene', (118, 124))	('reduce', 'NegReg', (152, 158))	('AKT', 'Gene', (159, 162))	('mTOR', 'Gene', '2475', (190, 194))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (190, 194))	('AKT', 'Gene', (56, 59))	('mTOR', 'Gene', (32, 36))	('activation', 'PosReg', (60, 70))	('IGF-1R', 'Gene', '3480', (82, 88))	('abrogate', 'NegReg', (140, 148))	('IGF-1R', 'Gene', (82, 88))	('inhibitors', 'Var', (125, 135))	('AKT', 'Gene', '207', (159, 162))	('IGF-1R', 'Gene', '3480', (118, 124))
578389	21750201	Patients must have absolute neutrophil count >= 1500/mL; platelets >= 100,000/mL; creatinine <= 2x ULN; bilirubin <= 1.5 x ULN; AST(SGOT) and/or ALT(SGPT) <= 5x ULN.	('AST', 'MPA', (128, 131))	('>= 1500/mL', 'Var', (45, 55))	('absolute neutrophil', 'MPA', (19, 38))	('creatinine', 'Chemical', 'MESH:D003404', (82, 92))	('bilirubin', 'MPA', (104, 113))	('ALT', 'MPA', (145, 148))	('bilirubin', 'Chemical', 'MESH:D001663', (104, 113))	('platelets', 'CPA', (57, 66))	('Patients', 'Species', '9606', (0, 8))	('creatinine', 'MPA', (82, 92))
578390	21750201	There was no limit to prior numbers of treatment, including IGF-1R inhibitors or mTOR inhibitors.	('inhibitors', 'Var', (67, 77))	('IGF-1R', 'Gene', '3480', (60, 66))	('IGF-1R', 'Gene', (60, 66))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))
578461	21750201	Among 17 patients with available SUV changes from Day 0 to Day 3, seven patients had a decrease in SUV in all locations, five patients had a mixture of SUV decrease/increase in different locations, and five patients had increased SUV in all disease sites.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (207, 215))	('SUV', 'MPA', (99, 102))	('changes', 'Var', (37, 44))	('decrease', 'NegReg', (87, 95))	('patients', 'Species', '9606', (126, 134))	('decrease/increase', 'PosReg', (156, 173))	('patients', 'Species', '9606', (72, 80))
578462	21750201	Among 14 patients with SUV changes available from Day 0 to Day 11, five patients had a decrease in all sites, five patients had a mixture of SUV decrease/increase in different sites, and four patients had increased SUV in all locations.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (192, 200))	('decrease', 'NegReg', (87, 95))	('changes', 'Var', (27, 34))	('patients', 'Species', '9606', (72, 80))
578463	21750201	Among nine patients with available SUV changes from Day 0 to Day 56, five patients had a decrease in all sites, one patient had a mixture of SUV decrease/increase in different locations, and three patients had an increased SUV in all sites where there was tumor.	('patient', 'Species', '9606', (74, 81))	('patients', 'Species', '9606', (197, 205))	('patient', 'Species', '9606', (116, 123))	('changes', 'Var', (39, 46))	('patients', 'Species', '9606', (74, 82))	('decrease', 'NegReg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('patients', 'Species', '9606', (11, 19))	('patient', 'Species', '9606', (197, 204))	('tumor', 'Disease', (256, 261))
578485	21750201	Overall, the plasma IGF-1 and IGFBP3 levels suggest that cixutumumab and its combination with temsirolimus facilitates upregulation of IGF-1 and IGFBP3.	('IGF-1', 'Gene', (135, 140))	('cixutumumab', 'Var', (57, 68))	('IGFBP3', 'Gene', '3486', (30, 36))	('cixutumumab', 'Chemical', 'MESH:C557414', (57, 68))	('IGFBP3', 'Gene', (145, 151))	('temsirolimus', 'Chemical', 'MESH:C401859', (94, 106))	('IGF-1', 'Gene', '3479', (20, 25))	('IGF-1', 'Gene', (20, 25))	('IGFBP3', 'Gene', '3486', (145, 151))	('IGFBP3', 'Gene', (30, 36))	('facilitates upregulation', 'PosReg', (107, 131))	('IGF-1', 'Gene', '3479', (135, 140))	('upregulation of IGF-1', 'Phenotype', 'HP:0030269', (119, 140))
578538	32432058	Human bladder TMAs (T121a, T122, T123, T124, T125, HBlaU066Su01) were purchased from US Biomax, Rockville, MD 20849, US.	('Human', 'Species', '9606', (0, 5))	('bladder TMAs', 'Disease', (6, 18))	('T123', 'Var', (33, 37))	('T125', 'Var', (45, 49))	('HBlaU066Su01', 'CellLine', 'CVCL:Y448', (51, 63))	('bladder TMAs', 'Disease', 'MESH:D001745', (6, 18))	('T121a', 'Var', (20, 25))	('T121a', 'Mutation', 'c.121T>A', (20, 25))	('T124', 'Var', (39, 43))	('T122', 'Var', (27, 31))
578570	32432058	As such, TM has been shown to be a sensitive biomarker for urothelial carcinoma and the loss of TM immunoexpression is associated with cell proliferation, increased malignancy and poor prognosis.	('urothelial carcinoma', 'Disease', 'MESH:D014523', (59, 79))	('TM', 'Gene', '7056', (9, 11))	('malignancy', 'Disease', 'MESH:D009369', (165, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('increased', 'PosReg', (155, 164))	('malignancy', 'Disease', (165, 175))	('TM', 'Gene', '7056', (96, 98))	('loss', 'Var', (88, 92))	('cell proliferation', 'CPA', (135, 153))	('urothelial carcinoma', 'Disease', (59, 79))	('associated', 'Reg', (119, 129))
578574	32432058	One proposed mechanism hypothesizes that downregulation of TM enhances the tumor cell migratory ability by increasing vimentin expression and decreasing expression of E-cadherin.	('decreasing', 'NegReg', (142, 152))	('vimentin', 'Gene', '7431', (118, 126))	('expression', 'MPA', (127, 137))	('vimentin', 'Gene', (118, 126))	('downregulation', 'Var', (41, 55))	('E-cadherin', 'Gene', (167, 177))	('E-cadherin', 'Gene', '999', (167, 177))	('TM', 'Gene', '7056', (59, 61))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('increasing', 'PosReg', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('expression', 'MPA', (153, 163))	('enhances', 'PosReg', (62, 70))	('tumor', 'Disease', (75, 80))
578605	32432058	In conclusion, our results would suggest that decreased expression of TM in bladder cancer tissue is associated with a poor prognosis; loss of TM expression may indicate increased malignancy and may be a clinically relevant predictor of tumor progression and patient survival.	('bladder cancer', 'Disease', (76, 90))	('tumor', 'Disease', (237, 242))	('malignancy', 'Disease', 'MESH:D009369', (180, 190))	('TM', 'Gene', '7056', (143, 145))	('increased', 'PosReg', (170, 179))	('malignancy', 'Disease', (180, 190))	('expression', 'MPA', (56, 66))	('loss', 'Var', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('decreased', 'NegReg', (46, 55))	('TM', 'Gene', '7056', (70, 72))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('patient', 'Species', '9606', (259, 266))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
578624	29269643	For the initial diagnosis, we performed an immunohistochemical analysis, which showed the atypical large cells to be positive for CD10, CD19, and CD79a, partially positive for CD20, but negative for CD3, CD5, and terminal deoxynucleotidyl transferase (TdT) (Figure d-g).	('(TdT)', 'Gene', '1791', (251, 256))	('CD19', 'Gene', (136, 140))	('TdT', 'Gene', (252, 255))	('CD10', 'Gene', (130, 134))	('CD20', 'Gene', '54474', (176, 180))	('CD5', 'Gene', (204, 207))	('CD20', 'Gene', (176, 180))	('CD19', 'Gene', '930', (136, 140))	('CD10', 'Gene', '4311', (130, 134))	('CD5', 'Gene', '921', (204, 207))	('CD79a', 'Var', (146, 151))
578631	29269643	A cytogenetic study including a fluorescence in situ hybridization (FISH) analysis revealed a normal karyotype (46, XX) without any rearrangement of BCR-ABL or MLL.	('t of ', 'Gene', (144, 149))	('46, XX', 'Var', (112, 118))	('t of ', 'Gene', '55079', (144, 149))
578639	29269643	According to the 2008 WHO classification of hematopoietic and lymphoid tissues, MPAL was divided into five categories composed of two genetic categories, MPAL with t(9;22)(q34;q11.2) or BCR/ABL1 and MPAL with t(v;11q23) or MLL rearrangement, and three other less-specific categories, B/myeloid not otherwise specified (NOS), T/myeloid NOS, and other rare type types of MPAL.	('B/myeloid not otherwise specified', 'Disease', (284, 317))	('t(9;22)(q34;q11.2', 'Var', (164, 181))	('t(9;22)(q34;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (164, 182))	('MLL', 'Gene', (223, 226))	('T/myeloid', 'Disease', (325, 334))
578640	29269643	Cases that meet the criteria for MPAL are not classified as MS. We diagnosed this case as MPAL, B/myeloid NOS because the tumor cells were positive on immunohistochemistry for myeloperoxidase, CD10, CD19, and CD79a without BCR-ABL or MLL rearrangement.	('CD10', 'Gene', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('CD10', 'Gene', '4311', (193, 197))	('CD79a', 'Var', (209, 214))	('CD19', 'Gene', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('positive', 'Reg', (139, 147))	('CD19', 'Gene', '930', (199, 203))	('tumor', 'Disease', (122, 127))
578724	26718726	Additionally, median OS from time of diagnosis of RM disease was better in the SC treatment group when compared to the GYN/ONC treatment group (2.97 years vs. 0.9 years, HR 0.49, 95% CI 0.26-0.92, p=0.014) (FIGURE 1B).	('OS', 'Chemical', '-', (21, 23))	('RM disease', 'Disease', (50, 60))	('SC treatment', 'Var', (79, 91))	('RM disease', 'Disease', 'MESH:D004194', (50, 60))
578772	25432018	The functional inhibition of the analogues was measured by an EWS-FLI1/NR0B1 reporter luciferase assay and a paired cell screening approach measuring effects on growth inhibition for human cells containing EWS-FLI1 (TC32 and TC71) and control PANC1 cell lines devoid of the oncoprotein.	('N', 'Chemical', 'MESH:D009584', (245, 246))	('PANC1', 'CellLine', 'CVCL:0480', (243, 248))	('EWS-FLI1', 'Var', (206, 214))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('C', 'Chemical', 'MESH:D002244', (246, 247))	('growth', 'MPA', (161, 167))	('human', 'Species', '9606', (183, 188))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('NR0B1', 'Gene', '190', (71, 76))	('NR0B1', 'Gene', (71, 76))	('C', 'Chemical', 'MESH:D002244', (217, 218))
578782	25432018	Elimination of EWS-FLI1 through small interfering and antisense RNA results in the prolonged survival of ES xenograft-bearing mice.	('EWS-FLI1', 'Gene', (15, 23))	('mice', 'Species', '10090', (126, 130))	('prolonged', 'PosReg', (83, 92))	('Elimination', 'NegReg', (0, 11))	('antisense RNA', 'Var', (54, 67))	('small interfering', 'Var', (32, 49))
578784	25432018	We previously reported the discovery of NSC635437 (1), identified through screening of small molecules against recombinant EWS-FLI1 using surface plasmon resonance, and we developed YK-4-279 (2) with limited SAR (Figure 1A).	('SAR', 'Gene', (208, 211))	('EWS-FLI1', 'Gene', (123, 131))	('SAR', 'Gene', '1757', (208, 211))	('NSC635437', 'Var', (40, 49))
578839	25432018	HRMS (ES) m/z calcd for C17H10Cl2N2O3 (M - H)+ 358.9990; found, 358.9990.	('358.9990', 'Var', (64, 72))	('C17H10Cl2N2O3', 'Chemical', '-', (24, 37))	('C17H10Cl2N2O3', 'Var', (24, 37))
578853	25432018	Crystal data for 10, C17H11Cl2NO3: M = 348.17 g/mol, yellow, prism, 0.65 x 0.56 x 0.49 mm3, monoclinic, P21/c (No.	('P21/c', 'Gene', '644914', (104, 109))	('P21/c', 'Gene', (104, 109))	('C17H11Cl2NO3', 'Var', (21, 33))
578854	25432018	14), a = 8.9990 (3) A, b = 15.8170 (5) A, c = 11.6532 (4) A, beta = 111.787  (1 ), V = 1540.20 (9) A3 (from 9955 reflections, theta = 2.3-29.7 ), Z = 4, Dc = 1.501 g/cm3, F000 = 712, Bruker APEXII CCD, Mo Kalpha radiation, lambda = 0.710 73 A, T = 223(2) K, 2thetamax = 56.0 , 14 380 reflections collected, 3711 unique (Rint = 0.0186).	('CCD', 'Disease', (197, 200))	('CCD', 'Disease', 'MESH:D020512', (197, 200))	('c =', 'Var', (42, 45))
578899	22465830	In vitro, in vivo, and tumor biopsy studies demonstrate that mammalian target of rapamycin (mTOR) inhibitors activate a feedback loop resulting in upregulated AKT phosphorylation in tumor tissue, which occurs via an IGF-1R-dependent mechanism.	('tumor', 'Disease', (182, 187))	('mammalian target of rapamycin', 'Gene', (61, 90))	('inhibitors', 'Var', (98, 108))	('AKT', 'Gene', (159, 162))	('mammalian target of rapamycin', 'Gene', '2475', (61, 90))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('upregulated', 'PosReg', (147, 158))	('mTOR', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mTOR', 'Gene', '2475', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (23, 28))	('IGF-1R', 'Gene', '3480', (216, 222))	('AKT', 'Gene', '207', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('IGF-1R', 'Gene', (216, 222))
578900	22465830	This feedback and can be abrogated, or at least limited, by IGF-1R pathway inhibition.	('IGF-1R', 'Gene', (60, 66))	('IGF-1R', 'Gene', '3480', (60, 66))	('inhibition', 'Var', (75, 85))
578901	22465830	These observations provide a rational basis for combining mTOR and IGF-1R inhibitors as a way to overcome resistance to the agents when given as monotherapy.	('mTOR', 'Gene', (58, 62))	('IGF-1R', 'Gene', '3480', (67, 73))	('IGF-1R', 'Gene', (67, 73))	('inhibitors', 'Var', (74, 84))	('mTOR', 'Gene', '2475', (58, 62))
578908	22465830	DSRCT is associated with a unique chromosomal translocation, t(11;22)(p13:q12).	('t(11;22)(p13:q12)', 'STRUCTURAL_ABNORMALITY', 'None', (61, 78))	('t(11;22', 'Var', (61, 68))	('DSRCT', 'Disease', (0, 5))	('associated', 'Reg', (9, 19))
578910	22465830	When tested in the treatment of the EWS family of tumors, single-agent IGF-1R inhibitors and the mTOR inhibitor, temsirolimus, have produced variable outcomes.	('men', 'Species', '9606', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mTOR', 'Gene', '2475', (97, 101))	('IGF-1R', 'Gene', '3480', (71, 77))	('mTOR', 'Gene', (97, 101))	('IGF-1R', 'Gene', (71, 77))	('EWS', 'Gene', (36, 39))	('inhibitors', 'Var', (78, 88))	('EWS', 'Gene', '2130', (36, 39))	('temsirolimus', 'Chemical', 'MESH:C401859', (113, 125))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
578994	22465830	One patient who had previously received a different IGF-1R inhibitor (R1507) with response and then resistance achieved a CR on the current study.	('patient', 'Species', '9606', (4, 11))	('IGF-1R', 'Gene', (52, 58))	('IGF-1R', 'Gene', '3480', (52, 58))	('R1507', 'Var', (70, 75))
579010	23036272	The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS.	('RECQL4', 'Gene', (27, 33))	('RECQL4', 'Gene', (117, 123))	('OS', 'Phenotype', 'HP:0002669', (85, 87))	('OS', 'Phenotype', 'HP:0002669', (150, 152))	('OS', 'Phenotype', 'HP:0002669', (19, 21))	('RECQL4', 'Gene', '9401', (27, 33))	('RECQL4', 'Gene', '9401', (117, 123))	('mutations', 'Var', (34, 43))
579011	23036272	Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS.	('OS', 'Phenotype', 'HP:0002669', (160, 162))	('OS', 'Phenotype', 'HP:0002669', (81, 83))	('mutations', 'Var', (32, 41))	('P53', 'Gene', (45, 48))	('murine', 'Species', '10090', (143, 149))	('RB', 'Gene', '5925', (53, 55))	('RB', 'Phenotype', 'HP:0009919', (53, 55))
579038	23036272	Li-Fraumeni syndrome, familial Retinoblastoma and RecQ helicase disorders such as Rothmund-Thomson Syndrome (RTS) are caused by germ-line mutations of P53, RB and RECQL4 respectively.	('RECQL4', 'Gene', '9401', (163, 169))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('RecQ', 'Gene', (50, 54))	('caused by', 'Reg', (118, 127))	('Rothmund-Thomson Syndrome', 'Disease', 'MESH:D011038', (82, 107))	('RTS', 'Gene', '4204', (109, 112))	('familial Retinoblastoma', 'Disease', 'MESH:D012175', (22, 45))	('RECQL4', 'Gene', (163, 169))	('P53', 'Gene', (151, 154))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (31, 45))	('RB', 'Phenotype', 'HP:0009919', (156, 158))	('Rothmund-Thomson Syndrome', 'Disease', (82, 107))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('RB', 'Gene', '5925', (156, 158))	('RTS', 'Gene', (109, 112))	('familial Retinoblastoma', 'Disease', (22, 45))	('mutations', 'Var', (138, 147))
579042	23036272	In particular, transgenic and germ-line loss of function alleles have demonstrated important roles for p53 mutations in generating experimental OS.	('rat', 'Species', '10116', (124, 127))	('transgenic', 'Species', '10090', (15, 25))	('mutations', 'Var', (107, 116))	('p53', 'Gene', (103, 106))	('rat', 'Species', '10116', (77, 80))	('experimental OS', 'Disease', (131, 146))	('OS', 'Phenotype', 'HP:0002669', (144, 146))	('loss of function', 'NegReg', (40, 56))
579043	23036272	More recently, lineage-restricted somatic deletion models that generate high penetrant metastatic disease have been described.	('high penetrant metastatic disease', 'CPA', (72, 105))	('rat', 'Species', '10116', (67, 70))	('deletion models', 'Var', (42, 57))
579046	23036272	LFS patients have a highly elevated risk of developing soft tissue sarcoma and osteosarcoma, and mutations in the "p53-pathway" are thought to be essential for the formation of human cancer.	('mutations', 'Var', (97, 106))	('sarcoma', 'Disease', 'MESH:D012509', (67, 74))	('cancer', 'Disease', (183, 189))	('LFS', 'Disease', (0, 3))	('osteosarcoma', 'Phenotype', 'HP:0002669', (79, 91))	('osteosarcoma', 'Disease', (79, 91))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('osteosarcoma', 'Disease', 'MESH:D012516', (79, 91))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (55, 74))	('sarcoma', 'Disease', (84, 91))	('sarcoma', 'Disease', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('patients', 'Species', '9606', (4, 12))	('LFS', 'Disease', 'MESH:D016864', (0, 3))	('human', 'Species', '9606', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
579047	23036272	Interestingly, the P53 allele itself is found to be mutated in human OS, most commonly as missense mutations.	('missense mutations', 'Var', (90, 108))	('P53', 'Gene', (19, 22))	('human', 'Species', '9606', (63, 68))	('OS', 'Phenotype', 'HP:0002669', (69, 71))
579048	23036272	Other reported lesions in the p53 pathway in human OS include amplification of MDM2 and loss of p19ARF.	('amplification', 'Var', (62, 75))	('p19ARF', 'Gene', '1029', (96, 102))	('p19ARF', 'Gene', (96, 102))	('loss', 'NegReg', (88, 92))	('human', 'Species', '9606', (45, 50))	('MDM2', 'Gene', '4193', (79, 83))	('MDM2', 'Gene', (79, 83))	('p53 pathway', 'Pathway', (30, 41))	('OS', 'Phenotype', 'HP:0002669', (51, 53))
579049	23036272	Patients with familial retinoblastoma possess germline mutations in the Retinoblastoma (RB) gene.	('familial retinoblastoma', 'Disease', (14, 37))	('germline mutations', 'Var', (46, 64))	('RB', 'Phenotype', 'HP:0009919', (88, 90))	('familial retinoblastoma', 'Disease', 'MESH:D012175', (14, 37))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (72, 86))	('RB', 'Gene', '5925', (88, 90))	('Patients', 'Species', '9606', (0, 8))	('Retinoblastoma', 'Gene', '5925', (72, 86))	('retinoblastoma', 'Phenotype', 'HP:0009919', (23, 37))	('Retinoblastoma', 'Gene', (72, 86))
579055	23036272	Studies of radiation induced OS has observed mutation of P53 and retention of the intact RB allele in hereditary retinoblastoma patients.	('OS', 'Phenotype', 'HP:0002669', (29, 31))	('P53', 'Gene', (57, 60))	('retinoblastoma', 'Phenotype', 'HP:0009919', (113, 127))	('RB', 'Phenotype', 'HP:0009919', (89, 91))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (102, 127))	('mutation', 'Var', (45, 53))	('hereditary retinoblastoma', 'Disease', (102, 127))	('patients', 'Species', '9606', (128, 136))	('RB', 'Gene', '5925', (89, 91))
579056	23036272	As with the p53 pathway, mutations in the members of the Rb pathway occur frequently in OS with known mutations including amplifications of Cyclin E and CDK4.	('amplifications', 'Var', (122, 136))	('mutations', 'Var', (25, 34))	('Rb', 'Chemical', 'MESH:D012413', (57, 59))	('Cyclin', 'Gene', '5111', (140, 146))	('CDK4', 'Gene', '1019', (153, 157))	('CDK4', 'Gene', (153, 157))	('OS', 'Phenotype', 'HP:0002669', (88, 90))	('Cyclin', 'Gene', (140, 146))
579057	23036272	The majority of murine OS models to date have been developed based on knowledge of the mutation of p53 and Rb pathways in both familial and sporadic human OS.	('murine', 'Species', '10090', (16, 22))	('OS', 'Phenotype', 'HP:0002669', (23, 25))	('human', 'Species', '9606', (149, 154))	('Rb', 'Chemical', 'MESH:D012413', (107, 109))	('p53', 'Gene', (99, 102))	('mutation', 'Var', (87, 95))	('Rb pathways', 'Pathway', (107, 118))	('OS', 'Phenotype', 'HP:0002669', (155, 157))
579059	23036272	Mice with tumour-associated p53 variants presented with a higher incidence of OS than germ-line p53 null animals, amongst the tumour spectrum these animals develop.	('p53', 'Gene', (28, 31))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('OS', 'Phenotype', 'HP:0002669', (78, 80))	('tumour', 'Disease', (126, 132))	('variants', 'Var', (32, 40))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('Mice', 'Species', '10090', (0, 4))	('tumour', 'Disease', (10, 16))
579062	23036272	However, neither p107-/- nor p130-/- mice (or compound mutants that are viable) have a reported susceptibility to OS and these genes are not frequently mutated in human cancers based on data available through the COSMIC database.	('OS', 'Phenotype', 'HP:0002669', (114, 116))	('cancers', 'Disease', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('OS', 'Phenotype', 'HP:0002669', (214, 216))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('human', 'Species', '9606', (163, 168))	('p107-/-', 'Var', (17, 24))	('p130-/-', 'Var', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('mice', 'Species', '10090', (37, 41))
579063	23036272	Utilising Prx1-Cre, which deletes LoxP flanked alleles in the early budding mesenchymal tissue of the limbs, 22% of mice with p53 heterozygosity develop OS.	('OS', 'Phenotype', 'HP:0002669', (153, 155))	('mice', 'Species', '10090', (116, 120))	('develop', 'PosReg', (145, 152))	('Lox', 'Gene', (34, 37))	('deletes', 'Var', (26, 33))	('p53 heterozygosity', 'Var', (126, 144))	('Lox', 'Gene', '4015', (34, 37))
579064	23036272	However, the deletion of Rb alone in mesenchymal progenitors failed to produce OS tumours.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('deletion', 'Var', (13, 21))	('Rb', 'Chemical', 'MESH:D012413', (25, 27))	('OS tumours', 'Disease', (79, 89))	('OS', 'Phenotype', 'HP:0002669', (79, 81))	('OS tumours', 'Disease', 'MESH:C567932', (79, 89))
579068	23036272	Over 60% of Prx1-Cre-p53fl/fl mice developed OS, while the homozygous deletion of Rb in isolation again yielded no tumours.	('deletion', 'Var', (70, 78))	('mice', 'Species', '10090', (30, 34))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('tumours', 'Disease', (115, 122))	('Rb', 'Chemical', 'MESH:D012413', (82, 84))	('developed', 'PosReg', (35, 44))	('Prx1-Cre-p53fl/fl', 'Var', (12, 29))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('OS', 'Phenotype', 'HP:0002669', (45, 47))
579069	23036272	The compound deletion of one Rb allele with homozygous p53 deletion increased the OS incidence rate to 92%.	('compound deletion', 'Var', (4, 21))	('p53', 'Gene', (55, 58))	('rat', 'Species', '10116', (95, 98))	('OS', 'Phenotype', 'HP:0002669', (82, 84))	('Rb', 'Chemical', 'MESH:D012413', (29, 31))	('increased', 'PosReg', (68, 77))
579073	23036272	Rb mutation does show a profound synergy with p53 mutation in the induction of experimental OS.	('p53', 'Gene', (46, 49))	('OS', 'Phenotype', 'HP:0002669', (92, 94))	('mutation', 'Var', (3, 11))	('Rb', 'Chemical', 'MESH:D012413', (0, 2))	('mutation', 'Var', (50, 58))
579075	23036272	The experimental approaches strongly suggest that mutation on the p53 pathway can serve as an initiating event in OS with mutation in the Rb pathway strongly synergizing in the immortalisation of osteoblastic cells.	('OS', 'Phenotype', 'HP:0002669', (114, 116))	('p53 pathway', 'Pathway', (66, 77))	('mutation', 'Var', (122, 130))	('immortalisation of osteoblastic cells', 'CPA', (177, 214))	('synergizing', 'Reg', (158, 169))	('Rb pathway', 'Pathway', (138, 148))	('Rb', 'Chemical', 'MESH:D012413', (138, 140))	('mutation', 'Var', (50, 58))
579077	23036272	Most RTS patients have germ-line mutations in the RECQL4 DNA helicase.	('RECQL4', 'Gene', '9401', (50, 56))	('patients', 'Species', '9606', (9, 17))	('RTS', 'Gene', '4204', (5, 8))	('mutations', 'Var', (33, 42))	('RECQL4', 'Gene', (50, 56))	('RTS', 'Gene', (5, 8))
579081	23036272	RTS patients with truncating Recql4 mutations associate with a higher risk of developing OS as compared to non-truncated mutations.	('RTS', 'Gene', (0, 3))	('OS', 'Phenotype', 'HP:0002669', (89, 91))	('mutations', 'Var', (36, 45))	('developing OS', 'Disease', (78, 91))	('RTS', 'Gene', '4204', (0, 3))	('truncating', 'Var', (18, 28))	('patients', 'Species', '9606', (4, 12))	('Recql4', 'Gene', (29, 35))
579084	23036272	Recql4 deficiency in mice is associated with karyotypic abnormalities and increased rates of aneuploidy.	('mice', 'Species', '10090', (21, 25))	('rat', 'Species', '10116', (84, 87))	('karyotypic abnormalities', 'CPA', (45, 69))	('deficiency', 'Var', (7, 17))	('aneuploidy', 'MPA', (93, 103))	('Recql4', 'Gene', (0, 6))
579085	23036272	Strikingly in contrast to p53 and Rb mutations, Recql4 mutations are not associated with sporadic human OS and appear restricted to familial RTS OS.	('OS', 'Phenotype', 'HP:0002669', (145, 147))	('restricted', 'Reg', (118, 128))	('mutations', 'Var', (55, 64))	('RTS', 'Gene', (141, 144))	('Rb', 'Chemical', 'MESH:D012413', (34, 36))	('associated', 'Reg', (73, 83))	('RTS', 'Gene', '4204', (141, 144))	('OS', 'Phenotype', 'HP:0002669', (104, 106))	('Recql4', 'Gene', (48, 54))	('human', 'Species', '9606', (98, 103))
579086	23036272	The failure to find RECQL4 mutations in sporadic OS raises several questions regarding the nature of the disease and whether it represents a distinct entity or subtype of OS.	('mutations', 'Var', (27, 36))	('RECQL4', 'Gene', '9401', (20, 26))	('OS', 'Phenotype', 'HP:0002669', (171, 173))	('RECQL4', 'Gene', (20, 26))	('OS', 'Phenotype', 'HP:0002669', (49, 51))
579092	23036272	The attempts at modeling of Recql4 deficiency in mice has led to confounding results.	('deficiency', 'Var', (35, 45))	('mice', 'Species', '10090', (49, 53))	('Recql4', 'Gene', (28, 34))
579093	23036272	The homozygous mutants were viable but exhibited severe growth retardation and multiple abnormalities and 95% of the mice died within 2 weeks of birth.	('severe growth retardation', 'Phenotype', 'HP:0008850', (49, 74))	('growth retardation', 'Phenotype', 'HP:0001510', (56, 74))	('mice', 'Species', '10090', (117, 121))	('mutants', 'Var', (15, 22))	('growth retardation', 'Disease', 'MESH:D006130', (56, 74))	('multiple abnormalities', 'Disease', (79, 101))	('multiple abnormalities', 'Disease', 'MESH:D000015', (79, 101))	('growth retardation', 'Disease', (56, 74))
579094	23036272	The third allele involved replacement of part of exon 9 through to exon 13 with a PGK-Hprt mini gene cassette.	('replacement', 'Var', (26, 37))	('Hprt', 'Gene', '3251', (86, 90))	('Hprt', 'Gene', (86, 90))
579096	23036272	Approximately 16% of mice with homozygous Recql4 mutations died within 24hrs of birth.	('mice', 'Species', '10090', (21, 25))	('mutations', 'Var', (49, 58))	('Recql4', 'Gene', (42, 48))
579105	23036272	As for RTS, the relevance of these mutations to sporadic OS is also unclear and further work is needed to clarify the relationship between these OS and their sporadic counterpart.	('OS', 'Phenotype', 'HP:0002669', (145, 147))	('RTS', 'Gene', (7, 10))	('OS', 'Phenotype', 'HP:0002669', (57, 59))	('RTS', 'Gene', '4204', (7, 10))	('mutations', 'Var', (35, 44))
579107	23036272	Mice with homozygous deletion of BLM were embryonic lethal by day 13.5 and presented with an increased level of apoptosis and anaemia.	('increased', 'PosReg', (93, 102))	('anaemia', 'Disease', 'MESH:D000740', (126, 133))	('deletion', 'Var', (21, 29))	('BLM', 'Gene', (33, 36))	('anaemia', 'Disease', (126, 133))	('Mice', 'Species', '10090', (0, 4))	('anaemia', 'Phenotype', 'HP:0001903', (126, 133))
579109	23036272	Heterozygous mutant mice were also viable, with a predisposition to develop tumours.	('mutant', 'Var', (13, 19))	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('tumours', 'Disease', (76, 83))	('mice', 'Species', '10090', (20, 24))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
579111	23036272	Interestingly, the combined deletions of p53 and WRN in mice resulted in various soft tissue sarcomas, where half of these mice developed tumours by 3 months of age.	('mice', 'Species', '10090', (123, 127))	('resulted in', 'Reg', (61, 72))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (81, 100))	('sarcomas', 'Disease', 'MESH:D012509', (93, 101))	('deletions', 'Var', (28, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (93, 101))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('mice', 'Species', '10090', (56, 60))	('sarcomas', 'Disease', (93, 101))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (81, 101))	('WRN', 'Protein', (49, 52))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('p53', 'Gene', (41, 44))	('tumours', 'Disease', (138, 145))
579121	23036272	Two separate groups generated transgenic mice that possessed the p62 mutation present in patients with Paget's disease.	('rat', 'Species', '10116', (8, 11))	("Paget's disease", 'Disease', (103, 118))	('p62', 'Var', (65, 68))	('transgenic mice', 'Species', '10090', (30, 45))	('patients', 'Species', '9606', (89, 97))	('rat', 'Species', '10116', (24, 27))
579129	23036272	In addition, genetically engineered mice that overexpressed c-Fos developed OS, thus suggestive of its role in OS pathogenesis.	('OS', 'Phenotype', 'HP:0002669', (111, 113))	('developed', 'PosReg', (66, 75))	('mice', 'Species', '10090', (36, 40))	('c-Fos', 'Var', (60, 65))	('OS', 'Phenotype', 'HP:0002669', (76, 78))
579133	23036272	Amplification of the c-MYC gene is more prominent in Paget's disease-related OS as compared to primary OS, although genetic rearrangement does not appear to be the cause.	('Amplification', 'Var', (0, 13))	('c-MYC', 'Gene', (21, 26))	('OS', 'Phenotype', 'HP:0002669', (77, 79))	('c-MYC', 'Gene', '4609', (21, 26))	('OS', 'Phenotype', 'HP:0002669', (103, 105))	("Paget's disease-related OS", 'Disease', (53, 79))
579137	23036272	In a subsequent report from the same group, the tumour regression from c-MYC inactivation in OS cells was attributed to the induction of senescence.	('c-MYC', 'Gene', '4609', (71, 76))	('OS', 'Phenotype', 'HP:0002669', (93, 95))	('senescence', 'MPA', (137, 147))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('c-MYC', 'Gene', (71, 76))	('inactivation', 'Var', (77, 89))
579138	23036272	The development of OS was also reported in retrovirally transdcued c-MYC-overexpressing mesenchymal progenitor cells derived from Ink4a/Arf mutant mice.	('mice', 'Species', '10090', (147, 151))	('c-MYC', 'Gene', '4609', (67, 72))	('Ink4a', 'Gene', (130, 135))	('OS', 'Phenotype', 'HP:0002669', (19, 21))	('c-MYC', 'Gene', (67, 72))	('Ink4a', 'Gene', '12578', (130, 135))	('mutant', 'Var', (140, 146))
579142	23036272	A recent study of mice that expressed the SV40 T antigen in mature osteoblasts using the osteocalcin promoter presented with bone tumours and were morbid by 21 weeks of age.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('osteocalcin', 'Gene', '632', (89, 100))	('bone tumours', 'Disease', (125, 137))	('SV40 T', 'Var', (42, 48))	('bone tumours', 'Disease', 'MESH:D001859', (125, 137))	('mice', 'Species', '10090', (18, 22))	('SV40', 'Species', '1891767', (42, 46))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('osteocalcin', 'Gene', (89, 100))
579143	23036272	This timeframe for tumour development is strikingly similar to that observed with Osx-Cre p53fl/flpRbfl/fl animals.	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('p53fl/flpRbfl/fl', 'Var', (90, 106))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('tumour', 'Disease', (19, 25))
579144	23036272	The tumours in Ocn-SV40Tag animals were histologically confirmed as OS and possessed various levels of calcification.	('calcification', 'Disease', 'MESH:D002114', (103, 116))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('SV40', 'Species', '1891767', (19, 23))	('calcification', 'Disease', (103, 116))	('OS', 'Phenotype', 'HP:0002669', (68, 70))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('Ocn-SV40Tag', 'Var', (15, 26))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('tumours', 'Disease', (4, 11))
579147	23036272	Correspondingly, deletion of 1 allele of Prkar1a dramatically accelerated OS formation in mice with Ocn-SV40 T antigen with tumours arising within 5 weeks of birth.	('OS formation', 'CPA', (74, 86))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('OS', 'Phenotype', 'HP:0002669', (74, 76))	('mice', 'Species', '10090', (90, 94))	('deletion', 'Var', (17, 25))	('accelerated', 'PosReg', (62, 73))	('rat', 'Species', '10116', (68, 71))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('Prkar1a', 'Gene', (41, 48))	('SV40', 'Species', '1891767', (104, 108))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
579148	23036272	The analysis of human tumours found a subset of human OS also habour a Prkar1a deletion, demonstrating the power of mouse models to uncover new information into the complex genetics of human OS.	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('human', 'Species', '9606', (185, 190))	('habour', 'Reg', (62, 68))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('OS', 'Phenotype', 'HP:0002669', (191, 193))	('human', 'Species', '9606', (48, 53))	('Prkar1a', 'Gene', (71, 78))	('OS', 'Phenotype', 'HP:0002669', (54, 56))	('tumours', 'Disease', (22, 29))	('rat', 'Species', '10116', (96, 99))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('human', 'Species', '9606', (16, 21))	('deletion', 'Var', (79, 87))	('mouse', 'Species', '10090', (116, 121))
579151	23036272	p15INK4b was demonstrated to be repressed by c-MYC expression.	('rat', 'Species', '10116', (20, 23))	('c-MYC', 'Gene', '4609', (45, 50))	('p15INK4b', 'Var', (0, 8))	('c-MYC', 'Gene', (45, 50))
579152	23036272	Mice deficient for p15INK4b (along with p14ARF and p16INK4a) developed a wide spectrum of cancers, including soft tissue sarcomas.	('p14ARF', 'Gene', (40, 46))	('cancers', 'Disease', (90, 97))	('p16INK4a', 'Gene', '12578', (51, 59))	('sarcomas', 'Disease', 'MESH:D012509', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (109, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('sarcomas', 'Disease', (121, 129))	('p14ARF', 'Gene', '1029', (40, 46))	('p16INK4a', 'Gene', (51, 59))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (109, 129))	('Mice', 'Species', '10090', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('developed', 'Reg', (61, 70))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('p15INK4b', 'Var', (19, 27))
579154	23036272	Deletions of the p16 genomic locus were apparent in samples from OS patients.	('p16', 'Gene', (17, 20))	('patients', 'Species', '9606', (68, 76))	('p16', 'Gene', '1029', (17, 20))	('OS', 'Phenotype', 'HP:0002669', (65, 67))	('Deletions', 'Var', (0, 9))
579175	23036272	For instance, the occurrence of OS in mice with homozygous p53 and Rb deletions mimics the clinical scenario of patients with autosomal-dominant hereditary disorders as well as lesions found in the sporadic OS population.	('p53', 'Gene', (59, 62))	('mice', 'Species', '10090', (38, 42))	('OS', 'Phenotype', 'HP:0002669', (207, 209))	('OS', 'Phenotype', 'HP:0002669', (32, 34))	('patients', 'Species', '9606', (112, 120))	('autosomal-dominant hereditary disorders', 'Disease', (126, 165))	('Rb', 'Chemical', 'MESH:D012413', (67, 69))	('deletions', 'Var', (70, 79))	('autosomal-dominant hereditary disorders', 'Disease', 'MESH:D030342', (126, 165))
579178	23036272	The murine models have suggested strongly that deficiency for p53 is a strong initiating event for the development of OS and that disruption of the Rb pathway is a strongly synergistic mutation.	('OS', 'Phenotype', 'HP:0002669', (118, 120))	('Rb pathway', 'Pathway', (148, 158))	('disruption', 'Var', (130, 140))	('murine', 'Species', '10090', (4, 10))	('Rb', 'Chemical', 'MESH:D012413', (148, 150))	('p53', 'Gene', (62, 65))	('deficiency', 'Var', (47, 57))
579180	23036272	An outstanding question is do mutations in all members of the p53 and Rb pathways contribute equally to tumour formation?	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('contribute', 'Reg', (82, 92))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('Rb', 'Chemical', 'MESH:D012413', (70, 72))	('mutations', 'Var', (30, 39))	('tumour', 'Disease', (104, 110))
579181	23036272	For example, null mutation of the cyclin-dependent kinase p27Kip1, which results in deregulation of the "Rb pathway" did not result in OS in these mice.	('p27Kip1', 'Var', (58, 65))	('mice', 'Species', '10090', (147, 151))	('Rb', 'Chemical', 'MESH:D012413', (105, 107))	('OS', 'Phenotype', 'HP:0002669', (135, 137))	('deregulation', 'MPA', (84, 96))	('cyclin', 'Gene', '5111', (34, 40))	('cyclin', 'Gene', (34, 40))	('null mutation', 'Var', (13, 26))
579182	23036272	When coupled with a p53 mutation would p27Kip1 or p21Cip1 deficiency recapitulate all or only partial aspects of the loss of Rb?	('p21Cip1', 'Gene', '1026', (50, 57))	('p53', 'Gene', (20, 23))	('p21Cip1', 'Gene', (50, 57))	('Rb', 'Chemical', 'MESH:D012413', (125, 127))	('p27Kip1', 'Var', (39, 46))
579189	23036272	In particular, the deletion of p53 in mesenchymal progenitor cells only yielded 61% of OS, with the rest being poorly differentiated soft-tissue sarcoma.	('p53', 'Gene', (31, 34))	('sarcoma', 'Disease', (145, 152))	('poorly', 'Disease', (111, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('deletion', 'Var', (19, 27))	('yielded', 'Reg', (72, 79))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (133, 152))	('OS', 'Phenotype', 'HP:0002669', (87, 89))	('sarcoma', 'Disease', 'MESH:D012509', (145, 152))
579192	23036272	For instance, the deletion of p53 in pre-osteoblasts and osteoblast progenitors resulted in significantly higher OS incidence rates than early multi-lineage potential cells (Figure 1 and Table 2).	('OS incidence rates', 'CPA', (113, 131))	('OS', 'Phenotype', 'HP:0002669', (113, 115))	('higher', 'PosReg', (106, 112))	('p53', 'Gene', (30, 33))	('rat', 'Species', '10116', (126, 129))	('deletion', 'Var', (18, 26))
579203	23036272	These mutations fulfill a range of the prerequisite requirements associated with the hallmarks of cancer, however the genes do not carry equal importance in tumour biology nor fully account for the pathogenesis of OS.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('OS', 'Phenotype', 'HP:0002669', (214, 216))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('tumour', 'Disease', (157, 163))	('mutations', 'Var', (6, 15))
579271	29765529	Of the 24 PDS cases, five specimen demonstrated MYC low level copy number gains.	('PDS', 'Disease', (10, 13))	('PDS', 'Disease', 'MESH:C536648', (10, 13))	('MYC', 'Gene', (48, 51))	('low level copy number gains', 'Var', (52, 79))	('MYC', 'Gene', '4609', (48, 51))
579285	29765529	Early publications showed a high rate of UV-induced mutations of the TP53 gene in AFX (75%; n = 8).	('mutations', 'Var', (52, 61))	('AFX', 'Chemical', '-', (82, 85))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('AFX', 'Disease', (82, 85))
579286	29765529	could demonstrate TP53 mutations in 100% (n = 5) of PDS and 20% (n = 5) of AFX.	('AFX', 'Chemical', '-', (75, 78))	('TP53', 'Gene', '7157', (18, 22))	('demonstrate', 'Reg', (6, 17))	('TP53', 'Gene', (18, 22))	('PDS', 'Disease', (52, 55))	('mutations', 'Var', (23, 32))	('PDS', 'Disease', 'MESH:C536648', (52, 55))
579288	29765529	MYC amplifications are supposed to induce tumorigeneses by increasing genomic instability.	('MYC', 'Gene', (0, 3))	('tumor', 'Disease', (42, 47))	('genomic', 'MPA', (70, 77))	('amplifications', 'Var', (4, 18))	('increasing', 'PosReg', (59, 69))	('induce', 'PosReg', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('MYC', 'Gene', '4609', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
579290	29765529	Recent genetic studies have identified similarities between AFX and PDS, such as deletions of chromosome arms 9p and 13q.	('deletions', 'Var', (81, 90))	('AFX', 'Chemical', '-', (60, 63))	('PDS', 'Disease', 'MESH:C536648', (68, 71))	('AFX', 'Disease', (60, 63))	('PDS', 'Disease', (68, 71))
579291	29765529	Sakamoto and colleagues could show that HRAS and KRAS mutations are only present in AFX, but not in PDS.	('PDS', 'Disease', (100, 103))	('KRAS', 'Gene', '3845', (49, 53))	('AFX', 'Chemical', '-', (84, 87))	('HRAS', 'Gene', '3265', (40, 44))	('mutations', 'Var', (54, 63))	('AFX', 'Disease', (84, 87))	('PDS', 'Disease', 'MESH:C536648', (100, 103))	('HRAS', 'Gene', (40, 44))	('KRAS', 'Gene', (49, 53))
579318	29765529	Like radiotherapy, UV-radiation can cause direct (UVB) and indirect (UVA) DNA damage and plays an important role in skin cancer development.	('skin cancer', 'Phenotype', 'HP:0008069', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('skin cancer', 'Disease', (116, 127))	('UV-radiation', 'Var', (19, 31))	('skin cancer', 'Disease', 'MESH:D012878', (116, 127))
579320	29765529	None of the PDS cases showed a MYC amplification and only 5 of 24 (21%) cases demonstrated MYC low level copy number gain.	('PDS', 'Disease', 'MESH:C536648', (12, 15))	('MYC', 'Gene', '4609', (91, 94))	('low level copy number gain', 'Var', (95, 121))	('MYC', 'Gene', (31, 34))	('MYC', 'Gene', (91, 94))	('PDS', 'Disease', (12, 15))	('MYC', 'Gene', '4609', (31, 34))
579332	29765529	Helbig and colleagues found amplifications and deletions in 6 of 27 PDS cases but not in AFX.	('deletions', 'Var', (47, 56))	('PDS', 'Disease', 'MESH:C536648', (68, 71))	('AFX', 'Chemical', '-', (89, 92))	('amplifications', 'Var', (28, 42))	('PDS', 'Disease', (68, 71))
579456	27990685	In this model tau plays a role comparable to the normalization of PET counts by dose concentration (usually carried out to form SUV data in the output PET image), in that for instance, E(Y0i) = taulambdai and Var(Y0i) = phitaulambdai, which is consistent with pseudo-Poisson property (1).	('Var(Y0i', 'Var', (209, 216))	('E(Y0i', 'Var', (185, 190))	('phi', 'Gene', (220, 223))	('phi', 'Gene', '2821', (220, 223))
579471	27990685	Note that here, sigmaDelta = 4 corresponds to a case of a typical mis-registration error of one quarter of the image.	('mis', 'Gene', '268', (66, 69))	('mis', 'Gene', (66, 69))	('sigmaDelta = 4', 'Var', (16, 30))
579663	29621244	Each center reviewed cases from the corresponding area using systematic molecular testing for every tumor that was suspected to have a specific genomic abnormality (e.g., KIT and PDGFRA mutations for GIST, CTNNB1 mutation for desmoid tumors, specific translocations for sarcomas with a recurrent translocation, and MDM2/CDK4 amplifications for atypical/well-differentiated and dedifferentiated liposarcomas).	('tumor', 'Disease', (234, 239))	('sarcomas', 'Phenotype', 'HP:0100242', (398, 406))	('tumor', 'Disease', (100, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (398, 405))	('sarcomas', 'Disease', (398, 406))	('MDM2', 'Gene', (315, 319))	('liposarcomas', 'Disease', 'MESH:D008080', (394, 406))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('KIT', 'Gene', (171, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (270, 277))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('desmoid tumors', 'Phenotype', 'HP:0100245', (226, 240))	('amplifications', 'Var', (325, 339))	('atypical/well-differentiated', 'Disease', (344, 372))	('MDM2', 'Gene', '4193', (315, 319))	('desmoid tumors', 'Disease', (226, 240))	('liposarcomas', 'Phenotype', 'HP:0012034', (394, 406))	('desmoid tumors', 'Disease', 'MESH:C535944', (226, 240))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('CTNNB1', 'Gene', '1499', (206, 212))	('CDK4', 'Gene', (320, 324))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('PDGFRA', 'Gene', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('PDGFRA', 'Gene', '5156', (179, 185))	('liposarcomas', 'Disease', (394, 406))	('GIST', 'Phenotype', 'HP:0100723', (200, 204))	('translocations', 'Var', (251, 265))	('mutations', 'Var', (186, 195))	('CDK4', 'Gene', '1019', (320, 324))	('GIST', 'Gene', (200, 204))	('mutation', 'Var', (213, 221))	('CTNNB1', 'Gene', (206, 212))	('sarcomas', 'Disease', 'MESH:D012509', (270, 278))	('sarcomas', 'Phenotype', 'HP:0100242', (270, 278))	('desmoid tumor', 'Phenotype', 'HP:0100245', (226, 239))	('sarcomas', 'Disease', (270, 278))	('sarcomas', 'Disease', 'MESH:D012509', (398, 406))
579725	29621244	As a diagnostic discrepancy may result in the patient's death or permanent disability and significant emotional damage, further analyses will need to be performed using a discrete-event simulation model for example.	('discrepancy', 'Var', (16, 27))	('patient', 'Species', '9606', (46, 53))	('emotional damage', 'Disease', (102, 118))	('permanent disability', 'CPA', (65, 85))	('result in', 'Reg', (32, 41))	('emotional damage', 'Disease', 'MESH:D004194', (102, 118))	('death', 'Disease', 'MESH:D003643', (56, 61))	('death', 'Disease', (56, 61))
579880	24590121	In the case of IGF-1R inhibitors, only a subset of patients has a clinical response, though with significant improvements in disease burden.	('inhibitors', 'Var', (22, 32))	('disease burden', 'MPA', (125, 139))	('IGF-1R', 'Gene', (15, 21))	('IGF-1R', 'Gene', '3480', (15, 21))	('improvements', 'PosReg', (109, 121))	('patients', 'Species', '9606', (51, 59))
579932	24590121	AQUA and standard immunohistochemistry were attempted for EGFR, IGF-1R, phospho-AKT, phospho-IGF-1R, phospho-70S6k and PTEN.	('EGFR', 'Gene', '1956', (58, 62))	('IGF-1R', 'Gene', (93, 99))	('AKT', 'Gene', '207', (80, 83))	('EGFR', 'Gene', (58, 62))	('IGF-1R', 'Gene', (64, 70))	('phospho-70S6k', 'Var', (101, 114))	('IGF-1R', 'Gene', '3480', (64, 70))	('PTEN', 'Gene', (119, 123))	('AKT', 'Gene', (80, 83))	('PTEN', 'Gene', '5728', (119, 123))	('IGF-1R', 'Gene', '3480', (93, 99))
579945	24590121	There was also no difference in mean expression by AQUA for all diagnostic samples compared to those obtained after initiation of treatment for IGF-1R (10330 vs. 10947; p = 0.55), EGFR (2912 vs. 2238; p = 0.4) and PTEN (2317 vs. 2359; p = 0.93).	('2912', 'Var', (186, 190))	('PTEN', 'Gene', (214, 218))	('10330', 'Var', (152, 157))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('PTEN', 'Gene', '5728', (214, 218))	('IGF-1R', 'Gene', '3480', (144, 150))	('IGF-1R', 'Gene', (144, 150))	('expression', 'MPA', (37, 47))
579967	24590121	A different report showed that patients whose tumors only showed nuclear staining of IGF-1R had better overall survival in a group of patients treated with an IGF-1R inhibitor.	('IGF-1R', 'Gene', (159, 165))	('overall survival', 'MPA', (103, 119))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('better', 'PosReg', (96, 102))	('IGF-1R', 'Gene', '3480', (85, 91))	('patients', 'Species', '9606', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('IGF-1R', 'Gene', (85, 91))	('patients', 'Species', '9606', (31, 39))	('tumors', 'Disease', (46, 52))	('nuclear staining', 'Var', (65, 81))	('IGF-1R', 'Gene', '3480', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
579979	32751922	Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes.	('NF2', 'Gene', (65, 68))	('OS', 'Phenotype', 'HP:0002669', (61, 63))	('PRKAR1A', 'Gene', (98, 105))	('BRCA2', 'Gene', '675', (76, 81))	('Osteosarcoma', 'Disease', (0, 12))	('WIF1', 'Gene', '11197', (70, 74))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('WIF1', 'Gene', (70, 74))	('NOTCH1', 'Gene', (52, 58))	('PRKAR1A', 'Gene', '5573', (98, 105))	('PTCH1', 'Gene', '5727', (88, 93))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('NOTCH1', 'Gene', '4851', (52, 58))	('APC', 'Disease', 'MESH:D011125', (83, 86))	('APC', 'Disease', (83, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('FOS', 'Gene', (60, 63))	('mutations', 'Var', (20, 29))	('FOS', 'Gene', '2353', (60, 63))	('BRCA2', 'Gene', (76, 81))	('NF2', 'Gene', '4771', (65, 68))	('PTCH1', 'Gene', (88, 93))
580002	32751922	The 5-year survival rate in patients with localized OS reaches 70-75%, but for metastatic disease, the long-term survival rate drops to only 30% and multidrug resistance is a common problem.	('localized OS', 'Disease', (42, 54))	('multidrug resistance', 'Var', (149, 169))	('drug resistance', 'Phenotype', 'HP:0020174', (154, 169))	('rat', 'Species', '10116', (122, 125))	('rat', 'Species', '10116', (20, 23))	('OS', 'Phenotype', 'HP:0002669', (52, 54))	('patients', 'Species', '9606', (28, 36))
580006	32751922	The genome analysis led to the identification of genetic heterogeneity, numerous chromosomal abnormalities, mutations and the most down- and upregulated genes, including candidate driver genes.	('mutations', 'Var', (108, 117))	('upregulated', 'PosReg', (141, 152))	('numerous chromosomal abnormalities', 'Disease', 'MESH:D002869', (72, 106))	('numerous chromosomal abnormalities', 'Phenotype', 'HP:0040012', (72, 106))	('down-', 'NegReg', (131, 136))	('numerous chromosomal abnormalities', 'Disease', (72, 106))
580007	32751922	As a neoplasm with numerous chromosomal abnormalities and mutations, OS appears to be a tumor that could potentially respond to immunotherapy.	('mutations', 'Var', (58, 67))	('numerous chromosomal abnormalities', 'Phenotype', 'HP:0040012', (19, 53))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('numerous chromosomal abnormalities', 'Disease', 'MESH:D002869', (19, 53))	('numerous chromosomal abnormalities', 'Disease', (19, 53))	('neoplasm', 'Disease', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('neoplasm', 'Disease', 'MESH:D009369', (5, 13))	('neoplasm', 'Phenotype', 'HP:0002664', (5, 13))	('tumor', 'Disease', (88, 93))	('OS', 'Phenotype', 'HP:0002669', (69, 71))
580008	32751922	A number of inherited germline mutations are responsible for syndromes that predispose to some neoplasms, including osteosarcomas.	('osteosarcomas', 'Phenotype', 'HP:0002669', (116, 129))	('osteosarcomas', 'Disease', (116, 129))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('osteosarcomas', 'Disease', 'MESH:D012516', (116, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('germline mutations', 'Var', (22, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (95, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('responsible', 'Reg', (45, 56))	('neoplasms', 'Disease', 'MESH:D009369', (95, 104))	('neoplasms', 'Disease', (95, 104))	('neoplasm', 'Phenotype', 'HP:0002664', (95, 103))
580012	32751922	Germline mutations in the TP53 gene are inherited in an autosomal dominant fashion and responsible for about 70% of the cases of this syndrome.	('TP53', 'Gene', (26, 30))	('Germline mutations', 'Var', (0, 18))	('TP53', 'Gene', '7157', (26, 30))	('responsible', 'Reg', (87, 98))
580017	32751922	In a study including 525 families according to various criteria, families with a mutation in the TP53 gene constitute from 14% to 56%.	('TP53', 'Gene', (97, 101))	('mutation', 'Var', (81, 89))	('TP53', 'Gene', '7157', (97, 101))
580018	32751922	In the group of patients with a germline mutation in TP53, bone tumors were found in 0.7%.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('found', 'Reg', (76, 81))	('bone tumors', 'Disease', (59, 70))	('germline mutation', 'Var', (32, 49))	('patients', 'Species', '9606', (16, 24))	('bone tumors', 'Disease', 'MESH:D001859', (59, 70))	('bone tumors', 'Phenotype', 'HP:0010622', (59, 70))	('TP53', 'Gene', '7157', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TP53', 'Gene', (53, 57))
580020	32751922	Additional rare exonic variants and rearrangements in the intron 1 TP53 gene may were also reported.	('rearrangements', 'Var', (36, 50))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
580023	32751922	One exception is R337H mutation in the TP53 gene that is more common in LFS/LFL families from Southeastern Brazil.	('LFS', 'Disease', 'MESH:D016864', (72, 75))	('R337H', 'Mutation', 'rs121912664', (17, 22))	('R337H', 'Var', (17, 22))	('LFS', 'Disease', (72, 75))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
580024	32751922	The primary symptom of germline mutations (autosomal dominant) in the RB1 gene is childhood retinoblastomas; however, in later life there is an increased risk of various neoplasms, especially OS.	('germline mutations', 'Var', (23, 41))	('RB1', 'Gene', (70, 73))	('neoplasms', 'Disease', 'MESH:D009369', (170, 179))	('neoplasms', 'Disease', (170, 179))	('retinoblastomas', 'Disease', (92, 107))	('neoplasm', 'Phenotype', 'HP:0002664', (170, 178))	('OS', 'Phenotype', 'HP:0002669', (192, 194))	('RB1', 'Gene', '5925', (70, 73))	('retinoblastomas', 'Disease', 'MESH:D012175', (92, 107))	('retinoblastomas', 'Phenotype', 'HP:0009919', (92, 107))	('neoplasms', 'Phenotype', 'HP:0002664', (170, 179))	('retinoblastoma', 'Phenotype', 'HP:0009919', (92, 106))
580025	32751922	There are over 180 mutations causing retinoblastoma.	('retinoblastoma', 'Phenotype', 'HP:0009919', (37, 51))	('mutations', 'Var', (19, 28))	('retinoblastoma', 'Disease', 'MESH:D012175', (37, 51))	('retinoblastoma', 'Disease', (37, 51))	('causing', 'Reg', (29, 36))
580029	32751922	Somatic RB1 mutations are also frequently occurring in OS patients, in a range of between 30% to 75%.	('RB1', 'Gene', (8, 11))	('mutations', 'Var', (12, 21))	('RB1', 'Gene', '5925', (8, 11))	('occurring', 'Reg', (42, 51))	('patients', 'Species', '9606', (58, 66))	('OS', 'Phenotype', 'HP:0002669', (55, 57))
580031	32751922	where a low penetrance germline mutation in the RB gene caused osteosarcomas as the first detected tumor, without the previous occurrence of retinoblastoma.	('tumor', 'Disease', (99, 104))	('retinoblastoma', 'Disease', 'MESH:D012175', (141, 155))	('retinoblastoma', 'Disease', (141, 155))	('germline mutation', 'Var', (23, 40))	('osteosarcomas', 'Disease', (63, 76))	('caused', 'Reg', (56, 62))	('osteosarcomas', 'Phenotype', 'HP:0002669', (63, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (63, 75))	('osteosarcomas', 'Disease', 'MESH:D012516', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('retinoblastoma', 'Phenotype', 'HP:0009919', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (68, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
580032	32751922	Syndromes with an increased osteosarcoma risk are caused by germline mutations in genes encoding DNA helicases of the RecQ family.	('caused by', 'Reg', (50, 59))	('osteosarcoma', 'Disease', (28, 40))	('osteosarcoma', 'Phenotype', 'HP:0002669', (28, 40))	('germline mutations', 'Var', (60, 78))	('osteosarcoma', 'Disease', 'MESH:D012516', (28, 40))	('Syndromes', 'Disease', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))
580033	32751922	These two syndromes are both caused by mutations in the RECQL4 gene:that possess single-stranded DNA annealing activity and functions in DNA repair.	('RECQL4', 'Gene', (56, 62))	('RECQL4', 'Gene', '9401', (56, 62))	('caused by', 'Reg', (29, 38))	('mutations', 'Var', (39, 48))
580034	32751922	Analysis of 33 RTS cases revealed an association between RECQL4 gene truncation (but not nonsense or missense point mutations) and osteosarcoma development.	('truncation', 'Var', (69, 79))	('RECQL4', 'Gene', (57, 63))	('osteosarcoma', 'Phenotype', 'HP:0002669', (131, 143))	('osteosarcoma', 'Disease', (131, 143))	('osteosarcoma', 'Disease', 'MESH:D012516', (131, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('RECQL4', 'Gene', '9401', (57, 63))	('gene truncation', 'Var', (64, 79))
580042	32751922	This disease, which is a progeria syndrome, is caused by mutations in the WRN gene, encoding a RECQ helicase.	('caused by', 'Reg', (47, 56))	('mutations', 'Var', (57, 66))	('WRN', 'Gene', (74, 77))	('WRN', 'Gene', '7486', (74, 77))
580046	32751922	This syndrome, first described in 1995, is related to mutations in another DNA helicase gene, BLM (RECQL3).	('BLM', 'Gene', (94, 97))	('RECQL3', 'Gene', (99, 105))	('mutations', 'Var', (54, 63))	('related', 'Reg', (43, 50))	('BLM', 'Gene', '641', (94, 97))	('RECQL3', 'Gene', '641', (99, 105))
580048	32751922	Bloom syndrome prevalence rate in Ashkenazi Jews is much higher than in other populations, i.e., 1%.	('Ashkenazi', 'Var', (34, 43))	('Bloom syndrome', 'Disease', (0, 14))	('rat', 'Species', '10116', (26, 29))	('higher', 'PosReg', (57, 63))
580050	32751922	This syndrome, in contrast to the previous ones, is due not to a mutation in a tumor suppressor gene or a DNA helicase but is classified as a ribosomopathy:a disease due to a mutation in a gene encoding a ribosomal protein.	('tumor', 'Disease', (79, 84))	('ribosomopathy', 'Disease', 'None', (142, 155))	('mutation', 'Var', (175, 183))	('ribosomopathy', 'Disease', (142, 155))	('due to', 'Reg', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
580051	32751922	The first one to be identified was a mutation in the gene encoding ribosomal protein S19; subsequently mutations in eight other genes encoding ribosomal proteins were discovered.	('ribosomal protein S19', 'Gene', (67, 88))	('ribosomal protein S19', 'Gene', '6223', (67, 88))	('mutation', 'Var', (37, 45))
580055	32751922	Mutations in this gene were observed in approximately half of all tumors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('Mutations', 'Var', (0, 9))	('observed', 'Reg', (28, 36))
580058	32751922	These crucial processes are unsettled in cancer cells, and they may result in inactivation of p53 directly by mutation or by inactivation of proteins that interact with p53.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('p53', 'Gene', (94, 97))	('interact', 'Interaction', (155, 163))	('inactivation', 'NegReg', (125, 137))	('proteins', 'Protein', (141, 149))	('result in', 'Reg', (68, 77))	('mutation', 'Var', (110, 118))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('inactivation', 'NegReg', (78, 90))
580059	32751922	Inhibiting this regulation by mutations may also drive to tumor development.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Inhibiting', 'NegReg', (0, 10))	('drive', 'Reg', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (30, 39))
580060	32751922	In several cancers, most mutations in the TP53 gene are missense mutations and are localized in the DNA binding domain.	('mutations', 'Var', (25, 34))	('TP53', 'Gene', '7157', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TP53', 'Gene', (42, 46))	('missense mutations', 'Var', (56, 74))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
580061	32751922	In osteosarcoma, mutations of TP53 were found with a frequency of about 20%.	('TP53', 'Gene', (30, 34))	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('found', 'Reg', (40, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('TP53', 'Gene', '7157', (30, 34))	('mutations', 'Var', (17, 26))
580063	32751922	An example gain-of-function mutation is R175H (dominant negative) that is generally common in broad spectrum of cancers.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('R175H', 'Mutation', 'rs28934578', (40, 45))	('R175H', 'Var', (40, 45))	('gain-of-function', 'PosReg', (11, 27))
580065	32751922	In vitro studies suggest that this mutation promotes centrosome amplification connected with disturbing mitosis, cytokinesis and increase of chromosome segregation errors (aneuploidy).	('disturbing mitosis', 'Disease', (93, 111))	('promotes', 'PosReg', (44, 52))	('chromosome segregation errors', 'CPA', (141, 170))	('aneuploidy', 'Disease', 'MESH:D000782', (172, 182))	('centrosome amplification', 'MPA', (53, 77))	('increase', 'PosReg', (129, 137))	('disturbing mitosis', 'Disease', 'MESH:D014832', (93, 111))	('cytokinesis', 'CPA', (113, 124))	('mutation', 'Var', (35, 43))	('aneuploidy', 'Disease', (172, 182))
580066	32751922	Expression of p53 R175H mutant results in reduced occurrence of apoptosis Expression of other p53 mutant R273H found in osteosarcoma patient derived samples increases the frequency of gene amplification, probably by the involvement of mutated protein with topoisomerase I interaction.	('gene amplification', 'MPA', (184, 202))	('reduced', 'NegReg', (42, 49))	('osteosarcoma', 'Disease', (120, 132))	('p53', 'Gene', (94, 97))	('R175H', 'Var', (18, 23))	('patient', 'Species', '9606', (133, 140))	('osteosarcoma', 'Disease', 'MESH:D012516', (120, 132))	('interaction', 'Interaction', (272, 283))	('R273H', 'Mutation', 'rs28934576', (105, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('mutant R273H', 'Var', (98, 110))	('apoptosis Expression', 'MPA', (64, 84))	('R175H', 'Mutation', 'rs28934578', (18, 23))	('osteosarcoma', 'Phenotype', 'HP:0002669', (120, 132))
580067	32751922	Increase of cisplatin resistance at low concentrations (2.5 microg/mL) was observed in vitro for both these mutations.	('mutations', 'Var', (108, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (12, 21))	('rat', 'Species', '10116', (47, 50))	('cisplatin resistance', 'MPA', (12, 32))	('Increase', 'PosReg', (0, 8))
580068	32751922	Expression of mutated R175H p53 resulted in increased resistance to etoposide other than expression of R273H p53.	('p53', 'Gene', (28, 31))	('resistance to etoposide', 'MPA', (54, 77))	('R175H', 'Mutation', 'rs28934578', (22, 27))	('mutated R175H', 'Var', (14, 27))	('R175H', 'Var', (22, 27))	('etoposide', 'Chemical', 'MESH:D005047', (68, 77))	('increased', 'PosReg', (44, 53))	('R273H', 'Mutation', 'rs28934576', (103, 108))
580069	32751922	Alterations such as structural variation (SV) and somatic nucleotide variants (SNVs) were found in 74% of osteosarcomas.	('found', 'Reg', (90, 95))	('structural variation', 'Var', (20, 40))	('osteosarcomas', 'Disease', 'MESH:D012516', (106, 119))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('osteosarcomas', 'Phenotype', 'HP:0002669', (106, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('rat', 'Species', '10116', (4, 7))	('osteosarcomas', 'Disease', (106, 119))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
580070	32751922	In the TP53 gene, structural variations are frequent in pediatric osteosarcoma.	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('frequent', 'Reg', (44, 52))	('osteosarcoma', 'Disease', (66, 78))	('structural variations', 'Var', (18, 39))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('osteosarcoma', 'Disease', 'MESH:D012516', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))
580071	32751922	These alterations were observed mainly in osteosarcoma and resulted in the loss of expression of the TP53 gene.	('alterations', 'Var', (6, 17))	('osteosarcoma', 'Disease', (42, 54))	('TP53', 'Gene', '7157', (101, 105))	('observed', 'Reg', (23, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))	('loss of', 'NegReg', (75, 82))	('TP53', 'Gene', (101, 105))	('expression', 'MPA', (83, 93))	('rat', 'Species', '10116', (10, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
580072	32751922	Mutations in introns (III,IV,V,VIII) were characterized as splice site changes.	('Mutations', 'Var', (0, 9))	('VIII', 'Gene', (31, 35))	('VIII', 'Gene', '1351', (31, 35))	('introns', 'Gene', (13, 20))
580073	32751922	There were several interesting rodent animal models with a mutation in TP53 that develop osteosarcoma.	('osteosarcoma', 'Disease', (89, 101))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('mutation', 'Var', (59, 67))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('develop', 'PosReg', (81, 88))
580074	32751922	In a mouse model with mutation p.R172H (p.R175H in humans) spectrum of tumors that were developed are predominantly osteosarcomas.	('osteosarcomas', 'Phenotype', 'HP:0002669', (116, 129))	('p.R172H', 'Var', (31, 38))	('osteosarcomas', 'Disease', (116, 129))	('mutation p.R172H', 'Var', (22, 38))	('osteosarcomas', 'Disease', 'MESH:D012516', (116, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('p.R172H', 'Mutation', 'rs372604524', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('p.R175H', 'Mutation', 'rs28934578', (40, 47))	('mouse', 'Species', '10090', (5, 10))	('tumors', 'Disease', (71, 77))	('humans', 'Species', '9606', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
580077	32751922	In another rat model Tp53Delta11/Delta11 (Sprague Dawley background) the tumor spectrum includes multiple sarcoma types, among others osteosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('osteosarcoma', 'Disease', (134, 146))	('osteosarcoma', 'Disease', 'MESH:D012516', (134, 146))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('sarcoma', 'Disease', 'MESH:D012509', (139, 146))	('Delta11', 'Mutation', 'c.del11', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Tp53Delta11/Delta11', 'Var', (21, 40))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('tumor', 'Disease', (73, 78))	('sarcoma', 'Disease', (139, 146))	('rat', 'Species', '10116', (11, 14))	('Delta11', 'Mutation', 'c.del11', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('sarcoma', 'Disease', (106, 113))	('osteosarcoma', 'Phenotype', 'HP:0002669', (134, 146))
580083	32751922	Other RB alterations include structural rearrangements presenting in 30% of all the cases and point mutations observed in only 10% of cases.	('rat', 'Species', '10116', (13, 16))	('point mutations', 'Var', (94, 109))	('structural rearrangements', 'Var', (29, 54))	('alterations', 'Var', (9, 20))
580084	32751922	Other components of the RB-pathway:including INK4, CDK4, p16 and cyclin D1:may also be subject to genetic alterations.	('rat', 'Species', '10116', (110, 113))	('cyclin D1', 'Gene', (65, 74))	('subject', 'Reg', (87, 94))	('p16', 'Gene', (57, 60))	('INK4', 'Gene', (45, 49))	('INK4', 'Gene', '1029', (45, 49))	('RB-pathway', 'Pathway', (24, 34))	('p16', 'Gene', '1029', (57, 60))	('CDK4', 'Gene', (51, 55))	('genetic alterations', 'Var', (98, 117))	('cyclin D1', 'Gene', '595', (65, 74))	('CDK4', 'Gene', '1019', (51, 55))
580086	32751922	showed that the targeted p53 and Rb mutation in murine osteoblasts is sufficient to induce metastatic osteosarcoma with features of the human disease.	('p53', 'Gene', (25, 28))	('human', 'Species', '9606', (136, 141))	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('osteosarcoma', 'Disease', 'MESH:D012516', (102, 114))	('Rb', 'Gene', '19645', (33, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('induce', 'Reg', (84, 90))	('murine', 'Species', '10090', (48, 54))	('mutation', 'Var', (36, 44))	('osteosarcoma', 'Disease', (102, 114))
580087	32751922	Mutations in the TP53 gene of these cells play a decisive role in proliferation, compromising the maturation, negatively regulating their differentiation and interfering with cellular processes such as ontogenesis.	('cellular processes', 'CPA', (175, 193))	('negatively', 'NegReg', (110, 120))	('maturation', 'CPA', (98, 108))	('compromising', 'NegReg', (81, 93))	('differentiation', 'CPA', (138, 153))	('rat', 'Species', '10116', (73, 76))	('Mutations', 'Var', (0, 9))	('rat', 'Species', '10116', (102, 105))	('ontogenesis', 'CPA', (202, 213))	('TP53', 'Gene', '7157', (17, 21))	('interfering', 'NegReg', (158, 169))	('TP53', 'Gene', (17, 21))
580089	32751922	Frequent alterations in CDK-related tumor suppressor genes (TP53, RB1, CDKN2A, PTEN) are deletion, loss of heterozygosity and mutations.	('loss of heterozygosity', 'Var', (99, 121))	('CDKN2A', 'Gene', (71, 77))	('RB1', 'Gene', '5925', (66, 69))	('CDKN2A', 'Gene', '1029', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('deletion', 'Var', (89, 97))	('TP53', 'Gene', '7157', (60, 64))	('rat', 'Species', '10116', (13, 16))	('PTEN', 'Gene', '5728', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutations', 'Var', (126, 135))	('TP53', 'Gene', (60, 64))	('PTEN', 'Gene', (79, 83))	('tumor', 'Disease', (36, 41))	('RB1', 'Gene', (66, 69))
580091	32751922	Amplification of 12q13-15 region containing CDK4, MDM2, SAS and other potential oncogenes is present in 10% of osteosarcomas and is associated with ring chromosomes in parosteal OS.	('MDM2', 'Gene', (50, 54))	('Amplification', 'Var', (0, 13))	('SAS', 'Gene', '6302', (56, 59))	('SAS', 'Gene', (56, 59))	('CDK4', 'Gene', '1019', (44, 48))	('CDK4', 'Gene', (44, 48))	('osteosarcomas', 'Disease', (111, 124))	('osteosarcomas', 'Phenotype', 'HP:0002669', (111, 124))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('OS', 'Phenotype', 'HP:0002669', (178, 180))	('osteosarcomas', 'Disease', 'MESH:D012516', (111, 124))	('associated with', 'Reg', (132, 147))	('parosteal OS', 'Disease', (168, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('MDM2', 'Gene', '4193', (50, 54))
580094	32751922	Inhibition of CDK4 decreases cell proliferation and migration along with arresting the cell cycle and inducing apoptosis in human OS cell lines.	('rat', 'Species', '10116', (55, 58))	('inducing', 'Reg', (102, 110))	('CDK4', 'Gene', '1019', (14, 18))	('OS', 'Phenotype', 'HP:0002669', (130, 132))	('human', 'Species', '9606', (124, 129))	('cell cycle', 'CPA', (87, 97))	('CDK4', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('cell proliferation', 'CPA', (29, 47))	('decreases', 'NegReg', (19, 28))	('rat', 'Species', '10116', (41, 44))	('arresting', 'CPA', (73, 82))	('apoptosis', 'CPA', (111, 120))
580095	32751922	More than 10% of OS cases possess mutation in the c-Myc gene (avian myelocytomatosis viral oncogene homolog).	('avian myelocytomatosis viral oncogene homolog', 'Gene', '4609', (62, 107))	('mutation', 'Var', (34, 42))	('c-Myc', 'Gene', '4609', (50, 55))	('OS', 'Phenotype', 'HP:0002669', (17, 19))	('c-Myc', 'Gene', (50, 55))	('avian myelocytomatosis viral oncogene homolog', 'Gene', (62, 107))
580096	32751922	MYC family genes amplifications are more common in PDS-related OS than primary osteosarcoma.	('MYC', 'Gene', (0, 3))	('osteosarcoma', 'Phenotype', 'HP:0002669', (79, 91))	('osteosarcoma', 'Disease', (79, 91))	('amplifications', 'Var', (17, 31))	('osteosarcoma', 'Disease', 'MESH:D012516', (79, 91))	('PDS-related OS', 'Disease', (51, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('MYC', 'Gene', '4609', (0, 3))	('OS', 'Phenotype', 'HP:0002669', (63, 65))	('common', 'Reg', (41, 47))
580112	32751922	Circulating DNA released from cancer cells carries much important information about changes in its structure such as deletion, insertion or translocation.	('structure', 'MPA', (99, 108))	('changes', 'Reg', (84, 91))	('translocation', 'CPA', (140, 153))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('insertion', 'Var', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('deletion', 'Var', (117, 125))
580114	32751922	Attempts to collect such a fluid biopsy and its evaluation were performed for the assessment of mutations in the TP53 gene.	('TP53', 'Gene', '7157', (113, 117))	('TP53', 'Gene', (113, 117))	('mutations', 'Var', (96, 105))
580116	32751922	By introducing such a division, we note that in children's samples, most tumors have a mutation in the TP53 or RB gene.	('TP53', 'Gene', '7157', (103, 107))	('children', 'Species', '9606', (48, 56))	('TP53', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('mutation', 'Var', (87, 95))
580121	32751922	Genes whose alteration may lead to cancerous process are summarized in Table 3.	('cancerous', 'Disease', (35, 44))	('alteration', 'Var', (12, 22))	('rat', 'Species', '10116', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancerous', 'Disease', 'MESH:D009369', (35, 44))	('lead to', 'Reg', (27, 34))
580122	32751922	A mutation in some inductor genes could promote tumorigenesis and proliferation of altered cells.	('promote', 'PosReg', (40, 47))	('mutation', 'Var', (2, 10))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('rat', 'Species', '10116', (73, 76))
580125	32751922	Animal experiments showed that mutations in a pair of genes: WIF1 and BRCA2 resulted in a negligible effect of tumor formation, in contrast to a mutation in a pair of TP53 and NOTCH genes.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mutations', 'Var', (31, 40))	('BRCA2', 'Gene', '675', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('WIF1', 'Gene', (61, 65))	('TP53', 'Gene', '7157', (167, 171))	('BRCA2', 'Gene', (70, 75))	('TP53', 'Gene', (167, 171))	('WIF1', 'Gene', '11197', (61, 65))
580139	32751922	Osteosarcoma patient derived samples share the same several characteristic features described in breast cancers, like the same type of substitutions, the same class of mutation, occurrence of hypermutated regions with structural variations breakpoints or rearrangement sites, occurrence of macro- and microclusters in hypermutated regions.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('substitutions', 'Var', (135, 148))	('patient', 'Species', '9606', (13, 20))	('breast cancers', 'Phenotype', 'HP:0003002', (97, 111))	('Osteosarcoma', 'Disease', (0, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('breast cancers', 'Disease', 'MESH:D001943', (97, 111))	('breast cancers', 'Disease', (97, 111))
580145	32751922	Other microRNAs of potential significance in osteosarcoma development are: miRNA-129-5p (miR-129-5p), miR-330-3p, miR-365, or miR-491-3p.	('miR-491-3p', 'Var', (126, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('osteosarcoma', 'Disease', (45, 57))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('miRNA-129-5p', 'Var', (75, 87))	('miR-129-5p', 'Gene', '100302178', (89, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('miR-330', 'Gene', '442902', (102, 109))	('miR-129-5p', 'Gene', (89, 99))	('miR-330', 'Gene', (102, 109))	('miR-365', 'Var', (114, 121))
580151	32751922	Some of them have been described as oncomiRs in other types of malignancies (miR-181a-5p, miR-181c-5p, miR-223-3p and miR-342-3p).	('miR-223-3p', 'Var', (103, 113))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('miR-342-3p', 'Var', (118, 128))	('miR-181c', 'Gene', (90, 98))	('miR-181c', 'Gene', '406957', (90, 98))	('malignancies', 'Disease', (63, 75))	('miR-181a-5p', 'Var', (77, 88))
580152	32751922	Downregulation of miR-374b and miR-543-3p and upregulation of miR-126 is associated with OS invasion and metastases and promotes angiogenesis by increasing expression of VEGF-A and angiopoietin-2.	('angiopoietin-2', 'Gene', (181, 195))	('miR-126', 'Gene', '406913', (62, 69))	('Downregulation', 'NegReg', (0, 14))	('angiogenesis', 'CPA', (129, 141))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('VEGF-A', 'Gene', (170, 176))	('upregulation', 'PosReg', (46, 58))	('metastases', 'Disease', (105, 115))	('miR-374b', 'Gene', (18, 26))	('miR-543-3p', 'Var', (31, 41))	('angiopoietin-2', 'Gene', '285', (181, 195))	('OS', 'Phenotype', 'HP:0002669', (89, 91))	('miR-126', 'Gene', (62, 69))	('miR-374b', 'Gene', '100126317', (18, 26))	('OS invasion', 'CPA', (89, 100))	('VEGF-A', 'Gene', '7422', (170, 176))	('increasing', 'PosReg', (145, 155))	('promotes', 'PosReg', (120, 128))	('expression', 'MPA', (156, 166))
580153	32751922	Downregulation of miR-539-3p, miR-218, miR-143-3p, miR-150 and miR-183 enhance the potential of cells to invade and migrate, among others by increasing expression of the matrix metalloproteinase 8 (MMP-8), MMP-2,-9, MMP13 and ezrin.	('matrix metalloproteinase 8', 'Gene', '4317', (170, 196))	('Downregulation', 'NegReg', (0, 14))	('ezrin', 'Gene', '7430', (226, 231))	('miR-539-3p', 'Var', (18, 28))	('rat', 'Species', '10116', (119, 122))	('miR-143-3p', 'Var', (39, 49))	('MMP-8', 'Gene', '4317', (198, 203))	('increasing', 'PosReg', (141, 151))	('miR-21', 'Gene', (30, 36))	('miR-150', 'Gene', (51, 58))	('expression', 'MPA', (152, 162))	('miR-183', 'Gene', '406959', (63, 70))	('matrix metalloproteinase 8', 'Gene', (170, 196))	('MMP13', 'Gene', (216, 221))	('MMP-2,-9', 'Gene', '4313;4318', (206, 214))	('miR-183', 'Gene', (63, 70))	('MMP-8', 'Gene', (198, 203))	('miR-21', 'Gene', '406991', (30, 36))	('ezrin', 'Gene', (226, 231))	('enhance', 'PosReg', (71, 78))	('MMP13', 'Gene', '4322', (216, 221))	('miR-150', 'Gene', '406942', (51, 58))
580165	32751922	The TIC subpopulations emerge after the accumulation of epigenetic and genetic alterations in a cell within the aberrant population, initially generated by the sarcoma cell-of-origin.	('rat', 'Species', '10116', (83, 86))	('TIC', 'Phenotype', 'HP:0100033', (4, 7))	('sarcoma', 'Disease', 'MESH:D012509', (160, 167))	('sarcoma', 'Disease', (160, 167))	('rat', 'Species', '10116', (147, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('epigenetic', 'Var', (56, 66))
580193	32751922	Additional markers should also be present on TICs as according to the International Society for Cellular Therapy (ISCT) mesenchymal stem cells (MSCs) should be positive for CD73, CD90 and CD105, but negative for CD34, CD45, CD11b or CD14, CD19 or CD79alpha and HLA-DR.	('mesenchymal stem cells', 'CPA', (120, 142))	('CD45', 'Gene', (218, 222))	('TICs', 'Phenotype', 'HP:0100033', (45, 49))	('CD34', 'Gene', '947', (212, 216))	('CD79alpha', 'Gene', '973', (247, 256))	('CD90', 'Gene', (179, 183))	('CD45', 'Gene', '5788', (218, 222))	('CD11b', 'Gene', '3684', (224, 229))	('TIC', 'Phenotype', 'HP:0100033', (45, 48))	('CD19', 'Gene', (239, 243))	('TICs', 'Disease', (45, 49))	('CD11b', 'Gene', (224, 229))	('CD79alpha', 'Gene', (247, 256))	('CD73', 'Gene', '4907', (173, 177))	('CD90', 'Gene', '7070', (179, 183))	('CD105', 'Var', (188, 193))	('CD73', 'Gene', (173, 177))	('CD14', 'Gene', (233, 237))	('TICs', 'Disease', 'MESH:D020323', (45, 49))	('CD34', 'Gene', (212, 216))	('CD19', 'Gene', '930', (239, 243))	('CD14', 'Gene', '929', (233, 237))
580214	32751922	OS-AF derived EVs were shown to increase OS cell survival and migration, especially under stress.	('migration', 'CPA', (62, 71))	('OS cell survival', 'CPA', (41, 57))	('increase', 'PosReg', (32, 40))	('stress', 'Disease', (90, 96))	('stress', 'Disease', 'MESH:D000079225', (90, 96))	('rat', 'Species', '10116', (65, 68))	('OS', 'Phenotype', 'HP:0002669', (0, 2))	('OS', 'Phenotype', 'HP:0002669', (41, 43))	('OS-AF', 'Disease', (0, 5))	('OS-AF', 'Disease', 'MESH:C567932', (0, 5))	('EVs', 'Var', (14, 17))
580221	32751922	In particular, autocrine VEGF-VEGFR-1-signaling was shown as associated with tumor angiogenesis, but also with increased tumor growth.	('VEGFR-1', 'Gene', (30, 37))	('increased', 'PosReg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('VEGF', 'Gene', '7422', (30, 34))	('VEGF', 'Gene', '7422', (25, 29))	('autocrine', 'Var', (15, 24))	('tumor', 'Disease', (121, 126))	('VEGFR-1', 'Gene', '2321', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('VEGF', 'Gene', (30, 34))	('associated', 'Reg', (61, 71))	('tumor', 'Disease', (77, 82))	('VEGF', 'Gene', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
580230	32751922	There are few identified factors contributing to invasion and metastasis, such as deletion of the TP53 gene and activation of the Notch pathway in OS cells.	('Notch pathway', 'Pathway', (130, 143))	('deletion', 'Var', (82, 90))	('TP53', 'Gene', '7157', (98, 102))	('OS', 'Phenotype', 'HP:0002669', (147, 149))	('TP53', 'Gene', (98, 102))
580247	32751922	A recent clinical trial has shown a correlation between the (18F) sodium fluoride-PET results and overall survival, while in FDG-PET there was no correlation.	('overall survival', 'CPA', (98, 114))	('sodium fluoride', 'Chemical', 'MESH:D012969', (66, 81))	('18F', 'Var', (61, 64))
580257	32751922	Despite the many compounds tested in preclinical tests, there are no drugs that restore the function of mutated p53 though a gene-altering therapy that has been successfully used for other cancer types may be feasible.	('mutated', 'Var', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('p53', 'Gene', (112, 115))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('function', 'MPA', (92, 100))	('cancer', 'Disease', (189, 195))
580260	32751922	Currently, there are studies using cell therapy with anti-GD2 lymphocytes or testing several anti-GD2 molecules like dinutuximab, Hu3F8 and Hu14.18K322A.	('Hu3F8', 'Var', (130, 135))	('GD2', 'Chemical', '-', (58, 61))	('dinutuximab', 'Chemical', 'MESH:C112746', (117, 128))	('anti-GD2', 'Gene', (93, 101))	('Hu14.18K322A', 'Var', (140, 152))	('GD2', 'Chemical', '-', (98, 101))
580266	32751922	Besides direct inhibition of osteosarcoma cell growth and viability due to inhibition of ERK and Akt-signaling pathways, cabozantinib can affect the tumor microenvironment by reducing the production of receptor activator of nuclear factor-kB ligand (RANKL) by osteoblasts.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('RANKL', 'Gene', (250, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('ERK', 'Gene', '5594', (89, 92))	('cabozantinib', 'Var', (121, 133))	('osteosarcoma', 'Disease', (29, 41))	('osteosarcoma', 'Disease', 'MESH:D012516', (29, 41))	('reducing', 'NegReg', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('ERK', 'Gene', (89, 92))	('receptor activator of nuclear factor-kB ligand', 'Gene', '8600', (202, 248))	('RANKL', 'Gene', '8600', (250, 255))	('production', 'MPA', (188, 198))	('affect', 'Reg', (138, 144))	('cabozantinib', 'Chemical', 'MESH:C558660', (121, 133))	('osteosarcoma', 'Phenotype', 'HP:0002669', (29, 41))	('receptor activator of nuclear factor-kB ligand', 'Gene', (202, 248))	('Akt', 'Gene', (97, 100))	('tumor', 'Disease', (149, 154))	('Akt', 'Gene', '207', (97, 100))
580274	32751922	Interestingly, 65% of patients who underwent metabolic assessment with 18F-FDG PET-CT had a partial metabolic response after the first cycle of cabozantinib what can be considered as a potential biomarker of cabozantinib efficacy in osteosarcoma.	('cabozantinib', 'Chemical', 'MESH:C558660', (144, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (233, 245))	('osteosarcoma', 'Disease', (233, 245))	('osteosarcoma', 'Disease', 'MESH:D012516', (233, 245))	('patients', 'Species', '9606', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('18F-FDG', 'Var', (71, 78))	('partial metabolic response', 'MPA', (92, 118))	('cabozantinib', 'Chemical', 'MESH:C558660', (208, 220))	('18F-FDG', 'Chemical', 'MESH:D019788', (71, 78))
580305	32751922	Although osteosarcoma occurs mostly in patients without germline mutations, hereditary syndromes associated with mutations in the TP53, RB, RECQ, WRN or BLM genes are also reported among osteosarcoma patients.	('patients', 'Species', '9606', (39, 47))	('osteosarcoma', 'Disease', (187, 199))	('hereditary syndromes', 'Disease', (76, 96))	('mutations', 'Var', (113, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (187, 199))	('RECQ', 'Gene', (140, 144))	('BLM', 'Gene', (153, 156))	('hereditary syndromes', 'Disease', 'MESH:D061325', (76, 96))	('TP53', 'Gene', (130, 134))	('BLM', 'Gene', '641', (153, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('WRN', 'Gene', (146, 149))	('WRN', 'Gene', '7486', (146, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (187, 199))	('osteosarcoma', 'Disease', (9, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('patients', 'Species', '9606', (200, 208))	('TP53', 'Gene', '7157', (130, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
580332	28794969	About 16% of patients carries nucleophosmin (NPM1) mutations, as shown by aberrant cytoplasmic NPM1 expression.	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (13, 21))	('NPM1', 'Gene', (95, 99))	('NPM1', 'Gene', (45, 49))	('expression', 'MPA', (100, 110))	('nucleophosmin', 'Gene', '4869', (30, 43))	('NPM1', 'Gene', '4869', (95, 99))	('NPM1', 'Gene', '4869', (45, 49))	('nucleophosmin', 'Gene', (30, 43))
580333	28794969	Furthermore, about 20-30% of MS, especially those evolving from AML, harbor mutations of FMS-like tyrosine kinase 3 (FLT3) gene, commonly Internal Tandem Duplications (ITD).	('mutations', 'Var', (76, 85))	('Internal Tandem Duplications', 'Var', (138, 166))	('FMS-like tyrosine kinase 3', 'Gene', (89, 115))	('FLT3', 'Gene', (117, 121))	('FMS-like tyrosine kinase 3', 'Gene', '2322', (89, 115))	('AML', 'Disease', 'MESH:D015470', (64, 67))	('AML', 'Phenotype', 'HP:0004808', (64, 67))	('AML', 'Disease', (64, 67))	('FLT3', 'Gene', '2322', (117, 121))
580337	28794969	Ten years later, he was admitted to our Institution and molecular evaluations were done, demonstrating the absence of JAK2V617F and MPL mutations, as well as BCR-ABL1 fusion gene.	('BCR-ABL1', 'Gene', (158, 166))	('MPL', 'Gene', '4352', (132, 135))	('fusion gene', 'Var', (167, 178))	('absence', 'NegReg', (107, 114))	('JAK2V617F', 'Var', (118, 127))	('MPL', 'Gene', (132, 135))
580351	28794969	Furthermore, patients carrying high risk mutations, namely ASXL1, IDH1-2, EZH2 and SRSF2 show a reduced leukemia-free survival.	('mutations', 'Var', (41, 50))	('EZH2', 'Gene', (74, 78))	('SRSF2', 'Gene', '6427', (83, 88))	('IDH1-2', 'Gene', '3417;3418', (66, 72))	('patients', 'Species', '9606', (13, 21))	('leukemia', 'Disease', (104, 112))	('IDH1-2', 'Gene', (66, 72))	('leukemia', 'Disease', 'MESH:D007938', (104, 112))	('ASXL1', 'Gene', '171023', (59, 64))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('SRSF2', 'Gene', (83, 88))	('EZH2', 'Gene', '2146', (74, 78))	('ASXL1', 'Gene', (59, 64))	('reduced', 'NegReg', (96, 103))
580356	28794969	performed next-generation sequencing analysis in six cases of isolated MS, and confirmed the frequent occurrence of FLT3 and NPM1 mutations.	('NPM1', 'Gene', '4869', (125, 129))	('occurrence', 'Reg', (102, 112))	('FLT3', 'Gene', '2322', (116, 120))	('mutations', 'Var', (130, 139))	('NPM1', 'Gene', (125, 129))	('FLT3', 'Gene', (116, 120))
580357	28794969	Furthermore, they identified other mutations in a broad spectrum of AML associated genes, including tumor suppressors (WT1), epigenetic modifiers (TET2, ASXL1, EZH2), spliceosome proteins (SF3B1) and tyrosine kinase (FLT3 and KIT).	('tumor', 'Disease', (100, 105))	('EZH2', 'Gene', '2146', (160, 164))	('EZH2', 'Gene', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('KIT', 'Gene', (226, 229))	('TET2', 'Gene', (147, 151))	('ASXL1', 'Gene', '171023', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('FLT3', 'Gene', (217, 221))	('WT1', 'Gene', (119, 122))	('SF3B1', 'Gene', (189, 194))	('TET2', 'Gene', '54790', (147, 151))	('FLT3', 'Gene', '2322', (217, 221))	('WT1', 'Gene', '7490', (119, 122))	('ASXL1', 'Gene', (153, 158))	('AML', 'Disease', 'MESH:D015470', (68, 71))	('AML', 'Disease', (68, 71))	('SF3B1', 'Gene', '23451', (189, 194))	('AML', 'Phenotype', 'HP:0004808', (68, 71))	('mutations', 'Var', (35, 44))
580358	28794969	showed the presence of somatically acquired mutation KITM541L in four of the six analyzed patients, being the latter previously associated with a variety of neoplasms including hematologic malignancies such as CML or Chronic Eosinophilic Leukemia.	('hematologic malignancies', 'Disease', 'MESH:D019337', (177, 201))	('KITM541L', 'Var', (53, 61))	('neoplasms', 'Disease', 'MESH:D009369', (157, 166))	('hematologic malignancies', 'Disease', (177, 201))	('CML', 'Disease', 'MESH:D015464', (210, 213))	('Chronic Eosinophilic Leukemia', 'Disease', 'MESH:D004802', (217, 246))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('Chronic Eosinophilic Leukemia', 'Disease', (217, 246))	('associated with', 'Reg', (128, 143))	('CML', 'Disease', (210, 213))	('patients', 'Species', '9606', (90, 98))	('neoplasms', 'Disease', (157, 166))	('Leukemia', 'Phenotype', 'HP:0001909', (238, 246))
580423	24678225	Myxoid liposarcomas are characterized by the presence of a TLS-CHOP fusion gene, resulting from the t (12;16) (q13-14, p-11) translocation in at least 95% of the cases.	('p-11', 'Gene', '8909', (119, 123))	('TLS', 'Gene', '2521', (59, 62))	('Myxoid liposarcoma', 'Phenotype', 'HP:0012268', (0, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('Myxoid liposarcomas', 'Phenotype', 'HP:0012268', (0, 19))	('t (12;16) (q13-14', 'Var', (100, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('CHOP', 'Gene', '1649', (63, 67))	('p-11', 'Gene', (119, 123))	('Myxoid liposarcomas', 'Disease', (0, 19))	('liposarcomas', 'Phenotype', 'HP:0012034', (7, 19))	('CHOP', 'Gene', (63, 67))	('Myxoid liposarcomas', 'Disease', 'MESH:D018208', (0, 19))	('TLS', 'Gene', (59, 62))	('liposarcoma', 'Phenotype', 'HP:0012034', (7, 18))
580424	24678225	The presence of TLS-CHOP fusion is highly sensitive and specific of myxoid/round cell liposarcomas, and, even in the presence of a predominantly myxoid component, the lack of TLS-CHOP rearrangement suggests that the tumor represents a genetically distinct group of liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (86, 97))	('liposarcoma', 'Disease', (265, 276))	('liposarcomas', 'Phenotype', 'HP:0012034', (86, 98))	('tumor', 'Disease', (216, 221))	('liposarcoma', 'Disease', 'MESH:D008080', (86, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('myxoid/round cell liposarcomas', 'Phenotype', 'HP:0012268', (68, 98))	('liposarcomas', 'Disease', (86, 98))	('liposarcoma', 'Phenotype', 'HP:0012034', (265, 276))	('CHOP', 'Gene', '1649', (20, 24))	('CHOP', 'Gene', '1649', (179, 183))	('TLS', 'Gene', (16, 19))	('liposarcoma', 'Disease', (86, 97))	('TLS', 'Gene', (175, 178))	('presence', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('liposarcoma', 'Disease', 'MESH:D008080', (265, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('TLS', 'Gene', '2521', (16, 19))	('CHOP', 'Gene', (20, 24))	('CHOP', 'Gene', (179, 183))	('TLS', 'Gene', '2521', (175, 178))	('liposarcomas', 'Disease', 'MESH:D008080', (86, 98))
580437	24678225	Myxoid variants are associated with higher rates of local control as compared to other soft tissue sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('sarcomas', 'Disease', (99, 107))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (87, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (87, 106))	('Myxoid variants', 'Var', (0, 15))	('sarcomas', 'Disease', 'MESH:D012509', (99, 107))	('local control', 'CPA', (52, 65))
580447	24678225	The presence of >5% of round cell component is associated with a significantly greater risk of metastatic disease and death.	('metastatic disease', 'CPA', (95, 113))	('round', 'Protein', (23, 28))	('presence', 'Var', (4, 12))	('death', 'Disease', 'MESH:D003643', (118, 123))	('death', 'Disease', (118, 123))
580465	21394244	Although there is no significant correlation among tumor location, metastases at time of diagnosis, age, sex, or the type of transcript, in patients with localized tumors, SYT-SSX2 fusion transcripts seem to predict significantly longer metastasis-free survival than SYT-SSX1 fusion transcripts.	('tumor', 'Disease', (164, 169))	('SYT', 'Gene', '6760', (172, 175))	('metastases', 'Disease', (67, 77))	('fusion transcripts', 'Var', (181, 199))	('SS', 'Phenotype', 'HP:0012570', (271, 273))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('SYT', 'Gene', '6760', (267, 270))	('metastasis-free survival', 'CPA', (237, 261))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('SSX1', 'Gene', '6756', (271, 275))	('SSX1', 'Gene', (271, 275))	('localized tumors', 'Disease', 'MESH:D009364', (154, 170))	('SYT', 'Gene', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('SSX2', 'Gene', (176, 180))	('localized tumors', 'Disease', (154, 170))	('longer', 'PosReg', (230, 236))	('SYT', 'Gene', (267, 270))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('SS', 'Phenotype', 'HP:0012570', (176, 178))	('SSX2', 'Gene', '6757', (176, 180))
580524	21394244	Specifically, high dose ifosfamide has been associated with improved disease-specific survival in adult patients with high-risk primary SS and should be considered a standard part of the chemotherapy regimen for this disease.	('ifosfamide', 'Chemical', 'MESH:D007069', (24, 34))	('SS', 'Phenotype', 'HP:0012570', (136, 138))	('high dose', 'Var', (14, 23))	('improved', 'PosReg', (60, 68))	('patients', 'Species', '9606', (104, 112))	('disease-specific', 'Disease', (69, 85))
580555	20362478	RUNX1 is required for early hematopoiesis and is altered in acute leukemias by point mutations and at least 30 different chromosomal translocations.	('acute leukemias', 'Disease', (60, 75))	('altered', 'Reg', (49, 56))	('hematopoiesis', 'Disease', (28, 41))	('RUNX1', 'Gene', '12394', (0, 5))	('point mutations', 'Var', (79, 94))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))	('RUNX1', 'Gene', (0, 5))	('hematopoiesis', 'Disease', 'MESH:C536227', (28, 41))	('acute leukemias', 'Phenotype', 'HP:0002488', (60, 75))	('leukemias', 'Phenotype', 'HP:0001909', (66, 75))	('acute leukemias', 'Disease', 'MESH:D015470', (60, 75))
580566	20362478	Functionally, Ddx5 augmented Runx2 transcriptional activity while CoAA repressed Runx factor-driven expression of reporter plasmids.	('Ddx5', 'Var', (14, 18))	('expression', 'Species', '29278', (100, 110))	('transcriptional activity', 'MPA', (35, 59))	('CoAA', 'Gene', (66, 70))	('Runx2', 'Gene', (29, 34))	('CoAA', 'Gene', '10432', (66, 70))	('augmented', 'PosReg', (19, 28))	('Runx2', 'Gene', '12393', (29, 34))
580569	20362478	Like RUNX1, FET proteins are frequently altered by chromosomal translocations.	('chromosomal translocations', 'Var', (51, 77))	('RUNX1', 'Gene', '12394', (5, 10))	('FET proteins', 'Protein', (12, 24))	('RUNX1', 'Gene', (5, 10))	('altered', 'Reg', (40, 47))
580583	20362478	Thus, FUS/TLS interacted well with Runx2 constructs containing residues 1-227, 1-327 and 1-383 from the MRIPV isoform.	('1-383', 'Var', (89, 94))	('TLS', 'Gene', '233908', (10, 13))	('interacted', 'Interaction', (14, 24))	('Runx2', 'Gene', (35, 40))	('FUS', 'Gene', '233908', (6, 9))	('1-327', 'Var', (79, 84))	('FUS', 'Gene', (6, 9))	('Runx2', 'Gene', '12393', (35, 40))	('TLS', 'Gene', (10, 13))
580584	20362478	EWSR1 also interacted strongly to Runx2 proteins containing amino acids 1-327 and 1-383, but did not bind well to a shorter protein with only residues 1-227.	('interacted', 'Interaction', (11, 21))	('Runx2', 'Gene', (34, 39))	('amino acids 1-327', 'Var', (60, 77))	('Runx2', 'Gene', '12393', (34, 39))	('proteins', 'Protein', (40, 48))	('EWSR1', 'Gene', (0, 5))	('EWSR1', 'Gene', '14030', (0, 5))	('1-383', 'Var', (82, 87))
580585	20362478	These data indicate subtle differences between how FUS/TLS and EWSR1 bind RUNX proteins and that sequences C-terminal to the Runt domain augment EWSR1 interactions.	('bind', 'Interaction', (69, 73))	('augment', 'PosReg', (137, 144))	('EWSR1', 'Gene', '14030', (63, 68))	('FUS', 'Gene', '233908', (51, 54))	('sequences', 'Var', (97, 106))	('interactions', 'Interaction', (151, 163))	('TLS', 'Gene', '233908', (55, 58))	('EWSR1', 'Gene', '14030', (145, 150))	('EWSR1', 'Gene', (145, 150))	('RUNX proteins', 'Protein', (74, 87))	('EWSR1', 'Gene', (63, 68))	('FUS', 'Gene', (51, 54))	('TLS', 'Gene', (55, 58))
580597	20362478	Interestingly, Ddx5 augmented Runx2 transcriptional activity while CoAA prevented Runx2 from binding DNA.	('CoAA', 'Gene', (67, 71))	('Runx2', 'Gene', '12393', (82, 87))	('CoAA', 'Gene', '10432', (67, 71))	('augmented', 'PosReg', (20, 29))	('Runx2', 'Gene', '12393', (30, 35))	('Ddx5', 'Var', (15, 19))	('Runx2', 'Gene', (82, 87))	('transcriptional activity', 'MPA', (36, 60))	('Runx2', 'Gene', (30, 35))
580603	20362478	The physical interactions between RUNX and FET/TET families of transcription factors are of interest because they functionally link two families of proteins that contribute to hematopoietic and mesenchymal tissue development and that are structurally altered by chromosomal translocations in acute leukemias and undifferentiated sarcomas.	('leukemia', 'Phenotype', 'HP:0001909', (298, 306))	('altered', 'Reg', (251, 258))	('undifferentiated sarcomas', 'Disease', (312, 337))	('acute leukemias', 'Disease', 'MESH:D015470', (292, 307))	('hematopoietic', 'CPA', (176, 189))	('acute leukemias', 'Disease', (292, 307))	('sarcoma', 'Phenotype', 'HP:0100242', (329, 336))	('leukemias', 'Phenotype', 'HP:0001909', (298, 307))	('acute leukemias', 'Phenotype', 'HP:0002488', (292, 307))	('sarcomas', 'Phenotype', 'HP:0100242', (329, 337))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (312, 337))	('contribute', 'Reg', (162, 172))	('chromosomal translocations', 'Var', (262, 288))
580605	20362478	Interestingly, no primary tumors have been described with alterations in genes from both families.	('tumors', 'Disease', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('alterations', 'Var', (58, 69))
580615	29626598	The most common molecular alterations detected in these tumors are gene rearrangements involving EWSR1 to one of many fusion partners.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EWSR1', 'Gene', (97, 102))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('men', 'Species', '9606', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('EWSR1', 'Gene', '2130', (97, 102))	('gene rearrangements', 'Var', (67, 86))
580616	29626598	Rare EWSR1-NFATC2 gene rearrangements, corresponding to a t(20;22) gene translocation, have been described in mesenchymal tumors with clear round cell morphology and a predilection for the skeleton.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('described', 'Reg', (97, 106))	('EWSR1', 'Gene', '2130', (5, 10))	('men', 'Species', '9606', (32, 35))	('NFATC2', 'Gene', '4773', (11, 17))	('EWSR1', 'Gene', (5, 10))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (110, 128))	('rearrangements', 'Var', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mesenchymal tumors', 'Disease', (110, 128))	('NFATC2', 'Gene', (11, 17))
580625	29626598	Other uncommon variant ETS fusions have been also been identified in Ewing sarcoma, including EWSR1-ETV1, EWSR1-ETV4, and EWSR1-FEV.	('ETV4', 'Gene', (112, 116))	('EWSR1', 'Gene', '2130', (106, 111))	('EWSR1', 'Gene', '2130', (122, 127))	('ETV1', 'Gene', (100, 104))	('EWSR1', 'Gene', (94, 99))	('variant', 'Var', (15, 22))	('identified', 'Reg', (55, 65))	('ETV4', 'Gene', '2118', (112, 116))	('Ewing sarcoma', 'Disease', (69, 82))	('ETV1', 'Gene', '2115', (100, 104))	('ETS', 'Gene', (23, 26))	('EWSR1', 'Gene', '2130', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('EWSR1', 'Gene', (122, 127))	('EWSR1', 'Gene', (106, 111))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (69, 82))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (69, 82))
580627	29626598	Collectively, these variant fusions account for less than 5% of all Ewing sarcoma cases.	('Ewing sarcoma', 'Disease', (68, 81))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (68, 81))	('variant', 'Var', (20, 27))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (68, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
580628	29626598	The list of tumors harboring EWSR1 gene rearrangements also includes cases within the poorly defined category of "Ewing-like" tumors, myoepithelial tumors, extraskeletal myxoid chondrosarcoma, and desmoplastic small round cell tumor, among others.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('EWSR1', 'Gene', (29, 34))	('myoepithelial tumors', 'Disease', (134, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('rearrangements', 'Var', (40, 54))	('men', 'Species', '9606', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Disease', (126, 132))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (177, 191))	('Ewing-like" tumors', 'Phenotype', 'HP:0012254', (114, 132))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (197, 232))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('desmoplastic small round cell tumor', 'Disease', (197, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (134, 154))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', (12, 18))	('EWSR1', 'Gene', '2130', (29, 34))	('myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (170, 191))	('myxoid chondrosarcoma', 'Disease', (170, 191))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
580629	29626598	We report a case of a mesenchymal tumor that harbors an EWSR1 gene rearrangement to nuclear factor of activated T cells, cytoplasmic and calcineurin-dependent 2 (NFATC2).	('EWSR1', 'Gene', (56, 61))	('rearrangement', 'Var', (67, 80))	('NFATC2', 'Gene', (162, 168))	('mesenchymal tumor', 'Disease', (22, 39))	('EWSR1', 'Gene', '2130', (56, 61))	('men', 'Species', '9606', (76, 79))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (22, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('NFATC2', 'Gene', '4773', (162, 168))
580630	29626598	Thus far, descriptions of tumors that harbor EWSR1-NFATC2 gene fusions have been limited with only 9 prior tumors reported, which have been categorized as "Ewing-like" or "myoepithelial-like."	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('EWSR1', 'Gene', (45, 50))	('NFATC2', 'Gene', (51, 57))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('EWSR1', 'Gene', '2130', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('NFATC2', 'Gene', '4773', (51, 57))	('myoepithelial-like', 'Disease', (172, 190))	('fusions', 'Var', (63, 70))
580688	29626598	A genomic breakpoint occurred in intron 10 of EWSR1 (NM_013986, genomic location: 29687751) and intron 2 of NFATC2 (NM_173091, genomic location: 50135065; Fig.	('EWSR1', 'Gene', (46, 51))	('NFATC2', 'Gene', (108, 114))	('NM_173091', 'Var', (116, 125))	('NM_013986', 'Var', (53, 62))	('NFATC2', 'Gene', '4773', (108, 114))	('EWSR1', 'Gene', '2130', (46, 51))
580693	29626598	The differential diagnosis of mesenchymal neoplasms that harbor EWSR1 gene rearrangements ranges from clinically indolent to frankly malignant tumors.	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (30, 51))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('neoplasms', 'Phenotype', 'HP:0002664', (42, 51))	('malignant tumors', 'Disease', (133, 149))	('EWSR1', 'Gene', '2130', (64, 69))	('neoplasm', 'Phenotype', 'HP:0002664', (42, 50))	('malignant tumors', 'Disease', 'MESH:D009369', (133, 149))	('men', 'Species', '9606', (84, 87))	('rearrangements', 'Var', (75, 89))	('mesenchymal neoplasms', 'Disease', (30, 51))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('EWSR1', 'Gene', (64, 69))
580694	29626598	We describe a case of a mesenchymal round cell tumor with abundant stroma that harbors an EWSR1 gene rearrangement to NFATC2.	('EWSR1', 'Gene', (90, 95))	('NFATC2', 'Gene', (118, 124))	('men', 'Species', '9606', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('rearrangement', 'Var', (101, 114))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('EWSR1', 'Gene', '2130', (90, 95))	('NFATC2', 'Gene', '4773', (118, 124))	('tumor', 'Disease', (47, 52))
580696	29626598	Ewing sarcoma is generally characterized by primitive round cells with EWSR1 fusions to ETS gene family members.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('fusions', 'Var', (77, 84))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('EWSR1', 'Gene', (71, 76))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('EWSR1', 'Gene', '2130', (71, 76))
580699	29626598	Ewing-like tumors are typified by Ewing morphology but display EWSR1 fusions with non-ETS family genes, which encompass those that encode for zinc finger proteins such as PATZ1 and SP3, and a case of SMARCA5, a member of the SWI/SNF chromatin-remodeling complex.	('SP3', 'Gene', (181, 184))	('SMARCA5', 'Gene', (200, 207))	('Ewing-like tumors', 'Disease', 'MESH:C563168', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Ewing-like tumors', 'Disease', (0, 17))	('PATZ1', 'Gene', '23598', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('EWSR1', 'Gene', '2130', (63, 68))	('Ewing-like tumors', 'Phenotype', 'HP:0012254', (0, 17))	('SP3', 'Gene', '6670', (181, 184))	('SMARCA5', 'Gene', '8467', (200, 207))	('EWSR1', 'Gene', (63, 68))	('PATZ1', 'Gene', (171, 176))	('fusions', 'Var', (69, 76))
580707	29626598	EWSR1 gene fusions are found in roughly half of the cases of soft tissue myoepithelial tumors and in up to 71% of cases in primary intraosseous myoepithelial tumors, with EWSR1-POU5F1 being the most common fusion and more common in tumors exhibiting clear cell morphology.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (73, 93))	('EWSR1', 'Gene', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('tumors', 'Disease', (158, 164))	('POU5F1', 'Gene', (177, 183))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (144, 164))	('EWSR1', 'Gene', '2130', (0, 5))	('tumors', 'Disease', (87, 93))	('fusions', 'Var', (11, 18))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('myoepithelial tumors', 'Disease', (73, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('EWSR1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('POU5F1', 'Gene', '5460', (177, 183))	('EWSR1', 'Gene', '2130', (171, 176))	('myoepithelial tumors', 'Disease', (144, 164))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Disease', (232, 238))
580709	29626598	Non-EWSR1-rearranged myoepithelial tumors have recently been shown to harbor FUS-KLF17 gene fusions, tend to affect younger patients, and often display more myxohyaline stroma.	('EWSR1', 'Gene', '2130', (4, 9))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (21, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('KLF17', 'Gene', (81, 86))	('myxohyaline stroma', 'CPA', (157, 175))	('myoepithelial tumors', 'Disease', (21, 41))	('fusions', 'Var', (92, 99))	('FUS', 'Gene', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('FUS', 'Gene', '2521', (77, 80))	('affect', 'Reg', (109, 115))	('EWSR1', 'Gene', (4, 9))	('more', 'PosReg', (152, 156))	('patients', 'Species', '9606', (124, 132))	('KLF17', 'Gene', '128209', (81, 86))
580710	29626598	A series of cutaneous myoepithelial tumors showed positive EWSR1 gene rearrangements in 3 of 8 of cases, 2 of which were localized to the subcutis.	('EWSR1', 'Gene', (59, 64))	('men', 'Species', '9606', (79, 82))	('cutaneous myoepithelial tumors', 'Disease', (12, 42))	('EWSR1', 'Gene', '2130', (59, 64))	('rearrangements', 'Var', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cutaneous myoepithelial tumors', 'Disease', 'MESH:D009208', (12, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
580723	29626598	The present case showed expression for NKX2.2, which is a relatively recently identified nuclear marker with high sensitivity for Ewing sarcoma; however, it lacks specificity and has been shown to be positive in a small subset of other round cell tumors with EWSR1 rearrangements, including desmoplastic small round cell tumor and soft tissue myoepithelial tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (343, 363))	('tumors', 'Disease', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (357, 363))	('NKX2.2', 'Gene', '4821', (39, 45))	('EWSR1', 'Gene', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('lacks', 'NegReg', (157, 162))	('Ewing sarcoma', 'Disease', (130, 143))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Disease', (357, 363))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (291, 326))	('positive', 'Reg', (200, 208))	('desmoplastic small round cell tumor', 'Disease', (291, 326))	('myoepithelial tumors', 'Disease', (343, 363))	('tumors', 'Disease', 'MESH:D009369', (357, 363))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('EWSR1', 'Gene', '2130', (259, 264))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (130, 143))	('rearrangements', 'Var', (265, 279))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (130, 143))	('men', 'Species', '9606', (274, 277))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('NKX2.2', 'Gene', (39, 45))
580736	29626598	The EWSR1-NFATC2 fusion results in a truncated NFATC2 protein with loss of the first 2 exons, which encode the regulatory region.	('NFATC2', 'Gene', (10, 16))	('EWSR1', 'Gene', '2130', (4, 9))	('NFATC2', 'Gene', '4773', (47, 53))	('fusion', 'Var', (17, 23))	('loss', 'NegReg', (67, 71))	('NFATC2', 'Gene', (47, 53))	('results in', 'Reg', (24, 34))	('NFATC2', 'Gene', '4773', (10, 16))	('protein', 'Protein', (54, 61))	('EWSR1', 'Gene', (4, 9))	('truncated', 'MPA', (37, 46))
580743	29626598	Overall, these cases contribute to the growing diversity of mesenchymal tumors harboring EWSR1 gene fusions and highlight a unique presentation of an EWSR1-NFATC2 tumor.	('fusions', 'Var', (100, 107))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('mesenchymal tumors', 'Disease', (60, 78))	('EWSR1', 'Gene', '2130', (89, 94))	('tumor', 'Disease', (72, 77))	('EWSR1', 'Gene', '2130', (150, 155))	('NFATC2', 'Gene', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (163, 168))	('EWSR1', 'Gene', (150, 155))	('EWSR1', 'Gene', (89, 94))	('gene fusions', 'Var', (95, 107))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('NFATC2', 'Gene', '4773', (156, 162))
580761	32411598	During the physical examination we observed facial plethora and fullness, lower limb edema, dorso-cervical fat pad ("buffalo hump"), hirsutism, obesity and hypertension (BP 135/80 mmHg, > 99  pct).	('hypertension', 'Disease', (156, 168))	('hirsutism', 'Disease', 'MESH:D006628', (133, 142))	('hirsutism', 'Phenotype', 'HP:0001007', (133, 142))	('facial plethora', 'CPA', (44, 59))	('dorso-cervical fat pad', 'Phenotype', 'HP:0025383', (92, 114))	('fullness', 'CPA', (64, 72))	('lower limb edema', 'Phenotype', 'HP:0010741', (74, 90))	('edema', 'Phenotype', 'HP:0000969', (85, 90))	('plethora', 'Phenotype', 'HP:0001050', (51, 59))	('hirsutism', 'Disease', (133, 142))	('hypertension', 'Phenotype', 'HP:0000822', (156, 168))	('obesity', 'Phenotype', 'HP:0001513', (144, 151))	('lower limb', 'Phenotype', 'HP:0006385', (74, 84))	('obesity', 'Disease', (144, 151))	('limb edema', 'Disease', 'MESH:D004487', (80, 90))	('BP 135/80 mmHg', 'Var', (170, 184))	('obesity', 'Disease', 'MESH:D009765', (144, 151))	('limb edema', 'Disease', (80, 90))	('hypertension', 'Disease', 'MESH:D006973', (156, 168))	('buffalo hump', 'Phenotype', 'HP:0025383', (117, 129))
580769	32411598	Due to the suspicion of a osteoporotic vertebral fracture, we decided to perform a total spine radiography which identified a lesion of the right ischio-pubic and ileo-pubic branches.	('lesion', 'Var', (126, 132))	('osteoporotic vertebral fracture', 'Phenotype', 'HP:0005625', (26, 57))	('vertebral fracture', 'Phenotype', 'HP:0002953', (39, 57))	('osteoporotic vertebral fracture', 'Disease', 'MESH:D058866', (26, 57))	('osteoporotic vertebral fracture', 'Disease', (26, 57))
580808	32411598	Despite several collateral effects, such as nausea, hepatotoxicity, and hypogonadism, ketoconazole is usually the most tolerated; instead, metyrapone, which results in eucortisolemia in 50% of patients, may cause hirsutism.	('metyrapone', 'Chemical', 'MESH:D008797', (139, 149))	('hirsutism', 'Disease', 'MESH:D006628', (213, 222))	('hirsutism', 'Phenotype', 'HP:0001007', (213, 222))	('eucortisolemia', 'Disease', (168, 182))	('ketoconazole', 'Chemical', 'MESH:D007654', (86, 98))	('nausea', 'Disease', 'MESH:D009325', (44, 50))	('hypogonadism', 'Disease', (72, 84))	('cause', 'Reg', (207, 212))	('hirsutism', 'Disease', (213, 222))	('metyrapone', 'Var', (139, 149))	('hypogonadism', 'Phenotype', 'HP:0000135', (72, 84))	('patients', 'Species', '9606', (193, 201))	('hepatotoxicity', 'Disease', (52, 66))	('nausea', 'Phenotype', 'HP:0002018', (44, 50))	('hypogonadism', 'Disease', 'MESH:D007006', (72, 84))	('eucortisolemia', 'Disease', 'None', (168, 182))	('hepatotoxicity', 'Disease', 'MESH:D056486', (52, 66))	('results in', 'Reg', (157, 167))	('nausea', 'Disease', (44, 50))
580884	31914068	In a phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line treatment for TRS, trabectedin improved progression-free survival (PFS) and OS, although there was no statistical difference between the 2 treatment groups.	('improved', 'PosReg', (119, 127))	('doxorubicin', 'Chemical', 'MESH:D004317', (43, 54))	('progression-free survival', 'CPA', (128, 153))	('trabectedin', 'Var', (107, 118))
580907	31427232	High SOX2 expression constitutes an independent prognostic biomarker for EwS patients with poor outcomes.	('EwS', 'Phenotype', 'HP:0012254', (73, 76))	('High', 'Var', (0, 4))	('EwS', 'Disease', (73, 76))	('SOX2', 'Protein', (5, 9))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (77, 85))
580911	31427232	The work of U. Dirksen is supported by grants from the German Cancer Aid (DKH-108128, DKH-70112018, and DKH-70113419), the ERA-Net-TRANSCAN consortium (project number 01KT1310), and Euro Ewing Consortium (EEC, project number EU-FP7 602,856), both funded under the European Commission Seventh Framework Program FP7-HEALTH (http://cordis.europa.eu/), the Barbara & Hubertus Trettner foundation, and the Gert & Susanna Mayer foundation.	('Euro', 'Species', '9319', (264, 268))	('DKH-70113419', 'Chemical', 'None', (104, 116))	('DKH-108128, DKH-70112018', 'Chemical', 'None', (74, 98))	('DKH-70113419', 'Var', (104, 116))	('Aid', 'Gene', (69, 72))	('Aid', 'Gene', '57379', (69, 72))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Euro', 'Species', '9319', (182, 186))
580924	31427232	Genetically, the hallmark of EwS is chromosomal translocations that generate chimeric proteins through fusion of the EWSR1 (Ewing sarcoma breakpoint region 1) gene to various members of the ETS (E26 transformation specific) family of transcription factors, in 85% FLI1 (Friend leukemia virus integration 1).	('leukemia', 'Phenotype', 'HP:0001909', (277, 285))	('EWSR1', 'Gene', (117, 122))	('FLI1', 'Gene', (264, 268))	('FLI1', 'Gene', '2313', (264, 268))	('Friend leukemia virus integration 1', 'Gene', '2313', (270, 305))	('EwS', 'Phenotype', 'HP:0012254', (29, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('EWSR1', 'Gene', '2130', (117, 122))	('fusion', 'Var', (103, 109))	('Ewing sarcoma breakpoint region 1', 'Gene', '2130', (124, 157))	('Ewing sarcoma breakpoint region 1', 'Gene', (124, 157))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (124, 137))	('Friend leukemia virus integration 1', 'Gene', (270, 305))
580933	31427232	Moreover, high expression of SOX2 is significantly correlated with local and/or metastatic tumour relapse.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Disease', (91, 97))	('SOX2', 'Gene', (29, 33))	('high', 'Var', (10, 14))	('local and/or', 'CPA', (67, 79))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('correlated', 'Reg', (51, 61))
580954	31427232	Stratifying our mRNA-cohort by a cut-off of the 80th percentile of SOX2 expression in SOX2-low or -high cases, we noted that patients with high intratumoural SOX2 expression had worse OS than patients with low SOX2 expression (p < 0 0001) (Fig.	('patients', 'Species', '9606', (192, 200))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('SOX2', 'Gene', (158, 162))	('high', 'Var', (139, 143))	('tumour', 'Disease', (149, 155))	('patients', 'Species', '9606', (125, 133))
580968	31427232	In fact, 58 3% of patients with high SOX2 expression had a tumour volume >= 200 ml compared to 41 7% patients with low SOX2 expression (p = 0 23) (Table 4).	('high', 'Var', (32, 36))	('patients', 'Species', '9606', (101, 109))	('tumour volume', 'Disease', (59, 72))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour volume', 'Disease', 'MESH:D009369', (59, 72))	('SOX2', 'Gene', (37, 41))	('expression', 'Var', (42, 52))	('patients', 'Species', '9606', (18, 26))
580970	31427232	Consistently, dox-induced silencing of SOX2 in POE cells xenografted in immunocompromised NSG mice significantly reduced tumour growth (appendix fig.	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour growth', 'Disease', (121, 134))	('mice', 'Species', '10090', (94, 98))	('tumour growth', 'Disease', 'MESH:D006130', (121, 134))	('silencing', 'Var', (26, 35))	('SOX2', 'Gene', (39, 43))	('reduced', 'NegReg', (113, 120))
580983	31427232	In fact, SOX2-high expression has been more frequently observed in relapsed tumours, and SOX2-high expression in primary tumours is significantly associated with early relapse in patients with localised disease and no other apparent clinical risk-factors.	('SOX2-high expression', 'Var', (89, 109))	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumours', 'Disease', (76, 83))	('early', 'Disease', (162, 167))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('patients', 'Species', '9606', (179, 187))	('associated with', 'Reg', (146, 161))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('observed', 'Reg', (55, 63))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
580984	31427232	In line with our findings in EwS, high expression or amplification of SOX2 has been reported to correlate with poor survival in breast, colorectal, esophageal, laryngeal, endometrial, and ovarian carcinomas.	('endometrial', 'Disease', 'MESH:D016889', (171, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('laryngeal', 'Disease', (160, 169))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (188, 206))	('high expression', 'Var', (34, 49))	('amplification', 'Var', (53, 66))	('SOX2', 'Gene', (70, 74))	('EwS', 'Phenotype', 'HP:0012254', (29, 32))	('colorectal', 'Disease', (136, 146))	('breast', 'Disease', (128, 134))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (188, 206))	('endometrial', 'Disease', (171, 182))	('esophageal', 'Disease', (148, 158))	('ovarian carcinomas', 'Disease', (188, 206))	('poor', 'NegReg', (111, 115))
580987	31427232	identified a polymorphic EWSR1-FLI1-bound enhancer-like GGAA-microsatellite near SOX2, and demonstrated that epigenetic silencing of this DNA sequence strongly reduced SOX2 expression in EwS cells.	('EwS', 'Phenotype', 'HP:0012254', (187, 190))	('EWSR1', 'Gene', (25, 30))	('SOX2', 'Gene', (168, 172))	('FLI1', 'Gene', (31, 35))	('FLI1', 'Gene', '2313', (31, 35))	('EWSR1', 'Gene', '2130', (25, 30))	('reduced', 'NegReg', (160, 167))	('epigenetic silencing', 'Var', (109, 129))	('expression', 'MPA', (173, 183))
580991	31427232	In support of our findings, it has been shown in sinonasal carcinomas that patients with SOX2 amplification have a significantly higher rate of tumour recurrence than those without SOX2 amplification.	('amplification', 'Var', (94, 107))	('sinonasal carcinomas', 'Disease', 'MESH:C537344', (49, 69))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('higher', 'PosReg', (129, 135))	('sinonasal carcinomas', 'Disease', (49, 69))	('patients', 'Species', '9606', (75, 83))	('tumour', 'Disease', (144, 150))	('SOX2', 'Gene', (89, 93))
581006	26158413	TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('TCF21', 'Gene', (0, 5))	('sarcoma', 'Disease', (59, 66))	('hypermethylation', 'Var', (6, 22))	('clear cell sarcoma of the kidney Clear', 'Phenotype', 'HP:0006770', (48, 86))	('Sarcoma of the Kidney', 'Phenotype', 'HP:0008663', (92, 113))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (59, 80))	('CCSK', 'Phenotype', 'HP:0006770', (115, 119))	('tumor', 'Disease', (141, 146))	('Clear Cell Sarcoma of the Kidney', 'Disease', 'MESH:D018227', (81, 113))	('CCSK', 'Chemical', '-', (115, 119))	('Clear Cell Sarcoma of the Kidney', 'Phenotype', 'HP:0006770', (81, 113))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('TCF21', 'Gene', '6943', (0, 5))	('Sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('Clear Cell Sarcoma of the Kidney', 'Disease', (81, 113))
581007	26158413	We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation.	('changes', 'Reg', (44, 51))	('CCSKs', 'Chemical', '-', (34, 39))	('CCSK', 'Phenotype', 'HP:0006770', (34, 38))	('rearrangements', 'Var', (90, 104))	('global', 'MPA', (106, 112))	('mutations', 'Var', (79, 88))
581009	26158413	Integrated analysis of expression and methylation data identified promoter hypermethylation and low expression of the tumor suppressor gene TCF21 (Pod-1/capsulin/epicardin) in all CCSKs except the case with t(10;17)(q22;p13).	('CCSK', 'Phenotype', 'HP:0006770', (180, 184))	('TCF21', 'Gene', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (207, 224))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('epicardin', 'Gene', '6943', (162, 171))	('capsulin', 'Gene', '6943', (153, 161))	('expression', 'MPA', (100, 110))	('CCSKs', 'Chemical', '-', (180, 185))	('low', 'NegReg', (96, 99))	('tumor', 'Disease', (118, 123))	('t(10', 'Var', (207, 211))	('epicardin', 'Gene', (162, 171))	('capsulin', 'Gene', (153, 161))
581010	26158413	TARID, the long noncoding RNA responsible for demethylating TCF21, was virtually undetectable in most CCSKs.	('TARID', 'Gene', '100507308', (0, 5))	('CCSK', 'Phenotype', 'HP:0006770', (102, 106))	('TARID', 'Gene', (0, 5))	('demethylating', 'Var', (46, 59))	('TCF21', 'Gene', (60, 65))	('CCSKs', 'Chemical', '-', (102, 107))
581011	26158413	TCF21 hypermethylation and decreased TARID expression were validated in an independent set of CCSK tumor samples.	('tumor', 'Disease', (99, 104))	('TCF21', 'Gene', (0, 5))	('TARID', 'Gene', (37, 42))	('hypermethylation', 'Var', (6, 22))	('decreased', 'NegReg', (27, 36))	('CCSK', 'Disease', (94, 98))	('CCSK', 'Chemical', '-', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CCSK', 'Phenotype', 'HP:0006770', (94, 98))	('TARID', 'Gene', '100507308', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
581012	26158413	The presence of significant hypermethylation of TCF21, a transcription factor known to be active early in renal development, supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs.	('CCSKs', 'Disease', (257, 262))	('hypermethylation', 'Var', (28, 44))	('TCF21', 'Gene', (174, 179))	('TARID', 'Gene', (197, 202))	('TCF21', 'Gene', (48, 53))	('expression', 'MPA', (203, 213))	('CCSKs', 'Chemical', '-', (257, 262))	('CCSK', 'Phenotype', 'HP:0006770', (257, 261))	('TARID', 'Gene', '100507308', (197, 202))	('decreased', 'NegReg', (187, 196))	('hypermethylation', 'Var', (154, 170))
581023	26158413	Of note, the same t(10;17)(q22;p13) translocation, involving the same introns, has been identified to be recurrent in high-grade endometrial stromal sarcomas.	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (18, 35))	('endometrial stromal sarcomas', 'Disease', (129, 157))	('sarcomas', 'Phenotype', 'HP:0100242', (149, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (149, 156))	('t(10;17)(q22;p13', 'Var', (18, 34))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (129, 157))
581024	26158413	Another fusion transcript involving IRX2 and TERT, caused by an interstitial deletion of 5p, was recently reported in a single tumor classified as CCSK.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('reported', 'Reg', (106, 114))	('CCSK', 'Chemical', '-', (147, 151))	('tumor', 'Disease', (127, 132))	('TERT', 'Gene', (45, 49))	('CCSK', 'Phenotype', 'HP:0006770', (147, 151))	('deletion', 'Var', (77, 85))	('TERT', 'Gene', '7015', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('IRX2', 'Gene', (36, 40))	('IRX2', 'Gene', '153572', (36, 40))
581025	26158413	The observation that CCSK tissue sections stained strongly with EGFR antibodies led to the identification of gene amplification of EGFR in 1/12 cases and somatic EGFR mutation in 1/12 cases, with both samples additionally harboring somatic mutations in PTEN.	('CCSK', 'Chemical', '-', (21, 25))	('EGFR', 'Gene', '1956', (162, 166))	('mutation', 'Var', (167, 175))	('EGFR', 'Gene', (162, 166))	('CCSK', 'Phenotype', 'HP:0006770', (21, 25))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('PTEN', 'Gene', (253, 257))	('PTEN', 'Gene', '5728', (253, 257))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('harboring', 'Reg', (222, 231))	('gene amplification', 'Var', (109, 127))
581028	26158413	SNP arrays and relative coverage generated by whole genome sequencing were used to analyze chromosome segment copy number gain and loss in the 13 paired normal and CCSK tumor samples of the discovery set.	('CCSK', 'Disease', (164, 168))	('CCSK', 'Chemical', '-', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('CCSK', 'Phenotype', 'HP:0006770', (164, 168))	('loss', 'NegReg', (131, 135))	('chromosome segment', 'Gene', (91, 109))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('copy number', 'Var', (110, 121))	('gain', 'PosReg', (122, 126))
581035	26158413	Of the 5 verified variants, one was a known polymorphism (TOP3B) and one was not predicted to be damaging by PolyPhen2 (PJA2); the 3 remaining variants (CAMSAP1, DHTKD1, KIF26A) involved genes present in COSMIC (version 69), and were predicted to be damaging by PolyPhen2.	('PJA2', 'Gene', '9867', (120, 124))	('CAMSAP1', 'Gene', (153, 160))	('DHTKD1', 'Gene', '55526', (162, 168))	('DHTKD1', 'Gene', (162, 168))	('CAMSAP1', 'Gene', '157922', (153, 160))	('KIF26A', 'Gene', (170, 176))	('KIF26A', 'Gene', '26153', (170, 176))	('PJA2', 'Gene', (120, 124))	('TOP3B', 'Gene', '8940', (58, 63))	('TOP3B', 'Gene', (58, 63))	('variants', 'Var', (143, 151))
581040	26158413	Of note, while the majority of high grade endometrial stromal sarcomas contained a balanced t(10;17)(q22;p13), one endometrial stromal sarcoma has similarly been reported with deletion of the derivative chromosome containing distal 17p, supporting the suggestion that the remaining derivative chromosome is responsible for biologic activity.	('deletion', 'Var', (176, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (115, 142))	('endometrial stromal sarcoma', 'Disease', (115, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (42, 70))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (42, 69))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (92, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('endometrial stromal sarcomas', 'Disease', (42, 70))
581046	26158413	The previously reported endometrial stromal sarcomas containing the t(10;17)(q22;p13) were shown to have a distinctive expression profile compared to endometrial stromal sarcomas without the translocation.	('t(10;17)(q22;p13', 'Var', (68, 84))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (24, 52))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (68, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('endometrial stromal sarcomas', 'Disease', (150, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (150, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('endometrial stromal sarcomas', 'Disease', (24, 52))
581051	26158413	To identify if differences in DNA methylation may be implicated in CCSK tumorigenesis, an integrative approach was used.	('CCSK', 'Chemical', '-', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CCSK', 'Phenotype', 'HP:0006770', (67, 71))	('implicated', 'Reg', (53, 63))	('tumor', 'Disease', (72, 77))	('CCSK', 'Disease', (67, 71))	('differences', 'Var', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
581058	26158413	The gene expression of TCF21 was down-regulated in CCSKs in comparison with favorable histology Wilms tumors (fold change 0.05, p-value <1E-09); the CCSK with the t(10;17) translocation showed a higher level of TCF21 expression (Figure 2).	('TCF21', 'Gene', (211, 216))	('Wilms tumors', 'Disease', (96, 108))	('t(10;17) translocation', 'Var', (163, 185))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('Wilms tumors', 'Phenotype', 'HP:0002667', (96, 108))	('CCSK', 'Chemical', '-', (51, 55))	('higher', 'PosReg', (195, 201))	('expression', 'MPA', (217, 227))	('Wilms tumors', 'Disease', 'MESH:D009396', (96, 108))	('CCSK', 'Phenotype', 'HP:0006770', (51, 55))	('CCSKs', 'Chemical', '-', (51, 56))	('gene expression', 'MPA', (4, 19))	('Wilms tumor', 'Phenotype', 'HP:0002667', (96, 107))	('CCSK', 'Chemical', '-', (149, 153))	('CCSK', 'Phenotype', 'HP:0006770', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('down-regulated', 'NegReg', (33, 47))	('TCF21', 'Gene', (23, 28))
581067	26158413	TCF21 methylation and expression has been shown to be governed by the antisense long noncoding RNA (lncRNA) TARID, which acts by demethylating the TCF21 promoter.	('demethylating', 'Var', (129, 142))	('TARID', 'Gene', (108, 113))	('TCF21', 'Gene', (0, 5))	('TARID', 'Gene', '100507308', (108, 113))	('TCF21', 'Gene', (147, 152))	('governed', 'Reg', (54, 62))	('expression', 'MPA', (22, 32))
581070	26158413	Expression of both TARID (NR_109982) and the TARID isoforms KF484511 and KF484512 (isoforms reported to have the strongest demethylation activity) was much lower in CCSKs than in Wilms tumors; in most CCSKs TARID was undetectable (Figure 5C, 5D).	('TARID', 'Gene', '100507308', (45, 50))	('TARID', 'Gene', (19, 24))	('TARID', 'Gene', '100507308', (19, 24))	('Wilms tumor', 'Phenotype', 'HP:0002667', (179, 190))	('Wilms tumors', 'Phenotype', 'HP:0002667', (179, 191))	('lower', 'NegReg', (156, 161))	('CCSK', 'Phenotype', 'HP:0006770', (165, 169))	('demethylation', 'MPA', (123, 136))	('CCSKs', 'Chemical', '-', (201, 206))	('CCSKs', 'Disease', (165, 170))	('Wilms tumors', 'Disease', (179, 191))	('Expression', 'MPA', (0, 10))	('TARID', 'Gene', (207, 212))	('TARID', 'Gene', '100507308', (207, 212))	('CCSK', 'Phenotype', 'HP:0006770', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('KF484511', 'Var', (60, 68))	('CCSKs', 'Chemical', '-', (165, 170))	('Wilms tumors', 'Disease', 'MESH:D009396', (179, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('KF484512', 'Var', (73, 81))	('TARID', 'Gene', (45, 50))
581088	26158413	We identified increased expression of YWHAE in all CCSKs, regardless of translocation status, although the expression level of this gene was somewhat lower in the t(10;17) CCSK case.	('increased', 'PosReg', (14, 23))	('lower', 'NegReg', (150, 155))	('expression level', 'MPA', (107, 123))	('YWHAE', 'Gene', (38, 43))	('expression', 'MPA', (24, 34))	('CCSK', 'Chemical', '-', (51, 55))	('CCSK', 'Chemical', '-', (172, 176))	('CCSK', 'Phenotype', 'HP:0006770', (51, 55))	('CCSK', 'Phenotype', 'HP:0006770', (172, 176))	('CCSKs', 'Chemical', '-', (51, 56))	('t(10;17', 'Var', (163, 170))	('YWHAE', 'Gene', '7531', (38, 43))
581089	26158413	Furthermore, we demonstrate that the unique gene expression pattern previously identified in high grade endometrial stromal sarcomas harboring the t(10;17)(q22;p13) is also seen in CCSKs, regardless of their translocation status.	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (104, 132))	('CCSKs', 'Chemical', '-', (181, 186))	('CCSK', 'Phenotype', 'HP:0006770', (181, 185))	('t(10;17)(q22;p13', 'Var', (147, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (124, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (147, 164))	('CCSKs', 'Disease', (181, 186))	('endometrial stromal sarcomas', 'Disease', (104, 132))
581094	26158413	Gene deletion studies in chimeric mice have shown that loss of TCF21 in the kidney prior to induction results in decreased tubulogenesis and glomerulogenesis and a failure of mesenchymal-to-epithelial transition.	('mesenchymal-to-epithelial transition', 'CPA', (175, 211))	('mice', 'Species', '10090', (34, 38))	('TCF21', 'Gene', (63, 68))	('loss', 'Var', (55, 59))	('tubulogenesis', 'CPA', (123, 136))	('failure', 'NegReg', (164, 171))	('glomerulogenesis', 'CPA', (141, 157))	('decreased', 'NegReg', (113, 122))
581095	26158413	Decreased expression of TCF21 by hypermethylation was first identified by Smith et al, who demonstrated a tumor suppressor function in head and neck squamous cell carcinoma and non-small-cell lung cancer.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (181, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (135, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('neck squamous cell carcinoma', 'Disease', (144, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('Decreased', 'NegReg', (0, 9))	('TCF21', 'Gene', (24, 29))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (144, 172))	('expression', 'MPA', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('hypermethylation', 'Var', (33, 49))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('non-small-cell lung cancer', 'Disease', (177, 203))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (177, 203))	('tumor', 'Disease', (106, 111))
581096	26158413	Since then, TCF21 promoter hypermethylation has been associated with poor outcome in various tumor types, including metastatic melanoma, lung adenocarcinomas, squamous cell lung cancers, clear cell renal cell carcinoma and other urological cancers.	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (159, 185))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancers', 'Phenotype', 'HP:0100526', (173, 185))	('squamous cell lung cancers', 'Disease', (159, 185))	('urological cancers', 'Disease', (229, 247))	('lung adenocarcinomas', 'Disease', (137, 157))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (187, 218))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('melanoma', 'Disease', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('associated', 'Reg', (53, 63))	('TCF21', 'Gene', (12, 17))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (187, 218))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (137, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('clear cell renal cell carcinoma', 'Disease', (187, 218))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (198, 218))	('tumor', 'Disease', (93, 98))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('urological cancers', 'Disease', 'MESH:D014571', (229, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('promoter hypermethylation', 'Var', (18, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (137, 157))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
581099	26158413	Recently Arab et al provided evidence that the antisense long noncoding RNA (lncRNA) TARID activates TCF21 expression by inducing promoter demethylation.	('promoter demethylation', 'MPA', (130, 152))	('inducing', 'Reg', (121, 129))	('expression', 'MPA', (107, 117))	('antisense', 'Var', (47, 56))	('TCF21', 'Gene', (101, 106))	('activates', 'PosReg', (91, 100))	('TARID', 'Gene', (85, 90))	('TARID', 'Gene', '100507308', (85, 90))
581102	26158413	This suggests the possibility that the direct cause of TCF21 hypermethylation in CCSKs may be decreased TARID expression, although we have not identified a genetic cause for this decreased expression (eg mutation or copy number loss).	('CCSKs', 'Chemical', '-', (81, 86))	('CCSK', 'Phenotype', 'HP:0006770', (81, 85))	('TARID', 'Gene', '100507308', (104, 109))	('decreased', 'NegReg', (94, 103))	('TCF21', 'Gene', (55, 60))	('copy number loss', 'Var', (216, 232))	('hypermethylation', 'Var', (61, 77))	('TARID', 'Gene', (104, 109))
581103	26158413	TCF21 has also been shown to be a target of the polycomb group repressor EZH2, whose function is to establish the H3K27me3 histone mark, and TCF21 is significantly up-regulated following silencing of EZH2, suggesting that histone modifications may ultimately regulate TCF21 expression, perhaps through TARID expression.	('expression', 'MPA', (274, 284))	('up-regulated', 'PosReg', (164, 176))	('TCF21', 'Gene', (0, 5))	('regulate', 'Reg', (259, 267))	('TARID', 'Gene', '100507308', (302, 307))	('EZH2', 'Gene', '2146', (73, 77))	('silencing', 'Var', (187, 196))	('TCF21', 'Gene', (268, 273))	('TCF21', 'Gene', (141, 146))	('EZH2', 'Gene', (73, 77))	('EZH2', 'Gene', (200, 204))	('EZH2', 'Gene', '2146', (200, 204))	('TARID', 'Gene', (302, 307))
581104	26158413	In summary hypermethylation and decreased expression of a tumor suppressor gene known to be active in renal development supports the hypothesis that epigenetic regulation of TCF21 very early in renal development may be involved in the pathogenesis of CCSKs.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('CCSKs', 'Disease', (251, 256))	('TCF21', 'Gene', (174, 179))	('epigenetic regulation', 'Var', (149, 170))	('CCSKs', 'Chemical', '-', (251, 256))	('CCSK', 'Phenotype', 'HP:0006770', (251, 255))	('expression', 'MPA', (42, 52))	('involved', 'Reg', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('decreased', 'NegReg', (32, 41))
581106	26158413	If hypermethylation of TCF21 is involved in the pathogenesis, this may provide a rationale for treatment of patients with CCSK with demethylating agents.	('patients', 'Species', '9606', (108, 116))	('CCSK', 'Chemical', '-', (122, 126))	('CCSK', 'Phenotype', 'HP:0006770', (122, 126))	('involved', 'Reg', (32, 40))	('hypermethylation', 'Var', (3, 19))	('CCSK', 'Disease', (122, 126))	('TCF21', 'Gene', (23, 28))
581121	26158413	Information regarding the transcript and protein effects of the variants, as well as the presence of the variants in a number of different lists, including the Catalogue of Somatic Mutations in Cancer (COSMIC) and The Cancer Genome Atlas (TCGA), is obtained using Oncotator (http://www.broadinstitute.org/oncotator).	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (218, 237))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Cancer Genome Atlas', 'Disease', (218, 237))	('variants', 'Var', (64, 72))
581141	23691400	Its biallelic inactivation is involved in the development of atypical teratoid tumors of the central nervous system and malignant rhabdoid tumors of renal or extra renal origin.	('teratoid tumors', 'Phenotype', 'HP:0009792', (70, 85))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (79, 115))	('involved', 'Reg', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('atypical teratoid tumors of the central nervous system and malignant rhabdoid tumors of renal', 'Disease', 'MESH:C000597569', (61, 154))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('biallelic inactivation', 'Var', (4, 26))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
581151	23691400	All the neoplastic cells exhibited loss of INI1 protein (Figure 3(a)) while they were positive for Ca-125 (Figure 3(b)), Podoplanin (D2-40) (Figure 3(c)), Vimentin, EMA, TLE1 (Figure 3(d)), Glut1, pankeratin AE1/AE3, low molecular weight cytokeratins CK8.18 and CK19 and high molecular weight cytokeratin CK34betaE12.	('CK19', 'Gene', (262, 266))	('AE3', 'Gene', (212, 215))	('EMA', 'Gene', (165, 168))	('CK19', 'Gene', '3880', (262, 266))	('TLE1', 'Gene', '7088', (170, 174))	('INI1', 'Gene', (43, 47))	('INI1', 'Gene', '6598', (43, 47))	('Vimentin', 'Gene', '7431', (155, 163))	('AE3', 'Gene', '6508', (212, 215))	('AE1', 'Gene', '6521', (208, 211))	('low', 'Var', (217, 220))	('Glut1', 'Gene', '6513', (190, 195))	('Vimentin', 'Gene', (155, 163))	('CK8', 'Gene', '3856', (251, 254))	('Podoplanin', 'Gene', (121, 131))	('loss', 'NegReg', (35, 39))	('AE1', 'Gene', (208, 211))	('TLE1', 'Gene', (170, 174))	('Podoplanin', 'Gene', '10630', (121, 131))	('CK8', 'Gene', (251, 254))	('Glut1', 'Gene', (190, 195))	('EMA', 'Gene', '4582', (165, 168))	('CK34betaE12', 'Var', (305, 316))
581166	23691400	The negativity of epithelioid sarcoma for p63, which is usually positive in adnexal neoplasms, as well as the loss of the protein SMARCB1/INI1 excludes the possibility of an adnexal neoplasm.	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (18, 37))	('adnexal neoplasm', 'Disease', (174, 190))	('epithelioid sarcoma', 'Disease', (18, 37))	('neoplasms', 'Phenotype', 'HP:0002664', (84, 93))	('loss', 'Var', (110, 114))	('neoplasm', 'Phenotype', 'HP:0002664', (182, 190))	('adnexal neoplasms', 'Disease', (76, 93))	('SMARCB1', 'Gene', (130, 137))	('adnexal neoplasm', 'Disease', 'MESH:D000292', (174, 190))	('p63', 'Gene', (42, 45))	('SMARCB1', 'Gene', '6598', (130, 137))	('adnexal neoplasms', 'Disease', 'MESH:D000292', (76, 93))	('p63', 'Gene', '8626', (42, 45))	('neoplasm', 'Phenotype', 'HP:0002664', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('INI1', 'Gene', (138, 142))	('INI1', 'Gene', '6598', (138, 142))	('adnexal neoplasm', 'Disease', 'MESH:D000292', (76, 92))
581176	30410720	Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy.	('CSC', 'Disease', (110, 113))	('sensitizes', 'Reg', (95, 105))	('mechanistic target of rapamycin', 'Gene', (56, 87))	('inhibition', 'Var', (38, 48))	('mechanistic target of rapamycin', 'Gene', '2475', (56, 87))	('mTOR', 'Gene', (89, 93))
581181	30410720	Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('sarcomas', 'Disease', (120, 128))	('inhibition', 'Var', (174, 184))	('mTOR', 'Gene', (169, 173))	('enhances', 'PosReg', (185, 193))	('efficacy', 'CPA', (198, 206))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('chemoresistant CSC population', 'CPA', (254, 283))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
581193	30410720	We subsequently demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) by sirolimus increases the sensitivity of ALDHhigh cells to doxorubicin and causes synergistic cytotoxicity when unsorted cells are treated in vitro.	('ALDH', 'Gene', '11670', (133, 137))	('ALDH', 'Gene', (133, 137))	('inhibition', 'Var', (34, 44))	('sirolimus', 'Chemical', 'MESH:D020123', (94, 103))	('cytotoxicity', 'Disease', 'MESH:D064420', (186, 198))	('increases', 'PosReg', (104, 113))	('mechanistic target of rapamycin', 'Gene', (52, 83))	('sensitivity', 'MPA', (118, 129))	('mechanistic target of rapamycin', 'Gene', '2475', (52, 83))	('sirolimus', 'Gene', (94, 103))	('doxorubicin', 'Chemical', 'MESH:D004317', (151, 162))	('cytotoxicity', 'Disease', (186, 198))	('causes', 'Reg', (167, 173))
581199	30410720	Additionally, patients were required to have an adequate performance status (ECOG <= 2; Karnofsky or Lansky >= 60% for children), a life expectancy greater than 3 months, and adequate organ function (absolute neutrophil count >= 1500/microl, platelet count >= 100,000/microl, total bilirubin <= 1.5x institutional upper limit of normal, AST and ALT <= 2.5x institutional upper limit of normal, and creatinine <= 1.5x institutional upper limit of normal for age or a creatinine clearance >= 60 ml/min/1.73 m2).	('platelet', 'MPA', (242, 250))	('total bilirubin', 'MPA', (276, 291))	('patients', 'Species', '9606', (14, 22))	('AST', 'Gene', (337, 340))	('children', 'Species', '9606', (119, 127))	('>= 1500/microl', 'Var', (226, 240))	('ALT', 'MPA', (345, 348))	('AST', 'Gene', '26503', (337, 340))	('creatinine', 'MPA', (398, 408))	('creatinine clearance', 'MPA', (466, 486))
581215	30410720	The sections were incubated overnight at 4  C in a humidor with monoclonal antibody to ALDH1 (1:100; BD bioscience, clone 44), diluted with 1% goat serum, 0.2% BSA and 0.3% Triton X-100 in PBS (pH 7.4), followed by washing with PBS.	('PBS', 'Gene', (189, 192))	('PBS', 'Gene', '1131', (189, 192))	('ALDH1', 'Gene', '216', (87, 92))	('goat', 'Species', '9925', (143, 147))	('PBS', 'Gene', (228, 231))	('1:100;', 'Var', (94, 100))	('PBS', 'Gene', '1131', (228, 231))	('Triton X-100', 'Chemical', 'MESH:D017830', (173, 185))	('ALDH1', 'Gene', (87, 92))
581222	30410720	In the phase II portion of the study, a total of 18 subjects were treated at the recommended phase II dose (RP2D), liposomal doxorubicin 30 mg/m2/dose monthly with temsirolimus 20 mg/m2/dose weekly (Table 1).	('RP2', 'Gene', '6102', (108, 111))	('liposomal', 'Var', (115, 124))	('temsirolimus', 'Chemical', 'MESH:C401859', (164, 176))	('doxorubicin', 'Chemical', 'MESH:D004317', (125, 136))	('RP2', 'Gene', (108, 111))
581248	30410720	Weight loss can be a surrogate for overall health in patients undergoing anti-cancer therapy, and mTOR inhibition has the potential to alter the metabolism of both normal and cancer cells.	('patients', 'Species', '9606', (53, 61))	('metabolism', 'MPA', (145, 155))	('Weight loss', 'Phenotype', 'HP:0001824', (0, 11))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('Weight loss', 'Disease', (0, 11))	('inhibition', 'Var', (103, 113))	('Weight loss', 'Disease', 'MESH:D015431', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('alter', 'Reg', (135, 140))	('mTOR', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
581262	30410720	The rationale for this study was our in vitro observation that mTOR inhibition increases the sensitivity of sarcoma stem cells to chemotherapy and our hypothesis that eliminating CSC would translate into improved survival.	('mTOR', 'Gene', (63, 67))	('sarcoma', 'Disease', (108, 115))	('increases', 'PosReg', (79, 88))	('inhibition', 'Var', (68, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sensitivity', 'MPA', (93, 104))	('improved', 'PosReg', (204, 212))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))
581273	30410720	We have shown in preclinical testing that ALDHhigh cells are resistant to chemotherapy agents commonly used to treat sarcomas, such as doxorubicin, and that inhibition of the mTOR pathway with agents such as rapamycin can overcome this chemoresistance seen in the ALDHhigh cells.	('rapamycin', 'Chemical', 'MESH:D020123', (208, 217))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('mTOR pathway', 'Pathway', (175, 187))	('ALDH', 'Gene', '11670', (264, 268))	('sarcomas', 'Disease', (117, 125))	('inhibition', 'Var', (157, 167))	('ALDH', 'Gene', '11670', (42, 46))	('ALDH', 'Gene', (42, 46))	('ALDH', 'Gene', (264, 268))	('doxorubicin', 'Chemical', 'MESH:D004317', (135, 146))
581349	29850320	In the absence of infection, C. perfringens has no clinical significance and causes clinical illness in only about 5% of isolates.	('clinical illness', 'Disease', (84, 100))	('absence of infection', 'Disease', (7, 27))	('C. perfringens', 'Var', (29, 43))	('causes', 'Reg', (77, 83))	('absence of infection', 'Disease', 'MESH:D004832', (7, 27))
581435	24897498	In addition, cancer cachexia symptoms developed in HF-fed animals but not chow-fed animals during the 18 day experiment.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cachexia', 'Phenotype', 'HP:0004326', (20, 28))	('cancer cachexia symptoms', 'Disease', (13, 37))	('HF-fed', 'Var', (51, 57))	('cancer cachexia symptoms', 'Disease', 'MESH:D002100', (13, 37))
581493	24897498	HF-fed rats also consumed significantly more calories per day on average, as compared to chow-fed animals (p < 0.0001).	('HF-fed', 'Var', (0, 6))	('calories', 'MPA', (45, 53))	('rats', 'Species', '10116', (7, 11))	('more', 'PosReg', (40, 44))
581494	24897498	Analysis of body adiposity revealed a significantly higher percentage of body fat in HF-fed rats, as compared to chow-fed rats (p < 0.0001).	('rats', 'Species', '10116', (92, 96))	('rats', 'Species', '10116', (122, 126))	('higher', 'PosReg', (52, 58))	('HF-fed', 'Var', (85, 91))
581497	24897498	Fasting blood glucose and plasma insulin levels were significantly higher in HF-fed animals, as compared to chow (p < 0.001, and p < 0.01, respectively).	('HF-fed', 'Var', (77, 83))	('higher', 'PosReg', (67, 73))	('insulin', 'Gene', (33, 40))	('insulin', 'Gene', '3630', (33, 40))	('glucose', 'Chemical', 'MESH:D005947', (14, 21))
581500	24897498	Following tumor implantation, analysis of the change in total weight by two-way ANOVA revealed a significantly greater change in body weight in HF-fed TB rats, as compared to both HF-fed control and chow-fed TB rats on Days 15-18 (p < 0.05 for all) (Figure 1A).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('HF-fed', 'Var', (144, 150))	('rats', 'Species', '10116', (154, 158))	('TB', 'Chemical', '-', (151, 153))	('body', 'MPA', (129, 133))	('greater', 'PosReg', (111, 118))	('rats', 'Species', '10116', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('TB', 'Chemical', '-', (208, 210))
581512	24897498	On the day of sacrifice, HF-fed rats also had heavier tumors, as compared to chow-fed rats (p < 0.05) (Figure 3C).	('HF-fed', 'Var', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('rats', 'Species', '10116', (86, 90))	('heavier', 'PosReg', (46, 53))	('rats', 'Species', '10116', (32, 36))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
581521	24897498	Analysis of terminal, non-fasting blood glucose levels revealed that HF-fed rats generally exhibited lower glucose levels than did chow-fed animals.	('glucose', 'Chemical', 'MESH:D005947', (107, 114))	('glucose', 'Chemical', 'MESH:D005947', (40, 47))	('lower', 'NegReg', (101, 106))	('rats', 'Species', '10116', (76, 80))	('HF-fed', 'Var', (69, 75))	('non-fasting blood glucose', 'Phenotype', 'HP:0003162', (22, 47))	('glucose levels', 'MPA', (107, 121))
581597	22904072	A DNA fragment between the ROREs, where the Top1-binding site is located, behaved like a right-handed superhelical twist, and modulation of Top1 activity by camptothecin and Top1 siRNA altered the footprint profile, indicating modulation of the chromatin structure.	('camptothecin', 'Chemical', 'MESH:D002166', (157, 169))	('altered', 'Reg', (185, 192))	('Top1', 'Enzyme', (140, 144))	('activity', 'MPA', (145, 153))	('footprint profile', 'MPA', (197, 214))	('modulation', 'Reg', (227, 237))	('modulation', 'Var', (126, 136))
581608	22904072	Stable cells containing the luciferase reporter gene driven by the Bmal1 promoter region (-197 to +27) were established from NIH3T3 and Sarcoma 180 cells.	('Sarcoma', 'Disease', (136, 143))	('Sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('NIH3T3', 'CellLine', 'CVCL:0594', (125, 131))	('-197', 'Var', (90, 94))	('Sarcoma', 'Phenotype', 'HP:0100242', (136, 143))
581651	22904072	Camptothecin activated Bmal1 promoter activity ~2.5-fold in the full construct (nucleotides -87 to +4) (Figure 7C), which was consistent with the results shown in Figure 7B as well as the knockdown of Top1 expression by siRNA (Figure 3A) and by camptothecin (Figure 3B), which enhanced Bmal1 transcription.	('enhanced', 'PosReg', (277, 285))	('Bmal1 transcription', 'MPA', (286, 305))	('Bmal1', 'Gene', (23, 28))	('Top1', 'Gene', (201, 205))	('knockdown', 'Var', (188, 197))	('Camptothecin', 'Chemical', 'MESH:D002166', (0, 12))	('camptothecin', 'Chemical', 'MESH:D002166', (245, 257))
581659	22904072	The encircled band between the ROREs appeared in both the naked and control samples but not in cells incubated with either camptothecin or Top1 siRNA, suggesting that a change in Top1 modulates the chromatin structure between the ROREs in vivo (Figure 9).	('camptothecin', 'Chemical', 'MESH:D002166', (123, 135))	('chromatin structure', 'MPA', (198, 217))	('Top1', 'Gene', (179, 183))	('modulates', 'Reg', (184, 193))	('change', 'Var', (169, 175))
581663	22904072	Both camptothecin and Top1 siRNA enhanced Bmal1 transcription in both NIH3T3-derived and sarcoma 180-derived cell lines (Figure 3A and B) and the Top1 mutant expressed more Bmal1 (Figure 3C), suggesting that a decrease in Top1 activity enhances Bmal1 expression.	('mutant', 'Var', (151, 157))	('enhances', 'PosReg', (236, 244))	('expression', 'MPA', (251, 261))	('transcription', 'MPA', (48, 61))	('NIH3T3', 'CellLine', 'CVCL:0594', (70, 76))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('Bmal1', 'MPA', (173, 178))	('sarcoma', 'Disease', (89, 96))	('camptothecin', 'Chemical', 'MESH:D002166', (5, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('Bmal1', 'Gene', (42, 47))	('enhanced', 'PosReg', (33, 41))
581664	22904072	The activity of Top1 is inhibited after modification by poly(ADP-ribosyl)ation, which reportedly contributes to setting the period length of the Arabidopsis central oscillator and its inhibition shortens period length.	('poly(ADP-ribosyl)ation', 'Var', (56, 78))	('central oscillator', 'Phenotype', 'HP:0032104', (157, 175))	('modification', 'Var', (40, 52))	('setting', 'PosReg', (112, 119))	('poly', 'Chemical', '-', (56, 60))	('inhibition shortens', 'NegReg', (184, 203))	('inhibited', 'NegReg', (24, 33))	('period length', 'MPA', (124, 137))	('Arabidopsis', 'Species', '3702', (145, 156))	('Top1', 'Gene', (16, 20))	('activity', 'MPA', (4, 12))	('period length', 'MPA', (204, 217))
581666	22904072	Top1 is post-transcriptionally modulated by proteolysis, phosphorylation and SUMO-1 modification.	('SUMO-1', 'Gene', '7341', (77, 83))	('modification', 'Var', (84, 96))	('SUMO-1', 'Gene', (77, 83))
581672	22904072	In fact, disrupting Top1 in the intermediate region between the ROREs with either camptothecin or Top1 siRNA changed the footprints (Figure 9), suggesting that Top1 is involved in Bmal1 transcription by altering the chromatin structure around the ROREs.	('altering', 'Reg', (203, 211))	('disrupting', 'Var', (9, 19))	('chromatin structure around the', 'MPA', (216, 246))	('camptothecin', 'Chemical', 'MESH:D002166', (82, 94))	('Bmal1', 'Gene', (180, 185))
581696	22655244	Genetic polymorphisms in the GST genes arise from nucleotide alterations that may change codons to generate unique alleles or even null genotypes.	('unique alleles', 'MPA', (108, 122))	('rat', 'Species', '10116', (103, 106))	('change', 'Reg', (82, 88))	('codons', 'MPA', (89, 95))	('nucleotide alterations', 'Var', (50, 72))	('GST', 'Gene', (29, 32))	('polymorphisms', 'Var', (8, 21))	('rat', 'Species', '10116', (65, 68))
581697	22655244	These amino acid substitutions cause steric changes in the substrate-binding site of the enzyme.	('steric changes', 'MPA', (37, 51))	('rat', 'Species', '10116', (64, 67))	('cause', 'Reg', (31, 36))	('amino acid substitutions', 'Var', (6, 30))	('substrate-binding site', 'MPA', (59, 81))
581698	22655244	As a consequence, a number of meta-analyses have been carried out as part of the Human Genome Epidemiology (HuGE) Network, which provided evidence that GST polymorphisms can result in a small but significant increase in risk of some types of cancers or diseases (Hayes and Strange,; Bolt and Their,; Di Pietro et al.,; Economopoulos and Sergentanis,; Josephy,; McMahon et al.,).	('Economopoulos', 'Disease', (319, 332))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancers or diseases', 'Disease', (242, 261))	('Human', 'Species', '9606', (81, 86))	('McMahon et al.', 'Disease', (361, 375))	('Hayes', 'Disease', (263, 268))	('cancers or diseases', 'Disease', 'MESH:D009369', (242, 261))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('GST', 'Gene', (152, 155))	('Sergentanis', 'Disease', (337, 348))	('increase', 'PosReg', (208, 216))	('polymorphisms', 'Var', (156, 169))	('Josephy', 'Disease', (351, 358))
581718	22655244	As in adult cancers, a large number of epidemiological studies have tested possible associations between GST polymorphic variants as well as deletions with susceptibility of pediatric cancers (Table 2).	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('pediatric cancers', 'Disease', 'MESH:D009369', (174, 191))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('pediatric cancers', 'Disease', (174, 191))	('associations', 'Interaction', (84, 96))	('tested', 'Reg', (68, 74))	('adult cancers', 'Disease', (6, 19))	('GST', 'Gene', (105, 108))	('adult cancers', 'Disease', 'MESH:C535836', (6, 19))	('deletions', 'Var', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('polymorphic variants', 'Var', (109, 129))
581719	22655244	GSTM1 is subject to a deletion polymorphism that is found in as many as 75% of Caucasians (Zhong et al.,; Huang et al.,).	('GSTM1', 'Gene', '2944', (0, 5))	('deletion polymorphism', 'Var', (22, 43))	('GSTM1', 'Gene', (0, 5))
581723	22655244	GSTP1 V105 was found to relate to increased susceptibility to childhood leukemia in Canada (Krajinovic et al.,).	('V105', 'Var', (6, 10))	('GSTP1', 'Gene', (0, 5))	('susceptibility', 'Reg', (44, 58))	('leukemia', 'Disease', (72, 80))	('leukemia', 'Phenotype', 'HP:0001909', (72, 80))	('leukemia', 'Disease', 'MESH:D007938', (72, 80))	('GSTP1', 'Gene', '2950', (0, 5))
581724	22655244	However, another group found that there was no statistically significant association between GSTP1 polymorphism and susceptibility to ALL in Thai children (Gatedee et al.,).	('polymorphism', 'Var', (99, 111))	('children', 'Species', '9606', (146, 154))	('GSTP1', 'Gene', '2950', (93, 98))	('GSTP1', 'Gene', (93, 98))
581729	22655244	However, the GSTT1 null genotype was also shown to be associated with an increased risk of death after chemotherapy in childhood AML (Davies et al.,).	('death', 'Disease', 'MESH:D003643', (91, 96))	('death', 'Disease', (91, 96))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('GSTT1', 'Gene', '2952', (13, 18))	('GSTT1', 'Gene', (13, 18))	('AML', 'Disease', (129, 132))	('null', 'Var', (19, 23))	('associated', 'Reg', (54, 64))
581730	22655244	As to the GSTM1-GSTT1 double-null genotype, one group reported an increased risk of early relapse of ALL with double-null genotype (Takanashi et al.,) while a subsequent study reported the opposite result (Kham et al.,).	('GSTT1', 'Gene', '2952', (16, 21))	('GSTT1', 'Gene', (16, 21))	('double-null', 'Var', (110, 121))	('GSTM1', 'Gene', '2944', (10, 15))	('early relapse', 'CPA', (84, 97))	('GSTM1', 'Gene', (10, 15))
581731	22655244	GSTP1 expression was significantly increased in relapsed AML, and GSTP1 V105 was found to be related to increased relapse rate of childhood leukemia (Sauerbrey et al.,; Beck et al.,; Zielinska et al.,).	('increased', 'PosReg', (35, 44))	('GSTP1', 'Gene', (0, 5))	('leukemia', 'Disease', (140, 148))	('increased', 'PosReg', (104, 113))	('leukemia', 'Disease', 'MESH:D007938', (140, 148))	('expression', 'MPA', (6, 16))	('AML', 'Disease', 'MESH:D015470', (57, 60))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('GSTP1', 'Gene', (66, 71))	('V105', 'Var', (72, 76))	('AML', 'Disease', (57, 60))	('rat', 'Species', '10116', (122, 125))	('GSTP1', 'Gene', '2950', (0, 5))	('GSTP1', 'Gene', '2950', (66, 71))
581733	22655244	The authors found that the expression of MGST1 clearly predict Ewing's sarcoma prognosis and to be associated with doxorubicin chemosensitivity (Townsend and Tew,; Schaefer et al.,; Scotlandi et al.,).	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (63, 78))	('associated with', 'Reg', (99, 114))	("Ewing's sarcoma", 'Disease', (63, 78))	('predict', 'Reg', (55, 62))	('MGST1', 'Gene', '4257', (41, 46))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (63, 78))	('doxorubicin', 'Chemical', 'MESH:D004317', (115, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('expression', 'Var', (27, 37))	('MGST1', 'Gene', (41, 46))	('doxorubicin chemosensitivity', 'MPA', (115, 143))
581742	22655244	Consistently, GSTM1 null genotype was associated with a reduced risk of relapse in ALL (Stanulla et al.,).	('reduced', 'NegReg', (56, 63))	('null genotype', 'Var', (20, 33))	('relapse', 'CPA', (72, 79))	('GSTM1', 'Gene', '2944', (14, 19))	('GSTM1', 'Gene', (14, 19))
581756	22655244	Other work has shown that the ability of EWS/FLI to activate gene expression through GGAA-microsatellite response elements is proportional to the length of the microsatellite, suggesting that microsatellite polymorphisms might affect target gene expression (Gangwal et al.,).	('affect', 'Reg', (227, 233))	('gene expression', 'MPA', (61, 76))	('microsatellite polymorphisms', 'Var', (192, 220))	('activate', 'PosReg', (52, 60))	('FLI', 'Gene', '2314', (45, 48))	('FLI', 'Gene', (45, 48))	('expression', 'MPA', (246, 256))	('EWS', 'Gene', '2130', (41, 44))	('EWS', 'Gene', (41, 44))
581774	22655244	For instance, JS-K selectively induces programmed cell death in breast cancer cells while sparing normal mammary epithelial cells under the same conditions (McMurtry et al.,; Figure 3).	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('JS-K', 'Var', (14, 18))	('induces', 'Reg', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('death', 'Disease', 'MESH:D003643', (55, 60))	('death', 'Disease', (55, 60))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
581776	22655244	Many epidemiological studies have investigated possible associations between GST polymorphisms with risk of pediatric cancers.	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('polymorphisms', 'Var', (81, 94))	('associations', 'Interaction', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('GST', 'Gene', (77, 80))	('pediatric cancers', 'Disease', 'MESH:D009369', (108, 125))	('pediatric cancers', 'Disease', (108, 125))
581777	22655244	Some studies have indicated increased risk for specific genotypes, such as the GSTT1 and GSTM1 deletions, while other studies have not confirmed this association.	('deletions', 'Var', (95, 104))	('GSTT1', 'Gene', (79, 84))	('GSTM1', 'Gene', '2944', (89, 94))	('GSTM1', 'Gene', (89, 94))	('GSTT1', 'Gene', '2952', (79, 84))
581864	30633211	Multi-modality treatment, including surgery and mammalian target of rapamycin (mTOR) inhibitors as targeted therapy, provided long-term disease-free survival (cure rate ranging from 50% to 100%, based on the different anatomic sites of the female genital tract).	('mTOR', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (79, 83))	('disease-free survival', 'CPA', (136, 157))	('inhibitors', 'Var', (85, 95))	('mammalian target of rapamycin', 'Gene', '2475', (48, 77))	('mammalian target of rapamycin', 'Gene', (48, 77))
581882	30633211	Pathology showed PEComa of the uterus, pT2bN0M0, with International Federation of Gynecology and Obstetrics stage IIB.	('pT2bN0M0', 'Var', (39, 47))	('PEComa', 'Disease', 'MESH:D054973', (17, 23))	('PEComa', 'Disease', (17, 23))
581919	30633211	PEComa is classified as benign, of uncertain malignant potential, or malignant, based on the following 6 worrisome features: tumor size (>5 cm), infiltration, high nuclear grade, increased cellularity, high mitotic activity (>=2 mitotic figure/50 HPF), tumor necrosis, and vascular invasion.	('PEComa', 'Disease', 'MESH:D054973', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cellularity', 'CPA', (189, 200))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (125, 130))	('PEComa', 'Disease', (0, 6))	('tumor necrosis', 'Disease', 'MESH:D009336', (253, 267))	('vascular invasion', 'CPA', (273, 290))	('tumor', 'Disease', (253, 258))	('increased', 'PosReg', (179, 188))	('tumor necrosis', 'Disease', (253, 267))	('high', 'Var', (159, 163))
581941	30633211	Genetically, TSC is associated with mutations in TSC1 or TSC2 (located on chromosomes 9q34 and 16p13, respectively), leading to impaired production of hamartin and tuberin, respectively.	('production of', 'MPA', (137, 150))	('associated', 'Reg', (20, 30))	('hamartin', 'Gene', '7248', (151, 159))	('TSC', 'Gene', '7248;7249', (49, 52))	('TSC', 'Gene', (57, 60))	('TSC', 'Gene', (13, 16))	('hamartin', 'Gene', (151, 159))	('tuberin', 'Gene', '7249', (164, 171))	('mutations', 'Var', (36, 45))	('TSC', 'Gene', '7248;7249', (13, 16))	('TSC1', 'Gene', '7248', (49, 53))	('TSC', 'Gene', (49, 52))	('TSC2', 'Gene', '7249', (57, 61))	('TSC2', 'Gene', (57, 61))	('TSC', 'Gene', '7248;7249', (57, 60))	('TSC1', 'Gene', (49, 53))	('tuberin', 'Gene', (164, 171))	('impaired', 'NegReg', (128, 136))
581942	30633211	TSC1 and TSC2 interact as heterodimers that inhibit the mechanistic mTOR pathway; inactivation leads to increased cell growth and proliferation.	('cell growth', 'CPA', (114, 125))	('increased', 'PosReg', (104, 113))	('inhibit', 'NegReg', (44, 51))	('TSC2', 'Gene', '7249', (9, 13))	('mTOR', 'Gene', '2475', (68, 72))	('TSC1', 'Gene', '7248', (0, 4))	('mTOR', 'Gene', (68, 72))	('TSC1', 'Gene', (0, 4))	('TSC2', 'Gene', (9, 13))	('inactivation', 'Var', (82, 94))
581987	26877775	A phase I clinical trial of one protease-activated probe, LUM015 (Lumicell, MA), has recently been completed (NCT01626066), showing that LUM015 is safe in humans and results in tumor-specific fluorescence.	('mice', 'Species', '10090', (68, 72))	('LUM015', 'Chemical', '-', (137, 143))	('results in', 'Reg', (166, 176))	('LUM015', 'Chemical', '-', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('LUM015', 'Var', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('humans', 'Species', '9606', (155, 161))
581996	26877775	To test the device, we used primary sarcomas that developed in genetically engineered mice with conditional expression of oncogenic K-ras or B-raf and deletion of p53 .	('primary sarcomas', 'Disease', (28, 44))	('B-raf', 'Gene', '109880', (141, 146))	('K-ras', 'Gene', '16653', (132, 137))	('p53', 'Gene', (163, 166))	('K-ras', 'Gene', (132, 137))	('mice', 'Species', '10090', (86, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('deletion', 'Var', (151, 159))	('B-raf', 'Gene', (141, 146))	('primary sarcomas', 'Disease', 'MESH:D012509', (28, 44))	('p53', 'Gene', '22060', (163, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))
582002	26877775	Tumors were initiated by intramuscular injection of adenovirus expressing Cre-recombinase as previously described into the hind limb of mice with the genotype BrafCa/+; p53Flox/Flox or LSL-YFP; LSL-KrasG12D/+, p53Flox/Flox.	('mice', 'Species', '10090', (136, 140))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('LSL-YFP; LSL-KrasG12D/+', 'Var', (185, 208))	('p53', 'Gene', '22060', (210, 213))	('p53', 'Gene', (169, 172))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p53', 'Gene', '22060', (169, 172))	('p53', 'Gene', (210, 213))
582005	26877775	Briefly, excitation of LUM015 is achieved using flood illumination by a Xe lamp (SolarMaxx 300, Sunoptics, California) filtered to excite in the Cy5 absorption band (620+-30 nm, Chroma, Vermont).	('Chroma', 'Disease', (178, 184))	('620+-30 nm', 'Var', (166, 176))	('Chroma', 'Disease', 'None', (178, 184))	('California', 'Disease', 'MESH:D004670', (107, 117))	('Cy5', 'Chemical', 'MESH:C085321', (145, 148))	('California', 'Disease', (107, 117))	('LUM015', 'Chemical', '-', (23, 29))
582020	26877775	We then used the integrated system to identify and ablate tissue on the tumor margin section with positive fluorescence.	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('ablate', 'Var', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))
582053	26877775	Two tissue sections that demonstrated neither Cy5 nor YFP signal were shown to be muscle without tumor on histopathology (Figure 3E).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Cy5', 'Chemical', 'MESH:C085321', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('Cy5', 'Var', (46, 49))
582069	26877775	This cohort was subsequently randomized to receive either no further treatment (n=12, + Implant/ - Laser Ablation, Figure 5D) or in vivo laser ablation of fluorescence detected in the tumor bed containing the tumor implant (n=14, + Implant/ + Laser Ablation, Figure 5E).	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('fluorescence', 'MPA', (155, 167))	('tumor', 'Disease', (184, 189))	('ablation', 'Var', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
582074	26877775	In mice treated with laser ablation (n=14), there was a significant improvement in recurrence free survival (P<0.0001, Figure 5F) relative to mice left untreated (+ Implant/ - Laser Ablation).	('recurrence free survival', 'CPA', (83, 107))	('laser ablation', 'Var', (21, 35))	('mice', 'Species', '10090', (3, 7))	('mice', 'Species', '10090', (142, 146))	('improvement', 'PosReg', (68, 79))
582075	26877775	The difference in recurrence between mice treated with laser ablation (+ Implant/ + Laser Ablation) and mice with no residual fluorescence in the tumor bed and no simulated residual disease (- Implant/ - Laser Ablation) was not statistically significant (P=0.18).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mice', 'Species', '10090', (104, 108))	('tumor', 'Disease', (146, 151))	('laser ablation', 'Var', (55, 69))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('mice', 'Species', '10090', (37, 41))
582090	26877775	One possible limitation of this technology is the increased operative time needed for the tumor bed to be scanned and residual tumor to be ablated during surgery; however, if this technology can improve recurrence free survival similar to our proof-of-principle experiment, then we believe this would outweigh the risks associated with increased operative time.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('improve', 'PosReg', (195, 202))	('technology', 'Var', (180, 190))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('recurrence free survival', 'CPA', (203, 227))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
582096	26877775	Here we have demonstrated the ability to detect simulated small volume residual disease and ablate it with high precision while improving outcomes in a murine model.	('murine', 'Species', '10090', (152, 158))	('small', 'Var', (58, 63))	('ablate', 'Var', (92, 98))	('improving', 'PosReg', (128, 137))
582174	32458628	Exploring Two Protocols of FISH Using Cytocell SYT-SSX Probe on Formalin Fixed Paraffin Embedded Tissue Sections Chromosomal translocation t(X;18)(p11.2;q11.2) is the cytogenetic hallmark of synovial sarcoma and have been identified as an alternative diagnostic strategy in differentiating synovial sarcoma from other histologic mimics.	('SYT', 'Gene', '6760', (47, 50))	('Formalin', 'Chemical', 'MESH:D005557', (64, 72))	('synovial sarcoma', 'Disease', (290, 306))	('Paraffin', 'Chemical', 'MESH:D010232', (79, 87))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (191, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (299, 306))	('SSX', 'Gene', '6757', (51, 54))	('synovial sarcoma', 'Disease', 'MESH:D013584', (191, 207))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (290, 306))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (139, 159))	('Chromosomal translocation t(X;18)(p11.2;q11.2', 'Var', (113, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('SS', 'Phenotype', 'HP:0012570', (51, 53))	('SSX', 'Gene', (51, 54))	('SYT', 'Gene', (47, 50))	('synovial sarcoma', 'Disease', 'MESH:D013584', (290, 306))	('synovial sarcoma', 'Disease', (191, 207))
582188	32458628	It was shown that the presence of translocation t(X;18)(p11.2;q11.2) is considered a cytogenetic hallmark of synovial sarcoma, as it is present in approximately 90 to 95% of cases of synovial carcinoma (Minami et al., 2014).	('synovial carcinoma', 'Disease', (183, 201))	('synovial sarcoma', 'Disease', (109, 125))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (48, 68))	('translocation t(X;18)(p11.2;q11.2', 'Var', (34, 67))	('synovial carcinoma', 'Phenotype', 'HP:0012570', (183, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (109, 125))	('synovial sarcoma', 'Disease', 'MESH:D013584', (109, 125))	('synovial carcinoma', 'Disease', 'MESH:D013581', (183, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
582190	32458628	We thus carried out the investigation to determine the incidence of t(X;18) translocations in synovial sarcoma cases.	('translocations', 'Var', (76, 90))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (94, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('synovial sarcoma', 'Disease', 'MESH:D013584', (94, 110))	('synovial sarcoma', 'Disease', (94, 110))
582198	32458628	These fusion transcripts appear to influence the histologic subtypes of synovial sarcoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (72, 88))	('synovial sarcoma', 'Disease', 'MESH:D013584', (72, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('fusion transcripts', 'Var', (6, 24))	('influence', 'Reg', (35, 44))	('synovial sarcoma', 'Disease', (72, 88))
582362	30889920	Our study of 123 patients with advanced soft tissue and bone sarcoma treated with pazopanib showed a higher response rate compared to that of the PALETTE trial, but lower DCR, median PFS, and SD rate, suggesting that the real-world experiences with such treatment may be different from the reported clinical trial results.	('SD rate', 'MPA', (192, 199))	('lower', 'NegReg', (165, 170))	('bone sarcoma', 'Disease', 'MESH:D001847', (56, 68))	('pazopanib', 'Var', (82, 91))	('DCR', 'Chemical', '-', (171, 174))	('soft tissue and bone sarcoma', 'Phenotype', 'HP:0030448', (40, 68))	('bone sarcoma', 'Disease', (56, 68))	('men', 'Species', '9606', (259, 262))	('PFS', 'MPA', (183, 186))	('patients', 'Species', '9606', (17, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('pazopanib', 'Chemical', 'MESH:C516667', (82, 91))	('DCR', 'MPA', (171, 174))	('bone sarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('response', 'MPA', (108, 116))
582364	29794783	Nerve damage may cause neuropathic pain (NP), which can result in persistent pain after surgery.	('neuropathic pain', 'Disease', 'MESH:D009437', (23, 39))	('pain', 'Phenotype', 'HP:0012531', (35, 39))	('cause', 'Reg', (17, 22))	('pain', 'Disease', 'MESH:D010146', (35, 39))	('pain', 'Disease', (35, 39))	('pain', 'Phenotype', 'HP:0012531', (77, 81))	('persistent pain', 'Phenotype', 'HP:0012532', (66, 81))	('pain', 'Disease', 'MESH:D010146', (77, 81))	('pain', 'Disease', (77, 81))	('Nerve damage', 'Var', (0, 12))	('neuropathic pain', 'Disease', (23, 39))
582396	29794783	Scores >=19 are considered indicative of NP, and scores 13 to 18 indicate a possible neuropathic component.	('scores 13 to 18', 'Var', (49, 64))	('neuropathic component', 'Disease', 'MESH:C562869', (85, 106))	('neuropathic component', 'Disease', (85, 106))
582489	28126006	The rationale for applying radiotherapy in addition to surgery comes from small randomized controlled trials showing evidence that radiotherapy enhances local control and resectability in soft tissue sarcoma of the limbs and RSTS without affecting survival.	('radiotherapy', 'Var', (131, 143))	('RSTS', 'Chemical', '-', (225, 229))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (188, 207))	('local control', 'CPA', (153, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (188, 207))	('resectability', 'CPA', (171, 184))	('enhances', 'PosReg', (144, 152))	('soft tissue sarcoma', 'Disease', (188, 207))
582571	28126006	In larger studies high grade tumors are related to a poorer 5-year-survival-rate.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('high grade', 'Var', (18, 28))	('tumors', 'Disease', (29, 35))
582602	27606158	We found that expression of HIF-1alpha was significantly associated with higher rate of metastasis (RR 3.21, 95 % CI 2.12-4.84, P < 0.001), poorer overall survival (HR 2.05, 95 % CI 1.51-2.77, P < 0.001) and poorer disease-free survival (HR 2.05, 95 % CI 1.55-2.70, P < 0.001).	('HIF-1alpha', 'Gene', (28, 38))	('expression', 'Var', (14, 24))	('metastasis', 'CPA', (88, 98))	('HIF-1alpha', 'Gene', '3091', (28, 38))	('higher', 'PosReg', (73, 79))	('poorer', 'NegReg', (208, 214))	('disease-free survival', 'CPA', (215, 236))	('overall survival', 'CPA', (147, 163))	('poorer', 'NegReg', (140, 146))
582615	27606158	It has been confirmed by a number of studies that expression of HIF-1alpha is correlated with poor prognosis in various cancers, including gastric, esophageal and lung cancers (Zhang et al.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('expression', 'Var', (50, 60))	('esophageal and lung cancers', 'Disease', 'MESH:D004938', (148, 175))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('HIF-1alpha', 'Gene', (64, 74))	('gastric', 'Disease', (139, 146))	('lung cancers', 'Phenotype', 'HP:0100526', (163, 175))
582632	27606158	The analysis indicated that expression of HIF-1alpha was significantly associated with poor disease-free survival under fixed effect model (HR 2.05, 95 % CI 1.55-2.70, P < 0.001) and random-effect model (HR 2.05, 95 % CI 1.55-2.70, P < 0.001) (Fig.	('HIF-1alpha', 'Gene', (42, 52))	('HIF-1alpha', 'Gene', '3091', (42, 52))	('expression', 'Var', (28, 38))	('poor', 'NegReg', (87, 91))	('disease-free survival', 'CPA', (92, 113))
582634	27606158	The analysis showed that HIF-1alpha expression was significantly associated with higher rate of metastasis under fixed effect model (RR 3.21, 95 % CI 2.13-4.84, P < 0.001) and random effect model (RR 2.79, 95 % CI 1.89-4.12, P < 0.001) (Fig.	('metastasis', 'CPA', (96, 106))	('higher', 'PosReg', (81, 87))	('expression', 'Var', (36, 46))	('HIF-1alpha', 'Gene', '3091', (25, 35))	('HIF-1alpha', 'Gene', (25, 35))
582645	27606158	Overall, the expression of HIF-1alpha contributes to the progression of many solid tumors through the way of sustaining energy metabolism, maintaining biosynthesis and promoting tumor cell invasion and migration (Stoeltzing et al.).	('promoting', 'PosReg', (168, 177))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('migration', 'CPA', (202, 211))	('HIF-1alpha', 'Gene', (27, 37))	('solid tumors', 'Disease', (77, 89))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', (83, 88))	('maintaining', 'PosReg', (139, 150))	('energy metabolism', 'MPA', (120, 137))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('expression', 'Var', (13, 23))	('biosynthesis', 'MPA', (151, 163))	('solid tumors', 'Disease', 'MESH:D009369', (77, 89))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('HIF-1alpha', 'Gene', '3091', (27, 37))	('sustaining', 'PosReg', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
582650	27606158	We found that expression of HIF-1alpha was significantly associated with poor overall survival, poor disease-free survival and higher rate of metastasis.	('HIF-1alpha', 'Gene', (28, 38))	('expression', 'Var', (14, 24))	('metastasis', 'CPA', (142, 152))	('HIF-1alpha', 'Gene', '3091', (28, 38))	('disease-free survival', 'CPA', (101, 122))	('poor', 'NegReg', (96, 100))	('overall survival', 'CPA', (78, 94))	('poor', 'NegReg', (73, 77))
582653	27606158	In majority of the included studies, the disease-free and overall survival rate of patients with positive expression of HIF-1alpha was lower than those with negative expression from the beginning of follow-up.	('positive expression', 'Var', (97, 116))	('HIF-1alpha', 'Gene', '3091', (120, 130))	('lower', 'NegReg', (135, 140))	('patients', 'Species', '9606', (83, 91))	('HIF-1alpha', 'Gene', (120, 130))
582679	25950696	Low HDL-C is also associated with increased postmenopausal breast cancer risk and high LDL-C levels promote breast cancer progression.	('LDL-C', 'Gene', '22796', (87, 92))	('LDL-C', 'Gene', (87, 92))	('increased postmenopausal breast cancer', 'Phenotype', 'HP:0008209', (34, 72))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('Low HDL', 'Phenotype', 'HP:0003233', (0, 7))	('HDL-C', 'Protein', (4, 9))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('promote', 'PosReg', (100, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('high LDL-C levels', 'Phenotype', 'HP:0003141', (82, 99))	('breast cancer', 'Disease', (108, 121))	('Low', 'Var', (0, 3))
582705	25950696	Among the 234 patients, local recurrence or metastatic disease after curative surgical resection was diagnosed in 87 of 179 (48.6%) patients with an HDL-C level <1.475 mmol/L and in 17 of 55 (32.1%) patients with an HDL-C level >=1.475 mmol/L (P = 0.021).	('<1.475', 'Var', (161, 167))	('local recurrence', 'CPA', (24, 40))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (132, 140))
582708	25950696	Patients with HDL-C <1.475 mmol/L showed a median OS of 71 months.	('<1.475', 'Var', (20, 26))	('Patients', 'Species', '9606', (0, 8))	('HDL-C', 'Gene', (14, 19))
582714	25950696	Previous studies proposed that abnormal lipid profiles may be associated with the occurrence and progression of cancers.	('lipid', 'Chemical', 'MESH:D008055', (40, 45))	('abnormal', 'Var', (31, 39))	('lipid profiles', 'MPA', (40, 54))	('abnormal lipid profiles', 'Phenotype', 'HP:0003119', (31, 54))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('associated', 'Reg', (62, 72))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
582717	25950696	Van Duijnhoven FJ reported that high concentrations of serum HDL are associated with a decreased risk of colon cancer based on cohort studies.	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('decreased', 'NegReg', (87, 96))	('high concentrations', 'Var', (32, 51))	('colon cancer', 'Disease', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('high concentrations of serum HDL', 'Phenotype', 'HP:0012184', (32, 64))	('HDL', 'Protein', (61, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))
582719	25950696	In prostate cancer, high HDL-C is regarded as a prognostic factor indicating a poor clinical outcome.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('high HDL', 'Phenotype', 'HP:0012184', (20, 28))	('high', 'Var', (20, 24))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('HDL-C', 'Protein', (25, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
582745	25568751	This is the first report of a case of an extraskeletal myxoid chondrosarcoma arising from the dura, confirmed to have rearrangement of the EWSR1 gene by FISH.	('extraskeletal myxoid chondrosarcoma', 'Disease', (41, 76))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (41, 76))	('EWSR1', 'Gene', (139, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (62, 76))	('rearrangement', 'Var', (118, 131))
582756	25568751	A clonal population of cells with rearrangement involving the EWSR1 locus was detected, confirming the histologic impression of extraskeletal myxoid chondrosarcoma (EMC) (Figure 3D).	('rearrangement', 'Var', (34, 47))	('EWSR1', 'Gene', (62, 67))	('extraskeletal myxoid chondrosarcoma', 'Disease', 'MESH:C563195', (128, 163))	('extraskeletal myxoid chondrosarcoma', 'Disease', (128, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (149, 163))
582768	25568751	EMCs harbor a balanced translocation involving the NR4A3 (TEC) gene on chromosome 9, that in approximately 75% of case results in a t(9;22)(q22;q12).	('t(9;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (132, 148))	('NR4A3 (TEC', 'Gene', (51, 61))	('t(9;22)(q22;q12', 'Var', (132, 147))	('results in', 'Reg', (119, 129))
582769	25568751	Although less common, occasionally the translocations involving the NR4A3 gene may result in a balanced translocation with other chromosomes, resulting in t(9;17)(q22;q11), t(9;15)(q22;q21) or t(9;3)(q22;q12) gene fusions.	('t(9;15)(q22;q21', 'Var', (173, 188))	('t(9;17)(q22;q11', 'Var', (155, 170))	('balanced translocation', 'MPA', (95, 117))	('t(9;3)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (193, 208))	('t(9;3)(q22;q12', 'Var', (193, 207))	('NR4A3', 'Gene', (68, 73))	('t(9;17)(q22;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (155, 171))	('translocations', 'Var', (39, 53))	('t(9;15)(q22;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (173, 189))	('result in', 'Reg', (83, 92))
582789	24726063	TERT promoter hotspot mutations are recurrent in myxoid liposarcomas but rare in other soft tissue sarcoma entities Recently, recurrent point mutations in the telomerase reverse transcriptase (TERT) promoter region have been found in many human cancers, leading to a new transcription factor binding site, increased induction of TERT and subsequently to telomere maintenance.	('myxoid liposarcomas', 'Disease', (49, 68))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('liposarcoma', 'Phenotype', 'HP:0012034', (56, 67))	('induction', 'MPA', (316, 325))	('human', 'Species', '9606', (239, 244))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (49, 68))	('telomerase reverse transcriptase', 'Gene', (159, 191))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('increased', 'PosReg', (306, 315))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('sarcoma', 'Disease', (60, 67))	('sarcomas', 'Phenotype', 'HP:0100242', (60, 68))	('TERT', 'Gene', (193, 197))	('sarcoma', 'Disease', (99, 106))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (87, 106))	('TERT', 'Gene', '7015', (193, 197))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('point mutations', 'Var', (136, 151))	('TERT', 'Gene', (329, 333))	('TERT', 'Gene', '7015', (329, 333))	('cancers', 'Disease', (245, 252))	('telomerase reverse transcriptase', 'Gene', '7015', (159, 191))	('telomere maintenance', 'CPA', (354, 374))	('mutations', 'Var', (22, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (49, 68))	('transcription factor', 'MPA', (271, 291))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('liposarcomas', 'Phenotype', 'HP:0012034', (56, 68))
582790	24726063	We determined the prevalence of TERT promoter mutations in soft tissue sarcomas of 341 patients comprising 16 entities and in 16 sarcoma cell lines covering 7 different soft tissue sarcoma types.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (59, 79))	('sarcomas', 'Disease', 'MESH:D012509', (71, 79))	('sarcoma', 'Disease', 'MESH:D012509', (181, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('sarcomas', 'Disease', (71, 79))	('sarcoma', 'Disease', (181, 188))	('mutations', 'Var', (46, 55))	('sarcoma type', 'Disease', (181, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('patients', 'Species', '9606', (87, 95))	('sarcoma type', 'Disease', 'MESH:D012509', (181, 193))	('sarcoma', 'Disease', (129, 136))	('TERT', 'Gene', (32, 36))	('TERT', 'Gene', '7015', (32, 36))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('sarcoma', 'Disease', (71, 78))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (59, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (169, 188))
582793	24726063	A 193 bp fragment of the TERT promoter region covering the hot-spot mutations C228T and C250T was amplified, and direct sequencing of the PCR products was performed.	('C250T', 'Mutation', 'c.250C>T', (88, 93))	('TERT', 'Gene', (25, 29))	('C228T', 'Mutation', 'rs763756456', (78, 83))	('TERT', 'Gene', '7015', (25, 29))	('C228T', 'Var', (78, 83))	('C250T', 'Var', (88, 93))
582798	24726063	TERT promoter mutations are frequent in MLSs including their round cell variants, representing the most prevalent mutation identified in this sarcoma entity to date, and in a minor fraction of SFTs, MPNSTs and SSs.	('MLS', 'Phenotype', 'HP:0012268', (40, 43))	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('round cell', 'Disease', (61, 71))	('MLS', 'Disease', 'MESH:C537466', (40, 43))	('sarcoma', 'Disease', (142, 149))	('MPNSTs', 'Phenotype', 'HP:0100697', (199, 205))	('SSs', 'Phenotype', 'HP:0012570', (210, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('TERT', 'Gene', (0, 4))	('MPNST', 'Phenotype', 'HP:0100697', (199, 204))	('TERT', 'Gene', '7015', (0, 4))	('SS', 'Phenotype', 'HP:0100242', (210, 212))	('frequent', 'Reg', (28, 36))	('mutations', 'Var', (14, 23))	('MLS', 'Disease', (40, 43))
582810	24726063	Specific genetic alterations are not only of diagnostic significance, but also might become relevant for tumor-targeted therapies.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (105, 110))	('genetic alterations', 'Var', (9, 28))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
582816	24726063	Recently, highly recurrent somatic mutations in the promoter region of the TERT gene have been detected.	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('mutations', 'Var', (35, 44))
582818	24726063	These TERT mutations lead to a new binding motif for E-twenty six/ternary complex factors (Ets/TCF) transcription factors and results in an up to 4-fold increase of TERT promoter activity in reporter gene assays.	('mutations', 'Var', (11, 20))	('binding', 'Interaction', (35, 42))	('TERT', 'Gene', (165, 169))	('TERT', 'Gene', '7015', (165, 169))	('TERT', 'Gene', (6, 10))	('increase', 'PosReg', (153, 161))	('TERT', 'Gene', '7015', (6, 10))	('TCF', 'Gene', (95, 98))	('TCF', 'Gene', '3172', (95, 98))
582819	24726063	First described in melanomas, TERT promoter mutations have subsequently been found in many other human cancer types, with highest frequencies in subtypes of CNS tumors, in a number of malignancies of epithelial origin including bladder carcinomas, thyroid carcinomas, and hepatocellular carcinomas, and in atypical fibroxanthomas and in dermal pleomorphic sarcomas.	('fibroxanthomas', 'Disease', (315, 329))	('melanomas', 'Disease', 'MESH:D008545', (19, 28))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (272, 297))	('human', 'Species', '9606', (97, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (287, 297))	('bladder carcinomas', 'Disease', (228, 246))	('malignancies', 'Disease', 'MESH:D009369', (184, 196))	('cancer', 'Disease', (103, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (256, 266))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (248, 266))	('sarcomas', 'Phenotype', 'HP:0100242', (356, 364))	('melanomas', 'Disease', (19, 28))	('malignancies', 'Disease', (184, 196))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (272, 297))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TERT', 'Gene', (30, 34))	('dermal pleomorphic sarcomas', 'Disease', (337, 364))	('hepatocellular carcinomas', 'Disease', (272, 297))	('TERT', 'Gene', '7015', (30, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (356, 363))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (236, 246))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('CNS tumors', 'Disease', (157, 167))	('CNS tumors', 'Disease', 'MESH:D009369', (157, 167))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('malignancies of epithelial origin', 'Phenotype', 'HP:0031492', (184, 217))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (228, 246))	('found', 'Reg', (77, 82))	('fibroxanthomas', 'Disease', 'None', (315, 329))	('mutations', 'Var', (44, 53))	('bladder carcinomas', 'Disease', 'MESH:D001749', (228, 246))	('dermal pleomorphic sarcomas', 'Disease', 'MESH:D008228', (337, 364))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (248, 266))	('thyroid carcinomas', 'Disease', (248, 266))
582822	24726063	Therefore, the present study was conducted to investigate the prevalence of TERT promoter mutations in a comprehensive series of 341 soft tissue tumors comprised of 16 types including rare entities and in 16 cell lines of seven sarcoma types.	('TERT', 'Gene', '7015', (76, 80))	('mutations', 'Var', (90, 99))	('sarcoma type', 'Disease', 'MESH:D012509', (228, 240))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('TERT', 'Gene', (76, 80))	('sarcoma type', 'Disease', (228, 240))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (133, 151))
582829	24726063	A 193 bp fragment of the TERT promoter region spanning the hotspot mutations at positions 1,295,228 and 1,295,250 on chromosome 5 was amplified by using GoTaq G2 Hot Start Polymerase (Promega, Madison, USA) and the following primers: hTERT-seq-for 5'-CACCCGTCCTGCCCCTTCACCTT-3' and hTERT-seq-rev 5'- GGCTTCCCACGTGCGCAGCAGGA-3'.	('TERT', 'Gene', '7015', (235, 239))	('Hot Start', 'Phenotype', 'HP:0031217', (162, 171))	('hTERT', 'Gene', (234, 239))	('TERT', 'Gene', (25, 29))	('TERT', 'Gene', '7015', (283, 287))	('hTERT', 'Gene', (282, 287))	('mutations', 'Var', (67, 76))	('TERT', 'Gene', '7015', (25, 29))	('hTERT', 'Gene', '7015', (234, 239))	('hTERT', 'Gene', '7015', (282, 287))	('TERT', 'Gene', (235, 239))	('TERT', 'Gene', (283, 287))
582833	24726063	Mutations were highly recurrent (29/39; 74%) in myxoid liposarcomas (MLS) and were almost exclusively found at position C228T with the exception for one case with a C250T mutation.	('myxoid liposarcomas', 'Disease', (48, 67))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (48, 67))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (48, 67))	('liposarcoma', 'Phenotype', 'HP:0012034', (55, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('C250T', 'Var', (165, 170))	('MLS', 'Disease', 'MESH:C537466', (69, 72))	('C250T', 'Mutation', 'c.250C>T', (165, 170))	('MLS', 'Disease', (69, 72))	('C228T', 'Mutation', 'rs763756456', (120, 125))	('MLS', 'Phenotype', 'HP:0012268', (69, 72))	('liposarcomas', 'Phenotype', 'HP:0012034', (55, 67))
582834	24726063	Remarkably, the 28 MLS carrying a C228T mutation were all positive for the FUS-DDIT3 fusion, while the C250T mutation was found in one of two MLS with an EWSR1-DDIT3 fusion transcript (Additional file 1: Table S2).	('C228T', 'Var', (34, 39))	('MLS', 'Disease', (19, 22))	('EWSR1', 'Gene', '2130', (154, 159))	('MLS', 'Phenotype', 'HP:0012268', (19, 22))	('DDIT3', 'Gene', '1649', (79, 84))	('FUS', 'Gene', (75, 78))	('MLS', 'Phenotype', 'HP:0012268', (142, 145))	('positive', 'Reg', (58, 66))	('FUS', 'Gene', '2521', (75, 78))	('MLS', 'Disease', 'MESH:C537466', (142, 145))	('C250T', 'Mutation', 'c.250C>T', (103, 108))	('DDIT3', 'Gene', (160, 165))	('MLS', 'Disease', (142, 145))	('DDIT3', 'Gene', (79, 84))	('C228T', 'Mutation', 'rs763756456', (34, 39))	('DDIT3', 'Gene', '1649', (160, 165))	('EWSR1', 'Gene', (154, 159))	('MLS', 'Disease', 'MESH:C537466', (19, 22))
582837	24726063	In addition, two malignant peripheral nerve sheath tumors (MPNSTs) harbored a TERT promoter mutation (2/35; 6%), one case with a C228T and the other one with a C250T mutation.	('nerve sheath tumors', 'Disease', 'MESH:D010524', (38, 57))	('nerve sheath tumors', 'Disease', (38, 57))	('TERT', 'Gene', (78, 82))	('C250T', 'Mutation', 'c.250C>T', (160, 165))	('TERT', 'Gene', '7015', (78, 82))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (17, 57))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('C228T', 'Mutation', 'rs763756456', (129, 134))	('MPNST', 'Phenotype', 'HP:0100697', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('C228T', 'Var', (129, 134))	('MPNSTs', 'Phenotype', 'HP:0100697', (59, 65))	('C250T', 'Var', (160, 165))	('harbored', 'Reg', (67, 75))
582840	24726063	We also sequenced 16 sarcoma cell lines for the TERT promoter hotspot mutations (Table 3).	('mutations', 'Var', (70, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('TERT', 'Gene', (48, 52))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('TERT', 'Gene', '7015', (48, 52))	('sarcoma', 'Disease', (21, 28))
582841	24726063	Mutations were found in both MLS cell lines and in one of three MPNST cell lines.	('MLS', 'Phenotype', 'HP:0012268', (29, 32))	('MPNST', 'Phenotype', 'HP:0100697', (64, 69))	('Mutations', 'Var', (0, 9))	('MLS', 'Disease', 'MESH:C537466', (29, 32))	('MLS', 'Disease', (29, 32))
582842	24726063	Mutations were restricted to the C228T locus.	('C228T', 'Var', (33, 38))	('Mutations', 'Var', (0, 9))	('C228T', 'Mutation', 'rs763756456', (33, 38))
582845	24726063	The recently described mutations in the promoter region of TERT provide new evidence for the important role of telomerase reactivation in human cancers.	('TERT', 'Gene', (59, 63))	('human', 'Species', '9606', (138, 143))	('mutations', 'Var', (23, 32))	('TERT', 'Gene', '7015', (59, 63))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
582846	24726063	The overall prevalence of TERT promoter hotspot mutations was low in the comprehensive series of soft tissue sarcomas examined in this study (36/341; 10.5%).	('sarcomas', 'Disease', (109, 117))	('TERT', 'Gene', (26, 30))	('TERT', 'Gene', '7015', (26, 30))	('sarcomas', 'Disease', 'MESH:D012509', (109, 117))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (97, 117))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('mutations', 'Var', (48, 57))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (97, 116))
582856	24726063	At the transcriptional level, alternative splicing of TERT mRNA itself might not only lead to TERT variants with impaired catalytic functions, but also to a variant that acts in a dominant-negative manner on telomerase activity.	('variants', 'Var', (99, 107))	('TERT', 'Gene', '7015', (54, 58))	('catalytic functions', 'MPA', (122, 141))	('impaired', 'NegReg', (113, 121))	('TERT', 'Gene', (94, 98))	('lead', 'Reg', (86, 90))	('TERT', 'Gene', '7015', (94, 98))	('TERT', 'Gene', (54, 58))
582857	24726063	Furthermore, post-translational modifications of the TERT protein through phosphorylation or ubiquitination have been shown to affect the catalytic activity and stability of TERT.	('phosphorylation', 'MPA', (74, 89))	('TERT', 'Gene', (53, 57))	('stability', 'MPA', (161, 170))	('TERT', 'Gene', '7015', (53, 57))	('catalytic activity', 'MPA', (138, 156))	('post-translational modifications', 'Var', (13, 45))	('TERT', 'Gene', (174, 178))	('TERT', 'Gene', '7015', (174, 178))	('ubiquitination', 'MPA', (93, 107))	('affect', 'Reg', (127, 133))
582858	24726063	Anyhow, our data suggest that mutation of the TERT promoter causes telomerase reactivation in MLS and thereby most probably provides unlimited proliferative potential.	('TERT', 'Gene', '7015', (46, 50))	('telomerase', 'Enzyme', (67, 77))	('mutation', 'Var', (30, 38))	('reactivation', 'MPA', (78, 90))	('MLS', 'Disease', 'MESH:C537466', (94, 97))	('MLS', 'Disease', (94, 97))	('MLS', 'Phenotype', 'HP:0012268', (94, 97))	('TERT', 'Gene', (46, 50))
582859	24726063	This assumption is also underpinned by a reporter gene assay of the two most common mutation variants within the promoter region of TERT, namely C228T and C250T, which were shown to lead to an augmented expression of TERT.	('C228T', 'Mutation', 'rs763756456', (145, 150))	('expression', 'MPA', (203, 213))	('C228T', 'Var', (145, 150))	('TERT', 'Gene', (217, 221))	('TERT', 'Gene', '7015', (217, 221))	('C250T', 'Var', (155, 160))	('C250T', 'Mutation', 'c.250C>T', (155, 160))	('TERT', 'Gene', '7015', (132, 136))	('TERT', 'Gene', (132, 136))	('augmented', 'PosReg', (193, 202))
582860	24726063	Further, the high prevalence of TERT promoter mutations not only in MLS round cell variants but also in MLS with a pure myxoid phenotype, and this irrespective of tumor grading, implies that these mutations act rather as driver than passenger mutations.	('TERT', 'Gene', '7015', (32, 36))	('MLS', 'Disease', 'MESH:C537466', (68, 71))	('mutations', 'Var', (46, 55))	('MLS', 'Disease', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('MLS', 'Phenotype', 'HP:0012268', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('MLS', 'Disease', 'MESH:C537466', (104, 107))	('MLS', 'Disease', (104, 107))	('MLS', 'Phenotype', 'HP:0012268', (104, 107))	('tumor', 'Disease', (163, 168))	('TERT', 'Gene', (32, 36))
582862	24726063	Mutations were found neither in dedifferentiated liposarcomasa (DDLS), nor in pleomorphic liposarcomas (PLS), which presented myxoid areas in many cases, and were also not detectable in our series of myxofibrosarcomas, extraskeletal myxoid chondrosarcomas, dermatofibrosarcomata protuberans, and low-grade fibromyxoid sarcomas.	('myxofibrosarcomas', 'Disease', 'None', (200, 217))	('myxoid sarcomas', 'Disease', (311, 326))	('dedifferentiated liposarcomasa', 'Disease', (32, 62))	('myxoid sarcomas', 'Disease', 'MESH:D045888', (311, 326))	('myxoid chondrosarcomas', 'Disease', 'MESH:C563195', (233, 255))	('myxoid chondrosarcomas', 'Disease', (233, 255))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('Mutations', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('dedifferentiated liposarcomasa', 'Disease', 'MESH:D008080', (32, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (53, 61))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (78, 102))	('dermatofibrosarcomata protuberans', 'Disease', (257, 290))	('dedifferentiated liposarcomasa', 'Phenotype', 'HP:0012034', (32, 62))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (240, 255))	('liposarcoma', 'Phenotype', 'HP:0012034', (90, 101))	('dermatofibrosarcomata protuberans', 'Disease', 'MESH:D018223', (257, 290))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (204, 216))	('DDLS', 'Phenotype', 'HP:0012034', (64, 68))	('liposarcomas', 'Phenotype', 'HP:0012034', (49, 61))	('PLS', 'Disease', 'MESH:D010214', (104, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('sarcomas', 'Phenotype', 'HP:0100242', (247, 255))	('liposarcomas', 'Phenotype', 'HP:0012034', (90, 102))	('liposarcoma', 'Phenotype', 'HP:0012034', (49, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (209, 217))	('PLS', 'Disease', (104, 107))	('pleomorphic liposarcomas', 'Disease', (78, 102))	('myxofibrosarcomas', 'Disease', (200, 217))	('sarcomas', 'Phenotype', 'HP:0100242', (318, 326))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (264, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (247, 254))
582863	24726063	The absence of TERT promoter hotspot mutations in our series of DDLS and PLS is in line with previous studies, which largely observed deficient telomerase activity in high-grade liposarcomas.	('TERT', 'Gene', '7015', (15, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('activity', 'MPA', (155, 163))	('deficient', 'NegReg', (134, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('PLS', 'Disease', (73, 76))	('liposarcomas', 'Disease', 'MESH:D008080', (178, 190))	('liposarcomas', 'Phenotype', 'HP:0012034', (178, 190))	('DDLS', 'Phenotype', 'HP:0012034', (64, 68))	('mutations', 'Var', (37, 46))	('PLS', 'Disease', 'MESH:D010214', (73, 76))	('liposarcomas', 'Disease', (178, 190))	('telomerase', 'Enzyme', (144, 154))	('liposarcoma', 'Phenotype', 'HP:0012034', (178, 189))	('TERT', 'Gene', (15, 19))
582868	24726063	MLS are characterized by a translocation that fuses the DDIT3 (CHOP) gene on chromosome 12q13 with the FUS (TLS) gene on chromosome 16p11 in approximately 90% of cases, or the DDIT3 (CHOP) with the EWSR1 on chromosome 22q12 in the remaining cases.	('CHOP', 'Gene', (183, 187))	('FUS', 'Gene', (103, 106))	('DDIT3', 'Gene', (176, 181))	('DDIT3', 'Gene', (56, 61))	('FUS', 'Gene', '2521', (103, 106))	('MLS', 'Disease', 'MESH:C537466', (0, 3))	('MLS', 'Disease', (0, 3))	('DDIT3', 'Gene', '1649', (176, 181))	('DDIT3', 'Gene', '1649', (56, 61))	('MLS', 'Phenotype', 'HP:0012268', (0, 3))	('CHOP', 'Gene', '1649', (63, 67))	('EWSR1', 'Gene', (198, 203))	('CHOP', 'Gene', '1649', (183, 187))	('CHOP', 'Gene', (63, 67))	('EWSR1', 'Gene', '2130', (198, 203))	('fuses', 'Var', (46, 51))
582869	24726063	By contrast, DDLS typically have complex karyotypic aberrations with amplification of the chromosome 12 subregion q13-15, which includes the murine double minutes (MDM2) and cyclin dependent kinase-4 (CDK4) genes among others.	('CDK4', 'Gene', (201, 205))	('MDM2', 'Gene', '17246', (164, 168))	('CDK4', 'Gene', '12567', (201, 205))	('cyclin dependent kinase-4', 'Gene', '12567', (174, 199))	('cyclin dependent kinase-4', 'Gene', (174, 199))	('DDLS', 'Phenotype', 'HP:0012034', (13, 17))	('MDM2', 'Gene', (164, 168))	('DDLS', 'Disease', (13, 17))	('murine', 'Species', '10090', (141, 147))	('amplification', 'Var', (69, 82))
582879	24726063	On the other hand, one out of three MPNST cell lines was revealed with a TERT promoter mutation, which supports the assumption that telomerase reactivation by TERT promoter mutations might contribute to immortalization of at least a small proportion of MPNSTs.	('MPNSTs', 'Phenotype', 'HP:0100697', (253, 259))	('MPNST', 'Phenotype', 'HP:0100697', (36, 41))	('immortalization', 'CPA', (203, 218))	('MPNST', 'Phenotype', 'HP:0100697', (253, 258))	('TERT', 'Gene', (73, 77))	('mutations', 'Var', (173, 182))	('TERT', 'Gene', '7015', (73, 77))	('mutation', 'Var', (87, 95))	('TERT', 'Gene', (159, 163))	('TERT', 'Gene', '7015', (159, 163))
582883	24726063	However, like in MPNSTs, TERT promoter hotspot mutations just play a minor role in SSs with merely a single mutated case in our series (1/25; 4%).	('SSs', 'Disease', (83, 86))	('TERT', 'Gene', (25, 29))	('SSs', 'Phenotype', 'HP:0012570', (83, 86))	('MPNSTs', 'Phenotype', 'HP:0100697', (17, 23))	('mutations', 'Var', (47, 56))	('TERT', 'Gene', '7015', (25, 29))	('MPNST', 'Phenotype', 'HP:0100697', (17, 22))	('SS', 'Phenotype', 'HP:0100242', (83, 85))
582886	24726063	We determined the prevalence of TERT promoter hotspot mutations in STS.	('TERT', 'Gene', '7015', (32, 36))	('mutations', 'Var', (54, 63))	('STS', 'Phenotype', 'HP:0030448', (67, 70))	('TERT', 'Gene', (32, 36))
582921	23213584	Our cytogenetics and molecular diagnostic laboratory examined the tissue by Interphase FISH with LSI EWSR1 break apart probe (Abbott, IL, USA) (22q12) with 200 cells scored finding nuc ish(5'EWSR1, 3'EWSR1)x2(5'EWSR1 con 3'EWSR1x2) consistent with no EWSR1 gene rearrangement.	('EWSR1', 'Gene', '2130', (211, 216))	('EWSR1', 'Gene', (251, 256))	('EWSR1', 'Gene', (101, 106))	('EWSR1', 'Gene', '2130', (191, 196))	('EWSR1', 'Gene', (200, 205))	('EWSR1', 'Gene', '2130', (223, 228))	('EWSR1', 'Gene', (211, 216))	('EWSR1', 'Gene', '2130', (251, 256))	('nuc ish', 'Var', (181, 188))	('EWSR1', 'Gene', (191, 196))	('EWSR1', 'Gene', '2130', (101, 106))	('break apart', 'Phenotype', 'HP:0001061', (107, 118))	('EWSR1', 'Gene', '2130', (200, 205))	('EWSR1', 'Gene', (223, 228))
582932	23213584	High cellularity correlates with poor overall survival and mitotic activity; more than 2 per 10 hpf or overall Ki67 more than 10% correlates with decreased metastasis-free survival.	('Ki67', 'Var', (111, 115))	('Ki67', 'Chemical', '-', (111, 115))	('metastasis-free survival', 'CPA', (156, 180))	('decreased', 'NegReg', (146, 155))
582934	23213584	Cytogenetic studies demonstrated the presence of a recurrent translocation t(9;22)(q22;q12) that results in the fusion of the EWSR1 gene on chromosome 22 with NR4A3 (TEC, CHN, NOR1) gene on chromosome 9.	('EWSR1', 'Gene', '2130', (126, 131))	('results in', 'Reg', (97, 107))	('t(9;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (75, 91))	('CHN', 'Gene', '8013', (171, 174))	('NR4A3', 'Gene', '8013', (159, 164))	('NOR1', 'Gene', '8013', (176, 180))	('NR4A3', 'Gene', (159, 164))	('NOR1', 'Gene', (176, 180))	('EWSR1', 'Gene', (126, 131))	('CHN', 'Gene', (171, 174))	('fusion', 'Var', (112, 118))
582936	23213584	Other clonal chromosome abnormalities have been reported including del(22)(q12-13) and variant translocations, including t(9;17)(q22;q11-12), t(7;9;17)(q32;q22;q11), and t(9;15)(q22;q21).	('t(9;15)(q22;q21', 'Var', (170, 185))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (13, 37))	('t(7;9;17)(q32;q22;q11', 'Var', (142, 163))	('del(22)(q12-13', 'Var', (67, 81))	('t(9;15)(q22;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (170, 186))	('t(9;17)(q22;q11-12', 'Var', (121, 139))
583068	33567553	; Writing:review and editing, D.J.G., W.J.V.H., P.M.B., V.L.M.N.S., J.A.V.d.H., J.J.D.H., K.B.M.I.K., O.H.	('J.J.D.H.', 'Var', (80, 88))	('K.B.M.I.K.', 'Var', (90, 100))	('P.M.B.', 'Var', (48, 54))	('V.L.M.N.S.', 'Var', (56, 66))	('J.J.D.H', 'CellLine', 'CVCL:M891', (80, 87))	('J.A.V.d.H.', 'Var', (68, 78))
583081	33287125	Both PRAME and NY-ESO-1 expression were more frequent in STS with low TIL counts.	('NY-ESO-1', 'Gene', '1485', (15, 23))	('low TIL counts', 'Var', (66, 80))	('STS', 'Phenotype', 'HP:0030448', (57, 60))	('PRAME', 'Gene', '23532', (5, 10))	('NY-ESO-1', 'Gene', (15, 23))	('PRAME', 'Gene', (5, 10))
583099	33287125	In multivariate analysis, high PRAME and low SSX2 expression levels as well as metastatic disease, non-radical resections, and not receiving chemotherapy are shown to be independent predictors of shorter overall survival.	('shorter', 'NegReg', (196, 203))	('high', 'Var', (26, 30))	('PRAME', 'Gene', '23532', (31, 36))	('PRAME', 'Gene', (31, 36))	('SSX2', 'Gene', '6757', (45, 49))	('low', 'NegReg', (41, 44))	('overall', 'MPA', (204, 211))	('expression levels', 'MPA', (50, 67))	('metastatic disease', 'CPA', (79, 97))	('SSX2', 'Gene', (45, 49))
583115	33287125	Patients with PRAME-positive tumours had statistically significant shorter median survival (23.0 (13.5-32.5) months vs. 69.0 (44.4-93.6) months, p = 0.005), while high NY-ESO-1 expression was associated with improved survival (>120 months vs. 58.0 (39.4-76.6) months, p = 0.037).	('PRAME', 'Gene', '23532', (14, 19))	('high', 'Var', (163, 167))	('median survival', 'MPA', (75, 90))	('PRAME', 'Gene', (14, 19))	('NY-ESO-1', 'Gene', (168, 176))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumours', 'Disease', (29, 36))	('improved', 'PosReg', (208, 216))	('Patients', 'Species', '9606', (0, 8))	('NY-ESO-1', 'Gene', '1485', (168, 176))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('shorter', 'NegReg', (67, 74))	('expression', 'MPA', (177, 187))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
583125	33287125	We found the expression of PRAME and the presence of a high number of TILs to be associated with shorter survival, while NY-ESO-1 expression was more frequent in patients with a more favourable prognosis.	('patients', 'Species', '9606', (162, 170))	('PRAME', 'Gene', '23532', (27, 32))	('PRAME', 'Gene', (27, 32))	('survival', 'MPA', (105, 113))	('NY-ESO-1', 'Gene', (121, 129))	('NY-ESO-1', 'Gene', '1485', (121, 129))	('shorter', 'NegReg', (97, 104))	('presence', 'Var', (41, 49))
583137	33287125	Currently, PRAME is a target antigen in a clinical phase I trial evaluating multi-tumour-associated antigen-specific cytotoxic T lymphocytes in rhabdomyosarcoma (NCT02239861, TACTASOM).	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (144, 160))	('PRAME', 'Gene', (11, 16))	('NCT02239861', 'Var', (162, 173))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('CTA', 'Chemical', '-', (177, 180))	('tumour', 'Disease', (82, 88))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (144, 160))	('rhabdomyosarcoma', 'Disease', (144, 160))	('PRAME', 'Gene', '23532', (11, 16))
583141	33287125	Radiotherapy potentially induces gene mutations and alters the expression of CTAs, which may have influenced our results.	('induces', 'Reg', (25, 32))	('CTAs', 'Gene', (77, 81))	('expression', 'MPA', (63, 73))	('gene mutations', 'Var', (33, 47))	('alters', 'Reg', (52, 58))	('CTA', 'Chemical', '-', (77, 80))
583145	33287125	In our cohort of soft tissue sarcoma patients, NY-ESO-1 expression was associated with lower grade, and it was prognostic of more favourable survival, as has been shown in a series of high-grade soft tissues sarcoma by Kakimoto et al.. Interestingly, in non-small-cell lung cancer, high NY-ESO-1 expression was associated with poor prognosis, while in epithelial ovarian cancer and breast cancer no relationship with survival has been found.	('NY-ESO-1', 'Gene', '1485', (287, 295))	('expression', 'MPA', (296, 306))	('epithelial ovarian cancer', 'Disease', (352, 377))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (17, 36))	('lung cancer', 'Disease', (269, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('NY-ESO-1', 'Gene', (287, 295))	('soft tissues sarcoma', 'Phenotype', 'HP:0030448', (195, 215))	('ovarian cancer', 'Phenotype', 'HP:0100615', (363, 377))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (352, 377))	('patients', 'Species', '9606', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('NY-ESO-1', 'Gene', '1485', (47, 55))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('sarcoma', 'Disease', (29, 36))	('NY-ESO-1', 'Gene', (47, 55))	('lung cancer', 'Disease', 'MESH:D008175', (269, 280))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (258, 280))	('lung cancer', 'Phenotype', 'HP:0100526', (269, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('high', 'Var', (282, 286))	('breast cancer', 'Phenotype', 'HP:0003002', (382, 395))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (254, 280))	('sarcoma', 'Disease', 'MESH:D012509', (208, 215))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (352, 377))	('sarcoma', 'Disease', (208, 215))	('breast cancer', 'Disease', 'MESH:D001943', (382, 395))	('breast cancer', 'Disease', (382, 395))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
583152	33287125	In a previous analysis of our cohort, the expression of PD-L1 on STS was associated with an infiltration by PD-1-positive TILs, high tumour grading, and short survival.	('PD-L1', 'Gene', '29126', (56, 61))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumour', 'Disease', (133, 139))	('expression', 'Var', (42, 52))	('associated with', 'Reg', (73, 88))	('PD-1', 'Gene', (108, 112))	('PD-1', 'Gene', '5133', (108, 112))	('STS', 'Phenotype', 'HP:0030448', (65, 68))	('PD-L1', 'Gene', (56, 61))
583394	32227347	One large field study of 6000 dogs showed that vaccinated puppies were actually more likely to have diarrhoea than unvaccinated puppies, and there was no difference between these groups with respect to cyst or antigen detection (Lund et al.	('dogs', 'Species', '9615', (30, 34))	('diarrhoea', 'Disease', (100, 109))	('diarrhoea', 'Phenotype', 'HP:0002014', (100, 109))	('vaccinate', 'Chemical', '-', (47, 56))	('diarrhoea', 'Disease', 'MESH:D003967', (100, 109))	('vaccinated', 'Var', (47, 57))	('vaccinate', 'Chemical', '-', (117, 126))
583423	32227347	Most vaccines contain either CPV2 or CPV2b and questions have been raised as to whether these provide adequate cross-protection against new virus variants (specifically CPV2c).	('CPV2', 'Species', '246878', (37, 41))	('CPV2', 'Var', (29, 33))	('CPV2b', 'Var', (37, 42))	('CPV2', 'Species', '246878', (29, 33))	('CPV2', 'Species', '246878', (169, 173))
583648	32227347	However, immunologically speaking, there is now much research that shows that parasite infestation can influence the nature of immune responses by skewing immunity towards a T regulatory response associated with immunological suppression and a T helper 2 type response dominated by humoral rather than cell-mediated immunity and this has also been shown for the dog (Junginger et al.	('dog', 'Species', '9615', (362, 365))	('infestation', 'Var', (87, 98))	('T regulatory response', 'MPA', (174, 195))	('influence', 'Reg', (103, 112))	('skewing', 'Reg', (147, 154))	('immunity', 'MPA', (155, 163))	('nature', 'MPA', (117, 123))
583844	32042403	PRAME siRNA knockdown significantly suppressed proliferation, induced cell cycle stop in the G1 phase, reduced the efficiency of colony formation of cultured cells by osteosarcoma.	('osteosarcoma', 'Disease', (167, 179))	('suppressed', 'NegReg', (36, 46))	('osteosarcoma', 'Disease', 'MESH:D012516', (167, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('reduced', 'NegReg', (103, 110))	('colony formation of cultured cells', 'CPA', (129, 163))	('knockdown', 'Var', (12, 21))	('induced', 'Reg', (62, 69))	('cell cycle stop in the G1 phase', 'CPA', (70, 101))	('PRAME', 'Gene', '23532', (0, 5))	('proliferation', 'CPA', (47, 60))	('PRAME', 'Gene', (0, 5))	('osteosarcoma', 'Phenotype', 'HP:0002669', (167, 179))
583845	32042403	PRAME knockdown significantly suppressed the proliferation, colony formation, and G1 cell cycle arrest in osteosarcoma cells.	('osteosarcoma', 'Disease', (106, 118))	('G1 cell cycle arrest', 'CPA', (82, 102))	('proliferation', 'CPA', (45, 58))	('suppressed', 'NegReg', (30, 40))	('osteosarcoma', 'Disease', 'MESH:D012516', (106, 118))	('colony formation', 'CPA', (60, 76))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('knockdown', 'Var', (6, 15))	('PRAME', 'Gene', '23532', (0, 5))	('PRAME', 'Gene', (0, 5))	('osteosarcoma', 'Phenotype', 'HP:0002669', (106, 118))
583855	32042403	It is known that mutation load and the number of neoantigens are essential for immunotherapy efficacy, while tumors with one driver mutation usually have a lower mutational burden and lower dependency from the immune system.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('lower', 'NegReg', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutational burden', 'MPA', (162, 179))	('mutation', 'Var', (132, 140))	('tumors', 'Disease', (109, 115))
583888	32839432	Thus, the combination of ABT-199 and BZB sensitizes STS cells to apoptosis by simultaneously releasing several defined apoptotic restraints.	('releasing', 'PosReg', (93, 102))	('combination', 'Var', (10, 21))	('ABT-199', 'Chemical', 'MESH:C579720', (25, 32))	('BZB', 'Gene', (37, 40))	('ABT-199', 'Gene', (25, 32))	('BZB', 'Chemical', 'MESH:D000069286', (37, 40))	('sensitizes', 'Reg', (41, 51))
583893	32839432	Sarcomagenesis arises from various alterations, such as fusion proteins resulting from genomic rearrangements, mutations in tumor-suppressor and cell cycle regulatory genes, and DNA copy-number variations.	('mutations', 'Var', (111, 120))	('fusion proteins', 'Protein', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('arises from', 'Reg', (15, 26))	('Sarcomagenesis', 'Disease', (0, 14))	('genomic rearrangements', 'Var', (87, 109))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
583894	32839432	Sarcomas are traditionally classified in two major genetic groups: the first group includes sarcomas with simple karyotypes and specific genetic alterations like EWS-ATF1 fusions in Ewing sarcomas, KIT mutations in GISTs, or PAX3-FKHR fusions in alveolar rhabdomyosarcomas.	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('FKHR', 'Gene', '2308', (230, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('sarcomas', 'Disease', 'MESH:D012509', (188, 196))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (246, 272))	('sarcomas', 'Phenotype', 'HP:0100242', (188, 196))	('sarcomas', 'Disease', (188, 196))	('fusions', 'Var', (235, 242))	('KIT', 'Gene', '3815', (198, 201))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('sarcomas', 'Disease', 'MESH:D012509', (92, 100))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (255, 272))	('fusions', 'Var', (171, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('GISTs', 'Gene', (215, 220))	('sarcomas', 'Disease', (92, 100))	('PAX3', 'Gene', (225, 229))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (255, 271))	('alveolar rhabdomyosarcomas', 'Disease', (246, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('FKHR', 'Gene', (230, 234))	('EWS-ATF1', 'Gene', (162, 170))	('Sarcomas', 'Disease', (0, 8))	('PAX3', 'Gene', '5077', (225, 229))	('EWS-ATF1', 'Gene', '466;2130', (162, 170))	('sarcomas', 'Disease', 'MESH:D012509', (264, 272))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (182, 196))	('sarcomas', 'Phenotype', 'HP:0100242', (264, 272))	('sarcomas', 'Disease', (264, 272))	('KIT', 'Gene', (198, 201))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (246, 272))	('Ewing sarcomas', 'Disease', (182, 196))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (182, 196))	('mutations', 'Var', (202, 211))
583895	32839432	The second group is represented by complex genetic aberrations associated with impaired p53 checkpoint function, dysfunctional DNA repair by homologous or nonhomologous end joining, and an increase of unrepaired double-strand breaks.	('unrepaired double-strand breaks', 'MPA', (201, 232))	('increase of unrepaired double-strand breaks', 'Phenotype', 'HP:0040012', (189, 232))	('dysfunctional', 'Var', (113, 126))	('p53', 'Gene', (88, 91))	('DNA repair', 'MPA', (127, 137))	('p53', 'Gene', '7157', (88, 91))	('impaired', 'NegReg', (79, 87))	('increase', 'PosReg', (189, 197))
583896	32839432	Complex karyotypes in STS are frequently related to BRAF, RAS (H-, K-, and N-), PTEN, RB1, BRCA2, APC, and PIK3CA mutations.	('RB1', 'Gene', (86, 89))	('BRCA2', 'Gene', '675', (91, 96))	('APC', 'Gene', (98, 101))	('PTEN', 'Gene', (80, 84))	('mutations', 'Var', (114, 123))	('PTEN', 'Gene', '5728', (80, 84))	('BRCA2', 'Gene', (91, 96))	('APC', 'Gene', '324', (98, 101))	('RB1', 'Gene', '5925', (86, 89))	('PIK3CA', 'Gene', (107, 113))	('related', 'Reg', (41, 48))	('BRAF', 'Gene', '673', (52, 56))	('RAS', 'Disease', (58, 61))	('PIK3CA', 'Gene', '5290', (107, 113))	('BRAF', 'Gene', (52, 56))
583926	32839432	Consequently, inhibition of BOK degradation by the proteasome inhibitor MG132 was shown to stabilize BOK and induce apoptosis, while knock-down of BOK attenuates MG132-induced apoptosis.	('BOK', 'Gene', (28, 31))	('knock-down', 'Var', (133, 143))	('apoptosis', 'CPA', (116, 125))	('BOK', 'Gene', '666', (147, 150))	('BOK', 'Gene', (101, 104))	('MG132', 'Chemical', 'MESH:C072553', (162, 167))	('degradation', 'MPA', (32, 43))	('BOK', 'Gene', '666', (28, 31))	('MG132', 'Chemical', 'MESH:C072553', (72, 77))	('BOK', 'Gene', '666', (101, 104))	('BOK', 'Gene', (147, 150))	('induce', 'PosReg', (109, 115))	('inhibition', 'NegReg', (14, 24))
583933	32839432	In line with the proposed mechanism, CRISPR/Cas9-mediated knock-out of BAX, but not BAK or BOK, significantly reduced apoptosis induction by ABT-199/BZB.	('reduced', 'NegReg', (110, 117))	('BZB', 'Chemical', 'MESH:D000069286', (149, 152))	('BOK', 'Gene', (91, 94))	('BAK', 'Gene', (84, 87))	('BAK', 'Gene', '578', (84, 87))	('ABT-199', 'Chemical', 'MESH:C579720', (141, 148))	('apoptosis induction', 'CPA', (118, 137))	('knock-out', 'Var', (58, 67))	('BOK', 'Gene', '666', (91, 94))	('BAX', 'Gene', '581', (71, 74))	('BAX', 'Gene', (71, 74))
583934	32839432	Moreover, the additional knock-down of NOXA in BAX-deficient cells most efficiently blocked apoptosis induction by ABT-199/BZB.	('apoptosis induction', 'CPA', (92, 111))	('BAX', 'Gene', '581', (47, 50))	('BAX', 'Gene', (47, 50))	('blocked', 'NegReg', (84, 91))	('knock-down', 'Var', (25, 35))	('NOXA', 'Gene', (39, 43))	('NOXA', 'Gene', '5366', (39, 43))	('BZB', 'Chemical', 'MESH:D000069286', (123, 126))	('ABT-199', 'Chemical', 'MESH:C579720', (115, 122))
583940	32839432	Initially, we performed dose-response viability assays in RD (rhabdomyosarcoma) and SW982 (synovial sarcoma) cells with mutant and wildtype p53, respectively.	('SW982', 'CellLine', 'CVCL:1734', (84, 89))	('synovial sarcoma', 'Disease', (91, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (62, 78))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (62, 78))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (91, 107))	('synovial sarcoma', 'Disease', 'MESH:D013584', (91, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('rhabdomyosarcoma', 'Disease', (62, 78))	('p53', 'Gene', (140, 143))	('mutant', 'Var', (120, 126))	('p53', 'Gene', '7157', (140, 143))
583946	32839432	p53 mutant RD cells revealed a high constitutive expression of p53, while p53 was upregulated by the proteasome inhibitor in p53wt SW982 cells.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (63, 66))	('mutant', 'Var', (4, 10))	('p53', 'Gene', '7157', (63, 66))	('p53', 'Gene', (125, 128))	('upregulated', 'PosReg', (82, 93))	('p53', 'Gene', '7157', (125, 128))	('p53', 'Gene', (74, 77))	('p53', 'Gene', '7157', (74, 77))	('SW982', 'CellLine', 'CVCL:1734', (131, 136))
583949	32839432	Moreover, although more pronounced in SW982 and to a lesser extent also in RD cells, ABT-199/BZB strongly augmented the expression of BOK, NOXA, and MCL-1 (Fig.	('expression', 'MPA', (120, 130))	('ABT-199', 'Chemical', 'MESH:C579720', (85, 92))	('BZB', 'Chemical', 'MESH:D000069286', (93, 96))	('BOK', 'Gene', '666', (134, 137))	('MCL-1', 'Gene', (149, 154))	('NOXA', 'Gene', (139, 143))	('MCL-1', 'Gene', '4170', (149, 154))	('SW982', 'CellLine', 'CVCL:1734', (38, 43))	('NOXA', 'Gene', '5366', (139, 143))	('BOK', 'Gene', (134, 137))	('augmented', 'PosReg', (106, 115))	('ABT-199/BZB', 'Var', (85, 96))
583955	32839432	These results are in line with the proposed hypothesis that inhibition of BCL-2 and the proteasome synergistically induce cell death.	('inhibition', 'Var', (60, 70))	('cell death', 'CPA', (122, 132))	('induce', 'PosReg', (115, 121))	('BCL-2', 'Gene', '596', (74, 79))	('BCL-2', 'Gene', (74, 79))
583960	32839432	Thus, the combination of ABT-199 and BZB induces cell death by apoptosis, as evidenced by DNA fragmentation, exposure of PS and loss of mitochondrial membrane potential.	('loss', 'NegReg', (128, 132))	('DNA fragmentation', 'CPA', (90, 107))	('PS', 'Chemical', 'MESH:D010718', (121, 123))	('combination', 'Var', (10, 21))	('induces', 'Reg', (41, 48))	('ABT-199', 'Chemical', 'MESH:C579720', (25, 32))	('BZB', 'Gene', (37, 40))	('ABT-199', 'Gene', (25, 32))	('apoptosis', 'CPA', (63, 72))	('mitochondrial membrane potential', 'MPA', (136, 168))	('cell death', 'CPA', (49, 59))	('BZB', 'Chemical', 'MESH:D000069286', (37, 40))
583964	32839432	RD and SW982 cells were incubated with the BCL-xL inhibitor A-1155463 or the MCL-1 specific inhibitor A-1210477 alone or in combination with BZB.	('A-1155463', 'Var', (60, 69))	('A-1210477', 'Var', (102, 111))	('BZB', 'Chemical', 'MESH:D000069286', (141, 144))	('A-1210477', 'Chemical', 'MESH:C000611392', (102, 111))	('BCL-xL', 'Gene', '598', (43, 49))	('A-1155463', 'Chemical', 'MESH:C000603579', (60, 69))	('MCL-1', 'Gene', '4170', (77, 82))	('SW982', 'CellLine', 'CVCL:1734', (7, 12))	('MCL-1', 'Gene', (77, 82))	('BCL-xL', 'Gene', (43, 49))
583965	32839432	Similar to ABT-199, A-1155463, and A-1210477, when applied alone, elicited only marginal exposure of PS or loss of mitochondrial membrane potential in ~20% of RD or SW982 cells (Fig.	('A-1155463', 'Chemical', 'MESH:C000603579', (20, 29))	('A-1155463', 'Var', (20, 29))	('A-1210477', 'Var', (35, 44))	('loss', 'NegReg', (107, 111))	('mitochondrial membrane potential', 'MPA', (115, 147))	('PS', 'Chemical', 'MESH:D010718', (101, 103))	('SW982', 'CellLine', 'CVCL:1734', (165, 170))	('ABT-199', 'Chemical', 'MESH:C579720', (11, 18))	('A-1210477', 'Chemical', 'MESH:C000611392', (35, 44))
583966	32839432	However, compared to ABT-199, the combination of the BCL-xL inhibitor A-1155463 and BZB resulted in reduced Annexin V+ and TMRMlow cells, with <45% of RD and SW982 being apoptotic (Fig.	('TMRM', 'Chemical', '-', (123, 127))	('reduced', 'NegReg', (100, 107))	('ABT-199', 'Chemical', 'MESH:C579720', (21, 28))	('Annexin V', 'Gene', '308', (108, 117))	('BZB', 'Gene', (84, 87))	('A-1155463', 'Var', (70, 79))	('TMRMlow cells', 'CPA', (123, 136))	('SW982', 'CellLine', 'CVCL:1734', (158, 163))	('BZB', 'Chemical', 'MESH:D000069286', (84, 87))	('Annexin V', 'Gene', (108, 117))	('BCL-xL', 'Gene', '598', (53, 59))	('BCL-xL', 'Gene', (53, 59))	('A-1155463', 'Chemical', 'MESH:C000603579', (70, 79))
583983	32839432	Because BZB enhances expression of NOXA that inhibits the BAK/BOK antagonist MCL-1, we further aimed to pinpoint the role of NOXA in the synergistic apoptosis induction.	('NOXA', 'Gene', (125, 129))	('inhibits', 'NegReg', (45, 53))	('BAK', 'Gene', '578', (58, 61))	('NOXA', 'Gene', (35, 39))	('BOK', 'Gene', '666', (62, 65))	('NOXA', 'Gene', '5366', (125, 129))	('expression', 'MPA', (21, 31))	('BZB', 'Chemical', 'MESH:D000069286', (8, 11))	('NOXA', 'Gene', '5366', (35, 39))	('BOK', 'Gene', (62, 65))	('MCL-1', 'Gene', '4170', (77, 82))	('MCL-1', 'Gene', (77, 82))	('BAK', 'Gene', (58, 61))	('BZB', 'Var', (8, 11))	('enhances', 'PosReg', (12, 20))
583984	32839432	Hence, we transfected SW982/wt and different KO cell lines with siRNA to knock-down expression of NOXA and subsequently analyzed apoptosis induction by ABT-199/BZB.	('ABT-199', 'Chemical', 'MESH:C579720', (152, 159))	('SW982', 'CellLine', 'CVCL:1734', (22, 27))	('BZB', 'Chemical', 'MESH:D000069286', (160, 163))	('NOXA', 'Gene', (98, 102))	('knock-down', 'Var', (73, 83))	('NOXA', 'Gene', '5366', (98, 102))
583985	32839432	In wt, BAKKO and BOKKO SW982 cells knock-down of NOXA had little impact on apoptosis induction, and ~80% of the cells were apoptotic in each cell line after incubation with ABT-199/BZB (Supplemental Fig.	('BAK', 'Gene', (7, 10))	('BZB', 'Chemical', 'MESH:D000069286', (181, 184))	('SW982', 'CellLine', 'CVCL:1734', (23, 28))	('NOXA', 'Gene', '5366', (49, 53))	('NOXA', 'Gene', (49, 53))	('BOK', 'Gene', '666', (17, 20))	('BAK', 'Gene', '578', (7, 10))	('knock-down', 'Var', (35, 45))	('BOK', 'Gene', (17, 20))	('ABT-199', 'Chemical', 'MESH:C579720', (173, 180))
583986	32839432	In contrast, in SW982/BAXKO cells knock-down of NOXA diminished cell death induction to 40% as compared to 80% in SW982/wt cells (Fig.	('SW982', 'CellLine', 'CVCL:1734', (114, 119))	('NOXA', 'Gene', (48, 52))	('diminished', 'NegReg', (53, 63))	('SW982', 'CellLine', 'CVCL:1734', (16, 21))	('knock-down', 'Var', (34, 44))	('NOXA', 'Gene', '5366', (48, 52))	('cell death induction', 'CPA', (64, 84))	('BAX', 'Gene', (22, 25))	('BAX', 'Gene', '581', (22, 25))
583987	32839432	Similar results were obtained in an inverse approach by knocking down BAX in SW982/NOXAKO cells (Fig.	('NOXA', 'Gene', (83, 87))	('NOXA', 'Gene', '5366', (83, 87))	('SW982', 'CellLine', 'CVCL:1734', (77, 82))	('knocking', 'Var', (56, 64))	('BAX', 'Gene', (70, 73))	('BAX', 'Gene', '581', (70, 73))
583992	32839432	We found that combined application of ABT-199/BZB effectively and in most cases synergistically reduced viability of STS cell lines, i.e., SW1353 (chondrosarcoma; CI: 0.78), SK-LMS (leiomyosarcoma; CI: 0.44), Sa-OS (osteosarcoma; CI: 0.83), and SW872 (liposarcoma; CI: 0.92; Fig.	('osteosarcoma', 'Phenotype', 'HP:0002669', (216, 228))	('SW1353', 'Var', (139, 145))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (147, 161))	('liposarcoma', 'Phenotype', 'HP:0012034', (252, 263))	('viability', 'CPA', (104, 113))	('leiomyosarcoma', 'Disease', (182, 196))	('reduced', 'NegReg', (96, 103))	('SW1353', 'CellLine', 'CVCL:0543', (139, 145))	('liposarcoma', 'Disease', 'MESH:D008080', (252, 263))	('SW872', 'Var', (245, 250))	('Sa-OS', 'CellLine', 'CVCL:0548', (209, 214))	('ABT-199/BZB', 'Gene', (38, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('osteosarcoma', 'Disease', (216, 228))	('osteosarcoma', 'Disease', 'MESH:D012516', (216, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('SW872', 'CellLine', 'CVCL:1730', (245, 250))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (182, 196))	('SK-LMS', 'CellLine', 'CVCL:0628', (174, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('chondrosarcoma', 'Disease', 'MESH:D002813', (147, 161))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (182, 196))	('chondrosarcoma', 'Disease', (147, 161))	('liposarcoma', 'Disease', (252, 263))	('BZB', 'Chemical', 'MESH:D000069286', (46, 49))	('ABT-199', 'Chemical', 'MESH:C579720', (38, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))
584009	32839432	Furthermore, we provide evidence that this drug combination efficiently induces cell death in several STS cell lines (RD, SW982, SW1353, SK-LMS, Sa-OS, and SW872).	('induces', 'Reg', (72, 79))	('SW982', 'CellLine', 'CVCL:1734', (122, 127))	('SW1353', 'CellLine', 'CVCL:0543', (129, 135))	('cell death', 'CPA', (80, 90))	('SK-LMS', 'CellLine', 'CVCL:0628', (137, 143))	('SW1353', 'Var', (129, 135))	('SW872', 'CellLine', 'CVCL:1730', (156, 161))	('Sa-OS', 'CellLine', 'CVCL:0548', (145, 150))
584019	32839432	ABT-199 is effective in CLL, AML, non-Hodgkin lymphoma, and likely in multiple myeloma with t11;14 translocation.	('lymphoma', 'Phenotype', 'HP:0002665', (46, 54))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('CLL', 'Disease', (24, 27))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (34, 54))	('multiple myeloma', 'Phenotype', 'HP:0006775', (70, 86))	('myeloma', 'Disease', 'MESH:D009101', (79, 86))	('t11', 'Var', (92, 95))	('ABT-199', 'Chemical', 'MESH:C579720', (0, 7))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (38, 54))	('ABT-199', 'Gene', (0, 7))	('AML', 'Disease', (29, 32))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (34, 54))	('myeloma', 'Disease', (79, 86))	('non-Hodgkin lymphoma', 'Disease', (34, 54))
584020	32839432	Interestingly, acquired resistance to ABT-199 in AML cell lines is overcome by the MCL-1 specific inhibitor VU661013, which synergizes with ABT-199 in apoptosis induction.	('MCL-1', 'Gene', (83, 88))	('AML', 'Disease', (49, 52))	('MCL-1', 'Gene', '4170', (83, 88))	('ABT-199', 'Chemical', 'MESH:C579720', (140, 147))	('ABT-199', 'Chemical', 'MESH:C579720', (38, 45))	('VU661013', 'Var', (108, 116))	('AML', 'Disease', 'MESH:D015470', (49, 52))
584021	32839432	The synergistic activity of ABT-199 and VU661013 is well compatible with the here proposed mechanism for the synergism of ABT-199 and BZB.	('ABT-199', 'Chemical', 'MESH:C579720', (122, 129))	('synergistic activity', 'MPA', (4, 24))	('ABT-199', 'Chemical', 'MESH:C579720', (28, 35))	('BZB', 'Chemical', 'MESH:D000069286', (134, 137))	('VU661013', 'Var', (40, 48))
584022	32839432	Proteasome inhibition acceptedly enhances expression of the MCL-1 inhibiting BH3-only protein NOXA.	('enhances', 'PosReg', (33, 41))	('expression', 'MPA', (42, 52))	('NOXA', 'Gene', (94, 98))	('Proteasome', 'Protein', (0, 10))	('inhibition', 'Var', (11, 21))	('BH3-only protein', 'Gene', (77, 93))	('BH3-only protein', 'Gene', '79680', (77, 93))	('NOXA', 'Gene', '5366', (94, 98))	('MCL-1', 'Gene', '4170', (60, 65))	('MCL-1', 'Gene', (60, 65))
584028	32839432	Additionally, BZB-mediated block of BOK degradation shifts the BCL-2 rheostat even further towards cell death.	('BCL-2', 'Gene', '596', (63, 68))	('shifts', 'Reg', (52, 58))	('BOK', 'Gene', (36, 39))	('BZB', 'Chemical', 'MESH:D000069286', (14, 17))	('block', 'Var', (27, 32))	('BCL-2', 'Gene', (63, 68))	('BOK', 'Gene', '666', (36, 39))
584048	32839432	Human STS cell lines including SW982, SK-LMS-1, SW872, RH30/RD, SW1353, and Sa-OS were authenticated by STR-profiling at the DSMZ and ATCC and cultured in medium as stated in Supplemental Table 2.	('Human', 'Species', '9606', (0, 5))	('Sa-OS', 'CellLine', 'CVCL:0548', (76, 81))	('SW872', 'CellLine', 'CVCL:1730', (48, 53))	('RH30', 'Gene', (55, 59))	('SW1353', 'CellLine', 'CVCL:0543', (64, 70))	('SW1353', 'Var', (64, 70))	('RH30', 'Gene', '6007', (55, 59))	('SW982', 'CellLine', 'CVCL:1734', (31, 36))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (38, 46))
584057	32839432	Secondary anti-mouse (#7076S), and anti-rabbit (#7074S) horseradish-coupled antibodies were from Cell Signaling.	('#7074S', 'Var', (48, 54))	('horseradish-coupled', 'Protein', (56, 75))	('horseradish', 'Species', '3704', (56, 67))	('#7076S', 'Var', (22, 28))
584076	29459674	The further functional enrichment on 889 genes with frequent copy number gains (CNGs) revealed that these genes were significantly associated with cancer pathways including regulation of cell cycle, cell differentiation and mitogen-activated protein kinase (MAPK) cascade.	('copy number', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('associated', 'Reg', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cell cycle', 'CPA', (187, 197))	('cancer', 'Disease', (147, 153))	('cell differentiation', 'CPA', (199, 219))
584080	29459674	This study provides the first observation of CNV in prognosis-related genes across pan-cancer.	('cancer', 'Disease', (87, 93))	('prognosis-related genes', 'Gene', (52, 75))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CNV', 'Var', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
584083	29459674	Examples of prognostic biomarkers are Prostate-Specific Antigen (PSA) in prostate cancer and the phosphatidylinositol 3-kinase (PIK3CA) mutation status of tumours - which are associated with human epidermal growth factor receptor 2 (HER2) in women with positive metastatic breast cancer.	('Prostate-Specific Antigen', 'Gene', (38, 63))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('PIK3CA', 'Gene', '5290', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('HER2', 'Gene', (233, 237))	('human', 'Species', '9606', (191, 196))	('prostate cancer', 'Disease', (73, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('mutation', 'Var', (136, 144))	('PIK3CA', 'Gene', (128, 134))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('epidermal growth factor receptor 2', 'Gene', '2064', (197, 231))	('breast cancer', 'Disease', (273, 286))	('tumours', 'Disease', (155, 162))	('women', 'Species', '9606', (242, 247))	('Prostate-Specific Antigen', 'Gene', '354', (38, 63))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('HER2', 'Gene', '2064', (233, 237))	('epidermal growth factor receptor 2', 'Gene', (197, 231))
584091	29459674	Cancer progression involves a series of genetic alterations involving mutations and copy number of variants (CNVs) in human genomes.	('mutations', 'Var', (70, 79))	('copy number of variants', 'Var', (84, 107))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('human', 'Species', '9606', (118, 123))
584100	29459674	Cancer results from a single somatic cell that has accumulated multiple DNA mutations and result in cell proliferation caused by mutations in genes that control proliferation and the cell cycle.	('mutations', 'Var', (76, 85))	('mutations', 'Var', (129, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cell proliferation', 'CPA', (100, 118))	('caused by', 'Reg', (119, 128))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('result in', 'Reg', (90, 99))
584105	29459674	Overexpression of BCL-2 and related anti-apoptotic proteins has been demonstrated to inhibit cell death induced by growth factor deprivation, hypoxia and oxidative stress.	('BCL-2', 'Gene', '596', (18, 23))	('growth', 'CPA', (115, 121))	('oxidative stress', 'Phenotype', 'HP:0025464', (154, 170))	('inhibit', 'NegReg', (85, 92))	('BCL-2', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('hypoxia', 'Disease', 'MESH:D000860', (142, 149))	('hypoxia', 'Disease', (142, 149))	('cell death', 'CPA', (93, 103))
584110	29459674	For example, the frequency of genetic alterations in TCGA oesophageal carcinoma that exhibited at least one copy number change for each gene was the highest with 157 cases (85.3%).	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (58, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('genetic alterations', 'Var', (30, 49))	('oesophageal carcinoma', 'Disease', (58, 79))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (58, 79))
584113	29459674	More than 80.0% of oesophagus-stomach cancer patients involved gene amplifications.	('oesophagus-stomach cancer', 'Disease', 'MESH:D013274', (19, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (45, 53))	('stomach cancer', 'Phenotype', 'HP:0012126', (30, 44))	('gene amplifications', 'Var', (63, 82))	('oesophagus-stomach cancer', 'Disease', (19, 44))	('involved', 'Reg', (54, 62))
584114	29459674	The same proportion of copy number changes in both CNGs and CNLs with more than 60.0% cases were identified in 14 cancer datasets from six types of cancer, including breast cancer, head and neck squamous cell carcinoma, lung cancer, bladder urothelial carcinoma, sarcoma and uterine carcinosarcoma.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('carcinosarcoma', 'Disease', (283, 297))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (181, 218))	('cancer', 'Disease', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (166, 179))	('carcinosarcoma', 'Disease', 'MESH:D002296', (283, 297))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('sarcoma', 'Disease', 'MESH:D012509', (290, 297))	('lung cancer', 'Disease', (220, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('sarcoma', 'Disease', (290, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (173, 179))	('copy number changes', 'Var', (23, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (275, 297))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('bladder urothelial carcinoma', 'Disease', (233, 261))	('cancer', 'Disease', (148, 154))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('sarcoma', 'Disease', 'MESH:D012509', (263, 270))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('sarcoma', 'Disease', (263, 270))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (233, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Disease', (114, 120))
584117	29459674	In addition to the sample analysis, we explored the genomic alterations in multiple genes across several tumour samples to further elaborate the prognosis-related genes (Fig.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('genomic alterations', 'Var', (52, 71))	('tumour', 'Disease', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
584148	29459674	Most studies show that the KRAS gene mutations are poor prognostic factors but that the upregulation of metadherin (MTDH) is associated with tumour progression in female reproductive system cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('KRAS', 'Gene', '3845', (27, 31))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('system cancers', 'Disease', (183, 197))	('system cancers', 'Disease', 'MESH:D009369', (183, 197))	('metadherin', 'Gene', '92140', (104, 114))	('upregulation', 'PosReg', (88, 100))	('mutations', 'Var', (37, 46))	('metadherin', 'Gene', (104, 114))	('MTDH', 'Gene', '92140', (116, 120))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', (141, 147))	('MTDH', 'Gene', (116, 120))	('KRAS', 'Gene', (27, 31))
584173	29459674	The frequency of the oncogenes with CNGs and overexpression across the tumour samples suggested that this could be a common mechanism in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CNGs', 'Var', (36, 40))	('cancer', 'Disease', (137, 143))	('oncogenes', 'Gene', (21, 30))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('overexpression', 'PosReg', (45, 59))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
584174	29459674	Using cBioPortal, the overall survival rates of patients in these cancer types was compared between tumour samples with or without alterations in each gene, and those which contained the highest number of tumour samples (Fig.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('tumour', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (131, 142))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (100, 106))	('patients', 'Species', '9606', (48, 56))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', (66, 72))
584175	29459674	Those patients with TCGA uterine corpus endometrial carcinoma had significant overall survival rates with p-value 1.930e-6.	('endometrial carcinoma', 'Disease', (40, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (40, 61))	('patients', 'Species', '9606', (6, 14))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (40, 61))	('TCGA', 'Var', (20, 24))
584176	29459674	We observed that TCGA uterine corpus endometrial carcinoma patients with genetic alterations in BIRC5 had significantly better overall survival rates when compared to TCGA sarcoma and ovarian serous cystadenocarcinoma patients with gene amplification in BIRC5 and EZH2.	('endometrial carcinoma', 'Disease', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('EZH2', 'Gene', (264, 268))	('EZH2', 'Gene', '2146', (264, 268))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('ovarian serous cystadenocarcinoma', 'Disease', (184, 217))	('sarcoma', 'Disease', (172, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (37, 58))	('genetic alterations', 'Var', (73, 92))	('patients', 'Species', '9606', (59, 67))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (184, 217))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (37, 58))	('overall', 'MPA', (127, 134))	('better', 'PosReg', (120, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('patients', 'Species', '9606', (218, 226))	('BIRC5', 'Gene', '332', (254, 259))	('BIRC5', 'Gene', '332', (96, 101))	('BIRC5', 'Gene', (254, 259))	('BIRC5', 'Gene', (96, 101))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (192, 217))
584177	29459674	The median month survival for sarcoma patients with genetic alterations was 32.13 while that of patients without genetic alterations was 76.35.	('genetic alterations', 'Var', (52, 71))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('sarcoma', 'Disease', (30, 37))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (38, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
584186	29459674	The desired Affymetrix was valid: 202666_s_at (ACTL6A), 226463_at (ATP6V1C1), 203140_at (BCL6), 204274_at (EBAG9), 204010_s_at (KRAS), 212248_at (MTDH), 216071_x_at (OPA1) and 213184_at (SENP5).	('203140_at', 'Var', (78, 87))	('EBAG9', 'Gene', '9166', (107, 112))	('EBAG9', 'Gene', (107, 112))	('204010_s_at', 'Var', (115, 126))	('MTDH', 'Gene', (146, 150))	('202666_s_at', 'Var', (34, 45))	('SENP5', 'Gene', (187, 192))	('MTDH', 'Gene', '92140', (146, 150))	('ATP6V1C1', 'Gene', '528', (67, 75))	('ACTL6A', 'Gene', (47, 53))	('KRAS', 'Gene', '3845', (128, 132))	('BCL6', 'Gene', '604', (89, 93))	('212248_at', 'Var', (135, 144))	('ACTL6A', 'Gene', '86', (47, 53))	('OPA1', 'Gene', '4976', (166, 170))	('KRAS', 'Gene', (128, 132))	('OPA1', 'Gene', (166, 170))	('ATP6V1C1', 'Gene', (67, 75))	('226463_at', 'Var', (56, 65))	('213184_at', 'Var', (176, 185))	('204274_at', 'Var', (96, 105))	('216071_x_at', 'Var', (153, 164))	('SENP5', 'Gene', '205564', (187, 192))	('BCL6', 'Gene', (89, 93))
584189	29459674	Interestingly, we identified that MTDH was not statistically associated with RFS in ovarian cancer (P = 0.59); however, the high expression of MTDH was associated with a poor prognosis in other three cancer types - breast (P = 3.5e-10), lung (P = 2.1e-06) and gastric (P = 3.5e-10; Sup Fig.	('ovarian cancer', 'Disease', (84, 98))	('MTDH', 'Gene', (34, 38))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('lung', 'Disease', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('gastric', 'Disease', (260, 267))	('MTDH', 'Gene', '92140', (143, 147))	('MTDH', 'Gene', (143, 147))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('MTDH', 'Gene', '92140', (34, 38))	('breast', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('high', 'Var', (124, 128))	('cancer', 'Disease', (200, 206))
584201	29459674	The cases with more than 40.0% genetic alterations and including both CNLs and CNGs were identified in six cancer datasets from four cancer types: ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, oesophageal carcinoma and uterine carcinosarcoma.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (238, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (212, 233))	('genetic alterations', 'Var', (31, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (182, 210))	('lung squamous cell carcinoma', 'Disease', (182, 210))	('cancer', 'Disease', (133, 139))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (155, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (212, 233))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('carcinosarcoma', 'Disease', (246, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('ovarian serous cystadenocarcinoma', 'Disease', (147, 180))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('oesophageal carcinoma', 'Disease', (212, 233))	('carcinosarcoma', 'Disease', 'MESH:D002296', (246, 260))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (147, 180))
584202	29459674	For example, the TCGA ovarian serous cystadenocarcinoma patients had more than 60.0% (360 cases) genetic alteration in CNGs.	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (30, 55))	('patients', 'Species', '9606', (56, 64))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (22, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('ovarian serous cystadenocarcinoma', 'Disease', (22, 55))	('genetic alteration', 'Var', (97, 115))
584204	29459674	The median month survival for ovarian serous cystadenocarcinoma patients with genetic alterations was 48.72, while that of patients without genetic mutation was 39.55.	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (38, 63))	('patients', 'Species', '9606', (64, 72))	('ovarian serous cystadenocarcinoma', 'Disease', (30, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('patients', 'Species', '9606', (123, 131))	('genetic alterations', 'Var', (78, 97))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (30, 63))
584206	29459674	This study has revealed some significant somatic mutational characteristics of prognosis-related genes in multiple cancer types, particularly with respect to the CNVs and their effects on gene expression.	('mutational', 'Var', (49, 59))	('multiple cancer', 'Disease', (106, 121))	('prognosis-related genes', 'Gene', (79, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('effects', 'Reg', (177, 184))	('multiple cancer', 'Disease', 'MESH:D009369', (106, 121))
584282	29074153	Thus, when characteristics of the primary tumor and metastatic disease are controlled for, repeat PM remains associated with a survival benefit (Fig.	('tumor', 'Disease', (42, 47))	('repeat PM', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('survival', 'MPA', (127, 135))	('benefit', 'PosReg', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
584338	27537574	In addition, women with low estrogen are at risk for osteoporosis, cardiovascular disease, and metabolic syndrome.	('osteoporosis', 'Disease', 'MESH:D010024', (53, 65))	('cardiovascular disease', 'Disease', 'MESH:D002318', (67, 89))	('estrogen', 'Protein', (28, 36))	('osteoporosis', 'Phenotype', 'HP:0000939', (53, 65))	('cardiovascular disease', 'Disease', (67, 89))	('women', 'Species', '9606', (13, 18))	('osteoporosis', 'Disease', (53, 65))	('metabolic syndrome', 'Disease', 'MESH:D008659', (95, 113))	('low', 'Var', (24, 27))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (67, 89))	('metabolic syndrome', 'Disease', (95, 113))
584478	27194075	Mechanical allodynia was observed in mice from the saline group and was improved in mice from the anti-NGF group.	('Mechanical allodynia', 'Disease', 'MESH:D006930', (0, 20))	('improved', 'PosReg', (72, 80))	('saline', 'Chemical', 'MESH:D012965', (51, 57))	('anti-NGF', 'Var', (98, 106))	('allodynia', 'Phenotype', 'HP:0012533', (11, 20))	('Mechanical allodynia', 'Disease', (0, 20))	('mice', 'Species', '10090', (84, 88))	('mice', 'Species', '10090', (37, 41))
584494	27194075	In animal models of neuropathic pain, such as nerve trunk or spinal nerve ligation, systemic injection of anti-NGF antibody reduces allodynia and hyperalgesia.	('hyperalgesia', 'Phenotype', 'HP:0031005', (146, 158))	('allodynia', 'Disease', 'MESH:D006930', (132, 141))	('pain', 'Phenotype', 'HP:0012531', (32, 36))	('nerve trunk', 'Disease', (46, 57))	('neuropathic pain', 'Disease', (20, 36))	('reduces', 'NegReg', (124, 131))	('nerve trunk', 'Disease', 'MESH:D016750', (46, 57))	('neuropathic pain', 'Disease', 'MESH:D009437', (20, 36))	('anti-NGF', 'Var', (106, 114))	('hyperalgesia', 'Disease', 'MESH:D006930', (146, 158))	('hyperalgesia', 'Disease', (146, 158))	('allodynia', 'Disease', (132, 141))	('spinal nerve ligation', 'Phenotype', 'HP:0100561', (61, 82))	('allodynia', 'Phenotype', 'HP:0012533', (132, 141))
584525	27194075	The ratio of the ipsi- and contralateral mean intensities was significantly higher in the Ca+anti-NGF group (87.6%) compared with the Ca+saline group (P<0.05).	('Ca', 'Phenotype', 'HP:0002664', (134, 136))	('ipsi', 'Chemical', '-', (17, 21))	('rat', 'Species', '10116', (4, 7))	('Ca+saline', 'Chemical', '-', (134, 143))	('higher', 'PosReg', (76, 82))	('Ca', 'Phenotype', 'HP:0002664', (90, 92))	('Ca+anti-NGF', 'Var', (90, 101))
584529	27194075	The proportion of CGRP-IR neurons among all DRG neurons in the Ca+anti-NGF group (19.2%) was significantly smaller than the corresponding proportion in the Ca+saline group (P<0.05).	('DRG neurons', 'CPA', (44, 55))	('Ca+anti-NGF', 'Var', (63, 74))	('Ca', 'Phenotype', 'HP:0002664', (63, 65))	('Ca+saline', 'Chemical', '-', (156, 165))	('Ca', 'Phenotype', 'HP:0002664', (156, 158))	('smaller', 'NegReg', (107, 114))	('CGRP', 'Gene', '12310', (18, 22))	('CGRP', 'Gene', (18, 22))
584531	27194075	The proportion of ATF-3-IR neurons among all DRG neurons in the Ca+anti-NGF group (4.7%) was significantly smaller than the corresponding proportion in the Ca+saline group (P<0.05).	('Ca+saline', 'Chemical', '-', (156, 165))	('Ca', 'Phenotype', 'HP:0002664', (156, 158))	('ATF-3', 'Gene', (18, 23))	('DRG neurons', 'CPA', (45, 56))	('Ca+anti-NGF', 'Var', (64, 75))	('ATF-3', 'Gene', '11910', (18, 23))	('Ca', 'Phenotype', 'HP:0002664', (64, 66))	('smaller', 'NegReg', (107, 114))
584533	27194075	The density of iba1-IR microglia in the Ca+anti-NGF group was significantly lower than the corresponding density in the Ca+saline group (P<0.05) (Fig.	('Ca', 'Phenotype', 'HP:0002664', (120, 122))	('Ca', 'Phenotype', 'HP:0002664', (40, 42))	('Ca+anti-NGF', 'Var', (40, 51))	('lower', 'NegReg', (76, 81))	('Ca+saline', 'Chemical', '-', (120, 129))	('density', 'CPA', (4, 11))
584549	27194075	The increase in mechanical allodynia seen in the behavioral study, the CGRP and ATF-3 immunoreactivity in the DRGs, and activation of microglia in the spinal dorsal horn can be suppressed by inhibiting NGF.	('suppressed', 'NegReg', (177, 187))	('mechanical allodynia', 'Disease', 'MESH:D006930', (16, 36))	('mechanical allodynia', 'Disease', (16, 36))	('CGRP', 'Gene', '12310', (71, 75))	('CGRP', 'Gene', (71, 75))	('allodynia', 'Phenotype', 'HP:0012533', (27, 36))	('ATF-3', 'Gene', (80, 85))	('inhibiting', 'Var', (191, 201))	('ATF-3', 'Gene', '11910', (80, 85))	('increase', 'PosReg', (4, 12))	('microglia', 'CPA', (134, 143))
584563	31649026	Inhibition of the ATR-CHK1 pathway in Ewing sarcoma cells causes DNA damage and apoptosis via the CDK2-mediated degradation of RRM2 Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ATR-CHK1 pathway.	('activates', 'PosReg', (279, 288))	('Inhibition', 'Var', (132, 142))	('CDK2', 'Gene', '1017', (98, 102))	('stress', 'Disease', 'MESH:D000079225', (268, 274))	('CHK1', 'Gene', '1111', (22, 26))	('deoxyribonucleotides', 'Chemical', 'MESH:D003854', (223, 243))	('CDK2', 'Gene', (98, 102))	('ATR', 'Gene', (293, 296))	('CHK1', 'Gene', '1111', (297, 301))	('stress', 'Disease', (268, 274))	('ATR', 'Gene', '545', (18, 21))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))	('causes', 'Reg', (245, 251))	('ATR', 'Gene', '545', (293, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('CHK1', 'Gene', (22, 26))	('Ewing sarcoma', 'Disease', (38, 51))	('ATR', 'Gene', (18, 21))	('CHK1', 'Gene', (297, 301))
584565	31649026	However, multiple, overlapping mechanisms are reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single-agents and in combination with RNR inhibitors, toward cancer cells.	('toxicity', 'Disease', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('inhibitors', 'Var', (92, 102))	('cancer', 'Disease', (173, 179))	('CHK1', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CHK1', 'Gene', '1111', (87, 91))	('ATR', 'Gene', '545', (83, 86))	('ATR', 'Gene', (83, 86))	('toxicity', 'Disease', 'MESH:D064420', (71, 79))
584566	31649026	Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR-CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors.	('depletes', 'NegReg', (103, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('DNA damage', 'MPA', (191, 201))	('inhibition', 'Var', (68, 78))	('exacerbates', 'PosReg', (148, 159))	('stress', 'Disease', (180, 186))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (39, 52))	('stress', 'Disease', 'MESH:D000079225', (180, 186))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('RRM2', 'Gene', '6241', (112, 116))	('CHK1', 'Gene', (90, 94))	('ATR', 'Gene', (86, 89))	('ATR', 'Gene', '545', (86, 89))	('RRM2', 'Gene', (112, 116))	('CHK1', 'Gene', '1111', (90, 94))	('Ewing sarcoma', 'Disease', (39, 52))
584567	31649026	Mechanistically, we identified that the inhibition of ATR-CHK1 activates CDK2, which targets RRM2 for degradation via the proteasome.	('inhibition', 'Var', (40, 50))	('ATR', 'Gene', '545', (54, 57))	('ATR', 'Gene', (54, 57))	('CDK2', 'Gene', (73, 77))	('RRM2', 'Gene', '6241', (93, 97))	('RRM2', 'Gene', (93, 97))	('CHK1', 'Gene', (58, 62))	('degradation', 'MPA', (102, 113))	('CDK2', 'Gene', '1017', (73, 77))	('CHK1', 'Gene', '1111', (58, 62))	('activates', 'PosReg', (63, 72))
584568	31649026	Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis.	('inhibition', 'Var', (33, 43))	('CDK2', 'Gene', (25, 29))	('causes', 'Reg', (99, 105))	('activation', 'PosReg', (11, 21))	('RRM2', 'Gene', '6241', (90, 94))	('RRM2', 'Gene', (90, 94))	('knockdown', 'Var', (47, 56))	('WEE1', 'Gene', (64, 68))	('CDK2', 'Gene', '1017', (25, 29))	('WEE1', 'Gene', '7465', (64, 68))	('depletes', 'NegReg', (81, 89))	('DNA damage', 'MPA', (106, 116))	('apoptosis', 'CPA', (121, 130))
584578	31649026	Notably, ATR-CHK1 inhibitors are also reported to sensitize a range of other tumor types to DNA-damaging agents and, in some cases, elicit single agent cytotoxicity.	('CHK1', 'Gene', (13, 17))	('ATR', 'Gene', (9, 12))	('DNA-damaging agents', 'MPA', (92, 111))	('sensitize', 'Reg', (50, 59))	('cytotoxicity', 'Disease', 'MESH:D064420', (152, 164))	('CHK1', 'Gene', '1111', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cytotoxicity', 'Disease', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('elicit', 'Reg', (132, 138))	('tumor', 'Disease', (77, 82))	('ATR', 'Gene', '545', (9, 12))	('inhibitors', 'Var', (18, 28))
584582	31649026	For example, ATR and/or CHK1 regulate chromosome segregation, the S/G2 checkpoint, the G2/M transition, double-strand DNA break repair, and the response to osmotic and mechanical stress.	('S/G2', 'Var', (66, 70))	('S/G2', 'SUBSTITUTION', 'None', (66, 70))	('stress', 'Disease', (179, 185))	('CHK1', 'Gene', (24, 28))	('stress', 'Disease', 'MESH:D000079225', (179, 185))	('ATR', 'Gene', '545', (13, 16))	('ATR', 'Gene', (13, 16))	('G2/M transition', 'CPA', (87, 102))	('CHK1', 'Gene', '1111', (24, 28))	('chromosome segregation', 'CPA', (38, 60))	('double-strand DNA break repair', 'MPA', (104, 134))	('regulate', 'Reg', (29, 37))
584585	31649026	Similarly, activation of CDK2 by inhibiting the WEE1 kinase with AZD1775, or knockdown of WEE1 with siRNA, also causes DNA damage and apoptosis.	('causes', 'Reg', (112, 118))	('CDK2', 'Gene', (25, 29))	('WEE1', 'Gene', (90, 94))	('WEE1', 'Gene', '7465', (90, 94))	('WEE1', 'Gene', '7465', (48, 52))	('apoptosis', 'CPA', (134, 143))	('knockdown', 'Var', (77, 86))	('AZD1775', 'Chemical', 'MESH:C549567', (65, 72))	('CDK2', 'Gene', '1017', (25, 29))	('DNA damage', 'MPA', (119, 129))	('activation', 'PosReg', (11, 21))	('inhibiting', 'NegReg', (33, 43))	('WEE1', 'Gene', (48, 52))
584588	31649026	Thus, we describe a novel feedback loop in Ewing sarcoma cells in which the inhibition of the ATR-CHK1 or WEE1 pathways during DNA replication stress, due to inhibition of RRM2 or other causes, leads to the aberrant activation of CDK2, degradation of RRM2, enhanced DNA replication stress, increased DNA damage, and apoptosis.	('CHK1', 'Gene', (98, 102))	('stress', 'Disease', 'MESH:D000079225', (282, 288))	('stress', 'Disease', (143, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('degradation', 'MPA', (236, 247))	('apoptosis', 'CPA', (316, 325))	('ATR', 'Gene', (94, 97))	('RRM2', 'Gene', '6241', (251, 255))	('Ewing sarcoma', 'Disease', (43, 56))	('stress', 'Disease', (282, 288))	('CDK2', 'Gene', '1017', (230, 234))	('CHK1', 'Gene', '1111', (98, 102))	('WEE1', 'Gene', (106, 110))	('activation', 'PosReg', (216, 226))	('increased', 'PosReg', (290, 299))	('RRM2', 'Gene', (251, 255))	('CDK2', 'Gene', (230, 234))	('RRM2', 'Gene', '6241', (172, 176))	('inhibition', 'Var', (158, 168))	('ATR', 'Gene', '545', (94, 97))	('DNA', 'MPA', (300, 303))	('DNA', 'MPA', (266, 269))	('stress', 'Disease', 'MESH:D000079225', (143, 149))	('enhanced', 'PosReg', (257, 265))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('RRM2', 'Gene', (172, 176))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('WEE1', 'Gene', '7465', (106, 110))
584599	31649026	Drug synergy testing was performed by treating cells for 72 h with drug combinations of up to 1000 nM AZD6738 and 500 nM AZD1775.	('AZD1775', 'Chemical', 'MESH:C549567', (121, 128))	('AZD1775', 'Var', (121, 128))	('AZD6738', 'Chemical', 'MESH:C000611951', (102, 109))	('AZD6738', 'Var', (102, 109))
584606	31649026	shERWOOD UltramiR Lentiviral Inducible shRNA plasmids targeting RRM1 (TLHSU2300-6240) and RRM2 (TLHSU2300-6241) were obtained from Transomic Technologies (Huntsville, AL).	('RRM1', 'Gene', (64, 68))	('TLHSU2300-6240', 'Var', (70, 84))	('RRM2', 'Gene', '6241', (90, 94))	('RRM2', 'Gene', (90, 94))	('RRM1', 'Gene', '6240', (64, 68))	('TLHSU2300-6241', 'Var', (96, 110))
584612	31649026	The full length RRM2 cDNA, with a Threonine-33 to Alanine-33 mutation and a FLAG-tag, was obtained as a gene block (IDT; Coralville, IA) and inserted into the Lenti-X-Tet-One vector (Clontech).	('Threonine-33 to Alanine-33 mutation', 'Var', (34, 69))	('RRM2', 'Gene', (16, 20))	('RRM2', 'Gene', '6241', (16, 20))	('Threonine-33 to Alanine', 'Mutation', 'p.T33A', (34, 57))	('Tet', 'Chemical', 'MESH:C010349', (167, 170))
584629	31649026	Next, to determine whether ATR-CHK1 signaling is required for cell survival in early S phase, we released Ewing sarcoma cells from a double thymidine double block in the presence of two different CHK1 inhibitors (LY2603618 and GDC-0575), an ATR inhibitor (AZD6738), or vehicle.	('LY2603618', 'Chemical', 'MESH:C582547', (213, 222))	('Ewing sarcoma', 'Disease', (106, 119))	('CHK1', 'Gene', (196, 200))	('GDC-0575', 'Chemical', 'MESH:C000628363', (227, 235))	('ATR', 'Gene', '545', (27, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (106, 119))	('LY2603618', 'Var', (213, 222))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (106, 119))	('ATR', 'Gene', '545', (241, 244))	('CHK1', 'Gene', (31, 35))	('ATR', 'Gene', (241, 244))	('ATR', 'Gene', (27, 30))	('AZD6738', 'Chemical', 'MESH:C000611951', (256, 263))	('CHK1', 'Gene', '1111', (196, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('GDC-0575', 'Var', (227, 235))	('CHK1', 'Gene', '1111', (31, 35))	('thymidine', 'Chemical', 'MESH:D013936', (140, 149))
584633	31649026	Figures 1E and 1F show that inhibition of ATR or CHK1 in cells released from a thymidine double block results in phosphorylation of H2AX (gammaH2AX), a marker of DNA damage, and cleavage of PARP, a marker of apoptosis.	('H2AX', 'Protein', (132, 136))	('thymidine', 'Chemical', 'MESH:D013936', (79, 88))	('phosphorylation', 'MPA', (113, 128))	('cleavage', 'MPA', (178, 186))	('inhibition', 'Var', (28, 38))	('CHK1', 'Gene', (49, 53))	('PARP', 'Gene', '1302', (190, 194))	('ATR', 'Gene', '545', (42, 45))	('ATR', 'Gene', (42, 45))	('gammaH2AX', 'Chemical', '-', (138, 147))	('CHK1', 'Gene', '1111', (49, 53))	('PARP', 'Gene', (190, 194))
584640	31649026	Figure 1H shows that a CHK1 inhibitor, even in the absence of thymidine treatment or a DNA replication stress inducer, caused DNA damage (gammaH2AX) in cells with active DNA replication.	('CHK1', 'Gene', (23, 27))	('thymidine', 'Chemical', 'MESH:D013936', (62, 71))	('stress', 'Disease', (103, 109))	('stress', 'Disease', 'MESH:D000079225', (103, 109))	('inhibitor', 'Var', (28, 37))	('CHK1', 'Gene', '1111', (23, 27))	('DNA damage', 'MPA', (126, 136))	('gammaH2AX', 'Chemical', '-', (138, 147))
584642	31649026	Finally, to ensure that the effects of the ATR and CHK1 inhibitors were on-target we used a siRNA, validated in our previous work, to knockdown CHK1 in cells treated with a double thymidine block.	('ATR', 'Gene', '545', (43, 46))	('ATR', 'Gene', (43, 46))	('CHK1', 'Gene', (51, 55))	('CHK1', 'Gene', (144, 148))	('thymidine', 'Chemical', 'MESH:D013936', (180, 189))	('knockdown', 'Var', (134, 143))	('CHK1', 'Gene', '1111', (144, 148))	('CHK1', 'Gene', '1111', (51, 55))
584649	31649026	Next, EW8 and TC71 cells were released from a thymidine double block in the presence of a CHK1 inhibitor (LY2603618), the CDK1/2 inhibitor RO-3306, or the combination of LY2603618 and RO-3306.	('TC71', 'CellLine', 'CVCL:2213', (14, 18))	('LY2603618', 'Chemical', 'MESH:C582547', (106, 115))	('RO-3306', 'Chemical', 'MESH:C512984', (139, 146))	('RO-3306', 'Chemical', 'MESH:C512984', (184, 191))	('LY2603618', 'Var', (106, 115))	('thymidine', 'Chemical', 'MESH:D013936', (46, 55))	('CHK1', 'Gene', (90, 94))	('CDK1/2', 'Gene', (122, 128))	('LY2603618', 'Chemical', 'MESH:C582547', (170, 179))	('CDK1/2', 'Gene', '51755;983;1017', (122, 128))	('LY2603618', 'Var', (170, 179))	('CHK1', 'Gene', '1111', (90, 94))
584655	31649026	Next, we used siRNA to knockdown CDK1, CDK2, and the combination of CDK1 and CDK2.	('CDK2', 'Gene', (77, 81))	('CDK1', 'Gene', (33, 37))	('CDK2', 'Gene', '1017', (39, 43))	('CDK2', 'Gene', '1017', (77, 81))	('knockdown', 'Var', (23, 32))	('CDK2', 'Gene', (39, 43))
584656	31649026	Supplementary Figure 2D shows that the knockdown of CDK1 and CDK2 did not impair the entry of cells into S phase at 24 h after siRNA transfection.	('CDK2', 'Gene', (61, 65))	('impair', 'NegReg', (74, 80))	('knockdown', 'Var', (39, 48))	('CDK2', 'Gene', '1017', (61, 65))	('CDK1', 'Gene', (52, 56))
584657	31649026	However, Figure 2E shows that the knockdown of CDK1 and CDK2 decreased the phosphorylation of H2AX in cells released from a thymidine double block in the presence of a CHK1 inhibitor.	('CDK2', 'Gene', '1017', (56, 60))	('H2AX', 'Protein', (94, 98))	('CDK1', 'Gene', (47, 51))	('decreased', 'NegReg', (61, 70))	('thymidine', 'Chemical', 'MESH:D013936', (124, 133))	('CHK1', 'Gene', (168, 172))	('CDK2', 'Gene', (56, 60))	('CHK1', 'Gene', '1111', (168, 172))	('knockdown', 'Var', (34, 43))	('phosphorylation', 'MPA', (75, 90))
584658	31649026	Figure 2F shows that the siRNA-mediated knockdown of CDC25A, which is regulated by ATR-CHK1 and de-phosphorylates CDK1/2, blocked the activation of CDK1/2 and significantly reduced the phosphorylation of H2AX caused by treatment of the cells with a CHK1 inhibitor.	('CDC25A', 'Gene', (53, 59))	('CHK1', 'Gene', '1111', (249, 253))	('CDC25A', 'Gene', '993', (53, 59))	('CDK1/2', 'Gene', (114, 120))	('CDK1/2', 'Gene', (148, 154))	('reduced', 'NegReg', (173, 180))	('phosphorylation', 'MPA', (185, 200))	('knockdown', 'Var', (40, 49))	('activation', 'PosReg', (134, 144))	('H2AX', 'Protein', (204, 208))	('CHK1', 'Gene', (87, 91))	('CDK1/2', 'Gene', '51755;983;1017', (114, 120))	('ATR', 'Gene', (83, 86))	('CDK1/2', 'Gene', '51755;983;1017', (148, 154))	('blocked', 'NegReg', (122, 129))	('CHK1', 'Gene', '1111', (87, 91))	('ATR', 'Gene', '545', (83, 86))	('CHK1', 'Gene', (249, 253))
584659	31649026	Similarly, treatment of EW8 cells with NSC663284, an inhibitor of CDC25A, also reduced phosphorylation of H2AX and cleavage of PARP (Figure 2G).	('reduced', 'NegReg', (79, 86))	('PARP', 'Gene', (127, 131))	('CDC25A', 'Gene', (66, 72))	('H2AX', 'Protein', (106, 110))	('NSC663284', 'Var', (39, 48))	('NSC663284', 'Chemical', 'MESH:C440614', (39, 48))	('phosphorylation', 'MPA', (87, 102))	('CDC25A', 'Gene', '993', (66, 72))	('PARP', 'Gene', '1302', (127, 131))	('cleavage', 'MPA', (115, 123))
584661	31649026	Figures 2H and 2I show that treatment of EW8 cells with LY2603618 after release from a thymidine block increased the unphosphorylated, or activated, forms of both CDK1 and CDK2.	('CDK1', 'Gene', (163, 167))	('thymidine', 'Chemical', 'MESH:D013936', (87, 96))	('increased', 'PosReg', (103, 112))	('activated', 'MPA', (138, 147))	('CDK2', 'Gene', (172, 176))	('LY2603618', 'Chemical', 'MESH:C582547', (56, 65))	('unphosphorylated', 'MPA', (117, 133))	('LY2603618', 'Var', (56, 65))	('CDK2', 'Gene', '1017', (172, 176))
584663	31649026	Thymidine causes DNA replication stress and, as shown above, increased the DNA damage and apoptosis caused by ATR and CHK1 inhibitors.	('DNA', 'MPA', (75, 78))	('CHK1', 'Gene', '1111', (118, 122))	('ATR', 'Gene', (110, 113))	('Thymidine', 'Var', (0, 9))	('Thymidine', 'Chemical', 'MESH:D013936', (0, 9))	('stress', 'Disease', (33, 39))	('increased', 'PosReg', (61, 70))	('stress', 'Disease', 'MESH:D000079225', (33, 39))	('ATR', 'Gene', '545', (110, 113))	('apoptosis', 'CPA', (90, 99))	('CHK1', 'Gene', (118, 122))
584665	31649026	In a previous publication, we showed that the knockdown of RRM1 or RRM2 using potent siRNAs caused replication stress, activation of ATR-CHK1 signaling, apoptosis, and cell death in Ewing sarcoma cells.	('CHK1', 'Gene', (137, 141))	('RRM1', 'Gene', '6240', (59, 63))	('ATR', 'Gene', (133, 136))	('CHK1', 'Gene', '1111', (137, 141))	('cell death', 'CPA', (168, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (182, 195))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (182, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('stress', 'Disease', 'MESH:D000079225', (111, 117))	('RRM1', 'Gene', (59, 63))	('activation', 'PosReg', (119, 129))	('RRM2', 'Gene', '6241', (67, 71))	('apoptosis', 'CPA', (153, 162))	('replication', 'MPA', (99, 110))	('ATR', 'Gene', '545', (133, 136))	('knockdown', 'Var', (46, 55))	('stress', 'Disease', (111, 117))	('Ewing sarcoma', 'Disease', (182, 195))	('RRM2', 'Gene', (67, 71))
584667	31649026	Figure 3B shows that this partial knockdown of RRM1 or RRM2 increased the percentage of cells in S phase, but did not arrest the cells.	('arrest', 'Disease', 'MESH:D006323', (118, 124))	('RRM2', 'Gene', '6241', (55, 59))	('RRM2', 'Gene', (55, 59))	('arrest', 'Disease', (118, 124))	('knockdown', 'Var', (34, 43))	('RRM1', 'Gene', '6240', (47, 51))	('increased', 'PosReg', (60, 69))	('RRM1', 'Gene', (47, 51))
584671	31649026	Figure 3F shows that treatment of the cells with a CHK1 inhibitor, in the presence of doxycycline and knockdown of RRM1 or RRM2, caused activation of CDK1/2, as well as cleavage of PARP and caspase-3.	('caspase-3', 'Gene', (190, 199))	('PARP', 'Gene', '1302', (181, 185))	('CHK1', 'Gene', (51, 55))	('PARP', 'Gene', (181, 185))	('knockdown', 'Var', (102, 111))	('caspase-3', 'Gene', '836', (190, 199))	('RRM1', 'Gene', '6240', (115, 119))	('activation', 'PosReg', (136, 146))	('CDK1/2', 'Gene', (150, 156))	('RRM1', 'Gene', (115, 119))	('CHK1', 'Gene', '1111', (51, 55))	('RRM2', 'Gene', (123, 127))	('doxycycline', 'Chemical', 'MESH:D004318', (86, 97))	('RRM2', 'Gene', '6241', (123, 127))	('CDK1/2', 'Gene', '51755;983;1017', (150, 156))	('cleavage', 'MPA', (169, 177))
584673	31649026	Figures 3I and 3J show that knockdown of CHK1 in the EW8-shRRM2 and EW8-shRRM1 cells using siRNA caused phosphorylation of H2AX, cleavage of PARP, and cleavage of caspase-3.	('RRM2', 'Gene', (59, 63))	('cleavage', 'MPA', (129, 137))	('RRM2', 'Gene', '6241', (59, 63))	('caspase-3', 'Gene', (163, 172))	('cleavage', 'MPA', (151, 159))	('CHK1', 'Gene', (41, 45))	('PARP', 'Gene', '1302', (141, 145))	('caspase-3', 'Gene', '836', (163, 172))	('phosphorylation', 'MPA', (104, 119))	('PARP', 'Gene', (141, 145))	('H2AX', 'Protein', (123, 127))	('CHK1', 'Gene', '1111', (41, 45))	('knockdown', 'Var', (28, 37))	('RRM1', 'Gene', '6240', (74, 78))	('RRM1', 'Gene', (74, 78))
584674	31649026	We also generated an additional cell line with doxycycline-inducible shRNA knockdown of RRM1.	('knockdown', 'Var', (75, 84))	('RRM1', 'Gene', '6240', (88, 92))	('doxycycline', 'Chemical', 'MESH:D004318', (47, 58))	('RRM1', 'Gene', (88, 92))
584678	31649026	Similarly, knockdown of WEE1 using siRNA caused activation of CDK1/2 (Figure 4B).	('CDK1/2', 'Gene', '51755;983;1017', (62, 68))	('WEE1', 'Gene', '7465', (24, 28))	('activation', 'PosReg', (48, 58))	('WEE1', 'Gene', (24, 28))	('knockdown', 'Var', (11, 20))	('CDK1/2', 'Gene', (62, 68))
584679	31649026	In addition, treatment with AZD1775 also caused cleavage of PARP, cleavage of caspase-3, activation of caspase 3/7 as assessed using a luminescence assay, and phosphorylation of H2AX (Figure 4C-D).	('AZD1775', 'Var', (28, 35))	('caspase-3', 'Gene', (78, 87))	('PARP', 'Gene', (60, 64))	('AZD1775', 'Chemical', 'MESH:C549567', (28, 35))	('cleavage', 'MPA', (48, 56))	('phosphorylation', 'MPA', (159, 174))	('caspase 3/7', 'Gene', '836;840', (103, 114))	('activation', 'PosReg', (89, 99))	('cleavage', 'MPA', (66, 74))	('caspase-3', 'Gene', '836', (78, 87))	('PARP', 'Gene', '1302', (60, 64))	('H2AX', 'Protein', (178, 182))	('caspase 3/7', 'Gene', (103, 114))
584680	31649026	However, the phosphorylation of H2AX induced by AZD1775 was blocked by concurrent treatment of the cells with the CDK1/2 inhibitor RO-3306 (Figure 4E).	('H2AX', 'Protein', (32, 36))	('blocked', 'NegReg', (60, 67))	('CDK1/2', 'Gene', (114, 120))	('phosphorylation', 'MPA', (13, 28))	('CDK1/2', 'Gene', '51755;983;1017', (114, 120))	('AZD1775', 'Var', (48, 55))	('AZD1775', 'Chemical', 'MESH:C549567', (48, 55))	('RO-3306', 'Chemical', 'MESH:C512984', (131, 138))
584681	31649026	Next, we treated Ewing sarcoma cells with AZD1775 and then pulse-labeled the cells with EdU to identify cells with active DNA replication.	('AZD1775', 'Var', (42, 49))	('Ewing sarcoma', 'Disease', (17, 30))	('AZD1775', 'Chemical', 'MESH:C549567', (42, 49))	('EdU', 'Chemical', '-', (88, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (17, 30))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (17, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))
584683	31649026	We then treated Ewing sarcoma cells with low doses of AZD1775 and a CHK1 inhibitor, LY2603618.	('LY2603618', 'Var', (84, 93))	('CHK1', 'Gene', (68, 72))	('CHK1', 'Gene', '1111', (68, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (16, 29))	('AZD1775', 'Var', (54, 61))	('LY2603618', 'Chemical', 'MESH:C582547', (84, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))	('Ewing sarcoma', 'Disease', (16, 29))
584686	31649026	Inhibition of ATR in combination with inhibition of WEE1 also caused cleavage of PARP and phosphorylation of H2AX (Figure 4I).	('WEE1', 'Gene', (52, 56))	('WEE1', 'Gene', '7465', (52, 56))	('PARP', 'Gene', (81, 85))	('H2AX', 'Protein', (109, 113))	('phosphorylation', 'MPA', (90, 105))	('cleavage', 'MPA', (69, 77))	('Inhibition', 'Var', (0, 10))	('ATR', 'Gene', (14, 17))	('ATR', 'Gene', '545', (14, 17))	('PARP', 'Gene', '1302', (81, 85))
584687	31649026	Next, BJ-tert cells and multiple Ewing sarcoma cell lines were incubated with different concentrations of inhibitors of WEE1 (AZD1775) and ATR (AZD6738) for 72 h before quantifying the surviving cells with Cell-Titer-Glo.	('ATR', 'Gene', '545', (139, 142))	('ATR', 'Gene', (139, 142))	('AZD6738', 'Chemical', 'MESH:C000611951', (144, 151))	('AZD1775', 'Chemical', 'MESH:C549567', (126, 133))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (33, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (33, 46))	('WEE1', 'Gene', '7465', (120, 124))	('inhibitors', 'Var', (106, 116))	('WEE1', 'Gene', (120, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('Ewing sarcoma', 'Disease', (33, 46))
584689	31649026	In contrast, the combination of AZD1775 and AZD6738 was highly synergistic with multiple Ewing sarcoma cell lines, as shown in a representative Loewe synergy matrix plot (Loewe Score 46.9) (Figure 4K) and summarized for multiple cell lines (Table 1) (Supplementary Figure 4C-E).	('Ewing sarcoma', 'Disease', (89, 102))	('AZD1775', 'Var', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (89, 102))	('AZD6738', 'Chemical', 'MESH:C000611951', (44, 51))	('AZD1775', 'Chemical', 'MESH:C549567', (32, 39))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (89, 102))	('AZD6738', 'Var', (44, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))
584690	31649026	AZD1775 also showed synergy (Loewe Score 44.9) with an additional ATR inhibitor, VX-970, in TC71 cells (Supplementary Figure 5).	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('ATR', 'Gene', '545', (66, 69))	('ATR', 'Gene', (66, 69))	('TC71', 'CellLine', 'CVCL:2213', (92, 96))	('synergy', 'MPA', (20, 27))
584691	31649026	Finally, the combination of AZD1775 and AZD6738 activated CDK1/2 in the A673 and EW8, but not BJ-tert, cells (Figure 4L).	('CDK1/2', 'Gene', '51755;983;1017', (58, 64))	('AZD1775', 'Var', (28, 35))	('activated', 'PosReg', (48, 57))	('AZD1775', 'Chemical', 'MESH:C549567', (28, 35))	('AZD6738', 'Chemical', 'MESH:C000611951', (40, 47))	('AZD6738', 'Var', (40, 47))	('CDK1/2', 'Gene', (58, 64))
584692	31649026	In a previous publication, and Supplementary Figure 6A, we showed that knockdown or inhibition of RRM2 caused apoptosis in Ewing sarcoma cells.	('inhibition', 'NegReg', (84, 94))	('Ewing sarcoma', 'Disease', (123, 136))	('knockdown', 'Var', (71, 80))	('RRM2', 'Gene', (98, 102))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (123, 136))	('apoptosis', 'CPA', (110, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('RRM2', 'Gene', '6241', (98, 102))
584697	31649026	Next, we treated Ewing sarcoma cells with AZD1775 in combination with the CDK1/2 inhibitor RO-3306.	('RO-3306', 'Chemical', 'MESH:C512984', (91, 98))	('AZD1775', 'Var', (42, 49))	('Ewing sarcoma', 'Disease', (17, 30))	('AZD1775', 'Chemical', 'MESH:C549567', (42, 49))	('CDK1/2', 'Gene', (74, 80))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (17, 30))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (17, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('CDK1/2', 'Gene', '51755;983;1017', (74, 80))
584700	31649026	Figure 5E shows that MG132 increased the levels of RRM2 in EW8 and TC71 cells after knockdown of WEE1.	('RRM2', 'Gene', (51, 55))	('WEE1', 'Gene', '7465', (97, 101))	('increased', 'PosReg', (27, 36))	('RRM2', 'Gene', '6241', (51, 55))	('MG132', 'Chemical', 'MESH:C072553', (21, 26))	('WEE1', 'Gene', (97, 101))	('knockdown', 'Var', (84, 93))	('MG132', 'Var', (21, 26))	('TC71', 'CellLine', 'CVCL:2213', (67, 71))	('levels', 'MPA', (41, 47))
584703	31649026	Next, we expressed a doxycycline-inducible FLAG-RRM2 transgene (TO-FLAG-RRM2-T33A) with a T33A mutation, which was previously shown to be resistant to the ubiquitin-mediated-proteolysis caused by inhibition of WEE1, in a Ewing sarcoma cell line.	('WEE1', 'Gene', (210, 214))	('T33A', 'Mutation', 'c.33T>A', (77, 81))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (221, 234))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (221, 234))	('RRM2', 'Gene', (48, 52))	('WEE1', 'Gene', '7465', (210, 214))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('RRM2', 'Gene', '6241', (48, 52))	('RRM2', 'Gene', '6241', (72, 76))	('RRM2', 'Gene', (72, 76))	('T33A', 'Mutation', 'c.33T>A', (90, 94))	('T33A mutation', 'Var', (90, 103))	('Ewing sarcoma', 'Disease', (221, 234))	('doxycycline', 'Chemical', 'MESH:D004318', (21, 32))
584704	31649026	Figure 5G shows that FLAG-RRM2-T33A, compared to the endogenous RRM2 protein, is resistant to the degradation caused by knockdown of WEE1.	('WEE1', 'Gene', '7465', (133, 137))	('knockdown', 'Var', (120, 129))	('T33A', 'Mutation', 'c.33T>A', (31, 35))	('WEE1', 'Gene', (133, 137))	('RRM2', 'Gene', '6241', (64, 68))	('RRM2', 'Gene', (64, 68))	('degradation', 'MPA', (98, 109))	('RRM2', 'Gene', (26, 30))	('RRM2', 'Gene', '6241', (26, 30))
584708	31649026	Consequently, in order to identify the functional consequences of activation of CDK1 or CDK2, we generated constitutively active mutants of CDK1 and CDK2 which substitute alanine for threonine at position 14 and phenylalanine for tyrosine at position 15.	('CDK2', 'Gene', '1017', (149, 153))	('CDK2', 'Gene', '1017', (88, 92))	('substitute', 'Var', (160, 170))	('alanine for threonine at position 14', 'Mutation', 'rs1428790346', (171, 207))	('CDK2', 'Gene', (149, 153))	('CDK1', 'Gene', (140, 144))	('alanine', 'MPA', (171, 178))	('mutants', 'Var', (129, 136))	('CDK2', 'Gene', (88, 92))	('phenylalanine for tyrosine at position 15', 'Mutation', 'p.Y15F', (212, 253))
584716	31649026	recently showed that depletion of EWSR1 increased the formation of R-loops, which are DNA-RNA hybrids that impair the progression of the DNA replication machinery, and activated ATR in Ewing sarcoma tumors.	('EWSR1', 'Gene', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('EWSR1', 'Gene', '2130', (34, 39))	('Ewing sarcoma tumors', 'Disease', (185, 205))	('impair', 'NegReg', (107, 113))	('ATR', 'Gene', (178, 181))	('ATR', 'Gene', '545', (178, 181))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (185, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('depletion', 'Var', (21, 30))	('increased', 'PosReg', (40, 49))	('activated', 'PosReg', (168, 177))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (185, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('formation', 'MPA', (54, 63))	('progression', 'MPA', (118, 129))
584717	31649026	In other work, depletion of EWSR1 was also reported to impact the splicing of genes involved in DNA repair and genotoxic stress signaling, which suggests the role of EWSR1 in replication stress may be multifactorial.	('depletion', 'Var', (15, 24))	('EWSR1', 'Gene', (166, 171))	('stress', 'Disease', (121, 127))	('stress', 'Disease', 'MESH:D000079225', (121, 127))	('stress', 'Disease', 'MESH:D000079225', (187, 193))	('EWSR1', 'Gene', '2130', (28, 33))	('genotoxic stress', 'Disease', (111, 127))	('EWSR1', 'Gene', '2130', (166, 171))	('stress', 'Disease', (187, 193))	('genotoxic stress', 'Disease', 'MESH:D000079225', (111, 127))	('DNA repair', 'MPA', (96, 106))	('impact', 'Reg', (55, 61))	('splicing of genes involved', 'MPA', (66, 92))	('EWSR1', 'Gene', (28, 33))
584718	31649026	Similarly, the EWS-FLI oncogene is reported to regulate multiple aspects of the cellular response to genotoxic stress, as reviewed by Ghosal et al.. For example, SLFN11 is a direct transcriptional target of EWS-FLI1 and overexpression of SLFN11 sensitizes cancer cells to a wide range of DNA-targeted therapies by blocking replication fork progression.	('FLI', 'Gene', '2314', (19, 22))	('replication fork', 'CPA', (323, 339))	('overexpression', 'Var', (220, 234))	('SLFN11', 'Gene', (162, 168))	('cancer', 'Disease', (256, 262))	('EWS', 'Gene', '2130', (15, 18))	('blocking', 'NegReg', (314, 322))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('sensitizes', 'Reg', (245, 255))	('SLFN11', 'Gene', (238, 244))	('EWS', 'Gene', (207, 210))	('FLI1', 'Gene', (211, 215))	('SLFN11', 'Gene', '91607', (162, 168))	('FLI', 'Gene', (211, 214))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('EWS', 'Gene', (15, 18))	('genotoxic stress', 'Disease', 'MESH:D000079225', (101, 117))	('SLFN11', 'Gene', '91607', (238, 244))	('genotoxic stress', 'Disease', (101, 117))	('FLI1', 'Gene', '2313', (211, 215))	('FLI', 'Gene', '2314', (211, 214))	('FLI', 'Gene', (19, 22))	('EWS', 'Gene', '2130', (207, 210))
584720	31649026	Furthermore, germline sequencing of patients with Ewing sarcoma tumors has identified a significant enrichment for mutations in genes involved in DNA damage repair.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (115, 124))	('patients', 'Species', '9606', (36, 44))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (50, 63))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (50, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('Ewing sarcoma tumors', 'Disease', (50, 70))
584722	31649026	Similarly, a number of different mechanisms have been reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single agents and in combination with other drugs, toward cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('CHK1', 'Gene', (95, 99))	('ATR', 'Gene', (91, 94))	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('toxicity', 'Disease', (79, 87))	('CHK1', 'Gene', '1111', (95, 99))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('inhibitors', 'Var', (100, 110))	('ATR', 'Gene', '545', (91, 94))
584724	31649026	In this work, we identified that inhibition of the ATR-CHK1 and WEE1 pathways in Ewing sarcoma cells causes activation of CDK1 and CDK2.	('inhibition', 'Var', (33, 43))	('CDK2', 'Gene', '1017', (131, 135))	('Ewing sarcoma', 'Disease', (81, 94))	('CDK1', 'Protein', (122, 126))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('WEE1', 'Gene', (64, 68))	('CHK1', 'Gene', (55, 59))	('WEE1', 'Gene', '7465', (64, 68))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('CDK2', 'Gene', (131, 135))	('ATR', 'Gene', '545', (51, 54))	('ATR', 'Gene', (51, 54))	('CHK1', 'Gene', '1111', (55, 59))	('activation', 'PosReg', (108, 118))
584725	31649026	In addition, inhibition or siRNA-mediated knockdown of CDK1/2 reduced DNA damage and apoptosis.	('CDK1/2', 'Gene', (55, 61))	('CDK1/2', 'Gene', '51755;983;1017', (55, 61))	('apoptosis', 'CPA', (85, 94))	('reduced', 'NegReg', (62, 69))	('DNA', 'CPA', (70, 73))	('knockdown', 'Var', (42, 51))
584726	31649026	Furthermore, using expression of constitutively active CDK1 and CDK2 mutants, we also identified that the aberrant activation of CDK2 leads to the degradation of RRM2 and, thereby, generates a feedback loop which exacerbates DNA replication stress, increases DNA damage, and induces apoptosis (Figure 6).	('activation', 'PosReg', (115, 125))	('DNA damage', 'MPA', (259, 269))	('CDK2', 'Gene', '1017', (64, 68))	('stress', 'Disease', 'MESH:D000079225', (241, 247))	('CDK2', 'Gene', '1017', (129, 133))	('apoptosis', 'CPA', (283, 292))	('aberrant', 'Var', (106, 114))	('stress', 'Disease', (241, 247))	('RRM2', 'Gene', '6241', (162, 166))	('RRM2', 'Gene', (162, 166))	('induces', 'Reg', (275, 282))	('increases', 'PosReg', (249, 258))	('CDK2', 'Gene', (129, 133))	('exacerbates', 'PosReg', (213, 224))	('CDK2', 'Gene', (64, 68))	('degradation', 'MPA', (147, 158))
584727	31649026	However, although overexpression of constitutively active CDK1 did not deplete RRM2 or induce DNA damage in Ewing sarcoma cells, we did note that knockdown of CDK1 with siRNA modestly reduced DNA damage in the setting of replication stress (Figure 2G) and, therefore, we cannot fully rule out a contribution from CDK1 in mediating the effects of inhibition of the ATR-CHK1 pathway.	('knockdown', 'Var', (146, 155))	('stress', 'Disease', (233, 239))	('RRM2', 'Gene', '6241', (79, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('RRM2', 'Gene', (79, 83))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('CHK1', 'Gene', '1111', (368, 372))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('reduced', 'NegReg', (184, 191))	('CHK1', 'Gene', (368, 372))	('ATR', 'Gene', (364, 367))	('DNA damage', 'MPA', (192, 202))	('ATR', 'Gene', '545', (364, 367))	('Ewing sarcoma', 'Disease', (108, 121))	('CDK1', 'Gene', (159, 163))	('stress', 'Disease', 'MESH:D000079225', (233, 239))
584729	31649026	However, there is significant functional overlap between these two kinases and the aberrant activation of both CDK1 and CDK2 have been reported to cause DNA damage and toxicity.	('CDK2', 'Gene', (120, 124))	('DNA damage', 'MPA', (153, 163))	('activation', 'PosReg', (92, 102))	('toxicity', 'Disease', 'MESH:D064420', (168, 176))	('cause', 'Reg', (147, 152))	('aberrant', 'Var', (83, 91))	('toxicity', 'Disease', (168, 176))	('CDK2', 'Gene', '1017', (120, 124))	('CDK1', 'Gene', (111, 115))
584732	31649026	Additional reports have also shown that CHK1 inhibitors, as single agents or in combination with gemcitabine, cause CDK2-dependent toxicity.	('CDK2', 'Gene', (116, 120))	('CHK1', 'Gene', '1111', (40, 44))	('CDK2', 'Gene', '1017', (116, 120))	('inhibitors', 'Var', (45, 55))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('toxicity', 'Disease', 'MESH:D064420', (131, 139))	('cause', 'Reg', (110, 115))	('toxicity', 'Disease', (131, 139))	('CHK1', 'Gene', (40, 44))
584737	31649026	RNR catalyzes the rate-limiting step in the synthesis of deoxyribonucleotides from ribonucleotides and inhibition of RRM2, or the RRM1 subunit of RNR, depletes nucleotides and causes DNA replication stress and DNA damage.	('deoxyribonucleotides', 'Chemical', 'MESH:D003854', (57, 77))	('stress', 'Disease', (199, 205))	('RRM1', 'Gene', (130, 134))	('ribonucleotides', 'Chemical', 'MESH:D012265', (62, 77))	('stress', 'Disease', 'MESH:D000079225', (199, 205))	('RRM2', 'Gene', '6241', (117, 121))	('RRM2', 'Gene', (117, 121))	('causes', 'Reg', (176, 182))	('inhibition', 'Var', (103, 113))	('nucleotides', 'MPA', (160, 171))	('depletes', 'NegReg', (151, 159))	('RRM1', 'Gene', '6240', (130, 134))	('DNA damage', 'MPA', (210, 220))	('DNA', 'MPA', (183, 186))	('ribonucleotides', 'Chemical', 'MESH:D012265', (83, 98))
584740	31649026	Notably, inhibition or knockdown of RRM2 causes DNA replication stress, DNA damage, and apoptosis in Ewing sarcoma tumors.	('stress', 'Disease', (64, 70))	('apoptosis', 'CPA', (88, 97))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (101, 121))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('knockdown', 'Var', (23, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('RRM2', 'Gene', '6241', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('RRM2', 'Gene', (36, 40))	('Ewing sarcoma tumors', 'Disease', (101, 121))	('stress', 'Disease', 'MESH:D000079225', (64, 70))	('inhibition', 'Var', (9, 19))	('DNA damage', 'MPA', (72, 82))
584741	31649026	Consequently, inhibition of the ATR-CHK1 pathway, or the WEE1 kinase, in Ewing sarcoma cells experiencing replication stress generates a feedback loop that depletes RRM2, exacerbates replication stress, and increases DNA damage.	('CHK1', 'Gene', '1111', (36, 40))	('WEE1', 'Gene', '7465', (57, 61))	('stress', 'Disease', (118, 124))	('DNA damage', 'MPA', (217, 227))	('exacerbates', 'PosReg', (171, 182))	('RRM2', 'Gene', '6241', (165, 169))	('stress', 'Disease', (195, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('Ewing sarcoma', 'Disease', (73, 86))	('ATR', 'Gene', '545', (32, 35))	('RRM2', 'Gene', (165, 169))	('ATR', 'Gene', (32, 35))	('WEE1', 'Gene', (57, 61))	('increases', 'PosReg', (207, 216))	('CHK1', 'Gene', (36, 40))	('depletes', 'NegReg', (156, 164))	('stress', 'Disease', 'MESH:D000079225', (118, 124))	('stress', 'Disease', 'MESH:D000079225', (195, 201))	('inhibition', 'Var', (14, 24))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (73, 86))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (73, 86))
584744	31649026	For example, the WEE1 inhibitor AZD1775 was able to activate CDK1/2 in both Ewing and non-Ewing sarcoma lines (Figure 5A-B).	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (90, 103))	('AZD1775', 'Var', (32, 39))	('activate', 'PosReg', (52, 60))	('WEE1', 'Gene', '7465', (17, 21))	('CDK1/2', 'Gene', (61, 67))	('WEE1', 'Gene', (17, 21))	('CDK1/2', 'Gene', '51755;983;1017', (61, 67))	('AZD1775', 'Chemical', 'MESH:C549567', (32, 39))	('Ewing and non-Ewing sarcoma', 'Disease', 'MESH:C563168', (76, 103))
584745	31649026	In contrast, inhibition of CHK1 activated CDK1/2 in the Ewing sarcoma cell lines, but not the control cell lines that we tested (Figure 2A and Supplementary Figure 2A).	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('CDK1/2', 'Gene', '51755;983;1017', (42, 48))	('activated', 'PosReg', (32, 41))	('CHK1', 'Gene', (27, 31))	('inhibition', 'Var', (13, 23))	('Ewing sarcoma', 'Disease', (56, 69))	('CHK1', 'Gene', '1111', (27, 31))	('CDK1/2', 'Gene', (42, 48))
584749	31649026	In addition, WEE1 inhibitors block the phosphorylation of both cyclin-bound and cyclin-unbound CDK2.	('phosphorylation', 'MPA', (39, 54))	('CDK2', 'Gene', (95, 99))	('cyclin-bound', 'Protein', (63, 75))	('CDK2', 'Gene', '1017', (95, 99))	('block', 'NegReg', (29, 34))	('WEE1', 'Gene', (13, 17))	('WEE1', 'Gene', '7465', (13, 17))	('inhibitors', 'Var', (18, 28))
584754	31649026	In other tumor types, inhibition of CHK1 has also been reported to activate CDK2, but it is unclear whether this also results in depletion of RRM2 and exacerbation of DNA replication stress as the downstream impact of active CDK2 appears variable between tumor types.	('CDK2', 'Gene', '1017', (76, 80))	('CHK1', 'Gene', '1111', (36, 40))	('CDK2', 'Gene', '1017', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('depletion', 'MPA', (129, 138))	('RRM2', 'Gene', '6241', (142, 146))	('CDK2', 'Gene', (76, 80))	('CDK2', 'Gene', (225, 229))	('RRM2', 'Gene', (142, 146))	('tumor', 'Disease', (9, 14))	('activate', 'PosReg', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (255, 260))	('stress', 'Disease', 'MESH:D000079225', (183, 189))	('CHK1', 'Gene', (36, 40))	('exacerbation', 'PosReg', (151, 163))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('inhibition', 'Var', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('stress', 'Disease', (183, 189))
584770	24216705	The first is characterized by a single recurrent genetic aberration, such as somatic mutations of the v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) proto-oncogene in gastrointestinal stromal tumors or chromosomal translocations causing fusion genes.	('sarcoma viral', 'Disease', (133, 146))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (188, 219))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (188, 219))	('fusion', 'Var', (258, 264))	('rat', 'Species', '10116', (61, 64))	('mutations', 'Var', (85, 94))	('sarcoma viral', 'Disease', 'MESH:D001102', (133, 146))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('gastrointestinal stromal tumors', 'Disease', (188, 219))	('KIT', 'Gene', (165, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('chromosomal translocations', 'Var', (223, 249))
584772	24216705	Many of the sarcomas characterised by tumor-specific chromosomal translocations tend to occur in younger patients.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('patients', 'Species', '9606', (105, 113))	('sarcomas', 'Disease', 'MESH:D012509', (12, 20))	('chromosomal translocations', 'Var', (53, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (12, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('sarcomas', 'Disease', (12, 20))
584779	24216705	In that system, category one sarcomas, consist of non-pleomorphic tumors with pathogenomic molecular events, e.g., gastrointestinal stromal tumors, KIT or platelet-derived growth factor receptor, alpha polypeptide (PDGFRA) mutations; dermatofibrosarcoma protuberans, t(17;22)(q22;q13), ring chromosomal alterations, involved genes COL1A1-PDGFRB; and Ewing's sarcoma, chromosomal translocation t(11:22; q24; q12), in 85% of cases, involved genes FLI1-EWS.	("Ewing's sarcoma", 'Disease', (350, 365))	('gastrointestinal stromal tumors', 'Disease', (115, 146))	('non-pleomorphic tumors', 'Disease', (50, 72))	('involved', 'Reg', (430, 438))	('sarcoma', 'Phenotype', 'HP:0100242', (358, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('FLI1', 'Gene', '2313', (445, 449))	('dermatofibrosarcoma protuberans', 'Disease', (234, 265))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (267, 284))	('EWS', 'Gene', '2130', (450, 453))	('mutations', 'Var', (223, 232))	('platelet-derived growth factor receptor, alpha polypeptide', 'Gene', '5156', (155, 213))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('PDGFRB', 'Gene', '5159', (338, 344))	('sarcomas', 'Disease', 'MESH:D012509', (29, 37))	('COL1A1', 'Gene', '1277', (331, 337))	('PDGFRB', 'Gene', (338, 344))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('sarcomas', 'Disease', (29, 37))	('rat', 'Species', '10116', (307, 310))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (234, 265))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (350, 365))	('COL1A1', 'Gene', (331, 337))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (115, 146))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (115, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (350, 365))	('EWS', 'Gene', (450, 453))	('non-pleomorphic tumors', 'Disease', 'MESH:C538229', (50, 72))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FLI1', 'Gene', (445, 449))	('PDGFRA', 'Gene', '5156', (215, 221))	('PDGFRA', 'Gene', (215, 221))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (241, 253))
584782	24216705	They have consistent molecular events, e.g., dedifferentiated liposarcoma, cyclin dependent kinase 4/mouse double minute 2 homolog (CDK4/MDM2) amplification; MPNST, deletion of NF1; myxo-inflammatory fibroblastic sarcoma, t(1;10) and 3p amplification.	('sarcoma', 'Disease', (66, 73))	('NF1', 'Gene', (177, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('mouse', 'Species', '10090', (101, 106))	('NF1', 'Gene', '18015', (177, 180))	('liposarcoma', 'Disease', (62, 73))	('amplification; MPNST', 'Var', (143, 163))	('deletion', 'Var', (165, 173))	('sarcoma', 'Disease', 'MESH:D012509', (213, 220))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('MPNST', 'Var', (158, 163))	('liposarcoma', 'Disease', 'MESH:D008080', (62, 73))	('sarcoma', 'Disease', (213, 220))
584868	24216705	Further diminishment in the rate of MFH diagnosis would be anticipated with gene profiling and recently array-comparative genomic hybridization (a-CGH) detecting microdeletions and duplications of DNA sequences.	('microdeletions', 'Var', (162, 176))	('rat', 'Species', '10116', (115, 118))	('duplications', 'Var', (181, 193))	('DNA', 'Gene', (197, 200))	('rat', 'Species', '10116', (28, 31))
584872	24216705	Minimum criteria have been proposed for defining ex-vivo mesenchymal stem cells in culture: (i) The cells must express CD73, CD 105 and CD90 and lack expression of CD34, CD45, CD11b, CD14, CD19, CD79b and HLA-DR; (ii) the cells when maintained in standard culture conditions must be plastic adherent; (iii) they should have the capacity to differentiate into osteoblasts, adipocytes and chondroblasts.	('CD73', 'Gene', (119, 123))	('CD11b', 'Gene', (176, 181))	('CD45', 'Gene', (170, 174))	('CD11b', 'Gene', '3684', (176, 181))	('CD45', 'Gene', '5788', (170, 174))	('chondroblasts', 'CPA', (387, 400))	('osteoblasts', 'CPA', (359, 370))	('adipocytes', 'CPA', (372, 382))	('CD34', 'Gene', '947', (164, 168))	('CD79b', 'Gene', '974', (195, 200))	('CD14', 'Gene', (183, 187))	('CD19', 'Gene', (189, 193))	('CD 105', 'Var', (125, 131))	('CD14', 'Gene', '929', (183, 187))	('CD90', 'Gene', (136, 140))	('CD79b', 'Gene', (195, 200))	('CD34', 'Gene', (164, 168))	('CD90', 'Gene', '7070', (136, 140))	('CD73', 'Gene', '4907', (119, 123))	('CD19', 'Gene', '930', (189, 193))
584878	24216705	However, in models of carcinomas activating mutations in WNT pathway components are observed such as loss of APC function or oncogenic mutations in beta-catenin in the majority of cases of sporadic colorectal cancer.	('WNT', 'Gene', (57, 60))	('colorectal cancer', 'Disease', (198, 215))	('loss of APC function', 'Disease', 'MESH:D011125', (101, 121))	('loss of APC function', 'Disease', (101, 121))	('beta-catenin', 'Gene', (148, 160))	('mutations', 'Var', (135, 144))	('WNT', 'Gene', '114487', (57, 60))	('beta-catenin', 'Gene', '1499', (148, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (198, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('carcinomas', 'Disease', (22, 32))	('mutations', 'Var', (44, 53))	('activating', 'PosReg', (33, 43))	('carcinomas', 'Disease', 'MESH:D002277', (22, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
584882	24216705	It was also shown that inhibition of Wnt signalling can transform human mesenchymal stem cells to form UPS like tumors in nude mice and that when Wnt signalling is appropriately re-established in UPS cells they can differentiate along mature connective tissue lineages.	('Wnt', 'Gene', (146, 149))	('Wnt', 'Gene', '114487', (146, 149))	('Wnt', 'Gene', (37, 40))	('inhibition', 'Var', (23, 33))	('human', 'Species', '9606', (66, 71))	('nude mice', 'Species', '10090', (122, 131))	('differentiate', 'CPA', (215, 228))	('Wnt', 'Gene', '114487', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('transform', 'Reg', (56, 65))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
584902	24216705	Detection of amplification of MDM2 and/or CDK4 is potentially informative with respect to this sarcoma type.	('sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('MDM2', 'Gene', (30, 34))	('amplification', 'Var', (13, 26))	('sarcoma', 'Disease', (95, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('CDK4', 'Gene', (42, 46))	('informative', 'Reg', (62, 73))
584904	24216705	A gene-set from the LSL-KrasG12D; p53Flox/Flox murine model of soft tissue sarcoma was found to be highly enriched in undifferentiated pleomorphic sarcoma.	('soft tissue sarcoma', 'Disease', (63, 82))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (118, 154))	('murine', 'Species', '10090', (47, 53))	('undifferentiated pleomorphic sarcoma', 'Disease', (118, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('p53Flox/Flox', 'Var', (34, 46))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (63, 82))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (63, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
584908	24216705	Fifteen percent of cutaneous melanoma have mutations of RAS.	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('cutaneous melanoma', 'Disease', (19, 37))	('mutations', 'Var', (43, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (19, 37))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (19, 37))	('RAS', 'Gene', (56, 59))
584909	24216705	NRAS mutant melanoma is mutually exclusive of BRAF mutant melanoma.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('NRAS mutant', 'Var', (0, 11))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('mutant', 'Var', (5, 11))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
584910	24216705	In 2012 an inducible mouse model of NRAS mutant melanoma and network modelling established the in-vivo therapeutic syngeristic efficacy of targeted inhibition of CDK4 and MEK to decrease melanoma survival and proliferation.	('proliferation', 'CPA', (209, 222))	('melanoma', 'Disease', (48, 56))	('MEK', 'Gene', (171, 174))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('inhibition', 'NegReg', (148, 158))	('melanoma', 'Disease', (187, 195))	('NRAS', 'Gene', (36, 40))	('mutant', 'Var', (41, 47))	('mouse', 'Species', '10090', (21, 26))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('decrease', 'NegReg', (178, 186))	('MEK', 'Gene', '17242', (171, 174))	('rat', 'Species', '10116', (216, 219))	('CDK4', 'Gene', (162, 166))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
584911	24216705	Perhaps, the methodologies used in this preclinical study of NRAS mutant melanoma may be used to evalute a strategy of vicarious RAS targeting to treat sarcomas with elevated Foxm1.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutant', 'Var', (66, 72))	('sarcomas', 'Disease', 'MESH:D012509', (152, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('rat', 'Species', '10116', (109, 112))	('sarcomas', 'Disease', (152, 160))	('NRAS', 'Gene', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
584920	24216705	As the gene set from the LSL-KrasG12D; p53Flox/Flox murine model was highly enriched for undifferentiated pleomorphic sarcoma, it may arise that this inference is particular pertinent for undifferentiated pleomorphic sarcomas.	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (188, 224))	('sarcomas', 'Phenotype', 'HP:0100242', (217, 225))	('p53Flox/Flox', 'Var', (39, 51))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (188, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('undifferentiated pleomorphic sarcomas', 'Disease', (188, 225))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (89, 125))	('undifferentiated pleomorphic sarcoma', 'Disease', (89, 125))	('murine', 'Species', '10090', (52, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))
584933	32451657	Delaying or stopping these treatments is life-threatening or can cause severe morbidity, pain, and loss of function.	('pain', 'Disease', 'MESH:D010146', (89, 93))	('Delaying', 'Var', (0, 8))	('pain', 'Disease', (89, 93))	('pain', 'Phenotype', 'HP:0012531', (89, 93))
584969	32451657	Already, scattered reported COVID-19 pandemic cutbacks on healthcare have caused a 25% reduction in major organ transplantations in Italy in four weeks due to the limited number of intensive care units.	('major organ transplantations', 'CPA', (100, 128))	('pandemic', 'Var', (37, 45))	('COVID-19', 'Disease', 'MESH:C000657245', (28, 36))	('cutbacks', 'Var', (46, 54))	('reduction', 'NegReg', (87, 96))	('COVID-19', 'Disease', (28, 36))
585005	30898143	Furthermore, whole-genome sequencing reveals the tremendous role BAF complex mutations have in both neurodevelopmental disorders and human malignancies.	('neurodevelopmental disorders', 'Phenotype', 'HP:0012759', (100, 128))	('BAF', 'Gene', '8815', (65, 68))	('malignancies', 'Disease', (139, 151))	('neurodevelopmental disorders', 'Disease', 'MESH:D002658', (100, 128))	('BAF', 'Gene', (65, 68))	('neurodevelopmental disorders', 'Disease', (100, 128))	('mutations', 'Var', (77, 86))	('human', 'Species', '9606', (133, 138))	('malignancies', 'Disease', 'MESH:D009369', (139, 151))	('neurodevelopmental disorder', 'Phenotype', 'HP:0012759', (100, 127))
585014	30898143	This complex was first discovered in screens to uncover genes that are able to suppress phenotypes caused by mutations in Polycomb genes.	('Polycomb', 'Gene', '40358', (122, 130))	('Polycomb', 'Gene', (122, 130))	('mutations', 'Var', (109, 118))
585048	30898143	Moreover, it is distinguishable by the incorporation of Baf250a not 250b, Baf60a/b not 60c and a Baf155::155 homodimer instead of a Baf155::170 heterodimer in murine ESC.	('murine', 'Species', '10090', (159, 165))	('Baf250a not 250b', 'Var', (56, 72))	('Baf60a', 'Gene', (74, 80))	('Baf60a', 'Gene', '83797', (74, 80))
585051	30898143	Unfortunately, loss of Brg1, Baf155 or Baf47 is lethal to these animals at a very early embryonic stage.	('Baf47', 'Gene', (39, 44))	('Baf155', 'Gene', (29, 35))	('Brg1', 'Gene', (23, 27))	('Baf47', 'Gene', '6598', (39, 44))	('loss', 'Var', (15, 19))
585052	30898143	Both Brg1 and BAF155 knockouts are peri-implantationally lethal and Baf47-depleted embryos do not survive beyond day 7.5.	('Brg1', 'Gene', (5, 9))	('BAF155', 'Gene', '6599', (14, 20))	('Baf47', 'Gene', (68, 73))	('Baf47', 'Gene', '6598', (68, 73))	('knockouts', 'Var', (21, 30))	('BAF155', 'Gene', (14, 20))
585064	30898143	Changes in gene transcription upon Brg1 knockout resemble those being caused by LIF withdrawal.	('knockout', 'Var', (40, 48))	('gene transcription', 'MPA', (11, 29))	('LIF', 'Gene', (80, 83))	('LIF', 'Gene', '3976', (80, 83))	('Changes', 'Reg', (0, 7))	('Brg1', 'Gene', (35, 39))
585080	30898143	Furthermore, Brg1 depletion in Nestin+-NSCs results in severe defects of proliferation and formation of the neural progenitor pool, causing thinning of the cortex and midbrain as well as a deficiency in cerebellar development, leading to perinatal death of the animals.	('formation', 'CPA', (91, 100))	('deficiency', 'Disease', (189, 199))	('thinning', 'CPA', (140, 148))	('proliferation', 'CPA', (73, 86))	('Brg1', 'Gene', (13, 17))	('deficiency', 'Disease', 'MESH:D007153', (189, 199))	('depletion', 'Var', (18, 27))	('leading to', 'Reg', (227, 237))	('cerebellar development', 'CPA', (203, 225))	('defects', 'NegReg', (62, 69))	('thinning of the cortex', 'Phenotype', 'HP:0002753', (140, 162))
585082	30898143	Whereas ES cells are still able to proliferate, when being depleted of SS18 until only 20% of wild-type levels are left, NSCs are much more sensitive to SS18 knockdown, losing their ability to self-renew after a reduction of 25% compared to wild-type levels.	('SS18', 'Gene', '6760', (71, 75))	('SS18', 'Gene', (153, 157))	('losing', 'NegReg', (169, 175))	('SS18', 'Gene', (71, 75))	('ability', 'MPA', (182, 189))	('knockdown', 'Var', (158, 167))	('SS18', 'Gene', '6760', (153, 157))	('self-renew', 'CPA', (193, 203))
585085	30898143	miRNA9* and miRNA124 are both specifically expressed in neural cells, and their expression is repressed by REST (repressor element-1-silencing transcription factor) in neural progenitors.	('miRNA124', 'Var', (12, 20))	('miRNA9*', 'Var', (0, 7))	('repressor element-1-silencing transcription factor', 'Gene', (113, 163))	('repressor element-1-silencing transcription factor', 'Gene', '5978', (113, 163))
585087	30898143	In this way, miRNA9* and miRNA124 can target BAF53a, which leads to its degradation and loss from the npBAF complex.	('BAF', 'Gene', '8815', (45, 48))	('BAF', 'Gene', '8815', (104, 107))	('BAF', 'Gene', (45, 48))	('BAF53a', 'Gene', (45, 51))	('loss', 'NegReg', (88, 92))	('miRNA124', 'Var', (25, 33))	('BAF', 'Gene', (104, 107))	('miRNA9*', 'Var', (13, 20))	('BAF53a', 'Gene', '86', (45, 51))	('degradation', 'MPA', (72, 83))
585102	30898143	Nonetheless, loss of subunits not needed for in vitro function, such as Baf53a or Baf250a, causes severely altered phenotypes resembling those of Brg1 loss, while there are many amongst the most frequently mutated subunits in cancer that are not necessary for in vitro function.	('phenotypes', 'MPA', (115, 125))	('Baf250a', 'Var', (82, 89))	('altered', 'Reg', (107, 114))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('loss', 'NegReg', (13, 17))	('Baf53a', 'Gene', (72, 78))	('loss', 'NegReg', (151, 155))	('Baf53a', 'Gene', '86', (72, 78))	('Brg1', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
585115	30898143	Its disruption can be responsible for tumour formation (see below).	('responsible', 'Reg', (22, 33))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('disruption', 'Var', (4, 14))	('tumour', 'Disease', (38, 44))
585117	30898143	The phenotype caused by Brg1 deletion can be rescued by knockdown of Suz12, indicating the important role the loss of Polycomb opposition has for the changes of chromatin accessibility.	('Suz12', 'Gene', '23512', (69, 74))	('deletion', 'Var', (29, 37))	('Polycomb', 'Gene', '40358', (118, 126))	('Polycomb', 'Gene', (118, 126))	('Brg1', 'Gene', (24, 28))	('Suz12', 'Gene', (69, 74))
585122	30898143	The corollary is also true, in that BAF removal is rapidly followed by Ezh2 (PRC2) and H3K27me3 reappearance.	('Ezh2', 'Gene', (71, 75))	('Ezh2', 'Gene', '2146', (71, 75))	('BAF', 'Gene', '8815', (36, 39))	('BAF', 'Gene', (36, 39))	('H3K27me3', 'Var', (87, 95))
585124	30898143	Loss of Brg1 causes weakening of the interaction and increases occupancy of PRC1 and PRC2.	('Brg1', 'Gene', (8, 12))	('PRC2', 'Gene', (85, 89))	('PRC1', 'Gene', (76, 80))	('occupancy', 'MPA', (63, 72))	('PRC1', 'Gene', '9055', (76, 80))	('increases', 'PosReg', (53, 62))	('weakening', 'NegReg', (20, 29))	('Loss', 'Var', (0, 4))	('interaction', 'Interaction', (37, 48))
585125	30898143	Furthermore, the opposition of Polycomb complexes is ATP dependent, illustrated by the fact that mutations in the ATPase domain cause the same epigenetic changes as a complete loss.	('mutations in', 'Var', (97, 109))	('ATPase', 'Gene', '1769', (114, 120))	('epigenetic changes', 'MPA', (143, 161))	('ATP', 'Chemical', 'MESH:D000255', (114, 117))	('ATPase', 'Gene', (114, 120))	('Polycomb', 'Gene', '40358', (31, 39))	('Polycomb', 'Gene', (31, 39))	('ATP', 'Chemical', 'MESH:D000255', (53, 56))
585128	30898143	With regard to the importance of the BAF complex and distinct subunit switches in neural development, it is not surprising that mutations in BAF-coding genes are associated with neurodevelopmental disorders such as Coffin-Siris syndrome, Nicolaides-Baraitser syndrome or autism spectrum disorders.	('neurodevelopmental disorders', 'Disease', (178, 206))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (215, 236))	('BAF', 'Gene', '8815', (141, 144))	('neurodevelopmental disorders', 'Disease', 'MESH:D002658', (178, 206))	('autism spectrum disorders', 'Disease', (271, 296))	('mutations', 'Var', (128, 137))	('BAF', 'Gene', (141, 144))	('associated', 'Reg', (162, 172))	('autism spectrum disorders', 'Disease', 'MESH:D000067877', (271, 296))	('BAF', 'Gene', '8815', (37, 40))	('autism', 'Phenotype', 'HP:0000717', (271, 277))	('Coffin-Siris syndrome', 'Disease', (215, 236))	('Nicolaides-Baraitser syndrome', 'Disease', (238, 267))	('neurodevelopmental disorder', 'Phenotype', 'HP:0012759', (178, 205))	('neurodevelopmental disorders', 'Phenotype', 'HP:0012759', (178, 206))	('BAF', 'Gene', (37, 40))	('autism spectrum disorders', 'Phenotype', 'HP:0000729', (271, 296))
585129	30898143	One of the syndromes commonly caused by mutations in BAF subunits is the Coffin-Siris syndrome (CSS), first described in 1970 as a combination of intellectual disability, growth retardation, joint malformations and brachydactyly combined with hypoplastic or missing fingernails at the fifth finger/toe.	('joint malformations', 'Disease', 'MESH:D000014', (191, 210))	('growth retardation', 'Disease', 'MESH:D006130', (171, 189))	('brachydactyly', 'Disease', (215, 228))	('joint malformations', 'Phenotype', 'HP:0001367', (191, 210))	('growth retardation', 'Disease', (171, 189))	('Coffin-Siris syndrome', 'Disease', (73, 94))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (73, 94))	('joint malformations', 'Disease', (191, 210))	('missing fingernails', 'Phenotype', 'HP:0001817', (258, 277))	('intellectual disability', 'Phenotype', 'HP:0001249', (146, 169))	('mutations', 'Var', (40, 49))	('BAF', 'Gene', (53, 56))	('brachydactyly', 'Phenotype', 'HP:0001156', (215, 228))	('fifth finger', 'Phenotype', 'HP:0009237', (285, 297))	('growth retardation', 'Phenotype', 'HP:0001510', (171, 189))	('hypoplastic', 'Disease', (243, 254))	('caused', 'Reg', (30, 36))	('hypoplastic or missing', 'Phenotype', 'HP:0009115', (243, 265))	('hypoplastic', 'Disease', 'MESH:D000741', (243, 254))	('BAF', 'Gene', '8815', (53, 56))	('intellectual disability', 'Disease', (146, 169))
585135	30898143	BAF47, the subunit known to be responsible for rhabdoid tumours, gives rise to a severe form of CSS.	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('gives rise to', 'Reg', (65, 78))	('rhabdoid tumours', 'Disease', 'MESH:D018335', (47, 63))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('CSS', 'Disease', (96, 99))	('rhabdoid tumours', 'Disease', (47, 63))	('BAF47', 'Var', (0, 5))
585138	30898143	It is primarily caused by missense mutations in the alternative ATPase subunit BRM.	('missense mutations', 'Var', (26, 44))	('ATPase', 'Gene', (64, 70))	('caused by', 'Reg', (16, 25))	('BRM', 'Gene', (79, 82))	('ATPase', 'Gene', '1769', (64, 70))	('BRM', 'Gene', '6595', (79, 82))
585140	30898143	In addition to Coffin-Siris syndrome and Nicolaides-Baraitser syndrome, there are many other neurodevelopmental disorders related to BAF subunit mutations, such as Kleefstra's syndrome, disorders of the autism spectrum, amyotrophic lateral sclerosis and schizophrenia.	('mutations', 'Var', (145, 154))	('neurodevelopmental disorder', 'Phenotype', 'HP:0012759', (93, 120))	('neurodevelopmental disorders', 'Disease', 'MESH:D002658', (93, 121))	("Kleefstra's syndrome", 'Disease', (164, 184))	('BAF', 'Gene', (133, 136))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (220, 249))	('amyotrophic lateral sclerosis', 'Disease', (220, 249))	('neurodevelopmental disorders', 'Phenotype', 'HP:0012759', (93, 121))	('disorders of the autism', 'Disease', 'MESH:D001321', (186, 209))	('Coffin-Siris syndrome', 'Disease', (15, 36))	('autism', 'Phenotype', 'HP:0000717', (203, 209))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (15, 36))	('related', 'Reg', (122, 129))	('schizophrenia', 'Disease', (254, 267))	("Kleefstra's syndrome", 'Disease', 'MESH:C563043', (164, 184))	('BAF', 'Gene', '8815', (133, 136))	('neurodevelopmental disorders', 'Disease', (93, 121))	('disorders of the autism', 'Disease', (186, 209))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (220, 249))	('schizophrenia', 'Disease', 'MESH:D012559', (254, 267))	('schizophrenia', 'Phenotype', 'HP:0100753', (254, 267))
585141	30898143	For a more detailed review concerning the role of BAF complexes in neural developmental disorders, see Ref.. BAF subunit mutations and their implication in human developmental disorders are summarised in Fig.	('neural developmental disorders', 'Disease', 'MESH:D009436', (67, 97))	('developmental disorders', 'Disease', 'MESH:D002658', (74, 97))	('human', 'Species', '9606', (156, 161))	('mutations', 'Var', (121, 130))	('developmental disorders', 'Disease', (162, 185))	('neural developmental disorders', 'Disease', (67, 97))	('BAF', 'Gene', '8815', (50, 53))	('developmental disorders', 'Disease', 'MESH:D002658', (162, 185))	('BAF', 'Gene', '8815', (109, 112))	('BAF', 'Gene', (50, 53))	('BAF', 'Gene', (109, 112))
585142	30898143	Given its immense influence on both differentiation and gene expression in general, it is not surprising that BAF complex subunits are frequently altered in cancer with up to 20% of human cancers bearing mutations in this ATP remodelling complex.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('ATP', 'Chemical', 'MESH:D000255', (222, 225))	('BAF', 'Gene', '8815', (110, 113))	('altered', 'Reg', (146, 153))	('mutations', 'Var', (204, 213))	('human', 'Species', '9606', (182, 187))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('BAF', 'Gene', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', (188, 194))
585144	30898143	Mirroring the tissue specificity of BAF complex assembly, the influence of subunit mutations depends on the BAF complex assembly and the tissue in which they occur.	('mutations', 'Var', (83, 92))	('BAF', 'Gene', '8815', (108, 111))	('BAF', 'Gene', (108, 111))	('BAF', 'Gene', '8815', (36, 39))	('BAF', 'Gene', (36, 39))
585147	30898143	The best studied examples of how mutations of chromatin remodellers can cause malignancies are BAF47 (= SmarcB1) loss in rhabdoid tumours and the SS18-SSX fusion protein in synovial sarcoma.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('SS18', 'Gene', (146, 150))	('mutations', 'Var', (33, 42))	('cause', 'Reg', (72, 77))	('SmarcB1', 'Gene', '6598', (104, 111))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('rhabdoid tumours', 'Disease', 'MESH:D018335', (121, 137))	('loss', 'NegReg', (113, 117))	('SS18', 'Gene', '6760', (146, 150))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('SmarcB1', 'Gene', (104, 111))	('synovial sarcoma', 'Disease', (173, 189))	('malignancies', 'Disease', (78, 90))	('synovial sarcoma', 'Disease', 'MESH:D013584', (173, 189))	('SSX', 'Gene', '6757', (151, 154))	('rhabdoid tumours', 'Disease', (121, 137))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (173, 189))	('SSX', 'Gene', (151, 154))
585151	30898143	Moreover, this clear correlation between loss of BAF47 and tumour formation can be remodelled in mice.	('loss', 'Var', (41, 45))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('mice', 'Species', '10090', (97, 101))	('BAF47', 'Gene', (49, 54))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))
585152	30898143	Conditional knockout of BAF47 at a distinct time point leads to tumour formation after 11 weeks with a penetrance of 100%, illustrating that loss of BAF47 is sufficient to drive tumour formation.	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('loss', 'Var', (141, 145))	('tumour', 'Disease', (64, 70))	('BAF47', 'Gene', (24, 29))	('drive', 'PosReg', (172, 177))	('leads to', 'Reg', (55, 63))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('tumour', 'Disease', (178, 184))	('BAF47', 'Gene', (149, 154))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
585153	30898143	Other studies have shown that loss of heterozygosity can also cause peripheral T cell lymphoma.	('peripheral T cell lymphoma', 'Disease', 'MESH:D016411', (68, 94))	('peripheral T cell lymphoma', 'Disease', (68, 94))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (79, 94))	('cause', 'Reg', (62, 67))	('cell lymphoma', 'Phenotype', 'HP:0012191', (81, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))	('loss of heterozygosity', 'Var', (30, 52))
585156	30898143	Upon loss of BAF47, the BAF complex itself is still able to assemble but displays a diminished chromatin affinity.	('BAF', 'Gene', '8815', (24, 27))	('chromatin affinity', 'MPA', (95, 113))	('BAF', 'Gene', (24, 27))	('loss', 'Var', (5, 9))	('BAF', 'Gene', '8815', (13, 16))	('diminished', 'NegReg', (84, 94))	('BAF', 'Gene', (13, 16))
585158	30898143	Consistent with this, genome-wide BAF complex occupancy increases significantly after BAF47 rescue.	('BAF', 'Gene', '8815', (86, 89))	('increases', 'PosReg', (56, 65))	('BAF', 'Gene', (34, 37))	('BAF', 'Gene', (86, 89))	('rescue', 'Var', (92, 98))	('occupancy', 'MPA', (46, 55))	('BAF', 'Gene', '8815', (34, 37))
585161	30898143	BAF complexes deficient of BAF47 can still be recruited to the genome but are unable to evict Polycomb, as they usually do.	('Polycomb', 'Gene', (94, 102))	('BAF', 'Gene', (27, 30))	('BAF', 'Gene', (0, 3))	('Polycomb', 'Gene', '40358', (94, 102))	('deficient', 'Var', (14, 23))	('BAF', 'Gene', '8815', (27, 30))	('BAF', 'Gene', '8815', (0, 3))
585165	30898143	Interestingly, the expression of other BAF complex subunits like BRM seems to determine the sensitivity of tumours with BAF subunit mutations to EZH2 inhibition, suggesting BRM expression as a possible biomarker for therapeutic response.	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', (107, 114))	('BRM', 'Gene', '6595', (173, 176))	('BAF', 'Gene', (120, 123))	('mutations', 'Var', (132, 141))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('BRM', 'Gene', (65, 68))	('EZH2', 'Gene', '2146', (145, 149))	('BRM', 'Gene', (173, 176))	('BAF', 'Gene', '8815', (39, 42))	('EZH2', 'Gene', (145, 149))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('determine', 'Reg', (78, 87))	('BRM', 'Gene', '6595', (65, 68))	('BAF', 'Gene', (39, 42))	('BAF', 'Gene', '8815', (120, 123))
585175	30898143	Mutations of BRG1, for instance, occur in over 90% of small cell ovarian cancers.	('small cell ovarian cancers', 'Disease', (54, 80))	('small cell ovarian cancers', 'Disease', 'MESH:D055752', (54, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('BRG1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('ovarian cancers', 'Phenotype', 'HP:0100615', (65, 80))	('BRG1', 'Gene', '6597', (13, 17))	('occur', 'Reg', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))
585180	30898143	It is an aggressive sarcoma arising in the soft tissue and specified by a t(X;18) chromosomal translocation, fusing 78 amino acids of the protein SSX to the dedicated BAF complex subunit SS18.	('SSX', 'Gene', '6757', (146, 149))	('BAF', 'Gene', (167, 170))	('sarcoma', 'Disease', (20, 27))	('SSX', 'Gene', (146, 149))	('SS18', 'Gene', (187, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('SS18', 'Gene', '6760', (187, 191))	('sarcoma', 'Disease', 'MESH:D012509', (20, 27))	('fusing', 'Var', (109, 115))	('BAF', 'Gene', '8815', (167, 170))
585189	30898143	These changes are sufficient to cause SOX2 expression, which is a typical feature of synovial sarcoma cell lines, that show stem cell-like expression patterns.	('SOX2', 'Gene', '6657', (38, 42))	('SOX2', 'Gene', (38, 42))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (85, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('synovial sarcoma', 'Disease', (85, 101))	('changes', 'Var', (6, 13))	('expression', 'MPA', (43, 53))	('synovial sarcoma', 'Disease', 'MESH:D013584', (85, 101))	('cause', 'Reg', (32, 37))
585194	30898143	Figure 3 shows an outline of BAF subunit mutations in human cancers.	('mutations', 'Var', (41, 50))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('BAF', 'Gene', '8815', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))	('BAF', 'Gene', (29, 32))
585195	30898143	Similar to the findings in rhabdoid tumours, ncBAF also seems to play a significant role in synovial sarcoma as cell lines of this tumour entity are sensitive to the loss of BRD9, BAF60A or GLTSCR1.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('loss', 'Var', (166, 170))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (92, 108))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('BRD9', 'Gene', '65980', (174, 178))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('BAF60A', 'Gene', (180, 186))	('BAF', 'Gene', (47, 50))	('tumour', 'Disease', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('BAF', 'Gene', (180, 183))	('rhabdoid tumours', 'Disease', (27, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('synovial sarcoma', 'Disease', 'MESH:D013584', (92, 108))	('BAF', 'Gene', '8815', (47, 50))	('synovial sarcoma', 'Disease', (92, 108))	('BAF60A', 'Gene', '6602', (180, 186))	('GLTSCR1', 'Gene', (190, 197))	('BAF', 'Gene', '8815', (180, 183))	('GLTSCR1', 'Gene', '29998', (190, 197))	('rhabdoid tumours', 'Disease', 'MESH:D018335', (27, 43))	('BRD9', 'Gene', (174, 178))
585202	30898143	It still localises to H3K4-trimethylated regions as well as to CTCF sites and most genes that are downregulated following BRD9 inhibition are independent from the SS18-SSX fusion protein.	('downregulated', 'NegReg', (98, 111))	('SS18', 'Gene', (163, 167))	('CTCF', 'Gene', (63, 67))	('SSX', 'Gene', '6757', (168, 171))	('BRD9', 'Gene', '65980', (122, 126))	('SSX', 'Gene', (168, 171))	('inhibition', 'Var', (127, 137))	('CTCF', 'Gene', '10664', (63, 67))	('SS18', 'Gene', '6760', (163, 167))	('BRD9', 'Gene', (122, 126))
585210	30898143	However, the discovery of EZH2 inhibitors and BRD9 inhibitors as possible therapeutic approaches for some cancers with BAF subunit mutations, illustrates why the comprehension of the precise mechanism by which subunit mutations result in tumour growth, is so important.	('BAF', 'Gene', (119, 122))	('EZH2', 'Gene', '2146', (26, 30))	('mutations', 'Var', (131, 140))	('EZH2', 'Gene', (26, 30))	('BRD9', 'Gene', '65980', (46, 50))	('result in', 'Reg', (228, 237))	('mutations', 'Var', (218, 227))	('BRD9', 'Gene', (46, 50))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('BAF', 'Gene', '8815', (119, 122))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('tumour growth', 'Disease', (238, 251))	('tumour growth', 'Disease', 'MESH:D006130', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
585213	30898143	However, these mechanisms first need to be fully understood making further elucidation of how BAF subunit mutations drive tumour formation essential.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('drive', 'Reg', (116, 121))	('BAF', 'Gene', '8815', (94, 97))	('BAF', 'Gene', (94, 97))	('tumour', 'Disease', (122, 128))	('mutations', 'Var', (106, 115))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
585223	28829837	Taken together, our data demonstrated that alterations in the TGF-beta1/Smad signaling pathway could regulate the expression of EMT-related factors and the EMT process, resulting in changes in tumor cell invasion, migration, and proliferation in synovial sarcoma cells.	('synovial sarcoma', 'Disease', (246, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (255, 262))	('TGF-beta1', 'Gene', '7040', (62, 71))	('TGF-beta1', 'Gene', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (246, 262))	('synovial sarcoma', 'Disease', 'MESH:D013584', (246, 262))	('proliferation', 'CPA', (229, 242))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('migration', 'CPA', (214, 223))	('changes', 'Reg', (182, 189))	('alterations', 'Var', (43, 54))	('expression', 'MPA', (114, 124))	('tumor', 'Disease', (193, 198))	('regulate', 'Reg', (101, 109))
585233	28829837	SS is thought to be a useful model for investigating the potential mechanisms involved in the aberrant EMT/MET in mesenchymal neoplasms because of the possibility of biphasic differentiation.	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('mesenchymal neoplasms', 'Disease', (114, 135))	('aberrant', 'Var', (94, 102))	('mesenchymal neoplasms', 'Disease', 'MESH:C535700', (114, 135))
585258	28829837	Conversely, after treatment with the inhibitor SB431542, the number and activity of cells were also significantly decreased in a concentration-dependent manner (Fig 1E-1H), particular at a concentration of 20nM(P< 0.01).	('SB431542', 'Var', (47, 55))	('activity of cells', 'CPA', (72, 89))	('SB431542', 'Chemical', 'MESH:C459179', (47, 55))	('decreased', 'NegReg', (114, 123))
585259	28829837	AndSB431542 also can suppressed the effects of TGF-beta1 to some degree (S1 Fig).	('AndSB431542', 'Var', (0, 11))	('suppressed', 'NegReg', (21, 31))	('TGF-beta1', 'Gene', '7040', (47, 56))	('SB431542', 'Chemical', 'MESH:C459179', (3, 11))	('TGF-beta1', 'Gene', (47, 56))	('effects', 'MPA', (36, 43))
585264	28829837	Conversely, SB431542inhibited the mRNA and protein expression of smad2(P = 0.001; Fig 2D-2F), and only slightly suppressed the expression of smad3.	('SB431542inhibited', 'Var', (12, 29))	('suppressed', 'NegReg', (112, 122))	('SB431542inhibited', 'NegReg', (12, 29))	('SB431542', 'Chemical', 'MESH:C459179', (12, 20))	('smad2', 'Gene', '4087', (65, 70))	('expression', 'MPA', (127, 137))	('smad3', 'Gene', '4088', (141, 146))	('smad3', 'Gene', (141, 146))	('smad2', 'Gene', (65, 70))
585268	28829837	Although E-cadherin was upregulated at lower concentrations, downregulation of E-cadherin was noted in the presence of 10ng/mL TGF-beta1.	('TGF-beta1', 'Gene', '7040', (127, 136))	('TGF-beta1', 'Gene', (127, 136))	('downregulation', 'NegReg', (61, 75))	('E-cadherin', 'Gene', '999', (9, 19))	('E-cadherin', 'Gene', (79, 89))	('upregulated', 'PosReg', (24, 35))	('10ng/mL', 'Var', (119, 126))	('E-cadherin', 'Gene', '999', (79, 89))	('E-cadherin', 'Gene', (9, 19))
585282	28829837	More than 90% of SS samples harbor a specific fusion gene, which can influence the maintenance of tumorigenicity through regulation of various transcription factors, including Snail, Slug, ZEB, and Twist.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('fusion gene', 'Var', (46, 57))	('SS', 'Phenotype', 'HP:0012570', (17, 19))	('Slug', 'Gene', '6591', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Slug', 'Gene', (183, 187))	('Snail', 'Gene', '6615', (176, 181))	('Snail', 'Gene', (176, 181))	('influence', 'Reg', (69, 78))	('tumor', 'Disease', (98, 103))	('regulation', 'MPA', (121, 131))
585283	28829837	Several recent studies have shown that the MET promotes the growth of epithelial tumor cells at distant sites during metastasis.	('epithelial tumor', 'Disease', 'MESH:D002277', (70, 86))	('promotes', 'PosReg', (47, 55))	('epithelial tumor', 'Disease', (70, 86))	('MET', 'Var', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('epithelial tumor', 'Phenotype', 'HP:0031492', (70, 86))
585304	28829837	Expression of the transcription factor Snail was not observed; however, Slug expression was significantly increased by TGF-beta1 treatment, facilitating the enhancement of cell invasion and proliferation.	('Snail', 'Gene', (39, 44))	('TGF-beta1', 'Gene', '7040', (119, 128))	('expression', 'MPA', (77, 87))	('TGF-beta1', 'Gene', (119, 128))	('cell invasion', 'CPA', (172, 185))	('Slug', 'Gene', '6591', (72, 76))	('increased', 'PosReg', (106, 115))	('Slug', 'Gene', (72, 76))	('enhancement', 'PosReg', (157, 168))	('treatment', 'Var', (129, 138))	('Snail', 'Gene', '6615', (39, 44))
585371	28234908	Postoperative morbidity after HIPEC/EPIC was significantly higher (p = 0.05), with a 40% complication rate compared with 10% in patients without HIPEC/EPIC.	('higher', 'PosReg', (59, 65))	('patients', 'Species', '9606', (128, 136))	('HIPEC/EPIC', 'Var', (30, 40))
585374	28234908	Six patients of the HIPEC/EPIC group (55%) had a peritoneal recurrence compared with 35 patients (73%) in the group without HIPEC/EPIC, after a median follow-up of 11 months and 34 months, respectively.	('peritoneal recurrence', 'CPA', (49, 70))	('HIPEC/EPIC', 'Var', (20, 30))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (4, 12))
585388	28234908	Even if striking differences remain among treatment protocols, a recent study reported a benefit of HIPEC over EPIC in peritoneal metastases of unusual origin, including DSRCT.	('HIPEC', 'Var', (100, 105))	('peritoneal', 'Disease', (119, 129))	('metastases', 'Disease', (130, 140))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('DSRCT', 'Disease', (170, 175))
585392	28234908	In the only study available, seven patients with DSRCT received HIPEC before WAP- intensity-modulated radiation therapy (WAP-IMRT) and none developed grade 3 or 4 toxicity after a median follow-up of 15 months.	('patients', 'Species', '9606', (35, 43))	('toxicity', 'Disease', 'MESH:D064420', (163, 171))	('toxicity', 'Disease', (163, 171))	('HIPEC', 'Var', (64, 69))
585472	25418440	In an effort to decrease RT related morbidity by decreasing RT dosing yet maintaining good local control rates, two recent COG STS studies including the current D9803 and low risk study D9602 provided the option of adjusted RT dose based upon the extent of resection at DPE.	('D9803', 'Chemical', '-', (161, 166))	('D9602', 'Var', (186, 191))	('local', 'MPA', (91, 96))	('decreasing', 'NegReg', (49, 59))	('RT dosing', 'MPA', (60, 69))	('COG', 'Chemical', '-', (123, 126))	('decrease RT', 'Phenotype', 'HP:0032198', (16, 27))
585473	25418440	D9602 and D9803 RT doses were based on studies suggesting efficacy in controlling local disease with 30-36 Gy for microscopic disease.	('D9602', 'Var', (0, 5))	('D9803', 'Chemical', '-', (10, 15))	('D9803', 'Var', (10, 15))	('local disease', 'Disease', (82, 95))
585486	25418440	In D9803 45% of Group III patients eligible for DPE received an operative procedure, most commonly a resection.	('D9803', 'Chemical', '-', (3, 8))	('resection', 'Disease', (101, 110))	('D9803', 'Var', (3, 8))	('patients', 'Species', '9606', (26, 34))
585494	25418440	Our approach in D9803 demonstrated local control rates similar to IRS-IV (which used similar systemic chemotherapy and had similar outcomes) for these select sites of disease.	('D9803', 'Chemical', '-', (16, 21))	('local control', 'CPA', (35, 48))	('D9803', 'Var', (16, 21))
585497	25418440	We did not compare DPE local control to no DPE local control within D9803 given the small number of patients would preclude any meaningful statistical conclusions to be reached and, since the treatment was not randomized, a significant amount of bias would have entered into the analysis.	('D9803', 'Var', (68, 73))	('D9803', 'Chemical', '-', (68, 73))	('entered', 'Reg', (262, 269))	('patients', 'Species', '9606', (100, 108))
585498	25418440	Nonetheless, even without a direct statistical comparison to IRS IV our data support the conclusion that for patients with primary sites amenable to surgery, DPE with adjusted RT dose results in local control rates similar to that achieved with conventional RT doses.	('local control', 'CPA', (195, 208))	('DPE', 'Var', (158, 161))	('patients', 'Species', '9606', (109, 117))
585499	25418440	Similar findings and conclusions were reached in low risk RMS patients (D9602), in which the 5 year cumulative local failure rate was 15% in the 62 patients treated with the same local control paradigm utilized in D9803 (week 12 DPE and modulated RT).	('patients', 'Species', '9606', (148, 156))	('local failure', 'CPA', (111, 124))	('D9803', 'Var', (214, 219))	('D9803', 'Chemical', '-', (214, 219))	('patients', 'Species', '9606', (62, 70))	('RMS', 'Disease', (58, 61))
585624	25512813	In addition, because of the rarity of these cancers, prognosis is often considered to be unpredictable or highly variable and appears to be related to specific parameters, such as the tumor grade (high vs. low), tumor size (<=5 cm vs. >5 cm), and anatomical site (i.e., resectability).	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', (184, 189))	('related', 'Reg', (140, 147))	('<=5', 'Var', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))
585783	23739689	Our results confirm that the detection of HHV8 is a valuable tool for diagnosing cutaneous lesions of KS and to differentiate it from its simulators.	('detection', 'Var', (29, 38))	('KS', 'Phenotype', 'HP:0100726', (102, 104))	('cutaneous lesions', 'Disease', (81, 98))	('HHV8', 'Species', '37296', (42, 46))	('HHV8', 'Gene', (42, 46))
585792	22655268	RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB.	('RH30', 'Gene', '6007', (0, 4))	('RH30', 'Gene', (0, 4))	('RH41', 'Var', (9, 13))	('took place', 'Reg', (33, 43))
585804	22655268	We could show that IL-15-activated CIK cells have an increased anti-leukemic potential in vitro compared to conventional IL-2-activated CIK cells.	('leukemic', 'Disease', (68, 76))	('IL-2', 'Gene', (121, 125))	('IL-2', 'Gene', '3558', (121, 125))	('IL-15-activated', 'Var', (19, 34))	('increased', 'PosReg', (53, 62))	('leukemic', 'Disease', 'MESH:D007938', (68, 76))
585847	22655268	Informative loci for the discrimination of THP-1 and CIK cells were D7S820 and for the discrimination of RH41 and CIK cells D3S1358, D13S317, and D18S51, respectively.	('D3S1358', 'Var', (124, 131))	('D7S820', 'Var', (68, 74))	('D13S317', 'Var', (133, 140))	('D18S51', 'Var', (146, 152))	('THP-1', 'Gene', '2736', (43, 48))	('THP-1', 'Gene', (43, 48))
585868	22655268	RH41 signals within analyzed compartments (BM, PB, liver, spleen, and lung) taken together were detected at day +15 (Figure 3E), and RH41 mice, which were observed for survival, showed signs of discomfort 45-51 days after transplantation.	('mice', 'Species', '10090', (138, 142))	('RH41', 'Gene', (0, 4))	('RH41', 'Var', (133, 137))
585887	22655268	Here, THP-1 cells were quantified by staining with human anti-CD45 and anti-CD33 antibodies.	('CD45', 'Gene', (62, 66))	('THP-1', 'Gene', '2736', (6, 11))	('THP-1', 'Gene', (6, 11))	('anti-CD33', 'Var', (71, 80))	('human', 'Species', '9606', (51, 56))	('CD45', 'Gene', '5788', (62, 66))
585904	22655268	The IL-2Rgammac-chain deficiency in NSG mice, also lacking functional B cells and T cells, impairs signaling through multiple cytokine receptors, which block NK cell development resulting in additional defects in innate immunity (Shultz et al.,).	('IL-2', 'Gene', '3558', (4, 8))	('innate', 'MPA', (213, 219))	('IL-2', 'Gene', (4, 8))	('signaling', 'MPA', (99, 108))	('lacking', 'NegReg', (51, 58))	('block', 'NegReg', (152, 157))	('defects', 'NegReg', (202, 209))	('mice', 'Species', '10090', (40, 44))	('impairs', 'NegReg', (91, 98))	('deficiency', 'Var', (22, 32))
585907	22655268	Total body irradiation in SCID mutant mice was reported to increase radiosensitivity, associated with some unpredictable mouse mortality (Shultz et al.,).	('mutant', 'Var', (31, 37))	('mice', 'Species', '10090', (38, 42))	('SCID', 'Gene', '19090', (26, 30))	('mouse', 'Species', '10090', (121, 126))	('SCID', 'Gene', (26, 30))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (59, 84))	('radiosensitivity', 'MPA', (68, 84))	('increase', 'PosReg', (59, 67))
585967	33322542	Substitution of this cysteine residue by a serine results in a catalytically inactive form (PTPN13-C/S).	('Substitution', 'Var', (0, 12))	('cysteine', 'Chemical', 'MESH:D003545', (21, 29))	('serine', 'Chemical', 'MESH:D012694', (43, 49))	('catalytically inactive form', 'MPA', (63, 90))
585978	33322542	Many cancer cell lines develop resistance to FAS-induced apoptosis by acquiring mutations in the FAS gene or by regulating FAS availability at the cell surface.	('regulating', 'Reg', (112, 122))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('mutations', 'Var', (80, 89))	('FAS', 'Gene', (97, 100))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
585986	33322542	Conversely, FAS surface expression is upregulated after transfection of TIG3 bladder carcinoma cells with PTPN13 dominant negative mutants or after PTPN13 silencing by siRNA.	('silencing', 'NegReg', (155, 164))	('TIG3', 'Gene', (72, 76))	('bladder carcinoma', 'Disease', (77, 94))	('negative', 'NegReg', (122, 130))	('PTPN13', 'Gene', (106, 112))	('TIG3', 'Gene', '5920', (72, 76))	('upregulated', 'PosReg', (38, 49))	('mutants', 'Var', (131, 138))	('FAS surface expression', 'MPA', (12, 34))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (77, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('bladder carcinoma', 'Disease', 'MESH:D001749', (77, 94))
585987	33322542	In line with these findings, PTPN13 overexpression in Capan-1 pancreatic carcinoma cells negatively regulate FAS-mediated apoptosis, and PTPN13 silencing by siRNA in SW480 colorectal cancer cells increases FAS/FasL-mediated apoptosis.	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('pancreatic carcinoma', 'Disease', (62, 82))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (62, 82))	('negatively', 'NegReg', (89, 99))	('FasL', 'Gene', (210, 214))	('increases', 'PosReg', (196, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('PTPN13', 'Gene', (137, 143))	('FasL', 'Gene', '356', (210, 214))	('regulate', 'Reg', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('colorectal cancer', 'Disease', (172, 189))	('FAS-mediated apoptosis', 'CPA', (109, 131))	('Capan-1', 'CellLine', 'CVCL:0237', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('SW480', 'CellLine', 'CVCL:0546', (166, 171))	('silencing', 'Var', (144, 153))	('rectal cancer', 'Phenotype', 'HP:0100743', (176, 189))
585989	33322542	Interestingly, another study reported that PTPN13 can dephosphorylate and inhibit c-Abl, suggesting a possible retro-control of ABL activity that is lost in the case of the BCR/ABL translocation.	('activity', 'MPA', (132, 140))	('c-Abl', 'Gene', (82, 87))	('inhibit', 'NegReg', (74, 81))	('PTPN13', 'Var', (43, 49))	('c-Abl', 'Gene', '25', (82, 87))	('dephosphorylate', 'MPA', (54, 69))
585991	33322542	BCR/ABL overexpression leads to a decrease in tyrosine phosphorylation of GSK3beta (an APC partner) and in serine phosphorylation of beta-catenin (a GSK3 substrate), and consequently to increased beta-catenin transcriptional activity.	('beta-catenin', 'Gene', '1499', (133, 145))	('beta-catenin', 'Gene', '1499', (196, 208))	('tyrosine', 'Chemical', 'MESH:D014443', (46, 54))	('transcriptional activity', 'MPA', (209, 233))	('GSK3beta', 'Gene', (74, 82))	('increased', 'PosReg', (186, 195))	('decrease', 'NegReg', (34, 42))	('APC', 'Phenotype', 'HP:0005227', (87, 90))	('serine', 'Chemical', 'MESH:D012694', (107, 113))	('BCR/ABL', 'Gene', (0, 7))	('APC', 'Disease', 'MESH:D011125', (87, 90))	('GSK3beta', 'Gene', '2931', (74, 82))	('overexpression', 'Var', (8, 22))	('beta-catenin', 'Gene', (133, 145))	('tyrosine phosphorylation', 'MPA', (46, 70))	('serine phosphorylation', 'MPA', (107, 129))	('APC', 'Disease', (87, 90))	('beta-catenin', 'Gene', (196, 208))
586000	33322542	In the pancreatic adenocarcinoma A818-6 cell line, anti-FAS antibodies induce apoptosis in cells grown in 2D- or 3D-polarized cell cultures, independently of PTPN13 and FAS colocalization.	('apoptosis', 'CPA', (78, 87))	('antibodies', 'Var', (60, 70))	('pancreatic adenocarcinoma', 'Disease', (7, 32))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (7, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('anti-FAS', 'Protein', (51, 59))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (7, 32))	('induce', 'Reg', (71, 77))
586009	33322542	Moreover, ephrinB1/ERBB2 complex formation is promoted by expression of a constitutively active oncogenic mutant of ERBB2.	('ERBB2', 'Gene', '2064', (19, 24))	('promoted', 'PosReg', (46, 54))	('mutant', 'Var', (106, 112))	('ERBB2', 'Gene', (19, 24))	('ERBB2', 'Gene', '2064', (116, 121))	('expression', 'MPA', (58, 68))	('ERBB2', 'Gene', (116, 121))	('complex', 'Interaction', (25, 32))
586010	33322542	Signaling by this complex is activated by SRC and is increased by transfection of the catalytically inactive PTPN13-C/S variant.	('activated', 'PosReg', (29, 38))	('PTPN13-C/S', 'Gene', (109, 119))	('increased', 'PosReg', (53, 62))	('variant', 'Var', (120, 127))	('SRC', 'Gene', '6714', (42, 45))	('Signaling', 'MPA', (0, 9))	('SRC', 'Gene', (42, 45))
586014	33322542	Transfection of HEK293 cells with the PTPN13-C/S mutant increases ephrinB1 phosphorylation, its association with ERBB1, and ERK1/2 phosphorylation.	('ERBB1', 'Gene', '1956', (113, 118))	('increases', 'PosReg', (56, 65))	('ephrinB1', 'Protein', (66, 74))	('PTPN13-C/S', 'Var', (38, 48))	('ERK1/2', 'Gene', (124, 130))	('ERBB1', 'Gene', (113, 118))	('association', 'Interaction', (96, 107))	('ERK1/2', 'Gene', '5595;5594', (124, 130))	('phosphorylation', 'MPA', (131, 146))	('phosphorylation', 'MPA', (75, 90))	('HEK293', 'CellLine', 'CVCL:0045', (16, 22))
586016	33322542	In vivo, in a mouse model of HPV-positive head and neck squamous cancer (HNSCC), tumor growth was reduced (p < 0.001) and survival was improved (p < 0.001) in mice injected with HNSCC cells transfected with ephrinB1 shRNA compared with cells transfected wild-type ephrinB1.	('squamous cancer', 'Phenotype', 'HP:0002860', (56, 71))	('ephrinB1 shRNA', 'Var', (207, 221))	('mouse', 'Species', '10090', (14, 19))	('survival', 'CPA', (122, 130))	('neck squamous cancer', 'Disease', 'MESH:D006258', (51, 71))	('mice', 'Species', '10090', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('improved', 'PosReg', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('neck squamous cancer', 'Disease', (51, 71))	('reduced', 'NegReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
586029	33322542	in a high-grade serous ovarian carcinoma (HGSOC) cell line (OV-90), in which PTPN13 transfection decreased the levels of IkappaBalpha phosphorylated at Y42 and of nuclear NF-kappaB, in contrast to transfection with PTPN13 siRNA.	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (16, 40))	('PTPN13', 'Gene', (77, 83))	('NF-kappaB', 'Gene', '4790', (171, 180))	('IkappaBalpha', 'Gene', '4792', (121, 133))	('levels', 'MPA', (111, 117))	('IkappaBalpha', 'Gene', (121, 133))	('NF-kappaB', 'Gene', (171, 180))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (23, 40))	('decreased', 'NegReg', (97, 106))	('serous ovarian carcinoma', 'Disease', (16, 40))	('transfection', 'Var', (84, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('OV-90', 'CellLine', 'CVCL:3768', (60, 65))
586030	33322542	By using a siRNA against PTPN13 in combination with an inhibitor of IkappaBalpha phosphorylation or an IkappaBalpha mutant (Y42A), they confirmed that PTPN13 exerts its tumor suppressive effect by dephosphorylating IkappaBalpha at Tyr42.	('IkappaBalpha', 'Gene', '4792', (103, 115))	('dephosphorylating', 'MPA', (197, 214))	('PTPN13', 'Var', (151, 157))	('IkappaBalpha', 'Gene', (103, 115))	('IkappaBalpha', 'Gene', '4792', (215, 227))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('Y42A', 'Mutation', 'p.Y42A', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Tyr42', 'Chemical', '-', (231, 236))	('IkappaBalpha', 'Gene', '4792', (68, 80))	('IkappaBalpha', 'Gene', (215, 227))	('tumor', 'Disease', (169, 174))	('IkappaBalpha', 'Gene', (68, 80))
586035	33322542	Although inhibition of miRNA-200c, which targets PTPN13, is associated with EMT, an in vivo study found no significant association between downregulation of the miRNA-200 family, PTPN13 expression, and colorectal cancer metastatic potential.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('miRNA-200c', 'Gene', (23, 33))	('colorectal cancer', 'Disease', (202, 219))	('rectal cancer', 'Phenotype', 'HP:0100743', (206, 219))	('PTPN13', 'Gene', (179, 185))	('PTPN13', 'Gene', (49, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))	('EMT', 'Disease', (76, 79))	('inhibition', 'Var', (9, 19))	('downregulation', 'NegReg', (139, 153))
586039	33322542	showing that PTPN13 stabilizes beta-catenin in megakaryocytes, found that inhibition of PTPN13 or beta-catenin in vivo increases HSC adhesion to their niche.	('increases', 'PosReg', (119, 128))	('inhibition', 'Var', (74, 84))	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))	('HSC adhesion to their niche', 'CPA', (129, 156))	('beta-catenin', 'Gene', (98, 110))	('PTPN13', 'Gene', (88, 94))	('beta-catenin', 'Gene', '1499', (98, 110))
586069	33322542	The authors then reported a drastic decrease in cell survival after transfection of the PTPN13-C/S mutant in Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (109, 122))	('cell survival', 'CPA', (48, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('mutant', 'Var', (99, 105))	('PTPN13-C/S', 'Gene', (88, 98))	('decrease', 'NegReg', (36, 44))
586077	33322542	found that the PTPN13 promoter is methylated in 60% of 47 diffuse large B cell lymphoma samples, compared with 6.3% of 16 non-tumor tissue samples.	('PTPN13', 'Gene', (15, 21))	('methylated', 'Var', (34, 44))	('lymphoma', 'Disease', (79, 87))	('lymphoma', 'Disease', 'MESH:D008223', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (72, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (79, 87))	('large B cell', 'Phenotype', 'HP:0005404', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('6.3', 'Gene', '55558', (111, 114))	('6.3', 'Gene', (111, 114))	('tumor', 'Disease', (126, 131))
586079	33322542	Specifically, it was methylated in 56% of 16 esophageal adenocarcinoma samples, and this was associated with decreased mRNA levels in 75% of cases.	('decreased', 'NegReg', (109, 118))	('methylated', 'Var', (21, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adenocarcinoma', 'Disease', (56, 70))	('mRNA levels', 'MPA', (119, 130))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 70))
586082	33322542	In tumor samples, miR30-e is decreased in bladder, breast, and rectal cancer, while it is overexpressed in salivary gland cancer and pulmonary adenocarcinoma.	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 157))	('salivary gland cancer', 'Disease', (107, 128))	('miR30-e', 'Var', (18, 25))	('rectal cancer', 'Phenotype', 'HP:0100743', (63, 76))	('pulmonary adenocarcinoma', 'Disease', (133, 157))	('tumor', 'Disease', (3, 8))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('overexpressed', 'PosReg', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('salivary gland cancer', 'Disease', 'MESH:D012468', (107, 128))	('cancer', 'Disease', (70, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast', 'Disease', (51, 57))	('decreased', 'NegReg', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('bladder', 'Disease', (42, 49))	('salivary gland cancer', 'Phenotype', 'HP:0100684', (107, 128))	('cancer', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (133, 157))
586084	33322542	They also showed that PTPN13 is a direct target of miR30-e. Tumor growth is promoted in mice xenografted with A549 cells transfected with miR30-e compared with cells transfected with vector alone.	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('miR30-e', 'Var', (138, 145))	('Tumor growth', 'CPA', (60, 72))	('promoted', 'PosReg', (76, 84))	('mice', 'Species', '10090', (88, 92))	('Tumor', 'Phenotype', 'HP:0002664', (60, 65))
586088	33322542	Indeed, miR-26a overexpression leads to wild-type PTPN13 protein level reduction, but has no effect on the expression of a PTPN13 variant harboring a mutation in the putative miR-26a binding site.	('miR-26a', 'Gene', '407015', (175, 182))	('reduction', 'NegReg', (71, 80))	('miR-26a', 'Gene', (175, 182))	('PTPN13', 'Gene', (123, 129))	('variant', 'Var', (130, 137))	('mutation', 'Var', (150, 158))	('PTPN13 protein level', 'MPA', (50, 70))	('miR-26a', 'Gene', '407015', (8, 15))	('miR-26a', 'Gene', (8, 15))
586089	33322542	In the SPCA-1 lung adenocarcinoma cell line, siRNA-mediated PTPN13 knockdown mimics the effect of miR26-a, promoting phosphorylation of SRC, Akt, and ERK, supporting miR26a oncogenic role in bronchial adenocarcinoma.	('lung adenocarcinoma', 'Disease', (14, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (201, 215))	('PTPN13', 'Gene', (60, 66))	('miR26a', 'Gene', '407015', (166, 172))	('SRC', 'Gene', '6714', (136, 139))	('SPCA-1', 'Gene', (7, 13))	('Akt', 'Gene', '207', (141, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (14, 33))	('promoting', 'PosReg', (107, 116))	('ERK', 'Gene', '5594', (150, 153))	('knockdown', 'Var', (67, 76))	('phosphorylation', 'MPA', (117, 132))	('SRC', 'Gene', (136, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('adenocarcinoma', 'Disease', (19, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('SPCA-1', 'Gene', '27032', (7, 13))	('miR26a', 'Gene', (166, 172))	('ERK', 'Gene', (150, 153))	('adenocarcinoma', 'Disease', (201, 215))	('miR26-a', 'Gene', (98, 105))	('miR26-a', 'Gene', '407015', (98, 105))	('adenocarcinoma', 'Disease', 'MESH:D000230', (19, 33))	('Akt', 'Gene', (141, 144))
586090	33322542	The miR-200 family contains five subtypes (miR-200a/b/c, miR-141, and miR-429), and is involved in maintaining the epithelial phenotype.	('miR-200a/b', 'Gene', '406983', (43, 53))	('miR-141', 'Var', (57, 64))	('miR-429', 'Gene', '554210', (70, 77))	('miR-200', 'Gene', (4, 11))	('miR-200', 'Chemical', '-', (4, 11))	('epithelial', 'MPA', (115, 125))	('miR-429', 'Gene', (70, 77))	('miR-200a/b', 'Gene', (43, 53))	('miR-200', 'Chemical', '-', (43, 50))
586097	33322542	However, two studies only on HGSOC, the most frequent ovarian cancer subtype, highlighted a correlation between high PTPN13 protein and mRNA expression and better prognosis in 97 and 58 HGSOC samples, respectively (p = 0.042 and p = 0.03).	('ovarian cancer', 'Disease', 'MESH:D010051', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mRNA expression', 'MPA', (136, 151))	('ovarian cancer', 'Disease', (54, 68))	('high', 'Var', (112, 116))	('PTPN13', 'Gene', (117, 123))	('ovarian cancer', 'Phenotype', 'HP:0100615', (54, 68))
586099	33322542	In breast cancer (n = 291 samples), we showed that high PTPN13 expression, measured by RT/PCR, is associated with better prognosis (p = 0.01 and RR = 0.48 in multivariate analysis).	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('expression', 'MPA', (63, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('PTPN13', 'Gene', (56, 62))	('high', 'Var', (51, 55))
586111	33322542	Overall, PTPN13 expression is linked to less aggressive tumors and better patient survival.	('patient', 'Species', '9606', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('expression', 'Var', (16, 26))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('aggressive tumors', 'Disease', 'MESH:D001523', (45, 62))	('PTPN13', 'Gene', (9, 15))	('better', 'PosReg', (67, 73))	('aggressive tumors', 'Disease', (45, 62))
586118	33322542	In line with these data, inhibition of the PTPN13/FAS interaction with the SLV peptide in PTPN13-overexpressing CD133+ colon cancer stem cells increases their sensitivity to oxaliplatin, restoring FAS-induced apoptosis.	('increases', 'PosReg', (143, 152))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('sensitivity to oxaliplatin', 'MPA', (159, 185))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('PTPN13-overexpressing', 'Gene', (90, 111))	('restoring', 'PosReg', (187, 196))	('colon cancer', 'Disease', (119, 131))	('CD133', 'Gene', (112, 117))	('inhibition', 'Var', (25, 35))	('CD133', 'Gene', '8842', (112, 117))	('interaction', 'Interaction', (54, 65))	('FAS-induced apoptosis', 'CPA', (197, 218))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (174, 185))
586120	33322542	On the other hand, in NSCLC cell lines (SPCA1 and PC-9), PTPN13 increases the sensitivity to an anti-EGFR TKI (gefitinib).	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('PC-9', 'Gene', '255738', (50, 54))	('gefitinib', 'Chemical', 'MESH:D000077156', (111, 120))	('SPCA1', 'Gene', '27032', (40, 45))	('SPCA1', 'Gene', (40, 45))	('PC-9', 'Gene', (50, 54))	('PTPN13', 'Var', (57, 63))	('NSCLC', 'Disease', (22, 27))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('sensitivity to', 'MPA', (78, 92))	('increases', 'PosReg', (64, 73))
586130	33322542	A recent study demonstrated PTPN13 involvement in cisplatin sensitivity of HNSCC cell lines (WSU-HN6 and CAL-27) where cancer-derived IgG inhibition upregulates PTPN13, resulting in the inhibition of the SRC/PKD1/AKT pathway.	('upregulates', 'PosReg', (149, 160))	('inhibition', 'NegReg', (186, 196))	('SRC', 'Gene', '6714', (204, 207))	('PKD1', 'Gene', '5310', (208, 212))	('SRC', 'Gene', (204, 207))	('PKD1', 'Gene', (208, 212))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('PTPN13', 'Gene', (161, 167))	('cancer', 'Disease', (119, 125))	('PTPN13', 'Gene', (28, 34))	('AKT', 'Gene', '207', (213, 216))	('inhibition', 'Var', (138, 148))	('IgG', 'Protein', (134, 137))	('AKT', 'Gene', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
586133	33322542	Similarly, PTPN13 LOH has been reported in 67% of HGSOC, and PTPN13 bi-allelic loss in 26% of NSCLC samples.	('PTPN13', 'Gene', (61, 67))	('NSCLC', 'Disease', (94, 99))	('LOH', 'Var', (18, 21))	('HGSOC', 'Disease', (50, 55))	('bi-allelic', 'Var', (68, 78))	('PTPN13', 'Gene', (11, 17))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))
586134	33322542	The Y2081D Tyr2081Asp (T > G), rs989902 (rs for SNP reference), in exon 39, near the PTPN13 phosphatase domain, is associated with colorectal cancer in Polish patients (relative risk compared to the "wild-type" genotype: 2.087), and with HNSCC in American patients (Odds Ratio, OR, =1.26).	('rectal cancer', 'Phenotype', 'HP:0100743', (135, 148))	('Tyr2081Asp', 'SUBSTITUTION', 'None', (11, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (256, 264))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('Y2081D', 'Var', (4, 10))	('Tyr2081Asp', 'Var', (11, 21))	('rs989902', 'Mutation', 'rs989902', (31, 39))	('Y2081D', 'SUBSTITUTION', 'None', (4, 10))	('colorectal cancer', 'Disease', (131, 148))	('patients', 'Species', '9606', (159, 167))	('associated with', 'Reg', (115, 130))	('rs989902', 'Var', (31, 39))
586136	33322542	In breast cancer, this meta-analysis found a protective role for this SNP (OR = 0.63), as well as a Chinese study on the C/A and G/C genotypes of this SNP (OR = 0.63 and OR= 0.66).	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('G/C', 'Var', (129, 132))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('C/A', 'Var', (121, 124))
586137	33322542	The I1522M Ile1522Met (A > G), rs2230600, in exon 29 within the third PTPN13 PDZ domain, has been associated with HNSCC occurrence (OR = 1.89).	('rs2230600', 'Var', (31, 40))	('HNSCC', 'Disease', (114, 119))	('I1522M', 'Mutation', 'rs2230600', (4, 10))	('rs2230600', 'Mutation', 'rs2230600', (31, 40))	('Ile1522Met', 'Chemical', '-', (11, 21))	('associated', 'Reg', (98, 108))
586140	33322542	Conversely, the E2455D and Y2260WX SNPs in the catalytic domain of PTPN13 that have been identified in colorectal cancer induce a loss of 50 to almost 100%, respectively, of the phosphatase activity.	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('phosphatase activity', 'MPA', (178, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('Y2260WX', 'Var', (27, 34))	('E2455D', 'Var', (16, 22))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('loss', 'NegReg', (130, 134))	('E2455D', 'Mutation', 'rs753760213', (16, 22))	('rectal cancer', 'Phenotype', 'HP:0100743', (107, 120))	('PTPN13', 'Gene', (67, 73))
586141	33322542	In addition, the nonsense Tyr1758*** (T > A) and missense Glu745Gln mutations have been found in hepatitis B virus-induced HCC samples, and the L1424P false-sense mutation, which is located in a protein-interacting PDZ domain (genomic position 87687597), may affect PTPN13 function.	('PTPN13', 'Gene', (266, 272))	('L1424P', 'Mutation', 'rs749353184', (144, 150))	('hepatitis B virus', 'Species', '10407', (97, 114))	('missense', 'Var', (49, 57))	('hepatitis', 'Phenotype', 'HP:0012115', (97, 106))	('Glu745Gln', 'Mutation', 'p.E745Q', (58, 67))	('found', 'Reg', (88, 93))	('affect', 'Reg', (259, 265))	('hepatitis B virus-induced HCC', 'Disease', (97, 126))	('Glu745Gln', 'Var', (58, 67))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('Tyr1758', 'Chemical', '-', (26, 33))	('function', 'MPA', (273, 281))	('L1424P', 'Var', (144, 150))
586142	33322542	Around 6% of TCGA gastric cancer samples harbor PTPN13 mutations that have been associated with poor prognosis.	('gastric cancer', 'Disease', (18, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('mutations', 'Var', (55, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('PTPN13', 'Gene', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('harbor', 'Reg', (41, 47))
586143	33322542	In 262 patients with familial lung cancer, a non-synonymous PTPN13 exon variant (rs115836094) at 4q21.3-28.3 could be involved in carcinogenesis.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('rs115836094', 'Var', (81, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('PTPN13', 'Gene', (60, 66))	('familial lung cancer', 'Disease', (21, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('carcinogenesis', 'Disease', (130, 144))	('rs115836094', 'Mutation', 'rs115836094', (81, 92))	('involved', 'Reg', (118, 126))	('patients', 'Species', '9606', (7, 15))	('familial lung cancer', 'Disease', 'MESH:D008175', (21, 41))
586144	33322542	Moreover, 8% of NSCLC samples harbored false-sense PTPN13 mutations with unknown functions (e.g., A808C leading to N270H in exon 7, and G1925A, leading to R482Q in exon 10).	('R482Q', 'Var', (155, 160))	('N270H', 'Var', (115, 120))	('N270H', 'Mutation', 'rs1275026116', (115, 120))	('A808C', 'Mutation', 'rs1275026116', (98, 103))	('G1925A', 'Var', (136, 142))	('PTPN13', 'Gene', (51, 57))	('A808C', 'Var', (98, 103))	('NSCLC', 'Disease', (16, 21))	('G1925A', 'Mutation', 'c.1925G>A', (136, 142))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('R482Q', 'Mutation', 'rs781154444', (155, 160))
586146	33322542	Overall, approximately 7-8% of lung cancer and 20% of HPV-negative HNSCC samples harbor PTPN13 mutations.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('harbor', 'Reg', (81, 87))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('PTPN13', 'Gene', (88, 94))
586147	33322542	A mutational analysis of data from a tyrosine phosphatome-wide study of 157 CRC samples showed that PTPN13 is the second most commonly mutated phosphatase in these cancers (n = 15 tumors with a mutation; 9% of the entire sample).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mutated', 'Var', (135, 142))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('tumors', 'Disease', (180, 186))	('tyrosine', 'Chemical', 'MESH:D014443', (37, 45))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('PTPN13', 'Gene', (100, 106))
586148	33322542	Nevertheless, all analyzed mutations have an inhibitory effect on PTPN13 activity, and their presence appears to be associated with poor prognosis in lung cancer (p = 0.02) and possibly in gastric cancer.	('mutations', 'Var', (27, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('lung cancer', 'Disease', (150, 161))	('activity', 'MPA', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('PTPN13', 'Gene', (66, 72))	('gastric cancer', 'Disease', (189, 203))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))
586169	29022531	While ART can cause remission in early-stage KS, advanced KS requires systemic chemotherapy .	('early-stage KS', 'Disease', (33, 47))	('KS', 'Phenotype', 'HP:0100726', (58, 60))	('ART', 'Chemical', '-', (6, 9))	('KS', 'Phenotype', 'HP:0100726', (45, 47))	('ART', 'Var', (6, 9))
586227	29022531	After we corrected for missing data, radiation therapy (HR 0.52; 95% CI 0.33-0.81) was also associated with better survival in the multivariable analyses.	('survival', 'MPA', (115, 123))	('mul', 'Gene', '4591', (131, 134))	('better', 'PosReg', (108, 114))	('radiation therapy', 'Var', (37, 54))	('mul', 'Gene', (131, 134))
586408	22523703	Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease Ewing's sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene.	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('EWS', 'Gene', (165, 168))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	("Ewing's sarcoma tumors", 'Disease', 'MESH:C563168', (84, 106))	('chromosomal translocation', 'Var', (127, 152))	('Sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('associated', 'Reg', (111, 121))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	("Ewing's Sarcoma", 'Disease', (0, 15))	("Disease Ewing's sarcoma", 'Phenotype', 'HP:0012254', (76, 99))	("Ewing's sarcoma tumors", 'Disease', (84, 106))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (84, 99))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (0, 15))
586425	22523703	Although preclinical studies demonstrate oncogenic properties of EWS/FLI-1 in murine models, transfer of EWS/FLI-1 to normal human cells in vitro is not sufficient to transform to a malignant phenotype.	('human', 'Species', '9606', (125, 130))	('EWS/FLI-1', 'Gene', (65, 74))	('EWS/FLI-1', 'Var', (105, 114))	('murine', 'Species', '10090', (78, 84))
586434	22523703	RNAi knockdown of EWS/FLI-1 in ES cell lines yields an MSC gene expression signaling profile.	('ES', 'Phenotype', 'HP:0012254', (31, 33))	('EWS/FLI-1', 'Gene', (18, 27))	('knockdown', 'Var', (5, 14))	('yields', 'Reg', (45, 51))	('MSC gene expression signaling profile', 'MPA', (55, 92))	('expression', 'Species', '29278', (64, 74))
586444	22523703	Dicer recognizes and preferentially binds to the terminal 2-nucleotide 3' over-hang and cleaves dsRNAs into 21 to 22 nucleotide siRNAs.	('cleaves', 'Var', (88, 95))	('2-nucleotide', 'Chemical', '-', (58, 70))	('Dicer', 'Gene', '23405', (0, 5))	('Dicer', 'Gene', (0, 5))	('binds', 'Interaction', (36, 41))	('preferentially', 'PosReg', (21, 35))
586453	22523703	There is also a cleavage-independent bypass pathway, in which the passenger strand with mismatches is induced to unwind and depart by an ATP-dependent helicase activity.	('mismatches', 'Var', (88, 98))	('ATP', 'Gene', '51761', (137, 140))	('ATP', 'Gene', (137, 140))	('unwind', 'MPA', (113, 119))
586476	22523703	Using siRNA treatment, inhibition of proliferation, dysregulation of molecules involved in signal transduction, and increased chemosensitivity of malignancies have been demonstrated.	('chemosensitivity', 'CPA', (126, 142))	('inhibition', 'NegReg', (23, 33))	('malignancies', 'Disease', 'MESH:D009369', (146, 158))	('dysregulation', 'Var', (52, 65))	('proliferation', 'CPA', (37, 50))	('increased', 'PosReg', (116, 125))	('malignancies', 'Disease', (146, 158))
586478	22523703	Therefore, it is important to find delivery systems that effectively knockdown gene targets in cancer cells while preserving normal, healthy cells.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('knockdown', 'Var', (69, 78))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))
586498	22523703	Studies have demonstrated fusion protein knockdown in vitro to correlate with a decreased tumor size and increased vulnerability of cells to apoptosis.	('vulnerability', 'MPA', (115, 128))	('decreased tumor', 'Disease', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('fusion protein', 'Protein', (26, 40))	('knockdown', 'Var', (41, 50))	('decreased tumor', 'Disease', 'MESH:D009369', (80, 95))
586513	22523703	When RNAi was used to knockdown GSTM4 levels in patient-derived Ewing's sarcoma cell lines, an increase in sensitivity to the chemotherapeutic drug, etoposide, was seen.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (64, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('GSTM4', 'Gene', (32, 37))	('etoposide', 'Chemical', 'MESH:D005047', (149, 158))	('increase', 'PosReg', (95, 103))	('knockdown', 'Var', (22, 31))	('GSTM4', 'Gene', '2948', (32, 37))	('sensitivity to the', 'MPA', (107, 125))	('patient', 'Species', '9606', (48, 55))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (64, 79))	("Ewing's sarcoma", 'Disease', (64, 79))
586518	22523703	An AURKA inhibitor, MLN8054, was analyzed in a phase I clinical study in patients with advanced solid tumors, but no complete or partial responses were seen.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('AURKA', 'Gene', (3, 8))	('solid tumors', 'Disease', (96, 108))	('MLN8054', 'Chemical', 'MESH:C518940', (20, 27))	('solid tumors', 'Disease', 'MESH:D009369', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('patients', 'Species', '9606', (73, 81))	('AURKA', 'Gene', '6790', (3, 8))	('MLN8054', 'Var', (20, 27))
586519	22523703	However, another small molecule inhibitor, MLN8237, was recently shown to have success in reducing levels of the kinase in ESFT xenografts, as well as increasing sensitivity to apoptosis in an early phase clinical study.	('sensitivity to apoptosis', 'MPA', (162, 186))	('MLN8237', 'Chemical', 'MESH:C550258', (43, 50))	('MLN8237', 'Var', (43, 50))	('increasing', 'PosReg', (151, 161))	('levels', 'MPA', (99, 105))	('reducing', 'NegReg', (90, 98))	('ES', 'Phenotype', 'HP:0012254', (123, 125))
586535	22523703	Currently, GANT58 and GANT61 small molecule modulators have been shown to inhibit the GLI1 pathway in Ewing's sarcoma, and GANT61 may even be effective in vivo.	("Ewing's sarcoma", 'Disease', (102, 117))	('GANT61', 'Gene', (22, 28))	('GANT58', 'Gene', (11, 17))	('GLI1', 'Gene', '2735', (86, 90))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (102, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('inhibit', 'NegReg', (74, 81))	('GLI1', 'Gene', (86, 90))	('small', 'Var', (29, 34))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (102, 117))
586539	22523703	Another study using mice showed decreased tumor size and levels of EWS/FLI-1 after the use of an antisense ODN nanocapsules.	('antisense', 'Var', (97, 106))	('decreased tumor', 'Disease', 'MESH:D009369', (32, 47))	('mice', 'Species', '10090', (20, 24))	('levels', 'MPA', (57, 63))	('decreased tumor', 'Disease', (32, 47))	('EWS/FLI-1', 'Gene', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
586540	22523703	In ES, as previously mentioned, siRNAs have been used to knockdown the expression of the EWS/FLI-1 fusion gene in SK-ES cell lines in vitro.	('ES', 'Phenotype', 'HP:0012254', (117, 119))	('expression', 'MPA', (71, 81))	('SK-ES', 'CellLine', 'CVCL:0627', (114, 119))	('knockdown', 'Var', (57, 66))	('ES', 'Phenotype', 'HP:0012254', (3, 5))	('EWS/FLI-1', 'Gene', (89, 98))	('expression', 'Species', '29278', (71, 81))
586541	22523703	Additionally, siRNA knockdown effectively inhibited the metastatic nature of the SK-ES cell lines, suggesting that the presence of EWS/FLI-1 fusion protein is required for in vitro invasion.	('metastatic nature of', 'CPA', (56, 76))	('ES', 'Phenotype', 'HP:0012254', (84, 86))	('SK-ES', 'CellLine', 'CVCL:0627', (81, 86))	('siRNA', 'Gene', (14, 19))	('inhibited', 'NegReg', (42, 51))	('knockdown', 'Var', (20, 29))
586542	22523703	Another study showed knockdown of EWS/FLI-1 and suppression of tumor growth by systemic administration of siRNA in mice.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('suppression', 'NegReg', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mice', 'Species', '10090', (115, 119))	('knockdown', 'Var', (21, 30))	('EWS/FLI-1', 'Gene', (34, 43))
586548	22523703	This study also uncovered TOPK as a new target gene of EWS/FLI-1, which was effectively downregulated following the knockdown of the fusion gene.	('TOPK', 'Gene', (26, 30))	('EWS/FLI-1', 'Gene', (55, 64))	('knockdown', 'Var', (116, 125))	('TOPK', 'Gene', '55872', (26, 30))	('downregulated', 'NegReg', (88, 101))
586550	22523703	Other studies of shRNA knockdown have likewise shown significant knockdown of the fusion gene, ultimately leading to attenuated oncogenicity and decreased proliferation of cancerous cells.	('oncogenicity', 'CPA', (128, 140))	('attenuated', 'NegReg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancerous', 'Disease', 'MESH:D009369', (172, 181))	('decreased', 'NegReg', (145, 154))	('knockdown', 'Var', (65, 74))	('cancerous', 'Disease', (172, 181))
586554	31772025	The molecular events underlying UCS are enigmatic, as cancer gene mutations are generally shared among UCS/EC.	('mutations', 'Var', (66, 75))	('UCS/EC', 'Disease', (103, 109))	('UCS', 'Phenotype', 'HP:0002891', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('UCS', 'Phenotype', 'HP:0002891', (32, 35))	('EC', 'Phenotype', 'HP:0012114', (107, 109))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('UCS', 'Disease', (32, 35))
586555	31772025	We take advantage of genetic approaches in mice to show that inactivation of Fbxw7 and Pten results in UCS through spontaneous acquisition of mutations in a third gene (Tp53), arguing for strong biological selection and synergism in UCS.	('inactivation', 'Var', (61, 73))	('Fbxw7', 'Gene', (77, 82))	('mutations', 'Var', (142, 151))	('mice', 'Species', '10090', (43, 47))	('UCS', 'Phenotype', 'HP:0002891', (103, 106))	('results in', 'Reg', (92, 102))	('UCS', 'Disease', (103, 106))	('Tp53', 'Gene', (169, 173))	('Pten', 'Gene', (87, 91))	('Tp53', 'Gene', '22059', (169, 173))	('UCS', 'Phenotype', 'HP:0002891', (233, 236))
586562	31772025	Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas.	('endometrioid adenocarcinomas', 'Disease', (146, 174))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (146, 173))	('precancerous lesions', 'Disease', 'MESH:D011230', (60, 80))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('neoplasia', 'Disease', 'MESH:D009369', (111, 120))	('Pten', 'Gene', (26, 30))	('neoplasia', 'Phenotype', 'HP:0002664', (111, 120))	('precancerous lesions', 'Disease', (60, 80))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (95, 120))	('resulted in', 'Reg', (31, 42))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('Fbxw7', 'Gene', (16, 21))	('Inactivation', 'Var', (0, 12))	('neoplasia', 'Disease', (111, 120))
586564	31772025	Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type.	('carcinosarcoma', 'Disease', 'MESH:D002296', (185, 199))	('mutations', 'Var', (70, 79))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('endometrial cancer', 'Disease', (248, 266))	('acquired', 'Reg', (55, 63))	('carcinosarcoma', 'Disease', (185, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('underpinning uterine', 'Phenotype', 'HP:0000013', (164, 184))	('endometrial cancer', 'Phenotype', 'HP:0012114', (248, 266))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (177, 199))	('endometrial cancer', 'Disease', 'MESH:D016889', (248, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Trp53', 'Gene', (64, 69))
586576	31772025	For example, UCS shares epidemiologic features and patterns of chromosomal instability with high-grade carcinomas, and also shares mutational spectra with ECs, including frequent mutations in loci encoding PI3K pathway components.	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('carcinomas', 'Disease', (103, 113))	('EC', 'Phenotype', 'HP:0012114', (155, 157))	('chromosomal instability', 'Phenotype', 'HP:0040012', (63, 86))	('UCS', 'Phenotype', 'HP:0002891', (13, 16))	('mutations', 'Var', (179, 188))	('PI3K pathway', 'Pathway', (206, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinomas', 'Disease', 'MESH:D009369', (103, 113))
586578	31772025	Systematic genomic characterizations of UCS have identified frequent mutations in some genes, most notably Tp53, but such mutations also frequently occur in serous and high-grade endometrioid cancers and are not specific to UCS.	('mutations', 'Var', (69, 78))	('UCS', 'Phenotype', 'HP:0002891', (224, 227))	('endometrioid cancers', 'Disease', 'MESH:D009369', (179, 199))	('endometrioid cancers', 'Disease', (179, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('Tp53', 'Gene', (107, 111))	('UCS', 'Phenotype', 'HP:0002891', (40, 43))	('occur', 'Reg', (148, 153))	('mutations', 'Var', (122, 131))	('Tp53', 'Gene', '22059', (107, 111))	('serous', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
586582	31772025	Fbxw7 mutations characterize diverse cancers (hematopoietic, colon, stomach, gallbladder/bile duct).	('Fbxw7', 'Gene', (0, 5))	('colon', 'Disease', (61, 66))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('stomach', 'Disease', (68, 75))	('mutations', 'Var', (6, 15))	('characterize', 'Reg', (16, 28))	('hematopoietic', 'Disease', (46, 59))
586583	31772025	In women, carcinomas of the lower female reproductive tract (the Mullerian system), including the uterine cervix and corpus, frequently harbor Fbxw7 mutations.	('carcinomas', 'Disease', 'MESH:D009369', (10, 20))	('mutations', 'Var', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (10, 20))	('Fbxw7', 'Gene', (143, 148))	('carcinomas', 'Disease', (10, 20))	('uterine cervix', 'Phenotype', 'HP:0030160', (98, 112))	('harbor', 'Reg', (136, 142))	('women', 'Species', '9606', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
586584	31772025	Indeed, uterine cancers have the highest incidence of Fbxw7 mutations among all human cancers, followed by colon cancer.	('colon cancer', 'Disease', (107, 119))	('cancers', 'Disease', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('uterine cancer', 'Phenotype', 'HP:0010784', (8, 22))	('uterine cancers', 'Phenotype', 'HP:0010784', (8, 23))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Disease', (86, 93))	('mutations', 'Var', (60, 69))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))	('Fbxw7', 'Gene', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
586585	31772025	Concordantly, in diverse nongynecologic mouse models, both the WD40 and truncating mutations have proven potently oncogenic.	('WD40', 'Var', (63, 67))	('mouse', 'Species', '10090', (40, 45))	('oncogenic', 'CPA', (114, 123))	('truncating mutations', 'Var', (72, 92))
586598	31772025	With the original Sprr2f-Cre allele, extensive Cre-mediated recombination was observed in the uterus (endometrial epithelium), kidney (tubular epithelium), and cerebellum (Purkinje cells), as previously reported.	('Sprr2f', 'Gene', '20760', (18, 24))	('Sprr2f', 'Gene', (18, 24))	('Cre-mediated', 'Var', (47, 59))
586603	31772025	Fbxw7 mutations in human EC were first reported in 2002, but their significance and high incidence (~20% of cases) was not fully appreciated until genome sequencing efforts confirmed and extended the initial results.	('Fbxw7', 'Gene', (0, 5))	('human', 'Species', '9606', (19, 24))	('mutations', 'Var', (6, 15))	('EC', 'Phenotype', 'HP:0012114', (25, 27))
586604	31772025	Despite the crucial contribution of Fbxw7 mutation in EC, few studies have focused on the biological basis of its function as an endometrial tumor suppressor in vivo.	('Fbxw7', 'Gene', (36, 41))	('EC', 'Phenotype', 'HP:0012114', (54, 56))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('endometrial tumor', 'Disease', (129, 146))	('mutation', 'Var', (42, 50))	('endometrial tumor', 'Disease', 'MESH:D016889', (129, 146))
586615	31772025	Fbxw7 mice exhibited only small increases in uterine weight, and, while Pten mice showed larger increases, this was due to florid endometrial hyperplasia (a.k.a.	('mice', 'Species', '10090', (77, 81))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (130, 153))	('Fbxw7', 'Var', (0, 5))	('mice', 'Species', '10090', (6, 10))	('uterine', 'MPA', (45, 52))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (130, 153))	('endometrial hyperplasia', 'Disease', (130, 153))	('increases', 'PosReg', (32, 41))
586617	31772025	By 24 wk of age, the difference in uterine weights between Fbxw7/Pten vs. control mice was statistically significant (P < 0.0025, t test), and this difference became even more significant at 36 wk of age (P < 0.0001, t test).	('mice', 'Species', '10090', (82, 86))	('Fbxw7/Pten', 'Var', (59, 69))	('uterine weights', 'CPA', (35, 50))
586618	31772025	Furthermore, 75% of Fbxw7/Pten mice exhibited myometrial invasion by 24 wk, vs. 0% for Pten.	('Fbxw7/Pten', 'Var', (20, 30))	('mice', 'Species', '10090', (31, 35))	('myometrial invasion', 'CPA', (46, 65))
586619	31772025	Per log-rank analysis, survival of Fbxw7/Pten mice was significantly decreased vs. Fbxw7, Pten, or control mice (P < 0.0001 for each of the pairwise comparisons).	('decreased', 'NegReg', (69, 78))	('Fbxw7', 'Var', (83, 88))	('Fbxw7/Pten', 'Var', (35, 45))	('mice', 'Species', '10090', (46, 50))	('mice', 'Species', '10090', (107, 111))	('survival', 'CPA', (23, 31))
586620	31772025	Fbxw7 mice showed slightly but significantly increased survival vs. Pten alone (P = 0.0151; Fig.	('Fbxw7', 'Var', (0, 5))	('mice', 'Species', '10090', (6, 10))	('survival', 'CPA', (55, 63))	('increased', 'PosReg', (45, 54))
586634	31772025	In mTmG;BAC-Sprr2f-Cre females, Cre activity was observed only in endometrial epithelium, with no recombination in endometrial stroma (only endometrial glands turned green).	('endometrial stroma', 'Disease', (115, 133))	('activity', 'MPA', (36, 44))	('Sprr2f', 'Gene', '20760', (12, 18))	('Cre', 'CPA', (32, 35))	('mTmG', 'Var', (3, 7))	('Sprr2f', 'Gene', (12, 18))	('endometrial stroma', 'Disease', 'MESH:D014591', (115, 133))
586638	31772025	All Fbxw7/Pten mice in the survival analysis had metastasis to adjacent organs (ovary, peritoneum), while 58% (15/26) showed distant metastasis.	('Fbxw7/Pten', 'Var', (4, 14))	('metastasis to adjacent organs', 'CPA', (49, 78))	('mice', 'Species', '10090', (15, 19))	('distant metastasis', 'CPA', (125, 143))
586646	31772025	Of the 76 genes, only one:Trp53, the murine homolog of human TP53:was mutated in >=1 tumor (Fig.	('tumor', 'Disease', (85, 90))	('murine', 'Species', '10090', (37, 43))	('human', 'Species', '9606', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Trp53', 'Gene', (26, 31))	('mutated', 'Var', (70, 77))
586647	31772025	All 4 of these tumors harbored mutations leading to amino acid substitutions (A135V, H165R, V170M, R172H) previously documented as recurring cancer drivers in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('A135V', 'Var', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('H165R', 'Mutation', 'rs876659477', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('R172H', 'Mutation', 'p.R172H', (99, 104))	('A135V', 'Mutation', 'p.A135V', (78, 83))	('cancer', 'Disease', (141, 147))	('tumors', 'Disease', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', (165, 171))	('V170M', 'Var', (92, 97))	('V170M', 'Mutation', 'p.V170M', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('H165R', 'Var', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('R172H', 'Var', (99, 104))
586648	31772025	For example, murine R172H corresponds to the human R175H dominant-negative hotspot mutation, and an engineered R172H allele also functions as a genetically dominant oncogene in mice, while murine A135V corresponds to the temperature-sensitive A138V TP53 mutation.	('R175H', 'Mutation', 'rs28934578', (51, 56))	('A135V', 'Var', (196, 201))	('R172H', 'Var', (111, 116))	('A135V', 'Mutation', 'p.A135V', (196, 201))	('human', 'Species', '9606', (45, 50))	('mutation', 'Var', (83, 91))	('murine', 'Species', '10090', (13, 19))	('R172H', 'Mutation', 'p.R172H', (20, 25))	('R172H', 'Var', (20, 25))	('A138V', 'Mutation', 'rs750600586', (243, 248))	('murine', 'Species', '10090', (189, 195))	('mice', 'Species', '10090', (177, 181))	('R172H', 'Mutation', 'p.R172H', (111, 116))
586649	31772025	Only one other mutation was identified among the 76 loci in the 7 cases: KrasG12D in a tumor with no Trp53 mutation but with a "mutant pattern" of p53 overexpression (as detailed later and in Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('KrasG12D', 'Var', (73, 81))	('overexpression', 'PosReg', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
586651	31772025	Intragenic or larger deletions spanning TP53/Trp53 are common cancer-driving events not detectable by exon resequencing, and may account for the observed overexpression/presumptive mutation of p53 protein in the UCS not harboring Trp53 missense mutations.	('UCS', 'Phenotype', 'HP:0002891', (212, 215))	('overexpression/presumptive', 'PosReg', (154, 180))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('deletions', 'Var', (21, 30))	('protein', 'Protein', (197, 204))	('TP53/Trp53', 'Gene', (40, 50))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
586655	31772025	However, the incidence of p53 clonal overexpression by IHC increased over time, reaching 80% in mice euthanized due to illness per tumor burden criteria (Fig.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('p53', 'Var', (26, 29))	('tumor', 'Disease', (131, 136))
586657	31772025	Thus, the incidence of p53 inactivation in these tumors may be >80%.	('inactivation', 'Var', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('p53 inactivation', 'Var', (23, 39))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
586658	31772025	Three of the 4 cases (75%) harboring Tp53 mutations exhibited metastases, vs. 4 of 6 (67%) with either Tp53 mutation or mutant-pattern expression p53 and 22 of 27 (78%) among all mice analyzed as part of the survival curve.	('Tp53', 'Gene', '22059', (37, 41))	('mice', 'Species', '10090', (179, 183))	('exhibited', 'Reg', (52, 61))	('metastases', 'Disease', 'MESH:D009362', (62, 72))	('Tp53', 'Gene', (103, 107))	('Tp53', 'Gene', '22059', (103, 107))	('mutant-pattern', 'Var', (120, 134))	('Tp53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('metastases', 'Disease', (62, 72))
586668	31772025	5A), demonstrating that these known Fbxw7 targets likely mediate the actions of Fbxw7 mutations in uterine cancer.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('uterine cancer', 'Phenotype', 'HP:0010784', (99, 113))	('Fbxw7', 'Gene', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
586672	31772025	In addition, several other EMT regulators, including Zeb-1, Twist, beta-catenin, and Snail were also down-regulated following Fbxw7 reexpression (Fig.	('Zeb-1', 'Gene', '21417', (53, 58))	('Fbxw7', 'Gene', (126, 131))	('reexpression', 'Var', (132, 144))	('Twist', 'Gene', (60, 65))	('beta-catenin', 'Gene', '12387', (67, 79))	('Snail', 'Gene', '20613', (85, 90))	('Snail', 'Gene', (85, 90))	('beta-catenin', 'Gene', (67, 79))	('down-regulated', 'NegReg', (101, 115))	('Zeb-1', 'Gene', (53, 58))	('Twist', 'Gene', '22160', (60, 65))
586675	31772025	Treatment with the PI3K inhibitor LY294002 greatly inhibited Gsk3beta(Ser9) phosphorylation, confirming that Gsk3beta is constitutively phosphorylated by Akt in UCS1/2.	('LY294002', 'Var', (34, 42))	('Ser9', 'Chemical', '-', (70, 74))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('UCS', 'Phenotype', 'HP:0002891', (161, 164))	('inhibited', 'NegReg', (51, 60))	('Gsk3beta', 'Protein', (61, 69))
586678	31772025	Gsk3beta phosphorylates c-Myc at T58, and the T58A mutation renders the c-Myc protein insensitive to Gsk3beta recognition and Fbxw7-mediated degradation.	('T58A', 'Mutation', 'c.58T>A', (46, 50))	('T58A', 'Var', (46, 50))	('insensitive', 'NegReg', (86, 97))
586681	31772025	We then assessed the properties of 3D organoids derived from Pten, Fbxw7, or Fbxw7/Pten adult uteri not harboring overt tumors and grown in defined media.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Fbxw7/Pten', 'Var', (77, 87))
586684	31772025	Fbxw7 mutations have been identified across several human EC histotypes, including endometrioid and serous adenocarcinomas, and also in UCS.	('Fbxw7', 'Gene', (0, 5))	('serous adenocarcinomas', 'Disease', (100, 122))	('human', 'Species', '9606', (52, 57))	('EC', 'Phenotype', 'HP:0012114', (58, 60))	('serous adenocarcinomas', 'Disease', 'MESH:D000230', (100, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('identified', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))	('UCS', 'Phenotype', 'HP:0002891', (136, 139))	('endometrioid', 'Disease', (83, 95))
586686	31772025	Tp53 and Fbxw7 mutations were much more likely to coexist in UCS vs. EC.	('Tp53', 'Gene', (0, 4))	('UCS', 'Disease', (61, 64))	('Tp53', 'Gene', '22059', (0, 4))	('mutations', 'Var', (15, 24))	('EC', 'Phenotype', 'HP:0012114', (69, 71))	('Fbxw7', 'Gene', (9, 14))	('UCS', 'Phenotype', 'HP:0002891', (61, 64))
586688	31772025	This supports our finding that Tp53 and Fbxw7 mutations synergize in the formation of UCS.	('synergize', 'Reg', (56, 65))	('mutations', 'Var', (46, 55))	('UCS', 'Phenotype', 'HP:0002891', (86, 89))	('Tp53', 'Gene', (31, 35))	('UCS', 'Disease', (86, 89))	('Tp53', 'Gene', '22059', (31, 35))	('Fbxw7', 'Gene', (40, 45))
586689	31772025	These findings raise the possibility that adenocarcinomas harboring Fbxw7 mutations are more likely to develop into UCS.	('adenocarcinomas', 'Disease', 'MESH:D000230', (42, 57))	('Fbxw7', 'Gene', (68, 73))	('mutations', 'Var', (74, 83))	('UCS', 'Disease', (116, 119))	('adenocarcinomas', 'Disease', (42, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('develop', 'Reg', (103, 110))	('UCS', 'Phenotype', 'HP:0002891', (116, 119))
586695	31772025	While Fbxw7 has been previously documented to undergo recurrent mutations in UCS, and could be surmised to be a tumor suppressor in UCS, prior studies had not pointed to Fbxw7 as a specific driver of the unique clinicopathologic phenotypes associated with UCS.	('UCS', 'Disease', (256, 259))	('UCS', 'Phenotype', 'HP:0002891', (132, 135))	('Fbxw7', 'Gene', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('UCS', 'Phenotype', 'HP:0002891', (77, 80))	('UCS', 'Phenotype', 'HP:0002891', (256, 259))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', (112, 117))
586696	31772025	Here, by taking advantage of defined genetic model systems, we showed that tumorigenesis driven by concurrent Fbxw7 and Pten mutations progresses in a stereotypical manner.	('mutations', 'Var', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Pten', 'Gene', (120, 124))	('stereotypical manner', 'Phenotype', 'HP:0000733', (151, 171))	('Fbxw7', 'Gene', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
586701	31772025	However, one interesting observation was that Trp53 mutations occurred as late events, since IHC showed that Trp53 mutant clones arose within already invasive endometrioid adenocarcinomas.	('mutant', 'Var', (115, 121))	('invasive endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (150, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('invasive endometrioid adenocarcinomas', 'Disease', (150, 187))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (159, 186))	('Trp53', 'Gene', (109, 114))
586702	31772025	For example, mutations in Fgfr2, Kras, Pik3ca, Pik3r1, or Akt1/2/3 lead to constitutive activation of PI3K/Akt signaling, the central pathway misregulated in essentially all ECs.	('Kras', 'Gene', (33, 37))	('activation', 'PosReg', (88, 98))	('PI3K/Akt signaling', 'Pathway', (102, 120))	('Fgfr2', 'Gene', '14183', (26, 31))	('Pik3r1', 'Gene', '18708', (47, 53))	('EC', 'Phenotype', 'HP:0012114', (174, 176))	('Pik3ca', 'Gene', (39, 45))	('Pik3ca', 'Gene', '18706', (39, 45))	('Pik3r1', 'Gene', (47, 53))	('Akt1/2/3', 'Gene', '11651;11652;23797', (58, 66))	('Fgfr2', 'Gene', (26, 31))	('mutations', 'Var', (13, 22))	('Akt1/2/3', 'Gene', (58, 66))
586703	31772025	This study also provides further evidence that Fbxw7 is a strong p53-dependent tumor suppressor in UCS, as in other human cancers.	('Fbxw7', 'Var', (47, 52))	('UCS', 'Disease', (99, 102))	('tumor', 'Disease', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('UCS', 'Phenotype', 'HP:0002891', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('human', 'Species', '9606', (116, 121))
586705	31772025	This genetic interaction is believed to be mediated by factors regulating cell cycle progression and cell growth, including Cyclin E, Notch, c-Jun, c-Myc, and mTOR, all of which are stabilized following Fbxw7 mutation.	('Notch', 'Gene', (134, 139))	('mediated', 'Reg', (43, 51))	('c-Myc', 'MPA', (148, 153))	('c-Jun', 'Gene', (141, 146))	('mTOR', 'Gene', (159, 163))	('Fbxw7', 'Gene', (203, 208))	('mTOR', 'Gene', '56717', (159, 163))	('mutation', 'Var', (209, 217))	('c-Jun', 'Gene', '16476', (141, 146))	('Notch', 'Gene', '4851;18128', (134, 139))
586706	31772025	Kras appears to be another cooperating oncogene, as evidenced by one murine UCS harboring a mutation (present study) and the presence of Kras mutations in primary UCS.	('mutations', 'Var', (142, 151))	('Kras', 'Gene', (137, 141))	('UCS', 'Phenotype', 'HP:0002891', (76, 79))	('UCS', 'Phenotype', 'HP:0002891', (163, 166))	('murine', 'Species', '10090', (69, 75))
586711	31772025	Using an addback system that permitted controlled reexpression of Fbxw7 in murine UCS lines, we demonstrated that Fbxw7 has an important and specific role as a driver of EMT:and one that is distinct from its cooperating drivers in UCS, Pten, and Trp53.	('murine', 'Species', '10090', (75, 81))	('EMT', 'CPA', (170, 173))	('UCS', 'Phenotype', 'HP:0002891', (231, 234))	('UCS', 'Phenotype', 'HP:0002891', (82, 85))	('Fbxw7', 'Var', (114, 119))
586713	31772025	Klf5 has been implicated in EMT, and, more recently, genetic alterations of the Klf5 locus have been proven oncogenic, including focal amplification of Klf5 superenhancers, as well as missense mutations in degron domains that disrupt Klf5-Fbxw7 interactions to stabilize Klf5 protein.	('disrupt', 'NegReg', (226, 233))	('stabilize', 'PosReg', (261, 270))	('Klf5', 'Gene', '12224', (0, 4))	('missense mutations', 'Var', (184, 202))	('Klf5', 'Gene', '12224', (271, 275))	('Klf5', 'Gene', (152, 156))	('Klf5', 'Gene', (80, 84))	('Klf5', 'Gene', '12224', (234, 238))	('Klf5', 'Gene', '12224', (152, 156))	('Klf5', 'Gene', '12224', (80, 84))	('interactions', 'Interaction', (245, 257))	('Klf5', 'Gene', (271, 275))	('Klf5', 'Gene', (234, 238))	('Klf5', 'Gene', (0, 4))
586724	31772025	Fbxw7 mutations are more frequent in UCS, but also occur in usual-type endometrioid adenocarcinomas, raising questions as to the natural progression of such tumors.	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (71, 98))	('Fbxw7', 'Gene', (0, 5))	('UCS', 'Disease', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('endometrioid adenocarcinomas', 'Disease', (71, 99))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('frequent', 'Reg', (25, 33))	('occur', 'Reg', (51, 56))	('UCS', 'Phenotype', 'HP:0002891', (37, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (71, 99))	('mutations', 'Var', (6, 15))
586727	31772025	This is further suggested by the fact that UCSs are more likely to harbor p53 mutations, and our finding that Fbxw7-mutant endometrioid adenocarcinomas are more likely to express L1CAM, a marker of EMT frequently overexpressed in UCS.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (123, 151))	('express', 'Reg', (171, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('Fbxw7-mutant', 'Var', (110, 122))	('L1CAM', 'Protein', (179, 184))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (123, 150))	('mutations', 'Var', (78, 87))	('p53', 'Gene', (74, 77))	('Fbxw7-mutant', 'Gene', (110, 122))	('endometrioid adenocarcinomas', 'Disease', (123, 151))	('UCSs', 'Disease', (43, 47))	('UCS', 'Phenotype', 'HP:0002891', (43, 46))	('UCSs', 'Disease', 'None', (43, 47))	('UCS', 'Phenotype', 'HP:0002891', (230, 233))
586779	29318761	A metastasis of an osteosarcoma was positive for SATB2 and 2 secondary chondrosarcomas showed expression of S-100, whereas an inguinal lymph node metastasis of a sacral chordoma was confirmed by IHC for the transcription factor brachyury.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (71, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('chondrosarcomas', 'Disease', (71, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('chordoma', 'Phenotype', 'HP:0010762', (169, 177))	('chondrosarcomas', 'Disease', 'MESH:D002813', (71, 86))	('sacral chordoma', 'Disease', 'MESH:D002817', (162, 177))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (71, 86))	('SATB2 and 2', 'Gene', '100687238', (49, 60))	('S-100', 'Var', (108, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (78, 86))	('positive', 'Reg', (36, 44))	('osteosarcoma', 'Disease', (19, 31))	('osteosarcoma', 'Disease', 'MESH:D012516', (19, 31))	('sacral chordoma', 'Disease', (162, 177))
586805	33980253	We further investigated the genomic alterations that may influence tumor infiltration by leukocytes including RB1 loss in undifferentiated pleomorphic sarcomas and ELK3 amplification in dedifferentiated liposarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('RB1', 'Gene', (110, 113))	('influence', 'Reg', (57, 66))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (122, 159))	('undifferentiated pleomorphic sarcomas', 'Disease', (122, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('tumor', 'Disease', (67, 72))	('liposarcomas', 'Disease', 'MESH:D008080', (203, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('RB1', 'Gene', '5925', (110, 113))	('liposarcomas', 'Phenotype', 'HP:0012034', (203, 215))	('liposarcoma', 'Phenotype', 'HP:0012034', (203, 214))	('amplification', 'Var', (169, 182))	('loss', 'NegReg', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ELK3', 'Gene', '2004', (164, 168))	('liposarcomas', 'Disease', (203, 215))	('sarcomas', 'Phenotype', 'HP:0100242', (207, 215))	('ELK3', 'Gene', (164, 168))
586817	33980253	In addition, we also found unique methylation patterns for gastrointestinal stromal tumors (GIST), solitary fibrous tumors (SFT) and myxoid liposarcoma (MLS).	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (133, 151))	('fibrous tumors', 'Disease', (108, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('methylation', 'Var', (34, 45))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (59, 90))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (59, 90))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (133, 151))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('MLS', 'Disease', 'MESH:C537466', (153, 156))	('liposarcoma', 'Phenotype', 'HP:0012034', (140, 151))	('myxoid liposarcoma', 'Disease', (133, 151))	('fibrous tumors', 'Disease', 'MESH:D054364', (108, 122))	('MLS', 'Disease', (153, 156))	('gastrointestinal stromal tumors', 'Disease', (59, 90))
586818	33980253	This procedure resulted in four LMC-specific combinations: hypo- or hypermethylated VMRs that are either positively or negatively correlated with gene expression, respectively (Additional file 1: Figure S6B).	('hypo-', 'Var', (59, 64))	('hypermethylated VMRs', 'Disease', 'None', (68, 88))	('hypermethylated VMRs', 'Disease', (68, 88))	('gene expression', 'MPA', (146, 161))	('negatively', 'NegReg', (119, 129))
586819	33980253	In particular, we were interested in methylation changes resulting in upregulation of gene expression, since these provide insights on gene activity in the LMC-associated tumors and might constitute potential new biomarkers.	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('upregulation', 'PosReg', (70, 82))	('methylation', 'Var', (37, 48))	('gene expression', 'MPA', (86, 101))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
586820	33980253	42 of these genes had hypomethylated and 58 had hypermethylated VMRs.	('hypermethylated VMRs', 'Disease', (48, 68))	('hypermethylated VMRs', 'Disease', 'None', (48, 68))	('hypomethylated', 'Var', (22, 36))
586828	33980253	Of these genes, which we termed 'TIL core signature', 33 had hypomethylated and 65 had hypermethylated regions.	('hypomethylated', 'Var', (61, 75))	('TIL', 'Gene', (33, 36))	('TIL', 'Gene', '7096', (33, 36))
586845	33980253	In UPS, we found a deletion of 13q14.2 with a higher frequency in tumors with low TIL score compared to tumors with high TIL score (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('TIL', 'Gene', (82, 85))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('deletion', 'Var', (19, 27))	('tumors', 'Disease', (66, 72))	('low', 'Var', (78, 81))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('TIL', 'Gene', '7096', (121, 124))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('13q14.2', 'Gene', (31, 38))	('TIL', 'Gene', '7096', (82, 85))	('TIL', 'Gene', (121, 124))
586846	33980253	The genes affected by the deletion events include RB1, ITM2B, LPAR6, LRCH1, RB1-DT, ARL11, EBPL, and KPNA3.	('EBPL', 'Gene', '84650', (91, 95))	('ITM2B', 'Gene', (55, 60))	('KPNA3', 'Gene', '3839', (101, 106))	('RB1', 'Gene', (76, 79))	('KPNA3', 'Gene', (101, 106))	('LPAR6', 'Gene', '10161', (62, 67))	('ITM2B', 'Gene', '9445', (55, 60))	('deletion', 'Var', (26, 34))	('LPAR6', 'Gene', (62, 67))	('ARL11', 'Gene', (84, 89))	('LRCH1', 'Gene', '23143', (69, 74))	('RB1', 'Gene', (50, 53))	('RB1', 'Gene', '5925', (76, 79))	('RB1', 'Gene', '5925', (50, 53))	('LRCH1', 'Gene', (69, 74))	('ARL11', 'Gene', '115761', (84, 89))	('EBPL', 'Gene', (91, 95))
586852	33980253	We also detected fusion events with genes known in the context of cancer such as LGR5-TSPAN8 in the low TIL group (Additional file 1: Table S2).	('LGR5', 'Gene', '8549', (81, 85))	('TSPAN8', 'Gene', '7103', (86, 92))	('TIL', 'Gene', '7096', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('fusion', 'Var', (17, 23))	('LGR5', 'Gene', (81, 85))	('TIL', 'Gene', (104, 107))	('TSPAN8', 'Gene', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
586859	33980253	Our novel approach enabled the discovery of unbiased profiles of methylation changes with altered gene expression, which were significantly associated with histopathological subtypes, tumor tissue localization and degree of immune cell infiltration.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('altered', 'Reg', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('gene expression', 'MPA', (98, 113))	('methylation changes', 'Var', (65, 84))	('tumor', 'Disease', (184, 189))
586885	33980253	In the low TIL UPS subgroup, we detected a 13q14.2 deletion including the tumor suppressor gene RB1.	('TIL', 'Gene', '7096', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('RB1', 'Gene', '5925', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TIL', 'Gene', (11, 14))	('tumor', 'Disease', (74, 79))	('deletion', 'Var', (51, 59))	('RB1', 'Gene', (96, 99))
586886	33980253	These results are in line with a recent pan-cancer analysis, where the authors reported a significant negative correlation between RB1 deletion and their derived immune signature score.	('negative', 'NegReg', (102, 110))	('deletion', 'Var', (135, 143))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('RB1', 'Gene', (131, 134))	('RB1', 'Gene', '5925', (131, 134))	('immune signature score', 'MPA', (162, 184))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
586890	33980253	In the low TIL DDLPS subgroup, we observed a recurrent amplification of chromosome 12q21.1 harboring the multipotent stem cell marker LGR5 and its corresponding upregulation.	('amplification', 'Var', (55, 68))	('TIL', 'Gene', '7096', (11, 14))	('LGR5', 'Gene', (134, 138))	('LGR5', 'Gene', '8549', (134, 138))	('TIL', 'Gene', (11, 14))	('upregulation', 'PosReg', (161, 173))
586897	33980253	We also observed frequent mutations of BAGE2, a cancer testis antigen, in the high TIL DDLPS group.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('TIL', 'Gene', '7096', (83, 86))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer testis', 'Phenotype', 'HP:0010788', (48, 61))	('TIL', 'Gene', (83, 86))	('BAGE2', 'Gene', (39, 44))	('BAGE2', 'Gene', '85319', (39, 44))
586898	33980253	Mutations in BAGE2 have been hypothesized to play a role in immune evasion in osteosarcomas.	('role', 'Reg', (52, 56))	('BAGE2', 'Gene', (13, 18))	('immune evasion', 'MPA', (60, 74))	('osteosarcomas', 'Disease', 'MESH:D012516', (78, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('BAGE2', 'Gene', '85319', (13, 18))	('Mutations', 'Var', (0, 9))	('play', 'Reg', (45, 49))	('osteosarcomas', 'Disease', (78, 91))	('osteosarcomas', 'Phenotype', 'HP:0002669', (78, 91))
586899	33980253	However, functional validations are required to test the role of these alterations in cancer with respect to TIL.	('TIL', 'Gene', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TIL', 'Gene', '7096', (109, 112))	('alterations', 'Var', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
586902	33980253	We used the TCGA legacy data portal (https://portal.gdc.cancer.gov/legacy-archive) to download molecular data including level 2 Infinium Illumina HumanMethylation450 BeadChip (HM450K) array, level 3 whole-transcriptome RNA-sequencing data, level 2 non-silent somatic single nucleotide variations called by MuTect (v.1.1.6), and copy number variation data (segmented data from Affymetrix SNP array 6.0, level 3) of the SARC cohort.	('copy number variation', 'Var', (328, 349))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('Illumina', 'Chemical', '-', (137, 145))
586970	32471035	We observed in total an overlay of 66 (2%) spliced RNAs between all three signatures, whereas the majority appears to be uniquely present in any of the signatures (for LGG: 1168/1711 (68%); for NSCLC: 533/1000 (53%); for sarcoma: 472/824 (57%), Figure S2).	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('sarcoma', 'Disease', 'MESH:D012509', (221, 228))	('NSCLC', 'Disease', (194, 199))	('sarcoma', 'Disease', (221, 228))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('RNAs', 'Var', (51, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('spliced', 'Var', (43, 50))
587020	32471035	(Nik Sol), F.v.C., R.L.H., J.H.B., T.W., W.J.v.H., N.S.	('Nik', 'Gene', '9020', (1, 4))	('R.L.H.', 'Var', (19, 25))	('J.H.B.', 'Var', (27, 33))	('W.J.v.H.', 'Var', (41, 49))	('Nik', 'Gene', (1, 4))
587022	32471035	(Nik Sol), F.v.C., R.L.H., J.H.B., W.J.v.H., N.S.	('Nik', 'Gene', '9020', (1, 4))	('R.L.H.', 'Var', (19, 25))	('J.H.B.', 'Var', (27, 33))	('Nik', 'Gene', (1, 4))	('W.J.v.H.', 'Var', (35, 43))
587189	30708357	However, according to the Rose criterion (CNR > 5) applied to the experimental results (see figure 5), the detectability limits were approximately 2.5 mg ml-1 for both DE-EID CT and PCD CT, even if the radiation dose was approximately 3.8 times lower with PCD CT.	('PCD', 'Chemical', '-', (182, 185))	('CNR > 5', 'Gene', '192164', (42, 49))	('DE-EID CT', 'Var', (168, 177))	('CNR > 5', 'Gene', (42, 49))	('PCD', 'Chemical', '-', (256, 259))	('DE-EID', 'Chemical', '-', (168, 174))
587202	22022506	TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt.	('decrease', 'NegReg', (177, 185))	('decreased', 'NegReg', (60, 69))	('IGF-1R', 'Gene', (191, 197))	('IGF-1R', 'Gene', '3480', (191, 197))	('Akt', 'Gene', '207', (214, 217))	('internalization/degradation', 'MPA', (110, 137))	('IRS-1', 'Gene', '3667', (201, 206))	('TC-71', 'CellLine', 'CVCL:2213', (0, 5))	('high levels of IGF-1R', 'Phenotype', 'HP:0030269', (27, 48))	('IRS-1', 'Gene', (201, 206))	('Akt', 'Gene', (214, 217))	('IGF-1R', 'Gene', '3480', (42, 48))	('R1507', 'Var', (54, 59))	('IGF-1R', 'Gene', (42, 48))
587214	22022506	We demonstrate that the anti-IGF-1R antibody (R1507) and small interfering RNA (siRNA) against the Ewing's fusion protein (EWS/FLI-1) suppress a common pathway involving the IGF/IGFR/Akt axis through inhibition of different targets in the IGF/IGF-1R cascade.	('FLI-1', 'Gene', (127, 132))	('IGF-1R', 'Gene', (29, 35))	('inhibition', 'NegReg', (200, 210))	('Akt', 'Gene', (183, 186))	('IGFR', 'Gene', (178, 182))	('R1507', 'Var', (46, 51))	('IGF-1R', 'Gene', (243, 249))	('FLI-1', 'Gene', '2313', (127, 132))	('EWS', 'Gene', '2130', (123, 126))	('EWS', 'Gene', (123, 126))	('IGF-1R', 'Gene', '3480', (243, 249))	('IGFR', 'Gene', '3480', (178, 182))	('suppress', 'NegReg', (134, 142))	('Akt', 'Gene', '207', (183, 186))	('IGF-1R', 'Gene', '3480', (29, 35))
587224	22022506	R1507, a fully human IgG1 monoclonal antibody to IGF-1R, (Roche Diagnostics, Penzberg, Germany), was diluted in medium immediately before use.	('IGF-1R', 'Gene', (49, 55))	('IGF-1R', 'Gene', '3480', (49, 55))	('human', 'Species', '9606', (15, 20))	('R1507', 'Var', (0, 5))
587226	22022506	Primary antibodies included rabbit polyclonal antibody against ERK1/2, p-ERK1/2, IGF-1Rbeta, phosphorylated (p)-IGF-1R (Tyr 1135/1136), Akt, and p-Akt, (ser 473) (Cell Signaling), anti -IRS-1 and -p-IRS-1 (Tyr 612) (Upstate Cell Signaling Solutions), anti-EWS, -IGF-2, -IGF-2R, and -GAPDH (Santa Cruz Biotechnology).	('IGF-2', 'Gene', (262, 267))	('ser', 'Chemical', 'MESH:D012694', (153, 156))	('IGF-2', 'Gene', '3481', (262, 267))	('IGF-1R', 'Gene', '3480', (81, 87))	('IGF-1R', 'Gene', '3480', (112, 118))	('IGF-1R', 'Gene', (81, 87))	('IGF-1R', 'Gene', (112, 118))	('Akt', 'Gene', '207', (136, 139))	('EWS', 'Gene', (256, 259))	('IRS-1', 'Gene', '3667', (199, 204))	('IGF-2R', 'Gene', '3482', (270, 276))	('IGF-2', 'Gene', (270, 275))	('IGF-2', 'Gene', '3481', (270, 275))	('IGF-2R', 'Gene', (270, 276))	('IRS-1', 'Gene', (186, 191))	('rabbit', 'Species', '9986', (28, 34))	('Akt', 'Gene', (147, 150))	('Akt', 'Gene', '207', (147, 150))	('EWS', 'Gene', '2130', (256, 259))	('GAPDH', 'Gene', '2597', (283, 288))	('Tyr', 'Chemical', 'MESH:D014443', (120, 123))	('Tyr', 'Chemical', 'MESH:D014443', (206, 209))	('IRS-1', 'Gene', (199, 204))	('IRS-1', 'Gene', '3667', (186, 191))	('Tyr 1135/1136', 'Var', (120, 133))	('GAPDH', 'Gene', (283, 288))	('Akt', 'Gene', (136, 139))
587234	22022506	Clonogenic assays were performed to determine the effect of R1507 antibody and EWS/FLI-1 siRNA on Ewing's sarcoma cell growth.	('EWS', 'Gene', '2130', (79, 82))	('EWS', 'Gene', (79, 82))	('FLI-1', 'Gene', (83, 88))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (98, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('FLI-1', 'Gene', '2313', (83, 88))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (98, 113))	('R1507', 'Var', (60, 65))	("Ewing's sarcoma", 'Disease', (98, 113))
587235	22022506	1x103 cells per well of a 6 well plate coated with 1% gelatin were seeded in media containing 10% FCS, and either treated with a single dose of 1-50 microg/ml R1507 or transfected with EWS/FLI-1 siRNA and allowed to grow for 1 week.	('EWS', 'Gene', '2130', (185, 188))	('EWS', 'Gene', (185, 188))	('1x', 'Chemical', '-', (0, 2))	('R1507', 'Var', (159, 164))	('FLI-1', 'Gene', '2313', (189, 194))	('FLI-1', 'Gene', (189, 194))
587240	22022506	A4573, RD-ES, TC-32, and TC-71 Ewing's sarcoma cell lines all contain the EWS/FLI-1 translocation t(11;22)(q24;q12).	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (31, 46))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (98, 115))	("Ewing's sarcoma", 'Disease', (31, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('TC-32', 'CellLine', 'CVCL:7151', (14, 19))	('EWS', 'Gene', (74, 77))	('EWS', 'Gene', '2130', (74, 77))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (31, 46))	('FLI-1', 'Gene', '2313', (78, 83))	('FLI-1', 'Gene', (78, 83))	('TC-71', 'CellLine', 'CVCL:2213', (25, 30))	('RD-ES', 'Chemical', '-', (7, 12))	('t(11;22)(q24;q12', 'Var', (98, 114))
587241	22022506	RT-PCR confirmed that A4573 expresses the type 3 fusion protein, RD-ES expresses type 2, and TC-32 and TC-71 express type 1 (Figure 1a).	('A4573', 'Var', (22, 27))	('TC-32', 'CellLine', 'CVCL:7151', (93, 98))	('TC-71', 'CellLine', 'CVCL:2213', (103, 108))	('RD-ES', 'Chemical', '-', (65, 70))	('type 3 fusion protein', 'Protein', (42, 63))
587244	22022506	Figure 1b shows the different types of fusion proteins predicted from variable exon joining of the EWS and FLI-1 genes.	('FLI-1', 'Gene', '2313', (107, 112))	('FLI-1', 'Gene', (107, 112))	('EWS', 'Gene', '2130', (99, 102))	('EWS', 'Gene', (99, 102))	('variable exon joining', 'Var', (70, 91))
587249	22022506	Expression of total IGF-1R was highest in TC-71 and A4573, followed by TC-32 and RD-ES cells, as determined by densitometry.	('Expression', 'MPA', (0, 10))	('A4573', 'Var', (52, 57))	('highest', 'Reg', (31, 38))	('IGF-1R', 'Gene', '3480', (20, 26))	('RD-ES', 'Chemical', '-', (81, 86))	('TC-71', 'CellLine', 'CVCL:2213', (42, 47))	('IGF-1R', 'Gene', (20, 26))	('TC-32', 'CellLine', 'CVCL:7151', (71, 76))
587252	22022506	RD-ES, TC-32, and TC-71 expressed similar baseline levels of total IRS-1, while A4573 contained the least (Figure 1d).	('TC-32', 'CellLine', 'CVCL:7151', (7, 12))	('IRS-1', 'Gene', '3667', (67, 72))	('TC-71', 'CellLine', 'CVCL:2213', (18, 23))	('A4573', 'Var', (80, 85))	('RD-ES', 'Chemical', '-', (0, 5))	('IRS-1', 'Gene', (67, 72))
587257	22022506	Mutations in IGF-2R have been found in many types of cancer (see Discussion), and may predict response to IGF-1R inhibitors.	('predict', 'Reg', (86, 93))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('found', 'Reg', (30, 35))	('IGF-1R', 'Gene', '3480', (106, 112))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('IGF-1R', 'Gene', (106, 112))	('IGF-2R', 'Gene', '3482', (13, 19))	('IGF-2R', 'Gene', (13, 19))
587258	22022506	Certain mutations reduce the amount of IGF-2R expressed on the cell surface, and increase the amount of free IGF-2, thereby allowing enhanced signaling through IGF-1R.	('IGF-1R', 'Gene', '3480', (160, 166))	('IGF-2', 'Gene', '3481', (109, 114))	('amount', 'MPA', (94, 100))	('IGF-2R', 'Gene', (39, 45))	('IGF-1R', 'Gene', (160, 166))	('amount', 'MPA', (29, 35))	('mutations', 'Var', (8, 17))	('reduce', 'NegReg', (18, 24))	('signaling', 'MPA', (142, 151))	('IGF-2R', 'Gene', '3482', (39, 45))	('IGF-2', 'Gene', (39, 44))	('increase the amount of free IGF-2', 'Phenotype', 'HP:0030269', (81, 114))	('IGF-2', 'Gene', '3481', (39, 44))	('increase', 'PosReg', (81, 89))	('IGF-2', 'Gene', (109, 114))	('enhanced', 'PosReg', (133, 141))
587261	22022506	A4573 cells contain the G>A single nucleotide polymorphism (SNP) (GA) at nucleotide position 5004 in the IGF-2R cDNA, which results in an arginine at amino acid position 1619 of the IGF-2 binding domain.	('IGF-2', 'Gene', (182, 187))	('binding', 'Interaction', (188, 195))	('results in an', 'Reg', (124, 137))	('arginine', 'Var', (138, 146))	('IGF-2', 'Gene', '3481', (182, 187))	('IGF-2R', 'Gene', (105, 111))	('single nucleotide polymorphism', 'Var', (28, 58))	('IGF-2R', 'Gene', '3482', (105, 111))	('arginine', 'Chemical', 'MESH:D001120', (138, 146))	('IGF-2', 'Gene', (105, 110))	('IGF-2', 'Gene', '3481', (105, 110))
587263	22022506	TC-32, TC-71, and RD-ES, which all express IGF-2, contain the A>G SNP (GG) at nucleotide position 5004 of IGF-2R, which corresponds to a glycine at amino acid position 1619 (Table 1).	('TC-32', 'CellLine', 'CVCL:7151', (0, 5))	('A>G', 'Var', (62, 65))	('RD-ES', 'Chemical', '-', (18, 23))	('TC-71', 'CellLine', 'CVCL:2213', (7, 12))	('IGF-2R', 'Gene', '3482', (106, 112))	('IGF-2R', 'Gene', (106, 112))	('IGF-2', 'Gene', (43, 48))	('IGF-2', 'Gene', '3481', (43, 48))	('IGF-2', 'Gene', (106, 111))	('IGF-2', 'Gene', '3481', (106, 111))	('glycine', 'Chemical', 'MESH:D005998', (137, 144))
587277	22022506	R1507 significantly decreased colony formation of TC-32 cells starting at 1 microg/ml (p = 0.025) and TC-71 starting at 5 microg/ml (p = 0.036) (Figure 3a).	('TC-32', 'CellLine', 'CVCL:7151', (50, 55))	('decreased', 'NegReg', (20, 29))	('TC-71', 'CellLine', 'CVCL:2213', (102, 107))	('colony formation', 'CPA', (30, 46))	('R1507', 'Var', (0, 5))
587278	22022506	Inhibition of colony formation appears to be dose-dependent in TC-71 cells, whereas colony formation in TC-32 cells drops off rapidly at 1 microg/ml R1507.	('Inhibition', 'NegReg', (0, 10))	('colony formation', 'CPA', (84, 100))	('drops off', 'NegReg', (116, 125))	('TC-71', 'CellLine', 'CVCL:2213', (63, 68))	('R1507', 'Var', (149, 154))	('TC-32', 'CellLine', 'CVCL:7151', (104, 109))	('colony formation', 'CPA', (14, 30))
587279	22022506	TC-71 cells were also treated with high dose (100 microg/ml) R1507 which resulted in a decrease in colony formation of 95% (data not shown).	('colony formation', 'CPA', (99, 115))	('TC-71', 'CellLine', 'CVCL:2213', (0, 5))	('decrease', 'NegReg', (87, 95))	('R1507', 'Var', (61, 66))
587283	22022506	TC-71 colony formation significantly decreased following transfection with EWS/FLI-1 specific siRNA (p<0.001, Figure 3b).	('TC-71', 'Gene', (0, 5))	('transfection', 'Var', (57, 69))	('TC-71', 'CellLine', 'CVCL:2213', (0, 5))	('EWS', 'Gene', '2130', (75, 78))	('EWS', 'Gene', (75, 78))	('FLI-1', 'Gene', '2313', (79, 84))	('decreased', 'NegReg', (37, 46))	('FLI-1', 'Gene', (79, 84))
587290	22022506	In contrast, there was no significant increase in the percent of TC-71 cells undergoing apoptosis following treatment with either 25 or 100 microg/ml R1507 compared to a non-specific isotypic control (Figure 3d).	('apoptosis', 'CPA', (88, 97))	('TC-71', 'CellLine', 'CVCL:2213', (65, 70))	('R1507', 'Var', (150, 155))
587293	22022506	IGF-BP3 increased 2-fold after EWS/FLI-1 siRNA transfection in TC-71 cells compared with non-targeted siRNA (p = 0.02, Figure 4a).	('EWS', 'Gene', (31, 34))	('FLI-1', 'Gene', '2313', (35, 40))	('FLI-1', 'Gene', (35, 40))	('transfection', 'Var', (47, 59))	('IGF-BP3', 'Gene', (0, 7))	('IGF-BP3', 'Gene', '3486', (0, 7))	('TC-71', 'CellLine', 'CVCL:2213', (63, 68))	('increased', 'PosReg', (8, 17))	('EWS', 'Gene', '2130', (31, 34))
587296	22022506	IGF-2, which also binds IGF-BP3, decreases following transfection with EWS/FLI-1 siRNA as measured by ELISA (n = 12 repeats, p = 0.02, data not shown).	('transfection', 'Var', (53, 65))	('IGF-2', 'Gene', '3481', (0, 5))	('EWS', 'Gene', '2130', (71, 74))	('EWS', 'Gene', (71, 74))	('IGF-BP3', 'Gene', (24, 31))	('FLI-1', 'Gene', '2313', (75, 80))	('decreases', 'NegReg', (33, 42))	('FLI-1', 'Gene', (75, 80))	('IGF-BP3', 'Gene', '3486', (24, 31))	('IGF-2', 'Gene', (0, 5))
587301	22022506	Phosphorylation of Akt indicates the activation of growth stimulatory pathways by IGF.	('Akt', 'Gene', '207', (19, 22))	('activation', 'PosReg', (37, 47))	('Phosphorylation', 'MPA', (0, 15))	('Akt', 'Gene', (19, 22))	('growth stimulatory pathways', 'Pathway', (51, 78))	('IGF', 'Var', (82, 85))
587303	22022506	R1507 down-regulated total IGF-1R levels because exposure to anti-IGF-1R antibody causes internalization and degradation of the receptor (Figure 4c, right-hand panel), which results in decreased p-IGF-1R.	('IGF-1R', 'Gene', (66, 72))	('decreased', 'NegReg', (185, 194))	('internalization', 'MPA', (89, 104))	('IGF-1R', 'Gene', '3480', (197, 203))	('down-regulated', 'NegReg', (6, 20))	('decreased p-IGF', 'Phenotype', 'HP:0002850', (185, 200))	('IGF-1R', 'Gene', (197, 203))	('degradation', 'MPA', (109, 120))	('IGF-1R', 'Gene', '3480', (27, 33))	('IGF-1R', 'Gene', (27, 33))	('IGF-1R', 'Gene', '3480', (66, 72))	('R1507', 'Var', (0, 5))
587304	22022506	Additionally, R1507 competes with IGF-1 and IGF-2 for binding to the IGF-1R, thus decreasing signaling (personal communication, K-P Kuenkele).	('IGF-1R', 'Gene', (69, 75))	('R1507', 'Var', (14, 19))	('binding', 'Interaction', (54, 61))	('IGF-1R', 'Gene', '3480', (69, 75))	('decreasing', 'NegReg', (82, 92))	('signaling', 'MPA', (93, 102))	('IGF-1', 'Gene', '3479', (34, 39))	('IGF-1', 'Gene', (34, 39))	('IGF-2', 'Gene', (44, 49))	('IGF-1', 'Gene', '3479', (69, 74))	('IGF-2', 'Gene', '3481', (44, 49))	('IGF-1', 'Gene', (69, 74))
587305	22022506	R1507 also decreased p-IRS-1, and down-regulated Akt phosphorylation in a dose-dependent manner as a downstream effect resulting from the decrease in p-IGF-1R, while total IRS-1 and Akt levels remained unchanged.	('R1507', 'Var', (0, 5))	('IRS-1', 'Gene', (172, 177))	('IGF-1R', 'Gene', '3480', (152, 158))	('down-regulated', 'NegReg', (34, 48))	('decreased', 'NegReg', (11, 20))	('IGF-1R', 'Gene', (152, 158))	('IRS-1', 'Gene', '3667', (23, 28))	('Akt', 'Gene', '207', (182, 185))	('IRS-1', 'Gene', (23, 28))	('Akt', 'Gene', '207', (49, 52))	('decrease', 'NegReg', (138, 146))	('Akt', 'Gene', (182, 185))	('IRS-1', 'Gene', '3667', (172, 177))	('Akt', 'Gene', (49, 52))
587307	22022506	rIGF-1 was unable to fully restore p-Akt or p-IGF-1R to pretreatment levels in the presence of EWS/FLI-1 siRNA or R1507 (lanes 1&6 left panel, lanes 1&8 right panel), but p-Akt and p-IGF-1R did increase slightly in the rIGF-1 plus EWS/FLI-1 siRNA or R1507 treated cells compared to cells treated with siRNA or R1507 alone (compare lanes 3&6 left panel and lanes 4&8, right panel, Figure 4c).	('rIGF-1', 'Gene', '24482', (219, 225))	('Akt', 'Gene', (173, 176))	('rIGF-1', 'Gene', (0, 6))	('Akt', 'Gene', '207', (173, 176))	('IGF-1R', 'Gene', '3480', (183, 189))	('IGF-1R', 'Gene', (183, 189))	('EWS', 'Gene', (231, 234))	('rIGF-1', 'Gene', (219, 225))	('FLI-1', 'Gene', '2313', (235, 240))	('Akt', 'Gene', (37, 40))	('EWS', 'Gene', (95, 98))	('IGF-1R', 'Gene', '3480', (46, 52))	('Akt', 'Gene', '207', (37, 40))	('IGF-1R', 'Gene', (46, 52))	('FLI-1', 'Gene', (235, 240))	('FLI-1', 'Gene', '2313', (99, 104))	('siRNA', 'Var', (241, 246))	('rIGF-1', 'Gene', '24482', (0, 6))	('EWS', 'Gene', '2130', (231, 234))	('EWS', 'Gene', '2130', (95, 98))	('FLI-1', 'Gene', (99, 104))
587308	22022506	The inability of R1507 or EWS/FLI-1 siRNA to completely abolish p-Akt, especially in the presence of rIGF-1, indicates that Akt is activated by other pathways in these cells, (e.g.	('Akt', 'Gene', (66, 69))	('Akt', 'Gene', (124, 127))	('R1507', 'Var', (17, 22))	('abolish', 'NegReg', (56, 63))	('EWS', 'Gene', (26, 29))	('Akt', 'Gene', '207', (66, 69))	('EWS', 'Gene', '2130', (26, 29))	('FLI-1', 'Gene', (30, 35))	('FLI-1', 'Gene', '2313', (30, 35))	('rIGF-1', 'Gene', '24482', (101, 107))	('Akt', 'Gene', '207', (124, 127))	('rIGF-1', 'Gene', (101, 107))
587311	22022506	Interestingly, R1507 treatment or EWS/FLI-1 siRNA transfection did not inhibit ERK 1/2 signaling, but rather resulted in increased ERK 1/2 phosphorylation (Figure 4c), perhaps because an alternative pathway to IGF was activated.	('EWS', 'Gene', (34, 37))	('FLI-1', 'Gene', (38, 43))	('ERK 1/2', 'Gene', (79, 86))	('ERK 1/2', 'Gene', '5595;5594', (131, 138))	('ERK 1/2', 'Gene', (131, 138))	('inhibit', 'NegReg', (71, 78))	('increased', 'PosReg', (121, 130))	('R1507 treatment', 'Var', (15, 30))	('ERK 1/2', 'Gene', '5595;5594', (79, 86))	('FLI-1', 'Gene', '2313', (38, 43))	('EWS', 'Gene', '2130', (34, 37))
587315	22022506	Down-regulation of p-Akt by anti-IGF-1R antibodies occurs in cells of many different lineages, including small cell lung cancer (SCLC), acute myeloid leukemia, and non-small cell lung cancer.	('IGF-1R', 'Gene', '3480', (33, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('IGF-1R', 'Gene', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (142, 158))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (136, 158))	('Akt', 'Gene', (21, 24))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (136, 158))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (164, 190))	('SCLC', 'Disease', (129, 133))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (105, 127))	('Akt', 'Gene', '207', (21, 24))	('Down-regulation', 'NegReg', (0, 15))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (168, 190))	('antibodies', 'Var', (40, 50))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (164, 190))	('small cell lung cancer', 'Disease', 'MESH:D055752', (105, 127))	('acute myeloid leukemia', 'Disease', (136, 158))	('SCLC', 'Disease', 'MESH:D018288', (129, 133))	('small cell lung cancer', 'Disease', 'MESH:D055752', (168, 190))	('non-small cell lung cancer', 'Disease', (164, 190))	('small cell lung cancer', 'Disease', (105, 127))
587317	22022506	Recent clinical trials have demonstrated that IGF-1R inhibitors can induce remarkable responses in some patients with advanced disease.	('inhibitors', 'Var', (53, 63))	('responses', 'MPA', (86, 95))	('IGF-1R', 'Gene', '3480', (46, 52))	('IGF-1R', 'Gene', (46, 52))	('advanced disease', 'Disease', (118, 134))	('advanced disease', 'Disease', 'MESH:D020178', (118, 134))	('patients', 'Species', '9606', (104, 112))
587318	22022506	The genetic hallmark of Ewing's sarcoma is the formation of the aberrant EWS/FLI-1 transcription factor.	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (24, 39))	('EWS', 'Gene', '2130', (73, 76))	('EWS', 'Gene', (73, 76))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (24, 39))	("Ewing's sarcoma", 'Disease', (24, 39))	('FLI-1', 'Gene', '2313', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('FLI-1', 'Gene', (77, 82))	('aberrant', 'Var', (64, 72))
587319	22022506	Our results suggest that EWS/FLI-1 siRNA and R1507, a fully human anti-IGF-1R antibody, inhibit a common IGF signaling pathway that converges on the suppression of p-Akt.	('IGF-1R', 'Gene', '3480', (71, 77))	('IGF-1R', 'Gene', (71, 77))	('Akt', 'Gene', (166, 169))	('R1507', 'Var', (45, 50))	('inhibit', 'NegReg', (88, 95))	('FLI-1', 'Gene', '2313', (29, 34))	('FLI-1', 'Gene', (29, 34))	('human', 'Species', '9606', (60, 65))	('Akt', 'Gene', '207', (166, 169))	('IGF signaling pathway', 'Pathway', (105, 126))	('EWS', 'Gene', '2130', (25, 28))	('EWS', 'Gene', (25, 28))
587322	22022506	R1507 exerts its negative impact on Akt phosphorylation by causing internalization and degradation of total IGF-1R, and by competing with IGF-1 and IGF-2 for binding to IGF-1R.	('IGF-1R', 'Gene', '3480', (169, 175))	('IGF-1R', 'Gene', (169, 175))	('degradation', 'MPA', (87, 98))	('internalization', 'MPA', (67, 82))	('IGF-1', 'Gene', (138, 143))	('IGF-1', 'Gene', (108, 113))	('IGF-2', 'Gene', (148, 153))	('Akt', 'Gene', (36, 39))	('IGF-2', 'Gene', '3481', (148, 153))	('IGF-1', 'Gene', '3479', (138, 143))	('Akt', 'Gene', '207', (36, 39))	('R1507', 'Var', (0, 5))	('IGF-1', 'Gene', '3479', (108, 113))	('IGF-1', 'Gene', (169, 174))	('negative', 'NegReg', (17, 25))	('binding', 'Interaction', (158, 165))	('IGF-1R', 'Gene', (108, 114))	('IGF-1R', 'Gene', '3480', (108, 114))	('IGF-1', 'Gene', '3479', (169, 174))	('competing', 'NegReg', (123, 132))
587324	22022506	Although many receptor tyrosine kinases (RTK) signal through the Akt pathway, treatment with R1507 specifically inhibits signaling through IGF-1R since R1507 does not cross-react with other receptors.	('IGF-1R', 'Gene', (139, 145))	('IGF-1R', 'Gene', '3480', (139, 145))	('Akt', 'Gene', (65, 68))	('R1507', 'Var', (93, 98))	('signal', 'Reg', (46, 52))	('signaling', 'MPA', (121, 130))	('Akt', 'Gene', '207', (65, 68))	('inhibits', 'NegReg', (112, 120))
587325	22022506	The decrease in p-Akt after treatment with increasing concentrations of R1507 reflects the change in phosphorylation due to increasing IGF-1R inhibition, and is dose-dependent (Figure 4c).	('IGF-1R', 'Gene', '3480', (135, 141))	('IGF-1R', 'Gene', (135, 141))	('Akt', 'Gene', (18, 21))	('inhibition', 'NegReg', (142, 152))	('R1507', 'Var', (72, 77))	('decrease', 'NegReg', (4, 12))	('Akt', 'Gene', '207', (18, 21))	('increasing IGF-1R', 'Phenotype', 'HP:0030269', (124, 141))	('increasing', 'PosReg', (124, 134))	('phosphorylation', 'MPA', (101, 116))
587326	22022506	Residual Akt phosphorylation seen after R1507 treatment may be due to other RTKs, whereas phosphorylation of IGF-1R is inhibited completely at the lowest dose of R1507 due to its specificity.	('Akt', 'Gene', (9, 12))	('IGF-1R', 'Gene', '3480', (109, 115))	('IGF-1R', 'Gene', (109, 115))	('due', 'Reg', (63, 66))	('R1507', 'Var', (40, 45))	('Akt', 'Gene', '207', (9, 12))
587327	22022506	MAP kinase signaling was not inhibited by R1507 or EWS/FLI-1 siRNA, however, p-ERK 1/2 levels increased after blocking the IGF-1 pathway with R1507 or EWS/FLI-1 siRNA, perhaps as a compensatory signaling pathway.	('EWS', 'Gene', '2130', (51, 54))	('EWS', 'Gene', (51, 54))	('ERK 1/2', 'Gene', (79, 86))	('FLI-1', 'Gene', '2313', (55, 60))	('FLI-1', 'Gene', '2313', (155, 160))	('FLI-1', 'Gene', (155, 160))	('blocking', 'NegReg', (110, 118))	('FLI-1', 'Gene', (55, 60))	('increased', 'PosReg', (94, 103))	('R1507', 'Var', (142, 147))	('ERK 1/2', 'Gene', '5595;5594', (79, 86))	('IGF-1', 'Gene', '3479', (123, 128))	('IGF-1', 'Gene', (123, 128))	('EWS', 'Gene', '2130', (151, 154))	('EWS', 'Gene', (151, 154))
587329	22022506	Ewing's sarcoma cell lines bearing type 1 EWS/FLI-1 fusion proteins have been postulated to be less virulent than their type 2- and 3- expressing counterparts and patients bearing the type 1 fusion protein were thought to have an improved outcome compared to those expressing other fusion protein types.	("Ewing's sarcoma", 'Disease', (0, 15))	('patients', 'Species', '9606', (163, 171))	('fusion proteins', 'Var', (52, 67))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('FLI-1', 'Gene', '2313', (46, 51))	('FLI-1', 'Gene', (46, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('less', 'NegReg', (95, 99))	('virulent', 'MPA', (100, 108))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
587333	22022506	Why some patients respond to anti-IGF-1R antibodies and others do not is much more complicated than just the type of fusion protein they harbor (Table 1).	('patients', 'Species', '9606', (9, 17))	('antibodies', 'Var', (41, 51))	('respond', 'Reg', (18, 25))	('IGF-1R', 'Gene', '3480', (34, 40))	('IGF-1R', 'Gene', (34, 40))
587334	22022506	The degree of inhibition of Ewing's sarcoma cell growth by R1507 may vary with assay conditions (K-P Kuenkele, personal communication).	('R1507', 'Var', (59, 64))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (28, 43))	("Ewing's sarcoma", 'Disease', (28, 43))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (28, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))
587336	22022506	Indeed, total IGF-1R expression level was not predictive of a response to R1507 in our cell lines, as previously reported for a different anti-IGF-1R antibody (h7C10, Merck) in rhabdomyosarcoma and R1507 and AMG479 in osteosarcoma.	('IGF-1R', 'Gene', (14, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('rhabdomyosarcoma', 'Disease', (177, 193))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (177, 193))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (177, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('AMG', 'Gene', '265', (208, 211))	('AMG', 'Gene', (208, 211))	('IGF-1R', 'Gene', '3480', (143, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (218, 230))	('IGF-1R', 'Gene', (143, 149))	('R1507', 'Var', (198, 203))	('IGF-1R', 'Gene', '3480', (14, 20))	('osteosarcoma', 'Disease', (218, 230))	('osteosarcoma', 'Disease', 'MESH:D012516', (218, 230))
587338	22022506	Several mutations inactivate and/or down-regulate IGF-2R, resulting in increased levels of IGF-2, and increased signaling through IGF-1R.	('down-regulate', 'NegReg', (36, 49))	('mutations inactivate', 'Var', (8, 28))	('signaling', 'MPA', (112, 121))	('IGF-1R', 'Gene', '3480', (130, 136))	('IGF-2', 'Gene', '3481', (91, 96))	('IGF-1R', 'Gene', (130, 136))	('IGF-2R', 'Gene', '3482', (50, 56))	('IGF-2R', 'Gene', (50, 56))	('inactivate', 'Var', (18, 28))	('increased levels of IGF', 'Phenotype', 'HP:0003496', (71, 94))	('increased', 'PosReg', (71, 80))	('increased', 'PosReg', (102, 111))	('IGF-2', 'Gene', (91, 96))	('increased levels of IGF-2', 'Phenotype', 'HP:0030269', (71, 96))	('IGF-2', 'Gene', (50, 55))	('IGF-2', 'Gene', '3481', (50, 55))
587340	22022506	This topic merits further investigation because preclinical studies have shown that several cancers expressing high levels of IGF-2 due to IGF-2R mutation and loss of heterozygosity (LOH) are more responsive to both anti-IGF-1R antibodies and anti-sense directed against IGF-2 or IGF-1R.	('IGF-1R', 'Gene', '3480', (280, 286))	('IGF-2', 'Gene', (271, 276))	('more', 'PosReg', (192, 196))	('IGF-1R', 'Gene', (280, 286))	('IGF-2', 'Gene', '3481', (271, 276))	('loss', 'Var', (159, 163))	('mutation', 'Var', (146, 154))	('IGF-2', 'Gene', (126, 131))	('IGF-2', 'Gene', '3481', (126, 131))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('IGF-1R', 'Gene', '3480', (221, 227))	('IGF-2R', 'Gene', '3482', (139, 145))	('IGF-1R', 'Gene', (221, 227))	('responsive', 'MPA', (197, 207))	('IGF-2', 'Gene', (139, 144))	('IGF-2', 'Gene', '3481', (139, 144))	('high levels of IGF-2', 'Phenotype', 'HP:0030269', (111, 131))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('IGF-2R', 'Gene', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', (92, 99))
587342	22022506	In conclusion, both EWS/FLI-1 siRNA and R1507 inhibit cellular proliferation by targeting a common pathway, namely the down-regulation of p-IGF-1R and p-Akt (Figure 5).	('EWS', 'Gene', (20, 23))	('FLI-1', 'Gene', (24, 29))	('Akt', 'Gene', '207', (153, 156))	('inhibit', 'NegReg', (46, 53))	('Akt', 'Gene', (153, 156))	('IGF-1R', 'Gene', (140, 146))	('cellular proliferation', 'CPA', (54, 76))	('down-regulation', 'NegReg', (119, 134))	('IGF-1R', 'Gene', '3480', (140, 146))	('R1507', 'Var', (40, 45))	('FLI-1', 'Gene', '2313', (24, 29))	('EWS', 'Gene', '2130', (20, 23))
587380	33963485	Furthermore, approximately 90% of PPAS lesions involve >= 2 parts of pulmonary arteries; most commonly affecting the lobar pulmonary artery (85%), followed thereafter by the right pulmonary artery (71%), left pulmonary artery (65%), and right ventricular outflow tract (10%).	('affecting', 'Reg', (103, 112))	('PPAS', 'Disease', (34, 38))	('PPAS', 'Chemical', '-', (34, 38))	('lesions', 'Var', (39, 46))
587382	33963485	This sign is defined as the presence of the following three findings: a low-density intraluminal mass of the pulmonary trunk, left pulmonary artery, or right pulmonary artery with near complete occlusion; proximal protrusion of the mass toward the right ventricular outflow tract; and eclipsing of one or both walls of the involved artery before the lesion infiltrates beyond the artery.	('pulmonary trunk', 'Disease', (109, 124))	('pulmonary trunk', 'Disease', 'MESH:D016750', (109, 124))	('low-density', 'NegReg', (72, 83))	('eclipsing', 'Var', (285, 294))
587482	32551218	It was revealed that the mean and SEM of the SOX9 mRNA level was 0.519 +- 0.02 and 0.03 +- 0.0043 in patients compared to controls.	('SOX9', 'Gene', (45, 49))	('patients', 'Species', '9606', (101, 109))	('0.519', 'Var', (65, 70))	('SOX9', 'Gene', '6662', (45, 49))
587586	31574457	Complete resection of tumors is very important, positive surgical margins are associated with a higher risk of local recurrence, distant metastasis and death.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('local recurrence', 'CPA', (111, 127))	('positive', 'Var', (48, 56))	('distant metastasis', 'CPA', (129, 147))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', (152, 157))	('tumors', 'Disease', (22, 28))
587587	31574457	In our case, puncture and partial resection may lead to rupture of tumors causing the spread of tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('partial resection', 'Var', (26, 43))	('rupture of tumors', 'Disease', 'MESH:D012421', (56, 73))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('lead to', 'Reg', (48, 55))	('tumors', 'Disease', (67, 73))	('rupture of tumors', 'Disease', (56, 73))
587621	29743654	Additional antibody staining was performed for CD1A (1:100, Clone 10, Dako #M3571), Langerin/CD207 (1:200, Clone 12D6, Leica - Ncl-Langerin), BRAF V600E (1:200, Clone VE1, Ventana #790-4855), S100 (1:1000, polyclonal, Dako #Z0311), and SOX-10 (1:30, polyclonal, Cell Marque #202M-96).	('Ncl', 'Gene', '4691', (127, 130))	('SOX-10', 'Gene', '6663', (236, 242))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('S100', 'Gene', (192, 196))	('Langerin', 'Gene', (131, 139))	('1:200', 'Var', (154, 159))	('Ncl', 'Gene', (127, 130))	('S100', 'Gene', '6271', (192, 196))	('Langerin', 'Gene', (84, 92))	('BRAF', 'Gene', '673', (142, 146))	('SOX-10', 'Gene', (236, 242))	('Langerin', 'Gene', '50489', (131, 139))	('Langerin', 'Gene', '50489', (84, 92))	('BRAF', 'Gene', (142, 146))
587624	29743654	The BCL2 separation probe (ZytoVision #Z-2192) identifies translocation-mediated rearrangement of the BCL2 gene on chromosome 18.	('translocation-mediated rearrangement', 'Var', (58, 94))	('BCL2', 'Gene', '596', (4, 8))	('BCL2', 'Gene', (102, 106))	('BCL2', 'Gene', (4, 8))	('BCL2', 'Gene', '596', (102, 106))
587663	29743654	Conversely, lack of ZBTB46 expression was also useful in eliminating dendritic cell tumors from the differential diagnosis.	('lack', 'Var', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('eliminating', 'NegReg', (57, 68))	('ZBTB46', 'Gene', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('ZBTB46', 'Gene', '140685', (20, 26))	('dendritic cell tumors', 'Disease', (69, 90))	('dendritic cell tumors', 'Disease', 'MESH:D054740', (69, 90))
587686	29113307	Ten lncRNAs, including RP11-560J1.2, AP001432.14, RP4-665J23.1, LINC00680, AC006129.2, RP11-230G5.2, BACH1-IT2, RP11-274B21.9, RP11-504A18.1 and RP11-713P17.3, were selected to calculate a risk score.	('LINC00680', 'Gene', (64, 73))	('RP11', 'Gene', (145, 149))	('BACH1', 'Gene', (101, 106))	('RP11', 'Gene', '26121', (87, 91))	('LINC00680', 'Gene', '106660612', (64, 73))	('RP11', 'Gene', (23, 27))	('RP11', 'Gene', (127, 131))	('AP001432.14', 'Var', (37, 48))	('RP11', 'Gene', '26121', (145, 149))	('RP11', 'Gene', '26121', (23, 27))	('RP11', 'Gene', (112, 116))	('RP11', 'Gene', '26121', (127, 131))	('AC006129.2', 'Var', (75, 85))	('BACH1', 'Gene', '571', (101, 106))	('RP4', 'Gene', (50, 53))	('RP11', 'Gene', '26121', (112, 116))	('RP11', 'Gene', (87, 91))	('RP4', 'Gene', '6010', (50, 53))
587708	29113307	Subsequently, multivariate Cox proportional hazards regression analysis was performed to further verify the prognostic roles of these 50 lncRNAs and eventually, a total of 10 lncRNAs (RP11-560J1.2, AP001432.14, RP4-665J23.1, LINC00680, AC006129.2, RP11-230G5.2, BACH1-IT2, RP11-274B21.9, RP11-504A18.1 and RP11-713P17.3) were identified to be independent prognostic indicators of soft-tissue sarcoma.	('RP11', 'Gene', '26121', (248, 252))	('RP11', 'Gene', '26121', (184, 188))	('AP001432.14', 'Var', (198, 209))	('Cox', 'Gene', '1351', (27, 30))	('RP11', 'Gene', (306, 310))	('RP11', 'Gene', (273, 277))	('RP11', 'Gene', (288, 292))	('BACH1', 'Gene', '571', (262, 267))	('AC006129.2', 'Var', (236, 246))	('RP11', 'Gene', (248, 252))	('LINC00680', 'Gene', '106660612', (225, 234))	('RP11', 'Gene', (184, 188))	('Cox', 'Gene', (27, 30))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (380, 399))	('RP4', 'Gene', '6010', (211, 214))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (380, 399))	('RP4', 'Gene', (211, 214))	('LINC00680', 'Gene', (225, 234))	('BACH1', 'Gene', (262, 267))	('RP11', 'Gene', '26121', (306, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (392, 399))	('RP11', 'Gene', '26121', (288, 292))	('soft-tissue sarcoma', 'Disease', (380, 399))	('RP11', 'Gene', '26121', (273, 277))
587745	29113307	Ten lncRNAs showed the most potent prognostic value, including four protective lncRNAs (LINC00680, AC006129.2, RP11-274B21.9 and RP11-713P17.3) and six risky lncRNA: RP11-560J1.2, AP001432.14, RP4-665J23.1, RP11-230G5.2, BACH1-IT2, and RP11-504A18.1).	('LINC00680', 'Gene', (88, 97))	('RP11', 'Gene', (207, 211))	('LINC00680', 'Gene', '106660612', (88, 97))	('RP11', 'Gene', (166, 170))	('RP11', 'Gene', (111, 115))	('BACH1', 'Gene', (221, 226))	('RP11', 'Gene', '26121', (111, 115))	('AP001432.14', 'Var', (180, 191))	('RP11', 'Gene', (129, 133))	('RP11', 'Gene', '26121', (207, 211))	('RP11', 'Gene', '26121', (166, 170))	('RP11', 'Gene', (236, 240))	('RP4', 'Gene', '6010', (193, 196))	('RP11', 'Gene', '26121', (129, 133))	('RP4', 'Gene', (193, 196))	('RP11', 'Gene', '26121', (236, 240))	('BACH1', 'Gene', '571', (221, 226))	('AC006129.2', 'Var', (99, 109))
587752	29113307	Interestingly, from KEGG analysis, the Neuroactive ligand-receptor interaction pathway and Calcium signaling pathway are the top 2 pathways for both AP001432.14 and RP11-230G5.2, indicating that these 2 lncRNAs may have similar functions via targeting comparable signaling pathways; however, validation with additional in vitro and in vivo experiments is requisite to uncover the underlying molecular mechanism of lncRNAs in soft-tissue sarcoma.	('soft-tissue sarcoma', 'Disease', (425, 444))	('RP11', 'Gene', '26121', (165, 169))	('Calcium', 'Chemical', 'MESH:D002118', (91, 98))	('AP001432.14', 'Var', (149, 160))	('soft-tissue sarcoma', 'Disease', 'MESH:D012509', (425, 444))	('sarcoma', 'Phenotype', 'HP:0100242', (437, 444))	('RP11', 'Gene', (165, 169))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (425, 444))
587793	28007021	We performed cancer whole exome sequencing (WES) of patient-matched tumor-normal samples and RNA sequencing (RNA-seq) of tumor to identify sequence variants, fusion transcripts, relative gene expression, and copy number variation (CNV).	('tumor', 'Disease', (68, 73))	('copy number variation', 'Var', (208, 229))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('patient', 'Species', '9606', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
587802	28007021	Known or likely pathogenic germline alterations were discovered in 18/90 patients (20%) with 14% having germline alternations in cancer predisposition genes.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('pathogenic', 'Reg', (16, 26))	('alternations', 'Var', (113, 125))	('alterations', 'Var', (36, 47))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('patients', 'Species', '9606', (73, 81))
587835	28007021	Results not reported included carrier status, variants of uncertain significance (VOUS) in secondary findings except as related to cancer, and mutations related to adult-onset conditions for which the genetic link is either unclear or for which no known intervention is of proven benefit (e.g.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('variants', 'Var', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('mutations', 'Var', (143, 152))
587843	28007021	In normal DNA, variants were passed through a "reference range filter" of cancer predisposition genes, genes relevant to pharmacogenomics, and variants relevant to patient care; a "reportable range filter" which includes COSMIC (cosmic70 provided by Annovar) variants in the patient's mutation report file and variants in genes recommended by the American College of Medical Genetics (ACMG) for the reporting of secondary findings; as well as a frequency filter, which includes variants whose minor allele frequency in the 1000 Genomes (phase 1, version 3, release date 23 November 2010) is less than 1%.	('patient', 'Species', '9606', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('variants', 'Var', (478, 486))	('patient', 'Species', '9606', (275, 282))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
587844	28007021	Somatic mutations in the tumor were identified by subtracting all variants called in normal tissue (output at minor allelic fraction of >=5%) from variants called in the tumor (output at a minor allelic fraction of >=10%).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (25, 30))	('variants', 'Var', (66, 74))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
587846	28007021	Variants in the tumor were further characterized as homozygous, compound heterozygous, somatic, and "disruptive" (loss of function, namely, nonsense, frame-shift, or splice site).	('Variants', 'Var', (0, 8))	('frame-shift', 'Var', (150, 161))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('nonsense', 'Var', (140, 148))	('tumor', 'Disease', (16, 21))	('splice site', 'Var', (166, 177))
587847	28007021	All DNA sequencing results were manually reviewed by molecular pathologists to prioritize variants for presentation at the multi-disciplinary tumor board and subsequent reporting of consensus variants.	('variants', 'Var', (90, 98))	('multi-disciplinary tumor board', 'Disease', (123, 153))	('multi-disciplinary tumor board', 'Disease', 'MESH:D015140', (123, 153))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))
587850	28007021	The allelic ratio at these genomic coordinates in the tumor was also output for viewing on the integrated genomic viewer to allow identification of copy number neutral loss of heterozygosity (LOH) and to support the CNVs identified by EXCAVATOR.	('loss of heterozygosity', 'NegReg', (168, 190))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('copy number neutral', 'Var', (148, 167))	('tumor', 'Disease', (54, 59))
587851	28007021	The laboratory detected all chromosome arm changes seen on karyotyping, losses of 26 Mb and greater seen on array CGH, and reproducibly identified all CNVs that involved at least ten exons at 40% tumor fraction (Additional file 1: Supplementary Methods).	('losses', 'NegReg', (72, 78))	('tumor', 'Disease', (196, 201))	('involved', 'Reg', (161, 169))	('26 Mb', 'Protein', (82, 87))	('changes', 'Var', (43, 50))	('CNVs', 'Disease', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
587855	28007021	well characterized hot spot mutations); unambiguous loss of function mutations in tumor suppressor genes (i.e.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('loss of function', 'NegReg', (52, 68))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
587856	28007021	nonsense or frame-shift mutations that resulted in loss of functional domains); mutations with published laboratory data documenting gain or loss of function in oncogenes and tumor suppressor genes, respectively; and previously reported fusions or fusions that were expected to have the same effect as previously reported fusions involving one of the partner genes.	('fusions', 'Var', (248, 255))	('tumor', 'Disease', (175, 180))	('mutations', 'Var', (80, 89))	('loss', 'NegReg', (141, 145))	('functional', 'MPA', (59, 69))	('frame-shift mutations', 'Var', (12, 33))	('oncogenes', 'Gene', (161, 170))	('fusions', 'Var', (237, 244))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('loss', 'NegReg', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('gain', 'PosReg', (133, 137))
587858	28007021	The final clinical cWES report included: known tumor type-specific actionable somatic mutations (Tier 1); somatic mutations in targetable pathways, actionable somatic mutations in other tumor types, somatic mutations in well-established cancer genes (Tier 2); other somatic mutations in cancer genes (Tier 3); and somatic VOUS (Tier 4).	('mutations', 'Var', (86, 95))	('clinical', 'Species', '191496', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('mutations', 'Var', (167, 176))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutations', 'Var', (207, 216))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutations', 'Var', (274, 283))	('cancer', 'Disease', (237, 243))	('tumor', 'Disease', (47, 52))
587859	28007021	Reporting of germline findings included: known pathogenic secondary ACMG variants; secondary non-ACMG variants and selected VOUS in known cancer genes with commentary; and known variants that influence pharmacogenomics.	('cancer', 'Disease', (138, 144))	('variants', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pathogenic', 'Reg', (47, 57))	('secondary', 'Disease', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
587865	28007021	Genetic alterations were considered targetable if: (1) an FDA approved drug or experimental drug was available that inhibited the target directly or inhibited its downstream signaling pathway; or (2) there was preclinical evidence to support efficient targeting of the aberrant function of the mutated gene and/or potential clinical benefit; and (3) there was some age-appropriate information on dosing.	('clinical', 'Species', '191496', (213, 221))	('aberrant function', 'Var', (269, 286))	('downstream signaling pathway', 'Pathway', (163, 191))	('inhibited', 'NegReg', (116, 125))	('clinical', 'Species', '191496', (324, 332))	('mutated gene', 'Var', (294, 306))	('inhibited', 'NegReg', (149, 158))
587885	28007021	After filtering, a total of 180 mutations (Additional file 2: Table S5) and 20 fusions were reported, 110 (including 10 fusions) from solid tumor samples (mean number of aberrations per sample, 2.91; median, 2.00; range, 1-6) and 90 (including 10 fusions) from hematologic samples (mean number of aberrations per sample, 5.2; median, 4.0; range, 1-12).	('mutations', 'Var', (32, 41))	('solid tumor', 'Disease', (134, 145))	('solid tumor', 'Disease', 'MESH:D009369', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
587888	28007021	A genetic variant was considered targetable if: (1) an FDA-approved drug or experimental drug was available that inhibited the target directly or inhibited its downstream signaling pathway; or 2) there was preclinical evidence to support efficient targeting of the aberrant function of the mutated gene and/or potential clinical benefit; and 3) there was some age-appropriate information on dosing.	('inhibited', 'NegReg', (113, 122))	('aberrant function', 'Var', (265, 282))	('clinical', 'Species', '191496', (320, 328))	('downstream signaling pathway', 'Pathway', (160, 188))	('inhibited', 'NegReg', (146, 155))	('mutated', 'Var', (290, 297))	('clinical', 'Species', '191496', (209, 217))
587893	28007021	Examples of targetable alterations include the identification of a cKIT (p.Asn655Lys) mutation in a 7-year-old boy with acute myeloid leukemia (AML), who was subsequently treated with palliative imatinib and achieved a near-complete clearing of peripheral blood leukemic blasts with a sustained response for 9 months.	('boy', 'Species', '9606', (111, 114))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (120, 142))	('p.Asn655Lys', 'Var', (73, 84))	('AML', 'Disease', (144, 147))	('peripheral blood leukemic', 'Disease', 'MESH:D007938', (245, 270))	('peripheral blood leukemic', 'Disease', (245, 270))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('p.Asn655Lys', 'Mutation', 'rs1057519708', (73, 84))	('acute myeloid leukemia', 'Disease', (120, 142))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (126, 142))	('AML', 'Disease', 'MESH:D015470', (144, 147))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (120, 142))	('imatinib', 'Chemical', 'MESH:D000068877', (195, 203))	('cKIT', 'Gene', (67, 71))
587895	28007021	Subsequent analysis identified a NUP214-ABL1 fusion by real-time polymerase chain reaction (RT-PCR) and the addition of dasatinib to the third-line induction regimen resulted in a deep remission allowing for a curative bone marrow transplant.	('dasatinib', 'Chemical', 'MESH:D000069439', (120, 129))	('ABL1', 'Gene', '25', (40, 44))	('fusion', 'Var', (45, 51))	('NUP214', 'Gene', (33, 39))	('ABL1', 'Gene', (40, 44))	('NUP214', 'Gene', '8021', (33, 39))	('deep remission', 'MPA', (180, 194))
587900	28007021	For example, the identification of a STAT5B mutation in a 5-year-old girl erroneously diagnosed with T-cell ALL helped to establish a diagnosis of gamma-delta T-cell lymphoma.	('STAT5B', 'Gene', '6777', (37, 43))	('mutation', 'Var', (44, 52))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (159, 174))	('gamma-delta T-cell lymphoma', 'Disease', (147, 174))	('gamma-delta T-cell lymphoma', 'Disease', 'MESH:D016399', (147, 174))	('girl', 'Species', '9606', (69, 73))	('STAT5B', 'Gene', (37, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (166, 174))	('cell lymphoma', 'Phenotype', 'HP:0012191', (161, 174))
587901	28007021	Also, identification of a PTPN11 mutation in a 4-year-old boy contributed to a change in his diagnosis from de novo AML to juvenile myelomonocytic leukemia (JMML) which evolved into AML.	('juvenile myelomonocytic leukemia', 'Disease', 'MESH:D054429', (123, 155))	('PTPN11', 'Gene', (26, 32))	('mutation', 'Var', (33, 41))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('boy', 'Species', '9606', (58, 61))	('juvenile myelomonocytic leukemia', 'Disease', (123, 155))	('AML', 'Disease', 'MESH:D015470', (182, 185))	('AML', 'Disease', 'MESH:D015470', (116, 119))	('PTPN11', 'Gene', '5781', (26, 32))	('juvenile myelomonocytic leukemia', 'Phenotype', 'HP:0012209', (123, 155))	('AML', 'Disease', (182, 185))	('AML', 'Disease', (116, 119))
587903	28007021	For example, in the 9-year-old girl with the relapsed NUP214-ABL1 B-ALL, the finding of a NT5C2 mutation associated with resistance to nucleoside analog therapies had clear implications for her salvage therapy.	('ABL1', 'Gene', (61, 65))	('girl', 'Species', '9606', (31, 35))	('NT5C2', 'Gene', (90, 95))	('NT5C2', 'Gene', '22978', (90, 95))	('mutation', 'Var', (96, 104))	('ABL1', 'Gene', '25', (61, 65))	('NUP214', 'Gene', (54, 60))	('associated', 'Reg', (105, 115))	('NUP214', 'Gene', '8021', (54, 60))	('nucleoside', 'Chemical', 'MESH:D009705', (135, 145))	('resistance to nucleoside analog', 'MPA', (121, 152))
587907	28007021	A novel EML4-NTRK3 fusion found in a 2-year-old boy supported a change in diagnosis from undifferentiated sarcoma to infantile fibrosarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('fusion', 'Var', (19, 25))	('EML4', 'Gene', '27436', (8, 12))	('NTRK3', 'Gene', (13, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('undifferentiated sarcoma to infantile fibrosarcoma', 'Disease', (89, 139))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (127, 139))	('NTRK3', 'Gene', '4916', (13, 18))	('boy', 'Species', '9606', (48, 51))	('undifferentiated sarcoma to infantile fibrosarcoma', 'Disease', 'MESH:D005354', (89, 139))	('EML4', 'Gene', (8, 12))
587910	28007021	Segmental and gene expression changes having prognostic implications were identified in 11 patients with a variety of diagnoses.	('changes', 'Var', (30, 37))	('patients', 'Species', '9606', (91, 99))	('gene expression changes', 'Var', (14, 37))
587911	28007021	Four patients diagnosed with neuroblastoma could be stratified based on RNA-seq and CNV: one high-risk patient with MYCN amplification, LOH at 1p and 11q, gain of 17q, and MYCN overexpression; one high-risk patient with MYCN amplification, LOH at 1p, gain of 17q, and MYCN overexpression; one high-risk patient without MYCN amplification or LOH at 1p and 11q, and no evidence of MYCN overexpression; and one intermediate-risk patient without MYCN amplification or LOH at 1p and 11q and no evidence of MYCN overexpression.	('MYCN', 'Gene', (220, 224))	('MYCN', 'Gene', (268, 272))	('MYCN', 'Gene', '4613', (501, 505))	('MYCN', 'Gene', (379, 383))	('patient', 'Species', '9606', (303, 310))	('patient', 'Species', '9606', (207, 214))	('MYCN', 'Gene', (442, 446))	('MYCN', 'Gene', (116, 120))	('patients', 'Species', '9606', (5, 13))	('MYCN', 'Gene', '4613', (319, 323))	('MYCN', 'Gene', (172, 176))	('patient', 'Species', '9606', (103, 110))	('neuroblastoma', 'Disease', (29, 42))	('MYCN', 'Gene', (501, 505))	('MYCN', 'Gene', '4613', (220, 224))	('patient', 'Species', '9606', (426, 433))	('neuroblastoma', 'Phenotype', 'HP:0003006', (29, 42))	('MYCN', 'Gene', '4613', (268, 272))	('MYCN', 'Gene', '4613', (379, 383))	('MYCN', 'Gene', '4613', (442, 446))	('gain', 'PosReg', (251, 255))	('MYCN', 'Gene', '4613', (116, 120))	('neuroblastoma', 'Disease', 'MESH:D009447', (29, 42))	('patient', 'Species', '9606', (5, 12))	('MYCN', 'Gene', (319, 323))	('MYCN', 'Gene', '4613', (172, 176))	('LOH at 1p', 'Var', (240, 249))
587914	28007021	Overexpression of CCND1 in a patient with hepatoblastoma was considered a good prognostic indicator.	('patient', 'Species', '9606', (29, 36))	('hepatoblastoma', 'Disease', (42, 56))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (42, 56))	('CCND1', 'Gene', '595', (18, 23))	('Overexpression', 'Var', (0, 14))	('hepatoblastoma', 'Disease', 'MESH:D018197', (42, 56))	('CCND1', 'Gene', (18, 23))
587915	28007021	One patient with AML with a CBFB-MYH11 fusion could be assigned to risk-based therapy and the diagnosis of gamma-delta T-cell lymphoma was also corroborated by CNV with isochromosome 7q.	('CBFB', 'Gene', (28, 32))	('MYH11', 'Gene', '4629', (33, 38))	('cell lymphoma', 'Phenotype', 'HP:0012191', (121, 134))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (119, 134))	('patient', 'Species', '9606', (4, 11))	('AML', 'Disease', 'MESH:D015470', (17, 20))	('lymphoma', 'Phenotype', 'HP:0002665', (126, 134))	('gamma-delta T-cell lymphoma', 'Disease', (107, 134))	('gamma-delta T-cell lymphoma', 'Disease', 'MESH:D016399', (107, 134))	('AML', 'Disease', (17, 20))	('MYH11', 'Gene', (33, 38))	('CBFB', 'Gene', '865', (28, 32))	('fusion', 'Var', (39, 45))
587920	28007021	In the solid tumor category, two alterations in APC were diagnostic: one in a patient with hepatoblastoma and a family history consistent with familial adenomatous polyposis (FAP; p.R1114) and one associated with newly appreciated Gardner's syndrome (p.E1554fs) in a 14-year-old boy with pilomatricomas and epidermoid cysts prior to his carcinoma diagnosis.	('pilomatricomas', 'Disease', 'MESH:D018296', (288, 302))	('APC', 'Disease', 'MESH:D011125', (48, 51))	('FAP', 'Disease', (175, 178))	('APC', 'Disease', (48, 51))	('hepatoblastoma', 'Disease', (91, 105))	('epidermoid cysts', 'Phenotype', 'HP:0200040', (307, 323))	('carcinoma', 'Disease', 'MESH:D002277', (337, 346))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (152, 173))	('FAP', 'Disease', 'MESH:C567782', (175, 178))	('hepatoblastoma', 'Disease', 'MESH:D018197', (91, 105))	('solid tumor', 'Disease', (7, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('pilomatricomas', 'Disease', (288, 302))	("Gardner's syndrome", 'Disease', 'MESH:D005736', (231, 249))	('patient', 'Species', '9606', (78, 85))	('familial adenomatous polyposis', 'Disease', (143, 173))	("Gardner's syndrome", 'Disease', (231, 249))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (143, 173))	('solid tumor', 'Disease', 'MESH:D009369', (7, 18))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (91, 105))	('p.E1554fs', 'Mutation', 'p.E1554fsX', (251, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (337, 346))	('carcinoma', 'Disease', (337, 346))	('p.E1554fs', 'Var', (251, 260))	('boy', 'Species', '9606', (279, 282))
587921	28007021	Two variants in ATM (p.R189K, p.K2756*) were found in a 16-year-old boy with medulloblastoma inferring an increased risk for developing other cancers.	('p.R189K', 'Mutation', 'rs1327622336', (21, 28))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('ATM', 'Gene', (16, 19))	('p.K2756*', 'Var', (30, 38))	('p.R189K', 'Var', (21, 28))	('cancers', 'Disease', (142, 149))	('medulloblastoma', 'Phenotype', 'HP:0002885', (77, 92))	('boy', 'Species', '9606', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('medulloblastoma', 'Disease', (77, 92))	('p.K2756*', 'Mutation', 'p.K2756*', (30, 38))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('found', 'Reg', (45, 50))	('medulloblastoma', 'Disease', 'MESH:D008527', (77, 92))
587924	28007021	A homozygous pathogenic variant in C1QA (p.Gln208Ter) diagnostic of C1Q deficiency was identified in a 2-year-old girl with HLH.	('C1Q deficiency', 'Disease', 'OMIM:613652', (68, 82))	('girl', 'Species', '9606', (114, 118))	('p.Gln208Ter', 'Var', (41, 52))	('C1Q deficiency', 'Disease', (68, 82))	('p.Gln208Ter', 'Mutation', 'rs121909581', (41, 52))	('pathogenic', 'Reg', (13, 23))	('C1QA', 'Gene', (35, 39))	('C1QA', 'Gene', '712', (35, 39))
587925	28007021	A homozygous pathogenic variant in PMS2 (p.S459X) diagnostic of congenital mismatch repair deficiency was identified in one patient with T-cell lymphoblastic lymphoma and consanguineous parentage.	('p.S459X', 'Var', (41, 48))	('PMS2', 'Gene', '5395', (35, 39))	('p.S459X', 'Mutation', 'rs587780724', (41, 48))	('congenital mismatch repair deficiency', 'Disease', (64, 101))	('lymphoma', 'Phenotype', 'HP:0002665', (158, 166))	('PMS2', 'Gene', (35, 39))	('patient', 'Species', '9606', (124, 131))	('pathogenic', 'Reg', (13, 23))	('T-cell lymphoblastic lymphoma', 'Disease', 'MESH:D016399', (137, 166))	('T-cell lymphoblastic lymphoma', 'Disease', (137, 166))
587926	28007021	A likely pathogenic variant in XIAP (p.R443P) was identified in a 6-year-old girl with HLH, recurrent EBV infections, and suspected underlying immunodeficiency.	('pathogenic', 'Reg', (9, 19))	('EBV infections', 'Disease', (102, 116))	('EBV infections', 'Disease', 'MESH:D020031', (102, 116))	('XIAP', 'Gene', (31, 35))	('XIAP', 'Gene', '331', (31, 35))	('p.R443P', 'Var', (37, 44))	('p.R443P', 'Mutation', 'p.R443P', (37, 44))	('girl', 'Species', '9606', (77, 81))	('immunodeficiency', 'Phenotype', 'HP:0002721', (143, 159))	('immunodeficiency', 'Disease', (143, 159))	('immunodeficiency', 'Disease', 'MESH:D007153', (143, 159))
587927	28007021	Germline testing also revealed a heterozygous pathogenic splicing variant in RUNX1 (c.806-2A > G, r.Spl) in a patient with AML referred for transplantation for persistent thrombocytopenia following chemotherapy.	('AML', 'Disease', 'MESH:D015470', (123, 126))	('pathogenic', 'Reg', (46, 56))	('thrombocytopenia', 'Disease', (171, 187))	('RUNX1', 'Gene', (77, 82))	('c.806-2A > G', 'Var', (84, 96))	('patient', 'Species', '9606', (110, 117))	('RUNX1', 'Gene', '861', (77, 82))	('c.806-2A > G', 'Mutation', 'c.806-2A>G', (84, 96))	('AML', 'Disease', (123, 126))	('thrombocytopenia', 'Disease', 'MESH:D013921', (171, 187))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (171, 187))	('Spl', 'Gene', '8879', (100, 103))	('Spl', 'Gene', (100, 103))
587932	28007021	A germline BRCA1 mutation was discovered in an 18-year-old boy with a rare hepatic tumor and a 17-year-old girl with ependymoma.	('ependymoma', 'Disease', 'MESH:D004806', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('hepatic tumor', 'Disease', (75, 88))	('ependymoma', 'Phenotype', 'HP:0002888', (117, 127))	('BRCA1', 'Gene', '672', (11, 16))	('hepatic tumor', 'Phenotype', 'HP:0002896', (75, 88))	('mutation', 'Var', (17, 25))	('BRCA1', 'Gene', (11, 16))	('hepatic tumor', 'Disease', 'MESH:D056486', (75, 88))	('boy', 'Species', '9606', (59, 62))	('girl', 'Species', '9606', (107, 111))	('ependymoma', 'Disease', (117, 127))
587933	28007021	A TP53 mutation was found in a 1-year-old girl with AML, a TNNT2 mutation associated with dilated cardiomyopathy was found in a 15-year-old boy with osteosarcoma, a RYR1 mutation associated with malignant hyperthermia was found in a 7-year-old girl with neuroblastoma, and a mutation in VHL was found in a 2-year-old boy with ependymoma.	('AML', 'Disease', (52, 55))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (90, 112))	('ependymoma', 'Disease', 'MESH:D004806', (326, 336))	('VHL', 'Gene', '7428', (287, 290))	('TP53', 'Gene', '7157', (2, 6))	('osteosarcoma', 'Disease', (149, 161))	('neuroblastoma', 'Disease', (254, 267))	('boy', 'Species', '9606', (317, 320))	('osteosarcoma', 'Disease', 'MESH:D012516', (149, 161))	('neuroblastoma', 'Phenotype', 'HP:0003006', (254, 267))	('dilated cardiomyopathy', 'Disease', (90, 112))	('malignant hyperthermia', 'Disease', (195, 217))	('neuroblastoma', 'Disease', 'MESH:D009447', (254, 267))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (98, 112))	('mutation', 'Var', (65, 73))	('TNNT2', 'Gene', '7139', (59, 64))	('girl', 'Species', '9606', (42, 46))	('malignant hyperthermia', 'Phenotype', 'HP:0002047', (195, 217))	('RYR1', 'Gene', '6261', (165, 169))	('hyperthermia', 'Phenotype', 'HP:0001945', (205, 217))	('boy', 'Species', '9606', (140, 143))	('TNNT2', 'Gene', (59, 64))	('ependymoma', 'Disease', (326, 336))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (90, 112))	('osteosarcoma', 'Phenotype', 'HP:0002669', (149, 161))	('RYR1', 'Gene', (165, 169))	('found', 'Reg', (117, 122))	('TP53', 'Gene', (2, 6))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('ependymoma', 'Phenotype', 'HP:0002888', (326, 336))	('malignant hyperthermia', 'Disease', 'MESH:D008305', (195, 217))	('VHL', 'Gene', (287, 290))	('mutation', 'Var', (7, 15))	('girl', 'Species', '9606', (244, 248))	('associated', 'Reg', (74, 84))	('AML', 'Disease', 'MESH:D015470', (52, 55))
587934	28007021	Germline variants classified as VOUS (Additional file 5: Table S6) were not returned to patients except if they met the following criteria: (1) the variant was predicted to be destructive; (2) the variant was in a well validated cancer-associated gene; and (3) a second somatic alteration was identified or the variant was reduced to homozygosity in the tumor.	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('variant', 'Var', (148, 155))	('variant', 'Var', (197, 204))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('tumor', 'Disease', (354, 359))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
587935	28007021	Clinical genetics returned a VOUS to four patient families meeting these criteria, including an ITK (p.V175V) mutation in a 7-year-old girl with Hodgkin lymphoma and Epstein-Barr virus, an SDHC (p.G75D) mutation was found in a 12-year-old boy with ALL, a DICER1 (p.D609Y) mutation in an 18-year-old boy with ALCL, and an APC (p.V1822D) mutation in a 7-year-old boy with Ewing sarcoma.	('p.D609Y', 'Var', (263, 270))	('boy', 'Species', '9606', (239, 242))	('p.G75D', 'Mutation', 'rs786205147', (195, 201))	('SDHC', 'Gene', (189, 193))	('Ewing sarcoma', 'Disease', (370, 383))	('Epstein-Barr virus', 'Species', '10376', (166, 184))	('patient', 'Species', '9606', (42, 49))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (145, 161))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (145, 161))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('p.V175V', 'Mutation', 'p.V175V', (101, 108))	('p.V1822D', 'Mutation', 'rs886037729', (326, 334))	('boy', 'Species', '9606', (299, 302))	('ITK', 'Gene', (96, 99))	('APC', 'Disease', 'MESH:D011125', (321, 324))	('APC', 'Disease', (321, 324))	('Clinical', 'Species', '191496', (0, 8))	('DICER1', 'Gene', '23405', (255, 261))	('ALCL', 'Disease', (308, 312))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (370, 383))	('mutation', 'Var', (110, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (370, 383))	('p.D609Y', 'Mutation', 'rs114947750', (263, 270))	('boy', 'Species', '9606', (361, 364))	('DICER1', 'Gene', (255, 261))	('ALCL', 'Disease', 'None', (308, 312))	('girl', 'Species', '9606', (135, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (376, 383))	('ITK', 'Gene', '3702', (96, 99))	('Hodgkin lymphoma', 'Disease', (145, 161))
587944	28007021	This platform provided several advantages over targeted cancer gene panels, including the ability to identify translocations, segmental chromosomal changes, and relative gene expression changes.	('translocations', 'Var', (110, 124))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
587945	28007021	Similar to other sequencing efforts in pediatric oncology, we found that the overall mutational load in our patients was relatively low by comparison to adult cancers.	('cancers', 'Disease', (159, 166))	('low', 'NegReg', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('oncology', 'Phenotype', 'HP:0002664', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('mutational', 'Var', (85, 95))	('patients', 'Species', '9606', (108, 116))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
587949	28007021	Although there is a paucity of Tier 1 actionable alterations in pediatric cancers, using a more lenient definition of actionable which includes same gene-different tumor type, likely pathogenic VOUS, and assessment of both clinical and preclinical data, resulted in the identification of potentially actionable alterations in 38% of all patients.	('tumor', 'Disease', (164, 169))	('pediatric cancers', 'Disease', 'MESH:D009369', (64, 81))	('pediatric cancers', 'Disease', (64, 81))	('clinical', 'Species', '191496', (223, 231))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('alterations', 'Var', (311, 322))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('clinical', 'Species', '191496', (239, 247))	('patients', 'Species', '9606', (337, 345))	('actionable', 'Reg', (300, 310))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
587955	28007021	MEK inhibition for RAS mutant tumors).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutant', 'Var', (23, 29))	('RAS', 'Protein', (19, 22))
587964	28007021	The importance of assessing germline in addition to cancer DNA is evident from the 14% incidence of germline variants that may predispose to cancer.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('variants', 'Var', (109, 117))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('predispose', 'Reg', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (52, 58))
587967	28007021	Similarly, existing NGS panels, which allow the detection of mutations and/or fusions of clear clinical relevance, may be adequate in certain clinical scenarios.	('clinical', 'Species', '191496', (95, 103))	('clinical', 'Species', '191496', (142, 150))	('fusions', 'Var', (78, 85))	('mutations', 'Var', (61, 70))
587969	28007021	While the frequency of finding actionable alterations is consistent with reports of other pediatric oncology sequencing endeavors, we feel this singular attribute grossly underestimates the potential clinical utility of these data.	('oncology', 'Phenotype', 'HP:0002664', (100, 108))	('clinical', 'Species', '191496', (200, 208))	('underestimates', 'NegReg', (171, 185))	('alterations', 'Var', (42, 53))
587971	28007021	Taking this more inclusive view, it is striking that the sequencing data were found to be clinically impactful in 66% of all cases tested through our program and in 75% of cases comprehensively assessed using cWES and RNA-seq.	('sequencing', 'Var', (57, 67))	('clinical', 'Species', '191496', (90, 98))	('impactful', 'Reg', (101, 110))
587973	28007021	ACMG American College of Medical Genetics CNV copy number variation cWES cancer whole exome sequencing EMR electronic medical record FFPE formalin fixed paraffin embedded HLA human leukocyte antigen HLH hemophagocytic lymphohistiocytosis VOUS variants of uncertain significance WES whole exome sequencing	('human', 'Species', '9606', (175, 180))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('paraffin', 'Chemical', 'MESH:D010232', (153, 161))	('formalin', 'Chemical', 'MESH:D005557', (138, 146))	('variants', 'Var', (243, 251))
587977	32842875	Lysine-specific demethylase 1 (LSD1) is a critical functional partner for EWS/FLI as inhibition of LSD1 reverses the transcriptional activity of EWS/FLI.	('FLI', 'Gene', '2314', (78, 81))	('l', 'Gene', '21832', (49, 50))	('FLI', 'Gene', (78, 81))	('inhibition', 'Var', (85, 95))	('reverses', 'NegReg', (104, 112))	('l', 'Gene', '21832', (131, 132))	('FLI', 'Gene', '2314', (149, 152))	('Lysine-specific demethylase 1', 'Gene', '23028', (0, 29))	('FLI', 'Gene', (149, 152))	('l', 'Gene', '21832', (23, 24))	('LSD1', 'Gene', (99, 103))	('l', 'Gene', '21832', (60, 61))	('Lysine-specific demethylase 1', 'Gene', (0, 29))
587992	32842875	As an alternative approach, we previously demonstrated that treatment with the lysine-specific demethylase 1 (LSD1) inhibitor SP2509 reverses the transcriptional activity of EWS/FLI, and the related EWS/ERG fusion, impairing tumour cell growth and viability.	('impairing tumour', 'Disease', (215, 231))	('l', 'Gene', '21832', (193, 194))	('SP2509', 'Chemical', 'MESH:C000594309', (126, 132))	('l', 'Gene', '21832', (79, 80))	('ERG', 'Gene', (203, 206))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('l', 'Gene', '21832', (253, 254))	('l', 'Gene', '21832', (39, 40))	('reverses', 'NegReg', (133, 141))	('lysine-specific demethylase 1', 'Gene', (79, 108))	('l', 'Gene', '21832', (160, 161))	('l', 'Gene', '21832', (102, 103))	('SP2509', 'Var', (126, 132))	('ERG', 'Gene', '2078', (203, 206))	('lysine-specific demethylase 1', 'Gene', '23028', (79, 108))	('inhibitor SP2509', 'Var', (116, 132))	('FLI', 'Gene', (178, 181))	('l', 'Gene', '21832', (7, 8))	('l', 'Gene', '21832', (234, 235))	('impairing tumour', 'Disease', 'MESH:D009369', (215, 231))	('FLI', 'Gene', '2314', (178, 181))	('l', 'Gene', '21832', (235, 236))
588005	32842875	In this study, we used genomic methods in multiple Ewing sarcoma cell lines, as well as in a specific cell line, A673, either with wildtype expression of EWS/FLI, with EWS/FLI knocked down as a model for a Ewing sarcoma precursor cell, or with EWS/FLI depletion rescued with ectopic expression of the wildtype fusion.	('l', 'Gene', '21832', (68, 69))	('l', 'Gene', '21832', (233, 234))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (51, 64))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (51, 64))	('FLI', 'Gene', (158, 161))	('FLI', 'Gene', '2314', (248, 251))	('l', 'Gene', '21832', (232, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('l', 'Gene', '21832', (105, 106))	('FLI', 'Gene', '2314', (158, 161))	('l', 'Gene', '21832', (48, 49))	('l', 'Gene', '21832', (255, 256))	('l', 'Gene', '21832', (104, 105))	('FLI', 'Gene', (172, 175))	('l', 'Gene', '21832', (303, 304))	('Ewing sarcoma', 'Disease', (51, 64))	('l', 'Gene', '21832', (198, 199))	('knocked down', 'Var', (176, 188))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (206, 219))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (206, 219))	('FLI', 'Gene', '2314', (172, 175))	('l', 'Gene', '21832', (70, 71))	('l', 'Gene', '21832', (133, 134))	('l', 'Gene', '21832', (83, 84))	('l', 'Gene', '21832', (107, 108))	('Ewing sarcoma', 'Disease', (206, 219))	('FLI', 'Gene', (248, 251))	('l', 'Gene', '21832', (67, 68))	('l', 'Gene', '21832', (82, 83))	('l', 'Gene', '21832', (44, 45))
588035	32842875	We examined the levels of H3K27ac, H3K4me1, H3K4me2, and H3K4me3 at loci with EWS/FLI and LSD1 colocalization in A673 cells (wildtype levels of EWS/FLI expression) or cells with EWS/FLI knockdown (EFKD cells).	('l', 'Gene', '21832', (68, 69))	('FLI', 'Gene', '2314', (82, 85))	('l', 'Gene', '21832', (121, 122))	('l', 'Gene', '21832', (97, 98))	('FLI', 'Gene', (182, 185))	('l', 'Gene', '21832', (169, 170))	('l', 'Gene', '21832', (120, 121))	('knockdown', 'Var', (186, 195))	('FLI', 'Gene', '2314', (182, 185))	('l', 'Gene', '21832', (16, 17))	('FLI', 'Gene', (148, 151))	('l', 'Gene', '21832', (134, 135))	('l', 'Gene', '21832', (127, 128))	('l', 'Gene', '21832', (101, 102))	('H3K27ac', 'Chemical', '-', (26, 33))	('l', 'Gene', '21832', (204, 205))	('l', 'Gene', '21832', (205, 206))	('FLI', 'Gene', '2314', (148, 151))	('l', 'Gene', '21832', (20, 21))	('FLI', 'Gene', (82, 85))	('l', 'Gene', '21832', (138, 139))	('l', 'Gene', '21832', (170, 171))
588040	32842875	Given that LSD1-bound regions more strongly associated with gene activation and that inhibition of LSD1 downregulates EWS/FLI-activated genes, we hypothesized that LSD1 would localize to GGAA-microsats as part of the co-activating machinery assembled by EWS/FLI.	('l', 'Gene', '21832', (179, 180))	('l', 'Gene', '21832', (247, 248))	('l', 'Gene', '21832', (172, 173))	('FLI', 'Gene', '2314', (122, 125))	('inhibition', 'Var', (85, 95))	('l', 'Gene', '21832', (41, 42))	('FLI', 'Gene', '2314', (258, 261))	('FLI', 'Gene', (122, 125))	('FLI', 'Gene', (258, 261))	('LSD1', 'Gene', (99, 103))	('l', 'Gene', '21832', (112, 113))	('activation', 'PosReg', (65, 75))	('l', 'Gene', '21832', (175, 176))
588053	32842875	Instead, the majority (62%) of SEs harboured non-microsat-bound EWS/FLI including 45% that had no GGAA-microsat-bound EWS/FLI and 17% that had both non-microsat- and GGAA-microsat-bound EWS/FLI (Figure 3(a)).	('FLI', 'Gene', '2314', (68, 71))	('FLI', 'Gene', '2314', (122, 125))	('FLI', 'Gene', (68, 71))	('FLI', 'Gene', (122, 125))	('non-microsat-bound', 'Var', (45, 63))	('l', 'Gene', '21832', (75, 76))	('FLI', 'Gene', '2314', (190, 193))	('SEs', 'Chemical', '-', (31, 34))	('FLI', 'Gene', (190, 193))
588066	32842875	Having observed that many Ewing sarcoma SEs also contain non-microsat sites, we next asked whether LSD1 was also present in these SEs, and whether the LSD1 harboured in SEs might be colocalized with, or bind independently from, EWS/FLI.	('FLI', 'Gene', (232, 235))	('l', 'Gene', '21832', (188, 189))	('Ewing sarcoma SEs', 'Disease', (26, 43))	('l', 'Gene', '21832', (219, 220))	('SEs', 'Chemical', '-', (169, 172))	('l', 'Gene', '21832', (45, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('SEs', 'Chemical', '-', (40, 43))	('Ewing sarcoma SEs', 'Disease', 'MESH:C563168', (26, 43))	('l', 'Gene', '21832', (184, 185))	('FLI', 'Gene', '2314', (232, 235))	('non-microsat', 'Var', (57, 69))	('l', 'Gene', '21832', (109, 110))	('SEs', 'Chemical', '-', (130, 133))
588069	32842875	We found 95% of A673 SEs overlapped an LSD1 peak.	('A673 SEs', 'Var', (16, 24))	('SEs', 'Chemical', '-', (21, 24))	('LSD1 peak', 'MPA', (39, 48))	('l', 'Gene', '21832', (29, 30))
588087	32842875	We additionally included EFKD cells rescued with ectopic expression of EWS/FLI, wtEF cells.	('FLI', 'Gene', (75, 78))	('l', 'Gene', '21832', (13, 14))	('l', 'Gene', '21832', (87, 88))	('l', 'Gene', '21832', (12, 13))	('l', 'Gene', '21832', (33, 34))	('l', 'Gene', '21832', (88, 89))	('l', 'Gene', '21832', (32, 33))	('l', 'Gene', '21832', (19, 20))	('FLI', 'Gene', '2314', (75, 78))	('ectopic expression', 'Var', (49, 67))
588092	32842875	Of these 'stable' peaks, 5687 show increased LSD1 binding in A673 as compared to EFKD, and 9271 show greater binding in EFKD cells as compared to A673, further supporting that EWS/FLI expression results in genome-wide reorganization of LSD1 (Figure 4(d)).	('9271', 'Var', (91, 95))	('5687', 'Var', (25, 29))	('increased', 'PosReg', (35, 44))	('l', 'Gene', '21832', (127, 128))	('l', 'Gene', '21832', (199, 200))	('l', 'Gene', '21832', (14, 15))	('FLI', 'Gene', '2314', (180, 183))	('l', 'Gene', '21832', (128, 129))	('A673', 'Var', (61, 65))	('LSD1', 'Protein', (45, 49))	('binding', 'Interaction', (50, 57))	('binding', 'Interaction', (109, 116))	('FLI', 'Gene', (180, 183))	('reorganization', 'MPA', (218, 232))
588094	32842875	Venn diagram analysis showed most LSD1 peaks present in A673 cells were also present in EFKD cells (Figure 4(c)).	('l', 'Gene', '21832', (64, 65))	('l', 'Gene', '21832', (63, 64))	('LSD1', 'MPA', (34, 38))	('l', 'Gene', '21832', (96, 97))	('A673', 'Var', (56, 60))	('l', 'Gene', '21832', (73, 74))	('l', 'Gene', '21832', (16, 17))	('l', 'Gene', '21832', (95, 96))
588106	32842875	However, only 320 A673 SCs (33%), 482 EFKD SCs (37%), and 510 wtEF SCs (38%) overlapped with SEs in their respective cells (Figure 5(e-g)), instead suggesting a heretofore unappreciated chromatin-associated LSD1-organizational structure.	('l', 'Gene', '21832', (120, 121))	('A673', 'Var', (18, 22))	('l', 'Gene', '21832', (11, 12))	('SEs', 'Chemical', '-', (93, 96))	('wtEF SCs', 'Disease', 'MESH:C535687', (62, 70))	('l', 'Gene', '21832', (225, 226))	('wtEF SCs', 'Disease', (62, 70))	('l', 'Gene', '21832', (81, 82))	('l', 'Gene', '21832', (119, 120))
588107	32842875	GSEA revealed that LSD1 SCs were associated with both LSD1-mediated gene activation (NES = 1.990, p < 0.001; Figure 5(h)) and EWS/FLI-mediated gene activation (NES = 2.358, p < 0.001; Figure 5(i)) in A673 cells, consistent with prior observations that LSD1 plays a role in EWS/FLI-mediated activation.	('LSD1-mediated gene', 'Gene', (54, 72))	('l', 'Gene', '21832', (258, 259))	('SCs', 'Var', (24, 27))	('FLI', 'Gene', '2314', (277, 280))	('FLI', 'Gene', '2314', (130, 133))	('l', 'Gene', '21832', (10, 11))	('FLI', 'Gene', (277, 280))	('FLI', 'Gene', (130, 133))	('LSD1 SCs', 'Var', (19, 27))	('l', 'Gene', '21832', (208, 209))	('l', 'Gene', '21832', (207, 208))	('l', 'Gene', '21832', (267, 268))	('GSEA', 'Chemical', '-', (0, 4))
588116	32842875	In all conditions, those SEs overlapping an LSD1 SC had greater H3K27ac scores than those with only a monopeak, or no LSD1 (Figure 5(m), Supplementary Figure 16C-D), suggesting a functional role for the factors that recruit LSD1 in promoting the establishment of enhancers.	('l', 'Gene', '21832', (188, 189))	('LSD1 SC', 'Var', (44, 51))	('l', 'Gene', '21832', (4, 5))	('l', 'Gene', '21832', (192, 193))	('l', 'Gene', '21832', (251, 252))	('l', 'Gene', '21832', (97, 98))	('H3K27ac', 'Protein', (64, 71))	('greater', 'PosReg', (56, 63))	('l', 'Gene', '21832', (141, 142))	('promoting', 'PosReg', (232, 241))	('l', 'Gene', '21832', (33, 34))	('l', 'Gene', '21832', (5, 6))	('H3K27ac', 'Chemical', '-', (64, 71))	('SEs', 'Chemical', '-', (25, 28))
588117	32842875	No significant difference was observed in basal expression of SE-associated genes based on LSD1 binding status (Supplementary Figure 16E-G), but genes near EFKD SEs containing an LSD1 SC showed greater downregulation with EWS/FLI expression than genes near SEs without an LSD1 SC (Figure 5(n)).	('FLI', 'Gene', '2314', (226, 229))	('l', 'Gene', '21832', (210, 211))	('l', 'Gene', '21832', (116, 117))	('expression', 'MPA', (230, 240))	('FLI', 'Gene', (226, 229))	('l', 'Gene', '21832', (46, 47))	('SE', 'Disease', 'None', (161, 163))	('SE', 'Disease', 'None', (62, 64))	('SEs', 'Chemical', '-', (161, 164))	('SE', 'Disease', 'None', (257, 259))	('LSD1', 'Var', (179, 183))	('SEs', 'Chemical', '-', (257, 260))
588122	32842875	The close phenotypic overlap between LSD1 inhibition (with SP2509) and EWS/FLI depletion in A673 (or EWS/ERG depletion in TTC-466 cells) suggested that LSD1 is closely linked to the genome-wide activity of oncogenic fusions in Ewing sarcoma.	('SP2509', 'Var', (59, 65))	('Ewing sarcoma', 'Disease', (227, 240))	('l', 'Gene', '21832', (112, 113))	('l', 'Gene', '21832', (25, 26))	('l', 'Gene', '21832', (168, 169))	('LSD1', 'Gene', (37, 41))	('ERG', 'Gene', (105, 108))	('TTC-466', 'CellLine', 'CVCL:A444', (122, 129))	('l', 'Gene', '21832', (165, 166))	('FLI', 'Gene', (75, 78))	('ERG', 'Gene', '2078', (105, 108))	('inhibition', 'NegReg', (42, 52))	('FLI', 'Gene', '2314', (75, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('l', 'Gene', '21832', (133, 134))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (227, 240))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (227, 240))	('SP2509', 'Chemical', 'MESH:C000594309', (59, 65))	('l', 'Gene', '21832', (132, 133))	('l', 'Gene', '21832', (5, 6))	('l', 'Gene', '21832', (82, 83))	('l', 'Gene', '21832', (161, 162))
588130	32842875	LSD1 is frequently recruited to these collaborating loci and the presence of LSD1 augments enhancer formation, resulting in increased H3K27ac deposition.	('enhancer formation', 'CPA', (91, 109))	('increased', 'PosReg', (124, 133))	('H3K27ac', 'Protein', (134, 141))	('l', 'Gene', '21832', (41, 42))	('l', 'Gene', '21832', (52, 53))	('augments', 'PosReg', (82, 90))	('l', 'Gene', '21832', (115, 116))	('LSD1', 'Gene', (77, 81))	('H3K27ac', 'Chemical', '-', (134, 141))	('l', 'Gene', '21832', (16, 17))	('l', 'Gene', '21832', (40, 41))	('presence', 'Var', (65, 73))
588153	32842875	In these cases, inhibition of LSD1 with derivatives of tranylcypromine restores enhancer function and disrupts oncogenic gene regulation.	('disrupts', 'NegReg', (102, 110))	('restores', 'PosReg', (71, 79))	('l', 'Gene', '21832', (130, 131))	('inhibition', 'Var', (16, 26))	('tranylcypromine', 'Chemical', 'MESH:D014191', (55, 70))	('LSD1', 'Gene', (30, 34))	('l', 'Gene', '21832', (60, 61))	('enhancer function', 'MPA', (80, 97))
588155	32842875	Indeed, knockdown of LSD1 results in the downregulation of activated genes nearby, indicating that LSD1 is not functioning to suppress over-activation, but is instead critically important to maintain gene activation.	('l', 'Gene', '21832', (174, 175))	('knockdown', 'Var', (8, 17))	('l', 'Gene', '21832', (49, 50))	('l', 'Gene', '21832', (30, 31))	('LSD1', 'Gene', (21, 25))	('l', 'Gene', '21832', (175, 176))
588158	32842875	Interestingly, both Ewing sarcoma and prostate cancer show sensitivity to reversible LSD1 inhibition with SP2509, but not other classes of irreversible LSD1 inhibitors related to tranylcypromine.	('inhibition', 'NegReg', (90, 100))	('l', 'Gene', '21832', (129, 130))	('LSD1', 'Enzyme', (85, 89))	('SP2509', 'Var', (106, 112))	('l', 'Gene', '21832', (11, 12))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('l', 'Gene', '21832', (170, 171))	('l', 'Gene', '21832', (149, 150))	('l', 'Gene', '21832', (184, 185))	('tranylcypromine', 'Chemical', 'MESH:D014191', (179, 194))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('Ewing sarcoma and prostate cancer', 'Disease', 'MESH:D011471', (20, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('SP2509', 'Chemical', 'MESH:C000594309', (106, 112))	('l', 'Gene', '21832', (82, 83))
588161	32842875	In conclusion, EWS/FLI interacts with LSD1 to mediate genome-wide epigenetic and transcriptional changes in Ewing sarcoma.	('changes', 'Reg', (97, 104))	('FLI', 'Gene', '2314', (19, 22))	('FLI', 'Gene', (19, 22))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('l', 'Gene', '21832', (7, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('Ewing sarcoma', 'Disease', (108, 121))	('l', 'Gene', '21832', (95, 96))	('epigenetic', 'Var', (66, 76))
588177	32842875	EWS-502 cells are derived from a Ewing sarcoma patient of unspecified sex and age, and have mutant TP53 (C135F) and STAG2 loss.	('C135F', 'Var', (105, 110))	('TP53', 'Gene', (99, 103))	('STAG2', 'Gene', '10735', (116, 121))	('patient', 'Species', '9606', (47, 54))	('l', 'Gene', '21832', (10, 11))	('l', 'Gene', '21832', (11, 12))	('unspecified', 'Species', '32644', (58, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (33, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (33, 46))	('C135F', 'Mutation', 'rs587781991', (105, 110))	('mutant', 'Var', (92, 98))	('TP53', 'Gene', '7157', (99, 103))	('STAG2', 'Gene', (116, 121))	('Ewing sarcoma', 'Disease', (33, 46))	('l', 'Gene', '21832', (122, 123))
588179	32842875	TC71 cells are derived from the tumour of a 22-year-old male, have mutated TP53 (R213*), and have wildtype STAG2.	('TC71', 'CellLine', 'CVCL:2213', (0, 4))	('R213*', 'Var', (81, 86))	('STAG2', 'Gene', (107, 112))	('l', 'Gene', '21832', (58, 59))	('STAG2', 'Gene', '10735', (107, 112))	('l', 'Gene', '21832', (7, 8))	('tumour', 'Disease', (32, 38))	('l', 'Gene', '21832', (100, 101))	('R213*', 'SUBSTITUTION', 'None', (81, 86))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('mutated', 'Var', (67, 74))	('l', 'Gene', '21832', (8, 9))	('l', 'Gene', '21832', (53, 54))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
588189	32842875	Membranes were blocked at 4 C overnight in Odyssey Blocking Buffer PBS (LI-COR), and incubated with primary antibody overnight at 4 C. Primary antibodies used for immunoblotting were: anti-FLI (Abcam ab15289), anti-H3 (Cell Signalling Technology #4499 - D1H2), anti-Lamin B1 (Abcam ab16048), and anti-FLAG M2 (Sigma F3165).	('L', 'Gene', '21832', (302, 303))	('L', 'Gene', '21832', (72, 73))	('Lamin B1', 'Gene', (266, 274))	('l', 'Gene', '21832', (241, 242))	('L', 'Gene', '21832', (190, 191))	('Lamin B1', 'Gene', '4001', (266, 274))	('l', 'Gene', '21832', (230, 231))	('l', 'Gene', '21832', (221, 222))	('FLI', 'Gene', (189, 192))	('l', 'Gene', '21832', (229, 230))	('l', 'Gene', '21832', (222, 223))	('l', 'Gene', '21832', (16, 17))	('anti-H3', 'Var', (210, 217))	('L', 'Gene', '21832', (266, 267))	('FLI', 'Gene', '2314', (189, 192))	('LI-COR', 'Chemical', '-', (72, 78))	('l', 'Gene', '21832', (52, 53))	('l', 'Gene', '21832', (170, 171))	('PBS', 'Chemical', 'MESH:D007854', (67, 70))
588190	32842875	For validation of protein depletion with knockdown, FLI, total H3, Lamin, and FLAG blots were incubated with IRDye secondary antibodies (LI-COR) and developed on the Odyssey.	('l', 'Gene', '21832', (6, 7))	('l', 'Gene', '21832', (61, 62))	('L', 'Gene', '21832', (53, 54))	('L', 'Gene', '21832', (67, 68))	('LI-COR', 'Chemical', '-', (137, 143))	('Lamin', 'Gene', (67, 72))	('l', 'Gene', '21832', (29, 30))	('FLI', 'Gene', '2314', (52, 55))	('l', 'Gene', '21832', (153, 154))	('l', 'Gene', '21832', (84, 85))	('Lamin', 'Gene', '4000', (67, 72))	('L', 'Gene', '21832', (137, 138))	('L', 'Gene', '21832', (79, 80))	('knockdown', 'Var', (41, 50))	('FLI', 'Gene', (52, 55))
588245	32842875	For CUT&RUN (EWS/FLI and LSD1) and ChIP-seq (H3K4me2, and H3K4me3), peaks were called using the default settings of MACS2 callpeak.	('FLI', 'Gene', '2314', (17, 20))	('FLI', 'Gene', (17, 20))	('l', 'Gene', '21832', (125, 126))	('l', 'Gene', '21832', (101, 102))	('and H3K4me3', 'Var', (54, 65))	('l', 'Gene', '21832', (124, 125))	('l', 'Gene', '21832', (81, 82))	('l', 'Gene', '21832', (82, 83))
588407	32011489	The immunological histological chemistry (IHC) results were as follows: ER(-), PR(+), CD31(-), CD34(-), DOG(-), SMA(+), Desmin(+), H- Caldesmon(+), EMA(-), CK(AE1/AE3)(+), Vimentin(+), S-100(-), K167(30%), LCA(-), ALK(-), CD30(-), CD17(-), DOG-1(-), WT19(-)and calretinin (-).	('Desmin', 'Gene', '497091', (120, 126))	('Vimentin', 'Gene', (172, 180))	('ALK', 'Gene', (214, 217))	('DOG', 'Species', '9615', (104, 107))	('CD34', 'Gene', '415130', (95, 99))	('CD17', 'Var', (231, 235))	('CD34', 'Gene', (95, 99))	('Vimentin', 'Gene', '477991', (172, 180))	('ALK', 'Gene', '483021', (214, 217))	('CD31', 'Var', (86, 90))	('Desmin', 'Gene', (120, 126))	('CD30(-', 'Var', (222, 228))	('DOG', 'Species', '9615', (240, 243))
588471	32346590	A 73-year-old P3003 female presented with a 2 month history of a right vulvar lesion and pain along the labia majora.	('pain', 'Disease', (89, 93))	('P3003', 'Var', (14, 19))	('right vulvar lesion', 'Disease', (65, 84))	('pain', 'Phenotype', 'HP:0012531', (89, 93))	('right vulvar lesion', 'Disease', 'MESH:D014845', (65, 84))	('pain', 'Disease', 'MESH:D010146', (89, 93))	('vulvar lesion', 'Phenotype', 'HP:0030416', (71, 84))
588487	32346590	Subsequent molecular testing showed that the tumor was negative for BRAF mutations.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('BRAF', 'Gene', '673', (68, 72))	('tumor', 'Disease', (45, 50))	('BRAF', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
588510	31909028	Ewing's sarcoma is derived from the cells of neural crest and has reciprocal translocation between chromosomes 11 and 22, t(11; 22).	("Ewing's sarcoma", 'Disease', (0, 15))	('t(11; 22', 'Var', (122, 130))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (0, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))
588552	31909028	Cytogenetic study for EWSR1-FLI1 fusion may be required for confirmation.	('EWSR1', 'Gene', '2130', (22, 27))	('FLI1', 'Gene', (28, 32))	('FLI1', 'Gene', '2313', (28, 32))	('EWSR1', 'Gene', (22, 27))	('fusion', 'Var', (33, 39))
588585	30988632	In terms of median survival, Shankar et al reported that for a group of 61 relapsed patients, the median survival for DFI <1 year was 3 months, compared with 8 months for those with DFI of 12-24 months, and 24 months for those with DFI >2 years.	('DFI <', 'Var', (118, 123))	('relapsed', 'Disease', (75, 83))	('patients', 'Species', '9606', (84, 92))
588636	30988632	TEM/IRN has been used in this fashion in recently completed studies combining this regimen with bevacizumab and temsirolimus, as well as ongoing clinical trials adding in metformin [NCT01528046], palbociclib [NCT03709680], PARP inhibitors [NCT01858168, NCT02044120], and immunotherapy [NCT03495921].	('TEM', 'Gene', (0, 3))	('[NCT03495921]', 'Var', (285, 298))	('bevacizumab', 'Chemical', 'MESH:D000068258', (96, 107))	('[NCT01528046]', 'Var', (181, 194))	('metformin', 'Chemical', 'MESH:D008687', (171, 180))	('PARP', 'Gene', (223, 227))	('TEM', 'Gene', '100188881', (0, 3))	('[NCT01858168', 'Var', (239, 251))	('temsirolimus', 'Chemical', 'MESH:C401859', (112, 124))	('[NCT03709680]', 'Var', (208, 221))	('NCT02044120]', 'Var', (253, 265))	('PARP', 'Gene', '142', (223, 227))
588647	30988632	Ewing sarcoma is one of the target tumors included in an ongoing single-agent Phase II trial of eribulin [NCT03441360], as well as in combination with irinotecan [NCT03245450].	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('coma', 'Phenotype', 'HP:0001259', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('Ewing sarcoma', 'Gene', '2130', (0, 13))	('Ewing sarcoma', 'Gene', (0, 13))	('[NCT03441360]', 'Var', (105, 118))	('irinotecan', 'Chemical', 'MESH:D000077146', (151, 161))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))
588668	30988632	Current trials now combine PARP inhibitors with DNA damaging agents such as temozolomide and/or irinotecan, based on preclinical demonstration of synergy.	('inhibitors', 'Var', (32, 42))	('PARP', 'Gene', (27, 31))	('irinotecan', 'Chemical', 'MESH:D000077146', (96, 106))	('temozolomide', 'Chemical', 'MESH:D000077204', (76, 88))	('PARP', 'Gene', '142', (27, 31))
588669	30988632	Other strategies include specifically focusing on the EWS-FLI1 translocation that characterizes this disease and drives tumor growth.	('translocation', 'Var', (63, 76))	('drives', 'PosReg', (113, 119))	('FLI1', 'Gene', (58, 62))	('FLI1', 'Gene', '2313', (58, 62))	('EWS', 'Gene', '2130', (54, 57))	('EWS', 'Gene', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
588674	30988632	Another rational strategy is inhibition of lysine-specific demethylase 1 (LSD-1), which is highly expressed in Ewing sarcoma and represses the transcriptional activation of downstream targets of EWS/FLI1 that lead to tumor growth.	('FLI1', 'Gene', (199, 203))	('lysine-specific demethylase 1', 'Gene', (43, 72))	('lysine-specific demethylase 1', 'Gene', '23028', (43, 72))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('tumor', 'Disease', (217, 222))	('FLI1', 'Gene', '2313', (199, 203))	('lead to', 'Reg', (209, 216))	('represses', 'NegReg', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('LSD-1', 'Gene', '23028', (74, 79))	('EWS', 'Gene', '2130', (195, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('coma', 'Phenotype', 'HP:0001259', (120, 124))	('Ewing sarcoma', 'Gene', (111, 124))	('LSD-1', 'Gene', (74, 79))	('inhibition', 'Var', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('Ewing sarcoma', 'Gene', '2130', (111, 124))	('transcriptional activation', 'MPA', (143, 169))	('EWS', 'Gene', (195, 198))
588705	30988632	The most common mutations occur in genes such as STAG2, CDKN2A, and TP53, which have not been easily targetable.	('STAG2', 'Gene', (49, 54))	('STAG2', 'Gene', '10735', (49, 54))	('common', 'Reg', (9, 15))	('mutations', 'Var', (16, 25))	('TP53', 'Gene', '7157', (68, 72))	('CDKN2A', 'Gene', (56, 62))	('TP53', 'Gene', (68, 72))	('CDKN2A', 'Gene', '1029', (56, 62))
588706	30988632	Although potentially actionable mutations have been reported with Ewing sarcoma, these are uncommon.	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('coma', 'Phenotype', 'HP:0001259', (75, 79))	('Ewing sarcoma', 'Gene', '2130', (66, 79))	('mutations', 'Var', (32, 41))	('Ewing sarcoma', 'Gene', (66, 79))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (66, 79))
588764	26802024	RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases.	('variant translocations', 'Var', (62, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (48, 56))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (37, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('Ewing-like sarcomas', 'Disease', (37, 56))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (37, 56))
588784	26802024	From recent sequencing studies it has become clear that with the exception of the well-known EWSR1-ETS gene fusions, which drive a complex tumor specific transcriptional program, the Ewing sarcoma genome is relatively quiet.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (183, 196))	('EWSR1', 'Gene', (93, 98))	('drive', 'Reg', (123, 128))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (183, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('EWSR1', 'Gene', '2130', (93, 98))	('Ewing sarcoma', 'Disease', (183, 196))	('fusions', 'Var', (108, 115))
588786	26802024	By RNA sequencing he demonstrated that tumors with FET-ETS gene fusions involving EWSR1 or FUS with members of the ERG (FLI1, ERG) or PEA3 (ETV1, ETV4) subfamily of ETS transcription factor genes cluster tightly together in a homogenous group, separate from Ewing-like sarcomas with EWSR1 fusions to non-ETS genes (i.e.	('ETV1', 'Gene', (140, 144))	('FUS', 'Gene', '2521', (91, 94))	('EWSR1', 'Gene', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('Ewing-like sarcomas', 'Disease', (258, 277))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	('ETV1', 'Gene', '2115', (140, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (269, 277))	('EWSR1', 'Gene', (82, 87))	('Ewing-like sarcomas', 'Phenotype', 'HP:0012254', (258, 277))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('PEA3', 'Gene', (134, 138))	('Ewing-like sarcomas', 'Disease', 'MESH:C563168', (258, 277))	('ETV4', 'Gene', (146, 150))	('PEA3', 'Gene', '2118', (134, 138))	('EWSR1', 'Gene', '2130', (283, 288))	('fusions', 'Var', (64, 71))	('FUS', 'Gene', (91, 94))	('ETV4', 'Gene', '2118', (146, 150))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('EWSR1', 'Gene', '2130', (82, 87))
588790	26802024	In Ewing sarcoma, widespread epigenetic rewiring of gene regulatory regions was recently demonstrated to be induced by EWS-FLI11.	('FLI11', 'Chemical', '-', (123, 128))	('EWS-FLI1', 'Gene', (119, 127))	('epigenetic', 'Var', (29, 39))	('Ewing sarcoma', 'Disease', (3, 16))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('EWS-FLI1', 'Gene', '2130;2313', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('induced', 'Reg', (108, 115))
588794	26802024	Paul Meltzer reported on differences in tumor transcriptomes of patients transiently responding or not to the R1507 IGF1R antibody in the SARC-011 trial.	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('IGF1R', 'Gene', (116, 121))	('R1507', 'Var', (110, 115))	('IGF1R', 'Gene', '3480', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
588802	26802024	Using the Infinium 450K methylation array to study promoter methylation, Oscar Tirado's group identified Ewing sarcoma specific inactivation of the PTRF/Cavin-1 gene, which, when co-expressed with the EWS-FLI1 activated target gene Caveolin-1 (CAV1), induced TP53 dependent cell death.	('CAV1', 'Gene', '857', (244, 248))	('Cavin-1', 'Gene', '284119', (153, 160))	('EWS-FLI1', 'Gene', '2130;2313', (201, 209))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('TP53', 'Gene', '7157', (259, 263))	('induced', 'Reg', (251, 258))	('CAV1', 'Gene', (244, 248))	('EWS-FLI1', 'Gene', (201, 209))	('Caveolin-1', 'Gene', '857', (232, 242))	('inactivation', 'Var', (128, 140))	('PTRF', 'Gene', (148, 152))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('TP53', 'Gene', (259, 263))	('PTRF', 'Gene', '284119', (148, 152))	('Cavin-1', 'Gene', (153, 160))	('Ewing sarcoma', 'Disease', (105, 118))	('Caveolin-1', 'Gene', (232, 242))
588805	26802024	Andrei Zinovyev described a computational method based on a Boolean mathematical model to predict genetic interactions and thus explain deviations of the phenotypic quantitative effect of multiple gene mutations from their simple additive effect as applied to Ewing sarcoma.	('interactions', 'Interaction', (106, 118))	('Ewing sarcoma', 'Disease', (260, 273))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (260, 273))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (260, 273))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('mutations', 'Var', (202, 211))
588811	26802024	Erika Brunet reported that though it was possible to induce the EWSR1-FLI1 gene rearrangement in adult mesenchymal stem cells by zinc finger nucleases or CRISPR/Cas9 mediated gene editing, the gene fusion was unstable and gradually counter-selected in this cell type.	('EWSR1', 'Gene', '2130', (64, 69))	('rearrangement', 'Var', (80, 93))	('men', 'Species', '9606', (89, 92))	('induce', 'PosReg', (53, 59))	('EWSR1', 'Gene', (64, 69))
588819	26802024	When activated (using a tamoxifen-inducible Cre recombinase) in a narrow time window around birth, EWS-FLI1 expression in the bone mesenchyme resulted in sarcomas that recapitulate the human Ewing sarcoma EWS-FLI1 transcriptional signature.	('EWS-FLI1', 'Gene', (205, 213))	('sarcomas', 'Phenotype', 'HP:0100242', (154, 162))	('sarcomas', 'Disease', (154, 162))	('human', 'Species', '9606', (185, 190))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (191, 204))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (191, 204))	('EWS-FLI1', 'Gene', '2130;2313', (205, 213))	('tamoxifen', 'Chemical', 'MESH:D013629', (24, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	('EWS-FLI1', 'Gene', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('EWS-FLI1', 'Gene', '2130;2313', (99, 107))	('resulted in', 'Reg', (142, 153))	('sarcomas', 'Disease', 'MESH:D012509', (154, 162))	('Ewing sarcoma', 'Disease', (191, 204))	('expression', 'Var', (108, 118))
588820	26802024	Consistent with this finding, Takuro Nakamura described their recently published transplantation model of tumors arising from EWS-FLI1 transgenic embryonic superficial zone cells from the articular cartilage at an ERG and PTHLH expressing developmental stage, and compared it to an unpublished similarly constructed model of CIC-DUX4 induced tumorigenesis from the same cell type.	('PTHLH', 'Gene', '5744', (222, 227))	('DUX4', 'Gene', '100288687', (329, 333))	('tumors', 'Disease', (106, 112))	('EWS-FLI1', 'Gene', (126, 134))	('tumor', 'Disease', (106, 111))	('transgenic', 'Var', (135, 145))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('articular cartilage', 'Disease', (188, 207))	('men', 'Species', '9606', (246, 249))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('EWS-FLI1', 'Gene', '2130;2313', (126, 134))	('tumor', 'Disease', (342, 347))	('PTHLH', 'Gene', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('articular cartilage', 'Disease', 'MESH:D002357', (188, 207))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('DUX4', 'Gene', (329, 333))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))
588821	26802024	He demonstrated that the CIC-DUX4 gene fusion activates PEA3 and ERG family ETS transcription factors and, similar to EWS-FLI1, down-regulates apoptosis genes.	('ERG family ETS', 'Gene', (65, 79))	('EWS-FLI1', 'Gene', '2130;2313', (118, 126))	('apoptosis genes', 'Gene', (143, 158))	('PEA3', 'Gene', '2118', (56, 60))	('activates', 'PosReg', (46, 55))	('PEA3', 'Gene', (56, 60))	('down-regulates', 'NegReg', (128, 142))	('EWS-FLI1', 'Gene', (118, 126))	('DUX4', 'Gene', (29, 33))	('DUX4', 'Gene', '100288687', (29, 33))	('fusion', 'Var', (39, 45))
588829	26802024	The chimeric oncogene would then perpetuate the progenitor-like state by hijacking the developmental transcription program.	('chimeric', 'Var', (4, 12))	('hijacking', 'NegReg', (73, 82))	('developmental transcription program', 'CPA', (87, 122))	('men', 'Species', '9606', (94, 97))
588842	26802024	Previously, the group of Franck Tirode demonstrated that sustained knockdown of EWS-FLI1 restores multipotency to Ewing sarcoma cell lines in vitro.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('EWS-FLI1', 'Gene', (80, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (114, 127))	('knockdown', 'Var', (67, 76))	('EWS-FLI1', 'Gene', '2130;2313', (80, 88))	('multipotency to Ewing sarcoma', 'Disease', (98, 127))	('restores', 'PosReg', (89, 97))	('multipotency to Ewing sarcoma', 'Disease', 'MESH:C563168', (98, 127))
588844	26802024	Similarly, Patrick Grohar observed replacement of the tumor tissue in Ewing sarcoma bearing mice by fat tissue of human origin upon treatment with PM01183, a second generation Trabectedin analog.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (70, 83))	('men', 'Species', '9606', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Ewing sarcoma', 'Disease', (70, 83))	('men', 'Species', '9606', (137, 140))	('human', 'Species', '9606', (114, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('tumor', 'Disease', (54, 59))	('PM01183', 'Var', (147, 154))	('mice', 'Species', '10090', (92, 96))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (70, 83))
588846	26802024	Thus, it appears that the tumor microenvironment has a profound effect on the differentiation route of Ewing sarcoma cells upon inactivation of the fusion gene in vivo.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (103, 116))	('Ewing sarcoma cells', 'Disease', (103, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('inactivation', 'Var', (128, 140))	('men', 'Species', '9606', (44, 47))	('Ewing sarcoma cells', 'Disease', 'MESH:C563168', (103, 122))	('tumor', 'Disease', (26, 31))	('effect', 'Reg', (64, 70))	('differentiation route', 'CPA', (78, 99))
588854	26802024	In light of recent evidence that suggests the EWS-FLI fusion protein may act as a pioneer factor capable of eliciting broad sweeping epigenetic effects, novel ex vivo models may provide an innovative platform to determine how microenvironmental cues:and their downstream signaling cascades:contribute to and/or reinforce epigenetic changes linked to the aberrant EWS-FLI fusion.	('contribute', 'PosReg', (290, 300))	('epigenetic changes', 'MPA', (321, 339))	('men', 'Species', '9606', (238, 241))	('aberrant', 'Var', (354, 362))	('reinforce', 'PosReg', (311, 320))	('EWS-FLI', 'Gene', (363, 370))
588865	26802024	The chromosome 1 susceptibility SNP rs9430161 is located in the vicinity of TARDBP, encoding an RNA binding protein that is structurally similar to and co-localizes with FUS and EWS to stress granules.	('rs9430161', 'Var', (36, 45))	('TARDBP', 'Gene', (76, 82))	('FUS', 'Gene', (170, 173))	('FUS', 'Gene', '2521', (170, 173))	('rs9430161', 'Mutation', 'rs9430161', (36, 45))	('TARDBP', 'Gene', '23435', (76, 82))
588866	26802024	Heinrich Kovar now reported on preliminary results generated by Dave Aryee suggesting that the chromosome 15 associated risk locus rs4924410 may affect the activity of a further stress granule associated protein, SRP14, via EWS-FLI1 dependent regulation of a novel long non-coding (lnc)RNA.	('affect', 'Reg', (145, 151))	('activity', 'MPA', (156, 164))	('EWS-FLI1', 'Gene', (224, 232))	('rs4924410', 'Mutation', 'rs4924410', (131, 140))	('regulation', 'MPA', (243, 253))	('SRP14', 'Gene', '6727', (213, 218))	('SRP14', 'Gene', (213, 218))	('EWS-FLI1', 'Gene', '2130;2313', (224, 232))	('rs4924410', 'Var', (131, 140))
588871	26802024	Importantly, knock-down of both lncRNAs interferes with tumor cell growth in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('knock-down', 'Var', (13, 23))	('tumor', 'Disease', (56, 61))	('interferes', 'NegReg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
588874	26802024	In fact, they found that the CDK4/6 inhibitor LEE011 (Novartis) has promising in vitro and in vivo cytostatic and cytotoxic activity on Ewing sarcoma cells.	('CDK4/6', 'Gene', (29, 35))	('Ewing sarcoma cells', 'Disease', 'MESH:C563168', (136, 155))	('cytotoxic activity', 'CPA', (114, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('LEE011', 'Var', (46, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (136, 149))	('Ewing sarcoma cells', 'Disease', (136, 155))	('CDK4/6', 'Gene', '1019;1021', (29, 35))	('LEE011', 'Chemical', 'MESH:C000589651', (46, 52))
588885	26802024	A siRNA screen performed in Lee Helman's lab to identify genes whose depletion recapitulates the transcriptional effects of EWS-FLI1 knockdown, identified several components of the splicing machinery.	('EWS-FLI1', 'Gene', (124, 132))	('knockdown', 'Var', (133, 142))	('EWS-FLI1', 'Gene', '2130;2313', (124, 132))	('depletion', 'MPA', (69, 78))
588886	26802024	In fact, knockdown of one of them, HNRNPH1, perturbed the correct splicing of primary EWS-FLI1 transcripts in cells with breakpoints in EWSR1 intron 8 leading to an out-of-frame fusion product.	('HNRNPH1', 'Gene', (35, 42))	('knockdown', 'Var', (9, 18))	('correct splicing', 'MPA', (58, 74))	('EWS-FLI1', 'Gene', '2130;2313', (86, 94))	('EWSR1', 'Gene', '2130', (136, 141))	('out-of-frame', 'NegReg', (165, 177))	('breakpoints', 'Var', (121, 132))	('HNRNPH1', 'Gene', '3187', (35, 42))	('EWSR1', 'Gene', (136, 141))	('perturbed', 'NegReg', (44, 53))	('EWS-FLI1', 'Gene', (86, 94))
588891	26802024	Using a targeted shRNA screen interrogating 21 Ewing sarcoma expressed deubiquitinating enzymes, Beat Schafer's group identified ubiquitin-specific protease USP19 as an EWS-FLI1 regulatory enzyme, whose knockdown destabilizes EWS-FLI1 protein and may therefore serve as an attractive therapeutic target.	('USP19', 'Gene', '10869', (157, 162))	('Ewing sarcoma', 'Disease', (47, 60))	('EWS-FLI1', 'Gene', (169, 177))	('EWS-FLI1', 'Gene', '2130;2313', (169, 177))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (47, 60))	('EWS-FLI1', 'Gene', (226, 234))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (47, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('USP19', 'Gene', (157, 162))	('destabilizes', 'NegReg', (213, 225))	('knockdown', 'Var', (203, 212))	('protein', 'Protein', (235, 242))	('EWS-FLI1', 'Gene', '2130;2313', (226, 234))
588909	26802024	In many cancers, the number of mutations predicts response to checkpoint targeting drugs (i.e.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('mutations', 'Var', (31, 40))	('cancers', 'Disease', (8, 15))	('response', 'MPA', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('predicts', 'Reg', (41, 49))
588937	29633281	In a multivariate Cox proportional hazards model, low-volume facilities demonstrated diminished overall survival at all time points (hazard ratio at 5 years = 1.24, 95% CI 1.10-1.39).	('low-volume', 'Var', (50, 60))	('Cox', 'Gene', '1351', (18, 21))	('diminished', 'NegReg', (85, 95))	('Cox', 'Gene', (18, 21))	('overall survival', 'MPA', (96, 112))
588971	29633281	In decreasing magnitude, risk factors for increased mortality at 5 years included size >10 cm (HR = 3.71, 95% CI 3.12-4.42), high-grade (HR = 3.17, 95% CI 2.63-3.81), size 5-10 cm (HR = 1.96, 95% CI 1.65-2.34), age >=60 years (HR = 1.52, 95% CI 1.27-1.81), Medicare insurance (HR = 1.49, 95% CI 1.26-1.77), positive margins (HR = 1.29, 95% CI 1.10-1.51), composite SES score <4 (HR = 1.25, 95% CI 1.05-1.50), treatment at a low-volume facility (HR = 1.24, 95% CI 1.10-1.39), and male sex (HR = 1.17, 95% CI 1.04-1.32).	('positive margins', 'CPA', (307, 323))	('high-grade', 'Var', (125, 135))	('SES', 'Chemical', 'MESH:D012643', (365, 368))
588991	29633281	Specifically, our data imply that changes in the delivery of care, in addition to the care itself, may make a tangible impact on patient survival.	('patient', 'Species', '9606', (129, 136))	('impact', 'Reg', (119, 125))	('changes', 'Var', (34, 41))
589027	29657999	reported that CIRT resulted in a local control rate of 62% in patients with unresectable osteosarcoma, and relatively small tumors were associated with a 5-year overall survival rate of 46% and a 5-year local control rate of 88%.	('osteosarcoma', 'Disease', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CIRT', 'Var', (14, 18))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcoma', 'Disease', 'MESH:D012516', (89, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (62, 70))
589083	29657999	Biopsy after CIRT may be associated with complications such as infection or chronic fistula, which were not observed in the present patients but were reported in another study patient.	('Biopsy', 'Var', (0, 6))	('associated', 'Reg', (25, 35))	('infection', 'Disease', (63, 72))	('infection', 'Disease', 'MESH:D007239', (63, 72))	('fistula', 'Disease', 'MESH:D005402', (84, 91))	('fistula', 'Disease', (84, 91))	('patient', 'Species', '9606', (176, 183))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))
589110	23580819	In conclusion, oligonucleotides targeting EWS-FLI1 RNA have shown interesting effects in cell culture and in animal preclinical models, and have the potential to be assayed as therapeutic agents either to keep residual disease at a low level or for enhancing the activity of conventional anticancer agents.	('oligonucleotides', 'Chemical', 'MESH:D009841', (15, 31))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('oligonucleotides', 'Var', (15, 31))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('activity', 'MPA', (263, 271))	('EWS-FLI1', 'Gene', (42, 50))	('cancer', 'Disease', (292, 298))	('enhancing', 'PosReg', (249, 258))
589115	23580819	Reduced EWS-FLI1 activity and tumorigenesis was observed after using mutation, peptide and small molecule approaches to disrupt RHA from binding to EWS-FLI1.	('binding', 'Interaction', (137, 144))	('RHA', 'Protein', (128, 131))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mutation', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('activity', 'MPA', (17, 25))	('EWS-FLI1', 'Gene', (8, 16))	('tumor', 'Disease', (30, 35))	('EWS-FLI1', 'Gene', (148, 156))
589124	23580819	Although the IGF pathway is often considered a "parallel" pathway to EWS-FLI1, recent work suggests that EWS-FLI1 may regulate IGF1 itself.	('IGF1', 'Gene', (127, 131))	('regulate', 'Reg', (118, 126))	('EWS-FLI1', 'Var', (105, 113))	('IGF1', 'Gene', '3479', (127, 131))
589130	23580819	In vitro and in vivo, Cixutumumab inhibits proliferation of a variety of human tumor cell lines.	('tumor', 'Disease', (79, 84))	('inhibits', 'NegReg', (34, 42))	('human', 'Species', '9606', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Cixutumumab', 'Var', (22, 33))	('Cixutumumab', 'Chemical', 'MESH:C557414', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
589137	23580819	In addition to blocking IGF1R, some of these IGF1R inhibitors may also inhibit insulin receptor A, and several have been shown to have promising preclinical ES activity.	('IGF1R', 'Gene', '3480', (45, 50))	('inhibit', 'NegReg', (71, 78))	('IGF1R', 'Gene', (24, 29))	('ES', 'Phenotype', 'HP:0012254', (157, 159))	('insulin', 'Gene', (79, 86))	('IGF1R', 'Gene', (45, 50))	('insulin', 'Gene', '3630', (79, 86))	('inhibitors', 'Var', (51, 61))	('IGF1R', 'Gene', '3480', (24, 29))
589142	23580819	Small-molecule inhibitors like BMS-554417, GSK1904529A and GSK1838705A have shown in vitro activity against ES.	('GSK1838705A', 'Var', (59, 70))	('ES', 'Phenotype', 'HP:0012254', (108, 110))	('GSK1904529A', 'Chemical', 'MESH:C000607695', (43, 54))	('GSK1904529A', 'Var', (43, 54))	('BMS-554417', 'Var', (31, 41))	('GSK1838705A', 'Chemical', 'MESH:C546191', (59, 70))
589149	23580819	However, as the expression of CD99 has been reported in a variety of other human tissues, such as testis, prostate and gastric mucosa, we cannot completely exclude the hypothetical toxicity of anti-CD99 MAb in human ES patients.	('hypothetical toxicity', 'Disease', (168, 189))	('anti-CD99', 'Var', (193, 202))	('CD99', 'Gene', (30, 34))	('human', 'Species', '9606', (210, 215))	('reported', 'Reg', (44, 52))	('patients', 'Species', '9606', (219, 227))	('hypothetical toxicity', 'Disease', 'MESH:D064420', (168, 189))	('human', 'Species', '9606', (75, 80))	('ES', 'Phenotype', 'HP:0012254', (216, 218))
589151	23580819	Earlier studies have shown that silencing of the EWS-FLI1 expression in ES cell lines increases p53 activity, suggesting that the EWS-FLI1 fusion protein plays a role in the constitutive silencing of p53 tumor suppressor activity.	('p53', 'Gene', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('p53', 'Gene', '7157', (96, 99))	('increases', 'PosReg', (86, 95))	('p53', 'Gene', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('silencing', 'Var', (32, 41))	('tumor', 'Disease', (204, 209))	('EWS-FLI1', 'Gene', (49, 57))	('p53', 'Gene', '7157', (200, 203))	('activity', 'MPA', (100, 108))	('ES', 'Phenotype', 'HP:0012254', (72, 74))
589155	23580819	At present, there is no evidence of permanent suppression of the p53 pathway by specific mutation of critical components.	('suppression', 'NegReg', (46, 57))	('p53', 'Gene', (65, 68))	('mutation', 'Var', (89, 97))	('p53', 'Gene', '7157', (65, 68))
589158	23580819	Small molecules like Nutlin-3a and MI-219 antagonize the p53-MDM2 interaction by blocking the p53-binding pocket of MDM2 and, as a consequence, there is a rapid stabilization and accumulation of p53 protein levels.	('p53', 'Gene', (195, 198))	('p53', 'Gene', '7157', (195, 198))	('p53', 'Gene', (94, 97))	('interaction', 'Interaction', (66, 77))	('accumulation', 'PosReg', (179, 191))	('p53', 'Gene', '7157', (94, 97))	('MI-219', 'Var', (35, 41))	('MDM2', 'Gene', '4193', (116, 120))	('MDM2', 'Gene', '4193', (61, 65))	('MDM2', 'Gene', (116, 120))	('MI-219', 'Chemical', 'MESH:C574930', (35, 41))	('MDM2', 'Gene', (61, 65))	('stabilization', 'MPA', (161, 174))	('p53', 'Gene', (57, 60))	('blocking', 'NegReg', (81, 89))	('antagonize', 'NegReg', (42, 52))	('p53', 'Gene', '7157', (57, 60))
589165	23580819	Further studies are warranted to evaluate the potential of incorporation of low-dose actinomycin D with the current standard of care for the treatment of patients with wild type p53 ESFTs [Table 4].	('ESFTs', 'Var', (182, 187))	('patients', 'Species', '9606', (154, 162))	('ES', 'Phenotype', 'HP:0012254', (182, 184))	('actinomycin D', 'Chemical', 'MESH:D003609', (85, 98))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))
589175	23580819	Concurrent administration of EWS-FLI1 antisense oligonucleotides and rapamycin efficiently induced the apoptotic death of ES cells in culture through a process involving TGF-beta.	('antisense oligonucleotides', 'Var', (38, 64))	('EWS-FLI1', 'Gene', (29, 37))	('induced', 'Reg', (91, 98))	('apoptotic death', 'CPA', (103, 118))	('ES', 'Phenotype', 'HP:0012254', (122, 124))	('rapamycin', 'Chemical', 'MESH:D020123', (69, 78))	('oligonucleotides', 'Chemical', 'MESH:D009841', (48, 64))
589176	23580819	Preclinical experiments conclusively showed that the combined treatment with antisense oligonucleotides and rapamycin caused a significant inhibition of tumor growth in mice.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('inhibition', 'NegReg', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('mice', 'Species', '10090', (169, 173))	('antisense oligonucleotides', 'Var', (77, 103))	('oligonucleotides', 'Chemical', 'MESH:D009841', (87, 103))	('rapamycin', 'Chemical', 'MESH:D020123', (108, 117))
589180	23580819	Overexpression of Bcl-2 results in a resistance to apoptosis-inducing agents, including radiation and chemotherapy, and has been associated with poor clinical response and shorter survival.	('Bcl-2', 'Gene', (18, 23))	('Bcl-2', 'Gene', '596', (18, 23))	('Overexpression', 'Var', (0, 14))	('resistance to apoptosis-inducing agents', 'MPA', (37, 76))
589181	23580819	Targeted downregulation of Bcl-2 expression by antisense oligodeoxynucleotide G3139 may result in apoptosis of tumor cells, especially when coadministered with cytotoxic drugs.	('downregulation', 'NegReg', (9, 23))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Bcl-2', 'Gene', (27, 32))	('apoptosis', 'CPA', (98, 107))	('G3139', 'Var', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('G3139', 'Chemical', 'MESH:C408162', (78, 83))	('antisense', 'Var', (47, 56))	('tumor', 'Disease', (111, 116))	('expression', 'MPA', (33, 43))	('Bcl-2', 'Gene', '596', (27, 32))
589183	23580819	Thus, pharmacologic downregulation of Bcl-2 by G3139 may potentially enhance the chemotherapy responsiveness of tumor cells to these drugs.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('downregulation', 'NegReg', (20, 34))	('enhance', 'PosReg', (69, 76))	('G3139', 'Var', (47, 52))	('G3139', 'Chemical', 'MESH:C408162', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('Bcl-2', 'Gene', (38, 43))	('Bcl-2', 'Gene', '596', (38, 43))
589185	23580819	The consistent characteristic chromosomal translocations of the ESFT, which result in the fusion of EWS-FLI1 critical for the maintenance of the tumor phenotype and the subsequent formation of novel chimeric proteins, offer promising molecular targets for developing new therapies.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('chimeric', 'MPA', (199, 207))	('tumor', 'Disease', (145, 150))	('fusion', 'Var', (90, 96))	('EWS-FLI1', 'Gene', (100, 108))	('ES', 'Phenotype', 'HP:0012254', (64, 66))
589197	22168313	In subjects from South Xinjiang, lower educational level and reported drinking were each independently associated with higher KSHV seroprevalence.	('lower education', 'Phenotype', 'HP:0001249', (33, 48))	('KSHV', 'Species', '37296', (126, 130))	('lower educational level', 'Phenotype', 'HP:0001249', (33, 56))	('seroprevalence', 'Var', (131, 145))	('higher', 'PosReg', (119, 125))	('KSHV', 'Disease', (126, 130))	('KS', 'Phenotype', 'HP:0100726', (126, 128))
589213	22168313	Recent studies have found KSHV seroprevalence correlates with the high incidence of KS in Xinjiang, which ranged from 12.5% to 48.0% in different study populations, including the general population, blood donors, tumor patients and HIV-infected individuals.	('tumor', 'Disease', (213, 218))	('HIV-infected', 'Disease', 'MESH:D015658', (232, 244))	('seroprevalence', 'Var', (31, 45))	('KSHV', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('KS', 'Phenotype', 'HP:0100726', (84, 86))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('HIV-infected', 'Disease', (232, 244))	('KS', 'Phenotype', 'HP:0100726', (26, 28))	('KSHV', 'Species', '37296', (26, 30))
589225	22168313	Moreover, place of residence was also independently associated with KSHV seroprevalence.	('seroprevalence', 'Var', (73, 87))	('associated', 'Reg', (52, 62))	('KSHV', 'Disease', (68, 72))	('KSHV', 'Species', '37296', (68, 72))	('KS', 'Phenotype', 'HP:0100726', (68, 70))
589231	22168313	More specifically, KSHV seroprevalence increased with age from 21.2% in those aged < 40 years to 21.3% in those aged 40-55, and to 30.7% in those aged >=55 years.	('KSHV', 'Gene', (19, 23))	('KSHV', 'Species', '37296', (19, 23))	('increased', 'PosReg', (39, 48))	('KS', 'Phenotype', 'HP:0100726', (19, 21))	('seroprevalence', 'Var', (24, 38))
589232	22168313	Furthermore, there was a significant difference in KSHV seroprevalence with respect to educational level (P = 0.020), from 17.7% in those educated to junior high school level, to 24.3% in those educated to elementary school level, and to 28.3% in those who were illiterate/semiliterate.	('KSHV', 'Species', '37296', (51, 55))	('seroprevalence', 'Var', (56, 70))	('KS', 'Phenotype', 'HP:0100726', (51, 53))	('KSHV', 'Gene', (51, 55))	('men', 'Species', '9606', (209, 212))
589233	22168313	An association of borderline significance was detected between KSHV seropositivity and the report of drinking (P = 0.058).	('seropositivity', 'Var', (68, 82))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('KSHV', 'Gene', (63, 67))	('KSHV', 'Species', '37296', (63, 67))
589235	22168313	Junior high school, OR = 1.67, 95% CI = 1.02-2.73) and reported drinking (yes vs. no, OR = 3.23, 95%CI = 1.07-9.78)were each independently associated with higher KSHV seroprevalence.	('KSHV', 'Disease', (162, 166))	('KSHV', 'Species', '37296', (162, 166))	('KS', 'Phenotype', 'HP:0100726', (162, 164))	('seroprevalence', 'Var', (167, 181))	('higher', 'PosReg', (155, 161))	('Junior high school', 'Var', (0, 18))
589244	22168313	The seroprevalence of KSHV in the general Uygur population in Xinjiang was significantly more prevalent in individuals aged >=55 years compared to those aged < 55 years.	('prevalent', 'Reg', (94, 103))	('seroprevalence', 'Var', (4, 18))	('KSHV', 'Gene', (22, 26))	('KS', 'Phenotype', 'HP:0100726', (22, 24))	('KSHV', 'Species', '37296', (22, 26))
589251	22168313	The seroprevalence of KSHV in this study population was independently associated with educational level.	('seroprevalence', 'Var', (4, 18))	('KSHV', 'Gene', (22, 26))	('associated', 'Reg', (70, 80))	('KS', 'Phenotype', 'HP:0100726', (22, 24))	('KSHV', 'Species', '37296', (22, 26))
589271	22168313	Serum samples that were highly positive for antibodies against KSHV in the ELISA assay and the sera of 51 KS patients were analyzed to determine their antibodiy titers using gradient serum dilutions (1:100,1:200,1:400,1:800, 1:1600 and 1:3200).	('1:100,1:200,1:400,1:800', 'Var', (200, 223))	('KS', 'Phenotype', 'HP:0100726', (106, 108))	('KSHV', 'Species', '37296', (63, 67))	('patients', 'Species', '9606', (109, 117))	('positive', 'Reg', (31, 39))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('KSHV', 'Gene', (63, 67))
589351	28146421	AR42 and pazopanib caused HSP90/HSP70 dissociation from RAF-1 and B-RAF that resulted in reduced 'RAF' expression.	('HSP90', 'Gene', (26, 31))	('RAF-1', 'Gene', '5894', (56, 61))	('HSP70', 'Gene', '3308', (32, 37))	('B-RAF', 'Gene', '673', (66, 71))	('reduced', 'NegReg', (89, 96))	('AR42', 'Var', (0, 4))	('RAF-1', 'Gene', (56, 61))	('RAF', 'Gene', (98, 101))	('HSP90', 'Gene', '3320', (26, 31))	('RAF', 'Gene', '22882', (56, 59))	('expression', 'MPA', (103, 113))	('B-RAF', 'Gene', (66, 71))	('pazopanib', 'Chemical', 'MESH:C516667', (9, 18))	('RAF', 'Gene', (56, 59))	('HSP70', 'Gene', (32, 37))	('RAF', 'Gene', '22882', (68, 71))	('RAF', 'Gene', (68, 71))	('AR42', 'Chemical', 'MESH:C524513', (0, 4))	('RAF', 'Gene', '22882', (98, 101))	('dissociation', 'MPA', (38, 50))
589358	28146421	Several clinical trials using HDAC inhibitors, including AR42, in combination with multi-kinase inhibitors are presently open at VCU Massey Cancer Center (NCT02349867; NCT01075113; NCT02795819; NCT01817751).	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('NCT01817751', 'Var', (194, 205))	('VCU Massey Cancer', 'Disease', (129, 146))	('NCT02349867; NCT01075113; NCT02795819; NCT01817751', 'Var', (155, 205))	('AR42', 'Chemical', 'MESH:C524513', (57, 61))	('HDAC', 'Gene', (30, 34))	('VCU Massey Cancer', 'Disease', 'MESH:D009369', (129, 146))	('HDAC', 'Gene', '9734', (30, 34))
589374	28146421	Our present pre-clinical findings argue that AR42 may have single agent activity against mutant B-RAF melanoma, and that AR42 facilitates tumor cell killing by the multi-kinase inhibitor pazopanib in vitro and in vivo.	('AR42', 'Var', (121, 125))	('AR42', 'Chemical', 'MESH:C524513', (121, 125))	('facilitates', 'PosReg', (126, 137))	('RAF melanoma', 'Disease', 'MESH:D008545', (98, 110))	('tumor', 'Disease', (138, 143))	('RAF melanoma', 'Disease', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('AR42', 'Chemical', 'MESH:C524513', (45, 49))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('B-RAF', 'Gene', '673', (96, 101))	('pazopanib', 'Chemical', 'MESH:C516667', (187, 196))	('B-RAF', 'Gene', (96, 101))	('mutant', 'Var', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
589375	28146421	AR42, at approximately 40% of its plasma C max, killed mutant B-RAF melanoma cells more effectively than it did sarcoma and renal carcinoma cells (Figure 1A).	('sarcoma and renal carcinoma', 'Disease', 'MESH:C538614', (112, 139))	('renal carcinoma', 'Phenotype', 'HP:0005584', (124, 139))	('RAF melanoma', 'Disease', (64, 76))	('RAF melanoma', 'Disease', 'MESH:D008545', (64, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('mutant', 'Var', (55, 61))	('B-RAF', 'Gene', '673', (62, 67))	('AR42', 'Chemical', 'MESH:C524513', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('B-RAF', 'Gene', (62, 67))
589376	28146421	Pazopanib, at approximately 50% of its free plasma C max, killed mutant B-RAF melanoma cells more effectively than it did sarcoma and renal carcinoma cells (Figure 1B).	('RAF melanoma', 'Disease', (74, 86))	('RAF melanoma', 'Disease', 'MESH:D008545', (74, 86))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('mutant', 'Var', (65, 71))	('sarcoma and renal carcinoma', 'Disease', 'MESH:C538614', (122, 149))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('renal carcinoma', 'Phenotype', 'HP:0005584', (134, 149))	('B-RAF', 'Gene', '673', (72, 77))	('B-RAF', 'Gene', (72, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
589377	28146421	The combination of [pazopanib + AR42] was also more effective at killing melanoma cells than sarcoma and kidney cancer cells (Figure 1C).	('melanoma', 'Disease', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('pazopanib', 'Chemical', 'MESH:C516667', (20, 29))	('sarcoma', 'Disease', (93, 100))	('AR42', 'Chemical', 'MESH:C524513', (32, 36))	('kidney cancer', 'Disease', 'MESH:D007680', (105, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('kidney cancer', 'Phenotype', 'HP:0009726', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('kidney cancer', 'Disease', (105, 118))	('[pazopanib + AR42]', 'Var', (19, 37))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
589378	28146421	The standard of care treatment for mutant B-RAF melanoma is the combination of the MEK1/2/5 inhibitor trametinib and the mutant B-RAF specific inhibitor dabrafenib.	('dabrafenib', 'Chemical', 'MESH:C561627', (153, 163))	('RAF melanoma', 'Disease', 'MESH:D008545', (44, 56))	('B-RAF', 'Gene', (128, 133))	('trametinib', 'Chemical', 'MESH:C560077', (102, 112))	('B-RAF', 'Gene', '673', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('mutant', 'Var', (35, 41))	('B-RAF', 'Gene', (42, 47))	('B-RAF', 'Gene', '673', (128, 133))	('RAF melanoma', 'Disease', (44, 56))
589379	28146421	In PDX models of mutant B-RAF melanoma AR42 and pazopanib, as single agents, and in combination were more effective at killing the melanoma cells than the combination of trametinib/dabrafenib at their individual 100% C max plasma concentrations (Figure 1D).	('trametinib', 'Chemical', 'MESH:C560077', (170, 180))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('pazopanib', 'Chemical', 'MESH:C516667', (48, 57))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('dabrafenib', 'Chemical', 'MESH:C561627', (181, 191))	('rat', 'Species', '10116', (237, 240))	('melanoma', 'Disease', (30, 38))	('B-RAF melanoma AR42', 'Disease', 'MESH:D008545', (24, 43))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('mutant', 'Var', (17, 23))	('B-RAF melanoma AR42', 'Disease', (24, 43))
589380	28146421	The TPF-12-293 isolate is vemurafenib resistant and in these cells both AR42 and [pazopanib + AR42] caused high levels of cell killing whereas treatment with trametinib/dabrafenib did not significantly enhance cell death.	('AR42', 'Var', (72, 76))	('AR42', 'Chemical', 'MESH:C524513', (94, 98))	('dabrafenib', 'Chemical', 'MESH:C561627', (169, 179))	('AR42', 'Chemical', 'MESH:C524513', (72, 76))	('cell killing', 'CPA', (122, 134))	('trametinib', 'Chemical', 'MESH:C560077', (158, 168))	('vemurafenib', 'Chemical', 'MESH:D000077484', (26, 37))	('pazopanib', 'Chemical', 'MESH:C516667', (82, 91))	('TPF-12-293', 'CellLine', 'CVCL:0045', (4, 14))
589394	28146421	In addition to BAX, BAK, NOXA and PUMA, knock down of the toxic BH3 domain proteins BIM, BAD or BID also suppressed killing by [pazopanib + AR42] (Figure 4A).	('suppressed', 'NegReg', (105, 115))	('BID', 'Gene', (96, 99))	('BIM', 'Gene', '10018', (84, 87))	('BIM', 'Gene', (84, 87))	('killing by [pazopanib + AR42]', 'MPA', (116, 145))	('BID', 'Gene', '637', (96, 99))	('knock down', 'Var', (40, 50))	('BAK', 'Chemical', '-', (20, 23))	('pazopanib', 'Chemical', 'MESH:C516667', (128, 137))	('AR42', 'Chemical', 'MESH:C524513', (140, 144))
589396	28146421	In Figure 3B we noted that knock down of FADD was more protective than knock down of CD95 at preventing cell killing.	('FADD', 'Gene', (41, 45))	('FADD', 'Gene', '8772', (41, 45))	('CD95', 'Gene', (85, 89))	('cell killing', 'CPA', (104, 116))	('CD95', 'Gene', '355', (85, 89))	('knock down', 'Var', (27, 37))
589397	28146421	Knock down of the death receptors DR4 or DR5 also partially, but significantly, reduced [pazopanib + AR42] killing (Figure 4C).	('DR5', 'Gene', '8795', (41, 44))	('pazopanib', 'Chemical', 'MESH:C516667', (89, 98))	('DR4', 'Gene', '3126', (34, 37))	('AR42', 'Chemical', 'MESH:C524513', (101, 105))	('reduced', 'NegReg', (80, 87))	('DR4', 'Gene', (34, 37))	('Knock down', 'Var', (0, 10))	('DR5', 'Gene', (41, 44))	('[pazopanib + AR42] killing', 'MPA', (88, 114))
589403	28146421	HDAC inhibitors can cause activation of the ataxia telangiectasia mutated protein (ATM).	('HDAC', 'Gene', (0, 4))	('telangiectasia', 'Phenotype', 'HP:0001009', (51, 65))	('ataxia', 'Phenotype', 'HP:0001251', (44, 50))	('HDAC', 'Gene', '9734', (0, 4))	('ATM', 'Gene', '472', (83, 86))	('inhibitors', 'Var', (5, 15))	('activation', 'PosReg', (26, 36))	('ataxia telangiectasia mutated protein', 'Gene', (44, 81))	('ATM', 'Gene', (83, 86))	('ataxia telangiectasia mutated protein', 'Gene', '472', (44, 81))
589407	28146421	Knock down of ATM or of AMPK prevented drug induced phosphorylation of ULK1 S317 and ATG13 S318 and drug-induced dephosphorylation of mTOR S2448, mTOR S2481, AKT T308 and ULK1 S757 (Figure 5A-5C).	('mTOR', 'Gene', (146, 150))	('ULK1', 'Gene', (71, 75))	('AMPK', 'Gene', '5562', (24, 28))	('dephosphorylation', 'MPA', (113, 130))	('ATG13', 'Gene', '9776', (85, 90))	('ULK1', 'Gene', '8408', (171, 175))	('mTOR', 'Gene', '2475', (146, 150))	('ATM', 'Gene', '472', (14, 17))	('AKT', 'Gene', '207', (158, 161))	('ULK1', 'Gene', (171, 175))	('prevented', 'NegReg', (29, 38))	('AMPK', 'Gene', (24, 28))	('mTOR', 'Gene', (134, 138))	('ATG13', 'Gene', (85, 90))	('ATM', 'Gene', (14, 17))	('ULK1', 'Gene', '8408', (71, 75))	('mTOR', 'Gene', '2475', (134, 138))	('phosphorylation', 'MPA', (52, 67))	('S317', 'Var', (76, 80))	('AKT', 'Gene', (158, 161))
589409	28146421	The drug combination activated eIF2alpha, and knock down of eIF2alpha prevented the drug-induced declines in MCL-1, BCL-XL and c-FLIP-s expression and the increase in Beclin1 expression (Figure 5D).	('Beclin1', 'Gene', (167, 174))	('increase', 'PosReg', (155, 163))	('expression', 'MPA', (175, 185))	('eIF2alpha', 'Gene', '83939', (60, 69))	('BCL-XL', 'Gene', '598', (116, 122))	('eIF2alpha', 'Gene', (31, 40))	('c-FLIP', 'Gene', '8837', (127, 133))	('declines', 'Disease', (97, 105))	('knock down', 'Var', (46, 56))	('eIF2alpha', 'Gene', '83939', (31, 40))	('prevented', 'NegReg', (70, 79))	('declines', 'Disease', 'MESH:D060825', (97, 105))	('MCL-1', 'Gene', '4170', (109, 114))	('eIF2alpha', 'Gene', (60, 69))	('BCL-XL', 'Gene', (116, 122))	('MCL-1', 'Gene', (109, 114))	('c-FLIP', 'Gene', (127, 133))
589413	28146421	It has been known for several decades that both HSP90 and HSP70 chaperone B-RAF and RAF-1 and that removal of these chaperones during 'RAF' chromatographic protein purification results in rapid RAF protein denaturation.	('HSP70', 'Gene', (58, 63))	('B-RAF', 'Gene', (74, 79))	('RAF-1', 'Gene', '5894', (84, 89))	('RAF', 'Gene', '22882', (76, 79))	('RAF', 'Gene', (76, 79))	('HSP90', 'Gene', (48, 53))	('RAF', 'Gene', (135, 138))	('HSP90', 'Gene', '3320', (48, 53))	('RAF', 'Gene', '22882', (135, 138))	('RAF', 'Gene', '22882', (194, 197))	('rat', 'Species', '10116', (212, 215))	('HSP70', 'Gene', '3308', (58, 63))	('RAF', 'Gene', (84, 87))	('RAF', 'Gene', (194, 197))	('B-RAF', 'Gene', '673', (74, 79))	('RAF', 'Gene', '22882', (84, 87))	('removal', 'Var', (99, 106))	('RAF-1', 'Gene', (84, 89))
589415	28146421	Using vemurafenib resistant TPF-12-293 cells we re-confirmed that pazopanib could alter the structure of chaperones in melanoma cells as judged by reduced immuno-fluorescence at the NH2-termini but not at their COOH termini (Supplementary Figure 5).	('vemurafenib', 'Chemical', 'MESH:D000077484', (6, 17))	('alter', 'Reg', (82, 87))	('TPF-12-293', 'CellLine', 'CVCL:0045', (28, 38))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('pazopanib', 'Chemical', 'MESH:C516667', (66, 75))	('melanoma', 'Disease', (119, 127))	('structure of chaperones', 'MPA', (92, 115))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('pazopanib', 'Var', (66, 75))	('COOH', 'Chemical', 'MESH:D002255', (211, 215))	('reduced', 'NegReg', (147, 154))	('immuno-fluorescence', 'MPA', (155, 174))
589416	28146421	Notably for HSP90 and HSP70, AR42 treatment of the cells enhanced the ability of pazopanib to occlude the epitope at the NH2-termini of the chaperone proteins.	('HSP90', 'Gene', '3320', (12, 17))	('AR42', 'Var', (29, 33))	('pazopanib', 'Chemical', 'MESH:C516667', (81, 90))	('HSP70', 'Gene', '3308', (22, 27))	('AR42', 'Chemical', 'MESH:C524513', (29, 33))	('epitope at the NH2-termini', 'MPA', (106, 132))	('ability', 'MPA', (70, 77))	('occlude', 'NegReg', (94, 101))	('enhanced', 'PosReg', (57, 65))	('HSP70', 'Gene', (22, 27))	('chaperone proteins', 'MPA', (140, 158))	('HSP90', 'Gene', (12, 17))
589418	28146421	Of greater interest, the ability of AR42 to interact with pazopanib to suppress chaperone ATPase activity was prevented by knock down of ATM (Figure 6B).	('ATPase', 'Gene', '1769', (90, 96))	('chaperone', 'MPA', (80, 89))	('pazopanib', 'Chemical', 'MESH:C516667', (58, 67))	('ATM', 'Gene', (137, 140))	('AR42', 'Chemical', 'MESH:C524513', (36, 40))	('ATPase', 'Gene', (90, 96))	('suppress', 'NegReg', (71, 79))	('ATM', 'Gene', '472', (137, 140))	('knock down', 'Var', (123, 133))
589420	28146421	Treatment of melanoma cells with [pazopanib + AR42] for one hour significantly reduced the amount of B-RAF and RAF-1 that co-precipitated with HSP90 and HSP70 (Figure 6D).	('HSP70', 'Gene', '3308', (153, 158))	('[pazopanib + AR42]', 'Var', (33, 51))	('reduced', 'NegReg', (79, 86))	('pazopanib', 'Chemical', 'MESH:C516667', (34, 43))	('HSP90', 'Gene', (143, 148))	('RAF-1', 'Gene', '5894', (111, 116))	('AR42', 'Chemical', 'MESH:C524513', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('HSP70', 'Gene', (153, 158))	('melanoma', 'Disease', (13, 21))	('HSP90', 'Gene', '3320', (143, 148))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('RAF-1', 'Gene', (111, 116))	('B-RAF', 'Gene', '673', (101, 106))	('B-RAF', 'Gene', (101, 106))
589422	28146421	AR42 is known to be a highly efficacious catalytic inhibitor of HDAC1, HDAC2, HDAC3, HDAC6, HDAC8 and HDAC10 (Figure 7A, upper).	('HDAC2', 'Gene', (71, 76))	('HDAC8', 'Gene', '55869', (92, 97))	('HDAC2', 'Gene', '3066', (71, 76))	('HDAC6', 'Gene', '10013', (85, 90))	('HDAC1', 'Gene', (102, 107))	('HDAC6', 'Gene', (85, 90))	('HDAC1', 'Gene', (64, 69))	('HDAC8', 'Gene', (92, 97))	('HDAC10', 'Gene', (102, 108))	('HDAC3', 'Gene', '8841', (78, 83))	('HDAC1', 'Gene', '3065', (102, 107))	('HDAC10', 'Gene', '83933', (102, 108))	('AR42', 'Var', (0, 4))	('HDAC1', 'Gene', '3065', (64, 69))	('AR42', 'Chemical', 'MESH:C524513', (0, 4))	('HDAC3', 'Gene', (78, 83))
589423	28146421	Individual knock down of HDAC1/2/3/6/8/10 did not significantly alter basal levels of cell viability and only knock down of HDAC6 modestly enhanced pazopanib lethality (data not shown).	('knock down', 'Var', (110, 120))	('HDAC1/2/3/6/8/10', 'Gene', '3065;3066', (25, 41))	('HDAC6', 'Gene', '10013', (124, 129))	('pazopanib', 'Chemical', 'MESH:C516667', (148, 157))	('HDAC6', 'Gene', (124, 129))	('pazopanib lethality', 'MPA', (148, 167))	('enhanced', 'PosReg', (139, 147))	('HDAC1/2/3/6/8/10', 'Gene', (25, 41))
589424	28146421	Knock down of HDAC6 combined with knock down of HDAC2 or of HDAC10 caused a significant high level of killing when combined with pazopanib (Figure 7A, lower).	('killing', 'MPA', (102, 109))	('HDAC6', 'Gene', '10013', (14, 19))	('HDAC10', 'Gene', (60, 66))	('HDAC6', 'Gene', (14, 19))	('HDAC2', 'Gene', (48, 53))	('HDAC2', 'Gene', '3066', (48, 53))	('HDAC10', 'Gene', '83933', (60, 66))	('pazopanib', 'Chemical', 'MESH:C516667', (129, 138))	('Knock down', 'Var', (0, 10))	('knock down', 'Var', (34, 44))
589428	28146421	Over-expression of wild type HDAC6 reduced the induction of GFP+ punctae.	('reduced', 'NegReg', (35, 42))	('Over-expression', 'Var', (0, 15))	('HDAC6', 'Gene', '10013', (29, 34))	('induction of GFP+ punctae', 'MPA', (47, 72))	('HDAC6', 'Gene', (29, 34))
589430	28146421	Knock down of HDAC6 did not alter the ability of the drug combination to elevate P-gammaH2AX levels arguing that the drug combination effects were more likely proximal to the autophagic apparatus than to ATM and DNA damage.	('P-gammaH2AX levels', 'MPA', (81, 99))	('ATM', 'Gene', (204, 207))	('HDAC6', 'Gene', '10013', (14, 19))	('rat', 'Species', '10116', (190, 193))	('HDAC6', 'Gene', (14, 19))	('P-gammaH2AX', 'Chemical', '-', (81, 92))	('ATM', 'Gene', '472', (204, 207))	('Knock down', 'Var', (0, 10))
589431	28146421	During these studies examining HDACs, we surprisingly discovered that AR42 also rapidly reduced the protein levels of HDAC2, HDAC5, HDAC6, HDAC10 and HDAC11 (Supplementary Figure 7A and 7B).	('HDAC', 'Gene', (139, 143))	('HDAC5', 'Gene', '10014', (125, 130))	('HDAC6', 'Gene', '10013', (132, 137))	('HDAC2', 'Gene', '3066', (118, 123))	('HDAC10', 'Gene', (139, 145))	('HDAC2', 'Gene', (118, 123))	('AR42', 'Chemical', 'MESH:C524513', (70, 74))	('reduced', 'NegReg', (88, 95))	('HDAC', 'Gene', '9734', (150, 154))	('AR42', 'Var', (70, 74))	('protein levels', 'MPA', (100, 114))	('HDAC11', 'Gene', '79885', (150, 156))	('HDAC', 'Gene', '9734', (125, 129))	('HDAC', 'Gene', '9734', (31, 35))	('HDAC', 'Gene', '9734', (132, 136))	('HDAC5', 'Gene', (125, 130))	('HDAC', 'Gene', '9734', (118, 122))	('HDAC', 'Gene', (150, 154))	('HDAC6', 'Gene', (132, 137))	('HDAC', 'Gene', (125, 129))	('HDAC10', 'Gene', '83933', (139, 145))	('HDAC', 'Gene', (31, 35))	('HDAC', 'Gene', (132, 136))	('HDAC', 'Gene', (118, 122))	('HDAC', 'Gene', '9734', (139, 143))	('HDAC11', 'Gene', (150, 156))
589435	28146421	Knock down of ATG5, an early essential inducer of autophagosome formation, or knock down of Beclin1, an intermediate essential inducer of autophagosome formation, both prevented [pazopanib + AR42] treatment from reducing HDAC6 expression (Figure 8A).	('Beclin1', 'Gene', (92, 99))	('reducing', 'NegReg', (212, 220))	('pazopanib', 'Chemical', 'MESH:C516667', (179, 188))	('ATG5', 'Gene', (14, 18))	('AR42', 'Chemical', 'MESH:C524513', (191, 195))	('expression', 'MPA', (227, 237))	('prevented', 'NegReg', (168, 177))	('HDAC6', 'Gene', '10013', (221, 226))	('HDAC6', 'Gene', (221, 226))	('ATG5', 'Gene', '9474', (14, 18))	('knock down', 'Var', (78, 88))
589438	28146421	This effect was reduced by knock down of AMPK, Beclin1 and to a lesser extent by eIF2alpha.	('Beclin1', 'Gene', (47, 54))	('eIF2alpha', 'Gene', '83939', (81, 90))	('reduced', 'NegReg', (16, 23))	('AMPK', 'Gene', '5562', (41, 45))	('AMPK', 'Gene', (41, 45))	('knock down', 'Var', (27, 37))	('eIF2alpha', 'Gene', (81, 90))
589442	28146421	Acetylation of HSP90 has been proposed to reduce the chaperoning ability of HSP90.	('Acetylation', 'Var', (0, 11))	('chaperoning', 'MPA', (53, 64))	('reduce', 'NegReg', (42, 48))	('HSP90', 'Gene', (76, 81))	('HSP90', 'Gene', '3320', (76, 81))	('HSP90', 'Gene', (15, 20))	('HSP90', 'Gene', '3320', (15, 20))
589443	28146421	Knock down of HDAC6 elevated the basal levels of HSP90 acetylation and prevented [pazopanib + AR42] from increasing HSP90 acetylation (Supplementary Figure 9A).	('increasing', 'PosReg', (105, 115))	('HSP90', 'Gene', (116, 121))	('HSP90', 'Gene', '3320', (116, 121))	('AR42', 'Chemical', 'MESH:C524513', (94, 98))	('HDAC6', 'Gene', '10013', (14, 19))	('HDAC6', 'Gene', (14, 19))	('HSP90', 'Gene', (49, 54))	('acetylation', 'MPA', (122, 133))	('elevated', 'PosReg', (20, 28))	('HSP90', 'Gene', '3320', (49, 54))	('Knock down', 'Var', (0, 10))	('pazopanib', 'Chemical', 'MESH:C516667', (82, 91))	('prevented', 'NegReg', (71, 80))	('[pazopanib + AR42]', 'MPA', (81, 99))
589449	28146421	Dysregulation of HDAC6 has also been linked to elevated production of reactive oxygen species and our prior data had shown the drug combination reduced TRX and SOD2 levels.	('TRX', 'Gene', '7295', (152, 155))	('reduced', 'NegReg', (144, 151))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (70, 93))	('SOD2', 'Gene', '6648', (160, 164))	('Dysregulation', 'Var', (0, 13))	('HDAC6', 'Gene', '10013', (17, 22))	('HDAC6', 'Gene', (17, 22))	('elevated', 'PosReg', (47, 55))	('SOD2', 'Gene', (160, 164))	('TRX', 'Gene', (152, 155))	('production of reactive oxygen species', 'MPA', (56, 93))
589450	28146421	Knock down of HDAC6 enhanced the abilities of our drug combination treatment to increase ROS levels (Figure 9A).	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('enhanced', 'PosReg', (20, 28))	('increase ROS levels', 'Phenotype', 'HP:0025464', (80, 99))	('increase', 'PosReg', (80, 88))	('HDAC6', 'Gene', '10013', (14, 19))	('HDAC6', 'Gene', (14, 19))	('Knock down', 'Var', (0, 10))	('ROS levels', 'MPA', (89, 99))
589452	28146421	Over-expression of HDAC6 reduced the ability of [pazopanib + AR42] to increase ROS levels.	('reduced', 'NegReg', (25, 32))	('increase', 'PosReg', (70, 78))	('ROS', 'Chemical', 'MESH:D017382', (79, 82))	('AR42', 'Chemical', 'MESH:C524513', (61, 65))	('pazopanib', 'Chemical', 'MESH:C516667', (49, 58))	('Over-expression', 'Var', (0, 15))	('increase ROS levels', 'Phenotype', 'HP:0025464', (70, 89))	('HDAC6', 'Gene', '10013', (19, 24))	('ability of', 'MPA', (37, 47))	('HDAC6', 'Gene', (19, 24))	('ROS levels', 'MPA', (79, 89))
589454	28146421	Knock down of HDAC6 was previously shown to enhance the ability of [pazopanib + AR42] to increase LAMP2 levels, and similarly, expression of dominant negative HDAC6 enhanced drug-induced LAMP2 levels (Figure 9B).	('Knock down', 'Var', (0, 10))	('AR42', 'Chemical', 'MESH:C524513', (80, 84))	('enhanced', 'PosReg', (165, 173))	('pazopanib', 'Chemical', 'MESH:C516667', (68, 77))	('LAMP2', 'Gene', (187, 192))	('HDAC6', 'Gene', '10013', (14, 19))	('HDAC6', 'Gene', (14, 19))	('HDAC6', 'Gene', '10013', (159, 164))	('LAMP2', 'Gene', (98, 103))	('HDAC6', 'Gene', (159, 164))	('LAMP2', 'Gene', '3920', (187, 192))	('LAMP2', 'Gene', '3920', (98, 103))	('enhance', 'PosReg', (44, 51))	('increase', 'PosReg', (89, 97))
589457	28146421	The alterations observed in autophagosome formation were also reflected in the ability of [pazopanib + AR42] to kill the melanoma cells, with expression of wild type HDAC6 reducing killing and expression of dominant negative HDAC6 promoting death (Figure 9C).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('AR42', 'Chemical', 'MESH:C524513', (103, 107))	('melanoma', 'Disease', (121, 129))	('pazopanib', 'Chemical', 'MESH:C516667', (91, 100))	('rat', 'Species', '10116', (8, 11))	('autophagosome formation', 'CPA', (28, 51))	('dominant negative', 'Var', (207, 224))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('reducing', 'NegReg', (172, 180))	('promoting', 'PosReg', (231, 240))	('killing', 'CPA', (181, 188))	('HDAC6', 'Gene', '10013', (166, 171))	('HDAC6', 'Gene', '10013', (225, 230))	('HDAC6', 'Gene', (166, 171))	('HDAC6', 'Gene', (225, 230))
589463	28146421	Animals exposed to pazopanib AR42 had a mean survival of 40.2 +/- 0.6 days which was significantly greater than the survival of animals treated only with AR42 or with pazopanib (p < 0.02).	('AR42', 'Var', (29, 33))	('AR42', 'Chemical', 'MESH:C524513', (29, 33))	('pazopanib AR42', 'Var', (19, 33))	('pazopanib', 'Chemical', 'MESH:C516667', (19, 28))	('greater', 'PosReg', (99, 106))	('AR42', 'Chemical', 'MESH:C524513', (154, 158))	('pazopanib', 'Chemical', 'MESH:C516667', (167, 176))
589470	28146421	Plasma from animals exposed to AR42, and generally though to a lesser extent [pazopanib + AR42], had reduced levels of human soluble CD163, human interferon alpha, interferon beta, interferon gamma (not shown), IL-10, IL-12 family cytokines and the metalloproteases MMP1-3 (Figure 11).	('CD163', 'Gene', (133, 138))	('human interferon alpha', 'MPA', (140, 162))	('interferon gamma', 'Gene', '3458', (181, 197))	('AR42', 'Chemical', 'MESH:C524513', (31, 35))	('MMP1-3', 'Gene', (266, 272))	('levels', 'MPA', (109, 115))	('AR42', 'Var', (31, 35))	('human', 'Species', '9606', (119, 124))	('IL-12 family cytokines', 'MPA', (218, 240))	('IL-10', 'Gene', '3586', (211, 216))	('CD163', 'Gene', '9332', (133, 138))	('interferon beta', 'Gene', '3456', (164, 179))	('pazopanib', 'Chemical', 'MESH:C516667', (78, 87))	('human', 'Species', '9606', (140, 145))	('IL-10', 'Gene', (211, 216))	('interferon gamma', 'Gene', (181, 197))	('AR42', 'Chemical', 'MESH:C524513', (90, 94))	('reduced', 'NegReg', (101, 108))	('MMP1-3', 'Gene', '4322;4312;4313;4314', (266, 272))	('interferon beta', 'Gene', (164, 179))
589473	28146421	In animals exposed to [pazopanib + AR42] the plasma levels of IL-8 were increased, a finding similar to our prior studies using [pemetrexed + sorafenib] and [ruxolitinib + afatinib].	('ruxolitinib', 'Chemical', 'MESH:C540383', (158, 169))	('pazopanib', 'Chemical', 'MESH:C516667', (23, 32))	('[pazopanib + AR42]', 'Var', (22, 40))	('increased', 'PosReg', (72, 81))	('pemetrexed', 'Chemical', 'MESH:D000068437', (129, 139))	('sorafenib', 'Chemical', 'MESH:D000077157', (142, 151))	('afatinib', 'Chemical', 'MESH:D000077716', (172, 180))	('AR42', 'Chemical', 'MESH:C524513', (35, 39))	('IL-8', 'Gene', '3576', (62, 66))	('IL-8', 'Gene', (62, 66))
589477	28146421	Our data demonstrated that AR42 reduced gp130 levels by ~40% and those of IL-6RA by ~80% which collectively argues that overall IL-6 paracrine/autocrine signaling may be reduced in AR42 treated melanoma tumors.	('rat', 'Species', '10116', (16, 19))	('melanoma tumors', 'Disease', (194, 209))	('reduced', 'NegReg', (170, 177))	('AR42', 'Chemical', 'MESH:C524513', (181, 185))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('reduced', 'NegReg', (32, 39))	('IL-6', 'Gene', '3569', (74, 78))	('gp130', 'Gene', (40, 45))	('AR42', 'Var', (181, 185))	('AR42', 'Chemical', 'MESH:C524513', (27, 31))	('gp130', 'Gene', '3572', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('IL-6', 'Gene', '3569', (128, 132))	('IL-6', 'Gene', (74, 78))	('IL-6', 'Gene', (128, 132))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('IL-6RA', 'Gene', '3570', (74, 80))	('IL-6RA', 'Gene', (74, 80))	('melanoma tumors', 'Disease', 'MESH:D008545', (194, 209))
589478	28146421	In contrast to our data examining the reduced expression of cytokines, both AR42 and [pazopanib + AR42] exposure increased the plasma levels of many growth factors including bFGF, HGF, PDGF, G-CSF and prolactin, though not of IL-6 which further validates our initial hypothesis over IL-6 signaling (Figure 12B and 12C).	('PDGF', 'Gene', (185, 189))	('bFGF', 'Gene', (174, 178))	('reduced expression of cytokines', 'Phenotype', 'HP:0031407', (38, 69))	('IL-6', 'Gene', '3569', (283, 287))	('IL-6', 'Gene', '3569', (226, 230))	('prolactin', 'Gene', (201, 210))	('prolactin', 'Gene', '5617', (201, 210))	('G-CSF', 'Gene', '1440', (191, 196))	('G-CSF', 'Gene', (191, 196))	('IL-6', 'Gene', (283, 287))	('IL-6', 'Gene', (226, 230))	('AR42', 'Chemical', 'MESH:C524513', (76, 80))	('plasma levels of', 'MPA', (127, 143))	('increased', 'PosReg', (113, 122))	('AR42', 'Chemical', 'MESH:C524513', (98, 102))	('exposure', 'Var', (104, 112))	('HGF', 'Gene', '3082', (180, 183))	('bFGF', 'Gene', '2247', (174, 178))	('pazopanib', 'Chemical', 'MESH:C516667', (86, 95))	('HGF', 'Gene', (180, 183))
589482	28146421	In agreement with reduced HB-EGF and TGFalpha levels and increased soluble ERBB1, the activity of ERBB1 was reduced in both AR42 and [pazopanib + AR42] treated tumors (Figure 13A).	('soluble', 'MPA', (67, 74))	('ERBB1', 'Gene', (75, 80))	('ERBB1', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('ERBB1', 'Gene', '1956', (75, 80))	('TGFalpha', 'Gene', (37, 45))	('ERBB1', 'Gene', '1956', (98, 103))	('AR42', 'Chemical', 'MESH:C524513', (124, 128))	('reduced', 'NegReg', (18, 25))	('AR42', 'Var', (124, 128))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('AR42', 'Chemical', 'MESH:C524513', (146, 150))	('activity', 'MPA', (86, 94))	('HB-EGF', 'Gene', '1839', (26, 32))	('reduced HB-', 'Phenotype', 'HP:0011905', (18, 29))	('TGFalpha', 'Gene', '7039', (37, 45))	('increased', 'PosReg', (57, 66))	('pazopanib', 'Chemical', 'MESH:C516667', (134, 143))	('reduced', 'NegReg', (108, 115))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('HB-EGF', 'Gene', (26, 32))
589487	28146421	Downstream of PTEN we discovered that AR42 had activated AKT ~1.7-fold whereas in [pazopanib + AR42] treated tumors no AKT activation was apparent (Figure 13C).	('PTEN', 'Gene', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('PTEN', 'Gene', '5728', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('pazopanib', 'Chemical', 'MESH:C516667', (83, 92))	('activated', 'PosReg', (47, 56))	('AKT', 'Gene', '207', (119, 122))	('AKT', 'Gene', '207', (57, 60))	('AR42', 'Var', (38, 42))	('AR42', 'Chemical', 'MESH:C524513', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('AKT', 'Gene', (119, 122))	('tumors', 'Disease', (109, 115))	('AKT', 'Gene', (57, 60))	('AR42', 'Chemical', 'MESH:C524513', (38, 42))
589491	28146421	The prior drug treatments, in a manner similar to that observed for mTOR and ERK1/2, modestly enhanced the phosphorylation of JNK1/2, p38MAPK and the substrate of p38MAPK, HSP27 by ~1.7-fold.	('HSP27', 'Gene', (172, 177))	('JNK1/2', 'Gene', (126, 132))	('HSP27', 'Gene', '3315', (172, 177))	('mTOR', 'Gene', '2475', (68, 72))	('mTOR', 'Gene', (68, 72))	('enhanced', 'PosReg', (94, 102))	('phosphorylation', 'MPA', (107, 122))	('rat', 'Species', '10116', (155, 158))	('p38MAPK', 'Var', (134, 141))	('JNK1/2', 'Gene', '5599;5601', (126, 132))
589492	28146421	The phosphorylation of STAT3 at S727 was not altered by drug exposure whereas the phosphorylation of STAT3 Y705 was elevated ~2.6-fold in drug combination treated cells.	('STAT3', 'Gene', '6774', (101, 106))	('Y705', 'Var', (107, 111))	('phosphorylation', 'MPA', (82, 97))	('STAT3', 'Gene', '6774', (23, 28))	('STAT3', 'Gene', (101, 106))	('elevated', 'PosReg', (116, 124))	('STAT3', 'Gene', (23, 28))
589495	28146421	Hence, we determined in MEL28-R cells isolated from tumors previously treated with [pazopanib + AR42] whether inhibition of c-MET could enhance cell killing.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('c-MET', 'Gene', (124, 129))	('tumors', 'Disease', (52, 58))	('cell killing', 'CPA', (144, 156))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('c-MET', 'Gene', '4233', (124, 129))	('inhibition', 'Var', (110, 120))	('pazopanib', 'Chemical', 'MESH:C516667', (84, 93))	('enhance', 'PosReg', (136, 143))	('AR42', 'Chemical', 'MESH:C524513', (96, 100))
589501	28146421	The present studies were initially conducted to determine whether the drug combination of [pazopanib + AR42], previously shown to kill sarcoma and renal carcinoma cells and now the subject of a phase I trial, could also kill melanoma cells expressing a mutated active B-RAF protein.	('AR42', 'Chemical', 'MESH:C524513', (103, 107))	('pazopanib', 'Chemical', 'MESH:C516667', (91, 100))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('melanoma', 'Disease', (225, 233))	('B-RAF', 'Gene', '673', (268, 273))	('mutated', 'Var', (253, 260))	('renal carcinoma', 'Phenotype', 'HP:0005584', (147, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('B-RAF', 'Gene', (268, 273))	('sarcoma and renal carcinoma', 'Disease', 'MESH:C538614', (135, 162))
589503	28146421	Using multiple PDX models of mutant B-RAF melanoma we determined that AR42 in vitro was a more potent anti-melanoma drug than was previously observed for the agent in sarcoma and kidney cancer cells.	('melanoma', 'Disease', (42, 50))	('B-RAF', 'Gene', '673', (36, 41))	('kidney cancer', 'Phenotype', 'HP:0009726', (179, 192))	('kidney cancer', 'Disease', (179, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('AR42', 'Chemical', 'MESH:C524513', (70, 74))	('B-RAF', 'Gene', (36, 41))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('AR42', 'Var', (70, 74))	('mutant', 'Var', (29, 35))	('RAF melanoma', 'Disease', (38, 50))	('RAF melanoma', 'Disease', 'MESH:D008545', (38, 50))	('kidney cancer', 'Disease', 'MESH:D007680', (179, 192))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('sarcoma', 'Disease', 'MESH:D012509', (167, 174))	('sarcoma', 'Disease', (167, 174))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
589504	28146421	The [pazopanib + AR42] combination at ~40-50% of their individual C max values caused significantly more in vitro melanoma cell killing, including killing vemurafenib resistant and trametinib/dabrafenib resistant cells, than did the standard of care combination of trametinib/dabrafenib each at their established full C max values.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('vemurafenib', 'MPA', (155, 166))	('vemurafenib', 'Chemical', 'MESH:D000077484', (155, 166))	('dabrafenib', 'Chemical', 'MESH:C561627', (276, 286))	('trametinib', 'Chemical', 'MESH:C560077', (181, 191))	('[pazopanib + AR42]', 'Var', (4, 22))	('more', 'PosReg', (100, 104))	('trametinib', 'Chemical', 'MESH:C560077', (265, 275))	('AR42', 'Chemical', 'MESH:C524513', (17, 21))	('dabrafenib', 'Chemical', 'MESH:C561627', (192, 202))	('pazopanib', 'Chemical', 'MESH:C516667', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
589505	28146421	In an animal model system using trametinib/dabrafenib resistant melanoma cells, AR42 as a single agent could significantly retard melanoma tumor growth and prolong animal survival.	('trametinib', 'Chemical', 'MESH:C560077', (32, 42))	('AR42', 'Var', (80, 84))	('dabrafenib', 'Chemical', 'MESH:C561627', (43, 53))	('AR42', 'Chemical', 'MESH:C524513', (80, 84))	('retard melanoma tumor', 'Disease', 'MESH:D008545', (123, 144))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('prolong', 'PosReg', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('retard melanoma tumor', 'Disease', (123, 144))	('animal survival', 'CPA', (164, 179))
589512	28146421	There are a number of recognized mechanisms by which mutant B-RAF melanoma cells evolve under therapeutic pressure to become trametinib/dabrafenib resistant.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('B-RAF', 'Gene', '673', (60, 65))	('B-RAF', 'Gene', (60, 65))	('dabrafenib', 'Chemical', 'MESH:C561627', (136, 146))	('RAF melanoma', 'Disease', (62, 74))	('mutant', 'Var', (53, 59))	('trametinib', 'Chemical', 'MESH:C560077', (125, 135))	('RAF melanoma', 'Disease', 'MESH:D008545', (62, 74))
589516	28146421	The [pazopanib + AR42] combination also caused high levels of killing in the MEL24 line that expresses mutant B-RAF and lacks PTEN expression as well as in the TPF-12-293 PDX isolate that is vemurafenib resistant.	('lacks', 'NegReg', (120, 125))	('killing', 'MPA', (62, 69))	('pazopanib', 'Chemical', 'MESH:C516667', (5, 14))	('mutant', 'Var', (103, 109))	('B-RAF', 'Gene', (110, 115))	('expression', 'MPA', (131, 141))	('TPF-12-293', 'CellLine', 'CVCL:0045', (160, 170))	('AR42', 'Chemical', 'MESH:C524513', (17, 21))	('vemurafenib', 'Chemical', 'MESH:D000077484', (191, 202))	('B-RAF', 'Gene', '673', (110, 115))	('PTEN', 'Gene', (126, 130))	('PTEN', 'Gene', '5728', (126, 130))
589519	28146421	These findings argue that efficient melanoma cell killing in our system requires dysregulation of multiple survival signaling modules, such as ERK-BAD/BIM and AMPK-mTOR-autophagy and ERK-STAT3-MCL-1, shifting their activities/functions from maintaining cell viability to permitting tumor cell death.	('tumor cell death', 'Disease', (282, 298))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('ERK', 'Gene', '5595;5594;26413;5595;26417', (183, 186))	('MCL-1', 'Gene', (193, 198))	('AMPK', 'Gene', '5562', (159, 163))	('mTOR', 'Gene', '2475', (164, 168))	('ERK', 'Gene', '5595;5594;26413;5595;26417', (143, 146))	('BIM', 'Gene', (151, 154))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('ERK', 'Gene', (183, 186))	('melanoma', 'Disease', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('dysregulation', 'Var', (81, 94))	('STAT3', 'Gene', (187, 192))	('tumor cell death', 'Disease', 'MESH:D003643', (282, 298))	('BIM', 'Gene', '10018', (151, 154))	('ERK', 'Gene', (143, 146))	('AMPK', 'Gene', (159, 163))	('STAT3', 'Gene', '6774', (187, 192))	('activities/functions', 'MPA', (215, 235))	('MCL-1', 'Gene', '4170', (193, 198))	('mTOR', 'Gene', (164, 168))
589520	28146421	The most likely explanation why [pazopanib + AR42] has so many pleiotropic toxic effects and inactivates so many cyto-protective pathways is that it inactivates HSP90 family, HSP70 family and particularly the ER localized HSP70 family chaperone GRP78; chaperones essential to maintain ERK1/2, AKT, STAT3 and mTOR activity and essential to keep PERK-eIF2alpha signaling dormant.	('inactivates', 'NegReg', (149, 160))	('HSP90', 'Gene', '3320', (161, 166))	('HSP70', 'Gene', '3308', (222, 227))	('AKT', 'Gene', (293, 296))	('AR42', 'Chemical', 'MESH:C524513', (45, 49))	('eIF2alpha', 'Gene', (349, 358))	('eIF2alpha', 'Gene', '83939', (349, 358))	('inactivates', 'NegReg', (93, 104))	('pazopanib', 'Chemical', 'MESH:C516667', (33, 42))	('cyto-protective', 'Pathway', (113, 128))	('HSP70', 'Gene', (175, 180))	('AKT', 'Gene', '207', (293, 296))	('PERK', 'Gene', (344, 348))	('HSP70', 'Gene', (222, 227))	('mTOR', 'Gene', (308, 312))	('STAT3', 'Gene', (298, 303))	('HSP90', 'Gene', (161, 166))	('[pazopanib + AR42]', 'Var', (32, 50))	('GRP78', 'Gene', (245, 250))	('HSP70', 'Gene', '3308', (175, 180))	('mTOR', 'Gene', '2475', (308, 312))	('STAT3', 'Gene', '6774', (298, 303))	('GRP78', 'Gene', '3309', (245, 250))	('PERK', 'Gene', '9451', (344, 348))
589522	28146421	the dabrafenib/trametinib combination against mutant B-RAF, we have been able to out-fox both the evolutionary survival responses of tumor cells as well as being able to kill tumor cells carrying a wide variety of upstream mutations that would predict for drug resistance and a shorter overall patient survival.	('patient', 'Species', '9606', (294, 301))	('tumor', 'Disease', (175, 180))	('B-RAF', 'Gene', (53, 58))	('predict', 'Reg', (244, 251))	('drug resistance', 'MPA', (256, 271))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutant', 'Var', (46, 52))	('drug resistance', 'Phenotype', 'HP:0020174', (256, 271))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('dabrafenib', 'Chemical', 'MESH:C561627', (4, 14))	('trametinib', 'Chemical', 'MESH:C560077', (15, 25))	('B-RAF', 'Gene', '673', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('mutations', 'Var', (223, 232))
589523	28146421	Our data demonstrating that AR42, in addition to being an HDAC inhibitor, can also rapidly reduce the expression of HDACs 2/5/6/10/11 was unexpected.	('AR42', 'Chemical', 'MESH:C524513', (28, 32))	('reduce', 'NegReg', (91, 97))	('HDAC', 'Gene', (58, 62))	('expression', 'MPA', (102, 112))	('rat', 'Species', '10116', (16, 19))	('HDAC', 'Gene', '9734', (58, 62))	('HDAC', 'Gene', (116, 120))	('HDAC', 'Gene', '9734', (116, 120))	('AR42', 'Var', (28, 32))
589528	28146421	In our present studies, although the AMPK was partially activated by AR42, HDAC6 degradation was not blocked by the E3 ligase inhibitor bortezomib.	('AR42', 'Chemical', 'MESH:C524513', (69, 73))	('bortezomib', 'Chemical', 'MESH:D000069286', (136, 146))	('AMPK', 'Gene', '5562', (37, 41))	('AMPK', 'Gene', (37, 41))	('HDAC6', 'Gene', '10013', (75, 80))	('AR42', 'Var', (69, 73))	('HDAC6', 'Gene', (75, 80))
589529	28146421	Instead, inhibition of autophagosome formation by knocking down either ATG5 or Beclin1 prevented the AR42-mediated reduction in HDAC6 levels.	('reduction', 'NegReg', (115, 124))	('AR42', 'Chemical', 'MESH:C524513', (101, 105))	('prevented', 'NegReg', (87, 96))	('Beclin1', 'Gene', (79, 86))	('knocking down', 'Var', (50, 63))	('ATG5', 'Gene', '9474', (71, 75))	('HDAC6', 'Gene', '10013', (128, 133))	('HDAC6', 'Gene', (128, 133))	('ATG5', 'Gene', (71, 75))
589539	28146421	Although the combination of trametinib/dabrafenib has considerably prolonged disease free progression and overall survival for patients with mutant B-RAF melanoma, eventually tumor cells under the restrictive pressure of the drug combination evolve mechanisms of resistance.	('tumor', 'Disease', (175, 180))	('evolve', 'Reg', (242, 248))	('mutant', 'Var', (141, 147))	('dabrafenib', 'Chemical', 'MESH:C561627', (39, 49))	('trametinib', 'Chemical', 'MESH:C560077', (28, 38))	('RAF melanoma', 'Disease', 'MESH:D008545', (150, 162))	('RAF melanoma', 'Disease', (150, 162))	('patients', 'Species', '9606', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('B-RAF', 'Gene', '673', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('B-RAF', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('disease free progression', 'CPA', (77, 101))	('prolonged', 'PosReg', (67, 76))
589545	28146421	The combination of [pazopanib + AR42] caused a further significant enhancement in animal survival over that afforded by either pazopanib or AR42 alone, and that was associated with an initial prolonged reduction in tumor mass below pre-treatment levels.	('pazopanib', 'Chemical', 'MESH:C516667', (20, 29))	('[pazopanib +', 'Var', (19, 31))	('pazopanib', 'Chemical', 'MESH:C516667', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('enhancement', 'PosReg', (67, 78))	('AR42', 'Chemical', 'MESH:C524513', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('animal survival', 'CPA', (82, 97))	('AR42', 'Chemical', 'MESH:C524513', (140, 144))	('reduction', 'NegReg', (202, 211))
589546	28146421	Collectively, the in vivo data using trametinib/dabrafenib resistant MEL28 cells argues that the combination of pazopanib with AR42, or with sodium valproate, should be explored as a new phase I/II trial in mutant B-RAF melanoma patients.	('pazopanib', 'Chemical', 'MESH:C516667', (112, 121))	('patients', 'Species', '9606', (229, 237))	('AR42', 'Chemical', 'MESH:C524513', (127, 131))	('B-RAF', 'Gene', (214, 219))	('sodium valproate', 'Chemical', 'MESH:D014635', (141, 157))	('RAF melanoma', 'Disease', (216, 228))	('RAF melanoma', 'Disease', 'MESH:D008545', (216, 228))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('mutant', 'Var', (207, 213))	('dabrafenib', 'Chemical', 'MESH:C561627', (48, 58))	('B-RAF', 'Gene', '673', (214, 219))	('trametinib', 'Chemical', 'MESH:C560077', (37, 47))
589549	28146421	Notably, AR42 doubled the already high expression of human PDGF in mouse plasma, a compensatory effect that may explain why the phase I trial in melanoma using panobinostat as a single agent failed; whatever anti-tumor effects panobinostat may have exhibited would have been swamped by the compensatory induction of PDGF expression.	('tumor', 'Disease', (213, 218))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('AR42', 'Var', (9, 13))	('PDGF', 'Gene', (59, 63))	('melanoma', 'Disease', (145, 153))	('panobinostat', 'Chemical', 'MESH:D000077767', (227, 239))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('panobinostat', 'Chemical', 'MESH:D000077767', (160, 172))	('AR42', 'Chemical', 'MESH:C524513', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('human', 'Species', '9606', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('expression', 'MPA', (39, 49))	('mouse', 'Species', '10090', (67, 72))
589554	28146421	We discovered that inhibition of MET-STAT3 signaling could enhance [pazopanib + AR42] lethality.	('inhibition', 'Var', (19, 29))	('AR42', 'Chemical', 'MESH:C524513', (80, 84))	('STAT3', 'Gene', '6774', (37, 42))	('enhance', 'PosReg', (59, 66))	('pazopanib', 'Chemical', 'MESH:C516667', (68, 77))	('STAT3', 'Gene', (37, 42))	('[pazopanib + AR42]', 'MPA', (67, 85))
589561	28146421	Characterized PDX melanoma isolates expressing mutated active B-RAF were from the University of Pittsburgh's melanoma cell bank.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('B-RAF', 'Gene', '673', (62, 67))	('mutated', 'Var', (47, 54))	("Pittsburgh's melanoma", 'Disease', 'MESH:D008545', (96, 117))	("Pittsburgh's melanoma", 'Disease', (96, 117))	('B-RAF', 'Gene', (62, 67))	('melanoma', 'Disease', (18, 26))
589619	26041735	These types of modifications have been shown to increase the immunogenicity of both peptide and DNA vaccines targeting different viral and tumor antigens that were otherwise weakly immunogenic.	('immunogenicity', 'MPA', (61, 75))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('modifications', 'Var', (15, 28))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('increase', 'PosReg', (48, 56))
589623	26041735	Recently, we identified that point mutations made to these epitopes could be used to immunize HLA-A2-expressing mice to elicit higher frequency of CD8+ T cells that recognized the native epitopes.	('point mutations', 'Var', (29, 44))	('elicit', 'Reg', (120, 126))	('CD8', 'Gene', (147, 150))	('CD8', 'Gene', '925', (147, 150))	('mice', 'Species', '10090', (112, 116))
589637	26041735	DNA vaccines encoding native or modified SSX2 were purified and used as previously described.	('modified', 'Var', (32, 40))	('SSX2', 'Gene', '6757', (41, 45))	('SSX2', 'Gene', (41, 45))
589647	26041735	For PD-L1 quantification, tumor suspensions were stained with anti-CD45 (30-F11, BD Bioscience), anti-CD11b (M1/70, eBioscience), anti-GR1 (1A8, BD Bioscience), anti-F4/80 (BM8.1, Tonbo Biosciences), anti-PD-L1 (MIH5, eBioscience) and DAPI.	('anti-PD-L1', 'Var', (200, 210))	('F4/80', 'Gene', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('CD45', 'Gene', '19264', (67, 71))	('F4/80', 'Gene', '13733', (166, 171))	('anti-GR1', 'Var', (130, 138))	('CD45', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('CD11b', 'Gene', (102, 107))	('CD11b', 'Gene', '16409', (102, 107))
589648	26041735	For PD-1 quantification on antigen-specific T cells, splenocytes obtained from immunized animals were enriched for CD8+ T cells and stained as above, along with tetramers specific for the SSX2 p41 or p103 epitopes (NIH Tetramer Core Facility, Atlanta GA), anti-PD-1 (J43, BD Bioscience, San Jose CA) and Ghost Dye-780 (Tonbo Bioscience, San Diego, CA).	('CD8', 'Gene', '925', (115, 118))	('SSX2', 'Gene', '6757', (188, 192))	('SSX2', 'Gene', (188, 192))	('p41', 'Gene', (193, 196))	('p103', 'Var', (200, 204))	('CD8', 'Gene', (115, 118))	('p41', 'Gene', '269587', (193, 196))
589652	26041735	For PD-1 and CD8 IF staining, FFPE tumor sections were stained using standard immunofluorescence methods with 10 mug/mL anti-CD8 (53-6.7, R&D Systems) and 5 mug/mL anti-PD-1 (ab117420, Abcam), followed by AlexaFluor-488 anti-rat IgG and AlexaFluor-647 anti-goat IgG (Life Technologies).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('CD8', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('rat', 'Species', '10116', (225, 228))	('CD8', 'Gene', '925', (13, 16))	('tumor', 'Disease', (35, 40))	('mug/mL', 'Var', (157, 163))	('goat', 'Species', '9925', (257, 261))	('AlexaFluor-488', 'Chemical', '-', (205, 219))	('AlexaFluor-647', 'Chemical', 'MESH:C569686', (237, 251))	('CD8', 'Gene', (125, 128))	('CD8', 'Gene', '925', (125, 128))
589663	26041735	These studies confirmed that the antitumor response was mediated by HLA-A2-restricted CD8+ T cells, as the ablation of the HLA-A2 epitopes abolished the antitumor effect observed.	('tumor', 'Disease', (157, 162))	('ablation', 'Var', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('CD8', 'Gene', (86, 89))	('HLA-A2', 'Gene', (123, 129))	('abolished', 'NegReg', (139, 148))	('tumor', 'Disease', (37, 42))	('CD8', 'Gene', '925', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
589680	26041735	Given that the expression of PD-L1 did not appear different between treatment groups receiving the native or optimized vaccine (Figure 2), and yet the expression of PD-L1 was responsible for the decreased antitumor effect observed with the optimized vaccine (Figure 3), we next assessed whether the expression of PD-1 on CD8+ TILs differed with respect to immunization.	('CD8', 'Gene', '925', (321, 324))	('tumor', 'Disease', (209, 214))	('men', 'Species', '9606', (73, 76))	('PD-L1', 'Gene', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('expression', 'Var', (151, 161))	('CD8', 'Gene', (321, 324))	('decreased', 'NegReg', (195, 204))
589686	26041735	Presumably ligation of PD-L1 expressed by tumors led to a decrease in effector function, as has been demonstrated by others.	('rat', 'Species', '10116', (108, 111))	('PD-L1', 'Gene', (23, 28))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('decrease', 'NegReg', (58, 66))	('effector function', 'MPA', (70, 87))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ligation', 'Var', (11, 19))
589689	26041735	This observation, plus the findings in both Figures 3 and 4, suggested that blocking the ligation of PD-1 on antigen-specific CD8+ T cells might restore or enhance the antitumor efficacy of the APL-encoding DNA vaccine, particularly given the persistence of PD-L1 expression in the tumor microenvironment demonstrated in Figure 3C.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Disease', (172, 177))	('CD8', 'Gene', (126, 129))	('men', 'Species', '9606', (300, 303))	('tumor', 'Disease', (282, 287))	('CD8', 'Gene', '925', (126, 129))	('restore', 'PosReg', (145, 152))	('rat', 'Species', '10116', (312, 315))	('blocking', 'Var', (76, 84))	('enhance', 'PosReg', (156, 163))	('PD-1', 'Gene', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
589698	26041735	In this report we sought to identify whether this vaccine encoding modified epitopes was able to elicit a stronger antitumor response against an SSX2-expressing tumor cell line in vivo.	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (119, 124))	('modified', 'Var', (67, 75))	('SSX2', 'Gene', (145, 149))	('stronger', 'PosReg', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('SSX2', 'Gene', '6757', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('elicit', 'Reg', (97, 103))
589708	26041735	In a report from Smith and colleagues, the authors demonstrated that epitopes with slightly weakened binding affinity led to lower levels of PD-1 expression, suggesting that modifications to DNA vaccines that decrease epitope-binding affinity, while simultaneously increasing epitope presentation, might be an approach to limit PD-1 expression and increase the antitumor efficacy of DNA vaccines.	('limit', 'NegReg', (322, 327))	('expression', 'MPA', (333, 343))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('PD-1', 'Gene', (328, 332))	('weakened', 'NegReg', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('increase', 'PosReg', (348, 356))	('decrease', 'NegReg', (209, 217))	('tumor', 'Disease', (365, 370))	('epitope-binding affinity', 'MPA', (218, 242))	('rat', 'Species', '10116', (58, 61))	('increasing', 'PosReg', (265, 275))	('modifications', 'Var', (174, 187))	('epitope presentation', 'MPA', (276, 296))
589722	26041735	Our data are also potentially relevant to the tumor immunology field given a recent surge in attention towards developing personalized tumor antigen-specific vaccines based on the identification of mutated tumor-specific epitopes.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('mutated', 'Var', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
589723	26041735	This method generally proposes to sequence individual tumor exomes to identify tumor-specific, MHC-restricted epitopes based on the presence of mutations leading to novel epitopes.	('MHC-restricted', 'Gene', (95, 109))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (54, 59))	('mutations', 'Var', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
589753	24280007	Cytogenetic analysis for EWSR1-WT1 rearrangement was performed when available.	('EWSR1', 'Gene', (25, 30))	('WT1', 'Gene', '7490', (31, 34))	('EWSR1', 'Gene', '2130', (25, 30))	('WT1', 'Gene', (31, 34))	('rearrangement', 'Var', (35, 48))	('men', 'Species', '9606', (44, 47))
589758	24280007	Cytogenetic testing for EWSR1-WT1 rearrangement was only routinely available in some centres after 2008, therefore only 14 patients were tested and found to be positive.	('WT1', 'Gene', (30, 33))	('EWSR1', 'Gene', (24, 29))	('rearrangement', 'Var', (34, 47))	('EWSR1', 'Gene', '2130', (24, 29))	('patients', 'Species', '9606', (123, 131))	('men', 'Species', '9606', (43, 46))	('WT1', 'Gene', '7490', (30, 33))
589769	24280007	As the effectiveness of second- or subsequent-line chemotherapy is also unproven, a number of newer agents had been given as part of a clinical trial, including inhibitor of the mammalian target of rapamycin (mTOR) pathway, tyrosine kinase inhibitors (TKIs), and antibody against the insulin-like growth factor-1 receptor (IGF-1R).	('IGF-1R', 'Gene', '3480', (323, 329))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (284, 321))	('IGF-1R', 'Gene', (323, 329))	('antibody', 'Var', (263, 271))	('mammalian target of rapamycin', 'Gene', '2475', (178, 207))	('mammalian target of rapamycin', 'Gene', (178, 207))	('mTOR', 'Gene', (209, 213))	('insulin-like growth factor-1 receptor', 'Gene', (284, 321))	('mTOR', 'Gene', '2475', (209, 213))
589838	24280007	Anecdotally, a patient in this series who received WAP-RT developed a serious malabsorption syndrome subsequent to gastrointestinal damage.	('patient', 'Species', '9606', (15, 22))	('malabsorption syndrome', 'Disease', 'MESH:D008286', (78, 100))	('gastrointestinal damage', 'Disease', (115, 138))	('malabsorption', 'Phenotype', 'HP:0002024', (78, 91))	('gastrointestinal damage', 'Disease', 'MESH:D005767', (115, 138))	('WAP-RT', 'Var', (51, 57))	('malabsorption syndrome', 'Disease', (78, 100))
589847	24280007	Chromosomal translocation resulting in the fusion of the EWSR1 and WT1 genes is the molecular characteristic of DSRCT.	('DSRCT', 'Disease', (112, 117))	('Chromosomal translocation', 'Var', (0, 25))	('WT1', 'Gene', '7490', (67, 70))	('EWSR1', 'Gene', (57, 62))	('fusion', 'Var', (43, 49))	('WT1', 'Gene', (67, 70))	('EWSR1', 'Gene', '2130', (57, 62))
589855	24280007	In particular, studies of anti-GD2 antibodies have shown some promising results in the treatment of neuroblastoma.	('neuroblastoma', 'Disease', (100, 113))	('anti-GD2', 'Gene', (26, 34))	('neuroblastoma', 'Phenotype', 'HP:0003006', (100, 113))	('antibodies', 'Var', (35, 45))	('men', 'Species', '9606', (92, 95))	('neuroblastoma', 'Disease', 'MESH:D009447', (100, 113))	('anti-GD2 antibodies', 'Var', (26, 45))
589856	24280007	Another potential therapeutic target is the lysine-specific demethylase 1, a key histone modification enzyme involved in controlling gene expression which if dysregulated, could result in tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', (188, 194))	('result in', 'Reg', (178, 187))	('dysregulated', 'Var', (158, 170))
589871	23580888	Myeloid sarcomas are associated with AML in 2-8% of the cases, especially in situations of cytogenetic abnormalities such as t(8;22), inv(16) and 11q23.	('Myeloid sarcomas', 'Disease', 'MESH:D023981', (0, 16))	('AML', 'Disease', 'MESH:D015470', (37, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (8, 16))	('inv(16', 'Var', (134, 140))	('t(8;22', 'Var', (125, 131))	('AML', 'Phenotype', 'HP:0004808', (37, 40))	('AML', 'Disease', (37, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('11q23', 'Var', (146, 151))	('Myeloid sarcomas', 'Disease', (0, 16))
589879	23580888	A bone marrow aspirate showed that 26% of the nucleated cells were blasts that, from flow cytometry, were defined as presenting an immunophenotype compatible with a myeloid origin (CD45+, CD13+, CD33+,HLADR+ and CD11c+).	('CD11c', 'Gene', '3687', (212, 217))	('CD13', 'Gene', '290', (188, 192))	('CD11c', 'Gene', (212, 217))	('CD45', 'Gene', '5788', (181, 185))	('CD13', 'Gene', (188, 192))	('CD45', 'Gene', (181, 185))	('CD33', 'Gene', '945', (195, 199))	('HLADR+', 'Var', (201, 207))	('CD33', 'Gene', (195, 199))
589900	31978118	The Brazilian TP53 mutation (R337H) and sarcomas Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children.	('Sarcomas', 'Disease', (49, 57))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('children', 'Species', '9606', (130, 138))	('Sarcomas', 'Disease', 'MESH:D012509', (49, 57))	('Sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('neoplasms', 'Disease', 'MESH:D009369', (94, 103))	('neoplasms', 'Disease', (94, 103))	('R337H', 'Mutation', 'p.R337H', (29, 34))	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('R337H', 'Var', (29, 34))	('neoplasms', 'Phenotype', 'HP:0002664', (94, 103))	('sarcomas', 'Disease', (40, 48))
589902	31978118	In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS.	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('LFS', 'Disease', 'MESH:D016864', (119, 122))	('p.Arg337His', 'Var', (34, 45))	('p.Arg337His', 'Mutation', 'p.R337H', (34, 45))	('LFS', 'Disease', (119, 122))
589903	31978118	In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('p.Arg337His', 'Mutation', 'p.R337H', (179, 190))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('sarcoma', 'Disease', 'MESH:D012509', (36, 43))	('TP53', 'Gene', '7157', (163, 167))	('tumor', 'Disease', (200, 205))	('p.Arg337His', 'Var', (179, 190))	('TP53', 'Gene', (163, 167))	('sarcoma', 'Disease', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))
589904	31978118	We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene.	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (48, 62))	('sarcoma', 'Disease', (55, 62))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcoma', 'Disease', (97, 104))	('patients', 'Species', '9606', (136, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leiomyosarcoma', 'Disease', (48, 62))	('patients', 'Species', '9606', (20, 28))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (48, 62))	('mutated', 'Var', (154, 161))	('sarcoma', 'Disease', 'MESH:D012509', (55, 62))
589911	31978118	Several different conditions may be involved, such as neurofibromatosis (NF1), mutations in the RB gene (retinoblastoma) and Li-Fraumeni syndrome (LFS, involving mutation of the TP53 gene).	('TP53', 'Gene', '7157', (178, 182))	('retinoblastoma', 'Phenotype', 'HP:0009919', (105, 119))	('neurofibromatosis', 'Disease', (54, 71))	('NF1', 'Gene', '4763', (73, 76))	('LFS', 'Disease', (147, 150))	('RB gene', 'Gene', (96, 103))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (125, 145))	('TP53', 'Gene', (178, 182))	('mutations', 'Var', (79, 88))	('retinoblastoma', 'Gene', '5925', (105, 119))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (54, 71))	('Li-Fraumeni syndrome', 'Disease', (125, 145))	('LFS', 'Disease', 'MESH:D016864', (147, 150))	('neurofibromatosis', 'Disease', 'MESH:D017253', (54, 71))	('retinoblastoma', 'Gene', (105, 119))	('NF1', 'Gene', (73, 76))
589913	31978118	In Brazil, LFS has a high prevalence, mainly due to a specific point mutation in the TP53 gene, p.Arg337His, also known as R337H.	('TP53', 'Gene', (85, 89))	('R337H', 'Mutation', 'p.R337H', (123, 128))	('p.Arg337His', 'Mutation', 'p.R337H', (96, 107))	('LFS', 'Disease', (11, 14))	('LFS', 'Disease', 'MESH:D016864', (11, 14))	('TP53', 'Gene', '7157', (85, 89))	('p.Arg337His', 'Var', (96, 107))
589914	31978118	Since the first description of this mutation, named "the Brazilian germline TP53 mutation", researchers have been trying to establish its clinical behavior.	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('mutation', 'Var', (81, 89))
589918	31978118	However, each tumor type has its own characteristics, hindering an application of these protocols in such heterogeneous families as those with "Brazilian germline TP53 mutation".	('tumor', 'Disease', (14, 19))	('TP53', 'Gene', '7157', (163, 167))	('hindering', 'NegReg', (54, 63))	('mutation', 'Var', (168, 176))	('TP53', 'Gene', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
589921	31978118	To clarify this issue, we evaluated the frequency of the TP53 p.Arg337His mutation in sarcoma patients not selected by family history in a Brazilian cancer reference center.	('sarcoma', 'Disease', (86, 93))	('cancer', 'Disease', (149, 155))	('p.Arg337His', 'Mutation', 'p.R337H', (62, 73))	('patients', 'Species', '9606', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('p.Arg337His', 'Var', (62, 73))	('sarcoma', 'Disease', 'MESH:D012509', (86, 93))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
589922	31978118	We intend to add information that contributes to the state of the art in sarcoma, a highly lethal tumor, as well as improves our understanding of frequency of the R337H mutation among sarcoma cases not selected based on clinical criteria.	('sarcoma', 'Disease', 'MESH:D012509', (184, 191))	('R337H', 'Mutation', 'p.R337H', (163, 168))	('sarcoma', 'Disease', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('sarcoma', 'Disease', (184, 191))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('R337H', 'Var', (163, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('tumor', 'Disease', (98, 103))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
589928	31978118	In cases where the R337H mutation could be identified in the tumor, DNA from blood or normal tissue was analyzed when available.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('R337H', 'Mutation', 'p.R337H', (19, 24))	('R337H', 'Var', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
589931	31978118	For the detection of TP53 p.Arg337His, samples were PCR-amplified and analyzed by RFLP using the HhaI enzyme as described elsewhere.	('p.Arg337His', 'Mutation', 'p.R337H', (26, 37))	('TP53', 'Gene', (21, 25))	('p.Arg337His', 'Var', (26, 37))	('TP53', 'Gene', '7157', (21, 25))
589948	31978118	The youngest patient with the TP53 mutation was 18 years old, and the oldest was 84 years old.	('patient', 'Species', '9606', (13, 20))	('TP53', 'Gene', '7157', (30, 34))	('TP53', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))
589949	31978118	Information regarding cancer history in families positive for the mutation was available for 87.5% of the cases.	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (22, 28))	('mutation', 'Var', (66, 74))	('cancer', 'Disease', 'MESH:D009369', (22, 28))
589952	31978118	Among the 40 patients positive for the TP53 mutation, 8 presented with more than one tumor.	('tumor', 'Disease', (85, 90))	('mutation', 'Var', (44, 52))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('TP53', 'Gene', '7157', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('TP53', 'Gene', (39, 43))
589957	31978118	Among the mutated cases, a total of 39 patients with the Brazilian founder pathogenic variant in TP53 (c.1010G>A; p.Arg337His) were analyzed (Fig 4).	('patients', 'Species', '9606', (39, 47))	('TP53', 'Gene', '7157', (97, 101))	('c.1010G>A; p.Arg337His', 'Var', (103, 125))	('p.Arg337His', 'Mutation', 'p.R337H', (114, 125))	('TP53', 'Gene', (97, 101))	('c.1010G>A', 'Mutation', 'c.1010G>A', (103, 112))	('p.Arg337His', 'Var', (114, 125))
589958	31978118	Using the Mann-Whitney test, we did not find any correlation between the ancestral profile and the presence/absence of the pathogenic variant in TP53 (p.Arg337His).	('TP53', 'Gene', (145, 149))	('p.Arg337His', 'Var', (151, 162))	('p.Arg337His', 'Mutation', 'p.R337H', (151, 162))	('TP53', 'Gene', '7157', (145, 149))
589959	31978118	It is known that the "Brazilian germline TP53 mutation" occurs predominantly in southern Brazil.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))
589962	31978118	This spread reflects the internal migration within Brazil and has a direct impact on public health care since the mutation predisposes carriers to multiple cancer types.	('multiple cancer', 'Disease', (147, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('predisposes', 'Reg', (123, 134))	('mutation', 'Var', (114, 122))	('multiple cancer', 'Disease', 'MESH:D009369', (147, 162))
589965	31978118	Previous Brazilian studies have found an unexpectedly high prevalence of this mutation in other types of LFS tumors, for instance, adrenocortical and plexus choroid carcinoma.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('mutation', 'Var', (78, 86))	('choroid carcinoma', 'Disease', (157, 174))	('LFS', 'Disease', 'MESH:D016864', (105, 108))	('choroid carcinoma', 'Disease', 'MESH:D002833', (157, 174))	('plexus choroid carcinoma', 'Phenotype', 'HP:0030392', (150, 174))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('LFS', 'Disease', (105, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('tumors', 'Disease', (109, 115))
589966	31978118	A review of the IARC TP53 database analyzed the types of mutations in and ages of sarcoma patients and demonstrated an age-dependent variation in these patients.	('TP53', 'Gene', (21, 25))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('mutations', 'Var', (57, 66))	('sarcoma', 'Disease', (82, 89))	('patients', 'Species', '9606', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('patients', 'Species', '9606', (152, 160))	('TP53', 'Gene', '7157', (21, 25))
589967	31978118	They concluded that for TP53 mutation carriers, 67% of sarcomas appeared before 20 years of age.	('mutation', 'Var', (29, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('TP53', 'Gene', (24, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('sarcomas', 'Disease', (55, 63))	('sarcomas', 'Disease', 'MESH:D012509', (55, 63))	('TP53', 'Gene', '7157', (24, 28))
589971	31978118	When only patients with the R337H mutation were analyzed, a particular subtype, leiomyosarcoma, was revealed, accounting for 52.5% of the sarcomas.	('R337H', 'Mutation', 'p.R337H', (28, 33))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (80, 94))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (80, 94))	('R337H', 'Var', (28, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('sarcomas', 'Disease', (138, 146))	('patients', 'Species', '9606', (10, 18))	('leiomyosarcoma', 'Disease', (80, 94))
589972	31978118	According to the IARC TP53 database, leiomyosarcoma corresponds to 9.1% of the sarcomas in TP53 mutation carriers, showing once again the particular behavior of the p.Arg337His pathogenic variant.	('TP53', 'Gene', (91, 95))	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('p.Arg337His', 'Mutation', 'p.R337H', (165, 176))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (37, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('leiomyosarcoma', 'Disease', (37, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Disease', (79, 87))	('to 9', 'Species', '1214577', (64, 68))	('p.Arg337His', 'Var', (165, 176))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (37, 51))	('TP53', 'Gene', '7157', (22, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('TP53', 'Gene', '7157', (91, 95))	('TP53', 'Gene', (22, 26))
589975	31978118	In our registry, 75% of the patients with the TP53 mutation had family members with cancer (85.7% of those whose information regarding cancer history in families was available).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (84, 90))	('TP53', 'Gene', '7157', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('patients', 'Species', '9606', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
589977	31978118	However, in approximately 15% of the mutated cases, there was no cancer family history.	('mutated', 'Var', (37, 44))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
589981	31978118	Since sarcomas appeared as a second tumor in 7 of 8 patients with multiple tumors in our data, cancer patients who carried the p.Arg337H mutation should continue to be monitored with clinical cancer surveillance protocols.	('multiple tumors', 'Disease', (66, 81))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', (192, 198))	('sarcomas', 'Disease', 'MESH:D012509', (6, 14))	('tumor', 'Disease', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', (75, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))	('sarcomas', 'Disease', (6, 14))	('cancer', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('patients', 'Species', '9606', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('p.Arg337H', 'Var', (127, 136))	('p.Arg337H', 'Mutation', 'p.R337H', (127, 136))	('multiple tumors', 'Disease', 'MESH:D009369', (66, 81))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (95, 101))
589984	31978118	In addition, somatic R337H mutations in the IARC TP53 database (R19) occurred in 4 tumors among 29895 investigated (0.013%).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('R337H', 'Mutation', 'p.R337H', (21, 26))	('R337H', 'Var', (21, 26))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('occurred', 'Reg', (69, 77))
589986	29731991	Targeted next generation sequencing of well-differentiated/dedifferentiated liposarcoma reveals novel gene amplifications and mutations Well-differentiated/dedifferentiated liposarcoma is a common soft tissue sarcoma with approximately 1500 new cases per year.	('liposarcoma', 'Phenotype', 'HP:0012034', (76, 87))	('liposarcoma', 'Disease', 'MESH:D008080', (76, 87))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (197, 216))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (197, 216))	('liposarcoma', 'Phenotype', 'HP:0012034', (173, 184))	('liposarcoma', 'Disease', 'MESH:D008080', (173, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('soft tissue sarcoma', 'Disease', (197, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('liposarcoma', 'Disease', (76, 87))	('mutations', 'Var', (126, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('liposarcoma', 'Disease', (173, 184))
589989	29731991	Out of the 27 mutations detected in 7 samples, 8 (CTNNB1, MECOM, ZNF536, EGFR, EML4, CSMD3, PBRM1, PPP1R3A) were identified as deleterious (on Condel, PolyPhen and SIFT) and a truncating mutation was found in NF2.	('CTNNB1', 'Gene', '1499', (50, 56))	('CSMD3', 'Gene', '114788', (85, 90))	('SIFT', 'Disease', (164, 168))	('ZNF536', 'Gene', (65, 71))	('EGFR', 'Gene', (73, 77))	('ZNF536', 'Gene', '9745', (65, 71))	('CSMD3', 'Gene', (85, 90))	('PPP1R3A', 'Gene', '5506', (99, 106))	('mutations', 'Var', (14, 23))	('CTNNB1', 'Gene', (50, 56))	('NF2', 'Gene', '4771', (209, 212))	('PPP1R3A', 'Gene', (99, 106))	('SIFT', 'Disease', 'None', (164, 168))	('PBRM1', 'Gene', '55193', (92, 97))	('NF2', 'Gene', (209, 212))	('PBRM1', 'Gene', (92, 97))	('EGFR', 'Gene', '1956', (73, 77))	('EML4', 'Gene', (79, 83))	('EML4', 'Gene', '27436', (79, 83))	('MECOM', 'Gene', (58, 63))	('MECOM', 'Gene', '2122', (58, 63))
589995	29731991	WD and DD liposarcomas universally exhibit amplification of chromosome 12q13-15.	('sarcomas', 'Phenotype', 'HP:0100242', (14, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('DD liposarcomas', 'Disease', 'MESH:D008080', (7, 22))	('amplification', 'Var', (43, 56))	('liposarcomas', 'Phenotype', 'HP:0012034', (10, 22))	('WD', 'Disease', 'MESH:D006527', (0, 2))	('DD liposarcomas', 'Disease', (7, 22))	('liposarcoma', 'Phenotype', 'HP:0012034', (10, 21))
590018	29731991	Of these, only EGFR (missense mutation; R108K aGa/aAa) and NF2 (nonsense mutation; K20* Aag/Tag) are driver mutations and the EGFR mutation is potentially actionable.	('K20*', 'Var', (83, 87))	('NF2', 'Gene', (59, 62))	('EGFR', 'Gene', (126, 130))	('Tag', 'Gene', (92, 95))	('K20*', 'SUBSTITUTION', 'None', (83, 87))	('NF2', 'Gene', '4771', (59, 62))	('EGFR', 'Gene', '1956', (15, 19))	('Tag', 'Gene', '404663', (92, 95))	('EGFR', 'Gene', (15, 19))	('Aag', 'Gene', (88, 91))	('R108K', 'Mutation', 'rs1057519828', (40, 45))	('Aag', 'Gene', '4350', (88, 91))	('EGFR', 'Gene', '1956', (126, 130))
590019	29731991	These mutations have not been reported previously in DD liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (56, 67))	('DD liposarcoma', 'Disease', 'MESH:D008080', (53, 67))	('DD liposarcoma', 'Disease', (53, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('mutations', 'Var', (6, 15))
590027	29731991	It is known that virtually all WD and DD liposarcomas have MDM2 amplification and close to 90% have CDK4 amplification and this is felt to be an early event in the pathogenesis of these tumors.	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('amplification', 'Var', (105, 118))	('DD liposarcomas', 'Disease', 'MESH:D008080', (38, 53))	('amplification', 'Var', (64, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('MDM2', 'Gene', (59, 63))	('liposarcomas', 'Phenotype', 'HP:0012034', (41, 53))	('tumors', 'Disease', (186, 192))	('DD liposarcomas', 'Disease', (38, 53))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('WD', 'Disease', 'MESH:D006527', (31, 33))	('CDK4', 'Gene', (100, 104))	('liposarcoma', 'Phenotype', 'HP:0012034', (41, 52))
590031	29731991	The targeted genotyping panels (T200/T200.1 and FM) detected several other CNAs, in addition to MDM2 and CDK4, and many of them were found in more than one tumor sample (Table 2).	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('detected', 'Reg', (52, 60))	('T200/T200.1', 'Var', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('CNAs', 'Disease', (75, 79))
590033	29731991	EGFR (R108K) and NF2 (K20*) were the two possible driver mutations that were detected in 2 separate samples and have not been described before in WD/DD liposarcoma.	('EGFR', 'Gene', (0, 4))	('liposarcoma', 'Phenotype', 'HP:0012034', (152, 163))	('DD liposarcoma', 'Disease', (149, 163))	('NF2', 'Gene', '4771', (17, 20))	('DD liposarcoma', 'Disease', 'MESH:D008080', (149, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('K20*', 'Var', (22, 26))	('EGFR', 'Gene', '1956', (0, 4))	('R108K', 'Mutation', 'rs1057519828', (6, 11))	('K20*', 'SUBSTITUTION', 'None', (22, 26))	('WD', 'Disease', 'MESH:D006527', (146, 148))	('NF2', 'Gene', (17, 20))
590036	29731991	EGFR missense mutations have shown to be oncogenic and can be inhibited by EGFR tyrosine kinase inhibitors, such as erlotinib.	('missense mutations', 'Var', (5, 23))	('oncogenic', 'CPA', (41, 50))	('EGFR', 'Gene', (0, 4))	('erlotinib', 'Chemical', 'MESH:D000069347', (116, 125))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (75, 79))
590037	29731991	No much is known about the NF2 (K20*) mutation in cancer patients.	('NF2', 'Gene', (27, 30))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('patients', 'Species', '9606', (57, 65))	('NF2', 'Gene', '4771', (27, 30))	('K20*', 'Var', (32, 36))	('K20*', 'SUBSTITUTION', 'None', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
590038	29731991	In patients with neurofibromatosis type 2, who have germline NF2 mutations and are predisposed to forming schwannomas, meningiomas, gliomas or neurofibromas; truncating mutations have been associated with a poorer prognosis.	('neurofibromatosis type 2', 'Disease', 'MESH:C537392', (17, 41))	('gliomas', 'Disease', (132, 139))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('neurofibromatosis type 2', 'Disease', (17, 41))	('mutations', 'Var', (65, 74))	('schwannomas', 'Phenotype', 'HP:0100008', (106, 117))	('neurofibromas', 'Disease', (143, 156))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('NF2', 'Gene', '4771', (61, 64))	('truncating mutations', 'Var', (158, 178))	('patients', 'Species', '9606', (3, 11))	('meningiomas', 'Disease', 'MESH:D008577', (119, 130))	('NF2', 'Gene', (61, 64))	('schwannomas', 'Disease', 'MESH:D009442', (106, 117))	('meningiomas', 'Phenotype', 'HP:0002858', (119, 130))	('neurofibromas', 'Phenotype', 'HP:0001067', (143, 156))	('meningiomas', 'Disease', (119, 130))	('schwannomas', 'Disease', (106, 117))	('neurofibromas', 'Disease', 'MESH:D009455', (143, 156))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (17, 34))
590039	29731991	In our study we also noted deleterious mutations in 7 other genes (CTNNB1 (R151H), MECOM (R208C), ZNF536 (T688M), EML4 (W729L), CSMD3 (P627S), PBRM1 (N639K), PPP1R3A (C788Y)) that have also not been described previously in WD/DD liposarcoma.	('PPP1R3A', 'Gene', (158, 165))	('ZNF536', 'Gene', (98, 104))	('CSMD3', 'Gene', (128, 133))	('liposarcoma', 'Phenotype', 'HP:0012034', (229, 240))	('CTNNB1', 'Gene', (67, 73))	('DD liposarcoma', 'Disease', (226, 240))	('W729L', 'Var', (120, 125))	('ZNF536', 'Gene', '9745', (98, 104))	('P627S', 'Var', (135, 140))	('C788Y', 'Mutation', 'rs766182437', (167, 172))	('WD', 'Disease', 'MESH:D006527', (223, 225))	('PBRM1', 'Gene', '55193', (143, 148))	('R208C', 'Var', (90, 95))	('R151H', 'Mutation', 'rs200968230', (75, 80))	('P627S', 'Mutation', 'p.P627S', (135, 140))	('PBRM1', 'Gene', (143, 148))	('R208C', 'Mutation', 'p.R208C', (90, 95))	('MECOM', 'Gene', (83, 88))	('EML4', 'Gene', (114, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (233, 240))	('W729L', 'Mutation', 'p.W729L', (120, 125))	('N639K', 'Mutation', 'p.N639K', (150, 155))	('EML4', 'Gene', '27436', (114, 118))	('MECOM', 'Gene', '2122', (83, 88))	('CTNNB1', 'Gene', '1499', (67, 73))	('T688M', 'Var', (106, 111))	('CSMD3', 'Gene', '114788', (128, 133))	('N639K', 'Var', (150, 155))	('T688M', 'Mutation', 'rs1278253484', (106, 111))	('PPP1R3A', 'Gene', '5506', (158, 165))	('DD liposarcoma', 'Disease', 'MESH:D008080', (226, 240))
590040	29731991	In a previous large-scale genomic sequencing study of soft tissue sarcoma specimens, that included 50 DD liposarcomas, a different CTNNB1 (T41I) mutation was described in a DD liposarcoma, including 3 other nonrecurring mutations (CDH1 (N238D), EPHA1 (A2127) and FBXW7 (E113fs)).	('T41I', 'Mutation', 'rs121913413', (139, 143))	('DD liposarcomas', 'Disease', 'MESH:D008080', (102, 117))	('FBXW7', 'Gene', (263, 268))	('DD liposarcoma', 'Disease', (173, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (109, 117))	('DD liposarcomas', 'Disease', (102, 117))	('CTNNB1', 'Gene', (131, 137))	('EPHA1', 'Gene', (245, 250))	('FBXW7', 'Gene', '55294', (263, 268))	('E113fs', 'Mutation', 'p.E113fsX', (270, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('liposarcomas', 'Phenotype', 'HP:0012034', (105, 117))	('mutation', 'Var', (145, 153))	('N238D', 'Mutation', 'p.N238D', (237, 242))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (54, 73))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (54, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('liposarcoma', 'Phenotype', 'HP:0012034', (105, 116))	('soft tissue sarcoma', 'Disease', (54, 73))	('CDH1', 'Gene', '999', (231, 235))	('DD liposarcoma', 'Disease', 'MESH:D008080', (102, 116))	('EPHA1', 'Gene', '2041', (245, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('CTNNB1', 'Gene', '1499', (131, 137))	('liposarcoma', 'Phenotype', 'HP:0012034', (176, 187))	('CDH1', 'Gene', (231, 235))	('DD liposarcoma', 'Disease', 'MESH:D008080', (173, 187))
590045	29731991	Genomic amplification of c-Jun and its upstream kinases is another interesting pathway that has been implicated as a mechanism of progression from WD to DD liposarcoma.	('Genomic amplification', 'Var', (0, 21))	('c-Jun', 'Gene', (25, 30))	('liposarcoma', 'Phenotype', 'HP:0012034', (156, 167))	('DD liposarcoma', 'Disease', (153, 167))	('c-Jun', 'Gene', '3725', (25, 30))	('WD', 'Disease', 'MESH:D006527', (147, 149))	('DD liposarcoma', 'Disease', 'MESH:D008080', (153, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))
590052	29731991	Deletions were reported include deletions at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1).	('deletions', 'Var', (32, 41))	('MIR16-1', 'Gene', '406950', (136, 143))	('CHEK1', 'Gene', '1111', (97, 102))	('MIR16-1', 'Gene', (136, 143))	('ATM', 'Gene', (92, 95))	('MIR15A', 'Gene', '406948', (128, 134))	('MIR15A', 'Gene', (128, 134))	('CHEK1', 'Gene', (97, 102))	('ATM', 'Gene', '472', (92, 95))	('RUNX3', 'Gene', (60, 65))	('RUNX3', 'Gene', '864', (60, 65))	('ARID1A', 'Gene', '8289', (67, 73))	('ARID1A', 'Gene', (67, 73))
590055	29731991	Notably P53 mutations are never seen in WD/DD liposaromas.	('WD', 'Disease', 'MESH:D006527', (40, 42))	('P53', 'Gene', '7157', (8, 11))	('DD liposaromas', 'Disease', 'MESH:C536170', (43, 57))	('mutations', 'Var', (12, 21))	('P53', 'Gene', (8, 11))	('DD liposaromas', 'Disease', (43, 57))
590057	29731991	Preclinical studies using Nutlin-3A, a selective MDM2 antagonist, stabilized p53 leading to downstream p53 dependent transcription and apoptosis in liposarcoma cells lines.	('apoptosis', 'CPA', (135, 144))	('p53 dependent transcription', 'MPA', (103, 130))	('liposarcoma', 'Phenotype', 'HP:0012034', (148, 159))	('liposarcoma', 'Disease', 'MESH:D008080', (148, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('p53', 'Gene', (77, 80))	('stabilized', 'Var', (66, 76))	('liposarcoma', 'Disease', (148, 159))
590077	29731991	Palbociclib (PD0332991) an oral CDK4/6 specific inhibitor was recently approved for the treatment of breast cancer in combination with tamoxifen.	('PD0332991', 'Var', (13, 22))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('CDK4/6', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('PD0332991', 'Chemical', 'MESH:C500026', (13, 22))	('tamoxifen', 'Chemical', 'MESH:D013629', (135, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('CDK4/6', 'Gene', '1019;1021', (32, 38))
590082	29731991	In this study, using the currently available clinical grade genotyping panels in WD/DD liposarcoma, 20/20 (100%) patient samples tested had CDK4 amplified and 16/16 (100%) patient samples tested had MDM2 amplified.	('patient', 'Species', '9606', (113, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('WD', 'Disease', 'MESH:D006527', (81, 83))	('patient', 'Species', '9606', (172, 179))	('amplified', 'Var', (145, 154))	('liposarcoma', 'Phenotype', 'HP:0012034', (87, 98))	('DD liposarcoma', 'Disease', 'MESH:D008080', (84, 98))	('DD liposarcoma', 'Disease', (84, 98))	('CDK4', 'Gene', (140, 144))
590084	29731991	The sequencing results also help confirm the liposarcoma subtype based on the presence or absence of MDM2 amplification, when it is not clear on imaging and histopathology.	('liposarcoma', 'Phenotype', 'HP:0012034', (45, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('liposarcoma', 'Disease', (45, 56))	('amplification', 'Var', (106, 119))	('absence', 'NegReg', (90, 97))	('liposarcoma', 'Disease', 'MESH:D008080', (45, 56))	('MDM2', 'Gene', (101, 105))
590160	26374100	I (Immune system status): I0 (good risk): CD4 cell count >200 cells/microl; I1 (poor risk): CD4 cell count <200 cells/microl.	('CD4', 'Gene', '920', (92, 95))	('CD4', 'Gene', (42, 45))	('CD4', 'Gene', '920', (42, 45))	('>200', 'Var', (57, 61))	('CD4', 'Gene', (92, 95))
590222	26374100	Using multivariate logistic regression analysis, poor ACTG stage (OR = 4.5, 95 % CI (2.3-8.6), p = 0.011), CD4+ count <200 cells/microl (OR = 3.9, 95 % CI (1.1-5.8), p = 0.000), associated co-morbid illness (OR = 4.1, 95 % CI (2.2-7.2), p = 0.032), disseminated disease (OR = 6.7, 95 % CI (2.1-8.9), p = 0.001) and poor adherent to chemotherapy (OR = 7.3, 95 % CI (3.3-9.2), p = 0.021) were the significant independent factors associated with deaths.	('CD4', 'Gene', (107, 110))	('disseminated disease', 'Disease', (249, 269))	('death', 'Disease', 'MESH:D003643', (443, 448))	('death', 'Disease', (443, 448))	('CD4', 'Gene', '920', (107, 110))	('poor', 'Var', (49, 53))
590265	26374100	Data from the Spectrum of Disease Study have indicated that correction of anaemia is associated with prolongation of survival in AIDS.	('AIDS', 'Disease', (129, 133))	('anaemia', 'Disease', 'MESH:D000740', (74, 81))	('AIDS', 'Disease', 'MESH:D000163', (129, 133))	('anaemia', 'Disease', (74, 81))	('prolongation', 'PosReg', (101, 113))	('anaemia', 'Phenotype', 'HP:0001903', (74, 81))	('survival', 'CPA', (117, 125))	('correction', 'Var', (60, 70))
590318	26123823	Here, we demonstrate in a genetically engineered mouse model of soft tissue sarcoma that loss of GCN2 has no effect on tumor growth or animal survival.	('tumor', 'Disease', (119, 124))	('loss', 'Var', (89, 93))	('GCN2', 'Gene', (97, 101))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (64, 83))	('mouse', 'Species', '10090', (49, 54))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (64, 83))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('soft tissue sarcoma', 'Disease', (64, 83))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
590335	26123823	Loss of GCN2 in xenograft models of cancer greatly inhibits or even prevents tumor growth.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('inhibits', 'NegReg', (51, 59))	('GCN2', 'Gene', (8, 12))	('cancer', 'Disease', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('prevents', 'NegReg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', (77, 82))
590342	26123823	PERKfl/fl;MMTV-cre mice crossed to MMTV-neu mice resulted in the specific deletion of PERK in the mammary glands of tumor-prone MMTV-neu mice.	('PERK', 'Gene', (0, 4))	('PERK', 'Gene', (86, 90))	('MMTV', 'Species', '11757', (128, 132))	('deletion', 'Var', (74, 82))	('PERK', 'Gene', '13666', (0, 4))	('MMTV', 'Species', '11757', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PERK', 'Gene', '13666', (86, 90))	('mice', 'Species', '10090', (44, 48))	('tumor', 'Disease', (116, 121))	('mice', 'Species', '10090', (19, 23))	('mice', 'Species', '10090', (137, 141))	('MMTV', 'Species', '11757', (10, 14))
590343	26123823	Results from this study showed that loss of PERK in mammary carcinomas slowed tumor growth and reduced the number of metastases to the lungs.	('PERK', 'Gene', '13666', (44, 48))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('loss', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PERK', 'Gene', (44, 48))	('carcinomas slowed tumor', 'Disease', 'MESH:D009369', (60, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('reduced', 'NegReg', (95, 102))	('carcinomas slowed tumor', 'Disease', (60, 83))	('metastases', 'Disease', (117, 127))
590344	26123823	In a second model, mice expressing SV40 large T antigen specifically in the beta cells of the pancreas were crossed to PERK-/- mice.	('mice', 'Species', '10090', (127, 131))	('pancreas', 'Disease', 'MESH:D010190', (94, 102))	('PERK', 'Gene', '13666', (119, 123))	('SV40 large T', 'Var', (35, 47))	('PERK', 'Gene', (119, 123))	('mice', 'Species', '10090', (19, 23))	('pancreas', 'Disease', (94, 102))
590348	26123823	Our previous studies in the HT1080 human sarcoma cell line revealed that knockdown of GCN2 completely blocked tumor growth in a xenograft model.	('sarcoma', 'Disease', (41, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('GCN2', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('human', 'Species', '9606', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('HT1080', 'CellLine', 'CVCL:0317', (28, 34))	('sarcoma', 'Disease', 'MESH:D012509', (41, 48))	('blocked', 'NegReg', (102, 109))	('knockdown', 'Var', (73, 82))
590350	26123823	Surprisingly, in autochthonous tumors, loss of GCN2 did not affect tumor initiation or progression and did not increase the lifespan of tumor-bearing mice.	('mice', 'Species', '10090', (150, 154))	('increase', 'PosReg', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('GCN2', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('loss', 'Var', (39, 43))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
590376	26123823	While tumors initiated in the C57BL6 mice within a much narrower window (40 to 50 days for most mice), loss of GCN2 still had no effect on tumor growth rate, tumor free survival, or overall survival of the mice (Supplementary Fig.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('GCN2', 'Gene', (111, 115))	('mice', 'Species', '10090', (96, 100))	('loss', 'Var', (103, 107))	('mice', 'Species', '10090', (206, 210))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (6, 12))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('mice', 'Species', '10090', (37, 41))
590377	26123823	Next, we wanted to determine if loss of GCN2 affected downstream signaling through the ISR in tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GCN2', 'Gene', (40, 44))	('tumor', 'Disease', (94, 99))	('affected', 'Reg', (45, 53))	('loss', 'Var', (32, 36))	('downstream signaling', 'MPA', (54, 74))	('ISR', 'Protein', (87, 90))
590378	26123823	Western blot analysis of tumor lysates revealed that loss of GCN2 did reduce levels of eIF2alpha phosphorylation in mixed background mice.	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('eIF2alpha', 'Gene', (87, 96))	('tumor', 'Disease', (25, 30))	('eIF2alpha', 'Gene', '13665', (87, 96))	('levels', 'MPA', (77, 83))	('GCN2', 'Gene', (61, 65))	('reduce', 'NegReg', (70, 76))	('loss', 'Var', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
590387	26123823	We repeated our study of ISR signaling in the C57BL6 tumors.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('C57BL6', 'Var', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
590390	26123823	As we observed in the mixed background tumors, PKR was phosphorylated in all C57BL6 tumors.	('tumors', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('PKR', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PKR', 'Gene', '19106', (47, 50))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('C57BL6', 'Var', (77, 83))
590392	26123823	This suggests that in the C57BL6 tumors, PERK compensates for loss of GCN2, resulting in maintenance of eIF2alpha phosphorylation levels.	('loss', 'NegReg', (62, 66))	('PERK', 'Gene', (41, 45))	('GCN2', 'Gene', (70, 74))	('eIF2alpha', 'Gene', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('PERK', 'Gene', '13666', (41, 45))	('eIF2alpha', 'Gene', '13665', (104, 113))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('C57BL6', 'Var', (26, 32))	('tumors', 'Disease', (33, 39))
590396	26123823	This situation is not unique to cancer, as in Alzheimer's disease, another pathological condition that activates the ISR, knockout of GCN2 also results in compensatory activation of PERK in the brains of affected animals, leading to no improvements in memory decline.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('PERK', 'Gene', (182, 186))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (46, 65))	('improvements', 'PosReg', (236, 248))	('cancer', 'Disease', (32, 38))	('memory decline', 'Phenotype', 'HP:0002354', (252, 266))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (46, 65))	('PERK', 'Gene', '13666', (182, 186))	('knockout', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('activation', 'PosReg', (168, 178))	('memory decline', 'CPA', (252, 266))	("Alzheimer's disease", 'Disease', (46, 65))	('GCN2', 'Gene', (134, 138))
590398	26123823	Enhanced XBP1 splicing in tumors was observed in GCN2-/- mice, suggesting that loss of GCN2 sensitizes cells to ER stress (Fig.	('mice', 'Species', '10090', (57, 61))	('GCN2', 'Gene', (87, 91))	('loss', 'Var', (79, 83))	('XBP1', 'Gene', '22433', (9, 13))	('sensitizes', 'Reg', (92, 102))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('XBP1', 'Gene', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
590400	26123823	As expected from the similar levels of eIF2alpha phosphorylation, GCN2 status did not affect ATF4 protein levels in C57BL6 tumors (Supplementary Fig.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('ATF4', 'MPA', (93, 97))	('C57BL6', 'Var', (116, 122))	('eIF2alpha', 'Gene', (39, 48))	('eIF2alpha', 'Gene', '13665', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
590408	26123823	ATF4 amplification was observed in two GCN2+/+ tumors, but no GCN2-/- tumors (Fig.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('amplification', 'Var', (5, 18))	('observed', 'Reg', (23, 31))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ATF4', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
590411	26123823	A second mechanism by which GCN2-/- tumors could upregulate ATF4 is through mutations in the protein that enhance its expression levels.	('enhance', 'PosReg', (106, 113))	('mutations', 'Var', (76, 85))	('ATF4', 'Gene', (60, 64))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('expression levels', 'MPA', (118, 135))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('upregulate', 'PosReg', (49, 59))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
590412	26123823	For example, mutations of the 5' uORFs could uncouple ATF4 expression from eIF2alpha phosphorylation, and mutations in the beta-TrCP recognition motif or the oxygen dependent degradation (ODD) domain could enhance ATF4 protein stability.	('eIF2alpha', 'Gene', '13665', (75, 84))	('ATF4', 'Gene', (54, 58))	('oxygen', 'Chemical', 'MESH:D010100', (158, 164))	('ATF4 protein', 'Protein', (214, 226))	('beta-TrCP', 'Protein', (123, 132))	('enhance', 'PosReg', (206, 213))	('expression', 'MPA', (59, 69))	('uncouple', 'NegReg', (45, 53))	('mutations', 'Var', (106, 115))	('mutations', 'Var', (13, 22))	('eIF2alpha', 'Gene', (75, 84))	('protein', 'Protein', (219, 226))
590418	26123823	Phosphorylation of ATF4 also regulates its stability, so changes in this post-translational modification could also impact ATF4 levels in GCN2-/- tumors.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('impact', 'Reg', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ATF4', 'Gene', (19, 23))	('ATF4 levels', 'MPA', (123, 134))	('changes', 'Var', (57, 64))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', (146, 152))	('stability', 'MPA', (43, 52))	('regulates', 'Reg', (29, 38))
590421	26123823	We chose to focus on undifferentiated pleomorphic sarcoma (UPS), also known as malignant fibrous histiocytoma (MFH), since the LSL-KrasG12D/wt;p53fl/fl model most closely resembles this sarcoma subtype at the genetic level.	('pleomorphic sarcoma', 'Disease', (38, 57))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('p53', 'Gene', '22060', (143, 146))	('histiocytoma', 'Phenotype', 'HP:0012315', (97, 109))	('pleomorphic sarcoma', 'Disease', 'MESH:D008228', (38, 57))	('sarcoma', 'Disease', (186, 193))	('sarcoma', 'Disease', (50, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('LSL-KrasG12D/wt', 'Var', (127, 142))	('p53', 'Gene', (143, 146))
590431	26123823	Although GCN2 was both overexpressed and activated in the sarcomas, loss of GCN2 had no effect on tumor growth or animal survival.	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('GCN2', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcomas', 'Disease', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('activated', 'PosReg', (41, 50))	('tumor', 'Disease', (98, 103))	('loss', 'Var', (68, 72))	('sarcomas', 'Disease', 'MESH:D012509', (58, 66))
590437	26123823	We previously utilized flank xenograft models to study the role of GCN2 in tumorigenesis and found that Ras transformed GCN2-/- MEFs formed extremely small tumors, while stable knockdown of GCN2 in the HT1080 human sarcoma cell line completely blocked tumor growth.	('human', 'Species', '9606', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (215, 222))	('tumor', 'Disease', (156, 161))	('blocked', 'NegReg', (244, 251))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('GCN2-/- MEFs', 'Var', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('HT1080', 'CellLine', 'CVCL:0317', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (156, 162))	('sarcoma', 'Disease', 'MESH:D012509', (215, 222))	('sarcoma', 'Disease', (215, 222))	('MEFs', 'CellLine', 'CVCL:9115', (128, 132))	('tumor', 'Disease', (252, 257))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
590439	26123823	Loss of GCN2 renders cells extremely sensitive to amino acid deprivation, and thus they probably undergo apoptosis before they can establish vasculature to deliver nutrients to the tumor site.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('sensitive', 'MPA', (37, 46))	('GCN2', 'Gene', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('Loss', 'Var', (0, 4))	('undergo', 'Reg', (97, 104))
590445	26123823	This could be modeled genetically by utilizing dual recombinase technology to excise GCN2 after activation of KrasG12D and deletion of p53 to initiate sarcomagenesis.	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('deletion', 'Var', (123, 131))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '22060', (135, 138))	('GCN2', 'Gene', (85, 89))	('KrasG12D', 'Gene', (110, 118))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('sarcoma', 'Disease', (151, 158))
590453	26123823	We previously showed that loss of GCN2 compromises autophagy induction in response to glutamine deprivation in human fibrosarcoma cells.	('autophagy induction', 'CPA', (51, 70))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (117, 129))	('fibrosarcoma', 'Disease', 'MESH:D005354', (117, 129))	('glutamine', 'Chemical', 'MESH:D005973', (86, 95))	('human', 'Species', '9606', (111, 116))	('compromises', 'NegReg', (39, 50))	('fibrosarcoma', 'Disease', (117, 129))	('loss', 'Var', (26, 30))	('GCN2', 'Gene', (34, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
590456	26123823	GCN2-/- mice (Jackson Laboratories), LSL-KrasG12D/wt mice, and p53fl/fl mice were previously described.	('p53', 'Gene', (63, 66))	('GCN2-/-', 'Var', (0, 7))	('p53', 'Gene', '22060', (63, 66))	('mice', 'Species', '10090', (72, 76))	('mice', 'Species', '10090', (8, 12))	('mice', 'Species', '10090', (53, 57))
590457	26123823	LSL-KrasG12D/wt;p53fl/fl mice were injected with 2.5 x 107 PFU of Ad5CMVcre (University of Iowa Gene Transfer Vector Core) in the upper leg muscle to induce sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('mice', 'Species', '10090', (25, 29))	('sarcomas', 'Disease', (157, 165))	('p53', 'Gene', (16, 19))	('Ad5CMVcre', 'Var', (66, 75))	('sarcomas', 'Disease', 'MESH:D012509', (157, 165))	('p53', 'Gene', '22060', (16, 19))	('induce', 'Reg', (150, 156))
590479	26123823	The following primary antibodies were used: beta-tubulin, eIF2alpha, GCN2, p-eIF2alpha, PERK, p-PERK (all from Cell Signaling), ATF4, PKR (both from Santa Cruz), p-GCN2 (Bioss), and p-PKR (Millipore).	('PERK', 'Gene', (96, 100))	('eIF2alpha', 'Gene', '13665', (77, 86))	('PERK', 'Gene', '13666', (88, 92))	('PKR', 'Gene', (184, 187))	('p-GCN2', 'Var', (162, 168))	('eIF2alpha', 'Gene', (58, 67))	('PKR', 'Gene', '19106', (184, 187))	('beta-tubulin', 'Protein', (44, 56))	('ATF4', 'Var', (128, 132))	('PERK', 'Gene', '13666', (96, 100))	('eIF2alpha', 'Gene', '13665', (58, 67))	('PKR', 'Gene', (134, 137))	('PKR', 'Gene', '19106', (134, 137))	('PERK', 'Gene', (88, 92))	('eIF2alpha', 'Gene', (77, 86))	('GCN2', 'Gene', (69, 73))
590491	24212944	Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients.	('IGF-1R', 'Gene', (111, 117))	('function', 'MPA', (119, 127))	('patients', 'Species', '9606', (407, 415))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('impaired tumor growth', 'Disease', (322, 343))	('mitigate', 'NegReg', (146, 154))	('impaired tumor growth', 'Disease', 'MESH:D006130', (322, 343))	('insulin', 'Gene', (72, 79))	('mTOR', 'Gene', (188, 192))	('mTOR', 'Gene', '2475', (188, 192))	('insulin', 'Gene', '3630', (72, 79))	('abrogate', 'NegReg', (63, 71))	('PI3K', 'Var', (194, 198))	('progression-free', 'CPA', (365, 381))
590516	24212944	Unlike other tyrosine kinase receptors, like her2/neu for example, gene amplification and/or mutations in the IGF-1R gene are distinctly uncommon, occurring in less than ten percent of breast cancers and rarely in pediatric wild-type gastrointestinal stromal tumors, pancreatic adenocarcinomas, and Wilms' tumors.	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('occurring', 'Reg', (147, 156))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('tyrosine', 'Chemical', 'MESH:D014443', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	("Wilms' tumors", 'Disease', 'MESH:D009396', (299, 312))	('gastrointestinal stromal tumors', 'Disease', (234, 265))	('breast cancers', 'Disease', 'MESH:D001943', (185, 199))	('her2/neu', 'Gene', '2064', (45, 53))	('breast cancers', 'Disease', (185, 199))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('breast cancers', 'Phenotype', 'HP:0003002', (185, 199))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (267, 293))	('IGF-1R', 'Gene', (110, 116))	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('carcinomas', 'Phenotype', 'HP:0030731', (283, 293))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	("Wilms' tumors", 'Phenotype', 'HP:0002667', (299, 312))	('pancreatic adenocarcinomas', 'Disease', (267, 293))	("Wilms' tumors", 'Disease', (299, 312))	('gene amplification', 'Var', (67, 85))	('her2/neu', 'Gene', (45, 53))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (234, 265))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (234, 265))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (267, 293))
590538	24212944	IGF-1R over-expression has been associated with resistance to trastuzumab and pertuzumab therapies in vitro and its inhibition, via IGF-1R targeted small interfering RNA (siRNA) or tyrosine kinase inhibitors (like NVP-AEW541) appears to counteract those resistance mechanisms.	('IGF-1R', 'Gene', (132, 138))	('over-expression', 'PosReg', (7, 22))	('small', 'Var', (148, 153))	('trastuzumab', 'Chemical', 'MESH:D000068878', (62, 73))	('inhibition', 'NegReg', (116, 126))	('pertuzumab', 'Chemical', 'MESH:C485206', (78, 88))	('resistance', 'MPA', (48, 58))	('associated', 'Reg', (32, 42))	('IGF-1R', 'Gene', (0, 6))	('tyrosine', 'Chemical', 'MESH:D014443', (181, 189))
590541	24212944	Antibody-mediated inhibition of IGF-1R can result in significant inhibition of tumor growth in both androgen independent and dependent xenograft models and IGF-1R/EGFR crosstalk has been associated with resistance to gefitinib in the well-characterized DU145 prostate cancer cell line.	('gefitinib', 'Chemical', 'MESH:D000077156', (217, 226))	('inhibition', 'NegReg', (65, 75))	('inhibition', 'NegReg', (18, 28))	('tumor', 'Disease', (79, 84))	('DU145', 'CellLine', 'CVCL:0105', (253, 258))	('IGF-1R', 'Gene', (32, 38))	('prostate cancer', 'Disease', (259, 274))	('EGFR', 'Gene', '1956', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('associated', 'Reg', (187, 197))	('EGFR', 'Gene', (163, 167))	('prostate cancer', 'Disease', 'MESH:D011471', (259, 274))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (259, 274))	('crosstalk', 'Var', (168, 177))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
590552	24212944	Deregulation of IGF signaling has been described in both non-small cell lung cancer (NSCLC) and SCLC.	('NSCLC', 'Disease', (85, 90))	('IGF signaling', 'Pathway', (16, 29))	('SCLC', 'Disease', (86, 90))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (57, 83))	('SCLC', 'Disease', 'MESH:D018288', (86, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('Deregulation', 'Var', (0, 12))	('SCLC', 'Phenotype', 'HP:0030357', (96, 100))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('SCLC', 'Phenotype', 'HP:0030357', (86, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('non-small cell lung cancer', 'Disease', (57, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SCLC', 'Disease', (96, 100))	('SCLC', 'Disease', 'MESH:D018288', (96, 100))
590555	24212944	As might be expected, there are several ongoing clinical trials combining IGF-1R targeted antibodies with traditional cytotoxics or EGFR inhibitors such as erlotinib in NSCLC patients.	('cytotoxics', 'Disease', (118, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('EGFR', 'Gene', '1956', (132, 136))	('erlotinib', 'Chemical', 'MESH:D000069347', (156, 165))	('NSCLC', 'Disease', (169, 174))	('EGFR', 'Gene', (132, 136))	('cytotoxics', 'Disease', 'MESH:D064420', (118, 128))	('SCLC', 'Phenotype', 'HP:0030357', (170, 174))	('IGF-1R', 'Gene', (74, 80))	('patients', 'Species', '9606', (175, 183))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('antibodies', 'Var', (90, 100))
590560	24212944	Although these studies were not designed to investigate the activity according to NSCLC histologies or EMT status, these results suggest rational strategy to enrich for lung cancer patients that might benefit from treatment with anti-IGF-1R antibodies.	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('SCLC', 'Phenotype', 'HP:0030357', (83, 87))	('anti-IGF-1R', 'Var', (229, 240))	('patients', 'Species', '9606', (181, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('lung cancer', 'Disease', (169, 180))	('NSCLC', 'Disease', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
590561	24212944	Furthermore, EGFR and K-ras mutations have been implicated as biomarkers for selecting patients in IGF-1R TKI-based therapy for NSCLC patients (Kim WY et al., AACR 2010 Annual Meeting, Abstract # 4127).	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('patients', 'Species', '9606', (134, 142))	('NSCLC', 'Disease', (128, 133))	('K-ras', 'Gene', (22, 27))	('K-ras', 'Gene', '3845', (22, 27))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('SCLC', 'Phenotype', 'HP:0030357', (129, 133))	('EGFR', 'Gene', '1956', (13, 17))	('patients', 'Species', '9606', (87, 95))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (28, 37))
590562	24212944	In this study, introduction of mutant K-Ras induced IGF-1R TKI resistance, while a knockout of mutant K-Ras restored the sensitivity in in vitro and in vivo models.	('mutant', 'Var', (31, 37))	('K-Ras', 'Gene', '3845', (102, 107))	('sensitivity', 'MPA', (121, 132))	('K-Ras', 'Gene', (102, 107))	('IGF-1R TKI resistance', 'MPA', (52, 73))	('K-Ras', 'Gene', '3845', (38, 43))	('K-Ras', 'Gene', (38, 43))	('induced', 'PosReg', (44, 51))
590566	24212944	IGF-1R activation is required for EWS-FLI-1 induced malignant transformation of murine fibroblasts and, when transfected in mouse progenitor cells, the EWS-FLI-1 fusion protein (but not native FLI-1 or ERG) is reported to induce a nearly nine-fold increase in IGF-1 expression - directly linking the most common EWS translocation to IGF-1 autocrine signaling.	('expression', 'MPA', (266, 276))	('increase', 'PosReg', (248, 256))	('EWS', 'Phenotype', 'HP:0012254', (152, 155))	('ERG', 'Gene', (202, 205))	('malignant transformation', 'CPA', (52, 76))	('IGF-1', 'Gene', (260, 265))	('mouse', 'Species', '10090', (124, 129))	('EWS', 'Phenotype', 'HP:0012254', (312, 315))	('EWS-FLI-1', 'Var', (152, 161))	('increase in IGF-1 expression', 'Phenotype', 'HP:0030269', (248, 276))	('ERG', 'Gene', '13876', (202, 205))	('EWS', 'Phenotype', 'HP:0012254', (34, 37))	('murine', 'Species', '10090', (80, 86))
590577	24212944	In preclinical animal models using antibodies to IGF-1R, no antibody dependent cellular toxicity (ADCC) or cross-reactivity to the insulin receptor has been observed.	('insulin receptor', 'Gene', '3643', (131, 147))	('insulin receptor', 'Gene', (131, 147))	('antibodies', 'Var', (35, 45))	('toxicity', 'Disease', 'MESH:D064420', (88, 96))	('toxicity', 'Disease', (88, 96))	('IGF-1R', 'Gene', (49, 55))
590585	24212944	Putative mechanisms of resistance may be conceptually grouped by two broad categories:  With respect to the first category or resistance, cross talk via alternative RTK or non-receptor transmembrane signalers (such as integrins) could potentially bypass the need for IGF-1R signaling.	('RTK', 'Gene', '5979', (165, 168))	('RTK', 'Gene', (165, 168))	('cross', 'Var', (138, 143))
590587	24212944	Imatinib-induced shutdown of c-kit receptor phosphorylation leads to a 20-30% reduction in EWS cell proliferation and suppressed tumor growth in xenograft models, albeit at doses 20-fold higher than that used for treatment of gastrointestinal stromal tumors (18-22 muM).	('tumor', 'Disease', (251, 256))	('EWS', 'Phenotype', 'HP:0012254', (91, 94))	('shutdown', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', (129, 134))	('gastrointestinal stromal tumors', 'Disease', (226, 257))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('c-kit', 'Gene', '3815', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('suppressed', 'NegReg', (118, 128))	('EWS cell proliferation', 'CPA', (91, 113))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('phosphorylation', 'MPA', (44, 59))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (226, 257))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (226, 257))	('reduction', 'NegReg', (78, 87))	('c-kit', 'Gene', (29, 34))
590600	24212944	Interestingly, whereas wild type-p53 down-regulates transcription of IGF-1R at the promoter level, mutant p53 induced the opposite effect in osteosarcoma and rhabdomyosarcoma cells.	('IGF-1R', 'Gene', (69, 75))	('down-regulates', 'NegReg', (37, 51))	('p53', 'Gene', '7157', (106, 109))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (158, 174))	('osteosarcoma and rhabdomyosarcoma', 'Disease', 'MESH:D012516', (141, 174))	('transcription', 'MPA', (52, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('osteosarcoma', 'Phenotype', 'HP:0002669', (141, 153))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('mutant', 'Var', (99, 105))	('p53', 'Gene', (106, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
590602	24212944	Though not yet confirmed to be prognostic in EWS, high levels of IGF-1R appear to confer sensitivity in rhabdomyosarcoma, and may serve as a valid prognostic biomarker for that cancer.	('sensitivity', 'MPA', (89, 100))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('high levels of IGF-1', 'Phenotype', 'HP:0030269', (50, 70))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (104, 120))	('high levels', 'Var', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (104, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('rhabdomyosarcoma', 'Disease', (104, 120))	('IGF-1R', 'Gene', (65, 71))	('EWS', 'Phenotype', 'HP:0012254', (45, 48))
590617	24212944	Similar in effect, small molecule inhibitors of IR and IGF-1R, such as OSI-906, have generated significant enthusiasm, given anecdotal reports of clinical response.	('IGF-1R', 'Gene', (55, 61))	('enthusiasm', 'Disease', 'None', (107, 117))	('inhibitors', 'Var', (34, 44))	('IR', 'Gene', '3643', (48, 50))	('OSI-906', 'Chemical', 'MESH:C551528', (71, 78))	('enthusiasm', 'Disease', (107, 117))
590626	24212944	A novel small molecule inhibitor of the IGF-1R/IR/ALK triad, GSK1838705A, has shown antitumor activity in human tumor models and should help elucidate the relationship of IGF-1R pathway activation in ALK-positive tumors noted within subtypes of NSCLC, lymphoma, and sarcoma.	('human', 'Species', '9606', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('activation', 'PosReg', (186, 196))	('NSCLC', 'Disease', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('lymphoma', 'Disease', (252, 260))	('NSCLC', 'Phenotype', 'HP:0030358', (245, 250))	('tumors', 'Disease', (213, 219))	('sarcoma', 'Disease', 'MESH:D012509', (266, 273))	('IR', 'Gene', '3643', (47, 49))	('lymphoma', 'Disease', 'MESH:D008223', (252, 260))	('sarcoma', 'Disease', (266, 273))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('GSK1838705A', 'Chemical', 'MESH:C546191', (61, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (266, 273))	('GSK1838705A', 'Var', (61, 72))	('tumor', 'Disease', (213, 218))	('lymphoma', 'Phenotype', 'HP:0002665', (252, 260))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (245, 250))	('SCLC', 'Phenotype', 'HP:0030357', (246, 250))
590628	24212944	Certainly with respect to cancers of the lung, prostate and colon, which rely in part upon EGFR signaling for tumor growth and survival, dual targeting of IGF-1R and EGFR has garnered much interest, given the fact that reciprocal inhibition of one RTK in epithelial cancers often enhances expression of the other.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('enhances', 'PosReg', (280, 288))	('EGFR', 'Gene', '1956', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('expression', 'MPA', (289, 299))	('epithelial cancers', 'Disease', (255, 273))	('RTK', 'Gene', (248, 251))	('cancers of the lung', 'Disease', 'MESH:D008175', (26, 45))	('EGFR', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('epithelial cancers', 'Disease', 'MESH:D000077216', (255, 273))	('RTK', 'Gene', '5979', (248, 251))	('reciprocal', 'Var', (219, 229))	('EGFR', 'Gene', (166, 170))	('EGFR', 'Gene', '1956', (91, 95))	('IGF-1R', 'Gene', (155, 161))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('tumor', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancers of the lung', 'Disease', (26, 45))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
590642	20627875	Results: Trabectedin   EST was associated with 14.0 (95% confidence interval 9.1-19.2) months longer survival, $36 778 higher costs ($32 816 using hospital price for trabectedin) and $31 590 ($28 192) incremental cost per LYG with an EVPI of $3008 ($3188) compared with EST.	('LYG', 'Chemical', '-', (222, 225))	('higher', 'PosReg', (119, 125))	('longer', 'PosReg', (94, 100))	('Trabectedin', 'Var', (9, 20))	('survival', 'CPA', (101, 109))	('costs', 'MPA', (126, 131))
590674	20627875	The transition probabilities were averaged >1000 simulations to determine the mean transition probabilities [beta, 95% confidence intervals (CIs)] for the TRA   EST arm: remaining SD 0.8476 (0.7741-0.9121), SD   PD 0.1457 (0.0840-0.2159), SD   death 0.0067 (0.0039-0.0100) and PD   death 0.1118 (0.0735-0.1570) and for the EST arm: remaining PD 0.8870 (0.8430-0.9265) and PD   death 0.1118 (0.0735-0.1570).	('TRA', 'Chemical', 'MESH:D000077606', (155, 158))	('PD   death', 'Disease', 'MESH:D010300', (277, 287))	('PD   death', 'Disease', (277, 287))	('PD', 'Disease', 'MESH:D010300', (277, 279))	('PD', 'Disease', 'MESH:D010300', (212, 214))	('PD   death', 'Disease', 'MESH:D010300', (372, 382))	('PD', 'Disease', 'MESH:D010300', (342, 344))	('SD   death', 'Disease', 'MESH:D029461', (239, 249))	('PD', 'Disease', 'MESH:D010300', (372, 374))	('SD   death', 'Disease', (239, 249))	('PD   death', 'Disease', (372, 382))	('0.0840-0.2159', 'Var', (223, 236))
590714	20627875	Consequently, the lowest QALYs gained due to TRA   EST compared with EST was 0.77 (95% CI 0.55-1.04) based on EQ-5D and the highest 0.86 (95% CI 0.61-1.16) based on 15D.	('TRA', 'Chemical', 'MESH:D000077606', (45, 48))	('lowest', 'NegReg', (18, 24))	('EQ-5D', 'Var', (110, 115))
590788	31847387	In pediatrics, variants of oncolytic Herpes simplex virus (oHSV) have been shown effective in a variety of solid tumors, such as glioblastoma, neuroblastoma, and sarcoma.	('Herpes simplex', 'Phenotype', 'HP:0012302', (37, 51))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('glioblastoma', 'Disease', (129, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (129, 141))	('sarcoma', 'Disease', (162, 169))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('solid tumors', 'Disease', (107, 119))	('neuroblastoma', 'Disease', (143, 156))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('variants', 'Var', (15, 23))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('solid tumors', 'Disease', 'MESH:D009369', (107, 119))
590797	31847387	A pre-clinical investigation of the TME in sarcoma showed that modulation of tumor-associated macrophages (TAMs) could potentiate an immune response.	('potentiate', 'PosReg', (119, 129))	('modulation', 'Var', (63, 73))	('immune response', 'CPA', (133, 148))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('sarcoma', 'Disease', (43, 50))	('tumor', 'Disease', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
590803	31847387	There are only four clinical trials listed on  that are actively recruiting for viral therapy in pediatric cancers: oHSV in cerebellar tumors (NCT03911388), oHSV in supratentorial brain tumors (NCT02457845), adenovirus in gliomas (NCT03178032), and an oncolytic poliovirus in gliomas (NCT03043391).	('cancers', 'Disease', (107, 114))	('brain tumors', 'Disease', (180, 192))	('poliovirus', 'Species', '138950', (262, 272))	('NCT03043391', 'Var', (285, 296))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('gliomas', 'Disease', 'MESH:D005910', (276, 283))	('gliomas', 'Disease', 'MESH:D005910', (222, 229))	('supratentorial brain tumors', 'Phenotype', 'HP:0030693', (165, 192))	('NCT02457845', 'Var', (194, 205))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('NCT03911388', 'Var', (143, 154))	('gliomas', 'Phenotype', 'HP:0009733', (276, 283))	('NCT03043391', 'Chemical', 'MESH:C079985', (285, 296))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('gliomas', 'Phenotype', 'HP:0009733', (222, 229))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cerebellar tumors', 'Disease', (124, 141))	('NCT03178032', 'Chemical', 'MESH:C079985', (231, 242))	('brain tumors', 'Disease', 'MESH:D001932', (180, 192))	('brain tumors', 'Phenotype', 'HP:0030692', (180, 192))	('cerebellar tumors', 'Disease', 'MESH:D002528', (124, 141))	('brain tumor', 'Phenotype', 'HP:0030692', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gliomas', 'Disease', (276, 283))	('NCT03911388', 'Chemical', 'MESH:C079985', (143, 154))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('gliomas', 'Disease', (222, 229))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('NCT03178032', 'Var', (231, 242))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
590809	31847387	An mAb targeting the ALK surface receptor, mAb30/49, led to decreased tumor cell proliferation and viability in vitro.	('viability', 'CPA', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ALK', 'Gene', (21, 24))	('mAb30/49', 'Var', (43, 51))	('decreased tumor', 'Disease', 'None', (60, 75))	('decreased tumor', 'Disease', (60, 75))	('ALK', 'Gene', '238', (21, 24))
590811	31847387	Investigators have demonstrated this concept using an anti-GD2 antibody, hu14.18K322A, combined with IL-15.	('hu14.18K322A', 'Var', (73, 85))	('IL-15', 'Gene', (101, 106))	('IL-15', 'Gene', '3600', (101, 106))
590819	31847387	Bispecific antibodies, unlike normal antibodies, elicit a cytotoxic T cell response against a specific tumor target.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cytotoxic T cell response against', 'CPA', (58, 91))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('elicit', 'Reg', (49, 55))	('Bispecific antibodies', 'Var', (0, 21))
590832	31847387	CTLA-4 binds to B7 molecules (CD80 and CD86) with greater affinity, thus out-competes CD28 for their shared ligands, preventing T cell activation.	('out-competes', 'NegReg', (73, 85))	('CD86', 'Var', (39, 43))	('binds', 'Interaction', (7, 12))	('CTLA-4', 'Gene', (0, 6))	('T cell activation', 'CPA', (128, 145))	('CD28', 'Gene', '940', (86, 90))	('B7 molecules', 'Protein', (16, 28))	('CD28', 'Gene', (86, 90))	('preventing', 'NegReg', (117, 127))
590834	31847387	Thus, CTLA-4 blockade potentiates effective immune responses against tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CTLA-4', 'Gene', (6, 12))	('blockade', 'Var', (13, 21))	('tumor', 'Disease', (69, 74))	('potentiates', 'PosReg', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
590847	31847387	Of note, PD-L1 staining was associated with inferior survival among neuroblastoma patients, and higher expression of PD-1 correlated with disease progression in patients with osteosarcoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (68, 81))	('osteosarcoma', 'Phenotype', 'HP:0002669', (175, 187))	('inferior', 'NegReg', (44, 52))	('higher', 'PosReg', (96, 102))	('osteosarcoma', 'Disease', (175, 187))	('osteosarcoma', 'Disease', 'MESH:D012516', (175, 187))	('patients', 'Species', '9606', (82, 90))	('expression', 'MPA', (103, 113))	('correlated with', 'Reg', (122, 137))	('survival', 'MPA', (53, 61))	('staining', 'Var', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('patients', 'Species', '9606', (161, 169))	('neuroblastoma', 'Disease', 'MESH:D009447', (68, 81))	('PD-1', 'Gene', (117, 121))	('neuroblastoma', 'Disease', (68, 81))	('PD-L1', 'Gene', (9, 14))
590858	31847387	In an implantable murine model of metastatic osteosarcoma, treatment with anti-PD-L1 antibody resulted in downregulation of PD-L1 expression and upregulation of CD80/CD86 expression on tumor cells, as well as upregulation of CTLA-4 on tumor infiltrating CD8+ T cells.	('expression', 'MPA', (130, 140))	('upregulation', 'PosReg', (145, 157))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('osteosarcoma', 'Disease', (45, 57))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('CD8', 'Gene', '925', (254, 257))	('CD8', 'Gene', '925', (166, 169))	('tumor', 'Disease', (185, 190))	('CD8', 'Gene', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('anti-PD-L1', 'Var', (74, 84))	('downregulation', 'NegReg', (106, 120))	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('CD8', 'Gene', (254, 257))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('CD8', 'Gene', (166, 169))	('expression', 'MPA', (171, 181))	('PD-L1', 'Gene', (124, 129))	('CD8', 'Gene', '925', (161, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('tumor', 'Disease', (235, 240))	('upregulation', 'PosReg', (209, 221))	('murine', 'Species', '10090', (18, 24))
590871	31847387	Furthermore, the presence of TAMs, detected by genome-wide mRNA profiling and immunohistochemistry, was shown to be associated with suppression of metastasis and improved overall survival in patients with high-grade osteosarcoma, thus providing a rationale for the use of macrophage-activating agents such as liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE).	('osteosarcoma', 'Phenotype', 'HP:0002669', (216, 228))	('patients', 'Species', '9606', (191, 199))	('osteosarcoma', 'Disease', (216, 228))	('osteosarcoma', 'Disease', 'MESH:D012516', (216, 228))	('suppression', 'NegReg', (132, 143))	('improved', 'PosReg', (162, 170))	('muramyl tripeptide phosphatidylethanolamine', 'Chemical', 'MESH:C037144', (319, 362))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('presence', 'Var', (17, 25))	('overall survival', 'CPA', (171, 187))	('L-MTP', 'Chemical', 'MESH:C541968', (364, 369))	('metastasis', 'CPA', (147, 157))
590872	31847387	L-MTP-PE is a synthetic analog of a bacterial wall component that induces the activation of monocytes and macrophages in the TME, thereby promoting their anti-tumor activity.	('promoting', 'PosReg', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('L-MTP-PE', 'Var', (0, 8))	('activation', 'PosReg', (78, 88))	('L-MTP', 'Chemical', 'MESH:C541968', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
590874	31847387	A report from the Children's Oncology Group (COG) analyzed whether the addition of L-MTP-PE would improve outcomes in patients with osteosarcoma and found a statistically significant improvement of the overall survival from 70 to 78%.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('L-MTP', 'Chemical', 'MESH:C541968', (83, 88))	('improve', 'PosReg', (98, 105))	('Children', 'Species', '9606', (18, 26))	('improvement', 'PosReg', (183, 194))	('osteosarcoma', 'Phenotype', 'HP:0002669', (132, 144))	('osteosarcoma', 'Disease', (132, 144))	('osteosarcoma', 'Disease', 'MESH:D012516', (132, 144))	('L-MTP-PE', 'Var', (83, 91))	('patients', 'Species', '9606', (118, 126))	('Oncology', 'Phenotype', 'HP:0002664', (29, 37))
590877	31847387	Inhibition of MDSCs in three different immunocompetent mouse models of neuroblastoma resulted in the inhibition of tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('neuroblastoma', 'Disease', 'MESH:D009447', (71, 84))	('inhibition', 'NegReg', (101, 111))	('tumor', 'Disease', (115, 120))	('neuroblastoma', 'Disease', (71, 84))	('mouse', 'Species', '10090', (55, 60))	('MDSCs', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('neuroblastoma', 'Phenotype', 'HP:0003006', (71, 84))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
590894	31847387	Currently, a combination of pegylated IFN-alpha, chemotherapy, and surgery is being tested in a phase III COG trial to treat patients, including children over the age of 5, with high-grade osteosarcoma (NCT00134030).	('children', 'Species', '9606', (145, 153))	('NCT00134030', 'Var', (203, 214))	('osteosarcoma', 'Phenotype', 'HP:0002669', (189, 201))	('osteosarcoma', 'Disease', (189, 201))	('osteosarcoma', 'Disease', 'MESH:D012516', (189, 201))	('IFN-alpha', 'Gene', '3439', (38, 47))	('IFN-alpha', 'Gene', (38, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('patients', 'Species', '9606', (125, 133))
590962	31847387	This phase I study was designed to determine the safety of infusing expanded NK cells, obtained from a patient's family member with partial HLA mismatch, into pediatric patients with Ewing sarcoma family of tumors (ESFT) and rhabdomyosarcoma.	('Ewing sarcoma family of tumors', 'Disease', 'MESH:D012512', (183, 213))	('rhabdomyosarcoma', 'Disease', (225, 241))	('patients', 'Species', '9606', (169, 177))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (183, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (225, 241))	('ESFT', 'Disease', 'MESH:D012512', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('HL', 'CellLine', 'CVCL:2492', (140, 142))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('ESFT', 'Disease', (215, 219))	('partial', 'Var', (132, 139))	('patient', 'Species', '9606', (103, 110))	('patient', 'Species', '9606', (169, 176))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (225, 241))	('Ewing sarcoma family of tumors', 'Disease', (183, 213))
590965	31847387	Ectopic HLA-G expression on Ewing sarcoma suppressed the activity of GD2-specific CAR-expressing NK cells.	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('GD2-specific', 'Protein', (69, 81))	('Ewing sarcoma', 'Disease', (28, 41))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (28, 41))	('suppressed', 'NegReg', (42, 52))	('Ectopic', 'Var', (0, 7))	('activity', 'MPA', (57, 65))	('HLA-G', 'Gene', (8, 13))	('HLA-G', 'Gene', '3135', (8, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (28, 41))
590977	31847387	The authors were able to demonstrate a decrease in tumor growth in vivo, and upon depletion of CD4+ and CD8+ T cells, a lack of tumor cell response, indicating the necessity of a T cell response for anti-tumor effects.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('decrease', 'NegReg', (39, 47))	('depletion', 'Var', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CD8', 'Gene', (104, 107))	('tumor', 'Disease', (204, 209))	('CD4', 'Gene', (95, 98))	('tumor', 'Disease', (128, 133))	('CD8', 'Gene', '925', (104, 107))	('CD4', 'Gene', '920', (95, 98))	('lack', 'NegReg', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
591013	29173170	In 2016, investigators at the MD Anderson Cancer Center in Texas, the University of California in San Francisco and the University of Pennsylvania in collaboration with the Parker Institute for Cancer Immunotherapy announced plans to proceed with a CRISPR gene editing trial using autologous T cells entitled "Phase I Trial of Autologous T Cells Engineered to Express NY-ESO-1 TCR and Gene Edited to Eliminate Endogenous TCR and PD-1".	('Gene Edited', 'Var', (385, 396))	('Cancer', 'Disease', 'MESH:D009369', (194, 200))	('Endogenous', 'MPA', (410, 420))	('Eliminate', 'NegReg', (400, 409))	('NY-ESO-1', 'Gene', '246100', (368, 376))	('TCR', 'Gene', (421, 424))	('PD-1"', 'Gene', (429, 434))	('NY-ESO-1', 'Gene', (368, 376))	('PD-1"', 'Gene', '5133', (429, 434))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('Cancer', 'Disease', (42, 48))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Cancer', 'Disease', (194, 200))
591025	29173170	The rationale for gene editing TCR alpha and TCR beta is to: (1) reduce TCR mispairing with NY-ESO-1 TCR and the possible formation of neo-reactivity [see, e.g., 8, 9]; (2) reduce the possibility of autoimmunity; as well as (3) promote the expression of exogenous NY-ESO-1 TCR.	('neo-reactivity', 'MPA', (135, 149))	('reduce', 'NegReg', (173, 179))	('NY-ESO-1', 'Gene', '246100', (264, 272))	('TCR mispairing', 'MPA', (72, 86))	('autoimmunity', 'Disease', 'MESH:D001327', (199, 211))	('NY-ESO-1', 'Gene', (264, 272))	('autoimmunity', 'Phenotype', 'HP:0002960', (199, 211))	('expression', 'MPA', (240, 250))	('NY-ESO-1', 'Gene', '246100', (92, 100))	('reduce', 'NegReg', (65, 71))	('NY-ESO-1', 'Gene', (92, 100))	('autoimmunity', 'Disease', (199, 211))	('pa', 'Chemical', 'MESH:D011478', (79, 81))	('TCR beta', 'Gene', (45, 53))	('gene editing', 'Var', (18, 30))	('TCR beta', 'Gene', '6962', (45, 53))	('promote', 'PosReg', (228, 235))
591026	29173170	It is hypothesized that gene editing PD-1 will prevent exhaustion and therefore maintain T cell activity in the presence of the checkpoint ligands, PD-L1 and PD-L2, including those expressed by tumor cells or with cells within the tumor micro-environment [see, e.g.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('maintain', 'Reg', (80, 88))	('exhaustion', 'MPA', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('prevent', 'NegReg', (47, 54))	('T cell activity', 'MPA', (89, 104))	('PD-L1', 'Gene', '29126', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (231, 236))	('men', 'Species', '9606', (250, 253))	('tumor', 'Disease', (194, 199))	('PD-L2', 'Gene', (158, 163))	('PD-L2', 'Gene', '80380', (158, 163))	('PD-1', 'Gene', (37, 41))	('gene editing', 'Var', (24, 36))	('PD-L1', 'Gene', (148, 153))
591089	29173170	The investigators should also have tested the efficacy of lentiviral transduction and gene editing in T cells from individuals with cancer, including patients with melanoma, synovial sarcoma, or multiple myeloma, and thereafter used the same T cells in pre-clinical animal studies to determine the two study endpoints of (1) tumor size and (2) percent survival.	('lentiviral', 'Var', (58, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('patients', 'Species', '9606', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('multiple myeloma', 'Phenotype', 'HP:0006775', (195, 211))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('synovial sarcoma', 'Disease', (174, 190))	('synovial sarcoma', 'Disease', 'MESH:D013584', (174, 190))	('multiple myeloma', 'Disease', 'MESH:D009101', (195, 211))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (174, 190))	('tested', 'Reg', (35, 41))	('tumor', 'Disease', (325, 330))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('melanoma', 'Disease', (164, 172))	('cancer', 'Disease', (132, 138))	('multiple myeloma', 'Disease', (195, 211))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
591090	29173170	Information about the efficacy of lentiviral transduction and gene editing in cancer patients would have been a prudent step prior to the RAC submission.	('gene editing', 'Var', (62, 74))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lentiviral', 'Var', (34, 44))
591095	29173170	The proposed Phase 1 CRISPR gene editing cancer trial may create as many as 16 populations of autologous NY-ESO-1 Redirected CRISPR Edited T Cells.7 This is because of the possible permutations and combinations resulting from the plan to first introduce a lentiviral vector to express NY-ESO-1 TCR and second to delete the gene loci for the TCR alpha, TCR beta and PD-1.	('NY-ESO-1', 'Gene', '246100', (285, 293))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('NY-ESO-1', 'Gene', (285, 293))	('TCR beta', 'Gene', (352, 360))	('gene editing cancer', 'Disease', (28, 47))	('TCR beta', 'Gene', '6962', (352, 360))	('gene editing cancer', 'Disease', 'MESH:D009369', (28, 47))	('TCR', 'Gene', (294, 297))	('NY-ESO-1', 'Gene', '246100', (105, 113))	('NY-ESO-1', 'Gene', (105, 113))	('delete', 'Var', (312, 318))	('PD-1', 'Gene', (365, 369))	('TCR alpha', 'Gene', (341, 350))
591101	29173170	Firstly, the investigators should have tested the efficacy of lentiviral transduction and gene editing in more than two sources, as well as used T cells from cancer patients (including perhaps prospective research participants) with melanoma, synovial sarcoma, or multiple myeloma.	('lentiviral', 'Var', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('participants', 'Species', '9606', (214, 226))	('synovial sarcoma', 'Disease', (243, 259))	('multiple myeloma', 'Phenotype', 'HP:0006775', (264, 280))	('multiple myeloma', 'Disease', 'MESH:D009101', (264, 280))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('multiple myeloma', 'Disease', (264, 280))	('cancer', 'Disease', (158, 164))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (243, 259))	('patients', 'Species', '9606', (165, 173))	('synovial sarcoma', 'Disease', 'MESH:D013584', (243, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('melanoma', 'Disease', (233, 241))
591163	29173170	The investigators should have tested the efficacy of lentiviral transduction and gene editing in T cells from cancer patients (including perhaps prospective research participants) with melanoma, synovial sarcoma, or multiple myeloma and thereafter used the same T cells in the pre-clinical animal study to determine the two study endpoints of (1) tumor size and (2) percent survival.	('multiple myeloma', 'Disease', (216, 232))	('patients', 'Species', '9606', (117, 125))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (195, 211))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('tested', 'Reg', (30, 36))	('multiple myeloma', 'Phenotype', 'HP:0006775', (216, 232))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('cancer', 'Disease', (110, 116))	('lentiviral', 'Var', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('participants', 'Species', '9606', (166, 178))	('multiple myeloma', 'Disease', 'MESH:D009101', (216, 232))	('tumor', 'Disease', (347, 352))	('synovial sarcoma', 'Disease', (195, 211))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('synovial sarcoma', 'Disease', 'MESH:D013584', (195, 211))
591182	29173170	[Emphasis added] [65: conclusion no.2] Similarly, fourteen months later, the February 2017 report Human Genome Editing: Science, Ethics and Governance authored by the United States National Academy of Science and the United States National Academy of Medicine assuredly concluded:  "... that clinical trials of genome editing in somatic cells for the treatment or prevention of disease or disability should continue, subject to the ethical norms and regulatory frameworks that have been developed for existing somatic gene therapy research and clinical use to treat or prevent disease and disability."	('disability', 'Disease', 'MESH:D009069', (589, 599))	('disability', 'Disease', 'MESH:D009069', (389, 399))	('disability', 'Disease', (589, 599))	('disability', 'Disease', (389, 399))	('genome editing', 'Var', (311, 325))	('Human', 'Species', '9606', (98, 103))	('men', 'Species', '9606', (356, 359))
591310	26563256	Moreover, the results suggested that the association of anthracyclines and ifosfamide is associated with an improved benefit.	('ifosfamide', 'Chemical', 'MESH:D007069', (75, 85))	('association', 'Interaction', (41, 52))	('anthracyclines', 'Var', (56, 70))	('anthracyclines', 'Chemical', 'MESH:D018943', (56, 70))
591362	26563256	However, the superiority of the combination of gemcitabine (1800 mg/m2 at 10 mg/m2/min) with DTIC (500 mg/m2) every 14 days versus DTIC alone has been reported in a randomized phase II trial in terms of median progression-free survival (PFS) and overall survival (OS), with a favourable toxicity profile.	('DT', 'Phenotype', 'HP:0100245', (93, 95))	('gemcitabine', 'Chemical', 'MESH:C056507', (47, 58))	('DTIC', 'Chemical', 'MESH:D003606', (93, 97))	('toxicity', 'Disease', 'MESH:D064420', (287, 295))	('toxicity', 'Disease', (287, 295))	('DTIC', 'Chemical', 'MESH:D003606', (131, 135))	('1800 mg/m2', 'Var', (60, 70))	('overall', 'MPA', (246, 253))	('DT', 'Phenotype', 'HP:0100245', (131, 133))
591385	26563256	Hormonal therapy with megestrol acetate, gonadotropin-releasing hormone (GnRH) analogues and aromatase inhibitors can delay progression for long periods of time in low-grade oestrogen receptor-positive endometrial stromal sarcoma, and it is preferred over chemotherapy as front-line palliative treatment (IV, C).	('low-grade', 'Var', (164, 173))	('gonadotropin-releasing hormone', 'Gene', (41, 71))	('gonadotropin-releasing hormone', 'Gene', '2796', (41, 71))	('endometrial stromal sarcoma', 'Disease', (202, 229))	('GnRH', 'Gene', (73, 77))	('GnRH', 'Gene', '2796', (73, 77))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (202, 229))	('megestrol acetate', 'Chemical', 'MESH:D019290', (22, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
591415	26563256	IMT is associated with rearrangements of the ALK (anaplastic lymphoma kinase) locus on chromosome 2p23.13.	('ALK', 'Gene', '238', (45, 48))	('IMT', 'Disease', (0, 3))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (50, 69))	('anaplastic lymphoma kinase', 'Gene', (50, 76))	('associated', 'Reg', (7, 17))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('ALK', 'Gene', (45, 48))	('rearrangements', 'Var', (23, 37))	('anaplastic lymphoma kinase', 'Gene', '238', (50, 76))
591501	24121178	These atypical MIFS variants occurred in 12 male and 10 female patients ranging in age from 15 to 77 (mean, 41; median, 34) years of age.	('MIFS', 'Gene', (15, 19))	('occurred', 'Reg', (29, 37))	('variants', 'Var', (20, 28))	('patients', 'Species', '9606', (63, 71))
591514	24121178	Anti-CD68 marked mostly small histiocytes, dendritic cells, and a small number of tumor cells in 4 of the 15 tumors tested.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Anti-CD68', 'Var', (0, 9))	('tumor', 'Disease', (82, 87))	('tumors', 'Disease', (109, 115))	('tumor', 'Disease', (109, 114))
591584	24121178	However, in our experience, positivity for CD163, which is considered a specific macrophage marker, is usually attributable to infiltrating reactive histiocytes and not to neoplastic fibroblasts.	('positivity', 'Var', (28, 38))	('CD163', 'Gene', (43, 48))	('CD163', 'Gene', '9332', (43, 48))
591597	24121178	Our study also emphasizes the fact that MIFS is capable of exhibiting a wide breadth of morphologies ranging from tumors with focal hypercellularity, sarcoma-like vascularity, or increased or atypical mitotic activity simulating more aggressive sarcomas to lesions mimicking an inflammatory process because of an extreme paucity or frank absence of hallmark lesional cells.	('simulating', 'Reg', (218, 228))	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('sarcoma', 'Disease', 'MESH:D012509', (245, 252))	('wide breadth', 'Phenotype', 'HP:0003981', (72, 84))	('aggressive sarcomas', 'Disease', (234, 253))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('atypical', 'Var', (192, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (245, 253))	('sarcoma', 'Disease', (150, 157))	('sarcoma', 'Disease', (245, 252))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('aggressive sarcomas', 'Disease', 'MESH:D012509', (234, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (245, 252))
591613	32792357	Of these tumors, 85%-90% harbor a mutation in the genes encoding the tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or platelet-derived growth factor receptor alpha, rendering these tumors highly sensitive to the targeted drug imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (248, 256))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('KIT', 'Gene', (93, 96))	('sensitive to the targeted drug imatinib', 'MPA', (217, 256))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutation', 'Var', (34, 42))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('CD117', 'Gene', (98, 103))	('cluster of differentiation 117) or platelet-derived growth factor receptor alpha', 'Gene', '5156', (105, 185))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('KIT', 'Gene', '3815', (93, 96))
591644	32792357	For these panels, the following monoclonal antibody (mAb) conjugates were used: CD3-Pacific Blue (clone UCHT1; BD Biosciences, San Jose, California, USA), CD4-BV785 (clone RPA-T4; Sony Biotechnology, San Jose, California, USA), CD8-BV605 (clone SK1, BD Biosciences), CD14-PerCP (clone MphiP9, BD Biosciences), CD272-APC (BTLA, clone MIH26, Sony Biotechnology), CD223-PE-Cy7 (LAG3, clone 3DS223H; eBioscience, San Diego, California, USA), CD279-APC-Cy7 (PD1, clone EH122H7; Biolegend, San Diego, California, USA), CD366-FITC (TIM3, clone F38-2E2, eBioscience), CCR7-PE (clone 150503, R&D Systems, Germany) and CD45RA-BV510 (clone HI100, BD Biosciences).	('CD366', 'Gene', (513, 518))	('SK1', 'Gene', (245, 248))	('BTLA', 'Gene', (321, 325))	('CD4', 'Gene', (609, 612))	('CD4', 'Gene', '920', (155, 158))	('CD223', 'Gene', '3902', (361, 366))	('CD279', 'Gene', (438, 443))	('CD366', 'Gene', '84868', (513, 518))	('CD8', 'Gene', '925', (228, 231))	('SK1', 'Gene', '8877', (245, 248))	('CD14', 'Gene', (267, 271))	('CCR7', 'Gene', (560, 564))	('CD14', 'Gene', '929', (267, 271))	('CD4', 'Gene', (155, 158))	('CD45', 'Gene', '5788', (609, 613))	('CCR7', 'Gene', '1236', (560, 564))	('TIM3', 'Gene', (525, 529))	('TIM3', 'Gene', '84868', (525, 529))	('CD8', 'Gene', (228, 231))	('CD45', 'Gene', (609, 613))	('BTLA', 'Gene', '151888', (321, 325))	('CD4', 'Gene', '920', (609, 612))	('clone 150503', 'Var', (569, 581))	('CD279', 'Gene', '5133', (438, 443))	('CD223', 'Gene', (361, 366))
591670	32792357	With respect to T-cell differentiation, we observed that leiomyosarcoma, myxofibrosarcoma and pleomorphic sarcoma showed the highest fractions of TEM and CD45RA+effector memory (TEMRA) cells (figure 2A).	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('leiomyosarcoma', 'Disease', (57, 71))	('CD45', 'Gene', '5788', (154, 158))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (57, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (57, 71))	('myxofibrosarcoma and pleomorphic sarcoma', 'Disease', 'MESH:D012509', (73, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('CD45', 'Gene', (154, 158))	('TEM', 'Var', (146, 149))	('TEMRA', 'Chemical', '-', (178, 183))
591723	32792357	The mutational load of tumors, often considered a surrogate marker for neoantigens, has been associated with better responses to immune checkpoint therapy and adoptive T-cell therapy with TIL.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('mutational load', 'Var', (4, 19))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('better', 'PosReg', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
591771	31543075	Activation markers, plasma cell markers, and associated markers that do not define the lineage are positive, such as human leukocyte antigen (HLA)-DR, CD30, CD38, and VS38c, a monoclonal antibody that recognizes a rough endoplasmic reticulum (rER) intracellular antigen termed "cytoskeleton-linking membrane protein 63."	('human', 'Species', '9606', (117, 122))	('VS38c', 'Var', (167, 172))	('CD38', 'Gene', '952', (157, 161))	('CD30', 'Gene', '943', (151, 155))	('CD30', 'Gene', (151, 155))	('CD38', 'Gene', (157, 161))
591830	31507324	Clonal T-cell receptor rearrangement eventually determined the cell of origin from ETPs, not myeloblasts.	('ETPs', 'Disease', (83, 87))	('Clonal T-cell receptor rearrangement', 'Phenotype', 'HP:0031430', (0, 36))	('T-cell receptor', 'Gene', (7, 22))	('ETP', 'Chemical', '-', (83, 86))	('rearrangement', 'Var', (23, 36))	('T-cell receptor', 'Gene', '6962', (7, 22))
591838	31507324	The diagnosis of ETP-ALL is mainly based on a set of unique immunophenotypes: expresses CD7, cytoplasmic CD3 (cCD3), and one or more of the myeloid/stem cell markers CD34, CD117, HLA-DR, CD33, CD13, CD11b, and CD65, but lacks CD8, CD1a, and MPO.	('CD34', 'Gene', '947', (166, 170))	('CD8', 'Gene', (226, 229))	('MPO', 'Gene', '4353', (241, 244))	('CD7', 'Gene', (88, 91))	('CD1a', 'Gene', '909', (231, 235))	('MPO', 'Gene', (241, 244))	('CD11b', 'Gene', (199, 204))	('CD11b', 'Gene', '3684', (199, 204))	('CD65', 'Var', (210, 214))	('ETP', 'Chemical', '-', (17, 20))	('CD34', 'Gene', (166, 170))	('CD13', 'Gene', (193, 197))	('CD117', 'Gene', '3815', (172, 177))	('CD1a', 'Gene', (231, 235))	('CD33', 'Gene', '945', (187, 191))	('CD33', 'Gene', (187, 191))	('CD8', 'Gene', '925', (226, 229))	('CD117', 'Gene', (172, 177))	('CD13', 'Gene', '290', (193, 197))	('CD7', 'Gene', '924', (88, 91))
591847	31507324	A CT-guided mediastinal biopsy in combination with immunohistochemistry showed that T-cell, stem cell, and myeloid-lineage antigens were present in the neoplasm tissues: LCA+, TdT+, CD7+, CD34+, Ki-67 (80%), MPO+, CD33+, CD8-, CD1a-, CD117-, CD15-, cCD3-, CD2-, CD10-, CD19-, PAX5-, CK-, S-100- (Figure 1).	('CD19', 'Gene', '930', (269, 273))	('CK-', 'Var', (283, 286))	('CD34', 'Gene', '947', (188, 192))	('TdT', 'Gene', (176, 179))	('neoplasm', 'Disease', 'MESH:D009369', (152, 160))	('CD1a', 'Gene', (227, 231))	('CD7', 'Gene', (182, 185))	('CD8', 'Gene', '925', (221, 224))	('CD15', 'Gene', '2526', (242, 246))	('neoplasm', 'Disease', (152, 160))	('CD33', 'Gene', '945', (214, 218))	('CD33', 'Gene', (214, 218))	('CD2', 'Gene', (256, 259))	('PAX5', 'Gene', (276, 280))	('CD2', 'Gene', '914', (256, 259))	('MPO', 'Gene', '4353', (208, 211))	('CD117', 'Gene', '3815', (234, 239))	('CD10', 'Gene', '4311', (262, 266))	('CD34', 'Gene', (188, 192))	('neoplasm', 'Phenotype', 'HP:0002664', (152, 160))	('MPO', 'Gene', (208, 211))	('TdT', 'Gene', '1791', (176, 179))	('PAX5', 'Gene', '5079', (276, 280))	('CD8', 'Gene', (221, 224))	('CD19', 'Gene', (269, 273))	('CD10', 'Gene', (262, 266))	('CD117', 'Gene', (234, 239))	('CD15', 'Gene', (242, 246))	('LCA', 'Gene', (170, 173))	('CD1a', 'Gene', '909', (227, 231))	('LCA', 'Gene', '5788', (170, 173))	('CD7', 'Gene', '924', (182, 185))
591895	26990975	Loss of H3K27 tri-methylation is a diagnostic marker for Malignant Peripheral Nerve Sheath Tumors and an indicator for an inferior survival Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that can show overlapping features with benign neurofibromas as well as high-grade sarcomas.	('Malignant Peripheral Nerve Sheath Tumors', 'Disease', 'MESH:D018319', (57, 97))	('sarcomas', 'Disease', 'MESH:D012509', (205, 213))	('H3K27', 'Protein', (8, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (205, 213))	('neurofibromas', 'Phenotype', 'HP:0001067', (261, 274))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('sarcomas', 'Disease', (205, 213))	('neurofibroma', 'Phenotype', 'HP:0001067', (261, 273))	('benign neurofibromas', 'Disease', (254, 274))	('Malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (140, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('benign neurofibromas', 'Disease', 'MESH:D009455', (254, 274))	('Malignant Peripheral Nerve Sheath Tumor', 'Phenotype', 'HP:0100697', (57, 96))	('Malignant Peripheral Nerve Sheath Tumors', 'Disease', (57, 97))	('tri-methylation', 'Var', (14, 29))	('Tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Malignant peripheral nerve sheath tumors', 'Disease', (140, 180))	('sarcomas', 'Disease', 'MESH:D012509', (297, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (297, 304))	('Malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (140, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (297, 305))	('Malignant Peripheral Nerve Sheath Tumors', 'Phenotype', 'HP:0100697', (57, 97))	('Tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Loss', 'Var', (0, 4))	('sarcomas', 'Disease', (297, 305))	('aggressive sarcomas', 'Disease', 'MESH:D012509', (194, 213))	('aggressive sarcomas', 'Disease', (194, 213))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
591896	26990975	Recently mutations in two critical components of the polycomb repressor 2 (PRC2) complex, SUZ12 and EED, were reported to occur specifically in MPNSTs while such mutations are absent in neurofibromas, both in the setting of neurofibromatosis (NF) and sporadic cases.	('occur', 'Reg', (122, 127))	('neurofibroma', 'Phenotype', 'HP:0001067', (224, 236))	('neurofibromas', 'Disease', 'MESH:D009455', (186, 199))	('MPNSTs', 'Disease', (144, 150))	('mutations', 'Var', (9, 18))	('EED', 'Gene', '8726', (100, 103))	('NF', 'Gene', '4763', (243, 245))	('SUZ12', 'Gene', '23512', (90, 95))	('neurofibroma', 'Phenotype', 'HP:0001067', (186, 198))	('neurofibromatosis', 'Gene', '4763', (224, 241))	('SUZ12', 'Gene', (90, 95))	('EED', 'Gene', (100, 103))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (224, 241))	('neurofibromatosis', 'Gene', (224, 241))	('neurofibromas', 'Phenotype', 'HP:0001067', (186, 199))	('PRC2', 'Gene', (75, 79))	('neurofibromas', 'Disease', (186, 199))
591902	26990975	Only 1 out of 44 schwannomas showed loss of H3K27me3 and all 4 perineuriomas showed intact H3K27me3.	('perineuriomas', 'Disease', 'MESH:D010524', (63, 76))	('schwannomas', 'Disease', 'MESH:D009442', (17, 28))	('H3K27me3', 'Var', (91, 99))	('perineuriomas', 'Disease', (63, 76))	('loss', 'NegReg', (36, 40))	('schwannomas', 'Phenotype', 'HP:0100008', (17, 28))	('schwannomas', 'Disease', (17, 28))	('schwannoma', 'Phenotype', 'HP:0100008', (17, 27))	('H3K27me3', 'Protein', (44, 52))
591903	26990975	Our results indicate that H3K27me3 immunohistochemistry is useful as a diagnostic marker in which loss of H3K27me3 favours MPNST above neurofibroma.	('H3K27me3', 'Protein', (106, 114))	('neurofibroma', 'Disease', (135, 147))	('neurofibroma', 'Phenotype', 'HP:0001067', (135, 147))	('MPNST', 'Disease', (123, 128))	('neurofibroma', 'Disease', 'MESH:D009455', (135, 147))	('loss', 'Var', (98, 102))	('favours', 'PosReg', (115, 122))
591905	26990975	Since loss of H3K27 tri-methylation was related to poorer survival in MPNST, chromatin modification mediated by this specific histone seems to orchestrate more aggressive tumour biology.	('loss', 'NegReg', (6, 10))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('aggressive tumour', 'Disease', 'MESH:D001523', (160, 177))	('poorer', 'NegReg', (51, 57))	('aggressive tumour', 'Disease', (160, 177))	('MPNST', 'Disease', (70, 75))	('tri-methylation', 'Var', (20, 35))	('H3K27', 'Protein', (14, 19))	('survival', 'MPA', (58, 66))
591914	26990975	Also within sporadic and radiotherapy-associated malignant peripheral nerve sheath tumors, 87.5 % showed a nonsense mutation or homozygous deletion in NF1.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (49, 89))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (49, 88))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('NF1', 'Gene', (151, 154))	('malignant peripheral nerve sheath tumors', 'Disease', (49, 89))	('NF1', 'Gene', '4763', (151, 154))	('nonsense mutation', 'Var', (107, 124))	('homozygous deletion', 'Var', (128, 147))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (49, 89))
591915	26990975	An additional third hit was proposed that could explain progression of neurofibromas towards malignant peripheral nerve sheath tumor, namely loss-of-function mutations in EED and SUZ12, both components of Polycomb Repressive Complex 2 (PRC2).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('neurofibromas', 'Disease', (71, 84))	('EED', 'Gene', '8726', (171, 174))	('SUZ12', 'Gene', (179, 184))	('EED', 'Gene', (171, 174))	('neurofibromas', 'Disease', 'MESH:D009455', (71, 84))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (93, 132))	('neurofibromas', 'Phenotype', 'HP:0001067', (71, 84))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (93, 132))	('malignant peripheral nerve sheath tumor', 'Disease', (93, 132))	('loss-of-function', 'NegReg', (141, 157))	('neurofibroma', 'Phenotype', 'HP:0001067', (71, 83))	('mutations', 'Var', (158, 167))	('SUZ12', 'Gene', '23512', (179, 184))
591916	26990975	Mutations in EED or SUZ12 were mutually exclusive and detected in 36-92% of sporadic, 23-70% of NF1-associated and 90% of radiotherapy-associated malignant peripheral nerve sheath tumors.	('EED', 'Gene', '8726', (13, 16))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (146, 186))	('SUZ12', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (146, 186))	('EED', 'Gene', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('detected', 'Reg', (54, 62))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (146, 185))	('Mutations', 'Var', (0, 9))	('malignant peripheral nerve sheath tumors', 'Disease', (146, 186))	('NF1', 'Gene', (96, 99))	('SUZ12', 'Gene', '23512', (20, 25))	('NF1', 'Gene', '4763', (96, 99))
591919	26990975	Both are chromatin-modifying proteins, which together with EZH1 and EZH2, establish and maintain the di- and trimethylation of lysine 27 of histone H3 (H3K27me2 and H3K27me3).	('EZH2', 'Gene', (68, 72))	('di-', 'MPA', (101, 104))	('trimethylation', 'MPA', (109, 123))	('EZH1', 'Gene', (59, 63))	('EZH1', 'Gene', '2145', (59, 63))	('H3K27me3', 'Var', (165, 173))	('EZH2', 'Gene', '2146', (68, 72))	('lysine', 'Chemical', 'MESH:D008239', (127, 133))
591920	26990975	Using immunohistochemistry, it was shown in a series of 62 malignant peripheral nerve sheath tumors, that malignant peripheral nerve sheath tumors with PRC2 loss, caused by mutations in SUZ12 or EED, showed complete loss of H3K27me3.	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (106, 146))	('caused by', 'Reg', (163, 172))	('EED', 'Gene', (195, 198))	('malignant peripheral nerve sheath tumors', 'Disease', (59, 99))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (106, 146))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (106, 145))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (59, 98))	('malignant peripheral nerve sheath tumors', 'Disease', (106, 146))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('loss', 'NegReg', (216, 220))	('SUZ12', 'Gene', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('EED', 'Gene', '8726', (195, 198))	('SUZ12', 'Gene', '23512', (186, 191))	('H3K27me3', 'Protein', (224, 232))	('mutations', 'Var', (173, 182))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (59, 99))	('PRC2', 'Gene', (152, 156))	('loss', 'NegReg', (157, 161))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (59, 99))
591922	26990975	The aim of our study was to investigate whether H3K27 tri-methylation is useful as a diagnostic and /or prognostic marker for malignant peripheral nerve sheath tumors.	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (126, 166))	('malignant peripheral nerve sheath tumors', 'Disease', (126, 166))	('tri-methylation', 'Var', (54, 69))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (126, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (126, 165))	('H3K27', 'Protein', (48, 53))
591938	26990975	The Cox-regression model included H3K27me3, age, sex, sporadic/NF associated disease and metastasis at diagnosis.	('NF', 'Gene', '4763', (63, 65))	('Cox', 'Gene', (4, 7))	('H3K27me3', 'Var', (34, 42))	('Cox', 'Gene', '1351', (4, 7))
591940	26990975	These cases were considered as malignant peripheral nerve sheath tumors with loss of H3K27 tri-methylation.	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (31, 71))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (31, 70))	('malignant peripheral nerve sheath tumors', 'Disease', (31, 71))	('tri-methylation', 'Var', (91, 106))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('loss', 'NegReg', (77, 81))	('H3K27', 'Protein', (85, 90))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (31, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
591942	26990975	We did not see any significant difference in frequency of loss of H3K27 tri-methylation between sporadic and neurofibromatosis-associated malignant peripheral nerve sheath tumors (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('neurofibromatosis', 'Gene', '4763', (109, 126))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (138, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tri-methylation', 'Var', (72, 87))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (138, 177))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (138, 178))	('neurofibromatosis', 'Gene', (109, 126))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (109, 126))	('neurofibroma', 'Phenotype', 'HP:0001067', (109, 121))	('malignant peripheral nerve sheath tumors', 'Disease', (138, 178))	('H3K27', 'Protein', (66, 71))
591952	26990975	Other high grade sarcomas that are difficult to distinguish from malignant peripheral nerve sheath tumor solely based on morphology, such as sarcoma not otherwise specified or undifferentiated pleomorphic (or spindle cell) sarcoma, demonstrated loss of H3K27 tri-methylation in a very low frequency (0% (0/26), and 2,8 % (5/177), respectively (Table 2)).	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcoma', 'Disease', (223, 230))	('sarcoma', 'Disease', (141, 148))	('H3K27', 'Protein', (253, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('malignant peripheral nerve sheath tumor', 'Disease', (65, 104))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (65, 104))	('sarcoma', 'Disease', 'MESH:D012509', (17, 24))	('tri-methylation', 'Var', (259, 274))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('sarcomas', 'Disease', 'MESH:D012509', (17, 25))	('sarcoma', 'Disease', (17, 24))	('sarcomas', 'Phenotype', 'HP:0100242', (17, 25))	('sarcomas', 'Disease', (17, 25))	('loss', 'NegReg', (245, 249))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (65, 104))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))	('sarcoma', 'Disease', 'MESH:D012509', (223, 230))
591953	26990975	Furthermore, loss of H3K27 tri-methylation was observed in small subsets of angiosarcomas (10% (2/21)), clear cell sarcomas (40% (2/5)), melanoma (11% (1/9)), osteosarcoma (50% (1/2)) and schwannoma (2% (1/44)).	('schwannoma', 'Disease', (188, 198))	('osteosarcoma', 'Phenotype', 'HP:0002669', (159, 171))	('angiosarcomas', 'Disease', (76, 89))	('angiosarcoma', 'Phenotype', 'HP:0200058', (76, 88))	('schwannoma', 'Disease', 'MESH:D009442', (188, 198))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('clear cell sarcomas', 'Disease', 'MESH:D018227', (104, 123))	('H3K27', 'Protein', (21, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('osteosarcoma', 'Disease', (159, 171))	('sarcomas', 'Phenotype', 'HP:0100242', (115, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (159, 171))	('angiosarcomas', 'Phenotype', 'HP:0200058', (76, 89))	('clear cell sarcomas', 'Disease', (104, 123))	('angiosarcomas', 'Disease', 'MESH:D006394', (76, 89))	('tri-methylation', 'Var', (27, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('schwannoma', 'Phenotype', 'HP:0100008', (188, 198))	('melanoma', 'Disease', (137, 145))	('loss', 'NegReg', (13, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
591954	26990975	Intact H3K27 tri-methylation was detected in myxofibrosarcoma (n=17), pleomorphic liposarcoma (n=5), rhabdomyosarcoma (n=2), dedifferentiated liposarcoma (n=1), leiomyosarcoma (n=5) and perineurioma (n=4) (Table 2).	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (101, 117))	('liposarcoma', 'Phenotype', 'HP:0012034', (142, 153))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (101, 117))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (70, 93))	('H3K27', 'Protein', (7, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('liposarcoma', 'Disease', 'MESH:D008080', (142, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('liposarcoma', 'Disease', (82, 93))	('myxofibrosarcoma', 'Disease', 'None', (45, 61))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (161, 175))	('tri-methylation', 'Var', (13, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (161, 175))	('detected', 'Reg', (33, 41))	('liposarcoma', 'Phenotype', 'HP:0012034', (82, 93))	('liposarcoma', 'Disease', (142, 153))	('perineurioma', 'Disease', 'MESH:D010524', (186, 198))	('perineurioma', 'Disease', (186, 198))	('rhabdomyosarcoma', 'Disease', (101, 117))	('pleomorphic liposarcoma', 'Disease', (70, 93))	('myxofibrosarcoma', 'Disease', (45, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('leiomyosarcoma', 'Disease', (161, 175))	('liposarcoma', 'Disease', 'MESH:D008080', (82, 93))
591955	26990975	Loss of H3K27 tri-methylation was an independent prognostic factor for a poor survival compared to intact H3K27me3 among malignant peripheral nerve sheath tumor patients of Cohort 1 MDACC (n=62) (Fig.	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (121, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('H3K27', 'Protein', (8, 13))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (121, 160))	('malignant peripheral nerve sheath tumor', 'Disease', (121, 160))	('Loss', 'NegReg', (0, 4))	('patients', 'Species', '9606', (161, 169))	('tri-methylation', 'Var', (14, 29))
591957	26990975	In a second cohort of malignant peripheral nerve sheath tumors of Cohort 3 LUMC (n=16) with available follow-up data, cases with loss of H3K27 tri-methylation showed a higher frequency of disease specific mortality compared to cases with intact H3K27, respectively 75% (3/4) and 50% (6/12).	('H3K27', 'Gene', (137, 142))	('malignant peripheral nerve sheath tumors', 'Disease', (22, 62))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (22, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('loss', 'Var', (129, 133))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (22, 61))	('higher', 'PosReg', (168, 174))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (22, 62))	('tri-methylation', 'Var', (143, 158))	('disease specific mortality', 'CPA', (188, 214))
591959	26990975	We show here, in a multicentre study, that loss of H3K27 tri-methylation can be used as a diagnostic and prognostic marker for malignant peripheral nerve sheath tumors.	('H3K27', 'Protein', (51, 56))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (127, 166))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tri-methylation', 'Var', (57, 72))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (127, 167))	('malignant peripheral nerve sheath tumors', 'Disease', (127, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('loss', 'Var', (43, 47))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (127, 167))
591960	26990975	Loss of H3K27 tri-methylation was found in 34% of malignant peripheral nerve sheath tumors compared to intact H3K27 tri-methylation in all neurofibromas, including morphological variants like atypical and plexiform neurofibromas, indicating that loss of H3K27 tri-methylation is highly specific for malignant peripheral nerve sheath tumors in the differential diagnosis with neurofibroma.	('neurofibromas', 'Disease', (139, 152))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (299, 338))	('neurofibromas', 'Phenotype', 'HP:0001067', (215, 228))	('neurofibroma', 'Phenotype', 'HP:0001067', (375, 387))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (50, 90))	('neurofibromas', 'Disease', 'MESH:D009455', (215, 228))	('neurofibroma', 'Phenotype', 'HP:0001067', (215, 227))	('neurofibroma', 'Disease', 'MESH:D009455', (375, 387))	('neurofibroma', 'Disease', 'MESH:D009455', (215, 227))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('loss', 'Var', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('malignant peripheral nerve sheath tumors', 'Disease', (50, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Loss', 'NegReg', (0, 4))	('H3K27', 'Gene', (8, 13))	('plexiform neurofibroma', 'Phenotype', 'HP:0009732', (205, 227))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (50, 89))	('neurofibroma', 'Disease', (139, 151))	('neurofibromas', 'Phenotype', 'HP:0001067', (139, 152))	('neurofibromas', 'Disease', 'MESH:D009455', (139, 152))	('neurofibromas', 'Disease', (215, 228))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (299, 339))	('neurofibroma', 'Disease', (375, 387))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (205, 228))	('neurofibroma', 'Disease', (215, 227))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (299, 339))	('neurofibroma', 'Phenotype', 'HP:0001067', (139, 151))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (50, 90))	('neurofibroma', 'Disease', 'MESH:D009455', (139, 151))	('malignant peripheral nerve sheath tumors', 'Disease', (299, 339))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))
591964	26990975	Although the specificity of loss of H3K27 tri-methylation for malignant peripheral nerve sheath tumors is high, the prevalence H3K27 tri-methylation loss ranged from 20% up to as high as 93%.	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (62, 101))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (62, 102))	('H3K27', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss', 'NegReg', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('malignant peripheral nerve sheath tumors', 'Disease', (62, 102))	('H3K27', 'Protein', (36, 41))	('tri-methylation', 'Var', (42, 57))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (62, 102))	('loss', 'NegReg', (28, 32))
591973	26990975	In contrast, staining for H3K27me3 seems to be a more promising and easy to use diagnostic tool, in which loss of H3K27me3 favours progression to malignant peripheral nerve sheath tumors above plexiform or atypical neurofibroma.	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (146, 186))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (146, 186))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (146, 185))	('neurofibroma', 'Phenotype', 'HP:0001067', (215, 227))	('atypical neurofibroma', 'Phenotype', 'HP:0007524', (206, 227))	('H3K27me3', 'Protein', (114, 122))	('neurofibroma', 'Disease', (215, 227))	('malignant peripheral nerve sheath tumors', 'Disease', (146, 186))	('neurofibroma', 'Disease', 'MESH:D009455', (215, 227))	('loss', 'Var', (106, 110))	('progression', 'PosReg', (131, 142))
591978	26990975	In line with this, according to our study, loss of H3K27 tri-methylation is a negligible finding in undifferentiated sarcomas that could mimic malignant peripheral nerve sheath tumors.	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (143, 182))	('H3K27', 'Protein', (51, 56))	('undifferentiated sarcomas', 'Disease', (100, 125))	('tri-methylation', 'Var', (57, 72))	('malignant peripheral nerve sheath tumors', 'Disease', (143, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('loss', 'NegReg', (43, 47))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (143, 183))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (143, 183))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (100, 125))
591979	26990975	Therefore, in the difficult differential diagnosis of high grade spindle cell lesions, loss of H3K27me3 is strongly indicative of malignant peripheral nerve sheath tumor and does not favor a cellular schwannoma or, undifferentiated sarcoma, or melanoma.	('H3K27me3', 'Protein', (95, 103))	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (130, 169))	('loss', 'Var', (87, 91))	('malignant peripheral nerve sheath tumor', 'Disease', (130, 169))	('schwannoma', 'Phenotype', 'HP:0100008', (200, 210))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (232, 239))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (215, 239))	('schwannoma', 'Disease', (200, 210))	('undifferentiated sarcoma', 'Disease', (215, 239))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (130, 169))	('schwannoma', 'Disease', 'MESH:D009442', (200, 210))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))
591984	26990975	Indeed, Garcia et al have shown H3K27me3 to be the dominant epigenetic marker associated with SYT-SSX2 binding and gene expression, which may explain the loss of H3K27 tri-methylation which we found in 60% of synovial sarcomas.	('SYT', 'Gene', (94, 97))	('H3K27me3', 'Var', (32, 40))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (209, 226))	('SSX2', 'Gene', '6757', (98, 102))	('SYT', 'Gene', '6760', (94, 97))	('synovial sarcomas', 'Disease', 'MESH:D013584', (209, 226))	('SSX2', 'Gene', (98, 102))	('synovial sarcomas', 'Disease', (209, 226))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (209, 225))	('sarcomas', 'Phenotype', 'HP:0100242', (218, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))
591985	26990975	In contrast to malignant peripheral nerve sheath tumors, mutations in SUZ12, EED, EZH1 and EZH2 are not described in synovial sarcomas and therefore could not explain the observed loss of H3K27 tri-methylation.	('EZH2', 'Gene', (91, 95))	('EZH2', 'Gene', '2146', (91, 95))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('SUZ12', 'Gene', (70, 75))	('mutations', 'Var', (57, 66))	('EED', 'Gene', '8726', (77, 80))	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('SUZ12', 'Gene', '23512', (70, 75))	('H3K27', 'Protein', (188, 193))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (15, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (15, 55))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (15, 54))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (117, 134))	('synovial sarcomas', 'Disease', (117, 134))	('EZH1', 'Gene', (82, 86))	('EED', 'Gene', (77, 80))	('malignant peripheral nerve sheath tumors', 'Disease', (15, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('EZH1', 'Gene', '2145', (82, 86))	('synovial sarcomas', 'Disease', 'MESH:D013584', (117, 134))
591989	26990975	In the study by Lee et al and Zhang et al, it was shown that loss of H3K27 tri-methylation was caused by mutations in SUZ12 or EED.	('EED', 'Gene', '8726', (127, 130))	('EED', 'Gene', (127, 130))	('tri-methylation', 'MPA', (75, 90))	('SUZ12', 'Gene', '23512', (118, 123))	('mutations', 'Var', (105, 114))	('loss', 'NegReg', (61, 65))	('SUZ12', 'Gene', (118, 123))	('H3K27', 'Protein', (69, 74))
591990	26990975	These two genes establish and maintain the di- and trimethylation of lysine 27 of histone H3 (H3K27me2 and H3K27me3) and methylation of this position results in transcriptional repression of target genes.	('lysine', 'Chemical', 'MESH:D008239', (69, 75))	('H3K27me2', 'Var', (94, 102))	('di-', 'MPA', (43, 46))	('methylation', 'Var', (121, 132))	('trimethylation', 'MPA', (51, 65))	('transcriptional', 'MPA', (161, 176))	('H3K27me3', 'Var', (107, 115))
591992	26990975	Since genes such as IGF2 play an important role in the growth and development of cells and have been implicated in oncogenesis and tumor progression, differential upregulation of these genes in malignant peripheral nerve sheath tumors with loss of H3K27 tri-methylation, could explain the observed effect on survival in our study.	('loss', 'NegReg', (240, 244))	('tri-methylation', 'Var', (254, 269))	('upregulation', 'PosReg', (163, 175))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (194, 234))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (194, 233))	('tumor', 'Disease', (131, 136))	('IGF2', 'Gene', '3481', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', (228, 233))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (194, 234))	('H3K27', 'Protein', (248, 253))	('IGF2', 'Gene', (20, 24))	('malignant peripheral nerve sheath tumors', 'Disease', (194, 234))
591993	26990975	Besides using H3K27me3 staining as a diagnostic and prognostic marker, loss of H3K27me3 may predict response to histone deacetylase (HDAC) inhibitors.	('histone deacetylase', 'Gene', (112, 131))	('loss', 'Var', (71, 75))	('H3K27me3', 'Protein', (79, 87))	('predict', 'Reg', (92, 99))	('histone deacetylase', 'Gene', '9734', (112, 131))	('HDAC', 'Gene', (133, 137))	('response', 'MPA', (100, 108))	('HDAC', 'Gene', '9734', (133, 137))
591995	26990975	However, resistance to histone deacetylase inhibitors has also been shown in malignant peripheral nerve sheath tumors and likely mutations in chromatin remodelling genes like SUZ12 or EED and thus H3K27 tri-methylation, play a mechanistic role in level of response to histone deacetylase inhibitors.	('histone deacetylase', 'Gene', '9734', (23, 42))	('SUZ12', 'Gene', '23512', (175, 180))	('EED', 'Gene', (184, 187))	('SUZ12', 'Gene', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutations', 'Var', (129, 138))	('histone deacetylase', 'Gene', (23, 42))	('H3K27', 'Var', (197, 202))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (77, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (77, 117))	('histone deacetylase', 'Gene', '9734', (268, 287))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (77, 116))	('EED', 'Gene', '8726', (184, 187))	('histone deacetylase', 'Gene', (268, 287))	('malignant peripheral nerve sheath tumors', 'Disease', (77, 117))
591996	26990975	In conclusion, our results show that loss of H3K27 favours the diagnosis of malignant peripheral nerve sheath tumor over neurofibroma, undifferentiated pleomorphic (or spindle) sarcoma / sarcoma not otherwise specified and melanoma but is not suitable to distinguish malignant peripheral nerve sheath tumors from its morphological mimickers, namely synovial sarcoma and fibrosarcomatous dermatofibrosarcoma protuberans.	('malignant peripheral nerve sheath tumors', 'Disease', (267, 307))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (76, 115))	('neurofibroma', 'Phenotype', 'HP:0001067', (121, 133))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('sarcoma', 'Phenotype', 'HP:0100242', (358, 365))	('neurofibroma', 'Disease', 'MESH:D009455', (121, 133))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (267, 306))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('melanoma', 'Disease', (223, 231))	('sarcoma', 'Disease', 'MESH:D012509', (187, 194))	('synovial sarcoma', 'Disease', (349, 365))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('sarcoma', 'Disease', (187, 194))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (76, 115))	('loss', 'Var', (37, 41))	('synovial sarcoma', 'Disease', 'MESH:D013584', (349, 365))	('sarcoma', 'Disease', 'MESH:D012509', (375, 382))	('fibrosarcomatous dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (370, 418))	('sarcoma', 'Disease', 'MESH:D012509', (399, 406))	('H3K27', 'Protein', (45, 50))	('sarcoma', 'Disease', (375, 382))	('sarcoma', 'Disease', 'MESH:D012509', (177, 184))	('neurofibroma', 'Disease', (121, 133))	('sarcoma', 'Disease', (399, 406))	('sarcoma', 'Disease', (177, 184))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (349, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (267, 307))	('fibrosarcomatous dermatofibrosarcoma protuberans', 'Disease', (370, 418))	('sarcoma', 'Disease', 'MESH:D012509', (358, 365))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (375, 382))	('sarcoma', 'Disease', (358, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (399, 406))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (267, 306))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (267, 307))	('malignant peripheral nerve sheath tumor', 'Disease', (76, 115))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))
591997	26990975	Since loss of H3K27 tri-methylation was related to poorer survival in malignant peripheral nerve sheath tumor, chromatin modification mediated by this specific histone might explain the more aggressive tumour biology.	('loss', 'NegReg', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (70, 109))	('aggressive tumour', 'Disease', 'MESH:D001523', (191, 208))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('poorer', 'NegReg', (51, 57))	('survival', 'CPA', (58, 66))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (70, 109))	('malignant peripheral nerve sheath tumor', 'Disease', (70, 109))	('aggressive tumour', 'Disease', (191, 208))	('tri-methylation', 'Var', (20, 35))	('H3K27', 'Protein', (14, 19))
592033	26166072	However, information was provided on associations between margins and LR: all 6 patients who had a wide resection remained relapse free, marginal resection was associated with LR in 1 of 6 patients (17%), and IL resection with LR in 3 of 12 patients (25%).	('marginal resection', 'Var', (137, 155))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (189, 197))	('patients', 'Species', '9606', (241, 249))	('associated', 'Reg', (160, 170))
592070	25098767	Next, we determined whether RAD001-induced AKT reactivation was blocked by silencing of c-MET or treatment with a selective c-MET inhibitor, INC280.	('c-MET', 'Gene', (124, 129))	('AKT', 'Gene', '207', (43, 46))	('c-MET', 'Gene', (88, 93))	('RAD001-induced', 'Gene', (28, 42))	('silencing', 'Var', (75, 84))	('c-MET', 'Gene', '4233', (124, 129))	('INC280', 'Chemical', 'MESH:C000613976', (141, 147))	('AKT', 'Gene', (43, 46))	('c-MET', 'Gene', '4233', (88, 93))
592075	25098767	INC280 inhibited phosphorylation of c-MET and its downstream molecules, and decreased RAD001-induced phosphorylation of both AKT and ERK in EpS.	('AKT', 'Gene', '207', (125, 128))	('c-MET', 'Gene', '4233', (36, 41))	('phosphorylation', 'MPA', (17, 32))	('INC280', 'Var', (0, 6))	('AKT', 'Gene', (125, 128))	('decreased', 'NegReg', (76, 85))	('ERK', 'Gene', '5594', (133, 136))	('ERK', 'Gene', (133, 136))	('c-MET', 'Gene', (36, 41))	('INC280', 'Chemical', 'MESH:C000613976', (0, 6))	('inhibited', 'NegReg', (7, 16))	('RAD001-induced', 'Gene', (86, 100))	('phosphorylation', 'MPA', (101, 116))
592083	25098767	Loss of INI-1 serves as a diagnostic feature in malignant rhabdoid tumors (MRTs) and atypical teratoid/rhabdoid tumors (AT/RTs).	('malignant rhabdoid tumors', 'Disease', (48, 73))	('AT', 'Disease', 'None', (120, 122))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (58, 73))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('INI-1', 'Gene', '6598', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('INI-1', 'Gene', (8, 13))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (48, 73))	('Loss', 'Var', (0, 4))	('rhabdoid tumors', 'Disease', (103, 118))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (103, 118))
592090	25098767	In addition, blocking mTOR activity inadvertently reactivates AKT signaling, which mitigates the antitumor effects of mTOR inhibitors, and this reactivation has been posited as a mechanism of intrinsic resistance to mTOR inhibitors.	('AKT', 'Gene', (62, 65))	('blocking', 'Var', (13, 21))	('reactivates', 'Reg', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('mTOR', 'Gene', (118, 122))	('mTOR', 'Gene', '2475', (118, 122))	('mTOR', 'Gene', '2475', (22, 26))	('mTOR', 'Gene', '2475', (216, 220))	('mTOR', 'Gene', (22, 26))	('AKT', 'Gene', '207', (62, 65))	('mTOR', 'Gene', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
592102	25098767	Further, AKT phosphorylation was stronger in VAESBJ cells than in Asra-EPS cells.	('stronger', 'PosReg', (33, 41))	('AKT', 'Gene', '207', (9, 12))	('VAESBJ', 'Var', (45, 51))	('Asra-EPS', 'Chemical', '-', (66, 74))	('AKT', 'Gene', (9, 12))	('VAESBJ', 'Chemical', '-', (45, 51))
592108	25098767	In addition, the silencing of mTOR expression suppressed VAESBJ cell proliferation and decreased the anti-proliferative effect of RAD001 on VAESBJ cells (Additional file 1: Figure S1B, C).	('anti-proliferative', 'MPA', (101, 119))	('decreased', 'NegReg', (87, 96))	('VAESBJ', 'Chemical', '-', (57, 63))	('VAESBJ', 'Chemical', '-', (140, 146))	('mTOR', 'Gene', '2475', (30, 34))	('VAESBJ cell proliferation', 'CPA', (57, 82))	('silencing', 'Var', (17, 26))	('mTOR', 'Gene', (30, 34))	('suppressed', 'NegReg', (46, 56))
592110	25098767	RAD001 exposure increased G0/G1 phase population and decreased S phase population in a dose-dependent manner in both EpS cell lines (Figure 2B), implying that the antitumor mechanism of RAD001 primarily appeared to be exerted by G0/G1 cell cycle arrest.	('RAD001', 'Var', (186, 192))	('G0/G1 phase population', 'CPA', (26, 48))	('RAD001', 'Gene', (0, 6))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (235, 252))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('increased', 'PosReg', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('decreased', 'NegReg', (53, 62))	('S phase population', 'CPA', (63, 81))	('tumor', 'Disease', (167, 172))
592114	25098767	The growth rate of Asra-EPS xenograft tumors was delayed in RAD001-treated mice compared with that in control-treated mice, although RAD001 treatment did not induce tumor shrinkage (Figure 3A, B).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mice', 'Species', '10090', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('growth rate', 'CPA', (4, 15))	('delayed', 'NegReg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Asra-EPS xenograft tumors', 'Disease', 'MESH:D001480', (19, 44))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mice', 'Species', '10090', (118, 122))	('Asra-EPS xenograft tumors', 'Disease', (19, 44))	('RAD001-treated', 'Var', (60, 74))	('tumor', 'Disease', (165, 170))
592118	25098767	These data showing tumor growth delay without shrinkage suggested that RAD001-induced AKT reactivation may decrease the activity of RAD001 and that agents blocking this reactivation could enhance the antitumor effects of RAD001 on the growth of EpS.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('AKT', 'Gene', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('RAD001-induced', 'Var', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('RAD001', 'Gene', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('growth delay', 'Phenotype', 'HP:0001510', (25, 37))	('tumor', 'Disease', (204, 209))	('decrease', 'NegReg', (107, 115))	('tumor', 'Disease', (19, 24))	('growth', 'CPA', (235, 241))	('activity', 'MPA', (120, 128))	('AKT', 'Gene', '207', (86, 89))	('enhance', 'PosReg', (188, 195))
592129	25098767	The silencing of c-MET expression decreased the proliferation and colony formation of EpS cells (Figure 4E, F).	('c-MET', 'Gene', (17, 22))	('decreased', 'NegReg', (34, 43))	('proliferation', 'CPA', (48, 61))	('c-MET', 'Gene', '4233', (17, 22))	('colony formation', 'CPA', (66, 82))	('silencing', 'Var', (4, 13))
592133	25098767	Proliferation of Asra-EPS and VAESBJ cells was suppressed in a dose-dependent manner by INC280 treatment, albeit with continuous proliferation of SYO-1 or HDF cells (Figure 5A).	('suppressed', 'NegReg', (47, 57))	('INC280', 'Chemical', 'MESH:C000613976', (88, 94))	('Asra-EPS', 'Chemical', '-', (17, 25))	('SYO-1', 'Gene', '55027', (146, 151))	('SYO-1', 'Gene', (146, 151))	('treatment', 'Var', (95, 104))	('VAESBJ', 'Chemical', '-', (30, 36))	('INC280', 'Gene', (88, 94))
592135	25098767	Flow cytometry analyses showed that INC280 induced a greater increase in G0/G1 phase population in Asra-EPS cells than in VAESBJ cells (Figure 5B).	('INC280', 'Chemical', 'MESH:C000613976', (36, 42))	('Asra-EPS', 'Chemical', '-', (99, 107))	('VAESBJ', 'Chemical', '-', (122, 128))	('increase', 'PosReg', (61, 69))	('G0/G1 phase population', 'CPA', (73, 95))	('INC280', 'Var', (36, 42))
592136	25098767	Cleavage of caspase-3 was induced after INC280 exposure in a dose-dependent manner in Asra-EPS cells, but its induction was hardly observed in VAESBJ cells (Figure 5C).	('INC280', 'Var', (40, 46))	('INC280', 'Chemical', 'MESH:C000613976', (40, 46))	('caspase-3', 'Gene', (12, 21))	('Asra-EPS', 'Chemical', '-', (86, 94))	('caspase-3', 'Gene', '836', (12, 21))	('Cleavage', 'MPA', (0, 8))	('VAESBJ', 'Chemical', '-', (143, 149))
592137	25098767	These data indicated that Asra-EPS cells were more sensitive to INC280 than VAESBJ cells because its effects inducing G0/G1 cell cycle arrest and apoptosis were higher on Asra-EPS cells than on VAESBJ cells.	('G0/G1 cell cycle arrest', 'CPA', (118, 141))	('VAESBJ', 'Chemical', '-', (76, 82))	('Asra-EPS', 'Chemical', '-', (26, 34))	('Asra-EPS', 'Chemical', '-', (171, 179))	('INC280', 'Chemical', 'MESH:C000613976', (64, 70))	('VAESBJ', 'Chemical', '-', (194, 200))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (124, 141))	('higher', 'PosReg', (161, 167))	('inducing', 'Reg', (109, 117))	('apoptosis', 'CPA', (146, 155))	('INC280', 'Var', (64, 70))
592140	25098767	INC280 strikingly inhibited phosphorylation of c-MET and its downstream molecules such as AKT and ERK in Asra-EPS cells but did not decrease phosphorylation of AKT or ERK in HDF cells (Figure 5D, Additional file 2: Figure S2).	('AKT', 'Gene', '207', (160, 163))	('c-MET', 'Gene', '4233', (47, 52))	('AKT', 'Gene', (90, 93))	('ERK', 'Gene', '5594', (98, 101))	('INC280', 'Var', (0, 6))	('phosphorylation', 'MPA', (28, 43))	('ERK', 'Gene', '5594', (167, 170))	('c-MET', 'Gene', (47, 52))	('INC280', 'Chemical', 'MESH:C000613976', (0, 6))	('ERK', 'Gene', (98, 101))	('inhibited', 'NegReg', (18, 27))	('AKT', 'Gene', (160, 163))	('ERK', 'Gene', (167, 170))	('Asra-EPS', 'Chemical', '-', (105, 113))	('AKT', 'Gene', '207', (90, 93))
592142	25098767	By contrast, INC280 remarkably blocked phosphorylation of c-MET and ERK in VAESBJ cells, but AKT phosphorylation was incompletely suppressed (Figure 5D).	('INC280', 'Var', (13, 19))	('phosphorylation', 'MPA', (39, 54))	('AKT', 'Gene', (93, 96))	('c-MET', 'Gene', '4233', (58, 63))	('VAESBJ', 'Chemical', '-', (75, 81))	('ERK', 'Gene', '5594', (68, 71))	('INC280', 'Chemical', 'MESH:C000613976', (13, 19))	('ERK', 'Gene', (68, 71))	('blocked', 'NegReg', (31, 38))	('AKT', 'Gene', '207', (93, 96))	('c-MET', 'Gene', (58, 63))
592146	25098767	The administration of INC280 delayed VAESBJ xenograft tumor growth compared with that of the vehicle control, whereas INC280-treated tumors grew gradually (Figure 6A, B).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('INC280', 'Chemical', 'MESH:C000613976', (118, 124))	('INC280', 'Chemical', 'MESH:C000613976', (22, 28))	('xenograft tumor', 'Disease', (44, 59))	('tumors', 'Disease', (133, 139))	('VAESBJ', 'Chemical', '-', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('xenograft tumor', 'Disease', 'MESH:D009369', (44, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('delayed', 'NegReg', (29, 36))	('INC280', 'Var', (22, 28))
592148	25098767	Immunohistochemical studies showed a decrease in the rate of Ki-67-positive tumor cells in INC280-treated tumors compared with that in the control-treated tumors (Figure 6D, E).	('tumors', 'Disease', (106, 112))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (155, 160))	('INC280-treated', 'Var', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('decrease', 'NegReg', (37, 45))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('INC280', 'Chemical', 'MESH:C000613976', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('Ki-67-positive', 'Gene', (61, 75))
592153	25098767	Furthermore, RAD001-induced phosphorylation of AKT and ERK was attenuated by silencing of c-MET in both EpS cell lines (Figure 7B).	('AKT', 'Gene', (47, 50))	('c-MET', 'Gene', (90, 95))	('attenuated', 'NegReg', (63, 73))	('AKT', 'Gene', '207', (47, 50))	('RAD001-induced', 'Gene', (13, 27))	('phosphorylation', 'MPA', (28, 43))	('silencing', 'Var', (77, 86))	('c-MET', 'Gene', '4233', (90, 95))	('ERK', 'Gene', '5594', (55, 58))	('ERK', 'Gene', (55, 58))
592162	25098767	Either RAD001 or INC280 as a single agent inhibited Asra-EPS and VAESBJ xenograft tumor growth compared with the vehicle control (Figure 9A-C).	('xenograft tumor', 'Disease', 'MESH:D009369', (72, 87))	('VAESBJ', 'Chemical', '-', (65, 71))	('INC280', 'Gene', (17, 23))	('Asra-EPS', 'Chemical', '-', (52, 60))	('inhibited', 'NegReg', (42, 51))	('xenograft tumor', 'Disease', (72, 87))	('INC280', 'Chemical', 'MESH:C000613976', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Asra-EPS', 'Disease', (52, 60))	('RAD001', 'Var', (7, 13))
592166	25098767	Immunohistochemical studies showed that phosphorylation of AKT and ERK in Asra-EPS and VAESBJ xenograft tumors was increased by RAD001 treatment but attenuated by the combination therapy with RAD001 and INC280 (Figure 10A, Additional file 3: Figure S3).	('RAD001', 'Var', (128, 134))	('ERK', 'Gene', '5594', (67, 70))	('ERK', 'Gene', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('AKT', 'Gene', (59, 62))	('increased', 'PosReg', (115, 124))	('VAESBJ', 'Chemical', '-', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('xenograft tumors', 'Disease', 'MESH:D009369', (94, 110))	('attenuated', 'NegReg', (149, 159))	('INC280', 'Chemical', 'MESH:C000613976', (203, 209))	('AKT', 'Gene', '207', (59, 62))	('Asra-EPS', 'Chemical', '-', (74, 82))	('xenograft tumors', 'Disease', (94, 110))	('phosphorylation', 'MPA', (40, 55))
592172	25098767	Activation of the AKT/mTOR signaling pathway through mutation of pathway components as well as through activation of upstream signaling molecules occurs in a majority of cancers and contributes to deregulation of proliferation and resistance to apoptosis.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('proliferation', 'CPA', (213, 226))	('mutation', 'Var', (53, 61))	('cancers', 'Disease', (170, 177))	('deregulation', 'MPA', (197, 209))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('AKT', 'Gene', (18, 21))	('resistance to apoptosis', 'CPA', (231, 254))	('mTOR', 'Gene', '2475', (22, 26))	('Activation', 'PosReg', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mTOR', 'Gene', (22, 26))	('activation', 'PosReg', (103, 113))	('AKT', 'Gene', '207', (18, 21))
592184	25098767	Here, we demonstrated that an mTOR inhibitor, RAD001, also inhibited EpS cell proliferation but induced reactivation of both AKT and ERK.	('reactivation', 'MPA', (104, 116))	('AKT', 'Gene', '207', (125, 128))	('EpS cell proliferation', 'CPA', (69, 91))	('RAD001', 'Var', (46, 52))	('inhibited', 'NegReg', (59, 68))	('AKT', 'Gene', (125, 128))	('ERK', 'Gene', '5594', (133, 136))	('ERK', 'Gene', (133, 136))	('mTOR', 'Gene', '2475', (30, 34))	('mTOR', 'Gene', (30, 34))
592185	25098767	These results suggested that blockade of this reactivation could enhance the antitumor effects of mTOR inhibitors on EpS.	('blockade', 'Var', (29, 37))	('enhance', 'PosReg', (65, 72))	('EpS', 'Disease', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mTOR', 'Gene', '2475', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mTOR', 'Gene', (98, 102))	('tumor', 'Disease', (81, 86))
592195	25098767	c-MET inhibitors have shown antitumor efficacy in preclinical studies and are currently being evaluated in human cancer clinical trials.	('c-MET', 'Gene', '4233', (0, 5))	('human', 'Species', '9606', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cancer', 'Disease', (113, 119))	('clinical', 'Species', '191496', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('inhibitors', 'Var', (6, 16))	('c-MET', 'Gene', (0, 5))	('tumor', 'Disease', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('clinical', 'Species', '191496', (120, 128))
592199	25098767	AKT activation was completely blocked by treatment with INC280 in Asra-EPS cells but not in VAESBJ cells.	('AKT', 'Gene', (0, 3))	('VAESBJ', 'Chemical', '-', (92, 98))	('INC280', 'Var', (56, 62))	('Asra-EPS', 'Chemical', '-', (66, 74))	('AKT', 'Gene', '207', (0, 3))	('INC280', 'Chemical', 'MESH:C000613976', (56, 62))	('activation', 'PosReg', (4, 14))
592204	25098767	We found that PTEN expression was much lower in VAESBJ cells than in Asra-EPS or control HDF cells, suggesting that epithelioid sarcomas were heterogeneous malignancies in terms of PTEN expression.	('malignancies', 'Disease', (156, 168))	('PTEN', 'Gene', (14, 18))	('expression', 'MPA', (19, 29))	('VAESBJ', 'Var', (48, 54))	('PTEN', 'Gene', '5728', (14, 18))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (116, 136))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('epithelioid sarcomas', 'Disease', (116, 136))	('Asra-EPS', 'Chemical', '-', (69, 77))	('malignancies', 'Disease', 'MESH:D009369', (156, 168))	('PTEN', 'Gene', (181, 185))	('VAESBJ', 'Chemical', '-', (48, 54))	('lower', 'NegReg', (39, 44))	('PTEN', 'Gene', '5728', (181, 185))
592226	25098767	Antibodies against c-MET (#8198; WB, 1:1000; IHC, 1:300), p-MET (Tyr1234/1235; #3077; WB, 1:1000; IHC, 1:150), AKT (#4691; 1:1000), p-AKT (Ser473; #4060; WB, 1:1000; IHC, 1:50), ERK (#4695; 1:1000), p-ERK (Thr202/Tyr204; #4370; WB, 1:2000; IHC, 1:400), mTOR (#2983; 1:1000), p-mTOR (Ser2448; #5536; 1:1000), S6RP (#2217; 1:1000), p-S6RP (Ser235/236; #2211; 1:1000), PTEN (#9188; 1:1000), cleaved caspase-3 (#9661; 1:1000), and beta-actin (#4970; 1:1000) were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('#9188;', 'Var', (372, 378))	('beta-actin', 'Gene', (427, 437))	('caspase-3', 'Gene', '836', (396, 405))	('AKT', 'Gene', (111, 114))	('ERK', 'Gene', (178, 181))	('#4970;', 'Var', (439, 445))	('AKT', 'Gene', (134, 137))	('caspase-3', 'Gene', (396, 405))	('ERK', 'Gene', (201, 204))	('AKT', 'Gene', '207', (111, 114))	('beta-actin', 'Gene', '728378', (427, 437))	('mTOR', 'Gene', (253, 257))	('mTOR', 'Gene', (277, 281))	('AKT', 'Gene', '207', (134, 137))	('PTEN', 'Gene', (366, 370))	('p-S6RP', 'Var', (330, 336))	('c-MET', 'Gene', '4233', (19, 24))	('c-MET', 'Gene', (19, 24))	('ERK', 'Gene', '5594', (178, 181))	('mTOR', 'Gene', '2475', (253, 257))	('mTOR', 'Gene', '2475', (277, 281))	('PTEN', 'Gene', '5728', (366, 370))	('ERK', 'Gene', '5594', (201, 204))
592227	25098767	An antibody against Ki-67 (M7240; 1:50) was purchased from Dako (Glostrup, Denmark).	('Ki-67', 'Gene', (20, 25))	('Dako', 'Chemical', '-', (59, 63))	('M7240;', 'Var', (27, 33))
592257	32939344	TMP3-NTRK1 rearranged uterine sarcoma: A case report Uterine sarcomas are a group of rare tumours with heterogeneous morphological and genetic features.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (22, 37))	('sarcomas', 'Disease', (61, 69))	('NTRK1', 'Gene', '4914', (5, 10))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('NTRK1', 'Gene', (5, 10))	('sarcoma', 'Disease', (30, 37))	('rearranged', 'Var', (11, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('sarcomas', 'Disease', 'MESH:D012509', (61, 69))	('sarcoma', 'Disease', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (90, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
592258	32939344	Recent advances in the molecular characterisation of these tumours have identified a novel clinicopathological category underpinned by NTRK gene fusions.	('gene fusions', 'Var', (140, 152))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('TRK', 'Gene', (136, 139))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('tumours', 'Disease', (59, 66))	('TRK', 'Gene', '7170', (136, 139))
592261	32939344	FISH analysis using a NTRK1 break-apart probe was above the threshold for translocation positivity and subsequent next-generation sequencing (NGS) identified a TPM3-NTRK1 fusion.	('fusion', 'Var', (171, 177))	('NTRK1', 'Gene', (165, 170))	('TPM3', 'Gene', (160, 164))	('NTRK1', 'Gene', '4914', (22, 27))	('NTRK1', 'Gene', '4914', (165, 170))	('TPM3', 'Gene', '7170', (160, 164))	('NTRK1', 'Gene', (22, 27))
592268	32939344	This is illustrated by the re-emergence of high-grade endometrial stromal sarcoma as an entity in the 4th edition of the WHO classification, which was predicated upon the identification of YWHAE-FAM22 translocations in a subset of tumours with high-grade morphology and aggressive clinical behaviour.	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('tumours', 'Disease', 'MESH:D009369', (231, 238))	('YWHAE', 'Gene', (189, 194))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (54, 81))	('translocations', 'Var', (201, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('tumours', 'Disease', (231, 238))	('YWHAE', 'Gene', '7531', (189, 194))	('aggressive clinical behaviour', 'Phenotype', 'HP:0000718', (270, 299))	('endometrial stromal sarcoma', 'Disease', (54, 81))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))
592269	32939344	The subsequent discovery of BCOR and SUZ12 gene rearrangements in high-grade endometrial stromal sarcomas has further refined our understanding of the clinico-pathological-genetic correlation of these tumours.	('tumours', 'Disease', 'MESH:D009369', (201, 208))	('rearrangements', 'Var', (48, 62))	('endometrial stromal sarcomas', 'Disease', (77, 105))	('BCOR', 'Gene', '54880', (28, 32))	('tumours', 'Disease', (201, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('SUZ12', 'Gene', '23512', (37, 42))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (77, 105))	('SUZ12', 'Gene', (37, 42))	('BCOR', 'Gene', (28, 32))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))
592283	32939344	FISH analysis of this specimen was performed using the Zytovision ZytoLight SPEC NTRK1 dual-colour break-apart probe (Z-2167-200) which detects translocations involving the chromosomal region 1q22-q23.1 harbouring the NTRK1 gene.	('NTRK1', 'Gene', '4914', (218, 223))	('NTRK1', 'Gene', '4914', (81, 86))	('NTRK1', 'Gene', (218, 223))	('translocations', 'Var', (144, 158))	('NTRK1', 'Gene', (81, 86))
592287	32939344	Next-generation sequencing revealed the presence of a rearrangement of the NTRK1 gene (NTRK1 (exon 9)-TMP3 (intron 6)).	('NTRK1', 'Gene', (87, 92))	('NTRK1', 'Gene', '4914', (75, 80))	('NTRK1', 'Gene', (75, 80))	('rearrangement', 'Var', (54, 67))	('NTRK1', 'Gene', '4914', (87, 92))
592290	32939344	We report a case of a TPM3-NTRK1 fusion in a uterine sarcoma.	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('NTRK1', 'Gene', (27, 32))	('sarcoma', 'Disease', (53, 60))	('TPM3', 'Gene', (22, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (45, 60))	('NTRK1', 'Gene', '4914', (27, 32))	('fusion', 'Var', (33, 39))	('TPM3', 'Gene', '7170', (22, 26))
592293	32939344	There is increasing recognition of the role of NTRK mutations in the pathogenesis of numerous solid tumours.	('mutations', 'Var', (52, 61))	('TRK', 'Gene', '7170', (48, 51))	('numerous solid tumours', 'Disease', 'MESH:D009369', (85, 107))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('numerous solid tumours', 'Disease', (85, 107))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('TRK', 'Gene', (48, 51))
592294	32939344	NTRK rearrangements are implicated in a range of adult malignant tumours and are recognised as driver mutations in a number of paediatric soft-tissue tumours, including infantile fibrosarcomas and locally aggressive lipofibromatosis-like neural tumours.	('fibrosarcomas', 'Disease', (179, 192))	('aggressive lipofibromatosis-like neural tumours', 'Disease', (205, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('malignant tumours', 'Disease', 'MESH:D009369', (55, 72))	('aggressive lipofibromatosis-like neural tumours', 'Disease', 'MESH:D001523', (205, 252))	('tumours', 'Disease', (65, 72))	('malignant tumours', 'Disease', (55, 72))	('tumours', 'Disease', (150, 157))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('TRK', 'Gene', '7170', (1, 4))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('implicated', 'Reg', (24, 34))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('TRK', 'Gene', (1, 4))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Disease', (245, 252))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (179, 191))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('rearrangements', 'Var', (5, 19))	('fibrosarcomas', 'Disease', 'MESH:D005354', (179, 192))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('sarcomas', 'Phenotype', 'HP:0100242', (184, 192))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))
592295	32939344	Larotrectinib, a pan-TRK inhibitor, has demonstrated tissue type-agnostic efficacy in tumours harbouring NTRK mutations.	('TRK', 'Gene', '7170', (106, 109))	('mutations', 'Var', (110, 119))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('TRK', 'Gene', (106, 109))	('TRK', 'Gene', (21, 24))	('Larotrectinib', 'Chemical', 'MESH:C000609083', (0, 13))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('TRK', 'Gene', '7170', (21, 24))
592301	32939344	NTRK rearranged uterine sarcomas present in a pre-menopausal age group, in contrast to leiomyosarcomas and endometrial stromal sarcomas, which typically present in post-menopausal women.	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('endometrial stromal sarcomas', 'Disease', (107, 135))	('sarcomas', 'Disease', (127, 135))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcomas', 'Disease', (24, 32))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (87, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('leiomyosarcomas', 'Disease', (87, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (87, 102))	('TRK', 'Gene', '7170', (1, 4))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (87, 101))	('sarcomas', 'Disease', (94, 102))	('women', 'Species', '9606', (180, 185))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (16, 31))	('TRK', 'Gene', (1, 4))	('endometrial stromal sarcomas', 'Disease', 'MESH:D018203', (107, 135))	('rearranged', 'Var', (5, 15))	('sarcomas', 'Disease', 'MESH:D012509', (127, 135))	('-menopausal age', 'Phenotype', 'HP:0008209', (49, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))
592308	32939344	Trk A and pan-Trk are the only reliable immunhistochemical investigations allowing distinction of NTRK rearranged sarcomas from these mimics.	('sarcomas', 'Disease', 'MESH:D012509', (114, 122))	('TRK', 'Gene', (99, 102))	('Trk', 'Gene', '7170', (14, 17))	('Trk A', 'Gene', (0, 5))	('sarcomas', 'Phenotype', 'HP:0100242', (114, 122))	('Trk', 'Gene', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('sarcomas', 'Disease', (114, 122))	('Trk', 'Gene', (14, 17))	('TRK', 'Gene', '7170', (99, 102))	('rearranged', 'Var', (103, 113))	('Trk A', 'Gene', '4914', (0, 5))	('Trk', 'Gene', '7170', (0, 3))
592313	32939344	The accurate identification of these rare tumours is clinically relevant given the tissue type-agnostic efficacy of tropomyosin receptor kinase inhibitors in the treatment of malignant tumours with NTRK mutations.	('TRK', 'Gene', '7170', (199, 202))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumours', 'Phenotype', 'HP:0002664', (185, 192))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('malignant tumours', 'Disease', 'MESH:D009369', (175, 192))	('TRK', 'Gene', (199, 202))	('tumours', 'Disease', 'MESH:D009369', (185, 192))	('tumours', 'Disease', (185, 192))	('malignant tumours', 'Disease', (175, 192))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('mutations', 'Var', (203, 212))	('tumours', 'Disease', (42, 49))
592335	30891319	FISH analysis showed a t(8;21)(q22;q22.1) in all myeloblasts on metaphase analysis, without any additional cytogenetic abnormalities, consistent with a diagnosis of acute myeloid leukemia (AML) with a balanced translocation of RUNX1-RUNX1T1.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (165, 187))	('RUNX1', 'Gene', '861', (227, 232))	('RUNX1', 'Gene', '861', (233, 238))	('AML', 'Phenotype', 'HP:0004808', (189, 192))	('leukemia', 'Phenotype', 'HP:0001909', (179, 187))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (171, 187))	('RUNX1T1', 'Gene', (233, 240))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (165, 187))	('t(8;21)(q22;q22.1', 'Var', (23, 40))	('AML', 'Disease', 'MESH:D015470', (189, 192))	('t(8;21)(q22;q22.1)', 'STRUCTURAL_ABNORMALITY', 'None', (23, 41))	('acute myeloid leukemia', 'Disease', (165, 187))	('RUNX1', 'Gene', (233, 238))	('RUNX1T1', 'Gene', '862', (233, 240))	('AML', 'Disease', (189, 192))	('RUNX1', 'Gene', (227, 232))
592336	30891319	Subsequent PCR-based testing demonstrated no mutations in c-KIT.	('c-KIT', 'Gene', '3815', (58, 63))	('mutations', 'Var', (45, 54))	('c-KIT', 'Gene', (58, 63))
592341	30891319	After 1 cycle, she presented with increasing fatigue and generalized weakness, and repeat bone marrow biopsy confirmed a relapse of AML, with 23% blasts negative for any evidence of the prior t(8;21), but demonstrating a new isolated del(20)(q11.2) in 9 out of 20 metaphases on karyotypic analysis.	('fatigue', 'Disease', (45, 52))	('AML', 'Disease', (132, 135))	('fatigue', 'Phenotype', 'HP:0012378', (45, 52))	('AML', 'Phenotype', 'HP:0004808', (132, 135))	('generalized weakness', 'Phenotype', 'HP:0003324', (57, 77))	('generalized', 'Disease', (57, 68))	('del(20)(q11.2', 'Var', (234, 247))	('fatigue', 'Disease', 'MESH:D005221', (45, 52))	('AML', 'Disease', 'MESH:D015470', (132, 135))
592347	30891319	Myeloid sarcoma has an association with several cytogenetic abnormalities, most commonly MLL rearrangements and t(8;21) and to a lesser degree monosomy 7, trisomy 8, inv(16), trisomy 4, monosomy 16, del(16q), del(5q), del(20q), and trisomy 11.	('MLL', 'Gene', (89, 92))	('MLL', 'Gene', '4297', (89, 92))	('inv', 'Var', (166, 169))	('trisomy 8', 'Var', (155, 164))	('trisomy 11', 'Var', (232, 242))	('del(5q', 'Var', (209, 215))	('association', 'Reg', (23, 34))	('Myeloid sarcoma', 'Disease', 'MESH:D023981', (0, 15))	('rearrangements', 'Var', (93, 107))	('del(20q', 'Var', (218, 225))	('monosomy 16', 'Var', (186, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('Myeloid sarcoma', 'Disease', (0, 15))	('del(16q', 'Var', (199, 206))	('trisomy 4', 'Var', (175, 184))
592349	30891319	Approximately 16% of myeloid sarcoma cases carry concurrent NPM mutations, which are often associated with normal cytogenetics and FAB M4 or M5 morphologic classification.	('NPM', 'Gene', (60, 63))	('NPM', 'Gene', '4869', (60, 63))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (21, 36))	('myeloid sarcoma', 'Disease', (21, 36))	('mutations', 'Var', (64, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))
592389	29510588	In the late 1990s, a c-kit (CD117) mutation was identified as a characteristic of GIST, and c-kit was focused on as the target of new drugs.	('CD117', 'Gene', '3815', (28, 33))	('CD117', 'Gene', (28, 33))	('c-kit', 'Gene', '3815', (21, 26))	('c-kit', 'Gene', (21, 26))	('mutation', 'Var', (35, 43))	('c-kit', 'Gene', (92, 97))	('c-kit', 'Gene', '3815', (92, 97))
592397	29510588	Most major KIT mutations occur in exon 11, and this mutation is favorable for imatinib therapy; however, patients with a KIT mutation in exon 9, which accounts for 10-20% of GIST cases, were poor responders to imatinib therapy.	('patients', 'Species', '9606', (105, 113))	('mutation in', 'Var', (125, 136))	('mutations', 'Var', (15, 24))	('imatinib', 'Chemical', 'MESH:D000068877', (78, 86))	('imatinib', 'Chemical', 'MESH:D000068877', (210, 218))
592398	29510588	For GIST patients with exon 9 mutation, dose escalation of imatinib up to 800 mg would be the beneficial option.	('patients', 'Species', '9606', (9, 17))	('mutation', 'Var', (30, 38))	('imatinib', 'Chemical', 'MESH:D000068877', (59, 67))	('exon 9', 'Gene', (23, 29))
592404	29510588	Therefore, the anti-PDGFR-specific agents crenolanib and olaratumab were tested as treatments for patients with imatinib-resistant GIST, mainly those with PDGFR mutation.	('PDGFR', 'Gene', (155, 160))	('PDGFR', 'Gene', '5159', (155, 160))	('mutation', 'Var', (161, 169))	('olaratumab', 'Chemical', 'MESH:C000589393', (57, 67))	('patients', 'Species', '9606', (98, 106))	('crenolanib', 'Chemical', 'MESH:C577197', (42, 52))	('PDGFR', 'Gene', (20, 25))	('imatinib', 'Chemical', 'MESH:D000068877', (112, 120))	('PDGFR', 'Gene', '5159', (20, 25))
592405	29510588	Second- or third-generation TKIs that are approved for treating CML such as dasatinib, nilotinib and ponatinib have also been examined as treatment for GIST, but the targets of those TKIs focus on BCR-ABL and its related mutations, specific targets of CML, and the patient responses in clinical trials have been modest.	('BCR-ABL', 'Gene', (197, 204))	('CML', 'Disease', 'MESH:D015464', (64, 67))	('mutations', 'Var', (221, 230))	('CML', 'Disease', (252, 255))	('BCR-ABL', 'Gene', '25', (197, 204))	('CML', 'Phenotype', 'HP:0005506', (64, 67))	('nilotinib', 'Chemical', 'MESH:C498826', (87, 96))	('CML', 'Disease', (64, 67))	('patient', 'Species', '9606', (265, 272))	('dasatinib', 'Chemical', 'MESH:D000069439', (76, 85))	('CML', 'Phenotype', 'HP:0005506', (252, 255))	('CML', 'Disease', 'MESH:D015464', (252, 255))	('ponatinib', 'Chemical', 'MESH:C545373', (101, 110))
592408	29510588	However, the investigations of sarcoma genomics and mutations of signaling pathways have indicated several candidates for targeted therapy for non-GIST STSs, and the angiogenetic pathway was revealed to be one of the promising targets, as in many solid tumors.	('mutations', 'Var', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('sarcoma', 'Disease', (31, 38))	('solid tumors', 'Disease', (247, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('STSs', 'Phenotype', 'HP:0030448', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('solid tumors', 'Disease', 'MESH:D009369', (247, 259))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))
592422	29510588	The relationship of TP53 mutational status and response to pazopanib was evaluated in a small study; the TP53 mutant STS patients showed longer PFS, but a verification of that study's results in a large-scale cohort has not been conducted.	('TP53', 'Gene', (20, 24))	('pazopanib', 'Chemical', 'MESH:C516667', (59, 68))	('mutant STS', 'Var', (110, 120))	('longer', 'PosReg', (137, 143))	('PFS', 'MPA', (144, 147))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('patients', 'Species', '9606', (121, 129))	('TP53', 'Gene', '7157', (20, 24))
592447	29510588	The subject of phase 3 trial of eribulin was limited to l-sarcoma same as trabectedin; the result, as described before, showed the OS prolongation of eribulin arm compare to dacarbazine (13.5 months vs. 11.5 months, p = 0.0169), but not the PFS improvement (2.6 months vs. 2.6 months; p = 0.23).	('eribulin', 'Var', (150, 158))	('dacarbazine', 'Chemical', 'MESH:D003606', (174, 185))	('prolongation', 'PosReg', (134, 146))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('trabectedin', 'Chemical', 'MESH:D000077606', (74, 85))	('sarcoma', 'Disease', (58, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
592460	29510588	More therapies targeted to specific fusion gene/proteins have been emerging; anaplastic lymphoma kinase (ALK) is well known as a treatment target of non-small cell lung cancer, and ALK-related fusion gene is also observed in an paricular STS, i.e., inflammatory myofibroblastic tumor (IMT).	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('anaplastic lymphoma kinase', 'Gene', (77, 103))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ALK', 'Gene', (181, 184))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (149, 175))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (153, 175))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('ALK', 'Gene', '238', (105, 108))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (149, 175))	('ALK', 'Gene', (105, 108))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (249, 283))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (77, 96))	('non-small cell lung cancer', 'Disease', (149, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('fusion gene', 'Var', (193, 204))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (262, 283))	('inflammatory myofibroblastic tumor', 'Disease', (249, 283))	('anaplastic lymphoma kinase', 'Gene', '238', (77, 103))	('ALK', 'Gene', '238', (181, 184))
592465	29510588	Translocation related to tropomysin receptor kinase (TRK) was recently detected in broad malignancies at low frequency, but this appears to be very promising treatment target.	('Translocation', 'Var', (0, 13))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('TRK', 'Gene', (53, 56))	('TRK', 'Gene', '4914', (53, 56))	('malignancies', 'Disease', (89, 101))	('detected', 'Reg', (71, 79))	('tropomysin receptor kinase', 'Gene', '4914', (25, 51))	('tropomysin receptor kinase', 'Gene', (25, 51))
592469	29510588	Recently new clinical trials of new targeted therapies for STSs, such as CDK4 inhibitors and a nuclear export inhibitor, the subtypes of STS targeted could be narrowed down from early phase of clinical trials.	('STSs', 'Phenotype', 'HP:0030448', (59, 63))	('CDK4', 'Gene', '1019', (73, 77))	('inhibitors', 'Var', (78, 88))	('nuclear export', 'MPA', (95, 109))	('CDK4', 'Gene', (73, 77))
592474	29510588	Insulin-like growth factor 1 receptor (IGF-1R) was a candidate as a treatment target of Ewing sarcoma, and early-phase clinical trials of IGF-1F inhibitors, especially of figitumumab, showed a modest response among recurrent/metastatic Ewing sarcoma patients, including complete remission.	('Insulin-like growth factor 1 receptor', 'Gene', (0, 37))	('IGF-1R', 'Gene', '3480', (39, 45))	('Ewing sarcoma', 'Disease', (236, 249))	('Insulin-like growth factor 1 receptor', 'Gene', '3480', (0, 37))	('IGF-1R', 'Gene', (39, 45))	('patients', 'Species', '9606', (250, 258))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (236, 249))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (88, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (88, 101))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (236, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('IGF-1F', 'Gene', (138, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('inhibitors', 'Var', (145, 155))	('Ewing sarcoma', 'Disease', (88, 101))	('complete remission', 'Disease', (270, 288))	('figitumumab', 'Chemical', 'MESH:C525021', (171, 182))
592487	29510588	A report from clinical trials suggests that the use of PD-1 targeted therapy might bring about the activation of indoleamine 2,3-dioxygenase 1 (IDO1), which could be a new target of combination immunotherapy.	('IDO1', 'Gene', (144, 148))	('indoleamine 2,3-dioxygenase 1', 'Gene', '3620', (113, 142))	('PD-1', 'Gene', (55, 59))	('PD-1', 'Gene', '5133', (55, 59))	('activation', 'PosReg', (99, 109))	('IDO1', 'Gene', '3620', (144, 148))	('targeted therapy', 'Var', (60, 76))
592494	29510588	A basket trial evaluates multiple diseases with a single target or mutation for specific targeted treatment, and an umbrella trial evaluates various subgroups within a single disease for multiple targeted therapies fitted to their own target.	('multiple diseases', 'Disease', 'MESH:D000015', (25, 42))	('mutation', 'Var', (67, 75))	('multiple diseases', 'Disease', (25, 42))
592518	28638113	Next-Generation Sequencing (NGS) was performed, and a total of 136 putative somatic variants and one gene fusion were identified, of which 16 variants were considered hot spot mutations, including the genes EGFR, EML4-ALK, MET, BRAF, PIK3CA, and TP53.	('BRAF', 'Gene', '673', (228, 232))	('ALK', 'Gene', (218, 221))	('variants', 'Var', (142, 150))	('BRAF', 'Gene', (228, 232))	('EGFR', 'Gene', '1956', (207, 211))	('EML4', 'Gene', (213, 217))	('PIK3CA', 'Gene', (234, 240))	('MET', 'Gene', (223, 226))	('EGFR', 'Gene', (207, 211))	('ALK', 'Gene', '238', (218, 221))	('EML4', 'Gene', '27436', (213, 217))	('TP53', 'Gene', '7157', (246, 250))	('PIK3CA', 'Gene', '5290', (234, 240))	('TP53', 'Gene', (246, 250))
592519	28638113	Of these hot spot mutations, one sample expressing an EML4-ALK fusion was further confirmed by Ventana IHC, and one sample containing an EGFR exon 19 deletion was also confirmed.	('EGFR', 'Gene', (137, 141))	('ALK', 'Gene', '238', (59, 62))	('EML4', 'Gene', '27436', (54, 58))	('EML4', 'Gene', (54, 58))	('ALK', 'Gene', (59, 62))	('EGFR', 'Gene', '1956', (137, 141))	('mutations', 'Var', (18, 27))
592520	28638113	The NGS results imply that TP53 mutations occur often in PSCs and that EML4-ALK fusion events and EGFR exon deletions also occur in these rare tumors.	('EGFR', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('ALK', 'Gene', '238', (76, 79))	('EML4', 'Gene', '27436', (71, 75))	('PSCs', 'Disease', (57, 61))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', '1956', (98, 102))	('ALK', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('EML4', 'Gene', (71, 75))
592534	28638113	NSCLC patients who carry an EGFR activating mutation and a fusion protein between the N-terminal portion of the echinoderm microtubule-associated protein-like 4 protein and the intracellular signaling portion of the anaplastic lymphoma kinase tyrosine kinase receptor (EML4-ALK) are sensitive to tyrosine kinase inhibitors (TKIs).	('ALK', 'Gene', (274, 277))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('EGFR', 'Gene', '1956', (28, 32))	('mutation', 'Var', (44, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (227, 235))	('anaplastic lymphoma kinase', 'Gene', '238', (216, 242))	('EGFR', 'Gene', (28, 32))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (216, 235))	('anaplastic lymphoma kinase', 'Gene', (216, 242))	('patients', 'Species', '9606', (6, 14))	('ALK', 'Gene', '238', (274, 277))	('activating', 'PosReg', (33, 43))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (112, 160))	('EML4', 'Gene', '27436', (269, 273))	('EML4', 'Gene', (269, 273))	('echinoderm microtubule-associated protein-like 4', 'Gene', (112, 160))	('NSCLC', 'Disease', (0, 5))
592578	28638113	TP53 point mutations were found in 4 cases (57.1% of cases), followed in frequency by FAT3, MET, NCOR1, TSHR, APC, HGF, PIK3CA, EGFR, BRAF, BRIP1, and KMT2D, which all appeared in only 1 case (14.3% of cases) each (Fig.	('PIK3CA', 'Gene', '5290', (120, 126))	('HGF', 'Gene', '3082', (115, 118))	('APC', 'Disease', 'MESH:D011125', (110, 113))	('HGF', 'Gene', (115, 118))	('APC', 'Disease', (110, 113))	('TSHR', 'Gene', '7253', (104, 108))	('point mutations', 'Var', (5, 20))	('TP53', 'Gene', '7157', (0, 4))	('NCOR1', 'Gene', (97, 102))	('EGFR', 'Gene', (128, 132))	('BRAF', 'Gene', '673', (134, 138))	('BRAF', 'Gene', (134, 138))	('NCOR1', 'Gene', '9611', (97, 102))	('KMT2D', 'Gene', (151, 156))	('BRIP1', 'Gene', '83990', (140, 145))	('PIK3CA', 'Gene', (120, 126))	('TSHR', 'Gene', (104, 108))	('FAT3', 'Gene', (86, 90))	('TP53', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (128, 132))	('BRIP1', 'Gene', (140, 145))	('KMT2D', 'Gene', '8085', (151, 156))	('FAT3', 'Gene', '120114', (86, 90))
592579	28638113	Four TP53 mutations were found on chromosome 17, but these mutations occurred in different exons: case 2 presented with a C to A mutation in exon 4, position 7577551; case 3 presented with a C to A mutation in exon 5, position 7578416; case 4 presented with a C to T mutation in exon 7, position 7577085; case 5 presented with an A to G mutation in exon 8, position 7579419 (Complementary Table 3).	('TP53', 'Gene', '7157', (5, 9))	('men', 'Species', '9606', (381, 384))	('TP53', 'Gene', (5, 9))	('mutation', 'Var', (129, 137))
592583	28638113	A BRAF.G469A mutation was detected in case 6 with an allele fraction of 0.24 on chromosome 7, position 140481402; this mutation resulted in the change of base C to G. A MET.S203F mutation was found in case 1 with an allele fraction of 0.16 on chromosome 7, position 116339746, exon 24; this mutation resulted in the change of base C to T. PIK3CA.H1047R and PIK3CA.H1048R mutations were found in case 3 with allele fractions of 0.33 and 0.34, respectively, on chromosome 3, positions 178952088 and 178952085; these mutations resulted in the change of base A to G. None of the TP53 point mutations appeared alone, as they were accompanied by other point mutations: in case 2, the TP53 mutation coincided with an HGF p. G520R mutation; in case 3, the TP53 mutation coincided with PIK3CA.H1047R and PIK3CA.H1048R mutations; in case 4, the TP53 mutation coincided with an EML4-ALK gene fusion; in case 5, the TP53 mutation coincided with an EGFR exon 19 deletion.	('mutation', 'Var', (909, 917))	('H1048R', 'Mutation', 'p.H1048R', (364, 370))	('S203F', 'Mutation', 'p.S203F', (173, 178))	('PIK3CA', 'Gene', (339, 345))	('BRAF', 'Gene', '673', (2, 6))	('TP53', 'Gene', '7157', (835, 839))	('BRAF', 'Gene', (2, 6))	('H1047R', 'Mutation', 'rs121913279', (784, 790))	('EGFR', 'Gene', '1956', (936, 940))	('H1047R', 'Mutation', 'rs121913279', (346, 352))	('PIK3CA', 'Gene', '5290', (795, 801))	('TP53', 'Gene', '7157', (904, 908))	('G520R', 'SUBSTITUTION', 'None', (717, 722))	('TP53', 'Gene', (575, 579))	('PIK3CA', 'Gene', '5290', (357, 363))	('TP53', 'Gene', (678, 682))	('TP53', 'Gene', (748, 752))	('G469A', 'Mutation', 'rs121913355', (7, 12))	('PIK3CA', 'Gene', '5290', (777, 783))	('TP53', 'Gene', (835, 839))	('PIK3CA', 'Gene', '5290', (339, 345))	('EGFR', 'Gene', (936, 940))	('EML4', 'Gene', (867, 871))	('PIK3CA', 'Gene', (795, 801))	('ALK', 'Gene', '238', (872, 875))	('HGF', 'Gene', '3082', (710, 713))	('EML4', 'Gene', '27436', (867, 871))	('TP53', 'Gene', (904, 908))	('PIK3CA', 'Gene', (357, 363))	('TP53', 'Gene', '7157', (575, 579))	('ALK', 'Gene', (872, 875))	('H1048R', 'Mutation', 'p.H1048R', (802, 808))	('TP53', 'Gene', '7157', (748, 752))	('PIK3CA', 'Gene', (777, 783))	('G520R', 'Var', (717, 722))	('TP53', 'Gene', '7157', (678, 682))	('HGF', 'Gene', (710, 713))
592584	28638113	As shown in Table 3, 2 of the 4 patients with TP53 mutations were males (50%, 2/4), and the other two were females.	('patients', 'Species', '9606', (32, 40))	('TP53', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (46, 50))
592585	28638113	No significant associations were detected between the gene fusion mutation and the cancer stage, metastatic status, or sex.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutation', 'Var', (66, 74))	('gene fusion mutation', 'Var', (54, 74))	('cancer', 'Disease', (83, 89))
592591	28638113	An EGFR exon 19 deletion and a BRAF point mutation were both found in the mixed type.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('deletion', 'Var', (16, 24))	('BRAF', 'Gene', '673', (31, 35))	('point mutation', 'Var', (36, 50))	('BRAF', 'Gene', (31, 35))
592592	28638113	The mutation map of the EGFR exon 19 deletion is shown in Complementary Fig.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('men', 'Species', '9606', (64, 67))	('deletion', 'Var', (37, 45))
592593	28638113	TP53 mutations were observed more frequently in pure PSCs (3 of 7 cases, 42.9%) than in mixed types (1 of 7 cases, 14.3%).	('TP53', 'Gene', '7157', (0, 4))	('pure PSCs', 'Disease', (48, 57))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('observed', 'Reg', (20, 28))
592620	28638113	found that TP53 point mutations appeared in approximately 27% of adenocarcinomas and in 43% of squamous cell carcinomas, with an incidence of 14% in pleomorphic carcinomas.	('point mutations', 'Var', (16, 31))	('squamous cell carcinomas', 'Disease', (95, 119))	('pleomorphic carcinomas', 'Disease', 'MESH:D008228', (149, 171))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (95, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('pleomorphic carcinomas', 'Disease', (149, 171))	('adenocarcinomas', 'Disease', 'MESH:D000230', (65, 80))	('adenocarcinomas', 'Disease', (65, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('appeared', 'Reg', (32, 40))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (95, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))
592621	28638113	Their results showed that TP53 mutations in pleomorphic carcinomas often appear in exon 7 in squamous cell carcinomas and often in exon 8 in adenocarcinomas.	('TP53', 'Gene', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mutations', 'Var', (31, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('adenocarcinomas', 'Disease', 'MESH:D000230', (141, 156))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (93, 117))	('squamous cell carcinomas', 'Disease', (93, 117))	('adenocarcinomas', 'Disease', (141, 156))	('pleomorphic carcinomas', 'Disease', 'MESH:D008228', (44, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('appear', 'Reg', (73, 79))	('TP53', 'Gene', '7157', (26, 30))	('pleomorphic carcinomas', 'Disease', (44, 66))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (93, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
592622	28638113	We discovered that 4 of the 7 patients (57.1%) harbored TP53 point mutations that occurred in distinct exons: exons 4, 5, 7, and 8.	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('point mutations', 'Var', (61, 76))	('patients', 'Species', '9606', (30, 38))
592623	28638113	This result is similar to a study by Filippo Lococo et al., who observed that the TP53 gene was mutated in 55% of PSC cases and that the mutations were highly heterogeneous, with a high number of private mutations detected in only one or two cases.	('mutated', 'Var', (96, 103))	('TP53', 'Gene', (82, 86))	('PSC', 'Disease', (114, 117))	('TP53', 'Gene', '7157', (82, 86))
592624	28638113	The authors suggested that these TP53 mutations are not the driver genes of PSC and that they could occur as a side effect of increased genetic instability.	('PSC', 'Disease', (76, 79))	('TP53', 'Gene', '7157', (33, 37))	('occur', 'Reg', (100, 105))	('TP53', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))
592625	28638113	However, the high incidence of TP53 mutations in human tumors and the fact that mutant TP53 often accumulates at high levels in tumor cells makes it a potential target for cancer therapy.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('TP53', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('accumulates', 'PosReg', (98, 109))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('TP53', 'Gene', '7157', (87, 91))	('mutant', 'Var', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('human', 'Species', '9606', (49, 54))	('tumors', 'Disease', (55, 61))	('TP53', 'Gene', '7157', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (55, 60))
592627	28638113	One patient had EGFR and TP53 mutations, and the other had an EML4-ALK gene fusion and a TP53 mutation, which have rarely been described in PSC tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (25, 29))	('PSC tumors', 'Disease', (140, 150))	('TP53', 'Gene', (89, 93))	('PSC tumors', 'Disease', 'MESH:D015209', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('ALK', 'Gene', '238', (67, 70))	('patient', 'Species', '9606', (4, 11))	('EML4', 'Gene', (62, 66))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', '1956', (16, 20))	('EML4', 'Gene', '27436', (62, 66))	('TP53', 'Gene', '7157', (25, 29))	('EGFR', 'Gene', (16, 20))	('ALK', 'Gene', (67, 70))
592628	28638113	Several studies have suggested that the reversion of functional TP53 can trigger tumor cell death and lead to tumor clearance, even if a tumor carries multiple genetic alterations that drive tumor growth.	('tumor cell death', 'Disease', 'MESH:D003643', (81, 97))	('lead to', 'Reg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('TP53', 'Gene', '7157', (64, 68))	('reversion', 'Var', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor cell death', 'Disease', (81, 97))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('TP53', 'Gene', (64, 68))	('trigger', 'Reg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
592629	28638113	Generally, mutant TP53 tumors are less sensitive to conventional chemotherapy and have a worse prognosis than wild type TP53 tumors.	('mutant', 'Var', (11, 17))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('TP53', 'Gene', '7157', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TP53', 'Gene', (18, 22))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('TP53', 'Gene', '7157', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('TP53', 'Gene', (120, 124))
592630	28638113	The development of mutant TP53-reactivating drugs is expected to be an effective antineoplastic therapy.	('TP53', 'Gene', (26, 30))	('mutant', 'Var', (19, 25))	('men', 'Species', '9606', (11, 14))	('TP53', 'Gene', '7157', (26, 30))
592633	28638113	However, the frequency of EGFR mutations in PSC is controversial.	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('PSC', 'Disease', (44, 47))
592634	28638113	reported that approximately 9% of patients with PSC contained EGFR exon 19 deletions, and Kaira K et al.	('EGFR', 'Gene', '1956', (62, 66))	('deletions', 'Var', (75, 84))	('EGFR', 'Gene', (62, 66))	('patients', 'Species', '9606', (34, 42))	('PSC', 'Disease', (48, 51))
592635	28638113	reported a 20% incidence of EGFR mutations in Asian patients.	('patients', 'Species', '9606', (52, 60))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
592636	28638113	Two other studies did not find EGFR mutations in European patients with PSCs.	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('patients', 'Species', '9606', (58, 66))	('PSCs', 'Disease', (72, 76))
592637	28638113	However, PSC patients with EGFR mutations did not show satisfactory therapeutic effects to TKIs.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('PSC', 'Disease', (9, 12))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (32, 41))
592641	28638113	However, ALK inhibitors and BRAF inhibitors used for the treatment of PSC represent strategies of questionable efficacy owing to the lower frequencies of rearrangements and mutations in the EML4-ALK and BRAF genes reported previously in PSCs.	('ALK', 'Gene', (9, 12))	('PSC', 'Disease', (70, 73))	('men', 'Species', '9606', (62, 65))	('BRAF', 'Gene', '673', (28, 32))	('EML4', 'Gene', '27436', (190, 194))	('men', 'Species', '9606', (163, 166))	('ALK', 'Gene', '238', (9, 12))	('mutations', 'Var', (173, 182))	('BRAF', 'Gene', '673', (203, 207))	('ALK', 'Gene', (195, 198))	('EML4', 'Gene', (190, 194))	('BRAF', 'Gene', (28, 32))	('PSCs', 'Disease', (237, 241))	('BRAF', 'Gene', (203, 207))	('ALK', 'Gene', '238', (195, 198))
592644	28638113	We will require more samples to evaluate the NGS data to determine the frequency of EML4-ALK gene fusions in PSC tumors and whether these EML4-ALK-positive patients are sensitive to ALK inhibitors.	('patients', 'Species', '9606', (156, 164))	('ALK', 'Gene', '238', (182, 185))	('PSC tumors', 'Disease', (109, 119))	('ALK', 'Gene', (89, 92))	('EML4', 'Gene', '27436', (84, 88))	('PSC tumors', 'Disease', 'MESH:D015209', (109, 119))	('fusions', 'Var', (98, 105))	('ALK', 'Gene', (143, 146))	('ALK', 'Gene', (182, 185))	('EML4', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('ALK', 'Gene', '238', (89, 92))	('ALK', 'Gene', '238', (143, 146))	('EML4', 'Gene', '27436', (138, 142))	('EML4', 'Gene', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
592647	28638113	This result was similar to a study conducted by Fallet V. et al., who found EGFR mutations in 18 patients (22.2%), of whom only two exhibited EGFR-sensitizing mutations (2.5%) as identified in exon 21 (L858R).	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (142, 146))	('L858R', 'Mutation', 'rs121434568', (202, 207))	('EGFR', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('patients', 'Species', '9606', (97, 105))
592650	28638113	identified MET mutations that caused exon 14 skipping in 8 of 36 (22%) patient cases.	('patient', 'Species', '9606', (71, 78))	('caused', 'Reg', (30, 36))	('mutations', 'Var', (15, 24))	('skipping', 'MPA', (45, 53))
592651	28638113	In addition, in their cohort, a 74-year-old woman with stage IV PSC (widespread disease with lung, liver, and bulky mesenteric disease) was noted 3 months after resection of a tumor that harbored MET exon 14 skipping.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('woman', 'Species', '9606', (44, 49))	('tumor', 'Disease', (176, 181))	('MET exon 14 skipping', 'Var', (196, 216))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
592652	28638113	Based on the presence of MET mutations, 250 mg of crizotinib was administered orally twice daily, which provided rapid and dramatic clinical improvement that was later confirmed radiographically as an excellent partial response using computed tomography scanning.	('improvement', 'PosReg', (141, 152))	('crizotinib', 'Chemical', 'MESH:D000077547', (50, 60))	('MET mutations', 'Var', (25, 38))	('men', 'Species', '9606', (148, 151))
592654	28638113	Although our sample size was small because of limitations in the sample time requirements, our genetic analysis confirms that PSC harbors a high frequency of mutations in the TP53 gene, similarly to some previous studies, suggesting that PSC is a distinct subtype of NSCLC.	('PSC', 'Disease', (238, 241))	('TP53', 'Gene', (175, 179))	('TP53', 'Gene', '7157', (175, 179))	('men', 'Species', '9606', (84, 87))	('PSC', 'Disease', (126, 129))	('NSCLC', 'Disease', (267, 272))	('mutations', 'Var', (158, 167))	('NSCLC', 'Disease', 'MESH:D002289', (267, 272))
592655	28638113	Furthermore, more functional studies should be conducted to identify new mechanisms and therapies for PSC patients with TP53 point mutations.	('PSC', 'Disease', (102, 105))	('patients', 'Species', '9606', (106, 114))	('point mutations', 'Var', (125, 140))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
592703	25745611	Further, a CD4+ count <100/mm3 belonged to major aphthous ulcers, necrotizing ulcerative periodontitis, Kaposi sarcoma, and HSV ulcers.	('necrotizing ulcerative periodontitis', 'Disease', (66, 102))	('aphthous ulcers', 'Disease', (49, 64))	('HSV ulcers', 'Disease', 'MESH:D014456', (124, 134))	('CD4+ count <100/mm3', 'Var', (11, 30))	('aphthous ulcer', 'Phenotype', 'HP:0032154', (49, 63))	('HSV ulcers', 'Disease', (124, 134))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (104, 118))	('periodontitis', 'Phenotype', 'HP:0000704', (89, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('aphthous ulcers', 'Phenotype', 'HP:0032154', (49, 64))	('Kaposi sarcoma', 'Disease', (104, 118))
592737	25435996	The risk of tumor recurrence, metastasis and mortality was higher in the patients with a tumor >5.0 cm in diameter compared with those with a tumor <=5.0 cm in diameter (Table III).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('metastasis', 'CPA', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('>5.0 cm', 'Var', (95, 102))	('tumor', 'Disease', (12, 17))	('patients', 'Species', '9606', (73, 81))	('mortality', 'CPA', (45, 54))	('tumor', 'Disease', (89, 94))
592767	24206917	Originally associated with hemotologic cancers, fusion genes have recently been discovered in a wide array of solid tumors, including sarcomas, carcinomas, and tumors of the central nervous system.	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (160, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('tumors of the central nervous system', 'Disease', (160, 196))	('carcinomas', 'Disease', 'MESH:D002277', (144, 154))	('sarcomas', 'Disease', (134, 142))	('hemotologic cancers', 'Disease', 'MESH:D009369', (27, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('hemotologic cancers', 'Disease', (27, 46))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('discovered', 'Reg', (80, 90))	('carcinomas', 'Disease', (144, 154))	('associated', 'Reg', (11, 21))	('fusion genes', 'Var', (48, 60))	('solid tumors', 'Disease', (110, 122))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (160, 196))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
592768	24206917	Fusion genes are attractive as both therapeutic targets and diagnostic tools due to their inherent expression in tumor tissue alone.	('tumor', 'Disease', (113, 118))	('Fusion', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))
592769	24206917	Therefore, the discovery and elucidation of fusion genes in various cancer types may provide more effective therapies in the future for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('patients', 'Species', '9606', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (68, 74))	('fusion genes', 'Var', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
592770	24206917	Genomic instability, or the rearrangement of the genome inside of a cell, can result in cancer as well as other diseases.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('result in', 'Reg', (78, 87))	('rearrangement', 'Var', (28, 41))	('Genomic', 'MPA', (0, 7))	('men', 'Species', '9606', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
592771	24206917	Genomic instability can describe gene mutations, translocations, copy number alterations, deletions, and inversions of pieces of DNA or even single nucleotides.	('translocations', 'Var', (49, 63))	('rat', 'Species', '10116', (81, 84))	('copy number alterations', 'Var', (65, 88))	('gene mutations', 'Var', (33, 47))	('inversions', 'Var', (105, 115))	('deletions', 'Var', (90, 99))
592774	24206917	Conversely, tumor suppressor genes also exist, and mutation or deletion of these genes can cause cancer.	('cause', 'Reg', (91, 96))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutation', 'Var', (51, 59))	('deletion', 'Var', (63, 71))	('tumor', 'Disease', (12, 17))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
592779	24206917	When mutated in a high-grade brain tumor, EGFR becomes constitutively activated.	('brain tumor', 'Disease', (29, 40))	('EGFR', 'Gene', '1956', (42, 46))	('brain tumor', 'Disease', 'MESH:D001932', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('EGFR', 'Gene', (42, 46))	('brain tumor', 'Phenotype', 'HP:0030692', (29, 40))	('mutated', 'Var', (5, 12))
592780	24206917	Other genetic events, including gene translocations and deletions, can also occur and lead to cancer.	('gene translocations', 'Var', (32, 51))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('deletions', 'Var', (56, 65))	('lead to', 'Reg', (86, 93))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
592792	24206917	Since then, dozens of fusions have been identified in hematologic cancers, some of which have exhibited vast therapeutic benefit when targeted.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('fusions', 'Var', (22, 29))	('hematologic cancers', 'Disease', 'MESH:D009369', (54, 73))	('hematologic cancers', 'Disease', (54, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('identified', 'Reg', (40, 50))
592795	24206917	For example, the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) fusion found in nearly 95% of acute promyelocytic leukemias occurs via reciprocal translocation of chromosomes 15 and 17, producing fusions that contain the oncogenic retinoic acid receptor alpha.	('leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('retinoic acid receptor alpha', 'Gene', '5914', (249, 277))	('fusions', 'Var', (214, 221))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (17, 39))	('RARA', 'Gene', (76, 80))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (118, 140))	('retinoic acid receptor alpha', 'Gene', (46, 74))	('promyelocytic leukemia', 'Disease', (17, 39))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('promyelocytic leukemias', 'Disease', (118, 141))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (118, 140))	('retinoic acid receptor alpha', 'Gene', '5914', (46, 74))	('fusion', 'Var', (82, 88))	('leukemias', 'Phenotype', 'HP:0001909', (132, 141))	('retinoic acid receptor alpha', 'Gene', (249, 277))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (17, 39))	('promyelocytic leukemias', 'Disease', 'MESH:D015473', (118, 141))	('RARA', 'Gene', '5914', (76, 80))	('PML', 'Phenotype', 'HP:0004836', (41, 44))	('acute promyelocytic leukemias', 'Phenotype', 'HP:0004836', (112, 141))
592797	24206917	With the development of more sophisticated sequencing technologies came the discovery of fusion genes in solid tumors, including sarcoma, carcinoma, and tumors of the central nervous system (Figure 2).	('carcinoma', 'Disease', 'MESH:D002277', (138, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('fusion genes', 'Var', (89, 101))	('solid tumors', 'Disease', 'MESH:D009369', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('carcinoma', 'Disease', (138, 147))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (153, 189))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('men', 'Species', '9606', (16, 19))	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (153, 189))	('tumors of the central nervous system', 'Disease', (153, 189))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('sarcoma', 'Disease', (129, 136))	('solid tumors', 'Disease', (105, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
592806	24206917	The first detected fusion genes in sarcoma were found in a patient with Ewing sarcoma in 1983.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('fusion', 'Var', (19, 25))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 85))	('sarcoma', 'Disease', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('patient', 'Species', '9606', (59, 66))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('Ewing sarcoma', 'Disease', (72, 85))	('sarcoma', 'Disease', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))
592811	24206917	Epidemiologic studies have illustrated that several cancers show a survival correlation with high IGF-1 (the ligand for IGF-1R) and low IGFBP-3 (a binding protein of IGF-1R).	('cancers', 'Disease', (52, 59))	('IGF-1R', 'Gene', (120, 126))	('rat', 'Species', '10116', (33, 36))	('IGF-1R', 'Gene', '3480', (120, 126))	('high IGF-1', 'Phenotype', 'HP:0030269', (93, 103))	('IGFBP-3', 'Gene', (136, 143))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (132, 143))	('IGF-1', 'Gene', '3480', (98, 103))	('IGF-1', 'Gene', (98, 103))	('IGFBP-3', 'Gene', '3486', (136, 143))	('high', 'Var', (93, 97))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('IGF-1R', 'Gene', '3480', (166, 172))	('IGF-1R', 'Gene', (166, 172))	('IGF-1', 'Gene', '3480', (120, 125))	('IGF-1', 'Gene', (120, 125))	('low', 'NegReg', (132, 135))	('IGF-1', 'Gene', (166, 171))	('IGF-1', 'Gene', '3480', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
592816	24206917	Recent studies have identified another small subset of Ewing sarcoma patients who have fusions between the nuclear factor of activated T-cell transcription factor family with EWSR1.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (55, 68))	('fusions', 'Var', (87, 94))	('EWSR1', 'Gene', '2130', (175, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('Ewing sarcoma', 'Disease', (55, 68))	('patients', 'Species', '9606', (69, 77))	('EWSR1', 'Gene', (175, 180))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (55, 68))
592819	24206917	As mentioned previously, Ewing sarcoma is characterized by exhibiting fusions between EWSR1 and the ETS family of transcription factors.	('EWSR1', 'Gene', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Ewing sarcoma', 'Disease', (25, 38))	('ETS', 'Chemical', '-', (100, 103))	('EWSR1', 'Gene', '2130', (86, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (25, 38))	('fusions', 'Var', (70, 77))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (25, 38))	('men', 'Species', '9606', (3, 6))
592821	24206917	Specifically, fusions between the BCL-6 corepressor (BCOR) gene and cyclin B3 (CCNB3) gene were identified in 4% (24/594) of EWSR1-ETS-negative patients.	('ETS', 'Chemical', '-', (131, 134))	('cyclin B3', 'Gene', (68, 77))	('identified', 'Reg', (96, 106))	('EWSR1', 'Gene', (125, 130))	('BCL-6 corepressor', 'Gene', (34, 51))	('CCNB3', 'Gene', '85417', (79, 84))	('BCL-6 corepressor', 'Gene', '54880', (34, 51))	('BCOR', 'Gene', (53, 57))	('patients', 'Species', '9606', (144, 152))	('EWSR1', 'Gene', '2130', (125, 130))	('BCOR', 'Gene', '54880', (53, 57))	('cyclin B3', 'Gene', '85417', (68, 77))	('fusions', 'Var', (14, 21))	('CCNB3', 'Gene', (79, 84))
592822	24206917	The authors concluded that they discovered a new subset of "Ewing-like" tumors that are characterized by this BCOR-CCNB3 fusion but lack other known Ewing sarcoma fusions.	('BCOR', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CCNB3', 'Gene', (115, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('BCOR', 'Gene', '54880', (110, 114))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (149, 162))	('Ewing-like" tumors', 'Disease', (60, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('fusion', 'Var', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Ewing-like" tumors', 'Disease', 'MESH:C563168', (60, 78))	('CCNB3', 'Gene', '85417', (115, 120))	('Ewing sarcoma', 'Disease', (149, 162))	('Ewing-like" tumors', 'Phenotype', 'HP:0012254', (60, 78))
592829	24206917	The primary function of the SS18-SSX1 and SS18-SSX2 fusions is purportedly to regulate transcription, although no canonical DNA-binding domain exists in the fusion.	('SSX1', 'Gene', (33, 37))	('SSX2', 'Gene', '6757', (47, 51))	('regulate', 'Reg', (78, 86))	('SS18', 'Gene', '6760', (42, 46))	('SS18', 'Gene', (42, 46))	('transcription', 'MPA', (87, 100))	('SS18', 'Gene', '6760', (28, 32))	('SSX2', 'Gene', (47, 51))	('SSX1', 'Gene', '6756', (33, 37))	('fusions', 'Var', (52, 59))	('SS18', 'Gene', (28, 32))
592833	24206917	These sarcomas commonly harbor a translocation fusing EWSR1 on chromosome 22 to ATF1 on chromosome 12.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', '2130', (54, 59))	('sarcomas', 'Disease', (6, 14))	('ATF1', 'Gene', (80, 84))	('ATF1', 'Gene', '466', (80, 84))	('EWSR1', 'Gene', (54, 59))	('translocation', 'Var', (33, 46))	('sarcomas', 'Disease', 'MESH:D012509', (6, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))
592843	24206917	Fusions containing another androgen-regulated promoter for the solute carrier family 45, member 3 (SLC45A3) gene have also been reported to be fused to the same three ETS family members and behave in a similar fashion to TMPRSS2, although this fusion occurs less commonly.	('Fusions', 'Var', (0, 7))	('TMPRSS2', 'Gene', '7113', (221, 228))	('ETS', 'Chemical', '-', (167, 170))	('solute carrier family 45, member 3', 'Gene', '85414', (63, 97))	('TMPRSS2', 'Gene', (221, 228))	('SLC45A3', 'Gene', '85414', (99, 106))	('SLC45A3', 'Gene', (99, 106))
592851	24206917	This fusion, originally characterized in congenital fibrosarcoma, was found to promote oncogenesis via activation of the Ras-MAPK and PI3K-AKT pathways.	('congenital fibrosarcoma', 'Disease', (41, 64))	('fusion', 'Var', (5, 11))	('congenital fibrosarcoma', 'Disease', 'MESH:D005354', (41, 64))	('AKT', 'Gene', '207', (139, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('MAPK', 'Gene', '5595;5594;5595', (125, 129))	('AKT', 'Gene', (139, 142))	('promote', 'PosReg', (79, 86))	('MAPK', 'Gene', (125, 129))	('activation', 'PosReg', (103, 113))	('oncogenesis', 'CPA', (87, 98))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (52, 64))
592856	24206917	Bladder cancer is historically associated with activating mutations in the FGFR3 gene but has recently been shown to also harbor FGFR3-TACC3 fusion in about 10% of patients.	('FGFR3', 'Gene', (129, 134))	('mutations', 'Var', (58, 67))	('FGFR3', 'Gene', (75, 80))	('Bladder cancer', 'Disease', (0, 14))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('TACC3', 'Gene', '10460', (135, 140))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGFR3', 'Gene', '2261', (129, 134))	('TACC3', 'Gene', (135, 140))	('FGFR3', 'Gene', '2261', (75, 80))	('patients', 'Species', '9606', (164, 172))	('activating', 'PosReg', (47, 57))
592883	24206917	The oncogenic function of the fusion is believed to be caused by overexpression of the ALK tyrosine kinase, which leads to constitutive activation of downstream signaling cascades, including Akt, MAPK, and signal transducer and activator of transcription 3 (STAT3).	('MAPK', 'Gene', '5595;5594;5595', (196, 200))	('Akt', 'Gene', '207', (191, 194))	('fusion', 'Var', (30, 36))	('MAPK', 'Gene', (196, 200))	('ALK', 'Gene', '238', (87, 90))	('Akt', 'Gene', (191, 194))	('activation', 'PosReg', (136, 146))	('STAT3', 'Gene', '6774', (258, 263))	('overexpression', 'PosReg', (65, 79))	('signal transducer and activator of transcription 3', 'Gene', '6774', (206, 256))	('ALK', 'Gene', (87, 90))	('STAT3', 'Gene', (258, 263))
592884	24206917	The ALK inhibitor PF02341066, known as crizontinib, is currently undergoing clinical trials and has demonstrated significant clinical efficacy thus far in patients with EML4-ALK-positive NSCLC.	('ALK', 'Gene', '238', (4, 7))	('EML4', 'Gene', '27436', (169, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('PF02341066', 'Chemical', 'MESH:D000077547', (18, 28))	('ALK', 'Gene', (174, 177))	('ALK', 'Gene', (4, 7))	('NSCLC', 'Disease', (187, 192))	('crizontinib', 'Chemical', '-', (39, 50))	('PF02341066', 'Var', (18, 28))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('patients', 'Species', '9606', (155, 163))	('EML4', 'Gene', (169, 173))	('ALK', 'Gene', '238', (174, 177))	('rat', 'Species', '10116', (107, 110))
592891	24206917	In 2009, a group discovered the MYB-nuclear factor 1 B-type (NFIB) fusion, which formed as a result of translocation between chromosomes 6 and 9, with on occurrence rate of 90%.	('rat', 'Species', '10116', (165, 168))	('MYB', 'Gene', '4602', (32, 35))	('translocation', 'Var', (103, 116))	('MYB', 'Gene', (32, 35))	('NFIB', 'Gene', (61, 65))	('NFIB', 'Gene', '4781', (61, 65))
592894	24206917	In fact, pleomorphic salivary gland adenomas have also been shown to harbor fusions of NFIB with high mobility group AT-Hook 2 (HMGA2).	('NFIB', 'Gene', (87, 91))	('high mobility group AT-Hook 2', 'Gene', (97, 126))	('HMGA2', 'Gene', (128, 133))	('high mobility group AT-Hook 2', 'Gene', '8091', (97, 126))	('pleomorphic salivary gland adenomas', 'Disease', 'MESH:C563250', (9, 44))	('NFIB', 'Gene', '4781', (87, 91))	('fusions', 'Var', (76, 83))	('pleomorphic salivary gland adenomas', 'Disease', (9, 44))	('HMGA2', 'Gene', '8091', (128, 133))
592895	24206917	The formation of the MYB-NFIB fusion resulted in the deletion of the 3' untranslated region of MYB.	('resulted in', 'Reg', (37, 48))	('deletion', 'Var', (53, 61))	('MYB', 'Gene', '4602', (95, 98))	('MYB', 'Gene', (95, 98))	('MYB', 'Gene', '4602', (21, 24))	('NFIB', 'Gene', (25, 29))	('MYB', 'Gene', (21, 24))	('NFIB', 'Gene', '4781', (25, 29))
592900	24206917	The mucoepidermoid carcinoma translocated 1 (MECT1)-Notch coactivator mastermind-like protein 2 (MAML2) fusion occurs in approximately 60% of patients with mucoepidermoid carcinoma and contains the MECT1 gene, also known as CREB-regulated transcription coactivator 1, fused to MAML2.	('MECT1', 'Gene', (198, 203))	('CREB-regulated transcription coactivator 1', 'Gene', '23373', (224, 266))	('CREB-regulated transcription coactivator 1', 'Gene', (224, 266))	('Notch', 'Gene', (52, 57))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (156, 180))	('MAML2', 'Gene', '84441', (277, 282))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (4, 28))	('MECT1', 'Gene', (45, 50))	('mucoepidermoid carcinoma translocated 1', 'Gene', '23373', (4, 43))	('mucoepidermoid carcinoma translocated 1', 'Gene', (4, 43))	('mastermind-like protein 2', 'Gene', '84441', (70, 95))	('Notch', 'Gene', '25496', (52, 57))	('MECT1', 'Gene', '23373', (198, 203))	('fusion', 'Var', (104, 110))	('MAML2', 'Gene', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('mastermind-like protein 2', 'Gene', (70, 95))	('MAML2', 'Gene', '84441', (97, 102))	('patients', 'Species', '9606', (142, 150))	('mucoepidermoid carcinoma', 'Disease', (156, 180))	('MAML2', 'Gene', (277, 282))	('MECT1', 'Gene', '23373', (45, 50))
592901	24206917	The fusion was found to induce Notch signaling and cause cellular transformation of RK3E epithelial cells.	('induce', 'Reg', (24, 30))	('Notch', 'Gene', '25496', (31, 36))	('cellular transformation', 'CPA', (57, 80))	('fusion', 'Var', (4, 10))	('Notch', 'Gene', (31, 36))	('cause', 'Reg', (51, 56))	('RK3', 'CellLine', 'CVCL:0503', (84, 87))
592902	24206917	Recent studies have shown that the presence of MAML2 rearrangements as measured by fluorescence in situ hybridization can be used as a mean to distinguish mucoepidermoid carcinoma from other oncocytic lesions.	('MAML2', 'Gene', (47, 52))	('men', 'Species', '9606', (62, 65))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (155, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('oncocytic lesions', 'Disease', (191, 208))	('mucoepidermoid carcinoma', 'Disease', (155, 179))	('rearrangements', 'Var', (53, 67))	('oncocytic lesions', 'Disease', 'MESH:C535584', (191, 208))	('MAML2', 'Gene', '84441', (47, 52))
592907	24206917	In 2000, the paired box gene 8 (PAX8)-peroxisome proliferator-activated receptor gamma (PPARG) fusion was identified in 60% of follicular thyroid cancer cases.	('thyroid cancer', 'Disease', (138, 152))	('paired box gene 8', 'Gene', '7849', (13, 30))	('thyroid cancer', 'Phenotype', 'HP:0002890', (138, 152))	('thyroid cancer', 'Disease', 'MESH:D013964', (138, 152))	('PPARG', 'Gene', (88, 93))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (38, 86))	('PAX8', 'Gene', '7849', (32, 36))	('peroxisome proliferator-activated receptor gamma', 'Gene', (38, 86))	('paired box gene 8', 'Gene', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (127, 152))	('PAX8', 'Gene', (32, 36))	('fusion', 'Var', (95, 101))
592936	24206917	Genomic instability is a hallmark of cancer and can be described as gene mutation, amplification, translocation, deletion, and inversion events.	('hallmark of cancer', 'Disease', (25, 43))	('deletion', 'Var', (113, 121))	('hallmark of cancer', 'Disease', 'MESH:D009369', (25, 43))	('Genomic', 'MPA', (0, 7))	('gene mutation', 'Var', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('translocation', 'Var', (98, 111))	('amplification', 'Var', (83, 96))
592937	24206917	The discovery of fusion genes in hematologic malignancies in the 1970s led to the development of potent therapeutics.	('fusion genes', 'Var', (17, 29))	('men', 'Species', '9606', (89, 92))	('hematologic malignancies', 'Disease', 'MESH:D019337', (33, 57))	('hematologic malignancies', 'Disease', (33, 57))
592955	23199369	It is possible that such damage facilitates entry of environmental pathogens and their dissemination in the human body leading to opportunistic infections.	('damage', 'Var', (25, 31))	('entry', 'MPA', (44, 49))	('opportunistic infections', 'Disease', (130, 154))	('leading to', 'Reg', (119, 129))	('human', 'Species', '9606', (108, 113))	('dissemination', 'CPA', (87, 100))	('opportunistic infections', 'Disease', 'MESH:D009894', (130, 154))	('facilitates', 'PosReg', (32, 43))	('opportunistic infections', 'Phenotype', 'HP:0031690', (130, 154))
592977	23199369	Low CD4 cell counts were also a risk factor for CM and PCP (Supplementary Table 2).	('PCP', 'Disease', (55, 58))	('CD4', 'Gene', (4, 7))	('CM', 'Disease', 'MESH:D009202', (48, 50))	('CD4', 'Gene', '920', (4, 7))	('Low', 'Var', (0, 3))
593142	33738084	Genetic mutations of the 12q14-15 chromosome and amplification of the oncogenes MDM2 and CDK4, are commonly found.	('MDM2', 'Gene', (80, 84))	('amplification', 'Var', (49, 62))	('CDK4', 'Gene', (89, 93))	('CDK4', 'Gene', '1019', (89, 93))	('MDM2', 'Gene', '4193', (80, 84))
593143	33738084	Myogenic dedifferentiation in other sarcomas such as UPS and malignant peripheral nerve sheath tumors (MPNST) have shown a worse prognosis: lower OS and lower DFS.	('malignant peripheral nerve sheath tumors', 'Disease', (61, 101))	('lower OS', 'Disease', (140, 148))	('dedifferentiation', 'Var', (9, 26))	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (61, 101))	('lower DFS', 'Disease', (153, 162))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('MPNST', 'Phenotype', 'HP:0100697', (103, 108))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (61, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('sarcomas', 'Disease', (36, 44))
593170	33738084	However, ddLPS has genetic differences: abnormalities of the c-Jun pathway characterized by co-amplifications of the 1p32 and 6q23 genes, this event is implicated in the progression from a WD to a DD liposarcoma.	('c-Jun', 'Gene', '3725', (61, 66))	('liposarcoma', 'Phenotype', 'HP:0012034', (200, 211))	('implicated', 'Reg', (152, 162))	('ddLPS', 'Disease', (9, 14))	('6q23', 'Gene', (126, 130))	('c-Jun', 'Gene', (61, 66))	('DD liposarcoma', 'Disease', (197, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (204, 211))	('1p32', 'Gene', (117, 121))	('abnormalities', 'Var', (40, 53))	('ddLPS', 'Disease', 'None', (9, 14))	('WD', 'Disease', 'MESH:D006527', (189, 191))	('DD liposarcoma', 'Disease', 'MESH:D008080', (197, 211))
593198	30210797	Positivity for CD5 and CD23 indicated the diagnosis of CLL.	('CLL', 'Phenotype', 'HP:0005550', (55, 58))	('CLL', 'Disease', (55, 58))	('CD23', 'Gene', '2208', (23, 27))	('CD5', 'Gene', (15, 18))	('Positivity', 'Var', (0, 10))	('CD5', 'Gene', '921', (15, 18))	('CD23', 'Gene', (23, 27))
593248	29884132	In the present report, we describe the results of a FIH, first in class phase I study evaluating the use of 111In-OTSA-101 and 90Y-OTSA-101 in patients with advanced synovial sarcoma following a theranostic approach.	('111In-OTSA-101', 'Var', (108, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (166, 182))	('111In-OTSA-101', 'Chemical', '-', (108, 122))	('synovial sarcoma', 'Disease', 'MESH:D013584', (166, 182))	('90Y-OTSA-101', 'Var', (127, 139))	('patients', 'Species', '9606', (143, 151))	('synovial sarcoma', 'Disease', (166, 182))
593259	29884132	The main aims were to evaluate the in vivo tumor binding 111In-OTSA-101 and the feasibility of a theranostic approach.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('111In-OTSA-101', 'Var', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('111In-OTSA-101', 'Chemical', '-', (57, 71))	('tumor', 'Disease', (43, 48))
593288	29884132	Among them, 10 had insufficient tumor uptake making them ineligible for Part 2 and 10 patients have shown significant tumor uptake of whom: i) 8 patients were randomized in the Therapeutic part (3 patients in Arm A (370 MBq of 90Y) and 5 patients in Arm B (1110 MBq of 90Y)) and ii) 2 patients were not randomized and not treated with 90Y-OTSA-101 due to rapid general health status deterioration leading to early deaths (Fig.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('patients', 'Species', '9606', (197, 205))	('deaths', 'Disease', 'MESH:D003643', (414, 420))	('patients', 'Species', '9606', (86, 94))	('deaths', 'Disease', (414, 420))	('370 MBq of', 'Var', (216, 226))	('health status deterioration', 'Phenotype', 'HP:0001268', (369, 396))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('insufficient tumor', 'Disease', 'MESH:D000309', (19, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (118, 123))	('patients', 'Species', '9606', (285, 293))	('tumor', 'Disease', (32, 37))	('patients', 'Species', '9606', (238, 246))	('insufficient tumor', 'Disease', (19, 37))
593333	29884132	Indeed, some patients had very low or no significant uptake of 111InOTSA-101 while in some patients we observed rapid uptake of target lesions.	('uptake', 'MPA', (53, 59))	('patients', 'Species', '9606', (91, 99))	('111InOTSA-101', 'Chemical', '-', (63, 76))	('patients', 'Species', '9606', (13, 21))	('111InOTSA-101', 'Var', (63, 76))
593346	29884132	Some bulky tumors demonstrated heterogeneous tracer uptake as a result of the various tumors vascularizations, tumor necrosis depending on tumor size, the capacity of the antibody to diffuse into the tumors, the expression of FZD10, the antibody internalization.	('heterogeneous tracer uptake', 'MPA', (31, 58))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Disease', (139, 144))	('expression', 'Var', (212, 222))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (11, 16))	('tumors', 'Disease', (86, 92))	('tumor', 'Disease', (200, 205))	('FZD10', 'Gene', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('diffuse', 'MPA', (183, 190))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (111, 116))	('internalization', 'MPA', (246, 261))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor necrosis', 'Disease', 'MESH:D009336', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', (200, 206))	('tumor necrosis', 'Disease', (111, 125))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
593354	29884132	Other isotopes such as Lutetium 177 (177Lu) for example are associated with reduced bone marrow suppression compared to 90Y, due to a shorter mean pathway of less energetic electrons emitted (12 mm mean pathway in the water and Maximum 2270 Kev for 90Y vs 1.5 mm and 497 Kev for 177Lu).	('reduced bone marrow suppression', 'Disease', (76, 107))	('less energetic electrons emitted', 'MPA', (158, 190))	('water', 'Chemical', 'MESH:D014867', (218, 223))	('reduced bone marrow suppression', 'Disease', 'MESH:D001855', (76, 107))	('Lutetium 177', 'Var', (23, 35))	('shorter', 'NegReg', (134, 141))	('Lutetium', 'Chemical', 'MESH:D008187', (23, 31))
593367	29884132	As a recent example, PSMA was first targeted with antibodies (J591) for diagnosis and therapeutic purpose of prostate adenocarcinoma.	('antibodies', 'Var', (50, 60))	('PSMA', 'Gene', (21, 25))	('prostate adenocarcinoma', 'Disease', (109, 132))	('PSMA', 'Gene', '2346', (21, 25))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (109, 132))
593368	29884132	The maximum tolerated dose (MTD) due to marrow toxicity was 4 times lower when using 90Y-J591 than with 177Lu-J591.	('marrow toxicity', 'Disease', 'MESH:D001855', (40, 55))	('marrow toxicity', 'Disease', (40, 55))	('90Y-J591', 'Var', (85, 93))	('lower', 'NegReg', (68, 73))
593446	27291997	Fatigue and neutropenia of grade 3 or higher were more frequent with olaratumab+doxorubicin (6 [9%] and 35 [55%]) than with doxorubicin (2 [3%] and 22 [34%]).	('olaratumab', 'Chemical', 'MESH:C000589393', (69, 79))	('Fatigue', 'Phenotype', 'HP:0012378', (0, 7))	('olaratumab+doxorubicin', 'Var', (69, 91))	('doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('neutropenia', 'Phenotype', 'HP:0001875', (12, 23))	('neutropenia', 'Disease', (12, 23))	('neutropenia', 'Disease', 'MESH:D009503', (12, 23))	('Fatigue', 'Disease', (0, 7))	('doxorubicin', 'Chemical', 'MESH:D004317', (80, 91))
593448	27291997	The percentage of patients who discontinued treatment because of an adverse event was lower with olaratumab+doxorubicin than with doxorubicin (8 [13%] vs 12 [19%]).	('olaratumab+doxorubicin', 'Var', (97, 119))	('doxorubicin', 'Chemical', 'MESH:D004317', (130, 141))	('olaratumab', 'Chemical', 'MESH:C000589393', (97, 107))	('lower', 'NegReg', (86, 91))	('patients', 'Species', '9606', (18, 26))	('doxorubicin', 'Chemical', 'MESH:D004317', (108, 119))
593572	24082913	AM is also positive for CEA, Ki67 (>50% of tumor nuclei) and p53 while it is negative for estrogen receptor, progesterone receptor and in the majority of cases also negative for high risk HPV DNA.	('CEA', 'Gene', (24, 27))	('N', 'Chemical', 'MESH:D009584', (193, 194))	('progesterone receptor', 'Gene', (109, 130))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('estrogen receptor', 'Gene', (90, 107))	('HPV', 'Species', '10566', (188, 191))	('estrogen receptor', 'Gene', '2099', (90, 107))	('positive', 'Reg', (11, 19))	('progesterone receptor', 'Gene', '5241', (109, 130))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CEA', 'Gene', '1048', (24, 27))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('tumor', 'Disease', (43, 48))	('Ki67', 'Var', (29, 33))
593587	24082913	As with all endometrial adenocarcinomas, other predisposing factors include nulliparity, diabetes and obesity.	('diabetes', 'Disease', (89, 97))	('obesity', 'Phenotype', 'HP:0001513', (102, 109))	('diabetes', 'Disease', 'MESH:D003920', (89, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('endometrial adenocarcinomas', 'Disease', (12, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (12, 38))	('obesity', 'Disease', 'MESH:D009765', (102, 109))	('nulliparity', 'Var', (76, 87))	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (12, 39))	('obesity', 'Disease', (102, 109))
593631	32922522	In contrast to other types of lung cancers, recent retrospective studies demonstrated that PSC shows frequent genetic mutations.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('genetic mutations', 'Var', (110, 127))	('lung cancers', 'Disease', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('lung cancers', 'Disease', 'MESH:D008175', (30, 42))	('PSC', 'Disease', (91, 94))	('lung cancers', 'Phenotype', 'HP:0100526', (30, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))
593647	32922522	Histologic type, time from symptom onset to diagnosis, tumor invasiveness, tumor growth, distant metastases, P stage, extent of surgical resection, vascular/lymphatic invasion, and gene mutations such as programmed cell death ligand-1 (PD-L1), TLG-P, and KRAS mutations are independent prognostic factors in PSC.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('KRAS', 'Gene', '3845', (255, 259))	('tumor invasiveness', 'Disease', (55, 73))	('metastases', 'Disease', (97, 107))	('PD-L1', 'Gene', (236, 241))	('tumor invasiveness', 'Disease', 'MESH:D009361', (55, 73))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('TLG-P', 'Gene', (244, 249))	('KRAS', 'Gene', (255, 259))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('PSC', 'Disease', (308, 311))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('PD-L1', 'Gene', '29126', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutations', 'Var', (260, 269))	('tumor', 'Disease', (75, 80))
593648	32922522	Patients with pStage >II showed a lower survival probability compared with the patients with lower-stage disease.	('lower', 'NegReg', (34, 39))	('lower-stage disease', 'Disease', 'MESH:D058625', (93, 112))	('Patients', 'Species', '9606', (0, 8))	('pStage >II', 'Var', (14, 24))	('survival probability', 'CPA', (40, 60))	('patients', 'Species', '9606', (79, 87))	('lower-stage disease', 'Disease', (93, 112))
593649	32922522	Patients with pN0 disease had a high rate of vascular invasion (57.1%), indicating that distant metastases may often occur in the early stage; this phenomenon might explain why N stage does not affect prognosis.	('vascular invasion', 'CPA', (45, 62))	('pN0', 'Var', (14, 17))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('Patients', 'Species', '9606', (0, 8))	('men', 'Species', '9606', (153, 156))	('metastases', 'Disease', (96, 106))
593670	32922522	Six patients with KRAS gene mutation showed a higher SUVmax than that of patients without mutation.	('KRAS', 'Gene', (18, 22))	('higher', 'PosReg', (46, 52))	('KRAS', 'Gene', '3845', (18, 22))	('SUVmax', 'MPA', (53, 59))	('mutation', 'Var', (28, 36))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (73, 81))
593726	32922522	SCC and pleomorphic carcinoma have TP53, KRAS and EGFR mutations, MET and FGFR2 amplification, EML4-ALK gene rearrangement, etc.	('EML4', 'Gene', (95, 99))	('TP53', 'Gene', '7157', (35, 39))	('EML4', 'Gene', '27436', (95, 99))	('FGFR2', 'Gene', (74, 79))	('ALK', 'Gene', (100, 103))	('EGFR', 'Gene', (50, 54))	('KRAS', 'Gene', '3845', (41, 45))	('MET', 'Gene', '79811', (66, 69))	('FGFR2', 'Gene', '2263', (74, 79))	('KRAS', 'Gene', (41, 45))	('mutations', 'Var', (55, 64))	('TP53', 'Gene', (35, 39))	('EGFR', 'Gene', '1956', (50, 54))	('SCC', 'Gene', '6317', (0, 3))	('men', 'Species', '9606', (118, 121))	('pleomorphic carcinoma', 'Disease', (8, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('amplification', 'Var', (80, 93))	('SCC', 'Gene', (0, 3))	('pleomorphic carcinoma', 'Disease', 'MESH:D008228', (8, 29))	('MET', 'Gene', (66, 69))	('ALK', 'Gene', '238', (100, 103))
593727	32922522	The most common change of gene in carcinosarcoma is TP53 mutation, while KRAS and EGFR mutations are relatively rare.	('mutation', 'Var', (57, 65))	('EGFR', 'Gene', (82, 86))	('KRAS', 'Gene', (73, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('TP53', 'Gene', '7157', (52, 56))	('KRAS', 'Gene', '3845', (73, 77))	('TP53', 'Gene', (52, 56))	('carcinosarcoma', 'Disease', (34, 48))	('EGFR', 'Gene', '1956', (82, 86))	('carcinosarcoma', 'Disease', 'MESH:D002296', (34, 48))
593728	32922522	Both low-grade fetal lung adenocarcinoma and lung blastoma are associated with missense mutations in exon 3 of the CTNNB1 gene, causing large expression of beta-catenin protein in the cytoplasm to enter the nucleus to activate Wnt signaling pathway activity.	('activate', 'PosReg', (218, 226))	('CTNNB1', 'Gene', '1499', (115, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (21, 40))	('associated', 'Reg', (63, 73))	('missense mutations in', 'Var', (79, 100))	('beta-catenin', 'Gene', (156, 168))	('Wnt signaling pathway', 'Pathway', (227, 248))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('activity', 'MPA', (249, 257))	('lung blastoma', 'Disease', 'MESH:D018202', (45, 58))	('expression', 'MPA', (142, 152))	('CTNNB1', 'Gene', (115, 121))	('lung blastoma', 'Disease', (45, 58))	('lung adenocarcinoma', 'Disease', (21, 40))	('beta-catenin', 'Gene', '1499', (156, 168))	('lung blastoma', 'Phenotype', 'HP:0100528', (45, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
593734	32922522	A total of 39 PSC cases (80%) showed at least one mutation (with the highest mutation rates in TP53, KRAS, PTEN, KDR, ERBB2 and PIK3CA), and 69% of variants were somatic mutations.	('PIK3CA', 'Gene', '5290', (128, 134))	('PSC', 'Disease', (14, 17))	('ERBB2', 'Gene', (118, 123))	('PTEN', 'Gene', (107, 111))	('PTEN', 'Gene', '5728', (107, 111))	('KRAS', 'Gene', (101, 105))	('KDR', 'Gene', '3791', (113, 116))	('KRAS', 'Gene', '3845', (101, 105))	('variants', 'Var', (148, 156))	('PIK3CA', 'Gene', (128, 134))	('KDR', 'Gene', (113, 116))	('TP53', 'Gene', '7157', (95, 99))	('ERBB2', 'Gene', '2064', (118, 123))	('TP53', 'Gene', (95, 99))
593739	32922522	In addition, a large diversity of alterations has been reported, based on NGS, including mutations in TP53, KRAS, PIK3CA, EGFR, NOTCH1, CDKN2A, CDKN2B, STK11, PTEN, NF1, and BRAF.	('KRAS', 'Gene', (108, 112))	('PIK3CA', 'Gene', '5290', (114, 120))	('TP53', 'Gene', (102, 106))	('PTEN', 'Gene', '5728', (159, 163))	('mutations', 'Var', (89, 98))	('CDKN2B', 'Gene', '1030', (144, 150))	('NOTCH1', 'Gene', '4851', (128, 134))	('NF1', 'Gene', '4763', (165, 168))	('EGFR', 'Gene', (122, 126))	('BRAF', 'Gene', '673', (174, 178))	('CDKN2A', 'Gene', (136, 142))	('BRAF', 'Gene', (174, 178))	('PIK3CA', 'Gene', (114, 120))	('STK11', 'Gene', (152, 157))	('NF1', 'Gene', (165, 168))	('TP53', 'Gene', '7157', (102, 106))	('CDKN2A', 'Gene', '1029', (136, 142))	('EGFR', 'Gene', '1956', (122, 126))	('STK11', 'Gene', '6794', (152, 157))	('PTEN', 'Gene', (159, 163))	('KRAS', 'Gene', '3845', (108, 112))	('CDKN2B', 'Gene', (144, 150))	('NOTCH1', 'Gene', (128, 134))
593740	32922522	There are several novel mutated genes, including LAMB4, CDH4, RASA1, CDK4, LMTK2, CDH7, BRCA1, BRCA2, SCAF1 and SMARCA4), ALK translocations, and MET alterations, have also been described, along with EGFR, TP53, PI3KCA, and other mutations.	('mutated', 'Var', (24, 31))	('SCAF1', 'Gene', '58506', (102, 107))	('SMARCA4', 'Gene', (112, 119))	('RASA1', 'Gene', '5921', (62, 67))	('CDK4', 'Gene', '1019', (69, 73))	('TP53', 'Gene', '7157', (206, 210))	('EGFR', 'Gene', (200, 204))	('MET', 'Gene', '79811', (146, 149))	('BRCA2', 'Gene', (95, 100))	('BRCA1', 'Gene', '672', (88, 93))	('ALK', 'Gene', '238', (122, 125))	('BRCA1', 'Gene', (88, 93))	('RASA1', 'Gene', (62, 67))	('LMTK2', 'Gene', '22853', (75, 80))	('CDH4', 'Gene', (56, 60))	('ALK', 'Gene', (122, 125))	('CDH7', 'Gene', (82, 86))	('CDH7', 'Gene', '1005', (82, 86))	('CDH4', 'Gene', '1002', (56, 60))	('LAMB4', 'Gene', '22798', (49, 54))	('SCAF1', 'Gene', (102, 107))	('BRCA2', 'Gene', '675', (95, 100))	('LMTK2', 'Gene', (75, 80))	('TP53', 'Gene', (206, 210))	('LAMB4', 'Gene', (49, 54))	('SMARCA4', 'Gene', '6597', (112, 119))	('EGFR', 'Gene', '1956', (200, 204))	('MET', 'Gene', (146, 149))	('CDK4', 'Gene', (69, 73))
593741	32922522	Patients with PSC showing a gene mutation had a lower rate of survival than those without mutations; multi-gene mutations were associated with a higher mortality rate than single-gene mutations.	('PSC', 'Disease', (14, 17))	('mortality', 'Disease', (152, 161))	('Patients', 'Species', '9606', (0, 8))	('mortality', 'Disease', 'MESH:D003643', (152, 161))	('multi-gene', 'Var', (101, 111))
593742	32922522	's research, KRAS mutations repel EGFR mutations, while EGFR and NOTCH1 mutations tended to correlate.	('EGFR', 'Gene', (34, 38))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', '1956', (34, 38))	('KRAS', 'Gene', (13, 17))	('mutations', 'Var', (39, 48))	('EGFR', 'Gene', (56, 60))	('NOTCH1', 'Gene', '4851', (65, 71))	('NOTCH1', 'Gene', (65, 71))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
593743	32922522	Compared with biphasic PSCs, pure tumors more commonly showed mutations of APC and KRAS.	('KRAS', 'Gene', (83, 87))	('tumors', 'Disease', (34, 40))	('KRAS', 'Gene', '3845', (83, 87))	('APC', 'Gene', '324', (75, 78))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('biphasic PSCs', 'Disease', (14, 27))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('biphasic PSCs', 'Disease', 'None', (14, 27))	('APC', 'Gene', (75, 78))	('mutations', 'Var', (62, 71))
593744	32922522	TP53 showed the opposite trend, with a higher rate of mutation in biphasic tumors.	('mutation', 'Var', (54, 62))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('biphasic tumors', 'Disease', 'MESH:D009369', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('biphasic tumors', 'Disease', (66, 81))
593745	32922522	PTEN and STK11 mutations occurred specifically in bipolar PSC.	('bipolar PSC', 'Disease', 'MESH:D015209', (50, 61))	('STK11', 'Gene', '6794', (9, 14))	('mutations', 'Var', (15, 24))	('PTEN', 'Gene', (0, 4))	('bipolar PSC', 'Disease', (50, 61))	('bipolar PSC', 'Phenotype', 'HP:0007302', (50, 61))	('STK11', 'Gene', (9, 14))	('occurred', 'Reg', (25, 33))	('PTEN', 'Gene', '5728', (0, 4))
593747	32922522	reported that blood vessel invasion had no correlation with PIK3CA, MET, or KRAS mutations.	('MET', 'Gene', (68, 71))	('blood vessel invasion', 'CPA', (14, 35))	('PIK3CA', 'Gene', (60, 66))	('KRAS', 'Gene', (76, 80))	('PIK3CA', 'Gene', '5290', (60, 66))	('KRAS', 'Gene', '3845', (76, 80))	('mutations', 'Var', (81, 90))	('MET', 'Gene', '79811', (68, 71))
593749	32922522	TP53 mutations are much more frequent in pure PSC than in mixed type tumors, TP53 mutations were found in approximately three quarters of patients.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('frequent', 'Reg', (29, 37))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (5, 14))	('pure PSC', 'Disease', (41, 49))	('type tumors', 'Disease', 'MESH:D009369', (64, 75))	('TP53', 'Gene', '7157', (77, 81))	('type tumors', 'Disease', (64, 75))	('TP53', 'Gene', (77, 81))	('patients', 'Species', '9606', (138, 146))
593751	32922522	A high rate of P53R2 protein was associated with poor OS; we can conclude that the presence of P53R2 is an important factor associated with poor prognosis in patients with PSC, and P53R2 expression is closely associated with the occurrence, development, and progression of PSC.	('associated with', 'Reg', (209, 224))	('P53R2', 'Gene', (15, 20))	('presence', 'Var', (83, 91))	('P53R2', 'Gene', '50484', (95, 100))	('men', 'Species', '9606', (248, 251))	('P53R2', 'Gene', '50484', (181, 186))	('P53R2', 'Gene', (181, 186))	('P53R2', 'Gene', (95, 100))	('PSC', 'Disease', (273, 276))	('associated', 'Reg', (124, 134))	('patients', 'Species', '9606', (158, 166))	('PSC', 'Disease', (172, 175))	('P53R2', 'Gene', '50484', (15, 20))
593752	32922522	Surprisingly, the rate of KRAS mutation is higher in pure PSC, occurring at a rate of 56% among 49 cases of PSC.	('KRAS', 'Gene', '3845', (26, 30))	('mutation', 'Var', (31, 39))	('pure PSC', 'Disease', (53, 61))	('KRAS', 'Gene', (26, 30))
593753	32922522	Codon 12/13 mutation in KRAS was the second most common mutation in the series by Mehrad et al.	('Codon 12/13 mutation', 'Var', (0, 20))	('KRAS', 'Gene', '3845', (24, 28))	('KRAS', 'Gene', (24, 28))
593755	32922522	In PSC cases, KRAS mutations seem to correlate with more aggressive tumor behavior, and were identified only in smokers, KRAS transversion mutations account for 79%.	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (57, 82))	('KRAS', 'Gene', (121, 125))	('KRAS', 'Gene', '3845', (14, 18))	('KRAS', 'Gene', '3845', (121, 125))	('aggressive tumor behavior', 'Disease', (57, 82))	('mutations', 'Var', (19, 28))	('PSC', 'Disease', (3, 6))	('more', 'PosReg', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('KRAS', 'Gene', (14, 18))
593756	32922522	stated that KRAS mutations would reduce the efficacy of chemotherapy drugs and oral targeted drugs in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('efficacy', 'MPA', (44, 52))	('KRAS', 'Gene', (12, 16))	('KRAS', 'Gene', '3845', (12, 16))	('chemotherapy drugs', 'CPA', (56, 74))	('NSCLC', 'Disease', (102, 107))	('mutations', 'Var', (17, 26))	('reduce', 'NegReg', (33, 39))
593767	32922522	Previous cases have shown that EGFR mutations could be detected in 8.8% of patients with lung sarcomatoid carcinoma.	('EGFR', 'Gene', '1956', (31, 35))	('detected', 'Reg', (55, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('EGFR', 'Gene', (31, 35))	('lung sarcomatoid carcinoma', 'Disease', (89, 115))	('mutations', 'Var', (36, 45))	('patients', 'Species', '9606', (75, 83))	('lung sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (89, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (94, 115))
593768	32922522	Adenocarcinomas with EGFR mutations are less likely to have high-grade sarcomatoid transformation than those with KRAS or ALK mutations, possibly because adenocarcinomas with EGFR mutations typically have low-level properties, lepidic growth areas, and a more indolent course than EGFR(-) tumors.	('Adenocarcinomas', 'Disease', 'MESH:D000230', (0, 15))	('mutations', 'Var', (26, 35))	('lepidic growth areas', 'CPA', (227, 247))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('sarcomatoid transformation', 'Disease', 'MESH:C538614', (71, 97))	('adenocarcinomas', 'Disease', 'MESH:D000230', (154, 169))	('EGFR', 'Gene', (281, 285))	('EGFR', 'Gene', '1956', (21, 25))	('adenocarcinomas', 'Disease', (154, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('KRAS', 'Gene', '3845', (114, 118))	('ALK', 'Gene', '238', (122, 125))	('sarcomatoid transformation', 'Disease', (71, 97))	('EGFR', 'Gene', (175, 179))	('mutations', 'Var', (180, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('KRAS', 'Gene', (114, 118))	('ALK', 'Gene', (122, 125))	('low-level properties', 'MPA', (205, 225))	('EGFR', 'Gene', '1956', (281, 285))	('EGFR', 'Gene', (21, 25))	('Adenocarcinomas', 'Disease', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumors', 'Disease', (289, 295))	('carcinomas', 'Phenotype', 'HP:0030731', (5, 15))	('EGFR', 'Gene', '1956', (175, 179))
593769	32922522	EGFR mutation plays an important role in the poor prognosis of NSCLC compared with classical NSCLC, which may explain the poorer outcome of PSC.	('NSCLC', 'Disease', (63, 68))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
593770	32922522	However, the incidence of EGFR mutation in patients with PSC in China is low.	('EGFR', 'Gene', (26, 30))	('patients', 'Species', '9606', (43, 51))	('mutation', 'Var', (31, 39))	('PSC', 'Disease', (57, 60))	('EGFR', 'Gene', '1956', (26, 30))
593773	32922522	Tobacco using, KRAS mutations, vascular invasion, CD163 positive cell level, and TTF-1 positivity were independent factors correlating with PD-L1 expression in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('KRAS', 'Gene', (15, 19))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('Tobacco', 'Species', '4097', (0, 7))	('PD-L1', 'Gene', (140, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('KRAS', 'Gene', '3845', (15, 19))	('PD-L1', 'Gene', '29126', (140, 145))	('expression', 'MPA', (146, 156))	('TTF-1', 'Gene', (81, 86))	('mutations', 'Var', (20, 29))	('lung cancer', 'Disease', (160, 171))	('TTF-1', 'Gene', '7270', (81, 86))
593782	32922522	Previous case reports have reported the following combinations: EGFR together with TP53 mutations; EML4-ALK fusion with a TP53 mutation; a positive EGFR mutation combined with PD-L1 overexpression; KRAS mutations in conjunction with TP53 mutations; JAK3 variant with a mutation in TP53; PIK3CA mutation plus KRAS mutation; and PHF20-NTRK1 fusion.	('PIK3CA', 'Gene', '5290', (287, 293))	('PD-L1', 'Gene', '29126', (176, 181))	('mutations', 'Var', (88, 97))	('JAK3', 'Gene', '3718', (249, 253))	('TP53', 'Gene', (83, 87))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (64, 68))	('PIK3CA', 'Gene', (287, 293))	('TP53', 'Gene', (281, 285))	('mutation', 'Var', (153, 161))	('TP53', 'Gene', (122, 126))	('EML4', 'Gene', (99, 103))	('TP53', 'Gene', (233, 237))	('mutation', 'Var', (127, 135))	('ALK', 'Gene', '238', (104, 107))	('EML4', 'Gene', '27436', (99, 103))	('NTRK1', 'Gene', '4914', (333, 338))	('KRAS', 'Gene', '3845', (198, 202))	('ALK', 'Gene', (104, 107))	('KRAS', 'Gene', '3845', (308, 312))	('mutations', 'Var', (203, 212))	('NTRK1', 'Gene', (333, 338))	('PHF20', 'Gene', '51230', (327, 332))	('TP53', 'Gene', '7157', (83, 87))	('JAK3', 'Gene', (249, 253))	('EGFR', 'Gene', (148, 152))	('KRAS', 'Gene', (198, 202))	('KRAS', 'Gene', (308, 312))	('PHF20', 'Gene', (327, 332))	('EGFR', 'Gene', '1956', (64, 68))	('TP53', 'Gene', '7157', (122, 126))	('TP53', 'Gene', '7157', (281, 285))	('mutation', 'Var', (269, 277))	('PD-L1', 'Gene', (176, 181))	('TP53', 'Gene', '7157', (233, 237))
593784	32922522	It's worth noting that the combination of KRAS and either TP53 or KRAS mutations independently correlated with OS in multivariable models.	('KRAS', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (42, 46))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (66, 70))	('correlated', 'Reg', (95, 105))	('mutations', 'Var', (71, 80))	('KRAS', 'Gene', (66, 70))
593785	32922522	Both the degree of mutation in KRAS and the presence of TP53 or KRAS mutations are associated with recurrence, especially in the context of local metastasis at relapse.	('mutations', 'Var', (69, 78))	('KRAS', 'Gene', (31, 35))	('mutation', 'Var', (19, 27))	('TP53', 'Gene', '7157', (56, 60))	('KRAS', 'Gene', '3845', (31, 35))	('KRAS', 'Gene', (64, 68))	('TP53', 'Gene', (56, 60))	('associated', 'Reg', (83, 93))	('KRAS', 'Gene', '3845', (64, 68))	('recurrence', 'Disease', (99, 109))
593786	32922522	Some studies have suggested that substantial tumor angiogenesis may lead to mutations in multiple genes, such as NF1, TP53, and others.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutations', 'Var', (76, 85))	('lead', 'Reg', (68, 72))	('tumor', 'Disease', (45, 50))	('NF1', 'Gene', (113, 116))	('TP53', 'Gene', '7157', (118, 122))	('NF1', 'Gene', '4763', (113, 116))	('TP53', 'Gene', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
593787	32922522	Mutations in the above genes lead to overexpression of proto-oncogenes and reduced expression of tumor-suppressor genes, which are involved in the occurrence and development of tumors.	('overexpression', 'PosReg', (37, 51))	('tumor-suppressor', 'Gene', (97, 113))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('men', 'Species', '9606', (169, 172))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('reduced', 'NegReg', (75, 82))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('expression', 'MPA', (83, 93))	('tumors', 'Disease', (177, 183))	('tumor-suppressor', 'Gene', '7248', (97, 113))
593790	32922522	For the genetic changes mentioned above, the therapeutic schedules, survival analyses, and prognoses of various targeted drug therapies are described in detail below.	('changes', 'Var', (16, 23))	('men', 'Species', '9606', (24, 27))	('genetic changes', 'Var', (8, 23))
593794	32922522	KRAS gene mutation may be sensitive to CDK 4/6 inhibitor (Abemaciclib) or MEK inhibitors (trametinib).	('CDK 4/6', 'Gene', (39, 46))	('KRAS', 'Gene', '3845', (0, 4))	('MEK', 'Gene', '5609', (74, 77))	('CDK 4/6', 'Gene', '1019;1021', (39, 46))	('mutation', 'Var', (10, 18))	('trametinib', 'Chemical', 'MESH:C560077', (90, 100))	('KRAS', 'Gene', (0, 4))	('MEK', 'Gene', (74, 77))
593795	32922522	TP53 mutations may be associated with the sensitivity of VEGF/VEGFR inhibitors.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('VEGFR', 'Gene', '3791', (62, 67))	('mutations', 'Var', (5, 14))	('VEGF', 'Gene', '7422', (62, 66))	('VEGF', 'Gene', (57, 61))	('VEGFR', 'Gene', (62, 67))	('associated', 'Reg', (22, 32))	('VEGF', 'Gene', (62, 66))	('VEGF', 'Gene', '7422', (57, 61))
593828	32922522	's investigation, for 45 of 114 patients receiving neoadjuvant or adjuvant chemotherapy, the survival rate was significantly improved compared with patients who did not receive neoadjuvant chemotherapy.	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (32, 40))	('survival rate', 'CPA', (93, 106))	('improved', 'PosReg', (125, 133))	('neoadjuvant', 'Var', (51, 62))
593854	32922522	However, discovery of a high proportion of mutant alleles in the same tumor leads to an expectation of good efficacy with the usage of targeted therapy.	('mutant', 'Var', (43, 49))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
593856	32922522	Recently, TKI has been recommended for the treatment of patients with EGFR mutations in NSCLC.	('patients', 'Species', '9606', (56, 64))	('men', 'Species', '9606', (28, 31))	('men', 'Species', '9606', (48, 51))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (70, 74))	('NSCLC', 'Disease', (88, 93))	('mutations', 'Var', (75, 84))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
593857	32922522	For patients with EGFR mutations who were initially treated with EGFR TKI, the mean OS was longer than that with platinum-based combination chemotherapy.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', (18, 22))	('platinum', 'Chemical', 'MESH:D010984', (113, 121))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (4, 12))
593867	32922522	Researchers, such as Hsieh et al., have used TKIs to treat patients with EGFR mutations (with or without other gene mutations) and found the MET copy numbers and gene expression were increased.	('EGFR', 'Gene', '1956', (73, 77))	('MET', 'Gene', '79811', (141, 144))	('Hsieh', 'Disease', (21, 26))	('Hsieh', 'Disease', 'None', (21, 26))	('increased', 'PosReg', (183, 192))	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('MET', 'Gene', (141, 144))	('patients', 'Species', '9606', (59, 67))	('gene expression', 'MPA', (162, 177))
593870	32922522	reported, one patient was positive for EGFR mutation, and gefitinib could be used.	('positive', 'Reg', (26, 34))	('mutation', 'Var', (44, 52))	('gefitinib', 'Chemical', 'MESH:D000077156', (58, 67))	('patient', 'Species', '9606', (14, 21))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
593875	32922522	's report, an elderly woman was diagnosed with SCC (stage IVb, T4N2M1) with an EGFR exon 19 deletion, and gefitinib was administered; however, the patients responded poorly to this EGFR TKI and progressed rapidly after a short-term response.	('woman', 'Species', '9606', (22, 27))	('EGFR', 'Gene', (181, 185))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('SCC', 'Gene', '6317', (47, 50))	('responded', 'MPA', (156, 165))	('deletion', 'Var', (92, 100))	('poorly', 'NegReg', (166, 172))	('patients', 'Species', '9606', (147, 155))	('gefitinib', 'Chemical', 'MESH:D000077156', (106, 115))	('EGFR', 'Gene', '1956', (181, 185))	('SCC', 'Gene', (47, 50))
593876	32922522	In a retrospective study, it was found that most patients with PSC were unlikely to benefit from anti-EGFR therapy due to low EGFR mutation rates and high KRAS mutation rates.	('KRAS', 'Gene', (155, 159))	('EGFR', 'Gene', (126, 130))	('KRAS', 'Gene', '3845', (155, 159))	('low', 'NegReg', (122, 125))	('EGFR', 'Gene', '1956', (126, 130))	('patients', 'Species', '9606', (49, 57))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('PSC', 'Disease', (63, 66))	('mutation', 'Var', (131, 139))
593881	32922522	For the rearrangement of rare genes, such as those of the ALK1 gene, patients can take a combination of crizotinib and ceritinib.	('rearrangement', 'Var', (8, 21))	('patients', 'Species', '9606', (69, 77))	('ALK1', 'Gene', (58, 62))	('ceritinib', 'Chemical', 'MESH:C586847', (119, 128))	('ALK1', 'Gene', '94', (58, 62))	('crizotinib', 'Chemical', 'MESH:D000077547', (104, 114))	('men', 'Species', '9606', (17, 20))
593886	32922522	The FDA has approved the new ALK inhibitor, brigatinib, which is effective in 55% of patients with lung cancer who have mutations that are drug resistant to crizotinib, with a control rate of 86%.	('ALK', 'Gene', (29, 32))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('patients', 'Species', '9606', (85, 93))	('brigatinib', 'Chemical', 'MESH:C000598580', (44, 54))	('crizotinib', 'Chemical', 'MESH:D000077547', (157, 167))	('ALK', 'Gene', '238', (29, 32))	('mutations', 'Var', (120, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
593889	32922522	In Liu's research, based on the presence of MET amplification, crizotinib brought about rapid dramatic clinical improvement.	('crizotinib', 'Gene', (63, 73))	('presence', 'Var', (32, 40))	('men', 'Species', '9606', (119, 122))	('improvement', 'PosReg', (112, 123))	('crizotinib', 'Chemical', 'MESH:D000077547', (63, 73))	('MET', 'Gene', '79811', (44, 47))	('MET', 'Gene', (44, 47))
593892	32922522	It has been reported that when patients with PSC have mutation in KRAS-ex2, as well as fusion in EML4-ALK, chemotherapy and crizotinib are not effective.	('mutation', 'Var', (54, 62))	('ALK', 'Gene', (102, 105))	('KRAS', 'Gene', '3845', (66, 70))	('crizotinib', 'Chemical', 'MESH:D000077547', (124, 134))	('patients', 'Species', '9606', (31, 39))	('EML4', 'Gene', (97, 101))	('ALK', 'Gene', '238', (102, 105))	('PSC', 'Disease', (45, 48))	('EML4', 'Gene', '27436', (97, 101))	('KRAS', 'Gene', (66, 70))
593895	32922522	MET gene mutations include amplification, point-mutation activation, and MET exon-14 skipping.	('MET', 'Gene', '79811', (0, 3))	('MET', 'Gene', '79811', (73, 76))	('activation', 'PosReg', (57, 67))	('MET', 'Gene', (0, 3))	('point-mutation', 'Var', (42, 56))	('MET', 'Gene', (73, 76))	('amplification', 'Var', (27, 40))
593896	32922522	The currently targeted drugs for MET mutations are crizotinib, capmatinib, tepotinib, and savolitinib (also known as AZD6094, HMPL-504, and volitinib, respectively).	('crizotinib', 'Chemical', 'MESH:D000077547', (51, 61))	('savolitinib', 'Chemical', 'MESH:C000593259', (90, 101))	('capmatinib', 'Chemical', 'MESH:C000613976', (63, 73))	('AZD6094', 'Chemical', 'MESH:C000593259', (117, 124))	('mutations', 'Var', (37, 46))	('tepotinib', 'Chemical', 'MESH:C582858', (75, 84))	('volitinib', 'Chemical', 'MESH:C000593259', (92, 101))	('HMPL-504', 'Chemical', 'MESH:C000593259', (126, 134))	('MET', 'Gene', '79811', (33, 36))	('volitinib', 'Chemical', 'MESH:C000593259', (140, 149))	('MET', 'Gene', (33, 36))
593899	32922522	As the patient's condition progressed, the research team found EGFR, fibroblast growth factor receptor 1 (FGFR1), and KRAS gene amplifications in tumor biopsies, from which it was speculated that targeted drug resistance could have been caused by the above genetic changes.	('EGFR', 'Gene', '1956', (63, 67))	('fibroblast growth factor receptor 1', 'Gene', (69, 104))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('FGFR1', 'Gene', (106, 111))	('patient', 'Species', '9606', (7, 14))	('EGFR', 'Gene', (63, 67))	('KRAS', 'Gene', (118, 122))	('fibroblast growth factor receptor 1', 'Gene', '2260', (69, 104))	('tumor', 'Disease', (146, 151))	('FGFR1', 'Gene', '2260', (106, 111))	('KRAS', 'Gene', '3845', (118, 122))	('amplifications', 'Var', (128, 142))	('drug resistance', 'Phenotype', 'HP:0020174', (205, 220))	('targeted drug resistance', 'MPA', (196, 220))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
593911	32922522	Programmed cell-death protein-1 (PD-1)/PD-L1 inhibition significantly enhances CD4+ and CD8+ T-lymphocyte cytokine secretion, cell proliferation, cytotoxicity, antitumor activity, and improves the clinical prognoses of patients with a variety of tumor types.	('CD8', 'Gene', '925', (88, 91))	('tumor', 'Disease', (164, 169))	('CD4', 'Gene', (79, 82))	('cytotoxicity', 'Disease', 'MESH:D064420', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('PD-L1', 'Gene', (39, 44))	('PD-L1', 'Gene', '29126', (39, 44))	('Programmed cell-death protein-1', 'Gene', (0, 31))	('clinical prognoses', 'CPA', (197, 215))	('patients', 'Species', '9606', (219, 227))	('PD-1', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('PD-1', 'Gene', '5133', (33, 37))	('CD8', 'Gene', (88, 91))	('cell proliferation', 'CPA', (126, 144))	('cytotoxicity', 'Disease', (146, 158))	('tumor', 'Disease', (246, 251))	('enhances', 'PosReg', (70, 78))	('improves', 'PosReg', (184, 192))	('CD4', 'Gene', '920', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('inhibition', 'Var', (45, 55))	('Programmed cell-death protein-1', 'Gene', '5133', (0, 31))
593932	32922522	Tumor lymphocyte infiltration is associated with positive PD-L1 expression and is a pre-existing immune response marker that has been used as an important predictor of the efficacy of these drugs.	('PD-L1', 'Gene', '29126', (58, 63))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('expression', 'MPA', (64, 74))	('positive', 'Var', (49, 57))	('Tumor lymphocyte infiltration', 'CPA', (0, 29))	('PD-L1', 'Gene', (58, 63))
593936	32922522	For PD-L1 positive patients, the ORR was 58.8%, and for PD-L1 negative patients, the ORR was 0% (p = 0.44).	('PD-L1', 'Gene', '29126', (56, 61))	('patients', 'Species', '9606', (19, 27))	('positive', 'Var', (10, 18))	('patients', 'Species', '9606', (71, 79))	('PD-L1', 'Gene', (4, 9))	('PD-L1', 'Gene', (56, 61))	('PD-L1', 'Gene', '29126', (4, 9))
593953	32922522	believe that when KRAS mutations and EML4-ALK rearrangements co-exist, TKIs, and first-line chemotherapy can be very beneficial in treating patients with PSC.	('men', 'Species', '9606', (55, 58))	('KRAS', 'Gene', (18, 22))	('ALK', 'Gene', '238', (42, 45))	('EML4', 'Gene', '27436', (37, 41))	('KRAS', 'Gene', '3845', (18, 22))	('PSC', 'Disease', (154, 157))	('mutations', 'Var', (23, 32))	('ALK', 'Gene', (42, 45))	('patients', 'Species', '9606', (140, 148))	('EML4', 'Gene', (37, 41))
593955	32922522	Genetic testing has suggested that a new PHF20-NTRK1 fusion mutation could be a driver of sarcomatous proliferation in patients with postoperative recurrences.	('mutation', 'Var', (60, 68))	('sarcomatous proliferation', 'Disease', 'MESH:D018316', (90, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('fusion mutation', 'Var', (53, 68))	('patients', 'Species', '9606', (119, 127))	('NTRK1', 'Gene', '4914', (47, 52))	('sarcomatous proliferation', 'Phenotype', 'HP:0100242', (90, 115))	('PHF20', 'Gene', (41, 46))	('PHF20', 'Gene', '51230', (41, 46))	('NTRK1', 'Gene', (47, 52))	('sarcomatous proliferation', 'Disease', (90, 115))
593956	32922522	Entrectinib/larotrectinib can be used to treat patients with this NTRK fusion mutation in solid tumors.	('larotrectinib', 'Chemical', 'MESH:C000609083', (12, 25))	('mutation', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('patients', 'Species', '9606', (47, 55))	('Entrectinib', 'Chemical', 'MESH:C000607349', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('NTRK', 'Gene', (66, 70))
593957	32922522	reported that patients with TPM3-ROS1 fusion mutations could benefit for long periods after crizotinib therapy.	('benefit', 'PosReg', (61, 68))	('crizotinib', 'Chemical', 'MESH:D000077547', (92, 102))	('TPM3', 'Gene', '7170', (28, 32))	('fusion mutations', 'Var', (38, 54))	('ROS1', 'Gene', (33, 37))	('patients', 'Species', '9606', (14, 22))	('TPM3', 'Gene', (28, 32))	('ROS1', 'Gene', '6098', (33, 37))
593960	32922522	STK11 is mutated in 'cold tumors,' which can be manifested as cerebral ischemic resistance and reduced CD8+ T cell infiltrations.	('ischemic', 'Disease', (71, 79))	('STK11', 'Gene', (0, 5))	('cold tumors', 'Disease', (21, 32))	('mutated', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('STK11', 'Gene', '6794', (0, 5))	('ischemic', 'Disease', 'MESH:D007511', (71, 79))	('cold tumors', 'Disease', 'MESH:D000067390', (21, 32))	('CD8', 'Gene', (103, 106))	('reduced', 'NegReg', (95, 102))	('CD8', 'Gene', '925', (103, 106))	('reduced CD8+ T cell', 'Phenotype', 'HP:0005415', (95, 114))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
593963	32922522	Abstracts published at the European Society of Medical Oncology Immuno-Oncology Conference in Neva, Italy, on 12 December 2019, described first-line AMG 510 treatments that improved OS, PFS, and ORRs in patients with metastatic non-squamous NSCLC.	('NSCLC', 'Disease', (241, 246))	('NSCLC', 'Disease', 'MESH:D002289', (241, 246))	('men', 'Species', '9606', (162, 165))	('Oncology', 'Phenotype', 'HP:0002664', (71, 79))	('PFS', 'Disease', (186, 189))	('ORRs', 'MPA', (195, 199))	('patients', 'Species', '9606', (203, 211))	('improved', 'PosReg', (173, 181))	('treatments', 'Var', (157, 167))	('Oncology', 'Phenotype', 'HP:0002664', (55, 63))
593965	32922522	No clinical trials have been reported on these targeted drugs in the treatment of PSCs with the above, rare, genetic mutations, and therefore, the therapeutic effect is unclear.	('PSCs', 'Disease', (82, 86))	('genetic mutations', 'Var', (109, 126))	('men', 'Species', '9606', (74, 77))
593974	32922522	In the near future, second-generation ALK inhibitors, such as serratinib, alectinib, and brigatinib, and third-generation ALK inhibitors, such as laratinib, may prolong the survival time of patients with PSC with ALK rearrangement compared with the first-generation ALK inhibitors, such as crizotinib.	('ALK', 'Gene', '238', (38, 41))	('laratinib', 'Chemical', '-', (146, 155))	('patients', 'Species', '9606', (190, 198))	('ALK', 'Gene', '238', (266, 269))	('ALK', 'Gene', (38, 41))	('survival time', 'CPA', (173, 186))	('prolong', 'PosReg', (161, 168))	('ALK', 'Gene', (266, 269))	('crizotinib', 'Chemical', 'MESH:D000077547', (290, 300))	('rearrangement', 'Var', (217, 230))	('brigatinib', 'Chemical', 'MESH:C000598580', (89, 99))	('ALK', 'Gene', '238', (122, 125))	('serratinib', 'Chemical', '-', (62, 72))	('ALK', 'Gene', (122, 125))	('ALK', 'Gene', '238', (213, 216))	('ALK', 'Gene', (213, 216))	('PSC', 'Disease', (204, 207))	('alectinib', 'Chemical', 'MESH:C582670', (74, 83))	('men', 'Species', '9606', (226, 229))
594087	31279261	While laterality does not seem to have a measurable relationship with patient outcomes, disease recurrence, or survival, there is an association between laterality, tumor histology, and resection of the kidney, spleen, or pancreas.	('resection', 'Var', (186, 195))	('patient', 'Species', '9606', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
594133	29889880	Tumours in soft tissue and bone (ICD-8; 170, 171, 192.49-99 and ICD-10; C40-41, C47, C49) were not included.	('C40', 'Gene', '55571', (72, 75))	('C40', 'Gene', (72, 75))	('C47', 'Var', (80, 83))	('C47', 'CellLine', 'CVCL:L675', (80, 83))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
594138	29889880	Disease-specific mortality was defined as death from sarcoma or death with known metastatic disease (ICD-8; 170, 171, 192.49-99 and ICD-10; C40-41, C47, C49).	('C47', 'CellLine', 'CVCL:L675', (148, 151))	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('death', 'Disease', 'MESH:D003643', (64, 69))	('death', 'Disease', 'MESH:D003643', (42, 47))	('death', 'Disease', (64, 69))	('death', 'Disease', (42, 47))	('C40', 'Gene', (140, 143))	('sarcoma', 'Disease', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('C40', 'Gene', '55571', (140, 143))	('C47', 'Var', (148, 151))
594152	29889880	Mortality significantly increased in patients with comorbidity and localized disease at the time of diagnosis, with a crude HR of 1.89 (95% CI 1.59-2.25) compared to patients without comorbidity.	('patients', 'Species', '9606', (37, 45))	('comorbidity', 'Var', (51, 62))	('patients', 'Species', '9606', (166, 174))	('crude HR', 'Disease', (118, 126))	('Mortality', 'MPA', (0, 9))	('localized disease', 'Disease', (67, 84))	('increased', 'PosReg', (24, 33))	('crude HR', 'Disease', 'MESH:D001919', (118, 126))
594296	33642764	In view of the rarity metastasis to the breast from synovial sarcoma diagnosis was confirmed with translocation studies, which confirmed synovial sarcoma specific chromosomal translocation t (X: 18)(p11.2;q11.2) [Figure 3e and f].	('synovial sarcoma', 'Phenotype', 'HP:0012570', (52, 68))	('synovial sarcoma', 'Disease', (137, 153))	('synovial sarcoma', 'Disease', 'MESH:D013584', (52, 68))	('t (X: 18)(p11.2;q11.2', 'Var', (189, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('synovial sarcoma', 'Disease', (52, 68))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (137, 153))	('synovial sarcoma', 'Disease', 'MESH:D013584', (137, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
594298	32848198	We present the results of an ex vivo pilot study involving 10 cases of biopsy-proven sarcoma and we propose a quantitative method to analyse 1H NMR relaxation dispersion profiles based on a model-free approach describing the main dynamical processes in the tissues and assessing the amplitude of the Quadrupole Relaxation Enhancement effects due to 14N.	('Quadrupole Relaxation', 'MPA', (300, 321))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('1H', 'Chemical', '-', (141, 143))	('sarcoma', 'Disease', (85, 92))	('14N', 'Chemical', '-', (349, 352))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('14N', 'Var', (349, 352))
594304	32848198	To simplify calculations one often uses their reciprocal values, R1 = 1/T1 and R2 = 1/T2, which are referred to as spin-lattice and spin-spin relaxation rates, respectively but convey the same information.	('spin', 'Gene', '10927', (115, 119))	('spin', 'Gene', (137, 141))	('spin', 'Gene', '10927', (137, 141))	('spin', 'Gene', (132, 136))	('R2 =', 'Var', (79, 83))	('spin', 'Gene', (115, 119))	('spin', 'Gene', '10927', (132, 136))
594352	32848198	For tumour dispersion profiles, the presence of myxoid components was found to significantly lower the scaling factor (- 0.71 +- 0.46, p-value < 0.005 from t-test).	('scaling factor', 'MPA', (103, 117))	('myxoid components', 'MPA', (48, 65))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('presence', 'Var', (36, 44))	('lower', 'NegReg', (93, 98))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))
594436	32493414	Aberrant IGFs signaling may lead to malignant transformation and tumor progression, thus providing the rationale for targeting IGF axis in cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('malignant transformation', 'CPA', (36, 60))	('IGFs', 'Protein', (9, 13))	('lead to', 'Reg', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Disease', (139, 145))
594464	32493414	Given the important roles of IGF-IR in tumor progression, inhibition of IGF-IR activity has been proposed as a therapeutic strategy for solid tumors and hematologic malignancies.	('activity', 'MPA', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('hematologic malignancies', 'Disease', 'MESH:D019337', (153, 177))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (142, 147))	('inhibition', 'Var', (58, 68))	('hematologic malignancies', 'Disease', (153, 177))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (142, 148))	('IGF-IR', 'Gene', (72, 78))	('tumor', 'Disease', (39, 44))	('IGF-IR', 'Gene', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('IGF-IR', 'Gene', '3480', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('IGF-IR', 'Gene', '3480', (29, 35))
594479	32493414	The InsR-A is generated by alternative splicing of exon 11 in InsR gene.	('InsR', 'Gene', (62, 66))	('alternative splicing of exon', 'Var', (27, 55))	('InsR-A', 'Chemical', '-', (4, 10))
594489	32493414	Phosphorylation of a triple-tyrosine cluster (Y1131/1135/1136) in the kinase domain of beta subunit can further amplify the kinase activity of IGF-IR.	('amplify', 'PosReg', (112, 119))	('kinase activity', 'MPA', (124, 139))	('IGF-IR', 'Gene', (143, 149))	('Y1131/1135/1136', 'Var', (46, 61))	('IGF-IR', 'Gene', '3480', (143, 149))	('tyrosine', 'Chemical', 'MESH:D014443', (28, 36))
594492	32493414	mTORC2 interacts with IGF-IR, and phosphorylates IGF-IR at Y1131/1136 thereby activating IGF-IR.	('IGF-IR', 'Gene', (22, 28))	('activating', 'PosReg', (78, 88))	('IGF-IR', 'Gene', '3480', (22, 28))	('IGF-IR', 'Gene', (89, 95))	('Y1131/1136', 'Var', (59, 69))	('IGF-IR', 'Gene', '3480', (89, 95))	('mTORC2', 'Gene', (0, 6))	('IGF-IR', 'Gene', (49, 55))	('interacts', 'Interaction', (7, 16))	('IGF-IR', 'Gene', '3480', (49, 55))	('mTORC2', 'Gene', '74343', (0, 6))
594493	32493414	The conformational changes in IGF-IR create docking sites for its substrates, such as Shc and InsR substrates (IRS), which relay the signaling to downstream effectors including PI3K, MAPK, and STAT3.	('signaling', 'MPA', (133, 142))	('Shc', 'Gene', '6464', (86, 89))	('relay', 'MPA', (123, 128))	('PI3', 'Gene', (177, 180))	('IR', 'Gene', '3643', (34, 36))	('IGF-IR', 'Gene', (30, 36))	('IR', 'Gene', '3643', (111, 113))	('STAT3', 'Gene', '6774', (193, 198))	('IGF-IR', 'Gene', '3480', (30, 36))	('Shc', 'Gene', (86, 89))	('STAT3', 'Gene', (193, 198))	('PI3', 'Gene', '5266', (177, 180))	('conformational', 'Var', (4, 18))
594503	32493414	One study even shows that luminal A/B breast cancer patients with high IGF-IRalpha and negative EGFR expression have better prognosis than the rest.	('EGFR', 'Gene', '1956', (96, 100))	('IGF-IR', 'Gene', '3480', (71, 77))	('high IGF-', 'Phenotype', 'HP:0030269', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('EGFR', 'Gene', (96, 100))	('B breast cancer', 'Disease', 'MESH:D001943', (36, 51))	('negative', 'NegReg', (87, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('luminal', 'Chemical', 'MESH:D010634', (26, 33))	('high', 'Var', (66, 70))	('B breast cancer', 'Disease', (36, 51))	('patients', 'Species', '9606', (52, 60))	('IGF-IR', 'Gene', (71, 77))
594507	32493414	Overexpression of IGF-IR in prostate cancer is associated with high Gleason grade and increased risk of tumor recurrence and metastasis.	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('IGF-IR', 'Gene', '3480', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Overexpression', 'Var', (0, 14))	('prostate cancer', 'Disease', (28, 43))	('IGF-IR', 'Gene', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
594510	32493414	Overexpression of IGF-IRbeta was correlated with a decreased survival in patients with cervical carcinoma.	('cervical carcinoma', 'Disease', 'MESH:D002583', (87, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('decreased', 'NegReg', (51, 60))	('cervical carcinoma', 'Disease', (87, 105))	('survival', 'MPA', (61, 69))	('Overexpression', 'Var', (0, 14))	('IGF-IR', 'Gene', (18, 24))	('patients', 'Species', '9606', (73, 81))	('IGF-IR', 'Gene', '3480', (18, 24))
594520	32493414	While PDK1 phosphorylates Akt at Thr308, mTORC2 phosphorylates Akt at Ser473.	('Ser473', 'Chemical', '-', (70, 76))	('Akt', 'Gene', '207', (26, 29))	('Thr308', 'Var', (33, 39))	('PDK1', 'Gene', '5163', (6, 10))	('PDK1', 'Gene', (6, 10))	('Akt', 'Gene', (26, 29))	('Akt', 'Gene', '207', (63, 66))	('mTORC2', 'Gene', '74343', (41, 47))	('mTORC2', 'Gene', (41, 47))	('Thr308', 'Chemical', '-', (33, 39))	('Akt', 'Gene', (63, 66))
594521	32493414	Phosphorylation of Akt at both Thr308 and Ser473 leads to full activation of Akt, thereby regulating glucose metabolism, protein synthesis, cell proliferation, survival, and apoptosis through multiple targets.	('survival', 'CPA', (160, 168))	('cell proliferation', 'CPA', (140, 158))	('glucose metabolism', 'Disease', (101, 119))	('Akt', 'Gene', '207', (19, 22))	('Akt', 'Gene', '207', (77, 80))	('Phosphorylation', 'Var', (0, 15))	('Akt', 'Gene', (77, 80))	('apoptosis', 'CPA', (174, 183))	('Thr308', 'Chemical', '-', (31, 37))	('glucose metabolism', 'Disease', 'MESH:D044882', (101, 119))	('Ser473', 'Var', (42, 48))	('Akt', 'Gene', (19, 22))	('regulating', 'Reg', (90, 100))	('Thr308', 'Var', (31, 37))	('Ser473', 'Chemical', '-', (42, 48))	('protein synthesis', 'MPA', (121, 138))	('activation', 'PosReg', (63, 73))
594522	32493414	After phosphorylation by Akt, Glut is translocated to cell membrane allowing glucose uptake.	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('Glut', 'Gene', '6513', (30, 34))	('Akt', 'Gene', '207', (25, 28))	('translocated to cell membrane', 'MPA', (38, 67))	('Glut', 'Gene', (30, 34))	('glucose uptake', 'CPA', (77, 91))	('phosphorylation', 'Var', (6, 21))	('Akt', 'Gene', (25, 28))
594523	32493414	Besides, Akt phosphorylates and inactivates GSK3, FOXO, and TSC1/2, leading to activation of Wnt signaling, inhibition of apoptosis, and activation of mTORC1, respectively.	('inhibition', 'NegReg', (108, 118))	('apoptosis', 'CPA', (122, 131))	('Akt', 'Gene', (9, 12))	('mTORC1', 'Gene', '382056', (151, 157))	('GSK3', 'Gene', (44, 48))	('TSC1/2', 'Gene', '7248;7249', (60, 66))	('TSC1/2', 'Gene', (60, 66))	('FOXO', 'Gene', (50, 54))	('activation', 'PosReg', (137, 147))	('activation', 'PosReg', (79, 89))	('inactivates', 'Var', (32, 43))	('Wnt signaling', 'Pathway', (93, 106))	('mTORC1', 'Gene', (151, 157))	('Akt', 'Gene', '207', (9, 12))
594536	32493414	Inhibition of IGF-IR enhances the susceptibility of cancer cells to anoikis, reduces circulating tumor cells in the blood, and inhibits cancer metastasis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inhibits', 'NegReg', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Disease', (97, 102))	('cancer', 'Disease', (136, 142))	('enhances', 'PosReg', (21, 29))	('Inhibition', 'Var', (0, 10))	('IGF-IR', 'Gene', (14, 20))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('reduces', 'NegReg', (77, 84))	('IGF-IR', 'Gene', '3480', (14, 20))	('susceptibility', 'MPA', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
594545	32493414	In addition, IGF induces the expression of the cystine/glutamate antiporter (SLC7A11), which promotes the uptake of cystine to counteract oxidation.	('SLC7A11', 'Gene', (77, 84))	('induces', 'Reg', (17, 24))	('SLC7A11', 'Gene', '23657', (77, 84))	('uptake of cystine', 'MPA', (106, 123))	('glutamate', 'Chemical', 'MESH:D018698', (55, 64))	('IGF', 'Var', (13, 16))	('promotes', 'PosReg', (93, 101))	('expression', 'MPA', (29, 39))	('cystine', 'Chemical', 'MESH:D003553', (116, 123))	('cystine', 'Chemical', 'MESH:D003553', (47, 54))
594546	32493414	Thus, inhibition of IGF-IR may lead to impaired mitochondrial functions and increased the production of reactive oxygen species.	('increased', 'PosReg', (76, 85))	('mitochondrial functions', 'MPA', (48, 71))	('IGF-IR', 'Gene', (20, 26))	('impaired', 'NegReg', (39, 47))	('IGF-IR', 'Gene', '3480', (20, 26))	('inhibition', 'Var', (6, 16))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (104, 127))	('production of reactive oxygen species', 'MPA', (90, 127))
594564	32493414	Although the SUMOylation of IGF-IR at three evolutionarily conserved lysine residues (K1025/1100/1120) in IGF-IRbeta is dispensible for its kinase activity, SUMOylation is essential for its nuclear translocation.	('lysine', 'Chemical', 'MESH:D008239', (69, 75))	('K1025/1100/1120', 'Var', (86, 101))	('IGF-IR', 'Gene', (106, 112))	('IGF-IR', 'Gene', (28, 34))	('IGF-IR', 'Gene', '3480', (28, 34))	('IGF-IR', 'Gene', '3480', (106, 112))
594573	32493414	Moreover, nuclear IGF-IR promotes slug expression through phosphorylating histone H3 at Y41.Thus, nuclear IGF-IR has both kinase-dependent and kinase-independent functions.	('IGF-IR', 'Gene', (106, 112))	('nuclear', 'Var', (98, 105))	('IGF-IR', 'Gene', '3480', (106, 112))	('slug', 'Gene', (34, 38))	('IGF-IR', 'Gene', (18, 24))	('slug', 'Gene', '6591', (34, 38))	('IGF-IR', 'Gene', '3480', (18, 24))
594577	32493414	Meanwhile, preclinical studies indicate that inhibition of IGF-IR may reverse the resistance to many drugs and improve the efficacy of those anti-cancer agents.	('reverse', 'NegReg', (70, 77))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('efficacy', 'MPA', (123, 131))	('resistance to many drugs', 'MPA', (82, 106))	('inhibition', 'Var', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('IGF-IR', 'Gene', (59, 65))	('improve', 'PosReg', (111, 118))	('IGF-IR', 'Gene', '3480', (59, 65))
594580	32493414	Inhibition of IGF-IR impairs the repair of radiation-induced double strand breaks and sensitizes cancer cells to radiotherapy.	('cancer', 'Disease', (97, 103))	('repair', 'MPA', (33, 39))	('impairs', 'NegReg', (21, 28))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Inhibition', 'Var', (0, 10))	('IGF-IR', 'Gene', (14, 20))	('IGF-IR', 'Gene', '3480', (14, 20))	('sensitizes', 'Reg', (86, 96))
594585	32493414	Hence, inhibition of IGF-IR represents a therapeutic strategy to target DNA repair and sensitize cancer cells to DNA-damaging agents.	('cancer', 'Disease', (97, 103))	('IGF-IR', 'Gene', (21, 27))	('inhibition', 'Var', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('IGF-IR', 'Gene', '3480', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
594586	32493414	Indeed, IGF-IR inhibition sensitizes cancer cells to ATM-related kinase inhibition, cisplatin, oxaliplatin, and doxorubicin.	('IGF-IR', 'Gene', '3480', (8, 14))	('ATM-related kinase', 'Gene', '545', (53, 71))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('ATM-related kinase', 'Gene', (53, 71))	('sensitizes', 'Reg', (26, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (95, 106))	('IGF-IR', 'Gene', (8, 14))	('inhibition', 'Var', (15, 25))
594590	32493414	Except for repression of DNA repair, IGF-IR inhibition may downregulate the synthesis of survivin, a dual regulator of cell proliferation and survival.	('survivin', 'Protein', (89, 97))	('IGF-IR', 'Gene', '3480', (37, 43))	('inhibition', 'Var', (44, 54))	('downregulate', 'NegReg', (59, 71))	('synthesis', 'MPA', (76, 85))	('IGF-IR', 'Gene', (37, 43))
594598	32493414	Given that ErbB contributes to IGF-IR/InsR and ER antagonist resistance, co-targeting ErbB, IGF-IR/InsR, and ER may achieve maximal anti-cancer effect on ER+ breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('ErbB', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ErbB', 'Gene', '1956', (86, 90))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('breast cancer', 'Disease', (158, 171))	('IGF-IR', 'Gene', (31, 37))	('IGF-IR', 'Gene', '3480', (31, 37))	('IGF-IR', 'Gene', (92, 98))	('IGF-IR', 'Gene', '3480', (92, 98))	('ER antagonist', 'MPA', (47, 60))	('co-targeting', 'Var', (73, 85))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (165, 171))	('ErbB', 'Gene', '1956', (11, 15))	('ErbB', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
594608	32493414	Accordingly, IGF-IR inhibition can enhance the efficacy of castration and abiraterone on prostate cancer.	('abiraterone', 'Chemical', 'MESH:C089740', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('inhibition', 'Var', (20, 30))	('prostate cancer', 'Disease', (89, 104))	('enhance', 'PosReg', (35, 42))	('IGF-IR', 'Gene', (13, 19))	('IGF-IR', 'Gene', '3480', (13, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (89, 104))	('castration', 'Disease', (59, 69))
594611	32493414	Inhibiting one of these RTKs may trigger system rewiring that allows other RTKs to compensate it.	('Inhibiting', 'Var', (0, 10))	('RTK', 'Gene', '5979', (24, 27))	('RTK', 'Gene', (75, 78))	('RTK', 'Gene', '5979', (75, 78))	('RTK', 'Gene', (24, 27))
594627	32493414	Inhibition of IGF-IR overcomes resistance to taselisib and idelalisib in ovarian cancer and chronic lymphocytic leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (112, 120))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (92, 120))	('chronic lymphocytic leukemia', 'Disease', (92, 120))	('taselisib and idelalisib in ovarian cancer', 'Disease', 'MESH:D010051', (45, 87))	('overcomes', 'NegReg', (21, 30))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('Inhibition', 'Var', (0, 10))	('IGF-IR', 'Gene', (14, 20))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (92, 120))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('IGF-IR', 'Gene', '3480', (14, 20))	('resistance', 'MPA', (31, 41))
594637	32493414	Combined treatment with CDK4/6 and IGF-IR inhibitors synergistically inhibits Ewing sarcoma.	('CDK4/6', 'Gene', '1019;1021', (24, 30))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (78, 91))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (78, 91))	('inhibits', 'NegReg', (69, 77))	('CDK4/6', 'Gene', (24, 30))	('IGF-IR', 'Gene', (35, 41))	('inhibitors', 'Var', (42, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('IGF-IR', 'Gene', '3480', (35, 41))	('Ewing sarcoma', 'Disease', (78, 91))
594642	32493414	Epigenetic dysregulation has emerged as one of the transcriptional vulnerabilities in human cancer.	('Epigenetic dysregulation', 'Var', (0, 24))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('human', 'Species', '9606', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
594649	32493414	EZH2 mutation or overexpression is detected in solid tumors and leukemia, and correlated with cancer metastasis.	('leukemia', 'Disease', (64, 72))	('detected', 'Reg', (35, 43))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('overexpression', 'PosReg', (17, 31))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('correlated', 'Reg', (78, 88))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('leukemia', 'Disease', 'MESH:D007938', (64, 72))	('tumors', 'Disease', (53, 59))	('mutation', 'Var', (5, 13))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
594656	32493414	A meta-analysis of 311 Ewing sarcoma patients in multiple trials demonstrates that treatment with anti-IGF-IR mAb figitumumab, R1507, or ganitumab results in complete response in 0.7% cases, partial response in 11% cases, and stable diseases in 21% cases .	('Ewing sarcoma', 'Disease', (23, 36))	('R1507', 'Var', (127, 132))	('patients', 'Species', '9606', (37, 45))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (23, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (23, 36))	('IGF-IR', 'Gene', (103, 109))	('figitumumab', 'Chemical', 'MESH:C525021', (114, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('ganitumab', 'Chemical', 'MESH:C545764', (137, 146))	('IGF-IR', 'Gene', '3480', (103, 109))
594661	32493414	Moreover, a randomized clinical trial in patients with advanced pancreatic carcinoma demonstrates that combination of the anti-IGF-IR mAb MK-0646 with gemcitabine is tolerable and associated with improvement in overall survival but not progression-free survival as compared with gemcitabine plus erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (296, 305))	('gemcitabine', 'Chemical', 'MESH:C056507', (151, 162))	('overall survival', 'MPA', (211, 227))	('gemcitabine', 'Chemical', 'MESH:C056507', (279, 290))	('IGF-IR', 'Gene', (127, 133))	('pancreatic carcinoma', 'Disease', (64, 84))	('combination', 'Var', (103, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('patients', 'Species', '9606', (41, 49))	('IGF-IR', 'Gene', '3480', (127, 133))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (64, 84))	('improvement', 'PosReg', (196, 207))	('MK-0646', 'Chemical', 'MESH:C569480', (138, 145))	('MK-0646', 'Gene', (138, 145))
594674	32493414	Despite these disappointing results, an early phase study suggests that AXL1717 may produce prolonged stable disease and survival of patients with relapsed malignant astrocytomas.	('malignant astrocytomas', 'Disease', (156, 178))	('AXL1717', 'Var', (72, 79))	('malignant astrocytomas', 'Disease', 'MESH:D020339', (156, 178))	('patients', 'Species', '9606', (133, 141))	('survival', 'CPA', (121, 129))	('stable disease', 'CPA', (102, 116))	('AXL1717', 'Chemical', 'MESH:C415032', (72, 79))
594676	32493414	While mutations in the drug target are involved in the resistance to many molecularly targeted agents, mutations in IGF-IR are barely detected in cancer cells resistant to anti-IGF-IR agents.	('IGF-IR', 'Gene', (177, 183))	('IGF-IR', 'Gene', (116, 122))	('mutations', 'Var', (103, 112))	('involved', 'Reg', (39, 47))	('cancer', 'Disease', (146, 152))	('IGF-IR', 'Gene', '3480', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('IGF-IR', 'Gene', '3480', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutations', 'Var', (6, 15))
594684	32493414	In a pancreatic neuroendocrine cancer model, InsR knockout tumors are suppressed by anti-IGF-IR therapy, whereas InsR-expressed tumors are resistant to this therapy.	('pancreatic neuroendocrine cancer', 'Phenotype', 'HP:0030405', (5, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('neuroendocrine cancer', 'Phenotype', 'HP:0100634', (16, 37))	('knockout', 'Var', (50, 58))	('IGF-IR', 'Gene', (89, 95))	('IGF-IR', 'Gene', '3480', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('InsR', 'Gene', (45, 49))	('pancreatic neuroendocrine cancer', 'Disease', (5, 37))	('tumors', 'Disease', (59, 65))	('suppressed', 'NegReg', (70, 80))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('pancreatic neuroendocrine cancer', 'Disease', 'MESH:D010190', (5, 37))
594691	32493414	Inhibition of integrin beta3 or Src can improve the anti-cancer activity of cixutumumab in cixutumumab-resistant cell lines and patient-derived tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('cixutumumab', 'Chemical', 'MESH:C557414', (76, 87))	('Src', 'Gene', '6714', (32, 35))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (57, 63))	('integrin beta3', 'Gene', '3690', (14, 28))	('integrin beta3', 'Gene', (14, 28))	('cixutumumab', 'Chemical', 'MESH:C557414', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('patient', 'Species', '9606', (128, 135))	('Src', 'Gene', (32, 35))	('improve', 'PosReg', (40, 47))
594696	32493414	Inhibition of one member of RTKs usually triggers the compensation by other members.	('RTK', 'Gene', (28, 31))	('triggers', 'Reg', (41, 49))	('Inhibition', 'Var', (0, 10))	('RTK', 'Gene', '5979', (28, 31))
594699	32493414	Inhibition of IGF-IR may enhance ErbB3-IRS1 interaction.	('enhance', 'PosReg', (25, 32))	('Inhibition', 'Var', (0, 10))	('IGF-IR', 'Gene', (14, 20))	('IRS1', 'Gene', '3667', (39, 43))	('IRS1', 'Gene', (39, 43))	('IGF-IR', 'Gene', '3480', (14, 20))	('ErbB3', 'Gene', (33, 38))	('ErbB3', 'Gene', '2065', (33, 38))
594704	32493414	In fact, upregulation of IRS1, PI3K, STAT3, and p38 MAPK is involved in resistance to dalotuzumab and linsitinib.	('dalotuzumab', 'Chemical', 'MESH:C569480', (86, 97))	('IRS1', 'Gene', (25, 29))	('upregulation', 'PosReg', (9, 21))	('STAT3', 'Gene', '6774', (37, 42))	('PI3', 'Gene', '5266', (31, 34))	('STAT3', 'Gene', (37, 42))	('linsitinib', 'Chemical', 'MESH:C551528', (102, 112))	('p38 MAPK', 'Var', (48, 56))	('resistance', 'MPA', (72, 82))	('IRS1', 'Gene', '3667', (25, 29))	('PI3', 'Gene', (31, 34))
594708	32493414	Although IGF-IR promotes EMT, it does not necessarily mean that inhibition of IGF-IR is able to reverse this phenotype, due to the compensation by other RTKs.	('EMT', 'CPA', (25, 28))	('promotes', 'PosReg', (16, 24))	('IGF-IR', 'Gene', (78, 84))	('RTK', 'Gene', (153, 156))	('inhibition', 'Var', (64, 74))	('IGF-IR', 'Gene', '3480', (78, 84))	('IGF-IR', 'Gene', (9, 15))	('RTK', 'Gene', '5979', (153, 156))	('IGF-IR', 'Gene', '3480', (9, 15))
594730	32493414	Preclinical studies have suggested potential biomarkers such as circulating free IGF levels, mutations of p53, BRCA1, KRAS and BRAF, IRS2 copy number gain, InsR/IGF-IR overexpression, InsR/IGF-IR pathway activation, PTEN loss, CD24, mesenchymal markers, beta-catenin/TCF activity, FUS-DDIT3 fusion, and ERG.	('p53', 'Gene', '7157', (106, 109))	('DDIT3', 'Gene', (285, 290))	('BRAF', 'Gene', '673', (127, 131))	('KRAS', 'Gene', (118, 122))	('IGF-IR', 'Gene', (161, 167))	('BRAF', 'Gene', (127, 131))	('IGF-IR', 'Gene', '3480', (161, 167))	('PTEN loss', 'Disease', 'MESH:D006223', (216, 225))	('FUS', 'Gene', (281, 284))	('p53', 'Gene', (106, 109))	('beta-catenin', 'Gene', (254, 266))	('beta-catenin', 'Gene', '1499', (254, 266))	('IRS2', 'Gene', '8660', (133, 137))	('TCF', 'Gene', '3172', (267, 270))	('FUS', 'Gene', '2521', (281, 284))	('CD24', 'Gene', (227, 231))	('mesenchymal markers', 'CPA', (233, 252))	('PTEN loss', 'Disease', (216, 225))	('mutations', 'Var', (93, 102))	('BRCA1', 'Gene', '672', (111, 116))	('ERG', 'Gene', (303, 306))	('IGF-IR', 'Gene', (189, 195))	('BRCA1', 'Gene', (111, 116))	('overexpression', 'PosReg', (168, 182))	('IGF-IR', 'Gene', '3480', (189, 195))	('gain', 'PosReg', (150, 154))	('IRS2', 'Gene', (133, 137))	('activation', 'PosReg', (204, 214))	('ERG', 'Gene', '2078', (303, 306))	('DDIT3', 'Gene', '1649', (285, 290))	('TCF', 'Gene', (267, 270))	('KRAS', 'Gene', '3845', (118, 122))	('copy number', 'Var', (138, 149))	('CD24', 'Gene', '100133941', (227, 231))
594770	32450373	Immunohistochemistry showed positivity for tumor biomarkers AE1, AE3, EMA, vimentin, and CD34 and negativity for INI1 and S100.	('EMA', 'Gene', '4582', (70, 73))	('INI1', 'Gene', '6598', (113, 117))	('S100', 'Gene', (122, 126))	('INI1', 'Gene', (113, 117))	('positivity', 'Var', (28, 38))	('AE3', 'Gene', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('AE3', 'Gene', '6508', (65, 68))	('S100', 'Gene', '6271', (122, 126))	('EMA', 'Gene', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('vimentin', 'Gene', '7431', (75, 83))	('CD34', 'Gene', (89, 93))	('CD34', 'Gene', '947', (89, 93))	('vimentin', 'Gene', (75, 83))	('tumor', 'Disease', (43, 48))	('AE1', 'Gene', '6521', (60, 63))	('AE1', 'Gene', (60, 63))
594774	32450373	It is also common to see negative biomarkers: S-100, CD31, and SMARCB1/INI1.	('INI1', 'Gene', (71, 75))	('INI1', 'Gene', '6598', (71, 75))	('CD31', 'Gene', (53, 57))	('CD31', 'Gene', '5175', (53, 57))	('S-100', 'Var', (46, 51))	('SMARCB1', 'Gene', '6598', (63, 70))	('SMARCB1', 'Gene', (63, 70))
594781	32450373	One of its major subunits is SMARCB1, which is usually completely lost by either deletion in epithelioid sarcomas or point mutations in malignant rhabdoid tumors.	('malignant rhabdoid tumors', 'Disease', (136, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('SMARCB1', 'Gene', '6598', (29, 36))	('deletion', 'Var', (81, 89))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('point mutations', 'Var', (117, 132))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (136, 161))	('SMARCB1', 'Gene', (29, 36))	('lost', 'NegReg', (66, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (93, 113))	('epithelioid sarcomas', 'Disease', (93, 113))
594783	32450373	Although these tumors are similar, there may be a strong possibility that the age at which SMARCB1 inactivation occurs is what dictates the earlier onset and predisposition to malignant rhabdoid tumors versus epithelioid sarcomas.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('dictates', 'Reg', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('SMARCB1', 'Gene', '6598', (91, 98))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('SMARCB1', 'Gene', (91, 98))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (221, 229))	('inactivation', 'Var', (99, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('malignant rhabdoid tumors versus epithelioid sarcomas', 'Disease', 'MESH:D018335', (176, 229))	('tumors', 'Disease', (15, 21))
594786	32450373	According to a clinicopathological analysis of 106 epithelioid sarcomas: having a proximal-type tumor, a tumor size greater than 5 cm, tumor multifocality, and high mitotic index had a shorter five-year survival rate; additionally, tumors greater than 5 cm and a high mitotic index had a shorter five-year metastasis-free survival rate.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('five-year survival rate', 'CPA', (193, 216))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('high mitotic index', 'Var', (263, 281))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', (105, 110))	('high mitotic index', 'Var', (160, 178))	('shorter', 'NegReg', (288, 295))	('shorter', 'NegReg', (185, 192))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (51, 71))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('epithelioid sarcomas', 'Disease', (51, 71))	('tumors', 'Disease', (232, 238))	('five-year metastasis-free survival rate', 'CPA', (296, 335))
594798	32450373	Losing SMARCB1 leads to hyperactivation of the AKT/mTOR pathway, which is involved in cell proliferation and cancer survival.	('mTOR', 'Gene', (51, 55))	('AKT', 'Gene', (47, 50))	('hyperactivation', 'PosReg', (24, 39))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('Losing', 'Var', (0, 6))	('AKT', 'Gene', '207', (47, 50))	('SMARCB1', 'Gene', '6598', (7, 14))	('SMARCB1', 'Gene', (7, 14))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mTOR', 'Gene', '2475', (51, 55))
594819	32085654	Mice lacking even a single VEGF-A allele exhibit impaired development of early vasculature and die at E11-E12.	('development of early vasculature', 'CPA', (58, 90))	('men', 'Species', '9606', (65, 68))	('E11-E12', 'Var', (102, 109))	('VEGF-A', 'Gene', (27, 33))	('Mice', 'Species', '10090', (0, 4))	('impaired', 'NegReg', (49, 57))
594854	32085654	As expected, VEGF-A overexpression frequently correlates not only with enhanced cancer invasiveness, but also with a high risk of tumor recurrence and unfavorable prognosis.	('enhanced', 'PosReg', (71, 79))	('overexpression', 'Var', (20, 34))	('cancer invasiveness', 'Disease', 'MESH:D009362', (80, 99))	('cancer invasiveness', 'Disease', (80, 99))	('VEGF-A', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
594855	32085654	On this basis, inhibition of the VEGF-A/VEGFRs signaling represents a widely used approach for cancer treatment through the use of the anti-VEGF-A and anti-VEGFR-2 monoclonal antibodies (mAbs) bevacizumab and ramucirumab, respectively; the chimeric molecule ziv-aflibercept; or a number of multi-targeted small-molecule TK inhibitors.	('bevacizumab', 'Chemical', 'MESH:D000068258', (193, 204))	('ramucirumab', 'Chemical', 'MESH:C543333', (209, 220))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('men', 'Species', '9606', (107, 110))	('VEGFR', 'Gene', (156, 161))	('anti-VEGF-A', 'Var', (135, 146))	('cancer', 'Disease', (95, 101))	('VEGFR', 'Gene', (40, 45))	(')', 'Gene', '7424', (191, 192))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('VEGFR', 'Gene', '3791', (156, 161))	('VEGFR', 'Gene', '3791', (40, 45))
594860	32085654	In regard to VEGF-B, ectopic expression of the growth factor in pancreatic beta-cells of transgenic mice prevented the formation of neuroendocrine tumors likely displacing VEGF-A or PlGF from VEGFR-1.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('displacing', 'NegReg', (161, 171))	('prevented', 'NegReg', (105, 114))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('formation', 'CPA', (119, 128))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('transgenic mice', 'Species', '10090', (89, 104))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (132, 153))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (132, 153))	('pancreatic', 'Disease', (64, 74))	('ectopic expression', 'Var', (21, 39))	('neuroendocrine tumors', 'Disease', (132, 153))
594873	32085654	The anti-VEGF-A bevacizumab is the standard regimen for advanced/metastatic non-squamous NSCLC in the first-line setting, in combination with platinum-based chemotherapy.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('platinum', 'Chemical', 'MESH:D010984', (142, 150))	('men', 'Species', '9606', (48, 51))	('bevacizumab', 'Chemical', 'MESH:D000068258', (16, 27))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('NSCLC', 'Disease', (89, 94))	('anti-VEGF-A', 'Var', (4, 15))
594876	32085654	NSCLC is often associated with a hypoxic environment leading to HIF-1alpha overexpression, and HIF-1alpha knockdown in the NCI-H157 lung carcinoma cell line has been shown to reduce VEGF-A expression and cell invasiveness.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('HIF-1alpha', 'Gene', '3091', (95, 105))	('men', 'Species', '9606', (48, 51))	('overexpression', 'PosReg', (75, 89))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('reduce', 'NegReg', (175, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('expression', 'MPA', (189, 199))	('knockdown', 'Var', (106, 115))	('VEGF-A', 'Protein', (182, 188))	('HIF-1alpha', 'Gene', (95, 105))	('NCI-H157 lung carcinoma', 'Disease', (123, 146))	('NCI-H157 lung carcinoma', 'Disease', 'MESH:D008175', (123, 146))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('HIF-1alpha', 'Gene', (64, 74))	('cell invasiveness', 'CPA', (204, 221))	('NSCLC', 'Disease', (0, 5))
594883	32085654	The sVEGFR-1-i13 splice variant was reported to increase during treatment with antiangiogenic therapies and to contribute to the progression of squamous lung carcinoma.	('splice variant', 'Var', (17, 31))	('men', 'Species', '9606', (69, 72))	('squamous lung carcinoma', 'Disease', (144, 167))	('sVEGFR-1-i13', 'Gene', (4, 16))	('squamous lung carcinoma', 'Phenotype', 'HP:0030359', (144, 167))	('squamous lung carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('contribute', 'Reg', (111, 121))	('increase', 'PosReg', (48, 56))
594884	32085654	In fact, besides acting as inhibitor of angiogenesis, this sVEGFR-1 variant is a component of the ECM that binds to the alpha5beta1 integrin and stimulates the adhesion and migration of endothelial cells.	('binds', 'Interaction', (107, 112))	('rat', 'Species', '10116', (176, 179))	('sVEGFR-1', 'Gene', (59, 67))	('variant', 'Var', (68, 75))	('adhesion', 'CPA', (160, 168))	('beta1 integrin', 'Gene', '3688', (126, 140))	('stimulates', 'PosReg', (145, 155))	('beta1 integrin', 'Gene', (126, 140))
594894	32085654	Furthermore, the VEGFR-1 relevance to NSCLC aggressiveness was confirmed by the observation that patients with squamous cell carcinoma and high VEGF-B expression showed poorer survival compared to those with low VEGF-B expression.	('NSCLC', 'Disease', (38, 43))	('aggressiveness', 'Disease', 'MESH:D001523', (44, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('aggressiveness', 'Disease', (44, 58))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('survival', 'MPA', (176, 184))	('aggressiveness', 'Phenotype', 'HP:0000718', (44, 58))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('VEGF-B', 'Gene', (144, 150))	('squamous cell carcinoma', 'Disease', (111, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('poorer', 'NegReg', (169, 175))	('SCLC', 'Phenotype', 'HP:0030357', (39, 43))	('high', 'Var', (139, 143))	('patients', 'Species', '9606', (97, 105))
594908	32085654	Nevertheless, after metastatic nodule formation, VEGFR-1 blockade led to a decrease of BMDCs infiltration inside and around the metastatic nodules.	('decrease', 'NegReg', (75, 83))	('blockade', 'Var', (57, 65))	('VEGFR-1', 'Gene', (49, 56))	('rat', 'Species', '10116', (99, 102))	('BMDCs infiltration', 'CPA', (87, 105))
594913	32085654	Hepatocellular carcinoma is a hypervascularized cancer type, and dysregulation of several angiogenic pathways, including those activated by the VEGF family members, has been involved in the development and progression of this tumor.	('involved', 'Reg', (174, 182))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('VEGF', 'Gene', '7422', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('dysregulation', 'Var', (65, 78))	('men', 'Species', '9606', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('hypervascularized cancer', 'Disease', 'MESH:D009369', (30, 54))	('hypervascularized cancer', 'Disease', (30, 54))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('VEGF', 'Gene', (144, 148))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('angiogenic pathways', 'Pathway', (90, 109))	('tumor', 'Disease', (226, 231))
594920	32085654	PlGF blockade resulted in normalization of tumor-associated vessels, reduced tumor nodule formation in the liver, and increased animal survival.	('blockade', 'Var', (5, 13))	('reduced', 'NegReg', (69, 76))	('animal survival', 'CPA', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PlGF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (77, 82))	('normalization', 'NegReg', (26, 39))
594921	32085654	Similar findings were obtained in chemically-induced hepatocellular and cholangiocarcinoma in vivo models, where treatment with the 5D11D4 mAb decreased tumor burden and infiltration by protumoral M2 cells.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (189, 194))	('rat', 'Species', '10116', (176, 179))	('decreased', 'NegReg', (143, 152))	('cholangiocarcinoma', 'Disease', (72, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('men', 'Species', '9606', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('tumoral', 'Disease', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('5D11D4', 'Var', (132, 138))	('tumoral', 'Disease', 'MESH:D009369', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hepatocellular', 'Disease', (53, 67))
594930	32085654	Consistently, patients with high PlGF and miR-19a levels in the tumor showed a shorter overall survival (OS) than patients with low expression.	('tumor', 'Disease', (64, 69))	('miR-19a', 'Gene', (42, 49))	(')', 'Gene', '7424', (107, 108))	('shorter', 'NegReg', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('miR-19a', 'Gene', '406979', (42, 49))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('overall survival', 'MPA', (87, 103))
594933	32085654	In fact, blockade of VEGFR-1 by the MF-1 mAb in syngeneic murine RCC models induced 31% reduction in the growth of liver metastases, whereas blockade of VEGFR-2 had minimal effects.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('blockade', 'Var', (9, 17))	('MF-1', 'Gene', (36, 40))	('VEGFR-1', 'Gene', (21, 28))	('reduction', 'NegReg', (88, 97))	('liver metastases', 'Disease', (115, 131))	('murine', 'Species', '10090', (58, 64))	('MF-1', 'Gene', '17300', (36, 40))	('liver metastases', 'Disease', 'MESH:D009362', (115, 131))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
594934	32085654	In the case of metastases from colon carcinoma, only the neutralization of both VEGFR-1 and VEGFR-2 was able to decrease the size of liver metastasis.	('liver metastasis', 'Disease', (133, 149))	('VEGFR-2', 'Gene', (92, 99))	('metastases', 'Disease', (15, 25))	('decrease', 'NegReg', (112, 120))	('neutralization', 'Var', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('colon carcinoma', 'Disease', 'MESH:D015179', (31, 46))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('size of liver', 'Phenotype', 'HP:0002240', (125, 138))	('colon carcinoma', 'Disease', (31, 46))	('VEGFR-1', 'Gene', (80, 87))	('liver metastasis', 'Disease', 'MESH:D009362', (133, 149))
594943	32085654	The ccRCC is characterized by mutations or epigenetic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which are considered to play a key role in VEGF-A overexpression.	('epigenetic inactivation', 'Var', (43, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (74, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ccRCC', 'Disease', (4, 9))	('ccRCC', 'Disease', 'MESH:C538614', (4, 9))	('mutations', 'Var', (30, 39))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))
594946	32085654	Thus, in the presence of low expression or dysfunctional VHL, the HIF-1alpha accumulates and activates a number of hypoxia-driven genes, including VEGF-A.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('dysfunctional', 'Var', (43, 56))	('activates', 'PosReg', (93, 102))	('HIF-1alpha', 'Gene', (66, 76))	('low expression', 'Var', (25, 39))	('accumulates', 'PosReg', (77, 88))	('VHL', 'Gene', (57, 60))	('HIF-1alpha', 'Gene', '3091', (66, 76))	('VHL', 'Gene', '7428', (57, 60))	('hypoxia', 'Disease', (115, 122))
594947	32085654	Several single nucleotide polymorphisms identified in the VEGF gene have been reported to be associated with RCC risk, tumor growth, and metastases.	('VEGF', 'Gene', (58, 62))	('tumor', 'Disease', (119, 124))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('VEGF', 'Gene', '7422', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('associated', 'Reg', (93, 103))	('RCC', 'Disease', (109, 112))	('single nucleotide polymorphisms', 'Var', (8, 39))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('metastases', 'Disease', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
594948	32085654	In particular, two meta-analysis studies indicated that the VEGF -2578C/A, +936C/T, and +405G/C polymorphisms correlated with elevated risk of RCC, especially in the Asian populations.	('VEGF', 'Gene', '7422', (60, 64))	('+405G/C', 'Mutation', 'rs2010963', (88, 95))	('VEGF', 'Gene', (60, 64))	('-2578C/A', 'Mutation', 'rs699947', (65, 73))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('+936C/T', 'Mutation', 'rs3025039', (75, 82))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('+405G/C', 'Var', (88, 95))
594963	32085654	However, PlGF neutralization by the TB403 mAb did not inhibit the growth of sunitinib-resistant ccRCC xenografts, which did not express VEGFR-1.	('TB403', 'Var', (36, 41))	('TB', 'Chemical', 'MESH:D013725', (36, 38))	('inhibit', 'NegReg', (54, 61))	('sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC', 'Disease', (96, 101))	('ccRCC', 'Disease', 'MESH:C538614', (96, 101))
594970	32085654	demonstrated that VEGFR-1 overexpression increases in vitro and in vivo glioma growth via modulation of the Sonic Hedgehog Homolog (SHH) signaling pathway.	('glioma', 'Disease', (72, 78))	('increases', 'PosReg', (41, 50))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('VEGFR-1', 'Gene', (18, 25))	('rat', 'Species', '10116', (7, 10))	('overexpression', 'Var', (26, 40))	('Sonic Hedgehog Homolog', 'Gene', '6469', (108, 130))	('Sonic Hedgehog Homolog', 'Gene', (108, 130))	('modulation', 'Reg', (90, 100))
594973	32085654	In vitro treatment with the anti-VEGFR-1 D16F7 mAb markedly inhibited receptor autophosphorylation and ERK1/2 activation and reduced glioblastoma cell invasive behavior.	('glioblastoma', 'Disease', (133, 145))	('anti-VEGFR-1', 'Gene', (28, 40))	('men', 'Species', '9606', (14, 17))	('ERK1/2', 'Gene', (103, 109))	('ERK1/2', 'Gene', '5595;5594', (103, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('receptor autophosphorylation', 'MPA', (70, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('reduced', 'NegReg', (125, 132))	('inhibited', 'NegReg', (60, 69))	('activation', 'MPA', (110, 120))	('D16F7', 'Var', (41, 46))	('D16F7', 'Chemical', 'MESH:C000627505', (41, 46))
594974	32085654	In vivo studies in glioblastoma murine models indicated that D16F7 was well-tolerated and confirmed its promising therapeutic potential, as the mAb induced a decrease in glioma growth and angiogenesis, as well as an increase in mice survival.	('glioblastoma', 'Disease', (19, 31))	('D16F7', 'Var', (61, 66))	('decrease in glioma growth', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (19, 31))	('rat', 'Species', '10116', (80, 83))	('D16F7', 'Chemical', 'MESH:C000627505', (61, 66))	('murine', 'Species', '10090', (32, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('angiogenesis', 'CPA', (188, 200))	('decrease in glioma growth', 'Disease', 'MESH:D005910', (158, 183))	('mice survival', 'CPA', (228, 241))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('increase', 'PosReg', (216, 224))	('mice', 'Species', '10090', (228, 232))
594975	32085654	In particular, the efficacy of D16F7 mAb was tested in heterotopic (intramuscular) and orthotopic (intracranial) models using rat C6 glioma sublines, transfected to overexpress VEGFR-1.	('C6 glioma sublines', 'Disease', 'MESH:C567307', (130, 148))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('overexpress', 'PosReg', (165, 176))	(')', 'Gene', '7424', (111, 112))	('rat', 'Species', '10116', (126, 129))	('tested', 'Reg', (45, 51))	('C6 glioma sublines', 'Disease', (130, 148))	('D16F7', 'Var', (31, 36))	('VEGFR-1', 'Gene', (177, 184))	(')', 'Gene', '7424', (81, 82))	('D16F7', 'Chemical', 'MESH:C000627505', (31, 36))
594976	32085654	In the heterotopic intramuscular model, treatment with D16F7 reduced tumor growth and in the orthotopic intracranial model the mAb increased animal survival by 40% and 65% at 10 and 20 mg/kg, respectively, with a remarkable percentage (46%) of long-term survivors at the higher dose.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('increased', 'PosReg', (131, 140))	('men', 'Species', '9606', (45, 48))	('tumor', 'Disease', (69, 74))	('animal survival', 'CPA', (141, 156))	('D16F7', 'Chemical', 'MESH:C000627505', (55, 60))	('D16F7', 'Var', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('reduced', 'NegReg', (61, 68))	(')', 'Gene', '7424', (239, 240))
594977	32085654	Additionally, immunohistochemical analysis of tumor sections from D16F7-treated animals showed a higher number of apoptotic cells and fewer blood vessels compared to untreated mice.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('apoptotic cells', 'CPA', (114, 129))	('mice', 'Species', '10090', (176, 180))	('fewer', 'NegReg', (134, 139))	('D16F7', 'Chemical', 'MESH:C000627505', (66, 71))	('D16F7-treated', 'Var', (66, 79))	('blood vessels', 'CPA', (140, 153))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
594999	32085654	Treatment of human (CR-Mel) and murine (B16F10) melanoma cells with the anti-VEGFR-1 D16F7 mAb strongly down-modulated the migration triggered by PlGF.	('melanoma cells', 'Disease', (48, 62))	('human', 'Species', '9606', (13, 18))	('melanoma cells', 'Disease', 'MESH:D008545', (48, 62))	('anti-VEGFR-1', 'Var', (72, 84))	('murine', 'Species', '10090', (32, 38))	('D16F7', 'Chemical', 'MESH:C000627505', (85, 90))	(')', 'Gene', '7424', (46, 47))	('men', 'Species', '9606', (5, 8))	('rat', 'Species', '10116', (126, 129))	('down-modulated', 'NegReg', (104, 118))	(')', 'Gene', '7424', (26, 27))	('migration', 'CPA', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
595000	32085654	Moreover, D16F7 inhibited vasculogenic mimicry (i.e., the formation of tube-like structures, resembling blood vessels) by melanoma cells in response to VEGF-A.	('inhibited', 'NegReg', (16, 25))	(')', 'Gene', '7424', (117, 118))	('D16F7', 'Var', (10, 15))	('melanoma cells', 'Disease', 'MESH:D008545', (122, 136))	('melanoma cells', 'Disease', (122, 136))	('vasculogenic mimicry', 'CPA', (26, 46))	('D16F7', 'Chemical', 'MESH:C000627505', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('formation of tube-like structures', 'CPA', (58, 91))
595001	32085654	In vivo studies performed in a syngeneic murine melanoma model (B16F10 cells injected in B6D2F1 mice) confirmed the efficacy of VEGFR-1 blockade by D16F7 and the good tolerability of the treatment.	('melanoma', 'Disease', (48, 56))	('blockade', 'NegReg', (136, 144))	('D16F7', 'Chemical', 'MESH:C000627505', (148, 153))	('murine', 'Species', '10090', (41, 47))	('VEGFR-1', 'Gene', (128, 135))	('men', 'Species', '9606', (192, 195))	('D16F7', 'Var', (148, 153))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
595003	32085654	Furthermore, immunohistochemical analysis of melanoma sections from D16F7-treated animals showed a reduction of tumor infiltration by monocytes/macrophages and a marked decrease of bone invasion by melanoma cells.	('rat', 'Species', '10116', (124, 127))	('decrease', 'NegReg', (169, 177))	('melanoma cells', 'Disease', 'MESH:D008545', (198, 212))	('melanoma cells', 'Disease', (198, 212))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('D16F7-treated', 'Var', (68, 81))	('reduction', 'NegReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('D16F7', 'Chemical', 'MESH:C000627505', (68, 73))	('tumor', 'Disease', (112, 117))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
595005	32085654	In fact, the expression of VEGFR-1 in melanoma cells resistant to the BRAFi vemurafenib was higher than in their BRAFi-sensitive counterparts, whereas the transient silencing of VEGFR-1 in resistant cells increased BRAFi sensitivity and in susceptible cells delayed resistance development.	('BRAF', 'Gene', (215, 219))	('VEGFR-1', 'Gene', (178, 185))	('delayed', 'NegReg', (258, 265))	('VEGFR-1', 'Gene', (27, 34))	('increased', 'PosReg', (205, 214))	('BRAFi vemurafenib', 'Chemical', '-', (70, 87))	('silencing', 'Var', (165, 174))	('higher', 'PosReg', (92, 98))	('melanoma cells', 'Disease', 'MESH:D008545', (38, 52))	('BRAF', 'Gene', '673', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRAF', 'Gene', (70, 74))	('men', 'Species', '9606', (284, 287))	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', (113, 117))	('expression', 'MPA', (13, 23))	('melanoma cells', 'Disease', (38, 52))	('resistance development', 'CPA', (266, 288))	('BRAF', 'Gene', '673', (215, 219))
595006	32085654	Furthermore, vemurafenib-resistant melanoma cells expressing VEGFR-1 showed a higher invasive behavior, compared to melanoma cells susceptible to the BRAFi.	('vemurafenib', 'Chemical', 'MESH:D000077484', (13, 24))	('VEGFR-1', 'Var', (61, 68))	('higher', 'PosReg', (78, 84))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('melanoma cells', 'Disease', (116, 130))	('melanoma cells', 'Disease', 'MESH:D008545', (116, 130))	('invasive behavior', 'CPA', (85, 102))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma cells', 'Disease', 'MESH:D008545', (35, 49))	('melanoma cells', 'Disease', (35, 49))
595007	32085654	Accordingly, treatment with D16F7 markedly reduced ECM invasion by resistant cells in response to VEGF-A and PlGF, suggesting that VEGFR-1 blockade in combination with the BRAFi might delay the acquisition of a resistance phenotype.	('resistance phenotype', 'CPA', (211, 231))	('men', 'Species', '9606', (18, 21))	('D16F7', 'Var', (28, 33))	('delay', 'NegReg', (184, 189))	('ECM invasion', 'CPA', (51, 63))	('D16F7', 'Chemical', 'MESH:C000627505', (28, 33))	('BRAF', 'Gene', '673', (172, 176))	('reduced', 'NegReg', (43, 50))	('VEGFR-1', 'Gene', (131, 138))	('BRAF', 'Gene', (172, 176))
595010	32085654	Indeed, PlGF silencing or inhibition of NF-kappaB restored melanoma cell sensitivity to the chemotherapeutic agent Finally, VEGF-B transcript levels in the tumor measured in a large cohort of melanoma patients inversely correlated with survival.	('patients', 'Species', '9606', (201, 209))	('PlGF', 'Gene', (8, 12))	('transcript levels', 'MPA', (131, 148))	('NF-kappaB', 'Gene', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('inhibition', 'NegReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('tumor', 'Disease', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('VEGF-B', 'Gene', (124, 130))	('restored', 'PosReg', (50, 58))	('correlated', 'Reg', (220, 230))	('silencing', 'Var', (13, 22))
595021	32085654	Moreover, a meta-analysis study performed in a Chinese population reported a link between VEGF-A gene polymorphisms (VEGF +936C/T and -634 G/C) and the risk of developing osteosarcoma.	('+936C/T', 'Mutation', 'rs3025039', (122, 129))	('VEGF', 'Gene', (117, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('VEGF', 'Gene', (90, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('-634 G/C', 'Var', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('VEGF', 'Gene', '7422', (117, 121))	('-634 G/C', 'SUBSTITUTION', 'None', (134, 142))	('VEGF', 'Gene', '7422', (90, 94))	('osteosarcoma', 'Disease', (171, 183))
595023	32085654	Indeed, HIF-1alpha and VEGF-A knockdown decreased the invasive potential of Saos-2 and U2-OS osteosarcoma cell lines.	('VEGF-A', 'Gene', (23, 29))	('HIF-1alpha', 'Gene', '3091', (8, 18))	('HIF-1alpha', 'Gene', (8, 18))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('invasive potential of Saos-2', 'CPA', (54, 82))	('osteosarcoma', 'Disease', (93, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (93, 105))	('knockdown', 'Var', (30, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('decreased', 'NegReg', (40, 49))
595030	32085654	Consistently with the in vitro data, tumors originated from high-VEGFR-1 K7M3 cells produced more VEGF-A than low-VEGFR-1 cells.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('high-VEGFR-1 K7M3', 'Var', (60, 77))	('K7M3', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('VEGF-A', 'MPA', (98, 104))
595054	32085654	Increased levels of PlGF were reported in obesity-associated pancreatic cancer patients and ablation of the VEGFR-1 signaling in pancreatic ductal adenocarcinoma murine models prevented obesity-induced tumor progression.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ablation', 'Var', (92, 100))	('obesity', 'Phenotype', 'HP:0001513', (42, 49))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (129, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('obesity', 'Disease', (186, 193))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic ductal adenocarcinoma', 'Disease', (129, 161))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('obesity', 'Disease', (42, 49))	('pancreatic cancer', 'Disease', (61, 78))	('obesity', 'Disease', 'MESH:D009765', (186, 193))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (129, 161))	('obesity', 'Disease', 'MESH:D009765', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('murine', 'Species', '10090', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('prevented', 'NegReg', (176, 185))	('VEGFR-1', 'Gene', (108, 115))	('patients', 'Species', '9606', (79, 87))	('obesity', 'Phenotype', 'HP:0001513', (186, 193))
595060	32085654	Moreover, triple VEGFRs downregulation synergized with standard chemotherapy (5-fluorouracil and cisplatin combination) in vivo.	('triple', 'Var', (10, 16))	('VEGFR', 'Gene', '3791', (17, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (78, 92))	('downregulation', 'NegReg', (24, 38))	(')', 'Gene', '7424', (118, 119))	('VEGFR', 'Gene', (17, 22))
595071	32085654	Patients with VEGF-A overexpression have a significantly increased risk (2-fold) of disease progression, with the development of distant metastases and shorter OS.	('metastases', 'Disease', 'MESH:D009362', (137, 147))	(')', 'Gene', '7424', (79, 80))	('overexpression', 'Var', (21, 35))	('men', 'Species', '9606', (121, 124))	('Patients', 'Species', '9606', (0, 8))	('disease', 'Disease', (84, 91))	('VEGF-A', 'Gene', (14, 20))	('metastases', 'Disease', (137, 147))
595073	32085654	Furthermore, a clinical study enrolling 334 patients with advanced esophageal squamous cell carcinoma revealed that the genetic polymorphism rs2010963 in VEGF-A gene independently correlated with worse OS, although this genotype was not associated with high pretreatment VEGF-A levels in the serum.	('patients', 'Species', '9606', (44, 52))	('VEGF-A', 'Gene', (154, 160))	('rs2010963', 'Mutation', 'rs2010963', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('rs2010963', 'Var', (141, 150))	('men', 'Species', '9606', (266, 269))	('worse OS', 'Disease', (196, 204))	('correlated with', 'Reg', (180, 195))	('esophageal squamous cell carcinoma', 'Disease', (67, 101))
595116	32085654	Overexpression of CSE also increased the levels of MMP2 and MMP9 in early metastatic breast cancer cells, allowing the degradation of the ECM and consequently the entering of tumor cells into the blood circulation.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('tumor', 'Disease', (175, 180))	('MMP2', 'Gene', (51, 55))	('increased', 'PosReg', (27, 36))	('breast cancer', 'Disease', (85, 98))	('entering', 'MPA', (163, 171))	('CSE', 'Gene', '1491', (18, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('degradation', 'MPA', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('MMP2', 'Gene', '4313', (51, 55))	('allowing', 'Reg', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MMP9', 'Var', (60, 64))	('CSE', 'Gene', (18, 21))	('levels', 'MPA', (41, 47))
595122	32085654	The addition of the anti-VEGFR-1 KM1732 mAb and a VEGFR-1 trap (sFlt-1-Fc) to CD34+ cultures, pretreated with the MDA-MB-231-conditioned medium or PlGF, prevented the generation of CD11b+ cells with sprouting-inducing ability.	('CD11b', 'Gene', (181, 186))	('CD34', 'Gene', (78, 82))	('CD34', 'Gene', '947', (78, 82))	('Flt-1', 'Gene', '2321', (65, 70))	('rat', 'Species', '10116', (171, 174))	(')', 'Gene', '7424', (73, 74))	('prevented', 'NegReg', (153, 162))	('Flt-1', 'Gene', (65, 70))	('CD11b', 'Gene', '3684', (181, 186))	('anti-VEGFR-1', 'Var', (20, 32))
595123	32085654	Furthermore, CD11b+ cells induced a significant angiogenic response in the murine corneal angiogenesis in vivo assay and PlGF silencing reduced the proangiogenic activity of circulating CD11b+ myelomonocytic cells in a breast cancer murine model.	('CD11b', 'Gene', (13, 18))	('corneal angiogenesis', 'Phenotype', 'HP:0011496', (82, 102))	('CD11b', 'Gene', '3684', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('murine', 'Species', '10090', (75, 81))	('CD11b', 'Gene', (186, 191))	('breast cancer', 'Disease', (219, 232))	('angiogenic response', 'CPA', (48, 67))	('murine', 'Species', '10090', (233, 239))	('CD11b', 'Gene', '3684', (186, 191))	('reduced', 'NegReg', (136, 143))	('silencing', 'Var', (126, 135))	('proangiogenic activity', 'CPA', (148, 170))	('PlGF', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
595127	32085654	Furthermore, while obesity promoted IL-6 and MMP9 expression in tumors, deletion of VEGFR-1 TK domain decreased the expression of these pro-M2 markers only in obese mice.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('expression', 'MPA', (116, 126))	('tumors', 'Disease', (64, 70))	('obese', 'Disease', (159, 164))	('IL-6', 'Gene', (36, 40))	('obesity', 'Disease', 'MESH:D009765', (19, 26))	('mice', 'Species', '10090', (165, 169))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('obese', 'Disease', 'MESH:D009765', (159, 164))	('IL-6', 'Gene', '16193', (36, 40))	('obesity', 'Disease', (19, 26))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('promoted', 'PosReg', (27, 35))	('MMP9 expression', 'MPA', (45, 60))	('obesity', 'Phenotype', 'HP:0001513', (19, 26))	('VEGFR-1', 'Gene', (84, 91))	('decreased', 'NegReg', (102, 111))	('deletion', 'Var', (72, 80))
595128	32085654	PlGF was identified as the VEGFR-1 ligand responsible for such effects since its plasma levels were elevated in diet-induced obese mice, and its deletion induced similar effects to those observed in VEGFR-1-TK-null obese mice.	('obese', 'Disease', (125, 130))	('obese', 'Disease', 'MESH:D009765', (215, 220))	('obese', 'Disease', (215, 220))	('mice', 'Species', '10090', (221, 225))	('PlGF', 'Gene', (0, 4))	('plasma levels', 'MPA', (81, 94))	('obese', 'Disease', 'MESH:D009765', (125, 130))	('mice', 'Species', '10090', (131, 135))	('elevated', 'PosReg', (100, 108))	('deletion', 'Var', (145, 153))
595139	32085654	Mice transplanted with human ovarian adenocarcinoma SKOV3 cells transfected with pLV-sFLT1 or exogenously (intraperitoneally) treated with recombinant sVEGFR-1, confirmed the antitumor effect of sVEGFR-1 also in vivo, in terms of reduced tumor size compared to control animals.	('reduced', 'NegReg', (230, 237))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('sVEGFR-1', 'Var', (195, 203))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (29, 51))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('ovarian adenocarcinoma', 'Disease', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	(')', 'Gene', '7424', (124, 125))	('tumor', 'Disease', (238, 243))	('Mice', 'Species', '10090', (0, 4))	('human', 'Species', '9606', (23, 28))	('SKOV3', 'CellLine', 'CVCL:0532;0.04086655203281981', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('tumor', 'Disease', (179, 184))
595141	32085654	VEGFR-1 as well VEGFR-2 expression levels in biopsy specimens have been recognized as prognostic factors for patients with cervical cancer: high VEGFR-1 expression was linked to distant metastases, together with poor OS and PFS, whereas high VEGFR-2 expression correlated with increased tumor size and reduced OS.	('metastases', 'Disease', (186, 196))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('cervical cancer', 'Disease', (123, 138))	('high', 'Var', (140, 144))	('cervical cancer', 'Disease', 'MESH:D002583', (123, 138))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('VEGFR-1', 'Gene', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('increased', 'PosReg', (277, 286))	('tumor', 'Disease', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('men', 'Species', '9606', (57, 60))	('linked to', 'Reg', (168, 177))
595143	32085654	On the other hand, a recent study reported that patients with high serum levels of both VEGF-A and VEGFR-2 presented bulky tumors, pelvic lymph node involvement, parametrial infiltration, and significantly lower OS than patients with low VEGF-A and VEGFR-2 expression.	('VEGFR-2', 'Gene', (99, 106))	('parametrial infiltration', 'CPA', (162, 186))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('rat', 'Species', '10116', (180, 183))	('pelvic lymph node involvement', 'CPA', (131, 160))	('men', 'Species', '9606', (156, 159))	('lower', 'NegReg', (206, 211))	('serum levels', 'MPA', (67, 79))	('patients', 'Species', '9606', (220, 228))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('VEGF-A', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
595147	32085654	Deregulation of cellular energetic metabolism has been recognized as another feature of cancer, aimed at increasing the production of lactate, whose efflux in the ECM induces angiogenesis.	('cellular energetic metabolism', 'MPA', (16, 45))	('increasing', 'PosReg', (105, 115))	('induces', 'Reg', (167, 174))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Deregulation', 'Var', (0, 12))	('lactate', 'Chemical', 'MESH:D019344', (134, 141))	('angiogenesis', 'CPA', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('efflux', 'MPA', (149, 155))	('production of lactate', 'MPA', (120, 141))
595169	32085654	Consistently, ectopic VEGF-A expression decreased miR-130b level and abrogated its antiangiogenic effect, thus promoting the angiogenic response.	('abrogated', 'NegReg', (69, 78))	('antiangiogenic effect', 'CPA', (83, 104))	('promoting', 'PosReg', (111, 120))	('miR-130b', 'Gene', '406920', (50, 58))	('miR-130b', 'Gene', (50, 58))	('ectopic', 'Var', (14, 21))	('angiogenic response', 'CPA', (125, 144))	('decreased', 'NegReg', (40, 49))	('VEGF-A', 'Gene', (22, 28))
595192	32085654	Thus, the authors suggested that blockade of VEGFR-1 by a selective therapeutic agent might counteract leukemia cell movement within the bone marrow, delaying the extra-medullary tumor growth.	('blockade', 'Var', (33, 41))	('men', 'Species', '9606', (121, 124))	('delaying', 'NegReg', (150, 158))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('VEGFR-1', 'Gene', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('leukemia', 'Disease', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
595198	32085654	Other approved agents that are endowed with antiangiogenic effects but do not directly target the VEGFRs or their ligands include (i) the mammalian target of rapamycin (mTOR) inhibitors temsirolimus (approved for RCC and mantle cell lymphoma) and everolimus (approved for advanced kidney and breast cancers, subependymal giant cell astrocytoma, pancreatic neuroendocrine tumors, neuroendocrine tumors of gastrointestinal or lung origin), and the (ii) the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide and pomalidomide, approved for the treatment of multiple myeloma (lenalidomide also for relapsed or refractory mantle cell lymphoma and myelodysplastic syndromes with deletion of the long arm of chromosome 5).	('men', 'Species', '9606', (552, 555))	('multiple myeloma', 'Phenotype', 'HP:0006775', (560, 576))	('breast cancers', 'Phenotype', 'HP:0003002', (292, 306))	(')', 'Gene', '7424', (484, 485))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (356, 377))	('subependymal giant cell astrocytoma', 'Disease', (308, 343))	('pancreatic neuroendocrine tumors', 'Disease', (345, 377))	('cell lymphoma', 'Phenotype', 'HP:0012191', (228, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('lymphoma', 'Phenotype', 'HP:0002665', (233, 241))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (379, 400))	('mantle cell lymphoma', 'Disease', (623, 643))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (623, 643))	('multiple myeloma', 'Disease', 'MESH:D009101', (560, 576))	('tumors', 'Phenotype', 'HP:0002664', (394, 400))	('subependymal giant cell astrocytoma', 'Phenotype', 'HP:0009718', (308, 343))	('myelodysplastic syndromes', 'Disease', (648, 673))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (648, 673))	('cell lymphoma', 'Phenotype', 'HP:0012191', (630, 643))	('lymphoma', 'Phenotype', 'HP:0002665', (635, 643))	(')', 'Gene', '7424', (173, 174))	('subependymal giant cell astrocytoma', 'Disease', 'MESH:D001254', (308, 343))	('mammalian target of rapamycin', 'Gene', '2475', (138, 167))	(')', 'Gene', '7424', (435, 436))	('everolimus', 'Chemical', 'MESH:D000068338', (247, 257))	('VEGFR', 'Gene', '3791', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('multiple myeloma', 'Disease', (560, 576))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (648, 673))	('deletion', 'Var', (679, 687))	('VEGFR', 'Gene', (98, 103))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	(')', 'Gene', '7424', (719, 720))	(')', 'Gene', '7424', (132, 133))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (221, 241))	('mammalian target of rapamycin', 'Gene', (138, 167))	('mantle cell lymphoma', 'Disease', (221, 241))	(')', 'Gene', '7424', (449, 450))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('astrocytoma', 'Phenotype', 'HP:0009592', (332, 343))	(')', 'Gene', '7424', (241, 242))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancers', 'Disease', 'MESH:D001943', (292, 306))	('breast cancers', 'Disease', (292, 306))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('neuroendocrine tumors of gastrointestinal', 'Disease', (379, 420))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (345, 377))	('tumors of gastrointestinal', 'Phenotype', 'HP:0007378', (394, 420))	('neuroendocrine tumors of gastrointestinal', 'Disease', 'MESH:D018358', (379, 420))
595202	32085654	Most of these mAbs prevent the interaction of VEGFR-1 ligands with the receptor (competitive inhibitors), whereas only D16F7 blocks receptor signal transduction without inhibiting ligand binding (non-competitive inhibitor).	('prevent', 'NegReg', (19, 26))	('D16F7', 'Var', (119, 124))	('interaction', 'Interaction', (31, 42))	(')', 'Gene', '7424', (103, 104))	('D16F7', 'Chemical', 'MESH:C000627505', (119, 124))	(')', 'Gene', '7424', (221, 222))	('receptor signal transduction', 'MPA', (132, 160))	('blocks', 'NegReg', (125, 131))	('VEGFR-1', 'Gene', (46, 53))
595205	32085654	This mAb has shown antitumor activity in human breast carcinoma xenograft models (i.e., DU4475, MDA-MB-231, and MDA-MB-435).	('DU4475', 'CellLine', 'CVCL:1183;-0.001036928386686134', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('breast carcinoma xenograft', 'Disease', (47, 73))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('human', 'Species', '9606', (41, 46))	('breast carcinoma xenograft', 'Disease', 'MESH:D001943', (47, 73))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('breast carcinoma', 'Phenotype', 'HP:0003002', (47, 63))	('tumor', 'Disease', (23, 28))	('DU4475', 'Var', (88, 94))
595207	32085654	Moreover, immunohistochemical analysis of tumor xenografts collected from treated mice showed an increase of tumor cell apoptosis and a decrease in MAPK and AKT activation and cell proliferation; (ii) The murine anti-human VEGFR-1 D16F7 mAb (mouse IgG1), which has a novel mechanism of action, as it interacts with a receptor site distinct from that involved in VEGF-A or PlGF binding and downregulates the signaling through the membrane receptor without affecting ligand binding.	(')', 'Gene', '7424', (199, 200))	('human', 'Species', '9606', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (42, 47))	('murine', 'Species', '10090', (205, 211))	('rat', 'Species', '10116', (188, 191))	('signaling through the membrane receptor', 'MPA', (407, 446))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	(')', 'Gene', '7424', (252, 253))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('D16F7', 'Var', (231, 236))	('mice', 'Species', '10090', (82, 86))	('MAPK', 'Pathway', (148, 152))	('mouse', 'Species', '10090', (242, 247))	('downregulates', 'NegReg', (389, 402))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('interacts', 'Interaction', (300, 309))	('D16F7', 'Chemical', 'MESH:C000627505', (231, 236))	('decrease', 'NegReg', (136, 144))	('tumor', 'Disease', (109, 114))
595209	32085654	Moreover, D16F7 leaves unaffected the sVEGFR-1 decoy function, as it neither affects sVEGFR-1 interaction with its ligands nor hampers the sVEGFR-1/VEGFR-2 inhibitory heterodimer formation.	('interaction', 'Interaction', (94, 105))	('D16F7', 'Var', (10, 15))	('D16F7', 'Chemical', 'MESH:C000627505', (10, 15))	('hampers', 'NegReg', (127, 134))	('sVEGFR-1/VEGFR-2 inhibitory heterodimer formation', 'MPA', (139, 188))
595210	32085654	D16F7 has shown antitumor efficacy in preclinical in vivo models against highly aggressive tumor types, such as glioblastoma and melanoma (see also Section 2.4 and Section 2.5).	('D16F7', 'Var', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('D16F7', 'Chemical', 'MESH:C000627505', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('aggressive tumor', 'Disease', 'MESH:D001523', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (112, 137))	('aggressive tumor', 'Disease', (80, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (20, 25))	(')', 'Gene', '7424', (175, 176))
595211	32085654	Its ability to recognize not only the human form of the VEGFR-1 but also the murine receptor has allowed the analysis of the effects of VEGFR-1 inhibition on tumor-associated microenvironment; (iii) The anti-human VEGFR-1 KM1730 and KM1732 mAbs (mouse IgG1), which recognize different epitopes of the second Ig-like domain.	(')', 'Gene', '7424', (256, 257))	('tumor', 'Disease', (158, 163))	('human', 'Species', '9606', (38, 43))	('murine', 'Species', '10090', (77, 83))	('KM1732', 'Var', (233, 239))	('men', 'Species', '9606', (187, 190))	('mouse', 'Species', '10090', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	(')', 'Gene', '7424', (197, 198))	('human', 'Species', '9606', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('KM1730', 'Var', (222, 228))
595213	32085654	Moreover, treatment with KM1732 mAb of primary cell cultures derived from bone marrow samples collected from patients with AML resulted in significant inhibition of cell growth.	('KM1732 mAb', 'Var', (25, 35))	('patients', 'Species', '9606', (109, 117))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('men', 'Species', '9606', (15, 18))	('AML', 'Phenotype', 'HP:0004808', (123, 126))	('AML', 'Disease', (123, 126))	('inhibition', 'NegReg', (151, 161))	('cell growth', 'CPA', (165, 176))
595220	32085654	The anti-PlGF mAb 5D11D4 is directed against the murine PlGF of which inhibits the interaction with VEGFR-1 and with NRP-1.	('VEGFR-1', 'Protein', (100, 107))	('interaction', 'Interaction', (83, 94))	('inhibits', 'NegReg', (70, 78))	('5D11D4', 'Var', (18, 24))	('murine', 'Species', '10090', (49, 55))
595221	32085654	The 5D11D4 mAb inhibited tumor growth and metastasis formation in melanoma, cholangiocarcinoma, pancreatic, hepatocellular, and colon cancer in vivo models.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('melanoma', 'Disease', (66, 74))	('cholangiocarcinoma', 'Disease', (76, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('hepatocellular', 'Disease', (108, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('5D11D4', 'Var', (4, 10))	('pancreatic', 'Disease', 'MESH:D010195', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('tumor', 'Disease', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('pancreatic', 'Disease', (96, 106))	('inhibited', 'NegReg', (15, 24))	('colon cancer', 'Disease', (128, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
595238	32085654	AEE788 is instead a dual inhibitor of epidermal growth factor and VEGF receptors and is currently under investigation in patients with recurrent glioblastoma, as single agent or in combination with everolimus.	('VEGF', 'Gene', (66, 70))	('AEE788', 'Var', (0, 6))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('everolimus', 'Chemical', 'MESH:D000068338', (198, 208))	('AEE788', 'Chemical', 'MESH:C489254', (0, 6))	('VEGF', 'Gene', '7422', (66, 70))	('epidermal', 'Protein', (38, 47))	('glioblastoma', 'Disease', (145, 157))	('patients', 'Species', '9606', (121, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))
595240	32085654	A total of thirty-two trials can be found in  where lucitanib is tested for solid tumors, breast cancer, NSCLC, SCLC, gastroesophageal reflux disease, and functional dyspepsia, with two of them including tumors with genetic alterations of the FGF receptor.	('gastroesophageal reflux disease', 'Disease', (118, 149))	('tumors', 'Disease', (82, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (118, 149))	('SCLC', 'Disease', 'MESH:D055752', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('genetic alterations', 'Var', (216, 235))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('rat', 'Species', '10116', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SCLC', 'Disease', 'MESH:D055752', (112, 116))	('SCLC', 'Disease', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('solid tumors', 'Disease', (76, 88))	('dyspepsia', 'Phenotype', 'HP:0410281', (166, 175))	('tumors', 'Disease', (204, 210))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))	('FGF receptor', 'Gene', (243, 255))	('SCLC', 'Disease', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('functional dyspepsia', 'Disease', 'MESH:D004415', (155, 175))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (118, 141))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('functional dyspepsia', 'Disease', (155, 175))	('breast cancer', 'Disease', (90, 103))	('lucitanib', 'Chemical', 'MESH:C000595232', (52, 61))	('NSCLC', 'Disease', (105, 110))	('tested', 'Reg', (65, 71))
595248	32085654	Inhibition of VEGF-A and its signaling through VEGFR-2, a receptor also involved in physiological angiogenesis, causes important adverse effects such as hypertension, proteinuria, bleeding, thromboembolism, delay in wound healing, and gastrointestinal perforation.	('bleeding', 'Disease', (180, 188))	('gastrointestinal', 'Disease', (235, 251))	('thromboembolism', 'Disease', 'MESH:D013923', (190, 205))	('thromboembolism', 'Phenotype', 'HP:0001907', (190, 205))	('VEGFR-2', 'Gene', (47, 54))	('hypertension', 'Disease', 'MESH:D006973', (153, 165))	('delay', 'CPA', (207, 212))	('proteinuria', 'Disease', (167, 178))	('hypertension', 'Disease', (153, 165))	('proteinuria', 'Disease', 'MESH:D011507', (167, 178))	('Inhibition', 'Var', (0, 10))	('rat', 'Species', '10116', (257, 260))	('thromboembolism', 'Disease', (190, 205))	('bleeding', 'Disease', 'MESH:D006470', (180, 188))	('proteinuria', 'Phenotype', 'HP:0000093', (167, 178))	('wound healing', 'CPA', (216, 229))	('hypertension', 'Phenotype', 'HP:0000822', (153, 165))	('VEGF-A', 'Gene', (14, 20))	('delay in wound healing', 'Phenotype', 'HP:0001058', (207, 229))
595251	32085654	Conversely, the neutralization of VEGFR-1 specific ligands, i.e., VEGF-B and PlGF, and the selective blockade of VEGFR-1 activation, represents a promising strategy to specifically counteract tumor-associated angiogenesis as well as malignant processes not directly related to new blood vessels formation.	('tumor', 'Disease', (192, 197))	('neutralization', 'Var', (16, 30))	('VEGFR-1', 'Gene', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('VEGF-B', 'Gene', (66, 72))	('rat', 'Species', '10116', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('VEGFR-1', 'Gene', (113, 120))
595252	32085654	Indeed, inhibition of VEGFR-1 signaling also reduces tumor cell survival and invasiveness, counteracts the mobilization of myeloid progenitors and prevents tumor infiltration by M2 protumoral macrophages.	('VEGFR-1', 'Gene', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumoral', 'Disease', 'MESH:D009369', (184, 191))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('reduces', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('prevents', 'NegReg', (147, 155))	('tumor', 'Disease', (184, 189))	('invasiveness', 'CPA', (77, 89))	('tumor', 'Disease', (156, 161))	('rat', 'Species', '10116', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (53, 58))	('inhibition', 'Var', (8, 18))	('tumoral', 'Disease', (184, 191))
595253	32085654	In this context, the D16F7 mAb is a promising tool to specifically and non-competitively interfere with VEGFR-1 signaling in the tumor.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('interfere', 'NegReg', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('D16F7', 'Chemical', 'MESH:C000627505', (21, 26))	('D16F7', 'Var', (21, 26))	('tumor', 'Disease', (129, 134))	('VEGFR-1 signaling', 'MPA', (104, 121))
595254	32085654	Conversely, other experimental mAbs designed to inhibit human VEGFR-1 signaling, like IMC-18F1/icrucumab, KM1730, or KM1732, possess a competitive mechanism of action, by inhibiting VEGF-A, VEGF-B, or PlGF binding to VEGFR-1.	('men', 'Species', '9606', (24, 27))	('PlGF', 'Protein', (201, 205))	('inhibiting', 'NegReg', (171, 181))	('binding', 'Interaction', (206, 213))	('icrucumab', 'Chemical', 'MESH:C000626257', (95, 104))	('IMC-18F1', 'Chemical', 'MESH:C548516', (86, 94))	('KM1730', 'Var', (106, 112))	('human', 'Species', '9606', (56, 61))	('VEGF-A', 'Protein', (182, 188))	('KM1732', 'Var', (117, 123))	('VEGF-B', 'Protein', (190, 196))	('inhibit', 'NegReg', (48, 55))
595255	32085654	Competitive VEGFR-1 inhibitors, by antagonizing ligand binding, may increase in the ECM the free VEGF-A available for VEGFR-2 activation and this may reduce the overall efficacy of the treatment.	('free VEGF-A', 'MPA', (92, 103))	('ligand binding', 'Interaction', (48, 62))	('reduce', 'NegReg', (150, 156))	('inhibitors', 'Var', (20, 30))	('antagonizing', 'Reg', (35, 47))	('men', 'Species', '9606', (190, 193))	('increase', 'PosReg', (68, 76))	('ECM', 'MPA', (84, 87))	('VEGFR-1', 'Gene', (12, 19))	('efficacy of the treatment', 'CPA', (169, 194))
595257	32085654	D16F7 mAb efficacy in monotherapy has already been demonstrated in in vivo preclinical models of highly aggressive tumors, showing significant inhibition of glioblastoma and melanoma growth, invasiveness and migration, impairment of endothelial cells chemotaxis and tumor-associated angiogenesis, as well as reduced myeloid progenitor mobilization and tumor infiltration by monocytes/macrophages.	('impairment', 'NegReg', (219, 229))	('aggressive tumors', 'Disease', 'MESH:D001523', (104, 121))	('tumor', 'Disease', (115, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('men', 'Species', '9606', (225, 228))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('tumor', 'Disease', (266, 271))	('inhibition', 'NegReg', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('invasiveness', 'CPA', (191, 203))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('melanoma growth', 'Disease', 'MESH:D008545', (174, 189))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', (352, 357))	('myeloid progenitor mobilization', 'CPA', (316, 347))	('rat', 'Species', '10116', (364, 367))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (157, 182))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('endothelial cells chemotaxis', 'CPA', (233, 261))	('rat', 'Species', '10116', (211, 214))	('D16F7', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('rat', 'Species', '10116', (58, 61))	('reduced', 'NegReg', (308, 315))	('melanoma growth', 'Disease', (174, 189))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('aggressive tumors', 'Disease', (104, 121))	('D16F7', 'Chemical', 'MESH:C000627505', (0, 5))	('migration', 'CPA', (208, 217))
595297	26583076	The confirmed presence of disease-driving, activating mutations in KIT or PDGFRalpha in GIST can today, e.g., be used to predict tumor recurrence and identify patients who are likely to benefit from adjuvant therapy.	('disease-driving', 'Reg', (26, 41))	('GIST', 'Phenotype', 'HP:0100723', (88, 92))	('KIT', 'Gene', (67, 70))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PDGFRalpha', 'Gene', '5156', (74, 84))	('tumor', 'Disease', (129, 134))	('activating', 'PosReg', (43, 53))	('patients', 'Species', '9606', (159, 167))	('PDGFRalpha', 'Gene', (74, 84))
595349	26583076	Angiogenesis was early predicted to be a common denominator for targeted therapy in a broad range of tumor types and multiple studies have confirmed that antiangiogenic therapy causes starvation and reduced growth of experimental tumors.	('tumor', 'Disease', (230, 235))	('starvation', 'MPA', (184, 194))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('growth', 'CPA', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('causes', 'Reg', (177, 183))	('antiangiogenic', 'Var', (154, 168))	('reduced', 'NegReg', (199, 206))
595437	24148102	Three patients displayed other chromosome complex changes: del(1)(p32p36), t(10;11)(p13;q13) in one patient, -3p, t(5:17)(q15;q22), t(11:19)(q23;p13), -17, +19p; der(19)t(17;19)(q11;p11), t(11;12)(p15;q13) in one patient, and 47 XXY with inv(11) in one patient.	('t(11;12)(p15;q13', 'Var', (188, 204))	('patient', 'Species', '9606', (253, 260))	('t(11:19)(q23;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (132, 149))	('der(19)t(17;19)(q11;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (162, 186))	('patient', 'Species', '9606', (213, 220))	('t(11;12)(p15;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (188, 205))	('del(1)(p32p36', 'Var', (59, 72))	('t(11:19)(q23;p13', 'Var', (132, 148))	('patient', 'Species', '9606', (6, 13))	('t(10;11)(p13;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (75, 92))	('patient', 'Species', '9606', (100, 107))	('t(5:17)(q15;q22', 'Var', (114, 129))	('patients', 'Species', '9606', (6, 14))	('t(5:17)(q15;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (114, 130))
595449	24148102	According to the logistic regression model, BMT prior to RT was also associated with marginally significant increased rate of CR following RT (OR = 0.099, 95% CI = 0.0086-1.135, P = 0.06).	('BMT prior', 'Var', (44, 53))	('increased', 'PosReg', (108, 117))	('CR', 'Chemical', '-', (126, 128))
595453	24148102	Of the 18 patients, 9 (50%) had normal cytogenetics and 9 (50%) displayed abnormal chromosomes, among which t(9;22) (in 4 (22.2%) of 9 patients) and t(8;21)(q22;q22) (in 2 (11.1%) of 9 patients) were the common abnormality.	('patients', 'Species', '9606', (135, 143))	('t(9;22', 'Var', (108, 114))	('abnormal chromosomes', 'Phenotype', 'HP:0031411', (74, 94))	('t(8;21)(q22;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (149, 165))	('patients', 'Species', '9606', (185, 193))	('patients', 'Species', '9606', (10, 18))	('t(8;21)(q22;q22', 'Var', (149, 164))
595454	24148102	Other observed abnormal cytogenetics included: t(9;11) in one patient, inv(7)(q22q36) in one patient, and del(7)(q32q36),del(18)(q21q23) in the other patient.	('del(18)(q21q23', 'Var', (121, 135))	('patient', 'Species', '9606', (150, 157))	('patient', 'Species', '9606', (62, 69))	('inv', 'Var', (71, 74))	('patient', 'Species', '9606', (93, 100))	('del(7)(q32q36', 'Var', (106, 119))
595464	24148102	In our cytogenetically abnormal patients, t(8;21)(q22;q22) was the most common cytogenetic change .	('t(8;21)(q22;q22', 'Var', (42, 57))	('patients', 'Species', '9606', (32, 40))	('t(8;21)(q22;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (42, 58))	('common', 'Reg', (72, 78))
595480	24148102	These deregulated signaling pathway variations may explain the poor response to RT in older patients with MS.	('variations', 'Var', (36, 46))	('deregulated', 'Reg', (6, 17))	('patients', 'Species', '9606', (92, 100))
595490	24148102	Diversified cytogenetic abnormalities can occur in MS; however, the most common MS-associated cytogenetic change is t(8;21)(q22;q22).	('t(8;21)(q22;q22', 'Var', (116, 131))	('t(8;21)(q22;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (116, 132))	('MS-associated', 'Disease', (80, 93))
595501	32859065	Discoveries of human genetic disorders due to genetic mutations in gap junction proteins (connexins) and experimental data using connexin knockout mice have provided significant evidence that gap-junctional intercellular communication (Gj) is crucial for tissue function.	('genetic mutations', 'Var', (46, 63))	('gap-junctional', 'MPA', (192, 206))	('mice', 'Species', '10090', (147, 151))	('genetic disorders', 'Disease', 'MESH:D030342', (21, 38))	('genetic disorders', 'Disease', (21, 38))	('human', 'Species', '9606', (15, 20))	('men', 'Species', '9606', (111, 114))	('mutations', 'Var', (54, 63))	('connexin', 'Gene', '100128922', (90, 98))	('connexin', 'Gene', (90, 98))	('connexin', 'Gene', '100128922', (129, 137))	('connexin', 'Gene', (129, 137))
595502	32859065	Thus, the dysfunction of Gj may be responsible for the development of some diseases.	('men', 'Species', '9606', (62, 65))	('responsible', 'Reg', (35, 46))	('dysfunction', 'Var', (10, 21))
595504	32859065	If it is well accepted that a low level of connexin expression favors cancer cell proliferation and therefore primary tumor development, more evidence is suggesting that a high level of connexin expression stimulates various cellular process such as intravasation, extravasation, or migration of metastatic cells.	('intravasation', 'MPA', (250, 263))	('men', 'Species', '9606', (131, 134))	('rat', 'Species', '10116', (286, 289))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('extravasation', 'MPA', (265, 278))	('cancer', 'Disease', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cellular', 'CPA', (225, 233))	('connexin', 'Gene', '100128922', (186, 194))	('stimulates', 'PosReg', (206, 216))	('high', 'Var', (172, 176))	('connexin', 'Gene', (186, 194))	('connexin', 'Gene', '100128922', (43, 51))	('migration of metastatic cells', 'CPA', (283, 312))	('favors', 'PosReg', (63, 69))	('connexin', 'Gene', (43, 51))	('rat', 'Species', '10116', (89, 92))	('primary tumor', 'Disease', (110, 123))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('primary tumor', 'Disease', 'MESH:D001932', (110, 123))
595522	32859065	The EL-1 and EL-2 extracellular loops contain cysteine residues that form intra-molecular disulfide bonds, which play a crucial role in the formation of the channel.	('EL-2', 'Gene', (13, 17))	('EL-2', 'Gene', '6708', (13, 17))	('disulfide', 'Chemical', 'MESH:D004220', (90, 99))	('EL-1', 'Gene', '2035', (4, 8))	('cysteine', 'Chemical', 'MESH:D003545', (46, 54))	('cysteine', 'Var', (46, 54))	('EL-1', 'Gene', (4, 8))
595528	32859065	Since Gj is an essential mechanism in this exchange process, it is not unsurprising to observe that a correlation has been observed between a deregulation of Gj and the development of various pathologies such as cancers.	('deregulation', 'Var', (142, 154))	('men', 'Species', '9606', (176, 179))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
595547	32859065	More recently, it has been proven that Gj can also promote the exchange of miRNA between cells, allowing, for example, the enhancement of the antiproliferative properties of miRNA-124-3p in glioblastoma cancer cells.	('miRNA-124-3p', 'Var', (174, 186))	('glioblastoma cancer', 'Disease', (190, 209))	('glioblastoma', 'Phenotype', 'HP:0012174', (190, 202))	('exchange', 'MPA', (63, 71))	('rat', 'Species', '10116', (153, 156))	('antiproliferative properties', 'CPA', (142, 170))	('promote', 'PosReg', (51, 58))	('glioblastoma cancer', 'Disease', 'MESH:D009369', (190, 209))	('enhancement', 'PosReg', (123, 134))	('men', 'Species', '9606', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
595563	32859065	Despite initial studies that have demonstrated a decrease in metastatic potential due to connexin43, an increasing amount of works demonstrate that connexin43 expression may potentiate the development of metastases.	('rat', 'Species', '10116', (138, 141))	('men', 'Species', '9606', (196, 199))	('metastases', 'Disease', (204, 214))	('potentiate', 'PosReg', (174, 184))	('metastases', 'Disease', 'MESH:D009362', (204, 214))	('decrease', 'NegReg', (49, 57))	('rat', 'Species', '10116', (41, 44))	('metastatic potential', 'CPA', (61, 81))	('expression', 'Var', (159, 169))	('connexin43 expression', 'Var', (148, 169))
595571	32859065	It has been demonstrated that connexin43 reverses the resistance of A549 lung adenocarcinoma cells to cisplatin by inhibiting EMT.	('reverses', 'NegReg', (41, 49))	('lung adenocarcinoma', 'Disease', (73, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('resistance', 'MPA', (54, 64))	('rat', 'Species', '10116', (19, 22))	('inhibiting', 'NegReg', (115, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('connexin43', 'Var', (30, 40))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
595594	32859065	In these cells, connexin43 controls migration because the knockdown of connexin43 leads to erratic, slow, and reverse migration.	('reverse migration', 'CPA', (110, 127))	('connexin43', 'Gene', (71, 81))	('slow', 'CPA', (100, 104))	('rat', 'Species', '10116', (39, 42))	('rat', 'Species', '10116', (93, 96))	('erratic', 'CPA', (91, 98))	('knockdown', 'Var', (58, 67))	('rat', 'Species', '10116', (121, 124))
595608	32859065	Interestingly, the deletion of Runx2 in mice results in a complete lack of bone formation.	('deletion', 'Var', (19, 27))	('Runx2', 'Gene', (31, 36))	('bone formation', 'CPA', (75, 89))	('mice', 'Species', '10090', (40, 44))	('lack', 'NegReg', (67, 71))
595610	32859065	Deletion of Osterix in mice thus leads to major defects in bone formation.	('bone formation', 'CPA', (59, 73))	('Deletion', 'Var', (0, 8))	('Osterix', 'Gene', (12, 19))	('mice', 'Species', '10090', (23, 27))	('defects', 'NegReg', (48, 55))
595619	32859065	Deletion of connexin43 in null mice leads to the delayed intramembranous and endochondral ossification of the cranial vault in mice embryos.	('mice', 'Species', '10090', (127, 131))	('connexin43', 'Gene', (12, 22))	('mice', 'Species', '10090', (31, 35))	('Deletion', 'Var', (0, 8))
595630	32859065	Notably, it has been recently demonstrated that another connexin, connexin37, plays a role in the regulation of osteoclast differentiation via the modulation of Gj.	('modulation', 'Var', (147, 157))	('rat', 'Species', '10116', (37, 40))	('connexin', 'Gene', '100128922', (66, 74))	('connexin', 'Gene', (66, 74))	('connexin37', 'Gene', (66, 76))	('connexin', 'Gene', (56, 64))	('connexin', 'Gene', '100128922', (56, 64))	('osteoclast differentiation', 'CPA', (112, 138))	('connexin37', 'Gene', '2701', (66, 76))
595639	32859065	Whole-genome sequencing analyses have demonstrated that OS displays high rates of genetic alterations and contain many somatic mutations and copy number alterations.	('rat', 'Species', '10116', (94, 97))	('genetic alterations', 'MPA', (82, 101))	('copy number alterations', 'Var', (141, 164))	('rat', 'Species', '10116', (45, 48))	('rat', 'Species', '10116', (157, 160))	('OS', 'Phenotype', 'HP:0002669', (56, 58))	('rat', 'Species', '10116', (73, 76))
595644	32859065	It is well established that a high-level expression of connexin43 represses OS cell proliferation and therefore primary tumor growth.	('represses', 'NegReg', (66, 75))	('primary tumor', 'Disease', 'MESH:D001932', (112, 125))	('rat', 'Species', '10116', (91, 94))	('primary tumor', 'Disease', (112, 125))	('OS cell proliferation', 'CPA', (76, 97))	('expression', 'Var', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('OS', 'Phenotype', 'HP:0002669', (76, 78))	('connexin43', 'Protein', (55, 65))
595645	32859065	Indeed, the regulation of connexin43 expression via various mechanisms drives OS cell proliferation in human U2OS cell lines or in rat UMR106 cell lines, for example.	('regulation', 'Var', (12, 22))	('rat', 'Species', '10116', (131, 134))	('OS', 'Phenotype', 'HP:0002669', (111, 113))	('human', 'Species', '9606', (103, 108))	('OS', 'Phenotype', 'HP:0002669', (78, 80))	('connexin43', 'Protein', (26, 36))	('U2OS', 'CellLine', 'CVCL:0042', (109, 113))	('OS cell proliferation', 'CPA', (78, 99))	('drives', 'PosReg', (71, 77))	('rat', 'Species', '10116', (93, 96))
595649	32859065	Finally, they proved that enforced connexin43 expression elevates the levels of p27 proteins through post-transcriptional regulatory mechanisms in which connexin43-driven Gj is the main instigator via cAMP diffusion.	('expression', 'Var', (46, 56))	('p27', 'Gene', '5715', (80, 83))	('p27', 'Gene', (80, 83))	('elevates', 'PosReg', (57, 65))	('cAMP', 'Chemical', '-', (201, 205))
595651	32859065	These authors demonstrated that the knockdown of connexin43 activated the Wnt/beta-catenin signaling pathway, promoted proliferation and inhibited apoptosis of U2OS cell lines.	('OS', 'Phenotype', 'HP:0002669', (162, 164))	('connexin43', 'Gene', (49, 59))	('inhibited', 'NegReg', (137, 146))	('knockdown', 'Var', (36, 45))	('activated', 'PosReg', (60, 69))	('U2OS', 'CellLine', 'CVCL:0042', (160, 164))	('rat', 'Species', '10116', (21, 24))	('beta-catenin', 'Gene', '1499', (78, 90))	('beta-catenin', 'Gene', (78, 90))	('apoptosis', 'CPA', (147, 156))	('rat', 'Species', '10116', (126, 129))	('promoted', 'PosReg', (110, 118))	('proliferation', 'CPA', (119, 132))
595676	32859065	In contrast, during the later stages of prostate carcinoma development, particularly during the development of secondary bone tumors, namely bone metastases, connexin43 appears to favor tumor dissemination (Figure 3B).	('men', 'Species', '9606', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('bone metastases', 'Disease', 'MESH:D009362', (141, 156))	('tumor', 'Disease', (186, 191))	('prostate carcinoma', 'Disease', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('favor', 'PosReg', (180, 185))	('bone tumors', 'Disease', (121, 132))	('bone tumors', 'Phenotype', 'HP:0010622', (121, 132))	('bone metastases', 'Disease', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('men', 'Species', '9606', (103, 106))	('bone tumors', 'Disease', 'MESH:D001859', (121, 132))	('bone tumor', 'Phenotype', 'HP:0010622', (121, 131))	('prostate carcinoma', 'Disease', 'MESH:D011471', (40, 58))	('connexin43', 'Var', (158, 168))	('tumor', 'Disease', (126, 131))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (40, 58))	('tumor', 'Disease', 'MESH:D009369', (126, 131))
595696	32859065	In this context, it was recently discovered that the bone niche serves as a calcium reservoir for cancer cells through gap junction and thus drive the metastatic process during the early-stage bone colonization.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gap', 'Var', (119, 122))	('metastatic process', 'CPA', (151, 169))	('calcium', 'Chemical', 'MESH:D002118', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))
595699	32859065	Intuitively, targeting connexin43 to limit bone tumorigenesis appeared to be a more promising therapeutic option in primary bone tumors than in secondary bone tumors.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('bone tumors', 'Disease', (124, 135))	('bone tumors', 'Phenotype', 'HP:0010622', (124, 135))	('bone tumors', 'Disease', (154, 165))	('bone tumors', 'Phenotype', 'HP:0010622', (154, 165))	('bone tumors', 'Disease', 'MESH:D001859', (124, 135))	('bone tumor', 'Phenotype', 'HP:0010622', (124, 134))	('bone tumor', 'Disease', (43, 53))	('bone tumors', 'Disease', 'MESH:D001859', (154, 165))	('bone tumor', 'Phenotype', 'HP:0010622', (43, 53))	('bone tumor', 'Phenotype', 'HP:0010622', (154, 164))	('connexin43', 'Protein', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('bone tumor', 'Disease', 'MESH:D001859', (124, 134))	('bone tumor', 'Disease', 'MESH:D001859', (43, 53))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('targeting', 'Var', (13, 22))	('bone tumor', 'Disease', 'MESH:D001859', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('limit', 'NegReg', (37, 42))
595715	32859065	Interestingly, considering that connexin43 has also been reported to promote the bystander effect of chemotherapeutic drugs, targeting connexin43 could combined with treatment for chemotherapy.	('connexin43', 'Gene', (135, 145))	('promote', 'PosReg', (69, 76))	('bystander effect', 'CPA', (81, 97))	('men', 'Species', '9606', (171, 174))	('targeting', 'Var', (125, 134))
595724	26355893	We report an alternate PAX3-FOXO1 oncogenic fusion in a case of SNS, which confirms the crucial role of PAX3 in SNS oncogenesis and underscores the critical contribution of the cell of origin to the tumor phenotype induced by aberrant transcription factor oncogenic reprogramming.	('tumor', 'Disease', (199, 204))	('fusion', 'Var', (44, 50))	('SNS', 'Disease', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('PAX3-FOXO1', 'Gene', (23, 33))
595747	26355893	A definitive diagnosis of synovial sarcoma can be obtained by molecular identification of SS18 rearrangement.	('SS18', 'Gene', (90, 94))	('synovial sarcoma', 'Disease', (26, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (26, 42))	('SS18', 'Gene', '6760', (90, 94))	('synovial sarcoma', 'Disease', 'MESH:D013584', (26, 42))	('rearrangement', 'Var', (95, 108))
595750	26355893	Molecularly, recurrent chromosomal translocations that create neomorphic chimeric fusion genes are common events in cancer, and are thought to be tumor-specific initiating oncogenic events in a growing number of sarcoma and carcinoma types.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', (146, 151))	('chromosomal', 'Var', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('sarcoma and carcinoma', 'Disease', 'MESH:D012509', (212, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('neomorphic', 'MPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
595751	26355893	Gene fusions involving transcription factors, such as PAX3-FOXO1, can induce transcriptional deregulation both as a result of juxtaposition of modular functional elements and haploinsufficiency of the genes involved.	('haploinsufficiency', 'Disease', 'MESH:D058495', (175, 193))	('Gene fusions', 'Var', (0, 12))	('induce', 'Reg', (70, 76))	('transcriptional deregulation', 'MPA', (77, 105))	('haploinsufficiency', 'Disease', (175, 193))	('PAX3-FOXO1', 'Gene', (54, 64))
595752	26355893	The distinctive tumor phenotypes associated with various transcription factor fusions may reflect fundamental differences in the biological properties of the component and chimeric proteins, but the cell of origin and the genomic context in which fusion events occur are also critical.	('fusions', 'Var', (78, 85))	('tumor', 'Disease', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (16, 21))
595753	26355893	Thus far, PAX3-FOXO1 has been exclusively associated with alveolar rhabdomyosarcoma, hence serving as a diagnostic and prognostic biomarker.	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (58, 83))	('associated', 'Reg', (42, 52))	('PAX3-FOXO1', 'Var', (10, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (58, 83))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (67, 83))	('alveolar rhabdomyosarcoma', 'Disease', (58, 83))
595754	26355893	High PAX3-FOXO1 expression in murine myogenic precursor cells causes alveolar rhabdomyosarcoma, when activated as a sole aberration (in differentiating myoblasts) or in collaboration with additional genetic hits, such as cell cycle checkpoint loss.	('High', 'Var', (0, 4))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (69, 94))	('murine', 'Species', '10090', (30, 36))	('causes', 'Reg', (62, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (69, 94))	('PAX3-FOXO1', 'Gene', (5, 15))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (78, 94))	('alveolar rhabdomyosarcoma', 'Disease', (69, 94))
595755	26355893	The discovery of a PAX3-FOXO1 gene fusion in SNS indicates a significant tumorigenic overlap with PAX3-MAML3, at least in some cellular contexts.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('MAML3', 'Gene', '55534', (103, 108))	('tumor', 'Disease', (73, 78))	('MAML3', 'Gene', (103, 108))	('fusion', 'Var', (35, 41))	('PAX3-FOXO1', 'Gene', (19, 29))
595759	26355893	Transcriptional reprogramming induced by PAX3-FOXO1 in mouse myogenic precursor cells, and in human alveolar rhabdomyosarcoma, induces expression of early myogenic markers including myogenin and myoD1, which are typically absent or expressed at only low levels in SNS.	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (100, 125))	('myogenin', 'Gene', (182, 190))	('PAX3-FOXO1', 'Var', (41, 51))	('induces', 'Reg', (127, 134))	('myogenin', 'Gene', '4656', (182, 190))	('alveolar rhabdomyosarcoma', 'Disease', (100, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('mouse', 'Species', '10090', (55, 60))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (100, 125))	('human', 'Species', '9606', (94, 99))	('expression', 'MPA', (135, 145))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (109, 125))	('myoD1', 'Gene', '4654', (195, 200))	('myoD1', 'Gene', (195, 200))
595763	26355893	The occurrence of PAX3-FOXO1 in SNS confirms that multiple translocation partners can create oncogenic PAX3 forms, contributing to SNS tumorigenesis, and suggests that SNS and alveolar rhabdomyosarcoma are genetically similar lesions arising in distinct progenitor cell pools.	('SNS', 'Disease', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (185, 201))	('SNS and alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (168, 201))	('tumor', 'Disease', (135, 140))	('PAX3-FOXO1', 'Var', (18, 28))	('contributing', 'Reg', (115, 127))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (176, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
595828	24022186	Cytogenetically, more than 95% of SS is characterised by the t(X; 18) (p11.2; q11.2) chromosomal translocation, which always represents the fusion of SS18 with either SSX1 or SSX2, or rarely with SSX4.	('SS', 'Phenotype', 'HP:0012570', (150, 152))	('SSX2', 'Gene', '6757', (175, 179))	('SSX1', 'Gene', (167, 171))	('SSX4', 'Gene', '6759', (196, 200))	('SS', 'Phenotype', 'HP:0012570', (34, 36))	('SSX4', 'Gene', (196, 200))	('SS', 'Phenotype', 'HP:0012570', (196, 198))	('SS', 'Phenotype', 'HP:0012570', (175, 177))	('SSX2', 'Gene', (175, 179))	('SS18', 'Var', (150, 154))	('SSX1', 'Gene', '6756', (167, 171))	('SS', 'Phenotype', 'HP:0012570', (167, 169))
595832	24022186	first reported that patients with the SS18-SSX1 fusion gene had a significantly worse outcome than patients with SS18-SSX2 fusion gene, and others found the same result.	('SSX1', 'Gene', '6756', (43, 47))	('fusion gene', 'Var', (48, 59))	('SS', 'Phenotype', 'HP:0012570', (113, 115))	('SS', 'Phenotype', 'HP:0012570', (43, 45))	('SSX2', 'Gene', (118, 122))	('SSX1', 'Gene', (43, 47))	('SS', 'Phenotype', 'HP:0012570', (38, 40))	('patients', 'Species', '9606', (99, 107))	('worse', 'NegReg', (80, 85))	('patients', 'Species', '9606', (20, 28))	('SSX2', 'Gene', '6757', (118, 122))	('SS', 'Phenotype', 'HP:0012570', (118, 120))
595833	24022186	However, some findings indicated that the SS18-SSX fusion gene variants were not prognostically important in patients with SS.	('patients', 'Species', '9606', (109, 117))	('variants', 'Var', (63, 71))	('SS', 'Phenotype', 'HP:0012570', (47, 49))	('SS', 'Phenotype', 'HP:0012570', (42, 44))	('SSX', 'Gene', (47, 50))	('SS', 'Phenotype', 'HP:0012570', (123, 125))	('SSX', 'Gene', '6757', (47, 50))
595861	24022186	In our series, 47 (51.1%) and 41 (44.6%) patients were detected to have the SS18-SSX1 and SS18-SSX2 fusion genes, respectively (Figure 1).	('SSX1', 'Gene', '6756', (81, 85))	('SSX2', 'Gene', '6757', (95, 99))	('SS', 'Phenotype', 'HP:0012570', (95, 97))	('SS', 'Phenotype', 'HP:0012570', (81, 83))	('SSX1', 'Gene', (81, 85))	('fusion', 'Var', (100, 106))	('patients', 'Species', '9606', (41, 49))	('SSX2', 'Gene', (95, 99))	('SS', 'Phenotype', 'HP:0012570', (76, 78))	('SS', 'Phenotype', 'HP:0012570', (90, 92))
595879	24022186	For SS with SS18-SSX2 fusion transcripts, there were 28 tumours (68.3%) smaller than 5 cm.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('fusion transcripts', 'Var', (22, 40))	('SSX2', 'Gene', '6757', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('SS', 'Phenotype', 'HP:0012570', (17, 19))	('SSX2', 'Gene', (17, 21))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('SS', 'Phenotype', 'HP:0012570', (4, 6))	('SS', 'Phenotype', 'HP:0012570', (12, 14))
595905	24022186	reported that tumours with the SS18-SSX1 fusion transcript were always located in the extremities, whereas tumours with the SS18-SSX2 fusion transcript were equally distributed between extremities and the trunk.	('SSX2', 'Gene', '6757', (129, 133))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', (107, 114))	('SSX1', 'Gene', (36, 40))	('SS', 'Phenotype', 'HP:0012570', (129, 131))	('SSX2', 'Gene', (129, 133))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('fusion', 'Var', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('SS', 'Phenotype', 'HP:0012570', (31, 33))	('SS', 'Phenotype', 'HP:0012570', (124, 126))	('SSX1', 'Gene', '6756', (36, 40))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))	('SS', 'Phenotype', 'HP:0012570', (36, 38))
595951	20660389	Specifically, if 18F-FDG PET would be able to discriminate among sarcoma subtypes, this would offer clinicians a noninvasive diagnostic tool to confirm histopathologic findings on core biopsy or fine-needle aspiration.	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('aspiration', 'Phenotype', 'HP:0002835', (207, 217))	('18F-FDG', 'Chemical', 'MESH:D019788', (17, 24))	('18F-FDG PET', 'Var', (17, 28))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (65, 81))	('sarcoma subtypes', 'Disease', (65, 81))
595993	20660389	Several studies have shown that extremely low-, low-, and intermediate-risk sarcomas show significantly prolonged overall survival compared with high-risk or overtly malignant GISTs.	('sarcomas', 'Disease', 'MESH:D012509', (76, 84))	('GISTs', 'Phenotype', 'HP:0100723', (176, 181))	('sarcomas', 'Phenotype', 'HP:0100242', (76, 84))	('overall', 'MPA', (114, 121))	('low-', 'Var', (48, 52))	('prolonged', 'PosReg', (104, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('sarcomas', 'Disease', (76, 84))
596109	33672607	In selected cases, radiation therapy may be added to the management of patients with low- or high-grade superficial, >=5 cm and low-grade, deep, <5 cm STS after multidisciplinary discussion.	('superficial', 'Disease', (104, 115))	('patients', 'Species', '9606', (71, 79))	('STS', 'Phenotype', 'HP:0030448', (151, 154))	('low-grade', 'Var', (128, 137))
596133	33672607	In a randomized phase 3 trial, doxorubicin plus ifosfamide showed a significantly higher response rate and longer progression-free survival (PFS) compared to single-agent doxorubicin, but no significant difference in overall survival (OS).	('doxorubicin', 'Var', (31, 42))	('ifosfamide', 'Chemical', 'MESH:D007069', (48, 58))	('higher', 'PosReg', (82, 88))	('doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('response', 'CPA', (89, 97))	('progression-free survival', 'CPA', (114, 139))	('doxorubicin', 'Chemical', 'MESH:D004317', (171, 182))	('longer', 'PosReg', (107, 113))
596144	33672607	The trial demonstrated significantly longer PFS in the trabectedin arm compared to the dacarbazine arm, but no significant difference in OS.	('longer', 'PosReg', (37, 43))	('PFS', 'MPA', (44, 47))	('trabectedin', 'Chemical', 'MESH:D000077606', (55, 66))	('trabectedin', 'Var', (55, 66))	('dacarbazine', 'Chemical', 'MESH:D003606', (87, 98))
596157	33672607	Pazopanib was shown to significantly prolong PFS.	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('prolong', 'PosReg', (37, 44))	('Pazopanib', 'Var', (0, 9))	('PFS', 'Disease', (45, 48))
596202	33672607	Morcellation bears the risk to disseminate tumor cells into the pelvis and peritoneal cavity, with a poorer prognosis as a major consequence.	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('Morcellation', 'Var', (0, 12))
596226	33672607	A total of 5% were incidentally found to have germline TP53 mutations.	('mutations', 'Var', (60, 69))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))
596233	33672607	NGS of tumor specimens allows identification of specific gene alterations that can aid with tumor classification and suggest potential mutation-specific therapeutic targets or clinical trials.	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('aid', 'Reg', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('alterations', 'Var', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
596234	33672607	Recently, NGS of 21 LMS from various sites revealed 86 non-synonymous, coding region somatic variants within 151 gene targets (mean of 4.1 variants per case); the most frequently altered genes were TP53 (36%), ATM and ATRX (16%) as well as EGFR and RB1 (12%).	('ATM', 'Gene', '472', (210, 213))	('altered', 'Reg', (179, 186))	('LMS', 'Phenotype', 'HP:0100243', (20, 23))	('RB1', 'Gene', '5925', (249, 252))	('EGFR', 'Gene', (240, 244))	('ATRX', 'Gene', '546', (218, 222))	('variants', 'Var', (93, 101))	('TP53', 'Gene', '7157', (198, 202))	('RB1', 'Gene', (249, 252))	('ATM', 'Gene', (210, 213))	('TP53', 'Gene', (198, 202))	('ATRX', 'Gene', (218, 222))	('EGFR', 'Gene', '1956', (240, 244))
596252	33672607	Unfortunately, difficulties distinguishing these entities preoperatively may lead to unplanned excisions or morcellation of uterine LMS adversely influencing patient's outcome (see Chapter 3).	('LMS', 'Phenotype', 'HP:0100243', (132, 135))	('lead to', 'Reg', (77, 84))	('morcellation', 'Var', (108, 120))	('patient', 'Species', '9606', (158, 165))
596447	30573690	Furthermore, we noted that patients receiving freshly infused transgenic cells displayed superior in vivo persistence of the cells and responsiveness to DC vaccine boost compared to those who received cryopreserved cell products.	('superior', 'PosReg', (89, 97))	('patients', 'Species', '9606', (27, 35))	('transgenic', 'Var', (62, 72))
596464	30573690	Patients received their first dose of 1mg/kg ipilimumab (if on the INY protocol), intradermal administration of NY-ESO-1157-165 peptide-pulsed DC, and began low-dose IL-2 therapy (500,000 IU/m2 subcutaneously) the following morning (day +1) twice daily for up to 28 doses (patients ESO-1, ESO-2, ESO-3, ESO-4, INY-1, INY-2) or 14 doses (patients ESO-5, ESO-6, INY-3, and INY-4), as tolerated.	('ESO-6', 'Chemical', '-', (353, 358))	('INY-3', 'Chemical', '-', (360, 365))	('ESO-2', 'Gene', (289, 294))	('ESO', 'Chemical', '-', (353, 356))	('IL-2', 'Gene', '3558', (166, 170))	('ESO', 'Chemical', '-', (346, 349))	('NY-ESO-1', 'Gene', (112, 120))	('ESO', 'Chemical', '-', (296, 299))	('INY', 'Chemical', '-', (317, 320))	('ESO', 'Chemical', '-', (289, 292))	('INY', 'Chemical', '-', (310, 313))	('ESO', 'Chemical', '-', (282, 285))	('ESO', 'Chemical', '-', (115, 118))	('INY', 'Chemical', '-', (371, 374))	('Patients', 'Species', '9606', (0, 8))	('ESO-4', 'Var', (303, 308))	('NY-ESO-1', 'Gene', '246100', (112, 120))	('rat', 'Species', '10116', (102, 105))	('INY', 'Chemical', '-', (67, 70))	('patients', 'Species', '9606', (337, 345))	('ESO', 'Chemical', '-', (303, 306))	('ESO-1', 'Gene', '246100', (115, 120))	('ESO-1', 'Gene', '246100', (282, 287))	('ESO-1', 'Gene', (282, 287))	('patients', 'Species', '9606', (273, 281))	('rat', 'Species', '10116', (386, 389))	('ESO-5', 'Chemical', '-', (346, 351))	('ESO-1', 'Gene', (115, 120))	('IL-2', 'Gene', (166, 170))	('ESO-2', 'Gene', '30848', (289, 294))	('ESO-3', 'Gene', '8270', (296, 301))	('ipilimumab', 'Chemical', 'MESH:D000074324', (45, 55))	('INY', 'Chemical', '-', (360, 363))	('INY-4', 'Chemical', '-', (371, 376))	('ESO-3', 'Gene', (296, 301))
596543	30573690	While there were no mutational events in HLA genes and the tumor cells maintained expression of MHC I in close proximity to infiltrating T cells in both biopsies (without basal MHC I expression elsewhere in the tumor tissue), the tumor invasive margin in the post-ESO biopsy was also characterized by proximal increases in PD-1 and PD-L1 expression in the lymphocytes and tumor cells in the invasive margin, respectively.	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('MHC', 'Gene', '3107', (177, 180))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('MHC', 'Gene', '3107', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('PD-L1', 'Gene', (332, 337))	('PD-L1', 'Gene', '29126', (332, 337))	('ESO', 'Chemical', '-', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (230, 235))	('increases', 'PosReg', (310, 319))	('tumor', 'Disease', (372, 377))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('MHC', 'Gene', (177, 180))	('expression', 'MPA', (338, 348))	('PD-1', 'Gene', (323, 327))	('rat', 'Species', '10116', (130, 133))	('PD-1', 'Gene', '5133', (323, 327))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('post-ESO', 'Var', (259, 267))	('MHC', 'Gene', (96, 99))
596545	30573690	To comprehensively characterize the transgenic T cell phenotypic subpopulations over time, we utilized a mass cytometry staining panel with 33 different surface and intracellular markers, and generated phenotypically similar clusters of transgenic TCR T cells as described above, which we were then able to compare between the two cohorts at infusion and day +70 (Figure 5A-D).	('TCR', 'Gene', (248, 251))	('TCR', 'Gene', '6962', (248, 251))	('transgenic', 'Var', (237, 247))	('rat', 'Species', '10116', (196, 199))
596546	30573690	Infusion products of both cohorts contained significantly greater proportions of transgenic regulatory CD4 transgenic T cells (Treg), which were almost completely depleted by day +70.	('transgenic', 'Var', (81, 91))	('CD4', 'Gene', (103, 106))	('CD4', 'Gene', '920', (103, 106))
596548	30573690	Within the CD8 transgenic T cell phenotypes, infusion products contained the greatest proportions of central memory (CM; CCR7+/CD45RO+), effector memory (EM; CCR7-/CD45RO+), and effector memory RA (EMRA; CCR7-/CD45RO-/CD45RA+) phenotypes with high Ki67 expression (although ESO did not achieve statistical significance in all of these clusters).	('CD4', 'Gene', '920', (164, 167))	('ESO', 'Chemical', '-', (274, 277))	('CD8', 'Gene', (11, 14))	('CCR7', 'Gene', '1236', (121, 125))	('CD4', 'Gene', (164, 167))	('CCR7', 'Gene', (158, 162))	('CD4', 'Gene', '920', (210, 213))	('CCR7', 'Gene', (204, 208))	('CD4', 'Gene', '920', (218, 221))	('CD4', 'Gene', (210, 213))	('Ki67 expression', 'Var', (248, 263))	('CCR7', 'Gene', '1236', (158, 162))	('CD8', 'Gene', '925', (11, 14))	('CCR7', 'Gene', '1236', (204, 208))	('CD4', 'Gene', (218, 221))	('CD4', 'Gene', '920', (127, 130))	('memory RA', 'Disease', 'MESH:D001172', (187, 196))	('memory RA', 'Disease', (187, 196))	('CCR7', 'Gene', (121, 125))	('CD4', 'Gene', (127, 130))
596557	30573690	Transgenic ACT has emerged as a potent and widely applicable form of cancer immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('Transgenic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (69, 75))
596566	30573690	Furthermore, there is evidence that high-dose IL-2 can impair the generation of memory T cells and compromise overall T cell effectiveness.	('memory T', 'Disease', (80, 88))	('rat', 'Species', '10116', (70, 73))	('compromise', 'NegReg', (99, 109))	('T cell effectiveness', 'CPA', (118, 138))	('IL-2', 'Gene', '3558', (46, 50))	('impair', 'NegReg', (55, 61))	('IL-2', 'Gene', (46, 50))	('memory T', 'Disease', 'MESH:D008569', (80, 88))	('high-dose', 'Var', (36, 45))
596576	30573690	These results imply that, while the addition of ipilimumab was associated with significant increases in the longitudinal serum levels of Flt-3L, this did not appear to lead to increased amounts of DC subpopulations over time.	('ipilimumab', 'Chemical', 'MESH:D000074324', (48, 58))	('Flt-3L', 'Gene', (137, 143))	('serum levels', 'MPA', (121, 133))	('ipilimumab', 'Gene', (48, 58))	('addition', 'Var', (36, 44))	('Flt-3L', 'Gene', '2323', (137, 143))	('increases', 'PosReg', (91, 100))
596585	30573690	Indeed, this phenomenon has been recently reported in CAR-T cells, where lentiviral insertion was shown to disrupt the TET2 gene, and give rise to a long-lived, highly functional memory phenotype T cell clone.	('lentiviral insertion', 'Var', (73, 93))	('give rise to', 'Reg', (134, 146))	('TET2', 'Gene', '54790', (119, 123))	('CAR-T', 'CellLine', 'CVCL:4140', (54, 59))	('disrupt', 'NegReg', (107, 114))	('TET2', 'Gene', (119, 123))
596594	30573690	PD1 blockade has been shown in preclinical models to enhance the antitumor efficacy of transgenic ACT.	('PD1', 'Gene', (0, 3))	('transgenic ACT', 'CPA', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('blockade', 'Var', (4, 12))	('enhance', 'PosReg', (53, 60))	('PD1', 'Gene', '5133', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
596597	30573690	Preclinical models have demonstrated that CD34+ peripheral blood stem cells carrying a transgenic TCR can endogenously differentiate into fully functional T cells expressing the TCR.	('TCR', 'Gene', '6962', (98, 101))	('transgenic', 'Var', (87, 97))	('TCR', 'Gene', '6962', (178, 181))	('TCR', 'Gene', (178, 181))	('TCR', 'Gene', (98, 101))	('CD34', 'Gene', (42, 46))	('CD34', 'Gene', '947', (42, 46))	('rat', 'Species', '10116', (31, 34))
596599	30573690	We have recently opened two phase I clinical trials which utilize this approach against NY-ESO-1 in solid tumors (NCT03240861) and multiple myeloma (NCT03506802).	('NCT03240861', 'Var', (114, 125))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('NCT03506802', 'Var', (149, 160))	('multiple myeloma', 'Disease', 'MESH:D009101', (131, 147))	('solid tumors', 'Disease', (100, 112))	('NY-ESO-1', 'Gene', '246100', (88, 96))	('multiple myeloma', 'Phenotype', 'HP:0006775', (131, 147))	('NY-ESO-1', 'Gene', (88, 96))	('multiple myeloma', 'Disease', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('solid tumors', 'Disease', 'MESH:D009369', (100, 112))
596629	21102637	The culmination of this first century of tumour virology would be celebrated with Nobel Prizes awarded in 2008 for the discovery by Harald zur Hausen of high-risk HPV strains that cause cervical cancer and the discovery of HIV, an agent that does not initiate cancer but indirectly 'sets the stage' for malignancy through immuno suppression, by Francois Barre-Sinoussi and Luc Montagnier.	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('HPV', 'Species', '10566', (163, 166))	('strains', 'Var', (167, 174))	('malignancy', 'Disease', (303, 313))	('Harald zur Hausen', 'Disease', (132, 149))	('HPV', 'Gene', (163, 166))	('cause', 'Reg', (180, 185))	('Harald zur Hausen', 'Disease', 'None', (132, 149))	("'sets the stage'", 'PosReg', (282, 298))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (195, 201))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', (260, 266))	('tumour', 'Disease', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cervical cancer', 'Disease', (186, 201))	('cervical cancer', 'Disease', 'MESH:D002583', (186, 201))	('malignancy', 'Disease', 'MESH:D009369', (303, 313))
596671	21102637	This can be seen with signalling lymphocytic activation molecule-associated protein (SAP) mutations in males that cause immunodeficiency and X-linked lymphoproliferative syndrome after EBV infection.	('SAP', 'Gene', (85, 88))	('immunodeficiency', 'Disease', (120, 136))	('X-linked lymphoproliferative syndrome', 'Disease', 'MESH:D008232', (141, 178))	('mutations', 'Var', (90, 99))	('X-linked lymphoproliferative syndrome', 'Disease', (141, 178))	('EBV infection', 'Disease', (185, 198))	('EBV infection', 'Disease', 'MESH:D020031', (185, 198))	('lymphoproliferative syndrome', 'Phenotype', 'HP:0005523', (150, 178))	('immunodeficiency', 'Phenotype', 'HP:0002721', (120, 136))	('cause', 'Reg', (114, 119))	('immunodeficiency', 'Disease', 'MESH:D007153', (120, 136))
596676	21102637	Infectious cancer agents (including, viruses, bacteria and parasites) have been divided into two broad categories: direct carcinogens, which express viral oncogenes that directly contribute to cancer cell transformation, and indirect carcinogens that presumably cause cancer through chronic infection and inflammation, which eventually leads to carcinogenic mutations in host cells.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('leads to', 'Reg', (336, 344))	('cancer', 'Disease', (193, 199))	('contribute', 'Reg', (179, 189))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cause', 'Reg', (262, 267))	('Infectious cancer', 'Disease', 'MESH:D009369', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('carcinogenic', 'Disease', (345, 357))	('mutations', 'Var', (358, 367))	('Infectious cancer', 'Disease', (0, 17))	('inflammation', 'Disease', 'MESH:D007249', (305, 317))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('chronic infection', 'Disease', 'MESH:D006505', (283, 300))	('carcinogenic', 'Disease', 'MESH:D063646', (345, 357))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('inflammation', 'Disease', (305, 317))	('cancer', 'Disease', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('chronic infection', 'Phenotype', 'HP:0031035', (283, 300))	('cancer', 'Disease', (11, 17))	('chronic infection', 'Disease', (283, 300))
596683	21102637	Simple retroviruses can become carcinogenic by recombination with cell-derived oncogenes (SRC in the case of Rous sarcoma virus and probably ERBB2 in the case of the Ellerman and Bang virus), which disrupt the viral genome, usually rendering it non-infectious or by insertional mutagenesis.	('non-infectious', 'MPA', (245, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('carcinogenic', 'Disease', 'MESH:D063646', (31, 43))	('rendering', 'Reg', (232, 241))	('Rous sarcoma virus', 'Species', '11886', (109, 127))	('carcinogenic', 'Disease', (31, 43))	('SRC', 'Gene', '1491925', (90, 93))	('insertional mutagenesis', 'Var', (266, 289))	('SRC', 'Gene', (90, 93))
596717	21102637	Deep sequencing of four human mesothelioma tumour cDNAs failed to identify SV40 viral transcripts, providing evidence against a long-standing hypothesis that SV40, a rhesus polyomavirus, is directly involved in the development of mesothelioma.	('rhesus polyomavirus', 'Species', '1891767', (166, 185))	('mesothelioma', 'Disease', (230, 242))	('mesothelioma', 'Disease', (30, 42))	('SV40', 'Var', (158, 162))	('human', 'Species', '9606', (24, 29))	('mesothelioma tumour', 'Disease', 'MESH:D008654', (30, 49))	('mesothelioma tumour', 'Phenotype', 'HP:0100001', (30, 49))	('involved', 'Reg', (199, 207))	('mesothelioma', 'Disease', 'MESH:D008654', (230, 242))	('mesothelioma', 'Disease', 'MESH:D008654', (30, 42))	('long-standing', 'Phenotype', 'HP:0003698', (128, 141))	('mesothelioma tumour', 'Disease', (30, 49))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))
596725	21102637	SV40, for example, transforms human cells efficiently only when mutations are introduced into its replication origin to prevent viral replication.	('human', 'Species', '9606', (30, 35))	('SV40', 'Gene', (0, 4))	('mutations', 'Var', (64, 73))
596736	21102637	Among the small DNA tumour viruses, fragmentation and integration of viral DNA into the nascent tumour cell eliminates their ability to replicate as virions, a state that we have termed 'pseudo-latency'.	('tumour viruses', 'Disease', (20, 34))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', (20, 26))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour viruses', 'Disease', 'MESH:D009369', (20, 34))	('replicate as virions', 'MPA', (136, 156))	('integration', 'Var', (54, 65))	('eliminates', 'NegReg', (108, 118))	('ability', 'MPA', (125, 132))	('tumour', 'Disease', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
596738	21102637	Although herpesviruses do not generally integrate into the host genome, recombination patterns for their terminal repeat sequences can also be used as markers for tumour cell clonality.	('herpesvirus', 'Species', '39059', (9, 20))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('recombination patterns', 'Var', (72, 94))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Disease', (163, 169))
596741	21102637	Randomized clinical trial data show, for example, that targeting the KSHV thymidine kinase and phosphotransferase proteins can prevent >90% of new Kaposi's sarcomas from forming but this targeting has no effect on established tumours.	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('prevent', 'NegReg', (127, 134))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	("Kaposi's sarcomas", 'Disease', (147, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (156, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('tumours', 'Disease', (226, 233))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (147, 163))	("Kaposi's sarcomas", 'Disease', 'MESH:D012514', (147, 164))	('targeting', 'Var', (55, 64))	("Kaposi's sarcomas", 'Phenotype', 'HP:0100726', (147, 164))
596749	21102637	Instead, most human tumour virus transmissions are asymptomatic or mildly symptomatic but do not lead to neoplasia.	('transmissions', 'Var', (33, 46))	('human', 'Species', '9606', (14, 19))	('human', 'Protein', (14, 19))	('neoplasia', 'Phenotype', 'HP:0002664', (105, 114))	('tumour virus', 'Disease', 'MESH:D009369', (20, 32))	('neoplasia', 'Disease', (105, 114))	('tumour virus', 'Disease', (20, 32))	('neoplasia', 'Disease', 'MESH:D009369', (105, 114))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
596755	21102637	Disruption of cell cycle regulation, however, also activates cell death signalling pathways, such as p53, and so apoptotic signalling should also be inhibited to allow the efficient manufacture and export of viruses before cell death.	('activates', 'PosReg', (51, 60))	('cell', 'MPA', (14, 18))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('cell death signalling pathways', 'Pathway', (61, 91))	('Disruption', 'Var', (0, 10))
596759	21102637	Rare mutations, however, that disrupt this lifecycle (such as an HPV integration event that results in the loss of early viral gene regulation) can set the stage for this molecular parasitism to turn into cancer cell transformation.	('early', 'Protein', (115, 120))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('HPV', 'Species', '10566', (65, 68))	('loss', 'NegReg', (107, 111))	('cancer', 'Disease', (205, 211))	('mutations', 'Var', (5, 14))	('parasitism', 'Disease', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('parasitism', 'Disease', 'MESH:D010272', (181, 191))	('turn', 'Reg', (195, 199))
596785	21102637	The relationship between tumour suppression and cellular antiviral activity was described by Takaoka and colleagues who showed that knock out of Trp53 (encoding p53) causes immune deficiency to virus infection, and that virus-induced inflammatory cytokines prime cellular pro-apoptotic signalling pathways.	('immune deficiency to virus infection', 'Disease', (173, 209))	('knock out', 'Var', (132, 141))	('immune deficiency to virus infection', 'Disease', 'MESH:D007153', (173, 209))	('immune deficiency', 'Phenotype', 'HP:0002721', (173, 190))	('Trp53', 'Gene', '7157', (145, 150))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('Trp53', 'Gene', (145, 150))	('cellular pro-apoptotic signalling pathways', 'Pathway', (263, 305))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('p53', 'Gene', '7157', (161, 164))	('p53', 'Gene', '7157', (147, 150))	('p53', 'Gene', (161, 164))	('tumour', 'Disease', (25, 31))	('causes', 'Reg', (166, 172))	('p53', 'Gene', (147, 150))
596798	21102637	Given these features, the strongest evidence to support MCV causing MCC comes from its random clonal integration into Merkel cell tumours and knockdown studies showing that T antigen expression is required for the survival of virus-positive Merkel cell lines.	('MCC', 'Disease', (68, 71))	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('MCV', 'Var', (56, 59))	('Merkel cell tumours', 'Disease', (118, 137))	('MCV', 'Species', '493803', (56, 59))	('Merkel cell tumours', 'Disease', 'MESH:D015266', (118, 137))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
596810	21102637	All MCV genomes that have been obtained from tumours so far, however, have inactivating secondary mutations in the T antigen gene that eliminate its DNA replication capacity.	('eliminate', 'NegReg', (135, 144))	('MCV', 'Species', '493803', (4, 7))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('T antigen', 'Gene', (115, 124))	('mutations', 'Var', (98, 107))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('inactivating', 'Var', (75, 87))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('tumours', 'Disease', (45, 52))	('DNA replication capacity', 'MPA', (149, 173))
596848	30533997	Adult patients (>=18 years old) with PBS diagnosed between 2004 and 2013 were identified using topographical codes (C40.0-C40.3, C40.8-C41.4, C41.8, C41.9) designated by International Classification of Disease for Oncology, Third Edition (ICD-O-3).	('Oncology', 'Phenotype', 'HP:0002664', (214, 222))	('C40.0-C40.3', 'Var', (116, 127))	('C40.8-C41.4', 'Var', (129, 140))	('C41.9', 'Var', (149, 154))	('C41.9', 'CellLine', 'CVCL:2253', (149, 154))	('C41.8', 'Var', (142, 147))
596877	26078988	Small-molecule inhibitors of these epigenetic regulators may provide a new targeted therapy approach to soft tissue sarcomas in the future.	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (104, 124))	('soft tissue sarcomas', 'Disease', (104, 124))	('Small-molecule', 'Var', (0, 14))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (104, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (104, 123))	('inhibitors', 'Var', (15, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
596892	26078988	Therefore, the use of imatinib, which targets active c-KIT, has dramatically improved clinical outcomes of adult GIST patients bearing mutations in this gene, with minimal side effects.	('c-KIT', 'Gene', '3815', (53, 58))	('GIST', 'Phenotype', 'HP:0100723', (113, 117))	('mutations', 'Var', (135, 144))	('GIST', 'Disease', 'MESH:D046152', (113, 117))	('c-KIT', 'Gene', (53, 58))	('imatinib', 'Chemical', 'MESH:D000068877', (22, 30))	('clinical', 'MPA', (86, 94))	('GIST', 'Disease', (113, 117))	('patients', 'Species', '9606', (118, 126))	('improved', 'PosReg', (77, 85))
596902	26078988	Recent reports have shown that mutations in retinoblastoma protein (Rb1) and isocitrate dehydrogenases 1 and 2 (IDH1/2) are involved in sarcoma initiation.	('Rb1', 'Gene', '5925', (68, 71))	('mutations', 'Var', (31, 40))	('retinoblastoma', 'Phenotype', 'HP:0009919', (44, 58))	('IDH1/2', 'Gene', (112, 118))	('sarcoma initiation', 'Disease', (136, 154))	('sarcoma initiation', 'Disease', 'MESH:D012509', (136, 154))	('involved', 'Reg', (124, 132))	('Rb1', 'Gene', (68, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('retinoblastoma', 'Disease', 'MESH:D012175', (44, 58))	('retinoblastoma', 'Disease', (44, 58))	('IDH1/2', 'Gene', '3417;3418', (112, 118))
596906	26078988	Among the novel and promising therapeutic targets for sarcoma are epigenetic regulators, which have been discovered recently as a new class of drug targets for human malignancies.	('sarcoma', 'Disease', 'MESH:D012509', (54, 61))	('sarcoma', 'Disease', (54, 61))	('malignancies', 'Disease', 'MESH:D009369', (166, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('epigenetic regulators', 'Var', (66, 87))	('malignancies', 'Disease', (166, 178))	('human', 'Species', '9606', (160, 165))
596907	26078988	Experimental evidence has revealed that aberrant DNA methylation of the promoter region of a gene is associated with abnormal gene expression, leading to various diseases and developmental defects.	('developmental defects', 'Disease', 'MESH:D003147', (175, 196))	('abnormal gene expression', 'MPA', (117, 141))	('diseases', 'Disease', (162, 170))	('aberrant DNA methylation', 'Var', (40, 64))	('associated', 'Reg', (101, 111))	('leading to', 'Reg', (143, 153))	('developmental defects', 'Disease', (175, 196))
596908	26078988	Aberrant DNA methylation patterns on genomic DNA have been shown to cause a variety of human cancers and are shown in two distinct forms: hypermethylation and hypomethylation compared to non-tumor tissue.	('cancers', 'Disease', (93, 100))	('hypermethylation', 'Var', (138, 154))	('Aberrant', 'Var', (0, 8))	('DNA', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('hypomethylation', 'Var', (159, 174))	('cause', 'Reg', (68, 73))	('human', 'Species', '9606', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('methylation patterns', 'Var', (13, 33))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
596943	26078988	Taken together, epigenetic regulation mechanisms, specifically DNA methylation and histone modification, have been implicated as having important roles in sarcoma pathology.	('histone', 'MPA', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('sarcoma pathology', 'Disease', 'MESH:D012509', (155, 172))	('sarcoma pathology', 'Disease', (155, 172))	('DNA methylation', 'Var', (63, 78))
596950	25915760	Consequently, we found that the ALDH1high cells comprised 3.9% and 8.2% of the total cell population, respectively, and showed a higher capacity for self-renewal and tumor formation than the ALDH1low cells.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('higher', 'PosReg', (129, 135))	('tumor', 'Disease', (166, 171))	('ALDH1high', 'Var', (32, 41))	('self-renewal', 'CPA', (149, 161))
596983	25915760	In the RD cells, the ratio of the ALDH1high cells stained with BAAA was 4.1%, while that of those stained with BAAA and DEAB as a negative control was 0.2%.	('ALDH1high', 'Gene', (34, 43))	('DEAB', 'Chemical', '-', (120, 124))	('BAAA', 'Var', (63, 67))	('BAAA', 'Chemical', '-', (63, 67))	('BAAA', 'Chemical', '-', (111, 115))
596985	25915760	The viability of the ALDH1high cells after culturing with vincristine, cyclophosphamide and etoposide was significantly higher than that of the ALDH1low cells treated with these chemotherapeutic agents, suggesting that the ALDH1high cells possessed a higher capacity for chemoresistance than the ALDH1low cells (Fig 3).	('ALDH1high', 'Var', (223, 232))	('vincristine', 'Chemical', 'MESH:D014750', (58, 69))	('higher', 'PosReg', (120, 126))	('etoposide', 'Chemical', 'MESH:D005047', (92, 101))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (71, 87))	('chemoresistance', 'CPA', (271, 286))
596990	25915760	Consequently, tumor formation was observed in two of the seven mice injected with 1x103 ALDH1high cells and five of the six mice injected with 1x104 ALDH1high cells, while no tumors were found in the mice injected with ALDH1low cells at either cell density (p<0.05, Table 2 and Fig 5A).	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('mice', 'Species', '10090', (124, 128))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mice', 'Species', '10090', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('1x103 ALDH1high cells', 'Var', (82, 103))
596991	25915760	These results show that the ALDH1high cells have a significantly higher tumor-initiating ability than the ALDH1high cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ALDH1high', 'Var', (28, 37))	('tumor', 'Disease', (72, 77))	('higher', 'PosReg', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
596992	25915760	The ALDH1high cells demonstrated a higher tumor-initiating ability than the ALDH1high cells.	('ALDH1high', 'Var', (4, 13))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('higher', 'PosReg', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
596998	25915760	Quantitative real-time PCR showed an increased expression of Sox2 in the ALDH1high cells relative to the ALDH1low cells, whereas no significant increases were observed in the expression of c-Myc (Fig 6B).	('c-Myc', 'Gene', (189, 194))	('ALDH1high', 'Var', (73, 82))	('Sox2', 'Gene', '6657', (61, 65))	('increased', 'PosReg', (37, 46))	('c-Myc', 'Gene', '4609', (189, 194))	('Sox2', 'Gene', (61, 65))	('expression', 'MPA', (47, 57))
597013	25915760	In the current study, ALDH1high cells exhibited colony formation, as well as an increased gene expression of ABC transporters (ABCB1, ABCG2 and ABCA2) and stemness markers (Sox2).	('colony formation', 'CPA', (48, 64))	('increased', 'PosReg', (80, 89))	('Sox2', 'Gene', '6657', (173, 177))	('ABCB1', 'Gene', (127, 132))	('ABC transporter', 'Gene', (109, 124))	('ABCB1', 'Gene', '5243', (127, 132))	('gene expression', 'MPA', (90, 105))	('stemness', 'Disease', (155, 163))	('ABC transporter', 'Gene', '9429', (109, 124))	('Sox2', 'Gene', (173, 177))	('stemness', 'Disease', 'MESH:D020295', (155, 163))	('ABCG2', 'Gene', (134, 139))	('ALDH1high', 'Var', (22, 31))	('ABCA2', 'Gene', '20', (144, 149))	('ABCG2', 'Gene', '9429', (134, 139))	('ABCA2', 'Gene', (144, 149))
597080	25628857	Three patients received post-operative anthracyclines which they tolerated without clinical cardiotoxicity.	('anthracyclines', 'Chemical', 'MESH:D018943', (39, 53))	('patients', 'Species', '9606', (6, 14))	('cardiotoxicity', 'Disease', 'MESH:D066126', (92, 106))	('anthracyclines', 'Var', (39, 53))	('cardiotoxicity', 'Disease', (92, 106))
597114	25628857	Even though PEA did not result in a clear survival benefit, it did provide a significant alleviation of symptoms (from NYHA class III/IV to I/II).	('PEA', 'Chemical', '-', (12, 15))	('PEA', 'Var', (12, 15))	('symptoms', 'MPA', (104, 112))	('alleviation', 'NegReg', (89, 100))
597135	25628857	A frequent observation in the molecular analysis of intimal sarcoma is gains and amplifications in the chromosomal region of 12q13-14 and the overexpression of Mdm2, a negative regulator of p53.	('Mdm2', 'Gene', (160, 164))	('overexpression', 'PosReg', (142, 156))	('amplifications', 'Var', (81, 95))	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('gains', 'PosReg', (71, 76))	('p53', 'Gene', (190, 193))	('Mdm2', 'Gene', '4193', (160, 164))	('p53', 'Gene', '7157', (190, 193))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))
597141	24887057	Expression of heparanase in soft tissue sarcomas of adults Heparanase is an endo-beta-D-glucuronidase that cleaves heparan sulfate chains of proteoglycans, resulting in the disassembly of the extracellular matrix.	('beta-D-glucuronidase', 'Gene', (81, 101))	('heparan sulfate chains', 'Protein', (115, 137))	('disassembly of the extracellular matrix', 'MPA', (173, 212))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (28, 48))	('beta-D-glucuronidase', 'Gene', '2990', (81, 101))	('sarcomas', 'Disease', (40, 48))	('Heparanase', 'Gene', '10855', (59, 69))	('heparanase', 'Gene', '10855', (14, 24))	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('cleaves', 'Var', (107, 114))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Heparanase', 'Gene', (59, 69))	('heparan sulfate', 'Chemical', 'MESH:D006497', (115, 130))	('heparanase', 'Gene', (14, 24))
597142	24887057	Heparanase has a central role in the development of various tumors, and its expression has been associated with increased tumor growth, angiogenesis and metastasis, but there is insufficient information about the function of heparanase in sarcomas.	('sarcomas', 'Disease', (239, 247))	('heparanase', 'Gene', (225, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('heparanase', 'Gene', '10855', (225, 235))	('tumor', 'Disease', (60, 65))	('expression', 'Var', (76, 86))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('angiogenesis', 'CPA', (136, 148))	('Heparanase', 'Gene', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increased', 'PosReg', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (60, 66))	('Heparanase', 'Gene', '10855', (0, 10))	('metastasis', 'CPA', (153, 163))	('sarcomas', 'Disease', 'MESH:D012509', (239, 247))	('sarcomas', 'Phenotype', 'HP:0100242', (239, 247))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
597463	30572031	Short answer: Focal positivity for TTF1 is considered a positive reaction indicating pulmonary adenocarcinoma in the proper clinical context, whereas for p40 the cut-off rate should be positivity in more than 50% of tumor nuclei.	('tumor', 'Disease', (216, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (85, 109))	('p40', 'Gene', '8626', (154, 157))	('Focal positivity', 'Var', (14, 30))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 109))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('TTF1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('p40', 'Gene', (154, 157))	('pulmonary adenocarcinoma', 'Disease', (85, 109))
597466	30572031	Regarding TTF1 immunoreactivity, focal positivity is considered a positive reaction (Figure 2), indicative of adenocarcinoma in the proper clinical context.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('focal positivity', 'Var', (33, 49))	('TTF1', 'Gene', (10, 14))	('adenocarcinoma', 'Disease', (110, 124))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))
597469	30572031	The cut-off value for p40 should be positivity in more than 50% of tumor nuclei.	('p40', 'Gene', '8626', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('p40', 'Gene', (22, 25))	('tumor', 'Disease', (67, 72))	('positivity', 'Var', (36, 46))
597478	30572031	Another challenging situation is the recurrence of EGFR mutated adenocarcinomas following targeted therapy that results in a pure squamous cell carcinoma that may be p40 positive and TTF1 negative while retaining the original EGFR mutation, sometime with an additional T790M mutation.	('negative', 'NegReg', (188, 196))	('EGFR', 'Gene', (51, 55))	('mutated', 'Var', (56, 63))	('T790M', 'Mutation', 'rs121434569', (269, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('squamous cell carcinoma', 'Disease', (130, 153))	('T790M', 'Var', (269, 274))	('results in', 'Reg', (112, 122))	('p40', 'Gene', (166, 169))	('EGFR', 'Gene', '1956', (226, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('EGFR', 'Gene', '1956', (51, 55))	('p40', 'Gene', '8626', (166, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('adenocarcinomas', 'Disease', 'MESH:D000230', (64, 79))	('adenocarcinomas', 'Disease', (64, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (130, 153))	('EGFR', 'Gene', (226, 230))
597480	30572031	A number of different TTF1 clones are commercially available including rabbit and goat polyclonal antibodies, mouse monoclonal antibodies including 8G7G3/1, SPT24, BGX-397A, SMP150 and 5S143 clones, and rabbit monoclonal antibodies including SP141, EP15844, C12-I and G21-G clones.	('rabbit', 'Species', '9986', (71, 77))	('rabbit', 'Species', '9986', (203, 209))	('EP15844', 'Var', (249, 256))	('TTF1', 'Gene', (22, 26))
597483	30572031	Focusing on TTF1 and the distinction between lung adenocarcinoma and squamous cell carcinoma, a review of the current literature revealed that the 8G7G3/1 clone was less sensitive for the detection of lung adenocarcinoma in comparison to the SPT24 clone (Table 3).	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (201, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (201, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('8G7G3/1', 'Var', (147, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('squamous cell carcinoma', 'Disease', (69, 92))	('lung adenocarcinoma', 'Disease', (201, 220))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('less', 'NegReg', (165, 169))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (45, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (45, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lung adenocarcinoma', 'Disease', (45, 64))
597484	30572031	However, when referring to TTF1 staining in lung squamous cell carcinoma, the specificity for adenocarcinoma is higher in 8G7G3/1 than SPT24 (Figure 3).	('specificity', 'MPA', (78, 89))	('higher', 'PosReg', (112, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung squamous cell carcinoma', 'Disease', (44, 72))	('8G7G3/1', 'Var', (122, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (44, 72))	('adenocarcinoma', 'Disease', (94, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (94, 108))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 72))
597485	30572031	It is noted that a certain percentage of squamous cell carcinoma are labelled with TTF1, particularly when applying a signal amplification system; the frequency of positivity in squamous cell carcinoma is higher with SPT24.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (178, 201))	('squamous cell carcinoma', 'Disease', (41, 64))	('squamous cell carcinoma', 'Disease', (178, 201))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('SPT24', 'Var', (217, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
597506	30572031	For these reasons, molecular testing is still recommended in the 2015 WHO classification in case of a CK5/6 (-), CK7 (+), TTF1 (-) p40 (-) and mucicarmine (-) NSCC.	('p40', 'Gene', '8626', (131, 134))	('TTF1', 'Gene', (122, 126))	('NSCC', 'Disease', 'MESH:D002289', (159, 163))	('mucicarmine', 'Var', (143, 154))	('NSCC', 'Phenotype', 'HP:0030358', (159, 163))	('mucicarmine', 'Chemical', 'MESH:C029618', (143, 154))	('CK7', 'Gene', (113, 116))	('CK5/6', 'Gene', '3852', (102, 107))	('NSCC', 'Disease', (159, 163))	('p40', 'Gene', (131, 134))	('CK5/6', 'Gene', (102, 107))	('CK7', 'Gene', '3855', (113, 116))
597509	30572031	TTF1 negativity correlates with invasive mucinous adenocarcinoma and solid adenocarcinoma with mucin (Figure 5), with only 10% to 15% of mucinous adenocarcinoma being TTF1 positive.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('mucin', 'Gene', (95, 100))	('TTF1', 'Gene', (0, 4))	('mucinous adenocarcinoma', 'Disease', (137, 160))	('mucin', 'Gene', '100508689', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (137, 160))	('invasive mucinous adenocarcinoma and solid adenocarcinoma', 'Disease', 'MESH:D002288', (32, 89))	('mucin', 'Gene', (137, 142))	('negativity', 'Var', (5, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('mucinous adenocarcinoma', 'Disease', (41, 64))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (41, 64))	('mucin', 'Gene', (41, 46))	('mucin', 'Gene', '100508689', (95, 100))	('mucin', 'Gene', '100508689', (137, 142))
597564	30572031	Recently, an excellent performance of GATA3 has been reported in this distinction, and 100% sensitivity for sarcomatoid/desmoplastic malignant mesothelioma in particular suggested that lack of GATA3 expression could be used to exclude the diagnosis of sarcomatoid mesothelioma.	('GATA3', 'Gene', '2625', (38, 43))	('sarcomatoid/desmoplastic malignant mesothelioma', 'Disease', (108, 155))	('GATA3', 'Gene', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (133, 155))	('sarcomatoid mesothelioma', 'Disease', 'MESH:D008654', (252, 276))	('lack', 'Var', (185, 189))	('GATA3', 'Gene', '2625', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('sarcomatoid/desmoplastic malignant mesothelioma', 'Disease', 'MESH:C562839', (108, 155))	('GATA3', 'Gene', (38, 43))	('sarcomatoid mesothelioma', 'Disease', (252, 276))
597570	30572031	Molecular testing may support the diagnosis of sarcomatoid carcinoma by identifying alterations typical of non-small cell carcinoma, such as EGFR, KRAS or MET exon 14 splice site mutations, of which the latter are associated with sarcomatoid histology.	('sarcomatoid', 'Disease', (230, 241))	('sarcomatoid carcinoma', 'Disease', (47, 68))	('MET exon 14 splice site mutations', 'Var', (155, 188))	('non-small cell carcinoma', 'Disease', 'MESH:D002289', (107, 131))	('sarcomatoid', 'Disease', (47, 58))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (111, 131))	('associated', 'Reg', (214, 224))	('KRAS', 'Gene', (147, 151))	('sarcomatoid carcinoma', 'Disease', 'MESH:D002292', (47, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('EGFR', 'Gene', '1956', (141, 145))	('sarcomatoid', 'Disease', 'MESH:D002292', (230, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (47, 68))	('sarcomatoid', 'Disease', 'MESH:D002292', (47, 58))	('non-small cell carcinoma', 'Phenotype', 'HP:0030358', (107, 131))	('non-small cell carcinoma', 'Disease', (107, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (230, 251))	('EGFR', 'Gene', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('KRAS', 'Gene', '3845', (147, 151))
597619	30572031	Further, nonspecific labeling with polyclonal Napsin-A in mucinous adenocarcinomas appears to have peculiar supranuclear localization opposed to the pan-cytoplasmic granular staining present with monoclonal Napsin-A, possibly due to cross-reaction with pan-mucin antigen by the polyclonal antibody (Figure 14).	('polyclonal', 'Var', (35, 45))	('mucin', 'Gene', '100508689', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('mucin', 'Gene', '100508689', (257, 262))	('supranuclear', 'MPA', (108, 120))	('mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (58, 82))	('mucin', 'Gene', (58, 63))	('Napsin-A', 'Gene', (207, 215))	('mucin', 'Gene', (257, 262))	('Napsin-A', 'Gene', '9476', (207, 215))	('Napsin-A', 'Gene', '9476', (46, 54))	('Napsin-A', 'Gene', (46, 54))	('mucinous adenocarcinomas', 'Disease', (58, 82))
597669	30572031	As aberrant TTF1 expression in schwannoma was recently reported, we do not still recognize all of them.	('aberrant', 'Var', (3, 11))	('schwannoma', 'Disease', (31, 41))	('schwannoma', 'Disease', 'MESH:D009442', (31, 41))	('TTF1', 'Gene', (12, 16))	('schwannoma', 'Phenotype', 'HP:0100008', (31, 41))
597703	30775238	Here we review the application of immune checkpoint therapies, including anti-PD-1/PD-L1 and anti-CTLA-4, for the treatment of common bone sarcomas.	('bone sarcomas', 'Disease', 'MESH:D001847', (134, 147))	('anti-PD-1/PD-L1', 'Var', (73, 88))	('bone sarcoma', 'Phenotype', 'HP:0002669', (134, 146))	('bone sarcomas', 'Disease', (134, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (139, 147))	('bone sarcomas', 'Phenotype', 'HP:0002669', (134, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('anti-CTLA-4', 'Var', (93, 104))
597718	30775238	While PD-L1 expression in osteosarcoma cell lines broadly ranges from low to high, the drug-resistant variants trend towards higher expression compared to their parental cell lines.	('variants', 'Var', (102, 110))	('osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('expression', 'MPA', (132, 142))	('PD-L1', 'Gene', (6, 11))	('osteosarcoma cell', 'Disease', 'MESH:D012516', (26, 43))	('higher', 'PosReg', (125, 131))	('expression', 'MPA', (12, 22))	('osteosarcoma cell', 'Disease', (26, 43))
597726	30775238	Similar results were seen in a study investigating the effects of a triple antibody therapy consisting of anti-PD-1, anti-PD-L1, and anti-OX40 (Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), CD134) in mice transplanted with osteosarcoma.	('Tumor', 'Phenotype', 'HP:0002664', (144, 149))	('anti-PD-1', 'Var', (106, 115))	('TNFRSF4', 'Gene', (198, 205))	('osteosarcoma', 'Phenotype', 'HP:0002669', (241, 253))	('osteosarcoma', 'Disease', (241, 253))	('CD134', 'Gene', '22163', (208, 213))	('osteosarcoma', 'Disease', 'MESH:D012516', (241, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (246, 253))	('mice', 'Species', '10090', (218, 222))	('Tumor necrosis factor receptor superfamily, member 4', 'Gene', '22163', (144, 196))	('TNFRSF4', 'Gene', '22163', (198, 205))	('CD134', 'Gene', (208, 213))	('anti-PD-L1', 'Var', (117, 127))
597732	30775238	We enumerate the ongoing early phase clinical trials using anti-PD-1 and anti-PD-L1 antibodies for osteosarcomas in Table 3.	('osteosarcomas', 'Disease', (99, 112))	('anti-PD-1', 'Var', (59, 68))	('anti-PD-L1', 'Var', (73, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('osteosarcomas', 'Phenotype', 'HP:0002669', (99, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('osteosarcomas', 'Disease', 'MESH:D012516', (99, 112))	('osteosarcoma', 'Phenotype', 'HP:0002669', (99, 111))
597736	30775238	Ewing sarcoma is well-known for its translocation of the EWS gene on chromosome 22 with the FLI1 gene on chromosome 11, as it occurs in more than 90% of cases.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('FLI1', 'Gene', '2313', (92, 96))	('Ewing sarcoma', 'Disease', (0, 13))	('FLI1', 'Gene', (92, 96))	('EWS', 'Gene', '2130', (57, 60))	('EWS', 'Gene', (57, 60))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('translocation', 'Var', (36, 49))
597763	30775238	Ongoing early phase clinical trials on chondrosarcomas are testing immune checkpoint blockades in combination with the anti-CTLA-4 inhibitor (NCT02982486) and mTOR inhibitor (NCT03190174), as shown in Table 3.	('chondrosarcomas', 'Disease', 'MESH:D002813', (39, 54))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (39, 53))	('NCT03190174', 'Var', (175, 186))	('chondrosarcomas', 'Disease', (39, 54))	('mTOR', 'Gene', (159, 163))	('mTOR', 'Gene', '2475', (159, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (46, 54))	('NCT02982486', 'Var', (142, 153))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (39, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
597783	30775238	As expected, blockade of the CTLA-4 receptor increases CD8+ T lymphocyte activation and depletes Treg action.	('increases', 'PosReg', (45, 54))	('CTLA-4 receptor', 'Gene', (29, 44))	('blockade', 'Var', (13, 21))	('depletes', 'NegReg', (88, 96))	('Treg action', 'CPA', (97, 108))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))
597784	30775238	Allison and co-workers demonstrated that combining anti-CTLA-4 antibody with tumor lysate-loaded dendritic cells increased CD8+ TIL, reduced Tregs, inhibited metastasis, and prolonged survival in a mouse model with colon cancer or fibrosarcoma.	('CD8', 'Gene', (123, 126))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (231, 243))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('metastasis', 'CPA', (158, 168))	('mouse', 'Species', '10090', (198, 203))	('colon cancer', 'Phenotype', 'HP:0003003', (215, 227))	('prolonged', 'PosReg', (174, 183))	('fibrosarcoma', 'Disease', 'MESH:D005354', (231, 243))	('Tregs', 'CPA', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('fibrosarcoma', 'Disease', (231, 243))	('colon cancer', 'Disease', 'MESH:D015179', (215, 227))	('CD8', 'Gene', '925', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('increased', 'PosReg', (113, 122))	('anti-CTLA-4', 'Gene', (51, 62))	('reduced', 'NegReg', (133, 140))	('colon cancer', 'Disease', (215, 227))	('anti-CTLA-4', 'Var', (51, 62))	('inhibited', 'NegReg', (148, 157))	('tumor', 'Disease', (77, 82))	('survival', 'CPA', (184, 192))
597789	30775238	Interestingly, the overall survival was better in patients with irAEs compared to those without irAEs.	('irAEs', 'Var', (64, 69))	('patients', 'Species', '9606', (50, 58))	('better', 'PosReg', (40, 46))
597794	30775238	In an osteosarcoma mouse model study, a combination therapy of anti-PD-L1 with anti-CTLA-4 antibody completely controlled metastatic osteosarcoma and showed a long-term disease-free survival of 60%.	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('anti-PD-L1', 'Var', (63, 73))	('osteosarcoma', 'Disease', (6, 18))	('combination', 'Interaction', (40, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (6, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('osteosarcoma', 'Disease', 'MESH:D012516', (6, 18))	('controlled', 'NegReg', (111, 121))	('mouse', 'Species', '10090', (19, 24))	('osteosarcoma', 'Disease', (133, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))
597807	30775238	Although studies of combination immune checkpoint blockade therapy, chemotherapy, or targeted therapy have expanded for soft tissue sarcomas, including with cyclophosphamide (NCT02406781), trabectedin (NCT03138161), doxorubicin (NCT02888665), gemcitabine (NCT03123276), or dasatinib (NCT01643278), recruitment for study in their bone sarcoma counterparts have been relatively limited.	('bone sarcoma', 'Phenotype', 'HP:0002669', (329, 341))	('doxorubicin', 'Chemical', 'MESH:D004317', (216, 227))	('NCT03138161', 'Var', (202, 213))	('sarcoma', 'Phenotype', 'HP:0100242', (334, 341))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (157, 173))	('NCT01643278', 'Var', (284, 295))	('soft tissue sarcomas', 'Disease', (120, 140))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (120, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (120, 140))	('NCT03123276', 'Var', (256, 267))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (120, 140))	('bone sarcoma', 'Disease', (329, 341))	('trabectedin', 'Chemical', 'MESH:D000077606', (189, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('NCT02406781', 'Var', (175, 186))	('dasatinib', 'Chemical', 'MESH:D000069439', (273, 282))	('NCT02888665', 'Var', (229, 240))	('bone sarcoma', 'Disease', 'MESH:D001847', (329, 341))	('gemcitabine', 'Chemical', 'MESH:C056507', (243, 254))
597816	30775238	It has also been reported that patients with high B7-H3 expression levels have significantly shorter survival and recurrence times compared to those with low expression.	('B7-H3', 'Protein', (50, 55))	('shorter', 'NegReg', (93, 100))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('survival', 'CPA', (101, 109))	('recurrence times', 'CPA', (114, 130))
597840	30775238	The authors posit that modulation of HLA-G expression within the tumor microenvironment might attenuate resistance to NK cell therapy and therefore enhance the efficacy of immunotherapy for Ewing sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('HLA-G', 'Gene', (37, 42))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (190, 203))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (190, 203))	('immunotherapy', 'CPA', (172, 185))	('resistance to NK cell therapy', 'MPA', (104, 133))	('attenuate', 'NegReg', (94, 103))	('enhance', 'PosReg', (148, 155))	('modulation', 'Var', (23, 33))	('Ewing sarcoma', 'Disease', (190, 203))	('HLA-G', 'Gene', '3135', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
597858	27207471	Cohesin Mutations in Human Cancer Cohesin is a highly-conserved protein complex that plays important roles in sister chromatid cohesion, chromatin structure, gene expression, and DNA repair.	('Mutations', 'Var', (8, 17))	('Human', 'Species', '9606', (21, 26))	('Cohesin', 'Gene', (0, 7))	('Cancer', 'Disease', (27, 33))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))
597862	27207471	In this review we summarize the findings reported to date and comment on potential functional implications of cohesin mutation in the pathogenesis of human cancer.	('human', 'Species', '9606', (150, 155))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mutation', 'Var', (118, 126))	('cohesin', 'Protein', (110, 117))
597868	27207471	Mutations in genes encoding components of the cohesin complex cause developmental disorders and cancer in humans.	('developmental disorders', 'Disease', 'MESH:D002658', (68, 91))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cause', 'Reg', (62, 67))	('Mutations', 'Var', (0, 9))	('humans', 'Species', '9606', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('developmental disorders', 'Disease', (68, 91))	('cancer', 'Disease', (96, 102))
597874	27207471	At the onset of anaphase, centromeric cohesion is alleviated via the cleavage of RAD21 by the cysteine protease separase, enabling sister chromatids to separate into the two daughter cells.	('separase', 'Gene', '9700', (112, 120))	('cleavage', 'Var', (69, 77))	('centromeric cohesion', 'CPA', (26, 46))	('separase', 'Gene', (112, 120))	('alleviated', 'NegReg', (50, 60))	('RAD21', 'Gene', (81, 86))	('enabling', 'PosReg', (122, 130))
597881	27207471	The cohesin complex has since been shown to be recruited to sites of DSBs in yeast and initiate de novo cohesion.	('cohesin complex', 'Protein', (4, 19))	('yeast', 'Species', '4932', (77, 82))	('recruited', 'PosReg', (47, 56))	('DSBs', 'Var', (69, 73))
597884	27207471	Heterozygous RAD21 deletion in mouse cells results in defective homologous recombination and increased sensitivity to ionizing radiation.	('defective', 'NegReg', (54, 63))	('increased', 'PosReg', (93, 102))	('deletion', 'Var', (19, 27))	('sensitivity to ionizing radiation', 'MPA', (103, 136))	('mouse', 'Species', '10090', (31, 36))	('RAD21', 'Gene', (13, 18))	('homologous recombination', 'CPA', (64, 88))
597885	27207471	Disruption of normal cohesin activity during human development can cause developmental disorders referred to as cohesinopathies.	('cause', 'Reg', (67, 72))	('developmental disorders', 'Disease', (73, 96))	('cohesinopathies', 'Disease', (112, 127))	('human', 'Species', '9606', (45, 50))	('developmental disorders', 'Disease', 'MESH:D002658', (73, 96))	('cohesin', 'Protein', (21, 28))	('Disruption', 'Var', (0, 10))
597887	27207471	Heterozygous mutations in NIPBL are the most common cause of CdLS, accounting for ~65% of cases.	('NIPBL', 'Gene', '25836', (26, 31))	('NIPBL', 'Gene', (26, 31))	('cause', 'Reg', (52, 57))	('Heterozygous mutations', 'Var', (0, 22))	('CdLS', 'Disease', (61, 65))
597888	27207471	NIPBL mutations range from nonsense/splice/frameshift mutations resulting in haploinsufficiency to missense mutations that are often associated with a milder phenotype.	('haploinsufficiency', 'Disease', 'MESH:D058495', (77, 95))	('missense mutations', 'Var', (99, 117))	('NIPBL', 'Gene', (0, 5))	('haploinsufficiency', 'Disease', (77, 95))	('nonsense/splice/frameshift mutations', 'Var', (27, 63))	('mutations', 'Var', (6, 15))	('NIPBL', 'Gene', '25836', (0, 5))
597889	27207471	CdLS can also be caused by mutations in SMC1A, SMC3, HDAC8 and RAD21.	('mutations', 'Var', (27, 36))	('CdLS', 'Disease', (0, 4))	('HDAC8', 'Gene', (53, 58))	('SMC3', 'Gene', (47, 51))	('caused by', 'Reg', (17, 26))	('RAD21', 'Gene', (63, 68))	('HDAC8', 'Gene', '55869', (53, 58))	('SMC1A', 'Gene', (40, 45))
597890	27207471	Another similar, but extremely rare disorder, termed Roberts syndrome (RBS), is caused by recessive mutations within ESCO2, which acetylates SMC3.	('RBS', 'Disease', (71, 74))	('mutations', 'Var', (100, 109))	('caused by', 'Reg', (80, 89))	('ESCO2', 'Gene', (117, 122))	('Roberts syndrome', 'Disease', (53, 69))	('RBS', 'Disease', 'MESH:C535687', (71, 74))	('ESCO2', 'Gene', '157570', (117, 122))	('Roberts syndrome', 'Disease', 'MESH:C535687', (53, 69))
597892	27207471	Most recently, microduplications involving STAG2 have also been associated with intellectual disability and behavioral problems.	('associated', 'Reg', (64, 74))	('intellectual disability', 'Phenotype', 'HP:0001249', (80, 103))	('disability', 'Disease', 'MESH:D009069', (93, 103))	('STAG2', 'Gene', (43, 48))	('behavioral problems', 'Phenotype', 'HP:0000708', (108, 127))	('disability', 'Disease', (93, 103))	('behavioral problems', 'Disease', (108, 127))	('microduplications', 'Var', (15, 32))
597894	27207471	identified heterozygous somatic missense mutations in the genes encoding SMC1A, SMC3, NIPBL, and STAG3 (a component of meiotic cohesin) in aneuploid colon cancers.	('missense mutations', 'Var', (32, 50))	('STAG3', 'Gene', '10734', (97, 102))	('SMC3', 'Gene', (80, 84))	('aneuploid colon cancers', 'Disease', 'MESH:D015179', (139, 162))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('NIPBL', 'Gene', '25836', (86, 91))	('colon cancers', 'Phenotype', 'HP:0003003', (149, 162))	('NIPBL', 'Gene', (86, 91))	('STAG3', 'Gene', (97, 102))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('aneuploid colon cancers', 'Disease', (139, 162))	('SMC1A', 'Gene', (73, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (149, 161))
597895	27207471	In 2010, individual deletions of RAD21 and STAG2 were reported in a chronic myelomonocytic leukemia (CML) and an acute myeloid leukemia (AML), respectively.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (113, 135))	('CML', 'Disease', (101, 104))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('RAD21', 'Gene', (33, 38))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (119, 135))	('acute myeloid leukemia', 'Disease', (113, 135))	('deletions', 'Var', (20, 29))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('AML', 'Disease', 'MESH:D015470', (137, 140))	('STAG2', 'Gene', (43, 48))	('chronic myelomonocytic leukemia', 'Disease', (68, 99))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (113, 135))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (68, 99))	('CML', 'Disease', 'MESH:D015464', (101, 104))	('AML', 'Disease', (137, 140))	('reported', 'Reg', (54, 62))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (68, 99))
597896	27207471	reported mutations of STAG2 in cell lines and primary tumors from glioblastoma multiforme (GBM), Ewing sarcoma, melanoma, cervical carcinoma, and hematological cancers.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (97, 110))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (97, 110))	('hematological cancers', 'Disease', 'MESH:D009369', (146, 167))	('mutations', 'Var', (9, 18))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cervical carcinoma', 'Disease', (122, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('Ewing sarcoma', 'Disease', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cervical carcinoma', 'Disease', 'MESH:D002575', (122, 140))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('STAG2', 'Gene', (22, 27))	('glioblastoma multiforme', 'Disease', (66, 89))	('primary tumors', 'Disease', (46, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (66, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('hematological cancers', 'Disease', (146, 167))	('primary tumors', 'Disease', 'MESH:D009369', (46, 60))
597897	27207471	Immunohistochemistry (IHC) analyses of primary tumor samples identified frequent STAG2 inactivation in GBM, Ewing sarcoma, and melanoma primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (144, 149))	('melanoma primary tumors', 'Disease', (127, 150))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (108, 121))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (108, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('GBM', 'Disease', (103, 106))	('inactivation', 'Var', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('STAG2', 'Gene', (81, 86))	('melanoma primary tumors', 'Disease', 'MESH:D008545', (127, 150))	('Ewing sarcoma', 'Disease', (108, 121))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (47, 52))
597899	27207471	These early manuscripts were followed by a host of additional studies reporting cohesin gene mutations in bladder cancer, Ewing sarcoma, myeloid leukemia, as well as other tumor types, as described in detail in the sections below.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Ewing sarcoma', 'Disease', (122, 135))	('mutations', 'Var', (93, 102))	('myeloid leukemia', 'Disease', 'MESH:D007951', (137, 153))	('tumor', 'Disease', (172, 177))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (137, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (122, 135))	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('leukemia', 'Phenotype', 'HP:0001909', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (122, 135))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('cohesin gene', 'Gene', (80, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))	('myeloid leukemia', 'Disease', (137, 153))
597900	27207471	A representative subset of the tumor-derived STAG2 mutations reported to date are depicted in Fig.	('STAG2', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
597907	27207471	identified frequent STAG2 mutations in bladder cancer by performing STAG2 IHC on >2000 tumors representing virtually all common cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('bladder cancer', 'Disease', (39, 53))	('cancer', 'Disease', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('STAG2', 'Gene', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', (128, 134))
597909	27207471	DNA sequence analysis performed on a separate cohort identified STAG2 mutations in 21% (23/111) of the bladder tumors studied.	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('bladder tumors', 'Disease', 'MESH:D001749', (103, 117))	('bladder tumors', 'Phenotype', 'HP:0009725', (103, 117))	('STAG2', 'Gene', (64, 69))	('bladder tumors', 'Disease', (103, 117))
597910	27207471	Strikingly, STAG2 mutations were much more common in nonmuscle-invasive tumors (36%) than in muscle-invasive tumors (16%).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (93, 115))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (56, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('STAG2', 'Gene', (12, 17))	('common', 'Reg', (43, 49))	('muscle-invasive tumors', 'Disease', (56, 78))	('muscle-invasive tumors', 'Disease', (93, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (18, 27))
597911	27207471	The authors also noted that TP53 mutation tended to co-occur with STAG2 mutation.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('co-occur', 'Reg', (52, 60))
597913	27207471	In contrast, loss of STAG2 in muscle-invasive tumors was associated with poor prognosis.	('muscle-invasive tumors', 'Disease', (30, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('loss', 'Var', (13, 17))	('STAG2', 'Gene', (21, 26))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (30, 52))
597917	27207471	16% (12/77) of tumors studied had a mutation in STAG2.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('mutation', 'Var', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('STAG2', 'Gene', (48, 53))	('tumors', 'Disease', (15, 21))
597918	27207471	In agreement with Solomon et al., STAG2 mutations were primarily truncating, and were more common in nonmuscle-invasive tumors (21%) than in muscle-invasive tumors (11%).	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (141, 163))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (104, 126))	('mutations', 'Var', (40, 49))	('common', 'Reg', (91, 97))	('muscle-invasive tumors', 'Disease', (104, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('muscle-invasive tumors', 'Disease', (141, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('STAG2', 'Gene', (34, 39))	('truncating', 'MPA', (65, 75))
597922	27207471	emphasized that since many STAG2 mutant tumors were euploid (not aneuploid), the role of STAG2 mutations in the pathogenesis of bladder cancer was unlikely to be via the initiation of chromosomal instability and aneuploidy.	('aneuploidy', 'Disease', (212, 222))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('aneuploidy', 'Disease', 'MESH:D000782', (212, 222))	('mutant', 'Var', (33, 39))	('mutations', 'Var', (95, 104))	('chromosomal instability', 'Phenotype', 'HP:0040012', (184, 207))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('STAG2', 'Gene', (89, 94))	('tumors', 'Disease', (40, 46))	('STAG2', 'Gene', (27, 32))
597924	27207471	In this cohort, 11% of tumors harbored mutations in STAG2, the majority of which were truncating.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('STAG2', 'Gene', (52, 57))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
597925	27207471	found that STAG2 mutant tumors had more chromosomal copy number alterations than STAG2 wild-type tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('STAG2', 'Gene', (11, 16))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutant', 'Var', (17, 23))	('chromosomal copy number alterations', 'MPA', (40, 75))
597926	27207471	In this cohort, both nonmuscle-invasive and muscle-invasive tumors harboring STAG2 mutations had worse clinical outcomes than tumors with wild-type STAG2.	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (126, 132))	('muscle-invasive tumors', 'Disease', (44, 66))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('STAG2', 'Gene', (77, 82))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (44, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (60, 66))
597928	27207471	identified mutations in 26% of primary tumors and 17% of cell lines.	('mutations', 'Var', (11, 20))	('primary tumors', 'Disease', (31, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('primary tumors', 'Disease', 'MESH:D009369', (31, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
597929	27207471	and Balbas-Martinez et al., STAG2 mutations were most commonly found in tumors of low stage and grade.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('found', 'Reg', (63, 68))	('STAG2', 'Gene', (28, 33))	('mutations', 'Var', (34, 43))
597930	27207471	In this cohort, positive correlations were identified between the presence of mutations in STAG2, FGFR3, and PI3KCA, and the presence of wild-type TP53.	('TP53', 'Gene', (147, 151))	('FGFR3', 'Gene', (98, 103))	('mutations', 'Var', (78, 87))	('STAG2', 'Gene', (91, 96))	('TP53', 'Gene', '7157', (147, 151))	('PI3', 'Species', '1196084', (109, 112))
597931	27207471	identified no correlation between the presence of STAG2 mutations and increased frequencies of copy number alterations, further suggesting that STAG2 mutations may not cause aneuploidy in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('mutations', 'Var', (56, 65))	('copy number alterations', 'MPA', (95, 118))	('aneuploidy in bladder cancer', 'Disease', 'MESH:D001749', (174, 202))	('STAG2', 'Gene', (50, 55))	('mutations', 'Var', (150, 159))	('STAG2', 'Gene', (144, 149))	('aneuploidy in bladder cancer', 'Disease', (174, 202))
597932	27207471	Taken together, these four studies indicate that the overall STAG2 mutation frequency in urothelial carcinoma of the bladder is ~15-20%.	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (89, 124))	('urothelial carcinoma of the bladder', 'Disease', (89, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('mutation', 'Var', (67, 75))	('STAG2', 'Gene', (61, 66))
597933	27207471	Mutations of STAG2 are more common in nonmuscle-invasive tumors (~30% mutation frequency) than in muscle invasive tumors (~10% mutation frequency).	('muscle invasive tumors', 'Disease', 'MESH:D009217', (98, 120))	('common', 'Reg', (28, 34))	('muscle-invasive tumors', 'Disease', 'MESH:D009217', (41, 63))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('muscle invasive tumors', 'Disease', (98, 120))	('muscle-invasive tumors', 'Disease', (41, 63))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('STAG2', 'Gene', (13, 18))
597934	27207471	In agreement, in 2014 The Cancer Genome Atlas (TCGA) reported an 11% STAG2 mutation frequency in muscle-invasive bladder cancer (TCGA has not studied nonmuscle-invasive bladder cancer).	('STAG2', 'Gene', (69, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('Cancer Genome Atlas', 'Disease', (26, 45))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (97, 127))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('muscle-invasive bladder cancer', 'Disease', (153, 183))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (26, 45))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutation', 'Var', (75, 83))	('invasive bladder', 'Phenotype', 'HP:0100645', (104, 120))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('bladder cancer', 'Phenotype', 'HP:0009725', (169, 183))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (153, 183))	('muscle-invasive bladder cancer', 'Disease', (97, 127))	('invasive bladder', 'Phenotype', 'HP:0100645', (160, 176))
597935	27207471	These findings, when considered in light of the related observation that non-muscle invasive tumors harboring STAG2 mutations appear less likely to recur than STAG2 wild-type tumors, suggest that STAG2 expression could be useful as a biomarker for predicting whether non-muscle invasive bladder tumors will recur and invade.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', (295, 301))	('bladder tumors', 'Phenotype', 'HP:0009725', (287, 301))	('invade', 'CPA', (317, 323))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('invasive bladder tumors', 'Disease', 'MESH:D001749', (278, 301))	('muscle invasive tumors', 'Disease', 'MESH:D009217', (77, 99))	('STAG2', 'Gene', (110, 115))	('mutations', 'Var', (116, 125))	('invasive bladder', 'Phenotype', 'HP:0100645', (278, 294))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('invasive bladder tumors', 'Disease', (278, 301))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('muscle invasive tumors', 'Disease', (77, 99))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
597936	27207471	The observation that bladder tumors harboring STAG2 mutations tend to be less aggressive than tumors with wild-type STAG2 was recently confirmed by Qiao et al..	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('aggressive', 'MPA', (78, 88))	('STAG2', 'Gene', (46, 51))	('bladder tumors', 'Phenotype', 'HP:0009725', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('bladder tumors', 'Disease', 'MESH:D001749', (21, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', (29, 35))	('less', 'NegReg', (73, 77))	('bladder tumors', 'Disease', (21, 35))
597937	27207471	There is some disagreement among these studies with regards to a potential role of STAG2 mutations in causing aneuploidy in bladder cancer.	('STAG2', 'Gene', (83, 88))	('causing', 'Reg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('aneuploidy in bladder cancer', 'Disease', (110, 138))	('mutations', 'Var', (89, 98))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('aneuploidy in bladder cancer', 'Disease', 'MESH:D001749', (110, 138))
597938	27207471	However, considering that STAG2 mutations are most common in the earliest stage tumors, many of which are euploid (ie.	('common', 'Reg', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('STAG2', 'Gene', (26, 31))
597939	27207471	non-aneuploid), the role of STAG2 mutations in the pathogenesis of bladder cancer seems most likely due to phenotype(s) other than the initiation of chromosome segregation and aneuploidy.	('aneuploidy', 'Disease', (176, 186))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('aneuploidy', 'Disease', 'MESH:D000782', (176, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('STAG2', 'Gene', (28, 33))	('mutations', 'Var', (34, 43))
597942	27207471	Ewing sarcoma is defined pathologically by the presence of a translocation involving the EWSR1 gene on chromosome 22, most commonly with the FLI1 gene on chromosome 11.	('translocation', 'Var', (61, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', '2130', (89, 94))	('FLI1', 'Gene', (141, 145))	('Ewing sarcoma', 'Disease', (0, 13))	('FLI1', 'Gene', '2313', (141, 145))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('EWSR1', 'Gene', (89, 94))	('presence', 'Reg', (47, 55))
597944	27207471	In the initial study identifying STAG2 mutations in multiple tumor types, frequent mutations of STAG2 were identified in Ewing sarcoma cell lines.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (121, 134))	('mutations', 'Var', (83, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('STAG2', 'Gene', (96, 101))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (121, 134))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Ewing sarcoma', 'Disease', (121, 134))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
597945	27207471	Subsequently, three comprehensive Ewing sarcoma sequencing studies were published, each of which identified somatic mutation of STAG2 as the most common mutational event in Ewing sarcoma other than the tumor-defining EWS-FLI1 translocation.	('Ewing sarcoma', 'Disease', (173, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('EWS', 'Gene', '2130', (217, 220))	('EWS', 'Gene', (217, 220))	('Ewing sarcoma', 'Disease', (34, 47))	('tumor', 'Disease', (202, 207))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('mutation', 'Var', (116, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (173, 186))	('FLI1', 'Gene', '2313', (221, 225))	('STAG2', 'Gene', (128, 133))	('FLI1', 'Gene', (221, 225))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (34, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (34, 47))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
597946	27207471	identified STAG2 mutations in 22% of tumors (14/65) and 44% (16/36) of cell lines.	('STAG2', 'Gene', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (17, 26))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
597947	27207471	Interestingly, 5 samples (4 tumors and 1 cell line) harbored the same nonsense mutation (R216X), indicating the presence of a minor mutational hotspot.	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('R216X', 'Mutation', 'p.R216X', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('R216X', 'Var', (89, 94))
597948	27207471	There was a statistically significant co-occurrence of STAG2 mutations and TP53 mutations in Ewing sarcoma cell lines; however, this correlation was less evident in primary tumor samples.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (93, 106))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('STAG2', 'Gene', (55, 60))	('mutations', 'Var', (80, 89))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (93, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Ewing sarcoma', 'Disease', (93, 106))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
597949	27207471	also identified STAG2 mutation as a common event in Ewing sarcoma, albeit with a lower frequency of mutations (8%) than Brohl et al., but with a higher frequency of loss of expression by IHC (15%).	('mutation', 'Var', (22, 30))	('Ewing sarcoma', 'Disease', (52, 65))	('STAG2', 'Gene', (16, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (52, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (52, 65))
597951	27207471	also noted a statistically significant co-occurrence of mutations in STAG2 and TP53.	('STAG2', 'Gene', (69, 74))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))
597952	27207471	Additionally, there was also evidence of convergent evolution of mutations in STAG2 and TP53.	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('STAG2', 'Gene', (78, 83))	('mutations', 'Var', (65, 74))
597954	27207471	reported a 15% overall frequency of STAG2 mutation in Ewing sarcoma tumors.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (54, 74))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (54, 67))	('mutation', 'Var', (42, 50))	('STAG2', 'Gene', (36, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Ewing sarcoma tumors', 'Disease', (54, 74))
597955	27207471	This study also identified the R216X hotspot, which was mutated in 5 cell lines and 2 primary tumors.	('R216X', 'Mutation', 'p.R216X', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('primary tumors', 'Disease', (86, 100))	('R216X', 'Var', (31, 36))	('primary tumors', 'Disease', 'MESH:D009369', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
597956	27207471	also identified co-occurrence of STAG2 mutations and TP53 mutations.	('mutations', 'Var', (58, 67))	('co-occurrence', 'Reg', (16, 29))	('STAG2', 'Gene', (33, 38))	('mutations', 'Var', (39, 48))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))
597957	27207471	In addition, mutual exclusivity was observed between STAG2 mutation and CDKN2A deletion in both tumors and cell lines of this cohort.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('CDKN2A', 'Gene', '1029', (72, 78))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('STAG2', 'Gene', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutation', 'Var', (59, 67))	('deletion', 'Var', (79, 87))	('CDKN2A', 'Gene', (72, 78))
597958	27207471	Patients whose tumors harbored both STAG2 and TP53 mutations had the worst outcomes.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (46, 50))	('STAG2', 'Gene', (36, 41))	('tumors', 'Disease', (15, 21))
597959	27207471	Taken together, these studies reported mutations in 15-20% of Ewing sarcoma tumors, identifying STAG2 as the most common somatic mutation in Ewing sarcoma other than the defining EWS-FLI translocation.	('EWS', 'Gene', '2130', (179, 182))	('EWS', 'Gene', (179, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (141, 154))	('STAG2', 'Gene', (96, 101))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (39, 48))	('Ewing sarcoma tumors', 'Disease', (62, 82))	('FLI', 'Gene', '2314', (183, 186))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('Ewing sarcoma', 'Disease', (141, 154))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (62, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('FLI', 'Gene', (183, 186))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (62, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (62, 75))
597960	27207471	Of note, unlike in bladder cancer and myeloid malignancies (see below), no cohesin genes other than STAG2 were found to be mutated in Ewing sarcoma at statistically significant frequencies.	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('bladder cancer', 'Disease', 'MESH:D001749', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Ewing sarcoma', 'Disease', (134, 147))	('bladder cancer', 'Disease', (19, 33))	('myeloid malignancies', 'Disease', (38, 58))	('cohesin genes', 'Gene', (75, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (134, 147))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (134, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('mutated', 'Var', (123, 130))	('myeloid malignancies', 'Disease', 'MESH:D009369', (38, 58))
597961	27207471	The finding of STAG2 mutation is particularly noteworthy since, like most pediatric cancers, Ewing sarcomas harbor very few somatic mutations.	('Ewing sarcomas', 'Disease', (93, 107))	('pediatric cancers', 'Disease', 'MESH:D009369', (74, 91))	('pediatric cancers', 'Disease', (74, 91))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (93, 107))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (93, 107))	('mutation', 'Var', (21, 29))	('STAG2', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (93, 106))
597962	27207471	In addition, STAG2 mutations appears to be a marker for worse clinical outcomes, and tend to co-occur with TP53 mutation.	('STAG2 mutations', 'Var', (13, 28))	('TP53', 'Gene', (107, 111))	('TP53', 'Gene', '7157', (107, 111))
597964	27207471	The subtypes of myeloid leukemia that are known to harbor cohesin gene mutations are discussed individually below, and an overview is provided in Table 2.	('leukemia', 'Phenotype', 'HP:0001909', (24, 32))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (16, 32))	('cohesin gene', 'Gene', (58, 70))	('mutations', 'Var', (71, 80))	('myeloid leukemia', 'Disease', (16, 32))	('myeloid leukemia', 'Disease', 'MESH:D007951', (16, 32))
597967	27207471	Several recent reports have identified cohesin gene mutations in both de novo and secondary AML.	('mutations', 'Var', (52, 61))	('AML', 'Disease', (92, 95))	('cohesin gene', 'Gene', (39, 51))	('AML', 'Disease', 'MESH:D015470', (92, 95))
597968	27207471	The first report of cohesin mutations in AML identified somatic mutations in SMC3 at a frequency of 3%.	('SMC3', 'Gene', (77, 81))	('AML', 'Disease', 'MESH:D015470', (41, 44))	('mutations', 'Var', (64, 73))	('AML', 'Disease', (41, 44))	('mutations', 'Var', (28, 37))
597972	27207471	assessed the mutation frequency of cohesin subunits in both de novo and secondary AML (as well as in other types of myeloid malignancies - see below).	('mutation', 'Var', (13, 21))	('AML', 'Disease', 'MESH:D015470', (82, 85))	('myeloid malignancies', 'Disease', 'MESH:D009369', (116, 136))	('AML', 'Disease', (82, 85))	('cohesin subunits', 'Protein', (35, 51))	('myeloid malignancies', 'Disease', (116, 136))
597973	27207471	In both studies, AML harbored the most frequent cohesin mutations, with only the genes encoding core cohesin subunits mutated at an appreciable frequency.	('AML', 'Disease', (17, 20))	('mutations', 'Var', (56, 65))	('cohesin', 'Protein', (48, 55))	('AML', 'Disease', 'MESH:D015470', (17, 20))
597974	27207471	identified cohesin mutations in 12% (19/157) of AML samples.	('mutations', 'Var', (19, 28))	('cohesin', 'Protein', (11, 18))	('AML', 'Disease', (48, 51))	('AML', 'Disease', 'MESH:D015470', (48, 51))
597975	27207471	The frequency of cohesin mutation was slightly higher in de novo AML (13%; 16/120 samples studied) than in secondary AML (8%; 3/37 samples studied).	('AML', 'Disease', (65, 68))	('AML', 'Disease', (117, 120))	('mutation', 'Var', (25, 33))	('AML', 'Disease', 'MESH:D015470', (65, 68))	('AML', 'Disease', 'MESH:D015470', (117, 120))	('cohesin', 'Gene', (17, 24))
597976	27207471	identified a higher frequency of mutations in secondary AML samples (20%; 30/149) than in de novo AML (11%; 32/301).	('AML', 'Disease', 'MESH:D015470', (98, 101))	('AML', 'Disease', (56, 59))	('mutations', 'Var', (33, 42))	('AML', 'Disease', (98, 101))	('AML', 'Disease', 'MESH:D015470', (56, 59))
597977	27207471	that cohesin mutations are more frequent in secondary AML than de novo AML, a recent report has identified STAG2 as one of eight mutated genes specific for secondary AML compared with de novo AML.	('AML', 'Disease', 'MESH:D015470', (54, 57))	('STAG2', 'Gene', (107, 112))	('AML', 'Disease', 'MESH:D015470', (71, 74))	('AML', 'Disease', (166, 169))	('AML', 'Disease', 'MESH:D015470', (192, 195))	('AML', 'Disease', (71, 74))	('cohesin', 'Protein', (5, 12))	('AML', 'Disease', (54, 57))	('AML', 'Disease', (192, 195))	('mutations', 'Var', (13, 22))	('AML', 'Disease', 'MESH:D015470', (166, 169))	('frequent', 'Reg', (32, 40))
597978	27207471	There is some evidence that cohesin gene mutations may be an initiating event in a subset of AMLs.	('mutations', 'Var', (41, 50))	('cohesin gene', 'Gene', (28, 40))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('AML', 'Disease', (93, 96))
597980	27207471	identified a STAG2 mutation in both a secondary AML and the precursor myelodysplastic syndrome from the same patient, implicating STAG2 mutation as an early event in the pathogenesis of this cancer.	('cancer', 'Disease', (191, 197))	('mutation', 'Var', (19, 27))	('patient', 'Species', '9606', (109, 116))	('AML', 'Disease', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (70, 94))	('myelodysplastic syndrome', 'Disease', (70, 94))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (70, 94))	('AML', 'Disease', 'MESH:D015470', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('STAG2', 'Gene', (13, 18))
597983	27207471	As mentioned above, MDS samples from patients whose disease later progressed to secondary AML have been shown to harbor STAG2 mutations.	('AML', 'Disease', (90, 93))	('patients', 'Species', '9606', (37, 45))	('harbor', 'Reg', (113, 119))	('STAG2', 'Gene', (120, 125))	('AML', 'Disease', 'MESH:D015470', (90, 93))	('mutations', 'Var', (126, 135))	('MDS', 'Disease', (20, 23))	('MDS', 'Disease', 'MESH:D009190', (20, 23))
597984	27207471	A subsequent study using a cohort of 150 MDS samples identified a 6% frequency (10/154) of STAG2 mutations.	('mutations', 'Var', (97, 106))	('MDS', 'Disease', (41, 44))	('MDS', 'Disease', 'MESH:D009190', (41, 44))	('STAG2', 'Gene', (91, 96))
597985	27207471	identified cohesin mutations in 8% (18/224) of MDS samples, the majority of which were in STAG2, with lower mutation frequencies in SMC3 and RAD21.	('SMC3', 'Gene', (132, 136))	('mutations', 'Var', (19, 28))	('MDS', 'Disease', (47, 50))	('MDS', 'Disease', 'MESH:D009190', (47, 50))	('cohesin', 'Protein', (11, 18))	('RAD21', 'Gene', (141, 146))
597986	27207471	studied cohorts of both high risk and low risk MDS, and identified cohesin mutations in 17% of high risk samples and 11% of low-risk samples.	('mutations', 'Var', (75, 84))	('MDS', 'Disease', (47, 50))	('MDS', 'Disease', 'MESH:D009190', (47, 50))	('cohesin', 'Gene', (67, 74))
597987	27207471	Cohesin mutations have also been identified in myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPN), and MDS/MPN (MPN and MDS overlap syndrome) at frequencies of 4-10%.	('MDS', 'Disease', (155, 158))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (87, 107))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (115, 143))	('myelomonocytic leukemia', 'Disease', 'MESH:D054429', (47, 70))	('identified', 'Reg', (33, 43))	('CMML', 'Disease', 'MESH:D054429', (72, 76))	('myeloproliferative neoplasms', 'Disease', (115, 143))	('MDS overlap syndrome', 'Disease', (172, 192))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (79, 107))	('mutations', 'Var', (8, 17))	('CMML', 'Disease', (72, 76))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (115, 143))	('CML', 'Disease', 'MESH:D015464', (109, 112))	('myelomonocytic leukemia', 'Disease', (47, 70))	('CML', 'Disease', (109, 112))	('MDS', 'Disease', 'MESH:D009190', (172, 175))	('MDS', 'Disease', 'MESH:D009190', (155, 158))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (79, 107))	('chronic myelogenous leukemia', 'Disease', (79, 107))	('Cohesin', 'Gene', (0, 7))	('MDS overlap syndrome', 'Disease', 'MESH:D009190', (172, 192))	('neoplasms', 'Phenotype', 'HP:0002664', (134, 143))	('MDS', 'Disease', (172, 175))
597988	27207471	A remarkably high cumulative mutation frequency (53%) of the cohesin components STAG2, RAD21, SMC3, SMC1A, and NIPBL has also been identified in Down syndrome-associated acute megakaryoblastic leukemia.	('mutation', 'Var', (29, 37))	('SMC3', 'Gene', (94, 98))	('identified', 'Reg', (131, 141))	('SMC1A', 'Gene', (100, 105))	('NIPBL', 'Gene', '25836', (111, 116))	('NIPBL', 'Gene', (111, 116))	('leukemia', 'Disease', (193, 201))	('leukemia', 'Disease', 'MESH:D007938', (193, 201))	('leukemia', 'Phenotype', 'HP:0001909', (193, 201))	('RAD21', 'Gene', (87, 92))
597989	27207471	The studies described above demonstrate that cohesin gene mutations are present in a substantial subset of myeloid malignancies.	('mutations', 'Var', (58, 67))	('cohesin', 'Gene', (45, 52))	('myeloid malignancies', 'Disease', 'MESH:D009369', (107, 127))	('present', 'Reg', (72, 79))	('myeloid malignancies', 'Disease', (107, 127))
597991	27207471	The presence of cohesin mutation in AML precursors and in AML genomes that do not contain well-characterized initiating genetic events suggests that cohesin mutations may function as an initiating event in a subset of myeloid malignancies.	('AML', 'Disease', 'MESH:D015470', (36, 39))	('cohesin', 'Gene', (149, 156))	('AML', 'Disease', (36, 39))	('AML', 'Disease', 'MESH:D015470', (58, 61))	('cohesin', 'Gene', (16, 23))	('mutations', 'Var', (157, 166))	('myeloid malignancies', 'Disease', 'MESH:D009369', (218, 238))	('mutation', 'Var', (24, 32))	('function', 'Reg', (171, 179))	('myeloid malignancies', 'Disease', (218, 238))	('AML', 'Disease', (58, 61))
597992	27207471	The generation of aneuploidy does not appear to be the primary role of cohesin mutations in myeloid malignancies, since many cohesin gene mutations have been identified in euploid samples.	('aneuploidy', 'Disease', (18, 28))	('myeloid malignancies', 'Disease', 'MESH:D009369', (92, 112))	('aneuploidy', 'Disease', 'MESH:D000782', (18, 28))	('cohesin gene', 'Gene', (125, 137))	('myeloid malignancies', 'Disease', (92, 112))	('mutations', 'Var', (79, 88))	('mutations', 'Var', (138, 147))
597993	27207471	Instead, as described in greater detail below, studies of mouse models have pointed to lineage skewing resulting from aberrant chromatin structure and transcription factor accessibility as a particularly important effect of cohesin mutations in myeloid precursor cells.	('mouse', 'Species', '10090', (58, 63))	('chromatin structure', 'MPA', (127, 146))	('cohesin', 'Gene', (224, 231))	('aberrant', 'Var', (118, 126))	('mutations', 'Var', (232, 241))	('lineage skewing', 'CPA', (87, 102))	('transcription factor accessibility', 'MPA', (151, 185))
597994	27207471	Cohesin gene mutations have also been identified in several other tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('identified', 'Reg', (38, 48))	('tumor', 'Disease', (66, 71))	('Cohesin', 'Gene', (0, 7))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
597996	27207471	Further support for a role of cohesin gene mutations in gliomas has been recently provided by Ceccarelli et al., who identified a 16% frequency of cohesin mutations and copy number alterations, including the first report of recurrent NIPBL mutations in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('gliomas', 'Disease', (56, 63))	('mutations', 'Var', (155, 164))	('NIPBL', 'Gene', '25836', (234, 239))	('NIPBL', 'Gene', (234, 239))	('gliomas', 'Disease', 'MESH:D005910', (253, 260))	('copy number alterations', 'Var', (169, 192))	('gliomas', 'Disease', (253, 260))	('gliomas', 'Phenotype', 'HP:0009733', (253, 260))	('mutations', 'Var', (43, 52))	('cohesin', 'Gene', (147, 154))	('mutations', 'Var', (240, 249))
597997	27207471	has suggested that GBM cells harboring STAG2 mutations may have enhanced susceptibility to PARP inhibitors.	('mutations', 'Var', (45, 54))	('PARP', 'Gene', (91, 95))	('STAG2', 'Gene', (39, 44))	('PARP', 'Gene', '1302', (91, 95))	('enhanced', 'PosReg', (64, 72))
597998	27207471	Additionally, TCGA has identified mutations in STAG2 (9%) and NIPBL (10%) in endometrial carcinoma.	('endometrial carcinoma', 'Disease', (77, 98))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (77, 98))	('NIPBL', 'Gene', '25836', (62, 67))	('NIPBL', 'Gene', (62, 67))	('STAG2', 'Gene', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (77, 98))	('mutations', 'Var', (34, 43))
598000	27207471	Lower frequencies of cohesin gene mutations have also been identified in medulloblastoma, pancreatic ductal carcinoma, breast cancer and colorectal cancer.	('pancreatic ductal carcinoma', 'Disease', (90, 117))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('medulloblastoma', 'Disease', (73, 88))	('colorectal cancer', 'Disease', (137, 154))	('cohesin gene', 'Gene', (21, 33))	('breast cancer', 'Disease', (119, 132))	('pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (90, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('medulloblastoma', 'Disease', 'MESH:D008527', (73, 88))	('medulloblastoma', 'Phenotype', 'HP:0002885', (73, 88))	('mutations', 'Var', (34, 43))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (101, 117))
598001	27207471	In addition to mutations of cohesin itself, mutations of cohesin/CTCF genomic binding sites are commonly found in diverse human cancers.	('binding', 'Interaction', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('human', 'Species', '9606', (122, 127))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('CTCF', 'Gene', (65, 69))	('found', 'Reg', (105, 110))	('CTCF', 'Gene', '10664', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (44, 53))
598002	27207471	It remains unclear why some tumor types such as Ewings sarcoma primarily harbor mutations in STAG2 (85% truncating), whereas other cancers such as myeloid leukemias harbor primarily heterozygous missense mutations in a wider range of cohesin genes.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('tumor', 'Disease', (28, 33))	('cancers', 'Disease', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Ewings sarcoma', 'Phenotype', 'HP:0012254', (48, 62))	('mutations', 'Var', (80, 89))	('leukemia', 'Phenotype', 'HP:0001909', (155, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('Ewings sarcoma', 'Disease', 'MESH:C563168', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('leukemias', 'Phenotype', 'HP:0001909', (155, 164))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('STAG2', 'Gene', (93, 98))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (147, 163))	('myeloid leukemias', 'Disease', (147, 164))	('myeloid leukemias', 'Disease', 'MESH:D007951', (147, 164))	('Ewings sarcoma', 'Disease', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (147, 164))
598004	27207471	There are many potential functional effects of cohesin mutations on human cells, including the initiation of genomic instability and aneuploidy, alterations in chromatin organization resulting in changes in gene expression and/or replication stress, and enhanced susceptibility to DNA damage.	('alterations', 'Reg', (145, 156))	('human', 'Species', '9606', (68, 73))	('mutations', 'Var', (55, 64))	('aneuploidy', 'Disease', 'MESH:D000782', (133, 143))	('enhanced', 'PosReg', (254, 262))	('replication', 'MPA', (230, 241))	('susceptibility', 'MPA', (263, 277))	('changes', 'Reg', (196, 203))	('aneuploidy', 'Disease', (133, 143))	('genomic instability', 'CPA', (109, 128))	('cohesin', 'Gene', (47, 54))	('gene expression', 'MPA', (207, 222))
598005	27207471	In the following sections we will present the current state of knowledge regarding the specific effects of cancer-causing cohesin gene mutations on the structure and function of cohesin.	('effects', 'Reg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (135, 144))	('function', 'MPA', (166, 174))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cohesin', 'Gene', (122, 129))	('cancer', 'Disease', (107, 113))
598006	27207471	The most straightforward hypothesis regarding the biochemical loss-of-function caused by tumor-derived mutations in cohesin is that the mutations uniformly abrogate the ability of the encoded protein to interact with the cohesin complex.	('interact', 'Interaction', (203, 211))	('mutations', 'Var', (103, 112))	('abrogate', 'NegReg', (156, 164))	('loss-of-function', 'NegReg', (62, 78))	('ability', 'MPA', (169, 176))	('cohesin complex', 'Protein', (221, 236))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutations', 'Var', (136, 145))	('cohesin', 'Gene', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
598007	27207471	Two groups have now independently tested this hypothesis and have demonstrated that the hypothesis, while appealing, is false - in many cases the cohesin subunits encoded by genes harboring tumor-derived mutations retain their ability to interact with cohesin.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutations', 'Var', (204, 213))	('interact', 'Interaction', (238, 246))	('cohesin', 'Protein', (252, 259))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('ability', 'MPA', (227, 234))
598008	27207471	created an epitope-tagged wild-type human STAG2 expression vector and derivatives with ~60 different tumor-derived mutations.	('mutations', 'Var', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('human', 'Species', '9606', (36, 41))	('STAG2', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
598010	27207471	These experiments demonstrated that STAG2 proteins encoded by genes with tumor-derived late truncating mutations and tumor-derived missense mutations both retained their ability to interact with the rest of the cohesin complex.	('interact', 'Interaction', (181, 189))	('ability', 'MPA', (170, 177))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('missense mutations', 'Var', (131, 149))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
598011	27207471	also tested the ability of AML-derived mutations in RAD21, STAG2, and SMC3 to interact with cohesin, and found that proteins encoded by missense mutations and a subset of truncating mutations retained their ability to interact with cohesin.	('SMC3', 'Gene', (70, 74))	('missense mutations', 'Var', (136, 154))	('cohesin', 'Protein', (232, 239))	('tested', 'Reg', (5, 11))	('AML', 'Disease', (27, 30))	('mutations', 'Var', (39, 48))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('interact', 'Interaction', (78, 86))	('interact', 'Interaction', (218, 226))	('STAG2', 'Gene', (59, 64))	('ability', 'MPA', (207, 214))	('RAD21', 'Gene', (52, 57))
598012	27207471	Taken together, these studies demonstrate that the loss of the ability to interact with cohesin is not the only key property targeted by tumor-derived mutations in cohesin subunits.	('tumor', 'Disease', (137, 142))	('cohesin', 'Protein', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('interact', 'Interaction', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mutations', 'Var', (151, 160))
598013	27207471	They found that the presence of a tumor-derived mutation in STAG2 reduced the ability of regulatory subunits WAPL, PDS5A, and PDS5B to interact with the core cohesin ring.	('reduced', 'NegReg', (66, 73))	('WAPL', 'Gene', '23063', (109, 113))	('tumor', 'Disease', (34, 39))	('PDS5B', 'Gene', '23047', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('ability', 'MPA', (78, 85))	('interact', 'Interaction', (135, 143))	('PDS5A', 'Gene', (115, 120))	('mutation', 'Var', (48, 56))	('PDS5A', 'Gene', '23244', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('WAPL', 'Gene', (109, 113))	('STAG2', 'Gene', (60, 65))	('PDS5B', 'Gene', (126, 131))
598015	27207471	In their initial study identifying STAG2 mutations in cancer, Solomon et al.	('mutations', 'Var', (41, 50))	('STAG2', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
598016	27207471	proposed that the mutations caused chromosomal instability and aneuploidy.	('caused', 'Reg', (28, 34))	('aneuploidy', 'Disease', (63, 73))	('chromosomal instability', 'Phenotype', 'HP:0040012', (35, 58))	('chromosomal', 'Disease', (35, 46))	('aneuploidy', 'Disease', 'MESH:D000782', (63, 73))	('mutations', 'Var', (18, 27))
598017	27207471	This conclusion was based on the observations that (i) targeted correction of endogenous mutant STAG2 in aneuploid human cancer cells led to a reduction in the number and variability of chromosome counts, and (ii) introduction of a non-tumor derived STAG2 nonsense mutation into a chromosomally stable, near-diploid cell line resulted in alterations in chromosome counts.	('alterations', 'Reg', (338, 349))	('STAG2', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('correction', 'Var', (64, 74))	('chromosome counts', 'CPA', (353, 370))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('human', 'Species', '9606', (115, 120))	('STAG2', 'Gene', (250, 255))	('cancer', 'Disease', (121, 127))	('mutant', 'Var', (89, 95))	('reduction', 'NegReg', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (236, 241))
598018	27207471	These findings were consistent with other observations in yeast, mice, and other model systems indicating that mutations in cohesin subunits lead to chromosomal non-disjunction and aneuploidy.	('mutations', 'Var', (111, 120))	('cohesin', 'Gene', (124, 131))	('chromosomal non-disjunction', 'CPA', (149, 176))	('aneuploidy', 'Disease', 'MESH:D000782', (181, 191))	('mice', 'Species', '10090', (65, 69))	('yeast', 'Species', '4932', (58, 63))	('lead to', 'Reg', (141, 148))	('aneuploidy', 'Disease', (181, 191))
598019	27207471	However, since this initial publication, other studies have reported little if any correlation between STAG2 mutational status and aneuploidy in human tumors, and have further shown that many STAG2 mutant tumors are, in fact, euploid.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('STAG2', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('aneuploidy', 'Disease', (131, 141))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('human', 'Species', '9606', (145, 150))	('mutant', 'Var', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('aneuploidy', 'Disease', 'MESH:D000782', (131, 141))	('tumors', 'Disease', (205, 211))	('STAG2', 'Gene', (192, 197))
598020	27207471	used human somatic cell gene targeting to introduce nine different tumor derived STAG2 mutations into HCT116 cells, a near-diploid human cancer cell line with wild-type cohesin genes and intact sister chromatid cohesion.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('HCT116', 'CellLine', 'CVCL:0291', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('human', 'Species', '9606', (131, 136))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (137, 143))	('STAG2', 'Gene', (81, 86))	('tumor', 'Disease', (67, 72))	('human', 'Species', '9606', (5, 10))	('mutations', 'Var', (87, 96))
598021	27207471	interpreted these findings as further calling into question whether the cancer-relevant phenotypes of STAG2 mutations are directly related to sister chromatid cohesion and aneuploidy.	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('aneuploidy', 'Disease', 'MESH:D000782', (172, 182))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('STAG2', 'Gene', (102, 107))	('aneuploidy', 'Disease', (172, 182))	('cancer', 'Disease', (72, 78))
598022	27207471	As described below, two groups have created and studied mice in which individual cohesin genes have been inactivated by either gene targeting or shRNA, and another group has used primarily tissue culture-based approaches.	('inactivated', 'NegReg', (105, 116))	('cohesin genes', 'Gene', (81, 94))	('mice', 'Species', '10090', (56, 60))	('gene targeting', 'Var', (127, 141))
598028	27207471	Upon heterozygous SMC3 knockout, animals were viable and bone marrow cells demonstrated enhanced self-renewal properties in vitro and in vivo that were especially pronounced when cells were also expressing the FLT3-ITD mutant (a mutation previously reported to co-occur with cohesin mutations in myeloid malignancies.	('cohesin', 'Gene', (275, 282))	('myeloid malignancies', 'Disease', 'MESH:D009369', (296, 316))	('knockout', 'Var', (23, 31))	('mutations', 'Var', (283, 292))	('myeloid malignancies', 'Disease', (296, 316))	('FLT3', 'Gene', '2322', (210, 214))	('self-renewal properties', 'CPA', (97, 120))	('enhanced', 'PosReg', (88, 96))	('FLT3', 'Gene', (210, 214))
598031	27207471	Reduced cellular differentiation was observed upon expression of mutant cohesin subunits in cell lines and CD34-enriched primary human cord blood cells upon relevant stimulation.	('cohesin subunits', 'Protein', (72, 88))	('mutant', 'Var', (65, 71))	('Reduced', 'NegReg', (0, 7))	('cellular differentiation', 'CPA', (8, 32))	('CD34', 'Gene', '947', (107, 111))	('human', 'Species', '9606', (129, 134))	('CD34', 'Gene', (107, 111))
598032	27207471	In addition, increased retention of hematopoietic stem and progenitor cells (HSPCs) was observed when cohesin mutant expressing CD34-enriched cells were treated with stem cell retention-promoting cytokines.	('mutant', 'Var', (110, 116))	('CD34', 'Gene', (128, 132))	('cohesin', 'Gene', (102, 109))	('CD34', 'Gene', '947', (128, 132))	('increased', 'PosReg', (13, 22))
598034	27207471	Interestingly, shRNA knockdown of ERG, GATA2 or RUNX1 along with expression of a cohesin mutant in CD34-enriched cord blood cells prevented any increase in CD34-enriched cell retention that would normally be seen with mutant cohesin expression alone.	('CD34', 'Gene', (156, 160))	('prevented', 'NegReg', (130, 139))	('GATA2', 'Gene', '2624', (39, 44))	('ERG', 'Gene', '2078', (34, 37))	('ERG', 'Gene', (34, 37))	('CD34', 'Gene', '947', (156, 160))	('CD34', 'Gene', '947', (99, 103))	('increase', 'PosReg', (144, 152))	('CD34', 'Gene', (99, 103))	('GATA2', 'Gene', (39, 44))	('cohesin', 'Gene', (81, 88))	('mutant', 'Var', (89, 95))	('RUNX1', 'Gene', (48, 53))	('RUNX1', 'Gene', '861', (48, 53))
598035	27207471	Since the initial discovery of cohesin mutations in colon cancer in 2008, numerous studies have demonstrated that cohesin gene inactivation is a common and important event in the pathogenesis of diverse human cancers.	('inactivation', 'NegReg', (127, 139))	('colon cancer', 'Disease', (52, 64))	('cohesin', 'Gene', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('human', 'Species', '9606', (203, 208))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('mutations', 'Var', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cohesin gene', 'Gene', (114, 126))	('cancers', 'Disease', (209, 216))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
598036	27207471	At present it appears that the tumor types harboring most frequent cohesin mutations include bladder cancer, Ewing sarcoma, and myeloid malignancies.	('myeloid malignancies', 'Disease', 'MESH:D009369', (128, 148))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Ewing sarcoma', 'Disease', (109, 122))	('bladder cancer', 'Disease', (93, 107))	('cohesin', 'Protein', (67, 74))	('tumor', 'Disease', (31, 36))	('myeloid malignancies', 'Disease', (128, 148))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (75, 84))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))
598037	27207471	Cohesin gene mutations are found in GBM, endometrial carcinoma, and other tumor types.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (41, 62))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('endometrial carcinoma', 'Disease', (41, 62))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (41, 62))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('GBM', 'Disease', (36, 39))	('tumor', 'Disease', (74, 79))	('found', 'Reg', (27, 32))	('Cohesin gene', 'Gene', (0, 12))	('mutations', 'Var', (13, 22))
598038	27207471	The most commonly mutated gene is STAG2, with other cohesin genes including RAD21, SMC1A, SMC3, NIPBL mutated in a smaller fraction of tumors, depending on tumor type.	('SMC3', 'Gene', (90, 94))	('RAD21', 'Gene', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (135, 140))	('SMC1A', 'Gene', (83, 88))	('NIPBL', 'Gene', '25836', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (135, 141))	('NIPBL', 'Gene', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', (156, 161))	('mutated', 'Var', (102, 109))	('STAG2', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
598039	27207471	The location and types of mutations in STAG2 (~85% truncating, spread evenly throughout the X-linked gene including in the first exons) indicate that the mutations are inactivating, identifying STAG2 as a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('STAG2', 'Gene', (39, 44))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('truncating', 'MPA', (51, 61))
598040	27207471	Initial studies suggested that the key role of cohesin inactivation was the initiation of aneuploidy, though more recent studies have called this conclusion into question.	('initiation of aneuploidy', 'Disease', (76, 100))	('inactivation', 'Var', (55, 67))	('cohesin', 'Protein', (47, 54))	('initiation of aneuploidy', 'Disease', 'MESH:D000782', (76, 100))
598041	27207471	Other possible effects of cohesin mutations include alterations in chromatin structure, transcriptional regulation, and DNA repair, though which (if any) of these is a key cancer-causing phenotype of cohesin inactivation remains unknown.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('transcriptional regulation', 'MPA', (88, 114))	('alterations', 'Reg', (52, 63))	('DNA repair', 'MPA', (120, 130))	('cohesin', 'Gene', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('chromatin structure', 'MPA', (67, 86))	('mutations', 'Var', (34, 43))
598042	27207471	In the coming years we are likely to see a dramatic improvement in our understanding of the key cancer-relevant biochemical effects and phenotype(s) of cohesin inactivation in the pathogenesis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cohesin', 'Protein', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('inactivation', 'Var', (160, 172))	('cancer', 'Disease', (96, 102))
598087	27091124	A Ki-67 score of 1 was assigned to lesions with 0-9 % of the tumor cells positive for Ki-67 immunostaining, a score of 2 was those with 10-29 %, and a score of 3 was those with >=30 % of the tumor cells positive for Ki-67 immunostaining, respectively.	('Ki-67', 'Chemical', '-', (2, 7))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('Ki-67', 'Chemical', '-', (216, 221))	('Ki-67', 'Var', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Ki-67', 'Chemical', '-', (86, 91))	('tumor', 'Disease', (61, 66))
598102	27091124	Seven tumors assessed as grade 2 using mitosis were evaluated as grade 3 using Ki-67, whereas three tumors assessed as grade 3 using mitosis were evaluated grade 2 using Ki-67, respectively.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Ki-67', 'Var', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mitosis', 'Disease', (39, 46))	('Ki-67', 'Chemical', '-', (79, 84))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (6, 12))	('mitosis', 'Disease', (133, 140))	('mitosis', 'Disease', 'None', (39, 46))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mitosis', 'Disease', 'None', (133, 140))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('Ki-67', 'Chemical', '-', (170, 175))
598112	27091124	The 5-year OS for grade 3 and grade 2 tumors using Ki-67 was 73.5 % (95 % CI 54.4-85.6) (n = 38) and 91.8 % (95 % CI 69.8-98.0) (n = 32), respectively (HR 4.12, 95 % CI 0.89-19.09, p = 0.070) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('OS', 'Chemical', '-', (11, 13))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('Ki-67', 'Var', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('Ki-67', 'Chemical', '-', (51, 56))
598132	27091124	It has been reported that overall percent agreement of Ki-67 and mitosis grading among four pathologists was reported to be 79 % (95 % CI, 76-83) and 69 % (95 % CI, 65-73).	('mitosis', 'Disease', 'None', (65, 72))	('mitosis', 'Disease', (65, 72))	('Ki-67', 'Var', (55, 60))	('Ki-67', 'Chemical', '-', (55, 60))
598141	27091124	The results suggested that the prognosis of the patients with STS in JCOG0304 was remarkably improved by the intensive pre- and postoperative chemotherapy with DOX and IFO.	('JCOG0304', 'Gene', (69, 77))	('IFO', 'Chemical', 'MESH:D007069', (168, 171))	('STS', 'Var', (62, 65))	('improved', 'PosReg', (93, 101))	('DOX', 'Chemical', 'MESH:D004317', (160, 163))	('STS', 'Phenotype', 'HP:0030448', (62, 65))	('patients', 'Species', '9606', (48, 56))	('prognosis', 'CPA', (31, 40))
598144	27091124	Since the trial was phase II study, JCOG0304 had selection biases including many patients with good prognosis histologic subtypes of the tumors, and the majority of grade 2 tumor in FNCLCC grading (47 patients out of 72).	('patients', 'Species', '9606', (201, 209))	('tumors', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('JCOG0304', 'Var', (36, 44))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
598149	23427295	However, the significance of FOXM1 in tumors harboring mutation in p53, which is very common, is unclear.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('p53', 'Gene', (67, 70))	('mutation', 'Var', (55, 63))
598152	23427295	In addition, deletion of FoxM1 induces apoptotic cell death of the p53 null tumors, accompanied by reduced expression of the FOXM1 target genes Survivin and Bmi1.	('Bmi1', 'Gene', '12151', (157, 161))	('Bmi1', 'Gene', (157, 161))	('Survivin', 'Gene', '11799', (144, 152))	('FoxM1', 'Gene', '14235', (25, 30))	('Survivin', 'Gene', (144, 152))	('apoptotic cell death', 'CPA', (39, 59))	('p53', 'Gene', (67, 70))	('induces', 'Reg', (31, 38))	('expression', 'MPA', (107, 117))	('deletion', 'Var', (13, 21))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('FoxM1', 'Gene', (25, 30))	('reduced', 'NegReg', (99, 106))
598154	23427295	Together, our observations suggest that FOXM1 is critical for survival and growth of the p53-null lymphoma and sarcoma, and provide proof-of-principle that FOXM1 is an effective therapeutic target for sarcoma and lymphoma carrying loss of function mutation in p53.	('lymphoma', 'Disease', (98, 106))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('sarcoma', 'Disease', 'MESH:D012509', (201, 208))	('lymphoma', 'Disease', (213, 221))	('lymphoma', 'Disease', 'MESH:D008223', (98, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Disease', (201, 208))	('FOXM1', 'Gene', (156, 161))	('mutation', 'Var', (248, 256))	('FOXM1', 'Gene', (40, 45))	('lymphoma', 'Disease', 'MESH:D008223', (213, 221))	('lymphoma', 'Phenotype', 'HP:0002665', (213, 221))	('p53', 'Gene', (260, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('lymphoma and sarcoma', 'Disease', 'MESH:D012509', (98, 118))	('loss of function', 'NegReg', (231, 247))
598157	23427295	Mice deficient in p53 develop spontaneous tumors including thymic lymphoma and sarcoma.	('p53', 'Gene', (18, 21))	('thymic lymphoma', 'Disease', (59, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('lymphoma and sarcoma', 'Disease', 'MESH:D012509', (66, 86))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('thymic lymphoma', 'Disease', 'MESH:D013953', (59, 74))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (66, 74))	('deficient', 'Var', (5, 14))
598159	23427295	Given the high prevalence of p53 inactivation in human cancers, it is important to validate therapeutic strategies targeting cancer cells with loss of p53 function.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('p53', 'Gene', (29, 32))	('cancer', 'Disease', (125, 131))	('inactivation', 'Var', (33, 45))	('cancer', 'Disease', (55, 61))
598193	23427295	Our database analyses indicated that FoxM1-mRNA is upregulated in cancers harboring mutations in p53 (Supplementary Fig.1).	('p53', 'Gene', (97, 100))	('FoxM1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (84, 93))	('FoxM1', 'Gene', '14235', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('upregulated', 'PosReg', (51, 62))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
598195	23427295	To investigate this, we generated a strain of triple transgenic mice harboring CreERT2, Foxm1 fl/fl and p53 -/- alleles by crossing the three individual strains.	('p53 -/- alleles', 'Var', (104, 119))	('fl/fl', 'Var', (94, 99))	('Foxm1', 'Gene', '14235', (88, 93))	('transgenic mice', 'Species', '10090', (53, 68))	('CreERT2', 'Gene', (79, 86))	('Foxm1', 'Gene', (88, 93))
598198	23427295	However, our attempts to study the effects of Foxm1 deletion on endogenous lymphomas/sarcomas were inconclusive mainly because the lymphomas/sarcomas developed at different times in the cohorts of mice used in the study.	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('Foxm1', 'Gene', '14235', (46, 51))	('lymphomas', 'Phenotype', 'HP:0002665', (75, 84))	('lymphomas/sarcomas', 'Disease', (131, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('lymphomas/sarcomas', 'Disease', 'MESH:D012509', (131, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('lymphomas', 'Phenotype', 'HP:0002665', (131, 140))	('lymphomas/sarcomas', 'Disease', (75, 93))	('Foxm1', 'Gene', (46, 51))	('lymphomas/sarcomas', 'Disease', 'MESH:D012509', (75, 93))	('mice', 'Species', '10090', (197, 201))	('deletion', 'Var', (52, 60))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
598203	23427295	We tested the deletion efficiency of FoxM1 by immunoblot and confirmed that FoxM1 expression was significantly reduced in triple transgenic lines L1, L2 and S but not in control line C upon treatments with 4-OH tamoxifen (Fig.1A-D).	('FoxM1', 'Gene', (76, 81))	('FoxM1', 'Gene', (37, 42))	('expression', 'MPA', (82, 92))	('L2 and S', 'Gene', '23960', (150, 158))	('4-OH tamoxifen', 'Chemical', '-', (206, 220))	('FoxM1', 'Gene', '14235', (76, 81))	('tested', 'Reg', (3, 9))	('reduced', 'NegReg', (111, 118))	('FoxM1', 'Gene', '14235', (37, 42))	('transgenic', 'Species', '10090', (129, 139))	('deletion', 'Var', (14, 22))
598207	23427295	FoxM1 deletion led to a profound decrease in the cell viability starting from early time point in all three of the triple transgenic lines L1, L2 and S (Fig.1A,B and D).	('decrease', 'NegReg', (33, 41))	('L2 and S', 'Gene', '23960', (143, 151))	('cell viability', 'CPA', (49, 63))	('FoxM1', 'Gene', (0, 5))	('deletion', 'Var', (6, 14))	('transgenic', 'Species', '10090', (122, 132))	('FoxM1', 'Gene', '14235', (0, 5))
598209	23427295	1D) did not exhibit inhibition, demonstrating that the phenotype was caused by FoxM1 ablation.	('ablation', 'Var', (85, 93))	('FoxM1', 'Gene', (79, 84))	('FoxM1', 'Gene', '14235', (79, 84))
598211	23427295	FoxM1 deletion significantly reduced the ability of cells to grow under anchorage-independent conditions (Supplemental Fig.2A).	('FoxM1', 'Gene', (0, 5))	('reduced', 'NegReg', (29, 36))	('deletion', 'Var', (6, 14))	('FoxM1', 'Gene', '14235', (0, 5))
598212	23427295	After FoxM1 deletion, cells formed about 60% less colonies on the soft agar plate compared to the control.	('deletion', 'Var', (12, 20))	('less', 'NegReg', (45, 49))	('FoxM1', 'Gene', (6, 11))	('colonies on the soft agar plate', 'CPA', (50, 81))	('FoxM1', 'Gene', '14235', (6, 11))
598223	23427295	In both lymphoma and sarcoma derived tumor sections, we observed an increased number of apoptotic cells following FoxM1 depletion, evidenced by increase number of TUNEL positive cells (Fig.2C-D, Supplemental Fig.3E-L).	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('TUNEL positive', 'MPA', (163, 177))	('depletion', 'Var', (120, 129))	('lymphoma and sarcoma', 'Disease', 'MESH:D012509', (8, 28))	('FoxM1', 'Gene', '14235', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('increased number of apoptotic cells', 'Phenotype', 'HP:0030887', (68, 103))	('apoptotic cells', 'CPA', (88, 103))	('increase', 'PosReg', (144, 152))	('FoxM1', 'Gene', (114, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (8, 16))
598224	23427295	We also assayed for cleaved caspase-3 and cleaved PARP, two apoptosis markers.	('caspase-3', 'Protein', (28, 37))	('cleaved', 'Var', (42, 49))	('cleaved', 'MPA', (20, 27))	('assayed', 'Reg', (8, 15))	('PARP', 'Gene', (50, 54))	('PARP', 'Gene', '11545', (50, 54))
598226	23427295	These observations suggested that the inhibition of the p53-/- tumors following loss of FoxM1 resulted from enhanced apoptosis of the tumor cells.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('FoxM1', 'Gene', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('loss', 'Var', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('enhanced', 'PosReg', (108, 116))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('inhibition', 'NegReg', (38, 48))	('apoptosis', 'CPA', (117, 126))	('p53-/-', 'Protein', (56, 62))	('FoxM1', 'Gene', '14235', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
598230	23427295	Consistent with this finding, we observed that expression of Survivin, which is abundant in control groups for both p53 null lymphoma and sarcoma, was down-regulated following depletion of FoxM1 (Fig.3A-D, Fig.4).	('FoxM1', 'Gene', '14235', (189, 194))	('Survivin', 'Gene', (61, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('down-regulated', 'NegReg', (151, 165))	('lymphoma and sarcoma', 'Disease', 'MESH:D012509', (125, 145))	('FoxM1', 'Gene', (189, 194))	('depletion', 'Var', (176, 185))	('expression', 'MPA', (47, 57))	('lymphoma', 'Phenotype', 'HP:0002665', (125, 133))	('Survivin', 'Gene', '11799', (61, 69))
598234	23427295	These observations suggest important roles of Bmi1 and Survivin in the survival of the p53-/- lymphoma and sarcoma.	('p53-/-', 'Var', (87, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('Survivin', 'Gene', '11799', (55, 63))	('lymphoma and sarcoma', 'Disease', 'MESH:D012509', (94, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('Survivin', 'Gene', (55, 63))	('Bmi1', 'Gene', '12151', (46, 50))	('Bmi1', 'Gene', (46, 50))
598241	23427295	In the DEN/PB induced mouse hepatocellular carcinoma model, the ARF-peptide is able to inhibit HCC progression by inducing apoptosis.	('DEN', 'Chemical', 'MESH:D004052', (7, 10))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (28, 52))	('inducing', 'PosReg', (114, 122))	('HCC', 'Disease', (95, 98))	('hepatocellular carcinoma', 'Disease', (28, 52))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (28, 52))	('HCC', 'Phenotype', 'HP:0001402', (95, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('ARF-peptide', 'Var', (64, 75))	('apoptosis', 'CPA', (123, 132))	('mouse', 'Species', '10090', (22, 27))	('PB', 'Chemical', 'MESH:D007854', (11, 13))	('inhibit', 'NegReg', (87, 94))
598248	23427295	However, compared to the sarcoma lines, the p53-/- lymphoma cells are more sensitive to the ARF-peptide, where 5 muM of peptide was able to cause significant apoptosis (Fig.6A).	('sarcoma', 'Disease', (25, 32))	('peptide', 'Var', (120, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('apoptosis', 'CPA', (158, 167))	('lymphoma', 'Disease', (51, 59))	('lymphoma', 'Disease', 'MESH:D008223', (51, 59))	('lymphoma', 'Phenotype', 'HP:0002665', (51, 59))	('sarcoma', 'Disease', 'MESH:D012509', (25, 32))
598254	23427295	Mice were randomized into three groups and treated with PBS, mutant-peptide or the wild type ARF-peptide for 10 injections every other day starting from day 0 by intraperitoneal injection.	('PBS', 'Disease', 'MESH:D011535', (56, 59))	('PBS', 'Disease', (56, 59))	('mutant-peptide', 'Var', (61, 75))	('Mice', 'Species', '10090', (0, 4))
598259	23427295	Moreover, Survivin and Bmi1 expression was inhibited in the colonized tumors from mice treated with the wild type ARF-peptide compared to those treated with the mutant peptide (Fig.7D).	('mice', 'Species', '10090', (82, 86))	('mutant', 'Var', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('inhibited', 'NegReg', (43, 52))	('Survivin', 'Gene', (10, 18))	('expression', 'MPA', (28, 38))	('Survivin', 'Gene', '11799', (10, 18))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Bmi1', 'Gene', '12151', (23, 27))	('Bmi1', 'Gene', (23, 27))
598262	23427295	Around 20 days after inoculation, PBS and the mutant ARF peptide treated mice displayed strong luciferase signals from the colonized lymphoma cells in the lower back region.	('signals', 'MPA', (106, 113))	('lymphoma', 'Disease', 'MESH:D008223', (133, 141))	('ARF', 'Gene', (53, 56))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('mice', 'Species', '10090', (73, 77))	('luciferase', 'Enzyme', (95, 105))	('PBS', 'Disease', (34, 37))	('mutant', 'Var', (46, 52))	('PBS', 'Disease', 'MESH:D011535', (34, 37))	('lymphoma', 'Disease', (133, 141))
598264	23427295	When the mice were sacrificed, large tumor masses were found in the kidney by microscopic examination in the PBS and in the mutant peptide treated mice.	('mice', 'Species', '10090', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutant', 'Var', (124, 130))	('PBS', 'Disease', 'MESH:D011535', (109, 112))	('PBS', 'Disease', (109, 112))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mice', 'Species', '10090', (9, 13))
598269	23427295	Moreover, we show that the ARF-derived peptide inhibitor of FOXM1 effectively inhibits colonization and growth of the p53-null lymphoma and sarcoma, which will have strong implications with regards to a new therapeutic application of the ARF-peptide against lymphomas and sarcomas.	('lymphomas', 'Disease', (258, 267))	('inhibitor', 'Var', (47, 56))	('lymphomas', 'Disease', 'MESH:D008223', (258, 267))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('growth', 'CPA', (104, 110))	('sarcomas', 'Phenotype', 'HP:0100242', (272, 280))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('sarcomas', 'Disease', (272, 280))	('lymphomas', 'Phenotype', 'HP:0002665', (258, 267))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('FOXM1', 'Gene', (60, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (258, 266))	('inhibits', 'NegReg', (78, 86))	('sarcomas', 'Disease', 'MESH:D012509', (272, 280))	('lymphoma and sarcoma', 'Disease', 'MESH:D012509', (127, 147))
598272	23427295	In the absence of p53, reduced DNA repair and apoptosis lead to the accumulation of mutant cells, which contribute to tumor development.	('apoptosis', 'CPA', (46, 55))	('accumulation', 'PosReg', (68, 80))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutant', 'Var', (84, 90))	('tumor', 'Disease', (118, 123))	('DNA repair', 'MPA', (31, 41))	('reduced', 'NegReg', (23, 30))
598275	23427295	Therefore it is not surprising that p53 mutation also leads to aggressive progression of already developed tumor cells because of increased survival and proliferation.	('mutation', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('leads to', 'Reg', (54, 62))	('survival', 'CPA', (140, 148))	('p53', 'Gene', (36, 39))	('proliferation', 'CPA', (153, 166))	('increased', 'PosReg', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
598276	23427295	Increased expression of FOXM1 in the p53 mutant tumors is expected to drive aggressive progression because of its role in cell proliferation and inhibition of apoptosis.	('mutant', 'Var', (41, 47))	('aggressive progression', 'CPA', (76, 98))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('expression', 'MPA', (10, 20))	('Increased', 'PosReg', (0, 9))	('drive', 'PosReg', (70, 75))	('p53', 'Gene', (37, 40))	('FOXM1', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cell proliferation', 'CPA', (122, 140))
598281	23427295	For example, deletion of FoxM1 in the adult mouse liver has not visible effect for at least one year.	('FoxM1', 'Gene', (25, 30))	('FoxM1', 'Gene', '14235', (25, 30))	('mouse', 'Species', '10090', (44, 49))	('deletion', 'Var', (13, 21))
598286	23427295	Our observations with p53-null lymphoma and sarcoma are significant in that regard because over 50% of tumors harbor p53 mutations.	('lymphoma and sarcoma', 'Disease', 'MESH:D012509', (31, 51))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutations', 'Var', (121, 130))	('p53', 'Gene', (117, 120))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))
598288	23427295	Cre-recombinase mediated deletion of FoxM1 inhibited tumor growth at least partly by inducing apoptosis.	('inducing', 'Reg', (85, 93))	('inhibited', 'NegReg', (43, 52))	('FoxM1', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('FoxM1', 'Gene', '14235', (37, 42))	('deletion', 'Var', (25, 33))	('tumor', 'Disease', (53, 58))	('apoptosis', 'CPA', (94, 103))
598289	23427295	Deletion of FoxM1 caused a reduction in the expression of Survivin, an anti-apoptotic protein.	('expression', 'MPA', (44, 54))	('FoxM1', 'Gene', (12, 17))	('Survivin', 'Gene', '11799', (58, 66))	('FoxM1', 'Gene', '14235', (12, 17))	('Survivin', 'Gene', (58, 66))	('reduction', 'NegReg', (27, 36))	('Deletion', 'Var', (0, 8))
598303	29162563	Therefore, mutant KIT and ETV1 form a positive feedback loop and cooperate in GIST oncogenesis.	('mutant', 'Var', (11, 17))	('rat', 'Species', '10116', (70, 73))	('KIT', 'Gene', (18, 21))	('GIST oncogenesis', 'Disease', (78, 94))	('cooperate', 'Reg', (65, 74))	('ETV1', 'Gene', (26, 30))
598311	29162563	We generated genome-wide localization of ETV1 by ChIP-seq in two human GIST cell lines (GIST-T1 and GIST48) and two prostate cancer cell lines that harbor aberrant expression of full-length ETV1 due to translocation of its entire coding locus (LNCaP and MDA-PCa2b).	('human', 'Species', '9606', (65, 70))	('MDA-PCa2b', 'CellLine', 'CVCL:4748', (254, 263))	('translocation', 'Var', (202, 215))	('expression', 'MPA', (164, 174))	('GIST-T1', 'CellLine', 'CVCL:4976', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('prostate cancer', 'Disease', (116, 131))	('rat', 'Species', '10116', (7, 10))	('LNCaP', 'CellLine', 'CVCL:0395', (244, 249))	('ETV1', 'Gene', (190, 194))	('prostate cancer', 'Disease', 'MESH:D011471', (116, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))
598318	29162563	1C), and high FOXA1 expression in prostate cancer and breast cancer (Fig.	('breast cancer', 'Disease', (54, 67))	('expression', 'MPA', (20, 30))	('FOXA1', 'Gene', (14, 19))	('prostate cancer', 'Disease', (34, 49))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('FOXA1', 'Gene', '3169', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (34, 49))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('high', 'Var', (9, 13))
598328	29162563	Gene Set Enrichment Analysis (GSEA) using >8,300 gene sets from the Molecular Signatures Database (MSigDB) and custom ICC and GIST signatures revealed that the human GIST (EXPO GIST Signature) and the myenteric ICC (Mouse ICC-MY Signature) were among the most negatively enriched gene sets with both siFOXF1 and siETV1-mediated perturbations in GIST (Fig.	('perturbations', 'Var', (328, 341))	('siFOXF1', 'Var', (300, 307))	('Mouse', 'Species', '10090', (216, 221))	('GSEA', 'Chemical', '-', (30, 34))	('siETV1-mediated', 'Gene', (312, 327))	('human', 'Species', '9606', (160, 165))
598329	29162563	Additional highly negatively enriched gene sets with FOXF1 knockdown included significantly downregulated genes with shRNA-mediated ETV1 knockdown in GIST cells (ETV1 KD GIST48 DN), significantly downregulated genes with imatinib (a KIT inhibitor) treatment in GIST882 cells, as well as cell cycle regulated genes (Supplementary Fig.	('imatinib', 'Chemical', 'MESH:D000068877', (221, 229))	('FOXF1', 'Gene', (53, 58))	('downregulated', 'NegReg', (196, 209))	('knockdown', 'Var', (137, 146))	('ETV1', 'Gene', (132, 136))	('knockdown', 'Var', (59, 68))	('genes', 'MPA', (106, 111))	('downregulated', 'NegReg', (92, 105))
598330	29162563	Integrative analyses of FOXF1 and ETV1-cistrome with corresponding transcriptome revealed that the genes with more FOXF1 or ETV1 enhancer peaks were significantly correlated with expression changes in FOXF1 knockdown (Fig.	('expression', 'MPA', (179, 189))	('FOXF1', 'Gene', (201, 206))	('knockdown', 'Var', (207, 216))	('ETV1', 'Gene', (124, 128))	('rat', 'Species', '10116', (5, 8))	('more', 'PosReg', (110, 114))	('enhancer', 'PosReg', (129, 137))	('FOXF1', 'Gene', (115, 120))
598335	29162563	Examination of representative ETV1/FOXF1 co-bound peaks (e.g., KIT and GPR20 loci) and ETV1 only enhancer and promoter peaks (e.g., HES1, ACTB, SNAP20) illustrates the differential effect of FOXF1 knockdown on ETV1 binding (Fig.	('ETV1/FOXF1', 'Gene', (30, 40))	('FOXF1', 'Gene', (191, 196))	('HES1', 'Gene', '3280', (132, 136))	('GPR20', 'Gene', '2843', (71, 76))	('knockdown', 'Var', (197, 206))	('GPR20', 'Gene', (71, 76))	('rat', 'Species', '10116', (158, 161))	('HES1', 'Gene', (132, 136))	('ACTB', 'Gene', '60', (138, 142))	('ACTB', 'Gene', (138, 142))
598337	29162563	While siFOXF1 did not significantly affect the HA-ETV1 protein level, it resulted in significant reduction of HA-ETV1 binding at the ETV1/FOXF1 co-localized KIT enhancers, but not in ETV1-only HES1 enhancers (Fig.	('reduction', 'NegReg', (97, 106))	('siFOXF1', 'Var', (6, 13))	('HES1', 'Gene', '3280', (193, 197))	('binding', 'Interaction', (118, 125))	('HES1', 'Gene', (193, 197))
598341	29162563	We confirmed doxycycline inducible FOXF1 knockdown and consequent downregulation of KIT and ETV1 protein (Fig.	('FOXF1', 'Gene', (35, 40))	('KIT', 'Protein', (84, 87))	('downregulation', 'NegReg', (66, 80))	('doxycycline', 'Chemical', 'MESH:D004318', (13, 24))	('ETV1 protein', 'Protein', (92, 104))	('knockdown', 'Var', (41, 50))
598342	29162563	Since the mutant KIT proteins have previously been shown to preferentially localize to the endoplasmic reticulum (ER) and the Golgi apparatus, and the wild-type KIT to the plasma membrane, we analyzed the cell-surface and total (including both intracellular and surface) KIT protein levels.	('localize', 'MPA', (75, 83))	('mutant', 'Var', (10, 16))	('rat', 'Species', '10116', (136, 139))	('preferentially', 'PosReg', (60, 74))	('proteins', 'Protein', (21, 29))	('KIT', 'Gene', (17, 20))
598343	29162563	S5B and C), suggesting that FOXF1 regulates both the wild-type and mutant KIT expression levels.	('S5B', 'Gene', '5711', (0, 3))	('regulates', 'Reg', (34, 43))	('S5B', 'Gene', (0, 3))	('KIT', 'Gene', (74, 77))	('mutant', 'Var', (67, 73))	('expression levels', 'MPA', (78, 95))
598345	29162563	In all three GIST cell lines, after doxycycline administration, there was an increased percentage of cells in G1-phase and decreased percentage of cells in S-phase (Fig.	('rat', 'Species', '10116', (56, 59))	('decreased', 'NegReg', (123, 132))	('doxycycline', 'Chemical', 'MESH:D004318', (36, 47))	('S-phase', 'MPA', (156, 163))	('increased', 'PosReg', (77, 86))	('doxycycline', 'Var', (36, 47))
598349	29162563	Homozygous Foxf1f-HA-Foxf1/f-HA-Foxf1mice were viable, fertile, and born with Mendelian ratios, indicating that the HA-tag did not perturb the normal function of Foxf1.	('Foxf1', 'Gene', (162, 167))	('Foxf1f-HA-Foxf1/f-HA-Foxf1mice', 'Var', (11, 41))	('rat', 'Species', '10116', (88, 91))	('perturb', 'Reg', (131, 138))
598354	29162563	We generated the compound KitV558Delta/+; Foxf1f-HA-Foxf1/f-HA-Foxf1f; Rosa26Cre-ERT2 mice and conditionally deleted the HA-Foxf1 by tamoxifen (TAM) administration in adult mice with already developed GIST-like tumors.	('Rosa26', 'Gene', '14910', (71, 77))	('GIST-like tumors', 'Disease', 'MESH:D046152', (201, 217))	('tamoxifen', 'Chemical', 'MESH:D013629', (133, 142))	('TAM', 'Chemical', 'MESH:D013629', (144, 147))	('GIST-like tumors', 'Disease', (201, 217))	('Rosa26', 'Gene', (71, 77))	('ERT2', 'Gene', '26417', (81, 85))	('mice', 'Species', '10090', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('rat', 'Species', '10116', (157, 160))	('rat', 'Species', '10116', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('ERT2', 'Gene', (81, 85))	('deleted', 'Var', (109, 116))	('KitV558Delta/+', 'Var', (26, 40))	('HA-Foxf1', 'Gene', (121, 129))	('mice', 'Species', '10090', (173, 177))
598355	29162563	Compared to corn oil control, TAM administration led to expected deletion of HA-Foxf1 in cecal GIST, and resulted in significant reduction of Kit protein levels by immunofluorescence and IHC (Fig.	('Kit protein levels', 'MPA', (142, 160))	('reduction', 'NegReg', (129, 138))	('corn', 'Species', '4577', (12, 16))	('TAM', 'Chemical', 'MESH:D013629', (30, 33))	('HA-Foxf1', 'Gene', (77, 85))	('deletion', 'Var', (65, 73))	('rat', 'Species', '10116', (42, 45))
598356	29162563	HA-Foxf1 deletion in murine GIST tumors also resulted in profound reduction of Etv1 and Kit levels by immunoblots, significant reduction of tumor weight and proliferation index by Ki67, as well as a significant increase in apoptosis measured by cleaved-caspase 3 IHC (Fig.	('GIST tumors', 'Disease', (28, 39))	('Ki67', 'Gene', (180, 184))	('deletion', 'Var', (9, 17))	('Kit levels', 'MPA', (88, 98))	('increase', 'PosReg', (211, 219))	('reduction of tumor weight', 'Disease', 'MESH:D015431', (127, 152))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('reduction of tumor weight', 'Disease', (127, 152))	('Ki67', 'Gene', '17345', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('apoptosis', 'MPA', (223, 232))	('HA-Foxf1', 'Gene', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('rat', 'Species', '10116', (164, 167))	('murine', 'Species', '10090', (21, 27))	('GIST tumors', 'Disease', 'MESH:D046152', (28, 39))	('Etv1', 'MPA', (79, 83))	('reduction', 'NegReg', (66, 75))
598358	29162563	Furthermore, HA-Foxf1 ablation also resulted in reduction of the ICC hyperplasia of the large intestine of the murine models (Supplementary Fig.	('reduction of the ICC hyperplasia', 'Disease', 'MESH:C566123', (48, 80))	('reduction of the ICC hyperplasia', 'Disease', (48, 80))	('ablation', 'Var', (22, 30))	('HA-Foxf1', 'Gene', (13, 21))	('murine', 'Species', '10090', (111, 117))
598366	29162563	It is conceivable that signaling can crosstalk with FOXF1 at multiple levels, including signaling dependent modification of FOXF1 itself that may affect FOXF1 binding affinity and/or specificity to chromatin and its transcriptional activity, signaling-dependent modification of the chromatin template that FOXF1 operates as recently demonstrated in breast cancer, or signaling-dependent modification of FOXF1 co-activator and other cofactor binding to chromatin.	('FOXF1', 'Gene', (124, 129))	('FOXF1', 'Gene', (153, 158))	('transcriptional activity', 'MPA', (216, 240))	('breast cancer', 'Disease', 'MESH:D001943', (349, 362))	('FOXF1', 'Gene', (403, 408))	('modification', 'Reg', (387, 399))	('breast cancer', 'Phenotype', 'HP:0003002', (349, 362))	('breast cancer', 'Disease', (349, 362))	('affect', 'Reg', (146, 152))	('rat', 'Species', '10116', (315, 318))	('specificity', 'MPA', (183, 194))	('modification', 'Var', (108, 120))	('binding', 'Interaction', (441, 448))	('rat', 'Species', '10116', (340, 343))	('FOXF1', 'Gene', (52, 57))	('binding affinity', 'Interaction', (159, 175))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))
598384	29162563	We performed GSEA on 2 transcriptional profiles: GIST48 cells treated with siETV1 vs. siSCR control; and GIST48 cells treated with siFOXF1 vs. siSCR control.	('siFOXF1', 'Var', (131, 138))	('siETV1', 'Var', (75, 81))	('GSEA', 'Chemical', '-', (13, 17))
598421	29162563	ES cells with the appropriate Foxf1f-HA-Foxf1 -targeted locus were used to generate chimeric mice by injecting Foxf1f-HA-Foxf1 ES cells into mouse blastocysts.	('blastocysts', 'Disease', (147, 158))	('mouse', 'Species', '10090', (141, 146))	('Foxf1f-HA-Foxf1', 'Var', (111, 126))	('mice', 'Species', '10090', (93, 97))	('rat', 'Species', '10116', (79, 82))	('blastocysts', 'Disease', 'MESH:D020964', (147, 158))
598425	29162563	Kit Delta558V/+;Foxf1f-HA-Foxf1/f-HA-Foxf1; Rosa26 Cre-ERT2/+ and KitDelta558V/+; Foxf1f-HA-Foxf1/f-HA-Foxf1; Rosa26 Cre-ERT2/Cre-ERT2 mice were generated through standard mouse breeding within the MSKCC animal facility.	('rat', 'Species', '10116', (149, 152))	('ERT2', 'Gene', (121, 125))	('ERT2', 'Gene', (55, 59))	('Rosa26', 'Gene', (110, 116))	('Rosa26', 'Gene', '14910', (44, 50))	('ERT2', 'Gene', '26417', (130, 134))	('Foxf1f-HA-Foxf1/f-HA-Foxf1', 'Var', (82, 108))	('mouse', 'Species', '10090', (172, 177))	('mice', 'Species', '10090', (135, 139))	('Rosa26', 'Gene', (44, 50))	('ERT2', 'Gene', '26417', (55, 59))	('ERT2', 'Gene', (130, 134))	('Rosa26', 'Gene', '14910', (110, 116))	('ERT2', 'Gene', '26417', (121, 125))
598432	29162563	The exposure, threshold, and maximum were identical between tamoxifen-treated and corn oil-treated controls of Foxf1f-HA-Foxf1/f-HA-Foxf1; Rosa26 CreERT2/+ or Kit Delta558V/+; Foxf1f-HA-Foxf1/f-HA-Foxf1; Rosa26 CreERT2/CreERT2 images.	('ERT2', 'Gene', '26417', (214, 218))	('tamoxifen', 'Chemical', 'MESH:D013629', (60, 69))	('Rosa26', 'Gene', (139, 145))	('ERT2', 'Gene', (149, 153))	('Delta558V/+; Foxf1f-HA-Foxf1/f-HA-Foxf1', 'Var', (163, 202))	('Rosa26', 'Gene', (204, 210))	('ERT2', 'Gene', '26417', (222, 226))	('ERT2', 'Gene', (214, 218))	('corn', 'Species', '4577', (82, 86))	('Foxf1f-HA-Foxf1/f-HA-Foxf1', 'Var', (111, 137))	('ERT2', 'Gene', '26417', (149, 153))	('Foxf1f-HA-Foxf1/f-HA-Foxf1', 'Var', (176, 202))	('Rosa26', 'Gene', '14910', (139, 145))	('ERT2', 'Gene', (222, 226))	('Rosa26', 'Gene', '14910', (204, 210))
598435	29162563	RNA-seq expression profile of ETV1 or FOXF1 knockdown (siSCR vs. siETV1 vs. siFOXF1) in GIST48 cells; ETV1 ChIP-seq in steady-state MDA-PCa2b cells; ETV1 ChIP-seq and FOXF1 ChIP-seq in steady-state GIST-T1 cells; FOXF1 ChIP-seq in steady-state GIST48 cells; ETV1 ChIP-seq, FOXF1 ChIP-seq, H3K4Me1 ChIP-seq and H3K4Me3 ChIP-seq of ETV1 or FOXF1 knockdown (siSCR vs. siETV1 vs. siFOXF1) in GIST48 cells; ATAC-seq of ETV1 or FOXF1 knockdown (siSCR vs. siETV1 vs. siFOXF1) in GIST48 cells, GIST882 and GIST-T1 cells.	('GIST-T1', 'CellLine', 'CVCL:4976', (498, 505))	('knockdown', 'Var', (428, 437))	('GIST-T1', 'CellLine', 'CVCL:4976', (198, 205))	('FOXF1', 'Gene', (422, 427))	('MDA-PCa2b', 'CellLine', 'CVCL:4748', (132, 141))	('ETV1', 'Gene', (414, 418))
598481	27043621	demonstrated that a mixture of amino acids and other substances (including l-arginine, l-histidine, l-methionine, l-phenylalanine, l-tyrosine, l-tryptophan, l-ascorbate, d-biotin, pyridoxine, riboflavin, adenine, l-malate) had a selective in vitro toxic effect against a variety of tumor cell lines, and that this active mixture selectively induced the apoptosis of cancer cells in vitro.	('tumor', 'Disease', (282, 287))	('l-histidine', 'Var', (87, 98))	('cancer', 'Disease', (366, 372))	('l-phenylalanine', 'Chemical', 'MESH:D010649', (114, 129))	('l-ascorbate', 'Chemical', 'MESH:D001205', (157, 168))	('d-biotin', 'Chemical', 'MESH:D001710', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('l-phenylalanine', 'Var', (114, 129))	('riboflavin', 'Chemical', 'MESH:D012256', (192, 202))	('pyridoxine', 'Chemical', 'MESH:D011736', (180, 190))	('adenine', 'Chemical', 'MESH:D000225', (204, 211))	('induced', 'Reg', (341, 348))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('l-tyrosine', 'Chemical', 'MESH:D014443', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('l-tyrosine', 'Var', (131, 141))	('apoptosis', 'CPA', (353, 362))	('l-tryptophan', 'Chemical', 'MESH:D014364', (143, 155))	('l-arginine', 'Chemical', 'MESH:D001120', (75, 85))	('l-arginine', 'Var', (75, 85))	('l-malate', 'Chemical', '-', (213, 221))	('l-histidine', 'Chemical', 'MESH:D006639', (87, 98))	('l-tryptophan', 'Var', (143, 155))	('l-methionine', 'Chemical', 'MESH:D008715', (100, 112))	('l-methionine', 'Var', (100, 112))
598485	27043621	Apoptosis and autophagy may be co-regulated in the same directions, and the anti-apoptotic Bcl-2 and Bcl-xL proteins negatively regulate autophagy by binding to Beclin-1 (mammalian Atg6), and apoptosis can suppress autophagy by upregulating the proapoptotic protein Bax and enhancing caspase-mediated cleavage of Beclin-1.	('apoptosis', 'Var', (192, 201))	('caspase-mediated cleavage', 'MPA', (284, 309))	('Atg6', 'Gene', (181, 185))	('negatively', 'NegReg', (117, 127))	('Bcl-xL', 'Gene', (101, 107))	('Bax', 'Protein', (266, 269))	('Atg6', 'Gene', '8678', (181, 185))	('enhancing', 'PosReg', (274, 283))	('Beclin-1', 'Protein', (313, 321))	('Bcl-xL', 'Gene', '598', (101, 107))	('autophagy', 'CPA', (137, 146))	('mammalian', 'Species', '9606', (171, 180))	('suppress', 'NegReg', (206, 214))	('autophagy', 'CPA', (215, 224))	('upregulating', 'PosReg', (228, 240))	('binding', 'Interaction', (150, 157))
598499	27043621	Group A received subcutaneous saline and 4 different doses of oral saline alone (0 mL/20 g, 0.03 mL/20 g, 0.06 mL/20 g, or 0.12 mL/20 g; n = 10 in each treatment).	('saline', 'Chemical', 'MESH:D012965', (67, 73))	('0.03 mL/20', 'Var', (92, 102))	('0.06 mL/20 g', 'Var', (106, 118))	('saline', 'Chemical', 'MESH:D012965', (30, 36))
598534	27043621	For mice with tumors that were given CTX, tumor growth was significantly less for mice given oral MAA (Group D) than for mice given oral saline, and this effect was dose-dependent in terms of tumor weight (D1.0x and D2.0x groups) and tumor weight/body weight (D2.0x group).	('tumor', 'Disease', (234, 239))	('saline', 'Chemical', 'MESH:D012965', (137, 143))	('MAA', 'Chemical', '-', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('less', 'NegReg', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('CTX', 'Disease', (37, 40))	('tumor', 'Disease', (42, 47))	('mice', 'Species', '10090', (4, 8))	('D2.0x', 'Var', (216, 221))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('mice', 'Species', '10090', (82, 86))	('tumor', 'Disease', (192, 197))	('tumors', 'Disease', (14, 20))	('mice', 'Species', '10090', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('CTX', 'Disease', 'MESH:D019294', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
598542	27043621	Thus, MAA increased CTX-induced tumor apoptosis in a dose-dependent manner.	('CTX', 'Disease', (20, 23))	('CTX', 'Disease', 'MESH:D019294', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('MAA', 'Var', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('MAA', 'Chemical', '-', (6, 9))	('tumor', 'Disease', (32, 37))	('increased', 'PosReg', (10, 19))
598567	27043621	Dysregulation of apoptosis frequently accompanies cancer pathogenesis.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Dysregulation', 'Var', (0, 13))	('apoptosis', 'CPA', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('accompanies', 'Reg', (38, 49))
598568	27043621	Diverse nutrient supplements or deprivations of substrates such as amino acids, selenium, and the cruciferous vegetable constituent phenethyl isothiocyanate, may promote apoptosis and tumor regression.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('selenium', 'Chemical', 'MESH:D012643', (80, 88))	('deprivations', 'Var', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('phenethyl isothiocyanate', 'Chemical', 'MESH:C058305', (132, 156))	('promote', 'PosReg', (162, 169))	('apoptosis', 'CPA', (170, 179))
598571	27043621	There is evidence that inhibition of autophagy can induce apoptosis in human hepatoma cell line HepG2.	('inhibition', 'Var', (23, 33))	('autophagy', 'CPA', (37, 46))	('apoptosis', 'CPA', (58, 67))	('hepatoma', 'Disease', (77, 85))	('hepatoma', 'Disease', 'MESH:D006528', (77, 85))	('human', 'Species', '9606', (71, 76))	('HepG2', 'CellLine', 'CVCL:0027', (96, 101))
598574	27043621	MAA, 3-methyladenine, and Atg5 siRNA inhibited autophagy, decreased LC3 II expression, and increased cell apoptosis.	('LC3', 'Gene', (68, 71))	('Atg5', 'Gene', (26, 30))	('cell apoptosis', 'CPA', (101, 115))	('inhibited', 'NegReg', (37, 46))	('decreased', 'NegReg', (58, 67))	('Atg5', 'Gene', '11793', (26, 30))	('3-methyladenine', 'Chemical', 'MESH:C025946', (5, 20))	('3-methyladenine', 'Var', (5, 20))	('MAA', 'Chemical', '-', (0, 3))	('increased', 'PosReg', (91, 100))	('autophagy', 'CPA', (47, 56))	('LC3', 'Gene', '66734', (68, 71))
598583	27043621	In agreement, previous research indicated that a mixture of amino acids with 5-fluorouracil or cisplatin led to enhanced tumor inhibition through the mitochondrial apoptosis pathway and to G1 arrest in cancer cells.	('enhanced', 'PosReg', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('arrest', 'Disease', (192, 198))	('5-fluorouracil', 'Var', (77, 91))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (77, 91))	('tumor', 'Disease', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('mitochondrial apoptosis pathway', 'Pathway', (150, 181))	('cancer', 'Disease', (202, 208))	('arrest', 'Disease', 'MESH:D006323', (192, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
598664	26363055	1A, we observed populations of ALDHbright cells for MDA-MB-231 (breast adenocarcinoma), U87MG (glioblastoma), A673 (Ewing's sarcoma), BxPC3 (pancreatic adenocarcinoma), and PANC-1 (pancreatic adenocarcinoma).	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (116, 131))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (52, 62))	('ALDH', 'Gene', '11670', (31, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (181, 206))	('BxPC3', 'CellLine', 'CVCL:0186', (134, 139))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (116, 131))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (141, 166))	('PANC-1', 'Gene', (173, 179))	('U87MG', 'CellLine', 'CVCL:0022', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (64, 85))	('A673', 'Var', (110, 114))	("Ewing's sarcoma", 'Disease', (116, 131))	('PANC-1', 'Gene', '104066', (173, 179))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (181, 206))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('pancreatic adenocarcinoma', 'Disease', (181, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('breast adenocarcinoma', 'Disease', (64, 85))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (141, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('U87MG', 'Var', (88, 93))	('pancreatic adenocarcinoma', 'Disease', (141, 166))	('MDA-MB-231', 'Gene', (52, 62))	('ALDH', 'Gene', (31, 35))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (64, 85))	('glioblastoma', 'Disease', (95, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))
598671	26363055	We then coincubated allogeneic activated human NK cells with the indicated tumor cell lines for 18 h. With increasing E:T ratios, we observed significant reductions in the frequency of remaining live tumor cells that were ALDHbright (Fig.	('ALDH', 'Gene', '11670', (222, 226))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('human', 'Species', '9606', (41, 46))	('ALDH', 'Gene', (222, 226))	('tumor', 'Disease', (200, 205))	('E:T ratios', 'Var', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('reductions', 'NegReg', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
598700	26363055	Surface expression of NCR ligands via receptor/Fc fragment chimeras did not reveal expression of NCR ligands on the primary tumors probed (data not shown).	('primary tumors', 'Disease', 'MESH:D009369', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('NCR', 'Gene', '4827', (97, 100))	('NCR', 'Gene', (97, 100))	('chimeras', 'Var', (59, 67))	('NCR', 'Gene', '4827', (22, 25))	('NCR', 'Gene', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('primary tumors', 'Disease', (116, 130))
598707	26363055	5A and 5C, blockade of NKG2D significantly inhibited NK killing of whole tumor populations in the primary pancreatic adenocarcinoma sample (FPA2) and PANC-1 cell line.	('pancreatic adenocarcinoma', 'Disease', (106, 131))	('NK killing', 'MPA', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('inhibited', 'NegReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (106, 131))	('PANC-1', 'Gene', '104066', (150, 156))	('NKG2D', 'Gene', '22914', (23, 28))	('tumor', 'Disease', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('PANC-1', 'Gene', (150, 156))	('blockade', 'Var', (11, 19))	('NKG2D', 'Gene', (23, 28))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (106, 131))
598709	26363055	Taken together, these data show that blockade of NKG2D ligands diminished the overall killing of unsorted target cells (Fig.	('killing of unsorted target cells', 'CPA', (86, 118))	('NKG2D', 'Gene', '22914', (49, 54))	('blockade', 'Var', (37, 45))	('NKG2D', 'Gene', (49, 54))	('diminished', 'NegReg', (63, 73))
598731	26363055	Twenty days after NK treatment, mice treated with NK cell transfer showed a trend toward decreased bioluminescence when compared with untreated mice (Fig.	('NK cell transfer', 'Var', (50, 66))	('mice', 'Species', '10090', (144, 148))	('mice', 'Species', '10090', (32, 36))	('bioluminescence', 'MPA', (99, 114))	('decreased', 'NegReg', (89, 98))
598745	26363055	These authors also reported that inhibition of differentiation or reversion of cells to a less differentiated phenotype by blocking NF-kappaB or targeted knockdown of COX2 significantly increased NK cell effector functions.	('differentiation', 'CPA', (47, 62))	('NF-kappaB', 'Protein', (132, 141))	('COX2', 'Gene', (167, 171))	('increased', 'PosReg', (186, 195))	('NK cell effector functions', 'CPA', (196, 222))	('COX2', 'Gene', '4513', (167, 171))	('knockdown', 'Var', (154, 163))	('blocking', 'NegReg', (123, 131))
598748	26363055	Additionally, CICs were shown to express lower levels of MHC class I on their surface than the "differentiated" tumor cells, and MHC class I molecules are known to inhibit NK recognition and function.	('CIC', 'Gene', (14, 17))	('MHC class I', 'Var', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('lower', 'NegReg', (41, 46))	('inhibit', 'NegReg', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('function', 'MPA', (191, 199))	('CIC', 'Gene', '23152', (14, 17))	('tumor', 'Disease', (112, 117))
598767	25500077	New biological knowledge such as the discovery of the important role played by cancer stem cells, genetics, and epigenetic changes on resistance to treatment and eventual prognosis has shown that factors other than those traditionally measured and tested can be detrimental to treatment outcome.	('epigenetic changes', 'Var', (112, 130))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
598809	25500077	When normalization of the three most stable genes to the geometric mean of the same three genes, the degradation was - 0.03 (95% CI: - 0.09 to 0.03), 0.00 (95% CI: - 0.03 to 0.03), and 0.00 (95% CI: - 0.04 to 0.03) for PPIA, SF3A1, and MRPL19, respectively (Figure 3b).	('MRPL19', 'Gene', (236, 242))	('SF3A1', 'Gene', (225, 230))	('MRPL19', 'Gene', '9801', (236, 242))	('0.00', 'Var', (185, 189))	('PPIA', 'Gene', (219, 223))	('SF3A1', 'Gene', '10291', (225, 230))	('PPIA', 'Gene', '5478', (219, 223))	('0.00', 'Var', (150, 154))
598830	24994062	We show that Atm plays a role in mediating survival in the face of both spontaneous and induced DNA damage, and that Aag deficiency not only promotes overall survival, but also alters the tumor spectrum in Atm-/- mice.	('tumor', 'Disease', (188, 193))	('Atm', 'Gene', (206, 209))	('mice', 'Species', '10090', (213, 217))	('Aag', 'Gene', (117, 120))	('deficiency', 'Var', (121, 131))	('Atm', 'Gene', '11920', (13, 16))	('Atm', 'Gene', '11920', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('promotes', 'PosReg', (141, 149))	('Atm', 'Gene', (13, 16))	('alters', 'Reg', (177, 183))
598834	24994062	Further demonstrating the importance of unrepaired DNA damage in aging, mice or patients carrying mutations in the transcription-coupled branch of nucleotide excision repair (NER) suffer from a premature onset of aging-related symptoms and consequent shortening of lifespan, but interestingly, with the exception of skin cancers, the decreased longevity occurs in the absence of increased cancer development (reviewed in ).	('premature onset of aging-', 'Phenotype', 'HP:0007495', (194, 219))	('skin cancers', 'Disease', 'MESH:D012878', (316, 328))	('cancers', 'Phenotype', 'HP:0002664', (321, 328))	('patients', 'Species', '9606', (80, 88))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('cancer', 'Disease', (321, 327))	('mutations', 'Var', (98, 107))	('decreased', 'NegReg', (334, 343))	('skin cancers', 'Phenotype', 'HP:0008069', (316, 328))	('skin cancers', 'Disease', (316, 328))	('mice', 'Species', '10090', (72, 76))	('longevity', 'CPA', (344, 353))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('lifespan', 'CPA', (265, 273))	('cancer', 'Disease', (389, 395))	('cancer', 'Disease', 'MESH:D009369', (389, 395))
598835	24994062	Inactivating mutations that disrupt the maintenance of genome stability can decrease longevity through either increasing cancer predisposition or causing more general premature aging and progeroid-like characteristics (reviewed in).	('longevity', 'CPA', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('premature aging', 'CPA', (167, 182))	('causing', 'Reg', (146, 153))	('Inactivating mutations', 'Var', (0, 22))	('increasing', 'PosReg', (110, 120))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('decrease', 'NegReg', (76, 84))	('cancer', 'Disease', (121, 127))	('progeroid-like characteristics', 'CPA', (187, 217))
598837	24994062	Cancer-prone Li-Fraumeni and ataxia telangiectasia (AT) patients exhibit germline mutations in two important DNA damage response proteins, namely p53 and ataxia telangiectasia mutated (ATM), respectively.	('Li-Fraumeni', 'Disease', (13, 24))	('ataxia telangiectasia', 'Disease', (29, 50))	('patients', 'Species', '9606', (56, 64))	('p53', 'Gene', (146, 149))	('telangiectasia', 'Phenotype', 'HP:0001009', (36, 50))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (29, 50))	('ataxia telangiectasia mutated', 'Gene', (154, 183))	('mutations', 'Var', (82, 91))	('ataxia', 'Phenotype', 'HP:0001251', (29, 35))	('ataxia telangiectasia mutated', 'Gene', '472', (154, 183))	('telangiectasia', 'Phenotype', 'HP:0001009', (161, 175))	('AT', 'Disease', 'None', (185, 187))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (13, 24))	('AT', 'Disease', 'None', (52, 54))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (154, 175))	('ataxia', 'Phenotype', 'HP:0001251', (154, 160))
598845	24994062	BER is initiated when a damaged DNA base is recognized and excised by a DNA glycosylase; alkyladenine DNA glycosylase (Aag, a.k.a Mpg) recognizes numerous alkylated DNA base lesions, including 3-methyladenine (3meA) and 7-methylguanine (7meG) in mammals.	('3-methyladenine', 'Chemical', 'MESH:C025946', (193, 208))	('3-methyladenine', 'Var', (193, 208))	('alkyladenine DNA glycosylase', 'Gene', (89, 117))	('Mpg', 'Gene', '268395', (130, 133))	('7-methylguanine', 'Chemical', 'MESH:C008450', (220, 235))	('alkyladenine DNA glycosylase', 'Gene', '268395', (89, 117))	('Mpg', 'Gene', (130, 133))
598849	24994062	The mismatch repair (MMR) pathway recognizes O6MeG:thymine (O6MeG:T) mismatches and subsequent MMR processing plays an essential role in alkylation-induced cytotoxicity.	('cytotoxicity', 'Disease', (156, 168))	('O6MeG', 'Chemical', 'MESH:C008449', (60, 65))	('mismatches', 'Var', (69, 79))	('cytotoxicity', 'Disease', 'MESH:D064420', (156, 168))	('O6MeG', 'Var', (45, 50))	('thymine', 'Chemical', 'MESH:D013941', (51, 58))	('O6MeG', 'Chemical', 'MESH:C008449', (45, 50))
598850	24994062	MutSalpha, a heterodimer of Msh2 and Msh6 MMR proteins, recognizes O6MeG:T mispairs, and this recognition is required for the induction of apoptosis.	('Msh2', 'Gene', '17685', (28, 32))	('O6MeG', 'Var', (67, 72))	('Msh2', 'Gene', (28, 32))	('O6MeG', 'Chemical', 'MESH:C008449', (67, 72))
598851	24994062	The MMR pathway then engages in futile cycles of Exonuclease 1 (Exo1)-mediated excision and DNA polymerase resynthesis at O6MeG:T mismatches, with excision and reinsertion of the thymine opposite O6MeG; this results in persistent strand breaks that ultimately culminate in the formation of double-strand DNA breaks at collapsed replication forks (reviewed in).	('results in', 'Reg', (208, 218))	('strand breaks', 'MPA', (230, 243))	('O6MeG', 'Chemical', 'MESH:C008449', (122, 127))	('Exo1', 'Gene', '26909', (64, 68))	('Exo1', 'Gene', (64, 68))	('O6MeG', 'Chemical', 'MESH:C008449', (196, 201))	('thymine', 'Chemical', 'MESH:D013941', (179, 186))	('Exonuclease 1', 'Gene', (49, 62))	('T mismatches', 'Var', (128, 140))	('Exonuclease 1', 'Gene', '26909', (49, 62))	('double-strand DNA breaks', 'MPA', (290, 314))
598854	24994062	Intriguingly, transgenic C3HeB/FeJ male mice overexpressing Mgmt are protected against spontaneous hepatocellular carcinomas in a susceptible mouse strain, suggesting a role for O6MeG lesions in spontaneous tumors in a predisposed background and perhaps enhanced overall survival.	('transgenic', 'Species', '10090', (14, 24))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (99, 124))	('Mgmt', 'Gene', (60, 64))	('hepatocellular carcinomas', 'Disease', (99, 124))	('O6MeG lesions', 'Var', (178, 191))	('mouse', 'Species', '10090', (142, 147))	('O6MeG', 'Chemical', 'MESH:C008449', (178, 183))	('enhanced', 'PosReg', (254, 262))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('Mgmt', 'Gene', '17314', (60, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (99, 124))	('mice', 'Species', '10090', (40, 44))
598856	24994062	Finally, we and others have illustrated the importance of Mgmt- and Aag-initiated DNA repair in chronic inflammation-associated cancer, a frequent aging-associated phenomenon; Aag-/- and Mgmt-/- mice are more susceptible to chronic inflammation-associated colon carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mice', 'Species', '10090', (195, 199))	('colon carcinogenesis', 'Disease', (256, 276))	('Mgmt', 'Gene', '17314', (187, 191))	('susceptible', 'Reg', (209, 220))	('Mgmt', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('chronic inflammation', 'Disease', (96, 116))	('chronic inflammation', 'Disease', (224, 244))	('chronic inflammation', 'Disease', 'MESH:D007249', (224, 244))	('chronic inflammation', 'Disease', 'MESH:D007249', (96, 116))	('Aag-/-', 'Var', (176, 182))	('Mgmt', 'Gene', (187, 191))	('Mgmt', 'Gene', '17314', (58, 62))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (256, 276))	('cancer', 'Disease', (128, 134))
598871	24994062	The large-scale aging studies included detailed histopathological examination to identify pathological features in the mice, including classification of any tumors, to determine whether modulating DNA repair altered tumor incidence and/or tumor spectrum.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (216, 221))	('mice', 'Species', '10090', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('modulating', 'Var', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumors', 'Disease', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Disease', (239, 244))	('altered', 'Reg', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('DNA repair', 'Gene', (197, 207))
598875	24994062	Mice deficient in these proteins exhibit drastically reduced longevity, developing thymic lymphoma within the first year of life.	('longevity', 'CPA', (61, 70))	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('thymic lymphoma', 'Disease', (83, 98))	('reduced', 'NegReg', (53, 60))	('thymic lymphoma', 'Disease', 'MESH:D013953', (83, 98))	('Mice', 'Species', '10090', (0, 4))	('developing', 'Reg', (72, 82))	('deficient', 'Var', (5, 14))
598891	24994062	In stark contrast to the effect of combining Aag-/- or Mgmt-/- with the Atm-/- genotype, we observe virtually identical survival in p53-/-, Aag-/-/p53-/-, and Mgmt-/-/p53-/- mice; all three genotypes exhibited significant and similarly-decreased survival compared to WT mice (p<0.0001) (Figure 3A).	('Mgmt', 'Gene', '17314', (55, 59))	('Mgmt', 'Gene', (159, 163))	('similarly-decreased', 'NegReg', (226, 245))	('Mgmt', 'Gene', '17314', (159, 163))	('mice', 'Species', '10090', (174, 178))	('Atm', 'Gene', (72, 75))	('mice', 'Species', '10090', (270, 274))	('Aag-/-/p53-/-', 'Var', (140, 153))	('p53-/-', 'Var', (132, 138))	('Mgmt', 'Gene', (55, 59))	('Atm', 'Gene', '11920', (72, 75))
598892	24994062	All p53 deficient genotypes exhibited an altered tumor spectrum compared to WT mice, but there was no difference in tumor spectrum between p53-/-, Aag-/-/p53-/-, and Mgmt-/-/p53-/- mice (Figure 3B).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Mgmt', 'Gene', '17314', (166, 170))	('tumor', 'Disease', (116, 121))	('mice', 'Species', '10090', (181, 185))	('altered', 'Reg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mice', 'Species', '10090', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Aag-/-/p53-/-', 'Var', (147, 160))	('p53-/-', 'Var', (139, 145))	('deficient', 'NegReg', (8, 17))	('p53', 'Gene', (4, 7))	('exhibited', 'Reg', (28, 37))	('Mgmt', 'Gene', (166, 170))
598893	24994062	Given the established link between Mgmt and MMR in modulating alkylation-induced cytotoxicity, we investigated whether deficiency of both Mgmt and MMR proteins may cooperate to alter longevity.	('Mgmt', 'Gene', '17314', (138, 142))	('Mgmt', 'Gene', '17314', (35, 39))	('deficiency', 'Var', (119, 129))	('cytotoxicity', 'Disease', (81, 93))	('alter', 'Reg', (177, 182))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('Mgmt', 'Gene', (138, 142))	('longevity', 'CPA', (183, 192))	('Mgmt', 'Gene', (35, 39))
598896	24994062	Figure 4A presents survival data for WT, Mgmt-/-, Msh6-/-, Exo1-/-, Mgmt-/-/Msh6-/- and Mgmt-/-/Exo1-/- mice.	('Mgmt', 'Gene', (88, 92))	('Mgmt', 'Gene', (68, 72))	('mice', 'Species', '10090', (104, 108))	('Msh6-/-', 'Var', (50, 57))	('Mgmt', 'Gene', '17314', (68, 72))	('Mgmt', 'Gene', '17314', (88, 92))	('Mgmt', 'Gene', (41, 45))	('Exo1', 'Gene', '26909', (59, 63))	('Exo1', 'Gene', (59, 63))	('Exo1', 'Gene', '26909', (96, 100))	('Exo1', 'Gene', (96, 100))	('Mgmt', 'Gene', '17314', (41, 45))
598897	24994062	Similar to previous reports, we observe significantly decreased survival in Msh6-/- and Exo1-/-mice compared to WT mice (p<0.0001).	('survival', 'CPA', (64, 72))	('mice', 'Species', '10090', (95, 99))	('Exo1', 'Gene', '26909', (88, 92))	('Msh6-/-', 'Var', (76, 83))	('Exo1', 'Gene', (88, 92))	('decreased', 'NegReg', (54, 63))	('mice', 'Species', '10090', (115, 119))
598902	24994062	Figure 4B shows the incidence of spontaneous pathology in animals with combinations of the Mgmt null allele with either Msh6 or Exo1 null alleles, namely Mgmt-/-, Msh6-/-, Exo1-/-, Mgmt-/-/Msh6-/-, and Mgmt-/-/Exo1-/- mice.	('Exo1', 'Gene', (128, 132))	('Msh6-/-', 'Var', (163, 170))	('Mgmt', 'Gene', (91, 95))	('Mgmt', 'Gene', (154, 158))	('Mgmt', 'Gene', '17314', (91, 95))	('Mgmt', 'Gene', (202, 206))	('Mgmt', 'Gene', '17314', (181, 185))	('Msh6', 'Gene', (120, 124))	('Mgmt', 'Gene', (181, 185))	('Mgmt', 'Gene', '17314', (154, 158))	('Exo1', 'Gene', (210, 214))	('Exo1', 'Gene', '26909', (210, 214))	('Exo1', 'Gene', (172, 176))	('Exo1', 'Gene', '26909', (172, 176))	('mice', 'Species', '10090', (218, 222))	('Mgmt', 'Gene', '17314', (202, 206))	('combinations', 'Interaction', (71, 83))	('Exo1', 'Gene', '26909', (128, 132))
598903	24994062	The majority of the MMR defective animals exhibit lymphomas at the time of death; 70% of Msh6-/-animals and 70.5% of Exo1-/- animals present with lymphoma, consistent with the published literature (Figure 4B).	('Exo1', 'Gene', (117, 121))	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('lymphomas', 'Disease', (50, 59))	('defective', 'Var', (24, 33))	('lymphomas', 'Disease', 'MESH:D008223', (50, 59))	('Msh6-/-animals', 'Var', (89, 103))	('lymphoma', 'Disease', (146, 154))	('lymphomas', 'Phenotype', 'HP:0002665', (50, 59))	('lymphoma', 'Disease', 'MESH:D008223', (146, 154))	('lymphoma', 'Disease', (50, 58))	('MMR', 'Gene', (20, 23))	('lymphoma', 'Phenotype', 'HP:0002665', (146, 154))	('Exo1', 'Gene', '26909', (117, 121))
598904	24994062	The additional inactivation of the Mgmt gene does not significantly alter the tumor spectrum in Msh6 mutant background; 73% of Mgmt-/-/Msh6-/- mice develop lymphoma (Figure 4B).	('Mgmt', 'Gene', '17314', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Mgmt', 'Gene', (127, 131))	('Mgmt', 'Gene', '17314', (127, 131))	('develop', 'PosReg', (148, 155))	('mutant', 'Var', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lymphoma', 'Disease', (156, 164))	('Msh6', 'Gene', (96, 100))	('tumor', 'Disease', (78, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))	('lymphoma', 'Disease', 'MESH:D008223', (156, 164))	('Mgmt', 'Gene', (35, 39))	('mice', 'Species', '10090', (143, 147))
598908	24994062	Aag deficiency resulted in a counter-intuitive increase in longevity in Atm-/- deficient mice, accompanied by alterations in the tumor spectrum (Figures 2A and 2B).	('Aag', 'Gene', (0, 3))	('alterations', 'Reg', (110, 121))	('longevity', 'CPA', (59, 68))	('Atm', 'Gene', (72, 75))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('deficiency', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('increase', 'PosReg', (47, 55))	('tumor', 'Disease', (129, 134))	('Atm', 'Gene', '11920', (72, 75))
598911	24994062	MMS is an SN2 alkylating agent that induces predominantly 7MeG and 3MeA DNA lesions, known Aag substrates.	('MMS', 'Chemical', 'MESH:D008741', (0, 3))	('MMS', 'Var', (0, 3))	('7MeG', 'MPA', (58, 62))	('SN2', 'Gene', (10, 13))	('SN2', 'Gene', '209837', (10, 13))	('induces', 'Reg', (36, 43))
598916	24994062	We also assessed the contribution of Atm to O6meG-mediated cytotoxicity following exposure to the SN1 alkylating agent, N-methyl-N-nitrosourea (MNU), which generates toxic and mutagenic O6MeG, in addition to 7meG and 3meA DNA base lesions.	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('O6MeG', 'Chemical', 'MESH:C008449', (186, 191))	('MNU', 'Chemical', 'MESH:D008770', (144, 147))	('Atm', 'Gene', '11920', (37, 40))	('O6meG', 'Chemical', '-', (44, 49))	('O6MeG', 'Var', (186, 191))	('to 7', 'Species', '1214577', (205, 209))	('cytotoxicity', 'Disease', (59, 71))	('mutagenic', 'Reg', (176, 185))	('N-methyl-N-nitrosourea', 'Chemical', 'MESH:D008770', (120, 142))	('Atm', 'Gene', (37, 40))
598921	24994062	We infer that when O6MeG base lesions are unrepaired (as in the Mgmt-/- cells), Atm plays a pivotal role in modulating the toxicity induced by MMR processing of DNA containing O6MeG DNA lesions.	('Atm', 'Gene', '11920', (80, 83))	('toxicity', 'Disease', (123, 131))	('Mgmt', 'Gene', (64, 68))	('Mgmt', 'Gene', '17314', (64, 68))	('O6MeG', 'Var', (176, 181))	('Atm', 'Gene', (80, 83))	('modulating', 'Reg', (108, 118))	('O6MeG', 'Chemical', 'MESH:C008449', (176, 181))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))	('O6MeG', 'Chemical', 'MESH:C008449', (19, 24))
598923	24994062	We show here that endogenously damaged DNA bases that are substrates for two DNA alkylation repair pathways contribute to long-term survival; mice deficient in both Aag and Mgmt activity exhibit decreased life-span that is statistically significant.	('Aag', 'Gene', (165, 168))	('Mgmt', 'Gene', (173, 177))	('Mgmt', 'Gene', '17314', (173, 177))	('mice', 'Species', '10090', (142, 146))	('deficient', 'Var', (147, 156))	('life-span', 'CPA', (205, 214))	('decreased', 'NegReg', (195, 204))
598925	24994062	We and others have demonstrated that for certain cell types Aag-mediated initiation of BER can lead to cell death, and that Aag deficiency can actually be protective.	('Aag deficiency can actually', 'Disease', (124, 151))	('lead to', 'Reg', (95, 102))	('Aag-mediated', 'Var', (60, 72))	('Aag deficiency can actually', 'Disease', 'MESH:D007153', (124, 151))	('cell death', 'CPA', (103, 113))	('BER', 'Gene', (87, 90))
598926	24994062	Here, we find that Aag deficiency protects Atm-/- mice both in terms of increasing overall longevity and in reducing the development of lymphoma; this protection is consistent with a role for Aag in generating toxic BER intermediates that trigger the DNA damage response orchestrated by Atm.	('deficiency', 'Var', (23, 33))	('lymphoma', 'Disease', (136, 144))	('Atm', 'Gene', '11920', (43, 46))	('Atm', 'Gene', '11920', (287, 290))	('lymphoma', 'Disease', 'MESH:D008223', (136, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('reducing', 'NegReg', (108, 116))	('Aag', 'Gene', (19, 22))	('mice', 'Species', '10090', (50, 54))	('increasing', 'PosReg', (72, 82))	('Atm', 'Gene', (43, 46))	('Atm', 'Gene', (287, 290))	('longevity', 'CPA', (91, 100))
598927	24994062	Further, Aag deficiency provided protection against MMS-induced toxicity in Atm-/- BM cells, ex vivo.	('Atm', 'Gene', '11920', (76, 79))	('deficiency', 'Var', (13, 23))	('Atm', 'Gene', (76, 79))	('MMS', 'Chemical', 'MESH:D008741', (52, 55))	('Aag', 'Gene', (9, 12))	('toxicity', 'Disease', 'MESH:D064420', (64, 72))	('toxicity', 'Disease', (64, 72))
598931	24994062	Interestingly, although ATM is known to phosphorylate, stabilize and activate p53, there is no change in survival in Aag-/-/p53-/- mice, in contrast to enhanced survival in Aag-/-/Atm-/- mice.	('Aag-/-/p53-/-', 'Var', (117, 130))	('Atm', 'Gene', '11920', (180, 183))	('activate', 'PosReg', (69, 77))	('Atm', 'Gene', (180, 183))	('mice', 'Species', '10090', (187, 191))	('p53', 'Gene', (78, 81))	('mice', 'Species', '10090', (131, 135))
598933	24994062	Alternatively, it has been shown previously that Aag physically interacts with and represses p53; therefore genetic deletion of both Aag and p53 would be epistatic and not alter overall survival compared to p53-/- mice.	('p53', 'Gene', (141, 144))	('mice', 'Species', '10090', (214, 218))	('represses', 'NegReg', (83, 92))	('genetic deletion', 'Var', (108, 124))	('Aag', 'Gene', (133, 136))
598946	24994062	EXO1 deficiency is not causative of CMMRD, but EXO1 mutations have been found in diffuse B-cell lymphoma.	('mutations', 'Var', (52, 61))	('found', 'Reg', (72, 77))	('EXO1', 'Gene', (47, 51))	('EXO1', 'Gene', '26909', (0, 4))	('lymphoma', 'Disease', (96, 104))	('EXO1', 'Gene', (0, 4))	('lymphoma', 'Disease', 'MESH:D008223', (96, 104))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (89, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('EXO1', 'Gene', '26909', (47, 51))
598947	24994062	The strong association between MSH6 mutations and lymphoma may explain why Mgmt deficiency was insufficient to change tumor spectrum in Msh6-/- mice, whereas Mgmt-/-/Exo1-/- mice exhibited a shift in tumor spectrum towards histiocytic sarcoma.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('histiocytic sarcoma', 'Disease', (223, 242))	('mice', 'Species', '10090', (174, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('MSH6', 'Gene', '17688', (31, 35))	('insufficient', 'Disease', 'MESH:D000309', (95, 107))	('MSH6', 'Gene', (31, 35))	('Mgmt deficiency', 'Disease', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Mgmt', 'Gene', (75, 79))	('tumor', 'Disease', (200, 205))	('Mgmt', 'Gene', '17314', (75, 79))	('lymphoma', 'Disease', (50, 58))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (223, 242))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('insufficient', 'Disease', (95, 107))	('Mgmt deficiency', 'Disease', 'MESH:D007153', (75, 90))	('Exo1', 'Gene', '26909', (166, 170))	('Exo1', 'Gene', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mice', 'Species', '10090', (144, 148))	('mutations', 'Var', (36, 45))	('Mgmt', 'Gene', (158, 162))	('tumor', 'Disease', (118, 123))	('Mgmt', 'Gene', '17314', (158, 162))
598956	24994062	Trp53-/- mice (B6.129S2-Trp53tm1Tyj, former name C57BL/6J-Trp53tm1Tyj) and Atm-/- mice (129S6/SvEvTac-Atmtm1Awb/J) were purchased from The Jackson Laboratory (Bar Harbor, Maine, USA).	('mice', 'Species', '10090', (82, 86))	('Atm', 'Gene', '11920', (75, 78))	('B6.129S2-Trp53tm1Tyj', 'Var', (15, 35))	('B6.129S2', 'CellLine', 'CVCL:C319', (15, 23))	('Atm', 'Gene', '11920', (102, 105))	('Atm', 'Gene', (75, 78))	('mice', 'Species', '10090', (9, 13))	('Atm', 'Gene', (102, 105))
599101	21264294	Consistent with its anti-neoplastic role, rapamycin can induce cell cycle arrest in a number of KSHV+ lymphoma cell lines.	('KSHV', 'Species', '37296', (96, 100))	('lymphoma', 'Disease', (102, 110))	('lymphoma', 'Disease', 'MESH:D008223', (102, 110))	('cell cycle arrest', 'CPA', (63, 80))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('rapamycin', 'Var', (42, 51))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('rapamycin', 'Chemical', 'MESH:D020123', (42, 51))
599200	21264294	More specifically, rapamycin can cause growth arrest in B cell lymphomas including subsets of EBV+ and of KSHV+ tumors.	('lymphomas', 'Disease', (63, 72))	('lymphomas', 'Disease', 'MESH:D008223', (63, 72))	('KS', 'Phenotype', 'HP:0100726', (106, 108))	('growth arrest', 'Disease', 'MESH:D006323', (39, 52))	('rapamycin', 'Chemical', 'MESH:D020123', (19, 28))	('growth arrest', 'Disease', (39, 52))	('lymphomas', 'Phenotype', 'HP:0002665', (63, 72))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('growth arrest', 'Phenotype', 'HP:0001510', (39, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (63, 71))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('KSHV', 'Species', '37296', (106, 110))	('rapamycin', 'Var', (19, 28))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (56, 72))
599203	21264294	By taking advantage of this cell line in which cell cycle arrest was dissociated from other rapamycin-mediated effects, we demonstrated that rapamycin treatment of cells inhibited the viral lytic cycle.	('viral lytic cycle', 'CPA', (184, 201))	('rapamycin', 'Chemical', 'MESH:D020123', (92, 101))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('rapamycin', 'Var', (141, 150))	('rapamycin', 'Chemical', 'MESH:D020123', (141, 150))	('inhibited', 'NegReg', (170, 179))
599214	21264294	Thus, the expression of vGPCR following the initiation of the lytic cycle likely enhances RTA levels by activating mTOR and enhancing SP1/SP3 mediated transcription of ORF50, providing a positive lytic feedback loop that may promote virion production.	('vGPCR', 'Gene', (24, 29))	('RTA levels', 'MPA', (90, 100))	('mTOR', 'Gene', '2475', (115, 119))	('SP3', 'Gene', (138, 141))	('mTOR', 'Gene', (115, 119))	('vGPCR', 'Gene', '4961465', (24, 29))	('ORF50', 'Gene', '4961526', (168, 173))	('virion production', 'MPA', (233, 250))	('enhances', 'PosReg', (81, 89))	('SP3', 'Gene', '6670', (138, 141))	('enhancing', 'PosReg', (124, 133))	('ORF50', 'Gene', (168, 173))	('promote', 'PosReg', (225, 232))	('expression', 'Var', (10, 20))
599235	21264294	The group's finding that RTA could be post-transcriptionally down-regulated via blockade of Mnk activity is of particular importance, however, as it suggests an additional path with which to block lytic KSHV, particularly in patient tumors that are resistant to rapamycin inhibition.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('lytic', 'MPA', (197, 202))	('blockade', 'Var', (80, 88))	('tumors', 'Disease', (233, 239))	('KSHV', 'Species', '37296', (203, 207))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('KS', 'Phenotype', 'HP:0100726', (203, 205))	('Mnk', 'Protein', (92, 95))	('patient', 'Species', '9606', (225, 232))	('block', 'NegReg', (191, 196))	('rapamycin', 'Chemical', 'MESH:D020123', (262, 271))	('down-regulated', 'NegReg', (61, 75))
599272	30040819	FusionPathway: Prediction of pathways and therapeutic targets associated with gene fusions in cancer Numerous gene fusions have been uncovered across multiple cancer types.	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gene fusions', 'Var', (78, 90))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
599283	30040819	Gene fusions resulting from chromosome rearrangements and chimeric RNAs generated by trans-splicing or read-through events play important roles in cancer.	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('roles', 'Reg', (138, 143))	('chromosome rearrangements', 'Var', (28, 53))	('chimeric RNAs', 'Var', (58, 71))
599285	30040819	Fusions, especially druggable kinase fusions, may serve as therapeutic targets in cancer.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Fusions', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))
599287	30040819	In addition, drug resistance to fusion-targeted therapies, such as resistance to imatinib in chronic myeloid leukemia (CML), may develop in some patients owing to mutations that render a drug unable to bind to its targeted fusion or to the activation of compensatory pathways.	('patients', 'Species', '9606', (145, 153))	('develop', 'Reg', (129, 136))	('drug', 'MPA', (13, 17))	('drug resistance', 'Phenotype', 'HP:0020174', (13, 28))	('mutations', 'Var', (163, 172))	('CML', 'Phenotype', 'HP:0005506', (119, 122))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (93, 117))	('imatinib', 'Chemical', 'MESH:D000068877', (81, 89))	('chronic myeloid leukemia', 'Disease', (93, 117))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (93, 117))	('bind', 'Interaction', (202, 206))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (101, 117))	('unable', 'NegReg', (192, 198))
599289	30040819	recently unified all the protein interactions of the parental proteins of a fusion and found a gene fusion may rewire the protein interaction network in cancer through connecting proteins that did not previously interact in the network.	('proteins', 'Protein', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('rewire', 'Reg', (111, 117))	('fusion', 'Var', (100, 106))	('connecting', 'Reg', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('protein', 'Pathway', (122, 129))
599290	30040819	We demonstrated the capabilities of our approach by applying it to the BCR-ABL1 fusion and two undruggable fusions, EWS-FL1 and FUS-DDIT3.	('FUS', 'Gene', (128, 131))	('FUS', 'Gene', '2521', (128, 131))	('DDIT3', 'Gene', (132, 137))	('BCR-ABL1', 'Gene', (71, 79))	('DDIT3', 'Gene', '1649', (132, 137))	('fusion', 'Var', (80, 86))	('BCR-ABL1', 'Gene', '613;25', (71, 79))	('EWS', 'Gene', '2130', (116, 119))	('EWS', 'Gene', (116, 119))
599303	30040819	The ABL1 portion of all three variants contains tandem SRC homology, the tyrosine kinase domains, SH3 binding sites, a DNA-binding domain, and an actin-binding domain.	('variants', 'Var', (30, 38))	('ABL1', 'Gene', (4, 8))	('binding', 'Interaction', (102, 109))	('ABL1', 'Gene', '25', (4, 8))
599319	30040819	Furthermore, we also compared our predictions of the three BCR-ABL1 variants.	('variants', 'Var', (68, 76))	('BCR-ABL1', 'Gene', '613;25', (59, 67))	('BCR-ABL1', 'Gene', (59, 67))
599320	30040819	Prediction evaluation using the 328 cancer pathway genes (Fig 3C) also indicated that these variants would have almost the same oncogenic impact.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('oncogenic impact', 'CPA', (128, 144))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('variants', 'Var', (92, 100))
599321	30040819	Some studies also have shown that these three variants are equally potent in inducing a CML-like disease in transplanted mice.	('inducing', 'Reg', (77, 85))	('CML-like disease', 'Disease', 'MESH:D015464', (88, 104))	('CML', 'Phenotype', 'HP:0005506', (88, 91))	('CML-like disease', 'Disease', (88, 104))	('variants', 'Var', (46, 54))	('mice', 'Species', '10090', (121, 125))
599322	30040819	Inhibition of BCR-ABL1 fusion by imatinib has proven to be a very successful treatment for CML with the BCR-ABL fusion.	('BCR-ABL', 'Gene', '25', (104, 111))	('CML', 'Disease', (91, 94))	('BCR-ABL1', 'Gene', '613;25', (14, 22))	('imatinib', 'Chemical', 'MESH:D000068877', (33, 41))	('Inhibition', 'Var', (0, 10))	('BCR-ABL', 'Gene', '25', (14, 21))	('BCR-ABL', 'Gene', (14, 21))	('BCR-ABL', 'Gene', (104, 111))	('CML', 'Phenotype', 'HP:0005506', (91, 94))	('BCR-ABL1', 'Gene', (14, 22))
599323	30040819	However, some patients develop imatinib resistance owing to the emergence of BCR-ABL1 point mutations.	('develop', 'Reg', (23, 30))	('imatinib', 'Chemical', 'MESH:D000068877', (31, 39))	('BCR-ABL1', 'Gene', (77, 85))	('point mutations', 'Var', (86, 101))	('patients', 'Species', '9606', (14, 22))	('BCR-ABL1', 'Gene', '613;25', (77, 85))	('imatinib resistance', 'MPA', (31, 50))
599336	30040819	For example, inhibition of JAK2 can overcome imatinib drug resistance in CML.	('imatinib', 'Chemical', 'MESH:D000068877', (45, 53))	('imatinib drug resistance', 'MPA', (45, 69))	('JAK2', 'Gene', '3717', (27, 31))	('inhibition', 'Var', (13, 23))	('CML', 'Phenotype', 'HP:0005506', (73, 76))	('overcome', 'NegReg', (36, 44))	('JAK2', 'Gene', (27, 31))	('drug resistance', 'Phenotype', 'HP:0020174', (54, 69))
599337	30040819	Inhibition of CSNK2A2 by CX-4945 also exhibits anti-tumor activity in chronic lymphocytic leukemia.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CX-4945', 'Var', (25, 32))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (70, 98))	('Inhibition', 'NegReg', (0, 10))	('tumor', 'Disease', (52, 57))	('CSNK2A2', 'Gene', (14, 21))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (78, 98))	('lymphocytic leukemia', 'Disease', (78, 98))	('leukemia', 'Phenotype', 'HP:0001909', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CSNK2A2', 'Gene', '1459', (14, 21))
599339	30040819	In addition, studies also showed that CBL-B is required for the leukemogenesis mediated by BCR-ABL through the negative regulation of bone marrow homing and that CML with the CBL-B mutation is resistant to imatinib.	('bone marrow homing', 'CPA', (134, 152))	('BCR-ABL', 'Gene', (91, 98))	('BCR-ABL', 'Gene', '25', (91, 98))	('CBL-B', 'Gene', (175, 180))	('CBL-B', 'Gene', '868', (175, 180))	('CBL-B', 'Gene', (38, 43))	('mutation', 'Var', (181, 189))	('negative regulation', 'NegReg', (111, 130))	('CBL-B', 'Gene', '868', (38, 43))	('CML', 'Phenotype', 'HP:0005506', (162, 165))	('imatinib', 'Chemical', 'MESH:D000068877', (206, 214))	('leukemogenesis', 'Disease', (64, 78))
599344	30040819	These fusions can produce tumor-specific proteins; thus are potential targets for the development of specific therapies for these sarcomas.	('sarcomas', 'Disease', (130, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('sarcomas', 'Disease', 'MESH:D012509', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('fusions', 'Var', (6, 13))	('proteins', 'Protein', (41, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))
599374	30040819	Diverse drug resistance mechanisms, including pathway-dependent mechanisms (e.g., target reactivation through secondary mutation, downstream activation, or bypass activation) and pathway-independent mechanisms (e.g., tumor microenvironment perturbation), remain major problems for targeted therapies.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('mutation', 'Var', (120, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (8, 23))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('activation', 'PosReg', (141, 151))
599376	30040819	Second, rather than doing pathway analysis of each fusion, ChiPPI performed a pathway enrichment analysis of all the predicted interactors of all the fusions in the three major disease types, leukemia/lymphoma, sarcoma or solid tumors, to identify the over-presented pathways in each of the three cancer types.	('leukemia/lymphoma', 'Disease', 'MESH:D007938', (192, 209))	('lymphoma', 'Phenotype', 'HP:0002665', (201, 209))	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('sarcoma', 'Disease', 'MESH:D012509', (211, 218))	('fusions', 'Var', (150, 157))	('sarcoma', 'Disease', (211, 218))	('solid tumors', 'Disease', 'MESH:D009369', (222, 234))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('leukemia/lymphoma', 'Disease', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('solid tumors', 'Disease', (222, 234))	('leukemia', 'Phenotype', 'HP:0001909', (192, 200))
599410	30083310	During normal development, cell proliferation significantly increases as a consequence of PDGF overexpression and decreases in PDGF null mutants.	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (90, 94))	('cell proliferation', 'CPA', (27, 45))	('PDGF', 'Gene', (90, 94))	('decreases', 'NegReg', (114, 123))	('overexpression', 'PosReg', (95, 109))	('null mutants', 'Var', (132, 144))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (127, 131))	('increases', 'PosReg', (60, 69))	('PDGF', 'Gene', (127, 131))
599415	30083310	The levels of phosphorylation of both PDGFRs and the downstream signaling proteins such as protein kinase B (AKT) and extracellular regulated kinase (ERK) are downregulated by PDGFR antibodies or small molecular tyrosine kinase inhibitors (TKIs).	('PDGFR', 'Gene', (176, 181))	('levels', 'MPA', (4, 10))	('extracellular regulated kinase', 'Gene', (118, 148))	('extracellular regulated kinase', 'Gene', '5594', (118, 148))	('AKT', 'Gene', '207', (109, 112))	('ERK', 'Gene', '5594', (150, 153))	('antibodies', 'Var', (182, 192))	('phosphorylation', 'MPA', (14, 29))	('PDGFRs', 'Gene', (38, 44))	('ERK', 'Gene', (150, 153))	('tyrosine', 'Chemical', 'MESH:D014443', (212, 220))	('downregulated', 'NegReg', (159, 172))	('AKT', 'Gene', (109, 112))
599424	30083310	Experiments using transgenic mice carrying PDGFR-beta receptor mutations suggest a function for PDGF signaling through PI3K in IFP homeostasis by modulating the tension between cells and extracellular matrix structures.	('PDGFR-beta', 'Gene', (43, 53))	('mutations', 'Var', (63, 72))	('transgenic mice', 'Species', '10090', (18, 33))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (96, 100))	('PI3K', 'Gene', (119, 123))	('PDGF', 'Gene', (96, 100))	('IFP homeostasis', 'MPA', (127, 142))	('modulating', 'Reg', (146, 156))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (43, 47))	('PDGFR-beta', 'Gene', '5159', (43, 53))	('PDGF', 'Gene', (43, 47))
599425	30083310	Previous studies reported that the inhibition of PDGFR reduced interstitial hypertension and increased transcapillary transport in tumors.	('hypertension', 'Disease', (76, 88))	('hypertension', 'Phenotype', 'HP:0000822', (76, 88))	('reduced', 'NegReg', (55, 62))	('increased', 'PosReg', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('transcapillary transport', 'MPA', (103, 127))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('hypertension', 'Disease', 'MESH:D006973', (76, 88))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('inhibition', 'Var', (35, 45))	('increased transcapillary transport', 'Phenotype', 'HP:0030005', (93, 127))	('PDGFR', 'Gene', (49, 54))
599434	30083310	A study with 57 osteosarcoma samples showed that high levels of PDGF-AA expression were associated with a significantly lower 5-year disease-free survival compared with low-level expression of PDGF-AA (21.22% vs. 42.72%).	('disease-free survival', 'CPA', (133, 154))	('lower', 'NegReg', (120, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('osteosarcoma', 'Disease', 'MESH:D012516', (16, 28))	('high levels', 'Var', (49, 60))	('PDGF-A', 'Gene', '5154', (193, 199))	('PDGF-A', 'Gene', (193, 199))	('osteosarcoma', 'Phenotype', 'HP:0002669', (16, 28))	('osteosarcoma', 'Disease', (16, 28))	('PDGF-A', 'Gene', '5154', (64, 70))	('PDGF-A', 'Gene', (64, 70))
599488	30083310	Data from phase I and phase 2 trials showed that the adverse effect of most PDGF/PDGFR inhibitors was mild, which allow the opportunity of delivering "add-on" therapy.	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (76, 80))	('PDGF', 'Gene', (76, 80))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (81, 85))	('inhibitors', 'Var', (87, 97))	('PDGF', 'Gene', (81, 85))
599492	30083310	Two possible mechanisms can explain the results of combination drug therapy using PDGF/PDGFR inhibitors.	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (87, 91))	('PDGF', 'Gene', (87, 91))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (82, 86))	('PDGF', 'Gene', (82, 86))	('inhibitors', 'Var', (93, 103))
599498	30083310	The use of PDGF inhibitors could improve hypoxia in tumor tissue, therefore leaving them more sensitive to other drugs.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('improve', 'PosReg', (33, 40))	('inhibitors', 'Var', (16, 26))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (11, 15))	('tumor', 'Disease', (52, 57))	('PDGF', 'Gene', (11, 15))	('leaving', 'Reg', (76, 83))	('hypoxia', 'Disease', (41, 48))	('hypoxia', 'Disease', 'MESH:D000860', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('sensitive', 'MPA', (94, 103))
599499	30083310	The second hypothesis is based on a regulation of tumor interstitial fluid pressure (IFP) brought by PDGF inhibition, which could eventually increase tumor uptake of other agents.	('increase', 'PosReg', (141, 149))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (101, 105))	('PDGF', 'Gene', (101, 105))	('inhibition', 'Var', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (50, 55))
599509	30083310	Although synergistic antiproliferative effects of PDGF/PDGFR inhibitors, such as imatinib and olaratumab, and classical cytotoxic agents (i.e., AMD, cisplatin) were observed in both in vitro and in vivo experiments, the effects of these inhibitors on drug-resistant cells have not been explored.	('olaratumab', 'Chemical', 'MESH:C000589393', (94, 104))	('antiproliferative', 'CPA', (21, 38))	('inhibitors', 'Var', (61, 71))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (55, 59))	('PDGF', 'Gene', (55, 59))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (50, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('PDGF', 'Gene', (50, 54))	('imatinib', 'Chemical', 'MESH:D000068877', (81, 89))	('AMD', 'Disease', 'MESH:D006009', (144, 147))	('AMD', 'Disease', (144, 147))
599512	30083310	The effect of PDGF inhibitors to upregulate drug uptake in tumor cells and to overcome tissue hypoxia has been described above, but the mechanism of reversal of drug is not well understood.	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (14, 18))	('upregulate', 'PosReg', (33, 43))	('PDGF', 'Gene', (14, 18))	('tumor', 'Disease', (59, 64))	('drug uptake', 'CPA', (44, 55))	('inhibitors', 'Var', (19, 29))	('hypoxia', 'Disease', 'MESH:D000860', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('hypoxia', 'Disease', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
599516	30083310	The "add-on" strategy, adding PDGF/PDGFR inhibitors to other existing agents, should be attempted in the future.	('PDGF', 'Gene', (30, 34))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (35, 39))	('PDGF', 'Gene', (35, 39))	('inhibitors', 'Var', (41, 51))	('PDGF', 'Gene', '5154;5155;18591;56034;80310', (30, 34))
599527	29853780	They have no known specific abnormalities (a notable exception is well-differentiated liposarcomas that frequently carry chromosome 12q amplification), and their complex karyotypes are believed to be the result of genomic instability, a hallmark of the cancer phenotype.	('liposarcoma', 'Phenotype', 'HP:0012034', (86, 97))	('liposarcomas', 'Disease', (86, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('chromosome 12q amplification', 'Var', (121, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('hallmark of the cancer', 'Disease', (237, 259))	('hallmark of the cancer', 'Disease', 'MESH:D009369', (237, 259))	('liposarcomas', 'Phenotype', 'HP:0012034', (86, 98))	('genomic instability', 'Var', (214, 233))	('liposarcomas', 'Disease', 'MESH:D008080', (86, 98))
599532	29853780	An even earlier event in the DNA DSB repair process is the phosphorylation of the histone molecule H2AX at serine 139 to gammaH2AX, which accumulates at the sites of damage and recruits other DNA repair proteins.	('serine 139', 'Var', (107, 117))	('serine', 'Chemical', 'MESH:D012694', (107, 113))	('phosphorylation', 'MPA', (59, 74))	('H2AX', 'Gene', '3014', (126, 130))	('H2AX', 'Gene', '3014', (99, 103))	('H2AX', 'Gene', (99, 103))	('gammaH2AX', 'Chemical', '-', (121, 130))	('H2AX', 'Gene', (126, 130))
599546	29853780	The frequency of early and late endogenous DNA DSB repair was measured using gammaH2AX and SCE, respectively, as surrogates for genomic instability and compared to those observed in long-established, commercially available sarcoma cell lines, low SCE tumour cells, and nontumour cells.	('sarcoma', 'Disease', (223, 230))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('tumour', 'Phenotype', 'HP:0002664', (272, 278))	('gammaH2AX', 'Chemical', '-', (77, 86))	('tumour', 'Disease', 'MESH:D009369', (272, 278))	('gammaH2AX', 'Var', (77, 86))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('low SCE tumour', 'Disease', (243, 257))	('tumour', 'Disease', (251, 257))	('tumour', 'Disease', (272, 278))	('low SCE tumour', 'Disease', 'MESH:D009800', (243, 257))	('sarcoma', 'Disease', 'MESH:D012509', (223, 230))
599579	29853780	There was no relationship between the SCE levels and frequency of gammaH2AX foci among the sarcoma cell lines (Spearman's r2=0.029; p=0.99).	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('SCE levels', 'MPA', (38, 48))	('sarcoma', 'Disease', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('gammaH2AX', 'Chemical', '-', (66, 75))	('gammaH2AX', 'Var', (66, 75))
599581	29853780	Conversely, the highest frequency of gammaH2AX foci (>65% of cells showing >10 foci) was observed in dedifferentiated liposarcoma cell lines Shef-DDLPS 01 and Shef-DDLPS 02, whose SCE levels were only moderately elevated with medians of 13 and 14 per 2n metaphase spread, respectively (Table 1 and Figure 2).	('liposarcoma', 'Disease', 'MESH:D008080', (118, 129))	('gammaH2AX', 'Chemical', '-', (37, 46))	('liposarcoma', 'Phenotype', 'HP:0012034', (118, 129))	('gammaH2AX', 'Var', (37, 46))	('liposarcoma', 'Disease', (118, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
599583	29853780	Another notable observation was the more than threefold difference in the frequency of cells showing >10 gammaH2AX foci between w1 and ws variants of Shef-LMS 01, which had very similar SCE levels (Figure 3).	('Shef-LMS 01', 'Gene', (150, 161))	('gammaH2AX', 'Gene', (105, 114))	('gammaH2AX', 'Chemical', '-', (105, 114))	('variants', 'Var', (138, 146))
599610	29853780	Overall, the data, while not sufficient to make firm conclusions about their utility as biomarkers, suggest that there is still much to understand about the relationship between gammaH2AX and SCE in sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (199, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('sarcomas', 'Disease', (199, 207))	('SCE', 'Disease', (192, 195))	('gammaH2AX', 'Chemical', '-', (178, 187))	('gammaH2AX', 'Var', (178, 187))	('sarcomas', 'Disease', 'MESH:D012509', (199, 207))
599631	25663866	Using core biopsy, the mass was determined to be a mammary parenchyma in continuity with hypercellular condroid tissue, with the presence of atypical, occasionally polynuclear elements, and rare mitosis.	('rare mitosis', 'Disease', (190, 202))	('polynuclear elements', 'Var', (164, 184))	('rare mitosis', 'Disease', 'MESH:D035583', (190, 202))
599736	31621382	In dogs, blood measurements for 90Y showed no significant 90Y activity postinjection; gelation entrapped 90Y particles in the tumor, preventing outmigration via blood circulation, and may have also blocked tumor interstitial fluid transport and respiration.	('90Y', 'Chemical', 'MESH:C000615496', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('90Y particles', 'Var', (105, 118))	('tumor', 'Disease', (206, 211))	('blocked', 'NegReg', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('dogs', 'Species', '9615', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('90Y', 'Chemical', 'MESH:C000615496', (32, 35))	('90Y', 'Chemical', 'MESH:C000615496', (105, 108))	('preventing', 'NegReg', (133, 143))	('outmigration', 'CPA', (144, 156))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', (126, 131))
599793	31621382	With intratumoral 90Y-radiogel therapy, the radiation dose to any other normal organ or tissue is negligible.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('90Y-radiogel', 'Chemical', '-', (18, 30))	('90Y-radiogel', 'Var', (18, 30))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
599812	31621382	Even at less-than-optimum doses, they observed tumor-tissue destruction associated with 90Y placement, therapy-related tumor necrosis, and in most cases, an acceptable treatment side effect profile.	('tumor', 'Disease', (119, 124))	('tumor necrosis', 'Disease', (119, 133))	('90Y placement', 'Var', (88, 101))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('90Y', 'Chemical', 'MESH:C000615496', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor necrosis', 'Disease', 'MESH:D009336', (119, 133))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (47, 52))
599984	31057950	While the origin of these tumours is still not definitively known, most cases of Ewing sarcoma (85%) are the result of a translocation between chromosomes 11 and 22, which fuses the EWS gene on chromosome 22 to the FLI1 gene on chromosome 11.	('Ewing sarcoma', 'Disease', (81, 94))	('translocation', 'Var', (121, 134))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('FLI1', 'Gene', '2313', (215, 219))	('result of', 'Reg', (109, 118))	('FLI1', 'Gene', (215, 219))	('EWS', 'Gene', '2130', (182, 185))	('EWS', 'Gene', (182, 185))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
600071	30366467	The protocol includes permeabilization by a kit detergent (5 min), fixation using a formaldehyde-based solution (10 min), conjugation of the mAb to the cytoskeletal CK (45 min in a humid and dark environment) and the use of a specific conjugate to bind the mAb.	('formaldehyde', 'Chemical', 'MESH:D005557', (84, 96))	('bind', 'Interaction', (248, 252))	('conjugation', 'Var', (122, 133))
600112	30366467	This proto-oncogene is implicated in cell growth signaling cascades, and its dysfunction may be associated with cancerogenesis.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('associated', 'Reg', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('implicated', 'Reg', (23, 33))	('dysfunction', 'Var', (77, 88))
600148	30366467	observed an association between 19p+ aberrations and unfavorable clinical outcome for MFS patients.	('MFS', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('19p+ aberrations', 'Var', (32, 48))
600256	29285193	Genetic studies on ASPS have confirmed a specific fusion gene involving the ASPS critical region-1 gene and TFE3 and the resultant fusion protein generated by the unbalanced chromosomal translocation [der(17)t(X:17)(p11;25)].	('ASPS', 'Gene', (76, 80))	('TFE3', 'Gene', '7030', (108, 112))	('[der(17)t(X:17)(', 'Var', (200, 216))	('ASPS', 'Gene', (19, 23))	('ASPS', 'Gene', '79058', (76, 80))	('TFE3', 'Gene', (108, 112))	('ASPS', 'Gene', '79058', (19, 23))
600257	29285193	Therefore, it is generally accepted that ASPS is a sarcoma associated with chromosomal translocation, therefore it is sorted into a class containing uncertain differentiated tumours.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('sarcoma', 'Disease', (51, 58))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('chromosomal', 'Var', (75, 86))	('ASPS', 'Gene', '79058', (41, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('associated', 'Reg', (59, 69))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('tumours', 'Disease', (174, 181))	('sarcoma', 'Disease', 'MESH:D012509', (51, 58))	('ASPS', 'Gene', (41, 45))
600282	29285193	It is notable that the Ki-67 proliferation index was 15% in these 2 cases, whereas it was <=10% in 5 cases, suggesting that the Ki-67 proliferation index may be associated with ASPS prognosis.	('ASPS', 'Gene', '79058', (177, 181))	('associated with', 'Reg', (161, 176))	('ASPS', 'Gene', (177, 181))	('Ki-67', 'Var', (128, 133))
600288	29119645	High Sensitivity of FISH Analysis in Detecting Homozygous SMARCB1 Deletions in Poorly Differentiated Chordoma: A Clinicopathologic and Molecular Study of 9 Cases Poorly differentiated chordomas (PDCs) represent a rare subset of notochordal neoplasms, affecting primarily children and associated with an aggressive outcome.	('notochordal neoplasms', 'Disease', (228, 249))	('neoplasm', 'Phenotype', 'HP:0002664', (240, 248))	('Deletions', 'Var', (66, 75))	('chordomas', 'Disease', 'MESH:D002817', (184, 193))	('Differentiated Chordoma', 'Disease', (86, 109))	('notochordal neoplasms', 'Disease', 'MESH:D009369', (228, 249))	('neoplasms', 'Phenotype', 'HP:0002664', (240, 249))	('SMARCB1', 'Gene', '6598', (58, 65))	('chordomas', 'Disease', (184, 193))	('Chordoma', 'Phenotype', 'HP:0010762', (101, 109))	('chordoma', 'Phenotype', 'HP:0010762', (184, 192))	('SMARCB1', 'Gene', (58, 65))	('children', 'Species', '9606', (271, 279))	('Differentiated Chordoma', 'Disease', 'MESH:D002817', (86, 109))
600290	29119645	Recent studies have shown that PDCs are characterized by recurrent deletions encompassing the SMARCB1 locus, resulting in consistent loss of nuclear SMARCB1 expression.	('SMARCB1', 'Gene', (94, 101))	('SMARCB1', 'Gene', (149, 156))	('deletions', 'Var', (67, 76))	('expression', 'MPA', (157, 167))	('nuclear', 'MPA', (141, 148))	('loss', 'NegReg', (133, 137))	('SMARCB1', 'Gene', '6598', (94, 101))	('PDCs', 'Disease', (31, 35))	('SMARCB1', 'Gene', '6598', (149, 156))
600291	29119645	Thus PDC joined the expanding family of SMARCB1-deficient tumors characterized by various SMARCB1 structural abnormalities, ranging from large homozygous deletions to small intragenic mutations.	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (40, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('SMARCB1-deficient tumors', 'Disease', (40, 64))	('SMARCB1', 'Gene', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('SMARCB1', 'Gene', '6598', (40, 47))	('deletions', 'Var', (154, 163))	('SMARCB1', 'Gene', (40, 47))	('SMARCB1', 'Gene', '6598', (90, 97))
600292	29119645	In the present study we investigate the SMARCB1 abnormalities in a group of 9 well characterized PDCs and to establish the sensitivity of FISH method in detecting these changes in the clinical setting.	('SMARCB1', 'Gene', (40, 47))	('abnormalities', 'Var', (48, 61))	('SMARCB1', 'Gene', '6598', (40, 47))
600294	29119645	FISH identified homozygous SMARCB1 deletions in all except one case; additionally 2 cases revealed a heterozygous EWSR1 locus co-deletion.	('SMARCB1', 'Gene', (27, 34))	('EWSR1', 'Gene', (114, 119))	('EWSR1', 'Gene', '2130', (114, 119))	('deletions', 'Var', (35, 44))	('SMARCB1', 'Gene', '6598', (27, 34))
600298	29119645	We conclude that PDC are highly aggressive tumors and the dominant mechanism of loss of SMARCB1 expression is through large, homozygous SMARCB1 deletions that can be readily detected by FISH.	('deletions', 'Var', (144, 153))	('loss', 'NegReg', (80, 84))	('SMARCB1', 'Gene', '6598', (88, 95))	('SMARCB1', 'Gene', (136, 143))	('PDC', 'Disease', (17, 20))	('expression', 'MPA', (96, 106))	('SMARCB1', 'Gene', '6598', (136, 143))	('SMARCB1', 'Gene', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
600304	29119645	Additionally, recent studies have shown that poorly differentiated chordomas (PDCs) are associated with recurrent deletions encompassing the SMARCB1 locus, resulting in consistent loss of nuclear INI1/SMARCB1 expression and implicating this abnormality as the leading pathogenetic mechanism in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('chordomas', 'Disease', 'MESH:D002817', (67, 76))	('SMARCB1', 'Gene', '6598', (201, 208))	('expression', 'MPA', (209, 219))	('chordoma', 'Phenotype', 'HP:0010762', (67, 75))	('SMARCB1', 'Gene', (201, 208))	('loss', 'NegReg', (180, 184))	('INI1', 'Gene', (196, 200))	('tumors', 'Disease', (300, 306))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('INI1', 'Gene', '6598', (196, 200))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('SMARCB1', 'Gene', '6598', (141, 148))	('chordomas', 'Disease', (67, 76))	('deletions', 'Var', (114, 123))	('SMARCB1', 'Gene', (141, 148))
600306	29119645	SMARCB1 functions as a classic tumor suppressor gene, homozygous loss of function mutations/deletions having been described initially as the hallmark of atypical teratoid/malignant rhabdoid tumors (AT/MRT) at different sites (brain, soft tissue, and kidney).	('malignant rhabdoid tumors', 'Disease', (171, 196))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('AT', 'Disease', 'None', (198, 200))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutations/deletions', 'Var', (82, 101))	('loss of function', 'NegReg', (65, 81))	('tumor', 'Disease', (190, 195))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (171, 196))	('SMARCB1', 'Gene', '6598', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('SMARCB1', 'Gene', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
600308	29119645	In this study, we sought to examine SMARCB1 abnormalities in a large series of PDCs diagnosed and managed at a single tertiary cancer institution and to establish the sensitivity of FISH method in detecting these changes as an adjunct for diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SMARCB1', 'Gene', '6598', (36, 43))	('SMARCB1', 'Gene', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('abnormalities', 'Var', (44, 57))
600319	29119645	Homozygous deletion of SMARCB1 was interpreted when both copies of the gene were lost, compared to the control probes, either telomeric-EWSR1 or 22q11.	('lost', 'NegReg', (81, 85))	('EWSR1', 'Gene', '2130', (136, 141))	('SMARCB1', 'Gene', '6598', (23, 30))	('SMARCB1', 'Gene', (23, 30))	('EWSR1', 'Gene', (136, 141))	('deletion', 'Var', (11, 19))
600331	29119645	FISH studies showed that all except one case of 8 evaluated harbored homozygous SMARCB1 deletions (Fig.	('deletions', 'Var', (88, 97))	('SMARCB1', 'Gene', (80, 87))	('SMARCB1', 'Gene', '6598', (80, 87))
600332	29119645	The deletions varied in size, with 2 cases showing that EWSR1 probe was heterozygously co-deleted with SMARCB1, in keeping with large deletions at chromosome 22q locus (Fig.	('SMARCB1', 'Gene', (103, 110))	('deletions', 'Var', (134, 143))	('EWSR1', 'Gene', (56, 61))	('EWSR1', 'Gene', '2130', (56, 61))	('SMARCB1', 'Gene', '6598', (103, 110))
600339	29119645	Recently, recurrent deletions at the SMARCB1 locus, resulting in loss of nuclear INI1/SMARCB1 expression, have been described as the leading pathogenetic mechanism in PDC.	('loss', 'NegReg', (65, 69))	('INI1', 'Gene', (81, 85))	('PDC', 'Disease', (167, 170))	('pathogenetic', 'Reg', (141, 153))	('deletions', 'Var', (20, 29))	('nuclear', 'MPA', (73, 80))	('SMARCB1', 'Gene', (37, 44))	('SMARCB1', 'Gene', '6598', (37, 44))	('INI1', 'Gene', '6598', (81, 85))	('expression', 'MPA', (94, 104))	('SMARCB1', 'Gene', (86, 93))	('SMARCB1', 'Gene', '6598', (86, 93))
600340	29119645	Our main goal was to evaluate the incidence and structural abnormalities of SMARCB1 deletions in PDC and to establish if FISH methodology is the appropriate tool to investigate this genetic mechanism in the clinical setting.	('SMARCB1', 'Gene', (76, 83))	('deletions', 'Var', (84, 93))	('SMARCB1', 'Gene', '6598', (76, 83))	('PDC', 'Disease', (97, 100))
600344	29119645	reported 2 PDC patients with SMARCB1 deletions, one developing distant recurrence 8 months after therapy and the other succumbing to disease only a few months after diagnosis.	('deletions', 'Var', (37, 46))	('patients', 'Species', '9606', (15, 23))	('SMARCB1', 'Gene', '6598', (29, 36))	('SMARCB1', 'Gene', (29, 36))	('PDC', 'Disease', (11, 14))
600351	29119645	Molecularly, PDCs harbor recurrent deletions encompassing the SMARCB1 region, which are not detected in conventional chordomas.	('chordomas', 'Disease', (117, 126))	('chordoma', 'Phenotype', 'HP:0010762', (117, 125))	('chordomas', 'Disease', 'MESH:D002817', (117, 126))	('deletions', 'Var', (35, 44))	('SMARCB1', 'Gene', '6598', (62, 69))	('SMARCB1', 'Gene', (62, 69))
600356	29119645	AT/RT is the prototypical lesion characterized by loss of function mutations involving the SMARCB1 locus, resulting in loss of SMARCB1 nuclear expression.	('SMARCB1', 'Gene', '6598', (91, 98))	('SMARCB1', 'Gene', (91, 98))	('mutations', 'Var', (67, 76))	('SMARCB1', 'Gene', '6598', (127, 134))	('AT', 'Disease', 'None', (0, 2))	('loss', 'NegReg', (119, 123))	('loss of function', 'NegReg', (50, 66))	('SMARCB1', 'Gene', (127, 134))	('nuclear expression', 'MPA', (135, 153))
600357	29119645	Intragenic mutations and large deletions in the SMARCB1 locus can be detected by FISH in AT/RT.	('mutations', 'Var', (11, 20))	('SMARCB1', 'Gene', (48, 55))	('AT', 'Disease', 'None', (89, 91))	('deletions', 'Var', (31, 40))	('SMARCB1', 'Gene', '6598', (48, 55))
600360	29119645	Epithelioid sarcoma (ES) is a rare and aggressive soft tissue neoplasm, both subtypes (proximal and distal) exhibiting SMARCB1 deletions.	('Epithelioid sarcoma', 'Disease', (0, 19))	('Epithelioid sarcoma', 'Disease', 'MESH:D012509', (0, 19))	('neoplasm', 'Phenotype', 'HP:0002664', (62, 70))	('aggressive soft tissue neoplasm', 'Disease', (39, 70))	('SMARCB1', 'Gene', '6598', (119, 126))	('deletions', 'Var', (127, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('SMARCB1', 'Gene', (119, 126))	('soft tissue neoplasm', 'Phenotype', 'HP:0031459', (50, 70))	('aggressive soft tissue neoplasm', 'Disease', 'MESH:D012983', (39, 70))
600361	29119645	identified 90% (36/40) of ES as having large, homozygous SMARCB1 deletions detected by FISH.	('SMARCB1', 'Gene', (57, 64))	('SMARCB1', 'Gene', '6598', (57, 64))	('deletions', 'Var', (65, 74))
600362	29119645	One proximal ES exhibited heterozygous deletion of SMARCB1, while remaining 3 cases had a normal SMARCB1 pattern by FISH resolution.	('SMARCB1', 'Gene', '6598', (97, 104))	('SMARCB1', 'Gene', (97, 104))	('deletion', 'Var', (39, 47))	('SMARCB1', 'Gene', '6598', (51, 58))	('SMARCB1', 'Gene', (51, 58))
600364	29119645	In the setting of SMARCB1-deficient tumors harboring large deletions covering the SMARCB1 locus, secondary abnormalities of the EWSR1 gene locus can occur, including unbalanced rearrangements or deletions.	('SMARCB1', 'Gene', (18, 25))	('deletions', 'Var', (195, 204))	('deletions', 'Var', (59, 68))	('SMARCB1', 'Gene', '6598', (82, 89))	('SMARCB1', 'Gene', (82, 89))	('occur', 'Reg', (149, 154))	('EWSR1', 'Gene', (128, 133))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (18, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('SMARCB1-deficient tumors', 'Disease', (18, 42))	('EWSR1', 'Gene', '2130', (128, 133))	('unbalanced rearrangements', 'Var', (166, 191))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('SMARCB1', 'Gene', '6598', (18, 25))
600365	29119645	Thus, diagnostic pitfalls are encountered when a FISH analysis for EWSR1 gene abnormality is interpreted in isolation, without appreciation of the larger chromosomal deletion that may encompass this region.	('EWSR1', 'Gene', (67, 72))	('abnormality', 'Var', (78, 89))	('EWSR1', 'Gene', '2130', (67, 72))
600366	29119645	Thus, false positive FISH results for EWSR1 gene rearrangements can occur in the setting of SMARCB1 gene abnormalities/deletions, triggering misdiagnosis of a EWSR1-fusion positive tumor such as Ewing sarcoma or myoepithelial carcinoma.	('rearrangements', 'Var', (49, 63))	('Ewing sarcoma', 'Disease', (195, 208))	('SMARCB1', 'Gene', '6598', (92, 99))	('SMARCB1', 'Gene', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (212, 235))	('EWSR1', 'Gene', '2130', (159, 164))	('abnormalities/deletions', 'Var', (105, 128))	('triggering', 'Reg', (130, 140))	('EWSR1', 'Gene', '2130', (38, 43))	('myoepithelial carcinoma', 'Disease', (212, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (195, 208))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (195, 208))	('tumor', 'Disease', (181, 186))	('EWSR1', 'Gene', (159, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('EWSR1', 'Gene', (38, 43))
600367	29119645	In fact, 2 of our PDCs exhibited heterozygous co-deletions of EWSR1 locus in the background of homozygous SMARCB1 deletions.	('EWSR1', 'Gene', (62, 67))	('EWSR1', 'Gene', '2130', (62, 67))	('SMARCB1', 'Gene', (106, 113))	('SMARCB1', 'Gene', '6598', (106, 113))	('co-deletions', 'Var', (46, 58))
600369	29119645	On re-evaluation, complex EWSR1 regional deletions rather than a balanced rearrangement were identified, which together with positive brachyury immunoexpression supported a diagnosis of PDC with co-deletions of SMARCB1 and EWSR1.	('EWSR1', 'Gene', '2130', (26, 31))	('PDC', 'Disease', (186, 189))	('SMARCB1', 'Gene', '6598', (211, 218))	('SMARCB1', 'Gene', (211, 218))	('EWSR1', 'Gene', '2130', (223, 228))	('brachyury', 'Gene', (134, 143))	('EWSR1', 'Gene', (26, 31))	('deletions', 'Var', (41, 50))	('brachyury', 'Gene', '6899', (134, 143))	('EWSR1', 'Gene', (223, 228))
600370	29119645	Furthermore, our previous study of SMARCB1-deleted epithelioid sarcomas showed that 25% of cases were associated with heterozygous telomeric EWSR1 deletions.	('sarcomas', 'Phenotype', 'HP:0100242', (63, 71))	('associated', 'Reg', (102, 112))	('EWSR1', 'Gene', (141, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('deletions', 'Var', (147, 156))	('EWSR1', 'Gene', '2130', (141, 146))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (51, 71))	('epithelioid sarcomas', 'Disease', (51, 71))	('SMARCB1', 'Gene', '6598', (35, 42))	('SMARCB1', 'Gene', (35, 42))
600371	29119645	Similarly, co-deletions in SMARCB1 and EWSR1 genes can also occur in malignant rhabdoid tumor and myoepithelial carcinoma.	('SMARCB1', 'Gene', (27, 34))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (98, 121))	('myoepithelial carcinoma', 'Disease', (98, 121))	('EWSR1', 'Gene', (39, 44))	('co-deletions', 'Var', (11, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (69, 93))	('SMARCB1', 'Gene', '6598', (27, 34))	('EWSR1', 'Gene', '2130', (39, 44))	('malignant rhabdoid tumor', 'Disease', (69, 93))	('occur', 'Reg', (60, 65))
600373	29119645	Our study specifically showed loss of SMARCB1 expression in 100% of PDCs and 87.5% (7/8) of evaluated PDC cases demonstrated homozygous deletions by FISH.	('PDCs', 'Disease', (68, 72))	('deletions', 'Var', (136, 145))	('loss', 'NegReg', (30, 34))	('SMARCB1', 'Gene', '6598', (38, 45))	('expression', 'MPA', (46, 56))	('SMARCB1', 'Gene', (38, 45))
600375	29119645	The loss of SMARCB1 expression in this case might be attributed either to intragenic mutations (beyond the FISH resolution) or to epigenetic silencing of SMARCB1 by microRNA (miRNA) activation.	('epigenetic silencing', 'Var', (130, 150))	('SMARCB1', 'Gene', '6598', (12, 19))	('expression', 'MPA', (20, 30))	('SMARCB1', 'Gene', (12, 19))	('SMARCB1', 'Gene', '6598', (154, 161))	('mutations', 'Var', (85, 94))	('SMARCB1', 'Gene', (154, 161))	('loss', 'NegReg', (4, 8))
600376	29119645	In this regard, a recent study found upregulation of miR-671-5p and miR-193a-5p in PDC with loss of SMARCB1 expression.	('SMARCB1', 'Gene', (100, 107))	('miR-671', 'Gene', (53, 60))	('miR-193a-5p', 'Var', (68, 79))	('upregulation', 'PosReg', (37, 49))	('loss', 'NegReg', (92, 96))	('expression', 'MPA', (108, 118))	('PDC', 'Disease', (83, 86))	('miR-671', 'Gene', '768213', (53, 60))	('SMARCB1', 'Gene', '6598', (100, 107))
600378	29119645	The study by Hasselblatt et al showed that SMARCB1 deletions were identified in 4/7 (57%) PDC cases by FISH, but only in 2/7 (29%) cases by multiplex ligation-dependent probe amplification (MLPA), suggesting that FISH is more sensitive method than MLPA in the context of large homozygous deletions of PDC.	('SMARCB1', 'Gene', (43, 50))	('SMARCB1', 'Gene', '6598', (43, 50))	('deletions', 'Var', (51, 60))	('PDC', 'Disease', (90, 93))
600379	29119645	showed that FISH method detected the presence of deletions in 95% of epithelioid sarcoma cases, while MLPA only in 73% of cases.	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (69, 88))	('deletions', 'Var', (49, 58))	('epithelioid sarcoma', 'Disease', (69, 88))
600380	29119645	These findings further confirm our prior results showing high sensitivity of FISH studies to detect homozygous deletions in epithelioid sarcomas compared to MLPA.	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (124, 144))	('deletions', 'Var', (111, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('epithelioid sarcomas', 'Disease', (124, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))
600381	29119645	In contrast to PDC and epithelioid sarcomas in which most SMARCB1 genetic abnormalities represent large, homozugous deletions, the spectrum of alterations in rhabdoid tumors are relatively evenly distributed between whole gene deletions, intragenic deletions and duplications, nonsense mutations and frameshift mutations.	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('duplications', 'Var', (263, 275))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (23, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('epithelioid sarcomas', 'Disease', (23, 43))	('frameshift mutations', 'Var', (300, 320))	('rhabdoid tumors', 'Disease', (158, 173))	('genetic abnormalities', 'Disease', 'MESH:D030342', (66, 87))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (158, 173))	('SMARCB1', 'Gene', '6598', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('SMARCB1', 'Gene', (58, 65))	('nonsense mutations', 'Var', (277, 295))	('genetic abnormalities', 'Disease', (66, 87))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
600382	29119645	In summary, our results reveal that the dominant mechanism of SMARCB1 loss of expression in PDC is through large, homozygous deletions at the 22q11 locus which can be detected by FISH in the clinical setting.	('loss of expression', 'NegReg', (70, 88))	('PDC', 'Disease', (92, 95))	('deletions', 'Var', (125, 134))	('SMARCB1', 'Gene', '6598', (62, 69))	('SMARCB1', 'Gene', (62, 69))
600394	29031130	ACBS 2 was independently associated with decreased DSS compared to ACBS 0, hazard ratio 2.3[95% confidence interval: 1.5-3.5], P < .001.	('DSS', 'Gene', '5376', (51, 54))	('ACBS', 'Chemical', '-', (67, 71))	('ACBS', 'Chemical', '-', (0, 4))	('decreased', 'NegReg', (41, 50))	('ACBS 2', 'Var', (0, 6))	('DSS', 'Gene', (51, 54))
600395	29031130	CONCLUSION: Patients with abnormal values in more than one serum biomarkers had a significant additional risk of dying compared to patients with only one abnormal value.	('patients', 'Species', '9606', (131, 139))	('abnormal', 'Var', (26, 34))	('Patients', 'Species', '9606', (12, 20))	('dying', 'Disease', (113, 118))
600429	29031130	Similarly, the 5-year DSS was 83% (95% CI: 80-86) in patients with GPS-0 compared to 64% (95% CI: 56-72) and 50% (95% CI: 35-66) in patients with GPS-1 and GPS-2, respectively.	('DSS', 'Gene', (22, 25))	('patients', 'Species', '9606', (53, 61))	('GPS-2', 'Gene', '2874', (156, 161))	('GPS-1', 'Gene', (146, 151))	('GPS-2', 'Gene', (156, 161))	('DSS', 'Gene', '5376', (22, 25))	('GPS-1', 'Gene', '2873', (146, 151))	('GPS', 'Chemical', '-', (146, 149))	('GPS', 'Chemical', '-', (156, 159))	('GPS', 'Chemical', '-', (67, 70))	('patients', 'Species', '9606', (132, 140))	('GPS-0', 'Var', (67, 72))
600431	29031130	The 5-year DSS was 86% (95% CI: 79-90) in patients with score 0 compared to 72% (95% CI: 61-80) and 49% (95% CI: 35-62) in patients with score 1 and score 2, respectively.	('score', 'Var', (56, 61))	('patients', 'Species', '9606', (123, 131))	('DSS', 'Gene', (11, 14))	('DSS', 'Gene', '5376', (11, 14))	('patients', 'Species', '9606', (42, 50))
600433	29031130	Cox proportional hazard analyses adjusted for age, comorbidity, tumor size, grade, histological type, and tumor depth confirmed that low albumin; high CRP; low hemoglobin; and elevated NLR, GPS 2, and ACBS 2 were independently associated with decreased DSS (Table 2) in the test cohort.	('ACBS 2', 'Gene', (201, 207))	('NLR', 'Gene', (185, 188))	('DSS', 'Gene', '5376', (253, 256))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (106, 111))	('albumin', 'MPA', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('CRP', 'Gene', '1401', (151, 154))	('GPS 2', 'Gene', '2874', (190, 195))	('low albumin', 'Phenotype', 'HP:0003073', (133, 144))	('elevated', 'PosReg', (176, 184))	('low', 'NegReg', (133, 136))	('low hemoglobin', 'Phenotype', 'HP:0001903', (156, 170))	('GPS 2', 'Gene', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('ACBS', 'Chemical', '-', (201, 205))	('high', 'Var', (146, 150))	('decreased', 'NegReg', (243, 252))	('low', 'NegReg', (156, 159))	('tumor', 'Disease', (64, 69))	('DSS', 'Gene', (253, 256))	('hemoglobin', 'MPA', (160, 170))	('CRP', 'Gene', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
600446	29031130	This test confirmed that ACBS 2 was associated with decreased DSS compared to ACBS 0, HR: 2.3 [95% CI: 1.5-3.5], P < .001.	('ACBS', 'Chemical', '-', (78, 82))	('ACBS', 'Chemical', '-', (25, 29))	('decreased', 'NegReg', (52, 61))	('DSS', 'Gene', (62, 65))	('ACBS 2', 'Var', (25, 31))	('DSS', 'Gene', '5376', (62, 65))
600459	29031130	Based on this suggested pathophysiological mechanism linking CRP, albumin, and anemia, one can reasonably assume that patients with abnormal levels of all three parameters may have a greater, albeit microscopic, tumor burden than patients with abnormality in only CRP.	('anemia', 'Disease', 'MESH:D000740', (79, 85))	('CRP', 'Gene', '1401', (264, 267))	('abnormality', 'Disease', (244, 255))	('abnormal', 'Var', (132, 140))	('patients', 'Species', '9606', (118, 126))	('anemia', 'Phenotype', 'HP:0001903', (79, 85))	('CRP', 'Gene', (61, 64))	('patients', 'Species', '9606', (230, 238))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('CRP', 'Gene', '1401', (61, 64))	('anemia', 'Disease', (79, 85))	('abnormality', 'Disease', 'MESH:D000014', (244, 255))	('tumor', 'Disease', (212, 217))	('CRP', 'Gene', (264, 267))
600506	28690678	Through a methodology called transfection, by which an exogenous DNA can be introduced in 'quasi' normal recipient cells, murine-immortalised fibroblasts, they were able to show that the DNA from a bladder cancer cell line of human origin but not the one from normal cells, was able to cause the complete transformation in a fully growing cancer of the recipient cells.	('human', 'Species', '9606', (226, 231))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('DNA', 'Var', (187, 190))	('bladder cancer', 'Disease', (198, 212))	('murine', 'Species', '10090', (122, 128))	('cancer', 'Disease', (339, 345))	('cause', 'Reg', (286, 291))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))
600513	28690678	Finally and most importantly, cancers can also develop without any apparent cause, that is, spontaneously or, as in a small percentage of cases, inherited.	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('inherited', 'Var', (145, 154))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
600514	28690678	The fact that cancer is caused by the alterations in normal genes, especially those regulating cell growth and differentiation processes is now firmly established.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('alterations', 'Var', (38, 49))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('rat', 'Species', '10116', (42, 45))	('caused', 'Reg', (24, 30))
600520	28690678	Focusing on their functional properties, we can summarise that while oncogenes can be considered the 'gas pedal', tumour suppressor genes act as a brake for cell growth.	('tumour', 'Disease', (114, 120))	('oncogenes', 'Var', (69, 78))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (114, 120))
600521	28690678	Transfection experiments using quasi-normal cell lines suggested that mutation of a single gene could cause cancer.	('cause', 'Reg', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutation', 'Var', (70, 78))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
600522	28690678	This shocking result was later in part mitigated by experiments performed by Weinberg's group in collaboration with Varda Rotter at Weizmann Institute in Israel, which proved that to fully transform a normal cell at least two different mutations are required: the activation of an oncogene and the inactivation of a tumour suppressor gene.	('inactivation', 'Var', (298, 310))	('shocking', 'Phenotype', 'HP:0031273', (5, 13))	('oncogene', 'Protein', (281, 289))	('tumour', 'Phenotype', 'HP:0002664', (316, 322))	('tumour', 'Disease', 'MESH:D009369', (316, 322))	('activation', 'PosReg', (264, 274))	('tumour', 'Disease', (316, 322))	('rat', 'Species', '10116', (104, 107))
600583	28494784	This translocation includes gene fusion between the SYT gene in chromosome 18 and the SSX1 or SSX2 gene in chromosome X and occasionally gene fusion with SSX4.	('SYT', 'Gene', (52, 55))	('SSX2', 'Gene', (94, 98))	('gene fusion', 'Var', (137, 148))	('SSX4', 'Gene', '6759', (154, 158))	('SSX4', 'Gene', (154, 158))	('gene fusion', 'Var', (28, 39))	('SYT', 'Gene', '6760', (52, 55))	('SSX1', 'Gene', '6756', (86, 90))	('SSX2', 'Gene', '6757', (94, 98))	('SSX1', 'Gene', (86, 90))
600625	28494784	The 5-year OS of the patients with a tumor size <=5 cm was 91.4%, and that of the patients with a tumor size >5 cm was only 73.1% (Fig.	('OS', 'Chemical', '-', (11, 13))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('patients', 'Species', '9606', (21, 29))	('<=5', 'Var', (48, 51))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
600730	22093140	The estimates suggested that those with a detectable KSHV viral load were more likely to be male (PR = 1.43; 95%CI 0.61-3.35), have a WHO stage III/IV illnesses (PR = 1.51; 95%CI 0.65-3.50) and hemoglobin <= 8 g/dL (PR = 1.42; 95%CI 0.37-5.43) compared to those without a detectable KSHV viral load, although these results lacked precision (as indicated by the wide confidence intervals).	('KSHV', 'Species', '37296', (53, 57))	('stage III/IV', 'Disease', (138, 150))	('KS', 'Phenotype', 'HP:0100726', (283, 285))	('KSHV', 'Species', '37296', (283, 287))	('KS', 'Phenotype', 'HP:0100726', (53, 55))	('KSHV', 'Var', (53, 57))
600733	22093140	In log-binomial regression models, adjusted prevalence ratios of KSHV seropositivity was increased for those with CD3 and CD8 counts >= 500 cells compared to those < 500 cells and also CD4 counts between 51 and 200 cells compared to CD4 counts <= 50, (Table 2) although some of these estimates lacked precision (i.e.	('CD4', 'Gene', (185, 188))	('KSHV', 'Species', '37296', (65, 69))	('CD4', 'Gene', '920', (233, 236))	('KS', 'Phenotype', 'HP:0100726', (65, 67))	('counts >= 500 cells', 'Var', (126, 145))	('CD4', 'Gene', '920', (185, 188))	('CD8', 'Gene', (122, 125))	('CD3', 'Gene', (114, 117))	('KSHV', 'Gene', (65, 69))	('CD8', 'Gene', '925', (122, 125))	('increased', 'PosReg', (89, 98))	('seropositivity', 'Var', (70, 84))	('CD4', 'Gene', (233, 236))
600738	22093140	Presence of antibodies to latent Orf73 was associated with higher median CD3 (863 vs. 720 cells/mm3; p = 0.019) and CD8 (706 vs. 569 cells/mm3; p = 0.026) cell counts.	('antibodies', 'Var', (12, 22))	('Orf73', 'Gene', (33, 38))	('CD8', 'Gene', (116, 119))	('CD8', 'Gene', '925', (116, 119))	('Orf73', 'Gene', '4961527', (33, 38))	('higher', 'PosReg', (59, 65))	('CD3', 'CPA', (73, 76))
600744	22093140	In fact, reactivity to latent KSHV antigen was associated with better markers of immunity in terms of higher CD3, CD4 and CD8 cell counts.	('KSHV', 'Species', '37296', (30, 34))	('CD3', 'CPA', (109, 112))	('CD4', 'Gene', (114, 117))	('higher', 'PosReg', (102, 108))	('CD8', 'Gene', (122, 125))	('KSHV', 'Gene', (30, 34))	('CD4', 'Gene', '920', (114, 117))	('CD8', 'Gene', '925', (122, 125))	('KS', 'Phenotype', 'HP:0100726', (30, 32))	('reactivity', 'Var', (9, 19))
600749	22093140	Among populations with a high prevalence of KSHV seropositivity, the route of infection is likely to be saliva and is acquired during childhood and early adult life.	('KSHV', 'Gene', (44, 48))	('infection', 'Disease', 'MESH:D007239', (78, 87))	('KSHV', 'Species', '37296', (44, 48))	('seropositivity', 'Var', (49, 63))	('infection', 'Disease', (78, 87))	('KS', 'Phenotype', 'HP:0100726', (44, 46))
600754	22093140	Among the KSHV infected individuals, however, those with a detectable KSHV viral load presented with signs of more advanced HIV disease including anemia and WHO stage 3 or 4 defining conditions compared to those in whom the virus was undetectable.	('anemia', 'Disease', (146, 152))	('HIV disease', 'Disease', (124, 135))	('KSHV', 'Species', '37296', (10, 14))	('anemia', 'Disease', 'MESH:D000740', (146, 152))	('viral load', 'Var', (75, 85))	('KS', 'Phenotype', 'HP:0100726', (10, 12))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('KSHV infected', 'Disease', (10, 23))	('KSHV', 'Species', '37296', (70, 74))	('HIV disease', 'Disease', 'MESH:D015658', (124, 135))	('anemia', 'Phenotype', 'HP:0001903', (146, 152))	('KSHV infected', 'Disease', 'MESH:C537372', (10, 23))	('KSHV', 'Gene', (70, 74))
600764	22093140	CD4 and 8 cells play important roles in cell-mediated immunity and control of viremia in the HIV-infected individual and low absolute numbers of CD4 and 8 cells have been associated with an increased risk of disease progression and mortality among HIV-infected persons.	('CD4', 'Gene', (145, 148))	('low absolute numbers', 'Var', (121, 141))	('CD4', 'Gene', '920', (0, 3))	('associated with', 'Reg', (171, 186))	('mortality', 'CPA', (232, 241))	('HIV-infected', 'Disease', (248, 260))	('viremia', 'Disease', 'MESH:D014766', (78, 85))	('HIV-infected', 'Disease', (93, 105))	('disease', 'Disease', (208, 215))	('CD4', 'Gene', '920', (145, 148))	('viremia', 'Phenotype', 'HP:0020071', (78, 85))	('persons', 'Species', '9606', (261, 268))	('viremia', 'Disease', (78, 85))	('HIV-infected', 'Disease', 'MESH:D015658', (248, 260))	('HIV-infected', 'Disease', 'MESH:D015658', (93, 105))	('CD4', 'Gene', (0, 3))
600772	22093140	Secondly, it is possible that the association we demonstrate between less suppression of the immune system and KSHV seropositivity is due, at least in part, to survival bias.	('seropositivity', 'Var', (116, 130))	('KSHV', 'Species', '37296', (111, 115))	('suppression of the immune system', 'Phenotype', 'HP:0002721', (74, 106))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('KSHV', 'Gene', (111, 115))
600783	22093140	Future research efforts in this field should be focused on longitudinal studies to determine if KSHV seropositivity, particularly viremia, poses a risk for HIV treatment outcomes, development of KS immune reconstitution inflammatory syndrome and mortality in the presence of antiretroviral therapy.	('men', 'Species', '9606', (165, 168))	('KS', 'Phenotype', 'HP:0100726', (195, 197))	('seropositivity', 'Var', (101, 115))	('KSHV', 'Species', '37296', (96, 100))	('KS', 'Phenotype', 'HP:0100726', (96, 98))	('risk', 'Reg', (147, 151))	('men', 'Species', '9606', (187, 190))	('viremia', 'Disease', (130, 137))	('KSHV', 'Gene', (96, 100))	('inflammatory syndrome', 'Disease', 'MESH:D007249', (220, 241))	('inflammatory syndrome', 'Disease', (220, 241))	('viremia', 'Phenotype', 'HP:0020071', (130, 137))	('viremia', 'Disease', 'MESH:D014766', (130, 137))
600870	31367736	The immunohistochemical analysis showed positivity for endothelial markers (CD-31, WT-1, FLI-1) (Figure 6).	('CD-31', 'Gene', (76, 81))	('CD-31', 'Gene', '5175', (76, 81))	('WT-1', 'Gene', (83, 87))	('FLI-1', 'Gene', '2313', (89, 94))	('WT-1', 'Gene', '7490', (83, 87))	('FLI-1', 'Gene', (89, 94))	('positivity', 'Var', (40, 50))
600879	31367736	The patient we described complained only of fatigue, loss of appetite, and weight loss, although the occlusion of the superior mesenteric artery did not reduce visceral blood flow, maintained by collateral reperfusion.	('visceral blood flow', 'MPA', (160, 179))	('weight loss', 'Phenotype', 'HP:0001824', (75, 86))	('loss of appetite', 'Disease', (53, 69))	('loss of appetite', 'Phenotype', 'HP:0004396', (53, 69))	('fatigue', 'Disease', 'MESH:D005221', (44, 51))	('patient', 'Species', '9606', (4, 11))	('occlusion', 'Var', (101, 110))	('weight loss', 'Disease', 'MESH:D015431', (75, 86))	('fatigue', 'Disease', (44, 51))	('loss of appetite', 'Disease', 'MESH:D001068', (53, 69))	('fatigue', 'Phenotype', 'HP:0012378', (44, 51))	('occlusion of the superior mesenteric artery', 'Phenotype', 'HP:0100859', (101, 144))	('weight loss', 'Disease', (75, 86))
600915	28969037	As a MMP-9 inhibitor, ATIQCTPC inhibited the metastasis of LLC, and slowed the growth of the primary tumor of LLC implanted C57BL/6 in mice.	('ATIQCTPC', 'Var', (22, 30))	('metastasis', 'CPA', (45, 55))	('slowed', 'NegReg', (68, 74))	('growth', 'CPA', (79, 85))	('ATIQCTPC', 'Chemical', '-', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('mice', 'Species', '10090', (135, 139))	('LLC', 'Disease', (59, 62))	('inhibited', 'NegReg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
600918	28969037	The minimal effective dose of ATIQCTPC inhibiting tumour growth and metastasis was 100-fold lower than that of (S)-3-acetyl- 4-oxo-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-6-carboxylic acid (ATIQC, parent compound).	('ATIQC', 'Chemical', '-', (194, 199))	('ATIQCTPC', 'Var', (30, 38))	('ATIQC', 'Chemical', '-', (30, 35))	('ATIQCTPC', 'Chemical', '-', (30, 38))	('(S)-3-acetyl- 4-oxo-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-6-carboxylic acid', 'Chemical', '-', (111, 192))	('tumour growth', 'Disease', (50, 63))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour growth', 'Disease', 'MESH:D006130', (50, 63))	('lower', 'NegReg', (92, 97))	('inhibiting', 'NegReg', (39, 49))
600928	28969037	The inhibition of MMP-9 can effectively attenuate cancer metastasis, and at early stages of cancer the inhibition of MMP-9 is essentially efficacy.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('MMP-9', 'Gene', (18, 23))	('inhibition', 'Var', (4, 14))	('cancer metastasis', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer metastasis', 'Disease', 'MESH:D009362', (50, 67))	('attenuate', 'NegReg', (40, 49))
600935	28969037	As seen, ATIQCTPC concentration-dependently inhibit the migration of A549 and LLC cells.	('inhibit', 'NegReg', (44, 51))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('ATIQCTPC', 'Var', (9, 17))	('ATIQCTPC', 'Chemical', '-', (9, 17))
600936	28969037	The migration number of A549 and LLC cells treated with 0.2 muM ATIQCTPC is significantly lower than that of A549 and LLC cells treated with phosphate-buffered saline (PBS), and equals to that of A549 and LLC cells treated with 20 muM ATIQC.	('0.2 muM ATIQCTPC', 'Var', (56, 72))	('A549', 'CellLine', 'CVCL:0023', (196, 200))	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('ATIQC', 'Chemical', '-', (235, 240))	('ATIQCTPC', 'Chemical', '-', (64, 72))	('ATIQC', 'Chemical', '-', (64, 69))	('phosphate-buffered saline', 'Chemical', '-', (141, 166))	('lower', 'NegReg', (90, 95))	('PBS', 'Chemical', '-', (168, 171))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('ATIQCTPC', 'Var', (64, 72))	('migration number', 'CPA', (4, 20))
600939	28969037	As seen, ATIQCTPC concentration-dependently inhibit the invasion of A549 and LLC cells.	('inhibit', 'NegReg', (44, 51))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('ATIQCTPC', 'Var', (9, 17))	('ATIQCTPC', 'Chemical', '-', (9, 17))
600940	28969037	The invasion number of A549 and LLC cells treated with 0.2 muM ATIQCTPC is significantly lower than that of A549 and LLC cells treated with PBS, and equals to that of A549 and LLC cells treat by 20 muM ATIQC.	('invasion number', 'CPA', (4, 19))	('lower', 'NegReg', (89, 94))	('A549', 'CellLine', 'CVCL:0023', (108, 112))	('ATIQCTPC', 'Var', (63, 71))	('ATIQC', 'Chemical', '-', (63, 68))	('PBS', 'Chemical', '-', (140, 143))	('ATIQCTPC', 'Chemical', '-', (63, 71))	('ATIQC', 'Chemical', '-', (202, 207))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('A549', 'CellLine', 'CVCL:0023', (167, 171))
600944	28969037	The number of lung metastasis nodules of the mice orally treated with 0.01 mumol/kg/day of ATIQCTPC for 11 days is significantly lower than that of lung metastasis nodules of the mice orally treated with NS for 11 days, and is equal to that of lung metastasis nodules of the mice orally treated with 1 mumol/kg of ATIQC for 11 days.	('ATIQCTPC', 'Chemical', '-', (91, 99))	('mice', 'Species', '10090', (45, 49))	('mice', 'Species', '10090', (179, 183))	('mice', 'Species', '10090', (275, 279))	('ATIQC', 'Chemical', '-', (91, 96))	('lung metastasis nodules', 'CPA', (14, 37))	('0.01 mumol/kg/day', 'Var', (70, 87))	('NS', 'Disease', 'MESH:D009404', (204, 206))	('ATIQCTPC', 'Var', (91, 99))	('ATIQC', 'Chemical', '-', (314, 319))	('lower', 'NegReg', (129, 134))
600952	28969037	These data suggest that the in vivo efficacy of ATIQCTPC (0.01 mumol/kg/day for 11 days) effectively inhibiting the metastasis of LLC toward lung could be the result of it decreasing MMP-9 level in the serum and the primary tumor of LLC sarcoma implanted C57BL/6 mice.	('sarcoma', 'Phenotype', 'HP:0100242', (237, 244))	('MMP-9 level', 'MPA', (183, 194))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('mice', 'Species', '10090', (263, 267))	('tumor', 'Disease', (224, 229))	('ATIQCTPC', 'Var', (48, 56))	('LLC sarcoma', 'Disease', 'MESH:D012509', (233, 244))	('decreasing', 'NegReg', (172, 182))	('LLC sarcoma', 'Disease', (233, 244))	('metastasis', 'CPA', (116, 126))	('ATIQCTPC', 'Chemical', '-', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('inhibiting', 'NegReg', (101, 111))
600954	28969037	ATIQCTPC inhibits ear edema of the mice in a dose (0.001, 0.01 and 1 mumol/kg) dependent manner.	('ear edema', 'Disease', 'MESH:D004487', (18, 27))	('ear edema', 'Disease', (18, 27))	('ATIQCTPC', 'Var', (0, 8))	('edema', 'Phenotype', 'HP:0000969', (22, 27))	('ATIQCTPC', 'Chemical', '-', (0, 8))	('mice', 'Species', '10090', (35, 39))	('inhibits', 'NegReg', (9, 17))
600955	28969037	The ear edema of the mice orally treated with 0.01 mumol/kg ATIQCTPC is significantly lower than those of the mice orally treated with NS and 1 mumol/kg ATIQC.	('mice', 'Species', '10090', (21, 25))	('ATIQCTPC', 'Chemical', '-', (60, 68))	('ATIQC', 'Chemical', '-', (60, 65))	('mice', 'Species', '10090', (110, 114))	('lower', 'NegReg', (86, 91))	('edema', 'Phenotype', 'HP:0000969', (8, 13))	('ATIQC', 'Chemical', '-', (153, 158))	('NS', 'Disease', 'MESH:D009404', (135, 137))	('0.01 mumol/kg ATIQCTPC', 'Var', (46, 68))	('ear edema', 'Disease', 'MESH:D004487', (4, 13))	('ATIQCTPC', 'Var', (60, 68))	('ear edema', 'Disease', (4, 13))
600957	28969037	Besides, the ear edema of the mice orally treated with 1 mumol/kg ATIQCTPC is equal to that of the mice orally treated with 110 mumol/kg aspirin.	('ear edema', 'Disease', (13, 22))	('mice', 'Species', '10090', (99, 103))	('mice', 'Species', '10090', (30, 34))	('aspirin', 'Chemical', 'MESH:D001241', (137, 144))	('ATIQCTPC', 'Chemical', '-', (66, 74))	('ATIQCTPC', 'Var', (66, 74))	('ear edema', 'Disease', 'MESH:D004487', (13, 22))	('edema', 'Phenotype', 'HP:0000969', (17, 22))
600962	28969037	These findings suggest that 0.01 mumol/kg ATIQCTPC is capable of simultaneous decrease the serum MMP-9, TNF-alpha and IL-8 in vivo.	('serum MMP-9', 'MPA', (91, 102))	('TNF-alpha', 'Gene', '21926', (104, 113))	('IL-8', 'Gene', (118, 122))	('decrease', 'NegReg', (78, 86))	('ATIQCTPC', 'Var', (42, 50))	('TNF-alpha', 'Gene', (104, 113))	('IL-8', 'Gene', '20309', (118, 122))	('ATIQCTPC', 'Chemical', '-', (42, 50))	('0.01 mumol/kg', 'Var', (28, 41))
600968	28969037	This ensures that ATIQCTPC induces no heart damage.	('ATIQCTPC', 'Var', (18, 26))	('heart damage', 'Disease', (38, 50))	('heart damage', 'Disease', 'MESH:D006331', (38, 50))	('ATIQCTPC', 'Chemical', '-', (18, 26))
600972	28969037	Figure 6 indicates that the signal of NO  free radicals is gradually decreased by ATIQCTPC in a concentration (final concentration: 10-5 M, 10-6 M, 10-7 M, 10-8 M and 10-9 M) dependent manner.	('NO  free radical', 'Chemical', '-', (38, 54))	('ATIQCTPC', 'Var', (82, 90))	('ATIQCTPC', 'Chemical', '-', (82, 90))	('decreased', 'NegReg', (69, 78))	('NO  free radicals', 'MPA', (38, 55))	('signal', 'MPA', (28, 34))
600989	28969037	On xylene-induced ear edema mouse model the anti-inflammation activity of ATIQCTPC is 100-fold higher than those of ATIQC and aspirin.	('ATIQCTPC', 'Chemical', '-', (74, 82))	('ATIQC', 'Chemical', '-', (74, 79))	('ear edema', 'Disease', 'MESH:D004487', (18, 27))	('mouse', 'Species', '10090', (28, 33))	('ear edema', 'Disease', (18, 27))	('aspirin', 'Chemical', 'MESH:D001241', (126, 133))	('inflammation', 'Disease', (49, 61))	('ATIQC', 'Chemical', '-', (116, 121))	('higher', 'PosReg', (95, 101))	('xylene', 'Chemical', 'MESH:D014992', (3, 9))	('edema', 'Phenotype', 'HP:0000969', (22, 27))	('inflammation', 'Disease', 'MESH:D007249', (49, 61))	('ATIQCTPC', 'Var', (74, 82))
601044	26455317	However, some tumors do exhibit mutations in TP53, deletions of the CDKN2A locus or mutations in STAG2.	('exhibit', 'Reg', (24, 31))	('TP53', 'Gene', (45, 49))	('STAG2', 'Gene', (97, 102))	('CDKN2A', 'Gene', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('mutations', 'Var', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (32, 41))	('deletions', 'Var', (51, 60))	('CDKN2A', 'Gene', '1029', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('TP53', 'Gene', '7157', (45, 49))
601045	26455317	Specifically, mutations in TP53 and STAG2 occur in ~5-10% and ~15-20% of tumors, respectively.	('TP53', 'Gene', '7157', (27, 31))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('TP53', 'Gene', (27, 31))	('occur', 'Reg', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('STAG2', 'Gene', (36, 41))	('tumors', 'Disease', (73, 79))	('mutations', 'Var', (14, 23))
601046	26455317	Interestingly, almost all Ewing sarcoma cell lines exhibit mutations in p53, or members of the p53 pathway, which has led to the hypothesis that loss of p53 is required for the in vitro culture of Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (26, 39))	('Ewing sarcoma', 'Disease', (197, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (197, 210))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (197, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('p53', 'Gene', (153, 156))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (153, 156))	('mutations', 'Var', (59, 68))	('p53', 'Gene', '7157', (95, 98))
601056	26455317	In this work, we demonstrate that the doxycycline-inducible expression of EWS-FLI1 in embryoid bodies derived from human embryonic stem cells (hESC) with knockdown of p53 generates cells with an Ewing sarcoma-like phenotype, including properties of transformation and dependency on persistent EWS-FLI1 expression for survival.	('EWS-FLI1', 'Gene', '2130;2313', (293, 301))	('EWS-FLI1', 'Gene', (74, 82))	('Ewing sarcoma', 'Disease', (195, 208))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (195, 208))	('human', 'Species', '9606', (115, 120))	('transformation', 'CPA', (249, 263))	('knockdown', 'Var', (154, 163))	('EWS-FLI1', 'Gene', '2130;2313', (74, 82))	('p53', 'Gene', '7157', (167, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (195, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('doxycycline', 'Chemical', 'MESH:D004318', (38, 49))	('p53', 'Gene', (167, 170))	('EWS-FLI1', 'Gene', (293, 301))
601062	26455317	Similarly, western blot analysis also demonstrates constitutive knockdown of p53 (Figure 1C).	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('knockdown', 'Var', (64, 73))
601079	26455317	In agreement with this data, the removal of doxycycline from the EF+ cells had only a minimal effect on CD99 expression, but did lead to a 10-fold loss of c-Kit expression (Figure 2D).	('CD99', 'Gene', '4267', (104, 108))	('expression', 'MPA', (109, 119))	('expression', 'MPA', (161, 171))	('CD99', 'Gene', (104, 108))	('doxycycline', 'Chemical', 'MESH:D004318', (44, 55))	('removal', 'Var', (33, 40))	('loss', 'NegReg', (147, 151))	('c-Kit', 'Gene', (155, 160))	('c-Kit', 'Gene', '3815', (155, 160))
601090	26455317	Similarly, the EF+ cells are also more sensitive than the EFFib cell to treatment with additional drugs with reported lethality toward Ewing sarcoma cell lines, including YK-4-279 (inhibitor of the interaction between RNA helicase A and EWS-FLI1), mithramycin (DNA-binding drug) and LY294002 (PI3K pathway inhibitor) (Supplemental Figure S5).	('RNA helicase A', 'Gene', '1660', (218, 232))	('EWS-FLI1', 'Gene', '2130;2313', (237, 245))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (135, 148))	('LY294002', 'Chemical', 'MESH:C085911', (283, 291))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (135, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('Ewing sarcoma', 'Disease', (135, 148))	('EWS-FLI1', 'Gene', (237, 245))	('LY294002', 'Var', (283, 291))	('RNA helicase A', 'Gene', (218, 232))	('interaction', 'Interaction', (198, 209))	('mithramycin', 'Chemical', 'MESH:D008926', (248, 259))
601092	26455317	The EF+ cells also exhibited anchorage-independent growth and formed colonies in a soft agar assay (Figure 4B).	('anchorage-independent growth', 'CPA', (29, 57))	('exhibited', 'Reg', (19, 28))	('colonies in a soft agar assay', 'CPA', (69, 98))	('EF+', 'Var', (4, 7))	('agar', 'Chemical', 'MESH:D000362', (88, 92))
601129	26455317	We chose to knockdown p53 in our model system because mutations in this tumor suppressor occur in vivo in a subset of patients and, importantly, almost all Ewing sarcoma cell lines exhibit mutations in p53.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (156, 169))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (156, 169))	('tumor', 'Disease', (72, 77))	('mutations', 'Var', (54, 63))	('p53', 'Gene', (22, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', '7157', (202, 205))	('Ewing sarcoma', 'Disease', (156, 169))	('mutations', 'Var', (189, 198))	('patients', 'Species', '9606', (118, 126))	('p53', 'Gene', (202, 205))
601135	26455317	Tetraploidy is a common feature of tumors and transformed cells.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Tetraploidy', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
601136	26455317	A recent study that included a spectrum of eleven different tumor types identified whole genome doublings in 37% of tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('whole genome doublings', 'Var', (83, 105))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (116, 121))
601138	26455317	Although the impact of genome doubling in Ewing sarcoma tumors is not known, tetraploidy is also consistent with a transformed phenotype in the EF+ cells.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (42, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('Ewing sarcoma tumors', 'Disease', (42, 62))	('tetraploidy', 'Var', (77, 88))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (42, 62))
601139	26455317	Notably, in our system, the knockdown of p53 may have also contributed to the propagation of the EF+ tetraploid cells since p53 is a well-described barrier to tetraploidy.	('contributed', 'Reg', (59, 70))	('p53', 'Gene', '7157', (41, 44))	('p53', 'Gene', (124, 127))	('p53', 'Gene', '7157', (124, 127))	('propagation', 'CPA', (78, 89))	('knockdown', 'Var', (28, 37))	('p53', 'Gene', (41, 44))
601144	26455317	For example, the lack of xenograft tumors could reflect the need for additional genetic events, such as the loss of STAG2 or trisomy 8, for growth of the cells in the mouse.	('xenograft tumors', 'Disease', 'MESH:D009369', (25, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('loss', 'Var', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('trisomy 8', 'Gene', (125, 134))	('xenograft tumors', 'Disease', (25, 41))	('STAG2', 'Gene', (116, 121))	('mouse', 'Species', '10090', (167, 172))
601148	26455317	In addition to Ewing sarcoma gene sets, GSEA also identified enrichment for cell cycle gene sets in the EF+ versus EF- comparison.	('EF+', 'Var', (104, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (15, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (15, 28))	('GSEA', 'Chemical', '-', (40, 44))	('cell cycle gene sets', 'Gene', (76, 96))	('Ewing sarcoma', 'Disease', (15, 28))
601150	26455317	Cyclin D1, for example, is an established target of EWS-FLI1 and this gene was upregulated 8-fold in the EF+ cells relative to the EF- cells .	('EWS-FLI1', 'Gene', '2130;2313', (52, 60))	('Cyclin D1', 'Gene', '595', (0, 9))	('EF+', 'Var', (105, 108))	('upregulated', 'PosReg', (79, 90))	('Cyclin D1', 'Gene', (0, 9))	('EWS-FLI1', 'Gene', (52, 60))
601172	26455317	The media was then switched to DMEM supplemented with 10% FBS, 100_IU_ml  penicillin, 100 mug_ml  streptomycin and 1 mugml-1 doxycycline.	('100_IU_ml', 'Var', (63, 72))	('FBS', 'Disease', 'MESH:D005198', (58, 61))	('FBS', 'Disease', (58, 61))	('doxycycline', 'Chemical', 'MESH:D004318', (125, 136))
601176	26455317	Published data sets used in the gene expression analysis included GSE34620 (Ewing sarcoma), GSE14827 (osteosarcoma), and the Cancer Cell Line Encyclopedia (http://www.broadinstitute.org/ccle/home).	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (76, 89))	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('GSE14827', 'Var', (92, 100))	('osteosarcoma', 'Disease', 'MESH:D012516', (102, 114))	('GSE34620', 'Var', (66, 74))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (125, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (76, 89))	('Ewing sarcoma', 'Disease', (76, 89))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Cancer Cell Line Encyclopedia', 'Disease', (125, 154))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('osteosarcoma', 'Disease', (102, 114))
601191	25395177	These differences may impact on the development of antibody responses to KSHV and on the pathogenesis of KS.	('impact', 'Reg', (22, 28))	('KSHV', 'Species', '37296', (73, 77))	('differences', 'Var', (6, 17))	('KS', 'Phenotype', 'HP:0100726', (73, 75))	('antibody responses', 'CPA', (51, 69))	('KS', 'Phenotype', 'HP:0100726', (105, 107))
601211	25395177	Controls were selected from among HIV-seropositive adults without a diagnosis of KS during the study period using the following procedure: each case was classified by sex, age band (<= median age of 37 years or >=38 years) and CD4 count band (<=200 cells per muL, 201-500 cells per muL, >=501 cells per muL) at the time of their KS diagnosis.	('<=200 cells per', 'Var', (243, 258))	('HIV-seropositive', 'Disease', (34, 50))	('HIV-seropositive', 'Disease', 'MESH:D006679', (34, 50))	('KS', 'Phenotype', 'HP:0100726', (329, 331))	('CD4', 'Gene', (227, 230))	('201-500 cells per', 'Var', (264, 281))	('CD4', 'Gene', '920', (227, 230))	('KS', 'Phenotype', 'HP:0100726', (81, 83))
601269	25984718	PARP1 promotes DNA repair by undergoing a conformational change in response to single-strand and double-strand DNA breaks.	('single-strand', 'Var', (79, 92))	('promotes', 'PosReg', (6, 14))	('conformational change', 'MPA', (42, 63))	('PARP1', 'Gene', '142', (0, 5))	('DNA repair', 'MPA', (15, 25))	('PARP1', 'Gene', (0, 5))
601270	25984718	PARylation by PARP1 then leads to the recruitment of early DNA damage response factors, such as XRCC1, among many others.	('PARP1', 'Gene', (14, 19))	('XRCC1', 'Gene', '7515', (96, 101))	('XRCC1', 'Gene', (96, 101))	('recruitment', 'MPA', (38, 49))	('PARylation', 'Var', (0, 10))	('PARP1', 'Gene', '142', (14, 19))
601274	25984718	These PD assays include measurements on tissue samples and traditional pharmacodynamic measurements of tumor volume following repeated inhibitor treatment in mice bearing BRCA wild-type or BRCA mutant tumors.	('BRCA', 'Gene', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('BRCA', 'Gene', '672', (189, 193))	('mice', 'Species', '10090', (158, 162))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('BRCA', 'Gene', (189, 193))	('mutant', 'Var', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('PD', 'Disease', 'MESH:D010300', (6, 8))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('BRCA', 'Gene', '672', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
601288	25984718	We chose a panel of breast and ovarian cancer cell lines with either BRCA1 wild-type or mutant status, as well as several Ewing's sarcoma cell lines that are BRCA1 wild-type, but had been shown to be sensitive to PARP inhibitors (Supplementary Table S1).	("Ewing's sarcoma", 'Disease', (122, 137))	('BRCA1', 'Gene', '672', (69, 74))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (122, 137))	('mutant status', 'Var', (88, 101))	('BRCA1', 'Gene', (158, 163))	('PARP', 'Gene', (213, 217))	('ovarian cancer', 'Phenotype', 'HP:0100615', (31, 45))	('BRCA1', 'Gene', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('PARP', 'Gene', '142', (213, 217))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (122, 137))	('BRCA1', 'Gene', '672', (158, 163))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (20, 45))
601291	25984718	Some BRCA mutant cell lines had very low PARP1 expression (HCC1937), while others had high PARP1 expression (MDA-MB-436).	('PARP1', 'Gene', '142', (41, 46))	('expression', 'MPA', (97, 107))	('low', 'NegReg', (37, 40))	('mutant', 'Var', (10, 16))	('PARP1', 'Gene', (41, 46))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (109, 119))	('HCC1937', 'CellLine', 'CVCL:0290', (59, 66))	('BRCA', 'Gene', '672', (5, 9))	('PARP1', 'Gene', (91, 96))	('PARP1', 'Gene', '142', (91, 96))	('BRCA', 'Gene', (5, 9))	('expression', 'MPA', (47, 57))
601295	25984718	As expected, the BRCA1 mutant cell lines generally exhibited increased sensitivity to olaparib compared to the wild-type cell lines (Table 1 and Supplementary Table S1, EC50 column; Supplementary Fig.	('BRCA1', 'Gene', '672', (17, 22))	('sensitivity to olaparib', 'MPA', (71, 94))	('BRCA1', 'Gene', (17, 22))	('increased', 'PosReg', (61, 70))	('olaparib', 'Chemical', 'MESH:C531550', (86, 94))	('mutant', 'Var', (23, 29))
601308	25984718	We thus asked if this BRCA1 mutant cell line is either insensitive to olaparib or whether it simply required longer drug incubation to observe an increase in DSBs?	('mutant', 'Var', (28, 34))	('DSBs', 'Chemical', 'MESH:C007563', (158, 162))	('BRCA1', 'Gene', '672', (22, 27))	('olaparib', 'Chemical', 'MESH:C531550', (70, 78))	('BRCA1', 'Gene', (22, 27))	('DSBs', 'MPA', (158, 162))
601316	25984718	In general, the data in Table 1 and Supplementary Table S1 show that the BRCA mutant cell lines and the expected Ewing's sarcoma cell lines were sensitive to olaparib.	('BRCA', 'Gene', '672', (73, 77))	('olaparib', 'Chemical', 'MESH:C531550', (158, 166))	('BRCA', 'Gene', (73, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('sensitive', 'Reg', (145, 154))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (113, 128))	("Ewing's sarcoma", 'Disease', (113, 128))	('mutant', 'Var', (78, 84))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (113, 128))
601318	25984718	Supplementary Figure S4 shows that cisplatin treatment resulted in a statistically significant increase in the mean number of foci per nucleus, indicating the 53BP1trunc-Apple reporter functions as expected in vivo.	('Apple', 'Species', '3750', (170, 175))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('increase', 'PosReg', (95, 103))	('53BP1', 'Gene', (159, 164))	('53BP1', 'Gene', '7158', (159, 164))	('cisplatin', 'Var', (35, 44))
601320	25984718	We focused on three representative models in which serial measurements were carried out at different doses (50 or 100 mg/kg olaparib): MDA-MB-436 (breast cancer), HCC1937 (breast cancer), and MHH-ES1 (Ewing's sarcoma).	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', (147, 160))	('ES1', 'Gene', (196, 199))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (201, 216))	('MDA-MB-436', 'Var', (135, 145))	('breast cancer', 'Disease', (172, 185))	("Ewing's sarcoma", 'Disease', (201, 216))	('olaparib', 'Chemical', 'MESH:C531550', (124, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (201, 216))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('HCC1937', 'CellLine', 'CVCL:0290', (163, 170))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (135, 145))	('ES1', 'Gene', '8209', (196, 199))
601345	25984718	This suggests that not all BRCA1 mutant tumors undergo a DNA damage response following olaparib treatment.	('BRCA1', 'Gene', '672', (27, 32))	('DNA damage response', 'MPA', (57, 76))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('BRCA1', 'Gene', (27, 32))	('olaparib', 'Chemical', 'MESH:C531550', (87, 95))	('mutant', 'Var', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
601346	25984718	However, it is possible that the BRCA1 mutant tumor would shrink and respond to olaparib, perhaps through a different and yet unrealized mechanism.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('respond to olaparib', 'MPA', (69, 88))	('tumor', 'Disease', (46, 51))	('BRCA1', 'Gene', '672', (33, 38))	('mutant', 'Var', (39, 45))	('olaparib', 'Chemical', 'MESH:C531550', (80, 88))	('BRCA1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
601353	25984718	Moreover, olaparib was reevaluated based on BRCA status, with results showing overall survival in patients with defective BRCA protein.	('defective', 'Var', (112, 121))	('olaparib', 'Chemical', 'MESH:C531550', (10, 18))	('patients', 'Species', '9606', (98, 106))	('BRCA', 'Gene', '672', (44, 48))	('BRCA', 'Gene', (44, 48))	('BRCA', 'Gene', (122, 126))	('BRCA', 'Gene', '672', (122, 126))
601360	25984718	This line is BRCA1 mutant and has a low PD50 value after 6 days of olaparib treatment, indicating a strong increase in DSBs, but a high EC50 value over the same time frame, which indicates the cells do not die readily in response to olaparib.	('BRCA1', 'Gene', '672', (13, 18))	('EC50 value', 'MPA', (136, 146))	('low', 'NegReg', (36, 39))	('PD', 'Disease', 'MESH:D010300', (40, 42))	('BRCA1', 'Gene', (13, 18))	('increase', 'PosReg', (107, 115))	('olaparib', 'Chemical', 'MESH:C531550', (233, 241))	('mutant', 'Var', (19, 25))	('DSBs', 'MPA', (119, 123))	('olaparib', 'Chemical', 'MESH:C531550', (67, 75))	('DSBs', 'Chemical', 'MESH:C007563', (119, 123))
601362	25984718	In vivo we show with three different tumor models, two of which are BRCA1 mutant, that there is a difference in the number of DSBs observed depending on the daily dose of olaparib.	('DSBs', 'Chemical', 'MESH:C007563', (126, 130))	('olaparib', 'Chemical', 'MESH:C531550', (171, 179))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('BRCA1', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutant', 'Var', (74, 80))	('BRCA1', 'Gene', '672', (68, 73))
601374	25984718	Furthermore, these studies suggest that olaparib is most effective in cell lines with mutated p53.	('olaparib', 'Chemical', 'MESH:C531550', (40, 48))	('mutated', 'Var', (86, 93))	('p53', 'Gene', '7157', (94, 97))	('p53', 'Gene', (94, 97))
601375	25984718	Here, the cell lines studied in vivo all have mutant p53 status (and canSAR database).	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))
601382	25984718	We believe that the methodology we have established here to measure DSBs will be applicable not only to PARP inhibitors, but to other agents that also induce DSBs.	('DSBs', 'Chemical', 'MESH:C007563', (158, 162))	('inhibitors', 'Var', (109, 119))	('PARP', 'Gene', (104, 108))	('DSBs', 'Chemical', 'MESH:C007563', (68, 72))	('PARP', 'Gene', '142', (104, 108))
601437	25464386	Tumoral TP53 and/or CDKN2A Alterations are Not Reliable Prognostic Biomarkers in Patients with Localized Ewing Sarcoma: A Report from the Children's Oncology Group A growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma.	('Localized Ewing Sarcoma', 'Disease', 'MESH:C563168', (95, 118))	('Children', 'Species', '9606', (138, 146))	('CDKN2A', 'Gene', '1029', (252, 258))	('CDKN2A', 'Gene', '1029', (20, 26))	('TP53', 'Gene', '7157', (230, 234))	('Sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (301, 314))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (301, 314))	('Patients', 'Species', '9606', (81, 89))	('TP53', 'Gene', '7157', (8, 12))	('Oncology', 'Phenotype', 'HP:0002664', (149, 157))	('mutations', 'Var', (235, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (307, 314))	('Ewing sarcoma', 'Disease', (301, 314))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('CDKN2A', 'Gene', (252, 258))	('TP53', 'Gene', (230, 234))	('CDKN2A', 'Gene', (20, 26))	('TP53', 'Gene', (8, 12))	('Localized Ewing Sarcoma', 'Disease', (95, 118))	('deletions', 'Var', (259, 268))
601439	25464386	Of the 568 patients enrolled on Children's Oncology Group protocol AEWS0031 (NCT00006734), 112 had tumor specimens of sufficient quality and quantity to allow for analysis of TP53 mutations status by DNA sequencing, and CDKN2A deletion by dual color fluorescent in situ hybridization.	('tumor', 'Disease', (99, 104))	('TP53', 'Gene', (175, 179))	('Oncology', 'Phenotype', 'HP:0002664', (43, 51))	('mutations', 'Var', (180, 189))	('Children', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('EWS', 'Gene', '2130', (68, 71))	('EWS', 'Gene', (68, 71))	('CDKN2A', 'Gene', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('patients', 'Species', '9606', (11, 19))	('TP53', 'Gene', '7157', (175, 179))	('deletion', 'Var', (227, 235))	('CDKN2A', 'Gene', '1029', (220, 226))
601440	25464386	Eight of 93 cases (8.6%) were found to have TP53 point mutations and 12 of 107 cases (11.2%) demonstrated homozygous CDKN2A deletion.	('TP53', 'Gene', '7157', (44, 48))	('CDKN2A', 'Gene', (117, 123))	('deletion', 'Var', (124, 132))	('TP53', 'Gene', (44, 48))	('CDKN2A', 'Gene', '1029', (117, 123))
601441	25464386	There was no significant difference in event-free survival of patients with TP53 mutations and/or CDKN2A deletions compared to patients with normal TP53/CDKN2A gene status, as demonstrated by log rank test (p = 0.58).	('CDKN2A', 'Gene', (153, 159))	('deletions', 'Var', (105, 114))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('CDKN2A', 'Gene', '1029', (153, 159))	('TP53', 'Gene', '7157', (76, 80))	('patients', 'Species', '9606', (127, 135))	('CDKN2A', 'Gene', (98, 104))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('CDKN2A', 'Gene', '1029', (98, 104))	('patients', 'Species', '9606', (62, 70))
601442	25464386	Although previous retrospective studies suggest their significance, TP53 mutation and/or CDKN2A deletion are not reliable prognostic biomarkers in localized Ewing sarcoma.	('localized Ewing sarcoma', 'Disease', 'MESH:C563168', (147, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (157, 170))	('CDKN2A', 'Gene', (89, 95))	('localized Ewing sarcoma', 'Disease', (147, 170))	('deletion', 'Var', (96, 104))	('CDKN2A', 'Gene', '1029', (89, 95))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))
601459	25464386	Therefore, deletion of the CDKN2A locus usually results in the loss of p14ARF and p16INK4a, thus eliminating the growth inhibition provided by both the p53 and RB pathways.	('growth inhibition', 'MPA', (113, 130))	('p16INK4a', 'Gene', (82, 90))	('p53', 'Gene', (152, 155))	('eliminating', 'NegReg', (97, 108))	('p53', 'Gene', '7157', (152, 155))	('p14ARF', 'Gene', '1029', (71, 77))	('p16INK4a', 'Gene', '1029', (82, 90))	('CDKN2A', 'Gene', (27, 33))	('CDKN2A', 'Gene', '1029', (27, 33))	('deletion', 'Var', (11, 19))	('p14ARF', 'Gene', (71, 77))	('loss', 'NegReg', (63, 67))
601460	25464386	Alterations in p53 and p16INK4a proteins have been identified in approximately 10% and 20% of Ewing sarcoma cases, respectively.	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (94, 107))	('p16INK4a', 'Gene', (23, 31))	('identified', 'Reg', (51, 61))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (94, 107))	('Alterations', 'Var', (0, 11))	('proteins', 'Protein', (32, 40))	('p53', 'Gene', (15, 18))	('p16INK4a', 'Gene', '1029', (23, 31))	('p53', 'Gene', '7157', (15, 18))	('Ewing sarcoma', 'Disease', (94, 107))
601461	25464386	Over the past twenty years a growing series of retrospective studies have suggested that alterations in the p53 and p16INK4a pathways have prognostic significance in Ewing sarcoma.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (166, 179))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (166, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('p16INK4a', 'Gene', (116, 124))	('p16INK4a', 'Gene', '1029', (116, 124))	('Ewing sarcoma', 'Disease', (166, 179))	('alterations', 'Var', (89, 100))
601472	25464386	Dual color fluorescent in situ hybridization (FISH) was used to assess for deletion of the CDKN2A gene locus.	('CDKN2A', 'Gene', (91, 97))	('deletion', 'Var', (75, 83))	('CDKN2A', 'Gene', '1029', (91, 97))
601475	25464386	Positive and negative controls were established with a Malignant Fibrous Histiocytoma sample with a del(9)(p12p24) karyotype, and with a Ewing sarcoma sample demonstrating a +9 karyotype, respectively.	('Ewing sarcoma', 'Disease', (137, 150))	('del(9)(p12p24', 'Var', (100, 113))	('Malignant Fibrous Histiocytoma', 'Disease', (55, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('Malignant Fibrous Histiocytoma', 'Disease', 'MESH:D051677', (55, 85))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (137, 150))	('Histiocytoma', 'Phenotype', 'HP:0012315', (73, 85))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (137, 150))
601478	25464386	Controls for normal and mutant TP53 were normal peripheral blood lymphocyte DNA and known TP53 mutation-containing cell line DNA, respectively.	('mutant', 'Var', (24, 30))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (31, 35))	('TP53', 'Gene', (90, 94))
601479	25464386	The WGA DNA was subjected to PCR and sequencing for TP53 mutations as described above.	('mutations', 'Var', (57, 66))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))
601482	25464386	The study population was segregated into two subpopulations according to the presence (yes v. no) of a TP53 gene mutation and/or CDKN2A allele deletion.	('TP53', 'Gene', '7157', (103, 107))	('mutation', 'Var', (113, 121))	('TP53', 'Gene', (103, 107))	('CDKN2A', 'Gene', (129, 135))	('CDKN2A', 'Gene', '1029', (129, 135))
601483	25464386	The prognostic significance of a TP53 mutation and/or CDKN2A deletion was assessed using a two-sided log rank test.	('deletion', 'Var', (61, 69))	('CDKN2A', 'Gene', (54, 60))	('TP53', 'Gene', '7157', (33, 37))	('CDKN2A', 'Gene', '1029', (54, 60))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))
601485	25464386	The secondary goals for the study were to estimate the incidence of TP53 mutations and CDKN2A deletion in tumor samples derived from the population of patients with localized Ewing sarcoma.	('deletion', 'Var', (94, 102))	('CDKN2A', 'Gene', '1029', (87, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('localized Ewing sarcoma', 'Disease', 'MESH:C563168', (165, 188))	('patients', 'Species', '9606', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('localized Ewing sarcoma', 'Disease', (165, 188))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (175, 188))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', (106, 111))	('CDKN2A', 'Gene', (87, 93))
601486	25464386	In determining whether the evaluated population of 112 patients was representative of the entire protocol population (n = 568) and the prognostic significance of TP53/CDKN2A alterations, subgroup analysis of standard and interval-compressed protocols was not performed in order to maintain statistically significant populations.	('TP53', 'Gene', '7157', (162, 166))	('CDKN2A', 'Gene', (167, 173))	('TP53', 'Gene', (162, 166))	('CDKN2A', 'Gene', '1029', (167, 173))	('alterations', 'Var', (174, 185))	('patients', 'Species', '9606', (55, 63))
601488	25464386	Chi-squared and Fisher's exact test were used as appropriate to identify significant demographic and/or outcome variances between the evaluated study group versus the protocol enrolled group at large, and between patients with versus without TP53/CDKN2A alterations.	('alterations', 'Var', (254, 265))	('CDKN2A', 'Gene', (247, 253))	('TP53', 'Gene', '7157', (242, 246))	('CDKN2A', 'Gene', '1029', (247, 253))	('TP53', 'Gene', (242, 246))	('patients', 'Species', '9606', (213, 221))
601491	25464386	Ninety-three of 112 patient tumor specimens (83%) yielded genomic DNA that was of sufficient quantity and quality to be evaluated for TP53 mutation.	('tumor', 'Disease', (28, 33))	('mutation', 'Var', (139, 147))	('TP53', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('patient', 'Species', '9606', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('TP53', 'Gene', '7157', (134, 138))
601493	25464386	Seven of eight TP53 alterations occurred within a region commonly affected by oncogenic mutations.	('alterations', 'Var', (20, 31))	('occurred', 'Reg', (32, 40))	('TP53', 'Gene', (15, 19))	('TP53', 'Gene', '7157', (15, 19))
601494	25464386	Dual color FISH identified homozygous CDKN2A deletions in 12 of 107 analyzable specimens, demonstrating a CDKN2A loss incidence of 11.2%.	('loss', 'NegReg', (113, 117))	('CDKN2A', 'Gene', (106, 112))	('deletions', 'Var', (45, 54))	('CDKN2A', 'Gene', (38, 44))	('CDKN2A', 'Gene', '1029', (106, 112))	('CDKN2A', 'Gene', '1029', (38, 44))
601497	25464386	Eighty-nine (79.5%) of the initial 112 specimens were analyzable for both TP53 mutation and CDKN2A deletion.	('CDKN2A', 'Gene', (92, 98))	('CDKN2A', 'Gene', '1029', (92, 98))	('TP53', 'Gene', '7157', (74, 78))	('mutation', 'Var', (79, 87))	('deletion', 'Var', (99, 107))	('TP53', 'Gene', (74, 78))
601504	25464386	Comparison in patient outcomes between those whose tumors harbored mutations in TP53 versus those who did not demonstrated a statistically similar EFS for the two groups (p = 0.26; Figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TP53', 'Gene', '7157', (80, 84))	('mutations', 'Var', (67, 76))	('TP53', 'Gene', (80, 84))	('tumors', 'Disease', (51, 57))	('patient', 'Species', '9606', (14, 21))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
601505	25464386	TP53 mutation was found to have an insignificant relative hazard ratio of 1.8288 [95% CI: 0.645 to 5.1856] compared to the wild-type gene (Table III).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
601506	25464386	It should be noted that in this study a trend was observed, that patients with TP53 mutations represented an older population compared to patients without TP53 mutations (p = 0.67, Table IV).	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', '7157', (155, 159))	('TP53', 'Gene', (79, 83))	('TP53', 'Gene', (155, 159))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (138, 146))
601507	25464386	Additionally, patients with TP53 mutations were racially diverse (75% Caucasian) compared to patients without TP53 mutation (95% Caucasian, p = 0.014, Table IV).	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (93, 101))
601508	25464386	However, given the small number of patients with p53 mutation (n = 8) the racial difference is accounted for by two patients, one who self-identified as Asian and another as African-American.	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (49, 52))	('mutation', 'Var', (53, 61))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (35, 43))
601509	25464386	Non-Caucasian race and older age at diagnosis portends a worse prognosis than Caucasian and younger patients, thus any difference between TP53 mutant and non-mutant populations should have been accentuated by the age and race differences between these groups; despite this, no difference was observed.	('TP53', 'Gene', '7157', (138, 142))	('mutant', 'Var', (143, 149))	('prognosis', 'MPA', (63, 72))	('TP53', 'Gene', (138, 142))	('patients', 'Species', '9606', (100, 108))
601510	25464386	Comparison in patient outcomes between those whose tumors contained CDKN2A deletion and those who did not, also demonstrated a statistically similar EFS (p = 0.91; Figure 2C) and an insignificant relative hazard ratio (0.9397 [95% CI: 0.3337 to 2.6459], Table III) between the two groups.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('deletion', 'Var', (75, 83))	('CDKN2A', 'Gene', (68, 74))	('tumors', 'Disease', (51, 57))	('patient', 'Species', '9606', (14, 21))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('CDKN2A', 'Gene', '1029', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
601511	25464386	Patients with and without CDKN2A deletions were demographically equivalent (Table IV).	('CDKN2A', 'Gene', '1029', (26, 32))	('Patients', 'Species', '9606', (0, 8))	('deletions', 'Var', (33, 42))	('CDKN2A', 'Gene', (26, 32))
601513	25464386	To determine if alteration in either TP53 and/or CDKN2A correlated with EFS in patients with localized Ewing sarcoma, we considered the evaluable population for either alteration in toto.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (103, 116))	('CDKN2A', 'Gene', '1029', (49, 55))	('alteration', 'Var', (16, 26))	('EFS', 'Disease', (72, 75))	('patients', 'Species', '9606', (79, 87))	('TP53', 'Gene', '7157', (37, 41))	('localized Ewing sarcoma', 'Disease', 'MESH:C563168', (93, 116))	('TP53', 'Gene', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('CDKN2A', 'Gene', (49, 55))	('correlated', 'Reg', (56, 66))	('localized Ewing sarcoma', 'Disease', (93, 116))
601514	25464386	This study identified an incidence of TP53 mutation (8.4%) and CDKN2A deletion (11.2%) in tumor specimens from patients with Ewing sarcoma that was consistent with rates identified in previous series.	('deletion', 'Var', (70, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('CDKN2A', 'Gene', '1029', (63, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('mutation', 'Var', (43, 51))	('TP53', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('patients', 'Species', '9606', (111, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Ewing sarcoma', 'Disease', (125, 138))	('CDKN2A', 'Gene', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('TP53', 'Gene', '7157', (38, 42))
601522	25464386	Regardless, the 112 specimens in the current study is a larger population than any prior which has shown prognostic significance of TP53/CDKN2A alterations.	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('CDKN2A', 'Gene', '1029', (137, 143))	('CDKN2A', 'Gene', (137, 143))	('alterations', 'Var', (144, 155))
601523	25464386	The largest retrospective review was able to assess 107 specimens for TP53 mutations and/or CDKN2A deletions; consistent with our findings, their multivariate analysis failed to demonstrate an association between these genetic alterations and progression free or disease specific survival.	('CDKN2A', 'Gene', (92, 98))	('progression free', 'CPA', (243, 259))	('deletions', 'Var', (99, 108))	('disease specific survival', 'CPA', (263, 288))	('TP53', 'Gene', '7157', (70, 74))	('CDKN2A', 'Gene', '1029', (92, 98))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))
601527	25464386	This region of p53 contains 90% of the identified oncogenic mutations and the DNA binding domain.	('mutations', 'Var', (60, 69))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (15, 18))
601528	25464386	Using this strategy we identified a TP53 mutation rate of 8.6%.	('mutation', 'Var', (41, 49))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
601531	25464386	While this may have caused false negative results if small deletion segments were missed, our CDKN2A homozygous deletion rate of 11.2% was consistent with previously published reports of 7% to 21%.	('CDKN2A', 'Gene', '1029', (94, 100))	('CDKN2A', 'Gene', (94, 100))	('deletion', 'Var', (112, 120))
601535	25464386	Although the evaluation of TP53 and CKDN2A alterations in patients with localized Ewing sarcoma is a meaningful clinical question, we recognize the value of other genomic questions and the scarcity of tumor specimen tissue.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('patients', 'Species', '9606', (58, 66))	('CKDN2A', 'Gene', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('localized Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 95))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (82, 95))	('alterations', 'Var', (43, 54))	('tumor', 'Disease', (201, 206))	('localized Ewing sarcoma', 'Disease', (72, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
601540	25464386	Despite early optimism, TP53/CDKN2A alterations prove to be unreliable biomarkers.	('CDKN2A', 'Gene', (29, 35))	('CDKN2A', 'Gene', '1029', (29, 35))	('TP53', 'Gene', (24, 28))	('alterations', 'Var', (36, 47))	('TP53', 'Gene', '7157', (24, 28))
601606	23785414	Compared to the general Italian population, there was a dramatic reduction in mortality over time in transplanted patients both without (standardized Mortality Ratios -SMR - from 59.7 in 1983-1989 to 2,9 in 2005-2010), and with DNT (SMR from 269.2 in 1983-1989 to 5.2 in 2005-2010) compared to the Italian Mortality Rates (data not shown).	('mortality', 'MPA', (78, 87))	('DNT', 'Var', (228, 231))	('DNT', 'Chemical', '-', (228, 231))	('patients', 'Species', '9606', (114, 122))	('reduction', 'NegReg', (65, 74))
601793	33218178	Support for this was provided in a more recent study, were mutations associated with ultraviolet radiation damage were found at similar rates among AYAs compared with older patients.	('radiation damage', 'Disease', (97, 113))	('radiation damage', 'Disease', 'MESH:D011832', (97, 113))	('mutations', 'Var', (59, 68))	('patients', 'Species', '9606', (173, 181))
601852	33218178	This likely relates in part to delays in diagnosis and higher frequencies of driver mutations (e.g., EGFR and ALK mutations in lung cancer patients).	('lung cancer', 'Disease', (127, 138))	('patients', 'Species', '9606', (139, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('mutations', 'Var', (114, 123))	('ALK', 'Gene', '238', (110, 113))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ALK', 'Gene', (110, 113))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('higher', 'PosReg', (55, 61))
601904	29721066	This loss of ASS1 expression makes cancers sensitive to arginine starvation that is induced by PEGylated arginine deiminase (ADI-PEG20).	('PEG', 'Chemical', '-', (95, 98))	('PEGylated', 'Var', (95, 104))	('PEG', 'Chemical', '-', (129, 132))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('arginine', 'Chemical', 'MESH:D001120', (56, 64))	('loss', 'NegReg', (5, 9))	('ASS1', 'Gene', (13, 17))	('arginine', 'Chemical', 'MESH:D001120', (105, 113))	('ASS1', 'Gene', '445', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('sensitive', 'Reg', (43, 52))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
601909	29721066	Methods: Within this study, we assess the utility of a novel positron emission tomography (PET) tracer to determine sarcomas reliant on extracellular arginine for survival by measuring changes in amino acid transport in arginine auxotrophic sarcoma cells treated with ADI-PEG20.	('sarcomas', 'Disease', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (241, 248))	('amino acid transport', 'MPA', (196, 216))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (268, 277))	('arginine', 'Chemical', 'MESH:D001120', (150, 158))	('arginine', 'Chemical', 'MESH:D001120', (220, 228))	('auxotrophic sarcoma', 'Disease', (229, 248))	('ADI-PEG20', 'Var', (268, 277))	('changes', 'Reg', (185, 192))	('sarcomas', 'Disease', 'MESH:D012509', (116, 124))	('auxotrophic sarcoma', 'Disease', 'MESH:D012509', (229, 248))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
601912	29721066	Results: In vitro studies revealed that in response to ADI-PEG20 treatment, arginine auxotrophs increase the uptake of L-[3H]arginine and [18F]AFETP due to an increase in the expression and localization to the plasma membrane of the cationic amino acid transporter CAT-1.	('AFETP', 'Chemical', 'MESH:C558631', (143, 148))	('[18F]AFETP', 'Var', (138, 148))	('expression', 'MPA', (175, 185))	('CAT-1', 'Gene', '6541', (265, 270))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (55, 64))	('uptake of L-[3H]arginine', 'MPA', (109, 133))	('18F', 'Chemical', 'MESH:C000615276', (139, 142))	('localization', 'MPA', (190, 202))	('L-[3H]arginine', 'Chemical', '-', (119, 133))	('CAT-1', 'Gene', (265, 270))	('arginine', 'Chemical', 'MESH:D001120', (76, 84))	('increase', 'PosReg', (96, 104))	('ADI-PEG20', 'Var', (55, 64))	('arginine', 'Chemical', 'MESH:D001120', (125, 133))	('increase', 'PosReg', (159, 167))
601913	29721066	Furthermore, in vivo PET imaging studies in mice with arginine-dependent osteosarcoma xenografts showed increased [18F]AFETP uptake in tumors 4 days after ADI-PEG20 treatment compared to baseline.	('arginine', 'Chemical', 'MESH:D001120', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('[18F]AFETP uptake', 'MPA', (114, 131))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (155, 164))	('increased', 'PosReg', (104, 113))	('18F', 'Chemical', 'MESH:C000615276', (115, 118))	('osteosarcoma', 'Phenotype', 'HP:0002669', (73, 85))	('osteosarcoma', 'Disease', (73, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (73, 85))	('tumors', 'Disease', (135, 141))	('ADI-PEG20', 'Var', (155, 164))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('mice', 'Species', '10090', (44, 48))	('AFETP', 'Chemical', 'MESH:C558631', (119, 124))
601915	29721066	These findings indicate that [18F]AFETP-PET may be suitable for the early detection of tumor response to arginine depletion due to ADI-PEG20 treatment.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (131, 140))	('tumor', 'Disease', (87, 92))	('18F', 'Chemical', 'MESH:C000615276', (30, 33))	('ADI-PEG20', 'Var', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('arginine', 'Chemical', 'MESH:D001120', (105, 113))	('AFETP', 'Chemical', 'MESH:C558631', (34, 39))
601921	29721066	Dysregulation of tumor metabolism is emerging as a key event in cancer growth and tumorigenesis.	('tumor', 'Disease', (17, 22))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
601922	29721066	The lack of ASS1 renders the tumors arginine auxotrophs, requiring exogenous arginine for cellular processes including growth, proliferation, and survival.	('arginine', 'Chemical', 'MESH:D001120', (77, 85))	('ASS1', 'Gene', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('ASS1', 'Gene', '445', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('lack', 'Var', (4, 8))	('tumors', 'Disease', (29, 35))	('arginine', 'Chemical', 'MESH:D001120', (36, 44))
601929	29721066	Several families of specialized biological transporter systems can mediate the uptake of L-arginine and other cationic amino acids from the extracellular space including systems y+, b0,+AT, ATB0,+ and y+L.	('uptake', 'MPA', (79, 85))	('b0,+AT', 'Gene', '11136;570', (182, 188))	('y+L', 'Var', (201, 204))	('ATB0', 'Gene', '6510', (190, 194))	('L-arginine', 'Chemical', 'MESH:D001120', (89, 99))	('ATB0', 'Gene', (190, 194))
601936	29721066	[18F]AFETP is structurally similar to the natural amino acid L-histidine and enters cells in part through the cationic amino acid transporters.	('amino acid L-histidine', 'Chemical', '-', (50, 72))	('AFETP', 'Gene', (5, 10))	('18F', 'Chemical', 'MESH:C000615276', (1, 4))	('AFETP', 'Chemical', 'MESH:C558631', (5, 10))	('[18F]', 'Var', (0, 5))	('cationic amino acid transporters', 'MPA', (110, 142))
601944	29721066	Furthermore, ASS1 expression was either increased or expressed upon ADI-PEG20 treatment (Fig 1A).	('ASS1', 'Gene', '445', (13, 17))	('ADI-PEG20 treatment', 'Var', (68, 87))	('expression', 'MPA', (18, 28))	('increased', 'PosReg', (40, 49))	('ASS1', 'Gene', (13, 17))	('expressed', 'Reg', (53, 62))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (68, 77))
601945	29721066	The effect of ADI-PEG20 on cell growth, in vitro, was assessed in both ASS-positive sarcoma cell lines and those lacking expression of the enzyme.	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Disease', (84, 91))	('ADI-PEG20', 'Var', (14, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (14, 23))
601948	29721066	In ASS1-negative cell lines unable to make arginine, normalized L-[3H]arginine uptake increased by 2.1 +- 0.8 fold (SKLMS1) and 3.2 +- 0.5 fold (MMNG) compared to control conditions after 72 hours of ADI-PEG20 treatment while the ASS1-positive cell line MG63 showed a 0.7 +- 0.2 fold change in normalized L-[3H]arginine uptake with ADI-PEG20 treatment (see Fig 1C).	('arginine', 'Chemical', 'MESH:D001120', (43, 51))	('ASS1', 'Gene', '445', (3, 7))	('L-[3H]arginine uptake', 'MPA', (305, 326))	('ADI-PEG20', 'Var', (332, 341))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (200, 209))	('arginine', 'Chemical', 'MESH:D001120', (311, 319))	('arginine', 'Chemical', 'MESH:D001120', (70, 78))	('L-[3H]arginine', 'Chemical', '-', (305, 319))	('L-[3H]arginine', 'Chemical', '-', (64, 78))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (332, 341))	('ASS1', 'Gene', '445', (230, 234))	('ASS1', 'Gene', (230, 234))	('SKLMS1', 'CellLine', 'CVCL:0628', (116, 122))	('ASS1', 'Gene', (3, 7))	('MG63', 'Chemical', '-', (254, 258))
601951	29721066	Immunoblot analysis of seven transporters, CAT-1, CAT-2, CAT-3, y+LAT1, y+LAT2, bo+AT and ATB0+0, demonstrated that only CAT-1 transporter expression was increased in response to ADI-PEG20 treatment, whereas CAT-2, CAT-3, y+LAT1, y+LAT2, bo+AT and ATB0,+ expression levels were found to remain constant or decrease upon arginine starvation (Fig 2).	('AT', 'Disease', 'None', (67, 69))	('y+LAT2', 'Gene', (72, 78))	('AT', 'Disease', 'None', (75, 77))	('ADI-PEG20', 'Var', (179, 188))	('AT', 'Disease', 'None', (122, 124))	('AT', 'Disease', 'None', (44, 46))	('CAT-3', 'Gene', '84889', (215, 220))	('AT', 'Disease', 'None', (209, 211))	('AT', 'Disease', 'None', (233, 235))	('AT', 'Disease', 'None', (58, 60))	('CAT-3', 'Gene', (57, 62))	('CAT-2', 'Gene', '6542', (208, 213))	('AT', 'Disease', 'None', (51, 53))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (179, 188))	('AT', 'Disease', 'None', (241, 243))	('AT', 'Disease', 'None', (83, 85))	('CAT-2', 'Gene', '6542', (50, 55))	('AT', 'Disease', 'None', (90, 92))	('y+LAT2', 'Gene', (230, 236))	('AT', 'Disease', 'None', (225, 227))	('AT', 'Disease', 'None', (216, 218))	('CAT-3', 'Gene', (215, 220))	('CAT-2', 'Gene', (208, 213))	('arginine', 'Chemical', 'MESH:D001120', (320, 328))	('increased', 'PosReg', (154, 163))	('CAT-2', 'Gene', (50, 55))	('AT', 'Disease', 'None', (248, 250))	('CAT-1', 'Gene', (43, 48))	('y+LAT2', 'Gene', '9057', (72, 78))	('CAT-1', 'Gene', (121, 126))	('ATB0', 'Gene', (248, 252))	('y+LAT1', 'Gene', (222, 228))	('CAT-1', 'Gene', '6541', (43, 48))	('ATB0', 'Gene', (90, 94))	('y+LAT1', 'Gene', (64, 70))	('CAT-1', 'Gene', '6541', (121, 126))	('y+LAT2', 'Gene', '9057', (230, 236))	('ATB0', 'Gene', '6510', (248, 252))	('y+LAT1', 'Gene', '9056', (222, 228))	('ATB0', 'Gene', '6510', (90, 94))	('y+LAT1', 'Gene', '9056', (64, 70))	('CAT-3', 'Gene', '84889', (57, 62))	('expression', 'MPA', (139, 149))
601952	29721066	CAT-1 protein expression was also found to increase in MG63 in response to extracellular arginine depletion with ADI-PEG20, but this finding did not correlate with increased extracellular L-[3H]arginine uptake (Fig 1C).	('protein', 'Protein', (6, 13))	('MG63', 'Chemical', '-', (55, 59))	('CAT-1', 'Gene', (0, 5))	('arginine', 'Chemical', 'MESH:D001120', (194, 202))	('ADI-PEG20', 'Var', (113, 122))	('arginine', 'Chemical', 'MESH:D001120', (89, 97))	('MG63', 'Gene', (55, 59))	('response to extracellular arginine depletion', 'MPA', (63, 107))	('expression', 'MPA', (14, 24))	('increase', 'PosReg', (43, 51))	('L-[3H]arginine', 'Chemical', '-', (188, 202))	('CAT-1', 'Gene', '6541', (0, 5))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (113, 122))
601954	29721066	In response to ADI-PEG20 treatment, CAT-1 was observed to alter its localization, with increased abundance seen at the plasma membrane (Fig 3).	('ADI-PEG20', 'Chemical', 'MESH:C512527', (15, 24))	('CAT-1', 'Gene', '6541', (36, 41))	('alter', 'Reg', (58, 63))	('localization', 'MPA', (68, 80))	('CAT-1', 'Gene', (36, 41))	('ADI-PEG20', 'Var', (15, 24))
601955	29721066	Though CAT-3 expression could not be reliably determined by IF after multiple attempts, the other five cationic amino acid transporters examined were not dramatically altered by ADI-PEG20 treatment (Fig 3).	('ADI-PEG20', 'Var', (178, 187))	('CAT-3', 'Gene', '84889', (7, 12))	('CAT-3', 'Gene', (7, 12))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (178, 187))
601959	29721066	After 72 h of ADI-PEG20-induced arginine starvation, [18F]AFETP uptake was increased in the ADI-sensitive SKLMS1 and MNNG cell lines by 2.2 +- 0.4 and 1.5 +- 0.3 respectively, but not the ADI-resistant cell line MG63 where a 1.1 +- 0.1 fold change was observed with ADI-PEG20 treatment.	('AFETP', 'Chemical', 'MESH:C558631', (58, 63))	('SKLMS1', 'CellLine', 'CVCL:0628', (106, 112))	('[18F]AFETP uptake', 'MPA', (53, 70))	('ADI-PEG20-induced', 'Var', (14, 31))	('18F', 'Chemical', 'MESH:C000615276', (54, 57))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (266, 275))	('increased', 'PosReg', (75, 84))	('arginine', 'Chemical', 'MESH:D001120', (32, 40))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (14, 23))	('MG63', 'Chemical', '-', (212, 216))
601963	29721066	To test the ability of [18F]AFETP to monitor response to ADI-PEG20 in vivo, small animal PET studies were performed before and after ADI-PEG20 treatment in a mouse model of arginine-dependent sarcoma.	('ADI-PEG20', 'Var', (133, 142))	('mouse', 'Species', '10090', (158, 163))	('AFETP', 'Chemical', 'MESH:C558631', (28, 33))	('arginine-dependent', 'Disease', (173, 191))	('sarcoma', 'Disease', 'MESH:D012509', (192, 199))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (57, 66))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (133, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('sarcoma', 'Disease', (192, 199))	('arginine', 'Chemical', 'MESH:D001120', (173, 181))	('18F', 'Chemical', 'MESH:C000615276', (24, 27))
601965	29721066	Once tumors volume reached between 200-500 mm3, mice were treated with 320 IU/m2 (29.1 mg/m2) ADI-PEG20 once every three days.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (94, 103))	('mice', 'Species', '10090', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('ADI-PEG20', 'Var', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
601967	29721066	In all animals, the tumors were clearly visualized above background tissues at baseline and after treatment with ADI-PEG20.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('ADI-PEG20', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (113, 122))
601968	29721066	These studies also demonstrated visually increased tracer uptake in the most of tumor xenografts at day 4 of ADI-PEG20 treatment (Fig 5A, B).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('ADI-PEG20', 'Var', (109, 118))	('increased', 'PosReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (109, 118))	('tracer uptake', 'MPA', (51, 64))
601969	29721066	The average tumor to skeletal muscle ratios +- SD were 2.3 +- 0.6 on day 0 (prior to ADI-PEG20), 2 and 4, 3.0 +- 1.5 on day 2 of ADI-PEG20 administration, and 3.2 +- 1 on day 4 of ADI-PEG20 administration (Fig 5B; n=6 animals).	('ADI-PEG20', 'Chemical', 'MESH:C512527', (180, 189))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (129, 138))	('tumor', 'Disease', (12, 17))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (85, 94))	('ADI-PEG20', 'Var', (129, 138))
601971	29721066	Changes in tumor size can affect PET measurements of standardized uptake values (SUVs) due to partial volume averaging, particularly when lesions are close to the resolution limits of PET.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('partial volume', 'Var', (94, 108))	('affect', 'Reg', (26, 32))	('standardized uptake values', 'MPA', (53, 79))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
601977	29721066	However, the present studies do not entirely exclude a contribution of increasing tumor size to the increased tumor to muscle ratios observed at day 4 of ADI-PEG20 therapy.	('increased', 'PosReg', (100, 109))	('ADI-PEG20', 'Var', (154, 163))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (154, 163))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
601982	29721066	Outside of the sarcoma field, ADI-PEG20 has been used in combination with other anti-proliferative drugs such as cisplatin, gemcitabine, and pemetrexed.	('ADI-PEG20', 'Var', (30, 39))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcoma', 'Disease', (15, 22))	('gemcitabine', 'Chemical', 'MESH:C056507', (124, 135))	('pemetrexed', 'Chemical', 'MESH:D000068437', (141, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (30, 39))
601986	29721066	In our study, the18F-labeled amino acid AFETP was used as a surrogate to monitor the upregulation of amino acids transport in response to ADI-PEG20 in an established preclinical animal model of sarcoma.	('ADI-PEG20', 'Chemical', 'MESH:C512527', (138, 147))	('amino acid AFETP', 'Chemical', '-', (29, 45))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('ADI-PEG20', 'Var', (138, 147))	('sarcoma', 'Disease', (194, 201))	('amino acids transport', 'MPA', (101, 122))	('18F', 'Chemical', 'MESH:C000615276', (17, 20))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('upregulation', 'PosReg', (85, 97))
601990	29721066	In addition, IF was done to see if transporter translocation changes occurred upon ADI-PEG20 treatment, as localization may be more important than total expression for arginine uptake.	('ADI-PEG20', 'Chemical', 'MESH:C512527', (83, 92))	('changes', 'Reg', (61, 68))	('ADI-PEG20', 'Var', (83, 92))	('transporter translocation', 'MPA', (35, 60))	('arginine', 'Chemical', 'MESH:D001120', (168, 176))
601991	29721066	Again, the results demonstrated that only CAT-1 translocated to the plasma membrane in response ADI-PEG20 treatment.	('CAT-1', 'Gene', (42, 47))	('translocated to the plasma membrane', 'MPA', (48, 83))	('ADI-PEG20 treatment', 'Var', (96, 115))	('CAT-1', 'Gene', '6541', (42, 47))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (96, 105))
601993	29721066	This would suggest that CAT1 expression and translocation may be controlled by sensing extracellular arginine concentrations, given the fact that MG63 can produce its own intracellular arginine because of its high ASS1 expression.	('intracellular arginine', 'MPA', (171, 193))	('CAT1', 'Gene', '6541', (24, 28))	('MG63', 'Chemical', '-', (146, 150))	('translocation', 'MPA', (44, 57))	('produce', 'MPA', (155, 162))	('ASS1', 'Gene', '445', (214, 218))	('arginine', 'Chemical', 'MESH:D001120', (185, 193))	('ASS1', 'Gene', (214, 218))	('CAT1', 'Gene', (24, 28))	('MG63', 'Var', (146, 150))	('arginine', 'Chemical', 'MESH:D001120', (101, 109))	('expression', 'MPA', (29, 39))
601994	29721066	ADI-PEG20 induces a starvation response that leads to the destruction of various proteins in an effort to provide a source of arginine.	('destruction of various proteins', 'MPA', (58, 89))	('leads to', 'Reg', (45, 53))	('ADI-PEG20', 'Var', (0, 9))	('arginine', 'Chemical', 'MESH:D001120', (126, 134))	('induces', 'Reg', (10, 17))	('starvation', 'MPA', (20, 30))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (0, 9))
601996	29721066	Altogether, this result could suggest that selective CAT-1 substrates inhibitors may be effective in improving the response to ADI-PEG20 for induced arginine starvation.	('improving', 'PosReg', (101, 110))	('CAT-1', 'Gene', '6541', (53, 58))	('arginine', 'Chemical', 'MESH:D001120', (149, 157))	('inhibitors', 'Var', (70, 80))	('CAT-1', 'Gene', (53, 58))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (127, 136))
601998	29721066	The glucose analogue [18F]FDG does not appear to be useful for monitoring response to ADI-PEG20 treatment, as demonstrated by the decreased uptake in bladder cancer, which could be due to the rewiring of glucose metabolism by the treatment ADI-PEG20 and not due to tumor death.	('glucose', 'Chemical', 'MESH:D005947', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('18F', 'Chemical', 'MESH:C000615276', (22, 25))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (86, 95))	('ADI-PEG20', 'Var', (240, 249))	('tumor death', 'Disease', 'MESH:D003643', (265, 276))	('glucose', 'Chemical', 'MESH:D005947', (204, 211))	('glucose metabolism', 'MPA', (204, 222))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('bladder cancer', 'Disease', (150, 164))	('uptake', 'MPA', (140, 146))	('tumor death', 'Disease', (265, 276))	('decreased', 'NegReg', (130, 139))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (240, 249))
601999	29721066	The uptake of [18F]AFETP is more closely related to the mechanism of cellular arginine uptake in response to ADI-PEG20 than is glucose metabolism measured with [18F]FDG.	('ADI-PEG20', 'Var', (109, 118))	('arginine', 'Chemical', 'MESH:D001120', (78, 86))	('cellular arginine uptake', 'MPA', (69, 93))	('18F', 'Chemical', 'MESH:C000615276', (15, 18))	('AFETP', 'Chemical', 'MESH:C558631', (19, 24))	('glucose', 'Chemical', 'MESH:D005947', (127, 134))	('ADI-PEG20', 'Chemical', 'MESH:C512527', (109, 118))	('18F', 'Chemical', 'MESH:C000615276', (161, 164))
602001	29721066	Given the possible heterogeneity of ASS1 expression in patients with multiple tumors and the unknown time frame of resistance due to ASS1 expression in patients with ASS1-deficient tumors, changes in [18F]AFETP uptake may be an early indication of tumor response to treatment.	('ASS1-deficient tumors', 'Disease', 'MESH:D009369', (166, 187))	('ASS1', 'Gene', (166, 170))	('ASS1', 'Gene', '445', (166, 170))	('ASS1', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ASS1', 'Gene', '445', (133, 137))	('ASS1-deficient tumors', 'Disease', (166, 187))	('AFETP', 'Chemical', 'MESH:C558631', (205, 210))	('changes', 'Var', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (248, 253))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('ASS1', 'Gene', (36, 40))	('multiple tumors', 'Disease', 'MESH:D009369', (69, 84))	('ASS1', 'Gene', '445', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('patients', 'Species', '9606', (152, 160))	('18F', 'Chemical', 'MESH:C000615276', (201, 204))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('multiple tumors', 'Disease', (69, 84))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('patients', 'Species', '9606', (55, 63))
602101	28619077	found that survival was higher in patients treated with surgery and PORT than in those treated with radiotherapy alone (81% and 78% vs 36% at 3 years, respectively).	('PORT', 'Var', (68, 72))	('higher', 'PosReg', (24, 30))	('patients', 'Species', '9606', (34, 42))	('survival', 'MPA', (11, 19))
602191	32776977	KSHV vIRFs (vIRF1 to vIRF4) are encoded by a cluster of ORFs (ORFs-K9, -K11/11.1, -K10.5/10.6, and -K10), which are resided between ORF57 and ORF58 of the viral genome and transcribed in the opposite orientation.	('vIRF4', 'Gene', (21, 26))	('K10', 'Gene', (83, 86))	('KSHV', 'Species', '37296', (0, 4))	('ORF58', 'Gene', '4961480', (142, 147))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('ORFs-K9', 'Var', (62, 69))	('vIRF4', 'Gene', '4961495', (21, 26))	('ORF58', 'Gene', (142, 147))	('K10', 'Gene', '3858', (100, 103))	('KSHV vIRFs', 'Gene', (0, 10))	('ORF57', 'Gene', '4961525', (132, 137))	('K10', 'Gene', '3858', (83, 86))	('K10', 'Gene', (100, 103))	('ORF57', 'Gene', (132, 137))
602196	32776977	In agreement with this finding, vIRF1 overexpression led to the activation of reporters of K3, vDHFR and vIL6 gene promoters, and knockdown of vIRF1 expression in KSHV-positive BCBL-1 cells suppressed vIL-6 transcription, suggesting that vIRF1 might play a role in regulating the transcription of certain KSHV genes.	('vIL-6', 'Gene', (201, 206))	('vIRF1', 'Gene', (143, 148))	('vIL6', 'Gene', '4961449', (105, 109))	('BCBL-1', 'CellLine', 'CVCL:0165', (177, 183))	('knockdown', 'Var', (130, 139))	('vDHFR', 'Gene', (95, 100))	('KS', 'Phenotype', 'HP:0100726', (163, 165))	('vIRF1', 'Gene', (32, 37))	('KSHV', 'Species', '37296', (163, 167))	('activation', 'PosReg', (64, 74))	('suppressed', 'NegReg', (190, 200))	('vIL6', 'Gene', (105, 109))	('KS', 'Phenotype', 'HP:0100726', (305, 307))	('KSHV', 'Species', '37296', (305, 309))
602205	32776977	Moreover, treatment with the JNK inhibitor, SP600125, abolished vIRF1-induced cell oncogenic behaviors.	('SP600125', 'Chemical', 'MESH:C432165', (44, 52))	('SP600125', 'Var', (44, 52))	('abolished', 'NegReg', (54, 63))	('cell oncogenic behaviors', 'CPA', (78, 102))	('vIRF1-induced', 'Gene', (64, 77))
602210	32776977	Deletion of vIRF1 from KSHV genome showed a decrease of SPAG9 protein expression in HUVECs (Fig 1C).	('KS', 'Phenotype', 'HP:0100726', (23, 25))	('protein', 'Protein', (62, 69))	('decrease', 'NegReg', (44, 52))	('SPAG9', 'Gene', (56, 61))	('vIRF1', 'Gene', (12, 17))	('KSHV', 'Species', '37296', (23, 27))	('Deletion', 'Var', (0, 8))
602213	32776977	In addition, the enhanced transcription activity of SPAG9 promoter was observed in KSHV-infected cells, and deletion of vIRF1 impaired KSHV-induced transcription activity of SPAG9 promoter (S4 Fig).	('enhanced', 'PosReg', (17, 25))	('KSHV', 'Species', '37296', (83, 87))	('transcription activity', 'MPA', (26, 48))	('KSHV-infected', 'Disease', 'MESH:D007239', (83, 96))	('KS', 'Phenotype', 'HP:0100726', (83, 85))	('KS', 'Phenotype', 'HP:0100726', (135, 137))	('KSHV', 'Species', '37296', (135, 139))	('impaired', 'NegReg', (126, 134))	('KSHV-infected', 'Disease', (83, 96))	('vIRF1', 'Gene', (120, 125))	('deletion', 'Var', (108, 116))
602221	32776977	As expected, knockdown of Lef1 decreased both mRNA and protein levels of SPAG9 induced by vIRF1 (Fig 2I and 2J).	('Lef1', 'Gene', (26, 30))	('vIRF1', 'Gene', (90, 95))	('decreased', 'NegReg', (31, 40))	('SPAG9', 'Gene', (73, 78))	('Lef1', 'Gene', '51176', (26, 30))	('knockdown', 'Var', (13, 22))
602222	32776977	The reduction of both mRNA and protein levels of SPAG9 was also observed in KSHV-infected cells with knockdown of Lef1 (S5A Fig and S5B Fig).	('Lef1', 'Gene', (114, 118))	('SPAG9', 'Protein', (49, 54))	('KS', 'Phenotype', 'HP:0100726', (76, 78))	('Lef1', 'Gene', '51176', (114, 118))	('KSHV-infected', 'Disease', 'MESH:D007239', (76, 89))	('reduction', 'NegReg', (4, 13))	('KSHV-infected', 'Disease', (76, 89))	('knockdown', 'Var', (101, 110))
602224	32776977	To examine the role of SPAG9 in vIRF1-induced malignant transformation, we performed chick chorioallantoic membranes assay (CAMs), which is an in vivo model of angiogenesis, following silencing of SPAG9 expression in vIRF1-transduced endothelial cell line with lentivirus-mediated shRNAs (Fig 3A).	('SPAG9', 'Gene', (197, 202))	('chick', 'Species', '9031', (85, 90))	('silencing', 'Var', (184, 193))
602227	32776977	We observed that SPAG9 knockdown reduced vIRF1-induced cell proliferation and migration (Fig 3F-3H).	('SPAG9', 'Gene', (17, 22))	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (81, 84))	('knockdown', 'Var', (23, 32))	('migration', 'CPA', (78, 87))	('reduced', 'NegReg', (33, 40))	('vIRF1-induced', 'Gene', (41, 54))
602229	32776977	We found that knockdown of SPAG9 in KSHV-infected HUVECs decreased cell proliferation and migration (Fig 3I-3K).	('KSHV-infected HUVECs', 'Disease', 'MESH:D007239', (36, 56))	('SPAG9', 'Gene', (27, 32))	('KS', 'Phenotype', 'HP:0100726', (36, 38))	('KSHV-infected HUVECs', 'Disease', (36, 56))	('knockdown', 'Var', (14, 23))	('rat', 'Species', '10116', (79, 82))	('cell proliferation', 'CPA', (67, 85))	('decreased', 'NegReg', (57, 66))	('rat', 'Species', '10116', (93, 96))
602231	32776977	As expected, vIRF1 overexpression activated JNK1/2 (Fig 4A), and knockdown of SPAG9 impaired vIRF1-induced JNK1/2 activation (Fig 4B).	('activation', 'PosReg', (114, 124))	('JNK1/2', 'Gene', (44, 50))	('impaired', 'NegReg', (84, 92))	('JNK1/2', 'Gene', '5599;5601', (107, 113))	('JNK1/2', 'Gene', (107, 113))	('SPAG9', 'Gene', (78, 83))	('knockdown', 'Var', (65, 74))	('JNK1/2', 'Gene', '5599;5601', (44, 50))
602237	32776977	As expected, treatment with SP600125, an inhibitor of JNK pathway, reduced JNK phosphorylation (Fig 5A), as well as cell proliferation and migration induced by vIRF1 (Fig 5B and 5C).	('cell proliferation', 'CPA', (116, 134))	('JNK phosphorylation', 'MPA', (75, 94))	('SP600125', 'Chemical', 'MESH:C432165', (28, 36))	('rat', 'Species', '10116', (142, 145))	('migration', 'CPA', (139, 148))	('reduced', 'NegReg', (67, 74))	('rat', 'Species', '10116', (128, 131))	('SP600125', 'Var', (28, 36))
602238	32776977	Silencing of SPAG9 in KSHV-infected cells also inhibited the activation of JNK1/2 (Fig 5D).	('activation', 'MPA', (61, 71))	('JNK1/2', 'Gene', (75, 81))	('inhibited', 'NegReg', (47, 56))	('KSHV-infected', 'Disease', 'MESH:D007239', (22, 35))	('KSHV-infected', 'Disease', (22, 35))	('KS', 'Phenotype', 'HP:0100726', (22, 24))	('Silencing', 'Var', (0, 9))	('JNK1/2', 'Gene', '5599;5601', (75, 81))	('SPAG9', 'Gene', (13, 18))
602239	32776977	Treatment with SP600125 not only decreased the activation of JNK1/2, but also reduced KSHV-induced cell proliferation, migration and angiogenesis (Fig 5E-5H).	('JNK1/2', 'Gene', (61, 67))	('rat', 'Species', '10116', (111, 114))	('SP600125', 'Chemical', 'MESH:C432165', (15, 23))	('SP600125', 'Var', (15, 23))	('KSHV', 'Species', '37296', (86, 90))	('angiogenesis', 'CPA', (133, 145))	('KS', 'Phenotype', 'HP:0100726', (86, 88))	('rat', 'Species', '10116', (122, 125))	('reduced', 'NegReg', (78, 85))	('decreased', 'NegReg', (33, 42))	('KSHV-induced', 'Gene', (86, 98))	('JNK1/2', 'Gene', '5599;5601', (61, 67))
602244	32776977	Knockdown of SPAG9 also diminished the production of VEGFA induced by KSHV (Fig 6D).	('production of VEGFA', 'MPA', (39, 58))	('Knockdown', 'Var', (0, 9))	('diminished', 'NegReg', (24, 34))	('KS', 'Phenotype', 'HP:0100726', (70, 72))	('KSHV', 'Species', '37296', (70, 74))	('SPAG9', 'Gene', (13, 18))
602245	32776977	Similarly, robust phosphorylated JNK1/2 and VEGFA were observed following KSHV reactivation in iSLK-RGB cells by treatment with doxycycline (Fig 6E), and this induction was successfully blocked by silencing SPAG9 (Fig 6F).	('KSHV', 'Species', '37296', (74, 78))	('doxycycline', 'Chemical', 'MESH:D004318', (128, 139))	('phosphorylated', 'MPA', (18, 32))	('silencing', 'Var', (197, 206))	('JNK1/2', 'Gene', '5599;5601', (33, 39))	('SPAG9', 'Gene', (207, 212))	('KSHV reactivation', 'Gene', (74, 91))	('JNK1/2', 'Gene', (33, 39))	('KS', 'Phenotype', 'HP:0100726', (74, 76))
602246	32776977	A decrease of VEGFA expression level was observed in iSLK-RGB-K9 mutant cells compared to iSLK-RGB cells in reactivated KSHV-infected cells (S7 Fig).	('decrease', 'NegReg', (2, 10))	('KSHV-infected', 'Disease', 'MESH:D007239', (120, 133))	('VEGFA expression level', 'MPA', (14, 36))	('mutant', 'Var', (65, 71))	('KSHV-infected', 'Disease', (120, 133))	('iSLK-RGB-K9', 'Gene', (53, 64))	('KS', 'Phenotype', 'HP:0100726', (120, 122))
602248	32776977	We also observed the reduction of phosphorylated JNK1/2 and VEGFA expression (Fig 6I), as well as VEGFA promoter activity (Fig 6J) following knockdown of Lef1.	('knockdown', 'Var', (141, 150))	('phosphorylated', 'MPA', (34, 48))	('Lef1', 'Gene', '51176', (154, 158))	('VEGFA', 'Protein', (98, 103))	('VEGFA expression', 'Protein', (60, 76))	('JNK1/2', 'Gene', '5599;5601', (49, 55))	('Lef1', 'Gene', (154, 158))	('JNK1/2', 'Gene', (49, 55))	('reduction', 'NegReg', (21, 30))
602249	32776977	In addition, knockdown of Lef1 in KSHV-infected cells not only inhibited the activation of JNK1/2 and expression of VEGFA (S8A Fig), but also impaired KSHV-induced cell proliferation, migration and angiogenesis (S8B-S8D Fig).	('KSHV', 'Species', '37296', (151, 155))	('rat', 'Species', '10116', (176, 179))	('knockdown', 'Var', (13, 22))	('activation', 'MPA', (77, 87))	('KS', 'Phenotype', 'HP:0100726', (34, 36))	('KSHV-infected', 'Disease', 'MESH:D007239', (34, 47))	('KSHV-infected', 'Disease', (34, 47))	('JNK1/2', 'Gene', '5599;5601', (91, 97))	('Lef1', 'Gene', '51176', (26, 30))	('KSHV-induced cell proliferation', 'CPA', (151, 182))	('rat', 'Species', '10116', (187, 190))	('angiogenesis', 'CPA', (198, 210))	('inhibited', 'NegReg', (63, 72))	('VEGFA', 'Gene', (116, 121))	('impaired', 'NegReg', (142, 150))	('JNK1/2', 'Gene', (91, 97))	('KSHV', 'Species', '37296', (34, 38))	('migration', 'CPA', (184, 193))	('expression', 'MPA', (102, 112))	('KS', 'Phenotype', 'HP:0100726', (151, 153))	('Lef1', 'Gene', (26, 30))
602250	32776977	Together these data suggested that by hijacking Lef1, vIRF1 transcriptionally activated SPAG9 to promote angiogenesis, cell proliferation and migration via activation of the JNK/VEGFA pathway.	('rat', 'Species', '10116', (131, 134))	('cell proliferation', 'CPA', (119, 137))	('migration', 'CPA', (142, 151))	('angiogenesis', 'CPA', (105, 117))	('activation', 'PosReg', (156, 166))	('Lef1', 'Gene', '51176', (48, 52))	('hijacking', 'Var', (38, 47))	('SPAG9', 'Gene', (88, 93))	('JNK/VEGFA pathway', 'Pathway', (174, 191))	('Lef1', 'Gene', (48, 52))	('vIRF1', 'Gene', (54, 59))	('rat', 'Species', '10116', (145, 148))	('promote', 'PosReg', (97, 104))
602251	32776977	To determine the role of vIRF1 in cellular transformation and angiogenesis, we examined cellular transformation of a KSHV mutant virus with deleted ORF-K9 in rat primary embryonic metanephric mesenchymal (MM) cells.	('ORF-K9', 'Gene', (148, 154))	('deleted', 'Var', (140, 147))	('KSHV', 'Species', '37296', (117, 121))	('KS', 'Phenotype', 'HP:0100726', (117, 119))	('embryonic metanephric mesenchymal', 'Disease', (170, 203))	('examined', 'Reg', (79, 87))	('embryonic metanephric mesenchymal', 'Disease', 'MESH:C535700', (170, 203))	('rat', 'Species', '10116', (158, 161))
602252	32776977	Soft agar assay showed that deletion of vIRF1 from KSHV genome abolished the ability of KSHV-infected cells to form colonies (Fig 7A).	('KS', 'Phenotype', 'HP:0100726', (88, 90))	('KSHV', 'Species', '37296', (51, 55))	('KSHV-infected', 'Disease', (88, 101))	('KS', 'Phenotype', 'HP:0100726', (51, 53))	('abolished', 'NegReg', (63, 72))	('vIRF1', 'Gene', (40, 45))	('KSHV', 'Species', '37296', (88, 92))	('deletion', 'Var', (28, 36))	('KSHV-infected', 'Disease', 'MESH:D007239', (88, 101))	('agar', 'Chemical', 'MESH:D000362', (5, 9))	('ability', 'MPA', (77, 84))
602253	32776977	Cells infected by the K9_mut virus also showed a lowered cell proliferation rate (Fig 7B).	('infected', 'Disease', 'MESH:D007239', (6, 14))	('rat', 'Species', '10116', (76, 79))	('infected', 'Disease', (6, 14))	('K9_mut', 'Var', (22, 28))	('lowered', 'NegReg', (49, 56))	('rat', 'Species', '10116', (69, 72))	('cell proliferation rate', 'CPA', (57, 80))
602254	32776977	Western-blotting confirmed that deletion of vIRF1 decreased expression levels of SPAG9, phosphorylated-JNK1/2 and VEGFA when compared to those of KSHV_WT virus-infected cells (Fig 7C).	('deletion', 'Var', (32, 40))	('VEGFA', 'Protein', (114, 119))	('WT virus-infected', 'Disease', (151, 168))	('KSHV', 'Species', '37296', (146, 150))	('JNK1/2', 'Gene', '5599;5601', (103, 109))	('WT virus-infected', 'Disease', 'MESH:D001102', (151, 168))	('JNK1/2', 'Gene', (103, 109))	('KS', 'Phenotype', 'HP:0100726', (146, 148))	('decreased', 'NegReg', (50, 59))	('expression levels', 'MPA', (60, 77))	('SPAG9', 'Protein', (81, 86))	('vIRF1', 'Gene', (44, 49))
602255	32776977	To further determine the role of Lef1/SPAG9 in KSHV-induced cell proliferation, we knockdown Lef1 and SPAG9, respectively, in KMM cells, and found that loss of Lef1 or SPAG9 impaired KSHV-induced cell proliferation (S9A-S9D Fig).	('Lef1', 'Gene', (33, 37))	('rat', 'Species', '10116', (72, 75))	('SPAG9', 'Gene', (168, 173))	('KSHV', 'Species', '37296', (183, 187))	('rat', 'Species', '10116', (208, 211))	('Lef1', 'Gene', '51176', (93, 97))	('loss', 'Var', (152, 156))	('Lef1', 'Gene', '51176', (160, 164))	('Lef1', 'Gene', '51176', (33, 37))	('KS', 'Phenotype', 'HP:0100726', (183, 185))	('impaired', 'NegReg', (174, 182))	('SPAG9', 'Gene', (102, 107))	('KSHV', 'Species', '37296', (47, 51))	('Lef1', 'Gene', (93, 97))	('Lef1', 'Gene', (160, 164))	('KS', 'Phenotype', 'HP:0100726', (47, 49))
602256	32776977	To examine the role of the JNK1/2 pathway in KSHV-induced cellular transformation, we treated KSHV-infected cells with SP600125, and found that inhibition of JNK activation not only reduced KSHV-induced efficiency of colony formation (Fig 7D) and cell proliferation (Fig 7E), but also decreased KSHV-induced angiogenesis (Fig 7F and 7G).	('KSHV-infected', 'Disease', (94, 107))	('KS', 'Phenotype', 'HP:0100726', (45, 47))	('SP600125', 'Chemical', 'MESH:C432165', (119, 127))	('KSHV', 'Species', '37296', (190, 194))	('JNK', 'Gene', (158, 161))	('KSHV', 'Species', '37296', (45, 49))	('KSHV-induced angiogenesis', 'CPA', (295, 320))	('cell proliferation', 'CPA', (247, 265))	('inhibition', 'Var', (144, 154))	('KSHV', 'Species', '37296', (94, 98))	('KS', 'Phenotype', 'HP:0100726', (295, 297))	('reduced', 'NegReg', (182, 189))	('JNK1/2', 'Gene', '5599;5601', (27, 33))	('rat', 'Species', '10116', (259, 262))	('decreased', 'NegReg', (285, 294))	('KS', 'Phenotype', 'HP:0100726', (190, 192))	('colony formation', 'CPA', (217, 233))	('KS', 'Phenotype', 'HP:0100726', (94, 96))	('JNK1/2', 'Gene', (27, 33))	('KSHV-infected', 'Disease', 'MESH:D007239', (94, 107))	('KSHV', 'Species', '37296', (295, 299))
602258	32776977	As shown in Fig 7H, there were reduced neovascularization and less SMA-positive cells in the SP600125-treated plugs of KMM cells than the untreated control cells.	('SP600125-treated', 'Var', (93, 109))	('reduced', 'NegReg', (31, 38))	('SP600125', 'Chemical', 'MESH:C432165', (93, 101))	('neovascularization', 'CPA', (39, 57))	('less', 'NegReg', (62, 66))	('SMA-positive cells', 'CPA', (67, 85))
602259	32776977	Similarly, HUVECs infected with K9_mut virus had reduced levels of SPAG9, phosphorylated JNKs and VEGFA expression compared to those infected by KSHV_WT virus (Fig 7I).	('infected', 'Disease', (133, 141))	('HUVECs infected', 'Disease', 'MESH:D007239', (11, 26))	('phosphorylated JNKs', 'MPA', (74, 93))	('reduced', 'NegReg', (49, 56))	('K9_mut virus', 'Var', (32, 44))	('VEGFA', 'Protein', (98, 103))	('infected', 'Disease', 'MESH:D007239', (18, 26))	('KSHV', 'Species', '37296', (145, 149))	('levels', 'MPA', (57, 63))	('HUVECs infected', 'Disease', (11, 26))	('KS', 'Phenotype', 'HP:0100726', (145, 147))	('infected', 'Disease', (18, 26))	('infected', 'Disease', 'MESH:D007239', (133, 141))	('SPAG9', 'MPA', (67, 72))
602260	32776977	vIRF1 complementation in cells infected by K9_mut virus completely reversed the effect (Fig 7I).	('complementation', 'Var', (6, 21))	('infected', 'Disease', 'MESH:D007239', (31, 39))	('infected', 'Disease', (31, 39))
602261	32776977	Importantly, loss of vIRF1 lowered KSHV-induced endothelial cell proliferation while complementation with vIRF1 was sufficient to rescue KSHV-induced the proliferation (Fig 7J).	('KS', 'Phenotype', 'HP:0100726', (137, 139))	('rat', 'Species', '10116', (72, 75))	('vIRF1', 'Gene', (21, 26))	('KS', 'Phenotype', 'HP:0100726', (35, 37))	('KSHV', 'Species', '37296', (35, 39))	('lowered', 'NegReg', (27, 34))	('rat', 'Species', '10116', (161, 164))	('loss', 'Var', (13, 17))	('KSHV', 'Species', '37296', (137, 141))
602281	32776977	Silencing of SPAG9 inhibited vIRF1-induced angiogenesis, cell proliferation, and migration, indicating the importance of SPAG9 in the development of KS.	('inhibited', 'NegReg', (19, 28))	('rat', 'Species', '10116', (84, 87))	('Silencing', 'Var', (0, 9))	('angiogenesis', 'CPA', (43, 55))	('KS', 'Phenotype', 'HP:0100726', (149, 151))	('vIRF1-induced', 'Gene', (29, 42))	('migration', 'CPA', (81, 90))	('rat', 'Species', '10116', (69, 72))	('cell proliferation', 'CPA', (57, 75))	('SPAG9', 'Gene', (13, 18))
602287	32776977	Inhibition of JNK blocks KSHV lytic replication at the early stage(s) of reactivation in TPA-induced PEL cells.	('JNK', 'Gene', (14, 17))	('KSHV', 'Species', '37296', (25, 29))	('TPA', 'Chemical', 'MESH:D013755', (89, 92))	('PEL', 'Phenotype', 'HP:0030069', (101, 104))	('KS', 'Phenotype', 'HP:0100726', (25, 27))	('Inhibition', 'Var', (0, 10))	('KSHV lytic replication', 'CPA', (25, 47))
602295	32776977	These include miR-K6-3p, miR-K3, viral FLICE-inhibitory protein (vFLIP), viral interleukin-6 (vIL-6), and ORF-K15.	('miR-K6-3p', 'Var', (14, 23))	('FLICE', 'Gene', (39, 44))	('FLICE', 'Gene', '841', (39, 44))	('ORF-K15', 'Var', (106, 113))	('miR-K3', 'Var', (25, 31))
602301	32776977	Furthermore, KSHV miRNAs also increased the expression of VEGFA, as well as the secretion of VEGFA protein.	('KSHV', 'Var', (13, 17))	('expression', 'MPA', (44, 54))	('KS', 'Phenotype', 'HP:0100726', (13, 15))	('KSHV', 'Species', '37296', (13, 17))	('secretion of', 'MPA', (80, 92))	('increased', 'PosReg', (30, 39))	('VEGFA', 'Protein', (58, 63))
602397	31186956	In the multivariate Cox regression, grade 3 (HR: 1.48, 95%CI: 0.46-2.86; P=.001) was the only factor independently affecting survival, as shown in Table 2.	('grade 3', 'Var', (36, 43))	('affecting', 'Reg', (115, 124))	('Cox', 'Gene', (20, 23))	('Cox', 'Gene', '1351', (20, 23))
602538	27549124	In vivo, however, GD2-CAR T cells mediated potent antitumor activity against neuroblastoma xenografts, but only minimal activity against osteosarcoma xenografts.	('osteosarcoma', 'Phenotype', 'HP:0002669', (137, 149))	('osteosarcoma', 'Disease', (137, 149))	('osteosarcoma', 'Disease', 'MESH:D012516', (137, 149))	('sarcoma xenograft', 'Disease', (142, 159))	('GD2-CAR', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('sarcoma xenograft', 'Disease', 'MESH:D012509', (142, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('neuroblastoma', 'Phenotype', 'HP:0003006', (77, 90))	('neuroblastoma xenografts', 'Disease', 'MESH:D009447', (77, 101))	('tumor', 'Disease', (54, 59))	('neuroblastoma xenografts', 'Disease', (77, 101))
602563	27549124	GD2 expression on tumor cell lines was performed using the anti-GD2 (clone 14g2a; BD Pharmingen) and compared to isotype controls.	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('anti-GD2', 'Var', (59, 67))	('tumor', 'Disease', (18, 23))
602587	27549124	We next sought to evaluate the capacity of T cells expressing a third generation GD2-CAR (14g2a.CD28.OX40.zeta) to kill GD2+ human sarcoma cell lines in vitro, compared to killing of GD2+ neuroblastoma cell lines.	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('GD2+', 'Var', (120, 124))	('neuroblastoma', 'Disease', 'MESH:D009447', (188, 201))	('human', 'Species', '9606', (125, 130))	('sarcoma', 'Disease', (131, 138))	('CD28', 'Gene', (96, 100))	('OX40', 'Gene', '7293', (101, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('OX40', 'Gene', (101, 105))	('neuroblastoma', 'Disease', (188, 201))	('neuroblastoma', 'Phenotype', 'HP:0003006', (188, 201))	('CD28', 'Gene', '940', (96, 100))
602593	27549124	Very little lysis of the GD2 negative line RH30 was observed, indicating high specificity of T cells expressing the GD2-CAR.	('RH30', 'Gene', '6007', (43, 47))	('RH30', 'Gene', (43, 47))	('GD2-CAR', 'Var', (116, 123))
602594	27549124	Thus, we conclude that T cells expressing the GD2-CAR have comparable efficacy against GD2+ sarcoma versus neuroblastoma tumor lines in vitro.	('sarcoma versus neuroblastoma tumor', 'Disease', 'MESH:D009447', (92, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('sarcoma versus neuroblastoma tumor', 'Disease', (92, 126))	('neuroblastoma', 'Phenotype', 'HP:0003006', (107, 120))	('GD2-CAR', 'Var', (46, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))
602597	27549124	This poor in vivo efficacy could not be fully attributed to T-cell exhaustion induced by antigen-independent signaling of GD2-specific CARs, because the same GD2-CAR T cells provided a significant antitumor benefit against Kelly neuroblastoma tumors in vivo (Fig.	('Kelly neuroblastoma tumors', 'Disease', 'MESH:D009447', (223, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('Kelly neuroblastoma tumors', 'Disease', (223, 249))	('T-cell exhaustion', 'Phenotype', 'HP:0005435', (60, 77))	('neuroblastoma', 'Phenotype', 'HP:0003006', (229, 242))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('GD2-CAR', 'Var', (158, 165))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
602606	27549124	NSG mice bearing 143b and EW8 tumors showed an increase in CD11b+Ly6G+ and CD11b+Ly6C+ myeloid cell populations, compared to nontumor-bearing controls (Fig.	('tumors', 'Disease', (30, 36))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('mice', 'Species', '10090', (4, 8))	('CD11b+Ly6C+', 'Var', (75, 86))	('Ly6G', 'Gene', '546644', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('increase', 'PosReg', (47, 55))	('Ly6G', 'Gene', (65, 69))	('tumor', 'Disease', (30, 35))
602611	27549124	Independent of tumor location and use of Matrigel, 143b tumors induced significantly larger MDSC populations that correlated with tumor burden (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('143b', 'Var', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('larger', 'PosReg', (85, 91))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('MDSC populations', 'CPA', (92, 108))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
602629	27549124	Treating tumor-bearing mice with both ATRA and GD2-CAR T cells led to an enhanced antitumor effect, with delayed tumor outgrowth and improved survival (Fig.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('enhanced', 'PosReg', (73, 81))	('ATRA', 'Chemical', 'MESH:D014212', (38, 42))	('GD2-CAR', 'Var', (47, 54))	('survival', 'CPA', (142, 150))	('improved', 'PosReg', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mice', 'Species', '10090', (23, 27))
602632	27549124	Further suggesting that ATRA mediated modulation of MDSCs led to enhanced T-cell reactivity, we observed that 143b tumor-bearing mice treated with GD2-CAR T cells and ATRA had a higher frequency of CD8+ CAR+ T cells in the peripheral blood compared to animals which did not receive ATRA (Fig.	('modulation', 'Var', (38, 48))	('CD8', 'Gene', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CD8', 'Gene', '925', (198, 201))	('ATRA', 'Chemical', 'MESH:D014212', (167, 171))	('tumor', 'Disease', (115, 120))	('enhanced', 'PosReg', (65, 73))	('T-cell reactivity', 'CPA', (74, 91))	('higher', 'PosReg', (178, 184))	('ATRA', 'Chemical', 'MESH:D014212', (24, 28))	('MDSCs', 'Gene', (52, 57))	('ATRA', 'Chemical', 'MESH:D014212', (282, 286))	('mice', 'Species', '10090', (129, 133))	('GD2-CAR', 'Var', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
602650	27549124	However, we observed poor in vivo activity of GD2-CAR T cells against the 143b osteosarcoma cell line, despite strong in vivo activity against the Kelly neuroblastoma cell line.	('osteosarcoma', 'Phenotype', 'HP:0002669', (79, 91))	('osteosarcoma', 'Disease', (79, 91))	('osteosarcoma', 'Disease', 'MESH:D012516', (79, 91))	('GD2-CAR', 'Var', (46, 53))	('Kelly neuroblastoma', 'Disease', 'MESH:C567101', (147, 166))	('neuroblastoma', 'Phenotype', 'HP:0003006', (153, 166))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('Kelly neuroblastoma', 'Disease', (147, 166))	('activity', 'MPA', (126, 134))
602653	27549124	Our data demonstrate that murine MDSCs can be expanded by human tumors in xenograft models of cancer, and that such murine MDSCs can suppress human T cells.	('human T cells', 'CPA', (142, 155))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('human', 'Species', '9606', (58, 63))	('murine', 'Species', '10090', (26, 32))	('murine', 'Species', '10090', (116, 122))	('human', 'Species', '9606', (142, 147))	('suppress', 'NegReg', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('murine', 'Var', (116, 122))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
602671	27549124	Use of our sarcoma xenograft models found that cotreatment with ATRA and GD2-CAR T cells led to enhanced antitumor effects compared to either single agent alone, which is likely mediated through a decreased number of monocytic MDSCs and potentially also via a reduction in the suppressive capacity of granulocytic MDSCs induced by sarcoma tumors.	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('tumor', 'Disease', (339, 344))	('sarcoma xenograft', 'Disease', 'MESH:D012509', (11, 28))	('sarcoma tumors', 'Disease', (331, 345))	('GD2-CAR', 'Var', (73, 80))	('sarcoma xenograft', 'Disease', (11, 28))	('enhanced', 'PosReg', (96, 104))	('ATRA', 'Chemical', 'MESH:D014212', (64, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('sarcoma', 'Phenotype', 'HP:0100242', (331, 338))	('monocytic MDSCs', 'CPA', (217, 232))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('decreased', 'NegReg', (197, 206))	('sarcoma tumors', 'Disease', 'MESH:D012509', (331, 345))	('tumor', 'Disease', (109, 114))
602674	27549124	Though ATRA can also induce FOXP3+ T regulatory cells in vivo, we found no evidence of such in our model system with adoptively transferred, activated human CAR T cells.	('human', 'Species', '9606', (151, 156))	('ATRA', 'Chemical', 'MESH:D014212', (7, 11))	('induce', 'Reg', (21, 27))	('FOXP3+', 'Var', (28, 34))
602678	27549124	Our findings demonstrate the need for enhanced understanding of the immunosuppressive mechanisms that may limit immunotherapies against solid tumors, and suggest that MDSCs may play a role in preventing CAR efficacy against solid tumors in patients.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('limit', 'NegReg', (106, 111))	('solid tumors', 'Disease', (136, 148))	('CAR efficacy against', 'CPA', (203, 223))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('solid tumors', 'Disease', (224, 236))	('patients', 'Species', '9606', (240, 248))	('immunotherapies against', 'CPA', (112, 135))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('preventing', 'NegReg', (192, 202))	('solid tumors', 'Disease', 'MESH:D009369', (224, 236))	('MDSCs', 'Var', (167, 172))
602682	25119929	One patient with both PTPRD and GRB10 mutations and one with a GRB10 mutation achieved a complete remission (CR) on an Insulin like growth factor 1 receptor (IGF1R) inhibitor based treatment.	('PTPRD', 'Gene', (22, 27))	('GRB10', 'Gene', '2887', (32, 37))	('GRB10', 'Gene', (63, 68))	('GRB10', 'Gene', '2887', (63, 68))	('IGF1R', 'Gene', (158, 163))	('patient', 'Species', '9606', (4, 11))	('men', 'Species', '9606', (186, 189))	('IGF1R', 'Gene', '3480', (158, 163))	('mutations', 'Var', (38, 47))	('GRB10', 'Gene', (32, 37))	('Insulin like growth factor 1 receptor', 'Gene', (119, 156))	('Insulin like growth factor 1 receptor', 'Gene', '3480', (119, 156))	('PTPRD', 'Gene', '5789', (22, 27))
602683	25119929	One patient, who achieved a partial remission (PR) with IGF1R inhibitor treatment, but later developed resistance, demonstrated a KRAS mutation in the post-treatment resistant tumor, but not in the pre-treatment tumor suggesting that the RAF/RAS/MEK pathway was activated with progression.	('RAF', 'Gene', '22882', (238, 241))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('men', 'Species', '9606', (161, 164))	('KRAS', 'Gene', '3845', (130, 134))	('IGF1R', 'Gene', '3480', (56, 61))	('tumor', 'Disease', (176, 181))	('men', 'Species', '9606', (207, 210))	('RAF', 'Gene', (238, 241))	('KRAS', 'Gene', (130, 134))	('IGF1R', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('men', 'Species', '9606', (77, 80))	('MEK', 'Gene', '5609', (246, 249))	('mutation', 'Var', (135, 143))	('tumor', 'Disease', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('MEK', 'Gene', (246, 249))
602684	25119929	Ewing's sarcoma (ES) and desmoplastic small round cell tumor (DSRCT) are small cell sarcomas characterized by the translocation of chromosome 22 to chromosome 11, resulting in fusion of the EWSR1 gene to the FLI1 gene (and several rarer fusion partners) in the case of ES (EWSR1-FLI1), and to the WT1 gene in the case of DSRCT (EWSR1-WT1).	('EWSR1', 'Gene', '2130', (328, 333))	("Ewing's sarcoma", 'Disease', (0, 15))	('EWSR1', 'Gene', '2130', (273, 278))	('desmoplastic small round cell tumor', 'Disease', 'MESH:D058405', (25, 60))	('FLI1', 'Gene', '2313', (279, 283))	('desmoplastic small round cell tumor', 'Disease', (25, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('FLI1', 'Gene', '2313', (208, 212))	('WT1', 'Gene', '7490', (297, 300))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('sarcomas', 'Disease', 'MESH:D012509', (84, 92))	('small cell sarcomas', 'Phenotype', 'HP:0030357', (73, 92))	('fusion', 'Var', (176, 182))	('EWSR1', 'Gene', (273, 278))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('WT1', 'Gene', (334, 337))	('EWSR1', 'Gene', (328, 333))	('EWSR1', 'Gene', '2130', (190, 195))	('sarcomas', 'Disease', (84, 92))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('WT1', 'Gene', '7490', (334, 337))	('EWSR1-FLI1', 'Gene', (273, 283))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('EWSR1-FLI1', 'Gene', '2130;2313', (273, 283))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	('FLI1', 'Gene', (279, 283))	('EWSR1', 'Gene', (190, 195))	('FLI1', 'Gene', (208, 212))	('WT1', 'Gene', (297, 300))
602696	25119929	While EWSR1-FLI1 and EWSR1-WT1 translocations occur in virtually all ES and DSRCT patients, respectively, the resulting fusion proteins have not proved to be druggable targets.	('EWSR1', 'Gene', (21, 26))	('WT1', 'Gene', '7490', (27, 30))	('EWSR1-FLI1', 'Gene', '2130;2313', (6, 16))	('EWSR1', 'Gene', '2130', (6, 11))	('patients', 'Species', '9606', (82, 90))	('EWSR1', 'Gene', '2130', (21, 26))	('WT1', 'Gene', (27, 30))	('occur', 'Reg', (46, 51))	('DSRCT', 'Disease', (76, 81))	('EWSR1', 'Gene', (6, 11))	('EWSR1-FLI1', 'Gene', (6, 16))	('translocations', 'Var', (31, 45))
602698	25119929	Toward that end, a recent study using sequence-based genotyping identified mutations in 4% (three of 75 patients or cell lines with ES), including BRAF, CTNNB1, and NRAS .	('CTNNB1', 'Gene', '1499', (153, 159))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('mutations', 'Var', (75, 84))	('NRAS', 'Gene', (165, 169))	('CTNNB1', 'Gene', (153, 159))	('patients', 'Species', '9606', (104, 112))	('NRAS', 'Gene', '4893', (165, 169))
602700	25119929	We recently reported germline Protein tyrosine phosphatase delta (PTPRD) mutations in a small pilot study in patients with Ewing's sarcoma.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (123, 138))	("Ewing's sarcoma", 'Disease', (123, 138))	('patients', 'Species', '9606', (109, 117))	('PTPRD', 'Gene', '5789', (66, 71))	('PTPRD', 'Gene', (66, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (123, 138))	('mutations', 'Var', (73, 82))
602702	25119929	The mutations include KRAS (G13N), PTPRD (W775D), GRB10 (Q107stop and V109A), MET (T1010I and N375S) and PIK3CA (M1040I and G1049S).	('N375S', 'Var', (94, 99))	('PIK3CA', 'Gene', '5290', (105, 111))	('M1040I', 'Var', (113, 119))	('Q107stop', 'Mutation', 'rs1223389447', (57, 65))	('PTPRD', 'Gene', '5789', (35, 40))	('W775D', 'Var', (42, 47))	('KRAS', 'Gene', (22, 26))	('GRB10', 'Gene', (50, 55))	('V109A', 'Var', (70, 75))	('Q107stop', 'Var', (57, 65))	('W775D', 'SUBSTITUTION', 'None', (42, 47))	('GRB10', 'Gene', '2887', (50, 55))	('PIK3CA', 'Gene', (105, 111))	('N375S', 'Mutation', 'rs33917957', (94, 99))	('V109A', 'Mutation', 'rs1311557029', (70, 75))	('G1049S', 'Mutation', 'rs121913277', (124, 130))	('T1010I', 'Mutation', 'rs752727004', (83, 89))	('M1040I', 'Mutation', 'rs765098424', (113, 119))	('PTPRD', 'Gene', (35, 40))	('G13N', 'Mutation', 'p.G13N', (28, 32))	('KRAS', 'Gene', '3845', (22, 26))	('G1049S', 'Var', (124, 130))
602716	25119929	Of interest, both of the patients with GRB10 mutations (cases #2 and #3, Table 1) responded to therapy with an IGF1R plus mTOR inhibitor and both achieved a complete remission (CR).	('mutations', 'Var', (45, 54))	('IGF1R', 'Gene', '3480', (111, 116))	('achieved', 'Reg', (146, 154))	('patients', 'Species', '9606', (25, 33))	('mTOR', 'Gene', (122, 126))	('GRB10', 'Gene', '2887', (39, 44))	('mTOR', 'Gene', '2475', (122, 126))	('IGF1R', 'Gene', (111, 116))	('responded', 'Reg', (82, 91))	('GRB10', 'Gene', (39, 44))
602719	25119929	Because of the finding of GRB10 mutation in case #2, mutational analysis of GRB10 was also performed on tumor from case #3 (who also achieved a CR after IGF1R inhibitor therapy) and, remarkably, was also positive by Sanger sequencing.	('GRB10', 'Gene', (26, 31))	('GRB10', 'Gene', '2887', (26, 31))	('IGF1R', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('IGF1R', 'Gene', '3480', (153, 158))	('GRB10', 'Gene', (76, 81))	('GRB10', 'Gene', '2887', (76, 81))	('mutation', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
602720	25119929	The Grb10 protein sends a negative feedback signal to IGF1R, hence inhibiting the IGF1R signal; a loss of function GRB10 mutation may therefore be expected to be associated with activated IGF1-R signaling (Figure 2).	('IGF1-R', 'Gene', (188, 194))	('IGF1R', 'Gene', (82, 87))	('loss of function', 'NegReg', (98, 114))	('IGF1R', 'Gene', (54, 59))	('IGF1R', 'Gene', '3480', (54, 59))	('IGF1R', 'Gene', '3480', (82, 87))	('activated', 'PosReg', (178, 187))	('GRB10', 'Gene', (115, 120))	('mutation', 'Var', (121, 129))	('GRB10', 'Gene', '2887', (115, 120))	('IGF1-R', 'Gene', '3480', (188, 194))	('Grb10', 'Gene', (4, 9))	('Grb10', 'Gene', '2887', (4, 9))	('inhibiting', 'NegReg', (67, 77))
602721	25119929	Case # 2 also demonstrated a protein tyrosine phosphatase receptor type D (PTPRD) mutation that would truncate this protein (Table 1).	('PTPRD', 'Gene', (75, 80))	('mutation', 'Var', (82, 90))	('protein tyrosine phosphatase receptor type D', 'Gene', '5789', (29, 73))	('truncate', 'NegReg', (102, 110))	('protein tyrosine phosphatase receptor type D', 'Gene', (29, 73))	('PTPRD', 'Gene', '5789', (75, 80))
602723	25119929	A PTPRD mutation would be expected to inhibit STAT3 dephosphorylation, resulting in accumulated phosphorylated STAT3 (Figure 2).	('PTPRD', 'Gene', (2, 7))	('STAT3', 'Gene', '6774', (46, 51))	('STAT3', 'Gene', (111, 116))	('STAT3', 'Gene', (46, 51))	('accumulated', 'PosReg', (84, 95))	('mutation', 'Var', (8, 16))	('inhibit', 'NegReg', (38, 45))	('STAT3', 'Gene', '6774', (111, 116))	('PTPRD', 'Gene', '5789', (2, 7))
602724	25119929	Because of the role of IGF1R in enabling STAT3 phosphorylation, inhibiting IGF1R might diminish the up regulation of STAT3 phosphorylation effected by mutated PTPRD.	('STAT3', 'Gene', (117, 122))	('mutated', 'Var', (151, 158))	('STAT3', 'Gene', (41, 46))	('up regulation', 'PosReg', (100, 113))	('IGF1R', 'Gene', (23, 28))	('diminish', 'NegReg', (87, 95))	('IGF1R', 'Gene', (75, 80))	('enabling', 'PosReg', (32, 40))	('IGF1R', 'Gene', '3480', (23, 28))	('PTPRD', 'Gene', '5789', (159, 164))	('IGF1R', 'Gene', '3480', (75, 80))	('PTPRD', 'Gene', (159, 164))	('STAT3', 'Gene', '6774', (117, 122))	('STAT3', 'Gene', '6774', (41, 46))	('inhibiting', 'Var', (64, 74))
602730	25119929	A fourth patient (Table 1, Case # 4), whose tumor demonstrated a MET mutation did not receive IGF1R inhibitor therapy.	('IGF1R', 'Gene', (94, 99))	('IGF1R', 'Gene', '3480', (94, 99))	('MET mutation', 'Var', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patient', 'Species', '9606', (9, 16))	('tumor', 'Disease', (44, 49))
602731	25119929	The mutation was detected in codon 1010 (ACT to ATT) of the MET gene that would change the encoding amino acid from Thr to Ile (p.T1010I) using a screening assay (PCR-based primer extension analysis).	('p.T1010I', 'Var', (128, 136))	('Thr', 'Chemical', 'MESH:D013912', (116, 119))	('1010 (ACT to ATT', 'Mutation', 'rs774433287', (35, 51))	('change', 'Reg', (80, 86))	('p.T1010I', 'Mutation', 'rs752727004', (128, 136))	('encoding amino acid', 'MPA', (91, 110))	('MET', 'Gene', (60, 63))	('Ile', 'Chemical', 'MESH:D007532', (123, 126))
602735	25119929	Mutation was detected in codon 1040 (ATG to ATA) in exon 20 of the PIK3CA gene that would change the encoding amino acid from Met to Ile (M1040I).	('PIK3CA', 'Gene', '5290', (67, 73))	('M1040I', 'Mutation', 'rs765098424', (138, 144))	('Ile', 'Chemical', 'MESH:D007532', (133, 136))	('encoding amino acid', 'MPA', (101, 120))	('change', 'Reg', (90, 96))	('PIK3CA', 'Gene', (67, 73))	('M1040I', 'Var', (138, 144))
602737	25119929	Our study shows that 21.4% of patients (6 of 28) with advanced, heavily pretreated Ewing's sarcoma family of tumors (ES, n = 18; DSRCT, n = 10) had secondary somatic molecular aberrations, including mutations in KRAS, PTPRD, GRB10, MET and PIK3CA.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (83, 98))	('GRB10', 'Gene', '2887', (225, 230))	('PIK3CA', 'Gene', '5290', (240, 246))	('mutations', 'Var', (199, 208))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (83, 98))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	("Ewing's sarcoma", 'Disease', (83, 98))	('PIK3CA', 'Gene', (240, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('PTPRD', 'Gene', (218, 223))	('KRAS', 'Gene', '3845', (212, 216))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('MET', 'Gene', (232, 235))	('KRAS', 'Gene', (212, 216))	('GRB10', 'Gene', (225, 230))	('PTPRD', 'Gene', '5789', (218, 223))
602738	25119929	Interestingly, we recently reported germline PTPRD mutations in three out of eight (37.5%) patients with metastatic Ewing's sarcoma.	("Ewing's sarcoma", 'Disease', (116, 131))	('reported', 'Reg', (27, 35))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (91, 99))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (116, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('PTPRD', 'Gene', '5789', (45, 50))	('PTPRD', 'Gene', (45, 50))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (116, 131))
602742	25119929	found BRAF, NRAS and CTNNB1 mutations in their ES patients and cell lines, while we found KRAS, PTPRD,GRB10 and MET.	('GRB10', 'Gene', (102, 107))	('GRB10', 'Gene', '2887', (102, 107))	('patients', 'Species', '9606', (50, 58))	('NRAS', 'Gene', (12, 16))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('PTPRD', 'Gene', '5789', (96, 101))	('PTPRD', 'Gene', (96, 101))	('CTNNB1', 'Gene', (21, 27))	('NRAS', 'Gene', '4893', (12, 16))	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', (6, 10))	('mutations', 'Var', (28, 37))	('CTNNB1', 'Gene', '1499', (21, 27))
602745	25119929	This result suggests an adaptive mechanism of resistance to IGF1R/mTOR attributable to the RAS/RAF/MEK pathway (Figure 2) and is consistent with those shown previously by morphoproteomic analysis where resistance to IGF1R/mTOR inhibitor was associated with ERK activation.	('MEK', 'Gene', '5609', (99, 102))	('mTOR', 'Gene', (66, 70))	('mTOR', 'Gene', '2475', (66, 70))	('resistance', 'Var', (202, 212))	('activation', 'PosReg', (261, 271))	('associated', 'Reg', (241, 251))	('IGF1R', 'Gene', (60, 65))	('IGF1R', 'Gene', (216, 221))	('IGF1R', 'Gene', '3480', (60, 65))	('mTOR', 'Gene', '2475', (222, 226))	('RAF', 'Gene', (95, 98))	('ERK', 'Gene', '5594', (257, 260))	('RAF', 'Gene', '22882', (95, 98))	('mTOR', 'Gene', (222, 226))	('IGF1R', 'Gene', '3480', (216, 221))	('ERK', 'Gene', (257, 260))	('MEK', 'Gene', (99, 102))
602748	25119929	In addition, it has been shown that the emergence of KRAS mutant clones can be detected months before radiographic progression.	('mutant', 'Var', (58, 64))	('KRAS', 'Gene', '3845', (53, 57))	('KRAS', 'Gene', (53, 57))
602752	25119929	After subsequent enrollment in a study of combined IGF1R/mTOR inhibition, she achieved a second CR that lasted two years.	('IGF1R', 'Gene', '3480', (51, 56))	('men', 'Species', '9606', (23, 26))	('mTOR', 'Gene', (57, 61))	('mTOR', 'Gene', '2475', (57, 61))	('inhibition', 'Var', (62, 72))	('IGF1R', 'Gene', (51, 56))
602753	25119929	Two mutations were identified in her tumor sample collected between the two lines of treatment, a GRB10 Q107stop mutation and a PTPRD W775 stop mutation.	('Q107stop', 'Var', (104, 112))	('Q107stop', 'Mutation', 'rs1223389447', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('men', 'Species', '9606', (90, 93))	('GRB10', 'Gene', '2887', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('W775 stop', 'Mutation', 'rs747543296', (134, 143))	('PTPRD', 'Gene', '5789', (128, 133))	('PTPRD', 'Gene', (128, 133))	('GRB10', 'Gene', (98, 103))
602757	25119929	One could reasonably speculate that patient 2 responded to IGF1R therapy, even in the presence of a mutated PTPRD, because p-STAT3 remains critically dependent on intact IGF-1R signaling for downstream effects.	('mutated', 'Var', (100, 107))	('IGF-1R', 'Gene', '3480', (170, 176))	('STAT3', 'Gene', (125, 130))	('IGF-1R', 'Gene', (170, 176))	('IGF1R', 'Gene', (59, 64))	('PTPRD', 'Gene', '5789', (108, 113))	('PTPRD', 'Gene', (108, 113))	('STAT3', 'Gene', '6774', (125, 130))	('IGF1R', 'Gene', '3480', (59, 64))	('patient', 'Species', '9606', (36, 43))
602758	25119929	As mentioned, patient 2 (Table 2) also had a GRB10 mutation.	('GRB10', 'Gene', '2887', (45, 50))	('patient', 'Species', '9606', (14, 21))	('GRB10', 'Gene', (45, 50))	('mutation', 'Var', (51, 59))	('men', 'Species', '9606', (3, 6))
602760	25119929	The mTORC1 protein regulates the phosphorylation of Grb10 at S501 and S503, which indirectly results in the inhibition of PI3K, and thus regulates the IGF1R pathway through a negative feedback (Figure 2).	('regulates', 'Reg', (19, 28))	('phosphorylation', 'MPA', (33, 48))	('IGF1R', 'Gene', '3480', (151, 156))	('inhibition', 'NegReg', (108, 118))	('Grb10', 'Gene', '2887', (52, 57))	('regulates', 'Reg', (137, 146))	('S503', 'Var', (70, 74))	('mTORC1', 'Gene', '382056', (4, 10))	('PI3K', 'Pathway', (122, 126))	('IGF1R', 'Gene', (151, 156))	('S501', 'Var', (61, 65))	('mTORC1', 'Gene', (4, 10))	('Grb10', 'Gene', (52, 57))
602761	25119929	Mutation of Q107 to a stop codon, as found in this patient, would be expected to lead to a truncated Grb10 protein and loss of the phosphorylation sites on Grb10.	('Grb10', 'Gene', (101, 106))	('Q107 to', 'Var', (12, 19))	('truncated', 'MPA', (91, 100))	('Grb10', 'Gene', '2887', (101, 106))	('Grb10', 'Gene', (156, 161))	('phosphorylation sites', 'MPA', (131, 152))	('patient', 'Species', '9606', (51, 58))	('Grb10', 'Gene', '2887', (156, 161))	('loss', 'NegReg', (119, 123))
602763	25119929	Among a number of possible mechanisms of acquired resistance, this mutation may therefore have contributed to the eventual development of resistance to the IGF1R inhibitor treatment.	('mutation', 'Var', (67, 75))	('IGF1R', 'Gene', (156, 161))	('IGF1R', 'Gene', '3480', (156, 161))	('men', 'Species', '9606', (177, 180))	('contributed', 'Reg', (95, 106))	('men', 'Species', '9606', (130, 133))	('resistance', 'MPA', (138, 148))
602765	25119929	This patient was specifically studied for a GRB10 mutation because of the similarity in his outcome to that of patient #2.	('GRB10', 'Gene', (44, 49))	('patient', 'Species', '9606', (5, 12))	('patient', 'Species', '9606', (111, 118))	('GRB10', 'Gene', '2887', (44, 49))	('mutation', 'Var', (50, 58))
602766	25119929	A GRB10 V109A mutation was identified in his tumor tissue, which would not be expected to abrogate GRB10 function as the Q107 stop mutation previously noted in patient 2.	('GRB10', 'Gene', '2887', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GRB10', 'Gene', (99, 104))	('tumor', 'Disease', (45, 50))	('Q107 stop', 'Mutation', 'rs1223389447', (121, 130))	('V109A', 'Var', (8, 13))	('V109A', 'Mutation', 'rs1311557029', (8, 13))	('patient', 'Species', '9606', (160, 167))	('GRB10', 'Gene', (2, 7))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('GRB10', 'Gene', '2887', (2, 7))
602767	25119929	However, it is possible that the V109A mutation resulted in a sufficient conformational change of the Grb10 protein to impair the negative feedback to the IGF1R pathway.	('impair', 'NegReg', (119, 125))	('IGF1R', 'Gene', '3480', (155, 160))	('Grb10', 'Gene', '2887', (102, 107))	('conformational change', 'MPA', (73, 94))	('negative feedback', 'MPA', (130, 147))	('Grb10', 'Gene', (102, 107))	('V109A', 'Var', (33, 38))	('IGF1R', 'Gene', (155, 160))	('V109A', 'Mutation', 'rs1311557029', (33, 38))
602768	25119929	In addition to the mutations in GRB10 and PTPRD that can directly affect IGF-1R signaling, an unexpected mutation in MET was identified in patients with ES and DSRCT.	('IGF-1R', 'Gene', (73, 79))	('affect', 'Reg', (66, 72))	('DSRCT', 'Disease', (160, 165))	('mutation', 'Var', (105, 113))	('patients', 'Species', '9606', (139, 147))	('PTPRD', 'Gene', (42, 47))	('PTPRD', 'Gene', '5789', (42, 47))	('GRB10', 'Gene', '2887', (32, 37))	('mutations', 'Var', (19, 28))	('MET', 'Gene', (117, 120))	('GRB10', 'Gene', (32, 37))	('IGF-1R', 'Gene', '3480', (73, 79))
602772	25119929	The mutation may compromise the negative feedback function of the MET pathway, and thus lead to tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lead to', 'Reg', (88, 95))	('negative feedback function', 'MPA', (32, 58))	('tumor', 'Disease', (96, 101))	('mutation', 'Var', (4, 12))	('compromise', 'NegReg', (17, 27))	('MET pathway', 'Pathway', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
602776	25119929	The N375S mutation has been previously observed as contributing to the resistance of MET to its inhibitors.	('MET to', 'MPA', (85, 91))	('contributing', 'Reg', (51, 63))	('resistance', 'MPA', (71, 81))	('N375S', 'Mutation', 'rs33917957', (4, 9))	('N375S', 'Var', (4, 9))
602777	25119929	Patient 20 (DSRCT, Table 2) demonstrated two PIK3CA mutations, M1040I and G1049S, both located in the kinase domain of p110alpha near the activation loop.	('G1049S', 'Mutation', 'rs121913277', (74, 80))	('G1049S', 'Var', (74, 80))	('PIK3CA', 'Gene', (45, 51))	('PIK3CA', 'Gene', '5290', (45, 51))	('M1040I', 'Var', (63, 69))	('p110alpha', 'Gene', (119, 128))	('M1040I', 'Mutation', 'rs765098424', (63, 69))	('p110alpha', 'Gene', '5290', (119, 128))	('Patient', 'Species', '9606', (0, 7))
602780	25119929	The M1040I and G1049S mutations are located in the kinase domain of p110alpha, near the activation loop.	('M1040I', 'Var', (4, 10))	('G1049S', 'Var', (15, 21))	('p110alpha', 'Gene', (68, 77))	('p110alpha', 'Gene', '5290', (68, 77))	('G1049S', 'Mutation', 'rs121913277', (15, 21))	('M1040I', 'Mutation', 'rs765098424', (4, 10))
602781	25119929	H1047 mutations have been reported to result in enhanced kinase activity, one may hypothesize that M1040 and G1049 mutations located in the same helix with H1047 would similarly bolster the kinase activity of p110alpha by inducing an active conformation of the kinase activation loop.	('bolster', 'PosReg', (178, 185))	('kinase activity', 'MPA', (57, 72))	('kinase activity', 'MPA', (190, 205))	('H1047', 'Gene', (156, 161))	('G1049 mutations', 'Var', (109, 124))	('enhanced', 'PosReg', (48, 56))	('active conformation', 'MPA', (234, 253))	('p110alpha', 'Gene', (209, 218))	('p110alpha', 'Gene', '5290', (209, 218))	('M1040', 'Var', (99, 104))	('inducing', 'Reg', (222, 230))	('mutations', 'Var', (6, 15))
602820	31645348	Histone H3K36I mutation in a metastatic histiocytic tumor of the skull and response to sarcoma chemotherapy Recurrent somatic missense mutations in histone H3 genes have been identified in subsets of pediatric cancers.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('histone H3', 'Gene', (148, 158))	('missense mutations', 'Var', (126, 144))	('tumor', 'Disease', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('identified', 'Reg', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('pediatric cancers', 'Disease', 'MESH:D009369', (200, 217))	('pediatric cancers', 'Disease', (200, 217))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
602821	31645348	H3K36 histone mutations have recently been recognized as oncogenic drivers in rare subsets of malignant soft tissue sarcomas but have not been reported in histiocytic neoplasms.	('malignant soft tissue sarcomas', 'Disease', 'MESH:D012509', (94, 124))	('H3K36', 'Gene', (0, 5))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (104, 124))	('histiocytic neoplasms', 'Disease', 'MESH:D016403', (155, 176))	('malignant soft tissue sarcomas', 'Disease', (94, 124))	('histiocytic neoplasms', 'Disease', (155, 176))	('neoplasms', 'Phenotype', 'HP:0002664', (167, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('mutations', 'Var', (14, 23))	('neoplasm', 'Phenotype', 'HP:0002664', (167, 175))
602823	31645348	We describe a pediatric patient with a HIST1H3B K36I-mutant histiocytic tumor arising in the skull.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('K36I', 'Mutation', 'p.K36I', (48, 52))	('patient', 'Species', '9606', (24, 31))	('K36I-mutant', 'Var', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('HIST1H3B', 'Gene', (39, 47))	('HIST1H3B', 'Gene', '8358', (39, 47))
602825	31645348	Our report expands the histological spectrum of H3K36M/I-mutant soft tissue malignancies to histiocytic neoplasms and indicates that multiagent sarcoma-like chemotherapy can be highly effective even in the setting of widely disseminated metastatic disease.	('sarcoma', 'Disease', (144, 151))	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('K36M', 'Mutation', 'p.K36M', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('neoplasm', 'Phenotype', 'HP:0002664', (104, 112))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('H3K36M/I-mutant', 'Var', (48, 63))	('malignancies to histiocytic neoplasms', 'Disease', 'MESH:D015620', (76, 113))	('malignancies to histiocytic neoplasms', 'Disease', (76, 113))
602826	31645348	Somatic missense mutations in histone H3 genes have been identified as recurrent events in a subset of pediatric high-grade gliomas, and less commonly found in soft tissue and bone tumors.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('gliomas', 'Disease', (124, 131))	('histone', 'Protein', (30, 37))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('bone tumors', 'Disease', (176, 187))	('bone tumors', 'Disease', 'MESH:D001859', (176, 187))	('bone tumors', 'Phenotype', 'HP:0010622', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('missense mutations', 'Var', (8, 26))	('gliomas', 'Disease', 'MESH:D005910', (124, 131))
602827	31645348	Lysine 36-to-methionine (K36M) mutations in H3F3B have been found in the majority of chondroblastomas, and more recently, H3 mutations at lysine 36 have also been identified in two children with undifferentiated sarcomas: a HIST1H3C K36M and a HIST1H3B K36I mutation.	('H3F3B', 'Gene', (44, 49))	('found', 'Reg', (60, 65))	('Lysine', 'Var', (0, 6))	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (195, 220))	('sarcomas', 'Phenotype', 'HP:0100242', (212, 220))	('HIST1H3B', 'Gene', (244, 252))	('HIST1H3B', 'Gene', '8358', (244, 252))	('HIST1H3C', 'Gene', '8352', (224, 232))	('chondroblastomas', 'Disease', (85, 101))	('Lysine 36-to-methionine', 'Mutation', 'p.K36M', (0, 23))	('mutations at', 'Var', (125, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('mutations', 'Var', (31, 40))	('HIST1H3C', 'Gene', (224, 232))	('children', 'Species', '9606', (181, 189))	('chondroblastomas', 'Disease', 'MESH:D002804', (85, 101))	('K36I', 'Mutation', 'p.K36I', (253, 257))	('undifferentiated sarcomas', 'Disease', (195, 220))	('identified', 'Reg', (163, 173))	('K36M', 'Mutation', 'p.K36M', (25, 29))	('K36M', 'Mutation', 'p.K36M', (233, 237))	('K36I', 'Var', (253, 257))	('K36M', 'Var', (233, 237))	('lysine', 'Chemical', 'MESH:C114808', (138, 144))	('H3F3B', 'Gene', '3021', (44, 49))
602829	31645348	H3K36M/I mutations lead to the reduction of H3K36 methylation and a simultaneous genome-wide gain in H3K27 methylation, resulting in a redistribution of Polycomb repressive complex 1 (PRC1) and derepression of PRC1 target genes associated with the blocking of mesenchymal differentiation.	('H3K36M/I', 'Gene', (0, 8))	('H3K27', 'Protein', (101, 106))	('reduction', 'NegReg', (31, 40))	('K36M', 'Mutation', 'p.K36M', (2, 6))	('mutations', 'Var', (9, 18))	('redistribution', 'MPA', (135, 149))	('H3K36', 'Protein', (44, 49))	('gain', 'PosReg', (93, 97))	('PRC1', 'Gene', (184, 188))	('methylation', 'MPA', (107, 118))	('methylation', 'MPA', (50, 61))	('derepression', 'MPA', (194, 206))
602843	31645348	Whole-exome sequencing (WES) of the tumor and matched germline identified 20 somatic nonsynonymous single-nucleotide variants (SNVs) and two insertions, a frameshift insertion involving SGSM1 and a nonframe insertion involving FAM194A (Table 1).	('SGSM1', 'Gene', '129049', (186, 191))	('FAM194A', 'Gene', (227, 234))	('FAM194A', 'Gene', '131831', (227, 234))	('frameshift insertion', 'Var', (155, 175))	('SGSM1', 'Gene', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('single-nucleotide variants', 'Var', (99, 125))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
602844	31645348	We identified a somatic mutation in HIST1H3B with an allele frequency of 20%, leading to a K36I amino acid substitution (Fig.	('K36I', 'Mutation', 'p.K36I', (91, 95))	('HIST1H3B', 'Gene', '8358', (36, 44))	('K36I amino acid substitution', 'Var', (91, 119))	('HIST1H3B', 'Gene', (36, 44))
602856	31645348	We report a diagnostically challenging tumor with histiocytic morphology harboring a HIST1H3B K36I mutation that did not respond to multiple histiocytosis regimens but had an excellent response to a chemotherapy and radiation therapy regimen used for soft tissue sarcomas.	('soft tissue sarcomas', 'Disease', (251, 271))	('HIST1H3B', 'Gene', (85, 93))	('HIST1H3B', 'Gene', '8358', (85, 93))	('histiocytosis', 'Phenotype', 'HP:0100727', (141, 154))	('K36I', 'Var', (94, 98))	('K36I', 'Mutation', 'p.K36I', (94, 98))	('challenging tumor', 'Disease', (27, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (251, 271))	('challenging tumor', 'Disease', 'MESH:D009369', (27, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (263, 271))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (251, 271))
602859	31645348	Diffuse histiocytic infiltration consisting of CD68-positive and CD1a-negative lipid-laden histocytes are the traditional histological hallmarks of ECD, and a high prevalence of somatic BRAF mutations has also recently been identified in this disease.	('BRAF', 'Gene', (186, 190))	('CD1a', 'Gene', '909', (65, 69))	('identified', 'Reg', (224, 234))	('Diffuse histiocytic infiltration', 'Disease', (0, 32))	('mutations', 'Var', (191, 200))	('BRAF', 'Gene', '673', (186, 190))	('ECD', 'Disease', 'MESH:D031249', (148, 151))	('CD68', 'Gene', (47, 51))	('CD68', 'Gene', '968', (47, 51))	('ECD', 'Disease', (148, 151))	('laden histocytes', 'Phenotype', 'HP:0003651', (85, 101))	('CD1a', 'Gene', (65, 69))
602866	31645348	Whole-exome sequencing of our patient's tumor revealed a single oncogenic driver alteration (i.e., a HIST1H3B K36I mutation) leading to a global reduction in H3K36me2 expression.	('K36I', 'Var', (110, 114))	('patient', 'Species', '9606', (30, 37))	('K36I', 'Mutation', 'p.K36I', (110, 114))	('reduction', 'NegReg', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('H3K36me2 expression', 'MPA', (158, 177))	('HIST1H3B', 'Gene', '8358', (101, 109))	('HIST1H3B', 'Gene', (101, 109))	('tumor', 'Disease', (40, 45))
602868	31645348	To our knowledge only a single pediatric cancer patient harboring a H3K36I has previously been described, an undifferentiated thoracic sarcoma occurring in a young child.	('undifferentiated thoracic sarcoma', 'Disease', (109, 142))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('K36I', 'Mutation', 'p.K36I', (70, 74))	('patient', 'Species', '9606', (48, 55))	('H3K36I', 'Var', (68, 74))	('child', 'Species', '9606', (164, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('undifferentiated thoracic sarcoma', 'Disease', 'MESH:D002277', (109, 142))
602869	31645348	No data on treatment modalities and outcome has been reported in pediatric patients with H3K36M/I-mutant sarcomas.	('H3K36M/I-mutant', 'Var', (89, 104))	('patients', 'Species', '9606', (75, 83))	('K36M', 'Mutation', 'p.K36M', (91, 95))	('sarcomas', 'Disease', 'MESH:D012509', (105, 113))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('sarcomas', 'Disease', (105, 113))
602872	31645348	Our report expands the histological spectrum of H3K36M/I-mutant soft tissue malignancies to histiocytic neoplasms, indicating that multiagent chemotherapy can be highly effective even in the setting of widely disseminated metastatic disease.	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('K36M', 'Mutation', 'p.K36M', (50, 54))	('neoplasm', 'Phenotype', 'HP:0002664', (104, 112))	('H3K36M/I-mutant', 'Var', (48, 63))	('malignancies to histiocytic neoplasms', 'Disease', 'MESH:D015620', (76, 113))	('malignancies to histiocytic neoplasms', 'Disease', (76, 113))
602882	31645348	The HIST1H3B K36I variant described in the manuscript will be deposited in ClinVar  under accession number SCV000993417.	('HIST1H3B', 'Gene', (4, 12))	('K36I', 'Mutation', 'p.K36I', (13, 17))	('HIST1H3B', 'Gene', '8358', (4, 12))	('K36I', 'Var', (13, 17))
602903	31452621	Postoperative radiotherapy was performed to patients who had factors associated with an increased risk of recurrence such as high grade tumor, large tumor, close or positive surgical margins.	('large', 'Disease', (143, 148))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('high', 'Var', (125, 129))
602925	31452621	Local control rate was significantly worse in patients who received less than 60 Gy radiotherapy dose (p=0.03).	('patients', 'Species', '9606', (46, 54))	('Local control', 'CPA', (0, 13))	('less than 60', 'Var', (68, 80))	('worse', 'NegReg', (37, 42))
602952	31452621	reported better survival rates in patients with low grade tumors than high grade tumors, although it did not influence the local control rates.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('low grade', 'Var', (48, 57))	('survival', 'MPA', (16, 24))	('patients', 'Species', '9606', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('better', 'PosReg', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
602986	30684955	Loss of 1p, 3p, and 11q is also observed in advanced neuroblastomas and is associated with an unfavorable prognosis.	('neuroblastomas', 'Phenotype', 'HP:0003006', (53, 67))	('neuroblastomas', 'Disease', 'MESH:D009447', (53, 67))	('observed', 'Reg', (32, 40))	('neuroblastomas', 'Disease', (53, 67))	('neuroblastoma', 'Phenotype', 'HP:0003006', (53, 66))	('Loss', 'Var', (0, 4))
602987	30684955	Genomic alterations, such as loss and single nucleotide variants, in the ATM gene and other DNA damage response (DDR)-associated genes were found in nearly half of neuroblastoma and neuroblastoma-derived cell lines, particularly in advanced stages.	('ATM', 'Gene', (73, 76))	('neuroblastoma', 'Phenotype', 'HP:0003006', (182, 195))	('ATM', 'Gene', '472', (73, 76))	('neuroblastoma', 'Phenotype', 'HP:0003006', (164, 177))	('loss', 'NegReg', (29, 33))	('neuroblastoma', 'Disease', 'MESH:D009447', (182, 195))	('neuroblastoma', 'Disease', 'MESH:D009447', (164, 177))	('neuroblastoma', 'Disease', (182, 195))	('single nucleotide variants', 'Var', (38, 64))	('neuroblastoma', 'Disease', (164, 177))
602991	30684955	However, loss of one or more DDR pathway(s) in response to oncogenic stress can leave tumor cells vulnerable to PARP inhibition and induce cancer-specific cell death through the process of synthetic lethality.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('DDR', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('PARP', 'Gene', (112, 116))	('tumor', 'Disease', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('induce', 'Reg', (132, 138))	('PARP', 'Gene', '142', (112, 116))	('loss', 'Var', (9, 13))	('leave', 'Reg', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cancer', 'Disease', (139, 145))
602992	30684955	Ewing's sarcoma cells exhibit high levels of DNA damage and similarity in phenotype to BRCA1/2 mutant breast cancer, providing a molecular basis for the high sensitivity of Ewing's sarcoma to PARP1 inhibitors.	('PARP1', 'Gene', (192, 197))	('BRCA1/2', 'Gene', (87, 94))	('breast cancer', 'Disease', (102, 115))	("Ewing's sarcoma", 'Disease', (0, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (0, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (173, 188))	('BRCA1/2', 'Gene', '672;675', (87, 94))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (0, 15))	("Ewing's sarcoma", 'Disease', (173, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (173, 188))	('mutant', 'Var', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('PARP1', 'Gene', '142', (192, 197))
602993	30684955	More than 80% of osteosarcomas show a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumors, indicating a BRCAness phenotype.	('BRCAness', 'Disease', 'None', (196, 204))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('osteosarcomas', 'Disease', (17, 30))	('single-base substitutions', 'Var', (62, 87))	('LOH', 'Disease', (89, 92))	('osteosarcomas', 'Phenotype', 'HP:0002669', (17, 30))	('BRCA1/2-deficient tumors', 'Disease', (157, 181))	('BRCA1/2-deficient tumors', 'Disease', 'OMIM:612555', (157, 181))	('osteosarcomas', 'Disease', 'MESH:D012516', (17, 30))	('genome instability', 'MPA', (109, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('BRCAness', 'Disease', (196, 204))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))
602994	30684955	It has also been shown that osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor.	('susceptible', 'Reg', (87, 98))	('osteosarcoma', 'Disease', (28, 40))	('PARP', 'Gene', (106, 110))	('genetic signatures', 'Var', (52, 70))	('osteosarcoma', 'Phenotype', 'HP:0002669', (28, 40))	('BRCAness', 'Disease', (74, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (28, 40))	('BRCAness', 'Disease', 'None', (74, 82))	('PARP', 'Gene', '142', (106, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))
603036	30684955	It acts against cancers in patients with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('hereditary BRCA1', 'Disease', (41, 57))	('prostate cancers', 'Disease', 'MESH:D011471', (118, 134))	('patients', 'Species', '9606', (27, 35))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Disease', (127, 134))	('hereditary BRCA1', 'Disease', 'MESH:D061325', (41, 57))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRCA2', 'Gene', (61, 66))	('ovarian', 'Disease', (97, 104))	('prostate cancers', 'Phenotype', 'HP:0012125', (118, 134))	('prostate cancers', 'Disease', (118, 134))	('breast', 'Disease', (106, 112))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('mutations', 'Var', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('BRCA2', 'Gene', '675', (61, 66))
603049	30684955	Patients who continue to benefit from treatment, that is, show complete response (CR), partial response (PR), or stable disease (SD), may have the option to continue treatment upon agreement between the investigator and sponsor, and upon study drug availability.	('stable', 'Disease', (113, 119))	('Patients', 'Species', '9606', (0, 8))	('SD', 'Disease', 'MESH:D029461', (129, 131))	('partial', 'Var', (87, 94))	('CR', 'Chemical', '-', (82, 84))
603072	30684955	The recent approval of olaparib for treating tumors harboring BRCA1 or BRCA2 mutations represents the first drug based on this principle.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('BRCA1', 'Gene', '672', (62, 67))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('BRCA2', 'Gene', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('BRCA1', 'Gene', (62, 67))	('mutations', 'Var', (77, 86))	('BRCA2', 'Gene', '675', (71, 76))	('olaparib', 'Chemical', 'MESH:C531550', (23, 31))
603074	30684955	Several cancers have mutations in or epigenetically silenced homologous recombination-associated genes, which explains the genetic instability that drives cancer development.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('epigenetically silenced', 'Var', (37, 60))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('homologous recombination-associated genes', 'Gene', (61, 102))	('mutations in', 'Var', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
603075	30684955	In the pediatric cancer field, inactivation of these genes has been reported in neuroblastoma, Ewing's sarcoma, and osteosarcoma.	('neuroblastoma', 'Disease', (80, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('inactivation', 'Var', (31, 43))	('neuroblastoma', 'Phenotype', 'HP:0003006', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (95, 110))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (95, 110))	('cancer', 'Disease', (17, 23))	("Ewing's sarcoma", 'Disease', (95, 110))	('reported', 'Reg', (68, 76))	('neuroblastoma', 'Disease', 'MESH:D009447', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('osteosarcoma', 'Disease', (116, 128))
603109	30544742	Mutations of MYCN and CDK4 are more common in ARMS and its appearance can mimic pulmonary parenchyma in IHC stains.	('MYCN', 'Gene', '4613', (13, 17))	('RMS', 'Phenotype', 'HP:0002859', (47, 50))	('CDK4', 'Gene', (22, 26))	('Mutations', 'Var', (0, 9))	('CDK4', 'Gene', '1019', (22, 26))	('pulmonary parenchyma', 'Disease', (80, 100))	('pulmonary parenchyma', 'Disease', 'MESH:D010195', (80, 100))	('MYCN', 'Gene', (13, 17))
603110	30544742	Patients with ARMS are noted to express fusion proteins arising from the fusion of the FOXO transcription factor gene with either PAX3 (55%) or PAX7 (23%) transcription factors.	('fusion', 'Var', (40, 46))	('FOXO transcription factor', 'Gene', (87, 112))	('PAX7', 'Gene', (144, 148))	('PAX3', 'Gene', '5077', (130, 134))	('PAX3', 'Gene', (130, 134))	('Patients', 'Species', '9606', (0, 8))	('RMS', 'Phenotype', 'HP:0002859', (15, 18))	('PAX7', 'Gene', '5081', (144, 148))	('fusion', 'Interaction', (73, 79))
603190	30544742	A recent report by the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) studied the outcomes of fusion status in 103 patients with alveolar RMS presenting with N1 disease, and showed that patients with positive fusion genes for forkhead box protein O1 (FOXO1) appear to have worse prognosis and affected the five-year EFS for these patients (43%) compared with alveolar RMS N1 fusion-negative patients (74%) in this cohort.	('alveolar RMS', 'Disease', 'MESH:D002282', (142, 154))	('Soft Tissue Sarcoma', 'Phenotype', 'HP:0030448', (43, 62))	('alveolar RMS', 'Disease', 'MESH:D002282', (372, 384))	('patients', 'Species', '9606', (404, 412))	('forkhead box protein O1', 'Gene', '2308', (239, 262))	('Sarcoma', 'Disease', (55, 62))	('forkhead box protein O1', 'Gene', (239, 262))	('Sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('patients', 'Species', '9606', (343, 351))	('FOXO1', 'Gene', '2308', (264, 269))	('affected', 'Reg', (306, 314))	('patients', 'Species', '9606', (128, 136))	('RMS', 'Phenotype', 'HP:0002859', (151, 154))	('alveolar RMS', 'Disease', (142, 154))	('RMS', 'Phenotype', 'HP:0002859', (381, 384))	('EFS', 'MPA', (329, 332))	('alveolar RMS', 'Disease', (372, 384))	('FOXO1', 'Gene', (264, 269))	('patients', 'Species', '9606', (199, 207))	('Sarcoma', 'Disease', 'MESH:D012509', (55, 62))	('positive fusion genes', 'Var', (213, 234))
603204	30544742	This t(11;22) (q24;q12) translocation creates a fusion with the FLI-1 gene, which can be detected with polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH).	('fusion', 'Interaction', (48, 54))	('t(11', 'Var', (5, 9))	('FLI-1', 'Gene', (64, 69))	('FLI-1', 'Gene', '2313', (64, 69))
603272	29487692	We demonstrate its down-regulation in multiple embryonic and cancer cell lines and show that its expression in adult cell lines is associated with hypomethylation.	('hypomethylation', 'Var', (147, 162))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('down-regulation', 'NegReg', (19, 34))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
603286	29487692	We found that COX7A1 was significantly methylated in human embryonic stem cell-derived progenitor cell lines corresponding to mesenchymal and endothelial phenotypes (4D20.8 and 30-MV2-6 respectively), as compared to human adult cell counterparts (HMSC and HAEC (Figure 3B)).	('methylated', 'Var', (39, 49))	('human', 'Species', '9606', (53, 58))	('human', 'Species', '9606', (216, 221))	('COX7A1', 'Gene', (14, 20))
603313	29487692	We reasoned that COX7A1 expression may provide increased capacity for OXPHOS, and therefore decided to test the influence of COX7A1 expression on energy production mode using a mouse COX7A1 knock-out model (Supplementary Figure 7) to determine whether the absence of COX7A1 would result in a glycolytic shift.	('glycolytic shift', 'MPA', (292, 308))	('COX7A1', 'Gene', (267, 273))	('capacity for OXPHOS', 'MPA', (57, 76))	('result in', 'Reg', (280, 289))	('absence', 'Var', (256, 263))	('increased', 'PosReg', (47, 56))	('COX7A1', 'Gene', (17, 23))	('mouse', 'Species', '10090', (177, 182))	('expression', 'Var', (24, 34))
603314	29487692	Primary cultures of cardiomyocytes obtained from COX7A1 -/- mouse displayed elevated ECAR levels compared to the equivalent control cell culture derived from COX7A1 +/+ littermate mouse (Figure 6C, 6D).	('elevated', 'PosReg', (76, 84))	('mouse', 'Species', '10090', (180, 185))	('COX7A1 -/-', 'Var', (49, 59))	('ECAR levels', 'MPA', (85, 96))	('mouse', 'Species', '10090', (60, 65))
603328	29487692	We hypothesize that variation of COX7A1 expression level in different cancer lines could correlate with the magnitude of glycolytic shift or OXPHOS capacity in these lines and consequently with the varying degrees of tumor aggression, invasiveness, and sensitivity to chemotherapeutic regimens.	('expression', 'MPA', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('COX7A1', 'Gene', (33, 39))	('glycolytic shift', 'MPA', (121, 137))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('variation', 'Var', (20, 29))	('OXPHOS capacity', 'MPA', (141, 156))	('aggression', 'Phenotype', 'HP:0000718', (223, 233))	('tumor aggression', 'Disease', (217, 233))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumor aggression', 'Disease', 'MESH:D001523', (217, 233))
603330	29487692	One explanation for the evolutionary selection for the repression of scarless regenerative potential after EFT is that for most vertebrates, repression of regenerative potential once organogenesis is complete functions as a tumor suppression mechanism.	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('repression', 'Var', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
603332	29487692	As a result, the repression of epimorphic potential at the EFT, evidenced by the onset of COX7A1 expression, may provide an important role in tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('epimorphic potential', 'Var', (31, 51))	('tumor', 'Disease', (142, 147))	('repression', 'NegReg', (17, 27))	('onset', 'PosReg', (81, 86))	('COX7A1', 'Gene', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('expression', 'MPA', (97, 107))
603335	29487692	Further research is warranted to determine the extent to which highly glycolytic/OXPHOS-compromised COX7A1 deficient cells have increased regenerative ability, and the role of the phenotype in diverse aspects of tumor cell biology.	('regenerative ability', 'CPA', (138, 158))	('increased', 'PosReg', (128, 137))	('tumor', 'Disease', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('deficient', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('COX7A1', 'Gene', (100, 106))
603354	29487692	Data normalized and expression profiles determined using lumi package in R. We utilized the following datasets found at GEO database: GSE49996 Lung adenocarcinoma, GSE58272 Squamous cell carcinoma, GSE73003 Hepatocellular carcinoma, and GSE35242 Prostate cancer cells.	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (207, 231))	('GSE49996', 'Var', (134, 142))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (143, 162))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (143, 162))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('Squamous cell carcinoma', 'Disease', (173, 196))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (173, 196))	('Prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('GSE73003', 'Var', (198, 206))	('GSE35242 Prostate cancer', 'Disease', (237, 261))	('Lung adenocarcinoma', 'Disease', (143, 162))	('GSE58272', 'Var', (164, 172))	('Hepatocellular carcinoma', 'Disease', (207, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (207, 231))	('GSE35242 Prostate cancer', 'Disease', 'MESH:D011471', (237, 261))
603403	22972658	For local relapse-free survival, we found two independent factors with a negative impact: (1) presence of clinical local recurrence at the start of therapy in a sarcoma center; and (2) microscopically positive margin after surgery (Table 4).	('microscopically', 'Var', (185, 200))	('sarcoma', 'Disease', (161, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))
603428	22972658	Myxoid/round-cell liposarcomas are the most common subtype of liposarcoma in the extremity/trunk wall localization, which shows histologically continuous morphologic spectrum-sharing characteristic chromosome rearrangement t(12;16) resulting in DDIT3-FUS (95%) or EWS-CHOP (5%) fusion with diagnostic and possible treatment implications.	('liposarcomas', 'Disease', (18, 30))	('liposarcoma', 'Disease', 'MESH:D008080', (18, 29))	('liposarcoma', 'Disease', 'MESH:D008080', (62, 73))	('EWS', 'Gene', (264, 267))	('CHOP', 'Gene', '1649', (268, 272))	('liposarcomas', 'Disease', 'MESH:D008080', (18, 30))	('liposarcoma', 'Disease', (18, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (22, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('liposarcoma', 'Disease', (62, 73))	('chromosome rearrangement t', 'Var', (198, 224))	('FUS', 'Gene', (251, 254))	('DDIT3', 'Gene', '1649', (245, 250))	('liposarcomas', 'Phenotype', 'HP:0012034', (18, 30))	('CHOP', 'Gene', (268, 272))	('EWS', 'Gene', '2130', (264, 267))	('liposarcoma', 'Phenotype', 'HP:0012034', (18, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('DDIT3', 'Gene', (245, 250))	('FUS', 'Gene', '2521', (251, 254))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))
603538	32590747	Reasons for end of treatment were disease progression (11/21, 52.4%), safety (5/21, 23.8%), death (1/21, 4.8%), non-adherence (1/21, 4.8%), medical decisions (1/21, 4.8%), and unknown reasons (2/21, 9.5%).	('death', 'Disease', 'MESH:D003643', (92, 97))	('medical', 'Disease', (140, 147))	('death', 'Disease', (92, 97))	('non-adherence', 'Var', (112, 125))	('safety', 'Disease', (70, 76))	('disease', 'Disease', (34, 41))
603763	26483610	Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('rat', 'Species', '10116', (90, 93))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('rat', 'Species', '10116', (24, 27))	('trigger', 'Reg', (103, 110))	('alterations', 'Var', (86, 97))
603823	26483610	For example, recently, a BRAFT1799A mutated melanoma model called HMEX1906 was developed by using an early passage, vemurafenib-naive, primary human-patient-derived xenograft.	('vemurafenib', 'Chemical', 'MESH:D000077484', (116, 127))	('human', 'Species', '9606', (143, 148))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('HMEX1906', 'CellLine', 'CVCL:9H95', (66, 74))	('BRAFT1799A', 'Mutation', 'rs113488022', (25, 35))	('patient', 'Species', '9606', (149, 156))	('BRAFT1799A', 'Var', (25, 35))
603854	26483610	Two well-established subclones of the B16 melanoma cell line, obtained from in vivo passaging, include the B16F1 and B16F10 variants.	('melanoma', 'Disease', (42, 50))	('B16', 'CellLine', 'CVCL:N540', (38, 41))	('B16', 'CellLine', 'CVCL:N540', (117, 120))	('B16', 'CellLine', 'CVCL:N540', (107, 110))	('B16F10', 'Var', (117, 123))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
603856	26483610	Conversely, B16F10 has high metastatic potential to distant visceral organs, most notably the lungs, and has been ideal for in vivo studies because of its swift growth pattern and high turnover, inducing death within two to four weeks after SC injection into mice.	('inducing', 'Reg', (195, 203))	('B16F10', 'Var', (12, 18))	('B16', 'CellLine', 'CVCL:N540', (12, 15))	('mice', 'Species', '10090', (259, 263))	('death', 'Disease', 'MESH:D003643', (204, 209))	('death', 'Disease', (204, 209))
603866	26483610	Analysis of the B16 mutanome has revealed inactivating mutations in Cdkn2a (responsible for cyclin-dependent kinase inhibitors, p16INK4a and p19Arf) but few activating mutations in BRAF, contrasting human melanomas in which at least 60% of tumors express BRAF mutations.	('cyclin-dependent kinase inhibitors', 'MPA', (92, 126))	('p19Arf', 'Gene', (141, 147))	('human', 'Species', '9606', (199, 204))	('mutations', 'Var', (55, 64))	('activating', 'MPA', (157, 167))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('B16', 'CellLine', 'CVCL:N540', (16, 19))	('p19Arf', 'Gene', '1029', (141, 147))	('melanomas', 'Phenotype', 'HP:0002861', (205, 214))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('melanomas', 'Disease', 'MESH:D008545', (205, 214))	('tumors', 'Disease', (240, 246))	('BRAF', 'Gene', (181, 185))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('Cdkn2a', 'Gene', (68, 74))	('Cdkn2a', 'Gene', '1029', (68, 74))	('melanomas', 'Disease', (205, 214))
603872	26483610	The Cloudman S91 cell line, isolated from DBA/2 mice, has been used to assess the efficacy of several novel anticancer therapies and drug delivery modalities, including targeted polyethylenimine polyplexes and nanotransporters.	('polyethylenimine', 'Chemical', 'MESH:D011094', (178, 194))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('mice', 'Species', '10090', (48, 52))	('S91', 'CellLine', 'CVCL:J817', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('polyethylenimine', 'Var', (178, 194))
603879	26483610	Furthermore, some of the genetic alterations have deleterious effects on reproductive fitness; hence, obtaining the desired genotypes would not be possible.	('effects', 'Reg', (62, 69))	('rat', 'Species', '10116', (37, 40))	('genetic alterations', 'Var', (25, 44))	('reproductive fitness', 'CPA', (73, 93))
603884	26483610	p16INK4a, also known as multiple tumor suppressor 1, acts as an inhibitor of G1/S cell cycle progression by blocking the phosphorylation of pRB protein via negatively regulating the kinase activity of cyclin D-CDK4 or cyclin D-CDK6 complexes.	('CDK6', 'Gene', '12571', (227, 231))	('blocking', 'NegReg', (108, 116))	('p16INK4a', 'Var', (0, 8))	('regulating', 'Reg', (167, 177))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('phosphorylation', 'MPA', (121, 136))	('pRB', 'Gene', (140, 143))	('pRB', 'Gene', '19645', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cyclin', 'Protein', (201, 207))	('cyclin', 'Protein', (218, 224))	('negatively', 'NegReg', (156, 166))	('kinase activity', 'MPA', (182, 197))	('tumor', 'Disease', (33, 38))	('CDK6', 'Gene', (227, 231))	('CDK4', 'Gene', (210, 214))	('CDK4', 'Gene', '12567', (210, 214))
603891	26483610	In 1996, Serrano et al developed a mouse strain with targeted deletion of CDKN2A locus.	('deletion', 'Var', (62, 70))	('CDKN2A', 'Gene', '12578', (74, 80))	('CDKN2A', 'Gene', (74, 80))	('mouse', 'Species', '10090', (35, 40))
603893	26483610	Later on, several studies suggested that loss of Ink4a or Arf was not enough to trigger melanoma development but makes animals susceptible to UVR or carcinogen-induced melanomagenesis.	('loss', 'Var', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('Ink4a', 'Gene', '12578', (49, 54))	('Ink4a', 'Gene', (49, 54))	('Arf', 'Gene', (58, 61))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('Arf', 'Gene', '12578', (58, 61))	('melanoma', 'Disease', (168, 176))	('makes', 'Reg', (113, 118))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
603894	26483610	In the late 1980s, RAS family of proteins was discovered to be frequently mutated in cutaneous melanoma.	('RAS family of proteins', 'Protein', (19, 41))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('mutated', 'Var', (74, 81))	('cutaneous melanoma', 'Disease', (85, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))
603895	26483610	About 15%-25% of human melanomas harbor activating mutations in NRAS, whereas Harvey rat sarcoma viral oncogene homolog (HRAS) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are very rare (<2%).	('activating', 'PosReg', (40, 50))	('melanomas', 'Disease', (23, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('mutations', 'Var', (51, 60))	('human', 'Species', '9606', (17, 22))	('rat', 'Species', '10116', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('rat', 'Species', '10116', (85, 88))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('NRAS', 'Gene', (64, 68))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', 'MESH:D012509', (143, 150))	('melanomas', 'Disease', 'MESH:D008545', (23, 32))	('sarcoma', 'Disease', (89, 96))	('KRAS', 'Gene', '24525', (175, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('KRAS', 'Gene', (175, 179))	('sarcoma', 'Disease', (143, 150))
603901	26483610	On the other hand, melanocyte-specific expression of NRASQ61K was able to trigger melanoma development with a low incidence rate and high latency (29% at 70 weeks).	('rat', 'Species', '10116', (124, 127))	('NRASQ61K', 'Var', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('trigger', 'PosReg', (74, 81))
603904	26483610	Another NRAS mutation (NRASG12D) was assessed for its potential to induce melanomagenesis when expressed in the melanocytes of developing mouse embryos.	('mouse', 'Species', '10090', (138, 143))	('mutation', 'Var', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('induce', 'PosReg', (67, 73))
603905	26483610	Despite this mutation was able to induce melanocytic lesions resembling blue nevi, it failed to induce spontaneous cutaneous melanoma up to 24 months.	('induce', 'Reg', (34, 40))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('blue nevi', 'Phenotype', 'HP:0100814', (72, 81))	('cutaneous melanoma', 'Disease', (115, 133))	('mutation', 'Var', (13, 21))	('blue nevi', 'Disease', (72, 81))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (115, 133))	('nevi', 'Phenotype', 'HP:0003764', (77, 81))	('melanocytic lesions', 'Disease', 'MESH:D009508', (41, 60))	('melanocytic lesions resembling blue nevi', 'Phenotype', 'HP:0000995', (41, 81))	('melanocytic lesions', 'Disease', (41, 60))
603908	26483610	Identification of the PTEN deletion and BRAF mutations were two of the greatest discoveries in melanoma field.	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (40, 44))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('deletion', 'Var', (27, 35))	('PTEN', 'Gene', (22, 26))
603909	26483610	In 2002, as an early product of Cancer Genome Project, BRAF was discovered to carry somatic missense mutations in >65% of malignant melanomas.	('Cancer', 'Disease', (32, 38))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('malignant melanomas', 'Disease', (122, 141))	('malignant melanomas', 'Disease', 'MESH:D008545', (122, 141))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('malignant melanomas', 'Phenotype', 'HP:0002861', (122, 141))	('malignant melanoma', 'Phenotype', 'HP:0002861', (122, 140))	('BRAF', 'Gene', (55, 59))	('missense mutations', 'Var', (92, 110))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
603910	26483610	BRAF mutations are mutually exclusive to RAS mutations, and taken together, the mitogen-activated protein kinase (MAPK) signaling is overactivated in more than ~85% of the malignant melanoma cases.	('malignant melanoma', 'Phenotype', 'HP:0002861', (172, 190))	('overactivated', 'PosReg', (133, 146))	('malignant melanoma', 'Disease', 'MESH:D008545', (172, 190))	('mutations', 'Var', (5, 14))	('malignant melanoma', 'Disease', (172, 190))	('mitogen-activated', 'MPA', (80, 97))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))
603911	26483610	Melanocyte-specific expression of BRAFV600E protein consistently leads to benign melanocytic lesions.	('BRAFV600E', 'Mutation', 'rs113488022', (34, 43))	('benign melanocytic lesions', 'Disease', (74, 100))	('benign melanocytic lesions', 'Phenotype', 'HP:0000995', (74, 100))	('leads to', 'Reg', (65, 73))	('benign melanocytic lesions', 'Disease', 'MESH:D009508', (74, 100))	('BRAFV600E', 'Var', (34, 43))
603913	26483610	However, loss of p16INK4a or p16INK4A/p19ARF decreases the latency and increases the tumor penetrance (~80% at 12 months).	('increases the tumor', 'Disease', 'MESH:D009369', (71, 90))	('p16INK4a', 'Var', (17, 25))	('p19ARF', 'Gene', (38, 44))	('decreases', 'NegReg', (45, 54))	('loss', 'Var', (9, 13))	('p19ARF', 'Gene', '12578', (38, 44))	('latency', 'CPA', (59, 66))	('increases the tumor', 'Disease', (71, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p16INK4A', 'Gene', (29, 37))	('p16INK4A', 'Gene', '12578', (29, 37))
603914	26483610	It has been shown that ~80% of the benign nevi carry BRAF V600E mutation, suggesting that BRAF mutation is not sufficient to drive melanoma development and requires additional alterations.	('nevi', 'Phenotype', 'HP:0003764', (42, 46))	('V600E', 'Var', (58, 63))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('rat', 'Species', '10116', (180, 183))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('BRAF', 'Gene', (53, 57))	('V600E', 'Mutation', 'rs113488022', (58, 63))
603915	26483610	In fact, virtually all the tumors that were developed in BRAF V600E mice had increased AKT activity and decreased p16INK4A expression.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('AKT', 'Gene', (87, 90))	('tumors', 'Disease', (27, 33))	('decreased', 'NegReg', (104, 113))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('p16INK4A', 'Gene', '12578', (114, 122))	('increased', 'PosReg', (77, 86))	('decreased p16INK4A expression', 'Phenotype', 'HP:0032429', (104, 133))	('BRAF V600E', 'Var', (57, 67))	('p16INK4A', 'Gene', (114, 122))	('AKT', 'Gene', '11651', (87, 90))
603916	26483610	Frequent loss of heterozygosity of chromosome 10q23 in melanoma led to the identification of PTEN phosphatase as a tumor suppressor protein that is deleted in ~20% of uncultured primary and 55% of metastatic melanoma tumors.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('PTEN', 'Gene', (93, 97))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma tumors', 'Disease', (208, 223))	('melanoma', 'Disease', (208, 216))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Disease', (115, 120))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('melanoma tumors', 'Disease', 'MESH:D008545', (208, 223))	('deleted', 'Var', (148, 155))	('loss of', 'NegReg', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
603917	26483610	Deletion of PTEN leads to overactivation of AKT signaling and frequently accompanies BRAF activation.	('overactivation', 'PosReg', (26, 40))	('accompanies', 'Reg', (73, 84))	('BRAF', 'Disease', (85, 89))	('AKT', 'Gene', '11651', (44, 47))	('PTEN', 'Gene', (12, 16))	('AKT', 'Gene', (44, 47))	('Deletion', 'Var', (0, 8))
603920	26483610	In these models, topical application of tamoxifen triggers melanocyte-specific expression of Cre recombinase to knockout floxed PTEN gene and/or activate the mutant BRAF protein expression.	('lox', 'Gene', (122, 125))	('PTEN', 'Gene', (128, 132))	('tamoxifen', 'Chemical', 'MESH:D013629', (40, 49))	('knockout', 'Var', (112, 120))	('expression', 'MPA', (178, 188))	('lox', 'Gene', '16948', (122, 125))	('BRAF', 'Gene', (165, 169))	('protein', 'Protein', (170, 177))	('activate', 'PosReg', (145, 153))	('mutant', 'Var', (158, 164))
603921	26483610	In 2009, using this model (Tyr:Cre-ERT2 BrafCA/+), Dankort et al reported that melanocyte-specific expression of V600E BRAF triggers formation of highly pigmented lesions in 21-28 days following topical tamoxifen application.	('formation', 'MPA', (133, 142))	('highly pigmented lesions', 'MPA', (146, 170))	('ERT2', 'Gene', (35, 39))	('BRAF', 'Gene', (119, 123))	('V600E', 'Mutation', 'rs113488022', (113, 118))	('tamoxifen', 'Chemical', 'MESH:D013629', (203, 212))	('V600E', 'Var', (113, 118))	('ERT2', 'Gene', '26417', (35, 39))	('triggers', 'Reg', (124, 132))	('Tyr', 'Chemical', 'MESH:D014443', (27, 30))
603925	26483610	However, combination of PTEN knockout with mutant BRAF activation (Tyr:Cre-ERT2 BrafCA/+; PTENlox/lox) significantly enhances melanocytic lesion development as early as 7-10 days following tamoxifen application.	('lox', 'Gene', (98, 101))	('BRAF', 'Gene', (50, 54))	('melanocytic lesion', 'Disease', (126, 144))	('ERT2', 'Gene', '26417', (75, 79))	('lox', 'Gene', '16948', (98, 101))	('Tyr', 'Chemical', 'MESH:D014443', (67, 70))	('mutant', 'Var', (43, 49))	('lox', 'Gene', (94, 97))	('tamoxifen', 'Chemical', 'MESH:D013629', (189, 198))	('lox', 'Gene', '16948', (94, 97))	('melanocytic lesion', 'Disease', 'MESH:D009508', (126, 144))	('ERT2', 'Gene', (75, 79))	('enhances', 'PosReg', (117, 125))	('PTEN', 'Gene', (24, 28))
603926	26483610	The cooperation between mutant BRAF and PTEN silencing was so strong that all mice rapidly developed advanced metastatic malignancy that required euthanasia in 25-50 days.	('mutant', 'Var', (24, 30))	('silencing', 'Var', (45, 54))	('developed', 'Reg', (91, 100))	('rat', 'Species', '10116', (9, 12))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('PTEN', 'Gene', (40, 44))	('malignancy', 'Disease', (121, 131))	('mice', 'Species', '10090', (78, 82))
603932	26483610	Ectopic expression of TVA in specific cell types or tissues renders their susceptibility to infection by RCAS.	('susceptibility to infection', 'Phenotype', 'HP:0002719', (74, 101))	('infection', 'Disease', 'MESH:D007239', (92, 101))	('TVA', 'Chemical', 'MESH:C050413', (22, 25))	('Ectopic expression', 'Var', (0, 18))	('infection', 'Disease', (92, 101))	('susceptibility', 'MPA', (74, 88))	('RCAS', 'Chemical', '-', (105, 109))	('TVA', 'Gene', (22, 25))
603941	26483610	VanBrocklin et al used the RCAS/TVA system to assess the NRASQ61R-driven melanoma in INK4A/ARFlox/lox mice.	('lox', 'Gene', (98, 101))	('melanoma', 'Disease', (73, 81))	('mice', 'Species', '10090', (102, 106))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('RCAS', 'Chemical', '-', (27, 31))	('INK4A', 'Gene', '12578', (85, 90))	('TVA', 'Chemical', 'MESH:C050413', (32, 35))	('lox', 'Gene', '16948', (98, 101))	('lox', 'Gene', (94, 97))	('NRASQ61R-driven', 'Var', (57, 72))	('INK4A', 'Gene', (85, 90))	('lox', 'Gene', '16948', (94, 97))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
603943	26483610	Administration of RCAS virus encoding NRASQ61R and Cre recombinase led to development of melanomas in 36% of the mice in as early as three weeks.	('NRASQ61R', 'Var', (38, 46))	('rat', 'Species', '10116', (8, 11))	('melanomas', 'Disease', (89, 98))	('RCAS', 'Chemical', '-', (18, 22))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('melanomas', 'Disease', 'MESH:D008545', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('mice', 'Species', '10090', (113, 117))
603944	26483610	Linking the expression of NRASQ61R and Cre by an internal ribosomal entry site (IRES) resulted in tumor formation in 63% of TVA-positive mice.	('TVA', 'Chemical', 'MESH:C050413', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('resulted in', 'Reg', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('NRASQ61R', 'Var', (26, 34))	('mice', 'Species', '10090', (137, 141))
603945	26483610	The same group crossed Dct-TVA; INK4A/ARFlox/lox mice with BRAFCA; +-PTENlox/lox mice that carry a Cre activated BRAFV600E floxed PTEN gene.	('Dct-TVA', 'Chemical', '-', (23, 30))	('lox', 'Gene', '16948', (73, 76))	('mice', 'Species', '10090', (81, 85))	('lox', 'Gene', '16948', (77, 80))	('lox', 'Gene', (41, 44))	('BRAFV600E', 'Mutation', 'rs113488022', (113, 122))	('lox', 'Gene', (45, 48))	('mice', 'Species', '10090', (49, 53))	('lox', 'Gene', (124, 127))	('lox', 'Gene', '16948', (41, 44))	('INK4A', 'Gene', (32, 37))	('lox', 'Gene', (73, 76))	('PTEN', 'Gene', (130, 134))	('lox', 'Gene', '16948', (45, 48))	('INK4A', 'Gene', '12578', (32, 37))	('BRAFV600E', 'Var', (113, 122))	('lox', 'Gene', '16948', (124, 127))	('lox', 'Gene', (77, 80))
603950	26483610	In this model, expression of RET under the control of ubiquitous metallothionein-1 promoter leads to melanoma development in a stepwise manner.	('metallothionein-1', 'Gene', '17748', (65, 82))	('expression', 'Var', (15, 25))	('RET', 'Gene', (29, 32))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('RET', 'Gene', '19713', (29, 32))	('metallothionein-1', 'Gene', (65, 82))	('leads to', 'Reg', (92, 100))
603958	26483610	Pollock et al accidentally developed mouse model of melanoma that involves aberrant expression of metabotropic glutamate receptor 1 (GRM1).	('aberrant', 'Var', (75, 83))	('GRM1', 'Gene', '14816', (133, 137))	('metabotropic glutamate receptor 1', 'Gene', '14816', (98, 131))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('metabotropic glutamate receptor 1', 'Gene', (98, 131))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('Pollock', 'Species', '8060', (0, 7))	('mouse', 'Species', '10090', (37, 42))	('GRM1', 'Gene', (133, 137))
603961	26483610	Aberrant GRM1 expression was discovered to contribute to some cases of melanoma.	('contribute', 'Reg', (43, 53))	('Aberrant', 'Var', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('GRM1', 'Gene', (9, 13))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('GRM1', 'Gene', '14816', (9, 13))
603962	26483610	A single-nucleotide polymorphism in this gene was significantly associated with melanoma susceptibility in patients with a low level of sun exposure.	('associated with', 'Reg', (64, 79))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('single-nucleotide polymorphism', 'Var', (2, 32))	('patients', 'Species', '9606', (107, 115))
603965	26483610	Another mouse model for a rare subtype of melanoma, which involves guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) mutation, was recently developed.	('melanoma', 'Disease', (42, 50))	('GNAQ', 'Gene', (122, 126))	('GNAQ', 'Gene', '14682', (122, 126))	('mouse', 'Species', '10090', (8, 13))	('mutation', 'Var', (128, 136))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
603966	26483610	Although mutation of this gene was rarely observed in cutaneous melanoma (<2%), it is constitutively activated ~50% of primary uveal melanomas because of mutation of codon 209.	('mutation of codon 209', 'Var', (154, 175))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('uveal melanomas', 'Disease', (127, 142))	('uveal melanomas', 'Phenotype', 'HP:0007716', (127, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('cutaneous melanoma', 'Disease', (54, 72))	('uveal melanomas', 'Disease', 'MESH:C536494', (127, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('activated', 'PosReg', (101, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (54, 72))
603971	26483610	Taken all together, many different melanoma mouse models have been established to investigate the significance of melanoma driving genetic mutations.	('melanoma', 'Disease', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('mutations', 'Var', (139, 148))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('mouse', 'Species', '10090', (44, 49))	('melanoma', 'Disease', (114, 122))
603972	26483610	Models involving deletion of CDKN2A locus, TP53 and PTEN genes; activation of GNAQ, GRM1, stem cell factor (SCF), hepatocyte growth factor/scatter factor (HGF/SF), Met, RAS, and most importantly, BRAF have been developed.	('GNAQ', 'Gene', (78, 82))	('HGF/SF', 'Gene', '15234', (155, 161))	('stem cell factor', 'Gene', '17311', (90, 106))	('PTEN', 'Gene', (52, 56))	('GNAQ', 'Gene', '14682', (78, 82))	('TP53', 'Gene', (43, 47))	('stem cell factor', 'Gene', (90, 106))	('GRM1', 'Gene', '14816', (84, 88))	('SCF', 'Gene', (108, 111))	('HGF/SF', 'Gene', (155, 161))	('activation', 'PosReg', (64, 74))	('GRM1', 'Gene', (84, 88))	('TP53', 'Gene', '22059', (43, 47))	('CDKN2A', 'Gene', '12578', (29, 35))	('CDKN2A', 'Gene', (29, 35))	('hepatocyte growth factor/scatter factor', 'Gene', (114, 153))	('deletion', 'Var', (17, 25))	('SCF', 'Gene', '17311', (108, 111))	('hepatocyte growth factor/scatter factor', 'Gene', '15234', (114, 153))
603988	26483610	Around 22% of the HGF/SF transgenic mice develop spontaneous melanomas with a mean onset of 15.6 months; however, these melanomas do not reflect the human melanomas as they demonstrate a dermal morphology.	('melanomas', 'Disease', 'MESH:D008545', (155, 164))	('develop', 'PosReg', (41, 48))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('HGF/SF', 'Gene', (18, 24))	('melanomas', 'Disease', (155, 164))	('transgenic', 'Var', (25, 35))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('melanomas', 'Disease', 'MESH:D008545', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('melanomas', 'Disease', (120, 129))	('rat', 'Species', '10116', (180, 183))	('HGF/SF', 'Gene', '15234', (18, 24))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('human', 'Species', '9606', (149, 154))	('melanomas', 'Disease', 'MESH:D008545', (61, 70))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('transgenic mice', 'Species', '10090', (25, 40))	('melanomas', 'Disease', (61, 70))
603995	26483610	UVB has been found to be more carcinogenic because it can generate direct cyclobutane pyrimidine dimers (CPDs) and 6-4PP lesions that are not effectively repaired.	('carcinogenic', 'Disease', 'MESH:D063646', (30, 42))	('carcinogenic', 'Disease', (30, 42))	('CPD', 'Disease', 'MESH:C565865', (105, 108))	('6-4PP', 'Var', (115, 120))	('cyclobutane pyrimidine', 'Chemical', '-', (74, 96))	('CPD', 'Disease', (105, 108))	('rat', 'Species', '10116', (62, 65))
603996	26483610	Upon UVR stimulation, host cells generate a p53-mediated stress response that attempts to repair UVB signature mutations.	('mutations', 'Var', (111, 120))	('rat', 'Species', '10116', (37, 40))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '22059', (44, 47))	('UVB', 'Gene', (97, 100))
604003	26483610	Furthermore, failure of DNA repair could result in mutations and become deleterious if it affects key oncogenes or tumor suppressors, such as p53.	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '22059', (142, 145))	('tumor', 'Disease', (115, 120))	('failure', 'NegReg', (13, 20))	('affects', 'Reg', (90, 97))	('result in', 'Reg', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
604007	26483610	It has been discovered that following UV treatment, various tumor suppressors are inactivated by DNA methylation, including CDKN2A and PTEN.	('CDKN2A', 'Gene', (124, 130))	('DNA methylation', 'Var', (97, 112))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('methylation', 'Var', (101, 112))	('CDKN2A', 'Gene', '12578', (124, 130))	('inactivated', 'NegReg', (82, 93))
604008	26483610	Further inactivating mutations in histone deacetylases such as HDAC1-3 maintain chromosomes in the relaxed state, increasing its accessibility to transcription factors that promote melanoma development.	('accessibility', 'MPA', (129, 142))	('melanoma', 'Disease', (181, 189))	('HDAC1', 'Gene', '433759', (63, 68))	('HDAC1', 'Gene', (63, 68))	('inactivating mutations', 'Var', (8, 30))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('promote', 'PosReg', (173, 180))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))	('increasing', 'PosReg', (114, 124))
604009	26483610	Other genetic risk factors to melanomagenesis have been determined in UVR models by additional genetic modifications, such as inactivating Ink4a/Arf, CDK4, or CDKN2A, which decreased the latency time to metastasis.	('CDKN2A', 'Gene', '12578', (159, 165))	('modifications', 'Var', (103, 116))	('CDK4', 'Gene', '12567', (150, 154))	('Ink4a/Arf', 'Gene', '12578', (139, 148))	('CDK4', 'Gene', (150, 154))	('latency time to metastasis', 'CPA', (187, 213))	('inactivating', 'Var', (126, 138))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Disease', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('decreased', 'NegReg', (173, 182))	('Ink4a/Arf', 'Gene', (139, 148))	('CDKN2A', 'Gene', (159, 165))
604060	26089739	Moreover, all grade 3/4 toxicities were more common with doxorubicin and ifosfamide than with doxorubicin alone (leucopenia 43% versus 40%, neutropenia 42% versus 37%, febrile neutropenia 46% versus 13%, anemia 35% versus 5%, and thrombocytopenia 33% versus <1%).	('febrile neutropenia', 'Disease', 'MESH:D009503', (168, 187))	('anemia', 'Disease', 'MESH:D000740', (204, 210))	('thrombocytopenia', 'Disease', (230, 246))	('leucopenia', 'Disease', (113, 123))	('doxorubicin', 'Var', (57, 68))	('leucopenia', 'Disease', 'MESH:C536227', (113, 123))	('neutropenia', 'Disease', 'MESH:D009503', (140, 151))	('neutropenia', 'Phenotype', 'HP:0001875', (140, 151))	('toxicities', 'Disease', 'MESH:D064420', (24, 34))	('ifosfamide', 'Chemical', 'MESH:D007069', (73, 83))	('anemia', 'Phenotype', 'HP:0001903', (204, 210))	('doxorubicin', 'Chemical', 'MESH:D004317', (94, 105))	('toxicities', 'Disease', (24, 34))	('thrombocytopenia', 'Disease', 'MESH:D013921', (230, 246))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (230, 246))	('febrile neutropenia', 'Disease', (168, 187))	('anemia', 'Disease', (204, 210))	('neutropenia', 'Disease', (176, 187))	('neutropenia', 'Disease', (140, 151))	('neutropenia', 'Phenotype', 'HP:0001875', (176, 187))	('neutropenia', 'Disease', 'MESH:D009503', (176, 187))	('doxorubicin', 'Chemical', 'MESH:D004317', (57, 68))
604080	26089739	In 2012, the European Medicines Agency and the U.S. Food and Drug Administration (FDA) have approved pazopanib based on the results of the pivotal, randomized, double-blind, placebo controlled, multicenter, phase III PALETTE study in 369 patients (165 with U-LMS), in which pazopanib significantly increased the time that patients remained progression-free compared with placebo (median PFS: 4.6 versus 1.6 months; p < 0.001).	('pazopanib', 'Chemical', 'MESH:C516667', (274, 283))	('patients', 'Species', '9606', (322, 330))	('pazopanib', 'Var', (274, 283))	('progression-free', 'CPA', (340, 356))	('pazopanib', 'Chemical', 'MESH:C516667', (101, 110))	('U-LMS', 'Phenotype', 'HP:0002891', (257, 262))	('increased', 'PosReg', (298, 307))	('patients', 'Species', '9606', (238, 246))
604194	25948942	Upregulation of NKX2.2, a target of EWSR1/FLI1 fusion transcript, in primary renal Ewing sarcoma Renal Ewing sarcoma (ES) is a rare malignant tumor characterized by fusion of the EWSR1 gene with a member of the ETS family of oncogenes, arising at a specific chromosomal translocation.	('primary renal Ewing sarcoma', 'Disease', 'MESH:C563168', (69, 96))	('EWSR1', 'Gene', '2130', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FLI1', 'Gene', '2313', (42, 46))	('fusion', 'Var', (165, 171))	('NKX2.2', 'Gene', '4821', (16, 22))	('EWSR1', 'Gene', (179, 184))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (103, 116))	('malignant tumor', 'Disease', (132, 147))	('malignant tumor', 'Disease', 'MESH:D018198', (132, 147))	('EWSR1', 'Gene', (36, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('ES', 'Phenotype', 'HP:0012254', (118, 120))	('Renal Ewing sarcoma', 'Disease', 'MESH:C563168', (97, 116))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (83, 96))	('primary renal Ewing sarcoma', 'Disease', (69, 96))	('Renal Ewing sarcoma', 'Disease', (97, 116))	('Upregulation', 'PosReg', (0, 12))	('FLI1', 'Gene', (42, 46))	('EWSR1', 'Gene', '2130', (179, 184))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('NKX2.2', 'Gene', (16, 22))
604210	25948942	Fluorescence in situ hybridization (FISH) was performed using probes made from BAC clone; RP11-945M21 for EWSR1 and RP11-75P14 for FLI1.	('EWSR1', 'Gene', '2130', (106, 111))	('FLI1', 'Gene', (131, 135))	('FLI1', 'Gene', '2313', (131, 135))	('RP11-945M21', 'Var', (90, 101))	('EWSR1', 'Gene', (106, 111))	('RP11-75P14', 'Var', (116, 126))
604212	25948942	Reverse transcription polymerase chain reaction (RT-PCR) using the removed tumor specimen could amplify the fusion transcript [Figure 2b], following sequence analysis revealed type 2 EWSR1/FLI1 fusion that involved EWSR1 exon 7 fused to FLI1 exon 5 [Figure 2c].	('FLI1', 'Gene', '2313', (189, 193))	('FLI1', 'Gene', (189, 193))	('FLI1', 'Gene', (237, 241))	('FLI1', 'Gene', '2313', (237, 241))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('EWSR1', 'Gene', (183, 188))	('EWSR1', 'Gene', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('EWSR1', 'Gene', '2130', (215, 220))	('EWSR1', 'Gene', '2130', (183, 188))	('fusion', 'Var', (194, 200))	('tumor', 'Disease', (75, 80))
604225	25948942	In the present study, the ES cells harboring EWSR1/FLI1 fusion showed diffuse nuclear expression of NKX2.2 with strong intensity.	('NKX2.2', 'Gene', '4821', (100, 106))	('FLI1', 'Gene', (51, 55))	('EWSR1', 'Gene', (45, 50))	('FLI1', 'Gene', '2313', (51, 55))	('EWSR1', 'Gene', '2130', (45, 50))	('NKX2.2', 'Gene', (100, 106))	('fusion', 'Var', (56, 62))	('ES', 'Phenotype', 'HP:0012254', (26, 28))
604239	25572477	TAAs are commonly divided into antigens that: contain novel peptide sequences created by gene fusions or mutations; are expressed at higher than normal levels in tumor tissues; and/or are normally expressed during fetal development or at immuno privileged sites, such as the testes.	('peptide sequences', 'MPA', (60, 77))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('mutations', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
604264	25572477	Strategies include enhancing DCs by genetic modification to increase their function, or combining DC vaccination with the administration of cytokines, chemotherapeutic agents that either deplete inhibitory T cells or upregulate TAA expression in tumor cells, or monoclonal antibodies (mAbs) that deplete inhibitory, regulatory T cells (Tregs) or block immune-cell-intrinsic checkpoints such as CTLA-4 or PD1/PD-L1 (see section 'Combining cell therapies with other therapies').	('function', 'MPA', (75, 83))	('rat', 'Species', '10116', (2, 5))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('PD1/PD-L1', 'Gene', (404, 413))	('increase', 'PosReg', (60, 68))	('inhibitory', 'MPA', (304, 314))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('rat', 'Species', '10116', (130, 133))	('upregulate', 'PosReg', (217, 227))	('genetic modification', 'Var', (36, 56))	('DCs', 'MPA', (29, 32))	('tumor', 'Disease', (246, 251))	('TAA', 'Gene', (228, 231))	('block', 'NegReg', (346, 351))	('deplete', 'NegReg', (296, 303))	('CTLA-4', 'Gene', (394, 400))
604284	25572477	These include the genetic modification of NK cells with chimeric antigen receptors (CARs), co-infusing NK cells with mAbs or arming NK cells with bispecific NK-cell engagers.	('CAR', 'Gene', (84, 87))	('CAR', 'Gene', '9970', (84, 87))	('chimeric', 'Var', (56, 64))	('genetic modification', 'Var', (18, 38))
604292	25572477	However, several studies suggest that the presence of TILs in sarcomas correlate with outcome.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('sarcomas', 'Disease', 'MESH:D012509', (62, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (62, 70))	('sarcomas', 'Disease', (62, 70))	('presence', 'Var', (42, 50))
604326	25572477	While 'original CARs' only contained the CD3zeta chain as an endodomain (first-generation CARs), signaling domains of co-stimulatory molecules such as CD28, 41BB, OX40 or ICOS have been added to enhance CAR function.	('rat', 'Species', '10116', (83, 86))	('enhance', 'PosReg', (195, 202))	('OS', 'Phenotype', 'HP:0002669', (173, 175))	('CD3zeta chain', 'Gene', (41, 54))	('CD3zeta chain', 'Gene', '919', (41, 54))	('CD28', 'Gene', (151, 155))	('CAR', 'Gene', (203, 206))	('41BB', 'Var', (157, 161))	('ICOS', 'Gene', (171, 175))	('CAR', 'Gene', (90, 93))	('CAR', 'Gene', '9970', (203, 206))	('OX40', 'Gene', '7293', (163, 167))	('OX40', 'Gene', (163, 167))	('CAR', 'Gene', '9970', (90, 93))	('CD28', 'Gene', '940', (151, 155))	('ICOS', 'Gene', '29851', (171, 175))	('CAR', 'Gene', (16, 19))	('CAR', 'Gene', '9970', (16, 19))
604334	25572477	Based on encouraging clinical data using T cells expressing a first-generation GD2-specific CAR in neuroblastoma patients, two clinical studies are in progress that evaluate the safety and efficacy of third-generation GD2-specific CAR T cells in patients with sarcoma (NCT01953900, NCT02107963).	('CAR', 'Gene', '9970', (231, 234))	('rat', 'Species', '10116', (72, 75))	('CAR', 'Gene', (92, 95))	('CAR', 'Gene', '9970', (92, 95))	('rat', 'Species', '10116', (211, 214))	('patients', 'Species', '9606', (246, 254))	('NCT01953900', 'Var', (269, 280))	('patients', 'Species', '9606', (113, 121))	('sarcoma', 'Disease', 'MESH:D012509', (260, 267))	('neuroblastoma', 'Disease', 'MESH:D009447', (99, 112))	('sarcoma', 'Disease', (260, 267))	('neuroblastoma', 'Disease', (99, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (260, 267))	('NCT02107963', 'Var', (282, 293))	('CAR', 'Gene', (231, 234))	('neuroblastoma', 'Phenotype', 'HP:0003006', (99, 112))
604343	25572477	Last, expression of a cell surface antigen on T cells such as truncated CD20 or EGFR allows the elimination of T cells with FDA-approved mAbs.	('truncated', 'Var', (62, 71))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('CD20', 'Gene', '931', (72, 76))	('elimination of T cells', 'Phenotype', 'HP:0005403', (96, 118))	('CD20', 'Gene', (72, 76))
604357	25572477	For example, the transgenic expression of IL15 has been shown in preclinical models to promote survival and expansion of gene-modified cells.	('transgenic expression', 'Var', (17, 38))	('expansion', 'CPA', (108, 117))	('IL15', 'Gene', (42, 46))	('IL15', 'Gene', '3600', (42, 46))	('promote', 'PosReg', (87, 94))	('survival', 'CPA', (95, 103))
604363	25572477	Several genetic modification strategies have been developed to render T cells resistant to this hostile environment, including silencing of inhibitory genes expressed by tumor cells, transgenic expression of dominant negative receptors, 'signal converters' and transgenic expression of secretable cytokines.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('dominant', 'Var', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('negative', 'NegReg', (217, 225))	('tumor', 'Disease', (170, 175))	('silencing', 'NegReg', (127, 136))	('inhibitory genes', 'Gene', (140, 156))	('rat', 'Species', '10116', (31, 34))
604364	25572477	For example, silencing Fas in T cells by using siRNA prevented FAS-induced apoptosis in the presence of FAS-ligand expressing tumors.	('prevented', 'NegReg', (53, 62))	('FAS', 'Chemical', 'MESH:C038178', (63, 66))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('FAS-induced', 'Disease', (63, 74))	('FAS', 'Chemical', 'MESH:C038178', (104, 107))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('Fas', 'Chemical', 'MESH:C038178', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('silencing', 'Var', (13, 22))
604369	25572477	For example, linking the extracellular domain of the TGF-beta RII to the endodomain of toll-like receptor (TLR) 4 results in a chimeric receptor that not only renders T cells resistant to TGF-beta, but also induces T-cell activation and expansion.	('T-cell activation', 'CPA', (215, 232))	('TGF-beta', 'Gene', (188, 196))	('TGF-beta', 'Gene', '7040', (53, 61))	('TGF-beta RII', 'Gene', (53, 65))	('TGF-beta', 'Gene', '7040', (188, 196))	('chimeric', 'Var', (127, 135))	('TGF-beta', 'Gene', (53, 61))	('induces', 'Reg', (207, 214))	('TGF-beta RII', 'Gene', '7048', (53, 65))	('expansion', 'CPA', (237, 246))
604373	25572477	In addition, transgenic expression of IL12 in CAR T cells reverses the immunosuppressive tumor environment and results in enhanced antitumor activity of adoptively transferred T cells in several preclinical animal models.	('enhanced', 'PosReg', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (71, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('IL12', 'Gene', (38, 42))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('CAR', 'Gene', (46, 49))	('transgenic expression', 'Var', (13, 34))	('CAR', 'Gene', '9970', (46, 49))	('tumor', 'Disease', (89, 94))	('immunosuppressive tumor', 'Disease', (71, 94))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
604379	25572477	For example, epigenetic modifiers such as HDAC inhibitors can upregulate expression of TAAs resulting in enhanced antitumor effects of T-cell therapies in preclinical models.	('TAAs', 'Protein', (87, 91))	('upregulate', 'PosReg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('expression', 'MPA', (73, 83))	('tumor', 'Disease', (118, 123))	('epigenetic modifiers', 'Var', (13, 33))	('enhanced', 'PosReg', (105, 113))
604380	25572477	Additionally, small molecule inhibitors that block pathways that are critical for the growth of malignant cells, such as BRAF inhibitors, also enhance the efficacy of adoptively transferred T cells in pre clinical models.	('small', 'Var', (14, 19))	('BRAF', 'Gene', (121, 125))	('enhance', 'PosReg', (143, 150))	('efficacy', 'CPA', (155, 163))	('BRAF', 'Gene', '673', (121, 125))	('pre clinical models', 'CPA', (201, 220))
604400	25572477	Genetically modifying immune cells has the potential to prevent on- or off-target toxicities; enhance their effector function in vivo; and overcome the immunosuppressive tumor microenvironment.	('Genetically modifying', 'Var', (0, 21))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (152, 175))	('on-', 'MPA', (64, 67))	('toxicities', 'Disease', 'MESH:D064420', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('enhance', 'PosReg', (94, 101))	('toxicities', 'Disease', (82, 92))	('effector function', 'CPA', (108, 125))	('immunosuppressive tumor', 'Disease', (152, 175))
604402	33469311	Case Report: Myeloid Sarcoma Development During Treatment for B Cell Lymphoblastic Lymphoma in a Boy with KRAS/NRAS Gene Mutations Here, we report a rare case of a 12-year-old boy who was initially diagnosed with B cell lymphoblastic lymphoma (BLBL) and developed myeloid sarcoma (MS) eight months after chemotherapy.	('NRAS', 'Gene', '4893', (111, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('B Cell Lymphoblastic Lymphoma', 'Disease', (62, 91))	('Mutations', 'Var', (121, 130))	('KRAS', 'Gene', '3845', (106, 110))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (264, 279))	('Boy', 'Species', '9606', (97, 100))	('Myeloid Sarcoma', 'Disease', 'MESH:D023981', (13, 28))	('KRAS', 'Gene', (106, 110))	('myeloid sarcoma', 'Disease', (264, 279))	('B cell lymphoblastic lymphoma', 'Phenotype', 'HP:0012191', (213, 242))	('Myeloid Sarcoma', 'Disease', (13, 28))	('Sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('BLBL', 'Phenotype', 'HP:0012191', (244, 248))	('NRAS', 'Gene', (111, 115))	('B Cell Lymphoblastic Lymphoma', 'Phenotype', 'HP:0012191', (62, 91))	('developed', 'Reg', (254, 263))	('B Cell Lymphoblastic Lymphoma', 'Disease', 'MESH:D016393', (62, 91))	('Lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	('lymphoma', 'Phenotype', 'HP:0002665', (234, 242))	('B cell lymphoblastic lymphoma', 'Disease', (213, 242))	('boy', 'Species', '9606', (176, 179))	('B cell lymphoblastic lymphoma', 'Disease', 'MESH:D016393', (213, 242))
604403	33469311	Next-generation sequencing (NGS) showed mutations of KRAS and NRAS genes in both the bone marrow and lymph node.	('NRAS', 'Gene', '4893', (62, 66))	('mutations', 'Var', (40, 49))	('KRAS', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (53, 57))	('NRAS', 'Gene', (62, 66))
604407	33469311	Again, NGS examination showed mutations of KRAS and NRAS genes.	('NRAS', 'Gene', (52, 56))	('NRAS', 'Gene', '4893', (52, 56))	('KRAS', 'Gene', (43, 47))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', '3845', (43, 47))
604415	33469311	Mutations of genes related to intracellular signaling pathways (such as the RAS/RAF/MAPK and phosphoinositide-3 pathways) may alter the cell cycle via abnormal proliferation, differentiation, and apoptosis of cells.	('differentiation', 'CPA', (175, 190))	('alter', 'Reg', (126, 131))	('RAF', 'Gene', (80, 83))	('Mutations', 'Var', (0, 9))	('apoptosis of cells', 'CPA', (196, 214))	('RAF', 'Gene', '673', (80, 83))	('cell cycle', 'CPA', (136, 146))
604416	33469311	Among these, alterations of genes involved in the receptor tyrosine kinase (RTK)-RAS pathway, including NRAS and KRAS, are suspected to contribute significantly to the regulation and pathogenesis of MS.	('RTK', 'Gene', '5979', (76, 79))	('NRAS', 'Gene', '4893', (104, 108))	('RTK', 'Gene', (76, 79))	('contribute', 'Reg', (136, 146))	('alterations', 'Var', (13, 24))	('KRAS', 'Gene', (113, 117))	('receptor tyrosine kinase', 'Gene', (50, 74))	('receptor tyrosine kinase', 'Gene', '5979', (50, 74))	('KRAS', 'Gene', '3845', (113, 117))	('NRAS', 'Gene', (104, 108))
604434	33469311	Mutations of KRAS (c.38G>A, p.G13D) and NRAS (c.35G>A, p.G12D) genes were detected from the bone marrow sample.	('p.G12D', 'Var', (55, 61))	('NRAS', 'Gene', (40, 44))	('p.G12D', 'Mutation', 'rs121913529', (55, 61))	('c.35G>A', 'Mutation', 'rs121913237', (46, 53))	('p.G13D', 'Mutation', 'rs112445441', (28, 34))	('NRAS', 'Gene', '4893', (40, 44))	('c.35G>A', 'Var', (46, 53))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('c.38G>A', 'Mutation', 'rs112445441', (19, 26))
604438	33469311	Next-generation sequencing (NGS) examination of the lymph node showed a mutation of the NRAS gene (c.35G>A, p.G12D).	('p.G12D', 'Var', (108, 114))	('NRAS', 'Gene', (88, 92))	('c.35G>A', 'Mutation', 'rs121913237', (99, 106))	('p.G12D', 'Mutation', 'rs121913529', (108, 114))	('NRAS', 'Gene', '4893', (88, 92))	('c.35G>A', 'Var', (99, 106))
604451	33469311	IHC of these cells revealed positive staining for lysozyme, MPO, CD33, Ki-67 (>95%+), CD4 (mild), and negative staining for CD3, CD7, CD20, PAX-5, CD117, CD163, CD123, TdT, CD30, ALK.	('TdT', 'Gene', (168, 171))	('CD33', 'Gene', '945', (65, 69))	('CD4', 'Gene', (86, 89))	('CD33', 'Gene', (65, 69))	('CD3', 'Var', (124, 127))	('MPO', 'Gene', '4353', (60, 63))	('CD20', 'Gene', '54474', (134, 138))	('CD117', 'Gene', (147, 152))	('lysozyme', 'Gene', '4069', (50, 58))	('CD30', 'Gene', '943', (173, 177))	('PAX-5', 'Gene', '5079', (140, 145))	('MPO', 'Gene', (60, 63))	('ALK', 'Gene', '238', (179, 182))	('CD163', 'Gene', '9332', (154, 159))	('CD123', 'Gene', (161, 166))	('ALK', 'Gene', (179, 182))	('TdT', 'Gene', '1791', (168, 171))	('CD163', 'Gene', (154, 159))	('PAX-5', 'Gene', (140, 145))	('CD123', 'Gene', '3563', (161, 166))	('CD7', 'Gene', '924', (129, 132))	('CD117', 'Gene', '3815', (147, 152))	('CD20', 'Gene', (134, 138))	('lysozyme', 'Gene', (50, 58))	('CD30', 'Gene', (173, 177))	('CD4', 'Gene', '920', (86, 89))	('CD7', 'Gene', (129, 132))
604452	33469311	NGS examinations of the skin and testicular samples showed mutations of both the KRAS (c.436G>A, p.A146T) and NRAS genes (c.35G>A, p.G12D).	('KRAS', 'Gene', '3845', (81, 85))	('NRAS', 'Gene', '4893', (110, 114))	('p.G12D', 'Mutation', 'rs121913529', (131, 137))	('c.436G>A', 'Var', (87, 95))	('c.35G>A', 'Mutation', 'rs121913237', (122, 129))	('KRAS', 'Gene', (81, 85))	('c.436G>A', 'Mutation', 'rs121913527', (87, 95))	('NRAS', 'Gene', (110, 114))	('p.A146T', 'Mutation', 'rs121913527', (97, 104))	('c.35G>A', 'Var', (122, 129))
604466	33469311	However, this is a pan-myeloid marker commonly seen in B-ALL, especially for B-ALL that involves the translocation of chromosomes 9 and 22 and fusion of BCR/ABL1 genes.	('ABL1', 'Gene', (157, 161))	('fusion', 'Var', (143, 149))	('ABL1', 'Gene', '25', (157, 161))
604474	33469311	An important aspect of this case was the mutation of both the NRAS and KRAS genes.	('NRAS', 'Gene', '4893', (62, 66))	('mutation', 'Var', (41, 49))	('KRAS', 'Gene', (71, 75))	('KRAS', 'Gene', '3845', (71, 75))	('NRAS', 'Gene', (62, 66))
604477	33469311	In this case, both NRAS and KRAS mutations were detected at initial diagnosis and at the development of MS.	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('NRAS', 'Gene', (19, 23))	('detected', 'Reg', (48, 56))	('mutations', 'Var', (33, 42))	('NRAS', 'Gene', '4893', (19, 23))
604479	33469311	Recent genomic studies reveal that mutations associated with the RTK-RAS pathway are frequently observed in pediatric patients with B-ALL and are probably more prevalent in the Chinese population.	('RTK', 'Gene', '5979', (65, 68))	('observed', 'Reg', (96, 104))	('RTK', 'Gene', (65, 68))	('patients', 'Species', '9606', (118, 126))	('mutations', 'Var', (35, 44))
604480	33469311	Although mutations of RAS genes have been shown associated with poorer outcomes in pediatric ALL, AML, MPAL, and infant leukemia patients, the association of RAS mutations and patient prognosis remains undefined, warranting larger cohort studies.	('leukemia', 'Disease', (120, 128))	('patients', 'Species', '9606', (129, 137))	('associated', 'Reg', (48, 58))	('MPAL', 'Disease', (103, 107))	('mutations', 'Var', (9, 18))	('RAS genes', 'Gene', (22, 31))	('leukemia', 'Disease', 'MESH:D007938', (120, 128))	('AML', 'Disease', 'MESH:D015470', (98, 101))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('ALL', 'Disease', (93, 96))	('AML', 'Phenotype', 'HP:0004808', (98, 101))	('patient', 'Species', '9606', (176, 183))	('AML', 'Disease', (98, 101))	('patient', 'Species', '9606', (129, 136))
604481	33469311	The high-intensity chemotherapy given to this patient may have accelerated the mutations that led to the development of MS as a second tumor.	('patient', 'Species', '9606', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('accelerated', 'PosReg', (63, 74))	('mutations', 'Var', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
604486	33469311	Most of these patients feature chromosomal and genetic abnormalities including the mutation of RAS genes.	('genetic abnormalities', 'Disease', (47, 68))	('RAS genes', 'Gene', (95, 104))	('mutation', 'Var', (83, 91))	('patients', 'Species', '9606', (14, 22))	('genetic abnormalities', 'Disease', 'MESH:D030342', (47, 68))
604493	33469311	NGS evaluations revealed mutations of both NRAS and KRAS genes that may contribute to the genetic origin of MS.	('mutations', 'Var', (25, 34))	('KRAS', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (52, 56))	('NRAS', 'Gene', (43, 47))	('contribute', 'Reg', (72, 82))	('NRAS', 'Gene', '4893', (43, 47))
604509	32629673	The translocation of the EWSR1 gene on to chromosome 22p12 next to the FLI1 gene may cause upregulation of insulin-like growth factor 1, playing a key role in cellular proliferation.	('translocation', 'Var', (4, 17))	('EWSR1', 'Gene', (25, 30))	('upregulation', 'PosReg', (91, 103))	('EWSR1', 'Gene', '2130', (25, 30))	('insulin-like growth factor 1', 'Gene', '3479', (107, 135))	('insulin-like growth factor 1', 'Gene', (107, 135))	('FLI1', 'Gene', (71, 75))	('FLI1', 'Gene', '2313', (71, 75))
604510	32629673	The common translocation and a strong membranous expression of CD99 could unify the diagnosis of extraosseous Ewing sarcoma.	('common translocation', 'Var', (4, 24))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (110, 123))	('CD99', 'Gene', '4267', (63, 67))	('osseous Ewing sarcoma', 'Disease', (102, 123))	('CD99', 'Gene', (63, 67))	('osseous Ewing sarcoma', 'Disease', 'MESH:C563168', (102, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))
604652	30093639	Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ).	('KIZ', 'Gene', '55857', (109, 112))	('KIZ', 'Gene', (109, 112))	('RREB1', 'Gene', (88, 93))	('RREB1', 'Gene', '6239', (88, 93))	('20p11.23', 'Var', (99, 107))
604659	30093639	A translocation between EWSR1 (22q12) and a member of the ETS transcription factor family, FLI1 (11q24), in ~85% of cases, is pathognomonic of EWS and provides a distinct and well-defined disease phenotype for genomic characterization.	('11q24', 'Var', (97, 102))	('EWS', 'Phenotype', 'HP:0012254', (24, 27))	('EWS', 'Gene', '2130', (24, 27))	('EWSR1', 'Gene', (24, 29))	('EWS', 'Gene', (24, 27))	('EWS', 'Gene', '2130', (143, 146))	('EWSR1', 'Gene', '2130', (24, 29))	('EWS', 'Phenotype', 'HP:0012254', (143, 146))	('FLI1', 'Gene', '2313', (91, 95))	('translocation', 'Var', (2, 15))	('pathognomonic', 'Reg', (126, 139))	('EWS', 'Gene', (143, 146))	('FLI1', 'Gene', (91, 95))
604663	30093639	The estimated incidence in Asian and African populations is substantially lower with annual rates of 0.8 and 0.2 cases per 106 children, respectively, implying genetic variants specific to European ancestry could influence EWS risk.	('EWS', 'Gene', '2130', (223, 226))	('EWS', 'Gene', (223, 226))	('variants', 'Var', (168, 176))	('influence', 'Reg', (213, 222))	('children', 'Species', '9606', (127, 135))	('EWS', 'Phenotype', 'HP:0012254', (223, 226))
604666	30093639	A follow-up functional study of the 10q21 region localized the association signal to variation in a GGAA microsatellite that, when bound by EWSR1-FLI1, functions as an active regulatory element of EGR2.	('variation', 'Var', (85, 94))	('active', 'MPA', (168, 174))	('EWSR1', 'Gene', '2130', (140, 145))	('EGR2', 'Gene', '1959', (197, 201))	('FLI1', 'Gene', (146, 150))	('FLI1', 'Gene', '2313', (146, 150))	('EWS', 'Phenotype', 'HP:0012254', (140, 143))	('EWSR1', 'Gene', (140, 145))	('EGR2', 'Gene', (197, 201))
604668	30093639	Interestingly, EGR2 knock down inhibits cell proliferation, clonogenicity and tumor growth of EWS cells.	('EWS', 'Phenotype', 'HP:0012254', (94, 97))	('EWS', 'Gene', '2130', (94, 97))	('EWS', 'Gene', (94, 97))	('knock down', 'Var', (20, 30))	('inhibits', 'NegReg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('EGR2', 'Gene', '1959', (15, 19))	('EGR2', 'Gene', (15, 19))	('cell proliferation', 'CPA', (40, 58))	('clonogenicity', 'CPA', (60, 73))
604669	30093639	Collectively, these findings indicate that germline variation predisposes to EWS risk and can interact with somatically acquired EWSR1-ETS fusion proteins to drive carcinogenesis of EWS.	('EWS', 'Phenotype', 'HP:0012254', (77, 80))	('interact', 'Interaction', (94, 102))	('carcinogenesis', 'CPA', (164, 178))	('drive', 'PosReg', (158, 163))	('EWS', 'Gene', (77, 80))	('EWS', 'Gene', '2130', (77, 80))	('EWS', 'Gene', '2130', (129, 132))	('EWSR1', 'Gene', (129, 134))	('predisposes', 'Reg', (62, 73))	('EWS', 'Gene', (129, 132))	('EWS', 'Phenotype', 'HP:0012254', (182, 185))	('EWS', 'Phenotype', 'HP:0012254', (129, 132))	('EWS', 'Gene', '2130', (182, 185))	('EWS', 'Gene', (182, 185))	('germline variation', 'Var', (43, 61))	('EWSR1', 'Gene', '2130', (129, 134))
604675	30093639	We observed rs113663169 as the most significant variant tagging the 1p36.22 locus (OR = 2.05, 95% CI = 1.71-2.45, P-valuemeta = 4.32x10-15).	('rs113663169', 'Var', (12, 23))	('tagging', 'NegReg', (56, 63))	('rs113663169', 'Mutation', 'rs113663169', (12, 23))
604678	30093639	This variant is correlated with the reported variant from the original GWAS, rs224278 (R2CEU = 0.52, D'CEU = 0.92; OR = 1.71, 95% CI = 1.49-1.96, P-valueassoc = 6.9x10-15), as well as the putatively functional variant, rs79965208 (R2CEU = 0.24, D'CEU = 0.57; OR = 1.42, 95% CI = 1.24-1.63, P-valueassoc = 5.3x10-7).	('rs79965208', 'Mutation', 'rs79965208', (219, 229))	('rs224278', 'Var', (77, 85))	('rs79965208', 'Var', (219, 229))	('rs224278', 'Mutation', 'rs224278', (77, 85))
604680	30093639	Finally, at 15q15.1 we observed rs2412476, a tagging variant strongly associated with EWS (OR = 1.73, 95% CI = 1.48-2.01, P-valuemeta = 1.45x10-12).	('rs2412476', 'Mutation', 'rs2412476', (32, 41))	('associated', 'Reg', (70, 80))	('rs2412476', 'Var', (32, 41))	('EWS', 'Phenotype', 'HP:0012254', (86, 89))	('EWS', 'Gene', '2130', (86, 89))	('EWS', 'Gene', (86, 89))
604681	30093639	This variant is in moderate LD with rs4924410 from the original GWAS (R2CEU = 0.18, D'CEU = 1.00; OR = 1.62, 95% CI = 1.41-1.86, P-valueassoc = 5.4x10-12) and is located near several genes including BMF, BUB1B and PAK6.	('PAK6', 'Gene', (214, 218))	('rs4924410', 'Var', (36, 45))	('BUB1B', 'Gene', '701', (204, 209))	('BUB1B', 'Gene', (204, 209))	('BMF', 'Gene', (199, 202))	('PAK6', 'Gene', '56924', (214, 218))	('rs4924410', 'Mutation', 'rs4924410', (36, 45))
604682	30093639	To validate signals from imputed variants in these regions, we performed allele-specific TaqMan PCR for a subset of 335 GWAS samples on the following variants: rs7744366 (6p25.1), rs7832583 (8q24.23), rs12106193 (20p11.22) and rs6106336 (20p11.23).	('rs7744366', 'Var', (160, 169))	('rs12106193', 'Var', (201, 211))	('rs7832583', 'Var', (180, 189))	('rs7832583', 'Mutation', 'rs7832583', (180, 189))	('rs12106193', 'Mutation', 'rs12106193', (201, 211))	('rs6106336', 'Mutation', 'rs6106336', (227, 236))	('rs6106336', 'Var', (227, 236))	('rs7744366', 'Mutation', 'rs7744366', (160, 169))
604685	30093639	The marker variant rs7742053 is telomeric to RREB1, SSR1 and CAGE1.	('rs7742053', 'Var', (19, 28))	('RREB1', 'Gene', (45, 50))	('CAGE1', 'Gene', '285782', (61, 66))	('SSR1', 'Gene', (52, 56))	('RREB1', 'Gene', '6239', (45, 50))	('CAGE1', 'Gene', (61, 66))	('SSR1', 'Gene', '6745', (52, 56))	('rs7742053', 'Mutation', 'rs7742053', (19, 28))
604686	30093639	Expression quantitative trait locus (eQTL) analysis using rs1286037, a correlated surrogate for rs7742053 (R2CEU = 0.49, D'CEU = 1.00), identified allele specific expression differences in RREB1, with the risk A allele of rs7742053 corresponding to increased levels of RREB1 expression (P-valueWald = 0.01, Table 2).	('rs1286037', 'Var', (58, 67))	('rs7742053', 'Mutation', 'rs7742053', (222, 231))	('RREB1', 'Gene', '6239', (189, 194))	('levels', 'MPA', (259, 265))	('rs7742053', 'Var', (222, 231))	('rs1286037', 'Mutation', 'rs1286037', (58, 67))	('rs7742053', 'Mutation', 'rs7742053', (96, 105))	('RREB1', 'Gene', (269, 274))	('increased', 'PosReg', (249, 258))	('expression', 'MPA', (275, 285))	('RREB1', 'Gene', '6239', (269, 274))	('RREB1', 'Gene', (189, 194))
604692	30093639	Further, knock down of EWSR1-FLI1 in xenografts derived from the A673/TR/shEF1 EWS cell line results in strong downregulation of RREB1 in vivo (Supplementary Figure 9).	('EWS', 'Gene', '2130', (79, 82))	('EWS', 'Gene', (79, 82))	('knock down', 'Var', (9, 19))	('EWS', 'Phenotype', 'HP:0012254', (23, 26))	('RREB1', 'Gene', (129, 134))	('FLI1', 'Gene', (29, 33))	('EWS', 'Phenotype', 'HP:0012254', (79, 82))	('FLI1', 'Gene', '2313', (29, 33))	('EWS', 'Gene', (23, 26))	('EWSR1', 'Gene', (23, 28))	('RREB1', 'Gene', '6239', (129, 134))	('downregulation', 'NegReg', (111, 125))	('EWS', 'Gene', '2130', (23, 26))	('EWSR1', 'Gene', '2130', (23, 28))
604693	30093639	Several variants correlated with rs7742053 are in contiguity with the GGAA repeat and may be candidate functional variants that disrupt EWSR1-FLI1 binding (Supplementary Table 5).	('rs7742053', 'Var', (33, 42))	('binding', 'Interaction', (147, 154))	('FLI1', 'Gene', (142, 146))	('EWSR1', 'Gene', '2130', (136, 141))	('FLI1', 'Gene', '2313', (142, 146))	('disrupt', 'NegReg', (128, 135))	('EWS', 'Phenotype', 'HP:0012254', (136, 139))	('EWSR1', 'Gene', (136, 141))	('rs7742053', 'Mutation', 'rs7742053', (33, 42))
604694	30093639	One such variant, rs10541084, a -/GAAG indel is located at the telomeric end of the nearest GGAA microsatellite, is in LD with rs7742053 (R2CEU = 0.15, D'CEU = 0.92), and is nominally associated with EWS (OR = 1.20, 95% CI = 1.04-1.37, P-valuemeta = 0.01).	('rs7742053', 'Mutation', 'rs7742053', (127, 136))	('EWS', 'Phenotype', 'HP:0012254', (200, 203))	('rs7742053', 'Var', (127, 136))	('EWS', 'Gene', '2130', (200, 203))	('EWS', 'Gene', (200, 203))	('associated', 'Reg', (184, 194))	('rs10541084', 'Mutation', 'rs10541084', (18, 28))	('rs10541084', 'Var', (18, 28))
604695	30093639	Interestingly, the rs7742053 risk A allele is correlated with the rs10541084 GAAG allele which is more common in Europeans, extends the microsatellite GGAA repeat sequence, and could enhance binding of EWSR1-FLI1.	('rs7742053', 'Var', (19, 28))	('EWSR1', 'Gene', (202, 207))	('rs10541084 GAAG', 'Var', (66, 81))	('extends', 'PosReg', (124, 131))	('microsatellite GGAA', 'MPA', (136, 155))	('FLI1', 'Gene', (208, 212))	('EWSR1', 'Gene', '2130', (202, 207))	('enhance', 'PosReg', (183, 190))	('rs10541084', 'Mutation', 'rs10541084', (66, 76))	('FLI1', 'Gene', '2313', (208, 212))	('binding', 'Interaction', (191, 198))	('rs7742053', 'Mutation', 'rs7742053', (19, 28))	('EWS', 'Phenotype', 'HP:0012254', (202, 205))
604696	30093639	This evidence suggests that a similar mechanism as in the 10q21 locus may be acting at the 6p25.1 locus in which variation of a GGAA repeat affects EWSR1-FLI1 binding leading to altered expression of RREB1 or an alternative nearby gene.	('variation', 'Var', (113, 122))	('FLI1', 'Gene', (154, 158))	('EWS', 'Phenotype', 'HP:0012254', (148, 151))	('EWSR1', 'Gene', (148, 153))	('RREB1', 'Gene', (200, 205))	('binding', 'Interaction', (159, 166))	('RREB1', 'Gene', '6239', (200, 205))	('affects', 'Reg', (140, 147))	('expression', 'MPA', (186, 196))	('EWSR1', 'Gene', '2130', (148, 153))	('altered', 'Reg', (178, 185))	('FLI1', 'Gene', '2313', (154, 158))
604698	30093639	While no statistically significant eQTL was observed between this locus and nearby genes (Table 2), the nearest transcript, NKX2-2, is of high interest; NKX2-2, NK2 homeobox 2, encodes a homeobox domain protein that is a likely nuclear transcription factor, which is overexpressed in the presence of EWSR1-FLI1 fusions in EWS tumors.	('EWS', 'Phenotype', 'HP:0012254', (300, 303))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('EWSR1', 'Gene', (300, 305))	('NK2 homeobox 2', 'Gene', '4821', (161, 175))	('NKX2-2', 'Gene', (124, 130))	('EWS', 'Phenotype', 'HP:0012254', (322, 325))	('NKX2-2', 'Gene', '4821', (153, 159))	('tumors', 'Disease', (326, 332))	('EWS', 'Gene', '2130', (300, 303))	('NKX2-2', 'Gene', (153, 159))	('EWS', 'Gene', '2130', (322, 325))	('tumors', 'Disease', 'MESH:D009369', (326, 332))	('fusions', 'Var', (311, 318))	('FLI1', 'Gene', (306, 310))	('EWSR1', 'Gene', '2130', (300, 305))	('EWS', 'Gene', (300, 303))	('NK2 homeobox 2', 'Gene', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('FLI1', 'Gene', '2313', (306, 310))	('NKX2-2', 'Gene', '4821', (124, 130))	('EWS', 'Gene', (322, 325))	('overexpressed', 'PosReg', (267, 280))
604699	30093639	Our analysis did not detect significant allele specific expression differences for NKX2-2 in association with rs6047482 (eQTL P-valueWald with rs12106193 = 0.17, R2CEU and D'CEU between rs6047482 and rs12106193 = 0.67 and 1.00, respectively).	('rs6047482', 'Var', (110, 119))	('rs6047482', 'Var', (186, 195))	('NKX2-2', 'Gene', (83, 89))	('rs12106193 =', 'Var', (143, 155))	('rs12106193', 'Var', (200, 210))	('rs12106193', 'Mutation', 'rs12106193', (143, 153))	('NKX2-2', 'Gene', '4821', (83, 89))	('rs12106193', 'Mutation', 'rs12106193', (200, 210))	('rs6047482', 'Mutation', 'rs6047482', (110, 119))	('rs6047482', 'Mutation', 'rs6047482', (186, 195))
604700	30093639	We explored eQTLs for other tissue types in GTEx with surrogate SNPs in moderate to high linkage disequilibrium with rs6047482, but found no evidence for an eQTL with NKX2-2 in these tissues likely due to EWS specific expression of NKX2-2 (Supplementary Table 6).	('EWS', 'Phenotype', 'HP:0012254', (205, 208))	('EWS', 'Gene', (205, 208))	('EWS', 'Gene', '2130', (205, 208))	('NKX2-2', 'Gene', (167, 173))	('rs6047482', 'Mutation', 'rs6047482', (117, 126))	('NKX2-2', 'Gene', (232, 238))	('NKX2-2', 'Gene', '4821', (232, 238))	('NKX2-2', 'Gene', '4821', (167, 173))	('rs6047482', 'Var', (117, 126))
604703	30093639	As with the 6p25.1 locus, ChIP-seq data show that EWSR1-FLI1 binds to one or more polymorphic GGAA microsatellites proximal to the tagging variants (Supplementary Figure 10) suggesting that variation in this region could exert an effect through NKX2-2 gene regulation in EWS progenitors and in turn through EWSR1-FLI1 binding in EWS cells.	('FLI1', 'Gene', (56, 60))	('EWS', 'Phenotype', 'HP:0012254', (329, 332))	('EWS', 'Gene', (50, 53))	('EWS', 'Gene', (271, 274))	('EWSR1', 'Gene', '2130', (50, 55))	('EWS', 'Gene', '2130', (307, 310))	('EWS', 'Phenotype', 'HP:0012254', (50, 53))	('FLI1', 'Gene', '2313', (56, 60))	('EWSR1', 'Gene', (307, 312))	('EWS', 'Gene', '2130', (329, 332))	('EWS', 'Phenotype', 'HP:0012254', (271, 274))	('FLI1', 'Gene', (313, 317))	('EWS', 'Gene', '2130', (50, 53))	('EWSR1', 'Gene', (50, 55))	('EWS', 'Gene', '2130', (271, 274))	('binding', 'Interaction', (318, 325))	('NKX2-2', 'Gene', '4821', (245, 251))	('FLI1', 'Gene', '2313', (313, 317))	('EWS', 'Gene', (307, 310))	('NKX2-2', 'Gene', (245, 251))	('EWS', 'Gene', (329, 332))	('EWSR1', 'Gene', '2130', (307, 312))	('variation', 'Var', (190, 199))	('EWS', 'Phenotype', 'HP:0012254', (307, 310))
604705	30093639	In the search for additional independent loci at each EWS susceptibility locus (Supplementary Figure 4), we identified a second, independent signal on 20p11.23 tagged by rs6106336 based on a conditional analysis using the discovery marker, rs6047482 (R2CEU = 0.003, D'CEU = 0.23; OR = 1.74, 95% CI = 1.43-2.12, P-valuemeta = 2.33x10-8, P-valueconditional = 5.2x10-8, Fig.	('EWS', 'Phenotype', 'HP:0012254', (54, 57))	('EWS', 'Gene', '2130', (54, 57))	('EWS', 'Gene', (54, 57))	('rs6047482', 'Mutation', 'rs6047482', (240, 249))	('rs6047482', 'Var', (240, 249))	('rs6106336', 'Mutation', 'rs6106336', (170, 179))	('rs6106336', 'Var', (170, 179))
604706	30093639	A distinct eQTL was observed between a highly correlated surrogate for rs6106336, rs6047241 (R2CEU = 1.00, D'CEU = 1.00), and KIZ, kizuna centrosomal protein, (also known as PLK1S1) with the risk G allele associated with increased expression (P-valueWald = 0.01, Table 2).	('rs6106336', 'Mutation', 'rs6106336', (71, 80))	('rs6106336', 'Var', (71, 80))	('PLK1S1', 'Gene', '55857', (174, 180))	('KIZ', 'Gene', '55857', (126, 129))	('kizuna', 'Gene', '55857', (131, 137))	('rs6047241', 'Mutation', 'rs6047241', (82, 91))	('KIZ', 'Gene', (126, 129))	('kizuna', 'Gene', (131, 137))	('rs6047241', 'Var', (82, 91))	('expression', 'MPA', (231, 241))	('PLK1S1', 'Gene', (174, 180))
604709	30093639	While limited evidence suggests EWSR1-FLI1 binding in this region, H3K27ac patterns suggest areas of open chromatin that may harbor variants important for regulation of nearby gene products (Supplementary Figure 11).	('H3K27ac', 'Gene', (67, 74))	('FLI1', 'Gene', '2313', (38, 42))	('FLI1', 'Gene', (38, 42))	('EWS', 'Phenotype', 'HP:0012254', (32, 35))	('variants', 'Var', (132, 140))	('EWSR1', 'Gene', (32, 37))	('EWSR1', 'Gene', '2130', (32, 37))
604719	30093639	Furthermore, our results suggest the underlying EWS genetic susceptibility architecture harbors a substantial number of moderate effect common variants, which is striking because Ewing sarcoma has not been considered to be highly heritable.	('EWS', 'Gene', (48, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('EWS', 'Gene', '2130', (48, 51))	('Ewing sarcoma', 'Gene', '2130', (179, 192))	('Ewing sarcoma', 'Gene', (179, 192))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (179, 192))	('EWS', 'Phenotype', 'HP:0012254', (48, 51))	('variants', 'Var', (143, 151))
604720	30093639	In conclusion, our study provides support for a strong inherited genetic component to EWS risk and suggests interactions between germline variation and somatically acquired EWSR1-FLI1 translocations are important etiologic contributors to EWS risk.	('FLI1', 'Gene', (179, 183))	('EWS', 'Phenotype', 'HP:0012254', (86, 89))	('EWS', 'Phenotype', 'HP:0012254', (173, 176))	('translocations', 'Var', (184, 198))	('EWS', 'Gene', (173, 176))	('EWS', 'Gene', '2130', (173, 176))	('etiologic', 'Reg', (213, 222))	('EWSR1', 'Gene', (173, 178))	('EWS', 'Phenotype', 'HP:0012254', (239, 242))	('EWS', 'Gene', '2130', (239, 242))	('EWS', 'Gene', (239, 242))	('interactions', 'Interaction', (108, 120))	('EWS', 'Gene', '2130', (86, 89))	('EWSR1', 'Gene', '2130', (173, 178))	('contributors', 'Reg', (223, 235))	('EWS', 'Gene', (86, 89))	('FLI1', 'Gene', '2313', (179, 183))
604748	30093639	Genetic risk scores (GRS) of the three previously discovered and three new independent loci were calculated to investigate the ability of tagging variants from these six loci to discriminate between EWS cases and controls.	('EWS', 'Gene', '2130', (199, 202))	('EWS', 'Gene', (199, 202))	('variants', 'Var', (146, 154))	('EWS', 'Phenotype', 'HP:0012254', (199, 202))
604752	30093639	The following SNPs were genotyped by TaqMan for each locus: rs7744366 (6p25.1), rs7832583 (8q24.23), rs12106193 (20p11.23) and rs6106336 (20p11.23).	('rs7832583', 'Var', (80, 89))	('rs7832583', 'Mutation', 'rs7832583', (80, 89))	('rs7744366', 'Mutation', 'rs7744366', (60, 69))	('rs7744366', 'Var', (60, 69))	('rs12106193', 'Var', (101, 111))	('rs6106336', 'Mutation', 'rs6106336', (127, 136))	('rs6106336', 'Var', (127, 136))	('rs12106193', 'Mutation', 'rs12106193', (101, 111))
604754	30093639	An independent set from the Institute Curie and European collaborators consisting of 480 EWS cases and 576 controls and an independent German set from LMU Munich containing 177 EWS cases and 3502 population-based controls from the KORA S4 study were used as a replication sets to confirm associations at the 6p25.1, 8q24.23, 20p11.22 and 20p11.23 regions.	('EWS', 'Phenotype', 'HP:0012254', (177, 180))	('EWS', 'Gene', '2130', (177, 180))	('EWS', 'Gene', (177, 180))	('EWS', 'Phenotype', 'HP:0012254', (89, 92))	('EWS', 'Gene', (89, 92))	('EWS', 'Gene', '2130', (89, 92))	('associations', 'Var', (288, 300))
604755	30093639	The following SNPs were genotyped by TaqMan for each locus: rs7744366 (6p25.1), rs7832583 (8q24.23), rs12106193 (20p11.23) and rs6106336 (20p11.23) (Supplementary Table 7).	('rs7832583', 'Var', (80, 89))	('rs7832583', 'Mutation', 'rs7832583', (80, 89))	('rs7744366', 'Mutation', 'rs7744366', (60, 69))	('rs7744366', 'Var', (60, 69))	('rs12106193', 'Var', (101, 111))	('rs6106336', 'Mutation', 'rs6106336', (127, 136))	('rs6106336', 'Var', (127, 136))	('rs12106193', 'Mutation', 'rs12106193', (101, 111))
604762	30093639	Peaks were called with MACS2 with the option narrow for FLI1 ChIP-seq and broad for H3K27ac ChIP-seq.	('FLI1', 'Gene', '2313', (56, 60))	('H3K27ac', 'Var', (84, 91))	('FLI1', 'Gene', (56, 60))
604763	30093639	Publicly available gene expression data for 19 different cancer entities comprising in total 616 tumor samples, which were all profiled on Affymetrix Human Genome U133 Plus 2.0 gene expression arrays, were downloaded from the GEO or the Array Express platform of the European Bioinformatics Institute (EBI) (accession codes: GSE68015, GSE13433, GSE32569, GSE19404, GSE35493, GSE58697, GSE34620, GSE34800, GSE60740, GSE19348, GSE17743, GSE8167, GSE53224, GSE16476, E-MEXP-3628, GSE14827, GSE33458, E-TABM-1202, GSE29683, GSE20196, GSE21050).	('GSE60740', 'Var', (405, 413))	('cancer', 'Disease', (57, 63))	('GSE21050', 'Var', (530, 538))	('GSE14827', 'Var', (477, 485))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('GSE17743', 'Var', (425, 433))	('GSE53224', 'Var', (444, 452))	('Human', 'Species', '9606', (150, 155))	('GSE16476', 'Var', (454, 462))	('GSE19348', 'Var', (415, 423))	('tumor', 'Disease', (97, 102))	('GSE29683', 'Var', (510, 518))	('GSE20196', 'Var', (520, 528))	('GSE34800', 'Var', (395, 403))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('GSE58697', 'Var', (375, 383))	('GSE32569', 'Var', (345, 353))	('GSE19404', 'Var', (355, 363))	('GSE35493', 'Var', (365, 373))	('GSE34620', 'Var', (385, 393))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('E-MEXP-3628', 'Var', (464, 475))	('GSE8167', 'Var', (435, 442))	('GSE33458', 'Var', (487, 495))	('GSE68015', 'Var', (325, 333))
604769	30093639	Knock down of EWSR1-FLI1 was confirmed by qRT-PCR as described, and proved to be downregulated onto 15% of the control (sucrose only).	('FLI1', 'Gene', (20, 24))	('sucrose', 'Chemical', 'MESH:D013395', (120, 127))	('FLI1', 'Gene', '2313', (20, 24))	('downregulated', 'NegReg', (81, 94))	('EWSR1', 'Gene', '2130', (14, 19))	('Knock down', 'Var', (0, 10))	('EWS', 'Phenotype', 'HP:0012254', (14, 17))	('EWSR1', 'Gene', (14, 19))
604793	28360472	Vascular resections included the excision of the brachiocephalic vein, ligation of the internal jugular vein, sacrificing the azygos vein, and phrenic nerve.	('brachiocephalic vein', 'Phenotype', 'HP:0011589', (49, 69))	('brachiocephalic vein', 'Disease', 'MESH:D020246', (49, 69))	('ligation', 'Var', (71, 79))	('brachiocephalic vein', 'Disease', (49, 69))
604834	22749036	Consequently, prior investigations attempting to address the aforementioned ethnic patterns of disease susceptibility have focused on identifying polymorphisms within the EWSR1 locus.	('polymorphisms', 'Var', (146, 159))	('EWSR1', 'Gene', (171, 176))	('EWSR1', 'Gene', '2130', (171, 176))
604835	22749036	Intron 6 of EWSR1 is known to house a high density of Alu repeat insertions, and a truncated allele of Alu repeats has been described in populations of African descent, although at a frequency of only 8%.	('EWSR1', 'Gene', '2130', (12, 17))	('EWSR1', 'Gene', (12, 17))	('Alu', 'Var', (54, 57))
604845	22749036	These EWS/FLI "microsatellite response elements" are instrumental for EWS/FLI DNA binding and subsequent gene activation and interestingly, an increasing number of GGAA repeats appears to substantially augment EWS/FLI-mediated gene activation.	('EWS', 'Gene', (6, 9))	('FLI', 'Gene', '2314', (214, 217))	('EWS', 'Gene', (210, 213))	('EWS', 'Gene', '2130', (210, 213))	('EWS', 'Gene', '2130', (70, 73))	('EWS', 'Gene', (70, 73))	('GGAA', 'Protein', (164, 168))	('FLI', 'Gene', (74, 77))	('FLI', 'Gene', (214, 217))	('augment', 'PosReg', (202, 209))	('FLI', 'Gene', '2314', (10, 13))	('FLI', 'Gene', (10, 13))	('repeats', 'Var', (169, 176))	('FLI', 'Gene', '2314', (74, 77))	('EWS', 'Gene', '2130', (6, 9))
604847	22749036	The NR0B1 promoter is the most highly EWS/FLI-bound sequence and aberrant expression of this orphan nuclear receptor is absolutely necessary for maintenance of oncogenic transformation in patient-derived Ewing sarcoma cell lines, characterized by anchorage independent growth, and xenograft tumor formation.	('EWS', 'Gene', '2130', (38, 41))	('EWS', 'Gene', (38, 41))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (204, 217))	('NR0B1', 'Gene', '190', (4, 9))	('patient', 'Species', '9606', (188, 195))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (204, 217))	('Ewing sarcoma', 'Disease', (204, 217))	('aberrant', 'Var', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('FLI', 'Gene', '2314', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('oncogenic transformation', 'CPA', (160, 184))	('FLI', 'Gene', (42, 45))	('tumor', 'Disease', (291, 296))	('NR0B1', 'Gene', (4, 9))
604848	22749036	Dysregulated CAV1 expression has been observed in numerous cancer types and is commonly associated with metastatic disease.	('numerous cancer', 'Disease', 'MESH:D009369', (50, 65))	('CAV1', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('CAV1', 'Gene', '857', (13, 17))	('expression', 'MPA', (18, 28))	('Dysregulated', 'Var', (0, 12))	('numerous cancer', 'Disease', (50, 65))	('associated', 'Reg', (88, 98))	('metastatic disease', 'Disease', (104, 122))	('observed', 'Reg', (38, 46))
604849	22749036	Similar to NR0B1, aberrant expression of CAV1 is necessary for tumorigenesis in Ewing sarcoma.	('tumor', 'Disease', (63, 68))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (80, 93))	('CAV1', 'Gene', '857', (41, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('NR0B1', 'Gene', (11, 16))	('NR0B1', 'Gene', '190', (11, 16))	('aberrant expression', 'Var', (18, 37))	('CAV1', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Ewing sarcoma', 'Disease', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (80, 93))
604850	22749036	The majority of microsatellite DNA is comprised of mono-, di-tri- and tetra-nucleotide repeats and these repetitive elements constitute ~3% of the human genome.	('microsatellite DNA', 'Var', (16, 34))	('tetra', 'Species', '42554', (70, 75))	('mono-', 'Var', (51, 56))	('human', 'Species', '9606', (147, 152))
604886	22749036	Based on these observations, the NR0B1 microsatellite data was further stratified into three categories: alleles of 20-30 GGAA motifs (3 repeat segments), alleles with less than 20 GGAA motifs (2 repeat segments) and alleles with greater than 30 GGAA motifs (>3 repeat segments) (Figure 4A).	('less than 20 GGAA', 'Var', (168, 185))	('NR0B1', 'Gene', '190', (33, 38))	('NR0B1', 'Gene', (33, 38))	('20-30 GGAA motifs', 'Var', (116, 133))
604887	22749036	For NR0B1, both European and African groups had a similar proportion of 3-segment microsatellites (p=0.49, Chi-square).	('NR0B1', 'Gene', (4, 9))	('NR0B1', 'Gene', '190', (4, 9))	('microsatellites', 'Var', (82, 97))
604889	22749036	The most frequent observation in both ethnic groups for the longest number of consecutive GGAA repeats was 11; therefore the NR0B1 data were stratified into repeats characterized by <10 motifs, >11 motifs and 10-11 motifs (Figure 4B).	('>11 motifs', 'Var', (194, 204))	('<10 motifs', 'Var', (182, 192))	('NR0B1', 'Gene', '190', (125, 130))	('NR0B1', 'Gene', (125, 130))
604892	22749036	With data also suggesting EWS/FLI-mediated gene expression is positively influenced by an increasing number of repeats, this novel mechanistic role of microsatellite DNA in Ewing sarcoma oncogenesis inspires alternative theories to explore the genetic influences governing disease epidemiology and biology.	('FLI', 'Gene', '2314', (30, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('FLI', 'Gene', (30, 33))	('microsatellite', 'Var', (151, 165))	('Ewing sarcoma oncogenesis', 'Disease', (173, 198))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('EWS', 'Gene', (26, 29))	('EWS', 'Gene', '2130', (26, 29))	('Ewing sarcoma oncogenesis', 'Disease', 'MESH:C563168', (173, 198))
604894	22749036	The 10-fold difference in the incidence of Ewing sarcoma in African populations, irrespective of geographic location suggests a strong genetic influence, and we therefore hypothesized that polymorphic differences in these microsatellite elements may provide an alternative molecular explanation for the observed ethnic patterns of susceptibility.	('Ewing sarcoma', 'Disease', (43, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (43, 56))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (43, 56))	('polymorphic differences', 'Var', (189, 212))
604901	22749036	Prior in vitro studies suggest an increasing number of GGAA motifs enhances EWS/FLI-mediated gene activation in key microsatellite containing target genes and since Europeans have a 10-fold greater susceptibility to Ewing sarcoma, our preliminary hypothesis favored larger microsatellites in Europeans.	('FLI', 'Gene', (80, 83))	('EWS', 'Gene', '2130', (76, 79))	('EWS', 'Gene', (76, 79))	('activation', 'PosReg', (98, 108))	('Ewing sarcoma', 'Disease', (216, 229))	('enhances', 'PosReg', (67, 75))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (216, 229))	('motifs', 'Var', (60, 66))	('FLI', 'Gene', '2314', (80, 83))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (216, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))
604904	22749036	Although not controlling for possible confounding variables such as access to health care resources or socioeconomic issues, these observations would support the hypothesis that the larger NR0B1 microsatellite may confer a worse clinical outcome in those who develop the disease.	('NR0B1', 'Gene', '190', (189, 194))	('larger', 'Var', (182, 188))	('develop', 'PosReg', (259, 266))	('NR0B1', 'Gene', (189, 194))
604907	22749036	This could prevent subsequent clonal proliferation of cells harboring chromosomal translocations characteristic of Ewing sarcoma, therefore rendering African populations less susceptible to tumorigenesis.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (115, 128))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('prevent', 'NegReg', (11, 18))	('tumor', 'Disease', (190, 195))	('Ewing sarcoma', 'Disease', (115, 128))	('clonal proliferation', 'CPA', (30, 50))	('chromosomal translocations', 'Var', (70, 96))
604908	22749036	On the other hand, it is possible that beyond a critical limit, an increasing number of GGAA repeats actually impairs EWS/FLI-mediated gene activation.	('FLI', 'Gene', '2314', (122, 125))	('EWS', 'Gene', '2130', (118, 121))	('EWS', 'Gene', (118, 121))	('FLI', 'Gene', (122, 125))	('impairs', 'NegReg', (110, 117))	('repeats', 'Var', (93, 100))	('GGAA', 'Gene', (88, 92))
604912	22749036	A recent ChIP-seq dataset, reported by Patel et al., specifically looked at the relationship of EWS/FLI-occupancy of GGAA-microsatellite containing target genes and observed maximal enrichment at microsatellites of 14 tandem GGAA motifs.	('EWS', 'Gene', '2130', (96, 99))	('EWS', 'Gene', (96, 99))	('FLI', 'Gene', '2314', (100, 103))	('FLI', 'Gene', (100, 103))	('microsatellites', 'Var', (196, 211))
604917	22749036	Presently, there is in vitro evidence to suggest both microsatellite characteristics influence EWS/FL1 DNA binding and gene activation.	('gene activation', 'CPA', (119, 134))	('FL1', 'Gene', (99, 102))	('microsatellite characteristics', 'Var', (54, 84))	('influence', 'Reg', (85, 94))	('EWS', 'Gene', '2130', (95, 98))	('EWS', 'Gene', (95, 98))	('FL1', 'Gene', '100306940', (99, 102))
604924	22749036	The NR0B1 promoter was the most highly enriched EWS/FLI target and dysregulation of CAV1 has been implicated in numerous other models of oncogenesis.	('EWS', 'Gene', (48, 51))	('CAV1', 'Gene', (84, 88))	('dysregulation', 'Var', (67, 80))	('NR0B1', 'Gene', '190', (4, 9))	('EWS', 'Gene', '2130', (48, 51))	('implicated', 'Reg', (98, 108))	('NR0B1', 'Gene', (4, 9))	('CAV1', 'Gene', '857', (84, 88))	('FLI', 'Gene', '2314', (52, 55))	('FLI', 'Gene', (52, 55))
604925	22749036	We observed significant inter-ethnic polymorphisms of the NR0B1 microsatellite, but not the CAV1 microsatellite and it is possible that these observations are limited to the NR0B1 microsatellite.	('polymorphisms', 'Var', (37, 50))	('NR0B1', 'Gene', (58, 63))	('CAV1', 'Gene', (92, 96))	('NR0B1', 'Gene', '190', (174, 179))	('NR0B1', 'Gene', '190', (58, 63))	('CAV1', 'Gene', '857', (92, 96))	('NR0B1', 'Gene', (174, 179))
604927	22749036	To address this potential concern, European and African datasets were compared with and without the inclusion of the transformed cell line data and the population differences remained highly significant favoring larger NR0B1 microsatellites in the African population (data not shown).	('NR0B1', 'Gene', '190', (219, 224))	('microsatellites', 'Var', (225, 240))	('NR0B1', 'Gene', (219, 224))	('larger', 'PosReg', (212, 218))
604929	22749036	Regardless, the exploratory nature of this study was successful in identifying significant inter-ethnic polymorphisms of the NR0B1 GGAA-microsatellite in two populations with well-established differences in Ewing sarcoma susceptibility and clinical outcome.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (207, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (207, 220))	('NR0B1', 'Gene', (125, 130))	('Ewing sarcoma', 'Disease', (207, 220))	('NR0B1', 'Gene', '190', (125, 130))	('polymorphisms', 'Var', (104, 117))
604933	22749036	Given the oncogenic importance of these GGAA microsatellite response elements, our data certainly validates the need to further assess additional microsatellite containing genes in Ewing sarcoma and more precisely understand how microsatellite polymorphisms influence disease susceptibility, EWS/FL1-mediated tumorigenesis and clinical outcomes.	('microsatellite polymorphisms', 'Var', (229, 257))	('tumor', 'Disease', (309, 314))	('Ewing sarcoma', 'Disease', (181, 194))	('influence', 'Reg', (258, 267))	('FL1', 'Gene', (296, 299))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (181, 194))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (181, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('disease susceptibility', 'CPA', (268, 290))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('EWS', 'Gene', '2130', (292, 295))	('EWS', 'Gene', (292, 295))	('FL1', 'Gene', '100306940', (296, 299))
604995	33229793	Recommended immunohistochemical histiocytic sarcoma markers in dogs, cats, ferrets and four-toed hedgehogs are CD1a, CD11c/CD18, CD204, Human leukocyte antigen-DR (HLA-DR) or MHC class II and Iba-1.	('four-toed hedgehogs', 'Species', '9368', (87, 106))	('MHC class', 'Gene', (175, 184))	('ferrets', 'Species', '9669', (75, 82))	('-toed', 'Phenotype', 'HP:0040083', (91, 96))	('dogs', 'Species', '9615', (63, 67))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (32, 51))	('CD11c/CD18', 'Gene', (117, 127))	('Iba-1', 'Gene', (192, 197))	('histiocytic sarcoma', 'Disease', (32, 51))	('cats', 'Species', '9685', (69, 73))	('CD204', 'Var', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('CD1a', 'Gene', (111, 115))
605003	33254023	Finally, in vitro and in vivo anti-tumor activity of FGFR inhibitor JNJ-42756493 was selectively shown in cell lines and patient-derived xenograft models derived from immune-low UPS.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('FGFR', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (68, 80))	('tumor', 'Disease', (35, 40))	('patient', 'Species', '9606', (121, 128))	('JNJ-42756493', 'Var', (68, 80))
605026	33254023	Image analysis was performed under the supervision of a pathologist (JA) to detect the density of CD8 and PD-1 positive cells in the tumor areas and the proportion of IDO1, CD68 and CD163 stained surface of tumor slides or spots, as previously described.	('CD68', 'Var', (173, 177))	('CD8', 'Gene', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('PD-1', 'Gene', (106, 110))	('CD163', 'Var', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('CD8', 'Gene', '925', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (207, 212))
605042	33254023	To analyze the FGFRs expression, the following human TaqMan Gene Expression Assays were used: RPLP0 Hs999999_m1, FGFR1 Hs00241111_m1, FGFR2 Hs01552918_m1, FGFR3 Hs00179829_m1, FGFR4 Hs00242558_ m1.	('Hs00242558_ m1', 'Var', (182, 196))	('FGFR4', 'Gene', '2264', (176, 181))	('RPLP0', 'Gene', '6175', (94, 99))	('FGFR4', 'Gene', (176, 181))	('Hs00241111_m1', 'Var', (119, 132))	('Hs01552918_m1', 'Var', (140, 153))	('FGFR1', 'Gene', (113, 118))	('FGFR3', 'Gene', '2261', (155, 160))	('RPLP0', 'Gene', (94, 99))	('FGFR1', 'Gene', '2260', (113, 118))	('Hs00179829_m1', 'Var', (161, 174))	('FGFR3', 'Gene', (155, 160))	('human', 'Species', '9606', (47, 52))
605075	33254023	S4A, S4B, S4C, S4D, and S4E).	('S4C', 'Mutation', 'p.S4C', (10, 13))	('S4E', 'Var', (24, 27))	('S4D', 'Mutation', 'p.S4D', (15, 18))	('S4E', 'Mutation', 'p.S4E', (24, 27))	('S4C', 'Var', (10, 13))	('S4D', 'Var', (15, 18))
605078	33254023	There is growing evidence that underlying genomic alterations may drive the composition of the tumor micro-environment in solid tumors.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('composition', 'MPA', (76, 87))	('alterations', 'Var', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('drive', 'Reg', (66, 71))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', (95, 100))
605079	33254023	There was notably a significant enrichment in deletions of tumor suppressor genes belonging to DNA repair, cell cycle, apoptosis, PI3K/mTOR, and Wnt/beta-catenin pathways (Fig.	('tumor', 'Disease', (59, 64))	('mTOR', 'Gene', '2475', (135, 139))	('beta-catenin', 'Gene', (149, 161))	('mTOR', 'Gene', (135, 139))	('apoptosis', 'CPA', (119, 128))	('cell', 'CPA', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('beta-catenin', 'Gene', '1499', (149, 161))	('deletions', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
605087	33254023	We then assessed several specific FGFR inhibitors and demonstrated that they all potently decreased in vitro viability, FGFR2 phosphorylation and downstream signaling, and induced G0-G1 arrest in cells derived from immune-low UPS, specifically (Fig.	('inhibitors', 'Var', (39, 49))	('arrest', 'Disease', 'MESH:D006323', (186, 192))	('phosphorylation', 'MPA', (126, 141))	('decreased', 'NegReg', (90, 99))	('arrest', 'Disease', (186, 192))	('induced', 'Reg', (172, 179))	('FGFR2', 'Gene', (120, 125))
605094	33254023	In this study, gene-expression profiling of more than 600 sarcomas of different histologies, including UPS, allowed establishing an immune-based classification of five different phenotypes: immune-low (A and B), immune high (D and E) and highly-vascularized (C).	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcomas', 'Disease', (58, 66))	('highly-vascularized', 'CPA', (238, 257))	('immune-low', 'Var', (190, 200))	('sarcomas', 'Disease', 'MESH:D012509', (58, 66))
605098	33254023	who reported significant enrichment for immune-related pathways in a subset of undifferentiated sarcomas (US) characterized by higher mutational burden, as well as another subset of US characterized by a high rearrangement level.	('undifferentiated sarcomas', 'Disease', 'MESH:D002277', (79, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('undifferentiated sarcomas', 'Disease', (79, 104))	('immune-related pathways', 'Pathway', (40, 63))	('mutational', 'Var', (134, 144))
605105	33254023	Our preclinical findings support the hypothesis that deregulated FGFR2 signaling is an important oncogenic pathway in the initiation and/or maintenance of immune-low UPS, and support recent clinical data showing significant activity of FGFR inhibitors in FGFR mRNA-overexpressing solid tumors without apparent FGFR gene fusion or mutation.	('FGFR', 'Gene', (236, 240))	('FGFR2', 'Gene', (65, 70))	('activity', 'MPA', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('FGFR', 'Gene', (255, 259))	('tumors', 'Disease', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('deregulated', 'Var', (53, 64))
605147	32110053	The findings from a phase IIb, placebo-controlled trial including 233 patients with recurrent advanced STS showed that anlotinib compared with a placebo significantly prolonged progression-free survival by 4.8 months (6.27 months vs 1.47 months, P< 0.0001).	('patients', 'Species', '9606', (70, 78))	('anlotinib', 'Var', (119, 128))	('STS', 'Disease', (103, 106))	('STS', 'Disease', 'MESH:D012509', (103, 106))	('progression-free survival', 'CPA', (177, 202))	('STS', 'Phenotype', 'HP:0030448', (103, 106))	('anlotinib', 'Chemical', 'MESH:C000625192', (119, 128))	('prolonged', 'PosReg', (167, 176))
605244	30555691	Researchers at the Mayo Clinic discovered that when the genes PAX3 and MAML3 manage to combine, the result is a chimera that causes biphenotypic sinonasal sarcoma.	('MAML3', 'Gene', (71, 76))	('sarcoma', 'Disease', (155, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('chimera', 'Var', (112, 119))	('Mayo', 'Species', '162683', (19, 23))	('causes', 'Reg', (125, 131))	('PAX3', 'Gene', '5077', (62, 66))	('PAX3', 'Gene', (62, 66))	('sarcoma', 'Disease', 'MESH:D012509', (155, 162))	('MAML3', 'Gene', '55534', (71, 76))
605254	30555691	The SNS phenotype is characterized by aberrant expression of Genes involved in neuro-ectodermal and myogenic differentiation closely simulating the development roles of PAX3.	('PAX3', 'Gene', (169, 173))	('aberrant', 'Var', (38, 46))	('SNS', 'Disease', (4, 7))	('expression', 'MPA', (47, 57))	('PAX3', 'Gene', '5077', (169, 173))
605262	30555691	Then, the tumor was mobilized and removed en-bloc by avulsing it from its attachment laterally (Fig 2).	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('avulsing', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
605286	28891906	LV305 is currently being evaluated in phase 1 and 2 trials in metastatic recurrent cancer patients with NY-ESO-1 positive solid tumors as a single agent and in combination with anti-PD-L1.	('NY-ESO-1', 'Gene', '246100', (104, 112))	('PD-L1', 'Gene', '29126', (182, 187))	('solid tumors', 'Disease', (122, 134))	('LV305', 'Var', (0, 5))	('NY-ESO-1', 'Gene', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('LV305', 'Chemical', '-', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('solid tumors', 'Disease', 'MESH:D009369', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('PD-L1', 'Gene', (182, 187))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', (83, 89))
605287	28891906	Here we report on the first patient treated with LV305, a young woman with metastatic, recurrent, therapy-refractive NY-ESO-1+ synovial sarcoma.	('NY-ESO-1', 'Gene', '246100', (117, 125))	('NY-ESO-1', 'Gene', (117, 125))	('synovial sarcoma', 'Disease', (127, 143))	('LV305', 'Var', (49, 54))	('woman', 'Species', '9606', (64, 69))	('patient', 'Species', '9606', (28, 35))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (127, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('synovial sarcoma', 'Disease', 'MESH:D013584', (127, 143))	('LV305', 'Chemical', '-', (49, 54))
605289	28891906	This case demonstrates that LV305 can be safely administered and has the potential to induce a significant clinical benefit and immunologic response in a patient with advanced stage cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('patient', 'Species', '9606', (154, 161))	('clinical benefit', 'CPA', (107, 123))	('LV305', 'Var', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('LV305', 'Chemical', '-', (28, 33))	('immunologic', 'CPA', (128, 139))
605302	28891906	Low-grade toxicities potentially attributable to LV305 included pain and stinging at the injection site, mild fatigue the day after injections, an episode of subjective palpitations, subjective fevers and myalgias in the days after vaccination, each of which resolved within 24 hours.	('toxicities', 'Disease', 'MESH:D064420', (10, 20))	('fatigue', 'Disease', 'MESH:D005221', (110, 117))	('myalgias', 'Disease', 'MESH:D063806', (205, 213))	('myalgias', 'Phenotype', 'HP:0003326', (205, 213))	('toxicities', 'Disease', (10, 20))	('mild', 'Disease', (105, 109))	('fevers', 'Phenotype', 'HP:0001945', (194, 200))	('palpitations', 'Phenotype', 'HP:0001962', (169, 181))	('fatigue', 'Disease', (110, 117))	('LV305', 'Var', (49, 54))	('pain', 'Phenotype', 'HP:0012531', (64, 68))	('fatigue', 'Phenotype', 'HP:0012378', (110, 117))	('myalgias', 'Disease', (205, 213))	('pain', 'Disease', 'MESH:D010146', (64, 68))	('pain', 'Disease', (64, 68))	('LV305', 'Chemical', '-', (49, 54))
605316	28891906	The majority of the top 20 clones from pre-LV305 TILs expanded in post-LV305 PBMC as compared with pre-Tx PBMC (Fig.	('PBMC', 'Chemical', '-', (77, 81))	('LV305', 'Chemical', '-', (71, 76))	('LV305', 'Chemical', '-', (43, 48))	('PBMC', 'Chemical', '-', (106, 110))	('expanded', 'PosReg', (54, 62))	('post-LV305', 'Var', (66, 76))
605327	28891906	LV305 is the first clinical candidate from the ZVex platform and encodes the tumor-specific cancer testis antigen, NY-ESO-1.	('cancer testis', 'Disease', (92, 105))	('LV305', 'Var', (0, 5))	('cancer testis', 'Phenotype', 'HP:0010788', (92, 105))	('NY-ESO-1', 'Gene', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('NY-ESO-1', 'Gene', '246100', (115, 123))	('LV305', 'Chemical', '-', (0, 5))	('cancer testis', 'Disease', 'MESH:D013736', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (77, 82))
605332	28891906	In this patient, LV305 induced a robust NY-ESO-1-specific CD4+ and CD8+ T-cell response, as demonstrated using multiple methodologies, which has been sustained for over 2 years, allowing this patient to improve clinically while maintaining an excellent quality of life.	('patient', 'Species', '9606', (192, 199))	('CD4', 'Gene', '920', (58, 61))	('LV305', 'Var', (17, 22))	('NY-ESO-1', 'Gene', '246100', (40, 48))	('NY-ESO-1', 'Gene', (40, 48))	('improve', 'PosReg', (203, 210))	('patient', 'Species', '9606', (8, 15))	('LV305', 'Chemical', '-', (17, 22))	('CD8', 'Gene', (67, 70))	('CD4', 'Gene', (58, 61))	('CD8', 'Gene', '925', (67, 70))
605333	28891906	LV305 immunotherapy significantly increased the NY-ESO-1-specific CD8+ response, but perhaps more importantly, also changed the quality of the response.	('NY-ESO-1', 'Gene', '246100', (48, 56))	('NY-ESO-1', 'Gene', (48, 56))	('LV305', 'Var', (0, 5))	('quality', 'MPA', (128, 135))	('CD8', 'Gene', (66, 69))	('LV305', 'Chemical', '-', (0, 5))	('CD8', 'Gene', '925', (66, 69))	('increased', 'PosReg', (34, 43))	('changed', 'Reg', (116, 123))
605336	28891906	As opposed to immunization with other viral vectors that induce strong inflammatory responses resulting in strong but brisk expansion and rapid contraction of the CD8+ T-cell effector repertoire, such as adeno and poxviral vectors, DC transduction with lentivectors tends to be low-inflammatory, resulting in protracted kinetics of the T-cell response but early induction of memory.	('CD8', 'Gene', (163, 166))	('CD8', 'Gene', '925', (163, 166))	('T-cell response', 'CPA', (336, 351))	('DC transduction', 'Var', (232, 247))
605337	28891906	In mice, LV305 induced vector persistence in lymph nodes draining the dermal injection site for over 28 days and induced long-lasting antitumor effector-memory T-cell responses, suggesting that persisting antigen expression combined with prolonged DC activation may have been responsible for the observed sustained immunologic changes in our patient.	('LV305', 'Chemical', '-', (9, 14))	('tumor', 'Disease', (138, 143))	('patient', 'Species', '9606', (342, 349))	('mice', 'Species', '10090', (3, 7))	('LV305', 'Var', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
605340	28891906	SS is an aggressive cancer-driven through the t(X;18)(p11;q11) translocation.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('t(X;18)(p11;q11', 'Var', (46, 61))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (46, 62))
605471	29267445	In this case report, the blood count and bone marrow biopsy findings are compatible with chronic myeloid leukemia, which was confirmed by the demonstration of BCR/ABL rearrangement in peripheral blood through the polymerase chain reaction (PCR).	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (89, 113))	('BCR/ABL', 'Gene', '25;613', (159, 166))	('chronic myeloid leukemia', 'Disease', (89, 113))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (89, 113))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('BCR/ABL', 'Gene', (159, 166))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (97, 113))	('rearrangement', 'Var', (167, 180))
605525	24765456	The presence of annexin II receptor on the surface of leukaemic promyelocytes has been shown to stimulate the production of t-PA-dependent plasmin more efficiently.	('t-PA', 'Gene', (124, 128))	('annexin II receptor', 'Gene', (16, 35))	('t-PA', 'Gene', '5327', (124, 128))	('production', 'MPA', (110, 120))	('stimulate', 'PosReg', (96, 105))	('annexin II receptor', 'Gene', '389289', (16, 35))	('presence', 'Var', (4, 12))
605561	24708915	Furthermore, the tumor cells exhibited positive immunohistochemical staining for vimentin, CD21, CD35, D2-40 and leukocyte common antigen (Figure 3A to 3E) as well as negative staining for cytokeratin (Figure 3F), CD20, CD30, CD117, epithelial membrane antigen and S-l00 (not shown).	('CD117', 'Gene', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('D2-40', 'Var', (103, 108))	('tumor', 'Disease', (17, 22))	('CD20', 'Gene', '54474', (214, 218))	('CD21', 'Gene', '1380', (91, 95))	('CD35', 'Gene', '1378', (97, 101))	('CD30', 'Gene', '943', (220, 224))	('vimentin', 'Gene', '7431', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('CD30', 'Gene', (220, 224))	('CD35', 'Gene', (97, 101))	('vimentin', 'Gene', (81, 89))	('CD117', 'Gene', '3815', (226, 231))	('CD21', 'Gene', (91, 95))	('CD20', 'Gene', (214, 218))
605613	32021240	Primary antibodies including anti-p62 (1:500, #sc-101542), anti-LC3 (1:500, #sc-398822), anti-FLI1 (1:500, #sc-22808) and anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (1: 1000, #sc-32233) were bought from Santa Cruz Biotechnology, Inc. (Dallas, TX, USA), anti-TRIM3 (1:1000, #ab111840), anti-Beclin1 (1:1000, #ab207612), anti-Myc (1: 1000, #ab32), anti-Flag (1:1000, #ab49763) and anti-HA (1:1000, #ab9110) were obtained from Abcam (Abcam, Cambridge, USA).	('anti-glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (122, 167))	('LC3', 'Gene', (64, 67))	('Myc', 'Gene', (335, 338))	('TRIM3', 'Gene', '10612', (269, 274))	('p62', 'Gene', '8878', (34, 37))	('FLI1', 'Gene', (94, 98))	('p62', 'Gene', (34, 37))	('anti-glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (122, 167))	('Beclin1', 'Gene', '8678', (301, 308))	('1:1000', 'Var', (310, 316))	('FLI1', 'Gene', '2313', (94, 98))	('GAPDH', 'Gene', '2597', (169, 174))	('1:1000', 'Var', (276, 282))	('GAPDH', 'Gene', (169, 174))	('LC3', 'Gene', '84557', (64, 67))	('Beclin1', 'Gene', (301, 308))	('Myc', 'Gene', '4609', (335, 338))	('TRIM3', 'Gene', (269, 274))
605628	32021240	Consistently, knockdown the expression of EWS-FLI1 also decreased TRIM3 expression.	('TRIM3', 'Gene', '10612', (66, 71))	('decreased', 'NegReg', (56, 65))	('FLI1', 'Gene', (46, 50))	('FLI1', 'Gene', '2313', (46, 50))	('knockdown', 'Var', (14, 23))	('TRIM3', 'Gene', (66, 71))	('EWS', 'Gene', '2130', (42, 45))	('EWS', 'Gene', (42, 45))
605636	32021240	ShRNA plasmid of TRIM3 was used to knockdown the expression of TRIM3, and the effect of shRNA was examined (Figure 4A).	('knockdown', 'Var', (35, 44))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('expression', 'MPA', (49, 59))	('TRIM3', 'Gene', (63, 68))	('TRIM3', 'Gene', (17, 22))	('TRIM3', 'Gene', '10612', (63, 68))	('TRIM3', 'Gene', '10612', (17, 22))
605638	32021240	Taken together, these data suggested that silencing of TRIM3 promotes autophagy in ES cells.	('TRIM3', 'Gene', '10612', (55, 60))	('silencing', 'Var', (42, 51))	('ES', 'Disease', 'MESH:D012512', (83, 85))	('promotes', 'PosReg', (61, 69))	('autophagy in', 'CPA', (70, 82))	('TRIM3', 'Gene', (55, 60))
605652	32021240	Autophagy plays great roles in the clearance of long-lived proteins, aggregates and damaged organelles, and dysregulation of autophagy is highly associated with cancer, particularly in tumorigenesis and chemotherapy resistance.	('chemotherapy resistance', 'CPA', (203, 226))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('autophagy', 'CPA', (125, 134))	('associated', 'Reg', (145, 155))	('tumorigenesis', 'CPA', (185, 198))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('dysregulation', 'Var', (108, 121))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
605659	32021240	In the study, we found that the expression of Beclin1 is down-regulated by TRIM3 overexpression in a dose-dependent manner.	('down-regulated', 'NegReg', (57, 71))	('TRIM3', 'Gene', (75, 80))	('Beclin1', 'Gene', '8678', (46, 53))	('TRIM3', 'Gene', '10612', (75, 80))	('Beclin1', 'Gene', (46, 53))	('expression', 'MPA', (32, 42))	('overexpression', 'Var', (81, 95))
605768	26547435	A new meta-analysis confirmed a marginal efficacy of adjuvant chemotherapy, with a significant decrease in local recurrence rate (OR 0.73, p = 0.02), distant recurrence rate (OR 0.67, p = 0.001), and overall recurrence rate (OR 0.67, p = 0.0001) in patients receiving chemotherapy with doxorubicin-based regimens or with doxorubicin/ifosfamide combination, which translated into a gain in OS (OR 0.77, p = 0.01) and absolute risk reduction of death of 6 %, when only doxorubicin plus ifosfamide-based regimens were considered (Pervaiz et al.).	('decrease', 'NegReg', (95, 103))	('doxorubicin', 'Chemical', 'MESH:D004317', (286, 297))	('gain', 'PosReg', (381, 385))	('ifosfamide', 'Chemical', 'MESH:D007069', (484, 494))	('doxorubicin', 'Chemical', 'MESH:D004317', (321, 332))	('doxorubicin-based regimens', 'Var', (286, 312))	('OS', 'Chemical', '-', (389, 391))	('patients', 'Species', '9606', (249, 257))	('doxorubicin/ifosfamide', 'Var', (321, 343))	('distant recurrence rate', 'CPA', (150, 173))	('doxorubicin', 'Chemical', 'MESH:D004317', (467, 478))	('local recurrence rate', 'CPA', (107, 128))	('ifosfamide', 'Chemical', 'MESH:D007069', (333, 343))
605769	26547435	conducted on individual patient data of 819 patients with median follow-up of 8.2 years shows that tumor size, high histological grade, and R1 resection are independent adverse prognostic factors for relapse-free survival (RFS) and OS, whereas adjuvant chemotherapy is an independent favorable prognostic factor for RFS but not for OS.	('tumor', 'Disease', (99, 104))	('relapse-free survival', 'CPA', (200, 221))	('patient', 'Species', '9606', (44, 51))	('patients', 'Species', '9606', (44, 52))	('patient', 'Species', '9606', (24, 31))	('OS', 'Chemical', '-', (232, 234))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('R1 resection', 'Var', (140, 152))	('OS', 'Chemical', '-', (332, 334))
605847	26204834	It is estimated that there are thousands of lncRNAs within the human genome, but very little is known about the function of the vast majority of these, as only a few have been studied to date, thereby revealing roles in X-chromosome inactivation, nuclear organization and compartmentalization, as well as nuclear-cytoplasmic trafficking.	('X-chromosome inactivation', 'Var', (220, 245))	('human', 'Species', '9606', (63, 68))	('nuclear-cytoplasmic', 'CPA', (305, 324))	('nuclear organization', 'CPA', (247, 267))	('revealing roles', 'Reg', (201, 216))
605883	26204834	Certain germline predispositions to osteosarcoma have long been known, including mutations of RB1 gene in hereditary retinoblastoma, TP53 as in the Li-Fraumeni syndrome, or various of the DNA helicases.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (148, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('RB1', 'Gene', (94, 97))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (106, 131))	('DNA helicases', 'Protein', (188, 201))	('Li-Fraumeni syndrome', 'Disease', (148, 168))	('osteosarcoma', 'Disease', 'MESH:D012516', (36, 48))	('RB1', 'Gene', '5925', (94, 97))	('retinoblastoma', 'Phenotype', 'HP:0009919', (117, 131))	('mutations', 'Var', (81, 90))	('hereditary retinoblastoma', 'Disease', (106, 131))	('osteosarcoma', 'Phenotype', 'HP:0002669', (36, 48))	('TP53', 'Gene', '7157', (133, 137))	('osteosarcoma', 'Disease', (36, 48))	('TP53', 'Gene', (133, 137))
605885	26204834	A comprehensive analysis of paired osteosarcoma and constitutional DNA by complementary genomic approaches recently showed that while TP53 mutations were identified in 22% osteosarcomas, complete P53 pathway inactivation was in fact seen in 75% cases, and in about a third of cases, multiple mechanisms of inactivation of P53 were observed.	('TP53', 'Gene', (134, 138))	('osteosarcomas', 'Disease', (172, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('P53', 'Gene', (135, 138))	('osteosarcomas', 'Phenotype', 'HP:0002669', (172, 185))	('osteosarcoma', 'Disease', (35, 47))	('osteosarcoma', 'Disease', (172, 184))	('P53', 'Gene', (196, 199))	('osteosarcoma', 'Disease', 'MESH:D012516', (35, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (172, 184))	('inactivation', 'NegReg', (208, 220))	('TP53', 'Gene', '7157', (134, 138))	('P53', 'Gene', '7157', (135, 138))	('P53', 'Gene', (322, 325))	('P53', 'Gene', '7157', (196, 199))	('mutations', 'Var', (139, 148))	('osteosarcoma', 'Phenotype', 'HP:0002669', (35, 47))	('osteosarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('osteosarcomas', 'Disease', 'MESH:D012516', (172, 185))	('P53', 'Gene', '7157', (322, 325))	('sarcoma', 'Phenotype', 'HP:0100242', (177, 184))	('sarcomas', 'Phenotype', 'HP:0100242', (177, 185))
605887	26204834	miR-31 targets the cell cycle regulator E2F2 and, upon over-expression, inhibits proliferation of osteosarcoma cell lines; loss of miR-31 produces defects in the TP53 pathway.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('E2F2', 'Gene', '1870', (40, 44))	('E2F2', 'Gene', (40, 44))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('miR-31', 'Gene', (0, 6))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('miR-31', 'Gene', (131, 137))	('rat', 'Species', '10116', (88, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('inhibits', 'NegReg', (72, 80))	('miR-31', 'Gene', '407035', (0, 6))	('defects', 'NegReg', (147, 154))	('loss', 'Var', (123, 127))	('proliferation', 'CPA', (81, 94))	('miR-31', 'Gene', '407035', (131, 137))	('osteosarcoma', 'Disease', (98, 110))
605891	26204834	reported genomic alterations in the PI3K/mTOR pathway in a full 24% of cases in their cohort, highlighting potential therapeutic targetability thereof.	('genomic alterations', 'Var', (9, 28))	('rat', 'Species', '10116', (21, 24))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))
605893	26204834	Indeed, combined low miR-223 with high target mRNA ECT2 expression in osteosarcoma was significantly associated with tumour grade, chemo-resistance, development of metastases and tumour recurrence, as was in that same cohort, the combined low miR-183 with high target mRNA EZRIN expression.	('ECT2', 'Gene', '1894', (51, 55))	('ECT2', 'Gene', (51, 55))	('miR-183', 'Gene', (243, 250))	('osteosarcoma', 'Disease', (70, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (70, 82))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('low', 'Var', (17, 20))	('tumour', 'Disease', (179, 185))	('miR-223', 'Gene', (21, 28))	('osteosarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('associated', 'Reg', (101, 111))	('metastases', 'Disease', 'MESH:D009362', (164, 174))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('miR-183', 'Gene', '406959', (243, 250))	('metastases', 'Disease', (164, 174))	('miR-223', 'Gene', '407008', (21, 28))	('tumour', 'Disease', (117, 123))
605915	26204834	In a further 10% of cases EWSR1 is fused to ERG1 on chromosome 21 resulting from the chromosomal translocation t(21;22)(q22;q12).	('t(21;22)(q22;q12', 'Var', (111, 127))	('ERG1', 'Gene', (44, 48))	('resulting from', 'Reg', (66, 80))	('ERG1', 'Gene', '3757', (44, 48))	('EWSR1', 'Gene', (26, 31))	('t(21;22)(q22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (111, 128))
605919	26204834	EWSR1-Fli1 was classified as an oncogene due to its ability to transform NIH3T3 cells; however, expression in most normal primary human cells induces cell death.	('cell death', 'CPA', (150, 160))	('NIH3T3', 'CellLine', 'CVCL:0594', (73, 79))	('induces', 'Reg', (142, 149))	('expression', 'Var', (96, 106))	('EWSR1-Fli1', 'Gene', (0, 10))	('human', 'Species', '9606', (130, 135))
605925	26204834	Based on these data, blockade of miR-106a-363 cluster and restoration of miR15a both offer promise as therapeutic options in Ewing sarcoma.	('miR-106a', 'Gene', '406899', (33, 41))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('restoration', 'Var', (58, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('miR15a', 'Gene', (73, 79))	('miR15a', 'Gene', '406948', (73, 79))	('miR-106a', 'Gene', (33, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('Ewing sarcoma', 'Disease', (125, 138))	('rat', 'Species', '10116', (63, 66))
605929	26204834	reported similar growth effects with ectopic expression of let-7 inhibiting cell proliferation, migration and invasion, arresting cell cycle progression and inducing apoptosis (Table 1).	('migration', 'CPA', (96, 105))	('ectopic expression', 'Var', (37, 55))	('rat', 'Species', '10116', (99, 102))	('cell proliferation', 'CPA', (76, 94))	('rat', 'Species', '10116', (88, 91))	('let-7', 'Gene', (59, 64))	('arresting', 'NegReg', (120, 129))	('inhibiting', 'NegReg', (65, 75))	('invasion', 'CPA', (110, 118))	('apoptosis', 'CPA', (166, 175))	('cell cycle progression', 'CPA', (130, 152))	('inducing', 'Reg', (157, 165))
605930	26204834	investigated miRNAs up-regulated following shRNA silencing of EWSR1-Fli1 and identified, amongst the top-ranking miRNAs, seven which target the IGF pathway specifically.	('EWSR1-Fli1', 'Gene', (62, 72))	('silencing', 'Var', (49, 58))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (13, 16))	('miR', 'Gene', (113, 116))	('up-regulated', 'PosReg', (20, 32))	('IGF pathway', 'Pathway', (144, 155))
605937	26204834	Of four predicted target genes involved in chromatin remodelling, miR-22 over-expression led to a 20% decrease in the histone demethylase KDM3A mRNA and silencing of KDM3A caused a robust inhibition of colony formation.	('KDM3A', 'Gene', (138, 143))	('miR-22', 'Gene', '407004', (66, 72))	('decrease', 'NegReg', (102, 110))	('silencing', 'Var', (153, 162))	('miR-22', 'Gene', (66, 72))	('KDM3A', 'Gene', (166, 171))	('histone demethylase', 'MPA', (118, 137))	('over-expression', 'PosReg', (73, 88))	('colony formation', 'CPA', (202, 218))	('mRNA', 'MPA', (144, 148))	('inhibition', 'NegReg', (188, 198))	('KDM3A', 'Gene', '55818', (166, 171))	('KDM3A', 'Gene', '55818', (138, 143))
605961	26204834	ES cells with p53 mutations (SK-N-MC, SKES1, TC71 & IOR/CAR) have lower expression levels of miR-34a compared to wild-type p53 ES cells (WE-68, IOR/RCH and LAP-53) and inhibition of miR-34a in p53 WT LAP-35 cells significantly increased anchorage-independent growth, while restoration of miR-34a in p53 mutant cells decreased anchorage independent growth.	('and', 'NegReg', (164, 167))	('p53', 'Gene', (193, 196))	('LAP', 'Gene', (200, 203))	('lower expression', 'MPA', (66, 82))	('miR-34a', 'Gene', (93, 100))	('RCH', 'Disease', (148, 151))	('rat', 'Species', '10116', (278, 281))	('miR-34a', 'Gene', '407040', (93, 100))	('have', 'NegReg', (61, 65))	('miR-34a', 'Gene', (288, 295))	('LAP', 'Gene', '7939', (156, 159))	('p53', 'Gene', '7157', (299, 302))	('LAP', 'Gene', (156, 159))	('SKES1', 'CellLine', 'CVCL:B526', (38, 43))	('p53', 'Gene', '7157', (14, 17))	('increased anchorage-independent', 'CPA', (227, 258))	('miR-34a', 'Gene', '407040', (288, 295))	('cells', 'NegReg', (310, 315))	('SK-N-MC', 'CellLine', 'CVCL:0530', (29, 36))	('p53', 'Gene', '7157', (123, 126))	('decreased anchorage independent', 'CPA', (316, 347))	('RCH', 'Disease', 'None', (148, 151))	('miR-34a', 'Gene', (182, 189))	('p53', 'Gene', (299, 302))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (193, 196))	('p53', 'Gene', (123, 126))	('miR-34a', 'Gene', '407040', (182, 189))	('significantly', 'PosReg', (213, 226))	('LAP', 'Gene', '7939', (200, 203))	('mutations', 'Var', (18, 27))
605962	26204834	Ectopic expression of miR-34a also sensitised ES cells to vincristine and doxorubicin, lowering the IC50 in the cells, raising consideration of miR-34a as a potential therapeutic agent in Ewing sarcoma.	('miR-34a', 'Gene', (144, 151))	('Ewing sarcoma', 'Disease', (188, 201))	('miR-34a', 'Gene', '407040', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('vincristine', 'Chemical', 'MESH:D014750', (58, 69))	('miR-34a', 'Gene', '407040', (22, 29))	('Ectopic expression', 'Var', (0, 18))	('IC50 in the cells', 'MPA', (100, 117))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (188, 201))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (188, 201))	('miR-34a', 'Gene', (22, 29))	('rat', 'Species', '10116', (134, 137))	('lowering', 'NegReg', (87, 95))
605967	26204834	EWSR1-Fli1 knock-down led to reduced EYA3 mRNA levels, and despite prior suggestions to the contrary, these investigators found no evidence of direct binding of the fusion protein to the EYA3 promoter and therefore opted to investigate the role of miRNAs in this context.	('EYA3', 'Gene', '2140', (187, 191))	('knock-down', 'Var', (11, 21))	('EYA3', 'Gene', (187, 191))	('EYA3', 'Gene', '2140', (37, 41))	('reduced', 'NegReg', (29, 36))	('miR', 'Gene', '220972', (248, 251))	('miR', 'Gene', (248, 251))	('EYA3', 'Gene', (37, 41))	('EWSR1-Fli1', 'Gene', (0, 10))	('binding', 'Interaction', (150, 157))
605970	26204834	Moreover, a clear trend emerged, whereby patients whose tumours had low levels of miR-708 and high EYA3 had worse three-year relapse-free survival rates.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('miR-708', 'Gene', '100126333', (82, 89))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('low', 'NegReg', (68, 71))	('patients', 'Species', '9606', (41, 49))	('worse', 'NegReg', (108, 113))	('rat', 'Species', '10116', (147, 150))	('EYA3', 'Gene', '2140', (99, 103))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('miR-708', 'Gene', (82, 89))	('high', 'Var', (94, 98))	('EYA3', 'Gene', (99, 103))
605975	26204834	Silencing of miR-125b in doxorubicin-resistant ES cells (VH-64/ADR & WE-68/ADR) significantly enhanced cell death by increasing sensitivity to doxorubicin, and this increased sensitivity to doxorubicin was also seen in the parental ES cells and in additional ES cell lines (RD-ES, SK-N-MC and TC-71 cells).	('significantly', 'PosReg', (80, 93))	('SK-N-MC', 'CellLine', 'CVCL:0530', (281, 288))	('doxorubicin', 'Chemical', 'MESH:D004317', (190, 201))	('enhanced cell', 'CPA', (94, 107))	('doxorubicin', 'Chemical', 'MESH:D004317', (143, 154))	('increasing sensitivity to', 'MPA', (117, 142))	('doxorubicin', 'Chemical', 'MESH:D004317', (25, 36))	('TC-71', 'CellLine', 'CVCL:2213', (293, 298))	('miR-1', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))	('miR-1', 'Gene', '83856', (13, 18))
605976	26204834	Down-regulation of miR-125b in doxorubicin-resistant cells increased their sensitivity to vincristine and etoposide, while over-expression of miR-125b in the parental cells reduced cytotoxicity; knockdown of miR-125b enhanced the sensitivity of both cell type to mafosfamide also.	('cytotoxicity', 'Disease', 'MESH:D064420', (181, 193))	('miR-1', 'Gene', (142, 147))	('miR-1', 'Gene', '83856', (142, 147))	('sensitivity', 'MPA', (230, 241))	('cytotoxicity', 'Disease', (181, 193))	('enhanced', 'PosReg', (217, 225))	('miR-1', 'Gene', (208, 213))	('miR-1', 'Gene', (19, 24))	('doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('Down-regulation', 'NegReg', (0, 15))	('miR-1', 'Gene', '83856', (208, 213))	('miR-1', 'Gene', '83856', (19, 24))	('etoposide', 'Chemical', 'MESH:D005047', (106, 115))	('vincristine', 'Chemical', 'MESH:D014750', (90, 101))	('knockdown', 'Var', (195, 204))	('increased', 'PosReg', (59, 68))	('mafosfamide', 'Chemical', 'MESH:C048341', (263, 274))
605982	26204834	In contrast, alveolar rhabdomyosarcomas (ARMS) are associated with t(2;13) or less commonly t(1;13) chromosomal translocations producing a PAX3-FOXO1 or PAX7-FOXO1 fusion gene respectively.	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (13, 38))	('FOXO1', 'Gene', (144, 149))	('FOXO1', 'Gene', '2308', (158, 163))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (13, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('FOXO1', 'Gene', (158, 163))	('ARMS', 'Phenotype', 'HP:0006779', (41, 45))	('PAX3', 'Gene', (139, 143))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (13, 39))	('PAX7', 'Gene', '5081', (153, 157))	('PAX7', 'Gene', (153, 157))	('PAX3', 'Gene', '5077', (139, 143))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (22, 39))	('FOXO1', 'Gene', '2308', (144, 149))	('associated', 'Reg', (51, 61))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (22, 38))	('t(2;13', 'Var', (67, 73))	('alveolar rhabdomyosarcomas', 'Disease', (13, 39))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
605998	26204834	Over-expression of miR-1 was found to play an instructive role in RMS cells and promoted differentiation with levels of myogenin and MyL1 five times higher in miR-1 transfected cells compared to controls.	('promoted', 'PosReg', (80, 88))	('myogenin', 'Gene', '4656', (120, 128))	('transfected', 'Var', (165, 176))	('levels', 'MPA', (110, 116))	('miR-1', 'Gene', (159, 164))	('miR-1', 'Gene', '83856', (159, 164))	('miR-1', 'Gene', (19, 24))	('MyL1', 'Gene', '4632', (133, 137))	('miR-1', 'Gene', '83856', (19, 24))	('Over-expression', 'Var', (0, 15))	('higher', 'PosReg', (149, 155))	('differentiation', 'CPA', (89, 104))	('myogenin', 'Gene', (120, 128))	('MyL1', 'Gene', (133, 137))
606023	26204834	Sustained expression of BAF53a interferes with myogenic differentiation, while silencing BAF53a in RMS cells increases expression of myogenic markers and inhibits proliferation and anchorage-independent growth.	('inhibits', 'NegReg', (154, 162))	('expression', 'MPA', (119, 129))	('BAF53a', 'Gene', (89, 95))	('myogenic', 'Protein', (133, 141))	('BAF53a', 'Gene', (24, 30))	('myogenic differentiation', 'CPA', (47, 71))	('rat', 'Species', '10116', (170, 173))	('BAF53a', 'Gene', '86', (89, 95))	('increases', 'PosReg', (109, 118))	('BAF53a', 'Gene', '86', (24, 30))	('silencing', 'Var', (79, 88))
606024	26204834	Thus silencing of BAF53a appears to have a prominent role in the transition from growth to myogenic differentiation.	('growth', 'CPA', (81, 87))	('silencing', 'Var', (5, 14))	('BAF53a', 'Gene', '86', (18, 24))	('BAF53a', 'Gene', (18, 24))
606034	26204834	siRNA knock-down of TGFbeta1 led to increased levels of miR-450b-5p.	('TGFbeta1', 'Gene', '7040', (20, 28))	('knock-down', 'Var', (6, 16))	('increased', 'PosReg', (36, 45))	('TGFbeta1', 'Gene', (20, 28))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))
606036	26204834	Moreover, progression of myogenic differentiation and increase in apoptosis were observed as results of knock-down of TGFbeta1.	('myogenic differentiation', 'CPA', (25, 49))	('apoptosis', 'CPA', (66, 75))	('knock-down', 'Var', (104, 114))	('TGFbeta1', 'Gene', '7040', (118, 126))	('TGFbeta1', 'Gene', (118, 126))
606041	26204834	Amplification of the 13q31 chromosomal region in ARMS is seen in up to 23% ARMS cases and is notably associated with PAX7-FOXO1 rearrangement.	('Amplification', 'Var', (0, 13))	('PAX7', 'Gene', '5081', (117, 121))	('FOXO1', 'Gene', (122, 127))	('FOXO1', 'Gene', '2308', (122, 127))	('ARMS', 'Phenotype', 'HP:0006779', (49, 53))	('PAX7', 'Gene', (117, 121))	('associated', 'Reg', (101, 111))	('rearrangement', 'Var', (128, 141))	('ARMS', 'Phenotype', 'HP:0006779', (75, 79))
606047	26204834	These are however a genetically homogeneous group of tumours sharing the underlying biallelic inactivation of SMARCB1, which encodes the SMARCB1/hSNF5/BAF47 subunit of the SWI/SNF chromatin remodelling complex.	('SMARCB1', 'Gene', (110, 117))	('hSNF5', 'Gene', (145, 150))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('BAF47', 'Gene', '6598', (151, 156))	('biallelic inactivation', 'Var', (84, 106))	('SMARCB1', 'Gene', '6598', (137, 144))	('BAF47', 'Gene', (151, 156))	('SMARCB1', 'Gene', (137, 144))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('hSNF5', 'Gene', '6598', (145, 150))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('SMARCB1', 'Gene', '6598', (110, 117))
606059	26204834	Differential expression of miR-193-5p was diametrically linked to SMARCB1 mutation, insofar as CES or PES without SMARCB1 inactivation showed high miR-193-5p levels which could provide an alternative mechanism for SMARCB1 inactivation (Table 1).	('miR-1', 'Gene', (27, 32))	('miR-1', 'Gene', (147, 152))	('mutation', 'Var', (74, 82))	('SMARCB1', 'Gene', '6598', (114, 121))	('CES', 'Disease', (95, 98))	('linked', 'Reg', (56, 62))	('miR-1', 'Gene', '83856', (27, 32))	('miR-1', 'Gene', '83856', (147, 152))	('SMARCB1', 'Gene', (114, 121))	('SMARCB1', 'Gene', '6598', (214, 221))	('CES', 'Disease', 'MESH:C535918', (95, 98))	('SMARCB1', 'Gene', (214, 221))	('SMARCB1', 'Gene', (66, 73))	('SMARCB1', 'Gene', '6598', (66, 73))
606062	26204834	In this vein, let-7 over-expression or HMGA2 knock-down both led to suppression of in vitro growth of G401 rhabdoid tumor cells, although the authors admit that HMGA2 is only one potential target of let 7a/7b and the study was focused on this axis only.	('HMGA2', 'Gene', (39, 44))	('HMGA2', 'Gene', '8091', (161, 166))	('over-expression', 'PosReg', (20, 35))	('in vitro growth', 'CPA', (83, 98))	('knock-down', 'Var', (45, 55))	('HMGA2', 'Gene', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('suppression', 'NegReg', (68, 79))	('let-7', 'Gene', (14, 19))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (107, 121))	('HMGA2', 'Gene', '8091', (39, 44))	('rhabdoid tumor', 'Disease', (107, 121))
606076	26204834	In SS cell line HS-SY-II, inhibition of let-7e and miR-99b significantly reduced cell proliferation compared to controls.	('cell proliferation', 'CPA', (81, 99))	('miR-99b', 'Gene', (51, 58))	('miR-99b', 'Gene', '407056', (51, 58))	('inhibition', 'Var', (26, 36))	('reduced', 'NegReg', (73, 80))	('SS', 'Phenotype', 'HP:0012570', (3, 5))	('let-7e', 'Gene', '406887', (40, 46))	('HS-SY-II', 'CellLine', 'CVCL:8719', (16, 24))	('let-7e', 'Gene', (40, 46))	('rat', 'Species', '10116', (93, 96))
606077	26204834	Target prediction algorithms suggest both HMGA2 and SMARCA5 are potential targets of miR-99b and let-7e and indeed, following silencing of miR-99b and let-7e, RT-PCR and Western blotting showed increased expression of both HMGA2 and SMARCA5.	('SMARCA5', 'Gene', (233, 240))	('HMGA2', 'Gene', '8091', (42, 47))	('miR-99b', 'Gene', '407056', (139, 146))	('miR-99b', 'Gene', (85, 92))	('SMARCA5', 'Gene', (52, 59))	('silencing', 'Var', (126, 135))	('HMGA2', 'Gene', '8091', (223, 228))	('increased', 'PosReg', (194, 203))	('let-7e', 'Gene', (97, 103))	('SMARCA5', 'Gene', '8467', (233, 240))	('let-7e', 'Gene', (151, 157))	('let-7e', 'Gene', '406887', (97, 103))	('SMARCA5', 'Gene', '8467', (52, 59))	('miR-99b', 'Gene', (139, 146))	('miR-99b', 'Gene', '407056', (85, 92))	('HMGA2', 'Gene', (42, 47))	('expression', 'MPA', (204, 214))	('let-7e', 'Gene', '406887', (151, 157))	('HMGA2', 'Gene', (223, 228))
606088	26204834	Inhibition of miR-17 was found to restore p21 protein levels and reduce cell growth (Table 1).	('cell growth', 'CPA', (72, 83))	('p21', 'Gene', '1026', (42, 45))	('miR-17', 'Gene', (14, 20))	('p21', 'Gene', (42, 45))	('restore', 'PosReg', (34, 41))	('miR-17', 'Gene', '406952', (14, 20))	('Inhibition', 'Var', (0, 10))	('reduce', 'NegReg', (65, 71))
606092	26204834	Following knockdown of miR-183, PTEN was also found to be up-regulated.	('up-regulated', 'PosReg', (58, 70))	('PTEN', 'Gene', (32, 36))	('miR-183', 'Gene', '406959', (23, 30))	('PTEN', 'Gene', '5728', (32, 36))	('miR-183', 'Gene', (23, 30))	('knockdown', 'Var', (10, 19))
606093	26204834	Global transcriptome analysis revealed that knockdown of miR-183 was able to modulate the transcriptional profiles of tumour cell lines in vitro.	('tumour', 'Disease', (118, 124))	('miR-183', 'Gene', '406959', (57, 64))	('miR-183', 'Gene', (57, 64))	('modulate', 'Reg', (77, 85))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('knockdown', 'Var', (44, 53))	('transcriptional profiles', 'MPA', (90, 114))	('tumour', 'Disease', 'MESH:D009369', (118, 124))
606095	26204834	Inhibition of miR-183 was found to decrease cell migration and EGR1 knockdown could functionally restore the anti-miR-183 migration phenotype (Table 1).	('EGR1', 'Gene', (63, 67))	('rat', 'Species', '10116', (52, 55))	('rat', 'Species', '10116', (125, 128))	('miR-183', 'Gene', '406959', (114, 121))	('miR-183', 'Gene', (114, 121))	('EGR1', 'Gene', '1958', (63, 67))	('decrease', 'NegReg', (35, 43))	('knockdown', 'Var', (68, 77))	('Inhibition', 'Var', (0, 10))	('miR-183', 'Gene', (14, 21))	('restore', 'PosReg', (97, 104))	('cell migration', 'CPA', (44, 58))	('miR-183', 'Gene', '406959', (14, 21))
606096	26204834	In conclusion, our understanding of the non-coding genome has been increasing rapidly in the past two decades, during which time miRNAs have enjoyed the greatest attention, revealing their importance in developmental processes but also the significance of their dysregulation in cancer development and progression.	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('dysregulation', 'Var', (262, 275))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))
606136	24831295	All new sequences are deposited in GenBank under accession numbers: JX290272 (O350805), JX290273 (Mezi5), JX290274 (AKO107), JX290275 (Lobak80), JX290276 (Mezi1), JX290277 (Ako381), JX290278 (BAD54), JX290279 (BAD84), JX290280 (BAD230), JX290281 (BAD337), JX290282 (CHAS59), JX290283 (CHAS80), JX290284 (Lobak42), JX290285 (lozi5), JX290286 (Lozi6), JX290287 (MEBAK55), JX290288 (MEZI8), JX290289 (MEZI11), JX290290 (O290107), JX290291 (AKO205), JX290292 (O300153), JX290293 (O300186), JX290294 (O300189), JX290295 (O300137), JX290296 (O300227), JX290297 (O300237), JX290298 (O300265), JX290299 (O300275), JX290300 (O323101).	('JX290293', 'CellLine', 'CVCL:M085', (466, 474))	('O300265', 'Var', (576, 583))	('O300275', 'Var', (596, 603))	('JX290299', 'CellLine', 'CVCL:M085', (586, 594))
606189	23410975	In the last decade, recognition of the characteristic t(12;22) (q13;q12) chromosomal translocation and its resultant fusion oncogene EWSR1-ATF1 (EWS-ATF1) has provided a means of defining CCS and distinguishing it from melanoma.	('EWSR1-ATF1', 'Gene', (133, 143))	('CCS', 'Disease', (188, 191))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('t(12;22) (q13', 'Var', (54, 67))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('EWSR1-ATF1', 'Gene', '14030;11908', (133, 143))	('melanoma', 'Disease', (219, 227))
606194	23410975	A small minority of CCS cases harbor a t(2;22) (q32;q12) translocation and the alternate CREB1 fusion partner replacing ATF1, with which CREB1 shares binding of an identical consensus sequence.	('t(2;22) (q32;q12', 'Var', (39, 55))	('CREB1', 'Gene', '12912', (137, 142))	('CREB1', 'Gene', '12912', (89, 94))	('CCS', 'Disease', (20, 23))	('ATF1', 'Gene', '11908', (120, 124))	('ATF1', 'Gene', (120, 124))	('CREB1', 'Gene', (89, 94))	('CREB1', 'Gene', (137, 142))
606196	23410975	The expression of melanocyte-specific markers in CCS tumors has been variably attributed to the effects of the cell of origin or the effects of aberrant M-Mitf expression, shown to be driven by EWS-ATF1 in CCS cell lines.	('CCS tumors', 'Disease', (49, 59))	('aberrant', 'Var', (144, 152))	('expression', 'MPA', (4, 14))	('CCS tumors', 'Disease', 'MESH:D009369', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('M-Mitf', 'Gene', (153, 159))
606249	23410975	As late as E14.5 Prx1-Cre;Rosa26EA1 mouse embryos remained viable, but demonstrated severe limb deformities (Figure 5A).	('limb deformities', 'Disease', (91, 107))	('limb deformities', 'Phenotype', 'HP:0002813', (91, 107))	('limb deformities', 'Disease', 'MESH:D017880', (91, 107))	('severe limb deformities', 'Phenotype', 'HP:0200083', (84, 107))	('E14.5', 'Var', (11, 16))	('mouse', 'Species', '10090', (36, 41))
606252	23410975	Mice bearing the Rosa26EA1 allele and Myf5-Cre, which activated the fusion gene expression in myoblasts, did not form tumors but demonstrated another phenotype in which EWS-ATF1 was also apparently toxic to cells.	('activated', 'PosReg', (54, 63))	('EWS-ATF1', 'Var', (169, 177))	('Myf5', 'Gene', '17877', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Myf5', 'Gene', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
606256	23410975	In order to test this hypothesis, we bred mice bearing the Rosa26EA1 allele to mice bearing either Pax7CreERT2 or Prx1-CreERT2, then administered tamoxifen after three weeks of age.	('mice', 'Species', '10090', (42, 46))	('mice', 'Species', '10090', (79, 83))	('Pax7', 'Gene', '18509', (99, 103))	('tamoxifen', 'Chemical', 'MESH:D013629', (146, 155))	('Rosa26EA1', 'Var', (59, 68))	('Pax7', 'Gene', (99, 103))
606265	23410975	Notably, some tumors induced by Prx1-CreERT2 expressed M-MITF but others did not (Figure 5D).	('Prx1-CreERT2', 'Var', (32, 44))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('M-MITF', 'Protein', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
606272	23410975	The Bmi1-lineage tumors consistently matched the clear cell morphology and immunohistochemical profile of human CCS tumors, uniformly demonstrating M-MITF and S100B (Figure 6B and C).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('human', 'Species', '9606', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('M-MITF', 'Var', (148, 154))	('CCS tumors', 'Disease', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('demonstrating', 'Reg', (134, 147))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('S100B', 'Var', (159, 164))	('CCS tumors', 'Disease', 'MESH:D009369', (112, 122))
606273	23410975	Prior reports have suggested a role for Bmi1 in mesenchymal stem cells based on depletion of the pool of osteochondroprogenitors in mice bearing homozygous disruption of Bmi1.	('disruption', 'Var', (156, 166))	('mesenchymal stem cells', 'CPA', (48, 70))	('mice', 'Species', '10090', (132, 136))	('Bmi1', 'Gene', (170, 174))	('Bmi1', 'Gene', (40, 44))	('depletion of the pool of osteochondroprogenitors', 'MPA', (80, 128))
606274	23410975	To follow up these studies and more fully characterize the Bmi1 lineage in mesenchyme, mice bearing Bmi1CreERT2 were crossed to a robust reporter mouse expressing tdTomato conditionally from the Rosa26 locus.	('Rosa26', 'Gene', '14910', (195, 201))	('mice', 'Species', '10090', (87, 91))	('Bmi1CreERT2', 'Var', (100, 111))	('mouse', 'Species', '10090', (146, 151))	('Rosa26', 'Gene', (195, 201))	('Tomato', 'Species', '4081', (165, 171))
606328	23410975	The epigenetic state may render the melanocytic markers unavailable for upregulation by ATF constitutive activation alone (Figure 8B).	('ATF', 'Gene', (88, 91))	('epigenetic', 'Var', (4, 14))	('ATF', 'Gene', '14573', (88, 91))
606357	23410975	A range of mouse cells tolerates EWS-ATF1 expression and subsequently yields tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mouse', 'Species', '10090', (11, 16))	('EWS-ATF1', 'Gene', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('expression', 'Var', (42, 52))	('yields', 'Reg', (70, 76))
606362	23410975	While a number of cell types can be rendered tumorigenic via expression of the fusion oncogene, the undifferentiated cells appear to enable the full melanoma-related phenotype.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('tumor', 'Disease', (45, 50))	('expression', 'Var', (61, 71))	('enable', 'PosReg', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
606464	22529843	In this context the cell autonomous G1 arrest phenotype is augmented by inhibition of IL-2, which is a paracrine and autocrine growth factor for T cells.	('men', 'Species', '9606', (62, 65))	('augmented', 'PosReg', (59, 68))	('IL-2', 'Gene', '3558', (86, 90))	('arrest', 'Disease', 'MESH:D006323', (39, 45))	('IL-2', 'Gene', (86, 90))	('inhibition', 'Var', (72, 82))	('arrest', 'Disease', (39, 45))
606471	22529843	KS lesions almost universally exhibit phosphorylated Akt, which activates mTOR kinase and phosphorylated S6, which is a biomarker for mTOR kinase activity (Roy and Dittmer,).	('lesions', 'Var', (3, 10))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('exhibit', 'Reg', (30, 37))	('activates', 'PosReg', (64, 73))	('mTOR', 'Gene', (134, 138))	('mTOR', 'Gene', '2475', (134, 138))
606476	22529843	Rapamycin blocks focus formation induced by oncogenic alleles of the upstream mTOR regulators, PI3K, or Akt (Aoki et al.,).	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('Akt', 'Pathway', (104, 107))	('PI3K', 'Gene', (95, 99))	('blocks', 'NegReg', (10, 16))	('mTOR', 'Gene', (78, 82))	('mTOR', 'Gene', '2475', (78, 82))	('alleles', 'Var', (54, 61))	('focus formation', 'CPA', (17, 32))
606490	22529843	These variants also carry the KSHV genome and express at least the KSHV latent genes (Nador et al.,; Said et al.,; Engels et al.,; Chadburn et al.,; Carbone et al.,; Deloose et al.,).	('KSHV', 'Species', '37296', (30, 34))	('KSHV', 'Species', '37296', (67, 71))	('KSHV latent genes', 'Gene', (67, 84))	('variants', 'Var', (6, 14))
606495	22529843	P53 mutations accumulate after chemotherapy (Petre et al.,; Chen et al.,).	('mutations', 'Var', (4, 13))	('P53', 'Gene', (0, 3))	('accumulate', 'PosReg', (14, 24))	('P53', 'Gene', '7157', (0, 3))
606499	22529843	Rapamycin (Sirolimus ) inhibits mTOR signaling, rituximab (Rituxan ) is a humanized monoclonal antibody against CD20, and bleomycin induces DNA breaks and eventually apoptosis in rapidly growing cells.	('CD20', 'Gene', (112, 116))	('Rituxan', 'Chemical', 'MESH:D000069283', (59, 66))	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('DNA breaks', 'MPA', (140, 150))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (32, 36))	('rituximab', 'Chemical', 'MESH:D000069283', (48, 57))	('Sirolimus', 'Chemical', 'MESH:D020123', (11, 20))	('induces', 'Reg', (132, 139))	('CD20', 'Gene', '54474', (112, 116))	('human', 'Species', '9606', (74, 79))	('inhibits', 'NegReg', (23, 31))	('bleomycin', 'Var', (122, 131))	('bleomycin', 'Chemical', 'MESH:D001761', (122, 131))	('apoptosis', 'CPA', (166, 175))
606563	21116412	Dose limiting toxicities according to the manufacturer's SPC: ANC < 500/muL for more than five days or neutropenia associated with fever/infection; thrombocytopenia < 25.000/muL; bilirubin > ULN; AP > 2.5x ULN; AST/ALT > 2.5x ULN.	('toxicities', 'Disease', (14, 24))	('neutropenia', 'Disease', 'MESH:D009503', (103, 114))	('bilirubin', 'MPA', (179, 188))	('neutropenia', 'Phenotype', 'HP:0001875', (103, 114))	('muL', 'Gene', '4591', (174, 177))	('fever/infection', 'Disease', 'MESH:D005334', (131, 146))	('muL', 'Gene', '4591', (72, 75))	('thrombocytopenia', 'Disease', (148, 164))	('bilirubin', 'Chemical', 'MESH:D001663', (179, 188))	('AST', 'Gene', '26503', (211, 214))	('ALT > 2', 'Gene', (215, 222))	('ALT > 2', 'Gene', '84706', (215, 222))	('ANC', 'MPA', (62, 65))	('fever/infection', 'Disease', (131, 146))	('fever', 'Phenotype', 'HP:0001945', (131, 136))	('thrombocytopenia', 'Disease', 'MESH:D013921', (148, 164))	('neutropenia', 'Disease', (103, 114))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (148, 164))	('muL', 'Gene', (174, 177))	('AST', 'Gene', (211, 214))	('toxicities', 'Disease', 'MESH:D064420', (14, 24))	('AP > 2.5x ULN', 'Var', (196, 209))	('muL', 'Gene', (72, 75))
606616	21116412	Furthermore, this might explain its particular activity in myxoid liposarcoma (MLS) characterized by the translocations t(12;16)(q13;p11) or t(12;22)(q13;q12) resulting in the formation of FUS-CHOP and EWS-CHOP fusion proteins, respectively.	('t(12;22)(q13;q12', 'Var', (141, 157))	('myxoid liposarcoma', 'Disease', (59, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('MLS', 'Disease', 'MESH:C537466', (79, 82))	('FUS-CHOP', 'Protein', (189, 197))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (59, 77))	('EWS-CHOP fusion proteins', 'Protein', (202, 226))	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (120, 137))	('MLS', 'Disease', (79, 82))	('liposarcoma', 'Phenotype', 'HP:0012034', (66, 77))	('MLS', 'Phenotype', 'HP:0012268', (79, 82))	('t(12;16)(q13;p11', 'Var', (120, 136))	('activity', 'MPA', (47, 55))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (59, 77))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (141, 158))
606628	21116412	However, progression-free survival and overall survival were significantly prolonged in responders and seem not to be inferior to other clinically used second-line treatments for the whole patient population.	('prolonged', 'PosReg', (75, 84))	('responders', 'Var', (88, 98))	('patient', 'Species', '9606', (189, 196))	('progression-free survival', 'CPA', (9, 34))	('overall survival', 'CPA', (39, 55))
606637	31766329	For subjects with short variant alterations and detectable tumor fractions, concordance with solid tumor CGP was 76% (13/17).	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (59, 64))	('tumor fraction', 'Disease', (59, 73))	('alterations', 'Var', (32, 43))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor fraction', 'Disease', 'MESH:D009369', (59, 73))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
606671	31766329	Mutations in NF1 and TP53 were the most concordant (NF1 = 3/3, TP53 = 6/11).	('NF1', 'Gene', (52, 55))	('TP53', 'Gene', (21, 25))	('TP53', 'Gene', '7157', (63, 67))	('NF1', 'Gene', '4763', (52, 55))	('TP53', 'Gene', (63, 67))	('NF1', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', '4763', (13, 16))	('TP53', 'Gene', '7157', (21, 25))
606673	31766329	Contrarily, mutations in CDKN2A, gene amplification, and losses were poorly recognized in F1ACT profiling (CDKN2A = 0/2, CDK4/MDM2 amplification = 2/12, loss = 0/4) (Figure 4).	('CDKN2A', 'Gene', '1029', (107, 113))	('CDK4', 'Gene', '1019', (121, 125))	('CDKN2A', 'Gene', '1029', (25, 31))	('mutations', 'Var', (12, 21))	('MDM2', 'Gene', '4193', (126, 130))	('MDM2', 'Gene', (126, 130))	('CDKN2A', 'Gene', (25, 31))	('CDKN2A', 'Gene', (107, 113))	('CDK4', 'Gene', (121, 125))
606690	31766329	The presence of germline mutations in ctDNA can significantly skew the estimated TF generated from the software.	('germline mutations', 'Var', (16, 34))	('skew', 'Reg', (62, 66))	('TF', 'Disease', 'MESH:D009369', (81, 83))	('ctDNA', 'Gene', (38, 43))	('presence', 'Var', (4, 12))
606731	29763379	Disruption of any of the links in this loop can lead to thyroid dysfunction .	('lead to', 'Reg', (48, 55))	('thyroid dysfunction', 'Disease', 'MESH:D013959', (56, 75))	('thyroid dysfunction', 'Disease', (56, 75))	('Disruption', 'Var', (0, 10))
606809	29763379	The linear component of the radiation dose-response relation for the pituitary, but not the thyroid, was significantly increased among persons treated with CCNU.	('CCNU', 'Var', (156, 160))	('CCNU', 'Chemical', 'MESH:D008130', (156, 160))	('linear component', 'MPA', (4, 20))	('persons', 'Species', '9606', (135, 142))	('increased', 'PosReg', (119, 128))
606832	29763379	Doses >= 30 Gy were associated with deficiencies of TSH and ACTH; doses of 22-< 30 Gy were associated with a deficiency of GH; and doses > 22 Gy were associated with deficiencies of LH and FSH.	('Doses', 'Var', (0, 5))	('deficiencies', 'MPA', (166, 178))	('deficiency of GH', 'Disease', 'MESH:D004393', (109, 125))	('ACTH', 'Gene', (60, 64))	('deficiencies of TSH', 'Disease', (36, 55))	('deficiencies of TSH', 'Disease', 'MESH:D007037', (36, 55))	('deficiency of GH', 'Disease', (109, 125))	('ACTH', 'Gene', '5443', (60, 64))	('FSH', 'CPA', (189, 192))
606888	29763379	This suggests that under-reporting or under-diagnosis of hypothyroidism may be a more important source of outcome misclassification than over-reporting of hypothyroidism.	('hypothyroidism', 'Phenotype', 'HP:0000821', (155, 169))	('hypothyroidism', 'Disease', (155, 169))	('hypothyroidism', 'Disease', 'MESH:D007037', (57, 71))	('under-diagnosis', 'Var', (38, 53))	('hypothyroidism', 'Phenotype', 'HP:0000821', (57, 71))	('hypothyroidism', 'Disease', (57, 71))	('hypothyroidism', 'Disease', 'MESH:D007037', (155, 169))
606907	28671673	EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential.	('EWS', 'Gene', (138, 141))	('Ewing sarcoma', 'Disease', (109, 122))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))	('TEAD', 'DomainMotif', 'Focus:9606|7003;8463;7005;7004', (30, 34))	('MRTFB', 'Gene', (18, 23))	('YAP-1', 'Gene', '10413', (24, 29))	('Ewing sarcoma', 'Disease', (123, 136))	('EWS', 'Gene', '2130', (0, 3))	('inhibiting', 'NegReg', (58, 68))	('bone cancer', 'Disease', 'MESH:D001859', (159, 170))	('bone cancer', 'Disease', (159, 170))	('EWS', 'Gene', (0, 3))	('EWS', 'Gene', '2130', (138, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('YAP-1', 'Gene', (24, 29))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('perturbs', 'Var', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('EWS-FLI1', 'Gene', (0, 8))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (123, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('MRTFB', 'Gene', '57496', (18, 23))
606918	28671673	EwS is characterized by the expression of an oncogenic E-twenty-six transformation specific (ETS) fusion product, most frequently EwS-FLI1, which drives proliferation and represses differentiation via global genetic and epigenetic deregulation.	('FLI1', 'Gene', (134, 138))	('differentiation', 'CPA', (181, 196))	('EwS', 'Gene', (130, 133))	('EwS', 'Gene', (0, 3))	('EwS', 'Phenotype', 'HP:0012254', (0, 3))	('EwS', 'Gene', '2130', (0, 3))	('epigenetic deregulation', 'Var', (220, 243))	('proliferation', 'CPA', (153, 166))	('EwS', 'Phenotype', 'HP:0012254', (130, 133))	('drives', 'PosReg', (146, 152))	('ETS', 'Chemical', '-', (93, 96))	('EwS', 'Gene', '2130', (130, 133))	('FLI1', 'Gene', '2313', (134, 138))	('represses', 'NegReg', (171, 180))
606930	28671673	To validate suppression of a Rho signature in EwS, we interrogated expression of a manually curated set of 14 well-characterized Rho/SRF/MRTF target genes in five EwS cell lines (WE68, TC252, SK-N-MC, STA-ET-7.2 and STA-ET-1) from previously published expression data (GSE14543) with a transient EWS-FLI1 knockdown (Figure 1b).	('SK-N-MC', 'CellLine', 'CVCL:0530', (192, 199))	('EWS-FLI1', 'Gene', '2130;2313', (296, 304))	('EwS', 'Phenotype', 'HP:0012254', (46, 49))	('EwS', 'Phenotype', 'HP:0012254', (163, 166))	('EwS', 'Gene', '2130', (163, 166))	('TC252', 'CellLine', 'CVCL:S866', (185, 190))	('EwS', 'Gene', '2130', (46, 49))	('EwS', 'Gene', (163, 166))	('knockdown', 'Var', (305, 314))	('EwS', 'Gene', (46, 49))	('EWS-FLI1', 'Gene', (296, 304))
606937	28671673	To this end, gene expression analysis was performed upon modulation of MRTFA/B under EWS-FLI1-high and -low conditions.	('MRTFA', 'Gene', (71, 76))	('modulation', 'Var', (57, 67))	('EWS-FLI1', 'Gene', (85, 93))	('EWS-FLI1', 'Gene', '2130;2313', (85, 93))	('MRTFA', 'Gene', '57591', (71, 76))
606938	28671673	Effective reduction of MRTFA and MRTFB protein was achieved using a double-targeting short hairpin RNA vector, which was combined with doxycycline (dox) treatment to induce the knockdown of EWS-FLI1 (Figure 2a and Supplementary Figure S2A).	('MRTFA', 'Gene', (23, 28))	('EWS-FLI1', 'Gene', (190, 198))	('dox', 'Chemical', 'MESH:D004318', (148, 151))	('EWS-FLI1', 'Gene', '2130;2313', (190, 198))	('dox', 'Chemical', 'MESH:D004318', (135, 138))	('doxycycline', 'Chemical', 'MESH:D004318', (135, 146))	('MRTFB', 'Gene', '57496', (33, 38))	('knockdown', 'Var', (177, 186))	('MRTFA', 'Gene', '57591', (23, 28))	('MRTFB', 'Gene', (33, 38))	('reduction', 'NegReg', (10, 19))
606941	28671673	Differential gene expression analysis revealed that gene sets affected by EWS-FLI1 knockdown and those affected by MRTFA/B knockdown did not correlate (Figure 2c).	('EWS-FLI1', 'Gene', (74, 82))	('MRTFA', 'Gene', '57591', (115, 120))	('EWS-FLI1', 'Gene', '2130;2313', (74, 82))	('MRTFA', 'Gene', (115, 120))	('knockdown', 'Var', (83, 92))
606942	28671673	We then studied the effect of combined EWS-FLI1 and MRTFA/B knockdown on gene expression.	('MRTFA', 'Gene', '57591', (52, 57))	('EWS-FLI1', 'Gene', (39, 47))	('EWS-FLI1', 'Gene', '2130;2313', (39, 47))	('MRTFA', 'Gene', (52, 57))	('knockdown', 'Var', (60, 69))
606944	28671673	Figure 2c shows that genome-wide gene expression changes upon MRTFA/B depletion antagonized the effects of EWS-FLI1 depletion upon combined knockdown (Figure 2c).	('MRTFA', 'Gene', '57591', (62, 67))	('EWS-FLI1', 'Gene', '2130;2313', (107, 115))	('antagonized', 'NegReg', (80, 91))	('MRTFA', 'Gene', (62, 67))	('changes', 'Reg', (49, 56))	('depletion', 'Var', (70, 79))	('EWS-FLI1', 'Gene', (107, 115))
606945	28671673	The impact of MRTFA/B knockdown on the EWS-FLI1 regulated transcriptome, and therefore the strength of the inverse correlation was similar under serum-starved (Supplementary Figure S2C) and serum-induced conditions (Figure 2c).	('MRTFA', 'Gene', '57591', (14, 19))	('EWS-FLI1', 'Gene', (39, 47))	('transcriptome', 'MPA', (58, 71))	('MRTFA', 'Gene', (14, 19))	('EWS-FLI1', 'Gene', '2130;2313', (39, 47))	('knockdown', 'Var', (22, 31))
606950	28671673	At a cutoff of  logFC >1, P<0.05 for the EWS-FLI1 knockdown and  logFC >0.7, P<0.05 for the combined MRTFA/B-EWS-FLI1 knockdown, 390 genes were activated by EWS-FLI1 and are further referred to as EWS-FLI1-correlated target genes (Figure 2d).	('EWS-FLI1', 'Gene', (197, 205))	('genes', 'Gene', (133, 138))	('EWS-FLI1', 'Gene', (109, 117))	('knockdown', 'Var', (118, 127))	('knockdown', 'Var', (50, 59))	('MRTFA', 'Gene', '57591', (101, 106))	('EWS-FLI1', 'Gene', '2130;2313', (197, 205))	('EWS-FLI1', 'Gene', '2130;2313', (109, 117))	('activated', 'PosReg', (144, 153))	('EWS-FLI1', 'Gene', (157, 165))	('MRTFA', 'Gene', (101, 106))	('EWS-FLI1', 'Gene', (41, 49))	('EWS-FLI1', 'Gene', '2130;2313', (157, 165))	('EWS-FLI1', 'Gene', '2130;2313', (41, 49))
606951	28671673	For 87 of these genes, MRTFA/B knockdown rescued the decline in expression upon EWS-FLI1 depletion.	('MRTFA', 'Gene', (23, 28))	('EWS-FLI1', 'Gene', (80, 88))	('expression', 'MPA', (64, 74))	('EWS-FLI1', 'Gene', '2130;2313', (80, 88))	('MRTFA', 'Gene', '57591', (23, 28))	('knockdown', 'Var', (31, 40))
606952	28671673	On the other hand, EWS-FLI1 repressed the expression of 1076 genes in A673/TR/shEF, further referred to as EWS-FLI1-anticorrelated genes, and MRTFA/B knockdown antagonized this effect for 166 of these genes.	('EWS-FLI1', 'Gene', '2130;2313', (107, 115))	('EWS-FLI1', 'Gene', (19, 27))	('MRTFA', 'Gene', '57591', (142, 147))	('EWS-FLI1', 'Gene', '2130;2313', (19, 27))	('knockdown', 'Var', (150, 159))	('MRTFA', 'Gene', (142, 147))	('antagonized', 'NegReg', (160, 171))	('A673/TR/shEF', 'Var', (70, 82))	('EWS-FLI1', 'Gene', (107, 115))
606955	28671673	Clusters 1 and 2 represent EWS-FLI1-anticorrelated gene sets, whose activation upon EWS-FLI1 depletion was counteracted by MRTFA/B knockdown.	('EWS-FLI1', 'Gene', (84, 92))	('MRTFA', 'Gene', '57591', (123, 128))	('MRTFA', 'Gene', (123, 128))	('EWS-FLI1', 'Gene', '2130;2313', (84, 92))	('activation', 'PosReg', (68, 78))	('EWS-FLI1', 'Gene', (27, 35))	('EWS-FLI1', 'Gene', '2130;2313', (27, 35))	('depletion', 'Var', (93, 102))
606956	28671673	Cluster 3 represents genes activated in response to MRTFA/B knockdown in presence of high EWS-FLI1, but even stronger under EWS-FLI1-low conditions.	('EWS-FLI1', 'Gene', '2130;2313', (90, 98))	('EWS-FLI1', 'Gene', '2130;2313', (124, 132))	('MRTFA', 'Gene', '57591', (52, 57))	('EWS-FLI1-low', 'Gene', (124, 136))	('activated', 'PosReg', (27, 36))	('MRTFA', 'Gene', (52, 57))	('EWS-FLI1-low', 'Gene', '2130', (124, 136))	('knockdown', 'Var', (60, 69))	('EWS-FLI1', 'Gene', (124, 132))	('EWS-FLI1', 'Gene', (90, 98))
606957	28671673	Cluster 4 contains EWS-FLI1-correlated target genes that show increased expression after the MRTFA/B knockdown under EWS-FLI1-low but not -high conditions.	('increased', 'PosReg', (62, 71))	('EWS-FLI1', 'Gene', '2130;2313', (117, 125))	('MRTFA', 'Gene', '57591', (93, 98))	('EWS-FLI1', 'Gene', (19, 27))	('EWS-FLI1', 'Gene', '2130;2313', (19, 27))	('EWS-FLI1-low', 'Gene', (117, 129))	('expression', 'MPA', (72, 82))	('EWS-FLI1-low', 'Gene', '2130', (117, 129))	('MRTFA', 'Gene', (93, 98))	('EWS-FLI1', 'Gene', (117, 125))	('knockdown', 'Var', (101, 110))
606958	28671673	In contrast, cluster 5 comprises EWS-FLI1-correlated genes strongly affected by MRTFA/B knockdown primarily under EWS-FLI1-high conditions.	('EWS-FLI1', 'Gene', '2130;2313', (114, 122))	('affected', 'Reg', (68, 76))	('EWS-FLI1', 'Gene', (33, 41))	('MRTFA', 'Gene', '57591', (80, 85))	('knockdown', 'Var', (88, 97))	('EWS-FLI1', 'Gene', '2130;2313', (33, 41))	('MRTFA', 'Gene', (80, 85))	('EWS-FLI1', 'Gene', (114, 122))
606963	28671673	Knockdown of MRTFA or MRTFB upon EWS-FLI1-high resulted in a weak positive correlation with the gene expression effects of EWS-FLI1 knockdown (Supplementary Figure S2G).	('gene expression effects', 'MPA', (96, 119))	('Knockdown', 'Var', (0, 9))	('MRTFA', 'Gene', (13, 18))	('EWS-FLI1', 'Gene', (33, 41))	('EWS-FLI1', 'Gene', (123, 131))	('MRTFB', 'Gene', '57496', (22, 27))	('EWS-FLI1', 'Gene', '2130;2313', (33, 41))	('MRTFB', 'Gene', (22, 27))	('EWS-FLI1', 'Gene', '2130;2313', (123, 131))	('MRTFA', 'Gene', '57591', (13, 18))
606964	28671673	The results for the individual MRTFs are consistent with the results obtained with sh-MRTFA/B; however, MRTFB can be inferred as the main driver of the transcriptional rescue from the EWS-FLI1 knockdown.	('EWS-FLI1', 'Gene', (184, 192))	('MRTFB', 'Gene', '57496', (104, 109))	('MRTFA', 'Gene', '57591', (86, 91))	('EWS-FLI1', 'Gene', '2130;2313', (184, 192))	('MRTFB', 'Gene', (104, 109))	('knockdown', 'Var', (193, 202))	('MRTFA', 'Gene', (86, 91))
606979	28671673	RNA expression data from EWS-FLI1 knockdown experiments were integrated with MRTFB ChIP-seq data.	('EWS-FLI1', 'Gene', (25, 33))	('MRTFB', 'Gene', '57496', (77, 82))	('knockdown', 'Var', (34, 43))	('MRTFB', 'Gene', (77, 82))	('EWS-FLI1', 'Gene', '2130;2313', (25, 33))
606996	28671673	To elucidate the role of TEADs in MRTFB-mediated transcriptional regulation in EwS cells, we analysed the expression signature of combinatorial knockdown of all four TEAD transcription factors (TEAD1-4) upon EWS-FLI1-high and -low conditions.	('EwS', 'Gene', '2130', (79, 82))	('TEAD1-4', 'Gene', (194, 201))	('TEAD', 'DomainMotif', 'Focus:9606|7003;8463;7005;7004', (25, 29))	('EWS-FLI1', 'Gene', (208, 216))	('MRTFB-', 'Gene', '57496', (34, 40))	('MRTFB-', 'Gene', (34, 40))	('EWS-FLI1', 'Gene', '2130;2313', (208, 216))	('EwS', 'Gene', (79, 82))	('TEAD', 'DomainMotif', 'Focus:9606|7003;8463;7005;7004', (166, 170))	('knockdown', 'Var', (144, 153))	('TEAD', 'DomainMotif', 'Focus:9606|7003;8463;7005;7004', (194, 198))	('TEAD1-4', 'Gene', '7003;8463;7005;7004', (194, 201))	('EwS', 'Phenotype', 'HP:0012254', (79, 82))
606998	28671673	Strikingly, similar to MRTFA/B knockdown, silencing of TEAD1-4 antagonized EWS-FLI1 modulation-mediated transcriptional effects.	('MRTFA', 'Gene', (23, 28))	('silencing', 'Var', (42, 51))	('antagonized', 'NegReg', (63, 74))	('EWS-FLI1', 'Gene', (75, 83))	('MRTFA', 'Gene', '57591', (23, 28))	('TEAD1-4', 'Gene', '7003;8463;7005;7004', (55, 62))	('EWS-FLI1', 'Gene', '2130;2313', (75, 83))	('TEAD1-4', 'Gene', (55, 62))
606999	28671673	In addition, unlike MRTFA/B knockdown, depletion of TEAD1-4 in presence of EWS-FLI1 also resulted in gene expression changes in the opposite direction as caused by EWS-FLI1 knockdown, although to a lesser extent than observed under EWS-FLI1-low conditions (R=-0.29 versusR=-0.57; Figure 5b).	('EWS-FLI1', 'Gene', '2130;2313', (164, 172))	('MRTFA', 'Gene', (20, 25))	('knockdown', 'Var', (173, 182))	('EWS-FLI1', 'Gene', (232, 240))	('depletion', 'MPA', (39, 48))	('TEAD1-4', 'Gene', '7003;8463;7005;7004', (52, 59))	('EWS-FLI1', 'Gene', (75, 83))	('EWS-FLI1', 'Gene', '2130;2313', (232, 240))	('EWS-FLI1', 'Gene', '2130;2313', (75, 83))	('EWS-FLI1', 'Gene', (164, 172))	('changes', 'Reg', (117, 124))	('TEAD1-4', 'Gene', (52, 59))	('EWS-FLI1-low', 'Gene', '2130', (232, 244))	('MRTFA', 'Gene', '57591', (20, 25))	('EWS-FLI1-low', 'Gene', (232, 244))	('gene expression', 'MPA', (101, 116))
607008	28671673	EWS-FLI1 ChIP showed enrichments in all tested regions with decreased occupancy upon knockdown of EWS-FLI1 for most of them (Figure 5e).	('decreased', 'NegReg', (60, 69))	('EWS-FLI1', 'Gene', (98, 106))	('EWS-FLI1', 'Gene', (0, 8))	('occupancy', 'MPA', (70, 79))	('knockdown', 'Var', (85, 94))	('EWS-FLI1', 'Gene', '2130;2313', (98, 106))	('EWS-FLI1', 'Gene', '2130;2313', (0, 8))
607015	28671673	Several studies proposed that high EWS-FLI1 suppresses migration and adhesion by disrupting EwS cell morphology.	('EwS', 'Gene', (92, 95))	('disrupting', 'NegReg', (81, 91))	('adhesion', 'CPA', (69, 77))	('suppresses', 'NegReg', (44, 54))	('high', 'Var', (30, 34))	('EwS', 'Phenotype', 'HP:0012254', (92, 95))	('EwS', 'Gene', '2130', (92, 95))	('EWS-FLI1', 'Gene', (35, 43))	('EWS-FLI1', 'Gene', '2130;2313', (35, 43))
607026	28671673	As YAP-1 and TEAD chromatin occupancy did not significantly increase upon EWS-FLI1 knockdown, the fusion oncogene is unlikely to compete with YAP-1 or TEAD DNA binding.	('TEAD', 'DomainMotif', 'Focus:9606|7003;8463;7005;7004', (151, 155))	('EWS-FLI1', 'Gene', (74, 82))	('YAP-1', 'Gene', '10413', (3, 8))	('TEAD chromatin occupancy', 'Disease', 'MESH:D009784', (13, 37))	('YAP-1', 'Gene', '10413', (142, 147))	('EWS-FLI1', 'Gene', '2130;2313', (74, 82))	('YAP-1', 'Gene', (3, 8))	('YAP-1', 'Gene', (142, 147))	('knockdown', 'Var', (83, 92))	('TEAD', 'DomainMotif', 'Focus:9606|7003;8463;7005;7004', (13, 17))	('TEAD chromatin occupancy', 'Disease', (13, 37))
607042	28671673	Notably, we found co-enrichment of AP-1 motifs with TEAD motifs in MRTFB-enriched sites of EWS-FLI1-anticorrelated genes and AP-1 has previously been demonstrated to bind to EWS-FLI1 at genomic regions equipped with AP-1-binding motifs.	('AP-1', 'Gene', (35, 39))	('MRTFB-', 'Gene', (67, 73))	('bind', 'Interaction', (166, 170))	('EWS-FLI1', 'Gene', (91, 99))	('TEAD', 'DomainMotif', 'Focus:9606|7003;8463;7005;7004', (52, 56))	('AP-1', 'Gene', '3725', (216, 220))	('AP-1', 'Gene', (216, 220))	('EWS-FLI1', 'Gene', (174, 182))	('EWS-FLI1', 'Gene', '2130;2313', (91, 99))	('MRTFB-', 'Gene', '57496', (67, 73))	('motifs', 'Var', (40, 46))	('EWS-FLI1', 'Gene', '2130;2313', (174, 182))	('AP-1', 'Gene', '3725', (125, 129))	('AP-1', 'Gene', (125, 129))	('AP-1', 'Gene', '3725', (35, 39))
607063	28671673	To simultaneously knockdown MRTFA and MRTFB, the pLKO sh-MKL-1/2 plasmid (Addgene, Cambridge, MA, USA) was transiently transfected into cells.	('knockdown', 'Var', (18, 27))	('MRTFA', 'Gene', '57591', (28, 33))	('MRTFB', 'Gene', (38, 43))	('MKL-1', 'Gene', '57591', (57, 62))	('MRTFA', 'Gene', (28, 33))	('MRTFB', 'Gene', '57496', (38, 43))	('MKL-1', 'Gene', (57, 62))
607064	28671673	For combined knockdown of EwS-FLI1, dox was added 48 h prior to harvest.	('FLI1', 'Gene', '2313', (30, 34))	('dox', 'Chemical', 'MESH:D004318', (36, 39))	('EwS', 'Phenotype', 'HP:0012254', (26, 29))	('EwS', 'Gene', '2130', (26, 29))	('knockdown', 'Var', (13, 22))	('EwS', 'Gene', (26, 29))	('FLI1', 'Gene', (30, 34))
607287	31157317	Ewing sarcoma is associated with a specific cytogenetic translocation t(11;22)(q24;q12) and is generally uncommon in black African children and almost exclusively limited to Caucasians.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('t(11', 'Var', (70, 74))	('children', 'Species', '9606', (131, 139))	('Ewing sarcoma', 'Disease', (0, 13))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (70, 87))
607303	30628187	Multivariate Cox proportional hazards regression analysis revealed that marital status was an independent prognostic and protective factor for survival among STS patients, and unmarried status was associated with higher mortality hazards for both OS and CSS.	('patients', 'Species', '9606', (162, 170))	('CSS', 'Chemical', '-', (254, 257))	('OS', 'Chemical', '-', (247, 249))	('Cox', 'Gene', (13, 16))	('unmarried status', 'Var', (176, 192))	('STS', 'Phenotype', 'HP:0030448', (158, 161))	('CSS', 'Disease', (254, 257))	('Cox', 'Gene', '1351', (13, 16))
607316	30628187	Patients were included when they met inclusion criteria as follow: (a) patients were aged 18 years or older at diagnosis; (b) the year of diagnosis was limited from 2004 to 2015; and (c) histological types were confined to fibromatous neoplasms (code: 8810, 8811, 8813, 8814, 8815, 8821, 8822, 8830, 8832, 8833, 8835, and 8836), rhabdomyosarcoma (8901, 8902, 8910, 8912, 8920, 8921, and 8991), specified (excluding Kaposi sarcoma; 8804, 8825, 8840, 8841, 8842, 8850, 8851, 8852, 8853, 8854, 8855, 8857, 8858, 8860, 8890, 8891, 8893, 8894, 8895, 8896, 8897, 8983, 8990, 8991, 9040, 9041, 9042, 9043, 9044, 9120, 9124, 9125, 9130, 9133, 9150, 9170, 9251, 9252, 9540, 9560, 9561, 9571, 9580, and 9581), Kaposi sarcoma (9140), and unspecified soft tissue sarcoma (8800, 8801, 8802, 8803, 8805, and 8806).	('8805', 'Var', (784, 788))	('sarcoma', 'Phenotype', 'HP:0100242', (422, 429))	('8806', 'Var', (794, 798))	('sarcoma', 'Phenotype', 'HP:0100242', (707, 714))	('neoplasms', 'Phenotype', 'HP:0002664', (235, 244))	('patients', 'Species', '9606', (71, 79))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (329, 345))	('Kaposi sarcoma', 'Disease', (415, 429))	('8896', 'Var', (545, 549))	('8802', 'Var', (772, 776))	('9125', 'Var', (617, 621))	('8897', 'Var', (551, 555))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (700, 714))	('8983', 'Var', (557, 561))	('9140', 'Var', (716, 720))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (739, 758))	('unspecified', 'Species', '32644', (727, 738))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (739, 758))	('8895', 'Var', (539, 543))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (329, 345))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (415, 429))	('soft tissue sarcoma', 'Disease', (739, 758))	('9170', 'Var', (641, 645))	('9560', 'Var', (665, 669))	('Patients', 'Species', '9606', (0, 8))	('fibromatous neoplasms', 'Disease', (223, 244))	('8800', 'Var', (760, 764))	('Kaposi sarcoma', 'Disease', (700, 714))	('8991', 'Var', (569, 573))	('9120', 'Var', (605, 609))	('sarcoma', 'Phenotype', 'HP:0100242', (338, 345))	('8803', 'Var', (778, 782))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (700, 714))	('9130', 'Var', (623, 627))	('9124', 'Var', (611, 615))	('9041', 'Var', (581, 585))	('9043', 'Var', (593, 597))	('sarcoma', 'Phenotype', 'HP:0100242', (751, 758))	('9044', 'Var', (599, 603))	('9540', 'Var', (659, 663))	('rhabdomyosarcoma', 'Disease', (329, 345))	('8990', 'Var', (563, 567))	('9251', 'Var', (647, 651))	('fibromatous neoplasms', 'Disease', 'MESH:D009369', (223, 244))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (415, 429))	('9133', 'Var', (629, 633))	('9042', 'Var', (587, 591))	('9040', 'Var', (575, 579))	('9252', 'Var', (653, 657))	('9150', 'Var', (635, 639))
607447	30108133	CLR127 is a novel, clinical-grade anti-tumor alkyl phospholipid ether analog, a subtype of synthetic alkyl phospholipids broadly targeting cancer cells with limited uptake in normal tissues.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CLR127', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('CLR127', 'Chemical', 'MESH:C503285', (0, 6))	('cancer', 'Disease', (139, 145))
607451	30108133	In animal models, CLR127 effectively increased the antitumor response to fractionated radiation therapy and led to delayed tumor regrowth at potentially clinically achievable doses.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CLR127', 'Chemical', 'MESH:C503285', (18, 24))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CLR127', 'Var', (18, 24))	('tumor', 'Disease', (55, 60))	('increased', 'PosReg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
607452	30108133	In conclusion, our study highlights the ability of CLR127 to increase radiation response in several cancer types.	('CLR127', 'Chemical', 'MESH:C503285', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CLR127', 'Var', (51, 57))	('increase', 'PosReg', (61, 69))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('radiation response', 'CPA', (70, 88))
607454	30108133	Our data provide a strong rationale for clinical testing of CLR127 as a tumor-targeted radiosensitizing agent.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('CLR127', 'Chemical', 'MESH:C503285', (60, 66))	('CLR127', 'Var', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
607466	30108133	CLR127 is classified as an alkyl phospholipid ether subtype of the APL that broadly targets cancer cells, with little uptake in healthy tissues.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('CLR127', 'Var', (0, 6))	('CLR127', 'Chemical', 'MESH:C503285', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
607469	30108133	Separately, we have shown that CLR127, in doses substantially higher than those used as a carrier molecule for radioactive iodine, is a potent anti-tumor compound and inhibitor of Akt phosphorylation in mouse models of neuroblastoma, in doses that were non-toxic to experimental animals and potentially achievable in patients.	('inhibitor', 'MPA', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CLR127', 'Var', (31, 37))	('mouse', 'Species', '10090', (203, 208))	('iodine', 'Chemical', 'MESH:D007455', (123, 129))	('neuroblastoma', 'Phenotype', 'HP:0003006', (219, 232))	('tumor', 'Disease', (148, 153))	('CLR127', 'Chemical', 'MESH:C503285', (31, 37))	('Akt phosphorylation', 'Pathway', (180, 199))	('neuroblastoma', 'Disease', 'MESH:D009447', (219, 232))	('patients', 'Species', '9606', (317, 325))	('neuroblastoma', 'Disease', (219, 232))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
607514	30108133	We next explored whether CLR127, beyond direct cytotoxicity to cancer cells, would enhance the effects of radiation.	('CLR127', 'Var', (25, 31))	('effects', 'MPA', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cytotoxicity', 'Disease', (47, 59))	('enhance', 'PosReg', (83, 90))	('CLR127', 'Chemical', 'MESH:C503285', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cytotoxicity', 'Disease', 'MESH:D064420', (47, 59))	('cancer', 'Disease', (63, 69))
607521	30108133	While normal cells (MCF10A) treated with both CLR127 and XRT exhibited steady state gamma-H2AX foci formation at 1h and activation of DNA damage response (DDR) signaling pathway by 24h, cancer cells Rh30 and PC-3 showed sustained gamma-H2AX foci formation up to 24h, confirmed by statistical analysis (Fig.	('CLR127', 'Chemical', 'MESH:C503285', (46, 52))	('Rh30', 'Gene', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DNA damage', 'Pathway', (134, 144))	('CLR127', 'Var', (46, 52))	('MCF10A', 'CellLine', 'CVCL:0598', (20, 26))	('Rh30', 'Gene', '6007', (199, 203))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
607527	30108133	The combination of CLR127 and fractionated radiation resulted in a significantly increased tumor response (average tumor volumes and growth rates) in the two sarcomas and prostate adenocarcinoma (P < 0.001) and improvement of the already pronounced radiation effect on SK-N-AS (neuroblastoma) when compared to mice that received excipient, CLR127 alone, or radiation alone (Fig.	('tumor', 'Disease', (115, 120))	('CLR127', 'Var', (19, 25))	('tumor', 'Disease', (91, 96))	('neuroblastoma', 'Disease', (278, 291))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('sarcomas', 'Phenotype', 'HP:0100242', (158, 166))	('neuroblastoma', 'Phenotype', 'HP:0003006', (278, 291))	('CLR127', 'Chemical', 'MESH:C503285', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('improvement', 'PosReg', (211, 222))	('neuroblastoma', 'Disease', 'MESH:D009447', (278, 291))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('sarcomas and prostate adenocarcinoma', 'Disease', 'MESH:D011471', (158, 194))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('increased', 'PosReg', (81, 90))	('mice', 'Species', '10090', (310, 314))	('growth rates', 'CPA', (133, 145))	('CLR127', 'Chemical', 'MESH:C503285', (340, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
607529	30108133	These in vivo data demonstrate a capacity of CLR127 to augment radiation response in vivo in tumors of ectodermal, neuroectodermal and mesenchymal origin.	('CLR127', 'Var', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CLR127', 'Chemical', 'MESH:C503285', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('augment', 'PosReg', (55, 62))	('radiation response', 'CPA', (63, 81))	('tumors', 'Disease', (93, 99))	('neuroectodermal', 'Disease', (115, 130))
607531	30108133	Tumors of mice that were treated with CLR127 plus XRT demonstrated a significantly higher fraction of gammaH2AX positive cells 24 hours after radiation treatment compared to tumor tissue of animals that received XRT only or CLR127 only, respectively (p<=0.001), confirming increased dsDNA radiation damage in the combination treatment cohort (Fig.	('tumor', 'Disease', (174, 179))	('CLR127', 'Var', (38, 44))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('gammaH2AX', 'Gene', '15270', (102, 111))	('mice', 'Species', '10090', (10, 14))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CLR127', 'Chemical', 'MESH:C503285', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('CLR127', 'Chemical', 'MESH:C503285', (224, 230))	('gammaH2AX', 'Gene', (102, 111))	('higher', 'PosReg', (83, 89))	('dsDNA', 'Disease', (283, 288))
607548	30108133	Normal cells (MCF10A) treated with both CLR127 and XRT exhibited steady state gamma-H2AX foci formation at 1h and DDR by 24h.	('MCF10A', 'CellLine', 'CVCL:0598', (14, 20))	('DDR', 'MPA', (114, 117))	('CLR127', 'Chemical', 'MESH:C503285', (40, 46))	('gamma-H2AX', 'Protein', (78, 88))	('CLR127', 'Var', (40, 46))
607557	30108133	Taken together, both imaging of gamma-H2AX foci and biochemical experiments of p-BRCA1 and XLF indicate that combined CLR127 and radiation have cell type specificity in terms of engaging the DSB repair and c-NHEJ processes.	('CLR127', 'Chemical', 'MESH:C503285', (118, 124))	('engaging', 'PosReg', (178, 186))	('BRCA1', 'Gene', (81, 86))	('c-NHEJ processes', 'CPA', (206, 222))	('XLF', 'Gene', (91, 94))	('CLR127', 'Var', (118, 124))	('XLF', 'Gene', '79840', (91, 94))	('DSB repair', 'CPA', (191, 201))	('BRCA1', 'Gene', '672', (81, 86))
607567	30108133	Given the almost universal and selective uptake of CLR127 in malignant cells and the intravenous formulation that is paired with a high therapeutic index in pre-clinical toxicity studies, CLR127 may afford a distinct and clinically valuable advantage over other commonly utilized radiosensitizing agents.	('CLR127', 'Var', (188, 194))	('CLR127', 'Chemical', 'MESH:C503285', (51, 57))	('CLR127', 'Chemical', 'MESH:C503285', (188, 194))	('toxicity', 'Disease', 'MESH:D064420', (170, 178))	('toxicity', 'Disease', (170, 178))	('uptake', 'MPA', (41, 47))
607599	29254498	However, this may be an issue of patient selection as genomic sequencing has shown lynch syndrome associated gene mutations in a subset of these patients.	('patients', 'Species', '9606', (145, 153))	('patient', 'Species', '9606', (33, 40))	('lynch syndrome', 'Disease', (83, 97))	('mutations', 'Var', (114, 123))	('lynch syndrome', 'Disease', 'MESH:D003123', (83, 97))	('patient', 'Species', '9606', (145, 152))
607660	29254498	Others have reported that mismatch repair pathway aberrations may be responsible for ASPS response to immunotherapy.	('mismatch repair pathway', 'Pathway', (26, 49))	('aberrations', 'Var', (50, 61))	('ASPS', 'Disease', (85, 89))	('ASPS', 'Disease', 'MESH:D018234', (85, 89))	('responsible', 'Reg', (69, 80))
607670	29254498	Patients were enrolled on a trial of imatinib and ipilimumab based on convincing pre-clinical rationale that showed imatinib reduced levels of indoleamine 2,3-dioxygenase (Ido).	('indoleamine 2,3-dioxygenase', 'Gene', '3620', (143, 170))	('Ido', 'Gene', (172, 175))	('imatinib', 'Chemical', 'MESH:D000068877', (37, 45))	('imatinib', 'Var', (116, 124))	('Patients', 'Species', '9606', (0, 8))	('reduced', 'NegReg', (125, 132))	('ipilimumab', 'Chemical', 'MESH:D000074324', (50, 60))	('imatinib', 'Chemical', 'MESH:D000068877', (116, 124))	('Ido', 'Gene', '3620', (172, 175))
607671	29254498	Ido is an immunosuppressive enzyme and inhibition of Ido led to regulatory T-cell destabilization, deactivation, and apoptosis.	('inhibition', 'Var', (39, 49))	('regulatory T-cell destabilization', 'CPA', (64, 97))	('Ido', 'Gene', (53, 56))	('Ido', 'Gene', (0, 3))	('Ido', 'Gene', '3620', (0, 3))	('apoptosis', 'CPA', (117, 126))	('Ido', 'Gene', '3620', (53, 56))	('deactivation', 'CPA', (99, 111))
607672	29254498	Treatment naive mice with KIT mutant GIST treated with imatinib showed decreased regulatory T cell activity.	('mice', 'Species', '10090', (16, 20))	('regulatory T cell activity', 'CPA', (81, 107))	('mutant', 'Var', (30, 36))	('decreased', 'NegReg', (71, 80))	('imatinib', 'Chemical', 'MESH:D000068877', (55, 63))
607683	29254498	One group reported that in their experience mutations in MDM2/MDM4 and EGFR predisposed to a hyper-progressor phenotype.	('hyper-progressor phenotype', 'MPA', (93, 119))	('MDM4', 'Gene', '4194', (62, 66))	('MDM2', 'Gene', '4193', (57, 61))	('MDM2', 'Gene', (57, 61))	('MDM4', 'Gene', (62, 66))	('EGFR', 'Gene', '1956', (71, 75))	('mutations', 'Var', (44, 53))	('EGFR', 'Gene', (71, 75))	('predisposed to', 'Reg', (76, 90))
607733	28413551	T4 N2 M1, Stage IV Carcinoma.	('IV Carcinoma', 'Disease', 'MESH:D030401', (16, 28))	('IV Carcinoma', 'Disease', (16, 28))	('T4 N2 M1', 'Var', (0, 8))	('Carcinoma', 'Phenotype', 'HP:0030731', (19, 28))
607921	32355494	Postoperative pathology of the resected specimen showed undifferentiated pulmonary sarcoma, pT4N0M1a stage IV A, and genetic analyses revealed the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation.	('sarcoma', 'Disease', 'MESH:D012509', (169, 176))	('sarcoma', 'Disease', (83, 90))	('KRAS', 'Gene', (201, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma', 'Disease', (169, 176))	('undifferentiated pulmonary sarcoma', 'Disease', 'MESH:D002277', (56, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('rat', 'Species', '10116', (7, 10))	('undifferentiated pulmonary sarcoma', 'Disease', (56, 90))	('rat', 'Species', '10116', (165, 168))	('mutation', 'Var', (207, 215))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('pulmonary sarcoma', 'Phenotype', 'HP:0031350', (73, 90))
607941	32355494	Genetic analyses by next-generation DNA sequencing revealed a positive v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (G12D) at codon 12; programmed death ligand 1 (PD-L1) expression was less than 1%.	('death', 'Disease', 'MESH:D003643', (171, 176))	('G12D', 'Mutation', 'rs121913529', (141, 145))	('PD-L1', 'Gene', (187, 192))	('KRAS', 'Gene', (125, 129))	('death', 'Disease', (171, 176))	('sarcoma', 'Disease', (93, 100))	('rat', 'Species', '10116', (29, 32))	('PD-L1', 'Gene', '29126', (187, 192))	('rat', 'Species', '10116', (89, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('G12D', 'Var', (141, 145))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
607979	32355494	reported that the mutation frequency of the tuberous sclerosis complex 2 gene was 15.64%, and this gene activates the mammalian target of rapamycin (mTOR) pathway.	('activates', 'PosReg', (104, 113))	('mammalian target of rapamycin', 'Gene', (118, 147))	('mammalian target of rapamycin', 'Gene', '2475', (118, 147))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (44, 62))	('mTOR', 'Gene', '2475', (149, 153))	('mTOR', 'Gene', (149, 153))	('tuberous sclerosis', 'Disease', (44, 62))	('mutation', 'Var', (18, 26))
607980	32355494	reported a case of concurrent KRAS mutation and phosphatidylinositol 3-kinase p110 subunit alpha (PIK3CA) mutation.	('PIK3CA', 'Gene', (98, 104))	('mutation', 'Var', (106, 114))	('PIK3CA', 'Gene', '5290', (98, 104))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (48, 77))	('mutation', 'Var', (35, 43))	('phosphatidylinositol 3-kinase', 'Gene', (48, 77))
608100	28656259	It is now widely accepted that both mutations of oncogenes and tumor suppressor genes lead to the switch into an angiogenic tumor.	('tumor', 'Disease', (63, 68))	('oncogenes', 'Gene', (49, 58))	('switch', 'Reg', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('lead to', 'Reg', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
608121	28656259	In addition, patients with high VEGF expression were obviously associated with lower overall survival (OR=0.22, 95% CI 0.13-0.35, P<0.001, I2=0.0 %).	('patients', 'Species', '9606', (13, 21))	('lower', 'NegReg', (79, 84))	('VEGF', 'Gene', (32, 36))	('high', 'Var', (27, 31))	('VEGF', 'Gene', '7422', (32, 36))	('overall survival', 'MPA', (85, 101))
608124	28656259	Kampmann et al reported in 2015 that the high expression of VEGFR1-3 and PDGFR-beta was significantly correlated with higher grading (G2 vs. G3, P<0.05), and high VEGFR-2 was significantly correlated with decreased patient survival (P<0.001).	('grading', 'CPA', (125, 132))	('higher', 'PosReg', (118, 124))	('VEGFR1-3', 'Gene', '2321;3791;2324', (60, 68))	('VEGFR-2', 'Gene', '3791', (163, 170))	('high', 'Var', (158, 162))	('PDGFR-beta', 'Gene', '5159', (73, 83))	('VEGFR1-3', 'Gene', (60, 68))	('VEGFR-2', 'Gene', (163, 170))	('patient survival', 'CPA', (215, 231))	('decreased', 'NegReg', (205, 214))	('PDGFR-beta', 'Gene', (73, 83))	('expression', 'MPA', (46, 56))	('patient', 'Species', '9606', (215, 222))
608180	28656259	R1507 did not seem to be effective with an ORR of 2.5% and 12-week-PFS of 17%, while dasatinib showed an ORR of 6.5% and duration of response of 5.7 months, which indicated that BCR/ABL, c-kit, and src might not be the target for osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (230, 242))	('dasatinib', 'Chemical', 'MESH:D000069439', (85, 94))	('osteosarcoma', 'Disease', (230, 242))	('osteosarcoma', 'Disease', 'MESH:D012516', (230, 242))	('BCR/ABL', 'Gene', (178, 185))	('src', 'Gene', (198, 201))	('BCR/ABL', 'Gene', '25;613', (178, 185))	('c-kit', 'Gene', (187, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('c-kit', 'Gene', '3815', (187, 192))	('src', 'Gene', '6714', (198, 201))	('R1507', 'Var', (0, 5))
608183	28656259	From the perspective of Versleijen-Jonkers et al, unlike chemotherapeutic agents, angiogenesis inhibitors slow or stop tumor growth rather than cause tumor shrinkage.	('tumor', 'Disease', (119, 124))	('stop', 'NegReg', (114, 118))	('inhibitors', 'Var', (95, 105))	('slow', 'NegReg', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (150, 155))	('angiogenesis', 'Protein', (82, 94))
608192	28656259	Mutation of VEGFR/PDGFR or altered receptors or polymorphisms may also have a role in the resistance to anti-VEGF/VEGFR therapy.	('PDGFR', 'Gene', '5159', (18, 23))	('resistance', 'MPA', (90, 100))	('VEGFR', 'Gene', (114, 119))	('VEGFR', 'Gene', (12, 17))	('VEGF', 'Gene', (114, 118))	('VEGF', 'Gene', (12, 16))	('Mutation', 'Var', (0, 8))	('VEGF', 'Gene', '7422', (109, 113))	('VEGF', 'Gene', (109, 113))	('role', 'Reg', (78, 82))	('VEGFR', 'Gene', '3791', (114, 119))	('VEGFR', 'Gene', '3791', (12, 17))	('VEGF', 'Gene', '7422', (114, 118))	('PDGFR', 'Gene', (18, 23))	('VEGF', 'Gene', '7422', (12, 16))
608200	28656259	Compared with conventional chemotherapy, the toxicity and side effects of anti-angiogenesis TKIs are mild and can be tolerated by most heavily pre-treated advanced osteosarcoma patients.	('osteosarcoma', 'Disease', (164, 176))	('toxicity', 'Disease', 'MESH:D064420', (45, 53))	('patients', 'Species', '9606', (177, 185))	('toxicity', 'Disease', (45, 53))	('osteosarcoma', 'Phenotype', 'HP:0002669', (164, 176))	('osteosarcoma', 'Disease', 'MESH:D012516', (164, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('anti-angiogenesis', 'Var', (74, 91))
608221	28656259	One explanation is that with the blockage of VEGF signaling, anti-angiogenetics induces a normalization of newly formed vessels, and thus, reduces the interstitial tissue pressure (ITP) within tumors, allowing enhanced delivery of chemotherapy to the tumors.	('interstitial tissue pressure', 'MPA', (151, 179))	('tumors', 'Disease', (251, 257))	('enhanced', 'PosReg', (210, 218))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('anti-angiogenetics', 'Var', (61, 79))	('VEGF', 'Gene', '7422', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('normalization', 'MPA', (90, 103))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('blockage', 'Var', (33, 41))	('reduces', 'NegReg', (139, 146))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('delivery', 'MPA', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('VEGF', 'Gene', (45, 49))	('induces', 'Reg', (80, 87))
608227	28656259	At present, there is a strong rationale for sequencing targeted therapy for metastatic clear cell renal cancer, but the timing of the switch and the best agent to switch to remains unclear.	('renal cancer', 'Phenotype', 'HP:0009726', (98, 110))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (87, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (87, 110))	('clear cell renal cancer', 'Disease', (87, 110))	('sequencing', 'Var', (44, 54))
608237	28656259	For non-small cell lung cancer (NSCLC) therapy, the reversible epidermal growth factor receptor (EGFR) TKIs gefitinib and erlotinib have been proven to be the first-line therapy for NSCLC harboring activating EGFR mutations.	('epidermal growth factor receptor', 'Gene', (63, 95))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('erlotinib', 'Chemical', 'MESH:D000069347', (122, 131))	('NSCLC', 'Disease', (32, 37))	('epidermal growth factor receptor', 'Gene', '1956', (63, 95))	('activating', 'PosReg', (198, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (4, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('NSCLC', 'Disease', (182, 187))	('EGFR', 'Gene', (209, 213))	('mutations', 'Var', (214, 223))	('EGFR', 'Gene', (97, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (8, 30))	('gefitinib', 'Chemical', 'MESH:D000077156', (108, 117))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (4, 30))	('EGFR', 'Gene', '1956', (209, 213))	('EGFR', 'Gene', '1956', (97, 101))	('non-small cell lung cancer', 'Disease', (4, 30))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))
608239	28656259	To explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target secondary driving gene mutation as well as signaling pathways downstream of EGFR are being studied in molecularly selected advanced NSCLC, which, in a certain sense, formulates a more logical therapeutic strategy for advanced solid tumors.	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('solid tumors', 'Disease', (332, 344))	('mutation', 'Var', (129, 137))	('EGFR', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('solid tumors', 'Disease', 'MESH:D009369', (332, 344))	('NSCLC', 'Disease', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (338, 344))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))
608249	31283560	Size, subtype, and R1 resection were independently associated with LR.	('associated', 'Reg', (51, 61))	('LR', 'Chemical', '-', (67, 69))	('R1 resection', 'Var', (19, 31))
608253	31283560	These data may guide selective use of systemic therapy for patients with round cell and pleomorphic LPS, which carry a high risk of DR, and radiotherapy for LPS subtypes at high risk of LR when treated with surgery alone.	('pleomorphic', 'Var', (88, 99))	('LPS', 'Disease', 'MESH:C536528', (157, 160))	('LR', 'Chemical', '-', (186, 188))	('LPS', 'Phenotype', 'HP:0012034', (100, 103))	('LPS', 'Disease', 'MESH:C536528', (100, 103))	('patients', 'Species', '9606', (59, 67))	('LPS', 'Phenotype', 'HP:0012034', (157, 160))	('LPS', 'Disease', (157, 160))	('round cell', 'Disease', (73, 83))	('LPS', 'Disease', (100, 103))
608263	31283560	Pleomorphic LPSs typically have multiple regions of significant copy number amplification and deletion and complex chromosomal rearrangements.	('LPS', 'Phenotype', 'HP:0012034', (12, 15))	('LPSs', 'Disease', 'None', (12, 16))	('deletion', 'Var', (94, 102))	('LPSs', 'Disease', (12, 16))
608304	31283560	In pleomorphic LPS, and to a lesser degree in myxoid LPS, size cut-offs of <= 5 cm, > 5- <= 10 cm, and > 10 cm stratified patients' risk of DSD.	('LPS', 'Disease', 'MESH:C536528', (53, 56))	('LPS', 'Phenotype', 'HP:0012034', (15, 18))	('LPS', 'Disease', (15, 18))	('LPS', 'Disease', (53, 56))	('patients', 'Species', '9606', (122, 130))	('LPS', 'Phenotype', 'HP:0012034', (53, 56))	('LPS', 'Disease', 'MESH:C536528', (15, 18))	('> 5- <= 10 cm', 'Var', (84, 97))
608338	31283560	In a previous analysis of patients treated for LPS at our institution, dedifferentiated and, to a lesser degree, ALT/well-differentiated LPS were associated with substantially worse survival than observed in this study.	('LPS', 'Disease', 'MESH:C536528', (137, 140))	('LPS', 'Disease', 'MESH:C536528', (47, 50))	('patients', 'Species', '9606', (26, 34))	('worse', 'NegReg', (176, 181))	('LPS', 'Phenotype', 'HP:0012034', (47, 50))	('LPS', 'Disease', (47, 50))	('LPS', 'Phenotype', 'HP:0012034', (137, 140))	('LPS', 'Disease', (137, 140))	('survival', 'MPA', (182, 190))	('dedifferentiated', 'Var', (71, 87))
608348	31283560	Although pleomorphic and round cell LPS, both considered high-grade subtypes, had the same cumulative incidence of DR (45% at 15 years), virtually all patients with pleomorphic LPS experienced DR within 3 years of diagnosis, compared with about 50% of those with round cell LPS, whose DRs occurred 3 to 15 years after initial diagnosis.	('pleomorphic', 'Var', (165, 176))	('LPS', 'Phenotype', 'HP:0012034', (177, 180))	('LPS', 'Disease', (177, 180))	('patients', 'Species', '9606', (151, 159))	('LPS', 'Phenotype', 'HP:0012034', (36, 39))	('LPS', 'Disease', (36, 39))	('LPS', 'Phenotype', 'HP:0012034', (274, 277))	('LPS', 'Disease', (274, 277))	('LPS', 'Disease', 'MESH:C536528', (177, 180))	('LPS', 'Disease', 'MESH:C536528', (36, 39))	('LPS', 'Disease', 'MESH:C536528', (274, 277))
608363	31283560	This finding is particularly noteworthy given the recent changes to the staging system in the 8th edition of the AJCC to create four different T stages (<= 5 cm, > 5-10 cm, > 10-15 cm, > 15 cm) for extremity sarcomas.	('<=', 'Var', (153, 155))	('sarcomas', 'Disease', 'MESH:D012509', (208, 216))	('sarcomas', 'Phenotype', 'HP:0100242', (208, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('sarcomas', 'Disease', (208, 216))
608399	28056517	Patients were selected using the International Classification of Diseases for Oncology, third edition (ICD-O-3) codes for Ewing sarcoma (9260/3) and peripheral neuroectodermal tumor (9364/3).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Ewing sarcoma', 'Disease', (122, 135))	('9364/3', 'Var', (183, 189))	('Oncology', 'Phenotype', 'HP:0002664', (78, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (122, 135))	('Patients', 'Species', '9606', (0, 8))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (122, 135))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (160, 181))	('peripheral neuroectodermal tumor', 'Disease', 'MESH:C563168', (149, 181))	('peripheral neuroectodermal tumor', 'Disease', (149, 181))	('9260/3', 'Var', (137, 143))
608421	28056517	Disease-specific survival was superior for ES-HN compared to ES-other only when stratified by treatment modality: both surgery and radiation (P = .018).	('ES', 'Chemical', 'MESH:D004540', (43, 45))	('Disease-specific survival', 'CPA', (0, 25))	('ES-HN', 'Var', (43, 48))	('superior', 'PosReg', (30, 38))	('ES', 'Chemical', 'MESH:D004540', (61, 63))
608424	28056517	This analysis found age, black race, Hispanic race, large tumor size, and distant disease to be independent predictors of worse 10-year DSS.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('DSS', 'Chemical', '-', (136, 139))	('Hispanic race', 'Var', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('distant', 'Disease', (74, 81))
608430	28056517	In addition, ES-HN was associated with an improved 10-year OS and DSS; however, this finding did not hold up on multivariate analysis.	('DSS', 'CPA', (66, 69))	('OS', 'Chemical', '-', (59, 61))	('improved', 'PosReg', (42, 50))	('ES', 'Chemical', 'MESH:D004540', (13, 15))	('DSS', 'Chemical', '-', (66, 69))	('ES-HN', 'Var', (13, 18))
608433	28056517	Likewise, a series of 29 patients with ES-HN observed a better survival for ES-HN compared to ES-other; however, of the 29 patients with ES-HN, only 10 were followed for more than 5 years.	('ES-HN', 'Var', (76, 81))	('ES', 'Chemical', 'MESH:D004540', (137, 139))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (25, 33))	('ES', 'Chemical', 'MESH:D004540', (76, 78))	('ES', 'Chemical', 'MESH:D004540', (94, 96))	('survival', 'MPA', (63, 71))	('ES', 'Chemical', 'MESH:D004540', (39, 41))
608516	27460384	Subsequent studies further demonstrated that this distinctive nuclear membrane staining pattern of ALK corresponded to ALK-RANBP2 fusions.	('RANBP2', 'Gene', (123, 129))	('ALK', 'Gene', (99, 102))	('ALK', 'Gene', (119, 122))	('fusions', 'Var', (130, 137))	('RANBP2', 'Gene', '5903', (123, 129))	('ALK', 'Gene', '238', (99, 102))	('ALK', 'Gene', '238', (119, 122))
608529	27460384	Approximately 50 % of IMTs aberrantly express ALK protein triggered by clonal rearrangements of ALK gene located on chromosome 2p23.	('ALK', 'Gene', '238', (96, 99))	('triggered by', 'Reg', (58, 70))	('ALK', 'Gene', '238', (46, 49))	('ALK', 'Gene', (96, 99))	('ALK', 'Gene', (46, 49))	('rearrangements', 'Var', (78, 92))
608532	27460384	IMT with TPM3, TPM4, CARS, ATIC, and SEC31L1 fusion often shows diffuse cytoplasmic staining of ALK, whereas with CLTC fusion, displays granular cytoplasmic staining.	('ATIC', 'Gene', (27, 31))	('ALK', 'Gene', '238', (96, 99))	('TPM3', 'Gene', (9, 13))	('ATIC', 'Gene', '471', (27, 31))	('CLTC', 'Gene', (114, 118))	('fusion', 'Var', (45, 51))	('diffuse cytoplasmic staining', 'MPA', (64, 92))	('CARS', 'Gene', '833', (21, 25))	('TPM4', 'Gene', '7171', (15, 19))	('TPM3', 'Gene', '7170', (9, 13))	('ALK', 'Gene', (96, 99))	('SEC31L1', 'Gene', (37, 44))	('TPM4', 'Gene', (15, 19))	('SEC31L1', 'Gene', '22872', (37, 44))	('CARS', 'Gene', (21, 25))	('CLTC', 'Gene', '1213', (114, 118))
608539	27460384	Several studies discovered that the chimeric RANPB2-ALK gene could promote cell growth and proliferation independent of cytokine in vitro.	('chimeric', 'Var', (36, 44))	('ALK', 'Gene', '238', (52, 55))	('cell growth', 'CPA', (75, 86))	('ALK', 'Gene', (52, 55))	('promote', 'PosReg', (67, 74))
608543	27460384	Therefore, for those cases with atypical morphology or immunoprofile, we recommend further genetic detection of ALK rearrangement by FISH or RT-PCR to confirm the diagnosis of EIMS.	('ALK', 'Gene', '238', (112, 115))	('rearrangement', 'Var', (116, 129))	('ALK', 'Gene', (112, 115))	('EIMS', 'Disease', (176, 180))
608545	27460384	Anaplastic large cell lymphoma (ALCL) is the most likely to be confused with EIMS, because both tumors have an overlapping immunophenotype and cytogenetic feature, including reactivity for CD30, ALK and SMA, and the presence of ALK rearrangement.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('reactivity', 'Var', (174, 184))	('cell lymphoma', 'Phenotype', 'HP:0012191', (17, 30))	('tumors', 'Disease', (96, 102))	('ALK', 'Gene', '238', (228, 231))	('Anaplastic large cell lymphoma', 'Disease', 'MESH:D017728', (0, 30))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('CD30', 'Gene', '943', (189, 193))	('SMA', 'Disease', (203, 206))	('lymphoma', 'Phenotype', 'HP:0002665', (22, 30))	('ALK', 'Gene', (195, 198))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('Anaplastic large cell lymphoma', 'Disease', (0, 30))	('ALK', 'Gene', (228, 231))	('CD30', 'Gene', (189, 193))	('ALK', 'Gene', '238', (195, 198))
608562	27460384	Detection of ALK rearrangement by FISH or RT-PCR will further confirm the diagnosis of EIMS and provide a reliable reference for ALK-targeted therapy.	('ALK', 'Gene', (129, 132))	('ALK', 'Gene', (13, 16))	('rearrangement', 'Var', (17, 30))	('ALK', 'Gene', '238', (129, 132))	('ALK', 'Gene', '238', (13, 16))	('EIMS', 'Disease', (87, 91))
608569	25999714	Ehrlich ascites carcinoma (EAC) cells, human breast cancer cell line HBL-100, and lung epithelial adenocarcinoma cell line A549 were used as test systems to compare Nano-MG with bare MG in vitro.	('MG', 'Chemical', 'MESH:D011765', (183, 185))	('MG', 'Chemical', 'MESH:D011765', (170, 172))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('EAC', 'Chemical', '-', (27, 30))	('lung epithelial adenocarcinoma', 'Disease', (82, 112))	('lung epithelial adenocarcinoma', 'Phenotype', 'HP:0030078', (82, 112))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('lung epithelial adenocarcinoma', 'Disease', 'MESH:D000077192', (82, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('breast cancer', 'Disease', (45, 58))	('Ehrlich ascites carcinoma', 'Disease', (0, 25))	('Ehrlich ascites carcinoma', 'Disease', 'MESH:D002286', (0, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('Nano-MG', 'Var', (165, 172))	('ascites', 'Phenotype', 'HP:0001541', (8, 15))	('A549', 'CellLine', 'CVCL:0023', (123, 127))	('human', 'Species', '9606', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
608571	25999714	In vivo studies were performed on both EAC cells inoculated and also in sarcoma-180-induced solid tumor-bearing Swiss albino mice to assess the anticancer activity of Nano-MG in comparison to bare MG with varying doses, times, and administrative routes.	('cancer', 'Disease', (148, 154))	('sarcoma', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('solid tumor', 'Disease', (92, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('solid tumor', 'Disease', 'MESH:D009369', (92, 103))	('Nano-MG', 'Var', (167, 174))	('mice', 'Species', '10090', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MG', 'Chemical', 'MESH:D011765', (172, 174))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('EAC', 'Chemical', '-', (39, 42))	('MG', 'Chemical', 'MESH:D011765', (197, 199))
608573	25999714	The zeta potential of Nano-MG was +21 mV and they contained approximately 100 mug of MG in 1 mL of solution.	('Nano-MG', 'Var', (22, 29))	('MG', 'Chemical', 'MESH:D011765', (27, 29))	('MG', 'Chemical', 'MESH:D011765', (85, 87))	('zeta potential', 'MPA', (4, 18))
608574	25999714	In vitro studies with Nano-MG showed higher cytotoxicity and enhanced rate of apoptosis in the HBL-100 cell line in comparison with bare MG, but no detrimental effect on normal mouse myoblast cell line C2C12 at the concerned doses.	('C2C12', 'CellLine', 'CVCL:0188', (202, 207))	('apoptosis', 'CPA', (78, 87))	('enhanced', 'PosReg', (61, 69))	('cytotoxicity', 'Disease', (44, 56))	('higher', 'PosReg', (37, 43))	('Nano-MG', 'Var', (22, 29))	('MG', 'Chemical', 'MESH:D011765', (137, 139))	('MG', 'Chemical', 'MESH:D011765', (27, 29))	('cytotoxicity', 'Disease', 'MESH:D064420', (44, 56))	('mouse', 'Species', '10090', (177, 182))
608577	25999714	In vivo studies further demonstrated the efficacy of Nano-MG over bare MG and found them to be about 400 times more potent in EAC-bearing mice and nearly 80 times more effective in sarcoma-180-bearing mice.	('sarcoma', 'Disease', (181, 188))	('MG', 'Chemical', 'MESH:D011765', (71, 73))	('EAC', 'Chemical', '-', (126, 129))	('EAC-bearing', 'Disease', (126, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('Nano-MG', 'Var', (53, 60))	('mice', 'Species', '10090', (138, 142))	('mice', 'Species', '10090', (201, 205))	('MG', 'Chemical', 'MESH:D011765', (58, 60))	('sarcoma', 'Disease', 'MESH:D012509', (181, 188))	('more', 'PosReg', (111, 115))
608578	25999714	Administration of ascorbic acid and creatine during in vivo treatments augmented the anticancer effect of Nano-MG.	('creatine', 'Chemical', 'MESH:D003401', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('ascorbic acid', 'Chemical', 'MESH:D001205', (18, 31))	('cancer', 'Disease', (89, 95))	('Nano-MG', 'Var', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('augmented', 'PosReg', (71, 80))	('MG', 'Chemical', 'MESH:D011765', (111, 113))
608579	25999714	The results clearly indicate that Nano-MG may constitute a promising tool in anticancer therapeutics in the near future.	('MG', 'Chemical', 'MESH:D011765', (39, 41))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('Nano-MG', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
608600	25999714	Ascorbic acid and creatine were administered in combination with Nano-MG and bare MG in murine models bearing EAC and sarcoma-180 cells to increase efficiency, as evidenced in our earlier observations.	('creatine', 'Chemical', 'MESH:D003401', (18, 26))	('murine', 'Species', '10090', (88, 94))	('MG', 'Chemical', 'MESH:D011765', (82, 84))	('EAC', 'Chemical', '-', (110, 113))	('sarcoma', 'Disease', (118, 125))	('Ascorbic acid', 'Chemical', 'MESH:D001205', (0, 13))	('efficiency', 'MPA', (148, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('increase', 'PosReg', (139, 147))	('MG', 'Chemical', 'MESH:D011765', (70, 72))	('Nano-MG', 'Var', (65, 72))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
608642	25999714	After treatment with MG or Nano-MG for 24 hours, cells were gently washed with phosphate-buffered saline (PBS) and treated with 3.7% formaldehyde and kept in a 37 C incubator for 15 minutes.	('MG', 'Chemical', 'MESH:D011765', (32, 34))	('phosphate-buffered saline', 'Chemical', '-', (79, 104))	('PBS', 'Disease', (106, 109))	('MG', 'Chemical', 'MESH:D011765', (21, 23))	('PBS', 'Disease', 'MESH:D011535', (106, 109))	('Nano-MG', 'Var', (27, 34))	('formaldehyde', 'Chemical', 'MESH:D005557', (133, 145))
608663	25999714	The mice were divided into the following groups: 1) control group, which was inoculated with either EAC or sarcoma-180 cells and received only normal saline as placebo but no drug; 2) EAC or sarcoma-180 cell-inoculated group receiving various doses of either Nano-MG or MG (in sterile saline); 3) EAC or sarcoma-180 cell-inoculated group treated with Nano-Chitosan; and 4) normal mice treated with Nano-Chitosan.	('mice', 'Species', '10090', (380, 384))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('MG', 'Chemical', 'MESH:D011765', (264, 266))	('MG', 'Chemical', 'MESH:D011765', (270, 272))	('saline', 'Chemical', 'MESH:D012965', (150, 156))	('EAC', 'Chemical', '-', (100, 103))	('mice', 'Species', '10090', (4, 8))	('Nano-MG', 'Var', (259, 266))	('EAC', 'Chemical', '-', (297, 300))	('saline', 'Chemical', 'MESH:D012965', (285, 291))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))	('sarcoma', 'Disease', 'MESH:D012509', (304, 311))	('sarcoma', 'Disease', (107, 114))	('Chitosan', 'Chemical', 'MESH:D048271', (356, 364))	('sarcoma', 'Disease', (304, 311))	('sarcoma', 'Disease', 'MESH:D012509', (191, 198))	('sarcoma', 'Disease', (191, 198))	('Chitosan', 'Chemical', 'MESH:D048271', (403, 411))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('EAC', 'Chemical', '-', (184, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))
608664	25999714	The EAC or sarcoma-180 cell-inoculated group receiving various doses of either Nano-MG or MG was fed orally with ascorbic acid and creatine as supplements.	('MG', 'Chemical', 'MESH:D011765', (84, 86))	('sarcoma', 'Disease', (11, 18))	('EAC', 'Chemical', '-', (4, 7))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('ascorbic acid', 'Chemical', 'MESH:D001205', (113, 126))	('creatine', 'Chemical', 'MESH:D003401', (131, 139))	('MG', 'Chemical', 'MESH:D011765', (90, 92))	('sarcoma', 'Disease', 'MESH:D012509', (11, 18))	('Nano-MG', 'Var', (79, 86))
608678	25999714	Significant morphological changes appeared in MG- and Nano-MG-treated HBL-100 cells as observed at 20x under a phase-contrast microscope.	('MG', 'Chemical', 'MESH:D011765', (46, 48))	('Nano-MG-treated', 'Var', (54, 69))	('MG', 'Chemical', 'MESH:D011765', (59, 61))	('HBL-100', 'Gene', (70, 77))	('morphological changes', 'CPA', (12, 33))
608679	25999714	With increases in the doses of MG and Nano-MG, the changes appeared greater and indicated greater loss of viability compared to untreated control cells (Figure 3A).	('MG', 'Chemical', 'MESH:D011765', (43, 45))	('loss', 'NegReg', (98, 102))	('MG', 'Chemical', 'MESH:D011765', (31, 33))	('Nano-MG', 'Var', (38, 45))	('viability', 'CPA', (106, 115))
608681	25999714	Results from the MTT assay were in accordance with the phase-contrast images and demonstrated that both MG and Nano-MG were detrimental and significantly cytotoxic towards HBL-100 in a dose-dependent manner as observed 24 hours (Figure 3B) and 48 hours (Figure 3C) after treatment.	('cytotoxic', 'NegReg', (154, 163))	('Nano-MG', 'Var', (111, 118))	('MG', 'Chemical', 'MESH:D011765', (116, 118))	('MG', 'Chemical', 'MESH:D011765', (104, 106))	('detrimental', 'NegReg', (124, 135))	('MTT', 'Chemical', '-', (17, 20))
608682	25999714	Interestingly, the potency of Nano-MG was found to be far greater at the higher doses.	('MG', 'Chemical', 'MESH:D011765', (35, 37))	('potency', 'MPA', (19, 26))	('Nano-MG', 'Var', (30, 37))
608684	25999714	At higher doses of Nano-MG (37.5 and 50 muM), the effectiveness was found to be as high as 35-40 times more compared to bare MG (750 and 1,000 muM).	('MG', 'Chemical', 'MESH:D011765', (24, 26))	('more', 'PosReg', (103, 107))	('MG', 'Chemical', 'MESH:D011765', (125, 127))	('Nano-MG', 'Var', (19, 26))
608686	25999714	The half-maximal inhibitory concentration (IC50) of MG and Nano-MG for HBL-100 was 1,000 muM and 37.5 muM, respectively, after 24 hours (Figure 3B).	('MG', 'Chemical', 'MESH:D011765', (64, 66))	('MG', 'Chemical', 'MESH:D011765', (52, 54))	('HBL-100', 'Gene', (71, 78))	('Nano-MG', 'Var', (59, 66))
608688	25999714	To determine the time of initiation of cell death, a time-dependent study was performed, which demonstrated the advent of cellular decease as early as 2 hours at higher doses of both MG and Nano-MG (Figure S1).	('MG', 'Chemical', 'MESH:D011765', (195, 197))	('cellular decease', 'CPA', (122, 138))	('Nano-MG', 'Var', (190, 197))	('initiation of cell death', 'Disease', (25, 49))	('initiation of cell death', 'Disease', 'MESH:D003643', (25, 49))	('MG', 'Chemical', 'MESH:D011765', (183, 185))
608689	25999714	The cytotoxic nature of Nano-MG was not only restricted to the HBL-100 cell line, but A549 also showed a sharp decrease in cell viability with Nano-MG, which again demonstrates the anticancer activity of Nano-MG (Figure S2).	('cell viability', 'CPA', (123, 137))	('MG', 'Chemical', 'MESH:D011765', (209, 211))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Nano-MG', 'Var', (143, 150))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('MG', 'Chemical', 'MESH:D011765', (29, 31))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('decrease', 'NegReg', (111, 119))	('A549', 'Var', (86, 90))	('MG', 'Chemical', 'MESH:D011765', (148, 150))	('cancer', 'Disease', (185, 191))
608695	25999714	Confocal microscopy revealed apoptotic nuclei after MG and Nano-MG treatments in HBL-100 cells.	('MG', 'Chemical', 'MESH:D011765', (64, 66))	('MG', 'Chemical', 'MESH:D011765', (52, 54))	('apoptotic nuclei', 'CPA', (29, 45))	('Nano-MG', 'Var', (59, 66))
608696	25999714	It was clear from the images that nuclear destruction occurred after treatment with 750 muM of MG and 37.5 muM of Nano-MG (Figure 4B), which supports our previous results from flow cytometric analysis (Figure 4A).	('nuclear destruction', 'CPA', (34, 53))	('Nano-MG', 'Var', (114, 121))	('MG', 'Chemical', 'MESH:D011765', (119, 121))	('MG', 'Chemical', 'MESH:D011765', (95, 97))
608700	25999714	The maximum inhibitory effect was observed when Nano-MG were combined with ascorbic acid, and it appeared that Nano-MG were by far more potent than bare MG. Nano-MG- and ascorbic acid-treated cells showed nearly 80% cell death and lost their transparency in comparison with MG and ascorbic acid, which showed nearly 50% cell death.	('MG', 'Chemical', 'MESH:D011765', (53, 55))	('MG', 'Chemical', 'MESH:D011765', (116, 118))	('transparency', 'MPA', (242, 254))	('ascorbic acid', 'Chemical', 'MESH:D001205', (75, 88))	('MG', 'Chemical', 'MESH:D011765', (274, 276))	('ascorbic acid', 'Chemical', 'MESH:D001205', (281, 294))	('Nano-MG-', 'Var', (157, 165))	('cell death', 'CPA', (216, 226))	('MG', 'Chemical', 'MESH:D011765', (153, 155))	('MG', 'Chemical', 'MESH:D011765', (162, 164))	('ascorbic acid', 'Chemical', 'MESH:D001205', (170, 183))	('lost', 'NegReg', (231, 235))
608709	25999714	The regression of EAC cells in mice by intravenous treatment with Nano-MG was 20 times more compared to bare MG at an 80 times lower dose (Table S1).	('EAC cells', 'Disease', (18, 27))	('MG', 'Chemical', 'MESH:D011765', (71, 73))	('regression', 'CPA', (4, 14))	('MG', 'Chemical', 'MESH:D011765', (109, 111))	('EAC', 'Chemical', '-', (18, 21))	('mice', 'Species', '10090', (31, 35))	('Nano-MG', 'Var', (66, 73))
608710	25999714	Solid tumor developed by sarcoma-180 cells showed gradual regression when treated with Nano-MG (MG content 80 times lower than bare MG) or MG via the intravenous route compared to untreated mice.	('sarcoma', 'Disease', (25, 32))	('MG', 'Chemical', 'MESH:D011765', (92, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('MG', 'Chemical', 'MESH:D011765', (96, 98))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('regression', 'NegReg', (58, 68))	('sarcoma', 'Disease', 'MESH:D012509', (25, 32))	('mice', 'Species', '10090', (190, 194))	('MG', 'Chemical', 'MESH:D011765', (139, 141))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MG', 'Chemical', 'MESH:D011765', (132, 134))	('Nano-MG', 'Var', (87, 94))	('tumor', 'Disease', (6, 11))
608711	25999714	The tumor size of Nano-MG-treated mice was approximately 7.5 times less than that of controls (receiving normal saline) and approximately three times less than in bare MG-treated mice after 35 days of treatment (Figure 9A and B).	('tumor', 'Disease', (4, 9))	('Nano-MG-treated', 'Var', (18, 33))	('saline', 'Chemical', 'MESH:D012965', (112, 118))	('mice', 'Species', '10090', (34, 38))	('mice', 'Species', '10090', (179, 183))	('MG', 'Chemical', 'MESH:D011765', (23, 25))	('less', 'NegReg', (67, 71))	('MG', 'Chemical', 'MESH:D011765', (168, 170))	('less', 'NegReg', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
608712	25999714	Ascorbic acid and creatine were fed orally to mice treated with MG or Nano-MG. An increase in survivality of sarcoma-180-bearing mice was apparent in the Nano-MG-treated group compared to the control or bare MG-treated counterparts (Figure 9C).	('creatine', 'Chemical', 'MESH:D003401', (18, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('MG', 'Chemical', 'MESH:D011765', (64, 66))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('Ascorbic acid', 'Chemical', 'MESH:D001205', (0, 13))	('Nano-MG-treated', 'Var', (154, 169))	('mice', 'Species', '10090', (46, 50))	('increase', 'PosReg', (82, 90))	('sarcoma', 'Disease', (109, 116))	('mice', 'Species', '10090', (129, 133))	('MG', 'Chemical', 'MESH:D011765', (159, 161))	('survivality', 'CPA', (94, 105))	('MG', 'Chemical', 'MESH:D011765', (208, 210))	('MG', 'Chemical', 'MESH:D011765', (75, 77))
608713	25999714	Histological analysis of tumor tissue cross-sections showed degenerating fibers, whereas treatment with Nano-MG revived the normal tissue architecture to a large extent (Figure 9D).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('MG', 'Chemical', 'MESH:D011765', (109, 111))	('tumor', 'Disease', (25, 30))	('normal tissue architecture', 'CPA', (124, 150))	('Nano-MG', 'Var', (104, 111))	('revived', 'PosReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('degenerating', 'NegReg', (60, 72))
608718	25999714	Chitosan acts as a carrier for controlled and sustained intracellular release of MG, thereby may help to retain it within cells and provide protection from in vivo enzymatic degradation making Nano-MG more tumoricidal.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('Nano-MG', 'Var', (193, 200))	('MG', 'Chemical', 'MESH:D011765', (198, 200))	('MG', 'Chemical', 'MESH:D011765', (81, 83))	('tumor', 'Disease', (206, 211))	('Chitosan', 'Chemical', 'MESH:D048271', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
608724	25999714	HBL-100 cells were shown to be nearly twice more prone to apoptosis when treated with Nano-MG where the amount of MG was 40 times lower than MG in bare form.	('MG', 'Chemical', 'MESH:D011765', (91, 93))	('apoptosis', 'CPA', (58, 67))	('MG', 'Chemical', 'MESH:D011765', (141, 143))	('MG', 'Chemical', 'MESH:D011765', (114, 116))	('Nano-MG', 'Var', (86, 93))
608736	25999714	In every case of our in vivo treatments, ascorbic acid and creatine acted synergistically with Nano-MG and bare MG in agreement with our previous observation.	('creatine', 'Chemical', 'MESH:D003401', (59, 67))	('MG', 'Chemical', 'MESH:D011765', (112, 114))	('Nano-MG', 'Var', (95, 102))	('creatine', 'MPA', (59, 67))	('ascorbic acid', 'Chemical', 'MESH:D001205', (41, 54))	('MG', 'Chemical', 'MESH:D011765', (100, 102))	('ascorbic acid', 'MPA', (41, 54))
608753	29935265	LFS is associated with germline mutations of the tumor suppressor gene p53 (TP53), which is implicated in cell proliferation, apoptosis, and genomic stability.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('germline mutations', 'Var', (23, 41))	('LFS', 'Disease', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TP53', 'Gene', '7157', (76, 80))	('associated', 'Reg', (7, 17))	('tumor', 'Disease', (49, 54))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('TP53', 'Gene', (76, 80))
608756	29935265	As many as 1:5000 individuals have TP53 germline mutations, which are familial; these are currently being identified more commonly due to increasing use of genetic screens.	('TP53', 'Gene', '7157', (35, 39))	('man', 'Species', '9606', (3, 6))	('germline mutations', 'Var', (40, 58))	('TP53', 'Gene', (35, 39))
608757	29935265	Carriers of TP53 gene mutation have the following probabilities of developing cancer: approximately 40% by age 20, more than 90% by age 70, and an 83-fold increased risk of developing multiple malignancies.	('malignancies', 'Disease', (193, 205))	('mutation', 'Var', (22, 30))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('TP53', 'Gene', '7157', (12, 16))	('malignancies', 'Disease', 'MESH:D009369', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TP53', 'Gene', (12, 16))
608780	29935265	Further genetic testing showed heterozygous change from thymine to adenine at nucleotide 712 and missense mutation from cysteine to serine at codon 238 in the p53 gene.	('change', 'Reg', (44, 50))	('cysteine to serine at codon 238', 'Mutation', 'rs730882005', (120, 151))	('p53', 'Gene', '7157', (159, 162))	('p53', 'Gene', (159, 162))	('adenine', 'Chemical', 'MESH:D000225', (67, 74))	('thymine', 'Chemical', 'MESH:D013941', (56, 63))	('missense mutation from', 'Var', (97, 119))
608804	29935265	Sequencing revealed the presence of a germline mutation (codon 1009C>T, protein Arg337Cys, exon 10 of TP53 gene) in both this patient and his nephew who died at the age of 20 from bone sarcoma.	('bone sarcoma', 'Phenotype', 'HP:0002669', (180, 192))	('TP53', 'Gene', (102, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('Arg337Cys', 'Var', (80, 89))	('1009C>T', 'SUBSTITUTION', 'None', (63, 70))	('patient', 'Species', '9606', (126, 133))	('1009C>T', 'Var', (63, 70))	('bone sarcoma', 'Disease', (180, 192))	('Arg337Cys', 'SUBSTITUTION', 'None', (80, 89))	('TP53', 'Gene', '7157', (102, 106))	('bone sarcoma', 'Disease', 'MESH:D001847', (180, 192))
608807	29935265	TP53 mutation was found in 80% of patients with ACC younger than 18-years-old.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (34, 42))	('found', 'Reg', (18, 23))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))	('mutation', 'Var', (5, 13))
608810	29935265	Although common GU malignancies were not associated with the TP53 syndrome (with the exception of ACC), the authors could not exclude the possibility of increased risk of these cancers in TP53 mutation carriers exposed to environmental carcinogens such as tobacco or other genetic factors.	('tobacco', 'Species', '4097', (256, 263))	('malignancies', 'Disease', (19, 31))	('TP53', 'Gene', (188, 192))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('GU malignancies', 'Phenotype', 'HP:0007379', (16, 31))	('ACC', 'Phenotype', 'HP:0006744', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', '7157', (188, 192))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('mutation', 'Var', (193, 201))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
608813	29935265	The rationale for surgical management of cancers in LFS patients with good performance status and adequate life expectancy resided in the relative radio- and chemo-resistance conferred to cancers by TP53 mutations, which render p53 dysfunctional.	('patients', 'Species', '9606', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TP53', 'Gene', (199, 203))	('mutations', 'Var', (204, 213))	('dysfunctional', 'MPA', (232, 245))	('p53', 'Gene', (228, 231))	('p53', 'Gene', '7157', (228, 231))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('man', 'Species', '9606', (27, 30))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('TP53', 'Gene', '7157', (199, 203))	('cancers', 'Disease', (41, 48))	('man', 'Species', '9606', (81, 84))
608815	29935265	Additionally, defective DNA repair due to mutant p53 increases the risk of radiation- and chemotherapy-induced malignancies in these patients.	('mutant', 'Var', (42, 48))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('radiation-', 'CPA', (75, 85))	('patients', 'Species', '9606', (133, 141))	('DNA repair', 'MPA', (24, 34))	('defective', 'NegReg', (14, 23))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('increases', 'PosReg', (53, 62))	('malignancies', 'Disease', (111, 123))
608817	29935265	It is currently not clear whether increased screening for TP53 mutation carriers would have an overall beneficial effect.	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))	('mutation', 'Var', (63, 71))
608823	29935265	At these institutions, consenting adult patients undergoing TP53 mutation screening should be provided with high-quality information and counseling, and made aware of their right to decide whether or not to have the genetic data disclosed to them.	('patients', 'Species', '9606', (40, 48))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('mutation', 'Var', (65, 73))
608825	29935265	However, in recent studies, genetic counseling and mutation testing, including TP53 mutation testing, have shown benefits in young patients with osteosarcoma and history of cancer in close relatives, and also in children and adolescents with cancer and a negative family history of malignancy.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('osteosarcoma', 'Phenotype', 'HP:0002669', (145, 157))	('mutation', 'Var', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('TP53', 'Gene', '7157', (79, 83))	('malignancy', 'Disease', 'MESH:D009369', (282, 292))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('patients', 'Species', '9606', (131, 139))	('cancer', 'Disease', (173, 179))	('benefits', 'PosReg', (113, 121))	('malignancy', 'Disease', (282, 292))	('mutation testing', 'Var', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('children', 'Species', '9606', (212, 220))	('osteosarcoma', 'Disease', (145, 157))	('osteosarcoma', 'Disease', 'MESH:D012516', (145, 157))	('cancer', 'Disease', (242, 248))	('TP53', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
608827	29935265	Although reliable screening tests for other LFS-related malignancies have yet to be established , the utilization of one such protocol resulted in a durable 3-year survival advantage of 100% vs. 21% (95% confidence interval 4-48%, p= .0155), for 7 TP53 mutation carriers with asymptomatic tumors who underwent surveillance compared to 10 individuals in the non-surveillance group who developed high-stage cancers.	('TP53', 'Gene', '7157', (248, 252))	('mutation', 'Var', (253, 261))	('advantage', 'PosReg', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('TP53', 'Gene', (248, 252))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('cancers', 'Phenotype', 'HP:0002664', (405, 412))	('tumors', 'Disease', (289, 295))	('cancers', 'Disease', (405, 412))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('cancers', 'Disease', 'MESH:D009369', (405, 412))	('malignancies', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))
608836	29935265	Other strategies aiming at the degradation or inhibition of aggregation of mutant TP53, or the reactivation of wild-type functions in mutant TP53, are pending clinical investigation in LFS patients with solid tumors.	('TP53', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('aggregation', 'MPA', (60, 71))	('solid tumors', 'Disease', (203, 215))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('mutant', 'Var', (75, 81))	('TP53', 'Gene', '7157', (82, 86))	('patients', 'Species', '9606', (189, 197))	('solid tumors', 'Disease', 'MESH:D009369', (203, 215))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
608840	29935265	Although definitive associations between common GU malignancies and LFS have not been elucidated to date, the concomitant presence of TP53 mutations, environmental carcinogens, and other genetic factors might increase the risk of developing GU malignancies in carriers.	('GU malignancies', 'Phenotype', 'HP:0007379', (241, 256))	('presence', 'Reg', (122, 130))	('TP53', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('malignancies', 'Disease', 'MESH:D009369', (51, 63))	('malignancies', 'Disease', 'MESH:D009369', (244, 256))	('GU malignancies', 'Phenotype', 'HP:0007379', (48, 63))	('malignancies', 'Disease', (51, 63))	('malignancies', 'Disease', (244, 256))	('TP53', 'Gene', '7157', (134, 138))	('increase', 'PosReg', (209, 217))
608923	28596939	HTLV-1 causes accumulation of genetic mutations in the host genome that could contribute to cellular transformation, one of the oncogenic features of HTLV-1.	('HTLV-1', 'Species', '11908', (150, 156))	('contribute', 'Reg', (78, 88))	('cellular transformation', 'CPA', (92, 115))	('HTLV-1', 'Gene', (0, 6))	('genetic mutations', 'Var', (30, 47))	('HTLV-1', 'Species', '11908', (0, 6))
608926	28596939	One year later, the patient developed a mild paraparesis in both extremities, anti-HTLV-1 antibodies were detected in plasma and in cerebrospinal fluid, and HAM/TSP was confirmed.	('HAM', 'Disease', (157, 160))	('anti-HTLV-1', 'Var', (78, 89))	('paraparesis', 'Disease', (45, 56))	('paraparesis', 'Disease', 'MESH:D020335', (45, 56))	('paraparesis', 'Phenotype', 'HP:0002385', (45, 56))	('HAM', 'Disease', 'MESH:D015493', (157, 160))	('patient', 'Species', '9606', (20, 27))	('HTLV-1', 'Species', '11908', (83, 89))	('detected', 'Reg', (106, 114))
608936	28596939	KRAS (located at 12p12.1) is frequently altered with mutations occurring in 17-25% of all cancers, while mutations in PIK3CA have been identified in several human solid tumors including breast, colon, ovarian, liver, and lung cancers.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (105, 114))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('identified', 'Reg', (135, 145))	('breast', 'Disease', (186, 192))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('PIK3CA', 'Gene', '5290', (118, 124))	('human', 'Species', '9606', (157, 162))	('colon, ovarian', 'Disease', 'MESH:D010051', (194, 208))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('KRAS', 'Gene', '3845', (0, 4))	('lung cancers', 'Disease', 'MESH:D008175', (221, 233))	('mutations', 'Var', (53, 62))	('lung cancers', 'Disease', (221, 233))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('liver', 'Disease', (210, 215))	('KRAS', 'Gene', (0, 4))	('lung cancers', 'Phenotype', 'HP:0100526', (221, 233))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('PIK3CA', 'Gene', (118, 124))	('tumors', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
608984	28596939	According to Osame criteria, HAM/TSP diagnosis is based on clinical findings and demonstration of anti-HTLV-1 antibodies in serum and CSF.	('anti-HTLV-1', 'Var', (98, 109))	('HAM', 'Disease', 'MESH:D015493', (29, 32))	('HAM', 'Disease', (29, 32))	('HTLV-1', 'Species', '11908', (103, 109))
608994	28596939	It has been reported that some sarcomas usually show a complex genomic profile, some of which present a frequent loss of RB1 and alterations of p53.	('p53', 'Gene', '7157', (144, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('RB1', 'Gene', (121, 124))	('sarcomas', 'Disease', (31, 39))	('loss', 'NegReg', (113, 117))	('RB1', 'Gene', '5925', (121, 124))	('alterations', 'Var', (129, 140))	('sarcomas', 'Disease', 'MESH:D012509', (31, 39))	('p53', 'Gene', (144, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))
609004	22690342	The EWS-ETS chimeric protein leads to aberrant transcription that promotes tumor initiation and propagation via prosurvival and antiapoptotic pathways.	('propagation', 'CPA', (96, 107))	('transcription', 'MPA', (47, 60))	('aberrant', 'Var', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('promotes', 'PosReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
609005	22690342	Recent research has identified cooperating mutations important for ES tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('ES', 'Phenotype', 'HP:0012254', (67, 69))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
609025	22690342	YK-4-279 induced the activation of caspase-3 and apoptosis in ES cell lines and inhibited tumor growth in an ES xenograft model but not in malignant non-EWS-FLI1-expressing cells.	('caspase-3', 'Gene', (35, 44))	('EWS-FLI1', 'Gene', (153, 161))	('ES', 'Phenotype', 'HP:0012254', (62, 64))	('caspase-3', 'Gene', '836', (35, 44))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('EWS-FLI1', 'Gene', '2130;2313', (153, 161))	('YK-4-279', 'Var', (0, 8))	('ES', 'Phenotype', 'HP:0012254', (109, 111))	('activation', 'PosReg', (21, 31))	('apoptosis', 'CPA', (49, 58))	('inhibited', 'NegReg', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
609035	22690342	Inhibition of TP53 bypassed an early growth arrest.	('TP53', 'Gene', '7157', (14, 18))	('growth arrest', 'Disease', (37, 50))	('TP53', 'Gene', (14, 18))	('growth arrest', 'Disease', 'MESH:D006323', (37, 50))	('growth arrest', 'Phenotype', 'HP:0001510', (37, 50))	('Inhibition', 'Var', (0, 10))
609040	22690342	By contrast, expression of EWS-FLI in murine bone-marrow-derived mesenchymal progenitor cells in the presence of functional tp53 generated tumors that displayed hallmarks of ES, providing a clue to the potential origin of ES.	('tp53', 'Gene', (124, 128))	('presence', 'Var', (101, 109))	('FLI', 'Gene', '2314', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('expression', 'Var', (13, 23))	('FLI', 'Gene', (31, 34))	('ES', 'Phenotype', 'HP:0012254', (222, 224))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('murine', 'Species', '10090', (38, 44))	('ES', 'Phenotype', 'HP:0012254', (174, 176))
609042	22690342	Another study using TP53 wt ES cell lines showed that disruption of NOTCH signalling by EWS-FLI1 through repression of JAG1 led to repression of TP53 and downstream P21-mediated cell cycle arrest.	('P21', 'Gene', (165, 168))	('JAG1', 'Gene', (119, 123))	('EWS-FLI1', 'Gene', (88, 96))	('repression', 'NegReg', (105, 115))	('TP53', 'Gene', (20, 24))	('ES', 'Phenotype', 'HP:0012254', (28, 30))	('disruption', 'Var', (54, 64))	('EWS-FLI1', 'Gene', '2130;2313', (88, 96))	('P21', 'Gene', '1026', (165, 168))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('NOTCH signalling', 'MPA', (68, 84))	('JAG1', 'Gene', '182', (119, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (178, 195))	('repression', 'NegReg', (131, 141))	('TP53', 'Gene', '7157', (20, 24))
609044	22690342	While mutations or deletions of a cell cycle checkpoint gene such as TP53 and CDKN2A are commonly encountered in many tumor types, in ES, specific mutation or deletion of these genes are rare events.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('CDKN2A', 'Gene', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CDKN2A', 'Gene', '1029', (78, 84))	('tumor', 'Disease', (118, 123))	('ES', 'Phenotype', 'HP:0012254', (134, 136))	('deletions', 'Var', (19, 28))	('mutations', 'Var', (6, 15))
609045	22690342	For example, most ES have TP53 wt and only 5% to 20% harbor deletions or point mutations of TP53, 30% show deletions of  p16INK4.	('TP53', 'Gene', (26, 30))	('TP53', 'Gene', '7157', (26, 30))	('deletions', 'Var', (60, 69))	('ES', 'Phenotype', 'HP:0012254', (18, 20))	('p16INK4', 'Gene', '1029', (121, 128))	('p16INK4', 'Gene', (121, 128))	('deletions', 'Var', (107, 116))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('point mutations', 'Var', (73, 88))
609046	22690342	Aberrations of TP53 or p16INK4/p14ARF, although rare, are associated with decreased overall survival and have been the strongest negative predictor of outcome in ES, even more than the presence of metastases at diagnosis in multivariate analysis.	('p16INK4', 'Gene', '1029', (23, 30))	('p14ARF', 'Gene', '1029', (31, 37))	('metastases', 'Disease', (197, 207))	('ES', 'Phenotype', 'HP:0012254', (162, 164))	('overall survival', 'MPA', (84, 100))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('p14ARF', 'Gene', (31, 37))	('decreased', 'NegReg', (74, 83))	('metastases', 'Disease', 'MESH:D009362', (197, 207))	('Aberrations', 'Var', (0, 11))	('p16INK4', 'Gene', (23, 30))
609047	22690342	The apparent contradiction between rare TP53 mutations and data suggesting a need of inhibition of the TP53 pathway to transform the cell of origin is yet not solved but could serve as a clue to understand the initial steps in development of ES.	('TP53', 'Gene', '7157', (103, 107))	('mutations', 'Var', (45, 54))	('TP53', 'Gene', (103, 107))	('ES', 'Phenotype', 'HP:0012254', (242, 244))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))
609049	22690342	Since inhibition of CDKs has been shown to trigger apoptosis via the intrinsic pathway in various tumor models, CDK may present a potential target for therapy in ES.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('ES', 'Phenotype', 'HP:0012254', (162, 164))	('intrinsic pathway', 'Pathway', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('inhibition', 'Var', (6, 16))	('CDKs', 'Protein', (20, 24))	('tumor', 'Disease', (98, 103))	('apoptosis', 'CPA', (51, 60))	('trigger', 'PosReg', (43, 50))
609052	22690342	Based on the observation that expression of EWS-FLI1 in nontransformed primary cells results in apoptosis and that ES cell lines are exquisitely chemosensitive, changes in ratios of pro- and antiapoptotic members like BAX/BAK, BH3-only proteins (i.e., BID, BAD, Puma, NOXA) and BCL-2/BCL-XL in ES may be supposed.	('ratios', 'MPA', (172, 178))	('BID', 'Gene', '637', (252, 255))	('BAX', 'Gene', '581', (218, 221))	('BAX', 'Gene', (218, 221))	('EWS-FLI1', 'Gene', (44, 52))	('BCL-2', 'Gene', '596', (278, 283))	('expression', 'Var', (30, 40))	('Puma', 'Disease', (262, 266))	('EWS-FLI1', 'Gene', '2130;2313', (44, 52))	('changes', 'Reg', (161, 168))	('ES', 'Phenotype', 'HP:0012254', (115, 117))	('results in', 'Reg', (85, 95))	('apoptosis', 'CPA', (96, 105))	('BCL-2', 'Gene', (278, 283))	('BID', 'Gene', (252, 255))	('ES', 'Phenotype', 'HP:0012254', (294, 296))	('BAD', 'Disease', (257, 260))
609055	22690342	In cellular model systems which are only partially comparable to the cell of origin, the accumulation of proapoptotic factors like caspase-3 leads to initiation of apoptosis in case of EWS-FLI1 expression.	('caspase-3', 'Gene', (131, 140))	('expression', 'Var', (194, 204))	('accumulation', 'PosReg', (89, 101))	('caspase-3', 'Gene', '836', (131, 140))	('apoptosis', 'CPA', (164, 173))	('EWS-FLI1', 'Gene', (185, 193))	('EWS-FLI1', 'Gene', '2130;2313', (185, 193))
609061	22690342	In cells with only low levels of activated caspase-8 generated (type II cells), activation of downstream caspases is mediated via the mitochondrial loop after cleavage of BID, a BH3 domain containing BCL-2 family protein, by caspase-8.	('BID', 'Gene', (171, 174))	('caspase-8', 'Gene', '841', (225, 234))	('caspase-8', 'Gene', '841', (43, 52))	('cleavage', 'Var', (159, 167))	('caspase-8', 'Gene', (225, 234))	('BCL-2', 'Gene', '596', (200, 205))	('caspases', 'Gene', '841;842', (105, 113))	('BID', 'Gene', '637', (171, 174))	('BCL-2', 'Gene', (200, 205))	('caspase-8', 'Gene', (43, 52))	('caspases', 'Gene', (105, 113))	('activation', 'PosReg', (80, 90))
609079	22690342	In a mouse model, combination treatment with TRAIL and the tyrosine kinase inhibitor imatinib reduced both the volume of primary tumours as well as pulmonary metastases possibly due to imatinib-induced enhancement of NK-cell sensitivity to IL-2 or IL-12 leading to increased IFN-gamma release and stimulation of TRAIL-downstream pathways.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('IL-2', 'Gene', (240, 244))	('increased', 'PosReg', (265, 274))	('reduced', 'NegReg', (94, 101))	('stimulation', 'Reg', (297, 308))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('imatinib-induced', 'Var', (185, 201))	('pulmonary metastases', 'Disease', 'MESH:D009362', (148, 168))	('pulmonary metastases', 'Disease', (148, 168))	('tumours', 'Disease', (129, 136))	('imatinib', 'Chemical', 'MESH:D000068877', (185, 193))	('mouse', 'Species', '10090', (5, 10))	('TRAIL-downstream pathways', 'Pathway', (312, 337))	('IFN-gamma release', 'MPA', (275, 292))	('enhancement', 'PosReg', (202, 213))	('IL-2', 'Gene', '16183', (240, 244))	('imatinib', 'Chemical', 'MESH:D000068877', (85, 93))
609089	22690342	Patients with metastatic disease and low IGF-I levels and high IGFBP3:IGF-I ratios showed a trend towards improved survival.	('improved', 'PosReg', (106, 114))	('low', 'NegReg', (37, 40))	('survival', 'MPA', (115, 123))	('IGFBP3', 'Gene', (63, 69))	('low IGF', 'Phenotype', 'HP:0002850', (37, 44))	('IGF-I levels', 'MPA', (41, 53))	('Patients', 'Species', '9606', (0, 8))	('high', 'Var', (58, 62))	('metastatic disease', 'Disease', (14, 32))
609100	22690342	Similar results were achieved in ES patients with another IgG1 anti-IGF-IR-antibody, R1507.	('R1507', 'Var', (85, 90))	('patients', 'Species', '9606', (36, 44))	('IGF-IR', 'Gene', (68, 74))	('ES', 'Phenotype', 'HP:0012254', (33, 35))	('IGF-IR', 'Gene', '3480', (68, 74))
609107	22690342	NVP-AEW541 and GSK1904529A also showed antitumor activity in xenograft tumors in mice.	('mice', 'Species', '10090', (81, 85))	('xenograft tumors', 'Disease', (61, 77))	('GSK1904529A', 'Var', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('NVP-AEW541', 'Var', (0, 10))	('xenograft tumors', 'Disease', 'MESH:D009369', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (71, 76))
609108	22690342	Similar results including apoptosis, G1 arrest, and inhibition of cell migration were observed with the tyrosine kinase signaling inhibitors, PD98059 and U0126, which inhibit MEK/MAPK, and LY294002, which inhibits PI3K when used in combination with chemotherapeutic drugs in vitro.	('G1 arrest', 'CPA', (37, 46))	('LY294002', 'Var', (189, 197))	('apoptosis', 'CPA', (26, 35))	('cell migration', 'CPA', (66, 80))	('U0126', 'Var', (154, 159))	('MEK', 'Gene', (175, 178))	('MEK', 'Gene', '5609', (175, 178))	('PI3K', 'Pathway', (214, 218))	('PD98059', 'Var', (142, 149))	('inhibit', 'NegReg', (167, 174))	('LY294002', 'Chemical', 'MESH:C085911', (189, 197))	('PD98059', 'Chemical', 'MESH:C093973', (142, 149))	('U0126', 'Chemical', 'MESH:C113580', (154, 159))	('inhibition', 'NegReg', (52, 62))
609109	22690342	Silencing EWS-FLI1, which leads to inhibition of IGF-IR expression, in combination with inhibitors of downstream kinases, NVP-AEW541, LY294002, and PD98059, had synergistic effect on apoptosis in one ES cell line raising the question whether direct IGF-IR blockade should be combined with inhibition of downstream pathway players to increase therapeutic responses.	('LY294002', 'Var', (134, 142))	('IGF-IR', 'Gene', (249, 255))	('PD98059', 'Chemical', 'MESH:C093973', (148, 155))	('ES', 'Phenotype', 'HP:0012254', (200, 202))	('IGF-IR', 'Gene', '3480', (249, 255))	('LY294002', 'Chemical', 'MESH:C085911', (134, 142))	('EWS-FLI1', 'Gene', (10, 18))	('IGF-IR', 'Gene', (49, 55))	('IGF-IR', 'Gene', '3480', (49, 55))	('Silencing', 'Var', (0, 9))	('apoptosis', 'CPA', (183, 192))	('inhibition', 'NegReg', (35, 45))	('EWS-FLI1', 'Gene', '2130;2313', (10, 18))
609111	22690342	Hyperphosphorylation of mTOR and other downstream IGF-IR mediators like ERK and AKT defines an unfavorable subgroup of ES patients.	('IGF-IR', 'Gene', (50, 56))	('Hyperphosphorylation', 'Var', (0, 20))	('ERK', 'Gene', (72, 75))	('AKT', 'Gene', '207', (80, 83))	('IGF-IR', 'Gene', '3480', (50, 56))	('ERK', 'Gene', '2048', (72, 75))	('AKT', 'Gene', (80, 83))	('patients', 'Species', '9606', (122, 130))	('ES', 'Phenotype', 'HP:0012254', (119, 121))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))
609129	22690342	In a resistant rhabdomyosarcoma cell line, combination of BMS-536924, with the pan-HER-2 inhibitor, gefitinib, had synergistic antiproliferative and apoptotic effects.	('antiproliferative', 'CPA', (127, 144))	('rhabdomyosarcoma', 'Disease', (15, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (15, 31))	('combination', 'Interaction', (43, 54))	('BMS-536924', 'Var', (58, 68))	('gefitinib', 'Chemical', 'MESH:D000077156', (100, 109))	('apoptotic effects', 'CPA', (149, 166))	('HER-2', 'Gene', '2064', (83, 88))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (15, 31))	('HER-2', 'Gene', (83, 88))
609179	32073912	Cancer types were grouped according to ICD-10: esophagus (C15), stomach (C16), colon and rectum (including anus; C18-21), liver (C22), pancreas (C25), lung (including trachea; C33-34), Kaposi sarcoma (C46), female breast (C50), cervix uteri (C53), ovary (C56), prostate (C61), kidney (including renal pelvis and ureter; C64-66), bladder (C67), brain and CNS (C70-72), Hodgkin lymphoma (C81), non-Hodgkin lymphoma (C82-85, C96), leukemia (C91-95), and all cancers combined.	('cancers', 'Phenotype', 'HP:0002664', (455, 462))	('renal pelvis', 'Phenotype', 'HP:0000125', (295, 307))	('cancers', 'Disease', (455, 462))	('C15', 'Gene', '51316', (58, 61))	('Kaposi sarcoma', 'Disease', (185, 199))	('C33', 'Gene', '3732', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (455, 461))	('C70-72', 'Var', (359, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))	('C18', 'Gene', '27241', (113, 116))	('leukemia', 'Phenotype', 'HP:0001909', (428, 436))	('C15', 'Gene', (58, 61))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (185, 199))	('colon and rectum', 'Disease', 'MESH:D012004', (79, 95))	('C18', 'Gene', (113, 116))	('leukemia', 'Disease', (428, 436))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (396, 412))	('leukemia', 'Disease', 'MESH:D007938', (428, 436))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (368, 384))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (396, 412))	('lymphoma', 'Phenotype', 'HP:0002665', (404, 412))	('cancers', 'Disease', 'MESH:D009369', (455, 462))	('non-Hodgkin lymphoma', 'Disease', (392, 412))	('C53', 'Gene', '80279', (242, 245))	('Hodgkin lymphoma', 'Disease', (368, 384))	('C82', 'Gene', (414, 417))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (392, 412))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('renal pelvis and ureter', 'Disease', 'MESH:D014516', (295, 318))	('C82', 'Gene', '732', (414, 417))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (392, 412))	('C33', 'Gene', (176, 179))	('cervix uteri', 'Phenotype', 'HP:0000139', (228, 240))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (185, 199))	('C53', 'Gene', (242, 245))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (368, 384))	('lymphoma', 'Phenotype', 'HP:0002665', (376, 384))
609266	32073912	These variations in common cancers provide a basis for additional studies to ascertain cancer incidence rates and survival probabilities.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('variations', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', (27, 34))
609314	29515415	The pathology report described a moderately differentiated uterine leiomyosarcoma (G2) according to TNM classification (p T1b [10 cm], L0, Nx, V0, R0, G2).	('leiomyosarcoma', 'Disease', (67, 81))	('TNM', 'Gene', '10178', (100, 103))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (67, 81))	('p T1b [10 cm]', 'Var', (120, 133))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (67, 81))	('TNM', 'Gene', (100, 103))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (59, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
609375	22401634	Defects in both T cells and DCs have been described in animal tumor models and in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('Defects', 'Var', (0, 7))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
609387	22401634	Teitz-Tennenbaum and colleagues reported confirmation of these observations and showed that radiotherapy potentiates the efficacy of intratumoral DC administration.	('Teitz-Tennenbaum', 'Disease', (0, 16))	('tumor', 'Disease', (138, 143))	('Teitz-Tennenbaum', 'Disease', 'None', (0, 16))	('potentiates', 'PosReg', (105, 116))	('radiotherapy', 'Var', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('efficacy', 'MPA', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
609406	22401634	Overexpression of survivin in tumors correlates with more aggressive disease and worse survival.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('survivin', 'Protein', (18, 26))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('aggressive disease', 'Disease', 'MESH:D001523', (58, 76))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Overexpression', 'Var', (0, 14))	('aggressive disease', 'Disease', (58, 76))
609417	22401634	It is a relatively immunogenic tumor that carries a mutant endogenous p53 gene.	('immunogenic tumor', 'Disease', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('p53', 'Gene', '7157', (70, 73))	('mutant', 'Var', (52, 58))	('p53', 'Gene', (70, 73))	('immunogenic tumor', 'Disease', 'MESH:D009369', (19, 36))
609427	22401634	Using fluorescence labeling, we observed that DCs indeed accumulate at the tumor site after irradiation and they engulf apoptotic tumor cells in situ.	('DCs', 'Var', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('accumulate', 'PosReg', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (75, 80))
609473	22401634	The presence of CD4+ T cells in the tumor positively correlated with tumor-specific immune responses that developed following combined therapy.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('correlated', 'Reg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CD4+', 'Var', (16, 20))	('tumor', 'Disease', (36, 41))
609503	22401634	The combination of intratumoral DC administration and EBRT is safe, results in the induction of strong antitumor immune response that are promising and warrants further testing in clinical trials designed to assess clinical efficacy Other strategies to elicit an enhanced antitumor immune responses such as utilizing a local radiotherapy boost or genetically engineered lymphocytes reactive to specific TAAs, are also being evaluated, with preliminary clinical success.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('EBRT', 'Chemical', '-', (54, 58))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumor', 'Disease', (276, 281))	('EBRT', 'Var', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('enhanced', 'PosReg', (263, 271))
609541	22484189	These KDR mutant tumors appear to occur in the same anatomic location, either breast or chest wall, as primary lesions of the breast or secondarily to prior radiation.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('KDR', 'Gene', (6, 9))	('mutant', 'Var', (10, 16))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('lesions of the breast', 'Phenotype', 'HP:0100013', (111, 132))	('KDR', 'Gene', '3791', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
609545	22484189	Similarly, coamplification of FLT4 (which encodes VEGFR3) with MYC was identified in 25% of secondary AS, but not in other vascular lesions.	('VEGFR3', 'Gene', (50, 56))	('MYC', 'Gene', (63, 66))	('coamplification', 'Var', (11, 26))	('FLT4', 'Gene', '2324', (30, 34))	('FLT4', 'Gene', (30, 34))	('VEGFR3', 'Gene', '2324', (50, 56))	('secondary AS', 'Disease', (92, 104))	('AS', 'Phenotype', 'HP:0200058', (102, 104))	('MYC', 'Gene', '4609', (63, 66))
609546	22484189	Interestingly, KDR mutant and coamplified MYC/FLT4 tumors have each been shown to be responsive to anti-angiogenesis directed therapies.	('KDR', 'Gene', '3791', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MYC', 'Gene', (42, 45))	('KDR', 'Gene', (15, 18))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('mutant', 'Var', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('MYC', 'Gene', '4609', (42, 45))	('FLT4', 'Gene', '2324', (46, 50))	('FLT4', 'Gene', (46, 50))
609553	22484189	A recent tissue microarray analysis of 222 historical AS specimen describes high levels of expression of VEGF-A, -C, KIT, phospho-AKT, phospho-4eBP1 and eIF4E with significant correlative associations between KIT and p-AKT, as well as p-AKT and VEGF-A, -C, p-4eBP1and eIF4E.	('eIF4E', 'Gene', '1977', (153, 158))	('VEGF-A', 'Gene', (105, 111))	('eIF4E', 'Gene', (268, 273))	('phospho-4eBP1', 'Var', (135, 148))	('p-AKT', 'Gene', (235, 240))	('eIF4E', 'Gene', (153, 158))	('KIT', 'Gene', (117, 120))	('AS', 'Phenotype', 'HP:0200058', (54, 56))	('p-AKT', 'Protein', (217, 222))	('phospho-AKT', 'Var', (122, 133))	('p-4eBP1and', 'Var', (257, 267))	('KIT', 'Gene', (209, 212))	('eIF4E', 'Gene', '1977', (268, 273))	('VEGF-A', 'Gene', '7422', (245, 251))	('VEGF-A', 'Gene', '7422', (105, 111))	('VEGF-A', 'Gene', (245, 251))
609569	22484189	Pegylated-liposomal doxorubicin has also been shown recently to have anti-AS activity and is an additional effective agent.	('doxorubicin', 'Chemical', 'MESH:D004317', (20, 31))	('anti-AS activity', 'CPA', (69, 85))	('Pegylated-liposomal', 'Var', (0, 19))	('AS', 'Phenotype', 'HP:0200058', (74, 76))
609593	22484189	In a phase II trial of 25 patients, 21 of which were found to have the COL1A1-PDGF-beta gene fusion, 9 patients were noted to have a clinical response and toxicities were limited such that no surgeries were delayed.	('toxicities', 'Disease', (155, 165))	('COL1A1', 'Gene', '1277', (71, 77))	('COL1A1', 'Gene', (71, 77))	('patients', 'Species', '9606', (26, 34))	('PDGF-beta', 'Gene', '5155', (78, 87))	('patients', 'Species', '9606', (103, 111))	('fusion', 'Var', (93, 99))	('PDGF-beta', 'Gene', (78, 87))	('toxicities', 'Disease', 'MESH:D064420', (155, 165))
609625	22484189	Of these, the closest to standard clinical use include tyrosine kinase inhibitors, such as imatinib, and other small molecules inhibiting the AKT/mTOR pathways.	('mTOR', 'Gene', '2475', (146, 150))	('mTOR', 'Gene', (146, 150))	('imatinib', 'Chemical', 'MESH:D000068877', (91, 99))	('tyrosine', 'Var', (55, 63))	('inhibiting', 'NegReg', (127, 137))
609631	22484189	As with TKI studies, inhibitors of these pathways have been observed to marked anti-tumor effect both in vitro and an increasing body of clinical observations has noted rapid resolution of both cutaneous and visceral Kaposi's lesions in response to transition from other immunosuppressive strategies to rapamycin analogs (mTOR inhibitors) in both the renal and cardiac transplant settings.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cutaneous', 'Disease', (194, 203))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mTOR', 'Gene', (322, 326))	('inhibitors', 'Var', (21, 31))	("visceral Kaposi's lesions", 'Disease', (208, 233))	('tumor', 'Disease', (84, 89))	('mTOR', 'Gene', '2475', (322, 326))	('rapamycin', 'Chemical', 'MESH:D020123', (303, 312))	("visceral Kaposi's lesions", 'Disease', 'MESH:D014983', (208, 233))	("Kaposi's lesions", 'Phenotype', 'HP:0100726', (217, 233))
609642	22484189	It is now clear that aberrant endothelial growth in KS is driven by vGPCR through activation of hypoxia inducible factor 1-alpha (HIF1alpha), and other viral encoded proteins, eventual leading to upregulation of VEGF.	('VEGF', 'Gene', '7422', (212, 216))	('aberrant', 'Var', (21, 29))	('HIF1alpha', 'Gene', '3091', (130, 139))	('KS', 'Phenotype', 'HP:0100726', (52, 54))	('activation', 'PosReg', (82, 92))	('hypoxia inducible factor 1-alpha', 'Gene', (96, 128))	('VEGF', 'Gene', (212, 216))	('hypoxia inducible factor 1-alpha', 'Gene', '3091', (96, 128))	('upregulation', 'PosReg', (196, 208))	('vGPCR', 'Gene', (68, 73))	('HIF1alpha', 'Gene', (130, 139))
609648	22484189	As described above for angiosarcoma, as the significance of other angiogenesis pathways, such as PGF, angiopoietins, NOTCH and others, become further elucidated in KS, inhibitors of these will likely have bearing on the treatment of KS patients.	('PGF', 'Gene', (97, 100))	('PGF', 'Gene', '5228', (97, 100))	('KS', 'Phenotype', 'HP:0100726', (233, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('angiosarcoma', 'Disease', 'MESH:D006394', (23, 35))	('patients', 'Species', '9606', (236, 244))	('angiosarcoma', 'Disease', (23, 35))	('inhibitors', 'Var', (168, 178))	('angiosarcoma', 'Phenotype', 'HP:0200058', (23, 35))	('bearing', 'Reg', (205, 212))	('KS', 'Phenotype', 'HP:0100726', (164, 166))
609709	22203850	P53 positivity of sarcoma elements helped us in differentiating true sarcoma from radiation-induced nonmalignant changes of the mesenchymal tissue.	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('sarcoma', 'Disease', (18, 25))	('sarcoma', 'Disease', (69, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('positivity', 'Var', (4, 14))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('sarcoma', 'Disease', 'MESH:D012509', (69, 76))
609747	29238287	Survival of patients with a LMS is strongly associated with the number of mitoses per 10 high power fields (x 100 magnification): 1-4, 98%; 5-9, 42%; >=10; 15%.	('associated', 'Reg', (44, 54))	('patients', 'Species', '9606', (12, 20))	('LMS', 'Disease', (28, 31))	('LMS', 'Phenotype', 'HP:0100243', (28, 31))	('mitoses', 'Var', (74, 81))
609950	28414726	In current tumor management, immunotherapy by improvising the host immune system enhances effective tumor clearance.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (11, 16))	('improvising', 'Var', (46, 57))	('enhances', 'PosReg', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
609951	28414726	Thus, modulation of a patient's immune system in such a way after surgery or surgery in combination to chemo/radiotherapy may result in prevention of tumor recurrence.	('modulation', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('prevention', 'NegReg', (136, 146))	('tumor', 'Disease', (150, 155))	('patient', 'Species', '9606', (22, 29))
610055	28414726	NLGP treatment results in significantly greater FasL expression on CD8+ T cells than PBS-treated controls (Fig 4C).	('NLGP', 'Gene', (0, 4))	('FasL', 'Gene', '14103', (48, 52))	('FasL', 'Gene', (48, 52))	('PBS', 'Chemical', '-', (85, 88))	('CD8+ T', 'Var', (67, 73))	('NLGP', 'Chemical', '-', (0, 4))	('greater', 'PosReg', (40, 47))
610063	28414726	It was observed that due to IFNgamma neutralization there was no change in the expression of FasR and cFLIP within MDSCs compared to the control group (Fig 4G2).	('FasR', 'Protein', (93, 97))	('expression', 'MPA', (79, 89))	('cFLIP', 'Gene', '12633', (102, 107))	('cFLIP', 'Gene', (102, 107))	('neutralization', 'Var', (37, 51))	('IFNgamma', 'Gene', (28, 36))	('IFNgamma', 'Gene', '15978', (28, 36))
610085	28414726	These T cells in operated animals are active (CD8+CD69+) and cytotoxic (CD8+GrB+), similar to our observation in NLGP-treated tumor hosts.	('CD69', 'Gene', '12515', (50, 54))	('NLGP', 'Chemical', '-', (113, 117))	('CD8+GrB+', 'Var', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cytotoxic', 'CPA', (61, 70))	('CD69', 'Gene', (50, 54))	('tumor', 'Disease', (126, 131))
610090	28414726	With depletion of CD8+ T cells such cytotoxic functions are diminished or abolished in NLGP-treated mice, which may be one of the reasons of recurrence in the same group of mice.	('depletion', 'Var', (5, 14))	('diminished', 'NegReg', (60, 70))	('mice', 'Species', '10090', (100, 104))	('abolished', 'NegReg', (74, 83))	('NLGP', 'Chemical', '-', (87, 91))	('mice', 'Species', '10090', (173, 177))
610097	28414726	Depletion of CD8+ T cells resulted in a proportionate increase of MDSCs, mediating their suppressive functions on different immune cells by implementing co-ordinated function between several biomolecules, like, Arginase1, iNOS2, STAT3, MMP9, etc.	('MDSCs', 'MPA', (66, 71))	('MMP9', 'Gene', '17395', (236, 240))	('STAT3', 'Gene', '20848', (229, 234))	('Arginase1', 'Gene', '11846', (211, 220))	('Arginase1', 'Gene', (211, 220))	('increase', 'PosReg', (54, 62))	('STAT3', 'Gene', (229, 234))	('CD8+ T', 'Var', (13, 19))	('MMP9', 'Gene', (236, 240))
610108	28414726	In presence of supernatant from these T cell culture, FasR expression was decreased in MDSCs of IFNgamma neutralized group compare to NLGP-treated group.	('FasR expression', 'MPA', (54, 69))	('NLGP', 'Chemical', '-', (134, 138))	('IFNgamma', 'Gene', (96, 104))	('decreased', 'NegReg', (74, 83))	('IFNgamma', 'Gene', '15978', (96, 104))	('neutralized group', 'Var', (105, 122))
610112	28414726	With assistance from CD8+ T cell depletion model, it was evidenced that NLGP by activating CD8+ T cells downregulate the proportion of MDSCs that helps in maintenance of optimum immune surveillance in tumor hosts to eliminate the residual tumor mass during recurrence.	('proportion', 'MPA', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('immune surveillance', 'MPA', (178, 197))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('activating', 'Var', (80, 90))	('CD8+ T', 'Var', (91, 97))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', (201, 206))	('downregulate', 'NegReg', (104, 116))	('optimum', 'MPA', (170, 177))	('NLGP', 'Chemical', '-', (72, 76))
610223	26714610	P4M is one of the youngest participants to suffer treatment-related impotence.	('men', 'Species', '9606', (55, 58))	('impotence', 'Disease', 'MESH:D007172', (68, 77))	('participants', 'Species', '9606', (27, 39))	('impotence', 'Phenotype', 'HP:0000802', (68, 77))	('impotence', 'Disease', (68, 77))	('P4M', 'Var', (0, 3))
610247	26714610	Extensive surgery in the hip-pelvic region or the lower extremities could result in a person becoming disabled and, thus, differing from what is deemed normal because of having to use a wheelchair or crutches or walking with a limp.	('limp', 'Phenotype', 'HP:0031955', (227, 231))	('result in', 'Reg', (74, 83))	('person', 'Species', '9606', (86, 92))	('Extensive surgery', 'Var', (0, 17))
610248	26714610	Additionally, scars and deformities engender a deviating appearance that others notice, and as a result, those affected may hide themselves when they are in social situations.	('scars', 'Phenotype', 'HP:0100699', (14, 19))	('deformities', 'Disease', (24, 35))	('scar', 'Phenotype', 'HP:0100699', (14, 18))	('engender', 'Reg', (36, 44))	('scars', 'Var', (14, 19))	('deviating appearance', 'MPA', (47, 67))	('deformities', 'Disease', 'MESH:D009140', (24, 35))
610262	26714610	However, recent research suggests that the extent to which a visible difference results in a social disability involves a complex interplay between social and individual factors.	('social disability', 'Disease', 'MESH:D003147', (93, 110))	('results in', 'Reg', (80, 90))	('social disability', 'Disease', (93, 110))	('difference', 'Var', (69, 79))
610276	24859338	FISH and RT-PCR studies confirmed the rearrangement of the PAX3 locus in 24 of 25 SNS tumors (96%) and the PAX3-MAML3 fusion gene in 19 of these (79%) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SNS tumors', 'Disease', (82, 92))	('rearrangement', 'Var', (38, 51))	('SNS tumors', 'Disease', 'MESH:D009369', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('PAX3', 'Gene', (59, 63))
610277	24859338	Five of the remaining SNS tumors exhibited rearrangement of the PAX3 locus without MAML3 involvement, and a single tumor showed rearrangement of the MAML3 locus without PAX3 involvement.	('SNS tumors', 'Disease', 'MESH:D009369', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('PAX3', 'Gene', (64, 68))	('tumor', 'Disease', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('exhibited', 'Reg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('rearrangement', 'Var', (43, 56))	('SNS tumors', 'Disease', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
610292	24859338	A MAML2 fusion gene occurs in most mucoepidermoid carcinomas, the most common malignant salivary gland tumor.	('salivary gland tumor', 'Phenotype', 'HP:0100684', (88, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('occurs', 'Reg', (20, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('mucoepidermoid carcinomas', 'Disease', (35, 60))	('fusion', 'Var', (8, 14))	('MAML2', 'Gene', (2, 7))	('malignant salivary gland tumor', 'Disease', (78, 108))	('malignant salivary gland tumor', 'Disease', 'MESH:D012468', (78, 108))	('mucoepidermoid carcinomas', 'Disease', 'MESH:D018277', (35, 60))	('MAML2', 'Gene', '84441', (2, 7))
610295	24859338	Interestingly, CRTC1-MAML2 is able to induce Notch signaling despite the deletion of the Notch/CSL binding domain in MAML2.	('CRTC1', 'Gene', '23373', (15, 20))	('induce', 'PosReg', (38, 44))	('MAML2', 'Gene', '84441', (21, 26))	('MAML2', 'Gene', (21, 26))	('MAML2', 'Gene', '84441', (117, 122))	('MAML2', 'Gene', (117, 122))	('CRTC1', 'Gene', (15, 20))	('deletion', 'Var', (73, 81))	('Notch signaling', 'MPA', (45, 60))
610298	24859338	Since nearly all SNS tumors examined showed either the PAX3-MAML3 fusion or PAX3 locus rearrangement, alterations in PAX3 activity may be crucial for the genesis and propagation of SNS.	('SNS tumors', 'Disease', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('PAX3 locus', 'Gene', (76, 86))	('PAX3-MAML3 fusion', 'Var', (55, 72))	('SNS tumors', 'Disease', 'MESH:D009369', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
610307	24859338	reported a malignant peripheral nerve sheath tumor histologically identical to SNS arising in the skull base with the similar chromosomal translocation t(2;4)(q35;q31), very likely representing the same entity.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (11, 50))	('malignant peripheral nerve sheath tumor', 'Disease', (11, 50))	('t(2;4)(q35;q31', 'Var', (152, 166))	('malignant peripheral nerve sheath tumor', 'Disease', 'MESH:D018319', (11, 50))	('t(2;4)(q35;q31)', 'STRUCTURAL_ABNORMALITY', 'None', (152, 167))
610328	24859338	BAC clones flanking two sides of MAML1 locus were CTD-3243D15, CTD-2335L20, RP11-1058J18 and RP11-983G15 (centromeric side probe size = 291 kb), and RP11-1148N14, CTD-3221P10, RP11-465D22, RP11-669B15 and RP11-282I19 (telomeric side probe size = 616 kb).	('RP11-282I19', 'Disease', (205, 216))	('RP11', 'Gene', (93, 97))	('CTD-2335L20', 'Var', (63, 74))	('RP11', 'Gene', (149, 153))	('RP11', 'Gene', '26121', (176, 180))	('RP11', 'Gene', (76, 80))	('RP11-282I19', 'Disease', 'MESH:C563991', (205, 216))	('MAML1', 'Gene', (33, 38))	('RP11', 'Gene', '26121', (205, 209))	('CTD-3243D15', 'Var', (50, 61))	('RP11', 'Gene', '26121', (189, 193))	('RP11', 'Gene', (176, 180))	('RP11', 'Gene', '26121', (93, 97))	('RP11', 'Gene', '26121', (149, 153))	('MAML1', 'Gene', '9794', (33, 38))	('CTD-3221P10', 'Var', (163, 174))	('RP11', 'Gene', (205, 209))	('RP11', 'Gene', '26121', (76, 80))	('RP11', 'Gene', (189, 193))
610329	24859338	BAC clones flanking two sides of MAML2 locus were CTD-544I7, CTD-2252L1, RP11-1123F20, RP11-936C10 and RP11-7D4 (centromeric probe size = 623 kb), and RP11-1056O10, CTD-2325K3 and RP11-8N17 (telomeric probe size = 372 kb).	('RP11', 'Gene', (103, 107))	('RP11', 'Gene', '26121', (151, 155))	('RP11', 'Gene', (73, 77))	('RP11', 'Gene', (180, 184))	('RP11', 'Gene', '26121', (103, 107))	('CTD-2325K3', 'Var', (165, 175))	('RP11', 'Gene', '26121', (73, 77))	('RP11', 'Gene', '26121', (87, 91))	('CTD-2252L1', 'Var', (61, 71))	('RP11', 'Gene', '26121', (180, 184))	('RP11', 'Gene', (151, 155))	('MAML2', 'Gene', '84441', (33, 38))	('MAML2', 'Gene', (33, 38))	('CTD-544I7', 'Var', (50, 59))	('RP11', 'Gene', (87, 91))
610330	24859338	BAC clones flanking two sides of PAX7 locus were CTD-2342P14, RP11-14K12 and RP11-632C1 (telomeric probe size = 411 kb), and RP11-998A17, RP4-540O3 and RP11-22M1 (centromeric probe size = 429 kb).	('RP11', 'Gene', (62, 66))	('RP11', 'Gene', (152, 156))	('RP11', 'Gene', (125, 129))	('RP11', 'Gene', '26121', (62, 66))	('PAX7', 'Gene', '5081', (33, 37))	('RP11', 'Gene', '26121', (125, 129))	('CTD-2342P14', 'Var', (49, 60))	('RP11', 'Gene', '26121', (152, 156))	('RP11', 'Gene', (77, 81))	('RP11', 'Gene', '26121', (77, 81))	('RP4-540O3', 'Var', (138, 147))	('PAX7', 'Gene', (33, 37))
610333	24859338	Human embryonic kidney (HEK) 293T cells were transiently transfected with pcDNA3-FLAG-PAX3-MAML3 or pcDNA-HA-PAX3 using Lipofectamine (Life Technologies).	('Human', 'Species', '9606', (0, 5))	('embryonic kidney', 'Disease', (6, 22))	('pcDNA3-FLAG-PAX3-MAML3', 'Var', (74, 96))	('293T', 'CellLine', 'CVCL:0063', (29, 33))	('Lipofectamine', 'Chemical', 'MESH:C086724', (120, 133))	('embryonic kidney', 'Disease', 'MESH:D007674', (6, 22))	('HEK', 'CellLine', 'CVCL:M624', (24, 27))
610336	24859338	For immunofluorescence assays, murine mesenchymal C2C12 cells were plated on cover slips and transfected with pcDNA3 or pcDNA3-FLAG-PAX3-MAML3.	('pcDNA3', 'Var', (110, 116))	('C2C12', 'CellLine', 'CVCL:0188', (50, 55))	('murine', 'Species', '10090', (31, 37))	('pcDNA3-FLAG-PAX3-MAML3', 'Var', (120, 142))
610343	24859338	RNA quality was evaluated by amplifying cDNA of housekeeping genes GAPDH or PGK.	('GAPDH', 'Gene', '2597', (67, 72))	('GAPDH', 'Gene', (67, 72))	('amplifying', 'Var', (29, 39))	('PGK', 'Gene', (76, 79))
610347	24859338	Hydrolysis probes for the target genes NTRK3, MYOD1, MLAN, MYOG and reference gene PGK1 were UPL probe # 71, # 70, # 56, # 20 and # 69 (Roche), respectively.	('MYOD1', 'Gene', '4654', (46, 51))	('# 69', 'Var', (130, 134))	('MYOG', 'Gene', '4656', (59, 63))	('PGK1', 'Gene', '5230', (83, 87))	('MYOD1', 'Gene', (46, 51))	('NTRK3', 'Gene', '4916', (39, 44))	('MYOG', 'Gene', (59, 63))	('NTRK3', 'Gene', (39, 44))	('PGK1', 'Gene', (83, 87))
610359	23895135	Next-generation sequencing showed 3 aberrant genes: activating mutation Q61L on NRAS; inactivating mutations Q504* and K740* on RB1; and TP53 loss.	('NRAS', 'Gene', (80, 84))	('loss', 'NegReg', (142, 146))	('Q61L', 'Mutation', 'rs11554290', (72, 76))	('RB1', 'Gene', (128, 131))	('Q61L', 'Var', (72, 76))	('Q504*', 'SUBSTITUTION', 'None', (109, 114))	('Q504*', 'Var', (109, 114))	('activating', 'PosReg', (52, 62))	('NRAS', 'Gene', '4893', (80, 84))	('RB1', 'Gene', '5925', (128, 131))	('TP53', 'Gene', '7157', (137, 141))	('K740*', 'Var', (119, 124))	('K740*', 'SUBSTITUTION', 'None', (119, 124))	('TP53', 'Gene', (137, 141))
610362	23895135	9 (CDKN2A gene) Deletions of chr.	('CDKN2A', 'Gene', '1029', (3, 9))	('CDKN2A', 'Gene', (3, 9))	('Deletions', 'Var', (16, 25))
610367	23895135	We describe for the first time an NRAS mutation with concomitant activation of PI3K/Akt/mTOR in phyllodes tumor.	('phyllodes', 'Chemical', '-', (96, 105))	('mutation', 'Var', (39, 47))	('Akt', 'Gene', '207', (84, 87))	('mTOR', 'Gene', (88, 92))	('Akt', 'Gene', (84, 87))	('PI3', 'Gene', '5266', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mTOR', 'Gene', '2475', (88, 92))	('NRAS', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PI3', 'Gene', (79, 82))	('activation', 'PosReg', (65, 75))	('NRAS', 'Gene', '4893', (34, 38))	('tumor', 'Disease', (106, 111))
610394	23895135	Three genes were identified with significant abnormalities: activating mutation Q61L on NRAS; inactivating mutations Q504* and K740* on RB1; and TP53 loss.	('activating', 'PosReg', (60, 70))	('K740*', 'SUBSTITUTION', 'None', (127, 132))	('Q61L', 'Mutation', 'rs11554290', (80, 84))	('RB1', 'Gene', '5925', (136, 139))	('Q61L', 'Var', (80, 84))	('NRAS', 'Gene', (88, 92))	('Q504*', 'SUBSTITUTION', 'None', (117, 122))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('NRAS', 'Gene', '4893', (88, 92))	('loss', 'NegReg', (150, 154))	('K740*', 'Var', (127, 132))	('RB1', 'Gene', (136, 139))	('Q504*', 'Var', (117, 122))
610413	23895135	Here we described a patient presenting stromal overgrowth and a metastatic recurrence with a genetic gain in 1q associated with CSK1B gene amplification, Amplification and over expression of the CSK1 gene inhibited apoptosis of cells through the MEK/ERK pathway and was associated with poor prognosis in breast cancer cells.	('inhibited', 'NegReg', (205, 214))	('overgrowth', 'Phenotype', 'HP:0001548', (47, 57))	('ERK', 'Gene', (250, 253))	('genetic gain', 'Disease', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('amplification', 'Var', (139, 152))	('over expression', 'PosReg', (172, 187))	('apoptosis of cells through', 'CPA', (215, 241))	('CSK1B', 'Gene', (128, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (304, 317))	('Amplification', 'Var', (154, 167))	('CSK1', 'Gene', (195, 199))	('stromal overgrowth', 'CPA', (39, 57))	('MEK', 'Gene', '5609', (246, 249))	('breast cancer', 'Disease', 'MESH:D001943', (304, 317))	('metastatic', 'CPA', (64, 74))	('breast cancer', 'Disease', (304, 317))	('ERK', 'Gene', '5594', (250, 253))	('genetic gain', 'Disease', 'MESH:D030342', (93, 105))	('patient', 'Species', '9606', (20, 27))	('MEK', 'Gene', (246, 249))
610415	23895135	In fact, mutations in the tumor suppressor gene TP53 appear to lead to a high level of chromosomal instability and drive oncogenesis in soft tissue sarcomas.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (136, 155))	('mutations', 'Var', (9, 18))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (136, 155))	('tumor suppressor', 'Gene', '7248', (26, 42))	('soft tissue sarcoma', 'Disease', (136, 155))	('TP53', 'Gene', '7157', (48, 52))	('sarcomas', 'Disease', 'MESH:D012509', (148, 156))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('chromosomal instability', 'Phenotype', 'HP:0040012', (87, 110))	('oncogenesis', 'CPA', (121, 132))	('sarcomas', 'Disease', (148, 156))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (136, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('tumor suppressor', 'Gene', (26, 42))	('TP53', 'Gene', (48, 52))	('lead to', 'Reg', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('drive', 'PosReg', (115, 120))	('chromosomal instability', 'MPA', (87, 110))
610416	23895135	Loss of TP53 in our patient might be associated with the higher level of chromosomal instability detected.	('chromosomal instability', 'Phenotype', 'HP:0040012', (73, 96))	('patient', 'Species', '9606', (20, 27))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))
610419	23895135	Other genetic abnormalities in phyllodes tumor that have been described in the COSMIC database (as of February 2013) are CDKN2A mutation (1/25 ptes), KIT mutation (1/26 ptes), and PI3KCA mutation (1/1 pte).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('CDKN2A', 'Gene', '1029', (121, 127))	('PI3', 'Gene', (180, 183))	('tumor', 'Disease', (41, 46))	('genetic abnormalities', 'Disease', 'MESH:D030342', (6, 27))	('genetic abnormalities', 'Disease', (6, 27))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('PI3', 'Gene', '5266', (180, 183))	('mutation', 'Var', (128, 136))	('KIT', 'Disease', (150, 153))	('CDKN2A', 'Gene', (121, 127))	('phyllodes', 'Chemical', '-', (31, 40))
610420	23895135	Our genomic analysis reports for the first time a mutation in the NRAS gene in breast sarcomas.	('NRAS', 'Gene', (66, 70))	('breast sarcomas', 'Disease', 'MESH:D012509', (79, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('NRAS', 'Gene', '4893', (66, 70))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('mutation', 'Var', (50, 58))	('breast sarcomas', 'Disease', (79, 94))
610421	23895135	The mutation detected here (Q61L) has been shown to markedly attenuate GTP hydrolysis maintaining NRAS in an active GTP state.	('GTP hydrolysis', 'MPA', (71, 85))	('Q61L', 'Mutation', 'rs11554290', (28, 32))	('Q61L', 'Var', (28, 32))	('GTP', 'Chemical', 'MESH:D006160', (116, 119))	('NRAS', 'Gene', (98, 102))	('NRAS', 'Gene', '4893', (98, 102))	('GTP', 'Chemical', 'MESH:D006160', (71, 74))	('attenuate', 'NegReg', (61, 70))
610422	23895135	Activation of this protein causes cell growth, differentiation, and survival mainly through the RAF/MAPK/ERK pathway.	('RAF', 'Gene', (96, 99))	('differentiation', 'CPA', (47, 62))	('RAF', 'Gene', '22882', (96, 99))	('survival', 'CPA', (68, 76))	('ERK', 'Gene', '5594', (105, 108))	('causes', 'Reg', (27, 33))	('ERK', 'Gene', (105, 108))	('cell growth', 'CPA', (34, 45))	('Activation', 'Var', (0, 10))
610423	23895135	Targeting this pathway with MEK inhibitors showed activity for patients with melanoma presenting with NRAS mutations.	('mutations', 'Var', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('MEK', 'Gene', (28, 31))	('melanoma', 'Disease', (77, 85))	('MEK', 'Gene', '5609', (28, 31))	('NRAS', 'Gene', (102, 106))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('patients', 'Species', '9606', (63, 71))	('NRAS', 'Gene', '4893', (102, 106))
610426	23895135	Recent evidence suggested that combining the targeting of both the MEK/ERK and PI3K/mTOR pathways might be a better strategy for the treatment of NRAS mutant tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('mutant', 'Var', (151, 157))	('NRAS', 'Gene', '4893', (146, 150))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('ERK', 'Gene', '5594', (71, 74))	('mTOR', 'Gene', '2475', (84, 88))	('PI3', 'Gene', '5266', (79, 82))	('ERK', 'Gene', (71, 74))	('mTOR', 'Gene', (84, 88))	('MEK', 'Gene', (67, 70))	('MEK', 'Gene', '5609', (67, 70))	('PI3', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('NRAS', 'Gene', (146, 150))
610427	23895135	Considering both the presence of the NRAS mutation and CSK1B amplification, the use of a MEK inhibitor (especially with agents blocking thePI3K pathway) would be reasonable for this patient.	('MEK', 'Gene', (89, 92))	('MEK', 'Gene', '5609', (89, 92))	('NRAS', 'Gene', (37, 41))	('CSK1B', 'Gene', (55, 60))	('patient', 'Species', '9606', (182, 189))	('PI3', 'Gene', (139, 142))	('mutation', 'Var', (42, 50))	('NRAS', 'Gene', '4893', (37, 41))	('PI3', 'Gene', '5266', (139, 142))
610429	23895135	The first acts downstream of beta-catenin influencing microtubule stability, and a previous study indicated that TLE3 expression was associated with improved response to taxane-based therapy in breast tumors.	('TLE3', 'Gene', (113, 117))	('expression', 'Var', (118, 128))	('breast tumors', 'Disease', 'MESH:D001943', (194, 207))	('breast tumors', 'Disease', (194, 207))	('improved', 'PosReg', (149, 157))	('taxane', 'Chemical', 'MESH:C080625', (170, 176))	('microtubule stability', 'MPA', (54, 75))	('beta-catenin', 'Gene', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('TLE3', 'Gene', '7090', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('beta-catenin', 'Gene', '1499', (29, 41))	('response', 'MPA', (158, 166))	('breast tumors', 'Phenotype', 'HP:0100013', (194, 207))	('breast tumor', 'Phenotype', 'HP:0100013', (194, 206))
610441	23895135	We described an NRAS mutation with concomitant activation of PI3K/Akt/mTOR, suggesting a potential role for a combination of MEK and PI3K inhibitors.	('Akt', 'Gene', (66, 69))	('PI3', 'Gene', '5266', (133, 136))	('mTOR', 'Gene', (70, 74))	('PI3', 'Gene', '5266', (61, 64))	('mTOR', 'Gene', '2475', (70, 74))	('NRAS', 'Gene', (16, 20))	('activation', 'PosReg', (47, 57))	('mutation', 'Var', (21, 29))	('Akt', 'Gene', '207', (66, 69))	('PI3', 'Gene', (133, 136))	('PI3', 'Gene', (61, 64))	('MEK', 'Gene', (125, 128))	('NRAS', 'Gene', '4893', (16, 20))	('MEK', 'Gene', '5609', (125, 128))
610466	32189990	Furthermore, response rates are doubled by the addition of RHT and are higher than agents approved for use in the second-line treatment of STS (such as trabectedin, eribulin, or pazopanib).	('higher', 'PosReg', (71, 77))	('pazopanib', 'Chemical', 'MESH:C516667', (178, 187))	('STS', 'Phenotype', 'HP:0030448', (139, 142))	('RHT', 'Protein', (59, 62))	('response', 'MPA', (13, 21))	('STS', 'Disease', (139, 142))	('RHT', 'Chemical', '-', (59, 62))	('addition', 'Var', (47, 55))	('STS', 'Disease', 'MESH:D012509', (139, 142))
610511	32189990	In nine patients with radiographic response (8% of all treated patients), tumor resection was facilitated by ICE + RHT (four in LA-STS and five in M-STS patients, respectively).	('STS', 'Phenotype', 'HP:0030448', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('patients', 'Species', '9606', (8, 16))	('patients', 'Species', '9606', (153, 161))	('STS', 'Disease', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('STS', 'Disease', (131, 134))	('ICE', 'Chemical', '-', (109, 112))	('STS', 'Disease', 'MESH:D012509', (149, 152))	('tumor', 'Disease', (74, 79))	('STS', 'Disease', 'MESH:D012509', (131, 134))	('patients', 'Species', '9606', (63, 71))	('ICE + RHT', 'Var', (109, 118))	('STS', 'Phenotype', 'HP:0030448', (149, 152))	('RHT', 'Chemical', '-', (115, 118))	('facilitated', 'PosReg', (94, 105))
610564	32189990	Tumor resection is a contributor with borderline significance in multivariate analyses for progression-free and overall survival in the LA-STS subcohort, and ICE + RHT might therefore lead to improved survival for patients with otherwise dismal prognosis due to the impossibility of sufficient tumor resection.	('improved', 'PosReg', (192, 200))	('tumor', 'Disease', (294, 299))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (214, 222))	('survival', 'MPA', (201, 209))	('STS', 'Phenotype', 'HP:0030448', (139, 142))	('RHT', 'Chemical', '-', (164, 167))	('STS', 'Disease', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('ICE', 'Chemical', '-', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('STS', 'Disease', 'MESH:D012509', (139, 142))	('ICE + RHT', 'Var', (158, 167))
610565	32189990	The strongest evidence for the favorable activity of ICE + RHT, however, derives from the observation that disease stabilization, or CR, or PR with ICE + RHT was associated with improved OS in the univariate analysis (Figure 3), which remained the only significant prognostic factor for improved overall survival in the multivariate analysis (Table 5) for both LA-STS and M-STS patients.	('improved', 'PosReg', (178, 186))	('STS', 'Disease', (374, 377))	('overall', 'MPA', (296, 303))	('RHT', 'Chemical', '-', (154, 157))	('STS', 'Disease', (364, 367))	('ICE', 'Chemical', '-', (148, 151))	('ICE + RHT', 'Var', (148, 157))	('ICE', 'Var', (53, 56))	('STS', 'Disease', 'MESH:D012509', (374, 377))	('STS', 'Disease', 'MESH:D012509', (364, 367))	('ICE', 'Chemical', '-', (53, 56))	('STS', 'Phenotype', 'HP:0030448', (374, 377))	('STS', 'Phenotype', 'HP:0030448', (364, 367))	('RHT', 'Chemical', '-', (59, 62))	('patients', 'Species', '9606', (378, 386))	('improved', 'PosReg', (287, 295))	('activity', 'MPA', (41, 49))
610571	32189990	As progression-free and overall survival were independent of STS subentities (lipo-/leiomyosarcoma vs. other subentities) in the multivariate analysis, ICE + RHT can be considered as salvage therapy in a wide range of STS histologies (Table 5 and Supplementary ).	('leiomyosarcoma', 'Disease', (84, 98))	('STS', 'Disease', 'MESH:D012509', (61, 64))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (84, 98))	('ICE', 'Chemical', '-', (152, 155))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (84, 98))	('STS', 'Phenotype', 'HP:0030448', (218, 221))	('RHT', 'Chemical', '-', (158, 161))	('STS', 'Disease', 'MESH:D012509', (218, 221))	('STS', 'Phenotype', 'HP:0030448', (61, 64))	('STS', 'Disease', (218, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('STS', 'Disease', (61, 64))	('ICE', 'Var', (152, 155))
610578	32189990	In patients with nonresectable localized relapse or with progression during anthracycline-based chemotherapy, ICE + RHT leads to disease stabilization in a significant proportion of patients and can facilitate resection in a subgroup of patients.	('localized relapse', 'Disease', (31, 48))	('resection', 'CPA', (210, 219))	('facilitate', 'PosReg', (199, 209))	('ICE', 'Chemical', '-', (110, 113))	('anthracycline', 'Chemical', 'MESH:D018943', (76, 89))	('RHT', 'Chemical', '-', (116, 119))	('ICE + RHT', 'Var', (110, 119))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (237, 245))	('disease', 'MPA', (129, 136))
610625	27649458	RT-PCR showed a t(X;18)(p11;q11) translocation, and fluorescence in situ hybridization (FISH) showed a rearrangement of the SS18 gene (Fig.	('SS18', 'Gene', (124, 128))	('SS18', 'Gene', '6760', (124, 128))	('rearrangement', 'Var', (103, 116))	('SS', 'Phenotype', 'HP:0012570', (124, 126))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (16, 32))
610672	25540587	The primary end point was the time to progression (TTP) and the q3w 24 h demonstrated a superior TTP of 3.7 months versus 2.3 months (hazard ratio [HR], 0.734; 95% confidence interval [CI], 0.554-0.974; P=0.0302).	('q3w', 'Var', (64, 67))	('TTP', 'Gene', '23677', (97, 100))	('TTP', 'Gene', (51, 54))	('TTP', 'Gene', (97, 100))	('TTP', 'Gene', '23677', (51, 54))
610676	25540587	Table 1 describes the early Phase II clinical trials with trabectedin in the second or subsequent line of treatment for ASTS and demonstrates the encouraging activity seen with this agent particularly in terms of PFS.	('PFS', 'Var', (213, 216))	('activity', 'MPA', (158, 166))	('ASTS', 'Chemical', '-', (120, 124))	('ASTS', 'Disease', (120, 124))	('trabectedin', 'Chemical', 'MESH:D000077606', (58, 69))
610679	25540587	This study is a randomized Phase III trial of first-line trabectedin versus doxorubicin- based chemotherapy and has been conducted in patients with translocation-related sarcoma subtypes.	('sarcoma subtypes', 'Disease', 'MESH:D012509', (170, 186))	('sarcoma subtypes', 'Disease', (170, 186))	('patients', 'Species', '9606', (134, 142))	('trabectedin', 'Chemical', 'MESH:D000077606', (57, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('doxorubicin', 'Chemical', 'MESH:D004317', (76, 87))	('translocation-related', 'Var', (148, 169))
610705	25540587	They are characterized molecularly by specific chromosomal trans-locations: the more commonly occurring t(12;16)(q13;p11) or the rarer t(12;22)(q13;q12), resulting in the formation of FUS-CHOP or EWS-CHOP fusion proteins, respectively.	('t(12;16)(q13;p11)', 'STRUCTURAL_ABNORMALITY', 'None', (104, 121))	('CHOP', 'Gene', (200, 204))	('FUS', 'Gene', (184, 187))	('CHOP', 'Gene', (188, 192))	('CHOP', 'Gene', '1649', (200, 204))	('FUS', 'Gene', '2521', (184, 187))	('q13;q12', 'Var', (144, 151))	('formation', 'Reg', (171, 180))	('EWS', 'Gene', '2130', (196, 199))	('EWS', 'Gene', (196, 199))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (135, 152))	('CHOP', 'Gene', '1649', (188, 192))
610714	25540587	The fusion proteins produced as a product of the translocations (FUS-CHOP or EWS-CHOP) act as abnormal transcription factors and are involved in the pathogenesis of the disease.	('involved', 'Reg', (133, 141))	('translocations', 'Var', (49, 63))	('FUS', 'Gene', '2521', (65, 68))	('CHOP', 'Gene', '1649', (81, 85))	('CHOP', 'Gene', '1649', (69, 73))	('EWS', 'Gene', '2130', (77, 80))	('EWS', 'Gene', (77, 80))	('CHOP', 'Gene', (81, 85))	('CHOP', 'Gene', (69, 73))	('transcription factors', 'MPA', (103, 124))	('FUS', 'Gene', (65, 68))
610722	25540587	The displacement of FUS-CHOP transcript variants (types I, II and III) from target promoters is similar but the kinetics of reattachment of the subtypes is different.	('CHOP', 'Gene', '1649', (24, 28))	('FUS', 'Gene', (20, 23))	('variants', 'Var', (40, 48))	('CHOP', 'Gene', (24, 28))	('FUS', 'Gene', '2521', (20, 23))
610781	25540587	Preclinical work has demonstrated that trabectedin causes necrosis of bile duct epithelial cells and that dexamethasone premedication in rats significantly reduces the hepatic levels of trabectedin in rats.	('rats', 'Species', '10116', (137, 141))	('dexamethasone', 'Chemical', 'MESH:D003907', (106, 119))	('necrosis', 'Disease', (58, 66))	('trabectedin', 'Chemical', 'MESH:D000077606', (186, 197))	('necrosis', 'Disease', 'MESH:D009336', (58, 66))	('trabectedin', 'Chemical', 'MESH:D000077606', (39, 50))	('rats', 'Species', '10116', (201, 205))	('hepatic levels of trabectedin', 'MPA', (168, 197))	('reduces', 'NegReg', (156, 163))	('trabectedin', 'Var', (39, 50))
610814	31565485	Although the etiology of STSs is still unclear, known risk factors include inherited syndromes, chemical and radiation exposures, viral infections and genetic mutations.	('STSs', 'Phenotype', 'HP:0030448', (25, 29))	('viral infections', 'Disease', (130, 146))	('viral infections', 'Disease', 'MESH:D014777', (130, 146))	('genetic mutations', 'Var', (151, 168))	('inherited syndromes', 'Disease', (75, 94))
610903	28451457	Common FISH-detected alterations are chromosome deletions, gains, translocations, amplifications and polysomy.	('translocations', 'Var', (66, 80))	('polysomy', 'Disease', (101, 109))	('amplifications', 'Var', (82, 96))	('chromosome', 'CPA', (37, 47))	('gain', 'Disease', (59, 63))	('gain', 'Disease', 'MESH:D015430', (59, 63))	('C', 'Chemical', 'MESH:D002244', (0, 1))
610904	28451457	These chromosome alterations may have diagnostic and therapeutic implications for many tumour types.	('alterations', 'Var', (17, 28))	('tumour', 'Disease', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
610908	28451457	These chromosome alterations may have diagnostic and therapeutic implications for many tumour types 5, 6.	('alterations', 'Var', (17, 28))	('tumour', 'Disease', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
610915	28451457	Most Ewing sarcoma cases result from EWSR1-FLI1 gene fusion deregulating the ETS transcription factor FLI1, leading to aberrant expression of Ewing sarcoma transforming genes.	('ETS', 'Chemical', '-', (77, 80))	('result from', 'Reg', (25, 36))	('EWSR1', 'Gene', (37, 42))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (142, 155))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (142, 155))	('FLI1', 'Gene', (102, 106))	('Ewing sarcoma', 'Disease', (5, 18))	('expression', 'MPA', (128, 138))	('FLI1', 'Gene', '2313', (102, 106))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (5, 18))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (5, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Ewing sarcoma', 'Disease', (142, 155))	('FLI1', 'Gene', (43, 47))	('deregulating', 'NegReg', (60, 72))	('EWSR1', 'Gene', '2130', (37, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('FLI1', 'Gene', '2313', (43, 47))	('fusion', 'Var', (53, 59))
610918	28451457	Chromosome rearrangement, whether intra-chromosomal or between chromosomes, invariably leads to a neoteric juxtaposition of previously unrelated gene elements into a new fusion gene that may or may not be transcribed.	('leads to', 'Reg', (87, 95))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('Chromosome rearrangement', 'Var', (0, 24))
610923	28451457	Recurrent gene fusions in soft tissue sarcomas tend to occur in tumours sharing similar morphological characteristics 27.	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (26, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (38, 46))	('gene fusions', 'Var', (10, 22))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (26, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('occur', 'Reg', (55, 60))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (26, 46))	('soft tissue sarcomas', 'Disease', (26, 46))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
610925	28451457	Most fusion genes are strongly associated with a particular tumour type, potentially making them ideal molecular diagnostic markers 10, 27, 28, 29.	('particular tumour type', 'Disease', 'MESH:D009369', (49, 71))	('particular tumour type', 'Disease', (49, 71))	('associated', 'Reg', (31, 41))	('fusion genes', 'Var', (5, 17))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
610927	28451457	The challenge now is to identify which of these recurring translocations truly have diagnostic, mechanistic, or therapeutic meaning for the associated sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcomas', 'Disease', (151, 159))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('translocations', 'Var', (58, 72))
610931	28451457	There is a specific balanced chromosomal rearrangement in most Ewing sarcomas, providing a valuable tool for diagnosis.	('Ewing sarcomas', 'Disease', (63, 77))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (63, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (63, 77))	('balanced chromosomal rearrangement', 'Var', (20, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (63, 76))
610934	28451457	This fusion not only abrogates the RNA splicing function of EWSR1 but also removes essential trans-activating control regions of the ETS gene partner.	('fusion', 'Var', (5, 11))	('ETS', 'Chemical', '-', (133, 136))	('EWSR1', 'Gene', '2130', (60, 65))	('essential trans-activating control regions', 'MPA', (83, 125))	('EWSR1', 'Gene', (60, 65))	('abrogates', 'NegReg', (21, 30))	('RNA splicing function', 'MPA', (35, 56))	('removes', 'NegReg', (75, 82))
610937	28451457	The ERG translocation, t(21;22)(q22;12), resulting in EWSR1-ERG fusion, represents only 10% of all Ewing sarcomas.	('EWSR1', 'Gene', '2130', (54, 59))	('Ewing sarcomas', 'Disease', (99, 113))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (99, 113))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (99, 112))	('t(21;22)(q22;12', 'Var', (23, 38))	('EWSR1', 'Gene', (54, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (99, 113))
610938	28451457	The functional consequences of these variant fusion proteins are similar to those of the more common EWSR1-FLI1 fusion.	('EWSR1', 'Gene', (101, 106))	('FLI1', 'Gene', (107, 111))	('FLI1', 'Gene', '2313', (107, 111))	('variant', 'Var', (37, 44))	('EWSR1', 'Gene', '2130', (101, 106))
610942	28451457	Chromosomal translocations t(12,16)(q13;p11) and t(12;22)(q13;q12), rendering gene fusions of DNA-damage inducible transcript 3 (DDIT3) with FUS or EWSR1, respectively, are characteristic of myxoid liposarcoma; one of these is identifiable in more than 95% of cases.	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (191, 209))	('EWSR1', 'Gene', (148, 153))	('myxoid liposarcoma', 'Disease', (191, 209))	('DDIT3', 'Gene', (129, 134))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (49, 66))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (191, 209))	('liposarcoma', 'Phenotype', 'HP:0012034', (198, 209))	('EWSR1', 'Gene', '2130', (148, 153))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('t(12;22)(q13;q12', 'Var', (49, 65))
610944	28451457	Synovial sarcoma is characterized by t(X;18)(p11;q11) translocation, which is present in virtually all tumours.	('tumours', 'Disease', 'MESH:D009369', (103, 110))	('tumours', 'Disease', (103, 110))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (37, 53))	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('t(X;18)(p11;q11) translocation', 'Var', (37, 67))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('sarcoma', 'Disease', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))
610947	28451457	A characteristic t(X;18)(p11;q11) translocation or variants were found in 90% of synovial sarcomas.	('synovial sarcomas', 'Phenotype', 'HP:0012570', (81, 98))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (17, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('synovial sarcomas', 'Disease', 'MESH:D013584', (81, 98))	('variants', 'Var', (51, 59))	('synovial sarcomas', 'Disease', (81, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('found', 'Reg', (65, 70))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (81, 97))	('t(X;18)(p11;q11) translocation', 'Var', (17, 47))
610948	28451457	The t(X;18) translocation has not been found in other sarcomas.	('t(X;18', 'Var', (4, 10))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcomas', 'Disease', (54, 62))
610951	28451457	Recurrent fusions of the two genes, NGFI-A-binding protein 2 (NAB2) and signal transducer and activator of transcription 6 (STAT6), both located near chromosomal region 12q13, have been identified in solitary fibrous tumours.	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('tumours', 'Phenotype', 'HP:0002664', (217, 224))	('identified', 'Reg', (186, 196))	('solitary fibrous tumours', 'Disease', (200, 224))	('NAB2', 'Gene', (62, 66))	('fusions', 'Var', (10, 17))	('solitary fibrous tumours', 'Disease', 'MESH:D054364', (200, 224))
610954	28451457	Mohajeri et al used six independent molecular genetic techniques directed at NAB2 or STAT6 rearrangement to identify NAB2-STAT6 fusion in 37 of 41 (90%) of the solitary fibrous tumours evaluated 37.	('solitary fibrous tumours', 'Disease', 'MESH:D054364', (160, 184))	('NAB2-STAT6', 'Gene', (117, 127))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('fusion', 'Var', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('solitary fibrous tumours', 'Disease', (160, 184))
610956	28451457	Recently cases of 'Ewing-like sarcoma' have been found to have a recurrent chromosomal translocation, t(4;19)(q35;q13), resulting in fusion of capicua homologue (CIC) and double homeobox 4 (DUX4) 38.	('t(4;19)(q35;q13', 'Var', (102, 117))	("'Ewing-like sarcoma", 'Phenotype', 'HP:0012254', (18, 37))	('C', 'Chemical', 'MESH:D002244', (162, 163))	("'Ewing-like sarcoma", 'Disease', (18, 37))	('fusion', 'Var', (133, 139))	('CIC', 'Gene', (162, 165))	("'Ewing-like sarcoma", 'Disease', 'MESH:C563168', (18, 37))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (65, 100))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (19, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (102, 118))	('C', 'Chemical', 'MESH:D002244', (164, 165))
610957	28451457	Fusion of the C-terminal fragment of DUX4 with CIC enhances the transcriptional activity of CIC and deregulates expression of its downstream targets.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('Fusion', 'Var', (0, 6))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('deregulates expression of', 'MPA', (100, 125))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('C', 'Chemical', 'MESH:D002244', (47, 48))	('C', 'Chemical', 'MESH:D002244', (92, 93))	('CIC', 'Gene', (92, 95))	('DUX4', 'Gene', (37, 41))	('enhances', 'PosReg', (51, 59))	('transcriptional activity', 'MPA', (64, 88))
610964	28451457	Roughly half of inflammatory myofibroblastic tumours have ALK rearrangements leading to elevated expression of ALK chimeric protein 40.	('inflammatory myofibroblastic tumours', 'Disease', 'MESH:D058922', (16, 52))	('rearrangements', 'Var', (62, 76))	('ALK', 'Gene', (58, 61))	('elevated', 'PosReg', (88, 96))	('inflammatory myofibroblastic tumours', 'Disease', (16, 52))	('ALK', 'Gene', '238', (111, 114))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('myofibroblastic tumour', 'Phenotype', 'HP:0020135', (29, 51))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('expression', 'MPA', (97, 107))	('ALK', 'Gene', (111, 114))	('ALK', 'Gene', '238', (58, 61))
610967	28451457	ALK rearrangements may prove useful for distinguishing inflammatory myofibroblastic tumour from morphologically similar neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (120, 128))	('rearrangements', 'Var', (4, 18))	('neoplasms', 'Phenotype', 'HP:0002664', (120, 129))	('inflammatory myofibroblastic tumour', 'Disease', (55, 90))	('neoplasms', 'Disease', 'MESH:D009369', (120, 129))	('ALK', 'Gene', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('myofibroblastic tumour', 'Phenotype', 'HP:0020135', (68, 90))	('inflammatory myofibroblastic tumour', 'Disease', 'MESH:D058922', (55, 90))	('neoplasms', 'Disease', (120, 129))	('ALK', 'Gene', '238', (0, 3))
610970	28451457	Antonescu et al reported six (10%) ROS1 related translocations in a group of 62 cases.	('ROS1', 'Gene', (35, 39))	('translocations', 'Var', (48, 62))	('ROS1', 'Gene', '6098', (35, 39))
610972	28451457	Two (3.2%) inflammatory myofibroblastic tumour cases showed TFG-ROS1 fusions, t(3;6)(q12;q22).	('ROS1', 'Gene', (64, 68))	('ROS1', 'Gene', '6098', (64, 68))	('inflammatory myofibroblastic tumour', 'Disease', (11, 46))	('inflammatory myofibroblastic tumour', 'Disease', 'MESH:D058922', (11, 46))	('t(3;6)(q12;q22', 'Var', (78, 92))	('myofibroblastic tumour', 'Phenotype', 'HP:0020135', (24, 46))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('t(3;6)(q12;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (78, 93))	('fusions', 'Var', (69, 76))
610980	28451457	Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive soft tissue sarcoma associated with translocations involving PAX3-FOXO1 [t(2;13)(q35;q14)] or PAX7-FOXO1 [t(1;13)(p36;q14)] reportedly accounting for 55-80% and 15-22% of ARMS, respectively 48.	('ARMS', 'Disease', 'None', (27, 31))	('ARMS', 'Disease', 'None', (227, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('ARMS', 'Phenotype', 'HP:0006779', (27, 31))	('PAX3-FOXO1 [t(2;13)(q35;q14)]', 'Var', (117, 146))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (129, 145))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('ARMS', 'Phenotype', 'HP:0006779', (227, 231))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (162, 178))	('Alveolar rhabdomyosarcoma', 'Disease', (0, 25))	('sarcoma', 'Disease', (68, 75))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (56, 75))	('Alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (0, 25))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (9, 25))	('ARMS', 'Disease', (27, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('ARMS', 'Disease', (227, 231))	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('sarcoma', 'Disease', (18, 25))	('PAX7-FOXO1 [t(1;13)(p36;q14)]', 'Var', (150, 179))	('Alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (0, 25))
610982	28451457	FISH analysis using the FOXO1split-apart probe adds the ability to detect variant FOXO1 rearrangements not detectable by PCR.	('C', 'Chemical', 'MESH:D002244', (122, 123))	('variant', 'Var', (74, 81))	('FOXO1', 'Gene', (82, 87))	('rearrangements', 'Var', (88, 102))
610985	28451457	Almost all (90%) clear cell sarcomas are associated with EWSR1-ATF1 translocation, t(12;22)(q13;q12), while a smaller subset of tumours (6%) bear an EWSR1-CREB1 translocation 50.	('sarcomas', 'Disease', 'MESH:D012509', (28, 36))	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumours', 'Disease', (128, 135))	('associated', 'Reg', (41, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('C', 'Chemical', 'MESH:D002244', (155, 156))	('EWSR1', 'Gene', (149, 154))	('sarcomas', 'Disease', (28, 36))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('EWSR1', 'Gene', (57, 62))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('EWSR1', 'Gene', '2130', (149, 154))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (83, 100))	('t(12;22)(q13;q12', 'Var', (83, 99))	('EWSR1', 'Gene', '2130', (57, 62))
610988	28451457	A growing number of fusion oncogenes have been also associated with some common adult epithelial tumors, such as adenocarcinomas of the lung, prostate, colon, kidney, breast and other epithelial solid tumours (Table 2).	('epithelial tumors', 'Disease', 'MESH:D002277', (86, 103))	('fusion', 'Var', (20, 26))	('associated', 'Reg', (52, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('epithelial solid tumours', 'Disease', (184, 208))	('adenocarcinomas of the lung', 'Disease', 'MESH:D000077192', (113, 140))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('colon', 'Disease', (152, 157))	('kidney', 'Disease', (159, 165))	('adenocarcinomas of the lung', 'Disease', (113, 140))	('breast', 'Disease', (167, 173))	('epithelial solid tumours', 'Disease', 'MESH:D000077216', (184, 208))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('epithelial tumors', 'Disease', (86, 103))	('prostate', 'Disease', (142, 150))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))
610990	28451457	Fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4), a protein involved in microtubule assembly, results in constitutive activation of the ALK kinase 52, 53.	('activation', 'PosReg', (145, 155))	('Fusions', 'Var', (0, 7))	('ALK', 'Gene', '238', (163, 166))	('ALK', 'Gene', (11, 14))	('EML4', 'Gene', (70, 74))	('ALK', 'Gene', (163, 166))	('ALK', 'Gene', '238', (11, 14))
610991	28451457	The ALK fusion oncogene was first identified in anaplastic large-cell lymphoma, in which a t(2;5) chromosome rearrangement activates the ALK kinase by fusion with the nucleophosmin gene (NPM1) on chromosome 5.	('lymphoma', 'Phenotype', 'HP:0002665', (70, 78))	('ALK', 'Gene', '238', (4, 7))	('cell lymphoma', 'Phenotype', 'HP:0012191', (65, 78))	('fusion', 'Var', (151, 157))	('ALK', 'Gene', (137, 140))	('ALK', 'Gene', (4, 7))	('anaplastic large-cell lymphoma', 'Phenotype', 'HP:0012193', (48, 78))	('lymphoma', 'Disease', (70, 78))	('lymphoma', 'Disease', 'MESH:D008223', (70, 78))	('ALK', 'Gene', '238', (137, 140))	('NPM1', 'Gene', (187, 191))	('activates', 'PosReg', (123, 132))	('rearrangement', 'Var', (109, 122))
610998	28451457	The ROS1 rearrangements lead to a constitutively activated fusion kinase, and are detected in 1.2-1.7% of lung adenocarcinoma cases 58, 59, 60.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('fusion kinase', 'MPA', (59, 72))	('ROS1', 'Gene', (4, 8))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('ROS1', 'Gene', '6098', (4, 8))	('rearrangements', 'Var', (9, 23))	('lead to', 'Reg', (24, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('lung adenocarcinoma', 'Disease', (106, 125))
611000	28451457	Patients with ROS1 translocation are significantly younger than most patients with lung cancer and are more likely to be never-smokers.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('ROS1', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('lung cancer', 'Disease', (83, 94))	('ROS1', 'Gene', '6098', (14, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (69, 77))	('translocation', 'Var', (19, 32))
611002	28451457	Several genes may serve as fusion partners for ROS1 including SDC4, SLC34A2, CD74, GOPC, and EZR, yet each of the ROS1 fusion products leads to constitutive ROS kinase activation 61.	('ROS1', 'Gene', (47, 51))	('ROS', 'Chemical', '-', (157, 160))	('ROS1', 'Gene', (114, 118))	('ROS1', 'Gene', '6098', (47, 51))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('ROS', 'Chemical', '-', (114, 117))	('fusion products', 'Var', (119, 134))	('activation', 'PosReg', (168, 178))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('leads to', 'Reg', (135, 143))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('constitutive ROS kinase', 'MPA', (144, 167))	('ROS', 'Chemical', '-', (47, 50))	('ROS1', 'Gene', '6098', (114, 118))
611003	28451457	A dual probe break-apart method is used to detect ROS1 rearrangement as with ALK rearrangement.	('ALK', 'Gene', (77, 80))	('ALK', 'Gene', '238', (77, 80))	('rearrangement', 'Var', (55, 68))	('ROS1', 'Gene', (50, 54))	('ROS1', 'Gene', '6098', (50, 54))
611005	28451457	ROS1 fusions are also found in meningioma, cholangiocarcinoma and glioblastoma, but no systematic investigation of tyrosine kinase inhibitors has been published for ROS1-fusion positive tumours of these primary sites 62, 63.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (43, 61))	('ROS1', 'Gene', (0, 4))	('meningioma', 'Disease', 'MESH:D008577', (31, 41))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('cholangiocarcinoma', 'Disease', (43, 61))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 61))	('ROS1', 'Gene', (165, 169))	('fusions', 'Var', (5, 12))	('ROS1-fusion positive tumours', 'Disease', 'MESH:D000069337', (165, 193))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('ROS1', 'Gene', '6098', (0, 4))	('glioblastoma', 'Disease', (66, 78))	('meningioma', 'Disease', (31, 41))	('meningioma', 'Phenotype', 'HP:0002858', (31, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('ROS1-fusion positive tumours', 'Disease', (165, 193))	('found', 'Reg', (22, 27))	('ROS1', 'Gene', '6098', (165, 169))
611020	28451457	It should be noted that EWSR1-CREB1 translocation is not unique for this entity; it can also be observed in clear cell sarcoma-like tumour of the gastrointestinal tract and angiomatoid fibrous histiocytoma (Table 1) Renal cell carcinomas associated with Xp11.2 translocation are uncommon renal tumours that were recognized as a distinct entity in the 2016 World Health Organization classification of Tumours of the Urinary System and Male Genital Organs 74.	('Renal cell carcinomas', 'Disease', (216, 237))	('Xp11.2', 'Gene', (254, 260))	('translocation', 'Var', (261, 274))	('Renal cell carcinomas', 'Phenotype', 'HP:0005584', (216, 237))	('tumour of the gastrointestinal tract', 'Disease', (132, 168))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('tumour of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (132, 168))	('angiomatoid fibrous histiocytoma', 'Disease', 'MESH:C563181', (173, 205))	('histiocytoma', 'Phenotype', 'HP:0012315', (193, 205))	('EWSR1', 'Gene', '2130', (24, 29))	('tumours', 'Disease', (294, 301))	('angiomatoid fibrous histiocytoma', 'Disease', (173, 205))	('tumours', 'Phenotype', 'HP:0002664', (294, 301))	('tumour of the gastrointestinal tract', 'Disease', 'MESH:D004067', (132, 168))	('tumours', 'Disease', 'MESH:D009369', (294, 301))	('Tumours', 'Phenotype', 'HP:0002664', (400, 407))	('Renal cell carcinomas', 'Disease', 'MESH:C538614', (216, 237))	('tumour', 'Phenotype', 'HP:0002664', (294, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('EWSR1', 'Gene', (24, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('sarcoma', 'Disease', (119, 126))	('C', 'Chemical', 'MESH:D002244', (30, 31))
611023	28451457	Variant translocations with unknown fusion partners include t(X;3)(p11.2;q23) and t(X;10)(11.2;q23).	('t(X;3)(p11.2;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (60, 77))	('t(X;3)(p11.2;q23', 'Var', (60, 76))	('t(X;10)(11.2;q23', 'Var', (82, 98))
611025	28451457	The TFE3 break-apart FISH assay has proven useful for detecting TFE3 gene fusions in Xp11.2 translocation renal cell carcinoma, and the FISH assay, in comparison with immunohistochemical evaluation, is less often adversely affected by technical and fixation issues.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('TFE3', 'Gene', (64, 68))	('translocation renal cell carcinoma', 'Disease', 'MESH:C538614', (92, 126))	('Xp11.2', 'Gene', (85, 91))	('fusions', 'Var', (74, 81))	('translocation renal cell carcinoma', 'Disease', (92, 126))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (106, 126))	('fixation issues', 'Phenotype', 'HP:0025405', (249, 264))
611027	28451457	Seventeen cases showed TFE3 rearrangement associated with Xp11.2 translocation by FISH, including seven previously unclassified renal cell tumours, supporting the diagnostic value and clinical application of FISH for enigmatic renal tumours.	('renal cell tumours', 'Disease', (128, 146))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('associated', 'Reg', (42, 52))	('TFE3', 'Gene', (23, 27))	('translocation', 'Var', (65, 78))	('rearrangement', 'Var', (28, 41))	('tumours', 'Phenotype', 'HP:0002664', (233, 240))	('enigmatic renal tumours', 'Disease', 'MESH:D007680', (217, 240))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('renal cell tumours', 'Disease', 'MESH:C538614', (128, 146))	('enigmatic renal tumours', 'Disease', (217, 240))
611029	28451457	The t(6;11) translocation renal cell carcinoma is rare and usually bears a translocation between transcription factor EB (TFEB) and MALAT1 on chromosome 11q12, but rarely TFEB may partner with KHDRBS2 on chromosome 6q11 (Figure 4B) 80.	('translocation', 'Var', (75, 88))	('translocation renal cell carcinoma', 'Disease', 'MESH:C538614', (12, 46))	('TFEB', 'Gene', '7942', (122, 126))	('TFEB', 'Gene', '7942', (171, 175))	('TFEB', 'Gene', (122, 126))	('translocation renal cell carcinoma', 'Disease', (12, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (26, 46))	('TFEB', 'Gene', (171, 175))
611030	28451457	Renal cell carcinomas with t(6;11)(p21;q12) are characterized by translocation involving TFEB.	('t(6;11)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (27, 43))	('Renal cell carcinomas', 'Disease', (0, 21))	('t(6;11)(p21;q12', 'Var', (27, 42))	('TFEB', 'Gene', '7942', (89, 93))	('TFEB', 'Gene', (89, 93))	('Renal cell carcinomas', 'Phenotype', 'HP:0005584', (0, 21))	('Renal cell carcinomas', 'Disease', 'MESH:C538614', (0, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
611039	28451457	Inactivation of tumour suppressor gene SMARCB1 is the hallmark of this tumour.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (71, 77))	('tumour', 'Disease', (16, 22))	('SMARCB1', 'Gene', (39, 46))	('C', 'Chemical', 'MESH:D002244', (43, 44))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('Inactivation', 'Var', (0, 12))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
611043	28451457	Another study by Calderaro et al found recurrent alterations involving chromosome 22q11 in each of four renal medullary carcinomas associated with sickle-cell trait.	('C', 'Chemical', 'MESH:D002244', (17, 18))	('renal medullary carcinomas', 'Phenotype', 'HP:0008659', (104, 130))	('alterations', 'Var', (49, 60))	('carcinomas', 'Disease', 'MESH:D002277', (120, 130))	('associated', 'Reg', (131, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('carcinomas', 'Disease', (120, 130))	('sickle-cell trait', 'Disease', (147, 164))
611044	28451457	Each of these showed hemizygous SMARCB1 deletion 84.	('C', 'Chemical', 'MESH:D002244', (36, 37))	('SMARCB1', 'Gene', (32, 39))	('deletion 84', 'Var', (40, 51))
611045	28451457	RNA sequencing further identified fusion transcripts involving SMARCB1 in these tumours.	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('tumours', 'Disease', (80, 87))	('fusion transcripts', 'Var', (34, 52))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('SMARCB1', 'Gene', (63, 70))
611048	28451457	The incidence of ALK rearrangement associated with all renal cell carcinomas is low, with an overall frequency of <1%.	('ALK', 'Gene', '238', (17, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (55, 75))	('renal cell carcinomas', 'Disease', (55, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('associated', 'Reg', (35, 45))	('ALK', 'Gene', (17, 20))	('rearrangement', 'Var', (21, 34))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (55, 76))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (55, 76))
611049	28451457	In a study including 534 adult renal cell carcinoma patients, ALK rearrangements occurred in two papillary renal cell carcinomas 86.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (107, 127))	('rearrangements', 'Var', (66, 80))	('papillary renal cell carcinomas', 'Disease', (97, 128))	('ALK', 'Gene', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (97, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('adult renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 51))	('occurred', 'Reg', (81, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (31, 51))	('adult renal cell carcinoma', 'Disease', (25, 51))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (107, 128))	('ALK', 'Gene', '238', (62, 65))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (97, 128))	('patients', 'Species', '9606', (52, 60))
611052	28451457	A significant event in prostate carcinogenesis involves gene fusion between members of the E-twenty-six transforming factor (ETS) family of genes, including ERG, and the transmembrane protease, serine 2 (TMPRSS2, 21q22.3) gene 88, 89, 90, 91.	('ERG', 'Gene', (157, 160))	('prostate carcinogenesis', 'Disease', (23, 46))	('prostate carcinogenesis', 'Disease', 'MESH:D063646', (23, 46))	('gene fusion', 'Var', (56, 67))	('ETS', 'Chemical', '-', (125, 128))
611060	28451457	The occurrence of the ETV6-NTRK3 translocation and consequential expression of the oncogene is an initiating event in the genesis of secretory breast cancer 97.	('secretory breast cancer', 'Disease', 'MESH:D001943', (133, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('ETV6-NTRK3', 'Gene', (22, 32))	('secretory breast cancer', 'Disease', (133, 156))	('translocation', 'Var', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
611064	28451457	Recurrent VTI1A-TCF7L2 fusion was identified in 3% of colorectal cancers 98.	('C', 'Chemical', 'MESH:D002244', (17, 18))	('colorectal cancers', 'Disease', (54, 72))	('fusion', 'Var', (23, 29))	('VTI1A-TCF7L2', 'Gene', (10, 22))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('colorectal cancers', 'Disease', 'MESH:D015179', (54, 72))
611067	28451457	Other translocations reported in recent years include EML4-ALK, C2orf44-ALK, SLC34A2-ROS1 and NAV2-TCF7L1 66.	('ALK', 'Gene', '238', (59, 62))	('ROS1', 'Gene', (85, 89))	('C', 'Chemical', 'MESH:D002244', (100, 101))	('ROS1', 'Gene', '6098', (85, 89))	('ALK', 'Gene', '238', (72, 75))	('NAV2-TCF7L1', 'Var', (94, 105))	('ALK', 'Gene', (59, 62))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('ALK', 'Gene', (72, 75))
611073	28451457	The t(2;3)(q13;p25) translocation, fusion of the thyroid transcription factor, paired box gene 8 (PAX8) with peroxisome proliferator activated receptor gamma (PPARG) is most commonly observed (30%) in follicular thyroid carcinoma 106.	('observed', 'Reg', (183, 191))	('PPARG', 'Gene', (159, 164))	('follicular thyroid carcinoma', 'Disease', (201, 229))	('PAX8', 'Gene', (98, 102))	('follicular thyroid carcinoma', 'Disease', 'MESH:D018263', (201, 229))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (212, 229))	('fusion', 'Var', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('t(2;3)(q13;p25)', 'STRUCTURAL_ABNORMALITY', 'None', (4, 19))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (201, 229))
611074	28451457	It is noteworthy that rearrangement of these genes has also been identified in benign thyroid adenomas with a break-apart frequency between 3% and 6% 107, 108.	('identified', 'Reg', (65, 75))	('thyroid adenomas', 'Disease', 'MESH:D013964', (86, 102))	('thyroid adenomas', 'Phenotype', 'HP:0000854', (86, 102))	('thyroid adenomas', 'Disease', (86, 102))	('rearrangement', 'Var', (22, 35))
611075	28451457	Approximately 20% of salivary gland tumours harbour chromosomal translocation 109.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('salivary gland tumour', 'Phenotype', 'HP:0100684', (21, 42))	('salivary gland tumours', 'Disease', (21, 43))	('chromosomal translocation 109', 'Var', (52, 81))	('salivary gland tumours', 'Disease', 'MESH:D012468', (21, 43))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))
611077	28451457	The identification of recurrent tumour-specific chromosomal translocations and novel fusion oncogenes has diagnostic, therapeutic, and prognostic implications.	('chromosomal translocations', 'Var', (48, 74))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
611084	28451457	The fusion oncogene derived from chromosomal translocation that binds cyclic-AMP response element protein related transcription co-factor 1 (CRTC1) with mastermind-like 2 NOTCH signalling coactivator (MAML2), t(11;19)(q12;p13) is aetiological for some mucoepidermoid carcinomas.	('mucoepidermoid carcinomas', 'Disease', (252, 277))	('t(11;19)(q12;p13', 'Var', (209, 225))	('mucoepidermoid carcinomas', 'Disease', 'MESH:D018277', (252, 277))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('cyclic-AMP', 'Chemical', 'MESH:D000242', (70, 80))	('t(11;19)(q12;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (209, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (267, 277))	('CRTC1', 'Gene', (141, 146))	('C', 'Chemical', 'MESH:D002244', (144, 145))	('binds', 'Interaction', (64, 69))	('C', 'Chemical', 'MESH:D002244', (174, 175))	('aetiological', 'Reg', (230, 242))
611086	28451457	Recurrent t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma results in a fusion of the MYB proto-oncogene with transcription factor gene NFIB 113.	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (49, 73))	('results in', 'Reg', (74, 84))	('adenoid cystic carcinoma', 'Disease', (49, 73))	('translocation', 'Var', (32, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('NFIB 113', 'Gene', (151, 159))	('fusion', 'Interaction', (87, 93))
611088	28451457	MYB-NFIB translocation was present in 49% of adenoid cystic carcinomas but not in other salivary gland tumours or non-salivary gland neoplasms 115.	('MYB-NFIB', 'Gene', (0, 8))	('salivary gland tumours', 'Disease', 'MESH:D012468', (88, 110))	('neoplasms', 'Phenotype', 'HP:0002664', (133, 142))	('salivary gland tumour', 'Phenotype', 'HP:0100684', (88, 109))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('adenoid cystic carcinomas', 'Disease', (45, 70))	('adenoid cystic carcinomas', 'Disease', 'MESH:D003528', (45, 70))	('salivary gland tumours', 'Disease', (88, 110))	('non-salivary gland neoplasms', 'Disease', 'MESH:D012468', (114, 142))	('translocation', 'Var', (9, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('salivary gland neoplasms', 'Phenotype', 'HP:0100684', (118, 142))	('neoplasm', 'Phenotype', 'HP:0002664', (133, 141))	('non-salivary gland neoplasms', 'Disease', (114, 142))
611089	28451457	A subset of about 20% of adenoid cyst carcinomas lacks any detectable MYB gene fusion 116, 117.	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('fusion 116', 'Var', (79, 89))	('MYB', 'Protein', (70, 73))	('adenoid cyst carcinomas', 'Disease', 'MESH:D003528', (25, 48))	('lacks', 'NegReg', (49, 54))	('adenoid cyst carcinomas', 'Disease', (25, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))
611093	28451457	MASC harbours a t(12;15) (p13;q25) translocation resulting in fusion of an E-twenty-six family member (ETV6) and the neurotrophic tyrosine kinase receptor type 3 (NTRK3) gene 119.	('C', 'Chemical', 'MESH:D002244', (3, 4))	('ETV6', 'Gene', (103, 107))	('t(12;15) (p13;q25', 'Var', (16, 33))	('NTRK3', 'Gene', (163, 168))	('fusion', 'Interaction', (62, 68))
611099	28451457	Gene fusion between Ewing sarcoma breakpoint region 1 (EWSR1) and the activating transcription factor 1 (ATF1) gene is a relatively consistent finding in HCCC 122.	('EWSR1', 'Gene', (55, 60))	('Ewing sarcoma', 'Disease', (20, 33))	('ATF1', 'Gene', (105, 109))	('EWSR1', 'Gene', '2130', (55, 60))	('HCCC', 'Disease', (154, 158))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (20, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (20, 33))	('Gene fusion', 'Var', (0, 11))
611103	28451457	Spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern 127.	('RET', 'Gene', (95, 98))	('ALK', 'Gene', '238', (70, 73))	('ROS1', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (81, 85))	('ROS1', 'Gene', '6098', (45, 49))	('neoplasms', 'Disease', (9, 18))	('BRAF', 'Gene', (81, 85))	('neoplasm', 'Phenotype', 'HP:0002664', (9, 17))	('neoplasms', 'Disease', 'MESH:D009369', (9, 18))	('RET', 'Gene', '5979', (95, 98))	('NTRK1', 'Gene', (57, 62))	('ALK', 'Gene', (70, 73))	('fusions', 'Var', (34, 41))	('neoplasms', 'Phenotype', 'HP:0002664', (9, 18))
611104	28451457	In a study of 140 spitzoid neoplasms, Wiesner et al demonstrated that kinase fusions were present in 18 of 30 Spitz nevi (60%) and within 6 of 8 atypical Spitz tumours (75%).	('neoplasm', 'Phenotype', 'HP:0002664', (27, 35))	('atypical Spitz tumours', 'Disease', 'MESH:D018332', (145, 167))	('neoplasms', 'Phenotype', 'HP:0002664', (27, 36))	('present', 'Reg', (90, 97))	('Spitz nevi', 'Disease', (110, 120))	('spitzoid neoplasms', 'Disease', 'MESH:D009369', (18, 36))	('spitzoid neoplasms', 'Disease', (18, 36))	('nevi', 'Phenotype', 'HP:0003764', (116, 120))	('atypical Spitz tumours', 'Disease', (145, 167))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('kinase fusions', 'Var', (70, 84))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))
611105	28451457	The kinase gene fusions involved ROS1 (26%, 16/73), ALK (11%, 8/75), NTRK1 (11%, 8/75), BRAF (5%, 4/75) and RET (3%, 2/75).	('fusions', 'Var', (16, 23))	('NTRK1', 'Gene', (69, 74))	('RET', 'Gene', '5979', (108, 111))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('ALK', 'Gene', '238', (52, 55))	('RET', 'Gene', (108, 111))	('ROS1', 'Gene', (33, 37))	('ALK', 'Gene', (52, 55))	('ROS1', 'Gene', '6098', (33, 37))
611107	28451457	Molecular alterations commonly seen in melanomas are typically absent from Spitz nevi and Spitz nevi contain translocations are not usually found in melanoma 91, 128, 129, 130.	('melanomas', 'Disease', (39, 48))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('melanomas', 'Disease', 'MESH:D008545', (39, 48))	('translocations', 'Var', (109, 123))	('Molecular alterations', 'Var', (0, 21))	('nevi', 'Phenotype', 'HP:0003764', (81, 85))	('nevi', 'Phenotype', 'HP:0003764', (96, 100))
611108	28451457	Translocations involving BRAF and MET genes have been recently reported in melanoma patients (Table 2).	('Translocations', 'Var', (0, 14))	('patients', 'Species', '9606', (84, 92))	('reported', 'Reg', (63, 71))	('MET', 'Gene', (34, 37))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('BRAF', 'Gene', '673', (25, 29))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('BRAF', 'Gene', (25, 29))
611113	28451457	MET translocations were found in six melanocytic tumours resulting in the following fusion genes: TRIM4-MET, ZKSCAN1-MET, PPFIBP1-MET LRRFIP1-MET, EPS15-MET and DCTN1-MET 134.	('melanocytic tumours', 'Disease', (37, 56))	('ZKSCAN1-MET', 'Gene', (109, 120))	('LRRFIP1-MET', 'Var', (134, 145))	('C', 'Chemical', 'MESH:D002244', (162, 163))	('melanocytic tumours', 'Disease', 'MESH:D009508', (37, 56))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('TRIM4-MET', 'Var', (98, 107))	('DCTN1-MET', 'Gene', (161, 170))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('EPS15-MET', 'Var', (147, 156))	('PPFIBP1-MET', 'Gene', (122, 133))
611115	28451457	More than 10 translocations have been reported in glioblastomas and gene fusions occur in approximately 30-50% of glioblastoma patients (Table 2) 136, 137, 138, 139.	('glioblastomas', 'Disease', 'MESH:D005909', (50, 63))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('glioblastomas', 'Disease', (50, 63))	('glioblastoma', 'Disease', (50, 62))	('patients', 'Species', '9606', (127, 135))	('glioblastoma', 'Disease', (114, 126))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('glioblastomas', 'Phenotype', 'HP:0012174', (50, 63))	('gene fusions', 'Var', (68, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
611116	28451457	PTPRZ1-MET translocation was detected in 15% of glioblastomas in independent cohorts, rendering it the most frequently recurring transcript in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('glioblastoma', 'Disease', (143, 155))	('translocation', 'Var', (11, 24))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('glioblastomas', 'Phenotype', 'HP:0012174', (48, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('glioblastomas', 'Disease', 'MESH:D005909', (48, 61))	('glioblastoma', 'Disease', (48, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('PTPRZ1-MET', 'Gene', (0, 10))	('glioblastomas', 'Disease', (48, 61))
611117	28451457	Recently, Bao et al investigated 272 gliomas by RNA seq and identified 67 in-frame fusion transcripts, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11 and PTPRZ1-MET 139.	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('FGFR3-TACC3', 'Gene', (149, 160))	('gliomas', 'Disease', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('RNF213-SLC26A11', 'Var', (162, 177))	('C', 'Chemical', 'MESH:D002244', (158, 159))
611119	28451457	Co-deletion of 1p/19q has been observed in up to 70% of oligodendrogliomas and 50% of mixed oligoastrocytomas 140, 141, 142, 143.	('oligodendrogliomas', 'Disease', (56, 74))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (92, 109))	('mixed', 'Disease', (86, 91))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('Co-deletion', 'Var', (0, 11))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (56, 74))	('astrocytoma', 'Phenotype', 'HP:0009592', (97, 108))	('observed', 'Reg', (31, 39))	('oligoastrocytomas', 'Disease', (92, 109))
611120	28451457	Deletions of 1p and 19q have been associated with prolonged survival in patients with oligodendrogliomas and mixed oligoastrocytomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (120, 131))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('oligoastrocytomas', 'Disease', (115, 132))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (86, 104))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (115, 132))	('prolonged', 'PosReg', (50, 59))	('Deletions', 'Var', (0, 9))	('oligodendrogliomas', 'Disease', (86, 104))	('patients', 'Species', '9606', (72, 80))
611121	28451457	Jenkins et al hypothesized that the majority of 1p and 19q deletions in gliomas were derived from a translocation t(1;19)(q10;p10), which has a prevalence of 81% in all 1p/19q deletion cases 144.	('t(1;19)(q10;p10', 'Var', (114, 129))	('deletions', 'Var', (59, 68))	('gliomas', 'Disease', 'MESH:D005910', (72, 79))	('t(1;19)(q10;p10)', 'STRUCTURAL_ABNORMALITY', 'None', (114, 130))	('gliomas', 'Phenotype', 'HP:0009733', (72, 79))	('gliomas', 'Disease', (72, 79))	('derived from', 'Reg', (85, 97))
611127	28451457	Parker et al showed that more than two-thirds of supratentorial ependymomas contained chromosomal translocations between avian reticuloendotheliosis viral oncogene homologue A (RELA) and chromosome 11 open reading frame 95(C11orf95) 147.	('C', 'Chemical', 'MESH:D002244', (223, 224))	('supratentorial', 'Disease', (49, 63))	('reticuloendotheliosis viral', 'Disease', 'MESH:C538362', (127, 154))	('ependymomas', 'Disease', (64, 75))	('reticuloendotheliosis viral', 'Disease', (127, 154))	('C11orf95', 'Gene', (223, 231))	('ependymomas', 'Disease', 'MESH:D004806', (64, 75))	('contained', 'Reg', (76, 85))	('chromosomal translocations', 'Var', (86, 112))
611141	27129148	Knock-down of TAZ and YAP demonstrate differential activity for the two proteins.	('activity', 'MPA', (51, 59))	('YAP', 'Gene', '10413', (22, 25))	('Knock-down', 'Var', (0, 10))	('TAZ', 'Gene', '6901', (14, 17))	('TAZ', 'Gene', (14, 17))	('YAP', 'Gene', (22, 25))
611149	27129148	Unexpectedly, mutations in the Hippo pathway or TAZ/YAP are rare.	('YAP', 'Gene', (52, 55))	('TAZ', 'Gene', '6901', (48, 51))	('TAZ', 'Gene', (48, 51))	('Hippo pathway', 'Pathway', (31, 44))	('mutations', 'Var', (14, 23))	('YAP', 'Gene', '10413', (52, 55))
611153	27129148	The observation that the WWTR1-CAMTA1 and YAP1-TFE3 gene fusions occur in a sarcoma suggests these cancers are particularly susceptible to perturbations within the Hippo pathway.	('CAMTA1', 'Gene', '23261', (31, 37))	('WWTR1', 'Gene', (25, 30))	('occur', 'Reg', (65, 70))	('sarcoma', 'Disease', 'MESH:D012509', (76, 83))	('YAP1', 'Gene', (42, 46))	('WWTR1', 'Gene', '25937', (25, 30))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('TFE3', 'Gene', (47, 51))	('YAP1', 'Gene', '10413', (42, 46))	('cancers', 'Disease', (99, 106))	('sarcoma', 'Disease', (76, 83))	('fusions', 'Var', (57, 64))	('TFE3', 'Gene', '7030', (47, 51))	('CAMTA1', 'Gene', (31, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
611177	27129148	Similarly, sarcomas expressing high levels of YAP1 had a median survival of 3.4 years, whereas those with low levels of YAP1 had a median survival of 7.1 years.	('YAP1', 'Gene', (120, 124))	('YAP1', 'Gene', '10413', (120, 124))	('high levels', 'Var', (31, 42))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcomas', 'Disease', (11, 19))	('YAP1', 'Gene', (46, 50))	('YAP1', 'Gene', '10413', (46, 50))
611233	27129148	To confirm that TAZ and YAP were oncoproteins in the above cell lines, we evaluated the effect of shRNA knock-down of TAZ and YAP by assaying various hallmarks of cancer including proliferation and anchorage-independent growth.	('TAZ', 'Gene', (16, 19))	('anchorage-independent growth', 'CPA', (198, 226))	('YAP', 'Gene', (126, 129))	('YAP', 'Gene', (24, 27))	('proliferation', 'CPA', (180, 193))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (150, 169))	('hallmarks of cancer', 'Disease', (150, 169))	('YAP', 'Gene', '10413', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('knock-down', 'Var', (104, 114))	('YAP', 'Gene', '10413', (126, 129))	('TAZ', 'Gene', '6901', (118, 121))	('TAZ', 'Gene', '6901', (16, 19))	('TAZ', 'Gene', (118, 121))
611235	27129148	Knock-down of TAZ markedly decreased proliferation of the SK-LMS-1 cell line.	('decreased', 'NegReg', (27, 36))	('Knock-down', 'Var', (0, 10))	('TAZ', 'Gene', '6901', (14, 17))	('proliferation of the SK-LMS-1 cell line', 'CPA', (37, 76))	('TAZ', 'Gene', (14, 17))	('SK-LMS-1', 'CellLine', 'CVCL:0628', (58, 66))
611237	27129148	However, while knock-down of TAZ resulted in complete abrogation of colony formation in soft agar, loss of expression of YAP did not have an effect of colony formation in soft agar (Figure 4f).	('TAZ', 'Gene', (29, 32))	('YAP', 'Gene', (121, 124))	('agar', 'Chemical', 'MESH:D000362', (176, 180))	('colony formation in soft agar', 'CPA', (68, 97))	('knock-down', 'Var', (15, 25))	('agar', 'Chemical', 'MESH:D000362', (93, 97))	('abrogation', 'NegReg', (54, 64))	('YAP', 'Gene', '10413', (121, 124))	('TAZ', 'Gene', '6901', (29, 32))
611239	27129148	Knock-down of TAZ caused a mild, but statistically significant decrease in proliferation, while knock-down of YAP did not significantly decrease proliferation (Figure S3b, S3c).	('Knock-down', 'Var', (0, 10))	('YAP', 'Gene', (110, 113))	('TAZ', 'Gene', '6901', (14, 17))	('decrease', 'NegReg', (63, 71))	('TAZ', 'Gene', (14, 17))	('proliferation', 'CPA', (75, 88))	('YAP', 'Gene', '10413', (110, 113))
611240	27129148	However, knock-down of TAZ and YAP both significantly decreased colony formation in soft agar (Figure S3d).	('TAZ', 'Gene', (23, 26))	('YAP', 'Gene', (31, 34))	('TAZ', 'Gene', '6901', (23, 26))	('agar', 'Chemical', 'MESH:D000362', (89, 93))	('colony formation in soft agar', 'CPA', (64, 93))	('knock-down', 'Var', (9, 19))	('decreased', 'NegReg', (54, 63))	('YAP', 'Gene', '10413', (31, 34))
611270	27129148	shRNA knock-down of both TAZ and YAP resulted in abrogation of various hallmarks of cancer.	('abrogation', 'NegReg', (49, 59))	('TAZ', 'Gene', '6901', (25, 28))	('hallmarks of cancer', 'Disease', (71, 90))	('YAP', 'Gene', '10413', (33, 36))	('knock-down', 'Var', (6, 16))	('TAZ', 'Gene', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('YAP', 'Gene', (33, 36))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (71, 90))
611302	27129148	Empty vector construct (SHC001), scrambled negative control (SHC002), and TAZ knock-down constructs TRCN0000319149 (shTAZ#1), TRCN0000319150 (shTAZ#2) (this is shTAZ#1 in Figure 4), TRCN0000319224 (shTAZ#3), TRCN0000370006 (shTAZ#4), TRCN0000370007 (shTAZ#5) (this is shTAZ#2 in Figure 4).	('TAZ', 'Gene', (252, 255))	('constructs TRCN0000319149', 'Disease', (89, 114))	('TRCN0000319224', 'Var', (182, 196))	('TAZ', 'Gene', '6901', (226, 229))	('TAZ', 'Gene', (226, 229))	('TAZ', 'Gene', '6901', (162, 165))	('TAZ', 'Gene', (162, 165))	('TAZ', 'Gene', '6901', (74, 77))	('TRCN0000370007', 'Var', (234, 248))	('TAZ', 'Gene', (74, 77))	('TAZ', 'Gene', '6901', (200, 203))	('TRCN0000370006', 'Var', (208, 222))	('constructs TRCN0000319149', 'Disease', 'MESH:D000381', (89, 114))	('TAZ', 'Gene', (200, 203))	('TAZ', 'Gene', (270, 273))	('TAZ', 'Gene', '6901', (270, 273))	('TAZ', 'Gene', '6901', (144, 147))	('TAZ', 'Gene', '6901', (118, 121))	('TAZ', 'Gene', (144, 147))	('TRCN0000319150', 'Var', (126, 140))	('TAZ', 'Gene', '6901', (252, 255))	('TAZ', 'Gene', (118, 121))
611389	21930769	In parallel experiments, blockade of IFN-gamma via treatment with neutralizing IFN-gamma-specific H22 mAb revealed a more prolonged requirement for the actions of IFN-gamma during H31m1 rejection (Fig.	('IFN-gamma', 'Gene', '15978', (37, 46))	('IFN-gamma', 'Gene', (79, 88))	('IFN-gamma', 'Gene', (163, 172))	('IFN-gamma', 'Gene', (37, 46))	('IFN-gamma', 'Gene', '15978', (79, 88))	('H31m1', 'Var', (180, 185))	('IFN-gamma', 'Gene', '15978', (163, 172))
611390	21930769	Cohorts of mice were also treated with a mixture of mAbs that deplete CD4+ and CD8+ cells and neutralize IFN-gamma (GK1.5, YTS169.4, and H22, respectively) to broadly disrupt host immunity.	('disrupt', 'NegReg', (167, 174))	('IFN-gamma', 'Gene', '15978', (105, 114))	('CD4', 'Gene', (70, 73))	('GK1.5', 'Gene', '16607', (116, 121))	('host immunity', 'CPA', (175, 188))	('CD8', 'Gene', (79, 82))	('CD4', 'Gene', '12504', (70, 73))	('mice', 'Species', '10090', (11, 15))	('CD8', 'Gene', '925', (79, 82))	('neutralize', 'Var', (94, 104))	('GK1.5', 'Gene', (116, 121))	('IFN-gamma', 'Gene', (105, 114))	('deplete', 'NegReg', (62, 69))
611396	21930769	We now show that both lines grew progressively in Ifnar1-/-   Ifnar1-/- bone marrow chimeras and Ifnar1-/-   Rag2-/- chimeras (IFN-alpha/beta sensitivity only in nonhematopoietic cells) but were rejected in WT   WT chimeras and WT   Ifnar1-/- chimeras (IFN-alpha/beta sensitivity only in hematopoietic cells).	('Rag2', 'Gene', (109, 113))	('Ifnar1-/-', 'Var', (50, 59))	('Ifnar1-/-', 'Var', (97, 106))	('Rag2', 'Gene', '19374', (109, 113))	('grew', 'CPA', (28, 32))
611409	21930769	When challenged with H31m1 or d38m2 cells, Rag2-/- and Ifnar1-/- control mice and globally unresponsive "neither" chimeras developed progressively growing tumors.	('Rag2', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mice', 'Species', '10090', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('d38m2', 'Var', (30, 35))	('Rag2', 'Gene', '19374', (43, 47))
611414	21930769	F515 tumor cells grew progressively when injected into Rag2-/- mice and WT mice treated with IFN-gamma-specific H22 mAb but were rejected in WT mice, WT mice treated with isotype control PIP mAb, and Ifnar1-/- hosts (Fig.	('mice', 'Species', '10090', (75, 79))	('IFN-gamma', 'Gene', (93, 102))	('PIP', 'Gene', '18716', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('mice', 'Species', '10090', (144, 148))	('Rag2', 'Gene', '19374', (55, 59))	('mice', 'Species', '10090', (63, 67))	('PIP', 'Gene', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('Rag2', 'Gene', (55, 59))	('grew', 'CPA', (17, 21))	('tumor', 'Disease', (5, 10))	('mice', 'Species', '10090', (153, 157))	('IFN-gamma', 'Gene', '15978', (93, 102))	('H22 mAb', 'Var', (112, 119))
611430	21930769	When PK136-treated WT mice were injected with unedited C57BL/6 tumor cells, they rejected these tumors with kinetics identical to control mice.	('tumor', 'Disease', (63, 68))	('PK136-treated', 'Var', (5, 18))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('mice', 'Species', '10090', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mice', 'Species', '10090', (22, 26))
611434	21930769	The resulting LysM-Cre+Ifnar1f/f mice displayed complete IFNAR1 deletion in peritoneal macrophages and PMNs and substantial deletion of IFNAR1 in monocytes (66%) and splenic macrophages (35%) but maintained undiminished IFNAR1 expression in DCs, NK cells, T cells, and B cells (Fig.	('IFNAR1', 'Gene', '15975', (220, 226))	('IFNAR1', 'Gene', '15975', (57, 63))	('IFNAR1', 'Gene', (57, 63))	('deletion', 'Var', (64, 72))	('LysM', 'Gene', (14, 18))	('IFNAR1', 'Gene', '15975', (136, 142))	('IFNAR1', 'Gene', (136, 142))	('mice', 'Species', '10090', (33, 37))	('LysM', 'Gene', '17105', (14, 18))	('IFNAR1', 'Gene', (220, 226))	('deletion', 'Var', (124, 132))
611445	21930769	Second, we assessed tumor rejection in mice that displayed a selective deletion of IFNAR1 in DCs.	('IFNAR1', 'Gene', (83, 89))	('deletion', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('mice', 'Species', '10090', (39, 43))	('IFNAR1', 'Gene', '15975', (83, 89))
611453	21930769	The selective nature of IFNAR1 deletion and loss of function in DCs allowed us to examine whether these cells were obligate targets of type I IFN during development of antitumor responses in vivo.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('loss', 'NegReg', (44, 48))	('IFNAR1', 'Gene', (24, 30))	('deletion', 'Var', (31, 39))	('IFNAR1', 'Gene', '15975', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
611471	21930769	Functionally active type I IFN receptors are expressed on nearly all nucleated cells, and previous studies documented effects of type I IFN on many immunologically relevant cell types (such as T cells, NK cells, and DCs) that theoretically should enhance the immune elimination of tumors.	('tumors', 'Disease', (281, 287))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('enhance', 'PosReg', (247, 254))	('effects', 'Reg', (118, 125))	('type I', 'Var', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))
611473	21930769	As further documented in vitro, type I IFN enhances the function of the CD8alpha+ DC subset, which in a previous study was shown to play a critical role in the development of tumor- and virus-specific immune responses through its capacity to cross-present antigen to CD8+ T cells.	('CD8alpha', 'Gene', (72, 80))	('CD8', 'Gene', (267, 270))	('tumor', 'Disease', (175, 180))	('CD8', 'Gene', '925', (267, 270))	('cross-present', 'Interaction', (242, 255))	('enhances', 'PosReg', (43, 51))	('type', 'Var', (32, 36))	('CD8alpha', 'Gene', '12525', (72, 80))	('function', 'MPA', (56, 64))	('CD8', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('antigen', 'Protein', (256, 263))	('CD8', 'Gene', '925', (72, 75))
611485	21930769	The resulting mice exhibited nearly complete deletion of IFNAR1 in peritoneal macrophages and PMNs and reduced levels of IFNAR1 in other myeloid populations including monocytes and splenic macrophages.	('reduced', 'NegReg', (103, 110))	('mice', 'Species', '10090', (14, 18))	('IFNAR1', 'Gene', (57, 63))	('IFNAR1', 'Gene', '15975', (57, 63))	('deletion', 'Var', (45, 53))	('IFNAR1', 'Gene', '15975', (121, 127))	('IFNAR1', 'Gene', (121, 127))
611501	21930769	When taken together with data demonstrating that (a) type I IFN promotes tumor-specific CTL priming, (b) type I IFN acts on innate immune cells to mediate its antitumor effects, (c) IFN-alpha/beta-responsive CD11c+ cells partially reconstitute in vivo CTL priming in Ifnar1-/- mice, (d) CD8alpha+ lineage DCs are required for CTL priming and tumor rejection, and (e) selective deletion of IFNAR1 in DCs abrogates tumor rejection, the collective evidence supports a host-protective function involving direct actions of type I IFN on CD8alpha+ lineage DCs.	('mice', 'Species', '10090', (277, 281))	('tumor', 'Phenotype', 'HP:0002664', (413, 418))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('abrogates', 'NegReg', (403, 412))	('CD8alpha', 'Gene', (532, 540))	('CD8alpha', 'Gene', (287, 295))	('tumor', 'Disease', (163, 168))	('CD8alpha', 'Gene', '12525', (532, 540))	('CD8alpha', 'Gene', '12525', (287, 295))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', (342, 347))	('IFNAR1', 'Gene', '15975', (389, 395))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('deletion', 'Var', (377, 385))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (413, 418))	('tumor', 'Disease', 'MESH:D009369', (413, 418))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('IFNAR1', 'Gene', (389, 395))
611516	21930769	129/SvEv Rag2-/-, C57BL/6 WT, and C57BL/6 Rag2-/- mice were obtained from Taconic.	('129/Sv', 'Species', '10090', (0, 6))	('C57BL/6', 'Var', (34, 41))	('Rag2', 'Gene', '19374', (42, 46))	('Rag2', 'Gene', '19374', (9, 13))	('Rag2', 'Gene', (42, 46))	('mice', 'Species', '10090', (50, 54))	('Rag2', 'Gene', (9, 13))
611523	21930769	C57BL/6 MHC class I-deficient Kb-/-Db-/-beta2m-/- mice were a gift from H. Virgin and T. Hansen (Washington University in St. Louis, St. Louis, MO).	('beta2m', 'Gene', '12010', (40, 46))	('beta2m', 'Gene', (40, 46))	('C57BL/6', 'Var', (0, 7))	('mice', 'Species', '10090', (50, 54))
611546	21930769	The following were obtained from BioLegend: anti-CD3-FITC (145-2C11), anti-CD4-PE (RMA4-5), anti-CD4-APC (GK1.5), anti-CD8alpha-APC (53-6.7), anti-CD8alpha-FITC (53-6.7), anti-B220-FITC (RA3-6B2), anti-CD11b-PE (M1/70), anti-CD11b-PerCP-Cy5.5 (and Pe-Cy7; M1/70), anti-DX5-PE (DX5), anti-DX5-APC (DX5), anti-Gr-1-FITC (RB6-8C5), anti-CD45-FITC (30-F11), anti-CD31-PE (MEC13.3), anti-CD24-FITC (M1/69), anti-CD103-PerCp-Cy5.5 (2E7), anti-Dec205-Pe-Cy7 (NLDC-145), anti-F4/80-PerCP-Cy5.5 (BM8), anti-CD11c-APC-Cy7 (N418), and SA-APC.	('anti-F4/80-PerCP-Cy5.5', 'Var', (463, 485))	('DX5', 'Gene', (277, 280))	('CD11b', 'Gene', (202, 207))	('CD24', 'Gene', '12484', (383, 387))	('GK1.5', 'Gene', '16607', (106, 111))	('CD8alpha', 'Gene', (119, 127))	('CD3', 'Gene', '12503', (49, 52))	('CD4', 'Gene', '12504', (334, 337))	('DX5', 'Gene', '16398', (297, 300))	('CD4', 'Gene', '12504', (97, 100))	('CD3', 'Gene', '12503', (359, 362))	('DX5', 'Gene', (297, 300))	('CD8alpha', 'Gene', '12525', (119, 127))	('CD45', 'Gene', (334, 338))	('CD103', 'Gene', (407, 412))	('M1/70', 'Gene', '22238', (256, 261))	('M1/70', 'Gene', (256, 261))	('CD3', 'Gene', (49, 52))	('CD4', 'Gene', (75, 78))	('M1/69', 'Gene', '22238', (394, 399))	('DX5', 'Gene', '16398', (288, 291))	('CD3', 'Gene', (359, 362))	('anti-CD11c-APC-Cy7', 'Var', (493, 511))	('DX5', 'Gene', (288, 291))	('M1/70', 'Gene', '22238', (212, 217))	('CD11b', 'Gene', '16409', (225, 230))	('CD8alpha', 'Gene', (147, 155))	('M1/70', 'Gene', (212, 217))	('CD4', 'Gene', '12504', (75, 78))	('CD24', 'Gene', (383, 387))	('M1/69', 'Gene', (394, 399))	('CD8alpha', 'Gene', '12525', (147, 155))	('DX5', 'Gene', '16398', (269, 272))	('CD11b', 'Gene', '16409', (202, 207))	('anti-Dec205-Pe-Cy7', 'Var', (432, 450))	('CD4', 'Gene', (97, 100))	('CD4', 'Gene', (334, 337))	('CD11b', 'Gene', (225, 230))	('DX5', 'Gene', (269, 272))	('CD103', 'Gene', '16407', (407, 412))	('GK1.5', 'Gene', (106, 111))	('DX5', 'Gene', '16398', (277, 280))	('CD45', 'Gene', '19264', (334, 338))
611567	21930769	In some assays, the irradiated target cells were mismatched (BALB/c) tumor cells expressing a truncated version of the IFN-gamma receptor to render them IFN-gamma insensitive and in which ovalbumin was retrovirally enforced (CMS-5-DeltaIC).	('IFN-gamma', 'Gene', (119, 128))	('IFN-gamma', 'Gene', '15978', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('truncated', 'Var', (94, 103))	('IFN-gamma', 'Gene', '15978', (119, 128))	('IFN-gamma', 'Gene', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('ovalbumin', 'Gene', '282665', (188, 197))	('ovalbumin', 'Gene', (188, 197))
611609	31492956	Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kalpha inhibition in medulloblastoma Despite recent advances in the treatment of medulloblastoma, patients in high-risk categories still face very poor outcomes.	('medulloblastoma', 'Disease', (104, 119))	('inhibition', 'NegReg', (90, 100))	('medulloblastoma', 'Disease', 'MESH:D008527', (164, 179))	('medulloblastoma', 'Phenotype', 'HP:0002885', (164, 179))	('PI3Kalpha', 'Gene', '5290', (80, 89))	('PI3Kalpha', 'Gene', (80, 89))	('enhances', 'PosReg', (31, 39))	('mTOR', 'Gene', '2475', (16, 20))	('targeting', 'Var', (21, 30))	('antineoplastic effects', 'MPA', (44, 66))	('patients', 'Species', '9606', (181, 189))	('mTOR', 'Gene', (16, 20))	('medulloblastoma', 'Disease', (164, 179))	('medulloblastoma', 'Disease', 'MESH:D008527', (104, 119))	('medulloblastoma', 'Phenotype', 'HP:0002885', (104, 119))
611614	31492956	Pharmacological mTOR inhibition potently enhanced the suppressive effects of alpelisib on cancer cell proliferation, colony formation and apoptosis and additionally blocked sphere-forming ability of medulloblastoma stem-like cancer cells in vitro.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('enhanced', 'PosReg', (41, 49))	('cancer', 'Disease', (225, 231))	('alpelisib', 'Chemical', 'MESH:C585539', (77, 86))	('medulloblastoma', 'Disease', 'MESH:D008527', (199, 214))	('inhibition', 'Var', (21, 31))	('alpelisib', 'Gene', (77, 86))	('cancer', 'Disease', (90, 96))	('apoptosis', 'CPA', (138, 147))	('medulloblastoma', 'Phenotype', 'HP:0002885', (199, 214))	('mTOR', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('blocked', 'NegReg', (165, 172))	('medulloblastoma', 'Disease', (199, 214))	('suppressive effects', 'MPA', (54, 73))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('colony formation', 'CPA', (117, 133))
611615	31492956	We identified the HH effector GLI1 as a target for dual PI3Kalpha and mTOR inhibition in SHH-type medulloblastoma and confirmed these results in HH-driven Ewing sarcoma cells.	('GLI1', 'Gene', (30, 34))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (155, 168))	('SHH-type medulloblastoma', 'Disease', 'MESH:D008527', (89, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('inhibition', 'NegReg', (75, 85))	('medulloblastoma', 'Phenotype', 'HP:0002885', (98, 113))	('mTOR', 'MPA', (70, 74))	('HH-driven Ewing sarcoma', 'Disease', 'MESH:C563168', (145, 168))	('GLI1', 'Gene', '2735', (30, 34))	('HH-driven Ewing sarcoma', 'Disease', (145, 168))	('SHH-type medulloblastoma', 'Disease', (89, 113))	('PI3Kalpha', 'Var', (56, 65))
611622	31492956	Due to the very poor clinical outcome of some SHH medulloblastoma patients, the WHO has recently revised this classification, with new subclasses distinguishing between SHH, TP53 wild-type and SHH, TP53 mutant medulloblastoma.	('mutant', 'Var', (203, 209))	('medulloblastoma', 'Phenotype', 'HP:0002885', (50, 65))	('TP53', 'Gene', (174, 178))	('medulloblastoma', 'Disease', (50, 65))	('medulloblastoma', 'Disease', 'MESH:D008527', (50, 65))	('medulloblastoma', 'Disease', 'MESH:D008527', (210, 225))	('TP53', 'Gene', '7157', (198, 202))	('patients', 'Species', '9606', (66, 74))	('medulloblastoma', 'Phenotype', 'HP:0002885', (210, 225))	('SHH medulloblastoma', 'Disease', 'MESH:D008527', (46, 65))	('TP53', 'Gene', (198, 202))	('medulloblastoma', 'Disease', (210, 225))	('TP53', 'Gene', '7157', (174, 178))	('SHH medulloblastoma', 'Disease', (46, 65))
611623	31492956	Patients with SHH-driven medulloblastoma frequently exhibit either germline or somatic mutations and copy-number alterations in genes that regulate the Hedgehog (HH) signalling pathway such as PTCH1, SUFU, SMO, GLI1, GLI2 and MYCN.	('MYCN', 'Gene', (226, 230))	('MYCN', 'Gene', '4613', (226, 230))	('GLI2', 'Gene', '2736', (217, 221))	('GLI1', 'Gene', '2735', (211, 215))	('exhibit', 'Reg', (52, 59))	('medulloblastoma', 'Disease', 'MESH:D008527', (25, 40))	('SUFU', 'Gene', (200, 204))	('Patients', 'Species', '9606', (0, 8))	('PTCH1', 'Gene', '5727', (193, 198))	('medulloblastoma', 'Phenotype', 'HP:0002885', (25, 40))	('GLI1', 'Gene', (211, 215))	('copy-number alterations', 'Var', (101, 124))	('SHH-driven', 'Gene', (14, 24))	('medulloblastoma', 'Disease', (25, 40))	('GLI2', 'Gene', (217, 221))	('SUFU', 'Gene', '51684', (200, 204))	('PTCH1', 'Gene', (193, 198))	('mutations', 'Var', (87, 96))
611624	31492956	As a consequence, these genetic changes result in constitutive transcriptional activation of HH target genes, such as glioma-associated oncogene (GLI) transcription factors, that can promote cell proliferation and tumorigenesis.	('transcriptional', 'MPA', (63, 78))	('GLI', 'Gene', (146, 149))	('glioma', 'Disease', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('genetic changes', 'Var', (24, 39))	('GLI', 'Gene', '2735', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('tumor', 'Disease', (214, 219))	('activation', 'PosReg', (79, 89))	('cell proliferation', 'CPA', (191, 209))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('promote', 'PosReg', (183, 190))	('changes', 'Var', (32, 39))
611626	31492956	However, SMO inhibitors in younger patients may result in complications due to the essential role of HH signalling during development.	('inhibitors', 'Var', (13, 23))	('SMO', 'Gene', (9, 12))	('complications', 'Disease', (58, 71))	('patients', 'Species', '9606', (35, 43))	('result in', 'Reg', (48, 57))
611631	31492956	One such pathway is triggered by mechanistic target of rapamycin (mTOR)/S6K1 mediated phosphorylation of GLI1, resulting in GLI1 nuclear translocation and activation of HH target genes.	('GLI1', 'Gene', '2735', (124, 128))	('GLI1', 'Gene', (124, 128))	('GLI1', 'Gene', '2735', (105, 109))	('S6K1', 'Gene', (72, 76))	('GLI1', 'Gene', (105, 109))	('mechanistic target of rapamycin', 'Gene', '2475', (33, 64))	('S6K1', 'Gene', '6198', (72, 76))	('mechanistic target of rapamycin', 'Gene', (33, 64))	('activation', 'PosReg', (155, 165))	('phosphorylation', 'Var', (86, 101))
611635	31492956	This key role for mTOR has recently been corroborated by another study, reporting that loss of mTORC1 function blocks development of SHH-driven medulloblastoma.	('loss', 'Var', (87, 91))	('medulloblastoma', 'Disease', 'MESH:D008527', (144, 159))	('medulloblastoma', 'Phenotype', 'HP:0002885', (144, 159))	('mTORC1', 'Gene', (95, 101))	('medulloblastoma', 'Disease', (144, 159))	('blocks', 'NegReg', (111, 117))	('development', 'CPA', (118, 129))	('mTORC1', 'Gene', '382056', (95, 101))
611639	31492956	Importantly, strategies targeting PI3K are not limited to SHH-driven medulloblastoma because pharmacological PI3K inhibition has also shown promise in MYC-driven Group 3 mouse models of medulloblastoma.	('medulloblastoma', 'Disease', (186, 201))	('medulloblastoma', 'Phenotype', 'HP:0002885', (186, 201))	('medulloblastoma', 'Disease', 'MESH:D008527', (69, 84))	('mouse', 'Species', '10090', (170, 175))	('medulloblastoma', 'Disease', 'MESH:D008527', (186, 201))	('PI3K', 'Var', (109, 113))	('medulloblastoma', 'Phenotype', 'HP:0002885', (69, 84))	('medulloblastoma', 'Disease', (69, 84))
611642	31492956	Accordingly, inhibition of PI3K signalling was shown to inhibit proliferation and promote differentiation of stem-like cancer cells in medulloblastoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (135, 150))	('differentiation', 'CPA', (90, 105))	('PI3K signalling', 'Pathway', (27, 42))	('medulloblastoma', 'Disease', (135, 150))	('promote', 'PosReg', (82, 89))	('inhibition', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('proliferation', 'CPA', (64, 77))	('medulloblastoma', 'Disease', 'MESH:D008527', (135, 150))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('inhibit', 'NegReg', (56, 63))
611643	31492956	Further, our own studies have demonstrated a key role for the PI3Kalpha catalytic isoform (p110alpha) in sphere forming medulloblastoma cells and showed disruption of cancer stem cell frequencies after PIK3CA knockdown.	('disruption of cancer', 'Disease', 'MESH:D019958', (153, 173))	('disruption of cancer', 'Disease', (153, 173))	('medulloblastoma', 'Disease', 'MESH:D008527', (120, 135))	('medulloblastoma', 'Phenotype', 'HP:0002885', (120, 135))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', '5290', (202, 208))	('p110alpha', 'Gene', (91, 100))	('p110alpha', 'Gene', '5290', (91, 100))	('knockdown', 'Var', (209, 218))	('medulloblastoma', 'Disease', (120, 135))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
611647	31492956	Here, we sought to investigate the therapeutic effects of combined PI3Kalpha and mTOR inhibition in medulloblastoma and in particular the effects on the CSC population.	('medulloblastoma', 'Disease', 'MESH:D008527', (100, 115))	('PI3Kalpha', 'Var', (67, 76))	('medulloblastoma', 'Phenotype', 'HP:0002885', (100, 115))	('mTOR', 'Gene', (81, 85))	('medulloblastoma', 'Disease', (100, 115))	('inhibition', 'NegReg', (86, 96))
611651	31492956	These results suggest that selective PI3Kalpha targeting combined with mTOR inhibition has a therapeutic effect in medulloblastoma and potentially other HH-driven paediatric cancers.	('medulloblastoma', 'Phenotype', 'HP:0002885', (115, 130))	('medulloblastoma', 'Disease', (115, 130))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Disease', (174, 181))	('PI3Kalpha targeting', 'Var', (37, 56))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('medulloblastoma', 'Disease', 'MESH:D008527', (115, 130))
611655	31492956	We chose two cell lines that represent the highest risk category with very poor prognosis; DAOY representing the SHH, TP53 mutated and D556 representing the Group 3 MYC amplified category.	('D556', 'Var', (135, 139))	('DAOY', 'CellLine', 'CVCL:1167', (91, 95))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('mutated', 'Var', (123, 130))
611656	31492956	Combined treatment with alpelisib and the catalytic mTOR inhibitor OSI-027 decreased phosphorylation of AKT (Ser473), S6K1 (Thr389), and 4E-BP1 (Thr37/46) (Fig.	('Thr389', 'Chemical', '-', (124, 130))	('E-BP1', 'Gene', '4790', (138, 143))	('Thr37', 'Chemical', '-', (145, 150))	('phosphorylation', 'MPA', (85, 100))	('E-BP1', 'Gene', (138, 143))	('Ser473', 'Var', (109, 115))	('Ser473', 'Chemical', '-', (109, 115))	('alpelisib', 'Chemical', 'MESH:C585539', (24, 33))	('OSI-027', 'Chemical', 'MESH:C568605', (67, 74))	('S6K1', 'Gene', '6198', (118, 122))	('AKT', 'Pathway', (104, 107))	('S6K1', 'Gene', (118, 122))	('decreased', 'NegReg', (75, 84))
611657	31492956	These results suggest that combined PI3Kalpha and mTOR inhibition potently blocks signalling of the PI3K-AKT-mTOR axis in medulloblastoma.	('mTOR', 'Protein', (50, 54))	('blocks', 'NegReg', (75, 81))	('medulloblastoma', 'Disease', 'MESH:D008527', (122, 137))	('medulloblastoma', 'Phenotype', 'HP:0002885', (122, 137))	('PI3Kalpha', 'Var', (36, 45))	('medulloblastoma', 'Disease', (122, 137))	('signalling', 'MPA', (82, 92))
611665	31492956	Together, these results suggest that catalytic mTOR inhibition strongly enhances the antineoplastic effects of selective PI3Kalpha inhibition in medulloblastoma cells.	('PI3Kalpha', 'Var', (121, 130))	('inhibition', 'Var', (52, 62))	('catalytic', 'MPA', (37, 46))	('medulloblastoma', 'Disease', 'MESH:D008527', (145, 160))	('antineoplastic effects', 'CPA', (85, 107))	('medulloblastoma', 'Phenotype', 'HP:0002885', (145, 160))	('enhances', 'PosReg', (72, 80))	('medulloblastoma', 'Disease', (145, 160))
611678	31492956	The reduction of GLI1 protein in the nucleus after dual PI3Kalpha and mTOR inhibition indicates a requirement for PI3Kalpha and mTOR activities to sustain nuclear GLI1 in HH-driven cancers.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('HH-driven cancers', 'Disease', (171, 188))	('inhibition', 'Var', (75, 85))	('GLI1', 'Gene', '2735', (163, 167))	('GLI1', 'Gene', '2735', (17, 21))	('GLI1', 'Gene', (163, 167))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('reduction', 'NegReg', (4, 13))	('GLI1', 'Gene', (17, 21))	('HH-driven cancers', 'Disease', 'MESH:D006432', (171, 188))
611682	31492956	Additionally, dual PI3Kalpha and mTOR inhibition significantly reduced anchorage-independent growth of TC71 and RDES cells in soft agar as compared to either drug alone (Fig.	('TC71', 'CellLine', 'CVCL:2213', (103, 107))	('anchorage-independent growth', 'CPA', (71, 99))	('reduced', 'NegReg', (63, 70))	('mTOR', 'Protein', (33, 37))	('PI3Kalpha', 'Var', (19, 28))	('inhibition', 'NegReg', (38, 48))	('agar', 'Chemical', 'MESH:D000362', (131, 135))
611683	31492956	These data support a role for PI3Kalpha and mTOR activities in maintaining nuclear GLI1 protein and inhibition of PI3Kalpha and mTOR disrupts the accumulation of GLI1 in the nucleus which may, at least in part, contribute to greatly reduced cell viability and colony formation in HH-driven paediatric cancers.	('reduced', 'NegReg', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (301, 308))	('GLI1', 'Gene', '2735', (162, 166))	('cancers', 'Disease', (301, 308))	('GLI1', 'Gene', (83, 87))	('cell viability', 'CPA', (241, 255))	('GLI1', 'Gene', (162, 166))	('cancers', 'Disease', 'MESH:D009369', (301, 308))	('PI3Kalpha', 'Gene', (114, 123))	('inhibition', 'Var', (100, 110))	('colony formation', 'CPA', (260, 276))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('accumulation', 'MPA', (146, 158))	('GLI1', 'Gene', '2735', (83, 87))	('disrupts', 'NegReg', (133, 141))
611689	31492956	These results indicate greatly reduced sphere-forming ability of medulloblastoma neurospheres after dual PI3Kalpha and mTOR inhibition.	('medulloblastoma', 'Disease', (65, 80))	('sphere-forming ability of', 'CPA', (39, 64))	('reduced', 'NegReg', (31, 38))	('medulloblastoma', 'Disease', 'MESH:D008527', (65, 80))	('medulloblastoma', 'Phenotype', 'HP:0002885', (65, 80))	('inhibition', 'Var', (124, 134))
611693	31492956	Also, our previous work has demonstrated that the effects of PIK3CA knockdown or pharmacological PI3Kalpha inhibition can be enhanced by concomitant inhibition of pro-survival pathways in medulloblastoma.	('PIK3CA', 'Gene', (61, 67))	('inhibition', 'NegReg', (149, 159))	('medulloblastoma', 'Disease', 'MESH:D008527', (188, 203))	('PIK3CA', 'Gene', '5290', (61, 67))	('medulloblastoma', 'Phenotype', 'HP:0002885', (188, 203))	('PI3Kalpha', 'Gene', (97, 106))	('pro-survival pathways', 'Pathway', (163, 184))	('knockdown', 'Var', (68, 77))	('medulloblastoma', 'Disease', (188, 203))	('enhanced', 'PosReg', (125, 133))	('inhibition', 'NegReg', (107, 117))
611694	31492956	Therefore, we used RNA interference (RNAi) to determine a possible role for mTOR activity in maintaining CSC frequencies after PIK3CA knockdown.	('knockdown', 'Var', (134, 143))	('PIK3CA', 'Gene', '5290', (127, 133))	('CSC frequencies', 'MPA', (105, 120))	('PIK3CA', 'Gene', (127, 133))
611695	31492956	PIK3CA knockdown strongly reduced the proportion of cells with self-renewal capacity in both DAOY (Fig.	('PIK3CA', 'Gene', (0, 6))	('reduced', 'NegReg', (26, 33))	('PIK3CA', 'Gene', '5290', (0, 6))	('knockdown', 'Var', (7, 16))	('DAOY', 'CellLine', 'CVCL:1167', (93, 97))
611696	31492956	Importantly, the combination of OSI-027 with PIK3CA knockdown significantly reduced stem cell frequencies over either PIK3CA knockdown or OSI-027 single agent alone.	('stem cell frequencies', 'CPA', (84, 105))	('OSI-027', 'Chemical', 'MESH:C568605', (138, 145))	('OSI-027', 'Chemical', 'MESH:C568605', (32, 39))	('PIK3CA', 'Gene', (45, 51))	('combination', 'Interaction', (17, 28))	('reduced', 'NegReg', (76, 83))	('PIK3CA', 'Gene', '5290', (45, 51))	('PIK3CA', 'Gene', (118, 124))	('knockdown', 'Var', (52, 61))	('PIK3CA', 'Gene', '5290', (118, 124))
611697	31492956	Specifically, stem cell frequencies in DAOY dropped from 1 in 394.2 cells for PIK3CA knockdown or 1 in 544 for OSI-027 to 1 in 1526.8 for the combination PIK3CA knockdown and OSI-027 (Fig.	('PIK3CA', 'Gene', (78, 84))	('PIK3CA', 'Gene', (154, 160))	('dropped', 'NegReg', (44, 51))	('DAOY', 'CellLine', 'CVCL:1167', (39, 43))	('OSI-027', 'Chemical', 'MESH:C568605', (111, 118))	('PIK3CA', 'Gene', '5290', (78, 84))	('PIK3CA', 'Gene', '5290', (154, 160))	('knockdown', 'Var', (85, 94))	('stem cell frequencies', 'CPA', (14, 35))	('OSI-027', 'Chemical', 'MESH:C568605', (175, 182))
611698	31492956	Similar results were observed for D556 where stem cell frequencies decreased from 1 in 221.1 for PIK3CA knockdown or 1 in 123.4 for OSI-027 to 1 in 1366.4 for the combination (Fig.	('PIK3CA', 'Gene', (97, 103))	('OSI-027', 'Chemical', 'MESH:C568605', (132, 139))	('decreased', 'NegReg', (67, 76))	('stem cell frequencies', 'CPA', (45, 66))	('knockdown', 'Var', (104, 113))	('PIK3CA', 'Gene', '5290', (97, 103))
611700	31492956	These results indicate that pharmacologic mTOR inhibition enhances the disruptive effects of PIK3CA knockdown on stem cell frequencies and suggest dual inhibition of PI3Kalpha and mTOR is required to efficiently block self-renewal capabilities of medulloblastoma CSCs.	('medulloblastoma CSCs', 'Disease', (247, 267))	('knockdown', 'Var', (100, 109))	('PIK3CA', 'Gene', '5290', (93, 99))	('inhibition', 'Var', (47, 57))	('stem cell frequencies', 'CPA', (113, 134))	('medulloblastoma', 'Phenotype', 'HP:0002885', (247, 262))	('self-renewal capabilities', 'CPA', (218, 243))	('block', 'NegReg', (212, 217))	('PIK3CA', 'Gene', (93, 99))	('medulloblastoma CSCs', 'Disease', 'MESH:D008527', (247, 267))	('disruptive effects', 'MPA', (71, 89))	('enhances', 'PosReg', (58, 66))
611707	31492956	Due to the poor prognosis of some SHH medulloblastomas, the 2016 WHO consensus conference has reclassified subgroups into: WNT, SHH and TP53 wild-type, SHH and TP53 mutant, and non-WNT/non-SHH (encompassing Group 3 and Group 4 within this subgroup).	('mutant', 'Var', (165, 171))	('TP53', 'Gene', '7157', (160, 164))	('SHH medulloblastomas', 'Disease', 'MESH:D008527', (34, 54))	('medulloblastoma', 'Phenotype', 'HP:0002885', (38, 53))	('TP53', 'Gene', (160, 164))	('TP53', 'Gene', '7157', (136, 140))	('SHH medulloblastomas', 'Disease', (34, 54))	('TP53', 'Gene', (136, 140))
611709	31492956	This very poor prognosis resulted in listing these patients with SHH, TP53 mutations as their own category by the WHO.	('SHH', 'Gene', (65, 68))	('TP53', 'Gene', '7157', (70, 74))	('TP53', 'Gene', (70, 74))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (75, 84))
611710	31492956	In the current study, we investigated the effects of combined PI3Kalpha and mTOR inhibition in two of the highest risk category medulloblastoma cells, with DAOY cells representing the SHH, TP53 mutant and D556 cells representing the Group 3 MYC amplified categories.	('PI3Kalpha', 'Var', (62, 71))	('DAOY', 'CellLine', 'CVCL:1167', (156, 160))	('TP53', 'Gene', '7157', (189, 193))	('medulloblastoma', 'Disease', (128, 143))	('TP53', 'Gene', (189, 193))	('inhibition', 'NegReg', (81, 91))	('mTOR', 'Pathway', (76, 80))	('medulloblastoma', 'Disease', 'MESH:D008527', (128, 143))	('medulloblastoma', 'Phenotype', 'HP:0002885', (128, 143))
611718	31492956	Additionally, knockdown of PIK3CA (encoding p110alpha) in combination with OSI-027 disrupted stem cell frequencies.	('stem cell frequencies', 'CPA', (93, 114))	('PIK3CA', 'Gene', (27, 33))	('OSI-027', 'Chemical', 'MESH:C568605', (75, 82))	('p110alpha', 'Gene', (44, 53))	('disrupted', 'NegReg', (83, 92))	('knockdown', 'Var', (14, 23))	('PIK3CA', 'Gene', '5290', (27, 33))	('p110alpha', 'Gene', '5290', (44, 53))
611723	31492956	We found nuclear GLI1 protein amounts were reduced in DAOY cells after combined PI3Kalpha and mTOR inhibition, indicating a role for PI3K/mTOR signalling in the regulation of GLI1 in the SHH subgroup.	('GLI1', 'Gene', (175, 179))	('PI3Kalpha', 'Var', (80, 89))	('DAOY', 'CellLine', 'CVCL:1167', (54, 58))	('inhibition', 'Var', (99, 109))	('GLI1', 'Gene', '2735', (17, 21))	('GLI1', 'Gene', '2735', (175, 179))	('reduced', 'NegReg', (43, 50))	('GLI1', 'Gene', (17, 21))
611724	31492956	This observation prompted us to further investigate the mechanistic role of PI3Kalpha and mTOR in additional HH-driven paediatric cancers.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('mTOR', 'Gene', (90, 94))	('PI3Kalpha', 'Var', (76, 85))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
611727	31492956	We chose Ewing sarcoma because this tumour type was shown to directly dependent on GLI1 and knockdown or inhibition of GLI1 exerts antineoplastic effects in this cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (9, 22))	('Ewing sarcoma', 'Disease', (9, 22))	('inhibition', 'Var', (105, 115))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (9, 22))	('tumour', 'Disease', (36, 42))	('cancer', 'Disease', (162, 168))	('GLI1', 'Gene', (83, 87))	('knockdown', 'Var', (92, 101))	('GLI1', 'Gene', '2735', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('GLI1', 'Gene', (119, 123))	('GLI1', 'Gene', '2735', (83, 87))	('antineoplastic effects', 'CPA', (131, 153))
611729	31492956	This suggests that continuous activity of the PI3K/mTOR axis is required to maintain high levels of GLI1 in the nucleus and inhibition of this pathway results in a reduction of nuclear GLI1 protein amounts.	('GLI1', 'Gene', (100, 104))	('GLI1', 'Gene', (185, 189))	('inhibition', 'Var', (124, 134))	('GLI1', 'Gene', '2735', (185, 189))	('GLI1', 'Gene', '2735', (100, 104))	('reduction', 'NegReg', (164, 173))
611739	31492956	Here, we demonstrate potent anti-tumor effects after dual PI3K/mTOR inhibition that may be mediated, at least in part, by disrupting nuclear GLI1.	('GLI1', 'Gene', '2735', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('disrupting', 'NegReg', (122, 132))	('GLI1', 'Gene', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('inhibition', 'NegReg', (68, 78))	('tumor', 'Disease', (33, 38))	('PI3K/mTOR', 'Var', (58, 67))
611776	29204207	The lesion was 62 mm x 5 mm x 65 mm in size and heterogeneously hyperintense on T2-weighted images and hypointense on T1-weighted images with internal areas of calcification which showed blooming on gradient-echo images.	('hypointense', 'Var', (103, 114))	('calcification', 'Disease', 'MESH:D002114', (160, 173))	('calcification', 'Disease', (160, 173))
611823	28316069	Individuals diagnosed with a SPT (OR (99% CI): 0.68 (0.52-0.88)), epilepsy (0.33 (0.27-0.42)), a hearing problem (0.75 (0.61-0.93)), visual problem (0.44 (0.36-0.54)) or recurrence (0.69 (0.58-0.84)) were all less likely to be in employment than those without such medical history.	('visual problem', 'Phenotype', 'HP:0000505', (133, 147))	('epilepsy', 'Disease', 'MESH:D004827', (66, 74))	('visual problem', 'Disease', (133, 147))	('SPT', 'Disease', (29, 32))	('epilepsy', 'Phenotype', 'HP:0001250', (66, 74))	('hearing problem', 'Disease', (97, 112))	('less', 'NegReg', (209, 213))	('0.44', 'Var', (149, 153))	('epilepsy', 'Disease', (66, 74))	('hearing problem', 'Phenotype', 'HP:0000365', (97, 112))
611884	28316069	As suggested by others interventions for childhood cancer survivors should target physical health barriers to employment, as well as screening for mental health and neurocognitive problems.30 The Department of Health 2011 Strategy for Cancer31 highlights deficiencies in current cancer follow-up which is failing to meet the psychosocial needs of patients following treatment.	('psychosocial', 'Disease', (325, 337))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('Cancer', 'Phenotype', 'HP:0002664', (235, 241))	('psychosocial', 'Disease', 'MESH:C535569', (325, 337))	('deficiencies', 'Var', (255, 267))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('patients', 'Species', '9606', (347, 355))
611891	27557633	To address this question, we utilized zebrafish mutants for ewsa and tp53.	('zebrafish', 'Species', '7955', (38, 47))	('mutants', 'Var', (48, 55))	('tp53', 'Gene', (69, 73))	('ewsa', 'Gene', (60, 64))
611893	27557633	However, when the ewsa and tp53 mutant lines were crossed with each other, the incidence of tumorigenesis drastically increased.	('tp53', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutant', 'Var', (32, 38))	('tumor', 'Disease', (92, 97))
611894	27557633	Furthermore, 27 hour post fertilization (hpf) MZ ewsam/m mutant embryos displayed a higher incidence of aberrant chromosome numbers and mitotic dysfunction compared to wildtype zebrafish embryos.	('mitotic dysfunction', 'Disease', (136, 155))	('aberrant chromosome numbers', 'CPA', (104, 131))	('aberrant chromosome numbers', 'Phenotype', 'HP:0031411', (104, 131))	('mitotic dysfunction', 'Disease', 'MESH:C536987', (136, 155))	('mutant', 'Var', (57, 63))	('zebrafish', 'Species', '7955', (177, 186))
611895	27557633	Consistent with this finding, tumor samples obtained from ewsam/m;tp53w/m zebrafish displayed loss of heterozygosity (LOH) for the wildtype tp53 locus.	('loss', 'NegReg', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('heterozygosity', 'MPA', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('zebrafish', 'Species', '7955', (74, 83))	('tp53w/m', 'Var', (66, 73))	('tumor', 'Disease', (30, 35))
611897	27557633	We propose that the loss of ewsa promotes tumorigenesis, and EWS deficiency may contribute to the pathogenesis of EWS-fusion-expressing sarcomas.	('promotes', 'PosReg', (33, 41))	('loss', 'Var', (20, 24))	('tumor', 'Disease', (42, 47))	('sarcomas', 'Disease', (136, 144))	('deficiency', 'Disease', (65, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('deficiency', 'Disease', 'MESH:D007153', (65, 75))	('sarcomas', 'Disease', 'MESH:D012509', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('ewsa', 'Gene', (28, 32))	('EWS', 'Gene', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))	('contribute', 'Reg', (80, 90))
611901	27557633	However, loss of one EWS allele is also a consequence of fusion gene formation and has been observed in EWS-associated sarcomas.	('sarcomas', 'Disease', (119, 127))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('fusion gene formation', 'Var', (57, 78))
611902	27557633	The functional significance of loss of EWS on the pathogenesis of EWS-fusion associated sarcomas is unknown.	('sarcomas', 'Disease', (88, 96))	('loss', 'Var', (31, 35))	('sarcomas', 'Disease', 'MESH:D012509', (88, 96))	('EWS', 'Gene', (39, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (88, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
611907	27557633	An animal model is a powerful approach for investigating the effect that loss of EWS has on transformation of normal cells into cancerous cells, because it enables the analysis of the molecular mechanism of transformation.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('loss', 'Var', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('EWS', 'Gene', (81, 84))	('cancer', 'Disease', (128, 134))
611910	27557633	In this study, we utilized a zebrafish ewsa loss of function mutant to analyze the effect that ewsa mutation has on tumorigenesis.	('ewsa', 'Gene', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mutation', 'Var', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutant', 'Var', (61, 67))	('zebrafish', 'Species', '7955', (29, 38))	('tumor', 'Disease', (116, 121))	('loss of function', 'NegReg', (44, 60))
611911	27557633	The zebrafish tp53(M214K) mutant, a well characterized cancer model, was utilized as a platform for studying tumor promotion.	('zebrafish', 'Species', '7955', (4, 13))	('M214K', 'Mutation', 'rs749320836', (19, 24))	('M214K', 'Var', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('tumor', 'Disease', (109, 114))
611912	27557633	reported that homozygous tp53M214K/M214K (subsequently referred to as tp53m/m) mutant zebrafish display a 28% incidence of tumorigenesis by 16.5 mpf, whereas no tumors were reported in heterozygous tp53w/m zebrafish.	('M214K', 'Mutation', 'rs749320836', (29, 34))	('tumor', 'Disease', (123, 128))	('tp53M214K/M214K', 'Var', (25, 40))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('zebrafish', 'Species', '7955', (86, 95))	('zebrafish', 'Species', '7955', (206, 215))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('M214K', 'Mutation', 'rs749320836', (35, 40))
611913	27557633	In our study, we discovered that the zebrafish ewsa mutant promotes tumorigenesis in the tp53w/m background by promoting loss of heterozygosity (LOH) of the wildtype tp53 locus (that was accompanied by the loss of tp53 wildtype allele), suggesting that Ewsa acts to suppress tumorigenesis.	('tumor', 'Disease', (68, 73))	('Ewsa', 'Chemical', '-', (253, 257))	('mutant', 'Var', (52, 58))	('tumor', 'Disease', (275, 280))	('loss', 'NegReg', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('promotes', 'PosReg', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('zebrafish', 'Species', '7955', (37, 46))
611920	27557633	Because tumorigenesis is a complex process requiring multiple mutations, and because 10-15% of Ewing sarcoma patients have mutations in the tumor suppressor gene TP53, we chose to utilize the zebrafish tp53 mutant to evaluate the synergistic effect of ewsa and tp53 mutations.	('zebrafish', 'Species', '7955', (192, 201))	('Ewing sarcoma', 'Disease', (95, 108))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (95, 108))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutations', 'Var', (123, 132))	('tumor', 'Disease', (140, 145))
611924	27557633	However, zebrafish with heterozygous or homozygous ewsa mutations in the heterozygous tp53w/m background displayed a much higher tumor incidence.	('mutations', 'Var', (56, 65))	('higher', 'PosReg', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ewsa', 'Gene', (51, 55))	('zebrafish', 'Species', '7955', (9, 18))	('tumor', 'Disease', (129, 134))
611927	27557633	Heterozygous or homozygous ewsa mutations in the homozygous tp53m/m background also increased tumor incidence.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('mutations', 'Var', (32, 41))	('increased', 'PosReg', (84, 93))
611928	27557633	While the tumor incidence in zebrafish with the ewsaw/w;tp53m/m genotype was 35% (n = 48), zebrafish with the ewsaw/m;tp53m/m genotype had a tumor incidence of 67% (n = 12), and those with the ewsam/m;tp53m/m genotype had a tumor incidence of 58% (n = 19).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', (141, 146))	('zebrafish', 'Species', '7955', (29, 38))	('ewsaw/m;tp53m/m', 'Var', (110, 125))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('zebrafish', 'Species', '7955', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
611929	27557633	The results suggest that loss of ewsa contributes to tumor formation, and Ewsa functions to suppress tp53-dependent tumorigenesis.	('Ewsa', 'Chemical', '-', (74, 78))	('ewsa', 'Gene', (33, 37))	('loss', 'Var', (25, 29))	('tp53-dependent', 'Protein', (101, 115))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('suppress', 'NegReg', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (116, 121))
611933	27557633	The ewsaw/m;tp53w/m zebrafish (19+/-4 months, n = 46) also had earlier onset of tumorigenesis than ewsaw/w;tp53w/m fish, but the difference was not significant.	('zebrafish', 'Species', '7955', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ewsaw/m;tp53w/m', 'Var', (4, 19))	('tumor', 'Disease', (80, 85))	('earlier', 'PosReg', (63, 70))
611934	27557633	In the homozygous tp53m/m background, zebrafish with homozygous ewsam/m mutations (16+/-3 months, n = 19) also displayed an earlier age of tumor onset than fish with wildtype ewsa (17+/-3 months, n = 48), but again, the difference was not significant.	('mutations', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('zebrafish', 'Species', '7955', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('ewsam/m', 'Gene', (64, 71))
611935	27557633	These results suggest that loss of ewsa contributes to tumor formation, and Ewsa suppresses tumorigenesis (Fig.	('loss', 'Var', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('suppresses', 'NegReg', (81, 91))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('Ewsa', 'Chemical', '-', (76, 80))	('ewsa', 'Gene', (35, 39))
611936	27557633	To address whether there is any tumor type specificity in the ewsa and tp53 mutants, H&E stained tumor samples were characterized based on cell morphology.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('H&E', 'Chemical', '-', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (97, 102))	('mutants', 'Var', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('tp53', 'Gene', (71, 75))
611937	27557633	The tumors were subclassified into four types: 1. small round blue cell tumor (SRBCT); 2. malignant peripheral nerve sheath tumor (MPNST)-like tumors (which resemble the predominant tumors associated with tp53 mutation as described in the original publication by Berghmans, et al.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Disease', (124, 129))	('mutation', 'Var', (210, 218))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (90, 129))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('peripheral nerve sheath tumor', 'Disease', (100, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('malignant', 'CPA', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tp53', 'Gene', (205, 209))	('MPNST', 'Phenotype', 'HP:0100697', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('peripheral nerve sheath tumor', 'Disease', 'MESH:D010524', (100, 129))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (143, 148))	('tumors', 'Disease', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
611944	27557633	Aberrant midzone formation leads to failure of cell division, and induces aberrant chromosome distribution to daughter cells, in an event known as chromosomal instability (CIN).	('CIN', 'Phenotype', 'HP:0040012', (172, 175))	('Aberrant', 'Var', (0, 8))	('midzone', 'Chemical', '-', (9, 16))	('induces', 'Reg', (66, 73))	('failure', 'CPA', (36, 43))	('chromosomal instability', 'Phenotype', 'HP:0040012', (147, 170))	('CIN', 'Disease', (172, 175))	('chromosomal instability', 'Disease', (147, 170))	('cell division', 'CPA', (47, 60))	('CIN', 'Disease', 'MESH:D007674', (172, 175))	('aberrant chromosome distribution to daughter cells', 'CPA', (74, 124))
611945	27557633	To address whether Ewsa regulates central spindle formation, maternal and zygotic ewsa mRNA was depleted from zebrafish embryos by incrossing homozygotic ewsam/m mutant zebrafish (Maternal-Zygotic (MZ) ewsam/m zebrafish).	('Maternal-Zygotic', 'Disease', 'MESH:D063130', (180, 196))	('zebrafish', 'Species', '7955', (210, 219))	('mutant', 'Var', (162, 168))	('zebrafish', 'Species', '7955', (169, 178))	('zebrafish', 'Species', '7955', (110, 119))	('Maternal-Zygotic', 'Disease', (180, 196))	('Ewsa', 'Chemical', '-', (19, 23))	('central spindle', 'Phenotype', 'HP:0003687', (34, 49))
611951	27557633	However, the MZ ewsam/m mutants displayed a higher percentage of cells with aberrant chromosome numbers compared to wildtype zebrafish (Fig.	('aberrant chromosome numbers', 'Phenotype', 'HP:0031411', (76, 103))	('higher', 'PosReg', (44, 50))	('zebrafish', 'Species', '7955', (125, 134))	('MZ ewsam/m mutants', 'Var', (13, 31))	('cells with aberrant chromosome numbers', 'CPA', (65, 103))
611955	27557633	Homozygous tp53m/m zebrafish displayed a high incidence of tumors (35%, n = 48), while zebrafish with the heterozygous tp53w/m genotype showed a low incidence of tumor development (8%, n = 28) over 26 mpf (Table 1).	('tp53m/m', 'Var', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (59, 64))	('zebrafish', 'Species', '7955', (87, 96))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('zebrafish', 'Species', '7955', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
611956	27557633	However, when we generated heterozygous tp53w/m zebrafish with homozygous ewsam/m mutations, we observed a significant increase in tumor incidence (23%, n = 39) (Table 1).	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('zebrafish', 'Species', '7955', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tp53w/m', 'Var', (40, 47))	('tumor', 'Disease', (131, 136))	('mutations', 'Var', (82, 91))	('increase', 'PosReg', (119, 127))
611957	27557633	We hypothesized that loss of ewsa may promote tumorigenesis by inducing LOH of the tp53 wildtype locus.	('loss', 'Var', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('inducing', 'Reg', (63, 71))	('LOH', 'MPA', (72, 75))	('tumor', 'Disease', (46, 51))	('promote', 'PosReg', (38, 45))	('ewsa', 'Gene', (29, 33))
611960	27557633	Conversely, RFLP analysis of the tumors demonstrated loss of the tp53 wildtype allele, suggesting that the tumors underwent LOH for tp53 (Fig.	('tp53', 'Var', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (33, 39))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('LOH', 'NegReg', (124, 127))
611962	27557633	Sequencing verified that all three fin samples were tp53w/m, whereas all tumors lost the tp53 wildtype allele (Fig.	('tp53 wildtype allele', 'MPA', (89, 109))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('lost', 'NegReg', (80, 84))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tp53w/m', 'Var', (52, 59))
611963	27557633	Our study suggests a novel mechanism for the pathogenesis of EWS fusion-associated sarcomas: loss of one EWS allele due to the formation of the EWS-fusion gene induces mitotic dysfunction accompanied by aberrant midzone formation, CIN, and promotion of tumorigenesis by inducing LOH.	('EWS-fusion', 'Gene', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('CIN', 'Phenotype', 'HP:0040012', (231, 234))	('EWS', 'Gene', (105, 108))	('midzone', 'Chemical', '-', (212, 219))	('inducing', 'Reg', (270, 278))	('CIN', 'Disease', 'MESH:D007674', (231, 234))	('LOH', 'CPA', (279, 282))	('loss', 'Var', (93, 97))	('mitotic dysfunction', 'Disease', 'MESH:C536987', (168, 187))	('sarcomas', 'Disease', 'MESH:D012509', (83, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('sarcomas', 'Disease', (83, 91))	('tumor', 'Disease', (253, 258))	('CIN', 'Disease', (231, 234))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('mitotic dysfunction', 'Disease', (168, 187))	('induces', 'Reg', (160, 167))	('promotion', 'PosReg', (240, 249))
611969	27557633	Although ewsaw/m and ewsam/m mutant zebrafish have no or a low incidence of tumors, heterozygous or homozygous ewsa mutation accelerated tumorigenesis in the tp53w/m background.	('tumor', 'Disease', (137, 142))	('mutation', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('zebrafish', 'Species', '7955', (36, 45))	('ewsa', 'Gene', (111, 115))	('accelerated', 'PosReg', (125, 136))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
611970	27557633	This result suggests that the loss of one or both alleles of ewsa promotes tumorigenesis.	('ewsa', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('promotes', 'PosReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('loss', 'Var', (30, 34))	('tumor', 'Disease', (75, 80))
611971	27557633	We also discovered that mutation of both ewsa alleles results in CIN.	('CIN', 'Phenotype', 'HP:0040012', (65, 68))	('results in', 'Reg', (54, 64))	('CIN', 'Disease', (65, 68))	('mutation', 'Var', (24, 32))	('CIN', 'Disease', 'MESH:D007674', (65, 68))
611977	27557633	Our previous study demonstrated that zebrafish ewsa knockdown induces chromosomal mis-segregation due to mitotic dysfunction.	('mitotic dysfunction', 'Disease', (105, 124))	('mitotic dysfunction', 'Disease', 'MESH:C536987', (105, 124))	('chromosomal mis-segregation', 'CPA', (70, 97))	('induces', 'Reg', (62, 69))	('knockdown', 'Var', (52, 61))	('zebrafish', 'Species', '7955', (37, 46))
611990	27557633	The mice from these crosses did not develop tumors, but EWS/FLI1 did accelerate the formation of sarcomas in Tp53 deleted mice.	('tumors', 'Disease', (44, 50))	('mice', 'Species', '10090', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('mice', 'Species', '10090', (4, 8))	('EWS/FLI1', 'Var', (56, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('accelerate', 'PosReg', (69, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('sarcomas', 'Disease', (97, 105))	('Tp53', 'Gene', (109, 113))	('Tp53', 'Gene', '22059', (109, 113))
611991	27557633	Zebrafish with mosaic expression of human EWS/FLI1 had a very low incidence of tumor formation, but crossing these with a tp53 mutant increased the incidence of tumorigenesis.	('mutant', 'Var', (127, 133))	('mosaic', 'Var', (15, 21))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('EWS/FLI1', 'Gene', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('human', 'Species', '9606', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('increased', 'PosReg', (134, 143))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('Zebrafish', 'Species', '7955', (0, 9))
611998	27557633	Therefore, it is possible that the high incidence of aberrant chromosome numbers observed in ewsa mutant zebrafish may be the result of mitotic defects due to the loss of Ewsa.	('Ewsa', 'Chemical', '-', (171, 175))	('loss', 'NegReg', (163, 167))	('Ewsa', 'Gene', (171, 175))	('aberrant chromosome numbers', 'CPA', (53, 80))	('aberrant chromosome numbers', 'Phenotype', 'HP:0031411', (53, 80))	('mitotic defects', 'CPA', (136, 151))	('ewsa', 'Gene', (93, 97))	('zebrafish', 'Species', '7955', (105, 114))	('mutant', 'Var', (98, 104))
612011	27557633	Loss of Ewing sarcoma EWS allele promotes tumorigenesis by inducing chromosomal instability in zebrafish.	('zebrafish', 'Species', '7955', (95, 104))	('promotes', 'PosReg', (33, 41))	('inducing', 'Reg', (59, 67))	('tumor', 'Disease', (42, 47))	('chromosomal instability', 'Phenotype', 'HP:0040012', (68, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (8, 21))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (8, 21))	('EWS', 'Gene', (22, 25))	('chromosomal instability', 'MPA', (68, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Ewing sarcoma', 'Disease', (8, 21))
612137	25026998	Twenty-three (69.6%) of 33 patients with WT1 expression had disease-related events, including recurrence, distant metastasis, and death, compared to 18 (60.0%) of 30 patients without WT1 expression; this difference was not statistically significant (P = 0.420) (Table 3).	('death', 'Disease', 'MESH:D003643', (130, 135))	('death', 'Disease', (130, 135))	('distant metastasis', 'CPA', (106, 124))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (166, 174))	('recurrence', 'CPA', (94, 104))	('WT1 expression', 'Var', (41, 55))
612168	23649384	The identification of characteristic genetic alterations in several of these tumors has opened the window for molecular targeted therapies in patients who have failed conventional chemotherapy.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('genetic alterations', 'Var', (37, 56))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patients', 'Species', '9606', (142, 150))
612185	23649384	Inhibitors of mammalian target of rapamycin (mTOR) have shown dramatic efficacy in mTOR-driven tumors such as perivascular epithelioid cell tumor (PEComas).	('PEComas', 'Disease', (147, 154))	('mTOR', 'Gene', (83, 87))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('epithelioid cell tumor', 'Phenotype', 'HP:0032060', (123, 145))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('Inhibitors', 'Var', (0, 10))	('PEComas', 'Disease', 'MESH:D054973', (147, 154))	('perivascular epithelioid cell tumor', 'Disease', 'MESH:D054973', (110, 145))	('perivascular epithelioid cell tumor', 'Disease', (110, 145))	('mammalian target of rapamycin', 'Gene', '2475', (14, 43))	('mammalian target of rapamycin', 'Gene', (14, 43))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mTOR', 'Gene', '2475', (45, 49))	('tumors', 'Disease', (95, 101))	('mTOR', 'Gene', '2475', (83, 87))	('mTOR', 'Gene', (45, 49))
612189	23649384	STSs with complex karyotypes are associated with a high frequency of chromosomal instability, p53 and retinoblastoma pathway mutations.	('chromosomal instability', 'MPA', (69, 92))	('mutations', 'Var', (125, 134))	('retinoblastoma', 'Phenotype', 'HP:0009919', (102, 116))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('retinoblastoma', 'Disease', 'MESH:D012175', (102, 116))	('retinoblastoma', 'Disease', (102, 116))	('high frequency of chromosomal instability', 'Phenotype', 'HP:0040012', (51, 92))	('STS', 'Phenotype', 'HP:0030448', (0, 3))
612190	23649384	Examples of fused genes resulting from translocations in STS include the FUS-CHOP [t(12; 16)(q13; q11)] seen in 95% of cases of myxoid LPS, EWS-FLI1 [t(11; 22)(q24; q12)] seen in 85% of cases of Ewing sarcoma and ASPSCR1-TFE3 [t(X; 17)(p11; q25)] seen in 99% of cases of alveolar soft part sarcoma.	('alveolar soft part sarcoma', 'Disease', (271, 297))	('Ewing sarcoma', 'Disease', (195, 208))	('LPS', 'Disease', 'MESH:C536528', (135, 138))	('FLI1', 'Gene', '2313', (144, 148))	('ASPSCR1', 'Gene', (213, 220))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (280, 297))	('translocations', 'Var', (39, 53))	('LPS', 'Phenotype', 'HP:0012034', (135, 138))	('EWS', 'Gene', (140, 143))	('FLI1', 'Gene', (144, 148))	('EWS', 'Gene', '2130', (140, 143))	('CHOP', 'Gene', '1649', (77, 81))	('TFE3', 'Gene', (221, 225))	('TFE3', 'Gene', '7030', (221, 225))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (271, 297))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (195, 208))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (195, 208))	('ASPS', 'Phenotype', 'HP:0012218', (213, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (271, 297))	('p11', 'Gene', '6281', (236, 239))	('CHOP', 'Gene', (77, 81))	('LPS', 'Disease', (135, 138))	('STS', 'Phenotype', 'HP:0030448', (57, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('ASPSCR1', 'Gene', '79058', (213, 220))	('p11', 'Gene', (236, 239))
612194	23649384	The mTOR pathway is the final merging point for several intracellular signal cascades and can be intrinsically activated by several mutations and deletions.	('mTOR', 'Gene', '2475', (4, 8))	('mTOR', 'Gene', (4, 8))	('mutations', 'Var', (132, 141))	('deletions', 'Var', (146, 155))
612242	23649384	Monoclonal antibodies to VEGF have an effect similar to TKI.	('VEGF', 'Gene', '7422', (25, 29))	('VEGF', 'Gene', (25, 29))	('Monoclonal antibodies', 'Var', (0, 21))
612244	23649384	TKI knock off the neoangiogenic pathways in sarcomas causing progressive decrease in density and enhancement on contrast-enhanced CT without necessarily causing shrinkage of the tumor (Fig.	('tumor', 'Disease', (178, 183))	('men', 'Species', '9606', (104, 107))	('TKI', 'Gene', (0, 3))	('density', 'MPA', (85, 92))	('neoangiogenic pathways', 'Pathway', (18, 40))	('knock', 'Var', (4, 9))	('sarcomas', 'Disease', 'MESH:D012509', (44, 52))	('decrease', 'NegReg', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('sarcomas', 'Disease', (44, 52))	('enhancement', 'MPA', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
612259	23649384	TKI can also cause acute acalculous cholecystitis due to gall bladder ischemia.	('acalculous cholecystitis', 'Disease', (25, 49))	('cause', 'Reg', (13, 18))	('TKI', 'Var', (0, 3))	('cholecystitis', 'Phenotype', 'HP:0001082', (36, 49))	('acalculous cholecystitis', 'Disease', 'MESH:D042101', (25, 49))	('gall bladder ischemia', 'Disease', 'MESH:D005705', (57, 78))	('gall bladder ischemia', 'Disease', (57, 78))
612261	23649384	TKI can cause ischemic colitis, pneumatosis and bowel perforation, which may come to attention for the first time at imaging.	('cause', 'Reg', (8, 13))	('colitis', 'Phenotype', 'HP:0002583', (23, 30))	('bowel perforation', 'Phenotype', 'HP:0031368', (48, 65))	('TKI', 'Var', (0, 3))	('ischemic colitis, pneumatosis and bowel', 'Disease', 'MESH:D017091', (14, 53))
612262	23649384	Given that TKIs cause endothelial injury, it is not unusual to see arterial and venous thromboembolic phenomena, which may necessitate drug discontinuation.	('venous thromboembolic phenomena', 'Disease', (80, 111))	('venous thromboembolic phenomena', 'Disease', 'MESH:D054556', (80, 111))	('endothelial injury', 'Disease', (22, 40))	('thromboembolic phenomena', 'Phenotype', 'HP:0001907', (87, 111))	('TKIs', 'Var', (11, 15))	('endothelial injury', 'Disease', 'MESH:D014947', (22, 40))	('cause', 'Reg', (16, 21))
612270	23649384	The mTOR serine/threonine kinase is an integral part of the PI3K pathway that is activated in several mTOR driven cancers such as renal cell carcinoma, either intrinsically or by mutations in regulatory genes such as TSC1 and 2, VHL, PTEN.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('TSC1 and 2', 'Gene', '7248;7249', (217, 227))	('PTEN', 'Gene', (234, 238))	('mTOR', 'Gene', '2475', (4, 8))	('VHL', 'Disease', 'MESH:D006623', (229, 232))	('PI3K pathway', 'Pathway', (60, 72))	('renal cell carcinoma', 'Disease', (130, 150))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (130, 150))	('PTEN', 'Gene', '5728', (234, 238))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('activated', 'PosReg', (81, 90))	('mTOR', 'Gene', (102, 106))	('mutations', 'Var', (179, 188))	('VHL', 'Disease', (229, 232))	('mTOR', 'Gene', '2475', (102, 106))	('mTOR', 'Gene', (4, 8))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (130, 150))
612300	23649384	Round cell LPS is now considered as a spectrum of myxoid LPS as both have a common translocation t(12; 16)(q13; q11) in excess of 90% of cases resulting in the formation of a chimeric fusion protein FUS-CHOP.	('resulting in', 'Reg', (143, 155))	('LPS', 'Disease', 'MESH:C536528', (57, 60))	('LPS', 'Disease', 'MESH:C536528', (11, 14))	('chimeric fusion protein', 'MPA', (175, 198))	('LPS', 'Phenotype', 'HP:0012034', (11, 14))	('CHOP', 'Gene', '1649', (203, 207))	('formation', 'MPA', (160, 169))	('t(12; 16)(q13; q11', 'Var', (97, 115))	('LPS', 'Phenotype', 'HP:0012034', (57, 60))	('LPS', 'Disease', (57, 60))	('CHOP', 'Gene', (203, 207))	('LPS', 'Disease', (11, 14))
612307	23649384	The mechanism of action of trabectidin is unknown, but in the case of myxoid LPS, it is postulated that trabectedin inactivates the fusion oncogene FUS-CHOP and removes the block in the cell cycle, thereby promoting differentiation of tumor cells.	('promoting', 'PosReg', (206, 215))	('CHOP', 'Gene', (152, 156))	('differentiation', 'CPA', (216, 231))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('removes', 'NegReg', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('LPS', 'Phenotype', 'HP:0012034', (77, 80))	('LPS', 'Disease', (77, 80))	('trabectedin', 'Var', (104, 115))	('cell cycle', 'CPA', (186, 196))	('tumor', 'Disease', (235, 240))	('LPS', 'Disease', 'MESH:C536528', (77, 80))	('inactivates', 'NegReg', (116, 127))	('CHOP', 'Gene', '1649', (152, 156))	('block', 'MPA', (173, 178))
612320	23649384	Recognition of a characteristic translocation t(11; 22) in 85% of cases of ESFT has created interest in MTT for these tumors.	('ESFT', 'Disease', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('translocation t', 'Var', (32, 47))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
612452	32195166	CRC etiology is characterized by acquisition and progressive accumulation of genetic and epigenetic mutations by the somatic cells that confer a malignant phenotype.	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('CRC', 'Disease', 'MESH:D015179', (0, 3))	('CRC', 'Disease', (0, 3))	('epigenetic mutations', 'Var', (89, 109))	('genetic', 'Var', (77, 84))
612482	32195166	demonstrated that mismatch repair-deficient and hypermutated MSI-H metastatic CRC patients could significantly benefit from treatment with anti-PD-1.	('patients', 'Species', '9606', (82, 90))	('CRC', 'Disease', (78, 81))	('benefit', 'PosReg', (111, 118))	('anti-PD-1', 'Gene', (139, 148))	('MSI', 'Gene', (61, 64))	('hypermutated', 'Var', (48, 60))	('mismatch repair-deficient', 'Var', (18, 43))	('MSI', 'Gene', '5928', (61, 64))	('CRC', 'Phenotype', 'HP:0003003', (78, 81))	('CRC', 'Disease', 'MESH:D015179', (78, 81))
612483	32195166	After the seminal observation, they demonstrated that mismatch repair and microsatellite instability status were able to predict clinical benefits to anti-PD1 treatment in metastatic CRC patients.	('patients', 'Species', '9606', (187, 195))	('CRC', 'Disease', (183, 186))	('PD1', 'Gene', (155, 158))	('CRC', 'Phenotype', 'HP:0003003', (183, 186))	('microsatellite instability', 'Var', (74, 100))	('CRC', 'Disease', 'MESH:D015179', (183, 186))	('mismatch repair', 'Var', (54, 69))	('PD1', 'Gene', '5133', (155, 158))
612494	32195166	demonstrated that the inactivation of tumor suppressor Smad4 gene, a late event on the carcinogenic chain of CRC, leads to a decreased expression of all three genes encoding laminin-5 that can favor invasion and metastasis spread.	('inactivation', 'Var', (22, 34))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('decreased', 'NegReg', (125, 134))	('CRC', 'Disease', (109, 112))	('Smad4', 'Gene', (55, 60))	('Smad4', 'Gene', '4089', (55, 60))	('favor', 'PosReg', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('expression', 'MPA', (135, 145))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))	('CRC', 'Disease', 'MESH:D015179', (109, 112))
612521	32195166	CD3+ (TILs), CD4+ (T-helper cells), CD8+ (cytotoxic T-cells), and FOXP3+ (Treg) lymphocytes were found in 98% of the biopsies, while macrophages were found in 90% of the cases.	('FOXP3', 'Gene', (66, 71))	('FOXP3', 'Gene', '50943', (66, 71))	('CD3+', 'Var', (0, 4))	('CD8', 'Gene', (36, 39))	('CD4', 'Gene', (13, 16))	('CD8', 'Gene', '925', (36, 39))	('CD4', 'Gene', '920', (13, 16))
612529	32195166	Regarding the relation between RMS cells and the immune system in vitro, it is shown that cytotoxic drugs such as doxorubicin provoke the translocation of calreticulin from the endoplasmic reticulum to the cell surface and, in combination with anti-PD-L1 antibody, increase the efficiency of phagocytosis by macrophages.	('calreticulin', 'Gene', '811', (155, 167))	('PD-L1', 'Gene', (249, 254))	('doxorubicin', 'Var', (114, 125))	('RMS', 'Disease', (31, 34))	('RMS', 'Phenotype', 'HP:0002859', (31, 34))	('calreticulin', 'Gene', (155, 167))	('phagocytosis by macrophages', 'CPA', (292, 319))	('PD-L1', 'Gene', '29126', (249, 254))	('translocation', 'MPA', (138, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (114, 125))	('RMS', 'Disease', 'MESH:D012208', (31, 34))	('increase', 'PosReg', (265, 273))
612532	32195166	However, inhibition of MIF impairs the migration potential of RMS cells, in contrast with the results obtained in the work previously mentioned.	('RMS', 'Disease', (62, 65))	('MIF', 'Gene', '4282', (23, 26))	('RMS', 'Phenotype', 'HP:0002859', (62, 65))	('impairs', 'NegReg', (27, 34))	('MIF', 'Gene', (23, 26))	('RMS', 'Disease', 'MESH:D012208', (62, 65))	('inhibition', 'Var', (9, 19))
612685	24146614	In addition to the stabilization by the hydrogen bonding network of the beta-barrel, hydrophobic amino acid side chains project into the core and form a tightly packed hydrophobic cluster.	('hydrogen', 'Chemical', 'MESH:D006859', (40, 48))	('stabilization', 'MPA', (19, 32))	('hydrophobic', 'Var', (85, 96))
612687	24146614	These form a hydrogen bonding network with the amino acid side chains Y1103 and Y1105 that are also part of the dimer interface.	('hydrogen', 'Chemical', 'MESH:D006859', (13, 21))	('Y1103', 'Var', (70, 75))	('Y1105', 'Var', (80, 85))	('hydrogen bonding network', 'MPA', (13, 37))
612693	24146614	As shown previously, substitution of these three residues to alanines abolishes binding of LANA to the LBS sites in the KSHV TR.	('substitution', 'Var', (21, 33))	('alanines', 'Chemical', 'MESH:D000409', (61, 69))	('binding', 'Interaction', (80, 87))	('KSHV', 'Species', '37296', (120, 124))	('abolishes', 'NegReg', (70, 79))
612695	24146614	We additionally tested the single point mutants S1086A and S1086E which remove a single OH group, or add a single negative charge in the center of the expected DNA binding site, respectively.	('S1086E', 'Var', (59, 65))	('S1086A', 'Var', (48, 54))	('OH group', 'MPA', (88, 96))	('S1086E', 'Mutation', 'p.S1086E', (59, 65))	('remove', 'NegReg', (72, 78))	('S1086A', 'Mutation', 'p.S1086A', (48, 54))	('negative charge', 'MPA', (114, 129))
612696	24146614	As expected, S1086E strongly reduced specific DNA binding and therefore also impaired latent replication, whereas S1086A had no effect on either of these functions (Figure S1F,G).	('S1086E', 'Mutation', 'p.S1086E', (13, 19))	('S1086A', 'Mutation', 'p.S1086A', (114, 120))	('S1086A', 'Var', (114, 120))	('impaired', 'NegReg', (77, 85))	('specific', 'Protein', (37, 45))	('reduced', 'NegReg', (29, 36))	('S1086E', 'Var', (13, 19))	('latent replication', 'CPA', (86, 104))
612702	24146614	We first determined the oligomerization state of recombinant kLANA(1013-1149) and mLANA(124-260) in solution.	('mLANA', 'Gene', (82, 87))	('1013-1149', 'Var', (67, 76))	('mLANA', 'Gene', '77836', (82, 87))	('kLANA', 'Gene', (61, 66))
612704	24146614	The substitution M1117D reduced and the substitution A1121E abolished kLANA oligomerization (Figure 2D).	('A1121E', 'Mutation', 'p.A1121E', (53, 59))	('abolished', 'NegReg', (60, 69))	('kLANA oligomerization', 'MPA', (70, 91))	('M1117D', 'Mutation', 'p.M1117D', (17, 23))	('A1121E', 'Var', (53, 59))	('M1117D', 'Var', (17, 23))
612705	24146614	While LBS binding was comparable to wt kLANA (Figure 2E), all lateral association mutants proved to be defective in their ability to replicate a plasmid containing four TR elements (Figure 2F).	('defective', 'NegReg', (103, 112))	('ability', 'MPA', (122, 129))	('plasmid', 'Species', '2625', (145, 152))	('lateral', 'CPA', (62, 69))	('mutants', 'Var', (82, 89))
612706	24146614	Notably, the lateral self-association of kLANA dimers appears to be independent of specific DNA binding, since kLANA CTD mutants defective in DNA binding are capable of self-association (Figure S1H).	('defective', 'NegReg', (129, 138))	('self-association', 'MPA', (169, 185))	('mutants', 'Var', (121, 128))	('kLANA', 'Gene', (111, 116))	('1H', 'Chemical', '-', (195, 197))
612715	24146614	The most affected backbone amide groups in the BRD4 ET domain comprise R616, S619 and E653-E657 (Figure 3E, top).	('affected', 'Reg', (9, 17))	('R616', 'Var', (71, 75))	('BRD4', 'Gene', (47, 51))	('E653-E657', 'Var', (86, 95))	('S619', 'Var', (77, 81))	('BRD4', 'Gene', '23476', (47, 51))	('amide', 'Chemical', 'MESH:D000577', (27, 32))
612716	24146614	The interaction with BRD2 ET(632-713) was observed to be virtually identical and to affect the corresponding amino acids R648, S651 and E685-E689 (Figure 3E, bottom).	('interaction', 'Interaction', (4, 15))	('BRD2', 'Gene', '6046', (21, 25))	('S651', 'Var', (127, 131))	('BRD2', 'Gene', (21, 25))	('affect', 'Reg', (84, 90))	('E685-E689', 'Var', (136, 145))	('R648', 'Var', (121, 125))
612717	24146614	In order to confirm the binding site for kLANA on the ET domain we generated mutations in the ET domain of FL GFP-BRD2 and tested them in co-immunoprecipitation experiments with FL wt kLANA (Figure 4A).	('GFP-BRD2', 'Gene', '6046', (110, 118))	('rat', 'Species', '10116', (71, 74))	('tested', 'Reg', (123, 129))	('GFP-BRD2', 'Gene', (110, 118))	('mutations', 'Var', (77, 86))
612718	24146614	The alanine substitution of any one of the negatively charged amino acids contained in the peptide segment BRD2-ET(682-687) resulted in the complete loss of kLANA binding (Figure 4A).	('alanine substitution', 'Var', (4, 24))	('loss', 'NegReg', (149, 153))	('alanine', 'Chemical', 'MESH:D000409', (4, 11))	('BRD2', 'Gene', '6046', (107, 111))	('BRD2', 'Gene', (107, 111))	('kLANA', 'Protein', (157, 162))
612720	24146614	The F688Y substitution also abolished binding to kLANA.	('abolished', 'NegReg', (28, 37))	('F688Y', 'Mutation', 'p.F688Y', (4, 9))	('binding', 'Interaction', (38, 45))	('kLANA', 'Protein', (49, 54))	('F688Y', 'Var', (4, 9))
612721	24146614	Only the R648A and E689A substitutions appeared not to affect kLANA binding.	('affect', 'Reg', (55, 61))	('E689A', 'Mutation', 'p.E689A', (19, 24))	('R648A', 'Mutation', 'p.R648A', (9, 14))	('R648A', 'Var', (9, 14))	('kLANA binding', 'Interaction', (62, 75))	('E689A', 'Var', (19, 24))
612722	24146614	Thus, most amino acid substitutions in the vicinity of the kLANA binding epitope of BRD2 ET reduced or abolished binding, confirming the interaction site as identified by NMR.	('abolished', 'NegReg', (103, 112))	('BRD2', 'Gene', (84, 88))	('amino acid substitutions', 'Var', (11, 35))	('MR', 'Disease', 'MESH:C564570', (172, 174))	('BRD2', 'Gene', '6046', (84, 88))	('binding', 'Interaction', (113, 120))
612723	24146614	We also generated a panel of mutants of FL kLANA and tested them in a co-immunoprecipitation assay with GFP-tagged BRD2 and BRD4 (Figure 4B).	('tested', 'Reg', (53, 59))	('rat', 'Species', '10116', (12, 15))	('BRD4', 'Gene', '23476', (124, 128))	('mutants', 'Var', (29, 36))	('FL kLANA', 'Gene', (40, 48))	('BRD2', 'Gene', '6046', (115, 119))	('BRD4', 'Gene', (124, 128))	('BRD2', 'Gene', (115, 119))
612724	24146614	The kLANA R1119M substitution impaired binding of the ET domains of both BET proteins.	('ET domains', 'Protein', (54, 64))	('kLANA R1119M', 'Var', (4, 16))	('R1119M', 'Mutation', 'p.R1119M', (10, 16))	('impaired', 'NegReg', (30, 38))	('binding', 'Interaction', (39, 46))
612725	24146614	R1119 forms a positive charge at the bottom of a cleft, which is occupied by anions in the kLANA crystals (Figure S2B).	('cleft', 'Disease', 'MESH:D002972', (49, 54))	('R1119', 'Var', (0, 5))	('cleft', 'Disease', (49, 54))
612726	24146614	The substitutions P1127R had no significant effect on ET binding, while the mutations H1126E and to a lesser degree L1128D, enhanced BET protein binding.	('ET binding', 'Interaction', (54, 64))	('P1127R', 'Var', (18, 24))	('BET protein', 'Protein', (133, 144))	('enhanced', 'PosReg', (124, 132))	('L1128D', 'Var', (116, 122))	('H1126E', 'Mutation', 'p.H1126E', (86, 92))	('L1128D', 'Mutation', 'p.L1128D', (116, 122))	('P1127R', 'Mutation', 'p.P1127R', (18, 24))	('H1126E', 'Var', (86, 92))
612729	24146614	We found that the binding of the BRD2-ET to LANA was much more susceptible to the LANA substitutions H1126E, L1128D, R1119M then binding of the FL BRD2 or the BRD2-CT (Figure S2B).	('BRD2', 'Gene', (147, 151))	('H1126E', 'Mutation', 'p.H1126E', (101, 107))	('BRD2', 'Gene', '6046', (147, 151))	('LANA', 'Gene', (82, 86))	('H1126E', 'Var', (101, 107))	('R1119M', 'Mutation', 'p.R1119M', (117, 123))	('binding', 'Interaction', (18, 25))	('BRD2', 'Gene', (33, 37))	('BRD2', 'Gene', '6046', (159, 163))	('BRD2', 'Gene', (159, 163))	('L1128D', 'Var', (109, 115))	('BRD2', 'Gene', '6046', (33, 37))	('binding', 'Interaction', (129, 136))	('susceptible', 'Reg', (63, 74))	('R1119M', 'Var', (117, 123))	('L1128D', 'Mutation', 'p.L1128D', (109, 115))
612733	24146614	In both models, F688 of BRD2 ET was placed near the N-terminus of helix alpha2 of kLANA.	('F688', 'Var', (16, 20))	('BRD2', 'Gene', '6046', (24, 28))	('BRD2', 'Gene', (24, 28))
612740	24146614	All mutants in the ET binding site, except for P1127R, were incapable of replicating a plasmid carrying 4 TR elements in transiently transfected cells (Figure 4E).	('P1127R', 'Var', (47, 53))	('incapable', 'NegReg', (60, 69))	('P1127R', 'Mutation', 'p.P1127R', (47, 53))	('plasmid', 'Species', '2625', (87, 94))
612741	24146614	With the exception of K1070E all mutants were still able to bind LBS (Figure 4F).	('K1070E', 'Mutation', 'p.K1070E', (22, 28))	('K1070E', 'Var', (22, 28))	('bind LBS', 'Interaction', (60, 68))
612745	24146614	Indeed, the alanine substitution of two single lysine side chains K1109 and K1138 severely reduced both BRD2 and BRD4 binding, while the double substitution K1109A/K1138A completely abolished it (Figure 5A).	('K1109A', 'Var', (157, 163))	('K1138A', 'Mutation', 'p.K1138A', (164, 170))	('BRD4', 'Gene', (113, 117))	('abolished', 'NegReg', (182, 191))	('K1138', 'Var', (76, 81))	('BRD2', 'Gene', '6046', (104, 108))	('BRD2', 'Gene', (104, 108))	('K1109', 'Var', (66, 71))	('BRD4', 'Gene', '23476', (113, 117))	('alanine', 'Chemical', 'MESH:D000409', (12, 19))	('lysine', 'Chemical', 'MESH:D008239', (47, 53))	('reduced', 'NegReg', (91, 98))	('K1109A', 'SUBSTITUTION', 'None', (157, 163))
612746	24146614	While the substitutions K1055A and K1113A did not significantly affect BRD4 binding, they abolished BRD2 binding by kLANA (Figure S3A).	('K1055A', 'Mutation', 'p.K1055A', (24, 30))	('BRD2', 'Gene', (100, 104))	('K1055A', 'Var', (24, 30))	('BRD4', 'Gene', (71, 75))	('BRD2', 'Gene', '6046', (100, 104))	('abolished', 'NegReg', (90, 99))	('K1113A', 'Var', (35, 41))	('K1113A', 'Mutation', 'p.K1113A', (35, 41))	('binding', 'Interaction', (76, 83))	('BRD4', 'Gene', '23476', (71, 75))
612754	24146614	Thus, two independent experimental approaches show that the serine-rich acidic sequence of BRD2/4 strongly enhances kLANA interactions with BRD2/4.	('enhances', 'PosReg', (107, 115))	('serine', 'Chemical', 'MESH:D012694', (60, 66))	('serine-rich acidic', 'Var', (60, 78))	('BRD2/4', 'Gene', (91, 97))	('kLANA interactions', 'MPA', (116, 134))
612755	24146614	The pull down of full-length LANA with a GST-fused LANA CTD was impaired by lysine to alanine substitutions in this region.	('lysine', 'Chemical', 'MESH:D008239', (76, 82))	('alanine', 'Chemical', 'MESH:D000409', (86, 93))	('impaired', 'NegReg', (64, 72))	('lysine to alanine substitutions', 'Var', (76, 107))	('pull down', 'CPA', (4, 13))
612756	24146614	In particular, K1109A/K1138A severely reduced kLANA oligomerization (Figure 5B).	('reduced', 'NegReg', (38, 45))	('K1109A', 'SUBSTITUTION', 'None', (15, 21))	('kLANA oligomerization', 'MPA', (46, 67))	('K1138A', 'Mutation', 'p.K1138A', (22, 28))	('K1109A', 'Var', (15, 21))
612758	24146614	However, in the transient replication assay (Figure 5D) the double mutant (K1109A/K1138A) showed a consistently reduced ability to replicate latent viral DNA, while the corresponding single substitutions had no significant effect.	('K1109A', 'Var', (75, 81))	('K1109A', 'SUBSTITUTION', 'None', (75, 81))	('replicate latent viral DNA', 'MPA', (131, 157))	('reduced', 'NegReg', (112, 119))	('K1138A', 'Mutation', 'p.K1138A', (82, 88))
612759	24146614	We have previously shown that residues 228-231 (KKLK), which are located on the basic surface of mLANA (Figure 5E), influence the interactions with BRD2 and BRD4, and affect mLANA-mediated transcriptional activation (see also Figure 5F).	('interactions', 'Interaction', (130, 142))	('residues 228-231', 'Var', (30, 46))	('mLANA', 'Gene', (174, 179))	('influence', 'Reg', (116, 125))	('mLANA', 'Gene', '77836', (174, 179))	('BRD2', 'Gene', '6046', (148, 152))	('BRD4', 'Gene', (157, 161))	('BRD2', 'Gene', (148, 152))	('affect', 'Reg', (167, 173))	('mLANA', 'Gene', '77836', (97, 102))	('mLANA', 'Gene', (97, 102))	('BRD4', 'Gene', '23476', (157, 161))
612760	24146614	In order to assess the functional role of this basic surface element in vivo, we inserted this mLANA mutant into a recombinant MHV-68 genome cloned into a bacterial artificial chromosome.	('mLANA', 'Gene', (95, 100))	('mLANA', 'Gene', '77836', (95, 100))	('mutant', 'Var', (101, 107))	('inserted', 'Reg', (81, 89))	('MHV-68', 'Species', '1440122', (127, 133))
612763	24146614	However, on day 17 after infection, when MHV-68 latency had been established, the 4A mutant showed a pronounced reduction of viral genome copy numbers in spleen cells approaching the phenotype seen with the mLANA deletion mutant (Figure 5G).	('viral genome copy numbers', 'MPA', (125, 150))	('MHV-68', 'Species', '1440122', (41, 47))	('reduction', 'NegReg', (112, 121))	('mutant', 'Var', (85, 91))	('mLANA', 'Gene', '77836', (207, 212))	('mLANA', 'Gene', (207, 212))
612766	24146614	We tested a selection of the kLANA mutants described above for their ability to form nuclear speckles in the presence of a TR containing plasmid (Figure 6A).	('plasmid', 'Species', '2625', (137, 144))	('kLANA', 'Gene', (29, 34))	('tested', 'Reg', (3, 9))	('mutants', 'Var', (35, 42))
612768	24146614	Individual substitutions of lysine residues on the 'basic top' of kLANA did not result in a loss of speckles, while the double mutant K1109A/K1138A showed an impairment of speckle formation (Figure 6A,B).	('K1138A', 'Mutation', 'p.K1138A', (141, 147))	('speckle formation', 'CPA', (172, 189))	('K1109A', 'SUBSTITUTION', 'None', (134, 140))	('K1109A', 'Var', (134, 140))	('impairment', 'NegReg', (158, 168))	('lysine', 'Chemical', 'MESH:D008239', (28, 34))
612769	24146614	Furthermore, mutants K1070E, R1119M and H1126E localized near the ET binding site were compromised in speckle formation, while the surface exposed residues P1127 and L1128 did not significantly affect this process (Figure 6A,B).	('H1126E', 'Mutation', 'p.H1126E', (40, 46))	('K1070E', 'Var', (21, 27))	('H1126E', 'Var', (40, 46))	('compromised', 'NegReg', (87, 98))	('K1070E', 'Mutation', 'p.K1070E', (21, 27))	('R1119M', 'Mutation', 'p.R1119M', (29, 35))	('speckle formation', 'MPA', (102, 119))	('R1119M', 'Var', (29, 35))
612780	24146614	While our oligomerization mutants of kLANA (M1117D and A1121E) could still bind DNA (Figure 2E) they were not able to promote KSHV episome replication (Figure 2F).	('kLANA', 'Gene', (37, 42))	('KSHV', 'Species', '37296', (126, 130))	('M1117D', 'Mutation', 'p.M1117D', (44, 50))	('A1121E', 'Var', (55, 61))	('bind', 'Interaction', (75, 79))	('M1117D', 'Var', (44, 50))	('A1121E', 'Mutation', 'p.A1121E', (55, 61))	('promote', 'PosReg', (118, 125))
612782	24146614	In particular the double mutant K1109A/K1138A, which removes four positive charges per kLANA dimer, shows reduced oligomerization (Figure 5B) and speckle formation (Figure 6).	('speckle formation', 'CPA', (146, 163))	('K1109A', 'SUBSTITUTION', 'None', (32, 38))	('K1109A', 'Var', (32, 38))	('K1138A', 'Mutation', 'p.K1138A', (39, 45))	('oligomerization', 'MPA', (114, 129))	('reduced', 'NegReg', (106, 113))
612791	24146614	Previous studies found that multiple alanine substitutions near residues 1125-1129 of the kLANA CTD abolish its association with the mitotic chromosomes (Figure S4C).	('association', 'Interaction', (112, 123))	('mitotic chromosomes', 'CPA', (133, 152))	('abolish', 'NegReg', (100, 107))	('alanine substitutions', 'Var', (37, 58))	('alanine', 'Chemical', 'MESH:D000409', (37, 44))
612794	24146614	A single point mutation at the critical kLANA interface has the potential to abolish KSHV persistence and thus provides a possible antiviral target.	('single point mutation', 'Var', (2, 23))	('KSHV', 'Gene', (85, 89))	('persistence', 'MPA', (90, 101))	('abolish', 'NegReg', (77, 84))	('KSHV', 'Species', '37296', (85, 89))
612799	24146614	Unlabeled proteins were produced in 1 L shaking flask cultures of ZYP-5052 auto-inducing rich medium, which were inoculated with a starting OD600 of 0.1 and were incubated over night at 37 C. For expression of seleno-methionine (SeMet) labeled KSHV LANA(1013-1149), a preculture of 2x1 L minimal medium was first grown from an OD600 of 0.1 to 1.0 at 37 C (80 mM K/Na-phosphate pH 7.0, 40 mM NH4Cl, 4 mM Na2SO4, 2 mM MgSO4, 0.5% (w/v) glucose, 33 microM thiamine chloride, 0.2x trace metals.The complete cell mass was then transferred to 500 mL expression culture (same as above without trace metal mixture but containing 100 mg/L lysine, phenylalanine, and threonine, 50 mg/L isoleucine, leucine, and valine, and 60 mg/L seleno-methionine).	('metal', 'Chemical', 'MESH:D008670', (483, 488))	('seleno-methionine', 'Chemical', 'MESH:D012645', (721, 738))	('leucine', 'Chemical', 'MESH:D007930', (688, 695))	('leucine', 'MPA', (688, 695))	('KSHV', 'Species', '37296', (244, 248))	('glucose', 'Chemical', 'MESH:D005947', (434, 441))	('threonine', 'Chemical', 'MESH:D013912', (657, 666))	('isoleucine', 'Var', (676, 686))	('leucine', 'Chemical', 'MESH:D007930', (679, 686))	('NH4Cl', 'Chemical', 'MESH:D000643', (391, 396))	('isoleucine', 'Chemical', 'MESH:D007532', (676, 686))	('Na2SO4', 'Chemical', 'MESH:C012036', (403, 409))	('lysine', 'Chemical', 'MESH:D008239', (630, 636))	('metal', 'Chemical', 'MESH:D008670', (592, 597))	('seleno-methionine', 'Chemical', 'MESH:D012645', (210, 227))	('valine', 'Chemical', 'MESH:D014633', (701, 707))	('SeMet', 'Chemical', 'MESH:D012645', (229, 234))	('thiamine chloride', 'Chemical', '-', (453, 470))	('MgSO4', 'Chemical', 'MESH:D008278', (416, 421))	('phosphate', 'Chemical', 'MESH:D010710', (367, 376))	('phenylalanine', 'Chemical', 'MESH:D010649', (638, 651))
612978	22593667	Radiation-induced neoplasms may form in the areas that receive a sufficient dose to induce mutation, but not enough to destroy the regenerative capacity of the bone or soft tissue.	('mutation', 'Var', (91, 99))	('Radiation-induced', 'Disease', (0, 17))	('neoplasm', 'Phenotype', 'HP:0002664', (18, 26))	('neoplasms', 'Disease', 'MESH:D009369', (18, 27))	('neoplasms', 'Disease', (18, 27))	('Radiation-induced neoplasms', 'Phenotype', 'HP:0010997', (0, 27))	('neoplasms', 'Phenotype', 'HP:0002664', (18, 27))
612979	22593667	Chemotherapy when combined with radiation is associated with increased risk of postradiation sarcoma.	('sarcoma', 'Disease', (93, 100))	('Chemotherapy', 'Var', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	('sarcoma', 'Disease', 'MESH:D012509', (93, 100))
613010	33381449	TAMs suppress immune cytolytic function, promote tumor growth and metastases, and are generally associated with a poor prognosis in most pediatric sarcoma subtypes.	('metastases', 'Disease', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('TAMs', 'Chemical', '-', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('immune cytolytic function', 'MPA', (14, 39))	('sarcoma subtype', 'Disease', 'MESH:D012509', (147, 162))	('suppress', 'NegReg', (5, 13))	('tumor', 'Disease', (49, 54))	('promote', 'PosReg', (41, 48))	('TAMs', 'Var', (0, 4))	('sarcoma subtype', 'Disease', (147, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))
613022	33381449	Higher mutational burden and presence of complex genomic aberrations that occur in adult patients may increase the presence and immune recognition of sarcoma neoantigens.	('sarcoma', 'Disease', 'MESH:D012509', (150, 157))	('immune recognition', 'MPA', (128, 146))	('patients', 'Species', '9606', (89, 97))	('sarcoma', 'Disease', (150, 157))	('increase', 'PosReg', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('mutational', 'Var', (7, 17))	('presence', 'MPA', (115, 123))
613045	33381449	Translocation of NF-kappaB into the nucleus leads to transcription of Th1 genes, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-12, IL-1beta, and IL-6, leading to expansion of effector T cells.	('tumor necrosis factor-alpha', 'Gene', '7124', (89, 116))	('interleukin (IL)-12', 'Gene', (130, 149))	('expansion', 'PosReg', (182, 191))	('TNF-alpha', 'Gene', '7124', (118, 127))	('NF-kappaB', 'Gene', (17, 26))	('IL-6', 'Gene', (165, 169))	('TNF-alpha', 'Gene', (118, 127))	('IL-1beta', 'Gene', '3552', (151, 159))	('Th1 genes', 'Gene', (70, 79))	('NF-kappaB', 'Gene', '4790', (17, 26))	('IL)-12', 'Gene', (143, 149))	('transcription', 'MPA', (53, 66))	('tumor necrosis factor-alpha', 'Gene', (89, 116))	('leads to', 'Reg', (44, 52))	('Translocation', 'Var', (0, 13))	('IL-1beta', 'Gene', (151, 159))	('IL-6', 'Gene', '3569', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('effector T cells', 'CPA', (195, 211))
613097	33381449	Increased phagocytosis of human RMS cells was observed in vitro when macrophages were treated with anti-CD47 monoclonal antibody.	('RMS', 'Phenotype', 'HP:0002859', (32, 35))	('anti-CD47', 'Var', (99, 108))	('human', 'Species', '9606', (26, 31))	('phagocytosis', 'CPA', (10, 22))
613100	33381449	However, in adults, there are several open clinical trials evaluating the safety profile and efficacy of anti-CD47 monoclonal antibody (Hu5F9-G4) in a variety of solid and hematologic malignancies (NCT02953509, NCT03248479, NCT03922477, NCT03869190).	('hematologic malignancies', 'Disease', (172, 196))	('NCT03869190', 'Var', (237, 248))	('NCT03922477', 'Var', (224, 235))	('NCT02953509', 'Var', (198, 209))	('NCT03248479', 'Var', (211, 222))	('hematologic malignancies', 'Disease', 'MESH:D019337', (172, 196))
613104	33381449	Conversely, inhibition of MERTK in preclinical studies has shown decreased leukemia-associated macrophage expression of inhibitory checkpoint ligands, including PD-L1 and PD-L2 (discussed below), demonstrating its role in immune tolerance.	('inhibition', 'Var', (12, 22))	('decreased leukemia', 'Disease', (65, 83))	('PD-L2', 'Var', (171, 176))	('decreased leukemia', 'Disease', 'MESH:D002303', (65, 83))	('MERTK', 'Gene', (26, 31))	('leukemia', 'Phenotype', 'HP:0001909', (75, 83))
613106	33381449	Pre-clinical studies of MERTK inhibitors in murine solid tumor models have shown decreased tumor growth and increased CTL infiltration, while others demonstrated a more profound effect when MerTK inhibition is used in combination with radiation therapy.	('MerTK', 'Gene', '17289', (190, 195))	('MerTK', 'Gene', (190, 195))	('CTL infiltration', 'CPA', (118, 134))	('solid tumor', 'Disease', 'MESH:D009369', (51, 62))	('increased', 'PosReg', (108, 117))	('inhibitors', 'Var', (30, 40))	('murine', 'Species', '10090', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('decreased tumor', 'Disease', (81, 96))	('solid tumor', 'Disease', (51, 62))	('MERTK', 'Gene', (24, 29))	('decreased tumor', 'Disease', 'MESH:D002303', (81, 96))
613112	33381449	TIM-3, a known co-inhibitory receptor on T cells, is also expressed on antigen presenting cells such as macrophages, aids in the binding and phagocytosis of apoptotic cells through the FG loop in the immunoglobulin variable region (IgV) domain.	('TIM-3', 'Gene', '84868', (0, 5))	('aids', 'PosReg', (117, 121))	('phagocytosis', 'CPA', (141, 153))	('binding', 'CPA', (129, 136))	('FG loop', 'Var', (185, 192))	('TIM-3', 'Gene', (0, 5))
613114	33381449	TIM-3 antibodies are being clinically tested and may be useful in both augmenting T cell activation, as well as diminishing the tolerogenic effects of efferocytosis.	('TIM-3', 'Gene', '84868', (0, 5))	('augmenting', 'PosReg', (71, 81))	('antibodies', 'Var', (6, 16))	('tolerogenic effects of efferocytosis', 'MPA', (128, 164))	('T cell activation', 'CPA', (82, 99))	('diminishing', 'NegReg', (112, 123))	('TIM-3', 'Gene', (0, 5))
613127	33381449	In contrast to the CD28 stimulatory effects on T cells, ligation of inhibitory B7 receptors, including programmed death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), can promote T cell suppression and/or dysfunction.	('cytotoxic T-lymphocyte associated protein 4', 'Gene', '1493', (133, 176))	('cytotoxic T-lymphocyte associated protein 4', 'Gene', (133, 176))	('ligation', 'Var', (56, 64))	('CD28', 'Gene', '940', (19, 23))	('T cell suppression', 'CPA', (199, 217))	('promote', 'PosReg', (191, 198))	('CD28', 'Gene', (19, 23))
613130	33381449	The treatment of murine and human macrophages with anti-PD-L1 antibodies promotes their proliferation and activation.	('anti-PD-L1', 'Var', (51, 61))	('human', 'Species', '9606', (28, 33))	('murine', 'Species', '10090', (17, 23))	('proliferation', 'CPA', (88, 101))	('promotes', 'PosReg', (73, 81))	('activation', 'CPA', (106, 116))
613131	33381449	Blockade of the PD-L1/PD-1 axis also enhances macrophage-mediated anti-tumor activity through efferocytosis.	('Blockade', 'Var', (0, 8))	('enhances', 'PosReg', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('efferocytosis', 'MPA', (94, 107))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
613132	33381449	Although blockade of this ligand/receptor binding is typically studied for its effects on T cell function, preclinical models of PD-L1/PD-1 blockade using BALB/c Rag2 -/- gammac -/- mice (which do not have functional T cells) showed TAM-mediated efferocytosis and clearance of tumor cells.	('TAM', 'Gene', (233, 236))	('clearance', 'CPA', (264, 273))	('Rag2', 'Gene', '19374', (162, 166))	('blockade', 'Var', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('mice', 'Species', '10090', (182, 186))	('TAM', 'Gene', '8205', (233, 236))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('Rag2', 'Gene', (162, 166))	('PD-L1/PD-1', 'Gene', (129, 139))	('tumor', 'Disease', (277, 282))
613133	33381449	Disruption of the PD-1/PD-L1 axis in osteosarcoma demonstrated decreased lung metastases, reduced numbers of tumor-promoting TAMs, and increased anti-tumor M1 macrophages in the absence of T cells.	('PD-1/PD-L1 axis', 'Gene', (18, 33))	('reduced', 'NegReg', (90, 97))	('decreased lung metastases', 'Disease', 'MESH:D009362', (63, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('TAMs', 'Chemical', '-', (125, 129))	('increased', 'PosReg', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('decreased lung', 'Phenotype', 'HP:0002089', (63, 77))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('osteosarcoma', 'Phenotype', 'HP:0002669', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('osteosarcoma', 'Disease', 'MESH:D012516', (37, 49))	('decreased lung metastases', 'Disease', (63, 88))	('tumor', 'Disease', (150, 155))	('osteosarcoma', 'Disease', (37, 49))	('tumor', 'Disease', (109, 114))	('Disruption', 'Var', (0, 10))
613161	33381449	Furthermore, blocking TNF-alpha using a soluble receptor (etanercept) to diminish chronic inflammation inhibited osteosarcoma tumor growth.	('inflammation', 'Disease', 'MESH:D007249', (90, 102))	('blocking', 'Var', (13, 21))	('osteosarcoma tumor', 'Disease', (113, 131))	('inflammation', 'Disease', (90, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('inhibited', 'NegReg', (103, 112))	('osteosarcoma tumor', 'Disease', 'MESH:D012516', (113, 131))	('TNF-alpha', 'Gene', '7124', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('TNF-alpha', 'Gene', (22, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))
613170	33381449	The use of ARG1 targeted small-molecule inhibitors demonstrated reversal of TAM-mediated immunosuppression including production of inflammatory cytokines, CTL, and NK cell tumor infiltration, T cell proliferation, expression of IFN-inducible genes, and restored cytolytic T cell function against solid malignancies in vitro and in vivo.	('TAM', 'Gene', '8205', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('inflammatory cytokines', 'MPA', (131, 153))	('ARG1', 'Gene', (11, 15))	('IFN', 'Gene', (228, 231))	('inhibitors', 'Var', (40, 50))	('NK cell tumor', 'Disease', 'MESH:D054066', (164, 177))	('T cell proliferation', 'CPA', (192, 212))	('CTL', 'MPA', (155, 158))	('TAM', 'Gene', (76, 79))	('NK cell tumor', 'Disease', (164, 177))	('malignancies', 'Disease', 'MESH:D009369', (302, 314))	('IFN', 'Gene', '3439', (228, 231))	('cytolytic', 'CPA', (262, 271))	('restored', 'PosReg', (253, 261))	('malignancies', 'Disease', (302, 314))	('expression', 'MPA', (214, 224))
613172	33381449	Additionally, there is an open-label phase 1/2 study investigating an arginase inhibitor (INCB00158) as single or combination therapy with other immune checkpoint therapy in adult patients with advanced/metastatic solid tumors (NCT02903914).	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('solid tumor', 'Disease', (214, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('solid tumor', 'Disease', 'MESH:D009369', (214, 225))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('INCB00158', 'Gene', (90, 99))	('NCT02903914', 'Var', (228, 239))	('patients', 'Species', '9606', (180, 188))
613176	33381449	On the contrary, M1 polarization of TAMs results in inhibition of angiogenesis through the upregulation of anti-angiogenic factors (such as CXCL8 and IFN-beta).	('CXCL8', 'Gene', (140, 145))	('upregulation', 'PosReg', (91, 103))	('M1 polarization', 'Var', (17, 32))	('IFN-beta', 'Gene', '3439', (150, 158))	('IFN-beta', 'Gene', (150, 158))	('TAMs', 'Chemical', '-', (36, 40))	('angiogenesis', 'CPA', (66, 78))	('inhibition', 'NegReg', (52, 62))	('CXCL8', 'Gene', '3576', (140, 145))
613189	33381449	Inhibition of CSF1R in neuroblastoma decreased TAM infiltration, improved T cell function, and decreased tumor progression compared to controls.	('neuroblastoma decreased TAM infiltration', 'Disease', (23, 63))	('improved T cell function', 'Phenotype', 'HP:0005435', (65, 89))	('improved', 'PosReg', (65, 73))	('T cell function', 'CPA', (74, 89))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('decreased tumor', 'Disease', (95, 110))	('CSF1R', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('neuroblastoma', 'Phenotype', 'HP:0003006', (23, 36))	('neuroblastoma decreased TAM infiltration', 'Disease', 'MESH:C563551', (23, 63))	('decreased tumor', 'Disease', 'MESH:D002303', (95, 110))
613206	33381449	Similar solid tumor models with high levels of TAM or MDSC infiltration found that inhibition of CSF1R increased the efficacy of adoptively transferred T cells.	('CSF1R', 'Gene', (97, 102))	('increased', 'PosReg', (103, 112))	('efficacy of adoptively transferred T cells', 'CPA', (117, 159))	('TAM', 'Gene', '8205', (47, 50))	('inhibition', 'Var', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('solid tumor', 'Disease', (8, 19))	('TAM', 'Gene', (47, 50))	('solid tumor', 'Disease', 'MESH:D009369', (8, 19))
613214	33381449	Similar approaches to inhibiting TAMs in combination with immunotherapy in development include use of bi- and tri-valent T cell engagers (BiTEs, TriTEs) to deplete CD206 and FRbeta expressing TAMs, inhibition of CXCR2 alongside T cell immunotherapy (e.g.	('inhibition', 'Var', (198, 208))	('TAMs', 'Chemical', '-', (192, 196))	('CXCR2', 'Gene', (212, 217))	('CXCR2', 'Gene', '3579', (212, 217))	('FRbeta', 'Gene', (174, 180))	('TAMs', 'Chemical', '-', (33, 37))	('CD206', 'Gene', '4360', (164, 169))	('FRbeta', 'Gene', '8061', (174, 180))	('CD206', 'Gene', (164, 169))
613229	33028642	Genetic analysis revealed biallelic pathogenic DICER1 variation.	('DICER1', 'Gene', '23405', (47, 53))	('variation', 'Var', (54, 63))	('pathogenic', 'Reg', (36, 46))	('DICER1', 'Gene', (47, 53))
613231	33028642	We believe this case to represent a new expression of the DICER1 tumor predisposition syndrome, an entity caused by deleterious germline mutations in the DICER1 gene, encoding a ribonuclease active in the processing of miRNA.	('DICER1', 'Gene', '23405', (154, 160))	('caused', 'Reg', (106, 112))	('DICER1', 'Gene', (58, 64))	('DICER1', 'Gene', '23405', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('mutations', 'Var', (137, 146))	('DICER1', 'Gene', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
613232	33028642	Patients with germline mutations in DICER1 develop a diverse group of benign and malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('malignant tumors', 'Disease', (81, 97))	('Patients', 'Species', '9606', (0, 8))	('malignant tumors', 'Disease', 'MESH:D009369', (81, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('DICER1', 'Gene', (36, 42))	('DICER1', 'Gene', '23405', (36, 42))	('germline mutations', 'Var', (14, 32))	('develop', 'PosReg', (43, 50))
613234	33028642	To our knowledge, abdominal sarcomas that resemble PNET histology with an EWSR1 rearrangement have not previously been described as a classical expression of the DICER1 syndrome phenotype.	('abdominal sarcomas', 'Disease', (18, 36))	('sarcomas', 'Phenotype', 'HP:0100242', (28, 36))	('PNET', 'Phenotype', 'HP:0030065', (51, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('EWSR1', 'Gene', (74, 79))	('DICER1', 'Gene', (162, 168))	('DICER1', 'Gene', '23405', (162, 168))	('rearrangement', 'Var', (80, 93))	('EWSR1', 'Gene', '2130', (74, 79))	('abdominal sarcomas', 'Disease', 'MESH:D012509', (18, 36))
613236	33028642	The DICER1 gene is located on Chromosome 14 and encodes a RNase III endoribonuclease that processes precursor micro RNAs (miRNAs) into functional mature miRNAs, which serve to negatively regulate gene expression by messenger RNA (mRNA) silencing or repressing translation.	('negatively', 'NegReg', (176, 186))	('DICER1', 'Gene', (4, 10))	('DICER1', 'Gene', '23405', (4, 10))	('gene expression', 'MPA', (196, 211))	('silencing', 'NegReg', (236, 245))	('translation', 'MPA', (260, 271))	('messenger', 'Var', (215, 224))
613237	33028642	The predicted effects of mutations in DICER1 include reduction of DICER1 protein level, consequently reduction of miRNA levels, and thereby reduction in tumor-suppression activity.	('DICER1', 'Gene', (38, 44))	('mutations', 'Var', (25, 34))	('reduction', 'NegReg', (101, 110))	('DICER1', 'Gene', '23405', (38, 44))	('protein level', 'MPA', (73, 86))	('DICER1', 'Gene', (66, 72))	('DICER1', 'Gene', '23405', (66, 72))	('tumor-suppression', 'Disease', (153, 170))	('miRNA levels', 'MPA', (114, 126))	('reduction', 'NegReg', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor-suppression', 'Disease', 'MESH:D009369', (153, 170))	('reduction', 'NegReg', (140, 149))
613238	33028642	DICER1 function in cancer, however, may vary, as its inactivation has been associated with tumorigenesis in some tumor types, whereas increased DICER1 protein expression has been associated with invasion and metastasis in others.	('DICER1', 'Gene', (0, 6))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('inactivation', 'Var', (53, 65))	('tumor', 'Disease', (91, 96))	('protein', 'Protein', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('expression', 'MPA', (159, 169))	('DICER1', 'Gene', '23405', (144, 150))	('tumor', 'Disease', (113, 118))	('associated', 'Reg', (179, 189))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('associated', 'Reg', (75, 85))	('DICER1', 'Gene', (144, 150))	('DICER1', 'Gene', '23405', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('increased', 'PosReg', (134, 143))
613240	33028642	Instances of global down-regulation of miRNAs in tumors have been reported, especially in poorly differentiated ones, and one explanation proposed is that the function of miRNAs is to define lineage-specific properties so that a low abundance of miRNAs could promote the undifferentiated state of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('poorly differentiated', 'CPA', (90, 111))	('promote', 'PosReg', (259, 266))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('low', 'Var', (229, 232))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumor', 'Disease', (49, 54))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('down-regulation', 'NegReg', (20, 35))	('tumor', 'Disease', (297, 302))	('miRNAs', 'Protein', (39, 45))
613243	33028642	Initially described in familial pleuropulmonary blastoma, in which 70% of cases harbor a germline heterozygous DICER1 loss-of-function mutation, DICER1 syndrome has since been associated with a variety of additional benign and malignant conditions including lung cysts, cystic nephroma, Wilms tumor, multinodular goiter, thyroid adenoma, juvenile-type intestinal polyps, ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, pituitary blastoma, pinealoblastoma, cervical embryonal rhabdomyosarcoma, Sertoli-Leydig tumors, and malignant sacrococcygeal tumors.	('medulloepithelioma', 'Disease', 'MESH:D008527', (384, 402))	('medulloepithelioma', 'Phenotype', 'HP:0030071', (384, 402))	('Wilms tumor', 'Disease', 'MESH:D009396', (287, 298))	('familial pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (23, 56))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (486, 512))	('familial pleuropulmonary blastoma', 'Disease', (23, 56))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (496, 512))	('tumor', 'Phenotype', 'HP:0002664', (529, 534))	('Leydig tumors', 'Disease', (522, 535))	('malignant sacrococcygeal tumors', 'Disease', 'MESH:D009369', (541, 572))	('Wilms tumor', 'Phenotype', 'HP:0002667', (287, 298))	('malignant sacrococcygeal tumors', 'Disease', (541, 572))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('DICER1', 'Gene', '23405', (145, 151))	('multinodular goiter', 'Disease', (300, 319))	('pituitary blastoma', 'Disease', (440, 458))	('embryonal rhabdomyosarcoma', 'Disease', (486, 512))	('pinealoblastoma', 'Disease', (460, 475))	('pinealoblastoma', 'Disease', 'None', (460, 475))	('tumors', 'Phenotype', 'HP:0002664', (529, 535))	('Sertoli-Leydig tumors', 'Phenotype', 'HP:0100619', (514, 535))	('Leydig tumors', 'Phenotype', 'HP:0100618', (522, 535))	('multinodular goiter', 'Phenotype', 'HP:0005987', (300, 319))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (32, 56))	('intestinal polyps', 'Disease', (352, 369))	('Wilms tumor', 'Disease', (287, 298))	('medulloepithelioma', 'Disease', (384, 402))	('lung cysts', 'Disease', (258, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (505, 512))	('DICER1', 'Gene', (145, 151))	('DICER1', 'Gene', '23405', (111, 117))	('cystic nephroma', 'Disease', (270, 285))	('hamartoma', 'Disease', 'MESH:D006222', (429, 438))	('Leydig tumors', 'Disease', 'MESH:D007984', (522, 535))	('thyroid adenoma', 'Disease', 'MESH:D013964', (321, 336))	('goiter', 'Phenotype', 'HP:0000853', (313, 319))	('lung cysts', 'Phenotype', 'HP:0032445', (258, 268))	('thyroid adenoma', 'Disease', (321, 336))	('loss-of-function', 'NegReg', (118, 134))	('intestinal polyps', 'Disease', 'MESH:D007417', (352, 369))	('tumor', 'Phenotype', 'HP:0002664', (566, 571))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (486, 512))	('mutation', 'Var', (135, 143))	('cystic nephroma', 'Disease', 'MESH:D018201', (270, 285))	('multinodular goiter', 'Disease', 'MESH:C564546', (300, 319))	('intestinal polyps', 'Phenotype', 'HP:0005266', (352, 369))	('hamartoma', 'Phenotype', 'HP:0010566', (429, 438))	('DICER1', 'Gene', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (566, 572))	('thyroid adenoma', 'Phenotype', 'HP:0000854', (321, 336))	('pinealoblastoma', 'Phenotype', 'HP:0030408', (460, 475))	('hamartoma', 'Disease', (429, 438))	('pituitary blastoma', 'Disease', 'MESH:D018202', (440, 458))
613271	33028642	Molecular testing for the EWSR1 gene rearrangement was performed by fluorescence in situ hybridization (FISH) and was positive for the EWSR1 rearrangement in ~16% of nuclei (Fig.	('EWSR1', 'Gene', '2130', (26, 31))	('EWSR1', 'Gene', (135, 140))	('positive', 'Reg', (118, 126))	('EWSR1', 'Gene', (26, 31))	('rearrangement', 'Var', (141, 154))	('EWSR1', 'Gene', '2130', (135, 140))
613273	33028642	Additional molecular profiling of the tumor was performed through a commercial platform (Personal Genome Diagnostics) and revealed a somatic missense G1809R mutation in DICER1 in 44% of transcripts, a previously described hotspot mutation affecting the RNaseIIIb domain.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('missense G1809R', 'Var', (141, 156))	('DICER1', 'Gene', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('DICER1', 'Gene', '23405', (169, 175))	('G1809R', 'Mutation', 'p.G1809R', (150, 156))
613276	33028642	Given the patient's history of multinodular goiter in conjunction with the somatic DICER1 mutation identified in the tumor, there was strong suspicion for inherited DICER1 syndrome.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('inherited DICER1 syndrome', 'Disease', 'MESH:D061325', (155, 180))	('DICER1', 'Gene', '23405', (165, 171))	('DICER1', 'Gene', (83, 89))	('DICER1', 'Gene', '23405', (83, 89))	('tumor', 'Disease', (117, 122))	('multinodular goiter', 'Phenotype', 'HP:0005987', (31, 50))	('patient', 'Species', '9606', (10, 17))	('multinodular goiter', 'Disease', (31, 50))	('inherited DICER1 syndrome', 'Disease', (155, 180))	('multinodular goiter', 'Disease', 'MESH:C564546', (31, 50))	('mutation', 'Var', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('DICER1', 'Gene', (165, 171))	('goiter', 'Phenotype', 'HP:0000853', (44, 50))
613277	33028642	Germline testing was performed and detected a heterozygous mutation in exon 3 of the DICER1 gene, with insertion of two nucleotides (NM_177438.2: c.282.283dupAA) causing a frameshift mutation leading to a premature translational stop signal (p.Arg95Lysfs*34).	('premature translational stop', 'MPA', (205, 233))	('p.Arg95Lysfs*34', 'Mutation', 'p.R95KfsX34', (242, 257))	('p.Arg95Lysfs*34', 'Var', (242, 257))	('NM_177438.2: c.282.283dupAA', 'Mutation', 'c.282.283dupAA', (133, 160))	('causing', 'Reg', (162, 169))	('DICER1', 'Gene', (85, 91))	('DICER1', 'Gene', '23405', (85, 91))
613286	33028642	Since the initial description of DICER1 as the causative gene in the pleuropulmonary blastoma inherited cancer syndrome, DICER1 mutations have been associated with an increasing number of childhood and adult cancers.	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('DICER1', 'Gene', (121, 127))	('DICER1', 'Gene', '23405', (121, 127))	('mutations', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancers', 'Disease', (208, 215))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (69, 93))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('DICER1', 'Gene', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('pleuropulmonary blastoma inherited cancer syndrome', 'Disease', 'MESH:C537516', (69, 119))	('associated with', 'Reg', (148, 163))	('DICER1', 'Gene', '23405', (33, 39))	('pleuropulmonary blastoma inherited cancer syndrome', 'Disease', (69, 119))
613287	33028642	Several unique cancer entities have been reported in patients with pathogenic DICER1 mutations and include cystic nephroma, anaplastic renal sarcoma, Wilms tumor, Sertoli-Leydig cell tumor (SLCT), embryonal rhabdomyosarcoma, and, more recently, intracranial sarcomas.	('Sertoli-Leydig cell tumor', 'Disease', 'MESH:D018310', (163, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (197, 223))	('DICER1', 'Gene', (78, 84))	('intracranial sarcomas', 'Disease', 'MESH:D012509', (245, 266))	('patients', 'Species', '9606', (53, 61))	('Wilms tumor', 'Disease', 'MESH:D009396', (150, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('cancer', 'Disease', (15, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (258, 266))	('Wilms tumor', 'Phenotype', 'HP:0002667', (150, 161))	('intracranial sarcomas', 'Disease', (245, 266))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (197, 223))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (171, 188))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutations', 'Var', (85, 94))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (207, 223))	('renal sarcoma', 'Phenotype', 'HP:0008663', (135, 148))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cystic nephroma, anaplastic renal sarcoma', 'Disease', 'MESH:D052177', (107, 148))	('embryonal rhabdomyosarcoma', 'Disease', (197, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('Wilms tumor', 'Disease', (150, 161))	('Sertoli-Leydig cell tumor', 'Disease', (163, 188))	('DICER1', 'Gene', '23405', (78, 84))
613289	33028642	To our knowledge, only one case of PNET of the abdomen/pelvis, which was reported to arise from the uterine cervix, in a patient with DICER1 mutation has been described.	('PNET', 'Disease', (35, 39))	('PNET', 'Phenotype', 'HP:0030065', (35, 39))	('DICER1', 'Gene', (134, 140))	('patient', 'Species', '9606', (121, 128))	('mutation', 'Var', (141, 149))	('uterine cervix', 'Phenotype', 'HP:0030160', (100, 114))	('DICER1', 'Gene', '23405', (134, 140))
613291	33028642	Here we describe the case of a 16-yr-old female with a metastatic high-grade malignancy that was difficult to characterize histologically and appeared to have rearrangement of the EWSR1 gene by FISH.	('malignancy', 'Disease', (77, 87))	('EWSR1', 'Gene', (180, 185))	('rearrangement', 'Var', (159, 172))	('EWSR1', 'Gene', '2130', (180, 185))	('malignancy', 'Disease', 'MESH:D009369', (77, 87))
613297	33028642	The finding of a subset of cells showing EWSR1 rearrangement raises the possibility that this additional mutation was the driver for malignant or more aggressive transformation.	('EWSR1', 'Gene', '2130', (41, 46))	('EWSR1', 'Gene', (41, 46))	('rearrangement', 'Var', (47, 60))
613300	33028642	EWSR1 rearrangements lead to formation of chimeric genes in which the EWSR1 amino-terminal transcriptional activation domain is fused to the carboxy-terminal DNS-binding domain of the partner gene, usually a transcription factor.	('rearrangements', 'Var', (6, 20))	('EWSR1', 'Gene', (70, 75))	('EWSR1', 'Gene', '2130', (0, 5))	('lead to', 'Reg', (21, 28))	('EWSR1', 'Gene', '2130', (70, 75))	('EWSR1', 'Gene', (0, 5))
613302	33028642	Of note, germline DICER1 mutations were not identified in a whole-genome sequencing study of Ewing sarcoma patients, which identified germline mutations most frequently affecting genes involved in DNA repair pathways.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (93, 106))	('DICER1', 'Gene', (18, 24))	('DICER1', 'Gene', '23405', (18, 24))	('DNA repair pathways', 'Pathway', (197, 216))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('Ewing sarcoma', 'Disease', (93, 106))	('affecting', 'Reg', (169, 178))	('patients', 'Species', '9606', (107, 115))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (93, 106))	('mutations', 'Var', (143, 152))
613304	33028642	Germline testing for DICER1, in fact, detected a mutation in exon 3 of the DICER1 gene with insertion of two nucleotides (c.282.283dupAA) causing a frameshift mutation leading to a premature translational stop signal (p.Arg95Lysfs*34).	('DICER1', 'Gene', (21, 27))	('c.282.283dupAA', 'Mutation', 'c.282.283dupAA', (122, 136))	('DICER1', 'Gene', '23405', (21, 27))	('p.Arg95Lysfs*34', 'Mutation', 'p.R95KfsX34', (218, 233))	('DICER1', 'Gene', '23405', (75, 81))	('p.Arg95Lysfs*34', 'Var', (218, 233))	('DICER1', 'Gene', (75, 81))	('premature translational stop', 'MPA', (181, 209))
613305	33028642	Consistent with a two-hit model, next-generation sequencing detected the G1809R missense mutation (variant allele frequency [VAF] 44%), confirming that this malignancy, although not a reported type in DICER1 syndrome, was potentially a novel cancer type in a syndrome increasingly being identified with predisposition to other sarcomas.	('malignancy', 'Disease', 'MESH:D009369', (157, 167))	('cancer type', 'Disease', 'MESH:D009369', (242, 253))	('malignancy', 'Disease', (157, 167))	('G1809R', 'Var', (73, 79))	('sarcomas', 'Disease', 'MESH:D012509', (327, 335))	('G1809R', 'Mutation', 'p.G1809R', (73, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (327, 335))	('sarcoma', 'Phenotype', 'HP:0100242', (327, 334))	('DICER1', 'Gene', (201, 207))	('sarcomas', 'Disease', (327, 335))	('DICER1', 'Gene', '23405', (201, 207))	('cancer type', 'Disease', (242, 253))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('VAF', 'Disease', 'None', (125, 128))	('VAF', 'Disease', (125, 128))
613314	33028642	This hypothesis may also be supported by a similar report of a woman with a malignant thyroid teratoma with neuroectodermal differentiation and a somatic DICER1 mutation.	('DICER1', 'Gene', '23405', (154, 160))	('malignant thyroid teratoma', 'Disease', 'MESH:D013724', (76, 102))	('malignant thyroid teratoma', 'Disease', (76, 102))	('mutation', 'Var', (161, 169))	('teratoma', 'Phenotype', 'HP:0009792', (94, 102))	('woman', 'Species', '9606', (63, 68))	('DICER1', 'Gene', (154, 160))
613317	33028642	Next-generation sequencing was conducted using the Cancer Select-203 panel commercially available from Personal Genome Diagnostics, which evaluates a total of 203 cancer-associated genes for mutations, copy-number variation, and/or translocations.	('mutations', 'Var', (191, 200))	('translocations', 'Var', (232, 246))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Cancer', 'Disease', (51, 57))	('Cancer', 'Disease', 'MESH:D009369', (51, 57))	('copy-number variation', 'Var', (202, 223))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
613323	33028642	The somatic DICER1 variant was submitted to ClinVar  and can be found under accession number SCV001429657.1.	('DICER1', 'Gene', (12, 18))	('DICER1', 'Gene', '23405', (12, 18))	('variant', 'Var', (19, 26))
613324	33028642	The germline DICER1 mutation was previously submitted to ClinVar by Invitae under accession number SCV000658204.1.	('DICER1', 'Gene', (13, 19))	('DICER1', 'Gene', '23405', (13, 19))	('mutation', 'Var', (20, 28))
613382	29780754	 Pleomorphic undifferentiated soft tissue sarcoma in patient with long standing inflammatory bowel disease Inflammatory bowel disease (IBD) has been associated with the development of both gastrointestinal and extraintestinal malignancy.	('sarcoma', 'Disease', (42, 49))	('malignancy', 'Disease', 'MESH:D009369', (226, 236))	('gastrointestinal', 'Disease', 'MESH:D005767', (189, 205))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (30, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('malignancy', 'Disease', (226, 236))	('Inflammatory bowel disease', 'Disease', (107, 133))	('Pleomorphic', 'Var', (1, 12))	('associated', 'Reg', (149, 159))	('Inflammatory bowel disease', 'Disease', 'MESH:D015212', (107, 133))	('gastrointestinal and extraintestinal malignancy', 'Disease', 'MESH:D005767', (189, 236))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (80, 106))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (80, 106))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('gastrointestinal', 'Disease', (189, 205))	('inflammatory bowel disease', 'Disease', (80, 106))	('Inflammatory bowel disease', 'Phenotype', 'HP:0002037', (107, 133))	('patient', 'Species', '9606', (53, 60))
613402	29780754	Anti-TNF antibodies and thiopurines have been associated with the development of lymphoproliferative disorders,  while thiopurines alone have been shown to increase the risk of non-melanoma skin cancer.	('non-melanoma skin cancer', 'Disease', (177, 201))	('antibodies', 'Var', (9, 19))	('Anti-TNF', 'Protein', (0, 8))	('associated with', 'Reg', (46, 61))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('lymphoproliferative disorders', 'Disease', (81, 110))	('skin cancer', 'Phenotype', 'HP:0008069', (190, 201))	('lymphoproliferative disorders', 'Disease', 'MESH:D008232', (81, 110))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (81, 110))
613404	29780754	Anti-TNF antibodies have been shown to promote neoplastic cell survival via the nuclear factor kappa B (NF-kB) pathway, while thiopurines are implicated in the pathogenesis of lymphomas related to a reactivation of latent Epstein-Barr virus (EBV) infection.	('lymphomas', 'Disease', (176, 185))	('promote', 'PosReg', (39, 46))	('Anti-TNF', 'Gene', (0, 8))	('lymphomas', 'Phenotype', 'HP:0002665', (176, 185))	('Epstein-Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (222, 256))	('antibodies', 'Var', (9, 19))	('neoplastic cell survival', 'CPA', (47, 71))
613633	23300824	Joyama reported that DCs inhibit primary tumors and metastatic tumors in an osteosarcoma model using LM8.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('osteosarcoma', 'Disease', (76, 88))	('osteosarcoma', 'Disease', 'MESH:D012516', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('inhibit', 'NegReg', (25, 32))	('DCs', 'Var', (21, 24))
613654	23300824	DC preparation was assessed by staining with the following monoclonal antibodies: (MoAb) for 30 min on ice, antilineage cocktail 1 (lin-1; CD3, CD14, CD16, CD19, CD20 and CD56)-fluorescein isothiocyanate (FITC), anti-HLA-DR peridinin chlorophyll protein (PerCP) (L243), anti-CD14-allophycocyanin (APC) (MOP9), anti-CD11c-APC (S-HCL-3), anti-CD123-phycoerythrin (PE) (9F5) (BD PharMingen, San Diego, CA, USA), anti-CD80-PE (MAB104), anti-CD83-PE (HB15a) and anti-CD86-PE (HA5.2B7) (Beckman Coulter, Fullerton, CA, USA).	('lin-1', 'Gene', (132, 137))	('CD14', 'Gene', (275, 279))	('MOP9', 'Gene', '56938', (303, 307))	('CD19', 'Gene', '930', (156, 160))	('CD14', 'Gene', '929', (275, 279))	('CD16', 'Gene', '2214', (150, 154))	('CD20', 'Gene', (162, 166))	('anti-CD14-allophycocyanin (APC)', 'Gene', '324', (270, 301))	('MOP9', 'Gene', (303, 307))	('CD80', 'Gene', '941', (414, 418))	('lin-1', 'Gene', '10421', (132, 137))	('CD86', 'Gene', '942', (462, 466))	('CD86', 'Gene', (462, 466))	('CD56', 'Gene', (171, 175))	('CD83', 'Gene', (437, 441))	('anti-CD14-allophycocyanin (APC', 'Gene', (270, 300))	('CD20', 'Gene', '54474', (162, 166))	('CD80', 'Gene', (414, 418))	('CD16', 'Gene', (150, 154))	('APC', 'Disease', 'MESH:D011125', (297, 300))	('APC', 'Disease', (297, 300))	('APC', 'Disease', 'MESH:D011125', (321, 324))	('CD56', 'Gene', '4684', (171, 175))	('APC', 'Disease', (321, 324))	('anti-CD123-phycoerythrin', 'Var', (336, 360))	('CD83', 'Gene', '9308', (437, 441))	('CD19', 'Gene', (156, 160))	('CD14', 'Gene', (144, 148))	('CD14', 'Gene', '929', (144, 148))
613777	20924475	The EFT in 85% of cases is associated with translocation t(11;22)(q24;q12).	('translocation t(11;22)(q24;q12', 'Var', (43, 73))	('EFT', 'Disease', (4, 7))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (57, 74))	('associated', 'Reg', (27, 37))
613779	20924475	Translocations involving EWS gene are observed in other tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Translocations', 'Var', (0, 14))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('observed', 'Reg', (38, 46))	('EWS', 'Gene', (25, 28))
613781	20924475	In addition, EWS-like gene, TLS/FUS, is involved in tumor-associated gene fusions in myxoid liposarcoma and acute myeloid leukemia.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('tumor', 'Disease', (52, 57))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (85, 103))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('involved', 'Reg', (40, 48))	('TLS', 'Gene', (28, 31))	('FUS', 'Gene', (32, 35))	('liposarcoma', 'Phenotype', 'HP:0012034', (92, 103))	('acute myeloid leukemia', 'Disease', (108, 130))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TLS', 'Gene', '2521', (28, 31))	('FUS', 'Gene', '2521', (32, 35))	('fusions', 'Var', (74, 81))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (114, 130))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (85, 103))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (108, 130))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (108, 130))	('myxoid liposarcoma', 'Disease', (85, 103))
613787	20924475	Overexpression of FLI1 is observed to promote self-renewal, repress Rb protein, and induce BCL2 expression in erythroid cells with a corresponding enhancement of cell survival.	('BCL2', 'Gene', (91, 95))	('FLI1', 'Gene', (18, 22))	('self-renewal', 'CPA', (46, 58))	('expression', 'MPA', (96, 106))	('Rb', 'Phenotype', 'HP:0009919', (68, 70))	('cell survival', 'CPA', (162, 175))	('Rb', 'Gene', '5925', (68, 70))	('Overexpression', 'Var', (0, 14))	('promote', 'PosReg', (38, 45))	('induce', 'PosReg', (84, 90))	('repress', 'NegReg', (60, 67))	('BCL2', 'Gene', '596', (91, 95))	('enhancement', 'PosReg', (147, 158))
613788	20924475	In immunocompromised mice, the expression of EWS-FLI1 in murine NIH-3T3 cells resulted in anchorage independent growth and accelerated tumorigenesis with a tumor phenotype reminiscent of human Ewing's sarcoma.	('NIH-3T3', 'CellLine', 'CVCL:0594', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('resulted in', 'Reg', (78, 89))	('mice', 'Species', '10090', (21, 25))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (193, 208))	('tumor', 'Disease', (156, 161))	('EWS-FLI1', 'Gene', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (193, 208))	('accelerated', 'PosReg', (123, 134))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	("Ewing's sarcoma", 'Disease', (193, 208))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('murine', 'Species', '10090', (57, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('anchorage independent growth', 'CPA', (90, 118))	('human', 'Species', '9606', (187, 192))	('expression', 'Var', (31, 41))
613791	20924475	Studies have demonstrated that antisense EWS-FLI1 and EWS-FLI1 siRNA expression in human Ewing's sarcoma cell lines results in decreased cell growth in vitro and tumorigenicity in in vivo.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (89, 104))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('decreased', 'NegReg', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('EWS-FLI1', 'Gene', (54, 62))	('tumor', 'Disease', (162, 167))	('human', 'Species', '9606', (83, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('EWS-FLI1', 'Gene', (41, 49))	('cell growth', 'CPA', (137, 148))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (89, 104))	("Ewing's sarcoma", 'Disease', (89, 104))	('antisense', 'Var', (31, 40))
613792	20924475	EWS-FLI1 may participate in Ewing's sarcoma pathogenesis by promoting at least two sets of events that synergize in tumor development and progression: cell proliferation and survival, by inducing among other candidate genes, PDGFC, insulin-like growth factor 1 (IGF-1), MYC, CCND-1 and NKX2-2, and escape from apoptosis and growth inhibition, by repressing p21, p57kip, TGFbetaRII, and IGFBP3.	('IGFBP3', 'Gene', '3486', (386, 392))	('survival', 'CPA', (174, 182))	('CCND-1', 'Gene', '595', (275, 281))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (28, 43))	('insulin-like growth factor 1', 'Gene', '3479', (232, 260))	('p21', 'Gene', (357, 360))	('CCND-1', 'Gene', (275, 281))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (28, 43))	('p21', 'Gene', '644914', (357, 360))	('NKX2-2', 'Gene', '4821', (286, 292))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('MYC', 'Gene', (270, 273))	('p57kip', 'Var', (362, 368))	('PDGFC', 'Gene', '56034', (225, 230))	('promoting', 'PosReg', (60, 69))	('NKX2-2', 'Gene', (286, 292))	('PDGFC', 'Gene', (225, 230))	("Ewing's sarcoma", 'Disease', (28, 43))	('cell proliferation', 'CPA', (151, 169))	('IGFBP3', 'Gene', (386, 392))	('TGFbetaRII', 'Gene', (370, 380))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('insulin-like growth factor 1', 'Gene', (232, 260))	('IGF-1', 'Gene', (262, 267))	('inducing', 'PosReg', (187, 195))	('MYC', 'Gene', '4609', (270, 273))	('EWS-FLI1', 'Gene', (0, 8))	('apoptosis', 'CPA', (310, 319))	('tumor', 'Disease', (116, 121))	('IGF-1', 'Gene', '3479', (262, 267))
613805	20924475	As the formalin-fixed paraffin-embedded tissue suffers from the problems of poor primary fixation, cross-linking of nucleic acids, and heterogeneity, a combination of RT-PCR and FISH may be a better approach to enhance the sensitivity and accuracy of detecting EFT translocations.	('enhance', 'PosReg', (211, 218))	('EFT translocations', 'Var', (261, 279))	('paraffin', 'Chemical', 'MESH:D010232', (22, 30))	('formalin', 'Chemical', 'MESH:D005557', (7, 15))
613812	20924475	In addition, some patients with more than 90% necrosis, who were positive for the chimeric transcript during follow-up, developed metastasis.	('developed', 'Reg', (120, 129))	('metastasis', 'CPA', (130, 140))	('necrosis', 'Disease', (46, 54))	('chimeric', 'Var', (82, 90))	('patients', 'Species', '9606', (18, 26))	('necrosis', 'Disease', 'MESH:D009336', (46, 54))
613816	20924475	p53 mutation was noted to be the most important independent prognostic factor.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('mutation', 'Var', (4, 12))
613826	30237864	Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic TP53 is the most commonly mutated gene in cancer and codes for the best studied tumor suppressor, p53.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('TP53', 'Gene', '7157', (117, 121))	('amplification', 'Var', (19, 32))	('TP53', 'Gene', (117, 121))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('p53', 'Gene', (215, 218))	('p53', 'Gene', '7157', (215, 218))	('MDM2', 'Gene', '4193', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('MDM2', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', (197, 202))
613828	30237864	In this retrospective study, we assessed the occurrence of MDM2 amplification among patients with various types of cancers and its association with clinical factors, other genetic aberrations, and response to targeted therapy in a phase I clinical trial setting.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('patients', 'Species', '9606', (84, 92))	('cancers', 'Disease', (115, 122))	('amplification', 'Var', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MDM2', 'Gene', (59, 63))
613830	30237864	Patients whose tumors expressed MDM2 amplification were compared to those with tumors of the same histologic types without MDM2 amplification.	('tumors', 'Disease', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('amplification', 'Var', (37, 50))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Disease', (79, 85))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('MDM2', 'Gene', (32, 36))
613831	30237864	We tested tumors from 523 patients, of which 23 (4.4%) had MDM2 amplification.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('amplification', 'Var', (64, 77))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tested', 'Reg', (3, 9))	('MDM2', 'Gene', (59, 63))	('patients', 'Species', '9606', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))
613832	30237864	The highest prevalence of MDM2 amplification was in sarcoma (57%), breast cancer (13%) and bladder cancer (9%).	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('sarcoma', 'Disease', (52, 59))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('MDM2', 'Gene', (26, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (31, 44))	('bladder cancer', 'Disease', (91, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', (67, 80))
613834	30237864	The most common molecular aberrations co-occurring with MDM2 amplification was CDK4 amplification (70%).	('amplification', 'Var', (84, 97))	('amplification', 'Var', (61, 74))	('CDK4', 'Gene', (79, 83))	('MDM2', 'Gene', (56, 60))	('CDK4', 'Gene', '1019', (79, 83))
613835	30237864	TP53 mutation was also detected in 7 patients (30%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (37, 45))	('detected', 'Reg', (23, 31))	('mutation', 'Var', (5, 13))
613836	30237864	MDM2 amplification was most commonly associated with liposarcoma.	('liposarcoma', 'Disease', (53, 64))	('liposarcoma', 'Disease', 'MESH:D008080', (53, 64))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (53, 64))	('MDM2', 'Gene', (0, 4))	('associated', 'Reg', (37, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
613837	30237864	Concomitant alterations in additional genes such as CDK4 amplification and TP53 mutations, along with variable responses to targeted therapies including MDM2 inhibitors, suggest that further combinational studies are needed to target this population.	('CDK4', 'Gene', (52, 56))	('mutations', 'Var', (80, 89))	('alterations', 'Reg', (12, 23))	('amplification', 'Var', (57, 70))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('CDK4', 'Gene', '1019', (52, 56))
613853	30237864	With the emergence of MDM2 inhibitors, an understanding of this particular patient population would provide a better rationale for the use of these inhibitors and help establish criteria for selection of patients most likely to benefit from them.	('patients', 'Species', '9606', (204, 212))	('MDM2', 'Gene', (22, 26))	('inhibitors', 'Var', (27, 37))	('patient', 'Species', '9606', (75, 82))	('patient', 'Species', '9606', (204, 211))
613855	30237864	We identified 523 patients who had undergone FoundationOne testing for MDM2 amplification and whose results were available for analysis.	('MDM2', 'Gene', (71, 75))	('patients', 'Species', '9606', (18, 26))	('amplification', 'Var', (76, 89))
613859	30237864	The highest prevalence of MDM2 amplification by histologic type was found in sarcoma patients (13 of 33 = 39% vs 10 of 114 non-sarcoma patients = 9%; p < 0.0001); the second highest was found in patients with metastatic breast cancer (3 of 56 = 5.3% vs 20 of 91 = 22%; p = 0.0071).	('patients', 'Species', '9606', (135, 143))	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('MDM2', 'Gene', (26, 30))	('breast cancer', 'Disease', (220, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('patients', 'Species', '9606', (85, 93))	('sarcoma', 'Disease', (77, 84))	('patients', 'Species', '9606', (195, 203))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('sarcoma', 'Disease', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('amplification', 'Var', (31, 44))
613860	30237864	Of the 13 sarcoma cases with MDM2 amplification, liposarcoma was the most common histologic subtype (9 patients).	('sarcoma', 'Disease', 'MESH:D012509', (53, 60))	('MDM2', 'Gene', (29, 33))	('liposarcoma', 'Phenotype', 'HP:0012034', (49, 60))	('sarcoma', 'Disease', (10, 17))	('common', 'Reg', (74, 80))	('amplification', 'Var', (34, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('sarcoma', 'Disease', (53, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('liposarcoma', 'Disease', (49, 60))	('patients', 'Species', '9606', (103, 111))	('sarcoma', 'Disease', 'MESH:D012509', (10, 17))	('liposarcoma', 'Disease', 'MESH:D008080', (49, 60))
613864	30237864	Among the 23 patients with MDM2 amplification, 11 had an RMH score of 0 with a median overall survival (OS) was 24 months, which was significantly longer than the median OS of 6 months among the 12 patients who had an RMH score > 0 (hazard ratio [HR], 3.6; confidence interval [CI], 1.1, 11.5; p = 0.031).	('OS', 'Chemical', '-', (104, 106))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (13, 21))	('amplification', 'Var', (32, 45))	('longer', 'PosReg', (147, 153))	('OS', 'Chemical', '-', (170, 172))	('MDM2', 'Gene', (27, 31))	('RMH', 'Chemical', '-', (218, 221))	('RMH', 'Chemical', '-', (57, 60))
613866	30237864	Sixteen of the 23 patients with MDM2 amplification were noted to have co-occurrence of CDK4 amplification, five had CDKN2A/B loss, and five had MYC amplification.	('MYC', 'Gene', (144, 147))	('amplification', 'Var', (37, 50))	('CDKN2A/B', 'Gene', '1029;1030', (116, 124))	('amplification', 'Var', (92, 105))	('MYC', 'Gene', '4609', (144, 147))	('patients', 'Species', '9606', (18, 26))	('CDKN2A/B', 'Gene', (116, 124))	('CDK4', 'Gene', '1019', (87, 91))	('CDK4', 'Gene', (87, 91))	('MDM2', 'Gene', (32, 36))
613867	30237864	Other aberrations that co-occurred with MDM2 amplification in this analysis include mutations in TP53 (7 patients), PIK3CA mutation (1), and CCND1 amplification (1).	('PIK3CA', 'Gene', (116, 122))	('MDM2', 'Gene', (40, 44))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (123, 131))	('TP53', 'Gene', '7157', (97, 101))	('amplification', 'Var', (45, 58))	('PIK3CA', 'Gene', '5290', (116, 122))	('CCND1', 'Gene', '595', (141, 146))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (84, 93))	('CCND1', 'Gene', (141, 146))
613868	30237864	Among the aberrations co-observed, CDK4 amplification was most commonly noted in patients with soft tissue liposarcoma (9 of 16 patients), and CDKN2A/B loss was seen in one patient each with breast cancer not otherwise specified (NOS), adenocarcinoma of the lung, soft tissue liposarcoma, squamous cell carcinoma of unknown primary, and bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('patient', 'Species', '9606', (81, 88))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (337, 365))	('soft tissue liposarcoma', 'Disease', (264, 287))	('adenocarcinoma of the lung', 'Disease', (236, 262))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (289, 312))	('liposarcoma', 'Phenotype', 'HP:0012034', (276, 287))	('soft tissue liposarcoma', 'Disease', (95, 118))	('patient', 'Species', '9606', (128, 135))	('soft tissue liposarcoma', 'Disease', 'MESH:D012983', (264, 287))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('CDKN2A/B', 'Gene', (143, 151))	('soft tissue liposarcoma', 'Disease', 'MESH:D012983', (95, 118))	('squamous cell carcinoma', 'Disease', (289, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('OS', 'Chemical', '-', (231, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('patient', 'Species', '9606', (173, 180))	('CDK4', 'Gene', (35, 39))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (236, 262))	('loss', 'NegReg', (152, 156))	('liposarcoma', 'Phenotype', 'HP:0012034', (107, 118))	('CDKN2A/B', 'Gene', '1029;1030', (143, 151))	('patients', 'Species', '9606', (128, 136))	('CDK4', 'Gene', '1019', (35, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (289, 312))	('patients', 'Species', '9606', (81, 89))	('bladder urothelial carcinoma', 'Disease', (337, 365))	('amplification', 'Var', (40, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (280, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
613870	30237864	TP53 mutation was seen in one patient each with kidney urothelial carcinoma, Ewing sarcoma, soft tissue liposarcoma, invasive ductal carcinoma of the breast, breast carcinoma NOS, hepatocellular carcinoma, and salivary adenocarcinoma NOS.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('Ewing sarcoma', 'Disease', (77, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (180, 204))	('salivary adenocarcinoma NOS', 'Disease', 'MESH:D000230', (210, 237))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (133, 156))	('TP53', 'Gene', '7157', (0, 4))	('invasive ductal carcinoma of the breast, breast carcinoma NOS, hepatocellular carcinoma', 'Disease', 'MESH:D018270', (117, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (126, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('kidney urothelial carcinoma', 'Disease', 'MESH:D007674', (48, 75))	('patient', 'Species', '9606', (30, 37))	('kidney urothelial carcinoma', 'Phenotype', 'HP:0030409', (48, 75))	('kidney urothelial carcinoma', 'Disease', (48, 75))	('seen', 'Reg', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('soft tissue liposarcoma', 'Disease', (92, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('salivary adenocarcinoma NOS', 'Disease', (210, 237))	('liposarcoma', 'Phenotype', 'HP:0012034', (104, 115))	('TP53', 'Gene', (0, 4))	('soft tissue liposarcoma', 'Disease', 'MESH:D012983', (92, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('breast carcinoma', 'Phenotype', 'HP:0003002', (158, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('mutation', 'Var', (5, 13))
613872	30237864	For the 23 patients with MDM2 amplification, we determined the copy numbers (CNs), as determined via next-generation sequencing by FoundationOne: total, 6-150 CNs; mean, 30.39; and median, 16.	('patients', 'Species', '9606', (11, 19))	('MDM2', 'Gene', (25, 29))	('amplification', 'Var', (30, 43))
613877	30237864	Two of the three tumors had TP53 mutation, and all three had MYC amplification.	('TP53', 'Gene', '7157', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutation', 'Var', (33, 41))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('TP53', 'Gene', (28, 32))	('MYC', 'Gene', '4609', (61, 64))	('MYC', 'Gene', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
613878	30237864	As shown in Figure 1, the median OS in patients with MDM2 amplification was 13.6 months versus 10.6 months in patients without amplification (p = 0.12).	('patients', 'Species', '9606', (39, 47))	('MDM2', 'Gene', (53, 57))	('OS', 'Chemical', '-', (33, 35))	('amplification', 'Var', (58, 71))	('patients', 'Species', '9606', (110, 118))
613880	30237864	The median overall age was 56 years (range = 15-81 years); the median age of patients with MDM2 amplification was 58 years (range = 23-77 years); and the median age of patients without MDM2 amplification was 55 years (range = 15-81 years).	('amplification', 'Var', (96, 109))	('patients', 'Species', '9606', (77, 85))	('MDM2', 'Gene', (91, 95))	('patients', 'Species', '9606', (168, 176))
613881	30237864	Of the 124 patients without MDM2 amplification, 53 (43%) patients had breast cancer while of the 23 patients with MDM2 amplification, 3 (13%) had breast cancer; the Fisher exact test p-value for breast cancer was 0.0090.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('patients', 'Species', '9606', (57, 65))	('breast cancer', 'Disease', (195, 208))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('breast cancer', 'Disease', (70, 83))	('patients', 'Species', '9606', (100, 108))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (11, 19))	('MDM2', 'Var', (114, 118))
613883	30237864	Six of the 23 patients with MDM2 amplification were enrolled in a trial involving an MDM2 inhibitor.	('amplification', 'Var', (33, 46))	('patients', 'Species', '9606', (14, 22))	('MDM2', 'Gene', (28, 32))
613887	30237864	TP53 mutation was noted in one of these six patients (this patient had enrolled prior to the availability of FoundationOne results).	('TP53', 'Gene', '7157', (0, 4))	('patient', 'Species', '9606', (44, 51))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (44, 52))	('patient', 'Species', '9606', (59, 66))	('mutation', 'Var', (5, 13))
613888	30237864	None of the 23 patients with MDM2 amplification was treated with prior immunotherapy.	('amplification', 'Var', (34, 47))	('patients', 'Species', '9606', (15, 23))	('MDM2', 'Gene', (29, 33))
613889	30237864	To our knowledge, this study is the largest analysis of MDM2 amplification in solid tumors reported in the current literature.	('solid tumors', 'Disease', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('amplification', 'Var', (61, 74))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('MDM2', 'Gene', (56, 60))
613891	30237864	MDM2 amplification was most frequent in patients with liposarcoma, followed by patients with metastatic breast cancer.	('liposarcoma', 'Disease', (54, 65))	('amplification', 'Var', (5, 18))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('liposarcoma', 'Phenotype', 'HP:0012034', (54, 65))	('liposarcoma', 'Disease', 'MESH:D008080', (54, 65))	('breast cancer', 'Disease', (104, 117))	('MDM2', 'Gene', (0, 4))	('frequent', 'Reg', (28, 36))	('patients', 'Species', '9606', (79, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
613892	30237864	Other aberrations that most frequently co-occurred with MDM2 amplification were CDK4 amplification, CDKN2A/B loss, and MYC amplification.	('CDK4', 'Gene', (80, 84))	('CDKN2A/B', 'Gene', (100, 108))	('CDK4', 'Gene', '1019', (80, 84))	('loss', 'NegReg', (109, 113))	('MYC', 'Gene', '4609', (119, 122))	('amplification', 'Var', (61, 74))	('amplification', 'Var', (85, 98))	('CDKN2A/B', 'Gene', '1029;1030', (100, 108))	('MYC', 'Gene', (119, 122))	('MDM2', 'Gene', (56, 60))
613893	30237864	Concomitant alterations of MDM2 and CDK4 are known and have been described in liposarcoma.	('described', 'Reg', (65, 74))	('liposarcoma', 'Disease', (78, 89))	('alterations', 'Var', (12, 23))	('CDK4', 'Gene', (36, 40))	('CDK4', 'Gene', '1019', (36, 40))	('MDM2', 'Gene', (27, 31))	('liposarcoma', 'Phenotype', 'HP:0012034', (78, 89))	('liposarcoma', 'Disease', 'MESH:D008080', (78, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
613894	30237864	Previous studies have suggested that the presence of neochromosomes in cancer and sarcoma in particular, could explain the mechanism of MDM2 amplification in these tumors.	('neochromosomes', 'Var', (53, 67))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', (164, 170))	('cancer', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('MDM2', 'Gene', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('sarcoma', 'Disease', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
613895	30237864	Neochromosomes, which are extra chromosomal structures that harbor oncogenes at high copy numbers, could incorporate Chr12q fragments including MDM2, and drive tumorigenesis.	('drive', 'PosReg', (154, 159))	('incorporate', 'Reg', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('MDM2', 'Gene', (144, 148))	('tumor', 'Disease', (160, 165))	('Chr12q fragments', 'Var', (117, 133))
613901	30237864	Grunewald et al reported co-expression of CDK4 amplification with MDM2 amplification in one patient with salivary duct carcinoma.	('CDK4', 'Gene', '1019', (42, 46))	('patient', 'Species', '9606', (92, 99))	('salivary duct carcinoma', 'Disease', 'MESH:D012465', (105, 128))	('amplification', 'Var', (71, 84))	('amplification', 'Var', (47, 60))	('salivary duct carcinoma', 'Disease', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('MDM2', 'Gene', (66, 70))	('CDK4', 'Gene', (42, 46))
613904	30237864	The significance of our study lies in the larger number of patients tested for MDM2 amplification in our analysis compared to what has been previously reported.	('amplification', 'Var', (84, 97))	('patients', 'Species', '9606', (59, 67))	('MDM2', 'Gene', (79, 83))
613909	30237864	Three of the 23 (13%) patients with MDM2 amplification had a diagnosis of metastatic breast cancer.	('MDM2', 'Gene', (36, 40))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('patients', 'Species', '9606', (22, 30))	('amplification', 'Var', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
613910	30237864	Despite the high percentage in this very limited series, two of these three patients harbored mutant TP53 and therefore were not eligible for enrollment in trials involving an MDM2 inhibitor.	('patients', 'Species', '9606', (76, 84))	('harbored', 'Reg', (85, 93))	('TP53', 'Gene', '7157', (101, 105))	('mutant', 'Var', (94, 100))	('TP53', 'Gene', (101, 105))
613911	30237864	Most MDM2 inhibitors under development target the MDM2-p53 complex, including Nutlin-3, RITA, MI-219, AMG232, and SAR405838.	('MI-219', 'Disease', (94, 100))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('RITA', 'Gene', '84934', (88, 92))	('MI-219', 'Disease', 'MESH:D009203', (94, 100))	('SAR405838', 'Var', (114, 123))	('RITA', 'Gene', (88, 92))
613912	30237864	These inhibitors have little or no effect on cancers with mutant TP53.	('mutant', 'Var', (58, 64))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))
613917	30237864	The frequency of mutant TP53 in breast cancer has been reported to be 30% to 73%, but it fluctuates widely between subclasses of breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Disease', (32, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('TP53', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('mutant', 'Var', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('TP53', 'Gene', '7157', (24, 28))
613918	30237864	As a result, MDM2 inhibitors have no significant anticancer activity in such tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('MDM2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('inhibitors', 'Var', (18, 28))
613920	30237864	One very interesting finding in our analysis was the presence of mutant TP53 in seven patients.	('TP53', 'Gene', '7157', (72, 76))	('mutant', 'Var', (65, 71))	('TP53', 'Gene', (72, 76))	('presence', 'Reg', (53, 61))	('patients', 'Species', '9606', (86, 94))
613922	30237864	Nonetheless, the co-existence of mutant TP53 with MDM2 amplification is surprising, as they have been thought to be alternative mechanisms for inactivating the suppressing cell growth pathway and thus mutually exclusive.	('suppressing cell growth pathway', 'Pathway', (160, 191))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('inactivating', 'NegReg', (143, 155))	('mutant', 'Var', (33, 39))
613923	30237864	A recent study by Sanchez-Vega et al reports the mutual exclusivity of TP53 mutations and MDM2 amplification in tumors profiled by The Cancer Genome Atlas (TCGA).	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (135, 154))	('mutations', 'Var', (76, 85))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TP53', 'Gene', '7157', (71, 75))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('TP53', 'Gene', (71, 75))	('MDM2', 'Gene', (90, 94))	('Cancer Genome Atlas', 'Disease', (135, 154))
613925	30237864	Tumors with mutant TP53 are canonically thought to not respond to MDM2 inhibition.	('mutant', 'Var', (12, 18))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('TP53', 'Gene', '7157', (19, 23))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TP53', 'Gene', (19, 23))
613926	30237864	Our analysis clearly shows that this is not a mutually exclusive phenomenon and that subsets of patients with MDM2 amplification also have a co-existing mutant TP53.	('amplification', 'Var', (115, 128))	('TP53', 'Gene', '7157', (160, 164))	('mutant', 'Var', (153, 159))	('TP53', 'Gene', (160, 164))	('patients', 'Species', '9606', (96, 104))	('MDM2', 'Gene', (110, 114))
613929	30237864	However, only one case had both TP53 mutation and high levels of MDM2 mRNA.	('MDM2 mRNA', 'MPA', (65, 74))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))	('mutation', 'Var', (37, 45))
613933	30237864	However, overexpression of MDM2 and p53 proteins in the nuclei of tumor cells is not correlated with MDM2 gene amplification or TP53 mutation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutation', 'Var', (133, 141))	('tumor', 'Disease', (66, 71))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('MDM2', 'Gene', (101, 105))
613934	30237864	Co-occurrence of MDM2 amplification and TP53 mutation was also noted in two patients by Grunewald et al as well.	('patients', 'Species', '9606', (76, 84))	('MDM2', 'Gene', (17, 21))	('amplification', 'Var', (22, 35))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('TP53', 'Gene', (40, 44))
613935	30237864	Drummond et al reported that TP53 mutant, MDM2 amplified cell lines that were resistant to MDM2 inhibitors retain sensitivity to ionizing radiation and suggested that such patients may have alternative treatment options like radiation therapy.	('TP53', 'Gene', '7157', (29, 33))	('sensitivity to ionizing radiation', 'MPA', (114, 147))	('TP53', 'Gene', (29, 33))	('patients', 'Species', '9606', (172, 180))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (114, 147))	('mutant', 'Var', (34, 40))
613936	30237864	Saiki et al demonstrated that MDM2 amplification and TP53 mutation are not mutually exclusive in tumor cell lines, possibly because of a misidentified TP53 mutation or heterozygous TP53 mutation or because cell lines harbor viral gene sequences known to inactivate p53.	('p53', 'Gene', (265, 268))	('p53', 'Gene', '7157', (265, 268))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('TP53', 'Gene', (181, 185))	('TP53', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (151, 155))	('TP53', 'Gene', '7157', (181, 185))	('mutation', 'Var', (186, 194))	('TP53', 'Gene', (53, 57))	('mutation', 'Var', (156, 164))
613938	30237864	On the basis of this observation and our results which also showed that MDM2 amplification and TP53 mutations are not mutually exclusive in advanced cancers, alteration in one gene should not preclude testing for the other.	('mutations', 'Var', (100, 109))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('TP53', 'Gene', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('MDM2', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (95, 99))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
613940	30237864	The reported incidence of MDM2 amplification in various series conducted in single tumor types (0% to 6.3%) is consistent with our findings.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('MDM2', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('amplification', 'Var', (31, 44))
613941	30237864	Grunewald et al, in a series of 51 patients with salivary duct carcinomas, reported MDM2 amplification in three patients (5.8%), as well as synchronous CDK4 and MDM2 amplification in one patient with a co-expression rate of 33.3%.	('MDM2', 'Gene', (84, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('patient', 'Species', '9606', (112, 119))	('CDK4', 'Gene', (152, 156))	('CDK4', 'Gene', '1019', (152, 156))	('MDM2', 'Gene', (161, 165))	('patients', 'Species', '9606', (112, 120))	('patient', 'Species', '9606', (35, 42))	('salivary duct carcinomas', 'Phenotype', 'HP:0100684', (49, 73))	('salivary duct carcinomas', 'Disease', (49, 73))	('salivary duct carcinomas', 'Disease', 'MESH:D012465', (49, 73))	('amplification', 'Var', (89, 102))	('patient', 'Species', '9606', (187, 194))	('patients', 'Species', '9606', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
613943	30237864	Michalk et al reported a 6.3% incidence of MDM2 amplification in esophageal carcinomas (adenocarcinoma and squamous cell carcinoma), and Schoolmeester et al found an incidence of 5% (2 of 43 cases) in endometrial stromal tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (65, 86))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('carcinoma', 'Disease', (121, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 130))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('carcinoma', 'Disease', 'MESH:D002277', (76, 85))	('MDM2', 'Gene', (43, 47))	('squamous cell carcinoma', 'Disease', (107, 130))	('tumors', 'Disease', (221, 227))	('carcinoma', 'Disease', 'MESH:D002277', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinoma', 'Disease', (93, 102))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('amplification', 'Var', (48, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('carcinoma', 'Disease', (76, 85))	('carcinoma', 'Disease', 'MESH:D002277', (93, 102))
613945	30237864	Zhu et al reported the first documented cases of MDM2 amplification in laryngeal and hypopharyngeal liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (100, 111))	('liposarcoma', 'Disease', 'MESH:D008080', (100, 111))	('amplification', 'Var', (54, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('laryngeal', 'Disease', (71, 80))	('liposarcoma', 'Disease', (100, 111))	('MDM2', 'Gene', (49, 53))
613947	30237864	None of the 23 patients with MDM2 amplification in our analysis was treated with prior immunotherapy as of the cut-off date.	('amplification', 'Var', (34, 47))	('patients', 'Species', '9606', (15, 23))	('MDM2', 'Gene', (29, 33))
613948	30237864	Our analysis constitutes, to our knowledge, one of the largest series of solid tumors tested for MDM2 amplification at a single center.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('amplification', 'Var', (102, 115))	('solid tumors', 'Disease', (73, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('MDM2', 'Gene', (97, 101))	('solid tumors', 'Disease', 'MESH:D009369', (73, 85))
613951	30237864	Regardless of these limitations, we found that MDM2 amplification in solid tumors was associated with liposarcoma, metastatic breast cancer, CDK4 amplification, TP53 mutation, CDKN2A/B loss, and MYC amplification.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('MYC', 'Gene', (195, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('CDKN2A/B', 'Gene', (176, 184))	('solid tumors', 'Disease', (69, 81))	('liposarcoma', 'Phenotype', 'HP:0012034', (102, 113))	('amplification', 'Var', (52, 65))	('amplification', 'Var', (146, 159))	('CDK4', 'Gene', '1019', (141, 145))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('associated', 'Reg', (86, 96))	('breast cancer', 'Disease', (126, 139))	('MYC', 'Gene', '4609', (195, 198))	('liposarcoma', 'Disease', 'MESH:D008080', (102, 113))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('solid tumors', 'Disease', 'MESH:D009369', (69, 81))	('TP53', 'Gene', (161, 165))	('CDKN2A/B', 'Gene', '1029;1030', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutation', 'Var', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('MDM2', 'Gene', (47, 51))	('liposarcoma', 'Disease', (102, 113))	('TP53', 'Gene', '7157', (161, 165))	('CDK4', 'Gene', (141, 145))
614064	26055407	Second, loss of E-cadherin involved in the regulation of EMT and metastasis, and its roles in both drug and immune resistance point out that Snail is a target for sensitization to cytotoxic drugs in cadherin signal pathway.	('E-cadherin', 'Gene', (16, 26))	('E-cadherin', 'Gene', '999', (16, 26))	('loss', 'Var', (8, 12))	('Snail', 'Gene', '6615', (141, 146))	('Snail', 'Gene', (141, 146))	('EMT', 'Gene', (57, 60))	('EMT', 'Gene', '3702', (57, 60))
614226	23382028	Our preliminary work (presented below) demonstrated that inhibition of mammalian target of rapamycin (mTOR) by sirolimus not only causes synergistic cytotoxicity with doxorubicin when the bulk tumor population is treated, but also increases the sensitivity of the ALDHhigh cells to chemotherapy in vitro, suggesting that the chemoresistance of sarcoma stem cells can be overcome, at least in vitro.	('sarcoma', 'Disease', 'MESH:D012509', (344, 351))	('cytotoxicity', 'Disease', (149, 161))	('inhibition', 'Var', (57, 67))	('mammalian target of rapamycin', 'Gene', '2475', (71, 100))	('doxorubicin', 'Chemical', 'MESH:D004317', (167, 178))	('sirolimus', 'Chemical', 'MESH:D020123', (111, 120))	('mammalian target of rapamycin', 'Gene', (71, 100))	('sarcoma', 'Disease', (344, 351))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('cytotoxicity', 'Disease', 'MESH:D064420', (149, 161))	('increases', 'PosReg', (231, 240))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (344, 351))	('mTOR', 'Gene', (102, 106))	('mTOR', 'Gene', '2475', (102, 106))	('tumor', 'Disease', (193, 198))	('sensitivity', 'MPA', (245, 256))
614244	23382028	In addition, patients were required to have an ECOG performance status <= 2 (Karnofsky or Lansky >= 60% for children), a life expectancy greater than 3 months, and adequate organ function (absolute neutrophil count >= 1500/mul, platelet count >= 100,000/mul, total bilirubin <= 1.5x institutional upper limit of normal, AST and ALT <= 2.5x institutional upper limit of normal, and creatinine <= 1.5x institutional upper limit of normal for age or a creatinine clearance >= 60 ml/min/1.73 m2).	('creatinine', 'MPA', (381, 391))	('ALT', 'MPA', (328, 331))	('children', 'Species', '9606', (108, 116))	('AST', 'Gene', (320, 323))	('>= 1500/mul', 'Var', (215, 226))	('total bilirubin', 'MPA', (259, 274))	('patients', 'Species', '9606', (13, 21))	('platelet', 'MPA', (228, 236))	('AST', 'Gene', '26503', (320, 323))	('creatinine clearance', 'MPA', (449, 469))
614246	23382028	Because temsirolimus can affect lipid metabolism, patients were also required to have a fasting cholesterol <= 350 mg/dl, fasting serum triglycerides <= 400 mg/dl, and amylase and lipase within normal limits (unless elevations were related to tumor involving the pancreas).	('lipid metabolism', 'MPA', (32, 48))	('lipase', 'Enzyme', (180, 186))	('tumor', 'Disease', (243, 248))	('patients', 'Species', '9606', (50, 58))	('cholesterol', 'MPA', (96, 107))	('temsirolimus', 'Chemical', 'MESH:C401859', (8, 20))	('cholesterol', 'Chemical', 'MESH:D002784', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor involving the pancreas', 'Phenotype', 'HP:0002894', (243, 271))	('temsirolimus', 'Var', (8, 20))	('triglycerides', 'Chemical', 'MESH:D014280', (136, 149))	('lipid', 'Chemical', 'MESH:D008055', (32, 37))	('amylase', 'Enzyme', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('affect', 'Reg', (25, 31))
614300	23382028	Our in vitro data demonstrate synergistic cytotoxicity of the combination of sirolimus and doxorubicin, and that sirolimus reverses the innate chemoresistance of Ewing sarcoma stem cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (162, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (162, 175))	('doxorubicin', 'Chemical', 'MESH:D004317', (91, 102))	('Ewing sarcoma', 'Disease', (162, 175))	('cytotoxicity', 'Disease', (42, 54))	('sirolimus', 'Chemical', 'MESH:D020123', (77, 86))	('sirolimus', 'Var', (113, 122))	('sirolimus', 'Chemical', 'MESH:D020123', (113, 122))	('reverses', 'NegReg', (123, 131))
614353	32871936	IHC showed the following profile: CD21 (+), CD23 (+), CD68 (+), CD20 (+) Vimentin (+), Ki- 67 (20%), CD1a (-), CD3 (-), CK (-), S-100 (-), SMA (-), EMA (-) (Fig.	('CD21', 'Gene', (34, 38))	('CD20', 'Gene', (64, 68))	('CD1a', 'Gene', (101, 105))	('CK (-', 'Var', (120, 125))	('CD21', 'Gene', '1380', (34, 38))	('Vimentin', 'Gene', (73, 81))	('CD3 (-', 'Var', (111, 117))	('CD23', 'Gene', '2208', (44, 48))	('CD1a', 'Gene', '909', (101, 105))	('S-100 (-', 'Var', (128, 136))	('CD68', 'Gene', (54, 58))	('CD68', 'Gene', '968', (54, 58))	('Vimentin', 'Gene', '7431', (73, 81))	('CD23', 'Gene', (44, 48))	('CD20', 'Gene', '54474', (64, 68))
614357	32871936	The etiology is unclear, but some studies have suggested FDCS might be associated with Castleman disease, which is a less common non-neoplastic lymphoproliferative disease.	('Castleman disease', 'Disease', 'MESH:C536362', (87, 104))	('Castleman disease', 'Disease', (87, 104))	('lymphoproliferative disease', 'Phenotype', 'HP:0005523', (144, 171))	('non-neoplastic lymphoproliferative disease', 'Disease', (129, 171))	('non-neoplastic lymphoproliferative disease', 'Disease', 'MESH:D008232', (129, 171))	('FDCS', 'Var', (57, 61))	('associated', 'Reg', (71, 81))
614376	32871936	FDCS tumor cells show an immunophenotype similar to that of normal FDC and express 1 or more of the markers CD21, CD23, CD35, R4/23, CNA42, Ki-M4P, EMA, and CD68.	('CD68', 'Gene', '968', (157, 161))	('CD35', 'Gene', (120, 124))	('R4/23', 'Var', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('CD21', 'Gene', (108, 112))	('CD23', 'Gene', '2208', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CD21', 'Gene', '1380', (108, 112))	('CD23', 'Gene', (114, 118))	('tumor', 'Disease', (5, 10))	('CD68', 'Gene', (157, 161))	('CD35', 'Gene', '1378', (120, 124))
614387	32871936	Starr et al analyzed potential DNA mutations in a thyroid FDCS and found mutations in the PTEN, RET, and TP53 genes, but not epithelium growth factor receptor.	('RET', 'Gene', '5979', (96, 99))	('PTEN', 'Gene', (90, 94))	('PTEN', 'Gene', '5728', (90, 94))	('RET', 'Gene', (96, 99))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('mutations', 'Var', (73, 82))	('mutations', 'Var', (35, 44))
614445	29570692	Methods: Four sarcoma cell lines harboring the BRAFV600E mutation, representing liposarcomas (SA-4 and SW872), Ewing sarcoma (A673) and atypical synovial sarcoma (SW982), were treated with vemurafenib and the effects on cell growth, apoptosis, cell cycle progression and cell signaling were determined.	('SA-4', 'Chemical', '-', (94, 98))	('BRAFV600E', 'Mutation', 'rs113488022', (47, 56))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))	('synovial sarcoma', 'Disease', (145, 161))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('sarcoma', 'Disease', (14, 21))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('liposarcomas', 'Disease', (80, 92))	('sarcoma', 'Disease', (117, 124))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('sarcoma', 'Disease', (84, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (145, 161))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (84, 92))	('sarcoma', 'Disease', (154, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('SW872', 'CellLine', 'CVCL:1730', (103, 108))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (145, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('Ewing sarcoma', 'Disease', (111, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('BRAFV600E', 'Var', (47, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('SW982', 'CellLine', 'CVCL:1734', (163, 168))	('liposarcomas', 'Disease', 'MESH:D008080', (80, 92))	('liposarcoma', 'Phenotype', 'HP:0012034', (80, 91))	('vemurafenib', 'Chemical', 'MESH:D000077484', (189, 200))	('liposarcomas', 'Phenotype', 'HP:0012034', (80, 92))
614449	29570692	Conclusions: These findings indicate that vemurafenib alone would not be an efficient therapy against BRAFV600E mutated sarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('sarcomas', 'Disease', (120, 128))	('vemurafenib', 'Chemical', 'MESH:D000077484', (42, 53))	('BRAFV600E mutated', 'Var', (102, 119))	('BRAFV600E', 'Mutation', 'rs113488022', (102, 111))	('sarcomas', 'Disease', 'MESH:D012509', (120, 128))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
614455	29570692	Inhibitors targeting cancer-specific mutations are ideal for repurposing.	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
614456	29570692	The presence of the exact same mutation in other cancer types suggests that the cancer may be driven by the same mechanism.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutation', 'Var', (31, 39))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', (80, 86))
614457	29570692	Mutated BRAF are described in several cancers and can be targeted by selective inhibitors, such as vemurafenib.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('BRAF', 'Gene', (8, 12))	('vemurafenib', 'Chemical', 'MESH:D000077484', (99, 110))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('described', 'Reg', (17, 26))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('Mutated', 'Var', (0, 7))	('cancers', 'Disease', (38, 45))
614460	29570692	Several mutations in the BRAF gene have been described, but the most common genetic alteration results in a substitution of the amino acid 600 from valine to glutamic acid (BRAFV600E).	('600 from valine to glutamic acid', 'Mutation', 'rs113488022', (139, 171))	('results in', 'Reg', (95, 105))	('BRAFV600E', 'Mutation', 'rs113488022', (173, 182))	('BRAF', 'Gene', (25, 29))	('substitution', 'Var', (108, 120))
614461	29570692	The BRAFV600E mutation accounts for more than 90% of all reported BRAF mutations.	('BRAF', 'Disease', (66, 70))	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))
614462	29570692	The BRAFV600E mutation is present in 50% of melanomas and has also been identified in subsets of many other cancer types, including colorectal cancer (10-15%), papillary thyroid carcinoma (30-50%) and non-small cell lung cancer (1.3%).	('BRAFV600E', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (201, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (160, 187))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('melanomas', 'Disease', (44, 53))	('identified', 'Reg', (72, 82))	('papillary thyroid carcinoma', 'Disease', (160, 187))	('non-small cell lung cancer', 'Disease', (201, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (160, 187))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (170, 187))	('cancer', 'Disease', (221, 227))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('colorectal cancer', 'Disease', (132, 149))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (201, 227))	('cancer', 'Disease', (108, 114))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (205, 227))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
614463	29570692	The BRAFV600E mutation has also been reported in GIST, several cases of clear cell sarcoma, and liposarcoma.	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (72, 90))	('liposarcoma', 'Phenotype', 'HP:0012034', (96, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('liposarcoma', 'Disease', 'MESH:D008080', (96, 107))	('GIST', 'Disease', (49, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('liposarcoma', 'Disease', (96, 107))	('reported', 'Reg', (37, 45))	('clear cell sarcoma', 'Disease', (72, 90))
614465	29570692	Vemurafenib was initially approved by the Food and Drug Administration (FDA) in 2011 as a therapy for melanoma patients with mutated BRAFV600E, and resulted in a response rate of >50% and approximately 7 months of median progression-free survival for melanoma patients.	('BRAFV600E', 'Mutation', 'rs113488022', (133, 142))	('BRAFV600E', 'Gene', (133, 142))	('mutated', 'Var', (125, 132))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('patients', 'Species', '9606', (260, 268))	('melanoma', 'Disease', (102, 110))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (251, 259))	('patients', 'Species', '9606', (111, 119))
614466	29570692	In colorectal patients with the BRAFV600E mutation; however, vemurafenib as monotherapy was unsuccessful due to resistance, which occurred as a consequence of a rapid, EGFR-induced reactivation of the MAPK pathway, observed already at 24-48 h after treatment.	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('vemurafenib', 'Chemical', 'MESH:D000077484', (61, 72))	('MAPK pathway', 'Pathway', (201, 213))	('colorectal', 'Disease', 'MESH:D015179', (3, 13))	('BRAFV600E', 'Var', (32, 41))	('BRAFV600E', 'Mutation', 'rs113488022', (32, 41))	('colorectal', 'Disease', (3, 13))	('patients', 'Species', '9606', (14, 22))	('reactivation', 'MPA', (181, 193))
614470	29570692	Here, we have further investigated the potential of vemurafenib as a therapy for BRAFV600E mutated sarcomas, by determining its efficacy in vitro in four BRAFV600E mutated sarcoma cell lines.	('sarcoma', 'Disease', (172, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('BRAFV600E', 'Mutation', 'rs113488022', (81, 90))	('sarcomas', 'Disease', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('sarcoma', 'Disease', 'MESH:D012509', (99, 106))	('vemurafenib', 'Chemical', 'MESH:D000077484', (52, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('BRAFV600E', 'Var', (81, 90))	('sarcoma', 'Disease', (99, 106))	('BRAFV600E', 'Mutation', 'rs113488022', (154, 163))	('sarcomas', 'Disease', 'MESH:D012509', (99, 107))
614472	29570692	The WM9 melanoma cell line, known to harbor a hemizygous BRAFV600E mutation, was included as a positive control, whereas the LPS510 liposarcoma cell line was included as a negative control line for all BRAFV600E mutated sarcoma cell lines, as it is wild-type for BRAF according to our DNA sequencing data.	('BRAFV600E', 'Gene', (57, 66))	('sarcoma', 'Disease', (220, 227))	('BRAFV600E', 'Mutation', 'rs113488022', (202, 211))	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('melanoma', 'Disease', (8, 16))	('mutation', 'Var', (67, 75))	('liposarcoma', 'Disease', 'MESH:D008080', (132, 143))	('sarcoma', 'Disease', 'MESH:D012509', (136, 143))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('liposarcoma', 'Phenotype', 'HP:0012034', (132, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('sarcoma', 'Disease', (136, 143))	('WM9', 'CellLine', 'CVCL:6806', (4, 7))	('BRAFV600E', 'Mutation', 'rs113488022', (57, 66))	('sarcoma', 'Disease', 'MESH:D012509', (220, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('liposarcoma', 'Disease', (132, 143))	('LPS510', 'Chemical', '-', (125, 131))
614473	29570692	We evaluated the expression of wild-type and mutated BRAF mRNA by next-generation sequencing and found similar levels of wild-type and mutated BRAF transcripts in both SA-4 and SW872 cell lines, whereas LPS510 only expressed wild-type BRAF (Table 1).	('SA-4', 'Chemical', '-', (168, 172))	('BRAF', 'Gene', (143, 147))	('mutated', 'Var', (135, 142))	('SW872', 'CellLine', 'CVCL:1730', (177, 182))	('LPS510', 'Chemical', '-', (203, 209))
614475	29570692	To determine the levels of total and BRAFV600E mutated protein in all cell lines, western blotting was performed using antibodies specific for pan-BRAF and BRAFV600E, respectively.	('BRAFV600E', 'Var', (37, 46))	('BRAFV600E', 'Mutation', 'rs113488022', (156, 165))	('BRAFV600E', 'Mutation', 'rs113488022', (37, 46))	('BRAFV600E', 'Var', (156, 165))
614487	29570692	The other BRAFV600E mutated sarcoma cell lines showed minor or no responses.	('sarcoma', 'Disease', (28, 35))	('BRAFV600E', 'Mutation', 'rs113488022', (10, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('BRAFV600E mutated', 'Var', (10, 27))	('sarcoma', 'Disease', 'MESH:D012509', (28, 35))
614501	29570692	To assess whether the sarcoma cell lines with a poor or short-term effect on cell growth circumvent the need for BRAF to be able to phosphorylate ERK, we evaluated the levels of p-ERK protein following treatment with vemurafenib for 3 or 72 h. The dual inhibitor RO5126766, targeting both BRAF and the downstream signaling molecule MEK, was included as a control.	('MEK', 'Gene', (332, 335))	('vemurafenib', 'Chemical', 'MESH:D000077484', (217, 228))	('MEK', 'Gene', '5609', (332, 335))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('RO5126766', 'Var', (263, 272))	('sarcoma', 'Disease', (22, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('RO5126766', 'Chemical', 'MESH:C577924', (263, 272))
614502	29570692	Treatment with either 5 microM vemurafenib or 300 nM RO5126766 for 3 h strongly reduced the level of phosphorylated ERK proteins in all the sarcoma cell lines harboring the mutation (Figure 7A).	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('RO5126766', 'Chemical', 'MESH:C577924', (53, 62))	('ERK proteins', 'Protein', (116, 128))	('vemurafenib', 'Chemical', 'MESH:D000077484', (31, 42))	('reduced', 'NegReg', (80, 87))	('sarcoma', 'Disease', 'MESH:D012509', (140, 147))	('RO5126766', 'Var', (53, 62))	('level of phosphorylated', 'MPA', (92, 115))	('sarcoma', 'Disease', (140, 147))	('mutation', 'Var', (173, 181))
614504	29570692	Precision cancer medicine is focused on targeting the tumor-specific mutations and affect mechanisms driving tumor growth.	('mutations', 'Var', (69, 78))	('affect', 'Reg', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Disease', (54, 59))	('cancer', 'Disease', (10, 16))	('tumor', 'Disease', (109, 114))
614506	29570692	The V600E mutation of BRAF occurs in approximately 50% of melanoma tumors, and in these the selective BRAFV600E inhibitor, vemurafenib, provides on average >7 months of progression-free survival, although as many as 50% of these patients do not respond in spite of having the mutation in their tumors.	('V600E', 'Var', (4, 9))	('patients', 'Species', '9606', (229, 237))	('melanoma tumors', 'Disease', 'MESH:D008545', (58, 73))	('vemurafenib', 'Chemical', 'MESH:D000077484', (123, 134))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (294, 300))	('V600E', 'Mutation', 'rs113488022', (106, 111))	('V600E', 'Mutation', 'rs113488022', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('BRAF', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('melanoma tumors', 'Disease', (58, 73))	('BRAFV600E', 'Mutation', 'rs113488022', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', (294, 300))
614507	29570692	BRAFV600E is found in many cancer types, including some sarcomas, suggesting that vemurafenib might have activity against such tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('vemurafenib', 'Chemical', 'MESH:D000077484', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (127, 133))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('sarcomas', 'Disease', (56, 64))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('activity', 'MPA', (105, 113))	('cancer', 'Disease', (27, 33))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('BRAFV600E', 'Var', (0, 9))
614510	29570692	The levels of mRNA and protein for both wild-type and mutated BRAF were similar in both SA-4 and SW872 sarcoma cell lines.	('sarcoma', 'Disease', (103, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('SW872', 'CellLine', 'CVCL:1730', (97, 102))	('mutated', 'Var', (54, 61))	('SA-4', 'Chemical', '-', (88, 92))	('mRNA', 'MPA', (14, 18))	('BRAF', 'Gene', (62, 66))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))
614511	29570692	However, the growth inhibitory responses to vemurafenib were variable, with a strong, dose-dependent effect observed for SA-4 and minor effects observed for SW872 and the remaining BRAFV600E mutated sarcoma cell lines, A673 and SW982.	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('SW872', 'CellLine', 'CVCL:1730', (157, 162))	('SW982', 'CellLine', 'CVCL:1734', (228, 233))	('mutated', 'Var', (191, 198))	('SA-4', 'Chemical', '-', (121, 125))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('sarcoma', 'Disease', (199, 206))	('growth inhibitory', 'MPA', (13, 30))	('vemurafenib', 'Chemical', 'MESH:D000077484', (44, 55))	('BRAFV600E', 'Var', (181, 190))	('BRAFV600E', 'Mutation', 'rs113488022', (181, 190))
614516	29570692	Importantly, the presence of BRAFV600E or de-phosphorylation of ERK upon vemurafenib treatment cannot be used to predict response in BRAFV600E mutated sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (151, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('sarcomas', 'Disease', (151, 159))	('vemurafenib', 'Chemical', 'MESH:D000077484', (73, 84))	('BRAFV600E', 'Var', (29, 38))	('BRAFV600E', 'Mutation', 'rs113488022', (29, 38))	('BRAFV600E mutated', 'Var', (133, 150))	('BRAFV600E', 'Mutation', 'rs113488022', (133, 142))	('sarcomas', 'Disease', 'MESH:D012509', (151, 159))	('ERK', 'Protein', (64, 67))	('de-phosphorylation', 'MPA', (42, 60))
614521	29570692	Our preclinical investigation of vemurafenib as treatment for patients with BRAFV600E mutated sarcomas is limited by the lack of suitable models.	('sarcomas', 'Disease', (94, 102))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('BRAFV600E', 'Var', (76, 85))	('BRAFV600E', 'Mutation', 'rs113488022', (76, 85))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('vemurafenib', 'Chemical', 'MESH:D000077484', (33, 44))	('patients', 'Species', '9606', (62, 70))
614526	29570692	The absence of the classical translocation (t12:16) indicative of myxoid liposarcomas suggests that SA-4 is of the third subgroup of liposarcoma, the pleomorphic subtype, which lacks specific genetic aberrations used for diagnosis.	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('liposarcoma', 'Phenotype', 'HP:0012034', (73, 84))	('liposarcoma', 'Disease', 'MESH:D008080', (73, 84))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (66, 85))	('SA-4', 'Chemical', '-', (100, 104))	('liposarcoma', 'Disease', (133, 144))	('sarcomas', 'Phenotype', 'HP:0100242', (77, 85))	('liposarcoma', 'Disease', 'MESH:D008080', (133, 144))	('liposarcoma', 'Disease', (73, 84))	('liposarcomas', 'Phenotype', 'HP:0012034', (73, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('liposarcoma', 'Phenotype', 'HP:0012034', (133, 144))	('t12:16', 'Var', (44, 50))	('myxoid liposarcomas', 'Disease', (66, 85))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (66, 85))
614527	29570692	The BRAFV600E mutation is only present in 2-5% of tumors derived from bone or soft tissue, according to the COSMIC database.	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
614531	29570692	This might indicate that the presence of both mutated BRAF and melanoma markers could be used to identify sarcoma patients expected to respond to vemurafenib.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('BRAF', 'Gene', (54, 58))	('mutated', 'Var', (46, 53))	('vemurafenib', 'Chemical', 'MESH:D000077484', (146, 157))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('patients', 'Species', '9606', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('sarcoma', 'Disease', (106, 113))	('melanoma', 'Disease', (63, 71))
614532	29570692	Although not yet supported by preclinical data, we would expect targeted treatment of BRAFV600E mutated sarcomas to improve with the use of next generation RAF inhibitors in combination with other treatments.	('sarcomas', 'Disease', 'MESH:D012509', (104, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('BRAFV600E', 'Var', (86, 95))	('BRAFV600E', 'Mutation', 'rs113488022', (86, 95))	('sarcomas', 'Disease', (104, 112))
614550	29570692	The dual BRAF/MEK inhibitor RO5126766 (Selleckchem, #S7170) was dissolved in DMSO to a 1 mM stock solution.	('RO5126766', 'Var', (28, 37))	('DMSO', 'Chemical', 'MESH:D004121', (77, 81))	('RO5126766', 'Chemical', 'MESH:C577924', (28, 37))	('MEK', 'Gene', (14, 17))	('MEK', 'Gene', '5609', (14, 17))
614559	29570692	We conclude that vemurafenib can have therapeutic potential for selected cases of BRAFV600E sarcoma; however others could benefit from vemurafenib in combination with additional therapies and further work is required to explore this.	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('vemurafenib', 'Chemical', 'MESH:D000077484', (135, 146))	('BRAFV600E', 'Mutation', 'rs113488022', (82, 91))	('BRAFV600E', 'Var', (82, 91))	('sarcoma', 'Disease', (92, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('vemurafenib', 'Chemical', 'MESH:D000077484', (17, 28))
614579	29621151	In addition, aberrant focal expression of cytokeratin has been reported in other tumours including angiosarcomas, epithelioid hemangioendotheliomas, epithelioid leiomyosarcomas and meningiomas, undifferentiated pleomorphic sarcomas, rhabdomyosarcomas, malignant rhabdoid tumours and peripheral nerve sheath tumours, clear cell sarcomas, plasmacytomas, diffuse large B-cell lymphomas, anaplastic large cell lymphomas and melanomas.	('anaplastic large cell lymphomas', 'Phenotype', 'HP:0012193', (384, 415))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (233, 250))	('lymphomas', 'Disease', 'MESH:D008223', (373, 382))	('tumours', 'Disease', 'MESH:D009369', (307, 314))	('sarcomas', 'Phenotype', 'HP:0100242', (223, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('lymphomas', 'Disease', (406, 415))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (161, 176))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (194, 231))	('epithelioid leiomyosarcomas', 'Disease', 'MESH:D007890', (149, 176))	('rhabdomyosarcomas', 'Disease', (233, 250))	('undifferentiated pleomorphic sarcomas', 'Disease', (194, 231))	('peripheral nerve sheath tumours', 'Disease', 'MESH:D010524', (283, 314))	('tumours', 'Disease', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (327, 334))	('lymphomas', 'Phenotype', 'HP:0002665', (373, 382))	('epithelioid hemangioendotheliomas', 'Disease', (114, 147))	('angiosarcomas', 'Phenotype', 'HP:0200058', (99, 112))	('tumour', 'Phenotype', 'HP:0002664', (307, 313))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (233, 250))	('meningiomas', 'Disease', (181, 192))	('tumours', 'Disease', (271, 278))	('epithelioid hemangioendotheliomas', 'Phenotype', 'HP:0032060', (114, 147))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (233, 249))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('lymphoma', 'Phenotype', 'HP:0002665', (406, 414))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('angiosarcomas', 'Disease', (99, 112))	('melanoma', 'Phenotype', 'HP:0002861', (420, 428))	('epithelioid hemangioendotheliomas', 'Disease', 'MESH:D018323', (114, 147))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('sarcomas', 'Phenotype', 'HP:0100242', (242, 250))	('tumours', 'Phenotype', 'HP:0002664', (271, 278))	('lymphoma', 'Phenotype', 'HP:0002665', (373, 381))	('meningiomas', 'Phenotype', 'HP:0002858', (181, 192))	('plasmacytomas', 'Disease', (337, 350))	('peripheral nerve sheath tumours', 'Disease', (283, 314))	('tumours', 'Disease', 'MESH:D009369', (271, 278))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (161, 175))	('lymphomas', 'Disease', (373, 382))	('plasmacytomas', 'Phenotype', 'HP:0011857', (337, 350))	('aberrant', 'Var', (13, 21))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('melanomas', 'Disease', 'MESH:D008545', (420, 429))	('clear cell sarcomas', 'Disease', 'MESH:D018227', (316, 335))	('lymphomas', 'Disease', 'MESH:D008223', (406, 415))	('epithelioid leiomyosarcomas', 'Disease', (149, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (366, 382))	('malignant rhabdoid tumours', 'Disease', 'MESH:C563738', (252, 278))	('melanomas', 'Phenotype', 'HP:0002861', (420, 429))	('lymphomas', 'Phenotype', 'HP:0002665', (406, 415))	('melanomas', 'Disease', (420, 429))	('malignant rhabdoid tumours', 'Disease', (252, 278))	('cytokeratin', 'Gene', (42, 53))	('tumours', 'Disease', (307, 314))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (327, 335))	('angiosarcomas', 'Disease', 'MESH:D006394', (99, 112))	('tumours', 'Phenotype', 'HP:0002664', (307, 314))	('clear cell sarcomas', 'Disease', (316, 335))	('meningiomas', 'Disease', 'MESH:D008577', (181, 192))
614633	29621151	In men, the useful markers for MPM are Calretinin, WT1 (nuclear reactivity) and D2-40.	('WT1', 'Gene', '7490', (51, 54))	('D2-40', 'Var', (80, 85))	('Calretinin', 'Gene', (39, 49))	('WT1', 'Gene', (51, 54))	('MPM', 'Disease', (31, 34))	('Calretinin', 'Gene', '794', (39, 49))	('men', 'Species', '9606', (3, 6))
614634	29621151	Finally, the useful markers for a non-serous carcinoma are: B72.3, MOC31, BG8 and Ber-EP4.	('serous carcinoma', 'Disease', 'MESH:D018284', (38, 54))	('BG8', 'CellLine', 'CVCL:M614', (74, 77))	('BG8', 'Gene', (74, 77))	('serous carcinoma', 'Disease', (38, 54))	('MOC31', 'Var', (67, 72))	('B72.3', 'Var', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
614643	29621151	CDX2 expression may be decreased in right-sided or proximally located colon carcinomas, in poorly differentiated colorectal carcinomas as well as in colorectal carcinomas with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).	('expression', 'MPA', (5, 15))	('dMMR', 'Chemical', '-', (246, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('colorectal carcinomas', 'Disease', (149, 170))	('mismatch repair', 'Var', (219, 234))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (149, 170))	('microsatellite instability-high', 'Var', (176, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('decreased', 'NegReg', (23, 32))	('CDX2', 'Gene', '1045', (0, 4))	('colorectal carcinomas', 'Disease', (113, 134))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (113, 134))	('MSI-H', 'Disease', (209, 214))	('CDX2', 'Gene', (0, 4))	('colon carcinomas', 'Disease', (70, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('colon carcinomas', 'Disease', 'MESH:D015179', (70, 86))	('MSI-H', 'Disease', 'MESH:D000848', (209, 214))
614659	29621151	CK34betaE12 is expressed in approximately 60% of urachal adenocarcinomas and in only 10% of colorectal adenocarcinomas (Figure 5).	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('urachal adenocarcinomas', 'Disease', 'MESH:C536474', (49, 72))	('CK34betaE12', 'Var', (0, 11))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('urachal adenocarcinoma', 'Phenotype', 'HP:0012618', (49, 71))	('colorectal adenocarcinomas', 'Disease', (92, 118))	('urachal adenocarcinomas', 'Phenotype', 'HP:0012618', (49, 72))	('urachal adenocarcinomas', 'Disease', (49, 72))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (92, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
614660	29621151	Loss of membrane localization and aberrant nuclear E-cadherin expression is often associated with aggressive progression of certain carcinomas, including primary urachal adenocarcinoma.	('associated with', 'Reg', (82, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('urachal adenocarcinoma', 'Disease', (162, 184))	('aberrant', 'Var', (34, 42))	('urachal adenocarcinoma', 'Phenotype', 'HP:0012618', (162, 184))	('expression', 'MPA', (62, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('Loss', 'NegReg', (0, 4))	('carcinomas', 'Disease', (132, 142))	('carcinomas', 'Disease', 'MESH:D002277', (132, 142))	('membrane localization', 'MPA', (8, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('urachal adenocarcinoma', 'Disease', 'MESH:C536474', (162, 184))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', '999', (51, 61))
614673	29621151	This oncogenic pathway results from the loss of function of the dMMR genes, most often of sporadic origin (80% of cases) by somatic inactivation of the MLH1 gene (hypermethylation of the MLH1 gene promoter), more rarely with genetic harbouring of a deleterious germline mutation in one of the four MMR genes associated with the Lynch syndrome.	('MLH1', 'Gene', (152, 156))	('dMMR', 'Gene', (64, 68))	('dMMR', 'Chemical', '-', (64, 68))	('MLH1', 'Gene', '4292', (152, 156))	('inactivation', 'Var', (132, 144))	('Lynch syndrome', 'Disease', (328, 342))	('Lynch syndrome', 'Disease', 'MESH:D003123', (328, 342))	('loss of function', 'NegReg', (40, 56))	('MLH1', 'Gene', '4292', (187, 191))	('MLH1', 'Gene', (187, 191))
614674	29621151	BRAF gene mutations in MSI-H colorectal cancers are associated with sporadic forms and can be used to rule out the Lynch syndrome.	('MSI-H colorectal cancers', 'Disease', 'MESH:D015179', (23, 47))	('Lynch syndrome', 'Disease', (115, 129))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('MSI-H colorectal cancers', 'Disease', (23, 47))	('Lynch syndrome', 'Disease', 'MESH:D003123', (115, 129))	('associated', 'Reg', (52, 62))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
614676	29621151	It is important to identify the colorectal origin of a metastatic neoplasm to propose the most appropriate therapy and to initiate molecular testing guiding this treatment: RAS mutations (KRAS and NRAS mutations on exons 2, 3 and 4) for the use of EGFR inhibitors, BRAF mutations on exon 15 for therapeutic intensification and dMMR testing for immunotherapy.	('EGFR', 'Gene', '1956', (248, 252))	('neoplasm', 'Disease', (66, 74))	('BRAF', 'Gene', '673', (265, 269))	('mutations', 'Var', (177, 186))	('NRAS', 'Gene', (197, 201))	('mutations', 'Var', (270, 279))	('EGFR', 'Gene', (248, 252))	('neoplasm', 'Disease', 'MESH:D009369', (66, 74))	('KRAS', 'Gene', (188, 192))	('RAS', 'Gene', (173, 176))	('neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('NRAS', 'Gene', '4893', (197, 201))	('dMMR', 'Chemical', '-', (327, 331))	('KRAS', 'Gene', '3845', (188, 192))	('men', 'Species', '9606', (167, 170))	('BRAF', 'Gene', (265, 269))
614690	29621151	A KRAS mutation was found in 56% of mucinous adenocarcinomas, while the mutational status correlated neither with the architectural pattern nor with survival of patients.	('mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (36, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('mucinous adenocarcinomas', 'Disease', (36, 60))	('KRAS', 'Gene', (2, 6))	('patients', 'Species', '9606', (161, 169))	('mutation', 'Var', (7, 15))	('found', 'Reg', (20, 25))	('KRAS', 'Gene', '3845', (2, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))
614698	29621151	NUT midline carcinomas are very aggressive tumours harbouring rearrangements in the NUT gene that can be detected by IHC using an anti-NUT-specific monoclonal antibody.	('NUT', 'Gene', (84, 87))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('rearrangements', 'Var', (62, 76))	('NUT midline carcinomas are very aggressive tumours', 'Disease', (0, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('men', 'Species', '9606', (71, 74))	('NUT', 'Gene', (0, 3))	('NUT midline carcinomas are very aggressive tumours', 'Disease', 'MESH:D000326', (0, 50))	('NUT', 'Gene', '256646', (0, 3))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('NUT', 'Gene', '256646', (135, 138))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('NUT', 'Gene', '256646', (84, 87))	('NUT', 'Gene', (135, 138))
614710	29621151	A panel of four markers, associating positivity for Maspin A (mammary serine protease inhibitor), S100P (placental S100 protein), IMP-3 (insulin-like growth factor II messenger RNA binding protein-3) and negativity for pVHL (von Hippel-Lindau tumour suppressor), has 100% sensitivity and specificity for distinguishing high grade dysplasia or malignancy from reactive atypia within the biliary-pancreatic system.	('dysplasia', 'Disease', (330, 339))	('malignancy', 'Disease', (343, 353))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (225, 249))	('atypia within the biliary-pancreatic system', 'Disease', 'MESH:D001929', (368, 411))	('dysplasia', 'Disease', 'MESH:D004476', (330, 339))	('IMP-3', 'Gene', (130, 135))	('atypia within the biliary-pancreatic system', 'Disease', (368, 411))	('positivity', 'Var', (37, 47))	('S100', 'Gene', (115, 119))	('Maspin A', 'Gene', (52, 60))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('S100', 'Gene', '6271', (115, 119))	('S100', 'Gene', (98, 102))	('S100', 'Gene', '6271', (98, 102))	('pVHL', 'Gene', '7428', (219, 223))	('pVHL', 'Gene', (219, 223))	('S100P', 'Gene', '6286', (98, 103))	('von Hippel-Lindau tumour', 'Disease', (225, 249))	('malignancy', 'Disease', 'MESH:D009369', (343, 353))	('S100P', 'Gene', (98, 103))	('IMP-3', 'Gene', '55272', (130, 135))
614714	29621151	Finally, activating mutations in the KRAS oncogene are likely the single most common genetic abnormality in pancreatic cancer, present in ~90-95% of cases.	('activating mutations', 'Var', (9, 29))	('genetic abnormality', 'Disease', 'MESH:D030342', (85, 104))	('genetic abnormality', 'Disease', (85, 104))	('pancreatic cancer', 'Disease', (108, 125))	('KRAS', 'Gene', (37, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('KRAS', 'Gene', '3845', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
614715	29621151	Despite the low specificity, a KRAS gene mutation could provide additional diagnostic criteria.	('mutation', 'Var', (41, 49))	('KRAS', 'Gene', (31, 35))	('KRAS', 'Gene', '3845', (31, 35))
614729	29621151	Other markers, described as highly specific of a prostate origin, can also be used alone or in combination to determine a prostate origin, such as P501S (prostein), PSAM (prostate-specific antigen membrane) and NKX3.1.	('PSA', 'Gene', (165, 168))	('NKX3.1', 'Gene', '4824', (211, 217))	('PSA', 'Gene', '354', (165, 168))	('P501S', 'Mutation', 'p.P501S', (147, 152))	('P501S', 'Var', (147, 152))	('NKX3.1', 'Gene', (211, 217))
614771	29621151	IHC may provide an efficient screening tool for "druggable" genomic alterations by taking advantage of a growing list of available mutation-specific antibodies (i.e., ALK rearrangements, D5F3 and 5A4 clones; ROS1 rearrangements, clone D4D6; BRAF V600E mutation, clone VE1; EGFR exon 19 E746_A750del, 6B6 clone; EGFR exon 21 L858R mutation, 43B2 clone).	('EGFR', 'Gene', (311, 315))	('ROS1', 'Gene', '6098', (208, 212))	('V600E', 'Mutation', 'rs113488022', (246, 251))	('A750del', 'Mutation', 'c.750delA', (291, 298))	('EGFR', 'Gene', '1956', (311, 315))	('ALK', 'Gene', (167, 170))	('men', 'Species', '9606', (180, 183))	('BRAF', 'Gene', '673', (241, 245))	('L858R', 'Var', (324, 329))	('L858R', 'Mutation', 'rs121434568', (324, 329))	('EGFR', 'Gene', '1956', (273, 277))	('men', 'Species', '9606', (222, 225))	('ALK', 'Gene', '238', (167, 170))	('E746_A750del', 'Var', (286, 298))	('BRAF', 'Gene', (241, 245))	('ROS1', 'Gene', (208, 212))	('EGFR', 'Gene', (273, 277))
614776	29621151	Aberrant or unexpected antigen expression should be considered as a source of a diagnostic pitfall in the evaluation of undifferentiated tumours.	('Aberrant', 'Var', (0, 8))	('undifferentiated tumours', 'Disease', 'MESH:D002277', (120, 144))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('undifferentiated tumours', 'Disease', (120, 144))	('antigen', 'Protein', (23, 30))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
614794	29621151	On the other hand, CD34 is almost always negative in both components and a positive CD34 rules out the diagnosis of synovial sarcoma.	('CD34', 'Gene', '947', (19, 23))	('CD34', 'Gene', '947', (84, 88))	('positive', 'Var', (75, 83))	('CD34', 'Gene', (19, 23))	('synovial sarcoma', 'Disease', (116, 132))	('CD34', 'Gene', (84, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('synovial sarcoma', 'Disease', 'MESH:D013584', (116, 132))
614795	29621151	More than 95% of synovial sarcomas are characterized by a recurrent, tumour-specific translocation t(X;18)(p11;q11), that can be detected by FISH in looking for the rearrangement in the SS18 (SYT) gene.	('tumour', 'Disease', (69, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (26, 34))	('SS18', 'Gene', (186, 190))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (99, 115))	('t(X;18)(p11;q11', 'Var', (99, 114))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (17, 34))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('SS18', 'Gene', '6760', (186, 190))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (17, 33))	('synovial sarcomas', 'Disease', 'MESH:D013584', (17, 34))	('synovial sarcomas', 'Disease', (17, 34))	('men', 'Species', '9606', (174, 177))
614805	29621151	About half of soft tissue myoepitheliomas show specific translocations involving the EWSR1 gene with variable partners such as the POU5F1, PBXI and ZNF444 genes.	('POU5F1', 'Gene', (131, 137))	('EWSR1', 'Gene', '2130', (85, 90))	('POU5F1', 'Gene', '5460', (131, 137))	('myoepitheliomas', 'Disease', (26, 41))	('myoepitheliomas', 'Disease', 'MESH:D009208', (26, 41))	('EWSR1', 'Gene', (85, 90))	('translocations', 'Var', (56, 70))
614806	29621151	These translocations can be detected by FISH by identifying a rearrangement in the EWSR1 gene.	('rearrangement', 'Var', (62, 75))	('EWSR1', 'Gene', (83, 88))	('EWSR1', 'Gene', '2130', (83, 88))	('men', 'Species', '9606', (71, 74))
614811	29621151	The search for the SS18 gene rearrangement gives a reliable diagnosis: the presence of a SS18 gene rearrangement in synovial sarcomas and the absence in MPNSTs.	('men', 'Species', '9606', (38, 41))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (116, 133))	('rearrangement', 'Var', (99, 112))	('SS18', 'Gene', (19, 23))	('SS18', 'Gene', '6760', (89, 93))	('men', 'Species', '9606', (108, 111))	('synovial sarcomas', 'Disease', 'MESH:D013584', (116, 133))	('synovial sarcomas', 'Disease', (116, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (116, 132))	('SS18', 'Gene', (89, 93))	('SS18', 'Gene', '6760', (19, 23))	('presence', 'Reg', (75, 83))
614914	28199377	Additionally, patients with high volume tumors tended to have a significantly higher risk for experiencing postoperative infection (p = 0.052, HR = 1.23), according to the multivariable regression model.	('postoperative infection', 'Disease', 'MESH:D010149', (107, 130))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('postoperative infection', 'Disease', (107, 130))	('high volume', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('patients', 'Species', '9606', (14, 22))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
614987	26002157	Overexpression of IGF-1R and its ligand IGF-1 in pediatric bone sarcomas is correlated with a poorer prognosis, and IGF pathway inhibition impeded tumor growth and metastasis in preclinical models.	('IGF-1R', 'Gene', '3480', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('IGF pathway', 'Pathway', (116, 127))	('IGF-1R', 'Gene', (18, 24))	('sarcomas', 'Phenotype', 'HP:0100242', (64, 72))	('IGF-1', 'Gene', '3479', (40, 45))	('IGF-1', 'Gene', (40, 45))	('inhibition impeded', 'NegReg', (128, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Overexpression', 'Var', (0, 14))	('pediatric bone sarcomas', 'Disease', 'MESH:D001847', (49, 72))	('bone sarcoma', 'Phenotype', 'HP:0002669', (59, 71))	('IGF-1', 'Gene', '3479', (18, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('IGF-1', 'Gene', (18, 23))	('pediatric bone sarcomas', 'Disease', (49, 72))	('bone sarcomas', 'Phenotype', 'HP:0002669', (59, 72))
614995	26002157	Two neutralizing antibodies against IGF-I/II are available: MEDI-573 and BI836845.	('BI836845', 'Var', (73, 81))	('IGF-I', 'Gene', '3479', (36, 41))	('IGF-I', 'Gene', (36, 41))
614997	26002157	Currently, five phase I clinical trials of BI836845 are ongoing in adult patients with various solid tumors, but there have been no specific studies in OS or ES patients.	('solid tumors', 'Disease', (95, 107))	('OS', 'Phenotype', 'HP:0002669', (152, 154))	('BI836845', 'Var', (43, 51))	('solid tumors', 'Disease', 'MESH:D009369', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('patients', 'Species', '9606', (161, 169))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('ES', 'Phenotype', 'HP:0012254', (158, 160))	('patients', 'Species', '9606', (73, 81))
615001	26002157	Novel IGF-1R tyrosine kinase inhibitors include linsitinib, XL-228, INSM-18, GSK1904529A, GSK1838705A, and BMS-554417, all of which have shown promising results in pediatric sarcoma models during preclinical studies.	('XL-228', 'Gene', (60, 66))	('pediatric sarcoma', 'Disease', (164, 181))	('pediatric sarcoma', 'Disease', 'MESH:D063766', (164, 181))	('GSK1838705A', 'Var', (90, 101))	('GSK1904529A', 'Var', (77, 88))	('BMS-554417', 'Var', (107, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (174, 181))	('linsitinib', 'Gene', (48, 58))	('IGF-1R', 'Gene', '3480', (6, 12))	('linsitinib', 'Chemical', 'MESH:C551528', (48, 58))	('IGF-1R', 'Gene', (6, 12))
615003	26002157	In recent years, targeted therapies against HER2 have achieved significant therapeutic benefits in the treatment of several solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('targeted therapies', 'Var', (17, 35))	('HER2', 'Gene', (44, 48))	('solid tumors', 'Disease', (124, 136))	('HER2', 'Gene', '2064', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
615028	26002157	For the 702 patients treated on that study (only 10 % had bone sarcoma), ridaforolimus increased progression-free survival by 28 % (p < 0.001), but greatly increased grade 3 or higher toxicities, especially stomatitis, cytopenias, and infection.	('increased', 'PosReg', (87, 96))	('patients', 'Species', '9606', (12, 20))	('stomatitis', 'Phenotype', 'HP:0010280', (207, 217))	('bone sarcoma', 'Disease', (58, 70))	('especially stomatitis', 'Disease', (196, 217))	('cytopenias', 'Disease', 'MESH:D006402', (219, 229))	('toxicities', 'Disease', 'MESH:D064420', (184, 194))	('ridaforolimus', 'Var', (73, 86))	('toxicities', 'Disease', (184, 194))	('cytopenias', 'Disease', (219, 229))	('increased', 'PosReg', (156, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('grade 3', 'MPA', (166, 173))	('especially stomatitis', 'Disease', 'MESH:D013280', (196, 217))	('bone sarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('infection', 'Disease', (235, 244))	('infection', 'Disease', 'MESH:D007239', (235, 244))	('bone sarcoma', 'Disease', 'MESH:D001847', (58, 70))
615036	26002157	Notch has been linked to increased invasion and metastasis in OS, in part through promoting a tumor-initiating cell phenotype.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('increased', 'PosReg', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('invasion', 'CPA', (35, 43))	('promoting', 'PosReg', (82, 91))	('OS', 'Phenotype', 'HP:0002669', (62, 64))	('Notch', 'Var', (0, 5))	('metastasis', 'CPA', (48, 58))
615047	26002157	Though constitutively active, Ras mutations are uncommon in pediatric sarcomas; targeting Ras reduced tumor growth, possibly due to the many pathways requiring Ras relay signals.	('pediatric sarcomas', 'Disease', (60, 78))	('tumor', 'Disease', (102, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('reduced', 'NegReg', (94, 101))	('sarcomas', 'Phenotype', 'HP:0100242', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('pediatric sarcomas', 'Disease', 'MESH:D063766', (60, 78))	('Ras', 'Protein', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('targeting', 'Var', (80, 89))
615072	26002157	High expression of RANKL is associated with reduced survival in OS, and some OS cell lines have functional RANK expression, allowing for possible autocrine stimulation of this pathway.	('RANKL', 'Gene', '8600', (19, 24))	('RANKL', 'Gene', (19, 24))	('High expression', 'Var', (0, 15))	('OS', 'Phenotype', 'HP:0002669', (77, 79))	('OS', 'Phenotype', 'HP:0002669', (64, 66))	('survival', 'CPA', (52, 60))	('reduced', 'NegReg', (44, 51))
615099	26002157	Inhibition of MMP2 and MMP9 affects OS and ES tumor growth and metastasis formation.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('OS', 'Phenotype', 'HP:0002669', (36, 38))	('ES tumor', 'Disease', 'MESH:C563168', (43, 51))	('ES tumor', 'Disease', (43, 51))	('MMP2', 'Gene', (14, 18))	('ES', 'Phenotype', 'HP:0012254', (43, 45))	('MMP2', 'Gene', '4313', (14, 18))	('Inhibition', 'Var', (0, 10))	('MMP9', 'Gene', (23, 27))	('MMP9', 'Gene', '4318', (23, 27))
615102	26002157	High levels of VEGF were predictive of pulmonary metastasis and poor prognosis for both diseases in several studies.	('pulmonary metastasis', 'Disease', 'MESH:D009362', (39, 59))	('VEGF', 'Gene', (15, 19))	('High levels', 'Var', (0, 11))	('VEGF', 'Gene', '7422', (15, 19))	('pulmonary metastasis', 'Disease', (39, 59))
615121	22918885	As a general approach to this question, we activated all Ras proteins in vivo by genetic deletion of the RasGAP protein Nf1 and examined mice doubly deficient in a Ras protein to determine its requirement in formation of TGFbeta-dependent neurofibromas that arise in Nf1-deficient mice.	('RasGAP', 'Gene', (105, 111))	('Ras proteins', 'Protein', (57, 69))	('mice', 'Species', '10090', (281, 285))	('neurofibromas', 'Disease', (239, 252))	('Nf1', 'Gene', (120, 123))	('Nf1', 'Gene', '18015', (267, 270))	('activated', 'PosReg', (43, 52))	('neurofibromas', 'Phenotype', 'HP:0001067', (239, 252))	('Nf1-deficient', 'Disease', (267, 280))	('neurofibromas', 'Disease', 'MESH:D009455', (239, 252))	('Nf1', 'Gene', '18015', (120, 123))	('RasGAP', 'Gene', '218397', (105, 111))	('deletion', 'Var', (89, 97))	('neurofibroma', 'Phenotype', 'HP:0001067', (239, 251))	('Nf1-deficient', 'Disease', 'MESH:C537392', (267, 280))	('mice', 'Species', '10090', (137, 141))	('Nf1', 'Gene', (267, 270))
615128	22918885	The commonly studied Ras oncogenic proteins encoded by the H-Ras, K-Ras and N-Ras genes (Ras) are activated by mutation in up to 50% of human cancers.	('human', 'Species', '9606', (136, 141))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('activated', 'PosReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('K-Ras', 'Gene', '3845', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('mutation', 'Var', (111, 119))	('K-Ras', 'Gene', (66, 71))
615133	22918885	Mutations in the NF1 gene result in neurofibromatosis type 1 (NF1).	('result in', 'Reg', (26, 35))	('neurofibromatosis type 1', 'Gene', '18015', (36, 60))	('neurofibroma', 'Phenotype', 'HP:0001067', (36, 48))	('NF1', 'Gene', (17, 20))	('Mutations', 'Var', (0, 9))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (36, 53))	('neurofibromatosis type 1', 'Gene', (36, 60))
615142	22918885	For example, TGFbeta can promote tumorigenesis through sequestration of mutant p53, and have non-autonomous effects on tumor stroma.	('tumor stroma', 'Disease', 'MESH:D009369', (119, 131))	('p53', 'Gene', (79, 82))	('tumor', 'Disease', (119, 124))	('tumor stroma', 'Disease', (119, 131))	('mutant', 'Var', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('TGFbeta', 'Gene', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('promote', 'PosReg', (25, 32))	('sequestration', 'MPA', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
615147	22918885	We found that Nf1 mutation renders SCPs insensitive to TGFbeta-mediated cell death and define a TGFbeta autocrine survival loop, correlating with benign neurofibroma formation.	('Nf1', 'Gene', (14, 17))	('neurofibroma', 'Phenotype', 'HP:0001067', (153, 165))	('mutation', 'Var', (18, 26))	('benign neurofibroma', 'Disease', (146, 165))	('benign neurofibroma', 'Disease', 'MESH:D009455', (146, 165))	('Nf1', 'Gene', '18015', (14, 17))
615148	22918885	Nf1 mutants lacking TC21 restore TGFbeta sensitivity and benign tumorigenesis is delayed.	('mutants', 'Var', (4, 11))	('Nf1', 'Gene', (0, 3))	('benign tumor', 'Disease', (57, 69))	('TGFbeta sensitivity', 'MPA', (33, 52))	('restore', 'PosReg', (25, 32))	('benign tumor', 'Disease', 'MESH:D009369', (57, 69))	('Nf1', 'Gene', '18015', (0, 3))	('TC21', 'Gene', (20, 24))	('lacking', 'NegReg', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
615149	22918885	Conversely, loss of TC21 increases TGFbeta-induced malignancy in the NPCis model.	('malignancy', 'Disease', 'MESH:D009369', (51, 61))	('increases TGFbeta', 'Phenotype', 'HP:0030269', (25, 42))	('increases', 'PosReg', (25, 34))	('loss', 'Var', (12, 16))	('malignancy', 'Disease', (51, 61))	('TC21', 'Gene', (20, 24))	('TGFbeta-induced', 'Gene', (35, 50))
615150	22918885	In NF1 MPNST xenografts, loss of TC21 accelerates tumor growth in a non-cell autonomous manner.	('loss', 'Var', (25, 29))	('TC21', 'Gene', (33, 37))	('accelerates', 'PosReg', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
615163	22918885	MPNST cell lines included 26T, T265, 8814 [WT for p53 ] and S462TY [derived from the S462 cell line by two rounds of in vivo growth as xenografts ].	('T265', 'CellLine', 'CVCL:S805', (31, 35))	('S462TY [', 'Var', (60, 68))	('T265', 'Var', (31, 35))	('S462TY', 'CellLine', 'CVCL:1Y70', (60, 66))
615168	22918885	We separated proteins on 4-20% TrisHCl acrylamide gels (Biorad, CA), transferred to PVDF membranes (Millipore, MA) and probed membranes with: anti-TC21 (Abnova, Taiwan), phospho-AKT, phospho-SMAD2/3, phospho-42/44-MAPK and beta-Actin (Cell Signaling).	('AKT', 'Gene', (178, 181))	('beta-Actin', 'Gene', (223, 233))	('acrylamide', 'Chemical', 'MESH:D020106', (39, 49))	('beta-Actin', 'Gene', '11461', (223, 233))	('AKT', 'Gene', '11651', (178, 181))	('PVDF', 'Chemical', 'MESH:C024865', (84, 88))	('TrisHCl', 'Chemical', '-', (31, 38))	('anti-TC21', 'Var', (142, 151))
615182	22918885	Loss of TC21 significantly extended survival in Nf1fl/fl;DhhCre mice (Figure 1A).	('TC21', 'Gene', (8, 12))	('Nf1', 'Gene', (48, 51))	('extended', 'PosReg', (27, 35))	('Loss', 'Var', (0, 4))	('survival', 'CPA', (36, 44))	('mice', 'Species', '10090', (64, 68))	('Nf1', 'Gene', '18015', (48, 51))
615188	22918885	Therefore, loss of TC21 in benign tumors extends survival, while paradoxically in a model of aggressive tumors, loss of TC21 decreases survival.	('extends', 'PosReg', (41, 48))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('aggressive tumors', 'Disease', (93, 110))	('TC21', 'Gene', (19, 23))	('decreases', 'NegReg', (125, 134))	('benign tumors', 'Disease', (27, 40))	('survival', 'MPA', (135, 143))	('loss', 'Var', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('TC21', 'Gene', (120, 124))	('loss', 'Var', (112, 116))	('benign tumors', 'Disease', 'MESH:D009369', (27, 40))	('aggressive tumors', 'Disease', 'MESH:D001523', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('survival', 'MPA', (49, 57))
615191	22918885	Toluidine blue+ metachromatic mast cells increased slightly in the absence of TC21 (not shown).	('absence', 'Var', (67, 74))	('increased', 'PosReg', (41, 50))	('TC21', 'Gene', (78, 82))	('Toluidine blue+', 'MPA', (0, 15))	('Toluidine blue', 'Chemical', 'MESH:D014048', (0, 14))
615193	22918885	To explain how loss of TC21 extends survival in Nf1fl/fl;DhhCre mice we postulated that TC21 diminishes numbers of neurofibroma-initiating or sustaining multipotent self-renewing cells.	('extends', 'PosReg', (28, 35))	('neurofibroma-initiating', 'Disease', (115, 138))	('neurofibroma', 'Phenotype', 'HP:0001067', (115, 127))	('TC21', 'Gene', (23, 27))	('TC21', 'Gene', (88, 92))	('neurofibroma-initiating', 'Disease', 'MESH:D009455', (115, 138))	('Nf1', 'Gene', (48, 51))	('loss', 'Var', (15, 19))	('diminishes', 'NegReg', (93, 103))	('mice', 'Species', '10090', (64, 68))	('Nf1', 'Gene', '18015', (48, 51))
615196	22918885	Importantly, TC21-/-;Nf1-/- DRG cells formed WT levels of spheres (Figure 2D) consistent with a role of TC21 regulating numbers of tumor-initiating cells early in Nf1 tumorigenesis.	('Nf1', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('Nf1', 'Gene', (163, 166))	('tumor', 'Disease', (131, 136))	('TC21-/-', 'Var', (13, 20))	('Nf1', 'Gene', '18015', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('Nf1', 'Gene', '18015', (163, 166))
615199	22918885	Nf1-/- SCPs had 20-fold higher levels of TGFbeta1 mRNA and protein compared to WT precursors (Figure 3B, 3C) and loss of TC21-/- rescued TGFbeta1 levels in Nf1-/- spheres.	('levels', 'MPA', (31, 37))	('Nf1', 'Gene', '18015', (156, 159))	('Nf1', 'Gene', (0, 3))	('higher', 'PosReg', (24, 30))	('TGFbeta1', 'Gene', (41, 49))	('TGFbeta1 levels', 'MPA', (137, 152))	('Nf1', 'Gene', (156, 159))	('loss', 'Var', (113, 117))	('Nf1', 'Gene', '18015', (0, 3))	('TC21-/-', 'Var', (121, 128))
615204	22918885	In contrast, TGFbeta1 mRNA was only slightly elevated in mature Schwann cells in sciatic nerves from Nf1fl/fl;DhhCre mice compared to WT sciatic nerve (2-fold change); Supplemental Figure 3B).	('Nf1', 'Gene', '18015', (101, 104))	('DhhCre', 'Var', (110, 116))	('TGFbeta1', 'Gene', (13, 21))	('mice', 'Species', '10090', (117, 121))	('mRNA', 'MPA', (22, 26))	('Nf1', 'Gene', (101, 104))	('elevated', 'PosReg', (45, 53))
615207	22918885	The mechanism(s) by which TC21 loss enhances TGFbeta expression may include alterations in signaling pathways that change in cell maturation and/or alterations due to as-yet-unidentified mutations in neurofibroma Schwann cells during tumor formation.	('enhances', 'PosReg', (36, 44))	('alterations', 'Reg', (76, 87))	('signaling pathways', 'Pathway', (91, 109))	('loss', 'NegReg', (31, 35))	('tumor', 'Disease', (234, 239))	('neurofibroma Schwann', 'Phenotype', 'HP:0100008', (200, 220))	('neurofibroma', 'Disease', (200, 212))	('neurofibroma', 'Phenotype', 'HP:0001067', (200, 212))	('mutations', 'Var', (187, 196))	('TC21', 'Gene', (26, 30))	('neurofibroma', 'Disease', 'MESH:D009455', (200, 212))	('TGFbeta', 'Gene', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('expression', 'MPA', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
615216	22918885	Nf1-/- spheres from E12.5 DRG grown in vitro also contained increased phospho-AKT compared to WT and TC21-/-;Nf1-/- spheres (Supplemental Figure 4B).	('E12.5 DRG', 'Var', (20, 29))	('Nf1', 'Gene', (109, 112))	('Nf1', 'Gene', (0, 3))	('Nf1', 'Gene', '18015', (109, 112))	('AKT', 'Gene', '11651', (78, 81))	('Nf1', 'Gene', '18015', (0, 3))	('AKT', 'Gene', (78, 81))	('increased', 'PosReg', (60, 69))
615222	22918885	In the NPCis model of GEM-sarcoma and GEM-GBM, loss of TC21 caused early lethality (Figure 1B).	('GEM-sarcoma', 'Disease', 'MESH:D012509', (22, 33))	('loss', 'Var', (47, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('early lethality', 'CPA', (67, 82))	('TC21', 'Gene', (55, 59))	('GEM-sarcoma', 'Disease', (22, 33))
615224	22918885	We demonstrated that TC21 activity is high in human MPNST S462TY cells that are NF1-/- in comparison to NF1 WT 26T cells, using a Ras pull-down assay and blotting with anti-TC21 antibody (Supplemental Figure 5A).	('NF1-/-', 'Var', (80, 86))	('S462TY', 'CellLine', 'CVCL:1Y70', (58, 64))	('human', 'Species', '9606', (46, 51))	('TC21', 'Gene', (21, 25))	('activity', 'MPA', (26, 34))	('high', 'Reg', (38, 42))
615227	22918885	Tumors with shTC21 cells were larger than tumors with NT cells (Figures 5A, 5B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('shTC21 cells', 'Var', (12, 24))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
615229	22918885	Thus, loss of TC21 in a human sarcoma xenograft increases tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('sarcoma xenograft increases tumor', 'Disease', 'MESH:D012509', (30, 63))	('human', 'Species', '9606', (24, 29))	('loss', 'Var', (6, 10))	('TC21', 'Gene', (14, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('sarcoma xenograft increases tumor', 'Disease', (30, 63))
615230	22918885	However, histological analysis of shTC21 MPNST xenografts revealed no differences in morphology (H&E) or cell proliferation (Ki67) compared to controls (not shown).	('MPNST', 'Var', (41, 46))	('Ki67', 'Gene', '17345', (125, 129))	('or cell', 'CPA', (102, 109))	('shTC21', 'Gene', (34, 40))	('Ki67', 'Gene', (125, 129))
615234	22918885	To investigate whether TGFbeta plays a causal role in malignant tumor growth when TC21 is lost, we treated mice harboring MPNST xenografts with function-blocking anti- TGFbeta1,2,3 in vivo.	('malignant tumor', 'Disease', (54, 69))	('TC21', 'Gene', (82, 86))	('mice', 'Species', '10090', (107, 111))	('TGFbeta1,2,3', 'Gene', '21803', (168, 180))	('lost', 'NegReg', (90, 94))	('anti-', 'Var', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('malignant tumor', 'Disease', 'MESH:D018198', (54, 69))
615236	22918885	Tumors expressing shTC21 were larger than those with NT (Figure 6A).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('shTC21', 'Var', (18, 24))
615237	22918885	Strikingly, mice injected with the anti-TGFbeta antibody had tumors of similar size whether the cells were expressing shTC21 or control (Figure 6B).	('anti-TGFbeta', 'Var', (35, 47))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mice', 'Species', '10090', (12, 16))	('anti-TGFbeta', 'Gene', (35, 47))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('shTC21', 'Var', (118, 124))
615239	22918885	Thus, loss of TC21 in NF1-/- MPNST cells increases tumor growth and requires TGFbeta.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('loss', 'Var', (6, 10))	('increases tumor', 'Disease', 'MESH:D009369', (41, 56))	('increases tumor', 'Disease', (41, 56))	('TC21', 'Gene', (14, 18))
615241	22918885	Phospho-SMAD was reduced in tumor cells and stroma from mice treated with the anti-TGFbeta antibody compared with those treated with IgG (Figures 6D, 6E).	('IgG', 'Gene', (133, 136))	('tumor', 'Disease', (28, 33))	('antibody', 'Var', (91, 99))	('Phospho-SMAD', 'MPA', (0, 12))	('mice', 'Species', '10090', (56, 60))	('anti-TGFbeta antibody', 'Var', (78, 99))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('IgG', 'Gene', '16059', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('reduced', 'NegReg', (17, 24))
615243	22918885	Indeed, phospho-AKT was elevated in tumor cells expressing shTC21.	('AKT', 'Gene', '11651', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('AKT', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('shTC21', 'Var', (59, 65))	('elevated', 'PosReg', (24, 32))	('tumor', 'Disease', (36, 41))
615244	22918885	Phospho-AKT levels were subsequently reduced upon treatment with anti-TGFbeta antibody (Figures 6C, 6E).	('AKT', 'Gene', '11651', (8, 11))	('AKT', 'Gene', (8, 11))	('reduced', 'NegReg', (37, 44))	('anti-TGFbeta', 'Gene', (65, 77))	('anti-TGFbeta', 'Var', (65, 77))
615245	22918885	The shTC21 tumors treated with anti-TGFbeta also had significantly fewer meca-32+ vessels than controls (Supplemental Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('fewer', 'NegReg', (67, 72))	('meca-32+ vessels', 'CPA', (73, 89))	('anti-TGFbeta', 'Var', (31, 43))	('shTC21', 'Gene', (4, 10))
615246	22918885	Together this data suggests that in the NF1-/- setting, in transformed cells, loss of TC21 drives tumorigenesis in a TGFbeta dependent manner; TGFbeta produced by MPNST cells acts in a non-autonomous fashion on stromal cells to increase blood vessels and promotes myofibroblasts formation.	('blood vessels', 'CPA', (237, 250))	('TC21', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('promotes', 'PosReg', (255, 263))	('myofibroblasts formation', 'CPA', (264, 288))	('increase', 'PosReg', (228, 236))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('loss', 'Var', (78, 82))	('tumor', 'Disease', (98, 103))
615253	22918885	In benign neurofibromas and SCPs loss of TC21 reduced TGFbeta1 mRNA levels in the Nf1-/- setting.	('TGFbeta1', 'Gene', (54, 62))	('Nf1', 'Gene', (82, 85))	('mRNA levels', 'MPA', (63, 74))	('benign neurofibromas', 'Disease', (3, 23))	('neurofibroma', 'Phenotype', 'HP:0001067', (10, 22))	('Nf1', 'Gene', '18015', (82, 85))	('benign neurofibromas', 'Disease', 'MESH:D009455', (3, 23))	('neurofibromas', 'Phenotype', 'HP:0001067', (10, 23))	('TC21', 'Gene', (41, 45))	('reduced', 'NegReg', (46, 53))	('loss', 'Var', (33, 37))
615254	22918885	In Nf1 mutant mouse NPCis tumors TGFbeta1 was elevated on loss of TC21, but TGFbeta2 mRNA was not (Supplemental Figure 5C, 5D).	('elevated', 'PosReg', (46, 54))	('loss', 'NegReg', (58, 62))	('mutant', 'Var', (7, 13))	('Nf1', 'Gene', (3, 6))	('NPCis tumors TGFbeta1', 'Disease', 'MESH:D009369', (20, 41))	('mouse', 'Species', '10090', (14, 19))	('Nf1', 'Gene', '18015', (3, 6))	('NPCis tumors TGFbeta1', 'Disease', (20, 41))	('TC21', 'Protein', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
615255	22918885	In NF1-/- human MPNST shTC21 xenotransplants, TGFbeta2 mRNA levels were significantly elevated in tumors (Figure 7B) while TGFbeta1 and TGFbeta3 levels were unchanged (Supplemental Figure 5E, 5F).	('elevated', 'PosReg', (86, 94))	('TGFbeta3', 'Gene', '7043', (136, 144))	('tumors', 'Disease', (98, 104))	('mRNA levels', 'MPA', (55, 66))	('human', 'Species', '9606', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NF1-/-', 'Var', (3, 9))	('TGFbeta2', 'Gene', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('shTC21', 'Gene', (22, 28))	('TGFbeta3', 'Gene', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
615263	22918885	The absence of TGFbetaRII in S462TY cells predicted that the cells would not respond to TGFbeta.	('TGFbetaRII', 'Gene', '7048', (15, 25))	('TGFbetaRII', 'Gene', (15, 25))	('S462TY', 'Var', (29, 35))	('absence', 'NegReg', (4, 11))	('S462TY', 'CellLine', 'CVCL:1Y70', (29, 35))
615268	22918885	Loss of TC21 in the setting of Nf1 deficiency delayed formation of benign neurofibromas, accelerated formation of aggressive brain tumors and nerve sarcomas, and uniquely regulated expression of TGFbeta.	('Nf1 deficiency', 'Disease', (31, 45))	('TC21', 'Gene', (8, 12))	('aggressive brain tumors', 'Disease', (114, 137))	('sarcomas', 'Phenotype', 'HP:0100242', (148, 156))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('aggressive brain tumors', 'Disease', 'MESH:D001927', (114, 137))	('nerve sarcomas', 'Disease', 'MESH:D012509', (142, 156))	('expression', 'MPA', (181, 191))	('neurofibromas', 'Phenotype', 'HP:0001067', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('Nf1 deficiency', 'Disease', 'MESH:C537392', (31, 45))	('TGFbeta', 'Gene', (195, 202))	('delayed', 'NegReg', (46, 53))	('benign neurofibromas', 'Disease', (67, 87))	('brain tumors', 'Phenotype', 'HP:0030692', (125, 137))	('Loss', 'Var', (0, 4))	('benign neurofibromas', 'Disease', 'MESH:D009455', (67, 87))	('regulated', 'Reg', (171, 180))	('accelerated', 'PosReg', (89, 100))	('nerve sarcomas', 'Disease', (142, 156))	('neurofibroma', 'Phenotype', 'HP:0001067', (74, 86))	('formation', 'CPA', (54, 63))	('aggressive brain', 'Phenotype', 'HP:0000718', (114, 130))
615272	22918885	Loss of TC21 in GEM neurofibroma extended mouse survival without affecting neurofibroma number or size, suggesting effects on early stages of tumor formation.	('mouse survival', 'CPA', (42, 56))	('neurofibroma', 'Disease', 'MESH:D009455', (20, 32))	('neurofibroma', 'Phenotype', 'HP:0001067', (75, 87))	('mouse', 'Species', '10090', (42, 47))	('neurofibroma number', 'Disease', 'MESH:D009455', (75, 94))	('TC21', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('neurofibroma number', 'Disease', (75, 94))	('tumor', 'Disease', (142, 147))	('extended', 'PosReg', (33, 41))	('neurofibroma', 'Disease', 'MESH:D009455', (75, 87))	('neurofibroma', 'Disease', (20, 32))	('effects', 'Reg', (115, 122))	('neurofibroma', 'Disease', (75, 87))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('neurofibroma', 'Phenotype', 'HP:0001067', (20, 32))
615277	22918885	Numbers of Nf1-/- primary sphere-forming cells, after acute inactivation at E12.5 using the DhhCre allele, were reduced by loss of TC21.	('TC21', 'Gene', (131, 135))	('Nf1', 'Gene', (11, 14))	('Nf1', 'Gene', '18015', (11, 14))	('reduced', 'NegReg', (112, 119))	('loss', 'Var', (123, 127))
615284	22918885	The idea that Nf1 regulates other Ras proteins: even in peripheral nerve cells: is supported by experiments in which farnesyl transferase inhibitors predominantly blocking H-Ras, blocks Nf1 mutant Schwann cell proliferation, and a report that N-Ras plays a major role in MPNST cells.	('H-Ras', 'Protein', (172, 177))	('Nf1', 'Gene', '18015', (186, 189))	('Nf1', 'Gene', (14, 17))	('blocking', 'NegReg', (163, 171))	('mutant', 'Var', (190, 196))	('blocks', 'NegReg', (179, 185))	('Nf1', 'Gene', (186, 189))	('Nf1', 'Gene', '18015', (14, 17))
615285	22918885	Our finding that loss of TC21 delayed Nf1-/- embryonic lethality --but did not rescue embryos to birth-- is also consistent with roles of multiple Ras proteins in development.	('delayed', 'NegReg', (30, 37))	('Nf1', 'Gene', (38, 41))	('TC21', 'Gene', (25, 29))	('Nf1', 'Gene', '18015', (38, 41))	('loss', 'Var', (17, 21))
615288	22918885	We found that loss of TC21 enhances tumorigenesis in malignancy.	('loss', 'Var', (14, 18))	('TC21', 'Gene', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('malignancy', 'Disease', 'MESH:D009369', (53, 63))	('enhances', 'PosReg', (27, 35))	('malignancy', 'Disease', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
615289	22918885	In the NPCis mouse model, loss of TC21 dramatically accelerated formation of brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mouse', 'Species', '10090', (13, 18))	('brain tumors', 'Phenotype', 'HP:0030692', (77, 89))	('brain tumors', 'Disease', 'MESH:D001932', (77, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('brain tumors', 'Disease', (77, 89))	('TC21', 'Gene', (34, 38))	('loss', 'Var', (26, 30))	('accelerated', 'PosReg', (52, 63))
615291	22918885	Furthermore, inhibiting TGFbeta blocked the elevated tumor growth caused by loss of TC21.	('TC21', 'Gene', (84, 88))	('loss', 'Var', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('elevated tumor', 'Disease', (44, 58))	('elevated tumor', 'Disease', 'MESH:D009369', (44, 58))	('TGFbeta', 'Gene', (24, 31))	('inhibiting', 'Var', (13, 23))
615293	22918885	Genomic mutation or loss of one or more TGFbetaRs is common in many tumor types.	('tumor', 'Disease', (68, 73))	('TGFbetaRs', 'Gene', (40, 49))	('Genomic mutation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('loss', 'NegReg', (20, 24))
615294	22918885	Despite absence of TGFbetaRII in S462TY cells, blocking TGFbeta led to decreased expression of phospho-SMAD.	('S462TY', 'CellLine', 'CVCL:1Y70', (33, 39))	('blocking', 'Var', (47, 55))	('TGFbetaRII', 'Gene', '7048', (19, 29))	('TGFbetaRII', 'Gene', (19, 29))	('phospho-SMAD', 'MPA', (95, 107))	('TGFbeta', 'Gene', (56, 63))	('decreased', 'NegReg', (71, 80))	('expression', 'MPA', (81, 91))
615296	22918885	A non-cell autonomous effect of TGFbeta in malignancy has been documented previously in models of carcinoma, using genetic loss of TGFbetaRII.	('TGFbetaRII', 'Gene', (131, 141))	('genetic loss', 'Var', (115, 127))	('carcinoma', 'Disease', 'MESH:D002277', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('malignancy', 'Disease', 'MESH:D009369', (43, 53))	('malignancy', 'Disease', (43, 53))	('carcinoma', 'Disease', (98, 107))	('TGFbeta', 'Gene', (32, 39))	('TGFbetaRII', 'Gene', '7048', (131, 141))
615297	22918885	In summary, TC21 has a dual effect: in developing Nf1 progenitor cells this Ras-related protein promotes cell survival by promoting TGFbeta production and formation of an autocrine survival loop, so that loss of TC21 results in decreased precursors and delayed tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('Nf1', 'Gene', '18015', (50, 53))	('TGFbeta production', 'MPA', (132, 150))	('precursors', 'CPA', (238, 248))	('TC21', 'Gene', (212, 216))	('loss', 'Var', (204, 208))	('promoting', 'PosReg', (122, 131))	('decreased', 'NegReg', (228, 237))	('Nf1', 'Gene', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('cell', 'CPA', (105, 109))
615299	22918885	In MPNST cells loss of TC21 dramatically increases TGFbeta production, increasing vascularization and tumor growth.	('increasing', 'PosReg', (71, 81))	('TGFbeta production', 'MPA', (51, 69))	('increases', 'PosReg', (41, 50))	('TC21', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('loss', 'Var', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('vascularization', 'CPA', (82, 97))	('increases TGFbeta', 'Phenotype', 'HP:0030269', (41, 58))
615300	22918885	Our results linking TC21 to regulation of TGFbeta production are likely to be relevant to cancer in general, as NF1 mutations are increasingly identified in sporadic cancers.	('identified', 'Reg', (143, 153))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('sporadic cancers', 'Disease', 'MESH:D009369', (157, 173))	('NF1', 'Gene', (112, 115))	('sporadic cancers', 'Disease', (157, 173))	('mutations', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
615320	20871855	The mass was relatively well defined and enhanced with Gd-DTPA on STIR sequences (Figure 2(c)).	('Gd-DTPA', 'Var', (55, 62))	('enhanced', 'PosReg', (41, 49))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (55, 62))
615379	33897913	Despite all the advantages, the values of NLR, PLR, and LMR would be altered by certain diseases (such as infections, cardiac events, atherosclerosis, and abnormal thyroid function) and drugs like nonsteroidal anti-inflammatory drugs (NSAIDS).	('infections', 'Disease', (106, 116))	('abnormal', 'Var', (155, 163))	('abnormal thyroid function', 'Phenotype', 'HP:0002926', (155, 180))	('atherosclerosis', 'Disease', 'MESH:D050197', (134, 149))	('atherosclerosis', 'Phenotype', 'HP:0002621', (134, 149))	('altered', 'Reg', (69, 76))	('cardiac events', 'Disease', (118, 132))	('infections', 'Disease', 'MESH:D007239', (106, 116))	('atherosclerosis', 'Disease', (134, 149))	('abnormal thyroid', 'Phenotype', 'HP:0000820', (155, 171))
615545	26107716	Infection of immunosuppressed mice with gammaHV68 carrying kGPCR, but not wild-type gammaHV68, induced tumors in mice that exhibited angiogenic and inflammatory features shared with human Kaposi's sarcoma.	('mice', 'Species', '10090', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('GPCR', 'Gene', (60, 64))	('GPCR', 'Gene', '227289', (60, 64))	('human', 'Species', '9606', (182, 187))	('inflammatory', 'CPA', (148, 160))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (188, 204))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (188, 204))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (197, 204))	("Kaposi's sarcoma", 'Disease', (188, 204))	('gammaHV68', 'Chemical', '-', (84, 93))	('gammaHV68', 'Var', (40, 49))	('mice', 'Species', '10090', (113, 117))	('gammaHV68', 'Chemical', '-', (40, 49))
615578	26107716	The gammaHV68 mGPCR demonstrated no basal level of signaling activity that was only detected upon ligand stimulation, behaving like a cellular GPCR in signal transduction.	('gammaHV68', 'Var', (4, 13))	('GPCR', 'Gene', (15, 19))	('gammaHV68', 'Chemical', '-', (4, 13))	('GPCR', 'Gene', '227289', (15, 19))	('GPCR', 'Gene', (143, 147))	('GPCR', 'Gene', '227289', (143, 147))	('mGPCR', 'Gene', '227289', (14, 19))	('signaling activity', 'MPA', (51, 69))	('mGPCR', 'Gene', (14, 19))
615591	26107716	In transfected 293T cells, kGPCR expression highly elevated the expression of an NFAT-dependent reporter (Fig 1A).	('expression', 'MPA', (64, 74))	('expression', 'Var', (33, 43))	('GPCR', 'Gene', '227289', (28, 32))	('293T', 'CellLine', 'CVCL:0063', (15, 19))	('elevated', 'PosReg', (51, 59))	('GPCR', 'Gene', (28, 32))
615669	26107716	To determine whether this is due to lack of antigen education, we further probed antigen-presenting cells with antibody against CD80 (also known as B7-1) that provides co-stimulatory signal for T cell activation.	('CD80', 'Gene', (128, 132))	('B7-1', 'Gene', '941', (148, 152))	('antibody', 'Var', (111, 119))	('B7-1', 'Gene', (148, 152))
615715	26107716	Events such as glycan modification/editing and tyrosine sulfation occur in the TGN and are relevant to the trafficking and signaling of GPCRs.	('modification/editing', 'Var', (22, 42))	('tyrosine sulfation', 'MPA', (47, 65))	('GPCR', 'Gene', (136, 140))	('GPCR', 'Gene', '227289', (136, 140))	('tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('glycan', 'Chemical', 'MESH:D011134', (15, 21))	('glycan', 'Protein', (15, 21))
615716	26107716	We previously reported that the N-terminal tyrosine-containing motif of kGPCR was sulfated within the TGN compartment and that sulfation promoted kGPCR signaling and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('rev', 'Gene', (4, 7))	('promoted', 'PosReg', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('rev', 'Gene', '19714', (4, 7))	('GPCR', 'Gene', '227289', (73, 77))	('tumor', 'Disease', (166, 171))	('GPCR', 'Gene', (147, 151))	('GPCR', 'Gene', '227289', (147, 151))	('tyrosine', 'Chemical', 'MESH:D014443', (43, 51))	('GPCR', 'Gene', (73, 77))	('sulfation', 'Var', (127, 136))
615720	26107716	Though these models excel in tumorigenesis induced by single gene product, they lack the viral infection component.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('single gene product', 'Var', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('viral infection component', 'Disease', 'MESH:D001102', (89, 114))	('viral infection component', 'Disease', (89, 114))
615745	26107716	HEK293T (ATCC), SV40-immortalized mouse endothelial cells SVEC (kindly provided by Dr. Philip Sharpe, UT Southwestern), NIH 3T12 cells (ATCC) were cultured in DMEM supplemented with 10% (vol/vol) FBS and 100 U penicillin/streptomycin.	('FBS', 'Disease', (196, 199))	('NIH 3T12', 'CellLine', 'CVCL:0594', (120, 128))	('mouse', 'Species', '10090', (34, 39))	('streptomycin', 'Chemical', 'MESH:D013307', (221, 233))	('DMEM', 'Chemical', '-', (159, 163))	('FBS', 'Disease', 'MESH:D005198', (196, 199))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('penicillin', 'Chemical', 'MESH:D010406', (210, 220))	('HEK293T', 'Var', (0, 7))	('SVEC', 'CellLine', 'CVCL:4393', (58, 62))
615770	26107716	Allelic exchange was performed using pGS284.kGPCR in S17lambdapir and gammaHV68.ORF73bla BACmid GS500 Escherichia coli, as previously described.	('rev', 'Gene', '19714', (124, 127))	('pGS284', 'Chemical', '-', (37, 43))	('rev', 'Gene', (124, 127))	('Escherichia coli', 'Species', '562', (102, 118))	('gammaHV68', 'Chemical', '-', (70, 79))	('GPCR', 'Gene', (45, 49))	('GPCR', 'Gene', '227289', (45, 49))	('gammaHV68.ORF73bla', 'Var', (70, 88))
615773	26107716	The frequency of splenocytes harboring gammaHV68 genome was measured by LD-PCR as previously described.	('gammaHV68', 'Chemical', '-', (39, 48))	('rev', 'Gene', (83, 86))	('gammaHV68 genome', 'Var', (39, 55))	('rev', 'Gene', '19714', (83, 86))
615841	23788856	Experimental evidence showed p53 gene alterations or increased p53 messenger ribonucleic acid (mRNA) levels in post-irradiation murine sarcomas.	('murine', 'Species', '10090', (128, 134))	('sarcomas', 'Disease', 'MESH:D012509', (135, 143))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('p53', 'Gene', (29, 32))	('increased', 'PosReg', (53, 62))	('gene', 'Var', (33, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('alterations', 'Reg', (38, 49))	('sarcomas', 'Disease', (135, 143))
615842	23788856	The retinoblastoma gen (Rb) mutations also have been detected.	('retinoblastoma', 'Disease', 'MESH:D012175', (4, 18))	('retinoblastoma', 'Disease', (4, 18))	('retinoblastoma', 'Phenotype', 'HP:0009919', (4, 18))	('mutations', 'Var', (28, 37))	('Rb', 'Gene', (24, 26))
615845	23788856	Holt suggested a two-mutation model of carcinogenesis, which fitted the influence of low dose irradiation: a specific mutation in a stem cell increases its rate of proliferation and pre-malignant cells will develop.	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))	('increases', 'PosReg', (142, 151))	('mutation', 'Var', (118, 126))	('carcinogenesis', 'Disease', (39, 53))
615852	23788856	In members of families with Li-Fraumeni syndrome, germline mutations in tumour suppressor genes may increase the risk of second cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('germline mutations', 'Var', (50, 68))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('Li-Fraumeni syndrome', 'Disease', (28, 48))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (28, 48))	('increase', 'PosReg', (100, 108))	('cancer', 'Disease', (128, 134))
615997	29733909	The study suggested one of the reasons for this difference may be an inherent radioresistance in rectal tumors due to the routine use of neoadjuvant radiation in primary management of the disease and recurrent cells arising from radioresistant clones as well as a higher rate of KRAS mutations in rectal lesions.	('KRAS', 'Gene', (279, 283))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('KRAS', 'Gene', '3845', (279, 283))	('radioresistance', 'CPA', (78, 93))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('rectal tumors', 'Disease', 'MESH:D012004', (97, 110))	('mutations', 'Var', (284, 293))	('rectal tumors', 'Disease', (97, 110))	('rectal tumors', 'Phenotype', 'HP:0100743', (97, 110))
616053	29152519	Kim et al discovered identical mutations of Kras gene accompanied with a strong nuclear p53 immunoreactivity in both sarcomatous and carcinomatous components indicating a monoclonal origin supporting metaplastic transformation of a carcinoma.	('mutations', 'Var', (31, 40))	('Kras', 'Gene', (44, 48))	('carcinomatous component', 'Disease', (133, 156))	('carcinoma', 'Disease', 'MESH:D002277', (232, 241))	('Kras', 'Gene', '3845', (44, 48))	('carcinomatous component', 'Disease', 'MESH:D055756', (133, 156))	('carcinoma', 'Disease', 'MESH:D002277', (133, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('sarcomatous and carcinomatous', 'Disease', 'MESH:D055756', (117, 146))	('nuclear', 'MPA', (80, 87))	('carcinoma', 'Disease', (232, 241))	('carcinoma', 'Disease', (133, 142))
616054	29152519	More recently, Bai et al investigated the origin of pancreatic carcinosarcomas and their findings were similar to earlier studies showing strong nuclear p53 immunoreactivity and a similar Kras gene mutation in both components, favoring the hypothesis of metaplastic transformation of a carcinoma.	('pancreatic carcinosarcomas', 'Disease', (52, 78))	('carcinoma', 'Disease', 'MESH:D002277', (286, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('pancreatic carcinosarcomas', 'Disease', 'MESH:D002296', (52, 78))	('Kras', 'Gene', (188, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('Kras', 'Gene', '3845', (188, 192))	('carcinoma', 'Disease', (286, 295))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '7157', (153, 156))	('mutation', 'Var', (198, 206))
616207	26850593	The cells were pre-treated with specific inhibitors of ERK1/2 (U0126), p38 MAPK (SB239063), and JNK (SP600125), and then stimulated with IL-17A.	('SB239063', 'Var', (81, 89))	('SP600125', 'Var', (101, 109))	('JNK', 'Gene', '5599', (96, 99))	('SP600125', 'Chemical', 'MESH:C432165', (101, 109))	('IL-17A', 'Gene', '3605', (137, 143))	('p38', 'Gene', (71, 74))	('ERK1/2', 'Enzyme', (55, 61))	('U0126', 'Var', (63, 68))	('IL-17A', 'Gene', (137, 143))	('U0126', 'Chemical', 'MESH:C113580', (63, 68))	('SB239063', 'Chemical', 'MESH:C406525', (81, 89))	('JNK', 'Gene', (96, 99))	('p38', 'Gene', '5594', (71, 74))
616214	26850593	Real time RT-PCR revealed that SR11302 pre-treatment effectively blocked IL-17A-induced MMP-3 mRNA expression in a dose-dependent manner (Fig.	('IL-17A', 'Gene', (73, 79))	('SR11302', 'Chemical', 'MESH:C106195', (31, 38))	('MMP-3', 'Gene', '4314', (88, 93))	('SR11302', 'Var', (31, 38))	('MMP-3', 'Gene', (88, 93))	('IL-17A', 'Gene', '3605', (73, 79))	('blocked', 'NegReg', (65, 72))
616216	26850593	HS-SY-II cells were pre-treated with the inhibitors U0126 (ERK1/2), SB239063 (p38 MAPK), and SP600125 (JNK) and then stimulated with IL-17A.	('HS-SY-II', 'CellLine', 'CVCL:8719', (0, 8))	('SB239063', 'Var', (68, 76))	('SP600125', 'Var', (93, 101))	('U0126', 'Chemical', 'MESH:C113580', (52, 57))	('p38', 'Gene', '5594', (78, 81))	('IL-17A', 'Gene', '3605', (133, 139))	('JNK', 'Gene', '5599', (103, 106))	('SP600125', 'Chemical', 'MESH:C432165', (93, 101))	('p38', 'Gene', (78, 81))	('IL-17A', 'Gene', (133, 139))	('SB239063', 'Chemical', 'MESH:C406525', (68, 76))	('U0126', 'Var', (52, 57))	('JNK', 'Gene', (103, 106))
616217	26850593	Western blotting revealed that U0126 and SP600125 attenuated the IL-17A-induced phosphorylation of c-Fos and c-Jun (Fig.	('c-Jun', 'Gene', '3725', (109, 114))	('IL-17A', 'Gene', (65, 71))	('U0126', 'Chemical', 'MESH:C113580', (31, 36))	('c-Fos', 'Gene', (99, 104))	('IL-17A', 'Gene', '3605', (65, 71))	('SP600125', 'Chemical', 'MESH:C432165', (41, 49))	('phosphorylation', 'MPA', (80, 95))	('c-Fos', 'Gene', '2353', (99, 104))	('attenuated', 'NegReg', (50, 60))	('c-Jun', 'Gene', (109, 114))	('SP600125', 'Var', (41, 49))	('U0126', 'Var', (31, 36))
616218	26850593	4a, c) whereas SB239063 suppressed the IL-17A-stimulated phosphorylation of c-Fos but not c-Jun (Fig.	('c-Jun', 'Gene', (90, 95))	('c-Fos', 'Gene', '2353', (76, 81))	('suppressed', 'NegReg', (24, 34))	('SB239063', 'Chemical', 'MESH:C406525', (15, 23))	('IL-17A', 'Gene', (39, 45))	('SB239063', 'Var', (15, 23))	('phosphorylation', 'MPA', (57, 72))	('c-Jun', 'Gene', '3725', (90, 95))	('c-Fos', 'Gene', (76, 81))	('IL-17A', 'Gene', '3605', (39, 45))
616237	26850593	The importance of AP-1 activation in IL-17A-stimulated MMP-3 expression was demonstrated clearly by the dramatic decrease in MMP-3 gene expression induced by SR11302.	('MMP-3', 'Gene', '4314', (125, 130))	('decrease', 'NegReg', (113, 121))	('SR11302', 'Var', (158, 165))	('MMP-3', 'Gene', (125, 130))	('MMP-3', 'Gene', (55, 60))	('MMP-3', 'Gene', '4314', (55, 60))	('IL-17A', 'Gene', (37, 43))	('SR11302', 'Chemical', 'MESH:C106195', (158, 165))	('AP-1', 'Gene', (18, 22))	('AP-1', 'Gene', '3725', (18, 22))	('IL-17A', 'Gene', '3605', (37, 43))
616301	25922657	32% of patients with a low albumin were admitted to hospital for chemotherapy related toxicity, compared to 24% of patients with a normal serum albumin (p = 0.02).	('patients', 'Species', '9606', (115, 123))	('low albumin', 'Phenotype', 'HP:0003073', (23, 34))	('albumin', 'Protein', (27, 34))	('low', 'Var', (23, 26))	('toxicity', 'Disease', 'MESH:D064420', (86, 94))	('toxicity', 'Disease', (86, 94))	('patients', 'Species', '9606', (7, 15))
616399	22567356	Most recently, the presence of TGFBR3 and MGEA5 rearrangements has been identified in a subset of MIFS.	('MIFS', 'Disease', (98, 102))	('identified', 'Reg', (72, 82))	('rearrangements', 'Var', (48, 62))	('TGFBR3', 'Gene', (31, 37))	('MGEA5', 'Gene', '10724', (42, 47))	('TGFBR3', 'Gene', '7049', (31, 37))	('MGEA5', 'Gene', (42, 47))
616417	22567356	Approximately one-third of all soft issue sarcomas exhibit a nonrandom chromosomal translocation.	('sarcomas', 'Disease', 'MESH:D012509', (42, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('nonrandom chromosomal translocation', 'Var', (61, 96))	('soft issue sarcomas', 'Phenotype', 'HP:0030448', (31, 50))	('sarcomas', 'Disease', (42, 50))
616418	22567356	In addition, a subset of soft-tissue tumors carries specific oncogenic mutations (e.g., KIT or PDGFRA mutations in gastrointestinal stromal tumor).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('soft-tissue tumors', 'Phenotype', 'HP:0031459', (25, 43))	('gastrointestinal stromal tumor', 'Disease', (115, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (115, 145))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('KIT', 'Gene', (88, 91))	('mutations', 'Var', (102, 111))	('soft-tissue tumor', 'Phenotype', 'HP:0031459', (25, 42))	('tumors', 'Disease', (37, 43))	('PDGFRA', 'Gene', (95, 101))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (115, 145))	('PDGFRA', 'Gene', '5156', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
616419	22567356	FISH and RT-PCR are commonly applied for the detection of specific genetic alterations in the differential diagnosis of soft-tissue sarcomas.	('genetic alterations', 'Var', (67, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (120, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('soft-tissue sarcomas', 'Disease', (120, 140))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (120, 140))
616440	22567356	reported that MLS with a type 1 EWSR1-DDIT3 fusion transcript may show more favorable clinical behavior than MLS with other types of fusion transcripts.	('MLS', 'Disease', 'MESH:C537466', (109, 112))	('MLS', 'Disease', (109, 112))	('EWSR1', 'Gene', '2130', (32, 37))	('MLS', 'Phenotype', 'HP:0012268', (109, 112))	('DDIT3', 'Gene', '1649', (38, 43))	('MLS', 'Disease', 'MESH:C537466', (14, 17))	('MLS', 'Disease', (14, 17))	('MLS', 'Phenotype', 'HP:0012268', (14, 17))	('EWSR1', 'Gene', (32, 37))	('DDIT3', 'Gene', (38, 43))	('fusion transcript', 'Var', (44, 61))
616443	22567356	demonstrated that mutation of PIK3CA, encoding the catalytic subunit of PI3K, is associated with AKT activation and poor clinical outcome.	('AKT', 'Gene', '207', (97, 100))	('PIK3CA', 'Gene', (30, 36))	('activation', 'PosReg', (101, 111))	('AKT', 'Gene', (97, 100))	('PIK3CA', 'Gene', '5290', (30, 36))	('mutation', 'Var', (18, 26))	('associated', 'Reg', (81, 91))
616475	22567356	EMC is characterized by a recurrent translocation t(9; 22)(q22; q12) in approximately 75% of cases, which fuses the EWSR1 gene on 22q12 with the NR4A3 gene on 9q22.	('EWSR1', 'Gene', '2130', (116, 121))	('EMC', 'Disease', (0, 3))	('fuses', 'Var', (106, 111))	('NR4A3', 'Gene', '8013', (145, 150))	('NR4A3', 'Gene', (145, 150))	('EWSR1', 'Gene', (116, 121))
616476	22567356	A second variant translocation, t(9; 17)(q22; q11), has been detected in approximately 15% of EMC and results in a TAF15-NR4A3 fusion gene.	('TAF15', 'Gene', '8148', (115, 120))	('t(9; 17)(q22; q11', 'Var', (32, 49))	('NR4A3', 'Gene', (121, 126))	('results in', 'Reg', (102, 112))	('NR4A3', 'Gene', '8013', (121, 126))	('TAF15', 'Gene', (115, 120))
616477	22567356	In addition, two additional variant translocations, t(9; 15)(q22; q21) resulting in a TCF12-NR4A3 fusion gene and t(3; 9)(q12; q22) resulting in a TFG-NR4A3 fusion gene, have also been identified, each only in a single case.	('NR4A3', 'Gene', (92, 97))	('t(9; 15)(q22; q21', 'Var', (52, 69))	('TCF12', 'Gene', '6938', (86, 91))	('TFG', 'Gene', (147, 150))	('NR4A3', 'Gene', '8013', (151, 156))	('NR4A3', 'Gene', (151, 156))	('t(3; 9)(q12; q22', 'Var', (114, 130))	('TCF12', 'Gene', (86, 91))	('TFG', 'Gene', '10342', (147, 150))	('NR4A3', 'Gene', '8013', (92, 97))
616519	22567356	A conventional CGH study of 22 myxofibrosarcomas showed gains of 19p and 19q, losses of 1q, 2q, 3p, 4q, 10q, 11q, and 13q, and high-level amplifications of the central regions of chromosome 1, 5p, and 20q.	('myxofibrosarcomas', 'Disease', 'None', (31, 48))	('myxofibrosarcomas', 'Disease', (31, 48))	('losses', 'NegReg', (78, 84))	('amplifications', 'Var', (138, 152))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (35, 47))	('gains', 'PosReg', (56, 61))
616521	22567356	In addition, array CGH studies showed gains of 7p21-22, 7q31-35, and 12q15-21 and losses of 10p13-14, 10q25-26, and 13q14-34.	('10q25-26', 'Var', (102, 110))	('p21', 'Gene', (48, 51))	('p21', 'Gene', '644914', (48, 51))	('10p13-14', 'Var', (92, 100))	('losses', 'NegReg', (82, 88))	('12q15-21', 'Gene', (69, 77))	('gains', 'PosReg', (38, 43))	('7q31-35', 'Var', (56, 63))
616522	22567356	These findings suggest that loss of chromosome 13q is the most frequent genomic imbalance in myxofibrosarcoma, leading to inactivation of the RB pathway.	('imbalance', 'Phenotype', 'HP:0002172', (80, 89))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (97, 109))	('myxofibrosarcoma', 'Disease', (93, 109))	('myxofibrosarcoma', 'Disease', 'None', (93, 109))	('RB pathway', 'Pathway', (142, 152))	('inactivation', 'MPA', (122, 134))	('loss of chromosome', 'Var', (28, 46))	('RB', 'Chemical', 'MESH:D012413', (142, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
616529	22567356	TNXB is thought to function in matrix maturation during wound healing, and its deficiency is associated with the connective tissue disorder Ehlers-Danlos syndrome.	('TNXB', 'Gene', (0, 4))	('deficiency', 'Var', (79, 89))	('Ehlers-Danlos syndrome', 'Disease', (140, 162))	('associated', 'Reg', (93, 103))	('TNXB', 'Gene', '7148', (0, 4))	('Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (140, 162))
616531	22567356	demonstrated that NF1 is mutated or deleted in 10.5% of myxofibrosarcomas.	('myxofibrosarcomas', 'Disease', 'None', (56, 73))	('myxofibrosarcomas', 'Disease', (56, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (60, 72))	('deleted', 'Var', (36, 43))	('NF1', 'Gene', (18, 21))	('NF1', 'Gene', '4763', (18, 21))
616540	22567356	demonstrated the presence of TGFBR3 (1p22) and MGEA5 (10q24) gene rearrangements by FISH in a subset of MIFS.	('TGFBR3', 'Gene', '7049', (29, 35))	('p22', 'Gene', (38, 41))	('rearrangements', 'Var', (66, 80))	('MGEA5', 'Gene', '10724', (47, 52))	('TGFBR3', 'Gene', (29, 35))	('MGEA5', 'Gene', (47, 52))	('p22', 'Gene', '1778', (38, 41))
616541	22567356	It is of interest that the t(1; 10) translocation and these gene rearrangements have also been identified in hemosiderotic fibrolipomatous tumor (HFLT).	('hemosiderotic fibrolipomatous tumor', 'Disease', (109, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('hemosiderotic fibrolipomatous tumor', 'Disease', 'MESH:C565226', (109, 144))	('translocation', 'Var', (36, 49))	('identified', 'Reg', (95, 105))
616546	22567356	These findings strongly suggest that VGLL3 is the main target of 3p11-12 amplification and this genetic event plays an important role in the development and progression of certain subsets of soft-tissue sarcomas.	('VGLL3', 'Gene', '389136', (37, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (203, 211))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('plays', 'Reg', (110, 115))	('p11', 'Gene', (66, 69))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (191, 211))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (191, 211))	('VGLL3', 'Gene', (37, 42))	('soft-tissue sarcomas', 'Disease', (191, 211))	('p11', 'Gene', '6281', (66, 69))	('amplification', 'Var', (73, 86))
616547	22567356	A recent gene expression analysis has shown that the FGF8 and NPM3 genes are upregulated in the t(1; 10) -positive tumors compared with tumors without such a translocation.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('upregulated', 'PosReg', (77, 88))	('NPM3', 'Gene', '10360', (62, 66))	('t(1; 10) -positive', 'Var', (96, 114))	('NPM3', 'Gene', (62, 66))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('FGF8', 'Gene', (53, 57))	('FGF8', 'Gene', '2253', (53, 57))
616551	22567356	Overexpression of FGF8 has been shown to increase tumor growth and angiogenesis.	('FGF8', 'Gene', (18, 22))	('angiogenesis', 'CPA', (67, 79))	('FGF8', 'Gene', '2253', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('increase', 'PosReg', (41, 49))	('tumor', 'Disease', (50, 55))
616552	22567356	suggested that deregulation of FGF8 may constitute an important event in the development of a subset of MIFS.	('FGF8', 'Gene', '2253', (31, 35))	('FGF8', 'Gene', (31, 35))	('deregulation', 'Var', (15, 27))	('MIFS', 'Disease', (104, 108))
616559	22567356	Recognition of this DFSP variant is important to avoid misdiagnosis of more or less aggressive myxoid soft-tissue tumors.	('soft-tissue tumor', 'Phenotype', 'HP:0031459', (102, 119))	('aggressive myxoid soft-tissue tumors', 'Disease', 'MESH:D012983', (84, 120))	('DFSP', 'Disease', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('DFSP', 'Disease', 'MESH:D018223', (20, 24))	('myxoid soft-tissue tumors', 'Phenotype', 'HP:0006769', (95, 120))	('variant', 'Var', (25, 32))	('soft-tissue tumors', 'Phenotype', 'HP:0031459', (102, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('aggressive myxoid soft-tissue tumors', 'Disease', (84, 120))
616580	22567356	These results support the concept that DFSP cells are dependent on aberrant activation of PDGFRB for cellular proliferation and survival.	('DFSP', 'Disease', 'MESH:D018223', (39, 43))	('cellular proliferation', 'CPA', (101, 123))	('PDGFRB', 'Gene', '5159', (90, 96))	('PDGFRB', 'Gene', (90, 96))	('aberrant', 'Var', (67, 75))	('activation', 'PosReg', (76, 86))	('DFSP', 'Disease', (39, 43))
616629	21139823	Sometimes the round cells and CD99 or desmin positivity raise concern for Ewing's sarcoma or rhabdomyosarcoma, respectively.	('rhabdomyosarcoma', 'Disease', (93, 109))	('CD99', 'Gene', '4267', (30, 34))	('desmin', 'Gene', (38, 44))	('positivity', 'Var', (45, 55))	('CD99', 'Gene', (30, 34))	('desmin', 'Gene', '1674', (38, 44))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (74, 89))	('desmin positivity', 'Phenotype', 'HP:0100300', (38, 55))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (93, 109))	("Ewing's sarcoma", 'Disease', (74, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (74, 89))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (93, 109))
616805	32117764	Phylogenetic trees were generated using PHYLIP with 1,000 bootstrap replicates per tree and visualized using the ape package in R. The number of shared mutations was calculated pairwise between the matched tumor-normal variants of each sample using VCFtools.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('variants', 'Var', (219, 227))	('tumor', 'Disease', (206, 211))	('VCFtools', 'Disease', 'None', (249, 257))	('VCFtools', 'Disease', (249, 257))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
616832	32117764	The pipeline included successful development of a matching PDX (designated "LMS-D48X") and low-passage cell line, a high throughput drug screen on the cell line, genomic profiling of mutations in the original tumors, PDX, and cell line, and in vivo validation of top drug candidates (Figure 2A).	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('LMS', 'Disease', (76, 79))	('mutations', 'Var', (183, 192))	('D48X', 'Mutation', 'p.D48X', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('LMS', 'Disease', 'MESH:D007890', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
616871	32117764	Analysis of unique and shared somatic mutations revealed that unique mutations dominate the genetic landscape of each tumor (Figure 6D).	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutations', 'Var', (69, 78))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (118, 123))
616873	32117764	Since bortezomib is a proteasome inhibitor, we analyzed proteins that were differentially ubiquitinated in the PDX treated with bortezomib as compared to vehicle-treated tumors.	('tumors', 'Disease', (170, 176))	('ubiquitinated', 'MPA', (90, 103))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('proteins', 'Protein', (56, 64))	('bortezomib', 'Chemical', 'MESH:D000069286', (6, 16))	('bortezomib', 'Chemical', 'MESH:D000069286', (128, 138))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('bortezomib', 'Var', (128, 138))
616879	32117764	Defective In Cullin Neddylation 1 Domain Containing 1 (DCUN1D1) is part of an E3 ubiquitin ligase complex for neddylation, and heat shock protein 70 kDa member 8 (HSPA8) is integral to the HSP70 pathway and cellular protein quality control systems.	('heat shock protein 70 kDa member 8', 'Gene', (127, 161))	('HSP70', 'Gene', (189, 194))	('shock', 'Phenotype', 'HP:0031273', (132, 137))	('HSP70', 'Gene', '3308', (189, 194))	('heat shock protein 70 kDa member 8', 'Gene', '3312', (127, 161))	('Defective', 'Var', (0, 9))	('DCUN1D1', 'Gene', '54165', (55, 62))	('HSPA8', 'Gene', (163, 168))	('DCUN1D1', 'Gene', (55, 62))	('HSPA8', 'Gene', '3312', (163, 168))
616880	32117764	Notably, the DCUN1D1 mutation was unique to the PDX and cell line (Figure 7E), suggesting the tumor from which this PDX was derived may have harbored unique genetics that could contribute to increased bortezomib sensitivity.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('DCUN1D1', 'Gene', '54165', (13, 20))	('mutation', 'Var', (21, 29))	('increased', 'PosReg', (191, 200))	('DCUN1D1', 'Gene', (13, 20))	('bortezomib sensitivity', 'MPA', (201, 223))	('tumor', 'Disease', (94, 99))	('bortezomib', 'Chemical', 'MESH:D000069286', (201, 211))
616896	32117764	A third possibility:and perhaps the most intriguing possibility:is that the recurrent and metastatic lesions acquired unique mutations in key cellular pathways that conferred bortezomib resistance.	('mutations', 'Var', (125, 134))	('bortezomib', 'MPA', (175, 185))	('bortezomib', 'Chemical', 'MESH:D000069286', (175, 185))	('metastatic lesions', 'CPA', (90, 108))	('key cellular pathways', 'Pathway', (138, 159))	('conferred', 'Reg', (165, 174))
616907	32117764	Multiple studies in mouse models of EGFR mutant lung cancer have shown the utility of combination therapies in overcoming treatment resistance.	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('mutant', 'Var', (41, 47))	('EGFR', 'Gene', '13649', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('EGFR', 'Gene', (36, 40))	('mouse', 'Species', '10090', (20, 25))
616909	32117764	In the context of multiple myeloma, for which bortezomib is a standard therapy, multiple cellular pathways have been associated with bortezomib resistance, including mutations in genes regulating the active site for bortezomib.	('multiple myeloma', 'Phenotype', 'HP:0006775', (18, 34))	('mutations', 'Var', (166, 175))	('associated', 'Reg', (117, 127))	('bortezomib', 'Chemical', 'MESH:D000069286', (133, 143))	('multiple myeloma', 'Disease', 'MESH:D009101', (18, 34))	('multiple myeloma', 'Disease', (18, 34))	('bortezomib', 'Chemical', 'MESH:D000069286', (216, 226))	('cellular pathways', 'Pathway', (89, 106))	('bortezomib', 'Chemical', 'MESH:D000069286', (46, 56))
616914	32117764	This integrated multi-omics analysis suggests that mutations within these two genes may explain, in part, the response to bortezomib.	('bortezomib', 'Chemical', 'MESH:D000069286', (122, 132))	('mutations', 'Var', (51, 60))	('explain', 'Reg', (88, 95))
616940	31317881	On immunohistochemistry, the cells express cd68, lysozyme, cd4 and cd163, but specific T and B cell markers, epithelial markers, myeloid cell markers (e.g., myeloperoxidase, cd33), cd1a, s100 protein are not expressed.	('cd1a', 'Gene', '909', (181, 185))	('myeloperoxidase', 'Gene', (157, 172))	('myeloperoxidase', 'Gene', '4353', (157, 172))	('cd1a', 'Gene', (181, 185))	('cd4', 'Gene', '920', (59, 62))	('s100', 'Gene', '6271', (187, 191))	('cd68', 'Gene', '968', (43, 47))	('cd68', 'Gene', (43, 47))	('cd33', 'Gene', (174, 178))	('cd163', 'Var', (67, 72))	('s100', 'Gene', (187, 191))	('cd33', 'Gene', '945', (174, 178))	('cd4', 'Gene', (59, 62))
616941	31317881	Our patient had cd 68, leucocyte common antigen (LCA) positivity, with myeloperoxidase (MPO) being negative.	('leucocyte common', 'Disease', (23, 39))	('MPO', 'Gene', '4353', (88, 91))	('MPO', 'Gene', (88, 91))	('patient', 'Species', '9606', (4, 11))	('myeloperoxidase', 'Gene', '4353', (71, 86))	('myeloperoxidase', 'Gene', (71, 86))	('cd 68', 'Var', (16, 21))
616951	29492209	At molecular level, the characteristic COL1A1-PDGFB rearrangement, leading to sustained PDGFR signaling, is not linked to the evolutive potential.	('COL1A1', 'Gene', (39, 45))	('PDGFB', 'Gene', (46, 51))	('PDGFR', 'Gene', (88, 93))	('PDGFR', 'Gene', '5159', (88, 93))	('rearrangement', 'Var', (52, 65))	('COL1A1', 'Gene', '1277', (39, 45))	('PDGFB', 'Gene', '5155', (46, 51))
616954	29492209	No cancer-associated EGFR gene mutation or copy-number variation, nor any KRAS, BRAF, NRAS hotspot mutations were found in any microdissected area.	('EGFR', 'Gene', '1956', (21, 25))	('NRAS', 'Gene', (86, 90))	('EGFR', 'Gene', (21, 25))	('BRAF', 'Gene', (80, 84))	('NRAS', 'Gene', '4893', (86, 90))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('KRAS', 'Gene', (74, 78))	('cancer', 'Disease', (3, 9))	('copy-number variation', 'Var', (43, 64))	('KRAS', 'Gene', '3845', (74, 78))	('BRAF', 'Gene', '673', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
616956	29492209	Using a proteome profiler phospho-kinase array on 3 DFSP and 3 DFSP-T cryopreserved tissue samples, EGFR phosphorylation was detected in each case.	('EGFR', 'Gene', '1956', (100, 104))	('DFSP', 'Disease', (63, 67))	('phosphorylation', 'Var', (105, 120))	('EGFR', 'Gene', (100, 104))	('detected', 'Reg', (125, 133))	('DFSP', 'Disease', (52, 56))	('DFSP', 'Disease', 'MESH:D018223', (52, 56))	('DFSP', 'Disease', 'MESH:D018223', (63, 67))
616964	29492209	Biologically, DFSP is characterized by a genomic rearrangement involving chromosomes 17 and 22, in a supernumerary ring chromosome, or in a reciprocal balanced translocation t(17;22)(q22;q13).	('DFSP', 'Disease', (14, 18))	('t(17;22)(q22;q13', 'Var', (174, 190))	('DFSP', 'Disease', 'MESH:D018223', (14, 18))	('t(17;22)(q22;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (174, 191))
616971	29492209	EGFR signaling through receptor phosphorylation and activation of downstream effectors contributes to tumor cell proliferation, apoptosis evasion, angiogenesis and metastasis.	('apoptosis evasion', 'CPA', (128, 145))	('EGFR', 'Gene', (0, 4))	('phosphorylation', 'Var', (32, 47))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('angiogenesis', 'CPA', (147, 159))	('metastasis', 'CPA', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('EGFR', 'Gene', '1956', (0, 4))	('activation', 'PosReg', (52, 62))
616976	29492209	All 22 cases presented COL1A1-PDGFB rearrangement and none had received imatinib before tumor sampling.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('imatinib', 'Chemical', 'MESH:D000068877', (72, 80))	('PDGFB', 'Gene', '5155', (30, 35))	('COL1A1', 'Gene', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('COL1A1', 'Gene', '1277', (23, 29))	('PDGFB', 'Gene', (30, 35))	('tumor', 'Disease', (88, 93))	('rearrangement', 'Var', (36, 49))
616982	29492209	We aimed to determine whether EGFR expression in the different microdissected areas was related to EGFR gene alterations, i.e.	('EGFR', 'Gene', (99, 103))	('EGFR', 'Gene', (30, 34))	('related', 'Reg', (88, 95))	('alterations', 'Var', (109, 120))	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', '1956', (30, 34))
616983	29492209	cancer hotspot point mutations, exon 19 deletion, or gene copy-number variations.	('cancer', 'Phenotype', 'HP:0002664', (0, 6))	('gene copy-number variations', 'Var', (53, 80))	('cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (0, 6))	('exon 19 deletion', 'Var', (32, 48))	('point mutations', 'Var', (15, 30))
616985	29492209	Each microdissected sample was also tested for cancer hotspot mutations on KRAS, BRAF and NRAS genes, and for the T790M EGFR resistanc e mutation, but no mutation was found.	('T790M', 'Mutation', 'rs121434569', (114, 119))	('NRAS', 'Gene', (90, 94))	('resistanc e', 'Gene', (125, 136))	('tested', 'Reg', (36, 42))	('T790M', 'Var', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('NRAS', 'Gene', '4893', (90, 94))	('cancer', 'Disease', (47, 53))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('KRAS', 'Gene', (75, 79))	('EGFR', 'Gene', '1956', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('KRAS', 'Gene', '3845', (75, 79))	('EGFR', 'Gene', (120, 124))
616987	29492209	In all DFSP and DFSP-T samples studied, the EGFR/RNaseP allele ratio was in the normal range, indicating no significant EGFR allele gain or loss in DFSP center, DFSP infiltrative periphery, or DFSP-T higher-grade sarcoma.	('DFSP', 'Disease', (161, 165))	('loss', 'NegReg', (140, 144))	('allele', 'Var', (125, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('DFSP', 'Disease', 'MESH:D018223', (16, 20))	('DFSP', 'Disease', 'MESH:D018223', (7, 11))	('EGFR', 'Gene', '1956', (44, 48))	('DFSP', 'Disease', 'MESH:D018223', (148, 152))	('DFSP', 'Disease', (16, 20))	('EGFR', 'Gene', (120, 124))	('DFSP', 'Disease', (7, 11))	('DFSP', 'Disease', (148, 152))	('DFSP', 'Disease', 'MESH:D018223', (193, 197))	('gain', 'PosReg', (132, 136))	('DFSP', 'Disease', 'MESH:D018223', (161, 165))	('DFSP', 'Disease', (193, 197))	('sarcoma', 'Disease', 'MESH:D012509', (213, 220))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (44, 48))	('sarcoma', 'Disease', (213, 220))
616988	29492209	Overall, these results indicated that EGFR expression in DFSP and DFSP-T was not associated with known cancer-associated EGFR gene alterations, whether mutations or copy-number variations.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', '1956', (121, 125))	('DFSP', 'Disease', (57, 61))	('DFSP', 'Disease', 'MESH:D018223', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('EGFR', 'Gene', (38, 42))	('DFSP', 'Disease', (66, 70))	('EGFR', 'Gene', (121, 125))	('DFSP', 'Disease', 'MESH:D018223', (66, 70))	('copy-number variations', 'Var', (165, 187))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
617029	29492209	In our cases, laser microdissection enabled us to localize EGFR phosphorylation in the areas of DFSP local extension and DFSP-T higher-grade sarcoma.	('DFSP', 'Disease', (96, 100))	('EGFR', 'Gene', (59, 63))	('sarcoma', 'Disease', (141, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('DFSP', 'Disease', (121, 125))	('phosphorylation', 'Var', (64, 79))	('DFSP', 'Disease', 'MESH:D018223', (96, 100))	('DFSP', 'Disease', 'MESH:D018223', (121, 125))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))	('EGFR', 'Gene', '1956', (59, 63))
617030	29492209	In these areas, EGFR phosphorylation was associated with downstream activation of TOR and STAT5a/b.	('STAT5a', 'Gene', (90, 96))	('activation', 'PosReg', (68, 78))	('EGFR', 'Gene', '1956', (16, 20))	('TOR', 'Gene', (82, 85))	('phosphorylation', 'Var', (21, 36))	('STAT5a', 'Gene', '6776', (90, 96))	('EGFR', 'Gene', (16, 20))
617032	29492209	As in our study, AKT/TOR pathway was reported to be predominantly activated in association with EGFR expression in 39 bone and soft-tissue tumors.	('AKT', 'Gene', (17, 20))	('EGFR', 'Gene', (96, 100))	('expression', 'Var', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('soft-tissue tumors', 'Disease', 'MESH:D012983', (127, 145))	('AKT', 'Gene', '207', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('activated', 'PosReg', (66, 75))	('soft-tissue tumors', 'Disease', (127, 145))	('soft-tissue tumors', 'Phenotype', 'HP:0031459', (127, 145))	('EGFR', 'Gene', '1956', (96, 100))
617061	29492209	Cancer hotspot mutation analyses were performed on microdissected cells from each area using: allelic discrimination method on an LC480 system (Roche) for KRAS G12S, G12R, G12C, G12D, G12A, G12V, G13D mutations, EGFR L858R, T790M mutations, BRAF V600E mutation; high-resolution melting (HRM) PCR mutation screening on LC480 system (Roche) for KRAS exons 2, 3, 4, NRAS exons 2,3, EGFR exons 18, 21, and BRAF exon 15; Sanger sequencing on an ABI3130 DNA sequencer (Applied Biosystems, Darmstadt, Germany) for each suspected mutation after HRM-PCR, and systematically for EGFR exons 19 and 20.	('EGFR', 'Gene', (569, 573))	('KRAS', 'Gene', '3845', (155, 159))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('NRAS', 'Gene', '4893', (363, 367))	('KRAS', 'Gene', '3845', (343, 347))	('EGFR', 'Gene', '1956', (212, 216))	('G12D', 'Mutation', 'rs121913529', (178, 182))	('KRAS', 'Gene', (155, 159))	('L858R', 'Mutation', 'rs121434568', (217, 222))	('EGFR', 'Gene', '1956', (379, 383))	('BRAF', 'Gene', (241, 245))	('KRAS', 'Gene', (343, 347))	('G13D', 'Mutation', 'rs112445441', (196, 200))	('EGFR', 'Gene', '1956', (569, 573))	('G12R', 'Mutation', 'rs121913530', (166, 170))	('G12S', 'Mutation', 'rs121913530', (160, 164))	('G12C', 'Mutation', 'rs121913530', (172, 176))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('NRAS', 'Gene', (363, 367))	('BRAF', 'Gene', '673', (402, 406))	('T790M', 'Mutation', 'rs121434569', (224, 229))	('BRAF', 'Gene', (402, 406))	('EGFR', 'Gene', (212, 216))	('V600E', 'Mutation', 'rs113488022', (246, 251))	('G12V', 'Mutation', 'rs121913529', (190, 194))	('Cancer', 'Disease', (0, 6))	('EGFR', 'Gene', (379, 383))	('mutation', 'Var', (522, 530))	('G12A', 'Mutation', 'rs121913529', (184, 188))	('BRAF', 'Gene', '673', (241, 245))
617063	29492209	The mix contained 20 ng of genomic DNA from microdissected cells, 10 microl of So Fast Eva Green Supermix (Bio Rad), 1 microl of EGFR probes (Hs00538812-cn, Life Technologies, Foster City, USA) and 1microl RnaseP probes (Taqman  copy number Reference Assay, 4403326, Life Technologies) per well and the final volume for the reaction was 20 mul.	('Rad', 'Gene', '6236', (111, 114))	('Rad', 'Gene', (111, 114))	('Hs00538812-cn', 'Var', (142, 155))	('EGFR', 'Gene', '1956', (129, 133))	('EGFR', 'Gene', (129, 133))
617067	29492209	For the ddPCR, the following probes were used: EGFR (Hs01076090-m1), SNAIL1 (Hs00195591-m1), SNAIL2 (Hs00950344-m1), Twist 1 (Hs01675818-s1), Twist 2 (Hs02379973-s1), Zeb1 (Hs00232783-m1), Zeb2 (Hs00207691-m1), and E-Cadherin (Hs01023894, all from Life Technologies).	('Twist 1', 'Gene', '7291', (117, 124))	('E-Cadherin', 'Gene', '999', (215, 225))	('Hs01076090-m1', 'Var', (53, 66))	('EGFR', 'Gene', '1956', (47, 51))	('SNAIL2', 'Gene', '6591', (93, 99))	('SNAIL2', 'Gene', (93, 99))	('SNAIL1', 'Gene', '6615', (69, 75))	('Hs00232783-m1', 'Var', (173, 186))	('Hs00195591-m1', 'Var', (77, 90))	('Twist 1', 'Gene', (117, 124))	('Twist 2', 'Gene', '117581', (142, 149))	('E-Cadherin', 'Gene', (215, 225))	('Hs00950344-m1', 'Var', (101, 114))	('Twist 2', 'Gene', (142, 149))	('EGFR', 'Gene', (47, 51))	('Zeb1', 'Gene', '6935', (167, 171))	('Hs02379973-s1', 'Var', (151, 164))	('Hs01675818-s1', 'Var', (126, 139))	('Zeb2', 'Gene', (189, 193))	('Zeb2', 'Gene', '9839', (189, 193))	('SNAIL1', 'Gene', (69, 75))	('Hs00207691-m1', 'Var', (195, 208))	('Zeb1', 'Gene', (167, 171))
617117	24950699	Gene expression identifies heterogeneity of metastatic behavior among high-grade non-translocation associated soft tissue sarcomas The biologic heterogeneity of soft tissue sarcomas (STS), even within histological subtypes, complicates treatment.	('soft tissue sarcomas', 'Disease', (161, 181))	('STS', 'Phenotype', 'HP:0030448', (183, 186))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (110, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('sarcomas', 'Disease', (122, 130))	('soft tissue sarcomas', 'Disease', (110, 130))	('sarcomas', 'Disease', 'MESH:D012509', (173, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('non-translocation', 'Var', (81, 98))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (161, 181))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (161, 180))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (110, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (173, 181))	('sarcomas', 'Disease', 'MESH:D012509', (122, 130))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (161, 181))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (110, 130))	('sarcomas', 'Disease', (173, 181))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
617122	24950699	One category has simple genomic profiles and specific cytogenetic changes, such as a point mutation or translocation (for example SYT-SSX in synovial sarcoma).	('point mutation', 'Var', (85, 99))	('SYT', 'Gene', '6760', (130, 133))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (141, 157))	('synovial sarcoma', 'Disease', 'MESH:D013584', (141, 157))	('translocation', 'Var', (103, 116))	('SYT', 'Gene', (130, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('synovial sarcoma', 'Disease', (141, 157))
617128	24950699	A recent study identified a set of 67 genes involved in mitosis and chromosome integrity, termed the complexity index in sarcomas (CINSARC), that can predict metastasis outcome in non-translocation dependent STS and also synovial sarcoma.	('mitosis', 'Disease', (56, 63))	('non-translocation dependent', 'Var', (180, 207))	('sarcomas', 'Disease', 'MESH:D012509', (121, 129))	('mitosis', 'Disease', 'None', (56, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (221, 237))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('STS', 'Phenotype', 'HP:0030448', (208, 211))	('synovial sarcoma', 'Disease', 'MESH:D013584', (221, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('sarcomas', 'Disease', (121, 129))	('predict', 'Reg', (150, 157))	('synovial sarcoma', 'Disease', (221, 237))
617152	24950699	In the current study, 309 cases of four histologic subtypes (LipoD, UPS, LMS, OTH) of non-translocation associated soft tissue sarcoma (STS) were separated into subsets with different probability of metastasis using gene sets derived from our earlier studies with ccRCC, AF, and OVCA.	('non-translocation', 'Var', (86, 103))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (115, 134))	('OVCA', 'Phenotype', 'HP:0025318', (279, 283))	('LMS', 'Phenotype', 'HP:0100243', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (266, 269))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('STS', 'Phenotype', 'HP:0030448', (136, 139))	('sarcoma', 'Disease', (127, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))
617186	24950699	Over-expression of SCARA5 suppressed some malignant behaviors in hepatoma cells, and SCARA5 knockdown was associated with activation of MMP9.	('SCARA5', 'Gene', '286133', (85, 91))	('SCARA5', 'Gene', (85, 91))	('SCARA5', 'Gene', (19, 25))	('suppressed', 'NegReg', (26, 36))	('hepatoma', 'Disease', 'MESH:D006528', (65, 73))	('knockdown', 'Var', (92, 101))	('malignant behaviors in', 'CPA', (42, 64))	('SCARA5', 'Gene', '286133', (19, 25))	('hepatoma', 'Disease', (65, 73))	('MMP9', 'Gene', (136, 140))	('MMP9', 'Gene', '4318', (136, 140))
617192	24950699	High STEAP1 expression in Ewing sarcoma has been reported to be associated with an improved outcome.	('STEAP1', 'Gene', '26872', (5, 11))	('Ewing sarcoma', 'Disease', (26, 39))	('STEAP1', 'Gene', (5, 11))	('High', 'Var', (0, 4))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (26, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (26, 39))	('expression', 'MPA', (12, 22))
617198	24950699	Over-expression of RRM2 has been reported to enhance the metastatic potential of some tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('enhance', 'PosReg', (45, 52))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('RRM2', 'Gene', '6241', (19, 23))	('Over-expression', 'Var', (0, 15))	('RRM2', 'Gene', (19, 23))
617212	23531088	The results showed that there was a variable Ki67 index in all 65 cases of nodular fasciitis, and the mean labeling index was 23.71+-15.01%.	('fasciitis', 'Phenotype', 'HP:0100537', (83, 92))	('Ki67', 'Chemical', '-', (45, 49))	('Ki67', 'Var', (45, 49))	('nodular fasciitis', 'Disease', 'MESH:D020518', (75, 92))	('nodular fasciitis', 'Disease', (75, 92))
617214	23531088	The Ki67 proliferative index was closely related to duration of lesion, but not to age distribution, lesion size, sites of lesions and gender.	('Ki67', 'Var', (4, 8))	('Ki67', 'Chemical', '-', (4, 8))	('related', 'Reg', (41, 48))
617222	23531088	Recently USP6 rearrangement and MYH9-USP6 gene fusions have been identified in a high percentage of NF suggestive that this is the driving translocation.	('rearrangement', 'Var', (14, 27))	('USP6', 'Gene', '9098', (9, 13))	('men', 'Species', '9606', (23, 26))	('MYH9', 'Gene', '4627', (32, 36))	('USP6', 'Gene', (9, 13))	('USP6', 'Gene', (37, 41))	('USP6', 'Gene', '9098', (37, 41))	('MYH9', 'Gene', (32, 36))
617256	23531088	Ki67 antigen is a marker of proliferating cells, and is rapidly degraded after mitosis.	('mitosis', 'Disease', 'None', (79, 86))	('Ki67', 'Chemical', '-', (0, 4))	('Ki67', 'Var', (0, 4))	('mitosis', 'Disease', (79, 86))	('degraded', 'NegReg', (64, 72))
617337	33629020	Auto-transplantation can raise the survival from malignant PCTs but has about a 15% perioperative mortality.	('raise', 'PosReg', (25, 30))	('Auto-transplantation', 'Var', (0, 20))	('mortality', 'Disease', (98, 107))	('mortality', 'Disease', 'MESH:D003643', (98, 107))
617353	29402700	Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('Aberrant organisation', 'Var', (0, 21))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('tumour', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('correlated', 'Reg', (38, 48))
617361	29402700	Genetic alterations in tumours occur on many different levels, ranging from single nucleotide changes and gene amplifications, to chromosome translocations and loss or gain of whole chromosomes.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('gain', 'PosReg', (168, 172))	('loss', 'NegReg', (160, 164))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('tumours', 'Disease', (23, 30))	('gene amplifications', 'Var', (106, 125))	('chromosome translocations', 'Var', (130, 155))	('single nucleotide changes', 'Var', (76, 101))
617362	29402700	Abnormal chromosome number is associated with poor prognosis in many common cancer types.	('Abnormal chromosome number', 'Phenotype', 'HP:0031411', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Abnormal chromosome number', 'Var', (0, 26))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
617367	29402700	We have previously shown that image patterns associated with aberrant chromatin organisation is associated with poor prognosis in many cancers, but none of the developed markers are suitable for validation on external cohorts of different cancer types.	('aberrant', 'Var', (61, 69))	('cancer', 'Disease', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', (239, 245))	('image', 'MPA', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
617369	29402700	Validation of the chromatin heterogeneity marker, termed Nucleotyping, in external cohorts shows that chromatin heterogeneity predicts cancer-specific survival of patients with colorectal cancer, ovarian carcinoma, uterine sarcoma, and endometrial cancer independently of established prognostic markers.	('sarcoma', 'Disease', (223, 230))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('chromatin', 'Var', (102, 111))	('predicts', 'Reg', (126, 134))	('endometrial cancer', 'Phenotype', 'HP:0012114', (236, 254))	('cancer', 'Disease', (248, 254))	('colorectal cancer', 'Disease', (177, 194))	('cancer', 'Disease', (135, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rectal cancer', 'Phenotype', 'HP:0100743', (181, 194))	('endometrial cancer', 'Disease', (236, 254))	('endometrial cancer', 'Disease', 'MESH:D016889', (236, 254))	('patients', 'Species', '9606', (163, 171))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (215, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (196, 213))	('cancer', 'Disease', (188, 194))	('ovarian carcinoma', 'Disease', (196, 213))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (196, 213))	('sarcoma', 'Disease', 'MESH:D012509', (223, 230))
617371	29402700	Implications of all the available evidence The generic utility of Nucleotyping warrants study of its molecular basis and suggests that it could enhance selection of patients for adjuvant treatment.	('patients', 'Species', '9606', (165, 173))	('Nucleotyping', 'Var', (66, 78))	('enhance', 'PosReg', (144, 151))
617408	29402700	After rehydration, the sections were enzymatically digested at room temperature at 200 rotations per min (rpm) for 70 min (for colorectal and prostate specimens) or 60 min (for other specimens) with 0 5 mg/mL protease (Sigma protease type XXIV [P5380] or type VIII [P8038]; Sigma Chemical, St Louis, MO, USA) to disaggregate the cells.	('VIII', 'Gene', '1351', (260, 264))	('[P5380]', 'Var', (244, 251))	('VIII', 'Gene', (260, 264))	('colorectal', 'Disease', 'MESH:D015179', (127, 137))	('colorectal', 'Disease', (127, 137))
617429	29402700	In an average chromatin heterogeneous tumour, 63% (IQR 52-73) of the nuclei expressed aberrant chromatin patterns.	('expressed', 'Reg', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('aberrant', 'Var', (86, 94))	('tumour', 'Disease', (38, 44))
617456	29402700	Cancer-specific survival was shorter in patients with chromatin heterogeneous tumours than in those with chromatin homogeneous tumour (HR 2 2, 95% CI 1 1-4 5 in univariable analysis; 2 6, 1 2-5 6 in multivariable analysis; figure 3C; table 2; appendix p 12).	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('patients', 'Species', '9606', (40, 48))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('chromatin heterogeneous', 'Var', (54, 77))	('tumour', 'Disease', (78, 84))	('tumours', 'Disease', (78, 85))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('p 12', 'Gene', (252, 256))	('shorter', 'NegReg', (29, 36))	('tumour', 'Disease', (127, 133))	('Cancer-specific survival', 'CPA', (0, 24))	('p 12', 'Gene', '56655', (252, 256))
617458	29402700	5-year cancer-specific survival was 94% (95% CI 90-97) for patients with chromatin homogeneous tumours (13 [5%] deaths out of 244 patients) and 88% (80-92) for patients with chromatin heterogeneous tumours (16 [11%] deaths out of 147 patients).	('death', 'Disease', (112, 117))	('death', 'Disease', 'MESH:D003643', (216, 221))	('tumours', 'Disease', (95, 102))	('patients', 'Species', '9606', (234, 242))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Disease', (7, 13))	('death', 'Disease', 'MESH:D003643', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumours', 'Disease', (198, 205))	('patients', 'Species', '9606', (130, 138))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('chromatin', 'Var', (73, 82))	('patients', 'Species', '9606', (160, 168))	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('tumours', 'Disease', 'MESH:D009369', (198, 205))	('death', 'Disease', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
617459	29402700	In a pooled analysis of all three colorectal cancer cohorts, chromatin heterogeneity was independent of sex, stage (II vs I), and pathological tumour stage (T4 vs T3 vs T2 vs T1; appendix p 13).	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('p 13', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('colorectal cancer', 'Disease', (34, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))	('rectal cancer', 'Phenotype', 'HP:0100743', (38, 51))	('tumour', 'Disease', (143, 149))	('T4', 'Var', (157, 159))	('p 13', 'Gene', '440926', (188, 192))
617461	29402700	Similar weak correlations were found for age, histological grade, microsatellite stability, and surgery type (appendix p 13).	('p 13', 'Gene', '440926', (119, 123))	('microsatellite', 'Var', (66, 80))	('p 13', 'Gene', (119, 123))
617463	29402700	Chromatin heterogeneity predicted cancer-specific survival more accurately than microsatellite stability status (stable vs unstable) and provided prognostic information for patients with microsatellite unstable and microsatellite stable stage II colorectal cancer (figure 5; appendix p 14).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('stage II colorectal cancer', 'Disease', 'MESH:D015179', (237, 263))	('p 14', 'Gene', (284, 288))	('predicted', 'Reg', (24, 33))	('p 14', 'Gene', '11102', (284, 288))	('patients', 'Species', '9606', (173, 181))	('rectal cancer', 'Phenotype', 'HP:0100743', (250, 263))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('microsatellite', 'Var', (187, 201))	('stage II colorectal cancer', 'Disease', (237, 263))	('appendix p 14', 'Phenotype', 'HP:0002825', (275, 288))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('colorectal cancer', 'Phenotype', 'HP:0003003', (246, 263))	('cancer', 'Disease', (257, 263))
617464	29402700	In a multivariable model with microsatellite stability status, cancer-specific survival was shorter in patients with stage II colorectal cancer with chromatin heterogeneous tumours compared with patients with chromatin homogeneous tumours (HR 1 9, 95% CI 1 3-2 8).	('chromatin heterogeneous', 'Var', (149, 172))	('stage II colorectal cancer', 'Disease', 'MESH:D015179', (117, 143))	('cancer', 'Disease', (137, 143))	('shorter', 'NegReg', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumours', 'Disease', (231, 238))	('patients', 'Species', '9606', (195, 203))	('cancer', 'Disease', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('tumours', 'Disease', (173, 180))	('tumours', 'Disease', 'MESH:D009369', (231, 238))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('stage II colorectal cancer', 'Disease', (117, 143))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('rectal cancer', 'Phenotype', 'HP:0100743', (130, 143))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('patients', 'Species', '9606', (103, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
617467	29402700	Patients with chromatin heterogeneous tumours had shorter cancer-specific survival than those with chromatin homogeneous tumours (figure 3D).	('tumours', 'Disease', (38, 45))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumours', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('shorter', 'NegReg', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('cancer', 'Disease', (58, 64))	('chromatin heterogeneous', 'Var', (14, 37))
617468	29402700	5-year cancer-specific survival was 88% (95% CI 82-92) for patients with chromatin homogeneous tumours (21 [12%] deaths out of 169 patients) and 68% (56-77) for patients with chromatin heterogeneous tumours (25 [32%] deaths out of 77 patients).	('death', 'Disease', (113, 118))	('death', 'Disease', 'MESH:D003643', (217, 222))	('tumours', 'Disease', (95, 102))	('patients', 'Species', '9606', (234, 242))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Disease', (7, 13))	('tumours', 'Disease', (199, 206))	('patients', 'Species', '9606', (131, 139))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('death', 'Disease', 'MESH:D003643', (113, 118))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('patients', 'Species', '9606', (161, 169))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('chromatin', 'Var', (73, 82))	('death', 'Disease', (217, 222))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
617470	29402700	Chromatin heterogeneity predicted 5-year cancer-specific survival in univariable analysis (figure 3E), performed consistently across a range of clinicopathological subgroups, and was significant in multivariable analyses (table 2; appendix pp 16, 25).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('predicted', 'Reg', (24, 33))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('Chromatin heterogeneity', 'Var', (0, 23))
617471	29402700	Chromatin heterogeneity remained prognostic in both univariable (HR 2 4, 95% CI 1 8-3 1) and multivariable (1 4, 1 0-2 0) analysis of cancer-specific survival, also when missing data were imputed.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (134, 140))	('Chromatin heterogeneity', 'Var', (0, 23))
617472	29402700	5-year cancer-specific survival was 67% (95% CI 61-74) for patients with chromatin homogeneous tumours (65 [32%] deaths out of 201 patients) and 35% (28-43) for patients with chromatin heterogeneous tumours (97 [63%] deaths out of 153 patients).	('death', 'Disease', (113, 118))	('patients', 'Species', '9606', (235, 243))	('death', 'Disease', 'MESH:D003643', (217, 222))	('tumours', 'Disease', (95, 102))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Disease', (7, 13))	('tumours', 'Disease', (199, 206))	('patients', 'Species', '9606', (131, 139))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('death', 'Disease', 'MESH:D003643', (113, 118))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('patients', 'Species', '9606', (161, 169))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('chromatin', 'Var', (73, 82))	('death', 'Disease', (217, 222))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
617475	29402700	5-year cancer-specific survival was 99% (95% CI 96-100) for patients with chromatin homogeneous tumours (three [1%] deaths out of 252 patients) versus 94% (83-98) for patients with chromatin heterogeneous tumours (three [5%] deaths out of 55 patients).	('death', 'Disease', 'MESH:D003643', (116, 121))	('patients', 'Species', '9606', (134, 142))	('death', 'Disease', 'MESH:D003643', (225, 230))	('tumours', 'Disease', (96, 103))	('patients', 'Species', '9606', (242, 250))	('patients', 'Species', '9606', (60, 68))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Disease', (7, 13))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('chromatin homogeneous', 'Var', (74, 95))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('death', 'Disease', (116, 121))	('tumours', 'Disease', (205, 212))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('death', 'Disease', (225, 230))	('tumours', 'Disease', 'MESH:D009369', (205, 212))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))
617477	29402700	Patients with chromatin heterogeneous tumours had shorter cancer-specific survival than those with chromatin homogeneous tumours (figure 3G).	('tumours', 'Disease', (38, 45))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumours', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('shorter', 'NegReg', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('cancer', 'Disease', (58, 64))	('chromatin heterogeneous', 'Var', (14, 37))
617478	29402700	5-year cancer-specific survival was 90% (95% CI 86-92) for patients with chromatin homogeneous tumours (50 [7%] deaths out of 673 patients) and 62% (49-72) for patients with chromatin heterogeneous tumours (32 [27%] deaths out of 118 patients).	('death', 'Disease', (112, 117))	('death', 'Disease', 'MESH:D003643', (216, 221))	('tumours', 'Disease', (95, 102))	('patients', 'Species', '9606', (234, 242))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Disease', (7, 13))	('death', 'Disease', 'MESH:D003643', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumours', 'Disease', (198, 205))	('patients', 'Species', '9606', (130, 138))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('chromatin', 'Var', (73, 82))	('patients', 'Species', '9606', (160, 168))	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('tumours', 'Disease', 'MESH:D009369', (198, 205))	('death', 'Disease', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
617489	29402700	Diploid chromatin homogeneous tumours were associated with longer cancer-specific survival than were non-diploid chromatin homogeneous tumours in all cohorts, whereas patients with chromatin heterogeneous tumours consistently had the worst survival (appendix p 22).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('p 22', 'Gene', '11331', (259, 263))	('Diploid chromatin homogeneous', 'Var', (0, 29))	('longer', 'PosReg', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('p 22', 'Gene', (259, 263))	('tumours', 'Disease', (205, 212))	('tumours', 'Disease', (135, 142))	('tumours', 'Disease', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('tumours', 'Disease', 'MESH:D009369', (205, 212))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('patients', 'Species', '9606', (167, 175))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (66, 72))
617507	29402700	Our data suggest that patients with chromatin heterogeneous tumours have poor cancer-specific survival irrespective of microsatellite stability status, and the slight difference in mortality between microsatellite unstable and microsatellite stable tumours in patients with chromatin homogeneous tumours was not significant.	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (249, 256))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumours', 'Phenotype', 'HP:0002664', (296, 303))	('tumours', 'Disease', 'MESH:D009369', (296, 303))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (249, 256))	('microsatellite stable tumours', 'Disease', 'MESH:D053842', (227, 256))	('tumours', 'Disease', 'MESH:D009369', (249, 256))	('patients', 'Species', '9606', (22, 30))	('tumour', 'Phenotype', 'HP:0002664', (296, 302))	('patients', 'Species', '9606', (260, 268))	('microsatellite stable tumours', 'Disease', (227, 256))	('poor', 'NegReg', (73, 77))	('microsatellite', 'Var', (199, 213))	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Disease', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumours', 'Disease', (60, 67))	('tumours', 'Disease', (296, 303))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
617516	29402700	In conclusion, our results indicate that chromatin heterogeneity behaves similarly in several human cancers and identifies patients at increased risk of cancer-specific death, independently of established prognostic markers, and could possibly aid clinical decision making around use of adjuvant or neoadjuvant therapy.	('death', 'Disease', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('chromatin', 'Var', (41, 50))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Disease', (153, 159))	('aid', 'Reg', (244, 247))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('human', 'Species', '9606', (94, 99))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('death', 'Disease', 'MESH:D003643', (169, 174))	('cancers', 'Disease', (100, 107))
617527	28424409	Of the 95 biopsy samples with identifiable genomic alterations, the most commonly affected genes were TP53 (31.4%), CDK4 (23.5%), MDM2 (21.6%), RB1 (18.6%), and CDKN2A/B (13.7%).	('alterations', 'Var', (51, 62))	('CDKN2A/B', 'Gene', (161, 169))	('TP53', 'Gene', (102, 106))	('affected', 'Reg', (82, 90))	('MDM2', 'Gene', '4193', (130, 134))	('RB1', 'Gene', '5925', (144, 147))	('MDM2', 'Gene', (130, 134))	('CDK4', 'Gene', '1019', (116, 120))	('CDK4', 'Gene', (116, 120))	('CDKN2A/B', 'Gene', '1029;1030', (161, 169))	('TP53', 'Gene', '7157', (102, 106))	('RB1', 'Gene', (144, 147))
617533	28424409	Over the last three decades recurrent translocations have been found that drive the development of certain sarcomas and are now used as an adjunctive diagnostic tool.	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('drive', 'PosReg', (74, 79))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('men', 'Species', '9606', (91, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('sarcomas', 'Disease', (107, 115))	('translocations', 'Var', (38, 52))
617536	28424409	A notable exception is non-fusion genomic alterations in kinases, with gastrointestinal stromal tumors serving as the paradigm of druggable c-Kit alterations by imatinib.	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (71, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('c-Kit', 'Gene', (140, 145))	('c-Kit', 'Gene', '3815', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('gastrointestinal stromal tumors', 'Disease', (71, 102))	('kinases', 'Enzyme', (57, 64))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (71, 102))	('imatinib', 'Chemical', 'MESH:D000068877', (161, 169))	('genomic alterations', 'Var', (34, 53))
617556	28424409	All 22 of these patients also had CDK4 amplifications.	('patients', 'Species', '9606', (16, 24))	('CDK4', 'Gene', '1019', (34, 38))	('amplifications', 'Var', (39, 53))	('CDK4', 'Gene', (34, 38))
617560	28424409	Other notable mutations include three FRS2 and FGF co-amplifications seen in a rhabdomyosarcoma, osteosarcoma, and dedifferentiated liposarcoma.	('FRS2', 'Gene', (38, 42))	('co-amplifications', 'Var', (51, 68))	('liposarcoma', 'Disease', 'MESH:D008080', (132, 143))	('FGF', 'Gene', (47, 50))	('liposarcoma', 'Phenotype', 'HP:0012034', (132, 143))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (79, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('FRS2', 'Gene', '10818', (38, 42))	('osteosarcoma', 'Disease', (97, 109))	('osteosarcoma', 'Disease', 'MESH:D012516', (97, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (136, 143))	('rhabdomyosarcoma', 'Disease', (79, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('mutations', 'Var', (14, 23))	('liposarcoma', 'Disease', (132, 143))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (79, 95))
617562	28424409	We also identified previously reported fusions of SSX with SS18 in synovial sarcoma, as well as HMGA2 in liposarcoma.	('liposarcoma', 'Disease', (105, 116))	('SS18', 'Gene', '6760', (59, 63))	('SSX', 'Gene', (50, 53))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (67, 83))	('synovial sarcoma', 'Disease', 'MESH:D013584', (67, 83))	('SSX', 'Gene', '727837', (50, 53))	('fusions', 'Var', (39, 46))	('liposarcoma', 'Disease', 'MESH:D008080', (105, 116))	('HMGA2', 'Gene', '8091', (96, 101))	('liposarcoma', 'Phenotype', 'HP:0012034', (105, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('SS18', 'Gene', (59, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('HMGA2', 'Gene', (96, 101))	('synovial sarcoma', 'Disease', (67, 83))
617563	28424409	Three of the leiomyosarcomas had a mutation in the Lynch syndrome gene MSH2 (two uterine and one non-uterine).	('Lynch syndrome', 'Disease', (51, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('MSH2', 'Gene', '4436', (71, 75))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (13, 28))	('Lynch syndrome', 'Disease', 'MESH:D003123', (51, 65))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (13, 28))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (13, 27))	('leiomyosarcomas', 'Disease', (13, 28))	('mutation', 'Var', (35, 43))	('MSH2', 'Gene', (71, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (20, 28))
617573	28424409	As noted above, dedifferentiated/well-differentiated liposarcomas had a preponderance of MDM2 and CDK4 mutations.	('mutations', 'Var', (103, 112))	('liposarcomas', 'Disease', 'MESH:D008080', (53, 65))	('liposarcomas', 'Phenotype', 'HP:0012034', (53, 65))	('liposarcoma', 'Phenotype', 'HP:0012034', (53, 64))	('CDK4', 'Gene', (98, 102))	('liposarcomas', 'Disease', (53, 65))	('MDM2', 'Gene', '4193', (89, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('MDM2', 'Gene', (89, 93))	('CDK4', 'Gene', '1019', (98, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
617574	28424409	Carcinosarcomas had targetable mutations in AKT2 and harbored a resistance mutation in ESR1 (Table 3).	('mutations', 'Var', (31, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (7, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (7, 15))	('ESR1', 'Gene', (87, 91))	('AKT2', 'Gene', (44, 48))	('Carcinosarcomas', 'Disease', 'MESH:D002296', (0, 15))	('AKT2', 'Gene', '208', (44, 48))	('resistance', 'MPA', (64, 74))	('ESR1', 'Gene', '2099', (87, 91))	('Carcinosarcomas', 'Disease', (0, 15))
617586	28424409	One of the most frequent mutations seen in our cohort was MDM2 amplification.	('MDM2', 'Gene', (58, 62))	('amplification', 'Var', (63, 76))	('MDM2', 'Gene', '4193', (58, 62))
617591	28424409	However, our small dataset suggests that such trials should be opened to all sarcoma subtypes and based on CGP rather than histology due to the occurrence of previously unreported mutations in the subtypes mentioned above.	('mutations', 'Var', (180, 189))	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('sarcoma', 'Disease', (77, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('men', 'Species', '9606', (206, 209))
617601	28424409	Successful treatment has been reported with PD-1 inhibitors in MSI-high colon cancer resulting in long-term disease control where chemotherapy had not been effective.	('PD-1', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('men', 'Species', '9606', (16, 19))	('MSI-high colon cancer', 'Disease', (63, 84))	('inhibitors', 'Var', (49, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (72, 84))	('MSI-high colon cancer', 'Disease', 'MESH:D015179', (63, 84))
617602	28424409	MSH mutations have been reported in sarcomas previously, especially in uterine sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('MSH', 'Gene', (0, 3))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('reported', 'Reg', (24, 32))	('MSH', 'Gene', '4488', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('sarcomas', 'Disease', (79, 87))	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('mutations', 'Var', (4, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('sarcomas', 'Disease', (36, 44))
617606	28424409	We report significantly fewer actionable mutations (61%) than previous studies of other cancers (>90%) and this may be related to the fusion proteins-associated sarcomas which comprise approximately 30% of all sarcomas.	('fusion proteins-associated', 'Protein', (134, 160))	('mutations', 'Var', (41, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (210, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('sarcomas', 'Disease', (161, 169))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('sarcomas', 'Disease', (210, 218))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('sarcomas', 'Disease', 'MESH:D012509', (210, 218))	('fewer', 'NegReg', (24, 29))
617607	28424409	Furthermore, this may suggest that many sarcomas are driven by copy number alterations rather than somatic mutations.	('sarcomas', 'Disease', 'MESH:D012509', (40, 48))	('copy number alterations', 'Var', (63, 86))	('sarcomas', 'Phenotype', 'HP:0100242', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('driven by', 'Reg', (53, 62))	('sarcomas', 'Disease', (40, 48))
617612	28424409	As in (Table 2) several patients with MDM2 aberration benefitted clinically from MDM2 inhibitors in early phase clinical trials.	('MDM2', 'Gene', '4193', (81, 85))	('MDM2', 'Gene', (81, 85))	('MDM2', 'Gene', '4193', (38, 42))	('benefitted', 'Reg', (54, 64))	('MDM2', 'Gene', (38, 42))	('patients', 'Species', '9606', (24, 32))	('aberration', 'Var', (43, 53))
617613	28424409	Clinical trials are underway in liposarcoma using MDM2 inhibitors either singly or in combination with CDK4 inhibitors.	('MDM2', 'Gene', (50, 54))	('CDK4', 'Gene', '1019', (103, 107))	('liposarcoma', 'Disease', (32, 43))	('liposarcoma', 'Disease', 'MESH:D008080', (32, 43))	('liposarcoma', 'Phenotype', 'HP:0012034', (32, 43))	('inhibitors', 'Var', (55, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('CDK4', 'Gene', (103, 107))	('MDM2', 'Gene', '4193', (50, 54))
617634	24723486	Distinct Transcriptional Signature and Immunoprofile of CIC-DUX4-Fusion Positive Round Cell Tumors Compared to EWSR1-Rearranged Ewing Sarcomas - Further Evidence Toward Distinct Pathologic Entities Round cell sarcomas harboring CIC-DUX4 fusions have recently been described as highly aggressive soft tissue tumors of children and young adults.	('Cell Tumors', 'Disease', (87, 98))	('Ewing Sarcomas', 'Disease', 'MESH:C563168', (128, 142))	('CIC', 'Gene', (56, 59))	('CIC', 'Gene', (228, 231))	('Tumors', 'Phenotype', 'HP:0002664', (92, 98))	('DUX4', 'Gene', '100288687', (232, 236))	('soft tissue tumors', 'Disease', (295, 313))	('Ewing Sarcomas', 'Disease', (128, 142))	('EWSR1', 'Gene', '2130', (111, 116))	('Cell Tumors', 'Disease', 'MESH:D005935', (87, 98))	('tumors', 'Phenotype', 'HP:0002664', (307, 313))	('DUX4', 'Gene', (60, 64))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (295, 313))	('CIC', 'Gene', '23152', (56, 59))	('CIC', 'Gene', '23152', (228, 231))	('children', 'Species', '9606', (317, 325))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('Sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('soft tissue tumors', 'Disease', 'MESH:D012983', (295, 313))	('sarcomas', 'Disease', 'MESH:D012509', (209, 217))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('DUX4', 'Gene', '100288687', (60, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (209, 217))	('sarcomas', 'Disease', (209, 217))	('EWSR1', 'Gene', (111, 116))	('fusions', 'Var', (237, 244))	('Ewing Sarcomas', 'Phenotype', 'HP:0012254', (128, 142))	('DUX4', 'Gene', (232, 236))
617648	24723486	We and others recently described a series of USTS with primitive round cell morphology harboring a novel gene fusion, CIC-DUX4, resulting from either t(4;19)(q35;q13) or a t(10;19)(q26;q13).	('CIC', 'Gene', '23152', (118, 121))	('DUX4', 'Gene', (122, 126))	('DUX4', 'Gene', '100288687', (122, 126))	('t(10;19)(q26;q13', 'Var', (172, 188))	('CIC', 'Gene', (118, 121))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (172, 189))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (150, 166))	('t(4;19)(q35;q13', 'Var', (150, 165))
617654	24723486	A total of 33 round cell USTS lacking EWSR1 gene rearrangements (or other common sarcoma-associated translocations) were identified.	('rearrangements', 'Var', (49, 63))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('EWSR1', 'Gene', '2130', (38, 43))	('EWSR1', 'Gene', (38, 43))	('sarcoma', 'Disease', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('lacking', 'NegReg', (30, 37))
617662	24723486	Total RNA from fresh-frozen tissue extracted from 5 CIC-DUX4 positive tumors, two with t(4;19)(q35;q13) and three with t(10;19)(q26;q13) translocation, was labeled and hybridized onto an Affymetrix U133A chip (22,000 transcripts), as previously described.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CIC', 'Gene', (52, 55))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (87, 103))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (119, 136))	('tumors', 'Disease', (70, 76))	('DUX4', 'Gene', (56, 60))	('t(4;19)(q35;q13', 'Var', (87, 102))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('DUX4', 'Gene', '100288687', (56, 60))	('CIC', 'Gene', '23152', (52, 55))
617671	24723486	Gene expression was assessed using RealTime ready single assays (Roche Diagnostics) for the target genes ETV1 (ID 140599), ETV4 (ID 137042), ETV5 (ID 127143) and the housekeeping gene ACTB (ID 101125).	('ID 127143', 'Var', (147, 156))	('ACTB', 'Gene', (184, 188))	('ETV4', 'Gene', (123, 127))	('ETV1', 'Gene', '2115', (105, 109))	('ACTB', 'Gene', '60', (184, 188))	('ETV5', 'Gene', (141, 145))	('ID 140599', 'Var', (111, 120))	('ETV4', 'Gene', '2118', (123, 127))	('ID 137042', 'Var', (129, 138))	('ETV1', 'Gene', (105, 109))	('ETV5', 'Gene', '2119', (141, 145))
617674	24723486	Subsequent FISH analysis confirmed the fusion of CIC with the DUX4 gene in either chromosome band 4q35 in 9 cases or in 10q26.3 in 6 cases.	('CIC', 'Gene', (49, 52))	('DUX4', 'Gene', (62, 66))	('DUX4', 'Gene', '100288687', (62, 66))	('CIC', 'Gene', '23152', (49, 52))	('fusion', 'Var', (39, 45))
617710	24723486	Round cell sarcomas harboring a t(4;19)(q35;q13) or a t(10;19)(q26;q13) with CIC-DUX4 fusion are recently described aggressive tumors arising in soft tissues of children and young adults.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('DUX4', 'Gene', (81, 85))	('DUX4', 'Gene', '100288687', (81, 85))	('sarcomas', 'Disease', 'MESH:D012509', (11, 19))	('children', 'Species', '9606', (161, 169))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (54, 71))	('CIC', 'Gene', '23152', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('sarcomas', 'Disease', (11, 19))	('aggressive tumors', 'Disease', 'MESH:D001523', (116, 133))	('t(10;19)(q26;q13', 'Var', (54, 70))	('CIC', 'Gene', (77, 80))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (32, 48))	('t(4;19)(q35;q13', 'Var', (32, 47))	('aggressive tumors', 'Disease', (116, 133))
617715	24723486	identified the genes CIC in chromosome band 19q13 and DUX4 in 4q35 resulting from the t(4;19)(q35;q13) in two round cell sarcoma cases of adults.	('DUX4', 'Gene', '100288687', (54, 58))	('t(4;19)(q35;q13', 'Var', (86, 101))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (86, 102))	('sarcoma', 'Disease', (121, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('CIC', 'Gene', '23152', (21, 24))	('DUX4', 'Gene', (54, 58))	('CIC', 'Gene', (21, 24))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))
152584	24723486	CIC is the human homologue of Drosophila capicua, a gene identified in a screen for mutations affecting the anterior-posterior pattern of Drosophila embryos.	('capicua', 'Gene', (41, 48))	('human', 'Species', '9606', (11, 16))	('Drosophila', 'Species', '7227', (30, 40))	('mutations', 'Var', (84, 93))	('CIC', 'Gene', '23152', (0, 3))	('capicua', 'Gene', '53560', (41, 48))	('affecting', 'Reg', (94, 103))	('Drosophila', 'Species', '7227', (138, 148))	('CIC', 'Gene', (0, 3))
617749	24723486	CIC gene abnormalities have been implicated in neoplasia - for example, CIC loss of function mutations are identified in 83% of oligodendrogliomas.	('CIC gene abnormalities', 'Disease', 'MESH:D025063', (0, 22))	('neoplasia', 'Phenotype', 'HP:0002664', (47, 56))	('CIC gene abnormalities', 'Disease', (0, 22))	('oligodendrogliomas', 'Disease', (128, 146))	('mutations', 'Var', (93, 102))	('CIC loss', 'Disease', (72, 80))	('neoplasia', 'Disease', (47, 56))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (128, 146))	('neoplasia', 'Disease', 'MESH:D009369', (47, 56))	('CIC loss', 'Disease', 'MESH:D015431', (72, 80))
152591	24723486	Aberrant expression of DUX4 has been implicated in the development of facioscapulohumeral muscular dystrophy.	('DUX4', 'Gene', '100288687', (23, 27))	('Aberrant expression', 'Var', (0, 19))	('implicated', 'Reg', (37, 47))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (90, 108))	('muscular dystrophy', 'Disease', 'MESH:D009136', (90, 108))	('muscular dystrophy', 'Disease', (90, 108))	('DUX4', 'Gene', (23, 27))	('facioscapulohumeral muscular dystrophy', 'Phenotype', 'HP:0008970', (70, 108))
617752	24723486	Although the transcriptional profile of CIC-DUX4-positive sarcomas is distinct from that of ES and other sarcoma subtypes, in keeping with them being separate tumor entities, CIC-DUX4 fusion overexpresses three ETS transcription factors (ETV4, ETV1 and ETV5) from the PEA3 (polyoma enhancer activator 3) subfamily.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ETV1', 'Gene', '2115', (244, 248))	('ETV4', 'Gene', (238, 242))	('overexpresses', 'PosReg', (191, 204))	('sarcoma subtypes', 'Disease', 'MESH:D012509', (105, 121))	('CIC', 'Gene', '23152', (40, 43))	('PEA3 (polyoma enhancer activator 3', 'Gene', '2118', (268, 302))	('ETV5', 'Gene', '2119', (253, 257))	('sarcoma subtypes', 'Disease', (105, 121))	('CIC', 'Gene', '23152', (175, 178))	('fusion', 'Var', (184, 190))	('DUX4', 'Gene', (44, 48))	('CIC-DUX4-positive sarcomas', 'Disease', 'MESH:D012509', (40, 66))	('ETV4', 'Gene', '2118', (238, 242))	('DUX4', 'Gene', (179, 183))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('DUX4', 'Gene', '100288687', (44, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('DUX4', 'Gene', '100288687', (179, 183))	('ETV1', 'Gene', (244, 248))	('CIC-DUX4-positive sarcomas', 'Disease', (40, 66))	('ETV5', 'Gene', (253, 257))	('CIC', 'Gene', (40, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('ES', 'Phenotype', 'HP:0012254', (92, 94))	('CIC', 'Gene', (175, 178))
617755	24723486	In analogy to EWS/ETS fusion-positive Ewing sarcoma, one might speculate that CIC-DUX4 fusion induces an aberrant transcriptional program with deregulation of overlapping/converging or functionally similar key oncogenic target genes, thereby sharing a basic pathogenesis with Ewing sarcoma.	('DUX4', 'Gene', (82, 86))	('DUX4', 'Gene', '100288687', (82, 86))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (276, 289))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (276, 289))	('EWS', 'Gene', '2130', (14, 17))	('EWS', 'Gene', (14, 17))	('aberrant transcriptional program', 'MPA', (105, 137))	('CIC', 'Gene', '23152', (78, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('induces', 'Reg', (94, 101))	('Ewing sarcoma', 'Disease', (38, 51))	('deregulation', 'MPA', (143, 155))	('CIC', 'Gene', (78, 81))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (38, 51))	('fusion', 'Var', (87, 93))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (38, 51))	('Ewing sarcoma', 'Disease', (276, 289))
617759	24723486	Their results further revealed that fusion of DUX4 to CIC sequence provides strong transcriptional activity, resulting in mostly upregulated gene expression, with minimal down-regulated genes, in keeping with our own results.	('CIC', 'Gene', '23152', (54, 57))	('upregulated', 'PosReg', (129, 140))	('transcriptional activity', 'MPA', (83, 107))	('CIC', 'Gene', (54, 57))	('DUX4', 'Gene', (46, 50))	('gene expression', 'MPA', (141, 156))	('DUX4', 'Gene', '100288687', (46, 50))	('fusion', 'Var', (36, 42))
617767	23540691	Reversible Disruption of mSWI/SNF (BAF) Complexes by the SS18-SSX Oncogenic Fusion in Synovial Sarcoma Recent exon sequencing studies have revealed that over 19% of human tumors have mutations in subunits of mSWI/SNF (BAF) complexes.	('BAF', 'Gene', '8815', (35, 38))	('SS18', 'Gene', '6760', (57, 61))	('human', 'Species', '9606', (165, 170))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('mutations', 'Var', (183, 192))	('Sarcoma', 'Disease', (95, 102))	('Synovial Sarcoma', 'Phenotype', 'HP:0012570', (86, 102))	('Sarcoma', 'Disease', 'MESH:D012509', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('BAF', 'Gene', (35, 38))	('SS18', 'Gene', (57, 61))	('SSX', 'Gene', '6757', (62, 65))	('Sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('SSX', 'Gene', (62, 65))	('BAF', 'Gene', '8815', (218, 221))	('BAF', 'Gene', (218, 221))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
617772	23540691	Increasing the concentration of wildtype SS18 leads to reassembly of wildtype complexes retargeted away from the Sox2 locus, polycomb-mediated repression of Sox2 and cessation of proliferation.	('proliferation', 'CPA', (179, 192))	('Sox2', 'Gene', '6657', (113, 117))	('cessation', 'NegReg', (166, 175))	('reassembly', 'CPA', (55, 65))	('Sox2', 'Gene', '6657', (157, 161))	('SS18', 'Gene', (41, 45))	('Sox2', 'Gene', (113, 117))	('polycomb-mediated repression', 'Var', (125, 153))	('Sox2', 'Gene', (157, 161))
617775	23540691	This correlative aspect has emerged particularly from recent exon sequencing studies of human cancers, which have defined frequent mutations in chromatin regulators.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('mutations', 'Var', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
617778	23540691	This process is achieved by several mechanisms including DNA-methylation, histone modifications and ATP-dependent chromatin remodeling.	('DNA-methylation', 'Var', (57, 72))	('histone', 'MPA', (74, 81))	('ATP', 'Chemical', 'MESH:D000255', (100, 103))
617788	23540691	Recent exome sequencing studies of primary, early human cancers have repeatedly discovered mutations to subunits of polymorphic BAF complexes.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('BAF', 'Gene', '8815', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BAF', 'Gene', (128, 131))	('mutations', 'Var', (91, 100))	('human', 'Species', '9606', (50, 55))	('discovered', 'Reg', (80, 90))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
617789	23540691	Indeed, analysis of the 44 exome sequencing studies published to date indicate that 19.6% of all human cancers have mutations in at least one subunit (Kadoch et al., submitted).	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('human', 'Species', '9606', (97, 102))	('mutations', 'Var', (116, 125))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
617790	23540691	For example, BAF250a is mutated in 57% of clear cell ovarian cancers, BAF180 (polybromo) is mutated in 41% of renal cancers, and medulloblastomas have frequent mutations in Brg, BAF53a or BAF60b.	('BAF180', 'Gene', '55193', (70, 76))	('mutations', 'Var', (160, 169))	('clear cell ovarian cancers', 'Disease', 'MESH:D008649', (42, 68))	('BAF60b', 'Gene', (188, 194))	('BAF250a', 'Gene', (13, 20))	('Brg', 'Gene', (173, 176))	('BAF180', 'Gene', (70, 76))	('medulloblastomas', 'Disease', (129, 145))	('renal cancers', 'Disease', 'MESH:D007680', (110, 123))	('BAF53a', 'Gene', (178, 184))	('clear cell ovarian cancers', 'Disease', (42, 68))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('medulloblastomas', 'Disease', 'MESH:D008527', (129, 145))	('BAF53a', 'Gene', '86', (178, 184))	('ovarian cancers', 'Phenotype', 'HP:0100615', (53, 68))	('BAF250a', 'Gene', '8289', (13, 20))	('BAF60b', 'Gene', '6603', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('renal cancers', 'Disease', (110, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))
617793	23540691	Conditional biallelic inactivation of Snf5 in mouse models results in a fully penetrant phenotype with median onset to tumor development at only 11 weeks.	('tumor', 'Disease', (119, 124))	('Snf5', 'Gene', (38, 42))	('biallelic', 'Var', (12, 21))	('Snf5', 'Gene', '20587', (38, 42))	('mouse', 'Species', '10090', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('fully penetrant phenotype', 'MPA', (72, 97))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
617794	23540691	The preference for mutation of specific subunits in specific malignancies suggests that different combinatorial assemblies have roles in tissue-specific oncogenic processes, consistent with roles for specialized BAF complexes in neurogenesis and other biologic processes.	('roles', 'Reg', (128, 133))	('malignancies', 'Disease', 'MESH:D009369', (61, 73))	('mutation', 'Var', (19, 27))	('BAF', 'Gene', (212, 215))	('malignancies', 'Disease', (61, 73))	('BAF', 'Gene', '8815', (212, 215))
617795	23540691	Because of the possibility that the frequent BAF subunit mutations might be playing a relatively non-specific role in oncogenesis, we initiated studies on a cancer type, human synovial sarcoma (SS) where nearly all tumors have a precise translocation involving a specific subunit, indicating that the translocation is the initiating oncogenic event.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('BAF', 'Gene', '8815', (45, 48))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (176, 192))	('BAF', 'Gene', (45, 48))	('synovial sarcoma', 'Disease', 'MESH:D013584', (176, 192))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('translocation', 'MPA', (237, 250))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', (157, 163))	('subunit', 'Protein', (272, 279))	('human', 'Species', '9606', (170, 175))	('synovial sarcoma', 'Disease', (176, 192))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))
617797	23540691	A recurrent chromosomal translocation, t(X;18)(p11.2;q11.2) fuses the SS18 gene on chromosome 18 to one of three closely related genes on the X chromosome, SSX1, SSX2 and rarely SSX4, resulting in an in-frame fusion protein in which the eight C-terminal amino acids of SS18 are replaced with 78 amino acids from the SSX C-terminus.	('SSX', 'Gene', '6757', (156, 159))	('SSX', 'Gene', '6757', (178, 181))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (39, 59))	('SSX1', 'Gene', '6756', (156, 160))	('SSX', 'Gene', '6757', (162, 165))	('SSX1', 'Gene', (156, 160))	('SSX', 'Gene', (156, 159))	('SSX', 'Gene', (178, 181))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (2, 37))	('SSX2', 'Gene', (162, 166))	('SSX', 'Gene', (162, 165))	('fusion protein', 'MPA', (209, 223))	('fuses', 'Var', (60, 65))	('SSX', 'Gene', '6757', (316, 319))	('SSX2', 'Gene', '6757', (162, 166))	('SSX4', 'Gene', (178, 182))	('in-frame', 'Reg', (200, 208))	('SS18', 'Gene', (70, 74))	('SS18', 'Gene', (269, 273))	('SSX4', 'Gene', '6759', (178, 182))	('SSX', 'Gene', (316, 319))
617807	23540691	We find that the fusion of SS18 with SSX produces a protein that binds to the complex and evicts both the wild-type SS18 and the tumor suppressor BAF47 (hSNF5).	('binds', 'Interaction', (65, 70))	('SSX', 'Gene', '6757', (37, 40))	('complex', 'Protein', (78, 85))	('SSX', 'Gene', (37, 40))	('fusion', 'Var', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('hSNF5', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('SS18', 'Gene', (27, 31))	('tumor', 'Disease', (129, 134))	('evicts', 'NegReg', (90, 96))	('hSNF5', 'Gene', '6598', (153, 158))
617839	23540691	To understand how incorporation of SS18-SSX alters the biochemical subunit composition of BAF complexes, we produced N-terminally GFP-tagged constructs of SS18 FL (full length, aa1-387), SS18 aa1-379 (lacking the last C-terminal 8 aa which are lost in the fusion), and SS18-SSX using a pEGFP-based expression system (Figure 3A).	('SS18', 'Var', (155, 159))	('BAF', 'Gene', '8815', (90, 93))	('alters', 'Reg', (44, 50))	('SS18', 'Var', (187, 191))	('SSX', 'Gene', '6757', (40, 43))	('SSX', 'Gene', '6757', (274, 277))	('SSX', 'Gene', (274, 277))	('SSX', 'Gene', (40, 43))	('BAF', 'Gene', (90, 93))
617841	23540691	Anti-GFP immunoprecipitations were performed to isolate BAF complexes which had incorporated the exogenously introduced SS18 or SS18-SSX variants.	('SSX', 'Gene', '6757', (133, 136))	('BAF', 'Gene', '8815', (56, 59))	('SSX', 'Gene', (133, 136))	('SS18', 'Var', (120, 124))	('BAF', 'Gene', (56, 59))	('variants', 'Var', (137, 145))
617843	23540691	Wild-type SS18 FL or SS18 1-379 both incorporated into BAF complexes but did not alter BAF47 binding to the complex.	('BAF', 'Gene', '8815', (55, 58))	('BAF', 'Gene', '8815', (87, 90))	('SS18 FL', 'Var', (10, 17))	('BAF', 'Gene', (55, 58))	('BAF', 'Gene', (87, 90))	('incorporated', 'Reg', (37, 49))	('SS18 1-379', 'Var', (21, 31))
617865	23540691	Intriguingly, KD of SS18 and BAF47 both resulted in a statistically significant increase in Sox2 mRNA to levels nearly comparable to those resulting from overexpression of SS18-SSX (Figure 4A).	('SSX', 'Gene', '6757', (177, 180))	('increase', 'PosReg', (80, 88))	('Sox2', 'Gene', '6657', (92, 96))	('BAF47', 'Var', (29, 34))	('Sox2', 'Gene', (92, 96))	('SS18', 'Var', (20, 24))	('SSX', 'Gene', (177, 180))
617876	23540691	In MEFs, there is a prominent H3K27me3 peak over the Sox2 locus as shown by MEF ChIP-seq studies, consistent with absent Sox2 expression in these cells (Figure S4B).	('Sox2', 'Gene', '6657', (121, 125))	('expression', 'MPA', (126, 136))	('Sox2', 'Gene', (121, 125))	('MEF', 'Gene', (3, 6))	('absent', 'NegReg', (114, 120))	('Sox2', 'Gene', '6657', (53, 57))	('MEF', 'Gene', '2000', (3, 6))	('H3K27me3', 'Var', (30, 38))	('Sox2', 'Gene', (53, 57))	('MEFs', 'CellLine', 'CVCL:9115', (3, 7))	('MEF', 'Gene', '2000', (76, 79))	('MEF', 'Gene', (76, 79))
617881	23540691	Because expression of SS18-SSX1 resulted in the ejection and subsequent degradation of the BAF47 subunit, we aimed to understand the features of the 78 amino acid SSX tail that could be responsible for this.	('resulted in', 'Reg', (32, 43))	('ejection', 'MPA', (48, 56))	('BAF47 subunit', 'Protein', (91, 104))	('expression', 'Var', (8, 18))	('SSX1', 'Gene', '6756', (27, 31))	('SSX1', 'Gene', (27, 31))	('SSX', 'Gene', (27, 30))	('SSX', 'Gene', '6757', (27, 30))	('SSX', 'Gene', '6757', (163, 166))	('SSX', 'Gene', (163, 166))	('degradation', 'MPA', (72, 83))
617884	23540691	Deleting 1/2SSXRD resulted in slightly decreased levels of BAF47.	('SSX', 'Gene', (12, 15))	('Deleting', 'Var', (0, 8))	('levels of BAF47', 'MPA', (49, 64))	('decreased', 'NegReg', (39, 48))	('SSX', 'Gene', '6757', (12, 15))
617885	23540691	Upon introduction of these variants into human fibroblasts, Sox2 mRNA induction was only observed with SS18-SSX1 (Figure 5B).	('variants', 'Var', (27, 35))	('Sox2', 'Gene', '6657', (60, 64))	('human', 'Species', '9606', (41, 46))	('SSX1', 'Gene', '6756', (108, 112))	('Sox2', 'Gene', (60, 64))	('SSX1', 'Gene', (108, 112))
617892	23540691	Given that SSX1 is a common fusion partner of SS18 in synovial sarcoma and SSX3 is not, we then sought to understand if SSX3 fused to SS18 could result in BAF47 ejection and Sox2 induction.	('synovial sarcoma', 'Disease', (54, 70))	('result in', 'Reg', (145, 154))	('fused', 'Var', (125, 130))	('SSX3', 'Gene', (75, 79))	('SSX3', 'Gene', (120, 124))	('induction', 'PosReg', (179, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (54, 70))	('SS18', 'Gene', (134, 138))	('SSX1', 'Gene', '6756', (11, 15))	('synovial sarcoma', 'Disease', 'MESH:D013584', (54, 70))	('SSX3', 'Gene', '10214', (75, 79))	('SSX3', 'Gene', '10214', (120, 124))	('Sox2', 'Gene', '6657', (174, 178))	('SSX1', 'Gene', (11, 15))	('Sox2', 'Gene', (174, 178))	('BAF47 ejection', 'MPA', (155, 169))
617895	23540691	Remarkably, replacement of amino acids 43,44 of SSX1 (KR) with those of SSX3 (MI) in the SS18-SSX1 fusion resulted in substantial loss of the ability to displace BAF47 (Figure 5F).	('displace BAF47', 'MPA', (153, 167))	('SSX1', 'Gene', (48, 52))	('SSX3', 'Gene', '10214', (72, 76))	('SSX1', 'Gene', '6756', (48, 52))	('replacement', 'Var', (12, 23))	('loss', 'NegReg', (130, 134))	('SSX1', 'Gene', '6756', (94, 98))	('ability', 'MPA', (142, 149))	('SSX3', 'Gene', (72, 76))	('SSX1', 'Gene', (94, 98))
617906	23540691	These studies indicate that the SS18-SSX fusion protein and the wild type SS18 protein compete for assembly into BAF complexes and that the transforming mutant protein can be displaced from BAF complexes to yield wild-type complexes by increasing the concentration of the wild-type protein.	('SSX', 'Gene', '6757', (37, 40))	('SSX', 'Gene', (37, 40))	('mutant', 'Var', (153, 159))	('BAF', 'Gene', '8815', (190, 193))	('BAF', 'Gene', '8815', (113, 116))	('BAF', 'Gene', (190, 193))	('BAF', 'Gene', (113, 116))
617909	23540691	Sox2 mRNA expression levels in Aska-SS cells were reduced by 3- and 4-fold, upon overexpression of SS18FL and SS18 1-379, respectively (Figure 6G).	('Sox2', 'Gene', (0, 4))	('SS18FL', 'Var', (99, 105))	('overexpression', 'PosReg', (81, 95))	('SS18FL', 'Chemical', '-', (99, 105))	('reduced', 'NegReg', (50, 57))	('Sox2', 'Gene', '6657', (0, 4))	('SS18 1-379', 'Var', (110, 120))	('Aska-SS', 'CellLine', 'CVCL:6C43', (31, 38))
617911	23540691	Finally, Aska-SS synovial sarcoma cells infected with SS18FL to reverse the BAF complex phenotype exhibited a dramatically decreased occupancy of BAF complexes at the human Sox2 locus with a concomitant increase in H3K27me3 occupancy (Figure 6H).	('Aska-SS synovial sarcoma cells infected', 'Disease', 'MESH:D013584', (9, 48))	('occupancy', 'MPA', (133, 142))	('decreased', 'NegReg', (123, 132))	('BAF', 'Gene', '8815', (76, 79))	('SS18FL', 'Var', (54, 60))	('Sox2', 'Gene', '6657', (173, 177))	('Aska-SS synovial sarcoma cells infected', 'Disease', (9, 48))	('occupancy', 'MPA', (224, 233))	('BAF', 'Gene', '8815', (146, 149))	('BAF', 'Gene', (146, 149))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (17, 33))	('Sox2', 'Gene', (173, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('BAF', 'Gene', (76, 79))	('SS18FL', 'Chemical', '-', (54, 60))	('human', 'Species', '9606', (167, 172))	('H3K27me3', 'Protein', (215, 223))	('increase', 'PosReg', (203, 211))
617914	23540691	Notably, overexpressed V5-tagged BAF47 was unable to bind SS18-SSX containing complexes in both SS cell lines tested, as evidenced by low protein levels on complexes detected by anti-Brg and anti-V5 immunoprecipitations as well as by total protein immunoblots, suggestive of rapid degradation (Figure 7A).	('protein levels', 'MPA', (138, 152))	('bind', 'Interaction', (53, 57))	('low', 'NegReg', (134, 137))	('SSX', 'Gene', '6757', (63, 66))	('unable', 'NegReg', (43, 49))	('SSX', 'Gene', (63, 66))	('BAF47', 'Gene', (33, 38))	('V5-tagged', 'Var', (23, 32))
617915	23540691	To test whether shifting aberrant complex assembly back to that of wild-type would allow for integration of the exogenous BAF47-V5 into complexes we infected SS cells containing BAF47-V5 with either SS18FL or shSS18-SSX.	('SSX', 'Gene', (216, 219))	('SS18FL', 'Var', (199, 205))	('SSX', 'Gene', '6757', (216, 219))	('SS18FL', 'Chemical', '-', (199, 205))
617916	23540691	Indeed, in both lines, overexpression of SS18FL or KD of the SS18-SSX fusion resulted in increased incorporation and stabilization of BAF47-V5 as indicated by anti-Brg immunoprecipitation (Figure 7B).	('incorporation', 'MPA', (99, 112))	('SS18FL', 'Chemical', '-', (41, 47))	('overexpression', 'PosReg', (23, 37))	('SS18FL', 'Var', (41, 47))	('SSX', 'Gene', '6757', (66, 69))	('stabilization', 'MPA', (117, 130))	('increased', 'PosReg', (89, 98))	('SSX', 'Gene', (66, 69))	('BAF47-V5', 'Protein', (134, 142))
617918	23540691	Our studies demonstrate that in the two synovial sarcoma cell lines we have used, the fusion of SS18 with SSX, which is diagnostic of this tumor type, leads to assembly of aberrant BAF complexes that become targeted to the Sox2 locus, with loss of repressive H3K27me3 marks, driving Sox2 expression and proliferation of these cells (Figure 7D).	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('Sox2', 'Gene', (223, 227))	('tumor', 'Disease', (139, 144))	('H3K27me3 marks', 'Protein', (259, 273))	('driving', 'PosReg', (275, 282))	('SS18', 'Gene', (96, 100))	('expression', 'MPA', (288, 298))	('synovial sarcoma', 'Disease', (40, 56))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('leads to', 'Reg', (151, 159))	('BAF', 'Gene', (181, 184))	('SSX', 'Gene', '6757', (106, 109))	('synovial sarcoma', 'Disease', 'MESH:D013584', (40, 56))	('Sox2', 'Gene', '6657', (223, 227))	('Sox2', 'Gene', (283, 287))	('loss', 'NegReg', (240, 244))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (40, 56))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('SSX', 'Gene', (106, 109))	('BAF', 'Gene', '8815', (181, 184))	('Sox2', 'Gene', '6657', (283, 287))	('proliferation', 'CPA', (303, 316))	('fusion', 'Var', (86, 92))
617928	23540691	Substitution of KR with MI, found in the non-transforming SSX3, restores normal complex assembly and gene regulation; substitution of MI with KR in SS18-SSX3 results in BAF47 ejection and increased Sox2 mRNA.	('substitution', 'Var', (118, 130))	('SSX3', 'Gene', '10214', (58, 62))	('SSX3', 'Gene', (153, 157))	('restores', 'PosReg', (64, 72))	('complex assembly', 'MPA', (80, 96))	('Sox2', 'Gene', '6657', (198, 202))	('SSX3', 'Gene', '10214', (153, 157))	('SSX3', 'Gene', (58, 62))	('Sox2', 'Gene', (198, 202))	('gene regulation', 'MPA', (101, 116))	('increased', 'PosReg', (188, 197))	('BAF47 ejection', 'MPA', (169, 183))
617930	23540691	However, the ability of such a small region to lead to complex dissolution and the observation that the wild type and malignant protein are in a dynamic equilibrium indicates that the fusion containing the two amino acid essential region in the SSX tail (K43, R44) is an excellent target for developing therapeutics for this disease.	('K43', 'Var', (255, 258))	('SSX', 'Gene', '6757', (245, 248))	('SSX', 'Gene', (245, 248))
617936	23540691	In some studies, polycomb was found to prevent Brahma (BAP) complex binding, while in others it seemed that BAP or SWI/SNF directly recruited PolII, thereby opposing polycomb.	('Brahma', 'Gene', '39744', (47, 53))	('BAP', 'Gene', (55, 58))	('prevent', 'NegReg', (39, 46))	('Brahma', 'Gene', (47, 53))	('binding', 'Interaction', (68, 75))	('BAP', 'Gene', (108, 111))	('BAP', 'Gene', '11331', (108, 111))	('BAP', 'Gene', '11331', (55, 58))	('polycomb', 'Var', (17, 25))
617937	23540691	Our studies suggest that somehow BAF complexes evict polycomb, however our temporal resolution is limited to the infection times (24-72 hrs) and hence we are unable to determine if the mechanism is direct physical eviction, or dilution of H3K27Me3 by nucleosome exchange with cell division since the measured rates of nucleosome turnover are sufficient to remove most H3K27Me3 if methylation were prevented by the SS BAF complex.	('remove', 'NegReg', (356, 362))	('BAF', 'Gene', '8815', (417, 420))	('polycomb', 'MPA', (53, 61))	('H3K27Me3', 'Var', (368, 376))	('BAF', 'Gene', (417, 420))	('BAF', 'Gene', '8815', (33, 36))	('BAF', 'Gene', (33, 36))
617938	23540691	Evidence for BAF-polycomb opposition in malignancy has also been found with inactivation of BAF47 (hSNF5 or Ini1) in human malignant rhabdoid sarcoma (MRTs).	('BAF', 'Gene', (92, 95))	('human', 'Species', '9606', (117, 122))	('hSNF5', 'Gene', '6598', (99, 104))	('BAF', 'Gene', (13, 16))	('malignant rhabdoid sarcoma', 'Disease', (123, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('Ini1', 'Gene', (108, 112))	('inactivation', 'Var', (76, 88))	('hSNF5', 'Gene', (99, 104))	('BAF', 'Gene', '8815', (92, 95))	('BAF', 'Gene', '8815', (13, 16))	('Ini1', 'Gene', '6598', (108, 112))	('malignant rhabdoid sarcoma', 'Disease', 'MESH:C563738', (123, 149))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('malignancy', 'Disease', (40, 50))
617958	23540691	ChIP antibodies: anti-BAF155 (in house generated), anti-H3K27me3 (Millipore, 07-449), V5 (Invitrogen, 46-0705).	('anti-H3K27me3', 'Var', (51, 64))	('BAF155', 'Gene', '6599', (22, 28))	('BAF155', 'Gene', (22, 28))
617982	33408094	Previous work has shown that knockout (KO) of germline HPK1 decreased the threshold for T-cell receptor (TCR) signaling and rendered T cells resistant to the suppressive effects of PGE2.	('T-cell receptor', 'Gene', (88, 103))	('decreased', 'NegReg', (60, 69))	('knockout', 'Var', (29, 37))	('PGE2', 'Chemical', 'MESH:D015232', (181, 185))	('HPK1', 'Gene', (55, 59))	('TCR', 'Gene', (105, 108))	('T-cell receptor', 'Gene', '6962', (88, 103))	('TCR', 'Gene', '6962', (105, 108))
617984	33408094	HPK1 KD mice exhibited normal bone marrow development and immune cell homeostasis.	('bone marrow development', 'CPA', (30, 53))	('mice', 'Species', '10090', (8, 12))	('HPK1 KD', 'Var', (0, 7))
617992	33408094	Substantial antitumor efficacy with CompK, in combination with anti-PD1, was demonstrated in a mouse syngeneic tumor model, which for the first time shows that enhanced immune response by HPK1 ablation is not a result of developmental alteration and can be recapitulated by pharmacological inhibition of HPK1 in the context of a fully matured immune system.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (111, 116))	('mouse', 'Species', '10090', (95, 100))	('tumor', 'Disease', (16, 21))	('immune', 'MPA', (169, 175))	('HPK1', 'Gene', (188, 192))	('enhanced', 'PosReg', (160, 168))	('ablation', 'Var', (193, 201))
617998	33408094	Human CD3 +T cells were treated for 24 hours with 2 nM PGE2 and/or 2 microM NECA in the presence of anti-CD3 and anti-CD28.	('Human', 'Species', '9606', (0, 5))	('CD28', 'Gene', (118, 122))	('anti-CD3', 'Var', (100, 108))	('CD28', 'Gene', '940', (118, 122))	('PGE2', 'Chemical', 'MESH:D015232', (55, 59))	('NECA', 'Chemical', 'MESH:D019830', (76, 80))
618030	33408094	Significantly higher IL-2 production was observed in HPK1 KO compared with wild-type (WT) Jurkat cells (online supplemental figure S2B).	('IL-2', 'Gene', '3558', (21, 25))	('Jurkat', 'CellLine', 'CVCL:0065', (90, 96))	('IL-2', 'Gene', (21, 25))	('HPK1 KO', 'Var', (53, 60))	('higher', 'PosReg', (14, 20))
618040	33408094	To interrogate the potential benefit of a HPK1 inhibitor in attenuating the influence of these suppressive factors, secretion of IL-2 and IFN-gamma was evaluated in human CD3+ T cells in the presence of PGE2 and a stable adenosine analog (NECA) on treatment with CompK.	('inhibitor', 'Var', (47, 56))	('human', 'Species', '9606', (165, 170))	('adenosine', 'Chemical', 'MESH:D000241', (221, 230))	('IFN-gamma', 'Gene', '3458', (138, 147))	('IFN-gamma', 'Gene', (138, 147))	('PGE2', 'Chemical', 'MESH:D015232', (203, 207))	('HPK1', 'Gene', (42, 46))	('IL-2', 'Gene', '3558', (129, 133))	('NECA', 'Chemical', 'MESH:D019830', (239, 243))	('IL-2', 'Gene', (129, 133))
618043	33408094	With the enhancement of T-cell polyfunctionality observed on treatment with CompK via engagement of TCR with anti-CD3 and anti-CD28, we next decided to investigate the impact of CompK on T-cell response to a specific antigen at various doses aiming to understand whether HPK1 inhibition leads to augmented functional avidity of T cells.	('TCR', 'Gene', (100, 103))	('T-cell polyfunctionality', 'MPA', (24, 48))	('HPK1', 'Gene', (271, 275))	('CD28', 'Gene', (127, 131))	('enhancement', 'PosReg', (9, 20))	('augmented', 'PosReg', (296, 305))	('TCR', 'Gene', '6962', (100, 103))	('CD28', 'Gene', '940', (127, 131))	('anti-CD3', 'Var', (109, 117))	('functional avidity', 'MPA', (306, 324))
618044	33408094	We hypothesized that inhibition of HPK1 kinase activity could reduce the TCR activation threshold and increase antigen sensitivity of TCR to recognize lower concentrations of antigens.	('TCR', 'Gene', (73, 76))	('antigen sensitivity', 'MPA', (111, 130))	('TCR', 'Gene', '6962', (134, 137))	('reduce', 'NegReg', (62, 68))	('inhibition', 'Var', (21, 31))	('increase', 'PosReg', (102, 110))	('HPK1', 'Gene', (35, 39))	('TCR', 'Gene', '6962', (73, 76))	('TCR', 'Gene', (134, 137))
618049	33408094	Treatment with 0.5 microM CompK led to a threefold leftward shift of the E7 EC50 response curve (figure 3A), suggesting that CompK reduced the threshold required to trigger TCR responses of antigen-specific CD8+ T cells, and increased their ability to recognize weak viral/tumor associated antigens.	('threshold required', 'MPA', (143, 161))	('CD8', 'Gene', '925', (207, 210))	('TCR', 'Gene', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('increased', 'PosReg', (225, 234))	('recognize', 'MPA', (252, 261))	('CompK', 'Var', (125, 130))	('reduced', 'NegReg', (131, 138))	('ability', 'MPA', (241, 248))	('TCR', 'Gene', '6962', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('CD8', 'Gene', (207, 210))
618053	33408094	To confirm this, we stimulated human T cells with various concentrations of anti-CD3 and anti-CD28.	('anti-CD3', 'Var', (76, 84))	('CD28', 'Gene', '940', (94, 98))	('CD28', 'Gene', (94, 98))	('human', 'Species', '9606', (31, 36))
618057	33408094	Treatment with CompK or anti-PD1 as a single agent increased IFN-gamma release, whereas the combination of CompK and anti-PD1 yielded remarkable synergy with robust IFN-gamma secretion (figure 3C), suggesting the combined utility of a HPK1 inhibitor and anti-PD1 in the clinic.	('increased', 'PosReg', (51, 60))	('IFN-gamma', 'Gene', '3458', (61, 70))	('anti-PD1', 'Var', (24, 32))	('IFN-gamma', 'Gene', (61, 70))	('anti-PD1', 'Var', (117, 125))	('IFN-gamma', 'Gene', '3458', (165, 174))	('IFN-gamma', 'Gene', (165, 174))
618063	33408094	To investigate if HPK1 kinase inhibition can result in similar benefit to promote human DC maturation, we elected to investigate the treatment effect of CompK by using human monocyte-derived DCs and DCs from peripheral blood.	('human', 'Species', '9606', (168, 173))	('inhibition', 'Var', (30, 40))	('promote', 'PosReg', (74, 81))	('HPK1', 'Gene', (18, 22))	('human DC maturation', 'CPA', (82, 101))	('human', 'Species', '9606', (82, 87))
618068	33408094	Our results indicate that HPK1 kinase inhibition is beneficial to promote cancer immunity via modulation of human DCs and associated network.	('HPK1', 'Gene', (26, 30))	('human DCs', 'Protein', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('promote', 'PosReg', (66, 73))	('inhibition', 'Var', (38, 48))	('human', 'Species', '9606', (108, 113))	('modulation', 'Reg', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
618071	33408094	At the end of treatment, blood samples were collected to measure pSLP76, IFN-gamma, CD25 and CD69 after stimulation with anti-CD3 and anti-CD28 ex vivo.	('CD25', 'Gene', (84, 88))	('IFN-gamma', 'Gene', (73, 82))	('SLP76', 'Gene', '3937', (66, 71))	('CD28', 'Gene', '940', (139, 143))	('IFN-gamma', 'Gene', '3458', (73, 82))	('anti-CD3', 'Var', (121, 129))	('CD69', 'Gene', '969', (93, 97))	('CD25', 'Gene', '3559', (84, 88))	('SLP76', 'Gene', (66, 71))	('CD69', 'Gene', (93, 97))	('CD28', 'Gene', (139, 143))
618092	33408094	A HPK1 inhibitor is expected to enhance activation of T cells and APC function of DCs to recognize low immunogenic tumor antigens, with potential benefit to treat multiple types of tumors and promote the performance of cell therapy.	('cell therapy', 'CPA', (219, 231))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('inhibitor', 'Var', (7, 16))	('APC', 'Gene', (66, 69))	('promote', 'PosReg', (192, 199))	('APC', 'Gene', '324', (66, 69))	('enhance', 'PosReg', (32, 39))	('low immunogenic tumor', 'Disease', 'MESH:D009800', (99, 120))	('low immunogenic tumor', 'Disease', (99, 120))	('HPK1', 'Gene', (2, 6))
618107	33408094	Our findings suggest potential utility of HPK1 inhibitors to combat the tolerance prone environment inside the tumor, with the enriched levels of PGE2, adenosine and TGF-beta observed in multiple tumor types.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tolerance prone environment', 'MPA', (72, 99))	('inhibitors', 'Var', (47, 57))	('tumor', 'Disease', (196, 201))	('adenosine', 'Chemical', 'MESH:D000241', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HPK1', 'Gene', (42, 46))	('PGE2', 'Chemical', 'MESH:D015232', (146, 150))	('tumor', 'Disease', (111, 116))	('PGE2', 'MPA', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('adenosine', 'MPA', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
618108	33408094	Our DC studies demonstrated that HPK1 inhibition by CompK promoted the maturation of monocyte-derived DCs and enhanced the TNF-alpha+DC population on stimulation in human whole blood, offering a potential underlying mechanism of CompK treatment in creating more optimal microenvironment to elicit an immune response to control tumor progression.	('TNF-alpha', 'Gene', (123, 132))	('human', 'Species', '9606', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('maturation', 'CPA', (71, 81))	('tumor', 'Disease', (327, 332))	('enhanced', 'PosReg', (110, 118))	('inhibition', 'Var', (38, 48))	('promoted', 'PosReg', (58, 66))	('HPK1', 'Gene', (33, 37))	('TNF-alpha', 'Gene', '7124', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (327, 332))
618112	33408094	Further studies are needed to interrogate this potential benefit and associated mechanism, which may have important clinical implication for HPK1 inhibitors in facilitating the sustainability of optimal tumor antigen presentation.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('inhibitors', 'Var', (146, 156))	('HPK1', 'Gene', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
618113	33408094	A significant percentage of tumor antigens are derivatives of normal or altered cellular genes, which typically are not sufficient to mount an effective immune response.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('altered', 'Var', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (28, 33))
618124	33408094	We propose that HPK1 inhibition could promote robust T-cell response to TAAs and increase polyclonality/functionality of CTLs to attack tumors, where most viable antigens are expressed at lower levels and more heterogeneously.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('TAA', 'Disease', 'None', (72, 75))	('polyclonality/functionality', 'MPA', (90, 117))	('TAA', 'Disease', (72, 75))	('inhibition', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('promote', 'PosReg', (38, 45))	('increase', 'PosReg', (81, 89))	('HPK1', 'Gene', (16, 20))
618125	33408094	Further studies are needed to interrogate this hypothesis and the potential of HPK1 inhibition to facilitate epitope spreading, which is considered necessary to stimulate self-sustaining and long-lasting antitumor immune responses.	('epitope spreading', 'MPA', (109, 126))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('HPK1', 'Gene', (79, 83))	('tumor', 'Disease', (208, 213))	('inhibition', 'Var', (84, 94))
618182	31220736	Cells were blocked with Duolink blocking solution and incubated overnight at 4 C in the cold room with the following primary antibodies: DDIT3 (L63F7) (Cell Signaling Technology, #2895), MAP4K4 (Bethyl, A3011-502A).	('MAP4K4', 'Gene', '9448', (187, 193))	('A3011-502A', 'Var', (203, 213))	('MAP4K4', 'Gene', (187, 193))
618229	31220736	Even though many FUS-DDIT3 fusion variants have lost the RNA-binding domain of FUS, the fusion protein retains the ability to bind wild type FUS, and by extension, the ability to associate with FUS interactors.	('variants', 'Var', (34, 42))	('associate', 'Interaction', (179, 188))	('lost', 'NegReg', (48, 52))	('ability', 'MPA', (168, 175))	('FUS-DDIT3', 'Gene', (17, 26))	('RNA-binding domain', 'MPA', (57, 75))	('bind', 'Interaction', (126, 130))	('ability', 'MPA', (115, 122))	('FUS-DDIT3', 'Gene', '1649', (17, 26))
618233	31220736	Since the RNA-binding domains of FUS are not retained in most FUS-DDIT3 variants, the fusion protein is not expected to retain the same RNA processing functions of wild type FUS.	('FUS-DDIT3', 'Gene', (62, 71))	('FUS-DDIT3', 'Gene', '1649', (62, 71))	('variants', 'Var', (72, 80))
618245	31220736	This has implications for tumorigenesis, as deregulation of SWI/SNF function would likely disrupt the tightly-regulated expression of genes involved in differentiation and development.	('implications', 'Reg', (9, 21))	('disrupt', 'NegReg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (26, 31))	('tightly-regulated expression of genes', 'MPA', (102, 139))	('deregulation', 'Var', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('SWI/SNF', 'Gene', (60, 67))
618449	29764855	Khurana et al described detection of tumor associated macrophages with 19F MRI after intravenous injection of a perfluorocarbon nanoemulsion and Shin et al described detection of macrophages in an animal model of colitis after intravenous injection of perfluorocarbon.	('perfluorocarbon', 'Chemical', 'MESH:D005466', (112, 127))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('19F MRI', 'Var', (71, 78))	('colitis', 'Phenotype', 'HP:0002583', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('colitis', 'Disease', 'MESH:D003092', (213, 220))	('perfluorocarbon', 'Chemical', 'MESH:D005466', (252, 267))	('colitis', 'Disease', (213, 220))
618493	26576131	Mutations in receptor tyrosine kinases (RTK), leading to aberrant pathway activation, have often been reported in cancer.	('receptor tyrosine kinase', 'Gene', '5979', (13, 37))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RTK', 'Gene', (40, 43))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('reported', 'Reg', (102, 110))	('receptor tyrosine kinase', 'Gene', (13, 37))	('cancer', 'Disease', (114, 120))
618494	26576131	Amplifications, mutations, and rearrangements of platelet-derived growth factor (PDGF) and its receptor PDGFR have been implicated in the pathophysiology of multiple tumor types including gastrointestinal stromal tumor (GIST), glioblastoma, and dermatofibrosarcoma protuberans.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('PDGF', 'Gene', (104, 108))	('GIST', 'Phenotype', 'HP:0100723', (220, 224))	('gastrointestinal stromal tumor', 'Disease', (188, 218))	('PDGF', 'Gene', '5154;5155', (104, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (227, 239))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (245, 276))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('multiple tumor', 'Disease', 'MESH:D009369', (157, 171))	('PDGF', 'Gene', (81, 85))	('PDGFR', 'Gene', (104, 109))	('PDGFR', 'Gene', '5159', (104, 109))	('PDGF', 'Gene', '5154;5155', (81, 85))	('mutations', 'Var', (16, 25))	('implicated', 'Reg', (120, 130))	('rearrangements', 'Var', (31, 45))	('glioblastoma', 'Disease', (227, 239))	('multiple tumor', 'Disease', (157, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (227, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (188, 218))	('dermatofibrosarcoma protuberans', 'Disease', (245, 276))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (188, 218))
618496	26576131	Furthermore, taking together results from three expression studies, 49/215 (23%) uLMS samples (from 128 patients) showed positivity for PDGFR-beta.	('PDGFR-beta', 'Gene', '5159', (136, 146))	('PDGFR-beta', 'Gene', (136, 146))	('uLMS', 'Phenotype', 'HP:0002891', (81, 85))	('positivity', 'Var', (121, 131))	('uLMS', 'Disease', (81, 85))	('patients', 'Species', '9606', (104, 112))
618529	26576131	Interestingly, targeting EGFR with gefitinib rendered uLMS cells sensitive to cytotoxic treatment, in vitro as well as in an in vivo xenograft model.	('targeting', 'Var', (15, 24))	('EGFR', 'Gene', (25, 29))	('gefitinib', 'Chemical', 'MESH:D000077156', (35, 44))	('EGFR', 'Gene', '1956', (25, 29))	('uLMS', 'Phenotype', 'HP:0002891', (54, 58))
618539	26576131	Moreover, in MES-SA-injected mouse models, administration of K252a resulted in smaller tumors, lower proliferation rates, and more apoptosis.	('lower', 'NegReg', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('K252a', 'Var', (61, 66))	('smaller', 'NegReg', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('mouse', 'Species', '10090', (29, 34))	('MES-SA', 'Chemical', '-', (13, 19))	('tumors', 'Disease', (87, 93))	('apoptosis', 'CPA', (131, 140))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
618545	26576131	While the progression-free survival was modestly increased in patients receiving ridaforolimus, no significant improvement in the overall survival was reached.	('ridaforolimus', 'Chemical', 'MESH:C515074', (81, 94))	('increased', 'PosReg', (49, 58))	('progression-free', 'CPA', (10, 26))	('patients', 'Species', '9606', (62, 70))	('ridaforolimus', 'Var', (81, 94))
618552	26576131	Also, combined targeting of the mTOR pathway and the mitotic checkpoint protein aurora kinase A, using rapamycin + MLN8237, synergistically reduced uLMS cell growth in vitro, as well as tumor growth in an in vivo model.	('MLN8237', 'Var', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('uLMS', 'Disease', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('mTOR', 'Gene', '2475', (32, 36))	('aurora kinase A', 'Gene', '6790', (80, 95))	('mTOR', 'Gene', (32, 36))	('tumor', 'Disease', (186, 191))	('aurora kinase A', 'Gene', (80, 95))	('uLMS', 'Phenotype', 'HP:0002891', (148, 152))	('MLN8237', 'Chemical', 'MESH:C550258', (115, 122))	('rapamycin', 'Chemical', 'MESH:D020123', (103, 112))	('reduced', 'NegReg', (140, 147))
618558	26576131	ROR2 suppression reduced invasiveness of an LMS cell line in vitro and ROR2 knockdown resulted in smaller tumor volumes in xenograft models.	('smaller', 'NegReg', (98, 105))	('ROR2', 'Gene', '4920', (71, 75))	('invasiveness of an LMS cell line', 'CPA', (25, 57))	('ROR2', 'Gene', (0, 4))	('knockdown', 'Var', (76, 85))	('ROR2', 'Gene', '4920', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('suppression reduced', 'NegReg', (5, 24))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('ROR2', 'Gene', (71, 75))	('tumor', 'Disease', (106, 111))
618561	26576131	Interestingly, in vitro knockdown of endoglin resulted in reduced migration, invasion, and VEGF secretion.	('VEGF', 'Gene', '7422', (91, 95))	('migration', 'CPA', (66, 75))	('endoglin', 'Gene', (37, 45))	('invasion', 'CPA', (77, 85))	('reduced', 'NegReg', (58, 65))	('VEGF', 'Gene', (91, 95))	('endoglin', 'Gene', '2022', (37, 45))	('knockdown', 'Var', (24, 33))
618565	26576131	Of note, a phase II trial evaluating the AURKA inhibitor alisertib (MLN8237) in pretreated LMS patients has been activated.	('AURKA', 'Gene', '6790', (41, 46))	('MLN8237', 'Chemical', 'MESH:C550258', (68, 75))	('patients', 'Species', '9606', (95, 103))	('AURKA', 'Gene', (41, 46))	('LMS', 'Disease', (91, 94))	('MLN8237', 'Var', (68, 75))	('alisertib', 'Chemical', 'MESH:C550258', (57, 66))
618569	26576131	MDM2 inhibitors have proven efficient in preclinical settings and, at present, agents such as AMG232 and RG7112 are clinically being explored in various cancer types, although not yet in uterine sarcomas.	('uterine sarcomas', 'Disease', 'MESH:D012509', (187, 203))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (195, 203))	('AMG232', 'Gene', (94, 100))	('cancer', 'Disease', (153, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('MDM2', 'Gene', '4193', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('MDM2', 'Gene', (0, 4))	('RG7112', 'Var', (105, 111))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (187, 202))	('uterine sarcomas', 'Disease', (187, 203))
618570	26576131	tested potential synergistic combinations of MDM2 antagonists with other compounds in vitro in 40 cell lines.	('synergistic', 'Reg', (17, 28))	('MDM2', 'Gene', '4193', (45, 49))	('MDM2', 'Gene', (45, 49))	('antagonists', 'Var', (50, 61))	('combinations', 'Interaction', (29, 41))
618572	26576131	Furthermore, MDM2 inhibitors were found to greatly synergize with histone deacetylase (HDAC) inhibitors, as detected by a tremendous increase in apoptosis and decrease in cell proliferation.	('HDAC', 'Gene', (87, 91))	('cell proliferation', 'CPA', (171, 189))	('HDAC', 'Gene', '9734', (87, 91))	('histone deacetylase', 'Gene', '9734', (66, 85))	('MDM2', 'Gene', '4193', (13, 17))	('MDM2', 'Gene', (13, 17))	('decrease', 'NegReg', (159, 167))	('histone deacetylase', 'Gene', (66, 85))	('increase', 'PosReg', (133, 141))	('inhibitors', 'Var', (18, 28))	('apoptosis', 'CPA', (145, 154))
618576	26576131	Also, combining vorinostat with the PI3K/AKT/mTOR pathway inhibitors rapamycin or LY294002 showed a synergistic effect on growth inhibition in MES-SA cells.	('LY294002', 'Chemical', 'MESH:C085911', (82, 90))	('growth inhibition', 'CPA', (122, 139))	('AKT', 'Gene', '207', (41, 44))	('vorinostat', 'Chemical', 'MESH:D000077337', (16, 26))	('rapamycin', 'Chemical', 'MESH:D020123', (69, 78))	('mTOR', 'Gene', '2475', (45, 49))	('MES-SA', 'Chemical', '-', (143, 149))	('LY294002', 'Var', (82, 90))	('AKT', 'Gene', (41, 44))	('mTOR', 'Gene', (45, 49))
618579	26576131	Interestingly, treatment of uLMS cells with anti-CD47 antibodies increased phagocytosis in vitro and reduced uLMS tumor volumes in vivo.	('increased', 'PosReg', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('CD47', 'Gene', '961', (49, 53))	('uLMS', 'Phenotype', 'HP:0002891', (109, 113))	('antibodies', 'Var', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CD47', 'Gene', (49, 53))	('tumor', 'Disease', (114, 119))	('reduced', 'NegReg', (101, 108))	('uLMS', 'Phenotype', 'HP:0002891', (28, 32))	('phagocytosis', 'CPA', (75, 87))
618586	26576131	Upon phosphorylation, RB1 releases the transcription factor E2F, stimulating cell cycle progression.	('phosphorylation', 'Var', (5, 20))	('RB1', 'Gene', (22, 25))	('stimulating', 'PosReg', (65, 76))	('cell cycle progression', 'CPA', (77, 99))	('RB1', 'Gene', '5925', (22, 25))
618587	26576131	reported on the inactivation of CDKN2A in soft-tissue LMS by promoter hypermethylation (11/49 cases) and homozygous deletion (3/49 cases).	('CDKN2A', 'Gene', (32, 38))	('CDKN2A', 'Gene', '1029', (32, 38))	('inactivation', 'NegReg', (16, 28))	('promoter hypermethylation', 'Var', (61, 86))	('soft-tissue LMS', 'Disease', (42, 57))
618591	26576131	It was shown recently that retinoblastoma patients with the hereditary type (RB1 deletion) have an increased risk of uLMS; 3,2% of patients developed uLMS, which corresponds to an excess risk of 3,9/10000 women.	('patients', 'Species', '9606', (131, 139))	('uLMS', 'Disease', (117, 121))	('developed', 'Reg', (140, 149))	('women', 'Species', '9606', (205, 210))	('deletion', 'Var', (81, 89))	('retinoblastoma', 'Phenotype', 'HP:0009919', (27, 41))	('uLMS', 'Phenotype', 'HP:0002891', (150, 154))	('RB1', 'Gene', (77, 80))	('RB1', 'Gene', '5925', (77, 80))	('uLMS', 'Phenotype', 'HP:0002891', (117, 121))	('patients', 'Species', '9606', (42, 50))	('uLMS', 'Disease', (150, 154))	('retinoblastoma', 'Disease', 'MESH:D012175', (27, 41))	('retinoblastoma', 'Disease', (27, 41))
618592	26576131	PTEN is a negative regulator of the PI3K-AKT-mTOR pathway, and loss of PTEN is associated with increased pathway activity, as found in many cancers (Figure 1).	('loss', 'Var', (63, 67))	('mTOR', 'Gene', '2475', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('PTEN', 'Gene', (71, 75))	('AKT', 'Gene', '207', (41, 44))	('pathway activity', 'MPA', (105, 121))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('increased', 'PosReg', (95, 104))	('AKT', 'Gene', (41, 44))	('mTOR', 'Gene', (45, 49))
618594	26576131	Of note, mice that carry homozygous deletions at the PTEN locus spontaneously develop LMS, suggesting a strong tumor suppressor role for PTEN in LMS.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('deletions', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('PTEN', 'Gene', (53, 57))	('mice', 'Species', '10090', (9, 13))	('LMS', 'Disease', (86, 89))	('develop', 'PosReg', (78, 85))
618595	26576131	In preclinical models, loss of PTEN has often been shown to be predictive for response to mTOR pathway inhibition.	('loss', 'Var', (23, 27))	('PTEN', 'Protein', (31, 35))	('mTOR', 'Gene', '2475', (90, 94))	('mTOR', 'Gene', (90, 94))
618602	26576131	For example, inhibition of poly ADP-ribose polymerase (PARP), which is involved in the repair of DNA single-strand breaks, selectively kills cells that are deficient in tumor suppressor protein BRCA1 or BRCA2, which repair double-strand breaks.	('PARP', 'Gene', '142', (55, 59))	('poly ADP-ribose polymerase', 'Gene', '142', (27, 53))	('BRCA2', 'Gene', '675', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('inhibition', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PARP', 'Gene', (55, 59))	('tumor', 'Disease', (169, 174))	('poly ADP-ribose polymerase', 'Gene', (27, 53))	('kills', 'NegReg', (135, 140))	('BRCA2', 'Gene', (203, 208))
618628	26576131	Interestingly, further blocking the PI3K/AKT/mTOR pathway using rapamycin or LY294002 in combination with vorinostat showed a synergistic effect on growth inhibition in the ESS-1 cell line.	('growth inhibition', 'CPA', (148, 165))	('AKT', 'Gene', (41, 44))	('vorinostat', 'Chemical', 'MESH:D000077337', (106, 116))	('LY294002', 'Chemical', 'MESH:C085911', (77, 85))	('AKT', 'Gene', '207', (41, 44))	('blocking', 'NegReg', (23, 31))	('rapamycin', 'Chemical', 'MESH:D020123', (64, 73))	('mTOR', 'Gene', '2475', (45, 49))	('LY294002', 'Var', (77, 85))	('mTOR', 'Gene', (45, 49))
618647	26576131	In a single study by Amant et al., one of four (25%) cases showed amplification and overexpression in the primary and the recurrent tumor.	('amplification', 'Var', (66, 79))	('overexpression', 'PosReg', (84, 98))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))
618661	26576131	The presence of cyclin D1 indicates activation of the Wnt/beta-catenin pathway (Figure 1).	('beta-catenin', 'Gene', (58, 70))	('cyclin D1', 'Gene', '595', (16, 25))	('activation', 'PosReg', (36, 46))	('beta-catenin', 'Gene', '1499', (58, 70))	('cyclin D1', 'Gene', (16, 25))	('presence', 'Var', (4, 12))
618669	26576131	However, mTOR inhibition leads to activation of AKT through upstream receptor tyrosine kinase signaling, due to interruption of feedback inhibition.	('feedback inhibition', 'MPA', (128, 147))	('AKT', 'Gene', (48, 51))	('receptor tyrosine kinase', 'Gene', (69, 93))	('mTOR', 'Gene', (9, 13))	('mTOR', 'Gene', '2475', (9, 13))	('receptor tyrosine kinase', 'Gene', '5979', (69, 93))	('activation', 'PosReg', (34, 44))	('inhibition', 'Var', (14, 24))	('AKT', 'Gene', '207', (48, 51))
618799	29533464	By applying RNA sequencing technology to investigate USRCS, we discovered a novel CRTC1-SS18 gene fusion in two samples from two different cancer centres.	('CRTC1', 'Gene', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('fusion', 'Var', (98, 104))	('SS18', 'Gene', (88, 92))	('CRTC1', 'Gene', '23373', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('SS18', 'Gene', '6760', (88, 92))	('cancer', 'Disease', (139, 145))
618809	29533464	The following antibodies were used: CD99 (12E7, Dako), EMA (E29, 1:50, Dako), desmin (D33, 1:80, Dako), cytokeratin AE1/AE3 (AE1/AE3, 1:50, Dako), caldesmon (h-CD, 1:100, Dako), myogenin (F5D, 1:100, Dako), S100 protein (Z0311, 1:800, Dako), CD34 (QBend-10, 1:25, Dako), INI1 (25, 1:50, BD Transduction Laboratories), BCOR (C-10, 1:50, Santa Cruz), ETV4 (16, 1:50, Santa Cruz).	('ETV4', 'Gene', (349, 353))	('AE1', 'Gene', '6521', (116, 119))	('AE3', 'Gene', '6508', (120, 123))	('AE1', 'Gene', (125, 128))	('BCOR', 'Gene', '54880', (318, 322))	('C-10', 'Gene', '3226', (324, 328))	('myogenin', 'Gene', (178, 186))	('desmin', 'Gene', (78, 84))	('AE1', 'Gene', (116, 119))	('ETV4', 'Gene', '2118', (349, 353))	('S100', 'Gene', '6285', (207, 211))	('BCOR', 'Gene', (318, 322))	('INI1', 'Gene', (271, 275))	('INI1', 'Gene', '6598', (271, 275))	('S100', 'Gene', (207, 211))	('AE3', 'Gene', (129, 132))	('myogenin', 'Gene', '4656', (178, 186))	('desmin', 'Gene', '1674', (78, 84))	('EMA', 'Gene', '4582', (55, 58))	('cytokeratin AE1/AE3', 'Gene', (104, 123))	('AE3', 'Gene', (120, 123))	('EMA', 'Gene', (55, 58))	('F5D', 'Var', (188, 191))	('AE3', 'Gene', '6508', (129, 132))	('C-10', 'Gene', (324, 328))	('AE1', 'Gene', '6521', (125, 128))	('cytokeratin AE1/AE3', 'Gene', '6508', (104, 123))	('caldesmon', 'Gene', (147, 156))	('caldesmon', 'Gene', '800', (147, 156))
618810	29533464	Immunohistochemistry for NTRK1 was performed using a 32 min incubation with the NTRK1 antibody (ab76291, clot EP1058Y, Abcam, dilution 1:200) on a Ventana ULTRA machine with Cell Conditioning Solution 1 pre-treatment for 64 min.	('NTRK1', 'Gene', (25, 30))	('clot EP1058Y', 'Var', (105, 117))	('NTRK1', 'Gene', (80, 85))	('NTRK1', 'Gene', '4914', (25, 30))	('NTRK1', 'Gene', '4914', (80, 85))
618825	29533464	A BigDye Terminator V3.1 kit (Applied Biosystems) was used for the cycle sequencing reaction, and PCR products of CRTC1-SS18 gene fusions were directly Sanger sequenced using an ABI 3730 DNA analyser (Applied Biosystems).	('SS18', 'Gene', '6760', (120, 124))	('fusions', 'Var', (130, 137))	('SS18', 'Gene', (120, 124))	('CRTC1', 'Gene', (114, 119))	('CRTC1', 'Gene', '23373', (114, 119))
618831	29533464	After confirming the breakpoint of CRTC1-SS18 gene fusion at the genomic level, LR-PCR was performed on both the tumour sample and the corresponding normal tissue to confirm that this fusion was somatic.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('SS18', 'Gene', '6760', (41, 45))	('tumour', 'Disease', (113, 119))	('fusion', 'Var', (51, 57))	('CRTC1', 'Gene', (35, 40))	('SS18', 'Gene', (41, 45))	('CRTC1', 'Gene', '23373', (35, 40))
618853	29533464	RNA-seq analysis of the index case (Case 1) revealed a novel gene fusion involving CRTC1 and SS18 genes in the tumour sample.	('SS18', 'Gene', (93, 97))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('CRTC1', 'Gene', (83, 88))	('CRTC1', 'Gene', '23373', (83, 88))	('SS18', 'Gene', '6760', (93, 97))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))	('gene fusion', 'Var', (61, 72))
618872	29533464	Furthermore, RNA-seq data revealed enhanced NTRK1 expression in the two cases with the CRTC1-SS18 gene fusion compared to other sarcomas with known translocations such as EWSR1-CREB1, BCOR-CCNB3, CIC-DUX4, EWSR1-FLI1, etc (Figure 4D) and this was confirmed at the protein level by immunohistochemistry (supplementary material, Figure S3).	('EWSR1', 'Gene', (206, 211))	('CREB1', 'Gene', '1385', (177, 182))	('NTRK1', 'Gene', '4914', (44, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('BCOR', 'Gene', '54880', (184, 188))	('CRTC1', 'Gene', (87, 92))	('EWSR1', 'Gene', (171, 176))	('SS18', 'Gene', '6760', (93, 97))	('NTRK1', 'Gene', (44, 49))	('CCNB3', 'Gene', (189, 194))	('FLI1', 'Gene', (212, 216))	('expression', 'MPA', (50, 60))	('BCOR', 'Gene', (184, 188))	('FLI1', 'Gene', '2313', (212, 216))	('CIC-DUX4', 'Disease', 'None', (196, 204))	('EWSR1', 'Gene', '2130', (206, 211))	('fusion', 'Var', (103, 109))	('CRTC1', 'Gene', '23373', (87, 92))	('SS18', 'Gene', (93, 97))	('EWSR1', 'Gene', '2130', (171, 176))	('sarcomas', 'Disease', 'MESH:D012509', (128, 136))	('CCNB3', 'Gene', '85417', (189, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('sarcomas', 'Disease', (128, 136))	('enhanced', 'PosReg', (35, 43))	('CREB1', 'Gene', (177, 182))	('CIC-DUX4', 'Disease', (196, 204))
618874	29533464	The clones expressing the CRTC1-SS18 fusion were morphologically distinct from control clones, showing extended pseudopodia and pronounced intracytoplasmic vacuoles (Figure 5A).	('CRTC1', 'Gene', (26, 31))	('SS18', 'Gene', (32, 36))	('CRTC1', 'Gene', '23373', (26, 31))	('fusion', 'Var', (37, 43))	('SS18', 'Gene', '6760', (32, 36))
618883	29533464	In this report we have identified by RNA sequencing a novel recurrent CRTC1-SS18 gene fusion in two USRCS that were negative for known gene fusions in this sarcoma type.	('SS18', 'Gene', (76, 80))	('sarcoma', 'Disease', 'MESH:D012509', (156, 163))	('sarcoma', 'Disease', (156, 163))	('fusion', 'Var', (86, 92))	('CRTC1', 'Gene', (70, 75))	('SS18', 'Gene', '6760', (76, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('CRTC1', 'Gene', '23373', (70, 75))
618885	29533464	CRTC1 has already been involved in other translocations such as the CRTC1-MAML2 fusion in mucoepidermoid carcinoma (MEC) of salivary, bronchial and thyroid glands and the CRTC1-TRIM1 fusion in cutaneous melanocytomas.	('CRTC1', 'Gene', (0, 5))	('TRIM1', 'Gene', '11043', (177, 182))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (90, 114))	('CRTC1', 'Gene', (68, 73))	('CRTC1', 'Gene', (171, 176))	('CRTC1', 'Gene', '23373', (171, 176))	('cutaneous melanocytomas', 'Disease', (193, 216))	('cutaneous melanocytomas', 'Disease', 'MESH:D017577', (193, 216))	('CRTC1', 'Gene', '23373', (0, 5))	('CRTC1', 'Gene', '23373', (68, 73))	('mucoepidermoid carcinoma', 'Disease', (90, 114))	('TRIM1', 'Gene', (177, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('fusion', 'Var', (80, 86))	('MAML2', 'Gene', (74, 79))	('MAML2', 'Gene', '84441', (74, 79))	('involved', 'Reg', (23, 31))
618887	29533464	The SS18-SSX fusion is a result of the chromosomal translocation t(X;18)(p11;q11) in virtually all cases of synovial sarcoma (SS), which accounts for approximately 10-20% of all soft tissue sarcomas.	('SSX', 'Gene', (9, 12))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (108, 124))	('SS18', 'Gene', '6760', (4, 8))	('synovial sarcoma', 'Disease', 'MESH:D013584', (108, 124))	('t(X;18)(p11;q11', 'Var', (65, 80))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (178, 197))	('sarcomas', 'Disease', 'MESH:D012509', (190, 198))	('SSX', 'Gene', '727837', (9, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (190, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('t(X;18)(p11;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (65, 81))	('synovial sarcoma', 'Disease', (108, 124))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (178, 198))	('SS18', 'Gene', (4, 8))	('sarcomas', 'Disease', (190, 198))
618891	29533464	Only one other ELS tumour with a CIC-FOXO4 gene fusion has been described with desmoplastic stroma which showed immunoreactivity with CD99 and focal WT1.	('FOXO4', 'Gene', (37, 42))	('ELS tumour', 'Disease', 'MESH:D009369', (15, 25))	('CIC', 'Gene', '23152', (33, 36))	('ELS tumour', 'Disease', (15, 25))	('fusion', 'Var', (48, 54))	('WT1', 'Gene', '7490', (149, 152))	('WT1', 'Gene', (149, 152))	('FOXO4', 'Gene', '4303', (37, 42))	('CIC', 'Gene', (33, 36))	('desmoplastic stroma', 'Disease', 'MESH:D018220', (79, 98))	('desmoplastic stroma', 'Disease', (79, 98))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
618893	29533464	DSRCT commonly arises in the abdominal cavity in children and young adults and are characterised histologically by nests of small round cells surrounded desmoplastic stroma, immunohistochemically by positive staining for keratins, desmin and WT1, and genetically by the presence of a recurrent translocation t(11;22)(p13;q12).	('desmoplastic stroma', 'Disease', (153, 172))	('desmin', 'Gene', '1674', (231, 237))	('DSRCT', 'Disease', (0, 5))	('WT1', 'Gene', '7490', (242, 245))	('t(11;22)(p13;q12', 'Var', (308, 324))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (308, 325))	('desmin', 'Gene', (231, 237))	('keratins', 'Protein', (221, 229))	('desmoplastic stroma', 'Disease', 'MESH:D018220', (153, 172))	('WT1', 'Gene', (242, 245))	('children', 'Species', '9606', (49, 57))
618903	29533464	The severe clinical phenotype (lung metastasis at an early age) of case 1 (Case 2 has 6 months of follow-up), the novel CRTC1-SS18 gene fusion and the expression profile data indicate that these tumours may be classified as a new type of USRCS.	('fusion', 'Var', (136, 142))	('CRTC1', 'Gene', (120, 125))	('SS18', 'Gene', '6760', (126, 130))	('CRTC1', 'Gene', '23373', (120, 125))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('SS18', 'Gene', (126, 130))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
618946	31975783	to assess doxorubicin combined with olaratumab, a platelet-derived growth factor receptor alpha- (PDGFRalpha-) blocking antibody, the combination of olaratumab plus doxorubicin showed a significant improvement in OS compared with doxorubicin alone, although the response rate and progression-free survival were slightly lower.	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (50, 95))	('improvement', 'PosReg', (198, 209))	('doxorubicin', 'Chemical', 'MESH:D004317', (165, 176))	('platelet-derived growth factor receptor alpha', 'Gene', (50, 95))	('doxorubicin', 'Chemical', 'MESH:D004317', (10, 21))	('doxorubicin', 'Chemical', 'MESH:D004317', (230, 241))	('olaratumab', 'Var', (149, 159))	('combination', 'Var', (134, 145))
618969	31975783	The presence of t(12;16) or t(12;22) translocations leads to FUS-CHOP or EWS-CHOP fusion proteins in myxoid liposarcomas.	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (101, 119))	('liposarcoma', 'Phenotype', 'HP:0012034', (108, 119))	('t(12;22', 'Gene', (28, 35))	('sarcomas', 'Phenotype', 'HP:0100242', (112, 120))	('myxoid liposarcomas', 'Disease', (101, 120))	('FUS-CHOP', 'MPA', (61, 69))	('translocations', 'Var', (37, 51))	('myxoid liposarcomas', 'Disease', 'MESH:D018208', (101, 120))	('fusion proteins', 'Protein', (82, 97))	('liposarcomas', 'Phenotype', 'HP:0012034', (108, 120))	('leads to', 'Reg', (52, 60))	('myxoid liposarcomas', 'Phenotype', 'HP:0012268', (101, 120))	('presence', 'Var', (4, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('EWS-CHOP', 'MPA', (73, 81))
619056	31975783	On the other hand, high-grade STS had a higher rate of local recurrence and metastases than low-grade STS, especially during the first two years, leading the authors to recommend follow-up:physical examination and MRI:every 3 months during the first two years, then every 6 months up to the fifth year, and annually from the sixth year until the tenth year.	('metastases', 'Disease', 'MESH:D009362', (76, 86))	('STS', 'Phenotype', 'HP:0030448', (30, 33))	('STS', 'Phenotype', 'HP:0030448', (102, 105))	('local recurrence', 'CPA', (55, 71))	('high-grade', 'Var', (19, 29))	('metastases', 'Disease', (76, 86))
619168	26637412	It has the highest spatial resolution and tissue contrasts compared to other imaging modalities, but metal implants after surgery have impeded its accuracy by causing artifacts that results from metal disturbing the main magnetic field and inducing strong and spatially - varying local gradients.	('impeded', 'NegReg', (135, 142))	('metal', 'Var', (195, 200))	('inducing', 'Reg', (240, 248))	('metal', 'Chemical', 'MESH:D008670', (195, 200))	('artifacts', 'MPA', (167, 176))	('local gradients', 'MPA', (280, 295))	('metal', 'Chemical', 'MESH:D008670', (101, 106))	('disturbing', 'NegReg', (201, 211))	('main magnetic field', 'MPA', (216, 235))
619218	32429395	Dysregulation of Wnt signaling has been implicated in synovial sarcoma.	('synovial sarcoma', 'Disease', (54, 70))	('Dysregulation', 'Var', (0, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (54, 70))	('Wnt signaling', 'Pathway', (17, 30))	('implicated', 'Reg', (40, 50))	('synovial sarcoma', 'Disease', 'MESH:D013584', (54, 70))
619234	32429395	The canonical (beta-catenin-dependent) Wnt signaling pathway plays crucial roles in the regulation of diverse biological processes including cell proliferation, survival, migration, and polarity, specification of cell fate, and self-renewal of embryonic stem cells, and its dysregulation has been implicated in the generation and progression of various malignancies.	('dysregulation', 'Var', (274, 287))	('malignancies', 'Disease', (353, 365))	('malignancies', 'Disease', 'MESH:D009369', (353, 365))	('implicated', 'Reg', (297, 307))
619236	32429395	SS18-SSX is responsible for the nuclear translocation of beta-catenin, and Wnt signaling is aberrantly activated by SS18-SSX in a transgenic mouse model; inhibition of Wnt signaling through genetic loss of beta-catenin blocks synovial sarcoma tumor formation.	('SSX', 'Gene', '6757', (5, 8))	('SSX', 'Gene', (5, 8))	('SSX', 'Gene', '6757', (121, 124))	('mouse', 'Species', '10090', (141, 146))	('blocks synovial sarcoma tumor', 'Disease', 'MESH:D013584', (219, 248))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (226, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('beta-catenin', 'Protein', (206, 218))	('loss', 'Var', (198, 202))	('blocks synovial sarcoma tumor', 'Disease', (219, 248))	('SSX', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
619240	32429395	More than 80% of colorectal cancers carry inactive mutations in the APC tumor-suppressor gene, and Wnt signaling is activated downstream of it.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('colorectal cancers', 'Disease', 'MESH:D015179', (17, 35))	('mutations', 'Var', (51, 60))	('APC tumor', 'Disease', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('activated', 'PosReg', (116, 125))	('colorectal cancers', 'Disease', (17, 35))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('APC tumor', 'Disease', 'MESH:D011125', (68, 77))
619255	32429395	Real-time monitoring revealed that knockdown of TNIK induced the almost complete growth arrest of HS-SY-II and SYO-1 cells (Figure 2B) and significantly reduced TCF/LEF transcription in HS-SY-II cells lentivirally engineered to stably carry a TOP-driven green fluorescent protein (GFP) reporter construct (Figure 2C), even after being normalized to cell viability (Figure 2D).	('knockdown', 'Var', (35, 44))	('SYO-1', 'Gene', (111, 116))	('growth arrest of HS-SY-II', 'Disease', (81, 106))	('reduced', 'NegReg', (153, 160))	('SYO-1', 'Gene', '55027', (111, 116))	('HS-SY-II', 'CellLine', 'CVCL:8719', (186, 194))	('growth arrest of HS-SY-II', 'Disease', 'MESH:D006323', (81, 106))	('growth arrest', 'Phenotype', 'HP:0001510', (81, 94))	('TNIK', 'Gene', '23043', (48, 52))	('TCF/LEF', 'Gene', '3172', (161, 168))	('TNIK', 'Gene', (48, 52))	('HS-SY-II', 'CellLine', 'CVCL:8719', (98, 106))	('TCF/LEF', 'Gene', (161, 168))	('transcription', 'MPA', (169, 182))
619257	32429395	TNIK knockdown significantly suppressed the viability of HS-SY-II, SYO-1, and Yamato cells, but not that of Aska cells (Figure 2E).	('viability', 'CPA', (44, 53))	('knockdown', 'Var', (5, 14))	('TNIK', 'Gene', '23043', (0, 4))	('SYO-1', 'Gene', '55027', (67, 72))	('TNIK', 'Gene', (0, 4))	('SYO-1', 'Gene', (67, 72))	('HS-SY-II', 'CellLine', 'CVCL:8719', (57, 65))	('suppressed', 'NegReg', (29, 39))
619259	32429395	TNIK knockdown induced cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) in HS-SY-II cells (Figure 2F), indicating induction of apoptosis.	('cleavage', 'MPA', (23, 31))	('knockdown', 'Var', (5, 14))	('PARP-1', 'Gene', (67, 73))	('TNIK', 'Gene', '23043', (0, 4))	('PARP-1', 'Gene', '142', (67, 73))	('TNIK', 'Gene', (0, 4))	('HS-SY-II', 'CellLine', 'CVCL:8719', (78, 86))	('poly (ADP-ribose) polymerase-1', 'Gene', '142', (35, 65))	('poly (ADP-ribose) polymerase-1', 'Gene', (35, 65))
619260	32429395	Based on the remarkable growth suppression and apoptosis induction in synovial sarcoma cells by silencing of the TNIK gene, the sensitivity of synovial sarcoma cell lines to a small-molecule TNIK inhibitor, NCB-0846, was then evaluated.	('silencing', 'Var', (96, 105))	('TNIK', 'Gene', '23043', (113, 117))	('TNIK', 'Gene', (113, 117))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (70, 86))	('synovial sarcoma', 'Disease', (143, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('growth suppression', 'CPA', (24, 42))	('apoptosis', 'CPA', (47, 56))	('synovial sarcoma', 'Disease', 'MESH:D013584', (70, 86))	('NCB-0846', 'Chemical', '-', (207, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (143, 159))	('synovial sarcoma', 'Disease', (70, 86))	('synovial sarcoma', 'Disease', 'MESH:D013584', (143, 159))	('TNIK', 'Gene', '23043', (191, 195))	('TNIK', 'Gene', (191, 195))
619261	32429395	Consistent with the siRNA to TNIK, NCB-0846 reduced the viability of HS-SY-II, SYO-1, and Yamato cells with a half maximal inhibitory concentration (IC50) of 339, 356, and 767 nM, respectively.	('TNIK', 'Gene', '23043', (29, 33))	('TNIK', 'Gene', (29, 33))	('HS-SY-II', 'CellLine', 'CVCL:8719', (69, 77))	('NCB-0846', 'Chemical', '-', (35, 43))	('viability', 'CPA', (56, 65))	('SYO-1', 'Gene', '55027', (79, 84))	('reduced', 'NegReg', (44, 51))	('NCB-0846', 'Var', (35, 43))	('SYO-1', 'Gene', (79, 84))
619265	32429395	Real-time monitoring of cell-surface phosphatidylserine (PS) revealed that NCB-0846, but not its diastereomer (named NCB-0970), induced apoptotic cell death of HS-SY-II cells within 6 h after the start of drug treatment (Figure 3C).	('NCB-0970', 'Chemical', '-', (117, 125))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (37, 55))	('NCB-0846', 'Var', (75, 83))	('men', 'Species', '9606', (215, 218))	('HS-SY-II', 'CellLine', 'CVCL:8719', (160, 168))	('death', 'Disease', (151, 156))	('death', 'Disease', 'MESH:D003643', (151, 156))	('PS', 'Chemical', 'MESH:D010718', (57, 59))	('induced', 'Reg', (128, 135))	('NCB-0846', 'Chemical', '-', (75, 83))
619267	32429395	An increase of the sub-G1 cell population (Figure 3D) and cleavage of PARP-1 (Figure 3E) confirmed the induction of apoptotic cell death by NCB-0846.	('NCB-0846', 'Chemical', '-', (140, 148))	('PARP-1', 'Gene', '142', (70, 76))	('cleavage', 'CPA', (58, 66))	('NCB-0846', 'Var', (140, 148))	('sub-G1 cell population', 'CPA', (19, 41))	('death', 'Disease', 'MESH:D003643', (131, 136))	('death', 'Disease', (131, 136))	('increase', 'PosReg', (3, 11))	('PARP-1', 'Gene', (70, 76))
619269	32429395	HS-SY-II cells were exposed to NCB-0846 or NCB-0970 for 6 h, and their relative RNA expression (FPKM, fragments per kilobase of exon per million mapped reads) was determined using a next-generation sequencer.	('HS-SY-II', 'CellLine', 'CVCL:8719', (0, 8))	('NCB-0846', 'Chemical', '-', (31, 39))	('NCB-0970', 'Chemical', '-', (43, 51))	('men', 'Species', '9606', (106, 109))	('NCB-0846', 'Var', (31, 39))	('NCB-0970', 'Var', (43, 51))
619281	32429395	A high degree (>2.0-fold) of MYC oncogene amplification is known to be infrequent in synovial sarcoma.	('MYC', 'Gene', '4609', (29, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('synovial sarcoma', 'Disease', (85, 101))	('MYC', 'Gene', (29, 32))	('amplification', 'Var', (42, 55))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (85, 101))	('synovial sarcoma', 'Disease', 'MESH:D013584', (85, 101))
619284	32429395	Knockdown of MYC gene expression by siRNA reduced the viability of HS-SY-II, SYO-1, and Yamato cells, but Aska cells were insensitive to silencing of MYC (Figure 6D) and NCB-0846 (Figure 3A), suggesting that NCB-0846 induces apoptotic cell death of synovial sarcoma at least partially through transcriptional suppression of MYC.	('synovial sarcoma', 'Disease', (249, 265))	('MYC', 'Gene', '4609', (13, 16))	('SYO-1', 'Gene', '55027', (77, 82))	('synovial sarcoma', 'Disease', 'MESH:D013584', (249, 265))	('SYO-1', 'Gene', (77, 82))	('reduced', 'NegReg', (42, 49))	('transcriptional', 'MPA', (293, 308))	('suppression', 'NegReg', (309, 320))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (249, 265))	('death', 'Disease', 'MESH:D003643', (240, 245))	('NCB-0846', 'Chemical', '-', (170, 178))	('MYC', 'Gene', (150, 153))	('NCB-0846', 'Var', (208, 216))	('MYC', 'Gene', (324, 327))	('HS-SY-II', 'CellLine', 'CVCL:8719', (67, 75))	('NCB-0846', 'Chemical', '-', (208, 216))	('MYC', 'Gene', (13, 16))	('MYC', 'Gene', '4609', (150, 153))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('death', 'Disease', (240, 245))	('MYC', 'Gene', '4609', (324, 327))
619296	32429395	Middeljans and colleagues reported that expression of the fusion oncogene induced depletion of the BAF47 (SMARCB1) subunit from the SWI/SNF complex.	('BAF47', 'Gene', (99, 104))	('expression', 'Var', (40, 50))	('depletion of', 'MPA', (82, 94))	('SMARCB1', 'Gene', (106, 113))	('SMARCB1', 'Gene', '6598', (106, 113))	('BAF47', 'Gene', '6598', (99, 104))
619297	32429395	Potential convergence may exist between the SWI/SNF complex and Wnt signaling, as loss of SMARCB1 reportedly activates Wnt signaling.	('Wnt signaling', 'MPA', (119, 132))	('SMARCB1', 'Gene', (90, 97))	('activates', 'PosReg', (109, 118))	('loss', 'Var', (82, 86))	('SMARCB1', 'Gene', '6598', (90, 97))
619299	32429395	The Wnt signaling pathway is aberrantly activated in an SS18-SSX2 transgenic mouse model, and genetic loss of beta-catenin (Ctnnb1) blocks tumor formation in this model.	('Ctnnb1', 'Gene', '12387', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('SSX2', 'Gene', '6757', (61, 65))	('Wnt signaling pathway', 'Pathway', (4, 25))	('activated', 'PosReg', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('SSX2', 'Gene', (61, 65))	('Ctnnb1', 'Gene', (124, 130))	('loss', 'Var', (102, 106))	('blocks', 'NegReg', (132, 138))	('mouse', 'Species', '10090', (77, 82))
619301	32429395	Synovial sarcoma cell lines (SYO-1, CME-1, and HS-SY-II) showed sensitivity to three small-molecule inhibitors of the TCF/beta-catenin complex (PKF115-584, CGP049090, and PKF118-310).	('PKF118-310', 'Var', (171, 181))	('TCF', 'Gene', '3172', (118, 121))	('SYO-1', 'Gene', '55027', (29, 34))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('Synovial sarcoma', 'Disease', (0, 16))	('TCF', 'Gene', (118, 121))	('PKF115-584', 'Var', (144, 154))	('SYO-1', 'Gene', (29, 34))	('Synovial sarcoma', 'Disease', 'MESH:D013584', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('HS-SY-II', 'CellLine', 'CVCL:8719', (47, 55))	('CGP049090', 'Var', (156, 165))
619302	32429395	beta-Catenin stabilization in a transgenic animal model reportedly enhanced SS18-SSX-driven tumorigenesis and produced more dedifferentiated tumors.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('SSX', 'Gene', '6757', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('SSX', 'Gene', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (141, 146))	('stabilization', 'Var', (13, 26))	('beta-Catenin', 'Gene', (0, 12))	('beta-Catenin', 'Gene', '12387', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('enhanced', 'PosReg', (67, 75))
619310	32429395	Synovial sarcoma cell lines with high c-MYC protein expression were sensitive to the compound (Figure 3) and to the gene silencing of MYC (Figure 6).	('MYC', 'Gene', (134, 137))	('MYC', 'Gene', '4609', (40, 43))	('gene silencing', 'Var', (116, 130))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('Synovial sarcoma', 'Disease', (0, 16))	('MYC', 'Gene', '4609', (134, 137))	('c-MYC', 'Gene', '4609', (38, 43))	('Synovial sarcoma', 'Disease', 'MESH:D013584', (0, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('MYC', 'Gene', (40, 43))	('c-MYC', 'Gene', (38, 43))
619313	32429395	Aberrant expression or gene amplification of MYC has been implicated in the aggressiveness of various malignancies.	('Aberrant expression', 'Var', (0, 19))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('MYC', 'Gene', (45, 48))	('aggressiveness', 'Disease', 'MESH:D001523', (76, 90))	('malignancies', 'Disease', (102, 114))	('aggressiveness', 'Disease', (76, 90))	('MYC', 'Gene', '4609', (45, 48))	('implicated', 'Reg', (58, 68))	('gene amplification', 'Var', (23, 41))	('aggressiveness', 'Phenotype', 'HP:0000718', (76, 90))
619339	32429395	and confirmed by the detection of SS18 rearrangement by fluorescence in situ hybridization (FISH) or RT-PCR and/or the reduced expression of SMARCB1.	('SMARCB1', 'Gene', '6598', (141, 148))	('men', 'Species', '9606', (48, 51))	('expression', 'MPA', (127, 137))	('SS18', 'Gene', (34, 38))	('reduced', 'NegReg', (119, 126))	('rearrangement', 'Var', (39, 52))	('SMARCB1', 'Gene', (141, 148))
619341	32429395	Cells seeded at 50-70% confluency were transfected with siTNIK (s22905, s22906, and s22907; Thermo Fisher Scientific) and siMYC (s9129 and s9130; Thermo Fisher Scientific) at a final concentration of 50 nM in accordance with the manufacturer's instructions.	('s9130', 'Var', (139, 144))	('s22907', 'Var', (84, 90))	('siMYC', 'Disease', 'None', (122, 127))	('siMYC', 'Disease', (122, 127))	('s22906', 'Var', (72, 78))	('TNIK', 'Gene', '23043', (58, 62))	('s22905', 'Var', (64, 70))	('TNIK', 'Gene', (58, 62))	('s9129', 'Var', (129, 134))
619353	32429395	When the average tumor volume reached ~200 mm3, the mice were randomized according to tumor volume (five mice/group) and administered water (vehicle alone) or 80 mg/kg (body weight) NCB-0846 HCl (NCB-1055) dissolved in water by oral gavage twice a day in a 7 day schedule of 5 days on and 2 days off.	('NCB-1055', 'Chemical', '-', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (86, 91))	('water', 'Chemical', 'MESH:D014867', (134, 139))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('NCB-0846 HCl', 'Chemical', '-', (182, 194))	('water', 'Chemical', 'MESH:D014867', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('NCB-0846', 'Var', (182, 190))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
619374	32429395	), a KAKENHI Grant-in-Aid for Challenging Research (16K14627 to M.M.	('16K14627', 'Var', (52, 60))	('Aid', 'Gene', '57379', (22, 25))	('Aid', 'Gene', (22, 25))
619375	32429395	), a Grant-in Aid for Scientific Research (B) (17H03603 to M.M.	('Aid', 'Gene', '57379', (14, 17))	('Aid', 'Gene', (14, 17))	('17H03603', 'Var', (47, 55))
619414	30652038	Overexpression of EGFR can potentially make myoepithelial carcinoma susceptible to cetuximab.	('cetuximab', 'Chemical', 'MESH:D000068818', (83, 92))	('EGFR', 'Gene', '1956', (18, 22))	('make', 'Reg', (39, 43))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (44, 67))	('myoepithelial carcinoma', 'Disease', (44, 67))	('EGFR', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
619417	30652038	At the time of this patient's diagnosis, there were no therapies that directly target SMARCB1 loss or inactivating mutations.	('loss', 'NegReg', (94, 98))	('patient', 'Species', '9606', (20, 27))	('inactivating mutations', 'Var', (102, 124))	('SMARCB1', 'Gene', (86, 93))	('SMARCB1', 'Gene', '6598', (86, 93))
619457	27016421	Nine of the 105 liposarcomas (8.6%) had activating PIK3CA mutation.	('activating', 'PosReg', (40, 50))	('liposarcomas', 'Disease', 'MESH:D008080', (16, 28))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('liposarcomas', 'Disease', (16, 28))	('liposarcoma', 'Phenotype', 'HP:0012034', (16, 27))	('mutation', 'Var', (58, 66))	('PIK3CA', 'Gene', (51, 57))	('liposarcomas', 'Phenotype', 'HP:0012034', (16, 28))
619458	27016421	PIK3CA mutations were more frequent in myxoid/round cell and pleomorphic tumors compared with well-differentiated/dedifferentiated tumors (13.3% vs. 2.2%, P=0.043).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('pleomorphic tumors', 'Disease', (61, 79))	('pleomorphic tumors', 'Disease', 'MESH:C538229', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PIK3CA', 'Gene', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('frequent', 'Reg', (27, 35))	('myxoid/round cell', 'Disease', (39, 56))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('mutations', 'Var', (7, 16))
619459	27016421	In FISH PIK3CA analysis, copy number gain was detected in 14 of the 101 tumors (13.9%): 11 (10.9%) tumors had increased gene copy number (polysomy) and 3 (3.0%) exhibited gene amplification.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('gene copy', 'MPA', (120, 129))	('increased', 'PosReg', (110, 119))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('copy number', 'Var', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('gain', 'PosReg', (37, 41))	('tumors', 'Disease', (99, 105))
619460	27016421	In survival analysis, patients with PIK3CA copy number gain had a worse prognosis compared to patients without PIK3CA amplification (median disease-free survival [DFS] 22.2 vs. 107.6 months p=0.005).	('patients', 'Species', '9606', (94, 102))	('gain', 'PosReg', (55, 59))	('patients', 'Species', '9606', (22, 30))	('copy number', 'Var', (43, 54))	('PIK3CA', 'Gene', (36, 42))
619461	27016421	We demonstrated PIK3CA mutation and amplification in liposarcoma.	('liposarcoma', 'Disease', (53, 64))	('mutation', 'Var', (23, 31))	('liposarcoma', 'Disease', 'MESH:D008080', (53, 64))	('liposarcoma', 'Phenotype', 'HP:0012034', (53, 64))	('amplification', 'Var', (36, 49))	('PIK3CA', 'Gene', (16, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
619471	27016421	Activation of the PI3K pathway occurs upon engagement with mutated or amplified phosphatidylinositol-4,5-bisphosphate 3-Kinase, catalytic subunit Alpha (PIK3CA) gene It increases p110alpha expression, PI3K activation, and phosphorylation of downstream signaling molecules.	('phosphorylation', 'MPA', (222, 237))	('increases', 'PosReg', (169, 178))	('expression', 'MPA', (189, 199))	('p110alpha', 'Gene', (179, 188))	('PI3K', 'Protein', (201, 205))	('p110alpha', 'Gene', '5290', (179, 188))	('activation', 'PosReg', (206, 216))	('PIK3CA', 'Gene', (153, 159))	('mutated', 'Var', (59, 66))	('PI3K pathway', 'Pathway', (18, 30))
619472	27016421	Akt-PIK3CA gene amplification was found in 10-30% of non-small cell lung cancer, breast cancer, and colon cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (53, 79))	('breast cancer', 'Disease', (81, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('amplification', 'Var', (16, 29))	('cell lung cancer', 'Disease', (63, 79))	('Akt', 'Gene', '207', (0, 3))	('colon cancer', 'Disease', 'MESH:D015179', (100, 112))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (57, 79))	('found', 'Reg', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cell lung cancer', 'Disease', 'MESH:D008175', (63, 79))	('Akt', 'Gene', (0, 3))	('colon cancer', 'Disease', (100, 112))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
619474	27016421	Recently, PIK3CA mutation was reported in 12% and 18% of myxoid/round-cell liposarcoma, and it was associated with Akt activation and poor clinical outcome.	('Akt', 'Gene', '207', (115, 118))	('liposarcoma', 'Disease', (75, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('Akt', 'Gene', (115, 118))	('PIK3CA', 'Gene', (10, 16))	('mutation', 'Var', (17, 25))	('liposarcoma', 'Disease', 'MESH:D008080', (75, 86))	('activation', 'PosReg', (119, 129))	('liposarcoma', 'Phenotype', 'HP:0012034', (75, 86))	('myxoid/round-cell liposarcoma', 'Phenotype', 'HP:0012268', (57, 86))
619476	27016421	In this study, we evaluated the frequency of PIK3CA amplification and mutation in surgically resected liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('liposarcoma', 'Disease', (102, 113))	('liposarcoma', 'Disease', 'MESH:D008080', (102, 113))	('PIK3CA', 'Gene', (45, 51))	('liposarcoma', 'Phenotype', 'HP:0012034', (102, 113))	('mutation', 'Var', (70, 78))
619484	27016421	Based on PIK3CA gene expression values, tumors were categorized into three groups: (I) normal copy number, tumors with <=2 copies per cell with a PIK3CA/CEN3 ratio < 2.0; (II) polysomy, tumors with an average PIK3CA signal per nucleus 4.0 >= to > 2.0; and (III) amplification, tumors with >4 copies per cell and/or a PIK3CA/CEN3 ratio >= 2.0.	('amplification', 'Var', (262, 275))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('polysomy', 'Var', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', (277, 283))
619485	27016421	By these criteria, of the 101 cases, 14 tumors (13.9%) demonstrated copy number gain, 11 (10.9%) had polysomy, and 3 (3.0%) had gene amplification (Table 2, Figure 1).	('14 tumors', 'Disease', (37, 46))	('gene amplification', 'Var', (128, 146))	('polysomy', 'Var', (101, 109))	('gain', 'PosReg', (80, 84))	('14 tumors', 'Disease', 'MESH:C567448', (37, 46))	('copy', 'MPA', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
619486	27016421	PIK3CA copy number gain was significantly associated with older age and larger tumor size (Table 1, P=0.023 and P=0.040, respectively).	('tumor', 'Disease', (79, 84))	('PIK3CA', 'Gene', (0, 6))	('copy number', 'Var', (7, 18))	('gain', 'PosReg', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
619488	27016421	Using the Cox proportional hazard model adjusted for gender, age, histology, and tumor location, PIK3CA copy number gain was an independent poor prognostic factor for DFS (Table 3, P=0.027; hazard ratio [HR], 2.400; 95% confidence interval [CI] 1.105 to 5.213).	('DFS', 'Disease', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('copy number', 'Var', (104, 115))	('PIK3CA', 'Gene', (97, 103))	('gain', 'PosReg', (116, 120))	('tumor', 'Disease', (81, 86))
619490	27016421	For PIK3CA exon 9, E542K mutations were identified in 2 tumors, Q546K mutations were identified in 2 tumors, and an E545K mutation was identified in 1 tumor.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('Q546K', 'Var', (64, 69))	('E545K', 'Mutation', 'rs104886003', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PIK3CA', 'Gene', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('E542K', 'Mutation', 'rs121913273', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('E542K', 'Var', (19, 24))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumors', 'Disease', (101, 107))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('Q546K', 'Mutation', 'rs121913286', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
619491	27016421	For exon 20, H1047R mutations were identified in 3 tumors, and an H1047L was identified in 1 tumor (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('H1047L', 'Mutation', 'rs121913279', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('H1047R mutations', 'Var', (13, 29))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (93, 98))	('H1047L', 'Var', (66, 72))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('H1047R', 'Mutation', 'rs121913279', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
619492	27016421	With respect to histologic subtype, PIK3CA mutations were more frequent in well-differentiated/dedifferentiated tumors compared with myxoid/round cell/pleomorphic tumors (Table 4, 13.3% vs. 2.2%, P=0.043).	('pleomorphic tumors', 'Disease', (151, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', (163, 169))	('frequent', 'Reg', (63, 71))	('mutations', 'Var', (43, 52))	('pleomorphic tumors', 'Disease', 'MESH:C538229', (151, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('PIK3CA', 'Gene', (36, 42))	('tumors', 'Disease', (112, 118))
619493	27016421	Of all mutated tumors, 6 tumors (66.7%) were myxoid/round cell, 2 tumors (22.2%) were pleomorphic, and 1 tumor (11.1%) was well-differentiated (Table 4, Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('myxoid/round cell', 'Disease', (45, 62))	('tumor', 'Disease', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (105, 110))	('tumors', 'Disease', (15, 21))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutated', 'Var', (7, 14))
619495	27016421	Of the 7 tumors with PIK3CA mutation, 3 tumors (21.4%) exhibited copy number gain, whereas only 4 tumors (5.9%) had normal copy numbers.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PIK3CA', 'Gene', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutation', 'Var', (28, 36))	('tumors', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('copy number', 'MPA', (65, 76))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('gain', 'PosReg', (77, 81))	('tumors', 'Disease', (40, 46))
619497	27016421	To our knowledge, this is the first study evaluating the prognostic impact of PIK3CA polysomy and amplification in a large cohort of Asian liposarcoma patients.	('liposarcoma', 'Disease', (139, 150))	('PIK3CA', 'Gene', (78, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('liposarcoma', 'Phenotype', 'HP:0012034', (139, 150))	('patients', 'Species', '9606', (151, 159))	('liposarcoma', 'Disease', 'MESH:D008080', (139, 150))	('amplification', 'Var', (98, 111))	('polysomy', 'Var', (85, 93))
619498	27016421	We demonstrated that PIK3CA aberration is a poor prognostic factor in liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (70, 81))	('liposarcoma', 'Disease', 'MESH:D008080', (70, 81))	('PIK3CA aberration', 'Var', (21, 38))	('liposarcoma', 'Disease', (70, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))
619502	27016421	Despite known targeted therapeutic options in solid tumors (KIT or PDGFRA mutations in gastrointestinal stromal tumors), STS still lacks therapeutically relevant genetic alterations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('STS', 'Phenotype', 'HP:0030448', (121, 124))	('gastrointestinal stromal tumors', 'Disease', (87, 118))	('solid tumors', 'Disease', 'MESH:D009369', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (74, 83))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (87, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDGFRA', 'Gene', (67, 73))	('KIT', 'Gene', (60, 63))	('solid tumors', 'Disease', (46, 58))	('PDGFRA', 'Gene', '5156', (67, 73))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (87, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
619504	27016421	Among them, PIK3CA mutation was observed in 18% of myxoid/round cell liposarcomas.	('myxoid/round cell liposarcomas', 'Phenotype', 'HP:0012268', (51, 81))	('liposarcomas', 'Disease', (69, 81))	('mutation', 'Var', (19, 27))	('observed', 'Reg', (32, 40))	('liposarcoma', 'Phenotype', 'HP:0012034', (69, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('liposarcomas', 'Disease', 'MESH:D008080', (69, 81))	('liposarcomas', 'Phenotype', 'HP:0012034', (69, 81))	('PIK3CA', 'Gene', (12, 18))
619506	27016421	Activation of the PI3K pathway, generally as result of PIK3CA amplification, has been demonstrated in 12% cases of lung cancer, 32% cases of head and neck cancer, and 24% cases of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (180, 194))	('neck cancer', 'Disease', 'MESH:D006258', (150, 161))	('Activation', 'PosReg', (0, 10))	('neck cancer', 'Disease', (150, 161))	('PIK3CA', 'Gene', (55, 61))	('head and neck cancer', 'Phenotype', 'HP:0012288', (141, 161))	('amplification', 'Var', (62, 75))	('PI3K pathway', 'Pathway', (18, 30))	('ovarian cancer', 'Disease', 'MESH:D010051', (180, 194))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('ovarian cancer', 'Disease', (180, 194))
619507	27016421	In head and neck squamous cell carcinoma, PIK3CA amplification led to earlier recurrence.	('PIK3CA amplification', 'Var', (42, 62))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (12, 40))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))
619508	27016421	For nasopharyngeal carcinoma, amplification was associated with distant metastasis, advanced stage, and poor OS.	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (4, 28))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (4, 28))	('nasopharyngeal carcinoma', 'Disease', (4, 28))	('associated', 'Reg', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('poor OS', 'Disease', (104, 111))	('advanced stage', 'CPA', (84, 98))	('amplification', 'Var', (30, 43))	('distant metastasis', 'CPA', (64, 82))
619512	27016421	Only The Cancer Genome Atlas (TCGA) data had reported 1% frequency of PIK3CA amplification and few comparable studies were reported with clinical cases.	('Cancer Genome Atlas', 'Disease', (9, 28))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (9, 28))	('amplification', 'Var', (77, 90))	('PIK3CA', 'Gene', (70, 76))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))
619514	27016421	PIK3CA amplification was significantly associated with poor DFS regardless of gender, age, histology, or tumor location, as an independent prognostic factor in curatively resected liposarcoma.	('liposarcoma', 'Phenotype', 'HP:0012034', (180, 191))	('liposarcoma', 'Disease', 'MESH:D008080', (180, 191))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('amplification', 'Var', (7, 20))	('tumor', 'Disease', (105, 110))	('liposarcoma', 'Disease', (180, 191))
619516	27016421	In our large cohort study, we used a combination of these criteria and demonstrated that amplification and polysomy have significant prognostic impacts on liposarcoma patients.	('polysomy', 'Var', (107, 115))	('patients', 'Species', '9606', (167, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('liposarcoma', 'Disease', (155, 166))	('impacts', 'Reg', (144, 151))	('amplification', 'Var', (89, 102))	('liposarcoma', 'Phenotype', 'HP:0012034', (155, 166))	('liposarcoma', 'Disease', 'MESH:D008080', (155, 166))
619518	27016421	PIK3CA mutation has been reported 14-18.3% of myxoid/round-cell liposarcoma and associated with shorter DFS with mass spectrometry-based genotyping.	('shorter', 'NegReg', (96, 103))	('liposarcoma', 'Disease', (64, 75))	('myxoid/round-cell liposarcoma', 'Phenotype', 'HP:0012268', (46, 75))	('PIK3CA', 'Gene', (0, 6))	('liposarcoma', 'Phenotype', 'HP:0012034', (64, 75))	('DFS', 'MPA', (104, 107))	('mutation', 'Var', (7, 15))	('liposarcoma', 'Disease', 'MESH:D008080', (64, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))
619519	27016421	Here, we report PIK3CA mutations in 8.6% of liposarcoma by employing a pyrosequencing approach and not associated with prognostic outcome.	('liposarcoma', 'Disease', (44, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (48, 55))	('mutations', 'Var', (23, 32))	('liposarcoma', 'Phenotype', 'HP:0012034', (44, 55))	('liposarcoma', 'Disease', 'MESH:D008080', (44, 55))	('PIK3CA', 'Gene', (16, 22))
619520	27016421	Although the majority of mutant tumors (66.6%) were of the myxoid/round-cell subtype, additional mutant cases were also detected in well-differentiated, dedifferentiated, and pleomorphic liposarcoma.	('pleomorphic liposarcoma', 'Disease', (175, 198))	('mutant', 'Var', (25, 31))	('liposarcoma', 'Phenotype', 'HP:0012034', (187, 198))	('pleomorphic liposarcoma', 'Disease', 'MESH:D008080', (175, 198))	('dedifferentiated', 'Disease', (153, 169))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
619529	27016421	PIK3CA amplification and/or mutation are associated with increased activity of the PI3K effector pAkt, suggesting that amplified or mutated tumors may be sensitive to PI3K inhibitors.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Akt', 'Gene', '207', (98, 101))	('PIK3CA', 'Gene', (0, 6))	('mutation', 'Var', (28, 36))	('activity', 'MPA', (67, 75))	('Akt', 'Gene', (98, 101))	('increased', 'PosReg', (57, 66))	('amplification', 'Var', (7, 20))
619532	27016421	Cell lines with PIK3CA amplification was positively associated with BYL719 sensitivity (P=0.0037) and tumor-bearing mice with PIK3CA amplification responded to BYL719, leading to a response rate of -18% (lung cancer) and -80% (gastric cancer).	('mice', 'Species', '10090', (116, 120))	('PIK3CA', 'Gene', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('amplification', 'Var', (23, 36))	('associated', 'Reg', (52, 62))	('sensitivity', 'MPA', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BYL719', 'MPA', (68, 74))	('lung cancer', 'Disease', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('PIK3CA', 'Gene', (16, 22))	('tumor', 'Disease', (102, 107))	('gastric cancer', 'Disease', (227, 241))	('gastric cancer', 'Disease', 'MESH:D013274', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
619533	27016421	In a phase I trial with GDC-0941, a heavily treated ovarian cancer patient with PIK3CA amplification experienced disease stabilization for 4 months with significant pharmacodynamic changes.	('ovarian cancer', 'Disease', (52, 66))	('patient', 'Species', '9606', (67, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('ovarian cancer', 'Disease', 'MESH:D010051', (52, 66))	('PIK3CA', 'Gene', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('GDC-0941', 'Chemical', 'MESH:C532162', (24, 32))	('amplification', 'Var', (87, 100))
619534	27016421	While previous trials with PI3K inhibitors have been conducted in non-selected patients, recent clinical trials with PI3K inhibitors are ongoing for those with PIK3CA gene alterations (ClinicalTrials.gov number NCT01928459 and NCT01608022).	('alterations', 'Var', (172, 183))	('patients', 'Species', '9606', (79, 87))	('PIK3CA', 'Gene', (160, 166))
619537	27016421	Here, we report PIK3CA aberration as an independent poor prognostic factor for curatively resected liposarcoma.	('liposarcoma', 'Disease', (99, 110))	('aberration', 'Var', (23, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('liposarcoma', 'Phenotype', 'HP:0012034', (99, 110))	('liposarcoma', 'Disease', 'MESH:D008080', (99, 110))	('PIK3CA', 'Gene', (16, 22))
619608	24843244	This gene is expressed as unbalanced der (17) t(X;17)(p11.2;q25) in ASPS while it is found as balanced t(X;17)(p11.2;q25) in some of RCC variants occurring in children or young adults.	('children', 'Species', '9606', (159, 167))	('ASPS', 'Gene', '79058', (68, 72))	('ASPS', 'Phenotype', 'HP:0012218', (68, 72))	('t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (103, 121))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('ASPS', 'Gene', (68, 72))	('RCC', 'Disease', (133, 136))	('t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (46, 64))	('variants', 'Var', (137, 145))
619621	23935076	In most of the patients, a chromosomal translocation leads to the expression of the EWS-FLI1 chimeric transcription factor that is the major oncogene in this pathology.	('patients', 'Species', '9606', (15, 23))	('EWS-FLI1', 'Gene', (84, 92))	('chromosomal translocation', 'Var', (27, 52))	('EWS-FLI1', 'Gene', '2130;2313', (84, 92))	('expression', 'MPA', (66, 76))	('leads to', 'Reg', (53, 61))
619623	23935076	Silencing EWS-FLI1 induces cell cycle alteration and ultimately leads to apoptosis, but the exact molecular mechanisms underlying this phenotype are unclear.	('cell cycle alteration', 'CPA', (27, 48))	('cell cycle alteration', 'Phenotype', 'HP:0011018', (27, 48))	('apoptosis', 'CPA', (73, 82))	('EWS-FLI1', 'Gene', (10, 18))	('Silencing', 'Var', (0, 9))	('leads to', 'Reg', (64, 72))	('induces', 'Reg', (19, 26))	('EWS-FLI1', 'Gene', '2130;2313', (10, 18))
619635	23935076	Moreover, knocking down EWS-FLI1 in Ewing sarcoma cell lines slows down proliferation and induces apoptosis in vitro and in vivo.	('knocking down', 'Var', (10, 23))	('apoptosis', 'CPA', (98, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('proliferation', 'CPA', (72, 85))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (36, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (36, 49))	('slows down', 'NegReg', (61, 71))	('induces', 'Reg', (90, 97))	('EWS-FLI1', 'Gene', (24, 32))	('Ewing sarcoma', 'Disease', (36, 49))	('EWS-FLI1', 'Gene', '2130;2313', (24, 32))
619646	23935076	Time-series of transcriptome response to silencing/re-expressing of EWS-FLI1 were published in.	('silencing/re-expressing', 'Var', (41, 64))	('EWS-FLI1', 'Gene', '2130;2313', (68, 76))	('EWS-FLI1', 'Gene', (68, 76))
619647	23935076	However, these experiments did not allow to follow the transcriptome response for a time period longer than a few days, whereas significant transcriptome changes after EWS-FLI1 inhibition can be observed even after 1 week.	('EWS-FLI1', 'Gene', (168, 176))	('EWS-FLI1', 'Gene', '2130;2313', (168, 176))	('inhibition', 'Var', (177, 187))	('transcriptome', 'MPA', (140, 153))
619661	23935076	The score for each fit is the ratio between an amplitude alpha and a mean-squared error delta multiplied by a transition time penalization factor tau:   For the hyperbolic tangent ('switch'), the inflexion point of the curve define naturally a transition time separating the time points in a high level and a low level window.	('error delta', 'Disease', (82, 93))	('error delta', 'Disease', 'MESH:D003699', (82, 93))	('hyperbolic', 'Var', (161, 171))
619674	23935076	This indicates that the switch-like (single transition) and pulse-like (double transition) modes of gene expression variation are predominant in such EWS-FLI1 inhibition and re-expression experiments.	('variation', 'Var', (116, 125))	('EWS-FLI1', 'Gene', '2130;2313', (150, 158))	('EWS-FLI1', 'Gene', (150, 158))
619676	23935076	Two time series models were considered: (i) one curve describing the switch-like (SL, single transition) profile, applied to EWS-FLI1 inhibition (DOX+); (ii) one curve describing pulse-like (PL, double transition) profile, applied to EWS-FLI1 inhibition/re-expression (DOX+, DOX-).	('EWS-FLI1', 'Gene', (125, 133))	('EWS-FLI1', 'Gene', '2130;2313', (125, 133))	('inhibition', 'Var', (134, 144))	('DOX', 'Chemical', 'MESH:D004318', (275, 278))	('EWS-FLI1', 'Gene', (234, 242))	('DOX', 'Chemical', 'MESH:D004318', (269, 272))	('DOX', 'Chemical', 'MESH:D004318', (146, 149))	('EWS-FLI1', 'Gene', '2130;2313', (234, 242))
619677	23935076	Global EWS-FLI1 transcriptional response is slightly different between the two clones: fitness scores are higher in clone shA673-1C.	('shA673-1C', 'Var', (122, 131))	('higher', 'PosReg', (106, 112))	('fitness scores', 'CPA', (87, 101))	('EWS-FLI1', 'Gene', (7, 15))	('EWS-FLI1', 'Gene', '2130;2313', (7, 15))
619683	23935076	Both functional characterization methods result in identification of multiple pathways potentially implicated in response to EWS-FLI1 inactivation.	('inactivation', 'Var', (134, 146))	('EWS-FLI1', 'Gene', (125, 133))	('EWS-FLI1', 'Gene', '2130;2313', (125, 133))
619684	23935076	Indeed, EWS-FLI1 knock-down inhibits proliferation in our cellular model and in other Ewing cell lines and can also drive cells to apoptosis.	('drive', 'Reg', (116, 121))	('inhibits', 'NegReg', (28, 36))	('EWS-FLI1', 'Gene', '2130;2313', (8, 16))	('cells to apoptosis', 'CPA', (122, 140))	('knock-down', 'Var', (17, 27))	('proliferation', 'CPA', (37, 50))	('EWS-FLI1', 'Gene', (8, 16))
619694	23935076	E2Fs, IGFs) and to add implicit connections (for instance, CDK4 positively influences the (CDK4:CCND) complex formation) (see Network curation framework in Materials and Methods and Protocol 1 in the web page of supplementary material).	('E2Fs', 'Var', (0, 4))	('CDK4', 'Gene', '1019', (91, 95))	('CDK4', 'Gene', (91, 95))	('CDK4', 'Gene', (59, 63))	('CDK4', 'Gene', '1019', (59, 63))	('influences', 'Reg', (75, 85))
619700	23935076	As expected, cyclin D and protein kinase C beta proteins (two direct EWS-FLI1 targets genes) were down-regulated in these cell lines upon EWS-FLI1 silencing (Figure 2B).	('EWS-FLI1', 'Gene', '2130;2313', (69, 77))	('cyclin', 'Gene', '394328', (13, 19))	('EWS-FLI1', 'Gene', '2130;2313', (138, 146))	('EWS-FLI1', 'Gene', (69, 77))	('protein kinase C beta proteins', 'Enzyme', (26, 56))	('cyclin', 'Gene', (13, 19))	('EWS-FLI1', 'Gene', (138, 146))	('down-regulated', 'NegReg', (98, 112))	('silencing', 'Var', (147, 156))
619704	23935076	In addition to the previously published induction of Cyclin D and Cyclin E by EWS-FLI1, we report here the down-regulation of Cyclin A upon EWS-FLI1 silencing (Figure 2).	('down-regulation', 'NegReg', (107, 122))	('Cyclin', 'Gene', (53, 59))	('Cyclin', 'Gene', '394328', (66, 72))	('EWS-FLI1', 'Gene', (78, 86))	('silencing', 'Var', (149, 158))	('Cyclin A', 'Gene', '890', (126, 134))	('Cyclin', 'Gene', '394328', (53, 59))	('EWS-FLI1', 'Gene', (140, 148))	('Cyclin', 'Gene', (126, 132))	('EWS-FLI1', 'Gene', '2130;2313', (78, 86))	('Cyclin A', 'Gene', (126, 134))	('EWS-FLI1', 'Gene', '2130;2313', (140, 148))	('Cyclin', 'Gene', (66, 72))	('Cyclin', 'Gene', '394328', (126, 132))
619705	23935076	Among other well described cell cycle regulators, E2F1, E2F2 and E2F5 were also consistently down-regulated after silencing of EWS-FLI1.	('E2F2', 'Gene', (56, 60))	('EWS-FLI1', 'Gene', '2130;2313', (127, 135))	('E2F1', 'Gene', '1869', (50, 54))	('E2F1', 'Gene', (50, 54))	('E2F5', 'Gene', (65, 69))	('EWS-FLI1', 'Gene', (127, 135))	('silencing', 'Var', (114, 123))	('E2F5', 'Gene', '1875', (65, 69))	('E2F2', 'Gene', '1870', (56, 60))	('down-regulated', 'NegReg', (93, 107))
619711	23935076	However, in the transient siRNA experiments where EWS-FLI1 was more efficiently knocked-down, apoptosis was monitored by induction of cleaved PARP in EW7, EW24 and SKNMC but not in A673 (Figure 2).	('EWS-FLI1', 'Gene', (50, 58))	('PARP', 'Gene', '142', (142, 146))	('EW7', 'Var', (150, 153))	('EW7', 'CellLine', 'CVCL:1217', (150, 153))	('cleaved', 'MPA', (134, 141))	('EWS-FLI1', 'Gene', '2130;2313', (50, 58))	('SKNMC', 'Var', (164, 169))	('knocked-down', 'Var', (80, 92))	('PARP', 'Gene', (142, 146))	('EW24', 'Var', (155, 159))	('apoptosis', 'CPA', (94, 103))
619712	23935076	It is to notice that full length PARP1 protein was not modulated upon silencing of EWS-FLI1 (Figure 2B, arrow band).	('EWS-FLI1', 'Gene', '2130;2313', (83, 91))	('silencing', 'Var', (70, 79))	('PARP1', 'Gene', (33, 38))	('PARP1', 'Gene', '142', (33, 38))	('EWS-FLI1', 'Gene', (83, 91))
619713	23935076	Interestingly, after EWS-FLI1 silencing, the potent anti-apoptotic CFLAR protein was strongly up-regulated in A673 but not in EW7 cells (Figure 2B).	('CFLAR', 'Gene', (67, 72))	('anti-apoptotic', 'MPA', (52, 66))	('up-regulated', 'PosReg', (94, 106))	('EW7', 'CellLine', 'CVCL:1217', (126, 129))	('EWS-FLI1', 'Gene', (21, 29))	('CFLAR', 'Gene', '8837', (67, 72))	('EWS-FLI1', 'Gene', '2130;2313', (21, 29))	('silencing', 'Var', (30, 39))	('A673', 'Var', (110, 114))
619757	23935076	At the contrary, CASP3 is shown to be induced by ectopic expression of EWS-FLI1 in primary murine fibroblast (MEF).	('MEF', 'Disease', (110, 113))	('induced', 'PosReg', (38, 45))	('MEF', 'Disease', 'None', (110, 113))	('CASP3', 'Gene', (17, 22))	('EWS-FLI1', 'Gene', (71, 79))	('murine', 'Species', '10090', (91, 97))	('EWS-FLI1', 'Gene', '2130;2313', (71, 79))	('ectopic expression', 'Var', (49, 67))
619761	23935076	According to the ENCODE histone methylation profiles of several cell lines, the EWS-FLI1-bound CUL1 region appears highly H3K4me1 positive but H3K4me3 negative (Supplementary Figure 5B).	('EWS-FLI1', 'Gene', (80, 88))	('CUL1', 'Gene', '8454', (95, 99))	('EWS-FLI1', 'Gene', '2130;2313', (80, 88))	('CUL1', 'Gene', (95, 99))	('H3K4me1', 'Var', (122, 129))
619765	23935076	Another example can be found in melanoma, where increased expression of CUL1 promotes cell proliferation through regulating p27 expression.	('increased', 'PosReg', (48, 57))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('promotes', 'PosReg', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('CUL1', 'Gene', (72, 76))	('regulating', 'Reg', (113, 123))	('p27', 'Gene', '3429', (124, 127))	('p27', 'Gene', (124, 127))	('expression', 'Var', (58, 68))	('cell proliferation', 'CPA', (86, 104))	('CUL1', 'Gene', '8454', (72, 76))	('expression', 'MPA', (128, 138))
619768	23935076	We confirmed here in our time series experiment that SKP2 is down-regulated on EWS-FLI1 inhibition.	('SKP2', 'Gene', '6502', (53, 57))	('SKP2', 'Gene', (53, 57))	('EWS-FLI1', 'Gene', (79, 87))	('down-regulated', 'NegReg', (61, 75))	('EWS-FLI1', 'Gene', '2130;2313', (79, 87))	('inhibition', 'Var', (88, 98))
619772	23935076	Interestingly, the cullin-RING ubiquitin ligase inhibitor MLN4924 was shown to trigger G2 arrest at subsaturating doses in several Ewing sarcoma cell lines.	('MLN4924', 'Var', (58, 65))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (131, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (131, 144))	('MLN4924', 'Chemical', 'MESH:C539933', (58, 65))	('G2 arrest', 'CPA', (87, 96))	('trigger', 'Reg', (79, 86))	('Ewing sarcoma', 'Disease', (131, 144))
619773	23935076	This arrest could only be rescued by WEE1 kinase inhibition or depletion.	('inhibition', 'Var', (49, 59))	('WEE1', 'Gene', (37, 41))	('WEE1', 'Gene', '7465', (37, 41))
619774	23935076	In addition, in vivo preclinical data emphasized the potential antitumoral activity of MLN4924.	('MLN4924', 'Var', (87, 94))	('antitumoral', 'CPA', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MLN4924', 'Chemical', 'MESH:C539933', (87, 94))
619778	23935076	However, milder EWS-FLI1 silencing (DOX-treated shA673-1C cells) had more subtle influence on MYC transcript (Figure 2A) though the protein level was clearly decreased (Figure 2B).	('decreased', 'NegReg', (158, 167))	('EWS-FLI1', 'Gene', (16, 24))	('protein level', 'MPA', (132, 145))	('MYC', 'Gene', (94, 97))	('EWS-FLI1', 'Gene', '2130;2313', (16, 24))	('milder', 'Var', (9, 15))	('DOX', 'Chemical', 'MESH:D004318', (36, 39))	('MYC', 'Gene', '4609', (94, 97))	('silencing', 'NegReg', (25, 34))
619791	23935076	In patients, such mutations clearly define a subgroup of highly aggressive tumors with poor chemoresponse and overall survival.	('aggressive tumors', 'Disease', 'MESH:D001523', (64, 81))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('aggressive tumors', 'Disease', (64, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (18, 27))
619792	23935076	Most of the results obtained in EW7 cells were consistent with data from other tested cell lines except for its poor survival capacity on EWS-FLI1 knock-down (Supplementary Figure S4).	('knock-down', 'Var', (147, 157))	('survival', 'CPA', (117, 125))	('EWS-FLI1', 'Gene', (138, 146))	('EW7', 'CellLine', 'CVCL:1217', (32, 35))	('EWS-FLI1', 'Gene', '2130;2313', (138, 146))
619793	23935076	However, procaspase 3 protein was not induced in EW7 cells on EWS-FLI1 knock-down (Figure 2B).	('EWS-FLI1', 'Gene', '2130;2313', (62, 70))	('EW7', 'CellLine', 'CVCL:1217', (49, 52))	('EWS-FLI1', 'Gene', (62, 70))	('procaspase 3', 'Gene', '836', (9, 21))	('knock-down', 'Var', (71, 81))	('procaspase 3', 'Gene', (9, 21))
619794	23935076	Similarly, the two anti-apoptotic factors CFLAR and IER3 were only moderately up-regulated or even repressed after silencing of EWS-FLI1 in EW7 cells, respectively (Figure 2A).	('EWS-FLI1', 'Gene', '2130;2313', (128, 136))	('CFLAR', 'Gene', '8837', (42, 47))	('silencing', 'Var', (115, 124))	('IER3', 'Gene', (52, 56))	('CFLAR', 'Gene', (42, 47))	('EW7', 'CellLine', 'CVCL:1217', (140, 143))	('up-regulated', 'PosReg', (78, 90))	('IER3', 'Gene', '8870', (52, 56))	('EWS-FLI1', 'Gene', (128, 136))
619817	31375594	Together, these findings suggest that mTORC1 is dispensable for viral protein synthesis and viral control of autophagy during lytic infection and that KSHV undermines mTORC1-dependent cellular processes during the lytic cycle to ensure efficient viral replication.	('KSHV', 'Species', '37296', (151, 155))	('KSHV', 'Var', (151, 155))	('mTORC1', 'Gene', '382056', (38, 44))	('undermines', 'NegReg', (156, 166))	('KS', 'Phenotype', 'HP:0100726', (151, 153))	('mTORC1', 'Gene', (167, 173))	('lytic infection', 'Disease', 'MESH:D007239', (126, 141))	('mTORC1', 'Gene', (38, 44))	('mTORC1', 'Gene', '382056', (167, 173))	('lytic infection', 'Disease', (126, 141))
619826	31375594	Inhibition of mTORC1 restricts PEL proliferation in vivo and in vitro by reducing the production of autocrine growth factors.	('mTORC1', 'Gene', (14, 20))	('production of autocrine growth factors', 'MPA', (86, 124))	('restricts', 'NegReg', (21, 30))	('reducing', 'NegReg', (73, 81))	('mTORC1', 'Gene', '382056', (14, 20))	('Inhibition', 'Var', (0, 10))	('PEL proliferation', 'CPA', (31, 48))	('PEL', 'Phenotype', 'HP:0030069', (31, 34))
619850	31375594	mTORC1 is also a key regulator of the bulk cellular catabolic process known as autophagy; in response to nutrients and mitogenic signals, mTORC1 phosphorylates and inactivates ULK1, ULK2, and ATG13, thereby preventing the initiation of autophagy.	('inactivates', 'Var', (164, 175))	('mTORC1', 'Gene', (138, 144))	('ULK1', 'Gene', (176, 180))	('ULK2', 'Gene', (182, 186))	('ULK1', 'Gene', '8408', (176, 180))	('mTORC1', 'Gene', '382056', (0, 6))	('preventing', 'NegReg', (207, 217))	('mTORC1', 'Gene', '382056', (138, 144))	('phospho', 'Chemical', 'MESH:C033601', (145, 152))	('ULK2', 'Gene', '9706', (182, 186))	('autophagy', 'CPA', (236, 245))	('mTORC1', 'Gene', (0, 6))	('ATG13', 'Gene', (192, 197))	('ATG13', 'Gene', '9776', (192, 197))
619854	31375594	In addition to the actions of these proteins, KSHV stimulation of mTORC1 activity during the lytic cycle would normally be expected to prevent the initiation of autophagy.	('prevent', 'NegReg', (135, 142))	('activity', 'MPA', (73, 81))	('mTORC1', 'Gene', '382056', (66, 72))	('KSHV', 'Species', '37296', (46, 50))	('KSHV stimulation', 'Var', (46, 62))	('KS', 'Phenotype', 'HP:0100726', (46, 48))	('mTORC1', 'Gene', (66, 72))	('autophagy', 'CPA', (161, 170))
619859	31375594	Likewise, KSHV lytic replication subverted normal mTORC1 control of autophagy.	('KSHV', 'Species', '37296', (10, 14))	('KSHV', 'Var', (10, 14))	('KS', 'Phenotype', 'HP:0100726', (10, 12))	('mTORC1', 'Gene', (50, 56))	('autophagy', 'CPA', (68, 77))	('mTORC1', 'Gene', '382056', (50, 56))	('subverted', 'NegReg', (33, 42))
619877	31375594	1B, lane 6), which indicated that mTORC1 inactivation increased the proportion of hypophosphorylated 4E-BP1 in the lysate, which was then able to inhibit eIF4F assembly on cap structures as expected.	('inhibit', 'NegReg', (146, 153))	('eIF4F', 'Gene', (154, 159))	('mTORC1', 'Gene', '382056', (34, 40))	('inactivation', 'Var', (41, 53))	('4E-BP1', 'Gene', (101, 107))	('increased', 'PosReg', (54, 63))	('mTORC1', 'Gene', (34, 40))	('eIF4F', 'Gene', '1977', (154, 159))	('phospho', 'Chemical', 'MESH:C033601', (86, 93))	('assembly on cap structures', 'MPA', (160, 186))	('4E-BP1', 'Gene', '1978', (101, 107))
619949	31375594	mTORC1 inhibition by rapamycin, Torin, or starvation activates autophagy through loss of ULK1 phosphorylation.	('loss', 'NegReg', (81, 85))	('ULK1', 'Gene', '8408', (89, 93))	('autophagy', 'CPA', (63, 72))	('mTORC1', 'Gene', '382056', (0, 6))	('Torin', 'Gene', '7001', (32, 37))	('Torin', 'Gene', (32, 37))	('activates', 'PosReg', (53, 62))	('inhibition', 'Var', (7, 17))	('rapamycin', 'Chemical', 'MESH:D020123', (21, 30))	('mTORC1', 'Gene', (0, 6))	('ULK1', 'Gene', (89, 93))	('phospho', 'Chemical', 'MESH:C033601', (94, 101))
619964	31375594	We noted that Beclin1 silencing decreased the accumulation of ATG14, which was reported previously; we speculate that ATG14 stability may depend on complex formation with Beclin1.	('Beclin1', 'Gene', '8678', (14, 21))	('Beclin1', 'Gene', (171, 178))	('ATG14', 'Gene', (118, 123))	('Beclin1', 'Gene', (14, 21))	('ATG14', 'Gene', '22863', (62, 67))	('silencing', 'Var', (22, 31))	('Beclin1', 'Gene', '8678', (171, 178))	('ATG14', 'Gene', '22863', (118, 123))	('accumulation', 'MPA', (46, 58))	('decreased', 'NegReg', (32, 41))	('ATG14', 'Gene', (62, 67))
619966	31375594	We observed that Beclin1 or ATG12 silencing moderately increased virion production, as measured by collecting cell supernatants at 96 hpi and determining the titer of infectious virions on recipient 293A cell monolayers, whereas ATG14 silencing did not have a statistically significant effect compared to controls (Fig.	('ATG12', 'Gene', '9140', (28, 33))	('Beclin1', 'Gene', (17, 24))	('ATG14', 'Gene', (229, 234))	('increased', 'PosReg', (55, 64))	('virion production', 'MPA', (65, 82))	('ATG12', 'Gene', (28, 33))	('Beclin1', 'Gene', '8678', (17, 24))	('ATG14', 'Gene', '22863', (229, 234))	('silencing', 'Var', (34, 43))
619968	31375594	As we observed previously, Torin treatment at the time of reactivation from latency dramatically decreased virion production, which was partially restored in cells deficient in ATG14 (Fig.	('ATG14', 'Gene', (177, 182))	('deficient', 'Var', (164, 173))	('decreased', 'NegReg', (97, 106))	('virion production', 'MPA', (107, 124))	('Torin', 'Gene', '7001', (27, 32))	('Torin', 'Gene', (27, 32))	('ATG14', 'Gene', '22863', (177, 182))
619972	31375594	Lysates were also collected from cells that had been reactivated from latency with dox for 24 h before exposure to Torin for 2 h. We observed that ATG14 silencing had no effect on the phosphorylation of canonical mTORC1 target proteins during either KSHV latency or lytic replication, suggesting that ATG14 deficiency does not influence the uptake of the drug, normal mTORC1 targeting, or the activity of relevant phosphatases (Fig.	('mTORC1', 'Gene', (368, 374))	('Torin', 'Gene', '7001', (115, 120))	('phospho', 'Chemical', 'MESH:C033601', (184, 191))	('Torin', 'Gene', (115, 120))	('uptake', 'MPA', (341, 347))	('silencing', 'NegReg', (153, 162))	('mTORC1', 'Gene', '382056', (213, 219))	('ATG14', 'Gene', '22863', (147, 152))	('ATG14', 'Gene', (301, 306))	('mTORC1', 'Gene', '382056', (368, 374))	('ATG14', 'Gene', '22863', (301, 306))	('activity', 'MPA', (393, 401))	('mTORC1', 'Gene', (213, 219))	('KS', 'Phenotype', 'HP:0100726', (250, 252))	('KSHV', 'Species', '37296', (250, 254))	('ATG14', 'Gene', (147, 152))	('deficiency', 'Var', (307, 317))	('phosphorylation', 'MPA', (184, 199))
620035	31375594	ATG14 silencing delayed endosomal maturation, as evidenced by slowed kinetics of internalized receptor degradation.	('ATG14', 'Gene', '22863', (0, 5))	('endosomal maturation', 'CPA', (24, 44))	('slowed', 'NegReg', (62, 68))	('kinetics of internalized receptor degradation', 'MPA', (69, 114))	('ATG14', 'Gene', (0, 5))	('delayed', 'NegReg', (16, 23))	('silencing', 'Var', (6, 15))
620036	31375594	In contrast, ATG14 silencing had no effect on autophagic degradation.	('ATG14', 'Gene', (13, 18))	('silencing', 'Var', (19, 28))	('ATG14', 'Gene', '22863', (13, 18))	('autophagic degradation', 'CPA', (46, 68))
620037	31375594	We speculate that dysregulation of endocytic trafficking in ATG14-deficient cells may affect the ability of mTORC1 to influence the latent-to-lytic switch.	('affect', 'Reg', (86, 92))	('ATG14', 'Gene', '22863', (60, 65))	('latent-to-lytic', 'MPA', (132, 147))	('dysregulation', 'Var', (18, 31))	('ATG14', 'Gene', (60, 65))	('mTORC1', 'Gene', '382056', (108, 114))	('endocytic trafficking', 'MPA', (35, 56))	('mTORC1', 'Gene', (108, 114))	('influence', 'Reg', (118, 127))
620114	30669277	The discovery of defectiveness in RSV was an exciting and important event in the evolution of tumor virology.	('defectiveness', 'Var', (17, 30))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('RSV', 'Gene', (34, 37))	('tumor', 'Disease', (94, 99))	('RSV', 'Species', '11886', (34, 37))
620132	30669277	Temperature-sensitive mutants affecting oncogenicity map to the genome section that is deleted in the transformation-defective viruses.	('oncogenicity', 'CPA', (40, 52))	('mutants', 'Var', (22, 29))	('rat', 'Species', '10116', (5, 8))
620162	30669277	The deletions of replicative genes in avian retroviruses have been observed, so there is precedence for such a genetic change.	('avian retroviruses', 'Species', '206036', (38, 56))	('deletions', 'Var', (4, 13))	('replicative genes', 'Gene', (17, 34))
620164	30669277	The conclusion that this also indicates defectiveness of the original isolate is not warranted, as deletion of the env gene could have occurred and could be selected for within the presumably short passage history of RSV29.	('RSV', 'Species', '11886', (217, 220))	('env', 'Gene', (115, 118))	('deletion', 'Var', (99, 107))
620187	29977304	PAIS involves the pulmonary trunk or proximal pulmonary arteries and exhibits clinical similarities to chronic pulmonary artery thromboembolism (CPTE), including dyspnea, chest pain, and hemosputum.	('PAIS', 'Phenotype', 'HP:0005312', (0, 4))	('dyspnea', 'Disease', (162, 169))	('pulmonary artery thromboembolism', 'Disease', (111, 143))	('dyspnea', 'Disease', 'MESH:D004417', (162, 169))	('chest pain', 'Disease', 'MESH:D002637', (171, 181))	('pulmonary artery thromboembolism', 'Phenotype', 'HP:0002204', (111, 143))	('thromboembolism', 'Phenotype', 'HP:0001907', (128, 143))	('chest pain', 'Disease', (171, 181))	('chest pain', 'Phenotype', 'HP:0100749', (171, 181))	('involves', 'Reg', (5, 13))	('pain', 'Phenotype', 'HP:0012531', (177, 181))	('dyspnea', 'Phenotype', 'HP:0002094', (162, 169))	('pulmonary artery thromboembolism', 'Disease', 'MESH:D011655', (111, 143))	('PAIS', 'Var', (0, 4))	('hemosputum', 'Disease', (187, 197))
620199	29977304	Fluorodeoxyglucose (FDG)-positron emission tomography (PET) showed a positive uptake of FDG to the pulmonary artery tumor (standardized uptake value, SUVmax 5.32), the chest wall tumor (SUVmax 9.56), and lung nodules (highest SUVmax 3.50) (Figures 1(e) and 1(f)), strongly suggesting a primary malignant tumor of the pulmonary artery, but not the thromboembolism.	('thromboembolism', 'Phenotype', 'HP:0001907', (347, 362))	('tumor of the pulmonary artery', 'Disease', (304, 333))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('FDG', 'Chemical', 'MESH:D019788', (88, 91))	('tumor', 'Disease', (304, 309))	('pulmonary artery tumor', 'Disease', (99, 121))	('FDG', 'Var', (88, 91))	('pulmonary artery tumor', 'Disease', 'MESH:D008175', (99, 121))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('Fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('thromboembolism', 'Disease', (347, 362))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('FDG', 'Chemical', 'MESH:D019788', (20, 23))	('tumor of the pulmonary artery', 'Disease', 'MESH:D008175', (304, 333))	('thromboembolism', 'Disease', 'MESH:D013923', (347, 362))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (179, 184))
620292	28716733	ML327 Induces Apoptosis and Sensitizes Ewing Sarcoma Cells to TNF-Related Apoptosis-Inducing Ligand Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (100, 114))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('Ewing sarcomas', 'Disease', (100, 114))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (100, 114))	('Ewing Sarcoma', 'Disease', (39, 52))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (153, 171))	('children', 'Species', '9606', (175, 183))	('Sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (39, 52))	('tumors', 'Disease', (165, 171))	('sarcomas', 'Phenotype', 'HP:0100242', (106, 114))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (100, 113))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('Induces', 'Reg', (6, 13))	('Sensitizes', 'Reg', (28, 38))	('ML327', 'Chemical', '-', (0, 5))	('ML327', 'Var', (0, 5))	('Apoptosis', 'CPA', (14, 23))
620297	28716733	ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838).	('increased', 'PosReg', (42, 51))	('multiple Ewing Sarcoma', 'Disease', 'MESH:C563168', (164, 186))	('changes', 'Reg', (33, 40))	('Sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('SK-N-MC', 'CellLine', 'CVCL:0530', (199, 206))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (173, 186))	('mesenchymal-to-epithelial transition', 'CPA', (124, 160))	('protein expression', 'MPA', (14, 32))	('multiple Ewing Sarcoma', 'Disease', (164, 186))	('ES', 'Phenotype', 'HP:0012254', (218, 220))	('vimentin', 'Gene', '7431', (77, 85))	('E-cadherin', 'Gene', (52, 62))	('TC71', 'CellLine', 'CVCL:2213', (208, 212))	('ML327', 'Chemical', '-', (0, 5))	('decreased', 'NegReg', (67, 76))	('E-cadherin', 'Gene', '999', (52, 62))	('ML327', 'Var', (0, 5))	('vimentin', 'Gene', (77, 85))
620302	28716733	This family of cancers arises due to a balanced chromosomal translocation of the EWS gene and a member of the ETS family of genes, most commonly friend leukemia virus integration 1 (FLI1).	('FLI1', 'Gene', (182, 186))	('FLI1', 'Gene', '2313', (182, 186))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('friend leukemia virus integration 1', 'Gene', (145, 180))	('balanced chromosomal translocation', 'Var', (39, 73))	('EWS', 'Gene', '2130', (81, 84))	('EWS', 'Gene', (81, 84))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('friend leukemia virus integration 1', 'Gene', '2313', (145, 180))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
620309	28716733	ML327 does not alter the cellular viability of colon and lung cancer cells, but is capable of blocking carcinoma cell invasiveness in vivo.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('blocking', 'NegReg', (94, 102))	('ML327', 'Chemical', '-', (0, 5))	('ML327', 'Var', (0, 5))	('colon and lung cancer', 'Disease', 'MESH:D008175', (47, 68))	('carcinoma cell invasiveness', 'Disease', (103, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinoma cell invasiveness', 'Disease', 'MESH:C538614', (103, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
620317	28716733	In the present study, we hypothesized that induction of MET using ML327 would block the growth of ES cells and sensitize to TRAIL-mediated apoptosis.	('growth of ES cells', 'CPA', (88, 106))	('sensitize', 'Reg', (111, 120))	('ML327', 'Chemical', '-', (66, 71))	('MET', 'Var', (56, 59))	('TRAIL', 'Gene', '8743', (124, 129))	('block', 'NegReg', (78, 83))	('TRAIL', 'Gene', (124, 129))	('ES', 'Phenotype', 'HP:0012254', (98, 100))
620318	28716733	Herein, we report that ML327 induces apoptosis in ES cells and has additive pro-apoptotic effects when used in combination with TRAIL in vitro.	('apoptosis', 'CPA', (37, 46))	('pro-apoptotic', 'MPA', (76, 89))	('ML327', 'Var', (23, 28))	('TRAIL', 'Gene', '8743', (128, 133))	('ES', 'Phenotype', 'HP:0012254', (50, 52))	('ML327', 'Chemical', '-', (23, 28))	('TRAIL', 'Gene', (128, 133))
620336	28716733	We therefore tested whether ML327 would induce MET features in ES cell lines.	('ML327', 'Var', (28, 33))	('ES', 'Phenotype', 'HP:0012254', (63, 65))	('tested', 'Reg', (13, 19))	('MET features', 'MPA', (47, 59))	('induce', 'Reg', (40, 46))	('ML327', 'Chemical', '-', (28, 33))
620343	28716733	Taken together, these findings demonstrate that ML327 is capable of inducing protein expression changes consistent with MET induction, but the predominant morphologic features elicited are most suggestive of apoptosis induction.	('ML327', 'Chemical', '-', (48, 53))	('protein expression changes', 'MPA', (77, 103))	('ML327', 'Var', (48, 53))	('inducing', 'PosReg', (68, 76))
620344	28716733	Our light microscopy observations led us to hypothesize that ML327 induces apoptosis in ES cells.	('apoptosis', 'CPA', (75, 84))	('ML327', 'Chemical', '-', (61, 66))	('ML327', 'Var', (61, 66))	('ES', 'Phenotype', 'HP:0012254', (88, 90))	('induces', 'Reg', (67, 74))
620348	28716733	These findings demonstrate that ML327 consistently induces the proteolytic activation of two critical apoptosis mediators in ES cells.	('ES', 'Phenotype', 'HP:0012254', (125, 127))	('induces', 'Reg', (51, 58))	('proteolytic activation', 'MPA', (63, 85))	('ML327', 'Var', (32, 37))	('ML327', 'Chemical', '-', (32, 37))
620350	28716733	In all 3 cell lines, ML327 treatment resulted in an increased percentage of cells in the Sub-G0 cell cycle phase (Fig.	('ML327', 'Chemical', '-', (21, 26))	('ML327', 'Var', (21, 26))	('increased', 'PosReg', (52, 61))	('cells in the Sub-G0 cell cycle phase', 'CPA', (76, 112))
620351	28716733	Specifically, ML327 induced a 26-fold and 12-fold increase in Sub-G0 population in SK-N-MC and TC71 cells, respectively (Fig.	('ML327', 'Var', (14, 19))	('SK-N-MC', 'CellLine', 'CVCL:0530', (83, 90))	('Sub-G0 population', 'CPA', (62, 79))	('increase', 'PosReg', (50, 58))	('TC71', 'CellLine', 'CVCL:2213', (95, 99))	('ML327', 'Chemical', '-', (14, 19))
620353	28716733	Overall, these findings demonstrate that ML327 successfully induces apoptosis in ES cells.	('induces', 'Reg', (60, 67))	('ML327', 'Chemical', '-', (41, 46))	('ML327', 'Var', (41, 46))	('apoptosis', 'CPA', (68, 77))	('ES', 'Phenotype', 'HP:0012254', (81, 83))
620358	28716733	These findings, together with our prior observations, suggest that ML327 likely induces apoptosis in a p53-independent manner.	('apoptosis', 'CPA', (88, 97))	('p53', 'Gene', '7157', (103, 106))	('p53', 'Gene', (103, 106))	('ML327', 'Chemical', '-', (67, 72))	('ML327', 'Var', (67, 72))	('induces', 'Reg', (80, 87))
620359	28716733	EMT in epithelial cancers has been shown to be associated with resistance to apoptosis inducing ligands.	('epithelial cancers', 'Disease', 'MESH:D000077216', (7, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('epithelial cancers', 'Disease', (7, 25))	('EMT', 'Var', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
620362	28716733	Three ES cell lines were pre-treated with ML327 (10 muM) for 24 h followed by TRAIL (50ng/mL) for 6 h. ML327 pre-treated cells demonstrated increased Caspase 3 and PARP cleavage after TRAIL treatment compared to vehicle pre-treatment as well as ML327 alone (Figs.	('ES', 'Phenotype', 'HP:0012254', (6, 8))	('TRAIL', 'Gene', (78, 83))	('PARP', 'Gene', '1302', (164, 168))	('ML327', 'Chemical', '-', (103, 108))	('ML327', 'Var', (103, 108))	('muM', 'Gene', '56925', (52, 55))	('TRAIL', 'Gene', '8743', (184, 189))	('PARP', 'Gene', (164, 168))	('Caspase 3', 'Gene', (150, 159))	('ML327', 'Chemical', '-', (245, 250))	('Caspase 3', 'Gene', '836', (150, 159))	('muM', 'Gene', (52, 55))	('TRAIL', 'Gene', (184, 189))	('TRAIL', 'Gene', '8743', (78, 83))	('increased', 'PosReg', (140, 149))	('ML327', 'Chemical', '-', (42, 47))
620363	28716733	ML327 has previously been shown to reduce cFLIPs expression in colon cancer cell lines, thereby sensitizing them to TRAIL-induced apoptosis.	('TRAIL', 'Gene', (116, 121))	('cFLIP', 'Gene', '8837', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (63, 75))	('colon cancer', 'Disease', 'MESH:D015179', (63, 75))	('cFLIP', 'Gene', (42, 47))	('reduce', 'NegReg', (35, 41))	('ML327', 'Chemical', '-', (0, 5))	('sensitizing', 'Reg', (96, 107))	('colon cancer', 'Disease', (63, 75))	('ML327', 'Var', (0, 5))	('TRAIL', 'Gene', '8743', (116, 121))
620369	28716733	E-cadherin is consistently upregulated by ML327 in all tested cell lines (colon, lung, breast, neuroblastoma, and ES cells) with the exception of RKO (colon) and MDA-MB-231 (breast) cancer cells, whose E-cadherin promoters are silenced by DNA hypermethylation.	('ML327', 'Var', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('neuroblastoma', 'Disease', 'MESH:D009447', (95, 108))	('ES', 'Phenotype', 'HP:0012254', (114, 116))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (162, 172))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('neuroblastoma', 'Disease', (95, 108))	('upregulated', 'PosReg', (27, 38))	('cancer', 'Disease', (182, 188))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', (202, 212))	('E-cadherin', 'Gene', '999', (202, 212))	('neuroblastoma', 'Phenotype', 'HP:0003006', (95, 108))	('E-cadherin', 'Gene', '999', (0, 10))	('ML327', 'Chemical', '-', (42, 47))
620379	28716733	Our findings support these observations, as ML327 induces epithelial-like features and sensitizes ES cells to TRAIL-mediated apoptosis.	('sensitizes', 'Reg', (87, 97))	('epithelial-like features', 'CPA', (58, 82))	('ML327', 'Chemical', '-', (44, 49))	('TRAIL', 'Gene', '8743', (110, 115))	('induces', 'PosReg', (50, 57))	('ML327', 'Var', (44, 49))	('TRAIL', 'Gene', (110, 115))	('ES', 'Phenotype', 'HP:0012254', (98, 100))
620384	28716733	Modification of the structure of ML327 in ways that would facilitate affinity purification of bound proteins has resulted in loss of biological activity.	('facilitate', 'PosReg', (58, 68))	('proteins', 'Protein', (100, 108))	('Modification', 'Var', (0, 12))	('ML327', 'Chemical', '-', (33, 38))	('biological activity', 'MPA', (133, 152))	('affinity purification', 'MPA', (69, 90))
620387	28716733	In contrast to prior characterizations in carcinoma and neural crest-derived tumors, ML327 elicits striking induction of apoptosis in all tested ES cell lines.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('carcinoma', 'Disease', (42, 51))	('carcinoma', 'Disease', 'MESH:D002277', (42, 51))	('ES', 'Phenotype', 'HP:0012254', (145, 147))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('apoptosis', 'CPA', (121, 130))	('ML327', 'Chemical', '-', (85, 90))	('ML327', 'Var', (85, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
620388	28716733	Furthermore, partial MET induction in ES cells using ML327 sensitized ES cells to TRAIL-mediated apoptosis.	('ES', 'Phenotype', 'HP:0012254', (38, 40))	('ES', 'Phenotype', 'HP:0012254', (70, 72))	('sensitized', 'Reg', (59, 69))	('partial MET induction', 'Var', (13, 34))	('ML327', 'Chemical', '-', (53, 58))	('TRAIL', 'Gene', '8743', (82, 87))	('TRAIL', 'Gene', (82, 87))
620390	28716733	ES Ewing Sarcoma TRAIL tumor necrosis factor-related apoptosis-inducing ligand EMT epithelial-to-mesenchymal transition MET mesenchymal-to-epithelial transition ML327 induces E-cadherin expression, an epithelial hallmark, in Ewing Sarcoma cells Induction of E-cadherin expression using ML327 is accompanied by apoptosis ML327 sensitizes Ewing Sarcoma cells to TRAIL-mediated apoptosis in vitro	('TRAIL', 'Gene', '8743', (360, 365))	('ML327', 'Chemical', '-', (286, 291))	('sensitizes', 'Reg', (326, 336))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (3, 16))	('Sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('E-cadherin', 'Gene', (258, 268))	('Sarcoma', 'Phenotype', 'HP:0100242', (231, 238))	('E-cadherin', 'Gene', '999', (258, 268))	('TRAIL', 'Gene', '8743', (17, 22))	('TRAIL', 'Gene', (360, 365))	('necrosis', 'Disease', 'MESH:D009336', (29, 37))	('ES', 'Phenotype', 'HP:0012254', (0, 2))	('E-cadherin', 'Gene', (175, 185))	('E-cadherin', 'Gene', '999', (175, 185))	('necrosis', 'Disease', (29, 37))	('TRAIL', 'Gene', (17, 22))	('ML327', 'Chemical', '-', (161, 166))	('Ewing Sarcoma', 'Disease', (337, 350))	('tumor', 'Disease', (23, 28))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (337, 350))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (3, 16))	('Ewing Sarcoma', 'Disease', (225, 238))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (225, 238))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('ML327', 'Var', (320, 325))	('ML327', 'Chemical', '-', (320, 325))	('Ewing Sarcoma', 'Disease', (3, 16))	('Sarcoma', 'Phenotype', 'HP:0100242', (343, 350))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (337, 350))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (225, 238))
620422	27542637	Large, high-grade UPS or leiomyosarcoma have rates of disease-specific death that may approach 50%, and distant metastases are common, so chest CT would be reasonable as a means of determining extent of disease for these high-risk patients.	('high-grade', 'Var', (7, 17))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (25, 39))	('patients', 'Species', '9606', (231, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('metastases', 'Disease', (112, 122))	('UPS', 'Disease', (18, 21))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (25, 39))	('leiomyosarcoma', 'Disease', (25, 39))	('UPS', 'Disease', 'MESH:D017118', (18, 21))
620437	27542637	Interruption of the tibial branches of the sciatic causes paresthesias on the plantar aspect of the foot, and patients should be instructed to monitor their feet routinely for trauma that may occur secondary to an insensate foot.	('paresthesias', 'Disease', (58, 70))	('trauma', 'Disease', (176, 182))	('Interruption', 'Var', (0, 12))	('plantar aspect', 'Phenotype', 'HP:0010612', (78, 92))	('trauma', 'Disease', 'MESH:D014947', (176, 182))	('patients', 'Species', '9606', (110, 118))	('paresthesias', 'Phenotype', 'HP:0003401', (58, 70))
620470	27542637	Previous studies have identified age greater than 50, microscopically positive margins, high grade, deep location, and recurrent tumors as risk factors for local recurrence.	('high', 'Var', (88, 92))	('tumors', 'Disease', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))
620543	24124230	This conditional system, driven by KrasG12D and loss of Trp53, recapitulates many of the clinical features of human UPS, including pulmonary metastasis.	('pulmonary metastasis', 'Disease', 'MESH:D009362', (131, 151))	('loss', 'Var', (48, 52))	('Trp53', 'Gene', (56, 61))	('human', 'Species', '9606', (110, 115))	('pulmonary metastasis', 'Disease', (131, 151))	('Trp53', 'Gene', '7157', (56, 61))
620553	24124230	This is most prominent in renal cancer where genetic inactivation of the VHL tumor suppressor leads to HIF stabilization and tumor initiation.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('VHL tumor', 'Disease', 'MESH:D006623', (73, 82))	('renal cancer', 'Phenotype', 'HP:0009726', (26, 38))	('HIF stabilization', 'CPA', (103, 120))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('renal cancer', 'Disease', 'MESH:D007680', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('genetic inactivation', 'Var', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('VHL tumor', 'Disease', (73, 82))	('tumor', 'Disease', (77, 82))	('renal cancer', 'Disease', (26, 38))
620554	24124230	However, epigenomic alterations can allow HIFs to acquire additional target genes, which promote renal cancer progression and metastasis through increased cancer cell survival and chemotactic migration.	('renal cancer', 'Disease', 'MESH:D007680', (97, 109))	('chemotactic migration', 'CPA', (180, 201))	('promote', 'PosReg', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('increased', 'PosReg', (145, 154))	('renal cancer', 'Disease', (97, 109))	('epigenomic alterations', 'Var', (9, 31))	('metastasis', 'CPA', (126, 136))	('renal cancer', 'Phenotype', 'HP:0009726', (97, 109))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
620570	33913810	Integrative next-generation sequencing approaches in human and murine cell lines showed that the fusion proteins drive a unique transcriptome by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex.	('chromatin environment', 'MPA', (232, 253))	('drive', 'Reg', (113, 118))	('modulating', 'Reg', (217, 227))	('interaction', 'Interaction', (258, 269))	('human', 'Species', '9606', (53, 58))	('hyperactivating', 'PosReg', (160, 175))	('fusion', 'Var', (97, 103))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (178, 182))	('transcriptome', 'MPA', (128, 141))	('TEAD', 'Gene', (178, 182))	('murine', 'Species', '10090', (63, 69))
620591	33913810	Despite this observation, point mutations within the Hippo signaling pathway are relatively rare in most cancers.	('point mutations', 'Var', (26, 41))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('Hippo', 'Gene', '37247', (53, 58))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Hippo', 'Gene', (53, 58))
620593	33913810	TAZ-CAMTA1 transforms cells by driving a predominantly TAZ-related transcriptional program that is mediated by binding to TEAD4.	('driving', 'Reg', (31, 38))	('TEAD4', 'Gene', '7004', (122, 127))	('TEAD4', 'Gene', (122, 127))	('TAZ-CAMTA1', 'Var', (0, 10))	('TAZ-related transcriptional program', 'MPA', (55, 90))
620598	33913810	Amplification of YEATS2 has been identified in ovarian cancer, head and neck cancer, esophageal cancer, and uterine cancer, as well as both well-differentiated and dedifferentiated liposarcoma.	('YEATS2', 'Gene', (17, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('well-differentiated', 'Disease', (140, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('identified', 'Reg', (33, 43))	('liposarcoma', 'Phenotype', 'HP:0012034', (181, 192))	('head and neck cancer', 'Disease', 'MESH:D006258', (63, 83))	('cancer', 'Disease', (96, 102))	('esophageal cancer', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('liposarcoma', 'Disease', 'MESH:D008080', (181, 192))	('cancer', 'Disease', (55, 61))	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))	('Amplification', 'Var', (0, 13))	('head and neck cancer', 'Phenotype', 'HP:0012288', (63, 83))	('uterine cancer', 'Phenotype', 'HP:0010784', (108, 122))	('liposarcoma', 'Disease', (181, 192))	('ovarian cancer', 'Disease', (47, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('YEATS2', 'Gene', '55689', (17, 23))
620599	33913810	The WWTR1 (TAZ)-CAMTA1 gene fusion fuses the end of exon 2 or exon 3 of WWTR1 to a breakpoint with exon 9 of CAMTA1(2, 3).	('WWTR1', 'Gene', (72, 77))	('WWTR1', 'Gene', '25937', (72, 77))	('fusion', 'Var', (28, 34))	('WWTR1', 'Gene', (4, 9))	('WWTR1', 'Gene', '25937', (4, 9))
620608	33913810	Both TAZ-CAMTA1 and YAP-TFE3 were able to promote colony formation in soft agar in SW872 cells (Figure 1:figure supplement 2E).	('agar', 'Chemical', 'MESH:D000362', (75, 79))	('promote', 'PosReg', (42, 49))	('colony formation in soft agar', 'CPA', (50, 79))	('TAZ-CAMTA1', 'Var', (5, 15))	('YAP-TFE3', 'Var', (20, 28))
620614	33913810	Taken together, the above data suggest that YAP-TFE3 is no longer subject to Hippo pathway-mediated suppression, likely because the key residues targeted by LATS1/2 (S127 and S381) are not present in YAP-TFE3.	('Hippo', 'Gene', (77, 82))	('S127', 'Var', (166, 170))	('S381', 'Var', (175, 179))	('Hippo', 'Gene', '37247', (77, 82))
620616	33913810	Mice with NIH 3T3-derived tumors expressing YAP-TFE3 or TAZ-CAMTA1 demonstrated a shorter overall survival compared to empty vector (p<0.0001 for both YAP-TFE3 and TAZ-CAMTA1) (Figure 1G).	('TAZ-CAMTA1', 'Var', (56, 66))	('overall survival', 'CPA', (90, 106))	('YAP-TFE3', 'Var', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('NIH 3T3', 'CellLine', 'CVCL:0594', (10, 17))	('tumors', 'Disease', (26, 32))	('shorter', 'NegReg', (82, 89))
620617	33913810	Tumors expressing YAP-TFE3 and TAZ-CAMTA1 formed palpable masses ~ 7 days post-injection (Figure 1H) indicating time to tumor initiation was similar for NIH 3T3 cells expressing either fusion protein.	('TAZ-CAMTA1', 'Var', (31, 41))	('NIH 3T3', 'CellLine', 'CVCL:0594', (153, 160))	('YAP-TFE3', 'Var', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('1H', 'Chemical', '-', (97, 99))	('tumor', 'Disease', (120, 125))
620622	33913810	NIH 3T3 cell-derived tumors expressing YAP-TFE3 or TAZ-CAMTA1 exhibited a more rounded (epithelioid) cytomorphology and a greater degree of cellular pleomorphism as compared to control tumors (Figure 1:figure supplement 3A).	('tumors', 'Disease', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('YAP-TFE3', 'Var', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('cellular pleomorphism', 'CPA', (140, 161))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('NIH 3T3', 'CellLine', 'CVCL:0594', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
620623	33913810	Necropsy and pathological evaluation of the lungs demonstrated the presence of microscopic metastases in the YAP-TFE3 (p=0.0299) but not the TAZ-CAMTA1 (not significant) cohorts (Figure 1I).	('YAP-TFE3', 'Var', (109, 117))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('metastases', 'Disease', (91, 101))
620624	33913810	In the mildly tumorigenic SW872 cell line, expression of YAP-TFE3 and TAZ-CAMTA1 decreased latency to tumor formation compared to empty vector in vivo (Figure 1J), similar to NIH 3T3 cells.	('decreased', 'NegReg', (81, 90))	('tumor', 'Disease', (14, 19))	('TAZ-CAMTA1', 'Gene', (70, 80))	('expression', 'Var', (43, 53))	('YAP-TFE3', 'Gene', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('NIH 3T3', 'CellLine', 'CVCL:0594', (175, 182))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
620625	33913810	Cytological changes in SW872 cell-derived tumors were less pronounced than in NIH 3T3 cells (Figure 1:figure supplement 3B).	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('NIH 3T3', 'CellLine', 'CVCL:0594', (78, 85))	('SW872', 'Var', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
620630	33913810	While the S51A mutant (disrupts TEAD binding) of TAZ-CAMTA1 significantly reduced colony formation in soft agar/growth on poly-HEMA, the TAZ-CAMTA1DeltaWW mutant did not (Figure 1:figure supplement 2F and G).	('poly-HEMA', 'Chemical', '-', (122, 131))	('TEAD', 'Gene', (32, 36))	('TAZ-CAMTA1', 'Gene', (49, 59))	('colony formation in', 'CPA', (82, 101))	('S51A', 'Mutation', 'p.S51A', (10, 14))	('agar', 'Chemical', 'MESH:D000362', (107, 111))	('S51A', 'Var', (10, 14))	('reduced', 'NegReg', (74, 81))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (32, 36))
620633	33913810	To test the hypothesis that TEAD binding is necessary to activate the oncogenic YAP-TFE3 transcriptional program, Tead1 was knocked down in NIH-3T3 cells expressing YAP-TFE3 (Figure 2A; Figure 2:source data 1).	('NIH-3T3', 'CellLine', 'CVCL:0594', (140, 147))	('knocked', 'Var', (124, 131))	('YAP-TFE3', 'Gene', (165, 173))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (28, 32))	('Tead1', 'Gene', (114, 119))	('TEAD', 'Gene', (28, 32))
620634	33913810	Knock-down of Tead1 reduced anchorage independent growth on poly-HEMA (Figure 2B) and in soft agar (Figure 2C) with two different short hairpin RNAs (shRNAs).	('poly-HEMA', 'Chemical', '-', (60, 69))	('reduced', 'NegReg', (20, 27))	('Knock-down', 'Var', (0, 10))	('Tead1', 'Gene', (14, 19))	('anchorage independent growth', 'CPA', (28, 56))	('agar', 'Chemical', 'MESH:D000362', (94, 98))
620635	33913810	A YAP-TFE3 S94A mutant was created to disrupt its interaction with TEAD (homologous to S94 in full-length YAP and required for TEAD binding, which was confirmed by co-immunoprecipitation (Figure 2D)).	('S94A', 'Mutation', 'rs760318833', (11, 15))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (67, 71))	('disrupt', 'NegReg', (38, 45))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (127, 131))	('TEAD', 'Gene', (67, 71))	('interaction', 'Interaction', (50, 61))	('TEAD', 'Gene', (127, 131))	('S94A mutant', 'Var', (11, 22))
620637	33913810	The S94A mutation completely abrogated YAP-TFE3-driven anchorage-independent growth on poly-HEMA (Figure 2E) and in soft agar (Figure 2F).	('S94A', 'Var', (4, 8))	('YAP-TFE3-driven', 'Gene', (39, 54))	('abrogated', 'NegReg', (29, 38))	('poly-HEMA', 'Chemical', '-', (87, 96))	('agar', 'Chemical', 'MESH:D000362', (121, 125))	('S94A', 'Mutation', 'rs760318833', (4, 8))	('anchorage-independent growth', 'CPA', (55, 83))
620638	33913810	By quantitative RT-PCR, the YAP-TFE3 S94A mutant showed a sevenfold decrease in expression of Ccn2(Ctgf), a YAP target gene, compared to the YAP-TFE3 control (Figure 2G).	('Ctgf', 'Gene', (99, 103))	('Ccn2', 'Gene', (94, 98))	('decrease', 'NegReg', (68, 76))	('S94A mutant', 'Var', (37, 48))	('S94A', 'Mutation', 'rs760318833', (37, 41))	('Ccn2', 'Gene', '1490', (94, 98))	('Ctgf', 'Gene', '1490', (99, 103))	('expression', 'MPA', (80, 90))
620639	33913810	Chromatin immunoprecipitation-quantitative PCR for the CCN2 promoter (which contains the TEAD-binding sequence) showed a sixfold decrease in CCN2 promoter binding by YAP-TFE3 S94A as compared to YAP-TFE3 control (Figure 2H).	('decrease', 'NegReg', (129, 137))	('binding', 'Interaction', (155, 162))	('CCN2', 'Gene', (55, 59))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (89, 93))	('S94A', 'Mutation', 'rs760318833', (175, 179))	('CCN2', 'Gene', (141, 145))	('CCN2', 'Gene', '1490', (55, 59))	('TEAD', 'Gene', (89, 93))	('YAP-TFE3 S94A', 'Var', (166, 179))	('CCN2', 'Gene', '1490', (141, 145))
620640	33913810	Using the 8XGTIIC luciferase reporter containing eight TEAD consensus binding sequences, YAP-TFE3 S94A showed decreased luciferase activity compared to the YAP-TFE3 control (Figure 2I and Figure 1:figure supplement 1E).	('S94A', 'Var', (98, 102))	('activity', 'MPA', (131, 139))	('luciferase', 'Enzyme', (120, 130))	('S94A', 'Mutation', 'rs760318833', (98, 102))	('decreased', 'NegReg', (110, 119))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (55, 59))	('TEAD', 'Gene', (55, 59))
620657	33913810	Comparison of TAZ-CAMTA1 and H3K27ac genomic occupancy around the TSS of MAFK and HOXA1 (Figure 4:figure supplement 1E,F), two differentially expressed genes in TAZ-CAMTA1-expressing cells (Figure 3:source data 2), showed that H3K27ac peaks closely overlapped and surrounded TAZ-CAMTA1 bound chromatin, validating the above approach.	('H3K27ac', 'Var', (227, 234))	('MAFK', 'Gene', (73, 77))	('HOXA1', 'Gene', (82, 87))	('MAFK', 'Gene', '7975', (73, 77))	('HOXA1', 'Gene', '3198', (82, 87))
620661	33913810	Interestingly, there was a decrease in the frequency of FOS/JUN binding sites in TAZ-CAMTA1 (31%) as compared to TAZ4SA (50%), which appeared to be offset by an increase in Early growth response gene-2 (EGR2) binding motifs (23% vs. 13% for TAZ4SA).	('binding', 'Interaction', (209, 216))	('TAZ4SA', 'Gene', (241, 247))	('EGR2', 'Gene', '1959', (203, 207))	('EGR2', 'Gene', (203, 207))	('decrease', 'NegReg', (27, 35))	('TAZ4SA', 'Gene', '21763', (113, 119))	('TAZ-CAMTA1', 'Var', (81, 91))	('TAZ4SA', 'Gene', '21763', (241, 247))	('FOS', 'Gene', (56, 59))	('increase', 'PosReg', (161, 169))	('TAZ4SA', 'Gene', (113, 119))	('FOS', 'Gene', '2353', (56, 59))
620668	33913810	Kyoto encyclopedia of genes and genomes (KEGG) analysis of TAZ-CAMTA1 bound genes that are also differentially expressed in SW872 TAZ-CAMTA1 cells showed enrichment for RHO GTPase-dependent pathways, EPHA-dependent pathways, RUNX2-dependent pathways, as well as other pathways known to be regulated by TAZ/YAP (; Figure 4:figure supplement 3C).	('RUNX2', 'Gene', '860', (225, 230))	('RHO GTPase-dependent pathways', 'Pathway', (169, 198))	('SW872', 'Var', (124, 129))	('SW872 TAZ-CAMTA1', 'CellLine', 'CVCL:1730', (124, 140))	('RUNX2', 'Gene', (225, 230))	('EPHA-dependent pathways', 'Pathway', (200, 223))
620669	33913810	Heat map and histogram analysis of ATAC peaks showed that TAZ-CAMTA1 and CAMTA1 preferentially opened chromatin in areas of the genome more distal to the TSS than TAZ4SA (Figure 5A, Figure 5:figure supplement 1A,B).	('opened', 'PosReg', (95, 101))	('TAZ4SA', 'Gene', (163, 169))	('CAMTA1', 'Var', (73, 79))	('TAZ-CAMTA1', 'Var', (58, 68))	('TAZ4SA', 'Gene', '21763', (163, 169))
620683	33913810	YEATS2 knock-down and a reduction in anchorage independent growth was validated in SW872 cells expressing YAP-TFE3 using the two shRNAs with the best knock-down (Figure 7:figure supplement 1G-I).	('anchorage independent growth', 'CPA', (37, 65))	('YEATS2', 'Gene', '55689', (0, 6))	('YEATS2', 'Gene', (0, 6))	('knock-down', 'Var', (7, 17))	('YAP-TFE3', 'Gene', (106, 114))	('reduction', 'NegReg', (24, 33))
620690	33913810	Knock-down of YEATS2 in SW872 TAZ-CAMTA1 cells was confirmed by quantitative RT-PCR (Figure 8:figure supplement 1A) and resulted in loss of anchorage-independent growth by soft agar assay (Figure 8:figure supplement 1B).	('YEATS2', 'Gene', '55689', (14, 20))	('loss', 'NegReg', (132, 136))	('Knock-down', 'Var', (0, 10))	('YEATS2', 'Gene', (14, 20))	('anchorage-independent growth', 'CPA', (140, 168))	('SW872 TAZ-CAMTA1', 'CellLine', 'CVCL:1730', (24, 40))	('agar', 'Chemical', 'MESH:D000362', (177, 181))
620691	33913810	Similarly, knock-down of ZZZ3 in SW872 TAZ-CAMTA1 cells was confirmed by western blot (Figure 8:figure supplement 1C) and the loss of anchorage-independent phenotype was replicated by soft agar assay (Figure 8:figure supplement 1D).	('SW872 TAZ-CAMTA1', 'CellLine', 'CVCL:1730', (33, 49))	('agar', 'Chemical', 'MESH:D000362', (189, 193))	('knock-down', 'Var', (11, 21))	('ZZZ3', 'Gene', (25, 29))	('ZZZ3', 'Gene', '26009', (25, 29))
620694	33913810	Principal component analysis showed that knock-down of YEATS2 and ZZZ3 altered both the TAZ-CAMTA1 and YAP-TFE3 transcriptomes, compared to shRNA control (Figure 8A).	('ZZZ3', 'Gene', '26009', (66, 70))	('ZZZ3', 'Gene', (66, 70))	('YEATS2', 'Gene', '55689', (55, 61))	('TAZ-CAMTA1', 'MPA', (88, 98))	('YEATS2', 'Gene', (55, 61))	('knock-down', 'Var', (41, 51))	('altered', 'Reg', (71, 78))
620695	33913810	Knock-down of YEATS2 and ZZZ3 had a greater effect on the final transcriptional program of YAP-TFE3 than TAZ-CAMTA1, likely reflecting the smaller number of epigenetic modifiers interacting with YAP-TFE3 as compared to TAZ-CAMTA1.	('YAP-TFE3', 'Gene', (91, 99))	('final transcriptional program', 'MPA', (58, 87))	('YEATS2', 'Gene', '55689', (14, 20))	('Knock-down', 'Var', (0, 10))	('YEATS2', 'Gene', (14, 20))	('effect', 'Reg', (44, 50))	('ZZZ3', 'Gene', (25, 29))	('ZZZ3', 'Gene', '26009', (25, 29))
620697	33913810	iPathwayGuide analysis showed that MAPK signaling, a pathway significantly upregulated in SW872 YAP-TFE3 cells (Figure 3I) was significantly down-regulated with YEATS2 knock-down (Figure 8D and Figure 8:figure supplement 2A).	('MAPK signaling', 'Pathway', (35, 49))	('upregulated', 'PosReg', (75, 86))	('YEATS2', 'Gene', (161, 167))	('knock-down', 'Var', (168, 178))	('down-regulated', 'NegReg', (141, 155))	('YEATS2', 'Gene', '55689', (161, 167))
620698	33913810	Further, PI3K-Akt signaling, activated in SW872 cells expressing TAZ-CAMTA1 or YAP-TFE3 (Figure 3H,I and Figure 8:figure supplement 2B), was also decreased in SW872 cells expressing YAP-TFE3 and either YEATS2 or ZZZ3 shRNA (Figure 8D and Figure 8:figure supplement 2C-D).	('YEATS2', 'Gene', '55689', (202, 208))	('Akt', 'Gene', (14, 17))	('activated', 'PosReg', (29, 38))	('TAZ-CAMTA1', 'Var', (65, 75))	('YEATS2', 'Gene', (202, 208))	('decreased', 'NegReg', (146, 155))	('Akt', 'Gene', '207', (14, 17))	('ZZZ3', 'Gene', '26009', (212, 216))	('YAP-TFE3', 'Var', (79, 87))	('ZZZ3', 'Gene', (212, 216))
620699	33913810	Since the ATAC complex is a HAT complex thought to increase the amount of transcriptionally available chromatin, we intersected genes differentially expressed with YEATS2 or ZZZ3 knockdown with open chromatin unique to SW872 YAP-TFE3 expressing cells.	('ZZZ3', 'Gene', (174, 178))	('YEATS2', 'Gene', (164, 170))	('amount of transcriptionally available', 'MPA', (64, 101))	('knockdown', 'Var', (179, 188))	('ZZZ3', 'Gene', '26009', (174, 178))	('YEATS2', 'Gene', '55689', (164, 170))
620700	33913810	We found that 71% of differentially expressed genes (DEG) with YEATS2 knock-down and 74% of DEG with ZZZ3 knock-down were within euchromatin unique to YAP-TFE3 expressing cells (Figure 8E,F).	('YEATS2', 'Gene', '55689', (63, 69))	('YEATS2', 'Gene', (63, 69))	('differentially expressed', 'MPA', (21, 45))	('ZZZ3', 'Gene', (101, 105))	('knock-down', 'Var', (70, 80))	('ZZZ3', 'Gene', '26009', (101, 105))
620707	33913810	This is consistent with recent findings identifying amplification of YEATS2 in sarcomas such as well differentiated liposarcoma and dedifferentiated liposarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('sarcomas', 'Disease', 'MESH:D012509', (79, 87))	('liposarcoma', 'Phenotype', 'HP:0012034', (149, 160))	('liposarcoma', 'Disease', 'MESH:D008080', (149, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('YEATS2', 'Gene', '55689', (69, 75))	('sarcomas', 'Disease', (79, 87))	('YEATS2', 'Gene', (69, 75))	('liposarcoma', 'Disease', (116, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('liposarcoma', 'Disease', (149, 160))	('liposarcoma', 'Phenotype', 'HP:0012034', (116, 127))	('liposarcoma', 'Disease', 'MESH:D008080', (116, 127))	('amplification', 'Var', (52, 65))
620716	33913810	This indicates that CAMTA1 and TFE3 confer chromatin remodeling properties to the fusion proteins, while the N termini of TAZ and YAP essentially contribute the TEAD binding domain.	('chromatin remodeling properties', 'MPA', (43, 74))	('CAMTA1', 'Var', (20, 26))	('TEAD', 'Gene', (161, 165))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (161, 165))
620718	33913810	Importantly, conjugation of Ncoa6 to Scalloped (TEAD orthologue) alone was sufficient to functionally activate the Yorkie transcriptional program.	('activate', 'PosReg', (102, 110))	('conjugation', 'Var', (13, 24))	('Ncoa6', 'Gene', '33761', (28, 33))	('Yorkie', 'Gene', '37851', (115, 121))	('Ncoa6', 'Gene', (28, 33))	('TEAD', 'Gene', (48, 52))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (48, 52))	('Yorkie', 'Gene', (115, 121))
620726	33913810	Instead of point mutations, gene fusions are the most common genetic alterations of TAZ(WWTR1) and YAP in cancer.	('TAZ', 'Gene', (84, 87))	('gene fusions', 'Var', (28, 40))	('WWTR1', 'Gene', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('WWTR1', 'Gene', '25937', (88, 93))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
620754	33913810	Dilution for the above antibodies were as follows: anti-Ki-67 (1:100), anti-vitronectin (1:400), anti-COL1A1 (1:200), anti-CTGF (1:200), and anti-fibulin 5 (1:200).	('anti-CTGF', 'Var', (118, 127))	('Ki-67', 'Gene', (56, 61))	('1:400', 'Var', (89, 94))	('fibulin 5', 'Gene', (146, 155))	('anti-vitronectin (1:400', 'Var', (71, 94))	('fibulin 5', 'Gene', '10516', (146, 155))	('Ki-67', 'Gene', '17345', (56, 61))
620794	33913810	A transposition reaction was prepared containing 25 microL Tagment DNA buffer (#15027866), 2.5 microL TDE1 Nextera Tn5 Transposase (#15027865), and 22.5 microL Nuclease Free H2O.	('#15027865', 'Var', (132, 141))	('TDE1', 'Gene', '10955', (102, 106))	('#15027866', 'Var', (79, 88))	('TDE1', 'Gene', (102, 106))	('H2O', 'Chemical', '-', (174, 177))
620795	33913810	Peaks were called with 'genrich' (https://github.com/jsh58/Genrich; RRID:SCR_002630 version 1.0.8) in 'atacseq' mode [with flags set as '-E blacklists/wgEncodeHg19ConsensusSignalArtifactRegions.bed -v -j -r -e MT,GL000191.1,GL000192.1,GL000193.1,GL000195.1,GL000199.1,GL000205.1,GL000206.1,GL000208.1,GL000212.1,GL000214.1,GL000216.1,GL000217.1,GL000219.1,GL000220.1,GL000222.1,GL000223.1,GL000224.1,GL000225.1,GL000226.1,GL000228.1,GL000235.1,GL000243.1'.]	('GL000226.1', 'Var', (411, 421))	('GL000235.1', 'Var', (433, 443))	('flags', 'Species', '34205', (123, 128))
620807	33913810	The accession number for the RNA-Seq data after YEATS2 and ZZZ3 knock-down is GEO: GSE168205.	('knock-down', 'Var', (64, 74))	('YEATS2', 'Gene', (48, 54))	('YEATS2', 'Gene', '55689', (48, 54))	('ZZZ3', 'Gene', (59, 63))	('ZZZ3', 'Gene', '26009', (59, 63))
620814	33913810	The authors show that ectopic expression of the fusion proteins in NIH3T3 fibroblasts and SW872 liposarcoma cells promote pro-tumorigenic properties, such as increased proliferation, anchorage independent growth, and increased growth in subcutaneous xenograft experiments in mice.	('growth', 'CPA', (227, 233))	('liposarcoma', 'Phenotype', 'HP:0012034', (96, 107))	('liposarcoma', 'Disease', 'MESH:D008080', (96, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('mice', 'Species', '10090', (275, 279))	('tumor', 'Disease', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ectopic expression', 'Var', (22, 40))	('NIH3T3', 'CellLine', 'CVCL:0594', (67, 73))	('liposarcoma', 'Disease', (96, 107))	('increased', 'PosReg', (217, 226))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('anchorage independent growth', 'CPA', (183, 211))	('increased', 'PosReg', (158, 167))	('promote', 'PosReg', (114, 121))
620819	33913810	For example, are these genes altered in expression following YEATS2 or ZZZ3 knockdown?	('expression', 'MPA', (40, 50))	('knockdown', 'Var', (76, 85))	('ZZZ3', 'Gene', (71, 75))	('ZZZ3', 'Gene', '26009', (71, 75))	('altered', 'Reg', (29, 36))	('YEATS2', 'Gene', '55689', (61, 67))	('YEATS2', 'Gene', (61, 67))
620821	33913810	While it is interesting that YEATS2 and ZZZ3 expression is associated with poor prognosis across sarcomas, this does not necessarily link to YAP/TAZ or fusion protein activity in EHE.	('expression', 'Var', (45, 55))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('YEATS2', 'Gene', '55689', (29, 35))	('ZZZ3', 'Gene', '26009', (40, 44))	('associated', 'Reg', (59, 69))	('YEATS2', 'Gene', (29, 35))	('EHE', 'Phenotype', 'HP:0032060', (179, 182))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('ZZZ3', 'Gene', (40, 44))	('sarcomas', 'Disease', (97, 105))	('poor', 'Disease', (75, 79))
620824	33913810	However, this is inconsistent with in vivo data in which the fusions only seem to impact the rate of tumor initiation while the rate of tumor growth was similar between EV and the YT or TC fusions.	('YT', 'Chemical', '-', (180, 182))	('EV', 'Chemical', '-', (169, 171))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('impact', 'Reg', (82, 88))	('fusions', 'Var', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('TC', 'Chemical', '-', (186, 188))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
620835	33913810	Does knockdown of YEATS2 or ZZZ3 alter expression of canonical TEAD-dependent YAP/TAZ target genes such as CTGF or CYR61?	('alter', 'Reg', (33, 38))	('CYR61', 'Gene', (115, 120))	('ZZZ3', 'Gene', (28, 32))	('ZZZ3', 'Gene', '26009', (28, 32))	('CYR61', 'Gene', '3491', (115, 120))	('YEATS2', 'Gene', '55689', (18, 24))	('knockdown', 'Var', (5, 14))	('CTGF', 'Gene', (107, 111))	('YEATS2', 'Gene', (18, 24))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (63, 67))	('expression', 'MPA', (39, 49))	('TEAD', 'Gene', (63, 67))
620836	33913810	Based on the ATAC-Seq data, is there a subset of genes that one could probe to determine if loss of YEATS2 or ZZZ3 impacts their expression?	('impacts', 'Reg', (115, 122))	('ZZZ3', 'Gene', '26009', (110, 114))	('YEATS2', 'Gene', '55689', (100, 106))	('expression', 'MPA', (129, 139))	('ZZZ3', 'Gene', (110, 114))	('YEATS2', 'Gene', (100, 106))	('loss', 'Var', (92, 96))
620838	33913810	YAP-TFE3 drives greater anchorage independent growth than YAP-TFE3 S94A despite YAP-TFE3 S94A demonstrating higher expression).	('S94A', 'Mutation', 'rs760318833', (67, 71))	('anchorage independent growth', 'CPA', (24, 52))	('expression', 'MPA', (115, 125))	('greater', 'PosReg', (16, 23))	('YAP-TFE3 S94A', 'Var', (80, 93))	('S94A', 'Mutation', 'rs760318833', (89, 93))	('higher', 'PosReg', (108, 114))
620841	33913810	This was performed to illustrate how YAP-TFE3 remains within the nucleus under confluent conditions (because it is not being negatively regulated by the Hippo pathway) while YAP expression in the nucleus decreases (because it is regulated normally by the Hippo pathway).	('Hippo', 'Gene', '37247', (153, 158))	('YAP-TFE3', 'Var', (37, 45))	('Hippo', 'Gene', (255, 260))	('decreases', 'NegReg', (204, 213))	('Hippo', 'Gene', (153, 158))	('Hippo', 'Gene', '37247', (255, 260))
620843	33913810	To determine whether the bHLH/leucine zipper domain is required for YAP-TFE3's oncogenic function, we evaluated the function of the YAP-TFE3 R358K-I354N (disrupts helix 1 of the bHLH domain) and showed that it altered anchorage independent growth (Figure S6A and discussed in lines 281-285).	('anchorage independent growth', 'CPA', (218, 246))	('YAP-TFE3', 'Gene', (132, 140))	('altered', 'Reg', (210, 217))	('R358K-I354N', 'Var', (141, 152))	('R358K', 'Mutation', 'p.R358K', (141, 146))	('leucine', 'Chemical', 'MESH:D007930', (30, 37))	('I354N', 'Mutation', 'p.I354N', (147, 152))
620848	33913810	We found by principal component analysis (Figure 8A) that both knock-down of YEATS2 or ZZZ3 altered the transcriptome of both TAZ-CAMTA1 and YAP-TFE3.	('ZZZ3', 'Gene', (87, 91))	('ZZZ3', 'Gene', '26009', (87, 91))	('knock-down', 'Var', (63, 73))	('transcriptome', 'MPA', (104, 117))	('YEATS2', 'Gene', '55689', (77, 83))	('altered', 'Reg', (92, 99))	('YEATS2', 'Gene', (77, 83))
620849	33913810	Comparison of genes within the TAZ-CAMTA1 and YAP-TFE3 transcriptomes with the largest decrease in expression after knock-down of YEATS2 and ZZZ3 showed that many of them were extracellular matrix proteins (Figure 8B) and were validated by qRT-PCR (Figure 8C); discussed in lines 416-419.	('expression', 'MPA', (99, 109))	('knock-down', 'Var', (116, 126))	('ZZZ3', 'Gene', (141, 145))	('ZZZ3', 'Gene', '26009', (141, 145))	('decrease', 'NegReg', (87, 95))	('YEATS2', 'Gene', '55689', (130, 136))	('YEATS2', 'Gene', (130, 136))
620850	33913810	MAPK and PI3K pathways) activated by YAP-TFE3 (Figure 3I) are inactivated with YEATS2 and ZZZ3 knock-down (Figure 8D and Figure S12A-D); discussed in lines 419-424.	('knock-down', 'Var', (95, 105))	('inactivated', 'NegReg', (62, 73))	('YEATS2', 'Gene', '55689', (79, 85))	('YAP-TFE3', 'Gene', (37, 45))	('ZZZ3', 'Gene', (90, 94))	('ZZZ3', 'Gene', '26009', (90, 94))	('YEATS2', 'Gene', (79, 85))	('S12A', 'SUBSTITUTION', 'None', (128, 132))	('S12A', 'Var', (128, 132))
620852	33913810	We showed that COL1A1, CTGF, FBLN5, and VTN were widely expressed in all of the EHE samples evaluated (Figures8H and Figure S12E-F).	('COL1A1', 'Gene', (15, 21))	('FBLN5', 'Gene', (29, 34))	('S12E', 'Var', (124, 128))	('S12E', 'SUBSTITUTION', 'None', (124, 128))	('FBLN5', 'Gene', '10516', (29, 34))	('EHE', 'Phenotype', 'HP:0032060', (80, 83))
620856	33913810	To address this, a discussion of the above has been included in the revised manuscript in lines 155-157, which reads: "In the mildly tumorigenic SW872 cell line (above references added), expression of YAP-TFE3 and TAZ-CAMTA1 decreased latency to tumor formation compared to empty vector in vivo (Figure 1J), similar to NIH 3T3 cells."	('expression', 'Var', (187, 197))	('YAP-TFE3', 'Var', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('NIH 3T3', 'CellLine', 'CVCL:0594', (319, 326))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('decreased', 'NegReg', (225, 234))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('TAZ-CAMTA1', 'Gene', (214, 224))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (246, 251))
620861	33913810	To further address the specificity of TEAD mediated DNA binding, we have performed ChIP-qPCR for CTGF (a well-established TEAD-bound gene) in SW872 cells overexpressing YAP-TFE3 or YAP-TFE3 S94A (mutant that abrogates TEAD binding) shown in Figure 2H.	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (218, 222))	('S94A', 'Mutation', 'rs760318833', (190, 194))	('CTGF', 'Gene', (97, 101))	('TEAD', 'Gene', (218, 222))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (122, 126))	('TEAD', 'Gene', '7003;21676;8463;7005;7004', (38, 42))	('S94A', 'Var', (190, 194))	('TEAD', 'Gene', (122, 126))	('TEAD', 'Gene', (38, 42))
620864	33913810	Evaluating chromatin accessibility by ATAC-Seq as a function of ZZZ3 or YEATS2 knock-down is important to do and will be part of future studies.	('YEATS2', 'Gene', '55689', (72, 78))	('knock-down', 'Var', (79, 89))	('chromatin accessibility', 'MPA', (11, 34))	('YEATS2', 'Gene', (72, 78))	('ZZZ3', 'Gene', '26009', (64, 68))	('ZZZ3', 'Gene', (64, 68))
620865	33913810	To do this we have performed the RNA-Seq experiment mentioned in point 4 and identified the resultant transcriptomes after YEATS2 and ZZZ3 knock-down.	('YEATS2', 'Gene', (123, 129))	('YEATS2', 'Gene', '55689', (123, 129))	('knock-down', 'Var', (139, 149))	('ZZZ3', 'Gene', (134, 138))	('ZZZ3', 'Gene', '26009', (134, 138))
620866	33913810	We have then intersected differentially expressed genes (DEGs) after YEATS2 and ZZZ3 knock-down in YAP-TFE3 expressing cells and intersected them with transposase accessible areas of the genome identified by ATAC-Seq (Figure 8E and 8F).	('knock-down', 'Var', (85, 95))	('ZZZ3', 'Gene', '26009', (80, 84))	('YEATS2', 'Gene', '55689', (69, 75))	('YEATS2', 'Gene', (69, 75))	('ZZZ3', 'Gene', (80, 84))
620867	33913810	We showed that 71% of DEGs after YEATS2 knock-down were present within transposase accessible areas of the genome (Figure 8E), while 74% of DEGs after ZZZ3 knock-down were present within transposase accessible portions of the genome (Figure 8F), linking the described chromatin accessibility due to expression of YAP-TFE3 to ATAC-dependent components of the YAP-TFE3 transcriptome.	('ZZZ3', 'Gene', '26009', (151, 155))	('knock-down', 'Var', (40, 50))	('YEATS2', 'Gene', '55689', (33, 39))	('YEATS2', 'Gene', (33, 39))	('chromatin', 'MPA', (268, 277))	('YAP-TFE3', 'Gene', (313, 321))	('ZZZ3', 'Gene', (151, 155))
620868	33913810	As mentioned above, to address whether knock-down of YEATS2 or ZZZ3 affected expression of CTGF or CYR61, we performed RNA-Seq on TAZ-CAMTA1 or YAP-TFE3 expressing cells with either YEATS2 or ZZZ3 knock-down.	('YEATS2', 'Gene', '55689', (182, 188))	('ZZZ3', 'Gene', (63, 67))	('expression', 'MPA', (77, 87))	('YEATS2', 'Gene', (182, 188))	('ZZZ3', 'Gene', '26009', (63, 67))	('affected', 'Reg', (68, 76))	('CYR61', 'Gene', (99, 104))	('YEATS2', 'Gene', '55689', (53, 59))	('YEATS2', 'Gene', (53, 59))	('CYR61', 'Gene', '3491', (99, 104))	('ZZZ3', 'Gene', '26009', (192, 196))	('knock-down', 'Var', (39, 49))	('CTGF', 'Gene', (91, 95))	('ZZZ3', 'Gene', (192, 196))
620869	33913810	Of the different combinations, only YAP-TFE3 expressing cells with YEATS2 or ZZZ3 knock-down demonstrated a modest reduction of CTGF (log2 of -0.64 and -0.91, respectively) (Table S7).	('reduction', 'NegReg', (115, 124))	('knock-down', 'Var', (82, 92))	('YEATS2', 'Gene', '55689', (67, 73))	('CTGF', 'MPA', (128, 132))	('YEATS2', 'Gene', (67, 73))	('ZZZ3', 'Gene', (77, 81))	('ZZZ3', 'Gene', '26009', (77, 81))
620870	33913810	As shown in Figures 8B and 8D genes encoding extracellular matrix proteins or resulting in activation of PI3K-Akt signaling were affected by ZZZ3 or YEATS2 knock-down.	('Akt', 'Gene', (110, 113))	('ZZZ3', 'Gene', (141, 145))	('ZZZ3', 'Gene', '26009', (141, 145))	('YEATS2', 'Gene', '55689', (149, 155))	('activation', 'PosReg', (91, 101))	('YEATS2', 'Gene', (149, 155))	('knock-down', 'Var', (156, 166))	('Akt', 'Gene', '207', (110, 113))
620871	33913810	As shown in Figure 8E 71% of DEGs after YEATS2 knock-down were present within transposase accessible areas of the genome as defined by ATAC-Seq.	('knock-down', 'Var', (47, 57))	('YEATS2', 'Gene', '55689', (40, 46))	('YEATS2', 'Gene', (40, 46))
620872	33913810	Similarly, 74% of DEGs after ZZZ3 knock-down were present within transposase accessible portions of the genome.	('knock-down', 'Var', (34, 44))	('ZZZ3', 'Gene', (29, 33))	('ZZZ3', 'Gene', '26009', (29, 33))
620984	28895916	The dysfunction of miRNAs in human cancer is caused by similar events to proteins: a deficiency in the processing pathway, epigenetic modifications or miRNA gene mutations all alter miRNA expression.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('mutations', 'Var', (162, 171))	('human', 'Species', '9606', (29, 34))	('epigenetic modifications', 'Var', (123, 147))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', '220972', (182, 185))	('miR', 'Gene', (151, 154))	('miR', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('deficiency', 'NegReg', (85, 95))	('processing pathway', 'Pathway', (103, 121))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('alter', 'Reg', (176, 181))	('cancer', 'Disease', (35, 41))
620998	28895916	It is a strong oncogene and promotes cellular growth by targeting casein kinase 1alpha (CK1alpha), which in turn enhances beta-catenin signalling and the expression of cyclin D1.	('cyclin D1', 'Gene', (168, 177))	('CK1alpha', 'Gene', (88, 96))	('cyclin D1', 'Gene', '595', (168, 177))	('enhances', 'PosReg', (113, 121))	('cellular growth', 'CPA', (37, 52))	('beta-catenin', 'Gene', '1499', (122, 134))	('promotes', 'PosReg', (28, 36))	('targeting', 'Var', (56, 65))	('CK1', 'Species', '2498238', (88, 91))	('beta-catenin', 'Gene', (122, 134))	('expression', 'MPA', (154, 164))
620999	28895916	The knockdown of miR-155 results in reduced tumour growth, in vitro and in vivo, as the Gap1 (G1)-synthesis (S) cell-cycle progression is blocked.	('tumour growth', 'Disease', (44, 57))	('cell-cycle progression', 'CPA', (112, 134))	('tumour growth', 'Disease', 'MESH:D006130', (44, 57))	('miR-155', 'Gene', (17, 24))	('reduced', 'NegReg', (36, 43))	('knockdown', 'Var', (4, 13))	('miR-155', 'Gene', '406947', (17, 24))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
621036	28895916	Additionally, the knockdown of miR-183 is associated with decreased tumour cell migration.	('knockdown', 'Var', (18, 27))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('decreased tumour', 'Disease', 'MESH:D009369', (58, 74))	('decreased tumour', 'Disease', (58, 74))	('miR-183', 'Gene', '406959', (31, 38))	('miR-183', 'Gene', (31, 38))
621040	28895916	Colony formation and cellular growth are enhanced by miR-17 overexpression, whilst cellular mobility and invasion remain unaffected.	('enhanced', 'PosReg', (41, 49))	('miR-17', 'Gene', (53, 59))	('cellular growth', 'CPA', (21, 36))	('miR-17', 'Gene', '406952', (53, 59))	('Colony formation', 'CPA', (0, 16))	('overexpression', 'Var', (60, 74))
621052	28895916	However, the PRC2 complex itself is frequently inactivated in MPNST, due to mutations in the SUZ12 and EED gene regions, which encode parts of the complex.	('SUZ12', 'Gene', '23512', (93, 98))	('mutations', 'Var', (76, 85))	('PRC2 complex', 'Gene', (13, 25))	('SUZ12', 'Gene', (93, 98))	('EED', 'Gene', '8726', (103, 106))	('MPNST', 'Phenotype', 'HP:0100697', (62, 67))	('EED', 'Gene', (103, 106))
621056	28895916	The knockdown of KPNB1 results in enhanced apoptosis of MPNST cells, an effect also observed with EZH2-knockdown and miR-30d overexpression.	('miR-30d', 'Gene', (117, 124))	('EZH2', 'Gene', (98, 102))	('enhanced', 'PosReg', (34, 42))	('apoptosis', 'CPA', (43, 52))	('KPNB1', 'Gene', (17, 22))	('KPNB1', 'Gene', '3837', (17, 22))	('miR-30d', 'Gene', '407033', (117, 124))	('MPNST', 'Phenotype', 'HP:0100697', (56, 61))	('knockdown', 'Var', (4, 13))	('EZH2', 'Gene', '2146', (98, 102))
621075	28895916	At the same time, the knockdown of miR-21 in MPNST cell lines results in enhanced expression of PDCD4.	('expression', 'MPA', (82, 92))	('miR-21', 'Gene', (35, 41))	('knockdown', 'Var', (22, 31))	('PDCD4', 'Gene', (96, 101))	('enhanced', 'PosReg', (73, 81))	('MPNST', 'Phenotype', 'HP:0100697', (45, 50))	('miR-21', 'Gene', '406991', (35, 41))
621076	28895916	Consequently, the blockage of miR-21 could be used in clinical practice to induce tumour cell apoptosis.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('blockage', 'Var', (18, 26))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('miR-21', 'Gene', '406991', (30, 36))	('tumour', 'Disease', (82, 88))	('induce', 'PosReg', (75, 81))	('miR-21', 'Gene', (30, 36))
621080	28895916	The knockdown of this miRNA leads to increased mRNA and protein levels of EGR1 and PTEN, two tumour suppressors.	('miR', 'Gene', '220972', (22, 25))	('PTEN', 'Gene', '5728', (83, 87))	('tumour', 'Disease', (93, 99))	('EGR1', 'Gene', (74, 78))	('increased', 'PosReg', (37, 46))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('knockdown', 'Var', (4, 13))	('EGR1', 'Gene', '1958', (74, 78))	('miR', 'Gene', (22, 25))	('PTEN', 'Gene', (83, 87))
621081	28895916	Moreover, cellular migration is mitigated by the knockdown of miR-183; therefore, it could serve as a therapeutic target in the treatment of rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (141, 157))	('knockdown', 'Var', (49, 58))	('rhabdomyosarcoma', 'Disease', (141, 157))	('cellular migration', 'CPA', (10, 28))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (141, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('miR-183', 'Gene', '406959', (62, 69))	('miR-183', 'Gene', (62, 69))
621085	28895916	Additionally, the presence of miR-378a-3p is associated with cell cycle arrest in the G2 phase.	('presence', 'Var', (18, 26))	('miR-378', 'Gene', '494327', (30, 37))	('miR-378', 'Gene', (30, 37))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (61, 78))	('associated', 'Reg', (45, 55))	('cell cycle arrest in the G2 phase', 'CPA', (61, 94))
621090	28895916	Therefore, the PAX3-FOXO1A fusion might hamper the regulation of PAX3 by miRNAs in alveolar rhabdomyosarcoma.	('regulation', 'MPA', (51, 61))	('PAX3', 'Gene', '5077', (15, 19))	('FOXO1A', 'Gene', '2308', (20, 26))	('PAX3', 'Gene', (15, 19))	('FOXO1A', 'Gene', (20, 26))	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (83, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('fusion', 'Var', (27, 33))	('hamper', 'NegReg', (40, 46))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (83, 108))	('miR', 'Gene', '220972', (73, 76))	('PAX3', 'Gene', '5077', (65, 69))	('miR', 'Gene', (73, 76))	('PAX3', 'Gene', (65, 69))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (92, 108))	('alveolar rhabdomyosarcoma', 'Disease', (83, 108))
621186	22858865	We have found that treatment of the Colon 26 adenocarcinoma with the AM or 5-FU inhibited the tumor growth with comparable efficacy.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Colon 26 adenocarcinoma', 'Disease', 'MESH:D003110', (36, 59))	('5-FU', 'Chemical', 'MESH:D005472', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('tumor', 'Disease', (94, 99))	('Colon 26 adenocarcinoma', 'Disease', (36, 59))	('5-FU', 'Var', (75, 79))	('inhibited', 'NegReg', (80, 89))
621207	22858865	These results suggest that upon treatment with AM the cells are transiently arrested in G1; however, additional experiments are needed to clarify whether the apoptotic cells originate from the G1-arrested population or become apoptotic during the S/G2 transition.	('G1-arrest', 'Disease', 'MESH:D006323', (193, 202))	('S/G2', 'Var', (247, 251))	('S/G2', 'SUBSTITUTION', 'None', (247, 251))	('G1-arrest', 'Disease', (193, 202))
621220	22858865	It has been reported that the inhibition of arginase I and l-arginine supplementation inhibits the growth of Lewis lung carcinoma, however the inhibitory effect could not be demonstrated in immunodeficient mice.	('immunodeficient', 'Disease', 'MESH:D007153', (190, 205))	('immunodeficient', 'Disease', (190, 205))	('l-arginine', 'Chemical', 'MESH:D001120', (59, 69))	('growth', 'MPA', (99, 105))	('mice', 'Species', '10090', (206, 210))	('inhibits', 'NegReg', (86, 94))	('l-arginine', 'Var', (59, 69))	('arginase I', 'Gene', '11846', (44, 54))	('inhibition', 'NegReg', (30, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Lewis lung carcinoma', 'Disease', (109, 129))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (109, 129))	('arginase I', 'Gene', (44, 54))
621222	22858865	These data support a direct tumor inhibitory effect of the AM, though participation of the components of innate immune mechanisms which are functional despite of the scid mutation could not be excluded.	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('mutation', 'Var', (171, 179))
621224	22858865	According to our results the antitumor activity of the AM is not dependent on P53 function, since inhibition of tumor growth could also be demonstrated in tumor models which have deleted or mutated P53 gene (P388, HL-60, HT-29).	('HT-29', 'CellLine', 'CVCL:0320', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('P388', 'Var', (208, 212))	('P53', 'Gene', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('HL-60', 'CellLine', 'CVCL:0002', (214, 219))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutated', 'Var', (190, 197))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', (112, 117))
621233	22858865	Moreover, combination of AM and 5-FU or cisplatin enhances the in vivo tumor growth inhibitory effect, which could provide rationale for the combined use of AM and cytostatic agents in clinical practice.	('enhances', 'PosReg', (50, 58))	('cisplatin', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('tumor', 'Disease', (71, 76))	('combination', 'Interaction', (10, 21))	('5-FU', 'Chemical', 'MESH:D005472', (32, 36))
621246	22858865	Indeed there are reports which demonstrate that the restriction of tyrosine, methionine and phenylalanine availability affects the invasion related signaling pathways, modulates the metastatic phenotype, causes cell cycle arrest, and induces apoptosis in melanoma and prostate cancer cell lines in vitro.	('apoptosis', 'CPA', (242, 251))	('methionine', 'Chemical', 'MESH:D008715', (77, 87))	('modulates', 'Reg', (168, 177))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (211, 228))	('restriction', 'Var', (52, 63))	('affects', 'Reg', (119, 126))	('induces', 'Reg', (234, 241))	('invasion related signaling pathways', 'Pathway', (131, 166))	('causes', 'Reg', (204, 210))	('tyrosine', 'Chemical', 'MESH:D014443', (67, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (268, 283))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('metastatic phenotype', 'CPA', (182, 202))	('cell cycle arrest', 'CPA', (211, 228))	('phenylalanine', 'Chemical', 'MESH:D010649', (92, 105))	('melanoma and prostate cancer', 'Disease', 'MESH:D011471', (255, 283))	('tyrosine', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
621247	22858865	In addition the in vivo metastasis or tissue infiltration inhibiting effect of tyrosine and phenylalanine restriction has also been demonstrated in murine melanoma, leukemia, lung carcinoma and hepatocarcinoma models.	('phenylalanine restriction', 'Var', (92, 117))	('tyrosine', 'Chemical', 'MESH:D014443', (79, 87))	('murine', 'Species', '10090', (148, 154))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('lung carcinoma and hepatocarcinoma', 'Disease', 'MESH:D008175', (175, 209))	('leukemia', 'Disease', (165, 173))	('leukemia', 'Phenotype', 'HP:0001909', (165, 173))	('tyrosine', 'Var', (79, 87))	('leukemia', 'Disease', 'MESH:D007938', (165, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('tissue infiltration', 'CPA', (38, 57))	('melanoma', 'Disease', (155, 163))	('phenylalanine', 'Chemical', 'MESH:D010649', (92, 105))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('metastasis', 'CPA', (24, 34))
621254	31275859	Exploiting Signaling Pathways and Immune Targets Beyond the Standard of Care for Ewing Sarcoma Ewing sarcoma (ES) family of tumors includes bone and soft tissue tumors that are often characterized by a specific translocation between chromosome 11 and 22, resulting in the EWS-FLI1 fusion gene.	('soft tissue tumors', 'Disease', 'MESH:D012983', (149, 167))	('tumors', 'Disease', (161, 167))	('Ewing Sarcoma', 'Disease', (81, 94))	('Ewing Sarcoma', 'Phenotype', 'HP:0012254', (81, 94))	('FLI1', 'Gene', (276, 280))	('Ewing Sarcoma', 'Disease', 'MESH:C563168', (81, 94))	('EWS', 'Gene', (272, 275))	('Sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (95, 108))	('FLI1', 'Gene', '2313', (276, 280))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (95, 108))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('ES', 'Phenotype', 'HP:0012254', (110, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('tumors', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('soft tissue tumors', 'Disease', (149, 167))	('EWS', 'Gene', '2130', (272, 275))	('Ewing sarcoma', 'Disease', (95, 108))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (149, 167))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('fusion gene', 'Var', (281, 292))
621271	31275859	A good example of the potential for immunotherapy in children is the use of anti-GD2 antibody in metastatic high risk neuroblastoma where cures beyond 10 years are now possible in the majority of patients without appreciable late effects from the anti-GD2 antibody.	('neuroblastoma', 'Disease', (118, 131))	('anti-GD2', 'Var', (76, 84))	('patients', 'Species', '9606', (196, 204))	('neuroblastoma', 'Phenotype', 'HP:0003006', (118, 131))	('children', 'Species', '9606', (53, 61))	('GD2', 'Chemical', '-', (81, 84))	('GD2', 'Chemical', '-', (252, 255))	('neuroblastoma', 'Disease', 'MESH:D009447', (118, 131))
621306	31275859	Additionally, tumorigenesis in ES is dependent on EWS-FLI1 fusion protein expression, with deletion resulting in ES cell death in pre-clinical studies.	('ES', 'Phenotype', 'HP:0012254', (31, 33))	('deletion', 'Var', (91, 99))	('tumor', 'Disease', (14, 19))	('ES', 'Phenotype', 'HP:0012254', (113, 115))	('EWS', 'Gene', '2130', (50, 53))	('EWS', 'Gene', (50, 53))	('FLI1', 'Gene', '2313', (54, 58))	('FLI1', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
621343	31275859	As such, IGF-R is another attractive target for ES, where its inhibition both in vitro and in vivo have impaired the migratory ability of ES cells thereby slowing tumor growth.	('impaired', 'NegReg', (104, 112))	('ES', 'Phenotype', 'HP:0012254', (48, 50))	('IGF-R', 'Gene', '3480', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('slowing', 'NegReg', (155, 162))	('ES', 'Phenotype', 'HP:0012254', (138, 140))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('inhibition', 'Var', (62, 72))	('migratory ability', 'CPA', (117, 134))	('IGF-R', 'Gene', (9, 14))
621344	31275859	Five human anti-IGF-1R antibodies for ES have been tested in phase II clinical trials: robatumumab (also known as SCH 717454 and MK-7454, Merck and Schering-Plow), R1507 (Roche), ganitumab (NantCell, previously known as AMG 479 by Amgen Inc), cixutumumab (IMC-A12, ImClone systems), and figitumumab (CP-751871, Pfizer).	('ES', 'Phenotype', 'HP:0012254', (38, 40))	('AMG', 'Gene', (220, 223))	('N', 'Chemical', 'MESH:D009584', (190, 191))	('R1507', 'Var', (164, 169))	('AMG', 'Gene', '265', (220, 223))	('IGF-1R', 'Gene', '3480', (16, 22))	('IGF-1R', 'Gene', (16, 22))	('cixutumumab', 'Chemical', 'MESH:C557414', (243, 254))	('figitumumab', 'Chemical', 'MESH:C525021', (287, 298))	('human', 'Species', '9606', (5, 10))	('robatumumab', 'Chemical', 'MESH:C573312', (87, 98))	('ganitumab', 'Chemical', 'MESH:C545764', (179, 188))
621363	31275859	Vascular endothelial growth factor (VEGF) inhibition similarly results in decreased cell growth as well as reduced tumor vessel density in preclinical models.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('VEGF', 'Gene', (36, 40))	('reduced', 'NegReg', (107, 114))	('tumor', 'Disease', (115, 120))	('inhibition', 'Var', (42, 52))	('cell growth', 'CPA', (84, 95))	('Vascular endothelial growth factor', 'Gene', '7422', (0, 34))	('VEGF', 'Gene', '7422', (36, 40))	('decreased', 'NegReg', (74, 83))	('Vascular endothelial growth factor', 'Gene', (0, 34))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
621369	31275859	The authors showed that silencing of ROR1 resulted in dysfunctional migration of ES cells in vitro, with the conclusion that ROR1 may also be a potential therapeutic target for ES.	('dysfunctional', 'MPA', (54, 67))	('ROR1', 'Gene', (37, 41))	('ES', 'Phenotype', 'HP:0012254', (177, 179))	('ROR1', 'Gene', '4919', (125, 129))	('ES', 'Phenotype', 'HP:0012254', (81, 83))	('ROR1', 'Gene', (125, 129))	('ROR1', 'Gene', '4919', (37, 41))	('silencing', 'Var', (24, 33))
621384	31275859	In addition, anti-GD2 antibodies have been actively tested in clinical trials for neuroblastoma for over two decades, with proven safety and efficacy.	('antibodies', 'Var', (22, 32))	('anti-GD2 antibodies', 'Var', (13, 32))	('neuroblastoma', 'Disease', 'MESH:D009447', (82, 95))	('GD2', 'Chemical', '-', (18, 21))	('neuroblastoma', 'Disease', (82, 95))	('neuroblastoma', 'Phenotype', 'HP:0003006', (82, 95))
621396	31275859	Radioimmunotherapy directed at B7-H3 using the antibody, 8H9, has been tested in the phase I setting for patients with DSCRT (NCT01099644), neuroblastoma with central nervous involvement (NCT00089245 and NCT03275402), and diffuse intrinsic pontine glioma (NCT01502917).	('glioma', 'Disease', (248, 254))	('N', 'Chemical', 'MESH:D009584', (204, 205))	('tested', 'Reg', (71, 77))	('patients', 'Species', '9606', (105, 113))	('DSCRT', 'Disease', (119, 124))	('N', 'Chemical', 'MESH:D009584', (256, 257))	('NCT01502917', 'Var', (256, 267))	('NCT03275402', 'Var', (204, 215))	('N', 'Chemical', 'MESH:D009584', (188, 189))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('neuroblastoma', 'Disease', 'MESH:D009447', (140, 153))	('NCT01099644', 'Var', (126, 137))	('NCT00089245', 'Var', (188, 199))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('neuroblastoma', 'Disease', (140, 153))	('neuroblastoma', 'Phenotype', 'HP:0003006', (140, 153))
621411	31275859	In addition, knockdown of CD99 in ES cell lines results in decreased oncogenic potential, including decreased growth in tissue culture, diminished colony formation in soft agar assays, reduced cell motility, and smaller tumors with less metastasis in xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('smaller', 'NegReg', (212, 219))	('CD99', 'Gene', (26, 30))	('diminished', 'NegReg', (136, 146))	('decreased', 'NegReg', (59, 68))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('colony formation in soft agar assays', 'CPA', (147, 183))	('tumors', 'Disease', (220, 226))	('oncogenic potential', 'CPA', (69, 88))	('growth in tissue culture', 'CPA', (110, 134))	('decreased', 'NegReg', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('ES', 'Phenotype', 'HP:0012254', (34, 36))	('cell motility', 'CPA', (193, 206))	('knockdown', 'Var', (13, 22))	('decreased growth', 'Phenotype', 'HP:0001510', (100, 116))	('reduced', 'NegReg', (185, 192))
621412	31275859	Cu-labeled anti-CD99 antibodies were shown to be superior to FDG-PET in detecting micrometastases in xenograft models.	('metastases', 'Disease', (87, 97))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('FDG', 'Chemical', 'MESH:D019788', (61, 64))	('anti-CD99', 'Var', (11, 20))	('Cu', 'Chemical', 'MESH:D003300', (0, 2))
621416	31275859	As a result, cancers develop a dependence on methionine, with deprivation of methionine resulting in cell cycle arrest and eventually apoptosis.	('deprivation', 'Var', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('methionine', 'Chemical', 'MESH:D008715', (77, 87))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (101, 118))	('apoptosis', 'CPA', (134, 143))	('methionine', 'MPA', (77, 87))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('arrest', 'Disease', 'MESH:D006323', (112, 118))	('methionine', 'Chemical', 'MESH:D008715', (45, 55))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Disease', (13, 20))	('arrest', 'Disease', (112, 118))
621417	31275859	Recombinant methioninase (L-methionine-cleaving enzyme from Pseudomonas putida) acts to deplete methionine and in a variety of tumors including ES, results in arrested cell growth in preclinical models (typically at the S/G2 phase).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('deplete methionine', 'Phenotype', 'HP:0003658', (88, 106))	('arrest', 'Disease', 'MESH:D006323', (159, 165))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('arrest', 'Disease', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('Pseudomonas putida', 'Species', '303', (60, 78))	('L-methionine', 'Chemical', 'MESH:D008715', (26, 38))	('methionine', 'Chemical', 'MESH:D008715', (28, 38))	('S/G2', 'Var', (220, 224))	('methionine', 'Chemical', 'MESH:D008715', (96, 106))	('ES', 'Phenotype', 'HP:0012254', (144, 146))	('deplete methionine', 'MPA', (88, 106))	('S/G2', 'SUBSTITUTION', 'None', (220, 224))
621418	31275859	Although prolonged use of recombinant methioninase is not feasible given the potential liver toxicity, there has been interest in combining recombinant methioninase with standard chemotherapeutic agents, especially those active in S/G2.	('S/G2', 'Var', (231, 235))	('toxicity', 'Disease', 'MESH:D064420', (93, 101))	('S/G2', 'SUBSTITUTION', 'None', (231, 235))	('toxicity', 'Disease', (93, 101))
621419	31275859	For example, in preclinical models of neuroblastoma, recombinant methioninase showed synergism with microtubule depolymerization agents, and in preclinical models of synovial sarcoma, overcame resistance to doxorubicin monotherapy.	('neuroblastoma', 'Phenotype', 'HP:0003006', (38, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (166, 182))	('synergism', 'MPA', (85, 94))	('synovial sarcoma', 'Disease', 'MESH:D013584', (166, 182))	('microtubule depolymerization agents', 'MPA', (100, 135))	('neuroblastoma', 'Disease', 'MESH:D009447', (38, 51))	('recombinant', 'Var', (53, 64))	('neuroblastoma', 'Disease', (38, 51))	('synovial sarcoma', 'Disease', (166, 182))	('overcame', 'PosReg', (184, 192))	('doxorubicin', 'Chemical', 'MESH:D004317', (207, 218))
621427	31275859	found that a modified peptide, YLNPSVDSV, induced strong CTL killing in ES cells, and the adoptive transfer of these specific CTLs into mice killed ES xenografts and increased survival.	('mice', 'Species', '10090', (136, 140))	('CTL killing', 'CPA', (57, 68))	('killed', 'NegReg', (141, 147))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('ES', 'Phenotype', 'HP:0012254', (72, 74))	('increased', 'PosReg', (166, 175))	('ES', 'Phenotype', 'HP:0012254', (148, 150))	('YLNPSVDSV', 'Var', (31, 40))	('survival', 'CPA', (176, 184))	('ES xenografts', 'CPA', (148, 161))
621445	31275859	Ongoing clinical trials testing checkpoint inhibitors in ES patients include: Ipilimumab (anti-CTLA4, NCT02304458), Nivolumab (Anti-PD1, NCT03190174), Ipilimumab + Nivolumab (NCT02982486), and Enoblituzumab (B7-H3, NCT02982941).	('NCT02982486', 'Var', (175, 186))	('N', 'Chemical', 'MESH:D009584', (116, 117))	('N', 'Chemical', 'MESH:D009584', (215, 216))	('CTLA4', 'Gene', (95, 100))	('Nivolumab', 'Chemical', 'MESH:D000077594', (116, 125))	('patients', 'Species', '9606', (60, 68))	('N', 'Chemical', 'MESH:D009584', (175, 176))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('Nivolumab', 'Chemical', 'MESH:D000077594', (164, 173))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (78, 88))	('ES', 'Phenotype', 'HP:0012254', (57, 59))	('N', 'Chemical', 'MESH:D009584', (164, 165))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (151, 161))	('CTLA4', 'Gene', '1493', (95, 100))	('NCT02304458', 'Var', (102, 113))	('Enoblituzumab', 'Chemical', '-', (193, 206))
621446	31275859	Given the paucity of mutations in ES (hence low frequency of neoantigens) accompanied by low expression levels of PD-1 and PD-L1, it remains questionable if patients with ES can derive significant clinical benefit from these agents.	('expression levels', 'MPA', (93, 110))	('patients', 'Species', '9606', (157, 165))	('ES', 'Phenotype', 'HP:0012254', (171, 173))	('PD-L1', 'Gene', (123, 128))	('PD-1', 'Gene', (114, 118))	('ES', 'Phenotype', 'HP:0012254', (34, 36))	('PD-L1', 'Gene', '29126', (123, 128))	('PD-1', 'Gene', '5133', (114, 118))	('mutations', 'Var', (21, 30))
621448	31275859	In one adoptive T cell study, patients are randomized to either EGFR-specific CAR T cells or CAR T cells directed at both EGFR and CD19 (NCT03618381).	('CD19', 'Gene', (131, 135))	('CD19', 'Gene', '930', (131, 135))	('NCT03618381', 'Var', (137, 148))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('patients', 'Species', '9606', (30, 38))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
621467	31275859	For many years, the heterogenous clinical presentations and outcomes of ES were at odds with its relative genomic homogeneity, consisting of near-universal EWS-FLI1 fusion alterations and relatively few other recurrent somatic alterations.	('EWS', 'Gene', '2130', (156, 159))	('EWS', 'Gene', (156, 159))	('FLI1', 'Gene', (160, 164))	('FLI1', 'Gene', '2313', (160, 164))	('fusion alterations', 'Var', (165, 183))	('ES', 'Phenotype', 'HP:0012254', (72, 74))
621470	31275859	This genetic and epigenetic intra-tumoral heterogeneity likely plays a substantial role in driving clonal evolution and clinical response to therapy.	('epigenetic', 'Var', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('intra-tumor', 'Disease', (28, 39))	('intra-tumor', 'Disease', 'MESH:D009369', (28, 39))
621481	29250195	Angiosarcomas can occur spontaneously or secondary to radiotherapy, chronic lymphoedema and in a variety of familial conditions including neurofibromatosis (NF-1), mutated breast cancer associated gene 1 or 2 (BRCA1 or BRCA2) and Maffucci syndrome.	('BRCA2', 'Gene', '675', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Angiosarcomas', 'Phenotype', 'HP:0200058', (0, 13))	('lymphoedema', 'Phenotype', 'HP:0001004', (76, 87))	('lymphoedema', 'Disease', (76, 87))	('mutated', 'Var', (164, 171))	('Maffucci syndrome', 'Disease', (230, 247))	('NF-1', 'Gene', '4763', (157, 161))	('BRCA1', 'Gene', '672', (210, 215))	('NF-1', 'Gene', (157, 161))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('BRCA1', 'Gene', (210, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('lymphoedema', 'Disease', 'None', (76, 87))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (138, 155))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('breast cancer', 'Disease', (172, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('BRCA2', 'Gene', (219, 224))	('neurofibromatosis', 'Disease', 'MESH:C537392', (138, 155))	('Angiosarcomas', 'Disease', (0, 13))	('Angiosarcomas', 'Disease', 'MESH:D006394', (0, 13))	('Angiosarcoma', 'Phenotype', 'HP:0200058', (0, 12))	('neurofibromatosis', 'Disease', (138, 155))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (230, 247))
621536	29250195	In a small cohort study, activating VEGFR2 mutations were identified in 14% (3/22) of angiosarcoma tumour samples.	('angiosarcoma tumour', 'Disease', 'MESH:D006394', (86, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('activating', 'PosReg', (25, 35))	('angiosarcoma', 'Phenotype', 'HP:0200058', (86, 98))	('VEGFR2', 'Gene', '3791', (36, 42))	('mutations', 'Var', (43, 52))	('angiosarcoma tumour', 'Disease', (86, 105))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('VEGFR2', 'Gene', (36, 42))
621537	29250195	No VEGFR2 mutations were identified in 27 tumour samples available for analysis from the French Sarcoma Group study of sorafenib for advanced angiosarcoma.	('angiosarcoma', 'Disease', 'MESH:D006394', (142, 154))	('Sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('angiosarcoma', 'Disease', (142, 154))	('VEGFR2', 'Gene', (3, 9))	('angiosarcoma', 'Phenotype', 'HP:0200058', (142, 154))	('Sarcoma', 'Disease', (96, 103))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('Sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('tumour', 'Disease', (42, 48))	('mutations', 'Var', (10, 19))	('sorafenib', 'Chemical', 'MESH:D000077157', (119, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('VEGFR2', 'Gene', '3791', (3, 9))
621538	29250195	In a separate study, mutations in angiogenesis-related genes were identified in 38% (15/39) of angiosarcoma tumour samples, including recurrent mutations in vascular endothelial-phosphotyrosine phosphatase (VE-PTP) and phospholipase gamma 1 (PLCG1).	('PLCG1', 'Gene', '5335', (242, 247))	('identified', 'Reg', (66, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('VE-PTP', 'Gene', (207, 213))	('angiosarcoma tumour', 'Disease', (95, 114))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('PLCG1', 'Gene', (242, 247))	('angiogenesis-related genes', 'Gene', (34, 60))	('angiosarcoma tumour', 'Disease', 'MESH:D006394', (95, 114))	('mutations', 'Var', (144, 153))	('angiosarcoma', 'Phenotype', 'HP:0200058', (95, 107))	('mutations', 'Var', (21, 30))
621539	29250195	The response of angiosarcomas harbouring mutations in angiogenesis-related genes to vascular targeted agents has not been correlated.	('mutations', 'Var', (41, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (21, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('angiosarcomas', 'Phenotype', 'HP:0200058', (16, 29))	('angiosarcomas', 'Disease', 'MESH:D006394', (16, 29))	('angiosarcoma', 'Phenotype', 'HP:0200058', (16, 28))	('angiosarcomas', 'Disease', (16, 29))
621615	26925391	Despite this histogenetic uncertainty, Ewing sarcoma is genetically well characterized by the presence of pathognomonic EWSR1-ETS gene fusions (usually EWSR1-FLI1), which drive this disease by acting as oncogenic transcription factors.	('FLI1', 'Gene', '2313', (158, 162))	('EWSR1', 'Gene', '2130', (120, 125))	('drive', 'PosReg', (171, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('EWSR1', 'Gene', (152, 157))	('fusions', 'Var', (135, 142))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (39, 52))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (39, 52))	('EWSR1', 'Gene', '2130', (152, 157))	('EWSR1', 'Gene', (120, 125))	('FLI1', 'Gene', (158, 162))	('Ewing sarcoma', 'Disease', (39, 52))
621618	26925391	In accordance, subsequent experiments showed that IL2 transgenic Ewing sarcoma cells elicit tumor-specific T and NK cell responses in vitro and in vivo.	('IL2', 'Gene', '3558', (50, 53))	('elicit', 'Reg', (85, 91))	('IL2', 'Gene', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Ewing sarcoma', 'Disease', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('transgenic', 'Var', (54, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('tumor', 'Disease', (92, 97))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (65, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (65, 78))
621619	26925391	In a subsequent study,  now investigate the role of immunostimulation by OX40 ligand (also known as CD252 or tumor necrosis factor ligand family member 4) transgenic Ewing sarcoma cells.	('transgenic', 'Var', (155, 165))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (166, 179))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (166, 179))	('tumor', 'Disease', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('OX40', 'Gene', '7293', (73, 77))	('OX40', 'Gene', (73, 77))	('necrosis', 'Disease', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CD252', 'Gene', '7292', (100, 105))	('Ewing sarcoma', 'Disease', (166, 179))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('necrosis', 'Disease', 'MESH:D009336', (115, 123))	('CD252', 'Gene', (100, 105))
621628	26925391	describe two disease-relevant mouse myogenic tumor models driven either by oncogenic Kras in p16p19null or by a mutant Smoothened allele.	('Kras in p16p19null', 'Var', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('p16p19null', 'Var', (93, 103))	('tumor', 'Disease', (45, 50))	('driven', 'Reg', (58, 64))	('mouse', 'Species', '10090', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
621632	26925391	In an accompanying article,  provide evidence that oncogenic RAS mutants confer resistance of RMS13 rhabdomyosarcoma cells to oxidative stress-induced ferroptotic cell death, which has important implications for the development of targeted therapies for rhabdomyosarcoma and which might at least partially explain heterogeneous responses on drug treatment depending on the RAS mutation status.	('resistance', 'MPA', (80, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('mutants', 'Var', (65, 72))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (100, 116))	('oxidative stress', 'Phenotype', 'HP:0025464', (126, 142))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (254, 270))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (254, 270))	('rhabdomyosarcoma', 'Disease', (100, 116))	('rhabdomyosarcoma', 'Disease', (254, 270))	('oxidative stress-induced ferroptotic', 'MPA', (126, 162))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (100, 116))	('RAS', 'Gene', (61, 64))
621638	26735530	Relationship Between 18F-Fluorodeoxyglucose Uptake and V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog Mutation in Colorectal Cancer Patients To evaluate clinical values of clinicopathologic and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT)-related parameters for prediction of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer (CRC) and to investigate their variability depending on C-reactive protein (CRP) levels.	('CRC', 'Phenotype', 'HP:0003003', (419, 422))	('colorectal cancer', 'Disease', (400, 417))	('sarcoma', 'Phenotype', 'HP:0100242', (350, 357))	('FDG', 'Gene', (228, 231))	('Sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (400, 417))	('sarcoma viral', 'Disease', 'MESH:D001102', (350, 363))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (120, 137))	('Colorectal Cancer', 'Disease', (120, 137))	('18F-Fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (21, 43))	('sarcoma viral', 'Disease', (350, 363))	('KRAS', 'Gene', (382, 386))	('Sarcoma Viral', 'Disease', 'MESH:D001102', (77, 90))	('rat', 'Species', '10116', (346, 349))	('Sarcoma Viral', 'Disease', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('colorectal cancer', 'Disease', 'MESH:D015179', (400, 417))	('mutation', 'Var', (388, 396))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (120, 137))	('Rat', 'Species', '10116', (73, 76))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (200, 222))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('FDG', 'Gene', '23583', (228, 231))
621642	26735530	Interestingly, the CRC patients (having CRP < 6.0 mg/L) with KRAS mutations had significantly higher (P < 0.05) SUVmax and SUVpeak values than the patients expressing wild-type KRAS mutations.	('mutations', 'Var', (66, 75))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (147, 155))	('KRAS', 'Gene', (61, 65))	('higher', 'PosReg', (94, 100))
621652	26735530	V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutational status as evaluated by histologic tumor examination is detected in approximately 30% to 40% of CRC patients.	('rat', 'Species', '10116', (18, 21))	('sarcoma viral', 'Disease', (22, 35))	('patients', 'Species', '9606', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('mutational', 'Var', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('sarcoma viral', 'Disease', 'MESH:D001102', (22, 35))	('detected', 'Reg', (119, 127))	('tumor', 'Disease', (98, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('CRC', 'Disease', (159, 162))
621654	26735530	Although preoperative imaging is important for making critical decisions for treatment planning, only a few studies have described relationships between scan findings and KRAS mutation in CRC patients.	('CRC', 'Phenotype', 'HP:0003003', (188, 191))	('rat', 'Species', '10116', (15, 18))	('patients', 'Species', '9606', (192, 200))	('KRAS', 'Gene', (171, 175))	('mutation', 'Var', (176, 184))
621655	26735530	Moreover, these studies report conflicting results: 2 clinical studies demonstrated that higher 18F-FDG uptake in CRC is associated with KRAS mutation, and a recent study by Iwamoto et al suggested that upregulation of glucose transporter-1 (GLUT1) is a possible mechanism of higher 18F-FDG accumulation in CRC with KRAS mutation.	('CRC', 'Disease', (307, 310))	('GLUT1', 'Gene', '6513', (242, 247))	('FDG', 'Gene', '23583', (287, 290))	('CRC', 'Phenotype', 'HP:0003003', (307, 310))	('FDG', 'Gene', (100, 103))	('FDG', 'Gene', (287, 290))	('higher', 'PosReg', (89, 95))	('rat', 'Species', '10116', (78, 81))	('FDG', 'Gene', '23583', (100, 103))	('glucose transporter-1', 'Gene', '6513', (219, 240))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('mutation', 'Var', (142, 150))	('glucose transporter-1', 'Gene', (219, 240))	('GLUT1', 'Gene', (242, 247))	('upregulation', 'PosReg', (203, 215))
621656	26735530	Meanwhile, Krikelis et al reported that there is a lack of any association between KRAS mutation and 18F-FDG-PET scan findings.	('KRAS', 'Gene', (83, 87))	('FDG', 'Gene', '23583', (105, 108))	('mutation', 'Var', (88, 96))	('FDG', 'Gene', (105, 108))
621661	26735530	In this study, we investigated clinicopathologic variables and PET/CT-related parameters that could potentially predict KRAS mutation in a large population of CRC patients and evaluated the variability of their predictive values according to CRP levels.	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('patients', 'Species', '9606', (163, 171))	('KRAS', 'Gene', (120, 124))	('mutation', 'Var', (125, 133))
621666	26735530	Among the 221 patients who underwent 18F-FDG PET/CT scan and KRAS mutation analysis for CRC during the study period, 179 with full clinicopathologic information were included in this study (Fig.	('CRC', 'Phenotype', 'HP:0003003', (88, 91))	('FDG', 'Gene', '23583', (41, 44))	('KRAS', 'Gene', (61, 65))	('FDG', 'Gene', (41, 44))	('mutation', 'Var', (66, 74))	('patients', 'Species', '9606', (14, 22))
621682	26735530	V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations were found in 60 patients (33.5%); 45 of these patients (75%) had normal CRP levels, whereas the other 15 patients (25%) showed elevated CRP levels.	('rat', 'Species', '10116', (18, 21))	('sarcoma viral', 'Disease', (22, 35))	('patients', 'Species', '9606', (169, 177))	('elevated', 'PosReg', (191, 199))	('patients', 'Species', '9606', (80, 88))	('elevated CRP', 'Phenotype', 'HP:0011227', (191, 203))	('CRP levels', 'MPA', (200, 210))	('mutations', 'Var', (53, 62))	('sarcoma viral', 'Disease', 'MESH:D001102', (22, 35))	('CRP levels', 'MPA', (136, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('patients', 'Species', '9606', (110, 118))
621684	26735530	A cutoff level was determined by receiver operating characteristic curve analysis for SUVmax, SUVpeak, MTV, and TLG, and the best discriminative values between those tumors with wild-type and mutated KRAS were 10 (g/mL), 7.4 (g/mL), 10 mL, and 50 g, respectively.	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('KRAS', 'Gene', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutated', 'Var', (192, 199))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('rat', 'Species', '10116', (45, 48))
621685	26735530	Among the 179 patients in total, the KRAS mutation group was found to have tumors with lower histologic grade and more positive lymph node (LN) metastasis, compared with the KRAS wild-type group (P < 0.05, all; Table 2).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('lower', 'NegReg', (87, 92))	('histologic grade', 'CPA', (93, 109))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('patients', 'Species', '9606', (14, 22))	('tumors', 'Disease', (75, 81))	('more', 'PosReg', (114, 118))	('KRAS mutation', 'Var', (37, 50))
621686	26735530	Multivariate analysis revealed that histologic grade and LN metastasis were independent predictors of KRAS mutation in CRC patients [histologic grade: odds ratio (OR), 5.6; 95% confidence interval (CI), 1.6-18.9; P = 0.006, and LN metastasis: OR, 3.4; 95% CI, 1.6-7.1; P = 0.001].	('CRC', 'Phenotype', 'HP:0003003', (119, 122))	('rat', 'Species', '10116', (156, 159))	('patients', 'Species', '9606', (123, 131))	('KRAS', 'Gene', (102, 106))	('mutation', 'Var', (107, 115))
621688	26735530	In contrast, both lower 18F-FDG uptake and positive LN metastasis were significantly associated with KRAS mutation in the elevated CRP group (CRP >= 6; n = 47; P < 0.05, all).	('KRAS', 'Gene', (101, 105))	('mutation', 'Var', (106, 114))	('lower', 'NegReg', (18, 23))	('positive LN metastasis', 'CPA', (43, 65))	('elevated CRP', 'Phenotype', 'HP:0011227', (122, 134))	('FDG', 'Gene', '23583', (28, 31))	('FDG', 'Gene', (28, 31))
621690	26735530	Second, because of the nonhomogeneous, scattered distribution of tumor tissue, there could be discordant results for KRAS mutation between the biopsy tissue and the resected tumor.	('tumor', 'Disease', (174, 179))	('KRAS', 'Gene', (117, 121))	('tumor', 'Disease', (65, 70))	('mutation', 'Var', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
621691	26735530	For these reasons, Miles et al insisted that identification of an imaging signature for the KRAS mutation would enable imaging to provide an adjunct to histologic assessment, and demonstrated that decision trees using imaging biomarkers could enhance the predictive accuracy of KRAS mutation in CRC.	('KRAS', 'Gene', (278, 282))	('CRC', 'Phenotype', 'HP:0003003', (295, 298))	('enhance', 'PosReg', (243, 250))	('rat', 'Species', '10116', (186, 189))	('mutation', 'Var', (97, 105))	('CRC', 'Gene', (295, 298))
621695	26735530	Another retrospective study also showed that SUVmax was an independent predictor of KRAS mutation in CRC, together with the PET-based maximal tumor width.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('CRC', 'Phenotype', 'HP:0003003', (101, 104))	('CRC', 'Gene', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('KRAS mutation', 'Var', (84, 97))
621696	26735530	Recently, Iwamoto et al suggested that mutated KRAS causes higher 18F-FDG accumulation, possibly by upregulation of GLUT1, through an in vitro study.	('GLUT1', 'Gene', (116, 121))	('FDG', 'Gene', (70, 73))	('GLUT1', 'Gene', '6513', (116, 121))	('mutated', 'Var', (39, 46))	('FDG', 'Gene', '23583', (70, 73))	('KRAS', 'Gene', (47, 51))	('higher', 'PosReg', (59, 65))	('upregulation', 'PosReg', (100, 112))
621697	26735530	In contrast, a recent clinical study reported a lack of association between KRAS mutation and 18F-FDG uptake in metastatic colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('KRAS', 'Gene', (76, 80))	('mutation', 'Var', (81, 89))	('FDG', 'Gene', '23583', (98, 101))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('FDG', 'Gene', (98, 101))	('colon cancer', 'Disease', (123, 135))
621699	26735530	Based on our results, we suppose that the lack of association between KRAS mutation and 18F-FDG uptake, however, might be because of improper patient selection.	('KRAS', 'Gene', (70, 74))	('mutation', 'Var', (75, 83))	('FDG', 'Gene', '23583', (92, 95))	('FDG', 'Gene', (92, 95))	('patient', 'Species', '9606', (142, 149))
621701	26735530	In the current study, 18F-FDG uptake represented as SUVmax and SUVpeak had a positive correlation with KRAS mutation only in the normal CRP group; meanwhile, it showed an inverse correlation in the elevated CRP group and lost its predictive power in the whole population.	('KRAS', 'Gene', (103, 107))	('FDG', 'Gene', '23583', (26, 29))	('elevated CRP', 'Phenotype', 'HP:0011227', (198, 210))	('FDG', 'Gene', (26, 29))	('correlation', 'Interaction', (86, 97))	('mutation', 'Var', (108, 116))
621722	26735530	Although the accuracy could be improved when combined with other clinicopathologic or imaging parameters, 18F-FDG PET/CT cannot replace conventional methods to confirm KRAS mutation, and it should rather be used as a complementary tool when histopathologic results are equivocal.	('FDG', 'Gene', (110, 113))	('rat', 'Species', '10116', (197, 200))	('FDG', 'Gene', '23583', (110, 113))	('KRAS', 'Gene', (168, 172))	('mutation', 'Var', (173, 181))
621727	26735530	In conclusion, 18F-FDG uptake in primary CRCs with mutated KRAS was significantly higher than in CRCs with wild-type KRAS, and SUVmax and SUVpeak were independent predictors of KRAS mutation together with positive LN metastasis.	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('FDG', 'Gene', '23583', (19, 22))	('higher', 'PosReg', (82, 88))	('FDG', 'Gene', (19, 22))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('KRAS', 'Gene', (177, 181))	('mutation', 'Var', (182, 190))	('KRAS', 'Gene', (59, 63))	('mutated', 'Var', (51, 58))
621729	26735530	The current study reinforced the predictive value of 18F-FDG uptake for KRAS mutation in addition to stressing the importance of proper patient selection in a correlative study.	('patient', 'Species', '9606', (136, 143))	('mutation', 'Var', (77, 85))	('FDG', 'Gene', '23583', (57, 60))	('FDG', 'Gene', (57, 60))	('KRAS', 'Disease', (72, 76))
621736	26449317	Fluorescence in situ hybridization assay using dual staining probes detected EWSR1-CREB3L1 fusion in each lesion, which is characteristic molecular findings of SEF.	('CREB3L1', 'Gene', '90993', (83, 90))	('fusion', 'Var', (91, 97))	('CREB3L1', 'Gene', (83, 90))	('detected', 'Reg', (68, 76))	('EWSR1', 'Gene', (77, 82))	('EWSR1', 'Gene', '2130', (77, 82))
621742	26449317	It has recently been characterized by recurrent FUS-CREB3L1, FUS-CREB3L2 or EWS1-CREB3L1 translocations and immunohistochemical MUC4 expression.	('FUS', 'Gene', '2521', (48, 51))	('CREB3L1', 'Gene', (52, 59))	('MUC4', 'Gene', '4585', (128, 132))	('CREB3L1', 'Gene', '90993', (52, 59))	('CREB3L2', 'Gene', (65, 72))	('MUC4', 'Gene', (128, 132))	('CREB3L1', 'Gene', '90993', (81, 88))	('CREB3L1', 'Gene', (81, 88))	('FUS', 'Gene', '2521', (61, 64))	('FUS', 'Gene', (61, 64))	('CREB3L2', 'Gene', '64764', (65, 72))	('translocations', 'Var', (89, 103))	('FUS', 'Gene', (48, 51))
621744	26449317	Here, we present two cases of SEF with primary renal origin bearing a EWS1-CREB3L1 gene fusion, as supported by MUC4 immunostaining and fluorescence in situ hybridization (FISH).	('CREB3L1', 'Gene', (75, 82))	('CREB3L1', 'Gene', '90993', (75, 82))	('MUC4', 'Gene', '4585', (112, 116))	('fusion', 'Var', (88, 94))	('MUC4', 'Gene', (112, 116))
621747	26449317	For characterization of the possible underlying gene rearrangement or fusion gene events, the following FISH probe sets were utilized on both cases: Vysis LSI EWSR1 (22q12) and Vysis LSI FUS (16p11) Dual Color Break Apart Probes (Abbott Molecular, Inc., Des Plaines, IL) and EWSR1 and CREB3L1 spanning probe sets using cocktails of BAC clones (RP11-945 M21 and RP11-1126O13, and RP11-1014A16, RP11-1106 J11 and RP11-481I24 respectively) selected on the basis of their location per the UCSC Human Genome Browser [http://genome.ucsc.edu/cgi-bin/hgGateway] and obtained from BAC/PAC Resources Center (Children's Hospital Oakland Research Institute, Oakland, CA, USA).	('CREB3L1', 'Gene', (285, 292))	('Human', 'Species', '9606', (490, 495))	('PAC', 'Phenotype', 'HP:0006699', (576, 579))	('EWSR1', 'Gene', (275, 280))	('CREB3L1', 'Gene', '90993', (285, 292))	('Vysis LSI FUS', 'Disease', (177, 190))	('EWSR1', 'Gene', (159, 164))	('Children', 'Species', '9606', (598, 606))	('RP11-1014A16', 'Var', (379, 391))	('EWSR1', 'Gene', '2130', (275, 280))	('RP11-1126O13', 'Var', (361, 373))	('EWSR1', 'Gene', '2130', (159, 164))	('RP11-481I24', 'Var', (411, 422))	('RP11-945 M21', 'Var', (344, 356))	('Break Apart', 'Phenotype', 'HP:0001061', (210, 221))	('Vysis LSI FUS', 'Disease', 'None', (177, 190))	('RP11-1106 J11', 'Var', (393, 406))
621755	26449317	The cutoff level for scoring a specimen as positive for a rearrangement of the FUS or EWSR1 locus or as positive for an EWSR1/CREB3L1 fusion was >15 % of the cells evaluated.	('FUS', 'Gene', '2521', (79, 82))	('EWSR1', 'Gene', '2130', (120, 125))	('EWSR1', 'Gene', (86, 91))	('rearrangement', 'Var', (58, 71))	('positive', 'Reg', (104, 112))	('CREB3L1', 'Gene', (126, 133))	('EWSR1', 'Gene', '2130', (86, 91))	('CREB3L1', 'Gene', '90993', (126, 133))	('EWSR1', 'Gene', (120, 125))	('positive', 'Reg', (43, 51))	('FUS', 'Gene', (79, 82))
621792	26449317	who have recently reported 2 well-documented cases with rearrangement involving EWSR1 and CREB3L1 genes (Table 2).	('CREB3L1', 'Gene', (90, 97))	('CREB3L1', 'Gene', '90993', (90, 97))	('EWSR1', 'Gene', (80, 85))	('rearrangement', 'Var', (56, 69))	('EWSR1', 'Gene', '2130', (80, 85))
621794	26449317	Two of these had rearranged EWSR1 with undocumented fusion gene partner.	('rearranged', 'Var', (17, 27))	('EWSR1', 'Gene', '2130', (28, 33))	('EWSR1', 'Gene', (28, 33))
621799	26449317	Most common genetic alteration described in pure SEFs is EWSR1-CREB3L1 fusion.	('CREB3L1', 'Gene', '90993', (63, 70))	('CREB3L1', 'Gene', (63, 70))	('EWSR1', 'Gene', (57, 62))	('fusion', 'Var', (71, 77))	('EWSR1', 'Gene', '2130', (57, 62))
621809	26449317	We report 2 distinctive, clinically malignant, renal SEF bearing EWSR1-CREB3L1 fusions through unbalanced translocation with unique histomorphologic features.	('EWSR1', 'Gene', (65, 70))	('CREB3L1', 'Gene', (71, 78))	('EWSR1', 'Gene', '2130', (65, 70))	('CREB3L1', 'Gene', '90993', (71, 78))	('fusions', 'Var', (79, 86))
621902	31467480	Over 90% are characterized by a t (X; 18) (p11; q11) chromosomal translocation which produces the SS18-SSX1 or SS18-SSX2 fusion genes that can be detected by various cytogenetic or molecular genetic techniques, increasing the diagnostic accuracy.	('p11', 'Gene', '8909', (43, 46))	('p11', 'Gene', (43, 46))	('produces', 'Reg', (85, 93))	('SS18', 'Gene', (111, 115))	('increasing', 'PosReg', (211, 221))	('SSX2', 'Gene', '6757', (116, 120))	('SSX1', 'Gene', '6756', (103, 107))	('fusion', 'Var', (121, 127))	('SS18', 'Gene', '6760', (111, 115))	('SS18', 'Gene', (98, 102))	('SSX2', 'Gene', (116, 120))	('SSX1', 'Gene', (103, 107))	('SS18', 'Gene', '6760', (98, 102))
621922	29245257	A woman presented to the hospital complaining of occasional abdominal pain and had high tumor markers: cancer antigen (CA) 19-9 (263.6 U/mL) and CA 125 (428.0 U/mL).	('woman', 'Species', '9606', (2, 7))	('abdominal pain', 'Disease', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('pain', 'Phenotype', 'HP:0012531', (70, 74))	('abdominal pain', 'Disease', 'MESH:D015746', (60, 74))	('occasional abdominal pain', 'Phenotype', 'HP:0002574', (49, 74))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('263.6', 'Var', (129, 134))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', (88, 93))	('abdominal pain', 'Phenotype', 'HP:0002027', (60, 74))
621946	29245257	The serum tumor markers determined were cancer antigen (CA) 19-9, 263.6 U/mL (normal range 0-27), and CA 125, 428.0 U/mL (normal range 0-35).	('CA 125', 'Var', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
622007	29245257	The correct diagnosis of the second component is crucial to determine treatment options and outcome for these patients, as it has been suggested that the presence of as little as 10% of a type II component can adversely affect patient's outcome.	('patient', 'Species', '9606', (227, 234))	('patient', 'Species', '9606', (110, 117))	('presence', 'Var', (154, 162))	('patients', 'Species', '9606', (110, 118))	('affect', 'Reg', (220, 226))
622009	29245257	In contrast, the microdissected SC component has molecular characteristics of SC (p53 mutations) but retains EEC features (Kirsten rat sarcoma [K-RAS] and phosphatase and tensin homolog deleted from chromosome 10 [PTEN] mutations).	('mutations', 'Var', (86, 95))	('rat', 'Species', '10116', (131, 134))	('K-RAS', 'Gene', (144, 149))	('K-RAS', 'Gene', '24525', (144, 149))	('sarcoma', 'Disease', 'MESH:D012509', (135, 142))	('PTEN', 'Gene', (214, 218))	('PTEN', 'Gene', '50557', (214, 218))	('sarcoma', 'Disease', (135, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))
622036	23833639	The local recurrence-free survival rate for patients with a high CD155 expression level was observed to be significantly poorer compared with that of patients with low CD155 expression levels (P=0.0401).	('high CD155 expression level', 'Var', (60, 87))	('patients', 'Species', '9606', (44, 52))	('local recurrence-free survival rate', 'CPA', (4, 39))	('poorer', 'NegReg', (121, 127))	('patients', 'Species', '9606', (150, 158))
622043	23833639	CD155/poliovirus receptor (PVR) was initially identified as a receptor for poliovirus, as a result of the observation that anti-CD155 antibodies were able to block viral entry into cells.	('block', 'NegReg', (158, 163))	('anti-CD155', 'Var', (123, 133))	('poliovirus', 'Species', '138950', (6, 16))	('PVR', 'Gene', (27, 30))	('anti-CD155', 'Gene', (123, 133))	('viral entry into cells', 'CPA', (164, 186))	('poliovirus', 'Species', '138950', (75, 85))	('PVR', 'Gene', '5817', (27, 30))
622044	23833639	CD155 is also known as nectin-like molecule-5 (Necl-5) and is one of the Necl family members.	('Necl-5', 'Gene', (47, 53))	('Necl-5', 'Gene', '5817', (47, 53))	('nectin-like molecule-5', 'Gene', '5817', (23, 45))	('nectin-like molecule-5', 'Gene', (23, 45))	('CD155', 'Var', (0, 5))
622083	23833639	Next, the local recurrence-free survival, metastasis-free survival and overall survival of the patients showing high CD155 expression levels were compared with those of patients showing low CD155 expression levels.	('local', 'CPA', (10, 15))	('metastasis-free', 'CPA', (42, 57))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (95, 103))	('high', 'Var', (112, 116))	('CD155', 'MPA', (117, 122))
622085	23833639	The soft tissue sarcoma patients with a higher CD155 expression exhibited poorer local recurrence-free survival compared with patients with lower CD155 expression levels.	('poorer', 'NegReg', (74, 80))	('higher', 'Var', (40, 46))	('soft tissue sarcoma', 'Disease', (4, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('CD155', 'Gene', (47, 52))	('patients', 'Species', '9606', (126, 134))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (4, 23))	('patients', 'Species', '9606', (24, 32))	('local recurrence-free survival', 'CPA', (81, 111))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (4, 23))
622093	23833639	In the present study, it was demonstrated that high levels of CD155 were associated with local recurrence in patients with soft tissue sarcomas.	('CD155', 'Gene', (62, 67))	('local recurrence', 'CPA', (89, 105))	('patients', 'Species', '9606', (109, 117))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (123, 143))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (123, 142))	('associated', 'Reg', (73, 83))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (123, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('high levels', 'Var', (47, 58))	('soft tissue sarcomas', 'Disease', (123, 143))
622100	23833639	In the present study, patients with high expression levels of CD155 had a significantly shorter local recurrence-free survival compared with those with low expression levels in the univariate and multivariate analyses.	('shorter', 'NegReg', (88, 95))	('high expression levels', 'Var', (36, 58))	('CD155', 'Gene', (62, 67))	('local recurrence-free survival', 'CPA', (96, 126))	('patients', 'Species', '9606', (22, 30))
622101	23833639	A previous study of lung cancer patients showed that CD155 overexpression was correlated with lymph node metastasis and the TNM stage and that the disease-free survival of patients with CD155 overexpression was significantly lower than in patients without CD155 overexpression.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('patients', 'Species', '9606', (32, 40))	('lymph node metastasis', 'CPA', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('disease-free survival', 'CPA', (147, 168))	('patients', 'Species', '9606', (239, 247))	('TNM', 'Gene', '10178', (124, 127))	('CD155', 'Var', (186, 191))	('CD155', 'Gene', (53, 58))	('lung cancer', 'Disease', (20, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('lower', 'NegReg', (225, 230))	('overexpression', 'PosReg', (59, 73))	('overexpression', 'PosReg', (192, 206))	('correlated', 'Reg', (78, 88))	('patients', 'Species', '9606', (172, 180))	('TNM', 'Gene', (124, 127))
622214	25077008	On the other hand, low- grade tumors carry significant risk of dedifferentiation into high-grade sarcomas.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('sarcomas', 'Disease', (97, 105))	('low- grade', 'Var', (19, 29))
622219	25077008	Necrotic and hemorrhagic parts are heterogeneously hyperintense on T2-weighted images, but dedifferentiation may also produce a hyperintense signal, which can also relate to high-grade components.	('dedifferentiation', 'Var', (91, 108))	('Necrotic', 'Disease', (0, 8))	('hyperintense signal', 'MPA', (128, 147))	('produce', 'Reg', (118, 125))	('Necrotic', 'Disease', 'MESH:D009336', (0, 8))
622292	22291503	DCA 10 mM significantly increased the cytotoxicity of the platinum-based drugs carboplatin, satraplatin, JM118, and oxoplatin, but not cisplatin, picoplatin, and oxaliplatin in vitro.	('oxoplatin', 'Chemical', 'MESH:C043804', (116, 125))	('DCA 10 mM', 'Var', (0, 9))	('platinum', 'Chemical', 'MESH:D010984', (58, 66))	('JM118', 'Chemical', 'MESH:C097758', (105, 110))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (162, 173))	('cytotoxicity', 'Disease', (38, 50))	('carboplatin', 'Chemical', 'MESH:D016190', (79, 90))	('DCA', 'Chemical', 'MESH:D003999', (0, 3))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('cytotoxicity', 'Disease', 'MESH:D064420', (38, 50))	('picoplatin', 'Chemical', 'MESH:C110525', (146, 156))	('increased', 'PosReg', (24, 33))	('satraplatin', 'Chemical', 'MESH:C081294', (92, 103))
622302	22291503	DCA-sensitive endometrial cancer cell lines treated with DCA 5-10 mM showed increased early and late apoptosis, decreased mitochondrial membrane potential and lower survivin transcript levels, consistent with a mitochondria-regulated mechanism.	('decreased mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (112, 154))	('DCA', 'Chemical', 'MESH:D003999', (57, 60))	('endometrial cancer', 'Disease', (14, 32))	('increased', 'PosReg', (76, 85))	('endometrial cancer', 'Phenotype', 'HP:0012114', (14, 32))	('lower', 'NegReg', (159, 164))	('DCA', 'Chemical', 'MESH:D003999', (0, 3))	('endometrial cancer', 'Disease', 'MESH:D016889', (14, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('survivin transcript levels', 'MPA', (165, 191))	('decreased', 'NegReg', (112, 121))	('mitochondrial membrane potential', 'MPA', (122, 154))	('DCA', 'Var', (57, 60))
622303	22291503	Treatment of representative colorectal cancer cell lines with DCA 20 mM caused significant decreases in cancer cell proliferation associated with cell-cycle arrest in G2 phase and apoptosis, in contrast to noncancerous cell lines.	('DCA', 'Chemical', 'MESH:D003999', (62, 65))	('cancer', 'Disease', (104, 110))	('apoptosis', 'CPA', (180, 189))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('cancer', 'Disease', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('decreases', 'NegReg', (91, 100))	('cell-cycle arrest in G2 phase', 'CPA', (146, 175))	('rat', 'Species', '10116', (123, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cell-cycle arrest in G2 phase', 'Phenotype', 'HP:0003214', (146, 175))	('colorectal cancer', 'Disease', (28, 45))	('cancer', 'Disease', (209, 215))	('DCA 20 mM', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
622338	22291503	Therefore, pretreatment of the two SCLC lines with DCA 10 mM reduced the chemosensitivity of the subsequently applied platinum drugs.	('platinum', 'Chemical', 'MESH:D010984', (118, 126))	('DCA 10 mM', 'Var', (51, 60))	('DCA', 'Chemical', 'MESH:D003999', (51, 54))	('reduced', 'NegReg', (61, 68))
622344	22291503	The cytotoxic activity of cisplatin was elevated in 1/9, carboplatin in 4/9, satraplatin in 8/9, and JM118 in 7/9 of the cell lines, respectively.	('JM118', 'Var', (101, 106))	('carboplatin', 'MPA', (57, 68))	('JM118', 'Chemical', 'MESH:C097758', (101, 106))	('elevated', 'PosReg', (40, 48))	('cytotoxic activity', 'CPA', (4, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('carboplatin', 'Chemical', 'MESH:D016190', (57, 68))	('satraplatin', 'Chemical', 'MESH:C081294', (77, 88))
622356	22291503	For example, in colon cancer cell lines, DCA 20 mM cause a selective increase in G2 phase-blocked and apoptotic cells after two days.	('apoptotic cells', 'CPA', (102, 117))	('G2 phase-blocked', 'CPA', (81, 97))	('increase', 'PosReg', (69, 77))	('colon cancer', 'Disease', (16, 28))	('DCA', 'Chemical', 'MESH:D003999', (41, 44))	('DCA 20 mM', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (16, 28))	('colon cancer', 'Disease', 'MESH:D015179', (16, 28))
622365	22291503	Furthermore, DCA abrogated the cytotoxicity of cisplatin in most cell lines without impairment of the in vitro stability or the cellular uptake of cisplatin.	('cytotoxicity', 'Disease', 'MESH:D064420', (31, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('DCA', 'Chemical', 'MESH:D003999', (13, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('cytotoxicity', 'Disease', (31, 43))	('abrogated', 'NegReg', (17, 26))	('DCA', 'Var', (13, 16))
622367	22291503	Supplementation of DCA in cytotoxicity assays sensitized tumor cells to selected platinum-based drugs, such as carboplatin, satraplatin, and its main metabolite, JM118, in addition to oxoplatin, but not cisplatin, oxaliplatin, and picoplatin.	('picoplatin', 'Chemical', 'MESH:C110525', (231, 241))	('JM118', 'Chemical', 'MESH:C097758', (162, 167))	('DCA', 'Chemical', 'MESH:D003999', (19, 22))	('cytotoxicity', 'Disease', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Supplementation', 'Var', (0, 15))	('satraplatin', 'Chemical', 'MESH:C081294', (124, 135))	('platinum', 'Chemical', 'MESH:D010984', (81, 89))	('carboplatin', 'Chemical', 'MESH:D016190', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('oxoplatin', 'Chemical', 'MESH:C043804', (184, 193))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (214, 225))	('sensitized', 'Reg', (46, 56))	('tumor', 'Disease', (57, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (203, 212))
622372	22291503	Proliferation of one Ewing's sarcoma cell line was stimulated by DCA, and the modulating effects of DCA were low in COLO 205 colon cancer cells and reversed in H835 carcinoid cells, with the exception of cisplatin.	('colon cancer', 'Disease', 'MESH:D015179', (125, 137))	('carcinoid', 'Phenotype', 'HP:0100570', (165, 174))	('colon cancer', 'Disease', (125, 137))	('low', 'NegReg', (109, 112))	("Ewing's sarcoma", 'Disease', (21, 36))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (21, 36))	('DCA', 'Var', (65, 68))	('COLO', 'Species', '307630', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (204, 213))	('DCA', 'Chemical', 'MESH:D003999', (100, 103))	('DCA', 'Chemical', 'MESH:D003999', (65, 68))	('rat', 'Species', '10116', (7, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (21, 36))	('Proliferation', 'CPA', (0, 13))	('stimulated', 'PosReg', (51, 61))
622621	26286851	Notably, we did not see any increase in regulatory T cells or LIN-CD33+HLA-DR- myeloid derived suppressor cells (MDSC) in peripheral blood of sarcoma patients as compared to HV.	('sarcoma', 'Disease', 'MESH:D012509', (142, 149))	('sarcoma', 'Disease', (142, 149))	('LIN-CD33+HLA-DR-', 'Var', (62, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('patients', 'Species', '9606', (150, 158))	('regulatory T cells', 'CPA', (40, 58))
622632	26286851	These results are similar to our findings observed in a larger cohort of adult cancer patients where the abnormal immune profiles adversely affected survival.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('affected', 'Reg', (140, 148))	('abnormal', 'Var', (105, 113))	('survival', 'CPA', (149, 157))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('patients', 'Species', '9606', (86, 94))
622662	26286851	CTLA-4 expression was noted in OS cell lines and patient tumor samples and CTLA-4 + 49G/A polymorphism was associated with increased risk of developing OS.	('49G/A', 'Var', (84, 89))	('developing OS', 'Disease', (141, 154))	('associated', 'Reg', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('49G/A', 'SUBSTITUTION', 'None', (84, 89))	('patient', 'Species', '9606', (49, 56))	('CTLA-4', 'Gene', (75, 81))	('polymorphism', 'Var', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
622663	26286851	Combined treatment with anti-CTLA-4 antibody and tumor lysate-pulsed dendritic cells in mice with OS lead to decreased Tregs and increased CD8 T cells in metastatic tumor leading to decreased metastasis and increased EFS.	('decreased', 'NegReg', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('CD8', 'Gene', (139, 142))	('CD8', 'Gene', '925', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Tregs', 'CPA', (119, 124))	('decreased', 'NegReg', (182, 191))	('EFS', 'CPA', (217, 220))	('increased', 'PosReg', (207, 216))	('increased', 'PosReg', (129, 138))	('tumor', 'Disease', (49, 54))	('anti-CTLA-4', 'Var', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('metastasis', 'CPA', (192, 202))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Disease', (165, 170))
622664	26286851	Taken together, CTL-4 targeted therapy may be beneficial, and it will be important to evaluate the effect of this therapy based on the expression on T cells or tumor tissue.	('CTL-4', 'Gene', '80736', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('targeted therapy', 'Var', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('CTL-4', 'Gene', (16, 21))	('tumor', 'Disease', (160, 165))
622718	25956832	Tumor incidences showed a similar increase for each increasing dose group when combining C3Hf/Kam and C57BL/6J mice (Figure 2A, p < 0.001).	('C57BL/6J', 'Var', (102, 110))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (111, 115))	('increase', 'PosReg', (34, 42))	('C3Hf/Kam', 'Var', (89, 97))	('Tumor incidences', 'CPA', (0, 16))
622722	25956832	Over the dose ranges investigated for single dose irradiation, increases in tumor incidences were observed up to 50 Gy for C57BL/6J mice and up to 60 Gy for C3Hf/Kam mice, with evidence of a plateau in the dose response for larger doses (Figure 2B).	('increases', 'PosReg', (63, 72))	('C57BL/6J', 'Var', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mice', 'Species', '10090', (132, 136))	('mice', 'Species', '10090', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
622726	25956832	Following single dose irradiation, the mean tumor latency time for C3Hf/Kam mice was significantly decreased compared to C57BL/6J mice (Figure 4A, p = 0.002); no significant difference in latency was observed between the two strains following fractionated radiation (Figure 4B, p = 0.858).	('mice', 'Species', '10090', (130, 134))	('decreased', 'NegReg', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('C3Hf/Kam', 'Var', (67, 75))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
622729	25956832	Following fractionated exposures, both C57BL/6J and C3Hf/Kam mice were more likely to develop osteosarcoma (p < 0.001) and hemangiosarcomas (p < 0.001) than other tumor types (Figure 5C).	('C3Hf/Kam', 'Var', (52, 60))	('mice', 'Species', '10090', (61, 65))	('hemangiosarcomas', 'Disease', (123, 139))	('angiosarcoma', 'Phenotype', 'HP:0200058', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('develop', 'PosReg', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('hemangiosarcomas', 'Disease', 'MESH:D006394', (123, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (131, 139))	('osteosarcoma', 'Disease', (94, 106))	('tumor', 'Disease', (163, 168))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('osteosarcoma', 'Phenotype', 'HP:0002669', (94, 106))	('osteosarcoma', 'Disease', 'MESH:D012516', (94, 106))	('C57BL/6J', 'Var', (39, 47))
622734	25956832	Following single dose exposure, significant differences in tumor incidences (Figure 2B, p < 0.001) and tumor latencies (Figure 4A, p = 0.002) were observed between C3Hf/Kam and C57BL/6J mice.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mice', 'Species', '10090', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('C3Hf/Kam', 'Var', (164, 172))
622756	25956832	Following single dose irradiation, evidence of a plateau in tumor incidence was observed at doses higher than 50 Gy for C57BL/6J mice and at doses higher than 60 Gy for C3Hf/Kam mice.	('C57BL/6J', 'Var', (120, 128))	('mice', 'Species', '10090', (178, 182))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mice', 'Species', '10090', (129, 133))	('tumor', 'Disease', (60, 65))
622758	25956832	Susceptibility to radiation induced osteosarcoma has been associated with a common promoter variant in Rb1 in mice.	('Rb1', 'Gene', (103, 106))	('Rb1', 'Gene', '19645', (103, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('associated', 'Reg', (58, 68))	('mice', 'Species', '10090', (110, 114))	('variant', 'Var', (92, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (36, 48))	('osteosarcoma', 'Disease', (36, 48))	('osteosarcoma', 'Disease', 'MESH:D012516', (36, 48))	('Susceptibility to radiation', 'Phenotype', 'HP:0011133', (0, 27))
622762	25956832	No significant differences were observed between these two strains following fractionated irradiation, however, fewer tumors and different histotypes were induced following fractionated exposures which decreased the power of the statistical analysis and, while not significant, the incidences of tumors were similarly increased in C3Hf/Kam mice compared to C57BL/6 mice (Figure 1B).	('mice', 'Species', '10090', (340, 344))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('C3Hf/Kam', 'Var', (331, 339))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Disease', (296, 302))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('increased', 'PosReg', (318, 327))	('mice', 'Species', '10090', (365, 369))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
622818	33888082	Detection of EWSR1 gene translocation or amplifcation is the most reliable marker of PNETs, including those of pulmonary origin.	('EWSR1', 'Gene', '2130', (13, 18))	('PNETs', 'Disease', (85, 90))	('EWSR1', 'Gene', (13, 18))	('amplifcation', 'Var', (41, 53))	('pulmonary origin', 'Disease', (111, 127))
622819	33888082	85% of patients had the identification t(11;22) (q24;q12) chromosome rearrangement by fluorescent in situ hybridization and/or reverse transcription-polymerase chain reaction is used to support the diagnosis, and the remaining 15% of the patients had variants of this translocation, including 22q12, 21q12 (10% of cases) and 7p22, 17q12, 2q36 (< 1% of cases).	('21q12', 'Var', (300, 305))	('22q12', 'Var', (293, 298))	('7p22', 'Var', (325, 329))	('patients', 'Species', '9606', (238, 246))	('patients', 'Species', '9606', (7, 15))
622853	31788245	Her IHC was positive for CD 117 (cytoplasmic membrane staining), CD45, Ki67 (Figure 2B-D), and negative for CD34, ER, PR, HER2, E-cadherin, AE1 and AE3 (Figure 3A-F).	('CD34', 'Gene', '947', (108, 112))	('E-cadherin', 'Gene', (128, 138))	('Ki67', 'Var', (71, 75))	('AE1', 'Gene', (140, 143))	('CD45', 'Gene', (65, 69))	('E-cadherin', 'Gene', '999', (128, 138))	('AE1', 'Gene', '6521', (140, 143))	('CD45', 'Gene', '5788', (65, 69))	('AE3', 'Gene', (148, 151))	('CD 117', 'Gene', (25, 31))	('HER2', 'Gene', (122, 126))	('HER2', 'Gene', '2064', (122, 126))	('CD 117', 'Gene', '3815', (25, 31))	('CD34', 'Gene', (108, 112))	('AE3', 'Gene', '6508', (148, 151))
622865	31788245	The condition may be misdiagnosed as a benign tumor or primary carcinoma of the breast by FNA.20 Many patients with isolated MS are mistakenly diagnosed, more often mistaken for non-Hodgkin's lymphoma, lymphoblastic leukemia, melanoma, Ewing's sarcoma, and extramedullary hematopoiesis.1, 2 Given that MS often displays positivity to markers of T cells (CD43, CD45 or CD3) and more rarely for B cell markers (CD79a), distinguishing between MS and lymphoma becomes quite challenging.	('carcinoma of the breast', 'Disease', 'MESH:D001943', (63, 86))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MS', 'Disease', 'MESH:D023981', (440, 442))	('patients', 'Species', '9606', (102, 110))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	("non-Hodgkin's lymphoma", 'Disease', (178, 200))	("Ewing's sarcoma", 'Disease', (236, 251))	('lymphoma', 'Phenotype', 'HP:0002665', (447, 455))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('CD45', 'Gene', (360, 364))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	("Ewing's sarcoma", 'Disease', 'MESH:D012512', (236, 251))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (202, 224))	('MS', 'Disease', 'MESH:D023981', (302, 304))	('CD3', 'Var', (368, 371))	('lymphoblastic leukemia', 'Disease', (202, 224))	('CD79a', 'Gene', '973', (409, 414))	('CD45', 'Gene', '5788', (360, 364))	('hematopoiesis', 'Disease', 'MESH:C536227', (272, 285))	('CD43', 'Gene', '6693', (354, 358))	('lymphoma', 'Disease', (192, 200))	('carcinoma of the breast', 'Disease', (63, 86))	('MS', 'Disease', 'MESH:D023981', (125, 127))	('hematopoiesis', 'Disease', (272, 285))	('lymphoma', 'Disease', 'MESH:D008223', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('tumor', 'Disease', (46, 51))	('lymphoma', 'Disease', (447, 455))	('CD79a', 'Gene', (409, 414))	('lymphoma', 'Disease', 'MESH:D008223', (447, 455))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (236, 251))	('melanoma', 'Disease', (226, 234))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (202, 224))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (178, 200))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('leukemia', 'Phenotype', 'HP:0001909', (216, 224))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (63, 86))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (178, 200))	('CD43', 'Gene', (354, 358))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (182, 200))
622881	29276684	Immunohistochemical analysis showed no expression of cheratin AE1/AE3, PSA; proliferation rate of Ki67 was >20%; smooth muscle actin, desmin, vimentin and calponin were expressed (Fig.	('desmin', 'Gene', (134, 140))	('vimentin', 'Gene', '7431', (142, 150))	('AE1', 'Gene', (62, 65))	('PSA', 'Gene', '9520', (71, 74))	('vimentin', 'Gene', (142, 150))	('Ki67', 'Var', (98, 102))	('AE3', 'Gene', (66, 69))	('desmin', 'Gene', '1674', (134, 140))	('AE1', 'Gene', '6521', (62, 65))	('calponin', 'Protein', (155, 163))	('PSA', 'Gene', (71, 74))	('AE3', 'Gene', '6508', (66, 69))
622887	29276684	The presence of necrosis, atypical mitotic figures, marked hypercellularity, and nuclear pleomorphism without degenerative features are features of sarcoma, rather than STUMP.	('necrosis', 'Disease', 'MESH:D009336', (16, 24))	('sarcoma', 'Disease', 'MESH:D012509', (148, 155))	('nuclear pleomorphism', 'CPA', (81, 101))	('sarcoma', 'Disease', (148, 155))	('atypical', 'Var', (26, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (148, 155))	('necrosis', 'Disease', (16, 24))
622920	24353913	Typically, EWS is driven by chromosomal translocations generating EWS-FLI1 fusions, which encode aberrant transcription factors.	('driven', 'Reg', (18, 24))	('fusions', 'Var', (75, 82))	('FLI1', 'Gene', '2313', (70, 74))	('FLI1', 'Gene', (70, 74))	('EWS', 'Phenotype', 'HP:0012254', (11, 14))	('EWS', 'Phenotype', 'HP:0012254', (66, 69))	('EWS', 'Gene', '2130', (66, 69))	('EWS', 'Gene', (66, 69))	('EWS', 'Gene', '2130', (11, 14))	('EWS', 'Gene', (11, 14))
622933	24353913	Furthermore, studies from our laboratory using HeLa (a human cervical adenocarcinoma cell line) have demonstrated that APLP2 increases the endocytosis of MHC class I molecules.	('APLP2', 'Var', (119, 124))	('increases', 'PosReg', (125, 134))	('endocytosis', 'MPA', (139, 150))	('HeLa', 'CellLine', 'CVCL:0030', (47, 51))	('human', 'Species', '9606', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('adenocarcinoma', 'Disease', (70, 84))	('MHC class I molecule', 'Gene', (154, 174))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))	('MHC class I molecule', 'Gene', '3106', (154, 174))
622936	24353913	Based on the aforementioned findings, we hypothesized that APLP2 is responsible, at least in part, for restricting MHC class I expression on the surface of EWS cells, thus potentially contributing to EWS immune evasion.	('MHC class I', 'Gene', (115, 126))	('EWS', 'Phenotype', 'HP:0012254', (156, 159))	('restricting', 'NegReg', (103, 114))	('expression', 'MPA', (127, 137))	('EWS', 'Phenotype', 'HP:0012254', (200, 203))	('EWS', 'Gene', '2130', (156, 159))	('EWS', 'Gene', (156, 159))	('APLP2', 'Var', (59, 64))	('EWS', 'Gene', '2130', (200, 203))	('EWS', 'Gene', (200, 203))	('immune evasion', 'MPA', (204, 218))	('contributing to', 'Reg', (184, 199))
622939	24353913	Altogether, our data indicate that APLP2 limits the expression of MHC class I molecules on the surface of EWS TC71 and A673 cells.	('MHC class I molecule', 'Gene', (66, 86))	('expression', 'MPA', (52, 62))	('MHC class I molecule', 'Gene', '3106', (66, 86))	('APLP2', 'Var', (35, 40))	('EWS', 'Phenotype', 'HP:0012254', (106, 109))	('EWS', 'Gene', '2130', (106, 109))	('EWS', 'Gene', (106, 109))	('limits', 'NegReg', (41, 47))
622941	24353913	Thus, APLP2 might allow EWS cells to evade recognition by T cells, hence interfering with the ability of radiation therapy to facilitate T cell-mediated elimination of EWS.	('EWS', 'Phenotype', 'HP:0012254', (24, 27))	('EWS', 'Gene', '2130', (24, 27))	('EWS', 'Gene', (24, 27))	('allow', 'Reg', (18, 23))	('APLP2', 'Var', (6, 11))	('interfering', 'NegReg', (73, 84))	('EWS', 'Phenotype', 'HP:0012254', (168, 171))	('EWS', 'Gene', '2130', (168, 171))	('EWS', 'Gene', (168, 171))
622943	24353913	The identification of an endogenous subpopulation of APLP2high EWS cells that expresses low levels of MHC class I molecules even upon irradiation adds to the growing body of knowledge on tumor immunoevasion, which is necessary to understand in order to design effective immunotherapeutic regimens for EWS patients.	('MHC class I molecule', 'Gene', '3106', (102, 122))	('low levels of MHC', 'Phenotype', 'HP:0025547', (88, 105))	('EWS', 'Gene', '2130', (63, 66))	('EWS', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('EWS', 'Phenotype', 'HP:0012254', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('EWS', 'Phenotype', 'HP:0012254', (301, 304))	('EWS', 'Gene', '2130', (301, 304))	('EWS', 'Gene', (301, 304))	('patients', 'Species', '9606', (305, 313))	('tumor', 'Disease', (187, 192))	('APLP2high', 'Var', (53, 62))	('MHC class I molecule', 'Gene', (102, 122))
622945	24353913	Furthermore, in an earlier study using HeLa cells, we found that APLP2 binds to MHC class I molecules at the cell surface and facilitates their endocytosis and routing to lysosomes.	('facilitates', 'PosReg', (126, 137))	('routing to lysosomes', 'MPA', (160, 180))	('HeLa', 'CellLine', 'CVCL:0030', (39, 43))	('APLP2', 'Var', (65, 70))	('endocytosis', 'MPA', (144, 155))	('MHC class I molecule', 'Gene', (80, 100))	('binds', 'Interaction', (71, 76))	('MHC class I molecule', 'Gene', '3106', (80, 100))
622958	24353913	2A and B), and we had previously found that APLP2 can inhibit MHC class I expression on the surface of HeLa cells, we next investigated whether such 3 EWS subpopulations would exhibit distinct MHC class I expression profiles.	('expression', 'MPA', (74, 84))	('APLP2', 'Var', (44, 49))	('inhibit', 'NegReg', (54, 61))	('MHC class I', 'Gene', (62, 73))	('EWS', 'Phenotype', 'HP:0012254', (151, 154))	('EWS', 'Gene', '2130', (151, 154))	('EWS', 'Gene', (151, 154))	('HeLa', 'CellLine', 'CVCL:0030', (103, 107))
622959	24353913	In line with our previous findings, lower levels of MHC class I molecules were observed on the surface of APLP2high cells, as compared with APLP2low cells, in both the TC71 and A673 cell lines (Fig.	('levels', 'MPA', (42, 48))	('lower', 'NegReg', (36, 41))	('MHC class I molecule', 'Gene', (52, 72))	('MHC class I molecule', 'Gene', '3106', (52, 72))	('APLP2high', 'Var', (106, 115))
622961	24353913	We identified 3 distinct subpopulations of cells within both EWS cell lines: APLP2lowMHCIhigh, APLP2intMHCIhigh, and APLP2highMHCIlow cells (Fig.	('APLP2lowMHCIhigh', 'Gene', '334', (77, 93))	('APLP2lowMHCIhigh', 'Gene', (77, 93))	('EWS', 'Phenotype', 'HP:0012254', (61, 64))	('APLP2highMHCIlow', 'Var', (117, 133))	('EWS', 'Gene', '2130', (61, 64))	('EWS', 'Gene', (61, 64))	('APLP2intMHCIhigh', 'Var', (95, 111))
622964	24353913	In contrast, the expression levels of MHC class I molecules on the surface of APLP2high MHCIlow cells did not markedly increase upon irradiation (Fig.	('MHC class I molecule', 'Gene', (38, 58))	('expression', 'MPA', (17, 27))	('MHC class I molecule', 'Gene', '3106', (38, 58))	('APLP2high', 'Var', (78, 87))	('high MHC', 'Phenotype', 'HP:0025548', (83, 91))
622966	24353913	Thus, even after exposure to ionizing radiation, APLP2highMHCIlow EWS cells maintain reduced expression of MHC class I molecules.	('APLP2highMHCIlow', 'Var', (49, 65))	('MHC class I molecule', 'Gene', (107, 127))	('MHC class I molecule', 'Gene', '3106', (107, 127))	('expression', 'MPA', (93, 103))	('reduced', 'NegReg', (85, 92))	('EWS', 'Phenotype', 'HP:0012254', (66, 69))	('EWS', 'Gene', '2130', (66, 69))	('EWS', 'Gene', (66, 69))
622969	24353913	Taken together with our findings on naturally occurring EWS cell subsets characterized by the reciprocal expression of APLP2 and MHC class I molecules, these functional data implicate endogenous APLP2 in the downregulation of MHC class I expression on the surface of EWS cells.	('downregulation', 'NegReg', (208, 222))	('EWS', 'Phenotype', 'HP:0012254', (56, 59))	('EWS', 'Gene', '2130', (56, 59))	('EWS', 'Gene', (56, 59))	('APLP2', 'Var', (195, 200))	('EWS', 'Phenotype', 'HP:0012254', (267, 270))	('EWS', 'Gene', '2130', (267, 270))	('EWS', 'Gene', (267, 270))	('MHC class I', 'Gene', (226, 237))	('MHC class I molecule', 'Gene', (129, 149))	('expression', 'MPA', (238, 248))	('MHC class I molecule', 'Gene', '3106', (129, 149))
622979	24353913	The radiation-induced upregulation of MHC class I molecules on the surface of APLP2low and APLP2int EWS cells may reflect multiple alternative (but not mutually exclusive) mechanisms.	('MHC class I molecule', 'Gene', (38, 58))	('MHC class I molecule', 'Gene', '3106', (38, 58))	('upregulation', 'PosReg', (22, 34))	('APLP2int', 'Var', (91, 99))	('EWS', 'Phenotype', 'HP:0012254', (100, 103))	('EWS', 'Gene', '2130', (100, 103))	('EWS', 'Gene', (100, 103))
622990	24353913	Allotypic differences would be consistent with the model proposing that APLP2-mediated endocytosis reduces the levels of surface-exposed MHC class I molecules, since we have previously shown APLP2 to have an avidity for MHC class I molecules that varies with allotype.	('levels of surface-exposed', 'MPA', (111, 136))	('MHC class I molecule', 'Gene', (220, 240))	('APLP2', 'Var', (191, 196))	('MHC class I molecule', 'Gene', '3106', (137, 157))	('MHC class I molecule', 'Gene', '3106', (220, 240))	('avidity', 'MPA', (208, 215))	('MHC class I molecule', 'Gene', (137, 157))	('reduces', 'NegReg', (99, 106))
622997	24353913	In support of this notion, we have demonstrated that APLP2 binds to MHC class I molecules in EWS cells, and that the siRNA-mediated knockdown of APLP2 increases the amount of surface-exposed MHC class I molecules.	('binds', 'Interaction', (59, 64))	('increases', 'PosReg', (151, 160))	('knockdown', 'Var', (132, 141))	('EWS', 'Gene', (93, 96))	('EWS', 'Gene', '2130', (93, 96))	('MHC class I molecule', 'Gene', (191, 211))	('MHC class I molecule', 'Gene', '3106', (191, 211))	('EWS', 'Phenotype', 'HP:0012254', (93, 96))	('APLP2', 'Gene', (145, 150))	('amount of surface-exposed', 'MPA', (165, 190))	('MHC class I molecule', 'Gene', (68, 88))	('MHC class I molecule', 'Gene', '3106', (68, 88))
623006	24353913	11360), 2 mM l-glutamine (Cat.	('Cat', 'Gene', (26, 29))	('l-glutamine', 'Chemical', 'MESH:D005973', (13, 24))	('2 mM', 'Var', (8, 12))	('Cat', 'Gene', '847', (26, 29))
623026	24353913	The percent change in MHC class I expression in response to siRNA-mediated APLP2 knockdown was derived by the following formula: MFUsiAPLP2/MFUsiControl x 100.	('MFUsiControl', 'Chemical', '-', (140, 152))	('MFUsiAPLP2', 'Gene', '334', (129, 139))	('APLP2', 'Gene', (75, 80))	('expression', 'MPA', (34, 44))	('MHC class I', 'Gene', (22, 33))	('MFUsiAPLP2', 'Gene', (129, 139))	('knockdown', 'Var', (81, 90))
623038	31365116	Interim results of a real-world observational study of eribulin in soft tissue sarcoma including rare subtypes Interim analysis from the first large-scale post-marketing surveillance study of eribulin treatment for soft tissue sarcomas (STSs) showed antitumor activity in both common and rare subtypes of STS (NCT03058406).	('sarcoma', 'Disease', (79, 86))	('STSs', 'Disease', (237, 241))	('STSs', 'Phenotype', 'HP:0030448', (237, 241))	('soft tissue sarcomas', 'Disease', (215, 235))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (215, 235))	('STS', 'Phenotype', 'HP:0030448', (305, 308))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (215, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (215, 235))	('sarcoma', 'Disease', 'MESH:D012509', (227, 234))	('sarcoma', 'Disease', (227, 234))	('tumor', 'Disease', (254, 259))	('eribulin', 'Chemical', 'MESH:C490954', (192, 200))	('sarcomas', 'Phenotype', 'HP:0100242', (227, 235))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('NCT03058406', 'Chemical', 'MESH:C079985', (310, 321))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (67, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('STS', 'Phenotype', 'HP:0030448', (237, 240))	('eribulin', 'Chemical', 'MESH:C490954', (55, 63))	('NCT03058406', 'Var', (310, 321))	('STSs', 'Disease', 'MESH:D012509', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('sarcoma', 'Disease', 'MESH:D012509', (79, 86))
623062	31365116	A phase 3 randomized, multicenter, clinical study reported that the OS of patients with advanced or metastatic liposarcoma, or leiomyosarcoma, was significantly improved in patients treated with eribulin compared with patients receiving dacarbazine treatment.	('leiomyosarcoma', 'Disease', 'MESH:D007890', (127, 141))	('liposarcoma', 'Phenotype', 'HP:0012034', (111, 122))	('liposarcoma', 'Disease', 'MESH:D008080', (111, 122))	('patients', 'Species', '9606', (173, 181))	('advanced', 'Disease', (88, 96))	('patients', 'Species', '9606', (74, 82))	('eribulin', 'Var', (195, 203))	('patients', 'Species', '9606', (218, 226))	('eribulin', 'Chemical', 'MESH:C490954', (195, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('leiomyosarcoma', 'Disease', (127, 141))	('dacarbazine', 'Chemical', 'MESH:D003606', (237, 248))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (127, 141))	('liposarcoma', 'Disease', (111, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('improved', 'PosReg', (161, 169))
623078	31365116	Dose reductions to 1.1 and 0.7 mg/m2 were permitted at the investigator's discretion and in accordance with the eribulin package insert, which instructs a dose reduction in the following cases: grade 4 neutropenia (<500/mm3) lasting more than 7 days, >=grade 3 febrile neutropenia, >=grade 3 neutropenia (<1000/mm3) requiring antibiotic treatment, >=grade 3 thrombocytopenia (<25 000/mm3), thrombocytopenia (<50 000/mm3) requiring blood transfusion, >=grade 3 nonhematologic toxicity, or discontinuation at day 8 due to adverse events (AEs).	('neutropenia', 'Disease', 'MESH:D009503', (292, 303))	('neutropenia', 'Disease', 'MESH:D009503', (269, 280))	('neutropenia', 'Phenotype', 'HP:0001875', (292, 303))	('neutropenia', 'Phenotype', 'HP:0001875', (269, 280))	('neutropenia', 'Disease', (202, 213))	('thrombocytopenia', 'Disease', 'MESH:D013921', (358, 374))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (358, 374))	('febrile neutropenia', 'Disease', 'MESH:D009503', (261, 280))	('thrombocytopenia', 'Disease', 'MESH:D013921', (390, 406))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (390, 406))	('toxicity', 'Disease', 'MESH:D064420', (475, 483))	('grade', 'Disease', (194, 199))	('neutropenia', 'Disease', 'MESH:D009503', (202, 213))	('neutropenia', 'Phenotype', 'HP:0001875', (202, 213))	('toxicity', 'Disease', (475, 483))	('neutropenia', 'Disease', (292, 303))	('discontinuation', 'NegReg', (488, 503))	('neutropenia', 'Disease', (269, 280))	('eribulin', 'Chemical', 'MESH:C490954', (112, 120))	('febrile neutropenia', 'Disease', (261, 280))	('thrombocytopenia', 'Disease', (358, 374))	('thrombocytopenia', 'Disease', (390, 406))	('<50 000/mm3', 'Var', (408, 419))
623154	31365116	Eribulin improved OS for liposarcoma compared with dacarbazine in a phase 3 study and showed potential efficacy for other subtypes of sarcoma in two phase 2 studies.	('liposarcoma', 'Phenotype', 'HP:0012034', (25, 36))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('sarcoma', 'Disease', 'MESH:D012509', (29, 36))	('liposarcoma', 'Disease', (25, 36))	('sarcoma', 'Disease', (29, 36))	('improved', 'PosReg', (9, 17))	('sarcoma', 'Disease', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('Eribulin', 'Var', (0, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('liposarcoma', 'Disease', 'MESH:D008080', (25, 36))	('dacarbazine', 'Chemical', 'MESH:D003606', (51, 62))
623196	31365116	There have been efforts to develop tumor-specific treatments by surveying genetic mutations in tumors from a variety of STS subtypes.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('genetic mutations', 'Var', (74, 91))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('STS', 'Phenotype', 'HP:0030448', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))
623214	31365116	One advantage of eribulin is that it has a lower drug-induced cardiotoxicity compared with other chemotherapy drugs.	('cardiotoxicity', 'Disease', 'MESH:D066126', (62, 76))	('eribulin', 'Var', (17, 25))	('eribulin', 'Chemical', 'MESH:C490954', (17, 25))	('cardiotoxicity', 'Disease', (62, 76))	('lower', 'NegReg', (43, 48))
623226	27102293	Orthologs of these viral oncogenes were then found in transforming DNA fragments in human cancers in the form of mutated versions of the HRAS and KRAS proto-oncogenes.	('cancers', 'Disease', (90, 97))	('KRAS', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('KRAS', 'Gene', '3845', (146, 150))	('mutated', 'Var', (113, 120))	('human', 'Species', '9606', (84, 89))	('HRAS', 'Gene', '3265', (137, 141))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('HRAS', 'Gene', (137, 141))
623228	27102293	Subsequent studies showed that mutated KRAS acted as an in vivo oncogenic driver, as indicated by studies of anti-EGFR therapy for metastatic colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('EGFR', 'Gene', '1956', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('KRAS', 'Gene', (39, 43))	('colorectal cancers', 'Disease', 'MESH:D015179', (142, 160))	('EGFR', 'Gene', (114, 118))	('KRAS', 'Gene', '3845', (39, 43))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('colorectal cancers', 'Disease', (142, 160))	('mutated', 'Var', (31, 38))
623229	27102293	This review addresses the historical background and experimental studies that led to the discovery ofKirsten Ras as an oncogene, the role of mutated KRAS in human carcinogenesis, and recent therapeutic studies of cancer cells with KRAS mutations.	('mutated', 'Var', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('carcinogenesis', 'Disease', (163, 177))	('KRAS', 'Gene', (149, 153))	('KRAS', 'Gene', (231, 235))	('KRAS', 'Gene', '3845', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('KRAS', 'Gene', '3845', (231, 235))	('cancer', 'Disease', (213, 219))	('carcinogenesis', 'Disease', 'MESH:D063646', (163, 177))	('Kirsten', 'Species', '11808', (101, 108))	('human', 'Species', '9606', (157, 162))
623231	27102293	Indeed, KRAS mutations occur in 22% of all tumors analyzed (the highest among RAS isoforms), while HRAS and NRAS mutations are less frequent (3% and 8%, respectively).	('HRAS', 'Gene', (99, 103))	('NRAS', 'Gene', (108, 112))	('NRAS', 'Gene', '4893', (108, 112))	('KRAS', 'Gene', (8, 12))	('HRAS', 'Gene', '3265', (99, 103))	('KRAS', 'Gene', '3845', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('mutations', 'Var', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
623242	27102293	The DNA had been extracted from hamster cells transformed by the ts mutant of Rous sarcoma virus (RSV).	('hamster', 'Species', '10034', (32, 39))	('sarcoma', 'Disease', (83, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('ts mutant', 'Var', (65, 74))
623255	27102293	Further, the number of publications with "oncogene" began to rise when alterations in cellular oncogenes related to retroviruses were found in human cancer.	('human', 'Species', '9606', (143, 148))	('cancer', 'Disease', (149, 155))	('rat', 'Species', '10116', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('alterations', 'Var', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
623258	27102293	At the end of 1983, a chemical carcinogen was found to induce a ras-activating mutation in rat mammary tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('rat', 'Species', '10116', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('induce', 'Reg', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('mutation', 'Var', (79, 87))	('ras-activating', 'Gene', (64, 78))
623262	27102293	In 2007, the European Medicines Evaluation Agency (EMEA) approved the use of a drug (panitumumab) for anti-EGFR monoclonal antibody therapy for metastatic colorectal cancer (mCRC) patients with wild-type, but not mutant, KRAS; KRAS mutations were reported to reduce the efficacy of this therapy, as reviewed by Normanno et al..	('KRAS', 'Gene', (227, 231))	('efficacy', 'MPA', (270, 278))	('EGFR', 'Gene', '1956', (107, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('KRAS', 'Gene', '3845', (227, 231))	('KRAS', 'Gene', (221, 225))	('panitumumab', 'Chemical', 'MESH:D000077544', (85, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('EGFR', 'Gene', (107, 111))	('KRAS', 'Gene', '3845', (221, 225))	('mutations', 'Var', (232, 241))	('colorectal cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('reduce', 'NegReg', (259, 265))	('patients', 'Species', '9606', (180, 188))
623271	27102293	EBV, one of the DNA tumor viruses, induces Burkitt's lymphoma, a cancer of B cells.	('EBV', 'Var', (0, 3))	("Burkitt's lymphoma", 'Disease', (43, 61))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('induces', 'Reg', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (43, 61))	('cancer', 'Disease', (65, 71))	('EBV', 'Species', '10376', (0, 3))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (43, 61))	('tumor', 'Disease', (20, 25))
623277	27102293	This finding was followed by demonstrations that single compounds in this mixture, such as 3, 4-benzopyrene and alpha-aminoazotoluene, induced tumors in experimental animals.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('induced', 'Reg', (135, 142))	('alpha-aminoazotoluene', 'Chemical', '-', (112, 133))	('rat', 'Species', '10116', (36, 39))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('3, 4-benzopyrene', 'Chemical', 'MESH:D001564', (91, 107))	('alpha-aminoazotoluene', 'Var', (112, 133))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
623284	27102293	"Oncogene theory" was based on cancer (mostly leukemia) incidence in the following different inbred mouse strains: AKR (high incidence), BALB/c (intermediate incidence), and C57BL (low incidence).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mouse', 'Species', '10090', (100, 105))	('C57BL', 'Var', (174, 179))	('mostly leukemia', 'Disease', 'MESH:D007938', (39, 54))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('mostly leukemia', 'Disease', (39, 54))	('leukemia', 'Phenotype', 'HP:0001909', (46, 54))	('cancer', 'Disease', (31, 37))
623295	27102293	Sarcoma-virus specific sequences were first prepared from viral particles produced by mouse 58-2T cells, developed by Masakazu Hatanaka, which produced a large excess of Ki-SV over helper MLV.	('Sarcoma', 'Phenotype', 'HP:0100242', (0, 7))	('MLV', 'Species', '11786', (188, 191))	('58-2T', 'CellLine', 'CVCL:5K05', (92, 97))	('mouse', 'Species', '10090', (86, 91))	('Ki-SV', 'Var', (170, 175))	('Sarcoma-virus', 'Disease', (0, 13))	('Sarcoma-virus', 'Disease', 'MESH:D012509', (0, 13))
623308	27102293	Although transforming human src stop-codon mutations were reported in colon cancer more than 10 years later, additional analyses failed to confirm these and other activating transforming mutations, as reviewed by Russello and Shore.	('colon cancer', 'Phenotype', 'HP:0003003', (70, 82))	('colon cancer', 'Disease', (70, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (43, 52))	('human', 'Species', '9606', (22, 27))	('colon cancer', 'Disease', 'MESH:D015179', (70, 82))	('human src stop-codon', 'Gene', (22, 42))
623311	27102293	It has been reported that src family kinases phosphorylated tyrosine residues of the Bcr-Abl protein, which conferred oncogenic activities.	('src family kinases', 'Enzyme', (26, 44))	('conferred', 'Reg', (108, 117))	('tyrosine residues', 'Var', (60, 77))	('tyrosine', 'Chemical', 'MESH:D014443', (60, 68))	('Bcr-Abl', 'Gene', '25', (85, 92))	('Bcr-Abl', 'Gene', (85, 92))	('oncogenic activities', 'CPA', (118, 138))
623315	27102293	However, the incidence of mos mutations was low in human cancer cells, while enhanced expression was observed.	('enhanced', 'PosReg', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('mos', 'Gene', (26, 29))	('expression', 'MPA', (86, 96))	('human', 'Species', '9606', (51, 56))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
623331	27102293	The v-Hras/has ORF in this segment was found to encode a 30 kDa protein starting 156 nucleotides upstream of the ATG codon of the internal p21 ORF (Figure 3B).	('encode', 'Reg', (48, 54))	('p21', 'Gene', '644914', (139, 142))	('v-Hras/has', 'Var', (4, 14))	('p21', 'Gene', (139, 142))
623332	27102293	The viral Kras/kis gene was localized by analysis of the transforming activities of deletion mutants of clone 4(E).	('transforming activities', 'MPA', (57, 80))	('kis', 'Gene', (15, 18))	('kis', 'Gene', '127933', (15, 18))	('deletion mutants', 'Var', (84, 100))
623348	27102293	This difference resulted in the substitution of glycine for valine.	('substitution', 'Var', (32, 44))	('glycine', 'MPA', (48, 55))	('resulted in', 'Reg', (16, 27))	('glycine', 'Chemical', 'MESH:D005998', (48, 55))	('valine', 'MPA', (60, 66))	('valine', 'Chemical', 'MESH:D014633', (60, 66))
623358	27102293	In 1983, the Wigler and Weinberg and Lowy groups found a transforming human KRAS DNA fragment in Calu-1 and SW480 cancer cells using the v-Kras probe and/or the cellular KRAS probe (a c-ki-ras2 fragment originally isolated with a v-Kras probe), respectively.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('KRAS', 'Gene', (170, 174))	('KRAS', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (76, 80))	('human', 'Species', '9606', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('KRAS', 'Gene', '3845', (170, 174))	('c-ki-ras2', 'Gene', (184, 193))	('c-ki-ras2', 'Gene', '3845', (184, 193))	('SW480', 'CellLine', 'CVCL:0546', (108, 113))	('v-Kras probe', 'Var', (137, 149))	('cancer', 'Disease', (114, 120))
623369	27102293	In addition, a KRAS mutation detected in a lung carcinoma was not present in normal tissues from the same patient, indicating an association between activation of oncogenes and the development of certain human cancers.	('association', 'Interaction', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lung carcinoma', 'Disease', 'MESH:D008175', (43, 57))	('KRAS', 'Gene', (15, 19))	('patient', 'Species', '9606', (106, 113))	('mutation', 'Var', (20, 28))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('lung carcinoma', 'Disease', (43, 57))	('KRAS', 'Gene', '3845', (15, 19))	('human', 'Species', '9606', (204, 209))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('cancers', 'Disease', (210, 217))	('activation', 'PosReg', (149, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
623371	27102293	Among these, RAS gene amplification has been reported in various tumors, but events (2) and (3) have not been reported.	('RAS gene', 'Gene', (13, 21))	('amplification', 'Var', (22, 35))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
623372	27102293	Chromosomal translocation also results in the formation of an activated oncogene product as a fusion protein, such as BCR-ABL and RET-PTC.	('BCR-ABL', 'Gene', (118, 125))	('BCR-ABL', 'Gene', '25', (118, 125))	('RET', 'Gene', (130, 133))	('Chromosomal translocation', 'Var', (0, 25))	('results in', 'Reg', (31, 41))	('RET', 'Gene', '5979', (130, 133))
623385	27102293	Inhibition of overexpressed EGFR has been used in cancer therapies.	('EGFR', 'Gene', '1956', (28, 32))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('EGFR', 'Gene', (28, 32))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
623386	27102293	For mCRC, it was reported that patients with amplified EGFR copies respond well to anti-EGFR treatment.	('EGFR', 'Gene', '1956', (55, 59))	('amplified', 'Var', (45, 54))	('EGFR', 'Gene', (55, 59))	('copies', 'Var', (60, 66))	('EGFR', 'Gene', '1956', (88, 92))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', (88, 92))
623387	27102293	However, starting in 2006, anti-EGFR therapy with a monoclonal anti-body (mAb) or tyrosine kinase inhibitor (TKI) was reported to be less effective in mCRC patients with KRAS mutations at codon 12/13 because the mutated KRAS oncogene is unaffected by EGFR signaling (Figure 5).	('patients', 'Species', '9606', (156, 164))	('EGFR', 'Gene', (251, 255))	('KRAS', 'Gene', '3845', (220, 224))	('KRAS', 'Gene', (170, 174))	('EGFR', 'Gene', '1956', (32, 36))	('KRAS', 'Gene', '3845', (170, 174))	('mutations', 'Var', (175, 184))	('EGFR', 'Gene', (32, 36))	('tyrosine', 'Chemical', 'MESH:D014443', (82, 90))	('KRAS', 'Gene', (220, 224))	('EGFR', 'Gene', '1956', (251, 255))
623388	27102293	Additional studies have shown that patients with NRAS, BRAF, and PIK3CA oncogene mutations (shown by circles with thick lines) are also resistant to anti-EGFR therapy.	('EGFR', 'Gene', (154, 158))	('NRAS', 'Gene', '4893', (49, 53))	('oncogene', 'Gene', (72, 80))	('PIK3CA', 'Gene', (65, 71))	('mutations', 'Var', (81, 90))	('BRAF', 'Gene', '673', (55, 59))	('NRAS', 'Gene', (49, 53))	('patients', 'Species', '9606', (35, 43))	('resistant', 'NegReg', (136, 145))	('PIK3CA', 'Gene', '5290', (65, 71))	('BRAF', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (154, 158))
623390	27102293	Thus, activated KRAS mutations were the first to be reported in anti-EGFR-resistant mCRC patients.	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', (69, 73))	('KRAS', 'Gene', (16, 20))	('patients', 'Species', '9606', (89, 97))	('KRAS', 'Gene', '3845', (16, 20))	('mCRC', 'Disease', (84, 88))	('mutations', 'Var', (21, 30))
623391	27102293	Some patients had both PIK3CA and KRAS mutations.	('KRAS', 'Gene', '3845', (34, 38))	('PIK3CA', 'Gene', (23, 29))	('patients', 'Species', '9606', (5, 13))	('PIK3CA', 'Gene', '5290', (23, 29))	('mutations', 'Var', (39, 48))	('KRAS', 'Gene', (34, 38))
623393	27102293	PTEN mutations also contribute to anti-EGFR treatment resistance, since, like PIK3CA mutations, they enhance AKT phosphorylation.	('PIK3CA', 'Gene', (78, 84))	('AKT', 'Gene', '207', (109, 112))	('contribute', 'Reg', (20, 30))	('mutations', 'Var', (5, 14))	('PIK3CA', 'Gene', '5290', (78, 84))	('mutations', 'Var', (85, 94))	('EGFR', 'Gene', '1956', (39, 43))	('enhance', 'PosReg', (101, 108))	('EGFR', 'Gene', (39, 43))	('PTEN', 'Gene', (0, 4))	('AKT', 'Gene', (109, 112))	('PTEN', 'Gene', '5728', (0, 4))
623399	27102293	Amplification/activation of these receptors or enhanced expression of their ligands, HGF and TGF alpha, also conferred resistance to anti-EGFR therapy.	('TGF alpha', 'Gene', '7039', (93, 102))	('enhanced', 'PosReg', (47, 55))	('HGF', 'Gene', (85, 88))	('EGFR', 'Gene', '1956', (138, 142))	('TGF alpha', 'Gene', (93, 102))	('HGF', 'Gene', '3082', (85, 88))	('EGFR', 'Gene', (138, 142))	('expression', 'MPA', (56, 66))	('Amplification/activation', 'Var', (0, 24))	('conferred', 'Reg', (109, 118))	('Amplification/activation', 'PosReg', (0, 24))
623400	27102293	Acquired EGFR mutation, which abrogates the binding of the mAb cetuximab has been reported.	('cetuximab', 'Chemical', 'MESH:D000068818', (63, 72))	('EGFR', 'Gene', '1956', (9, 13))	('mutation', 'Var', (14, 22))	('EGFR', 'Gene', (9, 13))	('abrogates', 'NegReg', (30, 39))	('binding', 'Interaction', (44, 51))
623402	27102293	As KRAS mutations predict the efficacy of anti-EGFR therapy, KRAS mutation testing is mandatory, and anti-EGFR therapy is only prescribed for mCRC patients with wild-type KRAS (see Figure 1).	('KRAS', 'Gene', '3845', (61, 65))	('KRAS', 'Gene', '3845', (3, 7))	('mutations', 'Var', (8, 17))	('KRAS', 'Gene', '3845', (171, 175))	('patients', 'Species', '9606', (147, 155))	('KRAS', 'Gene', (61, 65))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', '1956', (106, 110))	('KRAS', 'Gene', (171, 175))	('KRAS', 'Gene', (3, 7))	('EGFR', 'Gene', (47, 51))	('EGFR', 'Gene', (106, 110))
623403	27102293	Consequently, molecular epidemiological data of Kras mutations in mCRC patients has accumulated.	('patients', 'Species', '9606', (71, 79))	('Kras', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))
623409	27102293	This was accomplished by alkylating adenine N3 at the target sequence.	('adenine N3', 'Chemical', '-', (36, 46))	('alkylating', 'Var', (25, 35))	('adenine N3', 'Protein', (36, 46))
623410	27102293	The modification induced DNA strand cleavage and thereby suppressed the growth of KRAS-mutated human colon cancer cells.	('human', 'Species', '9606', (95, 100))	('colon cancer', 'Disease', 'MESH:D015179', (101, 113))	('growth', 'CPA', (72, 78))	('colon cancer', 'Disease', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('induced', 'Reg', (17, 24))	('DNA', 'MPA', (25, 28))	('modification', 'Var', (4, 16))	('KRAS', 'Gene', (82, 86))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))	('KRAS', 'Gene', '3845', (82, 86))	('suppressed', 'NegReg', (57, 67))
623411	27102293	This approach was suitable for inactivating either G12D or G12V mutated genes, which are frequent in mCRC,.	('G12V mutated', 'Var', (59, 71))	('G12D', 'Mutation', 'rs121913529', (51, 55))	('G12D', 'Var', (51, 55))	('G12V', 'Mutation', 'rs121913529', (59, 63))
623414	27102293	KRASG12C protein was modified by guanine nucleotide (GN) analogs so that the analogs formed a covalent bond to the cysteine residue at codon 12 in the GTP/GDP pocket.	('analogs', 'Var', (77, 84))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (33, 51))	('GTP', 'Chemical', 'MESH:D006160', (151, 154))	('cysteine', 'Chemical', 'MESH:D003545', (115, 123))	('GN', 'Chemical', 'MESH:D006150', (53, 55))	('covalent bond', 'MPA', (94, 107))	('GDP', 'Chemical', 'MESH:D006153', (155, 158))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
623415	27102293	The modified KRAS protein is unable to bind to downstream effector proteins, and oncogenic signaling is thereby attenuated, as reviewed by Wang et al..	('protein', 'Protein', (18, 25))	('KRAS', 'Gene', (13, 17))	('unable', 'NegReg', (29, 35))	('modified', 'Var', (4, 12))	('oncogenic signaling', 'CPA', (81, 100))	('attenuated', 'NegReg', (112, 122))	('KRAS', 'Gene', '3845', (13, 17))
623416	27102293	Most KRASG12C mutations are due to G to T nucleotide transversion in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('KRAS', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('KRAS', 'Gene', '3845', (5, 9))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('G to T nucleotide transversion', 'Var', (35, 65))	('mutations', 'Var', (14, 23))
623417	27102293	Therapeutic immunization (GI-4000 vaccine) with whole cell lysates of recombinant yeast that expresses a mutated KRAS protein has been reported.	('KRAS', 'Gene', (113, 117))	('yeast', 'Species', '4932', (82, 87))	('mutated', 'Var', (105, 112))	('KRAS', 'Gene', '3845', (113, 117))
623420	27102293	This method was effective in patients suffering from malignant melanoma with mutated NRAS or BRAF.	('BRAF', 'Gene', (93, 97))	('patients', 'Species', '9606', (29, 37))	('malignant melanoma', 'Disease', (53, 71))	('mutated', 'Var', (77, 84))	('NRAS', 'Gene', (85, 89))	('malignant melanoma', 'Phenotype', 'HP:0002861', (53, 71))	('NRAS', 'Gene', '4893', (85, 89))	('BRAF', 'Gene', '673', (93, 97))	('malignant melanoma', 'Disease', 'MESH:D008545', (53, 71))
623429	27102293	In conclusion, the discovery of Kirsten Ras oncogene sequences in both viral genomes and transforming DNA fragments in cancer cells lead to the discovery of crucial roles for KRAS in human carcinogenesis, as well as the high frequency of KRAS mutations in human cancer.	('cancer', 'Disease', (262, 268))	('human', 'Species', '9606', (256, 261))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('KRAS', 'Gene', (238, 242))	('mutations', 'Var', (243, 252))	('carcinogenesis', 'Disease', (189, 203))	('cancer', 'Disease', (119, 125))	('KRAS', 'Gene', '3845', (238, 242))	('human', 'Species', '9606', (183, 188))	('KRAS', 'Gene', (175, 179))	('Kirsten', 'Species', '11808', (32, 39))	('KRAS', 'Gene', '3845', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
623430	27102293	Furthermore, recent results regarding anti-EGFR therapeutic efficacy in patients bearing wild-type or mutant KRAS suggested that it is the most important cancer driver in vivo.	('mutant', 'Var', (102, 108))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('KRAS', 'Gene', (109, 113))	('EGFR', 'Gene', '1956', (43, 47))	('KRAS', 'Gene', '3845', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('EGFR', 'Gene', (43, 47))	('patients', 'Species', '9606', (72, 80))
623431	27102293	Improved knowledge of the complex mechanisms involved in KRAS activation and signaling is necessary in order to develop new therapeutic strategies directed against mutated KRAS.	('KRAS', 'Gene', (172, 176))	('rat', 'Species', '10116', (138, 141))	('KRAS', 'Gene', '3845', (172, 176))	('KRAS', 'Gene', (57, 61))	('KRAS', 'Gene', '3845', (57, 61))	('mutated', 'Var', (164, 171))
623600	21151695	Genetic diagnosis became possible with the identification of a characteristic chromosomal translocation in the 1980s, and the mechanism of tumorigenesis began to be elucidated with the cloning of the breakpoint, identifying the EWS-FLI1 fusion early the next decade.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('EWS', 'Gene', '2130', (228, 231))	('EWS', 'Gene', (228, 231))	('fusion', 'Var', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('FLI1', 'Gene', (232, 236))	('FLI1', 'Gene', '2313', (232, 236))
623620	32493277	We were able to establish 4 VCR-resistant cell lines (Ruch-2VR, Rh30VR, Rh41VR, and TC71VR).	('Rh30', 'Gene', '6007', (64, 68))	('TC71VR', 'CellLine', 'CVCL:2213', (84, 90))	('VCR', 'Chemical', 'MESH:D014750', (28, 31))	('Rh41VR', 'Var', (72, 78))	('Rh30', 'Gene', (64, 68))
623621	32493277	GLI1 was significantly up-regulated in the Rh30VR, Rh41VR, and TC71VR cells.	('GLI1', 'Gene', (0, 4))	('TC71VR', 'CellLine', 'CVCL:2213', (63, 69))	('Rh30', 'Gene', '6007', (43, 47))	('up-regulated', 'PosReg', (23, 35))	('Rh30', 'Gene', (43, 47))	('TC71VR', 'Var', (63, 69))	('Rh41VR', 'Var', (51, 57))
623625	32493277	These experiments demonstrate that GLI1 up-regulation contributes to VCR resistance in RMS and EWS cell lines and suggest that targeting GLI1 may benefit patients with RMS or EWS by reducing multidrug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (196, 211))	('EWS', 'Disease', (175, 178))	('RMS', 'Phenotype', 'HP:0002859', (168, 171))	('reducing', 'NegReg', (182, 190))	('multidrug resistance', 'MPA', (191, 211))	('EWS', 'Phenotype', 'HP:0012254', (95, 98))	('GLI1', 'Gene', (35, 39))	('targeting', 'Var', (127, 136))	('patients', 'Species', '9606', (154, 162))	('benefit', 'PosReg', (146, 153))	('VCR', 'Chemical', 'MESH:D014750', (69, 72))	('VCR resistance', 'MPA', (69, 83))	('RMS', 'Phenotype', 'HP:0002859', (87, 90))	('EWS', 'Phenotype', 'HP:0012254', (175, 178))	('up-regulation', 'PosReg', (40, 53))	('RMS', 'Disease', (168, 171))	('GLI1', 'Gene', (137, 141))
623645	32493277	Primers and probes for GLI1 (Hs00171790_ml), PTCH1 (Hs00970980_ml), and GAPDH (Hs99999905_ml) were purchased from Applied Biosystems (Foster City, CA).	('Hs00171790_ml', 'Var', (29, 42))	('Hs99999905_ml', 'Var', (79, 92))	('GAPDH', 'Gene', '2597', (72, 77))	('Hs00970980_ml', 'Var', (52, 65))	('GAPDH', 'Gene', (72, 77))
623703	32493277	Four genes were significantly down-regulated (>=2 fold and p <= 0.05) in both the Rh30VR and Rh41VR ARMS cell lines compared with their corresponding parental cells: CYP1A1 (2.6 fold decreased and p = 0.01), CYP2D6 (2.8 fold decreased and p = 0.008), cyclin E1 (CCNE1) (4.4 fold decreased and p = 0.008), and ERBB3 (6.8 fold decreased and p = 0.006).	('down-regulated', 'NegReg', (30, 44))	('cyclin E1', 'Gene', (251, 260))	('Rh30', 'Gene', (82, 86))	('Rh41VR', 'Var', (93, 99))	('ERBB3', 'Gene', '2065', (309, 314))	('ERBB3', 'Gene', (309, 314))	('Rh30', 'Gene', '6007', (82, 86))	('CYP1A1', 'Gene', (166, 172))	('decreased', 'NegReg', (183, 192))	('decreased', 'NegReg', (225, 234))	('CYP2D6', 'Gene', '1565', (208, 214))	('cyclin E1', 'Gene', '898', (251, 260))	('CCNE1', 'Gene', (262, 267))	('CCNE1', 'Gene', '898', (262, 267))	('CYP1A1', 'Gene', '1543', (166, 172))	('RMS', 'Phenotype', 'HP:0002859', (101, 104))	('CYP2D6', 'Gene', (208, 214))
623711	32493277	However, treatment of Rh30VR and Rh41VR ARMS cells with GLI1 siRNA alone impacted cell viability even at the lowest concentration we tested (Fig.	('cell viability', 'CPA', (82, 96))	('RMS', 'Phenotype', 'HP:0002859', (41, 44))	('Rh41VR', 'Var', (33, 39))	('impacted', 'Reg', (73, 81))	('Rh30', 'Gene', '6007', (22, 26))	('Rh30', 'Gene', (22, 26))
623712	32493277	In summary, these experiments demonstrate that GLI1 up-regulation contributes to VCR-resistance of RMS and EWS cell lines and suggest that targeting GLI1 may benefit patients with RMS or EWS by reducing multidrug resistance.	('RMS', 'Phenotype', 'HP:0002859', (99, 102))	('up-regulation', 'PosReg', (52, 65))	('VCR', 'Chemical', 'MESH:D014750', (81, 84))	('EWS', 'Phenotype', 'HP:0012254', (187, 190))	('VCR-resistance', 'MPA', (81, 95))	('benefit', 'PosReg', (158, 165))	('drug resistance', 'Phenotype', 'HP:0020174', (208, 223))	('RMS', 'Disease', (180, 183))	('GLI1', 'Gene', (149, 153))	('EWS', 'Disease', (187, 190))	('EWS', 'Phenotype', 'HP:0012254', (107, 110))	('RMS', 'Phenotype', 'HP:0002859', (180, 183))	('reducing', 'NegReg', (194, 202))	('GLI1', 'Gene', (47, 51))	('targeting', 'Var', (139, 148))	('patients', 'Species', '9606', (166, 174))	('multidrug resistance', 'MPA', (203, 223))
623728	32493277	The only other gene in the 86-gene drug resistance array that was up-regulated in Rh30VR, Rh41VR, and TC71VR cells was the known direct GLI1 target and multidrug resistance gene, MDR1.	('drug resistance', 'Phenotype', 'HP:0020174', (157, 172))	('Rh30', 'Gene', (82, 86))	('up-regulated', 'PosReg', (66, 78))	('drug resistance', 'Phenotype', 'HP:0020174', (35, 50))	('MDR1', 'Gene', (179, 183))	('Rh30', 'Gene', '6007', (82, 86))	('TC71VR', 'Var', (102, 108))	('MDR1', 'Gene', '5243', (179, 183))	('TC71VR', 'CellLine', 'CVCL:2213', (102, 108))	('Rh41VR', 'Var', (90, 96))
623739	32493277	Rh30VR and Rh41VR cells were sensitive to GLI1 siRNA treatment even at the lowest concentrations tested, suggesting that viability of these cell lines is dependent on GLI1.	('Rh30', 'Gene', '6007', (0, 4))	('Rh41VR', 'Var', (11, 17))	('Rh30', 'Gene', (0, 4))
623774	24485876	Mutations may lead to altered proteins that are presented to CD8 or CD4 T lymphocytes.	('CD4', 'Gene', '920', (68, 71))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('lead', 'Reg', (14, 18))	('Mutations', 'Var', (0, 9))	('altered', 'Reg', (22, 29))	('CD4', 'Gene', (68, 71))	('proteins', 'Protein', (30, 38))
623775	24485876	Examples include mutated beta-catenin, cyclin-dependent kinase 4, and caspase 8, found in melanoma, renal, and head and neck cancers, respectively.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('neck cancers', 'Disease', (120, 132))	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('neck cancers', 'Disease', 'MESH:D006258', (120, 132))	('caspase 8', 'Gene', '841', (70, 79))	('beta-catenin', 'Gene', '1499', (25, 37))	('caspase 8', 'Gene', (70, 79))	('renal', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('head and neck cancers', 'Phenotype', 'HP:0012288', (111, 132))	('cyclin-dependent kinase 4', 'Gene', '1019', (39, 64))	('found', 'Reg', (81, 86))	('cyclin-dependent kinase 4', 'Gene', (39, 64))	('beta-catenin', 'Gene', (25, 37))	('mutated', 'Var', (17, 24))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
623778	24485876	Finally, mutated tumor suppressor genes, such as p53, and oncogene products such as RAS, contain epitopes capable of inducing immune responses.	('p53', 'Gene', (49, 52))	('inducing', 'PosReg', (117, 125))	('tumor', 'Disease', (17, 22))	('p53', 'Gene', '7157', (49, 52))	('immune responses', 'CPA', (126, 142))	('mutated', 'Var', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('RAS', 'Gene', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
623799	24485876	As such, dialog between the host and tumor via secreted factors can result in a profoundly immunosuppressive milieu that prevents immune mediated tumor clearance and promotes aggressive tumor biology.	('aggressive tumor', 'Disease', 'MESH:D001523', (175, 191))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (146, 151))	('aggressive tumor', 'Disease', (175, 191))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('result in', 'Reg', (68, 77))	('tumor', 'Disease', (37, 42))	('promotes', 'PosReg', (166, 174))	('prevents', 'NegReg', (121, 129))	('dialog', 'Var', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
623810	24485876	CTLA-4 blockade also directly limits the suppressive activity of Treg, a cell type discussed in more detail below.	('CTLA-4', 'Gene', (0, 6))	('suppressive activity', 'MPA', (41, 61))	('CTLA-4', 'Gene', '1493', (0, 6))	('limits', 'NegReg', (30, 36))	('blockade', 'Var', (7, 15))	('Treg', 'CPA', (65, 69))
623818	24485876	Blockade of PD-1 can reinvigorate exhausted T cells and restore their antitumor function.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Blockade', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('reinvigorate exhausted T cells', 'Phenotype', 'HP:0031514', (21, 51))	('tumor', 'Disease', (74, 79))	('restore', 'PosReg', (56, 63))	('PD-1', 'Gene', (12, 16))	('PD-1', 'Gene', '5133', (12, 16))
623822	24485876	Although blockade of CTLA-4 or PD-1 may result in auto-immune sequelae and inflammatory tissue damage, targeting PD-1 may be safer.	('PD-1', 'Gene', '5133', (113, 117))	('CTLA-4', 'Gene', (21, 27))	('inflammatory tissue damage', 'CPA', (75, 101))	('auto-immune sequelae', 'CPA', (50, 70))	('result in', 'Reg', (40, 49))	('PD-1', 'Gene', (31, 35))	('CTLA-4', 'Gene', '1493', (21, 27))	('PD-1', 'Gene', '5133', (31, 35))	('auto-immune sequelae', 'Phenotype', 'HP:0002960', (50, 70))	('PD-1', 'Gene', (113, 117))	('blockade', 'Var', (9, 17))
623823	24485876	In an animal model, we have recently demonstrated that PD-1 blockade can resuscitate T cells within the liver while actually minimizing inflammatory injury to normal parenchyma.	('blockade', 'Var', (60, 68))	('minimizing', 'NegReg', (125, 135))	('PD-1', 'Gene', (55, 59))	('PD-1', 'Gene', '5133', (55, 59))	('inflammatory injury', 'MPA', (136, 155))
623824	24485876	Other investigators have also found that PD-1/PD-L1 inhibition can restore immunity while minimizing inflammation.	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('inflammation', 'Disease', (101, 113))	('PD-1', 'Gene', (41, 45))	('PD-1', 'Gene', '5133', (41, 45))	('immunity', 'MPA', (75, 83))	('inhibition', 'Var', (52, 62))	('restore', 'PosReg', (67, 74))
623826	24485876	As such, activation of antitumor T cells via PD-1/PD-L1 inhibition is particularly attractive given the favorable tradeoff between antitumor responses and toxicity.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('activation', 'PosReg', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (27, 32))	('PD-1', 'Gene', (45, 49))	('PD-1', 'Gene', '5133', (45, 49))	('tumor', 'Disease', (135, 140))	('toxicity', 'Disease', 'MESH:D064420', (155, 163))	('toxicity', 'Disease', (155, 163))	('inhibition', 'Var', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
623853	24485876	PA2024 is a fusion protein containing prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor (GM-CSF), the latter being capable of antigen presenting cell activation.	('prostatic acid phosphatase', 'Gene', '55', (38, 64))	('GM-CSF', 'Gene', (119, 125))	('prostatic acid phosphatase', 'Gene', (38, 64))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (69, 117))	('GM-CSF', 'Gene', '1437', (119, 125))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (69, 117))	('PA2024', 'Var', (0, 6))
623868	24485876	In murine models, lymphodepletion enhances the antitumor effects of transferred T cells by several mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lymphodepletion', 'Var', (18, 33))	('tumor', 'Disease', (51, 56))	('enhances', 'PosReg', (34, 42))	('murine', 'Species', '10090', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
623906	24485876	A phase III trial for stage IV melanoma patients demonstrated that ipilimumab was associated with an increase in median overall survival to 10.0 mo compared with 6.4 mo in the control group (P < 0.001).	('ipilimumab', 'Var', (67, 77))	('patients', 'Species', '9606', (40, 48))	('increase', 'PosReg', (101, 109))	('ipilimumab', 'Chemical', 'MESH:D000074324', (67, 77))	('IV melanoma', 'Disease', (28, 39))	('IV melanoma', 'Disease', 'MESH:D008545', (28, 39))	('overall survival', 'MPA', (120, 136))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))
623914	24485876	Blockade of the immunoinhibitory PD-1/PD-L1 axis enhances antitumor activity.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', (62, 67))	('PD-1', 'Gene', (33, 37))	('enhances', 'PosReg', (49, 57))	('PD-1', 'Gene', '5133', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
624019	32784588	Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe.	('kidney chromophobe', 'Disease', 'MESH:D000238', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (96, 120))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (96, 120))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('observed', 'Reg', (75, 83))	('adrenocortical carcinoma', 'Disease', (96, 120))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))	('kidney chromophobe', 'Disease', (126, 144))	('homologous recombination', 'Var', (35, 59))
624028	32784588	In addition, ALT-positive tumors have recurrent mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene and the gene encoding the death domain associated (DAXX) protein.	('alpha', 'Disease', (65, 70))	('DAXX', 'Gene', '1616', (183, 187))	('death', 'Disease', 'MESH:D003643', (158, 163))	('death', 'Disease', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('ATRX', 'Gene', (121, 125))	('DAXX', 'Gene', (183, 187))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (71, 119))	('ATRX', 'Gene', '546', (121, 125))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (71, 119))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mental retardation', 'Phenotype', 'HP:0001249', (83, 101))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', (26, 32))
624047	32784588	Three of these cancer types showed significantly greater enrichment of the ALT HR pathway in the Long TL group than in the Short TL group (SARC: p = 5.1 x 10-10, ACC: p = 4.4 x 10-4, KICH: p = 1.7 x 10-4).	('Long TL', 'Var', (97, 104))	('ACC', 'Phenotype', 'HP:0006744', (162, 165))	('SARC', 'Phenotype', 'HP:0100242', (139, 143))	('greater', 'PosReg', (49, 56))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('KICH', 'Disease', (183, 187))	('ALT HR pathway', 'Pathway', (75, 89))	('KICH', 'Disease', 'None', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
624059	32784588	PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence.	('PML', 'Gene', '5371', (0, 3))	('chromosomal abnormalities', 'Disease', (51, 76))	('depletion', 'Var', (4, 13))	('PML', 'Phenotype', 'HP:0004836', (0, 3))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (51, 76))	('induces', 'Reg', (14, 21))	('PML', 'Gene', (0, 3))	('senescence', 'CPA', (82, 92))	('telomere damage', 'CPA', (22, 37))
624060	32784588	It is commonly found in tumors with telomere shortening and high proliferation, which suggests its critical role in telomere maintenance and cell viability.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('telomere shortening', 'Phenotype', 'HP:0031413', (36, 55))	('high proliferation', 'CPA', (60, 78))	('telomere shortening', 'Var', (36, 55))
624063	32784588	We found that the cell proliferation rate differs noticeably based on the telomere length in three cancer types (Figure 2c).	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('telomere length', 'Var', (74, 89))	('cell proliferation rate', 'CPA', (18, 41))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
624075	32784588	In gliomas, TERT promoter mutations lead to higher telomerase activity but the associations between TERT promoter mutations and clinical outcomes are still controversial.	('TERT', 'Gene', '7015', (12, 16))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('higher', 'PosReg', (44, 50))	('TERT', 'Gene', (100, 104))	('mutations', 'Var', (26, 35))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('TERT', 'Gene', '7015', (100, 104))	('gliomas', 'Disease', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('TERT', 'Gene', (12, 16))	('telomerase activity', 'MPA', (51, 70))
624086	32784588	Cancers displaying unfavorable risk with high ALT (BRCA, SARC, and LUAD) may be regulated by the transcriptional factors E2F4, TFDP1, E2F1, E2F7, and SIN3A (FDR = 0.001) in the DNA repair pathway, including genes repairing DNA damage such as CENPI, CLSPN, TOPBP1, and MCM4 (Figure 4a).	('MCM4', 'Gene', (268, 272))	('CENPI', 'Gene', (242, 247))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('SIN3A', 'Gene', '25942', (150, 155))	('TOPBP1', 'Gene', '11073', (256, 262))	('BRCA', 'Gene', '672', (51, 55))	('E2F7', 'Gene', (140, 144))	('TFDP1', 'Gene', (127, 132))	('CLSPN', 'Gene', '63967', (249, 254))	('CENPI', 'Gene', '2491', (242, 247))	('CLSPN', 'Gene', (249, 254))	('TOPBP1', 'Gene', (256, 262))	('regulated', 'Reg', (80, 89))	('SARC', 'Disease', (57, 61))	('E2F4', 'Gene', (121, 125))	('BRCA', 'Gene', (51, 55))	('E2F1', 'Var', (134, 138))	('E2F4', 'Gene', '1874', (121, 125))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('MCM4', 'Gene', '4173', (268, 272))	('E2F7', 'Gene', '144455', (140, 144))	('SIN3A', 'Gene', (150, 155))	('TFDP1', 'Gene', '7027', (127, 132))	('SARC', 'Phenotype', 'HP:0100242', (57, 61))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('DNA', 'Pathway', (177, 180))	('BRCA', 'Phenotype', 'HP:0003002', (51, 55))
624087	32784588	In contrast, cancers displaying favorable risk with high ALT (GBM and LIHC) may be regulated by E2F4, TFDP1, FOXM1, E2F7, SIN3A, E2F1, MYBL2, and E2F2 (FDR = 0.0001) (Figure 4b).	('E2F1', 'Var', (129, 133))	('E2F2', 'Gene', '1870', (146, 150))	('FOXM1', 'Gene', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('TFDP1', 'Gene', (102, 107))	('SIN3A', 'Gene', (122, 127))	('E2F7', 'Gene', (116, 120))	('MYBL2', 'Gene', (135, 140))	('E2F4', 'Gene', (96, 100))	('MYBL2', 'Gene', '4605', (135, 140))	('E2F4', 'Gene', '1874', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('FOXM1', 'Gene', '2305', (109, 114))	('cancers', 'Disease', (13, 20))	('TFDP1', 'Gene', '7027', (102, 107))	('SIN3A', 'Gene', '25942', (122, 127))	('E2F7', 'Gene', '144455', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('E2F2', 'Gene', (146, 150))
624091	32784588	There is an unmet need for the development of drugs for ALT tumors associated with telomere lengthening.	('telomere', 'Var', (83, 91))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('associated', 'Reg', (67, 77))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
624095	32784588	We identified candidate drugs (CP724714, MP470, TGX221, and XMD8-85) for TOP2A in molecular subtypes of sarcoma (osteosarcoma and soft tissue) (Figure 4f).	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('sarcoma', 'Disease', (118, 125))	('CP724714', 'Var', (31, 39))	('TOP2A', 'Gene', '7153', (73, 78))	('MP470', 'Var', (41, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('TOP2A', 'Gene', (73, 78))	('osteosarcoma', 'Disease', (113, 125))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
624096	32784588	We found that XMD8-85, as an ERK5 target, was also predicted in the Long TL samples in SARC by DeSigN  (p = 0.032).	('XMD8-85', 'Var', (14, 21))	('SARC', 'Phenotype', 'HP:0100242', (87, 91))	('ERK5', 'Gene', (29, 33))	('ERK5', 'Gene', '5598', (29, 33))
624118	32784588	We also compared PML expression by telomere length and found that PML expression was higher in the Short TL group.	('higher', 'PosReg', (85, 91))	('Short', 'Var', (99, 104))	('PML', 'Gene', '5371', (17, 20))	('PML', 'Gene', '5371', (66, 69))	('PML', 'Phenotype', 'HP:0004836', (17, 20))	('PML', 'Phenotype', 'HP:0004836', (66, 69))	('PML', 'Gene', (17, 20))	('PML', 'Gene', (66, 69))
624119	32784588	In some cancer types, high PML expression is associated with telomere shortening for tumor suppression and apoptosis, cell cycle arrest, and senescence, owing to the lack of telomere maintenance.	('tumor', 'Disease', (85, 90))	('arrest', 'Disease', (129, 135))	('senescence', 'CPA', (141, 151))	('cancer', 'Disease', (8, 14))	('PML', 'Gene', '5371', (27, 30))	('telomere shortening', 'Phenotype', 'HP:0031413', (61, 80))	('high', 'Var', (22, 26))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('associated', 'Reg', (45, 55))	('telomere', 'MPA', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('PML', 'Gene', (27, 30))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('PML', 'Phenotype', 'HP:0004836', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('apoptosis', 'CPA', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
624147	32784588	Significant survival differences were observed in ALT-associated pathways, Figure S8: Box plot comparing the expression of hTERT repressors (CTCF, E2F1, and SIN3A).	('hTERT', 'Gene', (123, 128))	('CTCF', 'Gene', '10664', (141, 145))	('CTCF', 'Gene', (141, 145))	('E2F1', 'Var', (147, 151))	('ALT-associated pathways', 'Pathway', (50, 73))	('SIN3A', 'Gene', '25942', (157, 162))	('hTERT', 'Gene', '7015', (123, 128))	('SIN3A', 'Gene', (157, 162))
624157	32082672	The diagnoses of monophasic synovial sarcoma were rendered via core needle biopsies, with molecular FISH confirmation of SYT gene rearrangement.	('SYT', 'Gene', (121, 124))	('rearrangement', 'Var', (130, 143))	('synovial sarcoma', 'Disease', 'MESH:D013584', (28, 44))	('SYT', 'Gene', '6760', (121, 124))	('synovial sarcoma', 'Disease', (28, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (28, 44))
624204	32082672	Nevertheless, despite the complications of its nomenclature and the fact that its histogenesis remains unclear, synovial sarcoma is a recognized and well-defined clinicopathologic entity, which harbors a reproducible cytogenetic abnormality, t(X;18)(p11.2;q11.2), associated with the SYT/SSX fusion.	('SSX', 'Gene', '6757', (288, 291))	('SSX', 'Gene', (288, 291))	('t(X;18)(p11.2;q11.2', 'Var', (242, 261))	('synovial sarcoma', 'Disease', (112, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('SYT', 'Gene', (284, 287))	('t(X;18)(p11.2;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (242, 262))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (112, 128))	('synovial sarcoma', 'Disease', 'MESH:D013584', (112, 128))	('SYT', 'Gene', '6760', (284, 287))
624214	32082672	By MRI scan, intraosseous synovial sarcomas are typically isointense to hypointense on T1-weighted images and hyperintense on T2-weighted images.	('intraosseous synovial sarcomas', 'Disease', 'MESH:D013584', (13, 43))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (26, 43))	('sarcomas', 'Phenotype', 'HP:0100242', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('hypointense', 'Var', (72, 83))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (26, 42))	('intraosseous synovial sarcomas', 'Disease', (13, 43))
624258	31705593	Silencing of LIN28B changed the metabolism of osteosarcoma and induced the loss of SIC characteristics.	('SIC', 'MPA', (83, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('LIN28B', 'Gene', '389421', (13, 19))	('metabolism', 'MPA', (32, 42))	('osteosarcoma', 'Disease', (46, 58))	('LIN28B', 'Gene', (13, 19))	('osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('loss', 'NegReg', (75, 79))	('osteosarcoma', 'Disease', 'MESH:D012516', (46, 58))	('Silencing', 'Var', (0, 9))	('changed', 'Reg', (20, 27))
624281	31705593	LIN28B (Hs01013729_m1), SOX2 (Hs01053049_s1), POU5F1 (Hs00999632_g1), and NANOG (Hs04260366_g1) primers and probes were designed using the TaqMan Gene Expression assay (Applied Biosystems).	('SOX2', 'Gene', (24, 28))	('SOX2', 'Gene', '6657', (24, 28))	('Hs04260366_g1', 'Var', (81, 94))	('LIN28B', 'Gene', '389421', (0, 6))	('POU5F1', 'Gene', '5460', (46, 52))	('NANOG', 'Gene', '79923', (74, 79))	('POU5F1', 'Gene', (46, 52))	('LIN28B', 'Gene', (0, 6))	('Hs00999632_g1', 'Var', (54, 67))	('Hs01053049_s1', 'Var', (30, 43))	('NANOG', 'Gene', (74, 79))	('Hs01013729_m1', 'Var', (8, 21))
624330	31705593	Expression of mRNA and protein of LIN28B was decreased in short hairpin LIN28B (shLIN28B) cells (Figure 4A,B).	('LIN28B', 'Gene', '389421', (34, 40))	('short', 'Var', (58, 63))	('Expression', 'MPA', (0, 10))	('decreased', 'NegReg', (45, 54))	('LIN28B', 'Gene', '389421', (72, 78))	('LIN28B', 'Gene', (34, 40))	('LIN28B', 'Gene', (82, 88))	('LIN28B', 'Gene', (72, 78))	('LIN28B', 'Gene', '389421', (82, 88))
624337	31705593	These results suggested that knockdown of LIN28B might switch the metabolic status of OS13 cells to that of OSLOW cells.	('LIN28B', 'Gene', '389421', (42, 48))	('knockdown', 'Var', (29, 38))	('metabolic status', 'MPA', (66, 82))	('OS13', 'CellLine', 'CVCL:2860', (86, 90))	('switch', 'Reg', (55, 61))	('LIN28B', 'Gene', (42, 48))	('OS', 'Phenotype', 'HP:0002669', (86, 88))	('OS', 'Phenotype', 'HP:0002669', (108, 110))
624356	31705593	In the present study, a novel osteosarcoma cell line (OS13) was established and characterized as follows: (i) OSHIGH cells derived from OS13 bulk cells showed higher levels of in vitro and in vivo tumorigenesis and chemoresistance; (ii) the metabolic status of OSHIGH cells highly depended on glycolysis but not on OXPHOS; (iii) LIN28B was identified as a SIC-related protein and expressed in 85% of sarcoma primary tissues; (iv) knockdown of LIN28B led to an increase in mitochondrial respiration; and (v) manipulation of aerobic glycolysis combined with chemotherapy decreased in vitro and in vivo tumorigenesis of OS13 cells.	('tumor', 'Disease', (600, 605))	('OS13', 'CellLine', 'CVCL:2860', (617, 621))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('HOS', 'Disease', 'MESH:C535326', (318, 321))	('OS', 'Phenotype', 'HP:0002669', (54, 56))	('LIN28B', 'Gene', (443, 449))	('tumor', 'Disease', 'MESH:D009369', (600, 605))	('osteosarcoma', 'Disease', (30, 42))	('osteosarcoma', 'Disease', 'MESH:D012516', (30, 42))	('manipulation', 'Var', (507, 519))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (600, 605))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('mitochondrial respiration', 'MPA', (472, 497))	('LIN28B', 'Gene', '389421', (443, 449))	('sarcoma', 'Disease', (35, 42))	('sarcoma', 'Disease', 'MESH:D012509', (400, 407))	('sarcoma', 'Disease', (400, 407))	('OS', 'Phenotype', 'HP:0002669', (136, 138))	('LIN28B', 'Gene', (329, 335))	('OS', 'Phenotype', 'HP:0002669', (319, 321))	('knockdown', 'Var', (430, 439))	('osteosarcoma', 'Phenotype', 'HP:0002669', (30, 42))	('decreased', 'NegReg', (569, 578))	('OS13', 'CellLine', 'CVCL:2860', (136, 140))	('OS', 'Phenotype', 'HP:0002669', (261, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (400, 407))	('HOS', 'Disease', (318, 321))	('increase', 'PosReg', (460, 468))	('LIN28B', 'Gene', '389421', (329, 335))	('tumor', 'Disease', (197, 202))	('OS', 'Phenotype', 'HP:0002669', (110, 112))	('OS13', 'CellLine', 'CVCL:2860', (54, 58))
624360	31705593	This expression profile is the so-called "cancer stem cell/testis antigen" pattern and is an ideal target for immunotherapy using peptide vaccination or adoptive cell transfer of genetically engineered exogenous T-cell receptor-expressing T cells (TCR-T cells).3, 24  The molecular mechanisms underlying attenuation of resistance to Adriamycin by knockdown of LIN28B remain unclear.	('knockdown', 'Var', (347, 356))	('Adriamycin', 'Chemical', 'MESH:D004317', (333, 343))	('attenuation', 'NegReg', (304, 315))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('resistance to Adriamycin', 'MPA', (319, 343))	('LIN28B', 'Gene', (360, 366))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('LIN28B', 'Gene', '389421', (360, 366))
624368	31705593	In contrast, ATP levels and tumorigenesis of OS13 cells were greatly decreased by 2-DG treatment.	('ATP', 'Chemical', 'MESH:D000255', (13, 16))	('tumor', 'Disease', (28, 33))	('OS13', 'CellLine', 'CVCL:2860', (45, 49))	('ATP', 'MPA', (13, 16))	('decreased', 'NegReg', (69, 78))	('2-DG', 'Chemical', 'MESH:D003847', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('OS', 'Phenotype', 'HP:0002669', (45, 47))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('2-DG treatment', 'Var', (82, 96))
624371	31705593	Ribose-5-phosphate is essential for the biosynthesis of nucleic acids.27  In the in vivo study, a combination of 2DG and low-dose Adriamycin showed antitumor effects against xenografted OS13 cells.	('Adriamycin', 'Chemical', 'MESH:D004317', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('Ribose-5-phosphate', 'Chemical', 'MESH:C031626', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('2DG', 'Var', (113, 116))	('OS13', 'CellLine', 'CVCL:2860', (186, 190))	('OS', 'Phenotype', 'HP:0002669', (186, 188))
624380	31186687	Notably, inoculation of anti-CD151 antibody significantly suppressed the lymphatic invasion, peritoneal dissemination and distant metastasis of the present clear cell sarcoma model without affecting local tumor growth at the transplantation site.	('local tumor', 'Disease', 'MESH:D009364', (199, 210))	('lymphatic invasion', 'CPA', (73, 91))	('anti-CD151', 'Var', (24, 34))	('distant metastasis', 'CPA', (122, 140))	('clear cell sarcoma', 'Disease', (156, 174))	('suppressed', 'NegReg', (58, 68))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (156, 174))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('anti-CD151', 'Gene', (24, 34))	('local tumor', 'Disease', (199, 210))	('sarcoma', 'Phenotype', 'HP:0100242', (167, 174))
624445	31186687	High numbers of HS-MMhigh cells within lymphatic vessels are indicated by arrows, and a single inoculation of anti-CD151 antibody markedly impaired the infiltration of HS-MMhigh cells into lymphatic vessels (Fig.	('HS-MMhigh', 'CellLine', 'CVCL:W404', (168, 177))	('infiltration', 'CPA', (152, 164))	('impaired', 'NegReg', (139, 147))	('anti-CD151', 'Var', (110, 120))	('HS-MMhigh', 'CellLine', 'CVCL:W404', (16, 25))
624446	31186687	We did observe a small number of HS-MMhigh cells in lymphatic vessels following treatment as indicated by arrows; however, anti-CD151 antibody did not alter the tumor volume of HS-MMhigh cells at the injection site as demonstrated in Fig.	('anti-CD151', 'Var', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('HS-MMhigh', 'CellLine', 'CVCL:W404', (177, 186))	('HS-MMhigh', 'CellLine', 'CVCL:W404', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
624447	31186687	In contrast, administration of anti-CD151 antibody significantly decreased total weights of collected, disseminated mesenteric tumors (Student's t-test, P=0.0036).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('anti-CD151', 'Gene', (31, 41))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('decreased', 'NegReg', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('decreased total weights', 'Phenotype', 'HP:0004325', (65, 88))	('mesenteric tumors', 'Phenotype', 'HP:0011934', (116, 133))	('anti-CD151', 'Var', (31, 41))
624449	31186687	Given this, it is clear that anti-CD151 antibody treatment suppressed metastasis of HS-MMhigh cells in xenoplanted SCID-Beige mice.	('SCID', 'Disease', (115, 119))	('mice', 'Species', '10090', (126, 130))	('suppressed', 'NegReg', (59, 69))	('metastasis of HS-MMhigh cells', 'CPA', (70, 99))	('HS-MMhigh', 'CellLine', 'CVCL:W404', (84, 93))	('anti-CD151', 'Var', (29, 39))	('SCID', 'Disease', 'MESH:D053632', (115, 119))
624452	31186687	Downregulation of CD151 using SI02777257 did not affect the cell growth of HS-MMhigh cells in vitro (Student's t-test, P=0.54, Fig.	('Downregulation', 'NegReg', (0, 14))	('HS-MMhigh', 'CellLine', 'CVCL:W404', (75, 84))	('CD151', 'Gene', (18, 23))	('SI02777257', 'Var', (30, 40))
624453	31186687	Our results indicate that silencing of CD151 decreased the Matrigel invasion activity of metastatic HS-MMhigh cells without affecting cell proliferation.	('HS-MMhigh', 'CellLine', 'CVCL:W404', (100, 109))	('CD151', 'Gene', (39, 44))	('decreased', 'NegReg', (45, 54))	('silencing', 'Var', (26, 35))
624461	31186687	Immunoblot analysis demonstrated little or no phospho-SMAD family member 3 (pSMAD3), band in CD151 knockout HS-MMhigh cells.	('CD151', 'Gene', (93, 98))	('HS-MMhigh', 'CellLine', 'CVCL:W404', (108, 117))	('knockout', 'Var', (99, 107))	('SMAD3', 'Gene', '4088', (77, 82))	('SMAD3', 'Gene', (77, 82))
624466	31186687	Most CCS tumors are characterized by a t(12;22)(q13;q12) translocation harboring an EWS-ATF1 fusion gene.	('EWS-ATF1', 'Gene', (84, 92))	('CCS tumors', 'Disease', 'MESH:D009369', (5, 15))	('EWS-ATF1', 'Gene', '466;2130', (84, 92))	('t(12;22)(q13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (39, 56))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('t(12;22)(q13;q12', 'Var', (39, 55))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('CCS tumors', 'Disease', (5, 15))
624467	31186687	The resulting fusion protein directly activates expression of the melanocyte master transcription factor that drives the same down-stream pathways in both CCS and melanoma.	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('expression', 'MPA', (48, 58))	('fusion', 'Var', (14, 20))	('CCS', 'Disease', (155, 158))	('activates', 'PosReg', (38, 47))	('down-stream pathways', 'Pathway', (126, 146))
624471	31186687	The present study strongly suggests an important role for CD151 in lymphatic invasion, and we identify potent suppressor activity of anti-CD151 antibody in the context of lymphatic metastases using an orthotropic metastatic model of CCS.	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('anti-CD151', 'Var', (133, 143))	('lymphatic invasion', 'CPA', (67, 85))	('metastases', 'Disease', (181, 191))	('suppressor', 'NegReg', (110, 120))	('CD151', 'Gene', (58, 63))
624475	31186687	We expect that the combination of local surgical resection with anti-CD151 treatment may provide significant improvement in clinical outcomes for patients diagnosed with CCS.	('improvement', 'PosReg', (109, 120))	('patients', 'Species', '9606', (146, 154))	('CCS', 'Disease', (170, 173))	('anti-CD151', 'Var', (64, 74))
624481	31186687	In this study, silencing of CD151 impaired the Matrigel invasion activity of HS-MMhigh cells through downregulation of activated MMP-9.	('CD151', 'Gene', (28, 33))	('downregulation', 'NegReg', (101, 115))	('Matrigel invasion activity of HS-MMhigh cells', 'CPA', (47, 92))	('silencing', 'Var', (15, 24))	('MMP-9', 'Gene', (129, 134))	('MMP-9', 'Gene', '4318', (129, 134))	('HS-MMhigh', 'CellLine', 'CVCL:W404', (77, 86))	('impaired', 'NegReg', (34, 42))
624484	31186687	Anti-CD151 antibody may impair the homophilic interactions of CD151, resulting in decreased expression of MMP-9 and abrogation of the initiation of lymphatic vessel invasion.	('MMP-9', 'Gene', (106, 111))	('CD151', 'Gene', (62, 67))	('impair', 'NegReg', (24, 30))	('homophilic interactions', 'MPA', (35, 58))	('Anti-CD151', 'Var', (0, 10))	('Anti-CD151', 'Gene', (0, 10))	('MMP-9', 'Gene', '4318', (106, 111))	('abrogation', 'NegReg', (116, 126))	('decreased', 'NegReg', (82, 91))	('expression', 'MPA', (92, 102))
624488	31186687	Our results suggest that anti-CD151 antibody treatment may impair activation of MMP-9, thus decreasing the lymphatic invasion activity of HS-MMhigh cells.	('HS-MMhigh', 'CellLine', 'CVCL:W404', (138, 147))	('decreasing', 'NegReg', (92, 102))	('MMP-9', 'Gene', '4318', (80, 85))	('activation', 'MPA', (66, 76))	('impair', 'NegReg', (59, 65))	('anti-CD151', 'Var', (25, 35))	('MMP-9', 'Gene', (80, 85))	('lymphatic invasion activity of HS-MMhigh cells', 'CPA', (107, 153))	('anti-CD151', 'Gene', (25, 35))
624494	31186687	Another monoclonal antibody, SFA1.2B4, was also found to suppress the in vivo pulmonary metastasis of the CD151-overexpressing human colon cancer cell line RPMI4788 induced by direct intravenous challenge to BALB/c nu/nu mice.	('pulmonary metastasis', 'CPA', (78, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('human', 'Species', '9606', (127, 132))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('suppress', 'NegReg', (57, 65))	('colon cancer', 'Disease', (133, 145))	('SFA1.2B4', 'Var', (29, 37))	('mice', 'Species', '10090', (221, 225))
624495	31186687	These findings may indicate that anti-CD151 antibodies may be of clinical benefit to patients not only suffering from CSS, a rare soft part tumor, but also those diagnosed with other malignant tumors.	('malignant tumors', 'Disease', 'MESH:D018198', (183, 199))	('anti-CD151', 'Gene', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('anti-CD151 antibodies', 'Var', (33, 54))	('antibodies', 'Var', (44, 54))	('soft part tumor', 'Disease', 'MESH:D018227', (130, 145))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('soft part tumor', 'Disease', (130, 145))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('malignant tumors', 'Disease', (183, 199))	('CSS', 'Disease', (118, 121))
624496	31186687	We believe that anti-CD151 antibody treatment may impair activation of MMP-9 to decrease the lymphatic invasion activity of HS-MMhigh cells.	('HS-MMhigh', 'CellLine', 'CVCL:W404', (124, 133))	('impair', 'NegReg', (50, 56))	('anti-CD151', 'Var', (16, 26))	('lymphatic invasion activity of HS-MMhigh cells', 'CPA', (93, 139))	('MMP-9', 'Gene', '4318', (71, 76))	('MMP-9', 'Gene', (71, 76))	('activation', 'MPA', (57, 67))	('decrease', 'NegReg', (80, 88))
624497	31186687	Additionally, reduced amounts of phosphorylated SMAD3 may also inhibit lymphatic invasion by abrogating EMT activity.	('abrogating', 'NegReg', (93, 103))	('amounts', 'MPA', (22, 29))	('reduced', 'NegReg', (14, 21))	('phosphorylated', 'Var', (33, 47))	('SMAD3', 'Gene', '4088', (48, 53))	('EMT', 'Gene', (104, 107))	('EMT', 'Gene', '3702', (104, 107))	('lymphatic invasion', 'CPA', (71, 89))	('SMAD3', 'Gene', (48, 53))	('inhibit', 'NegReg', (63, 70))
624598	29527121	The use of alternating chemotherapeutic regimens is based on the Goldie-Coldman hypothesis that states that the proportion of resistant tumor cells increases over time and that alternating chemotherapy decreases the likelihood of mutations making tumor cells less resistant to a specific drug.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('decreases', 'NegReg', (202, 211))	('tumor', 'Disease', (247, 252))	('Goldie', 'Species', '1003695', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mutations', 'Var', (230, 239))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', (136, 141))
624654	25374341	additionally showed that PARP inhibition by olaparib potentiated DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes, thereby inhibiting growth of tumor subcutaneously implanted into SCID mice .	('expression', 'Var', (87, 97))	('tumor', 'Disease', (164, 169))	('EWS', 'Phenotype', 'HP:0012254', (101, 104))	('ERG', 'Gene', (117, 120))	('PARP', 'Protein', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('FLI1', 'Gene', '14247', (105, 109))	('EWS', 'Phenotype', 'HP:0012254', (113, 116))	('inhibition', 'NegReg', (30, 40))	('SCID', 'Disease', 'MESH:D053632', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('DNA damage', 'MPA', (65, 75))	('fusion genes', 'Var', (121, 133))	('FLI1', 'Gene', (105, 109))	('tumor subcutaneously', 'Phenotype', 'HP:0001482', (164, 184))	('olaparib', 'Chemical', 'MESH:C531550', (44, 52))	('SCID', 'Disease', (200, 204))	('potentiated', 'PosReg', (53, 64))	('inhibiting', 'NegReg', (143, 153))	('mice', 'Species', '10090', (205, 209))	('ERG', 'Gene', '13876', (117, 120))
624681	25374341	Several other factors that could explain the disparity include failure to achieve in vitro levels of olaparib at the clinical dose, secondary genomic or epigenomic alterations that might have activated other drivers of tumor cell proliferation that would render the PARP pathway nonessential, or yet unidentified mediators of PARP-rescue derived from tumor-environment interactions.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('alterations', 'Var', (164, 175))	('PARP pathway', 'Pathway', (266, 278))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', (351, 356))	('olaparib', 'Chemical', 'MESH:C531550', (101, 109))	('activated', 'PosReg', (192, 201))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (351, 356))
624714	21048999	The longest delays were caused by erroneous primary diagnosis (7, 16, and 40 months) and comorbidity that required complimentary medical procedures prior to surgery (5, 8, and 19 months).	('erroneous primary', 'Var', (34, 51))	('comorbidity', 'Disease', (89, 100))	('men', 'Species', '9606', (121, 124))
624770	31908727	Case 1: Laboratory tests showed seropositivity for HBsAg, HBeAb, and HBcAb.	('seropositivity', 'Var', (32, 46))	('HBcAb', 'Disease', (69, 74))	('HBeAb', 'Disease', (58, 63))	('HBsAg', 'Disease', (51, 56))	('HBsAg', 'Chemical', 'MESH:D006514', (51, 56))
624798	24113309	Genetic differences associated with rhabdomyosarcoma subclassification include the presence of reciprocal translocations and their associated fusions in ARMS, amplification of genes in ARMS and its fusion subsets, chromosomal losses and gains that mostly occur in ERMS, and allelic losses and mutations usually associated with ERMS.	('fusions', 'Var', (142, 149))	('allelic', 'Var', (274, 281))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (36, 52))	('chromosomal losses', 'Var', (214, 232))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (36, 52))	('RMS', 'Phenotype', 'HP:0002859', (154, 157))	('gains', 'PosReg', (237, 242))	('RMS', 'Phenotype', 'HP:0002859', (265, 268))	('genes', 'Gene', (176, 181))	('RMS', 'Phenotype', 'HP:0002859', (186, 189))	('RMS', 'Phenotype', 'HP:0002859', (328, 331))	('ARMS', 'Phenotype', 'HP:0006779', (185, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('ERMS', 'Phenotype', 'HP:0006743', (264, 268))	('ERMS', 'Phenotype', 'HP:0006743', (327, 331))	('ARMS', 'Phenotype', 'HP:0006779', (153, 157))	('ERMS', 'Disease', (327, 331))	('amplification', 'Var', (159, 172))	('rhabdomyosarcoma', 'Disease', (36, 52))
624850	24113309	The most common chromosomal translocation in ARMS is t(2;13)(q35;q14), and a second less frequent variant translocation is t(1;13)(p36;q14).	('ARMS', 'Phenotype', 'HP:0006779', (45, 49))	('t(1;13)(p36;q14', 'Var', (123, 138))	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (53, 69))	('RMS', 'Phenotype', 'HP:0002859', (46, 49))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (123, 139))	('t(2;13)(q35;q14', 'Var', (53, 68))
624861	24113309	Although ERMS tumors do not contain recurrent rearrangements, they demonstrate frequent allelic loss, which is the selective loss of one of the two parental alleles at one or more contiguous chromosomal loci.	('allelic loss', 'Var', (88, 100))	('ERMS tumors', 'Disease', (9, 20))	('loss', 'NegReg', (125, 129))	('RMS', 'Phenotype', 'HP:0002859', (10, 13))	('ERMS tumors', 'Disease', 'MESH:D009369', (9, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('ERMS', 'Phenotype', 'HP:0006743', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
624863	24113309	Allelic loss of this region has also been detected in fusion-positive ARMS tumors, but with a lower frequency than in ERMS tumors.	('RMS', 'Phenotype', 'HP:0002859', (119, 122))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('ERMS tumors', 'Disease', 'MESH:D009369', (118, 129))	('ARMS tumors', 'Disease', (70, 81))	('Allelic loss', 'Var', (0, 12))	('fusion-positive', 'Var', (54, 69))	('ARMS', 'Phenotype', 'HP:0006779', (70, 74))	('ERMS', 'Phenotype', 'HP:0006743', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('RMS', 'Phenotype', 'HP:0002859', (71, 74))	('ERMS tumors', 'Disease', (118, 129))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('ARMS tumors', 'Disease', 'MESH:D009369', (70, 81))
624868	24113309	Several studies have assayed ERMS and ARMS cases for point mutations of potential oncogenes and tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('oncogenes', 'Gene', (82, 91))	('ARMS', 'Phenotype', 'HP:0006779', (38, 42))	('tumor', 'Disease', (96, 101))	('ERMS', 'Phenotype', 'HP:0006743', (29, 33))	('RMS', 'Phenotype', 'HP:0002859', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('RMS', 'Phenotype', 'HP:0002859', (30, 33))	('point mutations', 'Var', (53, 68))	('ERMS', 'Disease', (29, 33))
624869	24113309	Mutations were detected in 28% of the ERMS cases, and included 7 RAS family mutations, 4 FGFR4 mutations, 3 PIK3CA mutations, 2 CTNNB1 mutations, and single mutations in BRAF and PTPN11.	('ERMS', 'Phenotype', 'HP:0006743', (38, 42))	('mutations', 'Var', (115, 124))	('mutations', 'Var', (76, 85))	('BRAF', 'Gene', (170, 174))	('BRAF', 'Gene', '673', (170, 174))	('PTPN11', 'Gene', '5781', (179, 185))	('CTNNB1', 'Gene', '1499', (128, 134))	('PTPN11', 'Gene', (179, 185))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', (108, 114))	('mutations', 'Var', (95, 104))	('FGFR4', 'Gene', (89, 94))	('CTNNB1', 'Gene', (128, 134))	('RMS', 'Phenotype', 'HP:0002859', (39, 42))	('FGFR4', 'Gene', '2264', (89, 94))	('PIK3CA', 'Gene', '5290', (108, 114))
624871	24113309	Therefore, point mutations appear to be significantly more frequent in ERMS than in ARMS tumors.	('RMS', 'Phenotype', 'HP:0002859', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('ERMS', 'Disease', (71, 75))	('ARMS tumors', 'Disease', 'MESH:D009369', (84, 95))	('point mutations', 'Var', (11, 26))	('RMS', 'Phenotype', 'HP:0002859', (72, 75))	('frequent', 'Reg', (59, 67))	('ARMS', 'Phenotype', 'HP:0006779', (84, 88))	('ARMS tumors', 'Disease', (84, 95))	('ERMS', 'Phenotype', 'HP:0006743', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
624872	24113309	At the genomic level, the 2;13 (or 1;13) translocation results in breaks within specific genes in the 2q35 (or 1p36) and 13q14 chromosomal regions followed by rejoining of portions of these genes to generate fusion genes.	('p36', 'Gene', '302', (112, 115))	('p36', 'Gene', (112, 115))	('breaks', 'Var', (66, 72))
624875	24113309	Though these translocations generate reciprocal fusions, PAX3-FOXO1 and FOXO1-PAX3 (or PAX7-FOXO1 and FOXO1-PAX7), the PAX3-FOXO1 and PAX7-FOXO1 genes are more highly and consistently expressed in ARMS tumors with the 2;13 and 1;13 translocations and are presumed to encode the products involved in ARMS pathogenesis.	('PAX7', 'Gene', '5081', (108, 112))	('FOXO1', 'Gene', '2308', (102, 107))	('ARMS', 'Phenotype', 'HP:0006779', (299, 303))	('highly', 'PosReg', (160, 166))	('PAX3', 'Gene', '5077', (57, 61))	('PAX3', 'Gene', (78, 82))	('PAX7', 'Gene', (134, 138))	('translocations', 'Var', (232, 246))	('PAX3', 'Gene', '5077', (119, 123))	('FOXO1', 'Gene', '2308', (62, 67))	('PAX7', 'Gene', (108, 112))	('FOXO1', 'Gene', (72, 77))	('RMS', 'Phenotype', 'HP:0002859', (300, 303))	('ARMS', 'Phenotype', 'HP:0006779', (197, 201))	('FOXO1', 'Gene', '2308', (92, 97))	('1;13 translocations', 'Var', (227, 246))	('FOXO1', 'Gene', (102, 107))	('PAX3', 'Gene', '5077', (78, 82))	('ARMS tumors', 'Disease', (197, 208))	('FOXO1', 'Gene', (62, 67))	('FOXO1', 'Gene', '2308', (124, 129))	('FOXO1', 'Gene', '2308', (139, 144))	('FOXO1', 'Gene', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('2;13', 'Var', (218, 222))	('FOXO1', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('PAX7', 'Gene', '5081', (87, 91))	('FOXO1', 'Gene', (139, 144))	('PAX3', 'Gene', (57, 61))	('ARMS tumors', 'Disease', 'MESH:D009369', (197, 208))	('PAX3', 'Gene', (119, 123))	('PAX7', 'Gene', (87, 91))	('FOXO1', 'Gene', '2308', (72, 77))	('PAX7', 'Gene', '5081', (134, 138))	('RMS', 'Phenotype', 'HP:0002859', (198, 201))
624876	24113309	The PAX3-FOXO1 and PAX7-FOXO1 fusion transcripts encode chimeric transcription factors containing the PAX3 or PAX7 DNA binding domain and the FOXO1 transcriptional activation domain.	('encode', 'Reg', (49, 55))	('fusion', 'Var', (30, 36))	('PAX7', 'Gene', '5081', (110, 114))	('PAX3', 'Gene', '5077', (102, 106))	('FOXO1', 'Gene', '2308', (24, 29))	('PAX7', 'Gene', (110, 114))	('PAX3', 'Gene', (102, 106))	('binding', 'Interaction', (119, 126))	('PAX3', 'Gene', '5077', (4, 8))	('FOXO1', 'Gene', (24, 29))	('PAX7', 'Gene', '5081', (19, 23))	('FOXO1', 'Gene', (142, 147))	('PAX3', 'Gene', (4, 8))	('FOXO1', 'Gene', '2308', (142, 147))	('FOXO1', 'Gene', '2308', (9, 14))	('FOXO1', 'Gene', (9, 14))	('PAX7', 'Gene', (19, 23))
624879	24113309	These expression and functional changes result in high expression of potent transcription factors that contribute to tumorigenesis by altering growth and apoptotic pathways, modulating myogenic differentiation, and stimulating motility and other metastatic pathways.	('modulating', 'Reg', (174, 184))	('altering', 'Reg', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('stimulating', 'Reg', (215, 226))	('motility', 'CPA', (227, 235))	('tumor', 'Disease', (117, 122))	('myogenic differentiation', 'CPA', (185, 209))	('expression', 'MPA', (55, 65))	('growth and', 'CPA', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('changes', 'Var', (32, 39))
624880	24113309	Recent studies have also identified gene fusions in a small subset of ERMS tumors.	('ERMS', 'Phenotype', 'HP:0006743', (70, 74))	('gene fusions', 'Var', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ERMS tumors', 'Disease', (70, 81))	('RMS', 'Phenotype', 'HP:0002859', (71, 74))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('ERMS tumors', 'Disease', 'MESH:D009369', (70, 81))
624881	24113309	In particular, rearrangements of the NCOA2 gene in the 8q11-13 chromosomal region were found in four ERMS cases.	('RMS', 'Phenotype', 'HP:0002859', (102, 105))	('NCOA2', 'Gene', (37, 42))	('ERMS', 'Phenotype', 'HP:0006743', (101, 105))	('rearrangements', 'Var', (15, 29))	('ERMS', 'Disease', (101, 105))	('NCOA2', 'Gene', '10499', (37, 42))	('found', 'Reg', (87, 92))
624884	24113309	In addition to these cases, there are reports of congenital/infantile ERMS cases with translocations involving the 8q11-13 region, including t(8;11)(q11.2;p15) and t(8;11)(q12-13;q21).	('congenital/infantile ERMS', 'Disease', (49, 74))	('t(8;11)(q11.2;p15)', 'STRUCTURAL_ABNORMALITY', 'None', (141, 159))	('ERMS', 'Phenotype', 'HP:0006743', (70, 74))	('t(8;11)(q11.2;p15', 'Var', (141, 158))	('t(8;11)(q12-13;q21', 'Var', (164, 182))	('RMS', 'Phenotype', 'HP:0002859', (71, 74))
624886	24113309	Multiple studies applied RT-PCR or FISH methodologies to sets of histopathologically diagnosed RMS cases to determine the frequency of the PAX3-FOXO1 and PAX7-FOXO1 fusions.	('PAX3', 'Gene', '5077', (139, 143))	('PAX3', 'Gene', (139, 143))	('FOXO1', 'Gene', (144, 149))	('PAX7', 'Gene', (154, 158))	('FOXO1', 'Gene', '2308', (144, 149))	('RMS', 'Disease', (95, 98))	('fusions', 'Var', (165, 172))	('FOXO1', 'Gene', '2308', (159, 164))	('PAX7', 'Gene', '5081', (154, 158))	('FOXO1', 'Gene', (159, 164))	('RMS', 'Phenotype', 'HP:0002859', (95, 98))
624887	24113309	In a study of RMS cases from the Intergroup Rhabdomyosarcoma Study (IRS)-IV protocol, 77% of the 78 ARMS cases were fusion-positive whereas 85 cases of ERMS (including botryoid and spindle cell subtypes) and 8 cases of undifferentiated sarcoma were fusion-negative.	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (44, 60))	('ARMS', 'Phenotype', 'HP:0006779', (100, 104))	('undifferentiated sarcoma', 'Disease', (219, 243))	('fusion-positive', 'Var', (116, 131))	('ERMS', 'Phenotype', 'HP:0006743', (152, 156))	('RMS', 'Phenotype', 'HP:0002859', (14, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('Rhabdomyosarcoma', 'Disease', (44, 60))	('RMS', 'Phenotype', 'HP:0002859', (101, 104))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (44, 60))	('ERMS', 'Disease', (152, 156))	('RMS', 'Phenotype', 'HP:0002859', (153, 156))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (219, 243))
624895	24113309	Application of several approaches to assay these fusion-negative cases for rearrangements of the PAX3, PAX7, and FOXO1 genes identified a small number of cases with variant fusions, such as fusion of PAX3 to the FOXO1-related locus FOXO4 (AFX); fusion of PAX3 to NCOA1 or NCOA2, encoding two similar transcription factors that are unrelated to FOXO1; and fusion of FOXO1 to FGFR1, encoding a receptor tyrosine kinase.	('PAX3', 'Gene', '5077', (200, 204))	('NCOA1', 'Gene', (263, 268))	('FOXO1', 'Gene', '2308', (212, 217))	('FOXO1', 'Gene', (113, 118))	('FGFR1', 'Gene', (374, 379))	('FOXO1', 'Gene', (365, 370))	('FOXO1', 'Gene', (212, 217))	('NCOA1', 'Gene', '8648', (263, 268))	('NCOA2', 'Gene', '10499', (272, 277))	('FOXO4', 'Gene', (232, 237))	('FGFR1', 'Gene', '2260', (374, 379))	('PAX3', 'Gene', (255, 259))	('variant', 'Var', (165, 172))	('FOXO1', 'Gene', '2308', (344, 349))	('fusion', 'Var', (190, 196))	('PAX3', 'Gene', (97, 101))	('PAX7', 'Gene', '5081', (103, 107))	('PAX3', 'Gene', (200, 204))	('FOXO1', 'Gene', '2308', (113, 118))	('PAX7', 'Gene', (103, 107))	('NCOA2', 'Gene', (272, 277))	('fusion', 'Var', (355, 361))	('PAX3', 'Gene', '5077', (255, 259))	('FOXO4', 'Gene', '4303', (232, 237))	('PAX3', 'Gene', '5077', (97, 101))	('FOXO1', 'Gene', '2308', (365, 370))	('fusion', 'Var', (245, 251))	('FOXO1', 'Gene', (344, 349))
624896	24113309	Though these variant fusions can explain the absence of a PAX3-FOXO1 or PAX7-FOXO1 fusion in a few cases, the far majority of "fusion-negative" cases do not have any rearrangements of PAX3, PAX7, or FOXO1 and thus appear to represent true fusion-negative cases with respect to these loci.	('PAX7', 'Gene', '5081', (72, 76))	('FOXO1', 'Gene', (77, 82))	('FOXO1', 'Gene', '2308', (77, 82))	('FOXO1', 'Gene', (199, 204))	('FOXO1', 'Gene', (63, 68))	('PAX7', 'Gene', '5081', (190, 194))	('FOXO1', 'Gene', '2308', (199, 204))	('FOXO1', 'Gene', '2308', (63, 68))	('PAX3', 'Gene', '5077', (58, 62))	('variant', 'Var', (13, 20))	('PAX3', 'Gene', (58, 62))	('PAX7', 'Gene', (72, 76))	('PAX7', 'Gene', (190, 194))	('PAX3', 'Gene', '5077', (184, 188))	('PAX3', 'Gene', (184, 188))
624899	24113309	For the rare ARMS cases with variant fusions, there is an example of one such case that clusters with the fusion-positive tumors and another such case that clusters with the fusion-negative tumors.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('fusions', 'Var', (37, 44))	('RMS', 'Phenotype', 'HP:0002859', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('variant fusions', 'Var', (29, 44))	('ARMS', 'Phenotype', 'HP:0006779', (13, 17))
624904	24113309	In addition, a high frequency of chromosome 11p15.5 allelic loss is found in fusion-negative ARMS as well as most ERMS cases.	('ERMS', 'Disease', (114, 118))	('ARMS', 'Phenotype', 'HP:0006779', (93, 97))	('RMS', 'Phenotype', 'HP:0002859', (94, 97))	('allelic loss', 'Var', (52, 64))	('ERMS', 'Phenotype', 'HP:0006743', (114, 118))	('RMS', 'Phenotype', 'HP:0002859', (115, 118))	('p15', 'Gene', (46, 49))	('p15', 'Gene', '1030', (46, 49))
624924	24113309	In a FISH analysis of 8 mixed histology cases, there was no evidence of PAX3, PAX7, or FOXO1 rearrangements in any of the analyzed regions.	('rearrangements', 'Var', (93, 107))	('FOXO1', 'Gene', '2308', (87, 92))	('PAX7', 'Gene', '5081', (78, 82))	('FOXO1', 'Gene', (87, 92))	('PAX3', 'Gene', '5077', (72, 76))	('PAX3', 'Gene', (72, 76))	('PAX7', 'Gene', (78, 82))
624925	24113309	Therefore, the previous inclusion of mixed and sclerosing cases in the ARMS category also contributed to an artefactual increase in the frequency of fusion-negative ARMS tumors as well as the overall frequency of ARMS tumors.	('ARMS tumors', 'Disease', (165, 176))	('RMS', 'Phenotype', 'HP:0002859', (214, 217))	('ARMS', 'Phenotype', 'HP:0006779', (213, 217))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('increase', 'PosReg', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ARMS tumors', 'Disease', 'MESH:D009369', (213, 224))	('RMS', 'Phenotype', 'HP:0002859', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('RMS', 'Phenotype', 'HP:0002859', (72, 75))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('ARMS tumors', 'Disease', 'MESH:D009369', (165, 176))	('ARMS', 'Phenotype', 'HP:0006779', (71, 75))	('ARMS tumors', 'Disease', (213, 224))	('fusion-negative', 'Var', (149, 164))	('ARMS', 'Phenotype', 'HP:0006779', (165, 169))
624926	24113309	in 2000 showed that strong myogenin expression typified ARMS, causing diffuse immunostaining that contrasts with the variable, focal, heterogeneous pattern of ERMS (Figure 3).	('myogenin', 'Gene', (27, 35))	('ARMS', 'Disease', (56, 60))	('causing', 'Reg', (62, 69))	('myogenin', 'Gene', '4656', (27, 35))	('diffuse immunostaining', 'MPA', (70, 92))	('expression', 'Var', (36, 46))	('ERMS', 'Phenotype', 'HP:0006743', (159, 163))	('ARMS', 'Phenotype', 'HP:0006779', (56, 60))	('RMS', 'Phenotype', 'HP:0002859', (160, 163))	('RMS', 'Phenotype', 'HP:0002859', (57, 60))
624931	24113309	As noted above, gene expression analyses have revealed other proteins whose expression corresponds to the presence or absence of the PAX-FOXO1 fusion.	('FOXO1', 'Gene', '2308', (137, 142))	('fusion', 'Var', (143, 149))	('FOXO1', 'Gene', (137, 142))	('PAX', 'Chemical', '-', (133, 136))	('expression', 'MPA', (76, 86))	('absence', 'NegReg', (118, 125))
624944	24113309	Genetic testing has revealed that the poor outcome associated with ARMS likely relates to the presence of PAX-FOXO1 fusion genes and not to histological features.	('fusion genes', 'Var', (116, 128))	('presence', 'Var', (94, 102))	('ARMS', 'Disease', (67, 71))	('PAX', 'Chemical', '-', (106, 109))	('ARMS', 'Phenotype', 'HP:0006779', (67, 71))	('FOXO1', 'Gene', (110, 115))	('FOXO1', 'Gene', '2308', (110, 115))	('RMS', 'Phenotype', 'HP:0002859', (68, 71))
624961	29263409	In 85-90% of EFTs cases, the tumor is characterized by a translocation involving the EWSR1 (EWS RNA-Binding Protein 1) gene on chromosome 22, and an ETS (E26 transformation-specific)-family gene such as FLI-1 or ERG.	('FLI-1', 'Gene', (203, 208))	('EWS RNA-Binding Protein 1', 'Gene', (92, 117))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('EWSR1', 'Gene', '2130', (85, 90))	('ERG', 'Gene', (212, 215))	('EWS RNA-Binding Protein 1', 'Gene', '2130', (92, 117))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('ERG', 'Gene', '2078', (212, 215))	('tumor', 'Disease', (29, 34))	('translocation', 'Var', (57, 70))	('EFTs', 'Disease', (13, 17))	('EWSR1', 'Gene', (85, 90))	('FLI-1', 'Gene', '2313', (203, 208))
624980	29263409	Molecular analysis was available for 53 patients (69%): EWSR1-FLI1 fusion was found in 26 patients, FUS-ERG in one patient and rearrangement of the EWSR1 gene not otherwise specified (NOS) in 22 patients (Table 1).	('EWSR1', 'Gene', (148, 153))	('fusion', 'Var', (67, 73))	('OS', 'Chemical', '-', (185, 187))	('patient', 'Species', '9606', (40, 47))	('FLI1', 'Gene', (62, 66))	('EWSR1', 'Gene', '2130', (56, 61))	('patients', 'Species', '9606', (195, 203))	('found', 'Reg', (78, 83))	('FLI1', 'Gene', '2313', (62, 66))	('ERG', 'Gene', (104, 107))	('EWSR1', 'Gene', '2130', (148, 153))	('patients', 'Species', '9606', (90, 98))	('FUS', 'Gene', (100, 103))	('ERG', 'Gene', '2078', (104, 107))	('EWSR1', 'Gene', (56, 61))	('rearrangement', 'Var', (127, 140))	('patients', 'Species', '9606', (40, 48))	('patient', 'Species', '9606', (195, 202))	('patient', 'Species', '9606', (90, 97))	('patient', 'Species', '9606', (115, 122))	('FUS', 'Gene', '2521', (100, 103))
625011	29263409	Several similarities in disease presentation with younger patients were noted such as a slight male predominance, a predominance of non-bulky tumors (<8 cm) and localized disease at presentation ( 75%).	('localized disease', 'Disease', (161, 178))	('<8', 'Var', (150, 152))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (58, 66))
625031	29263409	EFTs are characterized by pathognomonic EWSR1 gene translocation with a member of the ETS transcription factor family and genomic studies have shown that the number of additional mutations or genomic alterations increased with age, which suggests increasing genomic instability with age.	('EWSR1', 'Gene', '2130', (40, 45))	('EWSR1', 'Gene', (40, 45))	('mutations', 'Var', (179, 188))	('EFTs', 'Disease', (0, 4))	('gene translocation', 'Var', (46, 64))
625050	27486883	Independent factors that predicted shorter survival were male sex, >2 metastatic sites, >3 previous therapies, hemoglobin level <10.5 g/dL, platelet count >200 x103/L, creatinine level >=1.3 mg/dL, and lactate dehydrogenase level >ULN.	('>=1.3', 'Var', (185, 190))	('creatinine', 'Chemical', 'MESH:D003404', (168, 178))	('shorter', 'NegReg', (35, 42))	('creatinine level', 'MPA', (168, 184))	('>200 x103/L', 'Var', (155, 166))	('hemoglobin level', 'MPA', (111, 127))	('lactate dehydrogenase level', 'MPA', (202, 229))
625117	27486883	Similarly, the median OS duration of patients with MDACC prognosis scores of 0 or 1 (15 months) was significantly longer than that of patients who had MDACC scores of 2-4 (5 months HR = 3.2, 95% CI = 1.9-5.6; P < 0.0001) (Figure 2B).	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (134, 142))	('OS', 'Chemical', '-', (22, 24))	('longer', 'PosReg', (114, 120))	('OS duration', 'MPA', (22, 33))	('scores', 'Var', (67, 73))
625199	24975049	Taken together, these data suggested that the VEGF autocrine loop is involved in the surface growth of SS spheroids, and that VEGF inhibition had antitumor efficacy, at least in part, by inhibiting the VEGF autocrine loop.	('VEGF autocrine loop', 'MPA', (202, 221))	('inhibiting', 'NegReg', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('SS', 'Phenotype', 'HP:0012570', (103, 105))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('VEGF', 'Gene', (126, 130))	('inhibition', 'Var', (131, 141))	('tumor', 'Disease', (150, 155))
625201	24975049	We have previously reported that SS cells display marked shape changes, from spherical to adherent, upon SS18-SSX knockdown.	('SS', 'Phenotype', 'HP:0012570', (105, 107))	('SS18', 'Gene', (105, 109))	('knockdown', 'Var', (114, 123))	('adherent', 'CPA', (90, 98))	('spherical', 'CPA', (77, 86))	('SS', 'Phenotype', 'HP:0012570', (110, 112))	('SSX', 'Gene', '6757', (110, 113))	('SS18', 'Gene', '6760', (105, 109))	('SSX', 'Gene', (110, 113))	('SS', 'Phenotype', 'HP:0012570', (33, 35))
625203	24975049	SS18-SSX silencing did not affect protein and mRNA expression levels of VEGF-A or VEGFR2 (Figs2b,c,S3b).	('mRNA expression levels', 'MPA', (46, 68))	('SS', 'Phenotype', 'HP:0012570', (5, 7))	('VEGFR2', 'Gene', (82, 88))	('silencing', 'Var', (9, 18))	('SSX', 'Gene', '6757', (5, 8))	('SS18', 'Gene', '6760', (0, 4))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SSX', 'Gene', (5, 8))	('VEGF-A', 'Gene', (72, 78))	('SS18', 'Gene', (0, 4))	('protein', 'MPA', (34, 41))
625205	24975049	Thus, we speculated that with SS18-SSX knockdown, the VEGF signal in SS cells induces endothelial differentiation.	('SS18', 'Gene', '6760', (30, 34))	('VEGF', 'MPA', (54, 58))	('induces', 'Reg', (78, 85))	('SS', 'Phenotype', 'HP:0012570', (30, 32))	('knockdown', 'Var', (39, 48))	('endothelial differentiation', 'CPA', (86, 113))	('SS', 'Phenotype', 'HP:0012570', (35, 37))	('SS', 'Phenotype', 'HP:0012570', (69, 71))	('SS18', 'Gene', (30, 34))	('SSX', 'Gene', (35, 38))	('SSX', 'Gene', '6757', (35, 38))
625208	24975049	The expression of both proteins was detected under SS18-SSX knockdown conditions, but not under control siRNA conditions (Figs2e,f, S3d,e).	('SSX', 'Gene', (56, 59))	('SS18', 'Gene', '6760', (51, 55))	('detected', 'Reg', (36, 44))	('knockdown', 'Var', (60, 69))	('SS', 'Phenotype', 'HP:0012570', (56, 58))	('SS', 'Phenotype', 'HP:0012570', (51, 53))	('SS18', 'Gene', (51, 55))	('SSX', 'Gene', '6757', (56, 59))
625209	24975049	SS18-SSX knockdown resulted in the promotion of tube formation (a 5.7-6.2-fold increase in the presence of Bev, or a 4.3-4.7-fold increase in the presence of Pazo), whereas the promoted tube formation was inhibited by treatment with Bev (53.1-59.7%; Fig.2g, left) and Pazo (58.3-59.7%; Fig.2g, right) with SS18-SSX knockdown in Yamato-SS.	('increase', 'PosReg', (79, 87))	('SS18', 'Gene', (306, 310))	('Bev', 'Chemical', 'MESH:D000068258', (233, 236))	('SS', 'Phenotype', 'HP:0012570', (311, 313))	('promotion', 'PosReg', (35, 44))	('SS', 'Phenotype', 'HP:0012570', (335, 337))	('SSX', 'Gene', '6757', (5, 8))	('Bev', 'Chemical', 'MESH:D000068258', (107, 110))	('knockdown', 'Var', (315, 324))	('tube formation', 'CPA', (48, 62))	('SSX', 'Gene', '6757', (311, 314))	('SS', 'Phenotype', 'HP:0012570', (0, 2))	('SSX', 'Gene', (5, 8))	('SS18', 'Gene', '6760', (306, 310))	('SS18', 'Gene', (0, 4))	('SSX', 'Gene', (311, 314))	('knockdown', 'Var', (9, 18))	('SS', 'Phenotype', 'HP:0012570', (306, 308))	('SS', 'Phenotype', 'HP:0012570', (5, 7))	('Pazo', 'Chemical', 'MESH:C516667', (158, 162))	('SS18', 'Gene', '6760', (0, 4))	('Pazo', 'Chemical', 'MESH:C516667', (268, 272))
625210	24975049	Similar results were obtained in Aska-SS; SS18-SSX knockdown resulted in the promotion of tube formation (a 3.8-3.9-fold increase in the presence of Bev, or a 2.3-3.8-fold increase in the presence of Pazo).	('increase', 'PosReg', (121, 129))	('tube formation', 'CPA', (90, 104))	('Bev', 'Chemical', 'MESH:D000068258', (149, 152))	('SS18', 'Gene', '6760', (42, 46))	('SS18', 'Gene', (42, 46))	('SSX', 'Gene', (47, 50))	('SS', 'Phenotype', 'HP:0012570', (38, 40))	('SS', 'Phenotype', 'HP:0012570', (42, 44))	('SSX', 'Gene', '6757', (47, 50))	('SS', 'Phenotype', 'HP:0012570', (47, 49))	('Pazo', 'Chemical', 'MESH:C516667', (200, 204))	('promotion', 'PosReg', (77, 86))	('knockdown', 'Var', (51, 60))
625213	24975049	S3f, lower) in the presence of SS18-SSX knockdown.	('SSX', 'Gene', '6757', (36, 39))	('SSX', 'Gene', (36, 39))	('knockdown', 'Var', (40, 49))	('SS18', 'Gene', '6760', (31, 35))	('SS', 'Phenotype', 'HP:0012570', (31, 33))	('SS', 'Phenotype', 'HP:0012570', (36, 38))	('lower', 'NegReg', (5, 10))	('SS18', 'Gene', (31, 35))
625218	24975049	Tumors treated with Bev displayed a pale color, suggesting that Bev inhibited host angiogenesis (Fig.3a, right panel; Fig.	('Bev', 'Chemical', 'MESH:D000068258', (64, 67))	('Bev', 'Chemical', 'MESH:D000068258', (20, 23))	('inhibited', 'NegReg', (68, 77))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('host angiogenesis', 'CPA', (78, 95))	('Bev', 'Var', (64, 67))	('pale color', 'Phenotype', 'HP:0007513', (36, 46))
625255	24975049	In addition, proliferating cell nuclear antigen (PCNA) expression was reduced at 2-20 mug/mL aIFM (Figs5d, S10d), suggesting that aIFM inhibited cellular proliferation without inducing apoptosis.	('cellular proliferation', 'CPA', (145, 167))	('proliferating cell nuclear antigen', 'Gene', (13, 47))	('reduced', 'NegReg', (70, 77))	('proliferating cell nuclear antigen', 'Gene', '5111', (13, 47))	('aIFM', 'Var', (93, 97))	('expression', 'MPA', (55, 65))	('PCNA', 'Gene', (49, 53))	('inhibited', 'NegReg', (135, 144))	('PCNA', 'Gene', '5111', (49, 53))
625286	24975049	Therefore, we speculate that PI3K supports SS tumor growth through the VEGF and CXCL12/CXCR4 signaling axes and that VEGF signaling inhibitors and IFM show collaborative antitumor effects.	('tumor', 'Disease', (174, 179))	('SS tumor', 'Disease', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('SS tumor', 'Disease', 'MESH:D009369', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SS', 'Phenotype', 'HP:0012570', (43, 45))	('CXCL12', 'Gene', (80, 86))	('supports', 'PosReg', (34, 42))	('tumor', 'Disease', (46, 51))	('CXCR4', 'Gene', '7852', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('CXCL12', 'Gene', '6387', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PI3K', 'Var', (29, 33))	('CXCR4', 'Gene', (87, 92))
625324	33669719	Compared with effusion-only PEL, patients with extracavitary-only PEL were younger (median age, 42 vs. 52 years, p = 0.001), more likely to be HIV-positive (88.9% vs. 68.6%, p = 0.06) and EBV-positive (76.9% vs. 51.9%, p = 0.06), and less often positive for CD45 (69.2% vs. 96.2%, p = 0.01), EMA (26.7% vs. 100%, p = 0.0005), and CD30 (60% vs. 81.5%, p = 0.09).	('patients', 'Species', '9606', (33, 41))	('EMA', 'Gene', (292, 295))	('CD4', 'Gene', (258, 261))	('CD4', 'Gene', '920', (258, 261))	('PEL', 'Phenotype', 'HP:0030069', (28, 31))	('EMA', 'Gene', '4582', (292, 295))	('PEL', 'Phenotype', 'HP:0030069', (66, 69))	('CD30', 'Var', (330, 334))	('HIV', 'Species', '12721', (143, 146))
625345	33669719	Overall, the flow panels included antibodies for CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD19, CD20, CD22, CD30, CD38, CD45, CD138, kappa and lambda (surface and cytoplasmic) immunoglobulin light chains (Becton-Dickinson, Biosciences, San Jose, CA, USA).	('CD19', 'Var', (85, 89))	('kappa', 'Protein', (128, 133))	('CD138', 'Gene', (121, 126))	('CD2', 'Gene', (91, 94))	('CD2', 'Gene', '914', (91, 94))	('CD8', 'Gene', (74, 77))	('CD7', 'Gene', '924', (69, 72))	('CD4', 'Gene', '920', (59, 62))	('Biosciences', 'Disease', (218, 229))	('CD38', 'Var', (109, 113))	('CD4', 'Gene', '920', (115, 118))	('CD30', 'Var', (103, 107))	('CD4', 'Gene', (59, 62))	('CD2', 'Gene', (49, 52))	('CD7', 'Gene', (69, 72))	('CD4', 'Gene', (115, 118))	('San Jose', 'Disease', (231, 239))	('CD2', 'Gene', (97, 100))	('CD2', 'Gene', '914', (49, 52))	('CD2', 'Gene', '914', (97, 100))	('CD5', 'Gene', (64, 67))	('CD5', 'Gene', '921', (64, 67))	('CD8', 'Gene', '925', (74, 77))	('CD138', 'Gene', '6382', (121, 126))	('CD10', 'Var', (79, 83))	('lambda', 'Protein', (138, 144))
625350	33669719	The antibodies assessed were specific for CD3, CD20, CD30, CD45, CD79a, CD138, ALK-1, PAX-5, MUM-1, EMA, and HHV-8.	('CD138', 'Gene', '6382', (72, 77))	('CD2', 'Gene', '914', (47, 50))	('PAX-5', 'Gene', '5079', (86, 91))	('EMA', 'Gene', (100, 103))	('MUM-1', 'Gene', (93, 98))	('MUM-1', 'Gene', '84939', (93, 98))	('CD4', 'Gene', '920', (59, 62))	('CD138', 'Gene', (72, 77))	('PAX-5', 'Gene', (86, 91))	('CD3', 'Var', (42, 45))	('CD4', 'Gene', (59, 62))	('CD79a', 'Gene', '973', (65, 70))	('ALK-1', 'Gene', (79, 84))	('ALK-1', 'Gene', '6590', (79, 84))	('EMA', 'Gene', '4582', (100, 103))	('CD79a', 'Gene', (65, 70))	('CD30', 'Var', (53, 57))	('HHV-8', 'Species', '37296', (109, 114))	('CD2', 'Gene', (47, 50))
625378	33669719	FISH analysis was performed on five cases and showed an extra copy of MYC in 4 (80%) cases.	('extra copy', 'Var', (56, 66))	('MYC', 'Gene', '4609', (70, 73))	('MYC', 'Gene', (70, 73))
625425	33669719	In addition, a potential pitfall is that PEL can be confused with T-cell lymphoma due to frequent expression of CD30 and occasional aberrant expression of CD3 in PEL (73.3% and 21.5% of cases respectively in this study).	('cell lymphoma', 'Phenotype', 'HP:0012191', (68, 81))	('PEL', 'Phenotype', 'HP:0030069', (162, 165))	('PEL', 'Disease', (41, 44))	('CD3', 'Gene', (155, 158))	('aberrant', 'Var', (132, 140))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (66, 81))	('CD30', 'Gene', (112, 116))	('PEL', 'Phenotype', 'HP:0030069', (41, 44))	('T-cell lymphoma', 'Disease', (66, 81))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (66, 81))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))
625430	33669719	MYC rearrangement by FISH analysis might be considered as a part of the diagnostic work-up, as MYC rearrangement is most often associated with plasmablastic lymphoma and anaplastic plasmacytoma, but absent in ALK-positive large B-cell lymphoma and PEL.	('plasmablastic lymphoma', 'Disease', 'MESH:D000069293', (143, 165))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (228, 243))	('ALK', 'Gene', '238', (209, 212))	('PEL', 'Phenotype', 'HP:0030069', (248, 251))	('associated', 'Reg', (127, 137))	('rearrangement', 'Var', (99, 112))	('ALK', 'Gene', (209, 212))	('B-cell lymphoma', 'Disease', (228, 243))	('MYC', 'Gene', (95, 98))	('MYC', 'Gene', (0, 3))	('anaplastic plasmacytoma', 'Disease', (170, 193))	('plasmacytoma', 'Phenotype', 'HP:0011857', (181, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (157, 165))	('men', 'Species', '9606', (13, 16))	('plasmablastic lymphoma', 'Disease', (143, 165))	('MYC', 'Gene', '4609', (95, 98))	('anaplastic plasmacytoma', 'Disease', 'MESH:C537514', (170, 193))	('cell lymphoma', 'Phenotype', 'HP:0012191', (230, 243))	('lymphoma', 'Phenotype', 'HP:0002665', (235, 243))	('men', 'Species', '9606', (108, 111))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (228, 243))	('MYC', 'Gene', '4609', (0, 3))
625457	33238500	Here, we review various molecular pathways that are involved in colorectal carcinogenesis with driving mutations that could be targeted for precision approaches in the treatment of mCRC.	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (64, 89))	('mutations', 'Var', (103, 112))	('colorectal carcinogenesis', 'Disease', (64, 89))	('CRC', 'Phenotype', 'HP:0003003', (182, 185))
625462	33238500	These include rat sarcoma (RAS), epithelial growth factor receptor (EGFR), vascular endothelial growth factor VEGF, microsatellite instability, mismatch repair, and v-raf murine sarcoma viral oncogene homolog b1 (BRAF) with established clinical implications.	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('vascular endothelial growth factor', 'Gene', (75, 109))	('sarcoma', 'Disease', (18, 25))	('vascular endothelial growth factor', 'Gene', '7422', (75, 109))	('sarcoma', 'Disease', (178, 185))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('sarcoma', 'Disease', 'MESH:D012509', (178, 185))	('mismatch repair', 'Var', (144, 159))	('microsatellite', 'MPA', (116, 130))	('rat', 'Species', '10116', (14, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))
625463	33238500	RAS mutations and deficiencies in the mismatch repair pathway guide decisions regarding the administration of anti-EGFR-based therapies and immunotherapy, respectively.	('RAS', 'Gene', (0, 3))	('deficiencies', 'Var', (18, 30))	('mismatch repair pathway', 'Pathway', (38, 61))	('guide', 'Reg', (62, 67))	('mutations', 'Var', (4, 13))	('rat', 'Species', '10116', (100, 103))
625470	33238500	The adenoma-carcinoma sequence is a classic model detailing the progressive accumulation of genetic mutations leading from the transition of normal colonic or rectal tissue to an adenomatous polyp, with subsequent inactivation of tumor suppression genes (i.e., Adenomatous polyposis coli (APC), Tumor protein 53 (TP53)), activation of oncogenes (i.e., rat sarcoma (RAS)) and eventual development of CRC.	('inactivation', 'Var', (214, 226))	('Tumor', 'Phenotype', 'HP:0002664', (295, 300))	('adenomatous polyp', 'Disease', (179, 196))	('activation', 'PosReg', (321, 331))	('sarcoma', 'Disease', 'MESH:D012509', (356, 363))	('sarcoma', 'Disease', (356, 363))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (4, 21))	('TP53', 'Gene', (313, 317))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (179, 196))	('adenoma-carcinoma', 'Disease', (4, 21))	('Adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (261, 287))	('CRC', 'Phenotype', 'HP:0003003', (399, 402))	('colonic', 'Disease', (148, 155))	('Tumor protein 53', 'Gene', (295, 311))	('Adenomatous polyposis coli', 'Gene', (261, 287))	('sarcoma', 'Phenotype', 'HP:0100242', (356, 363))	('tumor', 'Disease', (230, 235))	('Adenomatous polyposis coli', 'Gene', '24205', (261, 287))	('Tumor protein 53', 'Gene', '24842', (295, 311))	('adenomatous polyp', 'Disease', 'MESH:D018256', (179, 196))	('colonic', 'Disease', 'MESH:D003110', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('mutations', 'Var', (100, 109))	('rat', 'Species', '10116', (352, 355))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('TP53', 'Gene', '24842', (313, 317))
625471	33238500	For instance, v-raf murine sarcoma viral oncogene homolog b1 (BRAF) mutations and microsatellite instability (MSI) have been implicated in the serrated pathway, in which serrated polyps develop activation of distinct oncogenes.	('polyps', 'Disease', 'MESH:D011127', (179, 185))	('rat', 'Species', '10116', (173, 176))	('activation', 'PosReg', (194, 204))	('rat', 'Species', '10116', (146, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('polyps', 'Disease', (179, 185))	('serrated polyps', 'Phenotype', 'HP:0032222', (170, 185))	('mutations', 'Var', (68, 77))	('BRAF', 'Gene', (62, 66))	('implicated', 'Reg', (125, 135))
625472	33238500	With advancements in our understanding of genetic alterations in CRC, the role of precision medicine is becoming more essential.	('CRC', 'Disease', (65, 68))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('rat', 'Species', '10116', (54, 57))	('genetic alterations', 'Var', (42, 61))
625479	33238500	Overexpression of epidermal growth factor receptor (EGFR) has been identified in 49-80% of CRC, and RAS mutations have been identified as a predictor of poor response to anti-EGFR mAb treatment in mCRC.	('mCRC', 'Disease', (197, 201))	('RAS', 'Gene', (100, 103))	('mutations', 'Var', (104, 113))	('CRC', 'Disease', (91, 94))	('epidermal growth factor receptor', 'Gene', (18, 50))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('epidermal growth factor receptor', 'Gene', '1956', (18, 50))	('CRC', 'Phenotype', 'HP:0003003', (198, 201))
625480	33238500	Both the National Comprehensive Cancer Network (NCCN, ) and American Society of Clinical Oncology (ASCO, ) guidelines suggest that all mCRC should be tested for extended RAS mutation in a certified laboratory and detection of specific mutations would preclude them from anti-EGFR treatment.	('Cancer', 'Disease', (32, 38))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('preclude', 'NegReg', (251, 259))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('mutation', 'Var', (174, 182))	('tested', 'Reg', (150, 156))	('extended RAS', 'Protein', (161, 173))	('Oncology', 'Phenotype', 'HP:0002664', (89, 97))	('rat', 'Species', '10116', (202, 205))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
625482	33238500	Furthermore, wt status in regard to other biomarkers, including BRAF/PIK3CA in addition to KRAS and NRAS (so called "quadruple negative tumors"), has been demonstrated to have favorable effects in regard to anti-EGFR mAb response.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('NRAS', 'Gene', '24605', (100, 104))	('rat', 'Species', '10116', (162, 165))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('PIK3CA', 'Gene', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('PIK3CA', 'Gene', '5290', (69, 75))	('KRAS', 'Var', (91, 95))	('NRAS', 'Gene', (100, 104))
625483	33238500	However, in patients with RAS wild-type (wt) tumors, the data supports anti-EGFR mAb as an effective adjunct in the treatment of mCRC as described below.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('anti-EGFR', 'Var', (71, 80))	('mCRC', 'Disease', (129, 133))
625490	33238500	showed improved PFS (PFS increased by 2.2 months with the addition of panitumumab; 10.1 months versus 7.9 months) and OS (OS increased by 5.8 months with the addition of panitumumab; 26 months compared to 20.2 months) with FOLFOX and panitumumab in comparison to FOLFOX alone after a post hoc evaluation with extending KRAS mutations.	('panitumumab', 'Chemical', 'MESH:D000077544', (170, 181))	('mutations', 'Var', (324, 333))	('FOLFOX', 'Chemical', '-', (223, 229))	('improved', 'PosReg', (7, 15))	('FOLFOX', 'Chemical', '-', (263, 269))	('panitumumab', 'Chemical', 'MESH:D000077544', (234, 245))	('panitumumab', 'Chemical', 'MESH:D000077544', (70, 81))	('PFS', 'MPA', (16, 19))	('KRAS', 'Gene', (319, 323))
625492	33238500	These findings were echoed in the phase III PRIME trial, in which patients were treated with either FOLFOX-4 or FOLFOX-4 plus panitumumab and investigators found improvements in PFS and a trend towards improvement in OS in a subset of KRAS wt patients only (median PFS 10.0 months versus 8.6 months, p = 0.01 and median OS 23.9 months versus 19.7 months, p = 0.17).	('PFS', 'MPA', (178, 181))	('improvements', 'PosReg', (162, 174))	('patients', 'Species', '9606', (243, 251))	('FOLFOX-4', 'Chemical', '-', (112, 120))	('FOLFOX-4', 'Chemical', '-', (100, 108))	('FOLFOX-4', 'Var', (112, 120))	('panitumumab', 'Chemical', 'MESH:D000077544', (126, 137))	('improvement', 'PosReg', (202, 213))	('patients', 'Species', '9606', (66, 74))
625498	33238500	Furthermore, findings of the CAPRI trial demonstrated improved progression-free survival (PFS) in RAS wt mCRC patients treated with anti-EGFR mAb by almost 2 months (PFS of 6.4 months in patients who were treated with cetuximab and FOLFOX compared to 4.5 months with FOLFOX alone).	('patients', 'Species', '9606', (187, 195))	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('progression-free survival', 'CPA', (63, 88))	('anti-EGFR', 'Var', (132, 141))	('CAPRI', 'Gene', (29, 34))	('FOLFOX', 'Chemical', '-', (267, 273))	('cetuximab', 'Chemical', 'MESH:D000068818', (218, 227))	('RAS', 'Disease', (98, 101))	('FOLFOX', 'Chemical', '-', (232, 238))	('improved', 'PosReg', (54, 62))	('patients', 'Species', '9606', (110, 118))	('rat', 'Species', '10116', (48, 51))	('CAPRI', 'Gene', '10156', (29, 34))
625499	33238500	Specifically, BRAFV600E, MET, MEK, PIK3CA, PTEN and HER2 are linked to innate EGFR resistance in mCRC.	('MET', 'Gene', '79811', (25, 28))	('BRAFV600E', 'Mutation', 'rs113488022', (14, 23))	('HER2', 'Gene', '2064', (52, 56))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))	('MET', 'Gene', (25, 28))	('PTEN', 'Gene', (43, 47))	('PIK3CA', 'Gene', (35, 41))	('PTEN', 'Gene', '5728', (43, 47))	('linked', 'Reg', (61, 67))	('MEK', 'Gene', (30, 33))	('PIK3CA', 'Gene', '5290', (35, 41))	('MEK', 'Gene', '5609', (30, 33))	('BRAFV600E', 'Var', (14, 23))	('HER2', 'Gene', (52, 56))
625503	33238500	Mounting evidence suggests that left-sided primary CRC benefits most from treatment with anti-EGFR mAb.	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('fits', 'Disease', (59, 63))	('anti-EGFR', 'Var', (89, 98))	('left-sided primary CRC', 'Disease', (32, 54))	('fits', 'Disease', 'MESH:D012640', (59, 63))
625504	33238500	In a review of the literature, Sandhu and colleagues found that mCRC patients with RAS wt left-sided lesions, in particular, have improved RR (RR ranging 66.4-72.5% with the addition of anti-EGFR mAb treatment compared to RR ranging 40.6-52.6% with chemotherapy alone), PFS (PFS ranging 9.2-12.9 months with the addition of anti-EGFR mAb treatment compared to PFS ranging 7.6-9.2 months with chemotherapy alone), and OS (OS ranging 22-30.3 months with the addition of anti-EGFR mAb treatment compared to OS ranging 18.7-23.6 months with chemotherapy alone) with anti-EGFR mAb treatment.	('rat', 'Species', '10116', (23, 26))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('patients', 'Species', '9606', (69, 77))	('anti-EGFR', 'Var', (468, 477))	('improved', 'PosReg', (130, 138))
625511	33238500	Deficiency in MMR genes (dMMR) is a known risk factor for CRC as a result of multiple successions of genetic mutations.	('result', 'Reg', (67, 73))	('CRC', 'Phenotype', 'HP:0003003', (58, 61))	('dMMR', 'Chemical', '-', (25, 29))	('CRC', 'Disease', (58, 61))	('Deficiency', 'Var', (0, 10))
625512	33238500	In this pathway, CRC develops as a result of the inactivation of DNA mismatch repair genes, including MSH2, MSH6, and MLH1, which leads to the accumulation of multiple mutations in long repetitive sequences of short DNA fragments (termed microsatellite), and subsequent microsatellite instability.	('accumulation', 'PosReg', (143, 155))	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('MSH2', 'Gene', (102, 106))	('inactivation', 'NegReg', (49, 61))	('MSH6', 'Gene', (108, 112))	('MSH2', 'Gene', '4436', (102, 106))	('MSH6', 'Gene', '2956', (108, 112))	('microsatellite instability', 'MPA', (270, 296))	('CRC', 'Disease', (17, 20))	('MLH1', 'Gene', '4292', (118, 122))	('mutations', 'Var', (168, 177))	('MLH1', 'Gene', (118, 122))
625517	33238500	demonstrated improved prognosis and lower risk of recurrence of CRC in patients with dMMR, with an 11% recurrence rate in dMMR, compared to a 26% recurrence rate in patients with no mutations or deficiencies in MMR; nonetheless, it was not predictive of chemotherapy response.	('rat', 'Species', '10116', (114, 117))	('dMMR', 'Chemical', '-', (122, 126))	('patients', 'Species', '9606', (71, 79))	('dMMR', 'Chemical', '-', (85, 89))	('CRC', 'Disease', (64, 67))	('rat', 'Species', '10116', (157, 160))	('rat', 'Species', '10116', (7, 10))	('patients', 'Species', '9606', (165, 173))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('improved', 'PosReg', (13, 21))	('dMMR', 'Var', (85, 89))
625518	33238500	Data from the NSABP C-07 trial support these conclusions and found that dMMR status had a favorable prognosis for recurrence (hazard ratio (HR) 0.48, 95% CI 0.33-0.70, p < 0.0001) and improved OS (HR 0.63, 95% CI 0.46-0.89, p = 0.0084) in CRC, although there was also demonstrable worse survival after recurrence in patients with dMMR (HR 1.60, 95% CI 1.07-2.41, p = 0.02).	('patients', 'Species', '9606', (316, 324))	('rat', 'Species', '10116', (133, 136))	('dMMR', 'Var', (72, 76))	('CRC', 'Phenotype', 'HP:0003003', (239, 242))	('CRC', 'Disease', (239, 242))	('dMMR', 'Chemical', '-', (330, 334))	('improved', 'PosReg', (184, 192))	('dMMR', 'Chemical', '-', (72, 76))
625521	33238500	Patients without MMR mutations or deficiencies had higher disease-free survival (DFS) after adjuvant treatment with FU-based adjuvant therapy in comparison to dMMR patients (HR 0.67, 95% CI 0.48-0.93, p = 0.02), and these were statistically significant findings.	('FU-based adjuvant', 'Chemical', '-', (116, 133))	('DFS', 'Disease', (81, 84))	('disease-free survival', 'CPA', (58, 79))	('deficiencies', 'Var', (34, 46))	('DFS', 'Disease', 'None', (81, 84))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (164, 172))	('higher', 'PosReg', (51, 57))	('MMR', 'Gene', (17, 20))	('dMMR', 'Chemical', '-', (159, 163))	('mutations', 'Var', (21, 30))
625523	33238500	Additionally, MMR mutations are known to affect immune checkpoint proteins PD1, PDL1, CTLA-4, LAG-3, and IDO and these have been investigated as possible immunotherapy targets.	('MMR', 'Gene', (14, 17))	('IDO', 'Gene', '3620', (105, 108))	('CTLA-4', 'Gene', (86, 92))	('LAG-3', 'Gene', (94, 99))	('IDO', 'Gene', (105, 108))	('PD1', 'Gene', '5133', (75, 78))	('PDL1', 'Gene', '29126', (80, 84))	('PD1', 'Gene', (75, 78))	('CTLA-4', 'Gene', '1493', (86, 92))	('PDL1', 'Gene', (80, 84))	('affect', 'Reg', (41, 47))	('LAG-3', 'Gene', '3902', (94, 99))	('mutations', 'Var', (18, 27))
625527	33238500	found that treatment with pembrolizumab in patients with dMMR resulted in a RR of 40% (versus 0%) and immune-related PFS of 78% (versus 11%) in comparison to those without MMR deficiency.	('dMMR', 'Chemical', '-', (57, 61))	('patients', 'Species', '9606', (43, 51))	('MMR deficiency', 'Disease', 'MESH:C536928', (172, 186))	('pembrolizumab', 'Chemical', 'MESH:C582435', (26, 39))	('dMMR', 'Var', (57, 61))	('MMR deficiency', 'Disease', (172, 186))
625545	33238500	The NSABP C-07 trial showed that BRAF mutations in CRC were also associated with dMMR, advanced age, a trend towards higher T stage, and decreased survival after recurrence (HR 2.31, 95% CI 1.83-2.95, p < 0.0001), and worse OS (HR 1.46, 95% CI 1.20-1.79, p = 0.0002).	('survival after', 'CPA', (147, 161))	('CRC', 'Gene', (51, 54))	('dMMR', 'Chemical', '-', (81, 85))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('associated', 'Reg', (65, 75))	('worse OS', 'Disease', (218, 226))	('T stage', 'CPA', (124, 131))	('dMMR', 'Disease', (81, 85))	('higher', 'PosReg', (117, 123))	('mutations', 'Var', (38, 47))	('decreased', 'NegReg', (137, 146))
625546	33238500	Similar to the NSABP C-07 results regarding MMR status and response to adjuvant therapy, BRAF mutations were not a significant predictor in response to oxaliplatin.	('BRAF', 'Gene', (89, 93))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (152, 163))	('mutations', 'Var', (94, 103))
625547	33238500	Of note, it is well established that BRAF mutations clinically translate to lack of response to anti-EGFR mAb in KRAS wt mCRC patients and the NCCN recommends BRAF testing for all patients with mCRC to assess appropriate candidates for anti-EGFR mAb treatment in this population.	('CRC', 'Phenotype', 'HP:0003003', (122, 125))	('CRC', 'Phenotype', 'HP:0003003', (195, 198))	('BRAF', 'Gene', (37, 41))	('patients', 'Species', '9606', (126, 134))	('mutations', 'Var', (42, 51))	('patients', 'Species', '9606', (180, 188))
625548	33238500	showed that anti-BRAF therapy (vemurafenib) was tolerated well when combined with panitumumab in BRAF V600E mutant mCRC patients who had disease progression on standard therapy.	('rat', 'Species', '10116', (52, 55))	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('vemurafenib', 'Chemical', 'MESH:D000077484', (31, 42))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('panitumumab', 'Chemical', 'MESH:D000077544', (82, 93))	('patients', 'Species', '9606', (120, 128))	('V600E', 'Var', (102, 107))	('BRAF', 'Gene', (97, 101))
625549	33238500	A phase 1B study by Hong and colleagues similarly showed that a combined regimen of vemurafenib, irinotecan and cetuximab was well tolerated in mCRC patients with BRAF mutations.	('BRAF', 'Gene', (163, 167))	('irinotecan', 'Chemical', 'MESH:D000077146', (97, 107))	('patients', 'Species', '9606', (149, 157))	('rat', 'Species', '10116', (135, 138))	('mCRC', 'Disease', (144, 148))	('CRC', 'Phenotype', 'HP:0003003', (145, 148))	('vemurafenib', 'Chemical', 'MESH:D000077484', (84, 95))	('cetuximab', 'Chemical', 'MESH:D000068818', (112, 121))	('mutations', 'Var', (168, 177))
625553	33238500	While the findings regarding V600E mutant mCRC have clinical implications for anti-BRAF therapy, non-V600E BRAF mutations in mCRC patients have been demonstrated to predict poor response to anti-EGFR therapy.	('V600E', 'Mutation', 'rs113488022', (29, 34))	('rat', 'Species', '10116', (156, 159))	('V600E', 'Mutation', 'rs113488022', (101, 106))	('CRC', 'Phenotype', 'HP:0003003', (126, 129))	('non-V600E', 'Var', (97, 106))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('patients', 'Species', '9606', (130, 138))	('V600E', 'Var', (29, 34))	('mCRC', 'Gene', (125, 129))
625554	33238500	Furthermore, V600E mutant CRC has been associated with older age, right-sided laterality, poorly differentiated status and advanced disease stage vs. non-V600L mutant CRC, which is associated with left-sided primary tumor location and well-differentiated histology.	('tumor', 'Disease', (216, 221))	('V600E', 'Var', (13, 18))	('CRC', 'Phenotype', 'HP:0003003', (167, 170))	('CRC', 'Disease', (26, 29))	('V600E', 'Mutation', 'rs113488022', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('V600L', 'Mutation', 'rs121913378', (154, 159))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
625565	33238500	Furthermore, genetic analysis of polymorphisms in ERCC1, XPD and GSTP1 did not show any effect on the safety or efficacy of bevacizumab in combination with standard chemotherapy for mCRC.	('ERCC1', 'Gene', '2067', (50, 55))	('bevacizumab', 'Chemical', 'MESH:D000068258', (124, 135))	('polymorphisms', 'Var', (33, 46))	('GSTP1', 'Gene', (65, 70))	('XPD', 'Gene', '2068', (57, 60))	('CRC', 'Phenotype', 'HP:0003003', (183, 186))	('GSTP1', 'Gene', '2950', (65, 70))	('ERCC1', 'Gene', (50, 55))	('XPD', 'Gene', (57, 60))
625577	33238500	The recent phase IIa MyPathway study showed a RR of 32% in refractory mCRC patients with HER2 amplification treated with dual anti-HER2 agents trastuzumab and pertuzumab.	('pertuzumab', 'Chemical', 'MESH:C485206', (159, 169))	('amplification', 'Var', (94, 107))	('trastuzumab', 'Chemical', 'MESH:D000068878', (143, 154))	('HER2', 'Gene', (131, 135))	('patients', 'Species', '9606', (75, 83))	('HER2', 'Gene', '2064', (131, 135))	('refractory mCRC', 'Disease', (59, 74))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('HER2', 'Gene', (89, 93))	('HER2', 'Gene', '2064', (89, 93))
625584	33238500	Current evidence suggests that PI3KCA mutations render anti-EGFR mAb treatment of CRC ineffective with lower response rates and is associated with worse outcomes overall.	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('response rates', 'MPA', (109, 123))	('anti-EGFR mAb', 'Gene', (55, 68))	('PI3KCA mutations', 'Var', (31, 47))	('rat', 'Species', '10116', (118, 121))	('CRC ineffective', 'Disease', (82, 97))	('lower', 'NegReg', (103, 108))
625586	33238500	demonstrated that patients with PI3KCA mutations who regularly took aspirin after CRC diagnosis had significantly longer cancer-specific survival at 5 years (HR 0.18, 95% CI 0.06-0.61, p < 0.001) and overall survival (HR 0.54, 95% CI 0.31-0.94, p = 0.01) compared to those who did not.	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('aspirin', 'Chemical', 'MESH:D001241', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (39, 48))	('overall survival', 'CPA', (200, 216))	('rat', 'Species', '10116', (7, 10))	('patients', 'Species', '9606', (18, 26))	('longer', 'PosReg', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PI3KCA', 'Gene', (32, 38))	('cancer', 'Disease', (121, 127))
625587	33238500	A phase II clinical trial was developed to investigate the use of MK-2206, a Protein kinase B (AKT)-inhibitor, in the treatment of PI3KCA mutant, KRAS wt mCRC, which had progressed on standard therapy; however, the trial was closed secondary to lack of accrual, with only one participant.	('MK-2206', 'Chemical', 'MESH:C548887', (66, 73))	('PI3KCA', 'Var', (131, 137))	('Protein kinase B', 'Gene', '2185', (77, 93))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('AKT', 'Gene', '207', (95, 98))	('participant', 'Species', '9606', (276, 287))	('AKT', 'Gene', (95, 98))	('Protein kinase B', 'Gene', (77, 93))
625588	33238500	Further evidence is required to demonstrate a survival benefit for ASA use in PI3KCA mutant tumors or PI3KCA targeted drugs.	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('rat', 'Species', '10116', (39, 42))	('ASA', 'Chemical', 'MESH:D001241', (67, 70))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mutant', 'Var', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('PI3KCA', 'Gene', (78, 84))
625597	33238500	Another phase I trial of reovirus serotype 3 has shown to be safe and well-tolerated with FOLFIRI co-treatment in KRAS mutant mCRC patients who had progression of disease on prior chemotherapy.	('patients', 'Species', '9606', (131, 139))	('CRC', 'Phenotype', 'HP:0003003', (127, 130))	('KRAS', 'Gene', (114, 118))	('rat', 'Species', '10116', (79, 82))	('FOLFIRI', 'Chemical', '-', (90, 97))	('mutant', 'Var', (119, 125))	('reovirus', 'Species', '10891', (25, 33))
625603	33238500	These strategies include genetic modifications to improve tumor-specific entry targeting and increase oncotropism, enhance viral replication and spread, detarget normal native tissue, and post-entry targeting, and arming OVs with therapeutic genes.	('increase oncotropism', 'Disease', (93, 113))	('tumor', 'Disease', (58, 63))	('rat', 'Species', '10116', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('increase oncotropism', 'Disease', 'MESH:D006973', (93, 113))	('viral replication', 'CPA', (123, 140))	('spread', 'CPA', (145, 151))	('modifications', 'Var', (33, 46))	('genetic modifications', 'Var', (25, 46))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('detarget', 'NegReg', (153, 161))	('enhance', 'PosReg', (115, 122))	('improve', 'PosReg', (50, 57))
625627	33238500	In a prospective study by van de Wetering et al., both normal and tumor tissue was extracted from CRC patients with active disease and the two organoids were compared to evaluate tumor-specific genetic mutations and identify drug sensitivities based on these mutations in a bid to better tailor therapeutic regimens.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mutations', 'Var', (259, 268))	('tumor', 'Disease', (66, 71))	('patients', 'Species', '9606', (102, 110))	('active disease', 'Disease', 'OMIM:612348', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('active disease', 'Disease', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('bid', 'Gene', (274, 277))	('tumor', 'Disease', (179, 184))	('bid', 'Gene', '637', (274, 277))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))	('mutations', 'Var', (202, 211))
625628	33238500	do note that feasibility concerns may pose an obstacle to more mainstream incorporation of organoid technology in cases of rare genetic alterations; however, they also recognize the benefits of organoids in identifying potential gene-drug interactions; examples include an association between RNF43 mutant tumors and Wnt inhibitors.	('RNF43', 'Gene', (293, 298))	('RNF43', 'Gene', '54894', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('rat', 'Species', '10116', (81, 84))	('mutant', 'Var', (299, 305))	('tumors', 'Disease', (306, 312))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('fits', 'Disease', 'MESH:D012640', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('rat', 'Species', '10116', (140, 143))	('fits', 'Disease', (186, 190))
625718	27512077	A hallmark of all herpesviruses is their biphasic life cycle:viral latency and the productive lytic cycle:and it is well established that reactivation of the KSHV lytic cycle is associated with KS pathogenesis.	('associated', 'Reg', (178, 188))	('KS', 'Phenotype', 'HP:0100726', (158, 160))	('reactivation', 'Var', (138, 150))	('herpesvirus', 'Species', '39059', (18, 29))	('KS', 'Phenotype', 'HP:0100726', (194, 196))	('KSHV', 'Species', '37296', (158, 162))
625723	27512077	We also show that small interfering RNA (siRNA) knockdown or overexpression of ARID3B led to an enhancement or inhibition of lytic reactivation, respectively.	('enhancement', 'PosReg', (96, 107))	('lytic reactivation', 'CPA', (125, 143))	('overexpression', 'PosReg', (61, 75))	('ARID3B', 'Gene', (79, 85))	('ARID3B', 'Gene', '10620', (79, 85))	('inhibition', 'NegReg', (111, 121))	('knockdown', 'Var', (48, 57))
625740	27512077	Further functional domains have also been identified, such as a leucine zipper domain that is important for homotetramer formation, a serine/threonine-rich region that is subject to phosphorylation, and a multitude of binding sites for various protein-protein interactions (PPIs).	('serine', 'Chemical', 'MESH:D012694', (134, 140))	('threonine', 'Chemical', 'MESH:D013912', (141, 150))	('protein-protein', 'Protein', (244, 259))	('leucine zipper', 'Var', (64, 78))	('binding', 'Interaction', (218, 225))
625742	27512077	Both genes are highly expressed during lytic reactivation, but their expression is prevented when DNA binding mutants of RTA are expressed.	('RTA', 'Gene', (121, 124))	('RTA', 'Gene', '23543', (121, 124))	('mutants', 'Var', (110, 117))
625745	27512077	There are several lytic genes that are activated via the indirect mechanism, including the RTA gene itself (ORF50), ORF57 (Mta), ORF6, ORF74 (vGCPR), K6 (vMIP-1), and ORF73 (LANA).	('RTA', 'Gene', (91, 94))	('ORF50', 'Gene', (108, 113))	('ORF57', 'Gene', (116, 121))	('ORF74', 'Var', (135, 140))	('LANA', 'Gene', (174, 178))	('lytic genes', 'Gene', (18, 29))	('ORF6', 'Gene', (129, 133))	('RTA', 'Gene', '23543', (91, 94))	('LANA', 'Gene', '4961527', (174, 178))	('ORF73', 'Var', (167, 172))	('ORF57', 'Gene', '4961525', (116, 121))	('ORF50', 'Gene', '4961526', (108, 113))
625755	27512077	Clearly, silencing of KSHV lytic gene expression, or inhibition of lytic DNA replication, is an important step in the life cycle of KSHV.	('inhibition', 'NegReg', (53, 63))	('silencing', 'Var', (9, 18))	('expression', 'MPA', (38, 48))	('KSHV', 'Species', '37296', (132, 136))	('KSHV lytic gene', 'Gene', (22, 37))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('lytic DNA replication', 'CPA', (67, 88))	('KS', 'Phenotype', 'HP:0100726', (22, 24))	('KSHV', 'Species', '37296', (22, 26))
625793	27512077	Other parameters used were (i) variable modifications, methionine oxidation, protein N-acetylation, and Gln to pyro-Glu; (ii) fixed modifications, cysteine carbamidomethylation; (iii) database, target-decoy human MaxQuant (ipi.HUMAN.v3.68); (iv) heavy labels, R10K8; (v) MS/MS tolerance, Fourier transform mass spectroscopy (FTMS), 10 ppm; ion trap mass spectroscopy (ITMS), 0.6 Da; (vi) maximum peptide length, 6; (vii) maximum missed cleavages, 2; (viii) maximum of labeled amino acids, 3; and (ix) false discovery rate (FDR), 1%.	('Gln', 'Chemical', 'MESH:D005973', (104, 107))	('pyro-Glu', 'Chemical', 'MESH:D011761', (111, 119))	('missed', 'NegReg', (429, 435))	('R10K8', 'Var', (260, 265))	('human', 'Species', '9606', (207, 212))	('methionine', 'Chemical', 'MESH:D008715', (55, 65))	('HUMAN', 'Species', '9606', (227, 232))	('cysteine', 'Chemical', 'MESH:D003545', (147, 155))
625816	27512077	Conditions for small interfering RNA (siRNA) knockdown of ARID3B followed previously reported protocols.	('ARID3B', 'Gene', (58, 64))	('ARID3B', 'Gene', '10620', (58, 64))	('knockdown', 'Var', (45, 54))
625831	27512077	After metabolically labeling cells in media containing different stable isotopes of arginine (R) and lysine (K) (e.g., R10K8 [heavy] or R0K0 [light]) for 2 weeks, we induced RTA expression from heavy-labeled cells for 12 h while leaving light-labeled cells untreated.	('induced', 'Reg', (166, 173))	('RTA', 'Gene', '23543', (174, 177))	('expression', 'MPA', (178, 188))	('RTA', 'Gene', (174, 177))	('lysine', 'Chemical', 'MESH:D008239', (101, 107))	('R0K0', 'Var', (136, 140))	('R10K8', 'Var', (119, 124))	('arginine', 'Chemical', 'MESH:D001120', (84, 92))
625848	27512077	To investigate how RTA expression might lead to an increase in ARID3B levels, we induced RTA expression in iRTA-293 cells in addition to reactivating the lytic cycle in TREx-BCBL-1-RTA cells (see Materials and Methods for a description of the cell lines used in this study).	('increase', 'PosReg', (51, 59))	('reactivating', 'MPA', (137, 149))	('293 cells', 'CellLine', 'CVCL:0045', (112, 121))	('RTA-293', 'CellLine', 'CVCL:0045', (108, 115))	('RTA', 'Gene', (19, 22))	('RTA', 'Gene', (89, 92))	('RTA', 'Gene', '23543', (181, 184))	('TREx', 'Chemical', '-', (169, 173))	('RTA', 'Gene', '23543', (89, 92))	('expression', 'Var', (23, 33))	('RTA', 'Gene', (181, 184))	('ARID3B', 'Gene', (63, 69))	('ARID3B', 'Gene', '10620', (63, 69))	('RTA', 'Gene', '23543', (108, 111))	('RTA', 'Gene', (108, 111))	('RTA', 'Gene', '23543', (19, 22))	('lead', 'Reg', (40, 44))	('lytic cycle', 'MPA', (154, 165))
625867	27512077	ARID3B knockdown was also associated with an approximately 2-fold increase in lytic protein expression (Fig.	('increase', 'PosReg', (66, 74))	('ARID3B', 'Gene', (0, 6))	('ARID3B', 'Gene', '10620', (0, 6))	('knockdown', 'Var', (7, 16))	('lytic', 'MPA', (78, 83))
625868	27512077	Accordingly, ARID3B knockdown, followed by reactivation of the lytic cycle, also led to a significant enhancement of KSHV genome replication compared to cells transfected with a scramble control siRNA (Fig.	('KS', 'Phenotype', 'HP:0100726', (117, 119))	('KSHV', 'Species', '37296', (117, 121))	('ARID3B', 'Gene', (13, 19))	('ARID3B', 'Gene', '10620', (13, 19))	('KSHV', 'Gene', (117, 121))	('enhancement', 'PosReg', (102, 113))	('knockdown', 'Var', (20, 29))
625872	27512077	Using RT-qPCR analysis of the KSHV ORF57 gene as a measure of virus infection, we demonstrated that knockdown of ARID3B led to an enhancement of virus infection, suggesting that ARID3B knockdown led to an increase of released virions (Fig.	('virus infection', 'Disease', (145, 160))	('KSHV', 'Species', '37296', (30, 34))	('ARID3B', 'Gene', (113, 119))	('knockdown', 'Var', (100, 109))	('ARID3B', 'Gene', '10620', (113, 119))	('virus infection', 'Disease', 'MESH:D015658', (62, 77))	('increase', 'PosReg', (205, 213))	('released virions', 'MPA', (217, 233))	('ARID3B', 'Gene', (178, 184))	('virus infection', 'Disease', 'MESH:D015658', (145, 160))	('ARID3B', 'Gene', '10620', (178, 184))	('ORF57', 'Gene', '4961525', (35, 40))	('enhancement', 'PosReg', (130, 141))	('virus infection', 'Disease', (62, 77))	('ORF57', 'Gene', (35, 40))	('KS', 'Phenotype', 'HP:0100726', (30, 32))
625873	27512077	Together, these data showed that ARID3B knockdown enhanced the KSHV lytic cycle, contrary to our initial hypothesis.	('KSHV', 'Species', '37296', (63, 67))	('KS', 'Phenotype', 'HP:0100726', (63, 65))	('knockdown', 'Var', (40, 49))	('enhanced', 'PosReg', (50, 58))	('ARID3B', 'Gene', '10620', (33, 39))	('KSHV lytic cycle', 'CPA', (63, 79))	('ARID3B', 'Gene', (33, 39))
625910	27512077	This included siRNA-mediated knockdown of ARID3B, which resulted in enhanced lytic gene expression and lytic protein expression and an increase in genome replication.	('enhanced', 'PosReg', (68, 76))	('genome replication', 'CPA', (147, 165))	('lytic', 'CPA', (103, 108))	('knockdown', 'Var', (29, 38))	('increase', 'PosReg', (135, 143))	('expression', 'MPA', (117, 127))	('ARID3B', 'Gene', (42, 48))	('ARID3B', 'Gene', '10620', (42, 48))	('lytic gene', 'Gene', (77, 87))
625911	27512077	Furthermore, knockdown of ARID3B potentially led to an increase in virion production, as suggested by reinfection assays.	('virion production', 'MPA', (67, 84))	('ARID3B', 'Gene', (26, 32))	('increase', 'PosReg', (55, 63))	('ARID3B', 'Gene', '10620', (26, 32))	('knockdown', 'Var', (13, 22))
625913	27512077	Importantly, knockdown of ARID3B in latently infected cells did not reactivate the lytic cycle, suggesting that it was not involved in the maintenance of latency.	('ARID3B', 'Gene', (26, 32))	('knockdown', 'Var', (13, 22))	('ARID3B', 'Gene', '10620', (26, 32))	('lytic cycle', 'CPA', (83, 94))
625915	27512077	KSHV reactivation leads to the upregulation of several negative feedback processes that temper the lytic cycle, many of which center on abrogating RTA's interaction with RBP-Jkappa (required for transactivating various lytic gene promoters via the "indirect" mechanism).	('KSHV', 'Species', '37296', (0, 4))	('negative feedback processes', 'MPA', (55, 82))	('RTA', 'Gene', '23543', (147, 150))	('KS', 'Phenotype', 'HP:0100726', (0, 2))	('abrogating', 'NegReg', (136, 146))	('reactivation', 'Var', (5, 17))	('interaction', 'Interaction', (153, 164))	('KSHV', 'Gene', (0, 4))	('RTA', 'Gene', (147, 150))	('RBP-Jkappa', 'Gene', '3516', (170, 180))	('RBP-Jkappa', 'Gene', (170, 180))	('upregulation', 'PosReg', (31, 43))
625922	27512077	Here, two possibilities exist: (i) RTA expression may promote a cellular response that is linked to ARID3B expression or (ii) RTA may sequester a repressor that would normally silence ARID3B.	('promote', 'PosReg', (54, 61))	('RTA', 'Gene', '23543', (126, 129))	('expression', 'Var', (39, 49))	('RTA', 'Gene', '23543', (35, 38))	('sequester', 'NegReg', (134, 143))	('RTA', 'Gene', (126, 129))	('ARID3B', 'Gene', (184, 190))	('ARID3B', 'Gene', (100, 106))	('RTA', 'Gene', (35, 38))	('ARID3B', 'Gene', '10620', (100, 106))	('cellular response', 'CPA', (64, 81))	('ARID3B', 'Gene', '10620', (184, 190))
625936	27512077	This was an important question as much of our data suggested that ARID3B's inhibitory properties were associated with RTA expression, which is silenced during latency; for example, and as mentioned above, knockdown of ARID3B from latently infected cells did not appear to stimulate lytic gene expression (suggesting that it does not have a role in the maintenance of latency).	('ARID3B', 'Gene', (218, 224))	('lytic', 'MPA', (282, 287))	('knockdown', 'Var', (205, 214))	('ARID3B', 'Gene', (66, 72))	('stimulate', 'PosReg', (272, 281))	('ARID3B', 'Gene', '10620', (66, 72))	('RTA', 'Gene', '23543', (118, 121))	('ARID3B', 'Gene', '10620', (218, 224))	('RTA', 'Gene', (118, 121))
625947	26752546	About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4 related fusions, while another small subset shows BCOR-CCNB3 X-chromosomal paracentric inversion.	('BCOR', 'Gene', (121, 125))	('CCNB3', 'Gene', '85417', (126, 131))	('EWSR1', 'Gene', '2130', (20, 25))	('BCOR', 'Gene', '54880', (121, 125))	('DUX4', 'Gene', (66, 70))	('DUX4', 'Gene', '100288687', (66, 70))	('SBRCTs', 'Disease', (35, 41))	('CIC', 'Gene', '23152', (62, 65))	('CCNB3', 'Gene', (126, 131))	('associated', 'Reg', (46, 56))	('EWSR1', 'Gene', (20, 25))	('fusions', 'Var', (79, 86))	('CIC', 'Gene', (62, 65))
625948	26752546	Applying paired-end RNA sequencing to an SBRCT index case of a 44 year-old male, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by RT-PCR and FISH techniques.	('BCOR', 'Gene', '54880', (103, 107))	('chimeric fusion', 'Var', (114, 129))	('MAML3', 'Gene', '55534', (108, 113))	('MAML3', 'Gene', (108, 113))	('BCOR', 'Gene', (103, 107))
625949	26752546	We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC and BCOR-CCNB3 abnormalities, for BCOR break-apart probes by FISH to detect potential recurrent BCOR gene rearrangements, outside the typical X-chromosomal inversion.	('CIC', 'Gene', (63, 66))	('BCOR', 'Gene', (101, 105))	('BCOR', 'Gene', (163, 167))	('SYT', 'Gene', '6760', (58, 61))	('EWSR1', 'Gene', (46, 51))	('CCNB3', 'Gene', (76, 81))	('EWSR1', 'Gene', '2130', (46, 51))	('FUS', 'Gene', (53, 56))	('BCOR', 'Gene', '54880', (101, 105))	('BCOR', 'Gene', '54880', (163, 167))	('BCOR', 'Gene', (71, 75))	('rearrangements', 'Var', (173, 187))	('FUS', 'Gene', '2521', (53, 56))	('SYT', 'Gene', (58, 61))	('CIC', 'Gene', '23152', (63, 66))	('BCOR', 'Gene', '54880', (71, 75))	('CCNB3', 'Gene', '85417', (76, 81))
625950	26752546	Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, while no fusion partner was detected in the remaining 4 cases.	('ZC3H7B', 'Gene', (133, 139))	('BCOR', 'Gene', '54880', (140, 144))	('BCOR', 'Gene', '54880', (103, 107))	('BCOR', 'Gene', '54880', (42, 46))	('rearrangements', 'Var', (52, 66))	('ZC3H7B', 'Gene', '23264', (133, 139))	('MAML3', 'Gene', '55534', (108, 113))	('MAML3', 'Gene', (108, 113))	('BCOR', 'Gene', (140, 144))	('BCOR', 'Gene', (103, 107))	('BCOR', 'Gene', (42, 46))
625952	26752546	The clinicopathologic features of the SRBCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion positive cases, combining 11 from our files with a meta-analysis of 42 published cases.	('BCOR', 'Gene', (117, 121))	('CCNB3', 'Gene', '85417', (122, 127))	('BCOR', 'Gene', '54880', (117, 121))	('BCOR', 'Gene', '54880', (62, 66))	('CCNB3', 'Gene', (122, 127))	('rearrangements', 'Var', (67, 81))	('BCOR', 'Gene', (62, 66))
625956	26752546	Ewing sarcoma (ES) is the prototypical SBRCT molecularly characterized by canonical fusions between EWSR1 and a gene of the ETS family of transcription factors.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', (100, 105))	('fusions', 'Var', (84, 91))	('Ewing sarcoma', 'Disease', (0, 13))	('EWSR1', 'Gene', '2130', (100, 105))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('ES', 'Phenotype', 'HP:0012254', (15, 17))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (0, 13))
625957	26752546	The molecular landscape of SBRCTs with Ewing-like morphology has been further expanded by the discovery of fusions of EWSR1 with alternative non-ETS partners, with EWSR1-NFATc2 fusion being one of the more common events in this class, being associated with amplification of the fusion transcript.	('fusions', 'Var', (107, 114))	('EWSR1', 'Gene', '2130', (164, 169))	('EWSR1', 'Gene', (118, 123))	('amplification', 'MPA', (257, 270))	('NFATc2', 'Gene', (170, 176))	('EWSR1', 'Gene', '2130', (118, 123))	('EWSR1', 'Gene', (164, 169))	('NFATc2', 'Gene', '4773', (170, 176))
625958	26752546	Another subset of SBRCTs sometimes referred to as 'ES-like' or 'atypical ES' are sarcomas with CIC-DUX4 fusion resulting from either a t(4;19)(q35;q13) or a t(10;19)(q26;q13).	('DUX4', 'Gene', (99, 103))	('t(10;19)(q26;q13', 'Var', (157, 173))	('ES', 'Phenotype', 'HP:0012254', (51, 53))	('sarcomas', 'Disease', (81, 89))	('CIC', 'Gene', '23152', (95, 98))	('DUX4', 'Gene', '100288687', (99, 103))	('ES', 'Phenotype', 'HP:0012254', (73, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('t(10;19)(q26;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (157, 174))	('CIC', 'Gene', (95, 98))	('SBRCTs', 'Disease', (18, 24))	('resulting from', 'Reg', (111, 125))	('t(4;19)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (135, 151))	('t(4;19)(q35;q13', 'Var', (135, 150))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
625962	26752546	More recently, Pierron et al identified a fusion between BCOR (encoding the BCL6 transcriptional co-repressor) and CCNB3 (encoding the testis-specific cyclin B3) in SBRCTs with ES-like morphology, resulting from an X-chromosomal paracentric inversion, which links the BCOR coding sequence to the CCNB3 exon 5.	('BCL6 transcriptional co-repressor', 'Gene', '54880', (76, 109))	('CCNB3', 'Gene', (115, 120))	('CCNB3', 'Gene', (296, 301))	('BCL6 transcriptional co-repressor', 'Gene', (76, 109))	('fusion', 'Var', (42, 48))	('BCOR', 'Gene', '54880', (268, 272))	('ES', 'Phenotype', 'HP:0012254', (177, 179))	('BCOR', 'Gene', (57, 61))	('CCNB3', 'Gene', '85417', (296, 301))	('CCNB3', 'Gene', '85417', (115, 120))	('BCOR', 'Gene', '54880', (57, 61))	('BCOR', 'Gene', (268, 272))
625967	26752546	Subsequently validated abnormalities were then screened in a large cohort of primitive unclassified SBRCTs negative for EWSR1/FUS/SYT/CIC-related fusions.	('EWSR1', 'Gene', '2130', (120, 125))	('fusions', 'Var', (146, 153))	('SYT', 'Gene', '6760', (130, 133))	('CIC', 'Gene', '23152', (134, 137))	('SYT', 'Gene', (130, 133))	('FUS', 'Gene', (126, 129))	('EWSR1', 'Gene', (120, 125))	('FUS', 'Gene', '2521', (126, 129))	('CIC', 'Gene', (134, 137))
625990	26752546	Among the 75 SBRCTs negative for all known fusions, such as EWSR1, FUS, SYT, CIC and the BCOR-CCNB3 inversion, a total of 8 (11%) tumors showed other BCOR gene rearrangements using the BCOR break-apart FISH assay (Table 1).	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('EWSR1', 'Gene', '2130', (60, 65))	('FUS', 'Gene', '2521', (67, 70))	('BCOR', 'Gene', '54880', (185, 189))	('CIC', 'Gene', (77, 80))	('BCOR', 'Gene', (185, 189))	('rearrangements', 'Var', (160, 174))	('BCOR', 'Gene', '54880', (89, 93))	('CCNB3', 'Gene', (94, 99))	('EWSR1', 'Gene', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('BCOR', 'Gene', (89, 93))	('BCOR', 'Gene', '54880', (150, 154))	('SYT', 'Gene', (72, 75))	('CIC', 'Gene', '23152', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('BCOR', 'Gene', (150, 154))	('tumors', 'Disease', (130, 136))	('FUS', 'Gene', (67, 70))	('showed', 'Reg', (137, 143))	('SYT', 'Gene', '6760', (72, 75))	('CCNB3', 'Gene', '85417', (94, 99))
625991	26752546	The subsequent FISH screening for potential partners identified BCOR-MAML3 fusion in an additional case, while the remaining 6 cases showed no abnormalities in MAML3.	('MAML3', 'Gene', (160, 165))	('fusion', 'Var', (75, 81))	('MAML3', 'Gene', '55534', (69, 74))	('BCOR', 'Gene', (64, 68))	('MAML3', 'Gene', (69, 74))	('BCOR', 'Gene', '54880', (64, 68))	('MAML3', 'Gene', '55534', (160, 165))
625992	26752546	Upon review of the literature for additional BCOR gene partners we identified ZC3H7B as a potential candidate, having been described in BCOR-ZC3H7B fusions in other sarcomas .	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('fusions', 'Var', (148, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('ZC3H7B', 'Gene', (78, 84))	('BCOR', 'Gene', '54880', (45, 49))	('ZC3H7B', 'Gene', '23264', (78, 84))	('sarcomas', 'Disease', (165, 173))	('ZC3H7B', 'Gene', (141, 147))	('BCOR', 'Gene', (136, 140))	('BCOR', 'Gene', (45, 49))	('BCOR', 'Gene', '54880', (136, 140))	('ZC3H7B', 'Gene', '23264', (141, 147))	('sarcomas', 'Disease', 'MESH:D012509', (165, 173))
625993	26752546	Thus we screened the remaining 6 BCOR-rearranged cases for ZC3H7B gene break-apart by FISH and found 2 positive cases.	('BCOR', 'Gene', (33, 37))	('ZC3H7B', 'Gene', (59, 65))	('break-apart', 'Var', (71, 82))	('BCOR', 'Gene', '54880', (33, 37))	('ZC3H7B', 'Gene', '23264', (59, 65))
625994	26752546	One of the cases showed an unbalanced ZC3H7B break-apart with deletion of the telomeric signal (SBRCT4, Supplementary Fig.	('deletion', 'Var', (62, 70))	('ZC3H7B', 'Gene', '23264', (38, 44))	('SBRCT4', 'Gene', (96, 102))	('ZC3H7B', 'Gene', (38, 44))
626021	26752546	The BCOR gene, located at Xp11.4, encodes a ubiquitously expressed transcriptional repressor that associates with the BCL6 oncoprotein and with a variety of histone modifying enzymes, resulting in direct gene silencing by a unique combination of epigenetic modifications  BCOR has a key role in the regulation of early development, hematopoiesis and mesenchymal stem cell function.	('BCOR', 'Gene', (272, 276))	('BCL6', 'Gene', '604', (118, 122))	('BCOR', 'Gene', '54880', (4, 8))	('BCOR', 'Gene', '54880', (272, 276))	('early development', 'CPA', (313, 330))	('hematopoiesis', 'Disease', 'MESH:C536227', (332, 345))	('gene', 'MPA', (204, 208))	('BCL6', 'Gene', (118, 122))	('BCOR', 'Gene', (4, 8))	('mesenchymal stem cell function', 'CPA', (350, 380))	('hematopoiesis', 'Disease', (332, 345))	('epigenetic modifications', 'Var', (246, 270))
626022	26752546	In human diseases, BCOR is targeted by both mutations and translocations: somatic BCOR mutations are implicated in a subset of acute myeloid leukemia, while germline BCOR mutations cause the oculo-facio-cardio-dental (OFCD) X-linked syndrome, characterized by microphthalmia, congenital cataracts, dysmorphic appearance, radiculomegaly and cardiac and digital defects.	('human', 'Species', '9606', (3, 8))	('oculo-facio-cardio-dental', 'Disease', (191, 216))	('congenital cataracts', 'Disease', (276, 296))	('BCOR', 'Gene', (19, 23))	('acute myeloid leukemia', 'Disease', (127, 149))	('BCOR', 'Gene', (82, 86))	('microphthalmia', 'Disease', (260, 274))	('mutations', 'Var', (87, 96))	('radiculomegaly', 'Disease', (321, 335))	('cataracts', 'Phenotype', 'HP:0000518', (287, 296))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (133, 149))	('cause', 'Reg', (181, 186))	('radiculomegaly', 'Disease', 'MESH:C537465', (321, 335))	('dysmorphic', 'Disease', 'None', (298, 308))	('BCOR', 'Gene', '54880', (166, 170))	('microphthalmia', 'Phenotype', 'HP:0000568', (260, 274))	('congenital cataracts', 'Disease', 'MESH:D002386', (276, 296))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	('X-linked syndrome', 'Disease', 'MESH:C564486', (224, 241))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (127, 149))	('congenital cataracts', 'Phenotype', 'HP:0000519', (276, 296))	('BCOR', 'Gene', (166, 170))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (127, 149))	('cardiac', 'Disease', (340, 347))	('mutations', 'Var', (171, 180))	('dysmorphic', 'Disease', (298, 308))	('X-linked syndrome', 'Disease', (224, 241))	('BCOR', 'Gene', '54880', (19, 23))	('microphthalmia', 'Disease', 'MESH:D008850', (260, 274))	('dysmorphic appearance', 'Phenotype', 'HP:0001999', (298, 319))	('BCOR', 'Gene', '54880', (82, 86))
626032	26752546	The prior reported evidence of ZC3H7B-BCOR fusion in either endometrial stromal sarcoma or OFMT obtained from RNA sequencing  points to the 3'position of BCOR, based on both unbalanced FISH pattern and predominance of the ZC3H7B-BCOR isoform detected by RT-PCR in a subset of these cases.	('BCOR', 'Gene', '54880', (154, 158))	('BCOR', 'Gene', '54880', (38, 42))	('ZC3H7B', 'Gene', '23264', (222, 228))	('ZC3H7B', 'Gene', (31, 37))	('BCOR', 'Gene', (229, 233))	('endometrial stromal sarcoma', 'Disease', 'MESH:D018203', (60, 87))	('BCOR', 'Gene', '54880', (229, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('ZC3H7B', 'Gene', '23264', (31, 37))	('BCOR', 'Gene', (154, 158))	('BCOR', 'Gene', (38, 42))	('ZC3H7B', 'Gene', (222, 228))	('fusion', 'Var', (43, 49))	('endometrial stromal sarcoma', 'Disease', (60, 87))
626039	26752546	Altogether, 8/75 (11%) of our cohort of SBRCTs were positive for a BCOR rearrangement using the BCOR break-apart FISH assay.	('BCOR', 'Gene', '54880', (96, 100))	('rearrangement', 'Var', (72, 85))	('positive', 'Reg', (52, 60))	('BCOR', 'Gene', (67, 71))	('BCOR', 'Gene', '54880', (67, 71))	('BCOR', 'Gene', (96, 100))
626048	26752546	RT-PCR techniques for detection of BCOR-CCNB3 fusions or CCNB3 immunohistochemistry are excellent and reproducible tools for diagnosis of these tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('CCNB3', 'Gene', '85417', (57, 62))	('BCOR', 'Gene', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('CCNB3', 'Gene', '85417', (40, 45))	('fusions', 'Var', (46, 53))	('BCOR', 'Gene', '54880', (35, 39))	('CCNB3', 'Gene', (57, 62))	('CCNB3', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
626050	26752546	In summary, we identify recurrent BCOR gene rearrangements in 11% of SBRCTs lacking other genetic abnormalities.	('BCOR', 'Gene', '54880', (34, 38))	('genetic abnormalities', 'Disease', (90, 111))	('genetic abnormalities', 'Disease', 'MESH:D030342', (90, 111))	('SBRCTs', 'Disease', (69, 75))	('BCOR', 'Gene', (34, 38))	('rearrangements', 'Var', (44, 58))
626053	26752546	Tumors harboring BCOR gene rearrangement occur preferentially in young adults and have a wide anatomic distribution.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('rearrangement', 'Var', (27, 40))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BCOR', 'Gene', (17, 21))	('BCOR', 'Gene', '54880', (17, 21))
626066	25994353	In the absence of adjuvant radiation therapy, microscopic disease left at the surgical site causes local recurrence in up to 31% of sarcoma patients .	('sarcoma', 'Disease', (132, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('patients', 'Species', '9606', (140, 148))	('microscopic disease', 'Var', (46, 65))	('local recurrence', 'CPA', (99, 115))	('sarcoma', 'Disease', 'MESH:D012509', (132, 139))
626070	25994353	This study was carried out using genetically engineered mice with conditional mutations in p53 and either K-ras or B-raf after they developed primary sarcomas .	('B-raf', 'Gene', '109880', (115, 120))	('sarcomas', 'Disease', (150, 158))	('mutations', 'Var', (78, 87))	('p53', 'Gene', (91, 94))	('mice', 'Species', '10090', (56, 60))	('K-ras', 'Gene', '16653', (106, 111))	('sarcomas', 'Disease', 'MESH:D012509', (150, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('K-ras', 'Gene', (106, 111))	('B-raf', 'Gene', (115, 120))	('sarcomas', 'Phenotype', 'HP:0100242', (150, 158))	('p53', 'Gene', '22060', (91, 94))
626078	25994353	Briefly, mice with conditional mutations in p53 and either oncogenic K-ras or B-raf  were injected with an adenovirus expressing Cre-recombinase, and palpable tumors could be detected approximately 30-60 days later.	('p53', 'Gene', '22060', (44, 47))	('mutations', 'Var', (31, 40))	('B-raf', 'Gene', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('B-raf', 'Gene', '109880', (78, 83))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('p53', 'Gene', (44, 47))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('mice', 'Species', '10090', (9, 13))	('K-ras', 'Gene', (69, 74))	('K-ras', 'Gene', '16653', (69, 74))
626105	25994353	Diseased features typically include increased nuclear density with aneuploidy and pleomorphism (the variation in size and shape of nuclei) .	('pleomorphism', 'Var', (82, 94))	('aneuploidy', 'Disease', (67, 77))	('increased', 'PosReg', (36, 45))	('nuclear', 'MPA', (46, 53))	('aneuploidy', 'Disease', 'MESH:D000782', (67, 77))
626111	25994353	Furthermore, a threshold of '7 mum' was chosen because approximately 75% of APFs were captured in the less than 7 mum (green) group within the tumor and T+M samples.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('less than 7 mum', 'Var', (102, 117))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
626138	25994353	This increased performance may correlate with the tumor volume left behind - specifically for LR+/Path+ margins, there may be a large amount of tumor present on the excised margin as well as in the in vivo tumor cavity.	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('LR+/Path+', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('increased', 'PosReg', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('performance', 'MPA', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', (50, 55))
626179	21234386	Survival is only 10% in tumor samples that express CXCR4 mRNA, compared to 90% survival in tumor samples that do not express CXCR4 mRNA.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CXCR4 mRNA', 'Var', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (91, 96))
626182	21234386	Osteosarcoma cells expressing CXCR4 migrate towards a CXCL12 gradient.	('CXCL12', 'Gene', (54, 60))	('Osteosarcoma', 'Disease', (0, 12))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('CXCL12', 'Gene', '6387', (54, 60))	('CXCR4', 'Var', (30, 35))
626186	21234386	The T134 peptide, a CXCR4 inhibitor, was found to prevent the development of lung metastasis after the injection of osteosarcoma cells in a mouse model.	('mouse', 'Species', '10090', (140, 145))	('prevent', 'NegReg', (50, 57))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('T134', 'Var', (4, 8))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('lung metastasis', 'Disease', (77, 92))	('lung metastasis', 'Disease', 'MESH:D009362', (77, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('osteosarcoma', 'Disease', (116, 128))
626187	21234386	In another study, administration of CTCE-9908, also a CXCR4 inhibitor, resulted in a 50% decrease in the number of metastases in mice injected with osteosarcoma cells.	('metastases', 'Disease', (115, 125))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('CTCE-9908', 'Var', (36, 45))	('decrease', 'NegReg', (89, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('osteosarcoma', 'Disease', (148, 160))	('CTCE-9908', 'Chemical', 'MESH:C540323', (36, 45))	('osteosarcoma', 'Phenotype', 'HP:0002669', (148, 160))	('osteosarcoma', 'Disease', 'MESH:D012516', (148, 160))	('mice', 'Species', '10090', (129, 133))
626210	21234386	The CXCR4 inhibitors T134 peptide and CTCE-9908 have both been shown to decrease or prevent the development the osteosarcoma metastases in mice.	('osteosarcoma', 'Phenotype', 'HP:0002669', (112, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('osteosarcoma metastases', 'Disease', (112, 135))	('CTCE-9908', 'Gene', (38, 47))	('mice', 'Species', '10090', (139, 143))	('CTCE-9908', 'Chemical', 'MESH:C540323', (38, 47))	('osteosarcoma metastases', 'Disease', 'MESH:D009362', (112, 135))	('prevent', 'NegReg', (84, 91))	('T134 peptide', 'Var', (21, 33))
626246	33466151	After injection of GD DTPA, the solid part of the mass was enhanced unevenly, and the necrotic cystic area was not obviously enhanced (Fig.	('necrotic cystic', 'Disease', (86, 101))	('necrotic cystic', 'Disease', 'MESH:C536230', (86, 101))	('enhanced', 'PosReg', (59, 67))	('GD DTPA', 'Var', (19, 26))	('solid', 'MPA', (32, 37))	('GD DTPA', 'Chemical', 'MESH:D019786', (19, 26))
626448	32722580	It was shown that inhibition of VEGFR and EGFR signaling pathways is an effective strategy in particular STS subtypes, and it also enhances the effect of RT in STS.	('VEGFR', 'Gene', (32, 37))	('a', 'Gene', '351', (15, 16))	('a', 'Gene', '351', (102, 103))	('a', 'Gene', '351', (95, 96))	('a', 'Gene', '351', (134, 135))	('a', 'Gene', '351', (119, 120))	('a', 'Gene', '351', (126, 127))	('a', 'Gene', '351', (38, 39))	('VEGFR', 'Gene', '7422', (32, 37))	('a', 'Gene', '351', (62, 63))	('EGFR', 'Gene', (42, 46))	('inhibition', 'Var', (18, 28))	('EGFR', 'Gene', (33, 37))	('a', 'Gene', '351', (85, 86))	('a', 'Gene', '351', (4, 5))	('STS', 'Phenotype', 'HP:0030448', (105, 108))	('a', 'Gene', '351', (69, 70))	('EGFR', 'Gene', '1956', (42, 46))	('a', 'Gene', '351', (58, 59))	('STS', 'Phenotype', 'HP:0030448', (160, 163))	('EGFR', 'Gene', '1956', (33, 37))	('a', 'Gene', '351', (51, 52))
626491	32722580	In the HT+EIA arm, the treatment response rate was significantly higher (28.8%) than in the EIA alone arm (12.7%, p = 0.002).	('a', 'Gene', '351', (59, 60))	('a', 'Gene', '351', (14, 15))	('a', 'Gene', '351', (48, 49))	('a', 'Gene', '351', (96, 97))	('HT+EIA', 'Var', (7, 13))	('EIA', 'Chemical', '-', (10, 13))	('a', 'Gene', '351', (102, 103))	('HT', 'Phenotype', 'HP:0001945', (7, 9))	('a', 'Gene', '351', (43, 44))	('a', 'Gene', '351', (82, 83))	('higher', 'PosReg', (65, 71))	('a', 'Gene', '351', (26, 27))	('EIA', 'Chemical', '-', (92, 95))
626536	32722580	A: no stainable tumor cells; B: single stainable tumor cells or small clusters (overall below 1% of the whole specimen); C: >=1%-<10% stainable tumor cells; D: >=10%-<50% stainable tumor cells; E: >=50% stainable tumor cells.	('a', 'Gene', '351', (41, 42))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('a', 'Gene', '351', (8, 9))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('a', 'Gene', '351', (84, 85))	('a', 'Gene', '351', (173, 174))	('a', 'Gene', '351', (205, 206))	('A', 'Gene', '351', (0, 1))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (49, 54))	('a', 'Gene', '351', (139, 140))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (16, 21))	('a', 'Gene', '351', (44, 45))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (181, 186))	('C: >=1%-<', 'Var', (121, 130))	('a', 'Gene', '351', (11, 12))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('a', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (176, 177))	('a', 'Gene', '351', (208, 209))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('a', 'Gene', '351', (136, 137))
626619	32722580	; writing:review and editing, K.K., A.M.C., E.B., A.B.	('a', 'Gene', '351', (17, 18))	('A', 'Gene', '351', (50, 51))	('E.B.', 'Var', (44, 48))	('K.K.', 'Var', (30, 34))	('A', 'Gene', '351', (36, 37))
626638	32164724	Rearrangement involving FUS (16p11.2) gene was identified with break-apart probe and confirmed by Anchored Multiplex PCR.	('Rearrangement', 'Var', (0, 13))	('FUS', 'Gene', (24, 27))	('FUS', 'Gene', '100856381', (24, 27))
626653	32164724	LGFMS can also demonstrate positivity of CD99 and BCL-2.	('BCL-2', 'Gene', (50, 55))	('positivity', 'Var', (27, 37))	('CD99', 'Gene', (41, 45))	('BCL-2', 'Gene', '403416', (50, 55))	('CD99', 'Gene', '609832', (41, 45))
626661	32164724	Immunohistochemical studies demonstrated that negativity of SMA, desmin, beta-catenin, S100, SOX10, AE1/3, EMA, CD117 and CD34 in the tumor cells.	('desmin', 'Gene', '497091', (65, 71))	('beta-catenin', 'Gene', (73, 85))	('negativity', 'Var', (46, 56))	('SOX10', 'Gene', (93, 98))	('SOX10', 'Gene', '481258', (93, 98))	('CD34', 'Gene', '415130', (122, 126))	('desmin', 'Gene', (65, 71))	('S100', 'Gene', (87, 91))	('CD34', 'Gene', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('beta-catenin', 'Gene', '477032', (73, 85))	('CD117', 'Gene', (112, 117))	('SMA', 'Protein', (60, 63))	('tumor', 'Disease', (134, 139))
626673	32164724	Rearrangement involving FUS (16p11.2) gene was identified with break-apart probe, while rearrangement of the MDM2 and DDIT3 gene regions was not present, excluding dedifferentiated and myxoid liposarcoma.	('Rearrangement', 'Var', (0, 13))	('MDM2', 'Gene', (109, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('FUS', 'Gene', '100856381', (24, 27))	('myxoid liposarcoma', 'Disease', 'MESH:D018208', (185, 203))	('DDIT3', 'Gene', (118, 123))	('MDM2', 'Gene', '403693', (109, 113))	('myxoid liposarcoma', 'Phenotype', 'HP:0012268', (185, 203))	('dedifferentiated', 'Disease', (164, 180))	('FUS', 'Gene', (24, 27))	('liposarcoma', 'Phenotype', 'HP:0012034', (192, 203))	('DDIT3', 'Gene', '607439', (118, 123))	('myxoid liposarcoma', 'Disease', (185, 203))
626674	32164724	Additional confirmatory RNA from formalin fixed paraffin embedded tissue was extracted, and targeted RNA sequencing using a customized FusionPlex 86 genes panel (Archer, Boulder, CO) was performed to reveal a confirmatory FUS-CREB3L2 fusion (Fig.	('CREB3L2', 'Gene', (226, 233))	('paraffin', 'Chemical', 'MESH:D010232', (48, 56))	('formalin', 'Chemical', 'MESH:D005557', (33, 41))	('CREB3L2', 'Gene', '491369', (226, 233))	('FUS', 'Gene', (222, 225))	('fusion', 'Var', (234, 240))	('FUS', 'Gene', '100856381', (222, 225))
626683	32164724	Immunostain with S100, EAAT4, INI1, MUC4 and FISH or PCR for FUS-CREB3L2 or EWSR1-CREB3L1 fusion can make the distinction, as OFMT is immunohistochemically positive for S100 AND EAATA, but negative for INI1, MUC4.	('CREB3L1', 'Gene', '483636', (82, 89))	('CREB3L2', 'Gene', (65, 72))	('EWSR1', 'Gene', (76, 81))	('S100', 'Var', (169, 173))	('MUC4', 'Gene', (36, 40))	('FUS', 'Gene', (61, 64))	('CREB3L1', 'Gene', (82, 89))	('EWSR1', 'Gene', '609786', (76, 81))	('MUC4', 'Gene', '488024', (36, 40))	('MUC4', 'Gene', (208, 212))	('CREB3L2', 'Gene', '491369', (65, 72))	('MUC4', 'Gene', '488024', (208, 212))	('FUS', 'Gene', '100856381', (61, 64))
626687	32164724	They carry rearrangement of the NR4A3 but lack translocations of t (7;16)(q34;p11) or t (11;16)(p11;p11).	('translocations', 'MPA', (47, 61))	('rearrangement', 'Var', (11, 24))	('NR4A3', 'Gene', '100684628', (32, 37))	('t (11;16)(p11;p11', 'Var', (86, 103))	('NR4A3', 'Gene', (32, 37))
626693	32164724	In contrast, GISTs show expression of CD117 and CD34 and are associated with Kit or PDGFRA mutations.	('GISTs', 'Disease', 'MESH:D046152', (13, 18))	('GISTs', 'Disease', (13, 18))	('PDGFRA', 'Gene', '442860', (84, 90))	('Kit', 'Gene', (77, 80))	('PDGFRA', 'Gene', (84, 90))	('mutations', 'Var', (91, 100))	('CD34', 'Gene', '415130', (48, 52))	('associated', 'Reg', (61, 71))	('CD117', 'Protein', (38, 43))	('CD34', 'Gene', (48, 52))
626694	32164724	A combination of cytogenetic analysis of gene fusion and immunohistochemical staining of MUC4, CD117 and CD34 will aid in correct diagnosis.	('CD117', 'Gene', (95, 100))	('CD34', 'Gene', (105, 109))	('gene fusion', 'Var', (41, 52))	('MUC4', 'Gene', (89, 93))	('MUC4', 'Gene', '488024', (89, 93))	('CD34', 'Gene', '415130', (105, 109))
626706	30066884	To explore the effect of autophagy on the viability of SW982 cells, Atg5 was knocked down using siRNA to inhibit the autophagic activity.	('knocked down', 'Var', (77, 89))	('inhibit', 'NegReg', (105, 112))	('Atg5', 'Gene', '9474', (68, 72))	('autophagic activity', 'CPA', (117, 136))	('SW982', 'CellLine', 'CVCL:1734', (55, 60))	('Atg5', 'Gene', (68, 72))
626720	30066884	Aberrant expression of autophagic genes, changes in autophagic activity and conversion of autophagic signaling pathways can affect the viability of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('Aberrant', 'Var', (0, 8))	('affect', 'Reg', (124, 130))	('tumor', 'Disease', (148, 153))	('autophagic signaling pathways', 'CPA', (90, 119))	('autophagic genes', 'Gene', (23, 39))	('expression', 'MPA', (9, 19))	('changes', 'Reg', (41, 48))	('autophagic activity', 'CPA', (52, 71))	('conversion', 'CPA', (76, 86))
626724	30066884	Beclin1 codes a sequence with 450 amino acid residues, which contains three special domains: The conserved BH3 domain (residues 107-135), the coiled coil domain (residues 140-268) and the evolutionarily conserved domain (residues 244-337).	('BH3', 'Chemical', 'MESH:C006008', (107, 110))	('residues 107-135', 'Var', (119, 135))	('coiled coil', 'MPA', (142, 153))	('residues 140-268', 'Var', (162, 178))
626785	30066884	Therefore, 3#siRNA which had the highest inhibition efficiency was used to knockdown Atg5 in SW982 cells of the OE group, and the Atg5-knockdown cells in the OE group were isolated as the OE-Atg5 group.	('Atg5', 'Gene', (85, 89))	('Atg5', 'Gene', '9474', (191, 195))	('Atg5', 'Gene', (191, 195))	('knockdown', 'Var', (75, 84))	('Atg5', 'Gene', '9474', (130, 134))	('Atg5', 'Gene', '9474', (85, 89))	('SW982', 'CellLine', 'CVCL:1734', (93, 98))	('Atg5', 'Gene', (130, 134))
626793	30066884	Phosphorylation of Akt was inhibited in the OE group, and Atg5 knockdown reversed this inhibition (Fig.	('Akt', 'Gene', '207', (19, 22))	('Atg5', 'Gene', (58, 62))	('Phosphorylation', 'MPA', (0, 15))	('Akt', 'Gene', (19, 22))	('inhibited', 'NegReg', (27, 36))	('knockdown', 'Var', (63, 72))	('Atg5', 'Gene', '9474', (58, 62))
626797	30066884	However, high expression of Bcl-2 inhibits the apoptosis of tumor cells, which is closely associated with tumorigenesis and tumor progress.	('Bcl-2', 'Gene', (28, 33))	('Bcl-2', 'Gene', '596', (28, 33))	('high expression', 'Var', (9, 24))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('inhibits', 'NegReg', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
626860	28845314	treated 43 metastatic, unresectable ASPS patients with cediranib (30 mg) once daily in 28-day cycles, and it was observed that cediranib has substantial single-agent activity, producing an overall remission rate of 35% and a disease control rate of 84% at 24 weeks.	('cediranib', 'Chemical', 'MESH:C500926', (55, 64))	('ASPS', 'Phenotype', 'HP:0012218', (36, 40))	('ASPS', 'Gene', (36, 40))	('cediranib', 'Var', (127, 136))	('patients', 'Species', '9606', (41, 49))	('ASPS', 'Gene', '79058', (36, 40))	('cediranib', 'Chemical', 'MESH:C500926', (127, 136))
626889	25922782	Approximately 85-90% of Ewing's sarcomas associate a functional oncogene resulting from the DNA translocation t(11;22)(q24;q12).	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (24, 40))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (24, 39))	('oncogene', 'Gene', (64, 72))	('t(11;22)(q24;q12', 'Var', (110, 126))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (24, 40))	('sarcomas', 'Phenotype', 'HP:0100242', (32, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (110, 127))	("Ewing's sarcomas", 'Disease', (24, 40))
626982	33293354	The neoplastic cells commonly harbor a translocation, which occurs between the central exons of the ES breakpoint region 1 (EWSR1 or EWS) gene on chromosome 22 to the central exons of an erythroblast transformation specific (ETS) family gene such as the Friend leukemia integration 1 (FLI1) on chromosome 11.	('ES', 'Phenotype', 'HP:0012254', (100, 102))	('EWSR1', 'Gene', (124, 129))	('FLI1', 'Gene', (285, 289))	('leukemia', 'Phenotype', 'HP:0001909', (261, 269))	('harbor', 'Reg', (30, 36))	('Friend leukemia integration 1', 'Gene', '2313', (254, 283))	('EWS', 'Gene', (133, 136))	('EWSR1', 'Gene', '2130', (124, 129))	('translocation', 'Var', (39, 52))	('Friend leukemia integration 1', 'Gene', (254, 283))
626987	33293354	EWS-FLI1 t(11;22)(q24;q12) is the most common translocation, seen in 85% of patients with ES tumors.	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ES', 'Phenotype', 'HP:0012254', (90, 92))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('EWS-FLI1', 'Gene', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('EWS-FLI1', 'Gene', '2130', (0, 8))	('t(11;22)(q24;q12', 'Var', (9, 25))	('t(11;22)(q24;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (9, 26))
626988	33293354	Two EWS-FLI1 fusions have been described: exon 7 of EWS to exon 6 of FLI1 and exon 7 of EWS to exon 5 of FLI1, referred as type 1 and type 2 fusions, respectively.	('EWS-FLI1', 'Gene', '2130', (4, 12))	('exon', 'Var', (78, 82))	('EWS-FLI1', 'Gene', (4, 12))	('FLI1', 'Gene', (69, 73))
626990	33293354	This leads to translocations such as EWS and ETS variant 1 (t(2;22)(p22;q12)), EWS and E1AF (ETS variant 4 - ETV4/E1A enhancer binding protein) (t(17;22)(q21;q12)), and EWS and fifth Ewing variant (FEV) (t(2;22)(q33;q12)).	('E1AF', 'Gene', (87, 91))	('E1AF', 'Gene', '2118', (87, 91))	('ETV4', 'Gene', '2118', (109, 113))	('t(17;22)(q21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (145, 162))	('ETV4', 'Gene', (109, 113))	('EWS', 'Disease', (169, 172))	('t(2;22)(q33;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (204, 220))	('leads to', 'Reg', (5, 13))	('t(2;22)(q33;q12', 'Var', (204, 219))	('t(2;22)(p22;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (60, 76))
626993	33293354	To date, four main types of Ewing-like sarcoma have been described, and these include BCL6 corepressor (BCOR)-rearranged sarcomas, capicua transcriptional repressor (CIC)-rearranged sarcomas, sarcomas that harbor a fusion between EWSR1 and a non-ETS family member gene, and unclassified round cell sarcomas.	('BCOR', 'Gene', '54880', (104, 108))	('CIC', 'Gene', (166, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('capicua transcriptional repressor', 'Gene', (131, 164))	('BCOR', 'Gene', (104, 108))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('Ewing-like sarcoma', 'Disease', (28, 46))	('EWSR1', 'Gene', '2130', (230, 235))	('Ewing-like sarcoma', 'Phenotype', 'HP:0012254', (28, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('Ewing-like sarcoma', 'Disease', 'MESH:C563168', (28, 46))	('sarcomas', 'Disease', (182, 190))	('BCL6 corepressor', 'Gene', (86, 102))	('sarcomas', 'Disease', 'MESH:D012509', (298, 306))	('sarcomas', 'Phenotype', 'HP:0100242', (298, 306))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('CIC', 'Gene', '23152', (166, 169))	('sarcomas', 'Disease', (298, 306))	('sarcomas', 'Disease', 'MESH:D012509', (192, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (298, 305))	('EWSR1', 'Gene', (230, 235))	('sarcomas', 'Phenotype', 'HP:0100242', (192, 200))	('fusion', 'Var', (215, 221))	('sarcomas', 'Disease', (192, 200))	('sarcomas', 'Disease', 'MESH:D012509', (121, 129))	('BCL6 corepressor', 'Gene', '54880', (86, 102))	('capicua transcriptional repressor', 'Gene', '23152', (131, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('sarcomas', 'Disease', (121, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
626998	33293354	This confers specificity to targeted approaches, and preclinical data have demonstrated that the deletion of EWS-FLI1 fusion protein resulted in ES cell.	('EWS-FLI1', 'Gene', '2130', (109, 117))	('EWS-FLI1', 'Gene', (109, 117))	('ES cell', 'CPA', (145, 152))	('ES', 'Phenotype', 'HP:0012254', (145, 147))	('resulted in', 'Reg', (133, 144))	('deletion', 'Var', (97, 105))
626999	33293354	There has been some promise with strategies targeted to inactivate or reduce the expression or function of the EWS-FLI1 oncoprotein; some of these approaches include inhibitory oligonucleotides and small-molecule inhibitors that can disrupt its transcriptional complex.	('EWS-FLI1', 'Gene', (111, 119))	('oligonucleotides', 'Chemical', 'MESH:D009841', (177, 193))	('transcriptional', 'MPA', (245, 260))	('reduce', 'NegReg', (70, 76))	('disrupt', 'Reg', (233, 240))	('inhibitory oligonucleotides', 'Var', (166, 193))	('function', 'MPA', (95, 103))	('EWS-FLI1', 'Gene', '2130', (111, 119))	('inactivate', 'NegReg', (56, 66))	('expression', 'MPA', (81, 91))
627017	33293354	Importantly, it has been demonstrated that MDSCs are also able to inhibit chimeric antigen receptor (CAR) T cells targeting different types of sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('chimeric antigen receptor', 'Gene', (74, 99))	('sarcoma', 'Disease', 'MESH:D012509', (143, 150))	('inhibit', 'NegReg', (66, 73))	('chimeric antigen receptor', 'Gene', '9970', (74, 99))	('MDSCs', 'Var', (43, 48))	('sarcoma', 'Disease', (143, 150))
627020	33293354	In patients with metastatic cancer the expansion of F2 fibrocytes correlates with a shift toward a Th2 phenotype and enhanced tumor growth via induction of angiogenesis as well as increased immunosuppression.	('shift', 'Reg', (84, 89))	('angiogenesis', 'CPA', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('expansion', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('enhanced', 'PosReg', (117, 125))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Th2 phenotype', 'MPA', (99, 112))	('cancer', 'Disease', (28, 34))	('tumor', 'Disease', (126, 131))
627023	33293354	Importantly, the presence of HLA-G can lead to direct inhibition of natural killer (NK) and T cells as well as induction and expansion of MDSCs.	('expansion', 'CPA', (125, 134))	('inhibition', 'NegReg', (54, 64))	('MDSCs', 'CPA', (138, 143))	('T cells', 'CPA', (92, 99))	('HLA-G', 'Gene', (29, 34))	('HLA-G', 'Gene', '3135', (29, 34))	('presence', 'Var', (17, 25))
627025	33293354	Accordingly, in a pooled meta-analysis looking at a variety of tumor types, CD3+ TILs as well as CD8+ TILs had a positive effect on survival.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('positive', 'PosReg', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CD8', 'Gene', (97, 100))	('survival', 'CPA', (132, 140))	('CD8', 'Gene', '925', (97, 100))	('CD3+ TILs', 'Var', (76, 85))
627028	33293354	Interestingly, tumor antigen-specific TILs in the tumor tissue are in principle capable of recognizing ES cells; however, deficient HLA expression on the sarcoma cells protects them from being killed.	('ES', 'Phenotype', 'HP:0012254', (103, 105))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('deficient', 'Var', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('sarcoma', 'Disease', 'MESH:D012509', (154, 161))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('sarcoma', 'Disease', (154, 161))	('HLA expression', 'Protein', (132, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('tumor', 'Disease', (50, 55))
627029	33293354	The expression of HLA is important for the recognition of tumors by tumor-reactive T cells (figure 1) and, accordingly, loss of HLA will affect a tumor's susceptibility to a variety of cell-mediated immunotherapies.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('HLA', 'Gene', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('affect', 'Reg', (137, 143))	('loss', 'Var', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
627055	33293354	Elevated CXCR4 gene expression has recently been associated with a metastatic phenotype in ES, and CXCL12 has been shown to lead to neovascularization and ES tumor growth in a mouse xenograft model.	('tumor', 'Disease', (158, 163))	('ES', 'Phenotype', 'HP:0012254', (155, 157))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('CXCL12', 'Var', (99, 105))	('mouse', 'Species', '10090', (176, 181))	('metastatic', 'CPA', (67, 77))	('neovascularization', 'CPA', (132, 150))	('associated with', 'Reg', (49, 64))	('ES', 'Phenotype', 'HP:0012254', (91, 93))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('CXCR4 gene', 'Gene', (9, 19))	('lead to', 'Reg', (124, 131))
627059	33293354	Though the disruption of the CXCR4-CXCL12 via a CXCR4 antagonist, as proposed by Berguis et al and supported by Krook et al, provides a rationale for exploring the use of CXCR4-targeted therapies for ES, more recent data suggest that AMD3100 might actually increase ES cell viability and proliferation in vitro, and further investigation is needed in this area before this target can be introduced into the clinic.	('ES', 'Phenotype', 'HP:0012254', (200, 202))	('AMD3100', 'Chemical', 'MESH:C088327', (234, 241))	('AMD3100', 'Var', (234, 241))	('ES', 'Phenotype', 'HP:0012254', (266, 268))	('increase', 'PosReg', (257, 265))	('ES cell viability', 'CPA', (266, 283))
627063	33293354	In ES, low or negative HLA class I surface expression theoretically prevents the recognition of intracellular antigens by tumor-specific cytotoxic T lymphocytes (CTL).	('prevents', 'NegReg', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('HLA class I surface', 'Protein', (23, 42))	('low', 'Var', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('ES', 'Phenotype', 'HP:0012254', (3, 5))	('recognition of intracellular antigens', 'MPA', (81, 118))	('tumor', 'Disease', (122, 127))
627079	33293354	However, MAGE-A6 was still detected in 39% of patients, followed by MAGE-A3 in 28%, MAGE-A4 and MAGE-A10 in 22%, and MAGE-C2 and GAGE-1/2/8 in 11%, respectively.	('patients', 'Species', '9606', (46, 54))	('MAGE-A3', 'Gene', '4102', (68, 75))	('MAGE-C2', 'Gene', (117, 124))	('MAGE-A10', 'Var', (96, 104))	('GAGE-1', 'Gene', (129, 135))	('MAGE-A3', 'Gene', (68, 75))	('MAGE-A6', 'Gene', (9, 16))	('MAGE-A4', 'Gene', '4103', (84, 91))	('GAGE-1', 'Gene', '2543', (129, 135))	('MAGE-C2', 'Gene', '51438', (117, 124))	('MAGE-A4', 'Gene', (84, 91))	('MAGE-A6', 'Gene', '4105', (9, 16))
627096	33293354	Small series of patients with ES received DC pulsed with peptides derived from the EWS-FLI1 fusion protein concomitant with continuous intravenous recombinant human interleukin (IL)-2.	('peptides', 'Var', (57, 65))	('patients', 'Species', '9606', (16, 24))	('human', 'Species', '9606', (159, 164))	('ES', 'Phenotype', 'HP:0012254', (30, 32))	('EWS-FLI1', 'Gene', (83, 91))	('EWS-FLI1', 'Gene', '2130', (83, 91))
627098	33293354	In another clinical trial targeting tumor-specific fusion proteins, patients with translocation-positive, recurrent or metastatic ES or alveolar rhabdomyosarcoma underwent prechemotherapy cell harvest.	('alveolar rhabdomyosarcoma', 'Disease', 'MESH:D018232', (136, 161))	('alveolar rhabdomyosarcoma', 'Phenotype', 'HP:0006779', (136, 161))	('translocation-positive', 'Var', (82, 104))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('patients', 'Species', '9606', (68, 76))	('ES', 'Phenotype', 'HP:0012254', (130, 132))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (145, 161))	('alveolar rhabdomyosarcoma', 'Disease', (136, 161))	('metastatic', 'CPA', (119, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))	('tumor', 'Disease', (36, 41))
627124	33293354	The tumor-associated vasculature can also be targeted by oncolytic viruses that lead to necrosis of the neoplastic cells.	('tumor', 'Disease', (4, 9))	('necrosis', 'Disease', 'MESH:D009336', (88, 96))	('necrosis', 'Disease', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('viruses', 'Var', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
627130	33293354	Trabectedin is a DNA intercalating agent that disrupts EWS/FLI1 transcription, and in some models, it resulted in single-agent antineoplastic activity, and in addition to inhibiting EWS/FLI-mediated tumor progression, trabectedin has been found to deplete TRAILR2+ tumor leukocytes (includingmacrophages and MDSCs).	('tumor', 'Disease', (199, 204))	('trabectedin', 'Var', (218, 229))	('FLI', 'Gene', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('inhibiting', 'NegReg', (171, 181))	('antineoplastic activity', 'CPA', (127, 150))	('TRAILR2', 'Gene', (256, 263))	('deplete', 'NegReg', (248, 255))	('tumor', 'Disease', (265, 270))	('FLI', 'Gene', '2314', (59, 62))	('FLI', 'Gene', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('TRAILR2', 'Gene', '8795', (256, 263))	('disrupts', 'NegReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('FLI', 'Gene', '2314', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('transcription', 'MPA', (64, 77))
627132	33293354	A proof of principle was provided by Zhang et al, who showed in a xenograft model of ES that the adoptive transfer of tumor-reactive, anti-CD3/4-1BBL expanded T cells controlled primary growth and prevented metastasis of autologous tumors, while anti-CD3/anti-CD28-activated CD8+ T cells did not.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('anti-CD3/4-1BBL', 'Var', (134, 149))	('ES', 'Phenotype', 'HP:0012254', (85, 87))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CD8', 'Gene', (275, 278))	('controlled primary growth', 'CPA', (167, 192))	('CD28', 'Gene', (260, 264))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (118, 123))	('CD28', 'Gene', '940', (260, 264))	('CD8', 'Gene', '925', (275, 278))	('tumor', 'Disease', (232, 237))	('tumors', 'Disease', (232, 238))	('prevented', 'NegReg', (197, 206))
627157	33293354	Inhibition of IGF-1R has been shown to result in reduced tumor growth in vitro and in vivo through the inhibition of the migration of ES cells.	('IGF-1R', 'Gene', (14, 20))	('reduced', 'NegReg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('migration of ES cells', 'CPA', (121, 142))	('Inhibition', 'Var', (0, 10))	('ES', 'Phenotype', 'HP:0012254', (134, 136))	('tumor', 'Disease', (57, 62))	('IGF-1R', 'Gene', '3480', (14, 20))	('inhibition', 'NegReg', (103, 113))
627164	33293354	Treatment of immune-deficient NOD scid gamma (NSG) mice with multiple myeloma with anti-ROR1 CAR T cells led to an accumulation of the effector cells with the pulmonary tissue where they caused vasculitis and interstitial pneumonia.	('vasculitis', 'Phenotype', 'HP:0002633', (194, 204))	('myeloma', 'Disease', 'MESH:D009101', (70, 77))	('mice', 'Species', '10090', (51, 55))	('vasculitis', 'Disease', 'MESH:D014657', (194, 204))	('anti-ROR1', 'Var', (83, 92))	('pneumonia', 'Phenotype', 'HP:0002090', (222, 231))	('caused', 'Reg', (187, 193))	('myeloma', 'Disease', (70, 77))	('accumulation', 'PosReg', (115, 127))	('pneumonia', 'Disease', (222, 231))	('pneumonia', 'Disease', 'MESH:D011014', (222, 231))	('multiple myeloma', 'Phenotype', 'HP:0006775', (61, 77))	('vasculitis', 'Disease', (194, 204))
627166	33293354	Nevertheless, other investigators found anti-ROR1 CAR T cells to be safe in in preclinical animal models including primates and have found it to be overall effective and safe and hypothesize that it might be due to the specificity of the single chain variable fragment (scFv) antibody used.	('scFv', 'Gene', (270, 274))	('scFv', 'Gene', '652070', (270, 274))	('anti-ROR1', 'Var', (40, 49))
627187	33293354	These different isoforms of the epitope of the target tumor antigens can result from mutations.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (85, 94))	('isoforms', 'MPA', (16, 24))	('result from', 'Reg', (73, 84))
627198	33293354	However, CAR T cell approaches are under investigation for different solid tumors including ES, and performing a database search, we were able to identify two clinical CAR T cell trials (NCT03356782 and NCT03618381) currently enrolling patients with ES.	('solid tumors', 'Disease', 'MESH:D009369', (69, 81))	('patients', 'Species', '9606', (236, 244))	('solid tumors', 'Disease', (69, 81))	('ES', 'Phenotype', 'HP:0012254', (250, 252))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('NCT03618381', 'Var', (203, 214))	('ES', 'Phenotype', 'HP:0012254', (92, 94))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
627204	33293354	At this time, ROR1 is being evaluated as a target in clinical trials with CAR T cells in patients with breast and lung cancer, as well as in hematological malignancies (NCT02194374 and NCT02706392); however, there are currently no trials using this target in ES.	('hematological malignancies', 'Phenotype', 'HP:0004377', (141, 167))	('malignancies', 'Disease', 'MESH:D009369', (155, 167))	('breast and lung cancer', 'Disease', 'MESH:D001943', (103, 125))	('ES', 'Phenotype', 'HP:0012254', (259, 261))	('NCT02194374', 'Var', (169, 180))	('patients', 'Species', '9606', (89, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('malignancies', 'Disease', (155, 167))	('NCT02706392', 'Var', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
627224	33293354	Accordingly, the adoptive transfer of CTL specific for the modified peptides resulted in enhanced survival of mice with established ES.	('survival', 'CPA', (98, 106))	('enhanced', 'PosReg', (89, 97))	('ES', 'Phenotype', 'HP:0012254', (132, 134))	('mice', 'Species', '10090', (110, 114))	('modified', 'Var', (59, 67))
627240	32340193	Numerous studies are also being conducted regarding the effects of oncolytic viruses, including ImlygicTM, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors.	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (219, 233))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', (259, 265))	('oHSV', 'Chemical', '-', (157, 161))	('tumors', 'Disease', (204, 210))	('herpes simplex virus-1', 'Species', '10298', (133, 155))	('brain tumors', 'Phenotype', 'HP:0030692', (253, 265))	('NCT04065152', 'Var', (235, 246))	('brain tumors', 'Disease', 'MESH:D001932', (253, 265))	('brain tumor', 'Phenotype', 'HP:0030692', (253, 264))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (219, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('brain tumors', 'Disease', (253, 265))	('Kaposi sarcoma', 'Disease', (219, 233))	('herpes simplex', 'Phenotype', 'HP:0012302', (133, 147))
627314	32340193	Athymic nude mice with subcutaneous A673 sarcoma tumors were injected with 5.5 x 106 pfu of PBS, rHSVQ, or RAMBO by intratumoral injection when the A673 tumor volumes reached an average size of 150-300 mm3, and tumor growth was measured daily and monitored for changes in tumor size (Figure 5E).	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('PBS', 'Chemical', 'MESH:D007854', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (211, 216))	('rHSVQ', 'Chemical', '-', (97, 102))	('RAMBO', 'Chemical', '-', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', (272, 277))	('nude mice', 'Species', '10090', (8, 17))	('sarcoma tumors', 'Disease', 'MESH:D012509', (41, 55))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('sarcoma tumors', 'Disease', (41, 55))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('A673', 'Var', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
627316	32340193	In contrast, the mean tumor volumes in the mice treated with rHSVQ or RAMBO were 649.98 +- 104.98 and 241.20 +- 49.93, respectively.	('mice', 'Species', '10090', (43, 47))	('RAMBO', 'Chemical', '-', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('rHSVQ', 'Chemical', '-', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('rHSVQ', 'Var', (61, 66))	('tumor', 'Disease', (22, 27))
627325	32340193	Nintedanib is an orally available agent being investigated in a phase I/II randomized trial in combination with immunotherapy drug Ipilimumab in Non Small Cell Lung Cancer (NSCLC) (NCT 03377023) as well as with cyclophosphamide in ovarian cancer patients (NCT 01610869).	('NSCLC', 'Phenotype', 'HP:0030358', (173, 178))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (149, 171))	('ovarian cancer', 'Disease', 'MESH:D010051', (231, 245))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (211, 227))	('patients', 'Species', '9606', (246, 254))	('Lung Cancer', 'Phenotype', 'HP:0100526', (160, 171))	('Non Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (145, 171))	('ovarian cancer', 'Disease', (231, 245))	('NSCLC', 'Disease', (173, 178))	('Non Small Cell Lung Cancer', 'Disease', (145, 171))	('Cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Non Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (145, 171))	('Nintedanib', 'Chemical', 'MESH:C530716', (0, 10))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('ovarian cancer', 'Phenotype', 'HP:0100615', (231, 245))	('NCT 03377023', 'Var', (181, 193))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
627389	32340193	Herpes simplex virus-1-derived oncolytic viruses (oHSVs) promise the development of novel biological therapeutic strategies for many potential applications, as the oHSVs selectively replicate in tumor cells to lyse and induce a concurrent immune response.	('induce', 'Reg', (219, 225))	('tumor', 'Disease', (195, 200))	('oHSV', 'Chemical', '-', (50, 54))	('oHSVs', 'Var', (164, 169))	('Herpes simplex', 'Phenotype', 'HP:0012302', (0, 14))	('lyse', 'MPA', (210, 214))	('Herpes simplex virus-1', 'Species', '10298', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('oHSV', 'Chemical', '-', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
627396	32340193	This work was supported by Research Scholar Grants (RSG-19-185-01-MPC) from the American Cancer Society to J.Y.Y, by National Institute of Health (NIH) grants R01 NS064607, P01CA163205, R01 CA150153 to B.K, and by The Ohio State University Comprehensive Cancer Center (OSUCCC) and the NIH P30 CA016058) to R.S.	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Cancer', 'Disease', (89, 95))	('Cancer', 'Disease', (254, 260))	('Cancer', 'Phenotype', 'HP:0002664', (254, 260))	('P01CA163205', 'Var', (173, 184))	('Cancer', 'Disease', 'MESH:D009369', (89, 95))	('Cancer', 'Disease', 'MESH:D009369', (254, 260))	('R01 CA150153', 'Var', (186, 198))	('R01 NS064607', 'Var', (159, 171))
627397	30340636	Increased LDH5/LDH1 ratio in preoperative diagnosis of uterine sarcoma with inconclusive MRI and LDH total activity but suggestive CT scan: a case report Morcellation of undiagnosed uterine sarcoma is cause of abdominal/pelvic dissemination, residual tumor and recurrence.	('uterine sarcoma', 'Phenotype', 'HP:0002891', (55, 70))	('tumor', 'Disease', (251, 256))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('sarcoma', 'Disease', (63, 70))	('abdominal/pelvic dissemination', 'Disease', (210, 240))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcoma', 'Disease', (190, 197))	('uterine sarcoma', 'Phenotype', 'HP:0002891', (182, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('abdominal/pelvic dissemination', 'Disease', 'MESH:D017699', (210, 240))	('sarcoma', 'Disease', 'MESH:D012509', (63, 70))	('Morcellation', 'Var', (154, 166))
627413	30340636	This leads to a worsening of prognosis, since several studies demonstrated that morcellation of sarcomas increases the risk of abdominal/pelvic dissemination, residual tumor and recurrence.	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('tumor', 'Disease', (168, 173))	('morcellation', 'Var', (80, 92))	('sarcomas increases', 'Disease', 'MESH:D012509', (96, 114))	('sarcomas increases', 'Disease', (96, 114))	('abdominal/pelvic dissemination', 'Disease', 'MESH:D017699', (127, 157))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('abdominal/pelvic dissemination', 'Disease', (127, 157))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
627527	30075583	Some patients with strong VEGFR2 expression did not benefit from the treatment with apatinib, whereas some patients with weak VEGFR2 expression were benefited by the treatment.	('VEGFR2', 'Gene', (26, 32))	('patients', 'Species', '9606', (5, 13))	('VEGFR2', 'Gene', (126, 132))	('expression', 'Var', (33, 43))	('apatinib', 'Chemical', 'MESH:C553458', (84, 92))	('VEGFR2', 'Gene', '3791', (26, 32))	('VEGFR2', 'Gene', '3791', (126, 132))	('patients', 'Species', '9606', (107, 115))
627544	30075583	The results showed that osteosarcoma patients with high levels of VEGFR2 have a poor prognosis and deactivation of the VEGFR2/STAT3/BCL2 signaling pathway leads to apatinib-induced growth inhibition of osteosarcoma.	('VEGFR2', 'Gene', (66, 72))	('deactivation', 'NegReg', (99, 111))	('BCL2', 'Gene', (132, 136))	('sarcoma', 'Phenotype', 'HP:0100242', (207, 214))	('STAT3', 'Gene', (126, 131))	('VEGFR2', 'Gene', '3791', (66, 72))	('osteosarcoma', 'Disease', (202, 214))	('osteosarcoma', 'Disease', 'MESH:D012516', (202, 214))	('patients', 'Species', '9606', (37, 45))	('osteosarcoma', 'Phenotype', 'HP:0002669', (24, 36))	('STAT3', 'Gene', '6774', (126, 131))	('VEGFR2', 'Gene', (119, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('VEGFR2', 'Gene', '3791', (119, 125))	('apatinib', 'Chemical', 'MESH:C553458', (164, 172))	('growth', 'CPA', (181, 187))	('osteosarcoma', 'Phenotype', 'HP:0002669', (202, 214))	('BCL2', 'Gene', '596', (132, 136))	('high levels', 'Var', (51, 62))	('apatinib-induced', 'MPA', (164, 180))	('osteosarcoma', 'Disease', (24, 36))	('osteosarcoma', 'Disease', 'MESH:D012516', (24, 36))
627570	25145434	Recent results from a randomized, phase III study showed that 2 year event-free survival of children with metastatic neuroblastoma improved from 44% to 64% when these patients were given infusions of ch14.18 along with 13-cis-retinoic acid (CRA), interleukin (IL)-2 and granulocyte monocyte-colony stimulating factor (GM-CSF) after standard multimodality therapy.	('GM-CSF', 'Gene', '1437', (318, 324))	('ch14.18', 'Var', (200, 207))	('CRA', 'Gene', '51747', (241, 244))	('neuroblastoma', 'Phenotype', 'HP:0003006', (117, 130))	('cis-retinoic acid', 'Chemical', 'MESH:D015474', (222, 239))	('patients', 'Species', '9606', (167, 175))	('improved', 'PosReg', (131, 139))	('children', 'Species', '9606', (92, 100))	('neuroblastoma', 'Disease', 'MESH:D009447', (117, 130))	('CRA', 'Gene', (241, 244))	('GM-CSF', 'Gene', (318, 324))	('interleukin (IL)-2', 'Gene', (247, 265))	('neuroblastoma', 'Disease', (117, 130))	('interleukin (IL)-2', 'Gene', '3558', (247, 265))
627576	25145434	3F8 conjugated to the radionuclide 131Iodine (I-131) has also shown efficacy in treatment of CNS/leptomeningeal metastases of neuroblastoma in a phase I study, and has shown activity in a phase I trial of advanced stage neuroblastoma patients when combined with an oral beta glucan, which prime leukocyte dectin and complement receptor 3.	('131Iodine', 'Chemical', 'MESH:C000614965', (35, 44))	('leptomeningeal metastases of neuroblastoma', 'Disease', (97, 139))	('neuroblastoma', 'Phenotype', 'HP:0003006', (220, 233))	('3F8', 'Chemical', '-', (0, 3))	('neuroblastoma', 'Phenotype', 'HP:0003006', (126, 139))	('beta glucan', 'Chemical', 'MESH:D047071', (270, 281))	('conjugated', 'Var', (4, 14))	('I-131', 'Chemical', 'MESH:C000614965', (46, 51))	('neuroblastoma', 'Disease', 'MESH:D009447', (220, 233))	('neuroblastoma', 'Disease', 'MESH:D009447', (126, 139))	('patients', 'Species', '9606', (234, 242))	('radionuclide', 'Chemical', 'MESH:D011868', (22, 34))	('neuroblastoma', 'Disease', (220, 233))	('neuroblastoma', 'Disease', (126, 139))	('leptomeningeal metastases of neuroblastoma', 'Disease', 'MESH:D009362', (97, 139))	('activity', 'MPA', (174, 182))
627590	25145434	R1507, another anti- IGF-1R antagonist moAb, did not show objective responses in a phase I study, whereas a 10% response rate was observed in a multicenter phase II study of Ewing sarcoma.	('Ewing sarcoma', 'Disease', (174, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (174, 187))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (174, 187))	('IGF-1R', 'Gene', (21, 27))	('IGF-1R', 'Gene', '3480', (21, 27))	('R1507', 'Var', (0, 5))
627676	25145434	In a pilot study of children with refractory solid tumors, haploidentical HSCT led to 50% survival at 14 months, with KIR mismatch correlating with complete and partial remissions, and in a separate study, resolution of lung metastases in a child with rhabdomyosarcoma.	('lung metastases', 'Disease', (220, 235))	('KIR', 'Gene', '3805', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (252, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('rhabdomyosarcoma', 'Disease', (252, 268))	('solid tumors', 'Disease', (45, 57))	('child', 'Species', '9606', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('haploidentical', 'Var', (59, 73))	('child', 'Species', '9606', (241, 246))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (252, 268))	('children', 'Species', '9606', (20, 28))	('KIR', 'Gene', (118, 121))	('lung metastases', 'Disease', 'MESH:D009362', (220, 235))
627687	25145434	Nevertheless for neuroblastoma, scientists have used peptides derived from the MYCN oncogene, which is amplified in a fraction of high-risk patients, and have shown that these peptides can induce immune responses that are able to lyse tumor cells in children with HLA A1+ tumors.	('peptides', 'Var', (176, 184))	('immune responses', 'MPA', (196, 212))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('children', 'Species', '9606', (250, 258))	('neuroblastoma', 'Disease', (17, 30))	('neuroblastoma', 'Phenotype', 'HP:0003006', (17, 30))	('tumor', 'Disease', (272, 277))	('MYCN', 'Gene', '4613', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('neuroblastoma', 'Disease', 'MESH:D009447', (17, 30))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('patients', 'Species', '9606', (140, 148))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('MYCN', 'Gene', (79, 83))	('induce', 'Reg', (189, 195))	('tumor', 'Disease', (235, 240))
627700	25145434	For Epstein Barr virus-positive lymphomas, manipulating the tumor to overexpress LMP2 has led to clinical responses.	('lymphomas', 'Phenotype', 'HP:0002665', (32, 41))	('lymphoma', 'Phenotype', 'HP:0002665', (32, 40))	('LMP2', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('manipulating', 'Var', (43, 55))	('Epstein Barr virus-positive lymphomas', 'Disease', (4, 41))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Epstein Barr virus-positive lymphomas', 'Disease', 'MESH:D020031', (4, 41))	('tumor', 'Disease', (60, 65))
627707	25145434	For example, the success of the moAb ch14.18 was contingent on combining it with GM-CSF and IL-2 to recruit and activate immune cells capable of initiating ADCC.	('GM-CSF', 'Gene', (81, 87))	('GM-CSF', 'Gene', '1437', (81, 87))	('ch14.18', 'Var', (37, 44))	('IL-2', 'Gene', '3558', (92, 96))	('IL-2', 'Gene', (92, 96))	('activate', 'PosReg', (112, 120))
627717	25145434	Ongoing phase I trials are also exploring the role of pegylated IFN-alpha2a for plexiform neurofibromas and brain tumors in children.	('pegylated', 'Var', (54, 63))	('neurofibromas', 'Disease', 'MESH:D009455', (90, 103))	('children', 'Species', '9606', (124, 132))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (80, 103))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('IFN-alpha2', 'Gene', '3440', (64, 74))	('neurofibromas', 'Phenotype', 'HP:0001067', (90, 103))	('brain tumors', 'Disease', 'MESH:D001932', (108, 120))	('brain tumors', 'Phenotype', 'HP:0030692', (108, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('IFN-alpha2', 'Gene', (64, 74))	('neurofibromas', 'Disease', (90, 103))	('brain tumors', 'Disease', (108, 120))
627721	25145434	In regards to adoptive cell therapies, activating toll like receptors (TLRs) is one potential strategy to further stimulate immune effector cells and/or directly cause anti-tumor effects.	('stimulate', 'PosReg', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('cause', 'Reg', (162, 167))	('immune effector cells', 'CPA', (124, 145))	('activating', 'Var', (39, 49))
627744	25145434	Treatment strategies, like the combination of ch14.18, IL-2 and GM-CSF, demonstrate that immune-based therapies can be incorporated into standard multimodality regimens, and improve survival, as demonstrated in randomized trials.	('ch14.18', 'Var', (46, 53))	('improve', 'PosReg', (174, 181))	('GM-CSF', 'Gene', (64, 70))	('GM-CSF', 'Gene', '1437', (64, 70))	('IL-2', 'Gene', (55, 59))	('IL-2', 'Gene', '3558', (55, 59))	('survival', 'MPA', (182, 190))
627751	25145434	The improvement of survival for children with metastatic neuroblastoma with ch14.18 in a phase III study demonstrates that immunotherapy can be successfully incorporated into traditional treatment approaches.	('ch14.18', 'Var', (76, 83))	('neuroblastoma', 'Disease', 'MESH:D009447', (57, 70))	('children', 'Species', '9606', (32, 40))	('neuroblastoma', 'Disease', (57, 70))	('survival', 'MPA', (19, 27))	('neuroblastoma', 'Phenotype', 'HP:0003006', (57, 70))	('improvement', 'PosReg', (4, 15))
627758	25145434	Haploidentical NK cell infusions have been shown to maintain remissions in children with AML.	('AML', 'Disease', 'MESH:D015470', (89, 92))	('remissions', 'MPA', (61, 71))	('Haploidentical', 'Var', (0, 14))	('children', 'Species', '9606', (75, 83))	('AML', 'Disease', (89, 92))
627847	25050069	On the other hand, trabectedin is expected to be more effective in cells lacking functional homologous recombinant repair (HRR) mechanisms, such as those endowed with BReast CAncer (BRCA) gene mutation or BRCAness phenotype: preclinical data confirm that, besides the requirement of a functional transcription coupled NER machinery, a deficient HRR system is also needed for in vitro sensitivity to trabectedin.	('BReast CAncer', 'Phenotype', 'HP:0003002', (167, 180))	('trabectedin', 'Chemical', 'MESH:D000077606', (399, 410))	('BRCAness', 'Disease', (205, 213))	('BReast CAncer (BRCA)', 'Gene', '672', (167, 187))	('BRCAness', 'Disease', 'None', (205, 213))	('trabectedin', 'Chemical', 'MESH:D000077606', (19, 30))	('mutation', 'Var', (193, 201))	('CAncer', 'Phenotype', 'HP:0002664', (174, 180))	('BReast CAncer (BRCA', 'Gene', (167, 186))
627850	25050069	Besides these direct effects on the DNA helix, trabectedin is able to interfere with transcription regulatory pathways in a promoter- and gene-dependent manner, as well as in a cell-dependent fashion; in particular, trabectedin has been shown to inhibit binding of transcription factors to DNA, thus blocking their transactivating effects.	('trabectedin', 'Var', (216, 227))	('transcription', 'Protein', (265, 278))	('transcription regulatory pathways', 'Pathway', (85, 118))	('inhibit', 'NegReg', (246, 253))	('blocking', 'NegReg', (300, 308))	('transactivating effects', 'MPA', (315, 338))	('binding', 'Interaction', (254, 261))	('trabectedin', 'Chemical', 'MESH:D000077606', (47, 58))	('trabectedin', 'Chemical', 'MESH:D000077606', (216, 227))
627861	25050069	Trabectedin is metabolized in the liver mainly by the CYP3A4 enzyme, but also through the CYPC29, CYP2C19, and CYP2D6 isoenzymes and glutathione transferases.	('CYP3A4', 'Gene', (54, 60))	('CYP2C19', 'Gene', (98, 105))	('Trabectedin', 'Chemical', 'MESH:D000077606', (0, 11))	('CYP3A4', 'Gene', '1576', (54, 60))	('CYP2D6', 'Gene', '1565', (111, 117))	('CYPC29', 'Var', (90, 96))	('CYP2D6', 'Gene', (111, 117))	('CYP2C19', 'Gene', '1557', (98, 105))
627923	25050069	In the whole series, the response rate, as assessed by independent radiology review by RECIST (Response Evaluation Criteria in Solid Tumors), was significantly higher in trabectedin/PLD than PLD alone group (27.6% versus 18.8%, P=0.008).	('higher', 'PosReg', (160, 166))	('Tumors', 'Disease', (133, 139))	('Tumors', 'Disease', 'MESH:D009369', (133, 139))	('Tumors', 'Phenotype', 'HP:0002664', (133, 139))	('trabectedin', 'Chemical', 'MESH:D000077606', (170, 181))	('response', 'MPA', (25, 33))	('trabectedin/PLD', 'Var', (170, 185))
627943	25050069	While awaiting for the identification of biomarkers predictive of trabectedin sensitivity, other specific ovarian cancer clinical settings more likely to benefit from trabectedin or trabectedin combinations are actively investigated; given the strong rationale sustaining the role of BRCA 1/2 mutation or BRCAness in conditioning responsiveness to trabectedin, the MITO-15 (Multicenter Italian Trials in Ovarian Cancer and Gynecology) study (NCT01772979) has been conducted to investigate the efficacy of single agent trabectedin in relapsed ovarian cancer with BRCA mutation or exhibiting the BRCAness phenotype.	('BRCA', 'Gene', '672', (594, 598))	('BRCAness', 'Disease', (594, 602))	('BRCAness', 'Disease', 'None', (594, 602))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (550, 556))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutation', 'Var', (567, 575))	('BRCA', 'Gene', (284, 288))	('trabectedin', 'Chemical', 'MESH:D000077606', (66, 77))	('BRCA', 'Gene', (562, 566))	('BRCA', 'Gene', (594, 598))	('ovarian cancer', 'Disease', 'MESH:D010051', (542, 556))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (404, 418))	('ovarian cancer', 'Disease', (106, 120))	('trabectedin', 'Chemical', 'MESH:D000077606', (518, 529))	('BRCAness', 'Disease', (305, 313))	('BRCAness', 'Disease', 'None', (305, 313))	('BRCA', 'Gene', '672', (305, 309))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))	('Cancer', 'Phenotype', 'HP:0002664', (412, 418))	('trabectedin', 'Chemical', 'MESH:D000077606', (167, 178))	('ovarian cancer', 'Disease', (542, 556))	('trabectedin', 'Chemical', 'MESH:D000077606', (182, 193))	('Ovarian Cancer', 'Disease', (404, 418))	('BRCA', 'Gene', (305, 309))	('ovarian cancer', 'Phenotype', 'HP:0100615', (542, 556))	('trabectedin', 'Chemical', 'MESH:D000077606', (348, 359))	('BRCA', 'Gene', '672', (284, 288))	('Ovarian Cancer', 'Disease', 'MESH:D010051', (404, 418))	('BRCA', 'Gene', '672', (562, 566))	('MITO', 'Species', '262676', (365, 369))
628046	24586608	This meta-analysis summarized the global researches on the relationship of aberrant miR-210 expression and cancer patient survival, and clarified that over-expression of miR-210 in several cancers does predict poor survival of patients.	('aberrant', 'Var', (75, 83))	('miR-210', 'Gene', '406992', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('miR-210', 'Gene', (84, 91))	('miR-210', 'Gene', '406992', (170, 177))	('patients', 'Species', '9606', (227, 235))	('miR-210', 'Gene', (170, 177))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('cancer', 'Disease', (107, 113))	('expression', 'MPA', (92, 102))	('cancers', 'Disease', (189, 196))	('cancer', 'Disease', (189, 195))	('over-expression', 'PosReg', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('patient', 'Species', '9606', (227, 234))	('poor survival', 'CPA', (210, 223))	('patient', 'Species', '9606', (114, 121))
628052	23961344	Experimental therapy in vivo also showed that PTL apparently inhibited transplanted tumor in mice.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('inhibited', 'NegReg', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('mice', 'Species', '10090', (93, 97))	('PTL', 'Var', (46, 49))
628100	23961344	The results showed that PTL apparently inhibited Sarcoma180 and transplanted tumor in mice, but the inhibition mechanism of PTL affecting proliferation and growth is still unknown.	('Sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('inhibited', 'NegReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Sarcoma', 'Disease', (49, 56))	('mice', 'Species', '10090', (86, 90))	('Sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('PTL', 'Var', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
628104	23961344	The results suggested that PTL could cause a significant decrease of S phase in Sarcoma180, which indicated that the inhibition of cell growth was due to the arrest of DNA replication in the cell cycle.	('Sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('decrease', 'NegReg', (57, 65))	('PTL', 'Var', (27, 30))	('Sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('S phase', 'MPA', (69, 76))	('Sarcoma', 'Disease', (80, 87))
628355	33557781	Macrophage M1 not only associated with the OS of sarcoma, but also significantly associated with recurrence of sarcoma.	('associated with', 'Reg', (81, 96))	('Macrophage', 'Var', (0, 10))	('associated with', 'Reg', (23, 38))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('sarcoma', 'Disease', (111, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('sarcoma', 'Disease', (49, 56))
628361	33557781	Although a lot of predictive models for sarcoma patients were constructed based on the clinicopathologic data, lncRNA, plasmacytoma variant translocation 1 and other predictors.	('plasmacytoma', 'Phenotype', 'HP:0011857', (119, 131))	('plasmacytoma', 'Disease', (119, 131))	('variant translocation', 'Var', (132, 153))	('plasmacytoma', 'Disease', 'MESH:D010954', (119, 131))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('sarcoma', 'Disease', (40, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('lncRNA', 'Disease', (111, 117))	('patients', 'Species', '9606', (48, 56))
628379	22991313	Teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.	('stimulation', 'PosReg', (130, 141))	('preferential', 'PosReg', (117, 129))	('Teriparatide', 'Chemical', 'MESH:D019379', (0, 12))	('stimulates', 'PosReg', (13, 23))	('Teriparatide', 'Var', (0, 12))	('osteoblastic activity', 'CPA', (145, 166))	('osteoclastic activity', 'CPA', (172, 193))
628400	22991313	For this study, we define osteosarcoma cases as histologically confirmed sarcoma that produces osseous matrix and falls within one of the following categories (International Classification of Diseases for Oncology, Third Edition ([ICD-O-3]): 9180, Osteosarcoma, NOS 9181, Chondroblastic osteosarcoma 9182, Fibroblastic osteosarcoma 9183, Telangiectatic osteosarcoma 9184, Osteosarcoma in Paget's disease of bone 9185, Small cell osteosarcoma 9186, Central osteosarcoma 9187, Intraosseous well-differentiated osteosarcoma 9192, Parosteal osteosarcoma 9193, Periosteal osteosarcoma 9194, High-grade surface osteosarcoma 9195, Intracortical osteosarcoma To conduct a broad-based review of possible bone sarcoma/osteosarcoma cases, data from the following five ICD O-3 morphology codes are also collected where site of the primary cancer was indicated as bone (8800 sarcoma, NOS; 8801 spindle cell sarcoma; 8810 fibrosarcoma, NOS; 8830 malignant fibrous histiocytoma; 9243 dedifferentiated chondrosarcoma).	('Periosteal osteosarcoma', 'Disease', (556, 579))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('fibrosarcoma', 'Disease', 'MESH:D005354', (908, 920))	('cancer', 'Disease', (827, 833))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (986, 1000))	('osteosarcoma', 'Disease', (353, 365))	('osteosarcoma', 'Phenotype', 'HP:0002669', (26, 38))	('Chondroblastic osteosarcoma', 'Disease', (272, 299))	('osteosarcoma', 'Disease', 'MESH:D012516', (353, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (456, 468))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (248, 260))	('sarcoma', 'Disease', 'MESH:D012509', (542, 549))	('sarcoma', 'Disease', 'MESH:D012509', (700, 707))	('sarcoma', 'Disease', (542, 549))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))	('ICD', 'Disease', 'OMIM:252500', (757, 760))	('sarcoma', 'Disease', (700, 707))	('osteosarcoma', 'Disease', (26, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (319, 331))	('sarcoma', 'Disease', (643, 650))	('sarcoma', 'Disease', (73, 80))	('osteosarcoma', 'Disease', (508, 520))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))	('Osteosarcoma', 'Disease', (248, 260))	('sarcoma', 'Disease', 'MESH:D012509', (913, 920))	('bone sarcoma/osteosarcoma', 'Disease', (695, 720))	('bone sarcoma/osteosarcoma', 'Disease', 'MESH:D012516', (695, 720))	('sarcoma', 'Disease', (31, 38))	('sarcoma', 'Disease', (913, 920))	('ICD', 'Disease', 'OMIM:252500', (231, 234))	('osteosarcoma', 'Disease', (537, 549))	('osteosarcoma', 'Disease', 'MESH:D012516', (537, 549))	('fibrosarcoma', 'Disease', (908, 920))	('osteosarcoma', 'Disease', 'MESH:D012516', (638, 650))	('osteosarcoma', 'Phenotype', 'HP:0002669', (319, 331))	('sarcoma', 'Phenotype', 'HP:0100242', (324, 331))	('8800', 'Var', (857, 861))	('osteosarcoma', 'Disease', (456, 468))	('Telangiectatic osteosarcoma', 'Disease', 'MESH:D012516', (338, 365))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('ICD', 'Disease', (757, 760))	('osteosarcoma', 'Disease', (605, 617))	('osteosarcoma', 'Disease', 'MESH:D012516', (605, 617))	('osteosarcoma', 'Disease', (287, 299))	('sarcoma', 'Disease', 'MESH:D012509', (643, 650))	('osteosarcoma', 'Disease', 'MESH:D012516', (287, 299))	('sarcoma', 'Disease', (993, 1000))	('osteosarcoma', 'Disease', (319, 331))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (908, 920))	('ICD', 'Disease', (231, 234))	('sarcoma', 'Disease', (572, 579))	('sarcoma', 'Disease', 'MESH:D012509', (461, 468))	('sarcoma', 'Disease', 'MESH:D012509', (610, 617))	('sarcoma', 'Disease', (324, 331))	('bone sarcoma', 'Phenotype', 'HP:0002669', (695, 707))	('sarcoma', 'Disease', 'MESH:D012509', (253, 260))	('sarcoma', 'Disease', (461, 468))	('Fibroblastic osteosarcoma', 'Disease', 'MESH:D012516', (306, 331))	('sarcoma', 'Disease', (610, 617))	('sarcoma', 'Disease', (253, 260))	('sarcoma', 'Disease', (713, 720))	('falls', 'Phenotype', 'HP:0002527', (114, 119))	('osteosarcoma', 'Phenotype', 'HP:0002669', (287, 299))	('osteosarcoma', 'Disease', (638, 650))	('sarcoma', 'Disease', (513, 520))	('cancer', 'Phenotype', 'HP:0002664', (827, 833))	('sarcoma', 'Phenotype', 'HP:0100242', (292, 299))	('sarcoma', 'Disease', (434, 441))	('osteosarcoma', 'Disease', 'MESH:D012516', (567, 579))	('sarcoma', 'Disease', (377, 384))	('osteosarcoma', 'Disease', 'MESH:D012516', (708, 720))	('Telangiectatic osteosarcoma', 'Disease', (338, 365))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (372, 384))	('Chondroblastic osteosarcoma', 'Disease', 'MESH:D012516', (272, 299))	('sarcoma', 'Disease', 'MESH:D012509', (993, 1000))	('chondrosarcoma', 'Disease', (986, 1000))	('chondrosarcoma', 'Disease', 'MESH:D002813', (986, 1000))	('osteosarcoma', 'Disease', 'MESH:D012516', (429, 441))	('sarcoma', 'Disease', 'MESH:D012509', (572, 579))	('sarcoma', 'Disease', 'MESH:D012509', (292, 299))	('sarcoma', 'Disease', 'MESH:D012509', (324, 331))	('sarcoma', 'Disease', (292, 299))	('sarcoma', 'Disease', 'MESH:D012509', (713, 720))	('Central osteosarcoma', 'Disease', 'MESH:D012516', (448, 468))	('sarcoma', 'Disease', 'MESH:D012509', (862, 869))	('histiocytoma', 'Phenotype', 'HP:0012315', (950, 962))	('Osteosarcoma', 'Disease', (372, 384))	('sarcoma', 'Disease', 'MESH:D012509', (513, 520))	('sarcoma', 'Disease', (862, 869))	('Oncology', 'Phenotype', 'HP:0002664', (205, 213))	('osteosarcoma', 'Phenotype', 'HP:0002669', (429, 441))	('sarcoma', 'Disease', 'MESH:D012509', (434, 441))	('Osteosarcoma', 'Disease', 'MESH:D012516', (372, 384))	('Central osteosarcoma', 'Disease', (448, 468))	('sarcoma', 'Disease', 'MESH:D012509', (894, 901))	('osteosarcoma', 'Disease', (567, 579))	('sarcoma', 'Disease', (894, 901))	('sarcoma', 'Disease', 'MESH:D012509', (377, 384))	('osteosarcoma', 'Disease', (708, 720))	('Periosteal osteosarcoma', 'Disease', 'MESH:D010522', (556, 579))	('cancer', 'Disease', 'MESH:D009369', (827, 833))	('osteosarcoma', 'Phenotype', 'HP:0002669', (353, 365))	('sarcoma', 'Disease', 'MESH:D012509', (358, 365))	('osteosarcoma', 'Disease', 'MESH:D012516', (26, 38))	('malignant fibrous histiocytoma', 'Disease', (932, 962))	('osteosarcoma', 'Disease', (429, 441))	('sarcoma', 'Disease', (358, 365))	('Fibroblastic osteosarcoma', 'Disease', (306, 331))	('osteosarcoma', 'Disease', 'MESH:D012516', (508, 520))	('Osteosarcoma', 'Disease', 'MESH:D012516', (248, 260))
628510	22566752	Despite its unique histology and well-characterized genetic translocation, many questions remain regarding the pathogenesis and treatment of this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('genetic translocation', 'Var', (52, 73))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
628542	22566752	The der(17)t(X;17)(p11;25) translocation is found in all ASPS tumors studied; in the majority of ASPS tumors, this translocation is found in an unbalanced form, resulting in loss of heterozygosity at 11q25.	('ASPS', 'Phenotype', 'HP:0012218', (97, 101))	('ASPS tumors', 'Disease', (97, 108))	('heterozygosity', 'MPA', (182, 196))	('ASPS tumors', 'Disease', (57, 68))	('der(17)t(X', 'Var', (4, 14))	('ASPS tumors', 'Disease', 'MESH:D018234', (97, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('ASPS', 'Phenotype', 'HP:0012218', (57, 61))	('p11', 'Gene', '6281', (19, 22))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('loss', 'NegReg', (174, 178))	('p11', 'Gene', (19, 22))	('ASPS tumors', 'Disease', 'MESH:D018234', (57, 68))
628555	22566752	For example, the presence of TEF3 can override Rb-induced cell cycle arrest, and can block the antimitogenic effects of TGF-beta in mammalian cells.	('TEF3', 'Gene', (29, 33))	('override', 'PosReg', (38, 46))	('TEF3', 'Gene', '7004', (29, 33))	('antimitogenic effects', 'MPA', (95, 116))	('cell cycle arrest', 'CPA', (58, 75))	('Rb', 'Chemical', 'MESH:D012413', (47, 49))	('mammalian', 'Species', '9606', (132, 141))	('Rb-induced', 'Protein', (47, 57))	('presence', 'Var', (17, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (58, 75))	('block', 'NegReg', (85, 90))
628556	22566752	TEF3 has an activating domain at both the N- and C-termini; in vitro deletion of the N-terminal domain results in a dominant negative form of the factor that interferes with the function of the full-length protein.	('function', 'MPA', (178, 186))	('form', 'MPA', (134, 138))	('TEF3', 'Gene', (0, 4))	('deletion', 'Var', (69, 77))	('TEF3', 'Gene', '7004', (0, 4))
628558	22566752	Interestingly, 15% of cases of renal cell carcinomas in which TFE3 gene fusions are detected is associated with prior exposure to chemotherapy.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('renal cell carcinomas', 'Disease', (31, 52))	('associated', 'Reg', (96, 106))	('detected', 'Reg', (84, 92))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (31, 51))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (31, 52))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (31, 52))	('gene fusions', 'Var', (67, 79))	('TFE3', 'Gene', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
628560	22566752	The ASPSCR-1 gene has been alternatively termed in the literature TUG (Tether-containing UBX domain for GLUT4), ASPL (alveolar soft part sarcoma locus), UBXN9, UBXD9, and FLJ45380.	('GLUT4', 'Gene', '6517', (104, 109))	('ASPSCR-1', 'Gene', '79058', (4, 12))	('GLUT4', 'Gene', (104, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('ASPL', 'Gene', '79058', (112, 116))	('alveolar soft part sarcoma locus', 'Gene', '79058', (118, 150))	('UBXD9', 'Gene', (160, 165))	('ASPL', 'Gene', (112, 116))	('UBXN9', 'Gene', '79058', (153, 158))	('ASPSCR-1', 'Gene', (4, 12))	('UBXN9', 'Gene', (153, 158))	('ASPS', 'Phenotype', 'HP:0012218', (4, 8))	('FLJ45380', 'Var', (171, 179))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (118, 144))	('UBXD9', 'Gene', '79058', (160, 165))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (127, 144))	('alveolar soft part sarcoma locus', 'Gene', (118, 150))
628566	22566752	The specific role of an N-terminal segment of the TUG protein is unclear, though hypotheses could be made that the presence of this peptide alters dimerization or activation of the TEF3 peptide component.	('alters', 'Reg', (140, 146))	('TEF3', 'Gene', (181, 185))	('presence', 'Var', (115, 123))	('dimerization', 'MPA', (147, 159))	('TEF3', 'Gene', '7004', (181, 185))	('activation', 'MPA', (163, 173))
628575	22566752	These data provide a mechanism, whereby the presence of the ASPSCR1-TFE3 fusion protein could potentially induce cell mitosis.	('ASPSCR1', 'Gene', (60, 67))	('cell mitosis', 'Disease', (113, 125))	('cell mitosis', 'Disease', 'MESH:C538614', (113, 125))	('induce', 'PosReg', (106, 112))	('ASPS', 'Phenotype', 'HP:0012218', (60, 64))	('presence', 'Var', (44, 52))	('ASPSCR1', 'Gene', '79058', (60, 67))
628616	22566752	This drug was tested in a Phase II study (NCI Clinical Trial NCT00557609) examining the drug's effect on Microphthalmia Transcription Factor Family (MiT) tumors, which include ASPS, clear cell carcinoma, and renal cell carcinomas bearing a TFE3 translocation.	('renal cell carcinomas', 'Disease', 'MESH:C538614', (208, 229))	('ASPS', 'Phenotype', 'HP:0012218', (176, 180))	('Microphthalmia', 'Phenotype', 'HP:0000568', (105, 119))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (208, 229))	('clear cell carcinoma', 'Disease', (182, 202))	('ASPS', 'Gene', (176, 180))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (182, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('TFE3 translocation', 'Var', (240, 258))	('renal cell carcinomas', 'Disease', (208, 229))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (208, 228))	('ASPS', 'Gene', '79058', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Microphthalmia Transcription Factor Family (MiT) tumors', 'Disease', 'MESH:D008850', (105, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))
628634	22566752	Recent data have linked the specific t(X;17)(p11;25) translocation found in all ASPS tumors studied to the overexpression of the promitotic MET receptor tyrosine kinase, providing a model for tumorigenesis.	('tumor', 'Disease', (85, 90))	('overexpression', 'MPA', (107, 121))	('tumor', 'Disease', (192, 197))	('receptor tyrosine kinase', 'Gene', (144, 168))	('receptor tyrosine kinase', 'Gene', '5979', (144, 168))	('p11', 'Gene', (45, 48))	('p11', 'Gene', '6281', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('t(X', 'Var', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('ASPS tumors', 'Disease', 'MESH:D018234', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ASPS tumors', 'Disease', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('ASPS', 'Phenotype', 'HP:0012218', (80, 84))
628663	28280643	90% of synovial sarcomas harbour a specific translocation between the SYT gene on chromosome 18 and either the SSX1 or SSX2 gene on the X chromosome.	('SYT', 'Gene', '6857', (70, 73))	('SSX1', 'Gene', (111, 115))	('SSX2', 'Gene', '6757', (119, 123))	('SYT', 'Gene', (70, 73))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (7, 24))	('SSX2', 'Gene', (119, 123))	('SSX1', 'Gene', '6756', (111, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('synovial sarcomas', 'Disease', 'MESH:D013584', (7, 24))	('synovial sarcomas', 'Disease', (7, 24))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (7, 23))	('translocation', 'Var', (44, 57))
628682	27764233	These interactions activate host cell pre-existing FAK, Src, PI3-K and RhoGTPase signaling cascades, c-Cbl mediated ubiquitination of receptors, recruitment of CIB1, p130Cas and Crk adaptor molecules, and membrane bleb formation leading to lipid raft dependent macropinocytosis of KSHV into human microvascular dermal endothelial (HMVEC-d) cells.	('HMVEC-d', 'CellLine', 'CVCL:6870', (331, 338))	('p130Cas', 'Gene', '9564', (166, 173))	('Src', 'Gene', (56, 59))	('c-Cbl', 'Gene', '867', (101, 106))	('FAK', 'Gene', (51, 54))	('CIB1', 'Gene', (160, 164))	('lipid', 'Chemical', 'MESH:D008055', (240, 245))	('c-Cbl', 'Gene', (101, 106))	('FAK', 'Gene', '5747', (51, 54))	('CIB1', 'Gene', '10519', (160, 164))	('Src', 'Gene', '6714', (56, 59))	('macropinocytosis of KSHV', 'Disease', 'MESH:C537372', (261, 285))	('activate', 'PosReg', (19, 27))	('Crk', 'Gene', '1398', (178, 181))	('macropinocytosis of KSHV', 'Disease', (261, 285))	('ubiquitination', 'MPA', (116, 130))	('human', 'Species', '9606', (291, 296))	('p130Cas', 'Gene', (166, 173))	('lipid', 'MPA', (240, 245))	('interactions', 'Var', (6, 18))	('Crk', 'Gene', (178, 181))
628710	27764233	Simultaneous PI3-K mediated tyrosine phosphorylation of the adaptor E3 ubiquitin ligase c-Cbl protein results in the monoubiquitination of alpha3beta1 and alphaVbeta3 integrins and rapid lateral translocation of virus-bound alpha3beta1 and alphaVbeta3 integrins into the lipid raft (LR) regions of the plasma membrane of HMVEC-d cells.	('alphaVbeta3 integrins', 'Protein', (155, 176))	('c-Cbl', 'Gene', (88, 93))	('lateral translocation', 'MPA', (187, 208))	('c-Cbl', 'Gene', '867', (88, 93))	('tyrosine phosphorylation', 'Var', (28, 52))	('alpha3beta1', 'Protein', (139, 150))	('lipid', 'Chemical', 'MESH:D008055', (271, 276))	('HMVEC-d', 'CellLine', 'CVCL:6870', (321, 328))	('results in', 'Reg', (102, 112))	('monoubiquitination', 'MPA', (117, 135))	('alpha3beta1', 'Protein', (224, 235))	('PI3-K', 'Var', (13, 18))	('alphaVbeta3 integrins', 'Protein', (240, 261))	('tyrosine', 'Chemical', 'MESH:D014443', (28, 36))
628722	27764233	A recent study reported that Tsg101 plays an important role during Crimean-Congo hemorrhagic fever virus (CCHFV) entry via the multi-vesicular body (MVB) pathway into host cells, and silencing Tsg101 and other ESCRT components prevented CCHFV infection.	('multi-vesicular body', 'Disease', (127, 147))	('CCHFV', 'Species', '11593', (106, 111))	('Tsg101', 'Gene', '7251', (193, 199))	('CCHFV infection', 'Disease', (237, 252))	('CCHFV infection', 'Disease', 'MESH:D007239', (237, 252))	('CCHFV', 'Species', '11593', (237, 242))	('Tsg101', 'Gene', (193, 199))	('Tsg101', 'Gene', (29, 35))	('silencing', 'Var', (183, 192))	('multi-vesicular body', 'Disease', 'MESH:D012872', (127, 147))	('prevented', 'NegReg', (227, 236))	('Crimean-Congo', 'Disease', (67, 80))	('Tsg101', 'Gene', '7251', (29, 35))	('fever', 'Phenotype', 'HP:0001945', (93, 98))
628768	27764233	To determine the potential role of ESCRT-I Tsg101 protein during KSHV entry in HMVEC-d and HUVEC cells, we knocked down (KD) the Tsg101 protein by specific siRNA and checked the knockdown efficiency.	('HMVEC-d', 'CellLine', 'CVCL:6870', (79, 86))	('KSHV', 'Species', '37296', (65, 69))	('Tsg101', 'Gene', '7251', (43, 49))	('Tsg101', 'Gene', '7251', (129, 135))	('Tsg101', 'Gene', (43, 49))	('Tsg101', 'Gene', (129, 135))	('HUVEC', 'CellLine', 'CVCL:2959', (91, 96))	('protein', 'Protein', (136, 143))	('knocked', 'Var', (107, 114))
628771	27764233	The results showed almost similar levels of KSHV entry in both control (2802 +- 140 DNA copy numbers) and siTsg101 (2612 +- 112 DNA copy numbers; ~10% inhibition) treated HMVEC-d cells (Fig 1B) and HUVEC cells (3686 +- 294 vs. 3424 +- 332 DNA copy numbers; 7% inhibition) (Fig 1C).	('KSHV', 'Gene', (44, 48))	('Tsg101', 'Gene', (108, 114))	('2612 +-', 'Var', (116, 123))	('HUVEC', 'CellLine', 'CVCL:2959', (198, 203))	('KSHV', 'Species', '37296', (44, 48))	('HMVEC-d', 'CellLine', 'CVCL:6870', (171, 178))	('Tsg101', 'Gene', '7251', (108, 114))	('3686 +- 294', 'Var', (211, 222))
628779	27764233	In contrast to the control siRNA transfected HMVEC-d cells with KSHV DNA copy numbers of about 2441 +- 92, in Tsg101 siRNA transfected cells, we observed a significant decrease (~ 54%) in the nuclei associated KSHV genome copy numbers (1123 +- 115) (Fig 1F).	('KSHV genome', 'Gene', (210, 221))	('Tsg101', 'Gene', (110, 116))	('KSHV', 'Species', '37296', (210, 214))	('nuclei associated', 'MPA', (192, 209))	('1123 +- 115', 'Var', (236, 247))	('KSHV', 'Species', '37296', (64, 68))	('decrease', 'NegReg', (168, 176))	('HMVEC-d', 'CellLine', 'CVCL:6870', (45, 52))	('Tsg101', 'Gene', '7251', (110, 116))
628780	27764233	A similar result was obtained for HUVEC cells transfected with siControl (2503 +- 150) compared to siTsg101 (1061 +- 89) cells with a decrease of ~ 58% in the nuclei associated KSHV genome copy numbers (Fig 1G).	('HUVEC', 'CellLine', 'CVCL:2959', (34, 39))	('Tsg101', 'Gene', '7251', (101, 107))	('KSHV', 'Gene', (177, 181))	('decrease', 'NegReg', (134, 142))	('siControl (2503 +- 150', 'Var', (63, 85))	('Tsg101', 'Gene', (101, 107))	('KSHV', 'Species', '37296', (177, 181))	('nuclei associated', 'MPA', (159, 176))
628808	27764233	These results corroborate our previous findings that EphA2R, c-Cbl, p130Cas, and Crk association is significantly enhanced by KSHV infection.	('c-Cbl', 'Gene', (61, 66))	('c-Cbl', 'Gene', '867', (61, 66))	('Crk', 'Gene', '1398', (81, 84))	('KSHV infection', 'Disease', 'MESH:C537372', (126, 140))	('p130Cas', 'Gene', (68, 75))	('EphA2R', 'Var', (53, 59))	('enhanced', 'PosReg', (114, 122))	('Crk', 'Gene', (81, 84))	('KSHV infection', 'Disease', (126, 140))	('p130Cas', 'Gene', '9564', (68, 75))
628812	27764233	The PLA results corroborated with the IP results and clearly demonstrated a significant increase in the association levels of Tsg101 with EphA2R (Fig 5B), c-Cbl (Fig 5D), p130Cas (Fig 5F) and Crk (Fig 5H) at 10 min p.i.	('p130Cas', 'Gene', '9564', (171, 178))	('Tsg101', 'Gene', '7251', (126, 132))	('Crk', 'Gene', '1398', (192, 195))	('increase', 'PosReg', (88, 96))	('association', 'Interaction', (104, 115))	('EphA2R', 'Var', (138, 144))	('c-Cbl', 'Gene', (155, 160))	('c-Cbl', 'Gene', '867', (155, 160))	('Tsg101', 'Gene', (126, 132))	('p130Cas', 'Gene', (171, 178))	('Crk', 'Gene', (192, 195))
628835	27764233	To determine how Tsg101 knockdown affects KSHV trafficking, IFA was carried out with KSHV infected siControl and siTsg101 RNA transfected HMVEC-d (Fig 10A and 10E) and HUVEC cells (Fig 10B and 10F).	('Tsg101', 'Gene', (115, 121))	('HUVEC', 'CellLine', 'CVCL:2959', (168, 173))	('HMVEC-d', 'CellLine', 'CVCL:6870', (138, 145))	('KSHV', 'Species', '37296', (42, 46))	('Tsg101', 'Gene', '7251', (17, 23))	('affects', 'Reg', (34, 41))	('Tsg101', 'Gene', (17, 23))	('knockdown', 'Var', (24, 33))	('Tsg101', 'Gene', '7251', (115, 121))	('KSHV', 'Species', '37296', (85, 89))
628836	27764233	KSHV association with Rab5 positive early endosomes (trafficking) was not significantly affected by Tsg101 knockdown (Fig 10A-10D).	('knockdown', 'Var', (107, 116))	('KSHV', 'Species', '37296', (0, 4))	('Rab5', 'Gene', '5868', (22, 26))	('Rab5', 'Gene', (22, 26))	('Tsg101', 'Gene', '7251', (100, 106))	('Tsg101', 'Gene', (100, 106))
628837	27764233	In contrast, viral trafficking to the Rab7 positive late endosomes was significantly affected in the Tsg101 knockdown HMVEC-d and HUVEC cells (Fig 10E and 10F, lower panels, and Fig 10G and 10H) compared to the control cells (Fig 10E and 10F, upper panels and Fig 10G and 10H).	('knockdown', 'Var', (108, 117))	('Tsg101', 'Gene', '7251', (101, 107))	('Rab7', 'Gene', '7879', (38, 42))	('HMVEC-d', 'CellLine', 'CVCL:6870', (118, 125))	('affected', 'Reg', (85, 93))	('Tsg101', 'Gene', (101, 107))	('Rab7', 'Gene', (38, 42))	('HUVEC', 'CellLine', 'CVCL:2959', (130, 135))
628841	27764233	We have shown that KSHV manipulates the host cell's pre-existing signal pathways via its interactions with cell surface receptors such as integrins and the entry receptor Ephrin A2 receptor tyrosine kinase (EphA2R) early during infection as one of the best strategies to overcome the obstacles imposed by the host cells and to create an environment that is conducive to infection.	('infection', 'Disease', (370, 379))	('interactions', 'Interaction', (89, 101))	('infection', 'Disease', 'MESH:D007239', (370, 379))	('tyrosine', 'Chemical', 'MESH:D014443', (190, 198))	('KSHV', 'Species', '37296', (19, 23))	('KSHV', 'Var', (19, 23))	('signal pathways', 'Pathway', (65, 80))	('infection', 'Disease', (228, 237))	('manipulates', 'Reg', (24, 35))	('infection', 'Disease', 'MESH:D007239', (228, 237))
628846	27764233	The CIB1 molecule promotes EphA2R associated signal events and its depletion by shRNA was shown to reduce the KSHV induced bleb formation and activation of EphA2R, Src, Erk1/2, virus entry, trafficking and productive infection.	('depletion', 'Var', (67, 76))	('KSHV', 'Species', '37296', (110, 114))	('CIB1', 'Gene', '10519', (4, 8))	('Src', 'Gene', (164, 167))	('activation', 'PosReg', (142, 152))	('Src', 'Gene', '6714', (164, 167))	('reduce', 'NegReg', (99, 105))	('infection', 'Disease', (217, 226))	('infection', 'Disease', 'MESH:D007239', (217, 226))	('virus entry', 'CPA', (177, 188))	('promotes', 'PosReg', (18, 26))	('CIB1', 'Gene', (4, 8))	('Erk1/2', 'Protein', (169, 175))	('EphA2R', 'Protein', (156, 162))	('trafficking', 'CPA', (190, 201))	('EphA2R associated signal events', 'MPA', (27, 58))
628856	27764233	Mutations in several ESCRT proteins have also been linked to a variety of diseases including cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('linked to', 'Reg', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Mutations', 'Var', (0, 9))	('ESCRT proteins', 'Gene', (21, 35))
628859	27764233	The lack of Tsg101 also resulted in a massive defect in the cellular secretory pathway.	('Tsg101', 'Gene', '7251', (12, 18))	('cellular secretory pathway', 'Pathway', (60, 86))	('Tsg101', 'Gene', (12, 18))	('lack', 'Var', (4, 8))	('defect', 'NegReg', (46, 52))
628860	27764233	Similarly, Tsg101 knockdown resulted in the absence of the macropinocytosed KSHV particles transiting from the early endosome to late endosomes, and consequently, localization of KSHV particles at the cell periphery and reduction of their traffic towards the nucleus.	('Tsg101', 'Gene', (11, 17))	('knockdown', 'Var', (18, 27))	('absence', 'NegReg', (44, 51))	('localization', 'MPA', (163, 175))	('KSHV', 'Species', '37296', (76, 80))	('macropinocytosed', 'MPA', (59, 75))	('reduction', 'NegReg', (220, 229))	('Tsg101', 'Gene', '7251', (11, 17))	('KSHV', 'Species', '37296', (179, 183))	('traffic towards the nucleus', 'MPA', (239, 266))	('KSHV', 'Gene', (76, 80))
628885	27764233	We also observed that KSHV trafficking was severely affected in the absence of Tsg101.	('Tsg101', 'Gene', (79, 85))	('absence', 'Var', (68, 75))	('Tsg101', 'Gene', '7251', (79, 85))	('affected', 'Reg', (52, 60))	('KSHV', 'Species', '37296', (22, 26))	('KSHV trafficking', 'MPA', (22, 38))
628886	27764233	Although KSHV traffics easily through the early endosome in both Tsg101 knockdown as well as control endothelial cells, transition of KSHV from the early to late endosome was significantly blocked in the Tsg101 knockdown cells.	('Tsg101', 'Gene', (65, 71))	('KSHV', 'Species', '37296', (134, 138))	('Tsg101', 'Gene', (204, 210))	('knockdown', 'Var', (211, 220))	('KSHV', 'Species', '37296', (9, 13))	('Tsg101', 'Gene', '7251', (65, 71))	('Tsg101', 'Gene', '7251', (204, 210))	('knockdown', 'Var', (72, 81))	('blocked', 'NegReg', (189, 196))
628890	27764233	Tsg101 knockdown blocking the viral transition from early to late endosomal stages adds a new dimension to the current understanding of host cellular transport proteins involved in KSHV entry and infection, and suggest that Tsg101 can serve as a potential target to control KSHV infection.	('Tsg101', 'Gene', (0, 6))	('KSHV', 'Species', '37296', (181, 185))	('infection', 'Disease', (196, 205))	('KSHV infection', 'Disease', 'MESH:C537372', (274, 288))	('infection', 'Disease', 'MESH:D007239', (196, 205))	('infection', 'Disease', (279, 288))	('Tsg101', 'Gene', '7251', (0, 6))	('infection', 'Disease', 'MESH:D007239', (279, 288))	('KSHV infection', 'Disease', (274, 288))	('KSHV', 'Species', '37296', (274, 278))	('Tsg101', 'Gene', '7251', (224, 230))	('knockdown', 'Var', (7, 16))	('Tsg101', 'Gene', (224, 230))	('blocking', 'NegReg', (17, 25))
628970	25865224	OS was significantly worse in the monocyte ratio > 1 group (median OS 625 days) than the monocyte ratio <= 1 group (median OS 3544 days) (P < 0.001).	('OS', 'Chemical', '-', (0, 2))	('worse', 'NegReg', (21, 26))	('monocyte ratio > 1', 'Var', (34, 52))	('OS', 'Chemical', '-', (67, 69))	('OS', 'Chemical', '-', (123, 125))
628992	25865224	Many sarcomas express highly immunogenic antigens, such as neo-antigens from specific translocations, cancer/testis antigens and microphthalmia transcription factor, and even the fusion proteins themselves, which could be seen as foreign by immune system and used as target of immunotherapy.	('microphthalmia', 'Disease', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('translocations', 'Var', (86, 100))	('sarcomas', 'Disease', 'MESH:D012509', (5, 13))	('microphthalmia', 'Phenotype', 'HP:0000568', (129, 143))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('sarcomas', 'Phenotype', 'HP:0100242', (5, 13))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('microphthalmia', 'Disease', 'MESH:D008850', (129, 143))	('sarcomas', 'Disease', (5, 13))
629023	24385845	Assessment of the relationship of stranding, nodularity, and size to correct diagnosis showed that the presence of each was associated with a decreased likelihood of a lipoma pathological diagnosis (P < 0.01).	('lipoma', 'Phenotype', 'HP:0012032', (168, 174))	('presence', 'Var', (103, 111))	('decreased', 'NegReg', (142, 151))	('lipoma', 'Disease', (168, 174))	('lipoma', 'Disease', 'MESH:D008067', (168, 174))
629053	24385845	Positive reader responses for stranding and nodularity were associated with an increased likelihood of liposarcoma diagnosis (P < 0.01).	('liposarcoma', 'Phenotype', 'HP:0012034', (103, 114))	('liposarcoma', 'Disease', 'MESH:D008080', (103, 114))	('nodularity', 'Var', (44, 54))	('stranding', 'Var', (30, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('liposarcoma', 'Disease', (103, 114))
629164	22754316	Modulation of oxidative damage as well as inflammation protect against hepatocarcinogenesis.	('Modulation', 'Var', (0, 10))	('inflammation', 'Disease', (42, 54))	('oxidative', 'MPA', (14, 23))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (71, 91))	('inflammation', 'Disease', 'MESH:D007249', (42, 54))	('hepatocarcinogenesis', 'Disease', (71, 91))
629178	22754316	The mice were divided into five random groups (10 in each): S180-bearing control, normal control, and three tea polyphenol treatments (50, 100, 150 mg/kg body weight for group III, IV and V).	('tea', 'Gene', '11988', (108, 111))	('mice', 'Species', '10090', (4, 8))	('50', 'Var', (135, 137))	('polyphenol', 'Chemical', 'MESH:D059808', (112, 122))	('tea', 'Gene', (108, 111))